One-pot synthesis of substituted pyridines via the Vilsmeier-Haack reaction of acyclic ketene-S,S-acetals

Article abstract of DOI:10.1055/s-2004-829547

A one-pot synthesis of substituted pyridines from acyclic ketene-S,S-acetals containing α-acetyl, α-vinyl or α-ethynyl group via the Vilsmeier-Haack reaction has been developed.

Full text of DOI:10.1055/s-2004-829547

LETTER
1731
One-Pot Synthesis of Substituted Pyridines via the Vilsmeier–Haack Reaction
of Acyclic Ketene-S,S-acetals
O
ne-Pot Synth
h
esis of Subs
a
d
Pyri
o
Department of Chemistry, Northeast Normal University, Changchun, 130024, P. R. China
Fax +86(431)5268966; E-mail: dongdw663@nenu.edu.cn
Received 15 May 2004
odorless thioacetalization reagent.11 As continuation of
these studies, we wish to report here a one-pot synthesis
of substituted pyridines directly from the Vilsmeier–
Haack reaction of a-oxo ketene-S,S-acetals.
Abstract: A one-pot synthesis of substituted pyridines from acyclic
ketene-S,S-acetals containing a-acetyl, a-vinyl or a-ethynyl group
via the Vilsmeier–Haack reaction has been developed.
Key words: a-oxo ketene-S,S-acetal, substituted pyridine, Vils-
meier–Haack reaction, Vilsmeier reagent
In this communication, a-oxo ketene-S,S-acetals 1a–e
containing methyl group adjacent to the carbonyl group
were prepared in high yields (up to 99%) according to our
earlier reported procedure.12
Functionalized pyridines and their benzo/hetero-fused an-
alogues represent an important class of organic molecules
for their presence in numerous natural products along with
useful bio-, physio- and pharmacological activities.1,2 The
synthesis of the pyridine derivatives can principally be re-
alized either by modification of the pre-constructed pyri-
dine nucleus or through the construction of the pyridine
ring from appropriately substituted open chain precursor,
which have been extensively reviewed.1 Nevertheless, it
is still of continued interest and great importance to ex-
plore novel and efficient synthetic approaches for this
class of compounds, especially those with wide general
applicability to achieve more flexible substitution pat-
terns.
X
X
O
i
i
ii
SR
2a–c, 2a'–c'
ii
N
SRRSH
N
RS
1a–e
SR
2d–e
Substrate
R
R
1a
1b
1c
1d
1e
CH3
CH3
CH2 CH3
CH2 Ph
CH2CH3
CH2Ph
(CH2)2
(CH2)3
Scheme 1 Reagents and conditions: (i) POCl3- or PBr3-DMF (2
equiv), 0 °C, 6–24 h; (ii) NH4OAc, 80 °C, 0.5 h.
Over the last two decades, a-oxo ketene-S,S-acetals are
emerging as versatile organic synthons in the formation of
heterocycles, aromatic compounds and various valuable
reactive intermediates.3 Indeed, the attempts have been
made by some research groups to synthesize pyridine de-
rivatives from such synthons. Potts and co-workers re-
ported earlier a one-pot two-component procedure
involving the in-situ generation of unsaturated 1,5-dike-
tones from the reaction of a-oxo ketene-S,S-acetals with
methyl ketone carbonions.4 Junjappa et al. prepared series
of substituted pyridines by the cycloaromatization of a-
oxo ketene-S,S-acetals with lithio acetonitrile.5 Wang and
co-workers synthesized poly-functionalized quinolines
and quinolones directly from the reaction of a-oxo ketene-
S,S-acetals with o-aminobenzoates.6 Recent researches
have revealed that pyridine derivatives can also be synthe-
sized by the Vilsmeier–Haack reaction7 of a-oxo ketene-
S,S-acetals derived intermediates such as a-hydroxy-
ketene-S,S-acetals8 and a-oxo ketene-N,S-acetals.9 Most
recently, we investigated the Vilsmeier–Haack reaction of
a-oxo ketene-S,S-acetals and developed a facile approach
for the synthesis of 2H-pyrans10 and a novel, nonthiolic,
In our previous work,10 it was found that the Vilsmeier–
Haack reaction of 1a could proceed and the haloformyla-
tion product was detected although it was not stable. The
result indicated the iminoalkylated salt could be formed at
that stage. In the present work, the initial studies were
performed on the reaction of a-oxo ketene-S,S-acetal 1a
with Vilsmeier reagent POCl3–DMF (2 equiv) at 0 °C
(Scheme 1).13 The resulting intermediate iminium salt
was further converted into 2-methylthio-4-chloro-pyri-
dine (2a) in the presence of ammonium acetate in moder-
ate yield (Table 1).
With expect to extend the scope of this reaction, the reac-
tions of other ketene-S,S-acetals with Vilsmeier reagent
POCl3–DMF proceeded in a similar fashion. Subsequent-
ly, substituted pyridines 2b and 2c were obtained from a-
oxo ketene-S,S-acetals 1b and 1c in moderate yields, re-
spectively. Some of the results are summarized in Table 1.
It is worth noting that other acyclic ketene-S,S-acetals
with a-vinyl or a-ethynyl group, such as 1f and 1g, could
also react with the Vilsmeier reagent to afford the corre-
sponding substituted pyridines 2f and 2g in 49.5% and
54.6% yields, respectively (Scheme 2). In contrast, a-oxo
cyclic ketene-S,S-acetals 1d and 1e could not undergo the
SYNLETT 2004, No. 10, pp 1731–1734
0
9
.0
8
.2
0
0
4
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829547; Art ID: U1410504
© Georg Thieme Verlag Stuttgart · New York

1732
S. Sun et al.
LETTER
Me
Table 1 The Vilsmeier–Haack Reaction of a-Oxo Ketene-S,S-
acetals 1a–c
O
Ar
Ar
MeS
ii
Ar
i
HO
Producta
2a
R
X
Yield (%)b State
SMe
MeS
SMe
SMe
MeS
CH3
Cl
Cl
Cl
Br
Br
Br
61.2
56.5
58.6
53.4
52.3
50.5
oil
oil
oil
oil
oil
oil
5
3
4
+
Ar
NMe2
2b
CH2CH3
PhCH2
CH3
iii
SMe
SMe
2c
SR
Ar
N
2a¢
6
7
2b¢
CH2CH3
PhCH2
Scheme 3 Reagents and conditions: (i) MeMgI–Et2O, (ii) POCl3–
DMF (2 equiv), r.t., 24 h; (iii) NH4OAc, 80 °C, 2 h.
2c¢
a All products were characterized by 1H NMR and IR, some products
were characterized by mass spectroscopy.
HO
O
O
HCl
POCl3-DMF
NMe2
b Yield refers to pure products after chromatography over silica gel.
RS
SR
RS
SR
RS
SR
10
Cl
1
N
N
Cl
9
Cl
N
POCl3-DMF
i
POCl3-DMF
+NMe2
i
ii
ii
MeS
SMe
SMe
SMe
SMe MeS
+NMe2
2g
1g
1f
2f
O
2Cl-
Cl-
O
Scheme 2 Reagents and conditions: (i) POCl3 (2 equiv), 0 °C, 6 h;
(ii) NH4OAc, 80 °C, 0.5 h.
+
NMe2
RS
SR
RS
SR
analogous cyclization to the corresponding pyridines; the
complex reaction mixtures were obtained in both cases.
8
11
-DMF
Cl
Cl
Cl
Generally, the carbonyl and the b-carbon atoms in a-oxo
ketene-S,S-acetals can be regarded as hard and soft elec-
trophilic centers, respectively.3b Therefore, many regio-
selective reagents can be selected either from hard
nucleophiles that can undergo 1,2-addition or from soft
nucleophiles that can add preferentially in 1,4-fashion.
Our earlier work on the addition of various Grignard re-
agents to a-oxo ketene-S,S-acetals with cyclic alkyldithio
group, e.g. S(CH2)2S and S(CH2)3S, revealed that only
1,2-addition products were formed,14 which was attribut-
ed to the steric hindered effect of the rigid cyclic dithio-
acetals moiety. The present work has further
demonstrated that there is great difference between a-oxo
cyclic ketene-S,S-acetals and a-oxo acyclic ketene-S,S-
acetals from the view of synthetic intermediates. Actually,
the reasons for the difference might be much complicated
and worthy of further investigation.
