Three component tandem reactions involving protected 2-amino indoles, disubstituted propargyl alcohols, and I2/ICl: Iodo-reactant controlled synthesis of dihydro-α-carbolines and α-carbolines via iodo-cyclization/iodo-cycloelimination

Article abstract of DOI:10.1016/j.tetlet.2010.10.147

Two simple, highly efficient three component tandem reactions for the synthesis of diversified N^a N^b di-carbamate-4,9-dihydro-3- iodo-α-carbolines and N^a-carbamate-3-iodo-α-carbolines have been described. The strategy invo

Full text of DOI:10.1016/j.tetlet.2010.10.147

Tetrahedron Letters 52 (2011) 65–68
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three component tandem reactions involving protected 2-amino indoles,
disubstituted propargyl alcohols, and I2/ICl: iodo-reactant controlled
synthesis of dihydro-
a-carbolines and a-carbolines via
iodo-cyclization/iodo-cycloelimination q
Sudhir K. Sharma a, Sahaj Gupta a, Mohammad Saifuddin a, Anil K. Mandadapu a, Piyush K. Agarwal a,
Harsh M. Gauniyal b, Bijoy Kundu a,
⇑
a Medicinal & Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow 226 001, India
b Sophisticated Analytical Instrument Facility, Central Drug Research Institute, CSIR, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Two simple, highly efficient three component tandem reactions for the synthesis of diversified Na b di-
N
Article history:
carbamate-4,9-dihydro-3-iodo-a a-carbolines have been described.
-carbolines and Na-carbamate-3-iodo-
Received 7 October 2010
Revised 22 October 2010
Accepted 28 October 2010
Available online 2 November 2010
The strategy involves one-pot condensation of bis-carbamate protected 2-amino indoles with disubsti-
tuted propargyl alcohols and I2/ICl. The salient feature of the reaction involves iodocyclo-elimination
of Nb-linked carbamate under mild condition in the final step.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
a-Carboline
Alkyne
Iodocycloelimination
Multicomponent reaction
Cyclization
a
-Carbolines (pyrido[2,3-b]indoles) are structural units found
In recent years one-pot multicomponent reactions (MCR)
involving condensation of three or more monomers either in a sin-
gle step or in tandem have become an integral part of drug discov-
ery program.10 In either situation inherent formation of several
bonds occurs without the isolation of the intermediate formed.
All or most of the parts of the participating monomers contribute
to the formation of a new molecule assembled in situ following a
cascade of irreversible chemical pathways. Thus, using simple
and readily available components in a highly diverse array, li-
braries of small molecules inspired either from natural products
or from other target structures of therapeutic interest has been re-
ported in the literature.11
In continuation of our studies aiming at the efficient construc-
tion of indole-based polyheterocycles12 involving multistep/multi-
component reaction format, we herein report one-pot three
component tandem reactions involving protected 2-aminoindoles,
disubstituted propargyl alcohols, and I2/ICl leading to the synthesis
in an array of natural products: Dendrodoine A, grossularines-1,
and -2, metabolites isolated from the tunicate Dendrodoa grossular-
ia,1 indoloquinoline alkaloid neocryptolepine from Cryptolepis
sanguinolenta2 kapakahines from the marine sponge Cribrochalina
olemda3 and mescengricin, isolated from Streptomyces griseoflavus.4
Besides, a-carbolines are also formed as pyrolysis product (2-ami-
no-alpha-carboline; mutagenic, and carcinogenic)5 during the high
temperature cooking of food/burning of tobacco and as bioactive
molecules with antitumor6 and antiviral7 properties. Such impor-
tant pharmacological activities5–7 have made the molecules of sig-
nificant synthetic targets and, therefore, have resulted in sustained
interest in developing new methods for the preparation of highly
diversified a-carbolines. However, despite being an attractive syn-
thetic target, a multicomponent reaction for the direct synthesis of
these tricyclic class of compounds is scarce.8 In addition to this,
most of the syntheses9 reported in the literature for
a-carbolines
are low yielding and require several steps from starting materials
of highly diversified 3-iodo-a-carboline derivatives. Although the
that are not commercially available.
use of I2/ICl has been documented in the literature for multistep
synthesis, their application in multicomponent format as reactant
is limited.13
In the first instance we subjected 2-aminoindole hydrochloride
to three component reaction by treating it with benzaldehyde and
q
CDRI Communication No. 7979.
