Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: The synthesis of 7-amino-6-azaindoles

Article abstract of DOI:10.1016/j.tet.2014.12.057

Derivatives of 7-amino-6-azaindole containing variable substituent in the amino group were synthesized via acid-catalyzed nucleophilic heteroaromatic substitution (S_NHetarH⁺) using 7-chloro-6-azaindoles as substrates and aliphatic an

Full text of DOI:10.1016/j.tet.2014.12.057

Accepted Manuscript
Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: the
synthesis of 7-amino-6-azaindoles
Maxim A. Nechayev, Nikolay Yu. Gorobets, Svetlana V. Shishkina, Oleg V. Shishkin,
Sergiy M. Kovalenko
PII:
S0040-4020(14)01761-X
10.1016/j.tet.2014.12.057
TET 26278
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 October 2014
Revised Date: 1 December 2014
Accepted Date: 15 December 2014
Please cite this article as: Nechayev MA, Gorobets NY, Shishkina SV, Shishkin OV, Kovalenko SM,
Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: the synthesis of 7-amino-6-
azaindoles, Tetrahedron (2015), doi: 10.1016/j.tet.2014.12.057.
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Graphical Abstract
Microwave-assisted acid-catalyzed
nucleophilic heteroaromatic substitution: the
synthesis of 7-amino-6-azaindoles
Leave this area blank for abstract info.
a,b
c
c
c
Maxim A. Nechayev, Nikolay Yu. Gorobets, * Svetlana V. Shishkina, Oleg V. Shishkin, Sergiy M.
a
Kovalenko
a
National University of Pharmacy, Pushkinska Str. 53, Kharkiv 61002, Ukraine
Enamine Ltd., Alexandra Matrosova Street, 23, Kiev 01103, Ukraine
SSI ‘Institute for Single Crystals’ of NAS of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine, fax: +380573409343, e-mail: gorobets@isc.kharkov.com
b
c

1
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Tetrahedron
journal homepage: www.elsevier.com
Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: the
synthesis of 7-amino-6-azaindoles
a,b
c
c
c
Maxim A. Nechayev, Nikolay Yu. Gorobets, * Svetlana V. Shishkina, Oleg V. Shishkin, Sergiy M.
Kovalenko
a
a
National University of Pharmacy, Pushkinska Str. 53, Kharkiv 61002, Ukraine
Enamine Ltd., Alexandra Matrosova Street, 23, Kiev 01103, Ukraine
SSI ‘Institute for Single Crystals’ of NAS of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine, fax: +380573409343, e-mail: gorobets@isc.kharkov.com
b
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Derivatives of 7-amino-6-azaindole containing variable substituent in the amino group were
+
N
synthesized via acid-catalyzed nucleophilic heteroaromatic substitution (S HetarH ) using 7-
Received in revised form
Accepted
Available online
chloro-6-azaindoles as substrates and aliphatic and aromatic amines as nucleophiles. The
protonation of the pyridine nitrogen in the starting 7-chloro-6-azaindoles is presumed to be the
key stage of the reaction mechanism discussed.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
6
-azaindole
β-carboline
microwave-assisted organic synthesis
nucleophilic heteroaromatic substitution
acidic catalysis
4
4,45
45
intercalate DNA helix
antimalarial
46and recognized as anticancer,
45,46
and antiprion agents.
1
. Introduction
Due to the continuous interest in novel approaches to
4
7-50
In the past 40 years the classical methods for the synthesis of
the 2-pyridone ring formation,
we have recently
1
indole core were effectively used for construction of indole aza-
analogues. As a result, several new heterocyclic scaffolds were
identified that possess a wide range of biological activities.
Consequently, the development of novel practically useful
approaches to the synthesis of this heterocyclic family has gained
considerable attention. The most widely usable strategies to the
azaindole core are based on the formation of pyrrole ring onto an
existing pyridine fragment using the classical methods for indole
developed an efficient synthesis of 1-substituted
2-5
5
1
pyrrolo[2,3-c]pyridine-7-ones
(1, Scheme 1). In
6
-10
current work we were intrigued by a possibility to apply
these synthetically available heterocycles as a cheap and
suitable starting material for the synthesis of substituted
7
-amino-6-azaindoles avoiding a low yielding Bartoli
reaction generally used in the synthesis of 5-halogeno-6-
19,20,52
1
1-15
azaindole intermediates.
synthesis such as Leimgruber-Batcho,
Hemetsberger-
reactions. On the other hand
more specific methods that start from a pyrrole derivative are still
16
17-20
21-26
Knittel, Bartoli,
or Larock
R1
2
7-29
much less explored and applicable.
R3
NH
N
6
-Azaindoles are not found in natural sources “as they are”,
R2
NH
N
but the fragment of 6-azaindole is presented in a considerable
number of alkaloids of β-carboline family
Another example is represented by the marine alkaloid
Marinoquinoline A isolated recently from the gliding bacterium
R. thailandica TISTR 1742. Nevertheless, different 7-amino-6-
30,31
N
N
Me
(Scheme 1).
H
Alk
O
β-Carboline Marinoquinoline A
1
32
1
R = H, Br
2
azaindole derivatives are suggested for treating kinase-associated
R = H, Me, Ph
33,34
35
8,36-38
3
diseases,
chronic pain,
related 1-amino-ß-carboline derivatives were shown to be able to
viral infections, such as HIV and AIDS,
R = H, Me
19,39
40-42
43
gastroesophageal reflux
and cancer. The
Scheme 1. Pyrrolo[2,3-c]pyridine-7-one scaffold 1 and
related natural products.

2
Tetrahedron
The main synthetic approach to 7-amino-6-azaindoles is
with piperazine in toluene, and this reaction was reported to be
ACCEPTED MANUSCRIPT
heteroaromatic nucleophilic substitution in 7-halogenated-6-
azaindole derivatives which is described mostly in patent
literature and exampled by uncatalyzed reactions of 7-halogeno-
1.8 times faster without the use of sodium carbonate as an acid
57
scavenger.
43
6
-azaindoles with amines in pyridine,
acid-catalyzed
or palladium
Table 1. Preparation and isolated yields of N1-substituted 7-
chloro-6-azaindoles 2a-d.
19,39,40
35-37,52
41
reactions,
as well as using copper
catalysts. Neat reagents were used to obtain related 1-amino-β-
45,46
carboline derivatives.
All these approaches require high
reaction temperatures and long heating time up to 40 h. Since
such reactions seems to be feasible only under vigorous
conditions, the simplicity of introduction of the amine component
into the azaindole ring using such methods is counterbalanced
with the loss of chemical flexibility: application of metal
catalysts, long reaction times and often low yields. The similar
44,45
difficulties also refer to the ß-carboline series.
In the current work a novel efficient synthetic pathway to 7-
amino-6-azaindoles is presented using combination of
a
Starting material
Product
Yield,
%
previously described pyrrole-2-carboxylic acid based synthesis of
51
heterocyclic core 1 (Scheme 1) followed by its transformation
into 7-chloro-6-azaindoles and acid-catalyzed heteroaromatic
nucleophilic chlorine substitution with aliphatic and aromatic
amines under microwave conditions.
NH
N
7
1
N
N
Cl
O
2
. Results and Discussions
Me 1a
Me 2a
The synthesis of initial compounds 1a-d (Table 1) was
accomplished starting from pyrrole-2-carboxylic acids as was
NH
51
previously described. The β-carboline derivative 1e was
synthesized from indole-2-carboxylic acid using the same general
procedures. Compounds 1a-e were transformed into required
N1-substituted 7-chloro-6-azaindoles 2a-d and 1-chloro-9-
methyl-9H-β-carboline 2e by heating in POCl3 with good to
excellent yields (Table 1) following the reported procedure for
91
76
N
O
1
b
Ph
Me
NH
O
53
2
a.
Br
To find acceptable conditions for nucleophilic substitution,
initially the excess of morpholine (5.0 equiv) was involved into
o
reaction with 2a under microwave irradiation at 190 C in butan-
1
-ol. It was convenient to use this polar and high boiling point
N
solvent to guarantee a satisfactory absorption of microwave
power and the safe level of internal pressure inside a closed vial
under such a high temperature. The reaction proceeded during
Me 1c
NH
1
50 min until no more starting material was observed on a TLC
plate (TLC control every 10-20 min) to give the desired product
9
2
3
a in 52% isolated yield (Table 2).
N
Ph
O
Reasoning about further direction of optimization, beside the
Me 1d
usual requirements of high isolated yields, the following
considerations have been taken into account. The reaction
conditions should allow: avoiding less facile metal-catalyzed
reaction conditions (a); ensuring the possibility to apply “small”
aliphatic amines (b). The “small” aliphatic amines are the first
option when a synthetic method is applied for medicinal
chemistry purposes because the low molecular weights of the
synthesized products are dictated by the leadlikeness criteria. On
the other hand, they are volatile or even gaseous and would
create additional pressure inside a sealed microwave vial under
evaluated temperatures. Among available catalytic systems, we
have examined the application of strong acidic catalysis as the
simplest option for the beginning that also meets criteria (a) and
NH
N
88
N
N
O
Cl
Me 1e
Me 2e
However, to our surprise, the use of acidic catalyst for
58,59
nucleophilic (hetero)aromatic substitution
is much less
described in the literature comparing with application of different
60
base- and transition metal-catalyzed approaches. Thus, the
model microwave-assisted reactions of 2a with morpholine and
aniline in the presence of methanesulfonic acid (MSA) were
further studied. As seen from Table 2 (Entries 1-4), the
application of MSA taken in 0 to 1.0 equiv resulted in shortening
of the reaction time from 150 to 40 min and increasing the
isolated yield from 52 to 80%. Further optimization of the
morpholine amount (Table 2, Entries 4-6) led to the acceptable
conditions (Entry 5).
(b). The application of such catalysis was previously described
for nucleophilic substitution with anilines for particular aza-
54-56
19,39
heterocycles
including 7-chloro-6-azaindole derivatives
with “active” halogen and this process was reported to be
autocatalytic, since hydrochloric acid is formed during the
reaction. The autocatalytic character of a similar substitution was
also observed in the reaction of 2-chloro-N-ethyl pyridin-3-amine

