A new one-pot, three-component synthesis of 2,3,5-substituted or annulated-6-(methylthio)pyridines

Article abstract of DOI:10.1055/s-0028-1083529

A new one-pot, three-component synthesis of 2,3,5-substituted (or 2,3-annulated)-6-(methylthio)pyridines by reacting acyclic or cyclic active methylene ketones, ammonium acetate, and bis(methylthio)acrolein (1) or its 2-phenyl analogue 8 (as 3-carbon-1,3-biselectrophilic components) in the presence of either AcOH-TFA (4:1) or ZnBr₂ (or ZnI₂) catalysts has been reported.

Full text of DOI:10.1055/s-0028-1083529

2674
LETTER
A New One-Pot, Three-Component Synthesis of 2,3,5-Substituted or
Annulated-6-(Methylthio)pyridines
S
ynthesis of 2,3,5-
.
Substituted o
K
r
Annulated-6-(
M
.
ethylthio)pyr
Y
idines adav, S. K. S. Yadav, I. Siddiqui, S. Peruncheralathan, H. Ila,* H. Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Fax +91(512)2597436; E-mail: hila@iitk.ac.in
Received 7 June 2008
sis of a library of functionalized pyridine scaffolds11 by
utilizing various enaminoesters and ethynyl ketones
(Bohlmann–Ratz synthesis). In subsequent papers, Bag-
ley and coworkers have further extended the scope and
Abstract: A new one-pot, three-component synthesis of 2,3,5-sub-
stituted (or 2,3-annulated)-6-(methylthio)pyridines by reacting acy-
clic or cyclic active methylene ketones, ammonium acetate, and
bis(methylthio)acrolein (1) or its 2-phenyl analogue 8 (as 3-carbon-
1,3-biselectrophilic components) in the presence of either AcOH– application by effecting this transformation in a one-pot,
TFA (4:1) or ZnBr2 (or ZnI2) catalysts has been reported.
three-component reaction [3C+2C+N] at lower tempera-
ture using either a Brønsted/Lewis acid catalyst, bromine
or iodine, or under neutral conditions.12–14 Recently, Mar-
coux and Davies15 have developed an efficient synthesis
of 2,3-diaryl pyridines as COX-2 specific inhibitors in-
volving vinamidinium salts16 as three-carbon biselectro-
philic partners in a one-step annulation with a-arylketones
and ammonia [3C+2C+N approach]. Katritzky and co-
workers have utilized a,b-unsaturated ketones as 1,3-elec-
trophilic components in a [3+3] annulation with either
a-benzotriazolylacetonitrile anion17a or iminophos-
phoranes17b as nucleophiles.
Key words: pyridines, cycloannulation, one-pot, three-component
synthesis, bis(methylthio)acrolein, ammonium acetate
Substituted pyridines and their benzo/hetero-fused ana-
logues represent an important class of heterocycles be-
cause of their presence in numerous natural products,
along with useful biological and pharmacological
activities1 displayed by these compounds. In particular,
the pyridine structural motif has assumed considerable
importance because of its presence in enzymes (NADP),
vitamins (niacin, pyridoxine), highly toxic alkaloids (nic-
otine),2 agrochemicals,3 and in several bioactive drugs
(isoniazide, sulfapyridines, and COX-2 specific inhibi-
tors).4,5 In addition, pyridine derivatives are extensively
utilized in preparative organic, coordination, analytical,
and supramolecular chemistry.6 Recently, certain pyridin-
ium salts have been used as ionic liquids with potential
scope in ‘green’ industrial applications.2,7 Therefore de-
velopment of new, efficient, and regiospecific methods
for the synthesis of pyridine scaffolds with diverse func-
tionalities and substituents remains an area of current in-
terest. Several elegant general syntheses of pyridine ring
systems8,9 have been developed in recent years which
have been elaborated in a review article published in
2004.2
Our own interest in pyridine synthesis relies upon the syn-
thetic application of a-oxoketene dithioacetal as 3-car-
bon-1,3-electrophilic component in aromatic and
heteroaromatic annulation18,19 and we have previously re-
ported efficient and highly regiospecific synthesis of
2,3,4,5,6-substituted and 4,5-annulated (or 5,6-annulated)
pyridines by [3+3] cyclocondensation of b-lithio-
aminoacrylonitriles20 or lithioacetonitrile21 with a-oxo-
ketene dithioacetals. In an earlier study, Potts and
coworkers22 have demonstrated a useful [5+1] approach
for 2,6-disubstituted pyridines via base-induced 1,4-addi-
tion of methyl ketones to a-oxoketene dithioacetals to
give 1,5-enediones followed by their ring closure with
ammonium acetate. We have recently reported the synthe-
sis of bis(methylthio)acrolein23 and its application as ‘sur-
rogate’ acrolein in a modified Skraup synthesis of
substituted 2-(methylthio)quinolines.24 In continuation of
these studies, we report herein a new general synthesis of
2,3,5-substituted/annulated-6-(methylthio)pyridines in-
volving cycloannulation of 3-bis(methylthio)acrolein and
its 2-phenyl analogue with various active methylene ke-
tones in a three-component, one-pot process.
Among the various routes towards substituted pyridines, a
[3+3] approach involving cyclocondensation of a C–C–N
fragment, more commonly an enaminone, enaminoester,
or enaminonitrile and a 3-carbon-1,3-electrophilic com-
ponent is the most useful and versatile,2 since it allows
construction of unsymmetrically substituted pyridines
from relatively simple precursors. Several variations of
this approach are available in the literature. Thus, Moody
and Bagley have applied this approach for the preparation
of a modified oxazole-thiazole pyridine core of the
promothiocin/sulfomycin antibiotics10 and for the synthe-
We first examined the two-step procedure by subjecting
4-methoxyacetophenone (2a) or the indane-1,3-dione
(5a) to aldol condensation with bis(methylthio)acrolein
(1) in the presence of sodium ethoxide in ethanol afford-
ing the aldol adducts 3a and 6a in high yields (Scheme 1).
Subsequent heterocyclization of 3a and 6a to the respec-
tive pyridines (4a and 7a) was investigated under various
conditions in the presence of Brønsted/Lewis acids or ion-
SYNLETT 2008, No. 17, pp 2674–2680
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083529; Art ID: D21008ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,3,5-Substituted or Annulated-6-(Methylthio)pyridines
2675
exchange resin (Scheme 1, Table 1). In all the reactions, 6 vs. Table 2, entry 1 and Table 3, entry 1). These reaction
the desired 2-(4-methoxyphenyl)-5-(methylthio)pyridine conditions were employed for the synthesis of other sub-
(4a) and the corresponding annulated pyridine 7a were stituted/annulated pyridines.25,26 Thus, the active methy-
formed in varying yields under these conditions lene ketones such as aryl/heteroaryl desoxybenzoins 2b–
(Table 1).25 Best yields of 4a or 7a were obtained either in d also underwent smooth cyclocondensation with 1 and
refluxing AcOH–TFA (4:1, Table 1, entry 3) or in the ammonium acetate in refluxing AcOH–TFA (conditions
presence of ZnBr2 catalyst when the reaction was carried A) to give 2,3-diarylpyridines 4b,c and 2-(3-pyridyl)-3-
out in a sealed tube at higher temperature (110 °C, entry phenylpyridine 4d in moderate to good yields whereas in
6). In parallel experiments, we also investigated the possi- the presence of ZnBr2 catalyst (conditions B) 4b–d were
bility of devising a multicomponent condensation process obtained in decreased yield (Table 2, entries 2–4).
with a view to develop a more efficient pyridine synthesis
by reacting the active methylene ketone, bis(methyl-
thio)acrolein (1) and ammonium acetate in a one-pot op-
eration in the presence of various acid catalysts and the
results are depicted in Scheme 2 and Tables 2 and 3.
O
R2
R2
H
A or B
H
+
R1
O
R1
N
SMe
MeS
SMe
2 or 5
1 (3 equiv)
4
O
Scheme 2 Reagents and conditions: A: NH4OAc (20 equiv),
AcOH–TFA (4:1), reflux, 8–12 h; B: NH4OAc (20 equiv), ZnBr2 (15
mol%), 110 °C, 5–6 h, sealed tube.
O
SMe
SMe
NaOEt, EtOH
+
0 °C to r.t.
3–4 h
H
MeO
1
2a
NH4OAc
(excess)
O
SMe
SMe
The versatility of this method was further demonstrated
by extending the heteroannulation reaction to few benzo-
and heterocyclic ketones 5a–d furnishing the correspond-
ing 2,3-annulated/heteroannulated pyridines 7a–d in good
yields under AcOH–TFA refluxing conditions (A) where-
as yields were lower with ZnBr2 catalyst (Scheme 2,
Table 3, entries 1–4).25,26
p-MeOC6H4
reaction
conditions
N
SMe
O
p-MeOC6H4
3a 68%
4a
O
SMe
NaOEt, EtOH
+
H
SMe 0 °C to r.t.
