A Short Synthesis of Polysubstituted Pyrrolidines via α-(Alkylidene­amino)nitriles

Abstract

α-(Alkylideneamino)nitriles can be deprotonated under mild conditions. Their conjugated anions react with enones in a 1,4-addition to yield δ-keto-α-(alkylideneamino)nitriles which in turn can be reduced to form pyrrolidines in a one-pot reaction sequence.

pyrrolidines - Michael additions - reductions - imines - combinatorial chemistry

References

1a Fisher LE. Rosenkranz RP. Clark RD. Muchowski JM. McClelland DL. Michel A. Caroon JM. Galezzi E. Eglen R. Whiting RL. Bioorg. Med. Chem. Lett.  1995,  5:  2371 

1b Sonesson C. Wikström H. Smith MW. Svensson K. Carlsson A. Waters N. Bioorg. Med. Chem. Lett.  1997,  7:  241 

1c Gerasimov M. Marona-Lewicka D. Kurrasch-Orbaugh DM. Qandil AM. Nichols DE. J. Med. Chem.  1999,  42:  4257 

1d Ahn KH. Lee SJ. Lee C.-H. Hong CY. Park TK. Bioorg. Med. Chem. Lett.  1999,  9:  1379 

1e A series of nine papers on the antinociceptive activity of various substituted 3-arylpyrrolidines has been published by a research group from Parke Davis between 1961 and 1973 in J. Med. Chem., the last one being: Bowman RE. Collier HOJ. Lockhart IM. Schneider C. Webb NE. Wright M. J. Med. Chem.  1973,  16:  1181 

2a Elliott RL. Ryther KB. Anderson DJ. Piattoni-Kaplan M. Kuntzweiler TA. Donnelly-Roberts D. Arneric SP. Holladay MW. Bioorg. Med. Chem. Lett.  1997,  7:  2703 

2b Kim KH. Lin N.-H. Anderson DJ. Bioorg. Med. Chem.  1996,  4:  2211 

2c Guzikowski AP. Tamiz AP. Acosta-Burruel M. Hong-Bae S. Cai SX. Hawkinson JE. Keana JFW. Kesten SR. Shipp CT. Tran M. Whittemore ER. Woodward RM. Wright JL. Zhou Z.-L. J. Med. Chem.  2000,  43:  984 

3a Basha FZ. DeBernardis JF. Pure Appl. Chem.  1994,  66:  2201 

3b Enyedy IJ. Zaman WA. Sakamuri S. Kozikowski AP. Johnson KM. Wang SM. Bioorg. Med. Chem. Lett.  2001,  11:  1113 

4a Wallén EAA. Christiaans JAM. Saario SM. Forsberg MM. Venalainen JI. Paso HM. Mannisto PT. Gynther J. Bioorg. Med. Chem.  2002,  10:  2199 

4b Feldman PL. Brackeen MF. Cowan DJ. Marron BE. Schoenen FJ. Stafford JA. Suh EM. Domanico PL. Rose D. Leesnitzer MA. Brawley ES. Strickland AB. Verghese MW. Connolly KM. Bateman-Fite R. Noel LS. Sekut L. Stimpson SA. J. Med. Chem.  1995,  38:  1505 

For reviews, see:

5a Pichon M. Figadère B. Tetrahedron: Asymmetry  1996,  7:  927 

5b 1,3-Dipolar Cycloaddition Chemistry   Padwa A. Wiley; New York: 1984. 

5c Pearson WH. Stoy P. Synlett  2003,  903 

5d For recent examples, see: Tietze LF. Evers H. Töpken E. Helv. Chim. Acta  2002,  85:  4200 

5e Casas J. Grigg R. Nájera C. Sansano JM. Eur. J. Org. Chem.  2001,  1971 

5f Davis AS. Gates NJ. Lindsay KB. Tang M. Pyne SG. Synlett  2004,  49 

5g Mota AJ. Chiaroni A. Langlois N. Eur. J. Org. Chem.  2003,  4187 

See for example:

6a Pearson WH. Szura DP. Postich MJ. J. Am. Chem. Soc.  1992,  114:  1329 

6b Zimmer R. Hoffmann M. Reissig H.-U. Chem. Ber.  1992,  125:  2243 

6c Pulz R. Al-Harrasi A. Reissig H.-U. Org. Lett.  2002,  4:  2353 

6d Vanucci C. Brusson X. Verdel V. Zana F. Dhimane H. Lhommet G. Tetrahedron Lett.  1995,  36:  2971 

