Simple (imidazol-2-ylidene)-Pd-acetate complexes as effective precatalysts for sterically hindered suzuki-miyaura couplings

Article abstract of DOI:10.1021/ol050472o

(Chemical Equation Presented) A simplified synthesis of N-heterocyclic carbene (NHC)Pd-carboxylate complexes and their activity in Suzuki-Miyaura cross-coupling reactions are described. Coupling of sterically hindered aryl and activated alkyl chlorides bearing β-hydrogens has been successfully achieved.

Full text of DOI:10.1021/ol050472o

ORGANIC
LETTERS
2
005
Vol. 7, No. 9
829-1832
Simple (Imidazol-2-ylidene)-Pd-Acetate
Complexes as Effective Precatalysts for
1
Sterically Hindered Suzuki
Couplings
−Miyaura
Rohit Singh, Mihai S. Viciu, Natalia Kramareva, Oscar Navarro, and
Steven P. Nolan*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
snolan@uno.edu
Received March 4, 2005
ABSTRACT
A simplified synthesis of N-heterocyclic carbene (NHC)Pd-carboxylate complexes and their activity in Suzuki−Miyaura cross-coupling reactions
are described. Coupling of sterically hindered aryl and activated alkyl chlorides bearing
â-hydrogens has been successfully achieved.
The versatility of the Suzuki-Miyaura reaction has greatly
pathway (Scheme 1). This undesired side reaction competes
with the transmetalation step, hindering a productive coupling
process.
1
progressed since its early reports. It serves as one of the
2
most useful cross-coupling tools in synthetic chemistry.
Remarkable progress in both volume of work and mecha-
nistic investigations has been achieved in recent years.
However, barring a few recent advances, the attempts to use
alkyl halides (especially chlorides) as electrophile partners
Scheme 1. Competing Pathways in Suzuki-Miyaura Coupling
3
have been largely unsuccessful. Moreover, examples of mild
reaction conditions are rare when the desirable coupling
products are sterically hindered di-ortho or tri-ortho substi-
tuted biaryls.4
,5
The major impediment in Suzuki-Miyaura coupling of
alkyl halides is the presence of a facile â-hydride elimination
(
1) (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992,
6
91-694. (b) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321. (c) Miyaura, N.;
Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513-519. (d) Miyaura,
N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437-3440.
Extensive studies by a number of groups have helped this
area take new strides. Elegant work by Fu has helped expand
(2) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
6
Chem. ReV. 2002, 102, 1359-1470. (b) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633-9695. (c) Miyaura, N. Top. Curr. Chem.
2
1
002, 219, 11-59. (d) Suzuki, A. J. J. Organomet. Chem. 1999, 576, 147-
68. (e) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(4) Room-temperature reactions: (a) Altenhoff, G.; Goddard, R.; Leh-
mann, C. W.; Glorius, F. Angew. Chem., Int. Ed. 2003, 42, 3690-3693.
(b) Navarro, O.; Kelly, R. A., III; Nolan, S. P. J. Am. Chem. Soc. 2003,
125, 16194-16195.
(3) (a) Cardenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-387. (b)
Luh, T.-Y.; Leung, M.-K.; Wong, K.-T Chem. ReV. 2000, 100, 3187-3204.
(c) Cardenas, D. J. Angew Chem., Int. Ed. 1999, 38, 3018-3020.
1
0.1021/ol050472o CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/26/2005

the scope of this reaction by including alkyl chlorides and
describe a simplified procedure for the synthesis of (NHC)-
Pd(OAc) complexes and Suzuki-Miyaura reaction involv-
ing coupling of activated, â-hydrogens containing C(sp )-
Cl with boronic acids. The system also allows for synthesis
of highly sterically hindered, di-ortho and tri-ortho substituted
biphenyls under mild conditions.
7
secondary alkyl bromides as substrates. The Suzuki-
2
3
3
Miyaura reactions utilizing C(sp )-chlorides reported so far
8
have been either with boranes as coupling partners or
catalyzed by phosphine ligands. However, both classes of
compounds suffer from drawbacks. Air sensitivity and
commercial unavailability of boranes increases the number
of steps required to perform the coupling reaction. The
boronic acids have been widely accepted as the more
convenient transmetalating agents for this reaction. Further-
more, toxic and pyrophoric phosphines can be replaced by
user-friendly N-heterocyclic carbenes (NHCs).9
We have improved upon our previously reported synthesis
1
4
2
of (NHC)Pd(OAc) complexes (Scheme 2).
Scheme 2. Synthesis of (IMes)Pd(OAc)
2
In previous studies, we have highlighted the use of
N-heterocyclic carbenes as efficient ligands in various cross-
10
coupling reactions including the Suzuki-Miyaura reaction.
In a recent communication, we reported the synthesis of
(
imidazol-2-ylidene)Pd(OAc)
2
complexes.1 The complexes
1,12
were found to be active catalysts for the hydroarylation of
alkynes.
To analyze the activity of this complex in mediating the
Suzuki-Miyaura reaction, coupling of phenylboronic acid
and 4-chlorotoluene was examined. The reaction proceeded
to furnish a 97% yield of the desired product in 1 h at room
In conjunction with extensive previous work with Pd-
(
OAc)
reaction,
OAc) complexes in this important transformation. We now
2
as the palladium source for the Suzuki-Miyaura
10c,13
we examine here the activity of (NHC)Pd-
temperature. Surprisingly, the IPr analogue, (IPr)Pd(OAc)
2
(
2
did not show appreciable formation of coupling product at
room temperature. However, on raising the temperature 40
°C, it provided quantitative yield in 45 min. To circumvent
the inconvenience of previously reported slow addition of
(
5) Harsh conditions for sterically hindered products: (a) Walker, S. D.;
Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
004, 43, 1871-1876. (b) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald,
2
S. L. J. Am. Chem. Soc. 2002, 124, 1162-1163. (c) Feuerstein, M.; Doucet,
H.; Santelli, M. Tetrahedron Lett. 2001, 42, 6667-6670. (d) Griffiths, C.;
Leadbeater, N. E. Tetrahedron Lett. 2000, 41, 2487-2490. (e) Wolfe, J.
P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
4
b
halides, the reactions were tested with a normal rate of
addition of the halide substrate (for experimental details see
Supporting Information). No formation of dehalogenation
byproducts rendered the slow-addition protocol obsolete.
Our previous work emphasizing the important role played
by the solvent in the reaction system prompted us to screen
various alcohols as solvents. Screening of alcohols indicated
that isopropanol (IPA) was the best solvent for these
1
21, 9550-9561.
(6) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, published ASAP March 8, 2005. (b) Barder, T. E.;
Buchwald, S. L. Org. Lett. 2004 6, 2649-2652. (c) Nguyen, H. N.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818-11819. (d)
Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002,
6
7, 5553-5566.
7) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341.
b) For use of alkyl halides in the Stille reaction, see: Tang, H.; Menzel,
(
1
5
(
systems. Use of technical grade IPA without prior drying
renders this protocol quite practical and amenable to large
scale synthesis.
K.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5079-5082. (c) For Suzuki
cross-coupling of â-hydrogen-containing tosylates, see: Netherton, M. R.;
Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910-3912. (d) Kirchoff, J.
H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945-1947. (e)
Coupling of boronic acids with alkyl bromides: Kirchoff, J. H.; Netherton,
J. H.; Hills, I. D. Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662-13663.
To increase the scope of the reaction, various bases were
1
6
also screened. In general, alkoxide bases yielded the best
results at room temperature. Milder bases such as Cs CO
and K PO performed moderately well (see Supporting
Information).
(
2
f) Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc.
001, 123, 10099-10100. (g) Littke, A. F.; Dai, C.; Fu G. C. J. Am. Chem.
Soc. 2000, 122, 4020-
028.
8) During preparation of this manuscript, Capretta et al. reported Suzuki-
2
3
3
4
4
(
3
As mentioned earlier, C(sp )-chlorides suffer from poor
activity in Suzuki-Miyaura coupling. Apart from difficulty
in the transmetalation step, the low reactivity of chlorides
in this reaction is attributable in part to the strength of the
3
Miyaura coupling of C(sp )-Cl with boronic acids: Brenstrum, T.; Gerristma,
D. A.; Adjabeng, G. M.; Frampton, C. S.; Britten, J.; Rabertson, A. J.;
Mcnulty, J.; Capretta, A. J. Org. Chem. 2004, 69, 7635-7639.
(
9) (a) Gstottmayr, C. W. K.; Bohm, V. P. W.; Herdtweck, E.; Grosche,
M.; Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363-1365. (b)
3
3
17
For the first application of imidazole salts in sp -sp Suzuki coupling, see:
Arensten, K.; Caddick, S.; Cloke, F. G. N.; Herring, A. P.; Hitchcock, P.
B. Tetrahedron Lett. 2004, 45, 3511-3515.
C-Cl bond. However, recently a few systems that allow
8,18
oxidative addition of alkyl chlorides have been reported.
(
10) (a) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. J. Org. Chem.
2
004, 69, 3173-3180. (b) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang,
C.; Trudell, M. L.; Nolan, S. P. Organometallics 2002, 21, 2866-2873.
c) Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001, 3, 1077-
080.
11) Viciu, M. S.; Stevens, E. D.; Peterson, J. L.; Nolan, S. P.
Organometallics 2004, 23, 3752-3755.
12) For other examples of (NHC)-palladium acetate systems, see: (a)
Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.; Sigman, M. S. J. Org. Chem.
004, published ASAP December 30, 2004. (b) Mueller, J. A.; Goller, C.
(13) For a few recent examples, see: (a) Itoh, T.; Hirai, K.; Tomioka,
H. J. Am. Chem. Soc. 2004, 126, 1130-1140. (b) Wei, H.; Sudini, R.; Yin,
H. Org. Process Res. DeV. 2004, 8, 955-957. (c) Barder, T. E.; Buchwald,
S. L. Org. Lett. 2003, 6, 2649-2652. (d) Andrus, M. B.; Song, C. Org.
Lett. 2001, 3, 3761-3764.
(14) Synthesis of (IMes)Pd(OAc)2: equimolar solutions of recrystallized
Pd(OAc)2 and IMes in hexanes are prepared. The solutions are mixed and
allowed to stir for 6 h at room temperature. The insoluble product is filtered
and washed with hexanes. See Supporting Information for details.
(15) For screening of solvents (Table 4) see Supporting Information.
(16) For detailed table of base screening (Table 5) and discussion see
Supporting Information.
(
1
(
(
2
P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724-9734. (c) Konnick,
M. M.; Guzei, I. A.; Stahl S. S. J. Am. Chem. Soc. 2004, 126, 10212-
1
0213.
1830
Org. Lett., Vol. 7, No. 9, 2005

Our desire to contribute to solving the problem of coupling
chloride substrates with â-hydrogens led us to explore this
aspect in Suzuki-Miyaura coupling.
Scheme 3. Competing Pathways in Suzuki-Miyaura Coupling
of Allylic Substrates
3
In this regard, our efforts with unactivated C(sp ) chlorides
such as lauryl and hexyl chloride did not result in the desired
coupling products. In these attempts, formation of dehalo-
genation products was observed, indicating a problem at the
transmetalation step rather than an unachievable oxidative
addition of the alkyl chloride to the palladium center.
3
However, reactions of activated C(sp )-chlorides (allylic
and benzylic) proceeded to give excellent yields of coupling
products despite the presence of â-hydrogens in the allylic
substrates (Table 1).
Table 1. Screening of Activated C(sp )-Chloridesa
3
electron-withdrawing (entries 9 and 10, Table 2) groups
containing chlorides. Formation of 2-phenylpyridine and
3
-phenylpyridine (entries 4 and 5, Table 2) demonstrated
compatibility of heteroaromatic aryl chlorides in the coupling
process.
Synthesis of sterically hindered products was also achieved
using this system. Whereas preparation of di-ortho biphenyls
proceeded at room temperature, the tri-ortho biphenyls
Table 2. Substrate Screeninga
a
Reaction conditions: 1 mol % of (IMes)Pd(OAc)2, 1 mmol of halide,
t
b
1
.1 mmol of phenylboronic acid, 1.2 mmol of KO Bu, 2 mL of IPA. GC
yield (isolated yield), average of two runs. Unidentified mixture of
products.
c
Conceivably, for allylic substrates, the transmetalation step
is more favored relative to the â-hydride elimination, which
if favored would lead to formation of allenes (Scheme 3).
Hence the final outcome is the coupling of the substrates
rather than dehalogenation of the chlorides.
As mentioned earlier, boronic acids serve as excellent
transmetalating agents. To test the limits of compatibility of
various functionalities using our protocol, various boronic
acids were tested for activity. Excellent yields were obtained
in most cases, including reactions leading to formation of
ortho-substituted products (entries 2, 3, and 8, Table 2).
Functional group variance on the halides was also studied
(entries 4-10, Table 2). We were able to achieve coupling
of electron-donating (entries 6-8, Table 2) as well as
(
17) The stronger C-Cl bond as compared to C-Br and C-I in alkyl
halides makes the alkyl chlorides more resistant to oxidative addition.
Initially, only the use of vinyl or aromatic substrates allowed for the use of
chlorides in this reaction. (Bond-dissociation energy values: CH3-Cl )
2
27 kcal/mol, CH3-Br ) 219 kcal/mol, CH3-I ) 212 kcal/mol, CH2d
a
CH-Cl ) 207 kcal/mol, Ph-Cl ) 219 kcal/mol). Morrison, R. T.; Boyd,
Reaction conditions:1 mol % of (IMes)Pd(OAc)2, 1 mmol of halide,
t
b
R. N. Organic Chemistry, 6th ed.; Prentice Hall: New York, 1996; p 22.
1.1 mmol of boronic acid, 1.2 mmol of KO Bu, 2 mL of IPA. GC yield
(isolated yield), average of two runs. c T ) 40 °C
(
18) Fu has reported Suzuki-Miyaura coupling of alkyl chlorides and
alkyl boranes in a palladium-phosphine system (See ref 7d).
Org. Lett., Vol. 7, No. 9, 2005
1831

required temperature of 40 °C and proceeded in excellent
yields using (IPr)Pd(OAc) as the catalyst (compare entries
and 6, Table 3).
molecule of acetone and acetic acid. This could finally
generate the required NHC-Pd(0) species available for
oxidative addition of the halide substrate.
2
5
Scheme 4. Proposed Activation of Catalyst
Table 3. Synthesis of Di- and Tri-Ortho Substituted Biarylsa
In summary, we have described a convenient synthetic
protocol for preparation of imidazol-2-ylidene-based pal-
ladium acetate complexes. We have established these com-
plexes as efficient mediators of Suzuki-Miyaura coupling.
A broad spectrum of parameters has been surveyed, optimiz-
ing reaction conditions to a protocol that is user-friendly and
2
0
environmentally benign. . The protocol has been used to
3
couple â-hydrogen-containing activated C(sp )-chlorides with
boronic acids, providing an alternative to the Friedel-Crafts
2
1
reaction for synthesis of allylic aromatics. Sterically
hindered substrates have also been coupled using mild
conditions. Ongoing studies are directed toward further
a
Reaction conditions: 1 mmol of halide, 1.1 mmol of boronic acid, 1.2
t
b
mmol of KO Bu, 2 mL of IPA. Method A: 1 mol % of (IMes)Pd(OAc)2,
rt. Method B: 1 mol % of (IPr)Pd(OAc)2, 40 °C. GC yield (isolated yields),
average of two runs. Unidentified mixture of products.
c
22
expanding the scope of these reactions.
d
Acknowledgment. The National Science Foundation is
gratefully acknowledged for financial support of this work
and Umicore AG is gratefully acknowledged for the gift of
A pathway for the activation of the catalyst is proposed
Scheme 4). Initial deprotonation of IPA by the base (KO Bu)
2
Pd(OAc) .
t
(
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
can generate an isopropoxide anion that can attack the
NHC)Pd(OAc) complex. Analogous to previously reported
(
2
â-hydride elimination from a palladium coordinated isopro-
poxide, formation of a Pd-hydride species with elimination
OL050472O
4b
of a molecule of acetone can be envisaged. Next, elimina-
tion of acetic acid from H-Pd(OAc) can generate a (NHC)-
(20) Palladium loadings have been reduced to 0.01 mmol, technical grade
2
solvents are used, base loading has been reduced to 1.2 equiv, presence of
additives (such as TBAB) is not required, slow addition of halide substrate
is not required and excellent yields can be obtained at room temperature.
Pd(OAc) species. Sigman has previously proposed this type
of pathway in the oxidation of alcohols.19 The monoacetate
species, (NHC)Pd(OAc), can then undergo a second isopro-
poxide anion attack, with subsequent elimination of a
(
21) (a) Moreno-Manas, M.; Pajuelo, F.; Pleixats, R. J. Org. Chem. 1995,
0, 2396-2397. (b) Chowdhury, S.; Georghiou, P. E. Tetrahedron Lett.
1999, 40, 7599-7603. (c) Botella, L.; Najera, C. J. Organomet. Chem. 2002,
63, 46-57.
22) Couplings of unactivated C(sp )-chlorides (lauryl chloride, hexyl
6
6
3
(
(
19) Jensen, D. R.; Schultz, M. J.; Mueller, J. A.; Sigman, M. S. Angew.
chloride) and secondary bromides (cyclohexyl bromide) with boronic acids
did not furnish the desired product.
Chem., Int. Ed. 2003, 42, 3810-3813.
1832
Org. Lett., Vol. 7, No. 9, 2005