Nickel-catalyzed addition of dimethylzinc to aldehydes across alkynes and 1,3-butadiene: An efficient four-component connection reaction

Article abstract of DOI:10.1021/ja0469030

In the presence of 10 mol % of Ni(acac)₂, four components comprising Me₂Zn, alkynes, 1,3-butadiene, and carbonyl compounds combine in this order in 1:1:1:1 ratio to furnish (3E,6Z)-octadien-1-ols 1 in good yields. Similarly, the coupling reaction of Me₂Zn, 1,ω-dienynes 5, and carbonyls furnishes 1-alkylidene-2-(4′-hydroxy- (1′E)-alkenyl)cyclopentanes and -cyclohexanes 6 and their oxygen and nitrogen heterocycle derivatives in good yield and an excellent level of 1,5-diastereoselectivity with respect to the cycloalkane methine carbon and the OH-bearing carbon of the C2 side chain. The reaction is completed in most cases within 1 h at room temperature under nitrogen, tolerates an ester, a hydroxy, an allyl and propargyl ethers, an allylamino, and a pyridyl functionalities, and accommodates a variety of aromatic and aliphatic alkynes and carbonyls (aldehydes and ketones).

Full text of DOI:10.1021/ja0469030

Published on Web 12/14/2004
Nickel-Catalyzed Addition of Dimethylzinc to Aldehydes
across Alkynes and 1,3-Butadiene: An Efficient
Four-Component Connection Reaction
Masanari Kimura, Akihiro Ezoe, Masahiko Mori, and Yoshinao Tamaru*
Contribution from the Department of Applied Chemistry, Faculty of Engineering,
Nagasaki UniVersity, 1-14 Bunkyo, Nagasaki 852-8521, Japan
Received May 26, 2004; E-mail: tamaru@net.nagasaki-u.ac.jp
Abstract: In the presence of 10 mol % of Ni(acac)2, four components comprising Me2Zn, alkynes, 1,3-
butadiene, and carbonyl compounds combine in this order in 1:1:1:1 ratio to furnish (3E,6Z)-octadien-1-ols
1 in good yields. Similarly, the coupling reaction of Me2Zn, 1,ω-dienynes 5, and carbonyls furnishes
1-alkylidene-2-(4′-hydroxy-(1′E)-alkenyl)cyclopentanes and -cyclohexanes 6 and their oxygen and nitrogen
heterocycle derivatives in good yield and an excellent level of 1,5-diastereoselectivity with respect to the
cycloalkane methine carbon and the OH-bearing carbon of the C2 side chain. The reaction is completed
in most cases within 1 h at room temperature under nitrogen, tolerates an ester, a hydroxy, an allyl and
propargyl ethers, an allylamino, and a pyridyl functionalities, and accommodates a variety of aromatic and
aliphatic alkynes and carbonyls (aldehydes and ketones).
Scheme 1. Ni-Catalyzed Multicomponent Connection Reactions
Introduction
Compared with many precedents for the nickel-catalyzed
linear and cyclic oligomerization (and cycloisomerization) of
alkynes and dienes,1,2 only a few have been reported for the
reactions involving nucleophilic and/or reductive addition of
alkynes and dienes toward carbonyl compounds. This is in
contrast to the early transition-metal catalyzed3 or promoted
reactions,4 which have been proved to be very efficient for the
reactions involving carbonyl components through the involve-
ment of oxametallacycles.1,3,4 This is mainly due to the high
oxophilicity of early transition metals (e.g., Do (Ti-O) ) 159.5
kcal‚mol-1).5 In this context, Montgomery’s report6 that ap-
peared in 1997 is remarkable, which has demonstrated that an
Ni0 complex nicely catalyzes addition of organozincs to car-
bonyls incorporating alkynes as a mediator and furnishes ster-
eochemically defined allyl alcohols 3 in good yields (eq c,
Scheme 1, Do (Ni-O)5 ) 89.2 kcal‚mol-1).7 Two years later,
we also reported that a similar type reaction takes place for 1,3-
dienes and provides (E)-homoallyl alcohols 2 in excellent yields
(eq b, Scheme 1).8
The two reactions b and c shown in Scheme 1 proceed with
similar ease under similar reaction conditions. Accordingly, we
(1) (a) Tsuji, J. In Transition Metal Reagents and Catalysts; Wiley: Chichester,
U.K., 2000. (b) Hegedus, L. S. Transition Metal Organometallics in Organic
Synthesis. In ComprehensiVe Organometallic Chemistry; Abel, E. W.,
Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Tokyo, 1995; Vol. 12.
(c) Shirakawa, E.; Hiyama, T. J. Organomet. Chem. 2002, 653, 114. (d)
Dunach, E.; Franco, D.; Olivero, S. Eur. J. Org. Chem. 2003, 9, 1605.
(2) (a) Jolly, P. W.; Wilke, G. The Organic Chemistry of Nickel; Academic:
New York, 1974; Vol. 1. (b) Jolly, P. W.; Wilke, G. The Organic Chemistry
of Nickel; Academic: New York, 1975; Vol. 2.
(7) Nickel-promoted or -catalyzed reductive coupling of dienes and carbon-
yls: (a) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsumata, T.; Takagi, K.;
Mori, M. J. Am. Chem. Soc. 1994, 116, 9771. (b) Kimura, M.; Ezoe, A.;
Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998, 120, 4033. (c) Kimura,
M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.;
Tamaru, Y. Angew. Chem. 1999, 111, 410; Angew. Chem., Int. Ed. 1999,
38, 397. (d) Sato, Y.; Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2000,
122, 1624. (e) Shibata, K.; Kimura, M.; Shimizu, M.; Tamaru, Y. Org.
