1-Bis(methoxy)-4-bis(methylthio)-3-buten-2-one: Useful three carbon synthon for synthesis of five and six membered heterocycles with masked (or unmasked) aldehyde functionality

Article abstract of DOI:10.1016/S0040-4020(03)00332-6

1-Bis(methoxy)-4-bis(methylthio)-3-buten-2-one has been shown to be a useful three carbon synthon for efficient regiospecific synthesis of a variety of five (pyrazole and isoxazole) and six membered (pyrimidines, pyridone and pyridines) heterocycles with masked (or unmasked) aldehyde functionality by cyclocondensation with bifunctional heteronucleophiles such as hydrazine, hydroxylamine, guanidine, thiourea, cyanoacetamide and substituted β-lithioaminoacrylonitriles. Reaction of 1-bis(methoxy)-4-bis(methylthio)-3-buten-2-one with methylene iodide and Zn-Cu couple under Simmons-Smith reaction conditions afforded 2-(methylthio)thiophene-4-aldehyde in good yield, whereas cycloaromatization with thiophene-2- and 3-acetonitriles gave the corresponding substituted benzothiophene-4- and 7-aldehydes in good yields.

Full text of DOI:10.1016/S0040-4020(03)00332-6

Tetrahedron 59 (2003) 2631–2639
1-Bis(methoxy)-4-bis(methylthio)-3-buten-2-one: useful three
carbon synthon for synthesis of five and six membered
heterocycles with masked (or unmasked) aldehyde functionality
†
*
*
Pranab K. Mahata, U. K. Syam Kumar, V. Sriram, H. Ila and H. Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur, 208016 India
Received 4 December 2002; revised 6 February 2003; accepted 28 February 2003
Abstract—1-Bis(methoxy)-4-bis(methylthio)-3-buten-2-one has been shown to be a useful three carbon synthon for efficient regiospecific
synthesis of a variety of five (pyrazole and isoxazole) and six membered (pyrimidines, pyridone and pyridines) heterocycles with masked (or
unmasked) aldehyde functionality by cyclocondensation with bifunctional heteronucleophiles such as hydrazine, hydroxylamine, guanidine,
thiourea, cyanoacetamide and substituted b-lithioaminoacrylonitriles. Reaction of 1-bis(methoxy)-4-bis(methylthio)-3-buten-2-one with
methylene iodide and Zn–Cu couple under Simmons–Smith reaction conditions afforded 2-(methylthio)thiophene-4-aldehyde in good yield,
whereas cycloaromatization with thiophene-2- and 3-acetonitriles gave the corresponding substituted benzothiophene-4- and 7-aldehydes in
good yields. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
variety of five and six membered heterocycles with masked
(or unmasked) aldehyde functionality.
The regiospecific introduction of a formyl group in five and
six membered heterocycles is a useful synthetic operation
since the formyl group is a versatile functionality for further
elaboration of these heterocyclic compounds through C–C
and C–heteroatom bond formation.1 The usual methods for
the synthesis of various heterocyclic aldehydes involve
electrophilic substitution (Vilsmeier–Haack reaction),2
formylation of metallated heterocycles,1a,b,3 oxidation of
methyl or hydroxymethyl groups4 and reduction methods.5
However, all these methods require preconstructed hetero-
cyclic precursors and suffer from some limitations such as
formation of inseparable regioisomeric mixtures of alde-
hydes, poor yields and drastic reaction conditions. On the
other hand, there are only a few examples in the literature
for the synthesis of heterocyclic aldehydes from acyclic
two or three carbon synthons with masked aldehyde
functionality (principal synthesis).6 During the course of
our continued interest in the development of new general
synthetic methods for regiospecifically substituted and
fused heterocycles based on a-oxoketene dithioacetals,7
we now report the synthesis and heterocyclization of
1-bis(methoxy)-4-bis(methylthio)-3-buten-2-one (2) as a
versatile multifunctional 1,3-bielectrophilic synthon for a
2. Results and discussion
The a-oxoketene dithioacetal 2 was obtained in 85% yield
by treatment of pyruvaldehyde dimethylacetal 1 with
sodium hydride and carbon disulfide in THF followed by
alkylation with 2 equiv. of methyl iodide (Scheme 1). When
2 was reacted with hydrazine hydrate in refluxing ethanol,
the corresponding 3(5)-[bis(methoxy)methyl]-5(3)-
(methylthio)pyrazole 3 was obtained in 80% yield.8
Hydrolysis of the dimethylacetal moiety of 3 with aqueous
acetic acid (50%) yielded the corresponding pyrazole-3(5)-
aldehyde 4 in 95% yield (Scheme 2). Similarly, treatment of
2 with hydroxylamine hydrochloride in ethanolic KOH
under neutral conditions afforded 3-[bis(methoxy)methyl]-
5-(methylthio)isoxazole 5 in 75% yield.9 The corresponding
5(3)-cycloaminopyrazole derivatives 6 and 7 were also
synthesized in a one pot sequence by prior displacement of
one of the methylthio groups of 2 by the respective amines
Keywords: a-oxoketene dithioacetals; pyruvaldehye dimethylacetal;
heterocyclization; heterocyclic aldehydes.
*
Corresponding authors. Tel.: þ91-512-597870; fax: þ91-512-597436;
e-mail: hila@iitk.ac.in
Deceased in November 2000.
†
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00332-6

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Scheme 2.
Scheme 3.
(i.e. piperidine and morpholine) in refluxing ethanol
followed by in situ cyclization of the resulting N,S-acetals
with hydrazine hydrate under similar reaction conditions
(Scheme 2). The ketene dithioacetal 2 was also converted
into the corresponding N,S-acetal 8 by treatment with
m-methoxyaniline in the presence of n-BuLi.10 Subsequent
cyclization of 8 with either hydrazine hydrate or hydroxyl-
amine hydrochloride afforded the corresponding 5(3)-(m-
methoxyanilino)-pyrazole 9 and the corresponding isoxa-
zole derivative 10 respectively in good yields (Scheme 3).
The N,S-acetal 8 was also subjected to intramolecular
cyclocondensation in the presence of POCl3 to afford the
corresponding 2-methylthio-7-methoxyquinoline-4-alde-
hyde 11 via Combes type synthesis (Scheme 4).11
characterized as 2-(methylthio)thiophene-4-aldehyde (12)
which is apparently derived from the initially formed
thiophene 14 through deacetylation under experimental
conditions. The probable mechanism for the formation of 14
from 2 appears to be similar as suggested earlier12 involving
carbenoid methylene addition to one of the methylthio
groups of 2 to give ylide 13A, which on intramolecular aldol
type condensation assisted by coordination of zinc with
carbonyl oxygen lone pair followed by demethylation of
S-methylthiophenium salt 13B affords the thiophene 14
(Scheme 5). The reaction provides a facile entry to not
The ketene dithioacetal 2 was next subjected to treatment
with methylene iodide and Zn–Cu couple with a view to
prepare the corresponding 2-methylthio-4-[bis(methoxy)-
methyl]thiophene (14) in line with our earlier observations
on Simmons–Smith reaction on a-oxoketene dithio-
acetals.12 However the product isolated (65%) was
Scheme 4.

P. K. Mahata et al. / Tetrahedron 59 (2003) 2631–2639
2633
Scheme 5.
easily accessible thiophene-3-(or 4-) aldehyde since direct
Vilsmeier formylation of thiophene affords only 2- (or 5-)
formyl derivatives.13
functionalized 6-[bis(methoxy)methyl]-3-cyano-4-(methyl-
thio)-2(1H)-pyridone 19 in 67% yield (Scheme 6).15
The oxoketene dithioacetal 2 was next subjected to
cyclocondensation with b-lithioaminocrotononitrile 20a
and other b-substituted b-lithioaminoacrylonitriles 20b,c
according to our earlier reported method7c,16 to afford the
Cyclocondensation of 2 with 1,3-heterobinucleophiles was
next examined with a view to synthesize six membered
heterocycles with a masked aldehyde group. Thus, cycliza-
tion of 2 with guanidine nitrate in the presence of the
appropriate sodium alkoxides (NaOMe or NaOEt) in
refluxing alkanols (methanol or ethanol) afforded the
corresponding 2-amino-4-[bis(methoxy)methyl]-6-methoxy
or ethoxypyrimidines 15a and 15b in 65 and 60% yields,
respectively, in accordance with our earlier reported
alkoxypyrimidine synthesis (Scheme 6).14 Similarly, treat-
ment of 2 with thiourea in the presence of either sodium
methoxide or ethoxide under refluxing conditions furnished
the respective 6-alkoxy-4-[bis(methoxy)methyl]-2-mer-
captopyrimidines 16a,b in good yields.14 One of the
alkoxypyrimidines 15b was hydrolyzed with dilute HCl in
ethanol to afford the corresponding 2-amino-6-ethoxy-
pyrimidine-4-aldehyde 17 in 85% yield. (Scheme 6).6c
Reaction of 2 with cyanoacetamide in the presence of
sodium t-butoxide in t-butanol yielded the highly
respective
6-[bis(methoxy)methyl]-2-substituted-4-
(methylthio)nicotinonitriles 22a–c with a masked 6-formyl
group in 57–65% overall yields (Scheme 7). The nicotino-
nitriles 22b,c were deprotected in the presence of dilute
hydrochloric acid to give the corresponding 6-formyl
derivatives 23b,c in 90 and 95% yield, respectively. It
should be noted that substituted pyridine-2-carbaldehydes
are usually synthesized by long and circuitous routes, most
commonly by oxidation of activated methyl group of the
picolines17 or their N-oxides18 or by oxidative cleavage of
2-vinylpyridine derivatives.19 Only recently, a short versa-
tile route to 2-formyl nicotinates has been reported by
cyclocondensation of methyl 3-amino-4-bis(methoxy)-
but-2-enoate (bearing masked aldehyde group) with a
variety of Mannich base hydrochlorides or b-aminovinyl
ketones.5b,20
Scheme 6.

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P. K. Mahata et al. / Tetrahedron 59 (2003) 2631–2639
Scheme 7.
Scheme 8.
Finally, the versatility of 2 for regiospecific introduction of
aldehyde functionality was demonstrated by its two step
cycloaromatization with isomeric 2- and 3-thiophene
acetonitriles 24 and 25 (Scheme 8).7d Thus compound 24
underwent base induced conjugate addition elimination with
2 to afford the conjugate adduct 26 in 78% yield. Acid
induced intramolecular cyclocondensation of 26 in refluxing
benzene directly afforded the multifunctional deprotected
7-cyano-6-(methylthio)benzothiophene-4-aldehyde 27 in
70% yield. The corresponding regioisomeric 4-cyano-5-
(methylthio)benzothiophene-7-aldehyde 29 was similarly
obtained in good yields by cyclocondensation of 2 with
3-cyanomethylthiophene 25 under identical conditions
(Scheme 8).
heterocycles with masked aldehyde functionality which can
be deprotected and utilized for further elaboration.
3. Experimental
3.1. General
1H NMR (300 and 400 MHz) and 13C NMR (75 and
100 MHz) spectra were recorded in CDCl3, DMSO-d6 and
TMS was used as internal reference. Melting points are
uncorrected. Chromatographic purification was done by
column chromatography using 60–120 mesh silica gel
obtained from Acme Synthetic Chemicals. All reactions
were monitored by TLC on glass plate coated with silica gel
(Acme) containing 13% calcium sulfate as binder and
visualization was effected with short wavelength UV light
(254 nm) or acidic KMnO4 solution. All reagents were used
directly as obtained commercially unless otherwise noted.
In summary, cyclocondensation of readily accessible
1-bis(methoxy)-4-bis(methylthio)-3-buten-2-one (2) with
various 1,2- and 1,3-binucleophiles provides efficient
regiospecific routes to a variety of five and six membered

P. K. Mahata et al. / Tetrahedron 59 (2003) 2631–2639
2635
DMF was distilled over CaH2 and stored over molecular
sieves. THF was distilled over sodium benzophenone ketyl
prior to use. n-BuLi (1.5 M) was purchased from Aldrich
Chemical Co.
chromatography using hexane–EtOAc (5:1) as eluent, to
give the title compound 4 as colorless crystals (CHCl3–
hexane); Rf 0.6 (8:2 hexane–EtOAc); mp 156–1578C.
