Page 5 of 7
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
3
4
Me: 6c
70%c
General procedure for Sonogashira coupling at C-3 position.
DOI: 10.1039/C7OB00624A
: 4a
: 4a
4a-b (0.5mmol, 1eq), PdCl2(PPh3)2 (35mg, 0.05mmol, 10%) and
CuI (10mg, 0.05mmol, 10%) were introduced into a screw-cap
test tube. The tube was sealed with a rubber septum and then
evacuated and refilled with argon thrice. DMF (2mL), Et3N
(278µL, 2mmol, 4eq) and alkyne (0.55mmol, 1.1eq) were then
added. The reaction mixture was stirred for 1h30 at 80°C. After
cooling, the reaction mixture was partitioned between CH2Cl2
(10mL) and brine (10mL). The aqueous phase was extracted
twice with CH2Cl2 (10mL). Organic phases were reunited, dried
over MgSO4 and evaporated to dryness. The crude mixture was
purified by column chromatography (silica, eluent: mixture of
petroleum ether and diethylether).
4-pyr: 6d
89%d
a) Isolated yield. b) Reagents and conditions: PdCl2(PPh3)2 10%, CuI 10%, alkynes (1.5eq),
Et3N (4eq), DMF, r.t. 3h30. c) 5% Pd(PPh3)4, boronic acid (1.1eq), Na2CO3 (2eq),
dioxane/H2O (2:1), 120°C (MW), 2h. d) 5% Pd(PPh3)4, boronic acid (1.1eq), Na2CO3 (2eq),
dioxane/H2O (2:1), 120°C (MW), 1h.
Conclusions
This work presents an efficient method for selective
functionalization of 2-iodo-3-bromoimidazo[1,2-a]pyridine by
Sonogashira and Suzuki-Miyaura cross-coupling reactions. This
strategy allows easy access to libraries of molecules, with every
possible combination of substituents at 2- and 3-positions, from
a simple, stable starting material and readily available boronic
acids or alkynes, and in a minimal number of steps. Various aryl,
heteroaryl, alkyl, and alkynyl groups can be introduced using
this method. Some of the products reported here (e.g. 2,3-
diynes) are otherwise difficult to access. Feasibility of additional
cross-coupling reaction (e.g. Stille or Buchwald cross-coupling)
are currently under investigation.
Acknowledgements
We thank the ‘Département d’analyses chimiques et S.R.M.
biologique et médicale’ (Tours, France) for chemical analyses.
Notes and references
1 a) C. Enguehard-Gueiffier, A. Gueiffier, Mini Rev. Med. Chem. 2007,
7, 888-899. b) R. Goel, V. Luxami, K. Paul, Curr. Top. Med. Chem.
2016, 16, 3590-3616. c) A. Deep, R. K. Bhatia, R. Kaur, S. Kumar, U.K.
Jain, H. Singh, S. Batra, D. Kaushik, P. K. Deb, Curr. Top. Med. Chem.
2017, 17, 238-250.
Experimental
General procedure for Suzuki coupling at C-2 position or C-3
position.
2 J. Koubachi, S. El Kazzouli, M. Bousmina, G. Guillaumet, Eur. J. Org
Chem. 2014, 5119-5138.
1b (646mg, 2mmol, 1eq or 2b-d for C-3 functionalization),
Pd(PPh3)4 (116mg, 0.1mmol, 5%), Na2CO3 (424mg, 4mmol, 2eq)
and boronic acid (2.2mmol, 1.1eq) were introduced into a
microwave tube. The tube was sealed with a rubber septum and
then evacuated and refilled with argon thrice. 1,4-Dioxane
(8mL) and water (4mL) were then added. The reaction mixture
was heated using microwave iradiation at 120°C for 1h. After
cooling, the reaction mixture was partitioned between EtOAc
(10mL) and water (10mL). The aqueous phase was extracted
twice with EtOAc (10mL). Organic phases were combined, dried
over MgSO4 and evaporated to dryness. The crude mixture was
purified by column chromatography (silica, eluent: mixture of
CH2Cl2 and EtOAc).
3
a) J. Koubachi, S. El Kazzouli, A. Berteina-Raboin, A. Mouaddib, G.
Guillaumet, J. Org. Chem. 2007, 72, 7650-7655. b) A. El Akkaoui, I.
Bassoude, J. Koubachi, S. Berteina-Raboin, A. Mouaddib, G.
Guillaumet, Tetrahedron 2011, 67, 7128-7138.
4
S. Marhadour, M.-A. Bazin, P. Marchand, Tetrahedron Lett. 2012,
53, 297-300.
5 A. K. Bagdi, S. Santra, K. Monir, A. Hajra, Chem. Commun. 2015, 51,
1555-1575.
6 Eur. Pat. Appl., 2650284, 16 oct 2013.
7 Y. Gao, M. Yin, W. Wu, H. Huang, H. Jiang, Adv. Synth. Catal. 2013,
355, 2263-2273.
8 X. Zhou, H. Yan, C. Ma, Y. He, Y. Li, J. Cao, R. Yan, G. Huang, J. Org.
Chem. 2016, 81, 25-31.
9
M.-A. Hiebel, Y. Fall, M.-C. Scherrmann, S. Berteina-Raboin, Eur. J.
Org. Chem. 2014, 4646-4650.
Electronic supplementary information (ESI) and crystallographic
General procedure for Sonogashira coupling at C-2 position.
10
1b (161mg, 0.5mmol, 1eq), PdCl2(PPh3)2 (35mg, 0.05mmol,
10%) and CuI (10mg, 0.05mmol, 10%) were introduced into a
screw-cap test tube. The tube was sealed with a rubber septum
and then evacuated and refilled with argon thrice. DMF (2mL),
Et3N (278µL, 2mmol, 4eq) and alkyne (0.55mmol, 1.1eq) were
then added. The reaction mixture was stirred for 30 minutes at
room temperature. The reaction mixture was partitioned
between CH2Cl2 (10mL) and brine (10mL). The aqueous phase
was extracted twice with CH2Cl2 (10mL). Organic phases were
reunited, dried over MgSO4 and evaporate to dryness. The
crude mixture was purified by column chromatography (silica,
eluent: mixture of petroleum ether and diethylether).
data in CIF. CCDC1537566
I. R. Baxendale, S. V. Ley, A. C. Mansfield, C. D. Smith, Angew.
11
Chem. Int. Ed. 2009, 48, 4017-4021.
12 D. Dheer, K. R. Reddy, S. K. Rath, P. L. Sangwan, P. Das, R. Shankar,
RSC Adv. 2016, 6, 38033-38036.
13 Z. Tber, M.-A. Hiebel, A. El Hakmaoui, M. Akssira, G. Guillaumet, S.
Berteina-Raboin, J. Org. Chem. 2015, 80, 6564-6573.
14
H. Kubas, U. Meyer, M. Hechenberger, K.-U. Klein, P. Plitt, R.
Zemribo, H. W. Spexgoor, S. G. A. Van Assema, U. Abel, Bioorg. Med.
Chem. Lett. 2013, 23, 6370-6376.
15
M. Henrich, U. Abel, S. Muller, H. Kubas, U. Meyer, M.
Hechenberger, V. Kauss, R. Zemribo, PCT Int. Appl., 2012052451, 26
Apr 2012.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins