Investigation into factors influencing stereoselectivity in the reactions of heterocycles with donor-acceptor-substituted rhodium carbenoids

Article abstract of DOI:10.1021/jo060779g

Rhodium-catalyzed decomposition of aryldiazoacetates in the presence of pyrroles or furans results in mono- or biscyclopropanation of the heterocycle, but with opposite enantioinduction, In the absence of sterically encumbering groups, the cyclopropanatio

Full text of DOI:10.1021/jo060779g

Investigation into Factors Influencing Stereoselectivity in the
Reactions of Heterocycles with Donor-Acceptor-Substituted
Rhodium Carbenoids
Simon J. Hedley, Dominic L. Ventura, Paulina M. Dominiak, Cara L. Nygren, and
Huw M. L. Davies*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260-3000
hdaVies@buffalo.edu
ReceiVed April 12, 2006
Rhodium-catalyzed decomposition of aryldiazoacetates in the presence of pyrroles or furans results in
mono- or biscyclopropanation of the heterocycle, but with opposite enantioinduction. In the absence of
sterically encumbering groups, the cyclopropanation of furan occurs with initial bond formation at the
2-position. If this pathway is sterically blocked, cyclopropanation can occur with initial bond formation
at the 3-position of the furan ring; in this case, the cyclopropanation reaction takes place on the opposite
face of the heterocycle, and the opposite enantioinduction is observed. Upon extension of this methodology
to benzofurans, a highly enantioselective monocyclopropanation reaction occurs to furnish a product
derived from initial bond formation at the 2-position of the benzofuran. When this reaction pathway is
inhibited by sterically encumbering substituents on the benzofuran, no cyclopropanation of the furan
ring is observed, and instead, double cyclopropanation of the benzene ring occurs. Double cyclopropanation
of the benzene ring was also observed in reactions with indoles.
Introduction
highly electrophilic and amenable to participate in a variety of
reactions.5 More recently, donor-acceptor carbenoids, which
are flanked by an electron-withdrawing group and an electron-
donating group, have come to prominence.3 These metal
carbenoids are considerably more stable than the traditional
rhodium carbenoids as a result of the presence of this electron-
donating moiety. Thus, this class of carbenoid is capable of
highly chemoselective reactions3 and, furthermore, is less prone
to dimer formation than carbenoids derived from alkyl diazo-
acetates.6
The cyclopropanation reactions of alkenes with donor-
acceptor carbenoids are highly diastereoselective,7 and in the
reaction of dienes with vinyldiazoacetates, the resultant cis-
divinylcyclopropanes undergo ring expansion via a Cope
rearrangement to generate seven-membered rings with full
control of the relative configuration at up to three stereogenic
Metal carbenoids, which are readily generated by metal-
catalyzed decomposition of diazoacetates, occupy an established
position as versatile synthetic intermediates in organic chem-
istry.1 In comparison to free carbenes, metal carbenoids have
increased stability and are capable of highly selective reactions.2
The reactivity profile of these transient metal-stabilized car-
benoids is very dependent on the structure of the carbenoid and
the metal.3 In recent years, dirhodium complexes have been
extensively used as catalysts.1,4 The most widely used classes
of rhodium carbenoids contain one or two electron-withdrawing
groups on the carbenoid, defined in Chart 1 as acceptor- and
acceptor-acceptor-substituted carbenoids. The presence of an
electron-withdrawing substituent causes the carbenoid to be
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York, 1997.
(2) Paulissenen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie,
Ph. Tetrahedron Lett. 1973, 14, 2233.
(3) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861.
(b) Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463.
(5) Dorwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-VCH:
Weinhem, Germany, 1999.
(6) Davies, H. M. L.; Hodges, L. M.; Matasi, J. J.; Hansen, T.; Stafford,
D. G. Tetrahedron Lett. 1998, 39, 4417.
(7) Davies, H. M. L.; Clark, T. J.; Church, L. A. Tetrahedron Lett. 1989,
30, 5057.
(4) Maas, G. Top. Curr. Chem. 1987, 137, 76.
10.1021/jo060779g CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/09/2006
J. Org. Chem. 2006, 71, 5349-5356
5349

Hedley et al.
