Transformation of zirconocene-olefin complexes into zirconocene allyl hydride and their use as dual nucleophilic reagents: Reactions with acid chloride and 1,4-diketone

Article abstract of DOI:10.1021/ja049184y

Zirconocene-olefin complexes Cp₂Zr(H₂C=CHR), prepared in benzene-THF at 0 °C, react with acid chlorides to provide homoallylic alcohols. The key is an equilibrium between the zirconocene-olefin complexes and the corresponding zircono

Full text of DOI:10.1021/ja049184y

Published on Web 05/07/2004
Transformation of Zirconocene-Olefin Complexes into
Zirconocene Allyl Hydride and Their Use as Dual Nucleophilic
Reagents: Reactions with Acid Chloride and 1,4-Diketone
Kazuya Fujita, Hideki Yorimitsu, Hiroshi Shinokubo, and Koichiro Oshima*
Contribution from the Department of Material Chemistry, Graduate School of Engineering,
Kyoto UniVersity, Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Received February 13, 2004; E-mail: oshima@fm1.kuic.kyoto-u.ac.jp
Abstract: Zirconocene-olefin complexes Cp2Zr(H2CdCHR), prepared in benzene-THF at 0 °C, react with
acid chlorides to provide homoallylic alcohols. The key is an equilibrium between the zirconocene-olefin
complexes and the corresponding zirconocene allyl hydride complexes via allylic C-H bond cleavage of
the coordinating alkenes. Furthermore, the zirconocene-olefin complexes are also available for the reaction
with 1,4-diketone to afford anti-1,4-diols with excellent diastereoselectivity. Thus, Cp2Zr(H2CdCHR) serves
as a donor of both hydride and an allylic group. These reactions also proceed efficiently by using
zirconocene-olefin complexes, derived from Cp2ZrCl2, Mg metal, and 1-alkenes.
Scheme 1
Introduction
Since the development of a convenient method for the
generation of low-valent zirconocene species by Negishi et al.,1
the reaction of zirconocene-olefin complexes Cp2Zr(H2-
CdCHR) (1) with a variety of unsaturated compounds has been
regarded as a powerful tool for regioselective C-C bond
formation reaction.2 For example, 1 reacted with another alkene
to afford zirconacyclopentane 2a or 2b and the substituted
butane 3a or 3b after hydrolysis (Scheme 1).3 In these reactions,
the alkyl groups R and R′ were at the â positions of zircona-
cyclopentane with >98% regioselectivity, whereas the aryl
group Ar was at the R position with >98% regioselectivity.
Scheme 2
Additionally, coupling reaction with aldehyde or ketone
afforded the corresponding saturated alcohol via an oxazircona-
cyclopentane intermediate (Scheme 2).4 It is noteworthy that
6a was obtained exclusively and that the regioisomer 6b was
not detected.
Scheme 3
Aside from the reaction in Scheme 2, little is known about
other polar addition reactions of zirconocene-olefin complexes.
Thus, we felt that this area clearly deserved further exploration
and set out to address the reaction of Cp2Zr(H2CdCHEt) with
acid halide. As a result, we found that Cp2Zr(H2CdCHEt) (1a),
prepared in benzene-THF at 0 °C, reacted with acid chloride
to furnish homoallylic alcohol.5 In this reaction, the key would
be an equilibrium between the zirconocene-olefin complex 1a
and a zirconocene allyl hydride complex 7a via allylic C-H
bond cleavage of the coordinating alkene (Scheme 3).6 We
propose that hydride attack on benzoyl chloride should result
in formation of benzaldehyde, which subsequently undergoes
allylation to form the desired homoallylic alcohol. Namely, the
zirconocene allyl hydride complex functions as the source of
(1) (a) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,
27, 2829. (b) Negishi, E.; Holms, S. J.; Tour, J. M.; Miller, J. A.;
Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989,
111, 3336.
(2) For leading reviews, see: (a) Negishi, E.; Takahashi, T. Acc. Chem. Res.
1994, 27, 124. (b) Negishi, E.; Kondakov, D. Y. Chem. Soc. ReV. 1996,
26, 417. (c) Negishi, E.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71,
755. (d) Takahashi, T.; Kotora, M.; Hara, R.; Xi, Z. Bull. Chem. Soc. Jpn.
1999, 72, 2591.
(5) (a) Fujita, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. J.
Am. Chem. Soc. 2001, 123, 12115. (b) Fujita, K.; Yorimitsu, H.; Oshima,
K. Chem. Rec. 2004, 4, 110.
(3) Swanson, D. R.; Rousset, C. J.; Negishi, E. J. Org. Chem. 1989, 54, 3521.
(4) (a) Takahashi, T.; Suzuki, N.; Hasegawa, M.; Nitto, Y.; Aoyagi, K.; Saburi,
M. Chem. Lett. 1992, 331. (b) Suzuki, N.; Rousset, C. J.; Aoyagi, K.;
Kotora, M.; Takahashi, T. J. Organomet. Chem. 1994, 473, 117.
