An organocatalytic direct Mannich-cyclization cascade as [3+2] annulation: Asymmetric synthesis of 2,3-substituted pyrrolidines

Article abstract of DOI:10.1039/c2cc33103a

A new method for asymmetric synthesis of 2,3-substituted pyrrolidines from N-PMP aldimines and succinaldehyde via formal [3+2] cycloaddition is reported. This reaction involves proline catalyzed direct Mannich reaction and acid catalyzed reductive cyclization with high yields (up to 78%) and excellent enantioselectivities (up to >99%).

Full text of DOI:10.1039/c2cc33103a

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An organocatalytic direct Mannich–cyclization cascade as [3+2]
annulation: asymmetric synthesis of 2,3-substituted pyrrolidinesw
Indresh Kumar,*ab Nisar A. Mir,b Vivek K. Guptac and Rajnikantc
Received 30th April 2012, Accepted 23rd May 2012
DOI: 10.1039/c2cc33103a
A new method for asymmetric synthesis of 2,3-substituted
pyrrolidines from N-PMP aldimines and succinaldehyde via
formal [3+2] cycloaddition is reported. This reaction involves
proline catalyzed direct Mannich reaction and acid catalyzed
reductive cyclization with high yields (up to 78%) and excellent
enantioselectivities (up to >99%).
Pyrrolidines are widely present in many bioactive synthetic and
natural products.1 The stereoselective synthesis of functionalized
pyrrolidines is of great interest due to their significance as
synthetic intermediates, as well as in chiral ligands2 and
organocatalysts.3 Consequently, significant efforts have been
devoted to the development of efficient routes to substituted
pyrrolidines.4 However, [3+2] cycloaddition of azomethine
ylide with activated olefin is the most effective method known
for the asymmetric synthesis of pyrrolidines.5 On the other hand,
the complementary [3+2] cycloaddition of suitable all-carbon
1,3-dipoles to imines has not been studied extensively, because
of the unavailability of suitable 1,3-dipoles and low reactivity
Fig. 1 [3+2] cycloaddition between imines and carbon 1,3-dipoles.
of imines (Fig. 1). As far as we know there are mainly two
main methods; in situ generation of 1,3-dipoles via the Lewis
an environmentally acceptable way and allow designing simple
acid-catalyzed ring-opening of cyclopropanes and subsequent
synthetic routes with high yields and selectivities.8 With the
one-pot cascade synthesis of pyrrolidines in mind, we report
here a highly asymmetric synthesis of 2,3-substituted pyrrolidines
from imines and succinaldehyde (eqn (3), Fig. 1).
cycloaddition to imines (eqn (1), Fig. 1)6 and metal catalyzed
[3+2] cycloaddition of trimethylenemethane with aromatic
and aliphatic imines, specially from the Trost group (eqn (2),
Fig. 1).7 Therefore, it will be interesting to develop a new in situ
1,3-carbon dipole for cycloaddition with imines to synthesize
substituted pyrrolidines in a highly asymmetric fashion.
As part of our interest in the development of synthetic
methods for heterocyclic compounds,9 we anticipated that
succinaldehyde 5, a synthetically useful 1,4-dicarbonyl unit,
might be explored as an in situ generated 1,3-dipole followed
by further cycloaddition with imines 4. This reaction involves
the direct Mannich reaction and intramolecular reductive
cyclization in one pot operation, as formal [3+2] cycloaddition.
The initial screening of catalysts, solvents, temperature with
N-PMP aldimine 4a preformed from p-nitrobenzaldehyde as a
model substrate was investigated and is summarized in Table 1.
