Pd-catalyzed three-component coupling of N-Tosylhydrazone, terminal alkyne, and Aryl halide

Article abstract of DOI:10.1021/ja105762n

A Pd-catalyzed three-component reaction of N-tosylhydrazone, terminal alkyne, and aryl halide follows a mechanism involving a sequence of Pd carbene migratory insertion-transmetalation-reductive elimination, leading to the formation of one sp²-sp³ C-C bond and one sp-sp ³ C-C bond.

Full text of DOI:10.1021/ja105762n

Published on Web 09/13/2010
Pd-Catalyzed Three-Component Coupling of N-Tosylhydrazone, Terminal
Alkyne, and Aryl Halide
Lei Zhou, Fei Ye, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, China
Received June 30, 2010; E-mail: wangjb@pku.edu.cn
metalation, is crucial for the reaction to proceed along the desired
pathway. In this context, we hypothesized that copper acetylide might
Abstract: A Pd-catalyzed three-component reaction of N-tosyl-
hydrazone, terminal alkyne, and aryl halide follows a mechanism
be a good candidate for this purpose. Herein, we wish to report a Pd-
involving a sequence of Pd carbene migratory insertion-trans-
catalyzed three-component coupling of N-tosylhydrazone, terminal
metalation-reductive elimination, leading to the formation of one
alkyne, and aryl halide, leading to the formation of two separate C-C
sp2-sp3 C-C bond and one sp-sp3 C-C bond.
bonds (one sp2-sp3 bond, one sp-sp3 bond6).
Initially, we studied the three-component reaction of N-tosyl-
Typical reactions of electron-deficient metal carbenes, such as Rh
carbene and Cu carbene, are C-H insertion, cyclopropanation, and
ylide generation.1 Cyclopropanation is the formation of two C-C
bonds between a carbenic carbon and a double bond of olefin.
However, the formation of two separate C-C bonds on a carbenic
carbon from two substrates will not be possible in conventional metal
carbene transformations, as restricted by their reaction pattern (eq 1).
hydrazone 1a, iodobenzene 2a′ (X ) I), and phenylacetylene 3a
with catalytic Pd2(dba)3 and CuI at 90 °C (Table 1, entry 1). An
anticipated competing process in such a reaction system is the direct
Sonogashira coupling reaction between 2a′ and 3a.7 Indeed, the
direct coupling product 5a was obtained in 55% yield. To our
delight, the desired three-component coupling product 4a was also
obtained, albeit in low yield (37%).
With the initial results, we proceeded to optimize the reaction
conditions. Slow addition of 3a with a syringe pump over a period
of 1 h failed to improve the reaction (entry 2). We conceived that
direct Sonogashira coupling could be attributed to slow formation
of Pd carbene, presumably due to the low concentration of a diazo
substrate which was generated in situ. To match the slow Pd carbene
formation, we switched the phenyl halide from iodide 2a′ to bromide
2a which was less reactive in the oxidative addition step. To our
delight, the yield of 4a was improved to 81% and the Sonogashira
coupling was reduced to 17% (entry 3). However, none of the
Recently, Pd-catalyzed cross-coupling of diazo compounds,
pioneered by Van Vranken, has been proven to be a reliable
methodology for the formation of C(sp2)-C(sp2) bonds.2-5 Fur-
thermore, Barluenga first employed N-tosylhydrazone in Pd-
catalyzed cross couplings, which significantly expanded the scope
of this type of reaction.3,4 In these transformations, the migratory
insertion of Pd carbene species a is suggested as the key step in
the mechanism, leading to intermediate b which is followed by ꢀ-H
elimination to afford olefin (Scheme 1). In 2001 Van Vranken and
co-workers reported a Pd-catalyzed three-component reaction of
trimethylsilyldiazomethane, aryliodide, and tributylphenyltin, af-
fording benzhydryl derivatives.2a Although the yields of three-
component coupling are rather low due to side reactions, this
seminal work indicates that the transmetalation from intermediate
b and thus the formation of two separate C-C bonds in a carbenic
center are indeed possible. More recently, the same group reported
a Pd carbene migratory insertion-carbopalladation sequence in the
intramolecular reaction, in which two C-C bonds were also formed
in a carbenic center.2e
Table 1. Optimization of Reaction Conditionsa
yield, %b
4a (5a)
entry
Pd/ligand
X )
solvent
1
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3
Pd2(dba)3/P(furyl)3
Pd2(dba)3/PPh3
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
Pd2(dba)3/Xphos
I
I
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
MeCN
THF
37 (55)
8 (85)
81 (17)
0 (21)
0 (39)
10 (63)
0 (70)
16 (29)
50 (23)
24 (57)
5 (78)
65 (26)
58 (40)
19 (33)
2c
3
Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
4
5
6
7
8d
9
Scheme 1. Formation of Two C-C Bonds on Metal Carbene
10
11
12e
13f
14g
toluene
toluene
toluene
a Unless otherwise noted, reaction conditions are as follows: 1a (0.2
mmol), 2 (1.1 equiv), 3a (1.1 equiv), Pd2(dba)3 (2.5 mol %), ligand (10
mol %), CuI (7.5 mol %), LiOBut (3.5 equiv), 90 °C for 1 h. b Yield
was determined by GC using dodecane as an internal standard. Yield of
5a was calculated based on 2. c 3a was added to the reaction mixture
over a 1 h period by using a syringe pump. d The reaction was carried
out in the absence of CuI. e 1a:2a:3a ) 1.0:1.2:1.5. f 1a:2a:3a )
1.0:1.5:1.5. g 1a:2a:3a ) 1.5:1.0:1.0.
The challenge in the development of an efficient sequence of
migratory insertion-transmetalation-reductive elimination lies in the
restraint of possible side reactions, such as overinsertion, direct
coupling, and ꢀ-H elimination. Obviously, a judicious choice of
reaction conditions, in particular a suitable R′M for efficient trans-
9
13590 J. AM. CHEM. SOC. 2010, 132, 13590–13591
10.1021/ja105762n  2010 American Chemical Society

C O M M U N I C A T I O N S
desired product was obtained when chlorobenzene 2a′′ was used
(entry 4). The ligand also plays an important role in the reaction
(entries 5-7). Use of Xphos as the ligand was essential for the
three-component coupling. CuI is also essential for the reaction
(entry 8). We noted that the reaction was significantly affected by
solvent, with toluene giving the best results for the three-component
coupling (entries 9-10). Finally, it was found that the reaction could
not be improved by adjusting the ratio of the substrates (entries
12-14).
intermediate D is generated by transmetalation of C with copper
acetylide, followed by reductive elimination to afford product 4
and to regenerate the palladium catalyst.
Scheme 2. Plausible Mechanism
With the optimized reaction conditions, we then studied the scope
of this reaction by using various N-tosylhydrazones, aryl bromides,
and terminal alkynes. As illustrated in Table 2, the three-component
cross coupling proceeds smoothly over a wide range of substrates with
moderate to good yields. For the aromatic bromide component, the
ortho substituent has a negative effect on the cross coupling (entries
5, 6). As for the terminal alkyne component, the reaction tolerates a
wide range of substituents and functional groups, except in the case
when there is an ester substituent, in which none of the desired product
was detected except a trace amount of direct Sonogashira coupling
byproduct (entry 16). Finally, the cross coupling seems not significantly
affected by the substituents on the aromatic moiety of the N-
tosylhydrazone component (entries 18-22).
In conclusion, we have developed a three-component coupling of
N-tosylhydrazones, terminal alkynes, and aryl halides Via a sequential
palladium carbene migratory insertion and reductive elimination
process, which forms two separate C-C bonds on a carbenic carbon.
This reaction provides a novel method for the synthesis of benzhydryl
acetylene derivatives from easily available starting materials.9 More
importantly, this study further demonstrates the possibility to incor-
porate Pd carbene migratory insertion with transmetalation of various
metal compounds. Investigation along this line is ongoing in our lab,
and the results will be reported in due course.
Table 2. Pd-Catalyzed Three-Component Coupling of Various
N-Tosylhydrazones, Terminal Alkynes, and Aryl Halidesa
Acknowledgment. The project was supported by the NSFC,
973 Program (No. 2009CB825300), GSK R&D China, and China
Postdoctoral Science Foundation.
entry
1, Ar )
2, Ar′ )
3, R )
yield, %b
Supporting Information Available: Additional mechanistic discus-
sion, experimental procedure, characterization data, and NMR spectra
for all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
m-tolyl
p-anisyl
p-F-C6H4
2-naphthyl
o-PhC6H4
2,6-Me2C6H3
Ph
Ph
Ph
Ph
Ph
Ph
4b, 72
4c, 72
4d, 84
4e, 62
4f, 51
4g, 21
4h, 64
4i, 63
4j, 66
4k, 62
4l, 56
4m, 47
4n, 59
4o, 73
4p, 51
N.R.c
References
Ph
Ph
Ph
Ph
p-tolyl
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p-ClC6H4
p-anisyl
p-CF3C6H4
2-(6-MeO)naph
PhCH2CH2
n-C4H9
TMS
CH2OTHP
CO2Et
3-thienyl
Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Ph
2-naphthyl
o-PhC6H4
2-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4q, 84
4r, 73
4s, 60
4t, 41
4u, 55
4v, 75
p-tolyl
3,4-(MeO)2-C6H3
3,4-Cl2C6H3
2-hexynlC6H4
p-tolyl
Ph
Ph
Ph
p-anisyl
3-thieny
a All the reactions were carried out with N-tosylhydrazone (0.2
mmol), aryl bromide (1.1 equiv), terminal alkyne (1.1 equiv) in the
presence of Pd2(dba)3 (2.5 mol %), Xphos (10 mol %), CuI (7.5 mol %),
and LiOBut in 0.8 mL of toluene at 90 °C for 1 h. b Isolated yield.
c N.R.: No reaction.
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A plausible mechanism is proposed as shown in Scheme 2.8 The
oxidative addition of Pd(0) to aryl bromide to afford intermediate
A, which may undergo a competing transmetalation with in situ
generated copper acetylide. Subsequently, reductive elimination
occurs to afford direct Sonogashira coupling product 5. Conversely,
a diazo substrate is generated in situ from N-tosylhydrazone in the
presence of base. Decomposition of the diazo compound by Pd(II)
species A leads to palladium carbene B. Migratory insertion of an
aryl group to the carbenic carbon gives intermediate C, from which
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