Synthesis of alicyclic esters via an intramolecular conjugate addition reaction. New method for generating (Z)-vinylcopper species from 1,1-dibromoalkenes

Article abstract of DOI:10.1016/j.tetlet.2005.12.002

A novel cyclization reaction of a 1,1-dibromoalkene derivative having an α,β-unsaturated ester moiety was developed. Under the influence of Me₂CuLi, the 1,1-dibromoalkene was converted into a (Z)-vinylcopper species which in turn underwent an i

Full text of DOI:10.1016/j.tetlet.2005.12.002

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 861–864
Synthesis of alicyclic esters via an intramolecular conjugate
addition reaction. New method for generating
(Z)-vinylcopper species from 1,1-dibromoalkenes
Keiji Tanino,* Keisuke Arakawa, Mikiya Satoh, Yasuhiro Iwata and Masaaki Miyashita*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 13 November 2005; revised 28 November 2005; accepted 1 December 2005
Available online 19 December 2005
Abstract—A novel cyclization reaction of a 1,1-dibromoalkene derivative having an a,b-unsaturated ester moiety was developed.
Under the influence of Me2CuLi, the 1,1-dibromoalkene was converted into a (Z)-vinylcopper species which in turn underwent
an intramolecular conjugate addition reaction with the a,b-unsaturated ester moiety. Five-, six-, and seven-membered carbocycles
were constructed by the present method. The substrate having an epoxide moiety also afforded a five-membered product via a 5-exo
type intramolecular cyclization reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Conjugate addition reactions of an organocopper spe-
OTIPS
CHO
OTIPS
Me
Ph3P C
cies with an a,b-unsaturated carbonyl compound have
found widespread use in organic synthesis.1 The intra-
molecular version of this type of reaction leads to for-
mation of a carbocyclic compound, and there have
been reported several methods for generating an
organocopper species possessing a Michael acceptor
moiety.2 Transmetalation reactions of organozinc,3
organotin,2,4 and organosilicon5 derivatives are particu-
larly advantageous for this purpose, because these orga-
nometallic compounds tolerate the presence of a wide
range of functional groups. While organozinc com-
pounds can be prepared from the corresponding organ-
ohalides by treating with activated zinc metal, there are
several reports on a halogen–metal exchange reaction
giving rise to an organocopper species directly.6
Me
I
I
1
2
3
Scheme 1. Synthetic plan of vinyl iodide 1 from aldehyde 2.
method on the basis of a halogen–metal exchange reac-
tion using an organocopper reagent. It is well known
that treatment of a 1,1-dihalocyclopropane derivative
with R2CuLi leads to stereoselective formation of an
endo cyclopropyl copper species (Scheme 2).8 The trans-
formation is initiated by a halogen–metal exchange reac-
tion at the less hindered exo halogen atom giving rise to
an a-halo organocopper intermediate, which in turn
undergoes 1,2-shift of the alkyl group with inversion
of the configuration at the a-carbon. We expected that
In the course of our studies toward the asymmetric total
synthesis of zincophorin,7 it was required to convert
optically active aldehyde 1 to tri-substituted vinyl iodide
2 with (Z)-configuration (Scheme 1).
X
X
Cu
–
X
CuR
R
R2CuLi
H
H
H
Since the Wittig reaction using phosphorane 3 failed to
give a satisfactory result, we planned to develop a new
H
H
H
C–uMe
Me
Cu
Me2CuLi
Br
Keywords: Cyclobutanone; Organocopper; Conjugate addition; Cycli-
zation; Dihaloalkene.
R
R
R
Br
Br
*
Corresponding authors. Tel.: +81 117062703; fax: +81 117064920
(K.T.); tel.: +81 117062705; fax: +81 117064920 (M.M.); e-mail
addresses: ktanino@sci.hokudai.ac.jp; miyasita@sci.hokudai.ac.jp
Scheme 2. Stereoselective formation of an organocopper species from
a 1,1-dihalo compound.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.002

