Copper-catalyzed acylations of o-vinylbenzylzirconocene intermediate and synthetic application toward steroid skeleton

Article abstract of DOI:10.1016/j.tetlet.2004.04.049

Benzylzirconocene intermediate, which was readily prepared by a reaction of o-alkoxymethylstyrene with 'Cp₂Zr' under mild conditions, reacted with acyl chlorides in the presence of a catalytic amount of CuBr-SMe ₂ to give ketone derivatives in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2004.04.049

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4495–4498
Copper-catalyzed acylations of o-vinylbenzylzirconocene
intermediate and synthetic application toward steroid skeleton
Yutaka Ikeuchi,a,b Takeo Taguchib and Yuji Hanzawac,*
aProcess Development Laboratories, Sankyo Co., Ltd, 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-8560, Japan
bSchool of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
cDepartment of Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuene, Machida-shi,
Tokyo 194-8543, Japan
Received 16 March 2004; revised 8 April 2004; accepted 9 April 2004
Abstract—Benzylzirconocene intermediate, which was readily prepared by a reaction of o-alkoxymethylstyrene with ‘Cp2Zr’ under
mild conditions, reacted with acyl chlorides in the presence of a catalytic amount of CuBr–SMe2 to give ketone derivatives in
moderate to good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Alkyl or alkenylzirconocene chlorides are easily pre-
pared by hydrozirconation of alkenes or alkynes with
Schwartz reagent (Cp2Zr(H)Cl, Cp ¼ cyclopentadienyl).
The nucleophilic reactivity of organozirconocene chlo-
ride complexes, however, is very poor, and the addition
to nucleophiles scarcely takes place. To increase the
reactivity of the organozirconocene complexes, a few
activation procedures have been devised, and thus the
utility of organozirconocene chloride complexes as an
organometallic reagent is highly recognized in organic
synthesis.1
In general, benzylic metal species that contain an o-vinyl
substituent would be a useful intermediate as it is a
reactive benzyl metal attached to a reactive styrene–
olefin unit. To the best of our knowledge, only a few
examples3 of o-vinylbenzyl metal species are known
because of the difficulty in their preparation due to the
high reactivity of the styrene–olefin unit.
Therefore, for the purpose of presenting further syn-
thetic use of 2a, we examined the acylation of 2a. The
reaction of acid chlorides with organometallic reagents
is one of the most direct and convenient procedures for
the synthesis of ketones.4
Recently, we reported on the generation and reaction of
o-vinylbenzylzirconocene intermediate 2a by treatment
of o-benzyloxymethylstyrene 1a with ‘Cp2Zr’ (zircono-
cene–butene complex, zirconocene equivalent) followed
by copper-catalyzed allylation with allyl halides or
phosphates (Scheme 1).2
Although it is well-known that alkylzirconocene species
can be directly acylated with acid chloride,5 the trans-
metalation of organozirconocene species to copper
species is more often employed.6 At the outset, various
copper salts acting as a catalyst for the reaction of 2b7
with acetyl chloride 3a at room temperature in THF
were examined (Scheme 2), and the results are summa-
rized in Table 1.
R
X
OBn
ZrCp2
"Cp2Zr"
(1.5 equiv)
OBn
R
THF, r.t.
> 90% yield
CuCl (10 mol %)
THF, reflux
1a
2a
OMe
ZrCp2
Me
Scheme 1.
AcCl 3a (3.0 equiv)
O
Cu Salts (20 mol %)
THF, r.t.
Keywords: Benzylzirconocene; Styrene; Acylation; Steroid skeleton.
* Corresponding author. Tel./fax: +81-42-721-1569; e-mail:
hanzaway@ac.shoyaku.ac.jp
2b
4a
Scheme 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.049

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Y. Ikeuchi et al. / Tetrahedron Letters 45 (2004) 4495–4498
Table 1. Copper-catalyzed reactions of 2b with 3aa
AcCl (3.0 equiv)
OR
ZrCp2
3a
Me
Entry
Cu salt (20 mol %)
4a Yield (%)b
O
CuBr-SMe2 or
CuCl (5-20 mol %)
THF, reflux
1
None
CuCl
No reaction
27
2
2a (R=Bn)
2b (R=Me)
4a
3
CuBr
CuBr–SMe2
CuI
Trace
29
4
5
Trace
Trace
Trace
No reaction
17
Scheme 3.
