Unexpected C - O bond formation in Suzuki coupling of 4-chlorothieno[2,3-d] pyrimidines

Article abstract of DOI:10.1002/jhet.107

(Chemical Equation Presented) Palladium-catalyzed Suzuki reactions were performed on 4-chlorothieno[2,3-d]pyrimidines under classical heating conditions and under microwave irradiation. Some unexpected results were obtained during this study as two kinds of compounds were isolated depending on the conditions used. A careful investigation of experimental details has shown that the expected CAC bond formation occurred when degassed solvents were used (both in classical and microwave heating) whereas an unexpected CAO bond formation happened when solvents were not degassed with argon-bubbling before use.

Full text of DOI:10.1002/jhet.107

May 2009
Unexpected CAO Bond Formation in Suzuki Coupling
of 4-Chlorothieno[2,3-d]pyrimidines
459
a
Enrico Perspicace, Stephanie Hesse, * Gilbert Kirsch,
a
a
´
Mehdi Yemloul,b and Claude Lecomtec
a
´
´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, Institut Jean Barriol,
Universite Paul Verlaine - Metz, 1 Boulevard Arago, 57070 Metz Technopole, France
´
ˆ
b
´
Laboratoire de Methodologie RMN, UMR 7565, Institut Jean Barriol, UHP Nancy 1, Boulevard
`
des Aiguillettes - BP 239 - 54506 Vandoeuvre-les-Nancy Cedex, France
´
c
´
´
Laboratoire de Cristallographie et Modelisation des Materiaux Mineraux et Biologiques,
UMR 7036, Institut Jean Barriol, UHP Nancy 1, Boulevard des Aiguillettes - BP 239 - 54506
`
Vandoeuvre-les-Nancy Cedex, France
*E-mail: hesse@univ-metz.fr
Received October 27, 2008
DOI 10.1002/jhet.107
Published online 26 May 2009 in Wiley InterScience (www.interscience.wiley.com).
Palladium-catalyzed Suzuki reactions were performed on 4-chlorothieno[2,3-d]pyrimidines under clas-
sical heating conditions and under microwave irradiation. Some unexpected results were obtained during
this study as two kinds of compounds were isolated depending on the conditions used. A careful investi-
gation of experimental details has shown that the expected CAC bond formation occurred when
degassed solvents were used (both in classical and microwave heating) whereas an unexpected CAO
bond formation happened when solvents were not degassed with argon-bubbling before use.
J. Heterocyclic Chem., 46, 459 (2009).
INTRODUCTION
drug discovery programs and practical strategies for the
construction of libraries have been developed [8].
Kinase insert domain (KDR)-containing receptor is
one of the human tyrosine kinases that has a high affin-
ity for vascular endothelial growth factor (VEGF) and is
believed to be a primary mediator of tumor-induced
angiogenesis [1]. Compounds which influence the KDR
kinase have attracted much attention and are of great in-
terest as potential therapeutic agents. Several compounds
with a quinazoline moiety have shown effective antitu-
RESULTS AND DISCUSSION
The interest in this heterocyclic core prompted us to
set up a short and efficient route toward this nucleus. In
2007, we have reinvestigated the synthesis of
thieno[2,3-d]pyrimidinone 1a and 4-chlorothieno[2,3-
d]pyrimidine 2a using microwave-assisted procedure
[9]. We now extended this procedure to compound 2b
(Scheme 1).
mor activity and have found clinical applications such
R
as gefitinib (IressaV from AstraZeneca) or erlotinib
R
(TarcevaV from Genentech) [2].
For many years, thieno[3,2-d]pyrimidines and
thieno[2,3-d]pyrimidines are known to be pharmaco-
phoric elements in numerous active compounds such as
analgesic [3], anticancer [4], mGluR1 antagonists [5], or
molecules having antimicrobial and anti-inflammatory
activities [6] (Fig. 1). Munchhof et al. [7] reported the
design and structure activity relationship (SAR) of
thieno[3,2-d]-pyrimidines and -pyridines as selective
VEGFR-2 kinase inhibitors. Since then, many patents
were filed and consequently, thienopyrimidines have
become a well-sought privileged class of compounds in
Aiming to extend thienopyrimidine libraries, we then
wanted to functionalize those compounds on position 4.
