Facile methods for the synthesis of 5-aryl and 5-iodo pyrrolo[2,3-d] pyrimidines

Article abstract of DOI:10.1002/jhet.1937

An efficient and environmentally benign one-pot method has been developed for the synthesis of 4-amino-5-arylpyrrolo[2,3-d]pyrimidines. Phthalimido acetophenones were reacted with cyanoacetamide to give 2-amino-4-phenyl-1H- pyrrole-3-carboxamides, which were further converted to 5-aryl-3H-pyrrolo[2,3-d] pyrimidin-4-ones. A novel method is also developed for the synthesis of 4-amino-5-iodopyrrolo[2,3-d]pyrimidines.

Full text of DOI:10.1002/jhet.1937

Month 2014
Facile Methods for the Synthesis of 5-Aryl and 5-Iodo Pyrrolo[2,3-d]
pyrimidines
a
b
c
*
K. Venkata Rao, M. Raghu Prasad, and A. Raghuram Rao
aPharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh 160014, India
bShri Vishnu College of Pharmacy, Bhimavaram, West Godavari Dist., A.P 534 202, India
cPharmaceutical Chemistry Division, University College of Pharmaceutical Sciences, Kakatiya University,
Warangal 510009, India
*
E-mail: raghumed@kakatiya.ac.in
Received July 19, 2012
DOI 10.1002/jhet.1937
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and environmentally benign one-pot method has been developed for the synthesis of
4-amino-5-arylpyrrolo[2,3-d]pyrimidines. Phthalimido acetophenones were reacted with cyanoacetamide to
give 2-amino-4-phenyl-1H-pyrrole-3-carboxamides, which were further converted to 5-aryl-3H-pyrrolo
[2,3-d]pyrimidin-4-ones. A novel method is also developed for the synthesis of 4-amino-5-iodopyrrolo
[2,3-d]pyrimidines.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
library of analogs without any substituent at C-2 of
IV. Although literature shows a number of methods
to synthesize pyrrolo[2,3-d]pyrimidines, most of them
needed desulfurization of 2-thioxopyrrolo[2,3-d]pyrimidines
(II or III, Fig. 1). This step involves the use of a large excess
of raney nickel thereby making the methods environmentally
unacceptable. Further, they also suffer from some practical
disadvantages such as longer reaction times and inconsistent
yields that are vital for process development [9,10]. On the
basis of these observations, we sought to develop a method
that is not only sufficiently facile and robust but also environ-
ment friendly.
During the course of our current research, two facile
methods (Scheme 1 and 3) were developed to synthesize
C-2 unsubstituted analogs of IV. These novel methods
are highly efficient in synthesis of several 5-iodo and 5-aryl
pyrrolo[2,3-d]pyrimidines. The details of the protocols are
described in this communication.
The fused heterocyclic framework of pyrrolo[2,3-d]
pyrimidine (I, Fig. 1) has been used as a prototype scaffold
for the synthesis of a wide variety of analogs to study and
improve their biological properties. Several of them have
been reported to exhibit tyrosine kinase [1], adenosine
kinase [2], and platelet-derived growth factor receptor
inhibitor activities [3]. They were also reported to possess
A1-adenosine receptor antagonist activity [4] and antican-
cer activities [5,6]. A number of multistep methodologies
have been reported to synthesize these compounds [6,7].
As shown in Figure 1, these target compounds are gener-
ally synthesized by two methods: initial synthesis of suit-
ably substituted pyrrole nucleus followed by conversion
to I (Method A, Fig. 1), and the latter is the other way
round, that is, initial formation of pyrimidine skeleton
followed by cyclization to I (Method B) [8].
In our drug discovery program, a variety of 5-aryl and
5-halopyrrolo[2,3-d]pyrimidin-4-amines revealed to be
interesting for tyrosine kinase and adenosine kinase inhib-
itor activities. For generating new ligands with better phar-
macological profiles, our structure-based drug design
studies propose that hydrophobic substituent’s such as
phenyl and halogen at C-5 and amines at C-4 positions of
pyrrolo[2,3-d]pyrimidine scaffold (IV, Fig. 2) can poten-
tially improve the desired affinities towards the target.
