Formal [3 + 2] cycloadditions of donor-acceptor cyclopropanes and nitriles

Article abstract of DOI:10.1021/ja029716f

Donor-acceptor cyclopropanes activated with Me₃SiOTf cleave to reactive intermediates that can be efficiently intercepted by nitriles in a formal [3 + 2] dipolar cycloaddition reaction. Aliphatic, aromatic, and α,β-unsaturated nitriles are exce

Full text of DOI:10.1021/ja029716f

Published on Web 06/13/2003
Formal [3 + 2] Cycloadditions of Donor-Acceptor Cyclopropanes and Nitriles
Ming Yu and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin, Austin, Texas 78712
Received December 12, 2002; E-mail: pagenkopf@mail.utexas.edu
Lewis acid promoted [3 + 2] cycloaddition reactions of donor-
acceptor cyclopropanes are valuable synthetic processes for the
construction of heterocyclic and carbocyclic structures (Scheme
1).1-3 In an effort to extend the versatility of cyclopropanes to the
synthesis and functionalization of carbohydrate derived systems,
we have recently reported the facile, stereospecific preparation of
4 and established its utility for the asymmetric synthesis of natural
products.4 Investigations into the unique chemistry of glycal-derived
cyclopropanes prepared by intramolecular cyclopropanation re-
vealed novel reactivity, and herein we report the highly stereose-
lective formal [3 + 2] cycloaddition of these cyclopropanes with a
wide variety of nitriles, affording synthetically versatile dihydro-
pyrroles in high yield (see Tables 1 and 2). To the best of our
knowledge, dipolar cycloaddition reactions of donor-acceptor
cyclopropanes with nitriles are unknown.5-7 The efficient and
stereoselective assembly of densely functionalized amine-containing
heterocycles is an active area of investigation due to wide
occurrence of these species in natural products and synthetic
materials. The 2H-3,4-dihydropyrrole products from the cycload-
dition contain an aminal, a functional group that has classically
served as a latent iminium ion.8
Figure 1. X-ray structure of 6a.
Scheme 1
Scheme 2
We have found that successfully revealing the dipolar nature of
glycal-derived cyclopropanes is highly dependent upon the Lewis
acid employed.9,10 Activation with Me3SiOTf, even in the presence
of potential nucleophiles such as allyltrimethylsilane, gave the
anhydrosugar 5 (Scheme 2). In stark contrast, when benzonitrile
was added to the reaction mixture, activation of 4 by Me3SiOTf at
room temperature gave the imine 6a in 81% isolated yield.11,12 The
structural assignment of 6a was unambiguously established by X-ray
crystallography (Figure 1).
Table 1. Nitrile Additions to Cyclopropane 4
A wide variety of nitriles were found to participate in the
cycloaddition reaction (Table 1).13 Aliphatic nitriles ranging from
MeCN to the much larger t-BuCN all gave the expected imine
adduct (entries 2-6). The nitrile could be used as solvent, and where
this was impractical, the use of MeNO2 or CH2Cl2 with 5 to 10
equiv of nitrile also gave excellent yields (compare entries 2 and
3). The cycloaddition of R,â-unsaturated nitriles in nitromethane
occurred exclusively at the nitrile functional group (entries 7-9).7a
Reaction with â-methoxy acrylonitrile proved useful for introducing
an aldehyde functional group (entry 9), and the vinylogous amide
6h was isolated in 78% yield. All the cycloaddition reactions
reported herein were highly stereoselective, providing solely one
diastereomeric product.
The di-tert-butylsilylene protective group is not a necessary
structural feature for successful [3 + 2] cycloaddition, and
cyclopropanes with distal acetate and benzyl ether protective groups
were equally effective substrates (Table 2, entries 1 and 2). In
addition to carbohydrate-derived substrates, cyclopropanes prepared
from other readily available γ-hydroxy dihydropyrans participate
in the cycloaddition reaction (entries 3 and 4).14 This and related