Usually, functionalities are introduced at C-4 via nucleo-
philic substitution reaction of the chlorothienopyrimidine
with amines [10]. In this study, we have decided to
focus our attention on the introduction of aromatics and
heterocycles at this position. Indeed, we thought that
easy modulation at C-4 could be done by palladium-cat-
alyzed cross-coupling of 4-chlorothieno[2,3-d]pyrimi-
dines 2a,b with different arylboronic acids.
C
V
2009 HeteroCorporation

460
E. Perspicace, S. Hesse, G. Kirsch, M. Yemloul, and C. Lecomte
Vol 46
Figure 1. Structures of quinazolines and thienopyrimidines with biological activities.
The electron-deficient nature of the pyrimidine ring
H2O as solvent. We worked under temperature/time con-
trol with 150ꢀC/30 min as parameters. At the end of the
time, the TLC control indicated that all starting material
was consumed. However, after purification, the 1H
NMR spectrum was not consistent with the one obtained
under classical conditions (Fig. 2). Two different prod-
ucts were obtained. First of all, to control these results,
we applied under microwave irradiation exactly the
same conditions as for classical heating (DME/H2O was
used as solvent and Na2CO3 as base). The same product
as before was obtained, different from the one resulting
from classical heating.
makes this system far more reactive in Suzuki coupling
compared with the analogous benzenoid halides. 2,4,6-
Trichloropyrimidines, 2,4- and 4,6-dihalo pyrimidines
have been successfully arylated under classical Suzuki
conditions (Pd(OAc)2, PPh3, Na2CO3, benzene/ethanol/
water or Pd(PPh3)4, toluene, Na2CO3 2M) [11,12]. A se-
quential Suzuki coupling/amination reaction was
recently described on 4,6-dichloropyrimidines under
microwave irradiation [13]. Some studies were also
done on condensed halopyrimidines as for example on
2,4-dichloropyridopyrimidines [14] or on 4-chloro-2-tri-
chloromethylquinazoline [15]. To the best of our knowl-
edge, there is only one publication with one example on
Suzuki coupling on 4-chlorothieno[2,3-d]pyrimidine
[4a].
1
As shown in Figure 2, in both H NMR spectra, the
same signals were present although their d values were
slightly different. The thiophene ring seemed to remain
unchanged in both compounds (two doublets at 7.63 and
7.94 ppm in compound A; two doublets at 7.75 and
8.01 ppm in compound B). The presence of an AB sig-
nal let us suppose that the p-disubstituted phenyl ring
was still present in both structures too (two doublets at
7.01 and 7.22 ppm in compound A, two doublets at
7.15 and 8.01 ppm in compound B). Moreover, NOESY
experiment and HMBC sequence showed that the pyrim-
idine proton was isolated and placed between the two
nitrogen atoms in both structures.
First, we investigated the reactivity of 4-chloro-
thieno[2,3-d]pyrimidine 2a with 4-methoxyphenylbor-
onic acid under classical Suzuki conditions. The reaction
was performed in DME with Pd(OAc)2/PPh3 catalysis in
the presence of Na2CO3 2M as base at 75–85ꢀC. The
reaction was stopped when the starting material had
completely disappeared (TLC control) and the product
was isolated by column chromatography (Scheme 2).
