Cyclopropanation of allylic alcohols using substituted haloalkylzinc reagents: Synthesis of gem-Dimethylcyclopropanes

Article abstract of DOI:10.1055/s-2002-19345

gem-Dimethylcyclopropanes were obtained by a cyclopropanation of allylic alcohols and ethers using a mixture of diethylzinc and 2,2-diiodopropane in 53-96% yields. Enantioenriched gem-dimethylcyclopropanes were also synthesized using a glucose-derived aux

Full text of DOI:10.1055/s-2002-19345

176
LETTER
Cyclopropanation of Allylic Alcohols using Substituted Haloalkylzinc
Reagents: Synthesis of gem-Dimethylcyclopropanes
Cyclopropanation
n
of
A
llylic
A
l
d
cohols ré B. Charette,* Nicole Wilb
Département de Chimie, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, Québec, H3C 3J7, Canada
E-mail: andre.charette@umontreal.ca
Received 18 July 2001
and an aluminium rod as anode.12 To the best of our
knowledge, the only examples of Simmons–Smith cyclo-
propanation under Furukawa’s conditions13 using 2,2-di-
iodopropane and diethylzinc were reported by Musso’s
group for cyclopentene and cyclohexene. Moderate yields
(45% and 59% respectively) of the corresponding gem-
dimethylcyclopropane were observed after 5 days.14
Herein, we report an efficient cyclopropanation of allylic
alcohols and ethers to generate gem-dimethylcyclopro-
panes using modified conditions involving an equimolar
amount of diethylzinc and 2,2-diiodopropane15 (Equa-
tion).
Abstract: gem-Dimethylcyclopropanes were obtained by a cyclo-
propanation of allylic alcohols and ethers using a mixture of dieth-
ylzinc and 2,2-diiodopropane in 53–96% yields. Enantioenriched
gem-dimethylcyclopropanes were also synthesized using a glucose-
derived auxiliary.
Key words: cyclopropanation, gem-dimethylcyclopropanes, car-
benoids, chiral auxiliaries, stereoselective synthesis
The synthesis of gem-dimethylcyclopropanes have at-
tracted great attention due to their presence in pyrethroid
esters, which are remarkable insecticides derived from
chrysanthemic acid1 and in a number of natural products.2
Several methods have therefore been developed to intro-
duce the dimethylcarbene unit on an alkene through a cy-
clopropanation reaction. One of the oldest method
involving a 1,3-dipolar addition of 2-diazopropane to ac-
tivated double bonds, afforded a mixture of pyrazolines
that could then be decomposed into the gem-dimethylcy-
clopropane through thermal or photolytic extrusion of ni-
trogen.3 Another efficient method for the generation of
gem-dimethylcyclopropane derivatives involves the addi-
tion-elimination sequence starting from an , -unsaturat-
ed carbonyl. Several reagents such as diphenyl sulfonium
isopropylidene,4 the related phosphonium isopropy-
lidene,5 or 2-methyl-1-propenylmagnesium bromide6
have been developed to achieve this transformation. Even
though these procedures usually give high yields of the
corresponding cyclopropane, the geometry of the double
bond is sometimes not preserved.4a,5d A variety of meth-
ods involving carbenes or radicals generated from 2,2-di-
halopropane, chromous sulfate,7 lithium cyclotetraene
dianion,8 or Co(0)- or Ni(0)-complex and zinc also allow
the introduction of the dimethylcarbene fragment.9 How-
ever, in these cases, the yields are usually poor. Finally,
electrosynthesis provides another route for generation of
gem-dimethylcyclopropanes. Sibille’s group succeeded in
cyclopropanating allylic alcohols using this process.10
However, an excess of 2,2-dibromopropane and a sacrifi-
cial zinc anode were necessary. A zinc carbenoid as pro-
posed for the classical Simmons–Smith reaction11 is
thought to be formed in solution, in contradiction to the
results obtained by Léonel’s group, using in this electro-
chemical process activated olefins, 2,2-dibromopropane
The carbenoids can usually be prepared efficiently from
diethylzinc and a dihalocompound,13 and are more reac-
tive in non-complexing solvents such as dichlo-
romethane.16 Furthermore, the stability of the carbenoid
can be greatly improved by addition of an equimolar
quantity of dimethoxyethane to the diethylzinc.17 Also
previous studies in our laboratory showed that the stoichi-
ometry of the diiodoalkane and diethylzinc is very impor-
tant for optimizing the yields and the diastereomeric ratios
when zinc reagents are used.18
R2
R2
Et2Zn
I2CMe2
R1
OR
R1
OR
CH2Cl2
Me
Me
R1, R2, R = H, alkyl, aryl
Equation
The initial optimization of the reaction conditions for gen-
eration of gem-dimethylcyclopropanes from allylic alco-
hols was done on cinnamyl alcohol using diethylzinc and
2,2-diiodopropane. The results are presented in Table 1.
The first conditions that employed 2 equivalents of dieth-
ylzinc, 2 equivalents of DME and 4 equivalents of 2,2-di-
1
iodopropane resulted in poor conversions (entry 1). H
NMR of the crude reaction mixture indicated that a large
quantity of 2,2-diiodopropane was left unreacted. Further-
more, an NMR study showed that diethylzinc reacted
within a few minutes with one equivalent of diiodopro-
pane to generate EtZnCMe2I, and that the second equiva-
lent remained untouched.19 This carbenoid is probably too
bulky to allow for the approach of the second equivalent
of diiodopropane to the zinc center. However, the reaction
of this species was very efficient and very clean when an
equimolar amount of diethylzinc and diiodopropane were
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0176,0178,ftx,en;S06901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Cyclopropanation of Allylic Alcohols
177
used (entries 2–4). High conversions were observed with Table 2 Cyclopropanation of Allylic Alcohols and Ethers using Di-
ethylzinc and 2,2-Diiodopropane
only 2 equivalents of the reagents but the optimal yields
were obtained when 4 equivalents of this reagent were
R2
Et2Zn (x equiv)
I2CMe2 (x equiv)
R2
used.20 The addition of DME was found to reduce the con-
version to the cyclopropane product (entry 5 vs. 4). The
use of carbenoids bearing a trifluoroacetate or a phenolate
group instead of the ethyl group21 resulted in the complete
decomposition of the starting material (entries 6–7).
R1
OR3
R1
OR3
CH2Cl2, –10 °C to r.t.
16 h
Me
Me
Entry
1
x
R1
H
R2
R3
H
H
H
H
Conversiona Yieldb
4
4
4
4
4
5
4
4
3
3
3
3
3
H
H
H
Et
91%
> 95%
90%
71%
96%
58%
64%
44%
53%
62%
75%
66%
80%
77%
n.d.
Table 1 Optimization of Reaction Conditions
2
Ph
Pr
H
Et2Zn (x equiv)
I2CMe2 (y equiv)
3
OH
OH
Ph
Ph
CH2Cl2, –10 °C to r.t.
16 h
Me
4
94%
Me
Conversiona
17%
5
H
BnOCH2
BnOCH2
H
66%
Entry
x
2
2
3
4
4
4
4
y
4
2
3
4
4
4
4
Additive (equiv)
DME (2)
none
6
H
H
73%
1
2
3
4
5
6
7
7
Me Me
H
94%
76%
8
Ph
Ph
Ph
Ph
Ph
Ph
Me
H
H
> 95%
> 95%
> 95%
> 95%
39%
none
94%
9
Me
Bn
none
95%
10
11
12
13
H
DME (4)
F3CCO2H (4)
78%
< 5%b
< 5%b
H
PMB
TBDMS
TIPS
H
2,4,6-trichlorophenol (4)
a Determined by 1H NMR of the crude reaction mixture.
b Decomposition of the starting material was observed.
H
<
5%
n.d.
a Determined by 1H NMR of the crude reaction mixture.
b Isolated yield of analytically pure product (1H, 13C, IR, HRMS).
The optimized reaction conditions were then applied to a
variety of allylic alcohols (Table 2, entries 1–8). The con-
versions were generally greater than 90% for a variety of
olefins bearing a mono-, di- or trisubstitution pattern, in-
dependently of the (Z)- or (E)-configuration (entries 1–8).
The lesser reactive 4-benzyloxy-2-buten-1-ol gave lower
conversions (entries 5–6).
initial addition of 1 equivalent of zinc iodide.24 Lower re-
action temperatures were found to decrease the conver-
sions of the reaction, and did not significantly increase the
diastereomeric ratio (entry 1 vs. 4). Also, increasing the
equivalents of the reagent from 4 to 10 did not improve the
diastereomeric ratio (entries 3 and 7 vs. 1 and 4). Even
though the pretreatment with ZnI2 did slightly increase the
conversions, no improvement in diastereomeric ratio was
noted (entry 2 and 5 vs. 1 and 4). The best results, 84%
conversion with 82:18 dr, were obtained with 4 equiva-
lents of reagent and overnight reaction at room tempera-
ture. The chiral auxiliary could be efficiently cleaved
using a method previously developed in the group,25
yielding the 3,3-dimethyl-2-phenylcyclopropylmethanol
in 65%, without any loss of selectivity.
Ethers derived from cinnamyl alcohol were also convert-
ed in very high yields to the corresponding cyclopropane
using 3 equivalents of the zinc carbenoid (Table 2, entries
9–13). No residual alkene could be observed by NMR in
the cases of methyl-, benzyl- or p-methoxybenzylether
(entries 9–11). Allylic ethers bearing protecting groups
such as tert-butyldimethylsilyl and triisopropylsilyl were
not as reactive probably for steric reasons. Accordingly,
low conversions were obtained with the ether bearing a
tert-butyldimethylsilyl group (entry 12), and only starting
material was recovered in the case of the tri-isopropylsi-
lylether (entry 13).
In conclusion, we have reported a new and effective pro-
cedure for the synthesis of gem-dimethylcyclopropanes,
employing diethylzinc, 2,2-diiodopropane. This method
should found extensive use in the synthesis of biologically
important products containing gem-dimethylcyclopro-
panes. Extension of this methodology to an enantioselec-
tive version of the reaction will be reported in due course.
We then applied this methodology to an asymmetric ver-
sion of the reaction using a known glucose derivative as a
chiral auxiliary.22 The 1-O-cinnamyl-3,4,6-tri-O-benzyl-
-D-glucose was prepared using the Schmidt’s trichloro-
acetimidate glycosylation method, as previously de-
scribed in the group.23 The results for the asymmetric Acknowledgement
cyclopropanation reaction are given in Table 3. Our re-
sults indicate that the conversions are sensitive to the re-
action temperature and can be favorably influenced by the
This work was supported by grants from the National Science and
Engineering Research Council (NSERC) of Canada and the Univer-
sité de Montréal.
Synlett 2002, No. 1, 176–178 ISSN 0936-5214 © Thieme Stuttgart · New York

178
A. B. Charette, N. Wilb
LETTER
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derived Chiral Auxiliary
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Entry
x
Temp. (°C)
–10 to r.t.
–10 to r.t.
–10 to r.t.
–20
Time (h) Conversiona
drb
1
2
3
4
5
6
7
4
16
18
18
16
16
69
16
84%
88%
75%
43%
67%
89%
59%
82:18
78:22
80:20
86:14
84:16
84:16
79:31
4c
10
4
4c
–20
4
–20
10
–20
a Determined by 1H NMR of the crude reaction mixture.
b Determined by quantitative 13C NMR of the crude reaction mixture.
c One equiv of ZnI2 was added.
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(20) Typical Experimental Procedure: To a solution of the alkene
(0.4 mmol) in anhyd CH2Cl2 (16 mL) at –10 °C was added
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Synlett 2002, No. 1, 176–178 ISSN 0936-5214 © Thieme Stuttgart · New York