Highly selective coupling of alkenes and aldehydes catalyzed by [Ni(NHC){P(OPh)3}]: Synergy between a strong σ donor and a strong π acceptor

Article abstract of DOI:10.1002/anie.200603907

(Chemical Equation Presented) Give and take: Both a strong electron donor (1) and a strong electron acceptor (P(OPh)₃) are necessary for a highly selective, nickel-catalyzed coupling reaction between alkenes, aldehydes, and silyl triflates (see

Full text of DOI:10.1002/anie.200603907

Communications
DOI: 10.1002/anie.200603907
Catalytic Coupling Reactions
Highly Selective Coupling of Alkenes and Aldehydes Catalyzed by
[Ni(NHC){P(OPh)3}]: Synergy between a Strong s Donor and a Strong
p Acceptor**
Chun-Yu Ho and Timothy F. Jamison*
Recently we described two new nickel-catalyzed, three-
component coupling reactions involving a-olefins, aldehydes,
and silyl triflates.[1] The appropriate choice of ligand favors
the production of either allylic (A) or homoallylic (H) alcohol
derivatives, both of which are synthetically useful intermedi-
ates.[2] In these studies we achieved greater than 95:5 H/A
selectivity using EtOPPh2 or Ph3P, but a general method for
with high A/H selectivity has remained elusive.
vious phosphine-based system, a-branched alkenes afforded
only traces of allylic product II. However, these reactions did
not appear to proceed catalytically. An additional complica-
tion was that significant quantities of two side products were
also observed, resulting from hydrosilylation of the aldehyde
(reduction) and hydrovinylation.[5]
We surmised that both problems (product distribution and
no discernable catalytic mechanism) might have a common
cause (Scheme 1): Formal reductive elimination of triflic acid
(HOTf) from 3 to regenerate a Ni0 species (for example, 1) is
likely retarded by the electron-rich ligand I.[3b,c,6] Stalling the
catalytic cycle at this point would result in an accumulation of
a [Ni(NHC)H](OTf) species 3 which is responsible for the
aforementioned side reactions. Our first attempts to render
this process catalytic involved the use of stronger organic and/
or inorganic bases to facilitate reductive elimination.
Unfortunately, this strategy summarily failed, perhaps
because I is a very strong s donor.[7]
Herein we describe a solution to this deficiency and
document a synergistic relationship between substoichiomet-
ric amounts of a strong s donor [I, (IPr) Eq. (1), Tf = tri-
fluoromethanesulfonyl, cod = cycloocta-1,5-diene] and
a
We thus required an alternative means to rescue the
catalytic cycle and considered the possibility of shunting 3
into a different manifold to make reductive elimination more
facile (Scheme 1). As the pioneering investigations of Yama-
strong p acceptor (PhO)3P. We believe that this phenomenon
is the result of attenuation of the strong electron-donating
ability of I by the electron-withdrawing phosphine (PhO)3P at
a specific point in the catalytic cycle that consequently
accelerates reductive elimination. This new strategy may have
many broader applications in certain metal-catalyzed reac-
tions, for example, the Heck reaction.[3]
Table 1: Evaluation of additives in the coupling reactions mediated by
[Ni(IPr)].
In preliminary investigations of imidazolinyl-derived
NHC ligands (NHC = N-heterocyclic carbene) in these trans-
formations, we found that I was exceptionally selective for the
allylic product (Table 1, entry 1), even when a rather encum-
bered alkene (vinylcyclohexane) was used.[4] With our pre-
Entry[a]
Additive
none
m(CF3)C6H4C CH2
CyPPh2
PPh3
EtOPPh2
(EtO)2PPh
P(OBu)3
P(OPh)3
Conv. [%][b]
Yield II
Yield III
[*] Dr. C.-Y. Ho, Prof. T. F. Jamison
Department of Chemistry
[%][b,c]
[%][b]
1
2
3
4
5
6
7
8
9
55
79
61
100
100
84
68
59
7
18 (33)
39 (49)
19 (31)
34 (34)
34 (34)
30 (35)
32 (47)
45 (76)
0 (0)
0
0
0
44
37
29
9
0
0
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-0253
=
E-mail: tfj@mit.edu
[**] 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)). NHC=N-heterocyclic carbene.
