Synthesis of cyclohexanes via [3 + 3] hexannulation of cyclopropanes and 2-chloromethyl allylsilanes

Article abstract of DOI:10.1021/ol900457z

Lewis acid-assisted ring-opening/allylation of 1,1-cyclopropane diesters, followed by base-mediated ring closure, generates functionalized exo-methylenecyclohexanes in good yield. This two-step procedure is highlighted by expedient preparation of a pyrido

Full text of DOI:10.1021/ol900457z

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2081-2084
Synthesis of Cyclohexanes via [3 + 3]
Hexannulation of Cyclopropanes and
2-Chloromethyl Allylsilanes
Katarina Sapeta and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London, Ontario,
Canada, N6A 5B7
makerr@uwo.ca
Received March 4, 2009
ABSTRACT
Lewis acid-assisted ring-opening/allylation of 1,1-cyclopropane diesters, followed by base-mediated ring closure, generates functionalized
exo-methylenecyclohexanes in good yield. This two-step procedure is highlighted by expedient preparation of a pyrido[1,2-a]indole skeleton
common to the chippiine class of Iboga indole alkaloids.
Since their first introduction by Trost and Chan,1 Pd-
trimethylenemethane (Pd-TMM) complexes (or their syn-
thetic equivalents)2 have proven to be versatile three-carbon
synthons in [3 + 2] cycloadditions with electron-deficient
olefins3 en route to functionalized cyclopentanes (Figure 1,
eq 1); more recent reports have described cycloadditions with
imines,4 and in a [3 + 3] sense, with aziridines,5 azomethine
imines,6 and nitrones.7 Such reaction diversity serves to
demonstrate the utility of these all-carbon dipole equivalents
in preparation of a broad array of carbo- and heterocycles.
Figure 1
equivalent.
. Reaction of 1,1-cyclopropane diesters with a TMM
(1) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1979, 101, 6429.
(2) For a review of Pd-TMM cycloadditions see: (a) Trost, B. M. Angew.
Chem., Int. Ed. 1986, 25, 1.
The reagent 2-(chloromethyl)-3-trimethylsilyl-1-propene
2a can be considered a synthetic equivalent of TMM
zwitterion 1 (Figure 1). This bifunctional reagent has found
use in [3 + 2] annulations for introduction of the exometh-
ylenic substituent by way of sequential allylation/annulation
reactions.8 In our ongoing research program concerning the
reactivity of donor-acceptor (D-A) cyclopropanes, we were
curious if an all-carbon dipole could be used in the context
of a [3 + 3] annulation9 to achieve the synthesis of
functionalized cyclohexane rings.
(3) For an asymmetric variant, see: Trost, B. M.; Stambuli, J. P.;
Silverman, S. M.; Schwo¨rer, U. J. Am. Chem. Soc. 2006, 128, 13328, and
references therein.
(4) (a) Yamago, S.; Nakamura, M.; Wang, X.-Q.; Yanagawa, M.;
Tokumitsu, S.; Nakamura, E. J. Org. Chem. 1998, 63, 1694. (b) Trost, B. M.;
Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc. 2007, 129, 12398.
(5) (a) Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 1596. (b) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. (c) Goodenough,
K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett. 2005, 7, 2993. (d) Mancey,
N. C.; Butlin, R. J.; Harrity, J. P. A. Synlett 2008, 2647.
(6) Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 6330.
(7) Shintani, R.; Park, S.; Duan, W.-L.; Hayashi, T. Angew Chem., Int.
Ed. 2007, 4, 6–5901.
10.1021/ol900457z CCC: $40.75
Published on Web 04/10/2009
 2009 American Chemical Society