NH4OAc
Cl-
Cl-
Me2N
SR
Me2N
N
SR
H2N
Me2N
Cl-
RS
SR
H2
12
14
13
Cl
Cl
Cl
-NHMe2
- HCl
Me2HN
SR
SR
N
H
N
H
SR
N
2
15
16
Scheme 4 A proposed mechanism for the Vilsmeier–Haack
reaction of a-oxo ketene-S,S-acetals 1a–c.
protocol to some other a-oxo ketene-S,S-acetals, such as
a-oxo ketene-S,S-acetal 1a, was unsuccessful.
In a further extension of these studies, we next investigat-
ed the Vilsmeier–Haack reaction of 1a–c with a different
type Vilsmeier reagent, PBr3–DMF, under the similar
conditions (Scheme 1). Accordingly, 4-bromo substituted
pyridines 2a¢–c¢ were successfully obtained in moderate
yields, and some of the results are also listed in Table 1.
Obviously, different results have been achieved from the
Vilsmeier–Haack reaction of different precursors, i.e. a-
oxo ketene-S,S-acetal 1a and a-hydroxyketene-S,S-acetal
derived from the Grignard Reaction between 1a and
methyl magnesium iodide. In our present work, the halo-
genated pyridines implied that the Vilsmeier–Haack reac-
tion might follow a mechanism different from that
described in Scheme 3. On the basis of our results, a
plausible mechanism has been proposed for the reactions
of a-oxo ketene-S,S-acetals to yield substituted pyridines,
as shown in Scheme 4.7d,15 The electrophilic attack by the
In this section, it is worth mentioning a most recent work
on the Vilsmeier–Haack reaction of a-hydroxy-ketene-
S,S-acetals reported by Asokan and co-workers.8 As
shown in Scheme 3, they synthesized substituted py-
ridines and proposed a mechanism for the Vilsmeier–
Haack reaction, however, their attempt to apply this
Synlett 2004, No. 10, 1731–1734 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Substituted Pyridines
1733
(7) For reviews on the Vilsmeier reaction and its synthetic
applications; see: (a) Burn, D. Chem. Ind. (London) 1973,
870. (b) Seshadri, S. J. Sci. Ind. Res. 1973, 32, 128.
(c) Tebby, J. C.; Willetts, S. E. Phosphorus, Sulfur Silicon
Relat. Elem. 1987, 30, 293. (d) Marson, C. M. Tetrahedron
1992, 48 (18), 3659.
(8) Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002, 43,
2273.
(9) Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2003, 68, 3966.
Vilsmeier reagent on the weakly basic carbonyl oxygen
atom of a-oxo ketene-S,S-acetals 1 slowly forms salt 8
and HCl. The released HCl catalyzes the equilibrium
between tautomers 1 and 9, the latter undergoes rapid sub-
stitution by the Vilsmeier reagent giving b-N,N-dimethyl
aminovinyketone 10. Additionally, salt 8 may formylate
the enol 9 to give 10, too. The further reaction of 10 with
the Vilsmeier reagent gives the labile bisiminium chloride
11, which readily collapses to the iminium salt 12. With
addition of ammonium acetate, a nucleophilic displace-
ment (sequential amino-addition and alkylthio-elimina-
tion) on 12 by amine occurs and leads to the intermediate
ketene-N,S-acetal 13. At 80 °C, the reaction proceeds
through the intramolecular nucleophilic attack of the
iminium species within 13 to yield the intermediate 14,
which is followed by elimination of dimethylamine group
and subsequent loss of HCl to give the corresponding
pyridines 2.
(10) Liu, Y.; Dong, D.; Liu, Q.; Qi, Y.; Wang, Z. Org. Biomol.
Chem. 2004, 2, 28.
(11) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.;
Dong, D. J. Org. Chem. 2003, 68, 9148. (b) Yu, H.; Liu, Q.;
Yin, Y.; Fang, Q.; Zhang, J.; Dong, D. Synlett 2004, 999.
(12) Wang, M.; Ai, L.; Zhang, J.; Liu, Q.; Gao, L. Chin. J. Chem.
2002, 20, 1591.
(13) Typical Procedure for 2a: The Vilsmeier reagent was
prepared by adding POCl3 (6.0 mmol, 0.56 mL) dropwise to
ice cold dry N,N-dimethylformamide (DMF, 10 mL) under
stirring. The mixture was then stirred for 10–15 min at 0 °C.
To the above Vilsmeier reagent was added 1a (3.0 mmol,
0.49 g) as a solution in DMF (5 mL). The starting material
was quickly consumed within 30 min monitored by TLC.
The mixture was allowed to warm to r.t. and stirred for about
6 h. Then NH4OAc (3.5 g, 45 mmol) was added as a solid
into the reaction system. After stirred at r.t. for 10 min., the
mixture was heated to 80 °C under stirring for 30 min.
Cooled down to r.t., the reaction mixture was poured into
cold sat. K2CO3 aq (50 mL), extracted with Et2O (3 × 10
mL). The combined organic extracts were washed with brine
(3 × 20 mL), dried over anhyd Na2SO4, filtered and
concentrated under reduced pressure to yield the crude
product 2a which was purified by chromatography over
silica gel using Et2O/petroleum ether (1:80) as eluent.
Compounds 2b and 2c were synthesized following the same
procedure. 2a¢-c¢ were also synthesized via the similar
procedure except that prolonging reaction time (18–24 h)
was needed before the feed of NH4OAc.
In summary, one-pot synthesis of substituted pyridines
from the Vilsmeier–Haack reaction of acyclic ketene-S,S-
acetals containing a-acetyl, a-vinyl or a-ethynyl group
(1a–c, 1f and 1g) has been developed and a mechanism
for the reaction was proposed. The alkylthio and halogen
substituents at a- and g-position to the ring nitrogen of py-
ridine are quite reactive groups, for example in nucleo-
philic substitution reaction and Suzuki Coupling reaction,
which makes this kind of compounds good candidates to
serve as precursors for further synthetic transformations.
The potential applications and extension of the scope of
the methodology are currently under investigation in our
laboratory.
Acknowledgment
2-Methylthio-4-chloropyridine 2a (light yellow liquid): 1H
NMR (400 MHz, CDCl3, 25 °C): d = 2.56 (3 H, s, -SCH3),
6.98 (1 H, dd, PyH-5, J1 = 1.6 Hz, J2 = 5.6 Hz), 7.19 (1 H, d,
PyH-3, J = 1.6 Hz), 8.32 (1 H, d, PyH-6, J = 5.6 Hz). IR
(KBr, neat): 3046, 2924, 1564, 1541, 1453, 1356, 1150, 793,
689 cm–1. MS: m/z [M – 1]+ = 159.
Financial supports of this research by the NNSFC (20272008) and
the Key Project of Chinese Ministry of Education (03059) are
greatly acknowledged.
References
2-Ethylthio-4-chloropyridine 2b (light yellow liquid): 1H
NMR (500 MHz, CDCl3, 25 °C): 1.37 (3 H, t, CH3, J = 7.5
Hz), 3.16 (2 H, q, -SCH2, J = 7.5 Hz), 6.97 (1 H, dd, PyH-5,
J1 = 1.5 Hz, J2 = 5.5 Hz), 7.17 (1 H, d, PyH-3, J = 1.5 Hz),
8.31 (1 H, d, PyH-6, J = 5.5 Hz). IR (KBr, neat): 3049, 2968,
2926, 1566, 1540, 1452, 1355, 1150, 785, 693 cm–1. MS:
m/z [M – 1]+ = 173.
(1) (a) Comprehensive Heterocyclic Chemistry, Vol. 2;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
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(2) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605.
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ketenedithioacetals, see: (a) Dieter, R. K. Tetrahedron 1986,
42, 3029. (b) Junjappa, H.; Ila, H.; Asokan, C. V.
Tetrahedron 1990, 46, 5423.
(4) (a) Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J.
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M. J.; Ralli, P.; Theodoridis, G. J. Org. Chem. 1982, 47,
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(5) (a) Gupta, A. K.; Ila, H.; Junjappa, H. Tetrahedron 1990, 46,
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J. Chem. 1994, 71, 501.
2-Benzylthio-4-chloropyridine 2c (light yellow liquid): 1H
NMR (400 MHz, CDCl3, 25 °C): d = 4.43 (2 H, s, -SCH2),
6.99 (1 H, dd, PyH-5, J1 = 1.6 Hz, J2 = 5.6 Hz), 7.17 (1 H, d,
PyH-3, J = 1.6 Hz), 7.29 (5 H, m, PhH), 8.33 (1 H, d, PyH-
6, J = 5.6 Hz). IR (KBr, neat): 3031, 1678, 1563, 1539, 1452,
1357, 791, 696 cm–1.
2-Methylthio-4-bromopyridine 2a¢ (light yellow liquid): 1H
NMR (400 MHz, CDCl3, 25 °C): d = 2.55 (3 H, s, -SCH3),
7.13 (1 H, dd, PyH-5, J1 = 1.5 Hz, J2 = 5.5 Hz), 7.35 (1 H, d,
PyH-3, J = 1.5 Hz), 8.24 (1 H, d, PyH-6, J = 5.5 Hz). IR
(KBr, neat): 3039, 2924, 1557, 1537, 1452, 1351, 771, 678
cm–1.
2-Ethylthio-4-bromopyridine 2b¢ (light yellow liquid): 1H
NMR (500 MHz, CDCl3, 25 °C): d = 1.37 (3 H, t, CH3,
J = 7.5 Hz), 3.15 (2 H, q, -SCH2, J = 7.5 Hz), 7.12 (1 H, d,
(6) Wang, M.; Liu, Y.; Huang, Z. Tetrahedron Lett. 2001, 42,
2553.
Synlett 2004, No. 10, 1731–1734 © Thieme Stuttgart · New York

1734
S. Sun et al.
LETTER
PyH-5, J = 5.5 Hz), 7.33 (1 H, s, PyH-3), 8.22 (1 H, d, PyH-
6, J = 5.5 Hz). IR (KBr, neat): 3049, 2968, 2926, 1558, 1541,
1451, 1350, 1136, 769 cm–1.
2-Methylthio-3-(1-chlorovinyl)-4-chloropyridine 2g (light
yellow liquid): 1H NMR (400 MHz, CDCl3, 25 °C), 2.54 (3
H, s, -SCH3), 5.55 (1 H, s, =CH2), 5.89 (1 H, s, =CH2), 7.08
(1 H, d, PyH-5, J = 3.6 Hz), 8.30 (1 H, d, PyH-6, J = 3.6 Hz).
IR (KBr, neat): 3101, 3036, 2926, 1635, 1545, 1438, 904,
807, 693 cm–1.
2-Benzylthio-4-bromopyridine 2c¢ (light yellow liquid): 1H
NMR (500 MHz, CDCl3, 25 °C): d = 4.43 (2 H, s, -SCH2),
7.15 (1 H, d, PyH-5, J = 5.0 Hz), 7.30 (1 H, PyH-3), 7.38 (5
H, m, PhH), 8.26 (1 H, d, PyH-6, J = 5.0 Hz). IR (KBr, neat):
3060, 3029, 2947, 1591, 1545, 1509, 1447, 1355, 765, 697
cm–1. MS: m/z [M – 1]+ = 279 (281).
(14) (a) Liu, Q.; Zhu, Z.; Yang, Z.; Hu, Y.; Jing, F.; Xiao, Y.
Chem. J. Chin. Univ. 1993, 14, 1538. (b) Liu, Q.; Dong, D.;
Yang, Z.; Hu, Y.; Zhang, C. Chem. J. Chin. Univ. 1994, 15,
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(15) Jutz, C. Iminium Salts in Organic Chemistry, In Advances in
Organic Chemistry, Part 1, Vol.9; Taylor, E. C., Ed.; John
Wiley: New York, 1976, 225.
5-(methylthio)-1,6-naphthyridine 2f(light yellow liquid): 1H
NMR (400 MHz, CDCl3, 25 °C): d = 2.48 (3 H, s, -SCH3),
7.45 (2 H, m, NapyH-3, NapyH-8), 7.57 (1 H, m, NapyH-4),
7.97 (2 H, m, NapyH-4, NapyH-7). IR (KBr, neat): 2922,
2857, 1687, 1514, 1401, 771, 678 cm–1.
Synlett 2004, No. 10, 1731–1734 © Thieme Stuttgart · New York