M. Jida et al. / Tetrahedron Letters 51 (2010) 5109–5111
5111
19. Characterization data for selected compounds: N-tert-Butyl-1-benzyl-2-methyl-
5-oxopyrrolidine-2-carboxamide (4k): Yield 138 mg, 96%. Yellow oil (100%) 1H
NMR (CDCl3, 300 MHz): d 0.94 (s, 9H); 1.32 (s, 3H); 1.80–1.87 (m, 1H); 2.13–
2.20 (m, 1H); 2.32–2.39 (m, 2H); 4.18 (d, J = 15.0 Hz, 1H); 4.45 (d, J = 15.0 Hz,
1H); 5.36 (br s, 1H, NH); 7.14–7.24 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz): d
22.2; 28.0; 29.3; 33.8; 44.5; 50.9; 67.9; 127.8; 128.4; 128.9; 137.9; 172.3;
176.4 ppm. [(M+H+)] m/z = 289.
References and notes
1. Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem. Rev.
2009, 109, 4140–4182.
2. Dandepally, S. R.; Williams, A. L. Tetrahedron Lett. 2009, 50, 1071–1074; Seijas,
J. A.; Vázquez-Tato, M. P.; Crecente-Campo, J. Tetrahedron 2008, 64, 9280–9285;
Rao, M. L. N.; Awasthi, D. K.; Banerjee, D. Tetrahedron Lett. 2007, 48, 431–438;
de Freitas, J. J. R.; de Freitas, J. C. R.; da Silva, L. P.; de Freitas Filho, J. R.; Kimura,
G. Y. V.; Srivastava, R. M. Tetrahedron Lett. 2007, 48, 6195–6198; Amore, K. M.;
Leadbeater, N. E.; Miller, T. A.; Schmink, J. R. Tetrahedron Lett. 2006, 47, 8583–
8586; Gelens, E.; Smeets, L.; Sliedregt, L. A. J. M.; van Steen, B. J.; Kruse, C. G.;
Leurs, R.; Orru, R. V. A. Tetrahedron Lett. 2005, 46, 3751–3754; Varma, R. S.;
Kumar, D. Tetrahedron Lett. 1999, 40, 7665–7669; Jida, M.; Deprez-Poulain, R.;
Malaquin, S.; Roussel, P.; Agbossou-Niedercorn, F.; Deprez, B.; Laconde, G.
Green Chem. 2010, 12, 961–964.
3. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 18, 3168–3210.
4. Dömling, A. Chem. Rev. 2006, 106, 17–89.
5. Marcaccini, S.; Torroba, T. Nat. Protocols 2007, 2, 632–639.
6. Tsirulnikov, S.; Nikulnikov, M.; Kysil, V.; Ivachtchenko, A.; Krasavin, M.
Tetrahedron Lett. 2009, 50, 5529–5531.
N-Cyclohexyl-1-isobutyl-2-methyl-5-oxopyrrolidine-2-carboxamide (4h): Yield
133 mg, 95%. Yellow oil (100%) 1H NMR (CDCl3, 300 MHz):
d 0.72 (d,
J = 4.5 Hz, 6H); 0.90–1.26 (m, 5H); 1.37 (s, 3H); 1.39–1.56 (m, 3H); 1.66–1.83
(m, 4H); 2.10–2.26 (m, 3H); 2.56 (dd, J = 14.0 Hz, J = 7.0 Hz, 1H); 3.14 (dd,
J = 14.0 Hz, J = 7.0 Hz, 1H); 3.52–3.62 (m, 1H); 6.15 (d, J = 8.1 Hz, 1H, NH) ppm.
13C NMR (CDCl3, 75 MHz): d 20.3; 20.7; 23.3; 24.8; 24.9; 25.3; 27.8; 29.6; 32.6;
32.7; 33.0; 48.6; 48.7; 67.5; 172.3; 175.9 ppm. [(M+H+)] m/z = 281.
N-Benzyl-2-methyl-5-oxo-1-[(pyridin-4-yl)methyl]pyrrolidine-2-carboxamide
(4b): Yield 141 mg, 87%. Yellow oil (100%) 1H NMR (CDCl3, 300 MHz): d 1.21 (s,
3H); 1.75–1.95 (m, 1H); 2.18–2.31 (m, 3H); 3.81 (d, J = 16.2 Hz, 1H); 4.13–4.29
(m, 2H); 4.68 (d, J = 16.2 Hz, 1H); 6.98 (d, J = 6.0 Hz, 2H); 7.03–7.13 (m, 5H);
7.60 (t, J = 5.7 Hz, 1H, NH); 8.30 (d, J = 6.0 Hz, 2H) ppm. 13C NMR (CDCl3,
75 MHz): d 23.4; 29.4; 32.8; 43.6; 44.0; 67.6; 122.4; 127.3; 127.5; 128.5;
138.4; 147.1; 149.7; 172.8; 176.2 ppm. [(M+H+)] m/z = 324.
7. Krasavin, M.; Parchinsky, V.; Shumsky, A.; Konstantinov, I.; Vantskul, A.
Tetrahedron Lett. 2010, 51, 1367–1370.
8. Malaquin, S.; Jida, M.; Gesquiere, J.-C.; Deprez-Poulain, R.; Deprez, B.; Laconde,
G. Tetrahedron Lett. 2010, 51, 2983–2985.
N-tert-Butyl-1-benzyl-2-methyl-6-oxopiperidine-2-carboxamide
(5g):
Yield
139 mg, 92%. Yellow oil (100%) 1H NMR (CDCl3, 300 MHz): d 1.22 (s, 9H);
1.42 (s, 3H); 1.75–1.80 (m, 3H); 2.18–2.29 (m, 1H); 2.55–2.59 (m, 2H); 4.24 (d,
J = 15.6 Hz, 1H); 4.96 (d, J = 15.6 Hz, 1H); 5.61(br s, 1H, NH); 7.20–7.30 (m, 5H)
ppm. 13C NMR (CDCl3, 75 MHz): d 17.6; 24.7; 28.4; 32.3; 36.5; 47.8; 51.5; 67.1;
127.0; 127.1; 128.7; 138.5; 172.0; 172.5 ppm. [(M+H+)] m/z = 303.
9. First description of this intramolecular Ugi reaction by Gross, H.; Gloede, J.;
Keitel, I.; Kunath, D. J. Prakt. Chem. 1968, 37, 192–199; for a recent chiral
application: Buller, M. J.; Gilley, C. B.; Nguyen, B.; Olshansky, L.; Fraga, B.;
Kobayashi, Y. Synlett 2008, 2244–2248.
10. Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591–5594.
11. Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359–362.
12. Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725–2728.
13. Heather, T.; Whittaker, M. Org. Biomol. Chem. 2004, 2, 813–815.
14. Vasily, V. T.; Alexander, A. T.; Herbert, M. Angew. Chem., Int. Ed. 2007, 46, 3563–
3566.
15. Krelaus, R.; Westermann, B. Tetrahedron Lett. 2004, 45, 5987–5990.
16. The Ugi transition state is the result of a rearrangement classically referred to
as the Mumm-rearrangement. For a discussion on the Ugi intermediates see:
Quast, H.; Aldenkortt, S. Chem. Eur. J. 1996, 2, 462–469.
17. The synthesis of seven-membered lactams is very difficult and depends on the
choice of the precursors. In that case, our solvent-free microwave Ugi
procedure did not improve the reported yields (0–70%).10,11
N-Cyclohexyl-1-isobutyl-2-methyl-6-oxopiperidine-2-carboxamide (5f): Yield
138 mg, 94%. Yellow oil (100%) 1H NMR (CDCl3, 300 MHz):
d 0.88 (d,
J = 6.6 Hz, 6H); 1.08–1.16 (m, 3H); 1.30–1.39 (m, 3H); 1.55 (s, 3H); 1.71–1.86
(m, 7H); 2.01–2.10 (m, 1H); 2.20–2.26 (m, 1H); 2.44–2.60 (m, 3H); 3.73–3.80
(m, 2H); 5.62 (d, J = 7.12 Hz, 1H, NH) ppm. 13C NMR (CDCl3, 75 MHz): d 17.8;
20.5; 20.8; 24.7; 25.3; 25.6; 28.6; 32.5; 32.8; 33.2; 36.6; 48.7; 51.6; 66.5;
172.2; 175.7 ppm. [(M+H+)] m/z = 295.
N-benzyl-2-methyl-6-oxo-1-[(pyridin-4-yl)methyl]piperidine-2-carboxamide
(5b): Yield 150 mg, 87%. Yellow oil (100%) 1H NMR (CDCl3, 300 MHz): d 1.34 (s,
3H); 1.72–1.79 (m, 3H); 2.22–2.41 (m, 3H); 3.78 (d, J = 16.8 Hz, 1H); 4.27–4.46
(m, 2H); 5.19 (d, J = 16.8 Hz, 1H); 7.00 (d, J = 6.0 Hz, 2H); 7.33–7.18 (m, 6H);
8.47 (d, J = 6.0 Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz): d 17.4; 25.3; 32.3; 36.2;
44.0; 47.6; 66.9; 121.6; 127.6; 127.9; 128.6; 138.3; 147.7; 149.8; 171.9;
172.9 ppm. [(M+H+)] m/z = 338.
N-tert-Butyl-1-benzyl-2-phenyl-5-oxopyrrolidine-2-carboxamide
(6):
Yield
18. General reaction protocol: In
a capped 10 mL MW-vessel, the ketoacid
56 mg, 67%. Colorless oil. (100%) 1H NMR (CDCl3, 300 MHz): d 1.03 (s, 9H);
2.63–2.42 (m, 3H); 2.96–2.90 (m, 1H); 3.77 (d, J = 15.3 Hz, 1H); 4.79 (d,
J = 15.3 Hz, 1H); 5.48 (br s, 1H, NH); 7.34–7.15 (m, 10H) ppm. 13C NMR (CDCl3,
75 MHz): d 28.0; 29.5; 35.1; 45.6; 51.6; 75.3; 127.7; 128.0; 128.5; 128.9;
137.5; 138.8; 170.1; 176.9 ppm. [(M+H+)] m/z = 351.
(0.5 mmol for 1a–c), the isocyanide (0.5 mmol 2a–c), and the amine
(0.5 mmol 3a–e) were mixed. The power was set at 75 W and the pressure
at 17 bar (average effective pressure = 4 bar). The mixture was heated at 100 °C
for 3 min. After completion the conversion was directly determined by HPLC–
MS. The crude product was dissolved in the minimum DCM (10 mL). The
organic layer was washed with 1 N HCl (5 mL), and satd aq NaHCO3 (5 mL), and
dried over MgSO4. The solvent was removed under reduced pressure.
20. The synthesis of lactams from 3-benzoylpropionic acid using classical
conditions in methanol gives the desired compounds in 20–75% yield in 48 h
(and requires heating to achieve good yields).10,11