Novel Solid-phase and solution-phase synthetic methods for trisubstituted Thieno[3,2-d]pyrimidine derivatives

Article abstract of DOI:10.1002/bkcs.10878

The coupling of 7-aryl-3,4-dihydro-4-oxothieno[3,2-d]pyrimidine-2-carboxylic acid with a primary alkylamineloaded acid-sensitive methoxy benzaldehyde (AMEBA) resin, a benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP)-mediated amination reaction, and cleavage from the solid support yielded N-alkyl-4-(alkylamino)-7-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The progress of the reactions on solid phase was monitored through attenuated total reflectance-FTIR spectroscopy and was compared with representative solution-phase surrogates. Additionally, N-acylation (acid chloride, InF₃ , CH₃ CN, room temperature) and cyclization (DBN, 1,4-dioxane, 80 ° C) of a 3-amino-4-(4-t-butoxycarbonylphenyl) thiophene-2-carboxamide intermediate under previously unreported conditions provided 2-substituted thieno[3,2-d]pyrimidin-4(3H)-one derivatives, which were subsequently converted to 2-substituted 4-alkylamino-7-[4-(alkylaminocarbonyl)phenyl]thieno[3,2-d]pyrimidine derivatives through a reaction sequence consisting of a BOP-mediated amination reaction, t-butyl deprotection, and amide formation.

Full text of DOI:10.1002/bkcs.10878

Article
DOI: 10.1002/bkcs.10878
BULLETIN OF THE
M.-K. Jeon et al.
KOREAN CHEMICAL SOCIETY
Novel Solid-phase and Solution-phase Synthetic Methods
for Trisubstituted Thieno[3,2-d]pyrimidine Derivatives
Moon-Kook Jeon,†, Jung-Gyu Kim,†,‡ and Duck-Hyung Lee‡
*
†Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro,
Yuseong-gu, Daejeon 305-600, Republic of Korea. *E-mail: moteta@krict.re.kr
‡Department of Chemistry, Sogang University, 1 Sogangdae-gil, Mapo-gu, Seoul 121-742, Republic of
Korea
Received March 24, 2016, Accepted June 19, 2016, Published online August 29, 2016
The coupling of 7-aryl-3,4-dihydro-4-oxothieno[3,2-d]pyrimidine-2-carboxylic acid with a primary alkylamine-
loaded acid-sensitive methoxy benzaldehyde (AMEBA) resin, a benzotriazol-1-yloxytris(dimethylamino)
phosphonium hexafluorophosphate (BOP)-mediated amination reaction, and cleavage from the solid support
yielded N-alkyl-4-(alkylamino)-7-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The progress of the
reactions on solid phase was monitored through attenuated total reflectance-FTIR spectroscopy and was com-
pared with representative solution-phase surrogates. Additionally, N-acylation (acid chloride, InF3, CH3CN,
room temperature) and cyclization (DBN, 1,4-dioxane, 80ꢀC) of a 3-amino-4-(4-t-butoxycarbonylphenyl)
thiophene-2-carboxamide intermediate under previously unreported conditions provided 2-substituted
thieno[3,2-d]pyrimidin-4(3H)-one derivatives, which were subsequently converted to 2-substituted
4-alkylamino-7-[4-(alkylaminocarbonyl)phenyl]thieno[3,2-d]pyrimidine derivatives through a reaction
sequence consisting of a BOP-mediated amination reaction, t-butyl deprotection, and amide formation.
Keywords: Screening library, Privileged structure, Heterocycle, Thienopyrimidine, Solid-phase organic
synthesis
Introduction
depending on the substitution pattern, functioning in its
own right, as a purine (2) mimic, or as a bioisosteric
replacement for the quinazoline ring system (3).7 Therefore,
the thieno[3,2-d]pyrimidine ring system can be regarded as
a privileged structure that exhibits a broad range of biologi-
cal activity across several target families, and that could
yield promising libraries when appropriately modified.
