A facile protocol for N-alkylation of azoles using KOtBu as base under NBS-promoted conditions

Article abstract of DOI:10.1016/j.tetlet.2012.11.030

A mild, transition metal-free, and environmentally benign NBS-promoted C-N bond formation of N-heterocycles is successfully demonstrated. A series of heterocyclic derivatives are readily prepared under mild conditions in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2012.11.030

Tetrahedron Letters 54 (2013) 295–299
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A facile protocol for N-alkylation of azoles using KOtBu as base under
NBS-promoted conditions
Wen-lin Chen a,b, Ji-hui Li a,b, Xu Meng a,b, Dong Tang a,b, Shuai-bo Guo a,b, Bao-hua Chen a,b,
⇑
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:
A mild, transition metal-free, and environmentally benign NBS-promoted C–N bond formation of
N-heterocycles is successfully demonstrated. A series of heterocyclic derivatives are readily prepared
under mild conditions in moderate to good yields.
Received 21 September 2012
Revised 2 November 2012
Accepted 6 November 2012
Available online 15 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
NBS-promoted
Azole
1,3-Dione
N-Alkylation
N-Acylation
In recent years, azoles have been developed as a widely used
activating auxiliary for numerous condensation reactions.1 Substi-
tuted azoles represent an important class of heterocyclic com-
pounds used in the pharmaceutical industry, since they form the
core structures of many commercial drugs.2 In addition, they have
also been frequently used as the mainstay in dyes 3 and high tem-
perature polymers.4 Benzotriazoles are stable, inexpensive, and
biologically innocuous compounds, and 1- and 2-alkylbenzotriaz-
oles are of wide interest due to their biological activities as herbi-
cides, insecticides, and acricides.5 Based on the above reasons, the
synthesis of N-heterocycle derivatives has been the subject of
continuing interest among organic and medicinal chemists for
many years.
It has been reported that the N-alkylation of azoles can be
achieved by different bases, such as potassium carbonate,6 sodium
hydroxide,7 sodium bicarbonate,8 or phase-transfer catalysis (PTC)
with quaternary ammonium salt.9,6b N-Alkylation of azoles can
also be achieved in ionic liquids or without a solvent. However,
some of these methods suffer from several drawbacks including
the use of hazardous and carcinogenic organic solvents such as
dimethylsulfoxide (DMSO), dimethylformamide (DMF), benzene,
or toluene; expensive reagents or catalysts; harsh reaction
conditions; difficulty in product separation; and/or long reaction
times. So, the development of an efficient, convenient, and
environmentally more benign method of the N-alkylation of azoles
is still a major challenge. In this Letter, we reported a facile proto-
col for N-alkylation of azoles using KOtBu as base under NBS-
promoted conditions.
In our initial study, we started the experiment by using
0.2 mmol of 1-phenylbutane-1,3-dione 1a and 0.2 mmol of 1H-
benzo[d][1,2,3]triazole 2a as model substrates for optimization of
the reaction conditions (Table 1). The reaction gave the mixtures
of 1-substituted 3a and 2-substituted 4a products in the presence
of NBS and base.10 The products 3 and 4 could stably exist and mu-
tual transformation between each other would not occur. To im-
prove the reaction efficiency, the effect of bases was then
investigated (Table 1, entries 1–5). It was found that KOtBu gave
the best result in 85% yield and the ratio of isomer (3:4) was
28:72, whereas other bases, such as NaHCO3, K2CO3, and Et3N were
less effective. With an attempt to optimize the yield of the product,
we further studied the influence of different reaction media (Ta-
ble 1, entries 6–10). From the results obtained, it can be seen that
changing the solvent from DCE, THF to DMF, CH3CH2OH failed to
improve the yield of the product. And when using CH2Cl2 as sol-
vent, we only got the product 3 in 37% yield. It should be noted that
the use of different bases and solvents had different regioselectiv-
ity. Considering that the synthesis methods of 4 were less than 3 in
the reported literatures,1,10 we chose the conditions in favor of
product 4. For solvents, the polarity of the solvent itself and the
solubility of raw material and base in the solvent led to different
selectivities: when the polarity of the solvent is relatively small
(EtOAc) and the steric hindrance of the base is relatively large
⇑
Corresponding author.
E-mail address: chbh@lzu.edu.cn (B.-h. Chen).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.030

296
W.-I. Chen et al. / Tetrahedron Letters 54 (2013) 295–299
Table 1
Optimization of the reaction conditionsa
O
Ο
O
H
N
N
N
N
NBS, Base
Solvent
N
+
N
N
N
+
N
O
2a
1a
3a
4a
Entry
Base
Solvent
Yieldb (%)
Ratio of isomer (3:4)
1
2
3
4
5
6
7
8
NaOCH3
NaHCO3
K2CO3
Et3N
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DCE
THF
C2H5OH
DMF
76
42
65
28
85
80
68
trace
trace
37
42:58
60:40
75:25
100% of 3
28:72
32:68
80:20
—
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
9
10
11
—
CH2Cl2
EtOAc
100% of 3
100% of 4,
36:64
42:58
35:65
—
38c
72d
26e
81f
0g
12
13
KOtBu
KOtBu
EtOAc
EtOAc
a
b
c
d
e
f
Reaction conditions: 1a (32.4 mg, 0.2 mmol), 2a (23.8 mg, 0.2 mmol), NBS (1.2 equiv, 39.2 mg), base (2.0 equiv, 0.4 mmol), solvent (2 mL), 60 °C, 6 h, under air.
Isolated yields.
Room temperature.
At 80 °C.
0.2 Equiv of NBS.
0.5 Equiv of NBS.
Without NBS.
g
Figure 1. X-ray crystal structure of 3a and 4a.
(KOtBu), we got the desired ratio of isomers (Table 1, entry 5). Fur-
thermore, the reaction temperature was also investigated, and the
yield was found to decrease with the temperature changed to rt or
80 °C (Table 1, entry 11). The NBS loading was also tested, and the
yield was good at 0.5 equiv of NBS but with a lower regioselectivity,
while it dropped evidently at 0.2 equiv (Table 1, entry 12), and this
reaction did not work in the absence of NBS (Table 1, entry 13).
With a series of detailed investigations mentioned above, the reac-
tion conditions were eventually optimized as follows: 0.2 mmol of
1, 0.2 mmol of 2, 1.2 equiv of NBS, 2.0 equiv of KOtBu as base, and

W. Chen et al. / Tetrahedron Letters 54 (2013) 295–299
297
Table 2
Substrate scope of aromatic N-Heterocyclesa
O
H
N
R1
N
N
NBS, KOtBu
EtOAc, 60 oC
O
Ο
N
R1
R2
N
+
X
R2
+
R1
X
R2
N
O
N
1
2
4
3
R1 = Phenyl, Me
R2 = Me, Cl
X=CH, N
Entry
1
1,3-Dione
Azole
Product
Yieldb (%)
Ratio of isomer (3:4)
O
O
H
N
O
N
N
85
28:72
N
N
N
N
1a
2a
N
N
3a
4a
O
H
O
O
N
N
N
N
N
N
N
N
2b
N
74
3bb
2
1a
3ba
30:70
3ba:3bb = 1.08:1
N
N
N
4b
O
H
N
O
N
N
Cl
N
N
N
2c
3c
Cl
Cl
3
1a
90
27:73
N
N
N
O
4c
O
O
O
N
4
5
2a
2b
82
67
24:76
26:74
1b
N
N
N
N
N
3d
O
4d
O
N
N
1b
N
N
N
N
O
3e
4e
O
N
N
6
7
8
1b
1a
1a
2c
86
72
67
22:78
N
N
N
N
Cl
3f
O
4f
Cl
H
N
Ο
—
N
N
N
2d
3g
H
N
O
—
N
N
N
2e
3h
H
N
O
N
9
1a
80
—
O2N
N
N
2f
3i
O2N
(continued on next page)

298
W.-I. Chen et al. / Tetrahedron Letters 54 (2013) 295–299
Table 2 (continued)
Entry
1,3-Dione
Azole
Product
Yieldb (%)
Ratio of isomer (3:4)
N
O
HN
N
N
N
N
N
10
1a
91
—
OMe
2g
N
OMe
3j
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), NBS (1.2 equiv, 39.2 mg), KOtBu (44.8 mg, 0.4 mmol), EtOAc (2 mL), 60 °C, 6 h, under air.
Isolated yields.
b
OC(CH3)3
O
O
Ο
Ο
O
OC(CH3)3
O
N
N
O
1
N
N
H
N
N
Br
N
N
O2
3
NBS
N
N
N
O
2
Ι
N
Scheme 1. Plausible reaction pathway.
O
HO
Table 3
Substrate scope of aliphatic N-heterocyclesa
_ OH
O
X
O
Ο
NBS, KOtBu
EtOAc, 60 oC
X
n
n
N
+
R1
R1
N
H
O
Ο
N
6
1
5
O
6
R1= Phenyl, Me X = CH2, O n = 1, 2
Scheme 2. Plausible reaction pathway.
Entry
1
1,3-Dione
1a
N-Heterocycle
Product
Yieldb (%)
58
O
O
O
N
N
N
N
5a
H
O
O
O
different azoles were also investigated. For electronic effects,
electron-deficient azoles showed better results than electron-rich
ones. But it should be noted that we only got one kind of product
when benzimidazoles were involved in the reaction, and the prod-
uct of 5-methyl-benzotriazole 3b was a mixture of regioisomers:
3ba:3bb = 1.08:1. Based on the above results, we found that the
type of products of benzotriazoles was determined by the com-
bined electronic effect of diones and benzotriazoles: the electron-
donating effect of both phenyl from dione 1a and methyl from
benzotriazole 2b led to a mixture of regioisomers 3b, while other
products did not appear in this kind of circumstance (3b vs 3a, 3c,
3e).
A plausible mechanism for this reaction was proposed in
Scheme 1. A deacylation followed by oxidative coupling would
likely attribute to the formation of the final products. What needs
to be emphasized was that 0.5 equiv of NBS also gave a 81% yield of
products (Table 1, entry 12). This result proved that there was a
catalytic cycle between 2 and I to some extent.
6a
2
3
1a
1a
64
76
N
H
5b
6b
O
O
N
H
5c
6c
O
N
O
4
5
1b
1a
5c
71
O
6d
5c
6c
87c21d
a
Reaction conditions: 1 (0.2 mmol), 5 (0.2 mmol), NBS (1.2 equiv, 39.2 mg),
KOtBu (44.8 mg, 0.4 mmol), EtOAc (2 mL), 60 °C, 6 h, under air.
b
Isolated yields.
Under oxygen.
Under nitrogen.
c
d
When the aliphatic N-heterocycles were used as the substrates,
we got a result that was different from the aromatic N-heterocy-
cles: the alkylation products were replaced by the acylation prod-
ucts (Table 3). The result showed that the yield of the product was
gradually increased from pyrrolidine to morpholine (Table 3, en-
tries 1–4), and this was probably due to the increased electron-
withdrawing effect from carbon atom to oxygen atom. Besides,
EtOAc (2.0 mL) as solvent at 60 °C. The structure of compounds 3a
and 4a was unambiguously confirmed by X-ray analysis (Fig. 1).
With the optimized conditions in hand, the scope of the reaction
was examined. As shown in Table 2, the reaction could be
performed with both aromatic and aliphatic 1,3-diones. And

W. Chen et al. / Tetrahedron Letters 54 (2013) 295–299
299
the yield was increased under oxygen while it reduced under nitro-
References and notes
gen (Table 3, entry 5), which proved that the oxygen participated
in the reaction system.
1. (a) Diness, F.; Fairlie, D. P. Angew. Chem. 2012, 124, 8136; (b) Katritzki, A. R.;
Rogovoy, B. V. Chem. Eur. J. 2003, 9, 4586; (c) Perez, E. R.; Loupy, A.; Liagre, M.;
de Guzzi Plepis, A. M.; Cordeiro, P. J. Tetrahedron 2003, 59, 865; (d) Uhde, M.;
Ziegler, T. Synth. Commun. 2010, 40, 3046; (e) Matos, I.; Pérez-Mayoral, E.;
Sorianoc, E.; Zukald, A.; Martín-Aranda, R. M.; López-Peinadoa, A. J.; Fonsecab,
I.; Cejka, J. Chem. Eng. J. 2010, 161, 377; (f) Pan, S. G.; Liu, J. H.; Li, H. R.; Wang, Z.
Y.; Guo, X. W.; Li, Z. P. Org. Lett. 1932, 2010, 12.
2. (a) De Wald, H. A.; Lobbestael, S.; Poschel, B. P. H. J. Med. Chem. 1981, 24, 982;
(b) Terret, N. K.; Bell, A. S.; Brown, D.; Ellips, P. Bioorg. Med. Chem. Lett. 1819,
1996, 6; (c) Paredes, E.; Kneeteman, M.; Gonzalez-Sierra, M.; Mancini, P. M. E.
Tetrahedron Lett. 2003, 44, 2943; (d) Wang, X.; Tan, J.; Zhang, L. Org. Lett. 2000,
2, 3107; (e) Mas-Marzá, E.; Mata, J. A.; Peris, E. Angew. Chem., Int. Ed. 2007, 46,
3729; (f) Zhang, F. Z.; Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49, 2768.
3. (a) Loewe, I.; Balzer, W. R.; Gerstung, S. Ger. Offen. 19619112, 1997; Chem.
Abstr. 1997, 128, 16281.; (b) Schwartz, G.; Fehse, K.; Pfeiffer, M.; Walzer, K.; Leo,
K. Appl. Phys. Lett. 2006, 89, 083509.
As shown in Scheme 2, the plausible reaction pathway of prod-
uct 6 was also investigated. Enolization product of 3 was oxidized
by oxygen, and then a dehydroxylation step produced the target
product 6. We will focus on the systematic investigation in future
studies.
In summary, a facile protocol for N-alkylation of azoles using
KOtBu as base under NBS-promoted conditions was successfully
demonstrated. This reaction system reveals several advantages,
such as simple operation, mild and transition metal-free reaction
conditions, easy availability, and moderate to good yields. Further
functionalization of azoles and other heterocycles are the future
goals of our research group.
4. Asensio, J. A.; Gomez-Romero, P. Fuel Cells. 2005, 5, 336.
5. (a) Sparatore, F.; La Rotonda, M. I.; Paglietti, G.; Ramundo, E.; Silipo, C.; Vittoria,
A. Farmaco Ed. Sci. 1978, 33, 901; (b) Katritzky, A. R.; Wu, J. Synthesis 1994, 6,
597.
Acknowledgment
6. (a) Swamy, S. N.; Basappa Sarala, G.; Priya, B. S.; Gaonkar, S. L.; Prasad, J. S.;
Rangappa, K. S. Bioorg. Med. Chem. Lett 2006, 16, 999; (b) Khalafi-Nezhad, A.;
Zare, A.; Parhami, A.; Rad, M. N. S.; Nejabat, G. R. J. Iran. Chem. Soc. 2008, 5, S40.
7. Katritzky, A. R.; Kuzmierkiewicz, W.; Greenhill, J. V. Reel. Trav. Chim. Pays-Bas.
1991, 110, 369.
We are grateful for support of the Project of National Science
Foundation of PR China (No. J1103307).
8. Chen, W. L.; Yan, R. L.; Tang, D.; Guo, S. B.; Meng, X.; Chen, B. H. Tetrahedron
2012, 68, 7956–7959.
Supplementary data
9. Ballesteros, P.; Elguero, J.; Claramunt, R. M. Tetrahedron 1985, 41, 5955.
10. (a) Le, Z. G.; Chen, Z. C.; Hu, Y.; Zheng, Q. G. J. Chem. Res. 2004, 344; (b) Le, Z. G.;
Zhong, T.; Xie, Z. B.; Lv, X. X.; Cao, X. Synth. Commun. 2010, 40, 2525; (c) Lee, H.
G.; Won, J. E.; Kim, M. J.; Park, S. E.; Jung, K. J.; Kim, B. R.; Lee, S. G.; Yoon, Y. J. J.
Org. Chem. 2009, 74, 5675.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.
030.