Communications
DOI: 10.1002/anie.200904033
Cross-Coupling
Palladium-Catalyzed Cross-Coupling of Aryl Halides Using
Organotitanium Nucleophiles**
Hang Wai Lee, Fuk Loi Lam, Chau Ming So, Chak Po Lau, Albert S. C. Chan, and
Fuk Yee Kwong*
[
15]
Palladium-catalyzed cross-coupling reactions constitute an
extremely versatile protocol in organic synthesis for the
connection of electrophilic to organometallic fragments
through the formation of either carbon–carbon or carbon–
limited scope. We report herein the first general palladium-
catalyzed cross-coupling of aryl titanium reagents with a
variety of aryl halides. In addition, we disclose here the use of
readily available aminophosphanes in the coupling of aryl
bromides, as well as the new indolyl ligands for the successful
coupling of aryl chlorides.
[1]
heteroatom bonds. During the past decade, enormous effort
[
2]
has been undertaken, especially in ligand design, to enhance
the capability of utilizing relatively inert electrophiles, such as
The palladium-catalyzed coupling of aryl bromides/chlor-
ides with aryl titanium nucleophiles has not yet been
reported. The feasibility of coupling aryl halides with aryl
titanium reagents was investigated by using a series of
[
3]
[4]
[5]
[6]
aryl chlorides, tosylates, mesylates, and pivalates, as
coupling partners. Yet, investigations on the development and
application of new nucleophilic partners in cross-coupling
2
2
[16]
reactions remain limited. The construction of C(sp )ÀC(sp )
indolylaminophosphanes. The most readily accessible ami-
bonds through the use of nucleophilic transmetalating agents,
nophosphanes, with either a diphenylphosphano or dicyclo-
hexylphosphano group (one step from commercially available
2-phenylindole), were initially employed in the study. Elec-
tronically neutral 5-bromo-m-xylene and sterically hindered
o-tolyltitanium derivative 2a were used as the model sub-
strates in our benchmark reaction (Table 1). In particular, we
chose the o-tolyl derivative (instead of phenyl) as the
prototypical substrate since the unsubstituted phenyl ring is
generally regarded as the substrate that undergoes cross-
coupling reactions easiest. We thus did not use the phenyl
[
7]
[8]
[9]
[10]
such as organotin, -boron, -zinc, -magnesium,
-sili-
[11]
[12]
con, and -aluminum, is well-known. However, there is
need for a versatile nucleophilic partner to realize the
potential benefits of these methodologies and to tackle
current difficulties in cross-coupling reactions. Such a nucle-
ophilic partner would allow the development of a protocol
that eliminates the need to add a solid inorganic base to the
reactions and would hence enable the effective application of
such reactions in microchannel reactors and flow systems.
[
13]
The pioneering studies by Hayashi and co-workers
demonstrated that MeTi(OiPr) and PhTi(OiPr) could be
3
3
Table 1: Initial screening of the palladium-catalyzed cross-coupling of
aryl bromide 1a with the aryl titanium nucleophilic partner 2a.
used for the methylation and phenylation, respectively, of
-naphthyl triflate. Knochel and co-workers also reported a
similar arylation using nickel complexes of N-heterocylic
[
a]
2
[14]
carbenes. However, a general palladium system suitable for
the reaction of aryl titanium nucleophiles with aryl halides is
not yet available. To our knowledge, there is only one
publication regarding the palladium-catalyzed coupling of an
aryl triflate with an organotitanium reagent, and this is only of
[
*] H. W. Lee, Dr. F. L. Lam, C. M. So, Prof. Dr. C. P. Lau,
Prof. Dr. A. S. C. Chan, Prof. Dr. F. Y. Kwong
Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis
and
[b]
Entry
Ligand
Solvent
T, t
Yield [%]
1
2
3
4
5
6
7
8
9
L1
L2
Ph3P
L2
L1
L1
L1
L1
L1
toluene
toluene
toluene
toluene
dioxane
THF
toluene
toluene
toluene
908C, 1 h
908C, 1 h
908C, 1 h
RT, 18 h
908C, 1 h
908C, 1 h
908C, 1 h
908C, 1 h
908C, 1 h
98
99
18
89
33
45
58
99
79
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Hung Hom, Kowloon, Hong Kong (Hong Kong)
Fax: (+852)2364-9932
E-mail: bcfyk@inet.polyu.edu.hk
[
[
[
c]
d]
e]
[
**] We thank the Research Grants Council of Hong Kong (CERG 2006:
PolyU5008/06P “Development and Exploration of New Versatile
Organotitanium Nucleophiles in Catalytic Carbon–Carbon Bond-
Forming and Related Reactions”) and UGC Areas of Excellence
Scheme (AoE/P-10/01) for financial support. F.L.L. acknowledges
the PolyU postdoctoral fellowship (G-YX1L).
[a] Reaction conditions: ArBr (0.2 mmol), Ar’Ti(OiPr) (0.3 mmol), Pd-
3
(OAc)2 (0.05 mol%, with respect to ArBr), L (0.1 mol%), solvent
(0.6 mL), under N for the specified time. [b] Calibrated GC yields were
2
reported using dodecane as the internal standard. [c] Pd/L=1:1.
[d] Pd/L=1:3. [e] Ar’Ti(OiPr) (0.2 mmol) was used.
3
7436
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7436 –7439