Accepted Manuscript

A solvent-free reaction between acetophenone oximes and epoxy styrenes: anefficient synthesis of 2,4,6-triarylpyridines under neutral conditions

Shabnam Mahernia, Mehdi Adib, Mohammad Mahdavi, Meisam Nosrati

PII: S0040-4039(14)00590-5DOI: http://dx.doi.org/10.1016/j.tetlet.2014.04.003Reference: TETL 44465

To appear in: Tetrahedron Letters

Received Date: 8 October 2013Revised Date: 13 February 2014Accepted Date: 1 April 2014

Please cite this article as: Mahernia, S., Adib, M., Mahdavi, M., Nosrati, M., A solvent-free reaction betweenacetophenone oximes and epoxy styrenes: an efficient synthesis of 2,4,6-triarylpyridines under neutral conditions,Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.003

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1

A solvent-free reaction between acetophenone oximes and epoxy

styrenes: an efficient synthesis of 2,4,6-triarylpyridines under neutral

conditions

Shabnam Mahernia, Mehdi Adib*, Mohammad Mahdavi, Meisam Nosrati

School of Chemistry, University College of Science, University of Tehran, PO Box

14155-6455, Tehran, Iran

Abstract-An efficient synthesis of 2,4,6-triarylpyridines is described which involves

heating a mixture of an acetophenone oxime and an epoxy styrene under neutral,

solvent-free conditions. Kröhnke pyridine products are obtained in excellent yields.

Keywords: acetophenone oximes; epoxy styrenes; 2,4,6-triarylpyridines; solvent-free

synthesis.

*Corresponding author. Tel./fax: +98(21)66495291; E-mail: madib@khayam.ut.ac.ir

2

Pyridines are of interest because of the occurrence of their saturated and partially

saturated derivatives in biologically active compounds and natural products such as

NAD nucleotides, vitamin B6, and pyridine alkaloids.1,2

Some examples are used as

pharmaceuticals, dyes, additives, agrochemicals and also in qualitative and

quantitative analysis.2–6

2,4,6-Triarylpyridines (TAPs, Kröhnke pyridines)7 and substituted phenylpyridines

8

are useful intermediates in the synthesis of drugs, herbicides, insecticides, desiccants

and surfactants.9 Due to their π-stacking ability, these pyridines are used in

supramolecular chemistry.10

Hence their synthesis has received much attention.

TAPs have been synthesized using various methods and procedures. Traditionally,

these compounds have been synthesized through the reaction of N-

phenacylpyridinium salts with α,β-unsaturated ketones in the presence of

NH4OAc.10,11a

However, the pyridinium salts and unsaturated ketones have to be

synthesized first, so this method is relatively expensive. Several new and improved

methods and procedures have been developed for the synthesis of these pyridines

which include: reactions of N-phosphinylethanimines with aldehydes,11b

reactions of

N-(diphenylphosphinyl)-1-aza-allyl anions with α,β-unsaturated carbonyl

compounds,11c

reactions of in situ generated α,β-unsaturated imines with CH–

nucleophiles,11d

arylation of methylthiopyridines via Ni-induced Grignard

reactions,11e

reactions of phenacylidenedimethylsulfurane with chalcones and

NH4OAc,11f

pyrolysis of 1-vinyl-1,2-dihydropyridines,11g

reactions of α-ketoketene

dithioacetals with methyl ketones in the presence of NH4OAc,11h

additions of lithiated

β-enaminophosphonates to chalcones,11i

reactions of α-benzotriazolyl ketones with

α,β-unsaturated ketones and NH4OAc,11j

and solvent-free reactions between

acetophenones, benzaldehydes, and NH4OAc in the presence of sodium hydroxide,11k

or without a catalyst under microwave irradiation.11l

However, most of these

syntheses of TAPs are multistep, low to moderate yielding processes.

As part of our studies on the design of efficient methods for the preparation of

heterocyclic compounds from readily available starting materials,12

we have described

an efficient synthesis of TAPs via a solvent-free reaction between chalcones and

NH4OAc.13

We have also reported that the solvent-free reaction between guanidine

hydrochloride and chalcones under microwave irradiation leads to TAPs.14

3

In continuation of our interest in developing new environmentally benign methods for

the synthesis of heterocyclic compounds, herein we report a new synthesis of TAPs.

Thus, acetophenone oximes 1 and epoxy styrenes 2 undergo a 2:1 addition reaction

under neutral and solvent-free conditions15

to produce 2,4,6-triarylpyridines 3a–r in

84–95% yields (Table 1). All the reactions were carried out at 200 °C and reached

completion within 3 hours. 1H NMR analysis of the reaction mixtures clearly

indicated formation of the corresponding TAPs 3 and the results are given in Table 1.

4

Table 1. Solvent-free synthesis of 2,4,6-triarylpyridines.

NCH

3

NOH O

2

+200 °C, 3 h

1 3

Ar1Ar2Ar1

Ar1

Ar2

solvent-free

Product Ar1 Ar2 m.p. (C) (lit) Yield (%)a

3a

135 (136–137)16 89

3b

Cl

128–129 (129–130)11b 90

3c

O2N

198–199 (202–203)11b 92

3d CH3

157–158 (159–160)16 91

3e CH3

Cl

200–201 (200.6–202)11l 89

3f CH3O

Br

164 (163.9–165)11l 86

3g CH3O

Cl

115–116 (113.8–115)11l 87

3h CH3O

O2N

143 (143.1–144.7)11l 90

3i O2N

Br

>30017 94

3j O2N

O2N

>30017 95

3k

O2N

Cl

283–284 (280–281)17 92

3l

O2N

Br

>30017 93

3m

O2N

F

>30017 94

3n F

Cl

207–208 (209.4–210.1)11l 85

3o Cl

179–180 (178–179)18 84

3p Br

99–100 (101–102)19 86

3q

N

204 (206–207)20 93

3r

N

Br

161 (158–160)20 92

aIsolated yield.

