Suzuki cross-coupling of 5-bromothieno[2,3-b]pyridines for the convenient synthesis of 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines

Article abstract of DOI:10.1016/j.tetlet.2012.12.077

For the first time, Suzuki cross-coupling reactions were used for introducing an aromatic group in position 8 of the pyridine ring of novel pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines. This reliable and simple method may be extended to various boronic acids for allowing preparation of a larger library of these compounds in the hope of further structure-activity relationship investigations.

Full text of DOI:10.1016/j.tetlet.2012.12.077

Tetrahedron Letters 54 (2013) 1160–1163
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Tetrahedron Letters
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Suzuki cross-coupling of 5-bromothieno[2,3-b]pyridines for the convenient
synthesis of 8-arylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines
Yvonnick Loidreau a,b, Vincent Levacher b,c, Thierry Besson a,b,
⇑
a Université de Rouen, Place Emile Blondel, 76821 Mont-Saint-Aignan, France
b Laboratoire Chimie Organique et Bioorganique, Réactivité et Analyse (C.O.B.R.A.), CNRS UMR 6014 & FR 3038, Institut de Recherche en Chimie Organique Fine (I.R.C.O.F.) rue
Tesnière, 76131 Mont-Saint-Aignan, France
c INSA de Rouen, Avenue de l’Université, 76801 Saint-Étienne-du-Rouvray Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
For the first time, Suzuki cross-coupling reactions were used for introducing an aromatic group in posi-
tion 8 of the pyridine ring of novel pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines. This reliable and
simple method may be extended to various boronic acids for allowing preparation of a larger library of
these compounds in the hope of further structure–activity relationship investigations.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 October 2012
Revised 12 December 2012
Accepted 18 December 2012
Available online 27 December 2012
Keywords:
Suzuki cross-coupling
Microwave-assisted chemistry
Thieno[2,3-b]pyridines
Pyrido[30,20:4,5]thieno[3,2-d]pyrimidines
The main interests of our research group include the synthesis
of C,N,S-containing heterocyclic precursors of bioactive molecules
able to modulate the role of kinases in signal transduction.1 As a
part of this work, the synthesis of N-arylbenzothieno[3,2-d]pyrim-
idin-4-amines and their pyrido and pyrazino analogues was pub-
lished.2 The inhibitory potency of the final products against five
ido[30,20:4,5]thieno[3,2-d]pyrimidines which can be functionalized
in position 8 of the pyridine ring for further structure–activity rela-
tionship investigations.5 This Letter describes the development of a
reliable and simple method that allows the preparation of a library
of these compounds for which interesting biological properties can
be expected. As a continuation of previous works, the main part of
the chemistry performed in this study was realized under micro-
wave irradiation for an efficient heating of the reaction mixtures
and a good control of reaction parameters.6
protein kinases (CDK5/p25, CK1d/
was evaluated. It was found that N-arylpyrido[30,20:4,5]thie-
no[3,2-d]pyrimidin-4-amine series of compounds (see in
e, GSK3ab, DYRK1A and CLK1)
I
Scheme 1) turned out to be particularly promising for the develop-
ment of new pharmacological inhibitors of CK1 and CLK1 kinases.
Among these compounds, II (Scheme 1) has been considered as the
most active product with submicromolar IC50 values for CK1
(31 nM) and CLK1 (680 nM). Pursuing our investigations in the de-
sign of potent kinase inhibitors we envisioned the synthesis of
functionalized pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines
of general structure 1 (Scheme 1).
A literature survey revealed that the synthesis of 8-substituted-
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines (1) has been
rarely described until now.3 In contrast, synthetic routes and bio-
logical activity of some pyrido[30,20:4,5]thieno[3,2-d]pyrimidine
analogues, substituted by various groups in position 7 of the pyrido
moiety, were already studied and published.4 We decided that it
would be an interesting challenge to synthesize novel pyr-
The target compounds we studied were 8-arylpyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines (1) which are substi-
tuted by an aromatic group in position 8 of the pyridine moiety.