We then carried out the same Suzuki coupling under
microwave irradiation hoping to enhance the yields and
decrease reaction times. Pd(OAc)2/PPh3 was used as cat-
alytic system, with Cs2CO3 as base and DME/EtOH/
The same coupling with 4-methoxyphenylboronic acid
was realized on chlorothienopyrimidine 2b in classical
Scheme 2
Scheme 1
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May 2009
Unexpected CAO Bond Formation in Suzuki Coupling
of 4-Chlorothieno[2,3-d]pyrimidines
461
Figure 2. 1H NMR spectra (aromatic part) of compound obtained by classical heating and under microwave irradiation: (a) classical heating and
(b) microwave irradiation.
conditions and under microwave irradiation. Two differ-
ent compounds were obtained and after several attempts,
we succeeded in isolating crystals. Those crystallo-
graphic data showed that the expected product was
obtained under microwave irradiation (with formation of
the CAC bond between chlorothienopyrimidine and bor-
onic acid), whereas the classical heating led to the for-
mation of a CAO bond. The compounds obtained are
shown in Scheme 3.
formed into p-methoxyphenol and after, the phenol
would have reacted with the chloropyrimidine under
SNAr process giving compounds 3. As a verification,
compound 3b was synthesized directly by the action of
p-methoxyphenate on 4-chloropyrimidine 2b in 55%
yield (Scheme 4).
Regarding the yield obtained for compound 3a (70%),
it would mean that the boronic acid was converted into
phenol near completely. It is well known that oxygen
should be avoided when working with boronic acids
since they could be oxidized to the corresponding phe-
nols [16,17]. That is why our reactions were performed
under an argon atmosphere both under classical heating
and under microwave irradiation. However, there was a
very small difference of manipulation when doing those
reactions. Under classical heating, the reactions were
performed in a Schlenk tube flushed with argon whereas
in microwave irradiation, a one-necked round-bottom
Once the structures were elucidated, we tried to
explain the formation of compounds 3. During those
first experiments, we have noticed that p-methoxyphenol
was detected as trace in the crude material. So, we
postulated that the boronic acid must have been trans-
Scheme 3
Scheme 4
Journal of Heterocyclic Chemistry
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462
E. Perspicace, S. Hesse, G. Kirsch, M. Yemloul, and C. Lecomte
Vol 46
Table 1
both classical heating and microwave irradiation in mod-
erate to good yields. Moreover, because of unexpected
results obtained under classical heating, we have shown
the importance to use degassed solvents in those reac-
tions and not working only under an argon stream. Fur-
ther investigation of the mechanism of CAO bond for-
mation in cross-coupling with boronic acid as well as its
application to other substrates are ongoing in our
laboratory.
Suzuki coupling of 4-chlorothienopyrimidines under classical heating
and microwave irradiation.
Entry Method
Product
Yield
1
A
R1 ¼ R2 ¼ H 5a 77%
R1,R2 ¼ (CH2)4 5b 25%a
2
B for 6a
C for 6b
R1 ¼ R2 ¼ H 6a 44%
R1,R2 ¼ (CH2)4 6b 75%
EXPERIMENTAL
General methods. Melting points were determined on a
Stuart SMP3 apparatus and are uncorrected. 1H NMR spectra
were measured at 250 MHz, and 13C NMR spectra were meas-
ured at 62.9 MHz on a Bruker AC 250 spectrometer at 25ꢀC
in DMSO-d6. IR spectra were recorded for neat samples on
KBr plates on a Perkin Elmer Spectrum Bx FTIR spectropho-
tometer. Standard mass spectrometry data were acquired by
using GC-MS system in EI mode with a maximum m/z range
of 400 on a GC Varian CP 3800 spectrometer and triple quad-
rupole 1200 Varian detector. HMRS were collected on a
Bruker MICROTOF-Q ESI/QqTOF spectrometer. Elemental
analyses were determined with a Thermofinnigan FlashEA
1112 elemental analyzer. Microwave monomode synthesizer,
(CEM Corporation) Discover model 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. When required, all solvents and reagents were
purified by standard techniques. All Suzuki cross-coupling
reactions were conducted under a positive pressure of argon.
Chromatographic separations were carried out with silica gel
3
4
A
C
7
8
67%
61%
5
C
R1 ¼ R2 ¼ H 9a 36%
R1,R2 ¼ (CH2)4 9b 51%
˚
60 A (70–200 lm) or alumina. Yields reported are for chroma-
tographically pure isolated product.
