A facile synthesis of 2,3-disubstituted-6-arylpyridines from enaminones using montmorillonite K10 as solid acid support

Article abstract of DOI:10.1016/j.tetlet.2004.11.071

A facile synthesis of 2,3-disubstituted-6-arylpyridines from enaminones using montmorillonite K10 as solid acid support is described. A facile synthesis of 2,3-disubstituted-6-arylpyridines from enaminones using montmorillonite K10 as solid acid support is reported herein.

Full text of DOI:10.1016/j.tetlet.2004.11.071

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 301–302
A facile synthesis of 2,3-disubstituted-6-arylpyridines from
enaminones using montmorillonite K10 as solid acid support
G. Jagath Reddy,* D. Latha, C. Thirupathaiah and K. Srinivasa Rao
R&D Laboratories, Dr. Jagath Reddy’s Heterocyclics, 81, S. V. Co-op Industrial Estate, Balanagar, Hyderabad 500 037, India
Received 21 July 2004; revised 1 November 2004; accepted 9 November 2004
Available online 30 November 2004
Abstract—A facile synthesis of 2,3-disubstituted-6-arylpyridines from enaminones using montmorillonite K10 as solid acid support
is reported herein.
Ó 2004 Published by Elsevier Ltd.
Substituted pyridines have become increasingly impor-
tant because of the diverse types of biological activities
they exhibit.1 A number of substituted pyridines such
as 6-aryl-2-methylnicotinates are also useful as building
blocks in the synthesis of pyridine fused ring systems.2
Enaminoketones are versatile and readily available
intermediates and play an important role in the synthe-
sis of a number of heterocyclic compounds.3 6-Aryl-2-
methylnicotinates can be synthesized by the reaction of
a 3-aminocrotonate with acetophenone Mannich base
hydrochlorides in refluxing ethanol for 12 h,4 with acet-
ylenic ketones at higher temperatures5 and with oxazoli-
dines possessing a CH2-EWG at C-2 in refluxing
acetonitrile in the presence of acetic acid.6 These pyri-
dines can also be prepared by the reaction of enamino-
ketones with b-dicarbonyl compounds in the presence
of ammonium acetate in refluxing acetic acid.7 However,
these methods are limited by the use of expensive and
commercially unavailable reagents, long reaction times,
acidic conditions and tedious end product isolation
procedures.
Recently, the use of solid acid catalysts, such as clays
has gained importance in organic synthesis, because they
are easy to handle, are noncorrosive, selective and inex-
pensive.8 In view of the limitations involved in the syn-
thesis of 6-aryl-2,3-disubstituted pyridines, the growing
importance of solid acid supports as ecofriendly re-
agents9 and our continued interest in the synthesis of
heterocycles,10 we report herein the synthesis of substi-
tuted pyridines using montmorillonite K10 as a solid
acid support (Scheme 1).
The reaction of enaminoketones 1 with ethyl acetoace-
tate 2 and ammonium acetate in refluxing isopropanol
in the presence of K10 clay afforded the corresponding
pyridine derivatives 3 in good yields.11 Thus the conden-
sation reaction of enaminoketone with ethyl acetoace-
tate takes place in totally acetic acid free conditions7
and in heterogeneous media. The generality of the pres-
ent method is evident from the reaction of a variety of
enaminoketones with 2 to give different 6-aryl-substi-
tuted 2-methylnicotinates 3. 3-Acetylpyridine 4 was
O
O
O
COR 1
NH4OAc
+
R1
NMe2
R
H3C
MK10, IPA
CH3
N
R
1
2
3 R1 = OC2H5
4 R1 = CH3
Scheme 1.
*
Corresponding author. Fax: +91 40 23773487; e-mail: jagathreddy@usa.net
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.11.071