The route envisioned is described in the retro-synthetic pathway
presented in Scheme 2. The multi-step synthetic pathway was in-
spired by our previous work on the utility of formamide to gener-
ate ammonia synthon for introducing a nitrogen atom into a
pyrimidine ring from anthranilic acids,7 anthranilonitrile8 or its
benzofuro or benzothieno analogues.9
Our approach consisted of preparing a brominated enaminonit-
rile (3) from the commercial 5-bromo-2-chloronicotinonitrile (2)
(Scheme 2). Transformation of thieno[2,3-b]pyridine (3) into its
corresponding formamidine derivative (4) and nucleophilic attack
by ammonia and cyclization will yield the expected brominated
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amine (5). At the end of
this process, incorporation of the phenyl moiety was envisioned
via a Suzuki cross-coupling reaction with various phenylboronic
acids.
⇑
Corresponding author. Tel.: +33 (0) 235522904; fax: +33 (0) 235522962.
E-mail address: thierry.besson@univ-rouen.fr (T. Besson).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.077

Y. Loidreau et al. / Tetrahedron Letters 54 (2013) 1160–1163
1161
R
N
N
N
HN
N
N
N
1
8
7
S
N
N
S
4
R
NH2
N
S
NH2
I
II
1
Scheme 1. Structure of target 8-arylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines (1) and their pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amine congeners previously
studied2 (I and II).
R
N
Br
Br
Br
NH2
CN
N
N
Br
CN
Cl
N
N
N
N
N
CN
N
N
N
S
S
S
S
NH2
NH2
2
3
4
5
1
Scheme 2. Synthetic routes envisioned for an access to the target products.
HS-(CH2)2-CN
BrCH2CN
Br
Br
N
DMF-DMA
Br
CN
Cl
NH2
CN
N
N
N
N
CN
90°C (µW)
30 min
(99%)
KOH, DMF, 0°C
180 min
S
S
2
(91%)
3
4
Scheme 3. Synthesis of 3-amino-5-bromothieno[2,3-b]pyridine-2-carbonitrile precursor (3) and its N,N-dimethylformimidamide derivative (4).
path A
R
Br
N
Br
boronic acid
Pd(PPh3)4
Na2CO3
N
N
N
NH2-CHO
N
N
N
CN
N
N
S
S
S
200°C (µW)
30 min
(87%)
NH2
NH2
DMF, 150°C (µW)
90min
4
5
1a (90%) and 1c (64%)
0% for R = 4-Cl, 3-Cl and 3,4-diCl
path B
R
R
boronic acid
Pd(PPh3)4
Na2CO3
N
Br
N
NH2-CHO
N
N
N
N
N
DMF, 150°C (µW)
N
CN
185°C (µW)
30 min
N
CN
S
S
S
90min
NH2
4
6a-g (55-99%)
1a-g (73-100%)
R = H; 4-Me; 4-OMe; 4-Cl;
3-Cl; 3,4-diCl; 2,4-diCl
Scheme 4. Synthesis of 8-arylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines (1); for reaction times and yields see Table 1.
The synthesis of the thieno[2,3-b]pyridine precursor (3) was in-
spired from a method previously described in the literature for the
preparation of benzothiophene analogues.9 5-Bromo-2-chloronico-
tinonitrile (2) was firstly treated by freshly prepared 3-mercapto-
propionitrile10 in the presence of aqueous potassium hydroxide,
in dimethylformamide (DMF) at 0 °C. After 1 h of stirring, the
alkylating agent (bromoacetonitrile) was added to the cold reac-
tion mixture to give the expected 3-amino-5-bromothieno

1162
Y. Loidreau et al. / Tetrahedron Letters 54 (2013) 1160–1163
Table 1
series (6a–g) (Table 1). Strong heating (185 °C) of these inter-
mediates in the presence of formamide allowed convenient for-
mation of novel pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-
amines (1a–g) substituted in position 8 by a phenyl ring, itself
substituted by various electro-donor or electro-withdrawing
groups.5 This second route can be considered more efficient
and easier in practice. It allowed good overall yields of the tar-
get molecules and the operating conditions were easy to apply.
Some comments can be made concerning the microwave proce-
dure as well as the technical and practical aspects. Microwave
heating was realized at atmospheric pressure in a well-controlled
multimode cavity12 and not in pressurized vials as described in
various papers, especially for Suzuki cross-coupling reactions.13
The choice of a reactor able to work at atmospheric pressure was
guided by our previous experience in the use of microwaves in or-
ganic synthesis.14 It has some advantages, such as the possibility of
easier work-up and the use of usual laboratory glassware. In the
main steps of the synthetic pathway described in this Letter, irra-
diation power at 200 or 800 W, was enough to efficiently reach
the programmed temperature with a short ramp time (3 min, not
added to the reaction time indicated in schemes). Temperature
was monitored via a contactless-infrared pyrometer which was
calibrated by control experiments with a fibre-optic contact
thermometer.
Synthesis of N,N-dimethylformimidamides 6a–g and final thieno[3,2-d]pyrimidines
1a–g
Ar
Starting
compound
Yielda,b,c (%)
Product
Yieldb,c,d (%)
6a
6b
6c
6d
99
99
79
94
1a
1b
1c
1d
87
93
85
78
Me
OMe
Cl
Cl
6e
98
1e
92
Cl
6f
55
90
1f
100
73
Cl
Cl
Cl
6g
1g
In conclusion, synthesis of functionalized pyrido[30,20:4,5]thie-
no[3,2-d]pyrimidin-4-amines was investigated with success. For
the first time, Suzuki cross-coupling reactions were used for intro-
ducing an aromatic group in position 8 of the pyridine ring of the
pyrido[30,20:4,5]thieno[3,2-d]pyrimidine core. This reliable and
simple method may be extended to various boronic acids to allow
the preparation of a larger library of these compounds in the hope
of further structure–activity relationship investigations. In this
point of view, the synthesis of the intermediate N,N-dimethylfor-
mimidamides (6a–g) is also promising for the synthesis of various
derivatives which can be substituted in position 3 or 4 of the
pyrimidine part of the tricyclic core.
a
Reactions were performed for 90 min at 150 °C and at atmospheric pressure
under microwave irradiation (800 W) on a 1.0 mmol scale from 4 with 1.5 equiv of
appropriate boronic acid.
b
Yield of isolated product.
c
Microwave reactor: RotoSYNTH™ from Milestone S.r.l, Italy.
d
Reactions were performed for 30 min at 185 °C and at atmospheric pressure
under microwaves (200 W) on
formamide.
a 0.2 mmol scale from 6a–g with 40 equiv of
[2,3-b]pyridine-2-carbonitrile (3) in high yield (91%). The synthe-
sis of
(E)-N0-(5-bromo-2-cyanothieno[2,3-b]pyridin-3-yl)-N,
N-dimethylformimidamide intermediate (4) was performed in
quantitative yield by reaction of cyanoenamine (3) with N,N-
dimethylformamide dimethylacetal (DMF-DMA) after 30 min of
microwave irradiation (800 W) at 90 °C (Scheme 3).
Acknowledgement
This work was supported by a PhD grant from the Région Haute-
Normandie (Y.L.) and the ISCE-CHEM program. We acknowledge
Milestone S.r.l. (Italy) for providing the microwave reactors and
financial and technical support. Y.L. also thank Charline Denneval
for preparation of the Pd(PPh3)4 catalyst.
As described in the retrosynthetic pathway (Scheme 2) the next
step of the synthesis consisted of a nucleophilic attack of ammonia
on the N,N-dimethylamidine 4 and cyclization of the intermediate
amidine to yield the expected 8-bromopyrido[30,20:4,5]thieno[3,2-
d]pyrimidin-4-amine (5) in a very good yield (87%). At this part of
the work, the Suzuki cross-coupling reactions of five phenylboronic
acids (Scheme 4) with 5 were investigated. Using freshly prepared
Pd(PPh3)4 as the catalyst,11 and applying usual conditions for the
Suzuki cross-coupling, we noticed that reaction from 8-bromopyr-
ido[30,20:4,5]thieno[3,2-d]pyrimidine (5) allowed the synthesis of
only two of the expected derivatives in good to modest yields
(90% for phenyl and 64% for p-methoxyphenyl derivatives, respec-
tively) (Scheme 4, path A). At this stage of the study, we observed
that the purification of the products obtained by reaction with hal-
ogenated boronic acids was difficult due to the high polarity of
molecules. Whatever be the method of purification used, the pro-
cess led to the expected product in very poor yields, or did not al-
low isolation of any compound. In view of these results we
considered trying the introduction of phenyl substituents before
cyclizing the pyrimidine ring via thermal decomposition of form-
amide (Scheme 4, path B).
Supplementary data
Supplementary data (1H and 13C spectra) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.12.077.
References and notes
1. (a) Logé, C.; Testard, A.; Thiéry, V.; Lozach, O.; Blairvacq, M.; Robert, J.-M.;
Meijer, L.; Besson, T. Eur. J. Med. Chem. 2008, 43, 1469; (b) Beauchard, A.;
Ferandin, Y.; Frère, S.; Lozach, O.; Blairvacq, M.; Meijer, M.; Thiéry, V.; Besson,
T. Bioorg. Med. Chem. 2006, 14, 6434; (c) Testard, A.; Logé, C.; Léger, B.; Robert,
J.-M.; Lozach, O.; Blairvacq, M.; Meijer, L.; Thiéry, V.; Besson, T. Bioorg. Med.
Chem. Lett. 2006, 16, 3419; (d) Testard, A.; Picot, L.; Lozach, O.; Blairvac, M.;
Meijer, L.; Murillo, L.; Piot, J.-M.; Thiéry, V.; Besson, T. J. Enzyme Inhib. Med.
Chem. 2005, 20, 557.
2. Loidreau, Y.; Marchand, P.; Dubouilh-Benard, C.; Nourrisson, M.-R.; Duflos, M.;
Lozach, O.; Loaëc, N.; Meijer, L.; Besson, T. Eur. J. Med. Chem. 2012, 58, 171.
3. The synthesis of some 8-bromo derivatives was described in: (a) Madkour, H.
M. F.; Afify, A. A. E.; Abdalha, A. A.; Elsayed, G. A.; Salem, M. S. Phosphorus, Sulfur
Silicon Relat. Elem. 2009, 184, 719; The synthesis of 8-phenylpyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-4-amine (1a) was described in: (b) Zhao, C.;
Tovar, C.; Yin, X.; Xu, Q.; Todorov, I. T.; Vassilev, L. T.; Chen, L. Bioorg. Med.
Chem. Lett. 2009, 19, 319.
Returning to the N,N-dimethylformimidamide intermediate (4),
we observed that Suzuki cross-coupling of various phenyl boronic
acids with 4 can be performed under usual conditions of tempera-
ture and time to give very good yields of (E)-N0-(5-aryl-2-
cyano)thieno[2,3-b]pyridin-3-yl)-N,N-dimethylformimidamide

Y. Loidreau et al. / Tetrahedron Letters 54 (2013) 1160–1163
1163
4. (a) Sleebs, B. E.; Levit, A.; Street, I. P.; Flak, H.; Hammonds, T.; Ching Wong, A.;
Charles, M. D.; Olson, M. F.; Baell, J. B. Med. Chem. Commun. 2011, 2, 977; (b)
Sleebs, B. E.; Ganame, D.; Levit, A.; Street, I. P.; Gregg, A.; Flak, H.; Baell, J. B.
Med. Chem. Commun. 2011, 2, 982; (c) Quintela, J. M.; peinador, C.; Veiga, C.;
Gonzalez, L.; Bonata, L. M.; Alfonso, A.; Riguera, R. Bioorg. Med. Chem. 1998, 6,
1911.
5. Topliss, J. G. J. Med. Chem. 1972, 15, 1006. In this Letter, proposals are presented
for the stepwise selection for synthesis of analogues of an active compound.
The diagrams are based on a fundamental assumption of the Hansch method
11. Tetrakis(triphenylphosphine)palladium(0) was prepared following the
procedure described in: Coulson, D. R.; Satek, L. C.; Grim, S. O. Inorg. Synth.
2007, 13, 121.
12. Microwave experiments were conducted in a commercial microwave reactor
especially designed for synthetic chemistry. RotoSYNTH™ (Milestone S.r.l.
Italy) is a multi-mode cavity with a microwave power delivery system ranging
from 0 to 1200 W. Open vessel experiments were carried out in 50, 100 or
250 mL round bottom flasks fitted with a reflux condenser. Temperature was
monitored via
control experiments with a
a
contactless-infrared pyrometer which was calibrated by
fibre-optic contact thermometer. The vessel
that
a
particular substituent may modify activity relative to the parent
compound by virtue of resulting changes in hydrophobic, electronic and steric
effects. In the case of our study, using the Topliss scheme allowed us to choose
certain reagents to check the interest of our methodology, while starting to
build a list of molecules with potential biological interest.
contents were stirred by means of an adjustable rotating magnetic plate
located below the floor of the microwave cavity and a Teflon-coated magnetic
stir bar inside the vessel. Temperature, pressure and power profiles were
monitored in both cases through the EASY-control software provided by the
manufacturer.
6. (a)For a book see: Microwaves in Organic Synthesis; Loupy, A., Ed.; Whiley-VCH
Gmbh & KGaA: Weinhein, 2006; For reviews see: (b) Caddick, S.; Fitzmaurice, R.
Tetrahedron 2009, 65, 3325; (c) Kappe, C. O.; Dallinger, D. Mol. Divers. 2009, 13,
71; (d) Larhed, M.; Allberg, A. Drug Discov. Today 2001, 6, 406.
7. (a) Nouira, I.; Kostakis, I. K.; Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T.
Tetrahedron Lett. 2008, 49, 7033; (b) Kostakis, I. K.; Elomri, H.; Seguin, E.;
Iannelli, M.; Besson, T. Tetrahedron Lett. 2007, 48, 6609.
13. For recent examples see: (a) Kabri, Y.; Crozet, M. D.; Primas, N.; Vanelle, P. Eur.
J. Org. Chem. 2012, 5595; (b) Ng-Choi, T.; Soler, M.; Cerezo, V.; Badosa, E.;
Montesinos, E.; Planas, M.; Feliu, L. Eur. J. Org. Chem. 2012, 4321; (c) Bretéché,
A.; Marchand, P.; Nourrisson, M.-R.; Hautefaye, P.; De Nanteuil, G.; Duflos, M.
Tetrahedron 2011, 67, 4767.
14. For recent examples see: (a) Foucourt, A.; Dubouilh-Benard, C.; Chosson, E.;
Corbière, C.; Buquet, C.; Iannelli, M.; Leblond, B.; Marsais, F.; Besson, T.
Tetrahedron 2010, 66, 4495; (b) Besson, T.; Chosson, E. Comb. Chem. High
Throughput Screen 2007, 10, 903; (c) Pereira, M. de F.; Thiéry, V.; Besson, T.
Tetrahedron Lett. 2007, 48, 7657.
8. Loidreau, Y.; Besson, T. Tetrahedron 2011, 67, 4852.
9. (a) Loidreau, Y.; Dubouilh-Benard, C.; Marchand, P.; Nourrisson, M.-R.; Duflos,
M.; Buquet, C.; Corbière, C.; Besson, T. J. Heterocycl. Chem. 2013. http://
dx.doi.org/10.1002/jhet.1716; (b) Beck, J. R.; Yahner, J. A. J. Org. Chem. 1974, 39,
3440.
10. 3-Mercaptopropionitrile was prepared following the procedure described in:
(a) Gerber, E.; Hasbun, C.; Dubenko, L. G.; King, M. F.; Bierer, D. E. Org. Synth.
2000, 77, 186; (b) Klose, J.; Reese, C. B.; Song, Q. Tetrahedron 1997, 53, 14411.