6
CuCN
CuCN–2LiCl
Cu2O
7
8
9
Cu(OTf)2
CuCl2
CuBr2
Table 3. Copper catalyzed acylations of benzylzirconocene interme-
diate 2b with acid chloridesa
10
11
10
17
Entry
Acyl halide
Product
Yield (%)b
a The reaction of 2b (0.1 mmol) with 3a (0.3 mmol) was carried out in
the presence of Cu salt (0.02 mmol) in THF (1 mL) at room tem-
perature for 5 h.
Me
93
1
AcCl
3a
O
b HPLC yields.
4a
Since the benzylic zirconocene complex 2a is considered
to be more reactive than the alkylzirconocene complex,
it is curious for us that 2a did not react with acetyl
chloride 3a in the absence of the copper catalyst (entry
1). Although CuCl and CuBr–SMe2 showed low cata-
lytic activity (entries 2 and 4), other CuI salts, such as:
CuBr, CuI, CuCN, and Cu2O, did not act as catalysts
for the reaction (entries 3, 5–8), and CuII salts, such as
Cu(OTf)2, CuCl2, and CuBr2, were inferior (entries 9–
11).
2
3
4
5
6
t-BuCOCl
3b
69
87
88
O
O
4b
4c
Ph
PhCOCl
3c
Ph
COCl
Ph
O
O
Based on the results shown in Table 1, we optimized the
reaction conditions for the acylation of 2a or 2b with 3a
(Table 2). It turned out that the reflux of the reaction
mixture dramatically increased yields of 4a (Scheme 3).
3d
4d
4e
Ph
Complex
mixture
Ph
COCl
O
3e
As a copper catalyst, CuBr–SMe2 was superior to CuCl
under the present conditions (entries 1 and 2). With a
reduction in the amount of CuBr–SMe2 (20, 10–
5 mol %), the yields of 4a were slightly lowered (entries
2–4). Using benzylzirconocene intermediate 2a instead
of 2b, ketone derivative 4a was obtained in an excellent
yield (93%) (entry 5).8 Therefore, the reaction conditions
described in entry 5 in Table 2 are optimal. The scope
and limitations of the present acylation of 2a are shown
in Table 3.
CO2Me
77
O
MeO2C
Cl
4f
3f
a Unless otherwise noted, the reaction of 2a (1 mmol) with acyl chloride
3a–f (3.0 mmol) was carried out in the presence of CuBr–SMe2
(0.2 mmol) in THF (10 mL) at reflux temperature for 5 h.
b Isolated yields.
All reactions were carried out by using 2a (1.0 equiv),
acid chlorides 3a–f (3.0 equiv), and CuBr–SMe2
(20 mol %) in THF at reflux temperature.9 A variety of
acid chlorides could be used in the present acylation.
Bulky pivaloyl chloride 3b reacted with 2a to give ketone
derivative 4b in a moderate yield (entry 2). Benzoyl
chloride 3c and alkenoyl chloride represented by cin-
namoyl chloride 3d gave the corresponding ketones 4c
and 4d in good yields (entries 3 and 4). Alkynoyl chlo-
ride, such as 3e, however, gave a complex mixture (entry
5). Other alkynoyl chlorides, such as 3-trimethylsilyl-
propynoyl chloride or 2-hexynoyl chloride also gave a
complex mixture. Thus, a,b-alkynoyl chlorides were
inadequate substrates for the present acylation. Acid
chloride 3f, which contained an ester group, gave a c-
keto ester derivative 4f in good yield (entry 6).
