Organic Syntheses Procedure

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Org. Synth. 2006, 83, 121

DOI: 10.15227/orgsyn.083.0121

(R,R)-2,2'-BISPYRROLIDINE AND (S,S)-2,2'-BISPYRROLIDINE: USEFUL LIGANDS FOR ASYMMETRIC SYNTHESIS

Submitted by Scott E. Denmark, Jiping Fu, and Michael J. Lawler¹.

Checked by Sandra Lee, Elliott Huntsman, and Edward J.J. Grabowski.

1. Procedure

Caution! This procedure should be carried out in a well-ventilated hood because of the stench of pyrrolidine and 2,2'-bispyrrolidine. The hood doors should be covered with an opaque sheet to shield the UV light.

A. , (R∗,R∗)-2,2'-Bispyrrolidine(R∗,R∗) and (R∗,S∗)-2,2'-Bispyrrolidine.²^,³ A three-necked, 500-mL flask equipped with three quartz refluxing columns and three water condensers (Figure 1) is charged with pyrrolidine (160 mL) and a drop of mercury (Notes 1 and 2). The water condensers are equipped with gas inlets connected to a single nitrogen source leading to an oil bubbler. The flask is placed in a Rayonet Photoreactor fitted with 14 × 8 Watt low pressure Hg lamps (254 nm). The reaction mixture is heated to reflux with a heating mantle. The lamps are turned on, after which the mixture is heated at reflux for 7 days. After the lamps are turned off, the system is allowed to cool to room temperature (Note 2). The liquid is then carefully decanted to a distillation flask and the mercury is recovered. Unreacted pyrrolidine and side products are removed by distillation at atmospheric pressure (Note 3). The residue is distilled to provide 67.6 g (50%) of a mixture of (R∗,R∗) and (R∗,S∗)-2,2'-bispyrrolidine as a clear, light yellow liquid (bp 79–81 °C at 3.0 mmHg) (Note 4). The product is of sufficient purity to be used in the resolution step (Note 5).

Figure 1. Apparatus for photodimerization of pyrrolidine.

B. Resolution of 2,2'-Bispyrrolidine³^,⁴

1. Preparation of (R,R)-2,2'-Bispyrrolidine·(L)-Tartrate To a solution of a 1/1 mixture of d,l- and meso-2,2'-bispyrrolidine (67.0 g, 479 mmol) in H₂O (240 mL) is added (L)-(+)-tartaric acid (36.0 g, 240 mmol, 0.5 equiv) and acetic acid (27.4 mL, 479 mmol, 1.0 equiv) (Note 6). The mixture is heated to 90 °C and the homogenous solution is allowed to cool to room temperature slowly before it is placed in an ice bath. After the solid precipitates (Note 7), the mixture is kept in an ice bath for another 2 h. The precipitate is then filtered and is washed with ice-cold water (20 mL). The mother liquor is saved for the recovery of the (S,S)-2,2'-bispyrrolidine. The collected solid is dried under high vacuum (0.5 mmHg) at 80 °C for 2 h to give 31.6 g of a light yellow powder. This solid is dissolved in hot water (90 mL) and the solution is allowed to cool slowly to room temperature before it is placed in an ice bath for 1 h. The precipitate is filtered and the solid is washed with ice-cold water (10 mL). The solid is dried under high vacuum (0.5 mmHg) at 80 °C for 2 h to give 23.0 g of white crystals. This recrystallization process is repeated using water (50 mL) to give 21.4 g (62% based on isomer content) of (R,R)-2,2'-bispyrrolidine·(L)-tartrate as white prismatic crystals (Note 8).

