A facile formal [2+1] cycloaddition of styrenes with alpha-bromocarbonyls catalyzed by copper: Efficient synthesis of donor-acceptor cyclopropanes

Article abstract of DOI:10.1039/c5cc04697a

Reactions of 2-bromoesters and styrenes underwent a [2+1] cycloaddition reaction, i.e., cyclopropanation, to produce donor-acceptor (D-A) cyclopropanes through a radical addition-ring closure process. In this reaction, the combination of copper(ii) comple

Full text of DOI:10.1039/c5cc04697a

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A Facile Formal [2+1] Cycloaddition of Styrenes with alpha-
Bromocarbonyls catalyzed by Copper: An Efficient
Synthesis of Donor-Acceptor Cyclopropanes
Received 00th January 20xx,
Accepted 00th January 20xx
Takashi Nishikata*a, Yushi Nodaa, Ryo Fujimotoa, and Shingo Ishikawaa
DOI: 10.1039/x0xx00000x
www.rsc.org/
Reactions of 2-bromoesters and styrenes underwent [2+1] deficient α,βꢀunsaturated carbonyl, nitro or sulfonyl
cycloaddition reactions, i.e., cyclopropanation, to produce donor- compounds (not styrene derivatives) can only be utilized in
acceptor (D-A) cyclopropanes through radical addition-ring closure MIRC reactions.
process. In this reaction, the combination of copper(II) complex
We recently reported that the reaction of alphaꢀ
bromocarbonyl compounds with styrenes gives tertiaryꢀ
alkyl olefinations in good yields via an atom transfer
and amines is found to be a good catalyst system to obtain cyclic
compounds in high yields. This reaction provides an efficient
protocol to synthesize D-A cyclopropanes, which are very
important building blocks in organic synthesis.
radical
addition
(ATRA)
and
a
subsequent
dehydrohalogenation (Heckꢀlike reaction)10. During the
Cyclopropanations have been studied extensively for many course of our research in radical chemistry, we also found
decades. A vast amount of cyclopropyl functional groups that cyclopropanation can occur via an ATRAꢀinitiated
can be found in natural compounds possessing biological ring closure reaction. Unlike MIRC, which is initiated by
activities1, pharmaceuticals2, agrochemicals3 and other the generation of anionic species A, our current
synthetic intermediates4. Among cyclopropane structures, cyclopropanation methodology begins with the reaction of
donorꢀacceptor (DꢀA) cyclopropanes are currently widely halocarbonyl compounds 1 and a copper(I) salt10,11 to
utilized
generate radical species C (Scheme 1). A key to success
intermediates in synthetic organic chemistry since they can for both the MIRC and our reaction methodology involves
easily undergo a ringꢀopening reaction in the presence of a the ringꢀclosing step of intermediate B or D, which is
Lewis acid to produce a [3 + n] annulation product5.
generated from the addition of A or C to olefin (2 or 2′).
The selective preparations of functionalized cyclopropanes The advantages of using halocarbonyl compounds 1
are accomplished by reacting olefins with carbonyl include 1) a facile generation of radicals without any
derivatives6. For example, a vast array of cyclopropyl excess initiator, 2) an easy preparation (simple
derivatives can be enantioselectively synthesized8 through bromination of carbonyl compounds or many
the Simmons–Smith reaction7 and the generation of commercially available sources), and 3)
a
good
organometallic carbenoids through the reactions of diazo susceptibility for added functional groups, which provides
compounds and transition metal catalysts. A Michael new opportunities or possibilities for the synthesis of DꢀA
initiated ring closure reaction (MIRC) is another option for cyclopropanes 3. There are reports in the literature where
the preparation of cyclopropanes9. One of the advantages halocarbonyl compounds
1
are utilized as
a
of using a MIRC for cyclopropanation is that stable cyclopropanation reagent12, which includes the efficient
halocarbonyl compounds instead of diazo compounds can cyclopropanation of [60] fullerene under mild conditions
be reacted with electron deficient olefins (Michael (Bingel reaction)13. However, a general methodology for
acceptors) under mild conditions. Although the MIRC is a the catalytic synthesis of DꢀA cyclopropanes 3 with 1 has
very convenient process for cyclopropanations, electron not yet been established. In this context, we envisaged a
formal [2+1] cycloaddition of halocarbonyl compounds 1
with styrene derivatives 2 using a copper(II) catalyst to
afford DꢀA cyclopropanes 3.
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Journal Name
O
C
O
O
C
A
B
R'
R
R'
X
Table 1 Optimization.
