Stereoselective construction of nitrile-substituted cyclopropanes

Article abstract of DOI:10.1039/b719175h

Nitrile-substituted cyclopropanes are readily synthesized in a stereocontrolled fashion from the intermolecular cyclopropanation between 2-diazo-2-phenylacetonitrile and electron-rich olefins, catalyzed by the chiral dirhodium complex, Rh₂(S-PTAD)₄. The Royal Society of Chemistry.

Full text of DOI:10.1039/b719175h

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Stereoselective construction of nitrile-substituted cyclopropaneswz
Justin R. Denton, Kevin Cheng and Huw M. L. Davies*
Received (in Maryland, MD, USA) 13th December 2007, Accepted 21st January 2008
First published as an Advance Article on the web 7th February 2008
DOI: 10.1039/b719175h
Nitrile-substituted cyclopropanes are readily synthesized in a
stereocontrolled fashion from the intermolecular cyclopropana-
tion between 2-diazo-2-phenylacetonitrile and electron-rich ole-
fins, catalyzed by the chiral dirhodium complex, Rh2(S-PTAD)4.
tion reactions of donor/acceptor-substituted diazo compounds
4 where the acceptor group is a cyano group.
Donor/acceptor carbenoids containing a cyano group are
not only of synthetic interest, but also offer further insight into
the postulated mechanism of the cyclopropanation. Theoreti-
cal and kinetic isotope studies have led to the proposal that the
cyclopropanation occurs in a concerted non-synchronous
manner with the alkene approaching in a side-on manner
(Fig. 1).7 The high diastereoselectivity is considered to be
due to the bulky nature of the electron-withdrawing group,
which avoids destabilizing the electrophilic carbenoid by
aligning out of the plane of the rhodium carbene p-bond.7a
In the case of the diazo compounds 4, the cyano group is not
sterically bulky, and how this would influence the diastereo-
selectivity has been an interesting question.7
Rhodium carbenoids, derived from diazo compounds, are
versatile synthetic intermediates, capable of a range of useful
transformations, such as cyclopropanation, C–H insertion and
ylide formation.1 It has become increasingly evident that the
structure of the carbenoid greatly influences the outcome of this
chemistry.2 Most notably, donor/acceptor-substituted carbe-
noids are capable of a much wider range of selective transfor-
mations than the other classes of carbenoids.3 A distinctive
feature of the cyclopropanation chemistry of donor/acceptor-
substituted carbenoids is the high diastereoselectivity exhibited
with virtually all substrates.4 Most of the early examples of
donor/acceptor carbenoids use a methyl ester as the acceptor
group,2,4 and Rh2(S-DOSP)4 has been found to be an excep-
tional chiral catalyst for this system (1). Recent studies have
been directed towards exploring the scope with other types of
donor/acceptor systems such as the phosphonate 25 and the
trifluoromethyl derivative 3.6 Rh2(S-DOSP)4 is not an effective
chiral catalyst with these systems but the new catalyst, Rh2(S-
PTAD)4,5b circumvented this problem. In this communication,
we describe the effect of chiral catalysts on the cyclopropana-
Several methods have been developed to synthesize nitrile-
substituted cyclopropanes,8 including the metal-catalyzed
intermolecular cyclopropanation by a-diazoacetonitriles.9
a-Diazoacetonitriles containing a donor group have not been
extensively studied and the reported cyclopropanations with
a-diazoacetonitriles lacking a donor group have proceeded
with variable diastereoselectivity and up to 70% ee.9c
2-Diazo-2-phenylacetonitrile (5)10 was used as the proto-
typical substrate in these studies. As a test reaction, the
cyclopropanation of styrene was examined using the most
generally effective chiral catalysts for the reactions of donor/
acceptor substituted carbenoids, Rh2(S-DOSP)4, Hashimoto’s
Rh2(S-PTTL)4,11 and Rh2(S-PTAD)4 (Table 1). All three
catalysts gave high yield of the cyclopropane 6a and good
diastereocontrol (B95 : 5 dr), although the diastereoselectivity
was lower than what had been observed with other types of
donor/acceptor carbenoids.4–6 Rh2(S-DOSP)4 gave relatively
low enantioinduction (34% ee), while Rh2(S-PTTL)4, and
Rh2(S-PTAD)4 gave far superior results (90% ee). The opti-
mal conditions were 2 mol% of catalyst in toluene at ꢀ78 1C
followed by slowly warming to room temperature. At higher
temperature, the enantioselectivity was significantly lower, and
erosion of enantioselectivity was also observed when just 1
mol% of catalyst was used.
The carbenoid reaction of 5 was applied to a range of olefins
using Rh2(S-PTAD)4 as catalyst and the results are
Department of Chemistry, University at Buffalo, State University of
New York, Buffalo, NY 14260-3000, USA. E-mail:
hdavies@buffalo.edu; Fax: 716-645-6547; Tel: 716-645-6800X2186
w CCDC 654356. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b719175h
z Electronic supplementary information (ESI) available: Experimental
details for the synthesis of all new compounds. See DOI: 10.1039/
b719175h
Fig. 1 The model for concerted non-synchronous cyclopropanation.
