Pd-catalyzed Heck-type cascade reactions with N-tosyl hydrazones: An efficient way to alkenes via in situ generated alkylpalladium

Article abstract of DOI:10.1021/ol402210a

A palladium-catalyzed Heck-type cascade reaction of aryl halides and N-tosyl hydrazones is reported. The neopentylpalladium species, generated from an intramolecular Heck-type insertion reaction of aryl halides, could efficiently react with carbenes to fo

Full text of DOI:10.1021/ol402210a

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4814–4817
Pd-Catalyzed Heck-Type Cascade
Reactions with N‑Tosyl Hydrazones:
An Efficient Way to Alkenes via in Situ
Generated Alkylpalladium
Xianglei Liu, Xinna Ma, Yunze Huang, and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China,
96 Jinzhai Road, Hefei, Anhui 230026, People’s Republic of China
zhgu@ustc.edu.cn
Received August 4, 2013
ABSTRACT
A palladium-catalyzed Heck-type cascade reaction of aryl halides and N-tosyl hydrazones is reported. The neopentylpalladium species, generated
from an intramolecular Heck-type insertion reaction of aryl halides, could efficiently react with carbenes to form highly functionalized alkenes. The
synthesis of spiro compounds was also explored via a multiple Heck-type insertion reaction with N-tosyl hydrazone.
Since the discovery of transition-metal-catalyzed asym-
metric cyclopropanation of alkenes with diazo compounds
in the 1960s,1 various useful transformations involving
active metalÀcarbene intermediates have been discovered,
which played an important role in the revolution of
modern organic synthetic methods.2 In contrast to the
well-documented rhodium-, copper-, and ruthenium-
catalyzed reactions, palladium-catalyzed transformations
that involve Pd carbene intermediates so far have received
less attention. Studies indicated that the reactivity of palladiumÀ
carbene species are fairly different from that of the cor-
responding Rh(II) and Cu(I) compounds.3 Although
several decades ago Pd carbenes as active intermediates
were already proposed in some reactions of nondiazo
compounds,4 the Pd carbene migration/insertion process
was firstproposed by VanVrankenand co-workers in their
seminal report in the palladium-catalyzed reaction of
benzyl halides and (trimethylsilyl)diazomethane in 2001.5
Subsequently, contributions from the groups of Van
6
7
8
9
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Vranken, Barluenga and Valdes, Wang, and others
greatly enriched the chemistry of palladium-catalyzed
(5) Greenman, K. L.; Carter, D. S.; Van Vranken, D. L. Tetrahedron
2001, 57, 5219.
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Devine, S. K.; Van Vranken, D. L. Org. Lett. 2008, 10, 1909. (d)
Kudirka, R.; Devine, S. K. J.; Adams, C. S.; Van Vranken, D. L. Angew.
Chem., Int. Ed. 2009, 48, 3677. (e) Khanna, A.; Maung, C.; Johnson,
K. R.; Luong, T. T.; Van, Vranken, D. L. Org. Lett. 2012, 14, 3233. (f)
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From Cyclopropanes to Ylides; Wiley: New York, 1998, pp 163À220. (d)
Evans, P. A. Modern Rhodium-Catalyzed Organic Reactions; Wiley-
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r
10.1021/ol402210a
Published on Web 09/09/2013
2013 American Chemical Society

cross-coupling reactions with carbenes,10 especially the
introduction of N-tosyl hydrazones as carbene precursors
Scheme 1. Reaction Patterns of Pd Carbene Involved Alkene
Synthesis
ꢀ
by Barluenga and Valdes. N-Tosyl hydrazones now are
known as valuable and convenient synthons for carbenes
and are used frequently in both metal-catalyzed and metal-
free cross-coupling reactions.11 However, there are still
limited reaction patterns for the construction of CdC
double bonds from Pd carbenes: (1) the reaction of
benzyl/allyl halides and carbene precursors can deliver styrene
or 1,3-diene derivatives (Scheme 1a);5,6a,8a,b (2) the reac-
tion of aryl halides or terminal alkynes with carbene pre-
cursors bearing β-hydride can construct polysubstituted
alkenes (Scheme 1b);7,8dÀf,9iÀl (3) the reaction of vinyl
halides and carbene precursors can generate an (η3-allyl)-
palladium intermediate, which can be terminated with both
inter- or intramolecular nucleophiles (Scheme 1c).6bÀe
Thus, the exploration of new reaction patterns for Pd
carbene involved reactions is still important and necessary.
Even though significant attention has been paid to
N-tosyl hydrazones as carbene precursors in Pd-catalyzed
cross-coupling reactions over the past decade, examples of
the reactions between alkylpalladium and carbenes are
rare,9f which might be a new way to synthesize functiona-
lized alkenes. The well-developed intramolecular Heck-
type reaction provides a good platform to study the
reaction between carbene and alkylpalladium.12 Despite
the fact that Heck reaction based cascades are very well
known, the integration of the chemistry of a cascade Heck
reactionwithPd carbenesobtainedfrom diazo compounds
or tosyl hydrazones has rarely been explored.6f We rea-
soned that alkylpalladium species B, which was extensively
studied by Overman and co-workers in the control of
further chemoselective transformations,13 could be formed
efficiently via classical oxidative addition and insertion reac-
tions of A (Scheme 1d). Subsequently the reaction of B with
carbenes could deliver the functionalized alkene C via a Pd
carbene migration/insertion and β-hydride elimination process.
We began our initial studies with the readily available
acrylamide 1a14 and benzaldehyde derived N-tosyl hydra-
zone 2a. Delightfully, heating a mixture of 1a and 2.0 equiv
of 2a in the presence of 5 mol % Pd(OAc)2 and 15mol % of
tri(2-furyl)phosphine (TFP) in toluene gave the expected
product 3aa in 73% yield, and no corresponding Z isomer
was detected (Table 1, entry 1). Both THF and CH3CN are
good solvents, with the yields being 95% and 98%,
respectively (entries 2 and 3). However, it was found by
(8) (a) Chen, S.; Wang, J. Chem. Commun. 2008, 4198. (b) Xiao, Q.;
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J. Angew. Chem., Int. Ed. 2011, 50, 3510. (f) Zhou, L.; Ye, F.; Zhang, Y.;
Wang, J. Org. Lett. 2012, 14, 922.
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Angew. Chem., Int. Ed. 2002, 41, 2363. (b) Lopez-Alberca, M. P.;
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Mancheno, M. J.; Fernandez, I.; Gomez-Gallego, M.; Sierra, M. A.;
Torres, R. Org. Lett. 2007, 9, 1757. (c) Goll, J. M.; Fillion, E. Organo-
metallics 2008, 27, 3622. (d) Zhou, F.; Ding, K.; Cai, Q. Chem. Eur. J.
2011, 17, 12268. (e) Chen, Z.-S.; Duan, X.-H.; Wu, L.-Y.; Ali, S.; Ji,
K.-G.; Zhou, P.-X.; Liu, X.-Y.; Liang, Y.-M. Chem. Eur. J. 2011, 17,
6918. (f) Chen, H.; Huang, L.; Fu, W.; Liu, X.; Jiang, H. Chem. Eur. J.
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2012, 18, 10497. (g) Meana, I.; Albeniz, A. C.; Espinet, P. Organome-
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tallics 2012, 31, 5494. (h) Meana, I.; Toledo, A.; Albeniz, A. C.; Espinet,
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Hamze, A.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Org. Lett. 2010, 12,
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J. Org. Chem. 2013, 78, 445.
1
crude H NMR analysis that the reaction in CH3CN is
cleaner than that in THF, and the isolated product from
the reaction in THF was contaminated with small amounts
of uncharacterized byproducts. Triphenylphosphine (PPh3)
is found to be as efficient as TFP (entry 4), while rac-
BINAP and dppe greatly decrease the reaction rate and
the reaction becomes complicated with prolonged reac-
tion times (entries 5 and 6). In the absence of a palladium
source there was no conversion of 1a. The reaction gave
limited conversion of the iodide to the desired product
(10) For some reviews, see: (a) Zhang, Z.; Wang, J. Tetrahedron 2008,
64, 6577. (b) Franssen, N. M. G.; Walters, A. J. C.; Reek, J. N. H.; de
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J. ACS Catal. 2011, 1, 1621. (e) Zhang, Y.; Wang, J. Top. Curr. Chem.
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Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236.
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Zhou, L.; Shi, Y.; Xiao, Q.; Liu, Y.; Ye, F.; Zhang, Y.; Wang, J. Org.
Lett. 2011, 13, 968. (b) Zhao, X.; Wu, G.; Zhang, Y.; Wang, J. J. Am.
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Org. Lett., Vol. 15, No. 18, 2013
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along with a wide range of additional side products in the
absence of phosphine ligands.
Table 3. Substrate Scope of Organic Halidesa
Table 1. Optimization of Reaction Conditionsa
ligand
time
(h)
yield of
3aa (%)b
entry
(amt (mol %))
solvent
1
2
3
4
5
6
TFP (15)
PhMe
3
2
1
1
5
5
73
95c
98
98
37
31
TFP (15)
THF
TFP (15)
CH3CN
CH3CN
CH3CN
CH3CN
PPh3 (15)
rac-BINAP (7.5)
dppe (7.5)
a The reactions were conducted with a 0.15À0.20 mmol amount of 1a.
b Isolated yields. c The isolated product was contaminated with a small
amount of an uncharacterized compound.
Table 2. Substrate Scope of N-Tosyl Hydrazonesa
a The reactions were conducted with 0.15À0.20 mmol of 1; for details
see the Supporting Information. b Isolated yields. c The conversion is
90%, and the yield in parentheses is based on recovery of SM.
It was found that the scope with respect to the N-tosyl
hydrazones was expansive, allowing for efficient coupling
with 1a (Table 2). The reaction of aryl hydrazones with
ortho substituents on the phenyl ring, i.e., methyl and
methoxyl, gave the corresponding products in almost
quantitative yields (entries 1 and 2), even when the loading
a The reactions were conducted with 0.20 mmol of 1; for details see
the Supporting Information. b Isolated yields. c 1 mol % of Pd(OAc)2
was used. Hydrazone 2i was fully decomposed and 1a was recovered in
65% yield.
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Org. Lett., Vol. 15, No. 18, 2013

of palladium catalyst was decreased to 1 mol % (entry 3).
Halogen atoms, i.e. bromide and chloride, at ortho and
para positions of the N-tosyl hydrazones were compatible
with the reaction conditions (entries 4 and 5). Several other
functionalities in hydrazones were tolerated, including
p-methoxyl (2f), p-tert-butyl (2g), and ester (2h) (entries
6À8). It is worth noting that the efficiency of the reaction
greatly depended on the catalyst loading when 2i was used
as the substrate (entries 9 and 10). When 5 mol % of
Pd(OAc)2 was used, the reaction afforded the correspond-
ing product in 70% yield, while only a trace amount of
product was detected when the amount of Pd(OAc)2 was
decreased to 1 mol %. This observation is presumably due
to the unmatched rates of different steps in the catalytic
cycle: alkylpalladium formation, N-tosyl hydrazone de-
composition, Pd carbene migration/insertion, etc. The
reaction with 2k, a hydrazone derived from m-nitroben-
zaldehyde, afforded the product in 95% yield. This stands
in contrast with the observation of the reaction with 2j, a
hydrazone derived from p-nitrobenzaldehyde, which failed
to deliver appreciable amounts of product (entries 11 and
12). 2l,m, hydrazones derived from 2-furylaldehyde and
2-naphthaldehyde, could also smoothly react with 1a to
give the corresponding products in moderate to good
yields (entries 13 and 14).
As illustrated in Table 3, the generality of the reaction
was additionally explored by subjecting various organic
halides to the optimized reaction conditions. Aryl bromide
1b and p-methyl (1c)- and p-chloro-substituted (1d) iodoa-
niline derivatives efficiently reacted with 2a to give the
corresponding products in almost quantitative yields
(Table 3, entries 1À3). The reaction of N-benzyl amide
1e afforded alkene 3ea in 99% yield, while an amide
bearing a free NÀH bond failed to undergo this cross-
coupling reaction (entries 4 and 5). The reaction of 2-phe-
nylacrylamide 1gwas alsohighly efficient and delivered the
product in 97% yield (entry 6). In addition to acrylamides,
we were pleased to find that 1h,i were competent substrates
and the reaction furnished the corresponding heterocycles
in good yields (entries 7 and 8). The reaction proceeded
equally efficiently in the synthesis of a five-membered
carbocycle (entry 9). The malonate-derived substrate 1k
could also smoothly couple with N-tosyl hydrazones 2f,l to
give the coresponding alkenes in moderate yields (entries
10 and 11).
process, which has been well studied in classic Heck
reactions. Indeed, by the use of diene 1m, the reaction
could smoothly give the spiro compounds 3mf in 81% com-
bined yield, with a 1.2:1 diastereoselectivity (Scheme 2).
The stereochemistry of the products was confirmed by the
X-ray analysis of trans-3mf (see the Supporting Information).
Scheme 2. Reaction of 1l,m with N-Tosyl Hydrazones
It is notable that the reaction is scalable, with no impact
on the yield, as demonstrated by the reaction of 1.51 g (5.0
mmol) of 1a with 2a (2.0 equiv), affording the product in
96% yield (see the Supporting Information for details).
In conclusion we have developed a palladium-catalyzed
Heck-type cascade reaction of organic halides with N-tosyl
hydrazones. It is the first example of the reaction of
neopentylpalladium intermediates with carbenes to form
steric alkenes. Spiro compounds could also be synthesized
efficiently in one step via a multiple Heck-type insertion
reaction. This method provided a new route to the diver-
gent synthesis of functionalized alkenes and extended the
broad utility of N-tosyl hydrazones.
Acknowledgment. This work was financially supported
by NSFC (No. 21272221), the Recruitment Program of
Global Experts. We thank Prof. K. P. C. Vollhardt (UC
Berkeley) for helpful suggestions.
Supporting Information Available. Experimental pro-
cedures, crystallographic data and a CIF file for trans-
3mf, characterization data, and 1H and 13C NMR
spectra for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
The reaction of 1l, which bears N-allyl and R-methyla-
cryl moieties, forms 2-indolinone 3la predominantly in
good yield (Scheme 2). This method was also applied to
the synthesis of spiro compounds via a multiple-insertion
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 18, 2013
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