Synthesis of 4-functionalized-1H-indoles from 2,3-dihalophenols

Article abstract of DOI:10.1039/c004360e

A new synthesis of 4-halo-1H-indoles has been developed from easily available 2,3-dihalophenol derivatives. The key steps are Smiles rearrangement and a one-pot or stepwise Sonogashira coupling/NaOH-mediated cyclization. Subsequent functionalization allows access to a wide variety of 2,4- or 2,3,4-regioselectively functionalized indoles.

Full text of DOI:10.1039/c004360e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of 4-functionalized-1H-indoles from 2,3-dihalophenols†
Roberto Sanz,* Vero´nica Guilarte and Nuria Garc´ıa
Received 17th March 2010, Accepted 21st June 2010
First published as an Advance Article on the web 8th July 2010
DOI: 10.1039/c004360e
A new synthesis of 4-halo-1H-indoles has been developed
from easily available 2,3-dihalophenol derivatives. The key
steps are Smiles rearrangement and a one-pot or stepwise
Sonogashira coupling/NaOH-mediated cyclization. Subse-
quent functionalization allows access to a wide variety of 2,4-
or 2,3,4-regioselectively functionalized indoles.
dihaloanilines could be obtained from 2,3-dihalophenols through
the “Smiles rearrangement” methodology.14
To the best of our knowledge, the only reported example of the
o-lithiation of a 3-haloaniline derivative and subsequent trapping
of the organolithium intermediate with electrophiles was due to
Soll and co-workers.15 These authors described the o-lithiation
of N-trifluoroacetyl-3-fluoroaniline 1a with tBuLi/TMEDA fol-
lowed by its treatment with bromine or methyldisulfide. So first,
we tried to apply these reaction conditions to get 3-fluoro-2-
iodotrifluoroacetanilide 2a from 1a using iodine as electrophilic
reagent. Under these conditions we were able to isolate 2a
in 58% yield (Scheme 2). This compound serves as a useful
starting material for the efficient preparation of 4-fluoro-2-phenyl-
1H-indole 3a through a domino palladium/copper-catalyzed
coupling-cyclization process (Scheme 2).16
The indole scaffold is a prominent structural motif found in
numerous natural products and biologically active compounds.1
The combination of classical and modern methods, mainly
transition-metal-based reactions, has provided access to a wide
variety of polysubstituted indoles.2 Despite the fact that many
methodologies are continuously being developed, the regioselec-
tive formation of 4-functionalized indoles is especially challeng-
ing. Some reported approaches to prepare 4-substituted indoles
involve thallation,3 mercuriation,4 or lithiation5 of adequately
3-functionalized indoles, as well as the palladium-catalyzed re-
gioselective reduction of 4,6-dibromoindoles,6 and the selective
7-lithiation of 4,7-dibromoindoles.7 In recent years, a few concrete
examples of 4-haloindoles have also been prepared by thermolytic
rearrangement of a-aryl azirines,8 Mo-catalyzed reductive cy-
clization of nitroaromatics,9 and Pd-catalyzed coupling of 1,3-
dichloro-2-iodobenzene with imines.10 Nevertheless, the most used
strategy to access to this type of indole derivatives involves the
heterocyclic construction by ring-closure methodologies starting
from properly substituted aromatic precursors.11 We envisagedthat
another entry to this interesting class of heterocycles could involve
the functionalization of 4-halo-1H-indoles, which could be easily
accessible from 3-halo-2-iodoaniline derivatives through tandem
Sonogashira coupling/heteroannulation reactions (Scheme 1).
Although no direct routes are known for these 2,3-dihaloanilines,12
we reasoned that they could be efficiently prepared from 3-
haloaniline derivatives through o-metallation reactions, in an
analogous way as our reported procedure for the synthesis of 2,3-
dihalophenols from 3-halophenol derivatives.13 Alternatively, 2,3-
Scheme 2 ortho-Lithiation of 3-haloaniline derivatives 1. Synthesis of
4-fluoroindole 3a. Reagents and conditions: (a) tBuLi/TMEDA (2.2 equiv),
THF, -78 ◦C, 40 min; (b) I2, -78 ◦C to rt; (c) PdCl2(PPh3)2 (3 mol%), CuI
(5 mol%), Et2NH (1.5 equiv), DMA, 80 ◦C.
However, when we tried to apply the o-lithiation strategy to
3-chlorotrifluoroacetanilide 1b we did not observe any lithiation
reaction. At low temperature (-78 ◦C) the starting material is
recovered and if the reaction mixture is allowed to reach room
temperature the addition of tBuLi to the trifluoroacetamide
moiety is observed.17 Moreover, it is known that although tBuLi is
able to metallate the meta isomers of N-(Boc)fluoro- and chloro-
anilines at low temperatures, it has been also shown that it was not
possible to prevent the subsequent elimination of lithium halide
and the generation of benzyne intermediates.18
Having seen that the o-lithiation methodology is not useful for
accessing 2,3-dihaloaniline derivatives other than those bearing a
fluorine atom at the meta position, we then turned our attention to
the use of 2,3-dihalophenol derivatives as starting materials. Sev-
eral methods have been developed for the conversion of phenols to
anilines such as the Bucherer reaction,19 the activation of phenols
with (EtO)2POCl,20 or 4-chloro-2-phenylquinazoline.21 Although
the Pd-catalyzed coupling of amines with aryl triflates or tosylates
Scheme
1
Retrosynthetic analysis for the synthesis of 4-halo-2-
substituted-1H-indoles.
´
Departamento de Qu´ımica, Area de Qu´ımica Orga´nica, Facultad de Ciencias,
Universidad de Burgos, Pza. Misael Ban˜uelos s/n, 09001, Burgos, Spain.
E-mail: rsd@ubu.es; Fax: (+34) 947258831; Tel: (+34) 947258036
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and copies of 1H and 13C NMR spectra
of new compounds. See DOI: 10.1039/c004360e
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has been recently developed,22 the presence of an iodine atom on
our substrate precludes the use of this strategy. Besides the Pd- and
Cu-catalyzed processes, Smiles rearrangement could be considered
the most suitable procedure for preparing N-arylamines from
phenols.23 This methodology requires the initial conversion of the
corresponding phenol into a 2-aryloxy-2-methylpropanamide.24
Under basic conditions, this intermediate undergoes rearrange-
ment to give a N-aryl-2-hydroxypropionamide, whose formation
must involve nucleophilic attack of the amide anion to give a
spiro intermediate followed by its breakdown and protonation
(Scheme 3). In addition, upon hydrolysis the generated anilide
could afford the corresponding aniline.
Table 1 Preparation of dihaloanilides 8 from O-2,3-dihalophenyl carba-
mates 4 or 2,3-dihaloanisoles 5
Entry
Starting material
X
Product
Yield (%)a
1
2
3
4
5
6
4a
4b
4c
4d
5a
5b
F
8a
8b
8c
8d
8b
8c
83
82
81
79
86
85
Cl
Br
I
Cl
Br
a Isolated yield with reference to starting material 4 or 5.
Table 2 Synthesis of 2-alkynyl-3-haloanilides 9 and 10
Scheme 3 Alkylation-Smiles rearrangement sequence.
Interestingly, some one-pot procedures have been described
in the literature for this two-steps sequence.25 The Smiles pro-
tocol proved suitable for our purpose and so the required 3-
halo-2-iodophenols 6 were generated by basic hydrolysis of the
corresponding O-2,3-dihalophenylcarbamates 4,13a or by BBr3-
mediated deprotection of 2,3-dihaloanisoles 513b,26 (Scheme 4).
The crude phenols 6 were treated with an excess of 2-bromo-
2-methylpropionamide27 and NaOH in DMF at room temper-
ature providing 2-aryloxy-2-methylpropionamides 7 (Scheme 4).
