Scandium triflate catalyzed cycloaddition of imines with 1,1-cyclopropanediesters: Efficient and diastereoselective synthesis of multisubstituted pyrrolidines

Article abstract of DOI:10.1039/b512195g

A tandem ring-opening-cyclization reaction of cyclopropanes with imines in the presence of 5 mol% of scandium triflate was developed for the highly diastereoselective synthesis of multisubstituted pyrrolidines. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b512195g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Scandium triflate catalyzed cycloaddition of imines with
1,1-cyclopropanediesters: efficient and diastereoselective synthesis of
multisubstituted pyrrolidines†
Yan-Biao Kang, Yong Tang* and Xiu-Li Sun
Received 31st August 2005, Accepted 14th November 2005
First published as an Advance Article on the web 6th December 2005
DOI: 10.1039/b512195g
A tandem ring-opening–cyclization reaction of cyclopropanes with imines in the presence of 5 mol% of
scandium triflate was developed for the highly diastereoselective synthesis of multisubstituted
pyrrolidines.
Introduction
Pyrrolidines are very important five-membered heterocycles
because of their frequent occurrence in biologically active
compounds,1 as well as their utilities as valuable synthetic
intermediates2 or organocatalysts.3 Of the synthetic methods
developed, [3 + 2] dipolar cycloaddition of azomethine ylides with
activated alkenes is one of the most convenient and efficient ways.4
The reaction of monoactivated cyclopropanes5,6 with imines is also
developed.7–8 Nakamura et al. described the thermal [3 + 2] cy-
cloaddition reactions of highly activated methylenecyclopropanes
Scheme 1
with imines to produce pyrrolidine derivatives.7 Recently, Carreira
et al.8a,8d pioneered a reaction of cyclopropanes with imines
To further improve the yield and the diastereoselectivity, several
promoted by MgI2, providing easy access to spiro[pyrrolidin-3,3ꢀ-
oxindoles]. Using stoichiometric MgI2, Lautens and coworkers
extended successfully the cyclopropanes to methylenecyclopropyl
amides and developed a good method for the synthesis of five-
and six-membered heterocyclic compounds.8b Olsson described
an iodide-promoted three-component synthesis of disubstituted
pyrrolidines.8c In our study on the synthesis and applications of
cyclopropanes,9 we found that the imines could directly attack
the 1,1-cyclopropane carboxylic esters to form tetrasubstituted
pyrrolidines stereoselectively in the presence of Lewis acid. In this
paper, we wish to report the results in details.10
Lewis acids were optimized. As shown in Table 1, Yb(OTf)3,
Table 1 Effects of Lewis acids on the annulation reactiona
Entry
R
LA
Drb
Conversion (%)b
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ts
Sc(OTf)3
Yb(OTf)3
Ga(OTf)3
In(OTf)3
Mg(ClO4)2
Ni(ClO4)2
Cu(ClO4)2
Zn(ClO4)2
AlCl3
Sc(OTf)3
Yb(OTf)3
Ga(OTf)3
In(OTf)3
Ni(ClO4)2
Mg(ClO4)2
Cu(ClO4)2
Zn(ClO4)2
FeCl3
1 : 1
—
—
—
—
—
—
—
—
1.5 : 1
1.8 : 1
1.8 : 1
1.7 : 1
—
60c
Trace
Trace
36
Trace
45
Trace
Trace
Trace
100
29
30
87
0
0
25
10
49
77
Results and discussion
Initially, an attempt to use stoichiometric magnesium iodide to
promote the cycloaddition of electron-deficient cyclopropane 1a
and imine 2a failed (Scheme 1). Although the cyclopropane disap-
peared in ca. 6 hours in THF, only a trace amount of the annulation
adduct with poor stereoselectivity was observed. Replacing the
solvent with CH2Cl2 did not give the desired product. Fortunately,
we found that this reaction could be catalyzed very well by using
5 mol% of Sc(OTf)3 instead of MgI2. In this case, the annulation
reaction of diethyl 2-phenyl-1,1-cyclopropane dicarboxylates with
2a gave pyrrolidine 3a in 60% yield in CH2Cl2 at room temperature.
