Exploration of copper and amine-free Sonogashira cross coupling reactions of 2-halo-3-alkyl imidazo[4,5-b]pyridines using tetrabutyl ammonium acetate as an activator under microwave enhanced conditions

Article abstract of DOI:10.1016/j.tetlet.2012.07.028

Enhancing the reactivity of the catalytic system by using palladium catalyst with sterically demanding and electron rich ligands attached to it has often been shown as an appropriate way of performing the copper-free Sonogashira reaction. In this paper, w

Full text of DOI:10.1016/j.tetlet.2012.07.028

Tetrahedron Letters 53 (2012) 5206–5210
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Tetrahedron Letters
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Exploration of copper and amine-free Sonogashira cross coupling reactions
of 2-halo-3-alkyl imidazo[4,5-b]pyridines using tetrabutyl ammonium
acetate as an activator under microwave enhanced conditions
Ayyiliath M. Sajith a, A. Muralidharan a,b,
⇑
a Organic Chemistry Division, School of Chemical Sciences, Kasargod Govt. College, Kannur University, Kasargod, India
b Organic Chemistry Division, School of Chemical Sciences, Nehru Arts and Science College, Kannur University, Kannur, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 March 2012
Revised 8 July 2012
Accepted 9 July 2012
Available online 24 July 2012
Enhancing the reactivity of the catalytic system by using palladium catalyst with sterically demanding
and electron rich ligands attached to it has often been shown as an appropriate way of performing the
copper-free Sonogashira reaction. In this paper, we report PdCl2(PCy3)2 as an efficient catalyst for the cop-
per and amine-free Sonogashira cross coupling reactions of 2-halo-3-alkyl imidazo[4,5-b]pyridines (I, Br,
Cl) using tetrabutyl ammonium acetate as an activator under microwave enhanced conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Microwave
Sonogashira coupling
Imidazo[4,5-b]pyridine
Purine derived structures, such as derivatives of imidazo[4,5-
b]pyridine (Scheme 2) have caused considerable attention because
of their significant bioactivities.1 Their activity includes antibacte-
rial,2 antimicrobial,3 mutagenic,4 antipholigistic,5 fungicidal,6 anti-
viral,7 anticancer,8 antimitotic,9 antituberculostatic,10 antiallergic11
and antihypertensive12 actions. The alkynylation reaction of het-
erocyclic based halides using Sonogashira reaction conditions has
been widely used for the preparations of many novel systems of
potential interest. Examples are the alkynylation of halogenated
pyrroles,13 phthalimides,14 benzofurans,15 pyridines,16 pyrimi-
dines17 etc. These wide range properties of imidazo[4,5-b]pyridine
based structures prompted us to synthesise more diverse ana-
logues which are potential to have medicinal relevance.
Palladium chemistry involving nitrogen containing heteroaro-
matics has been a recent challenge in drug discovery due to the dif-
ference in the structural and electronic properties in comparison to
the corresponding carbocyclic aryl compounds. ‘The inability of
these substrates to couple efficiently in metal catalysed cross cou-
pling reactions has been attributed to the potential binding nature
of these heteroaryl substrates to the metal centre resulting in the
formation of inactive (substrate)n—metal complexes’.19 As a part
of our research work aimed at microwave assisted palladium
catalysed cross coupling reactions,20 we were interested in the
Sonogashira cross coupling reactions of 2-halo imidazo[4,5-b]
pyridines. Despite the recent advancements, there still remains a
need for an efficient protocol employing low catalyst loadings for
the coupling of nitrogen containing heteroaromatics with terminal
alkynes. The Sonogashira cross coupling reaction21–23 of terminal
acetylenes with aryl or vinyl halides has been proved as a versatile
method for the creation of carbon-carbon bonds. To the best of our
Nowadays, microwave assisted organic synthesis (MAOS)18
plays a vital role in drug discovery laboratories. One of the most
extensively studied reaction types in microwave mediated reac-
tions is transition- metal catalysed reactions which usually takes
hours and days for completion. Rapid lead generation and optimi-
sation have recently been facilitated by the emergence of MAOS18
and the technique is today one of the major tool for the medicinal
chemist. MAOS can facilitate the discovery of new reactions and re-
duce the cycle time in optimisation of reactions. In addition, it
serves to expand the chemical space in compound library
synthesis.
Table 1
Effect of catalyst on the copper-free Sonogashira couplinga of 3a and 4a
Entry
Catalyst
Yield (%)
1
2
3
4
5
Pd(PPh3)4
Traces
40
35
45
58
PdCl2(PPh3)2
PdCl2(CH3CN)2
Pd2(dba)3
PdCl2(PCy3)2
⇑
Corresponding author. Tel.: +91 487 2283466; fax: +91 467 2280335.
E-mail addresses: sajithmeleveetil@gmail.com (A.M. Sajith), drmuralinasc@
a
Reagents and conditions: 3a (0.5 mmol), 4a (0.6 mmol), Cs2CO3 (3 mmol), Pd
catalyst (5 mol %), NMP (0.5 mL), 120° microwave.
yahoo.com (A. Muralidharan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.028

A. M. Sajith, A. Muralidharan / Tetrahedron Letters 53 (2012) 5206–5210
5207
Table 2
knowledge, this is the first report on Sonogashira cross-coupling
reactions using 3-alkyl2-haloimidazo[4,5-b]pyridine as heteroaro-
matic substrate. The Sonogashira reaction process usually runs
smoothly when the more expensive unstable aryl or vinyl iodides
are used. The conditions are more favourable if the electron-poor
organic halide system is ‘activated’. Thus, strongly activated sys-
Effect of base on the Sonogashira couplinga of 3a and 4a
Entry
Base
Base equivalents
Yield (%)
1
2
3
4
5
Na2CO3
K2CO3
KOAc
Cs2CO3
Bu4NOAc
2.0
1.5
2.0
2.5
2.5
30
40
NR
60
93
tems represent
methodology.
a
real challenge for any cross coupling
a
Reagents and conditions: 3a (0.5 mmol), 4a (0.6 mmol), base (1.5 mmol),
The most commonly used catalytic systems for Sonogashira
transformation include PdCl2(PPh3)2, PdCl2/PPh3 and Pd(Ph3)4 to-
gether with CuI as cocatalyst and large amounts of amines as the
solvents or cosolvents. The use of copper in these reactions is be-
lieved to assist the reaction through the formation of an acetylide
and then this group is transferred to Pd by a transmetalation step.
However, the formation of copper acetylides24 can also lead to
homocoupling products, so modifications of these conditions, and
in particular copper-free conditions,25 have been continued to be
investigated.
PdCl2(PCy3)2 (10 mol %), NMP (0.5 ml), microwave, 110°.
R1
4
PdCl2(PCy3)2
N
N
N
R1
X
Bu4NOAc
N
N
N
5
NMP
3
Microwave
R1= Aryl, Alkyl
70-95%
We chose the cross coupling of iodo intermediate, 3a with phe-
nyl acetylene as the model reaction to screen the catalyst and opti-
mise the reaction conditions. First, the catalytic activities of some
catalysts were tested in the presence of caesium carbonate at
110 °C in a microwave using NMP (N-methyl pyrolidinone) as a
solvent under copper-free conditions. Fortunately, we were able
to see 40% product formation as indicated by LCMS after 15 min
using PdCl2(PCy3)2, Table 1. PdCl2(PCy3)2, which has more basic
and bulky groups showing highest catalytic activity. These results
encouraged us to further optimise the reaction conditions in the
presence of PdCl2(PCy3)2 using different bases and solvents, as well
as changing the reaction temperatures. Different inorganic bases
like Na2CO3, Cs2CO3, KOAc, Bu4–NOAc were tried to find a suitable
X= I, Br, Cl
3a (X= I)
3b (X= Br)
3c (X= Cl)
Scheme 1. Synthesis of 3-cyclopentyl-2-alkynyl-3H-imidazo[4,5-b]pyridine.
N
N
N
N
N
N
N
(2)
(1)
Scheme 2.
