Copper-catalyzed allylations of o-vinylbenzylzirconocene intermediate

Article abstract of DOI:10.1016/j.tetlet.2004.03.097

Benzylzirconocene intermediate, which was readily prepared by the reaction of o-alkoxymethylstyrene with 'Cp₂Zr' under mild conditions, reacted with allylic halides or phosphates in the presence of catalytic amount of CuCl to give allylated pro

Full text of DOI:10.1016/j.tetlet.2004.03.097

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3717–3720
Copper-catalyzed allylations of o-vinylbenzylzirconocene
intermediate
Yutaka Ikeuchi,a Takeo Taguchib,* and Yuji Hanzawab,*
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
Received 27 January 2004; revised 13 March 2004; accepted 17 March 2004
Abstract—Benzylzirconocene intermediate, which was readily prepared by the reaction of o-alkoxymethylstyrene with ‘Cp2Zr’ under
mild conditions, reacted with allylic halides or phosphates in the presence of catalytic amount of CuCl to give allylated products in
good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Alkenyl- and alkylzirconocene species involving allyl-
zirconocene species prepared by hydrozirconation with
corresponding alkyne/alkene or reactions of allyl ether
derivatives with ‘Cp2Zr’ (zirconocene–butene complex;
zirconocene equivalent) are widely used in organic syn-
thesis.1 In contrast, benzylic-type zirconocene species
are rarely applied to organic synthesis.2 In general,
benzylic metal species that contains o-vinyl substituent
would be useful intermediate as it is a reactive benzyl
metal attached with a reactive and convertible styrene–
olefin unit. To the best of our knowledge, however, 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.
Br
(3.0eq)
3a
ZrCp2(OBn)
Cu salt (20mol%)
THF, room temp.
2
4a
Scheme 2.
For the purpose of synthetic use of 2, allylation,6 which
is the one of the most useful C–C bond forming reac-
tions, was examined, and the results of the copper-cat-
alyzed effective allylations of 2 with allylic halides or
phosphates are described in this letter.
It is known that alkylzirconocene species react with
allylic halides or phosphates to give allylated products in
the presence of catalytic amount of CuCN.6a Thus,
various copper salts for the reaction of 2 with allyl
bromide 3a were examined (Scheme 2), and the results
are summarized in Table 1.
We have reported on a generation of o-vinylbenzylzirco-
nocene intermediate 2 by the reaction of o-benzyl-
oxymethylstyrene 1 with ‘Cp2Zr’ in good yield under
mild conditions (Scheme 1).4;5 Preparation of 2 by
transmetalation procedure would be difficult because of
the reason described above.
Although the reaction did not proceed without a
copper catalyst (entry 1), most of the copper salts
investigated showed catalytic activity (entries 2–8).
Not only Cu(I) salt, but Cu(II) salt also catalyzed the
reaction to give an allylated product in moderate yield
(entry 6).
"Cp2Zr"
OBn
ZrCp2(OBn)
THF, r.t.
> 90% yield
1
2
Scheme 1.
Based on the results shown in Table 1, we examined the
optimal conditions for the reaction of 2 with 3a in the
presence of a CuCl catalyst (Table 2). All reactions were
carried out by using 2 (1.0 equiv), 3a (1.5 or 3.0 equiv)
and CuCl catalysts (5, 10 or 20 mol %) in THF. It is
Keywords: Benzylzirconocene; Styrene; Allylation.
* Corresponding authors. Tel.: +81-426-76-3274; fax: +81-426-76-
3274; e-mail: hanzaway@ps.toyaku.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.097