2. Preparation of (R,R)-2,2'-Bispyrrolidine To a mixture of the tartrate salt (9.1 g) in water (15 mL) at 0 °C are added KOH (20 g) pellets (Note 9). The mixture is then stirred at 0 °C for 10 min before diethyl ether (80 mL) is added, whereupon the solution is stirred at 0 °C for another 30 min. The aqueous layer is then separated and extracted with diethyl ether (6 × 50 mL) (Note 10). The diethyl ether extracts are combined, dried (K₂CO₃) and then are concentrated under vacuum (Note 11). The residue is transferred to a dry 25-mL, round-bottomed flask. To this is added a small piece of sodium (Note 12) and the mixture is stirred at room temperature under nitrogen for 30 min. The residue is distilled under vacuum to give 3.61 g (83%) of (R,R)-2,2'-bispyrrolidine as a clear colorless oil (bp 97–98 °C at 8.0 mmHg) (Note 13). The enantiomeric purity of product is determined by CSP-SFC and CSP-HPLC analysis of the corresponding dibenzoyl amide derivative (Note 14).

3. Preparation of (S,S)-2,2'-Bispyrrolidine·(D)-Tartrate The mother liquor from initial resolution is cooled to 0 °C and KOH pellets (80 g) are added slowly. The mixture is stirred vigorously at 0 °C for 10 min (Note 15). To this solution is added diethyl ether (500 mL) and the mixture is stirred at room temperature for 20 min. The aqueous layer is separated and then is extracted with diethyl ether (4 × 500 mL). The diethyl ether extracts are combined, dried (K₂CO₃), and then are concentrated under vacuum to give 48.4 g of a yellow oil. The oil is dissolved in H₂O (150 mL), then (D)-(−)-tartaric acid (34.5 g, 230 mmol) and acetic acid (27.0 mL, 473 mmol) are added (Note 16). The mixture is heated to 90 °C and the homogenous solution is allowed to cool to room temperature slowly before it is cooled in an ice bath. After the solid precipitates, the mixture is kept in an ice bath for another 2 h. The precipitate is filtered and the solid is washed with ice-cold water (10 mL), and then is dried under high vacuum (0.5 mmHg) at 80 °C for 2 h to give 23.5 g of a light-yellow powder. The solid is dissolved in hot water (60 mL) and the solution is allowed to cool slowly to room temperature before it is placed in an ice bath for another 2 h. The precipitate is filtered, washed with 10 mL of ice-cold water, and dried under high vacuum (0.5 mmHg) at 80 °C for 2 h to give 20.16 g of white prismatic crystals. This recrystallization process is repeated using water (55 mL) to give 18.4 g (55% based on isomer content) of (S,S)-2,2'-bispyrrolidine·(D)-(−)-tartrate as white prismatic crystals (Note 17).

4. Preparation of (S,S)-2,2'-Bispyrrolidine To a solution of the tartrate salt (9.3 g) in water (15 mL) at 0 °C are added KOH pellets (20 g). The mixture is stirred at 0 °C for 10 min before diethyl ether (80 mL) is added, whereupon it is stirred at 0 °C for another 30 min. The aqueous layer is separated and then is extracted with diethyl ether (6 × 50 mL). The diethyl ether extracts are combined, dried (K₂CO₃) and then are concentrated in vacuo (Note 11). The residue is then transferred to a dry 25-mL, round-bottomed flask. To this is added a piece of sodium (Note 12) and the mixture is stirred at room temperature under nitrogen for 30 min. The residue is then distilled under vacuum to give 3.51 g (80%) of (S,S)-2,2'-bispyrrolidine as a clear, colorless oil (bp 97–98 °C at 8.0 mmHg) (Note 18). The enantiomeric purity of product is determined by CSP-SFC and CSP-HPLC analysis of corresponding dibenzoyl amide derivative (Note 19).

2. Notes

1. The three quartz-refluxing columns are 34 cm long and 4.0 cm in diameter. All joints are well sealed with high vacuum grease to avoid leakage. Pyrrolidine (99 %) was purchased from Aldrich Chemical Company, Inc., and was used without further purification.

