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Acknowledgment Financial support by the CTQ2008-05027/BQU (2008-2011) and a grant, by Universidad de Alcalá (Spain) (M.C.) are gratefully acknowledged.
Conclusion In this communication we report the synthesis of a series of N-(5’-alkynylpiridin-2’-yl) pyridinium aminides, through a copper- and fosfine-free method, based on a catalytic system Pd(II)/DABCO, and using either conventional heating or microwaves.4
The use of another solvent non-toxic and non-flammable like water in presence of DABCO and Pd2(PPh3)2 in microwaves generates the Sonogashira coupling products, together with unexpected side products as a result of addition over the alkyne.
Introduction Palladium-catalyzed cross-coupling Sonogashira reaction is one of the most important methods for the formation of C-C bonds.1 Particularly, alkynes are useful building blocks in organic synthesis and a representative functional group in many natural and bioactive compounds. In the last year, our program has been related with the synthetic utility of N-(azin-2’-yl)pyridinium aminides 1, as building blocks in the synthesis of azine derivatives, using Sonogashira reaction (Scheme 1). Halogenation of pyridinium N-(pyridin-2’-yl)aminide 1 can be regioselectively achieved in the 5’-position of the pyridine with N-halosuccinimide in equimolar amount.2 The synthesis of substituted N-aminides 3 has been performed by treatment the N-(5’-iodopyridin-2’-yl)pyridinium aminide 2 with the corresponding acetylene in the presence of 1,4-diazabiciclo[2.2.2]octane (DABCO) and a palladium salt (Scheme 1).3 Additionally, a new environmentally friendly methodology has been developed carrying out the reaction under microwave irradiation.4
References 1. Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133-173. 2. Burgos, C.; Delgado, F.; García-Navío, J. L.; Izquierdo, M. L.; Álvarez-Builla, J. Tetrahedron 1995, 31, 8649-8654. 3. Li, J.H.; Liang, Y.; Xie, Y.X. J. Org.Chem. 2005, 70, 4393-4396.. 4. Kappe, O.C. Angew. Chem. Ed. 2004, 43, 6250-6284.
Me
S
MeO
CF3
CF3
CF3
NH2
N
Me
Me
H
O
(Me)3-Si
(i Pr)3-Si
R MethodCompound
3b
3c
3e
3f
3d
Yield (%)
A 45B 69C 65
3a
3h
3i
3g A 30B 60C 39
A 21B 57
A 15B 40C 18
3jA B 27C 10
3kA 9B 22C 43
B 46C
A 48B 22C
A 27B 75C 43
A 25B 68C 61
A 25B 47C 57
R MethodCompound Yield (%)
Córdoba López, Marta; Izquierdo Ceinos, Mª Luisa; Alvarez-Builla, Julio*. Departamento de Química Orgánica, Universidad de Alcalá, 28871- Alcalá de Henares, Madrid, Spain.
E-mail address: [email protected]
Synthesis of Substituted Pyridinium N-Aminides by Sonogashira Reactions
Method A: Aminide 2 (1mmol), alkyne (2 mmol), Pd(OAc)2 (5mmol %) and DABCO (6 mmol) in acetonitrile as solvent at 40ºC for 24 h. Method B: Aminide 2 (1mmol), alkyne (2 mmol), DABCO (6 mmol), PdCl2(PPh3)2 (5mmol %) in acetonitrile as solvent at 60ºC for 10 minutes using MW. Method C: Aminide 2 (1mmol), alkyne (2 mmol), DABCO (6 mmol), PdCl2(PPh3)2 (5mmol %) in water as solvent at 70ºC for 15 minutes using MW.
Me
S
CF3
CF3
CF3
RCompound
4b
4c
Yield (%)
4a
4e
4d 10
21
3
7
5
R
R
A) Pd(OAc)2, DABCO,
1.1 eq. NISN
N N
1
+-
N
N N
I
+-
2
N
N N
R
+-
3
N
N N
R
+-
R
4
Mw 15min, 70ºC
C) Pd2(PPh3)2, DABCO
Scheme 1
CH3CN
H2O
3 +
B) Pd2(PPh3)2, DABCO
Mw 10min, 60ºC
Sonogashira reaction have been performed in three different conditions; one using conventional heating and two using microwaves. Modifications in the solvent from acetonitrile to water do not improve the final result because the formation of compound 3 was detected in some cases.
Method C: Aminide 2 (1mmol), alkyne (2 mmol), DABCO (6 mmol), PdCl2(PPh3)2 (5mmol %) in water as solvent at 70ºC for 15 minutes using MW.
