* 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.
General procedure: In a round-bottomed flask, the substrate (1 mmol) and aqueous HBr(48percent) (1 mL) were mixed in DMSO (1 mL). The mixture was stirredat corresponding temperature for 1–4 h. After cooling to roomtemperature, the reaction was adjusted to pH 7–8 with aqueous NaOHsolution (4 M). Then the mixture was washed twice with EtOAc, andthe combined organic extracts were dried, filtered and concentratedunder reduced pressure to give bromination products.
61%
With N-Bromosuccinimide In acetonitrile at 0℃; for 0.25 h;
4-Bromo-1 H-pyrrole-2-carboxaldehyde (41). To a stirred solution of 1 H-pyrrole-2- carboxaldehyde 40 (1 g, 10.52 mmol) in CH3CN (10 mL) at 0°C was added N- bromosuccinimide (1 .872 g, 10.52 mmol) and the solution was stirred at 0°C for 15 minutes. Water was added and the resulting mixture was extracted with Et20. Organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. Crystallization of the crude mixture using cyclohexane/ethanol afforded compound 41 as white crystals (1 .125 g, 61 percent): f?f=0.22 (CH2CI2); mp: 121 -122 °C; 1 H NMR (400 MHz, [D6]DMSO): 5=7.12 (m, 1 H), 7.41 (m, 1 H), 9.48 (s, 1 H), 12.51 ppm (bs, 1 H); 13C NMR (100 MHz, [D6]DMSO): 5=97.0, 120.8, 126.5, 132.9, 179.1 ppm; IR (KBr): v=3238, 3108, 2926, 2860, 1655, 1380, 1357, 1 147, 1 104, 920, 827, 771 , 744, 598 cm 1 ; MS (ESI) m/z 173.9-175.9 [M+H]+.
55%
With N-Bromosuccinimide In tetrahydrofuran at -78℃; for 1 h;
The synthesis of an 8-bromo-substituted Western half is shown in Scheme 5. Treatment of pyrrole-2-carobxaldehyde with one molar equivalent of NBS at -78 °C gave 4-bromopyrrole-2-carboxaldehyde 17 (Anderson, J. H.; Lee, S.-F. Can. J. Chem. 1965, 43, 409-414) in 55percent yield after crystallization. This method of bromination of pyrrole-2-carboxaldehyde is superior to a reported method that uses Br2 (Anderson, J. H.; Lee, S.-F. Can. J. Chem. 1965, 43, 409-414). It should be mentioned here that careful handing of the crude product is required: the off-white solid often turns reddish (irrespective of preparation using Br2 or NBS), which complicates crystallization. Following a procedure for the synthesis of 2-(2-nitroethyl)pyrroles (Taniguchi, M. et al., J. Org. Chem. 2001, 66, 7342-7354), treatment of 17 with <n="92"/>excess nitromethane, sodium acetate and methylamine hydrochloride at room temperature for 16 h followed by reduction of the reaction mixture with NaBH4 gave 4-bromo-2-(2-nitroethyl)pyrrole (18) in variable yields (32-48percent). However, 18 was found to explode (CAUTION), which caused us to avoid handling this compound. Thus, we considered protection of the pyrrole nitrogen in 4-bromo-pyrrole-2- carboxaldehyde (17) for two purposes: (1) to render 4-bromo-2-(2-nitroethyl)pyrrole (18) as a stable compound, and (2) for efficient palladium-coupling in the latter part of the 8-ethynyl Western half synthesis. Considering the facile conditions for removal of a /j-toluenesulfonyl group coupled with the crystalline nature of 2-(2- nitroethyl)-W-/>-tosylpyrroles, λf-tosylation (Tietze, L. F. et al., Synthesis 1996, 851- 857) of compound 17 was carried out. Thus, treatment of 17 with NaH at 0 0C for 1 h followed by quenching with /?-toluenesulfonyl chloride gave 17-Ts as a pale yellow crystalline solid in 68percent yield. Following a reported procedure .for the synthesis of 2- (2-nitrovinyl)-iV-p-tosylpyrroles (Hamdan, A.; Wasley, J. W. F. Synth. Comrhun. 1985, 15, 71-74), a mixture of 17-Ts, excess nitromethane and ammonium acetate was refluxed for 3 h. The crude product was satisfactorily pure as evidenced by NMR spectroscopy and was directly used in the next step. NaBH4 reduction of the crude product in the presence of Montmorillonite KlO (Bahulayan, D. et al., J. Org. Chem. 2003, 68, 5735-5738), or silica gel (Ptaszek, M. et al., Org. Process Res. Dev. 2005, 9, 651-659) at room temperature afforded 2-(2-nitroethyl)-iV-/7-tosylpyrrole 18-Ts as a white solid in 40percent or 58percent yield, respectively. Michael addition of 18-Ts with mesityl oxide in the presence of TBAF (Battersby, A. R. et al., J. Chem. Soc, Perkin Trans. 1 1984, 2725-2732) and 3A molecular sieves gave the detosylated pyrrole- hexanone 19 in 47percent yield. The /?-toluenesulfonyl group is known to be cleaved by TBAF (Yasuhara,.A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595-596). Reduction (Ptaszek, M. et al., Org. Process Res. Dev. 2005, 9, 651-659) of 19 with excess zinc dust and HCOONH4 in THF at room temperature gave the 8-bromo Western half 20 in 45percent yield. ; 4-Bromopyrrole-2-carboxaldehyde (17). A solution of pyrrole-2- carboxaldehyde (4.75 g, 50.0 mmol) in dry THF (200 mL) was cooled to -78 0C under argon. NBS (8.90 g, 50.0 mmol) was added and the reaction mixture was stirred for 1 h at -78 0C. Hexanes and water were added and the reaction mixture was allowed to warm to 0 0C. The organic phase was extracted with hexanes and dried (Na2 SO4). Crystallization of the crude mixture using hexanes/THF afforded white crystals (4.83 g, 55percent): mp 120-121 0C [lit. 122-123 0C (Anderson, J. H.; Lee, S.-F. Can. J. Chem. 1965, 43, 409-414)]; 1H NMR δ 6.95 (m, IH), 7.12 (m, IH), 9.45 (s, IH), 9.65-9.85 (br s, IH); 13C NMR δ 99.0, 123.0, 127.0, 132.8, 179.3. Anal. Calcd for C5H4BrNO: C, 34.51; H, 2.32; N, 8.05; Found: C, 34.50; H, 2.26; N, 7.75.
