Reaction of o-iodoaniline with aromatic ketones in DMSO: Synthesis of 2- aryl or 2-hetarylindoles

Article abstract of DOI:10.1055/s-1999-3636

The reactions of o-iodoaniline (1) with the enolate anions from acetone (2), acetophenone (4), 2-acetylnaphthalene (6), 2-acetyl-1-methylpyrrole (8a) and 2-acetylthiophene (8b) in DMSO give respectively the corresponding 2- substituted indoles in 63, 88, 73, 93 and 82% yields. These reactions are proposed to take place by an S(RN)1 mechanism. Depending on the ketone enolate ion involved, the reactions can occur under light or Fe(II) salts initiation.

Full text of DOI:10.1055/s-1999-3636

PAPER
2053
Reaction of o-Iodoaniline with Aromatic Ketones in DMSO:
Synthesis of 2-Aryl or 2-Hetarylindoles
María T. Baumgartner, Mónica A. Nazareno, Marcelo C. Murguía, Adriana B. Pierini,* Roberto A. Rossi*
INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba-Ciudad Universitaria,
000 Córdoba, Argentina
5
Fax +54(351)4333030; E-mail: rossi@dqo.fcq.unc.edu.ar
Received 5 April 1999; revised 4 June 1999
13
phene. The latter carbanion has been reported to afford
the substitution product by reaction with phenyl azosul-
fides, which are very good electron acceptors that react
spontaneously or under laboratory light with different nu-
Abstract: The reactions of o-iodoaniline (1) with the enolate anions
from acetone (2), acetophenone (4), 2-acetylnaphthalene (6), 2-
acetyl-1-methylpyrrole (8a) and 2-acetylthiophene (8b) in DMSO
give respectively the corresponding 2-substituted indoles in 63, 88,
1
3
7
3, 93 and 82% yields. These reactions are proposed to take place cleophiles.
by an SRN1 mechanism. Depending on the ketone enolate ion in-
volved, the reactions can occur under light or Fe(II) salts initiation.
The difference in reactivity between enolate anions of ar-
omatic and aliphatic ketones toward phenyl halides in liq-
uid ammonia has been attributed to the lower efficiency of
the former in the photoinitiation step of the proposed
Key words: SRN1 reactions, 2-arylindoles, 2-hetarylindoles, photo-
stimulation, FeBr induced reaction, heterocycles, enols, carbanions
2
7
mechanism (Scheme 1). This situation can be overcome
by employing other methods of initiation like solvated
electrons from alkali metals; electrochemically; favoring
the initial ET at higher temperatures (DMSO, r.t.) or per-
forming the reaction in the presence of added nucleophiles
that are less reactive than the enolate anion of the aromatic
ketone toward phenyl radicals (Scheme 1, eq. 3), but are
The indole ring belongs to an important class of com-
pounds due to their pharmacological activity. The dis-
1
covery of many new structures from natural products,
including marine natural products, has increased the range
2
of the family of indole alkaloids.
Of the many procedures developed for indoles synthesis, better electron donors to initiate the chain (Scheme 1, eq.
the oldest and most widely used one is the Fisher method.3 1) (entrainment reaction).
This procedure has recently been improved by the palladi-
4
um-catalyzed synthesis of N-aryl hydrazones. Another
hν
route, the Bischler method, has been recently modified by
ArX + Nu-
(ArX)-
.
Initiation
(1)
(2)
the NH insertion of anilines with rhodium carbenoids.5
(ArX)-.
Ar + X-
.
Propagation
The development of synthetic methods for the construc-
tion of the indole nucleus, particularly under non-acidic
conditions is an area of current interest. Recently, the
preparation of indoles from o-haloanilines by the palladi-
um cross-coupling reaction followed by Rh-catalyzed hy-
droformylation of Heck adducts has been reported.6
.
(ArNu)-
.
Ar + Nu-
(3)
(ArNu)-.+ ArX
-
.
ArNu + (ArX)
(4)
ArX + Nu-
ArNu + X-
(2,4)
The S 1 mechanism is an important route to achieve the
RN
Scheme 1
formation of a new C–C bond by the reaction of aromatic
7
substrates with carbanions. Good percentages of substi-
tution are usually obtained in these reactions with the eno-
late ions of aliphatic ketones. These anions react with
aromatic substrates under photostimulation in liquid am-
monia or in DMSO at room temperature.