3
ACCEPTED MANUSCRIPT
Table 2. Search for acceptable conditions for the nucleophilic substitution using representative 7-chloro-6-azaindole 2a,
morpholine and aniline.
(a
Entry MeSO H, equiv Temperature, ºC Time, min
Amine, equiv Isolated yield, %
3
1
2
3
4
5
6
7
8
9
None
0.2
0.5
1.0
1.0
1.0
1.0
190
190
190
190
190
190
160
160
200
150
90
60
40
40
40
30
40
300
5.0
5.0
5.0
5.0
3.0
2.0
3.0
1.5
1.3
52
54
67
80
81(
70
75
67
b
0.2(
c
(d
1.0
24
a)
b)
Full conversion of starting material according to TLC. After evaporation of the solvent the mixture was neutralized with sodium
c)
d)
carbonate. 2.2 equiv of NEt were added. The yield was determined by LCMS analysis
3
These conditions were successfully applied for cheap liquid
water soluble amines (the excess of amine is removed during
aqueous workup, Method A, Table 3, Entries 1-4).
75% isolated yield (Table 2, Entry 7). Attempts to decrease the
catalyst amount or substitute the aniline excess with
triethylamine (even under higher temperature) led to the yield
lowering in both cases (Entries 8, 9). Thus, the initial conditions
In those cases where the application of the amine in excess is
undesirable due to its high cost or poor solubility in water, the
excess of reacting amine was replaced with a cheap base,
triethylamine, that can be easily removed from the reaction
mixture (Table 3, Entries 5-7). Thus 2.0 equiv of triethylamine
and 1.2 equiv of a reacting primary amine were used under the
same reaction conditions (Method B).
(
Table 2, Entries 7) for the reaction with aniline were applied for
aromatic amines as Method D (Table 3, Entries 16, 17).
Apparently the presence of both the excess of organic base
and the strong inorganic acid is required to promote the reaction
efficiently (Table 2). According to the previously proposed
54
mechanism for a similar transformation after protonation of the
+
pyridine nitrogen leading to 2aH , this already “activated” for
Also, gaseous or low boiling point amines available as
hydrochlorides were successfully applied in the reaction (3.0
equiv of the amine hydrochloride instead of using MSA) in the
presence of 2.2 equiv of triethylamine (Table 3, Entries 8-15,
Method C).
aromatic nucleophilic substitution substrate can effectively react
with N-nucleophile to give reaction product 3 after elimination of
hydrogen chloride (Scheme 2). In view of the important role of
the protonation of the heterocyclic fragment,
a specific
abbreviation for this mechanism type is proposed here,
+
Interestingly, the reaction of 2a with aniline already at 150 ºC
during 30 min resulted in formation of the desired product (3p) in
S HetarH .
N
Table 3. Preparation and isolated yields of 7-amino-6-azaindole derivatives 3a-p.
Entry Starting compound
Method Amine
Product
Yield, %
H
N
1
A
81
O
Br
Me
Br
H
N
Me
N
N
Me
2
A
30
N
N
N
O
O
Me
2c Cl
3b

4
Tetrahedron
ACCEPTED MANUSCRIPT
H
N
3
A
64
N
NH2
4
5
A
76
60
Me
HN
N
Me
Me 3d
H N
2
B
OMe
NH2
7
8
9
B
72
83
98
NH2 HCl
C
Me
NH2 HCl
C
Me
NH2 HCl
1
0
1
2
C
78
59
91
Me
Me
Me
NH2 HCl
1
1
C
C
N
N
NH2 HCl
Ph
HN
3k
Me

5
ACCEPTED MANUSCRIPT
Me
NH2 HCl
1
3
C
69
80
H
1
1
4
5
C
C
N
HCl
Me
Me
a
.
NH HCl
30
79
81
3
NH2
N
1
6
7
D
D
N
HN
Cl
Me
3
o
Cl
1
Ph NH2
a
The compound was not isolated, the yield was determined form LC/MS data.
+
Scheme 2. Possible reaction mechanism for the acid-catalyzed nucleophilic heteroaromatic substitution (S HetarH ) in 7-chloro-
N
6
-azaindole 2a
5
4,56
In the previous works
such reactions were concluded to be
amines compared with aromatic ones the solvolysis of their
conjugate acids requires higher temperatures. This solvolysis is
necessary for the studied precess to create a reasonable
concentration of the free acid catalyzing the reaction. Namely,
pH value of an aqueous solution of morpholinium/morpholine
(3:1 molar ratio) is changed from 8.7 at 25.5 ºC to 6.3 at
general for aromatic but not for aliphatic amines under acidic
conditions at 100 °C. In the case of aromatic amines, the reaction
proceeded rapidly already at this relatively low temperature
because of the lower basicity of the aromatic amines allowing
considerable hydrolysis of its conjugate acid simultaneously
liberating the free amine and mineral acid. In the present work,
the aromatic amines also reacted under lower temperature
without addition of an extra base.
56
65
200 ºC. Moreover, the difference in basicities of amines have
been shown earlier to decrease at elevated temperatures in
aqueous solution, and even reversals in relative base strengths
63
were seen. Thus, the protonation rate of a relatively weak at the
Base strength of amines at high temperatures is well-studied in
61-65
ambient temperature base 2 can be significantly increased at the
the literature.
Because of the higher basicity of the aliphatic

