Stereoselective synthesis of cis-2-aryl- and 2-alkyl-1-chlorocyclopropanecarboxaldehydes

Article abstract of DOI:10.1016/S0040-4039(01)02228-6

The title compounds were stereoselectively synthesized via a semi-benzilic Favorskii rearrangement of 3-aryl- and 3-alkyl-2,2-dichlorocyclobutanols, obtained by stereoselective reduction of the corresponding cyclobutanones. This synthetic pathway, starting from the synthesis of 3-substituted-2,2-dichlorocyclobutanones can be performed in one day with total yields up to 60% after purification. Reduction of the cyclobutanones yielded only cis-3-substituted cyclobutanols. Taking into account the stereoselectivity of the rearrangement, 1-halocyclopropanecarboxaldehydes, of which very few articles have been published, can be seen as highly interesting building blocks for further elaboration.

Full text of DOI:10.1016/S0040-4039(01)02228-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 599–602
Stereoselective synthesis of cis-2-aryl- and
2-alkyl-1-chlorocyclopropanecarboxaldehydes
Guido Verniest,a Filip Bombeke,a O. G. Kulinkovichb and Norbert De Kimpea,*
aDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University,
Coupure Links 653, B-9000 Gent, Belgium
bDepartment of Chemistry, Belarussian State University, Fr. Skariny Av. 4, Minsk 220050, Belarus
Received 24 October 2001; revised 20 November 2001; accepted 22 November 2001
Abstract—The title compounds were stereoselectively synthesized via a semi-benzilic Favorskii rearrangement of 3-aryl- and
3-alkyl-2,2-dichlorocyclobutanols, obtained by stereoselective reduction of the corresponding cyclobutanones. This synthetic
pathway, starting from the synthesis of 3-substituted-2,2-dichlorocyclobutanones can be performed in one day with total yields up
to 60% after purification. Reduction of the cyclobutanones yielded only cis-3-substituted cyclobutanols. Taking into account the
stereoselectivity of the rearrangement, 1-halocyclopropanecarboxaldehydes, of which very few articles have been published, can be
seen as highly interesting building blocks for further elaboration. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
a-halogenated cyclopropanecarboxaldehydes were (less
efficiently) accessible via dihalocarbene addition to O-
protected 2-halopropen-1-ols10 or via a lithium–halogen
exchange of geminal dihalocyclopropanes (synthesized
via dihalocarbene addition to olefins) and subsequent
reaction with formates or formamides.11–13 Also, oxida-
tion of mixtures of stereoisomers of 1-halocyclopropyl-
methanol derivatives leads to the corresponding
a-halogenated aldehydes.14 Another approach consists
of a carbene addition to a-haloacrylates or deriva-
tives.15–17 With the latter method 5-(1-halocyclopropyl)-
2,4-dienamides were synthesized and are patented as
acaricidal and insecticidal compounds.18,19
Readily available 2-halogenated cyclobutanones exhibit
interesting properties for ring transformation due to
their pronounced electrophilicity and ring strain. This is
proved by the numerous reactions described in the
literature,1 among which the well-known Favorskii
rearrangement has been used to synthesize cyclo-
propanecarboxaldehydes.2–9 Surprisingly, only very few
publications are found to exist regarding 1-halocyclo-
propanecarboxaldehydes, which are interesting building
blocks for further organic synthesis. In most cases the
synthetic pathways have no stereochemical impact, thus
chromatographic separation of the formed isomers is
required. Only two publications were found concerning
ring contraction of 2,2-dihalocyclobutanones towards
2. Results and discussion
1-halocyclopropanecarboxaldehydes.
One
article
describes the Favorskii rearrangement after chromato-
graphic separation of a diastereomeric mixture of
steroidal spirocyclobutanones towards the correspond-
ing spirocyclopropane steroids8 and a second publica-
tion deals with the ring contraction of 7,7-dichloro-
3-Substituted-2,2-dichlorocyclobutanones 2a–c were
easily synthesized via a [2+2]-cycloaddition of olefins
1a–c to dichloroketene, generated from trichloroacetyl
chloride and a Zn–Cu couple20 (Scheme 1). The
bicyclo[3.2.0]hept-2-en-6-one
(the
dichloroketene
1.05 equiv. Cl3CCOCl
adduct of cyclopentadiene).9 With our research, a gen-
eral, easy synthesis of 2-substituted 1-halocyclo-
propanecarboxaldehydes is established. Up to now,
O
1.05 equiv. POCl3
1.1 equiv. Zn-Cu
R
R
Cl
Cl
1a R = Ph
ether, ∆, 4 h
1b R = 4-Cl-C6H6
1c R = n-Bu
Keywords: cyclopropanes; 1-chlorocyclopropanecarboxaldehydes;
Favorskii rearrangement; cyclobutanones.
2a-c 74-80%
* Corresponding author. Tel.: +32 9 264 59 51; fax: +32 9 264 62 43;
e-mail: norbert.dekimpe@rug.ac.be
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02228-6

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G. Verniest et al. / Tetrahedron Letters 43 (2002) 599–602
cyclobutanones 2a,b thus obtained, were treated with
reducing agents to give the corresponding 3-aryl-2,2-
dichlorocyclobutanols 3 in a stereoselective way as
shown in Scheme 2.
In order to determine unambiguously the stereochem-
istry by DIFNOE-NMR techniques, cyclobutanol 3b
was derivatized to the 3,5-dinitrobenzoate. In the case
of 2,2-dichloro-3-(4-chlorophenyl)cyclobutyl 3,5-dinitro-
benzoate 5 (yield 90% from 3b) a significant Over-
hauser effect was observed between the hydrogen atoms
in the 1- and 3-positions of the cyclobutane ring, which
indicated that both hydrogens are positioned in cis-
configuration (Fig. 1).
Scheme 2.
Reductions of non-halogenated 3-substituted cyclobu-
tanones were previously described in the literature,
where the resulting alcohols were mixtures of iso-
mers.21,22 In our experiments, reduction of the cyclobu-
tanones 2a,b with LiAlH4 or LiAlH(OtBu)3 yielded
only cis-3-arylcyclobutanols 3 in yields around 60%.
HPLC-separation of the crude reaction mixture from
the reduction of cyclobutanone 2a resulted in the isola-
tion and characterization of 2-chloro-3-phenylcyclobu-
tanol 4a as a minor byproduct. A slight difference in
the ratio of 3/4 was observed when the reaction was
carried out using an excess of LiAlH4, LiAlH(OtBu)3 or
NaBH4. The ratio determined by gas chromatographic
analysis was 85/15, 93/7 and 94/6, respectively.
Figure 1.
In order to perform a ring contraction of cis-cyclobu-
tanols 3, the latter were treated with a 1 M solution of
sodium hydroxide in water. The reduction of cyclobu-
tanones 2 and subsequent ring contraction can be per-
formed in one step, without purification of the
cyclobutanols, by first adding NaBH4 to the ketones 2
in methanol at 0°C and after an appropriate time,
a basic workup (Scheme 4). When the reducing agent
was added at higher temperatures, formation of a
minor amount of 1-chlorocylopropylmethanols 7 was
observed due to overreduction. This compound can
also be obtained in high yield by reduction of the
a-halogenated aldehydes 6 with NaBH4 in methanol at
0°C.
The stereoselectivity of the reaction is not due to an
exo-attack of hydride, but due to steric hindrance of
the substituent in the 3-position. This effect appears to
be more important than the favorable exo-attack of
hydride to the cyclobutane ring with the substituent in
the equatorial position, as shown in Scheme 3. exo-
Attack yielding cis-substituted cyclobutanols is only
possible when the substituent is in the thermodynami-
cally less favorable axial position.
Conia and Salau¨n2,4 demonstrated in 1972 that the
mechanism of the ring contraction of halogenated
cyclobutanols involves a semi-benzilic Favorskii rear-
rangement where the hydroxyl function must be in the
equatorial position.23 The stereochemistry of the
obtained cyclopropanecarboxaldehydes 6 was analyzed
via DIFNOE experiments.
H
H
1 equiv. NaBH4
O
R
Cl
2a,b,c
B- +Na
CH3OH, 0 °C, 2 h
Cl
4
excess
NaOH 1 M
H
O
R
H
Cl
6a,b,c 92-99%
Scheme 4.
Scheme 3.

G. Verniest et al. / Tetrahedron Letters 43 (2002) 599–602
601
After distillation of cyclopropanecarboxaldehydes 6,
storage under inert atmosphere is needed, because after
a while auto oxidation of the aldehydes takes place.
Because no further reactions on 1-halocyclopropanecar-
boxaldehydes have been described, some simple trans-
formations were performed leading to alternative routes
to substituted cyclopropanes 7, 8 and 9. Controlled
oxidation of the aldehydes and subsequent esterification
was possible with sodium dichromate in acidic medium
followed by normal esterification procedures (Scheme
5).
eV): m/z (%): 180/82 (M+, 33); 145 (100); 127 (29), 117
(33), 116 (25), 115 (83), 91 (32).
3.1. 1-Chloro-2-phenylcyclopropanecarboxylic acid 8
Colorless solid, mp: 76.7°C, spectral data: 1H NMR
(CDCl3, 270 MHz): l 1.84 (dd, J=5.9; 8.6 Hz, 1H),
2.23 (dd, J=5.9; 10.2 Hz, 1H), 3.17 (dd, J=9.5 Hz 2×,
1H), 7.21–7.39 (m, 5H); 13C NMR (CDCl3, 68 MHz,
int. ref. 77.00 ppm): l 24.0, 34.7, 44.2, 127.8, 128.2,
129.4, 133.8, 177.0; IR (KBr, cm−1): 3414, 1693, 1636,
1617, 1498; MS (70 eV): m/z (%): 196/98 (M+, 20); 116
(44), 115 (100).
In conclusion, this paper describes an efficient and
facile synthesis to cis-2-substituted 1-chlorocyclo-
propanecarbox-aldehydes 6 and derived products 7–9 in
a stereoselective way. Keeping in mind the physiologi-
cal activity of 2-halogenated cyclopropyldienamides
and the very few articles published about this subject,
this pathway provides interesting results for further
elaboration of the cyclopropane chemistry.
3.2. Methyl 1-chloro-2-phenylcyclopropanecarboxylate 9
Colorless oil, Rf=0.38 (ethyl acetate/hexane:10/90),
1
spectral data: H NMR (CDCl3, 270 MHz): l 1.78 (dd,
J=5.9; 8.6 Hz, 1H), 2.16 (dd, J=5.9; 10.2 Hz, 1H),
3.09 (dd, J=9.4 Hz 2×, 1H), 3.84 (s, 3H), 7.21–7.39 (m,
5H); 13C NMR (CDCl3, 68 MHz, int. ref. 77.00 ppm):
l 22.8, 33.2, 44.2, 52.8, 127.1, 127.7, 128.9, 133.9, 169.9;
IR (KBr, cm−1): 1724, 1606, 1500, 1437, 1283; MS (70
eV): m/z (%): 210/2 (M+, 33); 178 (17), 174 (17), 131
(25), 116 (19), 115 (100).
3. Experimental
A typical procedure for the synthesis of aldehydes
6a,b,c can be given with 1-chloro-2-phenylcyclo-
propanecarboxaldehyde 6a as an example. To a cooled
solution of 1.0 g (4.65 mmol) 2,2-dichloro-3-phenylcy-
clobutanone 2a in 10 ml of methanol, 1 equiv. (0.18 g)
of sodium borohydride was added in portions at 0°C.
After stirring for 2 h at 0°C, 30 ml of a 1 M solution of
sodium hydroxide in water was added and stirred for
another 15 min at room temperature. After extraction
of the reaction mixture with chloroform (3×20 ml),
drying of the combined organic layers and evaporating
of the solvent, a colorless oil was obtained in 100%
yield. To remove impurities, aldehyde 6a can be dis-
Acknowledgements
The authors are indebted to the IWT and Ghent Uni-
versity (GOA) for financial support.
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