Vilsmeier-Haack reactions of carbonyl compounds: Synthesis of substituted pyrones and pyridines

Article abstract of DOI:10.1016/j.tet.2004.04.017

Vilsmeier-Haack reaction of substituted phenylacetones leads to the formation of conjugated iminium salts which on aqueous basic work up afford 3-formyl-4-pyrones and on ammonium acetate-induced cyclization afford 5-aryl-4-chloronicotinaldehydes in good y

Full text of DOI:10.1016/j.tet.2004.04.017

Tetrahedron 60 (2004) 5069–5076
Vilsmeier–Haack reactions of carbonyl compounds:
synthesis of substituted pyrones and pyridines
*
Ajith Dain Thomas, Josemin and C. V. Asokan
School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam 686560, India
Received 9 January 2003; revised 18 March 2004; accepted 8 April 2004
Abstract—Vilsmeier–Haack reaction of substituted phenylacetones leads to the formation of conjugated iminium salts which on aqueous
basic work up afford 3-formyl-4-pyrones and on ammonium acetate-induced cyclization afford 5-aryl-4-chloronicotinaldehydes in good
yields.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
having two enolizable sp2 or sp3 hybridized carbons
adjacent to the carbonyl group, and the cyclization reactions
of the resulting iminoalkylated intermediates to substituted
pyrones and pyridines.15
The Vilsmeier–Haack reaction is a widely used method for
the formylation of activated aromatic and heteroaromatic
compounds.1,2 The reactions of aliphatic substrates,3
particularly carbonyl compounds4 with chloromethylene-
iminium salts are highly versatile. They lead to multiple
iminoalkylations in the presence of excess reagent and the
resulting intermediates undergo cyclization to afford
aromatic or heterocyclic compounds.5,6 Multifunctional
intermediates derived from these reactions (e.g., b-chloro-
enaldehydes) are subsequently exploited for the synthesis of
functionalized heterocycles or other valuable target
molecules.7,8 Dibenzyl ketone on treatment with chloro-
methyleneiminium salt undergo multiple iminoalkylations
followed by cyclization to afford 3,5-diphenyl-4H-pyran-4-
one.9,10 The reaction of o-hydroxyacetophenones with
Vilsmeier-reagent also involve an iminoalkylation cycliza-
tion sequence, leading to the formation of 3-formyl
chromones.11–14
One of the general methods for the preparation of 4-pyrones
involve cyclization of 1,3-dicarbonyl compounds obtained
either by the addition of acyl ketenedithioacetals,16
enamines17 or enol ethers18 to carboxylates or acid chlorides
or by the addition of enamines to diketene.19 Another
approach towards the synthesis of 4-pyrones, particularly
those having substituents at 2 and 6 positions, involve
cyclization of 1,3,5-tricarbonyl compounds.20–22 We have
shown earlier that epoxidation of alkenoyl ketenedithio-
acetals followed by Lewis acid catalyzed rearrangement and
cyclization leads to 2,5-disubstituted-4-pyrones.23
When benzyl methyl ketone was treated with 3 equiv. of the
Vilsmeier–Haack reagent, prepared from DMF and POCl3,
for 72 h in DMF, 4-oxo-5-phenyl-4H-pyran-3-carbaldehyde
2a was obtained in 59% yield (Scheme 1). Other substituted
aryl acetones 1b-c also reacted similarly to afford respective
3-formyl pyrones 2b-c. We have recently shown that
treatment of the multiple iminoalkylated intermediates
derived from tertiary alcohols readily undergo cyclization
in the presence of ammonium acetate to afford substituted
pyridines.24,25 We have therefore examined the reactivity of
the intermediate iminium salt derived from aryl acetones
towards similar cyclization. The reaction mixture after
treatment of aryl acetones 1a and 1c with chloromethylene-
iminium salt for 48 h at room temperature was cooled to
0–5 8C, and 40 equiv. of ammonium acetate was added and
stirred for another 30 min, to afford the 5-aryl-4-chloro
nicotinaldehydes 3a-b.
We envisaged that methyl ketones having an additional
enolizable methylene group at the a0 position should
undergo multiple iminoalkylations on treatment with
chloromethyleneiminium salt and the resultant intermediate
on hydrolysis with saturated aq. potassium carbonate and
subsequent cyclization should afford a-formyl-4-pyrones.
Alternatively, cyclization of the multiple iminoalkylated
intermediate induced by ammonium acetate prior to the
work up would afford substituted pyridines. In this paper,
we describe the reactions of some carbonyl compounds
Keywords:
Iminoalkylations; Iminium salts; Aryl acetones.
Pyridines; Pyrones;
Vilsmeier–Haack reagents;
*
Corresponding author. Tel.: þ91-481-598015; fax: þ91-481-594432;
Enolization of aryl acetones promoted in the presence of a
e-mail address: asokancv@yahoo.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.017

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Scheme 1. Reagents and conditions: (i) DMF/POCl3 (3 equiv.), 72 h, rt; (ii) DMF/POCl3 (4 equiv.), 48 h, rt; (iii) NH4OAc, 0 8C, 30 min.
small amount of HCl followed by the addition of the enol to
chloromethyleneiminium salt leads to the formation of the
enaminoketone 6. Sequential addition of this enamino-
ketone to 2 mol of chloromethyleneiminium salt results in
the formation of the bis-iminium salt 8. Hydrolysis of 8
should lead to the formation of the pentadienaldehyde 9
which undergo addition of a molecule of water followed by
ring closure to afford an intermediate pyran 10. Loss of HCl
and dimethyl amine from 10 should lead to the formation of
pyran-4-one 2. Alternatively, cyclization of the intermediate
bis-iminium salt 8 induced by ammonium acetate would
give the iminium salt 11 which on aqueous work-up afford
the substituted nicotinaldehydes 3 (Scheme 2).
Treatment of benzyl ethyl ketone 13 with the Vilsmeier–
Haack reagent followed by hydrolysis gave the expected
3-methyl-5-phenyl-4H-pyran-4-one 12 in 63% yield.
Alternatively, treatment of 13 with chloromethylene-
iminium salt followed by ammonium acetate induced
cyclization gave 4-chloro-3-methyl-5-phenylpyridine 14 in
62% yield (Scheme 3).
The formation of 3,5-diphenyl-4H-pyran-4-one from
dibenzyl ketone on treatment with Vilsmeier reagent has
been reported in the literature.9,10 However, under our
reaction conditions 3,5-bis(dimethylamino)-2,4-diphenyl-
2,4-pentadienal 18 was formed as the only product in high
Scheme 2.
Scheme 3. Reagents and conditions: (i) DMF/POCl3 (3 equiv.), 72 h, rt; (ii) DMF/POCl3 (4 equiv.), 48 h, rt; (iii) NH4OAc, 0 8C, 30 min.

A. D. Thomas et al. / Tetrahedron 60 (2004) 5069–5076
5071
Scheme 4. Reagents and conditions: (i) DMF/POCl3 (3 equiv.), 72 h, rt; (ii) DMF/POCl3 (4 equiv.), 48 h, rt; (iii) NH4OAc, 0 8C, 30 min.
yield. It is interesting to note the introduction of N,N-
dimethylamino substituent at the 3-position. Apparently,
cyclization to the expected 4-pyrone is not favored by the
presence of the dimethylamino group at the 3-position.
However, the iminium salt 17 did undergo cyclization in the
presence of ammonium acetate to afford 3,5-diphenyl-4-
(N,N-dimethylamino)pyridine 19 (Scheme 4).
The reaction of benzylacetone 28 with Vilsmeier–Haack
reagent under these conditions gave an unexpected product,
5-benzyl-4-hydroxy-6-(phenylethyl)isophthalaldehyde 33
in low yield among other unidentified products. The
substituted phenol 33 must have resulted from the reaction
of the a,b-unsaturated ketone 29, which is the aldol type
self-condensation product of benzylacetone, with chloro-
methyleneiminium salt. The bisiminium salt 30 formed by
the multiple iminoalkylation of this ketone undergo
cyclization and elimination of dimethylamine to afford the
iminium salt 32 which on basic hydrolysis leads to the
formation of 33 (Scheme 7). Similar cyclizations involving
a,b-unsaturated ketones such as mesityloxide have been
reported earlier.27,28
In a related experiment the dithioketal 20, derived from the
dibenzyl ketone 15 and butanethiol,26 was subjected to
Vilsmeier–Haack reaction in the presence of 3 equiv. of
reagent prepared from POCl3 and DMF for 16 h at room
temperature. Subsequent basic hydrolysis gave 3,5-
diphenyl-4H-pyran-4-one 23 in 50% yield. Obviously, 23
has been formed by the cyclization of the intermediate
butylthio substituted pentadienaldehyde 22 (Scheme 5).
There are several approaches to the synthesis of 4-pyrones
starting from but-3-ene-2-ones having an amino or alkoxy
substituent at the 4-position.17,29 The acyl ketenedithio-
acetals have alkylthio substituents at the b-position making
them suitable candidates for the synthesis of 4-pyrones.16
Against this background we have attempted to employ the
Vilsmeier–Haack protocol for the synthesis of 4-pyrones
starting from some substituted acyl ketenedithioacetals.
Phenoxyacetone 24 on treatment with Vilsmeier–Haack
reagent followed by saturated aq. potassium carbonate gave
2[1-chloro-3-(dimethylamino)-2-phenoxy-2-propenyl-
idene] malonaldehyde 26 as a pale yellow crystalline solid
in 72% yield (Scheme 6). The fact that pentadienaldehyde
26, formed by the hydrolysis of the bisiminium salt 25,
did not undergo further cyclization to give the expected
3-formyl pyrone 27 may be attributed to the reduced
electrophilicity of C5 of the pentadienaldehyde 26 due to the
presence of the phenoxy substituent at C4.
The ketenedithioacetal 36a which was prepared from
phenylacetone was allowed to react with 3 equiv. of
Vilsmeier reagent for 72 h at room temperature. After the
Scheme 5. Reagents and conditions: (i) BuSH, TiCl4, CHCl3; (ii) DMF/POCl3 (3 equiv.), 16 h, rt; (iii) 2OH/H2O.

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A. D. Thomas et al. / Tetrahedron 60 (2004) 5069–5076
Scheme 6. Reagents and conditions: (i) DMF/POCl3 (3 equiv.), 72 h, rt; (ii) 2OH/H2O.
Scheme 7. Reagents and conditions: (i) DMF/POCl3 (3 equiv.), 72 h, rt; (ii) 2OH/H2O.
usual alkaline work up the S1-methyl 3-chloro-5-(methyl-
sulfanyl)-4-phenyl-2,4-pentadienethioate 37a was isolated
in 70% yield. Similarly p-methoxyphenyl substituted acyl
ketenedithioacetal afforded the corresponding thiol ester
37b (Scheme 8).
the carbonyl group from the ketenedithioacetal moiety. This
favors enolization of the ketenedithioacetal 36 which is
essential for the formation of iminium salt 38. An
intramolecular attack of the methylthio group to the
iminium moiety results in the migration of the methylthio
group which eventually lead to the formation of the iminium
salt 41 which on hydrolysis gives the thiol ester 37.
A plausible mechanism involving a 1,5-methylthio
migration for the formation of the thiol ester 37 is depicted
in Scheme 9. The initial iminoalkylation of the ketene-
dithioacetal leads to the formation of the iminium salt 38.
The presence of aryl substituent at the a-position of the
ketenedithioacetal reduces the extent of delocalization of
Treatment of the product mixture obtained by the addition
of Vilsmeier reagent to the acyl ketenedithioacetal 36a with
excess ammonium acetate prior to the basic hydrolysis gave
4-chloro-2-(methylsulfanyl)-3-phenylpyridine 42 in 64%
yield (Scheme 10). It is important to note that substituted
nicotinaldehyde was not formed when ketenedithioacetal
36a was used as the starting substrate, instead of
phenylacetone. This could be attributed to the higher
selectivity of ketenedithioacetals towards iminoalkylation
compared to the corresponding enaminoketones which are
the proposed intermediates involved in the direct reaction of
ketones with chloromethyleneiminium salt.
Scheme 8. Reagents and conditions: (i) DMF/POCl3 (3 equiv.), 72 h, rt; (ii)
2OH/H2O.
In summary, we have shown that the Vilsmeier–Haack

A. D. Thomas et al. / Tetrahedron 60 (2004) 5069–5076
5073
Scheme 9.
Scheme 10. Reagents and conditions: (i) DMF/POCl3 (3 equiv.), 72 h, rt; (ii) NH4OAc, 0 8C, 30 min.
reactions of substituted phenylacetones followed by treat-
ment with aq. K2CO3 or anhydrous NH4OAc lead to the
formation of 3-formyl-4-pyrones and 5-aryl-4-chloro-
nicotinaldehydes, respectively, in good yields. The
formation of 3-methyl-5-phenyl-4H-pyran-4-one and
4-chloro-3-methyl-5-phenylpyridine were observed in the
case of benzyl ethyl ketone. However, other aliphatic
ketones on treatment with the Vilsmeier reagent gave rather
complex product mixtures. The reaction of phenoxyacetone
and dibenzyl ketone did undergo multiple iminoalkylations
under these conditions, but failed to give the expected
pyran-4-one derivatives. But when the reaction was carried
out using dibenzyl ketone followed by treatment with
ammonium acetate 3,5-diphenyl-4-(N,N-dimethylamino)-
pyridine was obtained instead of the corresponding
chlorosubstituted pyridine. Nevertheless, the dithioketal of
dibenzyl ketone gave 3,5-diphenyl-4H-pyran-4-one. We have
also carried out some reactions on substituted ketenedithio-
acetals expecting the formation of substituted pyran-4-ones.
Though the substituted ketenedithioacetals underwent
Vilsmeier reaction smoothly, the product obtained were the
substituted conjugated pentadiene thioicacid S-methyl esters
on usual alkaline workup. However, on treatment with the
Vilsmeier reagent followed by ammonium acetate, acyl
ketenedithioacetal derived from phenylacetone afforded
4-chloro-2-(methylsulfanyl)-3-phenylpyridine.
Buchi-530 melting point apparatus. IR spectra were
recorded on a Shimadzu IR-470 spectrometer. NMR spectra
were recorded in deutereochloroform (internal standard
TMS) on JEOL EX90 or Bruker WM200 or Bruker WM300
spectrometers; 1H spectra at 90 or 200 or 300 MHz and 13
C
spectra at 22.4 or 50.3 or 75.5 MHz, respectively, and
coupling constants are given in Hz. Electron impact mass
spectra were obtained on a Finnigan-MAT 312 spec-
trometer. Solvents were dried and distilled before use:
N,N-dimethylformamide from P2O5·CHCl3 from anhydrous
CaCl2. Organic extracts were dried over anhydrous Na2SO4.
2.1.1. 4-Oxo-5-phenyl-4H-pyran-3-carbaldehyde (2a).
Vilsmeier reagent was prepared by mixing ice-cold, dry
DMF (50 mL) and POCl3 (2.8 mL, 30 mmol). The mixture
was then stirred for 15 min at room temperature. 1-Phenyl-
acetone 1a (1.34 g, 10 mmol) was dissolved in dry DMF
(5 mL) and added over about 15 min at 0–5 8C. The
reaction mixture was stirred for 72 h at room temperature.
The mixture was then added to cold, saturated aq. K2CO3
(200 mL) and extracted with diethyl ether (3£50 mL). The
organic layer was washed with water, dried over anhydrous
Na2SO4, and evaporated to afford the crude product, which
was column chromatographed over silica gel using hexane/
ethyl acetate (9:1) as eluent to give the title compound 2a
(1.1 g, 59%), as a colorless crystalline solid, mp 148–
149 8C. [Found: C, 71.92; H, 3.96. C12H8O3 requires C,
72.0; H, 4.03%]; nmax(KBr) 3020, 1700, (CvO), 1640,
(CvO), 1540, 1320, 1270, 1010 cm21; 1H NMR (90 MHz,
CDCl3): d 7.10–7.80 (5H, m, arom. H), 7.90 (1H, s,
vinylic), 8.40 (1H, s, vinylic), 10.35 (1H, s, CHO); 13C
NMR (22.64 MHz, CDCl3): d 124.32, 128.50, 129.00,
129.60, 132.55, 152.87, 159.20 (arom. and vinylic), 175.21
2. Experimental
2.1. General
Melting points are uncorrected and were obtained on a

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A. D. Thomas et al. / Tetrahedron 60 (2004) 5069–5076
(CvO), 188.70 (CvO); EI-MS m/z: 200 (Mþ), 172 (100%),
115 (50%), 102 (22%), 89 (11%).
(64%), 198 (41%), 187 (33%), 152 (29%), 125 (53%), 77
(18%).
2.1.2. 5-(2-Methoxyphenyl)-4-oxo-4H-pyran-3-carbalde-
hyde (2b). The title compound 2b (1.1 g, 59%) a pale
yellow crystalline solid, mp 127–129 8C was obtained by
the same procedure as 2a except using 1-(2-methoxy-
phenyl)acetone 1b (1.64 g, 10 mmol) instead of 1a. [Found:
C, 67.75; H, 4.27. C13H10O4 requires C, 67.82; H, 4.38%];
2.1.5. 4-Chloro-5-(4-methoxyphenyl)nicotinaldehyde
(3b). The title compound 3b (1.57 g, 34%, a white solid,
mp 94–96 8C) was obtained by the same procedure as 3a
except using 1-(4-methoxyphenyl)acetone 1c (1.64 g,
10 mmol) instead of 1a. [Found: C, 62.91; H, 3.93; N,
5.57. C13H10ClNO2 requires C, 63.04; H, 4.07; N, 5.66%];
n
max(KBr) 3015, 1685 (CvO), 1640 (CvO), 1600, 1540,
1485, 1455, 1305, 1285, 1260, 1240, 1080, 1020,
1005 cm21 1H NMR (90 MHz, CDCl3) d 3.80 (3H, s,
nmax(KBr) 1685, 1610, 1550, 1510, 1430, 1380, 1295, 1250,
1180, 1025 cm21; H NMR (300 MHz, CDCl3) d 3.89 (s,
3H, OCH3); 7.04 (d, 2H, J¼8 Hz, arom.); 7.39 (, d, 2H,
J¼8 Hz, arom.); 8.64 (1H, s, Py 6-H); 9.17 (1H, s, Py 2-H);
10.59 (1H, s, CHO); EI-MS m/z: 249 (Mþþ2, 3%), 248
(Mþþ1, 33%), 247 (Mþ, 10%) 246 (100%, Mþ21), 228
(83%), 140 (17%), 112 (18%).
1
;
OCH3); 6.90–7.60 (4H, m, arom. H); 7.90 (1H, s, vinylic);
8.40 (1H, s, vinylic); 10.35 (1H, s, CHO); 13C NMR
(22.64 MHz, CDCl3) d 55.64 (OCH3), 111.28, 118.74,
120.56, 124.17, 130.41, 130.52, 131.12, 154.30, 157.14,
159.17 (arom. and vinylic), 175.10 (CvO), 189.09 (CvO);
EI-MS m/z: 230 (10%, Mþ), 216 (20%), 202 (90%), 185
(21%), 159 (11%), 131 (66%), 115 (19%), 97 (18%), 85
(53%), 71 (56%).
2.1.6. 3-Methyl-5-phenyl-4H-pyran-4-one (12). The title
compound 12 (1.45 g, 63%, a colorless crystalline solid, mp
90–92 8C) was obtained by the same procedure as 2a except
using 1-phenyl-2-butanone (1.48 g, 10 mmol) instead of 1a.
[Found: C, 77.36; H, 5.38. C12H10O2 requires C, 77.40; H,
5.41%]; nmax(KBr) 3010, 1640, 1610, 1490, 1410, 1330,
1290, 1040, 1000 cm21; 1H NMR (200 MHz, CDCl3) d 2.0
(3H, s, CH3); 7.2–7.9 (7H, m, arom. and vinylic); 13C NMR
d (50.3 MHz, CDCl3) 11.24 (CH3), 126.28, 128.30, 128.41,
128.62, 128.80, 131.49, 151.24, 152.94 (arom. and vinylic),
177.50 (CvO); EI-MS m/z: 186 (100%, Mþ), 129 (12%),
102 (84%), 89 (24%), 76 (19%).
