Microwave-based synthesis of novel thienopyrimidine bioisosteres of gefitinib

Article abstract of DOI:10.1016/j.tetlet.2007.11.135

A series of novel 2-unsubstituted 4-(substituted)anilinothieno[2,3-d]pyrimidines is synthesized through the chlorination of the corresponding 2-unsubstituted-thieno[2,3-d]-pyrimidin-4-ones, followed by the nucleophilic displacement of the 4-Cl group of 9, with a variety of anilines. All four steps of this synthesis involve microwave irradiation (MWI) and the entire synthesis requires only 2 h.

Full text of DOI:10.1016/j.tetlet.2007.11.135

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1269–1273
Microwave-based synthesis of novel thienopyrimidine
bioisosteres of gefitinib
Manisha S. Phoujdar a, Muthu K. Kathiravan b, Jitender B. Bariwal c,
Anamik K. Shah c, Kishor S. Jain a,*
a Sinhgad College of Pharmacy, Pharmaceutical Chemistry, S. No. 44/1, Vadgaon (BK), Sinhgad Road, Pune 411 041, India
b Poona College of Pharmacy, Pune 411 038, India
c Department of Chemistry, Saurashtra University, Rajkot 360 005, India
Received 10 June 2007; revised 15 November 2007; accepted 21 November 2007
Available online 26 December 2007
Abstract
A series of novel 2-unsubstituted 4-(substituted)anilinothieno[2,3-d]pyrimidines is synthesized through the chlorination of the corres-
ponding 2-unsubstituted-thieno[2,3-d]-pyrimidin-4-ones, followed by the nucleophilic displacement of the 4-Cl group of 9, with a variety
of anilines. All four steps of this synthesis involve microwave irradiation (MWI) and the entire synthesis requires only 2 h.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Thieno[2,3-d]pyrimidines; MWI; Library synthesis
1. Introduction
sioned that a focused library of analogues of 6 would pro-
vide interesting SAR data and allow us to analyze and
improve the anticancer activity of this scaffold.
Several tyrosine kinase inhibitors such as gefitinib1
(IressaÒ) 1, erlotinib2 (TarcevaÒ) 2, lapatinib3 3 and can-
ertinib4 4 have been found to exhibit effective antitumour
activity. Bioisosterism between benzene and thiophene is
well known and widely documented.5 Based on this,
Munchhof et al.6 reported the design and structure activity
relationship (SAR) of the bioisosteric thieno[3,2-b]pyr-
imidines 5, as selective VEGFR-2 kinase inhibitors. This
prompted us to explore the synthesis of the isomeric
4-anilino-2-unsubstituted-5,6-disubstituted-thieno[2,3-d]pyr-
imidines 6 for the evaluation of their antitumour activity
(Fig. 1).
To meet the requirements of enhancing drug-like library
synthesis, we herein report the synthesis of the biologically
significant thienopyrimidine nucleus using microwave-
assisted organic synthesis (MAOS) which has evolved in
recent years as an important technique in Green chemis-
try.8 Though having the major drawback of not being suit-
able for scale-up to bulk quantities, it offers the advantages
of being efficient and rapid and thus finds great utility as a
tool in new drug discovery research (NDDR) for the high
throughput automated parallel syntheses of diverse com-
pound libraries. The synthesis of 6 is depicted in Scheme 1.
The conventional methods for the synthesis of the key
starting materials, thiophene o-amino esters 7 require
3–4 h using variants of the Gewald reaction.9–11 The use
of microwave irradiation7 offers an efficient method for
We initiated this study with the goal of expanding the
efficiency of our recently reported7 methodology for the
synthesis of 2-amino-3-carbethoxy-4,5-disubstituted thio-
phene by microwave irradiation and to prepare chemical
libraries by further compound functionalization. We envi-
the synthesis of 2-amino-3-carboethoxythiophenes
7
variously substituted at C-5 and C-6, in better yields
(Scheme 1) and with a substantial reduction in the reaction
time, compared to the conventional methods.9–11
*
Corresponding author. Tel.: +91 9422322070; fax: +91 20 24354720.
E-mail address: ks_jain@vsnl.net (K. S. Jain).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.135

1270
M. S. Phoujdar et al. / Tetrahedron Letters 49 (2008) 1269–1273
F
HN
N
O
HN
N
Cl
O
O
N
O
O
O
N
N
H3CO
2
1
F
O
S
Cl
O
O
HN
O
HN
N
N
F
3
H
N
O
NH
N
HN
N
Cl
HN
O
S
N
N
R
N
5
4
R4
O
HN
N
R3
R1
N
R2
S
H
6
R1, R2 = H, alkyl, cycloalkyl;
R3, R4 = H, halo, alkyl, alkoxy, etc
Fig. 1. Structures of some tyrosine kinase inhibitors.
For the conventional preparation of 2-unsubstituted-
5,6-disubstituted-thieno[2,3-d]pyrimidin-4(3H)-ones 8, the
thiophene o-amino esters are cyclized with the ‘C–N’ com-
ponent formamide at reflux for 8–12 h.
This same reaction under microwave irradiation at
350 W was accomplished in just 25–28 min to yield 8 in
excellent yields, as well as, purities. The best result was
obtained for compound 8a, (87%), in which the reaction
time was reduced from 8–10 h to 25 min.
The next step involved the chlorination of intermedi-
ates 8. This is normally achieved using dimethylformam-
ide and phosphorus oxychloride (POCl3) or by the
direct use of POCl3 at reflux. In contrast, when com-
pounds 8a,b were treated with POCl3 under MWI
(350 W) for 10–12 min, the reaction went to completion.
This microwave irradiation method for the chlorination
not only reduced the overall reaction time from 12–14 h
to 10–12 min, but also improved the purity and yields
of the product. The physical data of 8a,b and 9a,b are
shown in Table 1.
The final step in the synthesis of compounds 6 involved
nucleophilic displacements of the 4-chloride atom of 9a,b
with a variety of substituted anilines. Using the conven-
tional methodology this was achieved by treating 1 mol
equiv of the appropriate 4-chloro compound 9 with two
mol equivalents of the requisite aniline in iso-propanol at
reflux for 5–9 h. In contrast, irradiating (350 W) the reac-
tion mixture for 15–26 min yielded the target compounds
6a–n in excellent yields. The addition of a catalytic quantity
of concd HCl expedited the reaction. Such a synthesis

M. S. Phoujdar et al. / Tetrahedron Letters 49 (2008) 1269–1273
1271
O
R1
OC2H5
O
NC
COOC2H5
HCONH2
R2
R1
Secondary amine,
S8, DMF or EtOH
Reaction conditions b
R2
NH2
S
Reaction conditions a
7a, b
Cl
R1
O
R1
N
POCl3
NH
R2
R2
Reaction conditions c
S
N
H
S
N
H
9a, b
8a, b
R4
NH2
R4
HN
R3
R1
R3
N
R2
Iso-propanol
Reaction conditions d
S
N
H
6a-n
Scheme 1. Reaction conditions: (a) under microwave irradiation, 350 W, 2–5 min, (60–90%); (b) 350 W, 25–28 min, (87–92%); (c) 350 W, 10–12 min,
(81–84%); (d) 350 W, 15–26 min, (68–98%).
completely under microwave irradiation was hitherto,
unreported for these condensed thienopyrimidines (Table
2). The conventional reaction protocol requires long over-
all reaction times, often exceeding 24 h for the synthesis of
these target compounds, thus, representing a serious detri-
ment to adapting the conventional process for the parallel
library synthesis of these compounds. In contrast, micro-
wave irradiation greatly reduced the reaction times from
hours to minutes and the overall four-step synthesis
required a maximum of 2 h reaction time (not considering
the time required for work-up as well as recrystallizations).
Hence, the synthetic methodology reported herein is a very
efficient method for the parallel library synthesis of con-
densed pyrimidines.
2. Experimental
Microwave synthesizer, (Questron Technologies Corpo-
ration, Canada) QPro-M model monomode open-vessel
was used for the synthesis.
Table 1
Physical data of 2-unsubstituted-5,6-disubstituted[2,3-d]pyrimidin-4(3H)-ones (8a,b) and 2-unsubstituted-4-chlorothieno[2,3-d]pyrimidines (9a,b)12
R3
R1
N
R2
S
N
H
S. No.
R1
R2
R3
Conventional method
Microwave-assisted method
Yield (%)
Mp (°C)
Time (h)
Yield (%)
Mp (°C) (solv. of crystn.)
Time (min)
8a
8b
9a
9b
–(CH2)4–
C2H5
–(CH2)4–
C2H5
OH
OH
Cl
67
82
75
71
208–210
195–197
114–115
53–56
8–10
8–10
12–14
12–14
87
92
84
81
209–211 (DMF–MeOH)
195–197 (DMF–MeOH)
113–115 (n-hexane)
25
28
12
10
H
H
Cl
54–56 (n-hexane)

1272
M. S. Phoujdar et al. / Tetrahedron Letters 49 (2008) 1269–1273
Table 2
Physical data of 2-unsubstituted-4-arylaminothieno[2,3-d]pyrimidines (6a–n)12
R4
HN
R3
R1
N
R2
S
N
Conventional method
H
S. No.
R1
R2
R3
R4
Microwave-assisted method
Yield (%)
Mp (°C)
Time (h)
Yield (%)
Mp (°C)a (solv. of crystn.)b
Time (min)
6a
6b
6c
6d
6e
6f
6g
6h
6i
–( CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
H
H
H
H
Cl
H
H
H
H
H
H
Cl
H
H
H
Br
Cl
F
59
84
73
81
62
69
87
59
86
65
61
70
82
85
176–178
158–160
136–138
166–168
135–137
145–147
141–143
206–208
234–237
138–140
220–222
170–172
139–141
145–147
8–9
8–9
8–9
8–9
8–9
8–9
6–8
5–6
5–6
5–6
5–6
5–6
5–6
5–6
79
97
82
87
75
78
95
68
96
78
77
91
92
98
175–177 (I)
158–160 (I)
134–137 (I)
167–169 (I)
136–138 (I)
144–146 (I)
140–142 (I)
205–207 (B–M)
234–236 (M–C)
139–141 (B–M)
220–222 (I–C)
171–173 (M–C)
138–140 (I)
25
23
22
20
20
22
25
21
19
16
18
15
20
26
F
OCH3
CH3
H
Br
Cl
H
H
H
H
H
H
H
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
6j
6k
6l
F
F
6m
6n
a
OCH3
CH3
145–147 (B–C)
The newly synthesized compounds were characterized by spectroscopic data12 and by microanalysis (0.4% of calculated C and H).
b
I = iso-propanol, B = benzene, C = chloroform, M = methanol.
3. General procedures
neutralized with sodium bicarbonate. Recrystallization
from n-hexane yielded crystalline 4-chloro-thieno[2,3-d]-
pyrimidines (9a,b).
3.1. Reaction of 2-amino-3-carbethoxythiophenes (7a,b) with
formamide
3.3. Reaction of 4-chlorothieno[2,3-d]pyrimidines (9a,b)
with various anilines to afford target compounds (6a–n)
A
mixture of 2-amino-3-carbethoxythiophene (7;
0.02 mol) and formamide (15 ml) was irradiated at 350 W
for 25–28 min in a microwave synthesizer. The reaction
mixture was allowed to cool to room temperature, and then
poured on to ice water. The resulting precipitated solid was
filtered, washed with chilled water and dried. The crude
product on recrystallization from methanol–dimethylform-
amide (10:1) yielded the requisite thieno[2,3-d]pyrimidin-
4(3H)-ones (8a,b).
A mixture of the appropriate 4-chlorothieno[2,3-d]-
pyrimidine (9a,b; 0.022 mol) and the aniline (0.044 mol)
in iso-propanol (20 ml) was irradiated with microwaves
at 350 W for 15–26 min. The reaction mixture was chilled
overnight at 5 °C and the separated solid was filtered,
washed with cold iso-propanol and air-dried. The crude
product, then on recrystallization from iso- propanol,
afforded 4-arylaminothieno[2,3-d]pyrimidines (6a–n).
3.2. Chlorination of thieno[2,3-d]pyrimidin-4(3H)-ones
(8a,b) to 4-chlorothieno[2,3-d]pyrimidines (9a,b)
References and notes
1. Arteaga, C. L.; Johnson, D. H. Curr. Opin. Oncol. 2001, 13, 491–
498.
2. Higgins, B.; Kolinsky, K.; Smith, M.; Beck, G.; Rashed, M.; Adames,
V.; Linn, M.; Wheeldon, E.; Gand, L.; Birnboeck, H.; Hoffmann, G.
Anti-Cancer Drugs 2004, 15, 503–512.
A mixture of the appropriate thieno[2,3-d]pyrimidin-
4(3H)-one (8a,b; 0.02 mol) and phosphorus oxychloride
(15 ml) was irradiated with microwaves (350 W) for
10–12 min. The extent of reaction was monitored by
TLC. Thereafter, POCl3 was removed under vacuum and
the residue obtained was poured onto ice-cold water and
3. Burris, H. Oncologist 2004, 3, 10–15.
4. Galmarini, C. M. Invest. Drugs 2004, 7, 58–63.

M. S. Phoujdar et al. / Tetrahedron Letters 49 (2008) 1269–1273
1273
5. Knittel, J.; Zavod, Robin. In Foye’s Principles of Medicinal Chem-
istry; Williams, D. A., Lemke, T. L., Eds.; Lippincott Williams and
Wilkins: Baltimore, 2005; p 61.
(2H, s, CH2 at 5), 3.02 (2H, s, CH2 at 8), 7.24 (1H, s, CH at 2), 8.07
(1H, br d, J = 6.0 Hz, NH at 3); MS m/z 206 (M+); Anal. Calcd for
C
10H10N2OS: C, 58.23; H, 4.89. Found: C, 58.27; H, 4.69.
Cl
6. Munchhof, M. J.; Beebe, J. S.; Casavant, J. M.; Cooper, B. A.; Doty,
J. L.; Higdon, R. C.; Hillerman, S. M.; Soderstrom, C. I.; Knauth, E.
A.; Marx, M. A.; Rossi, A. M. K.; Sobolov, S. B.; Sun, J. Bioorg.
Med. Chem. Lett. 2004, 14, 21–24.
3
N
4
5
6
2
7. Kathiravan, M. K.; Shishoo, C. J.; Chitre, T. S.; Mahadik, K. R.;
Jain, K. S. Synth. Commun. 2008, in press.
N
7
1
S
8. Oliver Kappe, C.; Alexander, S. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005; pp 47–81.
9. (a) Gewald, K. Z. Chem. 1962, 305–306; Gewald, K. Chem. Abstr.
1963, 58, 6770; (b) Gewald, K. Z. Chem. 1961, 1, 349; Gewald, K.
Chem. Abstr. 1963, 58, 496.
10. Gewald, K. Chem. Ber. 1965, 98, 3571–3576.
11. Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber. 1966, 99, 94–99.
12. Analytical data for the representative compounds
O
8
9a
Compound 9a: IR KBr, cmꢀ1: 2934 ðmCH Þ, 730 (mC–Cl); 1H NMR
2
(300 MHz, CDCl3): d 1.91 (4H, d, J = 3.0 Hz, CH2 at 6 and 7), 2.86
(2H, s, CH2 at 5), 3.09 (2H, s, CH2 at 8), 8.69 (1H, s, CH at 2); MS
m/z 226 (M+2); Anal. Calcd for C10H9ClN2S: C, 53.45; H, 4.04.
Found: C, 53.55; H, 4.24.
OC2H5
4
HN
3
5
3
N
4
NH2
5
2
6
2
6
S
1
N
7
7
1
7a
Compound 7a: IR KBr, cmꢀ1: 3415 and 3305 ðmNH Þ, 2916 ðmCH Þ,
S
8
2
2
1651 (mCO); 1H NMR (300 MHz, CDCl3): d 1.33 (3H, t, J = 6.9 Hz,
COOCH2CH3), 1.75 (4H, d, J = 6.0 Hz, CH2 at 5 and 6), 2.51 (2H, s,
CH2 at 4), 2.68 (2H, s, CH2 at 7), 4.25 (2H, q, J = 7.2, COOCH2CH3),
5.87 (2H, br s, NH2); MS m/z 225 (M+); Anal. Calcd for
6a
Compound 6a: IR KBr, cmꢀ1: 3428 (mNH), 2925 ðmCH Þ, 1602 (mNH);
2
1H NMR (300 MHz, CDCl3): d 1.90 (4H, d, J = 9, CH2 at 6 and 7),
2.82 (2H, s, CH2 at 5), 3.03 (2H, s, CH2 at 8), 7.08–7.37 (3H, m, Ar-
H), 7.24 (1H, s, NH at 4), 7.61 (2H, d, J = 9.0 Hz, Ar-H), 8.41 (1H, s,
C
11H15NO2S: C, 58.64; H, 6.71. Found: C, 58.44; H, 6.61.
O
HO
H
3
4
3
N
4
N
5
8
2
5
2
6
7
6
N
1
N
1
7
S
S
8
8a ii
8ai
Compound 8a: IR KBr, cmꢀ1: 2938 ðmCH Þ, 1658 (mCO); 1H NMR
CH at 2); MS m/z 281 (M+); Anal. Calcd for C16H15N3S: C, 68.30; H,
5.37. Found: C, 68.39; H, 5.30.
2
(300 MHz, CDCl3): d 1.86 (4H, d, J = 6 Hz, CH2 at 6 and 7), 2.86