AlCl3-induced (hetero)arylation of thienopyrimidine ring: a new synthesis of 4-substituted thieno[2,3-d]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2010.04.057

AlCl₃ facilitated C-C bond forming reaction between 4-chloro-thieno[2,3-d]pyrimidines and (hetero)arenes affording a direct and single-step method for the synthesis of 4-(hetero)aryl substituted thieno[2,3-d]pyrimidines. A number of novel thien

Full text of DOI:10.1016/j.tetlet.2010.04.057

Tetrahedron Letters 51 (2010) 3269–3273
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AlCl3-induced (hetero)arylation of thienopyrimidine ring: a new synthesis
of 4-substituted thieno[2,3-d]pyrimidines
a,
K. Shiva Kumar a, Srinivas Chamakuri a, Peddy Vishweshwar b, Javed Iqbal a, , Manojit Pal
*
*
a Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
b Pharmaceutical Development, Aurigene Discovery Technologies Ltd., Miyapur, Hyderabad 500 049, India
a r t i c l e i n f o
a b s t r a c t
Article history:
AlCl3 facilitated C–C bond forming reaction between 4-chloro-thieno[2,3-d]pyrimidines and (hetero)are-
nes affording a direct and single-step method for the synthesis of 4-(hetero)aryl substituted thieno[2,3-
d]pyrimidines. A number of novel thienopyrimidines were prepared in good to excellent yields using this
methodology. The molecular structure of a representative compound was established unambiguously by
single crystal X-ray diffraction.
Received 9 March 2010
Revised 1 April 2010
Accepted 8 April 2010
Available online 18 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrimidine nucleus fused with another heterocycle has been
found to be an integral part of many natural products, agrochemi-
cals and veterinary products.1,2 This class of compounds has also
found wide applications in the design and discovery of novel bioac-
tive compounds and drugs.3 Recently, thienopyrimidine that be-
longs to this class have attracted considerable interest because of
their remarkable pharmacological properties.4–7 For example, 2-
alkoxy and 2-alkyl-subsituted thienopyrimidinones have shown
significant antifungal and antibacterial activities,4a–d whereas some
other derivatives exhibited promising anticonvulsant, angiotensin
II or H1 receptor antagonistic activities.4e–h Among thieno[2,3-
d]pyrimidine derivatives, 3-amino-5,6-dimethyl-2-[4-(1-phenyl-
In pursuance of our research under the new drug discovery
program, we became interested in the generation of a small-mol-
ecule library based on thieno[2,3-d]pyrimidine scaffold. Our li-
brary model is shown in Figure 2, which has three positions
for the introduction of diversity into this framework. Since the
C-4 substituent played a key role in displaying the pharmacolog-
ical activities of thienopyrimidine derivatives5–7 hence we fo-
cused on the C-4 position to introduce
a range of diverse
groups for the generation of a library of compounds. While a
methyl)-1-piperazinyl]thieno[2,3-d]pyrimidin-4(3H)-one5
A
and
various
R1
Various
groups
R2
4-(4-methyl-1-piperazinyl)-2-methylthio-6,7-dihydro-5H-cyclopenta
[4,5]thieno[2,3-d]pyrimidine6 B (Fig. 1) exhibited remarkable affin-
ity and selectivity for the 5-HT3 receptor.
substituents
4
N
3
R3
2
S
N
1
Figure 2. Diversity-based thieno[2,3-d]pyrimidine scaffold.
N
N
O
NH2
N
OH
S
N
N
N
S
N
N
SCH3
OH
OH
Cl
N
A
B
AlCl3
DCM
N
N
+
Figure 1. Examples of biologically active thieno[2,3-d]pyrimidin-2-ylmethan
S
S
N
amines.
OH
3a
1
2a
* Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: manojitpal@rediffmail.com, palmanojit@yahoo.co.uk (M. Pal).
Scheme 1. AlCl3-induced heteroarylation of resorcinol (2a) with 4-chloro thie-
no[2,3-d]pyrimidine (1).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.057

