A modular approach toward the synthesis of 2,4-disubstituted pyridines

Article abstract of DOI:10.1016/j.tetlet.2013.06.092

A number of 2,4-disubstituted pyridines have been synthesized using α,β,γ,δ-unsaturated aldehydes and ammonium chloride in the presence of triethylamine in acetonitrile solvent at 80 C under air balloon.

Full text of DOI:10.1016/j.tetlet.2013.06.092

Tetrahedron Letters 54 (2013) 4841–4843
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A modular approach toward the synthesis of
2,4-disubstituted pyridines
⇑
Raju Singha, Shubhendu Dhara, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of 2,4-disubstituted pyridines have been synthesized using a,b,c,d-unsaturated aldehydes and
ammonium chloride in the presence of triethylamine in acetonitrile solvent at 80 °C under air balloon.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 April 2013
Revised 17 June 2013
Accepted 20 June 2013
Available online 4 July 2013
Keywords:
a,b,c,d-Unsaturated aldehyde
Imine
Electrocyclization
2,4-Disubstituted pyridine
2,3-Disubstituted pyrrole
Heterocyclic compounds gradually become more attractive tar-
gets in organic and medicinal chemistry due to their great chemical
and biological importance.1Among numerous heterocycles, pyri-
dine moiety has always been one of the most important frame-
works. Substituted pyridines are important constituents of a
wide range of natural products, pharmaceutical drugs, and various
kinds of functional materials.2 As a consequence; different syn-
thetic methods are reported in the literature from early days for
the construction of pyridine rings. The traditional methods for
the synthesis of pyridine rings are based upon condensation reac-
tions of carbonyl compounds with amines, for example Hantzsch
synthesis, and Guareschi synthesis.3 However, from these meth-
ods, the high yields of single products are usually obtained for
symmetrically substituted systems. Other classical methods are
based upon thermal or metal-catalyzed cycloaddition reactions;
but allow a specific location of the substituents in the pyridine
core.4
CHO
Br
CHO
PBr3, DMF
PdCl2, TBAB, H2O
CHCl3
Ar
O
r.t.
R
Ar
Ar
R
0oC - r.t.
1
2 R = Ph
4 R = CO2Me
Scheme 1. Synthesis of a,b,c,d-unsaturated aldehydes.
Table 1
Screening of the reaction conditions*
CHO
NH4X, Et3N
solvent, 80 oC
4h
N
Ph
Ph
Ph
Ph
3a
2a
Entry Ammonium
salt
Solvent
EtOH
Toluene 80
MeCN
DCE
Temperature
(°C)
Time
(h)
Yield**
(%)
Although a large amount of work has been devoted for their
synthesis, versatile and flexible methodologies to construct
unsymmetrically substituted pyridines using readily accessible
starting materials are still of critical importance. In this communi-
cation we report the synthesis of a series of 2,4-disubstituted pyr-
1
2
3
4
5
6
7
8
9
NH4Cl
NH4Cl
NH4Cl
NH4Cl
80
6
6
4
4
4
4
4
24
3
64
61
82
79
80
76
72
56
80
80
80
80
80
80
60
90
NH4Cl
DMF
idines from a modular framework a,b,c,d-unsaturated aldehydes in
NH4OAc
(NH4)2CO3
NH4Cl
MeCN
MeCN
MeCN
MeCN
a single step under mild reaction conditions. The final step involves
three consecutive steps: imine formation,5 electrocyclization,6 and
aerial oxidation.3d,6b,7
NH4Cl
*
Reaction conditions: 2a (0.5 mmol), NH4X (1.5 equiv), Et3N (3 equiv), solvent
⇑
(3 mL) refluxed under air balloon.
Yields were calculated after purification of products.
Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
**
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.092

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R. Singha et al. / Tetrahedron Letters 54 (2013) 4841–4843
Table 2
Synthesis of 2,4-disubstituted pyridines*
CHO
NH4Cl, Et3N
MeCN, 80 oC
4h
N
N
Ar
Ph
Ph
Ar
Ph
3
2
N
N
N
Ph
Ph
Ph
MeO
Me
MeO
OMe
3d: 78 %
3a: 82 %
3c: 71 %
3b: 84 %
N
N
N
N
Ph
Ph
Ph
Ph
Me
O
NO2
O
3g: 73 %
3f: 81 %
3e: 83 %
3e: 79 %
*
Yields were determined after purification of products by column chromatography.
From Table 1, we concluded that the optimized reaction condi-
tions were substrate (0.5 equiv), NH4Cl (1.5 equiv), Et3N (3 equiv),
and acetonitrile (3 mL) refluxed under air balloon at 80 °C for 3–
4 h. These optimized reaction conditions were then applied for
the synthesis of different 2,4-disubstituted pyridines (Table 2).
The overall yields of compounds 3a–3g (Table 2) were moderate
to good. Now, for the substrates having an electron withdrawing
group at d-position, there is a possibility of nucleophilic attack at
Table 3
Synthesis of substituted pyridines and pyrroles
CHO
NH4Cl, Et3N
N
+
NH
CO2Me
Ar
MeCN, 80 o
4h
C
Ar
CO2Me
Ar
CO2Me
4
5
6
Entry
Substrate
Ar
Product
Yield* (%)
Ratio
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
C6H5–
p-MeO-C6H4–
3,4-(MeO)2-C6H3–
3,4-(CH2O2)-C6H3–
m-Me-C6H4–
5a + 6a
5b + 6b
5c + 6c
5d + 6d
5e + 6e
5f + 6f
37 + 24
25 + 38
30 + 32
28 + 38
40 + 25
43 + 26
60:40
40:60
48:52
42:58
61:39
62:38
c-carbon with respect to the aldehyde. Therefore two types of
products are expected from the substrates ,b, ,d-unsaturated
a
c
aldehydes bearing a methyl carboxylate as the functional group
at d-position and practically we got 2,3-disubstituted pyrroles
along with the normal product, 2,4-disubstituted pyridines. The
results are shown in Table 3.
naphthalen-2-yl–
*
Yield refers to the isolated yield after purification.
From the above results (Table 3), we observed that the nucleo-
philic addition becomes more favorable for the electron rich aro-
matic rings (Table 3, entries 2–4) and hence gave pyrrole rings as
the major product. Plausible rational for the formation of different
products is shown in Scheme 2. In the presence of triethylamine,
ammonium chloride releases ammonia which then forms an imine
B intermediate by reacting with the substrate A. Intermediate B is a
Attention was first focused on the synthesis of a suitably substi-
tuted starting framework ,b, ,d-unsaturated aldehydes and we
a
c
have performed the task efficiently in two steps starting from a
readily available starting material having a keto-methyl group.
First we synthesized b-bromovinylaldehydes (1) by Vilsmeier–
Haack type of reaction using PBr3 and DMF as the reagent.8 Then
PdCl2 catalyzed coupling reaction with styrene or methyl acrylate
correspondingly, in water afforded the desired framework
6p-electron system; thus it undergoes an electrocyclization reac-
tion under thermal condition and affords dihydropyridine interme-
diate C. Now our desired product 2,4-disubstituted pyridine is
formed by the aerial oxidation of C.
On the other hand, intermediate B remains in equilibrium with
its conformational isomer E. In the presence of an electron
withdrawing group at d-position, a nucleophilic addition occurs
at c-position by the lone pair electrons of imine nitrogen. Thus a
cationic intermediate F forms which finally gives 2,3-disubstituted
pyrroles G via bond rearrangement and loss of a proton.
a c
,d-unsaturated aldehydes (2 and 4) (Scheme 1).9
,b,
The initial experiment was carried out by heating a mixture of
compound 2a (1 equiv), NH4Cl (1.5 equiv), and Et3N (3 equiv) in
ethanol solvent under air balloon at 80 °C for 6 h and it afforded
2,4-diphenyl pyridine (3a) in 64% yield. After getting success we
used different ammonium salts and solvents to optimize the reac-
tion conditions. The results are summarized in Table 1.
CHO
+ NH3
- H2O
R = Ph, CO2Me
NH
[O]
-H2
NH
N
Ar
R
Ar
R
Ar
R
Ar
R
C
B
D
A
NH
R
R = CO2Me
- H
NH
H
NH
CO2Me
Ar
Ar
Ar
CO2Me
E
F
G
Scheme 2. Plausible rational for the formation of products.

