Microwave-assisted synthesis of 4-amino-2-arylthieno[2,3- d ]pyrimidines and their subsequent functionalization

Article abstract of DOI:10.1055/s-0029-1218770

New 4-amino-2-arylthieno[2,3-d]pyrimidines were synthesized by reacting 2-amino-3-cyanothiophenes and aryl nitriles under microwave irradiation. Functionalization of 4-amino group was made by acetic anhydride and several isocyanates. Georg Thieme Verlag S

Full text of DOI:10.1055/s-0029-1218770

PAPER
2413
Microwave-Assisted Synthesis of 4-Amino-2-arylthieno[2,3-d]pyrimidines and
Their Subsequent Functionalization
4
-Amino-2-arylth
i
ieno[
2
n
,3-
d
]pyrimid
bines in Chen, Enrico Perspicace, Stéphanie Hesse,* Gilbert Kirsch
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol FR CNRS 2843, Université Paul Verlaine-Metz,
1 Boulevard Arago, 57070 Metz, France
Fax +33(3)87315801; E-mail: hesse@univ-metz.fr
Received 11 March 2010; revised 23 March 2010
So far, only three 4-amino-2-arylthieno[2,3-d]pyrim-
Abstract: New 4-amino-2-arylthieno[2,3-d]pyrimidines were syn-
idines were previously described. Two of them were syn-
thesized by reacting 2-amino-3-cyanothiophenes and aryl nitriles
under microwave irradiation. Functionalization of 4-amino group
thesized in the presence of HCl gas in dioxane14 whereas
the last one was formed in the presence of MeONa in iso-
propanol on heating for 24 hours.15 Those compounds
were evaluated as antifungal and antibacterial agents.16
Our aim was to use a faster and more efficient protocol.
So, we first tried the conditions described for the synthesis
of pyrazolo[3,4-d]pyrimidines (microwave 145 °C, 10
min, t-BuOK cat.), but unfortunately these reactions
failed. We have then modified these conditions and finally
succeeded in coupling 2-amino-3-cyanothiophenes with
aromatic nitriles under microwave activation (Scheme 1).
Five different thiophenes were studied and condensed
with five different aromatic nitriles leading to 25 new
compounds (Table 1).
was made by acetic anhydride and several isocyanates.
Key words: 2-amino-3-cyanothiophenes,
4-amino-2-arylthi-
eno[2,3-d]pyrimidines, microwave irradiation
2-Amino-3-cyanothiophenes can be considered as useful
starting materials. Especially, we used this scaffold to ac-
cess thienopyridines,1 thienopyridinones,2 thienopyrimi-
din-4-ones,3 and 4-arylthienopyrimidines.4 We report
here the preparation of 4-amino-2-arylthieno[2,3-d]pyri-
midines by reacting the 2-amino-3-cyanothiophenes with
aromatic nitriles under microwave irradiation.
Indeed, the 4-aminothieno[2,3-d]pyrimidine core is
present in many compounds having biological activities:
4-amino-6-imidazolylthieno[2,3-d]pyrimidines were re-
ported as kinase inhibitors with activity against Tie-2 in
vitro and in vivo.5 2-Alkylthio-4-aminothieno[2,3-d]pyri-
midines were proved to be modulators of P-glycoprotein
substrate specificity.6 4-Amino-5-(4-substituted phe-
nyl)thieno[2,3-d]pyrimidines were described as inhibitors
of all the vascular endothelial growth factor and platelet-
derived growth factor receptor tyrosine kinases.7,8
H2N
R2
R2
CN
N
ArCN
Ar
t-BuOK, i-PrOH
MW, 60 °C, 30 min
R1
R1
N
NH2
S
S
Scheme 1
We next wanted to further functionalize the 4-amino
group and especially to introduce an amide or urea linker
by reaction with anhydride and isocyanate, respectively.
This was a challenging reaction as this amino group seems
to be poorly reactive. Indeed, Dai et al.7 have worked on
4-amino-5-[4-anilino]thieno[2,3-d]pyrimidines with iso-
cyanates and have shown that compounds with two poten-
tial reactive amine sites were acylated only at the aniline
moiety. Moreover, Barnes et al.8 have described that over-
acylation to form the bis-acyl product (one acyl on each of
the two amino groups) was always a minority process
whatever the conditions used. However, protection of the
4-amino group has been realized by using an excess of
pivaloyl anhydride17 or with a Boc by reaction with NaH
and Boc2O.7
The synthesis of heterocondensed 4-aminopyrimidines
starting from ortho-aminocyanoheterocycles often re-
quires harsch conditions9 or prolonged heating.10 Howev-
er since a few years, microwave-assisted organic
synthesis has allowed milder conditions and reduced reac-
tion times. The pioneering work of Seijas et al.11 using a
domestic microwave oven has demonstrated the power of
this methodology. Anthranilonitrile was efficiently cou-
pled with several aromatic nitriles in the presence of cata-
lytic amount of t-BuOK under microwave irradiation;
good yields were obtained after only few minutes of irra-
diation. Those conditions were successfully applied to 3-
amino-4-cyanopyrazoles by La Motta and Lavecchia.12
Recently, the synthesis of pyrazolo[3,4-d]pyrimidines
starting from 5-amino-4-cyanopyrazoles was reported un-
der almost the same conditions.13
We first started to study the reaction with acetic anhydride
to form an amide moiety. Acetylation of 2 and 8 with ace-
tic anhydride for six hours at reflux gave very good results
(compounds 26 and 27, respectively, in 79 and 52% yield)
(Scheme 2). Surprisingly the reaction led to the diacety-
lated compounds. Monoacetylation on similar compounds
has been described using acetic anhydride whereas di-
SYNTHESIS 2010, No. 14, pp 2413–2418
x
x.
x
x
.
