Cycloadditions of aromatic azomethine imines with 1,1-cyclopropane Diesters

Article abstract of DOI:10.1021/ol702414e

The cycloaddition of aromatic azomethine imines to 1,1-cyclopropane diesters was achieved using Ni(CIO₄)₂ as catalyst. The methodology gives access to unique tricyclic dihydroquinoline derivatives with dr up to 6.6:1. A nonconcerted

Full text of DOI:10.1021/ol702414e

ORGANIC
LETTERS
2008
Vol. 10, No. 5
689-692
Cycloadditions of Aromatic Azomethine
Imines with 1,1-Cyclopropane Diesters
Christian Perreault, Se´bastien R. Goudreau, Lucie E. Zimmer, and
Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received October 3, 2007
ABSTRACT
The cycloaddition of aromatic azomethine imines to 1,1-cyclopropane diesters was achieved using Ni(ClO4)2 as catalyst. The methodology
gives access to unique tricyclic dihydroquinoline derivatives with dr up to 6.6:1. A nonconcerted mechanism is proposed on the basis of
stereochemical analysis of the reaction.
Di- and tetrahydroquinoline derivatives are useful synthetic
intermediates, and their subunits are also found in alkaloids
and other biologically active compounds.1 Consequently,
there has been a lot of interest in the development of synthetic
methodologies to access new chiral derivatives and ways to
functionalize these scaffolds. The main methods to access
enantioenriched di- and tetrahydroquinolines are based on
asymmetric nucleophilic additions to activated quinolines.
However, few methods proved to be effective, both in terms
of yields and enantioselectivities.2
and N-iminoisoquinolinium ylides.3 We have demonstrated
that N-benzoyliminopyridinium ylides can undergo enantio-
selective hydrogenation4 or diastereoselective additions of
Grignards5 to give enantiopure piperidine derivatives. We
envisioned exploring a new reactivity of these ylides by
reacting them with electrophilic cyclopropane derivatives in
a cycloaddition reaction. This would enable the preparation
of novel 6,6,6-tricyclic dihydroquinoline derivatives. More-
over, if enantioenriched cyclopropanes are used, chiral
nonracemic products could be generated. These new mol-
ecules could become important scaffolds for drug discovery
and molecular diversity.1f
Our group has been interested in the synthesis and reac-
tions of N-iminopyridinium, N-iminoquinolinium (NAQBz),
Recently, cycloaddition reactions of activated cyclopro-
panes6 with aldehydes,7 imines,8 nitrones,9 allenes, acety-
(1) Selected examples: (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M.
J. Nat. Prod. 2005, 68, 1556. (b) Jacquemont-Collet, I.; Hannedouche, S.;
Fabre, N.; Fouraste´, I.; Moulis, C. Phytochemistry 1999, 51, 1167. (c)
Fensome, A.; Bender, R.; Chopra, R.; Cohen, J.; Collins, M. A.; Hudak,
V.; Malakian, K.; Lockhead, S.; Olland, A.; Svenson, K.; Terefenko, E.
A.; Unwalla, R. J.; Wilhelm, J. M.; Wolfrom, S.; Zhu, Y.; Zhang, Z.; Zhang,
P.; Winneker, R. C.; Wrobel, J. J. Med. Chem. 2005, 48, 5092. (d) Nallan,
L.; Bauer, K. D.; Bendale, P.; Rivas, K.; Yokoyama, K.; Horne´y, C. P.;
Pendyala, P. R.; Floyd, D.; Lombardo, L. J.; Williams, D. K.; Hamilton,
A.; Sebti, S.; Windsor, W. T.; Weber, P. C.; Buckner, F. S.; Chakrabarti,
D.; Gelb, M. H.; Van Voorhis, W. C. J. Med. Chem. 2005, 48, 3704. (e)
van Straten, N. C. R.; van Berkel, T. H. J.; Demont, D. R.; Karstens, W.-J.
F.; Merkx, R.; Oosterom, J.; Schulz, J.; van Someren, R. G.; Timmers, C.
M.; van Zandvoort, P. M. J. Med. Chem. 2005, 48, 1697. (f) Yokomoto,
M.; Yazaki, A.; Hayashi, N.; Hatono, S.; Inoue, S.; Kuramoto, Y. European
Patent EP 0470578, 1992.
(2) Selected examples: (a) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J.
Am. Chem. Soc. 2007, 129, 6686. (b) Takamura, M.; Funabashi, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6327. (c) Takamura, M.;
Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
6801.
(3) Legault, C.; Charette, A. B. J. Org. Chem. 2003, 68, 7119.
(4) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966.
(5) Legault, C.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 6360.
(6) For excellent reviews on the chemistry of donor-acceptor and
electrophilic cyclopropanes, see: (a) Yu, M.; Pagenkopf, B. L. Tetrahedron
2005, 61, 321. (b) Reiâig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151.
(c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.;
Hudlicky, T. Chem. ReV. 1989, 89, 165. (d) Danishefsky, S. Acc. Chem.
Res. 1979, 12, 66.
10.1021/ol702414e CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/08/2008