The initial experimentation showed that among the amine
catalysts screened (entries 1–3, Table 1), proline 1 catalyzes the
direct Mannich reaction of aqueous succinaldehyde 5 with
imine 4a, followed by acid catalyzed reductive cyclization as a one
pot cascade, affording substituted pyrrolidine 6a with good yield
and selectivity (entry 1, Table 1). Solvent screening (entries 4–7,
Table 1) suggested that the DMSO/MeOH was optimal for this
two step cascade process. Gratifyingly, enhancement in the yield
The organocatalytic cascade or tandem reactions involving
two or more selective transformations using single/multiple
catalysis allows the quick construction of complex structures
in a one-pot operation. These reactions work with the con-
servation of energy and waste from abundant raw materials in
a Department of Chemistry, Birla Institute of Technology & Science,
Pilani 333 031, Rajasthan, India. E-mail: indresh.chemistry@gmail.com,
indresh.kumar@bits-pilani.ac.in; Fax: +91 1596 244183;
Tel: +91 1596 245073 Ext 276
b School of Biology & Chemistry, College of Science,
Shri Mata Vaishno Devi University, Katra 182 320, India
c X-ray Crystallography Laboratory, Post-Graduate Department of
Physics & Electronics, University of Jammu, Jammu 180 006, India
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for new compounds. CCDC
864411 (6b). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc33103a
c
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Table 1 Optimization of reaction conditionsa
Table 2 Generality of formal [3+2] cycloaddition reactiona
Timeb
(h)
Yieldc
(%)
eee
(%)
Entry
R
6
drd
1
2
3
4
5
6
7
8
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-Cl-C6H4
3-ClC6H4
4-ClC6H4
2-FC6H4
8
8
8
8
8
8
8
8
8
9
9
9
9
8
8
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
70
76
78
61
65
69
63
75
73
71
62
56
>25 : 1 98
>25 : 1 92
>25 : 1 96
>25 : 1 >99
>25 : 1 92
>25 : 1 90
>25 : 1 93
>25 : 1 91
>25 : 1 90
>25 : 1 92
>25 : 1 90
>25 : 1 97
>25 : 1 90
>25 : 1 95
>25 : 1 98
>25 : 1 95
>25 : 1 96
>25 : 1 95
5
Yieldc
(%)
Entry (Â M sol)b Cat. Conditionsa
drd
eee (%)
1
2
3
4
5
6
7
8
6 M
6 M
6 M
6 M
6 M
6 M
4 M
3 M
3 M
3 M
2 M
3 M
3 M
1
2
3
1
1
1
1
1
1
1
1
1
1
DMSO, rt, 4 h
DMSO, rt, 5 h
DMSO, rt, 12 h
DMF, rt, 6 h
56
48
20 : 1
18 : 1
n.d.
20 : 1
n.d.
20 : 1
20 : 1
20 : 1
>25 : 1 96
>25 : 1 96
>25 : 1 95
>25 : 1 94
89
85
n.d.
88
n.d.
86
90
90
o5
4-FC6H4
50
9
4-BrC6H4
3-Br–4-FC6H3
Ph
1-Naphthyl
2-Naphthyl
2-Pyridyl
4-Pyridyl
2-Thiophene
5-NO2-2-furan
Toluene, rt, 12 h o5
10
11
12
13
14
15
16
17
18
19
20f
6j
6k
6l
CH3CN, rt, 8 h
DMSO, rt, 4 h
DMSO, rt, 4 h
45
65
72
6m 60
9
DMSO, 5 8C, 6 h 78
DMSO, 0 1C, 8 h 69
DMSO, 5 1C, 8 h 65
DMSO, 5 1C, 12 h 61
DMSO, 5 1C, 6 h o10
6n
6o
6p
6q
6r
6s
6t
63
68
66
78
10
11
12f
13g
n.d.
n.d.
