Synthesis of 2-alkylthio-6-methylpyridine-3-carbaldehydes

Article abstract of DOI:10.1007/s11172-005-0385-2

The action of sodium bis(2-methoxyethoxy)aluminum hydride and its complex with piperidine on 2-alkylthio-3-cyano-6-methylpyridines and on their esters in anhydrous ether yielded 2-alkylthio-3-formyl-6-methylpyridines. The aldehydes obtained undergo condensation with malononitrile and methyl cyanoacetate to give the corresponding hetarylidene derivatives.

Full text of DOI:10.1007/s11172-005-0385-2

Russian Chemical Bulletin, International Edition, Vol. 54, No. 5, pp. 1229—1232, May, 2005
1229
Synthesis of 2ꢀalkylthioꢀ6ꢀmethylpyridineꢀ3ꢀcarbaldehydes*
A. A. Zubarev, V. K. Zav´yalova,ꢀ and V. P. Litvinov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: zvk@ioc.ac.ru
The action of sodium bis(2ꢀmethoxyethoxy)aluminum hydride and its complex with pipꢀ
eridine on 2ꢀalkylthioꢀ3ꢀcyanoꢀ6ꢀmethylpyridines and on their esters in anhydrous ether yielded
2ꢀalkylthioꢀ3ꢀformylꢀ6ꢀmethylpyridines. The aldehydes obtained undergo condensation with
malononitrile and methyl cyanoacetate to give the corresponding hetarylidene derivatives.
Key words: 2ꢀalkylthioꢀ3ꢀcyanoꢀ6ꢀmethylpyridines, 2ꢀalkylthioꢀ3ꢀformylꢀ6ꢀmethylꢀ
pyridines, aldehydes, sodium bis(2ꢀmethoxyethoxy)aluminum hydride, reduction, malonoꢀ
nitrile, methyl cyanoacetate, condensation.
Earlier,1 we demonstrated that the action of lithium
aluminum hydride on substituted 3ꢀcyanopyridineꢀ
2(1H )ꢀthiones and 2ꢀ(alkylthio)ꢀ3ꢀcyanopyridines in
boiling anhydrous ether affords the corresponding
3ꢀaminomethyl derivatives. The use of sodium
bis(2ꢀmethoxyethoxy)aluminum hydride (BMA) under
analogous conditions leads to various products, dependꢀ
ing on the structure of the starting reagent. For instance,
pyridineꢀ2(1H )ꢀthiones yield aminomethyl derivatives,
3ꢀcyanoꢀ6ꢀmethylꢀ2ꢀmethylthiopyridine yields azoꢀ
methine, and 3ꢀcyanoꢀ4,6ꢀdimethylꢀ2ꢀmethylthiopyriꢀ
dine yields a mixture of an amine, azomethine, and
dipyridylmethane.2
ratio of 1 : 2 (1H NMR data); use of more BMA leads to
byꢀproducts. With a milder reducing agent, BMAP, preꢀ
pared from BMA by the reaction with piperidine,5 the
yield of the target product was not increased significantly.
1
According to the H NMR data, the content of aldehyde
2a (in the mixture with the starting nitrile 1) in this case is
60% at a nitrile : BMAP ratio of 1 : 3 (Scheme 1). An
increase in the amount of BMAP causes side processes to
occur.
With the aim of increasing the yield of the aldehyde
and avoiding side processes, we used esters 3a,b (syntheꢀ
sized according to known procedures8,9) in the reduction
instead of the corresponding nitriles.
Apart from amines, aldehydes of the pyridineꢀ2(1H )ꢀ
thione and 2ꢀalkylthiopyridine series are of considerable
interest as building blocks in heterocyclic synthesis.
