Iodine-induced regioselective direct alkylation of azoles via in situ formed alkyliodide

Article abstract of DOI:10.1016/j.tet.2012.07.008

We have developed an efficient, metal-free, convenient and relatively cheap method for iodine-induced direct alkylation of azoles via in situ formed alkyliodide. A series of heterocyclic derivatives are readily prepared under mild conditions in moderate t

Full text of DOI:10.1016/j.tet.2012.07.008

Tetrahedron 68 (2012) 7956e7959
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Iodine-induced regioselective direct alkylation of azoles via in situ formed
alkyliodide
,
,
,
,
,
,b,
Wenlin Chen a b, Rulong Yan a b, Dong Tang a b, Shuaibo Guo a b, Xu Meng a b, Baohua Chen a
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu, Lanzhou 730000, PR China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 May 2012
Received in revised form 20 June 2012
Accepted 3 July 2012
Available online 13 July 2012
We have developed an efficient, metal-free, convenient and relatively cheap method for iodine-induced
direct alkylation of azoles via in situ formed alkyliodide. A series of heterocyclic derivatives are readily
prepared under mild conditions in moderate to good yields and high regioselectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Iodine-induced
Metal-free
Direct-alkylation
Azoles
In situ
1. Introduction
Alami’s8 group synthesized the N-alkylation azoles from N-tosyl-
hydrazones. This reaction system showed broad scope and high
For the past few years, azoles have attracted much attention for
their significance in the pharmaceutical, biological, and chemical
industries.1 Azoles represent an important class of nitrogen-
containing heterocycles in view of their derivatives, which are
momentous components in a wide range of natural products and
have various pharmacological properties, such as antiulcers, anti-
hypertensibes, antivirals, antifungals, anticancers and anti-
histamins.2 In addition, they have also been frequently used as the
mainstay in dyes3 and high temperature polymers.4 As a conse-
quence, the development of highly efficient methods for the syn-
thesis of functional azoles has been an area of active research in the
field of organic synthesis, and N-alkylation of azoles plays a critical
role in the synthesis of their derivatives.5 Among the numerous
synthetic methods that have been reported, a deprotonation
step2b,6a followed by a nucleophilic substitution reaction with an
electrophile (RX, X¼halide, OTs, OTf, etc.) is the most common
route. However, their corresponding reaction systems have shown
several drawbacks, such as requiring strong bases, generating
stoichiometric amount of wasteful organic salts and low secondary/
tertiary amine product selectively. Le7 and co-workers reported the
N-alkylation of benzotriazole in basic ionic liquid [Bmin] OH (1-
butyl-3-methylmidazolium hydroxide) under solvent-free condi-
tions, but the system did not exhibit broad substrate generality.
efficiency under mild conditions, but the substrates need to be
prepared in advance. Our group9 also described different methods
for CeN bond-formation of azoles. These methods were efficient
and convenient, but metal catalysts were still needed.
Even though the transition metal catalysts10 have been widely
used in chemical synthesis, we believe that if they can be replaced
by metal-free catalysis systems, the non-metal catalyzed reactions
will have huge prospect to be developed, owing to the soaring
environmental friendly awareness. Molecular iodine catalyzed or
mediated reactions have been proved to be an effective method for
the organic synthesis.11 Liang and others12 have reported that the
iodine-induced CeC and CeN bond-formation can be a very useful
tool for the synthesis of numerous heterocyclic compounds, due to
the efficient, mild, and clean reactions. Taking into account with
this, we have been interested in searching for new processes that
would cope with the current demand for environmentally benign
chemical synthesis. In this communication, we reported a success-
ful example of iodine-induced regioselective direct alkylation of
azoles via in situ formed alkyliodide.
2. Results and discussion
In our initial study, we started by using benzotriazole 1a and
acetophenon 2a as model substrates for optimization of the re-
action conditions (Table 1). The desired product 3a was obtained in
* Corresponding author. E-mail address: truecwl123@126.com (B. Chen).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.008

W. Chen et al. / Tetrahedron 68 (2012) 7956e7959
7957
Table 1
Table 2
Optimization of the reaction conditions
Substrate scope of ketonesa
O
O
O
H
N
R2
H
N
I2, Base
O
R1
I2, NaHCO3
DCE, 80 o
+
N
R2
N
N
N
Solvent, 80 o
C
N
N
+
R1
N
N
N
C
N
2
2a
3
1a
1
3a
Entry
1
Ketone
Product
Yield (%)b
Entry
Base
I2 (equiv)
Solvent
T/ꢀC
Yield (%)b
1
2
3
4
5
6
7
8
tBuOK
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
d
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMSO
DMF
DME
80
80
80
80
80
80
80
80
80
80
80
80
80
66
94
28
32
46
58
tBuOLi
K2CO3
O
O
91
N
N
N
NaOCH3
NaOH
Et3N
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
d
2a
3a
91a, 78c, 82d
0
Trace
72
Trace
0
2
3
4
5
6
93
66
87
47
92
9
10
11
12
13
Dioxane
DCE
DCE
2.0
0
a
Reaction conditions: 1a (23.8 mg, 0.2 mmol), 2a (1.5 equiv, 35
m
L), I2 (2.0 equiv,
101.6 mg), base (2.0 equiv, 0.4 mmol), solvent (2 mL), 80 ꢀC, 24 h.
b
Isolated yields.
2a (1.0 equiv, 23
2a (2.0 equiv, 46
c
m
m
L).
L).
d
the presence of I2 and base. To improve the reaction efficiency, the
effect of bases was then investigated (Table 1, entries 1e7). It was
found that (CH3)3COLi gave the best result, and NaHCO3 was the
next, whereas other bases, such as K2CO3, NaOCH3, NaOH and Et3N,
were less effective in this reaction. Considering developing an eco-
friendly reaction system, the weak base NaHCO3 was clearly the
most appropriate.13 After that, the solvent effect was examined.
Among them, DME gave a lower yield, while DMSO, DMF and 1,4-
dioxane were unavailable to this transformation (Table 1, entries
8e11). It should be noted that this reaction didn’t work in the ab-
sence of I2 or base (Table 1, entries 12, 13). With a series of detailed
investigations mentioned above, the reaction conditions were
eventually optimized as follows: 0.2 mmol of 1a, 1.5 equiv of 2a,
2.0 equiv of I2, 2.0 equiv of NaHCO3 as the base, and DCE (2 mL) as
the solvent at 80 ꢀC. The structure of compound 3a was un-
ambiguously confirmed by X-ray analysis (Fig. 1).
7
8
9
88
82
86
10
11
90
87
Fig. 1. X-ray crystal structure of 3a.
With the optimized conditions in hand, a variety of ketones
were used as substrates to investigate the scope of the reaction as
shown in Table 2. The reaction can be performed with various ke-
tones with aromatic, aliphatic, and annular substituents. Generally,
the electronic effects affected the yields: electron-rich ketones
showed better results than electron-deficient ones (3b vs 3c, 3d,
12
37c
(continued on next page)