[d]
P(OPh)3
[a] See the Supporting Information for details. [b] Determined by
1H NMR analysis (relative to an external standard (CH3NO2)).
[c] Values in parentheses are yields based on conversion of aldehyde.
[d] Without added ligand I.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
782
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 782 –785

Angewandte
Chemie
It should be emphasized that both I and
(PhO)3P were necessary for catalysis, the
absence of one results in either no product (I
absent) or no turnover (phosphite absent).
Thus, unlike other electron-poor phosphorus
additives, (PhO)3P did not erode the allylic
selectivity, perhaps because it did not promote
the reaction on its own (Table 1, entry 9).
The scope of this synergistic NHC/phos-
phite effect and new [Ni(IPr)]-catalyzed trans-
formation are summarized in Table 2. Partic-
ularly noteworthy is that an A/H selectivity of
greater than 20:1 was observed in all cases
examined. Also, the range of suitable alkene
substrates was far broader than that found
in our previous Ni–phosphine-catalyzed
processes.[1]
Scheme 1. Proposed Mechanism.
Anisaldehydes substituted in the para,
ortho, and meta positions proved to be good-
to-excellent substrates (Table 2, entries 1–4).
moto et al. had demonstrated that electron-poor alkenes
dramatically accelerate the reductive elimination of R’–R’’
from species of the general form R’–Ni–R’’ by decreasing the
electron density at the metal center,[8] we examined the effect
of these electron-poor olefins on the reaction.
With meta-trifluoromethylstyrene and a catalyst loading
of 30 mol%, we observed a 39% yield of the desired coupling
product (Table 1, entry 2), but coupling products derived
from the added styrene were also observed in the reac-
tion.[9a–c] Nevertheless, catalysis had been achieved for the
first time, and we expanded our search to include electron-
withdrawing phosphorus-containing compounds to avoid
undesired coupling reactions between the additive and the
aldehyde.[10]
We were mindful of the fact that this approach could very
well have a fatal flaw related to ligand compatibility. In
previous studies we found electron-poor phosphinites, among
others, disfavored the formation of allylic alcohol derivatives
and, as mentioned above, were in fact superior to all other
additives for high H/A selectivity.[11] Thus, the electron-
deficient additive could erode or overturn the high
A/H selectivity provided by ligand I.
Table 1 summarizes the results of these studies. Moder-
ately electron-donating phosphines such as CyPPh2 (Cy =
cyclohexyl) proved ineffective (Table 1, entry 3). Substoichio-
metric amounts of certain electron-poor phosphines (relative
to CyPPh2) provided marginal catalytic activity (Table 1,
entries 4–6). Unfortunately, a significant amount of the
undesired homoallylic alcohol derivative III was observed,
presumably because of the competing homoallylic-favoring
reaction, the potential pitfall mentioned above.
Bulky silyl triflates such as TBDMSOTf (TBDMS = tert-
butyldimethylsilyl) could also be used as activating reagents
(Table 2, entry 2). Styrenes, which readily underwent self-
hydrovinylation in our earlier studies, became competent
starting materials in the presence of the phosphite (Table 2,
entry 5).
Allylbenzene and homoallylbenzene both displayed
excellent selectivity (Table 2, entries 6 and 7), despite a
reduced reaction rate. Sterically demanding a-branched
substrates underwent highly regioselective coupling
(Table 2, entries 8–10). Similarly, coupling reactions of b-
branched alkenes with the phosphite additive also showed a
marked increase in A/H selectivity (Table 2, entry 11). A
trisubstituted double bond was found to be inert, thus
enabling its use as a masked functional group for subsequent
modification (Table 2, entry 12).
Benzaldehyde and 2-naphthaldehyde also showed good
reactivity and high A/H ratios (Table 2, entries 13 and 14). A
chlorine atom attached to the aldehyde was tolerated
(Table 2, entries 15 and 16), but the reaction rate was much
slower, and the side reactions of hydrosilylation and hydro-
vinylation became significant. Furfural was found to behave
similarly (Table 2, entry 17).
We believe the high selectivity for the allylic alcohol and
the broader range of substrates tolerated in this new reaction
system are related to the sterically demanding and highly
electron-donating nature of the ligand I (Scheme 1). The
ligand not only orients the substituents of the alkene and
aldehyde away from the Ni center, but also accelerates the
oxidative coupling (1 to 2).
Conversely, the downside of this latter effect is perhaps
that, in the absence of the phosphite additive, reductive
elimination is much more difficult for the same reason that
oxidative addition is more facile. Thus, we propose that the
phosphite promotes this step in the catalytic cycle by reducing
the electron density at a coordinatively unsaturated Ni center.
A complex such as 4 (Scheme 1) would be expected to
undergo reductive elimination to 5 more readily than would 3
to 1.
However, highly electron-deficient phosphite ligands
were found to be very efficient additives (Table 1, entries 7
and 8). Not only did triphenylphosphite render the system
catalytic, but it also completely suppressed formation of the
homoallylic by-product (1H NMR, limit of detection approx.
2%). Furthermore, hydrosilylation of the aldehyde was not
observed and the amount of alkene hydrovinylation was
dramatically reduced.
Angew. Chem. Int. Ed. 2007, 46, 782 –785
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
783

Communications
Table 2: Alkene–aldehyde coupling reactions catalyzed by [Ni(I){P(OPh)3}].
While many electron-deficient
olefins have been used as additives
for similar purposes, this study rep-
resents a rare example of using an
additive other than an alkene in this
manner in a catalytic reaction.[9,12]
Remarkably, I and the phosphite
are compatible with one another in
this two-ligand system, neither
seems to impede the role of the
other. For this reason in particular,
this phosphite/NHC combination
may have several other applications
and broader implications in NHC–
Entry[a]
Alkene (R1)
Product
Conv. [%][b]
Yield [%][b,c]
96
1
nHex
95[d]
2
3
nHex
nHex
92[d,e]
82
75
80
4
nHex
Ph
86
98
84
99
99
96
metal-catalyzed
transformations.
For example, other reactions that
rely upon the reductive elimination
5
69
À
of H X from H–M–X (M = metal,
6[d]
PhCH2
PhCH2CH2
Cy
75
X = for example, halide, triflate,
sulfonate), particularly in the Heck
reaction, or of R’–M–R’’ in general,
such as catalytic cross-coupling
reactions, may also enjoy an accel-
erating effect by the use of a
phosphite.[13] While an electron-
deficient alkene may not be appro-
priate, as it may react in the Heck
reaction, an organophosphite may,
in contrast, be compatible. We are
currently exploring such possibili-
ties.
7
88
8
100
9[f,g]
10[g,h]
11
iPr
100
32
93
41
99
94
tBu
iBu
100
100
12
Experimental Section
General Procedure (see the Supporting
Information for examples): In a glove
box, [Ni(cod)2] (30 mol%), 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene
(I, 30 mol%), and a stirrer bar were
added to an oven-dried test tube
(10 mL). The tube was sealed with a
rubber septum, removed from the glove
box, and connected to an Ar line. The
catalyst mixture was dissolved in
degassed toluene (3 mL) under Ar and
stirred for 1 h at room temperature. The
13
nHex
nHex
nHex
95
74
88
96
99
73
14
15[h]
16
Cy
66
32
36
alkene
(500 mol%
or
indicated
amount), triethylamine (600 mol%),
aldehyde (0.25 mmol, 100 mol%), and
triphenylphosphite (45 mol%) were
added sequentially. Triethylsilyl triflate
(175 mol%) was added dropwise, and
the mixture was stirred for 48 h at 358C.
After cooling the mixture to room
temperature, it was diluted with diethyl
ether (5 mL) and stirred for 30 min in
open air. The resulting mixture was
filtered through a short plug of silica
gel and rinsed with 20% EtOAc/hexane
(50 mL). The solvent was removed
under reduced pressure, and purification
17[h,i]
nHex
100
[a] See the Experimental Section and the Supporting Information for details. [b] Determined by
integration (1H NMR spectroscopy) relative to an external standard (CH3NO2). [c] Based on conversion.
[d] 150 mol% of alkene used. [e] tBuMe2SiOTf used in place of Et3SiOTf. [f] 1 mL of alkene used.
[g] Reaction carried out in a sealed tube. [h] 40 mol% of catalyst used. [i] Reaction carried out at room
temperature.
784
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 782 –785

Angewandte
Chemie
by flash chromatography (SiO2, 1% EtOAc in hexane) afforded the
product.
[7] Bases including K2CO3, Cs2CO3, diisopropylethylamine, pyri-
dine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-
methylpyrrolidine, and N-methylmorpholine were examined.
[8] For the use of an electron-deficient alkene to facilitate the
reductive elimination of R–R from {R2Ni(bipy)} species, see: T.
Yamamoto, A. Yamamoto, S. Ikeda, J. Am. Chem. Soc. 1971, 93,
3350.
[9] For the use of electron-deficient styrenes as additives in catalysis,
see: a) R. Giovannini, T. Studemann, G. Dussin, P. Knochel,
Angew. Chem. 1998, 110, 2512; Angew. Chem. Int. Ed. 1998, 37,
2387; b) R. Giovannini, T. Studemann, A. Devasagayaraj, G.
Dussin, P. Knochel, J. Org. Chem. 1999, 64, 3544; c) E. A.
Bercot, T. Rovis, J. Am. Chem. Soc. 2002, 124, 174; d) methyl
acrylate: J. Lau, R. Sustmann, Tetrahedron Lett. 1985, 26, 4907;
e) fumaronitrile: R. Sustmann, J. Lau, M. Zipp, Tetrahedron
Lett. 1986, 27, 5207; f) dimethyl fumarate: R. van Asselt, C. J.
Elsevier, Tetrahedron 1994, 50, 323.
[10] a) It was shown that certain organophosphorus compounds
accelerated reductive elimination from a nickel complex (but
not in a catalytic reaction) and attributed the effect to the size of
the phosphorus additive, rather than its electronic nature; see: S.
Komiya, Y. Abe, A. Yamamoto, T. Yamamoto, Organometallics
1983, 2, 1466; b) for the use of PPh3 as an additive to stabilize an
[Ni(NHC)] catalyst, see: R. Sawaki, Y. Sato, M. Mori, Org. Lett.
2004, 6, 1131.
[11] Steric and electronic properties of organophosphines: a) M.
Rahman, H.-Y. Liu, K. Eriks, A. Prock, W. P. Giering, Organo-
metallics 1989, 8, 1; b) C. A. Tolman, Chem. Rev. 1977, 77, 313;
c) S. Otto, J. Chem. Crystallogr. 2001, 31, 185; d) H. Riihimaki, T.
Kangas, P. Suomalainen, H. K. Reinius, S. Jaaskelainen, M.
Haukka, A. O. I. Krause, T. A. Pakkanen, J. T. Pursiainen, J.
Mol. Catal. A 2003, 200, 81; e) W. E. Steinmetz, Quant. Struct.-
Act. Relat. 1996, 15, 1.
[12] The effects of phosphorous ligands upon reductive elimination
from [N(NHC)alkyl] complexes to give alkyl imidazolium salts
have been studied. In contrast, our observation that the NHC
was not consumed suggests that one of the other ligands (for
example, H or OTf) significantly affects the properties and
behavior of the metal complex; see: a) D. S. McGuinness, N.
Saendig, B. F. Yates, K. J. Cavell, J. Am. Chem. Soc. 2001, 123,
4029; b) N. D. Clement, K. J. Cavell, Angew. Chem. 2004, 116,
3933; Angew. Chem. Int. Ed. 2004, 43, 3845.
[13] For a recently reported Ni-catalyzed Heck reactions using
P(OPh)3 or an NHC as a ligand (1508C reaction temperature),
see: a) S. Iyer, C. Ramash, A. Ramani, Tetrahedron Lett. 1997,
38, 8533; b) K. Inamoto, J.-i. Kuroda, T. Danjo, T. Sakamoto,
Synlett 2005, 1624.
Received: September 22, 2006
Published online: December 8, 2006
À
Keywords: C C coupling · carbenes · nickel · P ligands ·
reductive elimination
.
[1] a) S.-S. Ng, T. F. Jamison, J. Am. Chem. Soc. 2005, 127, 14194;
b) C.-Y. Ho, S.-S. Ng, T. F. Jamison, J. Am. Chem. Soc. 2006, 128,
5362; c) S.-S. Ng, C.-Y. Ho, T. F. Jamison, J. Am. Chem. Soc.
2006, 128, 11513.
[2] See Ref. [1] and also: a) J. S. Yeston, Science 2005, 309, 2139; for
reviews of the preparation of homoallylic alcohols by carbonyl
ene reactions, see: b) B. B. Snider, Acc. Chem. Res. 1980, 13, 426;
c) K. Mikami, M. Shimizu, Chem. Rev. 1992, 92, 1021; d) L. C.
Dias, Curr. Org. Chem. 2000, 4, 305.
À
[3] For a review of the Heck reaction and Pd H chemistry, see:
a) E.-i. Negishi, Handbook of Organopalladium Chemistry for
Organic Synthesis, Wiley-Interscience, New York, 2002; Ni0
species are not effectively regenerated by a mechanism that is
common to the Pd-catalyzed Heck reaction through deprotona-
tion of H-Ni-X species by base, see: b) I. P. Beletskaya, A. V.
Cheprakov, Chem. Rev. 2000, 100, 3009; for theoretical compar-
ison of Pd- and Ni-catalyzed Heck reactions, see: c) B.-L. Lin, L.
Liu, Y. Fu, S.-W. Luo, Q. Chen, Q.-X. Guo, Organometallics
2004, 23, 2114.
[4] For recent reviews of NHC ligands in transition-metal catalysis,
see: a) T. Weskamp, V. P. W. Bohm, W. A. Herrmann, J. Organo-
met. Chem. 2000, 600, 12; b) W. A. Herrmann, Angew. Chem.
2002, 114, 1342; Angew. Chem. Int. Ed. 2002, 41, 1290; c) C. M.
Crudden, D. P. Allen, Coord. Chem. Rev. 2004, 248, 2247;
d) M. S. Viciu, S. P. Nolan, Top. Organomet. Chem. 2005, 8, 241;
e) R. H. Crabtree, J. Organomet. Chem. 2005, 690, 5451.
[5] a) Organometallic Catalysts and Olefin Polymerization (Ed.: R.
Blom), Springer, New York, 2001; b) For Ni-catalyzed hydro-
vinylations, see: T. V. RajanBabu, Chem. Rev. 2003, 103, 2845.
[6] For [M(NHC)H] complexes of unusually high stability, see:
a) N. D. Clement, K. J. Cavell, C. Jones, C. J. Elsevier, Angew.
Chem. 2004, 116, 1297; Angew. Chem. Int. Ed. 2004, 43, 1277;
b) M. Viciano, E. Mas-Marza, M. Poyatos, M. Sanaffl, R. H.
Crabtree, E. Peris, Angew. Chem. 2005, 117, 448; Angew. Chem.
Int. Ed. 2005, 44, 444.
Angew. Chem. Int. Ed. 2007, 46, 782 –785
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
785