3–4 h
In order to study the scope of this reaction and to establish
its tolerance towards different substrates, a few of the ac-
tive methylene compounds such as b-ketoesters (Table 2,
entries 6 and 7) and malononitrile (entry 5) were reacted
with bis(methylthio)acrolein and ammonium acetate fol-
lowing these standard conditions yielding the pyridines
4e–g in moderate yields under refluxing AcOH–TFA.
However, under ZnBr2-catalyzed conditions, only intrac-
table product mixtures were formed (Table 2, entries 5–
7).25
O
1
5a
O
O
SMe
SMe
NH4OAc
(excess)
reaction
O
conditions
N
SMe
7a
6a 78%
Scheme 1
Table 1 Two-Step Synthesis of Pyridines 4a and 7a under Different
Reaction Conditions
To further introduce a point of diversity at the 5-position
of pyridine ring, this three-component reaction was elab-
orated to 2-phenyl-3-bis(methylthio)acrolein (8)27 which
was reacted with a range of active methylene ketones in
the presence of excess of ammonium acetate in either re-
fluxing AcOH–TFA (conditions A) or in the presence of
ZnBr2 (or ZnI2) catalyst (conditions B)28 yielding various
substituted 5-phenyl pyridines 9 and 10c as depicted in
Scheme 3 and Table 4.25
Entry Reaction conditionsa
Yield of Yield of
4a (%)
7a (%)
1
2
3
4
5
6
NH4OAc, AcOH, D, 8–10 h
35
50
NH4OAc, toluene–AcOH (5:1), D, 7–8 h 47
NH4OAc, AcOH–TFA (4:1), D, 8–10 h 58
49
68
Amberlyst 15, toluene, D, 8–10 h
ZnBr2 (15 mol%), toluene, D, 5–6 h
32
40
50
40
A comparison of yields of product pyridines from bis(me-
thylthio)acrolein (1, Tables 2 and 3) and those from 2-
phenyl-3-bis(methylthio)acrolein (8, Table 4) shows that
higher yields of 5-phenylpyridines 9 and 10c are obtained
in the presence of ZnBr2 (or ZnI2)28 (conditions B) where-
as in refluxing AcOH–TFA (conditions), they are marked-
ly reduced, with the recovery of unreacted ketones. On the
other hand, with bis(methylthio)acrolein (1), higher yields
of product pyridines 4 and 7 are obtained in refluxing
AcOH–TFA (conditions A) in comparison to ZnBr2-cata-
lyzed conditions (B, Tables 2 and 3).29
45
ZnBr2 (15 mol%), sealed tube,
110 °C, 5–6 h
55
a General conditions: NH4OAc (30 mol), 1 (3 equiv).
Thus, under optimized conditions, it was found that the
pyridines 4a and 7a were formed in comparable yields to
the two-step procedure when the ketone 2a (or 5a), 1 (3
equiv) and excess of ammonium acetate were reacted in
refluxing AcOH–TFA (4:1) or in the presence of ZnBr2
catalyst (15 mol%) in a sealed tube (Table 1, entries 3 and
Synlett 2008, No. 17, 2674–2680 © Thieme Stuttgart · New York

2676
A. K. Yadav et al.
LETTER
Table 2 Synthesis of 2,3-Substituted-6-(methylthio)pyridines 4
Entry
Ketone 2
4
Yield (%)
Conditions A
Conditions B
O
1
63
50
N
SMe
MeO
MeO
2a
4a
X
X
2
3
4
57
63
67
48
55
57
O
N
SMe
X
X
2b, X = H
4b, X = H
2c, X = MeO
4c, X = MeO
O
N
SMe
N
N
4d
2d
NC
NC
5
57a
–
CN
H2N
N
SMe
2e
4e
6
7
2f, R = Ph
4f, R = Ph
42
–
–
2g, R = Me
4g, R = Me
47b
a Obtained as side product (24%):
H
CN
MeS
MeS
CONH2
H
b Could not be isolated under conditions A but in refluxing in toluene–AcOH (5:1) for 6 h.
O
Similarly, the parent tricyclic benzo[h][1,6]naphthyridine
14 could be prepared in high yield by aromatization of the
corresponding N-sulfonyl derivative 7c in the presence of
NaOH and n-Bu4NBr under refluxing conditions followed
by desulfurization of the resulting product 13 with Raney-
Ni in refluxing ethanol (Scheme 5).25
R2
R1
R2
R1
Ph
Ph
A or B
H
+
MeS
SMe
O
N
SMe
2 or 5c
9 or 10c
8 (1 equiv)
Scheme 3 Reagents and conditions: A: NH4OAc (20 equiv),
AcOH–TFA (4:1), reflux, 8–12 h; B: NH4OAc (20 equiv), ZnI2 or
ZnBr2 (15 mol%), 110 °C, 5–6 h, sealed tube.
