Enantioselective reactions of donor/acceptor carbenoids derived from α-aryl-α-diazoketones

Article abstract of DOI:10.1021/ol802614j

The reaction of a variety of α-aryl-α-diazo ketones with activated olefins, catalyzed by the adamantyl glycine-derived dirhodium complex Rh₂(S-PTAD)₄, generates cyclopropyl ketones with high diastereoselectivity (up to >95:5 dr) and enantioselectivity (up to 98% ee). Intermolecular C-H functionalization of 1,4-cyclohexadiene by means of carbenoid-induced C-H insertion was also possible with this type of carbenoid.

Full text of DOI:10.1021/ol802614j

ORGANIC
LETTERS
2009
Vol. 11, No. 4
787-790
Enantioselective Reactions of Donor/
Acceptor Carbenoids Derived from
r-Aryl-r-Diazoketones
Justin R. Denton† and Huw M. L. Davies*,‡
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260-3000, and Department of Chemistry, Emory UniVersity,
1515 Dickey DriVe, Atlanta, Georgia 30322
hdaVies@acsu.buffalo.edu
Received November 12, 2008
ABSTRACT
The reaction of a variety of r-aryl-r-diazo ketones with activated olefins, catalyzed by the adamantyl glycine-derived dirhodium complex
Rh2(S-PTAD)4, generates cyclopropyl ketones with high diastereoselectivity (up to >95:5 dr) and enantioselectivity (up to 98% ee). Intermolecular
C-H functionalization of 1,4-cyclohexadiene by means of carbenoid-induced C-H insertion was also possible with this type of carbenoid.
The metal-catalyzed reactions of diazo compounds, proceed-
ing Via metal carbenoid intermediates, have broad utility in
organic synthesis.1 Recent studies have shown that donor/
acceptor carbenoids offer many synthetic advantages over
the conventional carbenoids, which lack the combination of
a donor and an acceptor group.2 The acceptor group makes
this class of carbenoids electrophilic, while the donor group
modulates the reactivity sufficiently to allow highly regio-
and stereoselective reactions to occur.3 Major breakthroughs
within this class of carbenoids include diastereoselective
intermolecular cyclopropanations,4 [4 + 3] cycloadditions
between vinylcarbenoids and dienes,5 intermolecular C-H,2,6
Si-H,7 N-H,8 and O-H9 insertions, and a range of novel
(5) For recent examples, see: (a) Olson, J. P.; Davies, H. M. L. Org.
Lett. 2008, 10, 573. (b) Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc.
2007, 129, 10312. (c) Davies, H. M. L.; Loe, Ø.; Stafford, D. G. Org. Lett.
2005, 7, 5561.
† University at Buffalo, The State University of New York.
‡ Emory University.
(1) Doyle, M.; Mckervey, M.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides;
John Wiley & Sons Inc.: New York, 1998.
(6) For recent examples, see: (a) Davies, H. M. L.; Coleman, M. G.;
Ventura, D. L. Org. Lett. 2007, 9, 4971. (b) Dai, X.; Wan, Z.; Kerr, R. G.;
Davies, H. M. L. J. Org. Chem. 2007, 72, 1895. (c) Davies, H. M. L.; Ni,
(2) For reviews, see: (a) Davies, H. M. L.; Antoulnakis, E. G. Org. React.
2001, 57, 1. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003,
103, 2861. (c) Davies, H. M. L.; Loe, Ø., Synthesis 2004, 16, 2595. (d)
Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(3) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
(4) (a) Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett.
1996, 37, 4133. (b) Davies, H. M. L.; Bruzinski, P.; Lake, D.; Kong, N.;
Fall, M. J. Am. Chem. Soc. 1996, 118, 6897. (c) Davies, H. M. L.;
Nagashima, T.; Klino, J. L., III. Org. Lett. 2000, 2, 823. (d) Xu, Z.-H.;
Zhu, S.-N.; Sun, X.-L.; Tang, Y.; Dai, L.-X. Chem. Commun. 2007, 19,
1960. (e) Thompson, J. L.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
6090. (f) Bykowski, D.; Wu, K.-H.; Doyle, M. P. J. Am. Chem. Soc. 2006,
128, 16038.
A. Chem. Commun. 2006, 3110.
(7) (a) Davies, H. M. L.; Hansen, T.; Rutberg, J.; Bruzinski, P.
Tetrahedron Lett. 1997, 38, 1741. (b) Bulugahapitiya, P.; Landais, Y.; Parra-
Rapado, L.; Planchenault, D.; Weber, V. J. Org. Chem. 1997, 62, 1630.
(8) (a) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q. L. J. Am.
Chem. Soc. 2007, 129, 5834. (b) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc.
2007, 129, 12066. (c) Moody, C. J. Angew. Chem., Int. Ed. 2007, 46, 9148.
(d) Deng, Q.; Xu, H.; Yuen, A. W.; Xu, Z.; Che, C. Org. Lett. 2008, 10,
1529.
(9) (a) Maier, T. C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594. (b)
Chen, C.; Zhu, S.; Liu, B.; Wang, L.; Zhou, Q. J. Am. Chem. Soc. 2007,
129, 12616. (c) Zhu, S.; Chen, C.; Cai, Y.; Zhou, Q. Angew. Chem., Int.
Ed. 2008, 47, 932.
10.1021/ol802614j CCC: $40.75
Published on Web 01/15/2009
2009 American Chemical Society

reactions involving ylide intermediates.10 The most widely
used acceptor group has been a methyl ester (Figure 1).4
with diazoacetophenone using a chiral ruthenium porphyrin
catalyst.13a As far as we are aware, no examples of
intermolecular reactions by R-aryl-R-diazo ketones (5)15 have
been reported prior to this study.
1-Phenyl-1-diazoacetone (6) was used as a prototypical
substrate to inititate this study on the reactions of donor-
substituted ketocarbenoids (Table 1). The Rh2(S-DOSP)4-
Table 1. Optimization of the Intermolecular Cyclopropanation
of Styrene
yielda
(%)
drb
(E:Z) (%)
eec
entry
Rh(II)
solvent
temp
Figure 1. Optimal chiral catalysts for the different classes of donor/
1
2
3
4
5
6
7
8
Rh2(S-DOSP)4 hexanes rt
Rh2(S-PTAD)4 hexanes rt
Rh2(S-PTAD)4 hexanes reflux
70
18
80
93
92
72
80
90
>95:5 <5
>95:5 88
>95:5 81
>95:5 <5
>95:5 85
>95:5 77
>95:5 85
>95:5 85
acceptor-substituted diazo compounds.
Rh2(S-DOSP)4 DMBd
Rh2(S-PTAD)4 DMBd
Rh2(S-PTTL)4 DMBd
Rh2(S-PTAD)4 DMBd,e
Rh2(S-PTAD)4 DMBd,f
reflux
reflux
reflux
reflux
reflux
The dirhodium tetaprolinate Rh2(S-DOSP)4 is an exceptional
chiral catalyst with the donor-substituted methyl diazoacetates
(1) in cyclopropanations,4b C-H insertions,6 and Si-H
insertions.7a Various chiral copper catalysts have performed
well in enantioselective N-H8 and O-H9 insertions. Rh2(S-
DOSP)4 is not an effective chiral catalyst if the methyl ester
on the carbenoid is replaced by another acceptor group, and
Rh2(S-PTAD)411 has been found to be the catalyst of choice
in these cases.12 Excellent results have been obtained in
enantioselective cyclopropanation with the diazo-phospho-
nate (2),12a diazo-trifluoromethyl (3),12b and the diazo-nitrile
(4)12c systems. In this paper we expand the range of Rh2(S-
PTAD)4 catalysis and describe that R-aryl-R-diazo ketones
(5) can undergo highly enantioselective intermolecular reac-
tions.
a Isolated yield after purification. b Determined from crude material by
1H NMR. c Determined by chiral HPLC. d 2,2-Dimethylbutane. e 2 equiv
of styrene. f 1 mol % of Rh2(S-PTAD)4.
catalyzed (2 mol %) reaction of 6 in the presence of styrene
(7, 5 equiv) with hexane as solvent at room temperature
resulted in the formation of the cyclopropane 8 in 70% yield.
The diastereoselectivity is high (dr >95:5, entry 1), which
is a typical feature of cyclopropanation reactions with donor/
acceptor carbenoids. The enantioselectivity for the formation
of 8 was negligible (<5%), illustrating once again that Rh2(S-
DOSP)4 is ideally suited only for reactions of donor-
substituted methyl diazoacetates. In contrast, the Rh2(S-
PTAD)4-catalyzed reaction at room temperature gave much
higher asymmetric induction (88% ee); however, the reaction
was inefficient, resulting in only 18% yield of 8 (entry 2).
When the reaction was conducted in refluxing hexane,
however, 8 was formed in 80% yield with only a slight drop
in enantioselectivity (81% ee, entry 3). The reactions
conducted in refluxing 2,2-dimethylbutane gave similar
trends (entries 4 and 5). Hashimoto’s tert-butyl leucinate
catalyst, Rh2(S-PTTL)4,11 was also effective in this chemistry
but gave enantioselectivity (77% ee, entry 6) slightly lower
than that using Rh2(S-PTAD)4. Conducting the reaction with
only 2 equiv of styrene (entry 7) or with 1 mol % of catalyst
(entry 8) gave results comparable to those of the standard
reaction with 5 equiv of styrene and 2 mol % of catalyst.
Enantioselective intermolecular cyclopropanations with
R-diazo ketones have not been extensively explored.13,14 The
best results to date have been asymmetric cyclopropanation
(10) (a) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem.
Soc. ReV. 2001, 30, 50. (b) Doyle, M. P.; Hu, W.; Timmons, D. J. Org.
Lett. 2001, 3, 933. (c) Lu, C.-H.; Liu, H.; Chen, Z.-Y.; Hu, W.-H.; Mi,
A.-Q. Org. Lett. 2005, 7, 83. (d) Guo, Z.; Huang, H.; Fu, Q.; Hu, W. Synlett
2006, 15, 2486.
(11) Rh2(S-PTAD)4 is related to a series of rhodium phthalimidocar-
boxylate catalysts pioneered by Hashimoto. See: (a) Takahashi, T.; Tsutsui,
H.; Tamura, M.; Kitagaki, S.; Nakajima, M.; Hashimoto, S. Chem. Commun.
2001, 1604. (b) Minami, K.; Saito, H.; Tsutsui, H.; Nambu, H.; Anada,
M.; Hashimoto, S. AdV. Synth. Catal. 2005, 347, 1483.
(12) (a) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8,
3437. (b) Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org. Lett. 2007,
9, 2625. (c) Denton, J. R.; Cheng, K.; Davies, H. M. L. Chem. Commun.
2008, 1238.
(13) (a) Nicolas, I.; Maux, P. L.; Simmoneaux, G. Tetrahedron Lett.
2008, 49, 2111. (b) Nakamura, A.; Konishi, A.; Tatsuno, Y.; Otsuka, S.
J. Am. Chem. Soc. 1978, 100, 3443.
(14) For examples of alternative strategies for the stereoselective
synthesis of highly functionalized cyclopropyl ketones, see: (a) Concello´n,
J. M.; Rodr´ıguez-Solla, H.; Me´jica, C.; Blanco, E. G.; Garc´ıa-Granda, S.;
D´ıaz, M. R. J. Org. Chem. 2008, 73, 3828. (b) Yadav, A. K.; Peruncher-
alathan, S.; Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72, 138. (c) Chen,
(15) For examples of enantioselective intramolecular reactions of R-aryl-
R-diazo ketones, see: (a) Taber, D. F.; Tain, W. J. Org. Chem. 2008, 73,
7560. (b) Taber, D. F.; Tain, W. J. Org. Chem. 2007, 72, 3207.
(16) The X-ray crystallographic data has been submitted by Pitak, M.
and Coppens, P. 2008, CCDC 699498.
H.; Deng, M.-Z. Org. Lett. 2000, 2, 1649
.
788
Org. Lett., Vol. 11, No. 4, 2009

The next series of experiments evaluated the effect of the
carbenoid substituents on the cyclopropanation selectivity
(Table 2). These reactions were conducted using the optimum
enhanced enantioselectivity (entries 4-6). Increasing the
length of the alkyl chain beyond propyl was unproductive
as intramolecular C-H insertion became a competing
reaction. Bulky groups close to the carbonyl such as phenyl
or isopropyl were unfavorable. In the case of the phenyl
ketone 10g, the enantioselectivity dropped to 51% ee (entry
7), while only traces of cyclopropane were obtained with
isopropyl ketone 10h (entry 8).
Table 2. Intermolecular Cyclopropanation of Diazo Ketones
Further optimization studies were directed toward ketone
groups lacking bulk immediately adjacent to the carbonyl.
The chosen groups were also unlikely to undergo intramo-
lecular C-H insertion. The 3,3-dimethylbutyl derivative 10i
was very effective (entry 9), but the most impressive results
were obtained when alkynyl dervatives 10j-l were used. In
each case the cyclopropanes were produced in >90% yield,
>95:5 dr, and 95-98% ee (entries 10-13). Similar results
were obtained when the amount of Rh2(S-PTAD)4 was
reduced to 0.5 mol % (entry 13), while the Rh2(S-DOSP)4-
catalyzed reaction still gave much lower and opposite
enantioselectivity (56% ee, entry 14).
On the basis of the established model for asymmetric
cyclopropanation by donor/acceptor carbenoids, the major
cyclopropane formed in a Rh2(S-DOSP)4-catalyzed reaction
is predicted to be (1R,2S),4b whereas Rh2(S-PTAD)4 tends
to form the opposite enantiomer.12 The relative and absolute
configuration of 10l was determined to be (1S,2R) by X-ray
crystallographic analysis (Figure 2), in agreement with the
Figure 2. X-ray crystal structure of 10l.
predicted assignment.16 All other ketone-substituted cyclo-
propanes are assigned the same relative and absolute con-
figuration by analogy.
The scope of the intermolecular cyclopropanation was then
explored using the diazo ketone 9l (Table 3). In all cases in
a Isolated yield after purification. b Determined from crude material by
1H NMR. c Determined by chiral HPLC. d The reaction was run with 1.0
mol % of Rh2(S-PTAD)4. e The reaction was run with 0.5 mol % of
Rh2(S-PTAD)4. f The reaction was run with 1.0 mol % of Rh2(S-DOSP)4.
catalyst, Rh2(S-PTAD)4, and styrene as the trapping agent.
In all cases, the diastereoselectivity was uniformly high
(>95:5 dr). Three different donor groups (R1) were first
examined (entries 1-3). Substituting the aryl group with a
styryl group caused a drop in enantioselectivity (54% ee,
entry 1). Introduction of para-substituents on the phenyl ring
effected little change in enantioselectivity (entries 2 and 3).
Altering the structure of the ketone functionality (R2) had
an unexpected influence on the enantioselectvity of the
cyclopropanation. Increasing the size of the ketone group
from methyl to ethyl, propyl, and isobutyl resulted in
Scheme 1. Cyclopropanation of n-Butyl Vinyl Ether
Org. Lett., Vol. 11, No. 4, 2009
789

Another major reaction of donor/acceptor carbenoids is
intermolecular C-H functionalization by means of car-
benoid-induced C-H insertion.2,6 In order to evaluate if these
ketocarbenoids are capable of similar reactions, tests were
conducted with 1,4-cyclohexadiene (Table 4). The Rh2(S-
Table 3. Intermolecular Cyclopropanation of Various Alkenes
Table 4. Intermolecular C-H Insertion of 1,4-Cyclohexadiene
a Reported yields of isolated products. b Determined by chiral HPLC.
c The reaction was run at room temperature.
a Reported yields of isolated product. b Determined from crude material
by 1H NMR. c Determined by chiral HPLC. d Values are for the major
diastereomer only.
PTAD)4-catalyzed reactions gave excellent yields of the C-H
insertion products 13a-e. The enantioselectivities ranged
from 71% to 89% ee.
which the substrate alkene is electron-rich, the diastereose-
lectivity was very high. Styrene derivatives underwent the
cyclopropanation with high enantioselectivities (entries 1 and
2). Similarly, N-vinyl phthalimide generated the cyclopropane
with very high enantioselectivity (97% ee, entry 3). The
reactions with vinyl acetate and dienes were not as enanti-
oselective (86-88% ee, entries 4-6). The unactivated olefin
allyl benzene was not an effective substrate. The cyclopro-
pane 11g was formed in only 37% yield and as a 2: 1 mixture
of diastereomers, although the major diastereomer was still
produced in 88% ee (entry 7).
In summary, cyclopropylketones are readily synthesized
by Rh(II)-catalyzed intermolecular cyclopropanation of ole-
fins with R-aryl-R-diazo ketones. The reaction can proceed
in a stereocontrolled fashion utilizing the chiral catalyst
Rh2(S-PTAD)4. Intermolecular C-H insertions were also
feasible with these carbenoid precursors. These studies
further expand the range of donor/acceptor-substituted
rhodium carbenoids that are capable of highly stereoselective
transformations.
Acknowledgment. Financial Support of this work by the
National Science Foundation (CHE-0750273) is gratefully
acknowledged. We thank Dr. Mateusz Pitak, University at
Buffalo, for the X-ray crystallographic analysis.
The Rh2(S-PTAD)4-catalyzed reaction of 9l with n-butyl
vinyl ether did not result in the formation of a cyclopropyl
ketone. Instead, the dihydrofuran 12 was formed in 90% yield
and 62% ee. This type of [3 + 2] cycloadduct is typically
considered to be formed by means of zwitterionic
intermediates.2a The moderate level of enantioselectvity
observed in the formation of 12 suggests that the chiral
catalyst is still associated at the zwitterionic intermediate
stage.
Supporting Information Available: Experimental data
for the reported reactions and a CIF file for the X-ray
crystallogrphic data for 10l. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 11, No. 4, 2009