R'
C
X
R
R
EWG
2'
EWG
base
3'
carbanion
EWG
Cyclopropane
MIRC
1
O
C
R'
X
This work
R
H
O
O
R
O
R'
C
R'
D
Cu(I)
C
R'
C
C
Ar
R
3
R
H
Ar
Ar
X
radical
2
D-A
Cyclopropane
Scheme 1 The difference between MIRC and our formal [2+1]
cycloaddition.
All reactions were carried out for 20 h in toluene with 10 mol% Cu salt,
PMDETA (1.2 equiv), 1a (2.0 equiv.) and 2a (1.0 equiv.). Yields were
determined by 1HNMR.
As we expected, bromomalonate 1a selectively provided
cyclopropane 3a in the presence of pꢀmethoxystyrene 2a,
CuI,
PMDETA
N,N,N′,N″,N″ꢀ
pentamethyldiethylenetriamine (PMDETA), and toluene as
a solvent at room temperature (Table 1, Run 2). Without a
catalyst or an amine, no reaction occurred (Run 1). 1a
reacts with Cu(I) to produce the corresponding alkyl
radical species for the ATRA initiated ring closure
reaction. CuI gave 32% yield, whereas cationic copper
catalyst, [Cu(I)(MeCN)4]BF4, gave 81% yield (Runs 2 and
3). Cu(II) catalysts are not suitable for the generation of
alkyl radicals from bromocarbonyl compounds 1 without
reducing reagents; however, [Cu(II)(H2O)6](BF4)2 and
Cu(II)Cl2 underwent cyclopropanation efficiently (Runs 4
and 5). Although various copper(I) catalysts were
screened, [Cu(II)(H2O)6](BF4)2 gave the highest yield
(90%, Run 5). In this reaction, any reductants, such as lowꢀ
valent metals, Sn(II), glucose, hydrazine, and ascorbic
acid, were not used to generate active Cu(I) species from
Cu(II) species but Cu(I) is considered to be a real active
catalyst in this reaction11. Weiss and coꢀworkers have
reported that excess amine can reduce Cu(II) to Cu(I)14.
Therefore, PMDETA could act as a reductant and showed
the best yield of all alkylamines tested. We suspected that
this reaction occurs through carbene species, but
dimerization of 1 to give fumaric acid ester was not
detected. In addition, the reaction presented here did not
occur in the presence of 2,2,6,6ꢀtetramethylpiperidine 1ꢀ
Oxyl(TEMPO), which could indicate the radical reaction
(alkylated TEMPO was detected10c).
affect the yields. This reaction is expected to involve a
radical reaction; nevertheless, the double bonds remained
intact. Bulky malonate esters led to 3e in moderate yield,
and highly bulky malonate having tꢀBu groups did not
undergo cyclization. Malonamide leading to 3g was very
unstable during the reaction, and the corresponding
dehalogenated product was produced instead of
cyclopropane
3g.
Interestingly,
unsymmetrical
bromoesters leading to 3h and 3i enabled stereoselective
cyclopropanations with 59:41 and 85:15 for trans:cis
selectivity, respectively. In the MIRC reaction of bromoꢀ
phosphonomalonates, cisꢀcyclopropylphosphonates were
the main products; however, our reaction gave transꢀ
selectivity in spite of similar steric bulkiness between
sulfonyl and phosphonate groups15. The cyclopropanation
can be applied to various styrenes 2 with dimethyl
bromomalonate (1b) in moderate to good yields. Methoxyꢀ
and methylꢀsubstituted styrenes leading to 3j–3m resulted
in good yields. Simple styrene easily undergoes a
polymerization reaction in the presence of alkyl radicals;
however, 79% of 3n was obtained. Although, according to
our previous results10, electron deficient styrenes were not
suitable for the reaction with tertiaryꢀalkyl radicals, the
reactions proceeded smoothly and gave the corresponding
products 3o–3r in moderate to good yields. βꢀSubstituted
styrenes were not reacted, whereas αꢀmethylstyrene gave
the cyclopropane 3s in 76% yield.