2
0
1
0
Advanced online publication: 05.05.2010
DOI: 10.1055/s-0029-1218770; Art ID: Z06010SS
© Georg Thieme Verlag Stuttgart · New York

2414
B. Chen et al.
PAPER
H2N
Table 1 4-Amino-2-arylthieno[2,3-d]pyrimidines Prepared
R2
N
Thiophene
Ar
Product
Yield (%)
R1
N
R3
Ph
1
2
3
4
5
75
73
70
20
63
S
CN
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
R1, R2 = (CH2)4, R3 = OMe 2
R1, R2 = (CH2)4, R3 = Me
1 = R2 = Me, R3 = OMe
RNCO, MeCN
50 °C, overnight
3
8
NH2
S
R
O
R
Ph
6
7
8
9
10
49
62
49
28
62
NH
CN
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
HN
R2
N
NH2
CN
S
R1
N
R3
S
Ph
11
12
13
14
15
20
20
22
25
12
R1, R2 = (CH2)4, R3 = OMe, R = Me 28 22%
1 = R2 = Me, R3 = OMe, R = Me 29 56%
R1, R2 = (CH2)4, R3 = Me, R = Et
30 25%
R1, R2 = (CH2)4, R3 = OMe, R = Ph 31 19%
R1, R2 = (CH2)4, R3 = Me, R = Ph
32 22%
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
R
NH2
S
Ph
16
17
18
19
20
47
45
34
70
62
Scheme 3
CN
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
NH2
S
Melting points were determined on a Stuart SMP3 apparatus and are
uncorrected. 1H and 13C NMR spectra (d in parts per million) were
recorded on an AC Bruker 250 MHz spectrometer in DMSO-d6. MS
spectra were recorded on an Electrospray Ionization Fourier Trans-
form Ion Cyclotron Resonance Mass Spectrometry (ESI-FTICR/
MS, QFT-9, 4T, Varian-Ion Spec, CA, USA) with Omega 9, Vari-
an, Software for acquisition and analysis of Fourier transform mass
spectra and Exact Mass Calculator, Ion Spec, for calculate mass and
m/z values and isotope distribution from an elemental formula. A
CEM Discover microwave oven was used in open-vessel mode for
the microwave-assisted synthesis; the temperature was monitored
by an infrared sensor located in the microwave cavity floor.
Ph
21
22
23
24
25
45
24
18
28
87
CN
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
NH2
S
O
O
H2N
N
R2
R2
Ac2O
N
N
Ar
reflux, 6 h
Ar
4-Amino-2-arylthieno[2,3-d]pyrimidines 1–25; General Proce-
dure
R1
N
R1
N
S
S
R1, R2 = (CH2)4
1 = R2 = Me
2
8
R1, R2 = (CH2)4 26 79%
R
1 = R2 = Me 27 52%
A mixture of 2-amino-3-cyanothiophene (1 equiv), aromatic nitrile
(2 equiv), and t-BuOK (2–3 equiv) in i-PrOH (2.5 mL/mol) was
submitted to microwave irradiation for 30 min at 65 °C. After cool-
ing, the reaction mixture was poured onto H2O (100 mL). The pre-
cipitate was collected by filtration and washed with Et2O (50 mL)
(Table 1).
R
Scheme 2
acetylation was reported using a mixture of acetic anhy-
dride and pyridine.18
2-Phenyl-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-
amine (1)
In contrast, reactions with isocyanates were more difficult
and gave only moderate yields of urea derivatives. Using
Yield: 75%; brown solid; mp 200 °C (Lit.14b mp 195–197 °C).
10 equivalents of methyl isocyanate, compounds 28 and IR (KBr): 3428, 3308, 1608 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.81 (m, 4 H, 2 × CH2), 2.75
(m, 2 H, CH2), 2.92 (m, 2 H, CH2), 6.84 (br s, 2 H, NH2), 7.43–7.48
(m, 3 H), 8,33–8.37 (m, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 21.9, 22.2, 24.9, 25.4, 113.7,
126.9, 127.5, 128.2, 129.8, 131.2, 137.7, 157.9, 158.1, 166.5.
29 were isolated in 22 and 56% yield, respectively. Cou-
pling of 3 with ethyl isocyanate led to 30 in 25% yield
(Scheme 3). Results obtained with phenyl isocyanate
seemed at the beginning to be more complex: the 1H NMR
spectrum recorded in DMSO-d6 indicated the presence of
two isomers in a 2:1 ratio. Recording the 1H NMR spec-
trum in pyridine-d5 greatly simplified it, certainly due to
the absence of hydrogen bonding with solvent. Com-
pounds 31 and 32 were obtained in moderate yields.
HRMS (ESI): m/z calcd for [M + H] C16H16N3S: 282.1059; found:
282.1059.
2-p-Tolyl-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-
amine (2)
Yield: 73%; brown solid; mp 209 °C.