2.1.3. 5-(4-Methoxyphenyl)-4-oxo-4H-pyran-3-carbalde-
hyde (2c). The title compound 2c (1.61 g, 70%) a pale
yellow crystalline solid, mp 153–154 8C was obtained by
the same procedure as 2a except using 1-(4-methoxy-
phenyl)acetone 1c (1.64 g, 10 mmol) instead of 1a. [Found:
C, 67.76; H, 4.29. C13H10O4 requires C, 67.82; H, 4.38%];
n
max(KBr) 3060, 1685, (CvO), 1630, (CvO), 1600, 1535,
1500, 1350, 1320, 1290, 1275, 1250, 1180, 1100, 1030,
1015, 1005 cm21; 1H NMR (90 MHz, CDCl3) d 3.8 (3H, s,
OCH3); 6.95 (2H, d, J¼8 Hz, arom. H); 7.45 (2H, d,
J¼8 Hz, arom. H); 7.85 (1H, s, vinylic); 8.35 (1H, s,
vinylic), 10.35 (1H, s, CHO); 13C NMR (22.64 MHz,
CDCl3) d 55.16 (OCH3), 114.00, 121.78, 124.17, 129.72,
132.14, 152.18, 159.05 (arom. and vinylic), 160.24, 175.10
(CvO), 188.82 (CvO); EI-MS m/z: 230 (48%, Mþ), 202
(100%), 187 (21%), 159 (15%), 145 (13%), 132 (17%), 117
(12%), 89 (19%).
2.1.7.
4-Chloro-3-methyl-5-phenylpyridine
(14).
Vilsmeier reagent was prepared by mixing ice-cold, dry
DMF (50 mL) and POCl3 (3.7 mL, 40 mmol). The mixture
was then stirred for 15 min at room temperature. 1-Phenyl-
2-butanone (1.48 g, 10 mmol) was dissolved in dry DMF
(5 mL) and added over 15 min at 0–5 8C. The reaction
mixture was stirred for 48 h at room temperature. It was then
cooled to 0–5 8C in an ice bath and excess solid ammonium
acetate (40 equiv., 31 g) was slowly added to the reaction
mixture and stirred for another 30 min. The mixture was
then added to cold, saturated aq. K2CO3 (200 mL) and
extracted with diethyl ether (3£50 mL). The organic layer
was washed with water, dried over anhydrous Na2SO4, and
evaporated to afford the crude product, which was column
chromatographed over silica gel using hexane/ethyl
acetate (19:1) as eluent to give the title compound 14
(1.27 g, 62%) a brown viscous oil. [Found: C, 70.65; H,
4.88; N, 6.79. C12H10ClN requires C, 70.77; H, 4.95; N,
6.88%]; nmax(neat) 1550, 1450, 1400, 1270, 1230, 1170,
2.1.4. 4-Chloro-5-phenylnicotinaldehyde (3a). Vilsmeier
reagent was prepared by mixing ice-cold, dry DMF (50 mL)
and POCl3 (3.7 mL, 40 mmol). The mixture was then stirred
for 15 min at room temperature. 1-Phenylacetone 1a
(1.34 g, 10 mmol) was dissolved in dry DMF (5 mL) and
added over about 15 min at 0–5 8C. The reaction mixture
was stirred for 48 h at room temperature and was cooled to
0–5 8C in an ice bath and excess solid ammonium acetate
(40 equiv., 31 g) was slowly added to the reaction
mixture and stirred for another 30 min. The mixture was
then added to cold, saturated aq. K2CO3 (200 mL) and the
white precipitate formed was filtered and dried. It was
further purified by column chromatography over
silicagel using hexane/ethylacetate (19:1) as eluent to give
the title compound 3a (1.74 g, 40%) as a white crystalline
solid, mp 81–83 8C. [Found: C, 66.14; H, 3.68; N,
6.36. C12H8ClNO requires C, 66.22; H, 3.70; N, 6.44%];
1
1070 cm21; H NMR (300 MHz, CDCl3) d 2.45 (3H, s,
CH3), 7.39–7.44 (5H, m, arom.), 8.37 (1H, s, Py 6-H), 8.62
(1H, s, Py 2-H); 13C NMR (75.48 MHz, CDCl3) d 17.91
(CH3), 128.68, 128.73, 129.93, 130.01, 136.34, 142.97,
149.01; 149.11, 150.12; EI-MS m/z: 205 (Mþþ2, 8%), 204
(Mþþ1, 33%), 203 (Mþ, 25%) 202 (100%, Mþ21), 201
(24%), 185 (46%), 167 (54%), 141 (41%), 115 (45%).
n
max(KBr) 1690, 1550, 1430, 1380, 1305, 1260, 1070 cm21
;
1H NMR (300 MHz, CDCl3) d 7.27–7.50 (5H, m, arom.);
8.72 (1H, s, Py 6-H); 9.02 (1H, s, Py 2-H); 10.59 (1H, s,
CHO); 13C NMR (75.48 MHz, CDCl3) d 127.87, 128.60,
128.92, 129.48, 134.14, 137.40, 144.90, 149.63, 155.20
(arom.), 189.06 (CHO); EI-MS m/z: 219 (Mþþ2, 10%), 218
(Mþþ1, 33%), 217 (Mþ, 30%) 216 (100%, Mþ21), 215
2.1.8. 3,5-Bis(dimethylamino)-2,4-diphenyl-2,4-penta-
dienal (18). To the Vilsmeier reagent prepared from
POCl3 (2.8 mL, 30 mmol) and dry DMF (50 mL) 1,3-
diphenylacetone (2.1 g, 10 mmol) was added in dry DMF
(5 mL) at 0–5 8C and the reaction mixture was stirred at
room temperature for 72 h. It was then worked up using

A. D. Thomas et al. / Tetrahedron 60 (2004) 5069–5076
5075
cold, saturated aq. K2CO3 (200 mL) and extracted with
diethyl ether (3£50 mL). The organic layer was washed
with water, dried over anhydrous Na2SO4, and evaporated to
afford the yellow crystals of the product, which was
recrystallized from benzene to give the title compound 18
(2.56 g, 80%) a yellow crystalline solid, mp 140–142 8C.
[Found: C, 78.68; H, 7.47; N, 8.63. C21H24N2O requires C,
78.72; H, 7.55; N, 8.74%]; nmax(KBr) 2900, 1620 (CvO),
1580, 1380, 1285, 1085 cm21; 1H NMR (90 MHz, CDCl3) d
2.4 (6H, s, N(CH3)2), 2.8 (6H, s, N(CH3)2), 6.8 (1H, s,
vinylic), 7.0–7.5 (10H, m, arom.), 9.1 (1H, s, CHO); 13C
NMR (22.4 MHz, CDCl3) d 43.08 (CH3), 43.50 (CH3),
108.48, 121.22, 124.53, 125.30, 125.72, 127.51, 127.72,
128.29, 129.27, 129.96, 138.46, 138.70, 151.86, 173.84
(vinylic and arom.) 186.64 (CHO); EI-MS m/z: 320 (Mþ,
35%), 303 (13%), 276 (54%), 202 (19%), 178 (11%), 145
(73%), 103 (21%), 89 (23%), 72 (98%).
which was recrystallized from benzene to give the title
compound 26 (2 g, 72%) a pale yellow crystalline solid, mp
161–162 8C. [Found: C, 60.10; H, 4.92; N, 4.93.
C14H14ClNO3 requires C, 60.11; H, 5.04; N, 5.01%];
n
max(KBr) 2980, 2700, 1720, 1680, 1580, 1480, 1400,
;
1260, 1250, 1210, 1180, 1130, 1010 cm21 1H NMR
(300 MHz, CDCl3) d 3.25 (6H, s, N(CH3)2); 6.95–7.35
(6H, m, arom. and vinylic); 9.05 (1H, s, CHO), 9.45 (1H, s,
CHO); 13C NMR (75.48 MHz, CDCl3) d 39.81 (CH3), 47.59
(CH3), 115.21, 122.15, 129.66, 135.31, 147.51, 156.28,
160.11 (arom. and vinylic), 184.37 (CHO), 185.75 (CHO);
EI-MS m/z: 281 (Mþþ2, 3) 279 (Mþ, 12%), 278 (68%), 249
(27%), 186 (100%), 157 (38%), 94 (34%), 77 (56%).
2.1.12. 5-Benzyl-4-hydroxy-6-(phenylethyl)isophthal-
aldehyde (33). To the Vilsmeier reagent prepared from
POCl3 (2.8 mL, 30 mmol) and dry DMF (50 mL) 4-phenyl-
2-butanone (1.48 g, 10 mmol) was added in dry DMF
(5 mL) at 0–5 8C and the reaction mixture was stirred at
room temperature for 72 h. It was then worked up using
cold, saturated aq. K2CO3 (200 mL) and extracted with
diethyl ether (3£50 mL). The organic layer was washed
with water, dried over anhydrous Na2SO4, and column
chromatographed using hexane/ethyl acetate (9:1) as eluent
to give the title compound 33 (0.53 g, 31%) a colorless
crystalline solid. [Found: C, 80.14; H, 5.79. C23H20O3
requires C, 80.21; H, 5.85%]; nmax(KBr) 1680, 1620, 1580,
1480, 1400, 1365, 1265, 1245, 1200, 1180, 1165, 1125,
2.1.9. 3,5-Diphenyl-4-(N,N-dimethylamino)pyridine (19).
To the Vilsmeier reagent prepared from POCl3 (3.7 mL,
40 mmol) and dry DMF (50 mL) 1,3-diphenylacetone
(2.1 g, 10 mmol) was added in dry DMF (5 mL) at 0–5 8C
and the reaction mixture was stirred at room temperature for
48 h. It was then cooled to 0–5 8C in ice and excess solid
ammonium acetate (40 equiv., 31 g) was slowly added to
the reaction mixture and stired for 30 min more. The
mixture was then added to cold, saturated aq. K2CO3
(200 mL) and extracted with diethyl ether (3£50 mL). The
organic layer was washed with water, dried over anhydrous
Na2SO4, and evaporated to afford the product, which was
column chromatographed over silicagel using hexane/
ethylacetate (19:1) as eluent to give the title compound 19
(1.75 g, 62%) a brown viscous oil. [Found: C, 83.13; H,
6.57; N, 10.14. C19H18N2 requires C, 83.18; H, 6.61; N,
10.21%]; nmax(neat) 1580, 1510, 1435, 1420, 1310, 1230,
1135, 1070 cm21; 1H NMR (300 MHz, CDCl3) d 2.24 (6H,
s, N(CH3)2), 7.25–7.33 (10H, m, arom.), 8.19 (2H, s, Py,
2-H and 6-H); EI-MS m/z: 274 (100%, Mþ), 273 (82%), 271
(21%), 259 (36%), 105 (59%), 91 (26%), 77 (30%).
