* 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] Helvetica Chimica Acta, 1945, vol. 28, p. 1684,1690
2
[ 124-42-5 ]
[ 1655-07-8 ]
[ 19178-21-3 ]
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[1] Patent: US5234936, 1993, A,
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[ 143-37-3 ]
[ 1655-07-8 ]
[ 19178-21-3 ]
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[1] Journal of the American Chemical Society, 1952, vol. 74, p. 842
[2] Journal of the American Chemical Society, 1958, vol. 80, p. 6609,6611
4
[ 1655-07-8 ]
[ 36556-02-2 ]
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[1] Journal of the Chemical Society, 1932, p. 2426,2430
5
[ 1655-07-8 ]
[ 34170-21-3 ]
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[1] Journal of the Chemical Society, 1946, p. 362,365
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[ 2986-19-8 ]
[ 1655-07-8 ]
[ 34170-21-3 ]
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[1] Journal of Organic Chemistry, 1959, vol. 24, p. 922,924
[2] Journal of the Chemical Society, 1946, p. 362,365
Reference：
[1] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 6, p. 765 - 775
11
[ 1655-07-8 ]
[ 1461-96-7 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With bromine In chloroform at 0 - 20℃; Stage #2: With potassium hydroxide In water at 0℃; for 6 h; Stage #3: With hydrogenchloride In water
Br2 (112.8 g, 705.6 mmol) was added dropwise at 0 °C to a solution of ethyl 2- oxocyclohexanecarboxylate (120 g, 705.6 mmol) in chloroform (360 ml). The resulting reaction mixture was stirred at rt overnight, then washed with NaHC03 (2x200 ml) and brine (2x100 ml). The organic layer was dried over Na2S04 and concentrated and the residue was added dropwise to an ice-cold solution of KOH (168 g, 3 mol) in water (960 ml). The reaction mixture was stirred for 6 h at 0 °C, then extracted with diethyl ether. The aqueous phase was acidified with 4.0 M HCI (pH 5) and extracted with diethyl ether. The combined organic layers were washed with brine (200 ml), dried, filtered and concentrated. The afforded yellow oil was crystallized (EtOAc/diethyl ether) which gave the title compound as a colourless crystals (70 g, 63percent). MS (ESI): 159 [M+H]+.
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 4, p. 635 - 638
[2] Patent: WO2013/95275, 2013, A1, . Location in patent: Page/Page column 35
[3] Journal of the American Chemical Society, 2000, vol. 122, # 50, p. 12610 - 12611
[4] Journal of Organic Chemistry, 1989, vol. 54, # 4, p. 817 - 824
[5] Journal of Organic Chemistry, 1961, vol. 26, p. 22 - 27
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 380 - 383
[7] Patent: WO2007/137107, 2007, A2, . Location in patent: Page/Page column 54
12
[ 1655-07-8 ]
[ 1128-00-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With ammonium carbamate In methanol at 20℃;
a) To a solution of ethyl 2-oxocyclohexanecarboxylate (18.9 mL, 1 18 mmol) in methanol (120 mL) was added the ammonium carbamate (9.20 g, 1 18 mmol). The resulting mixture was stirred at rt for 1 h after which time the ammonium carbamate had completely dissolved. The reaction mixture was stirred for an additional 1 h before the volatiles were removed under reduced pressure to afford ethyl 2-aminocyclohexene- 1-carboxylate as a white-yellowish solid (19.9 g, quantitative yield). 1H NMR (400 MHz, CDCI3) δ 1.28 (t, J=7.2 Hz, 3H), 1.57 - 1.71 (m, 4H), 2.21 (t, J=6.1 Hz, 2H), 2.26 (t, J=6.1 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 6.06 (br s, 2H)
97%
With ammonia In methanol at 20℃; for 24 h;
A mixture of ethyl 2-oxocyclohexanecarboxylate (32) (3.43 g, 20.2 mmol) and ca. 7 N ammonia solution in methanol (25 ml, ca. 175 mmol) was stirred in a closed vessel at room temperature for 24 h. The solvent was evaporated and the residue was dried in vacuo over P2O5 to give 3.30 g (97percent) of known31 compound 33 as yellow crystalline substance which was immediately utilized in the next step. 1H NMR (CDCl3) δ: 1.26 (t, J = 7.1 Hz, 3H), 1.55–1.67 (m, 4H), 2.16–2.27 (m, 4H), 4.13 (q, J = 7.1 Hz, 2H), 6.00 (br s, 2H). GCMS m/z: 169.1 M+.
90%
With ammonia In methanol at 20℃;
To 7N-ammonia-methanol solution, 170 g of ethyl 2-oxocyclohexanecarboxylate was added and stirred for an overnight at room temperature. Concentrating the solvent under reduced pressure, crude crystals were obtained, which were recrystallized from ethyl acetate-n-hexane to provide 152 g (90percent) of 2-aminocyclohex-1-enecarboxylic acid ethyl ester. 1H-NMR(CDCl3)δ:4.14(q,J=7.3Hz,2H),2.25(d,J=5.9Hz,2H), 2.20(d,J=5.9Hz,2H), 1.67~1.56(m,4H). Mass,m/e:169(M+),96(base)Into 7N-ammonia-methanol solution, 170 g of ethyl 2-oxocyclohexanecarboxylate was added and stirred for an overnight at room temperature. Distilling the solvent off under reduced pressure, the resulting crude crystalline product was recrystallized from ethyl acetate-n-hexane to provide 152 g (90percent) of ethyl 2-aminocyclohex-1- enecarboxylate. 1H-NMR(CDCl3):4.14(q,J=7.3Hz,2H),2.25(d,J=5.9Hz,2H), 2.20(d,J=5.9Hz,2H),1.67~1.56(m,4H) Mass,m/e:169(M+),96(base)
60%
With ammonium acetate In methanol at 20℃; for 72 h;
5.2 Ethyl 2-aminocyclohex-1-ene-1-carboxylate (3b) In the same manner as in the preparation of 3a, the title compound (32.3 g, 60percent) was obtained as a white solid from 2b (53.9 g, 0.317 mol). 1H NMR (DMSO-d6) δ 1.16 (3H, t, J = 7.1 Hz), 1.45-1.59 (4H, m), 2.09-2.21 (4H, m), 4.00 (2H, q, J = 7.1 Hz), 7.09 (2H, br s).
Reference：
[1] Patent: WO2013/26900, 2013, A1, . Location in patent: Page/Page column 60
[2] New Journal of Chemistry, 2005, vol. 29, # 6, p. 769 - 772
[3] Tetrahedron Letters, 2013, vol. 54, # 9, p. 1133 - 1136
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3654 - 3669
[5] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 6, p. 765 - 775
[6] Patent: EP1724267, 2006, A1, . Location in patent: Page/Page column 52; 68
[7] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5507 - 5517
[8] Helvetica Chimica Acta, 1945, vol. 28, p. 1684,1690
[9] Journal of the Indian Chemical Society, 1935, vol. 12, p. 299,305
[10] Justus Liebigs Annalen der Chemie, 1901, vol. 317, p. 104
[11] Justus Liebigs Annalen der Chemie, 1901, vol. 317, p. 104
[12] Journal of Organic Chemistry, 1978, vol. 43, p. 1460 - 1462
[13] Acta Chemica Scandinavica, 1997, vol. 51, # 6-7, p. 785 - 790
[14] Journal of the American Chemical Society, 2003, vol. 125, # 32, p. 9570 - 9571
[15] Advanced Synthesis and Catalysis, 2014, vol. 356, # 5, p. 1113 - 1118
13
[ 7664-41-7 ]
[ 1655-07-8 ]
[ 1128-00-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1901, vol. 317, p. 104
14
[ 1655-07-8 ]
[ 1128-00-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1901, vol. 317, p. 104
15
[ 1655-07-8 ]
[ 3943-73-5 ]
[ 90536-71-3 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 37, p. 12271 - 12277
With sulfuric acid In ethanol at 0 - 20℃; for 18h;
96%
With aluminum(III) oxide; methanesulfonic acid at 20℃; for 0.166667h;
95%
In trifluoroacetic acid at 100℃; for 0.5h; microwave irradiation;
94%
With vanadium(III) trichloride at 50 - 55℃; for 2h;
91%
With zirconium tetrachloride at 70℃; for 0.166667h;
91%
With zirconium tetrachloride at 70℃;
1 Example 1 : 3-hydroxy-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one
Example 1 : 3-hydroxy-7,8,9, 10-tetrahydro-6H-benzo[c]chromen-6-one A mixture of resorcinol (5.0 gram, 45.45 mmol) and ethyl 2-oxocyclohexanecarboxylate (7.73 gram, 45.45 mmol) is heated at 70°C in the presence of zirconium (IV) chloride (1.06 gram, 10 mol%). After completion of the reaction, the reaction mixture is cooled to room temperature and poured onto crushed ice (200 g). The solid product obtained is filtered off, and washed with ice-cold water. Yield obtained: 91 %, H NMR (DMSO) δ 1.68-1.73 (m, 4H), 2.27-2.40 (m, 2H), 2.62-2.76 (m, 2H), 6.65 (d, 1 H), 6.74 (dd, 1 H), 7.47 (d, 1 H), 10.35 (s, 1 H).