lenes,10 nitriles,11 isocyanates,12 isothiocyanates,13 isocya-
nides,14 R,â-unsaturated ketones,15 and diazenes16 have
attracted considerable attention, since they allow access to
highly functionalized 5- and 6-membered rings. Notably,
Kerr and co-workers reported a cycloaddition of 1,1-
Table 1. Optimization of the Reaction between Ylide 1a and
Cyclopropane 2aa
9e,f
cyclopropane diesters with nitrones catalyzed by Yb(OTf)3
or MgI2.9d Asymmetric versions of this reaction have also
been reported using Ni(ClO4)2 in combination with dbfox9c
or tox9a ligands.
Herein, we describe the cycloaddition reaction of aromatic
azomethine imines with cyclopropanediesters. Studies into
the mechanism of this reaction will also be presented.
entry
Lewis acid
conversionb (%)
dr (cis/trans)b
1
2
0
0
MgI2
We initially examined the reaction of NAQBz (1a) and
cyclopropane 2a in the presence of various Lewis acids that
are commonly used to activate 1,3-dicarbonyl species (Table
1, entries 2-8). A control experiment established that a
Lewis acid is needed to activate the cyclopropane, since no
conversion was observed without it (Table 1, entry 1). While
Sc(OTf)3 and Mg(ClO4)2 proved to be good catalysts (Table
1, entries 5 and 7), MgI2, Yb(OTf)3, Cu(OTf)2, and Cu(ClO4)2
gave little or no conversion (Table 1, entries 2-4, 6). The
best result was obtained with Ni(ClO4)2 which gave 96%
conversion and 3.3:1 dr (Table 1, entry 8). Furthermore,
Ni(ClO4)2 has the added advantage of being relatively
inexpensive and easy to handle.
3
4
5
6
Yb(OTf)3
Cu(OTf)2
Sc(OTf)3
Cu(ClO4)2
Mg(ClO4)2
Ni(ClO4)2
Ni(ClO4)2
Ni(ClO4)2
Ni(ClO4)2
3
4
79
0
71
96
94
20
57
1:1
1:1
3.2:1
7
8c
9c,d
10c,e
11c,f
2.4:1
3.3:1
3.3:1
3.3:1
3.3:1
a All reactions were performed using an ylide/cyclopropane ratio of 1:1.
b Determined by 1H NMR using trimethoxybenzene as an internal standard.
c Reaction time ) 18 h. d Performed at -10 °C. e Performed at -40 °C.
f 5 mol % of Lewis acid.
In an attempt to increase the diastereoselectivity, the
reaction was performed at lower temperatures. At -10 °C,
there was no change in dr and little change in conversion.
At -40 °C, dr remained the same, but the conversion
significantly dropped. Likewise, reducing the catalyst loading
to 5 mol % resulted in lower conversion and unchanged dr.
Finally, the presence of water had a detrimental effect on
the yield.17
We next examined the effect of the quinolinium ylide
protecting group. Low conversions were observed with
pivaloyl and triflyl groups. Quinolinium N-oxide also gaved
poor results. In the end, the original benzoyl protecting group
proved to be the most effective. Its electronic nature makes
the nitrogen nucleophilic enough to add to the cyclopropane,
and, at the same time, activates the quinolinium to promote
the cyclization. We, therefore, examined the electronic effect
of this protecting group. An electron-withdrawing substituent
on the benzoyl group resulted in both higher conversion and
dr (Table 2, entry 3), whereas an electron-donating substitu-
ent gave a slightly higher dr but lower conversion (Table 2,
entry 2).
(7) (a) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127,
16014. (b) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057.
(c) Min, S.; Yang, Y. H.; Bo, X. Tetrahedron 2005, 61, 1893. (d) Bernard,
A. M.; Frongia, A.; Piras, P. P.; Secci, F.; Spiga, M. Org. Lett. 2005, 7,
4565. (e) Fuchibe, K.; Aoki, Y.; Akiyama, T. Chem. Lett. 2005, 34, 538.
(f) Reissig, H.-U. Tetrahedron Lett. 1981, 22, 2981. (g) Reissig, H.-U.;
Holzinger, H.; Glomsda, G. Tetrahedron 1989, 45, 3139.
We next evaluated the scope of the reaction by submitting
various 1,1-cyclopropanediesters to the optimized conditions.
In general, good results were obtained with electron-rich aryl
substituted cyclopropanes. The best case was with 4-MeO-
Ph (2c) which gave a 92% yield and 6.6:1 dr. In contrast,
an electron-poor nitro-substituted aryl group afforded the
product in a substantially lower yield, but with good dr. The
reaction also proceeds well with vinyl cyclopropanes, albeit
in modest yield and dr (Table 2, entry 8). This was also the
case for unsubstituted 1,1-cyclopropanediesters (2g) which
gave 32% yield (Table 2, entry 9).18
(8) (a) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242. (b)
Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313. (c) Kang, Y.-B.;
Tang, Y.; Sun, X.-L. Org. Biomol. Chem. 2006, 4, 299. (d) Christie, S. D.
R.; Davoile, R. J.; Jones, R. C. F. Org. Biomol. Chem. 2006, 4, 2683. (e)
Saigo, K.; Shimada, S.; Hasegawa, M. Chem. Lett. 1990, 905. (f) Sapeta,
K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597. (g) Karadeolian, A.; Kerr,
M. A. J. Org. Chem. 2007, 72, 10251.
(9) (a) Kang, Y.-B.; Sun, X. L.; Tang, Y. Angew. Chem., Int. Ed. 2007,
46, 3918. (b) Cardona, F.; Goti, A. Angew. Chem., Int. Ed. 2005, 44, 7832.
(c) Sibi, M. P.; Ma, Z. H.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127,
5764. (d) Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554. (e)
Young, I. S.; Kerr, K. A. Org. Lett. 2004, 6, 139. (f) Young, I. S.; Kerr, M.
A. Angew. Chem., Int. Ed. 2003, 42, 3023.
(10) (a) Yadav, V. K.; Sriramurthy, V. Org. Lett. 2004, 6, 4495. (b)
Yadav, V. K.; Sriramurthy, V. Angew. Chem., Int. Ed. 2004, 43, 2669.
(11) (a) Yu, M.; Pagenkopf, B. L. Org. Lett. 2001, 3, 2563. (b) Yu, M.;
Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122. (c) Yu, M.; Pagenkopf,
B. L. Org. Lett. 2003, 5, 5099.
(12) (a) Graziano, M. L.; Iesce, M. R. J. Chem Res., Synop. 1989, 42.
(b) Yamamoto, K.; Ishida, T.; Tsuji, J. Chem. Lett. 1987, 1157.
(13) Graziano, M. L.; Cimminiello, G. J. Chem Res, Synop. 1989, 42.
(14) Korotkov, V. S.; Larionov, O. V.; de Meijere, A. Synthesis 2006,
21, 3542.
The relative configuration of both diastereoisomers of 3a
was unambiguously established by X-ray crystallographic
analysis.
(17) Reaction was carried out in the absence of 3 Å molecular sieves to
give 45% conversion. Addition of water (30 equiv) in the reaction also
inhibited the formation of the desired product, giving 7% yield.
(18) 58% yield was obtained using 10 equiv of the commercially available
cyclopropane.
(15) Liu, L.; Montgomery, J. Org. Lett. 2007, 9, 3885.
(16) Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; de
Meijere, A. J. Org. Chem. 2007, 72, 7504.
690
Org. Lett., Vol. 10, No. 5, 2008

stereogenic information. These experiments eliminate the
possibility of mechanism (1), since a racemic mixture of
products would have been observed. In addition, the product
derived from the labeling experiment does not support a
concerted mechanism (3). However, it may be possible that
the reaction proceeds by a concerted pathway and that the
corresponding product undergoes ring-opening/ring-closing
through a retro-Mannich-type reaction to form the two
diastereomers. To test this possibility, we subjected the major
diastereomer of 3a to the reaction conditions, but we did
not observe any of the minor diastereomer. Thus, we
eliminated the possibility of a concerted mechanism followed
by a reversible ring opening process.
Table 2. Reaction of Azomethine Imines (1a-c) with
Different 1,1-Cyclopropane Diesters (2a-g)
yield
dr
entry
R1
R2
Ph (2a)
product (%) (cis/trans)a
1
2
3
4
5
6
7
8
9
H (1a)
OMe (1b) Ph (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
79
54
84
76
87
81
11
31
32
3.3:1
3.8:1
4.3:1
3.3:1
6.6:1
4.4:1
5.9:1
2.6:1
n/a
From these experimental observations, one reasonable
mechanism remains. The first step would be an nucleophilic
opening of the cyclopropane, whereby the nitrogen of the
ylide acts as a nucleophile and inverts the stereogenic center
of the cyclopropane (Scheme 2). This relatively long-lived
CF3 (1c)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
Ph (2a)
4-tBu-Ph (2b)
4-MeO-Ph (2c)
4-F-Ph (2d)
4-NO2-Ph (2e)
vinyl (2f)
H (2g)
1
a Determined by H NMR.
Scheme 2. Proposed Mechanism
Several mechanisms have been suggested for the cycload-
dition reaction of 1,1-cyclopropane diesters.19,20 Possible
pathways for the cycloaddition reaction with azomethine
imines include the following: (1) a stepwise process involv-
ing a Lewis acid mediated cyclopropane ring-opening,
followed by either the nucleophilic attack of the stabilized
anion onto the imine or the attack of the nitrogen nucleophile
onto the benzylic cation, and subsequent ring-closing;16 (2)
a stepwise SN2 process where the nitrogen of the ylide acts
as the nucleophile followed by a ring-closing reaction to form
the six-membered ring; and (3) a concerted process.
In an effort to gain insights into the mechanism, we
conducted a labeling experiment and a reaction with an
enantiopure cyclopropane.
intermediate could then attack either face of the quinolinium
moiety, resulting in both diastereomers. Degradation studies
on 3a indicated that the first step of the reaction proceeded
with complete inversion of the configuration.21 This reaction
is consistent with what Johnson proposed for the cycload-
dition of 1,1-cyclopropane diesters with aldehydes.7a It also
supports the highly diastereselective two-step process pro-
posed by Kerr for the cycloaddition of 1,1-cyclopropane
diesters with nitrones.19
Reacting ylide 1a with deuterated cyclopropane 4 led to
a complete loss of the stereogenic information at the carbon
bearing the two esters moieties (Scheme 1). In contrast,
In our system, the diastereoselectivity can be partly
explained by a pseudo-1,3-diaxial interaction between the
substituent on the cyclopropane and one of the ester groups
in a boat-like transition state (Scheme 3). Strong evidence
for this was obtained from single-crystal X-ray diffraction,
Scheme 1. Insights into the Mechanism
Scheme 3. Model of Two Possible Approaches for the
Cyclization Step
performing the reaction with enantiopure cyclopropane 2a
produced enantiopure products with total conservation of the
Org. Lett., Vol. 10, No. 5, 2008
691