BMA is known3—7 to be used for the synthesis of not
only amines but also aldehydes from both nitriles3 and
esters;4,7 BMA is employed alone or together with secꢀ
ondary amines such as pyrrolidine, morpholine, and pipꢀ
eridine.5,6
In contrast to nitrile, the reduction of ester 3a with
BMA in ether at 0 °C led to 3ꢀhydroxymethylꢀ6ꢀmethylꢀ
2ꢀmethylthiopyridine (4) in 99% yield (see Scheme 1).
The structure of compound 4 was confirmed by data
1
from IR and H NMR spectroscopy and mass spectroꢀ
metry. Its IR spectrum contains no absorption band of the
CO2Me group but shows a wide band of the hydroxyl
1
group at 3350 cm–1; the H NMR spectrum contains a
The goal of the present study was to develop methods
of preparing aldehydes of the 2ꢀ(alkylthio)pyridine series
with BMA and its complex with piperidine (BMAP) as
reducing agents.
singlet signal for the methylene group at δ 4.67.
In contrast to the reaction with BMA, the reactions of
BMAP with methyl 6ꢀmethylꢀ2ꢀmethylthiopyridineꢀ3ꢀ
carboxylate (3a) and ethyl 2ꢀethylthioꢀ6ꢀmethylpyridineꢀ
3ꢀcarboxylate (3b) in boiling ether gave 3ꢀformylꢀ6ꢀmeꢀ
thylꢀ2ꢀmethylthiopyridine (2a) and 2ꢀethylthioꢀ3ꢀformylꢀ
6ꢀmethylpyridine (2b) in 99 and 80% yields, respectively
(see Scheme 1). Such a difference in the properties of the
reducing agents used is due to the relative stabilities of
aldehydes in the presence of BMAP under the aforemenꢀ
tioned conditions.5
Results and Discussion
We found that the action of BMA on 3ꢀcyanoꢀ6ꢀmeꢀ
thylꢀ2ꢀmethylthiopyridine (1) in ether at 0 °C gives aldeꢀ
hyde 2a (as a mixture with the starting nitrile 1). The
aldehyde content of the mixture is 50% at a nitrile : BMA
The structures of aldehydes 2a,b were confirmed by
1
data from IR and H NMR spectroscopy and mass specꢀ
* Dedicated to Academician N. K. Kochetkov on the occasion
of his 90th birthday.
trometry. Their IR spectra show a characteristic absorpꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1195—1198, May, 2005.
1066ꢀ5285/05/5405ꢀ1229 © 2005 Springer Science+Business Media, Inc.

1230
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
Zubarev et al.
Scheme 1
2, 3, 5: R = Me (a), Et (b)
Z = CN (5), CO2Me (6)
Reagents and conditions: i. NaAlH2(OC2H4OMe)2, Et2O,
iii. ZCH2CN, Et3N, EtOH.
0
°C; ii. NaAlH2(OC2H4OMe)2/piperidine, boiling Et2O;
tion band of the formyl group at 1696 cm–1; the 1H NMR
spectrum contains a singlet signal for the formyl proton at
δ 10.20 (2a) and 10.21 (2b).
Compounds 2a,b exhibit properties typical of aldeꢀ
hydes, e.g., they undergo condensation with malononitrile
and methyl cyanoacetate to give the corresponding ylidene
derivatives 5a,b and 6 (see Scheme 1).
the proton at the double bond is shifted downfield to
δ 8.14 (5a), 8.13 (5b), and 8.58 (6). The characteristics of
compounds 2 and 4—6 are given in Tables 1 and 2.
Thus, we demonstrated that the action of sodium
bis(2ꢀmethoxyethoxy)aluminum hydride and its comꢀ
plex with piperidine on 3ꢀcyanoꢀ6ꢀmethylꢀ2ꢀmethylꢀ
thiopyridine in anhydrous ether affords the correspondꢀ
ing aldehyde. However, the yields of the aldehyde are
low and byꢀproducts are formed. A more advisable route
to aldehydes involves the reaction of BMAP with the
corresponding esters rather than nitriles. The aldeꢀ
hydes obtained undergo condensation with malonoꢀ
nitrile and methyl cyanoacetate to give hetarylidene deꢀ
rivatives.