Although these intermediates 7 could be easily isolated, it is not
necessary to do it and so, the addition of an excess of NaOH
to the DMF solution of 7 and subsequent warming to 60 ◦C
Entry
Starting material
X
Alkyne (R)
Product Yield (%)a
1
2
3
8b
8b
8b
8b
8b
8c
8c
8c
8c
8c
8c
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Ph
nBu
9a
86
90
81
80
81
80
85
79
86
71
74
9b
nC5H11
9c
b
4
cC6H9
9d
5c
6
SiMe3
Ph
9e
10a
10b
10c
10d
10e
10f
7
8
nBu
nC5H11
b
9
cC6H9
10c
11
SiMe3
3-Thd
a Isolated yield after column chromatography with reference to starting
material 8. b 1-Cyclohexenyl. c Carried out at 40 ◦C for 6 h. d 3-Thienyl.
afforded N-aryl-2-hydroxypropionamides 8 in high overall yields
from the starting 3-halo-2-iodophenol derivatives 4 or 5 (Scheme 4
and Table 1). It is remarkable that 3-halo-2-iodoanilides 8 could
be efficiently prepared from the corresponding phenol derivatives
4 or 5 in a three-step, two-pot process (phenol deprotection–
alkylation–rearrangement). Moreover, compounds 8 are easily
isolated at the end of the reaction by simple addition of water to
precipitate them. The filtered products proved to be pure enough
for the next step without further chromatographic purification.
With a reliable procedure for the preparation of 3-halo-2-
iodoanilides 8 and with the synthesis of 4-haloindoles in mind,
then we checked the suitability of these dihaloderivatives for a
selective Sonogashira coupling with terminal alkynes. By careful
control of the reaction temperature in order to avoid dialkynyla-
tion processes, 2-alkynyl-3-haloanilides 9 and 10 could be obtained
in good yields by Pd–Cu catalysis. Aryl-, alkyl-, heteroaryl-,
alkenyl-, and trialkylsilyl-substituted alkynes proved to be useful
partners for this coupling reaction that takes place in usually high
yields (Table 2).
Scheme 4 Synthesis of N-(3-halo-2-iodophenyl)-2-hydroxy-2-methylprop-
anamides 8 from 2,3-dihalophenol derivatives 4 and 5. Reagents and
conditions: (a) i) LDA, THF, -78 ◦C; ii) I2 (see ref. 13a and ESI); (b) i)
tBu2Zn(TMP)Li, THF; ii) I2 (see ref. 13b, 26 and ESI); (c) NaOH (10
equiv), EtOH; (d) i) BBr3, CH2Cl2; ii) NaHCO3, MeOH; (e) i) NaOH (3
equiv), DMF, rt; ii) BrC(Me)2CONH2 (3 equiv), rt; (f) NaOH (9 equiv),
60 ◦C.
By taking advantage of our reported procedure for the synthesis
of 2-substituted indoles by NaOH-mediated cyclization of 2-
alkynylaniline derivatives,28 4-halo-1H-indoles 11 and 12 were
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Table 3 Synthesis of 4-halo-1H-indoles 11 and 12 from 2-alkynyl-3-haloanilides 9 and 10
Entry
Starting material
X
R
Time/h
Product
Yield (%)a
1
2
3
4
5
6
7
8
9a
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Ph
nBu
nC5H11
cC6H9
SiMe3
Ph
4
11a
11b
11c
11d
11ec
12a
12b
12c
12d
12ed
12f
79
86
84
81
73
83
80
82
76
75
71
9b
2.5
2.5
2.5
4
5
3
2.5
4
5
9c
b
9d
9e
10a
10b
10c
10d
10e
10f
nBu
nC5H11
b
9
10
11
cC6H9
SiMe3
3-The
3
a Isolated yield after column chromatography referred to starting material 9 or 10. b 1-Cyclohexenyl. c 4-Chloro-1H-indole (R = H). d 4-Bromo-1H-indole
(R = H). e 3-Thienyl.
Table 4 One-pot synthesis of 4-halo-1H-indoles 3, 11 and 12 from 2,3-dihaloanilides 8
Entry
Starting material
X
R
Time/h
Product
Yield (%)a
1
2
3
4
8a
8a
8b
8b
8b
8b
8b
8b
8c
8c
8c
F
F
Ph
nBu
Ph
nBu
cC6H9
SiMe3
3-ClC6H4
4-F-3-MeC6H3
Ph
4
3
4
3
3
3
3
4
4
3
4
3a
85
77
81
71
82
61
75
72
49
55
48
3b
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
11a
11b
11d
11ed
11f
11g
12a
12b
12g
b
5
6c
7
8
9
10
11
nBu
3-ClC6H4
a Isolated yield after column chromatography with reference to starting material 8. b 1-Cyclohexenyl. c Sonogashira coupling was carried out at 40 ◦C for
6 h. d 4-Chloro-1H-indole (R = H).
obtained in high yields by treatment of o-alkynylanilides 9 and 10
with excess of NaOH at high temperature (Table 3). Interestingly,
in the case of starting from 3-halo-2-(trialkylsilylethynyl) anilides
9e or 10e, 4-chloro-1H-indole 11e or 4-bromo-1H-indole 12e were
respectively obtained by further cleavage of the silyl group under
the reaction conditions (Table 3, entries 5 and 10).
4-chloroindoles 11 (Table 4, entries 1–8), 3-bromo-2-iodoanilide
8c leads to lower yields of 4-bromoindoles 12 (Table 4, entries
9–11). The formation of several side-products from 8c is probably
be due to competitive Pd-catalyzed reactions involving the C–Br
bond. For the synthesis of these indole derivatives 12 the two-step
sequence was found more appropriate.
Moreover, 4-haloindoles 3, 11 or 12 could also be prepared by
a one-pot procedure starting from 2,3-dihaloanilides 8 without
isolation of any intermediate (Table 4). Whereas this one-pot
protocol nicely works for the synthesis of 4-fluoroindoles 3 and
Finally, we decided to check the usefulness of these 4-
haloindoles 11 and 12 as precursors of 4-functionalized-
1H-indoles (Scheme 5). For instance, chloro derivative
11b was subjected to Pd-catalyzed Stille coupling with
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a variety of substituents at C-2. In addition, the usefulness of
these 4-haloindoles produced by this chemistry as intermediates
for further transformations has been briefly outlined, including
reactions that afford 2,4- and 2,3,4-functionalized indoles.
Acknowledgements
We gratefully thank Junta de Castilla y Leo´n (BU021A09 and GR-
172) and Ministerio de Educacio´n y Ciencia (MEC) and FEDER
(CTQ2007-61436/BQU) for financial support. V. G. thanks MEC
for a predoctoral FPU fellowship.
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Scheme 5 Synthetic applications of 4-haloindoles.
2-(tributylstannyl)furan,29 affording 4-(2-furanyl)indole 13 in high
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1H-indole 12a by Suzuki and Sonogashira cross-coupling re-
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1H-indole like 17 by introduction of the arylthio group at C-3
under the basic conditions required for the cyclization step (eqn
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In summary, we have developed an efficient route to 4-halo-
1H-indoles from 3-halo-2-iodophenol derivatives using the Smiles
rearrangement and a NaOH-mediated cyclization as the key steps.
3-Halo-2-iodoanilides were obtained in high yields from O-3-halo-
2-iodophenyl N,N-diethylcarbamates or 3-halo-2-iodoanisoles
without any chromatographic purification. Their subsequent
coupling with terminal alkynes and cyclization under treatment
with NaOH allow the access to challenging 4-haloindoles with
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27 Easily prepared by reaction of commercially available 2-bromo-2-
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3864 | Org. Biomol. Chem., 2010, 8, 3860–3864
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