IR (KBr): 3486, 3296, 3163, 1634 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.83 (m, 4 H, 2 × CH2), 2.37
(s, 3 H, CH3), 2.77 (m, 2 H, CH2), 2.94 (m, 2 H, CH2), 6.83 (br s, 2
H, NH2), 7.27 (d, J = 8.0 Hz, 2 H), 8.25 (d, J = 8.0 Hz, 2 H).
In conclusion, we have achieved the synthesis and func-
tionalization of new 4-amino-2-arylthieno[2,3-d]pyrim-
idines. Evaluation of the biological potential will follow.
Synthesis 2010, No. 14, 2413–2418 © Thieme Stuttgart · New York

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Synthesis of 4-Amino-2-arylthieno[2,3-d]pyrimidines
2415
13C NMR (62.9 MHz, DMSO-d6): d = 20.9, 21.9, 22.2, 24.9, 25.4,
113.5, 126.9, 127.5, 128.8, 130.8, 135.0, 139.4, 157.9, 158.0, 166.5.
HRMS (ESI): m/z calcd for [M + H] C15H16N3S: 270.1059; found:
270.1056.
HRMS (ESI): m/z calcd for [M + Na] C17H17N3S + Na: 318.1035;
found: 318.1057.
2-(4-Methoxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-
amine (8)
Yield: 49%; brown solid; mp 217 °C.
IR (KBr): 3495, 3300, 1619 cm–1.
2-(4-Methoxyphenyl)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-
d]pyrimidin-4-amine (3)
Yield: 70%; brown solid; mp 200 °C.
IR (KBr): 3384, 1621 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.80 (m, 4 H, 2 × CH2), 2.73
(m, 2 H, CH2), 2.90 (m, 2 H, CH2), 3.80 (s, 3 H, CH3), 6.77 (br s, 2
H, NH2), 7.01 (d, J = 8.6 Hz, 2 H), 8.27 (d, J = 8.6 Hz, 2 H).
1H NMR (250 MHz, DMSO-d6): d = 2.40 (s, 3 H, CH3), 2.43 (s, 3
H, CH3), 3.83 (s, 3 H, CH3), 6.85 (br s, 2 H, NH2), 7.02 (d, J = 8.9
Hz, 2 H), 8.30 (d, J = 8.9 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 13.0, 13.8, 55.2, 113.6,
114.3, 124.8, 127.2, 129.0, 130.2, 157.8, 158.2, 160.7, 165.9.
13C NMR (62.9 MHz, DMSO-d6): d = 21.9, 22.2, 24.9, 25.4, 55.2,
113.2, 113.5, 126.9, 129.0, 130.2, 130.4, 157.9, 158.0, 160.7, 166.6.
HRMS (ESI): m/z calcd for [M + H] C15H16N3OS: 286.1009; found:
286.1002.
HRMS (ESI): m/z calcd for [M + H] C17H18N3OS: 312.1165; found:
312.1183.
2-(4-Chlorophenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-
amine (9)
Yield: 30%; brown solid; mp 215 °C.
IR (KBr): 3283, 1634 cm–1.
2-(4-Chlorophenyl)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]py-
rimidin-4-amine (4)
Yield: 20%; brown solid; mp 208 °C.
IR (KBr): 3511, 3465, 3269, 1621 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.80 (m, 4 H, 2 × CH2), 2.75
(m, 2 H, CH2), 2.91 (m, 2 H, CH2), 6.88 (br s, 2 H, NH2), 7.51 (d,
J = 8.6 Hz, 2 H), 8.32 (d, J = 8.6 Hz, 2 H).
1H NMR (250 MHz, DMSO-d6): d = 2.38 (s, 3 H, CH3), 2.42 (s, 3
H, CH3), 6.96 (br s, 2 H, NH2), 7,51 (d, J = 8.5 Hz, 2 H), 8.32 (d,
J = 8.5 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 13.0, 13.8, 114.8, 124.9,
128.3, 128.3, 129.2, 134.5, 136.6, 156.8, 158.2, 165.7.
13C NMR (62.9 MHz, DMSO-d6): d = 21.9, 22.2, 24.9, 25.3, 113.8,
127.0, 128,3, 129.2, 131.6, 134.6, 136.5, 156.9, 158.1, 166.4.
HRMS (ESI): m/z calcd for [M + H] C14H13ClN3S: 290.0513;
found: 290.0527.
HRMS (ESI): m/z calcd for [M + H] C16H15ClN3S: 316.0670;
found: 316.0695.
2-(2-Chlorophenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-
amine (10)
Yield: 62%; brown solid; mp 226 °C.
IR (KBr): 3508, 3283, 1634 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.40 (s, 3 H, CH3), 2.43 (s, 3
H, CH3), 7.00 (br s, 2 H, NH2), 7.40 (m, 2 H), 7.48 (m, 1 H), 7.59
(m, 1 H).
2-(2-Chlorophenyl)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]py-
rimidin-4-amine (5)
Yield: 63%; brown solid; mp 200 °C (Lit.15 mp 210–211 °C).
IR (KBr): 3506, 3272, 1631 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.81 (m, 4 H, 2 × CH2), 2.75
(m, 2 H, CH2), 2.93 (m, 2 H, CH2), 6.92 (br s, 2 H, NH2), 7.39–7.43
(m, 2 H), 7.49–7.52 (m, 1 H), 7.57–7.60 (m, 1 H).
13C NMR (62.9 MHz, DMSO-d6): d = 13.0, 13.8, 114.5, 124.7,
126.7, 128.3, 129.6, 129.8, 131.0, 131.3, 138.6, 158.1, 159.0, 165.0.
13C NMR (62.9 MHz, DMSO-d6): d = 22.0, 22.2, 24.9, 25.3, 113.5,
126.7, 126.9, 129.7, 129.8, 131.0, 131.3, 131.5, 138.6, 158.0, 159.2,
165.7.
HRMS (ESI): m/z calcd for [M + H] C14H13ClN3S: 290.0513;
found: 290.0527.
6,7,8,9-Tetrahydro-5H-cyclohepta[b]-2-phenylthieno[2,3-d]py-
rimidin-4-amine (11)
Yield: 20%; brown solid; mp 174 °C.
HRMS (ESI): m/z calcd for [M + H] C16H15ClN3S: 316.0670;
found: 316.0695.
5,6-Dimethyl-2-phenylthieno[2,3-d]pyrimidin-4-amine (6)
IR (KBr): 3438, 3333, 1609 cm–1.
Yield: 49%; brown solid; mp 186 °C.
IR (KBr): 3500, 3298, 1631 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.41 (s, 3 H, CH3), 2.45 (s, 3
H, CH3), 6.94 (br s, 2 H, NH2), 7.46 (m, 3 H), 8.35 (m, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 13.0, 13.8, 114.7, 124.8,
127.4, 127.9, 128.2, 129.8, 137.7, 157.8, 158.2, 165.8.
1H NMR (250 MHz, DMSO-d6): d = 1.68 (m, 4 H, 2 × CH2), 1.82
(m, 2 H, CH2), 2.84 (m, 2 H, CH2), 3.01 (m, 2 H, CH2), 6.96 (br s,
2 H, NH2), 7.44 (m, 3 H), 8.32 (m, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 26.4, 26.8, 28.5, 28.6, 30.8,
114.8, 127.4, 128.2, 129.7, 132.2, 135.2, 137.7, 157.5, 158.2, 165.3.
HRMS (ESI): m/z calcd for [M + H] C17H18N3S: 296.1216; found:
296.1221.
HRMS (ESI): m/z calcd for [M + H] C14H14N3S: 256.0903; found:
256.0904.
2-p-Tolyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[2,3-d]py-
rimidin-4-amine (12)
Yield: 20%; brown solid; mp 178 °C.
IR (KBr): 3469, 3364, 1603 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.67 (m, 4 H, 2 × CH2), 1.82
(m, 2 H, CH2), 2.34 (s, 3 H, CH3), 2.83 (m, 2 H, CH2), 3.02 (m, 2 H,
CH2), 6.91 (br s, 2 H, NH2), 7.25 (d, J = 8.0 Hz, 2 H), 8.22 (d,
J = 8.0 Hz, 2 H).
5,6-Dimethyl-2-p-tolylthieno[2,3-d]pyrimidin-4-amine (7)
Yield: 62%; brown solid; mp 216 °C.
IR (KBr): 3511, 3282, 1607 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.37 (s, 3 H, CH3), 2.40 (s, 3
H, CH3), 2.44 (s, 3 H, CH3), 6.90 (br s, 2 H, NH2), 7.28 (d, J = 8.0
Hz, 2 H), 8.25 (d, J = 8.0 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 13.0, 13.8, 20.9, 114.6,
124.8, 127.5, 127.7, 128.8, 135.0, 139.4, 157.9, 158.2, 165.9.
Synthesis 2010, No. 14, 2413–2418 © Thieme Stuttgart · New York

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B. Chen et al.
PAPER
7-Methyl-2-(4-methylphenyl)-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (17)
Yield: 45%; yellow solid; mp 221 °C.
13C NMR (62.9 MHz, DMSO-d6): d = 20.9, 26.4, 26.8, 28.6, 28.6,
30.7, 114.7, 127.4, 128.8, 132.1, 134.9, 134.9, 139.3, 157.0, 157.6,
165.4.
HRMS (ESI): m/z calcd for [M + H] C18H20N3S: 310.1372; found:
IR (KBr): 3494, 3295, 1635 cm–1.
310.1371.
1H NMR (250 MHz, DMSO-d6): d = 1.03–1.06 (d, J = 6.3 Hz, CH3,
3 H), 1.31–1.52 (m, 1 H), 1.88–1.91 (m, 2 H), 2.34 (s, 3 H, CH3),
2.37–2.41 (m, 1 H), 2.78–2.98 (m, 3 H), 6.80 (br s, 2 H, NH2), 7.25
(d, J = 8.1 Hz, 2 H), 8.22 (d, J = 8.1 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 20.9, 21.0, 25.1, 28.4, 30.0,
32.8, 113.4, 126.6, 127.5, 128.8, 130.4, 135.0, 139.3, 158.0, 158.0,
166.7.
2-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]thieno[2,3-d]pyrimidin-4-amine (13)
Yield: 22%; brown solid; mp 164 °C.
IR (KBr): 3464, 3357, 1605 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.68 (m, 4 H, 2 × CH2), 1.82
(m, 2 H, CH2), 2.83 (m, 2 H, CH2), 3.01 (m, 2 H, CH2), 3.80 (s, 3 H,
CH3), 6.88 (br s, 2 H, NH2), 6.99 (d, J = 8.8 Hz, 2 H), 8.27 (d,
J = 8.8 Hz, 2 H).
HRMS (ESI): m/z calcd for [M + H] C18H20N3S: 310.1372; found:
310.1373.
13C NMR (62.9 MHz, DMSO-d6): d = 26.4, 26.9, 28.6 (2 C), 30.8,
55.2, 113.5, 114.4, 129.0, 130.2, 132.1, 134.5, 157.4, 158.1, 160.7,
165.4.
2-(4-Methoxyphenyl)-7-methyl-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (18)
Yield: 34%; yellow solid; mp 217 °C.
HRMS (ESI): m/z calcd for [M + H] C17H18N3OS: 326.1322; found:
IR (KBr): 3520, 3378, 1621 cm–1.
326.1316.
1H NMR (250 MHz, DMSO-d6): d = 1.01–1.05 (d, J = 6.3 Hz, CH3,
3 H), 1.31–1.52 (m, 1 H), 1.87–1.91 (m, 2 H), 2.28–2.45 (m, 1 H),
2.77–2.97 (m, 3 H), 3.81 (s, 3 H, CH3), 6.77 (br s, 2 H, NH2), 6.99
(d, J = 7.0 Hz, 2 H), 8.27 (d, J = 7.0 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 21.1, 25.1, 28.4, 30.0, 32.8,
55.2, 113.0, 113.5, 126.5, 129.0, 130.0, 130.2, 157.9, 157.9, 160.7,
166.7.
2-(4-Chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]thieno[2,3-d]pyrimidin-4-amine (14)
Yield: 25%; brown solid; mp 182 °C.
IR (KBr): 3323, 1620 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.68 (m, 4 H, 2 × CH2), 1.82
(m, 2 H, CH2), 2.84 (m, 2 H, CH2), 3.01 (m, 2 H, CH2), 7.01 (br s,
2 H, NH2), 7.51 (d, J = 8.6 Hz, 2 H), 8.32 (d, J = 8.6 Hz, 2 H).
HRMS (ESI): m/z calcd for [M + H] C18H20N3SO: 326.1322; found:
326.1320.
13C NMR (62.9 MHz, DMSO-d6): d = 26.4, 26.8, 28.5, 28.6, 30.7,
114.9, 128.3, 129.1, 132.2, 134.5, 135.6, 136.5, 156.4, 158.2, 165.2.
2-(4-Chlorophenyl)-7-methyl-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (19)
Yield: 70%; brown solid; mp 255 °C.
IR (KBr): 3467, 3284, 1604 cm–1.
HRMS (ESI): m/z calcd for [M + H] C17H17ClN3S: 330.0826;
found: 330.0826.
2-(2-Chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]thieno[2,3-d]pyrimidin-4-amine (15)
Yield: 25%; brown solid; mp 182 °C.
IR (KBr): 3425, 3323, 1620 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.01–1.04 (d, J = 6.3 Hz, CH3,
3 H), 1.31–1.52 (m, 1 H), 1.86–1.89 (m, 2 H), 2.31–2.47 (m, 1 H),
2.79–2.97 (m, 3 H), 6.89 (br s, 2 H, NH2), 7.49 (d, J = 8.5 Hz, 2 H),
8.31 (d, J = 8.5 Hz, 2 H).
1H NMR (250 MHz, DMSO-d6): d = 1.68 (m, 4 H, 2 × CH2), 1.83
(m, 2 H, CH2), 2.86 (m, 2 H, CH2), 3.04 (m, 2 H, CH2), 7.04 (br s,
2 H, NH2), 7.39–7.42 (m, 2 H), 7.48–7.52 (m, 1 H), 7.56–7.60 (m,
1 H).
13C NMR (62.9 MHz, DMSO-d6): d = 26.4, 26.8, 28.5, 28.6, 30.8,
114.6, 126.7, 129.6, 129.8, 131.0, 131.3, 132.1, 135.6, 138.5, 158.0,
158.7, 164.5.
13C NMR (62.9 MHz, DMSO-d6): d = 21.0, 25.0, 28.4, 30.0, 32.8,
113.6, 126.6, 128.3, 129.2, 131.0, 134.5, 136.6, 156.9, 158.1, 166.5.
HRMS (ESI): m/z calcd for [M + H] C17H17ClN3S: 330.0826;
found: 330.0839.
2-(2-Chlorophenyl)-7-methyl-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (20)
Yield: 34%; yellow solid; mp 217 °C.
IR (KBr): 3502, 3307, 1629 cm–1.
HRMS (ESI): m/z calcd for [M + H] C17H17ClN3S: 330.0826;
found: 330.0826.
1H NMR (250 MHz, DMSO-d6): d = 1.01–1.07 (d, J = 6.3 Hz, CH3,
3 H), 1.31–1.52 (m, 1 H), 1.87–1.91 (m, 2 H), 2.22–2.56 (m, 1 H),
2.71–3.12 (m, 3 H), 6.93 (br s, 2 H, NH2), 7.38–7.42 (m, 2 H), 7.48–
7.52 (m, 1 H), 7.56–7.60 (m, 1 H).
13C NMR (62.9 MHz, DMSO-d6): d = 21.0, 25.0, 28.4, 30.0, 32.8,
113.3, 126.5, 126.7 129.6, 129.8, 131.0, 130.1, 131.3, 138.6, 158.0,
159.1, 165.8.
7-Methyl-2-phenyl-5,6,7,8-tetrahydro[b]benzothieno[2,3-d]py-
rimidin-4-amine (16)
Yield: 47%; yellow solid; mp 230 °C.
IR (KBr): 3492, 3284, 1596 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.01–1.06 (d, J = 6.3 Hz, CH3,
3 H), 1.31–1.52 (m, 1 H), 1.87–1.92 (m, 2 H), 2.37–2.41 (m, 1 H),
2.78–2.99 (m, 3 H), 6.84 (br s, 2 H, NH2), 7.41–7.47 (m, 3 H), 8.31–
8.35 (m, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 21.0, 25.1, 28.4, 30.0, 32.8,
113.5, 126.6, 127.5, 128.2, 129.8, 130.7, 137.7, 158.0, 158.1, 166.6.
HRMS (ESI): m/z calcd for [M + H] C17H17ClN3S: 330.0826;
found: 330.0822.
7-tert-Butyl-2-phenyl-5,6,7,8-tetrahydro[b]benzothieno[2,3-
d]pyrimidin-4-amine (21)
Yield: 45%; yellow solid; mp 246 °C.
IR (KBr): 3458, 3278, 1614 cm–1.
HRMS (ESI): m/z calcd for [M + H] C17H18N3S: 296.1216; found:
296.1211.
Synthesis 2010, No. 14, 2413–2418 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Amino-2-arylthieno[2,3-d]pyrimidines
2417
1H NMR (250 MHz, DMSO-d6): d = 0.93 [s, 9 H, C(CH3)3], 1.34
(m, 1 H), 1.49 (m, 1 H), 2.02 (m, 1 H), 2.58 (m, 1 H), 2.76–2.82 (m,
2 H), 3.07–3.13 (m, 1 H), 6.84 (br s, 2 H, NH2), 7.43–7.45 (m, 3 H),
8.31–8.35 (m, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 23.6, 26.3, 26.5, 27.0, 32.2,
44.0, 113.4, 126.9, 127.5, 128.2, 129.8, 131.8, 137.7, 157.9, 158.0,
166.7.
13C NMR (62.9 MHz, DMSO-d6): d = 23.6, 26.3, 26.5, 27.0, 32.2,
44.0, 113.2, 126.7, 129.6, 129.8, 131.0, 131.3, 132.1, 138.6, 157.9,
159.1, 165.9.
HRMS (ESI): m/z calcd for [M + H] C20H23ClN3S: 372.1296;
found: 372.1291.
Compounds 26 and 27; General Procedure
A mixture of 2-aminothienopyrimidine 2, 8 (0.5 mmol) and Ac2O
(5 mL) was stirred and refluxed for 6 h. After cooling, the reaction
mixture was hydrolyzed with H2O (50 mL), the precipitate was col-
lected by filtration, and dried.
HRMS (ESI): m/z calcd for [M + H] C20H24N3S: 338.1685; found:
338.1685.
7-tert-Butyl-2-(4-methylphenyl)-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (22)
Yield: 24%; yellow solid; mp 233 °C.
IR (KBr): 3498, 3306, 1635 cm–1.
N,N-[2-(4-Methylphenyl)-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-yl]diacetamide (26)
Yield: 79%; colorless solid; mp 210 °C.
1H NMR (250 MHz, DMSO-d6): d = 0.93 [s, 9 H, C(CH3)3], 1.34
(m, 1 H), 1.52 (m, 1 H), 2.01 (m, 1 H), 2.34 (s, 3 H, CH3), 2.49 (m,
1 H), 2.76–2.82 (m, 2 H), 3.05–3.13 (m, 1 H), 6.80 (br s, 2 H, NH2),
7.25 (d, J = 7.9 Hz, 2 H), 8.22 (d, J = 7.9 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 20.9, 23.6, 26.3, 26.5, 27.0,
32.2, 44.0, 113.2, 126.8, 127.4, 128.8, 131.5, 135.0, 139.3, 158.0 (2
C), 166.8.
IR (KBr): 1723, 1704 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.83 (m, 4 H, 2 × CH2), 2.29
(s, 6 H, 2 × CH3), 2.38 (s, 3 H, CH3), 2.58 (m, 2 H, CH2), 2.90 (m,
2 H, CH2), 7.34 (d, J = 8.1 Hz, 2 H), 8.29 (d, J = 8.1 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 21.0, 21.5, 21.9, 23.9, 25.3,
26.2, 125.6, 125.8, 127.8, 129.5, 133.3, 139.8, 140.9, 152.2, 158.7,
170.5, 171.8.
HRMS (ESI): m/z calcd for [M + H] C21H26N3S: 352.1842; found:
352.1842.
HRMS (APCI): m/z calcd for [M + H] C21H22N3SO2: 380.1428;
found: 380.1439; m/z calcd for [M – COCH3 + H] C19H20N3SO:
338.1322; found: 338.1332; m/z calcd for [M – 2 COCH3 + H]
C17H18N3S: 296.1216; found: 296.1227.
7-tert-Butyl-2-(4-methoxyphenyl)-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (23)
Yield: 18%; yellow solid; mp 215 °C.
IR (KBr): 3477, 3282, 1605 cm–1.