R2
R1
R3
R2
R1
R3
Raney-Ni, EtOH
reflux, 3–5 h
N
SMe
N
A few of the selected 6-(methylthio)pyridines were
dethiomethylated in the presence of Raney-Ni in refluxing
ethanol to afford 6-unsubstituted sulfur-free pyridines 11
and 12 in excellent yields as shown in Scheme 4.25,30
4, 9
11, 12
4c, 11c: R1 = R2 = 4-MeOC6H4; R3 = H; 93%
4d, 11d: R1 = 3-py; R2 = Ph; R3 = H; 95%
9h, 12h: R1 = 4-ClC6H4; R2 = H; R3 = Ph; 90%
9i, 12i: R1 = 3-py; R2 = H; R3 = Ph; 91%
Scheme 4
Synlett 2008, No. 17, 2674–2680 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3,5-Substituted or Annulated-6-(Methylthio)pyridines
2677
Table 3 Synthesis of 2,3-Annulated/Heteroannulated Pyridines 7a–d
Entry
Cyclic ketone 5
Product 7
Yield of 7 (%)
Conditions A
Conditions B
55
O
O
1
78
64
70
N
SMe
O
7a
5a
2
3
55
60
O
N
SMe
5b
PhO2S
N
7b
PhO2S
N
N
SMe
O
5c
7c
S
S
N
SMe
4
63
51
O
5d
7d
Table 4 Synthesis of Pyridines 9 and 10c
Entry Ketone 2 or 5
Product 9 or 10c
Yield (%)
Conditions A
Conditions B
Ph
Me
O
N
SMe
1
40
64
X
X
2a, X = OMe
9a, X = OMe
2
3
2h, X = Cl
9h, X = Cl
42
35
63
68
Ph
Me
O
N
SMe
N
N
2i
9i
Ph
4
5
43
41
60
64
O
N
SMe
2b
9b
Ph
O
N
SMe
N
N
2d
9d
Synlett 2008, No. 17, 2674–2680 © Thieme Stuttgart · New York

2678
A. K. Yadav et al.
LETTER
Table 4 Synthesis of Pyridines 9 and 10c (continued)
Entry
Ketone 2 or 5
Product 9 or 10c
Yield (%)
Conditions A
Conditions B
Ph
S
S
6
37
57
S
S
O
N
SMe
2j
9j
Ph
Me
N
O
SMe
SMe
Fe
Fe
7
36
44
55
66
O
N
Me
Ph
2k
9k
PhO2S
Ph
PhO2S
N
N
N
SMe
O
8
10c
5c
PhO2S
References and Notes
N
N
N
a
b
(1) (a) Balasubramaniam, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996, Chap. 5.06, 245. (b) Michael, J. P. Nat. Prod. Rep.
1997, 14, 605.
N
SMe
N
SMe
N
7c
13 85%
14 88%
Scheme 5 Reagents and conditions: (a) 50% NaOH, Bu4NBr, tolu-
ene, reflux, 2 h; (b) Raney-Ni, EtOH, reflux, 3 h.
(2) Review: Henry, G. D. Tetrahedron 2004, 60, 6043; and
references therein.
(3) Matolcsy, G. Pesticide Chemistry; Elsevier Scientific:
Amsterdam / Oxford, 1998, 427–430.
In conclusion, we have developed a novel one-pot, three
component reaction for the synthesis of 2,3,5-substituted
(or 2,3-annulated)-6-methylthiopyridines combining acy-
clic or cyclic active methylene ketones, ammonia, and
bis(methylthio)acrolein or its 2-phenyl analogue (as 3-
carbon 1,3-bielectrophilic component) in the presence of
either protic acid or ZnBr2/ZnI2 as catalysts. These reac-
tions proceed in moderate to high yields with total regio-
control for either ketones or bis(methylthio)acroleins
which can be considered as synthetic equivalents of vina-
midinium salts. The 2-methylthio group in these newly
synthesized pyridines can be replaced either by amines24
or can be reacted with carbon nucleophiles through nickel
chloride cross-coupling reactions.19d Further work to im-
prove the yield of pyridine derivatives and to expand the
scope of this heteroannulation reaction for acquiring more
functional group diversity is in progress.
(4) (a) Pharmaceutical Chemistry. Drug Synthesis, Vol 1; Roth,
H. J.; Kleeman, A., Eds.; Prentice Hall Europe: London,
1988, 407. (b) MDDR; MDL Drug Data Registry; by MDL
Informations System, Inc; San Leandro, California USA.
(5) Li, A.-H.; Moro, S.; Forsyth, N.; Melman, N.; Ji, X.-D.;
Jacobson, K. A. J. Med. Chem. 1999, 42, 706.
(6) Scriven, E.; Berry, D. Speciality Chem. Mag. 2001, May 24.
(7) (a) Heller, M.; Schubert, U. S. Eur. J. Org. Chem. 2003,
947. (b) Kozhevnikov, V. N.; Kozhevnikov, D. N.; Nikitina,
T. V.; Rusinov, V. L.; Chupakhin, O. L.; Zabel, M.; König,
B. J. Org. Chem. 2003, 68, 2882. (c) Branowska, D.
Synthesis 2003, 2096; and references therein.
(8) (a) Fischer, M.; Troschutz, R. Synthesis 2003, 1603.
(b) Keuper, R.; Risch, N. Eur. J. Org. Chem. 1998, 2609.
(c) Risch, N.; Esser, A. Synthesis 1988, 337. (d) Sharma,
U.; Ahmed, S.; Boruah, R. C. Tetrahedron Lett. 2000, 41,
3493. (e) Chetia, A.; Longchar, M.; Lekhok, K. C.; Boruah,
R. C. Synlett 2004, 1309. (f) Ramesh, S. S.; Douglas, D. Y.;
Alexander, D. Chem. Commun. 2006, 1313.
(9) (a) Hedge, V. B.; Renga, J. M.; Owen, J. M. Tetrahedron
Lett. 2001, 42, 1847. (b) Thomas, A. D.; Asokan, C. V.
Tetrahedron Lett. 2002, 43, 2273. (c) Bhandari, A.; Li, B.;
Gallop, M. A. Synthesis 1999, 1951. (d) Parthasarathy, K.;
Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325.
(e) Kase, K.; Goswami, A.; Ohtaki, K.; Tanabe, E.; Saino,
N.; Okamoto, S. Org. Lett. 2007, 9, 991. (f) Lu, J.-Y.;
Arndt, H.-D. J. Org. Chem. 2007, 72, 4205. (g) Gehre, A.;
Stanforth, S. P.; Tarbit, B. Tetrahedron Lett. 2007, 48, 6974.
Acknowledgment
AKY, IS, and SP thank CSIR, New Delhi for senior research fel-
lowship. SKSY thanks ICAR for financial assistance. Financial
assistance under CSIR project is also acknowledged.
Synlett 2008, No. 17, 2674–2680 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3,5-Substituted or Annulated-6-(Methylthio)pyridines
2679
(10) (a) Moody, C. J.; Bagley, M. C. Synlett 1998, 361.
(b) Moody, C. J.; Bagley, M. C. Chem. Commun. 1998,
2049. (c) Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.;
Moody, C. J. J. Am. Chem. Soc. 2000, 122, 3301.
(d) Bagley, M. C.; Dale, J. W.; Xiong, X.; Bower, J. Org.
Lett. 2003, 5, 4421.
(11) Bashford, K. E.; Burton, M. B.; Cameron, S.; Cooper, A. L.;
Hogg, R. D.; Kane, P. D.; MacManus, D. A.; Matrunola,
C. A.; Moody, C. J.; Robertson, A. A. B.; Warne, M. R.
Tetrahedron Lett. 2003, 44, 1627.
(20) (a) Gupta, A. K.; Ila, H.; Junjappa, H. Tetrahedron 1990, 46,
3703. (b) Satyanarayana, J.; Ila, H.; Junjappa, H. Synthesis
1991, 889.
(21) (a) Gupta, A. K.; Ila, H.; Junjappa, H. Tetrahedron Lett.
1988, 29, 6633. (b) Gupta, A. K.; Ila, H.; Junjappa, H.
Tetrahedron 1990, 46, 2572.
(22) (a) Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G.
J. Am. Chem. Soc. 1981, 103, 3584. (b) Potts, K. T.;
Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Org. Chem. 1982,
47, 3027.
(12) (a) Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001, 1149.
(b) Bagley, M. C.; Dale, J. W.; Hughes, D. D.; Ohnesorge,
M.; Phillips, N. G.; Bower, J. Synlett 2001, 1523.
(c) Bagley, M. C.; Singh, N. Synlett 2002, 1718.
(d) Bagley, M. C.; Hughes, D. D.; Sabo, H. M.; Taylor,
P. H.; Xiong, X. Synlett 2003, 1443. (e) Xiong, X.; Bagley,
M. C.; Chapaneri, K. Tetrahedron Lett. 2004, 45, 6121.
(f) Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.;
Phillips, N. G.; Xiong, X.; Bower, J. J. Chem. Soc., Perkin
Trans. 1 2002, 1663. (g) Xiong, X.; Bagley, M. C.;
Chapaneri, K. Tetrahedron Lett. 2004, 45, 6121.
