CuCl-Catalyzed direct C-H alkenylation of benzoxazoles with allyl halides

Article abstract of DOI:10.1039/c7ob01838j

An efficient and concise CuCl-catalyzed C2-alkenylation reaction of benzoxazoles with allyl halides has been established. The distinctive features of this protocol include the use of an inexpensive copper salt as a catalyst, simple and readily available starting materials, and ligand-free conditions. An important application of this method to the synthesis of 1,3-diene substituted benzoxazoles has also been achieved.

Full text of DOI:10.1039/c7ob01838j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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CuCl-Catalyzed Direct C-H Alkenylation of Benzoxazoles with Allyl
Halides
Die Li,a Xin-Xing Wu,a Tingyu Gao,a Baoguo Li*a and Shufeng Chen*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
workers (Scheme 1, eq 3).5
An efficient and concise CuCl-catalyzed C2-alkenylation reaction
of benzoxazoles with allyl halides has been established. The
distinctive features of this protocol include the use of an
inexpensive copper salt as catalyst, simple and readily available
starting materials, and ligand-free conditions. An important
application of this method to the synthesis of 1,3-diene
substituted benzoxazoles has also been achieved.
On the other hand, allyl halides are easily available and have been
used in a wide range of allylation reactions.6 However, the reports
for efficient and selective alkenylations of heteroarenes using allyl
halides as the alkenyl reagents are quite limited.7 Very recently,
Chang and co-workers discovered
a [Cu(NHC)]-catalyzed C-H
allylation/isomerization process to access both electron-deficient
and electron-rich alkenylated (hetero)arenes by using allyl halides
as the reactants for the first time.8 As a continuation of our interest
in the synthesis and transformations of heterocycles,9 herein we
report a convenient method for C2-alkenylbenzoxazoles synthesis
based on CuCl-catalyzed direct alkenylation reaction of
benzoxazoles with allyl halides (Scheme 1, eq 4). The distinctive
features of this new protocol include the use of inexpensive copper
salt as catalyst, simple and readily available starting materials, and
ligand-free conditions. An important application of this method to
the synthesis of 1,3-diene substituted benzoxazoles using 1,4-
dibromobut-2-ene as the reactant was also demonstrated.
Benzoxazole derivatives are important aromatic heterocycles
which exist in many natural products, agrochemicals as well as
biologically and pharmaceutically active molecules.1 They are also
widely used in numerous organic functional materials such as liquid
crystals and fluorescent materials.2 Therefore, much effort has been
devoted to developing efficient synthetic methods for synthesizing
this type of aromatic heterocycles, especially those with an alkenyl
substituent at C-2 position.3,4 Among these, transition-metal-
catalyzed C-H functionalizations of heterocycles have been
demonstrated to be the powerful tools to access C2-
alkenylbenzoxazoles.4 In this context, many catalytic approaches
using C−X/C−H direct alkenylaꢀon strategies from benzoxazoles
with various electrophilic coupling partners have been developed.
For instance, the groups of Doucet, Piguel and others have
independently reported several efficient alkenylation reactions of
oxazole derivatives employing alkenyl halides as coupling partners
(Scheme 1, eq 1).4a-f In addition to alkenyl halides, alkenyl
phosphates and tosylates as well as enol and unsaturated esters
derivatives were successfully demonstrated as the alternative
coupling partners for these C−X/C−H direct alkenylations by
Ackermann, Kwong, and Itami (Scheme 1, eq 2).4g-i However, the
use of above mentioned poorly available alkenyl reagents has
restricted applications of these reactions. In 2014, an alternative
R1
R1
N
O
N
O
Pd or Cu catalyst
phosphine ligand
R2
(eq 1)
(eq 2)
+
X
R2
R3
R3
R1
X = Br, I
R1
N
O
N
O
Pd or Ni catalyst
phosphine ligand
+
R2
Y
R2
Y = OPO(OPh)2, OCOR, OCONR2
COOPh or OTs
Pd(TFA)2 10 mol %
N
O
N
O
1,10-Phen 15 mol %
Ph
H
+
(eq 3)
(eq 4)
H
AgTFA 2 equiv
Ph
toluene, 130 o
C
and
more
straightforward
palladium-catalyzed
cross-
This work
dehydrogenative coupling of benzoxazoles with a vinyl moiety
without using prefunctionalized substrates to provide C2-
alkenylated benzoxazoles was successfully achieved by Ong and co-
N
N
CuCl 10 mol %
tBuOLi 3 equiv
X
R2
+
R1
O
O
R1
R2
X = Cl, Br, I
Scheme 1. Direct C2-alkenylation of benzoxazoles
a.Inner Mongolia Key Laboratory of Fine Organic Synthesis, Department of
Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot 010021,
People’s Republic of China. E-mail: shufengchen@imu.edu.cn (S. Chen);
baoguol@sohu.com (B. Li)
Electronic Supplementary Information (ESI) available: Detailed experimental
procedures and analytical data. See DOI: 10.1039/x0xx00000x
The reaction was initially optimized using benzoxazole 1a and
allyl bromide 2a as model substrates (Table 1). Gratifyingly, when
t
1a and 2a were mixed with Cu(OTf)2 in the presence of BuOLi in
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toluene at reflux temperature for 2 hours, the reaction afforded the
C2-alkenylbenzoxazole 3a in 40% isolated yield (entry 1).
Encouraged by this initial result, the effect of catalysts was
subsequently investigated. Among the copper sources used,
Cu(OAc)2 and Cu(acac)2 were found to be less efficient (entries 2 and
3). Interestingly, when CuCl was employed as the catalyst in this
coupling reaction, 3a could be obtained in 65% yield, whereas a low
yield of 3a was obtained when the reaction was catalyzed by CuI or
CuBr (entries 4-6). Two palladium catalysts, Pd(PPh3)4 and Pd2(dba)3,
were examined under the similar reaction conditions and only trace
of product 3a was detected by TLC (entries 7 and 8). Subsequently,
a range of inorganic as well as organic bases were examined for this
Table 2 Scope of substituted benzoxazoles and allyl bromide derivativesa
CuCl (10 mol %)
tBuOLi (3 equiv)
N
O
N
O
R
R
Br
R2
+
R1
toluene, reflux, N2
R1
R2
2a-c
1a-i
3a-m
O
O
O
N
N
N
H3C
3a, 1h, 90%
(E/Z = 78:22)
3b, 1h, 90% (88%)b
3c, 1h, 84%
t
reaction (entries 9–11), and only BuOLi proved competent. A rapid
H3C
O
N
O
N
O
N
solvent screening revealed that the reaction was sluggish in CH2Cl2,
but gave moderate yields of 3a in other solvents such as CH3CN,
THF and dioxane (entries 12–15). Predictably, when the reaction
was carried out under a N2 atmosphere, the highest yield of the
product was obtained (entry 16). For comparison, the reaction was
performed in the absence of a catalyst, but no reaction occurred
under such conditions (entry 17). Finally, the conditions in entry 16
(Table 1) were identified as the optimal conditions.
Cl
Br
3d, 1h, 89%
3e, 1h, 78%
3f, 1h, 78%
Br
O
Br
O
N
O
N
F3C
N
3g, 1h, 87%
3i, 1h, 73%
3h, 1h, 77%
After establishing standard reaction conditions, the scope of this
O
N
O
N
O
direct C2-alkenylation was investigated by using
a series of
benzoxazoles and allyl bromide derivatives. As illustrated in Table 2,
excellent product yield (90%) was obtained when methallyl bromide
2b was employed in this novel coupling reaction under the
optimized reaction conditions (3b). Next, several substituted
benzoxazoles have been subjected to the alkenylation conditions,
and generally high yields were obtained. For example, benzoxazoles
bearing methyl or halide groups on the 5, 6 or 7-position of the
N
O2N
H3C
3j, 10h, trace
3k, 4.5 h, 80%
3l, 4.5 h 69%
O
N
Cl
3m, 4.5 h, 75%
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), tBuOLi (3.0 mmol) and CuCl (0.1
mmol) in 3.0 mL of toluene at reflux temperature under N2 atmosphere and isolated
yields were reported. [b] The reaction was performed on a 1.2 g scale of benzoxazole.
