Alkylation of 4-substituted 1-acetoxy-2-cyclopentenes by using copper reagents derived from alkylmagnesium halides and copper(I) cyanide

Article abstract of DOI:10.1016/S0040-4039(02)00915-2

Alkylation of the acetates derived from 4-phenyl- and 4-butyl-2-cyclopenten-1-ols 2 was investigated with copper reagents derived from n-BuMgX (X=Cl, Br) and CuCN in 2:1 and 1:1 ratios in THF and in Et₂O. cis 1,4-Isomers 4a,b (R=Ph, n-Bu) were produced regioselectively from the corresponding trans acetates 3a,b with the reagent in a 2:1 ratio of BuMgCl and CuCN in THF, while the BuMgBr-based reagents of 2:1 and 1:1 ratios in Et₂O furnished cis 3,4-isomers 5a,b. A similar tendency was obtained with cis acetates 6a,b (R=Ph, n-Bu).

Full text of DOI:10.1016/S0040-4039(02)00915-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4829–4832
Alkylation of 4-substituted 1-acetoxy-2-cyclopentenes by using
copper reagents derived from alkylmagnesium halides and
copper(I) cyanide
Yuichi Kobayashi,* Michiko Ito and Junji Igarashi
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501,
Japan
Received 15 March 2002; revised 7 May 2002; accepted 10 May 2002
Abstract—Alkylation of the acetates derived from 4-phenyl- and 4-butyl-2-cyclopenten-1-ols 2 was investigated with copper
reagents derived from n-BuMgX (X=Cl, Br) and CuCN in 2:1 and 1:1 ratios in THF and in Et2O. cis 1,4-Isomers 4a,b (R=Ph,
n-Bu) were produced regioselectively from the corresponding trans acetates 3a,b with the reagent in a 2:1 ratio of BuMgCl and
CuCN in THF, while the BuMgBr-based reagents of 2:1 and 1:1 ratios in Et2O furnished cis 3,4-isomers 5a,b. A similar tendency
was obtained with cis acetates 6a,b (R=Ph, n-Bu). © 2002 Elsevier Science Ltd. All rights reserved.
Installation of carbon nucleophiles on the cyclopentane
(or -ene) ring is an important step for synthesis of
cyclopentanoids. Recently, we have published
arylation1a and alkenylation1b of monoacetate 1 using
borates and nickel catalysis, and later, alkylation2 of 1
using copper reagents derived from alkylmagnesium
halides and copper(I) salts (Scheme 1, Eq. (1)). The
allylic alcohol moiety on the ring of these reaction
products 2 is the reaction site for installation of a
second carbon nucleophile by allylation, and thence it is
practically worthwhile to find reagents which furnish
high regio- and stereoselectivities as well as efficient
reactivity in the allylation of easily preparable 2. How-
ever, to the best of our knowledge, this sort of reaction
was little studied even with related compounds. We
investigated alkylation of trans and cis acetates 3 and 6
derived from alcohols 2 with the reagents prepared
from butylmagnesium halides and CuCN, the result of
which is presented in this letter. In addition, we applied
the reaction to synthesis of dihydromultifidene.3
Standard acetylation of alcohols 2a (R=Ph) and 2b
(R=n-Bu) with Ac2O and pyridine afforded trans
acetates 3a and 3b in 91 and 99% yields, respectively,
while the Mitsunobu reaction4 (AcOH, DEAD, PPh3)
at −78°C in toluene furnished cis acetates 6a and 6b
with >99% diastereoselectivity in 90 and 84% yields,
respectively.
On the basis of the previous results that the reactivity
and regioselectivity in reaction of 1 are highly con-
trolled by the ratio of RMgX/CuCN and the solvent
(THF, Et2O),5 three reagents (each 3 equiv.) consisting
of different compositions of BuMgCl and CuCN in
THF were submitted to the reaction with trans acetate
3a (R=Ph) (Table 1, entries 1–3). The lower order
(LO)6 reagent (entry 1) was less reactive, producing cis
3,4-isomer 5a only in 18% yield. On the other hand, the
Scheme 1. Previous and present works. note: R for 2–8: a, Ph;
b, n-Bu.
Keywords: allylic coupling reaction; copper reagents; Grignard
reagents; dihydromultifidene.
* Corresponding author. Tel.: +81-45-924-5789; fax: +81-45-924-5789;
e-mail: ykobayas@bio.titech.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00915-2

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Y. Kobayashi et al. / Tetrahedron Letters 43 (2002) 4829–4832
Table 1. Butylation of trans acetates 3a and 3b
Entry
Acetate
Reagenta
Solvent
Temp. (°C)
Time (h)
Major
product
Combined
yieldb,c
Ratio of
Other compds. (%)
Acetatee Alcoholf
4:5d
1
2
3
3a
3a
3a
BuCu(CN)(MgCl)
Bu2Cu(CN)(MgCl)2
BuMgCl, CuCN
(cat.)g
THF
THF
THF
0
−18
−18
5
5
8
5a
4a
4a
18
82 (71)
19
1:\99
83:17
87:13
90
–
29
–
13
52
4
5
6
7
8
9
10
11
12
3a
3a
3a
3a
3a
3a
3b
3b
3b
BuCu(CN)(MgCl)
Bu2Cu(CN)(MgCl)2
BuCu(CN)(MgBr)
Bu2Cu(CN)(MgBr)2
BuCu(CN)(MgBr)
Bu2Cu(CN)(MgBr)2
BuCu(CN)(MgCl)
Bu2Cu(CN)(MgCl)2
BuMgCl, CuCN
(cat.)g
Et2O
Et2O
THF
THF
Et2O
Et2O
THF
THF
THF
0
−18
0
−18
0
−18
0
−18
−18
10
5
5
5
5
5
7
5
5
5a
5a
5a
5a
5a
5a
5b
4b
4b
74
90
20
1:\99
7:93
26
–
80
13
–
–
49
–
–
15
7
23
–
–
–
2
54
1:\99
47:53
1:\99
1:\99
1:\99
91:9
52
97 (91)
100 (94)
50
84
42
91:9
–
13
14
3b
3b
BuCu(CN)(MgBr)
Bu2Cu(CN)(MgBr)2
Et2O
Et2O
0
5
5
5b
5b
99 (85)
93 (73)
2:98
2:98
–
–
–
–
−18
a Three equiv. of the reagents were used.
b Determined by 1H NMR with pyridine as a standard.
c Isolated yields are given in parentheses.
d Determined by 1H NMR spectroscopy.
e 3a for entries 1, 3, 4, 6, and 7; 3b for entries 10 and 12.
f 2a for entries 2, 3, and 5–7; 2b for entries 11 and 12.
g 10 mol%.
higher order (HO)6 and CuCN-catalyzed reagents pro-
duced cis 1,4-isomer 4a though alcohol 2a and/or ace-
tate 3a were co-produced with 4a. In entry 2, the
isolated yield was 71%.7 These results are beyond our
prediction.8 Since the yield of 3,4-isomer 5a obtained in
THF was quite low (entry 1), the LO and HO reagents
were re-examined in Et2O (entries 4 and 5). Both
reagents furnished 5a with high product selectivity; of
the two reagents, higher reactivity and higher yield were
obtained with the HO reagent (entry 5). We also
checked the BuMgBr-based reagents in THF and in
Et2O (entries 6–9). Among them, the best results were
provided with Et2O (entries 8 and 9), giving 5a in 91
and 94% isolated yields, respectively.9
elucidated for the butylation of 3a (R=Ph) are applica-
ble to that of 3b (R=n-Bu), the conditions given in
entries 1–9 were investigated for butylation of 3b. Simi-
lar tendencies for the reactivity and the regioselectivity
were observed through the experiments; some of the
results are presented in entries 10–14. The regioisomers
4b and 5b were best synthesized in entry 11 for 4b and
in entries 13, 14 for 5b, respectively.
Next, butylation of cis acetates 6a (R=Ph) and 6b
(R=Bu) was investigated using the LO and HO
reagents. Among the eight experiments with 6a (combi-
nation of LO or HO, X=Cl or Br, and THF or Et2O),
the BuMgCl-based HO reagent in THF and the
BuMgBr-based LO reagent in Et2O provided the best
results producing trans 7a and 8a, respectively (Table 2,
Although it was conceived that the best conditions
Table 2. Butylation of cis acetates 6a and 6b
Entry
Acetate
Reagenta
Solvent
Temp. (°C)
Time (h)
Major
product
Combined
yieldb
Ratio of
Other compds. (%)
Acetated Alcohole
7:8c
1
2
3
4
6a
6a
6b
6b
Bu2Cu(CN)(MgCl)2
BuCu(CN)(MgBr)
Bu2Cu(CN)(MgCl)2
BuCu(CN)(MgBr)
THF
Et2O
THF
Et2O
−18
0
−18
0
5
7
5
7
7a
8a
7b
8b
96
67:33
3:97
55:45
5:95
–
–
–
–
2
–
–
–
100 (90)f
96
100
a Three equiv. of the reagents were used.
