Synthesis of 3-heteroaryloxindoles through t-BuOCl-mediated oxidation of 3-heteroarylindoles

Article abstract of DOI:10.1055/s-0030-1258289

The oxidation of 3-heteroarylindoles to the corresponding oxindoles with t-butyl hypochlorite has been investigated. Under carefully adjusted conditions, preparative scale of desired products can be achieved. Two competing pathways seem to contribute to the reaction mechanism, affording 3-heteroaryloxindoles bearing hydrogen or chlorine at C3, depending on stereoelectronic factors. The present methodology appears also generally applicable for the preparation of simple 3-aryloxindoles. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258289

PAPER
4075
Synthesis of 3-Heteroaryloxindoles through t-BuOCl-Mediated Oxidation of
3-Heteroarylindoles
S
ynthesis of 3-Heteroa
a
ryloxindole
r
s
co Baroni,a Giordano Lesma,b Letizia Puleio,a Alessandro Sacchetti,c Alessandra Silvani,*b Marco Zancheta
a
Sanofi-Aventis, Centro Ricerche Sanofi-Midy, Via G. Sbodio 2, 20134 Milano, Italy
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via G. Venezian 21, 20133 Milano, Italy
Fax +39(02)50314078; E-mail: alessandra.silvani@unimi.it
b
c
Politecnico di Milano, Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘Giulio Natta’, Via Mancinelli 7, 20131 Milano, Italy
Received 23 July 2010
compounds can be achieved. Reaction at the C3 isatine
position with organolithium derivatives is moreover high-
ly incompatible with halogenated isatine cores. On the
other hand, the strongly acidic conditions and high tem-
Abstract: The oxidation of 3-heteroarylindoles to the correspond-
ing oxindoles with t-butyl hypochlorite has been investigated. Un-
der carefully adjusted conditions, preparative scale of desired
products can be achieved. Two competing pathways seem to con-
tribute to the reaction mechanism, affording 3-heteroaryloxindoles peratures required for Friedel–Crafts cyclization limit the
bearing hydrogen or chlorine at C3, depending on stereoelectronic
range of tolerated functional groups. Also application of a
factors. The present methodology appears also generally applicable
for the preparation of simple 3-aryloxindoles.
palladium-catalyzed variant of the Friedel–Crafts proce-
dure, starting from properly functionalized a-chloroacet-
anilides,14 proved to be not applicable to obtain 3-
Key words: indole, oxindole, t-BuOCl, oxidation, heterocycles
heteroaryloxindoles, since nontrivial synthetic sequences
are required to prepare the appropriate precursors for the
Oxindole-containing heterocycles, particularly those sub- reaction.
stituted at the C3 position, are commonly encountered in
natural products1 and pharmaceutical compounds.2 They
display a wide range of biological properties, including
antitumoral3 and antiviral4 activities.
O
HO
Ar
O
O
R
R
N
N
Moreover, diverse oxindole derivatives are used as non-
peptide scaffolds5 in the search for peptidomimetics either
as enzyme inhibitors or as ligands of G-protein coupled
receptors.6 For instance, the oxindole framework is the
essential feature of orally active nonpeptide arginine-
vasopressin receptor antagonists,7 of growth hormone
secretagogue (ghrelin) receptors agonists,8 and of a potent
gastrin/CCK-B receptor antagonist.9 As a consequence,
the selective functionalization at C3 by alkyl, alkenyl,
aryl, or heteroaryl groups of N-unsubstituted oxindoles
has been a longstanding issue.10
H
H
Ar
Ar
OH
H
O
R
O
R
N
N
H
H
In the course of a program directed toward the search for
new pharmaceutically relevant oxindole scaffolds,11 we
became interested in developing the synthesis of several
unprecedented 3-amino-3¢-heteroaryloxindoles, especial-
ly those bearing chlorine on the aromatic ring. Preliminary
attempts were directed to apply a few synthetic methodol-
ogies that are known for the preparation 3-amino-3¢-aryl-
oxindoles, such as Grignard addition to isatine12 or in-
tramolecular Friedel–Crafts cyclization onto a-hydroxy-
acetanilides,13 according to Scheme 1. Widening the
scope to 3-amino-3¢-heteroaryloxindoles, we could point
out that, unfortunately, these approaches proved to be
quite often not applicable. In the case of Grignard addi-
tion, a limited range of organomagnesium heterocyclic
Ar
Ar
Hal
NH2
O
O
R
R
N
N
H
H
Scheme 1 Some approaches to 3-amino-3¢-aryloxindoles
Therefore, our efforts turned toward setting up an alterna-
tive approach to 3-heteroaryloxindoles, based on the oxi-
dation of the corresponding 3-heteroarylindoles by
treatment with electrophilic halogenating agents. Subse-
quent conversion into 3-amino-3¢-heteroaryloxindoles
would be straightforward.15
While many methods exist for the construction of oxin-
dole from non-indole precursors, fewer options are avail-
able for the direct conversion of indoles into the
corresponding oxindoles.16 These methods involve often
SYNTHESIS 2010, No. 23, pp 4075–4081
Advanced online publication: 07.10.2010
DOI: 10.1055/s-0030-1258289; Art ID: P12010SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

4076
M. Baroni et al.
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harsh conditions17 or aqueous enzymatic systems18 for the
oxidation step and their applicability is sometimes re-
stricted to a few substrates. To the best of our knowledge,
this conversion has never been applied for the synthesis of
3-heteroaryloxindoles.