which showed the favored boat conformation in both
diastereomers (Figure 1). However, it is not clear at this stage
Scheme 4. Reaction between Ylide 7 and Cyclopropane 2a
mechanism which consists of a nucleophilic opening of the
cyclopropane followed by a diastereoselective ring closure
reaction.
Figure 1. ORTEP representation of the two diastereoisomers of
product 3a.
Acknowledgment. This work was supported by NSERC
(Canada), Merck Frosst Canada Ltd., Boehringer Ingelheim
(Canada) Ltd., the Canada Research Chair Program, the
Canadian Foundation for Innovation, and the Universite´ de
Montre´al. We also thank Jad Tannous (Universite´ de
Montre´al) for SFC separations.
how the electronics of the aromatic group would affect the
diastereoselectivity.
N-Benzoyliminoisoquinolinium ylide was also submitted
to standard reaction conditions in the presence of cyclopro-
pane 2a (Scheme 4). The cycloaddition adduct was obtained
in modest yield but as a single diastereomer and only one
regioisomer.
Supporting Information Available: Experimental pro-
cedure for the preparation of compounds and spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
In summary, a cycloaddition of aromatic azomethine
imines with 1,1-cyclopropane diesters was achieved using
Ni(ClO4)2 as a catalyst. The methodology gives access to
unique tricyclic dihydroquinoline derivatives with dr up to
6.6:1. Complete retention of stereogenic information of the
cyclopropane was observed. Finally, we proposed a stepwise
OL702414E
(19) Wnapun, D.; Van Gorp, K. A.; Mosey, N. J.; Kerr, M. A.; Woo, T.
K. Can. J. Chem. 2005, 83, 1752.
(20) For a proposed mechanism of cycloaddition reactions, see refs 7a
and 16.
(21) See the Supporting Information for details.
692
Org. Lett., Vol. 10, No. 5, 2008