Contrary to this, any substituent bulkier than hydrogen at
C-2 was indicated to be detrimental for the biological
activity. Hence, it was felt worthwhile to synthesize a
RESULTS AND DISCUSSION
As shown in Scheme 1 (Method 1), 4-amino-6-chloro-
pyrimidine (1) was used as starting material to synthesize
the target molecules. Compound 3 is utilized either from
commercial sources or was synthesized by reported
methods [11]. Iodination followed by Sonagashira cross-
coupling reaction with TMS acetylene using Pd(PPh3)
2Cl2 as catalyst provided the alkyne 3 [12]. In the
presence of iodine, base catalyzed cyclization of 3 gave
© 2014 HeteroCorporation

K. Venkata Rao, M. Raghu Prasad, and A. Raghuram Rao
Vol 000
X
R
X
N
X
N
R
Scheme 1. General method for the synthesis of 5-iodopyrrolo[2,3-d]
pyrimidines; reagents and conditions: (a) I2 (2equiv), K2CO3, DMF/H2O,
45ꢀC, 65%.; (b) TMS-acetylene, Pd(PPh3)2Cl2, CuI, Et3N, MeCN, RT,
2 h; (c) (i) I2 (3 equiv), anhyd. K2CO3, MeCN; (ii) MeOH, K2CO3; (d)
R-NH2, K2CO3, DMF or Ar—NH2, Pyridine, 80ꢀC.; (e) Pd(PPh3)2Cl2,
Ar(BOH)2, DME, 80ꢀC, 8 h.
R
N
Raney-Nickel
Raney-Nickel
N
N
N
H
S
N
N
N
HS
H
H
III
I
II
pyrrolo[2,3-d ]pyrimidine
Cl
O
R
O
Method B
Method A
Method B
NH2
NH2
Cl
NH2
I
Si
a
I
b
c
N
N
O
N
R
N
O
R
Y
N
Cl
Cl
N
OEt
OEt
HN
N
2
N
4
Cl
N
H
HN
N
H2N
3
S
N
NH2
1
H
S
N
NH2
H
d
Y = CN, CONH2, COOEt
R
Figure 1. General methods for the synthesis of pyrrolo[2,3-d]pyrimidines.
R
N
R1
NH
N
NH
I
e
N
N
N
N
6
H
H
5-iodopyrrolo[2,3-d]pyrimidine (4). Different inorganic
bases were found to be suitable for this ring closure.
However, reactions with CsCO3, K2CO3 were found to
be favorable not only in obtaining automatic TMS depro-
tection but also to give good yields of 4.
5
of azides (11) followed by reduction with Fe/NH4Cl was
also low yielding. We surmise that rapid self-condensing
nature of 12 could be responsible for these low yields.
Thus, phthalimido acetophenones (13) were synthesized
and used as synthetic equivalents of 12 (Scheme 3)
[14,15]. Under basic reaction conditions, 13 readily
produced 12 (Scheme 2) that was utilized in situ for the
synthesis of 14 conveniently.
Because the pyrimidinone formation step requires strong
base, such as sodium ethoxide, it was chosen as the base
for the pyrrole formation as well. 2-Cyanoacetamide was
treated with sodium ethoxide at ice-bath temperature, fol-
lowed by 13 at 40–50ꢀC. Upon consumption of 13, triethyl
orthoformate was added, and reaction continued for 4–8 h
at 60–80ꢀC; the reaction mixtures were then quenched
with water, solvents evaporated, and 5-arylpyrrolo[2,3-d]
pyrimidinones (15) were isolated by adjusting the pH
to 7–8. Reactions with ethyl-2-cyanoacetate, instead of
2-cyanoacetamide, were also resulted in 14; in such
case, formamide is used to convert 14 to 15. This
one-pot method is highly efficient for the synthesis of
several 5-aryl and 4,5-diarylpyrrolo[2,3-d]pyrimidines.
Reflux of 15 with POCl3 followed by nucleophilic sub-
stitution of 4-chloro with different amines resulted in
4-substituted-5-arylpyrrolo[2,3-d]pyrimidines (6) in good
yields [some of the synthesized analogs are depicted in
Fig. 3(B), 6a–b, 15a–b].
Nucleophilic substitution of 4-chloro with different
alkyl/aryl amines generated a library of 4-amino-5-
iodopyrrolo[2,3-d]pyrimidines (5) in good yields [few of
the synthesized compounds are depicted in Fig. 3(A): 4 and
5a–d]. Similarly, Suzuki cross-coupling reaction of 5
with arylboronates provided 5-aryl analogs (6) in
moderate yields. However, the necessity of involving
different commercially inaccessible boronic acids hin-
dered the utility of this method. Consequently, we
decided to develop an alternative robust method to syn-
thesize diverse analogs of 6. It was envisaged that
method A (Fig. 1) could be a facile process for the syn-
thesis of target molecules (6). Therefore, Knorr pyrrole
synthesis was adopted to synthesize key intermediates
2-amino-4-arylpyrrole-3-carboxamides/carbonitriles (14)
[8,9]. Because several of the starting 2-aminoacetophe-
nones (12) are either not commercially available or
prohibitively expensive, an attempt was made to synthe-
size 12 from the respective 2-bromoacetophenones (9,
Scheme 2). Heating of acetophenones under reflux with
NBS and p-toluenesulfonic acid in acetonitrile resulted
in quantitative yields of 9 [13].
Unusually conversion of 9 to 12 using known proce-
dures resulted in poor yields in our hands. Synthesis of
hexamine salts (10) followed by an acid-catalyzed hydroly-
sis resulted in low yields of 12. In another attempt, synthesis
important for activity
R' = alkyl, aryl
R = Br, I, aryl, heteroaryl
R'
NH
R
5
3
important for activity
N
6
2
substituents detrimental
for activity
N
N
1
R''
R'' = H, CONHR
IV
Figure 2. Pyrrolo[2,3-d]pyrimidine scaffold of medicinal interest.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of 5-Aryl and 5-Iodo Pyrrolo[2,3-D]pyrimidines
B
O
A
Cl
N
NH2
N
O
I
I
O
O
N
N
N
HN
HN
N
N
H
H
N
N
H
N
H
5a
4
15a
15b
X
NH
N
I
O
N
NH
N
I
N
NH
N
NH
N
N
H
N
H
N
N
H
N
N
N
H
5b) X = OH
5c) X = Cl
H
5d
6a
6b
Figure 3. Few of the synthesized pyrrolo[2,3-d]pyrimidines.
Scheme 2. Synthesis of 2-aminoacetophenones and phthalimido aceto-
phenones; reagents and conditions: (a) ZnCl2/Ac2O, RT; (b) NBS,
p-toluenesulfonic acid, CH3CN, 80ꢀC; (c) hexamine, CHCl3, RT; (d) HCl,
0ꢀC – RT; (e) NaN3, THF, RT; (f) Fe/NH4Cl, THF/EtOH/H2O (4:1:0.5);
(g) DMF, pot.phthalimide, RT.
for the development of facile and environmental friendly
methods. Although several multistep methodologies are
existing for C-2 unsubstituted pyrrolo[2,3-d]pyrimidines,
most of them involve use of large excess of raney nickel
for desulfurization process making them environmentally
unacceptable. The present study reveals two novel methods
that are efficient to synthesize these analogs. Particu-
larly, phthalimidoacetophenone method (Scheme 3) is
highly useful for the synthesis of 5-aryl analogs of
pyrrolo[2,3-d]pyrimidines. This one-pot method com-
pletely circumvents the use of metal catalysts thereby
offers an environmental friendly protocol.
O
N
Br
H2N
O
O
N
f
O
N
N
a
d
b
c
R
R
R
R
12
R
10
7
8
9
f
g
e
R
N3
R
O
O
R
O
N
X
11
13
O
N
H2N
H
Acknowledgments. The authors thank the Chairman, University
Institute of Pharmaceutical Sciences (UIPS), Panjab University
(PU), Chandigarh for providing facilities. Authors thank to Shri
Avatar Singh, SAIF, Central Instrumentation Laboratory, PU for
recording NMR spectra. KVR thanks CSIR, New Delhi for
awarding a Senior Research Fellowship (Sanction No: 09/135/
0628/2011/EMR-I).
R = H, Br, OCH3, alkoxy
14
X = CN, CONH2, COOEt
Scheme 3. Synthesis of 5-arylpyrrolo[2,3-d]pyrimidines; reagents and
conditions: (a) DMF, 3 equiv NaoEt/EtOH; (b) 5 equiv CH(OEt)3
(if X = CONH2), HCONH2 (if X = COOEt), 60ꢀC; (c) POCl3, 4 h,
120ꢀC; (d) R—NH2, K2CO3, DMF; (e) PhNHCONH2, 12 h, 80ꢀC.
R
R
R
R
R1
N
Cl
N
O
N
NH
N
REFERENCES AND NOTES
b
c
d
N
X
HN
N
N
N
H
[1] (a) Widler, L.; Missbach, M.; Mira, S.; Altmann, E. Bioorg
Med Chem Lett 2001, 11, 849; (b) Altmann, E.; Missbach, M.; Green,
J.; Mira, S.; Wagenknecht H. A.; Widler, L. Bioorg Med Chem Lett
2001, 11, 853.
N
H
H2N
H
H
6a
16
14
15
e
a
[2] Ugarkar, B. G.; DaRe, J.; Kopcho, J.; Browne, C. E.;
Schanzer, J.; Wiesner, J. B.; Erion, M. D. J Med Chem 2000, 43, 2883.
[3] Zhang, J.; Yang, P. L.; Gray, N. S. Nature Rev Cancer 2009,
9, 28.
R
O
N
X
O
O
R
NH
N
H
N
N
[4] (a) Hess, S.; Mueller, C. E.; Frobenius, W.; Reith, U.; Klotz, K.
N.; Eger, K. J Med Chem 2000, 43, 4636; (b) Muller, C. E.; Geis, U.; Grah-
ner, B.; Lanzner, W.; Eger, K. J Med Chem 1996, 39, 2482.
[5] Jung M. H.; Kim, H.; Choi, W. K.; El-Gamal M. I.; Park, J. H.;
Yoo, K. H.; Sim, T. B.; Lee, S. H.; Baek, D.; Hah, J. M.; Cho, J. H.; Oh,
C. H. Bioorg Med Chem Lett 2009, 19, 6538.
[6] Taylor, E. C.; Liu, B.. J Org Chem 2003, 68, 9938.
[7] (a) West, R. A. J Org Chem 1961, 26, 4959; (b) Seela, F.; Zulauf,
M. Synthesis 1996, 726; (c) Ramzaeva, N.; Seela, F. Helv Chim Acta 1996,
79, 1549; (d) Seela, F.; Thomas, H. Helv Chim Acta 1995, 78, 94.
O
N
N
H
X = CONH2, CN, COOEt
13
6b
R = H, Br, OCH3, alkoxy
CONCLUSION
The immense biological significance of pyrrolo[2,3-d]
pyrimidine ring system generated considerable attention
Journal of Heterocyclic Chemistry
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K. Venkata Rao, M. Raghu Prasad, and A. Raghuram Rao
Vol 000
[8] Amarnath, V.; Madhav, R. Synthesis 1974, 837.
[9] (a) Noell, C. W. Robins, R. K. J. Heterocycl Chem 1964, 1, 34;
(b) Williams, D. M.; Loakes, D.; Brown, D. M. J Chem Soc, Perkin Trans
1 1998, 3565.
[10] (a) Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer,
T.; Lydon, N. J Med Chem 1996, 39, 2285; (b) El-Bayouki, K. A. M.;
Basyouni, W. M.; Hosni, H.; El-Deen, A. S. J Chem Res Synop 1995,
314; (c) Luepke, U.; Seela, F. Chem Ber 1979, 112, 799; (d) Okuma, K.
J Antibiot 1961, 14, 343; (e) Gerster, J. F.; Hinshaw, B. C.; Robins, R. K.;
Townsend, L. B. J Heterocycl Chem 1969, 6, 207.
[11] Gomtsyan, A.; Didomenico, S.; Lee, C. H.; Matulenko, M. A.;
Kim, K.; Kowaluk, E. A.; Wismer, C. T.; Joe, M.; Yu, H.; Kohlhaas, K.;
Jarvis, M. F.; Bhagwat, S. S. J Med Chem 2002, 45, 3639.
[12] Heravi, M. M.; Sadjadi, S. Tetrahedron 2009, 65, 7761.
[13] Lee, J. C.; Bae, Y. H.; Chang, S. K. Bull Korean Chem Soc
2003, 24, 407.
[14] Lei, A.; Wu, S.; He, M.; Zhang, X. J Am Chem Soc 2004, 126,
1626.
[15] Yumoto, M.; Kawabuchi, T.; Sato, K.; Takashima, M. Jpn
Kokai Tokkyo Koho 1998, JP 10316654 A2.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet