A general and efficient cobalt(II)-based catalytic system for highly stereoselective cyclopropanation of alkenes with α-cyanodiazoacetates

Article abstract of DOI:10.1021/ja1056246

[Co(P1)], the cobalt(II) complex of the D₂-symmetric chiral porphyrin 3,5-Di^tBu-ChenPhyrin, is an effective catalyst for catalyzing asymmetric olefin cyclopropanation with the acceptor/acceptor-type diazo reagent α-cyanodiazoacetates

Full text of DOI:10.1021/ja1056246

Published on Web 08/25/2010
A General and Efficient Cobalt(II)-Based Catalytic System for Highly
Stereoselective Cyclopropanation of Alkenes with r-Cyanodiazoacetates
†,‡
†
†
,†
Shifa Zhu, Xue Xu, Jason A. Perman, and X. Peter Zhang*
Department of Chemistry, UniVersity of South Florida, Tampa, Florida 33620-5250, and School of Chemistry and
Chemical Engineering, South China UniVersity of Technology, Guangzhou, 510640, China
Received June 27, 2010; E-mail: xpzhang@usf.edu
5-8
employed for asymmetric olefin cyclopropanation.
This catalytic
Abstract: [Co(P1)], the cobalt(II) complex of the D
2
-symmetric
process would be highly desirable, as the resulting cyclopropanes
bearing geminal nitrile and ester functionalities can be further
transformed into a number of densely functionalized chiral cyclo-
propane molecules, including synthetically and biologically im-
portant cyclopropyl-amino acids and -amino alcohols (Scheme 1).
While the only study on the intramolecular version of the catalytic
t
chiral porphyrin 3,5-Di Bu-ChenPhyrin, is an effective catalyst for
catalyzing asymmetric olefin cyclopropanation with the acceptor/
acceptor-type diazo reagent R-cyanodiazoacetates. The [Co(P1)]-
catalyzed reaction is versatile and suitable for both aromatic and
aliphatic olefins with varied electronic properties, including electron-
rich and -poor olefins. The Co(II)-based catalytic system can be
operated in a one-time protocol under mild conditions, affording
the desired cyclopropane products in high yields with both high
diastereo- and enantioselectivity. The resulting enantiomerically
enriched 1,1-cyclopropanenitrile esters provide convenient access
to a number of densely functionalized chiral cyclopropane deriva-
tives, including R-cyclopropyl-ꢀ-amino acids.
9
process gave results that are highly substrate-dependent (yield:
8
1
1-85%; ee: 29-91%), it is strikingly noted that there has been
no prior report on intermolecular asymmetric cyclopropanation with
CDA. Moreover, the only intermolecular report of the catalytic
process is nonasymmetric with poor diastereoselectivity (10-20%
de), which highlights the challenges of stereocontrol for cyclopro-
7
panation with acceptor/acceptor-substituted diazo reagents. It is
evident that this important catalytic cyclopropanation process is
largely undeveloped and that more reactive and stereodiscriminating
catalysts are needed to address this unsolved problem in the field.
Catalytic asymmetric cyclopropanation of alkenes with diazo
reagents represents one of the most general and direct approaches
for stereoselective synthesis of chiral cyclopropane derivatives,
1
Structurally well-defined cobalt(II) complexes of D -symmetric
2
which have found widespread applications. Considering the
chiral porphyrins [Co(D
effective catalysts for asymmetric cyclopropanation.
based metalloradical cyclopropanation (MRC) has been shown to
possess a different reactivity profile from the widely studied Rh - and
and can achieve highly stereoselective cyclo-
2
-Por*)] have emerged as a new class of
common existence of alkene units and the broad accessibility of
diazo reagents with various combinations of R-groups, this ther-
modynamically favorable approach should, in principle, permit the
construction of three-membered, all-carbon ring structures bearing
all types of substituted functionalities. During the past two decades,
a number of highly effective catalytic systems have been developed
for various asymmetric cyclopropanation reactions with donor/
3a,10
The Co(II)-
2
3a,11
Cu-based systems
propanation of electron-deficient olefins and with acceptor/acceptor-
substituted diazo reagents. In view of their unique catalytic activities,
we decided to investigate the potential of [Co(D -Por*)]-based catalysts
10f
4d
2
acceptor- and acceptor-substituted diazo reagents. The potential
2
of catalytic asymmetric cyclopropanation, however, has not been
fully extended to acceptor/acceptor-substituted diazo reagents owing
to their low reactivity and poor stereocontrollability.
for asymmetric cyclopropanation with R-cyano diazoacetates. As the
outcome of this investigation, herein we wish to report the first catalytic
system that is efficient for stereoselective cyclopropanation with
R-cyano diazoacetates. In addition to high yields, the Co(II)-catalyzed
reactions allow for excellent control of both diastereo- and enantiose-
lectivity. Furthermore, the catalytic process has a broad substrate scope
and can cyclopropanate both aromatic and aliphatic olefins having a
wide range of electronic properties.
2
-4
Scheme 1. Synthesis of 1,1-Cyclopropanenitrile Esters via
Catalytic Asymmetric Cyclopropanation and Their Further
Transformations
R-Cyanodiazoacetates (CDA) are a class of known acceptor/
acceptor-substituted diazo reagents that have not been successfully
†
University of South Florida.
South China University of Technology.
‡
2
Figure 1. Structures of D -symmetric chiral cobalt(II) porphyrins.
1
2796 9 J. AM. CHEM. SOC. 2010, 132, 12796–12799
10.1021/ja1056246  2010 American Chemical Society

C O M M U N I C A T I O N S
Regarding the family of [Co(D
steric, and chiral environments,
2
-Por*)] with tunable electronic,
enhanced to 95% ee without affecting the excellent diastereose-
lectivity when the reaction was executed at 0 °C (entry 7). A
continued increase in enantiocontrol was observed when the reaction
temperature was further lowered to -20 °C, achieving 98% ee and
with the preservation of the complete E-diastereoselectivity (entry
8). To our delight, the reaction yield surprisingly rose back to 96%,
presumably due to elimination of possible side reactions associated
with n-hexane at this low temperature.
3
a,10d,g
our previous study revealed
-symmetric chiral
that [Co(P1)], the cobalt(II) complex of the D
2
t
porphyrin 3,5-Di Bu-ChenPhyrin (Figure 1A), is the optimal catalyst
for asymmetric olefin cyclopropanation with R-nitrodiazoacetates
4
d
(
NDA). We rationalized the catalytic effectiveness of [Co(P1)]
toward NDA as a consequence of two potential N-H---O hydrogen
bonding interactions between two of the chiral cyclopropyl amide
N-H elements on the P1 ligand with both the NdO (sNO
2
group)
With the success of asymmetric cyclopropanation of styrene, the
scope of the [Co(P1)]/t-BCDA-based catalytic system was then
investigated in detail. As summarized in Table 2 (entries 1-5),
styrene derivatives bearing substituents with varied electronic
properties could also be successfully cyclopropanated under similar
reaction conditions. For example, the cyclopropanation of styrene
derivatives substituted with electron-donating MeO- as well as
and the CdO (sCO Et group) units of the carbene moiety,
2
4
d
respectively, in a postulated metallocarbene intermediate. Given
that a cyano group is normally considered a stronger hydrogen bond
12
acceptor than a nitro group, we envisioned a similar cobalt-carbene
intermediate with the unique double-hydrogen bonding to be also
potentially operative for CDA reactions (Figure 1B). On the basis
of this hypothesis, initial efforts were made to systematically
investigate asymmetric cyclopropanation reactions of styrene as a
model substrate with CDA by [Co(P1)] under different conditions.
3 2
electron-withdrawing CF - and NO -groups productively generated
the corresponding cyclopropanenitrile esters 1b-d with essentially
the same high stereoselectivities as the styrene product 1a, even
though in relatively lower yields (entries 1-4). Furthermore, even
the extremely electron-poor pentafluorostyrene could be cyclopro-
panated by [Co(P1)], affording the desired product 1e with
essentially complete control of both diastereo- and enantioselec-
tivity, albeit in a lower yield (entry 5). The absolute configuration
of 1e was established as [1R,2S] by anomalous-dispersion effects
in X-ray diffraction measurements on the crystal (see the Supporting
Information).
Table 1. Asymmetric Cyclopropanation of Styrene with R-Cyano
2
Diazoacetate by D -Symmetric Chiral Cobalt(II) Porphyrin
a
[Co(P1)]
In addition to aromatic olefins, [Co(P1)] was also shown to be
an effective catalyst for the cyclopropanation of electron-deficient
olefins with CDA, another unique catalytic property of [Co(Por)]-
based MRC that is absent in existing nonmetalloradical-based
1
0,11
catalytic systems.
As presented in Table 2 (entries 6-11),
various R,ꢀ-unsaturated carbonyl compounds and nitriles could be
selectively cyclopropanated with t-BCDA by [Co(P1)], furnishing
a series of densely functionalized cyclopropane structures. For
instance, under modified reaction conditions (Table S1 in the
Supporting Information), both methyl and ethyl acrylates could be
catalytically converted to the desired cyclopropanenitrile diesters
1f and 1g in 90% and 79% yields, respectively, as single
diastereomers with high enantiocontrol (entries 6 and 7). Both
substituted and primary acrylamides were also suitable substrates
for the catalytic system, providing the corresponding cyclopropane
derivatives 1h and 1i bearing three different electron-withdrawing
functionalities, including cyano, amido, and ester groups, in similar
high yields and stereoselectivities (entries 8 and 9). It is notable
that all the functional groups were well tolerated; potentially
competitive N-H carbene insertion was not observed. Similarly,
cyclopropane structures containing ketone, amido, and ester groups
as three different ring substituents could be stereoselectively
constructed from the reactions of acrylketones as demonstrated by
the formation of 1j (entry 10). Electron-deficient alkenes bearing
cyano groups, such as acrylonitriles, could also be successfully
cyclopropanated, as exemplified with the nearly quantitative forma-
tion of 1k, albeit in lower stereoselectivities (entry 11).
a
Performed in one-time fashion for 24 h using 1 mol % [Co(P1)]
under
N
2
with 1.0 equiv of styrene and 1.2 equiv of R-cyano
b
c
diazoacetates. [styrene] ) 0.25 M. Isolated yields. Determined by
NMR. Enantiomeric excess of E major diastereomer determined by
chiral HPLC.
d
As summarized in Table 1, using the typical one-time protocol
that has been enjoyed by Co(II)-based MRC,
1
0,11
styrene could be
effectively cyclopropanated by 1 mol % of [Co(P1)] in dichlo-
romethane with ethyl R-cyanodiazoacetate (ECDA) at room tem-
perature, affording the desired product in almost quantitative yield
with promising diastereo- and enantioselectivity (entry 1). To further
improve the stereoselectivities, different solvents were evaluated.
When the reaction was carried out in chlorobenzene, it increased
the enantiomeric excess with no change in the diastereomeric ratio
(
entry 2). Further improvement in enantioselectivity was observed
when dichloroethane was used as the solvent, but with a decreased
diastereoselectivity (entry 3). To diverge from using chlorinated
solvents, the reaction was then tested in toluene, resulting in
improved diastereo- and enantioselective controls (entry 4). Sub-
sequent experiments indicated n-hexane is the solvent of choice
for the catalytic reaction. It provided the best enantiomeric excess
and diastereomeric ratio while maintaining an excellent yield (entry
In addition to electron-deficient nonaromatic olefins, other
nonaromatic olefins were also found to be suitable substrates for
the [Co(P1)]/t-BCDA-based catalytic system. As displayed in Table
2 (entries 12-18), simple aliphatic olefins such as 1-hexene,
1-octene, and 4-phenyl-1-butene could be fruitfully converted to
the desired products in high yields as single diastereomers with
high enantioselectivities when the cyclopropanation reactions were
conducted under solvent-free conditions (entries 12-14). Under
similar conditions, electron-rich vinyl esters such as vinyl acetate,
pivalate, and benzoate could also be productively cyclopropanated,
5
). Under the same reaction conditions, use of tert-butyl R-cyano-
diazoacetate (t-BCDA) instead of ECDA afforded the corresponding
E-cyclopropane as the only diastereomer in 91% ee, albeit in a
relatively lower yield (entry 6). The enantioselectivity was further
J. AM. CHEM. SOC. 9 VOL. 132, NO. 37, 2010 12797

