Regiochemistry of the microwave-assisted reaction between aromatic amines and α-bromoketones to yield substituted 1H-indoles

Article abstract of DOI:10.1039/b719641e

The scope and regioselectivity of the Bischler (or Bischler-Moehlau) reaction between aromatic amines and α-bromoketones has been studied by computational and experimental techniques. It has been found that in many cases the reaction yields are improved under microwave irradiation and working in the absence of solvent. When di- and trisubstituted amines are used as substrates the regioselectivity of the reaction is different to that obtained with the corresponding primary anilines. The reaction between benzene-1,2-diamine and α-bromoacetophenones under the same conditions yields 2-substituted quinoxalines instead of indoles. Finally, when pyridin-2-amines and pyrimidine-2-amines are allowed to react with the corresponding α-bromoacetophenones, the corresponding imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines are obtained, respectively. The Royal Society of Chemistry.

Full text of DOI:10.1039/b719641e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Regiochemistry of the microwave-assisted reaction between aromatic amines
and a-bromoketones to yield substituted 1H-indoles†
Yosu Vara,a Eneko Aldaba,b Ana Arrieta,a Jose´ L. Pizarro,c Mar´ıa I. Arriortuac and Fernando P. Coss´ıo*a
Received 20th December 2007, Accepted 22nd February 2008
First published as an Advance Article on the web 25th March 2008
DOI: 10.1039/b719641e
The scope and regioselectivity of the Bischler (or Bischler–Mo¨hlau) reaction between aromatic amines
and a-bromoketones has been studied by computational and experimental techniques. It has been
found that in many cases the reaction yields are improved under microwave irradiation and working in
the absence of solvent. When di- and trisubstituted amines are used as substrates the regioselectivity of
the reaction is different to that obtained with the corresponding primary anilines. The reaction between
benzene-1,2-diamine and a-bromoacetophenones under the same conditions yields 2-substituted
quinoxalines instead of indoles. Finally, when pyridin-2-amines and pyrimidine-2-amines are allowed to
react with the corresponding a-bromoacetophenones, the corresponding imidazo[1,2-a]pyridines and
imidazo[1,2-a]pyrimidines are obtained, respectively.
Introduction
1H-Indoles are among the most important families of
heterocycles.1 These bicyclic compounds have been included in
the category of “privileged structures”2 since, according to the
definition proposed by Evans,3 indoles constitute a “molecular
framework able to provide ligands for diverse receptors”. There-
fore, there is a consensus in that indoles probably represent the
most important of all structural classes in drug discovery.2a,4
Among the different methods for the synthesis of 1H-indoles,5
those that rely on the simultaneous disconnection of the N1–
C2 and C3–C3a bonds are of special relevance in terms of
convergence and accessibility of the reactants (Scheme 1). The first
implementation of this approach is the well-known Fischer indole
synthesis,6 which has been extensively used since its discovery in
1883.7 Within this approach, other methods based on related [3,3]
sigmatropic rearrangements have been proposed.8
Another group of indole synthesis is based on the reaction
between ortho-iodo anilines and alkynes catalyzed by transition
metals (Scheme 1, entry b). The most prominent example of
this approach is the Larock synthesis9 and related methods.10,11
Alternatively, ketones can be used as electrophiles in this kind of
reaction (Scheme 1, entry c),12 thus complementing the Fischer
method.
Finally, another method based on the above-mentioned dis-
connection consists of the Bischler13 (or Bischler-Mo¨hlau14)
Scheme 1 Main indole syntheses based on the disconnection of the
N1–C2 and C3–C3a bonds. Substituents at the various positions are
aKimika Fakultatea, Kimika Organika I Saila, Universidad del Pa´ıs Vasco –
unspecified, unless indicated.
