Pd-catalyzed C=C double-bond formation by coupling of N-tosylhydrazones with benzyl halides

Article abstract of DOI:10.1021/ol901876w

Pd-catalyzed reaction of N-tosylhydrazones with benzyl halides affords di- and trisubstituted olefins In high yields with excellent stereoselectivity. This coupling reaction Is supposed to proceed through a migratory insertion of Pd carbene species.

Full text of DOI:10.1021/ol901876w

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4732-4735
Pd-Catalyzed CdC Double-Bond
Formation by Coupling of
N-Tosylhydrazones with Benzyl Halides
Qing Xiao, Jian Ma, Yang Yang, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking UniVersity, Beijing 100871, China, and the State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, China
wangjb@pku.edu.cn
Received August 13, 2009
ABSTRACT
Pd-catalyzed reaction of N-tosylhydrazones with benzyl halides affords di- and trisubstituted olefins in high yields with excellent stereoselectivity.
This coupling reaction is supposed to proceed through a migratory insertion of Pd carbene species.
CdC double-bond formation is one of the most fundamental
transformations in synthetic organic chemistry. Among the
various methods for constructing CdC double bonds from
ketone and halide, the Wittig reaction and its modified
versions are the most applicable and efficient choices.1 In
recent decades, Pd-catalyzed reactions have received increas-
ing attention in C-C single bond formation.2,3 However, to
our knowledge, no example of a Pd-catalyzed cross-coupling
reaction has been reported in the literature which can
construct CdC double bonds directly, except the recent
reports which involve Pd carbene species (vide infra). In the
Pd-catalyzed cross-coupling of organometallic reagents with
halides or triflates, the mechanism follows a common
catalytic cycle that involves oxidative addition, transmeta-
lation, and reductive elimination. It is thus not possible with
this type of reaction to construct a CdC bond in conjunction
with the coupling process.
(1) For reviews, see: (a) Boutagy, J.; Thomas, R. Chem. ReV. 1974, 74,
87. (b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (c)
Kawashima, T.; Okazaki, R. Synlett 1996, 7, 600. (d) Rein, T.; Pedersen,
T. M. Synthesis 2002, 5, 579.
(2) For selected reviews, see: (a) Negishi, E.-I. Handbook of Organo-
palladium Chemistry for Organic Synthesis; Wiley-Interscience: New York,
2002. (b) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953. (c)
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (d) Tsuji, J.
Palladium Reagents and Catalysts, New PerspectiVes For the 21st Century,
2nd ed.; Wiley: Chichester, 2004. (e) de Meijere, A.; Diederich, F. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim,
2004. (f) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453. (g)
Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (h) Christmann, U.;
Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366. (i) Campeau, L.-C.; Fagnou,
K. Chem. Commun. 2006, 1253. (j) Roglans, A.; Pla-Quintana, A.; Moreno-
Man˜as, M. Chem. ReV. 2006, 106, 4622. (k) Reiser, O. Angew. Chem., Int.
Ed. 2006, 45, 2838. (l) Liebscher, J.; Yin, L. Chem. ReV. 2007, 107, 133.
(m) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834. (n)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442.
Recent reports on a Pd-catalyzed cross-coupling reaction
of R-diazocarbonyl compounds, in which the migratory
insertion of Pd carbene species is suggested as the key step
in the mechanism, have demonstrated such a possibility of
(3) For selected recent examples of the cross-coupling of benzyl halides
with organometallic reagents, see: (a) Crawforth, C. M.; Burling, S.;
Fairlamb, I. J. S.; Taylor, R. J. K.; Whitwood, A. C. Chem. Commun. 2003,
2194. (b) Molander, G. A.; Elia, M. D. J. Org. Chem. 2006, 71, 9198. (c)
Crawforth, C. M.; Fairlamb, I. J. S.; Kapdi, A. R.; Serrano, J. L.; Taylor,
R. J. K.; Sanchez, G. AdV. Synth. Catal. 2006, 348, 405. (d) Burns, M. J.;
Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor, R. J. K. Org. Lett.
2007, 9, 5397. (e) Ine´s, B.; Moreno, I.; SanMartin, R.; Dom´ınguez, E. J.
Org. Chem. 2008, 73, 8448
.
10.1021/ol901876w CCC: $40.75
Published on Web 09/24/2009
 2009 American Chemical Society

constructing CdC double bonds through Pd catalysis (Scheme
1).4 Van Vranken et al. first reported the Pd-catalyzed cross-
coupling of trimethylsilyldiazomethane with benzyl halides,
affording styrene derivatives in low to moderate yields.4a
More recently, Yu and co-workers reported a Pd-catalyzed
reaction of benzyl bromide and R-aryldiazoacetate.4i
Table 1. Conditions on Pd-Catalyzed Reaction of 1a and 2aa
entry cat. (mol %)/Lb (mol %) solvent
base
yieldc (%)
1
2
3
Pd(PPh3)4(5)
PhMe
PhMe
PhMe
DCE
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
28
53
80
75
47
72
25
12
trace
17
92
68
94
67
Scheme 1. Pd-Catalyzed CdC Bond Formation
Pd(PPh3)2Cl2(5)/L(10)
Pd(OAc)2(5)/L(20)
Pd(OAc)2(5)/L(20)
Pd(OAc)2(5)/L(20)
Pd(OAc)2(5)/L(20)
Pd(OAc)2(5)/L(20)
Pd(OAc)2(5)/L(20)
Pd(OAc)2(5)/L(20)
Pd(OAc)2(5)/L(20)
Pd2(dba)3(2.5)/L(20)
4
5d
6
THF
dioxane LiOtBu
7
8
9
10
11
12
13e
14e
15
16
PhMe
PhMe
PhMe
PhMe
PhMe
Cs2CO3
K2CO3
KOtBu
NaOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
In Yu’s reports, R-diazocarbonyl compounds,5 which are
relatively stable due to the presence of an electron-withdrawing
carbonyl group, serve as substrates. Diazo compounds without
an electron-withdrawing substituent are usually unstable and
thus difficult to handle. This significantly limits the scope of
the above-mentioned Pd-catalyzed CdC double-bond-forming
reaction. However, it has been well documented that unstable
diazo compounds can be generated in situ from N-tosylhydra-
zones or N-tosylhydrazone salts through the Bamford-
Stevens-Shapiro reaction.6,7 This procedure of generating a
diazo compound may be compatible to the Pd-catalyzed
reaction conditions. Indeed, Barluenga and co-workers have
recently reported the Pd-catalyzed cross-coupling reaction
of N-tosylhydrazones and aromatic halides.4d,e Encouraged
by those reports and in connection with our interest in this
field,4g,h,8 we report here the Pd-catalyzed cross-coupling
reaction of N-tosylhydrazones and benzyl halides which
affords olefins with excellent yields and stereoselectivity.
At the outset of this investigation, we used benzyl bromide
1a and diphenylmethylene tosylhydrazone 2a as the sub-
strates (Table 1). When 1 and 2a were catalyzed with
Pd(PPh3)4 in toluene in the presence of LiOtBu, the coupling
product triphenylethene 3a was isolated in 28% yield (entry
1). Encouraged by this initial result, we proceeded to
optimize the reaction. We were delighted to find that adding
P(2-furyl)3 as ligand could significantly improve the reaction
(entries 2 and 3). With Pd(OAc)2/P(2-furyl)3, we went on to
screen other reaction parameters. The reaction was found to
proceed more efficiently in a nonpolar solvent such as toluene
than in polar solvent (entries 3-6). The inorganic bases, such
as K2CO3 and Cs2CO3, afforded poor results (entries 7 and
8). Surprisingly, although KOtBu and NaOtBu are similar
to LiOtBu, they afforded little coupling products (entries 9
and 10). Several other palladium catalysts and the ratio of
substrates were then examined (entries 11-14). Pd2(dba)3
(2.5 mmol %)/P(2-furyl)3 (20 mmol %) and 1a/2a ) 1:1
led to the highest yield of 3a (entry 13). It is worth noting
that the ligand P(2-furyl)3 plays a very important role in the
reaction (entries 14 and 15). Without the ligand, only trace
coupling product could be detected (entry 15). Finally, a
control experiment showed that in the absence of palladium
catalysts no product 3a could be detected under otherwise
identical conditions (entry 16).
[Pd(C3H5)Cl]2(2.5)/L(20) PhMe
Pd2(dba)3(2.5)/L(20)
Pd2(dba)3(2.5)/L(8)
Pd2(dba)3(2.5)
None
PhMe
PhMe
PhMe
PhMe
trace
0
a The reactions were carried out in 0.3 mmol scale of 2a in 5.0 mL solvent.
Ratio of 1a to 2a is 1.2:1 if not otherwise indicated. b L ) P(2-furyl)3. c Isolated
yield. d The reaction was run at 66 °C. e Ratio of 1a to 2a is 1:1.
A series of benzyl bromides were then subjected to the
optimized reaction conditions with diphenylmethylene
tosylhydrazone 2a (Table 2).9 Benzyl bromide and chlo-
Table 2. Pd-Catalyzed Reaction of 1a-k with 2aa
entry
1, Ar
1a, Ph
X
3, yieldb (%)
1
2
3
4
5
6
7
8
Br
Cl
Br
Cl
Br
Br
Cl
Br
Br
Cl
Br
3a, 94
3a, 84
3b, 87
3b, 83
3c, 84
3d, 87
3d, 74
3e, 83
3f, 87
3f, 87
3g, 80
1b, Ph
1c, p-MeC6H4
1d, p-MeC6H4
1e, p-PhC6H4
1f, m-ClC6H4
1f, m-ClC6H4
1h, 2,4-Cl2C6H3
1i, p-NO2C6H4
1j, p-NO2C6H4
1k, 2-naphthyl
9c
10c
11d
a The reactions were carried out on a 0.3 mmol scale of 1a-k and 0.3
mmol of 2a in 5.0 mL of PhMe. b Isolated yield. c The reaction was run for
5 h with1.5 equiv of 2a. d The conversion of 1k was 68%.
ride are both effective substrates, although a slightly lower
yield was observed for chloride (entries 1 and 2). The
reaction with ortho-, meta-, and para-substituted benzyl
halides all proceeded efficiently (entries 3-10). The
reaction was found to be not notably affected by electronic
Org. Lett., Vol. 11, No. 20, 2009
4733