6e Lorthiois E. Marek I. Normant JF. Tetrahedron Lett.  1997,  38:  89 

6f Broka CA. Shen T. J. Am. Chem. Soc.  1989,  111:  2981 

6g Coldham I. J. Chem. Soc., Perkin Trans. 1  1993,  1275 

7 Seebach D. Angew. Chem., Int. Ed. Engl.  1979,  18:  239 ; Angew. Chem. 1979, 91, 259

8 Meyer N. Opatz T. Synlett  2003,  1427 

9a Tsuge O. Ueno K. Kanemasa S. Yorozu K. Bull. Chem. Soc. Jpn.  1987,  60:  3347 

9b Tsuge O. Kanemasa S. Yorozu K. Ueno K. Bull. Chem. Soc. Jpn.  1987,  60:  3359 

9c Tsuge O. Ueno K. Kanemasa S. Yorozu K. Bull. Chem. Soc. Jpn.  1986,  59:  1809 

9d See also: Roux-Schmitt MC. Croisat D. Seyden-Penne J. Wartski L. Cossentini M. Pol. J. Chem.  1996,  70:  325 

9e Opio JO. Labidalle S. Galons H. Miocque M. Synth. Commun.  1991,  21:  1743 

10

General Procedure for the Preparation of α-(Alkylideneamino)nitriles 3a-c: To a solution of the aminonitrile (10 mmol) in dry CH₂Cl₂ (20 mL) were added MgSO₄ (1.1 equiv) and the aldehyde (1.1 equiv). The suspension was stirred overnight. The MgSO₄ was filtered off and the organic phase was partitioned between a sat. NaHCO₃ solution and CH₂Cl₂. The organic layer was dried over Na₂SO₄ and the solvent was evaporated in vacuo. Recrystallization yielded the pure imines. In the case of products 3a and 3b, aminoacetonitrile sulfate was used and 1 equiv of Et₃N was added to the reaction mixture.

11 Rodima T. Kaljurand I. Pihl A. Mäemets V. Leito I. Koppel IA. J. Org. Chem.  2002,  67:  1873 

12a Tatsukawa A. Kawatake K. Kanemasa S. Rudziski JM. J. Chem. Soc., Perkin Trans. 2  1994,  2525 

12b Domingo LR. J. Org. Chem.  1999,  64:  3922 

13

General Procedure for the Preparation of Pyrrolidines 8a-g: To a solution of the α-(alkylideneamino)nitrile (1.45 mmol) in THF (5 mL) was added a solution of DBU (1.59 mmol, 1.1 equiv) in THF (2 mL) under argon at r.t. After addition of a solution of methyl vinyl ketone (1.59 mmol, 1.1 equiv) in THF (3 mL), the mixture was stirred for 90 min. The reaction was stopped by addition of a mixture of EtOH (87 mmol, 60 equiv) and HOAc (11.6 mmol, 8 equiv). After NaBH₃CN (5.8 mmol, 4 equiv) was added, the mixture was stirred at r.t. overnight. The reaction mixture was washed twice with 1 N NaOH and the combined aqueous phases were reextracted with EtOAc. The combined organic layers were extracted three times with 1 N HCl and the combined aqueous phases were made alkaline by addition of NaOH. Extraction with CH₂Cl₂, drying over Na₂SO₄ and evapora-tion of the solvent in vacuo gave a crude product, which was further purified by column chromatography, preparative TLC or HPLC if necessary. Note: Compounds 8f and 8g were too lipophilic for an efficient extraction with 1 N HCl. They were directly purified by chromatographic methods.

14

Under identical conditions, compounds 3a and 3b could not be reacted cleanly with α,β-unsaturated aldehydes.

15

Spectroscopic Data of Compound cis -8e: ¹H NMR (400 MHz, CDCl₃): δ = 7.28-7.21 (m, 2 H, Ph), 7.19-7.10 (m, 3 H, Ph), 6.92 (d, 1 H, J _{2 ′ ,6 ′} = 1.8 Hz, H-2′), 6.90 (dd, 1 H, J _{5 ′ ,6 ′} = 8.1 Hz, J _{2 ′ ,6 ′} = 1.8 Hz, H-6′), 6.83 (d, 1 H, J _{5 ′ ,6 ′} = 8.1 Hz, H-5′), 3.90, 3.88 (2 s, 6 H, OCH₃), 3.81 [d, 1 H, J = 14.1 Hz, CH₂C₆H₃ (OMe)₂], 3.75 [d, 1 H, J = 14.1 Hz, CH₂C₆H₃ (OMe)₂], 2.93-2.81 (m, 2 H, CH₂Ph, H-2), 2.74-2.60 (m, 1 H, H-5), 2.38 (dd, 1 H, J _gem = 12.4 Hz, J _vic = 9.2 Hz, CH₂Ph), 1.81-1.70 (m, 1 H, H-4a), 1.67-1.44 (m, 2 H, H-3a, H-3b), 1.42-1.30 (m, 1 H, H-4b), 1.07 (d, 3 H, J = 6.0 Hz, CH₃). Irradiation (transient NOE) at δ = 2.68 ppm (H-5) enhances the signals at δ = 6.90 ppm (H-6′, 0.8%), 6.83 ppm (H-5′, 0.2%), 3.81 ppm [CH₂C₆H₃ (OMe)₂, 1.1%], 3.75 ppm [CH₂C₆H₃ (OMe)₂, 1.0%], 2.83 ppm (H-2, 0.6%), 1.72 ppm (H-4a, 2.2%), 1.55 ppm (H-3, 0.8%), 1.35 ppm (H-4b, 0.6%), 1.07 ppm (CH₃, 1.1%). ¹³C NMR (100.6 MHz, CDCl₃): δ = 148.60, 147.87 (C-3′, C-4′), 140.30 (C-1 Ph), 137.28 (C-1′), 129.18, 128.08, 125.77 (Ph), 121.14 (C-6′), 112.56 (C-2′), 110.65 (C-5′), 66.11 (C-2), 60.09 (C-5), 56.28 [CH₂C₆H₃ (OMe)₂], 55.85 (OCH₃), 42.46 (CH₂Ph), 31.55 (C-4), 28.80 (C-3), 20.80 (CH₃).
Spectroscopic Data of Compound trans -8e: ¹H NMR (400 MHz, CDCl₃): δ = 7.26-7.20 (m, 2 H, Ph), 7.18-7.12 (m, 1 H, Ph), 7.05 (d, 2 H, J = 7 Hz, H-2, H-6 Ph), 6.98 (br s, 1 H, H-2′), 6.92 (dd, 1 H, J _{5 ′ ,6 ′} = 8.1 Hz, J _{2 ′ ,6 ′}= 1.3 Hz, H-6′), 6.83 (d, 1 H, J _{5 ′ ,6 ′} = 8.1 Hz, H-5′), 3.92 [d, 1 H, J = 13.6 Hz, CH₂-C₆H₃ (OMe)₂], 3.90, 3.89 (2 s, 6 H, OCH₃), 3.62 [d, 1 H, J = 13.6 Hz, CH₂C₆H₃(OMe)₂], 3.17-3.05 (m, 2 H, H-2, H-5), 2.96 (dd, 1 H, J _gem = 12.9 Hz, J _vic = 3.5 Hz, CH₂Ph), 2.36 (dd, 1 H, Jgem = 12.9 Hz, J = 10.0 Hz, CH₂Ph), 2.05-1.92 (m, 1 H, H-4a), 1.83-1.70 (m, 1 H, H-3a), 1.56-1.46 (m, 1 H, H-3b), 1.44-1.33 (m, 1 H, H-4b), 0.99 (d, 3 H, J = 6.2 Hz, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 148.87, 147.69 (C-3′, C-4′); 140.49 (C-1 Benzyl), 136.52 (C-1′), 129.26, 128.12, 125.67 (Benzyl); 120.35 (C-6′); 111.72 (C-2′); 110.71 (C-5′); 61.91 (C-2); 55.89 (OCH₃); 55.40 (C-5); 51.71 [CH₂C₆H₃(OMe)₂]; 37.63 (CH₂Ph); 30.77 (C-4); 27.55 (C-3); 16.76 (CH₃).

16a van der Werf A. Kellogg RM. Tetrahedron Lett.  1991,  32:  3727 

16b Kanemasa K. Uchida O. Wada E. J. Org. Chem.  1990,  55:  4411 

16c Alvarez-Ibarra C. Csákӱ AG. Maroto M. Quiroga ML. J. Org. Chem.  1995,  60:  6700 

17 Scott WL. Alsina J. O’Donnell MJ. J. Comb. Chem.  2003,  5:  684 

18a O’Donnell MJ. Bennett WD. Wu S. J. Am. Chem. Soc.  1989,  111:  2353 

18b For a review, see: O’Donnell MJ. Aldrichimica Acta  2001,  34:  3