A novel and short synthesis of naturally occurring 5-(3′-indolyl) oxazoles

Article abstract of DOI:10.1002/jhet.472

A novel, concise, and convenient synthesis of 5-(3′-indolyl)oxazoles using relatively benign reagent [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo] benezene has been described. The advantages of this procedure include operational simplicity, good yield, and

Full text of DOI:10.1002/jhet.472

November 2010
A Novel and Short Synthesis of Naturally Occurring
5-(30-Indolyl)oxazoles
1425
Dalip Kumar,* Swapna Sundaree, Gautam Patel, and Anil Kumar
Chemistry Group, Birla Institute of Technology and Science, Pilani-333031, India
*E-mail: dalipk@bits-pilani.ac.in
Received December 22, 2009
DOI 10.1002/jhet.472
Published online 30 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
A novel, concise, and convenient synthesis of 5-(30-indolyl)oxazoles using relatively benign reagent
[hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benezene has been described. The advantages of this pro-
cedure include operational simplicity, good yield, and avoidance of the use of toxic metal.
J. Heterocyclic Chem., 47, 1425 (2010).
INTRODUCTION
Hypervalent iodine reagents have found broad utility
in organic synthesis due to their low toxicity, ready
availability, and ease of handling [3]. The a-[(2,4-dini-
trobenzene)sulfonyl]oxyketones are very useful interme-
diate in organic synthesis, and can be easily prepared
from the reaction of enolizable ketone with
[hydroxy(2,4-dinitrobenzene-sulfonyloxy)iodo]benzene
(PhI(ODNs)OH, HDNIB) [4]. More recently, we have
reported a multistep synthesis of 5-(30-indolyl)oxazoles
involving preparation of key intermediate a-aminoke-
tones and cyclization of acylamidoketones using p-tolue-
nesulfonic acid [5]. To further improve synthesis of 5-
(30-indolyl)-oxazoles, and to continue our efforts to
explore hypervalent iodine reagents in the syntheses of
biological important heterocyclic compounds [6], we
report herein HDNIB mediated one-pot conversion of 3-
acetyl-1-benzenesulfonylindole 1 into naturally occur-
ring 5-(30-indolyl)oxazoles 3.
The 5-(30-indolyl)oxazole is a naturally occurring an
important heterocyclic motif of immense medicinal and
therapeutic potential. Many 5-(30-indolyl)oxazoles have
been isolated from different microorganisms and are
known to display interesting biological activities [1].
The 2,5-disubstituted (30-indolyl)oxazoles, such as pim-
prinine (2-methyl-5-(30-indolyl)oxazole); pimprinethine
(2-ethyl-5-(30-indolyl)oxazole), and pimprinaphine (2-
benzyl-5-(30-indolyl)oxazole) were isolated from Strep-
toverficillium oliva reticuli. The pimprinine is known to
inhibit monoamine oxidase and showed antiepileptic
effects [1a]. Analogs WS-30581 A and B isolated from
Streptoverticillium waksmanii are shown to display
potent inhibitory effects of platelet aggregation [1b].
Recently isolated, the Labradorin 1 (2-isobutyl-5-(30-
indolyl)oxazole) and Labradorin 2 (2-n-pentyl-5-(30-
indolyl)oxazole) from Pseudomonas syringae pv. coro-
nafaciens are reported to exhibit very good inhibitory
activity against various human cancer cells [1c].
RESULTS AND DISCUSSION
Many procedures are reported for the synthesis of 5-
(30-indolyl)oxazoles, however, straightforward and sim-
ple methods are quite limited [2]. Direct synthesis of 5-
(30-indolyl)oxazoles involve rhodium catalyzed reaction
of diazoacetylindole with nitriles [2a] and aza-Wittig-
type reaction of iminophosphorane derived from 3-azi-
doacetyl-1-methylindole with isocyanates and acid
chlorides [2b]. In general, most of the methods involve
multiple synthetic steps, which often require harsh
reagents and reaction conditions and afford products in
moderate yields. Thus, it is desirable to develop a sim-
ple and direct method for the synthesis of 5-(30-indoly-
l)oxazoles that can be achieved under milder reaction
conditions from readily available starting material.
