Synthesis of non-glutamate-type pyrrolo[2,3-d]pyrimidines via direct aminocarbonylation of aryl halides using solid Co2(CO)8 as a CO source and their antibacterial activity

Article abstract of DOI:10.3184/174751917X14894997017658

The synthesis of pyrrolo[2,3-d]pyrimidine derivatives by direct aminocarbonylation was demonstrated using solid Co₂(CO)₈ as a CO source in an autoclave at elevated temperature by reacting an aryl halide scaffold with a variety of amines. Using this method, 12 non-glutamate-type pyrrolo[2,3-d]pyrimidine analogues were prepared. Some compounds exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria.

Full text of DOI:10.3184/174751917X14894997017658

230 RESEARCH PAPER
VOL. 41 APRIL, 230–234
JOURNAL OF CHEMICAL RESEARCH 2017
Synthesis of non-glutamate-type pyrrolo[2,3-d]pyrimidines via direct
aminocarbonylation of aryl halides using solid Co (CO) as a CO source and
2
8
their antibacterial activity
Balaraman Selvakumar and Kuppanagounder P. Elango *
a,b
b
a
Anthem Biosciences Private Limited, Bangalore 560 099, India
Department of Chemistry, Gandhigram Rural Institute (Deemed University), Gandhigram 624 302, India
b
The synthesis of pyrrolo[2,3-d]pyrimidine derivatives by direct aminocarbonylation was demonstrated using solid Co (CO) as a CO source
2
8
in an autoclave at elevated temperature by reacting an aryl halide scaffold with a variety of amines. Using this method, 12 non-glutamate-
type pyrrolo[2,3-d]pyrimidine analogues were prepared. Some compounds exhibited antibacterial activity against both Gram-positive and
Gram-negative bacteria.
Keywords: aminocarbonylation, aryl halide, pyrrolo[2,3-d]pyrimidine, antibacterial agent
Structural modification studies of naturally occurring folic acid
and its folate derivatives have been investigated extensively by
many researchers over several decades due to the impressive
biological activities of folic acid, such as dihydrofolatereductase
method of direct amino carbonylation on 2-amino-5-[2-(4-
bromophenyl)ethyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-
4-one (6) to synthesise novel non-glutamate-type pyrrolo[2,3-d]
pyrimidines using novel primary, secondary and aryl amines as
nucleophiles (a–l).
1
2
3,4
5
inhibition, enzyme inhibition, antiviral, anti-inflammatory,
6
7–9
10
anti-allergic, antitumour,
antibacterial and antifungal
Results and discussion
activities.Fromthesestudies,compoundscontainingtheprimary
skeleton pyrrolo[2,3-d]pyrimidine emerged as commercial
anticancer drugs, for example, methorexate and pemetrexed
The protocol employed in the synthesis of the new compounds
(7a–l) is shown in Scheme 1. The scaffold 6, which possesses
an aryl bromide, was prepared from commercially available
1-bromo-4-iodobenzene (1) and but-3-yn-1-ol using Sonogashira
coupling. The intermediate 4-(4-bromophenyl)but-3-yn-1-ol (2)
was subjected to alkyne to alkene reduction using Raney nickel
at various catalyst loads (20, 40, 60 and 80%) and pressures
11
1
2–14
(
LY231514).
Other promising folate compounds containing
15
16
the pyrimidine skeleton, such as trimetrexate, edatrexate,
17
18
lometrexol and PNU-142731A, are now at various stages of
clinical trials. A literature survey revealed that the search for
new folate molecules involves chemical modification of one of
four regions (heterocyclic,
and glutamic acid
11,15–17,19,20
11,15,16,20
15,21
−2
bridge,
benzyol
(0.5, 1.0, 1.5, 2.0 kg H cm ). It was found that an 80% catalyst
2
2
0–23
−2
) of pemetrexed (Fig. 1). Considering
load under 2 kg H cm pressure at ambient temperature gave
2
the huge commercial interest in pyrrolo[2,3-d]pyrimidine
derivatives, a novel synthetic methodology has been developed
wherein novel primary, secondary and aryl amines (a–l) were
directly substituted into an aryl halide to afford corresponding
non-glutamate-type pyrrolo[2,3-d]pyrimidines. In addition, all
the synthesised compounds were tested for antibacterial activity
against Gram-positive and Gram-negative bacterial strains
compared with the parent drug pemetrexed.
the optimum yield with minimal debrominated side products.
The resultant intermediate 3 bearing a terminal primary
alcohol was oxidised to an aldehyde, without any purification,
using TEMPO–NaOCl in a mixture of dichloromethane and
water. α-Bromination of the aldehyde intermediate 4 was
tried with various brominating agents, such as bromine-acetic
acid, bromine-sodium acetate and pyridinium tribromide,
and the results showed that pyridinium tribromide is the best
choice for this conversion. The intermediate 4 was brominated
using pyridinium tribromide in methyl t-butyl ether at ambient
temperature to afford intermediate 5 in optimum yield. Further,
5 was condensed with 2,4-diamino-6-hydroxypyrimidine (8) in
the presence of sodium acetate in a water–methanol mixture to
obtain the new scaffold 6 as a precipitate, which was isolated by
simple filtration.