However, efforts to construct screening libraries based on
the thieno[3,2-d]pyrimidine system in a combinatorial fash-
ion have only rarely been published.8 Given our continuing
interest in high-throughput chemistry for hit- and lead-
finding heterocyclic compound screening libraries,9 we
decided to utilize the thieno[3,2-d]pyrimidine system as a
candidate scaffold and to develop high-throughput synthetic
methods for its derivatives. Herein, we report preliminary
results from a study of solid- and solution-phase synthetic
methods for 2,4,7-trisubstituted thieno[3,2-d]pyrimidine
derivatives (4) as shown, simplified, in Figure 2. The syn-
thetic methods used are based on the sequential introduc-
tion of substituents onto the ring system via Suzuki
coupling reactions of 3-amino-4-bromothiophene-2-
carboxylic acid or ester, cyclization reactions for thieno
[3,2-d]pyrimidin-4(3H)-one ring formation, and direct ami-
nation reactions to give 2-substituted 4-amino-7-arylthieno
[3,2-d]pyrimidine derivatives. The solid-phase and
solution-phase synthetic methods share a common feature,
in that both utilize benzotriazol-1-yloxytris(dimethylamino)
Small organic molecule screening libraries, including diver-
sity libraries and focused libraries, have been important
sources for the hit generation and hit-to-lead stages of the
small molecule lead discovery process.1 Without considering
the strategic details of the construction of the screening librar-
ies or the odds of success in hit- and lead-finding efforts, the
crux of the design and synthesis processes for the screening
library approach lies in maximizing the structural diversity of
scaffolds and substituents, while simultaneously maintaining
the relevance of the library members to biological activities
or the suitability of their physicochemical properties, in order
to ensure their potential for achieving their specific purposes
and compromising on their specific evaluation methods.1b,2
The privileged substructure concept has prevailed over the
past two and a half decades, since its first introduction by
Evans and coworkers, as the most common approach to scaf-
fold selection for the production of both diversity and focused
screening libraries.3,4 Despite its conceptual ambiguity,4 it
has provided a useful starting point for efforts to enhance
screening libraries for use in the lead discovery process in the
search for novel ligands and inhibitors for both broad ranges
of and specific protein targets.5
As shown in Figure 1 (together with values for some of
its physicochemical properties),6 the thieno[3,2-d]pyrimi-
dine ring system (1) exhibits various biological activity
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KOREAN CHEMICAL SOCIETY
O
S
N
NH
N
O
N
O
Cl
O
HN
N
NH
H
N
N
NH
S
N
N
S
S
HN
N
N
N
N
O
NH
S
N
N
N
.MeSO3H
SNS-314 (ref. 7a)
GDC-0941 (ref. 7b)
PF-3758309 (ref. 7c)
Aurora kinase inhibitor, phase I (2007)
MW 430.93, CLogP 5.05
HBD 3, HBA 7
PI3K inhibitor, phase II (2011)
MW 513.63, CLogP 2.63
HBD 1, HBA 10
PAK4 inhibitor, discontinued (2011)
MW 490.63, CLogP 4.28
HBD 3, HBA 9
HO
O
N
O
N
H
N
H
N
HN
N
N
S
N
HN
S
S
S
N
N
.HCl
N
N
N
NH2
N
GDC-0980 (ref. 7d)
(ref. 7e)
PDE4 inhibitor
MW 289.44, CLogP 6.04
HBD 1, HBA 3
R-253 (ref. 7f)
microtubule binder
MW 369.51, CLogP 3.81
HBD 3, HBA 5
PI3K inhibitor, phase II (2011)
MW 498.61, CLogP 1.35
HBD 3, HBA 11
S
O
O
F
S
N
N
S
N
HN
N
Cl
H
HN
S
N
O
S
N
N
N
H
O
N
N
H
N
VER-6623 (ref. 7g)
A2A antagonist
MW 261.36, CLogP 3.23
HBD 0, HBA 3
(ref. 7h)
EGFR/ErbB-2 inhibitor
MW 566.05, CLogP 5.95
HBD 3, HBA 8
(ref. 7i)
A2B antagonist
MW 381.47, CLogP 3.85
HBD 2, HBA 6
NH2
N
HN
N
O
S
S
F
O
S
N
F3C
N
N
H
N
N
N
H
H
F
O
(ref. 7j)
B-Raf inhibitor
MW 427.44, CLogP 0.90
HBD 4, HBA 8
(ref. 7k)
Antiplasmodial activity
MW 409.48, CLogP 6.27
HBD 2, HBA 5
S
N
N
N
N
N
N
N
N
1
2
3
Figure 1. Representative biologically active thieno[3,2-d]pyrimidine derivatives.