Table 2. Optimization of reaction conditions of 2a or 2b with 3a in the
a
presence of CuCl or CuBr–SMe2
Entry
Cu salt (mol%)
2 (R ¼ )
4a Yield (%)b
1
2
3
4
5
CuCl (20)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2a (Bn)
68
78
75
72
93
CuBr–SMe2 (20)
CuBr–SMe2 (10)
CuBr–SMe2 (5)
CuBr–SMe2 (20)
a Unless otherwise noted, the reaction of 2a or 2b (1 mmol) with 3a
(3 mmol) was carried out in the presence of CuCl or CuBr–SMe2
(0.05–0.2 mmol) in THF (10 mL) at reflux for 5 h.
b Isolated yields.
As for the synthetic application of the present acylated
product, a preliminary study for the synthesis of a ste-
roid framework was examined. A retrosynthetic path-
way is shown in Scheme 4.

Y. Ikeuchi et al. / Tetrahedron Letters 45 (2004) 4495–4498
4497
a, b
CHO
COCl
5
6
7
OH
OH
OH
10
9
c, d
OBn
O
OBn
ZrCp2
+
ClOC
2a
8
2a
6
e
f
Scheme 4. Retrosynthetic analysis for the synthesis of steroid skeleton.
OH
8
The construction of steroid skeleton 10 would be
achieved by the intramolecular Diels–Alder reaction of
the styrene–olefin unit with the cyclic exo-1,3-diene unit
of 9, which would be prepared from ene–yne precursor
8.
H
H
OH
OH
10 (cis / trans = 2.3 / 1)
9
The ene–yne compound 8 would be prepared by the
acylation of 2a with acid chloride 6.
Scheme 6. Reagents and conditions: (a) (i) (EtO)2P(O)CH2CO2TMS,
n-BuLi, THF; (ii) H3Oþ, quant; (b) (COCl)2, CH2Cl2, 77%; (c)
Cp2ZrCl2, n-BuLi, THF; (d) 6, CuBr–SMe2, THF, reflux, 81% (two
steps); (e) LiAlH4, THF, 73%; (f) (dba)3Pd2–CHCl3, Ph3P, AcOH,
toluene, 60 °C, 74%.
The synthesis of 1,3-diene derivatives from nonconju-
gated ene–yne compounds using a Pd-catalyst and its
intramolecular Diels–Alder reaction were studied in
detail by Trost.10 It has also been suggested that the
hydroxy group adjacent to the internal alkenyl group
controls not only the regioselectivity in the Pd-catalyzed
cyclization, but also the diastereofacial-selectivity of the
subsequent intramolecular Diels–Alder reaction
(Scheme 5).
6.2
10.8
H
H
H
H
H
OH
H
OH
8.3
7.9
The ene–yne acid chloride 6 prepared from 5-hexynal 511
in two steps reacted with 2a to give a corresponding
ketone derivative 7 in 81% yield (Scheme 6). The x-
alkyne of 6 is tolerable in the present acylation. The
reduction of the carbonyl group by LiAlH4 gave an allyl
alcohol derivative 8 in 73% yield. Under the Pd-cata-
lyzed 1,3-diene synthesis conditions ((dba)3Pd2–CHCl3
(2.5 mol %), PPh3 (5 mol %), AcOH (5 mol %), toluene,
60 °C), tetracyclic compounds 10 were obtained directly
in 74% yield as a mixture of two diastereomers in the
ratio of 2.3/1 (cis/trans). The structures were determined
by NMR spectra (Fig. 1).12 In contrast to the results of
Trost et al., cis-product 10 was obtained as a major
product.13
10-major
10-minor
Figure 1. Coupling constants (Hz) of tetracyclic compounds 10.
In conclusion, a copper-catalyzed effective acylation of
o-vinylbenzylzirconocene intermediate 2a with various
acid chlorides was found. A wide variety of o-styryl-
methyl alkyl, alkenyl, and aryl ketone derivatives can be
synthesized by this protocol. Studies of the reactions of
2a with more functionalized acid chlorides and a stereo-
selective synthesis of optically pure steroid derivatives
are now in progress.
Although the more precise control for the stereoselec-
tivity in the intramolecular Diels–Alder reaction and
further introduction of functional groups are necessary
toward the synthesis of steroid derivatives, we were able
to achieve the construction of a steroid framework in
short steps and in good yields through a combination of
the ‘Cp2Zr’-mediated chemistry and the Pd-catalyzed
chemistry.
References and notes
1. For recent reviews, Titanium and Zirconium in Organic
Synthesis; (a) Marek, I., Ed.; Wiley–VCH: Germany,
2002; (b)‘Recent advances in the chemistry of zirconoc-
enes’ in Symposium-in print Tetrahedron, 2004, 60, 1267;
Suzuki, K.; Wipf, P., Eds.; (c) Wipf, P.; Jahn, H.
Tetrahedron 1996, 52, 12853, and references cited therein.
2. (a) Hanzawa, Y.; Ikeuchi, Y.; Nakamura, T.; Taguchi, T.
Tetrahedron Lett. 1995, 36, 6503; (b) Ikeuchi, Y.; Taguchi,
T.; Hanzawa, Y. Tetrahedron Lett. 2004, 45, 3717.
3. To the best of our knowledge, Li species is not known.
Although corresponding Mg species are known in several
examples, most synthetic applications of 2-vinylbenzyl
magnesium species are limited to polymer chemistry (a)
H
Pd (cat.)
170oC
HO
H
OH
OH
H
Scheme 5. Pd-catalyzed formation of tricycle by Trost et al.

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Y. Ikeuchi et al. / Tetrahedron Letters 45 (2004) 4495–4498
Hatada, K.; Shiozaki, T.; Ute, K.; Kitayama, T. Polym.
mixture was stirred for 3 h. To this solution, 3a (3.0 equiv)
in THF (2 mL) and CuBr–SMe2 (20 mol %) were added at
0 °C, and then refluxed for 5 h. After cooling to room
temperature, saturated NaHCO3 aq was added, filtration
on Celite, and extracted with ether. The organic layer was
washed with brine, dried over anhydrous MgSO4, and the
filtrate was concentrated to dryness. The residue was
purified by flash chromatography (n-hexane/AcOEt ¼ 20/
1), and further purification was carried out by MPLC (n-
hexane/AcOEt ¼ 9/1) to give 4a in 93% yield.
Bull. 1988, 19, 231; (b) Kuendig, E. P.; Perret, C. Helv.
Chim. Acta 1981, 64, 2606; (c) Duboudin, J. G.; Joussea-
ume, B.; Pinet, M. J. Chem. Soc., Chem. Commun. 1977,
23, 454.
4. For recent reviews, (a) Lawrence, N. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 1739; (b) Dieter, R. K. Tetrahedron
1999, 55, 4177.
5. Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96,
8115.
6. Wipf, P.; Xu, W. Synlett 1992, 718.
7. For an easy analysis on HPLC, intermediate 2b was used
instead of 2a, although the yield of 2b was lower than 2a.
8. Although the reason is unclear, the similar phenomenon
has been observed in the copper-catalyzed allylation of 2
(unpublished data). See also Ref. 7.
10. Trost, B. M. Acc. Chem. Res. 1990, 23, 34, and references
cited therein.
11. Adams, T. C.; Combs, D. W.; Daves, C. D., Jr.; Hauser,
F. M. J. Org. Chem. 1981, 46, 4582.
12. 1H, 13C, DEPT, COSY, HMQC, and decoupling mea-
surement.
9. Typical experimental procedure: A mixture of 1a (1 mmol)
and Cp2Zr(n-Bu)2, which was generated by the addition of
n-BuLi (2 equiv) to Cp2ZrCl2 in THF (5 mL) at )78 °C,
was gradually warmed to room temperature and the
13. The present cis-selective formation of 10 would be the
result of the enhanced endo-transition state due to the p-
orbital interaction between the phenyl and diene compo-
nents.