Euskal Herriko Unibertsitatea, Manuel de Lardizabal Etorbidea 3, 20018,
San Sebastia´n-Donostia, Spain. E-mail: fp.cossio@ehu.es; Fax: +34 943
015270; Tel: +34 943 015442
indole synthesis. This reaction takes place between an ortho-
unsubstituted aniline and an a-halogenated ketone (Scheme 2).
bIkerchem Ltd, Tolosa Etorbidea 72, 20018, San Sebastia´n-Donostia, Spain
Other suitable electrophiles can be a-diazo-b-ketoesters,15 a-
cZientzia eta Teknologia Fakultatea, Mineralogia eta Petrologia Saila,
hydroxyketones16 and a-aminoketones.17
Universidad del Pa´ıs Vasco – Euskal Herriko Unibertsitatea, P. K. 644,
Bilbao, Spain
† Electronic supplementary information (ESI) available: Temperature
profiles for the reaction between 1d and 2c; NMR spectra; experimental
procedures and characterization data; computational data; crystal struc-
ture data for compound 3e (CCDC reference number 605924). See DOI:
10.1039/b719641e
Although the reactants for the Bischler reaction are readily
available, two issues have hampered further developments: first,
the yields of the isolated indoles are usually low, and second, the
regiochemistry of the reaction is not predictable (Scheme 2). Very
recently, and during the studies described in this paper, it has
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Scheme 2 General reaction between anilines and a-haloketones.
been shown that the outcome of the reaction between anilines
and a-bromoketones can be improved by means of microwave
irradiation.18
Within this context and in view of the above-mentioned previous
work, the aim of the present work has been to improve our
knowledge of the Bischler reaction in order to understand the
reason for its regioselectivity and to explore the scope of this
interesting reaction, which has otherwise been largely ignored in
the recent indole literature.2a,5a,19
Results and discussion
Mechanistic considerations
Scheme 3 Mechanistic proposals based on 5-exo-tet cyclizations.
Despite its formal simplicity, the mechanism of the Bischler
reaction is not clear because many pathways can be operating
at the same time. Thus, the carbonyl group of the a-haloketone
2a can react with one equivalent of base or with the aniline 1a
to yield imino intermediates, whose 5-exo-tet SN2-type cyclization
(Scheme 3, steps A,B) should lead to 2-substituted-1H-indole 3a.
An alternative general mechanistic pathway consists of the inital
SN2 reaction between aniline 1a and a-haloketone 2a to yield
2-aminoketones, which can then cyclize by 5-exo-trig processes
to yield 3-substituted-1H-indole 4a (Scheme 4, path C). In
addition, the above-mentioned 2-aminoketones can rearrange to
the corresponding aldehydes both under acid catalysis20 or neutral
conditions.21 Reaction of these rearranged carbonyl compounds
by 5-exo-trig cyclization should yield the 2-substituted-1H-indoles
3 (Scheme 4, path D).
In order to test the feasibility of the 5-exo-tet and 5-exo-trig
cyclizations, we selected the model reactions shown in Scheme 5.
These reactions incorporate the main features of the cyclizations
A–D shown in Schemes 3 and 4. The main geometric data
of the corresponding transition structures TS1–4 are shown in
Fig. 1. According to our results, 5-exo-tet cyclizations are clearly
disfavoured, the activation energies associated with both 5a→6a
and 5b→6a being considerably higher than those found for the
alternative 5-exo-trig cyclizations of type 5c→6b and 5d→6c
(Scheme 5, Fig. 1).
In particular, the lowest calculated activation energy is for the
5d→6c transformation via TS4. This saddle point is earlier than
TS3, and the calculated activation energy is ca. 4 kcal mol−1 lower
than that computed for the 5c→6b transformation. This result is
in line with the higher electrophilicity of aldehydes with respect
to related ketones. Therefore, if only the cyclization step of the
Scheme 4 Mechanistic proposals based on 5-exo-trig cyclizations. For
further details on the rearrangement prior to the cyclization steps C and
D, see Scheme 6.
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Scheme 5 Model cyclization steps computed at the B3LYP/6-31G* level.
Fig. 1 Fully optimized structures (at the B3LYP/6-31G* level of theory)
associated with transition structures TS1–4 (Scheme 5). Bond distances
˚
and angles are given in A and deg, respectively. The activation energies
have been computed at the B3LYP/6-31G*+DZPVE level.
reaction is considered, preferential or exclusive formation of 2-
substituted-1H-indoles is predicted, via structures similar to TS4.