C O M M U N I C A T I O N S
Table 2. [Co(P1)]-Catalyzed Diastereo- and Enantioselective
Cyclopropanation of Alkenes with tert-Butyl R-Cyanodiazoacetate
a
With a viable route to these highly functionalized cyclopropyl
nitrile esters in enantioenriched forms by [Co(P1)]-catalyzed
cyclopropanation, we are currently working on exploring their
potential applications as chiral building blocks for various stereo-
selective syntheses (Scheme 1). As an initial part of this exploration,
the ester groups in both 1a and 1n could be selectively reduced to
the corresponding primary alcohols 2a and 2n with full retention
9d
of the configuration (eqs 1 and 2). Alternatively, the cyano group
in 1n was discriminately converted to a primary amine without
affecting the ester functionality under different reduction conditions
9
d
(
eq 3). Again, the stereochemistry was completely preserved.
In summary, we have demonstrated that [Co(P1)] is a versatile
and efficient catalyst for highly diastereo- and enantioselective
cyclopropanation of a broad range of different alkenes with
13
R-cyanodiazoacetates. The Co(II)-based system represents the first
successful example of using this class of acceptor/acceptor-
substituted diazo reagents for the asymmetric cyclopropanation
process. The resulting chiral nonracemic cyclopropane derivatives
bearing densely functionalized groups possess a myriad of potential
synthetic and biological applications (Scheme 1). More broadly,
the establishment of R-cyanodiazoacetates as effective and selective
carbene sources for cyclopropanation, taken together with other
4
recent successes in the area, may encourage further development
of new catalytic systems for the wide use of this and other acceptor/
acceptor-substituted diazo reagents for various stereoselective
carbene transfer processes.
Acknowledgment. We are grateful for financial support by the
National Science Foundation (CAREER Award: CHE-0711024).
Supporting Information Available: Experimental procedures,
analytical data for all compounds, and complete ref 9d. This material
is available free of charge via the Internet at http://pubs.acs.org.
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(
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tion for its X-ray structural determination and other characterization data.
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2
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panation) catalytic system enjoys a practical attribute that is atypical for
(
JA1056246
J. AM. CHEM. SOC. 9 VOL. 132, NO. 37, 2010 12799