Figure 2. Synthetic strategy for 2,4,7-trisubstituted thieno[3,2-d]pyrimidine derivatives.
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Novel Solid-phase and Solution-phase Synthetic Methods
KOREAN CHEMICAL SOCIETY
phosphonium hexafluorophosphate (BOP)-mediated SNAr
reactions10 of thieno[3,2-d]pyrimidin-4(3H)-one intermedi-
ates for directly introducing the amino substituents at the
4 position of the thieno[3,2-d]pyrimidine system.
4 positions during the solid-phase synthesis. When the final
crude products were obtained with satisfactory purities after
the cleavage step, the solid-phase synthetic method would
facilitate the construction of thieno[3,2-d]pyrimidine-2-car-
boxamide-based screening libraries. To test the feasibility
of the solid-phase synthetic method, we first performed a
solution-phase model study using 2,4-dimethoxybenzyl-
Experimental
protected isobutylamine 11,12,13
a surrogate for the
Experimental and characterization details may be found in
the Supporting Information.
AMEBA resin-loaded isobutylamine 17a (Scheme 2), as
shown in Scheme 1. Compound 10a was prepared starting
from methyl 3-amino-4-bromothiophene-2-carboxylate
(5).13,14 Methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-
carboxylate (7a),15a obtained in 83% yield from a Suzuki
coupling reaction of the starting material 5 with 4-
methoxyphenylboronic acid (6a) under typical conditions at
an 83% yield,15 was subjected to a cyclization reaction with
methyl cyanoformate (8) in the presence of 4N HCl in 1,4-
dioxane at 60ꢀC16 to give the ester intermediate 9a with a
94% yield. Another potential route to compound 9a (the
cyclization of 5 with 8, followed by using 6a for Suzuki
coupling) was not successful in the latter step, possibly due
to the cyclized intermediate having a solubility problem
under typical Suzuki coupling reaction conditions.13 The
ester 9a was readily hydrolyzed by treatment with lithium
hydroxide in MeOH/H2O at room temperature to give 3,4-
Results and Discussion
The thieno[3,2-d]pyrimidine-2-carboxamide derivatives 4a–
l (R2 = CONHR0) were selected as the target compounds
for the development of a solid-phase synthetic method. This
method is based on a reaction sequence consisting first of
loading 7-aryl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one-2-
carboxylic acids (10) onto aminated acid-sensitive MEth-
oxy BenzAldehyde (AMEBA)11 resins 17, followed by
BOP-mediated amination reactions, and finally cleavage
