Stereoselective synthesis of novel annulated thiopyrano indole derivatives from simple oxindole via intramolecular 1,3-dipolar cycloaddition reactions of nitrone and nitrile oxide

Article abstract of DOI:10.1016/j.tetlet.2011.11.136

Synthesis of some novel isoxazolidine/dihydroisoxazole annulated thiopyrano[2,3-b]indole derivatives from simple oxindole via 1,3-dipolar cycloaddition reaction involving nitrone and nitrile oxide as 1,3-dipole is reported.

Full text of DOI:10.1016/j.tetlet.2011.11.136

Tetrahedron Letters 53 (2012) 762–764
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Tetrahedron Letters
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Stereoselective synthesis of novel annulated thiopyrano indole derivatives
from simple oxindole via intramolecular 1,3-dipolar cycloaddition reactions
of nitrone and nitrile oxide
⇑
Swarup Majumder, Pulak J. Bhuyan
Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of some novel isoxazolidine/dihydroisoxazole annulated thiopyrano[2,3-b]indole derivatives
from simple oxindole via 1,3-dipolar cycloaddition reaction involving nitrone and nitrile oxide as 1,3-
dipole is reported.
Received 24 October 2011
Revised 28 November 2011
Accepted 29 November 2011
Available online 7 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective synthesis
Isoxazolidine
Thiopyrano[2,3-b]indole
Oxindole
1,3-Dipolar cycloaddition reaction
b-Halo aldehyde
Indole nucleus is a prominent structural subunit present in
numerous natural products and synthetic compounds with vital
medicinal value.1 Thiopyranoindole annulated heterocyclic com-
pounds are important due to their biological activity.2 Among the
wide variety of heterocycles, dihydroisoxazoles/tetrahydroisoxaz-
oles (isoxazolidines) are some very important and useful classes of
compounds which are widespread in nature. Isoxazolidine deriva-
tives possess antifungal,3a antiinflammatory,3b antimycobacterial3c
and cytotoxic activity,3d and they also act as DNA intercalators.3e
1,3-Dipolar cycloaddition4 of an alkene with nitrone and nitrile
oxide is one of the reliable strategies for the construction of the
dihydroisoxazoles/tetrahydroisoxazoles moieties. In fact, these
structural units can be obtained through in situ formation of nitrile
oxide/nitrone followed by 1,3-dipolar cycloaddition reaction se-
quence. For example, Oppolzer and co-workers reported the syn-
thesis of benzopyran derivatives by intramolecular cycloaddition
involving in situ nitrone preparation followed by the [3+2] cyclo
addition reaction.4f
pharmacological and medicinal importance.7 Hence, the develop-
ment of new and facile synthetic methods for such heterocycles
is considered to be of great significance.8
Recently, we have reported an efficient method for the synthe-
sis of
a-carbolines from oxindole by exploring three-component
reaction in one-pot protocol.9 As part of our continued interest
on indole and the synthesis of diverse heterocyclic compounds of
biological significance,10 we report here the synthesis of some
novel dihydroisoxazole/tetrahydroisoxazole annulated thiopyr-
ano[2,3-b]indole derivatives from simple oxindole via intramolec-
ular 1,3-dipolar cycloaddition reaction.
Oxoindole 1, was taken as the starting material in our reaction
strategy which on treatment with Vielsmeier reagent afforded the
CHO
Boc-anhydride
DMF+ POCl3
Cl
O
N
H
1
OR CH3I
N
H
2
There are several examples of the synthesis of benzopyran and
pyranobenzopyran moieties while those of their sulfur-containing
analogues are rare.5 A literature survey revealed that there are only
a few reports on the synthesis of polycyclic pyranothio pyrans.6
However, the interest in sulfur heterocycles of this class such as
thiopyrans is growing because of the recent reports of their
CHO
Cl
CHO
S
(NH2)2CS, NaOH,
N
R1
1-Bromo- 3-methyl-
2-butene
N
R2
3a. R1 = Boc,
4a. R2 = H,
3b. R1 = Me
4b. R2 = Me
⇑
Corresponding author. Tel.: +91 376 2370121; fax: +91 376 2370011.
E-mail address: pulak_jyoti@yahoo.com (P.J. Bhuyan).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.136

S. Majumder, P. J. Bhuyan / Tetrahedron Letters 53 (2012) 762–764
763
key b-halo aldehyde intermediate 2 (Scheme 1).11 The indole nitro-
R3
O
N
gen was readily protected by methyl iodide or di-tert-butyl dicar-
bonate (Boc2O).12 The unsaturated side chain could be smoothly
introduced by substitution of chloro group from 2-chloro-3-formyl
indole with prenyl thiolate.13 For this nucleophilic substitution at
the 2-position of the compound 3, first prenyl thiolate was gener-
ated by the decomposition of S-prenyl isothiouronium salt with
NaOH, to which N-protected 2-chloro-3-formyl indole 3 was added
and refluxed for half an hour. After work-up, the S-alkenyl alde-
hyde 4 was obtained in a 70–72% yield where Boc was also depro-
tected (Scheme 1).14 The nucleophilic substitution reaction did not
occur in compound 2.
CHO
S
NaOH
R3NHOH.HCl
S
N
R2
N
R2
4a. R2 = H
R3= CH3, C6H11
4b. R2 = CH3
R3
H
O
R3
O
N
N
H
H
H
S
S
N
N
R2
A plausible mechanism for the formation of indolo-S-alkenyl
aldehyde 4 is outlined in Scheme 2. This type of Boc deprotection
under basic conditions is well documented.15
R2
6a-d
5a-d
O
O
S
Ph
Ph
H
N
First, we utilised nitrone as 1,3-dipole. In a simple experimental
procedure, aldehyde 4a was reacted with methylhydroxy amine
hydrochloride in the presence of NaOH using ethanol as solvent
under refluxing conditions (Scheme 3). To our expectation, intra-
molecular 1,3-dipolar cycloaddition reaction of nitrone occurred
smoothly to give two isomers, 5a (cis) and 6a (trans) of tetrahyd-
roisoxazolo[3040:4,5]thiopyrano[2,3-b]indole in 75% and 12% yields,
respectively. The structures of 5a and 6a were determined from
spectroscopic data and elemental analysis.16 The stereochemistry
was determined from the coupling constant of the H-6b and
H-9a protons (for the cis isomer J = 3.2 Hz and for the trans isomer
J = 9.4 Hz). The chemical shifts values of the N-Me protons at d 2.90
and d 2.85, respectively, as singlets further confirmed the involve-
ment of the nitrone in the cycloaddition process. Both stereoiso-
mers 5a and 6a exhibited strong molecular ion peaks (M+H)+ at
275.5. Similarly, tetrahydroisoxazolo[30,40:4,5]thiopyrano[2,3-b]in-
dole derivatives 5b–d and 6b–d were synthesised by utilising
N-methylhydroxyamine hydrochloride and N-cyclohexyl hydroxy-
amine hydrochloride with 4a–b (Table 1). It is noteworthy that
although the nitrones form easily, the cycloaddition required forc-
ing conditions (refluxing ethanol). Phenyl hydroxyl amine formed
the nitrone [X] but has not given the cyclised product. The electron
withdrawing nature of the aromatic group might have prevented
the cyclisation. On the other hand the electron donating nature
of the methyl and the cyclohexyl groups might have facilitated
the cyclisation process to afford thiopyrano[2,3-b]indole deriva-
tives 5 and 6.
N
CHO
NaOH
H
PhNHOH.HCl
S
N
S
R2
N
R2
N
R2
[X]
5e/6e
4
Scheme 3.
Table 1
Synthesis of novel tetrahydroisoxazole- and dihydroisoxazole fused thiopyrano[2,3-
b]indole derivatives 5, 6, and 8
Entry
Product
R2
R3
Mp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
8a
8b
H
H
H
H
CH3
CH3
CH3
CH3
H
CH3
H
CH3
CH3
CH3
C6H11
C6H11
CH3
157–158
149–150
135–136
127–128
187–189
183–184
174–175
171–172
_
75
12
73
8
67
7
68
8
NR
NR
65
62
CH3
C6H11
C6H11
C6H5
C6H5
—
10
11
12
_
167–168
184–185
—
N OH
CHO
In order to prepare the dihydroisoxazolo[30,40:4,5]thiopyr-
ano[2,3-b]indole, we first prepared oximes 7a from 4a by treat-
ment with hydroxylamine hydrochloride in the presence of
aqueous sodium hydroxide (Scheme 4).17 The oximes on treatment
with NaOCl in the presence of Et3N at 0–20 °C afforded the desired
dihydroisoxazolo[30,40:4,5]thiopyrano[2,3-b]indole 8a in excellent
yields via the formation of the nitrile oxides [A].18 The structures
of 8a were determined from spectroscopic data and elemental
analysis. Similarly compound 8b was synthesised and character-
ised (Table 1).
NH2OH.HCl
NaOH
Aqu. NaOCl
Et3N
S
S
N
R2
N
R2
7a-b
4
_
O
N
O
N
S
N
R2
S
N
R2
8a-b
[A]
Scheme 4.
NH
2
_
SNa
Excess
NaOH
NH Br
S
NH
3
+
_
NH
Br
S
2
2
Ethanol/
Reflux
In conclusion, we have reported the synthesis of several novel
tetrahydroisoxazolo-, dihydroisoxazolo fused thiopyrano[2,3-b]in-
dole from simple oxindole via intramolecular 1,3-dipolar cycload-
dition reactions involving nitrones and nitrile oxides as 1,3-dipoles,
in a regioselective manner. The present intramolecular 1,3-dipolar
cycloaddition reaction strategy, which is the first application in the
synthesis of tetrahydroisoxazole- and dihydroisoxazole fused thio-
pyranoindoles, can be further explored for the synthesis of various
CHO
CHO
Cl
+
S
N
N
H
4a.
Boc
_
3a.
NaS
Scheme 2.

764
S. Majumder, P. J. Bhuyan / Tetrahedron Letters 53 (2012) 762–764
under reduced pressure and the residue was purified by preparative TLC using
ethyl acetate/hexane (4:6) as eluent to give 5a and 6a.
fused heterocyclic compounds of biological importance. Further
study of the reaction is in progress.
Compound 5a: Yield: 0.411 g (75%), mp 157–158 °C. 1H NMR (300 MHz,
CDCl3): d 1.35 (s, 6H), 2.90 (s, 3H), 3.15–3.29 (m, 1H), 3.86 (d, J = 3.2 Hz, 1H),
4.31–4.36 (m, 2H), 7.20–7.90 (m, 4H), 8.10 (s, 1H). 13C NMR (75 MHz, CDCl3): d
27.43 (2C), 29.56, 34.21, 66.51, 69.12, 106.49, 113.74, 119.82, 121.60, 126.02,
133.45 142.72, 148.15, 151.94. m/z [ M+H]+ 275.5. CHN analysis (calcd) C,
65.69; H, 6.56; N, 10.22; C15H18N2OS (found) C, 65.32; H, 6.48; N, 10.52.
Compound 6a: Yield: 0.065 g (12%), mp 149–150 °C. 1H NMR (300 MHz,
CDCl3): d 1.32 (s, 6H), 2.85 (s, 3H), 3.22–3.31 (m, 1H), 3.90 (d, J = 9.4 Hz, 1H),
3.92–3.99 (m, 2H), 7.2–8.0 (m, 4H), 8.15 (s, 1H). 13C NMR (75 MHz, CDCl3): d
26.74 (2C), 28.98, 33.45, 65.48, 69.03, 105.66, 111.80, 118.32, 120.73, 124.40,
131.54, 139.76, 147.90, 151.04. m/z [M+H]+ 275.5. CHN analysis (calcd) C,
65.69; H, 6.56; N, 10.22; C15H18N2OS (found) C, 65.20; H, 6.38; N, 10.58.
Compound 5b. Yield: 0.499 g (73%), mp 135–136 °C. 1H NMR (300 MHz,
CDCl3): d 1.13–1.30 (m, 4H), 1.33 (s, 6H), 1.56–1.97 (m, 6H), 2.59–2.65 (m, 1H),
3.12–3.25 (m, 1H), 3.88 (d, J = 4.1 Hz, 1H), 4.25–4.38 (m, 2H), 7.17–7.93 (m,
4H), 8.10 (s, br, 1H). 13C NMR (75 MHz, CDCl3): d 24.52 (2C), 25.84 (2C), 27.56,
27.97 (2C), 29.82, 66.51, 67.89 70.45, 107.80, 112.52, 120.68, 122.84, 127.06,
134.94, 143.60, 149.18, 153.02. m/z [M+H]+ 343.6. CHN analysis (calcd) C,
70.17; H, 7.60; N, 8.18; C20H26N2OS (found) C, 69.98; H, 7.64; N, 8.02.
Compound 6b: Yield: 0.054 g (8%), mp 127–128 °C. 1H NMR (300 MHz, CDCl3):
d): d 1.11–1.32 (m, 4H), 1.35 (s, 6H), 1.53–1.95 (m, 6H), 2.56–2.63 (m, 1H),
3.14–3.26 (m, 1H), 3.87 (d, J = 9.6 Hz, 1H), 4.22–4.33 (m, 2H), 7.16–7.91 (m,
4H), 8.18 (s, br,1H). 13C NMR (75 MHz, CDCl3): d 24.34 (2C), 26.03 (2C), 28.53,
28.92 (2C), 30.64, 65.72, 68.35 70.58, 107.51, 111.80, 121.40, 122.21, 126.85,
133.43, 143.75, 147.91, 152.52. m/z [M+H]+ 343.6. CHN analysis (calcd) C,
70.17; H, 7.60; N, 8.18; C20H26N2OS (found) C, 70.12; H, 7.01; N, 8.08.
Compound 5c. Yield: 0.385 g (67%), mp 187–189 °C. 1H NMR (300 MHz, CDCl3):
d 1.34 (s, 6H), 2.98 (s, 3H), 3.10–3.29 (m, 1H), 3.63 (s, 3H), 3.89 (d, J = 4.6 Hz,
1H), 4.29–4.41 (m, 2H), 7.22–7.78 (m, 4H), 8.23 (s, br, 1H). 13C NMR (75 MHz,
CDCl3): d 25.57 (2C), 29.31, 36.76, 39.60, 66.29, 70.12, 108.74, 113.93, 118.58,
Acknowledgments
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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T.; Yamada, T. Org. Lett. 2002, 4, 2457; (d) Stephens, B. E.; Liu, F. J. Org. Chem.
2009, 74, 254; (e) Legeay, J. C.; Langlois, N. J. Org. Chem. 2007, 72, 10108; (f)
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March, P.; Figueredo, M.; Font, J.; Monsalvatje, M.; Virgili, A.; Alvarez-Larena,
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Rev. 2005, 105, 2765.
121.65, 126.73, 136.45, 144.30, 148.45, 152.86. m/z
analysis (calcd) C, 66.66; H, 6.94; N, 9.72; C16H20N2OS (found) C, 66.54; H, 6.48;
N, 9.82.
[
M+H]+ 289.7. CHN
5. (a) Ingal, A. H. In Comprehensive Heterocyclic Chemistry; Boulton, A. S., McKillop,
A., Eds.; Pergamon press: Oxford, 1984; Vol. 3, p 773; (b) Talley, J. J. J. Org. Chem.
1985, 50, 1695; (c) Boger, D. L.; Weinreb, S. M. In Hetero Diels–AlderMethodology
in Organic Synthesis; Academic Press: New York, 1987; p 225; (d) Inamoto, N.
Heteroatom Chem. 2001, 12, 183; (e) Majumdar, K. C.; Jana, M. Synth. Commun.
2007, 37, 1375; (f) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.; Sarkar, S.;
Ghosh, S. K.; Biswas, P. Tetrahedron 2003, 59, 2151; (g) Majumdar, K. C.;
Mukhopadhyay, P. P. Synthesis 2003, 97.
6. (a) Jayashankaran, J.; Manian, R. D. R. S.; Raghunathan, R. Tetrahedron Lett.
2006, 47, 2265; (b) Matiychuk, V. S.; Lesyk, R. B.; Obushak, M. D.; Gzella, A.;
Atamanyuk, D. V.; Ostapiuk, Y. V.; Kryshchyshyn, A. P. Tetrahedron Lett. 2008,
49, 4648; (c) Majumdar, K. C.; Muhuri, S. Synthesis 2006, 2725; (d) Majumdar,
K. C.; Kundu, U. K.; Ghosh, S. K. Org. Lett. 2002, 4, 2629; (e) Majumdar, K. C.;
Taher, A.; Ray, K. Tetrahedron Lett. 2009, 50, 3889.
7. (a) Al-Nakib, T.; Bezjak, V.; Rashid, S.; Fullam, B.; Meegan, M. J. Eur. J. Med.
Chem. 1991, 26, 221; (b) Al-Nakib, T.; Bezjak, V.; Meegan, M. J.; Chandy, R. Eur. J.
Med. Chem. 1990, 25, 455; (c) Van Vliet, L. A.; Rodenhuis, N.; Dijkstra, D.;
Wikstroem, H.; Pugsley, T. A.; Serpa, K. A.; Meltzer, L. T.; Heffner, T. G.; Wise, L.
D.; Lajiness, M. E.; Huff, R. M.; Svensson, K.; Sundell, S.; Lundmark, M. J. Med.
Chem. 2000, 43, 2871.
8. (a) Katritzky, A. R.; Button, M. A. C. J. Org. Chem. 2001, 66, 5595; (b) Ram, V. J.;
Srivastava, P.; Saxena, A. S. J. Org. Chem. 2001, 66, 5333; (c) Hori, M.; Kataoka,
T.; Shimizu, H.; Imai, E.; Iwata, N.; Kawamura, N.; Kurono, M.; Nakano, K.; Kido,
M. Chem. Pharm. Bull. 1989, 37, 1282.
Compound 6c: Yield: 0.040 g (7%), mp 183–184 °C. 1 H NMR (300 MHz, CDCl3):
d 1.35 (s, 6H), 2.89 (s, 3H), 3.15–3.29 (m, 1H), 3.64 (s, 3H), 3.89 (d, J = 10.4 Hz,
1H), 4.18–4.35 (m, 2H), 7.19–7.88 (m, 4H), 8.29 (s, br,1H). 13C NMR (75 MHz,
CDCl3): d 25.53 (2C), 29.32, 35.86, 38.62, 67.54, 69.62, 107.98, 112.79 119.72,
121.50, 126.45, 135.57, 145.12, 146.58, 152.67. m/z [M+H]+ 289.7. CHN
analysis (calcd) C, 66.66; H, 6.94; N, 9.72; C16H20N2OS (found) C, 66.49; H,
6.61; N, 9.88. Compound 5d: Yield: 0.484 g (68%), mp 174–175 °C. 1H NMR
(300 MHz, CDCl3): d 1.12–1.33 (m, 4H), 1.34 (s, 6H), 1.57–1.98 (m, 6H), 2.53–
2.68 (m, 1H), 3.13–3.26 (m, 1H), 3.64 (s, 3H), 3.88 (d, J = 4.8 Hz, 1H), 4.23–4.38
(m, 2H), 7.21–7.96 (m, 4H), 8.26 (s, br, 1H). 13C NMR (75 MHz, CDCl3): d 24.12
(2C), 25.46 (2C), 26.86, 27.24 (2C), 29.74, 35.89, 65.72, 67.71, 70.08, 107.48,
113.86, 119.48, 121.35, 127.96, 135.08, 145.59, 148.98, 154.14. m/z [M+H]+
357.8. CHN analysis (calcd) C, 70.78; H, 7.86; N, 7.86; C21H28N2OS (found) C,
70.65; H, 7.57; N, 8.02. Compound 6d: Yield: 0.056 g (8%), mp 171–172 °C. 1H
NMR (300 MHz, CDCl3): d 1.18–1.36 (m, 4H), 1.33 (s, 6H), 1.50–1.98 (m, 6H),
2.48–2.68 (m, 1H), 3.13–3.28 (m, 1H), 3.64 (s, 3H), 3.87 (d, J = 10.9 Hz, 1H),
4.28–4.39 (m, 2H), 7.19–7.99 (m, 4H), 8.22 (s, br, 1H). 13C NMR (75 MHz,
CDCl3): d 24.14 (2C), 25.23 (2C), 26.41, 27.02 (2C), 30.01, 36.08, 65.68, 68.59,
70.12, 108.24, 112.89, 120.76, 121.29, 126.52, 134.71, 144.79, 147.99, 153.58.
m/z [M+H]+ 357.8 CHN analysis (calcd) C, 70.78; H, 7.86; N, 7.86; C21H28N2OS
(found) C, 70.62; H, 7.61; N, 7.98.
17. Compound 4a (2 mmol, 0.488 g) in 6 ml of EtOH was reacted with an aqueous
solution of hydroxylamine prepared by adding NaOH (0.175 g in 4 ml H2O) to a
solution of NH2OH/HCl (0.166 g, 2 mmol in 3 ml water), with stirring at room
temperature. After 10 min, the solution was clear. The reaction mixture was
allowed to stir at room temperature for 1 h after which the EtOH was
evaporated and the compound was separated by extraction with
dichloromethane. The organic extract was dried over anhydrous sodium
sulphate and then evaporated under reduced pressure to obtain 7a.
Recrystallised from chloroform. Yield: 72%, mp 147–148 °C. 1H NMR
(300 MHz, CDCl3): d 1.45 (s, 6H), 3.76 (d, J = 4.8 Hz, 2H), 5.96–6.05 (m, 1H),
7.24–7.68 (m, 4H), 8.15 (s, 1H), 8.46 (s, 1H). Compound 7b was prepared
similarly.
18. To a mixture of oxime 7a (2 mmol, 0.518 g) and Et3N (0.202 g, 2 mmol) in
dichloromethane (8 ml), 10% aqueous NaOCl solution (3.5 ml) was added
dropwise at ꢁ10 °C. The reaction mixture was allowed to stir for 1 h at room
temperature. The organic phase was separated and the solvent was removed
under reduced pressure. Product 8a was purified by preparative TLC using
EtOAc and hexane (7:3) as eluent. Yield: 0.335 g (65%), mp 167–168 °C. 1H
NMR (300 MHz, CDCl3): d 1.33 (s, 6H), 2.68–2.89 (m, 1H), 3.26–3.35 (m, 1H),
3.73–3.94 (m, 1H), 7.20–7.75 (m, 4H), 8.35 (s, 1H). 13C NMR (75 MHz, CDCl3): d
27.06 (2C), 32.34, 56.28, 69.26, 112.52, 115.18, 119.58, 121.04, 122.89, 128.60,
129.37, 142.66, 157.29. m/z [M+H]+ 259.4. CHN analysis (calcd) C, 65.11; H,
5.42; N, 10.85%; C14H14N2OS (found) C, 64.99; H, 5.32; N, 10.88%. Compound
8b. Yield: 0.337 g (62%), mp 184–185 °C. 1H NMR (300 MHz, CDCl3): d 1.33 (s,
6H), 2.69–2.92 (m, 1H), 3.23–3.37 (m, 1H), 3.63 (s, 3H), 3.72–3.95 (m, 1H),
7.23–7.77 (m, 4H), 8.39 (s, 1H). 13C NMR (75 MHz, CDCl3): d 27.12 (2C), 33.74,
36.78, 55.22, 69.69, 113.69, 115.84, 119.91, 121.58, 122.70, 127.25, 130.48,
143.74, 158.74. m/z [M+H]+ 273.6. CHN analysis (calcd) C, 66.17; H, 5.88; N,
10.29; C15H16N2OS (found) C, 65.98; H, 5.64; N, 10.58.
9. Majumder, S.; Bhuyan, P. J. Synlett 2011, 1547.
10. (a) Baruah, B.; Bhuyan, P. J. Tetrahedron 2009, 65, 7099; (b) Deb, M. L.;
Majumder, S.; Baruah, B.; Bhuyan, P. J. Synthesis 2010, 929; (c) Deb, M. L.;
Bhuyan, P. J. Synlett 2008, 325; (d) Deb, M. L.; Bhuyan, P. J. Synthesis 2008, 2891.
11. Lu, S. C.; Duan, X. Y.; Shi, Z. J.; Li, B.; Ren, Y. W.; Zhang, W.; Zhang, Y. H.; Tu, Z. F.
Org. Lett. 2009, 11, 3902.
12. Majumder, S.; Bhuyan, P. J. Synlett 2011, 2, 173.
13. Ceulemans, E.; Voets, M.; Emmers, S.; Uytterhoeven, K.; Meervelt, L. V.;
Dehaen, W. Tetrahedron 2002, 58, 531.
14.
A solution of 1-bromo-3-methyl-2-butene (2 mmol, 0.298 g), thiourea
(3 mmol, 0.228 g) in ethanol (5 mL) was refluxed for 1 h. After addition of
sodium hydroxide (10 mmol, 0.40 g) in ethanol (5 mL) the reaction was
continued for an additional 1 h and then N-Boc protected 2-chloro-3-indolo
carbaldehyde 3a (2 mmol, 0.558 g) was added. The mixture was refluxed for
half an hour and then water (10 mL) was added. The reaction mixture was
extracted with dichloromethane (3 ꢀ 20 mL). The combined extracts were
dried over anhydrous sodium sulphate, the solvent evaporated and the residue
was purified by column chromatography using petroleum ether–ethylacetate
as eluent (7:3). 4a. Yield: 0.352 g (72%), mp 114–115 °C. 1H NMR (300 MHz,
CDCl3): d 1.35 (s, 3H), 1.70 (s, 3H), 3.45 (d, J = 8.04 Hz, 2H), 5.30–5.34 (m, 1H),
7.2–7.38 (m, 4H), 8.78 (s, br, 1H), 10.18 (s, 1H).
15. Jacquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.; Merour, J.-Y.; Coudert, G.
Tetrahedron 2004, 60, 10039.
16. To a solution of 2-thioprenyl-3-indolo carbaldehyde 4a (2 mmol, 0.488 g) in
5 ml ethanol was added MeNHOH/HCl (3 mmol, 0.250 g) and the reaction
mixture was set on reflux. NaOH (0.120 g, 3 mmol) was added portion-wise
over a period of 5 min and refluxed for another 2 h. The solvent was removed