Highly diastereoselective synthesis of 1-pyrrolines via SnCl 4-promoted [3 + 2] cycloaddition between activated donor-acceptor cyclopropanes and nitriles

Article abstract of DOI:10.1021/ol2024423

Activated donor-acceptor cyclopropanes underwent formal [3 + 2] cycloaddition with nitriles in the presence of SnCl₄. The product 1-pyrrolines were isolated as single cis-diastereomers in moderate to good yields.

Full text of DOI:10.1021/ol2024423

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6002–6005
Highly Diastereoselective Synthesis of
1-Pyrrolines via SnCl4-Promoted [3 þ 2]
Cycloaddition between Activated
DonorꢀAcceptor Cyclopropanes and
Nitriles
Gopal Sathishkannan and Kannupal Srinivasan*
School of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu,
India
srinivasank@bdu.ac.in
Received September 9, 2011
ABSTRACT
Activated donorꢀacceptor cyclopropanes underwent formal [3 þ 2] cycloaddition with nitriles in the presence of SnCl4. The product 1-pyrrolines
were isolated as single cis-diastereomers in moderate to good yields.
The formal [3 þ 2] cycloaddition reaction of donorꢀ
acceptor (DꢀA) cyclopropanes has emerged as a powerful
tool for the construction of various five-membered carbo-
and heterocycles.1 The reactions involve in situ generation
of 1,3-dipoles through Lewis acid promoted ring opening
of the DꢀA cyclopropanes, followed by addition to dipo-
larophiles that bear CꢀC or CꢀX (X = O, N) multiple
bonds. The special features of the reactions include high
atom economy and excellent regio- and stereoselectivities
observed in the products.
The use of nitriles as dipolarophiles in such cycloaddi-
tionreactionsremainedunexploreduntil thepublication of
a seminal work by Pagenkopf and co-workers in 2003.2
Although this methodology affords the product 1-pyrro-
lines in excellent yields, it is applicable specifically to
carbohydrate-derived or pyran ring-fused, lactonized
DꢀA cyclopropanes prepared by intramolecular cyclo-
propanation. In the case of similar nonlactonized cyclo-
propanes prepared by intermolecular cyclopropanation,
the reaction failed to stop at the 1-pyrroline stage and
further structural transformation spontaneously occurred
to yield pyrroles.3 To address this issue, we planned to
examine DꢀA cyclopropanes 1 as the 1,3-dipole precur-
sors for cycloaddition reactions with nitriles (Scheme 1).
It is obvious that the presence of a gem-diester moiety will
arrest any further structural transformation in the product
1-pyrrolines.
Scheme 1. Synthesis of 1-Pyrrolines 3 via [3 þ 2] Cycloaddition
between DonorꢀAcceptor Cyclopropanes 1 and Nitriles 2
(1) For recent reviews, see: (a) Reissig, H.-U.; Zimmer, R. Chem. Rev.
2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321.
(c) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (d) De
Simone, F.; Waser, J. Syntheis 2009, 3353.
(2) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122. For
cycloaddition between other types of cyclopropanes and nitriles, see:
(a) Mizuno, K.; Nire, K.; Sugita, H.; Otsuji, Y. Tetrahedron Lett. 1993,
34, 6563. (b) Herbertz, T.; Roth, H. D. J. Am. Chem. Soc. 1996, 118,
10954. (c) Huang, J.-W.; Shi, M. Synlett 2004, 2343. (d) Li, W.; Shi, M. J.
Org. Chem. 2008, 73, 4151.
r
10.1021/ol2024423
Published on Web 10/20/2011
2011 American Chemical Society

Although the DꢀA cyclopropanes 1 and other related
cyclopropanes have previously been employed for the
synthesis of substituted tetrahydrofurans,4ꢀ7 their use in
the synthesisof 1-pyrrolines remains unexplored. Thus, the
present methodology would provide an easy and efficient
access to densely substituted 1-pyrrolines, possibly in a
highly diastereoselective manner. It is noteworthy to men-
tionthatthe 1-pyrrolineringisfeatured in several naturally
occurring compounds8 and many 1-pyrroline derivatives
havebeenrecognizedasvaluableintermediatesinsynthetic
and medicinal chemistry.8b In addition to conventional
cyclization methods,9 many other methods such as thermal
or photochemical rearrangements of cyclopropylimines,10
1,3-dipolar cycloadditions of azomethine11,12 and nitrile13
ylides with alkenes, intramolecular hydroamination of
aminoalkynes,14 and partial hydrogenation of pyrroles15
have been reported for the synthesis of 1-pyrrolines.
temperature for 30 min, the cyclopropanes 1aꢀg were
produced in excellent yields (Table 1). The main advantage
of our procedure is the formation of cyclopropanes 1aꢀg
as single trans-diastereomers with no sign of cis-diaster-
eomers. It has been reported that a diastereomeric mixture
of similar cyclopropanes could be isomerized to more
stable single trans-diastereomers by treatment with
DBU.19 This phenomenon would account for the exclusive
formation of the trans-diastereomers in our present study.
Table 1. Preparation of Precursor DꢀA Cyclopropanes 1
The DꢀA cyclopropanes 1 used in the present study
could be prepared by either the oxidative cyclization of the
Michael adducts of malonates with chalcones 4 using
PhIO/Bu4NI16 or the Michael-initiated ring closure (MIRC)
between diethyl benzylidenemalonates and chloro-
acetophenones.17 In the present study, we have developed
an alternative procedure which involves the ring closure of
the Michael adducts 4 using I2 and DBU. This reagent
combination has been previously used for the intermole-
cular cyclopropanation of fullerene C60 with diethyl-
malonate.18 Accordingly, when the Michael adducts
4aꢀg were stirred with I2 and DBU in toluene at room
entry
Ar1
C6H5
Ar2
C6H5
yield (%)a
1
2
3
4
5
6
7
92 (1a)
90 (1b)
93 (1c)
94 (1d)
89 (1e)
89 (1f)
85 (1g)
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
4-NO2C6H4
2-thienyl
4-ClC6H4
a Isolated yield; all are single trans-diastereomers.
In order to explore the [3 þ 2] cycloaddition reactions of
DꢀA cyclopropanes 1 with nitriles, the reaction between
1a and benzonitrile (2a) was chosen as a model reaction to
optimize the reaction conditions. The results are summa-
rized in Table 2.
(3) (a) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099. (b) Yu, M.;
Pantos, G. D.; Sessler, J. L.; Pagenkopf, B. L. Org. Lett. 2004, 6, 1057. (c)
Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008, 10, 157. (d) Moustafa,
M. M. A. R.; Pagenkopf, B. L. Org. Lett. 2010, 12, 3168.
(4) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023.
(5) (a) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057.
(b) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014.
(c) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 8642. (d) Parsons, A. T.; Johnson, J. S.
J. Am. Chem. Soc. 2009, 131, 3122.
(6) Xing, S.; Pan, W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int.
Ed. 2010, 49, 3215.
(7) Yang, G.; Shen, Y.; Li, K.; Sun, Y.; Hua, Y. J. Org. Chem. 2011,
76, 229.
(8) (a) Morris, B. D.; Prinsep, M. R. J. Nat. Prod. 1999, 62, 688. (b)
Dannhardt, G.; Kiefer, W. Arch. Pharm. Pharm. Med. Chem. 2001, 334,
183. (c) Hao, B.; Gong, W.; Ferguson, T. K.; James, C. M.; Krzyckl,
J. A.; Chan, M. K. Science 2002, 296, 1462. (d) Jones, T. H.; Zottig, V. E.;
Robertson, H. G.; Snelling, R. R. J. Chem. Ecol. 2003, 29, 2721. (e)
Clark, V. C.; Raxworthy, C. J.; Rakotomalala, V.; Sierwald, P.; Fisher,
B. L. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11617. (f) Bellina, F.;
Rossi, R. Tetrahedron 2006, 62, 7213.
(9) Shvekhgeimer, M.-G. A. Chem. Heterocycl. Compd. 2003, 39,
405.
(10) Soldevilla, A.; Sampedro, D.; Campos, P. J.; Rodriguez, A.
J. Org. Chem. 2005, 70, 6976.
(11) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776.
(12) Pandit, P.; Chatterjee, N.; Maiti, D. K. Chem. Commun. 2011,
47, 1285.
(13) Sibi, M. P.; Soeta, T.; Jasperse, C. P. Org. Lett. 2009, 11, 5366.
(14) Iska, V. B. R.; Verdolino, V.; Wiest, O.; Helquist, P. J. Org.
Chem. 2010, 75, 1325.
(15) Wang, D.-S.; Ye, Z.-S.; Chen, Q.-A.; Zhou, Y.-G.; Yu, C.-B.;
Fan, H.-J.; Duan, Y. J. Am. Chem. Soc. 2011, 133, 8866.
(16) Ye, Y.; Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156.
(17) Gaosheng, Y.; Yuanyuan, H.; Yue, S. Chin. J. Chem. 2009, 27,
1811.
To start, the reaction was conducted with 1 equiv of 1a
and 5 equiv of 2a using a stoichiometric amount of the
Lewis acid, AlCl3 in CH2Cl2 at room temperature. Pleas-
ingly, the cis-1-pyrroline 3a was obtained as the only
isolable product in 52% yield (entry 1). When conducted
at 0 °C, the reaction did not take place (entry 2). The use of
SnCl4 as the Lewis acid gave the product 3a in a slightly
better yield (55%), and the reaction time was also reduced
to 8 h (entry 3). This reaction also failed when conducted at
0 °C (entry 4). Switching the solvent to 1,2-dichloroethane
increased the yield to 66% while reducing the reaction time
to 7 h (entry 5). When nitromethane was used as the
solvent, the yield was reduced to 40% (entry 6). When
conducted at 0 °C in 1,2-dichloroethane, the reaction failed
(entry 7). The yield was reduced slightly when the reaction
was conducted at 60 °C (entry 8) or the amount of the
Lewis acid was decreased to 50 mol % (entry 9). When the
amount of the Lewis acid was reduced further to 20 mol %,
the reaction was incomplete evenafter 24h and the isolated
yield was only 19% (entry 10). The use of TiCl4 formed the
product only in trace amounts (entry 11) while BF3 Et2O
decomposed the starting cyclopropane (entry 12). Other
Lewis acids, viz., InBr3, In(OTf)3, Sc(OTf)3, and Yb(OTf)3,
3
(18) Nierengarten, J.-F.; Gramlich, V.; Cardullo, F.; Diederich, F.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2101.
(19) Arai, S.; Nakayama, K.; Hatano, K.; Shioiri, T. J. Org. Chem.
2010, 75, 1325.
Org. Lett., Vol. 13, No. 22, 2011
6003

