Regio- and stereoselective nickel-catalyzed homoallylation of aldehydes with 1,3-dienes

Article abstract of DOI:10.1021/ja0608904

Ni(acac)₂ catalyzes homoallylation of aldehydes with 1,3-dienes in the presence of triethylborane. Triethylborane serves as a reducing agent delivering a formal hydride to the C2 position of 1,3-dienes, thus generating a formal homoallyl anion species and enabling the novel homoallylation of aldehydes. The reaction proceeds smoothly at room temperature in the absence of any phosphane or nitrogen ligands and is highly regioselective and stereoselective for a wide variety combination of aldehydes and 1,3-dienes: e.g., isoprene and benzaldehyde combine to give a mixture of anti- and syn-1-phenyl-3-methyl-4-penten-1-ol (2.2) in a ratio of 15:1 in 90% yield. Under the conditions, sterically congested aliphatic aldehydes and ketones show low yields. In such cases, diethylzinc serves as a substitute for triethylborane and yields the expected products in good yields with similarly high regio- and stereoselectivity. 1,3-Cyclohexadiene is one exception among 24 kinds of dienes examined and undergoes allylation (not homoallylation) selectively.

Full text of DOI:10.1021/ja0608904

Published on Web 06/14/2006
Regio- and Stereoselective Nickel-Catalyzed Homoallylation of
Aldehydes with 1,3-Dienes
Masanari Kimura,† Akihiro Ezoe,† Masahiko Mori,† Keisuke Iwata,† and
Yoshinao Tamaru*
Contribution from the Department of Applied Chemistry, Faculty of Engineering, Nagasaki
UniVersity, 1-14 Bunkyo, Nagasaki 852-8521, Japan, and Graduate School of Science and
Technology, Nagasaki UniVersity, 1-14 Bunkyo, Nagasaki 852-8521, Japan
Received February 16, 2006; E-mail: tamaru@net.nagasaki-u.ac.jp
Abstract: Ni(acac)2 catalyzes homoallylation of aldehydes with 1,3-dienes in the presence of triethylborane.
Triethylborane serves as a reducing agent delivering a formal hydride to the C2 position of 1,3-dienes,
thus generating a formal homoallyl anion species and enabling the novel homoallylation of aldehydes. The
reaction proceeds smoothly at room temperature in the absence of any phosphane or nitrogen ligands and
is highly regioselective and stereoselective for a wide variety combination of aldehydes and 1,3-dienes:
e.g., isoprene and benzaldehyde combine to give a mixture of anti- and syn-1-phenyl-3-methyl-4-penten-
1-ol (2.2) in a ratio of 15:1 in 90% yield. Under the conditions, sterically congested aliphatic aldehydes and
ketones show low yields. In such cases, diethylzinc serves as a substitute for triethylborane and yields the
expected products in good yields with similarly high regio- and stereoselectivity. 1,3-Cyclohexadiene is
one exception among 24 kinds of dienes examined and undergoes allylation (not homoallylation) selectively.
Introduction
only a limited number of homoallylation reaction regarding the
nickel8 and other transition metal catalyses9 have been reported
so far. This is probably owing to the difficult availability and
the low nucleophilicity of homoallylic transition metal species.
Organonickel complexes are distinctive in their nucleophilic
reactivity from organometal complexes of the other group 10
elements.1 Nucleophilic allylation of carbonyl compounds2 and
alkyl halides3 with π-allyl nickels has proved to be particularly
useful and has been utilized widely for the synthesis of natural
and unnatural products. Unfortunately, however, this methodol-
ogy requires a stoichiometric amount of nickel.
Recently, useful versions of nickel-catalyzed allylation and
vinylation of aldehydes with 1,3-dienes4 and alkynes,5 allenes,6
and alkenes7 have been developed, which provide useful access
to homoallyl alcohols and allyl alcohols, respectively.1a,b
Compared with the catalytic allylation and vinylation, however,
In 1998, we disclosed for the first time that Ni(acac)2 [acac
) acetylacetonato] was able to promote the catalytic homoal-
lylation of benzaldehyde with a variety of 1,3-dienes in the
presence of triethylborane, stereoselectively yielding bis-ho-
moallyl alcohols anti-2 (eq 1).10
† Graduate School of Science and Technology, Nagasaki University.
(1) (a) Tamaru, Y., Ed. Modern Organic Chemistry; Wiley-VCH: Weinheim,
2005. (b) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890-3908.
(c) Tsuji, J. Transition Metal Regents and Catalysts; Wiley & Sons:
Chichester, 2000. (d) Davies, S. G. Organotransition Metal Chemistry:
Application to Organic Synthesis; Pergamon: Oxford, 1982; Chapter 6.
(2) Semmelhack, M. F. Organic Reactions; Wiley: New York, 1972; Vol.
19, Chapter 2.
(5) (a) Knapp-Reed, B.; Mahandru, G. M.; Montgomery, J. J. Am. Chem. Soc.
2005, 127, 13156-13157. (b) Mahandru, G. M.; Liu, G.; Montgomery, J.
J. Am. Chem. Soc. 2004, 126, 3698-3699. (c) Patel, S. J.; Jamison, T. F.
Angew. Chem., Int. Ed. 2004, 43, 3941-3944. (d) Miller, K. M.;
Lanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004,
126, 4130-4131.
(3) (a) Hegedus, L. S.; Varaprath, S. Organometallics 1982, 1, 259-263. (b)
Semmelhack, M. F.; Wu, E. S. C. J. Am. Chem. Soc. 1976, 98, 3384-
3386.
(6) (a) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 7320-7321.
(b) Montgomery, J.; Song, M. Org. Lett. 2002, 4, 4009-4011.
(7) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 14194-14195.
(8) Catalytic with respect to Ni: (a) Sato, Y.; Takimoto, M.; Mori, M. J. Am.
