Copper(I)-catalyzed carbometalation of nonfunctionalized cyclopropenes using organozinc and grignard reagents

Article abstract of DOI:10.1055/s-0034-1379959

A highly efficient method was developed for the copper(I)-catalyzed carbometalation of various nonfunctionalized and functionalized cyclopropenes. Electrophilic trapping of the cyclopropylmetal intermediates gave multifunctionalized cyclopropanes.

Full text of DOI:10.1055/s-0034-1379959

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 671–675
letter
671
T. Nakano et al.
Letter
Synlett
Copper(I)-Catalyzed Carbometalation of Nonfunctionalized
Cyclopropenes Using Organozinc and Grignard Reagents
Takeo Nakanoa
Kohei Endo*a,b
Yutaka Ukajia
R3M
R1
R2
R1
R2
R3
R1
R2
R3
Cu (cat.), L1
E+
M
E
a Division of Material Sciences, Graduate School of Natural
Science and Technology, Kanazawa University, Kakuma,
Kanazawa 920-1192, Japan
kendo@se.kanazawa-u.ac.jp
b PRESTO, Japan Science and Technology Agency (JST), 4-1-8
Honcho Kawaguchi, Saitama, 332-0012, Japan
Me2N
N
O
L1 =
NEt2
Received: 14.10.2014
Accepted after revision: 27.11.2014
Published online: 15.01.2015
We previously reported a tandem reaction using cyclo-
propene, organozinc reagents, and a hydrazone or carbonyl
compound.15 The reaction may take place through carboz-
incation of the cyclopropene to generate a cyclopropylzinc
intermediate, ring opening of which gives an allylzinc inter-
mediate in situ.16 However, cyclopropanes, other than cy-
clopropenone acetal showed low reactivities [Scheme 1
(a)]. We therefore examined the generation of cyclopro-
pylzinc intermediates through carbozincation of various cy-
clopropenes for subsequent ring opening to give allylzinc
intermediates. Here, we describe the efficient copper-cata-
lyzed carbometalation of nonfunctionalized cyclopropenes
by using organozinc or Grignard reagents [Scheme 1 (b)].
DOI: 10.1055/s-0034-1379959; Art ID: st-2014-u0860-l
Abstract A highly efficient method was developed for the copper(I)-
catalyzed carbometalation of various nonfunctionalized and functional-
ized cyclopropenes. Electrophilic trapping of the cyclopropylmetal in-
termediates gave multifunctionalized cyclopropanes.
Key words alkenes, catalysis, copper, magnesium, metalation, nucleo-
philic additions, organometallic reagents, zinc
The development of synthetic approaches to multifunc-
tionalized cyclopropanes is a challenging task in organic
chemistry. Nevertheless, because the multifunctional cy-
clopropane framework is found in various medicines and
natural products,1 many examples of syntheses of cyclopro-
panes have been reported in the literature. These involve
Simmons–Smith cyclopropanation,2 cyclopropanation of
diazo compounds with a rhodium,3 ruthenium,4 cobalt,5 sil-
ver,6 or iron catalysts,7 or addition of ylides to carbonyl
compounds.8 The carbometalation reaction of cyclopro-
penes is an efficient approach9 that has been extensively
developed by Fox10 and Marek11 and their respective co-
workers. In these reports, coordination to a copper center of
a hydroxy or ester group attached to a cyclopropene skele-
ton was shown to be essential for high reactivity and stere-
oselectivity. In contrast, a few methods have been reported
for carbometalation of 3,3-dialkylcyclopropenes with no
additional functional groups. In 2011, Lautens and co-
workers reported an enantioselective palladium-catalyzed
carbozincation of cyclopropenes;12–14 however, the use of a
fluorene derivative as a nonfunctionalized cyclopropene
was required to obtain a high yield of the desired product.
Therefore, the limited structural versatility available de-
mands the development of new and efficient catalysts for
the carbometalation of cyclopropenes.
previous work
Zn
R1
R1
R1
R22Zn, L1
(a)
R2
R1
R1 = OR
this work
low conversion
R1
R1
R2
R1
R1
R2M, Cu, L1
(b)
M
Me2N
N
O
L1 =
NEt2
Scheme 1 Reaction of cyclopropenes with organometallic reagents
The reaction conditions were optimized by using 3,3-di-
phenylcyclopropene (1a) as a substrate (Table 1). We found
that the reaction of 1a with diethylzinc (3 equiv) in the
presence of copper(I) iodide (20 mol%) and ligand L1 (25
mol%; Figure 1) promoted carbozincation to give the de-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 671–675