The S 1 mechanism has been shown to be a valuable re-
RN
action to the synthesis of heterocycles, 2-alkyl substituted
indoles being one of them. The discovery that the photo-
stimulated reactions of o-bromo- and o- iodoanilines with
aliphatic ketone enolate ions in liquid ammonia afford 2-
alkylindoles from spontaneous ring closure of the substi-
tution product in very good yields, has opened an impor-
tant synthetic route to substituted indoles in non-acidic
conditions (Scheme 2).1
Aromatic ketones behave somewhat differently. For ex-
ample, the enolate ion of acetophenone reacts sluggishly
with halobenzenes or halonaphthalenes in liquid ammo-
nia, under photostimulation. Heteroarylation of the anion
can be achieved in this solvent either under irradiation or
4,15
8
,9
even in the dark with highly electrophilic substrates. On
the other hand, phenylation as well as heteroarylation of
the anion is possible in DMSO under photostimula-
With the enolate ion of aldehydes, unsubstituted or 3-sub-
16
stituted indoles are obtained. Good yields of 2-alkylin-
doles are also obtained in the photostimulated reaction of
enolate ions of ketones with methyl substituted o-bromo-
anilines and with o-chloroanilines substituted at position
1
0,11
tion.
A similar behavior has been observed with the
1
2
enolate ions of 2-acetylnaphthalene and other aromatic
ketones such as 2-acetylfuran,
1
1,8b
and 2-acetylthio-
Synthesis 1999, No. 12, 2053–2056 ISSN 0039-7881 © Thieme Stuttgart · New York

2
054
M. T. Baumgartner et al.
PAPER
DMSO under the same experimental conditions gives the
CH COR
10, 23, 24
X
2
hν
substitution product in ca. 90% yields.
We per-
+ -
CH COR
2
formed the reactions with an excess of t-BuOK to avoid
NH3
NH2
NH2
condensation products of the ketones. The pKa of ace-
7
tone and t-BuOH in DMSO are 26.5 and 32.2 respective-
2
5
ly. If the pKa of 1 (at NH) is similar to that of t-BuOH,
the substrate could be ionized in the reaction media, con-
ditions under which it could be inhibited to react by the
R
N
H
2
6
S 1 mechanism. When we performed the photostimu-
RN
Scheme 2
lated reaction (1.5 h) without excess t-BuOK, 3 was ob-
tained in 63% yield (isolated product). This reaction is
inhibited by p-DNB, a good radical anion scavenger (Ta-
Even o-chloroaniline reacts ble, Entries 3, 4). Also good yield of 3 is obtained when
-
14,17
7
5
with Ph, MeO, or CO .
2
+
2
with acetone enolate ion in the presence of Fe in liquid the reaction is induced by FeBr (Table, Entry 6). Sub-
2
1
8
ammonia to afford 2-methylindole (51%). The reaction strate 1 does not react with the enolate anion of acetophe-
of o-iodoaniline with ketone or acetaldehyde enolate ions none 4 in the dark, but it reacts under irradiation to afford
27
induced by electrodes also affords very good yields of in- 88% yield of indole 5 (Scheme 5). When the reaction is
1
9
doles. Benzoindoles can be obtained in the photostimu- induced by FeBr , 5 is formed in 83% yield (Table, En-
2
lated reaction of 1-bromo-2-amino- or 1-amino-2- tries 7–9).
bromonaphthalenes with aliphatic ketone enolate ions.20
2
-Substituted azaindoles are obtained under irradiation in
COCH2-
2
1
the reaction of different o-iodoaminopyridines. 3-Ami-
no-2-chloropyridine also affords the azaindole in good
yields (Scheme 3).
hν (or FeBr2)
DMSO
1
4,19,22
1 +
N
H
5
4
N
N
Cl
hν
+ -
CH COR
R
2
Scheme 5
NH3
N
H
NH2
The photostimulated reaction of 1 with the enolate ions of
-acetylnaphthalene 6 affords 73% yield of indole 728
Scheme 6). Lower yields of indole 7 (43%) were ob-
Scheme 3
2
(
All these syntheses were carried out in liquid ammonia. tained in the presence of excess t-BuOK. The reaction in-
The reactions afforded poor results with aromatic ketones duced by FeBr gave 66% yields of 7 (Table, Entries 10–
2
in this solvent. Thus the photostimulated reaction of 3- 13).