862
K. Tanino et al. / Tetrahedron Letters 47 (2006) 861–864
a 1,1-dibromoalkene might undergo an analogous reac-
tion with Me2CuLi giving rise to a tri-substituted vinyl-
copper with (Z)-configuration.
CN OMe
OMe
a
CN OMe
( )n OMe
c, d
8
BnO
b
CN
Dibromoalkene 4 was prepared from aldehyde 1 via a
conventional method9 and reactions with an excess
amount of Me2CuLi were examined (Scheme 3).
Although a reaction in THF followed by quenching with
an aqueous NH4Cl solution gave a mixture of several
products, use of diethyl ether as a solvent led to selective
formation of (E)-alkene 5 in 88% yield. Further, addi-
tion of iodine to the reaction mixture gave rise to (Z)-
vinyl iodide 2 in 71% yield along with a small amount
of 1,1-dimethylalkene 6 and bromide 7.
BnO
9
CO2Et
Br
Br
CN
Br
Br
e, f
( )n
( )n
BnO
BnO
n = 1: 89% from 8
n = 2: 68% from 9
n = 1: 10 94%
n = 2: 11 97%
CN
a
CN
e, d
These results indicate that a vinylcopper species is gener-
ated smoothly from 4 in diethyl ether with high stereo-
selectivity. It is noteworthy that 1,1-dibromoalkenes
derived from ketones are known to undergo replacement
of both bromine atoms by methyl groups under the
influence of Me2CuLi.10 Interestingly, Harada and
Oku reported a similar transformation of a 1,1-di-
bromoalkene using an organozincate, which afforded a
vinylzinc species as a mixture of geometrical isomers.11
OBn
Br
84%
Br
Br
Br
g, f
EtO2C
OBn
OBn
12 79%
13 83%
Br
Br
The present method for generating a (Z)-vinylcopper
species led us to develop an intramolecular cyclization
reaction of 1,1-dibromoalkene derivatives having a
Michael acceptor moiety. Since an a,b-unsaturated
ketone was expected to undergo a rapid conjugate addi-
tion reaction with Me2CuLi, we chose an a,b-unsaturated
ester that generally exhibits lower reactivity as a Michael
acceptor. Several cyclization precursors were prepared
from nitriles having an acetal group or a prenyl group
as shown in Scheme 4.
d
h
O
H
(–)-citronellal
Br
Br
Br
Br
i, f
EtO2C
O
91% from citronellal
14 88%
Scheme 4. Synthesis of 1,1-dibromoalkene derivatives. Reagents and
conditions: (a) LDA, ICH2CH2OBn, THF; (b) LDA, BrCH2CH2-
CH(OMe)2, THF; (c) aq HCl, acetone; (d) CBr4, Ph3P, pyridine,
CH2Cl2; (e) DIBAL, hexane then aq HCl; (f) (EtO)2P(O)CH2CO2Et,
NaH, THF; (g) O3, MeOH then Me2S; (h) mCPBA, CH2Cl2; (i)
NaIO4, THF.
The cyclization reaction was performed by treating the
1,1-dibromoalkene derivative with an excess amount of
Me2CuLi at À78 °C followed by warming up to
À40 °C (Scheme 5). The desired products possessing a
five-, six-, or seven-membered ring were obtained in
good yield along with a small amount of an acyclic
a,b-unsaturated ester arising from a dimethylation reac-
tion of the 1,1-dibromoalkene moiety. Cyclopentene and
cyclohexene derivatives were obtained as an inseparable
10:1–2:1 mixture of diastereomers, while the cyclohep-
tene derivative was found to be a single isomer, though
the configuration of these products was not determined.
OTIPS
OTIPS
Me2CuLi
(3 eq)
Br
Me
Cu
ether
Br
–78 C
4
˚
OTIPS
aq. NH4Cl
Me
5 88%
Me2CuLi
Use of Bu2CuLi instead of Me2CuLi also effected a
smooth cyclization reaction of 10 giving rise to an ester
having a butyl group, while the corresponding (silyl-
methyl)copper reagent afforded an allylsilane in lower
yield (Scheme 6).
OTIPS
OTIPS
I2
(6 eq)
Br
Me
(3 eq)
ether
Br
I
4
–78 C
2
71%
˚
Finally, an intramolecular cyclization reaction of an
epoxide was briefly examined. Under the influence of
Me2CuLi, epoxide 16 derived from diene 12 underwent
a cyclization reaction to afford an alcohol in moderate
yield. On the other hand, the corresponding homologue
17 failed to form a six-membered ring, and acyclic epox-
ide was detected as the major product (Scheme 7).
Me
Me
+
+
Me
Br
6
7
Scheme 3. Selective synthesis of a vinyl iodide with (Z)-configuration
from a 1,1-dibromoalkene.