10d
11d
12d
13d
14d
15d
16d
17d
18d
19d,e
20d,f
21d
22d
—
1.7 : 1
1.2 : 1
2.1 : 1
1 : 1
1.3 : 1
—
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
54
0
85
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai,
200032, China. E-mail: tangy@mail.sioc.ac.cn; Fax: +86 21 5492 5078
Bn
24 : 1
a 10 mol% of Lewis acid. b Determined by 1H NMR. c Isolated yield. d 4 A
molecular sieves were added. e In toluene. f In diethyl ether.
˚
† Electronic supplementary information (ESI) available: Spectral data,
1H and 13C NMR spectra for all new compounds and stereochemical
assignments. See DOI: 10.1039/b512195g
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Ga(OTf)3, Mg(ClO4)2, Cu(ClO4)2, Zn(ClO4)2 and AlCl3 could
not catalyze this reaction well and only a trace amount of the
desired product was observed (Entries 2, 3, 5 and 7–9). In(OTf)3
and Ni(ClO4)2 gave moderate yields in CH2Cl2 (Entries 4 and 6).
Noticeably, the conversion of this reaction could be improved
Various 2-substituted 1,1-cyclopropane carboxylates proved to
be good substrates for the present cycloaddition. For example, the
reaction of both 2-vinyl- and 2-phenyl-1,1-cyclopropanes with 4-
chlorobenzylaldimne proceeded well to provide the pyrrolidines
in 92% and 85% yields, respectively (Entries 11 and 12). The
cyclopropane with substituent at 3-position, such as diethyl 2-
ethyl-3-styrylcyclopropane-1,1-dicarboxylate, was inactive in this
reaction.
Considering that the imine is readily available from aldehyde
and amine, we tried a three-component reaction and found that the
one-pot reaction by combination of the aldehyde (1.2 equivalent)
and the benzyl amine (1.2 equiv.) in CH2Cl2 in the presence
˚
to 100% using Sc(OTf)3 as a catalyst in the presence of 4 A
molecular sieves (Entry 10). Under these conditions, In(OTf)3 also
promoted this reaction well to give pyrrolidine in 87% conversion
(Entry 13). Solvent effects were also examined and we found
that THF, EtOAc, EtOH and CH3CN did not work. Diethyl
ether and toluene gave good yields (Entries 19–20) and CH2Cl2
proved to be the optimal solvent. The substituents on nitrogen
of imine 2 influenced the reaction strongly (Entries 10, 21–22).
N-Tosyl imine was not a good substrate. Compared with the N-
phenyl imine, N-benzyl gave the optimal results in both yield and
diastereoselectivity in our screened conditions.
˚
of 4 A molecular sieves and 5 mol% of Sc(OTf)3, followed by
addition of cyclopropane 1b (1.0 equiv.) in 0.5 mL of CH2Cl2
worked well to give the pyrrolidine in good yields with low to high
diastereoselectivities, providing an efficient access to pyrrolidines
(Scheme 2).
Having established the feasibility and optimal conditions for the
cycloaddition reaction, we surveyed the scope of the imines and
cyclopropanes. The imines were synthesized via a condensation
between amines and aldehydes with a ratio of 1 : 1 in the presence of
˚
4 A MS, followed by filtering off the molecular sieves and concen-
tration. They were used directly without further purification. As
shown in Table 2, the reaction of cyclopropane dicarboxylates with
imines gave good to high yields with high diastereoselectivities. The
ratio of cis-isomer to trans-isomer ranged from 8 : 1 to 30 : 1. It is
noteworthy that both electron-rich and electron-deficient imines
proceeded well. For instance, 3,4-methylenedioxybenzylaldimine
gave the desired product in 94% yield and 4-methoxycarbonyl
benzylaldimine afforded the corresponding pyrrolidine in 52%
yield, both with high diastereoselectivities. Compared with para-
substituted benzylaldimine, the ortho-substituted one was less
active (Entries 7–8) probably due to the steric hindrance. N-benzyl
isobutyraldimine didn’t work in this condition.