54%
With N-Bromosuccinimide In tetrahydrofuran at -78℃; for 1 h;
To a 100 mL 3-neck RB flask charged with 1H-pyrrole-2-carbaldehyde (1.0 g, 10.5 mmol) in THF(20 mL) at -78°C, NBS (1.87 g, 10.53 mmol) in THF(20 mL) was addedslowly and thenthe flaskw as maintained at the same temperature for 1 h. The reaction mixture was diluted with hexane and water mixture, the organic layer was decanted. The organic layer was dried over anhydrous Na2SO4 and then concentrated at low temperature under vacuo. It was recrystallized with n-hexane to yield the title compound (1 .0 g, 54.0percent) as a pale pink solid.
53%
With N-Bromosuccinimide In tetrahydrofuran at -78℃;
1H-Pyrrole-2-carbaldehyde (20g, 210mmol) was dissolved in 250ml tetrahydrofuran and the mixture was cooled to−78°C. N-Bromosuccinimide (37g, 210mmol) was added portion-wise over 1h with stirring and the mixture was stirred for a further 6.5at−78°C. The mixture was allowed to warm to 0°C and was partitioned between water and hexane and protected from the light. The aqueous phase was extracted with cold hexane and the combined organics were washed with water, dried over anhydrous sodium sulphate and filtered. The organics were concentrated under reduced pressure until a precipitate formed. The solid was cold-filtered, washed with cold hexane and dried under vacuum to give 12.8g of 80. The filtrates were concentrated again under reduced pressure until further precipitate formed. This was collected by filtration as before and combined with the first obtained solid to give 80 (18.9g, 109mmol, 53percent yield). Purity 96percent. Stored at 4°C in the dark. 1H NMR (400MHz, CDCl3) δ ppm 6.96–6.99 (m, 1H, H-3), 7.11–7.14 (m, 1H, H-5), 9.47 (s, 1H, CHO), 9.88 (br. s., 1H, NH). UPLC/MS (3min) retention time 1.18min. LRMS: m/z 172, 174 (M−1).
51%
With N-Bromosuccinimide In tetrahydrofuran at 0℃; for 0.25 h; Inert atmosphere
4.3.5 4-Bromopyrrole-2-carboxaldehyde (13) A solution of pyrrole-2-carboxaldehyde 12 (3.80 g, 40 mmol) in dry THF (40 mL) was cooled to 0 °C under Argon. NBS (7.12 g, 40 mmol) was added and the reaction mixture stirred for 15 min before the solvent was removed in vacuo. The crude product was dried under high vacuum for 30 min before the addition of distilled water (20 mL) and the resulting suspension filtered. The resulting solid was dissolved in a minimum amount of hot ethanol/water solution (9:1) before the addition of activated charcoal and filtration through a Celite plug. Upon cooling, the product recrystallised to give 4-bromopyrrole-2-carboxaldehyde 13 (3.54 g, 51percent) as an off white solid; Mp 119-122 °C. IR (neat, cm-1) 3204, 3108, 3982, 2861, 1653, 1378, 1354, 918, 769. 1H NMR (400 MHz, Acetone-d6) δ 11.39 (1 H, s, NH), 9.52 (1 H, d, 4JHH 1.0, CHO), 7.34-7.31 (1 H, m, C5H), 7.09-7.05 (1 H, m, C3H). 13C NMR (101 MHz, Acetone-d6) δ 179.4 (s, C=O), 134.3 (s, C2), 126.8 (s, C5), 121.5 (s, C3), 98.4 (s, C4). HRMS (ESI) m/z calcd for [M+H]+ C5H4BrNO 173.9554; found 173.9553.
Reference：
[1] Organic Letters, 2015, vol. 17, # 8, p. 1822 - 1825
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7286 - 7309
[3] Journal of Chemical Research, 2014, vol. 38, # 10, p. 593 - 596
[4] Patent: WO2017/20944, 2017, A1, . Location in patent: Page/Page column 32
[5] Journal of Organic Chemistry, 2006, vol. 71, # 11, p. 4092 - 4102
[6] Patent: WO2007/64842, 2007, A2, . Location in patent: Page/Page column 89-91; 104
[7] Patent: WO2014/202528, 2014, A1, . Location in patent: Page/Page column 78
[8] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 102 - 133
[9] Tetrahedron, 2016, vol. 72, # 19, p. 2456 - 2463
[10] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9350 - 9359
[11] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 7, p. 806 - 807[12] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 7, p. 998 - 999
[13] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 235 - 252
13
[ 1003-29-8 ]
[ 33515-62-7 ]
Yield
Reaction Conditions
Operation in experiment
81%
With N-iodo-succinimide In tetrahydrofuran at -75℃; for 2.33333 h;
A solution of lH-pyrrole-2-carbaldehyde (7.0 g, 73.6 mmol) in tetrahydrofuran (45 mL) was cooled to -750C. N-iodosuccinimide (19.8 g, 88.3 mmol) was added portionwise over 20 min and the reaction mixture was then stirred for 2 h at -75 °C. Water and petroleum ether were added and the reaction mixture warmed to ambient temperature. The organic layer was separated and the aqueous phase extracted with petroleum ether. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-iodo-lH- pyrrole-2-carbaldehyde (13.2 g, 81percent) as a black solid.
