Nickel-catalyzed coupling of alkenes, aldehydes, and silyl triflates

Article abstract of DOI:10.1021/ja062866w

A full account of two recently developed nickel-catalyzed coupling reactions of alkenes, aldehydes, and silyl triflates is presented. These reactions provide either allylic alcohol or homoallylic alcohol derivatives selectively, depending on the ligand em

Full text of DOI:10.1021/ja062866w

Published on Web 08/10/2006
Nickel-Catalyzed Coupling of Alkenes, Aldehydes, and Silyl
Triflates
Sze-Sze Ng, Chun-Yu Ho, and Timothy F. Jamison*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received April 25, 2006; E-mail: tfj@mit.edu
Abstract: A full account of two recently developed nickel-catalyzed coupling reactions of alkenes, aldehydes,
and silyl triflates is presented. These reactions provide either allylic alcohol or homoallylic alcohol derivatives
selectively, depending on the ligand employed. These processes are believed to be mechanistically distinct
from Lewis acid-catalyzed carbonyl-ene reactions, and several lines of evidence supporting this hypothesis
are discussed.
Introduction
the preparation of alcohol and amine derivatives. Nickel,
palladium, rhodium, and ruthenium catalysts have been found
Alkenes are one of the most versatile, utilized, and readily
available classes of functional groups. Simple alpha olefins are
produced in megaton scale each year industrially, highlighting
the importance of these organic feedstocks.1 Several indispen-
sable transformations utilize olefins, such as Ziegler-Natta
polymerization,2 the Heck reaction,3a-e Wacker oxidation,3a
hydroformylation,3a hydrometalation,3a alkene cross-metathesis,4
epoxidation,5 and dihydroxylation.5
The nickel-catalyzed coupling of alkenes, aldehydes, and silyl
triflates that we recently developed is the first example of a
transition metal-catalyzed coupling of simple, unactivated olefins
and aldehydes that provides allylic alcohol derivatives.6 With
careful choice of the supporting ligand on nickel, this coupling
reaction can also selectively provide homoallylic alcohol
derivatives that are generally not accessible using Lewis acid-
catalyzed carbonyl-ene reactions (eq 1).7
to be particularly effective in the intermolecular coupling of
alkynes, 1,3-enynes, 1,3-dienes, allenes, enoate esters, enones,
and enals with aldehydes, ketones, epoxides, glyoxylate esters,
and imines.8-11 A variety of reducing agents have been used in
these reductive couplings, such as triethylborane, organozinc
(4) Handbook of Metathesis; Grubbs, R. H., Ed.; John Wiley & Sons: New
York, 2003.
(5) Catalytic Asymmetric Synthesis; Ojima, I., Ed; Wiley-VCH: New York,
2000.
(6) Preliminary communications of this work: (a) Ng, S.-S.; Jamison, T. F. J.
Am. Chem. Soc. 2005, 127, 14194-14195. (b) Ho, C.-Y.; Ng, S.-S.;
Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 5362-5363.
(7) Carbonyl-ene reaction was first reported by Alder in 1943. (a) Alder, K.;
Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76, 27. For a review
of the carbonyl-ene reaction, see: (b) Hoffmann, H. M. R. Angew. Chem.,
Int. Ed. Engl. 1969, 8, 556-577. (c) Snider, B. B. Acc. Chem. Res. 1980,
13, 426-432. (d) Snider, B. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 527-
561. (e) Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92, 1021-1050. (f)
Dias, L. C. Curr. Org. Chem. 2000, 4, 305-342.
(8) For a review of the nickel-catalyzed reductive coupling reactions see: (a)
Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890-3908. (b) A general
reference of organonickel chemistry: Modern Organonickel Chemistry;
Tamaru, Y., Ed.; Wiley-VCH: Weinheim, Germany, 2005. Recent reports
of nickel-catalyzed reductive couplings: Alkynes: (c) Patel, S. J.; Jamison,
T. F. Angew. Chem., Int. Ed. 2004, 43, 3941-3944. (d) Kimura, M.; Ezoe,
A.; Mori, M.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 201-209. (e)
Knapp-Reed, B.; Mahandru, G. M.; Montgomery, J. J. Am. Chem. Soc.
2005, 127, 13156-13157. (f) Luanphaisarnnont, T.; Ndubaku, C. O.;
Jamison, T. F. Org. Lett. 2005, 7, 2937-2940. Enyne: (g) Miller, K. M.;
Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342-15343. (h) Miller, K.
M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc.
2004, 126, 4130-4131. (i) Miller, K. M.; Colby, E. A.; Woodin, K. S.;
Jamison, T. F. AdV. Synth. Catal. 2005, 347, 1533-1536. (j) Miller, K.
M.; Jamison, T. F. Org. Lett. 2005, 7, 3077-3080. (k) Moslin, R. M.;
Jamison, T. F. Org. Lett. 2006, 8, 455-458. Allene: (l) Takimoto, M.;
Kawamura, M.; Mori, M.; Sato, Y. Synlett 2005, 13, 2019-2022. (m) Ng,
S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 7320-7321. (n) Ng,
S.-S.; Jamison, T. F. Tetrahedron 2005, 61, 11405-11417. (o) Song, M.;
Montgomery, J. Tetrahedron 2005, 61, 11440-11448. Diene: (p) Takimoto,
M.; Nakamura, Y.; Kimura, K.; Mori, M. J. Am. Chem. Soc. 2004, 126,
5956-5957. (q) Sawaki, R.; Sato, Y.; Mori, M. Org. Lett. 2004, 6, 1131-
1133. (r) Takimoto, M.; Kajima, Y.; Sato, Y.; Mori, M. J. Org. Chem.
2005, 70, 8605-8606.
Transition metal-catalyzed intermolecular reductive and alkyl-
ative coupling reactions have emerged as useful methods for
(1) Alpha Olefins Applications Handbook; Lappin, G. R., Sauer, J. D., Eds.;
Marcel Dekker: New York, 1989.
(2) Organometallic Catalysts and Olefin Polymerization; Blom, R., Ed.;
Springer: New York, 2001.
(3) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; John Wiley & Sons: New York, 1995. (b) Review of the related
Heck reaction and palladium-hydride chemistry: Negishi, E.-i. Handbook
of Organopalladium Chemistry for Organic Synthesis; Wiley-Inter-
science: New York, 2002. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem.
ReV. 2000, 100, 3009-3066. Detection of a palladium-hydride species in
the Heck reaction: (d) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126,
13178-13179. Similar selectivity of the exo hydrogens over the endo
hydrogens has been reported in the Heck reaction literature: (e) Ono, K.;
Fugami, K.; Tanaka, S.; Tamaru, Y. Tetrahedron Lett. 1994, 35, 4133-
4136.
(9) Examples of palladium-catalyzed coupling reactions: (a) Anwar, U.; Grigg,
R.; Rasparini, M.; Savic, V.; Sridharan, V. Chem. Commun. 2000, 645-
646. (b) Ha, Y.-H.; Kang, S.-K. Org. Lett. 2002, 4, 1143-1146. (c) Kang,
S.-K.; Lee, S.-W.; Jung, J.; Lim, Y. J. Org. Chem. 2002, 67, 4376-4379.
(d) Hopkins, C. D.; Malinakova, H. C. Org. Lett. 2004, 6, 2221-2224. (e)
Hopkins, C. D.; Guan, L.; Malinakova, H. C. J. Org. Chem. 2005, 70,
6848-6862.
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J. AM. CHEM. SOC. 2006, 128, 11513-11528
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A R T I C L E S
Ng et al.