K. Tanino et al. / Tetrahedron Letters 47 (2006) 861–864
863
a,b-unsaturated ester moiety.12 Under the influence of
Me2CuLi, the 1,1-dibromoalkene was converted into a
(Z)-vinylcopper species which in turn underwent an
intramolecular conjugate addition reaction with the
a,b-unsaturated ester moiety. Five-, six-, and seven-
membered carbocycles were constructed by the present
method. The substrate having an epoxide moiety also
afforded a five-membered product via a 5-exo type intra-
molecular cyclization reaction. Applications to a total
synthesis of a natural product are currently under inves-
tigation in our laboratory.
EtO2C
EtO2C
Me2CuLi
(3 eq)
Br
Br
Cu
Me
Me
Me
ether
–78 ~ –40 C
BnO
˚
10
EtO2C
Me
+
aq. NH4Cl
EtO2C
BnO
BnO
trace
15 79%
Me
Me
Acknowledgements
EtO2C
BnO
EtO2C
Financial support from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan (a Grant-
in-Aid for Scientific Research on Priority Areas (No.
16073201), and a Grant-in-Aid for Scientific Research
(B) (No. 16350049)) is gratefully acknowledged.
OBn
79% from 13
EtO2C
61% from 11
Me
79% from 14
References and notes
Scheme 5. Cyclization reactions of 1,1-dibromoalkene derivatives
mediated by Me2CuLi.
1. (a) Posner, G. H. Org. React. 1972, 19, 1; (b) Chapdelaine,
M. J.; Hulce, M. Org. React. 1990, 38, 225; (c) Lipshutz,
B. H.; Sengupta, S. Org. React. 1992, 41, 135; (d) Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VHC:
Weinheim, 2002.
2. For an example, see: Piers, E.; McEachern, E. J.; Burns, P.
A. Tetrahedron 2000, 56, 2753.
3. Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E.
Org. React. 2001, 58, 417.
4. Behling, J. R.; Babiak, K. A.; Ng, S. J.; Campbell, A. L.;
Moretti, R.; Koerner, M.; Lipshutz, B. H. J. Am. Chem.
Soc. 1988, 110, 2641.
5. Miura, K.; Hosomi, A. In Main Group Metals in Organic
Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley-VHC:
Weinheim, 2004; Vol. 2, pp 541–543.
EtO2C
R
R2CuLi
(5 eq)
Br
Br
EtO2C
ether
BnO
BnO
–78 ~ 0 C
˚
10
R = Bu: 72%
R = CH2SiMe3: 47%
Scheme 6. Synthesis of cyclopentene derivatives having other
substituents.
6. (a) Corey, E. J.; Kuwajima, I. J. Am. Chem. Soc. 1970, 92,
395; (b) Corey, E. J.; Narisada, M.; Hiraoka, T.; Elljson,
R. A. J. Am. Chem. Soc. 1970, 92, 396; (c) Yamamoto, H.;
Kitatani, K.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 5816; (d) Szymoniak, J.; Thery, N.; Mo¨ıse, C.
Bull. Soc. Chim. Fr. 1997, 134, 85.
Br
Me
R2CuLi
(5 eq)
Br
Cu
OBn
ether
O
O
–78 ~ 0 C
˚
7. Komatsu, K.; Tanino, K.; Miyashita, M. Angew. Chem.,
Int. Ed. 2004, 43, 4341.
16
Me
8. Kitatani, K.; Hiyama, T.; Nozaki, H. Bull. Chem. Soc.
Jpn. 1977, 50, 1600; See also: Corey, E. J.; Posner, G. H. J.
Am. Chem. Soc. 1967, 89, 3911; Dauben, W. G.; Welch,
W. M. Tetrahedron Lett. 1971, 4531; Descoins, C.; Julia,
M.; van Sang, H. Bull. Soc. Chim. Fr. 1971, 4087.
9. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
10. Posner, G. H.; Loomis, G. L.; Sawaya, S. Tetrahedron
Lett. 1975, 1373.
11. Harada, T.; Katsuhira, T.; Hara, D.; Kotani, Y.; Mae-
jima, K.; Kaiji, R.; Oku, A. J. Org. Chem. 1993, 58, 4897.
12. Typical procedure: To a suspension of CuI (114 mg,
0.60 mmol) in diethyl ether (1.2 mL) was added a 1.2 M
diethyl ether solution of MeLi (1.0 mL, 1.20 mmol) at
0 °C. The resulting clear solution of Me2CuLi was cooled
to À78 °C, and a solution of ester 10 (89 mg, 0.20 mmol)
in diethyl ether (0.8 mL) was added. After being stirred for
30 min at À78 °C and for 30 min at À40 °C, saturated
aqueous NH4Cl solution was added. The aqueous layer
was extracted with diethyl ether and the combined organic
HO
65%
OBn
Br
Me
same
as above
Br
O
O
17
OBn
OBn
Scheme 7. Reactions of 1,1-dibromoalkene derivatives having an
epoxide moiety.
In conclusion, we have developed a novel cyclization
reaction of a 1,1-dibromoalkene derivative having an

864
K. Tanino et al. / Tetrahedron Letters 47 (2006) 861–864
layer was washed with brine and dried over MgSO4.
J = 14.7 Hz, 1H), 2.39–2.53 (m, 2H, involving a doublet at
2.45, J = 14.7 Hz), 2.53–2.63 (m, 1H), 3.48 (t, J = 7.4 Hz,
3H), 4.11 (q, J = 7.2 Hz, 2H), 4.48 (d, J = 11.8 Hz, 1H),
4.50 (d, J = 11.8 Hz, 1H), 5.25–5.30 (m, 1H), 7.25–7.32
(m, 5H); 13C NMR (67.5 MHz, CDCl3): d 14.32, 15.00,
35.86, 37.31, 38.23, 41.05, 51.15, 60.25, 68.98, 72.80,
124.35, 127.31, 127.45, 128.18, 138.53, 140.69, 172.94.
Concentration under reduced pressure followed by silica
gel column chromatography afforded the desired ester 15
(48 mg, 79%) as a 10:1 mixture of diastereomers: IR (neat)
1
2854, 1732 cmÀ1; H NMR (270 MHz, CDCl3): d 1.24 (t,
J = 7.2 Hz, 3 H), 1.55–1.71 (m, 4H, involving a singlet at
1.64), 1.76–1.97 (m, 2H), 2.02–2.13 (m, 1H), 2.25 (d,