A New Synthesis of 2-Aminoindoles and 6-Aminopyrrolo[3,2- d ]pyrimidines from π-Deficient 1,2-Dihaloarenes and Geminal Enediamines

Article abstract of DOI:10.1055/s-0035-1561645

An efficient approach for the synthesis of fused 2-aminopyrroles via geminal enediamines and π-deficient 1,2-dihaloarenes is presented. The two-step methodology includes aromatic nucleophilic substitution of the activated halogen of dihaloarene with enediamine C-nucleophilic center followed by Cu-catalyzed intramolecular N-arylation. This approach allows access to a variety of 2-amino-6-nitroindoles and 6-aminopyrrolo[3,2-d]pyrimidines (including N-mono- and N,N-disubstituted) in moderate and good yields under mild conditions.

Full text of DOI:10.1055/s-0035-1561645

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
M. S. Mishina et al.
Paper
Synthesis
A New Synthesis of 2-Aminoindoles and 6-Aminopyrrolo[3,2-
d]pyrimidines from π-Deficient 1,2-Dihaloarenes and Geminal
Enediamines
H
Maria S. Mishina
Alexander Yu. Ivanov
Pavel S. Lobanov
Dmitrii V. Dar’in*
R2 = R3 = H,
N
R2 + R3 = (CH2)4
NR2R3
R1
EWG
O2N
Br
F
O
R1
NR2R3
CuI/L-proline
Cs2CO3
DMSO
Hal
O
NH2
NR2R3
H2N
EWG
St. Petersburg State University, 198504 St. Petersburg,
Russian Federation
d.dariin@spbu.ru
R3
r.t. or 60 °C
DMF or DMSO
65–85 °C
50–80%
I
N
N
R1 = OEt
R1
O
NH2
CO2Et
EWG
EWG
X
N
Cl
R2 = H
3 = Me, Ar
X = SMe, SO2Me
R
H
N
NHR3
32–68%
for 2 steps
15 examples
CO2Et
Received: 26.02.2016
Accepted after revision: 18.04.2016
Published online: 24.05.2016
Currently known methods for the synthesis of 2-amino-
indoles cannot be considered as universal and are often
quite laborious,7 therefore the development of new ap-
proaches to the synthesis of the functional derivatives of 2-
aminoindoles and their aza-analogues is an important syn-
thetic task. One of the most effective and rapidly growing
strategies of the construction of the indole ring is the cy-
clization of β-(aryl)enamines, occurring as intramolecular
N-arylation.8 These concepts inspired us to develop a new
synthetic approach to the fused 2-aminopyrroles using
geminal enediamines.
DOI: 10.1055/s-0035-1561645; Art ID: ss-2016-z0140-op
Abstract An efficient approach for the synthesis of fused 2-aminopyr-
roles via geminal enediamines and π-deficient 1,2-dihaloarenes is pre-
sented. The two-step methodology includes aromatic nucleophilic sub-
stitution of the activated halogen of dihaloarene with enediamine C-
nucleophilic center followed by Cu-catalyzed intramolecular N-aryla-
tion. This approach allows access to a variety of 2-amino-6-nitroindoles
and 6-aminopyrrolo[3,2-d]pyrimidines (including N-mono- and N,N-
disubstituted) in moderate and good yields under mild conditions.
Not only are geminal enediamines 1, also called ketene
aminals, effective precursors for 2-aminopyridines and 2-
aminopyrroles,9a but they are also widely used in the syn-
thesis of various fused α-aminoazaheterocyclic systems.9b
In our previous work, we demonstrated the possibility of
producing fused α-aminopyrroles via the interaction of cy-
clic ketene aminal – ethyl 2-(imidazolidin-2-ylidene)ace-
tate – with π-deficient ortho-dihaloarenes (Scheme 1).10 In
the present work, we report on our investigation on this
synthetic approach extended to a number of acyclic enedi-
amines. The synthesis starting from geminal enediamines 1
and dihaloarenes 2 and 3a,b includes two steps. The first
step is the noncatalyzed aromatic nucleophilic substitution
of the activated halogen atom leading to intermediate com-
pounds 4, 7, and 8. The second step is the Cu(I)-catalyzed
cyclization resulting in the corresponding 2-aminoindoles
5, 6, and 6-aminopyrrolo[3,2-d]pyrimidines 9, 10, and 11
(Scheme 2).
Keywords 2-aminoindoles, pyrrolo[3,2-d]pyrimidines, geminal enedi-
amines, cyclization, copper catalyst, N-arylation
Indoles always attracted the interest of synthetic chem-
ists, which continues to grow in recent years.1 This is due to
the fact that the indole ring is found in many naturally oc-
curring compounds (tryptamine, serotonin, melatonin, etc.,
and indole alkaloids and terpenoids).2 Wide range of com-
pounds containing indole fragment in their structure
demonstrate various type of biological activity and are im-
portant from the pharmacological point of view.3 Moreover,
indole derivatives are widely used in agrochemistry, dyes
and pigments, and essential oils.4 In this connection, the
development of new effective approaches to the synthesis
of functionalized indole derivatives is strongly desired.
Heterocyclic systems with heteroatoms in the six-mem-
bered ring of the indole are also attractive for chemists and
biologists due to their remarkable pharmacological proper-
ties.5 However, there are only a few reported literature ex-
amples of the synthesis of such heterocyclic systems.6
The choice of starting dihaloarenes 2 and 3a,b was
mainly determined by the possibility of the first step of the
synthesis – aromatic nucleophilic substitution of the acti-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

B
M. S. Mishina et al.
Paper
Synthesis
Previous work:
O2N
I
Br
F
N
MeS
N
Cl
N
O2N
N
3a
2
HN
N
NH
NH
a, b
a, b
EtO2C
N
N
MeS
H
CO2Et
CO2Et
a) DMF, 80 °C
b) CuI/L-proline, Cs2CO3, DMSO, r.t.
Scheme 1 A new synthetic approach to fused imidazolinopyrroles via ethyl 2-(imidazolidin-2-ylidene)acetate
vated halogen atom. The progress of this reaction is provid-
ed by the high π-deficiency of selected dihaloarenes. Enedi-
amines are known as moderate C-nucleophiles. In the reac-
tions with the active haloarenes, the products of halogen
atom substitution by the carbon nucleophilic center are
formed.11 Bromofluorobenzene 2 and iodochloropyrimi-
dine 3b are sufficiently reactive and react smoothly with all
studied enediamines. At the same time 1,2-dichloro-4-ni-
trobenzene and 3-bromo-4-fluorobenzonitrile (similar to
arene 2) were not active enough and did not react with ene-
diamine 1а. Iodochloropyrimidine 3а reacted with more
active enediamines 1a,c, but its reactivity was not enough
for the reaction with less active enediamine 1b. Oxidation
of methylsulfanyl group in the pyrimidine 3a led to the ex-
pected increase in the π-deficit and the reactivity of the re-
sulting chloropyrimidine 3b.
hydrochloride to the free base form, diisopropylethylamine
(DIPEA) or K2CO3 were used as a base.
Reactions of enediamines 1a–h with bromofluoroben-
zene 2 leading to the formation of the compounds 4 were
performed in DMF or DMSO under moderate heating. In
most cases reactions occurred smoothly in moderate to
good yields (Tables 1 and 2). Generally compounds 4 were
isolated in pure form and fully characterized. However,
thorough purification prior to the cyclization step usually
was not required, only fairly rough treatment of the reac-
tion mixture was sufficient, as was done in the case of com-
pound 4d (Table 1, entry 4). Synthesis of indole 5c was per-
formed as a one-pot procedure, without any workup of the
reaction mixture after the first step (Table 1, entry 3). How-
ever, it must be realized that such an approach cannot be
extended to all syntheses. In some cases, the attempts to
perform the both steps of synthesis consecutively without
workup after first reaction led to a significantly lower yield
of the target product.
Enediamines 1a,b were used in the reaction as a free
base, whereas enediamines 1e–h were used as hydrochlo-
rides. In the case of enediamines 1c and 1d, hydrochlorides
as well as free base gave good results. In order to transfer
The cyclization step was performed under conditions
we had developed previously,9 namely using the catalyst
This work:
O2N
Br
F
R2
Br
O2N
H
O2N
NH2
NR2R3
O2N
N
N
2
b
NR2R3
R1
NH2
R1
a
O
R1
O
O
O
NH2
6
4
5
NR2R3
N
R1
1
I
R2
H
I
N
N
N
NH2
NR2R3
N
X
N
3a,b
Cl
N
NR2R3
R1
NH2
R1
b
X
N
X
N
X
N
a
O
R1
O
O
7,8
9,10
11
R1= OEt, Ph,
; R2, R3 = H, Alk, Ar
N
3a X = SMe, 3b SO2Me
a) DMF or DMSO, 65–85 °C
b) DMSO, Cs2CO3,CuI/L-proline, r.t. or 60 °C
Scheme 2 A new synthetic approach to fused 2-aminopyrroles via geminal enediamines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

C
M. S. Mishina et al.
Paper
Synthesis
Table 1 Synthesis of 2-Aminoindoles 5 from Bromofluorobenzene 2 and N,N′-Unsubstituted 1a–c or N,N-Disubstituted Enediamines 1d
O
NH2
NR2R3
H
R1
N
Br
O2N
O2N
CuI/L-proline
Cs2CO3
NH2
NR2R3
Br
F
O2N
1a–d
NR2R3
R1
DMSO
r.t. or 60 °C
DMF or DMSO
65 or 75 °C
O
O
R1
2
4a–d
5a–d
Entry
1
Enediamine 1
Compound 4a
Product 5a
NH2
H
N
Br
O2N
O2N
NH2
NH2
EtO2C
NH2
NH2
1a
1'
CO2Et
CO2Et
4a, 52% (DMF, 75 °C, 20 h)
5a, 81% (60 °C, 3 h)
2
3
Br
NH2
O2N
H
O
O2N
N
NH2
NH2
NH2
Ph
NH2
1'
1b
COPh
COPh
5b, 80% (60 °C, 7 h)
4b, 50% (DMF, 75 °C, 70 h)
NH2
Br
O2N
H
O
O2N
N
NH2
NH2
NH2
N
NH2
N
1c
O
N
O
5c, 68%c (r.t., 48 h)
4cb (DMSO, 65 °C, 1 h)
4
Br
O2N
H
O2N
N
NH2
N
N
N
EtO2C
NH2
CO2Et
CO2Et
5d, 52%c (60 °C, 15 h)
1d
4dd (DMSO, 75 °C, 7 h)
a Yields are indicated for isolated compounds.
b Compound 4c was not isolated. Synthesis of 5c was performed under ‘one pot’ conditions.
c Yield is given for 2 steps.
d Compound 4d was used in the 2nd step without purification.
system CuI/L-proline (0.1 equiv/0.2 equiv), base Cs2CO3 (3
equiv), and solvent DMSO. The cyclization of compounds 4
occurs under mild conditions (ambient temperature or 60
°C) and in high yields.
ence of substituents in the phenyl ring was not observed.