Yield 0.67 g, 95%; IR (KBr): 3154, 1696, 1535, 1468 cm21
;
dH (400 MHz, DMSO-d6) 9.80 (1H, s, CHO), 6.81 (1H, s,
CHv), 2.49 (3H, s, SCH3); dC (100 MHz, DMSO-d6) 184.2,
138.8, 106.2, 103.8, 16.7; MS: m/z (%): 142 (Mþ, 100).
Anal. calcd for C5H6N2OS (142.18): C, 42.23; H, 4.25; N,
19.70%. Found: C, 42.35; H, 4.23; N, 9.51%.
Pyruvaldehyde dimethylacetal (1), methoxyacetonitrile,
thiophene-2- (24) and 3-acetonitriles (25) were purchased
from Aldrich Chemical Co.
3.1.1. 1-Bis(methoxy)-4-bis(methylthio)-3-buten-2-one
(2). To a suspension of NaH (0.96 g, 20 mmol, 50%) in
THF (25 mL) under N2 atmosphere at 08C carbon disulfide
(0.62 mL, 10 mmol) in THF (25 mL) was added followed
by stirring for 20–30 min. A solution of pyruvaldehyde
dimethylacetal (1.2 mL, 10 mmol) in THF (25 mL) was
added over a period of 30 min at 08C followed by stirring at
room temperature for 7 h. The reaction mixture was then
cooled at 08C and a solution of methyl iodide (1.6 mL,
25 mmol) in THF (25 mL) was added and the reaction
mixture was further stirred for 6 h. It was then poured into
saturated ammonium chloride solution (50 mL), extracted
with chloroform (3£50 mL), washed with water (3£50 mL),
dried (Na2SO4) and the solvent evaporated under reduced
pressure to give the crude product which was purified by
column chromatography over silica gel using hexane–
EtOAc (9:1) as eluent, to give the title compound 2 as dark
red viscous liquid; Rf 0.40 (8.5:1.5 hexane–EtOAc). Yield
1.88 g, 85%; IR (CCl4): 1642, 1102, 1069, 1013 cm21; dH
(300 MHz, CCl4) 6.29 (1H, s, vCH), 4.43 [1H, s,
CH(OMe)2], 3.38 (6H, s, OCH3), 2.50 (3H, s, SCH3), 2.47
(3H, s, SCH3); dC (75 MHz, CCl4) 187.5, 107.8, 104.0, 96.0,
53.9, 16.9, 14.5; MS: m/z (%): 222 (Mþ, 14), 148 (100).
Anal. calcd for C8H14O3S2 (222.32): C, 43.22; H, 6.35%.
Found: C, 43.33; H, 6.25%.
3.1.4. 3-[Bis(methoxy)methyl]-5-(methylthio)isoxazole
(5). A suspension of 2 (1.1 g, 5 mmol), hydroxylamine
hydrochloride (0.52 g, 7.5 mmol) and potassium hydroxide
(0.42 g, 7.5 mmol) were refluxed in ethanol (25 mL) for 3 h
(monitored by TLC). The solvent was then removed under
reduced pressure and the residue was diluted with water,
extracted with chloroform. The combined extract was
washed with water (2£50 mL), dried (Na2SO4) and
evaporated to give the crude residue which was purified
by column chromatography over silica gel using hexane–
EtOAc as eluent, to give the title compound 5 as light brown
crystals (CHCl3–hexane); Rf 0.35 (1:1 hexane–EtOAc); mp
75–768C. Yield 0.71 g, 75%; IR (KBr): 2994, 2934, 1544,
1194, 1115 cm21; dH (300 MHz, CDCl3) 6.07 (1H, s,
CHv), 5.30 [1H, s, CH(OMe)2], 3.35 (6H, s, OCH3), 2.58
(3H, s, SCH3); dC (75 MHz, CCl4) 161.9, 99.8, 97.8, 96.2,
53.2, 15.1; MS: m/z (%): 187 (M22, 43.3), 156 (62.5%).
Anal. calcd for C7H11NO3S (189): C, 44.44; H, 5.82; N,
7.40%. Found: C, 44.56; H, 5.92; N, 7.51%.
3.2. 3(5)-[Bis(methoxy)methyl]-5(3)-aminopyrazoles 6
and 7: general procedure
To a solution of 2 (1.1 g, 5 mmol) in ethanol (25 mL), the
respective amine (5.1 mmol) was added at a time and the
reaction mixture was refluxed for 2 h. It was then brought to
room temperature and hydrazine hydrate (0.36 mL,
7.5 mmol) in ethanol (10 mL) was added dropwise over a
period of 10 min. Then the reaction mixture was refluxed for
another 3–4 h (monitored by TLC). The solvent was
removed under reduced pressure and the residue was
dissolved in chloroform (50 mL), washed with water
(3£50 mL), dried (Na2SO4) and concentrated to give
crude solid which on recrystallization from CHCl3–hexane
(1:3) yielded analytically pure compounds.
3.1.2. 3(5)-[Bis(methoxy)methyl]-5(3)-(methylthio)pyra-
zole (3). To a solution of 2 (1.1 g, 5 mmol) in ethanol
(50 mL), hydrazine hydrate (0.36 mL, 7.5 mmol) was added
and the reaction mixture was refluxed for 3 h. The solvent
was removed under reduced pressure and the residue was
dissolved in chloroform (100 mL), washed with water
(3£100 mL), dried (Na2SO4) and concentrated to give
crude product which was purified by column chromato-
graphy over silica gel using hexane–EtOAc (6:1) as eluent,
to give the title compound 3 as light brown crystals
(CHCl3–hexane); Rf 0.35 (1:1 hexane–EtOAc); mp 135–
1368C. Yield 0.75 g, 80%; IR (KBr): 3240, 1437, 1365,
1120, 1091 cm21; dH (300 MHz, CCl4) 6.25 (1H, s, vCH),
5.54 [1H, s, CH(OMe)2], 3.34 (6H, s, OCH3), 2.49 (3H, s,
SCH3); dC (75 MHz, CCl4) 144.3, 104.5, 97.3, 95.9, 51.8,
16.4; MS: m/z (%): 188 (Mþ, 43), 157 (100). Anal. calcd for
C7H12N2O2S (188.25): C, 46.66; H, 6.42; N, 14.88%.