5

All the products were characterized by 1H and

13C NMR analysis, and their melting

points were compared with those of authentic samples reported in the literature.

Mechanistically it is reasonable to assume that the first step may involve nucleophilic

attack of the N-hydroxy enamine tautomer of the ketoxime 1b on the epoxy styrene 2

and ring-opening to give the alcohol intermediate 4. Dehydration of this alcohol to

give alkene 5 and a subsequent proton shift would form the α,β-unsaturated oxime

intermediate 6. This intermediate may undergo Michael addition with another

ketoxime enamine tautomer 1b to yield adduct 7, which may cyclize to

tetrahydropyridine intermediate 8. Removal of a nitroxyl molecule and dehydration

may then lead to the 3,4-dihydropyridine intermediate 9, which may undergo

oxidative aromatization and removal of the methyl side chain to afford the TAP 3.

This type of oxidative dealkylation has been previously reported.21

Alternatively, a

hydroxylamine molecule may be removed from tetrahydropyridine intermediate 8 to

give the 1,4-dihydropyridine intermediate 10, which may undergo removal of methyl

and hydroxyl radicals to afford the TAP 3 (Scheme 1).

OOH

NOH

NOHCH

3NOH

..HNOH

HON

CH3

NOH

H..

CH3

N

OH

N

OH

H

CH3

N

NOH..HON

H

N

CH3

H

..

CH3

N

OH

N

CH3

OH

..

4

5

1b

2

6

8

7

H2O_

proton shift

Ar1

Ar2

Ar2

Ar2

Ar2

Ar2

Ar2 Ar2

Ar1

Ar1

Ar1

Ar1

Ar1

Ar1

Ar1

Ar1 Ar1 Ar1

9

1a 1bAr1

H2O_

HNO_

3

Ar1 Ar1

Ar2

_

_

10

Ar2

Ar1 Ar1 Ar1 Ar1

Ar2

_

_

3

NH2OH_

Scheme 1

6

In conclusion, we have developed a new reaction for the preparation of 2,4,6-

triarylpyridines which are of potential synthetic and chemical interest. Good to

excellent yields of the products, the use of simple and readily available starting

materials, and neutral and solvent-free conditions and short reaction times are the

main advantages of this reaction.

Acknowledgement

This research was supported by the Research Council of the University of Tehran as

research project (6102036/1/03).

References and notes:

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8

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22. General Procedure for the Preparation of 2,4,6-Triarylpyridines (3):

A stirred mixture of the respective acetophenone oxime (2 mmol) and epoxide

(1.2 mmol) was heated in a sealed tube at 200 °C in a silicone oil bath for 3 h. The

progress of the reaction was followed by TLC. The reaction mixture was cooled to

room temperature and the residue was purified by column chromatography using

n-hexane-EtOAc (4:1) as the eluent. The solvent was removed and the solid

residue was recrystallized from absolute EtOH.

Selected data for Compounds 3:

2,4,6-Triphenylpyridine (3a): Yield: 89%. Colorless crystals, mp 135 C. 1H

NMR (500.1 MHz, CDCl3): = 7.40–7.60 (m, 9 H, 9 CH), 7.78 (d, J = 8.0 Hz, 2

H, 2 CH), 7.92 (s, 2 H, 2 CH), 8.23 (d, J = 8.0 Hz, 4 H, 4 CH). 13

C NMR (125.8

MHz, CDCl3): = 117.2, 127.2, 127.3, 128.8 (4 CH), 129.0 (C), 129.1, 129.2 (2

CH), 139.1 (C), 139.6 (CH), 150.2, 157.5 (2 C).

4-(4-Nitrophenyl)-2,6-diphenylpyridine (3c): Yield: 92%. Colorless crystals, mp

198–199 C. 1H NMR (500.1 MHz, CDCl3): = 7.39 (t, J = 7.2 Hz, 2 H, 2 CH),

9

7.45 (t, J = 7.5 Hz, 4 H, 4 CH), 7.78 (s, 2 H, 2 CH), 7.79 (d, J = 8.6 Hz, 2 H, 2

CH), 8.11 (d, J = 7.3 Hz, 4 H, 4 CH), 8.29 (d, J = 8.6 Hz, 2 H, 2 CH). 13

C NMR

(125.8 MHz, CDCl3): = 116.9, 124.3, 127.1, 128.1, 128.8, 129.4 (6 CH), 139.0,

145.4, 147.8, 148.2, 157.9 (5 C).

1

A solvent-free reaction between acetophenone oximes and

epoxy styrenes: an efficient synthesis of 2,4,6-triarylpyridines

under neutral conditions

Shabnam Mahernia, Mehdi Adib, Mohammad Mahdavi, Meisam Nosrati

NCH

3

ONOH

+

Ar1Ar2Ar1

Ar1

Ar2

200 °C, 3 h

solvent-free