Variables that are difficult to control relative to the photolysis include the age and actual power of the Hg lamps, the actual length of the quartz tubes receiving the UV light and the rate of reflux. All affect the overall rate of photolysis. The checkers found it convenient to follow the progress of the photolysis by periodically sampling the reaction and analyzing it by ¹³C-NMR spectroscopy in CDCl₃. The peak heights for the methylene groups for pyrrolidine (47.1 ppm) and the bis-pyrrolidines (47.0 and 46.6) were used as measures of the relative ratios of these species. When the pyrrolidine is almost consumed in the photolysis, the reflux ceases. The submitters were able to recover ~50% of the bis-pyrrolidines after distillation following a seven-day photolysis (See Note 5). The checkers achieved the following results: 39% in seven days; 60% in nine days; 72% in 11.4 days and 60% in five days at half-scale.

2. The crude reaction mixture can be analyzed by ¹H NMR. The ratio of starting material to products can be estimated from the NMR spectrum.

3. The distillate contains 46.6 g of colorless liquid.

4. The distillation should be done carefully to avoid solidification of the diamine in the condenser.

5. The crude material (67.6 g, approximately 50% based on the pyrrolidine charged) contains a ca. 1/1 mixture of d,l and meso isomers: ¹H NMR pdf (500 MHz, CDCl₃) d: 1.32–1.46 (m, 2 H), 1.61–1.92 (m, 8 H), 2.82–2.98 (m, 6 H). The checkers obtained 52.6 g from the seven-day photolysis; 81.0 g from the nine day photolysis; 97.0 g from the 11.4 day photolysis and 41.5 g from the five day photolysis at half-scale.

6. L-(+)-Tartaric acid (99% GLC) was purchased from Aldrich Chemical Company, Inc., and was used without further purification. Acetic acid (glacial) was purchased from Fisher Scientific Company and was used without further purification. In completing the checking of this procedure, the subsequent reactions were scaled to reflect the quantity of bispyrrolidines obtained in the distillations. The reactions checked at the yields indicated.

7. The initial formation of crystals may take up to 16 h. The process can be facilitated by stirring the mixture with glass rod or by addition of small amount of seed crystals.

8. The analytical data for (R,R)-2,2'-bispyrrolidine·(L)-tartrate are as follows:⁴ mp 212–216 °C; ¹H NMR pdf (500 MHz, D₂O/DSS) d: 1.88–1.98 (m, 2 H), 2.08–2.28 (m, 4 H), 2.40–2.48 (m, 2 H), 3.51–3.55 (m, 4 H), 3.92–4.00 (m, 2 H), 4.43 (s, 2 H), 4.86 (br, 6 H); ¹³C NMR pdf (126 MHz, D₂O) d: 25.5, 31.0, 49.1, 63.2, 76.6, 181.4; IR (KBr) cm⁻¹: 3220, 2717, 2516, 1693, 1612, 1583, 1450, 1386, 1321, 1124, 1072, 709; [α]_D24 +17.9 (c = 1.00, H₂O); Anal. Calcd for C₁₂H₂₂N₂O₆: C, 49.65; H, 7.64, N, 9.65. Found: C, 49.80; H, 7.63; N, 9.65. The checkers noted slight chemical shift variations in the NMR spectra of this material, and attribute these to slight differences in concentration and apparent pH in the different samples.

9. Potassium hydroxide (87.7%) was purchased from Fisher Scientific Company and was used without further purification.

10. Diethyl ether was purchased from Mallinckrodt Inc. and was used without purification.

11. The water bath is kept at 0 °C to avoid loss of (R,R)-2,2'-bispyrrolidine.

12. The piece of sodium is about 0.5 cm² and it is washed with hexane before use. After distillation, the sodium was destroyed by the careful addition of isopropyl alcohol.