91%
With zirconium tetrachloride at 70℃; for 1h;
4.1.15. 3-Hydroxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one(15)
A mixture of resorcinol (5.0 g, 45.45 mmol) and ethyl 2-oxocyclohexanecarboxylate(7.73 g, 45.45 mmol) was heated at 70 Cin the presence of zirconium(IV) chloride (1.06 g, 10 mol %) for1 h. After completion of the reaction, the reaction mixture wascooled to room temperature and poured onto crushed ice (200 g).The solid product obtained was filtered off, and washed with icecoldwater. Yield obtained: 91%, 1H NMR (DMSO-d6) d 1.68-1.73(m, 4H, ACH2ACH2ACH2ACH2A), 2.27-2.40 (m, 2H, ACH2ACH2ACCA), 2.62-2.76 (m, 2H, ACH2ACH2ACACOOA), 6.65 (d,1H, Ar-H), 6.74 (dd, 1H, Ar-H), 7.47 (d, 1H, Ar-H), 10.35 (s, 1H,AOAH).
90%
With 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) at 120℃; for 1h;
87%
With zirconium tetrachloride In neat (no solvent) at 75℃; for 1h;
86%
With aminosulfonic acid at 130℃; for 0.416667h;
84%
With methanesulfonic acid 15 deg C to RT, 15 min;
80%
With zirconium tetrachloride at 80℃; for 1h;
2.1.3. 3-Hydroxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one (2)
A mixture of resorcinol (136 mmol) and ethyl2-oxocyclohexanecarboxylate (158 mmol) was heated at 80oCin the presence of zirconium (IV) chloride (1.06 g) for 1 h.At the end of the time, the reaction mixture was cooled toroom temperature and poured onto crushed ice (150 g). Thesolid product was filtered off, and washed with ice cold water.Yield obtained: 80 %, 1H NMR (DMSO-d6, 400 MHz): δ= 10.31 (s, 1H, OH), 7.46 (d, 1H, Ar-H), 6.74 (d, 1H, Ar-H),6.65 (d, 1H, Ar-H), 2.66-2.69 (m, 2H, -CH2-CH2-CCOO-),2.33-2.35 (m, 2H, -CH2-CH2-C=C-), 1.67-1.72 (m, 4H, -CH2-CH2-CH2-CH2-).
76%
With sulfuric acid In ethanol at 0 - 20℃;
71%
With sulfuric acid at 120℃; for 0.166667h; neat (no solvent);
70%
With sulfuric acid In ethanol at 0 - 20℃;
3.1.2. Synthesis of compounds 11-13
General procedure: Syntheses were carried out from resorcinol 7 (45 mmol) and appropriate β-keto esters (8-10) in accordance with article.35 Concd H2SO4 (5 mL, 94 mmol) was added dropwise to cooled (0-5 °C) solution of resorcinol 7 (45 mmol) and appropriate β-keto esters (8-10) (45 mmol) in dry ethanol (15 mL) with vigorously stirring. The mixture was stirred until to be congealed, left overnight at rt, and poured into ice water (150 mL). The resulting solid was filtered off and crystallized from ethanol-water (75%). The yields of 11, 12 and 13 were 70%, 64% and 95% respectively.
70%
With sulfuric acid In ethanol at 0 - 20℃;
Synthesis of compounds 5-7.
General procedure: Syntheses were carried out from resorcin 8 and appropriate β-keto esters (9 -11) in accordance with article.18 Conc. H2SO4 (5 mL, 94 mmol) was added dropwise to cooled (0-5 °C) solution of resorcin 8 (45 mmol) and appropriate β-keto esters (9-11) (45 mmol) in dry ethanol (15 mL) with vigorously stirring. The mixture was stirred until to be congealed, left overnight at r.t., and poured into ice water (150 mL). The resulting solid was filtered off and crystallized from ethanol-water (75%). The yields of 5-7 were 95%, 64% and 70% respectively.
70%
With sulfuric acid In ethanol at 0 - 20℃;
3.1.2. Synthesis of Coumarins 9, 10
General procedure: Syntheses were carried out from resorcinol 5 and appropriate -ketoesters 6, 7, inaccordance with [31]. Concentrated H2SO4 (5 mL, 94 mmol) was added dropwise to cooled(0-5 C) solution of resorcinol 8 (45 mmol) and appropriate -ketoesters (45 mmol) in dryethanol (15 mL), with vigorous stirring. The mixture was stirred until it congealed, leftovernight at r.t., and poured into ice water (150 mL). The resulting solid was filtered off andcrystallized from ethanol-water (75%). The yields of 9, 10 were 64% and 70%, respectively.
68%
With amberlyst-15 In toluene for 4h; Heating;
67%
With sulfuric acid at 0℃; for 2.5h;
1
A mixture of resorcinol (1.45 g, 10 mmol) and ethyl 2-oxocyclohexane carboxylate (2.04 g, 12 mmol) is cooled in an ice bath and sulfuric acid (5 ml) is added dropwise. The reaction mixture is stirred for 2.5 h and diluted with ice water (30 ml). The precipitate is collected on a filter and recrystallized from i-PrOH to give the title compound (1.44 g, 67% ) as colorless crystals. Physical characteristics are as follows:Mp 187-190 0C; 1H NMR (DMSO-d6, TMS) δ: 1.71 , 2.37, 2.72, 6.68, 6.77,7.52, 10.34; MS: 216 (M+).
65%
With methanesulfonic acid In neat (no solvent) for 2h; Milling;
64%
With sulfuric acid at 20℃; for 18h;
44%
With sulfuric acid at 0℃; for 5.5h;
With trichlorophosphate
With sulfuric acid In water monomer
With sulfuric acid; trifluoroacetic acid at 0 - 20℃; for 4h;
1.7 Synthesis and characterization of 5i-k
General procedure: To a mixture of resorcinol (0.5g, 4.54 mmol) dissolved in ethyl 2-oxocyclopentane-1-carboxylate (3a) or ethyl 2-oxocyclohexane-1-carboxylate (3b) or ethyl 2-oxocycloheptane-1-carboxylate (3c) (0.88 mL, 4.90 mmol) was added dropwise concentrated sulfuric acid (for 5i and 5j) or a mixed acid (for 5k) of concentrated sulfuric acid (2.19 mL, 29.52 mmol) and trifluoroacetic acid (1.61mL, 29.52 mmol) under the condition of magnetic stirring strongly at 0 oC, and then the reaction mixture was moved to room temperature and kept stirring for 4 h. The next purification steps were consistent with the procedure for 5a, 5d, and 5h.
With zirconium tetrachloride In neat (no solvent) at 85℃; for 1h;
2.2. Synthesis of 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (THU-OH)
THU-OH was synthesized according to the previously published methodology [20-21]. Briefly, 0.22 g resorcinol, 0.37g ethyl 2-oxo-cyclohexancarboxylate, and 0.4 g ZrCl4 were mixed in a 20 mL reaction flask and heated at 85 °C for 1 h.The precipitate formed was filtered off and washed with ice-cold water. The spectral analysis of the compound was foundidentical with our previous findings.
With aluminum oxide; methanesulfonic acid at 20℃; for 0.0833333h;
93%
With zirconium(IV) chloride In toluene at 80℃; for 0.333333h; Inert atmosphere;
92%
With magnetic nanoparticles functionalized ethane sulfonic acid at 90℃; for 2h;
General procedure for Pechmann reaction in the presence of MNESA catalyst
General procedure: A mixture of phenol (1.0 mmol), β-ketoester (1.5 mmol) and MNESA (0.075 g) was stirred at 90 °C in a round-bottomed flask for the appreciated time. After completion of the reaction as confirmed by TLC, the reaction mixture was cooled down to room temperature and the catalyst was separated from the reaction mixture using an external magnetic Some field. water was then added to the reaction mixture and the product was extracted using EtOAc (2 9 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuumto yield the crude product. For more purification, the crude product was purified by recrystallization in ethanol to obtain the desired purity.