Scheme 2
The relative configurations of the adducts were assigned by 1H–
1H NOESY as shown in Scheme 3.
Table 2 Reaction of cyclopropanes with iminesa
Scheme 3
The mechanism6 for this cycloaddition is proposed as in
Scheme 4. A possible path is that the imine SN2 attacks the
cyclopropane directly in the assistance of Sc(OTf)3 to form an
iminium-enolate zwitterionic intermediate, which cyclizes imme-
diately to afford the pyrrolidine. In this case, cis-isomer is produced
preferably due to the steric hindrance between R1 and R2. This
Entry R1
R2
R3
3
Drb
Yield (%)c
1
Styryl Me Ph
b
c
d
e
f
g
h
i
9 : 1 91
2
3
Styryl Me 4-FC6H4
Styryl Me 4-ClC6H4
Styryl Me 4-BrC6H4
Styryl Me 4-MeO2CC6H4
Styryl Me 4-MeC6H4
Styryl Me 4-MeOC6H4
Styryl Me 2-MeOC6H4
Styryl Me 2,4-Cl2C6H4
Styryl Me 3,4-
10 : 1 94
11 : 1 92
10 : 1 71
12 : 1 52e
8 : 1 86
4
5d
6d
7
9 : 1 86
8
9
10
10 : 1 59
30 : 1 59
10 : 1 94
j
k
Methylenedioxylphenyl
Me 4-ClC6H4
11f
12d
13f
14d
Vinyl
l
6 : 1 92
24 : 1 85
Phenyl Et
4-ClC6H4
4-ClC6H4
m
n
o
H
Et
>99 : 1 42
Phenyl Me 4-ClC6H4
30 : 1 98e
a Reaction conditions: 0.25 mmol scale, 5 mol% of scandium triflate, 2 :
1 = 0.3 : 0.25 (mmol : mmol), rt. b dr = cis : trans, determined by 1H
NMR. c Isolated yield. d 10 mol% of Sc(OTf)3 used. e At 40 ◦C. f 20 mol%
of Sc(OTf)3 used.
Scheme 4
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is consistent with the stereochemistry produced. This mechanism
can also explain that N-sulfonyl imine was inactive in this reaction.
In summary, we have developed an efficient method for the
diastereoselective synthesis of multisubstituted pyrrolidines via a
Lewis acid-catalyzed annulation reaction of cyclopropanes with
imines. Noticeably, a corresponding three-component one-pot
reaction, directly from aldehydes, amines and cyclopropanes, has
proved to work well. The readily available starting material, high
selectivity as well as high yield make this protocol potentially
useful in organic synthesis. Efforts to develop its asymmetric
version are in progress in our laboratory.
Acknowledgements
We are grateful for the financial support from the Natural
Sciences Foundation of China and The Science and Technology
Commission of Shanghai Municipality.
References
1 (a) W. H. Pearson, in Studies in Natural Products Chemistry, ed. Atta-
Ur-Rahman, Elsevier, New York, 1998, vol. 1, pp. 323–358; (b) D.
O’Hagan, Nat. Prod. Rep., 2000, 17, 435 and previous reports in this
series; (c) G. W. Gribble, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon, Oxford,
UK, 1996, vol. 2, pp. 207–257; (d) H. Fiaux, F. Popowycz, S. Favre, C.
Schutz, P. Vogel, S. Gerber-Lemaire and L. Juillerat-Jeanneret, J. Med.
Chem., 2005, 48, 4237; (e) P. R. Sebahar and R. M. Williams, J. Am.
Chem. Soc., 2000, 122, 5666; (f) D. J. Denhart, D. A. Griffith and C. H.
Heathcock, J. Org. Chem., 1998, 63, 9616; (g) P. Garner, P. B. Cox, J. T.
Anderson, J. Protasiewicz and R. Zaniewski, J. Org. Chem., 1997, 62,
493; (h) L. E. Overman and J. E. Tellew, J. Org. Chem., 1996, 61, 8338.
