Nickel-catalyzed homoallylation reaction of aldehydes with 1,3-dienes: Stereochemical and mechanistic studies

Article abstract of DOI:10.1021/ol026216i

(Matrix presented) Contrary to what was reported, the coupling reaction of nickel-catalyzed cyclic diene such as cyclohexadiene with carbonyl compounds in the presence of diethyl zinc afforded γ,δ-alkenyl alcohols in good yields.

Full text of DOI:10.1021/ol026216i

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2715-2717
Nickel-Catalyzed Homoallylation
Reaction of Aldehydes with 1,3-Dienes:
Stereochemical and Mechanistic Studies
Teck-Peng Loh,* Hong-Yan Song, and Yan Zhou
Department of Chemistry, Nantional UniVersity of Singapore, 3 Science DriVe 3,
Singpaore 117543
chmlohtp@nus.edu.sg
Received May 21, 2002 (Revised Manuscript Received June 19, 2002)
ABSTRACT
Contrary to what was reported, the coupling reaction of nickel-catalyzed cyclic diene such as cyclohexadiene with carbonyl compounds in the
presence of diethyl zinc afforded γ,δ-alkenyl alcohols in good yields.
Most recently, our group has developed a new method for
the synthesis of substituted tetrahydropyrans via a novel In-
(OTf)3-catalyzed (3,5)-oxonium ene type cyclization (Scheme
1).1 During the course of these studies, we are required to
styrene and 2,5-dimethyl-2,4-hexadiene were unreactive, and
cyclic dienes reacted slowly to provide intractable mixtures
of addition products in low yields.2a On the basis of this
information, they proposed the involvement of a trans nickel
oxametallacycle intermediate in the reaction pathway (Figure
1).6 Interestingly, in the course of our studies, we discovered
Scheme 1
(1) (a) Loh, T. P.; Hu, Q. Y.; Ma, L. T. J. Am. Chem. Soc. 2001, 123,
2450. (b) Loh T.-P.; Hu, Q. Y.; Tan, K. T.; Cheng, H. S. Org. Lett. 2001,
3, 2669. For examples on the synthetic application of In(OTf)3, see (c) Loh,
T. P.; Chua, G. L.; Vittal, J. J.; Wong, M. W. Chem. Commun. 1998, 861.
(d) Chauhan, K. K.; Frost, C. G.; Love, I.; Waite, D. Synlett 1999, 1743.
(e) Gadhwal, S.; Sandhu, J. S.; J. Chem. Soc., Perkin Trans. 1 2000, 2827.
(2) (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem.
Soc. 1998, 120, 4033. (b) Kimura, M.; Shibata, K.; Koudahashi, Y.; Tamaru,
Y. Tetrahedron Lett. 2000, 41, 6789. (c) Kimura, M.; Ezoe, A.; Tanaka,
S.; Tamaru, Y. Angew. Chem., Int. Ed. 2001, 40, 3600. (d) Shibata, K.;
Kimura, M.; Kojima, K. Tamaru, Y. J. Organomet. Chem. 2001, 624, 348.
(e) Shibata K.; Kimura M.; Shimizu M.; Tamaru Y. Org. Lett. 2001, 3,
2181.
(3) (a) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.;
Mori, M. J. Am. Chem. Soc. 1994, 116, 9771. (b) Sato Y.; Takimoto M.;
Mori M. Tetrahedron Lett. 1996, 37, 887. (c) Sato Y.; Takimoto M.; Mori
M. Synlett 1997, 734. (d) Sato Y.; Saito N.; Mori M. Tetrahedron 1998,
54, 1153. (e) Sato Y.; Takanashi T.; Mori M. Organometallics 1999, 18,
4891. (f) Sato, Y.; Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2000, 122,
1624. (g) Sato, Y.; Saito, N.; Mori, Y. J. Am. Chem. Soc. 2000, 122, 2371.
(h) Sato, Y.; Takimoto, M.; Mori, M. Chem. Pharm. Bull. 2000, 48, 1753.
(4) For NiH-mediated stoichiometric homoallylation of carbonyl com-
pounds with 1,3-dienes, see (a) Sato, Y.; Takimoto, M.; Mori, M. Synlett
1998, 734. For transition metal catalyzed allylation with 1,3-dienes, see
(b) Takimoto, M.; Hiraga, Y.; Sato, Y.; Mori, M. Tetrahedron Lett. 1998,
39, 4543. (c) Kitayama, K.; Tsuji, H.; Uozumi, Y.; Hayashi, T. Tetrahedron
Lett. 1996, 37, 4169.
prepare the requisite alkenyl alcohol (1) in optically pure
form. An attractive strategy is to apply the nickel(0)-catalyzed
coupling of 1,3-dienes to a chiral aldehyde elegantly
developed by Tamaru2 and Mori.3 This homoallylation of
carbonyl compounds has been demonstrated to be a useful
process because it produces synthetically useful γ,δ-alkenyl
alcohols.4,5
However, the major limitations of this reaction are the
difficulty of obtaining the product when cyclic dienes were
employed in the reaction and the lack of stereochemical
studies. For example, Tamaru and co-workers had found that
(5) For reviews, see: (a) Tamaru, Y. J. Organomet. Chem. 1999, 576
(1-2), 215. (b) Ikeda, S. I. Acc. Chem. Res. 2000, 33, 511. (c) Montgomery,
J. Acc. Chem. Res. 2000, 33, 467.
10.1021/ol026216i CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002