Table 1. Nickel-Catalyzed Coupling of Ethylene, Aldehydes, and Silyl Triflatesa
a Standard procedure: Ni(cod)2 (20 mol %) and (o-anisyl)3P (40 mol %) were dissolved in 2.5 mL of toluene under argon. Ethylene (balloon, 1 atm) was
substituted for argon. Triethylamine (600 mol %), the aldehyde (100 mol %, 0.5 mmol), and Et3SiOTf (175 mol %) were added. The reaction mixture was
1
stirred for 6-18 h at 23 °C. b (o-anisyl)3P was replaced by Cy2PhP. c (o-anisyl)3P was replaced by Ph3P. d Yields determined by H NMR using DMF as a
standard. e Conducted under 2 atm of ethylene. f Stirred at room temperature for 30 h.
reagents, organosilanes, and molecular hydrogen. As yet,
however, simple, unactivated alkenes such as ethylene and
1-octene have not been reported to undergo analogous catalytic
reductive coupling reactions.
As a part of our program directed toward developing C-C
bond forming reactions of “off-the-shelf”, simple starting
materials, we became very interested in catalytic alkene-
aldehyde coupling processes. Intramolecular versions of this
transformation have been reported, such as transition metal-
catalyzed cyclizations of enals and enones. For example, the
titanium-catalyzed intramolecular reductive cyclization of enals
and enones was first reported by Buchwald and Crowe.12a,b
Recently Ogoshi has demonstrated a nickel-catalyzed cyclization
of enones.12c R,ω-Enals also undergo cyclization by way of a
radical process13 and also in a Lewis acid-catalyzed carbonyl-
ene reaction.7
Intermolecular coupling of unactivated alkenes and aldehydes
is commonly mediated by a transition metal (stoichiometric)
or accomplished by way of a carbonyl-ene reaction.7,15 An
interesting process developed by Worpel combines an alkene
and an aldehyde through a silver-catalyzed silylene transfer
reaction.16
(13) Examples of radical cyclization: SmI2: (a) Molander, G. A.; McKie, J. A.
J. Org. Chem. 1994, 59, 3186-3192. Bu3SnH/PhSiH3: (b) Hays, D. S.;
Fu, G. C. Tetrahedron 1999, 55, 8815-8832. Cp2VCl2/Me3SiCl/Zn: (c)
Hirao, T. Synlett 1999, 2, 175-181. t-C12H25SH/AIBN: (d) Yoshikai, K.;
Hayama, T.; Nishimura, K.; Yamada, K.-I.; Tomioka, K. J. Org. Chem.
2005, 70, 681-683.
(14) Observation of oxametallacycle: Titanium: (a) Cohen, S. A.; Bercaw, J.
E. Organometallics 1985, 4, 1006-1014. (b) Thorn, M. G.; Hill, J. E.;
Waratuke, S. A.; Johnson, E. S.; Fanwick, P. E.; Rothwell, I. P. J. Am.
Chem. Soc. 1997, 119, 8630-8641. Zirconium: (c) Suzuki, N.; Rousset,
C. J.; Aoyagi, K.; Kotora, M.; Takahashi, T.; Hasegawa, M.; Nitto, Y.;
Saburi, M. J. Organomet. Chem. 1994, 473, 117-128. Rhodium: (d)
Godard, C.; Duckett, S. B.; Parsons, S.; Perutz, R. N. Chem. Commun.
2003, 2332-2333.
(15) Examples of intermolecular coupling of alkenes and aldehydes with
stoichiometric transition metals: Titanium: (a) Mizojiri, R.; Urabe, H.;
Sato, F. J. Org. Chem. 2000, 65, 6217-6222. (b) Epstein, O. L.; Seo, J.
M.; Masalov, N.; Cha, J. K. Org. Lett. 2005, 7, 2105-2108. Zirconium:
(c) Takahashi, T.; Suzuki, N.; Hasegawa, M.; Nitto, Y.; Aoyagi, K.-I.;
Saburi, M. Chem. Lett. 1992, 331-334.
(10) Examples of ruthenium-catalyzed coupling reactions: (a) Trost, B. M.;
Pinkerton, A. B.; Seidel, M. J. Am. Chem. Soc. 1999, 121, 10842-10843.
(b) Kang, S.-K.; Kim, K.-J.; Hong, Y.-T. Angew. Chem., Int. Ed. 2002,
41, 1584-1586.
(11) Examples of rhodium-catalyzed reductive coupling reactions: (a) Jang, H.-
Y.; Huddleston, R. R. J. Am. Chem. Soc. 2004, 126, 4664-4668. (b) Jang,
H.-Y.; Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J.
J. Am. Chem. Soc. 2005, 127, 6174-6175. (c) Kong, J.-R.; Cho, C.-W.;
Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269-11276. (d) Kong,
J.-R.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718-719.
(12) Examples of titanium-catalyzed reductive cyclization of enals: (a) Kablaoui,
N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117, 6785-6786. (b)
Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787-6788.
(c) For a nickel-catalyzed cyclization of enones, see ref 17b.
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Ni-Catalyzed Coupling of Alkenes/Aldehydes/Silyl Triflates
A R T I C L E S
Table 2. Ligand-Dependent Regioselectivity: Electron-Rich Phosphinesa
a Standard procedure: Ni(cod)2 (20 mol %) and a ligand (40 mol %) were dissolved in 1.5 mL of toluene. Alkene (500 mol %), triethylamine (600 mol
%), the aldehyde (100 mol %, 0.25 mmol), and Et3SiOTf (175 mol %) were added. The reaction mixture was stirred for 18 h at 23 °C. b See ref 20. c Yields
1
1
determined by H NMR using DMF as a standard. d Ratio was determined by H NMR of the crude reaction mixture. e 48 h reaction time. f 1250 mol %
alkene was used.
Formation of an oxametallacycle through the coupling of
simple alkenes and ketones has been observed with several
transition metals such as titanium, zirconium, and rhodium.14
These studies suggested that transition metal-catalyzed, inter-
molecular coupling of alkenes and aldehydes would be feasible
under the appropriate conditions. Ogoshi recently observed that
Lewis acids such as a silyl triflate and trimethylaluminum
facilitated the formation of an oxanickellacycle through cy-
clization of R,ω-enals and R,ω-enones.17 We proposed that if
the intermolecular coupling of an alkene and an aldehyde
occurred, the nickel alkyl bond could undergo a â-hydride
elimination, followed by the removal of triflic acid from nickel
to regenerate the nickel catalyst. This mechanistic framework
also resembles that in the Heck reaction, a very important ex-
ample of a catalytic coupling of an alkene and an electrophile.3a-e
The carbonyl-ene reaction has historically been the most direct
method to combine simple alkenes and carbonyl compounds to
provide homoallylic alcohol products. Recent efforts in this area
have focused on asymmetric induction through the use of Lewis
acids and chiral ligands, such as (bisoxazoline)CuX2, (pybox)-
ScX3, and (BINAP)TiX2 complexes.18a-f Typically the alkenes
that are employed in intermolecular carbonyl-ene reactions are
1,1-disubstituted and trisubstituted olefins. With respect to the
carbonyl component, electron-deficient enophiles such as gly-
oxylates, glyoxamides, and chloral are generally more efficient
than simple aromatic and aliphatic aldehydes. In fact, since the
report of the carbonyl-ene reaction in 19437a there have been
only a few scattered examples of intermolecular ene reactions
between monosubstituted alkenes and simple aromatic and
aliphatic aldehydes.19
(16) (a) Cirakovic, J.; Driver, T. G.; Woerpel, K. A. J. Am. Chem. Soc. 2002,
124, 9370-9371. (b) Cirakovic, J.; Driver, T. G.; Woerpel, K. A. J. Org.
Chem. 2004, 69, 4007-4012.