However, these latter cyclizations require the rearrangement
indicated in Scheme 4. Intensive experimental work21 led to the
mechanistic proposal shown in Scheme 6. According to this
proposal, the rearrangement requires the nucleophilic addition
of second equivalent of aniline to the cationic intermediate 7.
An intramolecular SN2 reaction on intermediate 8 leads to a
protonated oxirane intermediate, the cleavage of the C–O bond in
which yields the stabilized cation 10. Subsequent E1 reaction and
keto–enol isomerization leads to aldehyde 5d. This electrophilic
aldehyde is transformed into cyclic intermediate 6c via TS4.
Alternatively, an additional equivalent of aniline can directly yield
ketone 5c, 5-exo-trig cyclization of which should yield cation 6b
via TS3 and, finally, the unrearranged 3-phenyl-1H-indole 4a.
Scheme 6 Mechanistic proposals for the formation of rearranged and
unrearranged 1H-indoles.
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We have explored intensively the potential energy hypersurface
associated with this particular rearrangement and we have been
unable to locate and characterize the protonated epoxide 9, either
in the gas phase or in solution. Instead, all our attempts led to
the direct conversion of 8 to 10 via saddle point TS5 (Fig. 2). In
this transition structure the departure of the aniline group is more
advanced than the formation of the O1–C2 bond. The process
is exothermic and there is a strong resonance stabilization of the
C3 center. Thus, the C3–N5 bond distance in 10 is significantly
shorter than that computed for 8 (Fig. 2).
Scheme 7 Formation of 2-substituted indoles from intermediate imines.
Fig. 2 Fully optimized structures (at the B3LYP/6-31G* level of theory)
associated with the 8→10 transformation (Scheme 6). Bond distances
˚
are given in A. The relative Gibbs energies have been computed at the
B3LYP/6-31G*+DZPVE level and are given in kcal mol−1
.
Another pathway for the formation of 2-substituted 1H-
indoles consists of the dehydration of intermediate 8 to yield
12.22 Tautomerization of this imine to isomeric intermediate 14
and subsequent 5-exo-trig cyclization leads to intermediate 16,
whose elimination of one equivalent of aniline yields the 2-
phenyl-1H-indole 3a (Scheme 7). Exploration of this mechanistic
pathway from intermediate 14 to zwitterion 15 did not result in
an energetically accessible transition structure, probably because
of the penalty associated with charge separation and the lower
electrophilicity of the neutral imine moiety. However, activation
of the imine with one equivalent of HBr resulted in saddle point
TS6·HBr (Fig. 3), in which the C1–H bond is slightly relaxed with
respect to precursor 14·HBr. Our calculations also show a direct
obtention of intermediate 16·HBr, in which the aromaticity lost in
15 is recovered. The activation barrier computed for this step is
comparable to those obtained for the 5c,d→6b,c conversions via
TS3 and TS4 (Fig. 1), and significantly lower than the activation
energy associated with the 8→10 conversion via TS5 (Fig. 2).
Fig. 3 Fully optimized structures (B3LYP/6-31G* level theory) asso-
ciated with the 14→16 transformation (Scheme 7). Bond distances and
˚
angles are given in A and deg. The relative Gibbs energies have been
computed at the B3LYP/6-31G*+DZPVE level and are given in kcal mol−1
.
Therefore, we conclude that the mechanism shown in Scheme 7 is
the preferred one for the formation of 2-substituted 1H-indoles,
at least in the presence of an excess of aniline.
In summary, the kinetic 3:4 ratio obtained in the Bischler–
Mo¨hlau reaction results from a complex process that depends
on the relative activation energies associated with the possible
5-exo-trig processes (the latter in its activated version shown in
Fig. 3). It is also noteworthy that the different steps described
in Schemes 4–7 involve very polar reaction intermediates and
transition structures. Therefore, the whole reaction is a suitable
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Table 1 Formation of indoles 3,4b–j from anilines 1b–d and a-
bromoketones 2b–e (Scheme 7) under dielectric heating (Method A) and
thermal heating (Methods B and C)a
candidate for microwave-assisted acceleration, even in the absence
of solvents having large loss tangent values.23,24
Yield of 3 (%)b
Ratio 3:4c
Microwave-assisted Bischler reaction between anilines and
a-bromoketones
Entry
Reaction
A
B
C
A
B
We carried out the Bischler reactions shown in Scheme 8 in
order to test the mechanistic scheme that emerged from our
computational study on the key steps of this transformation.
