A new facile method for the stereoselective synthesis of trans-2-aryl-3,3-dimethylcyclopropane-1-carboxylic acids

Article abstract of DOI:10.1016/S0040-4039(01)01224-2

A new facile method for the preparation of trans-2-aryl-3,3-dimethylcyclopropane-1-carboxylic acids was developed. The new method involved [2+2]-cycloaddition of styrenes with N,N,2-trimethylpropionamide followed by bromination and rearrangement of the resulting 3-aryl-2,2-dimethylcyclobutanones, affording the title compounds in two steps in 60-84% overall yields.

Full text of DOI:10.1016/S0040-4039(01)01224-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6227–6229
A new facile method for the stereoselective synthesis of
trans-2-aryl-3,3-dimethylcyclopropane-1-carboxylic acids
Bang-Chi Chen,* Khehyong Ngu, Peng Guo, Wen Liu, Joseph E. Sundeen, David S. Weinstein,
Karnail S. Atwal and Saleem Ahmad*
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
Received 30 April 2001; accepted 5 July 2001
Abstract—A new facile method for the preparation of trans-2-aryl-3,3-dimethylcyclopropane-1-carboxylic acids was developed.
The new method involved [2+2]-cycloaddition of styrenes with N,N,2-trimethylpropionamide followed by bromination and
rearrangement of the resulting 3-aryl-2,2-dimethylcyclobutanones, affording the title compounds in two steps in 60–84% overall
yields. © 2001 Elsevier Science Ltd. All rights reserved.
2-Aryl-3,3-dimethylcyclopropane-1-carboxylic acids are
an important class of intermediates in organic synthesis.
For example, they were used in the synthesis of biolog-
ically active compounds such as fungicides,1 insecti-
cides,2–4 and acaricides.3–5 More recently, 2-aryl-3,3-
dimethylcyclopropane-1-carboxylic acids found applica-
tions in the synthesis of melatonergic agents,6 and in the
synthesis of sodium hydrogen exchanger inhibitors.7
steps as a mixture of trans/cis-isomers.10 In the fourth
approach, cinnamates and derivatives 4 were used as the
2-aryl contributing starting materials to react with an
isopropyl transfer reagent. While simple cinnamates 4
reacted successfully with diazoisopropane to give the
desired products,11 this reaction is also limited by its lack
of stereoselectivity as well as by the difficulty in generat-
ing and handling the hazardous diazopropane.11 A more
user friendly isopropyl transfer reagent used in the
cyclopropylation with 4 is i-propylidenetriphenylphos-
phorane.12 This cyclopropylation reaction was highly
stereoselective giving mainly the trans-products. The
yields were, however, poor to moderate due to side
reactions of the resulting products with i-propylidene-
triphenylphosphorane.12 While the side reactions associ-
ated with i-propylidenetriphenylphosphorane could be
minimized by using S,S-diisopropyl-N-(p-tolylsul-
fonyl)sulfoximine,13 application of the latter reagent is
hampered by its availability. A more readily available
and less expensive isopropyl transfer reagent is 2-nitro-
propane.14 Activated cinnamate derivatives 4 (Y=
CO2R, SO2R), however, were required for a successful
cyclopropylation because of the reduced reactivity of the
reagent. In addition, removal of the activating groups
(Y=CO2R, SO2R) was problematic due to side reactions
resulting from cyclopropane ring opening if a cyclo-
propane monocarboxylate product is desired.7
Consequently, a number of methods have been devel-
oped for the synthesis of 2-aryl-3,3-dimethylcyclo-
propane-1-carboxylic acids. All these methods can be
classified into four approaches according to the 2-aryl
contributing starting materials. In the first approach,
b,b-dimethylstyrenes 1 were used as the starting materi-
als. While the reaction of 1 with diazoacetate affords the
desired products, this approach is limited by the lack of
stereoselectivity of the cycloaddition reaction, in addition
to the hazards associated with diazoacetate.8 In the
second approach, a,a-dimethylacetophenones 2 were
reacted with ethyl bromoacetate to give 3,3-dimethyl-4-
aryl-g-ketoesters which were subsequently transformed
into the title compounds in four steps.9 In the third
approach, 2,2-dimethyl-3-arylbutan-2-ones 3 were used
as the starting materials, which were obtained from
benzyl halides and methyl isopropyl ketone.10 Benzylic
bromination of 3 followed by cyclobutanone ring forma-
tion and contraction gave the title compounds in three
O
O
OR
O
Me
Me
Me
Me
Me
Me
Ar
Y
Ar
Ar
Ar
Me
4
1
2
3
Y=H, CO2R, SO2R
* Corresponding authors.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01224-2

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B.-C. Chen et al. / Tetrahedron Letters 42 (2001) 6227–6229
O
O
N
1. Tf2O/collidine
1. LiHMDS/THF
2. NBS
+
2. H2O
Ar
Ar
80-95%
5
7
6
O
CO2H
3. NaOH
Ar
4. HCl
Ar
Br
9
72-88%
8
Scheme 1.
Table 1. Preparation of trans-2-aryl-3,3-dimethylcyclopropane-1-carboxylic acids 9
Entry
Ar
Product
Yield%a,b (7)
Product
Yield%a,b (9)
−
−
−
1
2
3
4
5
6
4-ClC6H4
3-ClC6H4
3-BrC6H4
7a
7b
7c
7d
7e
7f
93
80
86
80
86
95
9a
9b
9c
9d
9e
9f
76
81
80
75
72
88
−
3-MeOC6H4
3-MeO-5-ClC6H3
2-F-5-MeOC6H3
−
−
a Isolated yield by chromatography or crystallization.
b All new compounds gave satisfactory spectroscopic and analytical data.
In our program of design and synthesis of novel arylcy-
clopropanecarboxyl guanidines as potent and selective
sodium hydrogen exchanger inhibitors,7 we required
easy access to large amounts of various trans-2-aryl-
3,3-dimethylcyclopropane-1-carboxylic acids 9. While
many of the desired compounds could be prepared
using the first and fourth approaches described above,
attempts to prepare other analogs using these
approaches failed. Herein, we describe a new facile
method for the stereoselective synthesis of trans-2-aryl-
3,3-dimethylcyclopropane-1-carboxylic acids.15 Our
method begins with the readily available b,b-unsubsti-
tuted styrenes 5 as the 2-aryl contributing starting
materials (Scheme 1).15
76% isolated yield after acidification and product crys-
tallization. The reaction was highly stereoselective,
affording trans-9a as a single isomer based on HPLC
1
and H NMR analyses. Importantly, the [2+2]-cycload-
dition of styrenes 5 with 6 and subsequent bromination
and rearrangement reactions appeared to be general for
the preparation of a variety of 2-aryl-3,3-dimethylcyclo-
propane-1-carboxylic acids (Table 1). In all cases, the
product was obtained as a single trans-isomer.
In summary, a new facile method for the stereoselective
synthesis of trans-2-aryl-3,3-dimethylcyclopropane-1-
carboxylic acids was developed. The new method
involved [2+2]-cycloaddition of styrenes with N,N,2-
trimethylpropionamide followed by bromination and
rearrangement of the resulted 3-aryl-2,2-dimethylcy-
clobutanones, affording the title compounds in two
steps in 60–84% overall yields. Compared to the previ-
ous methods developed for preparation of the title
compounds, the new method not only uses more readily
available starting materials and avoids the use of haz-
ardous or difficult to obtain reagents, but is also manip-
ulatively simpler and gives higher overall yields. More
significantly, the new method is highly stereoselective,
affording the trans-product as a single isomer. The
application of trans-2-aryl-3,3-dimethylcyclopropane-1-
carboxylic acids to the synthesis of other biologically
active agents will be reported in due course.
Thus, treatment of N,N,2-trimethylpropionamide 6
with 1.1 equivalents of trifluoromethane-sulfonic anhy-
dride in methylene chloride at −15°C for 10 minutes
followed by addition of 4-chlorostyrene 5a and col-
lidine and heating the reaction mixture at reflux for 4
hours afforded 3-(4-chlorophenyl)-2,2-dimethylcyclobu-
tanone 7a in 93% isolated yield after aqueous work-
up.16 Treatment of 7a with 1.1 equivalents of LiHMDS
in THF at −78°C followed by quenching the resulted
enolate with one equivalent of N-bromo succinimide
at the same temperature and warming the reaction
mixture to 0°C for 20 minutes gave 2-bromo-
3-(4-chlorophenyl)-4,4-dimethylcyclobutanone 8a in
solution. The product 8a is expected to have the trans-
configuration as bromination of the enolate generated
from 7a should take place from the opposite side of the
4-chlorophenyl ring due to a steric effect. Addition of
aqueous sodium hydroxide to the in situ formed a-bro-
moketone 8a resulted in a fast rearrangement reac-
tion,17,18 giving the desired product 9a in one hour in
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