Dy(OTf)3-mediated selective substitution of N-(α-benzotriazolyl-alkyl)amides with active methylene compounds for synthesis of benzotriazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.07.098

A Dy(OTf)₃-mediated selective substitution reaction of N-(α-benzotriazolyl-alkyl)amides with active methylene compounds is reported. The present procedure provides a facile method for the synthesis of benzotriazole derivatives.

Full text of DOI:10.1016/j.tetlet.2009.07.098

Tetrahedron Letters 50 (2009) 5536–5538
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Tetrahedron Letters
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Dy(OTf)3-mediated selective substitution of N-(a-benzotriazolyl-alkyl)amides
with active methylene compounds for synthesis of benzotriazole derivatives
Weixun Li a, Yang Ye a, Jin Zhang b, Renhua Fan a,
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b Pharmacy School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Dy(OTf)3-mediated selective substitution reaction of N-(a-benzotriazolyl-alkyl)amides with active
methylene compounds is reported. The present procedure provides a facile method for the synthesis of
benzotriazole derivatives.
Received 19 June 2009
Revised 15 July 2009
Accepted 17 July 2009
Available online 22 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
N-(
a
-Benzotriazolyl-alkyl)amides, developed by the Katritzky
amide. These were assumed to be generated from the reaction
via path a. The structure of 2a was confirmed by spectral methods
and the single-crystal diffraction analysis (Fig. 1).
group, have been used advantageously as the key intermediates
in organic synthesis.1 As an alternative method to the Mannich
reaction, they can react with various nucleophiles,2,3 such as active
methylene and methine compounds,2d,3f alkyl vinyl ethers, silyl
enol ethers, enamines,2k propen-2-yl acetate,2f enolizable alde-
hydes,2m and allylsamarium bromide,3e to afford a variety of useful
compounds. N-(
structure (X–C–Y), in which two different leaving groups attach
to the same carbon. The high reactivity of N-( -benzotriazolyl-al-
kyl)amides in amidoalkylation reactions owes mainly to the good
leaving ability of the benzotriazolyl moiety (Scheme 1, path a).
The selective elimination of the amide moiety (Scheme 1, path
b),4 which provides a versatile method for the synthesis of benzo-
triazole derivatives,5 has received much less scrutiny.
We envisioned that the selective elimination of the two leaving
groups might be achieved by the proper choice of a Lewis acid and
the reaction conditions. In addition, it is desirable that the subse-
quent nucleophilic addition can be promoted by the Lewis acid
without isolation of the unstable imine intermediate.6 To verify
our hypothesis, a set of experiments were carried out using benzo-
triazolyl-substituted amide 1a and diethyl malonate as model sub-
strates. The expected product 2a was reported to have fungicidal
activities against glomerella gossypii and penicillium italicum.7
The preliminary survey, carried out in THF at 65 °C, allowed us
to evaluate the catalytic efficiency of various Lewis acids (Table 1).
Gratifyingly, in an initial experiment, we observed the formation of
desired product 2a when the reaction was catalyzed by FeCl3 (Ta-
ble 1, entry 1). Further investigation revealed that Dy(OTf)3 was
the best catalyst for the generation of 2a (Table 1, entry 18), while
inferior results were displayed in the presence of other Lewis acids
(Table 1, entries 2–17). The major byproducts of the reaction were
the normal amidoalkylation products, benzyl aldehyde and benz-
Motivated by the synthetic potential of the possible method, the
reaction was further optimized by examining various reaction con-
ditions, and some of the results are shown in Table 2. An increase
in the amount of Dy(OTf)3 did not improve the yield of 2a, while
the reaction could not be completed with the use of 0.5 equivalents
of Dy(OTf)3 (Table 1, entries 2 and 3). No product 2a was detected
when EtOH, t-BuOH, 1,4-dioxane, and EtOAc were used as the sol-
vent, while the reaction could proceed in THF, ClCH2CH2Cl2, and
toluene with varied efficiency (Table 1, entries 4–11). A higher
temperature resulted in a complicated reaction and a lower yield
of 2a, while no reaction occurred at a lower temperature (Table
1, entries 12 and 13). When Et3N and t-BuOK were introduced into
the reaction, complex reactions were observed, and no product 2a
was obtained (Table 1, entries 14 and 15). We were delighted to
find that the reaction was promoted and the yield of 2a was
improved to 68% when 1 equiv of benzotriazole was utilized as
the additive (Table 1, entry 16). When the reaction was conducted
in THF, product 2a was isolated in 78% yield (Table 1, entry 18).
a-Benzotriazolyl-alkyl)amides have a bifunctional
a
R2
N
R2
N
N
O
NH
N
path a
O
path b
N
+
N
O
NH
+
R1
N
N
R2
NH
N
R1
R1
Nucleophile
Nucleophile
R2
Nu
N
N
R1
N
O
NH
Nu
R1
* Corresponding author. Tel.: +86 21 6564 3462; fax: +86 21 6510 2412.
E-mail address: rhfan@fudan.edu.cn (R. Fan).
Scheme 1. The selective substitution reaction of N-(a-benzotriazolyl-alkyl)amide.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.098

W. Li et al. / Tetrahedron Letters 50 (2009) 5536–5538
5537
Table 1
Table 2
Evaluation of various Lewis acidsa
Optimization of the reaction conditionsa
Entry
Dy(OTf)3
(equiv)
Solvent
Temperature
(°C)
Additive
(equiv)
2ab
(%)
Ph
EtOOC
Ph
COOEt
O
NH
CH2(COOEt)2 (1.5 equiv)
Lewis acid (1.1 equiv)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1.1
2
THF
THF
THF
65
65
65
65
40
65
65
65
65
65
65
80
50
65
65
65
65
65
51
49
34
37
0
11
0
0
0
0
49
39
0
N
N
N
Ph
N
N
THF, 65oC
N
0.5
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
ClCH2CH2Cl
CH2Cl2
CH3CN
EtOH
t-BuOH
1,4-Dioxane
EtOAc
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
2a
1a
Entry
Lewis acid
2ab (%)
1
2
3
4
5
6
7
8
9
FeCl3
FeCl2
Fe(acac)3
BF3ÁEt2O
InCl3
BiCl3
YbCl3
PdCl2
ZnCl2
25
Trace
Trace
0
0
10
Trace
0
(1) Et3N
(1) t-BuOK
(1) Benzotriazole
(2) Benzotriazole
(1) Benzotriazole
0
0
68
67
78
0
0
10
11
12
13
14
15
16
17
18
CuBr
Pd(OAc)2
Bi(OTf)3
Zn(OTf)2
Cu(OTf)2
Yb(OTf)3
Sc(OTf)3
AgOTf
0
0
0
0
a
The reactions were performed with 1a (0.5 mmol), diethyl malonate
(0.75 mmol) in anhydrous solvent (2 mL).
b
Isolated yields.
Trace
Trace
Trace
51
Table 3
Dy(OTf)3
Extending of substrate scopea
a
The reactions were performed with 1a (0.5 mmol), diethyl malonate
(0.75 mmol), Lewis acid (0.55 mmol) in anhydrous THF (2 mL) at 65 °C.
Ph
b
E
R
E
N
Isolated yields.
O
NH
N
E
Dy(OTf)3 (1.1 equiv)
THF, 65oC
N
R
N
+
N
N
E
The scope of the present reaction was then investigated under
the established conditions.8 A moderate electronic substrate effect
was observed. The reactions of electron-poor substrates afforded
the corresponding products in better yields than those of elec-
tron-rich substrates (Table 3, entries 1–12). Aliphatic substrates
were unreactive under the same conditions (Table 3, entries 13
and 14). Moreover, the reactions with methyl or ethyl 3-oxobut-
anoate also gave the products 2r and 2s in good yields (Table 3,
entries 15 and 16). No corresponding products were obtained
when 2,4-pentanedione, ethyl 2-nitroacetate, and ethyl 2-cyanoac-
etate were employed (Table 3, entries 17–19).
(1.5 equiv)
1
2
Entry
R
CH2E2
2b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
C6H5
CH2(COOEt)2
2a (78)
2b (78)
2c (66)
2d (71)
2e (76)
2f (70)
2g (66)
2h (63)
2i (58)
2j (70)
2k (74)
2l (40)
2p (0)
4-NO2–C6H4
4-Cl–C6H4
2-Cl–C6H4
2,4-Di-Cl–C6H3
2-Br–C6H4
2-Br–5-F–C6H3
4-CH3–C6H4
4-CH3O–C6H4
4-PhCH2O–C6H4
3-PhCH2O–C6H4
3-CH3O–4-PhCH2O–C6H3
n-Pr
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
CH2(COOEt)2
In conclusion, we report here a Dy(OTf)3-mediated selective
substitution reaction of N-(a-benzotriazolyl-alkyl)amides with
t-Bu
C6H5
C6H5
C6H5
C6H5
C6H5
2q (0)
CH3COCH2COOCH3
CH3COCH2COOEt
CH3COCH2COCH3
NO2CH2COOEt
2r (83)
2s (69)
2t (0)
2u (0)
CNCH2COOEt
2v (0)
a
The reactions were performed with 1 (0.5 mmol), CH2E2 (0.75 mmol), Dy(OTf)3
(0.55 mmol) in anhydrous THF (2 mL) at 65 °C.
b
Isolated yields.
active methylene compounds. The present procedure will provide
a facile method for the synthesis of benzotriazole derivatives. Fur-
ther studies on the scope, mechanism, and the application of this
system are ongoing and will be reported in due course.
Acknowledgments
Financial support from National Natural Science Foundation of
China (20702006), the Shanghai Rising-Star program (07QA14007),
and Fudan University is gratefully acknowledged.
Figure 1. The ORTEP diagram of 2a.

5538
W. Li et al. / Tetrahedron Letters 50 (2009) 5536–5538
Li, J.; Zhang, Y. Synth. Commun. 2003, 33, 3575; (f) Wang, X.; Mao, H.; Yu, Y.; Zhu,
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8. General experimental procedure and spectroscopic data for 2a: A solution of N-
(
a
-benzotriazolyl-alkyl)amide
1
(0.5 mmol) and CH2E2 (0.75 mmol) in
anhydrous THF (2 mL) was treated with Dy(OTf)3 (309 mg, 0.55 mmol) and
benzotriazole (60 mg, 0.5 mmol). The resulted mixture was stirred at 65 °C.
After substrate disappeared (determined by TLC), the mixture was quenched
with saturated NaHCO3, and extracted by ethyl acetate (25 mL Â 3). The organic
layer was dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (20–30% ethyl acetate in
hexane) to provide the desired product. Diethyl 2-((1H-benzo[d][1,2,3]triazol-1-
yl)(phenyl)methyl)malonate:7 1H NMR (400 MHz, CDCl3) d 8.01 (d, J = 8.2 Hz, 1H),
7.58–7.50 (m, 3H), 7.34–7.27 (m, 5H), 6.38 (d, J = 11.4 Hz, 1H), 5.17 (d,
J = 11.4 Hz, 1H), 4.10–3.97 (m, 4H), 1.07 (t, J = 7.3 Hz, 3H), 1.01 (t, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 166.3, 166.1, 145.9, 135.4, 132.9, 129.2, 128.9,
128.0, 127.6, 124.2, 119.9, 109.7, 62.2, 62.1, 61.6, 57.2, 13.8, 13.7.