First, we included anilines possessing an activating group such
as methoxy at different positions of the phenyl group. We also
tested different experimental conditions in order to compare the
outcomes obtained under dielectric and thermal heating. Thus,
method A (Scheme 8, Table 1) consisted of heating a mixture of
aniline 1, the a-bromoketone 2, and N,N-dimethylaniline in the
absence of solvent at 150 ◦C for 10 min and under microwave
irradiation, with a power of 100 W and under 20 psi. The
conditions of method B were chosen to reproduce the usual
experimental conditions under thermal heating at 170 ◦C using
xylene as solvent. Under these conditions, the reaction time
required for good conversions was 3 hours. Finally, the reaction
conditions of method C were chosen to be as close as possible
to those using heating by microwave irradiation. Therefore, the
reaction time was 10 min, no solvent was used, the temperature was
monitored with a fibre-optic probe, and the reaction carried out
1
2
3
4
5
6
7
8
9
1b + 2b → 3b
30
52
48
43
61
16
80
75
28
10
53
19
45
51
0
55
4
43
17
31
0
45
51
0
37
4
37
>98 : 2
68 : 32
>98 : 2
65 : 35
82 : 18
>98 : 2
86 : 14
79 : 21
40 : 60
>98 : 2
77 : 23
>98 : 2
82 : 18
>98 : 2
—
90 : 10
50 : 50
65 : 35
1c + 2b → 3c + 4c
1d + 2c → 3d
1c + 2d → 3e + 4e
1c + 2e → 3f + 4f
1b + 2c → 3g
1c + 2c→ 3h + 4h
1e + 2b → 3i + 4i
1c + 2f → 3j + 4j
a Method A: Microwaves, 100 W, 20 psi, 10 min, 150 ◦C. Method B: Xylene,
reflux, 180 min, 170 ◦C. Method C: 150 ◦C, 10 min. b Yields of isolated
pure product 3. c Ratio determined by 1H-NMR on the crude reaction
mixtures.
at 150 ◦C in a closed vessel identical to that used in the microwave
experiments. It was observed that under these conditions the
selected temperature was reached in ca. 3 min, whilst under
microwave irradiation this temperature was obtained after 23 s
(See Fig. S1, ESI†). The results obtained for the Bischler–Mo¨hlau
reaction between anilines 1b–e and a-bromoketones 2b–f are
gathered in Table 1.
From these results, we conclude that when the starting amine has
favourable substituent effects, similar results are obtained under
microwave irradiation and thermal heating. For example, reaction
between aniline 1c, which incorporates two favourably oriented
methoxy groups, and a-bromoketone 2e results in the formation of
1H-indoles 3f and 4f with similar yields, the thermal reaction being
more regioselective (Table 1, entry 5). In contrast, when the aniline
incorporates the methoxy groups in an unfavourable orientation,
microwave irradiation is superior. For instance, the reaction
between a-bromoketone 2c and aniline 1b, which incorporates
two methoxy groups meta-oriented with respect to the C–C bond
to be formed, results in the formation of 1H-indole 3g with low
yield only when method A was used (Table 1, entry 6). These
results agree with the computational model in which the 5-exo-
trig cyclization step results in the formation of cyclic cations of
type 6 (Scheme 5). These cations can be stabilized by properly
located methoxy groups.
Our experimental results also indicate that the Bischler reaction
involving a-methyl-a-bromoacetophenone 2f is not regioselective.
Thus, reaction between aniline 1c an 2f (Table 1, entry 9) results
in similar quantities of 3j and 4j.
This result is also in line with those obtained in the computa-
tional study of the cyclization step, since in this case the 5-exo-
trig process involves nucleophilic additions on ketones or imines
having similar electrophilicities.