(h) Bagley, M. C.; Glover, C.; Chevis, D. Synlett 2005, 649.
(i) Bagley, M. C.; Glover, C.; Merritt, E. A.; Xiong, X.
Synlett 2004, 811.
(13) (a) Review: Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett
2007, 2459. (b) Bagley, M. C.; Dale, J. W.; Bower, J. Chem.
Commun. 2002, 1682. (c) Bagley, M. C.; Chapaneri, K.;
Dale, J. W.; Xiong, X.; Bower, J. J. Org. Chem. 2005, 70,
1389. (d) Bagley, M. C.; Dale, J. W.; Bower, J. Chem.
Commun. 2002, 1682. (e) Merritt, E. A.; Bagley, M. C.
Synlett 2007, 954.
(23) Mahata, P. K.; Barun, O.; Ila, H.; Junjappa, H. Synlett 2000,
1345.
(24) Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H.
Synlett 2004, 449.
(25) The structures of all newly synthesized compounds were
confirmed with the help of spectral and analytical data.
(26) General Procedure for One-Pot, Three-Component
Synthesis of 2,3,5-Substituted or 2,3-Annulated-6-
(methylthio)pyridines 4, 7, 9, and 10c
Procedure A
A solution of appropriate ketone (1.0 mmol), bis(methyl-
thio)acrolein (1, 3.0 mmol) or 2-phenyl-3-bis(methyl-
thio)acrolein (8, 1.1 mmol), and NH4OAc (20 mol) in
AcOH–TFA (5 mL, 4:1) was heated with stirring at 110 °C
for 8–10 h (monitored by TLC). The mixture was then
neutralized with sat. NaHCO3 solution (25 mL) and
extracted with CH2Cl2 (3 × 15 mL). The combined organic
extracts were washed with H2O (2 × 50 mL), brine (50 mL),
dried (Na2SO4), and evaporated under reduced pressure to
afford crude product which was purified by column
chromatography over SiO2 using EtOAc–hexane (1:9) as
eluent.
(14) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard,
G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans. 1 2000, 2311;
and references therein.
Procedure B
A mixture of appropriate ketone (1.0 mmol), bis(methyl-
thio)acrolein (1, 3.0 mmol) or 2-phenyl-3-bis(methyl-
thio)acrolein (8, 1.1 mmol), NH4OAc (20 mol), and ZnBr2 or
ZnI2 (15 mol%) was heated in a sealed tube at 110 °C for
5–8 h (monitored by TLC). The residue was partitioned
between sat. NaHCO3 solution (30 mL) and CHCl3 (30 mL),
and was extracted with CH2Cl2 (3 × 15 mL). The organic
layer was washed with H2O (2 × 50 mL), brine (50 mL),
dried (Na2SO4), and evaporated under reduced pressure to
give crude product which was purified by column
chromatography on SiO2 using EtOAc–hexane (1:9) as
eluent.
(15) (a) Marcoux, J.-F.; Corley, E. G.; Rossen, K.; Pye, P.; Wu,
J.; Robbins, M. A.; Davies, I. W.; Larsen, R. D.; Reider,
P. J. Org. Lett. 2000, 2, 2339. (b) Davies, I. W.; Marcoux,
J.-F.; Reider, P. J. Org. Lett. 2001, 3, 209. (c) Davies, I. W.;
Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai, D.-W.;
Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.;
DiMichele, L.; Dormer, P.; Reider, P. J. J. Org. Chem. 2000,
65, 8415.
(16) Review: Lloyd, D.; McNab, H. Angew. Chem., Int. Ed. Engl.
1976, 15, 459.
(17) (a) Katritzky, A. R.; Belyakov, S. A.; Sorochinsky, A. E.;
Henderson, S. A.; Chen, J. J. Org. Chem. 1997, 62, 6210.
(b) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko,
D. O.; Essawy, S. A. Synthesis 1999, 2114.
(18) Reviews: (a) Ila, H.; Junjappa, H.; Mohanta, P. K. In
Progress in Heterocyclic Chemistry, Vol. 13; Gribble,
G. W.; Gilchrist, T. L., Eds.; Pergamon: Oxford, 2001, Chap.
1, 1. (b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423. (c) Junjappa, H.; Ila, H. Phosphorus, Sulfur
Silicon Relat. Elem. 1994, 95, 35. (d) Ila, H.; Junjappa, H.;
Barun, O. J. Organomet. Chem. 2001, 624, 34.
(19) Recent papers: (a) Kumar, S.; Ila, H.; Junjappa, H.
Tetrahedron 2007, 63, 10067. (b) Misra, N. C.; Panda, K.;
Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72, 1246.
(c) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H.
J. Org. Chem. 2005, 70, 10030. (d) Venkatesh, C.; Singh,
B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7,
9644. (e) Panda, K.; Venkatesh, C.; Ila, H.; Junjappa, H.
Eur. J. Org. Chem. 2005, 2045. (f) Peruncheralathan, S.;
Khan, T. A.; Ila, H.; Junjappa, H. Tetrahedron 2004, 60,
3457. (g) Sundarum, G. S. M.; Venkatesh, C.; Syam Kumar,
U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2004, 69, 5760.
2-(4-Methoxyphenyl)-6-methylthiopyridine (4a)
Yield 63% (0.15 g); white solid; mp. 81–82 °C; Rf = 0.52
(hexane–EtOAc, 9:1). IR (KBr): 2919, 1602, 1555, 1448
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.99 (d, J = 9.0 Hz,
2 H, ArH), 7.49 (t, J = 7.8 Hz, 1 H, ArH), 7.35 (d, J = 7.6 Hz,
1 H, ArH), 7.05 (d, J = 7.8 Hz, 1 H, ArH), 6.92 (d, J = 8.8
Hz, 2 H, ArH), 3.85 (s, 3 H, OMe), 2.64 (s, 3 H, SMe). 13
C
NMR (100 MHz, CDCl3): d = 160.5, 159.1, 156.2, 136.6,
131.3, 128.1, 119.2, 114.8, 114.0, 55.3, 13.2. ESI-HRMS:
m/z calcd for C13H14NOS [M + H]+: 232.0796; found:
232.0794.
2,3-Bis(4-methoxyphenyl)-6-methylthiopyridine (4c)
Yield 63% (0.21 g); white solid; mp 161–162 °C; Rf = 0.50
(hexane–EtOAc, 19.1). IR (KBr): 2950, 1684, 1509 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.49 (d, J = 8.1 Hz, 1 H, ArH),
7.35 (dd, J = 6.7, 2.1 Hz, 2 H, ArH), 7.14 (d, J = 8.3 Hz, 1 H,
ArH), 7.07 (dd, J = 6.6, 2.2 Hz, 2 H, ArH), 6.74–6.81 (m, 4
H, ArH), 3.78 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 2.62 (s, 3
H, SMe). 13C NMR (100 MHz, CDCl3): d = 159.7, 158.8,
157.5, 155.1, 139.7, 131.5, 131.4, 131.2, 130.5, 130.4,
119.3, 113.9, 113.3, 55.2, 55.1, 13.7. MS: m/z (%) =
337(100) [M+]. Anal. Calcd (%) for C20H19NO2S (337.43):
Synlett 2008, No. 17, 2674–2680 © Thieme Stuttgart · New York

2680
A. K. Yadav et al.
LETTER
C, 71.19; H, 5.68; N, 4.15. Found: C, 71.23; H, 5.70; N, 4.18.
2-Methylthioindeno[1,2-b]pyridin-5-one (7a)
8.27 (d, J = 7.8 Hz, 1 H, ArH), 7.88 (td, J = 7.7, 1.7 Hz, 1 H,
ArH), 7.56 (d, J = 7.8 Hz, 1 H, ArH), 7.49–7.40 (m, 5 H,
Yield 78% (0.18 g); pale yellow solid; mp 145–146 °C; Rf =
0.54 (hexane–EtOAc, 9:1); IR (KBr): 2920, 1720, 1575,
1401 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.57 (d, J = 7.3
Hz, 1 H, ArH), 7.49 (d, J = 7.3 Hz, 1 H, ArH), 7.46 (d,
J = 8.0 Hz, 1 H, ArH), 7.37 (t, J = 7.4 Hz, 1 H, ArH), 7.24 (t,
J = 7.4 Hz, 1 H, ArH), 6.84 (d, J = 8.1 Hz, 1 H, ArH), 2.51
(s, 3 H, SMe). 13C NMR (100 MHz, CDCl3): d = 191.1,
167.1, 165.1, 142.7, 135.0, 134.4, 130.7, 130.3, 123.5,
123.4, 120.5, 119.8, 13.3. MS: m/z (%) = 227(100) [M+].
Anal. Calcd (%) for C13H9NOS (227.28): C, 68.70; H, 3.99;
N, 6.16. Found: C, 68.76; H, 4.00; N, 6.18.
6-Methylthio-3,5-diphenyl-[2,3¢]bipyridinyl (9d)
Yield 64% (0.23 g); light yellow solid; mp 160–161 °C; Rf =
0.45 (hexane–EtOAc, 5:1). IR (KBr): 2916, 1575, 1445,
1377 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.77 (br s, 1 H,
ArH), 8.50 (dd, J = 4.9, 1.4 Hz, 1 H, ArH), 7.71 (dt, J = 8.0,
1.9 Hz, 1 H, ArH), 7.55–7.52 (m, 2 H, ArH), 7.51 (s, 1 H,
ArH), 7.50–7.40 (m, 3 H, ArH), 7.33–7.27 (m, 3 H, ArH),
7.23–7.20 (m, 2 H, ArH), 7.17–7.15 (m, 1 H, ArH), 2.60 (s,
3 H, SMe). 13C NMR (100 MHz, CDCl3): d = 156.6, 151.4,
150.9, 148.7, 139.1, 138.9, 137.4, 137.1, 135.3, 135.0,
131.7, 129.5, 129.1, 128.7, 128.5, 128.4, 127.5, 122.6, 13.8.
MS: m/z (%) = 355(100) [M + 1], 354(60) [M+]. Anal. Calcd
(%) for C23H18N2S (354.46): C, 77.93; H, 5.12; N, 7.90.
Found: 77.97; H, 5.13; N, 7.93.
ArH), 7.37–7.34 (m, 1 H, ArH), 2.62 (s, 3 H, SMe). 13
C
NMR (100 MHz, CDCl3): d = 157.3, 155.2, 152.9, 148.3,
137.8, 137.3, 136.5, 129.1, 128.4, 128.3, 123.9, 121.4,
116.5, 13.8. MS: m/z (%): 279(100) [M + 1], 278(30). Anal.
Calcd (%) for C17H14N2S (278.37): C, 73.35; H, 5.07; N,
10.06. Found: C, 73.32; H, 5.09; N, 10.09.
(27) Rudorf, W. D. J. Prak. Chem. 1986, 328, 321.
(28) Comparable yields of pyridines 9 were obtained by using
either ZnBr2 or ZnI2 catalyst.
(29) Lower yields of pyridines 4a–g with ZnBr2 (conditions B)
catalyst at 110 °C are presumably due to the decomposition
of bis(methylthio)acrolein(1) at higher temperature.
(30) The 1H NMR of all desulfurized compounds 11c,d, 12h,i
displayed a low field signal between d = 8.63–8.96 ppm due
to the pyridine H-6 proton which further confirmed the
regiochemistry of the products.
2,3-Bis(4-methoxyphenyl)pyridine (11c)
Yield 93% (0.27 g); white solid; mp 82–83 °C; Rf = 0.5
(hexane–EtOAc, 19:1). IR (KBr): 2935, 2838, 1607, 1511,
1429 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.63 (dd,
J = 4.6, 1.7 Hz, 1 H, ArH), 7.67 (dd, J = 7.6, 1.7 Hz, 1 H,
ArH), 7.31 (dd, J = 6.7, 2.1 Hz, 2 H, ArH), 7.29–7.26 (m, 1
H, ArH), 7.11 (dd, J = 6.7, 2.1 Hz, 2 H, ArH), 6.83 (dd,
J = 6.8, 1.9 Hz, 2 H, ArH), 6.78 (dd, J = 6.8, 1.9 Hz, 2 H,
ArH), 3.81 (s, 3 H, OMe), 3.79 (s, 3 H, OMe). 13C NMR (100
MHz, CDCl3): d = 159.2, 158.8, 156.7, 147.9, 138.4, 135.3,
132.8, 132.5, 131.1, 130.6, 121.6, 113.8, 113.3, 55.22,
55.18. MS: m/z (%) = 292(100) [M + 1], 291(40) [M+]. Anal.
Calcd (%) for C19H17NO2 (291.34): C, 8.33; H, 5.88; N, 4.81.
Found: C, 78.39; H, 5.90; N, 4.84.
6-Methylthio-5-phenyl-[2,2¢]bipyridinyl (9i)
Yield 68% (0.19 g); colorless solid; mp 100–101 °C; Rf =
0.47 (hexane–EtOAc, 19:1). IR (KBr): 2916, 1546, 1428,
1354 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.71 (dd,
J = 4.9, 0.74 Hz, 1 H, ArH), 8.54 (d, J = 8.1 Hz, 1 H, ArH),
Synlett 2008, No. 17, 2674–2680 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.