reactions to produce the target products 4a–l, as shown in
Scheme 2. The aryl group at the 7 position of the thieno
[3,2-d]pyrimidine ring system is introduced in the course of
the solution-phase preparation of compounds 10; the car-
boxamide and amino groups are placed in the 2 and
6a:
6b:
MeO
F
B(OH)2
O
O
O
N
O
B(OH)2
8
S
S
S
OMe
NH2
OMe
NH2
NH
NC
OMe
ii)
O
i)
R1
Br
R1
OMe
7a: R1 = 4-MeO-C6H4
7b: R1 = 4-F-C6H4
5
9a: R1 = 4-MeO-C6H4
9b: R1 = 4-F-C6H4
OMe
O
O
N
N
H
11
OMe
S
NH
S
NH
iii)
O
OMe
N
10a
O
iv)
R1
N
R1
OH
OMe
10a: R1 = 4-MeO-C6H4
10b: R1 = 4-F-C6H4
12: R1 = 4-MeO-C6H4
NH
NH
NH2
13a
v)
S
S
N
N
vi)
O
OMe
O
N
N
R1
R1
N
HN
4a: R1 = 4-MeO-C6H4
OMe
14: R1 = 4-MeO-C6H4
Scheme 1. (i) Pd(OAc)2, PPh3, Na2CO3, 1,4-dioxane/H2O, 80ꢀC, 2 h, 83 and 86% for 7a and 7b; (ii) 4N HCl in 1,4-dioxane, 60ꢀC, 4 h,
94 and 80% for 9a and 9b; (iii) LiOH.H2O, MeOH/H2O, rt, 1 h, 96 and 98% for 10a and 10b; (iv) EDC, HOAt, DMF, rt, 6 h, 87% for
12; (v) BOP, DBU, DMF, rt, 2 h, 92% for 14; (vi) 25% TFA in DCM, rt, 2 h, 85% for 4a.
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O
16a
:
H2N
H2N
S
: R1 = 4-MeO-C6H4
: R1 = 4-F-C6H4
NH
10a
10b
16b
:
OMe
O
N
OMe
CHO
R1
R'
OH
N
H
ii)
i)
O
PS
O
PS
15
17a
17b: R' = Bn
: R' = i-Bu
13a
:
H2N
H2N
13b
:
R3 R4
N
R3 R4
N
O
13c
: HN
S
NH
S
S
O
N
N
N
iv)
PS
O
O
PS
O
O
O
N
N
iii)
R1
R1
R1
N
N
HN
R'
R'
R'
OMe
: R1 = 4-MeO-C6H4, R' = i-Bu
OMe
19a-l (Table 1)
- : R2 = CONHR'
4a l
18a
18b: R1 = 4-MeO-C6H4, R' = Bn
(Table 1)
: R1 = 4-F-C6H4, R' = i-Bu
18c
18d: R1 = 4-F-C6H4, R' = Bn
Scheme 2. (i) NaBH(OAc)3, DCE, rt, 1.5 h; (ii) EDC, HOAt, DMF, rt, 20 h; (iii) BOP, DBU, DMF, rt, 4 h; (iv) 25% TFA in DCM,
rt, 1 h.
dihydrothieno[3,2-d]pyrimidin-4-one-2-carboxylic
acid
the IR spectra clearly showed the disappearance of a car-
bonyl band at 1677 and 1701 cm−1, respectively. Further-
more, the IR spectra for resins 18a and 19a exhibited
comparable features to those of compounds 12 and 14,
respectively. The final product 4a was obtained at a reason-
10a, at a 96% yield. Compound 10a underwent an amide
coupling reaction with the protected isobutylamine 11 in
the presence of EDC and HOAt in DMF at rt to give the
carboxamide derivative 12 at an 87% yield and no signifi-
cant side reactions were observed.17 BOP-mediated amina-
tion reaction of 12 with the benzylamine 13a also
proceeded neatly under previously reported conditions,10b
giving the 4-benzylamino derivative 14 with a 92% yield.