CHART 1. Classification of Rhodium Carbenoids
SCHEME 1
SCHEME 2
Reactions With N-Boc-pyrrole. The rhodium-catalyzed
reaction between vinylcarbenoids and N-Boc-pyrrole generally
leads to tropane derivatives via the tandem cyclopropanation/
Cope rearrangement.11b A single example exists, however, where
the Cope rearrangement of the cyclopropane was comparatively
sluggish, and the reaction instead furnished a product where a
second cyclopropanation took place at the remaining enamine.12
This contrasts with the chemistry of acceptor-substituted metal
carbenoids, in which a monocyclopropanation product tends to
predominate.13,14 For example, copper(I) bromide-catalyzed
decomposition of ethyl diazoacetate with N-acylated pyrrole
substrates has been shown to be a rather poor reaction, leading
mainly to monocyclopropanation products in poor yield (17%),
with only a small amount of product (5%) arising from a double
cyclopropanation reaction.13 These cyclopropane products tend
to decompose on attempted distillation to give formal substitu-
tion products and a regenerated aromatic ring. A more recent
procedure,14 which utilizes catalytic copper(II) triflate activated
by phenylhydrazine, also gives monocyclopropanation product
in higher yield (39%), again with only a small amount (3%) of
the double cyclopropanation product.
centers.8 Furthermore, highly enantioselective cyclopropanations
can be achieved by utilizing R-hydroxy esters as chiral
auxiliaries on the carbenoid (1),9 or the chiral dirhodium
tetraprolinate, Rh2(S-DOSP)4 (2).10
The tandem cyclopropanation/Cope rearrangement between
vinylcarbenoids and furans or pyrroles has been developed into
a very attractive approach for the asymmetric synthesis of oxa-
and azabicyclic systems comprising a formal [4+3] cycload-
dition reaction.11 Chiral auxiliaries have been demonstrated to
be more effective than chiral catalysts in this chemistry, because
the reaction of these electron-rich heterocycles catalyzed by
dirhodium tetraprolinates leads to side products derived from
zwitterionic intermediates.11 A most intriguing feature of this
chemistry is the observation that the reaction of vinyldiazoac-
etates with furan and N-Boc pyrrole led to opposite asymmetric
induction, even though the same chiral auxiliary was used in
both cases (Scheme 1).11 This paper describes a systematic study
to explore further how the structure of the heterocycle influences
the enantioinduction in the rhodium-catalyzed reaction with
donor-acceptor carbenoids.
In the current study, aryldiazoacetates were used as the
precursors to the donor-acceptor carbenoids. These substrates
would limit further rearrangement of the products and the
formation of side products derived from zwitterionic intermedi-
ates, which tends to occur in the dirhodium tetraprolinate-
catalyzed reactions of vinyldiazoacetates.11b Even though a
variety of aryldiazoacetates are compatible with the carbenoid
chemistry,3 methyl para-bromophenyldiazoacetate 4 was used
as the source of carbenoid to simplify the determination of the
absolute configuration of the products. Decomposition of 4 in
the presence of N-Boc pyrrole 3 (Scheme 2) allowed clean
isolation of the biscyclopropane 5 as a single diastereomer in
high yield and good enantioselectivity. Biscyclopropane 5 was
preferentially formed even when 6 equiv of N-Boc-pyrrole 3
was used, which indicates that the monocyclopropane interme-
diate 6 is much more efficiently cyclopropanated by 4 than is
N-Boc pyrrole 3. The absolute configuration of 5 was assigned
(8) (a) Davies, H. M. L. Tetrahedron 1993, 49, 5203. (b) Davies, H. M.
L. In AdVances in Cycloaddition; Harmata, M., Ed.; JAI Press, Inc.:
Greenwich, CT, 1999; Vol. 5, pp 119-164.
(9) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L. J.
Am. Chem. Soc. 1993, 115, 9468.
(10) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M.
J. J. Am. Chem. Soc. 1996, 118, 6897.
(11) (a) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem.
Soc. 1996, 118, 10774. (b) Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.;
Huby, N. J. S.; Thornley, C.; Kong, N.; Houser, J. H. J. Org. Chem. 1997,
62, 1095.
(12) Davies, H. M. L.; Young, W. B.; Smith, H. D. Tetrahedron Lett.
1989, 30, 4653.
(13) (a) Tanny, S. R.; Grossman, J.; Fowler, F. W. J. Am. Chem. Soc.
1972, 94, 6495. (b) Biellmann, J. F.; Goeldner, M. P. Tetrahedron 1971,
27, 2957.
(14) Beumer, R.; Bubert, C.; Cabrele, C.; Vielhauer, O.; Pietzsch, M.;
Reiser, O. J. Org. Chem. 2000, 65, 8960.
5350 J. Org. Chem., Vol. 71, No. 14, 2006

StereoselectiVity in the Reactions of Heterocycles
SCHEME 3
derived from ethyl diazoacetate,16 which generated dienes
similar to 10 as the major reaction products. The absolute
stereochemistry of the biscyclopropane 9 was determined by
X-ray crystallography18 and is opposite to the biscyclopropane
5 derived from N-Boc pyrrole 3, despite the fact that the same
enantiomer of the catalyst (Rh2(S-DOSP)4) was used in these
reactions.17
SCHEME 4
The absolute stereochemistry of the monocyclopropane 8
could not be determined directly by X-ray crystallography, as
suitable enantioenriched crystals of 8 could not be obtained.
