Room-temperature palladium-catalyzed direct 2-alkenylation of azole derivatives with alkenyl bromides

Article abstract of DOI:10.1016/j.tetlet.2018.11.058

Pd-catalyzed direct C2-alkenylation of azole derivatives proceeds efficiently under mild conditions, and the reaction of substituted benzoxazoles, oxazole and benzothiazole occurred even at room temperature. The substrate scope of the reaction was turned out to include mono-, di- and trisubstituted alkenyl bromides. To validate the scalability of this method, 5-Methyl-2-(prop-1-en-2-yl)benzoxazole (3c) was prepared on one-gram scale at room temperature.

Full text of DOI:10.1016/j.tetlet.2018.11.058

Accepted Manuscript
Room-temperature palladium-catalyzed direct 2-alkenylation of azole deriva-
tives with alkenyl bromides
Yun-Xin Yao, Dong-Mei Fang, Feng Gao, Xiao-Xia Liang
PII:
S0040-4039(18)31405-9
https://doi.org/10.1016/j.tetlet.2018.11.058
TETL 50443
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 October 2018
21 November 2018
22 November 2018
Please cite this article as: Yao, Y-X., Fang, D-M., Gao, F., Liang, X-X., Room-temperature palladium-catalyzed
direct 2-alkenylation of azole derivatives with alkenyl bromides, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.11.058
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Graphical Abstract

1
Tetrahedron Letters
Room-temperature palladium-catalyzed direct 2-alkenylation of azole derivatives with
alkenyl bromides
Yun-Xin Yaoa,b, Dong-Mei Fangc, Feng Gaob,*, and Xiao-Xia Lianga,
a Agronomy College, Sichuan Agriculture University, Chengdu 611130, China
b School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
c Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pd-catalyzed direct C2-alkenylation of azole derivatives proceeds efficiently under mild
conditions, and the reaction of substituted benzoxazoles, oxazole and benzothiazole occurred
even at room temperature. The substrate scope of the reaction was turned out to include mono-,
di- and trisubstituted alkenyl bromides. To validate the scalability of this method, 5-Methyl-2-
(prop-1-en-2-yl)benzoxazole (3c) was prepared on one-gram scale at room temperature.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Azole
Alkenylation
Palladium-catalysis
NiXantphos
Room-temperature
Azoles are found in a myriad of natural products and bioactive
molecules.1-6 The therapeutic potential of azole scaffold has
pushed it to the forefront of metal-catalyzed development. There
are diverse direct C2-functionalizations of benzene-fused
derivatives, such as arylation,7-12 and other transformations.13-17
Of these reactions, the most widely accepted is arylation, while
much less attention has been given to alkenylation. Azole
derivatives bearing alkenyl substituents at the 2-position are
widely used in numerous organic functional materials, such as
liquid crystals and fluorescent agents.18-24 Therefore, there is a
demand for metal-catalyzed methodologies to efficiently
synthesize C2-alkenylated azole derivatives.
Efforts have been devoted to method development of the
alkenylation of benzo-fused azole derivatives. For instance,
several strategies have been established to synthesize
heterocyclic compounds in the presence of a C2-alkenyl group,
1) The metal-catalyzed coupling of heterocycles with alkenyl
halides (Figure 1 A.);25-37 2) The intra- and intermolecular
cyclization;38-40 3)The Cu-catalyzed coupling between
be successfully achieved by employing cyclization38-40 or direct
C-H alkenylation with alkenes.43,44 Among these works, Huang
and co-workers used C-H alkenylation to construct caffeine
scaffolds with C2-E-alkenyl constitutes.43 These existing
strategies employing copper (Cu), allyl halides or alkenes can
compensate shortcoming of coupling between heterocycles and
alkenyl halides, but they are still limited in substrate scope.
41, 42
heterocyclic rings and allyl halides;
4) The direct C-H
alkenylation using inactive alkenes. 43, 44
Despite the commercial availability of a wide range of allyl
halides that contributes to explore the scope of the reaction, these
direct functionalization reactions were restricted to particular
benzoheterocyclic compounds.41,42 Other groups have
demonstrated that the synthesis of C2-E-alkenylated azoles can
———
 Corresponding author. Tel./Fax: +86-028-87603202; e-mail: gaof@swjtu.edu.cn (F. G.); xiaoxialiang@sicau.edu.cn (X.-X. L.)

2
Tetrahedron
The C2-alkenylation of a variety of azole-based heterocycles
was achieved using alkenyl halides, and the synthesis of azole
heterocycle with triphenylvinyl group was successfully
there were slight increases in yields when organic and inorganic
bases (t-BuOK and KOH) were used (Entries 3 and 4). When t-
BuONa was used in the reaction, 56 per cent of yield could
significantly be obtained (Entry 2). A solvent screening revealed
that the reaction became less efficient in cyclopentyl methyl ether
(CPME), 2-methyltetrahydrofuran (2-Me-THF) and 1, 4-dioxane
(Entries 6, 8 and 9). The uses of both THF and 1, 2-
dimethoxyethane (DME) led to moderate yields (56% and 58%)
(Entries 2 and 7). When the reaction temperature was reduced to
room temperature, the assay yield slightly dropped to 52% (Entry
10). To get an increase in yield of product, the Pd loading was
given a rise to 5 mol% (Entry 11). Then, the reactions were
catalyzed with different palladium sources (Pd(OAc)2, Pd(dba)2
and Pd2(dba)3). During ensuing investigation on the effect of
catalysts, a mixture of 1a and 2a was treated with same catalytic
amount (5 mol% Pd loading) and t-BuONa and THF were
employed as parts of the condition. Among these palladium
sources, Pd(OAc)2 and Pd(dba)2 performed less efficient, so
Pd2(dba)3 was employed as the palladium catalyst in following
studies. According to previous study on the effect of Pd loading
(Entry 11), its amount was increased to 10 mol% and time was
extended to 24 hours, which the highest yield of the product was
obtained in 88% isolated yield (Entry 14). Eventually, the
conditions in entry 14 (Table 1) were identified as the best
condition.
a
performed using this strategy.25-37 The metal-catalyzed
alkenylation with alkeny halides is still the major strategy for
synthesis of C2-alkenylated azole derivatives. However, these
protocols all require high temperature (over 100℃) where low-
boiling-point and temperature sensitive alkenyl halides are
restricted. Under some high-temperature conditions, alkenyl
reagents were merely used with the help of autoclave, making
it inappropriate to scale up. Besides, reactions performed in high
boiling solvents, such as DMF,26 are complicated in product
isolation. Thus, the development of general and mild catalyst
systems for this type of transformation is strongly desired.
Given the high temperature for metal-catalyzed direct 2-
alkenylation of azole heterocycles, in combination with the
importance of these compounds, room-temperature palladium-
catalyzed direct 2-alkenylation of azole derivatives with alkenyl
bromides is reported here, aided by the highly active Nixantphos-
based palladium catalysts in our previous work.45 Also, as a part
of our continuing interest in the synthesis of heterocycles,46
herein we synthesized various C2-alkenylated azole heterocycles,
and all reactions were carried out without the use of autoclave
and the room temperature was employed for all reactions
involving liquid reagents.
With a favorable reaction condition in hand (Entry 14), the
scopes of the alkenylation of a series of benzoxazole derivatives,
oxazole and benzothiazole with alkenyl bromides were explored.
Firstly, we investigated the reaction scope of this Pd/NiXantphos
catalytic system by employing three alkenyl bromides, 2-
bromoprop-1-ene (2a), 2-bromobut-1-ene (2b) and 1-bromo-2-
methylprop-1-ene (2c). After couplings of benzoxazole and these
alkenyl bromides, using α-substituted alkenyl bromides including
2a and 2b contributed to give 88% and 89% yields of the
corresponding products (3a and 3b), but the process using 1-
bromo-2-methylprop-1-ene (2c) was performed less efficient in a
yield of 70% (3h). Subsequently, the couplings between several
substituted benzoxazole derivatives 1b-1f and α-substituted
alkenyl bromide 2a were investigated. Benzoxazoles bearing a
methyl or methoxy group at the 5-position of the phenyl ring
gave the corresponding products 3c and 3d in good yields (86%
and 84%). The halide-substituted benzoxazoles were employed to
test the effects of functional groups on the catalytic system. As
the halide groups were at the 5- or 6-position of the phenyl rings,
the yields declined to different extents. Among three halide
groups, bromine group led to an obvious decrease of yield at 66%
(3g). Benzothiazole was also subjected to the direct alkenylation,
but benzothiazole with 2a and 2c were apparently coupled less
efficiently (3k and 3l), compared with benzoxazole and
corresponding alkenyl bromides. The direct alkenylation of
oxazole with 2-bromo-1H-indene (2d) was also explored at room
temperature, and found that it gave 3j in 63% without the
presence of any dialkenylated product. In order to demonstrate
the potential of scaling up this alkenylation, the reaction of 1b
and 2a was run on a 1.2 g scale under the optimal conditions for
24 hours, providing 3c in 86% isolated yield. But several
reactions were much slower under 25 ℃ , when the C2-
alkenylations between one benzoxazole and N-substituted
benzimidazoles with alkenyl bromides were conducted (Table 2).
Increasing temperature could be an effective approach to this
problem. According to another good result of the solvent
screening in Table 1 (Entry 7), solvent was replaced to DME. As
the temperature from 25 to 70℃,there were obvious increases in
the yields of 3i and 3m (67% and 61%). The reaction of N-
benzyl-benzimidazole was less effective than that of N-methyl-
Table 1. Optimization of direct 2-alkenylation of
benzoxazoles 1a with 2-bromoprop-1-ene 2aa
Entry Pd source
Base
Solvent Pd/L (mol Tem.
Yieldb
(%)
%)
(
)
℃
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
t-BuOLi THF
t-BuONa THF
t-BuOK THF
1/1.5
65
65
65
65
65
65
65
65
29
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
56
35
KOH
THF
40
Cs2CO3 THF
t-BuONa CPME
t-BuONa DME
Trace
32
58
t-BuONa 2-Me-
37
THF
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
Pd2(dba)3
t-BuONa dioxane 1/1.5
65
24
24
24
24
24
44
52
73
84
87
88d
10
11
12
13
t-BuONa THF
t-BuONa THF
t-BuONa THF
t-BuONa THF
t-BuONa THF
1/1.5
5/7.5
5/5
2.5/5
5/10
14c Pd2(dba)3
a The reactions performed using 1.0 equiv of , 1.5 equiv of and 3.0
1a
2a
equiv of base on a 0.1 mmol scale in 12 hours. b NMR yields.
c This reaction performed in 24 hours. d Isolated yield.
1a and 2a were mixed with Pd(OAc)2 (1.0 mol%) and
NiXantphos (1.5 mol%) in the presence of t-BuOLi in
tetrahydrofuran (THF) at 65℃ for 12 hours, afforded the product
3a in 29% (Entry 1). Encouraged by this initial result, the study
of the effect of bases was conducted. The substitution of t-BuOLi
with Cs2CO3 resulted in lower yield of product (Entry 5), but