⇑
Corresponding author. Tel.: +91 522 2612411x18; fax: +91 522 2623405.
E-mail addresses: bijoy_kundu@yahoo.com, b_kundu@cdri.res.in (B. Kundu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.147

66
S. K. Sharma et al. / Tetrahedron Letters 52 (2011) 65–68
a terminal alkyne as the other two components in one pot. How-
ever, despite exploring reactions both with hydrochloride salt
and with free base generated in situ under a series of experimental
moted nucleophilic substitution of 1-(4-chloro-phenyl)-3-phenyl-
prop-2-yn-1-ol resulting in 3a, it failed to facilitate the subsequent
intramolecular electrophilic cyclization to furnish
a-carbolines.
conditions, we failed to observe the formation of
a
-carboline. This
We then screened several electrophilic reagents, with the view to
promote intramolecular electrophilic cyclization of the intermedi-
ate 3a and the results have been summarized in Table 1. As
observed, best results were obtained when cyclization of 3a was
carried out in the presence of ICl, furnishing Na-ethoxycarbonyl-
can be attributed to poor stability14 of 2-amino indole as free base
which prompted us to use protected 2-amino-indole derivative.
Initial attempts to use acid-labile amine protecting group, such
as t-Boc-reported earlier by us11e for the synthesis of d-carbolines
from N-Boc-3-amidoindole in multicomponent format, was not
feasible since in our hand synthesis of N-Boc-2-amidoindole using
(Boc)2O was obtained in poor yields (<10%).
3-iodo-a-carboline derivative 5a in 85% isolated yield. Analogous
iodo-cyclization using NIS produced 5a in 23% yield; in contrast,
bromocyclization using Br2/NBS and application of Bronsted
acids/metals failed to promote cyclizations. The most interesting
observation of our optimization studies was isolation of Na, Nb-
Using an alternative strategy, we then hypothesized that pro-
tecting the amine with the acid resistant acyl type protecting
group followed by condensation with 1,3-disubstituted propargyl
alcohol derivatives may furnish intermediate that could then be
subjected to intramolecular electrophilic (6-endo) cyclization in
the presence of iodo-reactant as electrophilic reagent to furnish
diethoxycarbonyl-4,9-dihydro-3-iodo-a
-carboline 4a17 as a single
product in the presence of I2/K2CO3 in 61% isolated yield instead
of 5a (Scheme 1). Compound 4a appeared to be the precursor of
5a and to support this we treated 4a with ICl in CH3CN at 0 °C
for 45 min. Since ICl is known to behave both as electrophilic
reagent (with ability to iodinate) and as oxidizing agent, formation
of 5a from 4a occurred in 88% isolated yield via concomitant oxida-
tive aromatization and elimination of Nb-carbamate (Scheme 1).
This gets support from a single report in the literature demonstrat-
ing elimination of N-linked ethoxycarbonyl group in dihydropyri-
iodo-a-carbolines. Initial experiments to acylate 2-amino indole
hydrochloride with acetic anhydride/acetyl chloride furnished
complex mixture comprising mono-, di-, and tri-acylated (one of
them being Friedal–Craft acylated product) indoles arising from
the acylation of Na, C-2-NbH2, and C-3. We next protected the ami-
no function in the 2-amino indole hydrochloride with ethoxycar-
bonyl chloride, which is relatively less electrophilic due to the
presence of C2H5O group attached to the –C@O than CH3–C@O in
the acetyl chloride and may preclude C-acylation at the 3-position
of the indole. Pleasingly, reaction of the 2-amino indole hydrochlo-
ride15 with ethoxycarbonyl chloride in the presence of NaHCO3 fur-
nished regioselective 2-ethoxycarbonylamino-indole-1-carboxylic
acid ethyl ester 1a16 (hitherto not reported in the literature) as
the only product in quantitative yield. Bis-ethoxy carbonylated
compounds have been reported17 for amidines bearing structural
resemblance to 2-amino-indole. Next, the resulting indole deriva-
tive 1a was treated with 1-(4-chloro-phenyl)-3-phenyl-prop-2-yn-
1-ol 2a15 at 0 °C to rt in the presence of iodine as an electrophilic
reagent (Scheme 1). The progress of the reaction was monitored
by TLC and within 30 min a new spot appeared which remained
unchanged even after extended stirring for 2 h at rt. After work-up,
dines, where aromatization was affected under
a stream of
oxygen.20 A plausible mechanism for the formation of 5 from 3 is
illustrated in Figure 1.
It is presumed that initially the alkyne in the intermediate 3
probably forms an iodonium complex in the presence of ICl there-
by enhancing the electrophilicity of the alkyne to generate inter-
mediate A. The activated (electron-deficient) triple bond then
undergoes nucleophilic attack by the nitrogen attached to the
C-2 of the indole thereby facilitating intramolecular 6-endo (elec-
trophilic cyclization) to furnish Na, Nb-dicarbamte-4,9-dihydro-3-
iodo-a-carboline as protonated intermediate B. Latter undergoes
deprotonation leading to the formation of 4a by releasing HCl.
Finally, spontaneous oxidative aromatization of 4a via elimination
of the Nb-linked carbamate results in the formation of Na-car-
bamte-3-iodo-a-carbolines 5. Encouraged by the above findings
instead of isolating
a
-carboline, we observed formation of 3a18 as
that offered opportunity for the selective multistep synthesis of
either 4 or 5, we next laid emphasis on their synthesis in multi-
component format (Scheme 2).
a C-3 nucleophilic substituted19 product of propargyl alcohol in
quantitative yields. This led us to believe that although iodine pro-
In the first instance we developed synthesis of 4,9-dihydro-a-
carboline 4a in a multicomponent tandem format by treating a
mixture of 1a and 2a with I2 for 30 min at 0 °C followed by addition
of K2CO3 and stirring the reaction mixture at rt for 2 h. The crude
product so obtained was purified by column chromatography fur-
nishing 4a in 61% isolated yield. We demonstrated the utility of the
Cl
O
O
OH
H
NH
N
(i)
I2
+
method by synthesizing four additional dihydro-a-carboline deriv-
+
N
O
N
O
Cl
O
O
O
O
2a
1a
3a
Table 1
Optimization of reaction conditions for the conversion of 3a to 5a
(iii)
Entry Electrophilic reagent
Temp
(°C)
Time
(h)
Yield of 4a/5a
(%)
(ii)
Cl
Cl
1
2
3
4
Iodine in CH3CN
Iodine in CH3CN
Iodine/K2CO3 in CH3CN
N-Iodosuccinimide in
CH3CN
Bromine in CH3CN
N-Bromosuccinimide in
CH3CN
0 to rt
1
12
2
0/0
rt
rt
rt
15/0
61/0
0/23
I
I
12
(iv)
N
N
N
O
N
5
6
rt
rt
12
12
0/0
0/0
O
O
O
O
O
5a
4a
7
Iodine monochloride in
CH3CN
0
1
0/85
Scheme 1. Optimized reaction conditions for the synthesis of 4a and 5a via
iodocyclization/iodocyclo-elimination. Reagents and conditions: (i) CH3CN, 0 °C to
rt, 30 min; (ii) I2/K2CO3, CH3CN 2 h, rt; (iii) ICl, CH3CN 0 °C, 1 h; (iv) ICl, 0 °C, CH3CN,
45 min.
8
9
p-TsOH in CH3CN
Copper iodide in CH3CN
80
80
12
16
0/0
0/0

S. K. Sharma et al. / Tetrahedron Letters 52 (2011) 65–68
67
atives 4b–e as summarized in Table 2. No further attempt was
made to optimize the conditions to improve the yield for 4 instead
we continued with our main objective for synthesizing a-carboline
I
Cl
I
R3
R3
N
I
R4
O
R3
N
R4
O
R4
R1
R1
R1
derivatives 5 in a multicomponent format.
N
N
H
H
NH
N
Cl
O
For the synthesis of 5 in multicomponent format, condensation
of bis-N-carbamate protected indole derivative 1a with 2a was ef-
fected either in the presence of a mixture I2 and ICl or in the pres-
ence of ICl alone, however, both the conditions failed to furnish the
compound 5a. This prompted us to carry out the multicomponent
reaction in tandem format for the one-pot synthesis of a-carboline
derivatives 5. Accordingly, 1a was initially treated with 2a in the
presence of iodine from 0 °C to rt for 30 min followed by addition
of ICl at 0 °C to yield 3-iodo-a-carboline derivative 5a in 86% yield
within 60 min (Scheme 2). On comparing the two multicomponent
tandem reactions, it is evident that whereas for the synthesis of 4
iodine remains source for the iodo group at position 3, the ICl re-
mains source for the iodo group at position 3 in compound 5.
The scope and limitation of the optimized reaction conditions
were examined by studying the effect of different substituent on
the indole (R1 and R2) and on the propargyl alcohols (R3 and R4).
In the indole derivatives, on one hand ethoxy carbonyl group in
1a has been replaced with isobutoxy- and benzyloxy-carbonyl
groups and on the other hand, substitution (R1) has been intro-
duced in the phenyl ring of the indole. The resulting substrates
1a–g15 were subjected to multicomponent tandem reaction by
treating them with structurally diverse 2 (The requisite propargyl
derivatives can be readily prepared in quantitative yields using
O
O
R2
R2
O
R2
O
O
O
R2
O
O
O
R2
R2
3
A
B
-HCl
H
I
R3
R3
I
R1
R4
O
R1
R4
N
N
N
R2
N
O
O
R2
-CO2
O
R2
O
O
5
4
Figure 1. A plausible mechanism for the formation of
elimination from 3.
a-carbolines 5 via iodo-cyclo-
(a) 0 oC-rt, 0.5 h
(a) 0 oC-rt, 0.5 h
(b) ICl; CH3CN
4a-e
+
5a-x
2a-j
1a-g
+
I2
(b) K2CO3; CH3CN
rt, 2 h
0
oC, 1 h
Scheme 2. Three component tandem reactions in one pot for the synthesis of 4 and
5.
Table 2
Synthesis of dihydro-
a-carbolines 4 from 1, 2 and I2/K2CO3 in three-component tandem formats
Entry
1
R1
R2
2
R3
R4
Product
Yield (%)
1
2
3
4
1a
1a
1e
1e
H
H
F
CH2CH3
CH2CH3
CH2CH3
CH2CH3
2a
2j
2c
2i
4-ClC6H4
C6H5
4-CH3C6H4
C6H5
4-(CH3)3
CC6H4
C6H5
4a
4b
4c
4d
61
73
75
69
4-EtOC6H4
2,3-diClC6H3
4-CH3C6H4
F
5
1g
CF3
CH2CH3
2c
2,3-diClC6H3
4e
72
Table 3
Synthesis of
a-carbolines 5 from 1, 2 and I2/ICl in three-component tandem formats
Entry
1
R1
R2
2
R3
R4
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
H
H
H
H
H
H
H
H
H
CH2CH3
CH2CH3
CH2CH3
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2C6H5
CH2C6H5
CH2C6H5
2a
2c
2d
2d
2g
2h
2g
2h
2i
4-ClC6H4
2,3-diClC6H3
4-BrC6H4
C6H5
C6H5
C6H5
C6H5
C6H9
C6H9
C6H9
C6H9
4-(CH3)3
CC6H4
4-CH3C6H4
C6H5
C6H5
C6H5
5a
5b
5c
5d
5e
5f
5g
5h
5i
86
88
85
81
72
68
78
65
83
4-BrC6H4
4-EtOC6H4
4-CH3C6H4
4-EtOC6H4
4-CH3C6H4
4-CH3C6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1c
1d
1d
1d
1d
1d
1d
1e
1e
1e
1e
1f
H
CH2C6H5
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH(CH3)2
2j
4-EtOC6H4
4-ClC6H4
2-ClC6H4
2,3-diClC6H3
4-BrC6H4
2-ClC6H4
2-BrC6H4
4-ClC6H4
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
5u
5v
5w
5x
90
80
81
87
83
50
46
84
80
86
82
85
87
78
50
CH3
CH3
CH3
CH3
CH3
CH3
F
F
F
F
2a
2b
2c
2d
2f
2e
2a
2b
2c
2d
2b
2c
2d
2f
C6H5
C6H13
C5H11
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2-ClC6H4
2,3-di ClC6H3
4-BrC6H4
2-ClC6H4
2,3-diClC6H3
4-BrC6H4
2-ClC6H4
CF3
CF3
CF3
CF3
1f
1f
1g
C6H13

68
S. K. Sharma et al. / Tetrahedron Letters 52 (2011) 65–68
procedure published in the literature21) and ICl. In all cases, the
substrates efficiently underwent intramolecular electrophilic cycli-
zation to furnish 24 compounds in good to excellent yields (Table
3). In general reactions were not sensitive either to the electronic
properties of the substituent on the phenyl ring of the indole or
to the nature of the carbamate group. Use of substituted phenyl
ring R3 in 3 with both electron-donating and withdrawing groups
8. Bansal, R. K.; Sharma, D.; Jain, J. K. Indian J. Chem. 1998, 27, 366–367.
´
9. (a) Vera-Luque, P.; Alajarın, R.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2006, 8,
415–418; (b) Hostyn, S.; Baelen, G. V.; Lemire, G. L. F.; Maesa, B. U. W. Adv.
Synth. Catal. 2008, 350, 2653–2660; (c) Molina, P.; Fresneda, P. M. Synthesis
1989, 878–880; (d) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron 2001,
57, 4787–4792; (e) Erba, E.; Gelmi, M. L.; Pocar, D. Tetrahedron 2000, 56, 9991–
9997; (f) Ono, A.; Narasaka, K. Chem. Lett. 2001, 146–147; (g) Achab, S.; Guyot,
M.; Potier, P. Tetrahedron Lett. 1995, 36, 2615 2618; (h) Forbes, I. T.; Johnson, C.
N.; Thompson, M. J. Chem. Soc., Perkin Trans. 1 1992, 275–281.
10. (a) Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem. Biol. 2010, 14,
371–382; (b) Tour, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486; (c) Lu, J.;
Gong, X.; Yang, H.; Fu, H. Chem. Commun. 2010, 4172–4174; (d) Zhu, Y.; Zhai,
C.; Yue, Y.; Yang, L.; Hu, W. Chem. Commun. 2009, 1362–1364.
had no effects on the yield of
a-carbolines. Similarly, employing
phenyl ring as R4 had no effect on the yield 78–90% but employing
aliphatic as R4 moiety reduced the yield of
a-carbolines to 46–78%.
As described elsewhere19, propargyl alcohol (R3 = R4 = H; unstab-
lized22) failed to undergo nucleophilic substitution by C-3 of the in-
doles to form 3.
11. For review see: (a) Weber, L. Drug Discovery Today 2002, 7, 143–147; (b)
Ulaczyk-Lesanko, A.; Hall, D. G. Curr. Opin. Chem. Biol. 2005, 9, 266–276.
12. (a) Agarwal, P. K.; Sawant, D.; Sharma, S.; Kundu, B. Eur. J. Org. Chem. 2009, 2,
292–303; (b) Sharma, S.; Kundu, B. Tetrahedron Lett. 2008, 49, 7062–7065; (c)
Sharma, S. K.; Sharma, S.; Agarwal, P. K.; Kundu, B. Eur. J. Org. Chem. 2009, 9,
1309–1312; (d) Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Tetrahedron Lett.
2007, 48, 1379–1383; (e) Saha, B.; Kumar, R.; Maulik, P. R.; Kundu, B.
