Rhodium-mediated enantioselective cyclopropanation of alienes

Article abstract of DOI:10.1021/ol9017968

Reaction of monosubstituted alienes with aryldiazoacetate esters under dlrhodium tetracarboxylate catalysis led to alkylidene cyclopropane products in 80-90% ee. Monosubstituted alkyl- and arylallene substrates gave 60-75% yield under standard conditions,

Full text of DOI:10.1021/ol9017968

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4434-4436
Rhodium-Mediated Enantioselective
Cyclopropanation of Allenes
Timothy M. Gregg,* Mark K. Farrugia, and John R. Frost
Department of Chemistry and Biochemistry, Canisius College,
Buffalo, New York 14208
greggt@canisius.edu
Received August 4, 2009
ABSTRACT
Reaction of monosubstituted allenes with aryldiazoacetate esters under dirhodium tetracarboxylate catalysis led to alkylidene cyclopropane
products in 80-90% ee. Monosubstituted alkyl- and arylallene substrates gave 60-75% yield under standard conditions, while yields for
1,1-disubstituted allenes were significantly lower. Cyclopropanation of 1-methyl-1-(trimethylsilyl)allene proceeded in higher yield than other
1,1-disubstituted substrates, suggesting rate enhancement mediated by a significant ꢀ-silicon effect.
Rhodium-stabilized carbenoid reactions are powerful
methods for synthesizing complex organic structures with
high levels of chemo-, diastereo-, and enantioselectivity.1
Cyclopropanation of alkenes with rhodium carbenoids has
been examined systematically, indicating the broad scope
of suitable alkenes and providing important mechanistic
insight into the reaction.2 Although a number of different
allene substrates have been reported in cyclopropanation
reactions,3 there has been no systematic investigation of
the scope of allene derivatives that can be used nor have
there been any reports on the degree of enantioselectivity
that might be feasible given the wide array of available
chiral catalysts.
include: use as mechanism-based enzyme inhibitors,5 use as
conformationally restricted ligand analogues,6 potential for
extending the serum stability of prodrugs,7 and applicability
toward development of cyclopropane and alkylidene cyclo-
propane nucleoside analogues as antiviral agents.8
To extend our understanding of allene cyclopropanation,
we investigated substituent effects and enantioselectivity in
cyclopropanation of allenes using rhodium carbenoids de-
rived from aryldiazoacetate esters (eq 1, Scheme 1).
The carbenoid intermediate derived under such conditions
is well suited for rapid cyclopropanation of styrene, so it
was surprising that reaction of 2 with phenylallene, 1a,
catalyzed by Rh2(S-DOSP)4, 4, with toluene as solvent, gave
A better understanding of allene cyclopropanation will
have an important impact on the chemistry of alkylidene
cyclopropanes (ACP).4 Applications of ACP synthesis
(3) (a) Huval, C. C.; Singleton, D. A. J. Org. Chem. 1994, 59, 2020–
2024. (b) Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 183–187. (c)
Ma, S.; Lu, L. J. Org. Chem. 2005, 70, 7629–7633. (d) Lu, L.; Chen, G.;
Ma, S. Org. Lett. 2006, 8, 835–838. (e) Yao, T.; Hong, A.; Sarpong, R.
Synthesis 2006, 2006, 3605–3610.
(1) For leading references on cyclopropanation, see: (a) Davies, H. M. L.;
Antoulinakis, E. G. Org. React. 2001, 57, 1–326. (b) Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977–1050. (c)
Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 107, 4538–4583. For C-H
activation, see: (d) Davies, H. M. L.; Manning, J. R. Nature 2008, 451,
417–424. (e) Liu, Y.; Xiao, W.; Wong, M.-K.; Che, C.-M. Org. Lett. 2007,
9, 4107–4110. (f) Doyle, M. P. Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 341-355.
For carbene-initiated ylide reactions, see: (g) Padwa, A. Progress Heterocycl.