Found: C, 46.51; H, 6.54; N, 14.90%.
3.2.1. 3(5)-[Bis(methoxy)methyl]-5(3)-(1-N-piperidino)-
pyrazole (6). Light brown crystals (CHCl3–hexane); Rf
0.2 (7:3 hexane–EtOAc); mp 84–858C. Yield 0.95 g, 85%;
IR (KBr): 3191, 2928, 1568, 1362, 1108 cm21; dH
(400 MHz, CDCl3) 8.03 (1H, brs, NH), 5.69 (1H, s,
CHv), 5.45 [1H, s, CH(OMe)2], 3.30 (6H, s, OCH3), 3.13
[4H, t, J¼5.4 Hz, N(CH2)2-], 1.61–1.67 (4H, m, CH2),
1.50–1.55 (2H, m, CH2); dC (100 MHz, CDCl3) 159.7,
142.2, 97.5, 89.9, 52.4, 49.3, 25.3, 24.2; MS: m/z (%): 225
(Mþ, 20). Anal. calcd for C11H19N3O2 (225.29): C, 58.64;
H, 8.50; N, 18.65%. Found: C, 58.50; H, 8.56; N, 18.69%.
3.1.3. 3(5)-(Methylthio)pyrazole-5(3)-aldehyde (4). The
pyrazole (0.94 g, 5 mmol) was added at a time to 20 mL of
ice cooled AcOH (50%) with stirring and the reaction
mixture was heated at 608C with continuous stirring for 4 h
(monitored by TLC). It was then cooled, poured over ice-
cooled saturated NaHCO3 solution and extracted with
CHCl3 (3£50 mL). The combined extract was washed
with water (1£50 mL), dried (Na2SO4) and evaporated to
give crude aldehyde which was purified by column
3.2.2. 3(5)-[Bis(methoxy)methyl]-5(3)-(1-N-morpholino)-
pyrazole (7). Colorless crystals (CHCl3–hexane); Rf 0.15
(6.5:3.5 hexane–EtOAc); mp 98–998C. Yield 0.87 g, 77%;
IR (KBr): 3290, 2827, 1560, 1490, 1121 cm21; dH
(400 MHz, CDCl3) 7.73 (1H, brs, NH), 5.73 (1H, s,

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P. K. Mahata et al. / Tetrahedron 59 (2003) 2631–2639
CHv), 5.52 [1H, s, CH(OMe)2], 3.83 [4H, t, J¼4.8 Hz,
O(CH2)2–], 3.34 (6H, s, OCH3), 3.20 [4H, t, J¼4.8 Hz,
N(CH2)2–]; dC (100 MHz, CDCl3) 157.3, 143.7, 96.9, 89.4,
66.3, 52.6, 48.3; MS: m/z (%): 227 (Mþ, 76), 196 (100).
Anal. calcd for C10H17N3O3 (227.26): C, 52.85; H, 7.54; N,
18.45%. Found: C, 52.69; H, 7.42; N, 18.90%.
CHv), 5.35 [1H, s, CH(OMe)2], 3.79 (3H, s, OCH3), 3.41
(6H, s, OCH3); dC (100 MHz, CDCl3) 165.4, 163.2, 160.7,
140.1, 130.4, 110.0, 108.0, 103.8, 98.3, 79.6, 55.3, 53.7;
MS: m/z (%): 264 (Mþ, 13). Anal. calcd for C13H16N2O4
(264.28): C, 59.08; H, 6.10; N, 10.60%. Found: C, 59.21; H,
6.05; N, 10.51%.
3.2.3. 1-Bis(methoxy)-4-(3-methoxyanilino)-4-(methyl-
thio)-3-buten-2-one (8). To a solution of m-anisidine
(1.23 g, 10 mmol) in dry THF (50 mL), n-BuLi (7.8 mL,
15 mmol) was added at 2788C under nitrogen atmosphere
and stirred at the same temperature for 30 min. A solution of
2 (2.23 g, 10 mmol) in 25 mL dry THF was added over a
period of 20 min at 2788C and the resulting suspension was
allowed to warm to room temperature followed by refluxing
for 10 h. It was then brought to room temperature, poured
into ice cold saturated NH4Cl solution (50 mL), extracted
with CHCl3 (3£50 mL), washed with water (3£50 mL),
dried (Na2SO4) and evaporated under reduced pressure to
give crude product which was further purified by column
chromatography over silica gel using hexane–EtOAc (9:1)
as eluent, to give the title compound 8 as deep red viscous
liquid; Rf 0.45 (8.5:1.5 hexane–EtOAc). Yield 2.23 g, 75%;
IR (DCM): 2952, 2839, 1554, 1477 cm21; dH (400 MHz,
CDCl3) 13.04 (1H, brs, NH), 7.17 (1H, t, J¼8.4 Hz, ArH),
6.79 (1H, d, J¼8.0 Hz, ArH), 6.74 (1H, s, ArH), 6.70 (1H, d,
J¼8.0 Hz, ArH), 5.52 (1H, s, CHv), 4.57 [1H, s,
CH(OMe)2], 3.70 (3H, s, OCH3), 3.36 (6H, s, OCH3),
2.29 (3H, s, SCH3); dC (100 MHz, CDCl3) 187.7, 168.9,
159.8, 138.6, 129.5, 117.0, 112.1, 110.3, 103.5, 87.4, 55.0,
53.8, 14.4. Anal. calcd for C14H19N2O4S (297.38): C, 56.54;
H, 6.43; N, 4.71%. Found: C, 56.49; H, 6.48; N, 4.76%.