effects of the substituents of benzyl halides (entries 3-10),
while 1.5 equiv of 2a was needed and a longer reaction
time was required when the substituent was p-NO2 (entries
9 and 10). It is noteworthy that chloro substituents are
tolerated in the reaction conditions, which is advantageous
for further transformations with palladium catalysis (en-
tries 6-8). Finally, for 2-(bromomethyl)naphthalene 1k,
the reaction became sluggish with lower substrate conver-
sion (entry 11).
selectivity (entries 1-3 and 8-10). However, when the steric
hindrances were similar for the E and Z isomers, the E
selectivity diminished (entries 5 and 7). Notably, for the
tosylhydrazones generated from alkyl aldehydes or ketones,
the reactions could be completed in moderate yields (entries
6-9). The reaction also worked well with the tosylhydra-
zones derived from cinnamaldehyde, affording 1, 3-diene
products (entry 10).
Scheme 2. Mechanistic Rationale
Table 3. Pd-Catalyzed Reaction of 1a with 2b-ka
A plausible mechanism is proposed as shown in Scheme
2. The reaction is initiated by oxidative addition of Pd(0)
to benzyl halide to afford Pd(II) intermediate A. Diazo
compound G is generated in situ from N-tosylhydrazone
E with treatment of base. Decomposition of diazo
compound G by Pd(II) species A leads to palladium
carbene intermediate B. Migratory insertion of benzyl
group to the carbenic carbon gives intermediate from
which ꢀ-hydride elimination affords the olefins and
regenerates the catalyst with the aid of base.
In summary, we have reported the first palladium-
catalyzed cross-coupling reaction of N-tosylhydrazones
(4) (a) Greenman, K. L.; Carter, D. S.; Van Vranken, D. L. Tetrahedron
2001, 57, 5219. (b) Greenman, K. L.; Van Vranken, D. L. Tetrahedron
2005, 61, 6438. (c) Devine, S. K. J.; Van Vranken, D. L. Org. Lett. 2007,
9, 2047. (d) Barluenga, J.; Moriel, P.; Valde´s, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 5587. (e) Barluenga, J.; Toma´s-Gamasa, M.; Moriel, P.;
Aznar, F.; Valde´s, C. Chem.sEur. J. 2008, 14, 4792. (f) Devine, S. K. J.;
Van Vranken, D. L. Org. Lett. 2008, 10, 1909. (g) Chen, S.; Wang, J. Chem.
Commun. 2008, 4198. (h) Peng, C.; Wang, Y.; Wang, J. J. Am. Chem. Soc.
2008, 130, 1566. (i) Yu, W.-Y.; Tsoi, Y.-T.; Zhou, Z.; Chan, A. S. C. Org.
Lett. 2009, 11, 469. (j) Kudirka, R.; Devine, S. K. J.; Adams, C. S.; Van
Vranken, D. L. Angew. Chem., Int. Ed. 2009, 48, 3677.
a The reactions were carried out in 0.3 mmol scale of 1a and 0.3 mmol
of 2b-k in 5.0 mL of PhMe. b Isolated yield. c The ratio of 1:1 (Z/E)
determined by GC. d The reactions were run in refluxing PhMe. e The Z/E
(5) For comprehensive reviews, see: (a) Doyle, M. P.; McKervey, M. A.;
Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998. (b) Ye, T.; McKervey,
M. A. Chem. ReV. 1994, 94, 1091. (c) Zhang, Z.; Wang, J. Tetrahedron
2008, 64, 6577.
1
ratio is 1:2 as determined by H NMR of the crude product.
Next, we studied the scope of the reaction with various
tosylhydrazones (Table 3). A series of tosylhydrazones were
examined, and all gave the cross-coupling products in good
yields. In the cases where di- and trisubstituted olefins were
formed, the reaction only afforded the products with E
(6) (a) Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735.
(b) Shapiro, R. H. Org. React. 1976, 23, 405. (c) Adlington, R. M.; Barrett,
A. G. M. Acc. Chem. Res. 1983, 16, 55.
(7) Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem.
2005, 1479.
(8) Peng, C.; Cheng, J.; Wang, J. J. Am. Chem. Soc. 2007, 129, 8708.
4734
Org. Lett., Vol. 11, No. 20, 2009