672
T. Nakano et al.
Letter
Synlett
Me2N
uct 2a-i-Pr; isopropylmagnesium chloride, however, gave a
high yield of 2a-i-Pr (entry 2). On the other hand, cyclopro-
pylzinc bromide gave the corresponding product 2a-c-Pr in
high yield (entry 3). When butyl- or allylmagnesium bro-
mide was used, the corresponding products 2a-n-Bu and
2a-Allyl were obtained in high yields (entries 4 and 6). On
the other hand, bulky tert-butyl and isopropenyl magne-
sium bromides did not give any of the corresponding prod-
ucts (entries 5 and 7). Benzyl- and phenylmagnesium bro-
mide can also be used in this reaction (entries 8 and 9).
Next, we examined the reactions of several 3,3-dialkylcy-
clopropenes. When 3,3-diarylcyclopropenes 1b–d (Figure
2) bearing an electron-donating or electron-withdrawing
group on the benzene ring were used, the corresponding
products 2b–d were obtained in high yields (entries 10–
12). The spirocyclopropene 1e also gave the desired prod-
uct 2e in high yield (entry 13). Furthermore, the cyclopro-
penedicarboxylate 1f gave the desired product 2f in good
yield (entry 14).
Me2N
N
O
O
N
O
O
NEt2
NMe2
NEt2
Ph
L1
Figure 1 List of ligands
L2
L3
sired product 2a-Et in high yield (Table 1, entry 1). In the
absence of the copper catalyst or ligand, 2a-Et was obtained
in a low yield (entries 2 and 3). With other ligands, such as
L2, L3, or N,N,N′,N′-tetramethylethylenediamine, product
2a-Et was obtained in good yield (entries 4–6). Further op-
timization of the reaction conditions (entries 7–10) showed
that the use of copper(I) iodide (5 mol%), diethylzinc (2
equiv), and ligand L1 (7.5 mol%) gave the desired product
2a-Et in 86% yield (entry 9). When the Grignard reagent
ethylmagnesium bromide was used instead of diethylzinc
in the presence of copper(I) iodide and ligand L1, product
2a-Et was obtained in high yield (entries 11 and 12). There-
fore, the catalyst system is suitable for use with both or-
ganozinc and Grignard reagents.
Table 2 Scope of Substrates
CuI (5 mol%)
R2M (2.0 equiv)
L1 (7.5 mol%)
R1
R1
R2
Table 1 Optimization of the Reaction Conditions
R1
R1
toluene, r.t.
16 h
CuI
1a–f
2
Et2Zn or EtMgBr
Ph
Ph
Ph
Ph
ligand
Entry
1
Reagent
Et2Zn
Product
Yield (%)
Et
toluene, r.t.
16 h
1
2
1a
2a-Et
2a-i-Pr
2a-c-Pr
2a-Bu
–
86
81
88
84
NDa
85
ND
77
93
73
82
98
91
68
2a-Et
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
i-PrMgBr
c-PrZnBr
BuMgBr
t-BuMgBr
AllylMgBr
CH2=C(Me)MgBr
BnMgBr
PhMgBr
Et2Zn
Entry
1
CuI (mol%)
Et2Zn (equiv)
Ligand (mol%)
L1 (25)
L1 (25)
–
Yield (%)
91
3
20
–
3.0
1.5
3.0
3.0
3.0
3.0
3.0
3.0
2.0
2.0
2.0b
2.0b
4
2
NDa
<30
87
5
3
20
20
20
20
10
5
6
2a-Allyl
–
4
L2 (25)
L3 (25)
TMEDA (25)
L1 (15)
L1 (7.5)
L1 (7.5)
L1 (3)
7
5
73
8
2a-Bn
2a-Ph
2b
6
77
9
7
85
10
11
12
13
14
8
89
Et2Zn
2c
9
5
86
Et2Zn
2d
10
11
12
1
<40
56
PhMgBr
Et2Zn
2e
5
–
2f
5
L1 (7.5)
81
a ND = not detected; unidentified products were obtained.
a ND = not detected.
b EtMgBr was used instead of Et2Zn.
We also examined the electrophilic trapping of the cy-
clopropylzinc intermediate A (Scheme 2).17 The reaction us-
ing diiodine or allyl bromide after carbozincation of 1a gave
the corresponding multifunctionalized cyclopropanes 3a-
Et-I and 3a-Et-Allyl in moderate to high yields. When ethyl-
magnesium bromide was used instead of diethylzinc, the
electrophilic trapping reaction proceeded more smoothly
Using the optimized reaction conditions, we performed
carbometalation of 3,3-diphenylcyclopropene (1a) with
various organometallic reagents (Table 2). Whereas dieth-
ylzinc gave the desired product in high yield (entry 1), di-
isopropylzinc gave a poor yield of the corresponding prod-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 671–675