(E)-CHCHC6H5 10
4-OMeC6H4
Me
57
o5
24
24
n.d.
n.d.
n.d.
n.d.
a
(i) Imine 4 (0.3 mmol), 5 (Â M sol, 0.9 mmol), catalyst (20 mol%),
n.r.
b
c
solvent (3.0 mL); (ii) MeOH (3.0 mL). See ESI. Isolated yield, refer to
a
4a (after two steps in one pot). Determined by 1H-NMR. Determined
by chiral phase HPLC analysis using the OD-H column and iPrOH/
d
e
(i) Imine 4 (0.3 mmol), 5 (3M sol, 0.9 mmol), 1 (20 mol%), DMSO
b
(3.0 mL); (ii) MeOH (3.0 mL). Time for Mannich reaction catalyzed
c
d
by 1 (20 mol%). Isolated yield, refer to 4. Determined by 1H-NMR.
f
g
hexane solvent. Catalyst (10 mol%). CH3CO2H was not added.
e
Determined by chiral phase HPLC analysis using the OD-H column
f
and iPrOH/hexane as solvents. Aldimines were prepared in situ.
(78%) and enantioselectivity (96%) was observed, when this
reaction was carried out at 5 1C and with 3 M sol of
succinaldehyde 5 (entry 9, Table 1). The positive impact of
water on organocatalytic direct Mannich reaction has been
discussed earlier by Barbas and others.10 Furthermore, a
decrease in the temperature (entry 10, Table 1), succinaldehyde
concentration (entry 11, Table 1), and catalyst loading (entry 12,
Table 1) led to the prolonged reaction with reduced yield due to
the lability of imines in the presence of water. The reaction could
not deliver the desired product, when acid was not employed,
showing the necessity of acid to accelerate the reductive cycliza-
tion step (entry 13, Table 1). Thus, we preferred to perform this
one-pot two step cascade sequence under optimized conditions
(entry 9, Table 1).
alkenyl imines (entry 18, Table 2), the reaction was sluggish
and continued with slightly low yields, while electron-rich
arylimines (entry 19, Table 2) and in situ generated alkyl
imines (entry 20, Table 2) failed to deliver the desired products,
may be because of their less reactivity.
The coupling constant determination at C2 (J2H r 5.5 Hz)
by an 1H-NMR technique confirmed the relative stereochemistry
of C2 and C3 to be trans for all products (see ESIw). Our X-ray
analysis of substituted pyrrolidine 6b has further established the
relative stereochemistry. The ORTP-model shown in Fig. 2 has
C2-S and C3-S stereochemistry, as expected through the L-proline
1 catalyzed syn-selective direct Mannich reaction, followed by
reductive cyclization.
With the identification of the optimal conditions, the generality
of this proline 1 catalyzed asymmetric [3+2] annulation was
examined using a variety of preformed aryl or hetero-aryl N-PMP
aldimines 4 and succinaldehyde 5. The results are summarized in
Table 2. All of the reactions progressed smoothly to give corre-
sponding product 6 in moderate to high yields (up to 78%) with
high diastereo- (>25 : 1) and excellent enantioselectivities (up to
>99% ee) under optimized conditions (Table 2). In the case
of electron-deficient arylimines reactions proceeded well
(entries 1–10, Table 2), however the reactions were rather slow
in cases of imines preformed from 2-substituted benzaldehydes
(entries 1, 4 and 7, Table 2) and naphthaldehydes (entries 12
and 13, Table 2), resulting in lower yields, perhaps because of
the steric crowding. Not only aryl imines (entry 11, Table 2)
but hetero-aryl imines too gave products in high yields and
high enantioselectivities (entries 14–17, Table 2). In the case of
Based on our study and literature examples on proline
catalyzed Mannich reaction, the following stepwise mecha-
nism was proposed to account for the reaction. As shown in
Scheme 1, enamine 7, generated from succinaldehyde 5 and
proline 1, reacts with N-PMP aldimines 4 to give syn-Mannich
type intermediate 8. The intermediate 8 undergoes cyclization to
hemiaminal 9 with the subsequent regeneration of catalyst 1.
The intramolecular reductive amination of 9 with NaBH4 in the
presence of acid, and simultaneous aldehyde reduction, affords
trans-2,3-disubstituted N-PMP pyrrolidine 6 in high yields and
excellent diastereo (>25 : 1) and enantioselectivities (up to
>99%). The formal [3+2] annulated products are versatile
intermediates in organic synthesis and can be readily con-
verted into important chiral building blocks.