The characterization of 1H-indoles 3 and 4 was carried out by
means of NMR and X-ray diffraction analysis of compound 3e
(see ESI†). Using this compound as a reference, the structure of the
remaining compounds was determined by correlation analysis of
the 1H-NMR and 13C-NMR spectra (See Fig. S2–S5, ESI†). Thus,
the C–H groups at the C-3 position of molecules 3b–j generated
diagnostic signals at ca. 6.8 ppm and ca. 95.0 ppm in the 1H-NMR
and 13C-NMR spectra, respectively. In contrast, the C–H groups
Scheme 8 Reagents and conditions: (a) Microwaves (lW), 100 W, 20 psi,
10 min, 150 ◦C (Method A). (b) Xylene, reflux, 170 ◦C, 180 min (Method
B). (c) 150 ◦C, 10 min (Method C).
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Table 2 Microwave-assisted synthesis of indoles 3 and 4c in the presence
of different bases
Table 3 Microwave-assisted synthesis of indoles 4a,k–n from a-
bromoacetophenone 2a and N-alkyl anilines 1a,f–i (Scheme 10)
Entry Base
Ratio 1:2:base Ratio 3c:4ca Yield (%)b
Entry
Reaction
R
3a (%)a
4 (%)a
1
2
3
4
5
6
Et3N
DIPEA
DIPEA
Py
2 : 1 : 3
2 : 1 : 3
1 : 1 : 3
2 : 1 : 3
1 : 1 : 3
35 : 65
35 : 65
0 : 100
85 : 15
50 : 50
78 : 22
40
45
36
63
20
22
1
2
3
4
5
1a + 2a → 3a + 4a
1f + 2a → 3a + 4k
1g + 2a → 3a+ 4l
1h + 2a → 3a+4m
1i + 2a → 3a + 4n
H
Me
Et
i-Pr
t-Bu
80
35
25
30
100
0
47
57
34
0
Py
Methyl nicotinate 2 : 1 : 3
a Yields of isolated pure products.
a Ratio determined by 1H-NMR on the crude reaction mixtures. b Yield of
isolated pure major product.
We also studied the behavior of N,N-dimethylaniline 1j in
the presence of a-bromoaketones 2a,f–h (Scheme 11) and under
microwave irradiation. The results obtained are shown in Table 4.
We have found that in the presence of 1j only the unrearranged
N-methyl-1H-indoles 4k,o–r are obtained. Therefore, opposite
at the C-2 position in regioisomers 4c–j appeared at ca. 7.00 ppm
and ca. 120.0 ppm in the respective 1H-NMR and 13C-NMR
spectra.
We also studied the effect of the base on the reaction. As model
system we selected the reaction between 1c and 2b to yield 3c and
4c (Table 1, entry 2; Scheme 9); the results are gathered in Table 2.
We observed that it is possible to modulate the regioselectivity of
the reaction. Thus, stronger bases such as triethylamine or DIPEA
(diisopropylethylamine) favour the formation of the unrearranged
product 4c (Table 2, entries 1–3), whereas in the presence of weaker
bases such as pyridine or methyl nicotinate the rearranged indole
3c is the major regioisomer (Table 2, entries 4–6). The obtention
of product 4c as the major regioisomer in the presence of stronger
bases is consistent with a lower participation of the mechanism
outlined in Scheme 7 and Fig. 3, since in this case the acidic
activation of the intermediate imine during the 5-exo-trig step is
less efficient.
Scheme 10 Microwave-assisted synthesis of N-alkyl-1H-indoles from
N-alkyl anilines.
Scheme 9 Reaction between 1c and 2c in the presence of different bases
(See Table 2).
The next step in our study was to analyze the regioselec-
tivity of the reaction between N-alkyl anilines 1a–i, and a-
bromobenzophenone 2a under microwave irradiation (Scheme 10,
Table 3). According to our results, when aniline 1a reacts with 2a,
only the rearranged 1H-indole 3a is obtained with good yields
under microwave irradiation. In contrast, the presence of N-alkyl
groups (Table 3, entries 2–4) results in the formation of variable
amounts of unrearranged 1-alkyl-3-phenyl-1H-indoles 4k–n. The
exception is the reaction with amine 1i, in which the presence
of the tert-butyl group results in the exclusive formation of the
rearranged 1H-indole 3a in quantitative yield.