302
G. Jagath Reddy et al. / Tetrahedron Letters 46 (2005) 301–302
Table 1. Physical data of the 6-aryl-2,3-disubstituted pyridines
prepared12
R.; Geethanjali. Synth. Commun. 2003, 33, 1179–1184; (c)
Singh, D. U.; Singh, P. R.; Samant, S. D. Tetrahedron
Lett. 2004, 45, 4805–4807.
Entry
R
Mp °C
(Lit. °C)
Yield %
76
10. (a) Jagath Reddy, G.; Latha, D.; Thirupathaiah, C.;
Srinivasa Rao, K. Tetrahedron Lett. 2004, 45, 847, 848; (b)
Jagath Reddy, G.; Latha, D.; Thirupathaiah, C.; Srinivasa
Rao, K. Org. Prep. Proced. Int. 2004, 36, 287–289.
11. Typical experimental procedure: a mixture of an amino-
ketone 1 (0.01 mol), ethyl acetoacetate (0.012 mol), ammo-
nium acetate (2 g), montmorillonite K10 (0.5 g) in
isopropanol (10 mL) was stirred at reflux for 2–4 h. After
completion of the reaction as indicated by TLC, the
catalyst was filtered off. The solvent was evaporated in
vacuo and the residual solid was recrystallized from
methanol to give pure 3 as a crystalline solid. 3-Acetyl-
pyridine 4 was also prepared in a similar manner using
acetylacetone in place of ethyl acetoacetate.
3a
C6H5
44–46
(46–47)4
(Oil)6
(76)7
—
3b
3c
3d
3e
3f
3g
3h
3i
4-ClC6H4
4-BrC6H4
4-FC6H4
74–75
72–74
62–63
53–54
65–67
59–61
71–73
65–67
58–60
110–112
79
81
82
78
77
75
83
73
71
75
—
4-CH3C6H4
4-CH3OC6H4
4-CH3SC6H4
4-NO2C6H4
2,4-Cl2C6H3
2-Thienyl
(55)7
(68)7
—
—
—
3j
—
—
4
C6H5
1
12. All new products were characterized by H NMR.
obtained when enaminoketone 1a was reacted with acet-
ylacetone using the same procedure. To study the role of
the clay, the reaction was also carried out in its absence,
however, the reaction took 24 h for completion com-
pared to refluxing for 2–4 h in the presence of clay or
in acetic acid. The structures of compounds 3 and 4 were
determined based on 1H NMR spectra and by compari-
son of physical data with known compounds (Table 1).
The reusability of the catalyst was also studied by reus-
ing the clay after filtering and drying. The yields were
not effected in the second cycle.
Ethyl (2-methyl-6-40-bromophenyl)nicotinate-3c. Yellow
solid. 1H NMR (200 MHz, CDCl3): d 1.43 (t, 3H,
J = 7.2 Hz), 2.91 (s, 3H), 4.37 (q, 2H, J = 7.1 Hz), 7.41
(d, 2H, J = 7.3 Hz), 7.58 (d, 1H, J = 7.2 Hz), 7.96 (d, 2H,
J = 7.2 Hz), 8.25 (d, 1H, J = 8.0 Hz). Anal. Calcd for
C15H14BrNO2: C, 56.25; H, 4.37; N, 4.37. Found: C,
56.37; H, 4.49; N, 4.53.
Ethyl (2-methyl-6-40-fluorophenyl)nicotinate-3d. Yellow
solid. 1H NMR (200 MHz, CDCl3): d 1.41 (t, 3H,
J = 7.4 Hz), 2.92 (s, 3H), 4.41 (q, 2H, J = 7.3 Hz), 7.42
(d, 2H, J = 7.8 Hz), 7.56 (d, 1H, J = 7.9 Hz), 7.98 (d, 2H,
J = 7.8 Hz), 8.24 (d, 1H, J = 8.0 Hz). Anal. Calcd for
C15H14FNO2: C, 69.49; H, 5.40; N, 5.40. Found: C, 69.62;
H, 5.26; N, 5.73.
In conclusion, we have reported a facile synthesis of 2,3-
disubstituted-6-arylpyridines in isopropanol under acetic
acid free conditions, demonstrating the use of mont-
