Organic Syntheses Procedure

^
Top

Org. Synth. 2009, 86, 236

DOI: 10.15227/orgsyn.086.0236

ENANTIOSELECTIVE PREPARATION OF DIHYDROPYRIMIDONES

[(S)-1-Benzyl-6-methyl-2-oxo-4-phenyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic methyl ester]

Submitted by Jennifer M. Goss, Peng Dai, Sha Lou, and Scott E. Schaus¹.

Checked by Tanja Brkovic and David Hughes.

1. Procedure

A. Allyl carbamate. An empty 3-necked, 1-L round-bottom flask is fitted with a stopper on the middle neck and septa on each of the outer necks. Through one septum of the empty flask is inserted a 6-mm glass tube which is connected to an ammonia gas cylinder via vacuum tubing. Through the other septum is inserted a 6-mm glass tube which is connected to the reaction flask via vacuum tubing. This empty flask serves as a trap to prevent backflow of the flask contents into the lecture bottle.

A trap to neutralize discharged ammonia gas is also constructed as follows. To a 3-necked, 1-L flask is added 400 mL of 10% HCl, which is gently stirred using a magnetic stir bar (3 cm). The middle neck of the flask is stoppered, one neck is left open to the atmosphere, and the third neck is fitted with a septum through which is inserted a 6 mm ID × 5 cm glass tube. The glass tube is situated well above the contents of the acid solution to prevent any back flow. The glass tube is connected via vacuum tubing to an empty 1-L 3-necked flask equipped with a stopper on the middle neck and septa on each of the outer necks, with each septa pieced with a 6 mm ID × 5 cm glass tube. The tube in one outer neck is connected via vacuum tubing to the HCl quench flask, while the tube in the other outer neck is connected via vacuum tubing to the reaction flask. The empty flask between the reaction flask and the flask containing aq. HCl ensures no back flow of the aq. solution or water vapor into the reaction flask.

An oven-dried, 1-L, three-necked round-bottom flask is equipped with an overhead mechanical stirrer. One neck of the flask is fitted with a septum through which has been inserted a 6-mm ID × 20 cm length glass tube that will extend into the contents of the flask (Note 1). A thermocouple probe is also inserted through this septum to monitor temperature. The outlet of this tube is connected to the empty 3-necked 1-liter flask and ammonia cylinder via vacuum tubing. The third neck of the reaction flask is similarly fitted with a septum pierced with a short 6 mm ID × 5 cm length glass tube, situated well above the contents of the flask, which is connected via the empty flask to the flask containing 10% aq. HCl.

To the reactor flask is charged by weight allyl chloroformate (84.0 g, 1.00 equiv, 697 mmol) and toluene (400 mL) (Notes 2, 3). The flask is immersed in a room temperature water bath. The solution is mechanically stirred at 300 rpm while bubbling ammonia gas through the solution at a rate to maintain the internal temperature below 45 °C. Ammonia addition is continued for 5.5 hours. Ammonium chloride (white solid) precipitates throughout the course of the reaction and the reaction mixture becomes quite thick. When complete consumption of the starting material is verified by NMR assay (Note 4), the reaction mixture is vacuum filtered through a 150-mL sintered glass funnel. The solids are washed with 3 × 70 mL portions of toluene and the resulting clear solution is concentrated under reduced pressure by rotary evaporation (30 mmHg, 35 °C water bath) to 75.4 g (Note 5). The remaining crude oil is distilled under vacuum at 65-67 °C (1-2 mmHg) to provide 63.2 g (89.7%) of allyl carbamate as a clear oil (Notes 6, 7).

B. (Benzenesulfonyl-phenyl-methyl)-carbamic acid allyl ester. An oven-dried, 1-L round-bottomed flask, equipped with a rubber septum and an oval 3-cm stir bar, is charged with benzenesulfinic acid sodium salt (25.6 g, 1.43 equiv, 154 mmol), allyl carbamate (15.5 g, 1.43 equiv, 154 mmol), methanol (100 mL) and water (200 mL). The reaction mixture is stirred at ambient temperature until homogeneous (about 5 min). Benzaldehyde (11.1 g, 1.00 equiv, 107 mmol) is added by syringe, weighing the syringe before and after addition, followed by addition of formic acid (39.5 g of 91 wt% solution, 7.3 equiv, 781 mmol). The reaction mixture is stirred for 4 days at room temperature (21-22 °C), during which time the formation of a heavy white precipitate occurs (Note 8). The mixture is vacuum filtered via a 150-mL medium porosity sintered glass funnel. The white solid is washed with two 40 mL portions of 3:1 water:methanol. The solid is air-dried to provide 21.8 g of (benzenesulfonyl-phenylmethyl)-carbamic acid allyl ester. The supernatant from the filtration is placed back in the 1-L flask and is stirred for an additional 4 days at ambient temperature. The mixture is then vacuum filtered via a 60-mL medium porosity sintered glass funnel, washed twice with 20 mL of 3:1 water:methanol, and air dried to afford 4.9 g as a second crop having comparable purity by NMR to the first crop. The total yield of the reaction is 26.7 g (75%) (Notes 9, 10).