N,N-[2-(4-Methoxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimi-
din-4-yl]diacetamide (27)
1H NMR (250 MHz, DMSO-d6): d = 0.93 [s, 9 H, C(CH3)3], 1.35
(m, 1 H), 1.52 (m, 1 H), 2.03 (m, 1 H), 2.49 (m, 1 H), 2.75–2.80 (m,
2 H), 3.05–3.12 (m, 1 H), 3.80 (s, 3 H, CH3), 6.75 (br s, 2 H, NH2),
6.99 (d, J = 8.6 Hz, 2 H), 8.27 (d, J = 8.6 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 23.6, 26.3, 26.5, 27.0, 32.2,
44.0, 55.2, 112.9, 113.5, 126.8, 129.0, 130.2, 131.0, 157.9, 158.0,
160.7, 166.8.
Yield: 52%; colorless solid; mp 205 °C.
IR (KBr): 1727, 1705 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.17 (s, 3 H, CH3), 2.29 (s, 6
H, 2 × CH3), 2.52 (s, 3 H, CH3), 3.83 (s, 3 H, CH3), 7.07 (d, J = 8
Hz, 2 H), 8.33 (d, J = 8 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 12.1, 13.6, 26.2, 55.3, 114.2,
123.5, 126.1, 128.4, 129.5, 136.3, 152.4, 158.4, 161.6, 170.0, 171.9.
HRMS (ESI): m/z calcd for [M + H] C21H26N3OS: 368.1791; found:
368.1786.
HRMS (APCI): m/z calcd for [M + H] C19H20N3SO3: 370.1238;
found: 370.1227; m/z calcd for [M – COCH3 + H] C17H18N3SO2:
328.1114; found: 328.1124; m/z calcd for [M – 2 COCH3 + H]
C15H16N3SO: 286.1009; found: 286.1015.
7-tert-Butyl-2-(4-chlorophenyl)-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (24)
Yield: 30%; colorless solid; mp 228 °C.
IR (KBr): 3436, 3289, 1602 cm–1.
Compounds 28 and 29; General Procedure
2-Aminothienopyrimidine 2, 8 (1 equiv) was dissolved in MeCN (5
mL/mmol) at 20–50 °C and methyl isocyanate (10 equiv) was add-
ed dropwise. The mixture was stirred overnight at 50 °C. The pre-
cipitate was isolated, filtered, and dried.
1H NMR (250 MHz, DMSO-d6): d = 0.93 [s, 9 H, C(CH3)3], 1.30
(m, 1 H), 1.47 (m, 1 H), 1.98 (m, 1 H), 2.49 (m, 1 H), 2.73–2.78 (m,
2 H), 3.02 (m, 1 H), 6.86 (br s, 2 H, NH2), 7.47 (d, J = 8.1 Hz, 2 H),
8.29 (d, J = 8.1 Hz, 2 H).
13C NMR (62.9 MHz, DMSO-d6): d = 23.6, 26.3, 26.5, 27.0, 32.1,
43.9, 113.5, 126.9, 128.3, 129.1, 132.1, 134.5, 136.6, 156.9, 158.0,
166.6.
N-[2-(4-Methoxyphenyl)-5,6,7,8-tetrahydro[b]benzothieno[2,3-
d]pyrimidin-4-yl]-N¢-methylurea (28)
Yield: 22%; colorless solid; mp 202 °C.
IR (KBr): 3374, 3265, 1686 cm–1.
1H NMR (250 MHz, pyridine-d5): d = 1.59 (m, 4 H, 2 × CH2), 2.60
(m, 2 H, CH2), 2.76 (m, 2 H, CH2), 3.13 (d, J = 4.7 Hz, 3 H, NCH3),
3.72 (s, 3 H, OCH3), 7.14 (d, J = 8.8 Hz, 2 H), 7.76 (br s, 1 H, NH),
8.51 (d, J = 8.8 Hz, 2 H), 9.65 (d, J = 4.7 Hz, 1 H, NH).
HRMS (ESI): m/z calcd for [M + H] C20H23ClN3S: 372.1296;
found: 372.1295.
7-tert-Butyl-2-(2-chlorophenyl)-5,6,7,8-tetrahydro[b]benzo-
thieno[2,3-d]pyrimidin-4-amine (25)
13C NMR (62.9 MHz, pyridine-d5): d = 22.8, 22.9, 26.1, 26.3, 27.2,
55.9, 115.1, 115.7, 126.2, 130.4, 130.8, 136.0, 153.5, 155.4, 157.8,
162.7, 169.2.
Yield: 87%; yellow solid; mp 224 °C.
IR (KBr): 3507, 3300, 1635 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 0.93 [s, 9 H, C(CH3)3], 1.36
(m, 1 H), 1.53 (m, 1 H), 2.01–2.06 (m, 1 H), 2.58 (m, 1 H), 2.77–
2.84 (m, 2 H), 3.07 (m, 1 H), 6.93 (br s, 2 H, NH2), 7.38–7.44 (m, 2
H), 7.49–7.52 (m, 1 H), 7.57–7.60 (m, 1 H).
HRMS (ESI): m/z calcd for [M + Na] C19H20N4O2S + Na: 391.1199;
found: 391.0826.
Synthesis 2010, No. 14, 2413–2418 © Thieme Stuttgart · New York

2418
B. Chen et al.
PAPER
N-[2-(4-Methoxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-
4-yl]-N¢-methylurea (29)
Yield: 56%; colorless solid; mp 204 °C.
13C NMR (62.9 MHz, pyridine-d5): d = 22.9, 24.0, 24.1, 27.3, 27.4,
116.4, 120.8, 124.3, 126.2, 128.9, 130.1, 130.4, 137.0, 139.7,
141.8, 152.2, 153.1, 157.9, 167.4, 169.5
IR (KBr): 3293, 1683 cm–1.
1H NMR (250 MHz, pyridine-d5): d = 2.22 (s, 3 H, CH3), 2.37 (s, 3
H, CH3), 3.11 (s, 3 H, CH3), 3.72 (s, 3 H, CH3), 7.14 (d, J = 8.9 Hz,
2 H), 8.07 (br s, 1 H, NH), 8.48 (d, J = 8.6 Hz, 2 H), 9.63 (br s, 1 H,
NH).
13C NMR (62.9 MHz, DMSO-d6): d = 13.7, 14.1, 27.2, 55.9, 115.1,
116.6, 124.1, 130.3, 130.7, 132.8, 153.6, 155.4, 167.7, 162.7, 168.5.
References
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HRMS (ESI): m/z calcd for [M + Na] C17H18N4O2S + Na: 365.1043;
found: 365.1057.
(5) (a) Luke, R. W. A.; Ballard, P.; Buttar, D.; Campbell, L.;
Curven, J.; Emery, S. C.; Griffen, A. M.; Hassall, L.; Hayter,
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N-[2-(4-Methylphenyl)-5,6,7,8-tetrahydro[b]benzothieno[2,3-
d]pyrimidin-4-yl]-N¢-ethylurea (30); Typical Procedure
Aminothienopyrimidine 2 (1 mmol) was dissolved in CHCl3 (10
mL) and ethyl isocyanate (0.5 mL) was added dropwise under stir-
ring. The mixture was stirred at r.t. for 48 h. The mixture was hy-
drolyzed with H2O (50 mL), and extracted with CHCl3 (2 × 50 mL)
(or EtOAc). The combined organic layers were washed with brine
(50 mL), dried (MgSO4), and evaporated to dryness. The residue
was triturated with Et2O, the precipitate formed was collected,
dried, and recrystallized from MeOH; yield: 81 mg (22%); colorless
solid; mp 195 °C.
IR (KBr): 3382, 3245, 1686 cm–1.
1H NMR (250 MHz, pyridine-d5): d = 1.32 (t, 3 H, J = 7.3 Hz, CH3),
1.60 (m, 4 H, 2 × CH2), 2.29 (s, 3 H, CH3), 2.61 (m, 2 H, CH2), 2.77
(m, 2 H, CH2), 3.57–3.65 (m, 2 H, CH2), 7.33 (d, J = 8.0 Hz, 2 H),
7.72 (br s, 1 H, NH), 8.42 (d, J = 8.0 Hz, 2 H), 9.75 (m, 1 H, NH).
13C NMR (62.9 MHz, pyridine-d5): d = 15.7, 21.7, 22.8, 22.9, 26.1,
26.3, 35.9, 116.0, 126.2, 128.7, 130.3, 135.7, 136.4, 141.6, 153.6,
154.5, 157.9, 169.1.
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HRMS: m/z calcd for [M + H] C20H23N4OS: 367.1587; found:
367.1585.
N-Phenyl-N¢-[2-(4-methoxyphenyl)-5,6,7,8-tetrahydro[b]ben-
zothieno[2,3-d]pyrimidin-4-yl]urea (31)
Yield: 19%; colorless solid; mp 226 °C.
IR (KBr): 3442, 1714 cm–1.
1H NMR (250 MHz, pyridine-d5): d = 1.63 (m, 4 H, 2 × CH2), 2.63
(m, 2 H, CH2), 2.84 (m, 2 H, CH2), 3.73 (s, 3 H, CH3), 7.23 (d,
J = 8.8 Hz, 2 H), 7.42–7.48 (m, 3 H), 7.98 (br s, 1 H, NH), 8.06 (d,
J = 8 Hz, 2 H), 8.57 (d, J = 8.8 Hz, 2 H), 12.17 (br s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 21.9, 22.0, 24.9, 25.4, 55.2,
113.2, 113.5, 113.8, 115.5, 118.1, 126.9, 128.7, 129.0, 130.2, 130.4,
148.5, 157.9, 158.0, 160.7, 166.6
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N-Phenyl-N¢-[2-(4-methylphenyl)-5,6,7,8-tetrahydro[b]ben-
zothieno[2,3-d]pyrimidin-4-yl]urea (32)
Yield: 22%; colorless solid; mp 228 °C.
IR (KBr): 3440, 1713 cm–1.
1H NMR (250 MHz, pyridine-d5): d = 1.63 (m, 4 H, 2 × CH2), 2.29
(s, 3 H, CH3), 2.61 (m, 2 H, CH2), 2.85 (m, 2 H, CH2), 7.38 (d,
J = 7.5 Hz, 2 H), 7.44–7.50 (m, 3 H), 7.97 (br s, 1 H, NH), 8.06 (d,
J = 6.8 Hz, 2 H), 8.49 (d, J = 6.8 Hz, 2 H), 12.17 (br s, 1 H, NH).
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Synthesis 2010, No. 14, 2413–2418 © Thieme Stuttgart · New York