One can only assume that since the N-arylation process oc-
curring in the basic media includes NH-deprotonation step
the formation of considerable amount of 1-arylindoles 6
may result from higher acidity of NH bearing aryl group
compared to NH2. This factor would be especially signifi-
cant in the case of NH-deprotonation (stabilized anion for-
mation) taking place prior to N–Cu bonding.
Iodochloropyrimidine 3а has proved to be less active
than bromofluorobenzene 2 in the first step of the synthe-
sis. In the case of enediamine 1а, substitution of active hal-
ogen occurs at a higher temperature and requires longer
time. Nevertheless, the product 7а was obtained in good
yield (Table 3, entry 1). However, our attempts to obtain the
substitution reaction product in the case of less reactive
enediamine 1b failed. The reaction did not take place at low
temperatures, and heating up to 100 °C led to an unidentifi-
able mixture. In the case of more active enediamine 1с, the
reaction occurred rapidly, but was accompanied by the for-
mation of considerable amounts of by-products.12 Even car-
Сyclization of N-monosubstituted compounds 4e–h re-
sulted in the mixtures of two isomeric indoles 5e–h and
6e–h (Table 2). As expected, in the reaction of N-methyl-
substituted derivative 4e, the major product turned out to
be indole 5е resulting from the intramolecular N-arylation
of unsubstituted sterically more accessible nitrogen atom of
enediamine moiety (Table 2, entry 1). Isomeric indole 6e
was formed in trace amounts, and the main product 5e was
purified and isolated in an individual form via crystalliza-
tion. At the same time cyclization of N-aryl-substituted de-
rivatives 4f–h led to the mixtures with comparable
amounts of isomeric indoles 5 and 6. In two of three cases,
cyclization took place mainly involving substituted nitro-
gen atom, giving 1-aryl-2-aminoindoles 6 as major prod-
ucts. Even though, quality correlation of the product mix-
ture composition (isomers 5 and 6) with electronic influ-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

D
M. S. Mishina et al.
Paper
Synthesis
rying out the reaction without heating did not prevent side
reactions to increase the yield of compound 7с. Thus, the
target product 9c was synthesized without isolation of pure
intermediate compound 7c in an overall yield of 37% (entry
3). In the same manner, starting from enediamine 1d pyrro-
lopyrimidine 9d was isolated in relatively low yield (entry
4). This was probably caused by the problems with the first
step.
Oxidation of methylsulfanyl group of iodochloropyrimi-
dine 3а afforded pyrimidine 3b, which, as expected, was
more reactive in reactions with enediamines than its syn-
thetic precursor. Use of more active substrate allowed to
obtain compound 8b in the reaction with enediamine 1b
and carry out its cyclization to pyrrolopyrimidine 10b (Ta-
ble 3, entry 2). The reaction of iodochloropyrimidine 3b
with enediamine 1d and subsequent cyclization also gave
significantly better results compared with use of 3a afford-
ing compounds 8d and 10d in high yields (entry 5).
In the case of compounds 7 and 8, cyclization occurs
very easily at room temperature, probably due to the higher
activity of iodine atom compared to bromine atom in Cu-
catalyzed N-arylation. Similarly, in the case of compounds
4, thorough purification of intermediates 7 and 8 prior to
the cyclization step was not usually required.
Table 2 Synthesis of 2-Aminoindoles 5 and 6 from Bromofluorobenzene 2 and N-Monosubstituted Enediamines 1e–ha
NH2
R2
EtO2C
NHR2
H
Br
O2N
O2N
CuI/L-proline
Cs2CO3
N
O2N
N
NH2
NHR2
1e–h .
HCl
NHR2
NH2
CO2Et
6e–h
2
DMSO, r.t.
24 h
DIPEA
DMF or DMSO
75 or 85 °C
CO2Et
CO2Et
4e–h
5e–h
Entry
1
Enediamine 1
Compound 4
Products 5 and 6
Me
O2N
Br
H
NH2
NH2
NHMe
O2N
O2N
N
N
EtO2C
NHMe
NH2
(9:1)b
NH
Me
1'
CO2Et
CO2Et
CO2Et
Me
1e
4e, 58% (DMF, 75 °C, 48 h)
5e, 61% and 6e (not isolated)
NH2
NH
Me
EtO2C
O2N
Br
Me
NH2
H
O2N
1'
N
1'
NH
2
3
4
O2N
O2N
O2N
N
1''
N
1'
H
(~1:1)
NH2
CO2Et
4f, 88% (DMSO, 75 °C, 48 h)
CO2Et
CO2Et
Me
1f
5f, 27% and 6f, 38%
OMe
NH2
NH
OMe
EtO2C
O2N
Br
OMe
NH2
H
1'
N
O2N
N
1'
NH
N
1''
1'
H
(~1:2)
NH2
CO2Et
4g, 49% (DMF, 75 °C, 48 h)
CO2Et
CO2Et
OMe
1g
5g, 21% and 6g, 52%
CF3
NH2
NH
CF3
EtO2C
Br
CF3
O2N
NH2
H
1'
N
O2N
N
1'
N
1'
1''
NH
H
NH2
(~1:4.5)
CO2Et
CO2Et
4h, 61% (DMSO, 85 °C, 72 h)
CF3
CO2Et
1h
5h, 20% and 6h, 58%
a The indicated yields are of isolated products.
b Ratio of regioisomers 5/6 in the reaction mixture, estimated by 1H NMR spectroscopy, is given in parentheses.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
M. S. Mishina et al.
Paper
Synthesis
The use of pyrimidine 3a in the synthesis of N-mono-
substituted enediamines 1e and 1f led to similar results as
for bromofluorobenzene 2. The cyclization of compound 7e
mainly afforded pyrrolopyrimidine 9е, which was isolated in
the individual form in good yield (Table 3, entry 6). N-Tolyl-
Table 3 Synthesis of 6-Aminopyrrolo[3,2-d]pyrimidines 9 and 10 from Iodochloropyrimidines 3a,b and Enediamines 1a–fa
O
NH2
NR2R3
R2
H
I
CuI/L-proline
Cs2CO3
N
R1
N
O
N
I
NR2R3
R1
N
N
N
1a–f
NH2
X
N
R1
NR2R3
X
N
DMSO
r.t., 24 h
DMF or DMSO
r.t. to 80 °C
X
N
Cl
MeS
N
CO2Et
H2N
O
3a,b
7, X = SMe
8, X = SO2Me
9, X = SMe
10, X = SO2Me
11e,f
Entry
1
Enediamine 1
Pyrimidine 3
3a, X = SMe
Compounds 7, 8
Products 9, 10, and 11
H
I
N
N
2'
NH2
NH2
NH2
NH2
N
NH2
EtO2C
MeS
N
4'
MeS
N
CO2Et
CO2Et
1a
7a, 75% (DMF, 80 °C, 24 h)
9a, 71%
H
I
N
N
2'
NH2
NH2
NH2
O
N
NH2
2
3
3b, X = SO2Me
4'
N
MeO2S
Ph
MeO2S
N
NH2
COPh
COPh
1b
8b, 53% (DMF, 45 °C, 40 h)
10b, 56%
I
H
N
2'
NH2
NH2
N
NH2
N
O
NH2
MeS
N
4'
O
MeS
N
N
3a, X = SMe
NH2
N
N
O
1c
9c, 37%c
7cb (DMSO, 65 °C, 6 h)
H
I
N
N
NH2
N
N
N
N
4
5
3a, X = SMe
MeS
N
N
MeS
N
EtO2C
NH2
CO2Et
CO2Et
7db (DMSO, 75 °C, 24 h)
9d, 32%c
1d
I
H
N
N
2'
NH2
N
N
3b, X = SO2Me
4'
MeO2S
N
N
MeO2S
N
EtO2C
CO2Et
NH2
CO2Et
1d
8d, 78% (DMF, r.t., 2 h)
10d, 72% (56% over 2 steps)
Me
I
H
NH2
N
2'
NH2
NHMe
N
N
N
N
(7:1)d
MeS
EtO2C
NHMe
NH2
6
7
3a, X = SMe
NH
Me
MeS
N
4'
MeS
N
N
CO2Et
CO2Et
CO2Et
1e
7e, 48% (DMF, 80 °C, 48 h)
9e, 61% and 11e (not isolated)
NH2
H
pTol
N
EtO2C
I
Me
N
N
2'
NH2
NH
N
N
NH-pTol
NH2
3a, X = SMe
MeS
N
N
1"
4'
MeS
N
(1.3:1)
H
MeS
N
CO2Et
CO2Et
CO2Et
7f, 54% (DMSO, 75 °C, 48 h)
9f + 11f, 92%
Me
1f
a The indicated yields are of isolated products.
b Compound was used in cyclization step without purification.
c Yield is given for 2 steps.
d Ratio of regioisomers 9/11 in the reaction mixture.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. S. Mishina et al.