6
Tetrahedron
elevated temperatures even in the presence of an aliphatic base
dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium (4b) iodides in about
ACCEPTED MANUSCRIPT
excess. From this viewpoint, it is clear why the similar reaction
conditions could be applied for the reactions with primary and
secondary aliphatic amines, and why the excess of a reacting
amine could be efficiently replaced with non-reacting
triethylamine. Taking into account these facts one can assume
that the rate of protonation of a relatively weak basic center, the
pyridine nitrogen, in 2a leading to formation of a key
10:1 molar ratio determined by LC/MS (Scheme 3). Similar
halide exchange has been described previously in the case of the
66
synthesis of 2-bromo-pyridine methiodide.
The obtained
mixture of 4a and 4b was considered to simulate intermediate
+
2aH in the reaction with nucleophile. It was treated with an
excess of methylamine (20% methanolic solution) and the full
consumption of the starting material was observed already within
10 min at r.t. yielding corresponding 1,6-dimethyl-7-
(methylamino)-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (5a). A
similar result was obtained for the reaction of 4a and 4b with
excess of aniline (3.0 equiv) at 50 °C after 1 hour giving
corresponding iodide 5b.
+
intermediate 2aH is increased under higher temperature
allowing subsequent nucleophilic substitution.
+
Assuming that the formation of 2aH is a crucial reaction step
+
in the above discussed reaction mechanism S HetarH we have
isolated this intermediate as hydrochloride salt (2a·HCl) to
compare its structure with the structure of starting azaindole 2a.
N
Me
N
N
MeI
I
acetone
Cl
Cl
N
N
o
40 C, 12 h
Me
Me
4
a (92%)
2
a
+
I
RNH2
Me
Me
N
N
MeOH
I
2
a
NHR
I
N
N
5
a: r.t., 10 min
o
Me
Me
5b: 65 C, 30 min
5
a,b
4b (8%)
5
a R = Me, 5b R = Ph
Scheme 3. The synthesis of pyridinium salts 4a and 4b and
their following conversion with methylamine and aniline
giving to 5a and 5b.
From these results one can assume that molecules containing
7
-halo-1
H-pyrrolo[2,3-c]pyridin-6-ium
fragment
possess
extremely high reactivity towards nucleophiles. These results are
also in good agreement with our proposed reaction mechanism
(
Scheme 2) and the data earlier obtained for aromatic
nucleophilic substitution in -halogenopyridines and
-halogenopyridinium salts with hydroxide anion. Namely, the
rate constant ratio of these reactions for 2-chloropyridine and 2-
2
a·HCl
α
α
8
66
Figure 1. Molecular structures of 2a and 2a·HCl according to
X-ray diffraction data. Thermal ellipsoids are shown at the 50%
probability level.
chloropiridinium iodide was defined to be 1:2.6·10 .
. Conclusion
Thus, we have developed an effective pyrrole-2-carboxylic
3
X-Ray diffraction study of 2a and its salt 2a·HCl (Fig. 1)
indicates that the protonation leads to increase of delocalization
of electrons within the pyridine ring. Elongation of the C6-N2
bond up to 1.338(2) Å is observed in 2a·HCl as compared to
acids based synthetic strategy towards 7-amino-6-azaindoles with
variable substituents. Application of a strong mineral acid as
catalyst at high temperature in the final reaction step allows 7-
chloro-6-azaindole derivatives 2 to be used as substrates for
nucleophilic substitution even without any activating electron
withdrawing groups in their molecules, vice versa, in the
presence of an electron donating fused pyrrole ring. The
activation of the heteroaromatic system towards the nucleophilic
substitution proceeds via protonation of the pyridine nitrogen.
1
.300(2) Å ÷ 1.305(2) Å in 2a and the shortening of the C6-Cl1
bond up to 1.707(2) Å (its value in 2a is 1.749(2) Å ÷ 1.755(2)
Å). The latest fact can be considered as an indirect confirmation
of the increased positive charge on the pyridine ring.
To confirm or disprove the assumption that the formation of
+
intermediate 2aH is a key reaction step in the suggested reaction
However, the application of a strong acid, at the same time,
decreases the equilibrium concentration of the reacting
nucleophile, especially in the case of aliphatic amines, which
have higher basicity compared to the aromatic ones. That is why
an excess of the reacting amine has to be generally applied. In
those cases, where the application of the reacting amine excess is
mechanism (Scheme 2) further additional experiments have been
carried out. The use of an activated analog of 2a bearing a stable
+
pyridinium moiety could be applied as a model of 2aH , since
the last is obviously unstable in the presence of base. For this
purpose 7-chloro-6-azaindole 2a was quaternized with methyl
iodide yielding a mixture of 7-chloro- (4a) and 7-iodo-1,6-

7
crushed ice (200 g) and then carefully neutralized with
undesirable, it can be equally substituted by cheap and easily
removable triethylamine used to liberate the nucleophilic reagent.
ACCEPTED MANUSCRIPT
potassium carbonate to pH~10. The resulting mixture was
extracted with ethyl acetate (2 × 100 mL), combined extracts
were evaporated and the residue was flash-chromatographed
on silica-gel (using EtOAc as eluent) yielding the targeted
compound after evaporation.
+
The active intermediate 2aH (Scheme 2) can be easily
obtained in a preparative manner as hydrochloride 2a·HCl, but it
is obviously unstable in the presence of aliphatic amines.
Nevertheless, at the evaluated temperatures under conditions
4
.1.1. 1-Benzyl-7-chloro-1H-pyrrolo[2,3-c]pyridine
+
stated in this paper, 2aH is presumably formed in a reasonable
(
2b)
concentration allowing the reaction to progress. Once formed, the
1
Brownish powder; yield 6.62 g. (91%); m.p. 75-76ºC; H
activated intermediate can efficiently react with nucleophiles
NMR (500 MHz, DMSO-d ) δ 7.93 (d, J = 5.2 Hz, 1H), 7.86
6
+
following the discussed S HetarH mechanism. Thus, the
(d, J = 1.8 Hz, 1H), 7.62 (d, J = 4.7 Hz, 1H), 7.27 - 7.34 (m,
N
+
2
1
1
1
H), 7.19 - 7.26 (m, 1H), 7.01 (d, J = 7.3 Hz, 2H), 6.73 (d, J =
formation of the intermediate 2aH is most likely the rate-
13
.6 Hz, 1H), 5.82 (s, 2H); C NMR (126 MHz, DMSO-d ) δ
6
limiting factor. This statement has another two indirect
confirmations. The aromatic amines are generally considered to
39.4, 137.8, 137.1, 136.5, 133.3, 129.1, 128.5, 127.8, 126.3,
16.0, 102.3, 51.4; LC/MS: m/z = 243.0; Anal. Calcd for
be weaker nucleophiles, but they react at lower temperatures (
i
)
C H ClN : C 69.28%, H 4.57%, Cl 14.61%, N 11.54%;
14
11
2
that correlates with the lower base strength of these amines. As
depicted in Scheme 3, the mixture of quaternized salts 4a and 4b
quickly reacts with both methylamine and aniline showing the
positive charge “fixed” onto the heterocyclic core allows extreme
acceleration of the nucleophilic substitution (ii). This is probably
not an ideal model of the final step in the reaction mechanism,
because of the solvation effects of the reaction media onto
found: C 69.26%, H 4.55%, N 11.57%.
4.1.2. 3-Bromo-7-chloro-1,5-dimethyl-1H-
pyrrolo[2,3-c]pyridine (2c)
1
Brownish powder; yield 5.92 g. (76%); m.p. 75-77 ºC; H
NMR (500 MHz, DMSO-d ) δ 7.79 (s, 1H), 7.18 (s, 1H), 4.05
6
3
1
(
1
3
s, 3H), 2.47 (s, 3H); C NMR (126 MHz, DMSO-d ) δ
6
47.0, 135.9, 135.6(CH), 132.4, 127.1, 111.8(CH), 87.0,
+
intermediate 2aH containing movable proton is obviously
6.8(CH ), 23.3(CH ); LC/MS: m/z = 259.0, 261.0; Anal.
3
3
stronger than that for quaternary salt 4a. This difference also can
Calcd. for C H BrClN : C 41.65%, H 3.11%, Br 30.79%, Cl
9
8
2
+
1
3.66%, N 10.79%; found: C 41.68%, H 3.14%, N 10.77%.
decrease the reactivity of 2aH under the applied reaction
conditions compared to the model quaternary salt.
4
.1.3. 7-Chloro-1-methyl-2-phenyl-1H-pyrrolo[2,3-
We believe that the microwave-assisted acid-catalyzed
nucleophilic heteroaromatic substitution is a powerful method for
the introduction of not only aromatic but also aliphatic amine
residues into the heterocyclic cores that are not limited by 6-
azaindole and can be applied for other ‘‘basic’’ heterocycles.
c]pyridine (2d)
1
Brown solid, yield 6.70 g. (92%); m.p. 79-80 ºC; H NMR
(500 MHz, DMSO-d ) δ 7.93 (d, J = 4.7 Hz, 1H), 7.48 - 7.68
6
13
(m, 6H), 6.72 (s, 1H), 3.99 (s, 3H); C NMR (126 MHz,
DMSO-d ) δ 147.1, 138.0, 135.9, 133.7, 131.3, 130.6, 130.1,
6
1
29.6, 129.3, 115.4, 102.4, 34.7; LC/MS: m/z = 243.0; Anal.
Calcd for C H ClN : C 69.28%, H 4.57%, Cl 14.61%, N
14
11
2
1
1.54%; found: C 69.29%, H 4.54%, N 11.51%.
4
. Experimental section
4
.1.4. 1-Chloro-9-methyl-9H-pyrido[3,4-b] indole
All starting materials were commercially available from
(
2e)
Enamine Ltd, and were used without additional purification.
1
1
White solid; yield 5.73 g. (88%); m.p. 115-116 ºC; H NMR
Melting points are uncorrected. H NMR spectra were
(
500 MHz, DMSO-d ) δ 8.17 (d, J = 6.8 Hz, 1H), 7.95 - 8.12
recorded on a Bruker Avance drx 500 (500 MHz)
6
1
3
(
m, 2H), 7.51 - 7.72 (m, 2H), 7.28 (br. s, 1H), 4.07 (s, 3H);
spectrometer with TMS as an internal standard. C NMR
13
C NMR (126 MHz, DMSO-d ) δ 142.4, 137.8, 132.6, 132.5,
(
126 MHz) were performed on the 500 MHz spectrometer.
6
1
31.4, 129.4, 122.0, 120.7, 120.3, 115.1, 110.9, 32.0; LC/MS:
The synthesis and spectral characteristics of compounds 1a-d
and compound 2a are identical to those described in the
m/z = 217.2; Anal. Calcd for C H ClN : C 66.52%, H 4.19%,
12
9
2
5
1,53
Cl 16.36%, N 12.93%; found: C 66.49%, H 4.21%, N
1
literature.
The preparation of compound 1e is described in
2.92%.
Supporting Information. Copies of NMR spectra were
prepared using ACD/NMR Processor software (academic
edition) and can be found in Supporting Information. LC/MS
4
.2. General procedure for microwave assisted chlorine
spectra were recorded using
a
chromatography/mass
substitution in N1-substituted 7–chloro-6-azaindoles and 1-
chloro-9-methyl-9H-β-carboline
spectrometric system that consists of high-performance liquid
chromatograph equipped with a diode-matrix and mass-
selective detector. Ionization method, chemical ionization
under atmospheric pressure (APCI). Ionization mode,
Method A. In a microwave process vial a mixture of N1-
substituted 7-chloro-6-azaindole (3.0 mmol) and a reacting
amine (9.0 mmol) was diluted with butan-1-ol up to 5 mL
total volume of the reaction mixture. Then methanesulfonic
acid (3.0 mmol, 290 mg) was added and the reaction vessel
was sealed and irradiated with microwaves at 190 ºC for 40
min. After cooling the reaction mixture was worked-up as
described below.
simultaneous scanning of positive ions in the mass range of
1
8
0–1000 m/z. According to HPLC MS and H NMR spectra
data, all synthesized compounds have purity >95%. For all
microwave-assisted reaction Emrys Creator (Biotage)
equipped with magnetic stirrer, pressure sensor and IR-
temperature sensor was used. The reactions were carried out
using microwave process vials for 5 mL maximal reaction
volume. The microwave absorption level was set as ‘high’
meaning that initial MW power was limited by 150 W. The
reaction time corresponds to the time of irradiating at set
temperature (fixed hold time). During all experiments, the
maximal internal pressure never excided the safety limit of 20
bar.
Method B. In a microwave process vial a mixture of N1-
substituted 7-chloro-6-azaindole (3.0 mmol), a reacting amine
(
3.6 mmol), and triethylamine (6.0 mmol, 610 mg) was
diluted with butan-1-ol up to 5 mL total volume of the
reaction mixture. Then methanesulfonic acid (3.0 mmol, 290
mg) was added and the reaction vessel was sealed and
irradiated with microwaves at 190 ºC for 40 min. After
cooling the reaction mixture was worked-up as described
below.
4
.1. General procedure for synthesis of 7-chloro-1H-pyrrolo[2,3-
[22]
c]pyridines (2a-2e)
Oxocompound 1a-e (30.0 mmol) was added portion wise to
Method C. In a microwave process vial a mixture of N1-
substituted 7-chloro-6-azaindole or 1-chloro-9-methyl-9H-β-
carboline (3.0 mmol), a reacting amine hydrochloride (9.0
phosphorus oxychloride (13.8 g., 90.0 mmol) and heated at
1
00 °C for 2 h, the mixture was cooled to r.t. and added to

8
Tetrahedron
mmol) and triethylamine (6.6 mmol, 670 mg) was diluted
Hz, 1H), 7.10 (d, J = 6.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H),
ACCEPTED MANUSCRIPT
with butan-1-ol up to 5 mL total volume of the reaction
mixture. Then the reaction vessel was sealed and irradiated
with microwaves at 190 ºC for 40 min. After cooling the
reaction mixture were worked-up as described below.
6.56 (d, J = 2.3 Hz, 1H), 4.90 (d, J = 5.2 Hz, 2H), 4.27 (s,
13
3H), 3.71 (s, 3H); C NMR (126 MHz, DMSO-d ) δ 159.1,
6
143.0, 138.5, 135.1, 129.5, 129.3, 125.3, 118.8, 114.3, 108.0,
103.0, 55.5, 44.7, 37.8; LC/MS: m/z = 268.2.
Method D. In a microwave process vial a mixture of N1-
substituted 7-chloro-6-azaindole (3.0 mmol) and an aromatic
amine (9.0 mmol) was diluted with butan-1-ol up to 5 mL
total volume of the reaction mixture. Then methanesulfonic
acid (3.0 mmol, 290 mg) was added and the reaction vessel
was sealed and irradiated with microwaves at 160 ºC for 30
min. After cooling the reaction mixture were worked-up as
described below.
4.2.6. N-cyclopentyl-1-methyl-1H-pyrrolo[2,3-
c]pyridin-7-amine (3f)
Brownish solid; yield 0.47 g. (72%); m.p. 75-76 ºC; H NMR
1
(
500 MHz, DMSO-d ) δ 7.55 (d, J = 5.5 Hz, 1H), 7.20 (d, J =
6
1
1
.9 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 6.25 (d, J = 2.2 Hz,
H), 5.50 (d, J = 5.5 Hz, 1H), 4.36 (d, J = 6.3 Hz, 1H), 4.08
(
(
s, 3H), 1.89 - 2.14 (m, 2H), 1.65 - 1.82 (m, 2H), 1.48 - 1.64
13
m, 4H); C NMR (126 MHz, DMSO-d ) δ 146.9, 136.0,
6
1
33.1, 132.0, 121.7, 106.5, 99.8, 52.5, 36.2, 32.7, 23.6;
Work-up procedure. The obtained reaction mixture was
diluted with water (20 mL), potassium carbonate (5.0 g) was
added to the mixture followed by extraction with ethyl acetate
LC/MS: m/z = 216.1; Anal. Calcd for C H N : C 72.52%, H
13
17
3
7
.96%, N 19.52%; found: C 72.54%, H 7.99%, N 19.49%.
(
2×10 mL). The extracts were combined, dried over
4
.2.7. N,1-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-
potassium carbonate and evaporated to dryness. The residue
was purified by column chromatography on silica gel (ethyl
acetate-hexane 1:1 v/v) to afford targeted compound after
evaporation.
amine (3g)
1
White powder; yield 0.40 g. (83%); m.p. 103-104 ºC; H
NMR (500 MHz, DMSO-d ) δ 7.56 (d, J = 5.5 Hz, 1H), 7.19
6
(
d, J = 1.9 Hz, 1H), 6.76 (d, J = 5.8 Hz, 1H), 6.25 (d, J = 2.5
Hz, 1H), 5.98 (br. s, 1H), 4.06 (s, 3H), 2.91 (d, J = 1.0 Hz,
4
.2.1. 1-Methyl-7-(morpholin-4-yl)-1H-pyrrolo[2,3-
c]pyridine (3a)
Brownish powder; yield 0.53 g. (81%); m.p. 107-108 ºC; H
13
3
1
H); C NMR (126 MHz, DMSO-d ) δ 147.6, 136.0, 132.9,
6
31.9, 121.5, 106.3, 99.8, 36.3, 28.6; LC/MS: m/z = 162.2
1
+
[
M+H] ; Anal. Calcd for C H N : C 67.06%, H 6.88%, N
9
11
3
NMR (500 MHz, DMSO-d ) δ 7.80 (d, J = 4.9 Hz, 1H), 7.43
6
26.07%; found: C 67.04%, H 6.89%, N 26.05%.
(
s, 1H), 7.24 (d, J = 4.7 Hz, 1H), 6.46 (s, 1H), 4.07 (s, 3H),
1
3
3
.81 (br. s, 4H), 3.09 (br. s, 4H); C NMR (126 MHz,
4
.2.8. 1-Benzyl-N-methyl-1H-pyrrolo[2,3-c]pyridin-
DMSO-d ) δ 150.4, 136.2, 135.4, 134.2, 125.9, 112.6, 101.2,
6
6
6.6, 52.2, 35.4; LC/MS: m/z = 218.2; Anal. Calcd for
7-amine (3h)
1
C H N O: C 66.34%, H 6.96%, N 19.34%, O 7.36%; found:
Yellow oil; yield 0.48 g. (98%); H NMR (500 MHz, DMSO-
1
2
15
3
C 66.36%, H 6.99%, N 19.32%.
d ) δ 7.63 (d, J = 5.5 Hz, 1H), 7.42 (d, J = 2.9 Hz, 1H), 7.26 -
6
7
6
4
.32 (m, 2H), 7.21 - 7.26 (m, 1H), 7.05 (d, J = 7.01 Hz, 2H),
.84 (d, J = 5.5 Hz, 1H), 6.40 (d, J = 2.9 Hz, 1H), 5.76 (d, J =
4
.2.2. 4-(3-Bromo-1,5-dimethyl-1H-pyrrolo[2,3-
c]pyridin-7-yl)morpholine (3b)
Yellowish solid; yield 0.12 g. (30%); m.p. 153-154 ºC; H
13
.9 Hz, 1H), 5.68 (s, 2H), 2.85 (d, J = 4.4 Hz, 3H); C NMR
(
126 MHz, DMSO-d ) δ 147.5, 139.6, 136.8, 134.2, 132.5,
6
1
1
29.0, 128.9, 127.8, 126.8, 121.2, 106.7, 101.6, 51.9, 29.0;
+
NMR (500 MHz, DMSO-d ) δ 7.60 (s, 1H), 6.91 (s, 1H), 4.02
6
LC/MS: m/z = 238.2 [M+H] ; Anal. Calcd for C H N : C
15 15 3
(
s, 3H), 3.73 - 3.85 (m, 4H), 2.97 - 3.18 (m, 4H), 2.43 (s, 3H);
7
5.92%, H 6.37%, N 17.71%; found: C 75.90%, H 6.37%, N
1
3
C NMR (126 MHz, DMSO-d ) δ 149.6, 145.2, 134.8, 133.2,
6
17.69%.
1
3
5
5
24.0, 108.0, 87.6, 66.5, 52.1, 35.6, 24.1; LC/MS: m/z =
10.0, 312.0; Anal. Calcd for C H BrN O: C 50.34%, H
1
3
16
3
4
.2.9. N,9-dimethyl-9H-pyrido[3,4-b]indol-1-amine
.20%, Br 25.76%, N 13.55%, O 5.16%; found: C 50.36%, H
.18%, N 13.58%.
(3i)
1
Yellowish powder; yield 0.38 g. (78%); m.p. 153-154 ºC; H
NMR (500 MHz, DMSO-d ) δ 8.07 (d, J = 7.7 Hz, 1H), 7.85
6
4
.2.3. 1-Methyl-2-phenyl-7-(pyrrolidin-1-yl)-1H-
(
d, J = 4.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.6
pyrrolo[2,3-c]pyridine (3c)
Yellow solid; yield 0.22 g. (64%); m.p. 83-84 ºC; H NMR
Hz, 1H), 7.36 (d, J = 4.9 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H),
1
13
6
.38 (br. s, 1H), 4.14 (s, 3H); C NMR (126 MHz, DMSO-d )
6
(
500 MHz, DMSO-d ) δ 7.75 (d, J = 5.5 Hz, 1H), 7.65 (d, J =
6
δ 147.5, 141.1, 136.0, 127.0, 126.9, 124.9, 121.1, 121.0,
19.2, 110.3, 105.2, 32.1, 29.0; LC/MS: m/z = 212.1; Anal.
7
7
.4 Hz, 2H), 7.51 (t, J = 7.1 Hz, 2H), 7.41 - 7.48 (m, 1H),
.09 (d, J = 5.2 Hz, 1H), 6.59 (s, 1H), 3.85 (s, 3H), 3.38 - 3.45
1
Calcd for C H N : C 73.91%, H 6.20%, N 19.89%; found: C
1
3
13 13
3
(
m, 4H), 1.73 - 1.98 (m, 4H); C NMR (126 MHz, DMSO-
7
3.94%, H 6.22%, N 19.88%.
d ) δ 149.0, 145.7, 136.3, 134.2, 131.8, 129.2, 128.8, 128.5,
6
1
27.7, 109.9, 101.9, 50.5, 33.6, 23.9; LC/MS: m/z = 278.2
+
4
.2.10. N-Ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-
[
M+H] ; Anal. Calcd for C H N : C 77.95%, H 6.90%, N
1
8
19
3
1
5.15%; found: C 77.93%, H 6.91%, N 15.12%.
7-amine (3j)
1
White powder; yield 0.31 g. (59%); m.p. 85-86 ºC; H NMR
(
500 MHz, DMSO-d ) δ 7.54 (d, J = 5.5 Hz, 1H), 7.19 (d, J =
6
4
7
.2.4. 1-Methyl-N-propyl-1H-pyrrolo[2,3-c]pyridin-
2
.7 Hz, 1H), 6.75 (d, J = 5.5 Hz, 1H), 6.24 (d, J = 3.0 Hz,
H), 5.85 (br. s, 1H), 4.07 (s, 3H), 3.31 - 3.54 (m, J = 5.6,
-amine (3d)
1
7
1
13
White solid; yield 0.43 g. (76%); m.p. 88-89 ºC; H NMR
.00 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); C NMR (126 MHz,
(
500 MHz, DMSO-d ) δ 7.56 (d, J = 5.5 Hz, 1H), 7.20 (d, J =
6
DMSO-d ) δ 147.0, 136.0, 133.1, 131.9, 121.4, 106.3, 99.8,
6
+
2
1
1
.6 Hz, 1H), 6.77 (d, J = 5.7 Hz, 1H), 6.26 (d, J = 2.9 Hz,
3
6.3, 35.7, 15.1; LC/MS: m/z = 176.2 [M+H] ; Anal. Calcd
H), 5.81 - 5.92 (m, 1H), 4.09 (s, 3H), 3.27 - 3.54 (m, 2H),
for C H N : C 68.54%, H 7.48%, N 23.98%; found: C
1
3
10 13
3
.55 - 1.78 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); C NMR (126
6
8.52%, H 7.50%, N 23.97%.
MHz, DMSO-d ) δ 147.4, 136.4, 133.5, 132.3, 121.8, 106.6,
6
1
00.2, 43.3, 36.7, 22.8, 12.1; LC/MS: m/z = 190.2; Anal.
4
.2.11. 1-Benzyl-N-ethyl-1H-pyrrolo[2,3-c] pyridin-
Calcd for C H N : C 69.81%, H 7.99%, N 22.20%; found: C
1
1
15
3
6
9.80%, H 7.82%, N 22.17%.
7-amine (3k)
1
Yellow oil; yield 0.47 g. (91%); H NMR (500 MHz, DMSO-
d ) δ 7.56 (d, J = 5.5 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.26 -
6
4
.2.5. N-(4-methoxybenzyl)-1-methyl-1H-
7
6
2
3
.33 (m, 2H), 7.21 - 7.26 (m, 1H), 7.04 (d, J = 7.1 Hz, 2H),
.80 (d, J = 5.5 Hz, 1H), 6.37 (d, J = 3.0 Hz, 1H), 5.66 (s,
H), 5.40 (br. s, 1H), 3.27 - 3.35 (m, 2H), 1.00 (t, J = 7.1 Hz,
pyrrolo[2,3-c]pyridin-7-amine (3e•HCl)
Was purified by recrystallization from ethanol as
13
hydrochloride. White solid; yield 0.55 g. (60%); m.p. 179-180
H); C NMR (126 MHz, DMSO-d ) δ 146.3, 139.2, 136.4,
1
6
ºC; H NMR (500 MHz, DMSO-d ) δ 8.47 (br. s, 1H), 7.75
6
134.0, 132.4, 128.7, 127.5, 126.3, 120.6, 106.3, 100.9, 51.6,
(
d, J = 2.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 6.2

9
+
3
5.6, 14.8; LC/MS: m/z = 252.2 [M+H] ; Anal. Calcd for
4.4. Synthesis of 1,6-dimethyl-7-(methylamino)-1H-pyrrolo[2,3-
c]pyridin-6-ium iodide (5a)
ACCEPTED MANUSCRIPT
C H N : C 76.46%, H 6.82%, N 16.72%; found: C 76.43%,
1
6
17
3
H 6.83%, N 16.70%.
The mixture of compounds 4a and 4b (200 mg) was added in
one portion to 10 mL of the 20% methanolic solution of
methylamine and stirred at r.t. for 5 min. The clear solution
was evaporated on a rotary evaporator at r.t. to afford 5a as a
white solid. The analytical sample of 5a was prepared by
suspending the obtained solid in a small amount of cold water
followed by filtration and drying under vacuum at r.t. (the
compound should be stored under argon atmosphere while
4
.2.12. N-ethyl-9-methyl-9H-pyrido[3,4-b]indol-1-
amine (3l)
White solid; yield 0.36 g. (69%); m.p. 100-101 ºC; H NMR
1
(
500 MHz, DMSO-d ) δ 8.07 (d, J = 8.0 Hz, 1H), 7.84 (d, J =
6
5
7
1
3
1
3
7
1
.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H),
.35 (d, J = 5.2 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 6.18 (br. s,
H), 4.14 (s, 3H), 3.45 - 3.62 (m, 2H), 1.28 (t, J = 7.0 Hz,
1
3
darkens upon standing on air). Brownish solid, m.p. >150 ºC
1
H); C NMR (126 MHz, DMSO-d ) δ 147.1, 141.2, 136.5,
6
(decomposition); H NMR (500 MHz, DMSO-d ) δ 7.92 (s,
6
27.2, 126.9, 125.0, 121.1, 120.9, 119.1, 110.2, 105.2, 36.1,
1
H), 7.83 (d, J = 4.1 Hz, 1H), 7.44 (d, J = 4.9 Hz, 1H), 6.70
13
2.1, 15.0; LC/MS: m/z = 226.2; Anal. Calcd for C H N : C
1
4
15
3
(s, 2H), 4.14 (s, 3H), 4.02 (s, 3H), 3.16 (s, 3H); C NMR
4.64%, H 6.71%, N 18.65%; found: C 74.67%, H 6.70%, N
(
126 MHz, DMSO-d ) δ 146.8, 140.6, 136.2, 132.2, 123.6,
6
+
8.66%.
1
10.6, 102.9, 42.2, 36.9, 36.2; LC/MS: m/z = 176.1 [M] .
4
7
.2.13. N,N,1-trimethyl-1H-pyrrolo[2,3-c]pyridin-
4
.5. Synthesis of 1,6-dimethyl-7-(phenylamino)-1H-pyrrolo[2,3-
-amine (3m)
c]pyridin-6-ium iodide (5b)
1
Yellow oil; yield 0.42 g. (80%); H NMR (500 MHz, DMSO-
d ) δ 7.77 (d, J = 5.5 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.17
The mixture of compounds 4a, 4b (300 mg) and aniline (0.45
g, 5 equiv) were heated at reflux in 20 mL of MeOH for 30
min. The clear solution was evaporated on a rotary evaporator
at r.t. and the residue was recrystallised from a small amount
of water to afford 5b (220 mg, 62%) as a white solid (the
compound should be stored under argon atmosphere while
6
(
d, J = 5.2 Hz, 1H), 6.44 (d, J = 2.9 Hz, 1H), 4.04 (s, 3H),
1
3
2
1
1
7
.79 (s, 6H); C NMR (126 MHz, DMSO-d ) δ 151.5, 136.0,
6
35.1, 133.9, 125.7, 111.9, 101.2, 43.6, 35.2; LC/MS: m/z =
+
76.2 [M+H] ; Anal. Calcd for C H N : C 68.54%, H
1
0
13
3
.48%, N 23.98%; found: C 68.55%, H 7.45%, N 23.97%.
darkens upon standing on air). Brownish solid, m.p. >150 ºC
1
(
decomposition); H NMR (500 MHz, DMSO-d ) δ 9.38 (s,
6
4
.2.14. N-(4-chlorophenyl)-1-methyl-1H-
1
H), 8.33 (d, J = 5.5 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J = 5.8
pyrrolo[2,3-c]pyridin-7-amine (3o)
White solid; yield 0.61 g. (79%); m.p. 123-124 ºC; H NMR
500 MHz, DMSO-d ) δ 8.33 (br. s, 1H), 7.72 (d, J = 4.9 Hz,
Hz, 1H), 7.29 (s, 2H), 6.84 - 7.05 (m, 2H), 6.75 (d, J = 6.6 Hz,
1
13
2H), 4.08 (s, 3H), 3.80 (s, 3H); C NMR (126 MHz, DMSO-
(
1
d ) δ 143.6, 143.0, 139.0, 137.8, 134.0, 130.0, 128.2, 121.5,
6
6
+
H), 7.40 (br. s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.5
115.5, 114.9, 103.2, 42.2, 36.1; LC/MS: m/z = 238.2 [M] .
Hz, 2H), 7.16 (d, J = 4.9 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H),
1
3
4
1
3
.07 (s, 3H); C NMR (126 MHz, DMSO-d ) δ 142.5, 141.9,
6
4
.6. X-Ray diffraction study
35.6, 135.0, 133.9, 128.3, 124.2, 123.1, 119.4, 110.9, 100.3,
5.9; LC/MS: m/z = 258.1 [M+H] ; Anal. Calcd for
+
The crystals of 2a (C H N Cl) are monoclinic. At 293 K a =
8
7
2
C H ClN : C 65.25%, H 4.69%, Cl 13.76%, N 16.30%;
1
4
12
3
1
,
d
4.0663(9), b = 15.1942(9), c = 7.5353(5) Å,
β
= 104.388(6)
°
found: C 65.22%, H 4.66%, N 16.28%.
3
V = 1560.0(2) Å , Mr = 166.61, Z = 8, space group P2 /c,
1
3
-1
= 1.419 g/cm , µ(MoKα) = 0.417 mm , F(000) = 688.
calc
4
.2.15. 1-Methyl-N-phenyl-1H-pyrrolo[2,3-
c]pyridin-7-amine (3p)
White solid; yield 0.5 g. (79%); m.p. 134-135 ºC; H NMR
500 MHz, DMSO-d ) δ 8.17 (br. s, 1H), 7.71 (d, J = 5.2 Hz,
Intensities of 15619 reflections (4546 independent, R
=
int
0.043) were measured on the«Xcalibur-3» diffractometer
1
(graphite monochromated MoK radiation, CCD detector, ω-
α
scaning, 2Θ = 60°).
max
(
6
1
H), 7.39 (br. s, 1H), 7.30 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.4
Hz, 2H), 7.14 (d, J = 5.2 Hz, 1H), 6.84 (t, J = 7.0 Hz, 1H),
The crystals of 2a·HCl (C
8
H
8
N
2
Cl ) are monoclinic. At 293 K
2
13
6
.41 (br. s, 1H), 4.06 (s, 3H); C NMR (126 MHz, DMSO-d )
6
a = 8.487(2), b = 13.020(1), c = 8.5440(8) Å, β = 103.55(2)°,
3
δ 143.7, 142.4, 135.8, 134.9, 133.7, 128.5, 124.3, 119.8,
V = 917.8(3) Å , Mr = 203.06, Z = 4, space group P2
/n, dcalc=
1
+
3
-1
1
17.9, 110.6, 100.2, 35.8; LC/MS: m/z = 224.2 [M+H] ; Anal.
1.470 g/cm ,
Intensities of 4702 reflections (2663 independent, Rint
0.017) were measured on the«Xcalibur-3» diffractometer
µ(MoKα) = 0.650 mm , F(000) = 416.
Calcd for C H N : C 75.31%, H 5.87%, N 18.82%; found: C
=
1
4
13
3
7
5.32%, H 5.89%, N 18.84%.
(
graphite monochromated MoK radiation, CCD detector, ω-
α
scaning, 2Θ = 60°).
max
4
.3. Reaction of 2a with methyl iodide. Synthesis of 7-chloro-1,6-
dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (4a) and 7-iodo-
,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (4b)
The structures were solved by direct method using SHELXTL
1
67
package. Position of the hydrogen atoms were located from
electron density difference maps and refined in isotropic
approximation. Full-matrix least-squares refinement of the
Compound 2a (5 g, 30 mmol) was dissolved in dry acetone
100 mL) followed by addition of methyl iodide (3 equiv., 4.3
(
g.). The mixture was heated at 40 °C for 12 h. The
precipitated product was filtered off, washed with dry acetone
and dried at r.t. under vacuum. According to LC/MS analysis
the resulting solid is a mixture of 7-chloro-1,6-dimethyl-1H-
pyrrolo[2,3-c]pyridin-6-ium iodide (92%) 4a and 7-iodo-1,6-
dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (8%) 4b.
Total yield 7.13 g (77%).
2
structures against F in anisotropic approximation for non-
hydrogen atoms using 4493 (2a), 2580 (2a
·HCl) reflections was
converged to: wR = 0.120 (R = 0.050 for 2409 reflections with
2
1
F>4
for 1873 reflections with F>4
HCl. The final atomic coordinates, and crystallographic data
for molecules 2a and 2a HCl have been deposited to with the
Cambridge Crystallographic Data Centre, 12 Union Road, CB2
1EZ, UK (fax: +44-1223-336033; e-mail:
σ(F), S = 0.937) for structure 2a and wR = 0.103 (R = 0.039
2 1
σ
(F), S = 0.963) for structure
2a·
·
4
.3.1. 7-chloro-1,6-dimethyl-1H-pyrrolo[2,3-
c]pyridin-6-ium iodide (4a)
1
H NMR (500 MHz, DMSO-d ) δ 8.52 (d, J = 6.9 Hz, 1H),
6
deposit@ccdc.cam.ac.uk) and are available on request quoting
the deposition numbers CCDC 961706 for 2a and CCDC 961707
8
2
.33 (d, J = 2.5 Hz, 1H), 8.10 (d, J = 6.6 Hz, 1H), 6.96 (d, J =
13
.7 Hz, 1H), 4.34 (s, 3H), 4.25 (s, 3H); C NMR (126 MHz,
DMSO-d ) δ 145.3, 138.5, 135.3, 132.9, 129.1, 116.2, 103.1,
6
for 2a
·HCl).
4
6
5.7, 37.5; For 7-iodo-1,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-
1
-ium iodide admixture (4a) the resulted signals in H NMR
Acknowledgments
(
500 MHz, DMSO-d ) δ (other signals are overlapped with
6
signals of the main product 4a) LC/MS (mix): m/z = 181.1
4a), 273.0 (4b).
(