Method A: Classical heating, nondegassed solvents (75ꢀC, 24 h);
Method B: Microwave irradiation (150ꢀC, 30 min); Method C: Classi-
cal heating, DME, and H2O degassed (75ꢀC, 24 h).
Details of synthesis, purification, and characterization of
starting materials 1a,b and 2a,b can be found in literature [9].
CCDC 716544 and CCDC 716545 contain the supplemen-
tary crystallographic data for this article (compounds 4b and
3b, respectively). These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
General procedure for Suzuki cross-coupling. Method A. To
a solution of 4-chlorothienopyrimidine (2a: 171 mg, 2b: 225
mg, 1 mmol), boronic acid (1.2 mmol) and PPh3 (39 mg, 0.15
mmol) in DME (12 mL) were added 2M Na2CO3 (10 mL) and
Pd(OAc)2 (10 mg, 0.04 mmol).The reaction mixture was
stirred at 75–80ꢀC for 24 h under argon. After filtration, the
aqueous layer was extracted with AcOEt (3 ꢁ 30 mL). The
combined organic layers were washed with 10% NaOHaq
and brine, and dried over MgSO4. The solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography to give products 3a, 3b, 5a, 5b,
and 7.
a Reaction was performed at room temperature.
flask was used and argon was bubbled directly in the so-
lution while loading the reagents. So, we performed the
Suzuki cross-coupling under classical heating conditions
but this time, solvents (DME and water) were degassed
with argon bubbling before being introduced in the reac-
tion mixture. In this case, we only observed CAC bond
formation. Compounds 6, 8–9 were synthesized in good
yields under classical heating with degassed solvents
whereas the formation of CAO bond occurred when
nondegassed solvents were used for compounds 5 and 7
(Table 1).
Method B. A 50-mL round-bottomed flask was charged
with 4-chlorothienopyrimidine (2a: 171 mg, 2b: 225 mg, 1
mmol), boronic acid (1.5 mmol), Cs2CO3 (1.01 g, 3.1 mmol),
PPh3 (66 mg, 0.25 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and
DME/EtOH/H20 (30 mL, ratio: 1/1/1) flushed with argon. The
reaction mixture was placed in a microwave synthesizer. The
CONCLUSIONS
In summary, we have demonstrated that 4-chloro-
thieno[2,3-d]pyrimidines undergo Suzuki coupling under
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Unexpected CAO Bond Formation in Suzuki Coupling
of 4-Chlorothieno[2,3-d]pyrimidines
463
microwave vial was purged three times with argon and then
heated under microwave irradiation (150ꢀC) for 30 min. After
this time, the reaction mixture was allowed to cool to room
temperature and was quenched with AcOEt/H20 (20 mL, ratio:
1/1). The water layer was extracted with AcOEt (3 ꢁ 30 mL).
The combined organic layers were washed with brine and
dried over MgSO4. The solvent was removed under reduced
pressure. The residue was purified by silica gel column chro-
matography to give products 4a, 4b, and 6a.
160.1, 168.0; GC MS (tR 11.32 min) m/z (%) ¼ 296 (100,
Mþ), 265 (12), 211 (9). Anal. Calcd. for C17H16N2OS: C,
68.89; H, 5.44; N, 9.45. Found: C, 69.10; H, 5.36; N, 9.53.
1-[3-(Thieno[2,3-d]pyrimidin-4-yloxy)phenyl]ethanone
(5a). Compound 5a was prepared according to Method A
from 2a (171 mg, 1 mmol) and 3-acetylphenylboronic acid
(197 mg, 1.2 mmol) and purified by column chromatography
(Silica, CH2Cl2 as eluent), the yield was 208 mg (77%), white
solid, mp 140–141ꢀC; IR: 1694, 1571, 1526 cmꢂ1 1H NMR:
;
Method C. Same procedure as Method A but with DME
and water degassed with argon bubbling.
d 2.59 (s, 3H), 7.64 (m, 2H), 7.69 (d, J ¼ 6 Hz, 1H), 7.90 (m,
2H), 7.99 (d, J ¼ 6 Hz, 1H), 8.61 (s, 1H); 13C NMR: d 26.8,
118.4, 118.6, 121.6, 125.7, 127.0, 127.5, 130.2, 138.5, 152.2,
152.8, 163.0, 169.1, 197.2; GC MS (tR 9.82 min) m/z (%) ¼
270 (100, Mþ), 255 (99), 242 (29), 227 (98), 135 (97); HRMS
calcd for [M þ Hþ] C14H11N2O2S 271.0536, found 271.0516.
