Intermolecular Cyclopropanation of Styrenes Using Iodine and Visible Light via Carbon-Iodine Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.5b02957

The intermolecular cyclopropanation of aromatic olefins with activated methylene compounds using iodine and visible light irradiation was described. This reaction proceeds under rare-metal-free conditions. Styrenes with various substituted groups (alkyl a

Full text of DOI:10.1021/acs.orglett.5b02957

Letter
pubs.acs.org/OrgLett
Intermolecular Cyclopropanation of Styrenes Using Iodine and
Visible Light via Carbon−Iodine Bond Cleavage
Kaoru Usami, Yoshitomo Nagasawa, Eiji Yamaguchi, Norihiro Tada, and Akichika Itoh*
Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
S
* Supporting Information
ABSTRACT: The intermolecular cyclopropanation of aromatic
olefins with activated methylene compounds using iodine and
visible light irradiation was described. This reaction proceeds
under rare-metal-free conditions. Styrenes with various sub-
stituted groups (alkyl and electron-withdrawing groups) provided
corresponding cyclopropanes in moderate to good yields.
unctionalized cyclopropanes are an important class of
organic compounds because of their unique biological
Scheme 1. Proposed Photomediated Construction of
Cyclopropanes
F
activities1 and physical properties.2 They have also been applied
as important synthetic intermediates in cyclopentannulation via
metal-catalyzed ring-opening reactions.3 Therefore, the devel-
opment of methods for the synthesis of members of this class is
highly important. Hence, a large number of synthesis methods
to access fused cyclopropanes have been developed.4
Furthermore, the total synthesis of naturally occurring products
containing cyclopropanes, such as Solanoeclepin A5 and
Mycorrhizin,6 has been achieved. To prepare cyclopropane
units, chemists can employ commonly developed methods,
including transition metal catalyzed carbene7 insertion into
alkenes,8 Simmons−Smith reactions,9 Corey−Chaykovsky
reactions,10 Kulinkovich−de Meijere reactions,11 and Michael-
initiated ring-closure (MIRC) reactions.12 In 2012, a silver- and
iodine-mediated radical pathway was reported by Kamimura for
the intramolecular construction of cyclopropanes from nitro-
methane derivatives (Scheme 1a).13 This reaction proceeds
with an unconjugated alkene. However, no conditions that
produce intermolecular reaction products have yet been found.
There we have speculated on the ability to realize the
intermolecular cyclopropanation with a radical pathway.
In our laboratory, a unique photo-oxidative approach based
on the ability of iodine, which led to the formation of tartaric
acids from β-ketoesters via tandem oxidation/rearrangement
reaction, has been introduced (Scheme 1b).14 Visible light
irradiation of the iodinated intermediate induced homolytic
carbon−iodine bond cleavage, allowing access to radical species
under moderate conditions. This reactivity enabled the
development of light-driven cyclopropanation of active
methylene compounds using styrenes, a process that could
not be realized under thermal activation (Scheme 1c).
Herein, we investigate the intermolecular cyclopropanation
of styrenes with active methylene compounds, mediated by
molecular iodine. This study demonstrates that a radical
intermediate (II), generated upon photoinduced homolytic
carbon−iodine bond cleavage of an iodinated starting material
I, can serve as a suitable precursor (III) for cyclopropanation
resulting from radical addition of II to styrenes.
We examined the reaction of ethyl cyanoacetate (1a) with
styrene (2a) in ethyl acetate under visible light irradiation. Only
a trace amount of the cyclopropanated product (3a) was
detected when 1a and 2a were reacted in the presence of
calcium iodide or magnesium iodide (Table 1, entries 1 and 2).
Fortunately, in the presence of iodine, the reaction occurred
and gave the desired cyclopropane in 66% yield (entry 3).
Changing the amount of iodine drastically decreased the yield
Received: October 12, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b02957
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Table 1. Optimization of the Reaction Conditions
Scheme 2. Synthesis of Cyclopropanes (3) Using Various
Styrenes (2)
a
a
b
entry iodine source (equiv)
base
solvent
yield (%)
dr
1
CaI2 (1.0)
MgI2 (1.0)
I2 (1.0)
I2 (0.2)
I2 (2.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
−
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOH
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
nHexane
CHCl3
MeCN
DMF
trace
0
−
−
2
3
66
4.5:1
4.5:1
6:1
6.5:1
5.5:1
−
4
12
5
46
6
66
7
58
8
CsOAc
pyridine
Et3N
trace
17
9
4:1
10
11
12
13
14
15
16
17
trace
0
−
−
−
4:1
5:1
7:1
6:1
5:1
K2CO3
−
0
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
31
10
52
45
c
EtOAc
80 (86)
a
1
Yield was determined by H NMR analysis of the crude reaction
b
mixture. The number in parentheses is the isolated yield. The
diastereomeric ratio was determined by 1H NMR analysis of the crude
c
reaction mixture. Reaction carried out with 3 mL of EtOAc and 3
equiv of styrene.
of the desired product (entries 4 and 5). Among the different
bases examined, K2CO3 was found to be the best base (entries
6−10). Conversely, performing the reaction in the absence of
either iodine or base led to no detectable product (entries 11
and 12). Subsequent screening for the best solvent showed
EtOAc to be the best solvent (entries 13−16). Finally, fine-
tuning the ratio of 1a and 2a as well as the concentration of the
solvent proved to give the best results, giving the product (3a)
in 86% isolated yield (entry 17).
a
General conditions: 1a (0.30 mmol), 2 (0.90 mmol), I2 (0.3 mmol),
and K2CO3 in EtOAc (3 mL) at rt for 20 h under an Ar atmosphere
and visible light irradiation. Yields refer to the isolated yield. Numbers
in parentheses refer to the diastereomeric ratio, and the ratios were
1
After obtaining optimized reaction conditions, we then