673
T. Nakano et al.
Letter
Synlett
tion and subsequent C–C bond cleavage seem to be essen-
tial for allylzincation.16 We hypothesized that cyclopropyl-
zinc intermediates generated by copper-catalyzed
carbozincation participate in the allylzincation of aldehydes
in the presence of an appropriate catalyst. However, the de-
sired allylation of benzaldehyde did not proceed, and only
the ethyl adduct 2g was observed on TLC analysis, even in
the presence of a stoichiometric amount of L1 (Scheme
4).18,19 The electrophilic trapping of cyclopropylmetal inter-
mediates by using a Grignard reagent and benzoyl chloride
gave the desired product 5a and 5b, whereas reactions us-
ing other electrophiles with diethylzinc gave complicated
mixtures (Table 3).20 These results suggest that the ring
opening of cyclopropene might not proceed through car-
bozincation of the cyclopropenes to generate allylmetal in-
termediates. Further studies will be required to elucidate
the mechanism of the generation of allylmetal intermedi-
ates derived from cyclopropenes.
1a
1c
1b
Cl
F
Cl
F
1d
O
O
MeO
OMe
1e
1f
Figure 2 List of cyclopropenes 1a–f
Table 3 Electrophilic Trapping of Alkyl- or Arylcyclopropenes
CuI (5 mol%)
to give 3a-Et-I and 3a-Et-Allyl, respectively, in high yields.
Furthermore, 3a-Et-Bz was obtained in high yield by using
benzoyl chloride.
Et–M (2.0 equiv)
R
Ph
L1 (7.5 mol%)
toluene, r.t.
6 h
1g (R = Me)
1h (R = i-Pr)
CuI (5 mol%)
Et2Zn (2 equiv)
L1 (7.5 mol%)
Ph
Ph
CuI (2 equiv)
E–X (3 equiv)
Ph
Ph
R
Ph
toluene, r.t.
6 h
EtZn
Et
r.t., 15 h
A
E
Et
1a
5a (R = Me)
5b (R = i-Pr)
CuI (2 equiv)
E-X (3 equiv)
Ph
Ph
Entry
Substrate
M
EX
Product
Yield (%)
E
Et
CH2Cl2, 60 °C,
15 h
3
1
2
3
4
5
6
7
1g
1g
1g
1g
1g
1g
1h
ZnEt
ZnEt
ZnEt
MgBr
MgBr
MgBr
MgBr
I2
–
NDa
E-X = I–I (3a-Et-I: 86%)
Allyl–Br (3a-Et-Allyl: 63%)
AllylBr
BzCl
I2
–
ND
–
ND
–
ND
CuI (5 mol%)
EtMgBr (2 equiv)
L1 (7.5 mol%)
AllylBr
BzCl
BzCl
–
ND
Ph
Ph
5a
5b
60 (dr 6:1)
39 (dr 3:1)
Ph
Ph
toluene, r.t.
6 h
BrMg
Et
a ND = not detected; unidentified products were obtained.
B
1a
CuI (2 equiv)
E-X (3 equiv)
Ph
Ph
In summary, we have developed a copper(I) iodide and
hydrazone amide catalyzed carbometalation of cyclopro-
penes. The present carbometalation does not require func-
tionalized substrates or expensive transition-metal cata-
lysts. Various organometallic reagents and cyclopropenes
can be used in this reaction for the synthesis of multifunc-
tional cyclopropanes. The reaction with additional electro-
philes after the carbometalation reaction of cyclopropenes
gave the corresponding multifunctional cyclopropanes
r.t., 15 h
E
Et
3
E-X = I–I (3a-Et-I: 88%)
Allyl–Br (3a-Et-Allyl: 98%)
Bz–Cl (3a-Et-Bz: 86%)
Scheme 2 Electrophilic trapping reaction
We previously reported the allylation of benzaldehyde
with an allylzinc intermediate derived from dialkylzinc re-
agents and a cyclopropene (Scheme 3).15a The carbozinca-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 671–675

674
T. Nakano et al.
Letter
Synlett
Me Ph
Et2Zn (1.3 equiv)
L1 (25 mol%)
Me
Ph
Ph
PhCHO
r.t., 18 h
Et
OH
toluene, r.t., 10 min
1g
(1.3 equiv)
4 31%
Scheme 3 Tandem reaction of cyclopropene, diethylzinc, and benzaldehyde
without the generation of a ring-opening product that we
reported previously.14 Further studies with cyclopropenes
and organometallic reagents are in progress.
(7) Hamaker, C. G.; Mirafzal, G. A.; Woo, L. K. Organometallics 2001,
20, 5171.
(8) (a) Tang, Y.; Huang, Y.-Z.; Dai, L.-X.; Sun, J.; Xia, W. J. Org. Chem.
1997, 62, 954. (b) Wurz, R. P.; Charette, A. B. Org. Lett. 2002, 4,
4531. (c) Akagawa, K.; Takigawa, S.; Nagamine, I. S.; Umezawa,
R.; Kudo, K. Org. Lett. 2013, 15, 4964.
(9) For recent examples of carbometalation reactions of C–C multi-
ple bonds, see: (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am.
Chem. Soc. 2000, 122, 978. (b) Zhang, D.; Ready, J. M. J. Am.
Chem. Soc. 2006, 128, 15050. (c) Negishi, E.-i. Bull. Chem. Soc.
Jpn. 2007, 80, 233. (d) Shirakawa, E.; Ikeda, D.; Masui, S.;
Yoshida, M.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 272.
(10) (a) Yan, N.; Liu, X.; Fox, J. M. J. Org. Chem. 2008, 73, 563.
(b) Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009,
131, 5382. (c) Tarwade, V.; Selvaraj, R.; Fox, J. M. J. Org. Chem.
2012, 77, 9900.
CuI (5 mol%)
Et2Zn (2.0 equiv)
L1 (7.5 mol%)
L1 (X mol%)
PhCHO (2.5 equiv)
Me
Ph
Me
Ph
r.t., 18 h
X = 0 or 100
Me Ph
Et
toluene, r.t.
6 h
2g
Me
1g
Ph
Ph
Ph
or
Et
Et
OH
OH
not obtained
(11) (a) Simaan, S.; Marek, I. Org. Lett. 2007, 9, 2569. (b) Didier, D.;
Delaye, P.-O.; Simaan, M.; Island, B.; Eppe, G.; Eijsberg, H.;
Kleiner, A.; Knochel, P.; Marek, I. Chem. Eur. J. 2014, 20, 1038.
(c) Delaye, P. O.; Didier, D.; Marek, I. Angew. Chem. Int. Ed. 2013,
52, 5333.
(12) Krämer, K.; Leong, P.; Lautens, M. Org. Lett. 2011, 13, 819.
(13) For reviews on cyclopropenes, see: (a) Nakamura, M.; Isobe, H.;
Nakamura, E. Chem. Rev. 2003, 103, 1295. (b) Rubin, M.; Rubina,
M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c) Zhu, Z.-B.;
Wei, Y.; Shi, M. Chem. Soc. Rev. 2011, 40, 5534.
(14) Nakamura has reported recent pioneering works on carbometa-
lation of cyclopropanes; see: (a) Nakamura, E.; Isaka, M.;
Matsuzawa, S. J. Am. Chem. Soc. 1988, 110, 1297. (b) Isaka, M.;
Nakamura, E. J. Am. Chem. Soc. 1990, 112, 7428. (c) Kubota, K.;
Nakamura, M.; Isaka, M.; Nakamura, E. J. Am. Chem. Soc. 1993,
115, 5867. (d) Nakamura, M.; Arai, M.; Nakamura, E. J. Am.
Chem. Soc. 1995, 117, 1179. (e) Kubota, K.; Isaka, M.; Nakamura,
E. Heterocycles 1996, 42, 565. (f) Nakamura, E.; Kubota, K. J. Org.
Chem. 1997, 62, 792.
(15) (a) Nakano, T.; Endo, K.; Ukaji, Y. Org. Lett. 2014, 16, 1418.
(b) Endo, K.; Nakano, T.; Fujinami, S.; Ukaji, Y. Eur. J. Org. Chem.
2013, 6514.
(16) Addition of R3Al to cyclopropenes and a subsequent ring
opening gave allylaluminum intermediates; see: (a) Richey, H.
G. Jr.; Kubala, B.; Smith, M. A. Tetrahedron Lett. 1981, 22, 3471.
(b) Smith, M. A.; Richey, H. G. Jr. Organometallics 2007, 26, 609.
(c) Wang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew.
Chem. Int. Ed. 2008, 47, 7350.
Scheme 4 Reaction of cyclopropylzinc intermediate with benzalde-
hyde
Acknowledgment
This work was supported by the JST PRESTO program and a Grant-in-
Aid for Scientific Research (B).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379959.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References
(1) (a) Wakamiya, T.; Oda, Y.; Fujita, H.; Shiba, T. Tetrahedron Lett.
1986, 27, 2143. (b) Donaldson, W. A. Tetrahedron 2001, 57,
8589. (c) Pietruszka, J. Chem. Rev. 2003, 103, 1051.
(d) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4493.
(2) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323.
(b) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256.
(c) Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632.
(d) Lorenz, J. C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. J. Org.
Chem. 2004, 69, 327. (e) Long, J.; Xu, L.; Du, H.; Li, K.; Shi, Y. Org.
Lett. 2009, 11, 5226.
(3) (a) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262.
(b) Panne, P.; DeAngelis, A.; Fox, J. M. Org. Lett. 2008, 10, 2987.
(c) Gregg, T. M.; Farrugia, M. K.; Frost, J. R. Org. Lett. 2009, 11,
4434. (d) Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem.
Soc. 2009, 131, 16383.
(17) Carbozincation and Subsequent Trapping; Typical Proce-
dures
1,1′-(2-Ethylcyclopropane-1,1-diyl)dibenzene
(2a-Et);
Typical Procedure
A 1.0 M solution of Et2Zn in toluene (0.6 mL) was added to a
solution of CuI (2.9 mg, 0.015 mmol) in toluene (1.5 mL) at r.t.,
and the mixture was stirred for 30 min. L1 (5.4 mg, 0.023
mmol) and 3,3-diphenylcyclopropene (1a; 57.7 mg, 0.3 mmol)
were added at r.t., and the mixture was stirred for 16 h. The
reaction was quenched with sat. aq NH4Cl (2 mL), and the
aqueous layer was separated and extracted with EtOAc (3 × 3 mL).
(4) Chanthamath, S.; Nguyen, D. T.; Shibatomi, K.; Iwasa, S. Org.
Lett. 2013, 15, 772.
(5) Fantauzzi, S.; Gallo, E.; Rose, E.; Raoul, N.; Caselli, A.; Issa, S.;
Ragaini, F.; Cenini, S. Organometallics 2008, 27, 6143.
(6) Thompson, J. L.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
6090.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 671–675