87%
In trifluoroacetic acid at 100℃; for 0.5h; microwave irradiation;
a) To a solution of ethyl 2-oxocyclohexanecarboxylate (18.9 mL, 1 18 mmol) in methanol (120 mL) was added the ammonium carbamate (9.20 g, 1 18 mmol). The resulting mixture was stirred at rt for 1 h after which time the ammonium carbamate had completely dissolved. The reaction mixture was stirred for an additional 1 h before the volatiles were removed under reduced pressure to afford ethyl 2-aminocyclohexene- 1-carboxylate as a white-yellowish solid (19.9 g, quantitative yield). 1H NMR (400 MHz, CDCI3) delta 1.28 (t, J=7.2 Hz, 3H), 1.57 - 1.71 (m, 4H), 2.21 (t, J=6.1 Hz, 2H), 2.26 (t, J=6.1 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 6.06 (br s, 2H)
97%
With ammonia; In methanol; at 20℃; for 24h;
A mixture of ethyl 2-oxocyclohexanecarboxylate (32) (3.43 g, 20.2 mmol) and ca. 7 N ammonia solution in methanol (25 ml, ca. 175 mmol) was stirred in a closed vessel at room temperature for 24 h. The solvent was evaporated and the residue was dried in vacuo over P2O5 to give 3.30 g (97%) of known31 compound 33 as yellow crystalline substance which was immediately utilized in the next step. 1H NMR (CDCl3) delta: 1.26 (t, J = 7.1 Hz, 3H), 1.55-1.67 (m, 4H), 2.16-2.27 (m, 4H), 4.13 (q, J = 7.1 Hz, 2H), 6.00 (br s, 2H). GCMS m/z: 169.1 M+.
90%
With ammonia; In methanol; at 20℃;Product distribution / selectivity;
To 7N-ammonia-methanol solution, 170 g of ethyl 2-oxocyclohexanecarboxylate was added and stirred for an overnight at room temperature. Concentrating the solvent under reduced pressure, crude crystals were obtained, which were recrystallized from ethyl acetate-n-hexane to provide 152 g (90%) of 2-aminocyclohex-1-enecarboxylic acid ethyl ester. 1H-NMR(CDCl3)delta:4.14(q,J=7.3Hz,2H),2.25(d,J=5.9Hz,2H), 2.20(d,J=5.9Hz,2H), 1.67~1.56(m,4H). Mass,m/e:169(M+),96(base)Into 7N-ammonia-methanol solution, 170 g of ethyl 2-oxocyclohexanecarboxylate was added and stirred for an overnight at room temperature. Distilling the solvent off under reduced pressure, the resulting crude crystalline product was recrystallized from ethyl acetate-n-hexane to provide 152 g (90%) of ethyl 2-aminocyclohex-1- enecarboxylate. 1H-NMR(CDCl3):4.14(q,J=7.3Hz,2H),2.25(d,J=5.9Hz,2H), 2.20(d,J=5.9Hz,2H),1.67~1.56(m,4H) Mass,m/e:169(M+),96(base)
60%
With ammonium acetate; In methanol; at 20℃; for 72h;
5.2 Ethyl 2-aminocyclohex-1-ene-1-carboxylate (3b) In the same manner as in the preparation of 3a, the title compound (32.3 g, 60%) was obtained as a white solid from 2b (53.9 g, 0.317 mol). 1H NMR (DMSO-d6) delta 1.16 (3H, t, J = 7.1 Hz), 1.45-1.59 (4H, m), 2.09-2.21 (4H, m), 4.00 (2H, q, J = 7.1 Hz), 7.09 (2H, br s).
With bromine In diethyl ether at 0 - 20℃; for 1.5h;
100%
With bromine In diethyl ether at 20℃; for 1h;
22.a
2-Carbethoxy-cyclohexanone (5.0 g, 29.4 mmol) was dissolved in diethyl ether (30 mL). To this solution bromine (4.93 g, 30.8 mmol) was added drop wise at room temperature. The reaction was stirred for 1 hour at room temperature, quenched with water and the layers were separated. The organic layer was washed with aqueous thiosulfate solution and brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to yield the crude title compound (7.48 g, 100%) which was used directly in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm)=4.94 (t, 1H), 4.20 (q, 1H), 2.37 (dt, 1H), 2.25 (m, 1H), 2.09 (m, 2H), 1.74 (m, 2H), 1.24 (t, 3H).
100%
With bromine In diethyl ether at 20℃; for 2h;
14.3 Step 3. Synthesis of compounds 6 (General procedure).
General procedure: To the solution of ketone 5 (12.4 mL, 77 mmol) in ether (100 mL), Br2 (4.0 mL, 77 mmol) was added dropwise at ambient temperature. The mixture was stirred for 2 h and quenched with an aqueous solution of sodium sulfite. The organic layer was separated, dried over MgSO4, concentrated under reduced pressure to afford compound 6 in quantitative yield (20 g) that was used further without additional purification.
99%
With bromine In chloroform at 0 - 20℃; for 22.75h;
98%
With bromine In diethyl ether at 20℃; for 2h;
98%
With bromine In dichloromethane at 0 - 5℃; for 3.5h;
1.1 Example 1-Comparative: 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (selisistat)
Step 1: To a solution of ethyl 2-oxocyclohexane-1-carboxylate (5 g, 29.38 mmol, 1.00 equiv) in dichloromethane (50 mL) was added Br2 (4.7 g, 29.41 mmol, 1.00 equiv) dropwise with stirring at 0-5° C. over 30 min. The resulting solution was stirred for 3 h at 0° C. The reaction was then quenched by the addition of sodium carbonate (50 mL). The resulting solution was extracted with ethyl acetate (3*50 mL). The organic layers were combined and washed with water (3*30 mL) and brine (3*30 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7.2 g (98%) of ethyl 3-bromo-2-oxocyclohexane-1-carboxylate as yellow oil. 1H NMR (400 MHz, CDCl3) δ:12.10 (s, 1H), 4.70 (m, 1H), 4.33-4.07 (m, 2H), 2.54-1.71 (m, 6H), 1.37-1.17 (m, 3H).
97%
With bromine In diethyl ether at 0 - 20℃; for 2h; Inert atmosphere;
97%
With bromine In diethyl ether at 0 - 6℃; for 0.333333h;
Ethyl-2-oxocyclohexanecarboxylate (12.5 g, 73 mmole) was dissolved in ether (50 mL) and chilled in a salt ice bath under N2 to 0° C. Bromine (11.7 g, 3.8 ml, 73 mmole) was added in portions over ~20 minutes allowing the exotherm to subside between additions. The temperature never rose above 6° C. during the addition of bromine. The reaction was worked up by diluting with an additional portion of ether (50 mL) and washing with water (50 mL) then saturated sodium bicarbonate (25 mL). The organic layer was then dried over sodium sulfate and the solvent removed in vacuo. To give 1 (17.5 g, 71 mmole, 97%) as a clear liquid that was of satisfactory purity to be carried on without further purification.
96%
With bromine In chloroform at 0℃;
92%
With bromine In dichloromethane at 0 - 20℃; for 20.5h;
40(A) Preparation 40 [2- (4-TRIFLUOROMETHYL-PHENYL)-4, 5,6, 7-TETRAHVDRO- BENZOTHIAZOL-4-VL]-METHANOL Step A
A solution of bromine (0.2056 mol, 32.85 g) in anhydrous dichloromethane (50 mL) is added dropwise over 2h. to a solution of 2-oxo-cyclohexanecarboxylic acid ethyl ester (0.2056 mol, 35 g) in dichloromethane (200 mL) at 0C-5C. After the addition, the mixture is allowed to stir 0.5h. at 0C, then the ice bath is removed and the mixture is allowed to stir at room temperature for 18h. The reaction is monitored by TLC and HPLC until complete consumtion of starting material, then ice water (200 mL) is added with stirring. The organic layer is collected and washed twice with ice water (200 mL), twice with 200 mL of 10% aqueous sodium thiosulfate, and 200 mL of brine. The filtered solution is dried over anhydrous sodium sulfate, then concentrated to a clear liquid, 0.189 mol, 47 g. 92% yield. *Actually a mix of methyl/ethyl ester due to impure starting ester (10% methyl ester)
79%
With bromine In chloroform
With bromine
With bromine In diethyl ether
With bromine In diethyl ether at 5 - 10℃; for 0.166667h;
With bromine In diethyl ether at 0℃;
With bromine In dichloromethane
With bromine In diethyl ether at 20℃; for 2h;
45 Preparation 45 3-BROMO-2-OXO-CYCLOHEXANECARBOXYLIC acid ethyl ester
To a solution of 2-oxo-cyclohexanecarboxylic acid ethyl ester (30 g, 0.176 mol) in ether is added bromine (29.6 g, 0.185 mol) dropwise at room temperature, then stirred at room temperature for 2 h. The reaction mixture is quenched by water, and layers are separated. Organic layer is washed with Na2S204 and brine, dried over sodium sulfate. Concentration under vacuum gave the title compound, which is used for next step without further purification.
With bromine; sodium carbonate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate
34.F F.
F. Preparation of ethyl 6-bromocyclohexanone-2-carboxylate To a stirred solution of 31 g. of ethyl cyclohexanone-2-carboxylate in 25 ml. of ether, cooled to -10° C., was added dropwise 35 g. of bromine. Stirring was continued one hour while the solution was allowed to come to room temperature. The solution was poured into ice water containing 20 g. sodium carbonate and was extracted with ether. The ether extract was washed with water, dried and evaporated to dryness to give 23 g. of the title compound; b.p. 88°-91°C. (0.2 mm).
With bromine In chloroform
1 EXAMPLES
Step 1 To a solution of ethyl 2-oxocyclohexanecarboxylate (50 g, 0.29 mol) in CHCl3 (150 mL) there was slowly added bromine (47 g, 0.29 mol) at 0° C. under a blanket of nitrogen as inert gas dropwise over a period of 45 minutes and the resultant mixture was stirred for a period of 6 hours at 0° C. and then for 16 hours at room temperature. Air was then passed into the reaction solution over a period of 2 hours. The organic phase was washed with aqueous saturated NaHCO3 solution (2*15 mL) and aqueous saturated NaCl solution (3*20 mL). Following drying of the organic phase over Na2SO4 and filtration, the solvent was removed. The product ethyl 3-bromo-2-oxocyclohexanecarboxylate was obtained in a yield of 72.6 g (corresponding to 99% of theory).
With bromine In diethyl ether
With bromine at 0 - 10℃; for 13h; Large scale;
2
Example 2: stage 1 procedure with no solventEthyl-2-cyclohexanone-carboxylate (497 kg) is cooled down to 0°C and bromine is added over 9h while stirring, keeping the temperature at 0°±10°C. After complete addition, the mixture is stirred at 0°C for 4 h (content of starting material 2.8% by GC), then it is warmed up to 20°C and nitrogen is bubbled through the reaction mixture to drive off the HBr gas. Then the reaction mixture is stirred for another 25 h at 5°C (content of HBr 0.8% by titration). 6-chloro-2,3,4,9-tetrahydro- lH-carbazole-l-carboxylic acid ethyl ester is drummed off and stored at 0°C prior to use as such in the subsequent step.Yield of crude product: 730.4 kg (100%)Purity (determined by ?-NMR with 3,4-Dimethoxybenzene as internal standard). 87% w/w.
With bromine In chloroform at 0℃; for 0.5h; Inert atmosphere;
With bromine In diethyl ether
With bromine In diethyl ether at 0 - 20℃;
With bromine In diethyl ether at 0 - 20℃; for 18h;
3.675 g
With bromine In diethyl ether at 0 - 20℃; for 1.5h;
1-3 Examples 1-3: Synthesis of 6-Bromo-N-(3-phenylpropyl)-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
Ethyl 2-cyclohexanonecarboxylate (12 mmol, 2042 mg) was dissolved in 4 mL of ether.Add bromine (0.61 mL) at 0 °C for 90 min,After the temperature was raised to room temperature, the reaction was completed. The reaction solution was poured into 30 mL of cold saturated Na2CO3, stirred and neutralized, extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. 2-bromo-6-(ethoxycarbonyl)cyclohexanone (3.675 g) was obtained.
With bromine In diethyl ether at 0 - 20℃; for 1.75h;
14.A
To a solution of 15 g (88 mmol) of ethyl 2-oxocycIohexanecarboxylate in 40 mL of anhydrous diethyl ether cooled to 0°C was added 4.5 mL (88 mmol) of bromine dropwise over 15 min. After complete addition the mixture was allowed to warm to ambient temperature over 90 min. The mixture was next diluted with 100 mL of ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was taken up in 100 mL of ethanol and 6.6 g (88 mmol) of thioacetamide was added. The mixture was stirred at ambient temperature for 1 h, then at reflux overnight. After evaporation of all volatiles in vacuo the residue was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane. The layers were separated and the organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by MPLC (Biotage Horizon: FLASH 65i) eluent: 100% Hexanes (500ml), gradient 0 to 25% EtOAc in hexanes (1200ml) then 25% EtOAc in hexanes (1200ml) to give the title compound as a pale orange oil. 1H NMR (500 MHz, CDCl3) δ: 4.22 (q, J= 7.1, 2H), 3.84 (t, J= 5.5, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.65 (s, 3H), 2.18 (m, 1H), 2.11-1.95 (m, 2H), 1.85 (m, 1H), 1.29 (t, J = 7.1, 3H).
With N-chloro-succinimide; C19H19F6N5 In toluene at -80℃; for 23h; enantioselective reaction;
Typical Procedure for α-Chlorination of β-Keto Esters 6 Using Organocatalyst 4 (Table 2)
General procedure: To a solution of methyl1-oxo-2,3-dihydro-1H-indene-2-carboxylate (6a, 38.0 mg,0.200 mmol) and organocatalyst 4 (0.9 mg, 0.002 mmol) intoluene (2.0 mL) was added NCS (40.1 mg, 0.300 mmol) at-80°C. After stirring in closed tube at -80°C for 23 h, thereaction mixture was directly purified by flash column chromatographyon silica gel with a 9 : 1 mixture of hexane andAcOEt to afford 7a (44.5 mg, 99%) as a yellow solid. All theproducts 7a-h in the paper are known compounds that exhibitedspectroscopic data identical to those reported in theliterature.
94%
With sodium hypochlorite In acetic acid; acetone at 0℃; for 1h;
91%
Stage #1: ethyl 2-oxocyclohexane carboxylate With titanium tetrachloride In acetonitrile
Stage #2: With [bis(acetoxy)iodo]benzene In acetonitrile at 20℃; for 0.05h;
91%
With [bis(acetoxy)iodo]benzene; tetraethylammonium chloride In water; acetonitrile at 20℃; for 0.0833333h;
90%
With N-chloro-succinimide; 2-phenyl-1,2-benzoisoselenazol-3(2H)-one In acetonitrile at 20℃; for 12h;
90%
With N-chloro-succinimide In dimethyl sulfoxide at 20℃; for 0.75h;
89%
With N-chloro-succinimide In various solvent(s) at 20℃; for 0.5h;
89%
With trimethylsilyl trifluoromethanesulfonate; racemic methyl phenyl sulfoxide; sodium chloride In acetonitrile at 20℃; for 6.5h; Inert atmosphere;
86%
With N-chloro-succinimide; thiourea In methanol at 23℃; for 0.166667h;
85%
Stage #1: ethyl 2-oxocyclohexane carboxylate With titanium tetrachloride In acetonitrile
Stage #2: With peracetic acid; acetic acid In acetonitrile at 20℃;
79%
With sodium hydride; copper dichloride In dimethyl sulfoxide 1.) 20 deg C, 2 h, 2.) r.t., 6 h;
77%
With N-chloro-succinimide; (S)-1-[(S)-2,2-diphenyl-1,3-dioxolan-4-yl]-N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-propen-1-amine In methyl cyclohexane at 0℃; for 24h; optical yield given as %ee;
57%
With potassium 1-hydroxy-1,3-dioxo-1,3-dihydro-1λ(5)-benziodoxol-5-sulfonate; Aliquat 336; sodium chloride In tetrahydrofuran; water at 50℃; for 24h;
General procedure: The carbonyl substrate (1 equiv) was dissolved in a mixture of THF and aq 1 M NaCl solution(1:2, 0.3 M regarding substrate). Then, MeOc3NCl (20mol%) and IBX-SO3K (3 equiv) were added and the suspension was heated to 50 °C for 24 h. After thesuspension was cooled to r.t., the organic phase and the aqueous phase were separated. The aqueous phase was extracted with Et2O (3×). The combined organic phase was washed with aq sat. NaHCO3 solution and dried over Na2SO4. After concentration, the residue was purified by flash chromatography.
With sulfuryl dichloride
With lithium chloride; dibenzoyl peroxide
With lithium chloride; dibenzoyl peroxide
(i) K2CO3, CCl4, (ii) SO2Cl2; Multistep reaction;
80 %Chromat.
With potassium peroxymonosulfate; ammonium chloride In methanol at 20℃; for 4h;
Stage #1: ethyl 2-oxocyclohexane carboxylate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: With methyl chlorosulfate In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
α-chlorination of ketones
General procedure: To a solution of diisopropylamine (170 µL, 1.2 eq.) in dry THF (2 mL) in a flame dried round bottom flask under argon at 0 °C was added n-butyllithium (690 µL, 1.6 M in hexanes, 1.1 eq.), and the reaction mixture was stirred at this temperature for 15 minutes. It was then cooled to -78 °C and a solution of ketone (1) (1 mmol) in THF (2 mL) slowly added. Stirring at -78 °C was continued for a further 30 minutes and methyl chlorosulfate (100 µL, 1.1 eq.) was then added. After stirring at -78 °C for 30 minutes, the reaction was quenched with an aqueous saturated ammonium chloride solution (5 mL). The mixture was then extracted with dichloromethane (3 x 5 mL), the combined organic phases were dried with anhydrous magnesium sulfate and the solvent evaporated under vacuum affording the desired α-chloroketone 2.
With hydrogenchloride; dihydrogen peroxide; potassium bromide In toluene at 20℃; for 0.5h;
99%
With dimethylbromosulphonium bromide In dichloromethane at 20℃; for 0.333333h;
98%
With N-Bromosuccinimide; toluene-4-sulfonic acid In dichloromethane at 20℃; for 0.333333h;
95%
With sodium hydroxide; bromine In acetic acid; acetone at 0℃;
95%
Stage #1: ethyl 2-oxocyclohexane carboxylate With titanium(IV) bromide In acetonitrile
Stage #2: With [bis(acetoxy)iodo]benzene In acetonitrile at 20℃; for 0.0166667h;
95%
With Oxone; ammonium bromide In methanol at 20℃; for 0.5h; regioselective reaction;
2. General procedure
General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3×25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
94%
With N-Bromosuccinimide In various solvent(s) at 20℃; for 0.333333h;
93%
With triphenylphosphine hydrobromide; dimethyl sulfoxide at 50℃; for 1.5h; Inert atmosphere; chemoselective reaction;
92%
With N-Bromosuccinimide In dimethyl sulfoxide at 20 - 65℃;
92%
Stage #1: ethyl 2-oxocyclohexane carboxylate With titanium(IV) bromide In acetonitrile
Stage #2: With peracetic acid; acetic acid In acetonitrile at 20℃;
92%
With phthaloyl peroxide; tetrabutylammomium bromide In 1,2-dichloro-ethane at 20℃; Inert atmosphere;
2 Carbonyl ortho halogenation (at R1 = R2 = H, n = 1 as an example)
0.24mmol TBAB,0.24mmol PPO and 0.2mmol of dicarbonyl compound were added to a 25mL reaction tube.The gas in the reaction tube is removed by a vacuum pump,Filled with nitrogen,Repeat the operation three times,Then add 2mL 1,2-dichloroethane DCE,Stir at room temperature,The reaction was detected with a TLC plate until the reaction of the starting material was completed.Finally, the solvent is removed by rotary evaporator to obtain crude product.The crude product was purified by column chromatography to afford 46 mg of y.Yield 92%,The eluent is a mixture of petroleum ether and ethyl acetate.
90%
With ammonium bromide; dihydrogen peroxide; vanadia In dichloromethane; water at 0 - 5℃; for 3h;
80%
With trimethylsilyl bromide; racemic methyl phenyl sulfoxide In acetonitrile at 25℃; for 24h; Inert atmosphere;
60%
With 3-bromo-6-chloroimidazo<1,2-b>pyridazine hydrobromide-bromine for 1.5h; Ambient temperature;
With tetrachloromethane; diethyl ether; bromine; potassium hydrogencarbonate
With tetrachloromethane; N-Bromosuccinimide
With magnesium bromide; dibenzoyl peroxide In diethyl ether
(i) aq. KHCO3, Et2O, CCl4, (ii) Br2; Multistep reaction;
With N-Bromosuccinimide In tetrachloromethane
With N-Bromosuccinimide
With 1,10-(ethane-1,2-diyl)phenanthrolinediium bistribromide In ethyl acetate at 5 - 10℃; for 0.45h; regioselective reaction;
12. Preparation of 1-bromo-2-oxocyclohexanecarboxylic acid ethyl ester (12b):
12. Preparation of 1-bromo-2-oxocyclohexanecarboxylic acid ethyl ester (12b): 0.6 mmol of EPDTB(0.818 g) and 1 mmol of 2-oxocyclohexanecarboxylic acid ethyl ester (0.160 mL) were dissolved in 5 mLof EtOAc. The resultant mixture was stirred maintaining cool condition (5-10oC) in a magnetic stirrer forca. 27 min until the solution becomes colourless. The progress of the reaction was monitored by doingTLC (10 % EtOAc/hexane). After the completion of reaction, the mixture was washed with water (2 X 5mL). The organic layer was dried over anhyd Na2SO4 after separating from aq layer. The excess solventwas removed by evaporation in a rotary evaporator to get the crude liquid product.
With N-Bromosuccinimide; magnesium(II) perchlorate In acetonitrile at 20℃; for 6h;
With bromine In diethyl ether; water at 0 - 20℃; for 1.75h; Inert atmosphere;
1.d Example 1(d) 3-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4)
3-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4) Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0° C. under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3*200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
94%
With bromine In diethyl ether at 0 - 20℃; for 1.75h; Inert atmosphere;
1.1(d) Example 1(d): 3-Bromo-2-hydroxy-cyclohex-l-enecarboxylic acid ethyl ester
Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0°C under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-l- enecarboxylic acid ethyl ester as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDC13): 5c 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
94%
With bromine In diethyl ether at 0 - 20℃; for 1.75h; Inert atmosphere;
1d 3-Bromo-2-hydroxycyclohex-1-enecarboxylic acid ethyl ester (4)
Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0°C under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 mm and the reaction mixture was allowed to warm to RT over 90mm. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz,CDCl3): δc 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
94%
With bromine In diethyl ether at 0 - 20℃; for 1.75h; Inert atmosphere;
1.d 3-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4)
Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0° C. under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3*200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
94%
With bromine In diethyl ether
1.d 3-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4)
Example 1(d) 3-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4) Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0° C. under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3*200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
94%
With bromine In diethyl ether at 0 - 20℃; for 1.75h; Inert atmosphere;
1.d 3-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4)
Example 1(d) 3-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4) (0161) Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0° C. under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
53%
With trimethylsilyl trifluoromethanesulfonate; racemic methyl phenyl sulfoxide; sodium bromide In acetonitrile at 25℃; for 3.5h; Inert atmosphere;
With bromine
With bromine at 0℃; for 0.5h; Yield given;
With bromine In diethyl ether at 0 - 20℃; for 1.75h; Inert atmosphere;
Step 1. Ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-enecarboxylate [0083] Sodium hydride (60 wt. % in oil, 228 mg, 5.70 mmol) was added to a 0 C solution of ethyl 2-oxocyclohexanecarboxylate (888 mg, 4.96 mmol) in THF (25 mL). After 40 min at 0 C, N-phenyl-bis(trifluoromethanesulfonimide) (2.14 g, 5.93 mmol) was added and the solution was allowed to warm to room temperature and stir overnight. The reaction mixture was quenched with saturated aqueous NaHC03 and extracted with CH2C12 (3x). The combined extracts were dried (MgS04), filtered and concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (120 g gold column, hexanes- 25% EtOAc/hexanes, gradient), to afford 879 mg (59%) of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l- enecarboxylate.
ethyl (E)-2-hydroxy-3-(3-oxobutylidene)-1-cyclohexene-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: ethyl 2-oxocyclohexane carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; for 1.08333h;
Stage #2: trans-4-methoxy-3-buten-2-one With aluminium tris(2,6-diphenylphenoxide) In tetrahydrofuran; dichloromethane at -78℃; for 0.5h;
Stage #3: With hydrogenchloride In tetrahydrofuran; dichloromethane; water
In a 500mL three-necked flask, add 60% sodium hydrogen (3.5g, 1.5eq.),Add 200 mL of dichloromethane and replace with nitrogen three times.Under the condition of 0-5C, add ethyl 2-cyclohexanone carboxylate (10.0 g, 1.0eq.) dropwise, keep the temperature and stir for 10 min,Subsequently, the temperature continued to drop to -70C, and Tf2O (24.3g, 1.5eq.) was added dropwise to the reaction solution (to control the dropping rate),Incubate and stir for 15 minutes, then naturally heat to 25C and stir overnight;Afterwards, a saturated NaHCO3 solution was added to adjust the pH to 8-9, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain Intermediate 1a (15.6g, 90.0% yield).
82%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78 - 20℃; for 18h;
Preparation 41; 2-Hydroxy-cyclohex-l-enecarboxylic acid ethyl ester; Et EPO <DP n="34"/>Combine 2-oxo-cyclohexanecarboxylic acid ethyl ester (10.0 g, 55.0 mmol), Hunig's base (23.0 mL, 132.0 mmol), dichloromethane (100.0 mL), and trifluoromethane sulphonic anhydride (11.1 mL, 66.0 mmol) at ""780C and then stir at room temperarture for 18 hours under a nitrogen atmosphere. Add water, then wash with sat sodium bicarbonate solution, citric acid, then brine, and dry over sodium sulfate. Concentrate under vacuum and flash chromatograph using 10% to 40% DCM/hexanes eluent to yield the titled compound (13.6 g, 82%). TLC Rf=0.25in 40% DCM/hexanes. 1H NMR (CDCl3): 4.26 (q, 2H, 7=7.0 Hz), 2.5 (m, 2H), 2.4 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H), 1.3 (t, 3H, 7=7 Hz).
76%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78 - 20℃; for 16h;
Ethyl 2-oxocyclohexanecarboxyla.te (170 mg, 1 .00 mmol) and DIEA (417 jjJL, 2,40 mmol) were dissolved in DCM (2 mL) and cooled to -78 C. To the stirring solution was added dropwise trifluoromethanesuiionic anhydride (202 μΤ, 1.20 mmol), then the resulting solution was allowed to warm to room temperature and stirred for 16 h. The solution was then diluted with DCM and washed with I M aqueous HCl and the solvent removed under reduced pressure. The crude residue was purified by flash column ehroniatograpliy using a gradient of hexanes : EtOAc (9 : 1 to 1 : 1) to give 29a (231 mg, 76%) as a clear oil. 1H~NMR (400 MHz, CDC13) δ 4.23 (q, J = 7.1 Hz, 2H), 2.51-2.40 (m, 2H), 2.40-2.31 (m, 2H), 1.81-1.70 (m, 2H), 1.70-1.57 (m, 2H), L28 (t, J= 7.1 Hz, 3H).
Example 1 (Intermediate); 2-Trifluoromethanesulfonyloxy-cyclohex-l-enecarboxylic acid ethyl (1); To a suspension of sodium hydride (1.35 g, 33.9 mmol) in diethyl ether (150 mL) was added dropwise a solution of ethyl 2-oxocyclohexanecarboxylate (5.00 g, 29.4 mmol) diethyl ether (30 mL). After stirring for 2 h at room temperature, trifluoromethanesulfonic anhydride (5.7 mL, 33.8 mmol) was added dropwise, and the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated ammonium chloride (200 mL), and the product was extracted with ether (3x 100 mL). The combined ether extracts were dried over MgSO4, filtered, and concentrated to provide compound (1), which was used in the next step without further purification.
Example 8A ethyl 2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate To a cooled (0 C.) stirring suspension of NaH (0.983 g 60% in mineral oil, washed with hexane three times) in ether (50 ml) was added ethyl 2-oxocyclohexanecarboxylate (3.2 g, 20.5 mmol). The mixture was stirred at 0 C. for 30 minutes before the addition of trifluoromethanesulfonic anhydride (4.2 mL, 25 mmol). The mixture was then stirred at room temperature overnight. The mixture was diluted with ether (200 mL) and washed with 5% HCl, water and brine. After drying over Na2SO4, evaporation of solvent gave crude product which was used without further purification.
General procedure: The NaH (60% oil dispersion, 23.4 mmol,0.94 g, 1.3 eq) was weighted into a 250-mL round-bottom flask, filled with 80 mL of CH2Cl2. Then the flask was placed into an ice bath and the β-ketoester (18 mmol, 5.0 g, 1.0 eq) was added dropwise over 10 min. This reaction mixture was stirred for 20 min at 0 C to complete deprotonation and then cooled down to -78 C. Trifluoromethanesulfonic anhydride (24.3 mmol, 6.90g, 1.35eq) was added dropwise and then warmed up slowly overnight for 12 h. It was quenched with brine, filtrated through Celite, extracted with CH2Cl2, concentrated in vacuo, and purified over silica gel to obtainedthe products.
To compound 1 (1 g, 5.88 mmol) in DCM (20 mL) was added NaH (0.29 g, 12 mmol) at 0 degrees. After replacing the nitrogen, stirring for 30 minutes, add trifluoromethanesulfonic anhydride Tf2O (2.0g, 7mmol) to the above reaction solution and slowly rise to room temperature and stir for 1-24 hours. After the reaction is complete, add 20ml of water to quench the reaction solution. Extract twice with methyl chloride (20 mL) and dry the organic phase. It was spin-dried to obtain 2.0 g of crude compound 2. The reaction is almost quantitative and can be used directly in the next step.
2-Oxo-1-[(E)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-thiophen-3-yl-allyl]-cyclohexanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: ethyl 2-oxocyclohexane carboxylate With sodium hydride In toluene at 20℃; for 1h;
Stage #2: 4,4,5,5-tetramethyl-2-(propa-1,2-dien-1-yl)-1,3,2-dioxaborolane; 3-thienyl iodide With tris(para-trifluoromethyl)phenyl phosphine In toluene at 80℃; for 24h;
2-(4-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In methanol; for 4h;Heating / reflux;
7.5 g of ethyl 2-oxocyclohexane-4-carboxylate and 9.6 g of <strong>[14401-51-5]4-chlorobenzamidine hydrochloride</strong> were introduced into 50 ml of methanol. 5.6 g of potassium tert-butylate were added with stirring. The reaction mixture was stirred under reflux for 4 hours and then poured onto ice water. The crystalline product was filtered off with suction, washed with water and recrystallized from dimethylformamide. Yield: 8.8 g; m.p.: >300 C.