Chem. Soc. 2000, 122, 1624-1634. Stoichiometric with respect to Ni: (b)
Sato, Y. Takimoto, M.; Mori, M. Synlett 1997, 734-736. (c) Sato, Y.;
Takimoto, M.; Mori, M. Tetrahedron Lett. 1996, 37, 887-890.
(9) Catalytic with respect to Rh: Kong, J.-R.; Ngai, M.-Y.; Krische, M. J. J.
Am. Chem. Soc. 2006, 128, 718-719 and references therein. (b) Jang, H.-
Y.; Krische, M. J. Eur. J. Org. Chem. 2004, 3953-3958. Stoichiometric
with respect to Zr: (b) Yasuda, H.; Tatsumi, K.; Nakamura, A. Acc. Chem.
Res. 1985, 18, 120-126. (c) Erker, G.; Engel, K.; Atwood, J. L.; Hunter,
W. E. Angew. Chem., Int. Ed. Engl. 1983, 22, 494-495. (d) Erker, G.;
Dorf, U. Angew. Chem., Int. Ed. Engl. 1983, 22, 777-778. (e) Bertelo, C.
A.; Schwartz, J. J. Am. Chem. Soc. 1976, 98, 262-264.
(4) (a) Kojima, K.; Kimura, M.; Tamaru, Y. Chem. Commun. 2005, 4717-
4719. (b) Kimura, M.; Ezoe, A.; Mori, M.; Tamaru, Y. J. Am. Chem. Soc.
2005, 127, 201-209. (c) Kimura, M.; Kojima, K.; Inoue, T.; Tamaru, Y.
Synthesis 2004, 3089-3091. (d) Ezoe, A.; Kimura, M.; Inoue, T.; Mori,
M.; Tamaru, Y. Angew. Chem., Int. Ed. 2002, 41, 2784-2786. (e) Sato,
Y.; Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 9310-9317. (f) Shibata,
K.; Kimura, M.; Kojima, K.; Tanaka, S.; Tamaru, Y. J. Organomet. Chem.
2001, 624, 348-353. (g) Kimura, M.; Shibata, K.; Koudahashi, Y.; Tamaru,
Y. Tetrahedron Lett. 2000, 41, 6789-6793. (h) Kimura, M.; Matsuo, S.;
Shibata, K.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 3386-3388. (i)
Sato, Y.; Saito, N.; Mori, M. Tetrahedron 1998, 54, 1153-1168. (j)
Takimoto, M.; Hiraga, Y.; Sato, Y.; Mori, M. Tetrahedron Lett. 1998, 39,
4543-4546. (k) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi,
K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771-9772.
(10) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998,
120, 4033-4034.
9
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J. AM. CHEM. SOC. 2006, 128, 8559-8568
8559

A R T I C L E S
Kimura et al.
Table 1. Ni0-Catalyzed Homoallylation of Benzaldehyde with a
Subsequently, we have also demonstrated that (1) a similar
homoallylation reaction is successful for aliphatic aldehydes and
ketones by making use of diethylzinc (Et2Zn)11 and (2) the
reaction with Et3B is compatible with water and even promotes
the homoallylation of commercial 50% aqueous glutaraldehyde
and ω-hydroxyaldehydes (lactols).12 All these reactions generally
proceed at room temperature or below without using any
phosphane or amine ligands and show excellent 1,2-anti- (R1
* H) and 1,3-anti-selectivity (R2 * H) (eq 1). The Et2Zn-Ni
catalytic system has been successfully extended to the homoal-
lylation of the less reactive aldimines, which shows an opposite
stereoselectivity and provides 1,3-syn-bishomoallylamines in
excellent yields.13
Variety of 1,3-Dienes Promoted by Et3Ba
This article describes a full scope of the homoallylation
reaction of a variety of combinations of dienes (24 kinds) and
aromatic, unsaturated, and aliphatic aldehydes (18 kinds) and
ketones (6 kinds).10,11 The most remarkable aspects, newly
developed and, demonstrated here, are that (1) some dienes,
bearing electron-donating substituents, such as OSiR3 and OMe,
not only provide 2 of useful levels of oxidation states and
molecular functional arrays but also show marked difference
in reactivity as large as 15 000 times, depending on the
substitution position at either C1 or C2 of dienes and (2)
cyclohexadiene is exceptional among dienes examined and
selectively furnishes allylation products, not homoallylation
products. Furthermore, the reaction conditions were modified
so as to be applicable to a 10-g scale preparation of 2. Aldehydes
possessing stereocenters at the R- or â-positions showed almost
no diastereofacial selectivity, i.e. the present homoallylation does
not follow the Cram model (or Felkin-Ahn model).
In the present homoallylation, a formal hydride that stems
from the methyl group of Et3B or Et2Zn is delivered regio- and
stereoselectively at the C2 positions of 1,3-dienes. The origin
of the regioselective hydride delivery at the C2 position rather
than at the allylically related C4 position of 1,3-dienes is
addressed. Furthermore, mechanistic rationale is given for the
1,2- and 1,3-diastereostereoselectivity and the enormous dif-
ference in the relative reactivity among dienes (e.g., 2-siloxy-
1,3-diene (1r)/1-siloxy-1,3-diene (1u) ) 15 000) as well as
unusual reactivity that cyclohexadiene displays.
Results and Discussion
1. Homoallylation of Aromatic and r,â-Unsaturated
Aldehydes with Dienes Promoted with Et3B. The reactions
of benzaldehydes with parent 1,3-butadiene (1a) and alkyl- and
aryl-substituted dienes 1b-q are summarized in Table 1, and
those with alkoxy-substituted dienes 1r-x in Table 2. These
reactions are performed uniformly at room temperature under
N2 using a diene (4 mmol), benzaldehyde (1 mmol), Ni(acac)2
(0.1 mmol), and Et3B (2.4 mmol, 1 M in hexane) in THF (5
mL).
As for the reaction site (regioselectivity) of unsymmetrical
dienes, Table 1 clearly indicates that C2 electron-donating
a Reaction conditions: 1 (4 mmol), benzaldehyde (1 mmol), Ni(acac)2
(10 mol %), and Et3B (240 mol %, 1 M in hexane) in THF (5 mL) at room
temperature under N2. b Only major isomers are shown. c 1i (1 mmol) was
used instead of 4 mmol.