(6) Harrod has proved that 1a and 7a are in an equilibrium which is significantly
shifted toward 1a: Dioumaev, V. K.; Harrod, J. F. Organometallics 1997,
16, 1452. Also see, Negishi, E.; Maya, J. P.; Choueiry, D. Tetrahedron
1995, 51, 4447.
9
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J. AM. CHEM. SOC. 2004, 126, 6776-6783
10.1021/ja049184y CCC: $27.50 © 2004 American Chemical Society

Zirconcocene−Olefin Complex as Dual Nucleophilic Reagant
A R T I C L E S
Scheme 4
Scheme 5
Table 1. Reaction of Zirconocene-1-Butene Complex with
Various Acid Chloridesa
Scheme 6
entry
R
product
yield/%
anti/syn
1
2
3
4
5
6
Ph
9aa
9ab
9ac
9ad
9ae
9af
82
63
67
60
22
65
69:31
71:29
67:33
58:42
64:36
62:38
2-CH3(C6H4)
4-Cl(C6H4)
furyl
4-CH3O(C6H4)
4-CF3(C6H4)
Scheme 7
Scheme 8
a Cp2ZrCl2 (2.0 mmol), butylmagnesium bromide (1.0 M in THF, 4.0
mL, 4.0 mmol), acid chloride (1.0 mmol), and benzene (20 mL) were
employed at 0 °C.
two different anion species, hydride and allylic anion. Although
the existence of the zirconocene allyl hydride complex is
known,6 there are only a few reports dealing with the formation
mechanism and no report on its application to organic synthesis.
Herein we wish to describe the full details of application of the
zirconocene allyl hydride complexes, tautomers of zirconocene-
olefin complexes, as dual nucleophilic reagents.
Conversion of Acid Chloride into Homoallylic Alcohol.
Cp2ZrCl2 (2 mmol) was treated with n-C4H9MgBr (1 M THF
solution, 4 mL, 4 mmol) in benzene (20 mL) with cooling in
an ice/water bath. After the reaction mixture was stirred at 0
°C for 30 min, benzoyl chloride (8a, 1 mmol) was added. The
whole mixture was stirred for 3 h at 0 °C. Usual workup
followed by silica gel column purification afforded 9aa in 82%
yield (Scheme 4).7 Pentyl-, octyl-, and 3-phenylpropylmagne-
sium bromide, instead of butylmagnesium bromide, were also
effective to yield the corresponding homoallylic alcohols. The
use of benzene as a solvent would be crucial for the successful
process. The use of THF as a solvent, instead of benzene,
decreased the yield of 9.
utilizing allylic C-H bond activation of 1-butene. Hydride attack
on benzoyl chloride followed by allylation furnishes 9aa. The
following experiments suggest the order of the sequential
nucleophilic attack (Scheme 6). Reaction of benzaldehyde with
crotylzirconium reagent, prepared from Cp2ZrCl2 and crotyl
Grignard reagent, yielded 9aa with anti selectivity (syn/anti )
27:73). The selectivity was similar to that observed in the
reaction in Scheme 4. On the other hand, treatment of ketone
12 with the Schwartz reagent led to slight syn selectivity.
In contrast to the reaction with aromatic acid chlorides, upon
treatment of octanoyl chloride with 1a, cyclopropanol 13 was
obtained in 25% yield, in addition to 9ag (Scheme 7). More
interestingly, the presence of PMePh2 in the reaction of benzoyl
chloride gave rise to the formation of trans-14a9 without
contamination by 9aa (Scheme 8). Coordination of PMePh2 to
the zirconium center would prevent the formation of zirconocene
crotyl hydride.
Furthermore, we found that treatment of ester, instead of
benzoyl chloride, with a zirconocene-olefin complex at 0 °C
cleanly furnished 1,2-disubstituted cyclopropanol 14 in good
yield (Scheme 9).10 This cyclopropanol formation proceeded
smoothly with aryl-, alkyl-, cycloalkyl-, and alkenylcarboxylates
(Table 2). γ-Lactone 17 could also be easily transformed into
Reactions with other aromatic acid chlorides are summarized
in Table 1. Most of the reactions proceeded smoothly to furnish
the corresponding desired products in satisfactory yields with
slight anti selectivity, although electron-rich acid chlorides such
as 8e resulted in lower yield (entry 5).
We are tempted to assume the reaction mechanism for the
formation of homoallylic alcohol as depicted in Scheme 5. There
exists an equilibrium between Cp2Zr(H2CdCHEt) (1a) and
zirconocene crotyl hydride (7a, Cp2Zr(crotyl)H) according to
the literature of Harrod.6,8 In this reaction, 7a functions as the
source of two different anion species, hydride and allyl anion,
(9) The relative configurations “cis” and “trans” are assigned by the Cahn-
Ingold-Prelog system throughout the present text.
(10) Titanium-alkene complexes induce formation of cyclopropanols: (a) Lee,
J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1995, 117, 9919. (b) Lee, J.;
Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 291. (c)
Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198. (d)
Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1995,
117, 3881. (e) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.
Synthesis 1991, 234. (f) Corey, E. J.; Rao, S. A.; Noe, M. C. J. Am. Chem.
Soc. 1994, 116, 9345. (g) Kulinkovich, O. G.; de Meijere, A. Chem. ReV.
2000, 100, 2789. Szymoniak also reported that the reaction of a zir-
conocene-ethylene complex with ester provided the corresponding cyclo-
propanol. (h) Gandon, V.; Bertus, P.; Szymoniak, J. Eur. J. Org. Chem.
2000, 6, 3713.
(7) Traces of benzyl alcohol and the saturated analogue of 9aa were detectable
byproducts in the crude oil. Other conceivable byproducts such as tertiary
alcohol, generated via double allylation, were not observed at all.
(8) Photolysis of Fe(CO)4(η2-CH2dCHCH3) resulted in similar rearrange-
ment: Barnhart, T. M.; McMahon, R. J. J. Am. Chem. Soc. 1992, 114,
5434.
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J. AM. CHEM. SOC. VOL. 126, NO. 21, 2004 6777

A R T I C L E S
Fujita et al.
Scheme 9
Scheme 11
Table 2. Reaction of Zirconocene-Olefin Complex with Various
Estersa
Table 3. Direct Synthesis of Homoallylic Alcohols from Alkenesa
a Cp2ZrCl2 (2.0 mmol), butylmagnesium bromide (1.0 M in THF, 4.0
mL, 4.0 mmol), ester (1.0 mmol), and benzene (20 mL) were employed at
0 °C. b Reference 9. c Propylmagnesium bromide was used instead of
butylmagnesium bromide.
Scheme 10
the corresponding diol 18 (Scheme 10).11 It is worth noting that
the products were formed with high trans diastereoselectivity.
The stereochemistry of the product was confirmed by NOE
study of 14b. The trans stereoselectivity was also found in the
reaction of titanium-catalyzed Kulinkovich hydroxycyclo-
propanation.10e,f This reaction would proceed via oxazircona-
cyclopentane 16 (Scheme 9).
Preparation of the requisite Grignard reagents is laborious.
Next, we investigated direct preparation of Cp2Zr(2-alkenyl)H
from Cp2ZrCl2 and alkene. Zirconocene dichloride was treated
with 2 equiv of cyclopentylmagnesium bromide in the presence
of 3 equiv of 1-pentene in benzene at 0 °C for 30 min and at
25 °C for an additional 1 h (Scheme 11, Method A). Initially
formed Cp2Zr(cyclopentene) (19) was anticipated to undergo
ligand exchange, forming Cp2Zr(1-pentene).12,13 This was indeed
the case, and 9ba was obtained in 76% yield upon treatment of
benzoyl chloride with the reagent at 0 °C (Table 3, entry 1).
Other alkenes could participate in the ligand exchange to furnish
the corresponding homoallylic alcohols (Table 3, Method A).14
a Method A: Cp2ZrCl2 (2.0 mmol), cyclopentylmagnesium bromide (1.0
M in THF, 4.0 mL, 4.0 mmol), alkene (6.0 mmol), acid chloride (1.0 mmol),
and benzene (20 mL) were employed. Method B: Cp2ZrCl2 (3.0 mmol),
Mg (4.5 mmol), alkene (6.0 mmol), acid chloride (1.0 mmol), and benzene
(25 mL) were employed.
Furthermore, reduction of Cp2ZrCl2 with Mg metal in the
presence of alkene also provided the reagent 7.13,15 In this
method, addition of benzene as a cosolvent prior to reaction
with PhCOCl was crucial for the successful formation of
homoallylic alcohols. Alcohol 9ba was formed in 46% yield in
the reaction without benzene. The results were comparable to
those obtained by Method A (Table 3, Method B). Advanta-
geously, ester and amide moieties could survive under the
reaction conditions (entries 12 and 13). Alkenes are much more
readily available than the corresponding allylic magnesium
reagents. Thus, this method promises rapid synthesis of a wide
spectrum of homoallylic alcohols.
(11) Esposite, A.; Taddei, M. J. Org. Chem. 2000, 65, 9245. Two examples of
the reductive coupling of lactone with terminal alkene according to the
Kulinkovich protocol have been described in ref 10c.
(12) A similar ligand exchange reaction of a titanium reagent was reported:
see ref 10c.
(13) It is possible that the zirconacyclopentanes resulting from addition of two
alkenes to a zirconocene-olefin complex can be formed. However, we
propose the zirconacyclopentane is also equilibrated with a zirconocene-
olefin complex and zirconocene allyl hydride. See ref 3.
(14) The reaction in THF itself resulted in the diminished yields of 9. For
instance, 9ea was obtained in 26% yield along with benzyl alcohol (17%).
(15) (a) Miura, K.; Funatsu, M.; Saito, H.; Ito, H.; Hosomi, A. Tetrahedron
Lett. 1996, 37, 9059. (b) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J.
A. J. Am. Chem. Soc. 1985, 107, 2568. (c) Thanedar, S.; Farona, M. F. J.
Organomet. Chem. 1982, 235, 65.