Scheme 1
.
Investigation of Cyclization Conditions
Table 1. Substrate Scope of a Stepwise Annulation of
1,1-Cyclopropane Diesters
Herein we describe a stepwise, formal [3 + 3] annulation
reaction of substituted 1,1-cyclopropane diesters with a TMM
equivalent, to provide exo-methylenecyclohexanes In addi-
tion, we describe its application to the rapid synthesis of a
pyrido[1,2-a]indole skeleton common to a subclass of Iboga
indole-containing natural products.
We began with a search for suitable cycloaddition condi-
tions using 2-phenyl-1,1-cyclopropanediester 3a (Scheme 1).
Conditions known to effect the cycloaddition of TMM
precursor 2b onto electron deficient olefins failed to provide
cycloadduct when using cyclopropane 3a. Altering the
strategy slightly, the cyclopropane 3a was treated with the
chlormethylallylsilane 2a under the influence of TiCl4
resultng in smooth allylation. The usefulness of such an
intermediate was not lost on us; a simple intramolecular SN2
reaction of 4a with a malonate anion would also provide
the target cyclohexanes; indeed, treatment of 4a with NaH
gave cyclohexane 5a in excellent yield. Of a brief survey of
common Lewis acids (including Yb(OTf)3, Sc(OTf)3,
11
BF3·OEt2, MgI2, AgOTf, SnCl4, EtAlCl210), TiCl4 was
found to provide the highest yields and cleanest reactivity
profiles for ring-opening. A screening of numerous additives
(organic/inorganic bases, Ag(I) sources) was carried out to
effect a one-pot cyclization, however with no success.
Variation of leaving group (I, OTs) also failed to achieve in
situ ring closure.
The scope of the allylation/ring closure protocol was
investigated (Table 1). A number of items are to be noted.
At present, we are limited to the use of aromatic, heteroaro-
(8) (a) Boto, A.; Herna´ndez, D.; Herna´ndez, R.; Montoya, A.; Sua´rez,
E. Eur. J. Org. Chem. 2007, 325. (b) Sadakane, M.; Vahle, R.; Schierle,
K.; Kolter, D.; Steckhan, E. Synlett 1997, 95. (c) D’Aniello, F.; Mattii, D.;
Taddei, M. Synlett 1993, 119. (d) Guiles, J. W.; Meyers, A. I. J. Org. Chem.
1991, 56, 6873. (e) Knapp, S.; O’Connor, U.; Mobilio, D. Tetrahedron
Lett. 1980, 21, 4557.
(9) Formal [3 + 3] annulations of 1,1-cyclopropane diesters and
azomethine imines: Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette,
A. B. Org. Lett. 2008, 10, 689. Formal [3 + 3] annulations of 1,1-
cyclopropane diesters and nitrones: (a) Carson, C. A.; Young, I. S.; Kerr,
M. A. Synthesis 2008, 485. (b) Karadeolian, A.; Kerr, M. A. J. Org. Chem.
2007, 72, 10251. (c) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597.
(d) Kang, Y.-B.; Sun, X. L.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46,
3918. (e) Sibi, M. P.; Ma, Z. H.; Jasperse, C. P. J. Am. Chem. Soc. 2005,
127, 5764. (f) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42,
3023.
a 2a (1.2 equiv), TiCl4 (1.0 M CH2Cl2, 1.0 equiv), CH2Cl2/-78 °C b NaH
(1.1 equiv), DMF/ 0 °C
(10) EtAlCl2 has been used to allylate D-A cyclopropanes: Bambal, R.
Kemmitt, R. D. W. J. Chem. Soc., Chem. Commun. 1988, 734. We chose
TiCl4 for cleanliness of the reaction and faster reaction times.
(11) For TiCl4-mediated allylations of D-A cyclopropanes, see: (a) Yu,
M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 4639. (b) Sugita, Y.; Yamadoi,
S.; Hosoya, H.; Yokoe, I. Chem. Pharm. Bull. 2001, 49, 657.
matic, vinylic and spiro-fused cyclopropanes. Reactivity is
presumably dependent on stability of a putative ring-opened
intermediate; cyclopropanes capable of supporting benzylic,
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Org. Lett., Vol. 11, No. 10, 2009

