Nucleophilic ring opening of cyclopropane hemimalonates using internal Bronsted acid activation

Article abstract of DOI:10.1021/ol201486x

The reaction of cyclopropanes, geminally disubstituted with one carboalkoxy and one carbohydroxy group, undergoes ring-opening reactions with indole nucleophiles under catalyst-free, hyperbaric (13 kbar) conditions. An internal hydrogen bond is postulated

Full text of DOI:10.1021/ol201486x

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4180–4183
Nucleophilic Ring Opening of
Cyclopropane Hemimalonates Using
Internal Brønsted Acid Activation
Michael R. Emmett and Michael A. Kerr*
Department of Chemistry, The University of Western Ontario, London, Ontario,
Canada N6A 5B7
makerr@uwo.ca
Received June 1, 2011
ABSTRACT
The reaction of cyclopropanes, geminally disubstituted with one carboalkoxy and one carbohydroxy group, undergoes ring-opening reactions
with indole nucleophiles under catalyst-free, hyperbaric (13 kbar) conditions. An internal hydrogen bond is postulated as the mode of activation
obviating the need for the Lewis acid catalyst normally used for such donorÀacceptor cyclopropane chemistry. These conditions avoid
decarboxylation and yield useful adducts with the carboxylic acid group intact for further elaboration.
Efficient means for the functionalization of indoles
remains an active challenge in the field of synthetic organic
chemistry.1 This challenge is fueled by the presence of the
indole structure as a scaffold for pharmaceutical drug
discovery and its prominence in natural product architec-
ture. A number of years ago, we reported the first example
of the nucleophilic ring opening of 1,1-cyclopropane die-
sters 1 by indoles 2 to yield adducts 4 (Figure 1).2 Sub-
sequent research found that, when the 3-position was
already alkylated, the putative intermediate 3 either under-
went pentannulation to 5 or underwent migration to the
2-position to yield products such as 6.3,4
In a research effort directed toward discovering new
modes of cyclopropane activation, we were surprised to
find that simply saponification of one of the geminal
Figure 1. Indole functionalization.
esters produced a hemimalonate 8, which was a reactive
electrophile in reactions with indoles 7 in the absence of the
lanthanide catalyst, and yielded malonic monoesters 9.
Herein we report the results of this research.5
We commenced this project with a short study to
determine the optimal reaction conditions (Table 1) for
the catalyst-free additions of indoles to cyclopropane-1,
1-hemimalonates. For this work, we chose cyclopropane
8dfor its ease ofpreparation via monosaponification of the
diester (vide infra) as well as its well-behaved performance
(1) For reviews on the synthesis and functionalization of indoles, see:
(a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (c)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (d) Sundberg, R. J.
Indoles; Academic: New York, 1996.
(2) Harrington, P. E.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949.
(3) (a) England, D. B.; Woo, T. K.; Kerr, M. A. Can. J. Chem. 2002,
80, 992. (b) England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J.
Org. Chem. 2001, 66, 4704. (c) Kerr, M. A.; Keddy, R. G. Tetrahedron
Lett. 1999, 40, 5671.
(4) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc.
2007, 129, 9631.
r
10.1021/ol201486x
Published on Web 07/18/2011
2011 American Chemical Society