R. Singha et al. / Tetrahedron Letters 54 (2013) 4841–4843
4843
3. (a) Bossart, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed. 1981, 20, 762; (b)
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Chem. Asian J. 2009, 4, 1573.
In conclusion, we have developed a modular and straight for-
ward method for the synthesis of 2,4-disubstituted pyridines from
readily available starting materials under mild reaction condi-
tions.10 In addition, 2,3-disubstituted pyrroles are also formed as
important side products. The use of this methodology for the syn-
thesis of a few natural products is under progress in our laboratory.
Acknowledgments
5. (a) Khalili, B.; Jajarmi, P.; Sis, B. E.; Hashemi, M. M. J. Org. Chem. 2008, 73, 2090;
(b) Augner, D.; Gerbino, D. C.; Slavov, N.; Neudorfl, J. M.; Schmalz, H. G. Org.
Lett. 2011, 13, 5374; (c) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756.
6. (a) Spanglert, C.; Jondahalnd, H.; Angler, B. J. Org. Chem. 1973, 38, 2478; (b) Lim,
C. H.; Kim, S. H.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2013, 54, 2476.
7. (a) Paine, T. K.; Weyhermiiller, T.; Wieghardt, K.; Chaudhuri, P. Dalton Trans.
2004, 2092; (b) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400; (c) Singha, R.;
Roy, S.; Nandi, S.; Ray, P.; Ray, J. K. Tetrahedron Lett. 2013, 54, 657.
8. (a) Ray, D.; Ray, J. K. Org. Lett. 2007, 9, 191; (b) Ray, D.; Paul, S.; Brahma, S.; Ray,
J. K. Tetrahedron Lett. 2007, 48, 8005; (c) Jana, R.; Samanta, S.; Ray, J. K.
Tetrahedron Lett. 2008, 49, 851; (d) Jana, R.; Paul, S.; Biswas, A.; Ray, J. K.
Tetrahedron Lett. 2010, 51, 273; (e) Nandi, S.; Ray, K. K. Tetrahedron Lett. 2011,
52, 6203.
We gratefully acknowledge DST for providing funds and CRF, IIT
Kharagpur for the HRMS facility. R.S. thanks CSIR, New Delhi for
the fellowship.
Supplementary data
Supplementary data (detailed experimental procedure and
spectral data for the compounds 3a–g, 5a–f and 6a–f) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.06.092.
9. (a) Samanta, S.; Jana, R.; Ray, J. K. Tetrahedron Lett. 2009, 50, 6751; (b) Yasmin,
N.; Ray, J. K. Synlett 2010, 924.
10. General procedure for the synthesis of 2,4-disubstituted pyridines: The
substrate (1 mmol) and NH4Cl (1.5 equiv) were taken in a two-necked round
bottomed flask fitted with a condenser. Then 3 mL of acetonitrile and Et3N
(3 equiv) were added and refluxed at 80 °C under air balloon for 3–4 h. After
completion of the reaction, the reaction mixture was allowed to cool to room
temperature, diluted with water, and extracted with ethyl acetate (3 Â 20 mL).
The combined organic layer was dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude product was purified by column
chromatography using silica gel (60–120 mesh) and hexane/EtOAc (10:1) as
eluent.
References and notes
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