explored the reaction scope and limitations. First, we
investigated a variety of styrenes (2) to assess their ability to
react with ethyl cyanoacetate (1a) (Scheme 2). Styrenes with
an electron-donating group showed poor reactivity and gave the
cyclopropanated product (3b) in 21% yield. Styrenes bearing
alkyl groups at the ortho, meta, and para positions reacted well
with 1a to give the corresponding cyclopropanes (3c−3f) in
good yield. Higher yields of cyclopropanes 3g−3i were
obtained when various styrenes substituted with electron-
withdrawing groups were employed in this transformation.
However, the product yields dropped drastically when 2-
vinylpyridine was used as the starting material. Alpha or beta
substituted styrenes gave corresponding cyclopropanes (3k−
3m) in moderate yields. An attempt to extend this reaction
system to olefin-bearing alkyl substituents was not successful;
no cyclopropanated product (3n) was observed for a 1-hexene
substituted styrene. Also, cinnnamate did not react with 1a and
only starting material was observed.
determined by H NMR analysis of the crude reaction mixture.
employed to evaluate the ability of our method. Methyl
cyanoacetate provided the desired product (3p) in good yield.
When acyloyl acetonitriles were investigated as the substrates
for this reaction, all the cyclopropanated products (3q−3s)
were obtained in good yield. Moreover, this reaction could be
applied to other active methylene compounds, such as
malononitrile and dimethyl malonate, providing the corre-
sponding cyclopropanes 3t and 3u in 75% and 51% yield,
respectively. However, the reaction of styrene (2a) with 2-
nitroacetophenone resulted in a lower yield. In addition, the
reaction of benzyl cyanide with styrene (2a) was unsuccessful,
leading to a complex mixture, and no desired product (3w) was
obtained.
To further investigate the primary reaction mechanism,
several controlled experiments were performed (Scheme 4).
First, we attempted the reaction of ethyl cyanoacetate (1a) with
styrene (2a) under dark reaction conditions, and a significantly
lower yield of the desired product (3a) was observed (Scheme
4, eq 1). Second, when TEMPO (1.0 equiv) was added under
the optimized reaction conditions, the reaction could not
produce 3a, possibly due to the fact that the radical
Diverse active methylene compounds (1) were next
examined to study the scope of this methodology (Scheme
3). At the outset, active methylene compounds possessing a
nitrile group and other electron-withdrawing groups were
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TEMPO under our reaction conditions could not furnish the
desired product. These experiments suggested that the
homolytic carbon−iodine bond cleavage to form the radical
intermediate could be involved in the transformation under
standard conditions. To gain insight into the cyclization
mechanism of this reaction, an iodinated precursor (4a) was
used under the standard conditions (Scheme 4, eq 4). The
results indicated that no cyclization product was formed when
the reaction was performed without potassium carbonate.
Unfortunately, precursor 4 was not observed under the
standard condition in all cases.
Scheme 3. Synthesis of Cyclopropanes (3) Using Various
Active Methylene Compounds (1)
a
From the above-mentioned experimental results, we
proposed a possible reaction mechanism that involved a
photoinduced homolytic carbon−iodine bond cleavage process
(Scheme 5). First, a radical intermediate 1′ was formed by the
Scheme 5. Plausible Reaction Mechanism for the
Cyclopropanation
a
General conditions: 1 (0.30 mmol), 2a (0.90 mmol), I2 (0.3 mmol),
and K2CO3 in EtOAc (3 mL) at rt for 20 h under an Ar atmosphere
and visible light irradiation. Yields refer to the isolated yield. Numbers
in parentheses refer to the diastereomeric ratio, and the ratios were
1
determined by H NMR analysis of the crude reaction mixture.
base-assisted iodination of 1, followed by the photoinduced
homolytic carbon−iodine bond cleavage of 1−I. The generated
carbon radical then attacks the alkene, producing intermediate
5, which abstracts the I atom from 1−I to generate radical 1′
and intermediate 4 in a chain reaction. Finally, 3-exo-tet
cyclization of 4 occurs to form the desired cyclopropane (3).
In conclusion, we have successfully developed a highly
efficient photoinduced intermolecular reaction of active
methylene compounds with styrenes, mediated by iodine for
the straightforward synthesis of cyclopropanes, which are
important and useful intermediates in organic chemistry. A
general reaction mechanism has been proposed involving the
generation of a radical intermediate via photoinduced
homolytic carbon−iodine bond cleavage, which could be
further applied for various types of reactions. Moreover, the
corresponding cyclopropane products could be obtained under
rare-metal-free conditions, constituting a green chemistry
approach for the synthesis of cyclopropane derivatives.
Scheme 4. Controlled Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02957.
intermediate that formed was blocked by the TEMPO and,
thus, could not aid cyclization (Scheme 4, eq 2). The above-
mentioned results clearly indicated that the visible light
irradiation played a significant role in forming the radical
intermediate and that the reaction proceeded via a radical
pathway. Moreover, we prepared iodinated ethyl cyanoacetate
(1a−I) and performed the photoinduced cyclopropanation of
1a−I with 2a under our optimized reaction conditions without
iodine; a 54% yield of the desired product (3a) was observed
(Scheme 4, eq 3). Furthermore, the reaction of 2a with
General experimental procedure and compound charac-
terization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Itoha@gifu-pu.ac.jp.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was supported by Asahi glass foundation.
■
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