Table 1. Nickel-Catalyzed Homoallylation of Chiral Steroidal
Aldehyde 3 with Various Dienesa
Figure 1.
that this nickel-catalyzed reaction also proceeded with
cyclohexadiene which greatly expanded the synthetic utility
of the reaction. In this paper, we report that Ni(acac)2-
catalyzed reaction of cyclohexadiene with a wide variety of
aldehydes in the presence of Et2Zn as the reducing reagent.
Initially, we carried out the reaction of various 1,3-dienes
with chiral steroidal aldehyde 3 catalyzed by Ni(acac)2 in
the presence of diethylzinc (Et2Zn) or triethyl borane (Et3B).
The results are shown in Table 1. It was found that the
reaction with Et2Zn was much faster than the reaction with
Et3B (entry 1 vs entry 2). Therefore, Et2Zn was used for all
the subsequent reactions. In all these cases, the reaction
proceeded smoothly to afford the desired products in good
yields with moderate to good selectivities. For the nickel-
catalyzed reaction of chiral steroidal aldehyde 3 with isoprene
under the treatment of Et2Zn, this reaction offered the
corresponding homoallylation product in good yield (82%)
and moderate stereoselectivity with 1,3-anti product as the
major product (5a/6a: 70/30). These reactions are highly
chemoselective, reacting only with the aldehyde functional
group without affecting the enone functionality. Furthermore,
all these reactions proceeded in very high facial selectivity
in which only the Felkin-Ahn’s product (22â)7 was ob-
served.
a Reaction conditions: Ni(acac)2 (0.1 mmol), aldehyde (1 mmol), dry
b
THF (5 mL), diene (4 mmol), and Et2Zn or Et3B (2.4 mmol). Based on
c
1
isolated product. Determined by the H NMR or weight of diastereomers
separated. dThe diene reacts only at the least substituted position. eProduct
was obtained in 45% yield when Et3B was used instead of Et2Zn.
entry 3 to 4 were based on comparison (1H NMR and 13C
NMR) with 5a and 6a.
Similarly, the product 9 obtained from cyclohexadiene
(entry 5) was oxidized to the corresponding ketone 10
(Scheme 2). The ratio of the two isomers (75:25) of ketone
1
10 observed in the H NMR, and 13C NMR was consistent
The stereochemistry of the homoallylation product 5a was
confirmed by a single-crystal X-ray crystallography (Figure
2).8 The stereochemical assignment of the minor product 6a
was assigned after comparing the spectroscopic data of the
corresponding ketone 8a with the ketone 7a obtained from
5a (Figure 2).9 The difference in the 13C NMR suggested
that it is most probably the Felkin-Ahn’s product of the
syn isomer. The stereochemical assignments of products of
with the diastereomeric ratio of alcohol 9, which indicated
the difference in the configuration of C-23.
Interestingly, cyclohexadiene reacted with steroidal alde-
hyde 3 to afford the desired product in moderate yield and
Scheme 2
(6) (a) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.;
Matsumoto, S.; Tamaru, Y. Angew. Chem. 1999, 111, 410-413; Angew.
Chem., Int. Ed. 1999, 38, 397-400. (b) Kimura, M.; Matsuo, S.; Shibata,
K.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 3386-3388.
(7) (a) Hein, S. J.; Keszler, D. A. Acta Crystallogr. C. 1987, 43, 2457-
2459. (b) Mulzer, J.; Schulze, T.; Strecker, A.; Denzer, W. J. Org. Chem.
1988, 53, 4098-4103. (c) Mulzer, J.; Kattner, L.; Strecker, A. R.; Schroder,
C.; Buschmann, J.; Lehmann, C.; Luger, P. J. Am. Chem. Soc. 1991, 113,
4218-4229. (d) Giese, B.; Damm, W.; Roth, M.; Zehnder, M. Synlett 1992,
5, 441-443.
(8) X-ray data for 5a: C27H42O2; Fw ) 398.61; Orthorhombic; space
group P2(1)2(1)2; a ) 11.9828(8), b ) 24.1612(16), c ) 8.1881(5) Å; V
) 2370.6(3) Å3; Z ) 4; R1 ) 0.0405, wR2 ) 0.0550; GOF ) 0.756 for
6678 observations with I > 2σ(I).
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Org. Lett., Vol. 4, No. 16, 2002

Figure 2. Single-crystal X-ray diffraction analysis of 5a and clarification of the structure of 6a.
selectivity. Since the cyclohexane moiety is featured in a
large number of biologically important natural products, and
the development of synthetic methods other than Diels-
Alder and olefin metathesis reactions is needed, the reaction
was studied in detail. Accordingly, we focused our attention
on the Et2Zn/Ni(acac)2 condition and expanded this condition
to other aldehydes. The results are listed in Table 2.
As shown in Table 2, most of the aldehydes reacted with
1,3-cyclohexadiene smoothly and gave the products in
moderate to good yields. It is interesting to note that this cis
diene afforded the product in low (1,2)-diastereoselectivity.
In conclusion, this work has demonstrated the utility of
nickel-catalyzed homoallylation strategy as an efficient
method for the synthesis of γ,δ-alkenyl alcohols. Excellent
Felkin-Ahn’s product was obtained for all the dienes when
chiral steroidal aldehyde was used. Moderate 1,3-diastereo-
selectivity was observed. Furthermore, we have found that
contrary to what was reported, nickel-catalyzed cyclic diene
such as cyclohexadiene afforded the products in good yields.
The ability to work with cyclic dienes indicates that a cis
nickel oxametallacycle does play a role in the reaction
pathway. Furthermore, to account for the low 1,2-diastereo-
selectivity observed even with this cis diene, we proposed
that a less rigid, open-chain transition state may be involved.
Efforts to further understand the mechanism and increase
the selectivity are currently in progress.
Table 2. Nickel-catalyzed Homoallylation of Aldehydes with
1,3-Cyclohexadienea
Acknowledgment. We thank the national university of
Singapore for generous financial support. We also thank Dr.
Jagadese J. Vittal and Ms. Tan Geok Kheng for determining
the crystal structure of 5a.
entry
R
yield (%)b
selectivityc (anti:syn)
Supporting Information Available: Complete experi-
ment details, including characterization data for all new
compounds and X-ray crystal data for 5a. This material is
available free of charge via the Internet http://pubs.acs.org.
1
2
3
4
5
a
b
c
d
e
PhCH2CH2
n-C5H11
n-C8H17
c-C6H11
Ph
92
60
55
65
62
58:42
60:40
61:39
68:32
72:28
OL026216I
a Reaction conditions: Ni(acac)2 (0.1 mmol), aldehyde (1 mmol), dry
THF (5 mL), 1,3-cyclohexadiene (4 mmol), and Et2Zn (2.2 mL, 1.1 M
solution in toluene, 2.4 mmol). The reaction mixture was stirred for 2 h at
room temperature. bBased on separated yield. cDetermined by the 1H NMR.
*Interconvertible (relative stereochemistry not determined).
(9) Products 5a (white solid) and 6a (oil) were isolated by flash column
chromatography. The structure of 5a was confirmed by single-crystal X-ray
diffraction analysis; treatment of 5a and 6a, respectively, with Dess-Martin
periodinane gave the corresponding ketone 7a and 8a as diastereomers, by
which the stereochemistry of 6a was determined to be 1,3-syn configuration.
Org. Lett., Vol. 4, No. 16, 2002
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