However, this could be determined later, as hydrogenation of 8
provided 12 (Scheme 6), where the absolute configuration was
shown to be the opposite enantiomer to ent-12 (see Scheme 7),
which itself was determined by X-ray crystallography.19
Upon resubjection of racemic 8 to the rhodium carbenoid
reaction, double cyclopropanation product 9 was isolated with
low (9% ee) enantioselectivity (Scheme 8). This again indicates
that the second cyclopropanation is not greatly influenced by
the chiral catalysts.
To probe further the change of enantioinduction for N-Boc-
pyrrole 3 and furan 7, the reaction of 2,3-dihydrofuran (13) was
examined. A very efficient cyclopropanation occurred to gener-
ate a single diastereomer of ent-12 in 81% yield and 77% ee
(Scheme 7). The absolute stereochemistry of ent-12 from this
reaction was determined by X-ray crystallography of an enriched
sample,19 and also shown by chiral HPLC to be the opposite
enantiomer to 12 derived from hydrogenation of 8 (see Scheme
6).
We reasoned that studying more substituted furan derivatives
would allow further insight into the stereoselectivity of this
reaction. Accordingly, 2,5-dimethylfuran 14 was subjected to
the reaction conditions (Scheme 9). This resulted in a clean
reaction to form a single diastereomer of the biscyclopropane
15 in 76% yield and 84% ee. X-ray crystallography of an
enriched sample of 15 showed that the sense of asymmetric
induction of 15 was the same as it was for the biscyclopropane
5,20 derived from the reaction of N-Boc pyrrole 3, and it was
opposite from that of the biscyclopropane 9, derived from furan
7. Notably, no diene products arising from the unraveling of
the heterocyclic ring were observed in this reaction.
Previous studies have shown that the reactions of vinyldia-
zoacetates with furans substituted at C-2 with electron-donating
groups strongly favor the unraveling of the heterocycle by means
of a zwitterionic reaction pathway.21 The same reactivity was
observed in the reaction of the aryldiazoacetate 4 with 2-meth-
by X-ray crystallographic analysis of material recrystallized to
high enantiomeric purity.15
The monocyclopropane 6 can be isolated when N-Boc pyrrole
3 is used in vast excess as the reaction solvent (Scheme 3).
The initial cyclopropanation was shown to proceed to furnish
product 6 in 79% ee, while subjection of racemic 6 to a
subsequent Rh2(S-DOSP)4-catalyzed cyclopropanation reaction
shows the biscyclopropane 5 is formed with only 10% ee
(Scheme 4). As a result of the lack of solubility of (()-6 at
room temperaure, these reactions had to be conducted in
refluxing hexanes. Even so, these results show that the most
significant step for asymmetric induction in the formation of
the biscyclopropane 5 is the first cyclopropanation event.
Reactions with Furans. The reaction of carbenoids with
furans usually leads to the unraveling of the heterocycle,
resulting in the formation of differentially functionalized dienes
in good yield.16 Additionally, the furanocyclopropane derived
from the Rh2(OAc)4-catalyzed reaction with ethyl diazoacetate
and furan is unstable and rearranges on standing to the (Z,E)-
diene.16 Reiser has reported some success in the enantioselective
cyclopropanation of furans using a copper(I)-bis(oxazoline)-
catalyzed procedure, although high enantioselectivity was only
observed when the furan was substituted at the 2-position with
an ethyl ester.17
Unlike the above reactions with N-Boc-pyrrole 3 (Scheme
2), the reaction with furan (7) provided a range of products,
with the distribution highly dependent on the reaction conditions.
When 4 was used as the limiting reagent, the major product 8
was found to arise from a single cyclopropanation reaction,
along with double cyclopropanation to provide 9 as a minor
product (Scheme 5, eq 1). Formation of 9 could be suppressed
by conducting the reaction with 7 as solvent (Scheme 5, eq 2).
Conversely, 9 could be generated in high yield by using a
relative excess of 4 (Scheme 5, eq 3). Additionally, relatively
minor amounts of diene products 10 and 11 were observed in
these reactions. This study indicates that donor-acceptor
carbenoids display a different reactivity profile to the carbenoids
(15) The crystal structure of 5 has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC 604170
has been allocated [Dominiak, P. A.; Coppens, P. Private communication].
(16) (a) Nvak, J.; Sorm, F. Collect. Czech. Chem. Commun. 1958, 23,
1126. (b) Schenck, G. O.; Steinmetz, R. Liebigs Ann. 1963, 668, 19. (c)
Wenkert, E.; Bakuzis, M. L. F.; Buckwalter, B. L.; Woodgate, P. D. Synth.
Commun. 1981, 11, 533. (d) Nevedov, O. M.; Shostakovsky, V. M.;
Samoilova, M. Y.; Kravchenko, M. I. IzV. Akad. Nauk, Ser. Khim. 1972,
2342. (e) Nevedov, O. M.; Saltykova, L. E.; Vasilvitskii, L. E.; Shostak-
ovsky, A. E. IzV. Akad. Nauk, Ser. Khim. 1986, 2625.
(18) The crystal structure of 9 has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC 603126
has been allocated [Dominiak, P. A.; Coppens, P. Private communication].
(19) The crystal structure of ent-12 has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC 603045
has been allocated [Nygren, C. L.; Coppens, P. Private communication].
(20) The crystal structure of 15 has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC 603125
has been allocated [Dominiak, P. L.; Coppens, P. Private communication].
(21) Davies, H. M. L.; Clark, D. M.; Alligood, D. B.; Eiband, G. R.
Tetrahedron 1987, 43, 4265.
(17) Schinnerl, M.; Bo¨hm, C.; Seitz, M.; Reiser, O. Tetrahedron:
Asymmetry 2003, 14, 765.
J. Org. Chem, Vol. 71, No. 14, 2006 5351

Hedley et al.
SCHEME 5
SCHEME 6
SCHEME 9
SCHEME 10
SCHEME 11
SCHEME 7
SCHEME 8
of the cyclopropane 20 in 61% yield with very high enantiose-
lectivity (96% ee; Scheme 11). An exceptionally efficient
reaction was also observed with 3-methylbenzofuran 19,
generating a single diastereomer of the cyclopropane 21 in 81%
yield and 97% ee. The absolute configuration of 20 was
determined by X-ray crystallography.23 Suitable crystals of 21
oxyfuran (16), as no cyclopropanation products were observed,
and dienes 17a,b were the only reaction products (Scheme 10).
The assigned diene geometry was determined by NOE experi-
ments.
Reaction with Benzofurans. Copper-catalyzed decomposi-
tion of ethyl diazoacetate in benzofuran has been reported to
proceed with cyclopropanation of the enol ether double bond
as a 7:1 mix of diastereoisomers.22 The Rh2(S-DOSP)4-catalyzed
reaction of benzofuran 18 with 4 provided a single diastereomer
(22) Wenkert, E.; Alonso, M. E.; Gottlieb, H. E.; Sanchez, E. L.;
Pellicciari, R.; Cogolli, P. J. Org. Chem. 1977, 42, 3945.
(23) The crystal structure of 20 has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC 270718
has been allocated [Dominiak, P. A.; Coppens, P. Private communication].
5352 J. Org. Chem., Vol. 71, No. 14, 2006

StereoselectiVity in the Reactions of Heterocycles
TABLE 1. Rh(II)-Catalyzed Decomposition of Methyl
Phenyldiazoaceate 29 in the Presence of tert-Butyl
SCHEME 12
3-((tert-Butyldimethylsilyloxy)methyl)-1H-indole-1-carboxylate 28
yield,
de,
ee,
yield,
ee,
entry
Rh cat.
% 30
% 30
% 30
% 31
% 31
1
2
3
Rh2(S-DOSP)4
25
70
0
91
87
n/a
36
n/a
n/a
66
0
91
64
Rh2(OOct)4
n/a
SCHEME 13
a
Rh2(S-PTTL)4
94b
a Reaction conducted at 50 °C. b Absolute stereochemistry of the product
ent-31 from Rh2(S-PTTL)4 (entry 3) is opposite to product 31 from the
Rh2(S-DOSP)4-catalyzed reaction (entry 1) and confirmed by X-ray crystal-
lography of derivative 32 (Scheme 14).
SCHEME 14
for X-ray crystallographic determination could not be formed
and, therefore, the absolute configuration of 21 was tentatively
assigned by circular dichroism (CD) comparison with both
enantiomers of 20.24
The substitution on the benzofuran has a major effect on the
outcome of the reaction with the donor-acceptor carbenoid.
This was clearly seen in the reaction of the aryldiazoacetate 4
with 2-methylbenzofuran (22). In this case, no cyclopropanation
of the furan ring was observed. Instead, the major product,
formed in 47% yield was a single diastereomer of 23 arising
from double cyclopropanation of the benzenoid ring (Scheme
12). The enantioinduction in this case was relatively low (51%
ee) and, because of this, the absolute configuration of the major
enantiomer was not determined.
Reaction with Indoles. The copper-catalyzed reaction of
ethyl diazoacetate with N-Boc-indole has been reported, resulting
in cyclopropanation of the heterocyclic ring.22,25 The Rh2(S-
DOSP)4-catalyzed reaction of aryldiazoacetate 4 with unsub-
stituted N-Boc-indole resulted in recovery of starting material
and the products of carbene dimerization. In contrast, effective
reactions were possible with the 2- and 3-methyl indoles 24
and 25, but the reaction resulted in the double cyclopropanation
of the benzenoid ring to provide 26 and 27 (Scheme 13) as
observed above (Scheme 12).
An understanding of the reactivity patterns of the heterocycles
can be used to develop strategies for selective transformations
in the presence of heterocycles. An example of this is shown
in the attempted intermolecular C-H insertion of the 3-substi-
tuted indole 28. As demonstrated in Scheme 13, the “pyrrole”
portion of the indole will be unreactive, and so, the competing
reactions are limited to C-H insertion to form 30 and the double
cyclopropanation of the “benzene” portion of the indole to form
31. The competition between the two processes is very depend-
ent on which catalyst is used. The Rh2(S-DOSP)4-catalyzed
reaction gave a 1:2.5 mixture of 30 and 31, while the
Rh2(OOct)4-catalyzed reaction gave exclusively the C-H inser-
tion product 30. In contrast, the reaction catalyzed by Rh2(S-
PTTL)4, the optimum catalyst for highly enantioselective C-H
insertion of benzyl silyl ethers,26 gave only the double cyclo-
propanation product 31.
The absolute stereochemistry of product ent-31, derived from
Rh2(S-PTTL)4 (Table 1, entry 3), was determined by the removal
of the silyl group and esterification to provide 32, which was
subjected to X-ray analysis to confirm the absolute stereochem-
istry (Scheme 14).27
Strategies are available to alter the reactivity profile of the
carbenoid to ensure that the C-H insertion becomes the
dominant process. One approach is to use (S)-lactate as a chiral
auxiliary. The effectiveness of this auxiliary in carbenoid
chemistry is proposed to arise from the coordination of the ester
carbonyl to the carbenoid, which leads to effective asymmetric
induction and modulation of the carbenoid reactivity.9 The Rh2-
(OOct)4-catalyzed reaction of the lactate 33 with the 3-substi-
tuted indole 28 generated the C-H insertion product 34 in 42%
yield as a 6.4:1 mixture of syn/anti diastereomers (Scheme 15).
Reduction of 34 with DIBAL generated the syn alcohol 35 in
50% yield and 72% ee. The absolute configuration of 35 has
not been assigned unequivocally, but when similar enantioin-
duction to the benzyl silyl ethers is assumed,26 the (S)-lactate-
mediated reaction has been shown to give the opposite
enantiomer to Rh2(S-DOSP)4 in C-H insertion reactions.
A benzene ring can be sterically protected from the double
cyclopropanation as long as it is at least 1,4-disubstituted.28
Thus, an even better method to suppress the double cyclopro-
(24) The CD spectra of both enantiomers of 20 (derived from using Rh2-
(S-DOSP)4 or Rh2(R-DOSP)4 as catalyst), where the absolute stereochemistry
has been verified by X-ray crystallography, were compared to the CD spectra
of both enantiomers of 21. This spectra suggests that the compounds have
the absolute configuration assigned above in Scheme 11 and Figure 3 (see
Supporting Information).
(26) Davies, H. M. L.; Hedley, S. J.; Bohall, B. R. J. Org. Chem. 2005,
70, 10737.
(27) The crystal structure of 32 has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC 603044
has been allocated [Nygren, C. L.; Coppens, P. Private communication].
(25) Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45,
4277.
J. Org. Chem, Vol. 71, No. 14, 2006 5353

Hedley et al.
SCHEME 15
TABLE 2. Rh(II)-Catalyzed C-H Activation Reaction of
tert-Butyl 5-Bromo-3-((tert-butyldimethylsilyloxy)methyl)-1H-
indole-1-carboxylate 36 with Methyl Phenyldiazoacetate 29
FIGURE 1. Predictive model for the Rh2(S-DOSP)4-catalyzed cyclo-
propanation reaction of simple alkenes.
totally inert to the carbenoid, even though it may be electroni-
cally very activated.3
entry
Rh cat.
yield, %
de, %
ee, %
1
2
3
Rh2(S-DOSP)4
Rh2(OOct)4
Rh2(S-PTTL)4
74
60
68
69
77
61
51
Dirhodium tetracarboxylate catalysts such as Rh2(S-DOSP)4
have been shown to be especially well-suited for the asymmetric
transformations of the donor-acceptor carbenoids.3 A very
effective predictive model has been developed for both the
diastereo- and the enantioselectivity, and this is summarized in
Figure 1.10 The catalyst is considered to behave as if it is D2
symmetric, which means that the catalyst can be viewed simply
as one surface with blocking groups in the front and back.