In conclusion, we have developed a simple and highly
stereoselective method for synthesis of substituted pyrrolidines
c
Chem. Commun.
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Tetrahedron, 1992, 48, 4045; (d) J. P. Michael, Nat. Prod. Rep.,
2005, 22, 603; (e) F. C. Biaggio, A. R. Rufino, M. H. Zaim, C. Y. H.
Zaim, M. A. Bueno and A. Rodrigues, Curr. Org. Chem., 2005, 9, 419.
2 (a) J. A. Sweet, J. M. Cavallari, W. A. Price, J. W. Ziller and D. V.
McGrath, Tetrahedron: Asymmetry, 1997, 8, 207; (b) F. Fache,
E. Schulz, M. L. Tommasino and M. Lemaire, Chem. Rev., 2000,
100, 2159.
3 (a) J. Seayad and B. List, Org. Biomol. Chem., 2005, 3, 719;
(b) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004,
43, 5138; (c) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed.,
2001, 40, 3726.
4 Recent examples: (a) T. J. Donohoe, H. O. Sintim and
J. Hollinshead, J. Org. Chem., 2005, 70, 7297; (b) D. V. Gribkov,
K. C. Hultzsch and F. Hampel, J. Am. Chem. Soc., 2006,
128, 3748; (c) J. Y. Kim and T. Livinghouse, Org. Lett., 2005,
7, 1737; (d) C. W. Roberson and K. A. Woerpel, J. Org. Chem.,
1999, 64, 1434; (e) K. Miura, T. Hondo, T. Nakagawa,
T. Takahashi and A. Hosomi, Org. Lett., 2000, 2, 385;
(f) S.-I. Fukuzawa and H. Okim, Org. Lett., 2008, 10, 1747;
(g) K. Daidouji, K. Fuchibe and T. Akiyama, Org. Lett., 2005,
7, 1051; (h) P. Restorp, A. Fischer and P. Somfai, J. Am. Chem.
Soc., 2006, 128, 12646; (i) W. Zeng, G.-Y. Chen, Y.-G. Zhou and
Y.-X. Li, J. Am. Chem. Soc., 2007, 129, 750; (j) S. Saito,
T. Tsubogo and S. Kobayashi, J. Am. Chem. Soc., 2007,
129, 5364; (k) A. S. Gothelf, K. V. Gothelf, R. G. Hazell and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2002, 41, 4236.
5 (a) A. Padwa and W. H. Pearson, Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products,
Wiley, New York, 2002; (b) S. Husinec and V. Savic, Tetrahedron:
Asymmetry, 2005, 16, 2047; (c) K. V. Gothelf and K. A. Jørgensen,
Chem. Rev., 1998, 98, 863; (d) C. Najera and J. M. Sansano, Angew.
Chem., Int. Ed., 2005, 44, 6272; (e) G. Pandey, P. Banerjee and
S. R. Gadre, Chem. Rev., 2006, 106, 4484.
Fig. 2 ORTP-diagram of 6b, thermal ellipsoids drawn at the 40%
probability level.
6 (a) P. B. Alper, C. Meyers, A. Lerchner, D. R. Siegel and
E. M. Carreira, Angew. Chem., Int. Ed., 1999, 38, 3186;
(b) C. A. Carson and M. A. Kerr, J. Org. Chem., 2005, 70, 8242;
(c) S. K. Jackson, A. Karadeolian, A. B. Driega and M. A. Kerr,
J. Am. Chem. Soc., 2008, 130, 4196; (d) S. Yamago, M. Nakamura,
X. Q. Wang, M. Yanagawa, S. Tokumitsu and E. Nakamura,
J. Org. Chem., 1998, 63, 1694.
7 (a) M. D. Jones and R. D. W. Kemmitt, J. Chem. Soc., Chem.