Lett. 2001, 3, 2181. (f) Loh, T. P.; Song, H. Y.; Zhou, Y. Org. Lett. 2002,
4, 2715. (g) Sawaki, R.; Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 656
and references therein. For a review, see: (h) Ikeda, S. Angew. Chem., Int.
Ed. 2003, 42, 5120.
(3) (a) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787. (b)
Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 3182 and
references therein.
(4) (a) Szymoniak, J.; Moise, C. Synthesis and Reactivity of Allyltitanium
Derivatives. In Titanium and Zirconium in Organic Synthesis; Marek, I.,
Ed.; Wiley: Weinheim, Germany, 2002, pp 451-474. (b) Sato, F. Yuki
Gosei Kagaku Kyokaishi 2002, 60, 891. (c) Fryatt, R.; Christie, S. D. R. J.
Chem. Soc., Perkin Trans. 1 2002, 447. (d) Taber, D. F.; Campbell, C. L.;
Louey, J. P.; Wang, Y.; Zhang, W. Curr. Org. Chem. 2000, 4, 809.
(5) (a) Bakalbassis, E. G.; Stiakaki, M.-A. D.; Tsipis, A. C.; Tsipis, C. A.
Chem. Phys. 1996, 205, 389. (b) Merer, A. J. Annu. ReV. Phys. Chem.
1989, 40, 407.
(8) (a) Kimura, M.; Matsuo, S.; Shibata, K.; Tamaru, Y. Angew. Chem., Int.
Ed. 1999, 38, 3386. (b) Kimura, M.; Shibata, K.; Koudahashi, Y.; Tamaru,
Y. Tetrahedron Lett. 2000, 41, 6789. (c) Shibata, K.; Kimura, M.; Kojima,
K.; Tanaka, S.; Tamaru, Y. J. Organomet. Chem. 2001, 624, 348.
(6) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065.
9
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J. AM. CHEM. SOC. 2005, 127, 201-209
201

A R T I C L E S
Kimura et al.
wondered what might take place if all the reactive components,
Me2Zn, an alkyne, 1,3-butadiene, and an aldehyde, were
subjected to a nickel-catalyzed reaction (eq a, Scheme 1).
Apparently, in terms of entropy, the reaction forming 1,
incorporating the four different reactants, one molecule each,
is at a disadvantage compared with the reactions giving 2 and
3. The objective 1 might form among a large number of hetero-
and/or homocoupling products9 including 2 and 3. In terms of
enthalpy, however, the reaction leading to 1, likely involving
I, is expected to be favored over the reactions leading to 2 and
3, which proceed through II and III, respectively, since for I
unsaturation number of reactants changes by 3 (from 4 to 1),
while for II and III they change by 2 (from 3 to 1 and from 2
to 0, respectively).
sults are shown pairwise all through Tables 1 and 2. At a glance
of these tables, it becomes apparent that the conditions b using
4 equiv each of an alkyne and a diene give better yields than
the conditions a with respect to the isolated yields of 1, with
only one exception of the reaction of 4c (runs 5 and 6, Table
1).
The reaction shows a wide spectrum of compatibility with
other aromatic (runs 7 and 8, Table 1) and aliphatic aldehydes
Table 1. Ni-Catalyzed Four-Component Connection Reaction of
Me2Zn, Symmetric Alkynes, Butadiene, and Carbonyl Compounds
Results and Discussion
1. Ni0-Catalyzed Intermolecular Four-Component Con-
nection Reaction of Me2Zn, Alkynes, 1,3-Butadiene, and
Carbonyl Compounds. To our delight, without any modulation
of our reaction conditions applied to the formation of 2,8 a
mixture of Me2Zn, 3-hexyne (4a), 1,3-butadiene, and benzal-
dehyde combined to one another in this order and selectively
provided 1a in 68% isolated yield (eq 1 and run 1, Table 1).
The anticipated 2a and 3a were also isolated, but only in lower
yields. The reaction proceeded smoothly at room temperature
and was completed within 1 h.
Under similar conditions, other two alkynes of significant
electronic difference, a conjugated alkyne 4b (runs 3 and 4,
Table 1) and an electron-deficient alkyne 4c (runs 5 and 6),
were examined and found to provide the corresponding four-
component connection products 1b and 1c, respectively, with
remarkably high selectivity. Fortunately, the reaction of these
alkynes turned out to be more selective than that of 4a; 2a was
obtained as a minor product in the lower yields, and no type 3
products were produced. These data clearly indicate that the
reaction leading to 1 proceeds faster than that leading to 2 and
the reaction rate leading to 3 is slowest.
The reactions were examined under two conditions that only
differ about the relative amounts of an alkyne and 1,3-butadiene
to the amounts of other reactants: conditions a: an alkyne (1.2
mmol), 1,3-butadiene (1.2 mmol), an aldehyde (1 mmol), Me2-
Zn (2.4 mmol), and Ni(acac)2 (10 mol %); conditions b: an
alkyne (4.0 mmol) 1,3-butadiene (4.0 mmol), an aldehyde (1
mmol), Me2Zn (2.4 mmol), and Ni(acac)2 (10 mol %). The re-
Scheme 2. Structure of Alkynes 4 Examined
a Reaction conditions: an alkyne (1.2 mmol), 1,3-butadiene (1.2 mmol),
an aldehyde (1.0 mmol), Me2Zn (2.4 mmol, 1 M hexane), and Ni(acac)2
(0.1 mmol) in THF (5 mL) at room temperature. The reaction time was 30
min, unless otherwise noted. b Reaction conditions: an alkyne (4.0 mmol),
1,3-butadiene (4.0 mmol), an aldehyde (1.0 mmol), Me2Zn (2.4 mmol, 1
M hexane), and Ni(acac)2 (0.1 mmol) in THF (5 mL) at room temperature.