3.2.6. 7-Methoxy-2-(methylthio)quinoline-4-carbalde-
hyde (11). The N,S-acetal 8 (1.49 g, 5 mmol) was dissolved
in POCl3 (20 mL) at 08C and was heated to 80–908C with
stirring for 3–4 h (monitored by TLC).The reaction mixture
was cooled and poured into ice cold saturated NaHCO3
solution. It was then extracted with chloroform, washed
with water and dried over Na2SO4 to give the crude product
which was further purified by column chromatography over
silica gel using hexane–EtOAc as the eluent, to give the title
compound 11 as yellow crystals (CHCl3–hexane); Rf 0.70
(9:1 hexane–EtOAc); mp 93–948C. Yield 0.79 g, 68%; IR
(KBr): 2925, 1708, 1611, 1509 cm21; dH (400 MHz,
CDCl3) 10.28 (1H, s, CHO), 8.75 (1H, d, J¼9.1 Hz, ArH),
7.44 (1H, s, CHv), 7.37 (1H, d, J¼2.4 Hz, ArH), 7.19 (1H,
dd, J¼9.1, 2.4 Hz, ArH), 3.95 (3H, s, OCH3), 2.71 (3H, s,
SCH3); dC (100 MHz, CDCl3) 192.8, 161.2, 160.6, 151.3,
136.4, 125.7, 124.2, 119. 8, 116.2, 107.1, 55.5, 13.1; MS:
m/z (%): 234 (Mþ1, 100). Anal. calcd for C12H11NO2S
(233.30): C, 61.78; H, 4.75; N, 6.00%. Found: C, 61.62; H,
4.85; N, 6.18%.
3.2.7. 2-(Methylthio)thiophene-4-carbaldehyde (12). To a
well stirred suspension of Zn–Cu couple (3.0 g, 30 mmol)
in dry Et2O (25 mL), under nitrogen atmosphere, a small
crystal of iodine and CH2I2 (1.34 g, 6.7 mmol) was added
and the reaction mixture was refluxed for 45 min. A solution
of 2 (1.5 g, 6.7 mmol) in dry THF (25 mL) was added to the
reaction mixture followed by further refluxing for 6 h
(monitored by TLC). The solvent was removed under
reduced pressure and the residue was diluted with CHCl3
(150 mL), washed with water (100 mL) and the organic
extract was filtered through sintered funnel to remove metal-
based residue. The organic filtrate was washed with
saturated NH4Cl solution (100 mL), water (3£50 mL),
dried (Na2SO4) and concentrated to give crude product
which was purified by column chromatography over silica
gel using hexane as eluent, to give the title compound 12 as
pale yellow viscous liquid; Rf 0.7 (9.5:0.5 hexane–EtOAc).
Yield 0.69 g, 65%; IR (CCl4): 1682, 1506, 1387 cm21; dH
(300 MHz, CDCl3) 9.74 (1H, s, CHO), 7.95 (1H, s, CHv),
7.38 (1H, s, CHv), 2.52 (3H, s, SCH3); dC (75 MHz,
CDCl3) 182.0, 143.2, 140.3, 136.6, 127.4, 20.9; MS: m/z
(%): 158 (Mþ, 48), 83 (100). Anal. calcd for C6H6OS2
(158.25): C, 45.54; H, 3.82%. Found: C, 45.60; H, 3.78%.
3.2.4. 3(5)-[Bis(methoxy)methyl]-5(3)-(3-methoxy)ani-
linopyrazole (9). The pyrazole 9 was prepared following
the earlier procedure for 3, by refluxing a solution of 12
(1.45 g, 5 mmol) and hydrazine hydrate (0.36 g, 5 mmol) in
40 mL of ethanol. Workup and column chromatography of
the reaction mixture using hexane–EtOAc (1:1) afforded
the title compound 9 as red viscous liquid; Rf 0.2 (7:3
hexane–EtOAc). Yield 0.98 g, 75%; IR (DCM): 2943,
1603, 1491, 1341 cm21; dH (400 MHz, CDCl3) 7.62 (1H,
brs, NH), 7.24 (1H, t, J¼8.4 Hz, ArH), 6.77–6.87 (2H, m,
ArH), 6.50 (1H, dd, J¼8.4, 2.0 Hz, ArH), 6.31 (1H, s,
CHv), 5.74 [1H, s, CH(OMe)2], 3.86 (3H, s, OCH3), 3.49
(6H, s, OCH3); dC (100 MHz, CDCl3) 160.6, 149.6, 144.6,
142.6, 130.0, 108.1, 104.6, 101.4, 97.6, 92.9, 55.1, 52.5;
MS: m/z (%): 263 (Mþ, 60), 188 (100). Anal. calcd for
C13H17N3O3 (263.29): C, 59.30; H, 6.50; N, 15.96%. Found:
C, 59.23; H, 6.66; N, 15.78%.
3.2.5. 3-[Bis(methoxy)methyl]-5-(3-methoxyanilino)-
isoxazole (10). The isoxazole 10 was prepared following
the similar procedure as for 5 by refluxing a suspension of 8
(1.45 g, 5 mmol), hydroxylamine hydrochloride (0.52 g,
7.5 mmol) and KOH (0.42 g, 7.5 mmol) in 25 mL of ethanol
for 3 h. Workup and chromatography (hexane–EtOAc, 9:1)
of the reaction mixture yielded the title compound 10 as red
viscous liquid; Rf 0.48 (8.5:1.5 hexane–EtOAc). Yield
0.92 g, 70%; IR (DCM): 2926, 1600, 1493 cm21; dH
(400 MHz, CDCl3) 7.21 (1H, t, J¼7.8 Hz, ArH), 6.77
(1H, brs, NH), 6.69 (1H, d, J¼1.2 Hz, ArH), 6.67 (1H, m,
ArH), 6.58 (1H, dd, J¼8.2, 2.4 Hz, ArH), 5.62 (1H, s,
3.3. 2-Amino-4-[bis(methoxy)methyl]-6-alkoxy-
pyrimidines 15a,b: general procedure
Guanidine nitrate (0.61 g, 5 mmol) was added to a solution
of sodium alkoxide (10 mmol, prepared in situ from 0.23 g
of sodium metal and 5 mL of the corresponding alkanol) in
alkanol (30 mL) and after 5 min of stirring at room
temperature, a solution of 2 (1.1 g, 5 mmol) in correspond-
ing alkanol (5 mL) was added. The reaction mixture was
refluxed for 10–14 h with stirring (monitored by TLC). The
solvent was removed under reduced pressure and the residue

P. K. Mahata et al. / Tetrahedron 59 (2003) 2631–2639
2637
was diluted with ice-cold water (50 mL). It was then
extracted with CHCl3 (3£50 mL), washed with water
(3£50 mL), dried (Na2SO4) and evaporated to give crude
product which was purified by column chromatography over
silica gel using hexane–EtOAc (1:1) as eluent.
3.4.3. 2-Amino-6-ethoxypyrimidine-4-carbaldehyde
(17). A solution of alkoxypyrimidine dimethylacetal (15b)
(1.06 g, 5 mmol) in 20 mL of ethanol and 40 mL of 0.4N
HCl was refluxed for 1 h. It was then heated with animal
charcoal, refluxed and filtered hot on a sintered funnel. The
filtrate was adjusted to pH 9–10 with 5% NaOH solution.
The resulting precipitate was dried in oven under reduced
pressure for 1 h to give the title compound 17 as colorless
crystals (ethanol). The aldehyde 17 was insoluble for
3.3.1. 2-Amino-4-[bis(methoxy)methyl]-6-methoxypyri-
midine (15a). Colorless crystals (CHCl3–hexane); Rf 0.15
(1:1 hexane–EtOAc); mp 105–1068C. Yield 0.65 g, 65%;
IR (KBr): 3438, 3267, 1624, 1581, 1105, 1061 cm21; dH
(300 MHz, CDCl3) 6.29 (1H, s, CHv), 5.51 (2H, brs, NH2),
5.10 [1H, s, CH(OMe)2], 3.88 (3H, s, OCH3), 3.36 (6H, s,
OCH3); dC (75 MHz, CDCl3) 171.5, 166.2, 163.2, 102.0,
95.5, 53.5, 53.2; MS: m/z (%): 199 (Mþ, 32), 153 (100).
Anal. calcd for C8H13N3O3 (199.20): C, 48.24; H, 6.53; N,
21.10%. Found: C, 48.35; H, 6.69; N, 21.20%.
1
recording H NMR spectra in CDCl3 or DMSO-d6. Mp
3908C (decomposed). Yield 0.71 g, 85%; IR (KBr): 3475,
1697, 1456 cm21, MS: m/z (%): 167 (Mþ, 100). Anal. calcd
for C7H9N3O2 (167.16): C, 50.29; H, 5.42; N, 25.13%.
Found: C, 50.12; H, 5.58; N, 25.21%.
3.4.4. 3-Cyano-6-[bis(methoxy)methyl]-4-(methylthio)-
2(1H)-pyridone (19). To a stirring suspension of sodium
t-butoxide [prepared by reacting molecular sodium (0.12 g,
5 mmol) in t-butanol (50 mL)], cyanoacetamide (0.42 g,
5 mmol) was added and the reaction mixture was further
stirred for 10 min. A suspension of 2 (1.19 g, 5 mmol) in
t-BuOH (5 mL) was then added followed by refluxing for
5 h. The solvent was removed under reduced pressure to
give orange colored sodium salt of the pyridone 19 which
was dissolved in water (30 mL) followed by acidification
with dilute HCl (10 mL, 8%) to afford the title compound 19
as yellow crystals (CHCl3); Rf 0.15 (1:1 hexane–EtOAc);
mp 149–1508C. Yield 0.80 g, 67%; IR (KBr): 2213, 1656,
1602, 1468, 1353, 1205 cm21; dH (300 MHz, DMSO-d6)
6.37 (1H, s, CHv), 5.22 [1H, s, CH(OMe)2], 3.34 (6H, s,
OCH3), 2.62 (3H, s, SCH3); dC (75 MHz, DMSO-d6) 164.2,
159.5, 153.7, 148.2, 114.8, 99.2, 98.8, 53.8, 13.9; MS: m/z
(%): 240 (Mþ, 33). Anal. calcd for C10H12N2O3S (240.28):
C, 49.99; H, 5.03; N, 11.66%. Found: C, 49.89; H, 5.10; N,
11.60%.
3.3.2. 2-Amino-4-[bis(methoxy)methyl]-6-ethoxypyrimi-
dine (15b). Colorless crystals (CHCl3–hexane); Rf 0.20
(1:1 hexane–EtOAc); mp 120–1228C. Yield 0.64 g, 60%;
IR (KBr): 3301, 1632, 1575, 1169, 1057 cm21; dH
(300 MHz, CDCl3) 6.27 (1H, s, CHv), 5.35 (2H, brs,
NH2), 5.08 [1H, s, CH(OMe)2], 4.31 (2H, q, J¼7.0 Hz,
OCH2CH3), 3.36 (6H, s, OCH3), 1.36 (3H, t, J¼7.0 Hz,
CH3CH2); dC (75 MHz, CDCl3) 171.1, 166.3, 163.1, 102.1,
95.7, 62.1, 53.2, 14.4; MS: m/z (%): 213 (Mþ, 25), 181
(100). Anal. calcd for C9H15N3O3 (213.23): C, 50.69; H,
7.09; N, 19.70%. Found: C, 50.55; H, 7.12; N, 19.68%.
3.4. 6-Alkoxy-4-[bis(methoxy)methyl]-2-mercapto-
pyrimidines 16a,b: general procedure
The 2-mercaptopyrimidines 16a,b were prepared following
the similar procedure for 2-aminopyrimidines 15a,b by
refluxing a suspension of 2 (1.1 g, 5 mmol), thiourea
(0.389 g, 5 mmol) and the corresponding sodium alkoxide
(6 mmol) in the appropriate alkanol (60 mL) for 6–7 h.
Workup and column chromatography (hexane–EtOAc 1:1)
of the reaction mixture afforded the mercaptopyrimidines
16a,b.
