Communication
good yields (entries 12, 13, 16). It is noteworthy that the reac-
tions of cis- and trans-b-styrenes under these conditions gave
the trans-cyclopropane 3n as major product in good yield, and
cis-cyclopropane 3o was detected only as a minor product (en-
tries 14, 15). The reaction of a,b-unsaturated ketone 1q afford-
ed corresponding cyclopropanes in low yields, and these yields
were not improved upon using 3 equivalents of both LiI and
tBuOCl (entries 17). Our procedure was more efficient com-
pared to the previously reported methods of cyclopropanation
of alkenes with malononitrile using hypervalent iodine re-
agents.[3i,l] Moreover, the previously reported reactions of a- or
b-methylstyrenes did not give any products of cyclopropana-
tion, while our method afforded these products in good yields.
The structure of dicyanocyclopropane 3k (Table 2, entry 11)
was established by a single crystal X-ray analysis (see Support-
ing Information for details).
Scheme 1. Proposed mechanism of tBuOI-mediated cyclopropanation.
In order to gain additional information on the mechanism of
this reaction, we have performed several control experiments
(see the Supporting Information for details). Most likely, this re-
action involves tBuOI as active species generated from LiI and
tBuOCl. The intermediacy of tBuOI was examined by generat-
ing it in situ by different methods using either NaI-tBuOCl[5] or
I2-tBuOK[8] in place of LiI-tBuOCl. In both cases, the cyclopro-
pane 3a was isolated in about 50% yield, which suggests that
in situ generated tert-butoxy hypoiodite species, tBuOI 4 are
the active species in this reaction. However, the yields of 3a
using our optimized condition compared to the other tBuOI
generation methods were much better. We have found that
the presence of LiCl, which is produced from LiI-tBuOCl, is im-
portant for this reaction. When LiCl was used as the additive in
NaI-tBuOCl and I2-tBuOK conditions, cyclopropane 3a was ob-
tained in 74% and 73% yields, respectively. As expected, the
addition of NaCl instead of LiCl was not effective under NaI-
tBuOCl or I2-tBuOK conditions. This result suggests that LiCl
may act as a Lewis acid facilitating the formation of tBuOI or
the LiCl-tBuOI complex in this reaction. During our mechanistic
studies, we observed isomerization of cis-b-styrene to trans-b-
styrene when the combinations of LiI-tBuOCl and I2-tBuOK
were used in the absence of malononitrile 2.
From these control experiments, we propose the hypoio-
dite-mediated cyclopropanation mechanism outlined in
Scheme 1. The active species, tBuOI 4, and LiCl generated in
situ from LiI-tBuOCl combination, form the LiCl-tBuOI complex
that reacts with alkene 1 to give the iodonium ion 5, which is
then opened at the benzylic position to give the cationic inter-
mediate 6. The intermediate 6 rotates to the thermodynamical-
ly more stable trans isomer 7, which reacts with malononitrile
anion, formed from 2 in the presence of tert-butoxy anion. This
sequence of events gives b-iodo compound 8, which upon
anionic cyclization affords cyclopropane 3.
Scheme 2. Synthesis of potential HIV-1 RT inhibitor 10.
In summary, we have developed a new procedure for the cy-
clopropanation of alkenes using malononitrile and the LiI-
tBuOCl combination. The reaction mechanism most likely in-
volves tBuOI generated in situ from LiI and tBuOCl. The syn-
thetic usefulness of this new procedure was demonstrated by
the synthesis of potential HIV-1 RT inhibitor.
Experimental Section
Malononitrile
2 (0.150 mmol), LiI (0.1875 mmol), and tBuOCl
(0.1875 mmol) were added to a solution of alkene 1 (0.125 mmol)
in dichloromethane (1.5 mL). The resulting light-brown suspension
was stirred at room temperature for 24 h. After reaction comple-
tion, the mixture was washed with 5% aqueous Na2S2O3 (5 mL),
and the solution was extracted with dichloromethane. The organic
phase was dried over anhydrous Na2SO4 and concentrated. Purifi-
cation by preparative TLC (hexane/ethyl acetate=3:1) afforded an-
alytically pure dicyanocyclopropane 3.
Acknowledgements
This work was supported by a research grant from the National
Science Foundation (CHE-1262479).
Our new cyclopropanation procedure was applied in the
synthesis of potential HIV-1 RT inhibitor. The dicyanocyclopro-
pane 3a upon partial hydrolysis under mild basic condition af-
forded the cyanocarboxamide cyclopropane 9 in moderate
yield (Scheme 2). This cyclopropane 9 has been used as a pre-
cursor for the preparation of the potential HIV-1 RT inhibitor
10 as previously described.[9]
Keywords: cyclopropanation reactions · hypoiodous acid ·
iodine · oxidation · small ring systems
[1] a) The Chemistry of the Cyclopropyl Group (Eds.: S. Patai, Z. Rappoport),
Chem. Eur. J. 2014, 20, 1 – 5
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