cycloadditions in which acetonitrile was employed as the
dipolarophile (entries 3, 6, 9, 12, and 15). This may be
attributable to the markedly different electronic and steric
nature of methyl group as compared with aryl groups. A
complete cis-diastereoselectivity was observed in the iso-
lated product in all cases, and the observation was unequi-
vocally supported by the X-ray analysis of one of the
products, 3b (Figure 1).20
Table 2. Optimization of Reaction Conditions for Cycloaddi-
tion of 1a with 2aa
Lewis acid
(equiv)
time
(h)
yield of
Table 3. [3 þ 2] Cycloaddition between DonorꢀAcceptor Cy-
clopropanes 1 and Nitriles 2
entry
solvent
temp
rt
3a (%)b
1
AlCl3 (1.0)
AlCl3 (1.0)
SnCl4 (1.0)
SnCl4 (1.0)
SnCl4 (1.0)
SnCl4 (1.0)
SnCl4 (1.0)
SnCl4 (1.0)
SnCl4 (0.5)
SnCl4 (0.2)
TiCl4 (1.0)
DCM
14
12
8
52
2
DCM
0 °C
rt
NRc
55
3
DCM
4
DCM
0 °C
rt
12
7
NRc
66
5
1,2-DCE
MeNO2
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
6
rt
12
12
6
40
7
0 °C
60 °C
rt
NRc
60
8
entry
Ar1
C6H5
Ar2
C6H5
R
yield (%)a
9
8
62
10
11
12
13
14
15
16
rt
24
10
8
19
1
C6H5
66 (3a)
62 (3b)
89 (3c)
52 (3d)
54 (3e)
88 (3f)
59 (3g)
67 (3h)
86 (3i)
51(3j)
rt
traced
dec.e
NRc
NRc
NRc
NRc
2
C6H5
C6H5
4-MeOC6H4
Me
BF3 Et2O (1.0)
0 °C-rt
rt
3
C6H5
C6H5
3
InBr3 (1.0)
12
12
12
12
4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-NO2C6H4
C6H5
C6H5
C6H5
In(OTf)3 (1.0)
Sc(OTf)3 (1.0)
Yb(OTf)3 (1.0)
rt
5
C6H5
4-MeOC6H4
Me
rt
6
C6H5
rt
7
C6H5
C6H5
8
C6H5
4-MeOC6H4
Me
a The reaction was conducted with 1a (1 mmol), 2a (5 mmol), Lewis
acid (x equiv), and solvent (2 mL). b Isolated yield. c No reaction. d Only a
trace of 3a was formed. e 1a was decomposed.
9
C6H5
10
11
12
13
14
15
16
C6H5
C6H5
C6H5
4-MeOC6H4
Me
48 (3k)
89 (3l)
10 (3m)b
62 (3n)
90 (3o)
52 (3p)
C6H5
were all ineffective in bringing about the reaction (entries
13ꢀ16). Therefore, the optimal reaction conditions for the
cycloaddition were identified as 1 equiv of SnCl4 in 1,2-
dichloroethane at room temperature.
C6H5
4-MeOC6H4
4-MeOC6H4
Me
4-NO2C6H4
4-NO2C6H4
2-thienyl
C6H5
4-ClC6H4
4-MeOC6H4
Next, the scope of the cycloaddition was investigated
with respect to various DꢀA cyclopropanes and nitriles
under the optimized reaction conditions. The results are
summarized in Table 3. Like 2a, 4-methoxybenzonitrile
(2b) also underwent cycloaddition readily with 1a, furnish-
ing 3b in a comparable yield (entries 1 and 2). When
acetonitrile (2c) was used as the dipolarophile in the
reaction, the yield steeply increased to 89% (entry 3).
The presence of a p-Me, p-OMe, or p-Cl group on the
Ar1 moiety of the cyclopropanes seemed to have no
influence on the yield of the products (entries 4ꢀ12).
However, the yield was dramatically reduced to 10%, in
addition to the reaction time becoming longer (48 h), when
a p-NO2 group was present on the Ar1 moiety (entry 13).
Obviously, this could be the result of destabilization of the
incipient positive charge on the adjacent carbon of the
dipole by the p-NO2C6H4 moiety during the course of
the reaction (see mechanism). This is further supported by
the fact that the presence of the p-NO2 group on the Ar2
moiety of the cyclopropane does not cause any detriment
tothe yield (entries 14and 15). The reaction was alsofound
to be tolerant to the presence of a thiophene moiety in the
starting cyclopropane (entry 16). A sharp increase in the
yield of the product was consistently found in all
a Isolated yield. b The reaction time was 48 h.
Figure 1. ORTEP plot of the crystal structure of 3b (at 30%
probability level).
(20) CCDC 827601 for compound 3b. See the Supporting Informa-
tion for details.
6004
Org. Lett., Vol. 13, No. 22, 2011