morillonite K10 as a heterogeneous acid catalyst. The
present procedure has the advantages of simple experi-
mental and product isolation procedures coupled with
high purity and yields.
Ethyl (2-methyl-6-40-methylthiophenyl)nicotinate-3g. Light
1
orange solid. H NMR (200 MHz, CDCl3): d 1.41 (t, 3H,
J = 7.4 Hz), 2.52 (s, 3H), 2.89 (s, 3H), 4.38 (q, 2H,
J = 7.3 Hz), 7.34 (d, 2H, J = 7.4 Hz), 7.57 (d, 1H, J =
7.3 Hz), 8.01 (d, 2H, J = 7.2 Hz), 8.23 (d, 1H, J = 8.0 Hz).
Anal. Calcd for C16H17NO2S: C, 66.89; H, 5.92; N, 4.87.
Found: C, 67.01; H, 6.23; N, 4.63.
Ethyl (2-methyl-6-40-nitrophenyl)nicotinate-3h. Yellow
1
References and notes
crystalline solid. H NMR (200 MHz, CDCl3): d 1.43 (t,
3H, J = 7.4 Hz), 2.93 (s, 3H), 4.36 (d, 2H, J = 7.4 Hz), 7.69
(d, 1H, J = 7.3 Hz), 8.26–8.36 (m, 5H). Anal. Calcd for
C15H14N2O4: C, 62.93; H, 4.90; N, 9.79. Found: C, 63.04;
H, 5.06; N, 9.62.
1. Balasubrahmanyam, M.; Keak, J. G. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon:
Oxford, 1996; Vol. 5, p 245.
2. (a) Troschutz, R.; Dennestedt, T. Arch. Pharm. 1993, 327,
¨
Pharm. 1995, 328, 535; (2) Troschutz, R.; Karger, A. J.
Ethyl (2-methyl-6-20,40-dichlorophenyl)nicotinate-3i. Light
¨
221; (b) Troschutz, R.; Zink, M.; Dennestedt, T. Arch.
1
cream solid. H NMR (200 MHz, CDCl3): d 1.41 (t, 3H,
¨
Heterocycl. Chem. 1996, 33, 1815–1821.
J = 7.4 Hz), 2.91 (s, 3H), 4.38 (q, 2H, J = 7.3 Hz), 7.41–
7.80 (m, 4H), 8.25 (d, 1H, J = 8.0 Hz). Anal. Calcd for
C15H13Cl2NO2: C, 58.06; H, 4.19; N, 4.51. Found: C,
58.21; H, 4.36; N, 4.67.
3. (a) Omran, F. A.; Awadi, N. A.; Khair, A. A. E.; Elnagdi,
M. H. Org. Prep. Proced. Int. 1997, 29, 285–292; (b) Saleh,
B. A.; Abdelkhalik, M. M.; Enzy, A. A.; Elnagdi, M. H. J.
Chem. Res. (S) 1999, 654.
Ethyl (2-methyl-6-thien-2-yl)nicotinate-3j. Pale yellow
solid. 1H NMR (200 MHz, CDCl3): d 1.40 (t, 3H,J =
7.4 Hz), 2.86 (s, 3H), 4.37 (q, 2H, J = 7.4 Hz), 7.12 (dd,
1H, J = 3.4, 1.5 Hz), 7.50 (dd, 1H, J = 4.8, 1.5 Hz), 7.52
(d, 1H, J = 8.0 Hz), 7.65 (dd, 1H, J = 5.5, 1.5 Hz), 8.21 (d,
1H, J = 8.0 Hz). Anal. Calcd for C13H13NO2S: C, 63.15;
H, 5.26; N, 5.66. Found: C, 63.28; H, 5.31; N, 5.74.
1-(2-Methyl-6-phenylpyridin-3-yl)ethanone-4. Yellow solid.
1H NMR (200 MHz, CDCl3): d 2.62 (s, 3H), 2.84 (s, 3H),
7.46 (m, 3H), 7.66 (d, 1H, J = 7.4 Hz), 8.07 (m, 3H). Anal.
Calcd for C14H13NO: C, 79.62; H, 6.16; N, 6.63. Found:
C, 79.69; H, 6.34; N, 6.84.
4. Gra¨f, E.; Troschutz, R. Synthesis 1999, 7, 1216–1222.
¨
5. Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody,
C. J. J. Am. Chem. Soc. 2000, 122, 3301–3313.
6. Singh, K.; Singh, J.; Singh, H. Tetrahedron 1998, 54, 935–
942.
7. Saleh, B. A.; Abdelkhalik, M. M.; Eltoukhy, A. M.;
Elnagdi, M. M. J. Heterocycl. Chem. 2002, 39, 1035–1038.
8. Varma, R. S. Tetrahedron 2002, 58, 1235–1255.
9. (a) Bigi, F.; Chesini, C.; Maggi, R.; Sartor, G. J. Org.
Chem. 1999, 64, 1033–1035; (b) Chowhan, S. M. S.; Singh,