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Structure of 1940-57-4 * 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.
With N-Bromosuccinimide In acetonitrile at 20℃; for 19 h;
General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
Reference:
[1] Organic Letters, 2010, vol. 12, # 17, p. 3874 - 3877
[2] Journal of the Chemical Society, 1949, p. 2186
[3] Journal of Organic Chemistry, 1948, vol. 13, p. 339,342
[4] Chemische Berichte, 1925, vol. 58, p. 2230
[5] Journal of the Chemical Society, 1929, p. 2361
[6] Chemische Berichte, 1906, vol. 39, p. 3065
[7] Journal of Organic Chemistry, 1968, vol. 33, # 3, p. 1123 - 1127
[8] Synthesis, 1988, # 11, p. 902 - 904
[9] Chemische Berichte, 1910, vol. 43, p. 2492
[10] Chemische Berichte, 1926, vol. 59, p. 640
[11] Chemical Biology and Drug Design, 2018, vol. 91, # 6, p. 1078 - 1086
3
[ 86-73-7 ]
[ 1940-57-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
With N-Bromosuccinimide; 1,1-bis(tert-butylperoxy)cyclohexane; nitric acid In dichloromethane at 20℃; for 1 h; Schlenk technique; Inert atmosphere
The inventors selected the radical bromination of fluorene 27 by N- bromosuccinimide (NBS) at room temperature as a benchmark reaction to evaluate their inventive initiator system (Scheme 4). NBS (1.1 equiv.) (0075) Scheme 5: Room temperature Wohl-Ziegler bromination of fluorene. All reactions were performed according to the following procedure: In an oven- dried Schlenk flask fluorene 27 (83 mg, 0.5 mmol, 1 eq) and N-bromosuccinimide (98 mg, 0.55 mmol, 1 .1 eq) were dissolved in dichloromethane (5 ml). The desired peroxide (0.025 mmol, 5 mol percent) was introduced and the resulting mixture was degassed by the freeze-pump-thaw method (3 cycles). After warming to room temperature, the acid catalyst was added under a stream of argon and after the desired reaction time, the reaction mixture was quenched with NEt3 (250 μΙ_), CH2Br2 (0.5 mmol) was added as a standard for analytical purposes only and an aliquot taken for direct H NMR analysis. Yield was determined by integrating a reference peak of 28 (5.9 ppm, s, 1 H; determined from an authentic sample) relative to the peak of CH2Br2. The results of the reactions are detailed in (Table 1). The bromination proceeded efficiently using a commercial solution of peroxyketal 1 (Trigonox® 22, 50percent weight in mineral oil) in combination with different Bronsted acids. Control experiments confirmed the requirement for both acid and peroxide, no conversion being observed after 24 hours if either one of these components was omitted. A clear trend following the pKa value of the acid catalyst can be seen : stronger acids give faster conversion. Sulfuric and para-toluene sulfonic acid have similar behaviour with 72percent and 67percent of 28 after one hour, respectively (entries 1 and 2). Methane sulfonic acid gave a slightly lower yield (45percent; entry 3) while acids weaker than trifluoroacetic acid (22percent, entry 5) or trichloroacetic acid (1 8percent, entry 6) failed to give any conversion (entry 7). Nitric acid is more efficient than its pKa value would suggest (96percent; entry 4). Eventually, all reactions gave high yields when allowed to reach full conversion (80-95percent yield of 28 after 24 to 72 hours), showing that the acid catalyst only influences the initiation rate. Scandium (II I) triflate, a Lewis acid, was also found to be competent (69percent; entry 8). Different commercial peroxyketal solutions were evaluated using methane sulfonic acid as a standard catalyst of medium reactivity. 2 (Trigonox® D; 50percent weight) proved to be less efficient than 1 (45percent, entry 3), giving 1 0percent of product 28 after one hour and 76percent after 48 hours (entry 1 1 ). 3 (Trigonox® 301 ; 41 percent weight) showed low conversion after two days of reaction (8percent, entry 15). 4 (Luperox® DHD-9, 32percent weight) was found to be slightly more reactive than 3, giving 12percent product after 48 hours (entry 16). Based on the observation of this strong influence of the peroxyketal structure on its reactivity, the inventors evaluated a series of structurally different peroxides. The effect of the group X of Formula (I) is shown by compounds 11a and 11 b. 11 b proved to be less reactive than 1 (21 percent, entry 9) while 11a was more efficient, giving 47percent of 28 after one hour (entry 10). Aromatic substituents around the peroxide moiety can have significant effects: 5 is more effective than 2 (20percent, entry 12 compared to entry 1 1 ), while 6 was much less efficient (33percent after 48 h, entry 13) 9 was found to be slightly more reactive than 1 (50percent, entry 17) while 10 was the most efficient of the structures evaluated, giving 74percent of 28 after one hour of reaction (entry 18).
88%
With tribromo-isocyanuric acid In ethyl acetate for 6 h; Reflux; Green chemistry
General procedure: a solution of the arene (2.0 mmol) and TBCA (0.25 g, 0.68 mmol) in EtOAc (20 mL) was refluxed for 6 h with stirring. At the end of the reaction, the precipitated cyanuric acid was then separated by filtration and the filtrate was evaporated to dryness under reduced pressure. The residue was passed through a short chromatographic column (SiO2, eluted with 15:1 hexane–ethyl acetate) to give the purified products.
Reference:
[1] Green Chemistry, 2011, vol. 13, # 4, p. 928 - 933
[2] Organic Letters, 2016, vol. 18, # 19, p. 4944 - 4947
[3] Patent: WO2017/108761, 2017, A1, . Location in patent: Page/Page column 15-18
[4] Advanced Synthesis and Catalysis, 2018, vol. 360, # 21, p. 4197 - 4204
[5] Tetrahedron Letters, 2015, vol. 56, # 49, p. 6843 - 6845
[6] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 228 - 229
[7] Synthetic Communications, 1999, vol. 29, # 5, p. 763 - 766
[8] Chemische Berichte, 1948, vol. 81, p. 368,371
[9] Journal of Organic Chemistry, 1949, vol. 14, p. 470,472
[10] Journal of the American Chemical Society, 1947, vol. 69, p. 234
[11] Chemische Berichte, 1948, vol. 81, p. 368,371
[12] Journal of Organic Chemistry, 1949, vol. 14, p. 470,472
[13] Journal of the American Chemical Society, 1947, vol. 69, p. 234
[14] Chemische Berichte, 1948, vol. 81, p. 368,371
[15] Journal of Organic Chemistry, 1949, vol. 14, p. 470,472
[16] Journal of the American Chemical Society, 1947, vol. 69, p. 234
[17] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
[18] Journal of the American Chemical Society, 1948, vol. 70, p. 895
[19] Justus Liebigs Annalen der Chemie, 1944, vol. 555, p. 133,137,144
[20] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
[21] Journal of the American Chemical Society, 1948, vol. 70, p. 895
[22] Justus Liebigs Annalen der Chemie, 1944, vol. 555, p. 133,137,144
[23] Chemische Berichte, 1948, vol. 81, p. 368,371
[24] Journal of Organic Chemistry, 1949, vol. 14, p. 470,472
[25] Journal of the American Chemical Society, 1947, vol. 69, p. 234
[26] Journal of the Chemical Society, 1961, p. 1291 - 1297
[27] Journal of the American Chemical Society, 1962, vol. 84, p. 3959 - 3962
[28] Tetrahedron Letters, 1984, vol. 25, # 31, p. 3369 - 3372
[29] Chemical Papers, 2013, vol. 67, # 7, p. 751 - 758
[30] Journal of Fluorescence, 2014, vol. 24, # 2, p. 523 - 531
[31] Journal of the Chinese Chemical Society, 2016, vol. 63, # 4, p. 368 - 375
4
[ 86-73-7 ]
[ 1133-80-8 ]
[ 1940-57-4 ]
Yield
Reaction Conditions
Operation in experiment
41 %Chromat.
With N-Bromosuccinimide In acetonitrile at 20℃; for 19 h;
General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
Reference:
[1] Journal of the American Chemical Society, 1975, vol. 97, # 9, p. 2438 - 2449
6
[ 486-25-9 ]
[ 1940-57-4 ]
Reference:
[1] Dyes and Pigments, 2013, vol. 96, # 3, p. 642 - 652
[2] Chemical Biology and Drug Design, 2018, vol. 91, # 6, p. 1078 - 1086
7
[ 506-96-7 ]
[ 1689-64-1 ]
[ 1940-57-4 ]
Reference:
[1] Journal of the American Chemical Society, 1933, vol. 55, p. 2135,2136
[2] Journal of the American Chemical Society, 1940, vol. 62, p. 2687,2689
8
[ 31859-93-5 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1910, vol. 43, p. 2492
[2] , 1967, vol. 3, p. 677 - 679[3] Zhurnal Organicheskoi Khimii, 1967, vol. 3, # 4, p. 709 - 711
9
[ 6630-65-5 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1910, vol. 43, p. 2492
10
[ 25017-68-9 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1926, vol. 59, p. 640
Reference:
[1] Chemische Berichte, 1948, vol. 81, p. 368,371
13
[ 86-73-7 ]
[ 77-48-5 ]
[ 1940-57-4 ]
Reference:
[1] Anales de la Asociacion Quimica Argentina (1921-2001), 1949, vol. 37, p. 263,266[2] Anales de la Asociacion Quimica Argentina (1921-2001), 1950, vol. 38, p. 5,10
14
[ 861373-58-2 ]
[ 467-69-6 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1926, vol. 59, p. 640
15
[ 86-73-7 ]
[ 58402-65-6 ]
[ 1940-57-4 ]
Reference:
[1] Anales de la Asociacion Quimica Argentina (1921-2001), 1949, vol. 37, p. 263,266[2] Anales de la Asociacion Quimica Argentina (1921-2001), 1950, vol. 38, p. 5,10
16
[ 56-23-5 ]
[ 128-08-5 ]
[ 86-73-7 ]
[ 1940-57-4 ]
Reference:
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 895
[3] Justus Liebigs Annalen der Chemie, 1944, vol. 555, p. 133,137,144
17
[ 75-15-0 ]
[ 86-73-7 ]
[ 7726-95-6 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1948, vol. 81, p. 368,371
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 234
18
[ 56-23-5 ]
[ 86-73-7 ]
[ 7726-95-6 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1948, vol. 81, p. 368,371
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 234
19
[ 86-73-7 ]
[ 67-66-3 ]
[ 7726-95-6 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1948, vol. 81, p. 368,371
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 234
20
[ 128-08-5 ]
[ 86-73-7 ]
[ 7726-95-6 ]
[ 71-43-2 ]
[ 1940-57-4 ]
Reference:
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 895
[3] Justus Liebigs Annalen der Chemie, 1944, vol. 555, p. 133,137,144
21
[ 1689-64-1 ]
[ 10035-10-6 ]
[ 1940-57-4 ]
Reference:
[1] Journal of Organic Chemistry, 1948, vol. 13, p. 339,342
22
[ 1689-64-1 ]
[ 10035-10-6 ]
[ 64-19-7 ]
[ 1940-57-4 ]
Reference:
[1] Journal of Organic Chemistry, 1948, vol. 13, p. 339,342
23
[ 56-23-5 ]
[ 86-73-7 ]
[ 127822-14-4 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1948, vol. 81, p. 368,371
24
[ 31859-93-5 ]
[ 10035-10-6 ]
[ 64-19-7 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1910, vol. 43, p. 2492
25
[ 2868-70-4 ]
[ 10035-10-6 ]
[ 64-19-7 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1926, vol. 59, p. 640
26
[ 861373-58-2 ]
[ 10035-10-6 ]
[ 64-19-7 ]
[ 467-69-6 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1926, vol. 59, p. 640
27
[ 10035-10-6 ]
[ 64-19-7 ]
[ 467-69-6 ]
[ 1940-57-4 ]
Reference:
[1] Chemische Berichte, 1926, vol. 59, p. 640
With ethanol; benzene zuletzt Behandeln bei Siedetemperatur, und Erhitzen des nach der Hydrolyse (wss. Kalilauge) erhaltenen Reaktionsprodukts auf 200grad;
With N-Bromosuccinimide; dibenzoyl peroxide In Diethyl carbonate for 0.333333h; Reflux; Microwave irradiation;
96%
With N-Bromosuccinimide; 1,1-bis(tert-butylperoxy)cyclohexane; nitric acid In dichloromethane at 20℃; for 1h; Schlenk technique; Inert atmosphere;
96%
With N-Bromosuccinimide; 1,1-bis(tert-butylperoxy)cyclohexane; nitric acid In dichloromethane at 20℃; for 1h; Schlenk technique; Inert atmosphere;
1 Radical bromination of benzylic compounds
The inventors selected the radical bromination of fluorene 27 by N- bromosuccinimide (NBS) at room temperature as a benchmark reaction to evaluate their inventive initiator system (Scheme 4). NBS (1.1 equiv.) (0075) Scheme 5: Room temperature Wohl-Ziegler bromination of fluorene. All reactions were performed according to the following procedure: In an oven- dried Schlenk flask fluorene 27 (83 mg, 0.5 mmol, 1 eq) and N-bromosuccinimide (98 mg, 0.55 mmol, 1 .1 eq) were dissolved in dichloromethane (5 ml). The desired peroxide (0.025 mmol, 5 mol %) was introduced and the resulting mixture was degassed by the freeze-pump-thaw method (3 cycles). After warming to room temperature, the acid catalyst was added under a stream of argon and after the desired reaction time, the reaction mixture was quenched with NEt3 (250 μΙ_), CH2Br2 (0.5 mmol) was added as a standard for analytical purposes only and an aliquot taken for direct H NMR analysis. Yield was determined by integrating a reference peak of 28 (5.9 ppm, s, 1 H; determined from an authentic sample) relative to the peak of CH2Br2. The results of the reactions are detailed in (Table 1). The bromination proceeded efficiently using a commercial solution of peroxyketal 1 (Trigonox 22, 50% weight in mineral oil) in combination with different Bronsted acids. Control experiments confirmed the requirement for both acid and peroxide, no conversion being observed after 24 hours if either one of these components was omitted. A clear trend following the pKa value of the acid catalyst can be seen : stronger acids give faster conversion. Sulfuric and para-toluene sulfonic acid have similar behaviour with 72% and 67% of 28 after one hour, respectively (entries 1 and 2). Methane sulfonic acid gave a slightly lower yield (45%; entry 3) while acids weaker than trifluoroacetic acid (22%, entry 5) or trichloroacetic acid (1 8%, entry 6) failed to give any conversion (entry 7). Nitric acid is more efficient than its pKa value would suggest (96%; entry 4). Eventually, all reactions gave high yields when allowed to reach full conversion (80-95% yield of 28 after 24 to 72 hours), showing that the acid catalyst only influences the initiation rate. Scandium (II I) triflate, a Lewis acid, was also found to be competent (69%; entry 8). Different commercial peroxyketal solutions were evaluated using methane sulfonic acid as a standard catalyst of medium reactivity. 2 (Trigonox D; 50% weight) proved to be less efficient than 1 (45%, entry 3), giving 1 0% of product 28 after one hour and 76% after 48 hours (entry 1 1 ). 3 (Trigonox 301 ; 41 % weight) showed low conversion after two days of reaction (8%, entry 15). 4 (Luperox DHD-9, 32% weight) was found to be slightly more reactive than 3, giving 12% product after 48 hours (entry 16). Based on the observation of this strong influence of the peroxyketal structure on its reactivity, the inventors evaluated a series of structurally different peroxides. The effect of the group X of Formula (I) is shown by compounds 11a and 11 b. 11 b proved to be less reactive than 1 (21 %, entry 9) while 11a was more efficient, giving 47% of 28 after one hour (entry 10). Aromatic substituents around the peroxide moiety can have significant effects: 5 is more effective than 2 (20%, entry 12 compared to entry 1 1 ), while 6 was much less efficient (33% after 48 h, entry 13) 9 was found to be slightly more reactive than 1 (50%, entry 17) while 10 was the most efficient of the structures evaluated, giving 74% of 28 after one hour of reaction (entry 18).
90%
With N-Bromosuccinimide; trityl tetrafluoroborate In dichloromethane; benzene at 20℃; Irradiation; Inert atmosphere; chemoselective reaction;
88%
With 1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione In ethyl acetate for 6h; Reflux; Green chemistry;
General procedure for benzylic bromination of arenes with TBCA
General procedure: a solution of the arene (2.0 mmol) and TBCA (0.25 g, 0.68 mmol) in EtOAc (20 mL) was refluxed for 6 h with stirring. At the end of the reaction, the precipitated cyanuric acid was then separated by filtration and the filtrate was evaporated to dryness under reduced pressure. The residue was passed through a short chromatographic column (SiO2, eluted with 15:1 hexane-ethyl acetate) to give the purified products.
73%
With pyridinium bromochromate In acetic acid for 3h; water-bath;
64%
With BIBC In acetic acid for 4h; Heating;
With bromine Irradiation.Einwirkung von Sonnenlicht oder UV-Licht bei Siedetemperatur;
With tetrachloromethane; bromine Irradiation.Einwirkung von Sonnenlicht oder UV-Licht bei Siedetemperatur;
With chloroform; bromine Irradiation.Einwirkung von Sonnenlicht oder UV-Licht bei Siedetemperatur;
With tetrachloromethane; N-Bromosuccinimide
With N-Bromosuccinimide; benzene
With carbon disulfide; bromine Einwirkung von Sonnenlicht oder UV-Licht;
(bromination);
With bromine Irradiation;
88 % Spectr.
With hexabromocyclopenta-1,3-diene In acetonitrile for 186h; Heating;
With bromine In tetrachloromethane Irradiation;
With bromine In tetrachloromethane UV-irradiation;
With bromine In tetrachloromethane UV-irradiation;
3 9-Azido-9H-fluorene (2j)
9-Bromo-9H-fluorene (1.00 g, 4.08 mmol) was dissolved in acetone (7 mL). To this was added a solution of NaN3 (1.33 g, 20.4 mmol) in H2O (3 mL). The resulting solution was stirred overnight. Acetone was removed by concentration under reduced pressure. The resulting aqueous mixture was extracted with CH2Cl2 (2×15 mL), and the organic layers were combined, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The resulting solid residue was purified by silica gel flash chromatography, eluting with hexanes, to give azide 2j as a white solid (0.74 g, 3.57 mmol, 87% yield).Data for 2j: 1H NMR (400 MHz, CDCl3) δ=7.74 (d, 2H, J=7.4 Hz, Ar.), 7.66 (d, 2H, J=7.4 Hz, Ar.), 7.47 (t, 2H, J=7.4 Hz, Ar.), 7.39 (t, 2H, J=7.4 Hz, Ar.), 5.23 (s, 1H, CHN3). 13C NMR (100 MHz, CDCl3) δ=141.6, 140.7, 129.4, 127.9, 125.2, 120.3, 64.3.
87%
With sodium azide In water; acetone
1
9-Bromo-9H-fluorene (1.00 g, 4.08 mmol) was dissolved in acetone (7 mL). To this was added a solution of NaN3 (1.33 g, 20.4 mmol) in H2O (3 mL). The resulting solution was stirred overnight. Acetone was removed by concentration under reduced pressure. The resulting aqueous mixture was extracted with CH2Cl2 (2*15 mL), and the organic layers were combined, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The resulting solid residue was purified by silica gel flash chromatography, eluting with hexanes, to give azide 2 as a white solid (0.74 g, 3.57 mmol, 87% yield). Data for 2: 1H NMR (400 MHz, CDCl3) δ=7.74 (d, 2H, J=7.4 Hz, Ar.), 7.66 (d, 2H, J=7.4 Hz, Ar.), 7.47 (t, 2H, J=7.4 Hz, Ar.), 7.39 (t, 2H, J=7.4 Hz, Ar.), 5.23 (s, 1H, CHN3). 13C NMR (100 MHz, CDCl3) δ=141.6, 140.7, 129.4, 127.9, 125.2, 120.3, 64.3.
67%
With sodium azide In water; acetone at 20℃;
66%
With sodium azide In acetone at 20℃; Inert atmosphere;
With methanol; sodium azide
With sodium azide; perchloric acid In water at 25℃; pH 6-7;
55 Diethyl 2-(9H-Fluoren-9-yl)malonate
EXAMPLE 55 Diethyl 2-(9H-Fluoren-9-yl)malonate 16.3 g (0.051 M) of ethyl malonate in 300 ml of toluene are introduced into a 500 ml reactor under a nitrogen atmosphere. 4.6 g (0.056 M) of 60% NaH in oil are added portionwise at room temperature. The temperature rises to 32° C. The reaction medium is then maintained at 80° C. for 15 minutes. A white broth forms. A solution of 25 g (0.051 M) of 9-bromofluorene in 60 ml of toluene is added at this temperature. The mixture is left to react for 8 h at 80° C. 100 ml of ice-cold water are added at a temperature below 20° C. The organic phase is separated out after settling has taken place and washed with water. It is dried over Na2SO4 and concentrated to dryness. An oil (31 g) which crystallizes is obtained. Recrystallization is carried out in 160 ml of diisopropyl ether to give 23.7 g of a product melting at 71° C. (70% yield). NMR (CDCl3): 1.0 (3H, t, J=7.1 Hz); 3.9 (1H, d, J=5.5 Hz); 4.0 (2H, q, J=7.1 Hz); 4.6 (1H, d, J=5.5 Hz); 7.1-7.3 (4H, m); 7.5 (2H, d, J=7.4 Hz); 7.7 (2H, d, J=7.4 Hz).
62%
With sodium carbonate In N,N-dimethyl-formamide for 24h; Reflux;
51 (2R*,4S*)-2-Benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine
(2R*,4S*)-2-Benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine 200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 25a with 138 mg (0.561 mmol) of 9-bromofluorene and 155 mg (1.12 mmol) of potassium carbonate in 2.5 ml of acetone. The title compound (131 mg, 47%) is obtained as oil. TLC: toluene/ethyl acetate (1:1) Rf =0.43; FD-MS: M+ =591.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;
36.iii
(iii) Synthesis of 1-(9H-fluoren-9-yl)piperazine14.7 g (60 mmol) of 9-bromofluorene, 6.85 g (60 mmol) of 1-formylpiperazine, and 8.29 g (60 mmol) of potassium carbonate were stirred in 70 ml of DMF at room temperature for 4 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. IPE was added to crystallize the obtained crude product, thus giving 10.8 g of 4-(9H-fluoren-9-yl)piperazin-1-carboxaldehyde (yield: 65%).1H-NMR (CDCl3) δ: 2.54 (2H, t, J=5.1 Hz), 2.69 (2H, t, J=5.1 Hz), 3.30 (2H, t, J=5.1 Hz), 3.54 (2H, t, J=5.1 Hz), 4.86 (1H, s), 7.25-7.42 (4H, m), 7.57-7.70 (4H, m), 7.97 (1H, s).Further, 5.01 g (18 mmol) of 4-(9H-fluoren-9-yl)piperazine-1-carboxaldehyde, and 6 ml of 6N hydrochloric acid were stirred in 24 ml of 1,4-dioxane at 80° C. for 6 hours. The reaction mixture was concentrated and then neutralized with aqueous ammonia. Water was added and the mixture was extracted with ethyl acetate. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Ethyl acetate-IPE was added to crystallize the obtained crude product, thus giving 1-(9H-fluoren-9-yl)piperazine (yield: 42%).1H-NMR (CDCl3) δ: 1.53 (1H, bs), 2.58-2.62 (4H, m), 2.81-2.86 (4H, m), 4.80 (1H, s), 7.23-7.40 (4H, m), 7.63-7.70 (4H, m).
With 18-crown-6 ether; potassium carbonate In acetonitrile for 18h; Reflux;
(R)-2-(9H-fluoren-9-ylamino)butan-1-ol (54)
To a solution of 0.53 ml (5.61 mmol) 1 in 50 ml dry acetonitrile 1.08 g (7.85 mmol) anhydrous K2CO3 and 2.89 g (11.78 mmol) 51 were added. Few crystals of 18-crown-6 were added and resulting suspension was refluxed for 18 h. The reaction was monitored by TLC (hexane:Et2O = 1:1) and the solvent was evaporated in vacuo. To the rest was added water and extracted with Et2O. The organic layer was separated, dried over K2CO3, filtered and volatile was removed in vacuo to afford the crude product. It was purified by column chromatography (70 g silica gel; a) hexane:MTBE = 5:1, b) hexane:MTBE = 2:1) to give 0.91 g (64%) of 54 as white crystals.
Stage #1: 2-propanethiol With sodium methylate for 0.5h; Cooling with ice;
Stage #2: 9H-fluoren-9-yl bromide at 78℃; for 1h; Inert atmosphere;
45%
Stage #1: 2-propanethiol With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; Inert atmosphere;
Stage #2: 9H-fluoren-9-yl bromide In tetrahydrofuran; water at 20℃; Inert atmosphere;
37%
Stage #1: 2-propanethiol With sodium hydroxide In tetrahydrofuran; water Inert atmosphere;
Stage #2: 9H-fluoren-9-yl bromide In tetrahydrofuran; water for 21h; Inert atmosphere;
3
Comparative Example 3Synthesis of 1-fluorenyl-1-azabicyclo[2.2.2]octanium bromide {a photobase generator represented by chemical formula (H3)}; In 250 g of toluene was dissolved 2.4 g of 9-bromofluorene (Tokyo Chemical Industry Co., Ltd.), and 1.2 g of quinuclidine (Aldrich) was added thereto. After a reaction was performed at room temperature (about 25° C.) for 18 hours, the formed solid was collected by filtration, so that 3.0 g of a photobase generator (H3) for comparison (white solid) was obtained. As a result of an analysis by 1H-NMR {300 MHz, DMSO-d6, δ (ppm): 8.0 (d, 2H), 7.9 (d, 2H), 7.6 (t, 2H), 7.4 (t, 2H), 5.7 (s, 1H), 3.5 (t, 6H), 2.0 (m, 1H), 1.9-1.85 (m, 6H)}, it was confirmed that this white solid was 1-fluorenyl-1-azabicyclo[2.2.2]octanium bromide.
With zinc(II) chloride In carbon disulfide for 48h; Reflux;
14 Synthesis of 9-bromo-10-(9H-fluoren-9-yl)anthracene (8)
9-Bromoanthracene (0.33 g, 1.28 mmol), ZnCl2 (0.8 g, 5.88 mmol), and the 9-bromo-9H-fluorene (0.5 g, 2.04 mmol) were stirred in CS2 (12 mL) and refluxed for 48 h. After the reaction was cooled to room temperature and the solvent was removed by distillation, the residue was extracted with methylene chloride (3 * 50 mL) and filtered to remove excess ZnCl2. The combined organic layer was washed with brine for three times and dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated to provide a crude product which was purified by recrystallization from petroleum ether to afford compound 8 as light yellow crystal 0.32 g (60%), m.p: 211.5-212.7 °C. IR (KBr, cm-1): 3080, 3038, 1622, 1442, 1341, 932, 788, 743. 1H NMR (500 Hz, CDCl3): δ 8.74-8.72 (m, 2H), 8.51-8.49 (m, 1H), 8.01-8.00 (d, J = 7.5, 2H), 7.71-7.69 (m, 2H), 7.46-7.43 (t, J = 7.5 Hz, 2H), 7.37-7.34 (m, 1H), 7.19-7.16 (m, 2H), 7.06-7.04 (dd, J = 1 Hz, 7 Hz, 2H), 6.86-6.89 (m, 1H), 6.70-6.68 (m, 1H), 6.50 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 148.8, 140.1, 132.7, 131.5, 129.9, 129.7, 129.1, 128.9, 127.5, 127.2, 126.8, 126.3, 126.3, 126.1, 126.0, 125.4, 125.3, 124.4, 124.3, 120.6, 48.9. MS (EI): m/z 420.4. Anal. Calcd for C27H17Br: C 76.97, H 4.07%. Found: C 76.82, H 3.88%.
(9H-fluoren-9-yl)tri(pyridin-2-yl)phosphonium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
In N,N-dimethyl-formamide at 150℃; for 1h; Inert atmosphere;
Quaternization of tris(2-pyridyl)phosphine (1) with 9-bromo-9H-fluorene and reaction ofresulting phosphonium salt 2h with alkali
A mixture of tris(2-pyridyl)phosphine (1) (133 mg, 0.5 mmol), 9-bromo-9H-fluorene (123 mg,0.5 mmol) and DMF (3 mL) was stirred at 150 for 1 h. The solvent was then removed invacuo. The residue obtained was washed two times with Et2O (2 × 1 mL), reprecipitated fromCH2Cl2 into Et2O and dried in vacuo to give 166 mg (65%) of salt 2h.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
methyl 2-(9H-fluoren-9-yl)-3,3,3-trifluoro-2-hydroxypropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
diethyl 2-(9H-fluoren-9-yl)-2-hydroxymalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With Tetrakis(dimethylamino)ethylen; sodium sulfate; In N,N-dimethyl-formamide; at -20 - 20℃; for 3h;
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
With sodium sulfate; triethylamine In N,N-dimethyl-formamide at -20 - 20℃; for 24h;
3.4. Reactivity of 9-Bromofluorene and 4-Cyanobenzaldehyde in the Presence of Triethylamine
Triethylamine (150 mg, 1.2 mmol) was added to a stirred solution of fluorenyl bromide 1 (100 mg,0.5 mmol) with the 4-cyanobenzaldehyde (160 mg, 1.2 mmol) and a spatula of sodium sulfate in 4 mLof DMF, under air. The mixture was then stirred at 20 C for 1 h and warmed to room temperatureover a period of 24 h. Then 0.5 mL of water was added to quench the reaction. The solution wasextracted with dichloromethane (3 30 mL), the combined organic layers were washed with brine(3 40 mL), and dried over MgSO4. The crude product was then obtained after evaporation of the solvent under reduced pressure. Purification by silica gel chromatographic column (dichloromethane:methanol) gave the 20% of the unreacted 9-bromofluorene with 15% yield of the 4-((9H-fluoren-9-ylidene)methyl)benzo-nitrile 8c and 7% yield of the 4-(spiro(fluorene-9,20-oxiran)-30-yl)benzonitrile 5fgave the unreacted 9-bromofluorene (20%) with 4-((9H-fluoren-9-ylidene)methyl)benzonitrile 6f (15%)and 4-(spiro(fluorene-9,20-oxiran)-30-yl)benzonitrile 5f (7%).
With Tetrakis(dimethylamino)ethylen; sodium sulfate In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
3.2. Typical Procedure
General procedure: The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at 20 C to a vigorouslystirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol,3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediatelydeveloped with the formation of a fine white precipitate. The mixture was then stirred at 20 C for 1 hand warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench thereaction. The solution was extracted with dichloromethane (3 30 mL), the combined organic layerswere washed with brine (3 40 mL), and dried over MgSO4. The crude product was then obtainedafter evaporation of the solvent under reduced pressure. Purification by silica gel chromatographiccolumn (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.
(E)-(1,3-diphenylallyl)(9H-fluoren-9-yl)sulfide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With tetra-(n-butyl)ammonium iodide; sodium thiosulfate In water at 80℃; for 5h; Sealed tube;
27 Synthesis of (E)-(1,3-diphenylallyl)(9H-fluoren-9-yl)sulfide
Weigh 0.3 mmol of (E)-1,3-diphenylprop-2-enyl-1-ol (0.0631 g), 0.6 mmol 9-bromofluorene (0.1471 g), 0.72 mmol sodium thiosulfate (0.1138 g), 0.06 mmol of tetrabutylammonium iodide (0.0222 g), in 20mL of the tube reaction tube, add 1mL of water as solvent, seal closed, 80 , stirring reaction for 5 hours; After the completion of the reaction, the reaction solution was subjected to ethyl acetate, dried over anhydrous sodium sulfate and separated by column chromatography (column chromatography, silica gel: 300-400 mesh, the mobile phase consisted of ethyl acetate (A) and petroleum ether (B), and the mobile phase change procedure (A: B) was 1: 20 → 1: 6) to give 0.0854 g of the reaction product.
With tri-tert-butyl phosphine; potassium <i>tert</i>-butylate; palladium diacetate In toluene at 80℃; for 6h; Inert atmosphere;
1.3 Example 1: Synthesis of Compound H-1
3, under nitrogen, the product prepared in step 2 and bromofluorene were mixed in a 1: 1 molar ratio,After dissolving with toluene,Potassium t-butoxide, tri-t-butylphosphine and palladium acetate were added as a catalyst. The reaction was heated to 80 ° C and allowed to react for 6 hours before cooling to room temperature. The reaction was filtered, the filtrate was washed with dichloromethane then the solvent was evaporated to dryness. The crude product is repeatedly washed with methanol and acetone and the product is obtained after purification by column chromatography. Yield 45%
With tri-tert-butyl phosphine; potassium <i>tert</i>-butylate; palladium diacetate In toluene at 80℃; for 6h; Inert atmosphere;
2.3 Example 2: Synthesis of Compound H-2
3, under nitrogen, the product prepared in step 2 and bromofluorene were mixed in a 1: 1 molar ratio,After being dissolved with toluene, potassium tert-butoxide, tri-tert-butylphosphine and palladium acetate were added as a catalyst,The reaction was heated to 80 ° C and allowed to cool to room temperature after 6 hours of reaction. The reaction was filtered,The filtrate was washed with dichloromethane and then the solvent was evaporated to dryness.The crude product is repeatedly washed with methanol and acetone and the product is obtained after purification by column chromatography. Yield 41%.
With sodium acetate In isopropyl alcohol for 1h; Reflux;
N-(9H-fluoren)-4-tert-butylaniline (7c)
The title compound was synthesized according to the reported method.S7 To a solution of 9-bromofluorene (490 mg, 2.00 mmol) in 2-propanol (5.0 mL) was added 4-tert-butylaniline (358mg, 2.40 mmol) and sodium acetate (213 mg, 2.60 mmol). After the mixture was refluxed for 1 h,the resulting hot white suspension was filtered. The filtrate was cooled to room temperature to affordwhite precipitate, which was collected by filtration. 378 mg (60%) of the title compound wasobtained as a colorless prism;
With potassium hydroxide In methanol; dimethyl sulfoxide for 0.5h;
3 [Preparation Example 3] Synthesis of Core3
2,9-dibromo-9H-fluorene (50g, 154.31mmol) and 9-bromo-9H-fluorene (37.8g, 154.31mmol) KOH were dissolved in a solvent mixed with DMSO : MeOH = 8 : 2 for 30 minutes. stirred for a while. After adding acetic acid and stirring for 10 minutes, the reactant was poured into water. At this time, the resulting precipitate was filtered under reduced pressure, and then recrystallized using Benzene and Ether to obtain 48 g of Core3 (yield 76%)
With tris[2-phenylpyridinato-C2,N]iridium(III) In acetonitrile at 20℃; for 48h; Inert atmosphere; Sealed tube; Irradiation;
Photoredox-Catalyzed Ring-Opening Reaction Between CyclicEthers and Substituted Benzyl Bromides; General Procedures
General procedure: Procedure A: THF (205 L, 2.5 mmol, 5 equiv) and CH3CN (5 mL) wereadded to 1 (0.5 mmol), ZnBr2 (56.3 mg, 0.25 mmol, 0.5 equiv), NaBr(23.3 g, 0.225 mmol, 0.45 equiv), and Ir(ppy)3 (1.5 mg, 2.5 mol, 0.5mol%) in a bulb under N2 atmosphere and the bulb was sealed. Themixture was stirred for 24 h at rt under blue LEDs. After completion ofthe reaction, the mixture was concentrated in vacuo. The product waspurified by flash column chromatography (PE) to give 3.Procedure B: THF (2.5 mL), CH3CN (2.5 mL), and 1 (0.5 mmol) wereadded to Ir(ppy)3 (3 mg, 5 mol, 1 mol%) in a bulb under N2 atmosphereand the bulb was sealed. The mixture was stirred for 48 h at rtunder blue LEDs. After completion of the reaction, the mixture wasconcentrated in vacuo. The product was purified by flash columnchromatography (PE/EtOAc 100:1) to give 3.Slight changes from Procedure A and Procedure B for some substratesare shown in Scheme 2.
With potassium carbonate In acetonitrile at 20℃; for 16h;
1.1 Step 3
General procedure: Final amine compounds were obtained by nucleophilic substitution reaction of 9-bromo-9 H- fluorene (1 equivalent) with the primary amino group of the product obtained in Step 2 (1 equivalent). These reactions were carried out in the presence of potassium carbonate (2 equivalents) in acetonitrile for 16 h at room temperature. The final product was purified by extraction (water/ethyl acetate) and flash column chromatography using a dichloromethane and methanol solvent mixture (isocratic or gradient system).
Stage #1: ethyl N-diphenylmethylene glycine; 9H-fluoren-9-yl bromide With potassium hydroxide In dimethyl sulfoxide at 10℃; for 0.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water; dimethyl sulfoxide for 0.25h;
Intermediate 4.2a: ethyl 2-amino-2-(9/-/-fluoren-9-yl)acetate
[00576] To a stirred solution of ethyl 2-(benzhydrylideneamino)acetate (3 g, 11.2 mmol, CAS: 69555-14-2) in DMSO (6 ml_) at 10°C was added potassium hydroxide (1.9 g, 33.7 mmol) and 9-bromo-9/-/-fluorene (2.8 g, 11.2 mmol, CAS: 1940-57-4) and the reaction mixture stirred at 10°C for 30 min. The reaction mixture was poured into HCI (2 M aqueous; 28 ml_, 56.1 mmol) and tetrahydrofuran (5 ml_) at rt and the reaction mixture stirred for 15 min. The reaction mixture was diluted with water and washed with EtOAc. The aqueous phase was basified with saturated aqueous Na2SO4 and the crude product extracted into EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound (1.150 g) which was used without further purification. LCMS (Method 2): 0.87 min, 268.1 [M+H]+
Stage #1: ethyl N-diphenylmethylene glycine; 9H-fluoren-9-yl bromide With potassium hydroxide In dimethyl sulfoxide at 10℃; for 0.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water; dimethyl sulfoxide for 0.25h;
Intermediate 4.2a: ethyl 2-amino-2-(9/-/-fluoren-9-yl)acetate
[00576] To a stirred solution of ethyl 2-(benzhydrylideneamino)acetate (3 g, 11.2 mmol, CAS: 69555-14-2) in DMSO (6 ml_) at 10°C was added potassium hydroxide (1.9 g, 33.7 mmol) and 9-bromo-9/-/-fluorene (2.8 g, 11.2 mmol, CAS: 1940-57-4) and the reaction mixture stirred at 10°C for 30 min. The reaction mixture was poured into HCI (2 M aqueous; 28 ml_, 56.1 mmol) and tetrahydrofuran (5 ml_) at rt and the reaction mixture stirred for 15 min. The reaction mixture was diluted with water and washed with EtOAc. The aqueous phase was basified with saturated aqueous Na2SO4 and the crude product extracted into EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound (1.150 g) which was used without further purification. LCMS (Method 2): 0.87 min, 268.1 [M+H]+
With 3,5-dichloro-2-pyridone; palladium diacetate; anhydrous silver carbonate; N-acetylglycine In 1,2-dichloro-ethane at 120℃; for 24h; regioselective reaction;
Stage #1: malononitrile With selenium(IV) dioxide In N,N-dimethyl-formamide for 0.5h;
Stage #2: 9H-fluoren-9-yl bromide In N,N-dimethyl-formamide at 25℃; for 5h;
General Procedure for the selenocyanation of bromo compounds
General procedure: A mixture of selenium dioxide (3 mmol, 3 equiv.) andmalononitrile (3 mmol, 3 equiv.) in DMF (1 mL) was stirred for30 min. Then bromo-compound 1 was added (1 mmol, 1 equiv.)After stirring at 24 °C for 5 hours, 10 mL of water was added. Theaqueous layer was extracted with dichloromethane (3 x 10 mL).Combined organic layers were dried over sodium sulfate thenfiltered off. The solvents were evaporated under vacuum and thecrude product was purified by column chromatography onsilicagel with eluant (0% to 40% dichloromethane in petroleumether) to give pure product 2. The same procedure was used for selenocyanation of chlorides 3under 10 h of stirring at 80 °C.
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere; Large scale;
Large scale synthesis (20 mmol) of N-Fluorenyl Tryptamine
To a flame dried 250 mL round bottom flask was added tryptamine (3.2 g, 20 mmol), 9-bromofluorene (5.88 g, 24mmol, 1.2 equiv), K2CO3 (5.53 g, 40 mmol, 2 equiv), and dry acetonitrile (0.2 M, 100 mL). The resulting mixturewas stirred at room temperature under inert atmosphere for 31 hours. The reaction mixture was then diluted withwater (150 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with water,brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue wasdirectly purified by flash chromatography on silica gel (using a gradient eluent from EtOAc/hexanes 10:90 v/v toEtOAc/hexanes 20:80 v/v to EtOAc) to obtain compound 1a as a white solid in 84% yield (5.4 g).
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere;
N-9-Fluorenyltryptamines 1; General Procedure A
General procedure: To a flame-dried round-bottom flask was added the tryptamine (1.0equiv), 9-bromofluorene (1.2 equiv), K2CO3 (2 equiv), and dry MeCN(0.2 M). The mixture was stirred at room temperature under inert atmosphereuntil the tryptamine was completely consumed. The crudereaction mixture was then diluted with water (10 mL) and extractedwith EtOAc (3 × 10 mL). The combined organic phases were washedwith water and brine, and dried over anhydrous Na2SO4. The solventwas removed under reduced pressure and the residue was purified bysilica gel chromatography (gradient from EtOAc/hexanes 10:90 v/v toEtOAc/hexanes 20:80 v/v to EtOAc).
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere;
N-9-Fluorenyltryptamines 1; General Procedure A
General procedure: To a flame-dried round-bottom flask was added the tryptamine (1.0equiv), 9-bromofluorene (1.2 equiv), K2CO3 (2 equiv), and dry MeCN(0.2 M). The mixture was stirred at room temperature under inert atmosphereuntil the tryptamine was completely consumed. The crudereaction mixture was then diluted with water (10 mL) and extractedwith EtOAc (3 × 10 mL). The combined organic phases were washedwith water and brine, and dried over anhydrous Na2SO4. The solventwas removed under reduced pressure and the residue was purified bysilica gel chromatography (gradient from EtOAc/hexanes 10:90 v/v toEtOAc/hexanes 20:80 v/v to EtOAc).
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere;
N-9-Fluorenyltryptamines 1; General Procedure A
General procedure: To a flame-dried round-bottom flask was added the tryptamine (1.0equiv), 9-bromofluorene (1.2 equiv), K2CO3 (2 equiv), and dry MeCN(0.2 M). The mixture was stirred at room temperature under inert atmosphereuntil the tryptamine was completely consumed. The crudereaction mixture was then diluted with water (10 mL) and extractedwith EtOAc (3 × 10 mL). The combined organic phases were washedwith water and brine, and dried over anhydrous Na2SO4. The solventwas removed under reduced pressure and the residue was purified bysilica gel chromatography (gradient from EtOAc/hexanes 10:90 v/v toEtOAc/hexanes 20:80 v/v to EtOAc).
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere;
N-9-Fluorenyltryptamines 1; General Procedure A
General procedure: To a flame-dried round-bottom flask was added the tryptamine (1.0equiv), 9-bromofluorene (1.2 equiv), K2CO3 (2 equiv), and dry MeCN(0.2 M). The mixture was stirred at room temperature under inert atmosphereuntil the tryptamine was completely consumed. The crudereaction mixture was then diluted with water (10 mL) and extractedwith EtOAc (3 × 10 mL). The combined organic phases were washedwith water and brine, and dried over anhydrous Na2SO4. The solventwas removed under reduced pressure and the residue was purified bysilica gel chromatography (gradient from EtOAc/hexanes 10:90 v/v toEtOAc/hexanes 20:80 v/v to EtOAc).
With potassium carbonate In acetonitrile at 20℃; Inert atmosphere;
N-9-Fluorenyltryptamines 1; General Procedure A
General procedure: To a flame-dried round-bottom flask was added the tryptamine (1.0equiv), 9-bromofluorene (1.2 equiv), K2CO3 (2 equiv), and dry MeCN(0.2 M). The mixture was stirred at room temperature under inert atmosphereuntil the tryptamine was completely consumed. The crudereaction mixture was then diluted with water (10 mL) and extractedwith EtOAc (3 × 10 mL). The combined organic phases were washedwith water and brine, and dried over anhydrous Na2SO4. The solventwas removed under reduced pressure and the residue was purified bysilica gel chromatography (gradient from EtOAc/hexanes 10:90 v/v toEtOAc/hexanes 20:80 v/v to EtOAc).