Pyrrolo[2,3-d]pyrimidine derivatives containing an amino-
carbonyl functional group were prepared from acid and
amine nucleophiles using coupling agents such as phosphorus
11
13,23
pentachloride ,
2-chloro-4,6-dimethoxy-1,3,5-triazine,
N,N’-dicyclohexylcarbodiimide, phosphorus trichloride and
2
0
diethyl phosphorocyanidate. Recently, we reported one-pot
2
4
25
synthesis of esters and benzamides directly from aryl halides
using solid Co (CO) as an in situ CO source. As part of our
ongoing research work on carbonylation reactions using solid
The scaffold 6, which contains an aryl bromide, was
subjected to direct aminocarbonylation using a variety of
amine nucleophiles (a–l) in the presence of 1.2 equivalents of
solid Co (CO) as an in situ CO source along with Pd(OAc) /
2
8
Co (CO) as an in situ CO source, here we report a robust
2
8
2
8
2
Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene),
as optimised and demonstrated in our earlier synthesis of
benzamides from aryl halides under microwave conditions.
However, in the present case, aminocarbonylation of 6 was
performed in an autoclave instead of microwave conditions,
considering the commercial interest in pyrrolo[2,3-d]
pyrimidine analogues. A variety of amine nucleophiles
O
N
2
5
HN
H N
H
N
N
2
H
R
O
(
primary, secondary and aryl amines a–l) were reacted with
7
the scaffold 6 to yield the respective benzamides (7a–l).
The results indicated that the yields of the corresponding
Fig. 1 General structure of pyrrolo[2,3-d]pyrimidine derivatives (7a–l).
*
Correspondent. E-mail: drkpelango@rediffmail.com

JOURNAL OF CHEMICAL RESEARCH 2017 231
OH
CuI, TEA,
Pd(Ph Cl , THF
Raney Ni (80% load),
2
3
)
2
2
2 kg/cm H
2
Br
I
Br
Br
OH
o
OH
Reflux, 4h
MeOH, 25-30 C, 8 h
3
1
2
KBr, TEMPO-NaOCl,
O
DCM-water
HN
o
25-30 C, 20 h
H N
N
8
NH2
Br
2
O
O
N
PyBr , MTBE
Br
3
NaOAc, MeOH-water
HN
Br
N
H
H N
o
2
o
O
H
50-55 C, 5 h
Br
25-30 C, 8 h
6
5
4
Pd(OAc) , Xantphos,
2
R-NH2 (a-l)
Co
2
8
(CO) , 1,4-dioxane,
o
90-95 C, 5 h
o
o
Where RNH = 1 ,2 and aryl amines
2
O
R
a. (S)-1-(4-fluorophenyl)ethanamine
b. 2-(4-fluorophenyl)ethanamine
g. 1-ethylpiperazine
h. 1-(pyridin-4-yl)piperazine
c. (1H-benzo[d]imidazol-2-yl)methanamine i. benzo[d]thiazol-2-amine
N
H
O
d. (5-methylfuran-2-yl)methanamine
e. (S)-1-(pyrrolidin-3-yl)piperidine
j. 5-ethyl-1,3,4-thiadiazol-2-amine
k. 5-methylthiazol-2-amine
HN
f. 1-(piperazin-1-yl)ethanone
l. 3,5-dimethylisoxazol-4-amine
N
H
H N
N
2
7a-l
Scheme 1 Synthesis of non-glutamate-type pyrrolo[2,3-d]pyrimidine derivatives (7a–l).
benzamides were found to be good to excellent with the chosen
amine nucleophiles. For aryl amine nucleophiles i–l, the
reaction was carried out with 3.5 equivalents of Co (CO) to
was found to be superior to the marketed drug linezolid, but
relatively less active compared with ciprofloxacin.
Further, it was observed that the compounds 7b–d, 7i and
7k showed better antibacterial activity than their parent drugs
pemetrexed and methotrexate. The antibacterial activities of
the newly synthesised compounds suggested that replacement
of the glutamate portion of pemetrexed with simple primary,
secondary and aryl amines potentially increases the inhibitory
activity against Gram-positive and Gram-negative bacterial
strains. Such an increase in the antibacterial activity may be due
to replacement of the glutamic acid moiety with heterocyclic
moieties, which are known to possess such activities. It
is interesting to note that compound 7c, which contains
an imidazole ring system, and 7i and 7k, which contain a
thiazole ring system, showed relatively higher activity among
the compounds, as expected due to their structure–activity
relationship. This study also revealed that glutamate replacement
in pemetrexed may provide promising lead molecules against
Gram-negative bacteria.
2
8
obtain an optimum yield owing to its poor reactivity with aryl
amines. The synthesised compounds were characterised using
1
13
H and C NMR, LCMS and IR (ATR) spectral studies (see
‘Experimental’).
All the newly synthesised compounds (7a–l) and their
analogue drugs pemetrexed and methotrexate were evaluated
for their in vitro antibacterial activity against human pathogens
by means of a standard twofold serial dilution method using agar
media. The in vitro antibacterial activity was determined for
five Gram-positive bacterial strains (strains of Staphylococcus
aureus, Enterococcus faecalis, Staphylococcus epidermidis,
and Bacillus subtilis) and four Gram-negative strains
(Escherichia coli, Pseudomonas aeruginosa, Enterobacter
aerogenes and Moraxella catarrhalis). In the antibacterial
screening study, commercially available antibiotics viz.
ciprofloxacin and linezolid were used as reference standards.
