Palladium-catalyzed coupling of N-tosylhydrazones and β-bromostyrene derivatives: New approach to 2H-chromenes

Article abstract of DOI:10.1039/c4ob01979b

2H-Chromene is an important structural motif that exists in natural products and non-natural compounds possessing interesting biological activities. In this investigation, a highly efficient approach toward 2H-chromenes has been developed based on palladium-catalyzed coupling of N-tosylhydrazones and β-bromostyrenes. The mechanism of this reaction is proposed that involves the formation of vinyl palladium by carbene migratory insertion and the intramolecular nucleophilic substitution. This journal is

Full text of DOI:10.1039/c4ob01979b

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Biomolecular Chemistry
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Palladium-catalyzed coupling of N-tosyl-
hydrazones and β-bromostyrene derivatives:
Cite this: Org. Biomol. Chem., 2014,
12, 9333
new approach to 2H-chromenes†
Received 17th September 2014,
Accepted 1st October 2014
Yamu Xia,a,b Ying Xia,b Yan Zhangb and Jianbo Wang*b
DOI: 10.1039/c4ob01979b
www.rsc.org/obc
2H-Chromene is an important structural motif that exists in natural ment of new synthetic methods to 2H-chromene is highly
products and non-natural compounds possessing interesting bio- desirable.
logical activities. In this investigation, a highly efficient approach
On the other hand, since the pioneering work of Van
toward 2H-chromenes has been developed based on palladium- Vranken and co-workers,5,6 the metal-catalyzed reactions with
catalyzed coupling of N-tosylhydrazones and β-bromostyrenes. the carbene migratory insertion have emerged as a new type of
The mechanism of this reaction is proposed that involves the cross-coupling reactions for the construction of carbon–carbon
formation of vinyl palladium by carbene migratory insertion and and carbon–heteroatom bonds.7 Based on the migratory inser-
the intramolecular nucleophilic substitution.
tion process, cascade reactions have been designed to con-
struct complex molecular structures.7e In particular, the
π-allyllic palladium intermediate can be generated from
carbene migratory insertion, which is further incorporated
into a series of transformations.8 In principle, the π-allyllic pal-
ladium intermediate is generated in two ways: (a) through the
migration of a vinyl ligand from palladium to carbenic carbon;
(b) through the migration of the R′ group (mostly an aromatic
group) from palladium to vinyl carbenic carbon (Scheme 1).
The π-allyllic palladium intermediate thus generated is
trapped by a nucleophile, in either an intramolecular or an
intermolecular manner. In the case of intramolecular reaction,
various ring structures can be constructed efficiently.
In this context, Van Vranken and co-workers have reported
a series of three-component cascade reactions, which involves
π-allyl palladium species generated from palladium carbene
migratory insertion and subsequent nucleophilic addition.8d–f
The intramolecular reaction of this type has been successfully
applied in the construction of pyrrollidines and piperidines
(Scheme 2, a).8g Liang and co-workers have reported similar
cascade reactions for the synthesis of 1,2-dihydroquinoline
and dihydronaphthalene derivatives.8h,i It is noteworthy that in
these transformations, only nitrogen and carbon nucleophiles
have been employed to trap the η3-allyl palladium species.
Herein we report the exploration of using hydroxyl group as an
2H-Chromene is a characteristic molecular structure, and the
compounds based on this skeleton exhibit interesting and
diverse biological activities, including anti-inflammatory, anti-
oxidant, anti-tumour and antibacterial activity.1 Due to their
potential applications, the synthesis of 2H-chromenes has
attracted significant attention. The typical approach toward
2H-chromenes is based on the condensation of salicylaldehyde
derivatives with various olefins and ester derivatives in the
presence of a base or an acid.2 Recently, transition-metal-cata-
lyzed reactions have been explored in the synthesis of 2H-chro-
menes.3 For example, Aponick and co-workers reported a gold(I)-
catalyzed synthesis of 2H-chromenes through endo-cyclization
reaction of o-(1-hydroxyallyl)phenols, which are readily pre-
pared from salicylaldehydes.3b Stratakis and co-workers
reported the application of Au/TiO2 as a heterogeneous gold-
based catalyst to catalyze the selective cycloisomerisation of
aryl propargyl ethers to afford 2H-chromenes.3c Recently, de
Bruin and co-workers have developed an approach to 2H-chro-
menes that involves the [CoII(Por)]-catalyzed metalloradical
coupling-cyclization.4 Although many efforts have been
devoted to the synthesis of 2H-chromenes, the existing
approaches still suffer from drawbacks such as complicated
catalytic systems and low efficiency, therefore further develop-
aCollege and Chemical Engineering, Qingdao University of Science & Technology,
Qingdao 266042, China
bBeijing 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. E-mail: wangjb@pku.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob01979b
Scheme 1 π-Allyllic palladium intermediate generated from carbene
migratory insertion.
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Scheme 2 The palladium-catalyzed cascade reactions involving
carbene migratory insertion.
Table 1 Optimization of the reaction conditionsa
Scheme 3 The scope of β-bromostyrenes.
Yieldb
Entry Cat. (mol%)/L (mol%)
2
Base
T (°C) (%)
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2(5)
Pd(PPh3)2(OAc)2(5)
2a K2CO3
2a K2CO3
2a K2CO3
2a K3PO4
2a Cs2CO3
90
90
90
90
90
90
90
90
100
120
100
100
100
100
Trace
Trace
31
15
Trace
12
41
61
67
58
75
90
91
83
strates (2b and 2c) were examined. The yields could be
improved to 61% in the presence of the PCy3·HBF4 ligand with
2b as the substrate (entry 8). The reaction temperature has
only a marginal effect on the reaction (entries 9 and 10). Since
the N-tosylhydrazone (1a) was observed to undergo side reac-
tions, the increase of 1a led to the improvement of the yield
(entries 11 and 12). Notably, it was observed that the more
readily available E-(2-bromovinyl)benzene 2c could provide the
product with comparable yields (entries 13 and 14).
With the optimized conditions, we set out to investigate the
scope of the reaction (Schemes 3 and 4). First, β-bromostyrenes
2a–m with various substituents on the aromatic ring were
employed in the reaction with 1a. The reaction in general
afforded the corresponding products in moderate to good
yields. The effect of alkyl substituents was trivial (3b); however,
both the strong electron-withdrawing and -donating groups led
Pd2(dba)3·CHCl3(2.5)/PPh3(15)
Pd2(dba)3·CHCl3(2.5)/PPh3(15)
Pd2(dba)3·CHCl3(2.5)/PPh3(15)
Pd2(dba)3·CHCl3(2.5)/DPPP(15)c 2a K2CO3
Pd2(dba)3·CHCl3(2.5)/L1(15)d
Pd2(dba)3·CHCl3(2.5)/L1(15)
Pd2(dba)3·CHCl3(2.5)/L1(15)
Pd2(dba)3·CHCl3(2.5)/L1(15)
Pd2(dba)3·CHCl3(2.5)/L1(15)
Pd2(dba)3·CHCl3(2.5)/L1(15)
Pd2(dba)3·CHCl3(2.5)/L1(15)
Pd2(dba)3·CHCl3(2.5)/L1(15)
2a K2CO3
2b K2CO3
2b K2CO3
2b K2CO3
2b K2CO3
2b K2CO3
2c K2CO3
2c K2CO3
9
10
11e
12f
13f
14f
a All the reactions were carried out with 1a (0.20 mmol), 2 (0.20 mmol)
and base (3.0 equiv.) in dioxane (2 mL) for 12 h. b Yield of the isolated
product.
PCy3·HBF4. e The ratio of 1a : 2 is 1.5 : 1. f The ratio of 1a : 2 is 2.0 : 1.
c DPPP:
1,3-bis(diphenylphosphino)propane. d L1
=
oxygen nucleophile in this type of reaction. The reaction con- to slightly diminished yields (3c–l). It was observed that β-bro-
stitutes an efficient approach toward 2H-chromenes starting mostyrene with fluoro substituents gave the corresponding
with readily accessible salicyl N-tosylhydrazones.
products in moderate to good yields (3j, 3k). It is also note-
At the outset of the investigation, N-tosylhydrazone (1a) and worthy that the reaction with (Z)-2-(2-bromovinyl)thiophene as
2-halovinyl benzene (2a–c) were used as the substrates to opti- the substrate afforded the product in 92% yield (3m). In
mize the reactions (Table 1). After some initial experiments, 3a addition, some β-bromostyrenes with the α- or β-substituent as
could be obtained in 31% yield under the following con- substrates were examined, but the reaction yields were not
ditions: with 2a as the substrate, 90 °C, PPh3 as the ligand, satisfactory.
K2CO3 as the base and dioxane as the solvent (entry 3).
Next, the substrate scope of N-tosylhydrazone was studied.
Since the substrates and the ligands may significantly affect We found that N-tosylhydrazones with the electron-withdraw-
the reaction, phosphine ligands and other β-halostyrene sub- ing substituents on the aromatic ring, such as nitro, chloro
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forms 2H-chromene 3, with regeneration of the palladium(0)
catalyst.
In summary, we have developed a new approach to syn-
thesize 2H-chromenes. The reaction uses salicyl N-tosylhydra-
zones and β-bromostyrenes as the substrates. The reaction
involves oxidative addition of β-bromostyrene to Pd(0), Pd(II)
carbene formation and migratory insertion, and intramolecu-
lar nucleophilic substitution. The mild conditions and an
effective cascade method make this reaction potentially useful
for the synthesis of 2H-chromenes.
This project was supported by 973 Program (2012CB821600)
and NSFC of China (grant 21272010 and 21332002).
Notes and references
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Scheme 4 The scope of N-tosylhydrazones.
and bromo groups, did not afford the corresponding 2H-chro-
mene product. However, the N-tosylhydrazones bearing elec-
tron-donating substituents could give the corresponding 2H-
chromenes in moderate to good yields (Scheme 4). N-Tosylhy-
drazones with alkyl substitutions provided good yields (3n–r).
In the case of strong electron-donating substituent, such as
methoxy, the reaction resulted in diminished yields (3s–u).
Furthermore, the position of the methoxy substituent on the
aromatic ring could obviously affect the reaction.
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possible mechanism as shown in Scheme 5. First, the Pd(II)
intermediates A is formed by the oxidative addition of β-bromo-
styrene 2 to Pd(0) catalyst. The diazo compound, generated
in situ from the N-tosylhydrazone 1, is decomposed by Pd(II)
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