Scheme 11 Microwave-assisted synthesis of N-alkyl-1H-indoles from
N,N-dialkyl anilines.
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Table 4 Microwave-assisted synthesis of indoles 3k,o–r and 4k,o–r from
a-bromoketones 2a,f–h and amines 1a,j (Scheme 9)
Entry
Reaction
R1
R2
R3
3 (%)a
4 (%)a
1
2
3
4
5
1j + 2a → 3k + 4k Me
Ph
H
H
H
H
0
31
0
0
0
53
0
34
60
51
1a + 2g → 3o + 4o
H
CO2Et
CO2Et
PMPb
Ph
1j + 2g → 3p + 4p Me
1j + 2b → 3q + 4q Me
1i + 2 f → 3a + 4r
Me
Me
a Yields of isolated pure products. b PMP: p-methoxyphenyl.
regiochemistries can be obtained depending on the substitution
pattern of the starting amine. For example, the reaction between
aniline 1a and a-bromoacetophenone 2a yields only 2-phenyl-1H-
indole 3a (Table 2, entry 1). In contrast, irradiation of N,N-
dimethylaniline 1j and 2a results in the exclusive formation of
1-methyl-3-phenyl-1H-indole 4k (Table 3, entry 1). The same
outcome was observed in the reaction of ethyl 3-bromo-2-
oxopropanate 2g and amines 1a,j (Table 3, entries 2 and 3). Finally,
it is interesting to note that the same result was obtained with
racemic 2-bromopropiophenone 2f and amine 1j, and only the
unrearranged 1,2-dimethyl-3-phenyl-1H-indole 4r was obtained
(Table 3, entry 5), in contrast with the lack of regiocontrol observed
in the reaction between 2f and a-bromoaketone 1c (Table 1, entry
9, vide supra).
Scheme 13 Possible pathways for the formation of N-alkyl-1H-indoles.
intermediates 18 and 19 to yield finally the corresponding 1H-
indoles 4. Our results also indicate that, in general, the distribution
of the intermediates 18 and 19 is shifted toward the formation of
the most substituted alkyl bromide.
We also explored the reaction between a-bromoketones 2 and
amines incorporating active substituents. We have found that when
1,2-phenylenediamine 10 was subjected to microwave irradiation
in the presence of a-bromoketones 2b,h the corresponding 2-
arylquinoxalines26 20a,b were obtained instead of 7-amino-2-aryl-
1H-indoles (Scheme 14). It is interesting to note that a similar
reaction in the absence of microwaves required overnight stirring
to proceed.27
In a different series of experiments, we analyzed the outcome
of the reaction between N,N-dialkylamines 1k–m and 2a under
microwave irradiation (Scheme 12, Table 5). We observed that in
the case of amines 1k,l, comparable distributions of the possible
1-alkyl-1H-indoles 4k–m were obtained. In contrast, when amine
1m was irradiated in the presence of 2a, only 1-methyl-3-phenyl-
1H-indole 4k was obtained.
We have also studied the reaction between amines 1p,q and
phenacyl bromides 2b,h in order to assess the role of additional
nitrogen atoms present in the aromatic ring. This reaction has
been studied by several authors under thermal conditions,28 and
very recently under microwave irradiation.29 In this latter case,
a
Dimauro et al.29 irradiated the reaction mixtures of phenacyl
Scheme 12 Microwave-assisted synthesis of N-alkyl-1H-indoles from
N,N-dialkyl anilines.
bromide 2a and boronic esters derived from 2-aminopyridine
at 130 ◦C for 30 min using ethanol as solvent, whereas Cai
et al.9b,29 carried out the reaction using titanium(IV) chloride as
a strong dehydrating agent. Since Ponnala et al.30 performed the
synthesis of these heterocycles using Al2O3 as a solid medium, we
decided to test the same reaction under microwave irradiation. We
observed that under solvent-free conditions and in the presence
of Al2O3, only 5 min was required to carry out the reaction
between compounds 1p,q and 2b,h (Scheme 15), working at 70 W,
These results indicate that trisubstituted anilines are much
more regioselective since only 3-substituted (i.e. unrearranged)
1H-indoles are obtained. This suggests that when only N,N-
dialkylanilines are present, the pathway shown in Scheme 7 and
Fig. 3 is not possible.25 Instead, the quaternary intermediates
17 are formed (Scheme 13). These intermediates evolve toward
◦
Table 5 Microwave-assisted synthesis of indoles 4k–n from amines 1k–m
and a-bromoacetophenone 2a
70 C and 20 psi. Therefore, these conditions appear to be very
convenient for the synthesis of 2-arylimidazo[1,2-a]pyridines (or
-pyrimidines) such as 21a,c (Scheme 15). We think that in these
cases the reaction proceeds by nucleophilic attack of the nitrogen
atom in the aromatic heterocycles, followed by ring closure of N-
alkylpyridinium (or -pyrimidinium) intermediates, according to
the mechanism proposed by Hand et al.31
Entry
Reaction
R1
R2
Isolated yield (%)
1
2
3
1k + 2a → 4k + 4m
1l + 2a → 4l + 4m
1m + 2a → 4k
Me
Et
Me
i-Pr
i-Pr
t-Bu
16 (4k) +30 (4m)
23 (4l) +12 (4m)
44 (4k)
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Experimental
Computational studies
All the calculations reported in this paper were performed within
Density Functional Theory,32 using the hybrid three-parameter
functional commonly denoted as B3LYP.33 The standard 6-31G*
basis set,34 as implemented in the GAUSSIAN 0335 suite of
programs, was used in all cases. All the stationary points were char-
acterized by harmonic analysis.36 Activation energies (DEa) and
reaction energies (DErxn) were computed at the B3LYP/6-31G*
level including zero-point vibrational energy (ZPVE) corrections.
General
Microwave irradiations were conducted in a focused microwave
reactor CEM Discover, at the power and for the time indicated. All
melting points are uncorrected. NMR data were obtained using
TMS as an internal standard. Column chromatographies were
carried out with 230–400 mesh silica gel. Reagents were purchased
from commercial suppliers or prepared according to literature
procedures. N-tert-Butylaniline 1i was obtained following the pro-
cedure described by Canle et al.37 N-Isopropyl-N-methylaniline
1l and N-methyl-N-tert-butylaniline 1m were prepared according
to the methods reported by Totah et al.38 and Hunter et al.,39
respectively. 2-Bromo-1-(3,5-dimethoxyphenyl)ethanone 8b was
prepared according to the method reported by Chen et al.40
Scheme 14 Synthesis of quinoxalines from 1,2-phenylendiamine and
a-bromoketones.
General methods for the synthesis of 1H-indoles
Method A. A mixture of the aniline 1 (2.0 mmol), the a-
bromoketone 2 (1.0 mmol), and N,N-dimethylaniline (0.42 ml,
3.3 mmol) was irradiated with microwaves (150 W) at 150 ◦C
and 20 psi for 10 min. The resulting mixture was dissolved in
EtOAc and washed with 2 N HCl. After drying (Na2SO4), the
solution was evaporated and purified by flash chromatography
(ethyl acetate–hexanes) to yield the corresponding 1H-indoles,
which were crystallized from Et2O–hexanes.
Method B. A mixture of the aniline 1 (2.0 mmol), the a-
bromoketone 2 (1.0 mmol), and N,N-dimethylaniline (0.42 ml,
3.3 mmol) was refluxed in xylene at 170 ◦C for 180 min. The
treatment described above led to the corresponding pure products
3 and 4.
Scheme 15 Synthesis of 2-arylimidazo[1,2-a]pyridines (X = CH) and
2-arylimidazo[1,2-a]pyrimidines (X = N)
Method C. A mixture of the aniline 1 (2.0 mmol), the a-
bromoketone 2 (1.0 mmol), and N,N-dimethylaniline (0.42 ml,
3.3 mmol) was heated in an oil bath at 150 ◦C (internal temperature
monitored by a fibre-optic probe) for 10 min. The treatment
described above led to the corresponding pure products 3 and 4.