The results obtained from the study are shown in Table
Conclusion
1. The results indicated that compounds 7b–d, 7i and 7k
exhibited moderate to good potency in inhibiting the growth of
Gram-positive and Gram-negative bacteria when used at a dose
We have demonstrated a direct aminocarbonylation method
for synthesising 12 novel non-glutamate-type pyrrolo[2,3-d]
pyrimidine derivatives from an aryl halide scaffold using solid
Co (CO) as an in situ CO source in an autoclave at elevated
−1
of 8 to 16 μg mL . Compounds showing inhibition of at least
8 mm were considered active and hence these compounds
1
2
8
were further evaluated for their minimum inhibitory
concentration (MIC). The in vitro activity of compounds 7b–
d, 7i and 7k against the Gram-negative bacteria Escherichia
coli, Pseudomonas aeruginosa and Enterobacter aerogenes
temperature. These findings open up a new pathway for future
commercialisation of similar synthetic products, as this reaction
condition gives optimum yields, is safe to execute and could be
scaled up to any scale. All these compounds were characterised

232 JOURNAL OF CHEMICAL RESEARCH 2017
Table 1 Antibacterial evaluation of non-glutamate-type pyrrolo[2,3-d]pyrimidine derivatives (7a–l)
−1a
−1
Gram-positive strains MIC/µg mL
Gram-negative strains MIC/µg mL
Bacillus
subtilis
ATCC
Staphylococcus Staphylococcus Staphylococcus Enterococcus
Escherichia Pseudomonas Enterobacter
Moraxella
catarrhalis
ATCC 25238
Compound
aureus ATCC aureus ATCC epidermidis faecalis
9213 (MSSA) 33591 (MRSA) ATCC 700565 ATCC 29212
coli ATCC
25922
aeruginosa
Aerogenes
2
ATCC 27853
ATCC 13048
6
633
7
7
7
7
7
a
b
c
d
e
>64
>16
>16
>16
>64
>64
>64
>64
>16
>64
8
>64
0.5
4
>64
>64
>64
>16
8
>64
>16
>16
>16
>64
>64
>64
>64
>16
>64
>16
>64
>4
>64
>16
8
>64
>16
>16
>16
>64
>64
>64
>64
>16
>64
>16
>64
>64
8
8
>64
8
8
>64
8
8
>64
8
8
>16
>64
>64
>64
>64
>16
>64
>16
>64
>16
>64
>64
>64
>64
>16
>64
8
>64
1
2
>64
>64
>16
>64
>64
>64
>64
>16
>64
>16
>64
<0.007
>64
>64
>64
>16
>64
>64
>64
>64
>16
>64
>16
>64
0.25
>64
>64
>64
>16
>64
>64
>64
>64
>16
>64
>16
>64
0.015
>64
>64
>64
>16
>64
>64
>64
>64
>16
>64
8
>64
0.03
8
>64
64
7
7
7
7
7
7
7
f
g
h
i
j
k
l
Ciprofloxacin
Linezolid
Pemetrexed
Methrotrexate
0.5
0.06
2
>64
>64
2
>64
>64
1
>64
>64
a
All reported compounds had a zone of inhibition of 18 mm and were used to establish MIC.
using spectral techniques. Furthermore, all the synthesised
compounds were screened for in vitro antibacterial activity
against Gram-positive and Gram-negative bacteria and it was
found that compounds with a heterocyclic ring, particularly
imidazole and thiazole rings, exhibited greater antibacterial
activity.
a celite bed. Bilayers of filtrate were separated and the organic layer
was distilled off under reduced pressure at below 45°C to afford a
brown crude product (10 g), which was further purified by column
chromatography using a mixture of ethyl acetate and hexane in a
gradient manner to afford pure compound 2 as: Pale brown solid;
1
yield 6.7 g (85%); H NMR (400 MHz, DMSO-d ): δ 2.52–2.55 (t, 2H,
6
J = 6.8 Hz), 3.55–3.59 (t, 2H, J = 6.8 Hz), 4.92 (bs, 1H, OH), 7.31–7.34
−1
(
d, 2H, J = 13.6 Hz), 7.52–7.55 (d, 2H, J = 13.2 Hz); IR (ATR) (υ cm ):
Experimental
8
55, 1044, 1482, 2882, 3229, 3323. Anal. calcd for C H BrO: C, 53.36;
10 9
All the chemicals used in the study are commercially available and
high-purity grade (Aldrich or Merck, India). The solvents were
reagent grade and used as supplied commercially. TLC experiments
were performed on alumina-backed silica gel 40F254 plates (Merck,
Darmstadt, Germany). The plates were illuminated under UV light
H, 4.03; found: C, 53.39; H, 4.00%.
4-(4-Bromophenyl)butan-1-ol (3)
To a solution of 4-(4-bromophenyl)but-3-yn-1-ol (2) (6.5 g, 0.029 mol)
in methanol (65 mL), Raney nickel (5 g) was added under a nitrogen
atmosphere at about 25 °C. The reaction mixture was degassed with
(
254 nm) and treated with KMnO . Melting points were determined
4
using a melting point apparatus (B-540 Buchi, Germany) without
−2
hydrogen twice and stirred under 2 kg H cm pressure for 8 h at
2
1
13
corrections. All H and C NMR spectra were recorded on a Bruker
Avance III HD 300 MHz or Bruker Avance III HD 400 MHz (Bruker
BioSpin Corp., Silberstreifen 4, Rheinstetten, Germany). Molecular
weights of unknown compounds were checked by LCMS 6200 series
Agilent Technology (Agilent, Bengaluru, India). Chemical shifts are
reported in ppm (δ) with reference to internal standard TMS. The signals
are designated as follows: singlet (s), doublet (d), triplet (t), doublet of
doublet (dd), doublet of triplet (dt), multiplet (m) and broad singlet (brs).
IR spectra were recorded using a Bruker Alpha FTIR spectrometer
2
5–30 °C. On reaction completion, residual Raney nickel was removed
by filtration through a sintered crucible. The resultant filtrate was
distilled off under reduced pressure at below 40 °C to obtain compound
3, which was used in the next step without any purification, as: Pale
1
brown liquid; yield 6.3 g (95 %); H NMR (400 MHz, DMSO-d ):
6
δ 1.38–1.41 (m, 2H), 1.54–1.55 (m, 2H), 3.16 (m, 2H), 4.08 (bs, 1H,
OH), 4.36 (m, 2H), 7.14–7.16 (d, 2H, J = 9.2 Hz), 7.43–7.45 (d, 2H,
−1
J = 8.4 Hz); IR (ATR) (υ cm ): 825, 1062, 1485, 2860, 2930, 3333.
Anal. calcd for C H BrO: C, 52.42; H, 5.72; found: C, 52.41; H,
10
13
(
Bruker, Rheinstetten, Germany) using a diamond attenuated total
5.75%.
-(4-Bromophenyl)butyraldehyde (4)
To a stirred solution of 4-(4-bromophenyl)butan-1-ol (3) (5.5 g,
reflectance (ATR) single reflectance module (24 scans). All reactions
were carried out under a nitrogen/argon atmosphere unless otherwise
stated. Elemental analysis was carried out with a Thermo Scientific
Flash 1112EA apparatus and Eager Xperience software.
4
0.024 mol) in dichloromethane (83 mL), a solution of potassium
bromide (0.42 g, 0.004 mol) in water (8. 3 mL) was added and cooled
to about 5 °C. The mixture was vigorously stirred and TEMPO
(0.18 g, 0.001 mol) was added. Aqueous sodium hypochlorite (2.68 g,
0.36 mol) was then added slowly over a period of 20 min, maintaining
the same temperature. The reaction mixture was warmed to ambient
temperature and then stirred for 20 h to reach reaction completion. On
reaction completion, the pH of the reaction mixture was adjusted to
about 4 using acetic acid and the bilayers were separated. The product-
containing organic layer was distilled off under reduced pressure
at below 35 °C to obtain the crude product, which was purified by
column chromatography using a mixture of ethyl acetate and hexane
in a gradient manner to afford pure compound 4 as: Pale brown liquid;
4
-(4-Bromophenyl)but-3-yn-1-ol (2)
To a stirred solution of 1-bromo-4-iodobenzene (1) (10 g, 0.035 mol)
in THF (100 mL), but-3-yn-1-ol (2.8 g, 0.042 mol) and copper (I)
iodide (1.4 g, 0.007 mol) were added at about 25 °C under an argon
atmosphere. To this, triethyl amine (17.9 g, 0.176 mol) was added
slowly over period of 10 min at the same temperature. After stirring
for 15 min, the mixture was degasified using argon for 30 min followed
by addition of bis(triphenylphosphine)palladium chloride (2.5 g,
0.004 mol). The reaction mixture was heated to reflux temperature
for 4 h. On reaction completion, the reaction mixture was cooled to
about 25 °C, diluted with ethyl acetate (100 mL) and filtered through

JOURNAL OF CHEMICAL RESEARCH 2017 233
1
−1
yield: 4.05 g (72%); H NMR (400 MHz, DMSO-d ): δ 1.78–1.83 (m,
(υ cm ): 829, 1223, 1504, 1631, 3221; LCMS (ESI) m/z: 420.3 ([M +
6
+
2
H), 2.41–2.42 (t, 2H, J = 13.6 Hz), 2.53–2.57 (m, 2H), 7.16–7.18 (d,
H] ). Anal. calcd for C H FN O : C, 65.86; H, 5.29; N, 16.70; found:
2
3
22
5
2
2
H, J = 8 Hz), 7.45–7.47 (d, 2H, J = 8 Hz), 9.65 (s, 1H, aldehyde); IR
C, 65.79; H, 5.40; N, 16.77%.
N-[(1H-Benzimidazol-2-yl)methyl]-4-[2-(2-amino-4-oxo-4,7-
dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzamide (7c):
−1
(
5
ATR) (υ cm ): 801, 1009, 1720, 2925. Anal. calcd for C H BrO: C,
10 11
2.89; H, 4.88; found: C, 52.90; H, 4.91%.
1
Pale pink solid; m.p. 201–203 °C; yield 61%; H NMR (300 MHz,
2
-Bromo-4-(4-bromophenyl)butyraldehyde (5)
DMSO-d ): δ 2.85–2.88 (m, 2H), 2.96–2.98 (m, 2H), 4.67–4.68 (d,
6
To
a stirred solution of 4-(4-bromophenyl)butyraldehyde (4)
2
H, J = 5.7 Hz), 6.01 (s, 2H), 6.31 (s, 1H), 7.12–7.14 (m, 2H), 7.29–7.32
(4 g, 0.176 mol) in methyl tertiary butyl ether (40 mL), pyridinium
(d, 2H, J = 8.1 Hz), 7.42–7.44 (d, 1H, J = 6.3 Hz), 7.53–7.55 (d, 1H,
tribromide (5.6 g, 0.176 mol) was added portion wise at about 25 °C
and stirred for 8 h at the same temperature. The solid precipitate was
removed by filtration and the filtrate was diluted with water and the
bilayers were separated. The organic layer was distilled off under
reduced pressure below 35°C to obtain compound 5, which was used in
the next step without any purification, as: Pale brown liquid; yield 4 g;
J = 6.3 Hz), 7.84–7.86 (d, 2H, J = 7.8 Hz), 9.09 (s, 1H), 10.16 (s, 1H,
13
NH), 10.62 (s,1H, NH–amide); C NMR (300 MHz, DMSO-d ):
6
δ 28.4, 36.6, 38.2, 99.2, 111.6, 113.9, 118.1, 118.7, 121.7, 127.8, 128.6,
−1
1
1
+
31.8, 146.6, 151.8, 152.7, 152.9, 159.8, 167.0; IR (ATR) (υ cm ): 826,
024, 1306, 1538, 1639, 1671, 2931, 3368; LCMS (ESI) m/z: 428.1 ([M
H] ). Anal. calcd for C H N O : C, 64.63; H, 4.95; N, 22.94; found:
+
−1
23 21 7 2
IR (ATR) (υ cm ): 809, 1069, 1486, 1724, 2926.