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Table 1 2-Diazo-2-phenylacetonitrile in intermolecular cyclopropa-
nation of styrene
Table 2 Intermolecular cyclopropanation of electron-rich olefins
Rh(II)
cat.
Yielda
eec
(%)
Entry
R
Yielda (%) drb
97 : 3 83
eec (%)
Loading Solvent Temp. (%)
drb
6b
80
89
82
80
83
84
88d
90d
Rh2(S-PTAD)4 2 mol% TFT
Rh2(S-PTAD)4 2 mol% Toluene rt
rt
83
77
93 : 7 65
89 : 11 60
95 : 5 34
96 : 4 90
97 : 3 90
97 : 3 85
b
Rh2(S-DOSP)4 2 mol% Toluene ꢀ78 1C 85
Rh2(S-PTTL)4 2 mol% Toluene ꢀ78 1C 84
Rh2(S-PTAD)4 2 mol% Toluene ꢀ78 1C 86
Rh2(S-PTAD)4 1 mol% Toluene ꢀ78 1C 80
a
Yield obtained after purification using flash chromatography. Dr
as judged by 1H NMR spectroscopy before purification. Ee as
6c
6d
6e
6f
497 : 3 84
95 : 5 78
96 : 4 90
95 : 5 83
497 : 3 90
c
determined by chiral HPLC. TFT = a,a,a,-Trifluorotoluene.
summarized in Table 2. Styrenes were very effective substrates,
generating cyclopropanes 6b–g in high yields (80–89%), high
diastereoselectivity (95 : 5 to 497 : 3 dr) and moderate to high
enantioselectivity (78–90% ee). The lowest enantioselectivity
was obtained with the most electron-rich styrene, which might
be expected as this would be the most reactive substrate. The
trend is the same as seen with vinyl diazoacetates and aryl
diazoacetates.4b,c Extension of the study to n-butyl vinyl ether
resulted in a dramatic drop in diastereoselectivity. The cyclo-
propane 6h was formed as a 62 : 38 mixture of diastereomers,
although the enantioselectivity remained moderate (80% ee
(major) and 79% ee (minor)). Very low diastereoselectivity
was also observed in the reaction with vinyl acetate, and
indeed, in this case the slightly preferred diastereomer was
the (Z) isomer of cyclopropane 6i, while the enantioselectivity
remained high (92% ee). The last result is markedly different
from the reaction of the diazo compound 1, which gave highly
diastereoselective reactions with vinyl ethers.4b,c Attempted
reactions with electron-neutral substrates such as 1-hexene
gave very low yields of cyclopropanes.
6g
6h
62 : 38 80 (major), 79 (minor)
6i
46 : 54 92 (major), 74 (minor)
a
b
Yield obtained after purification using flash chromatography. Dr (E : Z) as
judged by 1H NMR spectroscopy before purification. Ee as determined by
d
chiral HPLC. Combined yield of diastereomers.
c
One of the most distinctive aspects of the cyclopropanation
reactions with donor/acceptor carbenoids is that the diaster-
eoselectivity is generally not sensitive to catalyst structure.12
The reaction of 5 with 2,3-dihydrofuran did not follow this
trend (Scheme 1).12 The reaction catalyzed by Rh2(S-PTAD)4
gave the cyclopropane 7 in a 91 : 9 ratio of diastereomers while
the reaction catalyzed by Rh2(S-DOSP)4 gave virtually a 1 : 1
dr of 7. The enantioselectivity for the formation of 7 with
either catalyst was very low (o15% ee).
The diastereoselectivity observed in these studies offer inter-
esting insights into rhodium carbenoid chemistry. The reac-
tions with styrenes gave high diastereoselectivity, even though
it would have been predicted that the small cyano acceptor
group would be unable to influence the reaction in such a
way.7 In the case of alkenes lacking an aryl substituent the
diastereoselectivity was very low. As the cyano group would
Due to the variable stereoselectivity in these reactions,
efforts were made to unambiguously verify the stereochemical
assignments. The bromocyclopropane 6g was enriched to
498% ee by recrystallization from absolute ethanol. X-Ray
crystallographic analysis determined the relative and absolute
configurations to be 1S,2R (Fig. 2).13 The relative configura-
tion of the other cyclopropanes were readily assigned by a
distinctive 0.3–0.4 ppm shielding of the C-2 proton when cis to
the C-1 phenyl. The absolute configuration of the other
cyclopropanes is tentatively assigned by analogy to 6g.
Scheme 1 Cyclopropanation of 2,3-dihydrofuran.