Scheme 2
Figure 2. Representative Iboga alkaloids of Tabernaemontana sp.
and possible synthetic precursor 10.
allylic and 3° carbocations, respectively, are shown to be
ideal substrates.
There appears to be minimal reactivity difference between
electron-rich (3c, entry 3) and electron-poor (3b, entry 2)
aryl 1,1-cyclopropane diesters. Heteroaromatic systems are
well-tolerated (3e-f, entries 5-6 respectively), although
yields are diminished in the case of 2-thienyl-1,1-cyclopro-
pane diester 3e, most likely due to its sensitivity to acidic
conditions.
Both vinyl (3g, entry 7) and spiro-cyclohexyl 1,1-cyclo-
propane diesters (3h, entry 8) are allylated in respectrable
yields; a byproduct of elimination, 6, invariably accompanies
the formation of 4h as an inseparable mixture (2:1 4h:6). A
byproduct commonly observed under normal reaction condi-
tions is ring-opened 7 (Scheme 2); this is suppressed
considerably by conducting the reaction at lower tempera-
tures (-78 °C). In the case of unsubstituted, aliphatic or
acetoxy-substituted (R ) OAc) cyclopropanes, this byproduct
is obtained exclusively over prolonged reaction times with
no indication of desired allylated product being formed by
1H NMR analysis.
diester 3i in excellent yield over the two steps (87%, 84%
respectively). Sequential Lewis acid-mediated ring-opening
with allylsilane 2a and treatment with NaH in DMF
proceeded gratifyingly to give cyclohexene 5i in high yield
(92% over 2 steps). N-Tosyl removal was effected with
magnesium metal in methanol, providing the free indole in
addition to desired cyclized product 13 in a ratio of 1:3.
Subjection of this crude reaction mixture to K2CO3 in DMF
brought about clean cyclization of the remaining free indole,
to pyrido-indole 13 in 47% yield over the two steps. Spatial
contraints would dictate the major cyclization product to be
that of the reaction of methyl ester syn to the pendent
2-indolyl moiety; only one isomer was isolated and the
structure verified by 2D-NMR experiments.17
Scheme 3. Synthesis of Pyrido[1,2-a]indole 13
Encouraged by these preliminary results, we were eager
to re-examine a synthetic challenge explored previously in
our laboratory. As part of our research program directed at
the total synthesis of naturally occurring alkaloids, methods
for the construction of indole-containing natural products
have a central role. Of particular interest to us12 is a subclass
of Iboga alkaloids possessing complex molecular architecture
in the form of a pyrido[1,2-a]indole nucleus with all-carbon
quaternary center attachment at the indole 2-position. Two
relevant alkaloids, 10,11-demethoxychippine (8)13 and trono-
carpine (9)14 are shown in Figure 2; highlighted are the
cyclohexyl motifs accessible from this stepwise annulation
protocol. It is foreseen that access to both these alkaloids is
possible from an intermediate such as 10 (Figure 2).
The application of the above methodology to the synthesis
of a tetracyclic subunit common to these Iboga alkaloids is
shown in Scheme 3. As a straightforward model system, we
envisaged a monosubstituted 2-indolyl cyclopropane diester
3i (Vide infra) as the simple reaction partner. Thus, Knoev-
enagel condensation of N-tosyl indole-2-carboxaldehyde 1115
and dimethyl malonate, followed by cyclopropanation using
the Corey-Chaykovsky protocol16 furnished cyclopropane
In summary, we have demonstrated that a stepwise
annulation reaction of substituted 1,1-cyclopropane diesters
with TMM equivalent 2a provides exo-methylenecyclohex-
anes in good to excellent yields. Work is ongoing in making
this annulation a one-step procedure. Efforts are underway
(12) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561.
(13) Kam, T.-S.; Sim, K.-M. Nat. Prod. Res. 1999, 13, 143.
(14) Kam, T.-S.; Sim, K.-M.; Lim, T.-M. Tetrahedron Lett. 2000, 15,
2733.
(15) Riu, A.; Harrison-Marchand, A.; Maddaluno, J.; Gulea, M.; Albadri,
H.; Masson, S. Eur. J. Org. Chem. 2007, 29, 4948.
(16) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(17) Please see Supporting Information.
Org. Lett., Vol. 11, No. 10, 2009
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to employ this reaction sequence to the preparation of both
10,11-demethoxychippiine (8) and tronocarpine (9), which
will be the topic of further communication.
University of Western Ontario mass spectrometry facility for
performing MS analyses.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada and Merck-Frosst
for financial assistance. We thank Mr. Doug Hairsine of the
OL900457Z
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Org. Lett., Vol. 11, No. 10, 2009