Table 1 Synthesis of 3-Heteroarylindoles 3a–ja
R
R
R
Br
B(OH)2
ii,iii
Het
i
N
N
N
H
Cl
Cl
Cl
TIPS
TIPS
In our search for an efficient protocol, we drew our inspi-
ration from the well-known oxidative rearrangement of
indoles to oxindoles upon treatment with electrophilic ha-
logenating agents, such as tert-butyl hypochlorite. This
conversion has been investigated in simple indoles for
several decades19 and it has also found recent use in natu-
ral products chemistry.20 The generally accepted mecha-
nism is based on the key conversion of a 2,3-disubstituted
indole into the corresponding 3-haloindolenine and also
includes the migration of a R group from C2 to C3, afford-
ing the final 3,3¢-disubstituted oxindole.
1a R = H
1b R = Cl
2a R = H
3a–j
2b R = Cl
3-Bromoindole R
Het-Br
Product Yield (%)
1a
1a
H
H
3a
3b
65
69
N
N
Br
Br
It was reasoned that tert-butyl hypochlorite could be a
useful reagent also for our scope and so, in a first step, the
preparation of a wide range of 3-heteroarylindoles as sub-
strates was envisaged, with the aim of studying the poten-
tial applicability of this kind of oxidative process.
Preparation of 3-heteroarylindoles was performed accord-
ing to the general protocol reported in Table 1.21
1a
1a
H
H
3c
87
67
O
Br
O
3d
Br
O
The required 3-bromoindoles 1a,b were prepared accord-
ing to the literature.22 Starting from 1a,b, halogen–metal
exchange with BuLi at –78 °C achieved highly selective
3-lithiation. Transmetalation of the resulting 3-lithioin-
doles with B(O-iPr)3 afforded indol-3-ylboronic acids
2a,b in satisfactory yields.23 With the obtained electron-
rich indol-3-ylboronic acids 2a,b, the coupling with bro-
mide heterocycles, under the Suzuki–Miyaura conditions
was then examined.24 The desired cross-coupling prod-
ucts 3a–j were readily obtained in a range of moderate to
quantitative yields (Table 1).
1a
1b
H
3e
3f
79
95
Br
Br
Cl
F3C
N
N
1b
1b
1b
1b
1a
Cl
Cl
Cl
Cl
H
3g
3h
3i
72
96
50
63
65
Br
Br
N
With 3-heteroarylindoles in hand, the oxidation to the cor-
responding oxindoles (Table 2) was studied. To a freshly
prepared 1 M solution of t-BuOCl in CH2Cl2 (1 equiv)
was added a 0.3 M CH2Cl2 solution of 3a. After consump-
tion of the starting material, visualized by TLC, the sol-
vent was removed under a nitrogen stream and the residue
was dissolved in a 2:1 1,4-dioxane–aq 3 N H2SO4 solu-
tion. After two hours, only the corresponding 2-chloroin-
dole 4a was recovered quantitatively (Table 2, entry 1).
Treatment of 4a with one equivalent of t-BuOCl afforded
6a in high yield (entry 2). Reasoning on the reaction
mechanism, it was deduced that more t-BuOCl would be
necessary in order to carry out the oxidation and so the re-
action on 3a with two equivalents of t-BuOCl (entry 3)
was planned. In this case 3-chlorooxindole 6a was isolat-
ed, together again with 20% of 2-chloroindole 4a. The
best result was then achieved with three equivalents of t-
BuOCl, the reaction affording 3-chlorooxindole 6a in al-
most quantitative yield (entry 4). With substrates 3b–e the
corresponding 3-chlorooxindoles were produced, without
recovery of 2-chloroindole, already with two equivalents
of t-BuOCl. Attempts to get higher yields employing
more oxidant were not successful, since increasing
N
N
O
Br
O
3j
Br
3a
N
Br
a Reaction conditions: (i) BuLi (1.6 M; 1.1 equiv), B(Oi-Pr)3 (3
equiv), THF, –78 °C; (ii) HetBr (1 equiv), Pd(PPh3)4 (0.05 equiv), tol-
uene–MeOH, aq Na2CO3 (2 M), reflux; (iii) Bu4N+F– (1 M in THF),
THF, 0 °C.
amounts of chlorinated by-products started to appear (en-
tries 5–8).
The reaction of substrate 3f, bearing an additional chlo-
rine substituent at C4 of the indole nucleus with one
equivalent of t-BuOCl afforded a mixture of 2-chloroin-
dole 4f (53%) and oxindole 5f (38%), suggesting that a
slightly different reaction pathway would apply in this
case (entry 9). In fact, when two equivalents of t-BuOCl
Synthesis 2010, No. 23, 4075–4081 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Heteroaryloxindoles
4077
Table 2 Synthesis of 3-Heteroaryloxindoles 5 and 6a
lent of t-BuOCl was added, the initially formed 2-
chloroindole 4 was converted into the corresponding 3-
chlorooxindole 6, via the dichloroindolenine derivative 8.
In the case of substrates 3f–j bearing an additional chlo-
rine substituent at C4, the effect of the presence of the sub-
stituent on C3 seems to fade out, probably also due to the
lost of coplanarity imposed by steric hindrance of the
chlorine at C4. As a consequence, the competitive C3
electrophilic attack takes place all along, affording direct-
ly oxindoles 5, together with 3-chlorooxindoles 6. In these
cases, slight differences in the ratio between yields of
compounds 5 and 6 could be addressed to further less pre-
dictable stereoelectronic effects.
