Three-step α-acylation of (E)-cinnamate esters with inversion of stereochemistry through formation and cleavage of carbon- pentamethylcyclopentadienyl bonds

Article abstract of DOI:10.1246/cl.2006.408

The reaction of cinnamate esters with lithium pentamethylcyclopentadienide in the presence of chlorodiethylaluminum provides the corresponding 1,4-adducts in high yield. The adducts undergo α-acylation reaction upon treatment with lithium diisopropylamide

Full text of DOI:10.1246/cl.2006.408

408
Chemistry Letters Vol.35, No.4 (2006)
Three-step ꢀ-Acylation of (E)-Cinnamate Esters with Inversion
of Stereochemistry through Formation and Cleavage
of Carbon–Pentamethylcyclopentadienyl Bonds
Minoru Uemura, Hideki Yorimitsu,ꢀ and Koichiro Oshimaꢀ
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510
(Received February 2, 2006; CL-060147;
E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp, oshima@orgrxn.mbox.media.kyoto-u.ac.jp)
The reaction of cinnamate esters with lithium pentamethyl-
tios of 94:6 (Entries 4 and 7). The relative stereochemistry of the
diastereomers could not be determined. The acylation reactions
were performed at ꢁ50 ꢂC, since higher temperatures induced
the formation of 1 through liberation of Cpꢀꢁ from the corre-
sponding lithium enolate of 2. The acylation of 2 proceeded
not only with aromatic acid chlorides but also with cyclohexane-
carbonyl chloride (Entry 3). Attempted acylations with pivaloyl
chloride and with propanoyl chloride both resulted in the recov-
ery of most of 2a. The unsuccessful acylations are attributed to
the steric reason of pivaloyl chloride and to the facile deprotona-
tion reaction of propanoyl chloride with the enolate of 2a. Acyl-
ation with electron-rich p-methoxybenzoyl chloride also result-
ed in failure.
cyclopentadienide in the presence of chlorodiethylaluminum
provides the corresponding 1,4-adducts in high yield. The ad-
ducts undergo ꢀ-acylation reaction upon treatment with lithium
diisopropylamide and acid chlorides. Removal of the penta-
methylcyclopentadienyl group by the action of base affords ꢀ-
acylcinnamate esters, in which the aryl and alkoxycarbonyl
groups are in cis relationship.
One can accomplish transformation of 2-alkenoate ester into
2-acylalkenoate ester by the following two methods. One is the
Morita–Baylis–Hillman reaction followed by oxidation of the
resulting alcohol.1 The other is a sequence of hydrogenation of
2-alkenoate ester, base-mediated ꢀ-acylation with acid chloride,
and oxidation such as selenoxide elimination.2 Here, we report
an alternative method. Conjugate addition of pentamethylcyclo-
pentadienide (Me5C5ꢁ, Cpꢀꢁ) to (E)-cinnamate esters yielded
the corresponding adducts. The adducts sequentially underwent
ꢀ-acylation and elimination of pentamethylcyclopentadiene
(CpꢀH) to yield (Z)-ꢀ-acylcinnamate esters. The overall trans-
formation thus proceeded with inversion of configuration. The
elimination step includes carbon–carbon bond cleavage of the
Cpꢀ–C bonds, which we have been focusing on.3
Treatment of methyl cinnamate (1a) with lithium penta-
methylcyclopentadienide (LiCpꢀ) in the presence of chloro-
diethylaluminum in THF at ꢁ20 ꢂC provided the corresponding
1,4-adduct 2a in 98% yield (Eq 1).4 Both electron-donating and -
withdrawing groups on the phenyl ring of 1 did not retard the ad-
dition reactions. Unfortunately, the addition reactions to methyl
crotonate and butyl acrylate provided complex mixtures arising
from oligomerizations of the unsaturated esters. The addition of
lithium cyclopentadienide (LiC5H5), instead of LiCpꢀ, yielded a
complex mixture under the otherwise identical reaction condi-
tions. In the absence of chlorodiethylaluminum, the reaction
did not proceed smoothly, and a half of 1 was recovered.
Treatment of
3 with 1,8-diazabicyclo[5.4.0]undecene
(DBU) in dimethyl sulfoxide (DMSO) at 70 ꢂC gave rise to the
formation of the conjugated cinnamate skeleton, furnishing ꢀ-
acylcinnamate esters 4 in good yields (Table 1, second step).6
It is worth noting that the aryl and methoxycarbonyl groups
are on the same side of the double bond7 except for 4c and 4e.