Anal. Calcd. for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36.
Found: C, 62.48; H, 3.75; N, 10.55.
4-(4-Methoxyphenoxy)thieno[2,3-d]pyrimidine (3a). Compound
3a was obtained according to Method A from 2a (171 mg, 1
mmol) and 4-methoxyphenylboronic acid (182 mg, 1.2 mmol)
and isolated by column chromatography (Silica, CH2Cl2 as
eluent); the yield was 155 mg (64%), beige solid, mp 111–
1
112ꢀC; IR: 1572, 1534, 1503 cmꢂ1; H NMR: d 3.78 (s, 3H),
7.01 (d, J ¼ 9.1 Hz, 2H), 7.22 (d, J ¼ 9.1 Hz, 2H), 7.63 (d, J
¼ 6 Hz, 1H), 7.94 (d, J ¼ 6 Hz, 1H), 8.59 (s, 1H); 13C NMR:
d 55.3, 114.2, 118.4, 118.5, 122.8, 127.1, 145.3, 152.9, 156.9,
163.4, 168.8; GC MS (tR 9.19 min) m/z (%) ¼ 257 (100, Mþ),
244 (19), 134 (94); HRMS calcd for [M þ Hþ] C13H11N2O2S
259.0536, found 259.0534. Anal. Calcd. for C13H10N2O2S: C,
60.45; H, 3.90; N, 10.85. Found: C, 60.59; H, 3.88; N, 10.89.
4-(4-Methoxyphenoxy)-5,6,7,8-tetrahydrobenzothieno[2,3-
d]pyrimidine (3b). Compound 3b was obtained according to
Method A from 2b (225 mg, 1 mmol) and 4-methoxyphenyl-
boronic acid (182 mg, 1.2 mmol) and isolated by column chro-
matography (Silica, CH2Cl2 as eluent); the yield was 101 mg
1-[3-(5,6,7,8-Tetrahydrobenzothieno[2,3-d]pyrimidin-4-yl-oxy)-
phenyl]ethanone (5b). Compound 5b was prepared from 2b
(225 mg, 1 mmol) and 3-acetylphenylboronic acid (197 mg,
1.2 mmol) according to Method A working at room tempera-
ture and purified by column chromatography (Silica, Cyclohex-
ane/AcOEt 98:2 as eluent), the yield was 80 mg (25%), white
1
solid, mp 148–149ꢀC, IR: 1683, 1571, 1558 cmꢂ1; H NMR: d
1.85 (m, 4H), 2.58 (s, 3H), 2.86 (m, 2H), 3.02 (m, 2H), 7.55–
7.65 (m, 2H), 7.83–7.90 (m, 2H), 8.47 (s, 1H); 13C NMR: d
21.7, 22.3, 25.0, 25.4, 26.8, 118.4, 121.5, 125.5, 126.9, 127.0,
130.0, 135.9, 138.4, 151.9, 152.3, 162.6, 167.7, 197.2; HRMS
calcd for [M þ Hþ] C18H17N2O2S 325.1005, found 325.0985.
Anal. Calcd. for C18H16N2O2S: C, 66.64; H, 4.97; N, 8.64.
Found: C, 66.87; H, 4.90; N, 8.64.
(34%), brown solid, mp 83–84ꢀC, IR: 1570, 1560, 1498 cmꢂ1
;
1H NMR: d 1.85 (m, 4H), 2.85 (m, 2H), 3.00 (m, 2H), 6.99
(d, J ¼ 7.5 Hz, 2H), 7.19 (d, J ¼ 7.5 Hz, 2H), 8.45 (s, 1H);
13C NMR: d 21.8, 22.3, 24.9, 25.4, 55.4, 114.5, 118.3, 122.8,
126.9, 135.5, 145.4, 152.0, 156.7, 163.1, 167.4; GC MS (tR
11.62 min) m/z (%) ¼ 313 (100, Mþ), 298 (40), 205 (44).
Anal. Calcd. for C17H16N2O2S: C, 65.36; H, 5.16; N, 8.97.
Found: C, 65.60; H, 5.21; N, 9.06.
1-(3-Thieno[2,3-d]pyrimidin-4-ylphenyl)ethanone (6a). Compound
6a was prepared from 2a (171 mg, 1 mmol) and 3-acetylphe-
nylboronic acid (246 mg, 1.5 mmol) according to Method B.
The pure product was obtained by column chromatography
(Silica, CH2Cl2 as eluent), the yield was 111 mg (44%),
white solid, mp 129–130ꢀC, IR: 1683, 1603, 1545 cmꢂ1 1H
;
4-(4-Methoxyphenyl)thieno[2,3-d]pyrimidine (4a). Compound
4a was obtained according to the general procedure B from 2a
(171 mg, 1 mmol) and 4-methoxyphenylboronic acid (228 mg,
1.5 mmol) and isolated after purification by chromatography
on silica gel (CH2Cl2 as eluent), the yield was 155 mg (64%),
NMR: d 2.74 (s, 3H), 7.83 (m, 2H), 8.13–8.32 (m, 3H),
8.56 (s, 1H), 9.25 (s, 1H); 13C NMR: d 26.9, 120.7, 127.3,
128.7, 129.3, 129.4, 130.0, 133.5, 137.3, 137.4, 153.0, 158.9,
169.4, 197.5; GC MS (tR 9.76 min) m/z (%) ¼ 254 (100, Mþ),
239 (64), 211 (68); HRMS calcd for [M þ Hþ] C14H11N2OS
255.0587, found 255.0572. Anal. Calcd. for C14H10N2OS:
C, 66.12; H, 3.96; N, 11.02. Found: C, 66.26; H, 3.88; N,
10.99.
beige solid, mp 136–137ꢀC, IR: 1609, 1540, 1514 cmꢂ1 1H
;
NMR: d 3.85 (s, 3H), 7.15 (d, J ¼ 8.6 Hz, 2H), 7.75 (d, J ¼ 6
Hz, 1H), 7.98–8.02 (m, 3H), 9.08 (s, 1H); 13C NMR: d 55.4,
114.4, 121.1, 126.7, 128.3, 129.3, 130.8, 152.9, 159.3, 161.2,
169.1; GC MS (tR 9.34 min) m/z (%) ¼ 242 (100, Mþ), 211
(66), 134 (5); HRMS calcd for [M þ Hþ] C13H11N2OS
243.0587, found 243.0601. Anal. Calcd. for C13H10N2OS: C,
64.44; H, 4.16; N, 11.56. Found: C, 64.62; H, 4.17; N, 11.49.
4-(4-Methoxyphenyl)-5,6,7,8-tetrahydrobenzothieno[2,3-
d]pyrimidine (4b). Compound 4b was obtained according to
the general procedure B from 2b (225 mg, 1 mmol) and 4-
methoxyphenylboronic acid (228 mg, 1.5 mmol) and isolated
after purification by column chromatography on silica gel
(CH2Cl2 as eluent), the yield was 201 mg (68%), white solid,
1-[3-(5,6,7,8-Tetrahydrobenzothieno[2,3-d]pyrimidin-4-yl)
phenyl]ethanone (6b). Compound 6b was prepared from 2b
(225 mg, 1 mmol) and 3-acetylphenylboronic acid (197 mg,
1.2 mmol) according to Method C. The pure product was
obtained by column chromatography (Silica, CH2Cl2 as elu-
ent), the yield was 231 mg (75%), pale ꢂb1rown solid, mp 121–
122ꢀC, IR: 1684, 1579, 1560, 1523 cm
;
1H NMR: d 1.53–
1.58 (m, 2H), 1.77–1.82 (m, 2H), 2.02–2.07 (m, 2H), 2.63 (s,
3H), 2.86–2.91 (m, 2H), 7.68 (m, 1H), 7.80 (m, 1H), 8.10 (m,
1H), 8.30 (s, 1H), 9.02 (s, 1H); 13C NMR: d 21.2, 22.0, 25.4,
26.6, 26.8, 126.8, 128.1, 128.4, 128.6, 128.9, 133.6, 136.3,
138.4, 138.5, 151.6, 159.3, 168.1, 197.6; GC MS (tR 11.78
min) m/z (%) ¼ 307 (100, Mþ), 293 (56), 280 (93), 266 (16);
