There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 872-31-1 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 23, p. 8074 - 8078
2
[ 872-31-1 ]
[ 17249-80-8 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1993, vol. 29, # 8, p. 889 - 891[2] Khimiya Geterotsiklicheskikh Soedinenii, 1993, # 8, p. 1046 - 1048
[3] Chemical Communications, 2014, vol. 50, # 18, p. 2344 - 2346
3
[ 872-31-1 ]
[ 115-19-5 ]
[ 67237-53-0 ]
Reference：
[1] Journal of Physical Chemistry, 1994, vol. 98, # 3, p. 748 - 751
4
[ 872-31-1 ]
[ 1066-54-2 ]
[ 67237-53-0 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 9, p. 2133 - 2143
5
[ 872-31-1 ]
[ 124-41-4 ]
[ 17573-92-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 90℃; for 10 h;
EXAMPLE 2 Preparation of 3-methoxythiophene From 3-bromothiophene 185 g of 3-bromothiophene (1.13 mol) are introduced into a mixture of 3.24 g of copper(I) bromide (CuBr, 2 mol percent), 14.1 g of PEG DME 250 (5 mol percent) and 407 g of sodium methanolate solution in methanol (30percent strength) (precursor concentration 30.4) and heated to 90° C. After the conversion, determined by GC, it is >98percent (total of 10 h), the reaction mixture is added to 300 g of water. It is subsequently filtered through decalite, and the mixture is extracted twice with 120 g of MTBE each time. Vacuum fractionation of the combined organic phases results in 117.4 g of 3-methoxylthiophene (1.03 mol, 91percent), GC purity >99percent a/a.
88%
With copper(l) iodide In 1-methyl-pyrrolidin-2-one; methanol at 110℃; Reflux
To a stirred solution of sodium methanolate (3.18g, 58.88mmol) in methanol (50mL) were added with N-methyl pyrrolidone (50mL) and 3-bromothiophene (8g, 49.07mmol). The mixture was heated to 110°C and then CuI (934mg, 4.91mmol) was added in one portion and kept reflux overnight. The reaction was cooled to room temperature and water (100mL) was added. The crude product was extracted with dichloromethane and the combined organic layers were washed with water and saturated aqueous NH4Cl, dried with MgSO4, filtered, and concentrated via rotary evaporation. The residue was further distilled under reduced pressure to afford the title compound as a colorless liquid (4.95g, 88percent). 1H NMR (500MHz, CDCl3): δ (ppm) 7.19–7.16 (m, 1H), 6.76-6.74 (m, 1H), 6.26-6.24 (m, 1H), 3.81 (s, 3H).
78%
at 115℃; for 2 h; Autoclave; Green chemistry
General procedure: A Teflon-lined autoclave (25 mL) was charged with MeONa (1.08 g, 20.0 mmol), MeOH (10 mL), CuCl (40 mg, 0.40 mmol), HCOOMe (0.25 mL, 0.97 g/mL, 4.0 mmol), and monohaloarene (10.0 mmol) then heated to 115 °C, with stirring, for 2 h. After completion of the reaction, the reactor was cooled to room temperature. The mixture was stirred for 0.5 h in the open, then concentrated to recover pure MeOH. Diethyl ether (15 mL) and dilute hydrochloric acid (1.6 M, 15 mL) were added to the residue. The mixture separated into two layers, and the aqueous phase was extracted with diethyl ether (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue which was purified by column chromatography on silica gel (mobile phase: petroleum ether–ethyl acetate 15:1) to furnish 1 (conversion and selectivity were determined by GC–MS analysis). The purity of the recovered MeOH was measured as more than 99 percent by GC, and the water content of the recovered MeOH was measured as less than 0.12 percent by use of the Karl Fischer method.
Reference：
[1] Patent: US2008/71084, 2008, A1, . Location in patent: Page/Page column 4
[2] Polymer, 2013, vol. 54, # 18, p. 4930 - 4939
[3] Journal of Materials Chemistry C, 2015, vol. 3, # 7, p. 1595 - 1603
[4] Chemical Communications, 2013, vol. 49, # 49, p. 5538 - 5540
[5] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8651 - 8664
[6] Macromolecules, 2014, vol. 47, # 15, p. 5029 - 5039
[7] Arkiv foer Kemi, 1958, vol. 12, p. 239,243
[8] Tetrahedron, 1992, vol. 48, # 17, p. 3633 - 3652
[9] Canadian Journal of Chemistry, 2009, vol. 87, # 1 SPEC. ISS., p. 314 - 320
[10] Polyhedron, 2015, vol. 96, p. 25 - 32
6
[ 872-31-1 ]
[ 67-56-1 ]
[ 17573-92-1 ]
Yield
Reaction Conditions
Operation in experiment
78.59%
Stage #1: With sodium methylate; copper(I) bromide In 1-methyl-pyrrolidin-2-one at 110℃; for 0.25 h; Inert atmosphere Stage #2: at 110℃; for 3.25 h; Inert atmosphere
Copper bromide (9.629 g, 67mmol) was weighed in a 500mL round bottom flask and placed in a nitrogen atmosphere glove box. Within the glove box sodium methoxide(54.067 g, 1000mmol) and dry NMP (171.476 g, 1729 mmol) were added, and the flask was stoppered and removed from the glove box. With a syringe, 3-bromothiophene (108.130 g,663.2mmol) was added, and the solid reagents were allowed to dissolve at 110∘C for 15 min. After the addition of anhydrous methanol (100 mL), the reaction was allowed to reflux at 110∘Cfor 3 hours and 15 minutes. Throughout the reaction time a receiving flask collected vaporized methanol. At reaction end, the product was separated by vacuum distillation, followed by washing the organic layer with water (100mL × 3) and aqueous layer with pentane (100mL × 3). The organic layer was then dried with magnesium sulfate (MgSO4) and filtered, and all the solvent was removed by a rotary evaporator. The product was pale yellow oil with a 78.59percent yield. NMR data match with the literature data.
Reference：
[1] New Journal of Chemistry, 2015, vol. 39, # 3, p. 2248 - 2255
[2] Journal of Chemistry, 2014, vol. 2014,
[3] Organic Letters, 2013, vol. 15, # 15, p. 3998 - 4001
7
[ 872-31-1 ]
[ 107-31-3 ]
[ 17573-92-1 ]
Reference：
[1] Patent: US4495353, 1985, A,
8
[ 872-31-1 ]
[ 71637-34-8 ]
Reference：
[1] Patent: US2005/23507, 2005, A1,
9
[ 872-31-1 ]
[ 1072-53-3 ]
[ 13781-67-4 ]
Reference：
[1] Synthesis, 2008, # 11, p. 1793 - 1797
10
[ 75-21-8 ]
[ 872-31-1 ]
[ 13781-67-4 ]
Reference：
[1] Arkiv foer Kemi, 1955, vol. 8, p. 441,445
[2] Journal of Organic Chemistry, 1997, vol. 62, # 5, p. 1376 - 1387
Reference：
[1] Angewandte Chemie - International Edition, 2003, vol. 42, # 14, p. 1661 - 1664
13
[ 872-31-1 ]
[ 1641-09-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2008, # 20, p. 3524 - 3528
[2] Chemistry - A European Journal, 2012, vol. 18, # 10, p. 2978 - 2986
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 7984 - 7989
[2] Synthesis, 2004, # 1, p. 23 - 25
16
[ 872-31-1 ]
[ 773837-37-9 ]
[ 1641-09-4 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 28, p. 10999 - 11005
17
[ 872-31-1 ]
[ 557-21-1 ]
[ 1641-09-4 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 7040 - 7044
18
[ 872-31-1 ]
[ 1641-09-4 ]
Reference：
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2015, vol. 53, # 7, p. 854 - 862
19
[ 872-31-1 ]
[ 151-50-8 ]
[ 1641-09-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1993, vol. 66, # 9, p. 2776 - 2778
20
[ 872-31-1 ]
[ 111-34-2 ]
[ 1468-83-3 ]
Reference：
[1] Journal of Organometallic Chemistry, 2005, vol. 690, # 15, p. 3546 - 3551
21
[ 872-31-1 ]
[ 3140-93-0 ]
Yield
Reaction Conditions
Operation in experiment
89%
With N-Bromosuccinimide; perchloric acid In hexane; water at 20℃; for 24 h;
3-bromothiophene (16.3 g;100 mmol) was added to a suspension of NBS (17.8 g;100 mmol) in hexane (50 ml) followed by HClO4 (70percent solutionin H2O; 0.7 ml; 5 molpercent) addition. The reaction mixturewas stirred at room temperature for 24 h and than K2CO3(200 mg) was added. Reaction mixture was filtrated, solidswere washed with hexane. Organic phases were concentrated,and residue was distilled in vacuo. Yield is 89percent.
89%
With N-Bromosuccinimide; perchloric acid In hexane; water at 20℃; for 24 h;
3-bromothiophene (16.3 g;100 mmol) was added to a suspension of NBS (17.8 g;100 mmol) in hexane (50 ml) followed by HClO4 (70percent solutionin H2O; 0.7 ml; 5 molpercent) addition. The reaction mixturewas stirred at room temperature for 24 h and than K2CO3(200 mg) was added. Reaction mixture was filtrated, solids were washed with hexane. Organic phases were concentrated, and residue was distilled in vacuo. Yield is 89percent. Found, percent: C 19.60, H 0.88, S 13.53, Br 65.88; Calcd., percent: forC4H2Br2S, C 19.86, H 0.83, S 13.25, Br 66.05. 1H NMR (400.13 MHz; CDCl3; d, ppm.): 7.24 (c, 1H); 6.90 (c, 1H).
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 11, p. 3072 - 3075
[2] Acta chemica Scandinavica (Copenhagen, Denmark : 1989), 1992, vol. 46, # 7, p. 654 - 660
[3] RSC Advances, 2014, vol. 4, # 96, p. 53531 - 53542
[4] Organic Electronics: physics, materials, applications, 2015, vol. 17, p. 167 - 177
[5] Organic Electronics: physics, materials, applications, 2014, vol. 17, p. 167 - 177
[6] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 13, p. 1957 - 1961
[7] Zeitschrift fuer Physikalische Chemie (Muenchen, Germany), 1981, vol. 127, p. 13 - 22
[8] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1980, vol. 19, # 12, p. 1183 - 1187
[9] Arkiv foer Kemi, 1957, vol. 11, p. 373,379, 380
[10] Synlett, 2002, # 12, p. 2083 - 2085
[11] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 617 - 620
[12] Canadian Journal of Chemistry, 2013, vol. 91, # 8, p. 679 - 683
22
[ 3141-24-0 ]
[ 872-31-1 ]
[ 3140-93-0 ]
[ 3140-92-9 ]
Reference：
[1] Journal of Chemical Research - Part S, 1996, # 3, p. 150 - 151
[2] Organometallics, 2016, vol. 35, # 18, p. 3234 - 3239
23
[ 872-31-1 ]
[ 128-08-5 ]
[ 3140-93-0 ]
Reference：
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
Reference：
[1] Canadian Journal of Chemistry, 1985, vol. 63, p. 2669 - 2672
28
[ 3141-27-3 ]
[ 188290-36-0 ]
[ 1003-09-4 ]
[ 872-31-1 ]
[ 3141-26-2 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 23, p. 8074 - 8078
29
[ 872-31-1 ]
[ 68-12-2 ]
[ 18791-75-8 ]
[ 930-96-1 ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0℃; for 3 h; Inert atmosphere Stage #3: With ammonium chloride In tetrahydrofuranInert atmosphere
General procedure: To the solution of 1M NaHMDS (8.8 mL, 8.8 mmol) in THF was slowly added the substrate (6.8 mmol) at 0 oC. After stirring for 30 min at 0 oC, the solution of electrophile (8.3 mmol) in anhydrous THF (2 mL) was slowly added into the reaction mixture at 0 oC and stirred for an additional 3h. The reaction was quenched with NH4Cl (sat.) solution (5 mL) and diluted with hexanes (20 mL). The organic layer was separated, washed with 15 wt.percent NaCl aqueous solution (10 mL) and concentrated to give the crude product. The product was isolated by flash chromatography using a Et3N pre-treated silca gel column and 0.1percent Et3N / 4.9percent EtOAc / 95percent hexanes as the eluent.
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0 - 5℃; for 0.5 h; Inert atmosphere; Large scale Stage #2: at 0 - 5℃; for 3 h; Inert atmosphere; Large scale
Under a nitrogen atmosphere, diisopropylamine (51.6 Kg, 509.9 mol, 1 leq) and anhydrous THF (385.0 OKg) were added to a 1000 L autoclave. The temperature was lowered and maintained at 0-5 ° C. BuLi (131.4 Kg, 463.8 mol, 1.0 eq). After the addition was complete, stirring was continued for half an hour at 0-5 ° C. A solution of 3-bromothiophene (starting material 1) (75.0 Kg, 460. Omol, 1 Oeq) in THF (20.0 OKg) was added dropwise at 0-5 ° C. After the addition was complete, stirring was continued for half an hour at 0-5 ° C. A solution of DMF (35.3 kg, 473.3 mol, 1.0 eq) in THF (10Kg) was added dropwise at 0-5 ° C. After completion of the dropwise addition, the temperature was maintained at 0-5 ° C and stirring was continued for 3 hours. Aqueous 14percent NH4Cl (700.OKg) was added dropwise at 0-5 ° C. After completion of the addition, the mixture was stirred at 0 to 5 ° C for 15 minutes, allowed to stand for 15 minutes, and the organic phase was temporarily stored in a clean tetrafluoroethylene drum. The aqueous phase was pumped into the reaction kettle, methyl tert-butyl ether (150. OKg) was added, stirred for 15 minutes, allowed to stand for 15 minutes, phase separated and the upper organic phase taken. The above organic phases were combined, anhydrous sodium sulfate (85. OKg) was added, and dried for a few hours until moisture <1percent. After filtration, the filter cake was washed twice with methyl tert-butyl ether (20 mL) and concentrated under reduced pressure to remove the solvent to give 3-bromothiophene-2-carbaldehyde (Intermediate 2) (93.8 Kg, 100percent).
85%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - -30℃; for 1.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 6 h; Inert atmosphere
To a stirred solution of iPr2NH (5.0 mL, 3.6 g, 35.3 mmol) in THF (30 mL) in a 100-mL 2-neckedflask under dry argon nBuLi (13.7 mL, 2.35 M in hexanes, 32.2 mmol) was added dropwise during 10 minutes at 0 °C. After stirring for an additional 20 minutes at 0°C, the mixture was cooled to −78 °C and a solution of 3-bromothiophene (5.0 g, 30.6 mmol) in THF (30 mL) was added dropwise during 20 minutes. After stirring for 1 hour at −78°C, the mixture was allowed to warm to −30 °C for 30 minutes before cooling again back to −78 °C. A solution of DMF (2.9 g, 40.0 mmol) in THF (10 mL) was then added dropwise over 10 minutes the mixture was allowed to gradually warm to room temperature with stirring for 6 hours. The mixture was poured into 1M HCl (100 mL) and EtOAc (100 mL) mixture. The organic layer was separated out and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (100 mL) then dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil. The residue was subjected to column chromatography on SiO2 (eluent EtOAc/hexane, 1/25 → 1/10) to give SI-1i (5.0 g, 26.2 mmol, 85percent) as colorless oil crystallizing in refrigerator.
68%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 1 h; Stage #2: at 0 - 20℃; for 2 h;
EXAMPLE l.AP. Preparation of 3-bromothiophene-2-carbaldehyde (1-53). I-53 [0202] To a solution of 3-bromothiophene (25 g, 153 mmol) in tetrahydrofuran (250 mL) was added 2 M Lithium diisopropylamide in tetrahydrofuran (77 mL,154 mmol) at 0°C and the reaction mixture was stirred at 0°C for 1 h. N,N-dimethylformamide (12.2 g, 168 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for additional 2 h. Water (100 mL) was added and extracted with ethyl acetate (500 mLx 3) was performed. The combined organic layer were dried over anhydrous magnesium sulfate, solids were removed by filtration and the filtrate was concentrated by evaporation in vacuo. The residue was purified by silica gel chromatography (petrol ether/ethyl acetate = 10/1) to provide intermediate 1-53 (20 g, 68percent). MS (ESI): m/z 190 [M + H]+.
Reference：
[1] Patent: CN103172646, 2016, B, . Location in patent: Paragraph 0101-0104
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 31, p. 5263 - 5273
[3] Macromolecules, 2013, vol. 46, # 6, p. 2078 - 2091
[4] Tetrahedron Letters, 2012, vol. 53, # 2, p. 166 - 169
[5] Journal of the American Chemical Society, 2014, vol. 136, # 19, p. 7132 - 7139
[6] Tetrahedron Letters, 2016, vol. 57, # 1, p. 11 - 14
[7] Patent: WO2016/130790, 2016, A1, . Location in patent: Paragraph 0202
[8] Nippon Kagaku Zasshi, 1957, vol. 78, p. 950,962[9] Chem. Zentralbl., 1958, vol. 129, p. 13204
[10] Tetrahedron Letters, 1993, vol. 34, # 35, p. 5653 - 5656
[11] Advanced Functional Materials, 2010, vol. 20, # 10, p. 1661 - 1669
[12] Patent: US2012/116084, 2012, A1, . Location in patent: Page/Page column 16
[13] Bl. Univ. Osaka Prefect., 1958, vol. <A> 6, p. 127,131
31
[ 872-31-1 ]
[ 2591-86-8 ]
[ 930-96-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: for 1 h;
A solution of 3-bromothiophene (30.0 g, 184 mmol) in THF (200 mL) cooled to 0 °C was added slowly to a 2.0 M solution of LDA in THF (92 mL, 184 mmol; Aldrich Chemicals). The orange solution was stirred at 0 °C for 30 min, then piperidine-1-carbaldehyde (20.4 mL, 184 mmol) was added. The mixture was stirred for a further1 h then diluted with Et2O (300 mL), washed with brine (100 mL), dried, and concentrated. The resulting orange oil was purifiedby chromatography (silica gel, heptane–EtOAc). Product containing fractions were combined and concentrated to give an orange liquid; 21 yield: 29.3 g (85percent).
85%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 1.5 h; Stage #2: at 0 - 20℃; for 2 h;
Commercially available lithium diisopropylamide (LDA) solution (2 M, 27 mL, 53.4 mmol) wasdiluted in THE (100 mL)solution at0 °C. A solution of compound 6d (5.0 mL, 53.4 mmol) in THE(5 mL) was added drop wise to the dilute LDA solution at 0 °C over 60 minutes using a droppingfunnel. The reaction mixture was allowed to stir at 0 °C for 30 minutes. After 30 mins, 1-formyl-piperidine was added drop-wise to the reaction mixture. The resultant mixture was gradually warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with NH4CI (150 mL) and extracted with Et20 (3 x 100 mL). The combined organic layers were washed with brine and concentrated to give yellow oil, which was purified by col15 umn chromatography on silica gel using DCM: hexane (v/v 1:1)to yield compound 8a as a yellow oil (8.7 g, 85percent). 1H NMR (400 MHz, CDCI3) ö 9.99 (s, 1 H), 7.71 (d, 1 H, J = 5.2 Hz), 7.15 (d, 1H, J = 5.2 Hz).
79.2%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0 - 2℃; for 0.5 h; Stage #2: for 2 h;
Experimental procedure3-Bromo-thiophene (6.523 g, 40 mmol) was dissolved under N2 in THF (100 mL). After cooling to 0-2 °C it was mixed dropwise with a 2M LDA solution (20 mL, 40 mmol) and stirred for 0.5 h. Following that 1-Formylpiperidin (4.52 g, 40 mmol) was added. After 2 h the reaction was stopped by adding a surplus of a saturated solution of NH4CI. For purification it was extracted three times with Et2O (10 mL) and the pooled organic phases subsequently dried over Na2SO4. After filtration the solvent was removed under vacuum. The crude product (approx. 8.3 g) was purified using flash-chromatography (8 cm, cyclohexane:ethylacetate 9:1 , 30 mL, Rf = 0.65) and by distillation under vacuum (Bp. 62 0C, 5.6 -10"2 mbar).Colourless liquid, yield 6.05 g (79.2 percent). <n="42"/>C5H3BrOS (191.1)MS (EI): m/z = 190/192 [M+], 162 [M+ -CHO].IR (Film): v (crτT1) = 3103 (C-H)1 2843 (C-H), 1657 (C=O).1H-NMR (CDCI3):δ (ppm) = 7.15 (d, J = 5.5 Hz, 1 H, 4-H-Th), 7.71 (dd, J = 5.1/1.5 Hz, 1 H, 5-H-Th)1 9.99 (d, J = 1.5 Hz, 1 H, Th-CHO).
54%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 0℃; for 12 h;
[00174] To a solution of lithium diisopropylamide (31.6 mmol) in 50 mL of THF at -78 °C was added 3-bromothiophene (3.0 g, 31 mmol) (1). After stirring for 1 h, formylpiperidine (3.50 g, 31.6 mmol) (2) was added and the reaction was warmed to 0 °C. After 12 h, the reaction mixture was partitioned between DCM and sat. NH4C1 and the organic layer was separated, dried over MgS04, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to afford 1.90 g (54percent) of the title compound as a yellow oil. 'H NMR (400 MHz, CDCI3) δ 9.99 (s, 1H), 7.71 (d, J= 5.2 Hz, 1H), 7.15 (d, J= 4.8 Hz, 1H).
Reference：
[1] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 6, p. 1132 - 1136
[2] New Journal of Chemistry, 2015, vol. 39, # 3, p. 2248 - 2255
[3] Synthesis (Germany), 2014, vol. 46, # 1, p. 96 - 100
[4] Patent: WO2015/128779, 2015, A1, . Location in patent: Page/Page column 28
[5] Advanced Functional Materials, 2012, vol. 22, # 1, p. 48 - 60
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6531 - 6537
[7] Patent: WO2008/155132, 2008, A1, . Location in patent: Page/Page column 40-41
[8] Heterocyclic Communications, 2016, vol. 22, # 1, p. 1 - 5
[9] Patent: WO2015/197861, 2015, A1, . Location in patent: Paragraph 00173-00174
[10] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3465 - 3470
[11] Molecules, 2012, vol. 17, # 10, p. 12163 - 12171
[12] Patent: KR101540066, 2015, B1, . Location in patent: Paragraph 0021; 0022; 0023
32
[ 872-31-1 ]
[ 67-64-1 ]
[ 930-96-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Stage #2: at 20℃; for 12 h;
A round 500 mL flask was charged with tetrahydrofuran (200 mL) Cool to -78 ° C. Thereafter, 2.0 M LDA (55 mL, 0.11 mol) was added theretoAnd 3-bromothiophene (16.3 g, 0.1 mol) was added slowly.After stirring at the same temperature for 1 hourDimethyl formaldehyde(8.48 ml, 0.11 mol).Then, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was fractionally distilled through ethyl acetate,The remaining water was removed with anhydrous magnesium sulfate, and the solvent was evaporated,Pure Compound A was obtained by column chromatography (18 g, 94percent).
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0℃; for 3 h; Inert atmosphere Stage #3: With ammonium chloride In tetrahydrofuranInert atmosphere
General procedure: To the solution of 1M NaHMDS (8.8 mL, 8.8 mmol) in THF was slowly added the substrate (6.8 mmol) at 0 oC. After stirring for 30 min at 0 oC, the solution of electrophile (8.3 mmol) in anhydrous THF (2 mL) was slowly added into the reaction mixture at 0 oC and stirred for an additional 3h. The reaction was quenched with NH4Cl (sat.) solution (5 mL) and diluted with hexanes (20 mL). The organic layer was separated, washed with 15 wt.percent NaCl aqueous solution (10 mL) and concentrated to give the crude product. The product was isolated by flash chromatography using a Et3N pre-treated silca gel column and 0.1percent Et3N / 4.9percent EtOAc / 95percent hexanes as the eluent.
With acetic acid; diisopropylamine In tetrahydrofuran; water; N,N-dimethyl-formamide
Thieno[3,2-b]thiophene-2-carboxamidine hydrochloride n-Butyl lithium (2.5M in hexanes, 4.2 mL, 10.5 mmol) was added dropwise to a solution of diisopropylamine (1.112 g, 11 mmol) in THF (10 mL), stirred under N2 at 25° C. After 10 min the solution was added dropwise over 10 min via catheter to a solution of 3-bromothiophene (1.6302 g, 10 mmol) in (THF 10 mL), stirred under N2 at -78° C. After a further 1 h, DMF (1.0 mL, 12.5 mmol) was added dropwise, followed after 10 min by a rapid addition of acetic acid (2.0 mL). The resultant gel was quickly decomposed with water (50 mL), and the mixture was extracted with ether (3*20 mL). The combined extracts were washed with dilute HCl (1 m, 20 mL), water (2*20 mL), saturated Na2 CO3 solution (20 mL) and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was Kugelrohr distilled at 100° C./0.2 mmHg to give 3-bromothiophene-2-carbaldehyde (1.4276 g, 75percent) as a light yellow oil.
Reference：
[1] Patent: US5340833, 1994, A,
35
[ 872-31-1 ]
[ 4885-02-3 ]
[ 930-96-1 ]
Reference：
[1] Tetrahedron Letters, 2000, vol. 41, # 15, p. 2749 - 2752
[2] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 3, p. 670 - 684
36
[ 872-31-1 ]
[ 930-96-1 ]
Reference：
[1] Tetrahedron, 1980, vol. 36, p. 2505 - 2512
37
[ 872-31-1 ]
[ 201230-82-2 ]
[ 22913-26-4 ]
[ 88-13-1 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
38
[ 872-31-1 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 22913-26-4 ]
[ 88-13-1 ]
Reference：
[1] Synthetic Communications, 1993, vol. 23, # 10, p. 1361 - 1370
[2] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
Reference：
[1] Journal of Physical Chemistry B, 2010, vol. 114, # 16, p. 5275 - 5282
42
[ 872-31-1 ]
[ 6165-69-1 ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; diisopropopylaminoborane; triethylamine; triphenylphosphine In tetrahydrofuran at 65℃; for 12 h; Inert atmosphere Stage #2: With methanol In tetrahydrofuran at 0℃; Inert atmosphere
General procedure: Triphenylphosphene (0.131 g, 0.5 mmol, 20 mol percent), p-iodoanisol (0.585 g, 2.5 mmol), and triethylamine (1.78 mL, 12.5 mmol) were added to a 50 mL round-bottomed flask equipped with a sidearm, condenser, and stir bar. This solution was then degassed by alternating vacuum and argon three times. Palladium dichloride (0.023 g, 0.13 mmol, 5 mol percent) was then added under positive argon pressure. After stirring at room temperature for 15 min, diisopropylaminoborane (5 mL, 1 M solution in THF, 5 mmol) was added and the reaction mixture was degassed again by alternating vacuum and argon three times. The reaction solution was then heated to reflux. After 12 h of reflux the reaction was cooled to 0 °C and 6 mL of methanol was added through the condenser slowly (Caution: exothermic reaction with evolution of hydrogen). After 15 min of stirring all the solvent was removed under reduced pressure to yield a black solid. This solid was dissolved with sodium hydroxide (3 M, 8 mL) and subsequently washed with hexanes (3.x.10 mL). The aqueous layer was then cooled to 0 °C (ice bath) and acidified to pH <=1 with concentrated HCl, with the boronic acid usually precipitating out as a white solid. The aqueous fraction was then extracted with diethyl ether (3.x.10 mL). The organic fractions were combined, dried with magnesium sulfate and filtered. The solvent was then removed under reduced pressure yielding a white solid.
60%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1 h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane; toluene at -78℃; for 0.166667 h; Stage #3: With water In tetrahydrofuran; hexane; toluene
Preparation of Compound 1-1After 3-bormothiophene (50 g, 306 mmol) was dissolved in THF (300 mL) and toluen (1,200 mL), the mixture was cooled to -78 °C, and n-BuLi (150 mL, 2.5M in hexane, 367 mmol) was added thereto. After stirring the mixture for 1 hour, triisopropylborate (112 mL, 490 mmol) was added while maintaining temperature at -78 °C. The mixture was stirred for 10 minutes. Upon completion of the reaction, H2O was added and the mixture was extracted with EA/H2O. After removing moisture with MgSO4 and performing distillation under reduced pressure, Compound 1-1 (24 g, 60percent) was obtained by column (methylene chloride (MC)/Hexane) separation.
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[2] Organic Letters, 2011, vol. 13, # 17, p. 4479 - 4481
[3] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
[4] Patent: US6342610, 2002, B2, . Location in patent: Page column 77
[5] Tetrahedron, 2011, vol. 67, # 3, p. 576 - 583
[6] Patent: WO2011/99718, 2011, A1, . Location in patent: Page/Page column 13
[7] Journal of the American Chemical Society, 2007, vol. 129, # 50, p. 15436 - 15437
[8] Arkiv foer Kemi, 1957, vol. 11, p. 373,379, 380
[9] Arkiv foer Kemi, 1957, vol. 11, p. 373,379, 380
[10] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5394 - 5397
43
[ 872-31-1 ]
[ 5419-55-6 ]
[ 6165-69-1 ]
Yield
Reaction Conditions
Operation in experiment
57.3%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 1.33333 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexanes; water at -20℃;
A solution of 3-bromothiophene (30.67 mmol=5 g) and tri-isopropyl borate (40 mmol=8.33 g or 9 ml) in 30 ml THF was treated with n-BuLi (2.5M in hexanes, 40 mmol 16 ml) at -78° C. over a period of 20 minutes. The resulting solution was stirred at -78° C. for an hour, and was then warmed up to -20° C. slowly and quenched slowly using 2N HCl. The mixture was then warmed to room temperature, diluted with ethyl acetated and brine. The organic layer was separated, concentrated and dried in vacuo. The white crude residue was re-crystallized using hot water to give 2.25 g of pure thiophene-3-boronic acid (17.58 mmol, 57.3percent) with m.p at 126-128° C. [128-130° C. reported] (see Collis, G. E.; Burrell, A. K.; Scott, S. M.; Officer, D. L., J. Org. Chem. 2003, 68, (23), 8974-8983).
A. 3-Thiopheneboric acid n-Butyllithium (2.5 M solution in hexane, 20 ml, 50 mmol) was added dropwise to a solution of 3-bromothiophene (8.15 g, 50 mmol) in THF (20 ml) at -78° C. under an argon atmosphere. The resulting solution was stirred at -78° C. for 45 min, and then added to a solution of triisopropyl borate (9.4 g, 50 mmol) in THF at -78° C. over 30 min through a steel cannula. The resulting reaction mixture was stirred at room temperature for 12 h and was decomposed by the addition of 100 ml 1 N HCl. The aqueous layer was extracted with ether (2*100 ml) and the combined organic layers was extracted with 1 M NaOH (3*30 ml), the aqueous extract was acidified with concentrated HCl to pH 2 and extracted with ether (3*50 ml). The combined ether extract was washed once with water, dried over MgSO4 and filtered. Removal of the solvent gave 3-thienylboronic acid as a solid (5.2 g, 80percent yield).
80%
With hydrogenchloride In tetrahydrofuran; hexane
A. 3-Thiopheneboric acid n-Butyllithium (2.5M solution in hexane, 20 ml, 50 mmol) was added dropwise to a solution of 3-bromothiophene (8.15 g, 50 mmol) in THF (20 ml) at -78° C. under an argon atmosphere. The resulting solution was stirred at -78° C. for 45 min, and then added to a solution of triisopropyl borate (9.4 g, 50 mmol) in THF at -78° C. over 30 min through a steel cannula. The resulting reaction mixture was stirred at room temperature for 12 h and was decomposed by the addition of 100 ml 1N HCl. The aqueous layer was extracted with ether (2*100 ml) and the combined organic layers was extracted with 1M NaOH (3*30 ml), the aqueous extract was acidified with concentrated HCl to pH 2 and extracted with ether (3*50 ml). The combined ether extract was washed once with water, dried over MgSO4 and filtered. Removal of the solvent gave 3-thienylboronic acid as a solid (5.2 g, 80percent yield).
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
47
[ 872-31-1 ]
[ 108-24-7 ]
[ 7209-11-2 ]
[ 42877-08-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 10, p. 1558 - 1566
48
[ 872-31-1 ]
[ 75-36-5 ]
[ 7209-11-2 ]
[ 42877-08-7 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 2013, vol. 49, # 3, p. 386 - 391[2] Khim. Geterotsikl. Soedin., 2013, # 3, p. 416 - 422
49
[ 872-31-1 ]
[ 7311-64-0 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hydrogenchloride; diethyl ether; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at -72 - -68℃; for 2.66 h; Stage #2: With carbon dioxide In tetrahydrofuran; diethyl ether Stage #3: With hydrogenchloride In tetrahydrofuran; diethyl ether; water
[0526] 3-Bromo-thiophene-2-carboxylic acid. To a solution of 3-bromothiophene (600.0 g, 3.68 mol) in THF (3 L) cooled to -72° C. was added LDA (1.93 L, 3.86 mol, 2 N) slowly over 2 hours. The rate of LDA addition is such that the reaction temperature never exceeded -68° C. After complete addition, the solution is stirred for an additional 40 minutes. Diethyl ether (3 L) is then added via an addition funnel such that the temperature is maintained below -65° C. The addition funnel is then replaced with a dispersion tube and CO2 gas is bubbled through the solution for 3 hours. Dry ice (500 g) is then added and the mixture is stirred overnight. The reaction flask is then placed in an ice bath and 6 N HCl is added slowly to prevent excessive bubbling until the pH of the solution is adjusted to 1-2. The resulting mixture is then extracted with EtOAc. The extract is washed with brine then dried over MgSO4, filtered and evaporated. The product is dried under vacuum at room temperature yielding 585.15 g (77percent) as an off-white solid.
With sodium hydroxide; phenyllithium In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; acetonitrile
a. 3-Bromo-2-thiophenecarboxylic acid A stirred, ice-water chilled solution of 16.3 g of 3-bromothiophene and 100 ml of anhydrous ether was treated dropwise, under nitrogen, over 70 minutes with of 50 ml of phenyllithium in ether (2.0M solution), with exclusion of moisture. After stirring at ambient temperature for 1.5 hours, the solution was decanted into dry ice and 200 ml of anhydrous ether. The mixture was stirred and a small amount of dry ice was added. The suspension was treated with water and 10percent sodium hydroxide solution to pH=10. The phases were separated and the aqueous phase was extracted once with ether, and acidified with concentrated hydrochloric acid. The mixture was extracted with ether and the dried (over anhydrous sodium sulfate) organic phase was filtered and concentrated. Recrystallization of the residue from acetonitrile gave 10.38percent g (50percent) of product, m.p. 193°-196° C.
Reference：
[1] Bulletin of the Chemical Society of Japan, 2012, vol. 85, # 3, p. 369 - 371
[2] Heterocycles, 1993, vol. 36, # 8, p. 1867 - 1882
[3] Patent: US4560701, 1985, A,
51
[ 872-31-1 ]
[ 109-72-8 ]
[ 60-29-7 ]
[ 7311-64-0 ]
Reference：
[1] Arkiv foer Kemi, 1954, vol. 7, p. 361,366
52
[ 872-31-1 ]
[ 24430-27-1 ]
Reference：
[1] Patent: WO2019/6025, 2019, A1, . Location in patent: Paragraph 0008
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1673 - 1692
[3] Justus Liebigs Annalen der Chemie, 1934, vol. 512, p. 136,156
[4] Nippon Kagaku Zasshi, 1957, vol. 78, p. 950,962[5] Chemisches Zentralblatt, 1958, vol. 129, p. 13204
[6] Patent: US6583138, 2003, B1,
53
[ 872-31-1 ]
[ 51751-44-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: With copper dichloride In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere
The freshly prepared LDA solution (prepared by the addition ofn-BuLi (2.5 M in hexanes, 100 mmol, 40 mL) and diisopropylamine(11.1 g, 110 mmol) in 50 mL of anhydrous THF (78 C to roomtemperature)) was added drop wise to a solution of 3-bromothiophene (16.30 g, 100 mmol) in anhydrous THF (100 mL)at 78 C under nitrogen atmosphere. The reaction mixture wasstirred for 1 h at 78 C and CuCl2 (14.11 g, 105 mmol)was added inone portion. The reaction mixture was allowed towarm up to roomtemperature and treated with aqueous HCl. The organic phaseseparated was collected and the aqueous phase was extracted withdiethyl ether several times. The combined organic phase was driedover anhydrous Na2SO4 and the solution was filtered, concentratedand the residue was purified by silica gel column chromatography(hexane eluent) to afford a the required compound as white solid(yield 85percent).1H NMR (500 MHz, CDCl3, d ppm): 7.08 (d, J 5.0 Hz, 2H), 7.40(d, J 5.0 Hz, 2H).
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane for 1 h; Cooling with acetone-dry ice Stage #2: With copper dichloride In tetrahydrofuran; hexane
Example la - Lithium diisopropylamide (LDA) was prepared by the addition of n-BuLi (2.5 M in hexanes, 0.210 mol, 84 mL) to a solution of diisopropylamine (0.231 mol, 23.37 g) in 25 mL of anhydrous THF (-78 °C to room temperature). This LDA solution was added dropwise to a solution of 3-bromothiophene (0.200 mol, 32.607 g) in 200 mL of anhydrous THF cooled in acetone/dry ice bath. After stirring for 5 minutes precipitation was observed. The reaction mixture was stirred for 1 h and CuCl2 (1.1 eq., 0.210 mol, 28.23 g) was added in three portions (exothermic reaction). The mixture became blue-black, and then orange-brown with precipitate. The cooling bath was removed and the mixture was transferred into a round bottom flask. The solvents were removed by rotary evaporation and the residue (greenish- brownish oil) was applied to the silica gel pad. The product was eluted with hexanes (~1.5 L), and then CH2C12 (500 mL). The solvents were removed from the filtrate, and the part of the residue (7 g, brown solid) was transferred into a pear-shaped 50 mL flask, and the material was purified by Kugelrohr distillation and the product was collected as off-white solid at 190-200 °C/ ( recovery). The mother liquor was concentrated and additional amount of product crystallized. GC/MS analysis: 324 (molecular ion) (at) 11.6 min.
63%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine; lithium diisopropyl amide In tetrahydrofuran; hexane for 1.08333 h; Cooling with acetone-dry ice Stage #2: With copper dichloride In tetrahydrofuran; hexane
Example la - Lithium diisopropylamide (LDA) was prepared by the addition of n-BuLi (2.5 M in hexanes, 0.210 mol, 84 mL) to a solution of diisopropylamine (0.231 mol, 23.37 g) in 25 mL of anhydrous THF (-78 °C to room temperature). This LDA solution was added dropwise to a solution of 3-bromothiophene (0.200 mol, 32.607 g) in 200 mL of anhydrous THF cooled in acetone/dry ice bath. After stirring for 5 minutes precipitation was observed. The reaction mixture was stirred for 1 h and CuCl2 (1.1 eq., 0.210 mol, 28.23 g) was added in three portions (exothermic reaction). The mixture became blue-black, and then orange-brown with precipitate. The cooling bath was removed and the mixture was transferred into a round bottom flask. The solvents were removed by rotary evaporation and the residue (greenish- brownish oil) was applied to the silica gel pad. The product was eluted with hexanes (~1.5 L), and then CH2C12 (500 mL). The solvents were removed from the filtrate, and the part of the residue (7 g, brown solid) was transferred into a pear-shaped 50 mL flask, and the material was purified by Kugelrohr distillation and the product was collected as off-white solid at 190-200 °C/ ( recovery). The mother liquor was concentrated and additional amount of product crystallized. GC/MS analysis: 324 (molecular ion) (at) 11.6 min.
42%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.33333 h; Stage #2: With copper dichloride In tetrahydrofuran at -78 - 20℃; for 6 h;
In a 250 mL three neckflask, 3-bromothiophene (4.0 g, 24.54 mmol) was solved in anhydrous THF (50 mL). The solution was cooled to −78C and LDA solution was added dropwise over 20 min. Then the solution was stirred for 1 h at the same temperature and CuCl2 (6.56 g,49.08 mmol) was added in one portion. After being stirred for 1 h at−78 °C, the mixture was warmed to room temperature and stirred for another 5 h. The reaction was quenched with water. The crude compound was extracted with dichloromethane and washed by distilled water, dried over anhydrous MgSO4, and evaporated in vacuum. The residue was purified by silica gel column chromatography (eluent: petroleum ether). Compound 2 was obtained as a white solid (1.7 g, 42percent).1H NMR (CDCl3, 400 MHz): 7.41 (d,J = 5.4 Hz, 2H, SCH), 7.08 (d, J = 5.4 Hz, 2H, SCCH).
42%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.33333 h; Stage #2: With copper dichloride In tetrahydrofuran at -78 - 20℃; for 6 h;
In a 250mL three neck flask, 3-bromothiophene (4.0g, 24.54mmol) was solved in anhydrous THF (50mL). The solution was cooled to −78°C and LDA solution was added dropwise over 20min. Then the solution was stirred for 1h at the same temperature and CuCl2 (6.56g, 49.08mmol) was added in one portion. After being stirred for 1h at −78°C, the mixture was warmed to room temperature and stirred for another 5h. The reaction was quenched with water. The crude compound was extracted with dichloromethane and washed by distilled water, dried over anhydrous MgSO4, and evaporated in vacuum. The residue was purified by silica gel column chromatography (eluent: petroleum ether). Compound 2 was obtained as a white solid (1.7g, 42percent). 1H NMR (CDCl3, 400MHz): δ 7.41 (d, J=5.4Hz, 2H, SCH), 7.08 (d, J=5.4Hz, 2H, SCCH).
Reference：
[1] Organic Letters, 2010, vol. 12, # 18, p. 4054 - 4057
[2] Journal of Physical Organic Chemistry, 2017, vol. 30, # 9,
[3] Organic Electronics: physics, materials, applications, 2016, vol. 37, p. 312 - 325
[4] Physical Chemistry Chemical Physics, 2016, vol. 18, # 47, p. 32096 - 32106
[5] Journal of Organic Chemistry, 2012, vol. 77, # 23, p. 10931 - 10937
[6] Journal of Materials Chemistry, 2012, vol. 22, # 37, p. 19752 - 19760,9
[7] Journal of Materials Chemistry A, 2017, vol. 5, # 17, p. 7811 - 7815
[8] Journal of Materials Chemistry C, 2018, vol. 6, # 3, p. 500 - 511
[9] Inorganic Chemistry, 2016, vol. 55, # 13, p. 6653 - 6659
[10] Macromolecules, 2013, vol. 46, # 6, p. 2078 - 2091
[11] Patent: WO2013/23108, 2013, A1, . Location in patent: Page/Page column 41; 42
[12] Patent: WO2013/23106, 2013, A1, . Location in patent: Page/Page column 41; 42
[13] Patent: WO2013/23109, 2013, A1, . Location in patent: Page/Page column 39; 40
[14] RSC Advances, 2018, vol. 8, # 58, p. 33276 - 33290
[15] RSC Advances, 2015, vol. 5, # 127, p. 105435 - 105445
[16] Journal of Materials Chemistry C, 2017, vol. 5, # 45, p. 11927 - 11936
[17] Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 294, p. 54 - 61
[18] Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 294, p. 54 - 61
[19] Patent: WO2013/23107, 2013, A1, . Location in patent: Page/Page column 39
[20] Journal of Polymer Science, Part A: Polymer Chemistry, 2013, vol. 51, # 22, p. 4860 - 4872
[21] Dyes and Pigments, 2017, vol. 136, p. 168 - 174
[22] Chemistry - A European Journal, 2017, vol. 23, # 12, p. 2839 - 2851
[23] Advanced Materials, 2017, vol. 29, # 35,
[24] Physical Chemistry Chemical Physics, 2017, vol. 19, # 31, p. 20513 - 20522
54
[ 872-31-1 ]
[ 21308-82-7 ]
Reference：
[1] Synlett, 2011, # 16, p. 2392 - 2396
55
[ 872-31-1 ]
[ 93830-58-1 ]
[ 21308-82-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4755 - 4763
56
[ 872-31-1 ]
[ 17721-06-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 24, p. 8224 - 8227
[2] Chemical Communications, 2008, # 46, p. 6200 - 6202
[3] Advanced Synthesis and Catalysis, 2013, vol. 355, # 4, p. 627 - 631
57
[ 872-31-1 ]
[ 40032-73-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
With N-chloro-succinimide In acetic acid
Step A: Preparation of 2-chloro-3-bromothiophene To a round bottomed flask were added glacial acetic acid (115.0 mL) along with 3-bromothiophene (25.0 g, 153.3 mmole). The reaction mixture was heated to reflux and N-chlorosuccinimide (20.58 g, 154.0 mmole) was added portion-wise (Note: reaction vigorous upon each[addition]). After the addition was complete the reaction mixture was refluxed for three additional hours. The reaction mixture was cooled, poured onto ice/water and extracted (ethyl acetate). The combined extracts were washed with water, dilute HCl, and brine. Solvent removal yielded 27.91 g (87percent) of a dark liquid. The sample was distilled before further use.
Reference：
[1] Patent: US5276025, 1994, A,
58
[ 872-31-1 ]
[ 60404-24-2 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sulfuric acid; iodine; iodic acid; acetic acid In cyclohexane; water at 40℃; for 17 h;
In a 100-mL four mouth flask, 3-bromothiophene (10 g, 61.3mmol), Iodine (5.61 g, 22.1mmol), iodic acid (2.27 g, 12.9mmol), acetic acid (20 mL), cyclohexane (30 mL), water (8 mL), and concentrated sulfuric acid (0.4 mL) were added, and it was made to react at 40 degrees C for 17 hours. After ending reaction, after cooling to a room temperature, a saturated sodium bicarbonate aqueous solution (40 mL) and diethylether (30 mL) were added and extracted. The sodium-hydrogen-sulfite aqueous solution (30 mL) and the saturated sodium chloride solution solution (30 mL) washed the obtained organic layer in order 10percent, and it dried with magnesium sulfate. By carrying out distillation refining (- 125 degrees C - 9torr) of the gift obtained by filtration and concentration, the 3-bromo-2-iodothiophene was obtained as a substantially colorless liquid at 15.6 g (88percent of yield).
64%
With N-iodo-succinimide; toluene-4-sulfonic acid In ethanol at 50℃; for 0.166667 h; Green chemistry
General procedure: The thiophene derivative (1 mmol, 1 equiv) was dissolved in EtOH (2mL) at the temperature indicated in Tables 1–5. Then, NIS (1 or 1.1 equiv, see Tables 1–5) was added followed by PTSA (10percent mol). The mixture was stirred for 10 min, then sat. Na2S2O3 (2 mL) was added. The mixture was diluted with EtOAc (3 mL). After phase separation, the organic phase was washed with 1 M Na2CO3 solution, dried (MgSO4), filtered through cotton, and evaporated to give the iodinated thiophene derivative.
17 g
With sulfuric acid; iodine; iodic acid; acetic acid In hexane; water at 20℃;
Compound 1 was prepared as described in Jpn. Kokai Tokkyo Koho, 2014015436, 30 Jan 2014.Dry reaction flask 3-bromothiophene (10 g, 61.3 mmol) was dissolved in hexane solvent,To this solution was added iodine (2.27 g, 22.1 mmol),Iodic acid (2.27 g, 12.9 mmol), & lt; RTI ID = 0.0 & gt;Acetic acid (20 mL),Water (8 mL), and concentrated sulfuric acid (0.4 mL) were mixed and stirred at room temperature.The reaction solution was cooled to 0 ° C and the reaction was terminated while adding saturated aqueous bicarbonate solution,The organic layer was extracted with hexane and the remaining water was removed from the organic layer using sodium sulfate.The solution was then used to remove the sodium sulfate using a filter,The filtered organic solution was concentrated to give 17 g of compound 1 (3-bromo-2-iodothiophene) as a dark brown oil (Scheme 1).
Reference：
[1] Patent: JP6007631, 2016, B2, . Location in patent: Paragraph 0032
[2] Synthesis (Germany), 2015, vol. 47, # 24, p. 3901 - 3906
[3] Organic Letters, 2013, vol. 15, # 18, p. 4666 - 4669
[4] Patent: KR2017/26286, 2017, A, . Location in patent: Paragraph 0105-0109
59
[ 73882-41-4 ]
[ 872-31-1 ]
[ 60404-24-2 ]
[ 73882-40-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 1, p. 171 - 174
60
[ 73882-40-3 ]
[ 872-31-1 ]
[ 60404-24-2 ]
[ 73882-41-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 1, p. 171 - 174
61
[ 872-31-1 ]
[ 67-56-1 ]
[ 70260-17-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 18, p. 2661 - 2668
62
[ 872-31-1 ]
[ 3593-75-7 ]
Yield
Reaction Conditions
Operation in experiment
30.3%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.666667 h; Inert atmosphere Stage #2: With 1-bromo-butane; sulfur In diethyl ether at -78 - 0℃; for 0.5 h; Inert atmosphere
Was charged in a dry, continuous nitrogen-fed reactorBromothiophene(8 ml, 0.08 mol),Ether (32 ml),The temperature was lowered to -78 ° C, n-butyllithium (32 ml, 0.08 mol) was added slowly,Stir for 40 minutes. Then, the temperature of the reaction solution was raised to 0 ° C,Under vacuumButyl bromide,Ether (32 ml) was added,The solution was cooled to -78 ° C, sulfur (2.56 g, 0.08 mol) was added and stirred for 30 minutes.The temperature was raised to 0 ° C, and the mixture was stirred for 30 minutesP-toluenesulfonyl chloride(15.22 g, 0.08 mol),The reaction was kept at 0 ° C for 30 minutes. The temperature was raised to 40 ° C,Insulate for 4 hours. A second portion was prepared according to the procedure described above3-lithium-thiophene (1.2 eq.),N-butyllithium (38.4 ml, 0.096 mol) and 3-bromothiophene (8.93 ml, 0.072 mol).The reaction solution was allowed to warm to 0 ° C and the butyl bromide was removed in vacuo and the ether was reintroduced. At -78 & lt; 0 &A second portion of a solution of 3-lithium-thiophene in diethyl ether was added to the first portion of the reaction solution, held for 1 hour, then allowed to warm to room temperature and allowed to react overnight.The reaction solution was cooled to 0 ° C the next day, and n-butyllithium (70.4 ml, 0.176 mol) was slowly added thereto, stirred for 30 minutes, and then refluxed for 1 hour. The temperature was lowered to 0C, Copper dichloride (24.42 g, 0.184 mol) was added,Stirred for 1 hour, then allowed to warm to room temperature and allowed to react overnight. The resulting solid was filtered and the organic phase was collected and purified by column chromatography (n-hexane). Recrystallization from n-hexane gave a pale yellow powder (4.74 g, yield 30.3percent).
Reference：
[1] Patent: CN105646528, 2016, A, . Location in patent: Paragraph 0067; 0068
[2] Journal of the American Chemical Society, 1998, vol. 120, # 9, p. 2206 - 2207
63
[ 872-31-1 ]
[ 3761-92-0 ]
[ 1693-86-3 ]
Yield
Reaction Conditions
Operation in experiment
95.6%
at 0 - 20℃; Inert atmosphere
Starting from the commercially available products 3-bromothiophene (3-BT) and hexylmagnesiumbromide, 1 was produced using a Ni catalyst. In a three-necked flask, 100ml (1 eq, 166.0 g, 1.018 mol) of bromothiophene is stirred under nitrogen atmosphere with 0.01 equivalent of Ni(dppp)CI2 (5.19 g, 0.0102 mol) and 300ml dry diethylether. 1.2 equivalent (0.61 1 I of a 2.0M solution in diethyl ether, 1.22 mol) of hexylmagnesiumbromide was added dropwise at a temperature of O0C. The reaction was stirred overnight at room temperature before neutralisation by addition of a 1 M HCI solution. After extraction with diethyl ether, washing with a saturated NaHCO3 solution and drying over MgSO4 a brown liquid was obtained. This liquid was purified by short path distillation to obtain 1 in a yield of 95.6percent (163.73g, 0.973mol) at p= 7.103 mbar and T= 81 -840C.Characterization: TLC (hexane): Rf =0.81 ; 1H NMR (300MHz, CDCI3): δ 7.23(s, H), 6.95 (d, H), 6.92 (d, H), 2.63 (t, CH2), 1.63 (q, CH2), 1.32 (m, 3 CH2), 0.90 (t, CH3); 13C NMR (75MHz, CDCI3): δ 142.8, 130.8, 1 10.2, 107.2, 31.5, 29.4, 29.3, 28.7, 22.5, 14.0; GC/MS (m/z): 168 [M] M 53 [M-CH3] +, 139 [M - CH2CH3] +, 125 [M - (CH2)2CH3] +, 1 1 1 [M - (CH2)3CH3] +, 97 [M- (CHs)4CH3] +, 85 [M -(CH2)5CH3] +; FT-IR: 3000- 2800 cm"1 (C-H stretch alkyl), 1600-1500cm"1 (C=C stretch aromatic ring).
95.6%
at 0 - 20℃; Inert atmosphere
Starting from the commercially available products 3-bromothiophene (3- BT) and hexylmagnesiumbromide, 1 was produced using a Ni catalyst. In a three-necked flask, 100ml (1 eq, 166.0 g, 1 .018 mol) of bromothiophene is stirred under nitrogen atmosphere with 0.01 equivalent of Ni(dppp)Cl2 (5.19 g, 0.0102 mol) and 300ml dry diethylether. 1 .2 equivalent (0.61 1 I of a 2.0M solution in diethyl ether, 1 .22 mol) of hexylmagnesiumbromide was added dropwise at a temperature of 0°C. The reaction was stirred overnight at room temperature before neutralisation by addition of a 1 M HCI solution. After extraction with diethyl ether, washing with a saturated NaHCO3 solution and drying over MgSO4 a brown liquid was obtained. This liquid was purified by short path distillation to obtain 1 in a yield of 95.6percent (163.73g, 0.973mol) at p= 7.10"3 mbar and T= 81 -84°C.Characterization: TLC (hexane): Rf =0.81 ; 1 H NMR (300MHz, CDCI3): δ7.23(s, H), 6.95 (d, H), 6.92 (d, H), 2.63 (t, CH2), 1 .63 (q, CH2), 1 .32 (m, 3 CH2), 0.90 (t, CH3); 13C NMR (75MHz, CDCI3): δ 142.8, 130.8, 1 10.2, 107.2, 31 .5, 29.4, 29.3, 28.7, 22.5, 14.0; GC/MS (m/z): 168 [M] +,153 [M-CH3] +, 139 [M - CH2CH3] +, 125 [M - (CH2)2CH3] +, 1 1 1 [M - (CH2)3CH3] +, 97 [M- (CH2)4CH3] +, 85 [M -(CH2)5CH3] +; FT-IR: 3000- 2800 cm"1 (C-H stretch alkyl), 1600-1500cm"1 (C=C stretch aromatic ring).
Reference：
[1] Patent: WO2010/504, 2010, A1, . Location in patent: Page/Page column 25-26
[2] Patent: WO2011/69554, 2011, A1, . Location in patent: Page/Page column 28-29
[3] New Journal of Chemistry, 2001, vol. 25, # 2, p. 318 - 321
[4] Journal of Organic Chemistry, 2002, vol. 67, # 14, p. 4924 - 4936
[5] Angewandte Chemie - International Edition, 2009, vol. 48, # 43, p. 8014 - 8017
[6] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 1, p. 193 - 195
[7] Organic Letters, 2010, vol. 12, # 9, p. 2136 - 2139
[8] Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 15, p. 3331 - 3339
[9] Chinese Journal of Chemistry, 2012, vol. 30, # 3, p. 577 - 584
[10] Journal of Nanoscience and Nanotechnology, 2011, vol. 11, # 5, p. 4367 - 4372
[11] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 16, p. 3415 - 3424
[12] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 9, p. 3107 - 3110
[13] Chemical Science, 2013, vol. 4, # 8, p. 3317 - 3331
[14] Chinese Journal of Chemistry, 2013, vol. 31, # 11, p. 1385 - 1390
[15] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 28, p. 5690 - 5699
64
[ 872-31-1 ]
[ 111-25-1 ]
[ 1693-86-3 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: With magnesium In diethyl ether at 20℃; for 2 h; Reflux; Inert atmosphere Stage #2: With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II) In diethyl ether at 0 - 20℃; for 4.5 h; Inert atmosphere
3-Hexylthiophene was prepared similarly to a method described by Ng et al.9 and was modifiedas follows: magnesium (2.55 g, 105 mmol) was stirred without solvent under nitrogen for 1 h inorder to activate the surface. A solution of 1-bromohexane (14.9 g, 90.0 mmol) in dry diethyl ether (75 mL) was added dropwise to a suspension of the activated magnesium in diethyl ether(45 mL) within 1 h at 20 °C. The reaction mixture was heated to reflux for another 1 h. The resulting Grignard reagent was added to 3-bromothiophene (12.23 g, 75.00 mmol) and [Ni(dppp)Cl2] (81 mg, 15 mmol, 0.2 molpercent) in diethyl ether(45 mL) at 0 °C via syringe over the course of 30 min and the mixture was stirred for 4 h at 20 °C. The reaction mixture was quenched with aqueous hydrochloric acid (1 M, 60 mL) at 0 °C. Then the aqueous layer was extracted with diethyl ether (4 x 50 mL). The combined organic layers were dried over MgSO4 and the volatiles were removed in vacuo. The residue was purified by vigreux distillation (110 °C, 6 mbar) to yield 10.2 g (81percent, lit.9 71percent) of colorless oil.
54%
Stage #1: With magnesium In tetrahydrofuran at 70℃; for 2 h; Inert atmosphere Stage #2: With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II) In tetrahydrofuran for 24 h; Inert atmosphere; Reflux
After stirring a mixture of magnesium turnings (10.3 g, 421.2 mmol) and 1-bromohexane (59.3 mL, 422.2 mmol) in 80 mL of anhydrous THF for 2 h at 70 °C under argon atmosphere, the mixture was treated with a solution of 3-bromothiophene (20 mL, 211.1 mmol) and Ni(dppp)Cl2 (1.1 g, 2.1 mmol) in 30 mL of THF. The mixture was allowed to reflux for 24 h, treated with a solution of 2 N HCl, washed with a 10percent solution of NaHCO3, and extracted with ether. The organic layer was washed with brine, concentrated under reduce pressure and purified by flash chromatography to give 19.1 g (54percent) of compounds 1 as colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.28 (m, 1 H), 6.97 (m, 2H), 2.68 (t, 2H, J = 7.42 Hz), 1.67 (qi, 2H, J = 4.2 Hz), 1.36 (m, 6H), 0.95 (t, 3H, J = 6.59 Hz).; 13C NMR (75 MHz, CDCl3): δ (ppm) 143.14, 128.195, 124.958, 119.7, 31.688, 30.523, 30.265, 29.013, 22.617, 14.080. HRMS (m/z, FAB+) calcd for C10H16S, 168.0973, found 168.0974.
Reference：
[1] Macromolecules, 2013, vol. 46, # 15, p. 5985 - 5997
[2] Chemistry of Materials, 2011, vol. 23, # 18, p. 4250 - 4256
[3] Macromolecules, 2014, vol. 47, # 3, p. 1008 - 1020
[4] Organic Letters, 2013, vol. 15, # 18, p. 4666 - 4669
[5] Tetrahedron, 2015, vol. 71, # 33, p. 5399 - 5406
[6] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 12, p. 2715 - 2724
[7] Synthetic Communications, 1986, vol. 16, # 6, p. 689 - 696
[8] Journal of the Chemical Society. Perkin Transactions 2, 1997, # 8, p. 1597 - 1604
[9] Polymer, 2017, vol. 109, p. 115 - 125
[10] Macromolecules, 2004, vol. 37, # 23, p. 8577 - 8584
[11] Molecular Crystals and Liquid Crystals, 2007, vol. 470, # 1, p. 353 - 358
[12] Patent: US2010/217015, 2010, A1, . Location in patent: Page/Page column 5
[13] Journal of the American Chemical Society, 2011, vol. 133, # 27, p. 10390 - 10393
[14] Macromolecules, 2011, vol. 44, # 16, p. 6370 - 6381
[15] Macromolecules, 2015, vol. 48, # 10, p. 3269 - 3281
[16] Journal of Polymer Science, Part A: Polymer Chemistry, 2014, vol. 52, # 1, p. 76 - 86
65
[ 872-31-1 ]
[ 638-45-9 ]
[ 1693-86-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5448 - 5452
66
[ 872-31-1 ]
[ 111-25-1 ]
[ 3172-56-3 ]
[ 740804-46-0 ]
[ 1693-86-3 ]
Yield
Reaction Conditions
Operation in experiment
97.5 - 98.88 %Chromat.
Stage #1: With magnesium In 2-methyltetrahydrofuran at 60 - 85℃; for 4.5 h; Stage #2: at 15 - 20℃; for 20 h; Stage #3: With hydrogenchloride; water In 2-methyltetrahydrofuran
EXAMPLE 1; Added to a flask are 57.1 g (2.35 mol) of magnesium metal and 700 ml of 2-methyl-tetrahydrofuran. The flask contents are heated to 60-70° C. A reaction is initiated by adding 5 ml of hexylmagnesiumbromide (1 N) in 2-methyl-tetrahydrofuran to the flask. The Grignard reagent concentration in the solvent is 3.35 mol/L. The flask temperature is increased to 80-85° C. Next, 396 g of bromohexane (2.4 mol) is added to the flask over a period of 2.5 hours. The flask is then heated to reflux and stirred for an additional two hours. After two hours, the flask is cooled down to 15-20° C. Thereafter, add a suspension of 1.6 g of Ni(dppp)Cl2 catalyst in 5 ml of 2-methyltetrahydrofuran. Next, over a period of four hours, add 326.1 g (2 mol) of 3-bromothiophene. Let this stir for an additional 16 hours. The reaction mixture is then hydrolyzed on 1000 ml HCl (10percent w/w). A 100percent conversion is achieved with essentially no bis-thienyl side-product, and a crude assay of 98.5percent. According to this procedure 5 runs were carried out. EXAMPLE 2; Added to a flask are 58.3 g (2.4 mol) of magnesium metal and 500 ml of 2-methyl-tetrahydrofuran. The flask contents are heated to 60-70° C. A reaction is initiated by adding 5 ml of hexylmagnesiumbromide (1 N) in 2-methyl-tetrahydrofuran to the flask. The Grignard reagent concentration in the solvent is 4.8 mol/L. The flask temperature is increased to 80-85° C. Next, 396.2 g of bromohexane (2.4 mol) is added to the flask over a period of 2.5 hours. The flask is then heated to reflux and stirred for an additional two hours. After one hour, the flask is cooled down to 15-20° C. Thereafter, add a suspension of 1.6 g of Ni(dppp)Cl2 catalyst in 5 ml of 2-methyltetrahydrofuran. Next, over a period of four hours, add 326.1 g (2 mol) of 3-bromothiophene. Let this stir for an additional 16 hours. The reaction mixture is then hydrolyzed on 1000 ml HCl (10percent w/w). A 100percent conversion is achieved with no bis-thienyl side-product, and a crude assay of 98.5percent. Immediate gas chromatography of the reaction product showed 15.4percent 3-bromothiophene, 81.1percent 3-hexylthiophene and 0.0percent bis-thienyl side-product. GC after one hour showed 8.7percent 3-bromothiophene, 88.0percent 3-hexylthiophene and 0.0percent bis-thienyl side-product. GC after 15 hours showed 0.0percent 3-bromothiophene, 97.5percent 3-hexylthiophene, 0.0percent bis-thienyl side-product and 0.41percent 3-(1-methyl-pentyl)thiophene.
EXAMPLE 6 (COMPARATIVE); A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to a mixture of a 100percent tetrahydrofuran solvent, 3-bromothiophene (1 eq.) and with 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at 60° C. Immediate gas chromatography of the reaction product showed 9.6percent 3-bromothiophene, 36.2percent 3-hexylthiophene and 25.7percent bis-thienyl side-product. GC after one hour showed 6.6percent3-bromothiophene, 38.6percent 3-hexylthiophene and 27.1percent bis-thienyl side-product. GC after 2.5 hours showed 3.3percent 3-bromothiophene, 37.7percent 3-hexylthiophene and 20.3percent bis-thienyl side-product. The high temperature (60° C.) and 100percent tetrahydrofuran solvent gave low selectivity, incomplete conversion, and an undesirable amount of bis-thienyl side product; EXAMPLE 7 (COMPARATIVE); A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to a mixture of a 100percent tetrahydrofuran solvent, 3-bromothiophene (1 eq.) and with 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at 0° C. Immediate gas chromatography of the reaction product showed 0.09percent 3-bromothiophene, 82.7percent 3-hexylthiophene and 6.6percent bis-thienyl side-product. GC after one hour showed 0.09percent 3-bromothiophene, 82.3percent 3-hexylthiophene and 6.7percent bis-thienyl side-product. GC after 2.5 hours showed 0.5percent 3-bromothiophene, 81.5percent 3-hexylthiophene and 6.4percent bis-thienyl side-product. The low temperature (0° C.) gave satisfactory selectivity but an undesirable amount of bis-thienyl side product.
4.0 - 4.5 %Chromat.
at 20℃; for 2.5 h;
EXAMPLE 10 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with 200 mg of a dichloro-bis(triphenylphosphine) palladium(II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 77.2percent 3-bromothiophene, 4.2percent 3-hexylthiophene and 0.5percent bis-thienyl side-product. GC after one hour showed 78.1percent 3-bromothiophene, 4.0percent 3-hexylthiophene and 0.2percent bis-thienyl side-product. GC after 2.5 hours showed 76.8percent 3-bromothiophene, 4.5percent 3-hexylthiophene and 0.3percent bis-thienyl side-product. The diethylether solvent and dichloro-bis(triphenylphosphino) palladium(II) catalyst gave a bad conversion percentage.
1.7 - 3.1 %Chromat.
at 20℃; for 1 h;
EXAMPLE 15 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with 12.6 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 85.3percent 3-bromothiophene, 1.7percent 3-hexylthiophene and 0.5percent bis-thienyl side-product. GC after one hour showed 68.0percent 3-bromothiophene, 3.1percent 3-hexylthiophene, 6.3percent bis-thienyl side-product and 0.89percent. This shows bad conversion with a diethylether solvent and a dichloro-bis(triphenylphosphine) nickel (II) catalyst.
0.5 - 1.1 %Chromat.
at 20℃; for 1 h;
3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with no catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 85.7percent 3-bromothiophene, 0.5percent 3-hexylthiophene and 0.4percent bis-thienyl side-product. GC after one hour showed 85.7percent 3-bromothiophene, 1.1percent 3-hexylthiophene and 0.2percent bis-thienyl side-product. This shows almost no conversion with no catalyst.
A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to mixture of a 50:50 tetrahydrofuran/toluene solvent, 3-bromothiophene (1 eq.) and 200 mg of a dichloro-bis(triphenylphosphine) palladium(II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at 80° C. Immediate gas chromatography (GC) of the reaction product showed 15.2percent 3-bromothiophene, 38.0percent 3-hexylthiophene and 17.9percent bis-thienyl side-product. GC after one hour showed 2.0percent 3-bromothiophene, 40.7percent 3-hexylthiophene and 23.9percent bis-thienyl side-product. GC after 2.5 hours showed 1.3percent 3-bromothiophene, 42.1percent 3-hexylthiophene, 24.3percent bis-thienyl side-product and 2.53percent 3-(1-methylpentyl)thiophene. This results show a low selectivity using a dichloro-bis(triphenylphosphine) palladium(II) catalyst and 50:50 THF/toluene solvent. Also an undesirable amount of bis-thienyl and 3-(1-methylpentyl)thiophene side products.
5.7 - 12.7 %Chromat.
at 20℃; for 1 h;
3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with 200 mg of a Nickel (II) acetylacetonate catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 60.0percent 3-bromothiophene, 5.7percent 3-hexylthiophene and 5.9percent bis-thienyl side-product. GC after one hour showed 40.1percent 3-bromothiophene, 12.7percent 3-hexylthiophene, 16.2percent bis-thienyl side-product and 2.4percent 3-(1-methylpentyl)thiophene. The nickel (II) acetylacetonate catalyst and diethylether solvent gave incomplete conversion.
81.5 - 82.9 %Chromat.
at 20℃; for 2.5 h;
EXAMPLE 11 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with 200 mg of a dichloro-bis(triphenylphosphine) palladium(II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at 0° C. Immediate gas chromatography of the reaction product showed 0.09percent 3-bromothiophene, 81.5percent 3-hexylthiophene and 5.3percent bis-thienyl side-product. GC after one hour showed 0.09percent 3-bromothiophene, 82.5percent 3-hexylthiophene and 5.1percent bis-thienyl side-product. GC after 2.5 hours showed 0.07percent 3-bromothiophene, 82.9percent 3-hexylthiophene, 5.2percent bis-thienyl side-product and 0.09percent3-(1-methylpentyl)thiophene. The diethylether solvent, 0° C. reaction temperature and dichloro-bis(triphenylphosphine) palladium(II) catalyst gave complete conversion and good selectivity (80percent), but 5.2percent bis-thienyl side-product.
66.8 - 70.4 %Chromat.
at 20℃; for 2.5 h;
A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to a mixture of a 50:50 THF/toluene solvent, 3-bromothiophene (1 eq.) and 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 7.1percent 3-bromothiophene, 66.8percent 3-hexylthiophene and 12.6percent bis-thienyl side-product. GC after one hour showed 2.2percent 3-bromothiophene, 70.4percent 3-hexylthiophene and 13.3percent bis-thienyl side-product. GC after 2.5 hours showed 2.1percent 3-bromothiophene, 68.8percent 3-hexylthiophene, 14.0percent bis-thienyl side-product and 0.23percent 3-(1-methylpentyl)thiophene. The results show better selectivity using a dichloro-bis(triphenylphosphine) nickel (II) catalyst and 50:50 THF/toluene solvent than in Example 5, but incomplete conversion and an undesirable amount of bis-thienyl side product.
73.3 - 74.3 %Chromat.
at 0 - 20℃; for 2.5 h;
EXAMPLE 8 (COMPARATIVE) ; 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 0.2percent 3-bromothiophene, 74.3percent 3-hexylthiophene and 10.5percent bis-thienyl side-product. GC after one hour showed 0.1percent 3-bromothiophene, 73.6percent 3-hexylthiophene and 11.85percent bis-thienyl side-product. GC after 2.5 hours showed 0.3percent 3-bromothiophene, 73.3percent 3-hexylthiophene, 10.7percent bis-thienyl side-product and 0.09percent 3-(1-methylpentyl)thiophene. The diethylether solvent gave complete conversion but selectivity was only 70percent and an undesirable amount of bis-thienyl side product was formed.
27.2 - 91.2 %Chromat.
at 20℃; for 2.5 h;
EXAMPLE 9 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with 200 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 0.1percent 3-bromothiophene, 91.2percent 3-hexylthiophene and 0.13percent bis-thienyl side-product. GC after one hour showed 0.2percent 3-bromothiophene, 90.0percent 3-hexylthiophene and 0.2percent bis-thienyl side-product. GC after 2.5 hours showed 0.16percent 3-bromothiophene, 90.7percent 3-hexylthiophene, 0.2percent bis-thienyl side-product and 0.4percent 3-(1-methylpentyl)thiophene. The diethylether solvent and (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst gave a selectivity of 90percent. This reaction mixture undesirably forms a solid at the 2 mol/L concentration and therefore cannot be worked up in a plant scale due to the inability of the solid to be purged on water, which then requires the addition of water to the reaction. This may lead to accumulation of water which can suddenly react, leading to uncontrolled development of heat, and presenting serious safety concerns; EXAMPLE 13 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100percent diethylether solvent and with 12.6 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 60.9percent 3-bromothiophene, 27.2percent 3-hexylthiophene and 0.3percent bis-thienyl side-product. GC after one hour showed 45.6percent 3-bromothiophene, 42.9percent 3-hexylthiophene and 0.3percent bis-thienyl side-product. GC after 2.5 hours showed 35.6percent 3-bromothiophene, 51.8percent 3-hexylthiophene, 0.3percent bis-thienyl side-product and 0.31percent 3-(1-methylpentyl)thiophene. A reduced amount of (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst and diethylether solvent gave incomplete conversion.
Reference：
[1] New Journal of Chemistry, 2011, vol. 35, # 3, p. 558 - 567
[2] Soft Matter, 2012, vol. 8, # 42, p. 10921 - 10931,11
[3] Chemical Science, 2013, vol. 4, # 8, p. 3317 - 3331
75
[ 872-31-1 ]
[ 4248-19-5 ]
[ 19228-91-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5279 - 5285
[2] Tetrahedron Letters, 2002, vol. 43, # 41, p. 7365 - 7368
76
[ 60404-24-2 ]
[ 872-31-1 ]
[ 73882-41-4 ]
[ 73882-40-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 1, p. 171 - 174
77
[ 73882-40-3 ]
[ 872-31-1 ]
[ 60404-24-2 ]
[ 73882-41-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 1, p. 171 - 174
78
[ 872-31-1 ]
[ 111-83-1 ]
[ 65016-62-8 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With magnesium In diethyl ether for 2 h; Inert atmosphere Stage #2: for 24 h; Cooling with ice
Compound 9 was synthesized from the reported process (Chochos CL, Economopoulos SP, Deimede V, Gregoriou VG, Lloyd MT, Malliaras GG, Kallitsis JK, et al. Synthesis of a soluble n-type cyano substituted polythiophene derivative: solar cells. J Phys Chem C 2007; 111: 10732-40).1-Bromooctane (28.7 mL)Was added dropwise to a solution of magnesium (4.63 g, 193 mmol) in anhydrous diethyl ether (130 mL). The mixture,And stirred in a nitrogen atmosphere for 2 h.The final Grignard reagent was added dropwise to a flask containing 3-bromothiophene (19 g, 116.6 mmol) and Ni (dppp) Cl2 (0.31 g, 0.571 mmol). After stirring and heating for 24 h,Contained in an ice bath,HCl (2N) was extracted with diethyl ether.The organic layer was dehydrated with sodium sulfate,Concentrated by evaporation under reduced pressure and purified by column chromatography with hexane to give a colorless oil (15.54 g, 68percent).
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 13, p. 3894 - 3901
[2] Structural Chemistry, 2012, vol. 23, # 6, p. 1751 - 1760
[3] Patent: KR2018/17709, 2018, A, . Location in patent: Paragraph 0196; 0199; 0200-0202
[4] Macromolecules, 2011, vol. 44, # 16, p. 6370 - 6381
[5] RSC Advances, 2016, vol. 6, # 82, p. 78984 - 78993
79
[ 872-31-1 ]
[ 17049-49-9 ]
[ 65016-62-8 ]
Reference：
[1] Journal of Materials Chemistry C, 2015, vol. 3, # 6, p. 1301 - 1308
[2] European Journal of Organic Chemistry, 2001, # 7, p. 1249 - 1258
[3] Journal of Organic Chemistry, 1993, vol. 58, # 4, p. 904 - 912
[4] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 1994, vol. 247, p. 31 - 38
[5] Macromolecules, 2010, vol. 43, # 24, p. 10231 - 10240
[6] Macromolecules, 2011, vol. 44, # 12, p. 4711 - 4720
[7] Soft Matter, 2012, vol. 8, # 42, p. 10921 - 10931,11
[8] Chemical Science, 2013, vol. 4, # 8, p. 3317 - 3331
[9] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 28, p. 5690 - 5699
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5448 - 5452
82
[ 872-31-1 ]
[ 17049-49-9 ]
[ 145543-83-5 ]
Reference：
[1] Journal de Chimie Physique et de Physico-Chimie Biologique, 1998, vol. 95, # 6, p. 1180 - 1183
83
[ 872-31-1 ]
[ 143-15-7 ]
[ 104934-52-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: With iodine; magnesium In tetrahydrofuran at 70℃; for 2 h; Inert atmosphere Stage #2: With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II) In tetrahydrofuran at 20℃;
Under N2 atmosphere,To the possession of magnesium tablets(3.28 g, 0.135 mol),Anhydrous THF (30 mL)withA small amount of iodine mixture250 mL three-necked flask was added slowly1-bromododecane (28.75 g, 26.9 mL, 0.13 mol)In anhydrous THF (45 mL).The mixture was refluxed at 70 ° C for 2 hours,The system was cooled to room temperature with ice water,First Ni (dppp) Cl2 (0.54 g,1.00 mmol) was added,A solution of 3-bromothiophene (16.31 g, 0.10 mol) in dry THF (40 mL) was slowly added.The mixed solution was stirred overnight at room temperature,The reaction was quenched by the addition of cold HCl (1.50 mol / L) aqueous solution.The crude product was extracted with dichloromethane,Dried over anhydrous magnesium sulfate,And further purified by a column separation and purification method (n-hexane as an eluent)To clarify the liquid (22.18 g, 88percent).
Reference：
[1] Patent: CN106588867, 2017, A, . Location in patent: Paragraph 0022; 0023; 0024
[2] Journal of Physical Chemistry B, 2001, vol. 105, # 45, p. 11106 - 11113
[3] Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 18, p. 3942 - 3949
[4] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 5, p. 1659 - 1663
[5] Angewandte Chemie - International Edition, 2018, vol. 57, # 24, p. 7034 - 7039[6] Angew. Chem., 2018, vol. 130, p. 7152 - 7157,6
[7] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5448 - 5452
[8] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1993, # 3, p. 489 - 494
[9] Journal of Materials Chemistry, 1996, vol. 6, # 8, p. 1319 - 1324
[10] Patent: US4730005, 1988, A,
[11] Macromolecules, 2011, vol. 44, # 16, p. 6370 - 6381
[12] RSC Advances, 2016, vol. 6, # 5, p. 4070 - 4076
[13] Canadian Journal of Chemistry, 2016, vol. 94, # 6, p. 553 - 558
84
[ 872-31-1 ]
[ 869589-06-0 ]
[ 104934-52-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
With [1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex In N,N-dimethyl acetamide at 80℃; for 12 h;
3-Bromothiophene (3.26 g, 20 mmol) and Pd(dppf)C12CH2C12 (163.3 mg, 0.2 mmol) were dissolved in DIVIA (40 mL) and stirred at 80°C. The freshly prepared dodecylzinc(II) bromide was added dropwise. The reaction mixture was stirred at 80°C for 12 hours before cooled to room temperature. Hexane (50 mL) and saturated ammonium chloride solution (50 mL) were added. The mixture was stirred for 30 minutes and passed through a pad of Celite. The aqueous layer was extracted with hexane. The combined organic layer was washed with hydrochloric acid (1M) for three times, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, eluent: nhexane). The product was obtained as colorless oil (4.8 g, 95percent). The reaction is shown below.
Reference：
[1] Journal of Materials Chemistry C, 2015, vol. 3, # 6, p. 1301 - 1308
[2] Macromolecules, 2011, vol. 44, # 24, p. 9529 - 9532
[3] Journal of Organic Chemistry, 1993, vol. 58, # 4, p. 904 - 912
[4] Journal of the American Chemical Society, 2011, vol. 133, # 5, p. 1405 - 1418
[5] Angewandte Chemie - International Edition, 2009, vol. 48, # 43, p. 8014 - 8017
[6] Journal of Materials Chemistry, 2011, vol. 21, # 32, p. 11822 - 11830
[7] Chinese Journal of Chemistry, 2012, vol. 30, # 3, p. 577 - 584
[8] Chemical Science, 2013, vol. 4, # 8, p. 3317 - 3331
[9] Journal of Polymer Science, Part A: Polymer Chemistry, 2013, vol. 51, # 5, p. 1029 - 1039
[10] RSC Advances, 2016, vol. 6, # 18, p. 14893 - 14908
86
[ 872-31-1 ]
[ 4292-19-7 ]
[ 104934-52-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5448 - 5452
87
[ 872-31-1 ]
[ 17049-49-9 ]
[ 149703-84-4 ]
Reference：
[1] Journal de Chimie Physique et de Physico-Chimie Biologique, 1998, vol. 95, # 6, p. 1180 - 1183
88
[ 872-31-1 ]
[ 2050-77-3 ]
[ 65016-55-9 ]
Yield
Reaction Conditions
Operation in experiment
78%
With N,N,N,N,-tetramethylethylenediamine; di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium; zinc In water at 20℃; for 24 h; Inert atmosphere
General procedure: In a 5 mL round-bottom flask under argon containing zinc powder (197 mg, 3 mmol) and PdCl2(Amphos)2 (7 mg, 0.01 mmol) was added 2percent PTS solution in water (1.5 mL). N,N,N',N'-Tetramethylethylenediamine (TMEDA, 232 mg, 2 mmol) was added at rt followed by the addition of the alkyl halide (2 mmol) and the heteroaromatic halide (0.5 mmol). The flask was stirred vigorously at rt for the indicated time. The product was extracted with EtOAc.11 Silica gel (1 g) was added to the combined organic phase and solvents were removed under vacuum. The resulting dry, crude silica was introduced on top of a silica gel chromatography column to purify the product.
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 17, p. 2203 - 2205
[2] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5448 - 5452
89
[ 872-31-1 ]
[ 112-29-8 ]
[ 65016-55-9 ]
Reference：
[1] Journal of Materials Chemistry C, 2015, vol. 3, # 32, p. 8351 - 8357
[2] New Journal of Chemistry, 2015, vol. 39, # 12, p. 9700 - 9713
[3] Chemical Communications, 2011, vol. 47, # 33, p. 9471 - 9473
[4] Journal of Materials Chemistry, 2011, vol. 21, # 5, p. 1582 - 1592
[5] Macromolecules, 2011, vol. 44, # 16, p. 6370 - 6381
90
[ 872-31-1 ]
[ 17049-50-2 ]
[ 65016-55-9 ]
Reference：
[1] Journal of Materials Chemistry C, 2015, vol. 3, # 6, p. 1301 - 1308
[2] Journal of the American Chemical Society, 2011, vol. 133, # 5, p. 1405 - 1418
[3] Angewandte Chemie - International Edition, 2009, vol. 48, # 43, p. 8014 - 8017
[4] Organic Electronics: physics, materials, applications, 2012, vol. 13, # 2, p. 273 - 282
[5] Soft Matter, 2012, vol. 8, # 42, p. 10921 - 10931,11
[6] Chemical Science, 2013, vol. 4, # 8, p. 3317 - 3331
[7] Chemical Communications, 2013, vol. 49, # 17, p. 1756 - 1758
[8] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 28, p. 5690 - 5699
91
[ 872-31-1 ]
[ 3172-56-3 ]
[ 65016-55-9 ]
Yield
Reaction Conditions
Operation in experiment
30.0 - 94.6 %Chromat.
Stage #1: With magnesium In 2-methyltetrahydrofuran at 20℃; for 2.5 h; Stage #2: at 20℃;
1.2 mol of magnesium metal and 1.2 mol of 1-bromodecane are combined in a 100percent 2-methyl-tetrahydrofuran solvent, and with 300 mg of (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2.6 mol/L. Next, 3-bromothiophene (1 eq.) is added to the flask. The reactions were conducted at room temperature. Immediate gas chromatography of the reaction product showed 27.1percent 3-bromothiophene, 30.0percent 3-decylthiophene and 0.9percent bis-thienyl side-product. GC after one hour showed 0.0percent 3-bromothiophene, 92.6percent 3-decylthiophene and 2.3percent bis-thienyl side-product. GC after 2.5 hours showed 0.0percent 3-bromothiophene, 94.6percent 3-decylthiophene and 1.9percent bis-thienyl side-product.
Stage #1: With magnesium In tetrahydrofuran at 20℃; for 48 h; Stage #2: at 20℃;
EXAMPLE 16 (COMPARATIVE); 3-Bromothiophene (1 eq.) is combined in a flask with 1.1 mol of magnesium metal and 1.15 mol of 1-bromohexane in a 100percent THF solvent, and with 815 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst in suspension. The Grignard reagent concentration in the solvent is 2.2 mol/L. The reactions were conducted at room temperature. Immediate gas chromatography of the reaction product showed 85.3percent 3-bromothiophene, 1.7percent 3-hexylthiophene and 0.5percent bis-thienyl side-product. GC after 48 hours showed 2.9percent 3-bromothiophene, 64.5percent 3-hexylthiophene, 9.8percent bis-thienyl side-product and 3.34percent 3-(1-methylpentyl)thiophene. This shows bad selectivity with a 100percent THF solvent.
86.7 %Chromat.
Stage #1: With magnesium In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 15 h; Stage #2: at 20℃;
EXAMPLE 17 (COMPARATIVE); 3-Bromothiophene (1 eq.) is combined in a flask with 1.2 mol of magnesium metal and 1.2 mol of 1-bromohexane in a 50:50 THF/MTBE solvent, and with 600 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst in suspension. The Grignard reagent concentration in the solvent is 1.3 mol/L. The reactions were conducted at room temperature. Gas chromatography of the reaction product after 15 hours showed 0.2percent 3-bromothiophene, 86.7percent 3-hexylthiophene, 5.6percent bis-thienyl side-product and 1.59percent 3-(1-methylpentyl)thiophene. This shows high bis-thienyl and 3-(1-methylpentyl)thiophene side-product formation with a 50:50 THF/MTBE solvent. Overall, the comparative examples show that the main input factor for the selectivity is the catalyst, secondly the temperature and solvent is responsible for the final completion of the selectivity. Expressed in numbers: 60percent, 30percent, 10percent responsibility. In methyl-THF, a Grignard reagent concentration of up to 4 mol/L is possible.
With 1H-imidazole; palladium diacetate; triethylamine; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; magnesium chloride In tetrahydrofuran at 90℃; for 0.5 h; Microwave irradiation
To a stirred mixture of aryl or heteroaryl halide(Br, I) (0.5 mmol), potassium mono ethyl malonate (0.75 mmol) in THF (10 mL) taken in a 30 mL microwave vial, was added Pd(OAc)2(5 molpercent), Xantphos (5 mol percent), MgCl2 (0.75), Et3N ( 0.75mmol), imidazole (1 mmol) followed by Co2(CO)8 (0.15mmol). The vial was sealed immediately and microwave irradiated at 90°C for 30min. The reaction mixture was concentrated and diluted with ethyl acetate and water. The ethyl acetate layer was separated, dried over sodium sulphate and concentrated. The crude product obtained was purified by column chromatography to get the pure compound.
Stage #1: With pyridine; copper(l) iodide; potassium <i>tert</i>-butylate In toluene at 20℃; for 0.5 h; Stage #2: at 110℃; for 24 h;
(1) Synthesis of 3- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) thiophene (compound 9) :[0236]A dry 250 mL two-neck round bottom flask with condenser and magnetic stir bar was charged with potassium tertbutylate (10.5 g, 94 mmol) and cuprous iodide (2.34 g, 12 mmol) . Next, 10 mL pyridine and 100 mL toluene mixture solution was added and stirred until dissolved, and 15 mL triethylene glycol monomethyl ether was added. The reaction mixture was then allowed to stir at room temperature for 30 min. 3-bromothiophene (5.8 mL, 62 mmol) was then added in one portion and the reaction mixture was heated to 110 for 24 h. After cooling to room temperature, the reaction mixture was centrifuged and concentrated under vacuum. 50 mL dichloromethane was added and washed with 5 M HCl (aq) . The aqueous layers were extracted with DCM, and the combined organic portions were dried with MgSO4and concentrated under reduced pressure. The crude material was purified via column chromatography, eluting with 1: 1 ethyl ether in hexanes (v/v) . The desired product was isolated as a yellow tinted oil (10.35 g, 68yield) .[0237]1H-NMR (400 MHz, CDCl3) δ 7.18 (dd, J 5.3, 3.1 Hz, 1H) , 6.79 (dd, J 5.3, 1.5 Hz, 1H) , 6.28 (dd, J 3.1, 1.5 Hz, 1H) , 4.17 –4.10 (m, 2H) , 3.89 –3.83 (m, 2H) , 3.77 –3.72 (m, 2H) , 3.72 –3.64 (m, 4H) , 3.57 (dd, J 5.7, 3.6 Hz, 2H) , 3.40 (s, 3H) .
Reference：
[1] Patent: WO2017/190345, 2017, A1, . Location in patent: Page/Page column 33-34
[2] Journal of the American Chemical Society, 2016, vol. 138, # 32, p. 10252 - 10259
[3] Polymer, 2011, vol. 52, # 17, p. 3704 - 3709
[0526] 3-Bromo-thiophene-2-carboxylic acid. To a solution of 3-bromothiophene (600.0 g, 3.68 mol) in THF (3 L) cooled to -72 C. was added LDA (1.93 L, 3.86 mol, 2 N) slowly over 2 hours. The rate of LDA addition is such that the reaction temperature never exceeded -68 C. After complete addition, the solution is stirred for an additional 40 minutes. Diethyl ether (3 L) is then added via an addition funnel such that the temperature is maintained below -65 C. The addition funnel is then replaced with a dispersion tube and CO2 gas is bubbled through the solution for 3 hours. Dry ice (500 g) is then added and the mixture is stirred overnight. The reaction flask is then placed in an ice bath and 6 N HCl is added slowly to prevent excessive bubbling until the pH of the solution is adjusted to 1-2. The resulting mixture is then extracted with EtOAc. The extract is washed with brine then dried over MgSO4, filtered and evaporated. The product is dried under vacuum at room temperature yielding 585.15 g (77%) as an off-white solid.
With sodium hydroxide; phenyllithium; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; acetonitrile;
a. 3-Bromo-2-thiophenecarboxylic acid A stirred, ice-water chilled solution of 16.3 g of 3-bromothiophene and 100 ml of anhydrous ether was treated dropwise, under nitrogen, over 70 minutes with of 50 ml of phenyllithium in ether (2.0M solution), with exclusion of moisture. After stirring at ambient temperature for 1.5 hours, the solution was decanted into dry ice and 200 ml of anhydrous ether. The mixture was stirred and a small amount of dry ice was added. The suspension was treated with water and 10% sodium hydroxide solution to pH=10. The phases were separated and the aqueous phase was extracted once with ether, and acidified with concentrated hydrochloric acid. The mixture was extracted with ether and the dried (over anhydrous sodium sulfate) organic phase was filtered and concentrated. Recrystallization of the residue from acetonitrile gave 10.38% g (50%) of product, m.p. 193-196 C.
With triethylamine; palladium dichloride; at 20 - 100℃; for 1.45h;Green chemistry;
General procedure: To a flask containing DPPPEG200 (0.08 mmol, 0.05 g) andPdCl2 (0.04 mmol, 6.0 mg) in PEG200, aryl halides(1.0 mmol) and Et3N (2.0 mmol, 0.20 g) were added andstirred to complete. In the case of aryl iodides and activatedaryl bromides, the reaction mixture was placed in a 100 Coil bath and in the case of less and deactivated aryl bromidesand chlorides; the reaction mixture was placed in a130 C oil bath (Table 7). GC and TLC of the reaction mixture showed the completion of the reaction. Aftercompletion of reaction, the mixture was cooled to roomtemperature, and the catalyst was removed by addition ofEt2O and then centrifugated. Evaporation of the solvent oforganic layer followed by chromatography on a short columnof silica gel using n-hexane/ethyl acetate (5/1) aseluent gave the coupled product in 65-95 % yield(Table 7).
80%
With manganese; zirconocene dichloride; [(2,9-dimethyl-1,10-phenanthroline)dichloro nickel(II)]; lithium chloride; In 1,2-dimethoxyethane; at 20℃; for 48h;Inert atmosphere;
General procedure: To a suspension of a NiCl2-complex (0.01 mmol, 0.02 equiv), Zr(cp)2Cl2 (Strem, 99%; 7.3 mg, 0.025 mmol, 0.05 equiv), Mn powder (Aldrich, 99.99%; 54.9 mg, 1.0 mmol, 2.0 equiv) and LiCl (Aldrich, anhydrous, ground powder; 42.4 mg, 1.0 mmol, 2.0 equiv) in DME (Aldrich, anhydrous, 99.5%; 1.0 mL) was added an iodide (0.5 mmol) under nitrogen. The mixture was stirred at rt under nitrogen until the reaction completed (TLC). Except for the dipyridyls, the mixture was loaded on silica gel directly, and the flash chromatography on silica gel gave the homo-coupling product. For dipyridyls, the reaction was quenched with aq. NH4OH (27% w/w, 0.6 mL), stirred for 10 min, extracted with CH2Cl2 (10 mL × 3), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the homocoupling product. For alkenyl halide substrates (Fig. 3 and Table 3), the reaction was done in 0.2 mmol scale (C: 0.5 M) with added toluene (42 mul, 0.4 mmol, 2.0 equiv) as an internal standard. After the reaction was completed, a small portion (50 muL) of the mixture was passed through a small silica pad, and eluted with CDCl3 (1 mL). The yield was estimated from 1H NMR (600 MHz, CDCl3).
73.9%
With n-butyllithium; copper dichloride; In diethyl ether; at -78 - 20℃;Inert atmosphere;
In a 200ml single neck flask was added 10g (61.35mmol) tribromo-thiophene, purged with nitrogen three times, then after drying was added diethyl ether 80ml, cooled to -78 deg.] C, and slowly added dropwise 2.4mol / L of n-Buli (n-butyl lithium-yl) 26.25ml (63mmol), - 78 kept 15min, after raised to -55 deg.] C, held at this temperature was added 8.336gCuCl2 1h, at room temperature overnight, coupled with large amount of water to quench the reaction; the reaction solution was extracted with dichloromethane, after drying over anhydrous MgSO4, column chromatography (petroleum ether) to give a white solid 3.76g, yield 73.9%
69%
With palladium diacetate; bis(tri-n-butyltin); cesium fluoride; tricyclohexylphosphine; In neat (no solvent); at 110℃; for 24h;
A screw-cap vial equipped with a magnetic stir bar was charged with aryl halide (1 mmol), hexa-n-butylditin (0.5 mmol),palladium acetate (0.01 mmol) and tricyclohexylphosphine (0.02 mmol),followed by anhydrous cesium fluoride (1.5 mmol). The resulting mixture was manually homogenized with a magnet. A vial was transferred to a preheated oil bath (110 C). After 24 h, the mixture was cooled, dissolved in CH2Cl2-H2O mixture (1:1), the organic phase was separated, the solvent was evaporated in vacuo and the product was isolated by flash chromatography on a silica gel by elution with hexane-CH2Cl2 mixture.
48%
With bis(bipyridine)nickel(II) bromide; ethylene dibromide; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 5h;Electrochemical reaction; Inert atmosphere;
General procedure: DMF (40 mL), NaI (375 mg, 2.5 mmol), and 1,2-dibromoethane (100muL, 1.16 mmol) were added to an undivided electrochemical cell, fitted with an iron/nickel (64/36) anode, and surrounded by a nickel foam as the cathode (surface: 40 cm2, porosity: 500 mum, Goodfellow).The mixture was electrolyzed under argon at a constant current intensity of 0.2 A at r.t. for 15 min. The current was then stopped, then NiBr2bpy (187 mg, 0.5 mmol) and aryl or heteroaryl halide (5 mmol),were sequentially added. The solution was electrolyzed at 0.2 A untilthe starting aryl or heteroaryl halide had been totally consumed (2-5h). Sat. aq EDTA-Na2 solution (50 mL) was added, and the resultingsolution was extracted either with EtOAc (for aryl halides) or withCH2Cl2 (for heteroaryl halides) (3 × 50 mL). The combined organic layerswere washed with brine (50 mL), dried (MgSO4), filtered, and concentratedunder vacuum. The crude product was purified by flashchromatography (silica gel, 70-200 mum).
Synthesis 1.1 3,3'-bithiophene: In 200ml single neck flask was added 10g (61.35mmol) 3-bromothiophene, purged with nitrogen three times, 80ml of diethyl ether was added after the drying process, then was cooled to -78 deg C. Slowly added was 2.4mol/L of n-Buli(n-butyllithium) 26.25ml (63mmol) at -78C and maintained 15min. Later raised to -55C, then added 8.336g CuCl2 and maintained at that temperature 1h then at room temperature overnight. Mixed with large amount of water to quench the reaction; The reaction solution was extracted with methylene chloride, dried over anhydrous MgSO4, column chromatography (petroleum ether) to give a white solid, 3,3'-bithiophene.
[00379] In a reaction tube under nitrogen, a mixture of PdCl2(dppf)CH2Cl2 (21 mg; 0.026 mmol) and triethylamine (0.34 ml; 2.44 mmol) in dioxane (2.5 ml; dried over 4 A sieves) was sealed and stirred at 80 C. overnight (18 h). After cooling to room temperature, HB(pin) (0.19 ml; 1.31 mmol) was added followed by 3-bromothiophene (137 mg; 0.840 mmol) in dioxane (2.5 ml; dried over 4 A sieves) and the reaction mixture was stirred at 80 C. GC analysis after 18 hours showed the desired borate compound at 5.1 minutes.
With n-butyllithium; N-cyclohexyl-cyclohexanamine;bis(tri-t-butylphosphine)palladium(0); In toluene; for 24h;
A 1. 6 M solution of"butyllithium (25,0 mL, 40.0 mmol) was added to a solution of dicyclohexylamine (7.8 mL, 39.1 mmol) in toluene (60 mL). After stirring for 5 min, cyclohexanecarboxylic acid methyl ester (4.8 mL, 33.6 mmol) was added. After stirring for 10 min, 1-bromo-thiophene (2.8 mL, 29.6 mmol) and bis (tri-tert- butylphosphine) palladium (0) (312 mg, 610 umol) was sequentially added. After stirring for 24 h, the solution was diluted with 10% aqueous hydrochloric acid, filtered through a Buchner funnel, and the solid was washed with diethyl ether. The aqueous layer was extracted with diethyl ether, the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 99: 1,49 : 1, and 24: 1 hexanes: ethyl acetate as the eluant to yield 4.93 g (74% yield) of 1-thiophen-3-yl-cyclohexanecarboxylic acid methyl ester as a light yellow oil. 1H NMR (300 MHz, CDC13) 8 7.24 (m, 1 H), 7.10 (m, 2H), 3.65 (s, 3H), 2.46 (d, J=6.7 Hz, 2H), 1.78-1. 26 (broad m, 8H).
74%
A 1. 6 M solution of n butyllithium (25,0 mL, 40.0 mmol) was added to a solution of dicyclohexylamine (7.8 mL, 39.1 mmol) in toluene (60 mL). After stirring for 5 min, cyclohexanecarboxylic acid methyl ester (4. 8 mL, 33.6 mmol) was added. After stirring for 10 min, 1-bromo-thiophene (2.8 mL, 29.6 mmol) and bis (tri-tert- butylphosphine) palladium (O) (312 mg, 610 mol) was sequentially added. After stirring for 24 h, the solution was diluted with 10% aqueous hydrochloric acid, filtered through a Buchner funnel, and the solid was washed with diethyl ether. The aqueous layer was extracted with diethyl ether, the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 99: 1,49 : 1, and 24: 1 hexanes: ethyl acetate as the eluant to yield 4.93 g (74% yield) of 1-thiophen-3-yl-cyclohexanecarboxylic acid methyl ester as a light yellow oil. 1H NMR (300 MHz, CDCts) ; 6 7.24 (m, 1H), 7.10 (m, 2H), 3.65 (s, 3H), 2.46 (d, J=6.7 Hz, 2H), 1.78-1. 26 (broad m, 8H).
74%
A 1.6M solution of"butyllithium (25,0 mL, 40.0 mmol) was added to a solution of dicyclohexylamine (7.8 mL, 39.1 mmol) in toluene (60 mL). After stirring for 5 min, cyclohexanecarboxylic acid methyl ester (4.8 mL, 33.6 mmol) was added. After stirring for 10 min, 1-bromo-thiophene (2.8 mL, 29.6 mmol) and bis (tri-tert-butylphosphine) palladium (0) (312 mg, 610, mol) was sequentially added. After stirring for 24 h, the solution was diluted with 10% aqueous hydrochloric acid, filtered through a Buchner funnel, and the solid was washed with diethyl ether. The aqueous layer was extracted with diethyl ether, the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 99: 1,49 : 1, and 24: 1 hexanes: ethyl acetate as the eluant to yield 4.93 g (74% yield) of 1-thiophen-3-yl-cyclohexanecarboxylic acid methyl ester as a light yellow oil. 1H NMR (300 MHz, CDCI3) 8 7.24 (m, 1H), 7.10 (m, 2H), 3.65 (s, 3H), 2.46 (d, J=6.7 Hz, 2H), 1.78-1. 26 (broad m, 8H).
bis(triphenylphosphine)nickel(II) chloride; In tetrahydrofuran; at 0 - 60℃; for 2.5h;Product distribution / selectivity;
EXAMPLE 6 (COMPARATIVE); A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to a mixture of a 100% tetrahydrofuran solvent, 3-bromothiophene (1 eq.) and with 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at 60 C. Immediate gas chromatography of the reaction product showed 9.6% 3-bromothiophene, 36.2% 3-hexylthiophene and 25.7% bis-thienyl side-product. GC after one hour showed 6.6%3-bromothiophene, 38.6% 3-hexylthiophene and 27.1% bis-thienyl side-product. GC after 2.5 hours showed 3.3% 3-bromothiophene, 37.7% 3-hexylthiophene and 20.3% bis-thienyl side-product. The high temperature (60 C.) and 100% tetrahydrofuran solvent gave low selectivity, incomplete conversion, and an undesirable amount of bis-thienyl side product; EXAMPLE 7 (COMPARATIVE); A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to a mixture of a 100% tetrahydrofuran solvent, 3-bromothiophene (1 eq.) and with 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at 0 C. Immediate gas chromatography of the reaction product showed 0.09% 3-bromothiophene, 82.7% 3-hexylthiophene and 6.6% bis-thienyl side-product. GC after one hour showed 0.09% 3-bromothiophene, 82.3% 3-hexylthiophene and 6.7% bis-thienyl side-product. GC after 2.5 hours showed 0.5% 3-bromothiophene, 81.5% 3-hexylthiophene and 6.4% bis-thienyl side-product. The low temperature (0 C.) gave satisfactory selectivity but an undesirable amount of bis-thienyl side product.
0.2 - 0.5%Chromat.; 4.0 - 4.5%Chromat.
bis-triphenylphosphine-palladium(II) chloride; In diethyl ether; at 20℃; for 2.5h;Product distribution / selectivity;
EXAMPLE 10 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with 200 mg of a dichloro-bis(triphenylphosphine) palladium(II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 77.2% 3-bromothiophene, 4.2% 3-hexylthiophene and 0.5% bis-thienyl side-product. GC after one hour showed 78.1% 3-bromothiophene, 4.0% 3-hexylthiophene and 0.2% bis-thienyl side-product. GC after 2.5 hours showed 76.8% 3-bromothiophene, 4.5% 3-hexylthiophene and 0.3% bis-thienyl side-product. The diethylether solvent and dichloro-bis(triphenylphosphino) palladium(II) catalyst gave a bad conversion percentage.
0.5 - 6.3%Chromat.; 1.7 - 3.1%Chromat.
bis(triphenylphosphine)nickel(II) chloride; In diethyl ether; at 20℃; for 1h;Product distribution / selectivity;
EXAMPLE 15 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with 12.6 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 85.3% 3-bromothiophene, 1.7% 3-hexylthiophene and 0.5% bis-thienyl side-product. GC after one hour showed 68.0% 3-bromothiophene, 3.1% 3-hexylthiophene, 6.3% bis-thienyl side-product and 0.89%. This shows bad conversion with a diethylether solvent and a dichloro-bis(triphenylphosphine) nickel (II) catalyst.
0.2 - 0.4%Chromat.; 0.5 - 1.1%Chromat.
In diethyl ether; at 20℃; for 1h;Conversion of starting material;
3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with no catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 85.7% 3-bromothiophene, 0.5% 3-hexylthiophene and 0.4% bis-thienyl side-product. GC after one hour showed 85.7% 3-bromothiophene, 1.1% 3-hexylthiophene and 0.2% bis-thienyl side-product. This shows almost no conversion with no catalyst.
bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; toluene; at 80℃; for 2.5h;Product distribution / selectivity;
A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to mixture of a 50:50 tetrahydrofuran/toluene solvent, 3-bromothiophene (1 eq.) and 200 mg of a dichloro-bis(triphenylphosphine) palladium(II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at 80 C. Immediate gas chromatography (GC) of the reaction product showed 15.2% 3-bromothiophene, 38.0% 3-hexylthiophene and 17.9% bis-thienyl side-product. GC after one hour showed 2.0% 3-bromothiophene, 40.7% 3-hexylthiophene and 23.9% bis-thienyl side-product. GC after 2.5 hours showed 1.3% 3-bromothiophene, 42.1% 3-hexylthiophene, 24.3% bis-thienyl side-product and 2.53% 3-(1-methylpentyl)thiophene. This results show a low selectivity using a dichloro-bis(triphenylphosphine) palladium(II) catalyst and 50:50 THF/toluene solvent. Also an undesirable amount of bis-thienyl and 3-(1-methylpentyl)thiophene side products.
bis(acetylacetonate)nickel(II); In diethyl ether; at 20℃; for 1h;Product distribution / selectivity;
3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with 200 mg of a Nickel (II) acetylacetonate catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 60.0% 3-bromothiophene, 5.7% 3-hexylthiophene and 5.9% bis-thienyl side-product. GC after one hour showed 40.1% 3-bromothiophene, 12.7% 3-hexylthiophene, 16.2% bis-thienyl side-product and 2.4% 3-(1-methylpentyl)thiophene. The nickel (II) acetylacetonate catalyst and diethylether solvent gave incomplete conversion.
bis-triphenylphosphine-palladium(II) chloride; In diethyl ether; at 20℃; for 2.5h;Product distribution / selectivity;
EXAMPLE 11 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with 200 mg of a dichloro-bis(triphenylphosphine) palladium(II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at 0 C. Immediate gas chromatography of the reaction product showed 0.09% 3-bromothiophene, 81.5% 3-hexylthiophene and 5.3% bis-thienyl side-product. GC after one hour showed 0.09% 3-bromothiophene, 82.5% 3-hexylthiophene and 5.1% bis-thienyl side-product. GC after 2.5 hours showed 0.07% 3-bromothiophene, 82.9% 3-hexylthiophene, 5.2% bis-thienyl side-product and 0.09%3-(1-methylpentyl)thiophene. The diethylether solvent, 0 C. reaction temperature and dichloro-bis(triphenylphosphine) palladium(II) catalyst gave complete conversion and good selectivity (80%), but 5.2% bis-thienyl side-product.
bis(triphenylphosphine)nickel(II) chloride; In tetrahydrofuran; toluene; at 20℃; for 2.5h;Product distribution / selectivity;
A hexylmagnesiumbromide Grignard reagent (1 eq.) was added to a mixture of a 50:50 THF/toluene solvent, 3-bromothiophene (1 eq.) and 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 1 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 7.1% 3-bromothiophene, 66.8% 3-hexylthiophene and 12.6% bis-thienyl side-product. GC after one hour showed 2.2% 3-bromothiophene, 70.4% 3-hexylthiophene and 13.3% bis-thienyl side-product. GC after 2.5 hours showed 2.1% 3-bromothiophene, 68.8% 3-hexylthiophene, 14.0% bis-thienyl side-product and 0.23% 3-(1-methylpentyl)thiophene. The results show better selectivity using a dichloro-bis(triphenylphosphine) nickel (II) catalyst and 50:50 THF/toluene solvent than in Example 5, but incomplete conversion and an undesirable amount of bis-thienyl side product.
bis(triphenylphosphine)nickel(II) chloride; In diethyl ether; at 0 - 20℃; for 2.5h;Product distribution / selectivity;
EXAMPLE 8 (COMPARATIVE) ; 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with 200 mg of a dichloro-bis(triphenylphosphine) nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 0.2% 3-bromothiophene, 74.3% 3-hexylthiophene and 10.5% bis-thienyl side-product. GC after one hour showed 0.1% 3-bromothiophene, 73.6% 3-hexylthiophene and 11.85% bis-thienyl side-product. GC after 2.5 hours showed 0.3% 3-bromothiophene, 73.3% 3-hexylthiophene, 10.7% bis-thienyl side-product and 0.09% 3-(1-methylpentyl)thiophene. The diethylether solvent gave complete conversion but selectivity was only 70% and an undesirable amount of bis-thienyl side product was formed.
1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In diethyl ether; at 20℃; for 2.5h;Product distribution / selectivity;
EXAMPLE 9 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with 200 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 0.1% 3-bromothiophene, 91.2% 3-hexylthiophene and 0.13% bis-thienyl side-product. GC after one hour showed 0.2% 3-bromothiophene, 90.0% 3-hexylthiophene and 0.2% bis-thienyl side-product. GC after 2.5 hours showed 0.16% 3-bromothiophene, 90.7% 3-hexylthiophene, 0.2% bis-thienyl side-product and 0.4% 3-(1-methylpentyl)thiophene. The diethylether solvent and (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst gave a selectivity of 90%. This reaction mixture undesirably forms a solid at the 2 mol/L concentration and therefore cannot be worked up in a plant scale due to the inability of the solid to be purged on water, which then requires the addition of water to the reaction. This may lead to accumulation of water which can suddenly react, leading to uncontrolled development of heat, and presenting serious safety concerns; EXAMPLE 13 (COMPARATIVE); 3-Bromothiophene (1 eq.) is reacted with a hexylmagnesiumbromide Grignard reagent (1.2 eq.) in a 100% diethylether solvent and with 12.6 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2 mol/L. The reaction was conducted at room temperature. Immediate gas chromatography of the reaction product showed 60.9% 3-bromothiophene, 27.2% 3-hexylthiophene and 0.3% bis-thienyl side-product. GC after one hour showed 45.6% 3-bromothiophene, 42.9% 3-hexylthiophene and 0.3% bis-thienyl side-product. GC after 2.5 hours showed 35.6% 3-bromothiophene, 51.8% 3-hexylthiophene, 0.3% bis-thienyl side-product and 0.31% 3-(1-methylpentyl)thiophene. A reduced amount of (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst and diethylether solvent gave incomplete conversion.
EXAMPLE 1; Added to a flask are 57.1 g (2.35 mol) of magnesium metal and 700 ml of 2-methyl-tetrahydrofuran. The flask contents are heated to 60-70 C. A reaction is initiated by adding 5 ml of hexylmagnesiumbromide (1 N) in 2-methyl-tetrahydrofuran to the flask. The Grignard reagent concentration in the solvent is 3.35 mol/L. The flask temperature is increased to 80-85 C. Next, 396 g of bromohexane (2.4 mol) is added to the flask over a period of 2.5 hours. The flask is then heated to reflux and stirred for an additional two hours. After two hours, the flask is cooled down to 15-20 C. Thereafter, add a suspension of 1.6 g of Ni(dppp)Cl2 catalyst in 5 ml of 2-methyltetrahydrofuran. Next, over a period of four hours, add 326.1 g (2 mol) of 3-bromothiophene. Let this stir for an additional 16 hours. The reaction mixture is then hydrolyzed on 1000 ml HCl (10% w/w). A 100% conversion is achieved with essentially no bis-thienyl side-product, and a crude assay of 98.5%. According to this procedure 5 runs were carried out. EXAMPLE 2; Added to a flask are 58.3 g (2.4 mol) of magnesium metal and 500 ml of 2-methyl-tetrahydrofuran. The flask contents are heated to 60-70 C. A reaction is initiated by adding 5 ml of hexylmagnesiumbromide (1 N) in 2-methyl-tetrahydrofuran to the flask. The Grignard reagent concentration in the solvent is 4.8 mol/L. The flask temperature is increased to 80-85 C. Next, 396.2 g of bromohexane (2.4 mol) is added to the flask over a period of 2.5 hours. The flask is then heated to reflux and stirred for an additional two hours. After one hour, the flask is cooled down to 15-20 C. Thereafter, add a suspension of 1.6 g of Ni(dppp)Cl2 catalyst in 5 ml of 2-methyltetrahydrofuran. Next, over a period of four hours, add 326.1 g (2 mol) of 3-bromothiophene. Let this stir for an additional 16 hours. The reaction mixture is then hydrolyzed on 1000 ml HCl (10% w/w). A 100% conversion is achieved with no bis-thienyl side-product, and a crude assay of 98.5%. Immediate gas chromatography of the reaction product showed 15.4% 3-bromothiophene, 81.1% 3-hexylthiophene and 0.0% bis-thienyl side-product. GC after one hour showed 8.7% 3-bromothiophene, 88.0% 3-hexylthiophene and 0.0% bis-thienyl side-product. GC after 15 hours showed 0.0% 3-bromothiophene, 97.5% 3-hexylthiophene, 0.0% bis-thienyl side-product and 0.41% 3-(1-methyl-pentyl)thiophene.
1.2 mol of magnesium metal and 1.2 mol of 1-bromodecane are combined in a 100% 2-methyl-tetrahydrofuran solvent, and with 300 mg of (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst. The Grignard reagent concentration in the solvent is 2.6 mol/L. Next, 3-bromothiophene (1 eq.) is added to the flask. The reactions were conducted at room temperature. Immediate gas chromatography of the reaction product showed 27.1% 3-bromothiophene, 30.0% 3-decylthiophene and 0.9% bis-thienyl side-product. GC after one hour showed 0.0% 3-bromothiophene, 92.6% 3-decylthiophene and 2.3% bis-thienyl side-product. GC after 2.5 hours showed 0.0% 3-bromothiophene, 94.6% 3-decylthiophene and 1.9% bis-thienyl side-product.
EXAMPLE 16 (COMPARATIVE); 3-Bromothiophene (1 eq.) is combined in a flask with 1.1 mol of magnesium metal and 1.15 mol of 1-bromohexane in a 100% THF solvent, and with 815 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst in suspension. The Grignard reagent concentration in the solvent is 2.2 mol/L. The reactions were conducted at room temperature. Immediate gas chromatography of the reaction product showed 85.3% 3-bromothiophene, 1.7% 3-hexylthiophene and 0.5% bis-thienyl side-product. GC after 48 hours showed 2.9% 3-bromothiophene, 64.5% 3-hexylthiophene, 9.8% bis-thienyl side-product and 3.34% 3-(1-methylpentyl)thiophene. This shows bad selectivity with a 100% THF solvent.
5.6%Chromat.; 1.59%Chromat.; 86.7%Chromat.
EXAMPLE 17 (COMPARATIVE); 3-Bromothiophene (1 eq.) is combined in a flask with 1.2 mol of magnesium metal and 1.2 mol of 1-bromohexane in a 50:50 THF/MTBE solvent, and with 600 mg of a (1,3-bis (diphenylphosphino)propane)dichloro Nickel (II) catalyst in suspension. The Grignard reagent concentration in the solvent is 1.3 mol/L. The reactions were conducted at room temperature. Gas chromatography of the reaction product after 15 hours showed 0.2% 3-bromothiophene, 86.7% 3-hexylthiophene, 5.6% bis-thienyl side-product and 1.59% 3-(1-methylpentyl)thiophene. This shows high bis-thienyl and 3-(1-methylpentyl)thiophene side-product formation with a 50:50 THF/MTBE solvent. Overall, the comparative examples show that the main input factor for the selectivity is the catalyst, secondly the temperature and solvent is responsible for the final completion of the selectivity. Expressed in numbers: 60%, 30%, 10% responsibility. In methyl-THF, a Grignard reagent concentration of up to 4 mol/L is possible.
Step A: Preparation of 2-chloro-3-bromothiophene To a round bottomed flask were added glacial acetic acid (115.0 mL) along with 3-bromothiophene (25.0 g, 153.3 mmole). The reaction mixture was heated to reflux and N-chlorosuccinimide (20.58 g, 154.0 mmole) was added portion-wise (Note: reaction vigorous upon each[addition]). After the addition was complete the reaction mixture was refluxed for three additional hours. The reaction mixture was cooled, poured onto ice/water and extracted (ethyl acetate). The combined extracts were washed with water, dilute HCl, and brine. Solvent removal yielded 27.91 g (87%) of a dark liquid. The sample was distilled before further use.
EXAMPLE 1 Preparation of 3-bromothiophene using 2,5-dibromothiophene 2,5-Dibromothiophene (24.2 g, 0.1 mole), tris (3,6-dioxaheptyl) amine (0.1 g, 0.0003 mole), thiophene (60 cm3) and sodium amide (23.4 g, 0.6 mole) were successively charged to a 250cm3 three-necked round bottomed flask which had previously been purged with dry nitrogen gas for 1 hour. The reaction mixture was stirred and heated under nitrogen at 50°-60 C. for 4 hours. The reaction mixture was queched with butan-1-ol and then water. The organic layer was separated and the aqueous layer extracted with dichloromethane. The organic layer, after dichloromethane and thiophene removal by distillation, yielded 28.4 g of product. Analysis of the product by gas chromatography with internal standard showed the sample to be mainly mono-bromo thiophenes in the ratio 2 parts 2-bromothiophene to 98 parts 3-bromothiophene.
In thiophene;
Example 1 Preparation of 3-bromothiophene using 2,5-dibromothiophene 2,5-Dibromothiophene (24.2 g, 0.1 mole), tris (3,6-dioxaheptyl) amine (0.1 g, 0.0003 mole), thiophene (60 cm3) and sodium amide (23.4 g, 0.6 mole) were successively charged to a 250cm3 three-necked round bottomed flask which had previously been purged with dry nitrogen gas for 1 hour. The reaction mixture was stirred and heated under nitrogen at 50-60°C for 4 hours. The reaction mixture was quenched with butan-1-ol and then water. The organic layer was separated and the aqueous layer extracted with dichloromethane. The organic layer, after dichloromethane and thiophene removal by distillation, yielded 28.4 g of product. Analysis of the product by gas chromatography with internal standard showed the sample to be mainly mono-bromo thiophenes in the ratio 2 parts 2-bromothiophene to 98 parts 3-bromothiophene.
With bis(dicyclopentyl(2-methoxyphenyl)phosphine)dichloropalladium(II); In butan-1-ol; at 100℃; for 4h;Cooling;
10523] Into a glass reaction vessel equipped with a cooling apparatus were added 0.015 mmol of bis(dicyclopentyl(2- methoxyphenyl)phosphine)dichloropalladium(II), 1.5 mmol of 3-bromothiophene, 2.25 mmol of 3-thiopheneboronic acid, 3.0 mmol of potassium phosphate and 4 mL of n-butanol. The resultant mixture was stirred with heating at 1000 C. for 4 hours. The resultant reaction mixture was cooled down to room temperature, 20 mL of water was added, and the mixture was extracted with 20 mL of diethyl ether twice. The resultant organic layers were mixed, and dried over anhydrous magnesium sulfate, then, filtrated, to obtain a solution. This solution was concentrated, and purified by silica gel colunm chromatography, to obtain 3-(3-thienyl)-thiophene with a yield of 98%.
76.9%
With potassium hydroxide;palladium diacetate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 80℃; for 9.25h;
A 1000 mL three-necked round-bottom flask, equipped with a magnetic stirrer and a reflux condenser, was charged with 3 -bromothiophene (0.092 mol, 8.6 mL, 1 eq.), 3 -thiopheneboronic EPO <DP n="12"/>acid (0.110 mol, 14.08 g, 1.2 eq.), KOH (0.276 mol, 3 eq.), DME (d = 0.867, 3.07 mol, 319 mL) and H2O (54 mL).The reaction mixture was heated at 800C. In a separate Schlenk flask, PPh3 (7.36 mmol, 0.08 eq.) was dissolved in DME (59.8 mL) and then Pd(OAc)2 (1.84 mmol, 0.02 eq.) was added. The catalytic solution was stirred for 15 min, to preactivate the catalyst, and then was added to the reaction mixture at 800C. The reaction mixture turned immediately brown. The reaction took 9 h to completion. Reaction mixture was diluted with water, the two phases were separated and the aqueous phase was washed with toluene. The combined organic phases were washed with brine, with water and then dried on Na2SO4 and MgSO4. The solvents were eliminated under vacuum to give 13.88 g of a grey powder which was analyzed by GC-MS analysis and H NMR spectroscopy. The GC analysis showed the presence of the desired product 3,3'-dithiophene.Yield of pure product 76.9% ( 0.071 mol).1H NMR (delta, ppm, CD2Cl2): 7.50-7.36 (2 m, 6H).13C NMR (delta, ppm, CD2Cl2): 120.19(CHa); 126.56 (CHbeta); 126.71 (CHdelta); 137.61 (Cq). m/z (%): 166 [M +], 134 (32), 121 (45).