2 (a) J. Cossy, C. Dumas and D. G. Pardo, Eur. J. Org. Chem., 1999,
7, 1693; (b) J. Cossy, C. Dumas and D. G. Pardo, Eur. J. Org. Chem.,
1999, 7, 1693; (c) J. Cossy, O. Mirguet, D. G. Pardo and J.-R. Desmurs,
Eur. J. Org. Chem., 2002, 21, 3543; (d) T. Honda and F. Ishikawa,
Chem. Commun., 1999, 12, 1065; (e) T. Honda and M. Kimura, Org.
Lett., 2000, 2, 3925; (f) M. Ori, N. Toda, K. Takami, K. Tago and H.
Kogen, Angew. Chem., Int. Ed., 2003, 42, 2540.
Experimental
All reactions were carried out under a nitrogen atmosphere. All
of dialkyl 1,1-cyclopropanediesters11 and their derivates12 were
synthesized according to the literature. The N-benzyl imines were
synthesized via condensation of the corresponding aldehydes and
benzyl amine.13 MS 4 A was powdered and vacuum activated at
˚
250 ◦C before use.
General procedure
3 For reviews, see: (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed.,
2001, 40, 3726; (b) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed.,
2004, 43, 5138; (c) B. List, Synlett, 2001, 1675; (d) B. List, Tetrahedron,
2002, 58, 5573; (e) B. List, Acc. Chem. Res., 2004, 37, 548; (f) W. Notz,
F. Tanaka and C. F. Barbas, III, Acc. Chem. Res., 2004, 37, 580.
4 (a) J. M. Longmire, B. Wang and X. Zhang, J. Am. Chem. Soc., 2002,
124, 13400; (b) A. S. Gothelf, K. V. Gothelf, R. G. Hazell and K. A.
Jorgensen, Angew. Chem., Int. Ed., 2002, 41, 4236; (c) C. Chen, X.
Li and S. L. Schreiber, J. Am. Chem. Soc., 2003, 125, 10174; (d) Y.
Oderaotoshi, W. Cheng, S. Fujitomi, Y. Kasano, S. Minakata and M.
Komatsu, Org. Lett., 2003, 5, 5043; (e) P. D. Pohlhaus, R. K. Bowman
and J. S. Johnson, J. Am. Chem. Soc., 2004, 126, 2294; (f) S. Peddibhotla
and J. J. Tepe, J. Am. Chem. Soc., 2004, 126, 12776.
To an oven-dried reaction tube was sequentially added Sc(OTf)3
˚
(6.2 mg, 0.0125 mmol, 5 mol%), MS 4 A (250 mg), cyclopropane
(0.25 mmol in 1.5 mL of CH2Cl2) and imine (0.30 mmol in
1.0 mL of CH2Cl2). The resulting solution was further stirred at
25 ◦C. After the reaction was complete (monitored by TLC), the
mixture was filtered rapidly through a glass funnel with a thin layer
of silica gel, washed with CH2Cl2. The filtrate was concentrated
and the residue was purified by flash column chromatography to
afford the desired product.
5 For reactions of cyclopropanes with nitrones, see: (a) I. S. Young and
M. A. Kerr, Angew. Chem., Int. Ed., 2003, 42, 3023; (b) I. S. Young and
M. A. Kerr, Org. Lett., 2004, 6, 139; (c) M. D. Ganton, A. Michael
and M. A. Kerr, J. Org. Chem., 2004, 69, 8554; (d) I. S. Young, J. L.
Williams and M. A. Kerr, Org. Lett., 2005, 7, 953.
6 For a reaction of cyclopropane with aldehyde, see: P. D. Pohlhaus and
J. S. Johnson, J. Org. Chem., 2005, 70, 1057.
7 (a) S. Yamago, M. Nakamura, X. Q. Wang, M. Yanagawa, S. Tokumitsu
and E. Nakamura, J. Org. Chem., 1998, 63, 1694; (b) I. Nakamura, B. H.
Oh, S. Saito and Y. Yamamoto, Angew. Chem., Int. Ed., 2001, 40, 1298;
(c) B. H. Oh, I. Nakamura, S. Saito and Y. Yamamoto, Tetrahedron
Lett., 2001, 42, 6203; (d) E. Nakamura and S. Yamago, Acc. Chem.
