Organic-catalyst-mediated cyclopropanation reaction

Article abstract of DOI:10.1002/anie.200390222

A catalytic ammonium ylide based cyclopropanation process forms trans-disubstituted cyclopropanes in good yield upon reaction with electron-deficient alkenes (see scheme; EWG = electron-withdrawing group). The reaction is also highly enantioselective when

Full text of DOI:10.1002/anie.200390222

Communications
Table 1: Optimization of reaction conditions.[a]
Organocatalytic Cyclopropanation
Organic-Catalyst-Mediated Cyclopropanation
Reaction**
Solvent
Base
t [h]
Yield[b]
d.r.
(trans:cis)[c]
Charles D. Papageorgiou, Steven V. Ley, and
Matthew J. Gaunt*
MeCN
THF
DCE
DMSO
CH2Cl2
MeCNKOH
MeCN
MeCN
MeCNDABCO
MeCNEt
NaOH
NaOH
NaOH
NaOH
NaOH
6
96%
66%
73%
54%
65%
>95:5
15:1
>95:5
>95:5
>95:5
3.5
19
1.5
4.5
Cyclopropane units are a fundamental class of functional
group that are the focus of many organic synthesis programs
and perform a key structural role in a range of bioactive
natural and nonnatural molecules.[1] The importance of
cyclopropanes is reflected in the enormous effort that has
been invested in their diastereo- and enantioselective syn-
thesis.[1,2]
[d]
4.5
68%
15:1
Na2CO3
DBU
25
16
24
79%
87%
5%
>95:5
>95:5
>95:5
>95:5
[e]
3N24
10%
[a] Salt 1, acrylate 2a (1 equiv), base (2 equiv), solvent (0.25m), 808C (oil
Recently, a strong emphasis has been placed on the
development of catalytic methods to generate cyclopropanes.
While there have been significant advances in the develop-
ment of catalytic versions of the Simmons–Smith and carbene
transfer reactions, there are few reports of catalytic methods
based on the reaction of ylides with electron-deficient
alkenes.[2] The use of ylides as cyclopropanation reagents
dates back to work by Corey et al.[3] Of the many develop-
ments that have since been reported, the contributions from
the groups of Hanessian,[4] Dai and Tang,[5] and Aggarwal[6]
deserve special mention. In these processes, however, the
ylide precursor is usually generated in a separate step and
there is only one reported process that is catalytic in the ylide
species.[6,7]
We were interested in utilizing a nitrogen ylide to effect a
cyclopropanation reaction. Surprisingly, there are relatively
few examples that employ nitrogen-derived ylides.[8,9] An
ammonium ylide based reaction becomes an attractive target
for a general diastereo- and enantioselective cyclopropana-
tion process owing to the vast range of tertiary amines that are
commercially available. In this communication we describe
the development of a stoichiometric “one-pot” ammonium
ylide based cyclopropanation process and our initial studies
towards an enantioselective reaction. We also report the
development of the first catalytic cyclopropanation reaction
involving ammonium ylides where the catalyst is a tertiary
amine.
bath temperature). [b] Yield of isolated product after chromatography.
[c] Determined by H NMR spectroscopy. [d] Reaction stirred at 458C.
[e] 2.5 equiv of DABCO was used. DABCO=1,4-diazobicyclo[2.2.2]oc-
tane, DCE=1,2-dichloroethane, DBU=1,8-diazabicyclo[5.4.0]undec-7-
ene.
1
tert-butyl acrylate (2a) formed cyclopropane 3a in varying
yields depending on the conditions employed; the best results
are highlighted in Table 1. Of crucial importance was the
temperature, with little or no reaction observed at room
temperature. However, at 808C the reaction produced the
highest yield of trans-disubstituted cyclopropane. It is im-
portant to note that the corresponding reaction between
phenacyl chloride (instead of salt 1) and acrylate 2a does not
form the cyclopropane.[10]
To increase the efficiency of this process we investigated
the development of a stoichiometric “one-pot” cyclopropa-
nation reaction, in which the ammonium salt and hence the
ylide could be generated in situ from readily available starting
materials. Accordingly, DABCO (5) was added to phenacyl
chloride (4) in acetonitrile followed by the base and alkene
2a, and the reaction mixture was stirred at 808C. After 18 h,
cyclopropane 3a was isolated in 79% yield after chromatog-
raphy as a single diastereoisomer (Scheme 1).[11] It is note-
We began our study by investigating the reactivity of
preformed quaternary ammonium salts such as 1 as nitrogen
ylide precursors. Treatment of salt 1 with base followed by
N
1 equiv
5
N
O
O
OtBu
Cl
Ph
Ph
2a, NaOH, MeCN, 80 °C
4
79 %
3a
O
[*] Dr. M. J. Gaunt, C. D. Papageorgiou, Prof. Dr. S. V. Ley
University Chemical Laboratory
Scheme 1. One-pot cyclopropanation.
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)1223-336-442
E-mail: mjg32@cam.ac.uk
worthy that the reaction proceeds without the formation of
byproducts, and simple aqueous workup affords pure cyclo-
propane (1H NMR spectroscopy, LCMS) that does not
necessarily require further purification.
A stoichiometric “one-pot” cyclopropanation reaction
offers significant advantages over other similar methods as it
precludes the necessity to generate and isolate the ylide
precursor (1) in a separate step. The general utility of this
[**] We gratefully acknowledge financial support from the EPSRC and
Pfizer Global Research and Development (Sandwich, UK) for
Industrial Case Award (to C.D.P.), the Novartis Research Fellowship
(to S.V.L.), and the British Ramsay Memorial Trust and Magdalene
College for Research Fellowship (to M.J.G.). We also thank Dr. A. J.
Morrison for helpful advice and discussion.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Scope of reaction.
they are a potential source of chir-
ality for an enantioselective cyclo-
propanation reaction. The chiral
quaternary ammonium salt 11 was
readily formed in situ from the
addition of phenacyl bromide (8)
to amine 9.[14] Subsequent addition
of acrylate 2a and sodium hydrox-
ide (2 equiv), and stirring the reac-
tion at 808C for 24 h generated
cyclopropane (þ)-3a in 61% yield
(Table 3). The enantiomeric ratio
(e.r.) from this initial reaction was
91.5:8.5 (83% ee), as determined by
chiral HPLC.[15] While this result
displayed excellent enantioselectiv-
ity we were concerned for the
enantiomeric integrity of the cyclo-
propane in the reaction mixture. By
monitoring the e.r. over the course
of the reaction, we observed an
erosion in the enantiomeric purity
of the cyclopropane (Table 3, en-
try 1). However, reducing the
amount of base in the reaction to
1.3 equivalents generated (þ)-3a in
57% yield with an e.r. of 97:3
(94% ee). Furthermore, using dihy-
drocinchonine derivative 10 under
our modified reaction conditions
formed the opposite enantiomer,
(ꢀ)-3a, in 58% yield and an e.r. of
97:3 (94% ee). To the best of our
knowledge these are the first exam-
ples of an enantioselective cyclo-
propanation reaction based on a
chiral ammonium ylide. We are
currently screening the range of
alkenes and other chiral tertiary
Entry
a-Chloro-
carbonyl
Acceptor
Conditions[a]
Yield[b]
79%
Product
d.r.
(trans:cis)[c]
1
2
3
4
NaOH, MeCN
>95:5
>95:5
>95:5
>95:5
4
4
4
Na2CO3, MeCN77%
Na2CO3, MeCN96%
NaOH, THF
73%
5
6
4
4
NaOH, MeCN
81%
78%
>95:5
Na2CO3,
THF/DMSO
2.3:1
7
8
4
Na2CO3, MeCN40%
Na2CO3, MeCN70%
4.3:1
2c
2c
>95:5
9[d]
Na2CO3, MeCN70%
>95:5
[a] a-Chlorocarbonyl, DABCO (1.0 equiv), MeCN(0.25 m), room temperature, 30 min, then alkene
(1 equiv), base (1.5 equiv), 808C. [b] Yield of isolated product after chromatography. [c] Determined by
1H NMR spectroscopy. [d] Preformed salt 1 was used in this reaction.
process was demonstrated across a range of substrates which
established the efficacy of this new and versatile cyclopropane
Table 3: One-pot enantioselective cyclopropanation.
methodology (Table 2). The reaction worked well for a range
of alkenes, with acrylates 2a and 2b, enone 2c, acrylamide 2d,
and vinyl sulfone 2e all forming only the trans-substituted 1,2-
cyclopropanes 3a–3e in good to excellent yield.[12] Acryloni-
trile (2 f) gave a mixture of cyclopropanes (3 f; 2.3:1, trans:cis)
in good yield, although some polymerization was observed.
Acrolein (2g) also gave a separable mixture of cyclopropanes
(3g; 4.3:1, trans:cis) in 40% yield when the preformed salt 1
was used. Ammonium ylide species bearing other functional
groups were also investigated and produced cyclopropanes in
good yield (entries 8 and 9, Table 2). Ketone 7 formed
spiro[2.4]heptane derivative 3i as a single diastereomer when
reacted with 3 equivalents of 2c.
Entry[a]
1
Chiral
amine
equiv
NaOH
t [h]
Yield[b]
e.r. (ee)[c]
9
2
8
10%
46%
61%
57%
58%
97:3 (94) (þ)
92:8 (84) (þ)
91.5:8.5 (83) (þ)
97:3 (94) (þ)
97:3 (94) (ꢀ)
16
24
24
24
2
3
9
10
1.3
1.3
The simplicity of the one-pot ammonium ylide approach
to cyclopropanation should allow the use of any tertiary
amine.[13] DABCO (5) was chosen as a model tertiary amine
to mimic the core structure of the cinchona alkaloids because
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amine via an ammonium ylide intermediate, by using readily
available starting materials. We have demonstrated that this
reaction is both diastereo- and enantioselective and that the
reaction can be made catalytic.[18] We are currently exploring
the scope of an asymmetric process with the goal of
developing a catalytic enantioselective cyclopropanation
reaction. Furthermore, application of this methodology to
an intramolecular cyclopropanation system and to the syn-
thesis of small-ring heterocycles is also being explored.
Received: October 14, 2002 [Z50353]
[1] For reviews, see: a) J. Salaun, Chem. Rev. 1989, 89, 1247; b) A.-
H. Li, L.-X. Dai, V. K. Aggarwal, Chem. Rev. 1997, 97, 2341;
c) A. Pfaltz in Comprehensive Asymmetric Catalysis II (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yammamoto), Springer, Berlin,
1999, pp. 513 – 538.
Scheme 2. Proposed catalytic cycle for cyclopropanation.
[2] For recent developments, see: W. A. Donaldson, Tetrahedron
2001, 57, 8589, and references therein. For other examples see
ref. [1].
[3] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353;
E. J. Corey, M. Jautelat, J. Am. Chem. Soc. 1967, 89, 3912.
[4] S. Hanessian, D. Andreotti, A. Gomtsyan, J. Am. Chem. Soc.
1995, 117, 10393.
[5] S. Ye, Z.-Z. Huang, C.-A. Xia, Y. Tang, L.-X. Dai, J. Am. Chem.
Soc. 2002, 124, 2432.
[6] V. K. Aggarwal, A. Thompson, R. V. H. Jones, Chem. Commun.
1997, 1785 and ref. [7]. See also A. Solladie-Cavallo, A. Diep-
Vohuule, T. Isarno, Angew. Chem. 1998, 110, 1824; Angew.
Chem. Int. Ed. 1998, 37, 1689.
amines to investigate the scope of this new enantioselective
process.
With an efficient stoichiometric one-pot cyclopropanation
reaction in hand, we next investigated a catalytic process.
Examination of a possible reaction mechanism suggests that
the amine 12 should be released at the end of the reaction
when the cyclopropane ring forms (Scheme 2).[16] Thus, in
principle it should be possible to use the tertiary amine in
catalytic quantities without fear of a competing background
reaction. Accordingly, stirring a mixture of phenacyl chloride
(4), 2c (3 equiv),[17] sodium carbonate (1.2 equiv) and DAB-
CO (0.2 equiv) in acetonitrile at 808C for 24 h produced
cyclopropane 3c in 82% yield. tert-Butyl acrylate (2a) and
vinyl sulfone 2e also produce cyclopropanes 3a and 3e,
respectively, under catalytic conditions (Table 4). In the
absence of DABCO little or no reaction takes place which
proves that the tertiary amine is required as a catalyst. We are
currently exploring the scope of the reaction to develop a
general catalytic cyclopropanation reaction based on ammo-
nium ylides.
[7] a) V. K. Aggarwal, E. Alonso, G. Fang, M. Ferrara, G. Hynd, M.
Porcelloni, Angew. Chem. 2001, 113, 1482; Angew. Chem. Int.
Ed. 2001, 40, 1433; b) V. K. Aggarwal, H. W. Smith, G. Hynd,
R. V. H. Jones, R. Fieldhouse, S. E. Spey, J. Chem. Soc. Perkin
Trans. 1 2000, 3267.
[8] I. Zugravescu, M. Petrovanu, N-Ylid Chemistry, McGraw-Hill,
New York, 1976.
[9] a) S. S. Bhattacarjee, H. Ila, H. Junjappa, Synthesis 1982, 301;
b) A. Jonczyk, A. Konarska, Synlett 1999, 1085; for other
examples, see c) N. H. Vo, C. J. Eyermann, C. N. Hodge,
Tetrahedron Lett. 1997, 38, 7951; d) A. M. Shestopalov, V. P.
Litvinov, L. A. Rodinovskaya, Y. A. Sharanin, Zh. Org. Khim.
1991, 27, 146.
In summary, we have developed a practical and general
“one-pot” cyclopropanation process, mediated by a tertiary
[10] When Na2CO3 is used as the base, no reaction is observed. When
NaOH is used, decomposition is
Table 4: Initial results for a catalytic cyclopropanation.[a]
observed.
[11] All compounds were characterized
1
by H and 13C NMR spectroscopy,
high-resolution mass spectrometry
and infrared spectroscopy.
[12] trans-Stereochemistry was con-
a-Chlorocarbonyl
Acceptor
Yield[b]
69
Product
d.r. (trans:cis)[c]
firmed in 3a by hydrolysis of the
tert-butyl ester and comparison
with an authentic sample, and in
>95:5
3e by X-ray crystal-structure anal-
ysis.
[13] We also found that using quinucli-
4
4
82[d]
63
>95:5
dine in place of DABCO produced
3a in similar yield.
[14] Phenacyl chloride did not react
with the more hindered chiral
amine.
>95:5
[15] See supporting information for de-
tails chiral HPLC analysis.
[16] No cyclopropane formation was
observed when the reaction was
[a] Phenacyl chloride, DABCO (0.2 equiv), alkene (1.5 equiv), Na2CO3 (1.2 equiv), MeCN(0.25 m), 808C,
24 h. [b] Yield of isolated product after chromatography. [c] Determined by H NMR spectroscopy.
[d] 3 equiv Of 2c was used.
1
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carried out with styrene instead of the electron-deficient alkenes
which suggests that the reaction does not proceed through a
carbene mechanism.
[18] For an overview of organocatalysis, see: P. I. Dalko, L. Moisan,
Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. 2001, 40,
3726.
[17] In the case of methyl vinyl ketone, 3.0 equiv was used because of
its volatility. In the other cases only 1.5 equiv of the alkene was
used.
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