Table 1. Optimization of reaction conditionsa
N
O
N
O
catalyst, base
solvent, reflux
Br
+
phenyl rings gave the corresponding products (3c-h) in good yields.
1a
2a
3a
Moreover, the reaction also proceeded smoothly with
a
trifluoromethyl containing substrate, affording the corresponding
product 3i in 73% yield. However, substrate containing a nitro
group on the 5-position of the benzoxazole ring (3j) did not yield
any desired alkenylated product. Notably, when 3-bromocyclohex-
1-ene 2c was subjected to this transformation as the substrate, the
reaction also proceeded well and afforded the corresponding
products in good yields with various benzoxazoles (3k–m). Finally,
we also demonstrated the potential of scaling up this novel
alkenylation; the reaction of 1a and 2b was run on a 1.2 g scale
under standard conditions for 2 hours, providing 3b in 88% isolated
yield.
cat. (10
mol%)
base (3
equiv)
time
entry
1
solvent
toluene
yield (%)b
40 (42) c
(h)
Cu(OTf)2
tBuOLi
2
2
3
4
5
6
Cu(OAc)2
Cu(acac)2
CuCl
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
toluene
toluene
toluene
toluene
toluene
2
3
1
2
2
30 (30) c
29 (33) c
65
20 (30) c
30 (36) c
CuBr
CuI
7
Pd(PPh3)4
tBuOLi
tBuOLi
NaOH
toluene
9
trace
8
9
Pd2(dba)3
CuCl
toluene
toluene
13
24
trace
0
10
CuCl
Cs2CO3
toluene
24
0
CuCl (10 mol %)
tBuOLi (3 equiv)
N
O
N
O
11
12
13
14
15
16 c
17
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
---
DBU
toluene
CH2Cl2
CH3CN
THF
24
4
0
X
+
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
5
toluene
reflux, N2, 1h
3a
1a
4
46
40
30
90
0
1
4, X = Cl
5, X = I
56% (E/Z = 64:36) from 4
91% (E/Z = 1:1) from 5
90% (E/Z = 78:22) from 2a
dioxane
toluene
toluene
4
1
2a, X = Br
10
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), base (3.0 mmol) and catalyst (0.1
mmol) in 3.0 mL of solvent at reflux temperature. [b] Yield of isolated product after
chromatography. [c] The reaction was proceeded under N2 atmosphere.
Scheme 2. The reaction of allyl chloride 4 and allyl iodide 5 with benzoxazole 1a
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Moreover, it should be mentioned that the same C2-
alkenylbenzoxazole product 3a can be obtained in 56% and 91%
isolated yield respectively, under the identical conditions from the
O
H
R
N
O
N
t-BuOLi
1
D
O
Li
N
CuCl
Table 3. Synthesis of 1,3-diene containing benzoxazoles.a
isomerization
CuCl (10 mol %)
tBuOLi (3 equiv)
toluene, 50 oC, N2
N
O
N
O
A
Br
R
R
N
O
+
Br
2d
1a-i
6a-i
O
3
R
Cu
N
H3C
O
N
O
O
B
N
O
N
H3C
Cu
X
6a, 4h, 75%
6b, 4h, 72%
6c, 4h, 70%
N
R
X
R
C
2
Br
O
N
O
N
O
N
Scheme 3. Proposed mechanism of the reaction
Cl
Br
6d, 4h, 78%
6f, 4h, 76%
6e, 4h, 70%
On the basis of the above results and related literature,8, 11
a
Br
O
N
O
plausible mechanism is proposed as shown in Scheme 3. First, the
deprotonation of benzoxazole on C2-position occurred in the
O
N
O2N
F3C
t
N
presence of BuOLi, resulting in the formation of intermediate A,
6h, 4h, 40%
6g, 5h, 41%
6i, 5h, trace
which react with Cu(I) catalyst to form a copper-aryl intermediate B.