C. 2-[(R)-Allyloxycarbonylamino-phenyl-methyl)-3-oxo-butyric acid methyl ester. A 1-L, three-necked, round-bottom flask is equipped with an internal thermometer, an overhead mechanical stirrer and a 500-mL pressure-equalizing addition funnel. The three-necked flask is charged with (+)-cinchonine (1.77 g, 0.20 equiv, 6.0 mmol) and (benzenesulfonyl-phenyl-methyl)-carbamic acid allyl ester (9.97 g, 1.00 equiv, 30.1 mmol). Anhydrous dichloromethane (300 mL) is added, and the solution is stirred for about 5 min, during which time the majority of solids are dissolved. The flask is submerged in an isopropyl alcohol bath cooled to -25 °C (Note 11) and the solution is mechanically stirred at 500 rpm. Once the reaction mixture has cooled to -15 °C (monitored by the internal thermometer), methyl acetoacetate (10.7 g, 3.0 equiv, 92.3 mmol) is added via syringe over 2 minutes. After 10 min, 300 mL of an aqueous Na₂CO₃/NaCl solution (15.0 g of sodium carbonate is dissolved in 300 mL of water, and then saturated with 150 g of sodium chloride) is added to the 500-mL pressure-equalizing addition funnel. The aqueous solution is added dropwise to the reaction mixture over 1 h, while maintaining an internal temperature of -15 °C (Note 12). The heterogeneous solution is mechanically stirred at 500 rpm for 27 h while maintaining an internal temperature of -15 °C. At the end of the reaction, the cold solution is transferred to a 1-L separatory funnel and the bottom organic layer is separated (Note 13). The aqueous layer is washed with two 250 mL portions of dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered and concentrated by rotary evaporation (30 mmHg, 30 °C bath temperature). The remaining residue (17.8 g) is purified by column chromatography over silica gel (Note 14) to provide 8.69-9.00 g (95-98 %) of 2-[(R)-allyloxycarbonylamino-phenyl-methyl)-3-oxo-butyric acid methyl ester as a white solid (Notes 15, 16).

D. 2-[(R)-(3-Benzyl-ureido)-phenyl-methyl]-3-oxo-butyric acid methyl ester. An oven-dried, 500-mL round-bottom flask, equipped with a 3-cm oval magnetic stir bar, is charged with anhydrous BHT-free tetrahydrofuran (160 mL) and benzyl isocyanate (4.74 g, 1.46 equiv, 35.6 mmol). The flask is fitted with a vacuum adapter and is degassed via three vacuum/nitrogen purge cycles. Tetrakis(triphenylphosphine)palladium(0) (1.24 g, 0.045 equiv, 1.07 mmol) is then added and dissolved by stirring the mixture. The vacuum adapter is replaced with a rubber septum pierced with a needle connected to a nitrogen inlet. A second oven-dried, 250-mL round-bottom flask equipped with a 2-cm oval magnetic stir bar is charged with 1,3-dimethylbarbituric acid (2.09 g, 0.53 equiv, 12.9 mmol) and 2-[(R)-allyloxycarbonylamino-phenyl-methyl)-3-oxo-butyric acid methyl ester (7.44 g, 1.00 equiv, 24.40 mmol) (Note 17). Anhydrous BHT-free tetrahydrofuran (80 mL) is added, yielding a homogeneous solution upon stirring. The flask is fitted with a vacuum adapter and degassed with three vacuum/nitrogen purge cycles. The vacuum adapter is then removed and replaced with a septum. The solution in the second flask is transferred dropwise via cannula to the stirring solution of tetrakis(triphenylphosphine)palladium(0), benzyl isocyanate and anhydrous tetrahydrofuran over 5 min followed by a 5 mL tetrahydrofuran rinse of the flask. An exotherm of about 5 °C occurs over 10 min. The reaction is stirred for 5 h at 21-22 °C, during which time the solution changes from yellow to a pale orange (Note 18). The solution is concentrated by rotary evaporation (30 mmHg, 30 °C bath), and the resulting residue is purified by column chromatography over silica gel (Note 19) to afford 6.07 g (70%) of 2-[(S)-(3-benzyl-ureido)-phenyl-methyl]-3-oxo-butyric acid methyl ester (Note 20) as a pale yellow oil.