1
1000 cm21; H NMR (200 MHz, CDCl3) d 3.03 (2H, t,
J¼7 Hz, CH2), 3.20 (2H, t, J¼7 Hz, CH2), 4.03 (2H, s,
CH2), 7.23–7.25 (10H, m, arom.), 7.99 (1H, m, OH), 8.06
(1H, m, arom.), 9.91 (1H, s, CHO), 11.73 (1H, s, CHO); 13C
NMR (50.3 MHz, CDCl3) d 30.29, 34.99, 40.15 (CH2),
119.76, 126.29, 126.52, 128.46, 128.62, 128.64, 128.90,
129.11, 130.83, 132.93, 136.77, 139.19, 141.10, 163.27
(arom. and vinylic), 196.52, 196.78 (CHO); EI-MS m/z: 344
(44%, Mþ), 239 (100%), 161 (28%), 91 (32%).
2.1.13. S1-Methyl 3-chloro-5-(methylsulfanyl)-4-phenyl-
2,4-pentadienethioate (37a). To the Vilsmeier reagent
prepared from POCl3 (2.8 mL, 30 mmol) and dry DMF
(50 mL) 4,4-bis(methylsulfanyl)-3-phenyl-3-buten-2-one
36a (2.38 g, 10 mmol) was added in dry DMF (5 mL) at
0–5 8C and the reaction mixture was stirred at room
temperature for 72 h. It was then worked up using cold,
saturated aq. K2CO3 (200 mL) and extracted with diethyl
ether (3£50 mL). The organic layer was washed with water,
dried over anhydrous Na2SO4, and column chromato-
graphed over silica gel using hexane/ethyl acetate (9:1) as
eluent to give the title compound 37a (1.98 g, 70%) a yellow
crystalline solid, mp 97–98 8C. [Found: C, 54.78; H, 4.57.
C13H13ClOS2 requires C, 54.82; H, 4.60%]; nmax(KBr) 1636
(CvO), 1555, 1520, 1480, 1430, 1310, 1260, 1220, 1080,
2.1.10. 3,5-Diphenyl-4H-pyran-4-one (23). To the
Vilsmeier reagent prepared from POCl3 (2.8 mL,
30 mmol) and dry DMF (50 mL) dithioketal of 1,3-
diphenylacetone (3.7 g, 10 mmol) was added in dry DMF
(5 mL) at 0–5 8C and the reaction mixture was stirred at
room temperature for 72 h. It was then worked up using
cold, saturated aq. K2CO3 (200 mL) and extracted with
diethyl ether (3£50 mL). The organic layer was washed with
water, dried over anhydrous Na2SO4, and column chromato-
graphed over silica gel using hexane/ethyl acetate (9:1) as
eluent to give the title compound 23. (1.3 g, 50%) a colorless
crystalline solid, mp 185–186 8C (lit.,10 186–187 8C).
1
2.1.11. 2-[1-Chloro-3-(dimethylamino)-2-phenoxy-2-
propenylidene]malonaldehyde (26). To the Vilsmeier
reagent prepared from POCl3 (2.8 mL, 30 mmol) and dry
DMF (50 mL) 1-phenoxyacetone (1.5 g, 10 mmol) was
added in dry DMF (5 mL) at 0–5 8C and the reaction
mixture was stirred at room temperature for 72 h. It was then
worked up using cold, saturated aq. K2CO3 (200 mL) and
extracted with diethyl ether (3£50 mL). The organic layer
was washed with water, dried over anhydrous Na2SO4, and
evaporated to afford the yellow crystals of the product,
1045, 1025, 920, 845 cm21; H NMR (90 MHz, CDCl3) d
2.2 (3H, s, SCH3), 2.4 (3H, s, SCH3), 7.0–7.8 (7H, m, arom.
and vinylic); 13C NMR (22.64 MHz, CDCl3) d 13.21
(SCH3), 14.88 (SCH3), 118.74, 127.96, 128.44, 130.79,
131.63, 136.43, 140.61, 141.21 (arom. and vinylic), 191.42
(CvO); EI-MS m/z: 284 (2%, Mþ), 237 (100%), 189
(20%), 174 (46%), 115 (22%).
2.1.14. S1-Methyl 3-chloro-4-(4-methoxyphenyl)-5-
(methyl-sulfanyl)-2,4-pentadienethioate (37b). The title

5076
A. D. Thomas et al. / Tetrahedron 60 (2004) 5069–5076
compound 37b (2.24 g, 71%) a yellow crystalline solid, mp
97–99 8C was obtained by the same procedure as 37a
except using 3-(4-methoxyphenyl)-4,4-bis(methylsulfanyl)-
3-buten-2-one 36b (2.68 g, 10 mmol) instead of 36a.
[Found: C, 53.38; H, 4.76. C14H15ClO2S2 requires C,
53.41; H, 4.8%]; nmax(KBr) 2900, 1630 (CvO), 1600,
References and notes
1. Jutz, C. Adv. Org. Chem. 1976, 9, 225–342.
2. Seshadri, S. J. Sci. Ind. Res. 1973, 32, 128–149.
3. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–659.