The reaction time was 30 min, unless otherwise noted. c Except with alkyne
(2.0 mmol) under the same conditions as in footnote a. d 3a (13%) for run
1 and 3a (6%) for run 2. e 6,7,8,9-Tetramethoxycarbonyl-1-phenyldeca-
3,6,8-trien-1-ol (3′, 14%). f Fur ) 2-fury. g Cy ) cyclohexyl. h 24 h. i 17h.
9
202 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Ni-Catalyzed Addition of Dimethylzinc to Aldehydes
A R T I C L E S
(runs 9-14). Here again, no type 3 products were formed at
all. It should be noted that among aldehydes, phenylacetaldehyde
(runs 9 and 10) is notorious for its high tendency to undergo
aldol and many other side reactions, yet it behaves as usual as
other aliphatic aldehydes. It is also worth mentioning that, as
having been reported by us,8a the nickel-catalyzed three-
component connection reaction of Me2Zn, 1,3-butadiene, and
aldehydes (eq b, Scheme 1), especially with sterically demanding
aldehydes, suffers from a competitive formation of 1:2:1
adducts. For the reaction with more sterically demanding
ketones, the relative ratios of a 1:1:1 adduct to a 1:2:1 adduct
are inversed. For example, the reaction with cyclohexanone
gives rise to 2f in 37% yield (a 1:1:1 product) together with a
1:2:1 adduct, 1-cyclohexyl-deca-3,7-diene-1-ol in 60% yield (eq
2).10 In contrast to this, in the present reaction, no such a 1:2:1
adduct is formed at all (runs 15 and 16, Table 1). In this context,
the selective formation of the 1:1:1 adducts 2d-f, particularly
2f (run 15), suggests that an alkyne has a strong tendency to
prohibit 1:2:1 adduct formation, where an alkyne might occupy
one of the coordination sites of a nickel metal of an intermediate,
making coordination of a second molecule of 1,3-butadiene to
a nickel atom improbable (vide infra, Mechanistic Considera-
tion).8a The reaction giving rise to 2f, rather than an object 1h,
as a major product (run 15, Table 1) may be regarded as a nice
modification of the three-component connection reaction (eq
2), especially when a ketone is a reaction partner, where an
alkyne 4 serves mostly as a dummy component to prevent the
1:2:1 adduct formation. The situation changes dramatically in
the presence of large excesses of 4a and butadiene (conditions
b, run 16, Table 1), where no trace of 2f is formed; instead, the
objective 1h is obtained in greatly improved yield. Similar trends
are seen for the reactions of sterically demanding cyclohexane-
carboxaldehyde (runs 11 and 12) and pivalaldehyde (runs 13
and 14). This may be a natural consequence for reactions where
one of the reactants is unreactive, in this case an alkyne, where
the use of the particular reagent in excess facilitates the reaction
and improves the yield.
no apparent changes in regioselectivity were observed (runs
5-8). The regioselectivity does not depend on reaction condi-
tions a or b. The reactions under conditions b recorded ca. 10%
increase in the yields.
These results are in contrast to high regioselectivity reported
by Jamison12 for the reductive coupling of alkynes and aldehydes
promoted by a catalytic system, Ni-Et3B, which shows a strong
tendency to deliver an SiMe3 group at the â-position and a
phenyl group at the γ-position of the allyl alcohol products.
Interestingly, however, the byproducts 3b and 3c (runs 3, 4,
and 6, Table 2) were obtained as a single isomer; the regiose-
lectivity being in accord with Jamison’s observation.12 These
results suggest that the reactions leading to 2 and 3 proceed via
transition states polar in nature, while the reaction leading to 1
proceeds through a less polar transition state where an alkyne
participates (vide infra, Mechanistic Consideration).
Equation 3 shows the results of isoprene as a diene component
(under conditions a and b, the latter being shown in parentheses).
The expected four-component connection product 1m was
obtained as a major product together with the three-component
connection product 2g as a minor product. Although the
regioselectivity and the chemical yield of 1m are acceptable,
the stereoselectivity is not, giving rise to almost a random
mixture of (E)- and (Z)-isomers with respect to the double bond
originating from isoprene. Reactions with other symmetric
alkynes 4b and 4c showed almost the same results regarding
the yields and the regio- and stereoselectivities of 1 and 2.
Accordingly, we did not pursue further the reaction with
isoprene.
All the results shown in Table 1 combine to indicate that the
reaction giving rise to 1 proceeds much faster than that leading
to 2, and the process leading to 3 is the slowest, although the
relative rates slightly depend on the kinds of alkynes and
carbonyls. It should be noted that the electron-deficient alkyne
4c reacts exceptionally slowly and takes 24 h for completion
of the reaction even under conditions b, where an unique
byproduct, composed of Me2Zn, 4c, butadiene, and benzalde-
hyde in a ratio of 1:2:1:1, 6,7,8,9-tetramethoxycarbonyl-1-
phenyldeca-3,6,8-trien-1-ol (3′, 14%), is detected.
Table 2 summarizes the results for the four-component
connection reaction examined with unsymmetrical alkynes 4d-g
(Scheme 2). To our embarrassment, almost no regioselectivity
was observed, despite a large steric and electronic bias between
the alkyne substituents (runs 1-4).
To influence the regioselectivity, alkynes 4f and 4g bearing
substituents of coordination ability,11 such as 2-hydroxyethyl
and 2-(pyridin-2-yloxy)ethyl groups, were examined; however,
2. Ni0-Catalyzed Intramolecular Four-Component Con-
nection Reaction of Me2Zn, 1,ω-Dienynes 5, and Car-
bonyl Compounds. The entropic disadvantage and the poor
regioselectivity associated with the reaction of eqs 1 and 3
are expected to be settled by tethering the alkyne and the
diene moieties by a chain of an appropriate length. In fact, 1,ω-
dienyne 5 reacted with Me2Zn and aldehydes (and ketones) in
(9) Montgomery, J. Science of Synthesis; Trost, B. M., Lautens, M., Eds.;
Thieme: Stuttgart, 2001; Vol. 1, pp 11-62.