Chem. 2009, 20, 20–46. (h) DeAngelis, A.; Panne, P.; Yap, G. P. A.; Fox,
J. M. J. Org. Chem. 2008, 73, 1435–1439. For O-H instertion, see: (i)
Zhang, W.; Romo, D. J. Org. Chem. 2007, 72, 8939–8942.
(4) ACP references: (a) Lautens, M.; Delanghe, P. H. M. J. Am. Chem.
Soc. 1994, 116, 8526–8535. (b) Brandi, A.; Goti, A. Chem. ReV. 1998, 98,
589–636. (c) Zohar, E.; Stanger, A.; Marek, I. Synlett 2005, 14, 2239–
2241. (d) Scott, M. E.; Schwarz, C. A.; Lautens, M. Org. Lett. 2006, 8,
5521–5524. (e) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007,
107, 3117–3179.
(5) (a) Cane, D. E.; Bowser, T. E. Bioorg. Med. Chem. Lett. 1999, 9,
1127–1132. (b) Zhao, Z.; Chen, H.; Li, K.; Du, W.; He, S.; Liu, H.-w.
Biochemistry 2003, 42, 2089–2103.
(6) (a) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433–442.
(b) Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 107, 4538–4583.
(7) Bender, D. M.; Peterson, J. A.; McCarthy, J. R.; Gunaydin, H.;
Takano, Y.; Houk, K. N. Org. Lett. 2008, 10, 509–511.
(2) (a) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871–
4880. (b) Nowlan, D. T.; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A.
J. Am. Chem. Soc. 2003, 125, 15902–15911. (c) Doyle, M. P. J. Org. Chem.
2006, 71, 9253–9260. Howell, J. A. S. Dalton Trans. 2007, 3798–3803.
(8) Zhou, S.; Zemlicka, J.; Kern, E. R.; Drach, J. C. Nucleosides
Nucleotides Nucleic Acids 2007, 26, 231–43.
10.1021/ol9017968 CCC: $40.75
Published on Web 08/27/2009
 2009 American Chemical Society

Scheme 1
Table 1. Cyclopropanation of Monosubstituted Allenes
allene
R
product
% yield
% ee
1a
1b
1c
1d
a
Ph
3a
3b
3c
3d
76
61
60
54
90
84
p-ClC6H4
C5H11
CH2Ph
1
88
>80a
Estimated by H NMR in the presence of (+)-Eu(hfc)3.
of a second substituent to the allene had a profound effect
on reactivity. The reaction of 1-methyl-1-phenylallene, 5a,
under our conditions for cyclopropanation (Table 2) gave
only a trace of allene cyclopropanation and at least three
different products from reaction of the carbenoid with the
solvent.9 However, use of hexane as solvent gave a good
yield of benzylidene cyclopropane 3a. Though toluene is a
useful solvent for alkene cyclopropanation, the ability of
toluene to compete for the carbenoid when an allene is the
substrate, presumably via aromatic ring cyclopropanation
and/or R-methyl C-H bond insertion, suggests that reaction
of the allene is significantly slower than what is typically
seen for cyclopropanation of monosubstituted alkenes.2b,10
Under standard conditions, good yields of 3a were
reproducible, giving material of 90% ee. Compound 3a could
be recrystallized to greater than 99% ee.11 The E-alkene
geometry and the (R)-absolute configuration of 3a were
confirmed by single-crystal X-ray analysis (Figure 1). The
Table 2. Cyclopropanation of 1,1-Disubstituted Allenes
allene
R
R′
product
% yield
% ee
5a
5b
5c
Ph
CH3
(CH3)3Si
CH3
CH3
CH3
6a
6b
6c
33
30
79
86
90
85
the expected cyclopropane product, 6a, in 33% yield, the
other observed products being alkene and azine byproducts
derived from the diazoacetate starting material. Only a single
alkene geometry was observed in the crude reaction mixture,
and this was assigned the E configuration by analogy to 3a.
The reduced yield of 6a may be attributed to a decrease
in cyclopropanation rate due to the added methyl group.