Res., 2002, 35, 867–877.
8 (a) P. B. Alper, C. Meyers, A. Lerchner, D. R. Siegel and E. M. Carreira,
Angew. Chem., Int. Ed., 1999, 38, 3186; (b) M. Lautens and W. Han,
J. Am. Chem. Soc., 2002, 124, 6312; (c) F. Bertozzi, M. Gustafsson and
R. Olsson, Org. Lett., 2002, 4, 3147; (d) C. Marti and E. M. Carreira,
J. Am. Chem. Soc., 2005, 127, 11505.
9 (a) W.-W. Liao, K. Li and Y. Tang, J. Am. Chem. Soc., 2003, 125, 13030;
(b) S. Ye, Z. Z. Huang, C. A. Xia, Y. Tang and L.-X. Dai, J. Am. Chem.
Soc., 2002, 124, 2432; (c) S. Ye, L. Yuan, Z. Z. Huang, Y. Tang and
L.-X. Dai, J. Org. Chem., 2002, 65, 6257; (d) S. Ye, Y. Tang and L.-X.
Dai, J. Org. Chem., 2001, 66, 1517; (e) S. Ye, Y. Tang and L.-X. Dai,
J. Org. Chem., 2000, 65, 6257.
10 After submitting this paper, Kerr et al. published a similar result in
J. Org. Chem.: C. A. Carson and M. A. Kerr, J. Org. Chem., 2005, 70,
8242.
General procedure for three-component reaction
˚
To an oven-dried reaction tube was sequentially added MS 4 A
(250 mg), benzylamine and aldehyde in CH2Cl2 (2 mL) under
stirring at 25 ◦C. The resulting suspension was stirred for 30 min
and Sc(OTf)3 (6.2 mg, 0.0125 mmol, 5 mol%) and cyclopropane
(0.25 mmol in 0.5 mL of CH2Cl2) were added. The resulting
mixture was further stirred at 25 ◦C for the desired time and
filtered rapidly through a glass funnel with a thin layer of silica
gel, washed with CH2Cl2. The filtrate was concentrated and the
residue was purified by flash column chromatography to afford
the desired product.
All compounds gave satisfactory spectral data (1H NMR, 13C
NMR, IR, LRMS, HRMS, elemental analysis). Spectral data for
representative compound 3b: colorless oil (91% yield). H NMR
1
(300 MHz, CDCl3): d 7.44 (d, J = 6.9 Hz, 1H), 7.31–7.07 (m, 13H),
6.55 (d, J = 16.2 Hz, 1H), 6.16 (dd, J = 11.4, 15.9 Hz, 1H), 4.67 (s,
1H), 3.83 (d, J = 14.1 Hz, 1H), 3.70 (s, 3H), 3.64 (d, J = 14.1 Hz,
1H), 3.42–3.34 (m, 1H), 3.06 (s, 3H), 2.81 (dd, JAB = 13.5 Hz, JAX
= 10.8 Hz, 1H), 2.25 (dd, JAB = 13.5 Hz, JBX = 6.6 Hz, 1H); 13
C
NMR (75 MHz, CDCl3): d 171.96, 169.55, 139.24, 136.87, 136.51,
131.98, 131.66, 129.82, 128.84, 128.41, 127.75, 127.70, 127.54,
127.44, 126.73, 126.34, 70.54, 63.95, 63.92, 54.07, 52.77, 51.96,
39.23; LRMS-ESI: 456.1 (M + H)+; IR (thin film, cm−1): 3027,
2951, 2830, 1733, 967, 755, 699; HRMS-ESI: Exact mass calcd for
C29H30NO4 [M + H]+, 456.2169. Found 456.2167.
11 W. Dmowski and A. Wolniewicz, J. Fluorine Chem., 2000, 102,
141.
12 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1353.
13 (a) V. Derdau and V. Snieckus, J. Org. Chem., 2001, 66, 1992; (b) M.
Kim, B. W. Knettle, A. Dahlen, G. Hilmersson and R. A. Flowers,
Tetrahedron, 2003, 59, 10397.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 299–301 | 301
©