The DMF was selected as the solvent in place of acetoni-
trile on the basis of its expected favorable resin-swelling
properties when used in the solid-phase reaction.18 After
the deprotection of compound 14 under TFA/DCM condi-
tions, we obtained the final target compound 4a with an
85% yield. Subsequently, the reaction conditions set for the
conversion of 10a to 4a were applied to the AMEBA resin-
loaded isobutylamine 17a, which had been prepared from
reductive amination of AMEBA resin 1513,19 with isobuty-
lamine 16a under typical conditions, as shown in Scheme
2. Reaction progress was monitored by use of attenuated
total reflectance-FTIR (ATR-FTIR) spectroscopy on
sampled resins during the course of the reactions20; IR
spectra for 15, 17a, 18a, 18a after treatment only with
BOP/DBU, and 19a are presented in a stacked form in
Figure 3, together with those of the corresponding com-
pounds 11, 12, and 14 obtained from the above solution-
phase model study for comparison. For the transformations,
15–17a and 12–18a after treatment only with BOP/DBU,
1
able purity, as judged based on the H NMR spectrum of a
crude form after cleavage from the resin 19a under the
same conditions as those for compound 14.13 Further purifi-
cation of the crude product by silica gel column chromatog-
raphy afforded 4a in a 65% five-step overall isolated yield
from Merrifield resin (Table 1). The use of building blocks
16a–b, 10a–b, and 13a–c (Scheme 2) in each transforma-
tion step provided thieno[3,2-d]pyrimidine-2-carboxamide
derivatives 4b–l in 42–66% yields overall from Merrifield
resin. Building block 10b was prepared in the same manner
as 10a, as shown in Scheme 1.
The established solid-phase synthetic method would facil-
itate purification of resin-bound intermediates and prepara-
tion of 4-amino-7-aryl-2-carbamoylthieno[3,2-d]pyrimidine
compound library. Compounds 7a–b, 9a–b, 10a–b, 12, 14,
and 4a–l were all unknown except for 7a,15a and were char-
1
acterized on the basis of H NMR, 13C NMR, IR, MS, and
HRMS data. ATR-FTIR data were recorded for resins 17a–
b, 18a–d, and 19a–l.
To develop a solution-phase synthetic method for trisub-
stituted thieno[3,2-d]pyrimidine derivatives, compound 4m
was selected as the primary target product and we chose
the synthetic intermediate 23 to be utilized as a pivot point
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Figure 3. Stacked IR spectra of resins (15, 17a, 18a, 18a after treatment only with BOP/DBU, and 19a) and compounds (11, 12 and 14).
for the introduction of the substituents around the 4-phe-
nylthieno[3,2-d]pyrimidine scaffold, as presented in
Scheme 3. Starting with 3-amino-4-bromothiophene-2-
carboxylic acid (20),13,21 a Suzuki coupling reaction with t-
butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo-
ate (21),13,22 under typical conditions, followed by a carba-
moylation reaction of compound 22 gave the intermediate
23 in a satisfactory yield. We envisioned that the cycliza-
tion reaction for the thieno[3,2-d]pyrimidin-4(3H)-one ring
formation and the incorporation of a substituent at its 2 posi-
tion could be performed via an N-acylated intermediate
such as compound 25a, though the presence of the t-
butoxycarbonyl group would limit available conditions for
the cyclization step. The reaction conditions for the N-
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Table 1. Yields of compounds 4a–l.
Compound
R1
R0
NR3R4
Yield (%)a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
i-Bu
i-Bu
i-Bu
Bn
Bn
Bn
i-Bu
i-Bu
i-Bu
Bn
Bn
Bn
Benzylamino
i-Butylamino
Morpholino
Benzylamino
i-Butylamino
Morpholino
Benzylamino
i-Butylamino
Morpholino
Benzylamino
i-Butylamino
Morpholino
65
53
66
58
63
59
48
43
42
60
48
42
4j
4k
4l
4-F-C6H4
a
Five-step overall isolated yield from Merrifield resin (loading capacity 0.94 mmol/g).
