Cascade intermolecular Michael addition-intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction in one pot

Article abstract of DOI:10.1021/ol300399y

A rapid one-pot protocol for the synthesis of indole-based polyheterocycles via a sequential Lewis acid catalyzed intermolecular Michael addition and an intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction has been described. The genera

Full text of DOI:10.1021/ol300399y

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1804–1807
Cascade Intermolecular Michael
AdditionÀIntramolecular Azide/Internal
Alkyne 1,3-Dipolar Cycloaddition Reaction
in One Pot
Rajesh K. Arigela,† Anil K. Mandadapu,† Sudhir K. Sharma,† Brijesh Kumar,‡ and
Bijoy Kundu*,†
Medicinal & Process Chemistry Division and Sophisticated Analytical and Instrumental
Facility, Central Drug Research Institute, CSIR, Lucknow-226001, India
bijoy_kundu@yahoo.com; b_kundu@cdri.res.in
Received February 17, 2012
ABSTRACT
A rapid one-pot protocol for the synthesis of indole-based polyheterocycles via a sequential Lewis acid catalyzed intermolecular Michael addition
and an intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction has been described. The generality of the method has been
demonstrated by treating a series of aromatic/aliphatic 2-alkynyl indoles with substituted (E)-1-azido-2-(2-nitrovinyl)benzenes to furnish
annulated tetracyclic indolo[2,3-c][1,2,3]triazolo[1,5-a][1]benzazepines in good yields.
The intermolecular azideÀalkyne 1,3-dipolar cycloaddi-
the synthesis of 1,2,3-triazoles with widespread applica-
tions in medicinal chemistry, chemical biology, and mate-
rial science.1 The ease and efficacy of the reaction has been
successfully demonstrated in both aqueous2 and organic
solvents involving either metal-catalyzed3 or metal-free
conditions4 with temperatures ranging from ambient to
heating. Besides, the remarkable cycloaddition process
was found to be compatible with both terminal/internal
tion reaction has remained one of the classical methods for
† Medicinal & Process Chemistry Division.
‡ Sophisticated Analytical and Instrumental Facility.
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r
10.1021/ol300399y
Published on Web 03/22/2012
2012 American Chemical Society

alkynes and diynes5 resulting in triazoles with a high order
of regioselectivity. In addition to this intermolecular
azideÀalkyne 1,3-dipolar cycloaddition format, several
groups have also applied the intramolecular azideÀalkyne
1,3-dipolar cycloaddition strategy for the synthesis of
triazole linked amino acids/oligopeptides6 and triazole-
annulated polyheterocycles.7 However, most of these
intramolecular strategies predominantly involved termi-
nal alkynes in a multistep format8 to promote 1,3-dipolar
cycloaddition with limited applications9 to internal
alkynes. Ideally, an intramolecular 1,3-dipolar cyclo-
addition reaction in contrast to the intermolecular format
can be expected to furnish two annulated cyclic rings10
including a triazole ring in a single step and can thus be
considered as a useful strategy for generating molecular
complexity in a one-pot format. In our laboratory we had
been exploiting the nucleophilicities of the three N-1, C-3,
and C-2 positions in the indole by treating functionalized
indoles with alkynyl (electrophiles) components to access
annulated indoles, fused at either of the two positions
using one-pot strategies.11 In one-pot formats func-
tionalized indoles, in general, have remained relatively
underexplored.12 In continuation, we next directed our
effort to yet another class of functionalized indoles, i.e.
2-alkynyl-indoles, that will act as a combined source for
both indole (nucleophile) and an alkyne (electrophile)
moiety for the development of a one-pot strategy for the
synthesis of annulated indoles involving an intramolecular
1,3-dipolar cycloaddition reaction. To achieve this, we
envisaged that functionalizing position C-3 in the 2-alky-
nyl-indole with an azido arene moiety may enforce (due to
the close proximity of the azide and the alkyne moieties)
the formation of two annulated 7- and 5-membered het-
erocyclic rings via the intramolecular 1,3-dipolar cyclo-
addition reaction in a single step. Here, we report a fast and
versatile one-pot cascade intermolecularMichael addition-
intramolecular azide-internal alkyne 1,3-dipolar cycload-
dition reaction to furnish annulated tetracyclic indolo[2,3-c]-
[1,2,3]triazolo[1,5-a][1]benzazepines in good yields.
Our studies commenced with the development of a
methodology for the C-3 functionalization of 2-phenyl-
Table 1. Optimization for the Synthesis of C-3 Alkylated
Product 3aa
yield (%)
entry
catalyst
solvent
temp
of 3aa
1
2
3
4
5
6
7
8
9
10
Yb(OTf)3
toluene
toluene
MeCN
DMF
rt
10b
NR
61a
NR
NR
NR
NR
NR
<10b
55
c
À
rt
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Zn(OTf)2
AgOTf
rt
rt
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
rt
rt
rt
Hg(OAc)2
Cu(OTf)2
Sc(OTf)3
rt
rt
50 °C
a Isolated yields. b Yields based on HPLC (C18 reversed-phase
column; 150 mm  4.6 mm; 5 μm). c Reaction carried out without
catalyst; NR = No Reaction. All reactions were carried out on a 1 mmol
scale with 10 mol % of Lewis acid in 5 mL of solvent at rt and monitored
for 12 h.
ethynyl-1H-indole 1aby treating it with a (E)-1-azido-2-(2-
nitrovinyl)benzene 2a. Among several methods described
in the literature13 for the C-3 functionalization of the
indoles under mild conditions, we proposed to use a Lewis
acid catalyzed Michael addition, and the results have
been summarized in Table 1. Accordingly, 1a was initially
treated with 2a in the presence of Yb(OTf)3 in toluene at rt,
and after 12 h of stirring a new product was obtained in
∼10% isolated yield with a molecular weight of 407 Da
(entry 1). The structure of the product was elucidated by
the combined use of1H and 13C NMR experimentsthat led
to its identification as 3-[1-(2-azido-phenyl)-2-nitro-ethyl]-
2-phenylethynyl-1H-indole 3aa arising from the C-3 alky-
lation of the indole. Carrying out the same reaction in the
absence of catalyst failed to yield 3aa (entry 2). Switching
the solvent from toluene to acetonitrile at rt in the presence
of Yb(OTf)3 furnished 3aa in 61% isolated yield (entry 3),
whereas carrying out the reaction in DMF at rt failed to
(5) (a) Mandadapu, A. K.; Sharma, S. K.; Gupta, S.; Krishna,
D. G. V.; Kundu, B. Org. Lett. 2011, 13, 3162–3165. (b) Monkowius,
U.; Ritter, S.; Konig, B.; Zabel, M.; Yersin, H. Eur. J. Inorg. Chem. 2007,
4597–4606. (c) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.;
Quarta, M. R.; Fittipaldi, M. Synthesis 2009, 3853–3859. (d) Fiandanese,
V.; Bottalico, D.; Marchese, G.; Punzi, A.; Capuzzolo, F. Tetrahe-
dron 2009, 65, 10573–10580. (e) Aizpurua, J. M.; Azcune, I.; Fratila,
R. M.; Balentova, E.; Aizpurua, M. S.; Miranda, J. I. Org. Lett. 2010, 12,
1584–1587.
(6) (a) Sai Sudhir, V.; Nasir Baig, R. B.; Chandrasekaran, S. Eur. J.
Org. Chem. 2008, 2423–2429. (b) Turner, R. A.; Oliver, A. G.; Scott
Lokey, R. Org. Lett. 2007, 9, 5011–5014.
(7) (a) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2004, 45,
3725–3728. (b) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 8439–8441.
(8) (a) Yanai, H.; Taguchi, T. Tetrahedron Lett. 2005, 46, 8639–8643.
(b) Majumdar, K. C.; Ray, K.; Ganai, S. Synthesis 2010, 2101–2105.
(9) For a recent review: Majumdar, K. C.; Ray, K. Synthesis 2011,
3767–3783.
(10) Kunick, C. Liebigs Ann. Chem. 1993, 10, 1141–1143.
(11) (a) Sharma, S. K.; Mandadapu, A. K.; Saifuddin, M.; Gupta, S.;
Agarwal, P. K.; Mandwal, A. K.; Gauniyal, H. M.; Kundu, B. Tetra-
hedron Lett. 2010, 51, 6022–6024. (b) Sharma, S. K.; Gupta, S.;
Saifuddin, M.; Mandadapu, A. K.; Agarwal, P. K.; Gauniyal, H. M.;
Kundu, B. Tetrahedron Lett. 2011, 52, 65–68. (c) Gupta, S.; Kumar, B.;
Kundu, B. J. Org. Chem. 2011, 76, 10154–10162. (d) Gupta, S.; Sharma,
S. K.; Mandadapu, A. K.; Gauniyal, H. M.; Kundu, B. Tetrahedron
Lett. 2011, 52, 4288–4291. (e) Sharma, S. K.; Mandadapu, A. K.;
Kumar, B.; Kundu, B. J. Org. Chem. 2011, 76, 6798–6805.
