Hypoiodite-mediated catalytic cyclopropanation of alkenes with malononitrile

Article abstract of DOI:10.1002/adsc.201400627

An efficient synthetic procedure for di-cyano-cyclopropanation of alkenes using catalytic amounts of molecular iodine as a precatalyst and tert-butyl hydroperoxide (TBHP) as a terminal oxidant under mild conditions has been developed. This catalytic reaction works especially well for the aryl-substituted double bond affording products of cyclopropanation in high yields. A catalytic cycle based on the generated in situ hypoiodite species has been proposed,.

Full text of DOI:10.1002/adsc.201400627

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DOI: 10.1002/adsc.201400627
Hypoiodite-Mediated Catalytic Cyclopropanation of Alkenes with
Malononitrile
Akira Yoshimura,a,* T. Nicholas Jones,b Mekhman S. Yusubov,c,d
and Viktor V. Zhdankina,*
a
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, USA
Fax : (+1)-218-726-7394; e-mail: ayoshimu@d.umn.edu or vzhdanki@d.umn.edu
Department of Chemistry, College of St. Benedict/St. Johnꢀs University, St. Joseph, MN 56374, USA
The Tomsk Polytechnic University, 634050 Tomsk, Russia
The Siberian State Medical University, 634050 Tomsk, Russia
b
c
d
Received: June 27, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400627.
Abstract: An efficient synthetic procedure for di-
cyano-cyclopropanation of alkenes using catalytic
amounts of molecular iodine as a precatalyst and
tert-butyl hydroperoxide (TBHP) as a terminal oxi-
dant under mild conditions has been developed.
This catalytic reaction works especially well for the
aryl-substituted double bond affording products of
cyclopropanation in high yields. A catalytic cycle
based on the generated in situ hypoiodite species
has been proposed.
from the LiI–t-BuOCl combination.[5] However, to the
best our knowledge, the hypoiodite-mediated catalytic
cyclopropanation of alkenes with malononitrile has
not been reported.
Herein, we report the first hypoiodite-mediated cat-
alytic cyclopropanation of alkenes with malononitrile
using catalytic amounts of iodine as a precatalyst to
the active hypoiodite species and tert-butyl hydroper-
oxide (TBHP) as a terminal oxidant in the presence
of alkali metal salts under mild conditions. Recently,
catalytic reactions utilizing highly electrophilic hypo-
iodite species have attracted considerable atten-
tion.[6–8] Minakata and co-workers reported that t-
BuOI generated from the NaI–t-BuOCl combination
was a good oxidant for the cyclization of alkenes with
aldoximes[7a] and carboxamides,[7b,c] aziridination of al-
kenes,[7d,e] and the oxidative dimerization of aromatic
Keywords: cyclopropanation; hypoiodite; iodine;
organocatalysis; oxidation
Cyclopropanation of alkenes is an important chemical amines.[7f,g] Ishihara and co-workers reported an oxi-
transformation leading to cyclopropane systems com- dative cycloetherification of ketophenol and intra-
monly found in natural compounds, medicinal prod- and intermolecular oxidative coupling reactions using
ucts, and intermediates of organic reactions.[1] Numer- in situ generated quaternary ammonium hypoiodite
ous methods of cyclopropanation are known, and par- species from catalytic amounts of quaternary ammo-
ticularly important synthetic procedures are based on nium iodide salts as precatalysts in the presence of
the reactions of alkenes with organohypervalent common stoichiometric oxidants.[8] Our group has
iodine reagents,[2,3] such as iodonium ylides,[3a–d] also developed metal-free catalytic cyclization reac-
alkynyl[3e,f] and alkenyliodonium salts,[3g] iodosylben- tions based on the hypoiodite species generated in
ACHTUNGTRENNUNG
panation of alkenes using (diacetoxyiodo)benzene mediated catalytic reaction, we investigated the opti-
and malononitrile.[3j,m] However, the use of stoichio- mized conditions for the cyclopropanation of styrene
metric amounts of hypervalent iodine reagents should 1a (1 equiv.) with malononitrile 2 (1.2 equiv.) by
be avoided for environmental and economic reasons, screening several terminal oxidants in the presence of
and the development of a catalytic system for this re- catalytic amounts of different iodine sources as preca-
action is a highly desirable goal from the viewpoint of talysts under various conditions in cyclohexane solu-
green chemistry.[2,4] Very recently, our group reported tions (Table 1; for additional details see Table S1 in
a new procedure for the cyclopropanation of alkenes the Supporting Information). In the absence of an
with malononitrile using t-BuOI generated in situ iodine source as precatalyst, the desired cyclopropane
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Akira Yoshimura et al.
Table 1. Optimization of the catalytic cyclopropanation of
styrene 1a with malononitrile 2.[a]
naphthalenes (entries 11 and 12). In the reaction of a-
and b-substituted styrenes, the desired cyclopropanes
3 were obtained in good yields (entries 13–16). It is
noteworthy that reactions of cis- and trans-styrenes
under optimized conditions gave the trans-cyclopro-
pane as the major product and the cis-cyclopropane
was detected as a minor product (entries 15 and 16).
However, sterically hindered styrenes, 2-bromostyr-
ene (entry 7) and a-methyl- or a-phenylstyrene (en-
tries 13 and 14) gave lower yields of the respective cy-
clopropanes 3. Reactions of a,b-unsaturated ketone
and aliphatic alkenes, 1-octene or cyclooctene, afford-
ed the corresponding cyclopropanes in low yields.
When the reactions of aliphatic alkenes (1-octene and
cyclooctene) were performed using 0.5 equivalents of
I2, the desired products were obtained in better yields
(entries 18 and 19). The reaction of trans-chalcone 1q
proceeded stereoselectively giving product of cyclo-
propanation 3q in a low yield (entry 17). Increasing
the amount of I2 to 0.5 equivalents did not improved
the yield of 3q. The low yield of product 3q is proba-
bly explained by the low solubility of starting alkene
(80% of starting alkene is recovered as undissolved
solid from the reaction mixture). Unfortunately, the
cyclopropanation of styrene with diethyl malonate,
ethyl cyanoacetate, 3,3,3-trifluoropropionitrile, or bi-
s(phenylsulfonyl)methane using similar conditions did
not afford the corresponding cyclopropanes. Com-
pared to the previously reported method of cyclopro-
panation of a- and b-substituted styrenes using hyper-
valent iodine reagents, our new procedure gave better
yields of dicyanocyclopropanes.[3j] This new catalytic
procedure gave similar yields as obtained with the
previous method using in situ generated stoichiomet-
ric amount of t-BuOI from LiI–t-BuOCl combina-
tion.[5]
Entry
Oxidant
(equiv.)
Iodine source
(equiv.)
LiCl
(equiv.)
3a
G
E
N
[%][b]
1
2
3
4
5
6
7
8
TBHP (1.2)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
Oxone (3)
H2O2 (3)
m-CPBA (3)
TBHP (2)
TBHP (1.5)
TBHP (1.2)
TBHP (1.5)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
none
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.5
1.5
1.5
none
–
I2 (0.2)
NaI (0.4)
KI (0.4)
LiI (0.4)
TBAI (0.4)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.2)
81 (81)
(18)
(10)
(11)
(12)
(2)
(7)
(1)
9
10
11
12
13
14
15[c]
16[d]
17
(81)
(82)
90 (92)
(65)
(25)
(40)
(42)
(51)
[a]
Reaction conditions: styrene 1a (1 equiv.), malononitrile
2 (1.2 equiv.), oxidant (1.2–3 equiv.), iodine sources (0–
0.2 equiv.) and LiCl (0–1.5 equiv.) in cyclohexane at 508C
for 24 h.
[b]
Yields of isolated product 3a (numbers in parentheses
1
show yields determined from H NMR spectra of reac-
tion mixtures).
Reaction time is 48 h.
Reaction time is 72 h.
[c]
[d]
Several reaction mechanisms can be considered for
product 3a was not observed and unchanged styrene this catalytic cyclopropanation. In order to clarify the
1a was recovered (Table 1, entry 1). Screening of vari- mechanism of this reaction, we have performed sever-
ous iodine sources has demonstrated that elemental al control experiments (see the Supporting Informa-
iodine was the most efficient precatalyst (entries 2–6). tion for details). The reaction without alkali metal
From a study of different terminal oxidants, we have salts or in the presence of tetrabutylammonium chlo-
found that TBHP is the most effective oxidant in this ride (TBAC) instead of LiCl under similar conditions
reaction (entries 2 and 7–9). Decreasing the amount gave a lower yield of 3a. These results indicate that
of TBHP from 3 to 1.2 equivalents (entries 2 and 10– alkali metal salts play a critical role in this reaction.
12) resulted in increased yields of product 3a up to Most likely, this reaction involves t-BuOI as active
92%. However, in the presence of lower amounts of species generated from I2 and TBHP. When using the
iodine or in the absence of LiCl the yields of 3a were known procedure for the in situ generation of t-BuOI
significantly lower (entries 14-17).
from the I2–t-BuOK combination, cyclopropane 3a
Using the optimized reaction conditions with was obtained only in 35% yield. Iodocyclohexane as
20 mol% I2 as a precatalyst, we have investigated the by-product was also detected by GC-MS in several re-
conversion of various substituted alkenes 1 to the re- actions, and it was previously reported that in situ
spective dicyanocyclopropane derivatives 3 (Table 2). generated t-BuOI reacted with cyclohexane to give io-
In general, all styrenes with either electron-donating docyclohexane.[10] These results suggest that in situ
or electron-withdrawing substituents in the aromatic generated t-BuOI is the active species in this catalytic
ring afforded products 3 in good yields (entries 1–10). reaction. When TEMPO was added as a radical scav-
This reaction also gave good yields for 1- or 2-vinyl- enger to the reaction, 3a was not formed, although
2
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Hypoiodite-Mediated Catalytic Cyclopropanation of Alkenes
Table 2. Catalytic cyclopropanataion of alkenes 1 with malononitrile under optimized reaction conditions.[a]
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Akira Yoshimura et al.
the reaction with the addition of another radical scav- nism most likely involves t-BuOI generated in situ
enger 2,6-di-tert-4-methylphenol (BHT) gave 3a in from I2 and TBHP.
a moderate yield of 44%. The inhibiting effect of
TEMPO is most likely explained by its reaction with
iodine, which has been documented in the litera- Experimental Section
ture.[11] Nevertheless, we could not completely rule
out the radical mechanism of this reaction. We have General Procedure
also observed isomerization of cis-b-styrene 1o to
trans-b-styrene 1p under standard conditions but with-
(1.5 mL) were added malonodinitrile 2 (0.150 mmol), LiCl
To a solution of alkene 1 (0.125 mmol) in cyclohexane
out malononitrile 2, which explains the low stereose-
lectivity of this reaction (Table 2, entries 15 and 16).
From these control experiments and based on pre-
viously reported mechanistic studies of cyclopropana-
tion using t-BuOI,[5] we propose the catalytic cyclo-
propanation mechanism outlined in Scheme 1. The
active species, t-BuOI 4, which is generated from I2
and TBHP, reacts with alkenes 1 to give iodonium ion
5, which is then opened at the benzylic position to
give the cationic intermediate 6. The intermediate 6
rotates to the thermodynamically more stable trans
isomer 7, which then reacts with malononitrile anion,
formed from 2 in the presence of tert-butoxy anion.
This sequence of steps gives b-iodo compound 8, the
cyclization of which affords cyclopropane 3 and
iodide anion. The regenerated iodide anion continues
the catalytic cycle.
(0.1875 mmol), I2 (0.025 mmol) and 70% TBHP
(0.150 mmol). The reaction was stirred at 508C for 24 h.
After reaction completion, the mixture was washed with 5%
aqueous Na2S2O3 (5 mL), and the solution was extracted
with dichloromethane. The organic phase was dried over an-
hydrous Na2SO4 and concentrated. Purification by prepara-
tive TLC (hexane-ethyl acetate=3:1) afforded analytically
pure dicyanocyclopropane 3.
Acknowledgements
This work was supported by a research grant from the Na-
tional Science Foundation (CHE-1262479).
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6 Hypoiodite-Mediated Catalytic Cyclopropanation of
Alkenes with Malononitrile
Adv. Synth. Catal. 2014, 356, 1 – 6
Akira Yoshimura,* T. Nicholas Jones, Mekhman S. Yusubov,
Viktor V. Zhdankin*
6
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