Reference：
[1] Patent: WO2009/130481, 2009, A1, . Location in patent: Page/Page column 107
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4515 - 4518
14
[ 1003-29-8 ]
[ 2999-46-4 ]
[ 107407-80-7 ]
Yield
Reaction Conditions
Operation in experiment
97.3%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane for 3 h; Reflux
To a solution of 1H-pyrrole-2-carbaldehyde (9.51 g, 100.0 mmol, 1.0 eq) in DCM (150.0 mL) was added DBU (15.2 g, 100.0 mmol, 1.0 eq), followed by ethyl 2-isocyanoacetate (11.3 g, 100.0 mmol, 1.0 eq). The resulting mixture was heated to refluxed for 3 h, then 10percent AcOH (250 mL), and separated, the organic phase was washed with water (100 mL x 2), dried over anhydrous MgSO4, filtrated and concentrated. The residue was purified by column chromatography (PE/EA=4/1, vlv) to afford ethyl pyrrolo[1,2-cjpyrimidine-3-carboxylate as a yellow solid (18.5 g, 97.3percent).
61%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃;
[1114] A solution of pyrrole-2-carboxaldehyde (3.6 g, 38.1 mmol) in 40 mL dry THF is added to ethyl isocyanoacetate (4.3 g, 38.1 mmol) and DBU (5.8 g, 38.2 mmol) in 60 mL dry THF. After stirring at RT overnight, the reaction is neutralized with 10percent AcOH. The solvent is removed in vacuo. The residue is taken up in EtOAc/H2O, the aqueous layer is extracted with EtOAc, dried (MgSO4), filtered and concentrated. The residue is purified by flash chromatography on silica gel eluting with 30-70percent EtOAc/hexanes. The carboxylate is obtained (4.45 g, 61percent) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.86, 8.24, 7.54, 7.01, 6.78, 4.45, 1.44.
Reference：
[1] Patent: WO2018/35061, 2018, A1, . Location in patent: Paragraph 0448
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 14, p. 4231 - 4239
[3] Patent: US2003/236264, 2003, A1, . Location in patent: Page 49
[4] Tetrahedron Letters, 1996, vol. 37, # 24, p. 4263 - 4266
15
[ 1003-29-8 ]
[ 105-56-6 ]
[ 107407-80-7 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 21, p. 7788 - 7801
Pyrrole-2-carboxaldehyde (3.00 g, 0.0316 mole) was combined with hydroxylamine- O-sulfonic acid (12.5 g, 0.11 mole) in 100 ml water and stirred at room temperature overnight. The reaction mixture was cooled to 0C and a solution of potassium hydroxide (12.06 g, 0.603 mole) in 80ml water was added dropwise over 1 hour time period. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane (3 x 100 ml), the extract was dried over sodium sulfate (anh.). The solvent was removed to give 3.36 g of product as a liquid (yield: 100%)
100%
With hydroxylamine hydrochloride; In 1-methyl-pyrrolidin-2-one; at 125℃;
Step 10)lH-pyrrole-2-carbonitrile [0339] To a solution of lH-pyrrole-2-carbaldehyde (27.50 g, 0.29 mol) in NMP (300 mL) was added hydroxylamine hydrochloride (24.11 g, 0.35 mol). The reaction mixture was stirred at 125 C overnight, then cooled down to rt, and diluted with water (600 mL), then extracted with EtOAc (1 L x 8). The combined organic phases were dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/5) to give the title compound as yellow oil (26.71 g, 100%). MS (ESI, pos. ion) m/z: 93.1 [M+H]+; NMR (400 MHz, CDCb): delta (ppm) 9.27 (br. s, 1H), 6.99 (td, J = 2.7, 1.4 Hz, 1H), 6.90 (ddd, J = 3.8, 2.4, 1.4 Hz, 1H), 6.30 (dt, J= 3.6, 2.6 Hz, 1H).
100%
With 1-methyl-pyrrolidin-2-one; hydroxylamine hydrochloride; at 125℃;
1H-pyrrole-2-carbaldehyde (27.50 g, 0.29 mol) was dissolved in NMP (300 mL) and hydroxylamine hydrochloride (24.11 g, 0.35 mol) was added to the solution to obtain a reaction system. The resulting reaction was warmed to 125 C, stirred overnight and then cooled to room temperature. The reaction mixture was then diluted with water (600 mL) and extracted with ethyl acetate (1 L × 8), then the organic phases were combined. The combined organic phases were successively dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was then subjected to silica gel column chromatography (EtOAc / PE (v / v) = 1/5) to give the title compound as a yellow oil (26.71 g, 100%).
80%
To a cold solution of hydroxylamine hydrochloride (0.38 g, 5.5 mmol, 1.1 equiv.) in anhydrous acetonitrile (50 mL), triethylamine (0.77 mL, 5.5 mmol, 1.1 equiv.) and 1H-pyrrole-2-carboxaldehyde (5.0 mmol, 1.0 equiv.) were added and stirred for around 30 mins. Then phthalic anhydride (0.75 g, 5.05 mmol, 1.01 equiv.) was slowly added under nitrogen protection. The resulting mixture was stirred at 80 C for about 8 h. After concentration, the resulting residue was added cold CH2Cl2 (30 ml × 3) and stirred. The combined filtrates were washed with 5% ammonia water to remove phthalic acid completely. The separated organic layer was dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Finally the residue was purified by passing it through a short silica gel column using CHCl3 as eluent to give pure 1H-pyrrole-2-carbonitrile as yellow oil (80%).3 A mixture of 1H-pyrrole-2-carbonitrile (3.0 mmol, 1.0 equiv.), substituted methyl bromide (3.3 mmol, 1.1 equiv.) and K2CO3 (3.6 mmol, 1.2 equiv.) was stirred in CH3CN (20 mL) at room temperature. After being stirred for 12 h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc (30 mL), and washed with H2O (30 mL). The water layer was extracted with EtOAc (30 mL) one more time. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: EtOAc = 10:1) to afford 1b as white solid.