675
T. Nakano et al.
Letter
Synlett
The organic layers were combined, dried (Na2SO4), concentrated,
and purified by column chromatography (silica gel, hexane) to
give a colorless oil; yield: 57.2 mg (86%).
1,1′-(2-Ethyl-3-iodocyclopropane-1,1-diyl)dibenzene (3a-Et-
I); Typical Procedure
A 1.0 M soln of Et2Zn in toluene (0.6 mL) was added to a solu-
tion of CuI (2.9 mg, 0.015 mmol) in toluene (1.5 mL) at r.t. and
the mixture was stirred for 30 min. L1 (5.4 mg, 0.023 mmol)
and 3,3-diphenylcyclopropene (1a; 57.7 mg, 0.3 mmol) were
added at r.t. and the mixture was stirred for 6 h. CuI (116 mg,
0.6 mmol) and a solution of I2 (228 mg, 0.9 mmol) in CH2Cl2 (1.5
mL) were then added, and the mixture was stirred for addi-
tional 15 h at 60 °C. The reaction was quenched with sat. aq
NH4Cl (3 mL), and the aqueous layer was separated and
extracted with EtOAc (5 × 3 mL). The organic layers were com-
bined, dried (Na2SO4), concentrated, and purified by column
chromatography (silica gel, hexane) to give a colorless oil; yield
95.6 mg (86%).
(18) Spontaneous decomposition of product 2g occurred under neu-
tral, acidic, or basic conditions; the reason is unclear.
(19) When cyclopropene 1f was used as a substrate, ring opening of
the cyclopropylzinc intermediate also did not occur.
(20) The relative configuration of products 5a and 5b could not be
determined; see the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 671–675

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.