13. The analytical data for (R,R)-2,2'-bisyrrolidine are as follows:³^,⁴ ¹H NMR pdf (500 MHz, CDCl₃) d: 1.31–1.38 (m, 2 H), 1.65–1.84 (m, 6 H), 2.06 (br, 2 H), 2.82–2.97 (m, 6 H); ¹³C NMR pdf (126 MHz, CDCl₃) d: 25.4, 29.0, 46.4, 63.8; IR (KBr) cm⁻¹: 3270, 2956, 2867, 1282, 1118, 1076; MS (FAB) (m/z): 141; HRMS (m/z) C₈H₁₇N₂ (M + H): Calc.: 141.1386; Found: 141.1375; [α]_D24−14.91 (c = 1.03, MeOH); Anal. Calcd for C₈H₁₆N: C, 68.52; H, 11.50, N, 19.98. Found: C, 68.38; H, 11.64; N, 19.92. The free diamine is extremely hygroscopic, oxygen sensitive and absorbs CO₂ rapidly in air.

14. Procedure for derivatization is as follows (eq 1)³^,⁴: To a solution of (R,R)-2 (140 mg, 1.0 mmol) in 1.0 mL of methylene chloride (purchased from Fisher Scientific Company and distilled from P₂O₅) at 0 °C is added triethylamine (278 mL, 2.0 mmol, 2.0 equiv, purchased from Aldrich Chemical Company, Inc., and distilled from CaH₂) and benzoyl chloride (232 mL, 2.0 mmol, 2.0 equiv, purchased from Aldrich Chemical Company, Inc., and distilled before use). The mixture is stirred at room temperature for

4 h and then EtOAc (50 mL) and H₂O (10 mL) are added. The aqueous layer is separated and then is extracted with EtOAc (3 × 15 mL). The organic layers are combined, washed with 15 mL of saturated, aqueous sodium bicarbonate solution, dried over Na₂SO₄ and then concentrated under vacuum. The residue is purified by column chromatography (SiO₂, hexane/i-PrOH, 6/1) to give 295 mg (85%) of (R,R)-3 as a white solid. The analytical data for (R,R)-3 are as follows:⁴ ¹H NMR pdf (500 MHz, CDCl₃) d: 1.76–2.05 (m, 6 H) 2.20–2.28 (m, 2 H), 3.19 (dt, J = 10.3, 7.8, 2 H), 3.79 (ddd, J = 10.5, 8.8, 5.1, 2 H), 4.59–4.64 (m, 2 H), 7.22–7.36 (m, 6 H), 7.38–7.42 (m, 4 H); ¹³C NMR pdf (126 MHz, CDCl₃) d: 24.1, 28.2, 49.1, 58.8, 127.1, 128.2, 129.5, 137.2, 164.5; IR (CHCl₃) cm⁻¹: 2997, 2881, 1624, 1576, 1427, 700; MS (EI, 70 eV): 348, 175, 174, 105; HRMS (m/z): Calc. C₂₂H₂₅N₂O₂ (M + H): 349.1911; Found: 349.1900; Supercritical Fluid Chromatography: t_R (R,R)-3 2.86 min (100 %); t_R (S,S)-3 3.26 min (0 %) (Chiralpak AS, 40 °C, 150 bar, 15 % MeOH in CO₂, 3.0 mL/min, 220 nm); HPLC: t_R (S,S)-3 8.2 min (0%); t_R (R,R)-3 13.2 min (100%) (Chiralpak AD, i-PrOH/hexane, 95/5, 0.7 mL/min)

15. The submitters initially used 40 g of KOH pellets for the neutralization. The checkers found that the use of 80 g was necessary to assure extraction of all of the diamine.

16. D-(−)-Tartaric acid (97% GLC) was purchased from Aldrich Chemical Company, Inc., and was used without further purification.