Under the best conditions shown in Table 1 Run 5,
styrenes 2 was able to react with bromocarbonyl
compounds 1 in moderate to excellent yields at room
temperature (Table 2). 2ꢀBromomalonate derivatives 1
smoothly reacted with pꢀmethoxystyrene (2a) and gave the
products 3b–3e. Bromomalonic acid allyl ester leading to
3d has double bonds in the molecule; however, the double
bonds did not
The DꢀA cyclopropanes 3 obtained by the proposed
copperꢀcatalyzed cycloaddition are useful building blocks
that can be easily transformed into a wide variety of
functionalized cycloꢀcompounds by taking advantage of
the versatile reactivities of 3 (Scheme 2)16. For example,
syntheses of cyclic amidine 417 and tetrahydrofuran 518 via
Lewis acid catalyzed [3+2] cycloadditions of donorꢀ
acceptor cyclopropane 3n and imine or aldehyde have
2 | J. Name., 2012, 00, 1-3
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been achieved. 3n also can be transformed into
cyclopropane hemimalonate
6 stereoselectively, which is a useful reactant for a
nucleophilic ringꢀopening reaction using internal
carboxylic acid activation19.We also tried the reaction with
αꢀchloromalonate but no reaction occurred. In the case of
αꢀbromoꢀβꢀketoesters, no cyclopropanes were obtained.
Table 2 [2+1] Cycloadditions.
O
O
O
C
O
10 mol% [Cu(H2O)6](BF4)2
1.2 equiv PMDETA
R
R
R'
C
Br
+
R'
Ar
toluene, rt
Ar
The rationale behind the attention accorded cyclization
chemistry has been based, in part, on its potential to
streamline routes towards valuable synthetic targets. Thus,
we tried to synthesize the core structure of borreverine20.
Borreverine alkaloid, which demonstrates antimicrobial
action in vitro, has a cyclopropylꢀsubstituted core structure
8 (Scheme 3). This core can be synthesized from the
unstable vinylated indole 7. One of the most serious
problems in cyclopropanation reaction is the use of an
unstable olefin as a starting material. In rhodium catalyzed
cyclopropanation with diazoesters, almost all vinylated
compounds can be reacted to produce cyclopropanes;
however, 2ꢀvinylated indole 7 was not suitable for the
reaction because the vinylated indole is too unstable to
react with diazoesters in good yield20a. In this case, our
copper catalyzed system successfully gave 50% yield of
the borreverine core 8 from 7.
1
2
3
Yield of 3
O O
O O
O O
MeO
p-An
OMe
AllylO
p-An
OAllyl
BnO
OBn
p-An
3c: 88%
3b: 84%
3d: 92%
O O
O O
O O
t-BuO
Ot-Bu
Me2N
p-An
NMe2
i-PrO
Oi-Pr
p-An
3f: trace
p-An
3e: 42%
3g: trace
O O
O
O
PhSO2
MeSO2
MeO
OMe
OEt
OEt
p-An
3i: 86%
p-An
3h: 92%
OMe
3j: 73%
(trans:cis=59:41)
(trans:cis=85:15)
O O
O O
O O
MeO
OMe
MeO
OMe
OMe
MeO
OMe
N
N
O
OMe
CO2Me
CO2Me
OMe
OMe
7
Br
N
[Cu(H2O)6](BF4)2
TPMA
PMDETA, CH2Cl2
rt, 50%
O
1c
N
N
3k: 84%
O O
3l: 78%
3m: 72%
8
O O
O O
Borreverine
derivatives
MeO
MeO
OMe
MeO
OMe
Scheme 3 Synthesis of the core 8 of borreverine
.
F
Cl
3o: 69%
3p: 74%
O O
3n: 79%
O O
O O
MeO
OMe
MeO
OMe
Conclusions
MeO
OMe
In conclusion, we found a copperꢀcatalyzed cycloaddition
of bromocarbonyl compounds 1 and styrenes 2 to produce
DꢀA cyclopropanes 3, which are useful building blocks in
organic synthesis. Current our formal [2+1] cycloaddition
of 2ꢀbromoester 1 with styrene 2 through a radical
mechanism is very rare because 1 is generally used for
MIRC reaction with Michael acceptor such as α,βꢀ
unsaturated carbonylꢀ, and nitro compounds. The reaction
developed in this study provides facile access to a series of
core structures of natural products. Further investigations,
including asymmetric cycloaddition and mechanistic
studies, are currently underway.
Br
MeO2C
3q: 74%
3r: 44%
3s: 76%
All reactions were carried out for 20 h at rt in toluene with 10 mol%
[Cu(II)(H2O)6](BF4)2, PMDETA (1.2 equiv), 1 (2.0 equiv.) and 2 (1 equiv.).
Isolated yields.
Acknowledgements
Financial support provided by program to disseminate tenure
tracking system, MEXT, Japan is gratefully acknowledgement.
Scheme 2 Transformations of cyclopropane 3n
.
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HRMS.
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4 | J. Name., 2012, 00, 1-3
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