HRMS calcd for [M þ Hþ] C18H17N2OS 309.1056, found
309.1030. Anal. Calcd. for C18H16N2OS: C, 70.10; H, 5.23; N,
9.08. Found: C, 70.17; H, 5.35; N, 9.12.
mp 101–102ꢀC, IR: 1608, 1508 cmꢂ1 1H NMR: d 1.56–1.60
;
(m, 2H), 1.79–1.83 (m, 2H), 2.13–2.18 (m, 2H), 2.85–2.90 (m,
2H), 3.83 (s, 3H), 7.06 (d, J ¼ 8.6 Hz, 2H), 7.49 (d, J ¼ 8.6
Hz, 2H), 8.95 (s, 1H); 13C NMR: d 21.9, 22.1, 25.4, 26.8,
55.2, 113.2, 127.2, 128.0, 130.5, 130.6, 130.7, 137.6, 151.5,
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E. Perspicace, S. Hesse, G. Kirsch, M. Yemloul, and C. Lecomte
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`
Acknowledgments. The authors are grateful to the ‘‘Ministere
tert-Butyl 4-(thieno[2,3-d]pyrimidin-4-yloxy)phenylcarba-
´
de l’Education Nationale, de l’Enseignement Superieur et de la
mate (7). Compound 7 was prepared from 2a (171 mg, 1 mmol)
and 4-[(tert-butoxycarbonyl)amino]phenylboronic acid (285 mg,
1.2 mmol) according to Method A. The pure product was
obtained by column chromatography (Silica, CH2Cl2 as eluent),
the yield was 230 mg (67%), pale yellow solid, mp 141–142ꢀC,
IR: 1702, 1573, 1535 cmꢂ1; 1H NMR: d 1.46 (s, 9H), 7.17 (d, J
¼ 9 Hz, 2H), 7.49 (d, J ¼ 9 Hz, 2H), 7.61 (d, J ¼ 6 Hz, 1H), 7.91
(d, J ¼ 6 Hz, 1H), 8.56 (s, 1H), 9.41 (s, 1H); 13C NMR: d 28.0,
79.2, 115.0, 118.4, 118.5, 119.2, 122.0, 127.2, 137.1, 146.5,
152.9, 163.3, 168.8; GC MS (tR 9.74 min) m/z (%) ¼ 243 (100,
Mþ); HRMS calcd for [M þ Hþ] C17H18N3O3S 344.1063, found
344.1042. Anal. Calcd. for C17H17N3O3S: C, 59.46; H, 4.99; N,
12.24. Found: C, 59.62; H, 4.88; N, 12.29.
Recherche’’ for a PhD grant to E.P. They thank Paul Hannewald
for recording GC MS analysis, Daniel Canet for assistance on
COSY, NOESY, HMBC, HSQC spectra, Emmanuel Wenger for
`
crystallographic results, and Genevieve Balme for helpful
discussions.
