An expedient approach to substituted triazolo[1,5-a][1,4]benzodiazepines via Cu-catalyzed tandem Ullmann C-N coupling/azide-alkyne cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2013.08.125

An approach to the synthesis of triazolo[1,5-a][1,4]benzodiazepines comprising copper catalyzed tandem Ullmann C-N coupling followed by azide-alkyne cycloaddition has been described. The reaction of o-azidobenzylbromide and N-propargylated aniline derivat

Full text of DOI:10.1016/j.tetlet.2013.08.125

Accepted Manuscript
An expedient approach to substituted triazolo[1,5-a][1,4]benzodiazepines via
Cu-catalyzed tandem Ullmann C-N coupling/ azide-alkyne cycloaddition
K.C. Majumdar, Sintu Ganai
PII:
S0040-4039(13)01523-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.125
TETL 43488
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 June 2013
26 August 2013
30 August 2013
Please cite this article as: Majumdar, K.C., Ganai, S., An expedient approach to substituted triazolo[1,5-a]
[1,4]benzodiazepines via Cu-catalyzed tandem Ullmann C-N coupling/ azide-alkyne cycloaddition, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.125
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1
An expedient approach to substituted triazolo[1,5-a][1,4]benzodiazepines via
Cu-catalyzed tandem Ullmann C-N coupling/ azide-alkyne cycloaddition
K. C. Majumdar*, Sintu Ganai
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B India
Abstract: An approach to the synthesis of triazolo[1,5-a][1,4]benzodiazepines comprising copper
catalyzed tandem Ullmann C–N coupling followed by azide-alkyne cycloaddition has been
described. The reaction of o-azidobenzylbromide and N-propargylated aniline derivatives in
presence of CuI and base leads to the formation of triazolo[1,5-a][1,4]benzodiazepines. The
reaction has been successfully generalized by synthesizing a number of triazolo[1,5-
a][1,4]benzodiazepine derivatives in good to excellent yields.
Key-words: Fused triazoles; 1,4-Benzodiazepine; Azide-alkyne cycloaddition; Ullmann C–N
coupling; CuI; o-azido-benzylbromide, N-propargylated aniline
Corresponding author: Tel.: +9133-2582 8750; Fax: +9133-2582 8282
E-mail: kcm@klyuniv.ac.in; kcm_ku@yahoo.co.in

2
Benzodiazepines are known to provide ligands for many bio-receptors and widely used as the
privileged structures in medicinal chemistry1. Among them, 1,4-benzodiazepines are the most
important class of therapeutic agents with widespread biological activities2 including anti-anxiety,
anticonvulsant, tranquilizing, sedative effects3 and also act as antihistaminic agents4. Moreover,
these therapeutic activities have been significantly enhanced through the fusion of the 1,4-
benzodiazepine moiety with a triazole ring5. Several benzodiazepines fused with a triazole ring are
known to possess potent biological activity6. Diazepine7 (1) and estazolam8 (2) have achieved
clinical success in the treatment of CNS disorders. Again, alprazolam (3) and estazolam (2) are
used as anxiolytic agents9, whereas triazolam (4) and adinazolam (5) are known as
antidepressants10 (Figure 1).
Ph
Ph
Ph
Cl
N
N
Cl
Cl
N
N
N
Cl
N
O
Cl
N
N
N
N
N
N
N
N
CO2Et
N
N
N
N
N
N
N
1
2
3
5
4
Figure 1: Some biologically active fused benzodiazepines
Various approaches have been reported11 to synthesize triazole-fused 1,4-benzodiazepine
derivatives (Scheme 1). Akritopoulou-Zanze et al. reported12 a two-step synthesis of fused triazolo
derivatives using alkyne-azide cycloaddition reaction from the Ugi-product that required
isocyanide and o-azido benzaldehyde. Hemming and co-workers have reported13 the synthesis of
triazolobenzodiazepines and pyrrolobenzodiazepines using intramolecular 1,3-dipolar
cycloaddition reaction in a multistep process. Very recently, Van der Eycken et al the synthesis of
triazolo[1,5-a][1,4]benzodiazepinones by employing a post-Ugi Cu-catalyzed tandem azide-

3
alkyne cycloaddition/Ullmann coupling strategy. They used o-bromobenzaldehyde, amine,
isocyanide, and propiolic acid derivatives for the preparation of Ugi-product.
Livi et al.:11c
CN
N
CN
(i) H2,
Raney Ni
N3
COOR
O
DMAD
N
N
N
N
DEAD, 
(ii) MeI
COOR
COOR
N
N
overall yield upto 60%
Akritopoulou-Zanze and co-workers:12
CHO
Cy
Cy
HN
O
O
HN
O
O
Ph
N3
Benzene
reflux
NH2
N
Ph
N
Ugi-4CR
+
COOH
N
NC
N3
N
N
(96%)
Van der Eycken and co-workers:14
CHO
R1
HN
R1
HN
O
O
N
Ar
Ar
NaN3, CuI,
DMSO,
N
NH2
Ar
Br
Ugi-4CR
O
120 oC, 24h
O
+
N
N
COOH
Br
R2
R2
R1
N
NC
R2
(18-95%)
This work:
Br
R1
R3
HN
N
N3
R2
DMF, K2CO3
CuI, 110 oC
+
R2
N
R1
N
R3
N
(86-97%)
Scheme 1: Different approaches towards triazolo-fused [1,4]benzodiazepine derivatives
Development of mild and simple method to synthesize triazole-fused 1,4-benzodiazepines is still
desirable because of their biological significance. As part of our continuing efforts to synthesize
potentially bioactive heterocycles15 we have planned to develop a new protocol for synthesizing
triazolo[1,5-a][1,4]benzodiazepine by copper-catalyzed tandem Ullmann C-N coupling followed
by azide-alkyne cycloaddition reaction16. Herein we report our results.

4
At first o-toluidines (6a-c) were converted into their azide derivatives (7a-c) using diazotization
condition. Necessary precursors 8a-c were prepared in good yields from the reaction17 of o-
azidotoluene (7a-c) with N-bromosuccinimide and benzoyl peroxide in refluxing dry benzene. On
the other hand, N-propargylated anilines (10a-e) were prepared by the reaction of aniline 9 with
propargyl bromides in the presence of anhydrous potassium carbonate in DMF for five hours
(Scheme 1).
R1
R1
CH3
NH2
R1
CH3
N3
Br
(ii)
(i)
N3
R2
R2
R2
6a, R1 = H, R2 =H
6b, R1 = Cl, R2 =H
6c, R1 = H, R2 =Cl
8a, R1 = H, R2 =H
8b, R1 = Cl, R2 =H
8c, R1 = H, R2 =Cl
7a, R1 = H, R2 =H
7b, R1 = Cl, R2 =H
7c, R1 = H, R2 =Cl
NH2
HN
(iii)
10a, R3 = H
10b, R3 = CH3
10c, R3 = OCH3
R3
10d, R3 = Cl
R3
3
10e
9
, R = F
Scheme 1 Reagent and conditions: (i) NaNO2, 6(N) HCl, NaN3 (ii) NBS, benzoyl peroxide, benzene,
reflux, 4.5h (iii) propargyl bromide, DMF, K2CO3, r.t, 5h
We initiated our study by the reaction of o-azidobenzylbromide (8a) and N-propargylated aniline
10a at room temperature using DMF as solvent, K2CO3 as base and CuI as a catalyst. But this
reaction did not give any cyclized product (entry 1, Table 1).

5
Table 1. Tandem Ullmann C-N coupling/azide-alkyne cycloaddition using various conditionsa
Br
Ph
HN
N
N3
Solvent, Base
catalyst,Temp
+
N
N
11a
10a
N
8a
Entry Solvent
Base
Catalyst Temp (oC) Time (h) Yield (%)b
1
2
3
4
5
6
7
8
DMF
K2CO3 CuI
K2CO3 CuI
K2CO3 CuI
K2CO3 CuI
r.t.
12
5
0
DMF
110 oC
110 oC
110 oC
reflux
92
74
0
DMSO
Toluene
7
7
1,4-dioxane K2CO3 CuI
7
0
DMF
DMF
DMF
Cs2CO3 CuI
Et3N CuI
Na2CO3 CuI
CuI
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
5
85
77
<50
0
5
5
9c DMF
10 DMF
11 DMF
12 DMF
13d DMF
14e DMF
15f DMF
_
12
5
K2CO3 CuCl
K2CO3 CuBr
K2CO3 CuSO4
K2CO3 CuI
43
50
67
89
0
5
5
5
K2CO3
_
12
5
K2CO3 CuI
87
All the reactions were carried out using 1 equiv 8a and 1 equiv 10a and 1.5 equiv base and 10
mol% catalyst [b] isolated yields [c] no base was used [d] 20 mol% CuI was used as catalyst [e]
reaction was carried out without any catalyst [f] 20 mol % L-proline was used as ligand with 10
mol% CuI

6
Application of heat at 110 oC to this reaction gave satisfactory result affording the desired product
in 92% yield within 5h (entry 2, table 1). We have conducted the same reaction in other solvents
like DMSO, toluene, 1,4-dioxane, but none of them could improve the yield of the product (entry
3-5, Table 1). The use of DMF as solvent gives the desired product in highest yield. Then we
carried out some reaction by replacing the base K2CO3 with other bases like Cs2CO3, Et3N or
Na2CO3 but no improvement of the yield of cyclized product was observed (entry 6-8, Table 1).
The reaction did not occur at all in the absence of any base (entry 9, Table 1). To investigate the
role of catalyst used we set up some reaction using different Cu-sources. Use of CuCl, CuBr as
catalyst gave 43% and 50% yield of the cyclized product (entry 10, 11, Table 1), whereas the use
of CuSO4 as the Cu-source afforded 67% yield of the product (entry 12, Table 1). Further catalyst
loading (20 mol % CuI) did not improve the yield of the cyclized product (entry 13, Table 1). The
reaction without any catalyst did not give any cyclized product at all (entry 14, Table 1). Again no
significant change in the yield was observed by adding L-proline as a ligand (entry 15, Table 1).
From the above set of experiments, the optimized condition developed is to treat 1 equiv. of o-
azidobenzylbromide with 1 equiv. N-propargylated aniline, 1.5 equiv. K2CO3, 10 mol% CuI in
o
DMF at 110 C for 5-6h. To generalize this reaction we have synthesized various triazolo[1,5-
a][1,4]benzodiazepines (11a-i) and the results are summarized in Table 2.

7
Table 2: Cu-catalyzed tandem Ullmann C–N coupling/ azide-alkyne cycloaddition reactions with various substratesa
R1
Br
HN
R3
N3
DMF, K2CO3
N
+
R2
CuI, 110 oC
N
R1
R2
N
R3
10
8
11
N
Entry
1
Azide
Amine
Time (h)
5
Product
Yieldb (%)
92
8a, R1 = H, R2 = H
8a, R1 = H, R2 = H
8a, R1 = H, R2 = H
8a, R1 = H, R2 = H
8a, R1 = H, R2 = H
10a, R3 = H
11a, R1 = H, R2 = H, R3 = H
11b, R1 = H, R2 = H, R3 = Me
11c, R1 = H, R2 = H, R3 = OMe
11d, R1 = H, R2 = H, R3 = Cl
11e, R1 = H, R2 = H, R3 = F
11f, R1 = Cl, R2 = H, R3 = H
11g, R1 = Cl, R2 = H, R3 = Me
11h, R1 = Cl, R2 = H, R3 = F
11i, R1 = H, R2 = Cl, R3 = H
2
3
4
5
6
7
8
9
10b, R3 = Me
10c, R3 = OMe
10d, R3 = Cl
10e, R3 = F
6
6
5
5
5
6
5
6
95
91
88
86
90
89
85
82
8b, R1 = Cl, R2 = H 10a, R3 = H
8b, R1 = Cl, R2 = H 10b, R3 = Me
8b, R1 = Cl, R2 = H 10e, R3 = F
8c, R1 = H, R2 = Cl 10a, R3 = H
[a] Reaction conditions: compound 8 (1 equiv.), propargylated aniline 10 (1 equiv.), K2CO3 (1.5 equiv.), 10 mol%
CuI were heated at 110 oC in DMF, [b] isolated yields of 11
According to the literature, we know that copper-catalyzed cycloaddition reaction affords
exclusively the 1,4-regioisomers18 and initial formation of the intermediate B is not possible using
Cu-catalyst. Hence the reaction can go through the initial formation of intermediate A via Cu-
catalyzed intermolecular C-N coupling of compound 8 with amine 10. Intermediate A may
undergo intramolecular azide-alkyne cycloaddition yielding the triazole-fused benzodiazepines 11
(Scheme 2).

8
R3
Br
HN
R1
CuI, Base
N3
R2
N
+
Ullmann C-N coupling
R1
N3
R3
10
Cu
R2
8
A
1,3-dipolar
cycloaddition
R3
Br
H
R1
N
R1
N
N
N
R2
R3
N
N
R2
N
N
11
1,5-regeoisomer (B)
Scheme 2: Rationalization for the formation of compound 11
-11c, -12, -14
Most of the earlier protocols for the synthesis of triazole-fused benzodiazepines-
used
costly reagents and sometime occurs in a multistep manner, while our method is straightforward,
uses inexpensive reagent and is devoid of any ligand. In conclusion, we have developed a simple
approach for the synthesis of triazolo[1,5-a][1,4]benzodiazepines derivatives with potential
biological activity through the combination of C-N coupling reaction and intramoleculer 1,3-
dipolar cycloaddition reaction in a tandem fashion. This ligand-free protocol provides advantages
in terms of excellent yield, step-economy, ease of operation and substrate scope.
Acknowledgments:
We thank CSIR (New Delhi) and UGC (New Delhi) for financial assistance. S.G. is grateful to
CSIR (New Delhi) for his research fellowship and K.C.M. is thankful to UGC (New Delhi) for a
UGC Emeritus fellowship. We also thank DST (New Delhi) for providing Bruker NMR (400
MHz), Perkin-Elmer CHN Analyser, FT-IR and UV-Vis spectrometer.

9
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12
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Graphical Abstract
An expedient approach to substituted triazolo[1,5-
a][1,4]benzodiazepines via Cu-catalyzed tandem Ullmann C-N
coupling/ azide-alkyne cycloaddition
K. C. Majumdar*, Sintu Ganai
Department of Chemistry, University of Kalyani, Kalyani 741235,
W.B India
*Corresponding author. Tel.: +9133-2582 8750 ; Fax: +9133-2582
8282 ; E-mail: kcm@klyuniv.ac.in; kcm_ku@yahoo.co.in
R1
Br
HN
R3
N3
R2
DMF, K CO
2
3
N
+
R2
o
N
N
CuI, 110 C
R1
N
R3