(10) Unpublished results.
(11) (a) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J. Am.
Chem. Soc. 1994, 116, 12133. (b) Stu¨demann, T.; Ibrahim-Ouali, M.;
Knochel, P. Tetrahedron 1998, 54, 1299. (c) Na, Y.; Chang, S. Org. Lett.
2000, 2, 1887.
(12) (a) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (b)
Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156. (c) Miller, K.
M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 203

A R T I C L E S
Kimura et al.
Table 2. Ni-Catalyzed Four-Component Connection Reaction of
Me2Zn, Unsymmetrical Alkynes 4d-g, 1,3-Butadiene, and
Benzaldehydea
an expected fashion and provided 1-alkylidene-2-(4′-hydroxy-
(1′E)-alkenyl)cycloalkanes 6 in excellent yields (eq 4, Scheme
3).13
Scheme 3. Ni-Catalyzed Cyclization of 1,ω-Dienynes 5 and
1,ω-Alkyn-enals
It may be worth noting that the present four-component
connection reaction may be regarded as an extended version of
the nickel-catalyzed reactions portrayed in eq 5, two-component
connection reactions of alkynes and dienes,14 and in eq 6, three-
component connection reactions of alkylzincs, alkynes, and
enones.15 The structural similarity of the starting materials and
the dramatic difference in the product types in eqs 4-6 may
demonstrate the versatile reactivity of nickel catalysis.
Results for the reactions forming cyclopentane and cyclo-
hexane rings are summarized in Tables 3 and 4, respectively,
where an aldehyde is fixed as benzaldehyde and the tether
groups of 5 are varied widely.
As is apparent from Tables 3 and 4, all 1,ω-dienynes, except
5k and 5l, are so reactive that all reactions are completed within
1 h at room temperature, irrespective of the tether length and
the kind of its constituents (sp3-carbon, benzo-type sp2-carbon,
a nitrogen, and an oxygen atom). The exceptionally low
reactivity that 5k displays may be attributed to a large allylic
strain16 that the product 6k experiences between the trimeth-
ylsilyl group and the phenyl group, being placed in closeprox-
imity (run 5, Table 4). A similar retardation, but to a lesser
extent, was observed for the reaction of 5l (run 6, Table 4).
Terminal alkyne 5a provided a cyclization product 6a in
modest yield (run 1, Table 3), whereas all the internal alkynes
5b-l gave products 6b-l in good to excellent yields. Especially
rewarding here is that the 1,ω-dienynes tethered by an oxygen
atom reacted as usual and furnished tetrahydrofuran (6d,e, runs
4 and 5, Table 3), tetrahydropyran (6j, run 4, Table 4), and
chroman derivatives (6k,l, runs 5 and 6, Table 4) in reasonable
a See footnote a in Table 1. b See footnote b in Table 1. c Me2Zn (3.6
mmol, 1 M hexane) under conditions in footnote a. d Me2Zn (7.2 mmol, 1
M hexane) under conditions in footnote b. e Products 1 are mixtures of
regioisomers with respect to the substituents pointed with double-headed
arrows. The ratios are estimated by 13C NMR and shown in parentheses.
yields. We were afraid the reaction of substrates 5d,e,j-l,
commonly sharing an allylic C-O bond, might become very
complex because of the bond cleavage by an Ni0 complex.17
From a similar point of view, the selective formation of
pyrrolidines (run 3, Table 3) and piperidines (runs 2 and 3, Table
4) is also remarkable. The piperidines 6h and 6i are regio-
isomeric to each other with respect to the position of the nitrogen
atom. The reaction is also tolerant of a free hydroxy group (run
6, Table 3), though requiring an extra 1 equiv of Me2Zn to
quench the proton (footnote d, Table 3).
Table 5 summarizes the conjugative addition reactions of Me2-
Zn to a variety of carbonyl compounds across 5c and 5f, forming
cyclopentane derivatives. In Table 6 are also summarized the
reactions of 5m and some typical aliphatic aldehydes and
ketones forming methylenecyclohexane derivatives. No apparent
differences between aliphatic aldehydes (Tables 5 and 6) and
aromatic aldehydes (Tables 3 and 4) were observed in the
reactivity and yields, demonstrating a wide applicability of the
present nickel-catalyzed reaction. As usual, however, ketones
provided the expected products, albeit in somewhat lower but
still acceptable yields (runs 4-6, Table 5 and run 4, Table 6).
(13) Ezoe, A.; Kimura, M.; Inoue, T.; Mori, M.; Tamaru, Y. Angew. Chem.,
Int. Ed. 2002, 41, 2784.
(14) (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813. (b)
Tamao, K.; Kobayashi, K.; Ito, Y. SYNLETT 1992, 539.
The most interesting aspect of the present intramolecular four-
component connection reaction is the high remote 1,5-diastereo-
selectivity, giving rise to syn-6 in favor of anti-6, in ratios higher
than ca. 10:1.
(15) (a) Montgomery, J. Acc. Chem. Res. 2000, 33, 467. (b) Ni, Y.; Amarasinghe,
K. K. D.; Ksebati, B.; Montgomery, J. Org. Lett. 2003, 5, 3771. (c)
Mahandru, G. M.; Skauge, A. R. L.; Chowdhury, S. K.; Amarasinghe, K.
K. D.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2003, 125, 13481.
(d) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004,
126, 3698.
(16) (a) Gascon-Lopez, M.; Motevalli, M.; Paloumbis, G.; Bladon, P.; Wyatt,
P. B. Tetrahedron 2003, 59, 9349. (b) Sukopp, M.; Marinelli, L.; Heller,
M.; Brandl, T.; Goodman, S. L.; Hoffmann, R. W.; Kessler, H. HelV. Chim.