amino-2-chloropyridine with the enolate ions of pro-
piophenone and 2-acetylpyridine gave respectively only
1
9
3
0 and 21% yields of the azaindoles. As we found that
COCH2-
hν (or FeBr2)
DMSO
the enolate ions of aromatic ketones react readily with io-
doarenes to give good yields of substitution products in
DMSO, we decided to study the synthesis of 2-aryl or 2-
1 +
N
1
0
H
6
7
hetarylindoles through the S 1 mechanism in this solvent
RN
in order to increase its synthetic scope.
Scheme 6
o-Iodoaniline (1) does not react with acetone enolate ion
(
2) in DMSO (1.5 h). Under irradiation (1.5 h) 2-meth-
1
4
ylindole (3) was obtained in 10% yield (Scheme 4). Also Recently we have found that 2-acetyl-1-methylpyrrole
low yield of 3 is obtained (17%) in the reaction induced enolate ion 8a gives good yields of substitution products
by FeBr (Table, Entries 1, 2, 5).
in its photostimulated reaction with iodoarenes and neo-
2
29
pentyl iodide in DMSO. 2-Acetylthiophene enolate ion
b did not react under irradiation with iodobenzene, how-
8
I
hν (or FeBr2)
ever, it affords good yields of substitution by FeBr in-
+ -
2
CH COCH
CH3
2
3
ducement or when the photostimulated reaction is
performed in the presence of the enolate ion of acetone
DMSO
N
NH2
H
3
0
1
2
3
(entrainment reagent). The photostimulated reaction (2
3
1
h) of 8a with 1 gives the indole 9a in 63% yield, which
Scheme 4
increases up to 93% in the reaction induced by FeBr2
This is an unexpected result because it is well known that
the photostimulated reaction of iodobenzene with 2 in
(
Scheme 7, Table, Entries 14–15). Carbanion 8b does not
react with 1 under irradiation, or in the presence of ace-
Synthesis 1999, No. 12, 2053–2056 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Reaction of o-Iodoaniline with Aromatic Ketones in DMSO
2055
Table Reactions of o-Iodoanilines with Carbanions in DMSOa
Entry
1
Carbanion
(mmol)
Conditions
I– (%)b
Indol
Yieldc
(%)
(
mmol)
1d
0.88
1.14
0.51
0.48
0.52
0.48
0.54
0.50
0.52
0.48
0.51
0.56
0.51
0.49
0.48
0.48
0.46
0.51
4.44
2 (4.00)
2 (5.00)
2 (5.45)
2 (5.11)
2 (4.00)
2 (5.18)
4 (5.02)
4 (5.14)
4 (3.00)
6 (5.00)
6 (5.00)
6 (4.00)
6 (5.00)
8a (2.42)
8a (2.20)
8b ( 4.90)
8b (5.02)
8b (5.00)
8b (44.5)
dark, 1.5 h
hn, 1 h
<3
38
92
19
3
3
3
3
3
3
5
5
5
7
7
7
–
10
63
11
17
57
–
88
e,f
2
3
4
5
6
7
g
h
hn, 1.5 h
hn, 1.5 h
i,d
e
j
h
FeBr , 1 h
–
2
k
FeBr , 1.5 h
72
<3
90
2
d
dark, 1.5 h
8
9
hn, 3 h
j
h
FeBr , 1 h
–
83, 67
43
73
2
1
1
1
1
1
1
1
1
1
1
0e,f
1
hn, 3 h
hn, 2 h
hn, 2 h
64
87
88
h
2
53
j
3
FeBr , 1 h
–
7
66
63
93
–
3
82
2
l
4
5
6
7
hn, 2 h
84
100
<3
9a
9a
9b
9b
9b
9b
m
FeBr , 1 h
2
d
hn, 1.5 h
hn, 1.5 h
n,d
<12
93
o
8
FeBr , 1 h
2
j
h
9
FeBr , 1h
–
79
2
a
Reactions carried out under N at 40°C in DMSO (20 mL); t-BuOK used in 1–2% excess with respect to the ketone unless otherwise indicated.