Conclusions
Microwave irradiation is a convenient method for the Bischler
reaction between aromatic amines and a-bromoketones. Only
ca. 10 min is required to carry out the reaction at 150 ◦C and
20 psi. The reaction takes place by 5-exo-trig cyclizations involving
intermediate aldehydes, ketones or imines. A 1,2-migration of an
hydroxyl group or, more likely, the formation of an intermediate
imine are critical to obtain rearranged 2-substituted 1H-indoles.
Further N-substitution allows the modulation of the regioselec-
tivity of the reaction, the unrearranged 3-substituted-1H-indoles
being the major or exclusive products. The presence of active
functional groups results in the formation of other heterocycles
like quinoxalines or imidazo[1,2-a]pyridines (or -pyrimidines).
4,6-Dimethoxy-2-(2,4-dimethoxyphenyl)-1H-indole (3e). White
solid, 43% yield; mp 171–172 ◦C; mmax/cm−1 (KBr) 3427, 1587,
1472, 1301, 1216, 1126; 1H NMR (d/ppm, 500 MHz, CDCl3) 9.38
(s, 1H), 7.68 (d, 1H, J = 8.4 Hz), 6.77 (s, 1H), 6.57 (d, 1H, J =
8.7 Hz), 6.55 (s, 1H), 6.51 (s, 1H), 6.20 (s, 1H), 3.95 (s, 3H), 3.93
(s, 3H), 3.84 (s, 3H), 3.83 (s, 3H); 13C NMR (d/ppm, 500 MHz,
CDCl3) 159.9, 157.4, 156.7, 153.4, 137.2, 133.5, 128.6, 114.5, 113.8,
106.0, 99.5, 95.5, 91.7, 87.0, 56.0, 55.8, 55.6, 55.5. Anal. Calcd. For
C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 68.80; H, 6.11,
N, 4.62.
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4,6-Dimethoxy-3-(2,4-dimethoxyphenyl)-1H-indole (4e). Oil,
23% yield; mmax/cm−1 (KBr) 3407, 1552, 1211, 1161 cm−1; 1H NMR
(d/ppm, 500 MHz, CDCl3) 8.02 (s, 1H), 7.32 (d, 1H, J = 8.2 Hz),
7.01 (d, 1H, J = 2.0 Hz), 6.57–6.51 (m, 2H), 6.49 (d, 1H, J =
1.3 Hz), 6.21 (d, 1H, J = 1.3 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.77
(s, 3H), 3.73 (s, 3H); 13C NMR (d/ppm, 500 MHz, CDCl3) 159.6,
158.7, 157.5, 155.2, 137.8, 132.5, 120.9, 118.1, 113.4, 112.0, 103.5,
98.6, 92.2, 86.9, 55.7, 55.6, 55.5, 55.4.
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Synthesis of quinoxalines 20
A mixture of ortho-phenylendiamine (0.227 g, 2.1 mmol), the
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3.3 mmol) was microwave-irradiated (150 W) at 150 ◦C and 20 psi
for 10 min. The resulting mixture was dissolved in EtOAc and
washed with 2 N HCl. After drying (Na2SO4), the solution was
evaporated and purified by flash chromatography (ethyl acetate–
hexanes) to yield the corresponding product, which was purified
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Synthesis of 2-arylimidazo[1,2-a]pyridines and
arylimidazo[1,2-a]pyrimidines 21
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25 Black et al. have also obtained 3-substituted 1H-indoles by protecting
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26 For recent synthesis of quinoxalines using other methodologies involv-
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Acknowledgements
We thank the Ministerio de Educacio´n y Ciencia of Spain (Projects
CTQ2007-67528/BQU and Consolider-Ingenio 2010, CSD2007-
00006) and the Gobierno Vasco-Eusko Jaurlaritza (Grant 9/UPV
00170.215-13548/2001) for financial support. SGIker technical
support (MEC, CV/EJ, European Social Fund) is gratefully
acknowledged. Y. V. also thanks the Ministerio de Educacio´n y
Ciencia for a fellowship. We also thank the reviewers for their
valuable comments and suggestions.
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