Acta 2002, 85, 4442. (c) Fernandez-Zertuche, M.; Robledo-Perez, R.; Meza-
Avina, M. E.; Ordonez-Palacios, M. Tetrahedron Lett. 2002, 43, 3777. (d)
Hitchcock, S. R.; Nora, G. P.; Casper, D. M.; Squire, M. D.; Maroules, C.
D.; Ferrence, G. M.; Szczepura, L. F.; Standard, J. M. Tetrahedron 2001,
57, 9789.
(17) (a) Consiglio, G.; Piccolo, O.; Roncetti, L. Tetrahedron Lett. 1986, 42,
2043. (b) Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc.
1995, 117, 7273. (c) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H.
Tetrahedron Lett. 1996, 37, 3613. (d) Nomura, N.; RajanBabu, T. V.
Tetrahedron Lett. 1997, 38, 1713. (e) Didiuk, M. T.; Morken, J. P.;
Hoveyda, A. H. Tetrahedron 1998, 54, 1117. (f) Taniguchi, T.; Ogasawara,
K. Angew. Chem., Int. Ed. 1998, 37, 1136.
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204 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Ni-Catalyzed Addition of Dimethylzinc to Aldehydes
A R T I C L E S
Table 4. Ni-Catalyzed Conjugative Addition of Me2Zn toward
Table 3. Ni-Catalyzed Conjugative Addition of Me2Zn toward
Benzaldehyde across 1,ω-Dienynes: Formation of Five-Membered
Ringa
Benzaldehyde across 1,ω-Dienynes 5: Formation of
Six-Membered Ringa
a For reaction conditions, see footnote a in Table 3. E, Ts, and TMS
stand for CO2Et, p-toluenesulfonyl, and trimethylsilyl groups, respectively.
b Yield refers to the isolated, spectroscopically homogeneous material.
c Diastereomeric ratio determined by 1H NMR (400 MHz). Only the major
isomers are shown.
a Reaction conditions: 5 (1 mmol), benzaldehyde (2 mmol), Ni(acac)2
(10 mol %), Me2Zn (2.4 mmol, 1 M hexane) in THF (5 mL) at room
temperature under N2. E stands for CO2Et. b Yield refers to the isolated,
spectroscopically homogeneous material. c Diastereomeric ratio determined
by 1H NMR (400 MHz). Only the major isomers are shown. d Me2Zn (3.6
mmol) was applied. e Diastereomers arising from the configurational
isomerism of the carbon bearing the OH group.
to each other in manners completely different from those of
the tethered 5a-m (Tables 3-6) and also from those where
they are present free in space (Tables 1 and 2).
As is illustrated above, the reaction is applicable to cyclization
forming five- and six-membered rings; however, it has turned
out that it is not applicable to the cyclization forming larger
ring sizes. As is shown in Scheme 4, all the substrates
structurally designed to facilitate the cyclization either by the
Ingold-Thorpe effect18 with geminal phenyl groups, the
substrate 5n aimed to form seven-membered ring, or by making
an alkyne and a diene units close together with vicinal
substitution on cyclohexane and cyclopentane rings, the sub-
strates 5o and 5p aimed to form eight-membered rings, failed
to provide the expected products. Under usual conditions, 5n-p
reacted smoothly and disappeared within 1-2 h; however, even
under dilution conditions (5 times with THF), no discrete spots
ascribable to expected products were observed on the TLC of
the reaction mixtures, displaying continuous tailing bands. Only
the product isolated at random by means of flash column
chromatograph over silica gel, followed by the further purifica-
tion by means of GPC of the fraction was 7, a product of the
type 3 (eq 2). Curiously, no products of the type 2 were detected,
though in the intermolecular reaction the type 2 products were
the major side products (Tables 1 and 2 and eq 2). There results
indicate that the alkynyl and dienyl moieties of 5n-p participate
Finally, we examined Et2Zn and Ph2Zn in place of Me2Zn.
The reaction of 5b and benzaldehyde with Et2Zn is shown in
eq 8, which turned out to provide rich information from a
mechanistic point of view. The cyclization product 6m was
obtained as a minor product. Interestingly, no 6m′ was produced
at all. This is in good accord with Montgomery’s work,9,15 where
he states that even alkyl groups that bear â-hydrogens with
respect to the nickel metal of an alkyl(vinyl)nickel(II) intermedi-
ate selectively undergo reductive elimination without ac-
companying â-H elimination (cf., Mechanistic Consideration).
An alkynyl bishomoallyl alcohol 8 was obtained as a major
product, which is a product expected from our previous work:
the Ni-catalyzed, Et2Zn-promoted reductive coupling of 1,3-
dienes and carbonyls.7b,c,e
These results indicate that the reaction course hangs in a subtle
balance depending on the kind of organozincs; Me2Zn favors
course a over b in Scheme 1 (1 vs 2), while Et2Zn favors course
b over a. In course b, Et2Zn selectively delivers a hydrogen at
the proximal allylic position of a η3-allylnickel intermediate II
(R ) Et) and furnishes a bishomoallyl alcohol 8, not a homoallyl
alcohol 2 (R ) H) (vide infra, a scheme shown in the green
rectangle in Scheme 5).
(18) (a) Tei, T.; Sato, Y.; Hagiya, K.; Tai, A.; Okuyama, T.; Sugimura, T. J.
Org. Chem. 2002, 67, 6593. (b) Saettel, N. J.; Wiest, O. J. Org. Chem.
2003, 68, 4549. A review: (c) Cooper, N. J.; Knight, D. W. Tetrahedron
2004, 60, 243-269.
The reaction with Ph2Zn is shown in eq 9. Although the yield
of 6n was not optimized yet (a single experiment), Ph2Zn turned
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 205

A R T I C L E S
Kimura et al.
Scheme 4. Attempts for Seven- and Eight-Membered Ring
Table 5. Ni-Catalyzed Conjugative Addition of Me2Zn toward
Aliphatic Aldehydes and Ketones across 5c and 5f Forming
Five-Membered Ring Compoundsa
Formation
the tetrasubstituted exocyclic double bonds, which may further
demonstrate the synthetic utility of the present nickel-catalyzed
reaction.
Trialkylboranes work similarly,7b,8b but are somewhat inferior
to dialkylzincs. For example, Me3B (240 mol % in THF) reacted
with 5d and benzaldehyde to give 6d (>30:1) in 30% isolated
yield (cf., run 4, Table 3). Treatment of Et3B (240 mol %) with
5b and benzaldehyde yielded 6m and 8 in 8 and 50% isolated
yields, respectively (cf., eq 8).
a Reaction conditions: 5c or 5f (1 mmol), an aliphatic aldehyde or an
aliphatic ketone (2 mmol), Ni(acac)2 (10 mol %), Me2Zn (2.4 mmol for 5c
and 3.6 mmol for 5f, 1 M hexane) in THF (5 mL) at room temperature
under N2. b Yield refers to the isolated, spectroscopically homogeneous
material. c Diastereomeric ratio determined by 1H NMR (400 MHz). Only
the major isomers are shown. d Diastereomer due to OH stereochemistry.
Table 6. Ni-Catalyzed Conjugative Addition of Me2Zn toward
Aliphatic Aldehydes and Ketones across
2-[(2E,4)-Pentadienyl]-2-(3-pentynyl)Malonic Acid Dimethyl Ester
(5m) Forming Six-Membered Ring Compoundsa
3. Structure Determination of Products. The structures of
6c, 6h, and 6i were determined unequivocally by means of X-ray
crystallographic analyses.19 The structures of 1b, 6a, 6e, and
6n were determined on the basis of NOE experiments. It is
clarified that the diastereomeric isomers 6 are due to 1,5-
diasteremers and not due to the stereochemistry about the
exocyclic nor the side chain double bonds. Detail is described
in Supporting Information.
4. Mechanistic Consideration. In Scheme 5 are illustrated
four pathways, paths a-d, that the present nickel-catalyzed four-
component connection reaction might follow. In pathway a, a
nickel0 species undergoes oxidative cyclization across an
aldehyde and a diene and forms a square-planar (E)-2-oxa-1-
nickellacyclohept-5-ene IV, where the C5-C6-C7 unit forms
a Reaction conditions: 5m (1 mmol), an aliphatic aldehyde or an aliphatic
ketone (2 mmol), Ni(acac)2 (10 mol %), Me2Zn (2.4 mmol, 1 M hexane)
in THF (5 mL) at room temperature under N2. b Yield refers to the isolated,
spectroscopically homogeneous material. c Diastereomeric ratio determined
by 1H NMR (400 MHz). Only the major isomers are shown. d M stands
for CO2Me.
(19) Crystallographic data (excluding structure factors) for the structures reported
in this article have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication nos. CCDC-178844 (6h), CCDC-
201806 (a 3,5-dinitrobenzoic acid ester of 6c), and CCDC-201807 (a 3,5-
dinitrobenzoic acid ester of 6i). Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, U.K.
(fax: (+44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
out to react in a way similar to Me2Zn (run 4, Table 3). The
two products, 6n and 6e, obtained in eq 9 and in run 5 of Table
3, respectively, are stereoisomeric to each other with respect to
9
206 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Ni-Catalyzed Addition of Dimethylzinc to Aldehydes
A R T I C L E S
Scheme 5. Plausible Pathways for the Ni-Catalyzed Addition of Me2Zn toward an Aldehyde across 7,9-Dienyldecan-1-yne (a Model
Compound)a
a The symbol E in the green rectangle stands for CO2Et.
an η3-allylnickel bond and an alkyne coordinates to the NiII
center. During this event, the polarization of the aldehyde Cd
O by Me2Zn coordination to the oxygen atom might help the
nickel0 species undergo oxidative addition upon the diene unit.
At this stage, 1,5-anti-diastereoselection is established. An
alternative intermediate IV′ leading to 1,5-syn-6, shown in the
blue rectangle in Scheme 5, is apparently unfavorable as
compared with IV, since IV′ suffers from eclipsing repulsion
between the substituent R on the C3 and the ring C5 carbon.
Migration of a methyl group from ZnII to NiII forms an
intermediate V, which would undergo rearrangement, ac-
companying alkyne coordination, to give rise to a square-planar
intermediate VI, characterized by a methyl σ-bond, an η3-allyl,
and an η2-alkyne. Cis-addition of the allylnickel moiety of VI
upon the coordinating alkyne forms IX,19 which is destined to
undergo reductive elimination and liberate 1,5-anti-6 and an
active Ni0 species.
In pathway b, at first, oxidative cyclization of an Ni0 species
upon an alkyne and diene takes place to give an allylvinylnickel-
(II) intermediate VII, an intermediate having been invoked
frequently to rationalize the nickel-catalyzed [4 + 2]cycload-
dition reactions (cf., eq 5).13 However, in the presence of an
aldehyde, the intermediate VII might have an opportunity to
undergo nucleophilic addition to the aldehyde to furnish an
oxanickellacycle VIII, during which 1,5-anti-selection results,
placing the substituent of the aldehyde anti with respect to the
C4-C5 bond. Migration of a methyl group from ZnII to NiII
furnishes an intermediate IX, being the same as that derived
along pathway a. Pathway a might also merge pathway b
through isomerization of IV to VIII via a mechanism similar
to the isomerization of VI to IX.20
A third pathway, path c, starts with coordination of Me2Ni
upon an alkyne (η2) and an internal double bond (η2) of a diene.
