Microwave-assisted three-component domino reaction: Synthesis of indolodiazepinotriazoles

Article abstract of DOI:10.3762/bjoc.9.41

A microwave-assisted three-component protocol involving N-1 alkylation of 2-alkynylindoles with epichlorohydrin, ring opening of the epoxide with sodium azide, and an intramolecular Huisgen azide-internal alkyne 1,3-dipolar cycloaddition domino sequence has been described. The efficacy of the methodology has been demonstrated by treating various 2-alkynylindoles (aromatic/aliphatic) with epichlorohydrin and sodium azide furnishing annulated tetracyclic indolodiazepinotriazoles in satisfactory yields.

Full text of DOI:10.3762/bjoc.9.41

Microwave-assisted three-component domino
reaction: Synthesis of indolodiazepinotriazoles
Rajesh K. Arigela1, Sudhir K. Sharma1, Brijesh Kumar2 and Bijoy Kundu*1,2,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 401–405.
1Medicinal & Process Chemistry Division CSIR-Central Drug
Research Institute, Lucknow-226001, India and 2Sophisticated
Analytical and Instrumental Facility, CSIR-Central Drug Research
Institute, Lucknow-226001, India
doi:10.3762/bjoc.9.41
Received: 27 November 2012
Accepted: 23 January 2013
Published: 19 February 2013
Email:
Bijoy Kundu* - bijoy_kundu@yahoo.com
Associate Editor: J. P. Wolfe
* Corresponding author
© 2013 Arigela et al; licensee Beilstein-Institut.
License and terms: see end of document.
§ Tel.: +91 522 2612411-18-Ext 4383; fax: +91 522 2623405
Keywords:
2-alkynylindoles; azides; 1,3-dipolar cycloaddition; domino reaction;
indolodiazepinotriazoles
Abstract
A microwave-assisted three-component protocol involving N-1 alkylation of 2-alkynylindoles with epichlorohydrin, ring opening
of the epoxide with sodium azide, and an intramolecular Huisgen azide–internal alkyne 1,3-dipolar cycloaddition domino sequence
has been described. The efficacy of the methodology has been demonstrated by treating various 2-alkynylindoles (aromatic/ali-
phatic) with epichlorohydrin and sodium azide furnishing annulated tetracyclic indolodiazepinotriazoles in satisfactory yields.
Introduction
The intermolecular Huisgen azide–alkyne 1,3-dipolar cycload- heterocycles. Although these cyclizations have been success-
dition reaction [1-6] for the synthesis of 1,2,3-triazoles in both fully carried out in either one-pot [22-24] or multistep format
aqueous [7-10] and organic solvents under either metal- [25-28], reports involving their application in a three-compo-
catalyzed [11-13] or metal-free conditions [14-16] has received nent domino format are scarce [29,30]. In our laboratory, we
increasing attention in drug discovery processes [17,18]. The had been employing functionalized indoles for the synthesis of
ease of reaction in the intermolecular format has been success- annulated indole-based polyheterocycles either in a multicom-
fully demonstrated by using both organic/inorganic azides as ponent or in a one-pot format [31-35]. In this continuation, we
well as alkynes/diynes [19-21]. In contrast to its employment in next directed our efforts to the development of a three-compo-
an intermolecular format, intramolecular azide–alkyne 1,3- nent domino strategy for the synthesis of indole-based polyhete-