acylation of 23 were optimized using 4-methoxybenzoyl
chloride 24a, under a limited range of variations of the
choice of indium trihalide used, solvent used, and the reac-
tion temperature, as summarized in Table 2. The reactions
detailed by entries 2 and 8 gave better results for the forma-
tion of compound 25a, with 60 and 59% yields, respec-
tively, compared with the other tested reaction conditions;
the reaction at 60ꢀC (entry 11) had a deleterious effect on
the product formation due to deprotection of the t-butyl
group. Subsequently, cyclization of the N-acylated interme-
diate 25a was accomplished by treatment with DBU or
DBN in 1,4-dioxane at 80ꢀC to give the thieno[3,2-d]
pyrimidin-4(3H)-one derivative 26a with a 71 or 82%
yield, respectively (Table 3, entries 2 and 3); the use of
DIEA, proton sponge, and TMG as the base did not pro-
mote the reaction (Table 3, entries 1, 4, and 5). The next
reaction steps leading to the target product 4m (i.e., (1) a
BOP-mediated amination reaction with benzylamine 13a
and (2) t-butyl deprotection and amide formation with iso-
butylamine 16) proceeded readily as shown in Scheme 3.
The N-acylation conditions for the intermediate 23 were
applied to other acid chloride building blocks such as 2-
fluorobenzoyl chloride (24b), thiophene-2-carbonyl chlo-
ride (24c), cyclopropylcarbonyl chloride (24d), and methyl
Scheme 3. (i) PdCl2(PPh3)2, Na2CO3, 1,4-dioxane/H2O, 80ꢀC, 5 h, 63% for 22; (ii) NH4Cl, TEA, EDC, HOBt, DCM, rt, 2 d, 73% for 23;
(iii) InF3, MeCN, rt, 4 h, 60% for 25a; (iv) DBN, 1,4-dioxane, 80ꢀC, 3 days, 82% for 26a; v) BOP, DBU, 1,4-dioxane, rt to 60ꢀC, 1 h,
88% for 27a; (vi) 50% TFA in DCM, rt, 1 h, 100% for 28a; (vii) EDC, HOBt, TEA, DCM, rt, 2 h, 73% for 4m.
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Table 2. Variation experiments of reaction conditions for N-
acylation of compound 23–25a.a
produced 26b–e in 80–96% yields; their subsequent benzy-
laminations, t-butyl deprotection, and amide formation with
isobutylamine gave compounds 27b–e and 4n–q in high
yields. Table 4 includes the results obtained for compound
26a with variations of the substituent at the 4 position of
the thieno[3,2-d]pyrimidine ring system using primary
amine building blocks such as ethyl 4-aminopiperidine-1-
carboxylate (13b), 2-morpholinoethan-1-amine (13c), and
adamantan-1-amine (13d) (compounds 27f–h and 4r–t).
Compounds 22, 23, 25a–e, 26a–e, 27a–h, and 4m–t
were all unknown and were characterized through 1H
NMR, 13C NMR, IR, MS, and HRMS data. The acid inter-
mediates 28a–h were also unknown and were characterized
on the basis of 1H NMR, MS, and HRMS data.
Reaction
temp.
Yield (%)
for 25a
Entry InX3
Solvent
1
2
3
4
5
6
7
8
–
CH3CN
CH3CN
rt
rt
rt
rt
rt
rt
rt
35
60
46
33
44
23
30
59
Trace
–
InF3
InCl3 CH3CN
InBr3 CH3CN
InF3
InF3
InF3
InF3
InF3
InF3
InF3
DCM
THF
1,4-Dioxane
Isobutyronitrile rt
DMF
MeOH
CH3CN
9
rt
rt
60ꢀC
10
11
a
b
–
Conclusion
Each reaction was run for 23 (50 mg, 0.16 mmol) in the presence of
24a (1.2 M equiv) and of InX3 (10 mol%) in 2 mL of solvent
for 4 h.
We selected 2,4,7-trisubstituted thieno[3,2-d]pyrimidine deri-
vatives as target compounds for the development of solid-
phase and solution-phase synthetic methods. Coupling of 7-
aryl-3,4-dihydro-4-oxothieno[3,2-d]pyrimidine-2-carboxylic
acid with a primary alkylamine-loaded AMEBA resin, a
BOP-mediated amination reaction, and a subsequent cleavage
from the solid support afforded N-alkyl-4-(alkylamino)-7-
arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The
progress of the solid-phase reactions was monitored by ATR-
FTIR spectroscopy and was compared with representative
solution-phase surrogates. N-Acylation (acid chloride, InF3,
CH3CN, rt) and cyclization (DBN, 1,4-dioxane, 80ꢀC) of the
3-amino-4-(4-t-butoxycarbonylphenyl)thiophene-2-
b
Deprotection of t-butyl group of 25a occurred.
Table 3. Variation experiments of reaction conditions for
cyclization of N-acylated intermediate 25a–26a.a
Entry
Base
Reaction time
Yield (%) for 26a
1
2
3
4
5
a
DIEA
DBU
DBN
Proton sponge
TMG
8 h
–
71
82
–
3 days
3 days
8 h
8 h
–
Each reaction was run for 25a (60 mg, 0.13 mmol) in the presence
-carboxamide intermediate under previously unreported con-
ditions provided 2-substituted thieno[3,2-d]pyrimidin-4(3H)-
one derivatives, which were subsequently converted to
2-substituted 4-alkylamino-7-[4-(alkylaminocarbonyl)phenyl]
of a base (1.2 M equiv) in 1,4-dioxane (2 mL) at 80ꢀC.
2-chloro-2-oxoacetate (24e), as shown in Scheme 4, which
gave N-acylated derivatives 25b–e in 47–81% yields, as
summarized in Table 4. Cyclization of compounds 25b–e
in the presence of DBN in 1,4-dioxane at 80ꢀC also readily
thieno[3,2-d]pyrimidine derivatives through
a reaction
sequence consisting of BOP-mediated amination reaction/t-
butyl deprotection/amide formation. Despite structurally
Scheme 4. (i) InF3, MeCN, rt; (ii) DBN, 1,4-dioxane, 80ꢀC; (iii) BOP, DBU, 1,4-dioxane, rt to 60ꢀC; (iv) 50% TFA in DCM, rt;
(v) EDC, HOBt, TEA, DCM, rt.
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Novel Solid-phase and Solution-phase Synthetic Methods
KOREAN CHEMICAL SOCIETY
Table 4. Yields of compounds 25b–e, 26b–e, 27b–h, and 4n–t.
Compound
R2
NHR3
Yield (%)
25b
25c
25d
25e
26b
26c
26d
26e
27b
27c
27d
27e
27f
27g
27h
4n
2-F-C6H4
–
81
73
47
70
94
80
96
90
81
70
88
76
84
81
60
97
82
93
85
89
99
82
Thiophen-2-yl
Cyclopropyl
MeO2C
–
–
–
2-F-C6H4
–
Thiophen-2-yl
Cyclopropyl
MeO2C
–
–
–
2-F-C6H4
Benzylamino
Benzylamino
Benzylamino
Benzylamino
(1-Ethoxycarbonylpiperidin-4-yl)amino
(2-Morpholino)ethylamino
(Adamantan-1-yl)amino
Benzylamino
Benzylamino
Benzylamino
Benzylamino
(1-Ethoxycarbonylpiperidin-4-yl)amino
(2-Morpholino)ethylamino
(Adamantan-1-yl)amino
Thiophen-2-yl
Cyclopropyl
MeO2C
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
2-F-C6H4
Thiophen-2-yl
Cyclopropyl
MeO2C
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4o
4p
4q
4r
4s
4t
Drug Discovery, Z. Rankovic, R. Morphy Eds., John Wiley &
Sons, Inc., Hoboke, NJ, 2010, p. 259.
limited range of building blocks used in the experiments, the
above results suggest that the synthetic method would be a
viable route to creating more structurally diverse thieno[3,2-
d]pyrimidine-2-carboxamide derivatives in a high-throughput
fashion once adapted to suit more precisely selected individ-
ual building blocks.
3. B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo,
R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber,
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T. B. Chen, P. J. Kling, K. A. Kunkel, J. P. Springer,
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Acknowledgment. Financial support from Korea Research
Institute of Chemical Technology is gratefully acknowledged.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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