3
benzimidazole under the condition.
Table 3. Direct alkenylation of N-methyl-benzimidazole and
caffeine with alkenyl halidesa
In order to explore the generality of this process, the couplings
of (2-bromoethene-1,1,2-triyl) tribenzene (2e) with different
heterocyclic cores were investigated. Due to low efficiency of
reactions under 25℃ and reagent 2e with bulky structure, the
temperature was increased to 150℃. High-boiling-point solvents,
DMF and diethylene glycol dimethyl ether (diglyme), were
examined under same condition for the direct alkenylations of 1j
and 1k. The results were also shown in Table 3. The yields of
two corresponding products, 3p and 3q, were higher in diglyme
(42% and 77%).
Azoles
Alkenyl halides
Product
Yield %
42
77
Table 2. Direct alkenylation of substituted benzoxazoles,
oxazole, benzothiazole, N-substituted benzimidazoles with
alkenyl bromidesa
a
Reaction conditions: 1.0 equiv of 1, 1.5 equiv of 2e and 3.0 equiv of t-
BuONa on 0.2 mmol scale in 2 mL of diglyme under 150 ℃ and N2
atmosphere and isolated yields were reported
In conclusion, a mild Pd-catalyzed C-2 alkenylation of azole
derivatives is reported. The efficiency of NiXantphos-based
catalysts is now expanded to the constructing of C2-alkenylated
azole derivatives. In this method, the direct coupling of most
substituted benzoxazoles, oxazole and benzothiazole with alkenyl
bromides occured efficiently at room temperature. While higher
temperature should be employed in the synthesis of alkenylated
N-substituted benzimidazoles and caffeine. This method enables
the introduction of various mono-, di- or trisubstituted alkenyl
bromides. In addition, compound 3c was prepared on one-gram
scale to demonstrate protocol scalability, which offers a potential
of large-scale applications of 2-alkenylation under room
temperature.
Acknowledgments
This research was funded from NSFC (31570341 and 31870329)
and Key Technology Program from Sichuan Province, China
(Grant number 2015SZ0105).
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BuONa on 0.2 mmol scale in 2 mL of THF under N2 atmosphere and isolated
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5
Highlights




Direct 2-alkenylation of azoles with aryl
bromides at room-temperature.
Palladium/Nixantphos-base catalysis enables
this process.
Deprotonative cross-coupling process (DCCP)
in the alkenylation
Structural diverse 2-alkenylazoles were
prepared.