The (Z) stereoselectivity of the reactions is quite similar to that
of the Knoevenagel reaction.7 The stereochemistry of 4 would
thus be controlled at the elimination step. It is also probable that
isomerization of the disfavored (E)-form into the thermodynami-
cally stable (Z)-form occurred, which was indeed observed in the
synthesis of 4e (Entry 5). The substituent at the ortho position of
Table 1. Transformation of the Cpꢀ adducts 2 to 2-acylcinna-
mates 4
i
O
R
O
R
O
R
1) LiN Pr
2
Ar
OMe
2) RCOCl
DBU
Ar
OMe
OMe
DMSO
70 °C, 3 h
THF
−50 °C
Cp*
O
Cp*
Ar
O
4
2
3
Z/E > 95:5
Entry
Ar
3/%
4/%
1
2
3
4
5
6
7
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph
85, 3a
93, 4a
m-MeO-C6H4 83, 3b 81, 4b
+
Li
Et AlCl
2
Ar
OR
Ar
OR
c-C6H11
82, 3c
83, 3db 70, 4d
83, 3e
82, 3f
85, 3gb 70, 4g
69, 4ca
+
(1)
−
THF, −20 °C
p-Me-C6H4
o-Cl-C6H4
m-Cl-C6H4
O
Cp* O
38, 4ec
78, 4f
1
2
a: R = Me, Ar = Ph
98%
85%
81%
95%
b: R = Me, Ar = p-Br-C H
6
4
c: R = Me, Ar = p-MeO-C H
d: R = Et, Ar = p-NC-C H
p-Br-C6H4 (2b) Ph
6
4
6
4
b
aA 1:1 mixture of (E) and (Z) isomers. A 94:6 mixture of
diastereomers. Initially a 45:55 mixture of (E) and (Z) iso-
The adducts 2 were acylated with acid chlorides after depro-
c
tonation by lithium diisopropylamide (Table 1, first step).5 The
acylation provided products 3 as a single diastereomer whereas
3d and 3g were obtained as mixtures of two diastereomers in ra-
mers was obtained soon after aqueous workup. The isomeric
mixture was quantitatively converted to the pure (Z) isomer
(>95:5) upon standing the mixture overnight.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.4 (2006)
409
the acyl moiety interfered with the removal of the Cpꢀ group
(Entry 5). A catalytic amount of DBU also induced the elimina-
tion reaction, albeit the efficiency was unsatisfactory. Treatment
of 3a with 0.30 equiv of DBU in DMSO at 70 ꢂC for 6 h furnish-
ed 4a in 68% yield.
In conclusion, we have developed a three-step ꢀ-acylation
of (E)-cinnamate ester with inversion of configuration. The
transformation takes advantage of the facile Cpꢀ–carbon bond
cleavage.
9.6 Hz, 1H), 2.75 (dd, J ¼ 6:9, 9.6 Hz, 1H), 3.15 (s, 3H),
5.54 (dd, J ¼ 2:1, 6.9 Hz, 1H), 7.01–7.11 (m, 5H); 13C NMR
(C6D6) ꢂ 10.89, 11.04, 11.07, 11.88, 20.30, 34.79, 46.66,
50.94, 58.88, 126.72, 127.55 (ꢃ2), 128.29, 129.52 (ꢃ2),
131.48, 135.72, 140.31, 140.71, 172.87. Found: C, 80.50;
H, 8.78%. Calcd for C20H26O2: C, 80.80; H, 8.97%. mp
47–49 ꢂC.
5
General procedure for acylation of 1,4-adduct: A solution of
n-BuLi in hexane (1.55 M, 0.71 mL, 1.1 mmol) was added to
a solution of i-Pr2NH (0.17 mL, 1.2 mmol) in THF (10 mL)
at 0 ꢂC. The mixture was stirred for 30 min at the same tem-
perature. The reaction mixture was cooled to ꢁ50 ꢂC. Ester
2a (298 mg, 1.0 mmol) in THF (1 mL) was added to the re-
sulting mixture, and the reaction mixture was stirred for
5 h. Benzoyl chloride (0.14 mL, 1.2 mmol) was added to
the reaction mixture, and the mixture was stirred for 2 h at
ꢁ50 ꢂC. After being stirred for 2 h, the reaction was
quenched with water. The mixture was extracted with ethyl
acetate. The combined organic layers were washed with
brine, dried, and concentrated. The oil obtained was chroma-
tographed on silica gel (hexane/ethyl acetate = 10:1) to af-
ford 3a (342 mg, 0.85 mmol, 85% yield). Methyl 2-benzoyl-
3-(1,2,3,4,5-pentamethyl-2,4-cyclopentadienyl)-3-phenyl-
This work is supported by Grants-in-Aid for Scientific Re-
search, Young Scientists, and COE Research from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
References and Notes
1
a) N. J. Lawrence, J. P. Crump, A. T. McGown, J. A.
Hadfield, Tetrahedron Lett. 2001, 42, 3939. b) H. M. R.
Hoffmann, A. Gassner, U. Eggert, Chem. Ber. 1991, 124,
2475.
2
a) S. Danishefsky, S. Chackalamannil, B.-J. Uang, J. Org.
Chem. 1982, 47, 2231. b) T. R. Hoye, A. J. Caruso, A. S.
Magee, J. Org. Chem. 1982, 47, 4152. c) K. C. Nicolaou,
T. Montagnon, P. S. Baran, Angew. Chem., Int. Ed. 2002,
41, 993.
propanoate (3a): IR (nujol) 1736, 1686 cmꢁ1 1H NMR
;
3
4
a) K. Yagi, H. Yorimitsu, K. Oshima, Tetrahedron Lett.
2005, 46, 4831. b) M. Uemura, H. Yorimitsu, K. Oshima,
Tetrahedron Lett. 2006, 47, 163.
(CDCl3) ꢂ 0.79 (s, 3H), 1.62 (s, 3H), 1.66 (s, 3H), 1.81 (s,
3H), 2.02 (s, 3H), 3.62 (s, 3H), 3.98 (d, J ¼ 6:9 Hz, 1H),
5.11 (d, J ¼ 6:9 Hz, 1H), 6.94–7.02 (m, 5H), 7.34–7.38
(m, 2H), 7.46–7.50 (m, 1H), 7.76–7.80 (m, 2H); 13C NMR
(CDCl3) ꢂ 10.85, 11.21, 11.76, 12.18, 21.00, 49.65, 52.32,
55.52, 58.46, 125.96, 126.97 (ꢃ2), 128.10 (ꢃ2), 128.23
(ꢃ2), 129.11 (ꢃ2), 132.78, 135.73, 135.82, 137.12,
138.92, 139.48, 139.93, 168.23, 193.98. Found: C, 80.30;
H, 7.50%. Calcd for C27H30O3: C, 80.56; H, 7.51%. mp
135–136 ꢂC.
Typical procedure for elimination of CpꢀH: DBU (0.050 mL,
0.36 mmol) was added to a solution of 3a (121 mg, 0.30
mmol) in DMSO (6.0 mL). The reaction mixture was
warmed to 70 ꢂC and the mixture was stirred for 3 h. The
reaction was quenched with water, and the mixture was ex-
tracted with ethyl acetate. The combined organic parts were
washed with brine, dried, and concentrated. Chromatograph-
ic purification on silica gel (hexane/ethyl acetate = 5:1)
afforded 4a (62.4 mg, 0.28 mmol, 93%). The NMR spectra
of 4a were identical to those reported in Ref. 7.
Procedure for nucleophilic addition of CpꢀLi to ꢀ,ꢁ-unsatu-
rated ester: A solution of n-BuLi in hexane (1.67 M, 12.0 mL,
20 mmol) was added to a solution of 1,2,3,4,5-pentamethyl-
1,3-cyclopentadiene (3.3 mL, 21 mmol) in THF (100 mL) at
ꢁ20 ꢂC. The mixture was stirred for 30 min at the same tem-
perature to provide a white suspension of lithium penta-
methylcyclopentadienide. Chlorodiethylaluminum (2.5 mL,
21 mmol) was added to the resulting mixture, and the reac-
tion mixture was stirred for 30 min at ꢁ20 ꢂC. After an addi-
tion of 1a (1.62 g, 10 mmol) in THF (10 mL), the mixture
was stirred for an additional 1 h at ꢁ20 ꢂC. The reaction
was quenched with water, and the mixture was extracted
with ethyl acetate. The combined organic parts were washed
with brine, dried over anhydrous Na2SO4, and concentrated
in vacuo to give a crude oil. The oil was purified by chroma-
tography on silica gel (hexane/ethyl acetate = 30:1) to
afford 2a (2.92 g, 9.8 mmol, 98%). Methyl 3-(1,2,3,4,5-pen-
tamethyl-2,4-cyclopentadienyl)-3-phenylpropanoate (2a):
6
7
The stereochemistry of 4a was confirmed according to the
literature: R. Tanikaga, N. Konya, K. Hamamura, A. Kaji,
Bull. Chem. Soc. Jpn. 1988, 61, 3211.
1
IR (nujol) 1743 cmꢁ1; H NMR (C6D6) ꢂ 0.92 (s, 3H), 1.55
(s, 6H), 1.64 (brs, 3H), 1.82 (s, 3H), 2.44 (dd, J ¼ 2:1,
Published on the web (Advance View) March 18, 2006; DOI 10.1246/cl.2006.408