A Me2Ni species may be formed by transmetalation between
Ni(acac)2 and Me2Zn. Addition of a methyl group upon the
alkyne and bond formation between the internal termini of the
alkyne and the diene might generate a square-planar complex
X, which is apparently highly sterically congested and would
readily isomerize to X-â via rotation around the single bond
connecting the cyclohexane ring and further to X-R via an η3-
η1-η3 isomerization sequence. As is apparently seen from the
molecular models, steric repulsion becomes more substantial
as going from X-â to XI-â as well as from X-R to XI-R. Hence,
this route seems unlikely.
The fourth route, path d, proceeds through a transition state
XII, where all the reactants form a tetrahedron around an Ni0,
and they function in such a way as the nickel0 metal as a two-
electron donor, the alkyne as a 2π component, the diene as a
4π component, and the aldehyde as a two-electron acceptor,
totally comprising a cyclic 10-electron quasi-aromatic system.
The formation of 8 as a major product by the reaction with
Et2Zn (eq 8) seems to exclude an intermediacy of the common
intermediate VIII, involved in pathways b and d as well as in
a fork of pathway a. Instead, as is shown in the green rectangle
of Scheme 5, the results of eq 8 suggest that an intermediate V′
(Et-Ni in place of Me-Ni of V) is responsible for generation
of 6m and 8. The ethylnickel(II) intermediate V′, in addition to
being capable of giving rise to 6m, would undergo â-H
(20) (a) Llebaria, A.; Camps, F.; Moreto, J. M. Tetrahedron 1993, 49, 1283.
(b) Cui, D.-M.; Tsuzuki, T.; Miyake, K.; Ikeda, S.; Sato, Y. Tetrahedron
1998, 54, 1063. (c) Garcia-Gomez, G.; Moreto, J. M. J. Am. Chem. Soc.
1999, 121, 878.
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 207

A R T I C L E S
Kimura et al.
v/v) to give 1d in 76% yield (189 mg) and 2b in 15% yield (25 mg).
Rf (1d) ) 0.46, Rf (2b) ) 0.39 (hexane/ethyl acetate ) 4:1, v/v). The
structure of 2b was confirmed by comparison of the spectral data (IR,
1H NMR) with those of authentic sample.8a
elimination and reductive elimination delivering a hydrogen to
the allylic terminus proximal to the OH-bearing carbon and
finally liberates a mixture of 8, an Ni0 species, and ethylene.
The lack of regioselectivity encountered in the intermolecular
reactions of unsymmetrical alkynes (Table 2) might be rational-
ized on the basis of the structure of an intermediate XIV, shown
in the red rectangle of Scheme 5 (an equivalent to VI for an
intramolecular reaction). The central nickelII of XIV is coor-
dinatively saturated and located in the middle between an allylic
terminal CH2 group and a methyl group of a similar steric size;
hence, an access of unsymmetric alkynes to the NiII atom is
expected to be free from any restrictions imposed by steric,
electronic, and coordination effects. On the other hand, large
steric and coordination effects are expected, if an intermediate
such as VII were involved (path b), where the alkyne carbon
bearing bulky substituents as well as the substituents of
coordination ability would monopolize the C2 position, since
the position is free from strain and located nicely for the
coordinating groups to interact with the NiII metal as L.
(3E,6E)-6-Ethyl-1-(2-furyl)-7-methyl-3,6-nonadien-1-ol (1d). IR
(neat) 3361 (s), 2963 (s), 1439 (m), 1373 (m), 1149 (m), 1010 (s), 968
(m), 734 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J ) 7.7 Hz,
3 H), 0.95 (t, J ) 7.7 Hz, 3 H), 1.60 (s, 3 H), 1.98 (q, J ) 7.7 Hz, 2
H), 2.02 (q, J ) 7.7 Hz, 2 H), 2.56 (m, 2 H), 2.72 (d, J ) 6.2 Hz, 2
H), 4.68 (t, J ) 6.2 Hz, 1 H), 5.36 (dt, J ) 15.4, 7.1 Hz, 1 H), 5.52
(dt, J ) 15.4, 6.2 Hz, 1 H), 6.22 (br d, J ) 3.3 Hz, 1 H), 6.31 (dd, J
) 1.8, 3.3 Hz, 1 H), 7.36 (br d, J ) 1.8 Hz, 1 H); HRMS calcd for
C16H24O2: 248.1776, found m/z (relative intensity) 249 (M+ + 1, 7),
248.1777 (M+, 41), 230 (18), 152 (100), 136 (22).
Ni-Catalyzed Reaction of Me2Zn, 1,ω-Dienyne 5h and Benzal-
dehyde (run 2, Table 4). To a homogeneous solution of Ni(acac)2
(25.6 mg, 0.1 mmol) and 5h (303 mg, 1 mmol) in dry THF (5 mL)
were successively added benzaldehyde (212 mg, 2.0 mmol) and
dimethylzinc (2.4 mL, 1 M in hexane). The mixture was stirred at room
temperature for 1 h under N2 and then poured into ice-cold water. After
addition of 2M HCl (5 mL), the mixture was extracted twice with ethyl
acetate. The combined organic extracts were washed with saturated
NaHCO3 and with brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by flash column chromatography over silica
gel (hexane/ethyl acetate ) 12:1, v/v) to give 6h in 96% yield (408
mg). Rf (6h) ) 0.20 (hexane/ethyl acetate ) 4:1, v/v).