3.5. General procedure for synthesis of pyridines 22a–c
A solution of 2 (1.1 g, 5 mmol) in dry THF (25 mL) was
added dropwise to a solution of either lithioaminocrotono-
nitrile 20a [7.5 mmol, generated16 from acetonitrile
(0.8 mL, 15.3 mmol) and n-BuLi (5.0 mL, 7.5 mmol)] or
2-substituted-2-lithioaminoacrylonitrile 20b,c [generated16
from acetonitrile (0.4 mL, 7.5 mmol), alkyl/aryl nitrile
(7.5 mmol) and n-BuLi (5.0 mL, 7.5 mmol)] in THF
(25 mL) at 2788C and the reaction mixture was brought
to room temperature and refluxed for 2 days. It was then
cooled and poured into saturated NH4Cl (50 mL) solution,
extracted with CHCl3 (2£50 mL) and the combined organic
layer was washed with water (2£50 mL), dried (Na2SO4)
and concentrated to give crude product which was purified
by column chromatography over silica gel using hexane–
EtOAc (5:1) as eluent.
3.4.1. 4-[Bis(methoxy)methyl]-6-methoxy-2-mercapto-
pyrimidine (16a). Colorless crystals (CHCl3–hexane); Rf
0.30 (6:4 hexane–EtOAc); mp 107–1088C. Yield 0.59 g,
55%; IR (KBr): 3143, 1631, 1567, 1186, 1049 cm21; dH
(400 MHz, CDCl3) 6.26 (1H, s, CHv), 5.30 [1H, s,
CH(OMe)2], 3.40 (6H, s, OCH3), 3.10 (3H, s, OCH3); dC
(100 MHz, CDCl3) 182.7, 168.9, 154.6, 97.9, 97.3, 55.6,
55.3; MS: m/z (%): 216 (Mþ, 8). Anal. calcd for
C8H12N2O3S (216.35): C, 44.44; H, 5.55; N, 12.96%.
Found: C, 44.53; H, 5.61; N, 12.72%.
3.4.2. 4-[Bis(methoxy)methyl]-6-ethoxy-2-mercapto-
pyrimidine (16b). Colorless crystals (CHCl3–hexane); Rf
0.35 (6:4 hexane–EtOAc); mp 88–898C. Yield 0.61 g,
53%; IR (KBr): 3562, 3113, 1844, 1794 cm21; dH
(400 MHz, CDCl3) 6.22 (1H, s, CHv), 5.26 [1H, s,
CH(OMe)2], 4.54 (2H, q, J¼7.0 Hz, OCH2CH3), 3.39
(6H, s, OCH3), 1.38 (3H, t, J¼7.0 Hz, CH3CH2); dC
(100 MHz, CDCl3) 182.7, 168.6, 154.3, 98.1, 97.2, 64.3,
53.4, 14.2; MS: m/z (%): 230 (Mþ, 24). Anal. calcd for
C9H14N2O3S (230.29): C, 46.94; H, 6.12; N, 12.20%.
Found: C, 47.00; H, 6.20; N, 12.01%.
3.5.1. 3-Cyano-6-[bis(methoxy)methyl]-2-methyl-4-
methylthiopyridine (22a). Colorless crystals (CHCl3–
hexane); Rf 0.40 (8.5:1.5 hexane–EtOAc); mp 78–798C.
Yield 0.73 g, 62%; IR (KBr): 2923, 2218, 1742, 1541 cm21
;
dH (400 MHz, CDCl3) 7.27 (1H, s, CHv), 5.28 [1H, s,
CH(OMe)2], 3.42 (6H, s, OCH3), 2.74 (3H, s, CH3), 2.59
(3H, s, SCH3); dC (100 MHz, CDCl3) 161.5, 159.0, 156.6,
115.1, 112.7, 106.1, 103.6, 54.1, 23.7, 14.1; MS: m/z (%):
236 (M-1, 15). Anal. calcd for C11H13N2O2S (237.29): C,

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P. K. Mahata et al. / Tetrahedron 59 (2003) 2631–2639
55.44; H, 5.92; N, 11.78%. Found: C, 55.56; H, 5.83; N,
11.75%.
3.7. 7-Cyano-6-(methylthio)benzothiophene-4-
carbaldehyde (27) and 4-cyano-5-(methylthio)-
benzothiophene-7-carbaldehyde (28): general procedure
3.5.2. 3-Cyano-6-[bis(methoxy)methyl]-4-(methylthio)-
2-(methoxymethyl)pyridine (22b). Colorless crystals
(CHCl3–hexane); Rf 0.40 (8:2 hexane–EtOAc); mp 77–
798C. Yield 0.76 g, 57%; IR (KBr): 2935, 2218, 1570,
1445 cm21; dH (400 MHz, CDCl3) 7.37 (1H, s, CHv), 5.33
[1H, s, CH(OMe)2], 4.69 (2H, s, CH2OCH3), 3.50 (3H, s,
OCH3), 3.43 (6H, s, OCH3), 2.60 (3H, s, SCH3); dC
(100 MHz, CDCl3) 160.1, 159.3, 157.4, 114.5, 114.1, 106.4,
103.8, 74.1, 59.3, 54.3, 14.3; MS: m/z (%): 268 (Mþ, 10).
Anal. calcd for C12H16N2O3S (268.33): C, 53.70; H, 6.01;
N, 10.44%. Found: C, 53.92; H, 5.81; N, 10.35%.
To a stirred suspension of NaH (0.60 g, 40%, 10 mmol) in
DMF (10 mL) at 08C, a solution of 2- or 3-thiophene-
acetonitrile (5 mmol) in DMF (5 mL) was added dropwise
during 15 min and the reaction mixture was stirred at 08C
for 45 min. A solution of 2 (1.1 g, 5 mmol) in DMF (10 mL)
was slowly added and the reaction mixture was allowed to
warm to room temperature with stirring during 8–10 h. It
was then poured into saturated NH4Cl solution (200 mL)
and extracted with CHCl3 (3£50 mL). The combined
organic layer was washed with water (3£50 mL), dried
(Na2SO4) and evaporated to give the crude adducts (26, 28)
which were used as such for further cyclization. The crude
adduct (,5 mmol) dissolved in dry C6H6 (20 mL) was
refluxed with PTSA (1.9 g, 10 mmol) for 3–4 h (monitored
by TLC). It was then cooled, poured into ice-cold water
(150 mL), extracted with CHCl3 (3£50 mL), the combined
organic layer was washed with water (3£50 mL) and dried
over Na2SO4. The solvent was distilled under reduced
pressure to give crude product, which was purified by
column chromatography over silica gel using hexane–
EtOAc (97:3) as eluent.