Whereas a simple alkene can approach the carbenoid face-
on in a concerted transition state and project substituents
away from the reactive center, the 1,1-disubstituted allene
would project one of its groups away from, and one toward,
Figure 1. ORTEP drawing of (R)-3a.
1
(9) Inseparable byproducts were tentatively identified by H NMR and
GCMS.
(10) Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem.
2002, 67, 4165–4169.
(R)-stereocenter of 3a is consistent with the expected
approach of the substrate to the re face of the carbenoid
formed by the reaction of 2 and 4.2b
(11) A solution of 4 (0.01 mmol) and 1a (1.75 mmol) in hexane (2 mL)
was stirred at rt while a solution of 2 (1.15 mmol) in hexane (4 mL) was
added dropwise over 1 h. After stirring at rt overnight, the reaction was
concentrated at reduced pressure and chromatographed in 10% Et2O/ pet.
ether to give 0.87 mmol (76% yield) of 3a in 91% ee as a white solid: Rf
0.26 (10% Et2O/hexane); HPLC (RR-Whelk, 5% isopropanol/hexane), tR
As seen in Table 1, other monosubstituted allenes gave
similar yields and enantioselectivities. Chlorophenyl allene 1b
gave 61% yield and 84% ee. Alkyl-substituted allenes were
satisfactory substrates for cyclopropanation, giving 3c and 3d
in 60% yield and 88% ee and 54% yield and >80% ee,
respectively. In all of these reactions, NMR analysis revealed
a single alkene geometry, and 3b-d are all assigned E-alkene
configuration by analogy to that seen for compound 3a.
Although the nature of the substituent on allenes 1a-d
had minimal effect on the cyclopropanation reaction, addition
1
(major) 12.5 min, tR (minor) 18.2 min. H NMR (250 MHz) δ 7.50-7.57
(2H, m), 7.44 (2H, d, J ) 8.5 Hz), 7.22-7.40 (5H, m), 7.07 (1H, t, J ) 2.6
Hz), 3.67 (3H, s), 2.76 (1H, dd, J ) 9.4, 2.6 Hz), 1.99 (1H, dd, J ) 9.4,
2.6 Hz); 13C NMR (63 MHz). δ: 171.9 (C), 137.0 (C), 136.2 (C), 131.3
(CH), 130.8 (CH), 128.6 (CH), 127.9 (CH), 127.2 (CH), 126.7 (C), 121.4
(C), 120.1 (CH), 52.6 (CH3), 29.5 (C), 21.5 (CH2). IR (neat) cm-1: 3027,
2950, 1727, 1242. EIMS (70 eV) m/z: 342, 327, 205 (100). Anal. calcd for
C18H15BrO2: C, 62.99; H, 4.41. Found: C, 63.01; H, 4.32. Recrystallization
from warm hexane gave colorless needles: mp 119-122 °C; 99.6% ee;
25
[R]D +67.4 (c 1.0, CHCl3).
Org. Lett., Vol. 11, No. 19, 2009
4435

the approaching carbenoid. In this hypothesis, a second group
on the allene, even a methyl group, slows cyclopropanation
to the point that the diazoacetate competes more successfully
for the carbenoid, resulting in decreased yield and increased
byproduct. A similar decreased yield was observed for the
reaction of 1,1-dimethylallene, 5b, supporting the idea that
a methyl group represents sufficient steric bulk to interfere
with approach of the carbenoid.
In contrast to the reduced yields for 5a and 5b, 1-methyl-
1-(trimethylsilyl)allene, 5c, reacted cleanly under standard
conditions giving 6c in 79% yield and 85% ee. The silyl
allene substrate appears to be subject to significant rate
enhancement despite the steric hindrance caused by the
methyl substituent. This idea is supported by results of a
competition reaction between allenes 5c and 5b (eq 2). An
equimolar mixture of these substrates was allowed to react
with 0.1 equiv of diazoacetate 2 in the presence of catalyst
4. The crude reaction mixture was analyzed by NMR and
found to contain a 14:1 mixture of ACP products 6c and
6b. The silyl substituent is thus responsible for a more than
10-fold increase in cyclopropanation rate compared to the
methyl substituent.
Figure 2. Transition state model TS1. Allene Cyclopropanation
Model: A. DFT transition state model (B3LYP/LANL2DZ) of 1,2-
butadiene reacting with the carbenoid derived from methyl 2-diazo-
3-butenoate. B. Generalized TS model indicating buildup of positive
charge on the central carbon of the allene. Calculated bond lengths
(Å) and potential steric interactions with an allene substituent when
R2 * H are indicated.
The asynchronicity in TS1 would place partial positive
charge at the central carbon of the allene during the reaction.
In the case of allene 5c, the model has the Si-C bond at the
R1 position antiperiplanar to the forming cyclopropane C-C
bond, which would be well placed to provide stabilization
of this electron-deficient orbital through hyperconjugation.
Such an effect would rationalize the large rate enhancement
observed in the silyl allene cyclopropanation data.
The mechanistic model approximated by TS1 justifies the
high diastereoselectivity seen for monosubstituted allenes,
wherein a group, R1, projects away from the reaction center,
while a hydrogen (R2 ) H) projects directly toward it. For
1,1-disubstituted allenes where R1 is larger than R2, high
diastereoselectivity is still achieved, but the yields suffer due
to rate retardation and competition for the carbenoid.
In summary, we have reported the enantioselective cyclo-
propanation of monosubstituted allenes using methyl aryl-
diazoacetates mediated by the rhodium tetraprolinate catalyst,
Rh2(S-DOSP)4. Substitution with silicon on the allene
substrate has a strong accelerating effect on the reaction.
Steric, inductive, and hyperconjugative effects of allene
substituents in cyclopropanation are currently under inves-
tigation, and these and their correlation with a refined
computational model will be reported at a later time.
Davies reported electronic effects of para-substituents on
cyclopropanation of styrene derivatives, finding a good
correlation with σ+ Hammett substituent constants.8 This
direct resonance effect, interpreted as acting on partial
positive charge buildup at the benzylic position in the styrene
transition state, is not expected to apply in aryl allene
cyclopropanation due to the intervening orthogonal π-bond
separating the ring from the reacting π-bond. In the case of
substrate 5c, however, silicon hyperconjugation could be
providing analogous stabilization of positive charge and thus
the observed cyclopropanation rate increase.
To clarify the potential of steric and electronic effects to
influence the rate and diastereoselectivity of cyclopropana-
tion, we used DFT methods to investigate the transition state
for allene cyclopropanation. As a simplified model system,
we considered the reaction of 1,2-butadiene with methyl
2-diazo-3-butenoate. Transition state optimization using
Gaussian0312 gave structure TS1, illustrated in Figure 2,
wherein both cyclopropane bonds are forming simulta-
neously, though bonding at the allene terminal carbon is
significantly more advanced (C-C bond distance: 2.3 Å) than
that at the adjacent carbon (C-C bond distance: 2.8 Å). Bond
lengths in this model are consistent with a model for styrene
cyclopropanation that correlated well with observed kinetic
isotope effects (C-C bond distances were 2.4 and 2.9 Å).2b
Acknowledgment. We thank Huw Davies of Emory
University for a generous gift of Rh2(S-DOSP)4 catalyst and
Mateusz Pitak of the University at Buffalo for X-ray
crystallographic analysis. This work was supported by
Canisius College and a Howard Hughes Interdisciplinary
Research Fellowship to MKF.
Supporting Information Available: Experimental pro-
cedures, full characterization data for new compounds, and
atomic coordinates for TS1. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Frisch, M. J. Gaussian 03, revision B.05. The full citation,
coordinates, and computational details are found in the Supporting Informa-
tion.
OL9017968
4436
Org. Lett., Vol. 11, No. 19, 2009