Table 3
Sonogashira couplinga of 3a, 3b, 3c with various terminal alkynesb
Entry
Halo intermediate, 3
Alkynes, 4
Product, 5
Yield (%)
N
N
N
N
1
3a (3b) (3c)
93 (86) (79)
5a
5b
4a
N
N
2
3
3a (3b)
89 (88)
4b
N
N
N
N
3a
N
N
90
5c
4c
4d
N
N
N
N
5d
4
5
3a (3b)
85 (70)
Br
N
N
3a (3c)
94 (82)
N
5e
Br
4e
(continued on next page)

5208
A. M. Sajith, A. Muralidharan / Tetrahedron Letters 53 (2012) 5206–5210
Table 3 (continued)
Entry
Halo intermediate, 3
3a (3c)
Alkynes, 4
Product, 5
Yield (%)
92 (86)
F
N
6
7
N
N
N
5f
F
4f
N
N
5g
3a
95
4g
N
N
F
N
5h
5i
8
9
3a (3c)
3a (3b)
3a (3b)
88 (75)
78 (35)
92 (84)
4h
F
OH
OH
N
N
N
N
4i
N
N
5j
10
4j
N
N
O
N
5k
11
12
3a
3a
87
91
4k
O
N
N
N
N
4l
N
N
5l
N
N
13
14
3a (3c)
94 (88)
4m
5m
NH2
N
N
3c
72
70
N
N
NH2
4o
5n
4n
N
N
OH
5o
15
3b
OH
a
Reagents and conditions: Catalyst PdCl2(PCy3)2 (10 mol %), intermediate 3a, (0.1 mmol), alkyne 4, (0.13 mmol), Bu4NOAc (0.3 mmol), NMP (0.5 mL) at 110° in microwave,
15 mts.
b
When 3c was used, catalytic loading of 20 mol % was used to push the reactions to completion and reaction was conducted at 150° in microwave for 45 mts. Yields
mentioned correspond to isolated yields.

A. M. Sajith, A. Muralidharan / Tetrahedron Letters 53 (2012) 5206–5210
5209
H
N
N
N
POCl3
80
O
Cl
N
°
N
N
I
D
3c
2c
C
NH2
NH
H
N
C
O
O
N
H
N
°
tBuLi, - 78
1
Br
CBr4
N
N
N
N
3b
2b
Scheme 3. Synthesis of 2-halo-3-cyclopentyl-3H-imidazo[4,5-b]pyridine.
base that would affect the desired reaction, Table 2. Both Cs2CO3
and Bu4–NOAc were effective as bases, with Bu4–NOAc being the
more reactive, allowing the reaction to be completed in 30 min.
Among the solvents screened (THF, toluene, dioxane, CH3CN,
DMF and NMP), NMP proved to be the most efficient.
intermediate) should be easily susceptible to the oxidative addi-
tion to palladium complex. We have also investigated the influence
of the nature of the halogen (I, Br, Cl) on the reactivity of 3-
alkyl2-haloimidazo[4,5-b]pyridines (Scheme 1). The iodo interme-
diate reacted much faster (15 min) when compared to the bromo
intermediate which took 30 min in microwave conditions for com-
plete conversion to products. The chloro intermediate, 3c reacted
Due to the electronegativity of the nitrogen atoms, the C-2 po-
sition of 3-alkyl-2-haloimidazo[4,5-b]pyridine (activated halo
PdCl2(PCy3)2
2Cl
Pd(PCy3)2
N
PCy3
X
N
N
N
N
R
N
Pd(0)
P
X = I, Br, Cl
Y = OAc
P
[ArPd(II)X3]2- 2Bu4N+
16e Complex
N
N
P
Pd
N
N
N
Pd
N
X
R
R
H
TBAY
HY
TBA
R
TBAX
HY
Cl
P
P
Pd
Cl
TBAY : Tetra butyl ammonium acetate
PdCl2P(Cy3)2
Scheme 4. Proposed mechanism for Sonogashira coupling.

5210
A. M. Sajith, A. Muralidharan / Tetrahedron Letters 53 (2012) 5206–5210
2. Youssef, A. F.; E1-Gendy, M. A.; Aboutaleb, N. A. E.; Ahmed, S. H. Egypt. J. Pharm.
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much slowly and also required higher temperatures for complete
conversions to products. Having demonstrated that phenyl acety-
lene can be efficiently cross coupled with both 3a and 3b, we
investigated the scope of this methodology28 using various termi-
nal alkynes Table 3. The results described in table shows that much
slower reactions were observed using 3-butyn-2-ol instead of phe-
nyl acetylene. With this alkyne the iodo intermediate was coupled
more efficiently compared to the bromo derivative which reacted
very sluggishly. In the case of 3c higher mol% of the catalyst was
required to drive the reactions for completion. Compound 3a was
synthesised according to the procedure described in Ref. 20. The
synthesis of 3b and 3c27 is shown in Scheme 3.