2
In the reactions induced by FeBr , an equimolar amount of the inorganic salt and the substrate were used.
2
b
Determined potentiometrically.
Quantified by GC and the internal standard method (unless otherwise stated).
o-Iodoaniline recovered unchanged.
Reaction performed in the presence of excess t-BuOK (1.5 mmol).
Aniline and o-iodoaniline detected, but not quantified.
o-Iodoaniline (3%); aniline (13%).
c
d
e
f
g
h
Isolated product.
p-DNB (20 mol %) was added.
Not quantified.
o-Iodoaniline (16%).
Aniline (20%).
Aniline (4%).
i
j
k
l
m
n
In the presence of 2.28 mmol of 2.
o
Aniline (10%).
1H NMR and 13C NMR spectra were recorded on a Bruker 200 nu-
tone enolate ion as entrainment reagent, but in the pres-
clear magnetic resonance spectrometer with CDCl as solvent. Mass
3
2
3
ence of FeBr it gives 82% of indole 9b (Scheme 7,
2
spectra were obtained with a GC/MS Perkin Elmer Q-mass 910. GC
analyses were performed with a Hewlett Packard 5890 series II,
with a flame ionization detector and HP data system, 0.53 mm × 5m
column packed with HP1 or 0.53 mm × 10 m column packed with
HP50+. Column chromatography was performed on silica gel (70–
270 mesh ASTM). Radial TLC was done using silica gel 60 PF-254
with calcium sulfate (E. Merck). The distillation at reduced pressure
was performed in a Kugelrohr distillation apparatus. Irradiation was
conducted in a reactor equipped with two 400-W lamps emitting
maximally at 350 nm (Philips Model HPT, air and water refrigerat-
ed). Potentiometric titration of halide ions was performed in a pH-
Table, Entries 16–19).
hν (or FeBr2)
1
+
COCH -
2
Z
DMSO
N
Z
H
8
8
a: Z = NCH3
b: Z = S
9a: Z = NCH3
9b: Z = S
+
meter using a Ag/Ag electrode.
Scheme 7
t-BuOK was commercially available and used as received. DMSO
was distilled under vacuum and stored over molecular sieves (4Å).
In conclusion, all these results indicate that the reaction of Acetone and acetophenone were distilled and stored over molecular
1
(under irradiation or in the presence of FeBr ) with aro- sieve (4Å). 2-Acetylnaphthalene was recrystallized from petroleum
2
33
ether (bp 60–80°C). o-Iodoaniline, 2-acetyl-1-methylpyrrole and
-acetylthiophene were commercially available and distilled under
reduced pressure in a Kugelrohr distillation apparatus.
matic and heteroaromatic ketones is a very promising
route to the synthesis of 2-aryl or 2-hetarylindoles in DM-
SO. The good yields obtained in the presence of FeBr2
avoids the need of a special photochemical device to
achieve the synthesis here reported.
2
Synthesis 1999, No. 12, 2053–2056 ISSN 0039-7881 © Thieme Stuttgart · New York

2
056
M. T. Baumgartner et al.
PAPER
Photostimulated Reaction of Acetone Enolate Ions with o-Io-
doaniline; General Procedure
(b) Nair, V.; Chamberlain, S. D. J. Am. Chem. Soc. 1985, 107,
2183.
The reactions were carried out in a 50 mL three-neck round-bot-
(9) (a) Hay, J. V.; Wolfe, J. F. J. Am. Chem. Soc. 1975, 97, 3702.
Hay, V. J.; Hudlicky, T.; Wolfe, J. F. J. Am. Chem. Soc. 1975,
97, 374.
tomed flask equipped with a N inlet and a magnetic stirrer. To an-
2
hyd and degassed DMSO (20 mL) under N was added t-BuOK (5.5
2
mmol, 0.616 g) and acetone (0.316 g, 5.45 mmol). After 15 min, o-
(b) Carver, D. R.; Komin, A. P.; Hubbard, J. S.; Wolfe, J. F. J.
Org. Chem. 1981, 46, 294.