b Determined by 1H NMR with pyridine as a standard.
c Determined by 1H NMR spectroscopy.
d Acetates 6a and 6b were not recovered in entries 1–4.
e 9a for entry 1. In other entries, the corresponding alcohol 9a or 9b were not detected.
f Isolated yield.

Y. Kobayashi et al. / Tetrahedron Letters 43 (2002) 4829–4832
4831
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
AcOH
n-BuMgBr (3.0 equiv)
HO
OAc
PPh3, DEAD
CuCN (3.3 equiv)
HO
AcO
Pd(PPh3)4 (cat.)
63%
toluene, –78 °C
86%
Et2O, –45 °C, 5 h
63%
1
10
11
ref. 14
CO2Me
1) NaI, H2O
DMI
OH
two steps
ref. 3b
CO2Me
2) LiAlH4
81%
12
13
14
dihydromultifidene
Scheme 2. Racemic synthesis of dihydromultifidene.
entries 1 and 2), though the regioselectivity for the
former was moderate. Regarding cis acetate 6b, trans
1,4-isomer 7b was obtained with the HO reagent, but
with a poor regioselectivity (entry 3), while 3,4-isomer
8b was produced in high ratio and yield (entry 4).
using the LO reagent in Et2O (the conditions of entry 8
in Table 1), which required lower temperature of −45°C
to obtain a high diastereomeric ratio (91:1) of 12 and
an isomer.15,16 The acidic proton at the malonate part
did not quench the reagent. Demethoxycarbonylation
of 12 followed by reduction afforded alcohol 13 in good
yield. Finally, 13 was converted into 14 according to
the literature procedure.3b The 1H NMR spectra of
synthetic 14 was consistent with the data reported.3c,17
HO
R
9a: R = Ph
9b: R = Bu
The stereochemistry of the 1,4-regioisomers 4a,b and
Acknowledgements
1
7a,b was easily determined by H NMR spectroscopy:
in general, differences in chemical shifts between the
geminal protons at C(5) of cis and trans 1,4-disubsti-
tuted 2-cyclopentenes are >1 and <0.3 ppm, respec-
tively.10 In the spectra of 4a and 4b, the differences in
question were 1.3 and 1 ppm, respectively, thus sup-
porting the cis stereochemistry for them, while those
measured for 7a and 7b were 0.1 and 011 ppm, respec-
tively, by which the trans stereochemistry was assigned
for them (7a and 7b). These stereochemical outcomes
strongly suggest the inversion and the anti SN2% reac-
tions to be involved depending on the ratio of BuMgX/
CuCN and the solvent, the same reaction mode as that
observed for the alkylation of monoacetate 1.2 Further-
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
References
1. (a) Kobayashi, Y.; Takahisa, E.; Usmani, S. B. Tetra-
hedron Lett. 1998, 39, 597–600; (b) Usmani, S. B.;
Takahisa, E.; Kobayashi, Y. Tetrahedron Lett. 1998, 39,
601–604.
1
more, with the H NMR spectra of these products, no
2. Ito, M.; Matsuumi, M.; Murugesh, M. G.; Kobayashi, Y.
contamination of the corresponding stereoisomers in
the entries of Tables 1 and 2 was confirmed. Regarding
3,4-isomers, the cis stereochemistry of 5a was deter-
mined by an NOE experiment,12 while stereochemistries
of the other products 5b, 8a, and 8b were assigned by
analogy to the above assignments.
J. Org. Chem. 2001, 66, 5881–5889.
3. Previous syntheses: (a) Boland, W.; Mertes, K. Helv.
Chim. Acta 1984, 67, 616–624; (b) Kramp, P.; Helmchen,
G.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1993,
551–552; (c) Lebreton, J.; Alphand, V.; Furstoss, R.
Tetrahedron 1997, 53, 145–160.
4. Mitsunobu, O. Synthesis 1981, 1–28.
With the establishment of the product prediction in the
reaction of acetates 3a,b and 6a,b, application in
organic synthesis has now become quite feasible. As an
example, synthesis of alcohol 13 was achieved as sum-
marized in Scheme 2. This alcohol is the key
intermediate3b for synthesis of dihydromultifidene (14),
which is a pheromone of the brown algae, Dictyopteris
acrostichoides.13
5. For information in detail, see Table 1 of Ref. 2.
6. Although the structures of copper reagents derived from
butylmagnesium halides and Cu(I) salt are not deter-
mined, the terms ‘LO, HO, and CuCN-catalyzed
reagents’ are conveniently used to indicate the ratios of
1:1, 2:1, and 10:1 for the reagents derived from BuMgX
and CuCN. For the original LO and HO reagents derived
from RLi and CuCN, see the following: Liptshutz, B. H.
In Organometallics in Synthesis; Schlosser, M., Ed.;
Wiley: New York, 1994; Chapter 4, p. 283.
According to the literature,14 racemic acetate 1 was
converted into alcohol 10, which upon Mitsunobu
inversion with AcOH furnished 11 stereoselectively in
86% yield. Installation of the Bu group was carried out
7. To a slurry of CuCN (65 mg, 0.73 mmol) in THF (1 mL)
was added a solution of BuMgCl (1.0 mL, 1.50 M in
THF, 1.50 mmol) at −18°C. After 20 min of stirring,

4832
Y. Kobayashi et al. / Tetrahedron Letters 43 (2002) 4829–4832
R
acetate 3a (50 mg, 0.25 mmol) in THF (0.2 mL) was
H
injected. The reaction was carried out at −18°C for 5 h,
and quenched by addition of saturated NH4Cl and 28%
NH3. The resulting mixture was extracted with Et2O
three times, and the crude product was purified by chro-
matography to afford 71% yield (36 mg) of 4a and 5a in
6–8% NOE
H
Bu
5a
13. Wirth, D.; Fischer-Lui, I.; Boland, W.; Icheln, D.;
Runge, T.; Ko¨nig, W. A.; Phillips, J.; Clayton, M. Helv.
Chim. Acta 1992, 75, 734–744.
14. Deardorff, D. R.; Linde, R. G., II; Martin, A. M.;
Shulman, M. J. J. Org. Chem. 1989, 54, 2759–2762.
15. Probably the regioisomer. However, the full structure was
not characterized.
16. Reaction of acetate i derived from 10 (Ac2O, pyridine)
with the LO reagent efficiently afforded isomer ii, with
the supposed trans stereochemistry; the 1H NMR spec-
trum of ii is different from that of 12.
1
a 83:17 ratio: H NMR of 4a (300 MHz, CDCl3) l 0.89
(t, J=7 Hz, 3H), 1.1–1.4 (m, 7H), 2.58 (dt, J=15, 8 Hz,
1H), 2.71 (br s, 1H), 3.80–3.91 (m, 1H), 5.72 (dt, J=5, 2
Hz, 1H), 5.87 (dt, J=5, 2 Hz, 1H), 7.15–7.30 (m, 5H).
8. We had expected efficient (yield and regioselectivity) pro-
duction of 5a from entry 1 and 4a from entries 2 and 3 on
the basis of the previous results.2
9. According to the procedure described in Ref. 7, butyla-
tion of 3a (50 mg, 0.25 mmol) was performed with
BuMgBr (0.82 mL, 0.92 M in Et2O, 0.75 mmol), CuCN
(81 mg, 0.90 mmol), and Et2O (1.2 mL) at 0°C for 5 h to
afford 5a in 91% yield (46 mg): 1H NMR (300 MHz,
CDCl3) l 0.75 (t, J=7 Hz, 3H), 0.82–0.99 (m, 2H),
0.99–1.26 (m, 4H), 2.65 (dm, J=8 Hz, 2H), 2.76–2.88 (m,
1H), 3.55 (q, J=8 Hz, 1H), 5.88 (s, 2H), 7.15–7.30 (m,
5H).
CO2Me
CO2Me
CO2Me
CO2Me
n-BuMgBr (6.1 equiv)
AcO
CuCN (3.0 equiv)
Et2O, –45 °C, 5 h
i
ii
10. Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980,
102, 4730–4743.
11. Due to the existence of the C2 symmetry axis.
12. NOE experiment of 5a:
17. This result and that of Ref. 16 indirectly support the
stereochemical outcome for the 3,4-isomers synthesized in
Tables 1 and 2.