The synthesis of substituted pyrrolidines and 2,5-dihydropyrroles via 1,3-dipolar cycloaddition of nonstabilized azomethine ylides

Article abstract of DOI:10.1055/s-1999-2681

A novel method to generate nonstabilized azomethine ylides and subsequent cycloaddition with carbon, carbon multiple bonds is described.

Full text of DOI:10.1055/s-1999-2681

5
90
LETTER
The Synthesis of Substituted Pyrrolidines and 2,5-Dihydropyrroles via 1,3-
Dipolar Cycloaddition of Nonstabilized Azomethine Ylides
Alan R. Katritzky,* Daming Feng, Yunfeng Fang
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1 (613) 5332837
Received 14 February 1999
terial with trans-stilbene under the same reaction condi-
Abstract: A novel method to generate nonstabilized azomethine
tions afforded trans-4a in 81% yield.12 Introducing 1,4-
ylides and subsequent cycloaddition with carbon-carbon multiple
benzenediol to this reaction mixture before adding trans-
stilbene had no effect which suggests the absence of a rad-
ical chain. We conclude that the cycloaddition was con-
certed and the reactive intermediate was the azomethine
ylide (3). Under the same reaction conditions N,N-bis(to-
sylmethyl)butylamine (2b) reacted with trans- or cis stil-
bene to give trans- or cis- 4b in 84% or 65% yields,
respectively. The relatively low yields of cis-4a and cis-
bonds is described.
Key words: pyrrolidines, 2,5-dihydropyrroles, cycloaddition,
azomethine ylides, samarium diiodide
1
,3-Dipolar cycloadditions of azomethine ylides to dipo-
larophiles have been used widely to construct
1
2
pyrrolidines and other heterocycles. Extensive investi-
gations during the last two decades has shown that nonsta-
4
b, as compared to their trans isomers, are in agreement
5c
with the results published by Roussi. α-Methylstyrene,
β-methylstyrene and β-propylstyrene were also used as
dipolarophiles to trap azomethine ylides prepared from 2a
or 2b to give pyrrolidines 4c-g in good to excellent yields.
2
,3
bilized azomethine ylides
can be obtained by (i)
deprotonations of iminium salts4 or amine N-oxides6;
a,b
5a-e
(
ii) decarboxylations of pyridinium-1-acetic acid salts or
7
a,b
amino acids;
(iii) thermal and photochemical ring
8
a,b
Preliminary experiments were carried out with enol vinyl
ether and methyl acrylate as examples of electron rich or
electron deficient dipolarophiles. However, no useful re-
sults were obtained probably due to reaction of these ole-
fins with samarium diiodide. Fortunately, many other
procedures are successful for activated olefins.
opening of aziridines; (iv) and desilylations of N-(tri-
methylsilylmethyl)iminium cation. Of these methods, the
most useful and that most frequently applied has been the
desilylation approach. However, the ylides so obtained re-
act only with activated olefins.
9
1
0a-c
For additions to unac-
tivated olefins, ylides derived from the deprotonation of
amine N-oxides have been used.
5
b,c
In conclusion, samarium diiodide methodology allows a
novel generation of regioselective nonstabilized azome-
thine ylides from N,N-bis(sulfonylmethyl)alkylamines.
While most nonstabilized azomethine ylides generated by
We now report that N,N-bis(sulfonylmethyl)alkylamines
are also excellent precursors of nonstabilized azomethine
ylides which will subsequently undergo cycloadditions
with activated or unactivated carbon-carbon multiple
bonds to afford polysubstituted pyrrolidines and 2,5-dihy-
dropyrroles. N,N-Bis(sulfonylmethyl)alkylamines 2 were
easily prepared from primary amines 1 following litera-
the desilylation procedure only react with activated dipo-
larophiles,1
0a-c
intermediates 3 produced by our method
react with simple, unactivated alkenes to give products 4i-
l and with alkynes to give 1,3,4-trisubstituted-2,5-dihy-
dropyrroles 5a-b, all in good yields. Other advantages in-
clude ready availability of starting materials and mild
1
1
ture procedures. N,N-Bis(tosylmethyl)benzylamine (2a)
reacted with cis-stilbene in the presence of samarium di-
iodide in THF-HMPA to give cis-4a in 41% yield. We
have recently reported that reacting the same starting ma-
13
reaction conditions. To our knowledge, no previous pro-
cedures use samarium diiodide for the generation of non-
stabilized azomethine ylides.
Scheme 1
Synlett 1999, No. 5, 590–592 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Synthesis of Substituted Pyrrolidines and 2,5-Dihydropyrroles via 1,3-Dipolar Cycloaddition
591
Table. The Preparation of Polysubstituted Pyrrolidines 4 and 2,5-Dihydropyrroles 5
from N,N-Bis(sulfonylmethyl)alkyl amines 2.
1H NMR spectra were recorded on a Varian VXR-300 2H), 2.65 (t, 2H, J = 7.4 Hz), 2.95-3.05 (m, 2H), 3.15-3.28
spectrometer with tetramethylsilane (TMS) as an internal (m, 2H), 3.68-3.82 (m, 2H), 6.82-7.07 (m, 10H); 13
C
1
3
reference. C NMR spectra were recorded at 75 MHz on NMR: δ 14.1, 22.7, 27.3, 29.1, 31.8, 49.0, 56.8, 60.0,
the same instrument using the solvent peak (CDCl , δ = 125.6, 127.4, 128.9, 141.2; Anal calcd for C H N: C,
3
22 29
7
7.0 ppm) as reference. Microanalyses were carried out 85.94; H, 9.51; N, 4.56. Found: C, 85.52; H, 9.78; N, 4.82.
using a Carlo erba 1106 elemental analyzer. Tetrahydro-
furan was freshly distilled from sodium-benzophenone.
1
trans-1-Hexyl-3,4-diphenylpyrrolidine (4b). H NMR: δ
.90 (t, 3H, J = 6.8 Hz), 1.23-1.46 (m, 6H), 1.47-1.62 (m,
0
General procedure for the preparation of polysubstituted 2H), 2.37-2.50 (m, 1H), 2.56-2.68 (m, 1H), 2.80-2.92 (m,
pyrrolidines 4a-l and 2,5-dihydropyrroles 5a-b: Samari- 2H), 3.06-3.18 (m, 2H), 3.28-3.42 (m, 2H), 7.07-7.26 (m,
13
um(II) iodide was first prepared from Sm (1.50 g, 9.9 10H); C NMR: δ 14.1, 22.6, 27.3, 28.8, 31.8, 53.0, 56.7,
mmol) and I (2.28 g, 9 mmol) in THF (90 mL) under ni- 62.8, 126.2, 127.4, 128.3, 143.9; Anal calcd for C H N:
2
22 29
trogen. N,N-Bis(sulfonylmethyl)alkyl amines 2a-b (2 C, 85.94; H, 9.51; N, 4.56. Found: C, 85.68; H, 9.88; N,
mmol) and dipolarophiles (3 mmol) dissolved in THF (20 4.81.
mL) were added dropwise to the freshly prepared SmI2/
1
1
1
2
2
5
1
-Benzyl-3-methyl-3-phenylpyrrolidine (4c). H NMR: δ
THF-HMPA solution [0.1 N SmI in THF (90 mL),
2
.44 (s, 3H), 1.88-2.05 (m, 1H), 2.15-2.29 (m, 1H), 2.57-
.69 (m, 1H), 2.77 (s, 2H), 2.83-2.98 (m, 1H), 3.67 (s,
H), 7.10-7.45 (m, 10H); C NMR: δ 30.7, 39.9, 45.6,
3.8, 60.5, 67.4, 125.5, 125.9, 126.7, 128.1, 128.2, 128.5,
39.7, 150.6; Anal calcd for C H N: C, 86.01; H, 8.42;
HMPA (9 mL)] at 0 °C. The mixture was stirred at the
same temperature for 2 hours and at room temperature
overnight. The reaction was quenched with water, extract-
ed with ethyl acetate and dried over Na SO . After evapo-
13
2
4
18
21
ration of the solvent, the crude product was subjected to
column chromatography on silica gel (saturated with
N, 5.57. Found: C, 85.67; H, 8.68; N, 5.97.
1
1
0
1
2
2
-Hexyl-3-methyl-3-phenylpyrrolidine (4d). H NMR: δ
Et N) using hexanes/ethyl acetate/triethyl amine as eluent
3
.89 (t, 3H, J = 6.7 Hz), 1.21-1.40 (m, 6H), 1.43 (s, 3H),
.45-1.58 (m, 2H), 1.88-2.00 (m, 1H), 2.14-2.26 (m, 1H),
.38-2.52 (m, 2H), 2.54-2.64 (m, 1H), 2.77 (s, 2H), 2.80-
.92 (m, 1H), 7.16 (t, 1H, J = 6.7 Hz), 7.21-7.37 (m, 4H);
C NMR: δ 14.1, 22.6, 27.3, 28.9, 30.8, 31.8, 39.7, 45.4,
4.2, 56.9, 67.8, 125.5, 125.9, 128.1, 150.7; Anal calcd for
C H N: C, 83.20; H, 11.09; N, 5.71. Found: C, 82.76; H,
to afford the pure product 4a-l or 5a-b.
1
cis-1-Benzyl-3,4-diphenylpyrrolidine (4a). H NMR: δ
3
3
.03-3.13 (m, 2H), 3.14-3.24 (m, 2H), 3.74-3.82 (m, 2H),
.86 (s, 2H), 6.85-7.08 (m, 8H), 7.15-7.52 (m, 7H); 13
C
13
NMR: δ 49.1, 59.8, 60.8, 125.6, 126.9, 127.5, 128.3,
5
1
8
28.7, 128.9, 139.5, 141.1; Anal calcd for C H N: C,
8.14; H, 7.40; N, 4.47. Found: C, 87.99; H, 7.67; N, 4.47.
23 23
17
27
1
1.54; N, 5.94.
1
cis-1-Hexyl-3,4-diphenylpyrrolidine (4b). H NMR: δ
0
.92 (t, 3H, J = 6.6 Hz), 1.25-1.49 (m, 6H), 1.52-1.66 (m,
Synlett 1999, No. 5, 590–592 ISSN 0936-5214 © Thieme Stuttgart · New York

5
92
A. R. Katritzky et al.
LETTER
trans-1-Benzyl-4-methyl-3-phenylpyrrolidine (4e). 1H 6H), 1.39-1.55 (m, 2H), 2.20-2.41 (m, 3H), 2.40-2.50 (m,
NMR: δ 1.04 (d, 3H, J = 6.3 Hz), 2.20-2.40 (m, 2H), 2.68- 1H), 2.75-2.92 (m, 2H), 2.98-3.12 (m, 2H), 3.20 (dd, 1H,
2
1
5
1
.88 (m, 2H), 2.89-3.03 (m, 2H), 3.60, 3.62 (AB, 2H, J = J = 9.3 Hz, J = 12.9 Hz), , 3.74-3.85 (m, 1H), 7.05-7.20
1 2
2.9 Hz), 7.12-7.42 (m, 10H); 1 C NMR: δ 18.5, 42.2, (m, 4H); C NMR: δ 14.0, 22.6, 27.4, 28.8, 31.8, 38.1,
2.7, 60.7, 62.4, 126.1, 126.8, 127.5, 128.2, 128.3, 128.7, 40.9, 49.6, 56.3, 61.7, 62.1, 124.4, 124.7, 126.6, 143.2,
39.4, 144.7; Anal calcd for C H N: C, 86.01; H, 8.42; 146.4; Anal calcd for C H N: C, 83.89; H, 10.35; N,
3
13
1
8
21
17 25
N, 5.57. Found: C, 85.77; H, 8.78 N, 5.96.
5.75. Found: C, 83.52; H, 10.68; N, 5.84.
trans-1-Hexyl-4-methyl-3-phenylpyrrolidine (4f). 1H 1-Benzyl-3,4-diphenyl-2,5-dihydro-1H-pyrrole (5a). H
1
NMR: δ 0.89 (t, 3H, J = 6.7 Hz), 1.04 (d, 3H, J = 6.5 Hz), NMR: δ 3.90 (s, 2H), 3.98 (s, 4H), 7.08-7.20 (m, 11H),
1
3
1
2
2
1
1
8
5
.18-1.41 (m, 6H), 1.42-1.58 (m, 2H), 2.16-2.29 (m, 1H), 7.30-7.40 (m, 2H), 7.40-7.48 (m, 2H); C NMR: δ 60.4,
.30-2.45 (m, 2H), 2.46-2.60 (m, 1H), 2.67-2.74 (m, 2H), 64.8, 127.0, 127.1, 127.8, 128.2, 128.4, 128.7, 134.1,
.75-3.01 (m, 2H), 7.12-7.35 (m, 5H); C NMR: δ 14.0, 135.4, 139.1; Anal calcd for C H N: C, 88.71; H, 6.80;
1
3
23
21
8.3, 22.6, 27.3, 28.9, 31.8, 41.9, 52.6, 57.0, 62.6, 62.7, N, 4.50. Found: C, 88.52; H, 6.83; N, 4.81.
26.1, 127.5, 128.3, 144.3; Anal calcd for C H N: C,
-Hexyl-3,4-diphenyl-2,5-dihydro-1H-pyrrole (5b). 1H
1
8
21
1
3.20; H, 11.09; N, 5.71. Found: C, 82.93; H, 11.54; N,
.97.
NMR: δ 0.90 (t, 3H, J = 6.3 Hz), 1.25-1.47 (m, 6H), 1.52-
1
.64 (m, 2H), 2.70 (t, 2H, J = 7.4 Hz), 3.96 (s, 4H), 7.10-
trans-1-Benzyl-3-phenyl-4-propylpyrrolidine (4g). 1H 7.30 (m, 10H); C NMR: δ 14.1, 22.6, 27.2, 29.1, 31.9,
13
NMR: δ 0.80 (t, 3H, J = 7.2 Hz), 1.12-1.30 (m, 2H), 1.30- 56.3, 64.9, 127.1, 127.8, 128.2, 134.1, 135.6; Anal calcd
1
2
3
.40 (m, 1H), 1.40-1.55 (M, 1H), 2.14-2.28 (m, 1H), 2.28- for C H N: C, 86.51; H, 8.91; N, 4.59. Found: C, 86.05;
22 27
.40 (m, 2H), 2.65-2.75 (m, 1H), 2.80-3.03 (m, 2H), 3.62, H, 9.21; N, 4.92.
.70 (AB, 2H, J = 12.9 Hz), 7.13-7.43 (m, 10H); 13
C
NMR: δ 14.2, 21.5, 37.0, 47.5, 51.2, 60.7, 60.8, 62.6,
26.0, 126.8, 127.6, 128.2, 128.3, 128.7, 139.4, 145.5;
HRMS Calcd for C H N: 279.1987. Found: 279.1996.
trans-1-Hexyl-3-phenyl-4-propylpyrrolidine (4h). 1H
NMR: δ 0.81 (t, 3H, J = 7.1 Hz), 0.89 (t, 3H, J = 6.7 Hz),
References
1
(1) Person, W. H. In Studies in Natural Products Chemistry;
Rahman, A., ed.; Elsevier: Amsterdam, 1988; Vol. 1, p 323.
2
0
25
(
2) Lown, J. W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., ed.; John Wiley & Sons: New York, 1984; Vol. 1, p 653.
1
2
2
1
6
.15-1.40 (m, 9H), 1.40-1.60 (m, 3H), 2.11-2.27 (m, 1H),
.30-2.44 (m, 2H), 2.45-2.60 (m, 1H), 2.62-2.73 (m, 1H),
.78-2.98 (m, 3H), 7.13-7.33 (m, 5H); C NMR: δ 14.0,
4.2, 21.6, 22.6, 27.3, 28.9, 31.8, 36.9, 47.1, 51.2, 57.0,
1.1, 62.8, 126.0, 127.6, 128.3, 145.1; Anal calcd for
(3) Vedejs, E. In Advances in Cycloaddition; Curran, D. P., ed.;
JAI Press INC: London, 1988; Vol. 1, p 33.
(4) (a) Deyrup, J. A. and Szabo, W. A. J. Org. Chem. 1975, 40,
1
3
2048. (b) Deyrup, C. L.; Deyrup, J. A. and Hamilton, M.
Tetrahedron Lett. 1977, 39, 3437.
(
5) (a) Roussi, G. Trends in Organic Chemistry 1993, 4, 101.
(b) Chastanet, J. and Roussi, G. J. Org. Chem. 1985, 50, 2910.
C H N: C, 83.45; H, 11.43, N, 5.12. Found: C, 83.22; H,
1
1
9
31
1.82; N, 5.33.
(c) Chastanet, J. and Roussi, G. J. Org. Chem. 1988, 53, 3808.
1
(d) Beugelmans, R.; Negron, G. and Roussi, G. J. Chem. Soc.,
Chem. Commun. 1983, 31. (e) Chastanet, J. and Roussi, G.
Heterocycles 1985, 23, 653.
1
-Benzyl-3-hexylpyrrolidine (4i). H NMR: δ 0.87 (t, 3H,
J = 6.7 Hz), 1.14-1.50 (m, 10H), 1.88-2.48 (m, 5H), 2.65-
2
.78 (m, 1H), 2.82 (t, 1H, J = 7.9 Hz), 3.58, 3.59 (AB, 2H,
(
6) Ratts, K. W.; Howe, R. K. and Phillips, W. G. J. Am. Chem.
Soc. 1969, 91, 6115, and references therein.
1
3
J = 12.9 Hz), 7.17-7.45 (m, 5H); C NMR: δ 14.1, 22.6,
2
1
1
8.3, 29.4, 30.8, 31.8, 35.8, 37.6, 54.0, 60.7, 60.9, 126.8,
28.1, 128.8, 139.4; Anal calcd for C H N: C, 83.20; H,
1.09; N, 5.71. Found: C, 83.17; H, 11.59; N, 5.92.
(7) (a) Grigg, R. and Thianpatanagul, S. J. Chem. Soc., Chem.
Commun. 1984, 180. (b) Grigg, R.; Aly, M. F.; Sridharan, V.
and Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984,
1
7
27
182.
1
1
6
,3-Dihexylpyrrolidine (4j). H NMR: δ 0.80-0.95 (m,
(
8) (a) DeShong, P. and Kell, D. A. Tetrahedron Lett. 1986, 27,
3979. (b) DeShong, P.; Kell, D. A. and Sidler, D. R. J. Org.
Chem. 1985, 50, 2309.
H), 1.15-1.41 (m, 17H), 1.42-1.56 (m, 2H), 1.89-2.02
(m, 2H), 2.03-2.18 (m, 1H), 2.27-2.48 (m, 3H), 2.63-2.74
1
3
(
9) Vedejs, E. and West, F. G. Chem. Rev. 1986, 86, 941.
(m, 1H), 2.82 (t, 1H, J = 8.0 Hz); C NMR: δ 13.9, 14.0,
(
10) (a) Padwa, A.; Haffmanns, G. and Tomas, M. J. Org. Chem.
2
5
2.6, 27.4, 28.3, 29.0, 29.4, 30.8, 31.8, 35.8, 37.4, 54.1,
7.0; Anal calcd for C H N: N, 5.85. Found: N, 6.10.
1
1
984, 49, 3314. (b) Vedejs, E. and West, F. G. J. Org. Chem.
983, 48, 4773. (c) Padwa, A.; Chen, Y-Y.; Dent, W. and
1
6
33
2
-Benzyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
Nimmesgern, H. J. Org. Chem. 1985, 50, 4006.
11) Bäder, E. and Hermann, H. D. Chem. Ber. 1955, 88, 41.
12) Katritzky, A. R.; Feng, D. and Qi, M. Tetrahedron Lett. 1998,
in press.
1
(
(
(
2
4k). H NMR: δ 2.22-2.37 (m, 1H), 2.46-2.55 (m, 1H),
.72-2.90 (m, 2H), 2.97-3.25 (m, 3H), 3.52, 3.60 (AB, 2H,
J = 12.9 Hz), 3.72-3.85 (m, 1H), 7.00-7.20 (m, 4H), 7.20-
(
13) Molander, G. A. and Harris, C. R. Tetrahedron 1998, 54,
1
3
7
6
1
5
.40 (m, 5H); C NMR: δ 38.1, 41.0, 49.7, 60.0, 61.4,
1.7, 124.5, 124.6, 126.6, 126.8, 128.1, 128.7, 139.1,
43.3, 146.3; Anal calcd for C H N: N, 5.62. Found: N,
3321.
1
8
19
.60.
Article Identifier:
437-2096,E;1999,0,05,0590,0592,ftx,en;S07798ST.pdf
1
2
-Hexyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
1
(4l). H NMR: δ 0.86 (t, 3H, J = 6.7 Hz), 1.17-1.38 (m,
Synlett 1999, No. 5, 590–592 ISSN 0936-5214 © Thieme Stuttgart · New York