E. (S)-1-Benzyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic methyl ester. An oven-dried, 250-mL round-bottom flask, equipped with 2-cm oval magnetic stir bar and a water condenser, is charged with 2-[(R)-(3-benzyl-ureido)-phenyl-methyl]-3-oxo-butyric acid methyl ester (6.62 g having 85% purity (Note 20), 5.63 g corrected for purity, 1.00 equiv, 15.9 mmol), anhydrous 200-proof ethanol (15 mL) and anhydrous acetic acid (45 mL). The reaction solution is stirred at room temperature until homogeneous. The 250-mL round-bottomed flask is submerged in an oil bath and the solution is heated to reflux (107 °C) for 5 min. The solution is cooled to room temperature and transferred to a 250-mL separatory funnel. Dichloromethane (100 mL) and 5% aqueous brine (50 mL) are added, the two phases are mixed well by shaking, then the lower organic phase is separated. The organic layer is extracted with 2 × 50 mL portions of 5% aqueous brine (Note 21). The remaining organic layer is dried over sodium sulfate, filtered and concentrated via rotary evaporation (30 mmHg, 30 °C bath temperature) to an oil (7.2 g). The resulting residue is purified by column chromatography over silica gel (Note 22) to afford 4.13 g (77%) of (S)-1-benzyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic methyl ester as a white solid (Notes 23-25).

2. Notes

1. The inlet tube has to be sufficiently wide to prevent plugging as ammonium chloride buildup results in a thick mixture during the reaction. The tube is positioned to supply ammonia gas subsurface but not interfere with the stir blade.

2. The submitters used benzene in their procedure.

3. Allyl chloroformate (97%), formic acid (88%), cinchonine (85%), methyl acetoacetate (99%), sodium carbonate (>99.5%), 1,3-dimethylbarbituric acid (99%), benzyl isocyanate (99%), benzaldehyde (99+% redistilled), toluene (99%), methanol (99%), ethanol (99.5%), ethyl acetate (99.5%), hexanes (99.5%) and glacial acetic acid (99+%) were obtained from Aldrich Chemical Co., Inc. and were used as received. Sodium chloride (99%) was obtained from VWR and used as received. Tetrakis(triphenylphosphine)palladium(0) (99%) was obtained from Strem Chemicals Inc. and used as received. Benzenesulfonic acid sodium salt (97%) was obtained from Acros. Ammonia gas was obtained from Linde Gas LLC and was used as received. The submitters obtained all anhydrous solvents from Thermo Fisher Scientific Inc. and purified through use of a dry solvent system (pressure filtration under argon through activated alumina). The checkers used anhydrous solvents as received from Aldrich Chemical Co.

4. The reaction was followed by ¹H NMR by diluting a sample into CDCl₃ and integrating the methylene protons of the allyl group of the starting material and product. The reaction progressed as follows: 50% conversion at 1.5 h, 85% conversion at 3 h, and >99% conversion at 5 h.

5. NMR analysis indicated the mixture contained 89 % allyl carbamate by weight, along with 11 wt% toluene. The distillate from the concentration was analyzed by NMR and contained no product.

6. Two fractions were collected, a small forecut at 65-66 °C (3.87 g) and the main cut, 66-67 °C, (59.36 g). The fractions were combined after NMR analysis indicated similar purity. Approximately 3 mL remained as pot residue, and about 10 mL of toluene was collected in the dry-ice vacuum trap.