An intervention of XIV might also be supported by the results
in runs 11-16, Table 1. The alkyne in XIV might effectively
prevent another butadiene molecule from approaching the NiII
and, hence, prohibit a 1:2:1 adduct formation of Me2Zn,
butadiene, and a bulky carbonyl (cf., eq 2).8a
(3S*,4′S*)-4-Isopropylidene-3-[4-hydroxy-4-phenyl-(1E)-butenyl]-
N-(p-toluenesulfonyl)piperidine (6h). mp 92.0-93.0 °C (hexane-
dichloromethane); IR (KBr disk) 3460 (m), 1340 (s), 1169 (s), 1103
(m), 932 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 1.61 (s, 6 H), 2.08-
2.24 (m, 2 H), 2.32 (dd, J ) 3.7, 11.4 Hz, 1 H), 2.40 (s, 3 H), 2.43-
2.51 (m, 3 H), 3.37 (m, 1 H), 3.76 (m, 1 H), 3.78 (dm, J ) 11.4 Hz,
1 H), 4.73 (br dd, J ) 5.5, 7.0 Hz, 1 H), 5.50 (ddt, J ) 1.5, 15.6, 7.1
Hz, 1 H), 5.67 (br dd, J ) 5.7, 15.6 Hz, 1 H), 7.24-7.36 (m, 5 H),
7.30 (d, J ) 8.2 Hz, 2 H), 7.62 (d, J ) 8.2 Hz, 2 H); 13C NMR (100
MHz, CDCl3) δ 19.9, 20.1, 21.5, 25.4, 39.8, 42.7, 47.1, 51.1, 73.7,
125.9, 126.8, 127.2, 127.4, 127.7, 128.4, 129.6, 133.4, 134.0, 143.3,
144.1; HRMS calcd for C25H31O3NS: 425.2025. Found m/z (relative
intensity): 425.2042 (M+, 1), 407 (2), 319 (100), 278 (17).
To detect intermediates, we examined the reaction of 5b in
the absence of an aldehyde under catalytic (conditions a) and
stoichiometric conditions using 1 equiv of Ni(cod)2. However,
the reactions proceeded slowly, taking almost 2-3 h for
complete disappearance of 5b. In all cases, the reaction mixtures
became very dirty, showing many tailing spots on TLC. No
fractions separated at random by means of flash column
1
chromatography showed characteristic absorptions in the H
NMR spectra ascribable to compounds expected from the
intermediates in Scheme 5 (including a [4 + 2]cycloaddition
product). These results indicate that a carbonyl compound is
essential to selectively promote the facile connection reaction
of R2Zn, an alkyne, and a diene.
Conclusion
We have demonstrated that Ni(acac)2 can be nicely utilized
as a catalyst for the four-component connection reaction of Me2-
Zn, alkynes, 1,3-butadiene, and carbonyl compounds in this
order in 1:1:1:1 ratio to furnish (3E,6Z)-octadien-1-ols 1 with
high stereoselectivity and in excellent yields. The same condi-
tions are applicable to the coupling reaction of Me2Zn, 1,ω-
dienynes 5, and carbonyls, furnishing 1-alkylidene-2-(4′-hydroxy-
(1′E)-alkenyl)cyclopentanes and -cyclohexanes 6 and their
oxygen and nitrogen heterocycles with an excellent level of 1,5-
diastereoselectivity. The reaction proceeds smoothly at room
temperature, tolerates an ester, a hydroxy, an allyl ether, a
propargyl ether, an allylamino, and pyridyl functionalities,
andaccommodates a variety of aromatic and aliphatic alkynes
and carbonyls (aromatic and aliphatic aldehydes and ketones).21
The reaction constitutes one of the few Ni-catalyzed nucleophilic
addition reactions of alkynes and dienes toward carbonyl
compounds.
After all, pathway a seems to be the most plausible, which
accounts for all the observations, regardless of inter- and
intramolecular four-component connection reactions: the high
yield formation of 1, with no regioselectively for unsymmetric
alkynes, the 1,5-diastereoselective formation of 6, the selective
formation of 2 (1:1:1 adducts and not 1:2:1 adducts of Me2Zn,
butadiene, and carbonyls). The mechanism is especially backed
by the fact that the reaction in eq 8 gives rise to a mixture of
6m and 8.
Typical Experimental Procedure
Ni-Catalyzed Four-Component Connection Reaction of Me2Zn,
3-Hexyne, 1,3-Butadiene, and 2-Furaldehyde (run 7, Table 1). Into
a flask containing Ni(acac)2 (25.7 mg, 0.1 mmol) purged with N2 were
successively added THF (5 mL), 3-hexyne (98.6 mg, 1.2 mmol), 1,3-
butadiene (0.11 mL, 1.2 mmol), 2-furaldehyde (96.1 mg, 1.0 mmol),
and dimethylzinc (2.4 mL, 1 M in hexane) via syringe at room
temperature. The homogeneous solution was stirred at room temperature
for 30 min under N2 and then quenched by adding 2 M HCl (25 mL).
The mixture was extracted twice with ethyl acetate, and the combined
extracts were washed with saturated NaHCO3 and with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by flash
column chromatography over silica gel (hexane/ethyl acetate ) 16:1,
(21) The present catalytic system seems not to be applicable to thioether
compounds, e.g., phenyl 1-propynyl sulfide and 2-(2-butynyl)-2-(2,4-
pentadienyl)-1,3-dithiane. Under usual conditions, the reactions of these
sulfides proceeded slowly (at room temperature for 3-12 h) and provided
intractable mixtures of products. The reaction of bis(trimethylsilylmethyl)-
zinc with 5j and benzaldehyde was completed within 30 min; however, a
complex mixture of products resulted (7 to 8 spots on TLC).
9
208 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Ni-Catalyzed Addition of Dimethylzinc to Aldehydes
A R T I C L E S
Acknowledgment. We thank Mr. Y. Ohhama, NMR mea-
surement, and Mrs. J. Nagaoka, X-ray analysis, for their
technical assistance. Financial support by the Ministry of
Education, Culture, Sports, Science, and Technology, Japanese
Government is gratefully acknowledged.
Supporting Information Available: Experimental procedures
and characterization data and H NMR spectra for all new
compounds 1, 3-8. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
JA0469030
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J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 209