REFERENCES AND NOTES
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tert-Butyl 4-(5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-
4-yl)phenylcarbamate (8). Compound 8 was prepared from 2b
(225 mg, 1 mmol) and 4-[(tert-butoxycarbonyl)amino]phenyl-
boronic acid (285 mg, 1.2 mmol) according to Method C. The
pure product was obtained by column chromatography (Alu-
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mg (61%), white solid, mp 173–174ꢀC, IR: 1702, 1612, 1513
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cmꢂ1 1H NMR: d 1.46 (s, 9H), 1.61 (m, 2H), 1.79 (m, 2H),
,
2.15 (m, 2H), 2.87 (m, 2H), 7.44 (m, 2H), 7.60 (m, 2H), 8.95
(s, 1H), 9.62 (s, 1H); 13C NMR: d 22.0, 25.4, 26.2, 26.8, 28.1,
79.3, 116.9, 127.2, 128.3, 129.9, 131.7, 137.6, 140.7, 151.5,
152.7, 160.1, 168.0; GC MS (tR 12.23 min) m/z (%) ¼ 280
(100, Mþ); HRMS calcd for [M
þ
Hþ] C21H24N3O2S
382.1584, found 382.1545. Anal. Calcd. for C21H23N3O2S: C,
66.12; H, 6.08; N, 11.01. Found: C, 66.35; H, 6.10; N, 10.95.
tert-Butyl 2-thieno[2,3-d]pyrimidin-4-yl-1H-indole-1-carboxy-
late (9a). Compound 9a was prepared from 2a (171 mg, 1
mmol) and 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid
(313 mg, 1.2 mmol) according to Method C. The pure product
was obtained by column chromatography (Alumina, cyclohex-
ane/AcOEt 98:2 as eluent), the yield was 127 mg (36%), pale
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brown oil, IR: 1727, 1565, 1539, 1515 cmꢂ1; H NMR: d 1.11
1
(s, 9H), 7.29 (s, 1H), 7.34 (m, 1H), 7.47 (m, 1H), 7.57 (d, J ¼
6 Hz, 1H), 7.74 (d, J ¼ 7.7 Hz, 1H), 8.05 (d, J ¼ 6 Hz, 1H),
8.13 (d, J ¼ 8.3 Hz, 1H), 9.17 (s, 1H); 13C NMR: d 26.7,
83.9, 113.6, 114.4, 120.5, 121.9, 123.4, 126.1, 128.2, 128.3,
129.2, 134.7, 137.1, 148.9, 152.6, 154.2, 168.3; GC MS (tR
10.97 min) m/z (%) ¼ 251 (100, Mþ); HRMS calcd for [M þ
Hþ] C19H18N3O2S 352.1114, found 352.1099. Anal. Calcd. for
C19H17N3O2S: C, 64.94; H, 4.88; N, 11.96. Found: C, 65.21;
H, 4.88; N, 11.89.
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4-yl)-1H-indole-1-carboxylate (9b). Compound 9b was pre-
pared from 2b (225 mg, 1 mmol) 1-(tert-butoxycarbonyl)-1H-
indol-2-ylboronic acid (313 mg, 1.2 mmol) according to
Method C. The pure product was obtained by column chroma-
tography (Alumina, cyclohexane/AcOEt 98:2 as eluent), the
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yield was 207 mg (51%), yellow oil, IR: 1735, 1574, 1512 cmꢂ1
;
1H NMR: d 0.99 (s, 9H), 1.56 (m, 2H), 1.76 (m, 2H), 2.09 (m,
2H), 2.87 (m, 2H), 6.94 (s, 1H), 7.32 (m, 1H), 7.42 (m, 1H), 7.69
(d, J ¼ 7.2 Hz, 1H), 8.21 (d, J ¼ 7.9 Hz, 1H), 9.04 (s, 1H); 13C
NMR: d 21.6, 22.2, 24.2, 25.3, 26.6, 83.8, 111.6, 115.0, 121.5,
123.5, 125.4, 126.8, 128.3, 129.4, 134.4, 135.6, 138.8, 148.6,
151.5, 153.4, 167.2; GC MS (tR 13.97 min) m/z (%) ¼ 305 (100,
Mþ); HRMS calcd for [M þ Hþ] C23H24N3O2S 406.1584, found
406.1560. Anal. Calcd. for C23H23N3O2S: C, 68.12; H, 5.72; N,
10.36. Found: C, 68.13; H, 5.71; N, 10.40.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet