Nickel(0)-catalyzed heck cross-coupling via activation of aryl C-OPiv bonds

Article abstract of DOI:10.1021/ol203322v

Using a Ni(dppf) catalyst generated in situ, Heck cross-coupling of aryl pivalates with a variety of olefin partners has been accomplished. This method represents one of the first examples of a C-C cross-coupling via activation of a strong C-O bond with a

Full text of DOI:10.1021/ol203322v

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1202–1205
Nickel(0)-Catalyzed Heck Cross-Coupling
via Activation of Aryl CꢀOPiv Bonds
Andrew R. Ehle, Qi Zhou, and Mary P. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark,
Delaware 19716, United States
mpwatson@udel.edu
Received December 12, 2011
ABSTRACT
Using a Ni(dppf) catalyst generated in situ, Heck cross-coupling of aryl pivalates with a variety of olefin partners has been accomplished. This
method represents one of the first examples of a CꢀC cross-coupling via activation of a strong CꢀO bond with a nonorganometallic coupling
partner. It enables the transformation of phenol-based substrates into styrenyl products without generation of a halogenated byproduct or the use
of expensive triflate groups.
The development of greener and less expensive methods
is an ongoing challenge in the synthesis of organic com-
pounds. The ubiquity of inexpensive phenols makes them
attractive starting materials for the preparation of elabo-
rated aromatic targets. In general, transformation of the
CꢀO bond of such phenol substrates requires activation of
the oxygen functional group as a triflate.1 However, initial
reports by Wenkert2 and more recent efforts in this area
have been devoted to nickel-catalyzed activation and sub-
sequent functionalization of the much stronger CꢀO
bonds in aryl ethers, carboxylates, and carbamates, among
others.3 These efforts have resulted in powerful new cross-
coupling reactions to form CꢀC,4ꢀ6 CꢀN,7 and CꢀH8
bonds using inexpensive oxygen functional groups without
generation ofa halogenated byproduct. Notably, however,
the formation of CꢀC bonds via activation of such CꢀO
bonds has largely been accomplished with organometallic
coupling partners, such as Grignard or boronic reagents
(Scheme 1A). Itami recently reported the Ni-catalyzed
cross-coupling of azoles with phenol derivatives, including
aryl pivalates.9 However, the compatibility of activating
(1) (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25,
2271. (b) Scott, W.; Crisp, G.; Stille, J. J. Am. Chem. Soc. 1984, 106,
4630. (c) Chen, Q.-Y.; Yang, Z.-Y. Tetrahedron Lett. 1986, 27, 1171.
(2) (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem.
Soc. 1979, 101, 2246. (b) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.;
Tingoli, M. J. Org. Chem. 1984, 49, 4894.
(3) For reviews of cross-couplings via CꢀO bond cleavage, see: (a)
Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem.;Eur. J. 2011, 17, 1728.
(b) Rosen, B.; Quasdorf, K.; Wilson, D.; Zhang, N.; Resmerita, A.-M.;
Garg, N.; Percec, V. Chem. Rev. 2010, 111, 1346.
(6) For examples of aryl carbamates, carbonates, and sulfonates, see:
(a) Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am.
Chem. Soc. 2009, 131, 17748. (b) Quasdorf, K. W.; Antoft-Finch, A.;
Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Rambren,
S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011,
133, 6352. (c) Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem.
2011, 76, 1507. (d) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am.
Chem. Soc. 2009, 131, 17750.
(4) For examples of aryl and vinyl carboxylates, see: (a) Quasdorf,
K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422. (b) Li,
B.-J.; Xu, L.; Wu, Z.-H.; Guan, B.-T.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J.
J. Am. Chem. Soc. 2009, 131, 14656. (c) Sun, C.-L.; Wang, Y.; Zhou, X.;
Wu, Z.-H.; Li, B.-J.; Guan, B.-T.; Shi, Z.-J. Chem.;Eur. J. 2010, 16,
5844. (d) Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Am. Chem.
Soc. 2009, 131, 8815. (e) Guan, B.-T.; Wang, Y.; Li, B.-J.; Yu, D.-G.; Shi,
Z.-J. J. Am. Chem. Soc. 2008, 130, 14468.
(7) (a) Tobisu, M.; Shimasaki, T.; Chatani, N. Chem. Lett. 2009, 38,
710. (b) Shimasaki, T.; Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed.
2010, 49, 2929. (c) Ramgren, S. D.; Silberstein, A. L.; Yang, Y.; Garg,
N. K. Angew. Chem., Int. Ed. 2011, 50, 2171.
(8) (a) Sergeev, A.; Hartwig, J. Science 2011, 332, 439. (b) Alvarez-
Bercedo, P.; Martin, R. J. Am. Chem. Soc. 2010, 132, 17352. (c) Tobisu,
M.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Chem. Commun. 2011,
47, 2946.
(5) For examples of aryl and vinyl ethers and alcohols, see: (a)
Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008, 47,
4866. (b) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.; Wang, B.-Q.;
Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 1437. (c) Dankwardt,
J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. (d) Hayashi, T.; Katsuro,
Y.; Kumada, M. Tetrahedron Lett. 1980, 21, 3915. (e) Yu, D.-G.; Li,
B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi, Z.-J. Angew. Chem.,
Int. Ed. 2010, 49, 4566. (f) Ueno, S.; Mizushima, E.; Chatani, N.;
Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516. (g) Kakiuchi, F.; Usui,
M.; Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004, 126, 2706.
(9) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134,
169.
r
10.1021/ol203322v
Published on Web 02/15/2012
2012 American Chemical Society

strong CꢀO bonds with other nonorganometallic partners
has not yet been demonstrated, despite its potential utility
in both the preparation of synthetic building blocks and
late-stage functionalization of complex molecules. To this
end, we have developed a Ni(0)-catalyzed cross-coupling
of aryl pivalates with olefins (Scheme 1B). This Heck
reaction allows facile preparation of 1,2-disubstituted
olefins without use of an expensive triflate group or
formation of a halogenated byproduct.
observed (entry 11). Lower yields were also observed with
less than 2 equiv of styrene (not shown). In addition, we
must emphasize that efficient stirring is necessary to
achieve a high yield in this heterogeneous reaction.
Table 1. Optimization of Cross-Couplinga
Scheme 1. CꢀC Bond Formation via Activation of Strong CꢀO
ligand
temp
yield
(%)b
Bonds
entry
(mol %)
base
(°C)
solvent
1
PCy3 (24)
PPh3 (24)
bpyc (12)
BINAP (12)
BINAP (12)
dppf (12)
dppf (12)
PCy3 (24)
dppf (12)
dppf (12)
dppf (6)
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
110
110
110
110
110
110
125
125
125
125
125
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
(n-Bu)2O
PhMe
PhMe
<1
2
<1
3
<1
4
11
5
26
6
40
7
56
8
28
9
12
10d
11d,e
99 (82)
84
a Conditions: Substrate 1A (0.10 mmol), styrene (2a, 0.20 mmol, 2.0
equiv), Ni(cod)2 (0.010 mmol, 10 mol %), ligand, base (1.0 equiv),
solvent (0.25 mL, 0.4 M), 24 h, unless otherwise noted. b Determined by
GC using dodecane as internal standard. Numbers in parentheses are
isolatedyields. c bpy= bipyridine. d Reactionmixture washeatedfor 48h.
e 5 mol % Ni(cod)2 used.
We selected the reaction of 2-naphthyl pivalate (1A) and
styrene (2a) for optimization studies. Based on conditions
reported for other Ni-catalyzed cross-couplings via
activation of strong CꢀO bonds, we anticipated that
tricyclohexylphosphine (PCy3) would be a suitable ligand
for our desired Heck cross-coupling.4,6 However, only
a trace amount of product formed when PCy3 was
used with Ni(cod)2 and K2CO3 (Table 1, entry 1).
A screen of ligands showed that higher yields are obtained
with bidentate phosphine ligands, such as racemic 2,20-
bis(diphenylphosphino)-1,10-binapthyl (BINAP) (entries
2 and 3 vs 4). By changing the base to K3PO4, which is
more commonly used in Ni-catalyzed CꢀO activations
thanK2CO3, a further increase inyield was observed (entry
5). Use of organic bases such as Et3N, pyridine, and
i-Pr2NEt led to no reaction. A broader screen of bidentate
phosphine ligands under these conditions led to identifica-
tion of 1,10-bis(diphenylphosphino)ferrocene (dppf) as the
best ligand (entry 6). By increasing the reaction tempera-
ture and time, an 82% isolated yield of product 3Aa was
obtained (entry 10).10 We reinvestigated PCy3 under these
optimized conditions and again found dppf to be superior
(entry 7 vs 8).11 Solvents other than PhMe were less
effective in this reaction (entry 9). The cross-coupling can
be performed with lower catalyst loading, but a somewhat
diminished yield and recovered starting material were
We also examined the possibility of activating alterna-
tive CꢀO bonds, which have been successfully cleaved in
other Ni-catalyzed cross-couplings (Table 2).3 No other
naphthol derivative was as reactive as pivalate 1A under
the optimized reaction conditions. The reaction of
2-naphthyl tosylate resulted in a 55% yield (GC) of styrene
3Aa (entry 2).12 In the reactions of 2-naphthyl mesylate,
acetate, and carbamate, yields were substantially less than
that with pivalate 1A (entries 3ꢀ5). 2-Napthylmethyl ether
failedtoreact atall (entry 6). Inthese reactions, thestarting
material was largely recovered, although a trace amount of
naphthol was also observed in the case of the acetate and
carbamate.
Under our optimized conditions (Table 1, entry 10), a
number of disubstituted olefins can be formed by reaction of
naphthyl pivalate 1A and various olefin partners (Table 3).13
Styrenes with bulky aromatic groups were well tolerated
(entries 2, 3). Good yields were also obtained using
electron-poor and -rich styrenes (entries 4ꢀ8). Notably,
the nitrile functional group is unaffected by this transfor-
mation (entry 4). Further, selective activation of the
CꢀOPiv bond occurs in the presence of CꢀOMe bonds
(entry 6). Silyl ethers and amines are also tolerated under
(10) Reactions were conducted in 1-dram vials, capped with Teflon-
lined caps, and heated using aluminum heating blocks deep enough to
completely enclose the glass of the vial.
(11) Dppf has been used in Ni-catalyzed cross-couplings via activa-
tion of benzylic CꢀOMe bonds. See: (a) Taylor, B. L. H.; Swift, E. C.;
Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389. (b) Guan,
B.-T.; Xiang, S.-K.; Wang, B.-Q.; Sun, Z.-P.; Wang, Y.; Zhao, K.-Q.;
Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 3268.
(12) The Ni-catalyzed Heck reaction of this tosylate with an enol
ether was recently reported. See: Gøgsig, T. M.; Kleimark, J.; Lill,
S. O. N.; Korsager, S.; Lindhardt, A. T.; Norrby, P.-O.; Skrydstrup, T.
J. Am. Chem. Soc. 2012, 134, 443.
(13) Increasing the amount of K3PO4 to 1.5 equiv led to more
reproducible yields.
Org. Lett., Vol. 14, No. 5, 2012
1203

Table 2. Various Oxygen Functional Groupsa
Table 3. Scope of Olefin Partnera
entry
R
yield (%)b
1
2
3
4
5
6
Piv
Ts
99
55
26
29
25
0
Ms
Ac
C(O)NEt2
Me
a Conditions: Substrate (0.10 mmol), styrene (2a, 0.20 mmol, 2.0
equiv), Ni(cod)2 (0.010 mmol, 10 mol %), dppf (0.012 mmol, 12 mol %),
K3PO4 (0.10 mmol, 1.0 equiv), PhMe (0.25 mL, 0.4 M), 125 °C, 48 h.
b Determined by GC using dodecane as internal standard.
these reaction conditions (entries 7ꢀ8). R-Olefins can also
be used in this cross-coupling (entry 9). Although olefin
isomers of styrene 3Ai were observed as minor byproducts,
an 87% yield of the major isomer was isolated cleanly.
However, lower yields are observed with heteroaromatic
styrenes, such as 2- or 4-vinylpyridine (2-vinylpyridine
shown, entry 10). In these cases, remaining pivalate is
observed. R-Methylstyrene was reactive as an olefin part-
ner but resulted in a 1.6:1 mixture of olefin isomers, 1-(2-
naphthyl)-2-phenylpropene and 2-phenyl-3-(2-naphthyl)-
propene (entry 11). With 1,2-disubstituted olefins, such as
cyclohexene, only a trace amount of cross-coupling pro-
duct was observed, and pivalate 1A was largely recov-
ered (not shown). Electron-poor methyl vinyl ketone and
benzyl acrylate failed to react under these conditions.
Consistent with other Ni-catalyzed cross-couplings via
CꢀO bond activation,5a,e,8b we found that the reaction of
phenyl pivalate (1B) resulted in a lower yield than in the
case of naphthyl pivalate (1A) (Table 4, entry 1). Longer
reaction times were ineffective in substantially increasing
the yield of product 3Bb (entry 2), but increasing the
reaction temperature provided synthetically useful yields
(entries 3 and 4). Because of difficulties in purification
caused by using mesitylene as solvent, we ultimately chose
touse PhMe assolventand heatthese reactions at150°C in
sealed vials. This method enabled a 57% isolated yield of
stilbene 3Bb (entry 4).
a Conditions: Pivalate 1A (0.20 mmol), styrene (2, 0.40 mmol, 2.0
equiv), Ni(cod)2 (0.020 mmol, 10 mol %), dppf (0.024 mmol, 12 mol %),
K3PO4 (0.30 mmol, 1.5 equiv), PhMe (0.5 mL, 0.4 M), 125 °C, 48 h.
b Average isolated yield from duplicate experiments ((3%), unless
otherwise noted. c Combined yield of 1.6:1 mixture of 1-(2-naphthyl)-
2-phenylpropene (3Ak) and 2-phenyl-3-(2-naphthyl)propene (3Ak0).
Result of a single reaction.
Ni(0) for researchers with access to a glovebox, its instabil-
ity in air limits the utility of our method. However, we have
found that this Heck reaction can be set up on the bench by
using NiCl2 DME and zinc to form Ni(0) in situ (eq 1).14
3
Although the yields are somewhat diminished, this proce-
dure still provides synthetically useful yields of product
3Ab.
At this higher temperature, the Heck cross-couplings of
various aryl pivalates were accomplished in moderate to
good yields (Table 4). The CꢀOPiv bond could be selec-
tively activated in the presence of aryl ether bonds and
acetals (entries 6ꢀ8). Nitrile groups were also tolerated
(entry 9). However, pivalates with electron-rich substitu-
ents were sluggish in this reaction, resulting in a low yield
(entry 10). Finally, vinyl pivalates also underwent reaction
using these conditions (entry 12).
We hypothesize that the mechanism of this Heck reac-
tion follows the general mechanism of oxidative addition,
migratory insertion, and β-hydride elimination. However,
In contrast to cross-couplings with organometallic re-
agents, our olefins cannot reduce a Ni(II) precatalyst in
situ. Although Ni(cod)2 provides a convenient source of
(14) See Supporting Information for full experimental details.
1204
Org. Lett., Vol. 14, No. 5, 2012

aryl acetates and aryl carbamates, Liu and Garg have
shown that monophosphine nickel(0) complexes undergo
oxidative addition more readily than bisphosphine nickel-
(0).4d,6b Further, Liu was unable to computationally locate
a pathway for transmetalation of the coordinatively satu-
rated bisphosphine nickel arylacetate complex. Indeed, the
relatively high temperatures required to achieve the Heck
coupling are consistent with slower oxidative addition of a
bisphosphine nickel catalyst. The higher yields observed
with dppf then may be due to its ability to stabilize the
resting state of the nickel catalyst and/or to facilitate a
different step of the catalytic cycle. It is possible that a
bidentate phosphine promotes a cationic mechanism, in
which pivalate dissociates from the Ni(II) intermediate
after oxidative addition. Such a cationic Ni(II) species
would undergo faster olefin coordination and subsequent
migratory insertion than a neutral Ni(II) species. Use
of a monophosphine ligand would likely favor a neutral
Ni(II) intermediate, because the phosphine would dissoci-
ate instead of the more tightly bound pivalate.16 Studies
are underway to investigate this interesting observation
further.
Table 4. Scope of Arylpivalatea
As discussed above, we have developed the first CꢀC
cross-coupling of an aryl carboxylate with an olefin part-
ner. This Heck reaction enables aryl and vinyl pivalates to
be efficiently coupled with both styrenes and R-olefins,
providing facile access to 1,2-disubstituted olefin products
without generation of a halogenated waste stream or use of
triflate groups. Ongoing efforts in our labratory are direc-
ted toward expanding the scope of this useful trans-
formation and understanding how the Ni(dppf) catalyst
promotes this coupling.
Acknowledgment. Acknowledgement is made to the
Donors of the American Chemical Society Petroleum
Research Fund and the University of Delaware for sup-
port of this research. Acknowledgement is also made to
Dr. Shi Bai for assistance with NMR experiments. NMR
data were acquired at UD on instruments obtained with
the assistance of NSF funding (NSF MIR 0421224, NSF
CRIF MU CHE0840401).
a Conditions: Pivalate (1, 0.20 mmol), styrene (2, 0.40 mmol, 2.0
equiv), Ni(cod)2 (0.020 mmol, 10 mol %), dppf (0.024 mmol, 12 mol %),
K3PO4 (0.30 mmol, 1.5 equiv), PhMe (0.5 mL, 0.4 M), 150 °C, 48 h,
unless otherwise noted. b Average isolated yield from duplicate experi-
ments ((4%) unless otherwise noted. Numbers in parentheses are GC
yields. c Reaction conducted in mesitylene. d Result of
experiment.
a single
Supporting Information Available. Experimental pro-
cedures, characterization data, and spectra of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
we do not yet understand why a bisphosphine ligand
provides higher yields than a monophosphine ligand.15
Intheir computational studiesofSuzuki cross-couplingsof
(16) Lin, B.-L.; Liu, L.; Fu, Y.; Luo, S.-W.; Chen, Q.; Guo, Q.-X.
Organometallics 2004, 23, 2114.
(15) A bisphosphine ligand is also optimal in Itami’s cross-coupling
of azoles with aryl pivalates. See ref 9.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
1205