C, 64.65; H, 4.96; N, 22.89%.
-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-
4
2
-Amino-5-[2- (4-bromophenyl)ethyl]-3,7-dihydro-4H-pyr-
yl)ethy])-N-[(5-methylfuran-2-yl)methyl]benzamide (7d): Pale pink
rolo[2,3-d]pyrimidin-4-one (6)
1
solid; m.p. 236–238 °C; yield 68%; H NMR (300 MHz, DMSO-d ): δ
To a solution of 2,4-diamino-6-hydroxypyrimidine (5 g, 0.04 mol)
in a 50:50 mixture of water and methanol (100 mL), 2-bromo-4-(4-
bromophenyl)butyraldehyde (5) (12 g, 0.04 mol) was added. To this,
sodium acetate (4.9 g, 0.06 mol) was added and the resultant mixture
was stirred for 5 h at about 50 °C. On reaction completion, the reaction
mixture was cooled and the solid obtained was collected by filtration.
The wet cake was washed with water (20 mL) and dried to afford
6
2
.22 (s, 3H), 2.83–2.86 (m, 2H), 2.93–2.96 (m, 2H), 4.37–4.39 (d, 2H,
J = 5.1Hz), 5.98 (s, 2H), 6.04 (s, 1H), 6.12 (s, 1H), 6.3 (s, 1H), 7.26–7.28
(
1
(
d, 2H, J = 7.8 Hz), 7.76–7.79 (d, 2H, J = 8.1 Hz), 8.83 (m, 1H), 10.2 (s,
−1
H), 10.61 (s, 1H); IR (ATR) (υ cm ): 833, 1360, 1633, 3369; LCMS
+
ESI) m/z: 392.2 ([M + H] ). Anal. calcd for C H N O : C, 64.44; H,
21 21 5 3
5.45; N, 17.89; found: C, 64.40; H, 5.53; N, 17.84%.
1
(S)-2-Amino-5-{4-[3-(piperidin-1-yl)pyrrolidine-1-carbonyl]
pure compound 6 as: Pale brown solid; yield 7.9 g (60%); H NMR
phenethyl}-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (7e): Pale pink
(
(
400 MHz, DMSO-d ): δ 2.78–2.82 (m, 2H), 2.86–2.9 (m, 2H), 5.99
6
1
solid; m.p. 210–212 °C; yield 68%; H NMR (300 MHz, DMSO-d ):
bs, 2H, NH ), 6.29 (s, 1H), 7.13–7.16 (d, 2H, J = 11.2 Hz), 7.41–7.4 (d,
6
2
δ 1.34–1.68 (m, 7H), 1.71–2.07 (m, 1H), 2.10–2.5 (m, 5H), 2.8–2.9 (m,
2H), 2.92–3.05 (m, 2H), 3.4–3.82 (m, 4H), 6.03 (s, 2H), 6.33 (s, 1H),
7.25–7.27 (d, 2H, J = 6.3 Hz), 7.39–7.45 (m, 2H), 10.17 (s, 1H, NH),
2
H, J = 13.2 Hz), 10.13 (bs, 1H, NH–amide), 10.57–10.6 (d, 1H, NH);
13
C NMR (100 MHz, DMSO-d ): δ 28.5, 36.1, 90.8, 113.9, 118.1, 119.0,
6
−1
131.1, 131.5, 142.3, 151.8, 152.6, 165.0, 180.2; IR (ATR) (υ cm ): 803,
13
+
10.63 (s,1H, NH–amide); C NMR (300 MHz, DMSO-d ): δ 24.2,
1010, 1435, 1634, 2924, 3151; ESI-MS m/z: 333.1 (M ). Anal. calcd for
6
2
1
5.6, 28.5, 36.6, 45.3, 48.3, 49.8, 52.5, 63.4, 64.8, 99.1, 113.7, 118.2,
C H BrN O: C, 50.47; H, 3.93; N, 16.82; found: C, 50.46; H, 3.98; N,
14
13
4
27.6, 128.5, 134.4, 144.9, 151.8, 152.8, 159.7, 168.8; IR (ATR) (υ
16.83%.
−1
cm ): 1091, 1433, 1588, 1664, 2923, 3217; LCMS (ESI) m/z: 435.3 ([M
+ H] ). Anal. calcd for C H N O : C, 66.34; H, 6.96; N, 19.34; found:
C, 66.31; H, 6.71; N, 19.32%.
Synthesis of 7a–l; general procedure
+
2
4
30
6
2
To a suspension of 6 (0.1 mol) in 1,4-dioxane (5 mL), amine
nucleophiles R (a–l) (0.2 mol), Pd(OAc)2 (5 mol%) and Xantphos
5-[4-(4-Acetylpiperazine-1-carbonyl)phenethyl]-2-amino-3H-
pyrrolo[2,3-d]pyrimidin-4(7H)-one (7f): Pale grey solid; m.p.