7. Allyl carbamate has the following physical properties: clear oil; bp 207-208 °C. ¹H NMR pdf (CDCl₃, 400 MHz) δ: 4.55 (dd, J = 5.6, 1.5 Hz, 2 H), 5.2 (br, 2 H, NH₂), 5.21 (dd, J = 10.5, 1.4 Hz, 1 H), 5.31 (dd, J = 17.1, 1.4 Hz, 1 H), 5.90 (m, 1 H); ¹³C NMR pdf (CDCl₃, 100 MHz) δ: 65.8, 117.9, 132.8, 157.2; IR (thin film, cm^-1): 2400, 1728, 1216; HRMS m/z 124.0368 [(M + Na⁺) calcd for C₄H₇NO₂Na⁺: 124.0374]. The purity (>99%) was determined by GC with a Agilent J&W HP-5 column (0.32 mm × 30 m)(oven temperature: 110 °C; head pressure: 60 kPa; retention time: 3.8 min).

8. The reaction is monitored by ¹H NMR by taking an aliquot of the reaction, diluting in DMSO-d₆, and integrating the benzaldehyde resonance at 10 ppm relative to the total aromatic protons. The reaction is about 80% complete in 4 days.

9. The submitters dried the material by addition of 100 mL toluene and concentrating to a solid by rotary evaporation.

10. (Benzenesulfonyl-phenyl-methyl)-carbamic acid allyl ester has the following physical properties: white solid; mp 148-150 °C. (Submitters report mp 162-165 °C). ¹H NMR pdf (CDCl₃, 400 MHz) δ: 4.42 (d, J = 5.2 Hz, 2 H), 5.22 (m, 2 H), 5.76 (m, 1 H), 6.01 (dd, J = 10.8, 10.5 Hz, 2 H), 7.39-7.46 (m, 5 H), 7.53 (m, 2 H), 7.66 (m, 1 H), 7.86 (m, 2 H); ¹³C NMR pdf (CDCl₃, 75.0 MHz) δ: 66.7, 74.7, 118.7, 129.0 (degenerate), 129.0, 129.4, 129.7, 130.1, 132.1, 134.3, 136.8, 154.7; IR (thin film, cm^-1): 3334, 3063, 1730, 1527, 1496, 1448, 1308, 1235, 1141, 1081, 691; HRMS m/z 354.0796 [(M + Na⁺) calcd for C₁₇H₁₇NO₄NaS⁺: 354.0776]. The purity (>95%) was determined by ¹H NMR.

11. Chilling system Thermo NESLAB CB-60 with cryotrol probe was used by the submitters; a Julabo FT 901 chiller was used by the checkers The isopropyl alcohol bath temperature is monitored using a thermometer.

12. Maintaining the temperature near -15 °C during the addition of base is critical. In one run by the checkers, the temperature rose to -6 °C during the addition, which resulted in a decrease in the ee (85% vs 91%).

13. The initial extraction is carried out at 0 °C to prevent racemization of the product. The 2-phase mixture contains solids (which were determined to be cinchonine and related by-products by NMR). The solids are kept with the upper aqueous phase in all the separations.

14. The residue is dissolved in 40 mL of anhydrous dichloromethane and is loaded onto a 3-in.×12-in. column, wet-packed (10% ethyl acetate in hexanes) with 300 g of silica gel (submitters used Sorbent Technologies, 60 Å; checkers used EM Sciences, EM60, 230-400 mesh), and eluted with a gradient of ethyl acetate in hexanes (1 L of 20%, 2.5 L of 30%). The desired product is collected in fractions of 100-mL volume. TLC analysis is performed on silica gel with 30% ethyl acetate in hexanes as eluent, visualization with ultraviolet light and by staining with ceric ammonium molybdate. R_f = 0.3. Methyl acetoacetate elutes just before the product. If less silica gel is used, methyl acetoacetate is not fully separated from the product. ¹H NMR analysis of the combined fractions indicates the product is a ~1:1 mixture of diastereomers.