10. Bukowski, L.; Janowiec, M. Pharmazie 1989, 44, 267.
The outstanding activity of this catalyst employed for Sono-
gashira coupling of 3-alkyl-2-haloimidazo[4,5-b]pyridines has
been attributed to a combination of electronic and steric properties
that enhance the rates of oxidative addition, transmetalation, and
reductive elimination steps in the catalytic cycle. The rates of all
the three steps in the catalytic cycle are believed to be maximised
by employing the conditions that favour the formation of interme-
diates bearing a singlet phosphine ligand, (Scheme 4). This can be
explained as follows: (a) In the catalytic cycle, monoligated species
are believed to be formed which are stabilised by electron rich and
sterically demanding ligands attached to the palladium centre. (b)
The oxidative addition of halides is faster with L1Pd(0) (monoligat-
ed) species than with other highly ligated complexes. (Due to the
smaller size of a L1Pd(0), substrate can approach the latter more
closely and, hence, react at a faster rate). L1Pd(Ar)X undergoes fas-
ter transmetalation than L2Pd(Ar)X complex. (c) Literature survey
indicates that rate of reductive elimination from LPd(Ar)R (R= aryl,
NR2, OR) is faster than that for the same process for an analogous
L2Pd(Ar)R complex26 due to steric reasons.
11. Giani, R.; Parini, E.; Borsa, M.; Lavezzo, A. Eur. Pat. Appl. EP 397,615, 1990, p 10;
Chem. Abstr. 1991, 114, 16423lz.
12. Herold, P.; Buehlmayer, P. Eur. Pat. Appl. EP 415,886, 1991, p 30; Chem. Abstr.
1991, 114, 207263f.
13. Ullah, F.; Dang, T. T.; Heinicke, J.; Villiger, A.; Langer, P. Synlett 2009, 838–842.
14. Wolff, O.; Waldvogel, S. R. Synthesis 2007, 761–765.
15. Manarin, F.; Roehrs, J. A.; Branda, O.; Nogueira, C. W.; Zeni, G. Synthesis 2009,
4001.
16. Majumdar, K. C.; Chattopadhyay, B.; Samanta, S. Synthesis 2009, 211–317.
17. Mayusundari, A.; Fujii, N. Tetrahedron. Lett. 2010, 51, 3597–3598.
18. Some recent reactions facilitated by microwave irradiations. Synthesis of
heterocycles: Triazoles: (a) Bentiss, F.; Lagrenee, M.; Barby, D. Tetrahedron Lett.
2000, 41, 1539; Thiazoquinazolines: (b) Besson, T.; Guil-lard, J.; Rees, C. W.
Tetrahedron Lett. 2000, 41, 1027; Quinolines: (c) Ranu, B. C.; Hajra, A.; Jana, U. C.
Tetrahedron Lett. 2000, 41, 5891.
19. Itoh, T.; Mase, T. Tetrahedron Lett. 2005, 46, 3573–3577.
20. Sajith, A. M.; Muralidharan, A. Tetrahedron Lett. 2012, 53, 1036–1041.
21. Doucet, Henri; Hierso, Jean-Cyrille Angew. Chem., Intl. Ed. 2007, 46, 834–871.
22. Gelman, Dmitri; Buchwald, Stephen L. Angew. Chem., Intl. Ed. 2003, 42, 5993–
5996.
23. Chinchilla, Rafael; Najera, Carmen Chem. Rev. 2007, 107, 874–922.
24. Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422.