processes offer a new approach to the functionalization and
utilization of the growing number of enantiomerically pure dihy-
ropyrans available from hetero-Diels-Alder cycloadditions.15 Ring
expansion of the pyran to the seven-membered oxacycle was not
observed from any of these cycloaddition reactions.16,17 Reaction
with the furanose substrate in entry 5 gave the imine addition
product in 43% yield. Intramolecular cyclopropanation of dihy-
drofuran substrates was not possible due to facile furan formation.4,18
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10.1021/ja029716f CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Nitrile [3 + 2] Cycloadditions Acetonitrile
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(5) For a conceptually similar nitrile [4 + 2] cycloaddition, see: Stevens, R.
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a Isolated yields. b Reaction solvent ) CH2Cl2.
(7) Cycloaddition reactions with the cyano group have been reviewed, see:
(a) Myers, A. I.; Sircar, J. C. In The Chemistry of the Cyano Group;
Rapporport, Z., Ed.; John Wiley: Belfast, 1970, Chapter 8. For a recent
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Figure 2.
The intramolecular glycal cyclopropanation strategy4 appears to
have been an important advance necessary for accessing the 3,4-
dihydro-2H-pyrrole cycloaddition products. The substrates in Figure
2 were prepared by intermolecular cyclopropanation,19 but attempted
nitrile [3 + 2] cycloaddition reactions with these cyclopropanes
gave multiple products. The 1H NMR spectra of the crude reaction
mixtures suggested imine formation, but decomposition occurred
before purification was possible.
In summary, a novel Me3SiOTf-activated [3 + 2] cycloaddition
reaction between donor-acceptor cyclopropanes and nitriles has
been described. Excellent yields of 3,4-dihydro-2H-pyrrole cy-
cloaddition products are generally observed with aliphatic, aromatic,
and R,â-unsaturated nitriles.
(9) Reactions with BF3‚OEt2: Yu, M.; Pagenkopf, B. L. J. Org. Chem. 2002,
67, 4553-4558.
(10) Reactions with TiCl4: Yu, M.; Pagenkopf, B. L. Tetrahedron 2003, 59,
2765-2771.
(11) Traditional dipolarophiles are compatible, including aldehydes, imines,
and silyl enol ethers. These results will be described elsewhere.
(12) For examples of nitriles as glycosyl acceptors, see: (a) Ratcliffe, A. J.;
Mootoo, D. R.; Andrews, C. W.; Fraser-Reid, B. J. Am. Chem. Soc. 1989,
111, 7661-7662. (b) Nair, L. G.; Fraser-Reid, B.; Szardenings, A. K.
Org. Lett. 2001, 3, 317-319.
(13) Standard procedure: To a solution of cyclopropane (1 mmol) in CH2Cl2
(4 mL) at room temperature were added the nitrile (5.0 equiv) and
trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.0 equiv) sequen-
tially. After 5 min the reaction mixture was poured into vigorously stirred
saturated aqueous NaHCO3 (10 mL). Pure product is obtained by standard
purification and silica gel chromatography (See Supporting Information).
Acknowledgment. We thank the Robert A. Welch Foundation,
the Texas Advanced Research Program 003658-0455-2001, and the
DOD Prostate Cancer Research Program DAMD17-01-1-0109 for
partial financial support. M.Y. thanks the Dorothy B. Banks
Charitable Trust Fund for a graduate scholarship.
(14) Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321-3323.
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(16) Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org. Chem. 1997, 62, 7694-
Supporting Information Available: X-ray structure data, CIF file
for 6a, and detailed experimental procedures and characterization of
all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
7703.
(17) Cousins, G. S.; Hoberg, J. O. Chem. Soc. ReV. 2000, 29, 165-174.
(18) Timmers, C. M.; Verheijen, J. C.; van der Marel, G.; van Boom, J. H.
Synlett 1997, 851-853.
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References
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