dipolar cycloaddition reactions have been also applied by us rocycles by incorporating the intramolecular azide–alkyne 1,3-
and others with the view to synthesize triazole-annulated poly- dipolar cycloaddition reaction as one of the domino steps. Here
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Beilstein J. Org. Chem. 2013, 9, 401–405.
we propose a strategy where N-1 of 2-alkynylindole [36,37] can
be first functionalized with epoxide by reacting 2-alkynylindole
with epichlorohydrin. This can then be followed by ring
opening of the oxirane by azide to furnish a bis-functionalized
indole intermediate having azide and alkyne groups in close
proximity. Such an intermediate may then undergo annulation
following an intramolecular 1,3-dipolar cycloaddition pathway
and in turn lead to the sequential formation of 7- or
5-membered diazepine and triazole rings in a single step. In this
communication, we report a versatile microwave-assisted three
component domino reaction to furnish annulated tetracyclic
indolodiazepinotriazoles in good yields.
Table 1: Optimization of reaction conditions for the synthesis of 6a in a
three-component domino format.
Entry
Base
Solvent Temp (°C) Time
Yield (%)a
of 4a/5a/6a
1
–
toluene
rt
15 h
15 h
15 h
15 h
15 h
1 h
NR
NR
2
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 CH3CN
rt
3
110
90
NR
4
65/–/–
NR
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
rt
6
120
120
120
120
120
120
120
120
77/–/–
40/30/–
–/15/50
–/–/60
82/–/–
42/40/–
–/20/52
–/–/64
80/–/–
7
4 h
8
15 h
18 h
1 h
9
Results and Discussion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
4 h
We commenced our studies with the development of a one-pot
three-component strategy involving the condensation of the
2-(4-methylphenylethynyl)-1H-indole (1a) with epichloro-
hydrin (2) and sodium azide (3, Scheme 1, Table 1). Initially, a
mixture of 1a, 2 and 3 was allowed to react both in the absence
and presence of Cs2CO3 in toluene at rt. The reactants under
both the conditions remained unchanged even after prolonged
stirring for 15 h (Table 1, entries 1–3) and at higher tempera-
ture (110 °C).
10 h
15 h
120 MW 10 min
120 MW 30 min 20/45/10b
120 MW
120 MW
120 MW
90 MW
1 h
–/18/42
–/–/71
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
Cs2CO3
DMF
–/–/64
Cs2CO3 CH3CN
Cs2CO3 CH3OH
K2CO3 DMSO
Na2CO3 DMSO
K3PO4 DMSO
t-BuOK DMSO
80/–/–
90 MW
NR
120 MW
120 MW
120 MW
120 MW
120 MW
120 MW
–/10/54b
–/12/52b
–/–/62
However, a change in the nature of solvent from toluene to
CH3CN, DMF or DMSO produced a dramatic effect on the
outcome of the reaction, resulting in the formation of products
comprising intermediates (4a and/or 5a) and/or indole-based
polyheterocycle indolodiazepinotriazole 6a. Use of the polar
solvent CH3CN at 90 °C for 15 h furnished a single product in
65% isolated yield, which was characterized as 2-[2-(4-methyl-
–/–/65
DBU
TEA
DMSO
DMSO
–/15/48b
–/20/45b
aIsolated yields. bYields based on HPLC (C18 reversed-phase column,
150 × 4.8 mm, 5 µm). NR = no reaction.
Scheme 1: One-pot three-component domino reaction furnishing indole derivatives (4a and 5a) and indolodiazepinotriazole 6a.
402