15. A single diastereomer can be isolated by crystallization of the diastereomeric mixture, as follows. 400 mg of the diastereomeric mixture is added to 20 mL hexanes and heated to reflux. Ethyl acetate (1.5 mL) is added to fully dissolve all solids, then the solution is allowed to cool to ambient temperature with stirring. After stirring overnight (15 hours) the mixture is filtered and washed with 5 mL hexanes to provide 320 mg of white needles after drying in ambient air. ¹H NMR analysis indicated an 88:12 mixture of diastereomers. The high recovery (80%) and the fact that the supernatant contained a 1:1 mixture of diastereomers suggested a racemization/crystallization process was occurring, funneling the mixture to the less soluble diastereomer. One additional recrystallization under the same procedure provided one diastereomer (97.5:2.5 diastereomeric ratio and >99% ee by the chiral HPLC method outlined below). 2-[(R)-Allyloxycarbonylamino-phenyl-methyl)-3-oxo-butyric acid methyl ester has the following physical properties: white solid, single diastereomer; mp 96-98 °C. ¹H NMR pdf (CDCl₃, 400 MHz) less soluble diastereomer δ: 2.15 (s, 3 H), 3.70 (s, 3 H), 4.07 (d, J = 5.5 Hz, 1 H), 4.55 (dd, J = 4.3, 1.0 Hz, 2 H), 5.20 (d, J = 10.3 Hz, 1 H), 5.27 (d, J = 17.0 Hz, 1 H), 5.48 (dd, J = 6.2, 9.1 Hz, 1 H), 5.88 (m, 1 H), 6.12 (br d, J = 9 Hz, 1 H), 7.24-7.35 (m, 5 H). More soluble diastereomer δ: 2.33 (s, 3 H), 3.65 (s, 3 H), 4.02 (br s, 1 H), 4.55 (m, 2 H), 5.20 (d, J = 10.0 Hz, 1 H), 5.29 (d, J = 16.5 Hz, 1 H), 5.58 (m, 1 H), 5.90 (m, 1 H), 6.40 (s, 1 H), 7.22-7.37 (m, 5 H); ¹³C NMR pdf (100 MHz, CDCl₃) less soluble diastereomer, δ: 31.0, 53.0, 54.6, 63.2, 66.0, 117.9, 126.3, 126.6, 128.0, 128.7, 128.9, 132.9, 139.6, 155.7, 167.9, 203.3; more soluble diastereomer, δ: 29.1, 52.6, 53.5, 64.3, 66.0, 118.3, 126.3, 126.6, 128.0, 128.5, 128.9, 132.8, 139.4, 155.9, 169.2, 201.0; IR (thin film, cm^-1), both diastereomers reported: 3374, 2955, 1718, 1527, 1434, 1360, 1248, 1048, 993, 904, 730. HRMS m/z 328.1167 [(M + Na⁺) calcd for C₁₆H₁₉NO₅Na⁺: 328.1161]. The purity (>98%) was determined by HPLC-ELSD (210 nm).

16. The four diastereomers were separated by a normal phase HPLC method using a Chiralpak AD-H column (250 × 4.6 mm, 5 micron) with isocratic elution consisting of 15% (1:1 MeOH:EtOH) and 85% heptane, a flow rate of 1.0 mL/min and detection at 210 nm. Elution times: major enantiomeric pair (13.5 and 16 min), minor enantiomeric pair (10.5 and 11.5 min). The enantiomeric ratio was determined to be 95:5 on the diastereomeric mixture isolated from the silica gel chromatography. The material that was recrystallized twice showed none of the minor enantiomer (detection limit 0.5%). This diastereomer reverts back to a 1:1 mixture in a solution of methanol over a 24 hour period. The opposite enantiomeric pair was prepared by carrying out the reaction using cinchonidine instead of cinchonine. The reaction with cinchonidine carried out at 0-5 °C provided an 89:11 enantiomeric ratio.

17. The weight is corrected for 4% residual ethyl acetate present from the previous step.

18. The reaction was followed by TLC on silica gel with 1:1 ethyl acetate/hexanes as eluent (R_f = 0.3). The reaction was >90% complete by TLC analysis in 2 hours.

19. The residue is combined with 6 mL of dichloromethane to make the oil mobile and is loaded onto a 3-in.×12-in. column, wet-packed (10% ethyl acetate in hexanes) with 380 g of silica gel (submitters used Sorbent Technologies, 60 Å; checkers used EM Sciences EM60, 230-400 mesh), and eluted with a gradient of ethyl acetate in hexanes (2 L of 25%, 1 L of 33%, 2 L of 40%, 1.5 L of 50%). The desired product is collected in fractions of 100-mL volume. TLC analysis is performed on silica gel with 50% ethyl acetate in hexanes as eluent, visualization with ultraviolet light and by staining with ceric ammonium molybdate. R_f = 0.30.