3.5.3. 3-Cyano-6-[bis(methoxy)methyl]-2-(4-methoxy-
phenyl)-4-(methylthio)pyridine (22c). Colorless crystals
(CHCl3–hexane); Rf 0.30 (9.5:0.5 hexane–EtOAc); mp
107–1088C. Yield 1.07 g, 65%; IR (KBr): 3447, 2926,
2852, 2217, 1607, 1512 cm21; dH (400 MHz, CDCl3) 7.88
(2H, dd, J¼9.6, 2.9 Hz, ArH), 7.33 (1H, s, CHv), 7.01 (2H,
dd, J¼9.6, 2.9 Hz, ArH), 5.33 [1H, s, CH(OMe)2], 3.87 (3H,
s, OCH3), 3.47 (6H, s, OCH3), 2.62 (3H, s, SCH3); dC
(100 MHz, CDCl3) 161.2, 160.5, 159.3, 157.9, 130.6, 129.4,
115.9, 113.9, 112.5, 104.3, 103.9, 55.4, 54.5, 14.4; MS: m/z
(%): 330 (Mþ, 10). Anal. calcd for C17H18N2O3S (330.39):
C, 61.79; H, 5.40; N, 8.48%. Found: C, 61.52; H, 5.62; N,
8.59%.
3.7.1. 7-Cyano-6-(methylthio)benzothiophene-4-car-
baldehyde (27). Yellow crystals (CHCl3–hexane); Rf 0.75
(9.5:0.5 hexane–EtOAc); mp 197–1998C. Yield 0.82 g,
70%; IR (KBr): 3123, 2919, 2218, 1681 cm21; dH
(400 MHz, CDCl3) 10.32 (1H, s, CHO), 8.27 (1H, d,
J¼5.6 Hz, CHv), 7.83 (1H, s, ArH), 7.76 (1H, d, J¼5.6 Hz,
CHv), 2.73 (3H, s, SCH3); dC (100 MHz, CDCl3) 190.1,
143.3, 141.1, 135.0, 134.0, 132.4, 128.4, 121.1, 115.4,
111.0, 17.1; MS: m/z (%): 233 (Mþ, 100). Anal. calcd for
C11H7NOS2 (233.32): C, 56.63; H, 3.02; N, 6.00%. Found:
C, 56.68; H, 3.01; N, 5.90%.
3.6. Acid induced hydrolysis of 22b,c to 23b,c
To an ice cold solution of dimethylacetal 22b,c (1 mmol) in
(CH3)2CO (22b) or CH2Cl2 (22c), 5 mL of 2N HCl was
added and the reaction mixture was stirred at room
temperature for 1 h. It was then neutralized with ice cooled
saturated NaHCO3 solution and the precipitated aldehydes
were filtered, dried and crystallized from hexane–CHCl3 to
give analytically pure products.
3.7.2. 4-Cyano-5-(methylthio)benzothiophene-7-car-
baldehyde (29). Yellow crystals (CHCl3–hexane); Rf 0.75
(9.5:0.5 hexane–EtOAc); mp 199–2008C. Yield 0.78 g,
67%; IR (KBr): 3113, 2208, 1688, 1308 cm21; dH
(400 MHz, CDCl3) 10.28 (1H, s, CHO), 7.88 (1H, d,
J¼5.6 Hz, CHv), 7.84 (1H, s, ArH), 7.61 (1H, d, J¼5.6 Hz,
CHv), 2.73 (3H, s, SCH3); dC (100 MHz, CDCl3) 190.1,
143.4, 141.1, 135.0, 134.2, 132.4, 128.5, 121.1, 115.4,
111.0, 17.1; MS: m/z (%): 233 (Mþ, 100). Anal. calcd for
C11H7NOS2 (233.32): C, 56.63; H, 3.02; N, 6.00%. Found:
C, 56.42; H, 3.10; N, 6.24%.
3.6.1. 3-Cyano-2-methoxymethyl-4-(methylthio)pyri-
dine-6-carbaldehyde (23b). Orange crystals (CHCl3–
hexane); Rf 0.5 (1:1 hexane–EtOAc); mp 114–1158C.
Yield 0.21 g, 95%; IR (KBr): 3158, 2274, 1651, 1438 cm21
;
dH (400 MHz, CDCl3) 10.08 (1H, s, CHO), 8.02 (1H, s,
CHv), 4.78 (2H, s, CH2OCH3), 3.56 (3H, s, OCH3), 2.66
(3H, s, SCH3); dC (100 MHz, CDCl3) 192.3, 161.2, 158.8,
152.0, 114.1, 113.4, 109.5, 73.7, 59.5, 14.3; MS: m/z (%):
224 (Mþ2, 15). Anal. calcd for C10H10N2O2S (222.26): C,
54.03; H, 4.50; N, 12.60%. Found: C, 54.20; H, 4.45; N,
12.81%.
3.6.2. 3-Cyano-4-(methylthio)-2-(4-methoxyphenyl)pyri-
dine-6-carbaldehyde (23c). Pale yellow crystals (CHCl3–
hexane); Rf 0.65 (8.5:1.5 hexane–EtOAc); mp 203–2048C.
Acknowledgements
P. K. M. and U. K. S. thank CSIR, New Delhi for Senior
Research Fellowships. Financial assistance under DST
project is also acknowledged.
Yield 0.27 g, 95%; IR (KBr): 3099, 2360, 2338, 1711 cm21
;
dH (400 MHz, CDCl3) 10.10 (1H, s, CHO), 7.95 (2H, dd,
J¼6.8, 1.9 Hz, ArH), 7.66 (1H, s, CHv), 7.06 (2H, dd,
J¼6.8, 1.9 Hz, ArH), 3.89 (3H, s, OCH3), 2.68 (3H, s,
SCH3); dC (100 MHz, CDCl3) 192.7, 161.7, 161.5, 159.4,
152.1, 130.7, 128.6, 115.3, 114.2, 112.2, 107.2, 55.5, 14.5;
MS: m/z (%): 284 (Mþ, 76.6). Anal. calcd for C15H12N2O2S
(284.33): C, 63.35; H, 4.20; N, 9.85%. Found: C, 63.26; H,
4.35; N, 9.95%.
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