70%
With hydroxylamine hydrochloride; In 1-methyl-pyrrolidin-2-one; at 110 - 115℃;
Pyrrole-2-carbaldehyde (10 mmol), NMP (15 mL), and NH2OH·HCl (12 mmol) were refluxed at 110-115 C. After cooling to room temperature, H2O (50 mL) was added. The mixture was then extracted with ethyl acetate (3 × 20 mL), dried over MgSO4, and filtered. After evaporation of the solvent, the crude product was purified by flash column chromatography (EtOAc/hexane, 1:6) to give compound 2 in 70% yield; bp: 92-94 C; Rf: 0.70 (EtOAc/Hex, 1:3); 1H NMR (400 MHz, CDCl3) delta (ppm) 6.18 (br s, 1H) 6.80 (br s,1H) 6.94 (br ss, 1H) 9,43 (s, 1H); 13C NMR (100 MHz, CDCl3) delta (ppm) 100.41, 110.29, 115.08, 120.64, 124.11.
With hydrogen bromide; dimethyl sulfoxide; at 50℃; for 2h;
General procedure: In a round-bottomed flask, the substrate (1 mmol) and aqueous HBr(48%) (1 mL) were mixed in DMSO (1 mL). The mixture was stirredat corresponding temperature for 1-4 h. After cooling to roomtemperature, the reaction was adjusted to pH 7-8 with aqueous NaOHsolution (4 M). Then the mixture was washed twice with EtOAc, andthe combined organic extracts were dried, filtered and concentratedunder reduced pressure to give bromination products.
61%
With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.25h;
4-Bromo-1 H-pyrrole-2-carboxaldehyde (41). To a stirred solution of 1 H-pyrrole-2- carboxaldehyde 40 (1 g, 10.52 mmol) in CH3CN (10 mL) at 0C was added N- bromosuccinimide (1 .872 g, 10.52 mmol) and the solution was stirred at 0C for 15 minutes. Water was added and the resulting mixture was extracted with Et20. Organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. Crystallization of the crude mixture using cyclohexane/ethanol afforded compound 41 as white crystals (1 .125 g, 61 %): f?f=0.22 (CH2CI2); mp: 121 -122 C; 1 H NMR (400 MHz, [D6]DMSO): 5=7.12 (m, 1 H), 7.41 (m, 1 H), 9.48 (s, 1 H), 12.51 ppm (bs, 1 H); 13C NMR (100 MHz, [D6]DMSO): 5=97.0, 120.8, 126.5, 132.9, 179.1 ppm; IR (KBr): v=3238, 3108, 2926, 2860, 1655, 1380, 1357, 1 147, 1 104, 920, 827, 771 , 744, 598 cm 1 ; MS (ESI) m/z 173.9-175.9 [M+H]+.
55%
With N-Bromosuccinimide; In tetrahydrofuran; at -78℃; for 1h;
The synthesis of an 8-bromo-substituted Western half is shown in Scheme 5. Treatment of pyrrole-2-carobxaldehyde with one molar equivalent of NBS at -78 C gave 4-bromopyrrole-2-carboxaldehyde 17 (Anderson, J. H.; Lee, S.-F. Can. J. Chem. 1965, 43, 409-414) in 55% yield after crystallization. This method of bromination of pyrrole-2-carboxaldehyde is superior to a reported method that uses Br2 (Anderson, J. H.; Lee, S.-F. Can. J. Chem. 1965, 43, 409-414). It should be mentioned here that careful handing of the crude product is required: the off-white solid often turns reddish (irrespective of preparation using Br2 or NBS), which complicates crystallization. Following a procedure for the synthesis of 2-(2-nitroethyl)pyrroles (Taniguchi, M. et al., J. Org. Chem. 2001, 66, 7342-7354), treatment of 17 with <n="92"/>excess nitromethane, sodium acetate and methylamine hydrochloride at room temperature for 16 h followed by reduction of the reaction mixture with NaBH4 gave 4-bromo-2-(2-nitroethyl)pyrrole (18) in variable yields (32-48%). However, 18 was found to explode (CAUTION), which caused us to avoid handling this compound. Thus, we considered protection of the pyrrole nitrogen in 4-bromo-pyrrole-2- carboxaldehyde (17) for two purposes: (1) to render 4-bromo-2-(2-nitroethyl)pyrrole (18) as a stable compound, and (2) for efficient palladium-coupling in the latter part of the 8-ethynyl Western half synthesis. Considering the facile conditions for removal of a /j-toluenesulfonyl group coupled with the crystalline nature of 2-(2- nitroethyl)-W-/>-tosylpyrroles, lambdaf-tosylation (Tietze, L. F. et al., Synthesis 1996, 851- 857) of compound 17 was carried out. Thus, treatment of 17 with NaH at 0 0C for 1 h followed by quenching with /?-toluenesulfonyl chloride gave 17-Ts as a pale yellow crystalline solid in 68% yield. Following a reported procedure .for the synthesis of 2- (2-nitrovinyl)-iV-p-tosylpyrroles (Hamdan, A.; Wasley, J. W. F. Synth. Comrhun. 1985, 15, 71-74), a mixture of 17-Ts, excess nitromethane and ammonium acetate was refluxed for 3 h. The crude product was satisfactorily pure as evidenced by NMR spectroscopy and was directly used in the next step. NaBH4 reduction of the crude product in the presence of Montmorillonite KlO (Bahulayan, D. et al., J. Org. Chem. 2003, 68, 5735-5738), or silica gel (Ptaszek, M. et al., Org. Process Res. Dev. 2005, 9, 651-659) at room temperature afforded 2-(2-nitroethyl)-iV-/7-tosylpyrrole 18-Ts as a white solid in 40% or 58% yield, respectively. Michael addition of 18-Ts with mesityl oxide in the presence of TBAF (Battersby, A. R. et al., J. Chem. Soc, Perkin Trans. 