55%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 10h;Heating / reflux;
Step 1 : 3,3'-bithiophene; To a mixture of 3-bromothiophene (2 g, 12.2 mmol) and 3-thienylboronic acid (2.4 g, 18.4 mmol) in DME (100 mL), was added sodium carbonate (2M, 18.4 mL). The mixture was degassed under vacuum and backfilled with nitrogen. Pd(PPh3)4 (707 mg, 0.61 mmol) was added and the reaction mixture heated at reflux for 1O h, after which it was diluted in ethyl acetate and water. The aqueous layer was extracted with diethyl ether, the organic layers washed with brine, dried over Na2SO4, filtered and concentrated. The material was purified by flash chromatography on silica (10% ethyl acetate in hexanes) to afford 3,3'-bithiophene (1.1 g, 55%).
1-butyl-4-[hydroxy(di-3-thienyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9.4%
Example 32 Preparation of 1-butyl-4-[hydroxy(di-3-thienyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide A solution of n-Butyl lithium (2.5M in hexanes, 5.0 mL, 12.5 mmol) was chilled to -78 C. under Ar. 3-Bromothiophene (1.15 mL, 12.3 mmol) dissolved in ethyl ether (4.0 mL) was slowly added to the reaction mixture. The reaction was stirred for 30 min and then <strong>[22766-68-3]ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate</strong> (0.7640 g, 4.16 mmol) in THF/Et2O (4 mL/4 mL) was added. The reaction was allowed to warm up from -78 C. to room temperature over 16 h then slowly quenched with water. The reaction was concentrated and the resulting brown solid was taken up in water and DCM. The organic phase was separated, dried over MgSO4, filtered and concentrated under vacuum to give a brown solid. The solid was dissolved in DMSO and purified by preparatory HPLC to give the title compound (0.1736 g, 9.4%). EI-MS m/z 362(M+) Rt (1.73 min).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 130℃; for 3h;
A mixture of 3-bromothiophene (3.07 g, 18.86 mmol), 3-isopropyl phenylboronic acid (4.02 g, 24.5 mmol), Pd(PPh3)4 (2.18 g, 1.9 mmol) and solid sodium carbonate (2 g, 18.9 mmol) were suspended in DMF (100 mL) and heated to 130 0C for 3 h. The reaction mixture was cooled, poured onto water and extracted with EtOAc. Organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. This was then purified by silica gel flash chromatography affording the title compound (2.62 g, 69%).
With potassium phosphate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 18h;
Step 1: ferf-Butyl 3-oxo-4-(3-thienyl)piperazine-l-carboxylate (Hl)A mixture of l-Boc-3-oxopiperazine (1.0 eq.), 3-bromothiophene (1.5 eq.), K3PO4 (2.0 eq.), CuI (0.4 eq.) and lambda^-dimethylethylendiamine (0.8 eq.) in 1,4-dioxane (0.5M) was put in a sealed vial and stirred at 1100C for 18 hr. Reaction mixture was diluted with EtOAc and filtered through a pad of SolcaFloc 200 FCC. After removal of the solvent, the crude product was purified by flash column chromatography on silica gel using 10- 40% EtO Ac/Petroleum ether as eluent to afford the desired product Hl as pink solid (80% yield). 1H NMR (400 MHz, CDCl3, 300K) delta 7.32-7.28 (3H, m), 4.25 (2H, s), 3.82-3.75 (4H, m), 1.49 (9H, s). MS (ES) CnHi8N2 O3S requires: 282, found: 283 (M+H)+.
53%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; for 24h;Inert atmosphere; Reflux;
A mixture of 1 ,1 -dimethylethyl 3-oxo-1 -piperazinecarboxylate (0.489 g, 2.44 mmol), 3-bromothiophene (0.332 g, 2.036 mmol), copper(l) iodide (0.019 g, 0.102 mmol), potassium carbonate (0.563 g, 4.07 mmol) and trans-N,N-dimethyl-cyclohexane-1 ,2- diamine (0.029, 0.204 mmol) in 1 ,4-dioxane (5 mL) was heated at reflux under nitrogen for 24 hours. After cooling to room temperature, the reaction mixture was filtered through silica ge. eluting with DCM:EtOAc/1 :1 , The filtrate was concentrated and the residue was purified by silica gel chromatography to afford 1 ,1 -dimethylethyl 3-oxo-4-(3-thienyl)-1 - piperazinecarboxylate (0.305 g, 53%) as a white solid.
With N,N,N,N,-tetramethylethylenediamine; di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium; zinc; In water; at 20℃; for 24h;Inert atmosphere;
General procedure: In a 5 mL round-bottom flask under argon containing zinc powder (197 mg, 3 mmol) and PdCl2(Amphos)2 (7 mg, 0.01 mmol) was added 2% PTS solution in water (1.5 mL). N,N,N',N'-Tetramethylethylenediamine (TMEDA, 232 mg, 2 mmol) was added at rt followed by the addition of the alkyl halide (2 mmol) and the heteroaromatic halide (0.5 mmol). The flask was stirred vigorously at rt for the indicated time. The product was extracted with EtOAc.11 Silica gel (1 g) was added to the combined organic phase and solvents were removed under vacuum. The resulting dry, crude silica was introduced on top of a silica gel chromatography column to purify the product.
Example 3Poly{5,5-[2,6-bis[3-(2-hexyldecyl)-2-thienyl]-4,8-di(2-ethylhexyl)benzo[1,2- b:4,5-b']dithiophene]-a/f-4,7-(2,1 ,3-benzothiadiazole)} (3) was prepared as follows:3.1 3-(2-Hexyldecyl)hiophene A solution of <strong>[52997-43-0]7-bromomethyl-pentadecane</strong> (34.00 g, 111.4 mmol) in anhydrous tetrahydrofuran (180 cm3) was added dropwise to a mixture of magnesium turnings (2.70 g, 111.0 mmol), a crystal of iodine and anhydrous tetrahydrofuran (20 cm3). The reaction mixture was heated at 67 C for 4 hours. The formed Grignard solution was allowed to cool to 23 C and a mixture of 3-bromothiophene (5.49 g, 33.6 mmol) and [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.10 g, 1.35 mmol) was added dropwise over 5 minutes. The reaction mixture was heated at 67 C for 17 hours. The mixture was allowed to cool and poured into water (400 cm3) and the product was extracted with dichloromethane (2 * 300 cm3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (40-60 petrol) to give the product as a colourless oil (10.94 g, 89%): MS (m/e): 308 (M+, 10%), 223, 195, 98.
General procedure: To the solution of 1M NaHMDS (8.8 mL, 8.8 mmol) in THF was slowly added the substrate (6.8 mmol) at 0 oC. After stirring for 30 min at 0 oC, the solution of electrophile (8.3 mmol) in anhydrous THF (2 mL) was slowly added into the reaction mixture at 0 oC and stirred for an additional 3h. The reaction was quenched with NH4Cl (sat.) solution (5 mL) and diluted with hexanes (20 mL). The organic layer was separated, washed with 15 wt.% NaCl aqueous solution (10 mL) and concentrated to give the crude product. The product was isolated by flash chromatography using a Et3N pre-treated silca gel column and 0.1% Et3N / 4.9% EtOAc / 95% hexanes as the eluent.
With potassium phosphate; copper(l) iodide; at 100℃; for 48h;
3-Bromothiophene (7.3 g, 44.8 mmol), <strong>[62281-06-5]2-octyldodecan-1-amine</strong> (20 g, 67.2 mmol), copper (I) iodide (0.43 g, 2.2 mmol) and potassium phosphate tribasic (19.0 g, 89.5 mmol) were dissolved in dimethylaminoethanol (85 ml) and stirred at 100 C for two days gave. Next, the mixture was cooled to room temperature and filtered under reduced pressure. The filtered mixture was washed with ethyl acetate and then separated into a column to obtain 6.0 g (35%) of N-(2-octyldodecyl)thiophene-3-amine (Compound 7).
With 1H-imidazole; palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; magnesium chloride; In tetrahydrofuran; at 90℃; for 0.5h;Microwave irradiation;
To a stirred mixture of aryl or heteroaryl halide(Br, I) (0.5 mmol), potassium mono ethyl malonate (0.75 mmol) in THF (10 mL) taken in a 30 mL microwave vial, was added Pd(OAc)2(5 mol%), Xantphos (5 mol %), MgCl2 (0.75), Et3N ( 0.75mmol), imidazole (1 mmol) followed by Co2(CO)8 (0.15mmol). The vial was sealed immediately and microwave irradiated at 90C for 30min. The reaction mixture was concentrated and diluted with ethyl acetate and water. The ethyl acetate layer was separated, dried over sodium sulphate and concentrated. The crude product obtained was purified by column chromatography to get the pure compound.
With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); lithium carbonate; In N,N-dimethyl acetamide; at 160℃; for 24h;Molecular sieve; Inert atmosphere;
General procedure: To an 10 mL vial reaction vessel equipped with a magnetic stirring bar was added <strong>[2164-61-6]pyridazine-3-carboxylic acid</strong> (0.6 mmol, 1.0 eq), aryl- and heteroaryl-bromides (1.2 mmol, 2.0 eq), Pd(PPh3)4 (35 mg, 0.03 mmol, 5.0 mol %), Cu2O (84 mg, 0.6 mmol, 1.0 eq), Li2CO3 (107 mg, 1.8 mmol, 3.0 eq), 3A MS (200 mg) and DMA (4.0 mL). The mixture was stirred at 160 C for 24 h under N2. After the reaction was complete, the mixture was washed with brine and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate / petroleum ether = 1/5 - 1/1), the eluent need bubbled NH3 five seconds. The eluent of TLC (ethyl acetate / petroleum ether 1:1) need bubbled NH3 two seconds.
2-dicyclohexylphosphino-2',6'-bis(3-thienyl)biphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.4 mg
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 140℃; for 36h;Schlenk technique; Inert atmosphere;
In a 25 mL Schlenk tube,70.1 mg (0.2 mmol) of 2-dicyclohexylphosphine biphenyl (<strong>[247940-06-3]CyJohnPhos</strong>)(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), replacing argon Gas three times, under the protection of argon by adding 1,4-dioxane 1mL,3-bromofuran 70.5 mg (0.48 mmol). After stirring at 140 C for 36 hours, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The solvent was separated on a 200-300 mesh silica gel column. The petroleum ether: ethyl acetate = 100: 1And the product was dried in vacuo to give 66.2 mg of a colorless viscous product with a gas chromatographic purity of 74%.
Magnesium, Turnings (1.147 g, 47.17 mmol) and iodine (76.6 mg, 0.3018 mmol) was dissolved in 50 mL of THF under an Ar atmosphere. 2-Butyl-1-octylbromide (9.496g, 38.1 mmol) in 25 mL was added over 10 mm and the mixture was refluxed for 2 h to afford the Grignard reagent. 3-Bromothiophene (4.891g, 3Ommol) and NiC12(dppp) (256 mg, 0.4725 mmol) was dissolved in 25 mL of THF and the Grignard reagent was added slowly keeping with the reaction temperature at 0 C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 2 M of hydrochloric acid (l5rnL).DCM was added and the organic layer was washed three times with water. The organic layer was dried over Mg504 and the solvent was removed under reduced pressure. The crude product was passed through silica gel using PE as an eluent to give colorless oil(3g, 39.6%).?H NMR (400 MHz, CDC13) 7.23 (dd, J = 4.9, 3.0 Hz, 1H), 6.90 (t, J = 4.2 Hz, 2H), 2.56 (d, J = 6.8 Hz, 2H), 1.67 - 1.58 (m, 1H), 1.25 (d, J = 3.7 Hz, 19H), 0.88 (t, J= 6.7 Hz, 7H). ?3C NMR (100MHz, CDCT3) 142.07, 128.96, 124.91 , 120.78 , 39.08 , 37.88,34.86 , 33.86, 33.53 (d, J= 6.0 Hz), 33.17 , 32.10 (d, J= 7.3 Hz), 29.92 (d, J= 15.2Hz), 29.10 (d, J= 14.2 Hz), 26.80 (d, J= 9.7 Hz), 23.27 (d, J 13.7 Hz), 22.86 (d, J= 3.2 Hz), 14.30 (t, J= 3.8 Hz).
(3-bromo-2-thienyl)-(4,4-difluorocyclohexyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
700 mg
A solution of n-butyllithium (2.5 M, 2.29 mL) in diethyl ether (10.00 mL) was cooled down to -78C and slowly added with diisopropylamine (663.06 mg, 6.26 mmol), and 3-bromothiophene (850 mg, 5.21 mmol) was added after 1 hour. The mixture was maintained at -78C and stirred for 1 h. 4,4-Difluorocyclohexanecarboxaldehyde (772.37 mg, 5.21 mmol) was further added, and the reaction solution was stirred at -78C for 1 h. The reaction solution was quenched with ammonium chloride solution (30 mL), diluted with water (30 mL) and extracted with ethyl acetate (30 mL * 3). The organic phase was washed with brine (30 mL * 3), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (colorless oil, 700 mg, yield of 43.18%). 1H NMR (400MHz, CHLOROFORM-d) delta = 7.30 (d, J=5.3 Hz, 1H), 6.94 (d, J=5.3 Hz, 1H), 4.86 (dd, J=2.4, 7.9 Hz, 1H), 2.29 (d, J=3.0 Hz, 1H), 2.19 - 2.07 (m, 3H), 1.82 - 1.63 (m, 4H), 1.52 - 1.46 (m, 2H).
(3-bromothiophen-2-yl)(1-phenylpiperidin-4-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42.74%
n-Butyllithium (2.5 M, 7.21 mL) was slowly added into a solution of diisopropylamine (1.99 g, 19.66 mmol, 2.76 mL) in diethyl ether (30.00 mL) at - 65C, and then tribromothiophene (2.67 g, 16.38 mmol, 1.53 mL) was injected thereto after one hour, with stirring at -65C for 1 h. 1-Phenylpiperidine-4-carboxaldehyde (3.10 g, 16.38 mmol) was then added, and the reaction mixture was stirred at -65C for another 1 h. The reaction solution was quenched with ammonium chloride (30 mL), then diluted with water (30 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (yellow oil, 3.00 g, 7.00 mmol, yield of 42.74%). 1H NMR (400MHz, CHLOROFORM-d) delta = 7.30 (d, J=5.3 Hz, 1H), 7.27 - 7.22 (m, 2H), 6.98 - 6.91 (m, 3H), 6.84 (t, J=7.3 Hz, 1H), 4.89 (d, J=8.0 Hz, 1H), 3.75 (br d, J=12.3 Hz, 1H), 3.66 (br d, J=13.1 Hz, 1H), 2.75 - 2.61 (m, 2H), 1.94 - 1.81 (m, 1H), 1.61 - 1.47 (m, 4H), 1.27 (t, J=7.2 Hz, 1H).
To a solution of 3-bromo-thiophene (30.9 g, 189 mmol) and anhydrous diethyl ether (310 cm3) at -78 C was added n-butyllithium (83.4 cm3, 208 mmol, 2.5 M in hexanes) dropwise over 50 minutes and then stirred for 1 hour. Zinc chloride (1 16 cm3, 221 mmol, 1.9 M in 2-methyltetrahydrofuran) was then added dropwise over 20 minutes and the reaction mixture warmed to 0 C and stirred for a further 1 hour. 2,5-Dibromo-terephthalic acid diethyl ester (24.0 g, 63.2 mmol) and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (2.77 g, 3.79 mmol) were then added. The resulting reaction mixture was then heated at reflux for 17 hours. After allowing to cool to 23 C, water (250 cm3) was added and the organics extracted with ethyl acetate (4 x 200 cm3). The combined organics were washed with brine (100 cm3), dried over anhydrous magnesium sulphate, filtered and the solvent removed in vacuo. The crude was purified by silica plug (dichloromethane) followed by recrystallisation (heptane) to give compound 14-1 (19.8 g, 81 %) as an off white solid. 1H-NMR (400 MHz, CDCIs) 1.14 (6H, t, J 7.1), 4.20 (4H, q, J 7.1), 7.1 1 - 7.17 (2H, m), 7.32 (2H, dd, J 2.9, 1.2), 7.37 (2H, dd, J 4.9, 2.9), 7.81 (2H, s).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 10h;
Add 100 mL of tetrahydrofuran and 20 mL of water to a three-neck round bottom flask.Further added 6.52 g (0.04 mol) of 3-bromothiophene, 8.54 g (0.048 mol) of p-butylbenzeneboronic acid, 2.31 g (0.002 mol) of tetrakis(triphenylphosphine)palladium, 11.04 g (0.08 mol) of potassium carbonate, 70 C reaction for 10 hours,The temperature was lowered to room temperature, and the organic phase was dried over anhydrous magnesium sulfate and filtered.The solvent is distilled off, and the residue is separated by column chromatography (eluent is petroleum ether).7.44 g of the compound of the formula 1 was obtained in a yield of 86%. The chemical reaction equation is as follows:
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