Tetrahedron Lett. 2006, 47, 2765–2769; (f) Sawant, D.; Kumar, R.; Maulik, P. R.;
Kundu, B. Org. Lett. 2006, 8, 1525–1528; (g) Sharma, S. K.; Mandadapu, A. K.;
Saifuddin, M.; Gupta, S.; Agarwal, P. K.; Mandwal, A. K.; Gauniyal, H. M.; Kundu,
B. Tetrahedron Lett. 2010, 51, 6022–6024.
In summary, we have developed two simple and highly efficient
multicomponent tandem reactions for the selective synthesis of Na
Nb dicarbamate-4,9-dihydro-3-iodo- -carbolines and Na-carba-
a
mate-3-iodo-a-carbolines via iodo-cyclization/iodo-cyclo-elimina-
tion in good to excellent yields. Haloheterocycles have been
documented to play a central role as intermediates in organic syn-
thesis, due to their ability to undergo numerous palladium-cata-
lyzed reactions for the substitution of halide atom. Studies to
extend the scope of the procedure to other iodoheterocycles via
iodocyclization of substrates containing carbamate-protected ami-
no groups are in progress in our laboratory and results will be pub-
lished elsewhere.
13. Ye, S.; Gao, K.; Wu, J. Adv. Synth. Catal. 2010, 352, 1746–1751.
14. (a) Hino, T.; Nakagawa, M.; Hashizume, T.; Yamaji, N.; Miwa, Y. Tetrahedron
Lett. 1970, 11, 2205–2208; (b) Nakagawa, M.; Yamaguchi, H.; Hino, T.
Tetrahedron Lett. 1970, 11, 4035–4038. and references cited therein; (c) Roy,
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Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257–4260.
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16. See Supplementary data.
17. Stykala, J.; Slouka, J.; Svecova, V. ARKIVOC 2006, 68–75.
18. General procedure for the three component tandem synthesis of 4,9-dihydro-3-
iodo
a-carbolines 4: To a solution of 2-ethoxycarbonylamino-indole-1-
Acknowledgment
carboxylic acid ethyl ester 1a (0.200 g, 0.73 mmol) and 1-(4-chloro-phenyl)-
3-phenyl-prop-2-yn-1-ol 2a (0.175 g, 0.73 mmol) in acetonitrile (10 ml), iodine
(0.920 g, 3.62 mmol) was added and stirred for 0.5 h at 0 °C to rt. Next, K2CO3
(0.250 g, 1.81 mmol) was added to the reaction mixture at 0 °C and the
reaction mixture was allowed to stir at room temperature for 1 h. After
completion of the reaction as analyzed by TLC, it was diluted with saturated
sodium thiosulphate solution and extracted with EtOAc (20 mL Â 3). The
organic layer was washed with brine (10 mL), dried over anhydrous sodium
sulfate and evaporated to dryness under reduced pressure. The crude product
so obtained was purified on a silica gel column using hexane: ethyl acetate
S.K.S., S.G., M.S., A.K.M., and P.K.A. are thankful to CSIR, New
Delhi, India for fellowships.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.147.
(1:9, v/v) as eluent to afford dihydro-
General procedure for the one-pot three-component tandem reaction leading to the
synthesis of 3-iodo- -carbolines 5: To a solution of 2-ethoxycarbonylamino-
a-carbolines 4.
a
References and notes
indole-1-carboxylic acid ethyl ester 1a (0.200 g, 0.73 mmol) and 1-(4-chloro-
phenyl)-3-phenyl-prop-2-yn-1-ol 2a (0.175 g, 0.73 mmol) in acetonitrile
(10 ml), iodine (0.920 g, 3.62 mmol) was added and stirred for 0.5 h at 0 °C
to rt. Next, ICl (1 M solution in DCM, 3.4 ml) was added to the reaction mixture
at 0 °C and the reaction mixture was allowed to stir at room temperature for
1 h. After completion of the reaction as analyzed by TLC, it was diluted with
saturated sodium thiosulphate solution and extracted with EtOAc (20 mL Â 3).
The organic layer was washed with brine (10 mL), dried over anhydrous
sodium sulfate and evaporated to dryness under reduced pressure. The crude
product so obtained was purified on a silica gel column using hexane: ethyl
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