Paper
Synthesis
substituted derivative 7f gave comparable amounts of the
isomeric cyclization products (entry 7).
13С NMR (101 MHz, DMSO-d6): δ = 185.7 (COPh), 162.4 (С=С–NH2),
148.4, 147.0 (2′-C, 4′-C), 144.5 (i-C, C6H5), 137.9 (6′-C), 130.2, 128.4,
128.0 (1′-С, 3′-C, p-CH, C6H5), 127.9, 127.7 (о-CH, m-CH, C6H5), 123.0
(5′-C), 94.5 (С=С–NH2).
In summary, we have developed a new synthetic ap-
proach to fused 2-aminopyrroles from electron-deficient
ortho-dihaloarenes and geminal enediamines. This meth-
odology can be considered as very efficient due to the syn-
thetic availability and variety of the starting enediamines,
the mild reaction conditions, the low cost of the N-arylation
catalyst, and the procedural ease. It should be also noted
that the proposed synthetic strategy may be used to pro-
duce structures containing a 2-aminopyrrole cycle fused
with other cyclic π-deficient systems.
Anal. Calcd for C15H12BrN3O3: С, 49.74; H, 3.34; N, 11.60. Found: С,
49.89; H, 3.60; N, 11.72.
Ethyl 3-Amino-2-(2-bromo-4-nitrophenyl)-3-(methylamino)acry-
late (4e)
A mixture of compound 2 (374 mg, 1.7 mmol), enediamine 1e hydro-
chloride (354 mg, 2.0 mmol), and DIPEA (348 mg, 2.7 mmol) in anhyd
DMF (3.5 mL) was stirred at 75 °С for 48 h and concentrated in vacuo.
The oily residue was treated with H2O (30 mL) and extracted with
EtOAc (2 × 40 mL). The combined organic phases were washed with
brine, dried (MgSO4), and evaporated. The residue was purified by
flash chromatography (EtOAc) to yield 340 mg (58%) of the title com-
pound as a red solid; mp 149–151 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 8.36 (d, J = 2.4 Hz, 1 H, 3′-H), 8.10
(dd, J = 8.5, 2.5 Hz, 1 H, 5′-H), 7.47 (d, J = 8.5 Hz, 1 H, 6′-H), 7.20–6.50
(br s, 3 H, NH, NH2), 3.90 (q, J = 7.0 Hz, 2 H, CH2CH3), 2.75 (d, J = 5.0 Hz,
3 H, NHCH3), 1.03 (t, J = 7.0 Hz, 3 H, CH2CH3).
All commercial reagents and solvents were used without further pu-
rification, unless otherwise noted. DMF for the synthesis was distilled
over CaH2 and stored over freshly activated molecular sieves 4Å. NMR
spectra were recorded on a Bruker Avance III 400 spectrometer [1H:
400.13 MHz; 13С: 100.61 MHz; chemical shifts are reported as parts
per million (δ, ppm)]; the residual solvent peaks were used as inter-
1
13С NMR (101 MHz, DMSO-d6): δ = 167.2 (C=O), 160.8 (C=C–NH2),
147.0, 146.4 (2′-C, 4′-C), 136.6 (6′-C), 129.9 (1′-C), 127.5 (3′-C), 122.8
(5′-C), 77.4 (C=C–NH2), 57.6 (CH2CH3), 28.4 (NHCH3), 15.3 (CH2CH3).
nal standards: 7.28 (CHCl3) and 2.50 (DMSO-d5) ppm for H in CDCl3
and DMSO-d6 respectively, 40.01 and 77.02 ppm for 13C in DMSO-d6
and CDCl3 respectively. Standard abbreviations for multiplicities were
used; coupling constants, J, are reported in Hz. Mass spectra were re-
corded on a Bruker micrOTOF spectrometer (ESI ionization). Elemen-
tal analysis was performed on a Hewlett-Packard HP-185B CHN ana-
lyzer. Melting points were determined in open capillary tubes on a
Stuart SMP30 melting point apparatus.
HRMS (ESI-TOF): m/z [M
+
H]+ calcd for C12H14BrN3O4:
344.0240/346.0220; found: 344.0243/346.0224.
Ethyl 3-Amino-2-(2-bromo-4-nitrophenyl)-3-(p-tolylamino)acry-
late (4f)
A mixture of compound 2 (600 mg, 2.7 mmol), enediamine 1f hydro-
chloride (821 mg, 3.2 mmol), and DIPEA (555 mg, 4.3 mmol) in anhyd
DMSO (4 mL) was stirred at 75 °С for 48 h and concentrated in vacuo.
The residue was treated with H2O (30 mL), the crystals formed were
filtered, and dried in air to yield 1.01 g (88%) of the title compound as
a red solid; mp 151–153 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6, 80 °С): δ = 8.80 (br s, 1 H, NH), 8.38 (d,
J = 2.4 Hz, 1 H, 3′-H), 8.13 (dd, J = 8.5, 2.4 Hz, 1 H, 5′-H), 7.56 (d, J = 8.5
Hz, 1 H, 6′-H), 7.17 (d, J = 7.9 Hz, 2 H, 2′′-H, 6′′-H), 7.07 (d, J = 7.9 Hz, 2
H, 3′′-H, 5′′-H), 6.50 (br s, 2 H, NH2), 3.94 (q, J = 7.0 Hz, 2 H, CH2CH3),
2.28 (s, 3 H, 4′′-CH3), 1.04 (t, J = 7.0 Hz, 3 H, CH2CH3).
Ethyl 3,3-Diamino-2-(2-bromo-4-nitrophenyl)acrylate (4a)
A mixture of compound 2 (0.8 g, 3.6 mmol) and enediamine 1a (0.59
g, 4.5 mmol) in anhyd DMF (3 mL) was stirred at 75 °С for 20 h and
concentrated in vacuo. The oily residue was treated with H2O (20 mL),
the crystals formed were filtered, dried in air, and recrystallized from
MeCN to yield 0.62 g (52%) of the title compound as an orange solid;
mp 233–235 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 8.35 (d, J = 2.0 Hz, 1 H, 3′-Н), 8.02
(dd, J = 8.0, 2.0 Hz, 1 H, 5′-Н), 7.41 (d, J = 8.0 Hz, 1 H, 6′-Н), 6.30–7.70
(br s, 2 H, NH2), 4.95 (br s, 2 H, NH2), 3.80–4.00 (m, 2 H, СН2), 1.02 (t,
J = 7.0 Hz, 3 H, СН3).
13С NMR (101 MHz, DMSO-d6, 80 °С): δ = 167.5 (C=O), 157.9 (C=C–
NH2), 146.2, 146.1 (2′-C, 4′-C), 136.3 (6′-C), 135.3, 134.1 (1′′-C, 4′′-C),
129.8 (2′′-C, 6′′-C), 129.3 (1′-C), 124.3 (3′′-C, 5′′-C), 127.3 (3′-C), 122.5
(5′-C), 79.4 (C=C–NH2), 57.9 (CH2CH3), 20.6 (4′′-CH3), 14.9 (CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 167.2 (C=O), 160.4 (С=С–NH),
147.0, 146.4 (2′-С, 4′-С), 136.2 (6′-С), 129.6 (1′-С), 127.4 (3′-С), 122.8
(5′-С), 78.1 (С=С–NH), 57.7 (СН2СН3), 15.3 (СН3).
Anal. Calcd for C11H12BrN3O4: С, 40.02; H, 3.66; N, 12.73. Found: С,
40.31; H, 3.74; N, 13.00.
HRMS (ESI-TOF): m/z [M
+
H]+ calcd for C18H18BrN3O4:
420.0553/422.0534; found: 420.0565/422.0548.
3,3-Diamino-2-(2-bromo-4-nitrophenyl)-1-phenylprop-2-en-1-
one (4b)
Ethyl 3-Amino-2-(2-bromo-4-nitrophenyl)-3-[(4-methoxyphe-
nyl)amino]acrylate (4g)
A mixture of compound 2 (1.05 g, 4.8 mmol) and enediamine 1b (1.0
g, 6.2 mmol) in anhyd DMF (5 mL) was stirred at 75 °С for 70 h and
concentrated in vacuo. The oily residue was treated with H2O (30 mL)
and extracted with EtOAc (2 × 50 mL). The combined organic phases
were washed with brine, dried (MgSO4), and evaporated. The residue
was purified by flash chromatography (EtOAc) to yield 0.87 g (50%) of
the title compound as an orange solid; mp 234–235 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 10.70 (br s, 1 Н, NH), 8.27 (d, J = 2.0
Hz, 1 Н, 3′-Н), 7.83 (dd, J = 8.0, 2.0 Hz, 1 H, 5′-Н), 7.23 (d, J = 8.0 Hz, 1
Н, 6′-Н), 6.90–7.10 (m, 5 H, C6H5), 6.60 (br s, 1 Н, NH), 5.11 (br s, 2 Н,
NH2).
A mixture of compound 2 (330 mg, 1.5 mmol), enediamine 1g hydro-
chloride (354 mg, 2.0 mmol), and DIPEA (310 mg, 2.4 mmol) in anhyd
DMF (3 mL) was stirred at 75 °С for 48 h and concentrated in vacuo.