The reaction of 3-acetyl-1-benzenesulfonylindole 1
with 2-(pyridin-3-yl)acetonitrile in presence of HDNIB
at 100ꢀC produced pure 5-(10-benzenesulfonylindol-30-
yl)-2-(30-pyridinylmethyl)oxazole (2a) in 63% yield
(Scheme 1). The benzenesulfonyl moiety of oxazole 2a
was removed by treatment with sodium hydroxide to
obtain pure 2-(30-pyridinylmethyl)-5-(30-indolyl)oxazole
3a in quantitative yield. Similarly, analogs 5-(30-indoly-
l)oxazoles 2b–h were obtained and removal of benzene-
sulfonyl group led to the corresponding 5-(30-indolyl)
oxazoles 3b–h (Table 1). The spectral data of 5-(30-
indolyl)]oxazoles 3a–h are in agreement with the pro-
posed structures.
C
V
2010 HeteroCorporation

1426
D. Kumar, S. Sundaree, G. Patel, and A. Kumar
Vol 47
Scheme 1
Scheme 2
In the reaction of 3-acetyl-1-benzenesulfonylindole 1
with HDNIB in 2-(pyridin-3-yl)acetonitrile, two addi-
tional spots on TLC were initially observed, probably
corresponding to the 3-a-(2,4-dinitrobenzenesulfony-
loxy)-acetylindole and 2a, which upon further heating
converted exclusively to a single spot, that is, 2a. The
3-acetyl-1-benzenesulfonylindole 1 reacted equally well
with benzonitrile, alkylnitriles, and heteroaryl nitriles to
afford corresponding oxazoles 2. Attempts to isolate
probable intermediate 3-a-(2,4-dinitrobenzenesulfony-
loxy)acetyl indole could not be successful because of its
instability. It is, however, to be noted that the reaction
of 3-acetylindole with HDNIB in acetonitrile generated
a complex mixture.
dolyl)-oxazoles from readily available 3-acetylindole 1
using metal free [hydroxy(2,4-dinitrobenzenesulfonylox-
y)iodo]benezene. This protocol should be complemen-
tary to other approaches in the synthesis of 5-(30-indoly-
l)oxazoles described.
It is proposed that initial nucleophilic addition of enol
I on HDNIB forms species II, which subsequently loses
iodobenzene and water to afford intermediate 3-[a-(2,4-
dinitrobenzenesulfonyloxy)]acetyl indole III (Scheme
2). The nucleophilic displacement of ODNs in III by
nitrile, results in the formation of species IV, which
finally cyclizes to oxazole 2. Apparently, ODNs being a
better leaving group may be responsible for the efficient
cyclization, but reaction fails to proceed with the inter-
mediacy of 3-[a-(tosyloxy)]acetylindole obtained from
the reaction of 3-acetyl-1-benzenesulfony-lindole 1 with
[hydroxy(tosyloxy)iodo]benzene.
EXPERIMENTAL
Melting points were recorded on EZ-Melt automated melt-
ing point apparatus (Stanford Research Systems, USA) and are
uncorrected. IR spectra were recorded on Jasco IR-Report-100
using KBr pellet. 1H and 13C NMR spectra were recorded on
Bruker Avance II (400 MHz) and Bruker (200 MHz) spectro-
photometer using CDCl3 and DMSO as solvent. Mass spectra
were taken on a Agilent Mass spectrometer using FAB mode.
All the reagents and solvents were commercially purchased
and further purified according to the standard procedures.
General procedure for the preparation of 2-substituted-
5-(10-benzenesulfonylindol-30-yl)oxazoles (2a–h). A mixture
of 3-acetyl-1-benzenesulfonylindole 1 [7] (0.150 g, 0.501
mmol), HDNIB (0.281 g, 0.602 mmol) and appropriate nitrile
(2.51 mmol) were heated at 100ꢀC for 18 h. After completion
of the reaction, the crude reaction mixture was percolated
through a silica-gel column using ethyl acetate-hexane elution
system.
CONCLUSIONS
We have introduced a novel, short, and efficient pro-
tocol for the preparation of naturally occurring 5-(30-in-
5-(10-Benzenesulfonylindol-30-yl)-2-(30-pyridinylmethyl)oxa-
1
zole (2a) m.p. 185ꢀC; H NMR (200 MHz, CDCl3): d ¼ 4.40
(s, 2H, CH2), 7.25–7.55 (m, 10H, Ar-H), 7.90–8.04 (m, 5H,
Ar-H); 13C NMR (50 MHz, CDCl3): d ¼ 39.73, 113.63,
113.67, 118.06, 121.09, 123.78, 124.43, 125.02, 126.84,
127.20, 128.40, 128.80, 129.09, 129.28, 133.89, 135.37,
137.67, 137.99, 148.09, 170.43; HRMS for C23H17N3aO3S,
calcd. (M)þ: 415.0991; found: 415.1201 (M)þ.
Table 1
Synthesis of 5-(30-indolyl)oxazoles 2 and 3.
Entry
R
Yield (%)a
(2a–h)
63
65
Overall Yield
(%)b (3a–h)
5-(10-Benzenesulfonylindol-30-yl)-2-phenyloxazole (2b). m.p.
153–156ꢀC (Lit. [5] m.p. 156ꢀC); 1H NMR (400 MHz,
CDCl3): d ¼ 7.26–7.59 (m, 9H, Ar-H), 7.83 (dd, 1H, J ¼ 1.2,
8.0 Hz, Ar-H), 7.95–7.97 (m, 2H, Ar-H), 7.99 (s, 1H, Ar-H),
8.06 (dd, 1H, J ¼ 1.2, 7.6 Hz, Ar-H), 8.13–8.15 (m, 2H, Ar-
H); 13C NMR (100 MHz, CDCl3): d ¼ 103.86, 111.63,
119.20, 119.94, 120.20, 121.87, 122.35, 123.47, 123.52,
125.26, 127.15, 128.24, 129.26, 129.73, 133.90, 134.63,
136.27, 145.00, 158.42; MS(EI) for C23H16N2O3S, calcd. (M
þ H)þ: 401.0; found: 401.0 (M þ H)þ.
a
b
c
d
e
f
3-Pyridinylmethyl
C6H5
CH3
60
61
60
60
59
65
66
61
66
65
65
71
70
65
CH3CH2CH2
(CH3)2CHCH2
C6H5CH2
CH3CH2CH2CH2
3-Pyridinyl
g
h
a Isolated yields.
b Combined isolated yields of both the steps.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
A Novel and Short Synthesis of Naturally Occurring 5-(30-Indolyl)oxazoles
1427
1H, Ar-H), 8.09–8.11 (m, 2H, Ar-H), 11.03 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3): d ¼ 103.86, 111.63, 119.00, 119.91,
120.16. 121.87, 122.43, 123.47, 125.26, 127.15, 128.27,
129.26, 136.15, 147.97, 158.38; MS(EI) for C17H12N2O, calcd.
(M þ H)þ: 261.1; found: 261.1 (M þ H)þ.
5-(10-Benzenesulfonylindol-30-yl)-2-methyloxazole (2c). m.p.
145ꢀC (Lit. [5] m.p. 143ꢀC); 1H NMR (400 MHz, CDCl3): d
¼ 2.32 (s, 3H, CH3), 7.18 (s, 1H, Ar-H), 7.26–7.49 (m, 5H,
Ar-H), 7.50 (m, 2H, Ar-H), 7.54 (s, 1H, Ar-H), 7.75–7.82 (m,
2H, Ar-H); MS(EI) for C18H14N2O3S, calcd. (M þ H)þ:
339.1; found: 339.1 (M þ H)þ.
2-(Methyl)-5-(30-indolyl)oxazole (3c). Yield 83%; m.p.
1
201ꢀC (Lit. [8] mp 204–205ꢀC); H NMR (400 MHz, CDCl3):
5-(10-Benzenesulfonylindol-30-yl)-2-propyloxazole (2d). m.p.
135ꢀC; 1H NMR (400 MHz, CDCl3): dH ¼ 1.05 (t, 3H, J ¼
6.9 Hz, CH3), 1.88 (m, 2H, CH2), 2.82 (t, 2H, J ¼ 7.1 Hz,
CH2), 7.14 (s, 1H, Ar-H), 7.48–7.53 (5H, m, Ar-H), 7.61 (s,
1H, Ar-H), 7. 69 (m, 2H, Ar-H), 7.83 (m, 2H, Ar-H); HRMS
d ¼ 2.53 (s, 3H, CH3), 7.10 (s, 1H, Ar-H), 7.17–7.25 (m, 2H,
Ar-H), 7.44 (d, 1H, J ¼ 7.60 Hz, Ar-H), 7.50 (d, 1H, J ¼ 2.56
Hz, Ar-H), 7.80 (d, 1H, J ¼ 7.64 Hz, Ar-H), 10.12 (s, 1H,
NH); 13C NMR (100 MHz, CDCl3): d ¼ 13.39, 104.53,
111.27, 118.89, 119.07, 119.76, 121.50, 121.86, 123.47,
135.95, 147.18, 158.34; MS(EI) for C12H10N2O, calcd. (M þ
H)þ: 199.1; found: 199.1 (M þ H)þ.
for C20H18N2O3S, calcd. (M
þ
H)þ: 367.1116; found:
367.1162 (M þ H)þ.
5-(10-Benzenesulfonylindol-30-yl)-2-(i-butyl)oxazole (2e). m.p.
182–184ꢀC (Lit. [5] m.p. 185ꢀC); 1H NMR (400 MHz,
CDCl3): dH ¼ 1.13 (d, 6H, J ¼ 6.6 Hz, 2CH3), 2.26 (m, 1H,
CH), 2.70 (d, 2H, J ¼ 7.6 Hz, CH2), 7.17 (s, 1H, Ar-H), 7.26–
7.39 (m, 5H, Ar-H), 7.52 (s, 1H, Ar-H), 7.83 (dd, 2H, J ¼ 1.2,
8.0 Hz, Ar-H), 7.95–7.97 (dd, 2H, J ¼ 1.2, 7.6 Hz, Ar-H);
MS(EI) for C21H20N2O3S, calcd. (M þ H)þ: 381.1, found:
381.0 (M þ H)þ.
2-(Propyl)-5-(30-indolyl)oxazole (3d). Yield 81%; m.p.
124ꢀC (Lit. [1b] m.p. 128–130ꢀC); 1H NMR (400 MHz, DMSO-
d6): dH ¼ 1.05 (t, 3H, J ¼ 6.9 Hz, CH3), 1.88 (m, 2H, CH2),
2.82 (t, 2H, J ¼ 7.1 Hz, CH2), 7.12–7.53 (5H, m, Ar-H), 7.83
(m, 1H, Ar-H), 9.58 (s, 1H, NH); HRMS for C20H18N2O3S,
calcd. (M þ H)þ: 367.1116; found: 367.1162 (M þ H)þ.
2-(Isobutyl)-5-(30-indolyl)oxazole(3e). Yield 74%; m.p.
143ꢀC (Lit. [1c] m.p. 147–148ꢀC); 1H NMR (400 MHz,
DMSO-d6): dH ¼ 1.06 (d, 6H, J ¼ 6.6 Hz, 2CH3), 2.27 (m,
1H, CH), 2.76 (d, 2H, J ¼ 7.8 Hz, CH2), 7.20 (s, 1H, Ar-H),
7.26–7.29 (m, 2H, Ar-H), 7.44 (d, 1H, J ¼ 7.8 Hz), 7.53 (d,
1H, J ¼ 2.93 Hz, Ar-H), 7.87 (d, 1H, J ¼ 7.8 Hz, Ar-H), 9.30
(s, 1H, NH); MS(EI) for C15H16N2O, calcd. (M þ H)þ: 241.1,
found: 241.3 (M þ H)þ.
5-(10-Benzenesulfonylindol-30-yl)-2-benzyloxazole (2f). m.p.
1
140ꢀC (Lit. [5] mp 138–142ꢀC); H NMR (400 MHz, CDCl3):
dH ¼ 3.28 (s, 2H, CH2), 7.16 (s, 1H, Ar-H), 7.26–7.59 (m,
10H, Ar-H), 7.58 (s, 1H, Ar-H), 7.83 (dd, 2H, J ¼ 1.2, 8.0 Hz,
Ar-H), 8.06 (dd, 2H, J ¼ 1.2, 7.6 Hz, Ar-H); MS(EI) for
C24H18N2O3S, calcd. (M þ H)þ: 415.1, found: 415.2 (M þ
H)þ.
2-(Benzyl)-5-(30-indolyl)oxazole (3f). Yield 79%; m.p.
5-(10-Benzenesulfonylindol-30-yl)-2-butyloxazole (2g). m.p.
1
1
174ꢀC (Lit. [5] m.p. 172ꢀC); H NMR (400 MHz, DMSO-d6):
148ꢀC; H NMR (400 MHz, CDCl3): dH ¼ 0.96 (t, 3H, J ¼
dH ¼ 3.24 (s, 2H, CH2), 7.19 (s, 1H, Ar-H), 7.22–7.25 (m, 5H,
Ar-H), 7.56 (d, 1H, J ¼ 2.53 Hz, Ar-H), 7.79 (dd, 2H, J ¼
1.2, 8.0 Hz, Ar-H), 7.93 (dd, 2H, J ¼ 1.2, 7.6 Hz, Ar-H), 9.82
(s, 1H, NH); MS(EI) for C18H14N2O, calcd. (M þ H)þ: 275.1,
found: 275.0 (M þ H)þ.
6.8 Hz, CH3), 1.43 (m, 2H, CH2), 1.77 (m, 2H, CH2), 2.83
(t, 2H, J ¼ 6.7 Hz), 7.15 (s, 1H, Ar-H), 7.24–7.29 (m,
5H, Ar-H), 7.55–7.82 (5H, m, Ar-H); HRMS for
C21H20N2O3S, calcd. (M
381.1285 (M þ H)þ.
þ
H)þ: 381.1273; found:
2-(Butyl)-5-(30-indolyl)oxazole (3g). Yield 84%; m.p. 119ꢀC
(Lit. [1b] m.p. 123–125ꢀC); 1H NMR (400 MHz, DMSO-d6):
dH ¼ 1.01 (t, 3H, J ¼ 7.0 Hz, CH3); 1.45 (m, 2H, CH2), 1.80
(m, 2H, CH2), 2.84 (t, 2H, J ¼ 6.8 Hz), 7.15 (s, 1H, Ar-H),
7.53 (d, 1H, J ¼ 2.52 Hz, Ar-H), 7.62–7.92 (4H, m, Ar-H),
9.10 (s, 1H, NH); HRMS for C21H20N2O3S, calcd. (M þ H)þ:
381.1273; found: 381.1285 (M þ H)þ.
5-(10-Benzenesulfonylindol-30-yl)-2-(pyridin-300-yl)oxazole
1
(2h). m.p. 194ꢀC; H NMR (400 MHz, CDCl3): dH ¼ 7.24 (s,
1H, Ar-H), 7.32–7.36 (m, 5H, Ar-H), 7.45 (d, 1H, J ¼ 7.56
Hz, Ar-H), 7.51 (dd, 2H, J ¼ 1.7, 8.0 Hz, Ar-H), 7.55–7.59
(m, 4H, Ar-H), 7.76 (dd, 2H, J ¼ 1.8, 7.6 Hz, Ar-H); HRMS
for C22H15N3O3S, calcd. (M)þ: 401.0834; found: 401.1001
(M)þ.
2-(Pyridin-300-yl)-5-(30-indolyl)oxazole (3h). Yield 79%,
General procedure for the preparation of 2-substituted-
5-(30-indolyl)oxazoles 3. A stirred solution of oxazole 2 (0.19
mmol) and sodium hydroxide (0.02 g, 0.50 mmol) in aqueous
ethanol (6 mL) was refluxed for 2 h. After removal of ethanol
under vacuum, the aqueous phase was extracted with dichloro-
methane (3 ꢁ 5 mL). The combined organic phase was dried
over anhydrous sodium sulfate and concentrated under
vacuum.
1
m.p. 142–144ꢀC; H NMR (400 MHz, DMSO-d6): dH ¼ 7.22
(s, 1H, Ar-H), 7.47 (d, 1H, J ¼ 7.60 Hz, Ar-H), 7.53 (dd,
2H, J ¼ 1.7, 8.0 Hz, Ar-H), 7.57–7.62 (m, 4H, Ar-H),
7.78 (dd, 2H, J ¼ 1.8, 7.8 Hz, Ar-H), 9.58 (s, 1H, NH);
HRMS for C16H11N3O, calcd. (M)þ: 261.0902; found:
261.1102 (M)þ.
2-(30-Pyridinylmethyl)-5-(30-indolyl)oxazole
(3a). Yield
Acknowledgment. The financial support received from Univer-
sity Grants Commission, New Delhi, is thankfully
acknowledged.
1
95%; m.p. 195–198ꢀC; H NMR (200 MHz, CDCl3): d ¼ 4.39
(s, 2H, CH2), 7.15–7.40 (m, 7H, Ar-H), 7.69 (s, 1H, Ar-H),
8.00 (s, 1H, Ar-H), 8.61 (s, 1H, Ar-H); 13C NMR (50 MHz,
CDCl3): d ¼ 39.68, 110.28, 111.49, 112.51, 119.95, 120.48,
122.40, 123,79, 125.04, 127.08, 128.72, 129.11, 136.49,
137.92, 150.41, 169.82; HRMS for C17H13N3O, calcd. (M)þ:
275.1059; found: 275.1123 (M)þ.
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Journal of Heterocyclic Chemistry
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D. Kumar, S. Sundaree, G. Patel, and A. Kumar
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