(11) (a) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.;
Matsumoto, S.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 397-400.
(b) Shibata, K.; Kimura, M.; Shimizu, M.; Tamaru, Y. Org. Lett. 2001, 3,
2181-2183.
substituents (e.g., Me, CH2SiMe3) strongly favor the reaction
at the C1 butadiene terminal, giving rise to 2 exclusively (runs
2, 3, and 5), whereas C2 phenyl substituent does not, furnishing
a mixture of C1- and C4-coupling products in ∼10 to 1 ratio
(12) Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru, Y. Angew. Chem., Int. Ed.
2001, 40, 3600-3602.
(13) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka, S.; Tamaru, Y. J. Am. Chem.
Soc. 2004, 126, 14360-14361; Kimura, M.; Miyachi, A.; Kojima, K.;
Tanaka, S.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 10117.
9
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Ni-Catalyzed Homoallylation of Aldehydes with 1,3-Dienes
A R T I C L E S
Scheme 1. Siloxydienes as the Synthetic Equivalents of
Table 2. Ni0-Catalyzed Homoallylation of Benzaldehyde with
Siloxy-1,3-Butadienes Promoted by Et3Ba,b
Functionalized Butenyl and Butyl Anions; TIPS ) Si(i-Pr)3
syn-2 with high selectivity (runs 9-11). Enrichment of 1,2-
syn-isomers 2.9 and 2.10 as compared with the Z contents of
the starting dienes 1i and 1j, respectively, may be attributed to
the high reactivity of the (Z)-isomers as compared with the (E)-
isomers. In fact, as illustrated in run 10, where 1 equivalent of
1i was used with respect to benzaldehyde, as opposed to 4
equivalents under usual conditions, the 1,2-syn-2.10/1,2-anti-
2.10 ratio was reduced to 1/2.
a See footnote a, Table 1. b TIPS ) Si(i-Pr)3.
(2.4 and 4.1, respectively, run 4). C1 substituents are not so
influential to determine the regioselectivity, and both C1-Me
butadiene 1f and C1-Ph butadiene 1g form mixtures of C4- and
C1-adducts in ∼2:1 ratio (runs 6 and 7).14
As is apparent from Table 1, homoallylation is a quite general
reaction pattern for a wide structural variety of dienes. The
parent 1,3-butadiene (1a) is only one exception that provides
an allylation product 3.1 as a minor product together with a
homoallylation product 2.1 as a major product. This exceptional
result might be attributed to isomerization of the primary product
2.1 to the thermodynamically more stable isomer 3.1, as is
sometimes observed for transition metal catalysis, especially for
nonbranched alkenes.
The results listed in runs 8-11 are in accord with these
substituent effects. For example, both methyl groups of 1h
cooperate to promote the reaction at C4 and provide 2.8 as a
single regioisomer in excellent yield. C1- and C2-methyl groups
of 1i are expected to operate oppositely; however, the result
indicates that C2-Me is more influential than C1-Me, furnishing
a C1-adduct 2.9 exclusively (runs 9 and 10). A triene 1j is, in
principle, capable of reacting at C1, C3, C4, and C6; in fact,
however, it reacted selectively at C1 and furnished 2.10
exclusively in excellent yield (run 11). Interestingly, an electron-
deficient and electronically strongly biased diene, methyl sorbate
(1l), reacted with similar ease and furnished a C1-adduct 2.12
in good yield and with excellent regio- and stereoselectivity.
The experiments of runs 14 and 15 clearly indicate that the
regioselectivity displayed by methyl sorbate stems from elec-
tronic factors rather than from other factors such as coordination
of an oxygen atom to a nickel species. The formation of 4.6 in
a considerable amount for the reaction of 1o is quite unexpected
since, first of all, the product 4.6 is sterically congested and,
furthermore, both the C1 substituents are expected to promote
C-C formation at a distal diene terminal to give 2.15 selectively
(cf., runs 6, 7, and 11). Cyclohexadiene (1p) turned out to be
unreactive, and no reaction was observed.8a,c The low reactivity
of 1q may be attributed to its low coordination ability to a nickel
species.
As summarized in Table 2, C1- and C2-siloxydienes react
with benzaldehyde highly regio- and stereoselectively and
furnish homoallylation products 2.16-2.21 as single regio- and
stereoisomers in good to excellent yields. A siloxy group
surpasses a methyl group in regiocontrolling effect and C2-
siloxy directs butadiene to react at C1, and C1-siloxy does at
C4 exclusively. For example, 1s reacted at C1 exclusively, and
1u provided a C4 addition product 2.19 exclusively.
Tri-alkoxydiene 1x suddenly turned the reaction course and
underwent the hetero Diels-Alder reaction (run 7). The reaction
was complete within a short period of time at room temperature
and provided a cycloaddition product 5 as a single product.
As illustrated in Scheme 1, the present homoallylation with
siloxy- and methoxy-substituted dienes is of great synthetic
value. The product 2.21 is easily converted to anti-5-phenyl-5-
hydroxy-3-methylpentanal; hence, the diene 1v may be regarded
as a synthetic equivalent of a bis-homoenolate of an aldehyde,
3-methylbutanal. The same product may be obtained by the
reaction with the corresponding lithium or magnesium reagent
with protection of the aldehyde group; in this reaction, however,
one can hardly expect such a high 1,3-anti-selectivity of 2.21.
Similarly, 1r may be regarded as a synthetic equivalent of
2-hydroxy-3-butenylmetal species, which is capable of introduc-
ing 1,3-anti stereoselectivity in the product, 2.16 (run 1, Table
2). In the rectangle in Scheme 1 are shown the examples of
synthetic equivalents of other siloxydienes, among which 1w
As for the stereoselectivity, in most cases, C2-substituted
dienes generally provide 1,3-anti-2 exclusively. The stereose-
lectivity of C1-substituted dienes depends on the geometry of
the starting dienes. (E)-Dienes provide 1,2-anti-2 almost
exclusively (runs 13-15), and (Z)-dienes seem to provide 1,2-
(14) Sato, Y.; Sawaki, R.; Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 656-
662.