With hydrogen In dichloromethane at 40 - 60℃; for 113h;
3 Example 3; Synthesis of ethyl(R,R)-2-hydroxycyclohexanecarboxylate
To a one-liter autoclave was added 0.539 g (0.588 mmol) of [{RuCl (p-cymene) (R) -segphos} Cl, then a solution containing 100.0 g (587.5 mmol) of degassed ethyl 2-oxocyclohexanecarboxylate and 400 mL of methylene chloride was added and the mixture was stirred at 40°C for 22 hours and then at 60°C for 91 hours under 2 MPa of hydrogen pressure. After cooling, hydrogen was discharged, the solvent was recovered and the residue (123.91 g) was distilled under reduced pressure (80 to 90°C/93.3 Pa) to give 99.37 g of the title compound. The yield was 98%. The resulting product was analyzed and measured by the same manner as in Example 1 and the results were 97.5%ee and 87.5%de. 1H-NMR (200 MHz) δ (CDCl3): 1.3 (t, J = 7.1 Hz, 3H), 1.2-1.4 (m, 3H), 1.6-1.8 (m, 3H), 2.0 (m, 2H), 2.2 (m, 1H), 2.8 (d, J = 3.2 Hz, 1H), 3.8 (m, 1H), 4.2 (q, J = 7.1 Hz, 2H)
24; 28
For asymmetric conjugate additions generating 6Aa, 6Ba, 6Bb, 6Bc, 6Ea, 0.4 mmol of 3A, 3B and 3E (2.0 equiv. ) and 0.2 mmol of 5a-c were used; for reactions generating 6Ca, 0.8 mmol of 3C (4 equiv. ) and 0.2 mmol of 5a were used; for other reactions, 0.2 mmol of 3 and 0.4 mmol of 5 were used. Yields were calculated based on the limiting reagent. The choice of using either a donor or acceptor as the limiting reagent is based on how readily the product (6) can be separated from the excessive starting materials (3 or 5). Changing the ratio of 3 and 2 has no impact on both the diastereoselectivity and enantioselectivity of the asymmetric conjugate addition. When catalyst Q-4b was used, it is first suspended in THF. The resulting suspension was subjected to ultrasound for 10-15 min. and became a milky mixture. To this solution, the starting materials were added according to the procedure described below. Procedure: At the temperature specified in Tables 3 and 4 to a solution of the limiting reagent (3 or 5, 0.2 mmol) and the chiral catalyst (Q-4, QD-4 or 7, 10-20 mol %.) in THF (0.2 mL) was added the other reagent (5 or 3, 2 or 4 eq. ). The resulting mixture was kept at the temperature until the limiting reagent is consumed. The reaction mixture was then passed through a plug of silica gel for the removal of the catalyst. The plug of silica gel was eluted with ether or ethyl acetate (2-3 mL). The combined filtrate was concentrated in vacuo and the residue was subjected to purification by flash chromatography on silica gel.Q-4a (10 mol %) catalyzed reaction was run in THF at-20 °C for 74 h to furnish the crude product [dr > 98: 2, determined by integration of one set of ¹H NMR signal (No.major 4.88-4.85 ppm, No.minor 5.14-5.08 ppm, the minor peak cannot be detected by ¹H NMR) ]. Crude product was purified by flash chromatography (hexane: ethyl acetate = 10:1) to give adduct 6Bb as a colorless oil in 91 % yield (dr > 98: 2) and 99% ee (major diastereomer) [determined by HPLC, Chiralcel OD, hexane: isopropanol = 95:5, 0.9 mL/min, No. = 220 nm, t (major) = 14.9 min, t (minor) = 24.6 min]. [α]D25 = - 69.0 (c, 1.06 CHC13); ¹H NMR (400 MHz, CDCl3) 8 7.20 (d, J= 4.8 Hz, 1H), 6.89-6.85 (m, 2H), 4.86 (dd, J= 3.2 Hz, 13.6 Hz, 1H), 4.77 (dd, J = 10.4 Hz, 1H), 4.31 (dd, J = 4.0 Hz, 10.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 2.52 (m, 2H), 2.32-2.28 (m, 1H), 2.01-1.97 (m, 1H), 1.79-1.77 (m, 1H), 1.69-1.56 (m, 3H), 1.22 (t, J = 7.2 Hz, 3H); ¹3C NMR (100 MHz, CDCI3) 8 206.9,169.6, 137.7,128.4, 126.5,126.1, 78.7,63.7, 62.1,43.3, 41.0,36.1, 27.5,22.1, 13.9; IR (neat) v 2942,1718, 1702,1559, 1543,1524, 1437,1376, 1232 cm-1; HRMS (CI) m/z calcd for (C1sH19NOsS + H+) : 326.1055, found: 326.1058.
70%
With C45H40N4O5 In dichloromethane at 20℃; for 36h; Inert atmosphere; enantioselective reaction;
4.1.2. General procedure for the asymmetric Michael addition
General procedure: In a 10 mL round-bottomed flask, 1,3-dicarbonyl compound 3 (0.4 mmol) was added to an agitated solution of nitroolefin 2 (0.2 mmol) and catalyst 1a (0.7 mg, 0.001 mmol) in 1 mL of dicholomethane at room temperature. After 36 h, the reaction was monitored by TLC, condensed under reduced pressure and subjected to flash chromatography column to give the pure product 4.
Part A The preparation of 5,6,7,8-tetrahydro-2-methyl-4-quinazolone To 50 mL of absolute ethanol under a nitrogen atmosphere was added 5.65 g of sodium metal. After all the sodium had reacted, 20.15 g of 2-carboethoxycyclohexanone was added followed by 14.50 g of acetamidine hydrochloride. The reaction was refluxed gently overnight. The reaction was cooled to room temperature and all solvents were removed by evaporation. The pH of the residue was adjusted to 6 with dilute hydrochloric acid and refluxed briefly and allowed to cool. The resulting solid was collected. Successive crops of solid were collected by concentration of the mother liquors (13.1 g, 65%): 1 H NMR (DMSO-d6, 300 MHz) delta 12.18 (s, 1H), 2.22 (m, 2H), 2.15 (m, 2H), 2.10 (s, 3H), 1.65 (m, 4H).
(1,2,3,4-tetrahydro-9-acridinimino)cyclohexane carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene
1 2-(1,2,3,4-Tetrahydro-9-acridinimino)cyclohexanecarboxylic acid
EXAMPLE 1 2-(1,2,3,4-Tetrahydro-9-acridinimino)cyclohexanecarboxylic acid A solution prepared from 9-amino-1,2,3,4-tetrahydroacridine (5.0 g), ethyl cyclohexanone-2-carboxylate (25.2 g) and toluene (75 ml) was stirred and heated at reflux with azeotropic removal of water for 12 hours. The resultant crystalline precipitate was filtered, washed with hexane (500 ml) and ether (300 ml), and dried in vacuo at 50° C. to give 2-(1,2,3,4-tetrahydro-9-acridinimino)cyclohexanecarboxylic
EXAMPLE 83 0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02 moles of 2-amino-5-ethoxycarbonyl-pyridine according to Examples 1 to 20. 2,3-tetramethylene-7-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine is obtained. Yield: 67%. Melting point after recrystallization from ether: 100-102 C. Analysis for the formula C15 H16 N2 O3: Calculated: C, 66.16%; H, 5.92%; Found: C, 66.20%; H, 6.02%.
49%
EXAMPLE 86 0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02 moles of <strong>[39658-41-8]2-amino-5-ethoxycarbonylpyridine</strong> according to Example 85. 2,3-Tetramethylene-7-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine is obtained. Yield: 49%. The product is recrystallized from ether, melting point: 100-102 C. The product does not give melting point depression with a product of Example 83 or 85.
With sodium methylate; In 1,4-dioxane; methanol; at 0℃; for 1h;Heating / reflux;Product distribution / selectivity;
Dissolved 2-methoxy-benzamidine (150 mg, 1.0 mmol) in MeOH/dioxane (15 ml/5 ml) and cooled to 0 0C. 25% NaOCH3 in MeOH (0.44ml) was then added and stirred for 15mins. 2-oxo-cyclohexanecarboxylic acid ethyl ester (260 mg, 1.5 mmol) was introduced and the reaction mixture was heated to reflux for 1 h. The reaction was concentrated and the residue was taken up in 10 mL H2O and acetic acid was used to adjust pH to 7-8. Extracted with CH2CI2 (3x 100ml). The combined organic layers were dried over Na2SO4. Purified by flash column chromatography, (70% ethylacetate/hexane) to produce the product 220 mg in 86% yield.
E-1-(4-benzyloxy-phenylazo)-2-oxo-cyclohexanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
<strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> (24.5 g, 99 mmol, 1.0 equiv) was crushed into a free-flowing powder and suspended in 100 g of ice-water in a 500 rnL round-bottomed flask with a stir bar. Concentrated HCl (16.8 rnL) was added and the flask was immersed in an ice-water bath and stirring was begun. A solution of sodium nitrite (6.8 g, 99 mmol, 1.0 equiv) in 25 mL of deionized water was slowly added over a period of 15 min to the aniline mixture. At each 5 min interval 5 g of ice was added to the reaction mix to maintain the internal temperature close to 0 0C. After the addition of the nitrite, most of the solid had dissolved and the tan solution was stirred at O 0C for 10 min.A second round-bottomed- flask (1000 mL in size with a stir bar) was charged with potassium hydroxide (17.5 g, 312 mmol, 3.15 equiv) and 100 mL of water. After the base dissolved (about 1 min), 100 g of ice was added followed by addition of ethyl 2-oxocyclohexanecarboxylate (16.4 g, 96 mmol, 0.97 equiv) which quickly dissolved in the basic solution. The beta-keto ester <n="45"/>anion solution was vigorously stirred while the diazonium solution was slowly poured into the cold basic solution. Immediately, a bright yellow-orange precipitate formed which hindered the stir bar. After the addition, the flask was swirled for 10 min on the rotovap and then 26 mL of concentrated HCl was added. The precipitate immediately began to coalesce into a dark red- orange gum. The water was carefully decanted and the gum was washed 3 x 250 mL of water followed by decantation of the supernatant. The red-orange gum was dried at 30 0C under high- vacuum. The crude l-(4-benzyloxy-phenylazo)-2-oxo-cyclohexanecarboxylic acid ethyl ester (35g, 93%) was used in the next step without further manipulation.