The oily residue was treated with H2O (25 mL) and extracted with
EtOAc (2 × 40 mL). The combined organic phases were washed with
brine, dried (MgSO4), and evaporated. The residue was purified by
flash chromatography (n-hexane–EtOAc, 4:1) to yield 323 mg (49%) of
the title compound as a red solid; mp 177–178 °С (MeCN).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

G
M. S. Mishina et al.
Paper
Synthesis
1Н NMR (400 MHz, DMSO-d6): δ = 8.38 (d, J = 2.4 Hz, 1 H, 3′-H), 8.13
(dd, J = 8.5, 2.4 Hz, 1 H, 5′-H), 7.60 (br s, 1 H, NH), 7.57 (d, J = 8.5 Hz, 1
H, 6′-H), 7.11 (d, J = 8.3 Hz, 2 H, 2′′-H, 6′′-H), 6.93 (d, J = 8.3 Hz, 2 H, 3′′-
H, 5′′-H), 6.40 (br s, 2 H, NH2), 3.93 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.75 (s,
3 H, 4′′-OCH3), 1.04 (t, J = 7.0 Hz, 3 H, CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 167.8 (C=O), 158.6 (C=C–NH2),
157.4 (4′′-C), 146.5, 146.4 (2′-C, 4′-C), 136.7 (6′-C), 130.6 (1′′-C), 129.6
(1′-C), 127.5 (2′′-C, 6′′-C), 127.0 (3′-C), 122.8 (5′-C), 114.9 (3′′,5′′-C),
79.1 (C=C–NH2), 58.1 (CH2CH3), 55.7 (4′′-OCH3), 15.2 (CH2CH3).
was purified by flash chromatography (EtOAc–MeOH, from 20:1 to
5:1) to yield 25 mg (7%) of the title compound as a beige solid; mp
184–186 °С.
1Н NMR (400 MHz, DMSO-d6): δ = 8.43 (s, 1 H, 6′-H), 7.80–7.10 (br s, 4
Н, 2 × NH2), 3.14–2.97 (m, 4 H, NCH2CH2), 2.43 (s, 3 Н, SCH3), 1.75–
1.67 (m, 4 H, NCH2CH2).
13С NMR (101 MHz, DMSO-d6): δ = 168.0 (C=O), 167.8 (2′-C), 164.8,
164.2 (4′-C, 6′-C), 160.9 (С=С–NH2), 86.4 (5′-C), 84.8 (С=С–NH2), 47.3
(NCH2CH2), 25.3 (NCH2CH2), 14.0 (SСН3).
HRMS (ESI-TOF): m/z [M
+
H]+ calcd for C18H18BrN3O5:
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H16IN5OSNa: 428.0012;
found: 428.0014.
458.0323/460.0302; found: 458.0320/460.0301.
Ethyl 3-Amino-2-(2-bromo-4-nitrophenyl)-3-{[4-(trifluorometh-
yl)phenyl]amino}acrylate (4h)
Ethyl 3-Amino-2-[5-iodo-2-(methylsulfanyl)pyrimidin-4-yl]-3-
(methylamino)acrylate (7e)
A mixture of compound 2 (270 mg, 1.2 mmol), enediamine 1h hydro-
chloride (435 mg, 1.4 mmol), and DIPEA (245 mg, 1.9 mmol) in anhyd
DMSO (3 mL) was stirred at 85 °С for 72 h and concentrated in vacuo.
The oily residue was treated with H2O (30 mL) and extracted with
EtOAc (2 × 40 mL). The combined organic phases were washed with
brine, dried (MgSO4), and evaporated. The residue was purified by
flash chromatography (n-hexane–EtOAc, 4:1) to yield 350 mg (61%) of
the title compound as an orange solid; mp 168–170 °С (MeCN).
A mixture of compound 3a (487 mg, 1.7 mmol), enediamine 1e hy-
drochloride (365 mg, 2.0 mmol), and DIPEA (555 mg, 4.3 mmol) in
anhyd DMF (4 mL) was stirred at 80 °С for 48 h and concentrated in
vacuo. The residue was treated with H2O (30 mL) and extracted with
EtOAc (2 × 40 mL). The combined organic phases were washed with
brine, dried (MgSO4), and evaporated. The residue was purified by
flash chromatography (n-hexane–EtOAc, 5:2) to yield 220 mg (48%) of
the title compound as a colorless solid; mp 203–205 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 8.50–7.00 (br s, 3 H, NH, NH2), 8.37
(d, J = 2.3 Hz, 1 H, 3′-H), 8.12 (dd, J = 8.5, 2.3 Hz, 1 H, 5′-H), 7.62 (d, J =
7.8 Hz, 2 H, 3′′-H, 5′′-H), 7.55 (d, J = 8.5 Hz, 1 H, 6′-H), 7.33 (d, J = 7.3
Hz, 2 H, 2′′-H, 6′′-H), 3.97 (q, J = 7.0 Hz, 2 H, CH2CH3), 1.06 (t, J = 7.0 Hz,
3 H, CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 168.1 (C=O), 157.3 (C=C–NH2),
146.5, 146.0 (2′-C, 4′-C), 143.6 (1′′-C), 136.4 (6′-C), 131.4 (4′′-C), 129.2
(1′-C), 127.4 (3′-C), 126.5 (3′′-C, 5′′-C), 124.9 (q, J = 271.0 Hz, CF3),
122.6 (5′-C), 122.0 (2′′-C, 6′′-C), 82.7 (C=C–NH2), 58.6 (CH2CH3), 15.0
(CH2CH3).
1Н NMR (400 MHz, DMSO-d6): δ = 8.69 (s, 1 H, 6′-H), 7.95 (br s, 1 H,
NH), 7.25 (br s, 2 Н, NH2), 3.94 (q, J = 7.1 Hz, 2 H, CH2CH3), 2.77 (d, J =
5.0 Hz, 3 H, NHCH3), 2.45 (s, 3 Н, SCH3), 1.09 (t, J = 7.1 Hz, 3 H,
CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 169.6 (C=O), 168.5, 167.6, 164.0
(2′-C, 4′-C, 6′-C), 161.0 (С=С–NH2), 97.1 (5′-C), 80.7 (С=С–NH2), 58.3
(CH2CH3), 28.3 (NHCH3), 15.0 (CH2CH3), 14.1 (SСН3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H15IN4O2SNa: 395.0034;
found: 395.0036.
HRMS (ESI-TOF): m/z [M
474.0271/476.0250; found: 474.0288/476.0271.
+
H]+ calcd for C18H15BrF3N3O5:
Ethyl 3-Amino-2-[5-iodo-2-(methylsulfanyl)pyrimidin-4-yl]-3-(p-
tolylamino)acrylate (7f)
A mixture of compound 3a (0.8 g, 2.8 mmol), enediamine 1f hydro-
chloride (872 mg, 3.4 mmol), and DIPEA (774 mg, 6.0 mmol) in anhyd
DMSO (3 mL) was stirred at 75 °С for 48 h and concentrated in vacuo.
The residue was treated with H2O (30 mL), the crystals formed were
collected, dried in air, and recrystallized from MTBE to yield 712 mg
(54%) of the title compound as a colorless solid; mp 132–134 °С
(MTBE).
1Н NMR (400 MHz, DMSO-d6): δ = 9.25 (br s, 1 H, NH), 8.73 (s, 1 H, 6′-
H), 7.20 (d, J = 8.1 Hz, 2 H, 2′′,6′′-H), 7.10 (d, J = 8.1 Hz, 2 H, 3′′-H, 5′′-
H), 6.95 (br s, 2 H, NH2), 3.99 (q, J = 7.1 Hz, 2 H, CH2CH3), 2.45 (s, 3 Н,
SCH3), 2.30 (s, 3 H, 4′′-CH3), 1.11 (t, J = 7.1 Hz, 3 H, CH2CH3).
Ethyl 3,3-Diamino-2-[5-iodo-2-(methylsulfanyl)pyrimidin-4-
yl]acrylate (7a)
A mixture of compound 3a (0.6 g, 2.1 mmol) and enediamine 1a (0.6
g, 4.6 mmol) in anhyd DMF (3 mL) was stirred at 80 °С for 24 h and
concentrated in vacuo. The residue was treated with H2O (20 mL), the
crystals formed were filtered and dried in air to yield 598 mg (75%) of
the title compound as a colorless solid; mp 187–189 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 8.69 (s, 1 H, 6′-H), 7.80–5.30 (br s, 4
Н, 2 × NH2), 3.94 (q, J = 7.0 Hz, 2 H, CH2CH3), 2.45 (s, 3 Н, SCH3), 1.08 (t,
J = 7.0 Hz, 3 H, CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 170.0, 168.9, 167.8, 164.4 (C=O, 2′-
C, 4′-C, С=С–NH2), 161.4 (6′-C), 97.2 (5′-C), 81.6 (С=С–NH2), 58.8
(СН2СН3), 15.4, 14.5 (СН2СН3, SСН3).
13С NMR (101 MHz, DMSO-d6): δ = 169.8 (C=O), 168.0, 167.9, 164.1
(2′-C, 4′-C, 6′-C), 158.4 (С=С–NH2), 135.0, 134.9 (1′′-C, 4′′-C), 130.3
(2′′-C, 6′′-C), 124.7 (3′′-C, 5′′-C), 97.1 (5′-C), 82.4 (С=С–NH2), 58.7
(CH2CH3), 20.9 (4′′-CH3), 15.0 (CH2CH3), 14.2 (SСН3).
Anal. Calcd for C10H13IN4O2S: С, 31.59; H, 3.45; N, 14.74. Found: С,
31.66; H, 3.29; N, 14.77.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H18IN4O2S: 471.0346;
found: 471.0345.
3,3-Diamino-2-[5-iodo-2-(methylsulfanyl)pyrimidin-4-yl]-1-(pyr-
rolidin-1-yl)prop-2-en-1-one (7с)
3,3-Diamino-2-[5-iodo-2-(methylsulfonyl)pyrimidin-4-yl]-1-
phenylprop-2-en-1-one (8b)
A mixture of compound 3a (250 mg, 0.87 mmol) and enediamine 1c
(310 mg, 2.0 mmol) in anhyd DMSO (2 mL) was stirred at 65 °С for 6 h
and concentrated in vacuo. The residue was treated with H2O (20 mL)
and extracted with EtOAc (2 × 40 mL). The combined organic phases
were washed with brine, dried (MgSO4), and evaporated. The residue
A mixture of compound 3b (255 mg, 0.8 mmol) and enediamine 1b
(292 mg, 1.8 mmol) in anhyd DMF (2.5 mL) was stirred at 45 °С for
40 h and concentrated in vacuo. The residue was treated with H2O (25
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

H
M. S. Mishina et al.
Paper
Synthesis
mL), the crystals formed were collected and purified by flash chroma-
tography (CH2Cl2–MeOH, 15:1) to yield 188 mg (53%) of the title com-
pound as a pale brown solid; mp 140–142 °С (dec.).
1Н NMR (400 MHz, DMSO-d6): δ = 9.02 (s, 1 H, 6′-H), 7.50 (br s, 4 H, 2
× NH2), 7.18 (t, J = 7.3 Hz, 1 H, p-CH, C6H5), 7.11 (t, J = 7.3 Hz, 2 H, m-
CH, C6H5), 7.02 (d, J = 7.3 Hz, 2 H, o-CH, C6H5), 3.07 (s, 3 H, SO2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 186.7 (C=O), 166.2 (6′-C), 171.3,
164.5 (2′-C, 4′-C), 161.9 (С=С–NH2), 143.7 (i-C, C6H5), 129.0 (p-CH,
C6H5), 128.1 (m-CH, C6H5), 127.6 (o-CH, C6H5), 107.4 (5′-C), 96.2 (С=С–
NH2), 39.5 (SO2CH3).
separated, washed with H2O and brine, dried (MgSO4), and evaporat-
ed. The crystalline residue was washed with n-hexane and filtered to
yield 425 mg (80%) of the title compound as a pale orange solid; mp
293–294 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 11.34 (s, 1 Н, 1-NH), 8.10 (s, 2 H,
NH2), 8.02 (d, J = 2.0 Hz, 1 H, 7-Н), 7.66 (dd, J = 8.0, 2.0 Hz, 1 H, 5-Н),
7.65–7.45 (m, 5 H, C6H5), 6.47 (d, J = 8.0 Hz, 1 H, 4-Н).
13С NMR (101 MHz, DMSO-d6): δ = 190.4 (C=O), 158.5 (2-C), 142.7,
141.0, 133.5, 133.4 (3a-C, 6-C, 7a-C, i-C, C6H5), 131.2 (p-CH, C6H5),
129.4, 127.8 (о-CH, m-CH, C6H5), 117.5, 116.8 (4-C, 5-C), 106.8 (7-С),
97.3 (3-C).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H13IN4O3SNa: 466.9646;
found: 466.9653.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H11N3O3: 282.0873; found:
282.0870.
Ethyl 3-Amino-2-[5-iodo-2-(methylsulfonyl)pyrimidin-4-yl]-3-
(pyrrolidin-1-yl)acrylate (8d)
(2-Amino-6-nitro-1H-indol-3-yl)(pyrrolidin-1-yl)methanone (5c)
A mixture of compound 3b (382 mg, 1.2 mmol), enediamine 1d hy-
drochloride (287 mg, 1.3 mmol), and K2CO3 (360 mg, 2.6 mmol) in an-
hyd DMF (3 mL) was stirred at r.t. for 2 h and concentrated in vacuo.
The residue was treated with H2O (15 mL) and extracted with EtOAc
(2 × 40 mL). The combined organic phases were washed with brine (2
×), dried (MgSO4), and evaporated to yield 440 mg (78%) of the title
compound as a colorless solid; mp 98–100 °С.
1Н NMR (400 MHz, DMSO-d6): δ = 8.81 (s, 1 H, 6′-H), 7.60 (br s, 2 Н,
NH2), 3.99 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.25 (s, 3 H, SO2CH3), 1.86–1.77
(m, 4 H, NCH2CH2), 3.16–3.05 (m, 4 H, NCH2CH2), 1.14 (t, J = 7.1 Hz, 3
H, CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 169.8 (C=O), 164.4 (6′-С), 166.0,
163.8, 162.0 (2′-C, 4′-C, С=С–NH2), 100.4 (5′-C), 84.5 (С=С–NH2), 58.4
(СН2СН3), 49.4 (NCH2CH2), 39.3 (SO2CH3), 25.3 (NCH2CH2), 15.0
(CH2CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H19IN4O4SNa: 489.0064;
found: 489.0073.
A mixture of compound 2 (330 mg, 1.55 mmol) and enediamine 1c
(300 mg, 1.9 mmol) in anhyd DMSO (2 mL) was stirred at 65 °С for 1
h. After cooling to r.t., Cs2CO3 (1.96 g, 6.0 mmol), CuI (29 mg, 0.15
mmol), and L-proline (35 mg, 0.3 mmol) were added and the mixture
was stirred for 48 h. The solvent was partially removed in vacuo and
H2O (20 mL) was added to the residue. The crystals formed were fil-
tered and purified by flash chromatography (CH2Cl2–MeOH, 20:1) to
yield 280 mg (68%) of the title compound as an orange solid; mp 280–
283 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 11.01 (s, 1 Н, 1-NH), 8.01 (d, J = 2.0
Hz, 1 H, 7-Н), 7.85 (dd, J = 8.7, 2.0 Hz, 1 H, 5-Н), 7.17 (d, J = 8.7 Hz, 1 H,
4-Н), 6.81 (br s, 2 H, NH2), 3.52–3.38 (m, 4 H, NCH2CH2), 1.78–1.87 (m,
4 H, NCH2CH2).
13С NMR (101 MHz, DMSO-d6): δ = 166.5 (C=O), 154.5 (2-C), 138.6 (6-
С), 133.2 (7a-С), 131.5 (3a-С), 116.9 (5-C), 115.8 (4-C), 106.0 (7-С),
91.6 (3-C), 47.3 (NCH2CH2), 25.4 (NCH2CH2).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H14N4O3Na: 297.0958;
found: 297.0954.
Ethyl 2-Amino-6-nitro-1H-indole-3-carboxylate (5a)
Ethyl 6-Nitro-2-(pyrrolidin-1-yl)-1H-indole-3-carboxylate (5d)
A mixture of compound 4a (400 mg, 1.2 mmol), Cs2CO3 (1.17 g, 3.6
mmol), CuI (23 mg, 0.12 mmol), and L-proline (28 mg, 0.24 mmol) in
DMSO (3 mL) was stirred at 60 °С for 3 h and then concentrated in
vacuo. H2O (20 mL) and EtOAc (50 mL) were added, the mixture was
shaken, and filtered through a pad of Celite. The organic layer was
separated, washed with H2O and brine, dried (MgSO4), and evaporat-
ed. The crystalline residue was washed with n-hexane and filtered to
yield 242 mg (81%) of the title compound as a pale orange solid; mp
276–280 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 11.10 (s, 1 Н, 1-NH), 8.01 (d, J = 2.2
Hz, 1 H, 7-Н), 7.91 (dd, J = 8.6, 2.2 Hz, 1 H, 5-Н), 7.62 (d, J = 8.6 Hz, 1 H,
4-Н), 7.31 (br s, 2 H, NH2), 4.27 (q, J = 7.0 Hz, 2 H, СН2СН3), 1.33 (t, J =
7.0 Hz, 3 H, СН2СН3).
A mixture of compound 2 (250 mg, 1.1 mmol), enediamine 1d hydro-
chloride (265 mg, 1.2 mmol), and K2CO3 (331 mg, 1.2 mmol) in DMSO
(2 mL) was stirred at 75 °С for 7 h and then concentrated in vacuo.
The residue was treated with H2O (15 mL) and extracted with EtOAc
(2 × 35 mL). The combined organic layers were dried (MgSO4) and
passed through a pad of silica gel. After evaporation of solvent, the
oily residue was dissolved in anhyd DMSO (4 mL). Cs2CO3 (1.08 g, 3.3
mmol), CuI (21 mg, 0.11 mmol), and L-proline (25 mg, 0.22 mmol)
were added and the mixture was stirred at 60 °С for 12 h. The solvent
was partially removed in vacuo and the residue was partitioned be-
tween H2O (20 mL) and EtOAc (100 mL). The organic layer was sepa-
rated, washed with brine, and evaporated. The crude product was pu-
rified by flash chromatography (EtOAc) to yield 175 mg (52%) of the
title compound as a pale orange solid; mp 208–210 °С (MeCN).
13С NMR (101 MHz, DMSO-d6): δ = 165.9 (C=O), 157.2 (2-C), 140.7 (6-
С), 134.1 (7a-С), 132.7 (3a-С), 117.9, 117.4 (4-C, 5-C), 106.5 (7-С),
86.4 (3-C), 59.5 (СН2СН3), 15.5 (СН2СН3).
1Н NMR (400 MHz, DMSO-d6): δ = 11.09 (br s, 1 Н, NH), 7.97 (d, J = 2.1
Hz, 1 H, 7-Н), 7.92 (dd, J = 8.7, 2.1 Hz, 1 H, 5-Н), 7.76 (d, J = 8.7 Hz, 1 H,
4-Н), 4.25 (q, J = 7.1 Hz, 2 H, СН2СН3), 3.72–3.56 (m, 4 H, NCH2CH2),
2.06–1.92 (m, 4 H, NCH2CH2), 1.34 (t, J = 7.1 Hz, 3 H, СН2СН3).
Anal. Calcd for C11H11N3O4: С, 53.01; H, 4.45; N, 16.86. Found: С,
52.81; H, 4.42; N, 16.61.
13С NMR (101 MHz, DMSO-d6): δ = 163.8 (C=O), 154.0 (2-C), 140.0 (6-
С), 135.5 (7a-С), 132.1 (3a-С), 117.7 (5-C), 117.3 (4-C), 105.4 (7-С),
88.3 (3-C), 59.2 (СН2СН3), 51.3 (NCH2CH2), 25.7 (NCH2CH2), 15.0
(СН2СН3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H17N3O4Na: 326.1112;
found: 326.1108.
(2-Amino-6-nitro-1H-indol-3-yl)(phenyl)methanone (5b)
A mixture of compound 4b (695 mg, 1.9 mmol), Cs2CO3 (1.86 g, 5.7
mmol), CuI (36 mg, 0.19 mmol), and L-proline (44 mg, 0.38 mmol) in
DMSO (4.5 mL) was stirred at 60 °С for 7 h and then concentrated in
vacuo. H2O (40 mL) and EtOAc (120 mL) were added, the mixture was
shaken, and filtered through a pad of Celite. The organic layer was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. S. Mishina et al.
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Ethyl 2-(Methylamino)-6-nitro-1H-indole-3-carboxylate (5e)
Ethyl 2-(4-Methoxyphenylamino)-6-nitro-1H-indole-3-carboxyl-
ate (5g) and Ethyl 2-Amino-1-(4-methoxyphenyl)-6-nitro-1H-in-
dole-3-carboxylate (6g)
A mixture of compound 4e (340 mg, 1.3 mmol), Cs2CO3 (1.27 g, 3.9
mmol), CuI (19 mg, 0.1 mmol), and L-proline (23 mg, 0.2 mmol) in
DMSO (3 mL) was stirred at r.t. for 24 h and then concentrated in vac-
uo. The residue was treated with H2O (20 mL), the crystals formed
were filtered, and recrystallized from MeCN to yield 162 mg (61%) of
the title compound as an orange solid; mp 266–268 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 11.61 (br s, 1 Н, 1-NH), 7.97–7.90
(m, 2 H, 5-H, 7-H), 7.64–7.59 (m, 1 H, 4-Н), 7.51–7.59 (m, 1 H,
NHCH3), 4.27 (q, J = 7.1 Hz, 2 H, СН2СН3), 3.05 (d, J = 5.1 Hz, 3 H,
NHCH3), 1.34 (t, J = 7.1 Hz, 3 H, СН2СН3).
A mixture of compound 4g (166 mg, 0.38 mmol), Cs2CO3 (359 g, 1.1
mmol), CuI (8 mg, 0.04 mmol), and L-proline (9 mg, 0.08 mmol) in
DMSO (2 mL) was stirred at r.t. for 48 h and then concentrated in vac-
uo. The residue was treated with H2O (15 mL), the crystals formed
were filtered, dried in air, and subjected to column chromatography
on silica gel (n-hexane–EtOAc, 3:2) to yield 28 mg (21%) of compound
5g and 70 mg (52%) of compound 6g.
5g
13С NMR (101 MHz, DMSO-d6): δ = 165.5 (C=O), 157.3 (2-C), 139.8 (6-
С), 134.1 (7a-С), 132.5 (3a-С), 117.9 (5-C), 116.8 (4-C), 105.8 (7-С),
85.7 (3-C), 59.1 (СН2СН3), 30.2 (NHCH3), 15.1 (СН2СН3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H13N3O4Na: 286.0799;
found: 286.0798.
Orange solid; mp 221–223 °C.
1Н NMR (400 MHz, DMSO-d6): δ = 11.52 (br s, 1 Н, 1-NH), 9.15 (s, 1 H,
2-NH) 8.00 (d, J = 2.0 Hz, 1 H, 7-Н), 7.95 (dd, J = 8.7, 2.0 Hz, 1 H, 5-Н),
7.70 (d, J = 8.7 Hz, 1 H, 4-Н), 7.37 (d, J = 8.6 Hz, 2 H, 2′-H, 6′-H), 7.06 (d,
J = 8.6 Hz, 2 H, 3′-H, 5′-H), 4.34 (q, J = 7.0 Hz, 2 H, СН2СН3), 3.81 (s, 3 H,
OCH3), 1.38 (t, J = 7.0 Hz, 3 H, СН2СН3).
13С NMR (101 MHz, DMSO-d6): δ = 165.7 (C=O), 157.8 (4′-C), 153.9 (2-
C), 140.6 (6-С), 133.2 (3a-C), 132.3 (7a-С), 130.8 (1′-C), 125.8 (2′-C, 6′-
C), 117.8 (5-C), 117.5 (4-C), 115.4 (3′-C, 5′-C), 106.8 (7-С), 87.0 (3-C),
59.5 (СН2СН3), 55.9 (OCH3), 15.1 (СН2СН3).
Ethyl 6-Nitro-2-(p-tolylamino)-1H-indole-3-carboxylate (5f) and
Ethyl 2-Amino-6-nitro-1-p-tolyl-1H-indole-3-carboxylate (6f)
A mixture of compound 4f (250 mg, 0.6 mmol), Cs2CO3 (587 g, 1.8
mmol), CuI (12 mg, 0.06 mmol), and L-proline (14 mg, 0.12 mmol) in
DMSO (3 mL) was stirred at r.t. for 48 h and then concentrated in vac-
uo. The residue was treated with H2O (20 mL), the crystals formed
were filtered, dried in air, and subjected to column chromatography
on silica gel (n-hexane–EtOAc, 3:2) to yield 55 mg (27%) of compound
5f and 77 mg (38%) of compound 6f.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H17N3O5: 356.1241; found:
356.1243.
6g
Orange solid; mp 228–230 °C.
5f
1Н NMR (400 MHz, DMSO-d6): δ = 8.01 (dd, J = 8.7, 2.1 Hz, 1 H, 5-Н),
7.77 (d, J = 8.7 Hz, 1 H, 4-Н), 7.48 (d, J = 8.8 Hz, 2 H, 2′-H, 6′-H), 7.43 (d,
J = 2.1 Hz, 1 H, 7-H), 7.23 (d, J = 8.8 Hz, 2 H, 3′-H, 5′-H), 7.19 (br s, 2 H,
NH2), 4.33 (q, J = 7.1 Hz, 2 H, СН2СН3), 3.89 (s, 3 H, OCH3), 1.37 (t, J =
7.1 Hz, 3 H, СН2СН3).
13С NMR (101 MHz, DMSO-d6): δ = 165.6 (C=O), 160.5 (4′-C), 156.7 (2-
C), 140.6 (6-C), 134.8 (7a-C), 132.9 (3a-C), 130.0 (2′-C, 6′-C), 125.7 (1′-
C), 118.4 (5-C), 117.6 (4-C), 116.1 (3′-C, 5′-C), 104.5 (7-С), 85.6 (3-C),
59.5 (СН2СН3), 56.0 (OCH3), 15.1 (СН2СН3).
Pale orange solid; mp 243–245 °C.
1Н NMR (400 MHz, DMSO-d6): δ = 11.66 (s, 1 Н, 1-NH), 9.26 (s, 1 H, 2-
NH) 8.04 (d, J = 2.0 Hz, 1 H, 7-Н), 7.98 (dd, J = 8.7, 2.0 Hz, 1 H, 5-Н),
7.73 (d, J = 8.7 Hz, 1 H, 4-Н), 7.34 (d, J = 8.5 Hz, 2 H, 3′-H, 5′-H), 7.30 (d,
J = 8.5 Hz, 2 H, 2′-H, 6′-H), 4.35 (q, J = 7.1 Hz, 2 H, СН2СН3), 2.36 (s, 3 H,
4′-CH3), 1.38 (t, J = 7.1 Hz, 3 H, СН2СН3).
13С NMR (101 MHz, DMSO-d6): δ = 165.8 (C=O), 153.0 (2-C), 140.8 (6-
С), 135.6, 135.1, 132.9, 132.3 (3a-C, 7a-С, 1′-C, 4′-C), 130.7 (2′-C, 6′-C),
123. 2 (3′-C, 5′-C), 117.8 (5-C), 117.7 (4-C), 107.0 (7-С), 87.4 (3-C),
59.6 (СН2СН3), 21.0 (4′-CH3), 15.0 (СН2СН3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H17N3O4Na: 378.1061;
found: 378.1061.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H17N3O4Na: 362.1111;
found: 326.1120.
Ethyl 6-Nitro-2-[4-(trifluoromethyl)phenylamino]-1H-indole-3-
carboxylate (5h) and Ethyl 2-Amino-6-nitro-1-[4-(trifluorometh-
yl)phenyl]-1H-indole-3-carboxylate (6h)
6f
Pale orange solid; mp 206–208 °C.
A mixture of compound 4h (217 mg, 0.46 mmol), Cs2CO3 (456 mg, 1.4
mmol), CuI (10 mg, 0.05 mmol), and L-proline (11 mg, 0.1 mmol) in
DMSO (2.5 mL) was stirred at r.t. for 24 h and then concentrated in
vacuo. The residue was treated with H2O (15 mL), the crystals formed
were filtered, dried in air, and subjected to column chromatography
on silica gel (n-hexane–EtOAc, 5:2) to yield 36 mg (20%) of compound
5h and 105 mg (58%) of compound 6h.
1Н NMR (400 MHz, DMSO-d6): δ = 8.02 (dd, J = 8.7, 2.2 Hz, 1 H, 5-Н),
7.77 (d, J = 8.7 Hz, 1 H, 4-Н), 7.51 (d, J = 8.1 Hz, 2 H, 2′-H, 6′-H), 7.47–
7.42 (m, 3 H, 7-H, 3′-H, 5′-H), 7.18 (br s, 2 H, NH2), 4.34 (q, J = 7.1 Hz, 2
H, СН2СН3), 2.47 (s, 3 H, 4′-CH3), 1.37 (t, J = 7.1 Hz, 3 H, СН2СН3).
13С NMR (101 MHz, DMSO-d6): δ = 165.6 (C=O), 156.5 (2-C), 140.6,
140.0, 134.5, 133.0 (3a-C, 6-C, 7a-С, 1′-C), 131.5 (2′-C, 6′-C), 130.8 (4′-
C), 128. 3 (3′-C, 5′-C), 118.5 (5-C), 117.6 (4-C), 104.5 (7-С), 85.7 (3-C),
59.5 (СН2СН3), 21.3 (4′-CH3), 15.1 (СН2СН3).
5h
Orange solid; mp 228–230 °C.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H17N3O4: 340.1292; found:
340.1303.
1Н NMR (400 MHz, DMSO-d6): δ = 12.12 (s, 1 Н, 1-NH), 9.61 (s, 1 H, 2-
NH) 8.09 (d, J = 2.0 Hz, 1 H, 7-Н), 8.02 (dd, J = 8.7, 2.0 Hz, 1 H, 5-Н),
7.86–7,75 (m, 3 H, 4-H, 2′-H, 6′-H), 7.66 (d, J = 8.2 Hz, 2 H, 3′-H, 5′-H),
4.36 (q, J = 7.0 Hz, 2 H, СН2СН3), 1.39 (t, J = 7.0 Hz, 3 H, СН2СН3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. S. Mishina et al.
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Synthesis
13С NMR (101 MHz, DMSO-d6): δ = 165.5 (C=O), 153.9 (2-C), 151.2 (1′-
C), 142.8 (7a-С), 141.2 (6-С), 132.6 (3a-C), 127.2 (q, J = 3.6 Hz, 3′-C, 5′-
C), 124.8 (q, J = 268.1 Hz, CF3), 124.3 (q, J = 32.1 Hz, 4′-C), 121.3 (2′-C,
6′-C), 118.3 (5-C), 117.7 (4-C), 107.4 (7-С), 89.6 (3-C), 59.8 (СН2СН3),
15.0 (СН2СН3).
13С NMR (101 MHz, DMSO-d6): δ = 165.4 (C=O), 160.9 (2-C), 156.6 (6-
C), 149.8 (7a-C), 134.2 (4-C), 122.4 (4a-C), 88.7 (7-C), 46.4, 48.2 (br s,
NСH2CH2), 24.4, 26.2 (br s, NСH2CH2), 14.2 (SCH3).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H15N5OS: 278.1071; found:
278.1079.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H14F3N3O5Na: 416.0829;
found: 416.0842.
Ethyl 2-(Methylsulfanyl)-6-(pyrrolidin-1-yl)-5H-pyrrolo[3,2-d]py-
rimidine-7-carboxylate (9d)
6h
A mixture of compound 3a (350 mg, 1.2 mmol), enediamine 1d hy-
drochloride (331 mg, 1.5 mmol), and DIPEA (361 mg, 2.8 mmol) in
anhyd DMSO (3 mL) was stirred at 75 °С for 24 h and then concentrat-
ed in vacuo. The residue was treated with H2O (30 mL) and extracted
with CH2Cl2 (2 × 50 mL). The combined organic phases were dried
(MgSO4) and evaporated. The oily residue was dissolved in anhyd
DMSO (5 mL); Cs2CO3 (1.17 g, 3.6 mmol), CuI (23 mg, 0.12 mmol), and
L-proline (28 mg, 0.24 mmol) were added and the mixture was stirred
at r.t. for 24 h. The solvent was partially removed in vacuo, H2O (25
mL) was added followed by extraction with EtOAc (3 × 30 mL). The
organic phase was washed with brine and evaporated to yield 116 mg
(32%) of the title compound as a colorless solid; mp 227–228 °С
(MeCN).
Orange solid; mp 211–213 °C.
1Н NMR (400 MHz, DMSO-d6): δ = 8.08 (d, J = 8.3 Hz, 2 H, 2′-H, 6′-H),
8.05 (dd, J = 8.7, 2.0 Hz, 1 H, 5-Н), 7.84 (d, J = 8.3 Hz, 2 H, 3′-H, 5′-H),
7.80 (d, J = 8.7 Hz, 1 H, 4-Н), 7.52 (d, J = 2.0 Hz, 1 H, 7-H), 7.39 (s, 2 H,
NH2), 4.35 (q, J = 7.1 Hz, 2 H, СН2СН3), 1.38 (t, J = 7.1 Hz, 3 H, СН2СН3).
13С NMR (101 MHz, DMSO-d6): δ = 165.5 (C=O), 156.4 (2-C), 140.7 (6-
C), 137.3 (7a-C), 133.9 (3a-C), 133.2 (1′-C), 130.3 (q, J = 32.2 Hz, 4′-C),
129.7 (2′-C, 6′-C), 128.1 (q, J = 3.7 Hz, 3′-C, 5′-C), 124.4 (q, J = 272.5 Hz,
CF3), 118.8 (5-C), 117.7 (4-C), 104.6 (7-С), 86.0 (3-C), 59.6 (СН2СН3),
15.1 (СН2СН3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H14F3N3O4Na: 416.0829;
found: 416.0840.
1Н NMR (400 MHz, DMSO-d6): δ = 11.05 (br s, 1 H, NH), 8.15 (s, 1 H, 4-
H), 4.20 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.59–3.45 (m, 4 H, NCH2CH2), 2.51
(s, 3 Н, SCH3), 2.03–1.90 (m, 4 H, NCH2CH2), 1.31 (t, J = 7.0 Hz, 3 H,
CH2CH3).
Ethyl 6-Amino-2-(methylsulfanyl)-5H-pyrrolo[3,2-d]pyrimidine-
7-carboxylate (9a)
A mixture of compound 7a (515 mg, 1.4 mmol), Cs2CO3 (1.37 g, 4.2
mmol), CuI (27 mg, 0.14 mmol), and L-proline (32 mg, 0.28 mmol) in
DMSO (3 mL) was stirred at r.t. for 6 h and then concentrated in vac-
uo. The residue was treated with H2O (15 mL), the crystals formed
were filtered, dissolved in warm i-PrOH (100 mL), and passed through
a pad of silica gel. The solvent was evaporated to yield 252 mg (71%)
of the title compound as a colorless solid; mp 296–298 °С (MeCN).
1Н NMR (400 MHz, DMSO-d6): δ = 10.83 (s, 1 H, 5-NH), 8.15 (s, 1 H, 4-
H), 7.42 (s, 2 Н, NH2), 4.22 (q, J = 7.0 Hz, 2 H, CH2CH3), 2.49 (s, 3 Н,
SCH3), 1.29 (t, J = 7.0 Hz, 3 H, CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 163.5 (C=O), 161.8 (2-C), 153.3 (6-
C), 152.9 (7a-C), 134.6 (4-C), 122.9 (4a-C), 87.2 (7-C), 59.2 (СН2СН3),
50.8 (NCH2CH2), 25.6 (NCH2CH2), 15.0 (CH2CH3), 14.1 (SCH3).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H18N4O2S: 307.1224;
found: 307.1226.
Ethyl 6-(Methylamino)-2-(methylsulfanyl)-5H-pyrrolo[3,2-d]py-
rimidine-7-carboxylate (9e)
A mixture of compound 7e (311 mg, 0.79 mmol), Cs2CO3 (782 mg, 2.4
mmol), CuI (15 mg, 0.08 mmol), and L-proline (18 mg, 0.16 mmol) in
DMSO (3 mL) was stirred at r.t. for 24 h and then concentrated in vac-
uo. The residue was treated with i-PrOH (30 mL) and passed through
a pad of silica gel. Evaporation of solvent afforded a mixture of iso-
mers 9e and 11e (~7:1), which was recrystallized from MeCN to yield
121 mg (57%) of the title compound as a beige solid; mp 253–255 °С
(MeCN).
13С NMR (101 MHz, DMSO-d6): δ = 165.5, 162.4 (C=O, 2-C), 157.3 (6-
C), 151.9 (7a-C), 135.3 (4-C), 123.5 (4a-C), 84.9 (7-C), 59.3 (СН2СН3),
15.4, 14.7 (СН2СН3, SСН3).
Anal. Calcd for C10H12N4O2S: С, 47.61; H, 4.79; N, 22.21. Found: С,
47.60; H, 4.80; N, 22.25.
1Н NMR (400 MHz, DMSO-d6): δ = 11.20 (br s, 1 H, 5-NH), 8.15 (s, 1 H,
4-H), 7.72 (q, J = 5.1 Hz, 1 H, NHCH3), 4.26 (q, J = 7.0 Hz, 2 H, CH2CH3),
3.06 (d, J = 5.2 Hz, 3 H, NHCH3), 2.51 (s, 3 Н, SCH3), 1.32 (t, J = 7.0 Hz, 3
H, CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 165.2 (C=O), 162.3 (2-C), 157.3 (6-
C), 151.7 (7a-C), 134.5 (4-C), 123.4 (4a-C), 84.2 (7-C), 58.9 (СН2СН3),
29.9 (NHCH3), 15.0 (CH2CH3), 14.1 (SCH3).
{6-Amino-2-(methylsulfanyl)-5H-pyrrolo[3,2-d]pyrimidin-7-
yl}(pyrrolidin-1-yl)methanone (9c)
A mixture of compound 3a (600 mg, 2.1 mmol) and enediamine 1c
(714 mg, 4.6 mmol) in anhyd DMSO (4 mL) was stirred at 65 °С for 2 h
and then concentrated in vacuo. The residue was dissolved in CH2Cl2
(20 mL) and passed through silica gel, washing out with EtOAc–MeOH
(8:1). After evaporation of solvents, the residue was dissolved in
DMSO (4 mL); Cs2CO3 (2.05 g, 6.3 mmol), CuI (40 mg, 0.21 mmol), and
L-proline (48 mg, 0.42 mmol) were added and the mixture was stirred
at r.t. for 24 h. The solvent was partially removed in vacuo, the residue
was dissolved in i-PrOH (20 mL), and passed through a pad of silica
gel. After evaporation of solvent, the crude product was purified by
flash chromatography (CH2Cl2–acetone, 1:1) and crystallized from
MeCN to yield 216 mg (37%) of the title compound as a colorless sol-
id; mp 230–231 °С (dec.).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H14N4O2SNa: 267.0910;
found: 267.0911.
Ethyl 6-Amino-5-methyl-2-(methylsulfanyl)-5H-pyrrolo[3,2-d]py-
rimidine-7-carboxylate (11e)
This compound was not isolated.
1Н NMR (400 MHz, DMSO-d6): δ (isomeric mixture) = 8.31 (s, 1 H, 4-
H), 7.63 (br s, 2 H, NH2), 4.24 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.55 (s, 1 H,
NCH3), 2.55 (s, 3 Н, SCH3), 1.31 (t, J = 7.0 Hz, 3 H, CH2CH3).
1Н NMR (400 MHz, DMSO-d6): δ = 10.82 (s, 1 H, 5-NH), 8.11 (s, 1 H, 4-
H), 7.16 (s, 2 Н, NH2), 3.65–3.96 (m, 2 H, NCH2CH2), 3.35–3.65 (m, 2 H,
NCH2CH2), 2.47 (s, 3 Н, SCH3), 1.74–1.89 (m, 4 H, NCH2CH2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
M. S. Mishina et al.
Paper
Synthesis
Mixture of Ethyl 2-(Methylsulfanyl)-6-(p-tolylamino)-5H-pyrro-
lo[3,2-d]pyrimidine-7-carboxylate (9f) and Ethyl 6-Amino-2-
(methylsulfanyl)-5-(p-tolyl)-5H-pyrrolo[3,2-d]pyrimidine-7-car-
boxylate (11f)
Acknowledgment
We are grateful for the financial support from Saint Petersburg State
University (Grant No. 12.38.195.2014). NMR and mass spectrometry
studies were performed at Research Centre for Magnetic Resonance
and Centre for Chemical Analysis and Materials Research of Saint Pe-
tersburg State University.
A mixture of compound 7f (126 mg, 0.27 mmol), Cs2CO3 (264 mg, 0.81
mmol), CuI (6 mg, 0.03 mmol), and L-proline (6 mg, 0.06 mmol) in
DMSO (2 mL) was stirred at r.t. for 24 h and then concentrated in vac-
uo. The residue was treated with H2O (15 mL), the crystals formed
were filtered, and dried in air to yield 86 mg (92%) of a mixture of iso-
mers 9f and 11f (~1.3:1).
Supporting Information
1Н NMR (400 MHz, DMSO-d6): δ (signals of 9f) = 11.96 (s, 1 H, 5-H),
9.44 (s, 1 H, 6-NH), 8.18 (s, 1 H, Н-4), 7.33 (d, J = 8.4 Hz, 2 H, 2′-H, 6′-
H), 7.29 (d, J = 8.4 Hz, 2 H, 3′-H, 5′-H), 4.30 (q, J = 7.0 Hz, 2 H, CH2CH3),
2.53 (s, 3 H, SCH3), 2.44 (s, 3 H, 4′-CH3), 1.34 (t, J = 7.0 Hz, 3 H,
CH2CH3); δ (signals of 11f) = 7.82 (s, 1 H, Н-4), 7.46 (d, J = 8.2 Hz, 2 H,
2′-H, 6′-H), 7.42 (d, J = 8.2 Hz, 2 H, 3′-H, 5′-H), 7.36 (s, 2 H, NH2), 4.28
(q, J = 7.0 Hz, 2 H, CH2CH3), 2.55 (s, 3 H, SCH3), 2.35 (s, 3 H, 4′-CH3),
1.33 (t, J = 7.0 Hz, 3 H, CH2CH3).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561645.
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References
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Shi, F. Synthesis 2015, 47, 1990.
(2) For reviews on indole-containing natural compounds, see:
(a) Marcos, I. S.; Moro, R. F.; Costales, I.; Basabe, P.; Díez, D. Nat.
Prod. Rep. 2013, 30, 1509. (b) Lindel, T.; Marsch, N.; Adla, S. K.
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dron 2014, 70, 6363. (f) Almagro, L.; Fernández-Pérez, F.;
Angeles, Pedreño. M. Molecules 2015, 20, 2973.
{6-Amino-2-(methylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-7-
yl}(phenyl)methanone (10b)
A mixture of compound 8b (550 mg, 1.24 mmol), Cs2CO3 (1.21 g, 3.72
mmol), CuI (24 mg, 0.124 mmol), and L-proline (29 mg, 0.25 mmol) in
DMSO (6 mL) was stirred at r.t. for 24 h and then concentrated in vac-
uo. The residue was dissolved in acetone (70 mL) and passed through
a pad of silica gel. After evaporation of solvent, the residue was treat-
ed with H2O (25 mL), the crystals were filtered, and dried in air to
yield 223 mg (56%) of the title compound as a beige solid; mp 180–
183 °С (dec.).
1Н NMR (400 MHz, DMSO-d6): δ = 11.70 (br s, 1 H, 5-NH), 8.47 (s, 1 H,
4-H), 8.43 (s, 2 Н, NH2), 7.78 (d, J = 7.2 Hz, 2 H, o-CH, C6H5), 7.54 (t, J =
7.0 Hz, 1 H, p-CH, C6H5), 7.46 (t, J = 7.2 Hz, 2 H, m-CH, C6H5), 3.05 (s, 3
H, SO2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 189.8 (C=O), 159.6 (6-C), 158.7 (2-
C), 150.0 (7a-C), 140.7 (i-C, C6H5), 134.7 (4-C), 131.1 (p-CH, C6H5),
129.0 (o-CH, C6H5), 127.8 (m-CH, C6H5), 126.5 (4a-C), 95.7 (7-C), 39.7
(SO2CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H12N4O3SNa: 339.0523;
found: 339.0534.
(3) For reviews on biologically active indole derivatives, see:
(a) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620. (b) Lalit, K.;
Shashi, B.; Kamal, J. Int. J. Res. Pharm. Sci. 2012, 2, 23.
(c) Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010,
47, 491. (d) Biswal, S.; Sahoo, U.; Sethy, S.; Kumar, H. K. S.;
Banerjee, M. Asian J. Pharm. Clin. Res. 2012, 5, 1. (e) Zhang, M.-
Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89, 421.
(f) Sherer, C.; Snape, T. J. Eur. J. Med. Chem. 2015, 97, 552.
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2015, 94, 218.
Ethyl 2-(Methylsulfonyl)-6-(pyrrolidin-1-yl)-5H-pyrrolo[3,2-d]py-
rimidine-7-carboxylate (10d)
A mixture of compound 8d (300 mg, 0.64 mmol), Cs2CO3 (626 g, 1.92
mmol), CuI (12 mg, 0.064 mmol), and L-proline (15 mg, 0.13 mmol) in
DMSO (3 mL) was stirred at r.t. for 24 h and then concentrated in vac-
uo. The residue was treated with H2O (30 mL) and extracted with
EtOAc (2 × 30 mL). The residue after evaporation of solvent was crys-
tallized from MeCN to yield 157 mg (72%) of the title compound as a
colorless solid; mp 233–235 °С.
1Н NMR (400 MHz, DMSO-d6): δ = 11.75 (br s, 1 H, NH), 8.40 (s, 1 H, 4-
H), 4.24 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.66–3.53 (m, 4 H, NCH2CH2), 3.35
(s, 3 H, SO2CH3), 2.05–1.94 (m, 4 H, NCH2CH2), 1.32 (t, J = 7.1 Hz, 3 H,
CH2CH3).
13С NMR (101 MHz, DMSO-d6): δ = 163.0 (C=O), 158.8 (6-C), 154.2 (2-
C), 151.9 (7a-C), 133.3 (4-C), 126.4 (4a-C), 88.2 (7-C), 59.6 (СН2СН3),
51.1 (NCH2CH2), 39.7 (SO2CH3), 25.6 (NCH2CH2), 14.9 (CH2CH3).
HRMS (ESI-TOF): m/z [M + K]+ calcd for C14H18N4O4SK: 377.0680;
found: 377.0688.
(4) Barden, T. C. Top. Heterocycl. Chem. 2011, 26, 31.
(5) (a) Clinch, K.; Evans, G. B.; Fröhlich, R. F. G.; Gulab, S. A.;
Gutierrez, J. A.; Mason, J. M.; Schramm, V. L.; Tyler, P. C.;
Woolhouse, A. D. Bioorg. Med. Chem. 2012, 20, 5181. (b) Diana,
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Cirrincione, G. ChemMedChem 2011, 6, 1291. (c) Kawakita, Y.;
Banno, H.; Ohashi, T.; Tamura, T.; Yusa, T.; Nakayama, A.; Miki,
H.; Iwata, H.; Kamiguchi, H.; Tanaka, T.; Habuka, N.; Sogabe, S.;
Ohta, Y.; Ishikawa, T. J. Med. Chem. 2012, 55, 3975.
(d) Haraguchi, K.; Horii, C.; Yoshimura, Y.; Ariga, F.; Tadokoro,
A.; Tanaka, H. J. Org. Chem. 2011, 76, 8658. (e) Sogabe, S.;
Kawakita, Y.; Igaki, S.; Iwata, H.; Miki, H.; Cary, D. R.; Takagi, T.;
Takagi, S.; Ohta, Y.; Ishikawa, T. ACS Med. Chem. Lett. 2013, 4,
201.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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M. S. Mishina et al.
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1
(12) The two main by-products identified by means of H NMR and
HRMS proved to be 4-amino- and 4-(pyrrolidin-1-yl)-substi-
tuted 5-iodo-2-methylsulfanylpyrimidines, resulting from
pyrimidine 3a via substitution of chlorine atom with NH3 and
pyrrolidine, respectively. Ammonia and pyrrolidine are proba-
bly the products of enediamine 1c degradation during the reac-
tion.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L