An efficient one-pot, three-component reaction: Synthesis of complex-annelated α-carbolines via an intramolecular [3+2]-dipolar cycloaddition reaction

Article abstract of DOI:10.1055/s-0030-1260787

Novel annelated α-carbolines have been synthesized from oxindole using three components in a one-pot procedure involving an intramolecular [3+2]-dipolar cycloaddition reaction of azides to nitriles. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260787

LETTER
1547
An Efficient One-Pot, Three-Component Reaction: Synthesis of
Complex-Annelated a-Carbolines via an Intramolecular [3+2]-Dipolar
Cycloaddition Reaction
Synthesis of
C
w
omplex-Annelated
a
a
-Carboli
r
Medicinal Chemistry Division, North East Institute of Science & Technology (CSIR), Jorhat 785006, Assam, India
Fax +91(376)2370011; E-mail: pulak_jyoti@yahoo.com
Received 17 March 2011
wide range of biological activity and as important synthet-
ic precursors.11 These nitrogen-rich ring systems are also
used in propellants and explosives.12
Cycloaddition reactions13 allow the direct construction of
Abstract: Novel annelated a-carbolines have been synthesized
from oxindole using three components in a one-pot procedure in-
volving an intramolecular [3+2]-dipolar cycloaddition reaction of
azides to nitriles.
Key words: a-carboline, oxindole, [3+2]-dipolar cycloaddition re- new rings with a variety of substituents by simple addition
action, b-halo aldehyde, multicomponent reaction
of two or more reagents. Within this class, inter- and in-
tramolecular dipolar cycloaddition reactions have found
extensive use as efficient regio- and stereoselective meth-
odologies.14 With the current emphasis towards green
chemistry, chemical processes with high atom economy
have received growing attention from the scientific com-
munity. The [3+2]-dipolar cycloaddition of azides to ni-
triles being a typical case, leading to the formation of
1,2,3,4-tetrazoles.15
The a-carboline {pyrido[2,3-b]indole} system and its an-
nelated (Figure 1) comprise compounds possessing di-
verse biological activity such as antitumour,1 anti-HIV,2
antiviral,3 anxiolytic, anti-inflammatory, CNS stimulat-
ing,4 and antileukemia activity.5 Possibly the activities
that have attracted most attention to the a-carbolines are
CDK-1, CDK-5, and GSK-3 kinase inhibition.6 Further-
more, certain a-carbolines have found clinical application
for treatment of hypertension.7
One-pot multicomponent reactions (MCR), by virtue of
their convergence have attracted considerable attention.16
In the past decade there have been developments in three-
and four-component reactions and great efforts have been
made to develop new MCR.17
R1
As part of our continued interest in the area of synthesis of
diverse heterocyclic compounds of biological impor-
tance,18 we report herein an efficient method for the syn-
thesis of novel annelated a-carbolines by a three-
component, one-pot reaction involving intramolecular
[3+2]-dipolar cycloaddition reaction of azides to nitriles
(Scheme 1).
N
N
HN
NMe
R2
N
cryptotackieine
N
H
COOEt
Me
H2N
grossularine 1
R
1 = 3-acyl indole, R2 = NMe2
grossularine 2
1 = p-HOC6H4CO, R2 = NMe2
(cytotoxic)
Oxoindole (1), the starting material in our reaction strate-
gy, on treatment with the Vilsmeier reagent, afforded the
key b-halo aldehyde 2.9 Boc-protected indole 3a was pre-
pared in high yield by employing standard Boc-protection
protocol using di-tert-butyl dicarbonate (Boc2O).9 In the
three-component reaction19 equimolar amounts of 3a, eth-
yl cyanoacetate 4a, and sodium azide 5 were treated at
50 °C in the presence of a catalytic amount of triethyl-
amine for three hours using DMF as solvent. The solid ob-
tained on pouring the reaction mixture into water and after
workup afforded the compound 6a in good yield. The
structure of the compound was ascertained from spectro-
N
R
N
H
GABAA modulator
(treatment for anxiety)
Figure 1
Unsurprisingly, considering the importance of a-carbo-
lines, much effort has been made towards the synthesis of
these compounds.8 Recently, we have reported an effi-
cient method for the synthesis of a-carbolines by explor-
ing the ‘tertiary amino effect’ reaction strategy.9
1
scopic and elemental analysis. The H NMR spectrum
Five-membered nitrogen heterocycles play an important
role in biological systems.10 Among these,1,2,3,4-tetra-
zoles have received considerable attention due to their
showed the absence of the aldehyde proton and the pres-
ence of the ethyl group of the ester. The IR spectrum
showed the absence of the cyanide group, which evi-
denced its involvement in the cycloaddition reaction. The
mass spectrum revealed a strong peak at 382.4 [M+ + Na].
With suitable conditions established for the three-compo-
SYNLETT 2011, No. 11, pp 1547–1550
x
x
.x
x
.2
0
1
1
Advanced online publication: 15.06.2011
DOI: 10.1055/s-0030-1260787; Art ID: D08511ST
© Georg Thieme Verlag Stuttgart · New York

1548
S. Majumder, P. J. Bhuyan
LETTER
nent reaction, a series of compounds 6a–i was synthe- catalyst at room temperature to give the Knoevenagel con-
sized, utilizing various 2-chloro-3-formyl indoles 3a–c20 densation product [A] in quantitative yield.21 In order to
with alkyl nitriles 4a–c and sodium azide 5. The structures introduce the azido group at the 2-position of the indole
of the compounds were determined from their spectro- molecules, the compound [A] was treated with NaN3 (5)
scopic data and elemental analyses (Table 1). Although in DMF at 50 °C with stirring.22 However, the intermedi-
there was a possibility of the formation of the compound ate [B] could not be isolated but spontaneously underwent
7 from compound 3c via intramolecular 1,3-dipolar cy- intramolecular cycloaddition to the cyanide group to pro-
cloaddition of the azide to the isolated double bond, we duce the product 6a. The compound was comparable in all
have not observed the formation of such a cycloadduct.
respects to the compound obtained from the three-compo-
nent reaction.
O
R2
N
H
CHO
Cl
1
NaN3
5
C
N
i
base
CHO
R2CH2CN
+
CHO
CHO
Cl
DMF
N
N
R1
ii
Cl
iii
4a–c
Cl
R1
Cl
3a–c
[A]
N
R2
R2
N
N
H
Me
3b
2
Boc
3a
N
_
iv
N
C
CHO
Cl
N
NH
N
N
+
N
N
N
N
R1
R1
N
[B]
6a–i
3c
R2
Scheme 2
CHO
Cl
N
DMF
R2CH2CN
N
N
NaN3
The N-Boc deprotection could be achieved with standard
method.23 However, we report herein the N-Boc-protected
compounds because of their very good solubility, which
helps in their characterization (N-deprotected compounds
have very poor solubility).
+
N
50 °C
N
N
R1
4a R2 = CO2Et
4b R2 = CN
R1
5
3a R1 = Boc
3b R1 = CH3
3c R1 = Allyl
6a–i
4c R2 = CONH2
2
Table 1 Synthesis of Compound 6 via the Three-Component Reac-
tion
CHO
Cl
H
N
C=CCNR
+ R2CH2CN
N
N
NaN3
+
Product R1
R2
Temp Time Mp
(°C) (h) (°C)
Yield
(%)
N
N
7
3c
6a
6b
6c
6d
6e
6f
BOC
CO2Et
CO2Et
CO2Et
CN
60
60
60
50
50
50
60
60
60
3
3
3
222–223 71
229–230 70
189–190 67
Scheme 1 Reaction conditions: (i) DMF, POCl3; (ii) Boc2O; (iii)
MeI, NaH; (iv) allyl bromide, PTC, NaOH.
Me
CH2CH=CH2
Boc
Initially, we studied the reaction without protecting the ni-
trogen atom of the indole moiety but nucleophilic substi-
tution by azide did not occur, even under forcing
conditions. However, when the nitrogen atom was pro-
tected, nucleophilic substitution and the subsequent cy-
clization steps occurred very smoothly to give the desired
compounds in excellent yields. Cyanoacetamides are
found to be least reactive.
2.5 175–176 66
2.5 181–182 65
2.5 173–174 62
Me
CN
CH2CH=CH2
Boc
CN
6g
6h
6i
CONH2
CONH2
CONH2
3
3
3
210–211 55
239–240 59
207–208 57
Me
A plausible mechanism for the reaction is outlined in
Scheme 1. Initial Knoevenagel condensation of 3 and 4 in
the presence of triethylamine gives intermediate [A]
CH2CH=CH2
which then reacts with sodium azide to give [B]. The In conclusion, we report the synthesis of a novel class of
azide then undergoes an intramolecular [3+2]-dipolar cy- complex a-carboline derivatives from a simple oxindole
cloaddition to the pendant cyano group to afford the a-car- by exploring the intramolecular [3+2]-dipolar cycloaddi-
boline 6.
tion of azides to nitriles using a three-component, one-pot
protocol under mild conditions. The pathway for forma-
tion of the products in the three-component process was
established by performing the reaction stepwise. This very
simple protocol for the synthesis of tetracyclic angularly
The path of the reaction and hence the proposed mecha-
nism was established by performing the reaction stepwise
(Scheme 2). First, we treated 1-Boc-2-chloro-3-formyl in-
dole (3a) with ethyl cyanoacetate (4a) using piperidine as
Synlett 2011, No. 11, 1547–1550 © Thieme Stuttgart · New York

LETTER
Synthesis of Complex-Annelated a-Carbolines
1549
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank DST, New Delhi for financial support. Mr. S.
Majumder thanks CSIR for a research fellowship.
References and Notes
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(19) General Procedure for Three-Component Reaction
To a mixture of 1-Boc-2-chloro-3-formylindole (3a, 279
mg, 1 mmol), ethyl cyanoacetate (4a, 170 mg, 1.5 mmol),
and NaN3 (5, 80 mg, 1.24 mmol) in DMF (5 mL) were added
2 drops of H2O. A catalytic amount (1–2 drops) of Et3N was
then added, and the reaction mixture allowed to stir for 3 h
at 50–60 °C. After completion of the reaction, the mixture
was cooled to r.t. and poured into H2O with continuous
stirring. A yellow-brownish solid product was formed after
keeping the mixture inside the freezer overnight. Product 6a
was purified by preparative TLC using EtOAc–hexane (3:7).
Compound 6a
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Yao, C.-F. Tetrahedron 2009, 65, 5799.
Yield 270 mg (71%); mp 221–223 °C. 1H NMR (300 MHz,
CDCl3): d = 1.25 (t, J = 7.07 Hz, 3 H), 1.72 (s, 9 H), 4.17–
4.23 (m, 2 H), 7.20–7.86 (m, 3 H), 8.18 (s, 1 H), 8.57–8.63
(m, 1 H). 13C NMR (75 MHz, CDCl3): d = 14.23, 28.08,
62.20, 86.81, 105.09, 113.52, 115.22, 115.66, 121.09,
124.08, 124.40, 125.77, 130.83, 135.66, 146.37, 147.89,
Synlett 2011, No. 11, 1547–1550 © Thieme Stuttgart · New York

1550
S. Majumder, P. J. Bhuyan
LETTER
162.57. MS (EI): m/z = 382.4 [M + H]+. Anal. Calcd (%) for
C19H19N5O4: C, 59.84; H, 4.98; N, 18.37. Found: C, 59.65;
H, 4.93; N, 18.42. IR (CHCl3): nmax = 2983.00, 2856.50,
1751.90, 1728.10 cm–1. Similar compounds 6b–i were
synthesized and characterized.
mmol) using acetone (10 mL) as solvent for 10 h to afford
3c, 1.69 g (76%) as a colorless solid, mp 148–149 °C. 1H
NMR (300 MHz, CDCl3): d = 4.80 (d, J = 11.4 Hz, 2 H),
5.10–5.27 (d, J = 10.2 Hz, 2 H), 5.95–6.07 (m, 1 H), 7.20–
8.26 (m, 4 H), 10.16 (s, 1 H).
(20) Synthesis of Compound 3a
(21) Synthesis of Compound [A]
Equimolar amounts of 2-chloro-3-formyl indole (2, 10
mmol, 1.79 g) and Boc-anhydride (10 mmol, 2.18 g) were
stirred in the presence of catalytic amount of DMAP (0.12 g)
and Et3N (0.10 g) at 0–5 °C for 1 h using CH2Cl2 as solvent.
The solvent was evaporated under reduced pressure, and the
solid compound obtained was purified by column
chromatography using PE–EtOAc (9:1) as eluent. The
product 3 was obtained in 70% yield (1.20 g) as white
crystalline compound; mp 89–90 °C. 1H NMR (300 MHz,
CDCl3): d = 1.72 (s, 9 H), 7.26–7.40 (m, 2 H), 8.02–8.06 (m,
1 H), 8.27–8.30 (m, 1 H), 10.29 (s, 1 H).
1-Boc-2-chloro-3-formylindole (3a, 558 mg, 2 mmol) was
treated with ethyl cyanoacetate (4a, 283 mg, 2.5 mmol) in
EtOH (8 mL). One drop of piperidine was added, and the
reaction mixture was allowed to stir at r.t. for 30 min. The
reaction mixture was kept inside the freezer overnight. The
yellow solid which appeared in the reaction mixture was
filtered, washed with cold EtOH and dried. Yield 508 mg
(75%); mp 87–88 °C. 1H NMR (300 MHz, CDCl3): d = 1.43
(t, J = 3.6 Hz, 2 H), 1.72 (s, 9 H), 4.36–4.44 (m, 2 H), 7.20–
8.10 (m, 4 H), 8.49 (s, 1 H).
(22) Synthesis of a-Carboline 6a from [A]
Synthesis of Compound 3b
The condensed product [A] (339 mg, 1 mmol) was mixed
with NaN3 (5, 80 mg, 1.24 mmol) in DMF (5 mL) and 2
drops of H2O were added. A catalytic amount (1–2 drops) of
Et3N was then added to the reaction mixture, and the whole
was stirred for 3 h at 50–60 °C After completion of reaction,
the mixture was cooled to r.t. and poured into H2O with
stirring. A yellow-brownish solid was formed after keeping
the mixture inside the freezer overnight. Product 6a was
purified by preparative TLC using EtOAc–hexane (3:7);
yield 251 mg (66%); mp 221–223 °C.
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was taken in
a round-bottom flask in DMF (10 mL) on magnetic stirrer.
NaH (0.48 g, 20 mmol) was added into the mixture. When
the temperature reached 0 °C, MeI (1.42 g, 10 mmol) was
added gradually, and the reaction mixture allowed to stir for
1.5 h. An off-white solid formed which was almost pure
product. Yield 1.59 g (82%); mp 79–80 °C. 1H NMR (300
MHz, CDCl3): d = 3.80 (s, 3 H), 7.20–8.30 (m, 4 H), 10.12
(s, 1 H).
Synthesis of Compound 3c
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was refluxed
with allyl bromide(10 mmol) in the presence of K2CO3 (10
(23) Soledade, M.; Pedras, C.; Suchy, M.; Ahiahonu, W. K. Org.
Biomol. Chem. 2006, 4, 691.
Synlett 2011, No. 11, 1547–1550 © Thieme Stuttgart · New York