9
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A R T I C L E S
Kimura et al.
Table 3. Ni0-Catalyzed Homoallylation of Aromatic and
Table 4. Ni0-Catalyzed Homoallylation of Aliphatic Aldehydes with
Unsaturated Aldehydes with Isoprene Promoted by Et3Ba,b
Isoprene Promoted by Et3Ba
a See footnote a, Table 3. b Only major isomers are shown.
isoprene is reactive enough under usual conditions toward
primary alkyl aldehydes (runs 1-3) and sterically less-hindered
secondary alkyl aldehydes (runs 4 and 5), providing homoal-
lylation products in good yields and with excellent stereose-
lectivity.
a Isoprene (4 mmol), an aldehyde (1 mmol), Ni(acac)2 (10 mol %), and
Et3B (240 mol %, 1 M in hexane) in THF (5 mL) at room temperature
under nitrogen. b TIPS ) Si(i-Pr)3.
The yields suddenly are lower for the homoallylation of
sterically demanding cyclohexanecarbaldehyde and pivalalde-
hyde (runs 6 and 7). However, even in these cases, the reactions
showed high 1,3-anti-selectivity. The homoallylation of such
aldehydes could be performed successfully with diethylzinc
(section 4).
The examples shown in runs 2, 4, and 5 indicate that the
present homoallylation with isoprene shows almost no diaste-
reofacial selectivity with respect to the R- and â-stereocenters
of aldehydes.17 Other electron-rich and electron-deficient dienes
also showed almost no diastereofacial selectivity (eqs 3 and 4).
may be of particular importance in view of the synthesis of
polyketide natural products.15
In Table 3 are summarized the reactions of isoprene with o-,
m-, p-hydroxybenzaldehydes, furfural, and unsaturated alde-
hydes. As observed in runs 1-3, Et3B seems to withstand
hydrolysis by acidic phenols16 under the conditions and provides
expected products in excellent yields. No extra amounts of Et3B
were applied in these experiments. Salicylaldehyde forms a
cyclic boronic acid ester 2.22, which is stable toward hydrolysis
during aqueous workup and can be isolated by means of column
chromatography over silica gel. Furfural reacts as usual and
provides an expected product 2.25 with excellent stereoselec-
tivity. Unsaturated aldehydes, irrespective of their substitution
pattern, undergo homoallylation selectively with very high 1,3-
anti selectivity (runs 5-9, Table 3). In every case, the geometry
of the double bond of the starting aldehydes remains intact.
2. Reaction of Aliphatic Aldehydes with Dienes Promoted
with Et3B. The addition reaction of organometallics of low
nucleophilicity upon aliphatic aldehydes sometimes suffers from
low yields, not only because of their diminished electrophilic
reactivity, as compared with those of aromatic aldehydes but
also because of their propensity to undergo enolization and many
other side reactions. As is apparent from runs 1-5 in Table 4,
3. Relative Reactivity of Dienes. Through experiments, we
have realized that 1-siloxy- and 1-methoxybutadiene show
apparently lower reactivity than other dienes. In fact, the
(15) (a) Beaudry, C. M.; Trauner, D. Org. Lett. 2005, 7, 4475-4477. (b) Smith,
A. B., III; Walsh, S. P.; Frohn, M.; Duffey, M. O. Org. Lett. 2005, 7,
139-142. (c) Subba R. G. S. R. Pure Appl. Chem. 2003, 75, 1443-1451.
(d) Shepherd, J. N.; Myles, D. C. Org. Lett. 2003, 57, 1027-1030.
(16) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagent; Academic: London,
1988.
(17) Jurczak, J.; Pikul, S. Bauer, T. Tetrahedron 1986, 42, 447-488.
9
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Ni-Catalyzed Homoallylation of Aldehydes with 1,3-Dienes
A R T I C L E S
Scheme 2. Relative Reactivity of Dienes Determined by
Competition Reaction with 1,3-Dienes (2 equiv each) Against
Benzaldehyde for the Ni0-Catalyzed, Et3B-Promoted
Homoallylation; (a) Relative Amounts of Products Isolated; (b)
Relative Reactivity; (c) Selected Examples of Relative Reactivity;
TIPS ) Si(i-Pr)3; TMS ) SiMe3
Table 5. Ni0-Catalyzed Homoallylation of Aromatic and Aliphatic
Aldehydes with Isoprene Promoted by Et2Zna
a Isoprene (4 mmol), an aldehyde (1 mmol), Ni(acac)2 (10 mol %), and
Et2Zn (240 mol %, 1 M in hexane) in THF (5 mL) at room temperature
under nitrogen. b Only major isomers are shown. c At 0 °C. d 1-Phenyl-
propan-1-ol (6.1: 16%). e 1-(2-Furyl)propan-1-ol (6.2: 3%). f 3-Phenyl-
pentanal (28%).
reactivity than Et3B. Hence, we tried Et2Zn in place of Et3B to
promote the homoallylation of particular combinations of
aldehydes and dienes that is not successful by making use of
Et3B. We soon realized that Et2Zn is too reactive to promote
selectively the homoallylation of aryl aldehydes and unsaturated
aldehydes (runs 1-3, Table 5). Aryl aldehydes were so reactive
that they always accompanied the direct reaction with Et2Zn
and formed ethylation products 6 as undesirable side products
(footnotes d and e, Table 5).18 Unsaturated aldehyde was subject
to the Michael addition of an ethyl group of Et2Zn; cinnama-
ldehyde did not produce the expected product 2.27 at all; instead,
3-phenylpentanal was furnished as the major isolated product
(run 3).