20. The weight of the isolated oil is 7.14 g. The yield of 6.07g is corrected based on a purity of 85%, which includes 10% ethyl acetate by weight and an estimated 5% impurity. 2-[(R)-(3-Benzyl-ureido)-phenyl-methyl]-3-oxo-butyric acid methyl ester has the following physical properties: white solid; mp 100-102 °C. ¹H NMR pdf (CDCl₃, 400 MHz, both diastereomers reported) δ: 2.22 (s, 3 H), 2.30 (s, 3 H), 3.53 (s, 3 H), 3.60 (s, 3 H), 4.01 (d, J = 8.4 Hz, 1 H), 4.06 (d, J = 4.5 Hz, 1 H), 4.28 (m, 4 H), 5.38 (t, J = 5.8 Hz, 1 H), 5.47 (t, J = 5.8 Hz, 1 H), 5.62 (dd, J = 9.4, 7.7 Hz, 1 H), 5.79 (dd, J = 9.7, 4.8 Hz, 1 H), 6.13 (d, J = 9.4 Hz, 1 H), 6.40 (d, J = 9.8 Hz, 1 H), 7.17-7.30 (m, 20 H). ¹³C NMR pdf (CDCl₃, 100 MHz, both diastereomers reported) δ: 29.1, 30.1, 44.5, 44.6, 52.3, 52.4, 52.7, 53.8, 64.2, 64.6, 126.3, 126.7, 127.5, 127.6, 128.7, 128.8, 139.3, 139.4, 140.1, 140.3, 157.5, 157.6, 168.1, 169.8, 202.2, 204.0. IR (thin film, cm^-1): 3408, 3019, 1740, 1709, 1687, 1527, 1453, 1364, 1216, 929, 909, 700. HRMS m/z 355.1690 [(M + H⁺) calcd for C₂₀H₂₂N₂O₄⁺: 355.1613]. The purity (>90%) was determined by HPLC-ELSD (210 nm).

21. When just water is employed for the extractions, the separation is very slow and incomplete.

22. The residue is loaded onto a 3-in.×12-in. column, wet-packed (10% ethyl acetate in hexanes) with 220 g of silica gel (submitters used Sorbent Technologies, 60 Å; checkers used EM Sciences EM60, 230-400 mesh), and eluted with a gradient of ethyl acetate in hexanes (1 L of 20%, 1L of 30%, 500 mL of 40%, 1 L 50%). The desired product is collected in fractions of 100-mL volume. TLC analysis on silica gel with 50% ethyl acetate in hexanes as eluent and visualization with ultraviolet light and stained with ceric ammonium molybdate. R_f = 0.6.

23. (S)-1-Benzyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic methyl ester has the following physical properties: white solid; mp 136-137 °C. ¹H NMR pdf (CDCl₃, 400 MHz) δ: 2.45 (s, 3 H), 3.64 (s, 3 H) 4.88 (d, J = 16.4 Hz, 1 H), 5.21 (d, J = 16.1 Hz, 1 H), 5.45 (s, 1 H), 5.99 (s, 1 H), 7.11 (d, J = 7.7 Hz, 2 H), 7.22-7.29 (m, 10 H). ¹³C NMR pdf (CDCl₃, 100 MHz) δ: 16.7, 46.2, 51.6, 54.0, 104.9, 126.5, 126.6, 127.4, 128.0, 128.90, 128.93, 138.1, 143.2, 149.5, 154.2, 166.7. IR (thin film, cm^-1): 3234, 2948, 1685, 1623, 1456, 1387, 1257, 1203, 1164, 1106, 696. HRMS m/z 359.1375 [(M + Na⁺) calcd for C₂₀H₂₀N₂O₃⁺: 359.1372]. [a]²³_D -29.8 (c 1.00, CHCl₃). The purity (>95%) was determined by HPLC-ELSD (210 nm).

24. The enantiomeric ratio of the product was determined to be 95:5 using the following reverse phase HPLC method: Chiralcel OD-RH, (150 × 4.6 mm), 5 micron, isocratic elution, A: 0.1% H₃PO₄, B: MeCN, A: 45: B: 55; flow of 1.0 mL/min., ambient temp., detection at 210 nm. Major enantiomer elutes at 6.5 min, minor at 8 min. A normal phase HPLC method can also be employed: Chiralcel OD, (250 × 4.6 mm), 10 micron, isocratic elution, A: 2-propanol, B: heptane, A: 5: B: 95, flow of 1.0 mL/min., ambient temp., detection at 210 nm; Major enantiomer elutes at 31 min, minor at 39 min.

25. The checkers used the following recrystallization procedure to upgrade the final product to optical purity: In a 100-mL round-bottomed flask equipped with a 1.5 cm oval magnetic stir bar is added (S)-1-benzyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic methyl ester (2.00 g, 95:5 er) and ethyl acetate (20 mL). The mixture is warmed to 50 °C in a water bath with stirring to dissolve the solids. While warm, n-heptane (20 mL) is added dropwise with stirring over 5 min, resulting in crystallization of a white solid. The mixture is cooled over 20 min to ambient temperature and is stirred for 1 h to afford a thick slurry. The mixture is vacuum filtered through a 30 mL sintered glass funnel and washed with 10 mL of 1:1 heptane/EtOAc to provide 1.59 g (80%) of white needles after air drying. The ee was determined to be >99.5% based on the limit of detection of the reverse phase HPLC method in Note 24. The submitters used the following recrystallization procedure to upgrade the final product to optical purity: In a 150-mL Erlenmeyer flask, (S)-1-benzyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic methyl ester (3.5 g, 95:5 er) is added to boiling diethyl ether (60 mL). The solution is boiled until most of the solid has dissolved. The solution is cooled in an ice-water bath until complete crystallization is observed (approximately 20 minutes). The pure dihydropyrimidone crystals are vacuum filtered, and are rinsed with two 20 mL portions of cold diethyl ether. The remaining mother liquor is concentrated under reduced pressure, and the resulting solid is transferred to a 150-mL Erlenmeyer flask containing boiling diethyl ether (30 mL). The solution is boiled until most solid has dissolved, and subsequently cooled in an ice-water bath until complete crystallization is observed (approximately 20 minutes). The crystals are filtered, and rinsed with 2 × 10 mL portions of cold diethyl ether. The solids are combined and dried under reduced pressure to yield 2.70 g (77 %) of (S)-1-benzyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetra-hydropyrimi-dine-5-carboxylic methyl ester. The enantiomeric ratio of the product was determined to be >99:1 using the normal phase HPLC method in Note 24.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

Chiral dihydropyrimidones are an important class of heterocycles that range in biological and pharmacological behavior.² While racemic dihydropyrimidones are easily prepared through use of the Biginelli reaction,³ few methods provide dihydropyrimidinones in enantioenriched form.⁴ The Mannich addition of ß-ketoesters to acyl imines catalyzed by the cinchona alkaloids provides a chiral amine precursor to the enantioenriched dihydropyrimidinone core.⁵

The Mannich reaction proceeds well for aryl imines, however, in the case of aliphatic imines, tautomerization to the enamine restricts reactivity for nucleophilic addition. Recent methodology overcomes this challenge through the development of a biphasic cinchona alkaloid-catalyzed Mannich reaction utilizing a-amido sulfones.⁶ The bench-stable and easily prepared a-amido sulfones serve as precursors to acyl imines; the acyl imine is formed in situ in the presence of sodium carbonate and the cinchona alkaloid catalyst.⁷ Utilization of the a-amido sulfones in the cinchona alkaloid-catalyzed asymmetric Mannich reaction provides good control of enantioselectivity and scalability.

Conversion of the chiral amine precursor to the asymmetric dihydropyrimidone proceeds through two high yielding synthetic steps. Formation of the chiral primary amine and addition of benzyl isocyanate provides the benzyl ureido intermediate in high yield. The heterocycle is formed using reflux or microwave conditions in the presence of acetic acid and ethanol. Both methods provide the dihydropyrimidone in high yield with retention of stereochemistry.

With this methodology, a library of dihydropyrimidones was synthesized with three points of diversity (Table 1). The a-amido sulfone, ß-ketoester and isocyanate were each altered to provide a diverse set of heterocycles in high yields and enantioselectivities. The stereochemical configuration of the dihydropyrimidone is dictated by the choice of cinchona alkaloid catalyst used in the Mannich reaction.

Table 1. Diverse Library of Asymmetric Dihydropyrimidones

References and Notes

Department of Chemistry, Boston University, Boston, MA 02215.
For reviews on dihydropyrimidones, see: (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879-888. (b) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043-1058.
(a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360-416. (b) Kappe, C. O. Tetrahedron 1993, 49, 6937-6963.
(a) Chen, X.; Yu, X.; Liu, H.; Chun, L.; Gong, L. J. Am. Chem. Soc. 2006, 128, 14802-14803. (b) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386-16387. (c) Schnell, B.; Strauss, U.T.; Verdino, P.; Faber, K.; Kappe, C. O.; Tetrahedron: Asymmetry 2000, 11, 1449-1453. (d) Kleidernigg, O.P.; Kappe, C.O. Tetrahedron: Asymmetry 1997, 8, 2057-2067. (e) Lewandowske, K.; Murer, P.; Svec, F.; Frechet, J.M. J. J. Comb. Chem. 1999, 1, 105-112. (d) Kappe, C. O.; Uray, G.; Roschger, P.; Lindner, W.; Kratky, C.; Keller, W. Tetrahedron 1992, 48, 5473-5480. (e) Kontrec, D.; Vinkovic, V.; Sunjic, V.; Schuiki, B.; Fabian, W. M.; Kappe, C. O. Chirality 2003, 15, 550. (f) Muñoz-Muñiz, O.; Juaristi, E. ARKIVOC 2003, 11, 16-26. (g) Guillena, G.; Ramon, D.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693-700.
(a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256-11257. (b) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003-2006. (c) Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, ASAP, DOI: 10.1021/jo701777g.
Review: Petrini, M. Chem. Rev. 2005, 105, 3949-3977.
(a) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75. (b) Kanazawa, S. M.; Denis, J. N.; Greene, S. E. J. Org. Chem. 1994, 59, 1238-1240. (c) Zawadzki, S.; Zwierzak, A. Tetrahedron Lett. 2004, 45, 8505-8506. (d) Morton, J.; Rahim, A.; Walker, E. R. H. Tetrahedron Lett. 1982, 23, 4123-4126.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Carbamic acid, 2-propen-1-yl ester; (2114-11-6)

Carbamic acid, N-[phenyl(phenylsulfonyl)methyl]-, 2-propen-1-yl ester; (921767-12-6)

(ß R)-Benzenepropanoic acid, a-acetyl-ß-[[(2-propen-1-yloxy)carbonyl]amino]-, methyl ester; (921766-57-6)

(ß R)-Benzenepropanoic acid, a-acetyl-ß-[[[(phenylmethyl)amino]carbonyl]amino]-, methyl ester; (865086-76-6)

(4S)-5-Pyrimidinecarboxylic acid, 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-1-(phenylmethyl)-, methyl ester; (865086-56-2)

	Scott E. Schaus studied chemistry at Boston University, where he completed his undergraduate degree in 1995. He received his Ph.D. in organic chemistry from Harvard University in 1999 under the direction of Professor Eric N. Jacobsen. His graduate work focused on the development of chiral salen transition metal catalysts and reactions for use in synthesis. He carried out his postdoctoral research as an NIH Postdoctoral Fellow in Professor Andrew G. Myers's laboratories studying the use of genomic technologies to facilitate drug target identification. In 2001 he joined the Department of Chemistry at Boston University as an Assistant Professor and, in 2002, he became one of the co-principal investigators of the Center for Chemical Methodology and Library Development at Boston University. His research interests include the development of asymmetric catalytic reactions for synthesis, new methodologies for library synthesis, and drug target identification and validation.
	Jennifer Goss was born in Houston, Texas, in 1983. She received a B.S. in Chemistry in at Texas A&M University in College Station, Texas, where she performed undergraduate research in polymer chemistry with Professor Steven Miller. She began pursuing a doctorate degree in Organic chemistry in 2005 in the lab of Professor Scott E. Schaus. Her research focuses on catalytic asymmetric syntheses of dihydropyrimidones.
	Peng Dai obtained his B. S. degree from the University of Science and Technology of China in 1997. He completed his Ph. D. studies in December 2004 under the guidance of Prof. Patrick H. Dussault at the University of Nebraska-Lincoln, where he studied asymmetric synthesis of peroxide natural products. He joined the CMLD-BU in November 2005 and works on the synthesis of dihydropyrimidones and related chemical libraries.
	Sha Lou was born in He Bei, China, in 1979. He received a B.S. in Chemistry at Beijing University of Chemical Technology in 2002, where he conducted undergraduate research in fullerene functionalizations with Professor Shen-yi, Yu. He is currently pursuing a Ph.D. degree under the direction of Professor Scott E. Schaus. His research has focused on transition metal- and organic molecule-catalyzed asymmetric carbon-carbon bond forming reactions and synthesis.

Notes

References/EndNotes

Article Compounds

Authors