The structures of compounds 5a,b and 6 were conꢀ
1
firmed by data from IR and H NMR spectroscopy. The
IR spectra of ylidenes 5a,b show an absorption band of
the nitrile groups at 2224 (5a) and 2236 cm–1 (5b). The
IR spectrum of compound 6 contains absorption bands at
1
2224 (CN) and 1720 cm–1 (CO2Me). In the H NMR
spectra of the compounds obtained, the signal for
Table 1. Yields and physicochemical characteristics of compounds 2 and 4—6
Comꢀ
pound
Yield
(%)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
C
H
N
S
2a
2b
4
99
80
99
42
34
69
31—33
57.29
57.46
59.47
59.64
56.64
56.78
61.25
61.37
62.65
62.86
57.89
58.05
5.49
5.42
6.22
6.12
6.61
6.55
4.26
4.21
4.89
4.84
4.94
4.87
8.25
8.38
7.61
7.73
8.19
19.28
19.17
17.80
17.69
19.09
18.94
15.03
14.89
14.16
13.98
13.03
12.91
C8H9NOS
(C6H14
)
Liquid
C9H11NOS
C8H11NOS
C11H9N3S
59—61
(C6H14
)
8.28
5a
5b
6
107—109
19.43
19.52
18.43
18.33
11.16
11.28
(C6H14
)
64—66
C12H11N3S
C12H12N2O2S
(C6H14
)
139—141
(C6H14
)

Aldehydes of the 2ꢀalkylthiopyridine series
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
1231
Table 2. Spectroscopic characteristics of compounds 2 and 4—6
Comꢀ
pound
IR,
ν/cm–1
MS,
m/z (I (%))
1H NMR,
δ (J/Hz)
2a
2b
4
1696 (CH=O) 167 [M]+ (36.5), 150 (16.5), 139 (48.3), 2.58 (s, 3 H, SMe); 2.60 (s, 3 H, Me); 7.00 (d, 1 H, H(5),
125 (16.8), 111 (23.8), 85 (47.1),
69 (62.5), 57 (93.4), 43 (100)
—
J = 7.4); 7.89 (d, 1 H, H(4), J = 7.4);
10.20 (s, 1 H, CH=O)
1.40 (t, 3 H, CH2CH3); 2.58 (s, 3 H, Me);
3.29 (q, 2 H, CH2); 6.99 (d, 1 H, H(5), J = 7.4);
7.89 (d, 1 H, H(4), J = 7.4); 10.21 (s, 1 H, CH=O)
1696 (CH=O)
3350 (OH)
169 [M]+ (35.7), 154 (100), 136 (58.9), 2.50 (s, 3 H, SMe); 2.50 (s, 3 H, Me);
122 (35.6), 106 (15.5), 92 (36.3),
77 (12.2), 73 (12.9), 65 (25.4)
4.67 (s, 2 H, CH2OH); 6.87 (d, 1 H, H(5), J = 7.4);
7.48 (d, 1 H, H(4), J = 7.4)
5a
2224 (CN)
215 [M]+ (100), 200 (22.1), 189 (80.5), 2.60 (s, 3 H, SMe);
182 (22.6), 175 (32.4), 156 (23.4),
150 (67.3), 142 (17.4), 118 (17.5),
91 (20.3), 64 (10.6), 47 (10.7),
43 (21.7), 39 (19)
2.67 (s, 3 H, Me);
7.02 (d, 1 H, H(5), J = 7.4);
8.14 (s, 1 H, C=CH);
8.19 (d, 1 H, H(4), J = 7.4)
1.39 (t, 3 H, CH2CH3);
2.59 (s, 3 H, Me);
3.31 (q, 2 H, CH2);
7.01 (d, 1 H, H(5), J = 7.4);
8.13 (s, 1 H, C=CH);
8.18 (d, 1 H, H(4), J = 7.4)
2.58 (s, 3 H, SMe); 2.64 (s, 3 H, Me);
3.95 (s, 3 H, CO2Me);
6.99 (d, 1 H, H(5), J = 7.4);
8.25 (d, 1 H, H(4), J = 7.4);
8.58 (s, 1 H, C=CH)
5b
2236 (CN)
229 [M]+ (72.7), 214 (60.9), 200 (55),