1 1984, 2725-2732) and 3A molecular sieves gave the detosylated pyrrole- hexanone 19 in 47% yield. The /?-toluenesulfonyl group is known to be cleaved by TBAF (Yasuhara,.A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595-596). Reduction (Ptaszek, M. et al., Org. Process Res. Dev. 2005, 9, 651-659) of 19 with excess zinc dust and HCOONH4 in THF at room temperature gave the 8-bromo Western half 20 in 45% yield. ; 4-Bromopyrrole-2-carboxaldehyde (17). A solution of pyrrole-2- carboxaldehyde (4.75 g, 50.0 mmol) in dry THF (200 mL) was cooled to -78 0C under argon. NBS (8.90 g, 50.0 mmol) was added and the reaction mixture was stirred for 1 h at -78 0C. Hexanes and water were added and the reaction mixture was allowed to warm to 0 0C. The organic phase was extracted with hexanes and dried (Na2 SO4). Crystallization of the crude mixture using hexanes/THF afforded white crystals (4.83 g, 55%): mp 120-121 0C [lit. 122-123 0C (Anderson, J. H.; Lee, S.-F. Can. J. Chem. 1965, 43, 409-414)]; 1H NMR delta 6.95 (m, IH), 7.12 (m, IH), 9.45 (s, IH), 9.65-9.85 (br s, IH); 13C NMR delta 99.0, 123.0, 127.0, 132.8, 179.3. Anal. Calcd for C5H4BrNO: C, 34.51; H, 2.32; N, 8.05; Found: C, 34.50; H, 2.26; N, 7.75.
54%
With N-Bromosuccinimide; In tetrahydrofuran; at -78℃; for 1h;
To a 100 mL 3-neck RB flask charged with 1H-pyrrole-2-carbaldehyde (1.0 g, 10.5 mmol) in THF(20 mL) at -78C, NBS (1.87 g, 10.53 mmol) in THF(20 mL) was addedslowly and thenthe flaskw as maintained at the same temperature for 1 h. The reaction mixture was diluted with hexane and water mixture, the organic layer was decanted. The organic layer was dried over anhydrous Na2SO4 and then concentrated at low temperature under vacuo. It was recrystallized with n-hexane to yield the title compound (1 .0 g, 54.0%) as a pale pink solid.
53%
With N-Bromosuccinimide; In tetrahydrofuran; at -78℃;
1H-Pyrrole-2-carbaldehyde (20g, 210mmol) was dissolved in 250ml tetrahydrofuran and the mixture was cooled to-78C. N-Bromosuccinimide (37g, 210mmol) was added portion-wise over 1h with stirring and the mixture was stirred for a further 6.5at-78C. The mixture was allowed to warm to 0C and was partitioned between water and hexane and protected from the light. The aqueous phase was extracted with cold hexane and the combined organics were washed with water, dried over anhydrous sodium sulphate and filtered. The organics were concentrated under reduced pressure until a precipitate formed. The solid was cold-filtered, washed with cold hexane and dried under vacuum to give 12.8g of 80. The filtrates were concentrated again under reduced pressure until further precipitate formed. This was collected by filtration as before and combined with the first obtained solid to give 80 (18.9g, 109mmol, 53% yield). Purity 96%. Stored at 4C in the dark. 1H NMR (400MHz, CDCl3) delta ppm 6.96-6.99 (m, 1H, H-3), 7.11-7.14 (m, 1H, H-5), 9.47 (s, 1H, CHO), 9.88 (br. s., 1H, NH). UPLC/MS (3min) retention time 1.18min. LRMS: m/z 172, 174 (M-1).
51%
With N-Bromosuccinimide; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
4.3.5 4-Bromopyrrole-2-carboxaldehyde (13) A solution of pyrrole-2-carboxaldehyde 12 (3.80 g, 40 mmol) in dry THF (40 mL) was cooled to 0 C under Argon. NBS (7.12 g, 40 mmol) was added and the reaction mixture stirred for 15 min before the solvent was removed in vacuo. The crude product was dried under high vacuum for 30 min before the addition of distilled water (20 mL) and the resulting suspension filtered. The resulting solid was dissolved in a minimum amount of hot ethanol/water solution (9:1) before the addition of activated charcoal and filtration through a Celite plug. Upon cooling, the product recrystallised to give 4-bromopyrrole-2-carboxaldehyde 13 (3.54 g, 51%) as an off white solid; Mp 119-122 C. IR (neat, cm-1) 3204, 3108, 3982, 2861, 1653, 1378, 1354, 918, 769. 1H NMR (400 MHz, Acetone-d6) delta 11.39 (1 H, s, NH), 9.52 (1 H, d, 4JHH 1.0, CHO), 7.34-7.31 (1 H, m, C5H), 7.09-7.05 (1 H, m, C3H). 13C NMR (101 MHz, Acetone-d6) delta 179.4 (s, C=O), 134.3 (s, C2), 126.8 (s, C5), 121.5 (s, C3), 98.4 (s, C4). HRMS (ESI) m/z calcd for [M+H]+ C5H4BrNO 173.9554; found 173.9553.
With N-Bromosuccinimide; In tetrahydrofuran; at 0℃; for 0.25h;
General procedure: N-bromosuccinimide (561mg, 3.15mmol) was added as a single portion to a solution of pyrrole-2-carboxaldehyde (300mg, 3.15mmol) in THF (3.3mL) at 0C. The mixture was stirred at 0C for 15min, and the solvent was removed under reduced pressure. The crude product was suspended in water, the suspension was filtered, washed with water, recrystallized from EtOH and dried to afford 4-bromo-1H-pyrrole-2-carbaldehyde. Pd(PPh3)4 (147mg, 0.13mol) was added to a degassed mixture of 4-bromo-1H-pyrrole-2-carbaldehyde (219mg, 1.27mmol), phenylboronic acid (221mg, 1.81mmol), K2CO3 (501mg, 3.63mmol) in dioxane (4mL) and water (2mL) under argon. The mixture was heated at 105C for 24h, cooled to room temperature and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (6/1) to afford 9 [40]. Cyanuric chloride (28mg, 0.15mmol) was added to a mixture of 3a (136mg, 1mmol) and 9 (205mg, 1.2mmol) in DMSO (3mL). The mixture was stirred at room temperature for 2h. After completion, the mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (30/1) to afford C8.
With N-iodo-succinimide; In tetrahydrofuran; at -75℃; for 2.33333h;
A solution of lH-pyrrole-2-carbaldehyde (7.0 g, 73.6 mmol) in tetrahydrofuran (45 mL) was cooled to -750C. N-iodosuccinimide (19.8 g, 88.3 mmol) was added portionwise over 20 min and the reaction mixture was then stirred for 2 h at -75 °C. Water and petroleum ether were added and the reaction mixture warmed to ambient temperature. The organic layer was separated and the aqueous phase extracted with petroleum ether. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-iodo-lH- pyrrole-2-carbaldehyde (13.2 g, 81percent) as a black solid.
With piperidine; In isopropyl alcohol; at 85℃; for 2h;
A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (0.2 g, 0.94 mmol) (see T. Kosuge et. al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85 C for 2 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%)
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.50 g, 0.01 mol) and pyrrole-2-carboxaldehyde (1.58 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 48 h, then cooled to room temperature, poured into crushed ice and left overnight at 4 C. The precipitated solid was filtered off, washed with water and dried. The dark solid was boiled with ethanol (150 ml) and filtered hot to remove impurities. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatographed using (95:5) toluene:ethyl acetate as the mobile phase.
Step A. 1-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde To a suspension of sodium hydride (0.724 g, 60% suspension in oil) in N,N -dimethyl formamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. It was then cooled to 0 C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate (450 mL), washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was triturated with water, filtered and washed with water. This material was dried over anhydrous potassium carbonate in vacuo to provide the title compound as a yellow crystalline solid (4.97 g), m.p. 109-112 C., which was used in the next step.
In N,N-dimethyl-formamide;
Step A. 1-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde To a suspension of sodium hydride (0.724 g, 60% suspension in oil) in N,N-dimethylformamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. It was then cooled to 0 C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate (450 mL), washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was triturated with water, filtered and washed with water. This material was dried over anhydrous potassium carbonate in vacuo to provide the title compound as a yellow crystalline solid (4.97 g), m.p. 109-112 C., which was used as such in the next step.
In N,N-dimethyl-formamide;
Step A. 1-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde To a suspension of sodium hydride (0.724 g, 60% suspension in oil) in N,N-dimethyl formamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. It was then cooled to 0 C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate (450 mL), washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was triturated with water, filtered and washed with water. This material was dried over anhydrous potassium carbonate in vacuo to provide the title compound as a yellow crystalline solid (4.97 g), m.p. 109-112 C., which was used in the next step.
1-(2'-chloro-4'-trifluoromethylphenyl)pyrrole-2-carboxaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide;
Step 1 A solution of pyrrole-2-carboxaldehyde (19.0 g, 0.2 mol) in N,N-dimethylformamide (50 ml) was added dropwise to a suspension of sodium hydride (80% dispersion in oil, 6.3 g, 0.21 mol) in N,N-dimethylformamide (100 ml), maintaining the temperature of the reaction between 5-10 C. by means of ice-bath cooling. When the addition was complete, stirring was continued for 30 minutes, and then <strong>[78068-85-6]3-chloro-4-fluorobenzotrifluoride</strong> (39.7 g, 0.20 mol) added. The mixture was stirred for 3 hours, then warmed to 50 C. for 18 hours. The mixture was cooled to room temperature and partitioned between diethyl ether and water. The ethereal extract was washed sequentially with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. Trituration with hexane gave 1-(2'-chloro-4'-trifluoromethylphenyl)pyrrole-2-carboxaldehyde as a pale yellow solid (30.6 g), m.p. 119-120 C.
General procedure: Solutions of nitrile dissolved in Toluene (5 mL) and DIBAL (1 M) in Toluene were pumped at the appropriate flow rate and mixed in a 0.85 mL Microreactor Explorer Kit chip reactor. For longer residence times extra 20 ml tubing was added at the end of the reactor. The solution at the microreactor outlet was poured into a 1% Sodium Tartrate solution at 0 C. The crude solution was extracted with EtOAc. The extracts were dried over MgSO4, filtered and evaporated to yield the desired product. All products obtained and discussed in this work have been previously reported and characterized.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h;
General procedure: A flask was charged with 2-formylpyrrole 1 (5.00 g, 52.6 mmol), K2CO3 (8.72 g, 63.1 mmol), 2-fluoropyridine 2 (9.0 mL, 105.2 mmol) and DMF (26 mL).The mixture was heated at 100 °C for 20 h and then cooled to rt. The reaction mixturewas diluted with water, extracted with MTBE, and the organic phase was dried (MgSO4), filtered, and concentrated. The crude product was purified by chromatography on SiO2(hexanes/EtOAc, 95:5 to 85:15 v/v) to give the product 3 (5.71 g, 63percent) as a tan solid.
With toluene-4-sulfonic acid; In methanol; at 65℃; for 20h;Inert atmosphere; Reflux;
General procedure: 1a was synthesized by modifying the reported procedure [44]. Catalytic amount of p-toluene sulfonic acid (20mg, 0.10mmol) was added to a mixture of pyrrole-2-carbaldehye (380mg, 4.0mmol) and 1-amino-2-methoxybenzene (490mg, 4.0mmol) in methanol (10mL) under stirring condition in nitrogen atmosphere. The resulting mixture was heated to reflux for 20h, and then cooled to room temperature. After removal of volatiles under reduced pressure, the residue was mixed with THF and filtered through a pad of celite. The resulting solution was concentrated to give a brown solid, which was further purified by re-dissolved in THF/ether (1:4). The solution was kept at -18C for overnight, and brown crystalline solid was collected by filtration. The solid was washed with ether and further dried under vacuum to obtain 1a. Yield 270mg (68%). m.p. 235-236C. 1H NMR (400MHz, CDCl3) delta 10.07 (s, 1H, NH), 8.30 (s, 1H, CH=N), 7.20 (dt, J=7.6, 1.6Hz, 1H, Ar-H), 7.05 (d, J=1.6Hz, 1H, Ar-H), 7.01 (d, J=7.6Hz, 1H, Ar-H), 6.98 (d, J=7.6Hz, 1H, Ar-H), 6.88 (d, J=1.2Hz, 1H, Py-H), 6.70 (dd, J=1.2, 3.6Hz, 1H, Py-H), 6.30 (d, J=3.6Hz, 1H, Py-H), 3.88 (s, 3H, CH3). 13C NMR (100MHz, CDCl3) delta 152.52, 150.71, 141.82, 130.95, 126.63, 123.32, 121.36, 120.74, 116.69, 111.42, 110.47, 55.84. MS (ESI) m/z: 200.5. Anal. Calcd for C12H12N2O: C 71.98, H 6.04, N 13.99. Found: C 71.96, H 6.30, N 13.83.
1-([1,1'-biphenyl]-3-ylmethyl)-1H-pyrrole-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; water; at 0 - 20℃;
To a stirred mixture of 1H-pyrrole-2-carbaldehyde 39 (200 mg, 2.10 mmol), TBAB (68 mg, 0.21 mmol) and <strong>[14704-31-5]3-(bromomethyl)-1,1'-biphenyl</strong> 38 (624 mg, 2.52 mmol ) in DCM was added aqueous NaOH solution (1.2 mL, 1.25 M in H2O) dropwise over a period of 30 min at 0 C. Then the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was diluted with water, and extracted with DCM (3 x 30 mL). The combined organic phases were washed with 2 M HCl, saturated NaHCO3 and brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 43 (540 mg, 98%) as a white solid.
ethyl Pyrrolo[1,2-a]quinoline-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
With potassium phosphate; In dimethyl sulfoxide; at 150℃; for 48h;Inert atmosphere;
General procedure: A flask was equipped with a magnetic stir bar and charged with 1Hpyrrole-2-carbaldehyde (2a; 19.0 mg, 0.2 mmol, 1.0 equiv), 2-bromophenylacetonitrile(1a; 39.2 mg, 0.2 mmol, 1.0 equiv), and K3PO4(63.6 mg, 0.3 mmol, 1.5 equiv). The flask was evacuated and filledwith N2, and then anhydrous DMSO (2.0 mL) was introduced via a syringe.The flask was heated in a 130 °C oil bath for 24 h, at which timeTLC analysis [petroleum ether (bp 60?90 °C)?EtOAc, 10:1] indicatedcomplete consumption of 2a and 1a. The reaction mixture was cooledto r.t. and added to a sat. solution of NaCl (20 mL) and extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4)and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 [petroleum ether (bp 60?90°C)?EtOAc, 10:1 to 30:1] to give 3da; Yield: 16.1 mg (34percent); light yellow solid; mp 186.5?188.4 °C.
6-fluoro-2-[2-((1H-pyrrol-2-yl)methylene)hydrazino]benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: 2-(2-Arylidenehydrazino)-6-fluorobenzothiazoles 6a-r. General Procedure D. A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from the appropriate solvent to give the desired compounds 6a-r.
(E)-5-(((1H-pyrrol-2-yl)methylene)amino)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With acetic acid; In ethanol; dimethyl sulfoxide;Reflux;
General procedure: A solution of 1.0 mmol of N-heterocyclic aldehyde in 10 mL of ethanol was added to a hot solution of 1.0 mmol of 5- or 6-aminouracil in 10 mL of DMSO. A few drops of glacial acetic acid were then added, and the mixture was refluxed for 6-8 h. The solution was cooled to room temperature, filtered, and evaporated to dryness using a rotary evaporator. The resulting solid was washed with cold ethanol followed by anhydrous diethyl ether.
With [Ru(L1)Cl(CO)(PPh3)2]; hydroxylamine hydrochloride; sodium hydrogencarbonate; In toluene; for 12h;Inert atmosphere; Reflux;Catalytic behavior;
General procedure: Conversion of aldehydes to amides was carried out using the procedure described in the literature [34]. Under nitrogen atmosphere, the corresponding aldehyde (1mmol), NH2OH·HCl (1mmol), NaHCO3 (1mmol), toluene (3mL) and ruthenium(II) catalyst 1 (0.01mmol) were introduced into a RB flask, and the reaction mixture was stirred at 120C in an oil bath for 12h. After the completion of reaction, 2-3mL of MeOH was added to the reaction mixture. The catalyst and NaHCO3 which settled down the flask was removed by filtration through Celite. The filtrate has been dried and the crude product was purified by the use of column chromatography (MeOH/CH2Cl2). Finally, the isolated amide was characterized by the aid of 1H NMR.
With C33H27ClN3OPRu; hydroxylamine hydrochloride; sodium hydrogencarbonate; In toluene; at 20 - 110℃; for 8.25h;Inert atmosphere; Schlenk technique;Catalytic behavior;
General procedure: The reaction vessel was charged with aldehyde (1mmol), NH2OH·HCl (1 mmol), NaHCO3 (1 mmol),[Ru-NHC] catalyst (0.5 mol %) and the mixture wasplaced under an atmosphere of N2. About 2 mL of dryand degassed toluene was added and the mixture wasstirred for 15 min at room temperature followed byreflux for 8 h. On completion of the reaction, 2-3 mLmethanol was added to the mixture followed by filtrationthrough Celite to remove the catalyst and NaHCO3.The crude product was then purified by column chromatography(MeOH/CH2Cl2, 1:1) using silica (200-400 mesh) as solid phase provided the amide in goodyield. The resultant amide solution was subjected to GCanalysis and the product was identified in comparisonwith authentic samples
98%Chromat.
With C23H27Cl2N3Rh(1+)*C24H20B(1-); hydroxylamine hydrochloride; sodium hydrogencarbonate; In toluene; at 110℃; for 2h;Inert atmosphere; Schlenk technique;
General procedure: Compound 3 (0.002 mmol), the aldehyde (1 mmol), NH2OHHCl(1 mmol) and NaHCO3 (1 mmol) were introduced in a dried schlenktube and purged with N2. Then, to the mixture, dried and degassedtoluene (2 ml) was added and the mixture was stirred for about10 min at room temperature, before the solution was refluxed understirring for 2 h. The mixture was cooled and the products wereextracted with methanol and dichloromethane before beingfiltered through celite to remove the remaining catalyst andNaHCO3. The crude amide was purified using column chromatography,and dried under vacuum.
General procedure: A 100mL round bottom flask was charged with 1H-pyrrole-2-carboxaldehyde (1.862g, 20mmol), 2?Phenoxybenzenamine (3.704g, 20mmol) and 30mL methanol. After adding formic acid (0.01equiv, 0.2mmol), the mixture was stirred for 24h. The solution was evaporated to dryness, and recrystallized from CH2Cl2/n-hexane.
With trichlorophosphate; In dichloromethane; at 0 - 20℃; for 6.25h;Inert atmosphere;
3-(2,4-Dimethyl-1H-pyrrol-3-yl)propanoic acid (2) (1.45 g, 0.00867 mol) and 2-pyrrole aldehyde (0.91 g, 1.1 eq, 0.00954 mol) were dissolved in 10 mL 10:1 (v:v) anhydrous dichloromethane: methanol and stirred at 0 C. under nitrogen protection. POCl3 (1.46 g, 1.1 eq, 0.00954 mol) was added drop-wise (15 min) to the mixture and the resulting solution was stirred and allowed to heat to room temperature over 6 hrs. The reaction mixture was then evaporated under reduced pressure (0.5 mL) and then re-dissolved with 10 mL of anhydrous dichloromethane. The reaction mixture was stirred at 0 C. under nitrogen protection and then, sequentially, boron trifluoride ethyl etherate (4.31 g, 4 eq, 0.0347 mol) and di-isopropylethylamine (4.92 g, 4 eq, 0.0347 mol) were added drop-wise over 30 min. The reaction was left to stir overnight (13 hr) at room temperature under nitrogen protection. The reaction mixture was added to deionized H2O (100 mL) and then extracted three times with dichloromethane (150 mL total). The combined organic layers were then washed with brine, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The resultant metallic green oil was dissolved in 10 mL dichloromethane and then absorbed onto 10 g celite and evaporated to dryness under reduced pressure. The crude reaction mixture was then purified using dry column vacuum chromatography (silica gel, 100:1 (v:v) dichloromethane:methanol) affording 2.65 g (87%) of compound (4). High resolution mass spectrometry (HRMS) as shown in FIG. 7: C15H17BF2N2O2 [M+Na]+ Calculated: 329.1249. Found: 329.1242. 1H NMR as shown in FIG. 8 (600 MHz, CDCl3, 24.97 C., TMS) delta (ppm) 7.60 (s, 1H), 7.15 (s, 1H), 6.89 (s, 1H), 6.41 (s, 1H), 3.67 (s, 1H), 2.73 (t, j=7.89 Hz, 2H), 2.57 (s, 3H), 2.46 (t, j=7.52 Hz, 2H), 2.21 (s, 3H). 13C NMR as shown in FIG. 9 (150 MHz, CDCl3) delta (ppm) 172.72, 162.48, 142.06, 138.73, 135.84, 132.52, 130.78, 126.06, 124.15, 116.04, 51.78, 33.64, 19.35, 13.29, 9.63.
N-(2-(cyclohexylamino)-2-oxo-1-(1H-pyrrol-2-yl)ethyl)-2,4-dimethyl-N-(p-tolyl)thiazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds.
With sodium cyanoborohydride; acetic acid; In methanol; at 20 - 50℃;pH 6-7;
General procedure: To a stirring solution of 8 (0.3 mmol) in MeOH (5 mL) was added the corresponding aldehyde (0.4 mmol) and NaCNBH3 (0.5 mmol)at room temperature. The mixture was adjusted to pH 6-7 by acetic acid, stirred overnight at room temperature, and quenched by 1M NaOH solution (5 mL). The mixture was diluted by H2O (15 mL), and extracted by DCM (10mL x 3). The combined organic layer waswashed by brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified over silica gel column(DCM: MeOH = 20 : 1) to yield oils 9b-s (70-93%).
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