(19) Carbonyl-ene reaction examples that use simple aldehydes: (a) Snider, B.
B.; Rodini, D. J. Tetrahedron Lett. 1980, 21, 1815-1818. (b) Snider, B.
B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am. Chem. Soc. 1982, 104,
4, 555-563. (c) Majewski, M.; Bantle, G. W. Synth. Commun. 1990, 20,
2549-2558. (d) Houston, T. A.; Tanaka, Y.; Koreeda, M. J. Org. Chem.
1993, 58, 4287-4292. (e) Aggarwal, V. K.; Vennall, G. P.; Davey, P. N.;
Newman, C. Tetrahedron Lett. 1998, 39, 1997-2000. (f) Ellis, W. W.;
Odenkirk, W.; Bosnich, B. Chem. Commun. 1998, 1311-1312. (g) Loh,
T. P.; Feng, L. C.; Yang, J. Y. Synthesis 2002, 7, 937-940. Pioneering
examples with aliphatic aldehydes and monosubstituted alkenes: (h) Snider,
B. B.; Phillips, G. B. J. Org. Chem. 1983, 48, 464-469. One isolated
example of a carbonyl-ene reaction of an aromatic aldehyde and a
monosubstituted alkene has been described (yield not reported): (i) Epifani,
E.; Florio, S.; Ingrosso, G. Tetrahedron 1988, 44, 5869-5877. For
intramolecular examples of a carbonyl-ene reaction between monosubsti-
tuted alkenes and sterically demanding aldehydes, see: (j) Andersen, N.
H.; Hadley, S. W.; Kelly, J. D.; Bacon, E. R. J. Org. Chem. 1985, 50,
4144-4151. (k) Fujita, M.; Shindo, M.; Shishido, K. Tetrahedron Lett.
2005, 46, 1269-1271.
(17) (a) Ogoshi, S.; Oka, M.-a.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126,
11802-11803. (b) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am.
Chem. Soc. 2005, 127, 12810-12811.
(18) Examples of highly enantioselective carbonyl-ene reactions: (a) Maruoka,
K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H. Tetrahedron Lett. 1988,
29, 3967-3970. (b) Mikami, K.; Terada, M.; Narisawa, S.; Nakai, T. Synlett
1992, 255-265. (c) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky,
T.; Tregay, S. W. J. Am. Chem. Soc. 1998, 120, 5824-5825. (d) Evans,
D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am.
Chem. Soc. 2000, 122, 7936-7943. (e) Yuan, Y.; Zhang, X.; Ding, K.
Angew. Chem., Int. Ed. 2003, 42, 5478-5480. (f) Evans, D. A.; Wu, J. J.
Am. Chem. Soc. 2005, 127, 8006-8007. Chiral Pt catalyst: (g) Koh, J.-
H.; Larsen, A. O.; Gagne´, M. R. Org. Lett. 2001, 3, 1233-1236. Chiral
Pd catalyst: (h) Aikawa, K.; Mikami, K. Angew. Chem., Int. Ed. 2003, 42,
5458-5461. Chiral Ni catalyst: (i) Mikami, K.; Aikawa, K. Org. Lett.
2002, 4, 99-101.
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Ng et al.
Table 3. Ligand-Dependent Regioselectivity: Electron-Poor Phosphinesa
a Standard procedure: Ni(cod)2 (20 mol %) and a ligand (40 mol %) were dissolved in 2.5 mL of toluene. Alkene (1 mL), triethylamine (600 mol %),
the aldehyde (100 mol %, 0.5 mmol), and Et3SiOTf (175 mol %) were added. The reaction mixture was stirred for 18 h at 23 °C. b See ref 20. c Yields were
1
1
determined by H NMR using DMF as a standard. d Ratio was determined by H NMR after the products were treated with TBAF. e 48 h reaction time.
To summarize, Lewis acid-catalyzed carbonyl-ene reactions
are typically not feasible for the most readily available alkene
and aldehyde building blocks. One of the nickel-catalyzed
couplings of alkenes and aldehydes described herein is thus
complementary in scope to the carbonyl-ene reaction; mono-
substituted alkenes couple with simple aldehydes to provide a
carbonyl-ene-type product in high yield.
As an additional advantage, other common silyl triflates can
be used in the coupling reaction, providing orthogonal protection
of the hydroxyl group when necessary (entries 5-7).
Remarkably, sterically demanding tertiary aliphatic aldehydes
such as pivaldehyde and 2,2-dimethyl-3-oxo-propionic acid methyl
ester couple with ethylene with the same efficacy as that for
benzaldehyde (entries 12 and 13). Enolizable aldehydes are not
appropriate substrates in this system, however, since they react
rapidly with the silyl triflate and triethylamine to form alkenyl
silyl ethers. The coupling of ethylene with cyclohexanecarbox-
aldehyde is fast enough, however, that a significant amount of
coupling product is observed and can be isolated (entry 14).
Results
Our investigations commenced with the simplest olefin,
ethylene, and benzaldehyde. After a brief examination of
phosphorus-based additives, we found that a combination of
Ni(cod)2, tris-(o-methoxyphenyl)-phosphine ((o-anisyl)3P), tri-
ethylamine, and triethylsilyl triflate (Et3SiOTf) promoted the
coupling of ethylene with a variety of aldehydes. In all cases a
triethylsilyl ether of an allylic alcohol is obtained in good to
excellent yield (Table 1), providing ready access to a class of
allylic alcohol derivatives that have been used in cross-
metathesis reactions, for example.4
Tris-(o-methoxyphenyl)-phosphine is the ligand of choice for
the ethylene-aldehyde coupling. Other phosphines such as dicy-
clohexylphenylphosphine and triphenylphosphine provide lower
yield under the same reaction conditions (entries 1-5, 13).
An interesting electronic effect is observed in these coupling
reactions. Electron-rich aromatic aldehydes are more efficient
substrates than electron-poor aromatic aldehydes. Among the
four para-substituted aromatic aldehydes examined, electron-
donating para-substituents (-Me and -OMe) improve the yield
of the coupling reaction (entries 2 and 4). Electron-withdrawing
para-substituents (-CF3 and -CO2Me) suffer from incomplete
conversion, even after prolonged reaction time (entries 10 and
11). In such cases, products resulting from a pinnacol coupling
are observed but are not observed in any other example.
Under 1 atm of ethylene, simple aromatic aldehydes such as
benzaldehyde and p-tolylaldehyde undergo efficient coupling
(entries 1 and 2). Ortho substitution on the aromatic aldehyde
does not appear to deter the coupling process (entry 3), and
notably, acid-sensitive heteroaromatic aldehydes such as 1-methyl-
2-indolecarboxaldehyde (entry 8) and 2-furaldehyde (entry 9)
are tolerated, even in the presence of Lewis acidic silyl triflates.
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Ni-Catalyzed Coupling of Alkenes/Aldehydes/Silyl Triflates
A R T I C L E S
Figure 1. Plot of H:A ratio against the σ-electron-donating ability of various phosphines.20
Table 4. Effect of Bases in the Ethylene-Benzaldehyde
possible coupling product depending on where the new carbon-
carbon bond is formed. The examination of a series of ligands
revealed several interesting observations regarding ligand-
dependent regioselectivity.
Couplinga
Ligand Effect. Under similar reaction conditions as the
ethylene-aldehyde cases, 1-octene and benzaldehyde undergo
coupling in the presence of Ni(cod)2, a ligand, triethylamine,
and Et3SiOTf. Two distinct types of coupling products are
typically observed, namely a 1,2-disubstituted allylic alcohol
product (A) and a homoallylic alcohol product (H). Different
classes of phosphine ligands favor one or the other coupling
products, as summarized in Tables 2 and 3 and Figure 1.