7958
W. Chen et al. / Tetrahedron 68 (2012) 7956e7959
Table 2 (continued )
3e). Under the joint action of the electronic and steric effects, we
Yield (%)b
got the corresponding product 3j as 1-(1H-benzo[d][1,2,3]triazol-1-
yl)-4-methylpentan-2-one instead of 3-(1H-benzo[d][1,2,3]triazol-
Entry
Ketone
Product
1-yl)-4-methylpentan-2-one (3j vs 3h, 3i). The
a-H of 2,3-
dihydroinden-1-one 2l was very active, as a result, we got the di-
substituted product 3l (Table 2, entry 12). When 4-methylpent-3-
en-2-one (2n) and cyclohex-2-enone (2o) were tested, the simple
CeN couplings were replaced by azaemichael additions14 (Table 2,
entries 13, 14).
13
88
14
84
To further explore the generality and scope of this protocol,
several azoles were also investigated. As illustrated in Table 3, the
5-substituted azoles 1 containing electron-rich group (Table 3,
entry 1) resulted in higher yield than electron-deficient ones (Table
3, entries 2, 3, 5). Unfortunately, the former gave a mixture of
regioisomers, which demonstrated that electron-rich group
showed poorly regioselectivity in this transformation. Since the 3-
position of indole is more active than 1-position,15 we got the CeC
coupling product 3t (Table 3, entry 7) when using 5-bromo-1H-
indole 1g as the reagent. Because of the hydrogen bond formation
between hydrogen atom on the hydroxyl and nitrogen atom at 4-
position of 1h, we obtained 3u (Table 3, entry 8) as the product
of enolization. In addition, new product 3v (Table 3, entry 9) was
observed when 3,5-dimethyl-1-H-pyrazole 1i was reacted with
acetophenone.
a
Reaction conditions: 1a (23.8 mg, 0.2 mmol), 2 (1.5 equiv, 35
m
L), I2 (2.0 equiv,
101.6 mg), NaHCO3 (2.0 equiv, 33.6 mg), DCE (2 mL), 80 ꢀC, 24 h.
b
Isolated yields.
Disubstituted yields.
c
Table 3
Substrate scope of azolesa
O
O
I2, NaHCO3
R2
+
R
H
R2
R1
DCE, 80 o
C
R1
R
3
1
2
Entry
Azole
Ketone
Product
Yield (%)b
Interestingly, when taking benzotriazole (1a) and cyclohexane-
1,4-dione (2m) as the substrates, we discovered an amusing prod-
uct: 2-(1H-benzo[d][1,2,3]triazol-1-yl)benzene-1,4-diol (3m). We
conjectured that this might be a result of an enolization step, which
was followed by further oxidative dehydrogenation (Scheme 1).
N
N
H
O
N
N
N
3na
3nb
N
O
1
97 (3na:3nb¼1.6:1)
2a
1b
N
N
N
HO
O
I2, NaHCO3
DCE, 80 °C
H
N
OH
N
+
N
N
2
3
4
5
2a
58
53
78
44
N
N
O
1a
3m, yield 61%
2m
Scheme 1. Reaction between 1a and cyclohexane-1,4-dione (2m).
1c
Another interesting reaction was between benzotriazole (1a)
and vinyl acetate (2p). We also got the product 1-(1H-benzo[d]
[1,2,3]triazol-1-yl)ethyl acetate (3w) beyond expectations, owing to
the combined action of the strong inductive effect of the oxygen
atom and the p-
double bond (Scheme 2).
p conjugation effect between oxygen atom and
2a
2a
H
N
O
O
I2, NaHCO3
DCE, 80 o
+
N
N
N
O
O
N
C
N
6
52
1a
2p
3w, yield 66%
Scheme 2. Reaction between 1a and vinyl acetate (2p).
As shown in Scheme 3, to probe the mechanism of this trans-
formation, we first obtained A and B, and then the reaction of A
7
8
2a
2a
58
72
I
N
HO
N
H
N
R2
I2
N
R1
X
X
O
2
O
N
N
N
R1
Br
3u
R2
X=C,N
A
N
N
1
X
I
9
2a
43
H
3
R2
I2
R2
N
R1
R1
X
O
O
2
N
1
a
B
Reaction conditions: 1 (23.8 mg, 0.2 mmol), 2 (1.5 equiv, 35
mL), I2 (2.0 equiv,
X=C,N
101.6 mg), NaHCO3 (2.0 equiv, 33.6 mg), DCE (2 mL), 80 ꢀC, 24 h.
b
Isolated yields.
Scheme 3. Plausible reaction pathway.

W. Chen et al. / Tetrahedron 68 (2012) 7956e7959
7959
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In conclusion, an efficient and metal-free method has been
successfully developed for iodine-induced regioselective direct al-
kylation of azoles. This reaction system reveals several advantages,
such as simple operation, mild reaction conditions, easy availability,
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Supplementary data
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Supplementary data related to this article can be found online at
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this article.
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