Computational studies have indicated that the alkene would
approach end-on with substituents facing the side of the donor
group, and this is fully consistent with the observed selectivity
in the cyclopropanation of simple alkenes.31
A most interesting phenomenon in these studies is that the
sense of asymmetric induction can vary depending on which
heterocycle is used. The enantioinduction in the reaction with
furan 7 is opposite to the enantioinduction in the reactions with
dihydrofuran 13, 2,5-dimethylfuran 14, and N-Boc-pyrrole 3,
even though the same chiral catalyst (Rh2(S-DOSP)4) is used
in all cases. This apparent anomaly has been observed previously
in the [4+3] cycloaddition reactions of vinyldiazoacetates with
furans and N-acyl pyrroles.11 When the current model for
cyclopropanation reactions is applied where the substrate alkene
approaches the rhodium carbenoid core in an end-on trajectory
(Figure 2),30 there are two possible approach vectors for the
five-membered ring heterocycles. Furan (7) proceeds through
the cyclopropanation pathway with initial bond formation at the
2-position, following the expected regiochemistry for aromatic
electrophilic substitution of electron-rich five-membered het-
erocycles.32 This model would explain the observed relative and
absolute stereochemistry of the reaction with furan to form 8.
The more surprising result is the reaction with N-Boc pyrrole 3
because in order to obtain the opposite enantioinduction the
reaction would need to proceed through an alternative pathway
with initial bond formation at the 3-position to form 6.
Presumably, the steric influence of the N-Boc group overrides
the usual electronic bias of N-Boc-pyrrole.33 An intriguing
n/a
94a
a Absolute stereochemistry of 37 when Rh2(S-PTTL)4 is used (entry 3)
is opposite to that shown.
panation is to use the brominated indole 36. With this substrate,
all three catalysts give only the C-H insertion product 37 (Table
2). No trace of any cyclopropanation products was observed.
In accordance with previously reported results using benzyl silyl
ether derivatives,26 Rh2(S-PTTL)4 was the most effective chiral
catalyst resulting in the formation of syn-37 in 94% ee and 61%
de. The absolute configuration of 37 has not been assigned
unequivocally, but when similar enantioinduction to the benzyl
silyl ethers is assumed,26 the predicted configuration would be
(2S,3S)-37 for the Rh2(S-DOSP)4-catalyzed reaction and (2R,3R)-
37 for the Rh2(S-PTTL)4-catalyzed reaction.29
Discussion
Donor-acceptor rhodium carbenoids display a very different
reactivity profile to the more traditional types of rhodium
carbenoids.3 The presence of the donor group greatly stabilizes
the carbenoid, and this results in greatly increased selectivity
in the resulting reactions of the carbenoid. For example,
cyclopropanation reactions are routinely highly diastereoselec-
tive,7 and selective intermolecular C-H insertions3 are readily
achieved. Hammett studies have shown that positive charge
build-up at the carbene occurs during both the cyclopropana-
tion30 and C-H insertion,28a and electronic factors are much
more pronounced in the donor-acceptor carbenoids compared
to those of the carbenoids lacking an acceptor group. Further-
more, these carbenoids appear to be sterically quite demanding,
and if the intended site of reaction is too crowded, it will be
(28) (a) Davies, H. M. L.; Jin, Q.; Ren, P. Kovalevsky, A. J. Org. Chem.
2003, 67, 4165. (b) Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry
2003, 14, 941.
(29) For a discussion of the predictive models used in Rh2(S-DOSP)4
and Rh2(S-PTTL)4-catalyzed C-H insertion reactions, see ref 3a. Rh2(S-
DOSP)4 and Rh2(S-PTTL)4 have been shown to give the opposite enantiomer
in intermolecular C-H insertion reactions: see ref 26 and Mu¨ller, P.; Tohill,
S. Tetrahedron 2000, 56, 1725.
(31) Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D.
A. J. Am. Chem. Soc. 2003, 125, 15902.
(32) Gilchrist, T. L. Heterocyclic Chemistry; Pitman Publishing, Ltd.:
London, 1985.
(33) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.;
Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990, 55, 6317.
(30) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
5354 J. Org. Chem., Vol. 71, No. 14, 2006

StereoselectiVity in the Reactions of Heterocycles
FIGURE 2. Predictive model for the Rh2(S-DOSP)4-catalyzed cyclo-
propanation reaction: the consequenes of the different facial selectivities
of furan 7 and N-Boc pyrrole 3 (Ar ) para-bromophenyl).
FIGURE 3. Predictive model for the Rh2(S-DOSP)4-catalyzed cyclo-
propanation reactions of benzofuran derivatives 18 (RdH) and 19 (Rd
Me; Ar ) para-bromophenyl).
feature of this analysis is the conclusion that the diastereose-
lectivity is independent of whether bond formation is initiated
at the 2- or 3-positions, but the enantioselection is totally
switched. This model can also readily explain the change in
enantioinduction upon moving from furan to 2,3-dihydrofuran
13 or 2,5-dimethylfuran 14. As an enol ether, electronically
dihydrofuran would greatly favor initial bond formation at the
C-3 position,34 while this position would also be favored by
2,5-dimethylfurans as a result of the steric influence of the
methyl groups.