1
0
Tetrahedron
Authors are very thankful to Prof. Nikolay O. Mchedlov-
22. Wensbo, D.; Eriksson, A.; Jeschke, T.; Annby, U.; Gronowitz,
ACCEPTED MANUSCRIPT
Petrossyan, (V. N. Karazin Kharkiv National University) for his
valuable discussion of the physico-chemical aspects of this work.
S.; Cohen, L. A. Tetrahedron Lett. 1993, 34, 2823.
2
2
2
3. Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355.
4. Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42, 6441.
5. Riether, D.; Harcken, C.; Razavi, H.; Kuzmich, D.; Gilmore, T.;
Bentzien, J. r.; Pack, E. J.; Souza, D.; Nelson, R. M.; Kukulka,
A.; Fadra, T. N.; Zuvela-Jelaska, L.; Pelletier, J.; Dinallo, R.;
Panzenbeck, M.; Torcellini, C.; Nabozny, G. H.; Thomson, D.
S. J. Med. Chem. 2010, 53, 6681.
Supplementary Material
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.tet...
References and notes
2
6. Livecchi, M.; Calvet, G.; Schmidt, F. J. Org. Chem. 2012, 77,
5
006.
1
2
.
.
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
Popowycz, F.; Mérour, J.-Y.; Joseph, B. Tetrahedron 2007, 63,
2
2
7. Rousseau, J.-F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731.
8. Johnson, T. W.; Tanis, S. P.; Butler, S. L.; Dalvie, D.; DeLisle,
D. M.; Dress, K. R.; Flahive, E. J.; Hu, Q.; Kuehler, J. E.; Kuki,
A.; Liu, W.; McClellan, G. A.; Peng, Q.; Plewe, M. B.;
Richardson, P. F.; Smith, G. L.; Solowiej, J.; Tran, K. T.; Wang,
H.; Yu, X.; Zhang, J.; Zhu, H. J. Med. Chem. 2011, 54, 3393.
9. Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651.
0. Allen, J. R. F.; Holmstedt, B. R. Phytochemistry 1980, 19, 1573.
1. Herraiz, T. In Bioactive Compounds in Foods; Gilbert, J.;
Şenyuva, H. Z. Eds.; Blackwell Publishing Ltd., 2009; pp. 199.
2. Yutthapong, S.; Sakulkeo, O.; Yuenyongsawad, S.; Kanjana-
opas, A.; Ingkaninan, K.; Plubrukarn, A.; Suwanborirux, K.
Marine Drugs 2008, 6, 578.
8
689.
3
4
.
.
Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y.
Tetrahedron 2007, 63, 1031.
Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120.
Zhao, S.-B.; Wang, S. Chem. Soc. Rev. 2010, 39, 3142.
Hyaric, M.; Viera, d. A. M.; Nora, d. S. M. V. Quim. Nova
2
3
3
5
6
.
.
2
002, 25, 1165.
7
8
.
.
Scios Inc. Exp. Opin. Ther. Patents 2005, 15, 227.
Kadow, J. F.; Bender, J.; Regueiro-Ren, A.; Ueda, Y.; Wang, T.;
Yeung, K.-S.; Meanwell, N. A. In Antiviral Drugs: From Basic
Discovery through Clinical Trials; Kazmierski, W. M. Ed.; John
Wiley & Sons, Inc., 2011; pp. 149.
Plewe, M. B.; Johnson, T. W. In HIV-1 Integrase: Mechanism
and Inhibitor Design; Neamati, N. Ed.; John Wiley & Sons,
Inc., 2011; pp. 265.
3
3
3. Das, S.; Brown, J. W.; Dong, Q.; Gong, X.; Kaldor, S. W.; Liu,
Y.; Paraselli, B. R.; Scorah, N.; Stafford, J. A.; Wallace, M. B.
Int. Patent Appl. 044779A1, 2007; Chem. Abstr. 2007, 146,
9
.
4
41771.
3
4. Brown, J. W.; Dong, Q.; Gangloff, A. R.; Paraselli, B. R.;
Stafford, J. A.; Scorah, N.; Salsbury, J. S.; Das, S. Int. Patent
Appl. 129401A1, 2009; Chem. Abstr. 2009, 151, 491106.
1
1
0. Matter, H.; Scheiper, B.; Steinhagen, H.; Böcskei, Z.; Fleury,
V.; McCort, G. Bioorg. Med. Chem. Lett. 2011, 21, 5487.
1. Filla, S. A.; Mathes, B. M.; Johnson, K. W.; Phebus, L. A.;
Cohen, M. L.; Nelson, D. L.; Zgombick, J. M.; Erickson, J. A.;
Schenck, K. W.; Wainscott, D. B. J. Med. Chem. 2003, 46,
3
3
5. Kadow, J. F.; Regueiro-Ren, A. US Patent Appl. 0142298A1,
2
006; Chem. Abstr. 2006, 145, 103690
6. Wang, T.; Kadow, J. F.; Meanwell, N. A.; Yeung, K.-S.; Zhang,
Z.; Yin, Z.; Qiu, Z.; Deon, D. H.; James, C. A.; Ruediger, E. H.;
Bachand, C. Int. Patent Appl. 0186292A1, 2004; Chem. Abstr.
3
060.
1
2. Plewe, M. B.; Butler, S. L.; R. Dress, K.; Hu, Q.; Johnson, T.
W.; Kuehler, J. E.; Kuki, A.; Lam, H.; Liu, W.; Nowlin, D. J.
Med. Chem. 2009, 52, 7211.
2
004, 141, 296001.
3
3
3
4
7. Regueiro-Ren, A.; Swidorski, J.; Liu, Z.; Wang, T.; Zhang, Z.;
Hamann, L. G.; Meanwell, N. A.; Carini, D. J.; Li, W. Int.
Patent Appl. 158396A1, 2009; Chem. Abstr. 2009, 152, 119660.
8. Kim, J. T.; Hamilton, A. D.; Bailey, C. M.; Domoal, R. A.;
Wang, L.; Anderson, K. S.; Jorgensen, W. L. J. Am. Chem. Soc.
1
1
1
1
1
1
3. Andaloussi, M.; Moreau, E.; Chavignon, O.; Teulade, J. C.
Tetrahedron Lett. 2007, 48, 8392.
4. Linz, S.; Müller, J.; Hübner, H.; Gmeiner, P.; Troschütz, R.
Bioorg. Med. Chem. 2009, 17, 4448.
5. Zhu, J.; Wong, H.; Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow,
J. F.; Wang, T. Tetrahedron Lett. 2006, 47, 5653.
6. Roy, P. J.; Dufresne, C.; Lachance, N.; Leclerc, J. P.; Boisvert,
M.; Wang, Z.; Leblanc, Y. Synthesis 2005, 2751.
7. Yoon, Y.; Kim, D. H.; Lee, B. M.; Kim, T. K.; Cha, M. H.; Sim,
J. Y.; Kim, J. G. Bioorg. Med. Chem. Lett. 2010, 20, 5237.
8. Blaazer, A. R.; Lange, J. H. M.; van der Neut, M. A. W.;
Mulder, A.; den Boon, F. S.; Werkman, T. R.; Kruse, C. G.;
Wadman, W. J. Eur. J. Med. Chem. 2011, 46, 5086.
9. Giblin, G. M. P.; Billinton, A.; Briggs, M.; Brown, A. J.;
Chessell, I. P.; Clayton, N. M.; Eatherton, A. J.; Goldsmith, P.;
Haslam, C.; Johnson, M. R.; Mitchell, W. L.; Naylor, A.;
Perboni, A.; Slingsby, B. P.; Wilson, A. W. J. Med. Chem.
2
006, 128, 15372.
9. Eatherton, A. J.; Giblin, G. M. P.; Johnson, M. R.; Mitchell, W.
L.; Perboni, A.; Slingsby, B. P. Int. Patent Appl. 121140A1,
2
005; Chem. Abstr. 2005, 144, 69741.
0. Choi, R.; Kim, J.-G.; Ahn, B.-N.; Lee, H.-W.; Yoon, S.-W.;
Yoon, Y.-A.; Kim, D.-H.; Park, C.-S.; Han, S.-H.; Cha, M.-H.;
Kang, H.-I. Int. Patent Appl. 025717A1, 2006; Chem. Abstr.
2
006, 144, 292741.
4
1. Choi, R.; Kim, J.-G.; Ahn, B.-N.; Lee, H.-W.; Yoon, S.-W.;
Yoon, Y.-A.; Kim, D.-H.; Park, C.-S.; Han, S.-H.; Cha, M.-H.;
Kang, H.-I. Int. Patent Appl. 25716A1, 2006; Chem. Abstr.
1
2
011, 155, 40964.
4
4
4
2. Hasuoka, A.; Arikawa, Y. Int. Patent Appl. 011670A1, 2006;
Chem. Abstr. 2006, 144, 150354
3. Liou, J.-P.; Chang, J.-Y. Int. Patent Appl. 019634A2, 2011;
Chem. Abstr. 2011, 154, 234673
4. Ma, C.; Cao, R.; Shi, B.; Zhou, X.; Ma, Q.; Sun, J.; Guo, L.; Yi,
W.; Chen, Z.; Song, H. Eur. J. Med. Chem. 2010, 45, 5513.
2
009, 52, 5785.
2
2
0. Zhang, Z.; Yang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T.
J. Org. Chem. 2002, 67, 2345.
1. Walsh, T. F.; Toupence, R. B.; Ujjainwalla, F.; Young, J. R.;
Goulet, M. T. Tetrahedron 2001, 57, 5233.