(
5 mol%) were added in an autoclave at about 25 °C. To this, Co (CO)
2 8
1
(
0.25 mol for primary and secondary amine nucleophiles, 0.7 mol
309–312 °C; yield 70%; H NMR (300 MHz, DMSO-d ): δ 2.01 (s,
6
for aryl amine nucleophiles) was added and the resultant reaction
mixture was heated to about 90 °C for 5 h in the autoclave. On reaction
completion, the reaction mixture was quenched using water and the
solid obtained was stirred for 30 min and collected by filtration. The
crude material was further purified by hot methanol to afford the
desired benzamides 7a–l.
3H), 2.84–2.89 (m, 2H), 2.92–2.95 (m, 2H), 3.47 (s, 8H), 6.02 (s, 2H),
6.34 (s, 1H), 7.26–7.34 (dd, 4H, J = 7.5 Hz, J = 10.5 Hz), 10.16 (s,
1
2
13
1H ,NH), 10.65 (s, 1H, NH–amide); C NMR (300 MHz, DMSO-d ):
6
δ 21.7, 28.5, 36.5, 99.2, 113.8, 118.2, 127.5, 128.7, 133.3, 144.7, 151.8,
−1
152.7, 159.7, 168.9, 169.8; IR (ATR) (υ cm ): 821, 997, 1256, 1426,
+
1614, 1676, 3359; LCMS (ESI) m/z: 407.2 ([M − H] ), 435.3 ([M +
+
(
S) -4-[2- (2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]
H] ). Anal. calcd for C H N O : C, 61.75; H, 5.92; N, 20.58; found: C,
21
24
6
3
pyrimidin-5-yl)ethyl]-N-[1-(4-fluorophenyl)ethyl]benzamide (7a):
Pale grey solid; m.p. 246–249 °C; yield 70%; H NMR (300 MHz,
61.71; H, 5.95; N, 20.55%.
1
2-Amino-5-[4-(4-ethylpiperazine-1-carbonyl)phenethyl]-3H-
pyrrolo[2,3-d]pyrimidin-4(7H)-one (7g): Pale pink solid; m.p.
DMSO-d ): δ 1.44–1.47 (d, 3H, J = 7.2), 2.84–2.87 (m, 2H), 2.94–2.97
6
1
(m, 2H), 5.13–5.17 (m, 1H), 6.16 (bs, 1H), 6.33 (s, 1H), 7.1–7.17 (t, 2H,
178–181 °C; yield 63%; H NMR (300 MHz, DMSO-d ): δ 0.97–1.02
6
J = 8.7 Hz, J = 9 Hz), 7.26–7.29 (d, 2H, J = 8.1 Hz), 7.39–7.44 (dd,
(t, 3H, J = 6.9 Hz), 2.33–2.35 (m, 6H), 2.85–2.86 (m, 2H), 2.91–2.94
1
2
2
H, J = 5.4 Hz, J = 8.4 Hz), 7.76–7.79 (d, 2H, J = 8.4 Hz), 8.69–8.71
(m, 2H), 3.3–3.66 (m, 4H), 6.03 (s, 2H), 6.33 (s, 1H), 7.27 (s, 4H),
1
2
13
−1
(d, 1H, J = 7.5 Hz), 10.29 (s, 1H), 10.68 (s, 1H); C NMR (100 MHz,
10.2(s, 1H, NH), 10.61 (s,1H, NH–amide); IR (ATR) (υ cm ): 817,
+
DMSO-d ): δ 22.7, 28.3, 36.4, 99.2, 114.3, 115.2, 115.4, 118.4, 127.7,
1012, 1440, 1583, 1644, 3255.66; LCMS (ESI) m/z: 395.2 ([M + H] ).
6
128.5 (t), 132.3, 141.6–141.7, 146.2, 148.6, 152.3, 159.2, 160.2, 162.6,
Anal. calcd for C H N O : C, 63.94; H, 6.64; N, 21.30; found: C,
21
26
6
2
−1
1
65.9; IR (ATR) (υ cm ): 678, 832, 1505, 1631, 1664, 2923; LCMS
63.92; H, 6.69; N, 21.1%.
2-Amino-5-{4-[4-(pyridin-4-yl)piperazine-1-carbonyl]phenethyl}-
+
(
ESI) m/z: 420.0 ([M + H] ). Anal. calcd for C H FN O : C, 65.86; H,
2
3
22
5
2
5
.29; N, 16.70; found: C, 65.81; H, 5.25; N, 16.73%.
-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-
yl)ethyl]-N-(4-fluorophenethyl)benzamide (7b): Off-white solid; m.p.
3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (7h): Pale pink solid; m.p.
1
4
263–265 °C; yield 59%; H NMR (300 MHz, DMSO-d ): δ 2.87–2.89
6
(m, 2H), 2.94–2.96 (m, 2H), 3.45–3.67 (m, 8H), 6.09 (s, 2H), 6.34
1
2
75–278 °C; yield: 71%; H NMR (300 MHz, DMSO-d ): δ 2.80–2.85
(s, 1H), 6.81–6.83 (d, 2H, J = 5.7 Hz), 7.28–7.36 (dd, 4H, J = 7.5 Hz,
6
1
(m, 4H), 2.93–2.96 (m, 2H), 3.42–3.48 (m, 2H), 6.0 (s, 2H), 6.32
J = 10.5 Hz), 8.17–8.18 (d, 2H, J = 5.4 Hz), 10.32 (s, 1H, NH), 10.63
2
−1
(s, 1H), 7.08–7.14 (t, 2H, J = 9.0 Hz), 7.25–7.28 (d, 4H, J = 7.8 Hz),
(s,1H, NH–amide); IR (ATR) (υ cm ): 703, 829, 997, 1367, 1600, 1650,
3144; LCMS (ESI) m/z: 444.3 ([M + H] ). Anal. calcd for C H N O :
+
7.69–7.72 (d, 2H, J = 7.8 Hz), 8.43–8.45 (m, 1H), 10.14 (bs, 1H, NH),
2
4
25
7
2
13
1
3
0.62 (s,1H, NH–amide); C NMR (300 MHz, DMSO-d ): δ 28.4,
C, 65.00; H, 5.68; N, 22.11; found: C, 65.03; H, 5.68; N, 22.12%.
4-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-
5-yl)ethyl]-N-(benzo[d]thiazol-2-yl)benzamide (7i): Pale pink
6
4.6, 36.5, 99.2, 113.8, 115.2–115.5, 118.1, 127.4, 128.6, 130.8–130.9,
132.4, 136.1–136.2, 146.2, 151.8, 152.6, 159.6, 162.8,166.6; IR (ATR)

234 JOURNAL OF CHEMICAL RESEARCH 2017
1
solid; m.p. 262–265 °C; yield 47%; H NMR (300 MHz, DMSO-d ):
Received 16 January 2017; accepted 27 February 2017
Paper 1704538
https://doi.org/10.3184/174751917X14894997017658
Published online: 4 April 2017
6
δ 2.89–2.98 (m, 4H), 6.03 (s, 2H), 6.33 (s, 1H), 7.03–7.06 (m, 1H),
.20–7.22 (m, 1H), 7.20–7.26 (d, 2H, J = 7.5 Hz), 7.46–7.49 (m, 1H),
.68–7.71 (m, 1H), 8.04–8.06 (d, 2H, J = 7.8 Hz), 10.2 (s, 1H, NH),
0.62 (s,1H, NH–amide); IR (ATR) (υ cm ): 701, 831, 993, 1354, 1621,
658.58, 1917, 3208; LCMS (ESI) m/z: 429.1 ([M − H] ). Anal. calcd
for C H N O S: C, 61.38; H, 4.21; N, 19.52; S, 7.45; found: C, 61.35;
H, 4.27; N, 19.50; S, 7.47%.
-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-
7
7
1
−1
+
1
References
2
2
18
6
2
1
2
E.M. Berman and L.M. Werbel, J. Med. Chem., 1991, 34, 479.
C.T. Supuran, A. Scozzafava, B.C. Jurca and M.A. Iiies, Eur. J. Med. Chem.,
1998, 3, 83.
4
3
X. Guo, Y. Li, L. Tao, Q. Wang, S. Wang, W. Hu, Z. Pan, Q. Yang, Y. Cui,
Z. Ge, L. Dong, X. Yu, H. An, C. Song and J. Chang, Bioorg. Med. Chem.
Lett., 2011, 22, 6770.
yl)ethyl]-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzamide (7j): Pale brown
1
solid; m.p. 241–243 °C; yield 52%; H NMR (300 MHz, DMSO-d ):
6
δ 1.27–1.32 (t, 3H, J = 7.5 Hz), 2.86–2.88 (m, 2H), 2.94–2.97 (m, 4H),
.01 (s, 2H), 6.32 (s, 1H), 7.3–7.33 (d, 2H, J = 8.1 Hz), 8.00–8.02 (d,
H, J = 7.8 Hz), 10.17 (s, 1H, NH), 10.62 (s, 1H, NH–amide); IR (ATR)
υ cm ): 799, 1309, 1431, 1658, 2926, 3323; LCMS (ESI) m/z: 408.1
[M − H] ). Anal. calcd for C H N O S: C, 55.73; H, 4.68; N, 23.95; S,
.83; found: C, 55.71; H, 4.71; N, 23.94; S, 7.83%.
-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-
4
5
6
C.V. Varaprasad, K.S. Ramasamy, J.L. Girardet, E. Gunic, V. Lai, W. Zhong,
H. An and Z. Hong, Bioorg. Chem., 2007, 35, 25.
M.S. Mohamed, A.E. Rashad, M. Adbel-onem and S.S. Fatahalla, Z.
Naturforsch. C, 2007, 62, 27.
S. Nagashima, T. Hondo, H. Nagata, T. Ogiyama, J. Maeda, H. Hoshii,
T. Kontani, S. Kuromitsu, K. Ohga, M. Orita, K. Ohno, A. Moritomo, K.
Shiozuka, M. Furutani, M. Takeuchi, M. Ohta and S. Tsukamoto, Bioorg.
Med. Chem., 2009, 17, 6926.
6
2
(
−1
+
(
19
19
7
2
7
4
5
-yl)ethyl]-N-(5-methylthiazol-2-yl)benzamide (7k): Pale pink
7
M.H. Jung, H. Kim, W.K. Choi, M.I. El-Gamal, J.H. Park, K.H. Yoo, T.B.
Sim, S.H. Lee, D. Baek, J.M. Hah, J.H. Cho and C.H. Oh, Bioorg. Med.
Chem. Lett., 2009, 19, 6538.
1
solid; m.p. 305–308 °C; yield 45%; H NMR (300 MHz, DMSO-d ):
6
δ 0.93–0.95 (d, 3H, J = 6.3 Hz), 2.37 (s, 3H), 2.86–2.89 (m, 2H),
.97–3.0 (m, 2H), 6.02 (s, 2H), 6.33 (s, 1H), 7.2 (s, 1H), 7.33–7.36 (d,
H, J = 7.8 Hz), 7.97–8.00 (d, 2H, J = 8.1 Hz), 10.17 (s, 1H, NH), 10.63
s, 1H, NH–amide), 12.3 (bs, 1H, NH–amide); IR (ATR) (υ cm ): 706,
306, 1548, 1651, 3215; LCMS (ESI) m/z: 395.0 ([M + H] ). Anal.
calcd for C H N O S: C, 57.85; H, 4.60; N, 21.31; S, 8.13; found: C,
8
9
Y. Asukai, A. Valladares, C. Camps, E. Wood, K. Taipale, J. Arellano, A.
Cassinello, J.A. Sacristán and T. Dilla, BMC Cancer, 2010, 10, 26.
T. McHardy, J.J. Caldwell, K.M. Cheung, L.J. Hunter, K. Taylor, M.
Rowlands, R. Ruddle, A. Henley, A. de-HavenBrandon, M. Valenti, T.G.
Davies, L. Fazal, L. Seavers, F.I. Raynaud, S.A. Eccles, G.W. Aherne, M.D.
Garrett and I. Collins, J. Med. Chem., 2010, 53, 2239.
2
2
(
1
−1
+
19
18
6
2
10
K.M.H. Hilmy, M.M.A. Khalifa, M.A.A. Hawata, R.M.A. Keshk and A.A.
El-Torgman, Eur. J. Med. Chem., 2010, 45, 5243.
5
7.84; H, 4.65; N, 21.30; S, 8.11%.
-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-
-yl)ethyl]-N-(3,5-dimethylisoxazol-4-yl)benzamide (7l): Pale pink
4
11
D.C. Suster, E. Tarnauceanu, D. Ionescu, V. Dobre and I. Niculescu-Duvaz,
J. Med. Chem., 1978, 21, 1162.
5
1
solid; m.p. 247–250 °C; yield 45%; H NMR (300 MHz, DMSO-d ):
6
12 W. John, J. Picus, C.D. Blanke, J.W. Clark, L.N. Schulman, E.K. Rowinsky,
D.E. Thornton and P.J. Loehrer, Cancer, 2000, 88, 1807.
13 E.C. Taylor and B. Liu, J. Org. Chem., 2003, 68, 9938.
δ 2.12 (s, 3H), 2.29 (s, 3H), 2.87 (m, 2H), 3.01 (m, 2H), 6.01 (s, 2H),
.33 (s, 1H), 7.33–7.36 (d, 2H, J = 7.2 Hz), 7.86–7.88 (d, 2H, J = 7.2
Hz), 9.7 (bs, 1H, NH), 10.16 (s, 1H, NH–amide), 10.63 (s,1H, NH–
amide); C NMR (300 MHz, DMSO-d ): δ 10.1, 11.3, 28.4, 36.5, 99.2,
13.9, 114.9, 118.0, 128.1, 128.8, 131.3, 147.2, 151.8, 152.6, 158.3, 159.7,
63.1, 166.1; IR (ATR) (υ cm ): 884, 1239, 1363, 1630, 2933, 3311;
LCMS (ESI) m/z: 393.3 ([M + H] ). Anal. calcd for C H N O : C,
1.21; H, 5.14; N, 21.42; found: C, 61.19; H, 5.18; N, 21.39%.
6
1
4
E.C. Taylor, D. Kuhnt, C. Shih, S.M. Rinzel, G.B. Grindey, J. Barredo, M.
Jannatipour and R.G. Moran, J. Med. Chem., 1992, 35, 4450.
H.O. Smith, J.A. Blessing and L. Vaccarello, Gynecol. Oncol., 2002, 84, 140.
S.C. Grant, M.G. Kris, C.W. Young and F.M. Sirotnak, Cancer Invest., 1993,
11, 36.
13
6
1
5
1
1
16
−1
+
17 J.D. Roberts, E.A. Poplin, M.B. Tombes, B. Kyle, D.V. Spicer, S. Grant, T.
2
0
20
6
3
Synold and R. Moran, Cancer Chemother. Pharmacol., 2000, 45, 103.
6
18
A. Gangjee, J. Yu, R.L. Kisliuk, W.H. Haile, G. Sobrero and J.J. McGuire, J.
Med. Chem., 2003, 46, 591.
Acknowledgements
19
M. Shohreh, J.M. Falcón-Pérez, E. González, O. Millet, J.M. Mato and K.
Farzad, Chem. Pharm. Bull., 2012, 60, 70.
We thank the management, Anthem Biosciences, Bangalore,
India, for their invaluable support and allocation of resources
for this work. We thank the analytical chemistry team of
Anthem Biosciences for carrying out all the analytical work.
We also thank the discovery team of Anthem Biosciences for
executing the antibacterial studies.
20 F. Itoh, Y. Yoshioka, K. Yukishige, S. Yoshida, M. Wajima, K. Ootsu and H.
Akimoto, Chem. Pharm. Bull., 1996, 44, 1498.
21
F. Itoh, K. Yukishige, M. Wajima, K. Ootsu and H. Akimoto, Chem. Pharm.
Bull., 1995, 43, 230.
2
2
2
2
3
4
F. Itoh, Y. Yoshioka, K. Yukishige, S. Yoshida, K. Ootsu and H. Akimoto,
Chem. Pharm. Bull. 2000, 48, 1270.
C.J. Barnett, T.M. Wilson and M.E. Kobierski, Org. Process Res. Dev., 1999,
3
, 184.
P. Baburajan, R. Senthilkumaran and K.P Elango, New. J. Chem., 2013, 37,
050.
25 P. Baburajan and K.P. Elango, Tetrahedron Lett., 2014, 55, 1006.
Electronic Supplementary Information
The ESI is available from:
3
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data