Subsequently, an oxidative insertion of allyl halides into
intermediate B take place to produce an π-allyl CuIII complex
intermediate C. Next, reductive elimination of the intermediate C
affords the allylated intermediate D with the regeneration of
catalyst. Finally, fast isomerization of intermediate D delivers the
alkenyl product 3.
[a] Reaction conditions: 1 (1.5 mmol), 2d (1.0 mmol), tBuOLi (3.0 mmol) and CuCl (0.1
mmol) in 3.0 mL of toluene at 50 oC under N2 atmosphere and isolated yields were
reported.
reaction of allyl chloride 5 or allyl iodide 6 with benzoxazole 1a,
albeit with low diastereoselectivities (Scheme 2).
In conclusion, we have developed an efficient and concise
CuCl-catalyzed C2-alkenylation reaction of benzoxazoles with
allyl halides. Furthermore, this method has been successfully
applied in the synthesis of 1,3-diene substituted benzoxazoles
using 1,4-dibromobut-2-ene as the reactant. The distinctive
features of this new protocol include the use of inexpensive
copper salt as catalyst, simple and readily available starting
materials as well as ligand-free conditions.
Finally, this coupling reaction was successfully applied to the
synthesis of benzoxazole containing 1,3-butadiene derivatives.
Integration of
a 1,3-butadiene moiety into heteroarenes is
synthetically valuable because both of them are all widely utilized in
polymer and materials chemistry. However, the synthetic methods
to access such type of compounds are very limited.10
We found that under slightly modified reaction conditions, the
CuCl-catalyzed coupling of benzoxazole with 1,4-dibromobut-2-ene
led to the formation of 2-(buta-1,3-dienyl)benzo[d]oxazole in 75%
yield (6a). Subsequently investigation indicated that various
substituents on the aromatic ring were all compatible with the
present catalytic system and afforded the desired 2-(1,3-diene)
substituted benzoxazoles in moderate to good yields (6b–h).
This work was supported by the National Natural Science
Foundation of China (21662025) and the Natural Science
Foundation of Inner Mongolia of China (2014JQ02). We thank
Mrs. Yupeng Zhao and Yanru Ren from our group for repeating
and adding some experiments during the correction of this
manuscript.
However, just as the result in Table 2,
a nitro substituted
benzoxazole was also failed in this transformation (6i).
Notes and references
1
T. Eicher, S. Hauptmann, The Chemistry of Heterocycles;
Wiley-VCH: Weinheim, 2003. (b) G. V. Boyd, Science of
Synthesis: Houben-Weyl Methods of Molecular
Transformation, Category 2; E. Schaumann, Ed.; Thieme:
Stuttgart, 2002; Vol. 11, Product Class 13 (Benzoxazoles and
Other Annulated Oxazoles), pp 481−492.
2
(a) V. B. Kovalska, D. V. Kryvorotenko, A. O. Balanda, M. Y.
Losytskyy, V. P. Tokar, S. M. Yarmoluk, Dyes Pigm., 2005, 67
47. (b) P. C. Xue, P. Chen, J. H. Jia, Q. X. Xu, J. B. Sun, B. Q.
Yao, Z. Q. Zhang, R. Lu, Chem. Commun., 2014, 50, 2569. (c)
D. Wee, S. Yoo, Y. H. Kang, Y. H. Kim, J. W. Ka, S. Y. Cho, C.
,
Lee, J. Ryu, M. H. Yi, K. S. Jang, J. Mater. Chem. C 2014, 2,
This journal is © The Royal Society of Chemistry 20xx
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6395. (d) P. Xue, B. Yao, J. Sun, Z. Zhang, K. Li, B. Liu, R. Lu,
Dyes Pigm. 2015, 112, 255.
3
4
(a) J. S. Fisk, R. A. Mosey, J. J. Tepe, Chem. Soc. Rev., 2007,
36, 1432. (b) H. Hachiya, K. Hirano, T. Satoh, M. Miura,
Angew. Chem. Int. Ed., 2010, 49, 2202. (c) X. Song, Y. Qiu, B.
Song, X. Hao, Y. Han, P. Gao, X. Liu, Y. Liang, J. Org. Chem.,
2015, 80, 2263. (d) X. Zhang, Y. Lin, J. Zhang, S. Cao, RSC Adv.,
2015, 5, 7905.
(a) A. L. Gottumukkala, F. Derridj, S. Djebbar, H. Doucet,
Tetrahedron Lett., 2008, 49, 2926. (b) F. Besselièvre, S.
Piguel, F. Mahuteau-Betzer, D. S. Grierson, Org. Lett., 2008,
10, 4029. (c) F. Besselièvre, S. Lebrequier, F. Mahuteau-
Betzer, S. Piguel, Synthesis 2009, 3511. (d) S. Sahnoun, S.
Messaoudi, J.-D. Brion, M. Alami, Eur. J. Org. Chem., 2010,
6097. (e) M. Gerelle, A. J. Dalencon, M. C. Willis, Tetrahedron
Lett., 2012, 53, 1954. (f) W. Zhang, Y. Tian, N. Zhao, Y. Wang,
J. Li, Z. Wang, Tetrahedron 2014, 70, 6120. (g) L. Ackermann,
S. Barfüsser, J. Pospech, Org. Lett., 2010, 12, 724. (h) L.
Meng, Y. Kamada, K. Muto, J. Yamaguchi, K. Itami, Angew.
Chem., Int. Ed., 2013, 52, 10048. (i) W. C. Fu, Y. Wu, C. M. So,
S. M. Wong, A. Lei, F. Y. Kwong, Org. Lett., 2016, 18, 5300.
5
6
W.-C. Lee, T.-H. Wang, T.-G. Ong, Chem. Commun., 2014, 50
3671.
For selected reviews, see: (a) U. K. Roy, S. Roy, Chem. Rev.,
2010, 110, 2472. (b) Z. L. Shen, S. Y. Wang, Y. K. Chok, Y. H.
,
Xu, T.-P. Loh, Chem. Rev., 2013, 113, 271. (c) N. K. Mishra, S.
Sharma, J. Park, S. Han, I. S. Kim, ACS Catal., 2017, , 2821.
C. Verrier, C. Hoarau, F. Marsais, Org. Biomol. Chem., 2009,
, 647.
7
7
7
8
9
W. Xie, S. Chang, Angew. Chem., Int. Ed., 2016, 55, 1876.
(a) W. Liu, Y. Sun, H. Zhao, B. Li, S. Chen, ChemCatChem,
2016, 8, 2894. (b) Y. Sun, Y. Qiao, H. Zhao, B. Li, S. Chen, J.
Org. Chem., 2016, 81, 11987. (c) N. Li, B. Li, S. Chen, Synlett,
2016, 27, 1597. (d) W. Liu, H. Wang, H. Zhao, B. Li, S. Chen,
Synlett, 2015, 26, 2170. (e) S. Chen, L. Li, H. Zhao, B. Li,
Tetrahedron 2013, 69, 6223.
10 (a) G. Evindar, R. A. Batey, J. Org. Chem., 2006, 71, 1802. (b)
H. Thakellapalli, S. Li, B. Farajidizaji, N. N. Baughman, N. G.
Akhmedov, B. V. Popp, K. K. Wang, Org. Lett., 2017, 19, 2674.
11 (a) E. R. Bartholomew, S. H. Bertz, S. Cope, M. Murphy, Ogle,
C. A. J. Am. Chem. Soc., 2008, 130, 11244. (b) T. Yao, K.
Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed., 2011, 50
2990. (c) A. E. Wendlandt, A. M. Suess, S. S. Stahl, Angew.
Chem. Int. Ed. 2011, 50, 11062.
,
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