1
1
4
4
5. Boursereau, Y.; Coldham, I. Bioorg. Med. Ch
A
em
C
. L
C
et
E
t.
P
20
TED
4, MANUSCRIPT
04
, 1
5
841.
6. Thompson, M. J.; Louth, J. C.; Little, S. M.; Jackson, M. P.;
Boursereau, Y.; Chen, B.; Coldham, I. ChemMedChem 2012, 7,
5
78.
4
4
7. Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
8. Yermolayev, S. A.; Gorobets, N. Y.; Desenko, S. M. J. Comb.
Chem. 2009, 11, 44.
4
9. Yermolayev, S. A.; Gorobets, N. Y.; Lukinova, E. V.; Shishkin,
O. V.; Shishkina, S. V.; Desenko, S. M. Tetrahedron 2008, 64,
4
649.
5
5
5
0. Yermolayev, S. A.; Gorobets, N. Y.; Shishkin, O. V.; Shishkina,
S. V.; Leadbeater, N. E. Tetrahedron 2011, 67, 2934.
1. Nechayev, M. A.; Gorobets, N. Y.; Borisov, A. V.; Kovalenko,
S. M.; Tolmachev, A. A. Mol. Divers. 2012, 16, 749.
2. Lu, R.-J.; Tucker, J. A.; Zinevitch, T.; Kirichenko, O.;
Konoplev, V.; Kuznetsova, S.; Sviridov, S.; Pickens, J.; Tandel,
S.; Brahmachary, E.; Yang, Y.; Wang, J.; Freel, S.; Fisher, S.;
Sullivan, A.; Zhou, J.; Stanfield-Oakley, S.; Greenberg, M.;
Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs, P.; Khasanov, A.;
Ma, Y.-A.; Jeffries, C.; Liu, C.; Proskurina, T.; Zhu, T.;
Chucholowski, A.; Li, R.; Sexton, C. J. Med. Chem. 2007, 50,
6
535.
5
3. Nechayev, M. A.; Gorobets, N. Y.; Kovalenko, S. M.;
Tolmachev, A. A. Synthesis 2013, 45, 919.
5
5
5
5
4. Banks, C. K. J. Am. Chem. Soc. 1944, 66, 1127.
5. Morley, J. S.; Simpson, J. C. E. J. Chem. Soc. 1949, 1014.
6. Maggiolo, A.; Phillips, A. P. J. Org. Chem. 1951, 16, 376.
7. Perrault, W. R.; Shephard, K. P.; LaPean, L. A.; Krook, M. A.;
Dobrowolski, P. J.; Lyster, M. A.; McMillan, M. W.; Knoechel,
D. J.; Evenson, G. N.; Watt, W.; Pearlman, B. A. Org. Process
Res. Dev. 1997, 1, 106.
5
5
6
6
8. Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273.
9. Vlasov, V. M. Russ. Chem. Rev. 2003, 72, 681.
0. Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
1. Hetzer, H. B.; Bates, R. G.; Robinson, R. A. J. Phys. Chem.
1
966, 70, 2869.
6
6
6
2. Bolton, P. D.; Hall, F. M. Aust. J. Chem. 1967, 20, 1797.
3. Mesmer, R. E.; Hitch, B. F. J. Solution Chem. 1977, 6, 251.
4. Tremaine, P. R.; Shvedov, D.; Xiao, C. J. Phys. Chem. B 1997,
1
01, 409.
6
6
6
5. Ridley, M. K.; Xiao, C.; Palmer, D. A.; Wesolowski, D. J. J.
Chem. Eng. Data 2000, 45, 502.
6. Barlin, G. B.; Benbow, J. A. J. Chem. Soc., Perkin Trans. 2
1
974, 790.
7. Sheldrick G. M. SHELXTL PLUS. PC Version. A System of
Computer Programs for the Determination of Crystal Structure
from X-ray Diffraction Data. Rev. 5.1, 1998.