R
Het
X
R
Het
R
Het
O
and/or
Cl
N
Cl
N
Cl
N
Cl
H
H
H
3a–j
4a–j
5a–j (X = H)
6a–j (X = Cl)
Entry Substrate R
t-BuOCl Yield (%) Yield (%) Yield (%)
(equiv) 4a–j
5a–j
6a–j
1
2
3a
4a
3a
3a
3b
3c
3d
3e
3f
H
1
1
2
3
2
2
2
2
1
2
1
2
2
2
2
96
–
–
–
H
–
96
65
91
85
66b
64b
60
–
R1
3
H
20
–
–
Het
4
H
–
3a–j
R2
N
5
H
–
–
H
6
H
–
–
t-BuOCl (1 equiv)
7
H
–
–
path a
path b
R1
Het
R1
8
H
–
–
Het
Cl
9
Cl
Cl
Cl
Cl
Cl
Cl
Cl
53
–
38
40
–
Cl
R2
N
R2
N
10
11
12
13
13
14
3f
55
96
16
17
18
17
H
4
7
4f
–
t-BuOCl (1 equiv)
3g
3h
3i
–
81
70
78
48
–
R1
R1
Het
Cl
Het
–
Cl
N
O
3j
–
R2
R2
N
H
8
a Reaction conditions: (i) 1 M t-BuOCl in CH2Cl2, CH2Cl2, r.t.; (ii)
then dioxane–aq 3 N H2SO4 (2:1).
5
b Some traces of halogenated by-products were detected.
R1
Het
Cl
were employed, almost the same amount of 5f was ob-
tained, together with 55% of 3-chlorooxindole 6f (entry
10). Also in this case, quantitative conversion of 2-chlor-
oindole 4f into 3-chlorooxindole 6f was realized with one
equivalent of t-BuOCl (entry 11). Finally, starting from
substrates 3g–j, high conversions into the corresponding
oxindoles were always observed, albeit as mixtures of
compounds 5 and 6 (entries 12–15).
O
R2
N
H
6
Scheme 2 Proposed mechanism for the reaction of 3-heteroarylin-
doles 3a–j with t-BuOCl
In summary, by means of a careful adjustment of the reac-
tion conditions, the synthesis of 3-heteroaryloxindoles by
t-BuOCl-mediated oxidation of 3-heteroarylindoles was
found to be general. It can be applied to a variety of func-
tionalized indoles yielding products, which are at this time
hardly achievable by other methods. It should be high-
lighted that both oxindoles 5 and 3-chlorooxindoles 6
proved to be well suited for subsequent transformation
towards 3-amino-3¢-heteroaryloxindoles.
Reasoning on the reaction mechanism and in accordance
with the well-known25 oxidative rearrangement of indoles
to oxindoles, promoted by electrophilic halogenating
agents, the first chlorination step should afford preferen-
tially the 3-chloroindolenine derivative 7 (Scheme 2, path
a), which is the precursor of the oxindole 5. From our re-
sults, however, it was deduced that the presence of a het-
eroaryl substituent at C3 affects deeply the outcome of
this reaction, leading primarily the electrophilic attack of
t-BuOCl at C2, probably for both steric and electronic rea-
sons (path b). In particular, electronic effects would play
a key role, due to the extensive conjugation of the all co-
planar aromatic ring system. When an additional equiva-
All solvents were distilled and properly dried, when necessary, prior
to use. All chemicals were purchased from commercial sources and
used directly, unless indicated otherwise. All reactions were run un-
Synthesis 2010, No. 23, 4075–4081 © Thieme Stuttgart · New York

4078
M. Baroni et al.
PAPER
der N2, unless otherwise indicated. All reactions were monitored by
TLC on precoated silica gel 60 F254; spots were visualized with UV
light or by treatment with 1% aq KMnO4. Products were purified by
flash chromatography (FC) on silica gel 60 (230–400 mesh). 1H and
13C NMR spectra were recorded using 300 and 400 MHz spectrom-
eters. Chemical shifts (d) are expressed in ppm relative to TMS at
d = 0 for 1H NMR and to CDCl3 at d = 77.16 for 13C NMR spectros-
copy. High-resolution MS spectra were recorded using an FT-ICR
(Fourier Transform Ion Cyclotron Resonance) instrument,
equipped with ESI source, or a standard MS instrument, equipped
with EI source. IR spectra were recorded using an FTIR instrument.
6-Chloro-3-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)-1H-in-
dole (3d)
Compound 3d (67% yield, foam) was prepared starting from 2a and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 98:2).
1H NMR (400 MHz, DMSO-d6): d = 11.40 (br s, 1 H), 7.85 (d,
J = 8.5 Hz, 1 H), 7.67 (s, 1 H), 7.66 (s, 1 H), 7.51 (br s, 1 H), 7.51–
7.47 (m, 2 H), 7.10 (dd, J = 8.5, 1.9 Hz, 1 H), 2.75 (br t, J = 5.8 Hz,
2 H), 2.65 (br t, J = 5.8 Hz, 2 H), 1.94–1.89 (m, 2 H), 1.86–1.79 (m,
2 H).
HRMS (EI): m/z calcd for C20H16ClNO: 321.0920; found:
321.0931.
3-Heteroarylindoles 3; 6-Chloro-3-(5-methylpyridin-2-yl)-1H-
indole (3a); Typical Procedure
Anal. Calcd for C20H16ClNO: C, 74.65; H, 5.01; N, 4.35; Cl, 11.02.
Found: C, 74.71; H, 5.09; N, 4.25; Cl, 11.09.