3270
K. S. Kumar et al. / Tetrahedron Letters 51 (2010) 3269–3273
Table 1
idine ring introduction of an aryl or heteroaryl moiety at the
Heteroarylation of 2a with 1 under various conditions
same position via C–C bond forming reaction is not common in
the literature. Only one method based on Suzuki coupling reac-
tion involving the use of palladium catalysts and boronic acids
at 75–80 °C for 24 h has been reported recently.9 The methodol-
ogy required the use of degassed solvent to prepare the expected
C–C coupled product. Moreover, the preparation of boronic acids
is often cumbersome while we required a simple and straightfor-
ward method to prepare our target compounds. Herein, we de-
scribe our recent studies on the AlCl3-induced C–C bond
forming reaction10 between thieno[2,3-d]pyrimidines and various
(hetero)arenes leading to a direct and new synthesis of 4-(het-
ero)aryl substituted thieno[2,3-d]pyrimidines. To the best of our
knowledge, this demonstration represents the first AlCl3-induced
Entry
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH3CN
EtOAc
THF
rt
rt
14
48
8
18
12
15
15
78
73
75
65
60
60
55
40
60
60
60
60
a
Isolated yields after column chromatography.
number of reports are available on the introduction of aliphatic
and aromatic amines at the C-4 position8 of thieno[2,3-d]pyrim-
Table 2
Synthesis of 4-(hetero)aryl substituted 5,6,7,8 tetrahydrobenzothieno[2,3-d]pyrimidines (3) via AlCl3-mediated C–C bond forming reaction between 1 and (hetero)arenes (2)a
Entry
Reactant (2)
Product (3)
Time (h)
Yieldb (%)
OH
HO
OH
N
1
8.0
75
3a
OH
2a
2b
2c
N
S
OH
2
12.0
75
HO
N
N
3b
3c
S
N
H
HN
3
8.0
75
N
N
S
N
N
4
5
6
7.0
7.0
7.0
73
72
74
N
N
3d
3e
2d
2e
S
N
N
N
N
S
Br
Br
HN
N
H
N
2f
3f
N
S
a
All the reactions were carried out using compound 1 (1.0 equiv), an appropriate arene or heteroarene 2 (1.0 equiv) and AlCl3 (1.2 equiv) in dichloromethane (5 mL) at
refluxing temperature.
b
Isolated yields after column chromatography.

K. S. Kumar et al. / Tetrahedron Letters 51 (2010) 3269–3273
3271
Initially, we decided to use 4-chloro thieno[2,3-d]pyrimidine11a
(1) as a key starting material, which was reacted with resorcinol 2a
in the presence of AlCl3 (Scheme 1).
Cl
S
N
N
R
N
The results of this study are summarized in Table 1. A mixture
of 1 (1.0 equiv), 2a (1.0 equiv) and AlCl3 (1.2 equiv) in dichloro-
methane (5 mL) was stirred at room temperature for 14 h when
both the reactants were consumed (monitored by TLC). After usual
work-up the desired compound 3a was isolated in 78% yield (Table
1, entry 1). Encouraged by this result, we then decided to examine
the effect of time, temperature and solvents on this heteroarylation
process. It was observed that the longer reaction time, for example,
48 h did not improve the product yield (Table 1, entry 2), whereas
the reaction was completed within 8 h when carried out at reflux
(Table 1, entry 3). Though the reaction was carried out initially in
dichloromethane, a number of other solvents were examined
(Table 1, entries 4–7). Despite the longer time allowed for the reac-
tion to proceed, none of these solvents provided a better yield of
3a.
4
N
S
5
AlCl3, DCM
reflux
RH
R
N
2
N
Cl
S
N
7
N
S
6
Scheme 2. AlCl3-induced heteroarylation of 2 with 4 and 6.
To test the generality and scope of this AlCl3-mediated C–C
bond forming process we then examined the reaction of chloro
derivative 1 with a range of arene and heteroarenes 2 (Table 2).
(hetero)arylation of
formation.
a thienopyrimidine ring via C–C bond
Table 3
AlCl3-mediated synthesis of 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine (5) and 6-methylthieno[2,3-d]pyrimidine (7)a
Entry
Reactant (2)
Product (5 or 7)
Time (h)
12.0
Yieldb (%)
5b
5c
1
2b
72
HO
HN
N
N
S
2
2c
8.0
75
N
N
S
N
3
4
5
2e
2a
2b
7.0
74
N
5d
7a
N
S
HO
OH
N
8.0
75
N
S
12.0
70
HO
N
N
7b
S
(continued on next page)

3272
K. S. Kumar et al. / Tetrahedron Letters 51 (2010) 3269–3273
Table 3 (continued)
Entry
Reactant (2)
Product (5 or 7)
Time (h)
Yieldb (%)
HN
6
7
8
2c
8.0
74
N
7c
N
S
N
2d
2e
7.0
75
N
7d
N
S
N
7.0
75
N
7e
N
S
Br
HN
9
2f
7.0
73
N
7f
N
S
a
All the reactions were carried out using compound 4 or 6 (1.0 equiv), an appropriate arene or heteroarene 2 (1.0 equiv) and AlCl3 (1.2 equiv) in dichloromethane (5 mL) at
refluxing temperature.
b
Isolated yields after column chromatography.
The reaction of chloro derivatives of other thieno[2,3-d]pyrimi-
dine such as 4-chloro-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-
d]pyrimidine11b (4) and 4-chloro-5-methylthieno[2,3-d]pyrimi-
dine11c (6) with various (hetero)arenes (2) (Scheme 2) was also
investigated (Table 3). Based on the results summarized in Tables
2 and 3 it was evident that the heteroarylation of 2 proceeded
well to give the desired products 3, 5 and 7 in good yields. All
the compounds synthesized were well characterized by spectral
data (NMR, MS and IR). Additionally, the molecular structure of
a representative compound 3d was established unambiguously
by single crystal X-ray diffraction (Fig. 3).12
All the chloro compounds, for example, 1, 4 and 6 used in the
present AlCl3-mediated C–C bond forming reaction were prepared
via a three-step method as shown in Scheme 3.11 Thus construction
of the appropriately substituted thiophene ring (8) in the first step
followed by the fused pyrimidine ring in second step provided the
desired thieno[2,3-d]pyrimidin-4(3H)-one derivative 9. Chlorina-
tion of compound 9 using POCl3 provided the required chloro
derivatives.
Mechanistically the present C–C bond forming reaction pro-
ceeds via (i) complexation of the azometine nitrogen of 4-chloro
thieno[2,3-d]pyrimidine with AlCl3 followed by (ii) nucleophilic at-
tack by arenes or heteroarenes at the chlorine bearing carbon atom
and finally and (iii) release of AlCl3 affording the desired product
(Fig. 4). It is evident that the complexation step is facilitated by
the resonance stabilization of the complex formed (e.g., X and Y,
Fig. 4). Nucleophilicity of the reacting arenes or heteroarenes is
crucial in the present reaction, and therefore, the reaction proceeds
Figure 3. ORTEP of compound 3d. The displacement ellipsoids are drawn at the 50%
probability level. H atoms are shown by small circles of arbitrary radii.
smoothly with electron-rich arenes or heteroarenes, leading to the
formation of desired compound. Notably, though a variety of het-
eroaryl chlorides containing the @C–C(Cl)@N– moiety have been
utilized successfully earlier,10 the reactivity of –C(Cl)@N–C@N–
moiety fused with a thiophene ring towards an AlCl3-induced C–
C bond forming reaction has not been examined. Here, we have

K. S. Kumar et al. / Tetrahedron Letters 51 (2010) 3269–3273
3273
O
O
H
O
O
R
N
R
OEt
NH2
R1
R
H
NH2
S8, morpholine
R1
R1
N
S
S
reflux
EtOH, reflux
12h
OEt
1
1
8a;
R, R = - (CH2)4
-
-
NC
9a;
R, R = - (CH2)4
-
-
8b; R, R1= - (CH2)3
9b; R, R1= - (CH2)3
O
8c; R1= H, R = -CH3
9c; R1= H, R = -CH3
Cl
R
N
POCl3
reflux
R1
N
S
1
1;
4;
R, R = - (CH2)4
-
-
1
R, R = - (CH2)3
6; R1= H, R = -CH3
Scheme 3. Preparation of 4-chloro thieno[2,3-d]pyrimidine (1), 4-chloro-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine (4) and 4-chloro-5-methylthieno[2,3-
d]pyrimidine (6).
Supplementary data
AlCl3
Cl
AlCl3
Cl
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.057.
N
N
N
N
S
References and notes
S
1. Brown, D. J. Pyrimidines and Their Benzo Derivatives. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984; Vol. 3, p 443.
X
Y
2. Roth, B.; Cheng, C.. In Progress in Medicinal Chemistry; Ellis, G. P., West, G. B.,
Eds.; Elsevier Biomedical Press: New York, 1982; Vol. 19, p 267.
3. Petrie, C. R.; Cottam, H. B.; Mckernan, P. A.; Robins, R. K.; Revankar, G. R. J. Med.
Chem. 1985, 28, 1010.
R
N
AlCl3
R
S
4. (a) Walter, H. World Patent Application WO 9911631, 1999; Chem. Abstr. 1999,
130, 237580e.; (b) Walter, H. World Patent Application WO 9914202, 1999;
Chem. Abstr. 1999, 130, 252368k.; (c) Aboulwafa, O. M.; Ismail, K. A.; Koreshin,
E. A. Farmaco 1992, 47, 631; (d) Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.;
Bahekar, R. H. Eur. J. Med. Chem. 2003, 38, 89; (e) Santagati, M.; Modica, M.;
Santagati, A.; Russo, F.; Spampinato, S. Pharmazie 1996, 51, 7; (f) Taguchi, M.;
Ota, T.; Hatayama, K. World Patent Application WO 9303040, 1993; Chem.
Abstr. 1993, 119, 160309m.; (g) Shishoo, C. J.; Shirsath, V. S.; Radhod, I. S.;
Yande, V. D. Eur. J. Med. Chem. 2000, 35, 351; (h) De Laszlo, S. E.; Patchett, A. A.;
Allen, E. E.; Greenlee, W. J. European Patent Application EP 502725, 1992;
Chem. Abstr. 1992, 118, 22249v.
RH
HCl
N
N
S
N
AlCl3
Figure 4. Proposed mechanism of the heteroarylation reaction.
shown that the chloro group of a thienopyrimidine (i.e., –C(Cl) @N–
C@N– moiety) ring participated smoothly in the (hetero)arylation
reaction affording a variety of novel heterocyclic compounds in
good yields.
5. Modica, M.; Santagati, M.; Guccione, S.; Russo, F.; Cagnotto, A.; Goegan, M.;
Mennini, T. Eur. J. Med. Chem. 2000, 35, 1065.
6. Modica, M.; Romeo, G.; Materia, L.; Russo, F.; Cagnotto, A.; Mennini, T.; Gaspar,
R.; Falkay, G.; Fulop, F. Bioorg. Med. Chem. 2004, 12, 3891.
7. (a) Wang, Y. D.; Johnson, S.; Powell, D. P.; McGinnis, J. P.; Miranda, M.;
Rabindran, S. K. Bioorg. Med. Chem. Lett. 2005, 15, 3763; (b) Jennings, L. D.;
Kincaid, S. L.; Wang, Y. D.; Krishnamurthy, G.; Beyer, C. F.; McGinnis, J. P.;
Miranda, M.; Discafani, C. M.; Rabindran, S. K. Bioorg. Med. Chem. Lett. 2005, 15,
4731.
8. (a) Kemnitzer, W.; Sirisoma, N.; May, C.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg.
Med. Chem. Lett. 2009, 19, 3536; (b) Dhanoa, D. S.; Becker, O.; Noiman, S.;
Reddy, A.S.; Cheruku, S. R.; Melendez, R. S.; Sharadendu, A.; Chen, D.; Marantz,
Y.; Shacham, S.; Heifetz, A.; Inbal, B.; Kesavan, V.; Bar-Haim, S. US patent
application US7612078 B2, Nov. 3, 2009.
In conclusion, we have developed a new, operationally simple
and direct method for the preparation of 4-(hetero)aryl substituted
thieno[2,3-d]pyrimidines using readily available raw materials and
AlCl3. A variety of novel thienopyrimidines have been prepared by
using this single-step methodology. Though the methodology
works well only with electron-rich arenes or heteroarenes, the
reaction however can be carried out at lower temperature for a
shorter period of time.9 Moreover, the methodology does not re-
quire the use of expensive transition metal catalysts or organome-
tallic reagents, and therefore has potential to become a useful
alternative towards the direct synthesis of diversity based thieno-
pyrimidines of potential pharmacological interest.
9. Perspicace, E.; Hesse, S.; Krisch, G.; Yemloul, M.; Lecomte, C. J. Heterocycl. Chem.
2009, 46, 459.
10. For recent references, see: (a) Kodimuthali, A.; Nishad, T. C.; Prasunamba, P. L.;
Pal, M. Tetrahedron Lett. 2009, 50, 354; (b) Kodimuthali, A.; Chary, B. C.;
Prasunamba, P. L.; Pal, M. Tetrahedron Lett. 2009, 50, 1618.
11. (a) Vishnu, J. R.; Hrishi, K. P.; Arnold, J. V. J. Heterocycl. Chem. 1981, 18, 1277; (b)
Boehm, R.; Pech, R.; Haubold, G.; Hannig, E. Pharmazie 1986, 41, 23; (c) Kim,
M.-H.; Park, C.-H.; Chun, K.; Oh, B.-K.; Joe, B.-Y.; Choi, J.-H.; Kwon, H.-M.; Huh,
S.-C.; Won, R.; Kim, K. H.; Kim, S.-M. World Patent Application WO2007/
102679, Sept 13, 2007.
Acknowledgements
12. Crystallographic data (excluding structure factors) for 3d (Aurigene reference
No. ADT-HY-005) have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication number CCDC 763783.
The authors thank the management of Institute of Life Sciences
for continuous encouragement and support. The authors also thank
Aurigene Discovery Technologies Ltd., Hyderabad, for spectral data.