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6778 J. AM. CHEM. SOC. VOL. 126, NO. 21, 2004

Zirconcocene−Olefin Complex as Dual Nucleophilic Reagant
A R T I C L E S
Scheme 12
Scheme 14
Scheme 13
The allylic C-H bond cleavage as shown in Scheme 5 was
further confirmed by employing 3,3-dideuterio-1-octene (21).
Zirconium complex 23 was prepared from 21 by Method B,
and benzoyl chloride was added to 23 to afford dideuterated
homoallylic alcohol 24 (Scheme 12).
Scheme 15
There is a controversy over the pathway of the conversion
of dialkylzirconocene into the corresponding zirconocene-olefin
complex (Scheme 13). The primary reaction of Cp2ZrCl2 and
butyl Grignard reagent is simple and leads to the formation of
Cp2Zr(n-C4H9)2 (10). Negishi et al. assumed that decomposition
of dialkylzirconocene 10 occurs through â-H abstraction to form
butane and 1a (Scheme 13).16 On the other hand, Harrod’s group
suggested that 10 decomposes via γ-H abstraction which leads
to zirconacyclobutane 26. Strained zirconacycle 26 rearranges
to form zirconocene crotyl hydride (7a), which undergoes further
rearrangement to produce 1a.6
we attempted further application of a zirconocene-olefin
complex as a dual nucleophilic reagent in reactions with various
substrates bearing two electrophilic centers intramolecularly. As
a result, we discovered that a tandem reduction-allylation
reaction of 1,4-diketones takes place in the presence of a
By taking advantage of the present reaction, we examined
the following investigation to clarify the mechanism of the
conversion of dialkylzirconocene into the zirconocene-olefin
complex. Reaction of benzoyl chloride with dialkylzirconocene
28, derived from Cp2ZrCl2 and 2,2-dideuteriooctylmagnesium
bromide (27), yielded 31 (Scheme 14). Deuterium was incor-
porated perfectly at the internal olefinic position. We could not
observe any deuterium of significance at other positions. The
formation of 31 which possesses only one deuterium provides
strong evidence for the â-H abstraction. If zirconacyclobutane
32 is formed through the γ-H abstraction, the products such as
34 and 37 would contain two deuteriums. In practice, neither
of the products were detected. Thus, the result proves that this
process cannot proceed via the γ-H abstraction.
(17) Deuterium was not completely incorporated at the allylic and benzylic
positions in 24. Additionally, the examination of the 1H and 2D NMR of
the product 24 indicates that deuterium was also found at the methylene
and methyl groups of the pentyl chain. This migration of deuterium can be
explained by the following mechanism.
We also tried subsequent examination to get further confi-
dence. Zirconium complex 39 was also prepared from Cp2ZrCl2
and 3,3-dideuteriooctylmagnesium bromide (38), and benzoyl
chloride was added to 39. As expected, deuterium was incor-
porated at the allylic and benzylic positions (Scheme 15).17
Tandem Reduction-Allylation Reactions of 1,4-Diketones.
As mentioned above, Cp2Zr(H2CdCHEt) serves as a donor of
both hydride and an allyl group. On the basis of this finding,
First, treatment of Cp2ZrCl2 and 38 forms zirconocene-olefin complex 22
through the â-H abstraction. Complex 22 is equilibrated with zirconocene
allyl deuteride complex 23 via allylic C-D bond activation. It is assumed
that 61 is then produced via reductive elimination, because the nucleophi-
licity of the deuteride in 23 is weaker than the hydride in zirconocene allyl
hydride complex 7, probably due to isotope effect. By a similar allylic
C-H activation-reductive elimination sequence, 64 is finally formed.
Complex 64 reacts with benzoyl chloride to provide homoallyl alcohol
derivative 65. Thus, the desired product 24 in which deuteriums are
incorporated at the allylic and benzylic positions would be contaminated
with 65.
(16) (a) Negishi, E.; Swanson, D. R.; Takahashi, T. J. Chem. Soc., Chem.
Commun. 1990, 1254. (b) Negishi, E.; Holms, S. J.; Tour, J. M.; Miller, J.
A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc.
1989, 111, 3336.
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A R T I C L E S
Fujita et al.
Table 4. Reduction-Allylation Reactions of 1,4-Diketonesa
Scheme 16
Scheme 17
product yield/
yield/
%
entry
40
Ar
41
%
anti/syn
42
1
2
3
4
5
6
7
8
9
40a 3,5-F2(C6H3)
40b Ph
40c 3-CF3(C6H4)
40d 4-CF3(C6H4)
40e 4-Br(C6H4)
41a
41b
41c
41d
41e
41f
41g
41h
41i
64
57
60
62
52
60
62
29
62
96:4 42a
94:6 42b
92:8 42c
92:8 42d
>99:1 42e
96:4 42f
96:4 42g
91:9 42h
97:3 42i
6
18
11
16
13
9
7
36
13
40f
4-Cl(C6H4)
Table 5. Reduction-Crotylation Reactions of 1,4-Diketonesa
40g 4-F(C6H4)
40h 4-MeO(C6H4)
40i
4-t-BuOCO(C6H4)
a Cp2ZrCl2 (2.0 mmol), propylmagnesium bromide (1.0 M in THF, 4.0
mL, 4.0 mmol), 1,4-diketone (1.0 mmol), and benzene (30 mL) were
employed.
zirconocene-olefin complex with a high level of 1,4-diastereo-
selectivity.18 To our knowledge, this is the first example of the
1,4-diastereoselective allylation of ketones.19
Treatment of Cp2ZrCl2 (2.0 mmol) with n-C3H7MgBr (1.0
M THF solution, 4.0 mL, 4.0 mmol) in benzene (30 mL) at 0
°C provided Cp2Zr(propene) (1b). 1,4-Diketone 40a (1.0 mmol)
was added to this mixture, and the reduction of one carbonyl
group and allylation at the other occurred to provide 1,4-diol
41a in 64% yield with excellent diastereoselectivity. Byproduct
42a was also obtained in 6% yield.20 The reaction of 1b with
other aromatic 1,4-diketones is summarized in Table 4.21 Most
of the reactions proceeded in satisfactory yields, although the
use of electron-rich aromatic 1,4-diketones such as 40h resulted
in lower yields (entry 8).22 Ether and ester functionalities were
also tolerated under the reaction conditions (entries 8 and 9).
Especially rewarding was the high level of anti/syn stereo-
selectivity displayed by the reaction (>95:5 in most cases), with
respect to the two OH-bearing carbon centers.23 The relative
1,4-stereochemistry of the major isomer was assigned as anti
based on the X-ray crystallographic analysis of 41e.
product yield/
yield/
%
entry 40
Ar
40a 3,5-F2(C6H3) Me
40b Ph Me
R
47
%
1,4-anti/syn 42
1
2
3
4
5
6
7
8
9
47a
47b
47c
47d
47e
47f
76
54
78
62
70
81
62
66
59
71
97:3
95:5
96:4
92:8
97:3
97:3
96:4
95:5
96:4
>99:1
42a
5
42b 17
42c 11
42d 16
42e 14
11
7
42a 16
42a 21
40c 3-CF3(C6H4) Me
40d 4-CF3(C6H4) Me
40e 4-Br(C6H4)
40f 4-Cl(C6H4)
40g 4-F(C6H4)
Me
Me
Me
42f
42g
47g
47h
40a 3,5-F2(C6H3) Et
40a 3,5-F2(C6H3) n-C3H7 47i
47j
10 40a 3,5-F2(C6H3) Ph
42a
6
a Cp2ZrCl2 (2.0 mmol), butylmagnesium bromide (1.0 M in THF, 4.0
mL, 4.0 mmol), 1,4-diketone (1.0 mmol), and benzene (30 mL) were
employed.
reactivity of zirconocene complex 1b toward phenyl propyl
ketone (Scheme 16). Analysis of the crude mixture indicated
predominant formation of 43 along with a trace amount of the
allylated adduct 44.
This result clearly suggests that hydride transfer occurs prior
to allyl transfer, which is the same order as the reaction with
acid chloride. Consequently, we propose the reaction mechanism
depicted in Scheme 17 for the formation of the anti-1,4-diols.
Thus, Cp2Zr(propene) (1b), through its equilibrium with 7b,
delivers hydride to one of the carbonyl carbon centers of 1,4-
diketone 40 to yield allylzirconium alkoxide 45. Subsequent
intramolecular addition of the allyl group on zirconium then
takes place to form anti-1,4-diol 41.
To elucidate the order in which the nucleophilic attacks by
hydride and the allyl group take place, we examined the
(18) Fujita, K.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 2003, 42,
2550.
(19) The 1,4-diastereoselective methylation of γ-alkoxy aldehydes has been
reported: (a) Reetz, M. T.; Kesseler, K.; Schmidtberger, S.; Wenderoth,
B.; Steinbach, R. Angew. Chem., Int. Ed. Engl. 1983, 22, 989. (b) Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(20) 13C NMR spectroscopic analysis indicated that 1,4-diol 42a had formed as
a mixture of isomers. We assume that 42 resulted from the intermolecular
reduction of intermediate 45 by zirconocene hydride 7b. The formation of
double reduction product 42 was suppressed by conducting the reaction
under high dilution conditions.
(21) When 1,5-diketones or 1,6-diketones were used in place of 1,4-diketones,
trace amounts of the expected products were isolated along with products
of double reduction. Nucleophilic addition reactions did not occur with
1,3-diketones because of enolization of these substrates.
We turned our attention to a tandem reduction-crotylation
reaction. The results are listed in Table 5. For example, treatment
of 1,4-diketone 40a with 1a (2.0 equiv) resulted in the formation
of 47a in 76% yield (entry 1). It deserves comment that the
crotylation reaction proceeded with perfect 4,5-syn selectivity
as well as with excellent 1,4-anti stereoselectivity.24 The use of
pentyl, hexyl, and 3-phenylpropyl Grignard reagents also
allowed the formation of the corresponding homoallylic alcohols
with excellent stereoselectivity (entries 8, 9, and 10).
(22) In contrast to aromatic 1,4-diketones, the reaction of 5,8-dodecanedione
with 1b afforded the desired adduct in only 15% yield.
(23) The reaction of γ-hydroxyketone 66 with allylmagnesium chloride exhibited
no diastereoselectivity.
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6780 J. AM. CHEM. SOC. VOL. 126, NO. 21, 2004

Zirconcocene−Olefin Complex as Dual Nucleophilic Reagant
Table 6. Synthesis of Anti 1,4-Diols from 1-Alkenesa
A R T I C L E S
Scheme 18
poured into aqueous HCl (50 mL, 3 M) and extracted with
hexane/ethyl acetate (5:1 ) v/v%, 25 mL × 3). The combined
organic layer was dried over Na2SO4 and concentrated in vacuo.
The crude oil was purified on silica gel (hexane/ethyl acetate
) 10:1) to furnish 2-methyl-1-phenyl-3-buten-1-ol (9aa, 133
mg, 0.82 mmol) in 82% yield.
General Procedure for Reaction of Zirconocene-Olefin
Complex with Ester. To a solution of Cp2ZrCl2 (585 mg, 2.0
mmol) in benzene (20 mL), butylmagnesium bromide (4.0 mL,
1.0 M THF solution, 4.0 mmol) was added at 0 °C. After the
mixture was stirred for 30 min at the same temperature, methyl
benzoate (136 mg, 1.0 mmol) was then added dropwise to the
resulting mixture at 0 °C. Then, the reaction mixture was stirred
for another 3 h at 0 °C. Quenching the reaction with hydro-
chloric acid followed by extraction, concentration, and column
purification yielded 2-ethyl-1-phenylcyclopropanol (14a, 148
mg, 0.91 mmol) in 91% yield.
a Cp2ZrCl2 (3.0 mmol), Mg (4.5 mmol), alkene (6.0 mmol), 1,4-diketone
(1.0 mmol), and benzene/THF (25:5 mL) were employed.
In this tandem reduction-allylation reaction, zirconocene-
olefin complexes, derived from Cp2ZrCl2 and Mg metal in the
presence of the 1-alkene, were also found to serve as dual
nucleophilic reagents, and the desired 1,4-diols were obtained
in reasonable yields with excellent stereoselectivity. Table 6
summarizes the reduction-allylation reactions of 1,4-diketone
40a with several olefins. Advantageously, various functional
groups such as ether and ester groups could survive under the
reaction conditions (entries 3 and 4). Thus, the reaction allows
facile preparation of various functionalized 1,4-diols.
Typical Procedure via Olefin Exchange (Method A).
Cyclopentylmagnesium bromide (4.0 mL, 1.0 M THF solution,
4.0 mmol) was added to a solution of Cp2ZrCl2 (585 mg, 2.0
mmol) and 1-hexene (505 mg, 6.0 mmol) in benzene (20 mL)
at 0 °C. The reaction mixture was stirred for 30 min at 0 °C
and then for an additional 1 h at 25 °C. Next, the resulting
mixture was cooled to 0 °C again, and benzoyl chloride (141
mg, 1.0 mmol) was added. After being stirred for another 3 h
at 0 °C, the mixture was poured into hydrochloric acid (50 mL,
3 M). Extraction with hexane/ethyl acetate (5:1 ) v/v%, 25
mL × 3) followed by silica gel column purification afforded
1-phenyl-2-vinyl-1-pentanol (9ea, 141 mg, 0.74 mmol) in 74%
yield.
Conclusion
In conclusion, we found that zirconocene-olefin complexes
functioned as the source of two different anion species, hydride
and allyl anion in the reaction with substrate bearing two
electrophilic centers intramolecularly. The key intermediate is
zirconocene allyl hydride, formed through reversible allylic
C-H bond cleavage of the coordinating alkene of the zir-
conocene-olefin complex. The reaction with acid chloride
afforded the corresponding homoallylic alcohol by sequential
H/allyl attacks. Furthermore, in the reaction with 1,4-diketone,
it was also found that the high level of stereoselectivity was
displayed by utilizing the reagent. To date, zirconocene-olefin
complexes have served only as precursors of various zircona-
cycles. Thus, the use of the dual nucleophilic reagent, zir-
conocene allyl hydride, will provide unprecedented synthetic
routes to organic compounds.
General Procedure for Synthesis of Homoallylic Alcohol
with Zirconocene Dichloride and a Grignard Reagent.
Benzene (20 mL) was added to Cp2ZrCl2 (585 mg, 2.0 mmol)
in a 50-mL reaction flask under argon. After the mixture was
cooled to 0 °C in an ice/water bath, butylmagnesium bromide
(4.0 mL, 1.0 M THF solution, 4.0 mmol) was added. The
solution immediately turned into a viscous black suspension,
and the resulting mixture was stirred for 30 min at 0 °C. Benzoyl
chloride (141 mg, 1.0 mmol) was then added at 0 °C, and the
mixture was stirred for another 3 h at 0 °C. The mixture was
Procedure with Cp2Zr(H2CdCHR) Prepared from Olefin,
Magnesium Metal, and Zirconocene Dichloride (Method B).
THF (1 mL) was added to Cp2ZrCl2 (877 mg, 3.0 mmol) and
magnesium metal (109 mg, 4.5 mmol) in a 50-mL flask filled
with argon. 1,2-Dibromoethane (85 mg, 0.45 mmol) was added
to activate the magnesium metal, and the mixture was stirred
for 15 min. After the solution was cooled to 0 °C, a solution of
1-pentene (421 mg, 6.0 mmol) in THF (4 mL) was added. The
reaction mixture was stirred for 3 h at 0 °C to form the
zirconocene-olefin complex. Benzene (25 mL) was then added
as cosolvent, and benzoyl chloride (141 mg, 1.0 mmol) was
dropped. The resulting mixture was stirred for 30 min at 0 °C.
Quenching the reaction with hydrochloric acid followed by
extraction, concentration, and silica gel column purification
yielded 2-ethyl-1-phenyl-3-buten-1-ol (9ba, 136 mg, 0.77 mmol)
in 77% yield as a colorless oil.
Preparation of 3,3-Dideuterio-1-octene (21). 3,3-Dideuterio-
1-octene (21) was prepared as shown in Scheme 18. First, to a
suspension of lithium aluminum deuteride (1.05 g, 25.0 mmol)
in dry THF (10 mL) was added a solution of methyl hexanoate
(6.51 g, 50.0 mmol) at 0 °C. The mixture was warmed to room
(24) The relative 4,5-configuration of the diols was assigned by comparison of
their spectral data with those reported for analogues. See: Kataoka, Y.;
Makihara, I.; Yamagata, T.; Tani, K. Organometallics 1997, 16, 4788.
(25) Sui-Seng. C.; Soleihavoup, M.; Maurette, L.; Tedeschi, C.; Donnadieu, B.;
Chauvin, R. Eur. J. Org. Chem. 2003, 9, 1641.
9
J. AM. CHEM. SOC. VOL. 126, NO. 21, 2004 6781

A R T I C L E S
Fujita et al.
Scheme 19
Scheme 20
temperature and then stirred for another 3 h at 25 °C. Quenching
the reaction with aqueous HCl followed by extraction, concen-
tration, and silica gel column purification yielded 1,1-dideuterio-
1-hexanol (48, 4.81 g, 46.2 mmol) in 92% yield. Next, pyridine
(5.14 g, 65.0 mmol) was added dropwise to a solution of 1,1-
dideuterio-1-hexanol (48, 4.81 g, 46.2 mmol) and tosyl chloride
(9.53 g, 50.0 mmol) in CH2Cl2 at room temperature. After being
stirred for 24 h at the same temperature, the reaction mixture
was poured into saturated NH4Cl. Usual work up and column
purification afforded 1,1-dideuteriohexyl tosylate (49, 10.3 g,
45.3 mmol) in 98% yield. LiBr (7.81 g, 90.0 mmol) was added
to a solution of 49 (10.3 g, 45.3 mmol) in acetone at room
temperature, and the resulting mixture was stirred for 12 h at
55 °C. Usual workup and purification by column chromatog-
raphy on silica gel provided 1-bromo-1,1-dideuteriohexane (50,
7.27 g, 43.5 mmol) in 96% yield. Magnesium metal (0.73 g,
30.0 mmol) and THF (10 mL) were placed in a 50-mL reaction
flask under argon. Alkyl bromide 50 (4.17 g, 25.0 mmol) in
THF (2 mL) was added dropwise to the mixture at room
temperature. The resulting mixture was stirred for 5 h at 25 °C,
and alkylmagnesium bromide 51 was formed. Finally, alkyl-
magnesium bromide 51 (4.0 mL, 1.0 M THF solution, 4.0
mmol) was added at 0 °C to a stirred mixture of NiCl2 (0.03 g,
0.25 mmol), DPPP (0.03 g, 0.25 mmol), and vinyl bromide (2.67
g, 25.0 mmol) in Et2O (15 mL). The mixture was stirred at 35
°C for 5 h. After the mixture was quenched with aqueous HCl,
it was extracted with hexane/ethyl acetate (5:1 ) v/v%, 25 mL
× 3). The crude product was purified by silica gel column
chromatography to afford 3,3-dideuterio-1-octene (21, 2.54 g,
22.3 mmol).
Synthesis of 2,2-Dideuteriooctylmagnesium Bromide (28).
2,2-Dideuteriooctylmagnesium bromide could be synthesized
from acetic acid-d4 (52) as shown in Scheme 19. Diisopropyl-
amine (19.4 g, 192.0 mmol) and butyllithium (108 mL, 1.6 M
hexane solution, 173 mmol) were mixed in THF (60 mL) under
argon and were stirred for 30 min at 0 °C to form lithium
diisopropylamide. The resulting mixture and HMPA (14 mL)
were successively added to a solution of 52 (5.28 g, 80.0 mmol)
in THF (10 mL) at -40 °C. After the mixture was warmed to
0 °C, hexyl bromide (14.0 g, 85.0 mmol) was added dropwise
to the reaction mixture at the same temperature and the reaction
temperature was gradually raised to ambient temperature. The
mixture was stirred for another 5 h at 25 °C and poured into
aqueous HCl (50 mL, 3 M) and extracted with hexane/ethyl
acetate (1:1 ) v/v%, 25 mL × 3). The combined organic layer
was dried over Na2SO4 and concentrated in vacuo. The crude
oil was purified on silica gel (hexane/ethyl acetate ) 3:1) to
furnish 2,2-dideuteriooctanoic acid (53, 6.55 g, 44.8 mmol) in
56% yield. As for the following procedure, a similar procedure
described in Scheme 18 was used to afford 2,2-dideuteriooct-
ylmagnesium bromide (28).
octylmagnesium bromide 38 can be prepared as shown in
Scheme 20.
General Procedure for Synthesis of anti-1,4-Diol with
Zirconocene Dichloride and Propylmagnesium Bromide.
Benzene (30 mL) and Cp2ZrCl2 (585 mg, 2.0 mmol) were placed
in a 50-mL reaction flask under argon. After the mixture was
cooled to 0 °C in an ice/water bath, propylmagnesium bromide
(4.0 mL, 1.0 M THF solution, 4.0 mmol) was added dropwise.
The solution immediately turned into a viscous black suspension,
and the resulting mixture was stirred for 30 min at 0 °C. A
solution of 1,4-bis(3,5-difluorophenyl)-1,4-butanedione (40a,
310 mg, 1.0 mmol) in benzene (2 mL) was then added at 0 °C,
and the mixture was stirred for another 5 h at 0 °C. The mixture
was poured into aqueous HCl (50 mL, 3 M) and extracted with
hexane/ethyl acetate (5:1, 25 mL × 3). The combined organic
layer was dried over Na2SO4 and concentrated in vacuo. The
crude oil was purified on silica gel (hexane/ethyl acetate )
10:1) to yield 1,4-bis(3,5-difluorophenyl)-6-heptene-1,4-diol
(41a, 228 mg, 0.64 mmol) in 64% yield along with 6% yield
of 1,4-bis(3,5-difluorophenyl)-1,4-butanediol (42a).
General Procedure with Butylmagnesium Bromide. But-
ylmagnesium bromide (4.0 mL, 1.0 M THF solution, 4.0 mmol)
was added dropwise to a solution of Cp2ZrCl2 (585 mg, 2.0
mmol) in benzene (20 mL) at 0 °C, and the mixture was stirred
at the same temperature for 30 min. To the reaction mixture
was added a solution of 1,4-bis(3,5-difluorophenyl)-1,4-butane-
dione (40a, 310 mg, 1.0 mmol) at 0 °C. After being stirred for
another 5 h at 0 °C, the mixture was poured into aqueous
hydrochloric acid (50 mL, 3 M). Extraction with hexane/ethyl
acetate (5:1, 25 mL × 3) followed by silica gel column
purification afforded 1,4-bis(3,5-difluorophenyl)-5-methyl-6-
heptene-1,4-diol (47a, 280 mg, 0.76 mmol) in 76% yield.
Synthesis of anti-1,4-Diols from 1-Alkenes. Magnesium
turnings (109 mg, 4.5 mmol) in THF (1 mL) were treated with
1,2-dibromoethane (85 mg, 0.45 mmol). After the mixture was
stirred for 15 min, 1-pentene (421 mg, 6.0 mmol) was introduced
at ambient temperature. The mixture was cooled to 0 °C, and a
solution of Cp2ZrCl2 (877 mg, 3.0 mmol) in THF (4 mL) was
added. The reaction mixture was stirred for 3 h at 0 °C. Benzene
(30 mL) was then added, and 1,4-bis(3,5-difluorophenyl)-1,4-
butanedione (40a, 310 mg, 1.0 mmol) was dropped. The
resulting mixture was stirred for 5 h at 0 °C. Quenching the
reaction with aqueous hydrochloric acid followed by extraction,
concentration, and silica gel column purification provided 1,4-
bis(3,5-difluorophenyl)-5-ethyl-6-heptene-1,4-diol (47h, 259 mg,
0.68 mmol) in 68% yield as a colorless oil.
Preparation of 3,3-Dideuteriooctylmagnesium Bromide
(38). By a similar procedure described above, 3,3-dideuterio-
9
6782 J. AM. CHEM. SOC. VOL. 126, NO. 21, 2004

Zirconcocene−Olefin Complex as Dual Nucleophilic Reagant
A R T I C L E S
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research and COE Research from the Ministry
of Education, Culture, Sports, Science, and Technology, Japan.
K.F. acknowledges JSPS for financial support.
Supporting Information Available: Experimental details.
This material is available free of charge via the Interent at
http://pubs.acs.org.
JA049184Y
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J. AM. CHEM. SOC. VOL. 126, NO. 21, 2004 6783