Chem. Commun., 2008, 1238–1240 | 1239
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Notes and references
y General cyclopropanation procedure: To a flame-dried round bottom
flask under argon, equipped with a stir bar, was added toluene, the
electron rich olefin (5.0 equiv., B1.0 M solution), and the Rh(II)
catalyst (2 mol%). The green solution was then cooled to ꢀ78 1C and
the diazo compound solution of 5 (1.0 equiv. in toluene, B0.1 M) was
then added dropwise over 15 min. The resulting orange solution was
then allowed to warm to room temperature over 6 h. After which, the
resulting green solution was then concentrated in vacuo and the dr was
determined by 1H NMR. The crude cyclopropane was then further
purified by column chromatography and the ee of the pure cyclopro-
pane was determined by chiral HPLC.
1 (a) M. Doyle, M. McKervey and T. Ye, Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes
to Ylides, John Wiley & Sons Inc., New York, 1998, pp. 163–220;
(b) H. M. L. Davies, Eur. J. Org. Chem., 1999, 2459; (c) T. Ye and
A. McKervey, Chem. Rev., 1994, 94, 1091.
2 (a) H. M. L. Davies and R. Beckwith, Chem. Rev., 2003, 103, 2861;
(b) H. M. L. Davies and T. Hansen, J. Am. Chem. Soc., 1997, 119,
9075.
Fig. 2 X-Ray crystal structure of 6g.
3 Recent examples: (a) E. C. Lee and G. C. Fu, J. Am. Chem. Soc.,
2007, 129, 12066; (b) T. C. Mair and G. C. Fu, J. Am. Chem. Soc.,
2006, 128, 4594; (c) S. Paddibhotla, Y. Dang, J. O. Liu and D.
Romo, J. Am. Chem. Soc., 2007, 129, 12222; (d) J. Yang, H. Wu, L.
Shen and Y. Qin, J. Am. Chem. Soc., 2007, 129, 13794; (e) W. Guo,
H. Huang, L. Yang and W. Hu, Org. Lett., 2007, 9, 4721.
4 (a) H. M. L. Davies and R. J. Townsend, J. Org. Chem., 2001, 66,
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Fall, J. Am. Chem. Soc., 1996, 118, 6897; (c) H. M. L. Davies, P. R.
Bruzinski and M. J. Fall, Tetrahedron Lett., 1996, 37, 4133; (d) J.
L. Thompson and H. M. L. Davies, J. Am. Chem. Soc., 2007, 129,
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Fig. 3 The proposed charge-transfer complex.
5 (a) H. M. L. Davies and G. Lee, Org. Lett., 2004, 6, 2117;
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3437.
not be blocking approach of the alkene, a reasonable explana-
tion for the high diastereoselectivity with styrenes would be the
occurrence of an attractive p stacking interaction between the
aryl rings during the cyclopropanation (Fig. 3). This would
also explain the extremely high diastereoselectivity observed in
styrene cyclopropanations with diazo compounds 1–3, as the
carbenoid in these cases would block approach of the substrate
over the acceptor group7 and have an attracting p stacking
interaction with the donor group.
6 J. R. Denton, D. Sukumaran and H. M. L. Davies, Org. Lett.,
2007, 9, 2625.
7 (a) D. Nowlan, T. Gregg, H. M. L. Davies and D. Singleton, J.
Am. Chem. Soc., 2003, 125, 15902; (b) J. M. Fraile, J. I. Garcia, V.
Martinez-Merino, J. A. Mayoral and L. Salvatella, J. Am. Chem.
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Yamada, Bull. Chem. Soc. Jpn., 2001, 74, 2151.
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Tetrahedron, 1990, 46, 7341; (c) R. Wurz and A. Charette,
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K. Minami, H. Saito, H. Tsutsui, H. Nambu, M. Anada and S.
Hashimoto, Adv. Synth. Catal., 2005, 347, 1483.
In summary, the intermolecular cyclopropanation reactions
of 2-diazo-2-phenylacetonitrile with various styrene deriva-
tives afforded the nitrile-substituted cyclopropanes in high
yield, high diastereoselectivity, and with moderate to high
enantioselectivity. These studies underscore the impor-
tance of having both donor and acceptor groups on the
carbenoid for diastereoselective cyclopropanation reactions,
and suggest that even a small acceptor group such as cyano
can be effective due to attractive p stacking interactions at the
donor group.
Financial support of this work by the National Science
Foundation (CHE-0350536) is gratefully acknowledged. We
thank Dr. Mateusz Pitak from SUNY at Buffalo for the X-ray
crystallographic analysis of 6g.
12 S. J. Hedley, D. L. Ventura, P. M. Dominiak, C. L. Nygren and H.
M. L. Davies, J. Org. Chem., 2006, 71, 5349.
13 The X-ray crystallographic data has been submitted to the Cam-
bridge Structure Database:w M. Pitak and P. Coppens, 2007.
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1240 | Chem. Commun., 2008, 1238–1240