Table 1. Optimization Studies
entry
cyclopropane
temp
indole equiv
conditions
24 h
conversion (%)
product (yield)
N/A
1
2
3
4
5
6
7
8
9
8d
8d
8d
8d
8d
1d
10
8d
8d
rt
2
0
0
82 °C
80 °C
rt
2
24 h
N/A
2
30 min, MW
48 h, 13 kbar
48 h, 13 kbar
48 h, 13 kbar
48 h, 13 kbar
1 h, 13 kbar
1 h, 13 kbar
0
N/A
2
100
50
0
9d (70%)
9d (not obtained)
N/A
rt
1.2
2
rt
rt
2
0
N/A
50 °C
50 °C
2
100
100
9d (76%)
9d (73%)
1.2
(as the diester) in our previous work. Several points from
Table 1 are worthy ofmention, themostnotableofwhich is
the fact that the reaction proceeded only under the influ-
ence of hyperbaric conditions (entry 4). Ambient, conven-
tionally thermal, and microwave conditions failed to
induce a detectable conversion to the ring-opened adduct
4 (entries 1À3). Perhaps this is not so unexpected since the
volume of activation for such a ring-opening reaction is
expected to be significantly negative. While specific data
for cyclopropane ring openings are not documented (to
our knowledge), the related ring-opening reactions of
epoxidesare knowntohaveasignificantlynegativevolume
of activation.6 Moreover, indoles have been shown to
effectively add to epoxides under hyperbaric (10 kbar)
conditions.7 An important consequence of the hyperbaric
conditions used here is the suppression of the decarboxyla-
tion that one might expect under conventional thermal
conditions. This allows for use of the carboxylic acid at a
later stage.
number of equivalents of the indole to 1.2 lowered the
conversion to 50% over the 48 h reaction period. Elevation
of the temperature to 50 °C at 13 kbar drastically reduced
the reaction time from 48 to 1 h (entries 4 and 8). These
conditions also allowed for the lowering of the indole
stoichiometry from 2 to 1.2 equiv, without sacrifice of
the conversion or yield, thus obtaining the optimal condi-
tions (entry 9).
As a control experiment, we evaluated the reactivity of
the parent 1d, as well as the related cyclopropane 10, which
bore a single carboxylic acid as the only electron-with-
drawing group. When entries 4 and 6 were compared, we
observed that while hemimalonate 8d proceeded to 100%
conversion, the diester 1d was inert under these reaction
conditions, failing to yield adduct 4. The cyclopropane 10
bearing only a single carboxylic acid moiety (and no ester)
alsofailedtoundergo reactiontoproduce11. Loweringthe
(5) For reviews on donorÀacceptor cyclopropanes, see: (a) Carson,
C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (b) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (d) Reissig, H.-U.; Zimmer,
R. Chem. Rev. 2003, 103, 1151. (e) Wong, H. N. C.; Hon, M. Y.; Tse,
C. W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (f)
Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
(6) Asano, T.; le Nobel, W. J. Chem. Rev. 1978, 78, 411.
(7) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.; Nishizawa, N. J.
Figure 2. Variation of the indole nucleophile.
Org. Chem. 1996, 61, 984.
Org. Lett., Vol. 13, No. 16, 2011
4181