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Y. Ikeuchi et al. / Tetrahedron Letters 45 (2004) 3717–3720
Table 1. Investigation for copper saltsa
reduced the product yield slightly (entry 5). It can thus
be considered that the reaction conditions described in
entry 4 in Table 2 would be optimal. The scope and
limitations of the present allylation of 2 are shown in
Tables 3 and 4.
Entry
Cu salts (20 mol %)
Yield (%)b
1
2
3
4
5
6
7
8
None
CuCl
CuBr
No reaction
77
55
67
56
47
34
33
CuBr–SMe2
CuI
CuBr2
A variety of allylic halides or phosphates could be used
in the present allylation,7 and allylic chlorides, bromides
and phosphates all reacted in similar efficiency. Sym-
metrical allylic halide, such as allyl bromide 3a and
methallyl chloride 3b, gave the corresponding allylated
products 4a8 and 4b in good yields (Table 3, entries 1
and 2). Allylation with unsymmetrical allylic halide 3c
or 3d gave SN20 product (4c or 4d) as a sole or major
product (SN2/SN20 ¼ 9/91) (entries 3 and 4). In the
reaction of prenyl bromide 3e, which is sterically bulky
at c-position, SN2 product 5e was obtained as a major
product (SN2/SN20 ¼ 69/31) (Table 4, entry 1). Lipshutz
and co-workers reported6a that SN20 product was formed
predominantly in the copper-catalyzed allylation of
alkylzirconocene derivatives with prenyl bromide. Thus,
the present copper-catalyzed reaction of 2 would suggest
that the steric effect is decisive for the regio-selectivity.
Phosphate 3f prepared from cinnamyl alcohol reacted
with 2 also gave allylated products in good yield with
similar SN20 selectivity (entry 2). The reaction of 2 with
propargyl bromide 3g produced allene derivative 4g as a
sole product, and acetylene derivative 5g was not
detected at all (entry 3). 1,3-Diene derivatives 4h could
be obtained in a moderate yield as a mixture of E=Z
isomers (E=Z ¼ 2:4=1) along with 1,4-diene compound
5h by the reaction of phosphate 3h (entry 4).
CuCN
CuCN–2LiCl
a The reaction of 2 (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 temperature for 5 h.
b HPLC yields.
Table 2. Optimization of reaction conditions of 2 with 3a in the
presence of CuCla
Entry
CuCl (mol %)
3a (equiv)
4a Yield (%)b
1
2
3
4
5
20
20
20
10
5
3.0
3.0
1.5
1.5
1.5
77c
95
95
95 (88)
90
a Unless otherwise noted, the reaction of 2 (0.1 mmol) with 3a (0.15 or
0.3 mmol) was carried out in the presence of CuCl (5–20 lmol) in
THF (1 mL) at reflux for 5 h.
b HPLC yields. Isolated yield was shown in parentheses.
c Reaction was carried out at room temperature.
essential to heat the reaction mixture to reflux to bring
about an efficient formation of 4a (entries 1 and 2).
At a reduction of the amount of 3a (1.5 equiv) or CuCl
(10 mol %), no significant change was observed (entries 3
and 4). Further reduction of CuCl (5 mol %), however,
As a synthetic application of allylated product,9 intra-
molecular Diels–Alder reaction of diene 4h was carried
Table 3. CuCl-catalyzed allylation of benzylzirconocene intermediate 2a with allyl- or mono-methylated allyl halides
Product(s)b
Entry
Halide/phosphate
Yield (%)c
SN20
SN2
1
88
Br
3a
4a
4b
Cl
2
3
4
87
87
87
3b
Cl
3c
4c (100)d
5c (0)
5d (9)
Cl
3d
4d (91)
a Unless otherwise noted, the reaction of 2 (1 mmol) with halide/phosphate 3a–h (1.5 mmol) was carried out in the presence of CuCl (0.1 mmol) in
THF (10 mL) at reflux temperature for 5 h.
b Ratios of SN20 and SN2 were determined by 1H NMR and are shown in parentheses.
c Isolated yields.
d Ratio was determined by 1H NMR as major/minor ¼ 2.8/1. Geometry was not determined.

Y. Ikeuchi et al. / Tetrahedron Letters 45 (2004) 3717–3720
3719
Table 4. CuCl-catalyzed allylation of benzylzirconocene intermediate 2a with allyl-related halides or phosphates
Entry
Halide/phosphate
Product(s)b
SN2
Yield (%)c
SN20
1
92
Br
4e (31)
5e (69)
3e
Ph
2
3
Ph
OP(O)(OEt)2
86
84
Ph
3f
4f (92)
5f (8)
•
Br
4g (100)
3g
5g (0)
4d
75
OP(O)(OEt)2
4h (78)e
5h (22)
3h
a Unless otherwise noted, the reaction of 2 (1 mmol) with halide/phosphate 3a–h (1.5 mmol) was carried out in the presence of CuCl (0.1 mmol) in
THF (10 mL) at reflux temperature for 5 h.
b Ratios of SN20 and SN2 were determined by 1H NMR and are shown in parentheses.
c Isolated yields.
d Phosphate (2 equiv), which was prepared in situ, was used.
e Ratio was determined by 1H NMR as E=Z ¼ 2:4=1.
H
toluene
3. To the best of our knowledge, Li species is not known.
Although corresponding Mg species are known in several
examples, most of synthetic applications of 2-vinylbenzyl
magnesium species are limited to polymer chemistry. (a)
Hatada, K.; Shiozaki, T.; Ute, K.; Kitayama, T. Polymer
Bull. 1988, 19, 231; (b) Kuendig, E. P.; Perret, C. Helv. Chim.
Acta 1981, 64, 2606; (c) Duboudin, J. G.; Jousseaume, B.;
Pinet, M. J. Chem. Soc., Chem. Commun. 1977, 454.
4. Hanzawa, Y.; Ikeuchi, Y.; Nakamura, T.; Taguchi, T.
Tetrahedron Lett. 1995, 36, 6503.
5. ‘Cp2Zr’-Catalyzed alkylation of styrene–olefin has been
reported. (a) Cesati, R. C.; Armas, J.; Hoveyda, A. H.
Org. Lett. 2002, 4, 395; (b) Armas, J.; Hoveyda, A. H.
Org. Lett. 2001, 3, 2097; (c) Armas, J.; Kolis, S. P.;
Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 5977; (d)
Terao, J.; Torii, K.; Saito, K.; Kambe, N.; Baba, A.;
Sonoda, N. Angew. Chem., Int. Ed. 1998, 37, 2653; (e)
Terao, J.; Watanabe, T.; Saito, K.; Kambe, N.; Sonoda,
N. Tetrahedron Lett. 1998, 39, 9201; (f) Swanson, D. R.;
Rousset, C. J.; Negishi, E.; Takahashi, T.; Seki, T.; Saburi,
M.; Uchida, Y. J. Org. Chem. 1989, 54, 3521.
6. Organozirconium-mediated allylation for (a) Venanzi, L.
M.; Lehmann, R.; Keil, R.; Lipshutz, B. H. Tetrahedron
Lett. 1992, 33, 5857; (b) Heron, N. M.; Adams, J. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 6205; (c)
Takahashi, T.; Kotora, M.; Kasai, K.; Suzuki, N.
Organometallics 1994, 13, 4183.
7. Typical experimental procedure: A mixture of 1 (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
mixture was stirred for 3 h. To this solution, 3a (1.5 equiv)
in THF (2 mL) and CuCl (10 mol %) were added and
refluxed for 5 h. After cooling to room temperature, 1 N
HCl was added and extracted with ether. The organic
layer was washed with brine, dried over anhydrous MgSO4
reflux
(78%)
H
6
(E)-4h
cis/trans =1.7/1
Scheme 3.
out in toluene under reflux temperature. It should be
mentioned that only (E)-4h was consumed to give a cis/
trans mixture of tricyclic products 610 in a 1.7/1 ratio in
76% yield (Scheme 3). On the other hands, (Z)-4h was
recovered in a quantitative yield under the same conditions.
In conclusion, we found an effective allylation of benzyl-
zirconocene intermediate 2 with various allylic halides
or phosphates. A wide variety of 2-(30-alkenyl)-styrene
derivatives can be synthesized by this protocol. Studies
of the reactions of 2 with more functionalized allylic
halides or phosphates and synthetic applications of the
allylated products are now in progress.
References and notes
1. For a recent reviews, (a) Titanium and Zirconium in
Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Germany,
2002; (b) Recent advances in the chemistry of zircono-
cenes, Suzuki, K.; Wipf, P. Eds.; Symposium-in print
Tetrahedron 2004, 60, 1267; (c) Wipf, P.; Jahn, H.
Tetrahedron 1996, 52, 12853, and references cited therein.
2. Although hydrozirconation of 1-phenyl-1-propene and its
related compounds gave benzylic zirconocene species, the
regio-selectivity and yield were not satisfactory; Gibson,
T. Organometallics 1987, 6, 918.

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Y. Ikeuchi et al. / Tetrahedron Letters 45 (2004) 3717–3720
and the filtrate was concentrated to dryness. The residue
In molecular model study of possible transition states
for the intramolecular Diels–Alder reaction of (E)- or
(Z)-4h, two exo- and endo-transition states derived from
(E)-4h showed feasible transition states (see below). On
the contrary, (Z)-4h forms sterically and conforma-
tionally reluctant transition states. A detailed discussion
will be reported in due course.
was purified by flash chromatography (n-hexane), and
further purification was carried out by MPLC (n-hexane)
to give 4a8 in 88% yield.
8. Padwa, A.; Ku, A. J. Am. Chem. Soc. 1978, 100, 2181.
9. Synthetic applications of 2-(30-alkenyl)-styrene derivatives
are studied vigorously by Taylor et al. (a) Bird, A. J.;
Taylor, R. J. K.; Wei, X. Synlett 1995, 1237; (b) Wei, X.;
Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 6467; (c) Wei,
X.; Taylor, R. J. K. Tetrahedron: Asymmetry 1997, 8, 665;
(d) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37,
4209; (e) Wei, X.; Taylor, R. J. K. J. Chem. Soc., Chem.
Commun. 1996, 187.
cis-6
10. The structure and stereochemistry of 6 were determined by
transformation (reduction of C@C double bond under the
H2/Pd–C in AcOEt) to known compounds 7,11 and ratio
was determined by GC.
trans-6
H2, Pd-C
H
H
H
H
AcOEt
(quant.)
11. Bansal, R. C.; Browne, C. E.; Eisenbraun, E. J. J. Org.
Chem. 1988, 53, 452.
6
7