To a solution of 2-bromo-5-methylpyridine (172 g/mol, 2 g, 11.6
mmol, 1 equiv) and [6-chloro-1-(triisopropylsilyl)-1H-indol-3-
yl]boronic acid (2a; 351 g/mol, 4 g, 11.6 mmol, 1 equiv) in a tolu-
ene–MeOH (4:1) solution (50 mL) were added aq 2 M Na2CO3 (9
mL), and Pd(PPh3)4 (1155.5 g/mol, 670 mg, 0.6 mmol, 0.05 equiv).
The mixture was heated at reflux under stirring for 4 h, cooled, and
then partitioned between EtOAc (50 mL) and H2O (50 mL). After
extraction, the organic phase was washed with brine (50 mL), dried
(MgSO4), filtered, and concentrated. The residue was dissolved in
THF (30 mL) at 0 °C and a 1 M solution of Bu4N+F– in THF (2
equiv) was added. After stirring for 2 h, the reaction mixture was di-
luted with CH2Cl2 (30 mL) and the CH2Cl2 was washed with H2O
(30 mL). The organic phase was dried (MgSO4), filtered, and con-
centrated; the residue was purified by FC (n-hexane–EtOAc, 98:2)
to give 3a (1.83 g, 65%) as a foam.
3-(Benzofuran-5-yl)-6-chloro-1H-indole (3e)
Compound 3e (79% yield, foam) was prepared starting from 2a and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 98:2).
1H NMR (400 MHz, DMSO-d6): d = 11.40 (br s, 1 H), 7.99 (d,
J = 2.0 Hz, 1 H), 7.91 (d, J = 1.3 Hz, 1 H), 7.87 (d, J = 8.3 Hz, 1 H),
7.70 (d, J = 2.3 Hz, 1 H), 7.65 (d, J = 8.2 Hz, 1 H), 7.59 (dd, J = 8.3,
1.3 Hz, 1 H), 7.50 (d, J = 1.8 Hz, 1 H), 7.11 (dd, J = 8.3, 1.8 Hz, 1
H), 6.99 (dd, J = 2.0, 0.7 Hz, 1 H).
HRMS (EI): m/z calcd for C16H10ClNO: 267.0451; found:
267.0444.
Anal. Calcd for C16H10ClNO: C, 71.78; H, 3.77; N, 5.23; Cl, 13.24.
Found: C, 71.68; H, 3.65; N, 5.31; Cl, 13.28.
1H NMR (300 MHz, CDCl3): d = 8.76 (br s, 1 H), 8.44 (br s, 1 H),
8.20 (d, J = 8.8 Hz, 1 H), 7.65 (d, J = 1.9 Hz, 1 H), 7.59–7.51 (m, 2
H), 7.36 (d, J = 1.4 Hz, 1 H), 7.17 (dd, J = 8.8, 1.4 Hz, 1 H), 2.35 (s,
3 H).
4,6-Dichloro-3-[5-(trifluoromethyl)pyridin-2-yl]-1H-indole (3f)
Compound 3f (95% yield, foam) was prepared starting from 2b and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 9:1).
1H NMR (300 MHz, CDCl3): d = 8.85 (br s, 1 H), 8.72 (br s, 1 H),
8.01 (br d, J = 7.5 Hz, 1 H), 7.71 (d, J = 7.5 Hz, 1 H), 7.39 (br s, 1
H), 7.29 (d, J = 2.1 Hz, 1 H), 7.19 (br s, 1 H).
HRMS (EI): m/z calcd for C14H11ClN2: 242.0611; found: 242.0622.
Anal. Calcd for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54; Cl, 14.61.
Found: C, 69.33; H, 4.47; N, 11.61; Cl, 14.64.
6-(6-Chloro-1H-indol-3-yl)quinoline (3b)
HRMS (EI): m/z calcd for C14H7Cl2F3N2: 329.9938; found:
329.9951.
Compound 3b (69% yield, foam) was prepared starting from 2a and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 98:2).
1H NMR (400 MHz, DMSO-d6): d = 12.20 (s, 1 H), 8.89 (dd,
J = 5.2, 1.5 Hz, 1 H), 8.33 (dd, J = 7.8, 1.5 Hz, 1 H), 8.04 (br d,
J = 8.7 Hz, 1 H), 8.00 (br s, 1 H), 7.99 (dd, J = 8.7, 1.9 Hz, 1 H),
7.59 (d, J = 1.6 Hz, 1 H), 7.57 (dd, J = 7.8, 5.2 Hz, 1 H), 8.22 (d,
J = 7.5 Hz, 1 H), 7.19 (dd, J = 7.5, 1.4 Hz, 1 H), 7.39 (br s, 1 H).
Anal. Calcd for C14H7Cl2F3N2: C, 50.78; H, 2.13; N, 8.46; Cl, 21.41.
Found: C, 50.61; H, 2.15; N, 8.52; Cl, 21.49.
6-(4,6-Dichloro-1H-indol-3-yl)quinoline (3g)
Compound 3g (72% yield, foam) was prepared starting from 2b and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 98:2).
1H NMR (300 MHz, DMSO-d6): d = 11.87 (br s, 1 H), 8.90 (dd,
J = 4.1, 1.9 Hz, 1 H), 8.37 (dd, J = 8.2, 1.6 Hz, 1 H), 8.02 (d, J = 7.5
Hz, 1 H), 8.01 (s, 1 H), 7.89 (dd, J = 7.5, 1.9 Hz, 1 H), 7.67 (d,
J = 1.9 Hz, 1 H), 7.56 (d, J = 1.6 Hz, 1 H), 7.55 (dd, J = 8.2, 5.2 Hz,
1 H), 7.17 (d, J = 1.6 Hz, 1 H).
HRMS (EI): m/z calcd for C17H11ClN2: 278.0611; found: 278.0622.
Anal. Calcd for C17H11ClN2: C, 73.25; H, 3.98; N, 10.05; Cl, 12.72.
Found: C, 73.28; H, 3.88; N, 9.94; Cl, 12.69.
6-Chloro-3-[4-(furan-2-yl)phenyl]-1H-indole (3c)
Compound 3c (87% yield, foam) was prepared starting from 2a and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (cyclohexane).
HRMS (EI): m/z calcd for C17H10Cl2N2: 312.0221; found:
312.0226.
1H NMR (400 MHz, DMSO-d6): d = 11.6 (s, 1 H), 7.89 (d, J = 8.5
Hz, 1 H), 7.79 (d, J = 2.2 Hz, 1 H), 7.76–7.71 (m, 5 H), 7.53 (br d,
J = 1.3 Hz, 1 H), 7.12 (dd, J = 8.5, 1.3 Hz, 1 H), 6.91 (d, J = 3.5 Hz,
1 H), 6.61–6.59 (m, 1 H).
Anal. Calcd for C17H10Cl2N2: C, 65.20; H, 3.22; N, 8.94; Cl, 22.64.
Found: C, 65.28; H, 3.31; N, 8.83; Cl, 22.54.
3-(4,6-Dichloro-1H-indol-3-yl)quinoline (3h)
Compound 3h (96% yield, foam) was prepared starting from 2b and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 98:2).
1H NMR (300 MHz, DMSO-d6): d = 12.01 (br s, 1 H), 9.19 (d,
J = 1.6 Hz, 1 H), 8.40 (br s, 1 H), 8.09 (d, J = 8.1 Hz, 1 H), 8.03 (d,
HRMS (EI): m/z calcd for C18H12ClNO: 293.0607; found:
293.0616.
Anal. Calcd for C18H12ClNO: C, 73.60; H, 4.12; N, 4.77; Cl, 12.07.
Found: C, 73.67; H, 4.01; N, 4.67; Cl, 12.09.
Synthesis 2010, No. 23, 4075–4081 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Heteroaryloxindoles
4079
J = 8.1 Hz, 1 H), 7.80 (m, 2 H), 7.64 (t, J = 8.1 Hz, 1 H), 7.58 (d,
J = 1.4 Hz, 1 H), 7.25 (br s, 1 H).
Anal. Calcd for C14H10Cl2N2: C, 60.67; H, 3.64; N, 10.11; Cl, 25.58.
Found: C, 60.58; H, 3.54; N, 10.26; Cl, 25.52.
HRMS (EI): m/z calcd for C17H10Cl2N2: 312.0221; found:
312.0218.
3,6-Dichloro-3-(5-methylpyridin-2-yl)indolin-2-one (6a)
FC (hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 8.78 (br s, 1 H), 8.32 (d, J = 1.1
Hz, 1 H), 7.87 (d, J = 9.8 Hz, 1 H), 7.58 (dd, J = 9.8, 1.1 Hz, 1 H),
7.21 (d, J = 8.9 Hz, 1 H), 7.01 (dd, J = 8.9, 2.8 Hz, 1 H), 6.89 (d,
J = 2.8 Hz, 1 H), 2.33 (s, 3 H).
Anal. Calcd for C17H10Cl2N2: C, 65.20; H, 3.22; N, 8.94; Cl, 22.64.
Found: C, 65.18; H, 3.26; N, 8.88; Cl, 22.55.
6-(4,6-Dichloro-1H-indol-3-yl)quinoxaline (3i)
Compound 3i (50% yield, foam) was prepared starting from 2b and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 98:2).
HRMS (EI): m/z calcd for C14H10Cl2N2O: 292.0170; found:
292.0155.
1H NMR (300 MHz, DMSO-d6): d = 12.01 (s, 1 H), 9.00–8.94 (m,
2 H), 8.13 (d, J = 2.9 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1H), 8.02 (dd,
J = 8.0, 2.9 Hz, 1 H), 7.80 (s, 1 H), 7.58 (d, J = 1.8 Hz, 1 H), 7.24
(d, J = 1.8 Hz, 1 H).
Anal. Calcd for C14H10Cl2N2O: C, 57.36; H, 3.44; N, 9.56; Cl,
24.19. Found: C, 57.39; H, 3.34; N, 9.65; Cl, 24.16.
3,6-Dichloro-3-(quinolin-6-yl)indolin-2-one (6b)
FC (hexane–EtOAc, 8:2).
HRMS (EI): m/z calcd for C16H9Cl2N3: 313.0174; found: 313.0153.
1H NMR (300 MHz, DMSO-d6): d = 10.80 (s, 1 H), 8.90 (dd,
J = 4.0, 1.9 Hz, 1 H), 8.35 (d, J = 8.5 Hz, 1 H), 7.93 (d, J = 8.7 Hz,
1 H), 7.77 (d, J = 1.7 Hz, 1 H), 7.55 (dd, J = 8.5, 4.0 Hz, 1 H), 7.42
(dd, J = 8.7, 1.8 Hz, 1 H), 7.23 (d, J = 1.7 Hz, 1 H), 7.13–7.00 (m,
2 H).
Anal. Calcd for C16H9Cl2N3: C, 61.17; H, 2.89; N, 13.38; Cl, 22.57.
Found: C, 61.08; H, 2.95; N, 13.27; Cl, 22.50.
1-[5-(4,6-Dichloro-1H-indol-3-yl)benzofuran-2-yl]ethanone(3j)
Compound 3j (63% yield, foam) was prepared starting from 2b and
from the proper heteroaryl bromide, according to the procedure de-
scribed for 3a and purified by FC (n-hexane–EtOAc, 98:2).
HRMS (EI): m/z calcd for C17H10Cl2N2O: 328.0170; found:
328.0187.
1H NMR (400 MHz, DMSO-d6): d = 11.76 (s, 1 H), 7.91 (br s, 1 H),
7.85 (br d, J = 1.3 Hz, 1 H), 7.71 (br d, J = 8.5 Hz, 1 H), 7.61 (dd,
J = 8.5, 1.9 Hz, 1 H), 7.56 (s, 1 H), 7.53 (d, J = 1.9 Hz, 1 H), 7.14
(d, J = 1.9 Hz, 1 H), 2.59 (s, 3 H).
Anal. Calcd for C17H10Cl2N2O: C, 62.03; H, 3.06; N, 8.51; Cl,
21.54. Found: C, 62.23; H, 3.15; N, 8.47; Cl, 21.45.
3,6-Dichloro-3-[4-(furan-2-yl)phenyl]indolin-2-one (6c)
FC (hexane–EtOAc, 9:1).
HRMS (EI): m/z calcd for C18H11Cl2NO2: 343.0167; found:
343.0176.
1H NMR (400 MHz, DMSO-d6): d = 11.14 (br s, 1 H), 7.86 (d,
J = 2.0 Hz, 1 H), 7.72–7.70 (m, 2 H), 7.53–7.51 (m, 3 H), 7.44 (d,
J = 8.2 Hz, 1 H), 7.18 (dd, J = 8.2, 1.9 Hz, 1 H), 7.04 (d, J = 3.5 Hz,
1 H), 6.62–6.64 (m, 1 H).
Anal. Calcd for C18H11Cl2NO2: C, 62.81; H, 3.22; N, 4.07; Cl,
20.60. Found: C, 62.99; H, 3.31; N, 4.00; Cl, 20.55.
Preparation of t-BuOCl
HRMS (EI): m/z calcd for C18H11Cl2NO2: 343.0167; found:
343.0176.
In a flask containing commercial bleach (50 mL) cooled at 10 °C
were quickly added t-BuOH (74.1 g/mol, 3.7 mL, 39 mmol, 0.79 g/
mL, 1 equiv) and glacial AcOH (60.0 g/mol, 2.45 mL, 43 mmol,
1.05 g/mL, 1.1 equiv). This mixture was stirred for 5 min, then the
organic layer was separated and washed with 10% aq NaHCO3 (5
mL) and then with H2O (5 mL). The organic phase (yellow oil, t-
BuOCl, 3 g) was dried with CaCl2 and conserved in freezer. CAU-
TION: avoid exposure to light and contact with plastic material and
metallic needles.
Anal. Calcd for C18H11Cl2NO2: C, 62.81; H, 3.22; N, 4.07; Cl,
20.60. Found: C, 62.88; H, 3.26; N, 4.00; Cl, 20.62.
3,6-Dichloro-3-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)indo-
lin-2-one (6d)
FC (hexane–EtOAc, 95:5).
1H NMR (400 MHz, DMSO-d6): d = 10.50 (s, 1 H), 7.45 (d, J = 1.8
Hz, 1 H), 7.37 (d, J = 8.6 Hz, 1 H), 7.12–7.10 (m, 1 H), 7.05–6.99
(m, 2 H), 6.93 (d, J = 1.7 Hz, 1 H), 2.73–2.70 (m, 2 H), 2.57–2.54
(m, 2 H), 1.90–1.87 (m, 2 H), 1.81–1.78 (m, 2 H).
Oxidation of 3-Heteroarylindoles 3 with t-BuOCl;
General Procedure
To a solution of t-BuOCl (108.4 g/mol, 0.24 mL, 2.0 mmol, 2.0
equiv, 0.91 g/mL) in anhyd CH2Cl2 (3 mL) was added a solution of
indole 3 (1.0 mmol) in anhyd CH2Cl2 (3 mL) and the reaction mix-
ture was stirred at r.t. for 1 h. Then, the solvent was evaporated un-
der a N2 stream and the residue was treated with 3 N aq 1,4-
dioxane–H2SO4 (2:1, 3 mL) and stirred for 1 h. Sat. aq NaHCO3 (10
mL) was added and the mixture was extracted with CH2Cl2 (2 × 2
mL). The combined organic layers were dried (Na2SO4), filtered,
and evaporated to dryness. The residue was purified by FC on silica
gel (see below) to give the products as foams.
HRMS (EI): m/z calcd for C20H15Cl2NO2: 371.0480; found:
371.0489.
Anal. Calcd for C20H15Cl2NO2: C, 64.53; H, 4.06; N, 3.76; Cl,
19.05. Found: C, 64.64; H, 4.12; N, 3.66; Cl, 19.10.
3-(Benzofuran-5-yl)-3,6-dichloroindolin-2-one (6e)
FC (hexane–EtOAc, 97:3).
1H NMR (400 MHz, DMSO-d6): d = 10.50 (s, 1 H), 7.96 (d, J = 2.2
Hz, 1 H), 7.58 (d, J = 1.8 Hz, 1 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.23
(dd, J = 8.7, 1.9 Hz, 1 H), 7.14 (d, J = 8.1 Hz, 1 H), 7.04–7.02 (m,
1 H), 6.96–6.94 (m, 2 H).
2,6-Dichloro-3-(5-methylpyridin-2-yl)-1H-indole (4a)
FC (hexane–EtOAc, 1:1).
HRMS (EI): m/z calcd for C16H9Cl2NO2: 317.0010; found:
317.0019.