25. For copper-free Sonogashira reactions: (a) Liang, Bo; Huang, Mengwei; You,
Zejin; Xiong, Zhengchang; Lu, Kui; Fathi, Reza; Chen, Jiahua; Yang, Zhen
Tetrahedron Lett. 2004, 45, 4337–4340; (b) Arques, Antonio; Auꢀnon, David;
Molina, Pedro Tetrahedron Lett. 2004, 45, 4337–4340; (c) Bohm, V. P. M.;
Hermann, W. A. Eur. J. Org. Chem. 2000, 6, 3679–3681; (d) Alonso, D. A.; Najera,
C.; Pacheco, M. C. Tetrahedron Lett. 2002, 43, 9365–9368; (e) Leadbeater, N. E.;
Tominack, B. J. Tetrahedron Lett. 2003, 44, 8653–8656; (f) Djakovitch, L.; Rollet,
P. Tetrahedron Lett. 2004, 45, 1367–1370.
Bu4NOAc is thought to act as a mild base to deprotonate the
most acidic hydrogen in the alkyne. Moreover, the formation of
Pd(0) species in these reactions may be facilitated by the use of
Bu4NOAc.
26. Hartwig, J. F. Inorg. Chem. 2007, 46, 1936–1947.
In summary, we have established that PdCl2(PCy3)2 catalytic
system catalyses the Sonogashira coupling reaction of 3-cyclopentyl-
2-halo imidazo[4,5-b]pyridines (I, Br, Cl) to yield various 2-alkynyl
imidazo[4,5-b]pyridines in excellent yields. The choice of tetrabu-
tyammoniumacetate as the base was important for the high yields
of the cross coupled products. Work aimed at further synthetic
utility of the halo intermediate is being pursued.
27. Grivas, S.; Lindström, S. J. Heterocycl. Chem. 1995, 32, 467.
28. General procedure for coupling of 2-halo imidazo[4,5-b] pyridine derivative with
different terminal acetylenes. (Sonogashira coupling)
To
a
solution of 3-substituted-2-haloimidazo[4,5-b]pyridine derivative
(1 equiv) in NMP, were added terminal acetylene (1.5 equiv) and tetrabutyl
ammonium acetate (1.5 equiv). The solution was purged with nitrogen and
stirred at room temperature for 0.15 h, at that time PdCl2(PCy3)2 was added.
The reaction solution was purged again with nitrogen and then placed in the
microwave and heated for 10 to 30 min at 110 °C (for iodide and bromide
intermediates). When chloro intermediate was used, the reaction contents
were heated at 150 °C. When TLC and LCMS showed full consumption of
starting materials, the reaction mixture was diluted with ethyl acetate,
separated the ethyl acetate layer, given water wash, brine wash and was
dried over anhydrous sodium sulphate and concentrated to get the crude
material. The crude product was directly purified by column chromatography
(0–15% hexane/EtOAc) to isolate the 3-alkyl-2-akynyl imidao[4,5-b] pyridine
derivatives. The characterisation details of compounds 5a and 5e are given
below.
Acknowledgments
The authors are thankful to Organic Chemistry Division, School
of Chemical Science Department, Kannur University and the Head
of chemistry department, Professor Gopalan, Govt. College Kasar-
god for providing facilities and good support for research work.
2-(2-(3-Bromophenyl)ethynyl)-3-cyclopentyl-3H-imidazo[4,5-b]pyridine
Brown solid, Yield 94%, mp (102.6–102.4 °C); 1H NMR (300 MHz, CDCl3) d:
1.80–1.81 (m, 2H), 2.06–2.22 (m, 4H), 2.46–2.59 (m, 2H), 5.27–5.33 (m, 1H),
7.23–7.25 (m, 2H), 7.27–7.32 (m, 2H), 7.57–7.59 (m, 1H), 8.01–8.04 (m, 1H),
8.42–8.43 (m, 1H); 13C NMR(75 MHz, CDCl3) d: 24.82, 30.97, 56.56, 93.90,
118.65, 122.22, 125.84, 127.36, 129.89, 130.44, 132.46, 134.37, 135.30, 144.76;
IR (KBr) 3425, 3054, 2950, 2868, 2221, 2157, 1942, 1724, 1592, 1552, 1492,
1424, 1399, 1370, 1276, 1243, 1069, 771, 705, 676, 653, 620 cmÀ1; LCMS
368.12 (M+H); Anal. Calcd for C19H16BrN3: C, 62.31; H, 4.40; N, 11.47%. Found:
C, 62.34; H, 4.37; N, 11.35%.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.028.
References and notes
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2006, 41, 268–275. and references cited ‘therein’.