Synthesis of pseudo-indoxyl derivatives via sequential Cu-catalyzed S NAr and Smalley cyclization

Article abstract of DOI:10.1039/c3cc41348a

Ortho-Bromophenyl sec-alkyl/sec-alkenyl ketones, on reaction with sodium azide in the presence of copper salts, undergo sequential S_NAr followed by Smalley cyclization to provide pseudo-indoxyl derivatives. Some of these pseudo-indoxyl derivati

Full text of DOI:10.1039/c3cc41348a

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Synthesis of pseudo-indoxyl derivatives via sequential
Cu-catalyzed SNAr and Smalley cyclization
The pseudo-indoxyl framework was constructed in one step from
easily accessible α-bromophenyl sec-alkyl/sec-alkenyl ketones.
The photophysical studies of a wide range of pseudo-indoxyl
derivatives reveal that they display interesting fluorescence
properties with Stokes shifts up to 120 nm and varied emission
wavelengths.
See Chepuri V. Ramana
and Yogesh Goriya,
Chem. Commun., 2013, 49, 6376.
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Synthesis of pseudo-indoxyl derivatives via sequential
Cu-catalyzed SNAr and Smalley cyclization†‡
Cite this: Chem. Commun., 2013,
49, 6376
Yogesh Goriya and Chepuri V. Ramana*
Received 21st February 2013,
Accepted 4th April 2013
DOI: 10.1039/c3cc41348a
www.rsc.org/chemcomm
ortho-Bromophenyl sec-alkyl/sec-alkenyl ketones, on reaction with The addition of Grignard reagents to 2-arylindolone followed by
sodium azide in the presence of copper salts, undergo sequential the acid-catalyzed pinacol rearrangement,6 as well as the addi-
SNAr followed by Smalley cyclization to provide pseudo-indoxyl tion of carbon-centered nucleophiles to spiro[furan/pyran-2,20-
derivatives. Some of these pseudo-indoxyl derivatives exhibit indolin]-30-ones5g,7 are some of the methods which offer the
interesting fluorescent properties and broad Stokes shifts.
provision to vary the substituents at the C(2)-position. The
CuI-catalyzed intramolecular amination,8 an interrupted Ugi
2,2-Disubstituted 1,2-dihydro-3H-indol-3-one (trivially known reaction comprising of an internal attack of the electron-rich
as pseudo-indoxyl) is one of the important structural units aromatic ring on an electrophilic nitrilium ion,9 the gold-
present in many natural products and biologically active small mediated cycloisomerization of 2-alkynyl aryl azides,10 the
molecules.1 Apart from their use as intermediates in the Mannich–Henry reaction of cyclic a-carbonyl ketimines11 and
synthesis of natural products,2 in recent years, the indol-3- the reaction of amino acids with arynes12 are some of the
one derivatives have also found important applications in the important methods that have been developed recently in the
areas of fluorescence dyeing and in solar cell applications context of the synthesis of 2,2-disubstituted indolin-3-ones.
(Fig. 1).3 The rearrangement of 2,3-dihydroxyindolines and
In 1979, Ardakani and Smalley reported the base-induced
3H-indol-3-ols (acid-, base- or thermal-induced) is one of intramolecular cyclization of a-azidophenyl sec-alkyl ketones
the earlier methods reported for the preparation of indoxyl leading to 2,2-disubstituted indolin-3-ones – trivially known as
derivatives.4 The oxidative rearrangements of 2,3-disubstituted the Smalley cyclization (eqn (1), Scheme 1).13 This reaction has
indoles or the tetrahydrocarbolines is one of more popular methods served as the key step in the total synthesis of lapidilectine B.2d
used in the synthesis of the indoxyl class of natural products.5 The substrates that are generally used for the Smalley rearran-
gement require free fabricated a-azidophenyl sec-alkyl ketones
which, in general, are prepared by multi-step procedures.
Recently, we documented the SNAr reaction of o-/p-nitrophenyl
halides with sodium azide under the classical Cu(II)-ascorbate
redox system. On one hand, when an alkyne derivative is
Fig. 1 Natural products and Lipid Green having the indol-3-one structural unit.
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune-411008,
India. E-mail: vr.chepuri@ncl.res.in; Fax: +91 20 2590 2629;
Tel: +91 20 2590 2578
† Dedicated to Professor Andrea Vasella on the occasion of his 70th Birthday.
‡ Electronic supplementary information (ESI) available: Characterization data
Scheme 1 Smalley cyclization (eqn (1)) and a concept for indol-3-one ring
and NMR spectra of compounds 2a–2n. See DOI: 10.1039/c3cc41348a
system (eqn (2)).
c
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Table 1 Scope of the [Cu]-catalyzed one-pot SNAr–Smalley cyclization
present in the same pot, the resulting azide intermediates
undergo copper-catalyzed azide–alkyne cycloaddition (CuAAC)
leading to 1,4-diaryltriazoles.14 On the other hand, if there is no
dipolarophile to trap these azides, these intermediate azides
are reduced further to anilines.15 Given our current interest in the
synthesis of natural products having the indolin-3-one core,16 we
speculated on the possibility of a one-pot [Cu]-catalyzed SNAr
and the Smalley rearrangement of a-halophenyl sec-alkyl ketones
(eqn (2), Scheme 1).
The work in this direction began with the identification
of the optimum leaving group for the SNAr with azide. The
screening of the four a-halophenyl isopropyl ketones under the
previously optimized conditions for the SNAr reactions with
sodium azide revealed that the bromo-derivative 1a is the better
substrate. The conditions employed involve the use of 20 mol%
of each of CuSO4ꢀ5H2O, sodium ascorbate and L-proline,
1.5 equivalents of K2CO3, and DMSO as the solvent. The
reactions with the fluoro- and chloro-substrates were found to
be incomplete even after prolonged heating under the above-
mentioned conditions. Along with the requisite SNAr – Smalley
cyclization, the dehalogenation of the starting halo-derivatives
and also the in situ reduction of the intermediate azide are the
competing reactions. The SNAr reaction with the iodo derivative
was found to be facile. However, the corresponding dehalo-
genated derivative was isolated in substantial amounts. For the
bromo-derivative 1a, although the displacement reaction was
slow, the required 2a was obtained as the main product in 65%
yield. Control experiments employing substrate 1a revealed
that the presence of the copper salt is essential. Among the
various Cu-sources investigated (for details see ESI,‡ Table S1,
entries 7–14), the outcome showed that the CuSO4 was the best
(Scheme 2).
The scope of the current reaction has been investigated
employing variously substituted a-bromophenyl sec-alkyl
ketones (Table 1). As indicated in Table 1, the yields with the
electron-rich aryl derivatives are comparatively better than with
the simple unsubstituted benzene derivatives. The reaction was
also compatible with the a-keto esters and resulted in the
preparation of 3-oxoindoline-2-carboxylate; the main core of
the Lipid Green dye (2j).3c
Next, the feasibility of this SNAr–Smalley rearrangement
reaction was examined with the corresponding a-bromophenyl
sec-alkenyl ketones. The synthesis of model substrates 1l–1q
involves the crotylation of a 2-bromobenzladehyde derivative
under Barbier conditions and subsequent oxidation of the
resulting homoallylic alcohols (for details see ESI‡ Scheme S1).
The one pot SNAr–Smalley cyclization of a,b-unsaturated
ketones 1l–1n and b,g-unsaturated ketones 1o–1q gave exclu-
sively the 2-vinylindolin-3-one derivatives in very good yields
(Table 2).
From these experiments it seems reasonable that the
Smalley cyclization of all the substrates 1l–1n proceeds through
Table 2 Synthesis of 2-vinylindolin-3-one derivatives
Entry
1
Substrate
Product
Yield (%)
67
2
3
4
72
69
71
5
6
74
72
Scheme 2 One-pot synthesis of the indol-3-one ring system.
c
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Table 3 Optical properties of compounds 2a–2o
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Compound
lmaxa/nm
lema/nm
Stokes shiftb/nm
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
395
395
421
370
405
400
425
406
401
415
402
396
421
406
425
473
467
523
430
499
493
528
499
492
536
509
477
527
504
503
78
72
98
60
94
93
103
93
91
121
107
81
106
98
78
a
b
Measured in MeOH. Stokes shift = lem ꢁ lmax
.
the 2-methyl-1-phenylbuta-1,3-dien-1-olate intermediate in
which the a-carbon preferentially adds across the azide.
After having a set of indol-3-ones which are fluorescent in
nature, their photophysical properties were studied.3b,17 In the
1,2-dihydroindol-3-one core structure, the amino group acts as a
donor and the carbonyl group as an acceptor, which are con-
nected via a benzene ring. The optical data revealed that the
compounds with a methoxy group on the phenyl ring showed
absorption and emission at longer wavelengths than those sub-
strates having no substituent on the benzene ring or trimethoxy-
substituted benzene (Table 3). This indicates that the –OMe group
placed para to the amino group enhanced the donor capacity of
the amino group and thereby shifted the peak to a longer
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A similar trend was also noticed in the Stokes shifts (ranging from
70 to 130 nm) displayed by these indol-3-ones. The indol-3-one 2j
having a single methoxy substituent on the aryl ring and a
carboxylate group at C2 displayed a large Stokes shift (121 nm).
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system for the SNAr with azide, followed by Smalley cyclization from
a-bromophenyl sec-alkyl/sec-alkenyl ketones has been documented.
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structural optimization of these fluorophores and their application
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Notes and references
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c
6378 Chem. Commun., 2013, 49, 6376--6378
This journal is The Royal Society of Chemistry 2013