1H NMR (300 MHz, CDCl3): d = 8.81 (br s, 1 H), 8.56 (br s, 1 H),
8.02 (d, J = 8.9 Hz, 1 H), 7.66–7.63 (m, 1 H), 7.58–7.55 (m, 1 H),
7.19 (br s, 1 H), 7.11 (dd, J = 8.9, 2.3 Hz, 1 H), 2.32 (s, 3 H).
Anal. Calcd for C16H9Cl2NO2: C, 60.40; H, 2.85; N, 4.40; Cl, 22.29.
Found: C, 60.30; H, 2.79; N, 4.35; Cl, 22.22.
HRMS (EI): m/z calcd for C14H10Cl2N2: 276.0221; found:
276.0231.
Synthesis 2010, No. 23, 4075–4081 © Thieme Stuttgart · New York

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M. Baroni et al.
PAPER
2,4,6-Trichloro-3-[5-(trifluoromethyl)pyridin-2-yl]-1H-indole
(4f)
(d, J = 9.2 Hz, 1 H), 7.78 (t, J = 8.2 Hz, 1 H), 7.63 (t, J = 8.2 Hz, 1
H), 7.23 (br s, 1 H), 7.02 (br s, 1 H), 5.05 (s, 1 H).
FC (hexane–EtOAc, 9:1).
HRMS (EI): m/z calcd for C17H10Cl2N2O: 328.0170; found:
328.0179.
1H NMR (300 MHz, CDCl3): d = 9.09 (br s, 1 H), 8.82 (d, J = 1.4
Hz, 1 H), 7.97 (dd, J = 8.2, 1.4 Hz, 1 H), 7.77 (d, J = 8.2 Hz, 1 H),
7.32 (d, J = 2.8 Hz, 1 H), 7.17 (d, J = 2.8 Hz, 1 H).
Anal. Calcd for C17H10Cl2N2O: C, 62.03; H, 3.06; N, 8.51; Cl,
21.54. Found: C, 62.12; H, 3.17; N, 8.45; Cl, 21.50.
HRMS (EI): m/z calcd for C14H6Cl3F3N2: 363.9549; found:
363.9557.
3,4,6-Trichloro-3-(quinolin-3-yl)indolin-2-one (6h)
FC (hexane–EtOAc, 9:1).
Anal. Calcd for C14H6Cl3F3N2: C, 46.00; H, 1.65; N, 7.66; Cl, 29.09.
Found: C, 45.88; H, 1.54; N, 7.75; Cl, 29.01.
1H NMR (300 MHz, DMSO-d6): d = 11.58 (s, 1 H), 8.88 (d, J = 1.1
Hz, 1 H), 8.46 (d, J = 1.1 Hz, 1 H), 8.14 (d, J = 8.9 Hz, 1 H), 8.09
(d, J = 8.9 Hz, 1 H), 7.86 (t, J = 7.5 Hz, 1 H), 7.7 (t, J = 7.5 Hz, 1
H), 7.44 (s, 1 H), 7.15 (s, 1 H).
4,6-Dichloro-3-[5-(trifluoromethyl)pyridin-2-yl]indolin-2-one
(5f)
FC (hexane–EtOAc, 9:1).
HRMS (EI): m/z calcd for C17H9Cl3N2O: 361.9780; found:
361.9787.
1H NMR (300 MHz, CDCl3): d = 8.62 (s, 1 H), 8.48 (br s, 1 H), 7.64
(s, 2 H), 7.09 (d, J = 1.3 Hz, 1 H), 6.92 (d, J = 1.3 Hz, 1 H), 4.68 (s,
1 H).
Anal. Calcd for C17H9Cl3N2O: C, 56.15; H, 2.49; N, 7.70; Cl, 29.25.
Found: C, 56.23; H, 2.42; N, 7.60; Cl, 29.21.
HRMS (EI): m/z calcd for C14H7Cl2F3N2O: 345.9888; found:
345.9903.
4,6-Dichloro-3-(quinoxalin-6-yl)indolin-2-one (5i)
FC (hexane–EtOAc, 9:1).
Anal. Calcd for C14H7Cl2F3N2O: C, 48.44; H, 2.03; N, 8.07; Cl,
20.43. Found: C, 48.52; H, 2.11; N, 8.01; Cl, 20.39.
1H NMR (400 MHz, DMSO-d6): d = 11.08 (s, 1 H), 8.98 (br s, 2 H),
8.08 (d, J = 8.5 Hz, 1 H), 7.93 (d, J = 1.5 Hz, 1 H), 7.54 (dd, J = 8.6,
1.5 Hz, 1 H), 7.18 (d, J = 1.7 Hz, 1 H), 7.02 (d, J = 1.7 Hz, 1 H),
5.23 (s, 1 H).
3,4,6-Trichloro-3-[5-(trifluoromethyl)pyridin-2-yl]indolin-2-
one (6f)
FC (hexane–EtOAc, 9:1).
HRMS (EI): m/z calcd for C16H9Cl2N3O: 329.0123; found:
329.0115.
1H NMR (300 MHz, CDCl3): d = 8.66 (br s, 1 H), 8.33 (br s, 1 H),
8.13 (dd, J = 8.9, 1.3 Hz, 1 H), 7.75 (d, J = 8.9 Hz, 1 H), 7.17 (s, 1
H), 6.97 (br s, 1 H).
Anal. Calcd for C16H9Cl2N3O: C, 58.20; H, 2.75; N, 12.73; Cl,
21.48. Found: C, 58.25; H, 2.68; N, 12.69; Cl, 21.58.
HRMS (EI): m/z calcd for C14H6Cl3F3N2O: 379.9498; found:
379.9507.
3,4,6-Trichloro-3-(quinoxalin-6-yl)indolin-2-one (6i)
FC (hexane–EtOAc, 9:1).
Anal. Calcd for C14H6Cl3F3N2O: C, 44.07; H, 1.58; N, 7.34; Cl,
27.87. Found: C, 44.00; H, 1.71; N, 7.39; Cl, 27.81.
1H NMR (400 MHz, DMSO-d6): d = 10.97 (s, 1 H), 9.11 (br s, 2 H),
8,24 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 1.6 Hz, 1 H), 7.82 (dd, J = 8.5,
1.5 Hz, 1 H), 7.43 (d, J = 1.6 Hz, 1 H), 7.14 (d, J = 1.6 Hz, 1 H).
4,6-Dichloro-3-(quinolin-6-yl)indolin-2-one (5g)
FC (hexane–EtOAc, 8:2).
HRMS (EI): m/z calcd for C16H8Cl3N3O: 362.9733; found:
362.9726.
1H NMR (300 MHz, DMSO-d6): d = 10.90 (s, 1 H), 8.90 (dd,
J = 4.1, 1.9 Hz, 1 H), 8.37 (d, J = 8.5 Hz, 1 H), 7.98 (d, J = 8.8 Hz,
1 H), 7.78 (d, J = 1.8 Hz, 1 H), 7.55 (dd, J = 8.2, 4.0 Hz, 1 H), 7.46
(dd, J = 8.8, 1.8 Hz, 1 H), 7.16 (d, J = 1.7 Hz, 1 H), 6.98 (d, J = 1.7
Hz, 1 H), 5.08 (s, 1 H).
Anal. Calcd for C16H8Cl3N3O: C, 52.71; H, 2.21; N, 11.52; Cl,
29.17. Found: C, 52.80; H, 2.25; N, 11.48; Cl, 29.12.
3-(2-Acetylbenzofuran-5-yl)-4,6-dichloroindolin-2-one (5j)
HRMS (EI): m/z calcd for C17H10Cl2N2O: 328.0170; found:
FC (hexane–EtOAc, 8:2).
328.0175.
1H NMR (400 MHz, DMSO-d6): d = 10.85 (s, 1 H), 7.84 (s, 1 H),
7.67 (d, J = 8.8 Hz, 1 H), 7.59 (d, J = 1.3 Hz, 1 H), 7.26 (dd, J = 8.6,
1.7 Hz, 1 H), 7.15 (d, J = 1.5 Hz, 1 H), 6.97 (d, J = 1.5 Hz, 1 H), 5.0
(s, 1 H), 2.56 (s, 3 H).
Anal. Calcd for C17H10Cl2N2O: C, 62.03; H, 3.06; N, 8.51; Cl,
21.54. Found: C, 62.13; H, 3.09; N, 8.48; Cl, 21.50.
3,4,6-Trichloro-3-(quinolin-6-yl)indolin-2-one (6g)
FC (hexane–EtOAc, 8:2).
HRMS (EI): m/z calcd for C18H11Cl2NO3: 359.0116; found:
359.0131.
1H NMR (300 MHz, DMSO-d6): d = 10.87 (s, 1 H), 8.88 (dd,
J = 4.1, 1.8 Hz, 1 H), 8.35 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.8 Hz,
1 H), 7.76 (d, J = 1.8 Hz, 1 H), 7.52 (dd, J = 8.2, 4.0 Hz, 1 H), 7.44
(dd, J = 8.7, 1.8 Hz, 1 H), 7.23 (d, J = 1.7 Hz, 1 H), 7.03 (d, J = 1.7
Hz, 1 H).
Anal. Calcd for C18H11Cl2NO3: C, 60.02; H, 3.08; N, 3.89; Cl,
19.69. Found: C, 60.12; H, 3.15; N, 3.82; Cl, 19.63.
3-(2-Acetylbenzofuran-5-yl)-3,4,6-trichloroindolin-2-one (6j)
FC (hexane–EtOAc, 8:2).
HRMS (EI): m/z calcd for C17H9Cl3N2O: 361.9780; found:
361.9787.
1H NMR (400 MHz, DMSO-d6): d = 11.38 (s, 1 H), 7.90 (m, 2 H),
7.76 (d, J = 8.8 Hz, 1 H), 7.51 (dd, J = 8.8, 2.0 Hz, 1 H), 7.35 (d,
J = 1.5 Hz, 1 H), 7.08 (d, J = 1.5 Hz, 1 H), 2.57 (s, 3 H).
Anal. Calcd for C17H9Cl3N2O: C, 56.15; H, 2.49; N, 7.70; Cl, 29.25.
Found: C, 56.21; H, 2.57; N, 7.67; Cl, 29.23.
HRMS (EI): m/z calcd for C18H10Cl3NO3: 392.9726; found:
392.9732.
4,6-Dichloro-3-(quinolin-3-yl)indolin-2-one (5h)
Anal. Calcd for C18H10Cl3NO3: C, 54.78; H, 2.55; N, 3.55; Cl,
26.95. Found: C, 54.85; H, 2.60; N, 3.51; Cl, 26.94.
FC (hexane–EtOAc, 9:1).
1H NMR (300 MHz, DMSO-d6): d = 11.12 (s, 1 H), 8.78 (d, J = 2.1
Hz, 1 H), 8.10 (d, J = 1.4 Hz, 1 H), 8.05 (d, J = 9.2 Hz, 1 H), 8.01
Synthesis 2010, No. 23, 4075–4081 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Heteroaryloxindoles
4081
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