For the less reactive aliphatic aldehydes, Et2Zn turned out to
be the choice of reagents, and the expected homoallylation
products were obtained in greatly improved yields (runs 4-6,
Table 5, vs runs 3, 6, and 7, Table 4). In these small-scale
experiments, no direct ethylation was observed; however, for
large-scale experiments, the ethylation sometimes becomes a
serious side reaction (section 5)
competition experiments that were performed using two kinds
of dienes (2 mmol each) and benzaldehyde (1 mmol) in the
presence of Ni(acac)2 (10 mol %) and Et3B (240 mmol) at room
temperature revealed that 2-siloxydiene (1r) was ∼3 times as
reactive as isoprene; while, surprisingly, 1-siloxydiene (1u) was
less reactive more than 100 times than isoprene (Scheme 2a);
in the competition reaction between isoprene and 1u, only an
isoprene-benzaldehyde adduct 2.2 was formed in a quantitative
yield, and no trace of a 1u-benzaldehyde adduct 2.19 was
detected. In Scheme 2a are summarized the results obtained for
the three series of experiments using isoprene (1b), 1,3-
pentadiene (1f), and 3-methyl-1-siloxy-1,3-butadiene (1v) as the
standards. On the basis of these results, the relative reactivity
among dienes is estimated as shown in Scheme 2b.
Interestingly, the relative reactivity seems to have nothing to
do with the nucleophilic reactivity (e.g., HOMO) of dienes. For
example, electron-deficient methyl sorbate (1l) is 5 times as
reactive as 1-methyl-1,3-butadiene (1f). The most striking is
that 2-siloxy-1,3-butadiene (1r) is 15 000 times as reactive as
1-siloxy-1,3-butadiene (1u) and the former is the most reactive
and the latter is the least reactive among 1,3-dienes examined
(Scheme 2c). Generally, 1-siloxy group seems to greatly retard
the reaction. On the other hand, 2-siloxy group seems to slightly
accelerate the reaction.
Under the Et3B-Ni catalysis, no productive results were
obtained for the reaction with ketones. In sharp contrast, as
exemplified in Scheme 3 and Table 6, the Et2Zn-Ni catalysis
nicely promoted the homoallylation of ketones. However, we
met for the first time small erosion in regioselectivity in these
reactions (eqs 5 and 6); isoprene reacted with acetone, cyclo-
hexanone, and protected dihydroxyacetone19 both at C1 and C4
positions and provided mixtures of homoallylation products 2
and 4 in a ratio of ∼5-6:1.
The conformation of dienes (s-cis vs s-trans) seems to be
another important factor by which to determine their reactivity
toward the present homoallylation, since cyclohexadiene, a s-cis
diene, hardly participates in the reaction (run 17, Table 1).
Mechanistic rationale for the unique reactivity of dienes is given
in section 6 (Mechanistic Consideration).
As observed for chiral aldehydes (Table 4), the diastereofacial
selectivity for ketones was also modest; irrespective of the steric
(18) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2005, 7, 4689-4691.
(19) Gonza´lez-Garc´ıa, E. M.; Grognux, J.; Wahler, D.; Reymond, J.-L. HelV.
Chim. Acta 2003, 86, 2458-2470.
4. Homoallylation of Aldehydes and Ketones Promoted
with Et2Zn. Diethylzinc (Et2Zn), in general, shows higher
9
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A R T I C L E S
Kimura et al.
Table 7. Ni0-Catalyzed, Et3B-Promoted Homoallylation of
Scheme 3. Ni0-Catalyzed Homoallylation of Ketones with
Isoprene or 2,3-Dimethyl-1,3-butadiene Promoted by Et2Zn: Steric
Effects of Ketone on Regio- and Stereoselectivity
Benzaldehyde with Dienes with Reduced Amounts of Ni(acac)2
and Dienesa
diene
Ni(acac)2
(mol %)
Et3B
scaleb
time
(h)
product 2
run
(mol %)
(mol %)
(mmol)
(% isolated yield)
1
2
3
4
5
6
7
8
9
1b (400)
1b (400)
1b (400)
1b (200)
1l (400)
1l (400)
1r (400)
1r (200)
1r (110)
10.0
2.5
1.0
1.4
10.0
1.0
10.0
5.0
5.0
240
240
240
200
240
240
240
240
240
1
2
5
50
1
5
1
1
2
35
35
48
24
47
66
68
65
65
2.2 (90)
2.2 (94)
2.2 (82)
2.2 (93)
2.12 (79)
2.12 (91)
2.16 (65)
2.16 (65)
2.16 (62)
a A mixture of a diene (indicated amount), benzaldehyde (1 mmol),
Ni(acac)2 (indicated amount), and Et3B (indicated amount) at room
temperature under N2. b The scale of reaction based on the amount of
benzaldehyde.
Ni did promote the reaction (eq 8).20 The reaction proceeded
smoothly at room temperature and was complete within 30 min.
According to the results reported by Loh,21 we have long
regarded the product structure as 4.50′. However, the major
isomer of 2.50 showed the 13C NMR (100 MHz) and 1H NMR
(400 MHz) spectra completely superimposable to those of the
product, syn-1-(2-cyclohexenyl)-1-phenylmethanol, obtained
exclusively by the allylation of benzaldehyde with 2-cyclohex-
enyl benzoate through umpolung reaction catalyzed by pal-
ladium.22 The structure of 2.50 was further determined un-
equivocally by a chemical transformation technique (eq h,
Scheme 9). This indicates that cyclohexadiene is unique both
in its reactivity and regioselectivity among dienes and selectively
undergoes allylation, not homoallylation.13
Table 6. Ni0-Catalyzed Homoallylation of Protected
Dihydroxyacetone with 1,3-Dienes Promoted by Et2Zna
The diene 1w is so unreactive that, under the Et3B-Ni
catalysis, it is only reactive enough toward aromatic aldehydes
(cf. run 6, Table 2); it failed to react with less electrophilic
unsaturated aldehydes and aliphatic aldehydes, e.g., cinnama-
ldehyde and dihydrocinnamaldehyde. In sharp contrast, under
the Et2Zn-Ni catalysis, 1w reacted successfully with dihydro-
cinnamaldehyde and provided a homoallylation product 4.51,
although in modest yield (eq 9, Scheme 4). As a consequence
of low reactivity of 1w, an ethylation product 6.3 was obtained
in an almost equal amount.
5. Optimization of Reaction Conditions For Practical
Use: Reduced Loading of Ni(acac)2 and Dienes and Ap-
plication to Multigram-Scale Experiments. To compare the
reactivity and selectivity of dienes and aldehydes, the reactions
discussed so far have been undertaken uniformly under the
conditions using Ni(acac)2 (10 mol %), a diene (400 mol %),
an aldehyde or ketone (1 mmol), and Et3B (240 mol %) or Et2Zn
(240 mol %). The conditions are not satisfactory for practical
use with respect to the turnover numbers of the catalyst, diene
loadings, and the scales of experiments. Accordingly, we next
tested the reaction with reduced loadings of the catalysts and
dienes in large-scale experiments. In Table 7 are summarized
the results. The homoallylation of benzaldehyde with isoprene
(1b) is summarized in runs 1-4, which clearly indicate that
Ni(acac)2 loading can be reduced to 1 mol % without significant
a Reaction conditions: 1 (4 mmol), 2,2-dimethyl-1,3-dioxacyclohexan-
5-one (1 mmol),19 Ni(acac)2 (10 mol %), and Et2Zn (240 mol %, 1 M in
hexane) in THF (5 mL) at room temperature for 2 h under N2.
Scheme 4. Reactions of Unreactive Dienes: Homoallylation with
Electron-Rich Diene 1w and Allylation with Cyclohexadiene (1p),
Both Being Effected Only with Et2Zn, but Not with Et3B
size of the C4 substituents of 4-substituted cyclohexanones,
∼4-5:1 mixtures of the equatorial/axial approach products
resulted (eq 7, Scheme 3).
(20) Ni-Catalyzed intramolecular reductive cyclization of cyclohexadienyl
aldehydes provides mixtures of allylation and homoallylation products: Yeh,
M.-C. P.; Liang, J.-H.; Jiang, Y.-L.; Tsai, M.-S. Tetrahedron 2003, 59,
3409-3415.
(21) Loh, T.-P.; Song, H.-Y.; Zhou, Y. Org. Lett. 2002, 4, 2715-2717.
(22) Tamaru, Y.; Tanaka, A.; Yasui, K.; Goto, S.; Tanaka, S. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 787-789.
The reactions shown in Scheme 4 clearly demonstrate the
utility of Et2Zn as a promoter. As mentioned before (run 17,
Table 1), cyclohexadiene failed to react with benzaldehyde under
the Et3B-Ni catalysis; however, the catalytic system Et2Zn-
9
8564 J. AM. CHEM. SOC. VOL. 128, NO. 26, 2006

Ni-Catalyzed Homoallylation of Aldehydes with 1,3-Dienes
A R T I C L E S
Scheme 5. Plausible Reaction Pathway Selectively Leading to 1,3-anti-2
decrease in the yields. Especially rewarding are the results in
run 4 that has been undertaken with a 50 mmol scale of
benzaldehyde and 2 equiv of Et3B; the product 2.2 was obtained
in 93% isolated yield (1,3-anti/1,3-syn ) 30:1, 8.09 g) by a
single Kugelrohr distillation of the reaction mixture after an
appropriate aqueous workup. Methyl sorbate (1l) also reacts with
benzaldehyde using reduced amount of Ni(acac)2 in a 5 mmol
scale experiment (run 6).
(eq 11).23 According to this procedure, dihydrocinnamaldehyde
Reduced diene loadings may be a strong concern when dienes
are expensive and/or require multisteps for the preparation. The
results in runs 7-9 indicate that 2-siloxy-1,3-diene (1r) loading
could be reduced to 1.1 equiv to an aldehyde without significant
loss in the yield.
(25 mmol) and cyclohexanecarboxaldehyde (25 mmol) provided
the homoallylation products 2.33 (80%, anti/syn ) 30:1) and
2.36 (85%, anti exclusive, not shown), respectively, both not
being contaminated with the corresponding ethylation products.
Taking the results of runs 3 and 6 in Table 4 into consideration,
these results suggest that a catalytic amount of Zn(II) species
plays a pivotal role in acceleration of the homoallylation with
Et3B.
6. Mechanistic Consideration. In Scheme 5 is proposed the
most plausible reaction pathway that accommodates all reaction
features characteristic of the present homoallylation reaction:
e.g., stereoselectivity leading to anti-2 selectively over syn-2
and regioselectivity leading to the homoallylation products 2
selectively over the allylation products 3, using isoprene as a
representative of dienes.
In eq 10 is shown a 10 g-scale reaction of isoprene and
dihydrocinnamaldehyde using reduced loading of Ni(acac)2,
where 2.33 was obtained in 85% yield (8.67 g, anti/syn ) 20:
1) together with a ethylation product 6.3 (10%). In this large-
The regioselectivity of dienes (reacting either at C1 or C4
with an aldehyde) might be mainly under the control of the
electron densities on the diene termini, and the terminal bearing
the highest electron density would enter into the reaction with
an aldehyde. A transition state I might lead to an intermediate
II and/or II′ through oxidative cyclization of a Ni(0) species
across isoprene and an aldehyde. The oxidative cyclization might
be accelerated by coordination of Et3B (or Et2Zn) to an
aldehyde.24,25 In this process, as illustrated by curved arrows,
dienes might serve not only as an electron-push toward
aldehydes but also as an electron-pull from a nickel(0) species
(electron donation from Ni(0)). For electron-rich dienes the
former factor might be important, and for electron-deficient
dienes the latter factor might be crucial. Thanks to these two
mechanisms, many kinds of electron-rich and electron-deficient
dienes might be able to engage in the present homoallylation.
scale experiment, both the yield and diastereoselectivity are
significantly improved as compared with those under the usual
1 mmol-scale reaction conditions (run 4, Table 5); however,
the ethylation became a serious side reaction. The ethylation
seems to be subject of the steric size of aldehydes, and under
the identical reaction conditions sterically hindered cyclohex-
anecarboxaldehyde (50 mmol) provided 2.36 in 93% yield (8.46
g, anti exclusive, not shown) together with a reduced amount
of the ethylation product, 1-cyclohexyl-1-ethylmethanol (6.4)
in 5% yield.
After many experimentations in pursuit of suppressing the
ethylation in large-scale experiments, we have finally reached
a satisfactory procedure: a pretreatment of Ni(acac)2 (3 mol
%) with one equivalent of Et2Zn (3 mol %) at ambient
temperature, followed by addition of Et3B (240 mol %), an
aldehyde, and isoprene (300 mol %) at ambient temperature
(23) Tamaru, Y.; Kimura, M. Org. Synth. 2006, 83, 88-96.
(24) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126, 11802-
11803.
(25) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc. 2005,
127, 12810-12811.
9
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A R T I C L E S
Kimura et al.
Scheme 6. A Rationale for Allylation (not Homoallylation) with
Cyclohexadiene
Scheme 7. Stronger Coordination of Vinyl Ether and Allyl Ether
(Σ2,Σ2) than Diene (Σ2,Σ2) to Ni0; Σ ) Me3 or (i-Pr)3
Scheme 8. A Rationale for Erosion of Regioselectivity (Giving 4
as a Minor Product) in Homoallylation of Ketones
Intermediates II and II′ are diastereomeric to each other.
Since the latter suffers from 1,3-diaxial repulsion between an
aldehyde R and isoprene Me, the reaction might proceed
selectively through II. Ethyl transfer from B to Ni, accompanied
by an ionic Ni-O bond cleavage, would form an intermediate
III, which might undergo â-H elimination in two ways. The
route leading to V is expected to be much favored over the one
leading to V′, since â-agostic interaction of the Et group with
the vacant site on Ni, cis to the Et group, created by dissociation
of an oxygen ligand, would readily take place (a transition state
IV). On the other hand, the route leading to V′ requires
geometrical change around Ni from trans to cis with respect to
the ethyl and alkoxy groups before â-H elimination takes place,
hence, having to pass through barrier(s) high in energy.26
Reductive elimination of Ni(0) from V might provide a
homoallylation product, anti-2, whereas the same process via
V′ might result in the formation of an allylation product, 3.
tion of a reactive Ni(0)/diene complex XII should be much
smaller than those of η2,η2-nickel complexes of usual dienes
under comparable conditions (e.g., [XV], Scheme 7c). However,
the high nucleophilicity of XII, bestowed by electron donation
of the siloxy group, might well compensate for its low
concentration, resulting in the relative reactivity of 1r/1b ) ∼3.
Here, we expect that complexes X-XII readily isomerize to
one another, just swinging ∼60° around η2-olefin/nickel bonds.
In the case of 1-siloxy dienes, e.g., 1u, on the other hand, a
vinyl ether/nickel complex XIII is hardly expected to isomerize
to XIV, since this process requires 180° rotation around the
η2-olefin/nickel bond (inversion of configuration on the Ni
center) and must be associated with barriers high in energy. As
a consequence, despite the greatest reactivity (the highest
HOMO) among dienes examined, 1u is least reactive in the
present Ni-catalyzed homoallylation reaction.
The cyclic oxa-π-allylnickel structures II and II′ are geo-
metrically possible only for s-trans dienes, and cyclohexadiene,
a s-cis diene, might be obliged to form a less stable cyclic oxa-
σ-allylnickel complex VI (Scheme 6). The two factors, (1)
formation of VI through activation of an aldehyde by the
coordination with strongly Lewis acidic and sterically small Et2-
Zn, and not Et3B, and (2) a facile Ni-O bond cleavage and
ethyl group transfer from Zn to Ni, forming a π-allyl(ethyl)-
nickel(II) intermediate VII would be essential to put the reaction
forward; otherwise, VI might be fragmented into the starting
materials through which cyclohexadiene would be able to restore
its conjugate stabilization. The crucial role of Lewis acids to
promote the oxidative cyclization of Ni(cod)2 upon olefinic
aldehydes and ketones (e.g., o-allylbenzaldehyde24 and o-
allylacetophenone)25 has been demonstrated by Ogoshi and
Kurosawa. The π-allyl(ethyl)nickel(II) intermediate VII, being
cis with respect to ethyl and alkoxy groups, might undergo â-H
elimination via a transition state VIII and provide an intermedi-
ate IX, which might be destined to undergo reductive elimination
to provide an allylation product 2.50 (eq 8).
Unlike excellent levels of diastereofacial selectivity that
organolithium and -magnesium reagents frequently display for
the addition reactions to chiral R-alkoxyaldehydes,27 the present
homoallylation shows almost no diastereofacial selectivity (eqs
2-4 and runs 4 and 5, Table 4), suggesting no chelate formation
either in a transition state I or in an intermediate II (or II′). In
fact, as apparently seen in II (or II′), its cyclic structure and
square-planar geometry of Ni(II) prohibit the oxygen of R )
CH(R′)OSiR′′3 from coordination to Ni(II).
The erosion of regioselectivity with respect to the reaction
site of isoprene observed for the homoallylation of ketones (eqs
5 and 6 in Scheme 3 and run 2 in Table 6) might be due to
1,3-diaxial repulsion between isoprene Me and ketone R in an
intermediate XVI that is inevitable for the reaction with ketones
(Scheme 8). In such cases, an intermediate XVII would be
formed at the expense of favorable electronic effects in forming
XVI.