Beilstein J. Org. Chem. 2013, 9, 401–405.
phenyl)ethynyl]-1-(oxiran-2-ylmethyl)-1H-indole (4a, Table 1, furnished the intermediate 4a as the only product in 80%
entry 4). In contrast, use of the polar aprotic solvent DMF with isolated yield (Table 1, entry 14), whereas a 30 min irradiation
high dielectric constant produced both intermediates 4a/5a as resulted in a mixture of 4a/5a/6a in 20/45/10% yields as evident
well as the annulated product 6a. Interestingly, a significant from HPLC (Table 1, entry 15). Extending exposure to
increase in the yield of the title compound 6a was observed by microwave conditions for 1 h produced a mixture of 5a and 6a
prolonging the reaction. Carrying out the reaction in DMF at rt (Table 1, entry 16); however, a further exposure up to 1.5 h
also failed to promote annulation even after 15 h of prolonged furnished the desired compound 6a as the only product in 71%
stirring (Table 1, entry 5). Increasing the temperature to 120 °C isolated yield (Table 1, entry 17). Thus, under microwave ir-
furnished the intermediate 4a as a single product in 77% radiation conditions, not only the isolated yield of 6a increased
isolated yield within 1 h (Table 1, entry 6). Further stirring up to from 60% under conventional heating to 71%, but the duration
4 h at 120 °C led to the partial conversion of 4a (by ring of reaction was also reduced from 15 h to 1.5 h. Switching the
opening of the epoxide with NaN3) into yet another intermedi- solvent from DMSO to DMF under microwave conditions
ate 1-azido-3-{2-[2-(4-methylphenyl)ethynyl]-1H-indol-1- furnished 6a in slightly reduced yield (Table 1, entry 18) while
yl}propan-2-ol (5a, Table 1, entry 7) in 30% isolated yield. the use of CH3CN and CH3OH failed to produce the desired
Nonetheless, extending the reaction times up to 15 h, led to the product (Table 1, entry 19 and 20). Replacing Cs2CO3 with
complete disappearance of 4a and furnished a mixture of the other bases such as K2CO3, Na2CO3, K3PO4, t-BuOK, DBU
intermediate 5a in 15% isolated yield and the title compound 6a and TEA either produced a mixture of 5a/6a or furnished 6a in
characterized as 1-(4-methylphenyl)-6,7-dihydro-5H-[1,2,3]tri- reduced yields (Table 1, entries 21–26). The observations
azolo[5',1':3,4][1,4]diazepino[1,2-a]indol-6-ol in 50% isolated clearly suggest that the formation of 6a in the three-component
yield (Table 1, entry 8). The findings clearly suggest that the format involved intermolecular N-1 alkylation of the
formation of indole-based annulated product 6a in the three- 2-alkynylindole 1a with epichlorohydrin to form 4a, ring
component domino format occurs via 4a and 5a intermediacy opening of 4a with sodium azide to form 5a, and finally an
and requires higher temperature and prolonged stirring. This intramolecular Huisgen azide–internal alkyne 1,3-dipolar cyclo-
was again evident from the fact that a prolonged stirring up to addition reaction.
18 h led to the complete disappearance of the intermediates 4a
and 5a and afforded 6a as a single product in 60% isolated yield Once the reaction conditions for the three-component format
(Table 1, entry 9). The role of intermediates 4a and 5a in the had been optimized, several 2-alkynylindoles bearing different
formation of 6a was further substantiated by treating 4a with functional groups were treated with epichlorohydrin and sodium
NaN3 in DMF at 120 °C and by heating 5a in DMF at 120 °C. azide in order to establish the scope and limitation of the
As envisaged, both reactions furnished 6a as a single product in strategy. In total 22 compounds 6a–v (Scheme 3) were synthe-
87% and 90% isolated yield, respectively (Scheme 2). sized, with their isolated yields varying from 54–73%. The find-
Replacing DMF with yet another polar aprotic solvent, i.e., ings suggest that although the electronic properties of the
DMSO, produced similar results except for a marginal increase substitution (R1) on the phenyl ring of the indole had no effect
in the isolated yield of 6a to 64% in 15 h (Table 1, entries on the outcome of the isolated yield of the final products, the
10–13).
nature of R2 had a profound effect on the yields. When the
aromatic group was used as R2, the final products 6a–c and
6e–q were obtained in isolated yields ranging from 66–73%,
whereas substituting R2 with aliphatic/trimethylsilyl moieties
furnished the cyclized products (6d and 6r–v) in diminished
(54–65%) isolated yields.
Conclusion
In conclusion, we have developed a simple and efficient three-
Scheme 2: Transformation of intermediates 4a and 5a to 6a.
component domino reaction for the synthesis of highly substi-
Next, in order to reduce the reaction times and to enhance the tuted indolodiazepinotriazoles in good yields under microwave
isolated yield of the annulated product 6a, we applied conditions. The domino sequence comprising N-1 alkylation,
microwave conditions instead of conventional heating and ring opening of the epoxide, and intramolecular Huisgen
monitored the progress of the reaction at different time inter- azide–internal alkyne 1,3-dipolar cycloaddition reaction, led to
vals. A significant increase in the yield of 6a resulting from the the generation of the diazepine and triazole rings annulated to
increase in the reaction times under microwave conditions was the indole through the formation of four new sigma bonds in a
observed. Initially, a 10 min irradiation of the reaction mixture single step.
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Beilstein J. Org. Chem. 2013, 9, 401–405.
Scheme 3: Three-component domino reaction for the synthesis of tetracyclic indolodiazepinotriazole compounds based on 6a. Reaction conditions:
1a (1.0 mmol), 2 (1.1 mmol), 3 (1.5 mmol) and Cs2CO3 (1.5 mmol) in DMSO (2.5 mL) at 120 °C, MW under N2 atmosphere.
404

Beilstein J. Org. Chem. 2013, 9, 401–405.
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Supporting Information
Supporting Information File 1
Experimental section, copies of 1H, 13C NMR and HRMS
spectra of starting and final compounds 1e, 1h, 1j–1l,
1n–1t, 1v, 4a, 5a and 6a–6v.
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The definitive version of this article is the electronic one
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