The ratio of the allylic to the homoallylic products is opposite
for trialkylphosphines in which all alkyl groups are linear
(entries 1 and 2), relative to those in which the three alkyl groups
are branched (entries 3-5) or tertiary (entry 6). Among six
trialkylphosphines with very similar electron-donating abilities,20a
tri-n-butylphosphine, the smallest of the trialkylphosphines
examined, favors the homoallylic alcohol product, while tricy-
clohexylphosphine and tri-tert-butylphosphine, the largest among
these, favor the 1,2-disubstituted allylic product. However, these
sterically demanding ligands are not nearly as effective, afford-
ing the coupling products in low yield.
(20) (a) The stretching frequency (νCO, cm-1) of terminal CO of CpFe(CO)-
LCOMe (in cyclohexane at room temperature) is a measure of the
σ-electron-donating ability to a metal center. A less electron-donating ligand
usually has a higher frequency: Rahman, M.; Liu, H.-Y.; Eriks, K.; Prock,
A.; Giering, W. P. Organometallics 1989, 8, 1-7. (b) Tri-p-tolylphosphine
(Table 3, entry 5), triphenylphosphine (entry 6), tris-(p-fluoro-phenyl)-
phosphine (entry 7), and tris-(p-trifluoromethyl-phenyl)-phosphine (entry
9) have the same cone angle (145°) according to ref 20a. (c) The frequency
for (o-anisyl)3P was estimated from (p-anisyl)3P assuming they have
similarly electron-donating properties. Cone angle values and νCO values
were obtained from ref 20a and the following: (d) Tolman, C. A. Chem.
ReV. 1977, 77, 313-348. (e) Otto, S. J. Chem. Crystallogr. 2001, 31, 185-
190. (f) Riihima¨ki, H.; Kangas, T.; Suomalainen, P.; Reinius, H. K.;
Ja¨a¨skela¨inen, S.; Haukka, M.; Krause, A. O. I.; Pakkanen, T. A.; Pursiainen,
J. T. J. Mol. Catal. A: Chem. 2003, 200, 81-94. (g) Steinmetz, W. E.
Quant. Struct.-Act. Relat. 1996, 15, 1-6.
a Standard procedure: Ni(cod)2 (20 mol %) and (o-anisyl)3P (40 mol
%) were dissolved in 2.5 mL of toluene under argon. Ethylene (balloon, 1
atm) was substituted for argon. A base (600 mol %), benzaldehyde (100
mol %, 0.5 mmol), and Et3SiOTf (175 mol %) were added. The reaction
mixture was stirred for 18 h at 23 °C. b Yields were determined by 1H NMR
using DMF as a standard. c Benzaldehyde was replaced by 2-naphthalde-
hyde, and the reaction was run at 0.25 mmol scale.
The encouraging results in these ethylene-aldehyde coupling
reactions prompted us to examine the scope of the alkenes in
detail. Unlike ethylene, 1-octene can afford more than one
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A R T I C L E S
Ng et al.
Table 5. Effect of Bases in the 1-Octene-Benzaldehyde Coupling (Cy2PhP)a
a Standard procedure: Ni(cod)2 (20 mol %) and Cy2PhP (40 mol %) were dissolved in 1.5 mL of alkene. A base (600 mol %), benzaldehyde (100 mol
%, 0.1 mmol), and Et3SiOTf (100 mol %) were added. The reaction mixture was stirred for 18 h at 23 °C. b Yields were determined by 1H NMR using DMF
1
as a standard. c Ratio was determined by H NMR of the crude reaction mixture.
Table 6. Effect of Bases in the 1-Octene-Benzaldehyde Coupling (Ph3P)a
a Standard procedure: Ni(cod)2 (20 mol %) and Ph3P (40 mol %) were dissolved in 2.5 mL of toluene. 1-Octene (1 mL), a base (600 mol %), benzaldehyde
(100 mol %, 0.5 mmol), and Et3SiOTf (175 mol %) were added. The reaction mixture was stirred 18 h at 23 °C. b Yields and ratios were determined by 1H
1
NMR using DMF as a standard. c Ratio was determined from the desilylated product by H NMR.
Notably, replacing one of the alkyl substituents of the
tricyclohexylphosphine with a phenyl ring dramatically improves
the yield (53% vs 16%; Table 2, entries 5 and 7) with a slightly
diminished A:H ratio. Other aryldicyclohexylphosphines also
display a similar yield enhancement (entries 8 and 9, as
compared to entries 4-6). The bulky and electron-rich dicy-
clohexylferrocenylphosphine, however, seems to be more closely
related to tri-tert-butylphosphine (poor yield for both the allylic
and homoallylic alcohol products, entry 10).21 All of the
sterically demanding dicyclohexylarylderivatives examined favor
the allylic alcohol product, and dicyclohexylphenylphosphine
is the optimal ligand in terms of yield and selectivity.
The pronounced ligand effects prompted us to examine other
organophosphorus ligands (Table 3). Among the four tri-
arylphosphine ligands with a similar cone angle but different
para-substituents (entries 5-7 and 9),20b,c tris-(p-trifluoromethyl-
phenyl)-phosphine, the least electron-rich ligand of the four,
(21) Application of dicyclohexylferrocenylphosphine as a bulky and elec-
tron-rich ligand: (a) Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2003, 5, 1301-1303. (b) Baillie, C.; Zhang, L.; Xiao, J. J. Org.
Chem. 2004, 69, 7779-7782. (c) Thalji, R. K.; Ahrendt, K. A.; Bergman,
R. G.; Ellman, J. A. J. Org. Chem. 2005, 70, 6775-6781. (d) Pereira, S.
I.; Adrio, J.; Silva, A. M. S.; Carretero, J. C. J. Org. Chem. 2005, 70,
10175-10177.
(22) A set of four control experiments in which Ni(cod)2, ligand, silyl triflate,
and the base was each removed from the ethylene-benzaldehyde coupling
reaction. No coupling product was detected in any of the four experiments.
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Ni-Catalyzed Coupling of Alkenes/Aldehydes/Silyl Triflates
A R T I C L E S
Table 7. Examination of Other Nickel Precatalystsa
a Standard procedure: The nickel precatalyst system (20 mol %) was dissolved in 2.5 mL of toluene. The alkene (1 mL), triethylamine (600 mol %), the
aldehyde (100 mol %, 0.5 mmol), and Et3SiOTf (175 mol %) were added. The reaction mixture was stirred for 48 h at 23 °C. b Yields were determined by
1
1H NMR using DMF as a standard. c Ratios were determined by H NMR of the crude reaction mixture.
Table 8. Examination of Other Nickel Precatalystsa
a Standard procedure: The nickel precatalyst system (20 mol %) was dissolved in toluene. The alkene (500 mol %), triethylamine (600 mol %), the
1
aldehyde (100 mol %), and Et3SiOTf (175 mol %) were added. The reaction mixture was stirred for 48 h at 23 °C. b Yields were determined by H NMR
1
using DMF as a standard. c Ratios were determined by H NMR of the crude reaction mixture. d 1 mL of 1-octene was used.
has the highest H:A ratio (entry 9), whereas tri-p-tolylphosphine,
the most σ-electron-donating among these four ligands, has the
lowest H:A ratio (entry 5).
the electron-donating ability and the cone angle of the phosphine
ligands. High H:A ratios can be achieved by using less electron-
rich phosphines with a small cone angle such as (EtO)Ph2P,
while high A:H ratios can be obtained by using electron-rich
phosphines with a large cone angle such as Cy2PhP.22
Effects of the Base. Tertiary amines are the optimal bases
for the nickel-catalyzed coupling of alkenes and aldehydes.
Among different types of amine bases examined in ethylene
couplings, only tertiary amines provide >20% yield of coupling
products (Table 4, entries 1 and 3). Amines that likely are able
to interact with nickel to a greater degree, such as pyridine
(Table 4, entry 5 and Table 6, entry 6), are not effective. No
coupling products are detected when inorganic bases are used
in place of triethylamine (Table 4, entries 6-8).
These data suggest that a higher H:A ratio can be achieved
by decreasing the electron-donating ability of the phosphine
ligand. In accord with this hypothesis, ethyldiphenylphosphinite
((EtO)Ph2P) further improves the H:A ratio in the case of
1-octene and benzaldehyde (entry 8, 95:5). The hypothesis
becomes even more convincing when the H:A ratio is plotted
against the σ-electron-donating ability of various phosphines
in Table 3 (Figure 1).20 Very electron-deficient phosphonites
and phosphites are not effective ligands, however (entries 10
and 11). It should be noted that the cone angle of the ligands
also affects the observed H:A ratio. Many of the less electron-
rich ligands that favor the homoallylic product in Table 3 are
also among the smaller ligands.
Tertiary amines were further examined in the 1-octene
coupling reaction (Tables 5 and 6), and triethylamine was
consistently superior to other tertiary amines (Table 5, entries
1-4 and Table 6, entries 1-5). Tertiary amines smaller or larger
Based on the results of this study, we surmised that the
coupling product ratio is determined by a combined effect of
9
J. AM. CHEM. SOC. VOL. 128, NO. 35, 2006 11519

A R T I C L E S
Ng et al.
than triethylamine compromised the yield of the coupling
reaction (Table 5, entries 2-4).
couplings. The product derived from p-chlorobenzaldehyde can
be elaborated further by way of a cross-coupling reaction.
Allylbenzene is an excellent substrate, and the homoallylic
products are useful styrene derivatives. The E-isomer is observed
exclusively. Oligomerization of the coupling product is not
observed, as evidenced by the excellent yield of the coupling
reactions (entries 9-14).
Linear monosubstituted olefins such as propene and 1-octene
are not the only terminal olefins that can participate in this
nickel-catalyzed reaction (entries 1, 2, 9, 15). Alkenes with
substitution at the homoallylic position couple with benzalde-
hyde in similar regioselectivity and E/Z selectivity as in the case
of 1-octene (entry 16, as compared to entry 2).
The nature of the tertiary amines in determining the yield
deserves further comment. It appears that a balance of the
nucleophilicity, basicity, and steric bulk of the amine base is
required for the coupling reaction to occur efficiently. Amines
can compete with the phosphorus ligand, alkene, and aldehyde
for a coordination site on nickel. A more nucleophilic (σ-
electron-donating) or smaller amine might hinder the coordina-
tion of any of the other required components to the nickel
catalyst. For instance, the less nucleophilic N-methylmorpholine
(Table 6, entry 3) provides a better yield than N-methylpiperi-
dine (Table 6, entry 4).
In summary, triethylamine is the best base for the nickel-
catalyzed coupling of alkenes and aldehydes, probably because of
a combination of low coordinating ability and appropriate basicity.
Source of Nickel. Since the precatalyst Ni(cod)2 has two
chelating diene ligands (1,5-cyclo-octadiene), other nickel(II)
precatalysts without alkene ligands were examined, including
Ni(Ph3P)4, Ni(acac)2/Ph3P/DIBAL-H, Ni(Ph3P)2Cl2/n-BuLi, and
Ni(Ph3P)2Br2/n-BuLi (Table 7). Only the Ni(acac)2/Ph3P/
DIBAL-H system is as efficient as Ni(cod)2/Ph3P (entry 3). Ni-
(Ph3P)4 is saturated with phosphine ligand, and perhaps alkene
coordination to the nickel catalyst is thus inhibited. Similarly,
Ni(cod)2/Cy2PhP is more efficient than Ni(acac)2/Cy2PhP/
DIBAL-H and Ni(Cy2PhP)2Cl2/n-BuLi (Table 8).23 Therefore
Ni(cod)2 was used in all subsequent investigations.
Substrate Scope. The substrate scope of the nickel-catalyzed
coupling of alkenes, aldehydes, and silyl triflates was next
examined, applying the results of the studies of ligand and base
effects (Tables 9-129). In general, ethylene and monosubstituted
alkenes are superior substrates in this coupling reaction, while
1,1-disubstituted alkenes and acyclic 1,2-disubstituted (cis or
trans) alkenes are significantly less reactive. Trisubstituted
alkenes do not react under the standard reaction conditions.
The Ni-EtOPh2P system efficiently catalyzes the coupling
of monosubstituted alkenes and simple aromatic aldehydes such
as benzaldehyde (Table 9). While the couplings of ethylene with
most aldehydes usually take less than 8 h to reach completion,
those involving monosubstituted alkenes typically require more
than 18 h (entries 2 and 3). Nevertheless, with EtOPh2P as the
ligand, nickel catalyzes the coupling of several monosubstituted
alkenes and aldehydes in excellent yield. The reaction is also
highly regioselective and E/Z selective, favoring an E-homoal-
lylic alcohol product.
Alkenes with substituents at the allylic position, on the other
hand, afford different results. A homoallylic alcohol derivative
is still the major coupling product in the coupling of 2-methyl-
butene (entry 17) and vinylcyclohexane (entry 18) with ben-
zaldehyde. However, the minor product is an E-1,3-disubstituted
allylic alcohol, rather than the usual 1,2-disubstituted allylic
alcohol obtained from the coupling of unbranched alkenes (eqs
2 and 3). The coupling of 3,3-dimethyl-butene and benzaldehyde
yields exclusively 1,3-disubstituted allylic alcohol product (eq
4). This observation maybe important in understanding the
mechanism of these transformations, which is discussed in more
detail in the discussion section below.
Allylic, rather than homoallylic, alcohol derivatives can be
prepared by the nickel-catalyzed coupling of alkenes and
aldehydes simply by substituting Cy2PhP for EtOPh2P (Table
10). Hence, propene couples with naphthaldehyde to provide
the allylic alcohol product in good yield and with the highest
selectivity (Table 10, entry 1). In contrast to the Ni-EtOPh2P
system, the homoallylic alcohol is the minor product in this
case.
Once again, aromatic aldehydes and heteroaromatic aldehydes
couple with straight chain monosubstituted alkenes in good yield
(entries 1-2, 4). Electron-donating p-anisaldehyde is, as before,
more reactive than benzaldehyde (entries 1 and 3). Therefore,
based on all the data that we gathered so far, it seems to be the
trend that generally electron-donating aldehydes are more
reactive than electron-poor aldehydes.
There are, however, some differences in the substrate scope
of the alkene in the Ni-Cy2PhP system relative to that of the
Ni-EtOPh2P system. While branching at the homoallylic position
of the alkene does not affect the coupling efficiency (entry 5),
branching at the allylic position significantly attenuates the yield
of the allylic alcohol product (entry 7). For example, vinylcy-
clohexane has a dramatically lower A:H ratio (entry 7), and
the homoallylic alcohol and a 1,3-disubstituted allylic alcohol
are the major products.
Aromatic aldehydes (Table 9, entries 2, 6, 9, 12), heteroaro-
matic aldehydes (entries 7 and 13), and sterically demanding
aldehydes (entries 8 and 14) are excellent coupling partners with
monosubstituted alkenes, affording an E-homoallylic alcohol
derivative as the major product and an allylic alcohol derivative
as the minor product, with a selectivity >95:5 in most cases.
Monosubstituted aromatic aldehydes of all substitution patterns
are tolerated (ortho-, meta-, and para-, entry 10). Aldehydes
with an electron-donating substituent in the para position (p-
MeO-, entry 4) are more reactive than aldehydes with an
electron-withdrawing group in the same position (Cl-, entry
5), consistent with the observation in the ethylene-aldehyde
In a competition study, benzaldehyde undergoes coupling with
a monosubstituted alkene selectively in the presence of a
trisubstituted alkene (entry 6); the trisubstituted double bond is
stable to the reaction conditions. Carbocyclization is not
observed, nor do we observe any isomerization of the trisub-
stituted double bond in the coupling product. This result enables
the use of a trisubstituted double bond as a masked version of
other functional groups.
Given that heteroaromatic aldehydes are competent substrates
in these coupling reactions, we became interested in the effect
of heteroatoms on the alkene. N-Allylphthalimide, N-homo-
(23) (a) Nickel/phosphine ratio is also important. A 1:2 Ni/phosphine ratio pro-
vides a higher yield than a 1:1 Ni:phosphine ratio in the coupling reaction.
(b) No coupling was observed when Ni(cod)2/Ph3P was replaced with Pd-
(Ph3P)4.
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Ni-Catalyzed Coupling of Alkenes/Aldehydes/Silyl Triflates
A R T I C L E S
Table 9. Preparation of Homoallylic Alcohol Products from Nickel-Catalyzed Alkene-Aldehyde Couplingsa
a Standard procedure: (entries 1-8, 15-18): To a solution of Ni(cod)2 (0.1 mmol) and EtOPPh2 (0.2 mmol) in toluene (2.5 mL) at 23 °C under Ar were
added the alkene (0.5 mL), triethylamine (3.0 mmol), the aldehyde (0.5 mmol), and Et3SiOTf (0.875 mmol). The mixture was stirred for 48 h at room
temperature and purified by chromatography (SiO2). Entries 9-14: Ph3P was used in place of EtOPPh2. b Yields were determined by 1H NMR using DMF
as a standard. c See Supporting Information for structures of the minor products (2a′-2p′). d Propene (1 atm) was used in place of Ar. e Reaction time 18
h. f Reaction temperature 35 °C. g Fivefold larger reaction scale. h Ratio of 2:3. i Ratio of 3:(2q + 2q′).
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A R T I C L E S
Ng et al.
Table 10. Preparation of Allylic Alcohol Products from Nickel-Catalyzed Alkene-Aldehyde Couplingsa
a Standard procedure: Ni(cod)2 (20 mol %) and Cy2PhP (40 mol %) were dissolved in 2.5 mL of toluene. Excess alkene, triethylamine (600 mol %), the
aldehyde (100 mol %, 0.5 mmol), and Et3SiOTf (175 mol %) were added. The reaction mixture was stirred for 18 h at 23 °C. b Unless specified, isolated
yield of all coupling products. c Ratios were determined by 1H NMR of the crude reaction mixture. d 1 atm of propene (balloon) was used, and naphthaldehyde
(100 mol %) was mixed with Ni(cod)2 and Cy2PhP before the addition of toluene. e Yields were determined by 1H NMR using DMF as a standard. f Isolated
yield of the allylic product 2p′.
allylphthalimide, and N-homoallyloxazolidinone undergo cou-
pling in both the Ni-Cy2PhP and Ni-EtOPh2P systems (Table
11, entries 1-3). In particular, the coupling of N-allylphthal-
imide and benzaldehyde in the Ni-EtOPh2P system affords an
enamine that appears to be stable to the coupling conditions. In
contrast, allylbenzoate and homoallylbenzoate esters are much
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Ni-Catalyzed Coupling of Alkenes/Aldehydes/Silyl Triflates
A R T I C L E S
Table 11. Coupling of Nitrogen-Containing Alkenes with Aldehydesa
a Standard procedure: To a solution of Ni(cod)2 (0.1 mmol) and ligand (0.2 mmol) in toluene (2.5 mL) at 23 °C under Ar were added the alkene (1.5
mmol), triethylamine (3.0 mmol), the aldehyde (0.5 mmol), and Et3SiOTf (0.875 mmol). The mixture was stirred for 48 h at room temperature and purified
1
1
by chromatography (SiO2). b Determined by H NMR of the crude reaction mixture using DMF as a standard. c The ratio was determined by H NMR of
the mixture of E and Z homoallylic alcohols after the silyl group of the coupling product was removed by TBAF.
Discussion
less efficient (Table 12, entries 1-4). A small amount of the
allylic product is detected only with homoallylbenzoate (entry
2). When the benzoate group is further away from the terminal
double bond, a better yield of the desired coupling product is
observed (entry 3). These findings suggest an interaction of the
heteroatoms on the alkenes to the nickel catalyst. We propose
that since the oxygen on the phthalimide is less nucleophilic, it
does not bind to the nickel as tightly as the benzoate oxygen.
Therefore the coupling of N-allylphthalimide occurs more
efficiently than allylbenzoate (Table 11, entry 1 and Table 12,
entry 1). As the benzoate becomes further away from the double
bond, the benzoate is less likely to coordinate to the nickel
catalyst, and the reactivity of the alkene is restored (Table 12,
entry 3). The silyl-ether-tethered alkene (entry 4) does not
experience the heteroatom attenuation effect, likely for the same
reason as the benzoate ester in entry 3.
General Mechanistic Framework. We believe that the
nickel species that catalyzes the alkene-aldehyde coupling
reactions above is not functioning simply as a Lewis acid. We
propose that the coupling reaction proceeds through the forma-
tion of oxanickellacycle from a nickel(0) complex (Scheme 1).
A syn â-hydride elimination would afford the coupling product
and a nickel-hydride species, analogous to a Heck reaction.3a-c
Finally, base-promoted reductive elimination of the nickel-
hydride intermediate could regenerate the nickel(0) catalyst.
Note that a base-mediated â-elimination of the oxanickellacycle
via an E2-like mechanism cannot be completely ruled out. Based
on our observations and in analogy to the Heck reaction,3a-c
we believe the nickel-hydride pathway is operative (see below).
Ligand Effects. The interactions of nickel with the ligand,
alkene, and aldehyde govern the assembly of the oxanickella-
cycle, and the oxanickellacycle in turn determines the product
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A R T I C L E S
Ng et al.
Table 12. Coupling of Oxygen-Containing Alkenes with Aldehydesa
a Standard procedure: To a solution of Ni(cod)2 (0.1 mmol) and ligand (0.2 mmol) in toluene (2.5 mL) at 23 °C under Ar were added the alkene (2.5
mmol), triethylamine (3.0 mmol), the aldehyde (0.5 mmol), and Et3SiOTf (0.875 mmol). The mixture was stirred for 48 h at room temperature and purified
1
1
by chromatography (SiO2). b Determined by H NMR of the crude reaction mixture using DMF as a standard. c The ratio was determined by H NMR of
the mixture of E and Z homoallylic alcohols after the silyl group of the coupling product was removed by TBAF. d Isolated yield. e 1.5 mmol of alkene were
used.
distribution. Scheme 2 summarizes the factors that control the
product ratio in the alkene-aldehyde coupling reactions. In
general, use of large phosphines favors the allylic alcohol
product (A) (e.g., the coupling of 1-octene with benzaldehyde
with Cy2PhP as ligand yielded allylic alcohol as the major
product). The use of small phosphines (Bu3P, (EtO)Ph2P, Ph3P,
etc.) on the other hand affords the homoallylic alcohol (H) as
the major product.
Size of Coupling Partners. The substituents on the alkene
and aldehyde also affect the ratio of the coupling products. The
alkene substituents can be closer to either the ligand or the
aldehyde substituent in the oxanickellacycle. Allylic alcohol
product A is obtained in a significant amount when the alkene
has no branching at the allylic position. On the other hand,
branching at the allylic position does not affect the coupling
process when a small ligand, such as (EtO)Ph2P, is used, and
homoallylic allylic alcohol H is formed in good yield. 3,3-
Dimethyl-1-butene, a sterically demanding monosubstituted
alkene with no allylic hydrogen, provides 1,3-disubstituted
allylic alcohol A′ as the sole product.
A large substituent on aldehyde favors the production of
homoallylic alcohol. Less than 5% allylic alcohol product is
observed when propene or 1-octene is coupled with pivaldehyde
with Cy2PhP as the ligand. In the following sections, we propose
a detailed model consistent with all of these observations.
We begin by examining oxanickellacycle 1 in more detail
(Scheme 3). The â-hydrogen of the oxanickellacycle 1 is not
aligned with the C-Ni bond. Since â-hydride elimination
generally occurs in the syn orientation, The -OSiEt3 group must
dissociate from nickel to allow bond rotation such that the
â-hydrogen can align with the C-Ni bond. At this stage,
â-hydride elimination occurs and allylic product A is formed.
The larger the phosphine ligand relative to the aldehyde
substituent, the more likely oxanickellacycle 1 dominates
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Ni-Catalyzed Coupling of Alkenes/Aldehydes/Silyl Triflates
A R T I C L E S
Scheme 1
Scheme 2
because the alkene substituent would thus avoid severe steric
repulsion with this ligand. The data shown in Table 2 support
this proposal; the A:H ratio increases with the cone angle of
the trialkylphosphine.
instead of the exo-â-hydrogen (Hexo). Such a process requires
dissociation of -OSiEt3 and is maybe favored when the exo-
â-hydrogen is not aligned with the C-Ni bond or when there
is no exo-â-hydrogen (Scheme 5).
Oxanickellacycle 2 accounts for the formation of homoallylic
alcohol H and allylic alcohol A′. Examination of oxanickella-
cycle 2 reveals that although the â-hydrogen in the oxanickel-
lacycle (Hendo) is not aligned with the C-Ni bond, there are
â-hydrogens outside the oxanickellacycle (Hexo) that are ap-
propriately poised for â-hydride elimination once a free
coordination site is available (Scheme 4).3e The preferred
conformation would align R2 of the alkene trans to the C-C
bond of the oxanickelacycle 2. Dissociation of one of the ligands
on nickel provides a free coordination site for the syn â-hydride
elimination to occur and provides the E-homoallylic alcohol H.
In order for the unusual allylic alcohol (A′) to form, the
â-hydrogens in the oxanickellacycle (Hendo) must be eliminated
The coupling of vinylcyclohexane and benzaldehyde serves
as a good example to illustrate the formation of 1,3-disubstituted
allylic alcohol A′ (Scheme 5). Neither R1 nor R2 of vinylcy-
clohexane is a hydrogen atom, and hence the allylic position is
very sterically encumbered. The usual allylic alcohol product
A is not favored because the large substituent of vinylcyclo-
hexane will not be accommodated next to the aldehyde
substituent (R) in oxanickellacycle 1 (Scheme 3) due to severe
steric repulsion.
Experimental data support this theory: The coupling of
vinylcyclohexane with benzaldehyde using Cy2PhP as ligand
yields only 5% of the allylic alcohol product A (Table 10, entry
7, as compared with other unbranched alkenes in Table 10,
9
J. AM. CHEM. SOC. VOL. 128, NO. 35, 2006 11525

A R T I C L E S
Scheme 3
Ng et al.
catalyst system also supports the presence of a Ni-H species.
A â-hydride elimination and subsequent base-assisted removal
of triflic acid (reductive elimination) from the Ni-H species
regenerates the Ni(0) catalyst (Scheme 1) and may also minimize
side reactions by suppressing the presence of the Ni-H species.
We do not believe the direct precursor to the oxanickellacycle
in this coupling reaction is a cationic nickel (II) species. Ni2+
,
Pd2+, and Pt2+ catalysts have been reported to be effective Lewis
acids for carbonyl-ene reactions.18g-i The nickel-catalyzed
coupling of alkenes, aldehydes, and silyl triflates affords
carbonyl-ene-type products in good yield, but the substrate scope
is entirely different from that of a Lewis acid-catalyzed carbonyl-
ene reaction. While the three cationic group 10 transition metal
catalysts are effective in the carbonyl-ene reaction of the more
nucleophilic alkenes such as 1,1-disubstituted alkenes and the
more electrophilic aldehydes such as glyoxylate esters, they do
not promote the coupling of monosubstituted alkenes and simple
aldehydes.
Scheme 4
The nickel catalyst system has the opposite alkene and
aldehyde substrate scopes relative to those of the carbonyl-ene
reaction. The nickel-phosphine catalyst selectively reacts with
monosubstituted olefins, and we observe that electron-rich
aldehydes, such as p-anisaldehyde, consistently provide better
yield than benzaldehyde and electron-deficient aldehydes.
Although this coupling reaction readily provides homoallylic
alcohol products corresponding to a carbonyl-ene reaction, it is
more likely that the oxanickellacycle precursor is a Ni(0) species
and probably not just a Lewis acid catalyst.
To illustrate the difference between the Ni(0)-phosphine
system and a Lewis acid system, â-citronellene and benzalde-
hyde were coupled under two conditions; using a classical Lewis
acid and the Ni-EtOPh2P conditions.6b As expected, the Lewis
acid-catalyzed reaction reacts at the more nucleophilic trisub-
stituted double bond. For the Ni-EtOPh2P system, however,
the monosubstituted double bond reacts preferentially because
it is the kinetically more accessible double bond (Scheme 6).
These observations are also in accord with many palladium-
catalyzed reactions of alkenes (such as Wacker oxidation and
alkene hydroamination), in that a monosubstituted double bond
is usually more reactive than a more substituted double bond.3a
The difference in substrate scope between the nickel-catalyzed
alkene-aldehyde coupling and the carbonyl-ene reaction is
further illustrated by competition experiments between a mono-
substituted alkene and a 1,1-disubstituted alkene (Scheme 7).25,26
Equal amounts of allylbenzene and methylenecyclohexane were
included in the otherwise standard coupling conditions. The
coupling reaction was highly selective; 92% of all of the
coupling products detected are derived from allylbenzene. The
entries 1-6). Using a smaller ligand, such as (EtO)Ph2P, the
large substituents in vinylcyclohexane can be accommodated
by being closer to the ligand than to the aldehyde substituent,
favoring oxanickellacycle 2 (Scheme 5). The exo-â-hydrogen
of the oxanickellacycle, when aligned to with C-Ni bond,
induces an unfavorable steric interaction between the cyclohexyl
group and the C-C bond of the oxanickellacycle. Therefore
the rate of â-hydride elimination from the exo-â-hydrogen
decreases, and that of the endo-â-hydrogen increases, resulting
in a greater amount of the unusual E-allylic product A′. The
E-double-bond geometry of A′ is obtained by minimizing steric
repulsion during the â-H elimination step.
Alkenes without an allylic hydrogen cannot afford homoal-
lylic alcohol products in the nickel-catalyzed alkene-aldehyde
coupling reaction. For example, 3,3-dimethyl-1-butene, with no
allylic hydrogen, couples with benzaldehyde to give exclusively
E-1,3-disubstituted allylic alcohol product (A′).24 Also, it appears
that the steric bulk of the tert-butyl group renders formation of
oxanickellacycle 1 extremely difficult, eliminating the possibility
of affording 1,2-disubstituted allylic alcohol product A.
The proposed mechanistic framework is also supported by
Ogoshi’s observation that cyclization of an R,ω-enal to form
an oxanickellacycle is facilitated by the presence of a silyl
triflate.17 A control experiment confirms that without silyl
triflate, no coupling product is observed.22
(25) Procedure of the competition experiment: To a solution of Ni(cod)2 (0.1
mmol) and the ligand (Ph3P or (EtO)Ph2P, 0.2 mmol) in toluene (2.5
mL) at 23 °C under Ar were added a monosubstituted alkene (2.5
mmol), methylenecyclohexane (2.5 mmol), triethylamine (3.0 mmol),
p-anisaldehyde (0.5 mmol), and triethylsilyltriflate (0.875 mmol). The
mixture was stirred for 48 h at room temperature. The yields and ratios
were determined by 1H NMR of the crude reaction mixture. Ph3P was the
ligand in the reaction between allylbenzene and methylenecyclohexane.
(EtO)Ph2P was the ligand in the reaction between 1-octene and methyl-
enecyclohexane.
(26) As a control experiment, methylenecyclohexane (300 mol %) was coupled
with p-anisaldehyde under standard conditions (Ni(cod)2, EtOPh2P, Et3-
SiOTf, Et3N) to give 13% yield of the homoallylic alcohol product. To
determine whether the formation of this coupling product requires Ni(cod)2,
another control experiment was carried out by stirring methylenecyclo-
hexane, p-anisaldehyde, and Et3SiOTf at room temperature. No alkene-
aldehyde coupling product was observed.
The evidence for the â-hydride elimination as the next step
is the observation of isomerization and dimerization (hydrovi-
nylation) of the starting olefins, which suggests the presence
of a nickel-hydride (Ni-H) species, likely formed by a
â-hydride elimination.3d The requirement of a base in this
(24) Coupling of 3,3-dimethyl-1-butene and benzaldehyde under the standard
coupling conditions (EtOPh2P, rt, 48 h) affording an E-1,2-allylic alcohol
product in 14% yield.
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11526 J. AM. CHEM. SOC. VOL. 128, NO. 35, 2006

Ni-Catalyzed Coupling of Alkenes/Aldehydes/Silyl Triflates
A R T I C L E S
Scheme 5
Scheme 6
Scheme 7. Competition Experiments between Monosubstituted and 1,1-Disubstituted Alkenes25,26
presence of methylenecyclohexane does not change the H:A
ratio of the coupling products of allylbenzene (as compared to
Table 9, entry 10). A similar trend is observed between 1-octene
and methylenecyclohexane (as compare to Table 9, entry 4),
but the presence of excess methylenecyclohexane in the reaction
mixture seems to lower the yield of the coupling reaction. This
lower efficiency might be due to competition for a coordination
site on nickel between monosubstituted alkenes and methyl-
enecyclohexane.
the starting olefin. One explanation for the requirement of excess
alkenes in this coupling reaction is that the terminal alkene is
isomerized to an internal alkene and that this new internal alkene
is not reactive in the coupling process. While isomerization of
olefin is common in the coupling reaction, hydrovinylation of
olefins is observed in small amounts only when the alkene-
aldehyde coupling process is not efficient. The presence of a
base in the coupling reaction may keep the Ni-H concentration
to a minimum, thus suppressing some of these side reactions.
Further evidence that supports the notion that the nickel-
catalyzed coupling of alkenes, aldehydes, and silyl triflates does
not involve a carbonyl-ene reaction mechanism is that ethylene,
with no allylic hydrogen, also participates in this coupling
reaction using the same Ni-phosphine catalyst system.
Common side reactions in these nickel-catalyzed reactions
are the dimerization (hydrovinylation)27 and isomerization28 of
Summary. The nickel-catalyzed coupling of alkenes, alde-
hydes, and silyl triflates represents a new alternative to both
allylmetal reagents and alkenylmetal reagents (Scheme 8). The
parent allylmetal reagent and vinylmetal reagent can now be
replaced by propene and ethylene, respectively, using the nickel-
catalyzed processes as described herein. The preparation of a
terminal, monosubstituted alkene is generally more straightfor-
ward than that of the allylmetal species such as those shown in
Scheme 8.
(27) A recent review of the nickel-catalyzed hydrovinylation: (a) RajanBabu,
T. V. Chem. ReV. 2003, 103, 2845-2860. Dimerization of ethylene and
propylene: (b) Pillai, S. M.; Ravindranathan, M.; Sivaram, S. Chem. ReV.
1986, 86, 353-399.
(28) Examples of isomerization of olefins by transition-metal hydrides: Nick-
el: (c) Tolman, C. A. J. Am. Chem. Soc. 1972, 94, 2994-2999.
Ruthenium: (d) Wakamatsu, H.; Nishida, M.; Adachi, N.; Mori, M. J. Org.
Chem. 2000, 65, 3966-3970. Rhodium: (e) Morrill, T. C.; D’Souza, C.
A. Organometallics 2003, 22, 1626-1629.
The transformation in this nickel-catalyzed alkene-aldehyde
coupling reaction is, in effect, a C-H functionalization reaction
of the alkene, involving addition to an aldehyde. Mechanisti-
cally, an entirely different process likely occurs, rather than
9
J. AM. CHEM. SOC. VOL. 128, NO. 35, 2006 11527

A R T I C L E S
Scheme 8
Ng et al.
Scheme 9
oxidative addition into a C-H bond that would be expected to
have a relatively high energy activation barrier.
unique, nonreductive coupling processes that allow the prepara-
tion of derivatives of allylic alcohols or homoallylic alcohols
from readily available olefins. The selectivity for these two
products is highly ligand dependent, and high selectivity in either
direction is possible. These coupling reactions are mechanisti-
cally different from Lewis acid-catalyzed carbonyl-ene reactions,
and conceptually, alkenes serve as substitutes for both allylmetal
reagents and alkenylmetal reagents.
Unlike the related transition metal-catalyzed reductive cou-
pling reactions developed by our group and others,8 the nickel-
catalyzed coupling of alkenes, aldehydes, and silyl triflates
described in this work is not an overall reductive process
(Scheme 9). Thus, the coupling of an alkene and an aldehyde,
in theory, does not require a third component to form the allylic
or homoallylic alcohol derivatives. However, both alkenes and
aldehydes are generally unreactive toward each other. Thus,
activation of either or both components is necessary. The Lewis
acid-catalyzed carbonyl-ene reaction serves as a good example.
Intermolecular carbonyl-ene reaction between monosubstituted
alkene and unactivated aldehydes such as acetaldehyde is not a
practical method under thermal conditions. The presence of a
Lewis acid, however, allows the coupling to proceed at room
temperature. The Lewis acidic nature of silyl triflate in the
nickel-catalyzed alkene-aldehyde coupling reaction likely plays
a similar role, providing sufficient activation of the electrophile
for the nickel catalyst to promote the coupling reaction.
The two classes of the nickel-catalyzed coupling reactions
of alkene, aldehyde, and silyl triflate presented here represent
Acknowledgment. Support for this work was provided by
the National Institute of General Medical Sciences (GM-
063755). C.-Y.H. thanks The Croucher Foundation for a
postdoctoral fellowship. We are grateful to Dr. Li Li for
obtaining mass spectrometric data for all compounds (MIT
Department of Chemistry Instrumentation Facility, which is
supported in part by the NSF (CHE-9809061 and DBI-9729592)
and the NIH (1S10RR13886-01)).
Supporting Information Available: Experimental procedures
and characterization data for all new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA062866W
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11528 J. AM. CHEM. SOC. VOL. 128, NO. 35, 2006