The main contribution to the enantioselectivity appears to be
governed by the initial step. The products 6 and 8, derived from
a single cyclopropanation of N-Boc pyrrole 3 (Scheme 3) and
furan 7 (Scheme 5, eq 2), respectively, are isolated in high
enantioselectivity. In contrast, the subjection of racemic cyclo-
propanes 6 or 8 to a second cyclopropanation reaction allows
the isolation of products 5 and 9 only in low enantioselectivity
(9-10% ee). These results indicate that the effect of the chiral
catalyst is relatively minor in the second cyclopropanation
reaction, and, hence, the initial cyclopropanation is the most
important for enantioselectivity.
It is well-known that, unlike indoles, benzofurans react with
electrophiles at the 2-position.35 The same trend is observed in
the cyclopropanation of 18, as from the X-ray crystal data, and
it is apparent that the product 20 arises from initial bond
formation at the 2-position. A reasonable explanation for the
lack of product arising from initial bond formation at the
3-position may be due to steric clash between the rhodium
catalyst core and the benzenoid ring, especially the hydrogen
atoms at the 4- and 5-positions. This is further supported by
the fact that 3-methylbenzofuran (19) does not have an adverse
effect on the efficiency or selectivity of the reaction. In fact, a
higher yield of product was obtained with 19 compared to 18
(Scheme 11), and this may be due to increased stabilization of
the developing positive charge at the 3-position of the inter-
mediate through hyperconjugation (Figure 3). Furthermore,
when 2-methylbenzofuran 22 is subjected to the reaction
conditions, no cyclopropanation of the furan ring occurs
(Scheme 12). It is particularly noteworthy that the steric
demands of this reaction lead to the disruption of a more stable
benzenoid ring over a more electron-rich heterocycle. According
FIGURE 4. Rh2(S-DOSP)4-catalyzed double cyclopropanation reac-
tion of 2-methylbenzofuran 22 and consequences for the enantioselec-
tivity of product 23 (Ar ) para-bromophenyl).
to the model proposed in Figure 3, 2-methylbenzofuran 22
would not be expected to favor initial bond formation at C-2
because the methyl group would interfere sterically. The inability
of benzofurans 18, 19, or 22 to undergo the cyclopropanation
reaction with initial bond formation at the 3-position is reflected
in the high enantioselectivity (96-97% ee) of 20 and 21 in these
reactions, and verified by the formation of double cyclopropa-
nation product 23.
The enantioselectivity of the double cyclopropanation product
23 derived from 22 is significantly lower than the double
cyclopropanation products derived from furans and pyrroles.
This could possibly be attributed to the fact that in the case of
22, there is not much differentiation between the two alkenes
of the benzenoid ring. Following the initial cyclopropanation
reaction to generate 38a and 38b, the second reaction with the
rhodium carbenoid must then take place on the opposite face
(Figure 4). Both transition states are reasonable on steric
grounds.
The inability of indoles to undergo cyclopropanation of the
pyrrole ring with donor-acceptor compounds is not surprising
given the trends that have been observed with other heterocycles
in this study. The N-Boc group on pyrrole 3 effectively blocks
cyclopropanation with initial bond formation at the 2-position
(Scheme 2), while the studies with benzofurans show that these
substrates do not undergo cyclopropanation with initial bond
formation at the 3-position (Schemes 11 and 12). Therefore, in
(34) Davies, H. M. L.; Kong, N.; Churchill, M. R. J. Org. Chem. 1998,
63, 6586.
(35) Sargent, M. V.; Dean, F. M. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 4, pp 599-656.
J. Org. Chem, Vol. 71, No. 14, 2006 5355

Hedley et al.
that of traditional carbenoids in regard to their reactivity with
a variety of standard heterocycles. Efficient reactions can be
achieved, and the products are often inaccessible by other means.
An interesting effect in these reactions is that the enantioin-
duction is markedly influenced by the structure of the hetero-
cyclic substrate. The cyclopropanation is considered to proceed
in a concerted nonsynchronous manner, and depending on which
bond of the heterocycle initially interacts with the carbenoid,
either face of the heterocycle can be attacked under the influence
of the same chiral catalyst. Control is governed by a delicate
interplay of steric and electronic influences.
FIGURE 5. Steric and electronic considerations in the cyclopropa-
nation reaction of 8, catalyzed by Rh2(S-DOSP)4, with initial bond
formation at C-2 or C-3.
Experimental Section
the case of indoles 24 and 25, the cyclopropanation of the
pyrrole ring is effectively blocked at both positions and, hence,
reactivity takes place on the benzenoid ring in a manner similar
to 22.