(10) Borosky, G. L.; Pierini, A. B.; Rossi, R. A. J. Org. Chem.
1992, 57, 247
3
4
iodoaniline (0.45 mmol, 0.099 g) was added and the mixture was
irradiated for 90 min. The reaction was quenched with an excess of
NH NO and H O (60 mL). The mixture was extracted twice with
4
3
2
CH Cl (20 mL), the organic extract was washed with water (2 × 20
(11) Beugelmans, R.; Bois-Choussy, M. Heterocycles 1987, 26,
1863.
(12) Beugelmans, R.; Bois-Choussy, M.; Tang, Q. J. Org. Chem.
1987, 52, 3880.
(13) (a) Dell'Erba, C.; Novi, M.; Petrillo, G.; Tavani, C.
Tetrahedron 1993, 49, 235.
2
2
mL), dried, and quantified by GC. The iodide ions in the aqueous
solution were determined potentiometrically. The solvent was re-
moved under reduced pressure. The residue, after column chroma-
tography on silicagel or radial TLC (eluted with petroleum ether (bp
6
0–80°C)/ acetone, 90:10) gave the products. The spectroscopic
data and melting point of products are in agreement with that re-
(b) Dell'Erba, C.; Novi, M.; Petrillo, G.; Tavani, C.
Phosphorus, Sulfur and Silicon 1993, 74, 409.
(14) Bard, R. R.; Bunnett, J. F. J. Org. Chem. 1980, 45, 1546.
(15) Beugelmans, R.; Roussi, G. J. Chem. Soc., Chem. Commun.
1979, 950.
1
4
ported in the literature; 3: mp 57–60 °C (Lit. mp 58–60°C); 5: mp
7
27b,28
1
2
1
88–190 °C (Lit.2 mp 187°C); 7: mp 199–201 °C (Lit.
mp
3
1
03–204 °C); 9a: mp 89–91 °C (Lit. mp 91–92°C); and 9b: mp
63–165 °C Lit.32 mp 167–168°C).
(
(
16) Beugelmans, R.; Roussi, G. Tetrahedron 1981, 37, 393.
17) Beugelmans, R.; Chbani, M. Bull. Soc. Chim. Fr. 1995, 132,
306.
Fe(II) Induced Reaction of Acetone Enolate Ion with o-Iodoa-
niline
The reactions were carried out in a 50 mL three-neck round-bot-
(
18) Galli, C.; Bunnett, J. F. J. Org. Chem. 1984, 49, 3041.
tomed flask equipped with a N inlet and a magnetic stirrer. To an-
(19) Fontan, R.; Galvez, C.; Viladoms, P. Heterocycles 1981, 16,
473.
2
1
hyd and degassed DMSO (20 mL) under N was added t-BuOK (5.3
2
(
(
(
20) Beugelmans, R.; Chbani, M. Bull. Soc. Chim. Fr. 1995, 132,
mmol, 0.594 g), acetone (0.302 g, 5.2 mmol) and FeBr2 (0.114 g,
0
.53 mmol). After a few minutes o-iodoaniline (0.48 mmol, 0.105
729.
21) Estel, L.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988, 53,
2740.
22) Beugelmans, R.; Boudet, B.; Quintero, L. Tetrahedron Lett.
g) was added. The reaction was quenched after 90 min and worked
up as given above.
1
980, 21, 1943.
(23) Scamehorn, R. G.; Bunnett, J. F. J. Org. Chem. 1977, 42,
457.
24) Bunnett, J. F.; Scamehorn, R. G.; Traber, R. P. J. Org. Chem.
976, 41, 3677.
Acknowledgement
1
This work was supported in part by the Consejo de Investigaciones
de la Provincia de Córdoba (CONICOR), the Consejo Nacional de
Investigaciones Científicas y Técnicas (CONICET) and SECYT,
Universidad Nacional de Córdoba.
(
1
(
25) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
26) It is known that ionized halophenols are nonreactive in SRN
reactions, see
(
1
(
2
a) Bunnett, J. F.; Sundberg, J. E. Chem. Pharm. Bull. 1975,
3, 2620.
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Article Identifier:
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Synthesis 1999, No. 12, 2053–2056 ISSN 0039-7881 © Thieme Stuttgart · New York