(12) For review, see: Sapi, J.; Laronze, J. Y. ARKIVOC 2004, 208–
222 and references cited therein.
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76, 2909–2912. (b) Epifano, F.; Genovese, S.; Rosati, O.; Tagliapietra,
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Org. Lett., Vol. 14, No. 7, 2012
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yield any product (entry 4). Replacementof Yb(OTf)3 with
other Lewis acid catalysts Sc(OTf)3, Zn(OTf)2, Cu(OTf)2,
AgOTf, and Hg(OAc)2 played a detrimental role in the
reaction (entries 5À9). However, carrying out the reaction
in the presence of Sc(OTf)3 at 50 °C in MeCN furnished
3aa in 55% isolated yield (entry 10).
Next we examined the ability of intermediate 3aa to
undergo an intramolecular azide-internal alkyne 1,3-dipo-
lar cycloaddition reaction, and the results have been
summarized in Table 2. For this 3aa was subjected to
heating in toluene under reflux in the presence of Yb(OTf)3,
and to our delight within 30 min we obtained an annulated
reaction in the presence of Yb(OTf)3 using toluene as
solvent under reflux afforded 4aa within 30 min in 86%
isolated yield (entry 2). Switching the solvent from toluene
to acetonitrile and heating at 90 °C furnished a mixture of
3aa and 4aa in 14% and 42% yields (entry 3), whereas in
xylene at 145 °C 4aa was furnished in 38% yield (entry 4).
Carrying out the reaction in DMF and heating at 120 °C
failed to furnish 4aa; instead 3aa was obatined in 45%
isolated yield (entry 5). Replacing Yb(OTf)3 with other
Lewis acids resulted in only Sc(OTf)3 and Zn(OTf)2 fur-
nishing 4aa in 58% (entry 6) and 35% isolated yield (entry 7);
AgOTf, Cu(OTf)2, and Hg(OAc)2 failed to even promote
the formation of 3aa and 4aa (entries 8À10).
Table 2. Optimization for the Conversion of 3aa to 4aa
Table 3. Optimization of Reaction Conditions for the One-Pot
Synthesis of 4aa
temp
time
(h)
yield (%)
entry
catalyst
solvent
(°C)
of 3aa/4aa
temp
time
(h)
yield (%)a
b
1
2
À
toluene
toluene
MeCN
xylene
DMF
120
120
90
0.5
12
12
12
12
12
12
12
12
12
NR
entry
catalyst
solvent
(°C)
of 4aa
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Zn(OTf)2
AgOTf
0/86a
14/42c
0/38a
45a/0
0/58a
0/35a
NR
3
1
2
3
4
5
6
Yb(OTf)3
toluene
toluene
MeCN
MeCN
tylene
xylene
120
120
90
0.5
0.5
12
88
90
52
45
85
86
b
4
145
120
120
120
120
120
120
À
5
Yb(OTf)3
b
6
toluene
toluene
toluene
toluene
toluene
À
90
12
7
Yb(OTf)3
145
145
0.5
0.5
b
8
À
9
Cu(OTf)2
Hg(OAc)2
NR
a Isolated yields. b Reaction carried out without catalyst.
10
NR
a Isolated yields. b Reaction carried out without catalyst. c Yields
based on HPLC (C18 reversed-phase column; 150 mm  4.6 mm; 5 μm).
NR = No Reaction. All reactions were carried out on a 1 mmol scale
with 10 mol % of Lewis acid in 5 mL of solvent.
tetracyclic compound 4aa comprising a benzazepine ring
and a triazole ring annulated to the indole in 88% isolated
yield (entry 1).
In order to establish the role of Yb(OTf)3 in the 1,3-
dipolar cycloaddition reaction, we carried out the same
reaction in the absence of catalyst and gratifyingly product
4aa was isolated in 90% yield (entry 2). Switching the
solvent from toluene to acetonitrile in both the presence
and absence of Yb(OTf)3 furnished 4aa (entries 3 and 4) in
reduced yield. However carrying out the reaction in xylene
had no effect on the yield of 4aa (entries 5 and 6). From the
above studies it is apparent that while the Lewis acid
played a crucial role in the C-3 functionalization of the
indole for introducing azido arenes to furnish 3aa, the
intramolecular 1,3-dipolar cycloaddition occurred without
the involvement of the catalyst and remained a thermally
induced reaction.
Once the reaction conditions for the synthesis of 3aa and
4aa were optimized, we proceeded with the development of
a one-pot strategy for the synthesis of 4aa from 1a and 2a,
and the results have been summarized in Table 3. We
commenced our studies by treating 1a with 2a in toluene
under reflux in the absence of a Lewis acid, which failed to
yield the desired product (entry 1). Carrying out the
Following the optimization of reaction conditions for
the synthesis of indole-based tetracyclic 4aa was estab-
lished, the scope and limitation of the one-pot strategy
was established by treating a variety of 2-alkynyl indoles
with a range of preformed substituted (E)-1-azido-2-
(2-nitrovinyl)benzenes. The R1 in the aromatic ring of
the indole has been substituted with 7-methoxy, 5,6-di-
methoxy, and 5,6-methylenedioxy groups whereas R2 in
the alkyne included aliphatic, aromatic, and trimethylsilyl
moieties. The R3 in the aromatic ring of the nitrostyrene
has been substituted by a 4-chloro as well as a 6-methoxy
group. In all, 26 compounds based on 4aaÀmc were
synthesized in isolated yields of 40À88% (Table 4), and
in all cases, the one-pot reactions were found to be
complete with 30À90 min. As is evident from Table 4,
the electronic properties of the substituent on the phenyl
ring of the indole moiety or nitrostyrene had no effect on
the yields of the final compounds. Similarly, replacing
R2 with an aliphatic moiety or an aromatic ring had a
negligible effect on the reactions, offering products with
1806
Org. Lett., Vol. 14, No. 7, 2012

Table 4. One-Pot Synthesis of Tetracyclic Compounds Based on 4a
no.
R1
R2
C6H5
R3
time (min)
product
% yield
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
30
35
30
40
30
35
35
40
30
35
45
45
30
35
45
40
35
35
40
45
40
35
40
45
90
90
4aa
4ba
4ca
4ea
4ab
4bb
4cb
4eb
4ac
4cc
4ec
4dc
4kb
4kc
4la
86
85
84
80
86
80
83
78
88
85
83
82
80
84
79
78
81
77
80
82
76
82
84
77
40
42
2
4-CH3-C6H4
4-t-Bu-C6H4
C6H9
3
4
5
C6H5
11-Cl
11-Cl
11-Cl
11-Cl
13-CH3O
13-CH3O
13-CH3O
13-CH3O
11-Cl
13-CH3O
H
6
4-CH3-C6H4
4-t-Bu-C6H4
C6H9
7
8
9
C6H5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-t-Bu-C6H4
C6H9
C6H13
5-CH3O
C6H5
5-CH3O
C6H5
5-CH3O
C4H9
5-CH3O
C4H9
13-CH3O
H
4lc
6,7-di-CH3O
6,7-di-CH3O
6,7-di-CH3O
6,7-di-CH3O
6,7-di-CH3O
6,7-OCH2O-
6,7-OCH2O-
6,7-OCH2O-
H
C6H5
4fa
4-CH3-C6H4
C6H5
H
4ga
4fb
4gb
4ha
4ia
11-Cl
11-Cl
H
4-CH3-C6H4
C6H9
C6H5
H
C6H5
13-CH3O
H
4ic
C6H9
4ja
H
H
4ma
4mc
H
H
13-CH3O
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), and Yb(OTf)3 (0.1 mmol) in toluene (5 mL) at 120 °C under N2 atmosphere.
minimal variation in yields. However, substituting R2 with
a trimethyl silyl group furnished 4ma (R2 = H) and 4mc
(R2 = H) in reduced yields of 40 and 42% respectively. In
general, internal alkynes with R2 as the aromatic ring
furnished products in 77À88% isolated yield, whereas R2
having an aliphatic and trimethyl silyl moiety furnished
products in 40À83% isolated yields.
toextendthisone-pot intramolecular azide/internal alkyne
1,3-dipolar cycloaddition strategy to other functionalized
indoles, and findings shall be published elsewhere.
Acknowledgment. R.K.A., A.K.M., and S.K.S. are
thankful to CSIR, New Delhi, India for financial support.
The authors also would like to thank SAIF, CDRI, India
for providing analytical data.
In conclusion, we have developed a simple and efficient
cascade reaction for the synthesis of highly substituted
indolo[2,3-c][1,2,3]triazolo[1,5-a][1]benzazepines in good
yields under mild reaction conditions. The salient feature
of the protocol involves a Lewis acid catalyzed intermole-
cular Michael addition followed by a thermal induced
intramolecular azide/internal alkyne 1,3-dipolar cycload-
dition reaction in one pot. Further studies are in progress
1
Supporting Information Available. Copies of H, 13C
NMR spectra and HRMS of all final and starting com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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