With trifluoromethylsulfonic anhydride; N-ethyl-N,N-diisopropylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Step 1: ethyl 2-[(trifluoromethyl)sulfonyl]oxy}cyclohex-1-ene-1-carboxylate To a solution of ethyl cyclohexanone-2-carboxylate (5.02 g, 29.5 mmol) in DCM (100 mL) cooled to -78 C. was added DIPEA (25.4 mL, 146 mmol) and then triflic anhydride (5.98 mL, 35.4 mmol) dropwise. The mixture was then warmed to r.t. and stirred overnight. The reaction was then quenched with aqueous citric acid and extracted with additional water. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified on silica (100% DCM) to give the title product as an oil.
Stage #1: Methyl 2-acetamidoacrylate; ethyl 2-oxocyclohexane carboxylate With n-butyllithium In tetrahydrofuran; hexanes at 0 - 22℃;
Stage #2: With acetic acid In tetrahydrofuran; hexanes for 0.0833333h;
8.2
Ethyl 2-oxocyclohexanecarboxylate (1.23 g, 95%, 6.85 mmol) was dissolved in dry THF (10 ml.) at O0C and a solution of n-BuLi in hexanes (15% w/w, 1.50 ml_, 2.39 mmol) was added dropwise. After stirring the solution for 5 min, solid methyl 2-acetamidoacrylate (0.600 g, 4.19 mmol) was added and 5 min later, the cold bath was removed and the reaction was stirred for 4 days at 220C. Then, acetic acid (0.140 ml.) was added and the solution was stirred for 5 min and then concentrated in vacuo and the residue was purified by silica gel flash chromatography to give the product as a colorless oil (ca. 2:3 mixture of two diastereomers. Weight 850 mg, 65% yield 1H NMR (CDCI3): δ 6.53 (br d, 0.4H, minor diastereomer), 5.99 (d, 0.6H, major diastereomer),4.55 (ddd, 0.6H, major diastereomer), 4.37-4.23 (m, 0.4H), 4.21-4.04 (m, 2H), 3.65 (s, 3H), 2.55-2.36 (m, 3H), 2.32-2.08 (m, 2H), 2.00-1.90 (m, 1 H), 1.90 (s, 1.8H, major diasteromer), 1.87 (s, 1.2H, minor diastereomer), 1.77-1.46 (m, 4H), 1.21 (t, 1.2H, minor diastereomer), 1.20 (t, 1.8H, major diastereomer).
Stage #1: ethyl 2-oxocyclohexane carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.16667h; Inert atmosphere;
Stage #2: 5-iodopent-1-yne In tetrahydrofuran; mineral oil at 20℃; for 18h; Inert atmosphere;
78%
Stage #1: ethyl 2-oxocyclohexane carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;
Stage #2: 5-iodopent-1-yne In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil
70%
Stage #1: ethyl 2-oxocyclohexane carboxylate With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
Stage #2: 5-iodopent-1-yne In N,N-dimethyl-formamide at 20℃; for 18h;
ethyl-1-(2-ethoxy-1-((4-methoxyphenyl)amino)-2-oxo-ethyl)-2-oxo-cyclohexyl carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With copper(II) bis(trifluoromethanesulfonate) In acetonitrile for 1h; Irradiation;
84
10 ml test tube reaction of adding 0.2mmol2 - (4-methoxyphenylamino) ethyl acetate and 0.01mmol trifluoro methane sulfonic acid copper, in order to 3 ml acetonitrile as the reaction solvent, added under stirring 0.1mmol ethyl 2-carbonyl cyclohexyl carboxylic acid ester, the (green) LED illumination the reaction solution 1h rear, turns on lathe does reaction solvent, after column separation, the obtained product is nuclear magnetism hydrogen spectrum carbon spectrum and mass spectrum is identified as ethyl 1 - (2-ethoxy-1 - ((4-methoxylphenyl) amino) - 2-oxo-ethyl) - 2-oxo-cyclohexyl carboxylic acid ester.
With copper(II) bis(trifluoromethanesulfonate); 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran at 20℃; Inert atmosphere;
Example 286-Chloro-8-fluoro-l-(trifluoromethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-oIIntermediate 28a2-(2-(4-Chloro-2-fluorophenyl) hydrazono) cyclohexanoneTo <strong>[57946-56-2]4-chloro-2-fluoroaniline</strong> (2.7 g, 19.0 mmol) in H20 (12 mL), cooled to 0 C, cone. HCl (4.5 mL) was added and stirred for 10 min. NaN02 (1.3 g, 18.8 mmol), dissolved in water (13 mL), was added slowly to the reaction mixture and stirred at 0 C for an additional 30 min., the solids were filtered to give the diazonium salt. In another set up, to ethyl 2-oxocyclohexanecarboxylate (3 g, 19.3 mmol) in H20 (10 mL), 5N NaOH (5 mL) was added. The reaction mixture was stirred at room temperature for 24 h and washed with EtOAc (15 mL). The aqueous layer was separated, cooled to 0 C and cone. HCl (5 mL) was added dropwise to obtain 2-oxocyclohexanecarboxylic acid (2.7 g, crude). 2- oxocyclohexanecarboxylic acid (2.7 g, 19.0 mmol) and diazonium salt (prepared above) were mixed together at 0 C and the reaction mixture was slowly warmed to room temperature and stirred for 1 h during which time a solid precipitated out which was filtered, washed with hexane (20 mL) and air dried to give the title compound as a yellow solid (2.2 g, 45%). 1H NMR (200 MHz, CDC13, delta in ppm) 13.64 (bs, IH), 7.684 (t, J= 8.8Hz, IH), 7.10 (t, J=10.0 Hz, 2H), 2.74-2.67 (m, 2H), 2.56-2.50 (m, 2H), 1.90-1.83 (m, 4H).
2-(chloromethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With triethylamine; In methanol; at 20℃; for 60h;
Intermediate 51 : 2-(Chloromethyl)-5,6, 7,8-tetrahydroquinazolin-4(3H)-oneTo a solution of ethyl 2-cyclohexanone-carboxylate (5.5 g, 32 mmol) in methanol was added <strong>[10300-69-3]chloroacetamidine hydrochloride</strong> (4.2 g, 32 mmol) and triethylamine (14 mL, 97 mmol). The mixture was stirred at ambient temperature for 60 h. It was then concentrated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (0.82 g, 13% yield). 1H NMR (400 MHz, CD3OD) delta 4.40 (s, 2 H), 2.61 (t, J=6.3 Hz, 2 H), 2.45 (t, J=6.3 Hz, 2 H), 1 .68 - 1 .87 (m, 4 H). MS m/z 199.2 (M+1 ), retention time = 0.94 min.
N-(2-methoxyphenyl)-N-methyl-2-oxocyclohexanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
for 24h; Reflux;
Preparation of Materials
General procedure: A mixture of N-methylaniline (0.650 mL) and ethyl 2-oxocyclohexane-1-carboxylate (0.170 g) was heated under reflux for 24 h, then the crude products were separated by silica gel column chromatography eluting with EtOAc/hexane/acetone (2:7:1 v/v), giving N-methyl-2-oxo-N-phenylcyclohexane-1-carboxamide (1a) (0.126 g; 54% yield). The other N-alkyl-2-oxocycloalkane-1-carboxamides 1b-y were prepared according to a procedure similar to that already described.
7-phenoxy-1,2,3,4,9,10-hexahydroacridin-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: ethyl 2-oxocyclohexane carboxylate; 4-phenoxyanilin With toluene-4-sulfonic acid In toluene at 150℃; Dean-Stark;
Stage #2: In diphenylether at 230 - 240℃; for 2h; Dean-Stark;
2.1.1. 7-phenoxy-1,2,3,4,9,10-hexahydroacridin-9-one (1)
4-Phenoxyaniline (5.00 g; 26.99 mmol), ethyl 2-oxocyclohexane-1- carboxylate (5.05 g; 29.69 mmol) and p-toluenesulfonic acid monohydrate (0.15 g; cat.) were dissolved in toluene (150 ml) and heated at 150 °C under Dean-Stark trap overnight to collect water. The reaction mixture was cooled to room temperature and the solvent evaporated under reduced pressure. Diphenyl ether (80 mL) was added and the reaction mixture heated for 2 h at 230-240 °C using a Dean-Stark apparatus. After cooling to room temperature, 100 mL of hexane was slowly added, observing the precipitation of intermediate 1. The product was collected by filtration and washed with hexane (2 × 100 mL) to give the title compound as a yellow solid (6.70 g; 85% yield). The compound was immediately used without further purification in the next step. Chemical structure and purity were verified by HPLC/HRMS: HRMS [M + H]+: 292.1324 (calculated for [C19H18NO2] +: 292.1293); HPLC purity 95.4%.
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