Commun., 1986, 1201; (b) B. M. Trost and C. M. Marrs, J. Am.
Chem. Soc., 1993, 115, 6636; (c) B. M. Trost, S. M. Silverman and
J. P. Stambuli, J. Am. Chem. Soc., 2007, 129, 12398; (d) B. M. Trost
and S. M. Silverman, J. Am. Chem. Soc., 2012, 134, 4941.
8 For reviews on organocatalytic cascade reactions, see:
(a) D. Enders, C. Grondal and M. R. M. Huttl, Angew. Chem.,
Int. Ed., 2007, 46, 1570; (b) Ł. Albrecht, H. Jiang and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492;
(c) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010,
2, 167; (d) X. Yu and W. Wang, Org. Biomol. Chem., 2008,
6, 2037; (e) D. B. Ramachary and S. Jain, Org. Biomol. Chem.,
2011, 9, 1277.
9 (a) I. Kumar, N. A. Mir and B. P. Wakhloo, 2012, manuscript
communicated; (b) I. Kumar, N. A. Mir, C. V. Rode and
B. P. Wakhloo, Tetrahedron: Asymmetry, 2012, 23, 225;
(c) I. Kumar and C. V. Rode, Tetrahedron: Asymmetry, 2010,
21, 2703; (d) I. Kumar, S. Rana, J. W. Cho and C. V. Rode,
Tetrahedron: Asymmetry, 2010, 21, 352; (e) I. Kumar and
C. V. Rode, Tetrahedron: Asymmetry, 2007, 18, 1975;
(f) I. Kumar, S. R. Bhide and C. V. Rode, Tetrahedron: Asym-
metry, 2007, 18, 1210; (g) I. Kumar and C. V. Rode, Tetrahedron:
Asymmetry, 2006, 17, 763; (h) I. Kumar and C. V. Rode, Chem.
Lett., 2007, 5, 592.
10 (a) A. Cordova and C. F. Barbas III, Tetrahedron Lett., 2003,
44, 1923; (b) W. Notz, F. Tanaka, S. Watanabe, N. S. Chowdari,
J. M. Turner, R. Thayumanavan and C. F. Barbas III, J. Org.
Chem., 2003, 68, 9624; (c) Y.-C. Teo, J.-J. Lau and M.-C. Wu,
Tetrahedron: Asymmetry, 2008, 19, 186; (d) Y. Hayashi,
T. Urushima, S. Aratake, T. Okano and K. Obi, Org. Lett.,
2008, 10, 21; (e) T. Hamada, K. Manabe and S. Kobayashi,
Chem.–Eur. J., 2006, 12, 1205; (f) T. Hamada, K. Manabe and
S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7768; (g) R.-G. Han,
Y. Wang, Y.-Y. Li and P.-F. Xu, Adv. Synth. Catal., 2008,
350, 1474.
Scheme 1 Proposed reaction mechanism for formal [3+2] cycloaddition.
from readily available precursors like N-PMP aldimines and
succinaldehyde as new 1,3-carbon dipoles. The present one-pot
protocol involves the L-proline catalyzed direct Mannich reaction
and reductive cyclization sequence as formal [3+2] cycloaddition
under mild conditions, affording a wide access to trans-2,3-
substituted pyrrolidines. Further potential applications of this
methodology utilizing aliphatic imines and the synthesis of
biologically active pyrrolidines are currently under investiga-
tion in our laboratory and will be reported in due course.
We acknowledge the financial support of ‘‘Fast-track Scheme
for Young Scientist’’ from Department of Science and Technology
(DST), New Delhi. Instrumental analysis support from
Dr Subrayashastry Aravinda and Deepika Singh (Scientist),
IIIM (CSIR-Lab) Jammu, is also gratefully acknowledged.
Notes and references
1 (a) J. R. Liddell, Nat. Prod. Rep., 1999, 16, 499; (b) D. O’Hagan,
Nat. Prod. Rep., 2000, 17, 435; (c) K. Burgess and I. Henderson,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.