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Supplemental Material
Microwave-Assisted Acid-Catalyzed
Nucleophilic Heteroaromatic Substitution:
the Synthesis of 7-Amino-6-azaindoles
Maxim A. Nechayev, Nikolay Yu. Gorobets, Svetlana V. Shishkina,
Oleg V. Shishkin, Sergiy M. Kovalenko
Synthesis of 9-methyl-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one 1e
MeO
OMe
OH
O
NH
O
NH
O
1
.MeI, DMF, NaH
CDI, DXN
N
N
2. TFA, r.t.
N
Me
H
H
1e
Amide-coupling procedure (synthesis of N-(2,2-dimethoxyethyl)-1H-indole-2-carboxamide)
Indole-2carboxylic acid (100 mmol) was suspended in 200 mL of dry dioxane and heated to
6
0°C then CDI (100 mmol) was added portion wise. The reaction mixture was stirred at this
temperature until no more liberation of CO is observed then 2,2-dimethoxyethanamine was
2
added in one portion. The mixture was heated at 70°C for 3 hours. The solvent was removed on a
rotary evaporator, residue was dissolved in 100 mL of ethyl acetate and extracted three times
with 100 mL portions of water following by flash chromatography (ethyl acetate as eluent)
1
yielding the compound . H NMR (500 MHz, DMSO-d ) δ 11.60 (br. s., 1H), 8.57 (br. s., 1H),
6
7
1
.63 (d, J = 7.53 Hz, 1H), 7.46 (d, J = 7.78 Hz, 1H), 7.12 - 7.27 (m, 2H), 7.05 (t, J = 7.14 Hz,
1
3
H), 4.54 (d, J = 5.19 Hz, 1H), 3.42 (br. s., 2H), 3.33 (d, J = 1.56 Hz, 6H); C NMR (126 MHz,
DMSO-d ) δ 161.7, 136.9, 132.0, 127.6, 123.8, 122.0, 120.2, 112.8, 103.3, 102.6, 53.8, 41.2;
6

ACCEPTED MANUSCRIPT
Synthesis of 9-methyl-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one 1e
Amidoacetal (50 mmol) was dissolved in 40 mL of dry DMF and the mixture was cooled to 0°C.
Sodium hydride (60% in mineral oil, 55 mmol) was added portion wise with stirring to the
cooled solution. The mixture was stirred for 20 min and then heated to 50°C and stirred at this
temperature for additional 30 min, then cooled to rt. Methyl iodide (55 mmol) was added portion
wise in such a rate to keep temperature below 40°C and then the mixture was stirred at 50°C for
5
h. The resulted reaction mixture was extracted two times with hexane (30 mL) to remove
mineral oil, DMF was evaporated under reduced pressure, the residue was dissolved in 50 mL of
ethyl acetate and extracted three times with 50 mL portions of water followed by flash
chromatography (using ethyl acetate as an eluent) yielding the product as oily substance. This
was added in one portion at r.t. to vigorously stirred trifluoroacetic acid (50 mL). The mixture
was stirred for 12 h and then methyl alcohol (100 mL) was added to the reaction media. The
precipitate was filtered off, washed with MeOH (50 mL) and water (100 mL), then suspended in
water (150 mL). Potassium carbonate was added to this suspension to make pH ~ 10 and the
1
product was filtered off, washed with water to give compound 1e as a white solid. H NMR (500
MHz, DMSO-d ) δ 11.33 (br. s., 1H), 8.03 (d, J = 7.53 Hz, 1H), 7.58 (d, J = 8.30 Hz, 1H), 7.49
6
(t, J = 7.53 Hz, 1H), 7.22 (t, J = 7.14 Hz, 1H), 7.09 (d, J = 6.49 Hz, 1H), 6.98 (d, J = 6.75 Hz,
1
3
1
1
H), 4.24 (s, 3H); C NMR (126 MHz, DMSO-d ) δ 156.9, 140.7, 127.2, 127.0, 125.4, 125.1,
6
21.8, 121.6, 120.2, 110.8, 100.1, 31.5;

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1 13
Copies of H nad C NMR-spectra.
The NMR reports were created by ACD/NMR Processor Academic Edition (for more information go to www.acdlabs.com/nmrproc/).
1
H DMSOd6

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13
C DMSOd6

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H DMSOd6

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C DMSOd6

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C DMSOd6

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H DMSOd6
N
N
Cl
2b

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C DMSOd6
N
N
Cl
2b

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C DMSOd6
N
N
Cl
2b

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H DMSOd6
Br
N
Cl
N
2
c

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C DMSOd6
Br
N
Cl
N
2
c

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H DMSOd6
2
d

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C DMSOd6
2
d

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C DMSOd6
2
d

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H DMSOd6
2
e

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C DMSOd6
2
e