With optimized conditions in hand (Table 1, entry 9), we
subjected cyclopropane 8d to a reaction with a variety of
indoles (Figure 2). The reaction was tolerant of substitu-
tion on the indole to a large extent. The fact that 5-meth-
oxyindole 7b gave modest yields may be attributed to its
innate instability. Perhaps the most important observation
is that the indoles which had no N-substituent gave higher
yields than the substituted examples. We are, at this time,
unsure of the reason for this. Not surprisingly, t-Boc
derivatization of the indole nitrogen attenuated the nu-
cleophilicity such that no reaction was observed. The
presence of a methyl group at the 2-position was beneficial,
presumably due to its ability to enhance the stability of the
iminium ion intermediate (see compound 3 in Figure 1).
The presence of a methyl group at the 3-position was not
tolerated.
Using indole itself as the nucleophile, we commenced a
study of the cyclopropane scope using the hemimalonates
8aÀk (Figure 3), prepared via simple monosaponificaiton
in methanolic sodium hydroxide.8 In addition to preparing
the cyclopropane 8a with no additional substituent, we
were able to efficiently prepare a variety of cyclopropanes
vicinally (with respect to the geminal dicarbonyl moiety)
substituted with alkyl, aryl, heteroaryl, and vinyl groups.
The hydrolysis of the ester trans to the vicinal cyclopropyl
substituent is sufficiently more rapid than the cis-disposed
ester so as to allow not only clean monosaponification but
also a reasonable diastereoselection (inconsequential in the
context of this work).
substantial polymerization. Alkyl-substituted cyclopro-
pane 8c as well as the parent cyclopropane 8a failed to
undergo reaction under these conditions. This is in line
with the necessity of the cyclopropane to bear a group
capable of stabilizing a developing positive charge in the
putative transition state.
The fact that this reaction proceeds in the absence of a
Lewis acid catalyst was initially surprising to us. Our
supposition is that the presence of a carboxylic acid moiety
allows for the formation of a favorable hydrogen bond
(Figure 5). It is tempting to assume that this hydrogen
bonding enhances the electron-withdrawing ability of the
ester moiety (thus facilitating the ring-opening reaction by
nucleophiles); however, this would come at the expense of
depositing an equal amount of electron density on the
carboxylate moiety (making it less electron-withdrawing).
Simply stated, the net activation should be close to zero. A
more likely reasoning for the increased reactivity of the
hemimalonates is that the hydrogen bond stereoelectroni-
cally aligns the two carbonyl groups to receive electron
density in the ring-opening event. The zwitterion resulting
from cyclopropane ring opening would be a highly delo-
calized 6-electron species.
Figure 3. Monosaponification of cyclopropane diesters.
Figure 4. Variation of the cyclopropane electrophile.
In the nucleophilic ring-opening event, aryl and hetero-
aryl substitution of the cyclopropane was well-tolerated
and resulted in the production of the expected adducts in
good yields (Figure 4). Cyclopropane 8b underwent
While it is not surprising that hyperbaric conditions
facilitate the nucleophilic ring-opening reaction, it is unu-
sual that the reactions do not occur under conventional
thermal conditions. In the Lewis-acid-catalyzed reactions
of cyclopropane diesters, thermal conditions are quite
effective. We postulate, then, that high pressures induce
(8) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B.
Org. Lett. 2008, 10, 689.
4182
Org. Lett., Vol. 13, No. 16, 2011

Scheme 1. Elaboration of the Adducts
Figure 5. Intramolecular hydrogen bond forces coplanarity of
the hemimalonate carbonyls.
the required hydrogen bonding situation. Efforts are on-
going to support this postulate by calculating molar
volumes of the various putative hydrogen-bonded (and
non-hydrogen-bonded) species. This may not be as simple
as it may seem at first blush. Upon hydrogen bond forma-
tion, there willlikely beanelectrostriction bythe surround-
ing solvent. This effect can often lead to significant
reductions in system volume.9 Thus the solvent and pres-
sure effects may complicate the task of computational
modeling. We continue, however, to seek computational
methods to address this.
Finally, to show the potential utility of the indolyl hemi-
malonates, a representative adduct 9a was subjected to
FriedelÀCrafts and Curtius reaction conditions (Scheme 1).
In the first case, the crude reaction mixture containing 9a
was treated with TFAA in refluxing toluene to produce
tetrahydrocarbazole 12 in 40% overall yield from cyclopro-
pane 8d. When the crude 9a was treated with DPPA in
refluxing benzene, a Curtius rearrangement ensued, followed
by trapping of the isocyanate by the nucleophilic indole to
form the azepinoindole 13 in 33% overall yield from 8d.
In summary, we have shown the first nucleophilic ring-
opening reactions of cyclopropane hemimalonates. The reac-
tion is facilitated by the enforcement of an intramolecular
hydrogen bond under hyperbaric conditions. This obviates
the need for the Lewis acid catalyst normally required for
such reactivity. The high pressure conditions allow for the
suppression of decarboxylation, allowing maintenance of
the carboxylic acid moiety. The resulting adducts are
intermediates for elaboration to other useful species.
Further exploration of this mode of cyclopropane activa-
tion is underway.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for funding. We
are grateful to Mr. Doug Hairsine of the University of
Western Ontario mass spectrometry facility for perform-
ing MS analyses.
Supporting Information Available. Full experimental
procedures and spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
€
(9) Klarner, F.-G.; Diedrich, M. K.; Wigger, A. E. Effect of Pressure
on Organic Reactions. In Chemistry under Extreme or Non-classical
Conditions; van Eldik, R., Hubbard, C. D., Eds.; Wiley: New York, 1997; pp
109À110.
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