As mentioned before (Scheme 2), 1-siloxy and 2-siloxy
groups exert a contrasting effect on the reactivity of dienes; the
former greatly diminishes the reactivity of dienes toward the
homoallylation of aldehydes, whereas the latter slightly increases
the reactivity. A rationale for this unique behavior of siloxy
group is given in Scheme 7, where it is supposed that both vinyl
ethers and allyl ethers coordinate to Ni(0) more strongly than
dienes do (e.g., [X], [XI] > [XII]). Accordingly, the concentra-
The reversible formation of oxa-π-allylnickel acycle com-
plexes between like II and II′ (Scheme 5) and XVI and XVII
(Scheme 8) was verified by Ogoshi and Kurosawa.28 They have
succeeded in the isolation and the X-ray structure determination
of these complexes and also 2-oxa-nickelacyclopentanes such
as VI with a monodentate phosphane as a ligand.24,25
(27) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John
Wiley & Sons: New York, 1994; Chapter 12.
(28) Ogoshi, S.; Tonomori, K.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2006.
Published online May 5, 2006, http://dx.doi.org/10.1021/ja060580l.
(26) Espinet, P.; Albe´niz, A. C. In Fundamentals of Molecular Catalysis;
Kurosawa, H.; Yamamoto, A., Eds.; Elsevier Science B. V.: Amsterdam,
2003; Chapter 6.
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8566 J. AM. CHEM. SOC. VOL. 128, NO. 26, 2006

Ni-Catalyzed Homoallylation of Aldehydes with 1,3-Dienes
A R T I C L E S
Scheme 9. Structure Determinationa of 2
a Figures are chemical shifts δ in ppm for 13C NMR (100 MHz), coupling constants J in Hz for 1H NMR (400 MHz), and % increments of area intensities
for NOE (the boldface atoms being irradiated).
7. Structure Determination of Products. The structures of
products were determined unequivocally by converting them
to cyclic five- and/or six-membered oxygen heterocycles by
using standard transformations. The reaction procedures and the
diagnostic 1H and 13C NMR data are summarized in Scheme 9.
For example, the structure of 2.9 with 1,2-syn-1,3-anti and
1,2-anti-1,3-anti in a ratio of 8:1 was confirmed by the formation
of cis,cis-lactone 7.3 as a major product together with trans,-
trans-lactone 7.3 as a minor product (eq c, Scheme 9). The
relative configuration of substituents was determined on the basis
of the increments of area intensities by irradiations at the
â-protons (boldface). The perfect 1,3-anti stereochemistry and
1,2-syn/1,2-anti stereoisomerism in a ratio of 1:1 of 2.38 were
confirmed similarly by the transformation to a 1:1 mixture of
cis- and trans-acetonides 7.6 (eq f, Scheme 9).
3
All the J values of 7.5 were identical by chance, probably
owing to a rapid equilibrium between the two conformers (eq
e) as a consequence of similar 1,3-diaxial repulsions in the left
(between one of the acetonide Me groups and vinyl group) and
in the right conformer (between the other acetonide Me and
Ph) (eq e, Scheme 9).
9
J. AM. CHEM. SOC. VOL. 128, NO. 26, 2006 8567

A R T I C L E S
Kimura et al.
Discrimination of the two structures 2.50 and 2.50′ (Scheme
4) was achieved by ozonolysis and reduction with NaBH4,
followed by acetonization (eq h, Scheme 9). Only two isomers,
cis- and trans-7.8 with a 1,3-dioxacyclohexane skeleton were
obtained in a reasonable overall yield, instead of six isomers as
expected from 2.46′: two with a 1,3-dioxacycloheptane skeleton,
two with a 1,3-dioxacyclooctane skeleton, and two with a 1,3-
dioxacyclononane skeleton.
high regio- and stereoselectivity. 1,3-Cyclohexadiene is one
exception among 24 kinds of dienes examined, and undergoes
allylation (not homoallylation) selectively only by the Et2Zn-
Ni catalysis. Under the Et3B-Ni catalysis, the relative reactivity
of dienes is as follows: 2-siloxy-1,3-butadiene > isoprene >
methyl sorbate > 1,3-pentadiene > 1-siloxy-1,3-butadine.
2-Siloxy-1,3-butadiene is almost 15 000 times as reactive as
1-siloxy-1,3-butadine. Mechanistic rationale is given for the
salient reaction features associated with the reaction: (1)
regioselectivity of the reaction site of unsymmetrical dienes (C1
vs C4), (2) 1,3-anti- selectivity for 2-substituted dienes and 1,2-
syn and 1,2-anti- selectivity for (Z)- and (E)-1-substituted dienes,
respectively, (3) homoallylation (vs allylation) with 1,3-dienes,
(4) high reactivity of 2-siloxydienes and very low reactivity of
1-siloxydienes, (5) allylation (not homoallylation) with cyclo-
hexadiene.
Conclusions
Ni(acac)2 catalytically promotes the homoallylation of alde-
hydes and ketones with 1,3-dienes in the presence of trieth-
ylborane or diethylzinc. These organometallics serves as a
reducing agent delivering a formal hydride to the C2 position
of 1,3-dienes and hence generating a formal homoallyl anion
species and enabling the novel homoallylation of aldehydes and
ketones. The reaction proceeds smoothly at room temperature
in the absence of any phosphane or nitrogen ligands and is
highly regioselective and stereoselective for a variety of
aldehydes and 1,3-dienes. Unsymmetrical dienes react at the
termini with the highest electron density. (E)- and (Z)-1-
substituted dienes selectively provide 1,2-anti- and 1,2-syn-4-
penten-1-ols, respectively, and 2-substituted dienes furnish 1,3-
anti-4-penten-1-ols with high stereoselectivity. With triethylborane,
sterically congested aliphatic aldehydes and ketones fail to react.
In such cases, diethylzinc serves as a substitute for triethylborane
and yields the expected products in good yields with similarly
Acknowledgment. Financial support from the Ministry of
Education, Culture, Sports, Science and Technology, Japanese
Government (Grant-in-Aid for Scientific Research (B) 16350058
and Priority Areas 17035065) is gratefully acknowledged.
Supporting Information Available: Experimental section
including analytical data and 1H NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0608904
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8568 J. AM. CHEM. SOC. VOL. 128, NO. 26, 2006