with benzyl halides. This reaction represents a case of
constructing a CdC double bond by a Pd-catalyzed
coupling reaction. As outlined in Scheme 3, starting with
ketones and benzyl halides, a classic method of synthesiz-
ing aromatic substituted olefins involves (1) converting
the halides into Grignard or Gellman reagents, which add
to the carbonyl group and then followed by dehydration
(path a), and (2) converting benzyl halides into phosphine
ylide, followed by a Wittig reaction (path b). The reaction
reported in this paper represents an alternative way to
achieve such a transformation by converting the ketones
or aldehydes into N-tosylhydrazones, which are then
coupled with benzyl halides with Pd catalysis (path c).
of two coupling partners. Moreover, conversion of carbonyl
compounds into N-tosylhydrazones is very easy and straight-
forward. Thus, in addition to the conventional Grignard- and
Wittig-type approaches, this reaction provides an alternative
method to prepare various di- and trisubstituted olefins.
Mechanistically, this reaction again demonstrates the gen-
erality and importance of a migratory insertion process of
Pd carbene species, which will inspire further exploration
of these important intermediates.3,10
Acknowledgment. The project is generously supported
by Natural Science Foundation of China (Grant Nos.
20832002, 20772003, 20821062), National Basic Research
Program of China (973 Program, Grant No. 2009CB825300),
and the MOE of China (Cheung Kong Scholars Program).
Scheme 3
.
Different Pathways of Converting Ketones and
Benzyl Halides to Olefins
Supporting Information Available: Experimental pro-
cedure and characterization data. These materials are avail-
able free of charge via the Internet at http://pubs.acs.org.
OL901876W
(9) Typical experimental procedure for the Pd-catalyzed reaction of
N-tosylhydrazones with benzyl halides: Under a nitrogen atmosphere, to a
mixture of Pd2(dba)3 (7 mg, 0.075 mmol), LiOtBu (72 mg, 0.9 mmol), and
P(2-furyl)3 (14 mg, 0.06 mmol) in PhMe (5 mL) was added benzyl bromide
(1a, 51 mg, 0.3 mmol) and 1-(diphenylmethylene)-2-tosylhydrazone (2a,
105 mg, 0.3 mmol). The mixture was then stirred at 80 °C for 3 h. The
reaction was monitored through TLC. Solvent was removed in vacuo to
leave a residue which was purified by column chromatography to afford
pure 3a as a white solid (72 mg, 94%).
(10) (a) Danopoulos, A. A.; Tsoureas, N.; Green, J. C.; Hursthouse, M. B.
Chem. Commun. 2003, 756. (b) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-
Bardia, M.; Bonjoch, J. Organometallics 2004, 23, 1438. (c) Albe´niz, A. C.;
Espinet, P.; Manrique, R.; Pe´rez-Mateo, A. Chem.sEur. J. 2005, 11, 1565.
(d) Lo´pez-Alberca, M. P.; Manchen˜o, M. J.; Ferna´ndez, I.; Go´mez-Gallego,
M.; Sierra, M. A.; Torres, R. Org. Lett. 2007, 9, 1757.
The Pd-catalyzed reaction reported in this paper has the
advantages of mild reaction conditions and use of a 1:1 ratio
Org. Lett., Vol. 11, No. 20, 2009
4735