standard imine chemistry. For example, reduction of 3l
with NaCNBH3 gave the cis-pyrrolidine 5 in 92% yield
(Scheme 3).
Scheme 2. Plausible Reaction Mechanism
Scheme 3. Synthetic Transformation of 1-Pyrroline 3l
In summary, we have developed an SnCl4-promoted
[3 þ 2] cycloaddition strategy for the highly diastereose-
lective synthesis of 1-pyrrolines from DꢀA cyclopropanes
and nitriles. The various aspects of the strategy including
the synthetic applications of the resulting 1-pyrrolines and
the replacement of nitriles with other carbonꢀheteroatom
dipolarophiles are under investigation.
The mechanism outlined in Scheme 2 could be postu-
lated to explain the formation of the 1-pyrrolines as single
cis-diastereomers. The mechanism is analogous to the one
reported for the [3 þ 2] cycloaddition reaction between
similar DꢀA cyclopropanes and aldehydes.5c,7,21 The
Lewis acid coordinates with the malonate moiety of cyclo-
propanes thereby weakening the C1ꢀC2 bond and making
C1 vulnerable to nucleophilic attack. The lone pair on the
nitrogen atom of the nitrile attacks C1 in SN2 fashion to
generate the 1,5-dipole A. The C1ꢀC3 bond of A under-
goes a 120° rotation to form the conformer A0 which brings
the aryl substituents at C1 and C3 to a cis-orientation
despite steric crowding and, also, the nitrile carbon in the
vicinity of the malonate carbanion for the ensuing nucleo-
philic attack. The rotation is instantly followed by the
nucleophilic attack furnishing 1-pyrrolines with the sub-
stituents at C1 and C3 frozen in the cis-configuration.
The products are resourceful intermediates and could be
transformed in to a wide range of other compounds using
Acknowledgment. The authors thank DST, India (No.
SR/FT/CS-032/2008) for financial support; DST-FIST for
NMR and X-ray facilities at School of Chemistry, Bhar-
athidasan University, India; Prof. P. Thomas Muthiah,
School of Chemistry, Bharathidasan University, India and
Dr. N. Sampath, Department of Advanced Technology
Fusion, Konkuk University, Korea for X-ray structure
determination.
Supporting Information Available. Experimental pro-
cedures and characterization data for all products, in-
1
cluding copies of H and 13C NMR spectra and X-ray
structural information of 3b (CIF). This material is
available free of charge via the Internet at http://pubs.
acs.org.
(21) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597.
Org. Lett., Vol. 13, No. 22, 2011
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