Representative Experimental Procedure: Preparation of
Compound 5. A solution of methyl para-bromophenyldiazoacetate
(4; 457 mg, 1.79 mmol, 3.00 equiv) in hexanes (10 mL) was added
by syringe pump over 1 h to a solution of N-Boc-pyrrole 3 (0.10
mL, 0.61 mmol, 1.00 equiv) and Rh2(S-DOSP)4 (34 mg, 0.018
mmol, 0.01 equiv) in hexanes (5 mL). The reaction mixture was
stirred for an additional 1 h and then concentrated in vacuo.
Purification by flash chromatography on silica gel using 9:1 to 5:1
hexane/Et2O as eluent gave 5 as a white solid (354 mg, 93%). Mp
One of the most intriguing features of the chemistry of the
donor-acceptor carbenoid with heterocycles is the tendency to
form the double cyclopropanation products, essentially as single
diastereomers, even though six new stereogenic centers are
formed. This reactivity is different from the reactions of ethyl
diazoacetate with N-Boc-pyrrole or furan, where the monocy-
clopropane is typically formed.13,14,16,17 This behavior presum-
ably demonstrates the greater selectivity of the donor-acceptor
carbenoids because they are able to selectively react with the
monocyclopropane even in the presence of an excess of aromatic
starting material. The reaction with N-Boc-pyrrole 3 is a clear
example of this trend because no monocyclopropane product 6
is observed even when 6 equiv of the N-Boc-pyrrole 3 is used
(Scheme 2), and even when 3 is used as solvent, a significant
amount (34%) of 5 is isolated (Scheme 3). The double
cyclopropanation of furan 7 is more complex, especially when
the enantioinduction of the process is considered. As already
explained in Figure 2, the Rh2(S-DOSP)4-catalyzed cyclopro-
panation would be expected to generate the monocyclopropane
8. As 8 is a dihydrofuran derivative, the second cyclopropanation
would be expected to initiate at C-3, but this is only possible
for ent-8 (Figure 5). A reasonable model for the Rh2(S-DOSP)4-
catalyzed cyclopropanation of 8 is only possible if the reaction
initiates at the C-2 position. On electronic grounds, this would
appear to be a mismatched reaction, but the control experiments
with racemic monocyclopropane 6 or 8 show that the chiral
influence of the catalyst is not very pronounced in the second
cyclopropanation (Schemes 3 and 8).
1
196-199 °C. [R]D 234.4 (83% ee; c 1.00, CHCl3). H NMR (300
MHz, CDCl3): δ 7.55-7.48 (m, 4H), 7.16 (d, 2H, J ) 8.5 Hz),
7.11 (d, 2H, J ) 8.0 Hz), 3.56 (s, 3H), 3.52 (s, 3H), 3.07 (d, 1H,
J ) 6.5 Hz), 2.98 (d, 1H, J ) 6.5 Hz), 2.59 (d, 1H, J ) 6.5 Hz),
2.56 (d, 1H, J ) 6.5 Hz), 1.51 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 171.1, 170.9, 154.3, 133.4, 133.0, 132.0, 131.8, 130.9,
130.7, 122.2, 122.1, 81.5, 52.7, 52.6, 47.7, 47.1, 37.0, 36.8, 32.9,
31.7, 28.4. IR (CHCl3): 2973, 1714, 1699, 1409, 1346, 1324, 1237,
1128, 965, 868, 739, 703 cm-1. EI (m/z): 623 (M81Br2Na+, 33%),
621 (M81Br79BrNa+, 65%), 619 (M79Br2Na+, 32%), 591 (55%), 589
(100%), 587 (48%). Anal Calcd for C27H27Br2NO6: C, 52.19; H,
4.38; N, 2.25. Found: C, 51.87; H, 4.14; N, 2.25. HPLC analysis:
83% ee (Chiralcel AD-H, 1.0% i-PrOH in hexane, 0.8 mL/min, λ
) 254 nm, tR ) 32.1 min, minor; tR ) 47.5 min, major).
Acknowledgment. Financial support from the National
Science Foundation (CHE-0350536) is gratefully acknowledged.
We thank the Coppens Group for the facilities to conduct X-ray
crystallographic analysis and Mr. Prashant Girinath for as-
sistance in obtaining CD spectra of compounds 20 and 21.
Supporting Information Available: Experimental procedures
and spectral data for all novel compounds; X-ray data for
compounds 5, 9, ent-12, 15, 20, and 32; and CD spectra for
compounds 20 and 21. This material is available free of charge via
the Internet at http://pubs.acs.org.
Conclusion
These studies demonstrate that donor-acceptor carbenoids
have a markedly different reactivity profile in comparison to
JO060779G
5356 J. Org. Chem., Vol. 71, No. 14, 2006