17. The analytical data for (S,S)-2,2'-bispyrrolidine·(D)-(−)-tartrate are as follows: mp 214–218 °C; ¹H NMR pdf (500 MHz, D₂O/DSS) d: 1.88–1.99 (m, 2 H), 2.08–2.29 (m, 4 H), 2.41–2.49 (br, 2 H), 3.52–3.57 (m, 4 H), 3.94–4.01 (m, 2 H), 4.44 (s, 2 H), 4.84 (br, 6 H); ¹³C NMR pdf (126 MHz, D₂O) d: 25.5, 31.0, 49.1, 63.16, 76.6, 181.4; IR (KBr) cm⁻¹: 3384, 3242, 2997, 2885, 2717, 2517, 1693, 1610, 1583, 1387, 1124, 1072, 710; [α]_D24−17.7 (c = 1.02, H₂O); Anal. Calcd for C₁₂H₂₂N₂O₆: C, 49.65; H, 7.64, N, 9.65. Found: C, 49.98; H, 7.43; N, 9.37. The checkers noted slight chemical shift variations in the NMR spectra of this material, and attribute these to slight differences in concentration and apparent pH in the different samples.

18. The analytical data for (S,S)-2,2'-bisyrrolidine are as follows: ¹H NMR pdf (500 MHz, CDCl₃) d: 1.31-1.38 (m, 2 H), 1.65-1.84 (m, 6 H), 2.06 (br, 2 H), 2.82-2.97 (m, 6 H); ¹³C NMR pdf (126 MHz, CDCl₃) d: 25.4, 29.0, 46.4, 63.8; IR (KBr) cm⁻¹: 3263, 2954, 2867, 2821, 1457, 1442, 1280, 1118, 1076, 892, 869; MS (FAB) (m/z) 141; HRMS (m/z) C₈H₁₇N₂ (M + H): Calc: 141.1386; Found: 141.1373; [α]_D24 14.82 (c = 1.01, MeOH); Anal. Calcd for C₈H₁₆N: C, 68.52; H, 11.50, N, 19.98. Found: C, 68.45; H, 11.64; N, 19.79.

19. For the derivatization procedure see (Note 14). The analytical data for (S,S)-3 are as follows: ¹H NMR pdf (500 MHz, CDCl₃) d: 1.78–2.05 (m, 6 H), 2.20–2.27 (m, 2 H), 3.22 (dt, J = 10.4, 7.8, 2 H), 3.80 (ddd, J = 10.6, 8.8, 5.1, 2 H), 4.60–4.64 (m, 2 H), 7.23–7.33 (m, 6 H), 7.38–7.44 (m, 4 H); ¹³C NMR pdf. The analytical data for (S,S)-3 are as follows: (126 MHz, CDCl₃) d: 24.3, 28.4, 49.3, 59.0, 127.4, 128.4, 129.8, 137.4, 171.2; MS (EI, 70 eV): 348, 175, 174, 105; HRMS (m/z) Calc. C₂₂H₂₅N₂O₂ (M + H): 349.1911; Found: 349.1917; Supercritical Fluid Chromatography: t_R (R,R)-3 2.86 min (0%); t_R (S,S)-3 3.26 min (100%) (Chiralpak AS, 40 °C, 150 bar, 15% MeOH in CO₂, 3.0 mL/min, 220 nm); HPLC: (S,S)-3 t_R 8.2 min (100%); (R,R)-3 t_R 13.2 min (0%) (Chiralpak AD, i-PrOH/hexane, 95/5, 0.7 mL/min)

Working with 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

C₂-Symmetric chiral diamines have found extensive application as additives, auxiliaries and catalysts in asymmetric synthesis.⁵ (R,R)-2,2'-Bispyrrolidine, initially developed by Hirama, has been successfully applied as a ligand for osmium tetraoxide in the asymmetric dihydroxylation of olefins⁶ (eq 2) and as a ligand in asymmetric hydrogenation.⁷

Several syntheses of enantiopure 2,2'-bispyrrolidine have been reported.⁴^,⁸^,⁹ The first synthesis described by Masamune and coworkers requires only two steps, but produces a d,l/meso mixture of isomers in a sluggish and irreproducible heterogeneous hydrogenation. This short synthesis arrives as the final product by direct resolution of the d,l/meso mixture of 2,2'-bispyrrolines.⁴ The other routes produce enantiopure 2,2'-bispyrrolines without resolution, but they require multiple-step syntheses from chiral starting materials. For example, the synthesis developed by Kotsuki and coworkers takes 11 steps from (D)-tartaric acid.⁸ Most recently, Alexakis reported a five-step synthesis of (R,R)-2,2'-bispyrrolidine by asymmetric addition to a chiral imine.⁹ In the procedure described herein, the d,l/meso mixture of 2,2'-bispyrrolidines is easily synthesized on a large scale by the photodimerization of pyrrolidine developed by Crabtree.² The previously reported resolution⁴ has been modified such that both enantiomers can be obtained.

Figure 2: Stair-like structure of two pyrrolidine rings.

This diamine possesses very interesting structural features that impart useful characteristics as a bidentate ligand. When the two nitrogen atoms function either in a chelate or are covalently bonded to another atom, the two pyrrolidines adopted a stair-like structure, which creates a highly asymmetric environment (Figure 2). This feature was recently exploited in the development of a highly selective catalyst for asymmetric allylations (Figure 3).³ The addition of allylic trichlorosilanes to unsaturated aldehydes can be catalyzed by chiral bisphosphoramide 4 derived from 2,2'- bispyrrolidine to give homoallylic alcohols with excellent diastereo- and enantioselectivities. Of particular note is the catalytic enantioselective construction of quaternary centers by the use of γ-disubstituted allylic silanes. The unique structural features of this diamine together with the ease of preparation bode well for further application in asymmetric synthesis.

Figure 3. Enantioselective addition of allylic trichlorosilanes catalyzed by 2,2-bispyrrolidine-derived bisphosphoramide 4

References and Notes

Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801.
Ferguson, R. R.; Boojamra, C. G.; Brown, S. H.; Crabtree, R. H. Heterocycles 1989, 28, 121.
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.
Oishi, T.; Hirama, M.; Sita, L. R.; Masamune, S. Synthesis 1991, 789.
(a) Bennani, Y. L.; Hannessian, S. Chem. Rev. 1997, 97, 3161. (b) Lucet, D.; Le Gell, T.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580.
(a) Hirama, M.; Oishi, T.; Ito, S. J. Chem. Soc., Chem. Commun. 1989, 665. (b) Oishi, T.; Hirama, M. J. Org. Chem. 1989, 54, 5834.
Hamada, T.; Izawa, K. Eur. Pat. Appl. 987271, 2000.
Kotsuki, H.; Kuzume, H.; Gohda, T.; Fukuhara, M.; Ochi, M.; Oishi, T.; Hirama, M.; Shiro, M. Tetrahedron: Asymmetry, 1995, 6, 2227.
Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.; Mangeney, P.; Bernardinelli, G. Angew. Chem. Int. Ed. 2000, 39, 4093.

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

2,2-Bispyrrolidine; 2,2-Bipyrrolidine; (74295-58-2)

(R,R)-2,2'-bispyrrolidine·(L)-tartrate:
2,2'-Bipyrrolidine,
(2R,2'R)-, (2R,3R)-2,3-dihydroxybutanedioate (1:1)-; (137037-21-9)

(S,S)-2,2'-bispyrrolidine·(D)-tartrate:
2,2'-Bipyrrolidine, [S-(R∗,R∗)]-, [S-(R∗,R∗)]-2,3-dihydroxybutanedioate (1:1); (136937-03-6)

(R,R)-2,2'-Bispyrrolidine:
2,2'-Bipyrrolidine, (2R,2'R)-; (137037-20-8)

(S,S)-2,2'-Bispyrrolidine:
2,2'-Bipyrrolidine, (2S,2'S)-; (124779-66-4)

Notes