4. Marson, C. M. Tetrahedron 1992, 48, 3659–3726.
5. Meth-Cohn, O. Heterocycles 1993, 35, 539–557.
6. Perumal, P. T. Indian J. Heterocyl. Chem. 2001, 11, 1–8.
7. Abramov, M. A.; Dehaen, W. Synthesis 2000, 1529–1531.
8. Smeets, S.; Asokan, C. V.; Motmans, F.; Dehaen, W. J. Org.
Chem. 2000, 65, 5882–5885.
1555, 1525, 1490, 1290, 1240, 1170, 1050, 1030, 925 cm21
;
1H NMR (90 MHz, CDCl3) d 2.2 (3H, s, SCH3), 2.4 (3H, s,
SCH3), 3.85 (3H, s, OCH3), 6.8–7.6 (6H, m, arom. and
vinylic); 13C NMR (22.64 MHz, CDCl3) d 13.27 (SCH3),
14.85 (SCH3), 55.01 (OCH3), 113.37, 118.83, 128.53,
130.41, 131.36, 132.11, 140.49, 140.82, 159.67 (arom. and
vinylic), 191.89 (CvO); EI-MS m/z: 316 (2%, Mþþ2), 314
(6%, Mþ), 313 (14%), 266 (100%), 238 (17%), 223 (21%),
203 (78%), 188 (32%), 180 (18%), 160 (15%), 145 (45%).
9. Weissenfels, M.; Pulst, M.; Schneider, P. Z. Chem. 1973, 13,
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10. Fischer, G. W.; Schroth, W. Chem. Ber. 1969, 102, 590–602.
11. Sabitha, G. Aldrichim. Acta 1996, 29, 13–25.
12. Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron Lett. 1973,
22, 1995–1998.
2.1.15. 4-Chloro-2-(methylsulfanyl)-3-phenylpyridine
(42). To the Vilsmeier reagent prepared from POCl3
(2.8 mL, 30 mmol) and dry DMF (50 mL) 4,4-bis(methyl-
sulfanyl)-3-phenyl-3-buten-2-one 36a (2.38 g, 10 mmol)
was added in dry DMF (5 mL) at 0–5 8C and the reaction
mixture was stirred at room temperature for 72 h. It was then
cooled to 0–5 8C in ice and solid ammonium acetate
(40 equiv., 31 g) was slowly added to the reaction mixture
in excess and stirred 30 min more. The reaction mixture was
then worked up using cold, saturated aq. K2CO3 (200 mL)
and extracted with diethyl ether (3£50 mL). The organic
layer was washed with water, dried over anhydrous Na2SO4,
and column chromatographed over silica gel using hexane
as eluent to give the title compound 42 (1.5 g, 64%) a red
liquid which turns to a purple colored liquid on solvent
evaporation. [Found: C, 61.11; H, 4.21; N, 5.86.
13. Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron 1974, 30,
3553–3561.
14. Klutchko, S.; Kaminsky, D.; Von Strandtmann, M. U.S.
Patent, 4098, 799, 1978; Chem. Abstr. 1979, 90, 22813c..
15. For a preliminary report see Josemin; Nirmala, K. N.; Asokan,
C. V. Tetrahedron Lett. 1997, 38, 8391–8394.
16. Singh, L. W.; Ila, H.; Junjappa, H. Synthesis 1987, 873–875.
17. Mc Combie, S. W.; Metz, W. A.; Nazareno, D.; Shankar, B. B.;
Tagat, J. J. Org. Chem. 1991, 56, 4963–4967.
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1197–1200.
19. Huenig, S.; Benzing, E.; Huebner, K. Chem. Ber. 1961, 94,
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20. Light, R. J.; Hauser, C. R. J. Org. Chem. 1960, 25, 538–546.
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22. Harris, T. M.; Murphy, G. P.; Poje, A. J. J. Am. Chem. Soc.
1976, 98, 7733–7741.
C12H10ClNS requires C, 61.14; H, 4.28; N, 5.94%];
1
n
max(neat) 2923, 1676, 1547, 1437, 1359, 1207 cm21; H
NMR (300 MHz, CDCl3) d 2.38 (3H, s, SCH3); 7.05 (1H, d,
J¼5.5 Hz, Py 5-H); 7.17–7.21 (2H, m, Ph); 7.36–7.42 (3H,
m, Ph); 8.24 (1H, d, J¼5.5 Hz, Py 6-H); 13C NMR
(75.48 MHz, CDCl3) d 13.11 (SCH3), 118.96, 127.67,
128.57, 132.91, 133.84, 141.36, 147.31, 160.18 (arom.);
EI-MS m/z: 237 (Mþþ2, 8%), 236 (Mþþ1, 44%), 235 (Mþ,
36%) 234 (100%, Mþ21), 233 (50%), 201 (58%), 200
(29%), 199 (50%), 154 (79%), 127 (24%), 105 (57%), 77
(43%).
23. Deb, B.; Asokan, C. V.; Ila, H.; Junjappa, H. Synthesis 1987,
893–895.
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H. F. Z. Chem. 1977, 17, 56–58.
29. Beak, P.; Carls, G. A. J. Org. Chem. 1964, 29, 2678–2681.
Acknowledgements
We thank Director, CDRI Lucknow and Prof. S. Perumal,
M. K. University, Madurai for providing spectral and
analytical data. A. D. T. thanks the Mahatma Gandhi
University for the award of a Junior Research Fellowship.