196 (59.5), 175 (71.4), 169 (66.5),
164 (100), 142 (46.2), 131 (32.5),
118 (53.2), 114 (56.4), 93 (19.8),
88 (21.8), 77 (14.6), 69 (15.5),
57 (16), 43 (25.1)
6
2224 (CN);
248 [M]+ (17.6), 233 (9.8), 217 (7.2),
1720 (CO2Me) 189 (100), 174 (7.6), 156 (24.7),
150 (20.4), 144 (10.6), 117 (8.7),
104 (13.7), 91 (13.4), 77 (7), 63 (9.4),
45 (6.2), 43 (16.2), 39 (15.2)
rated, washed with water, dried over MgSO4, and concentrated
to give the product (0.48 g) as a yellow liquid. The content of
aldehyde 2a in the liquid was 60% (1H NMR data).
Experimental
Melting points were determined on a Kofler hot stage.
IR spectra were recorded on a Specord Mꢀ80 spectrophotoꢀ
meter (KBr pellets); 1H NMR spectra were recorded on a Bruker
WMꢀ250 spectrometer (250 MHz) in CDCl3 with a signal for
the solvent as the internal standard (δH 7.25). Mass spectra were
recorded on a Finnigan MAT INCOSꢀ50 instrument (ionizing
energy 70 eV). Elemental analysis was carried out with a
Perkin—Elmer 2400 instrument. 3ꢀCyanoꢀ6ꢀmethylꢀ2ꢀmethylꢀ
thiopyridine (1)10 and esters 3a,b 8,9 were prepared according
to known procedures. A commercial 70% solution of BMA
(Synthesia kolin Co.) in benzene was used.
3ꢀFormylꢀ6ꢀmethylꢀ2ꢀmethylthiopyridine (2a). A. Sodium
bis(2ꢀmethoxyethoxy)aluminum hydride (1.7 mL, 6.5 mmol)
was added for 30 min to a stirred solution of nitrile 1 (0.5 g,
3 mmol) in Et2O (30 mL), while maintaining the reaction temꢀ
perature at 0 °C. The red solution was stirred at the same temꢀ
perature for 3 h and then 10% aqueous H2SO4 (15 mL) was
added dropwise. The organic layer was separated, washed with
water, dried over MgSO4, and concentrated to give the product
(0.47 g) as an opaque yellow liquid. The content of aldehyde 2a
in the liquid was 50% (1H NMR data).
C. A 1 M solution of BMAP (6 mL, 6 mmol) in Et2O was
added dropwise for 20 min to a stirred boiling solution of ester 3a
(0.4 g, 2 mmol) in Et2O (20 mL). The yellow solution was
refluxed with stirring for 3.5 h and cooled and 10% HCl (10 mL)
was added dropwise. The organic layer was separated, washed
with water, dried over MgSO4, and concentrated to give aldeꢀ
hyde 2a (0.335 g, 99%) as yellow crystals.
2ꢀ(Ethylthio)ꢀ3ꢀformylꢀ6ꢀmethylpyridine (2b) was obtained
from ester 3b as described in procedure B for aldehyde 2a.
3ꢀHydroxymethylꢀ6ꢀmethylꢀ2ꢀmethylthiopyridine
(4).
Sodium bis(2ꢀmethoxyethoxy)aluminum hydride (1.15 mL,
4.1 mmol) was added dropwise for 25 min to a stirred solution of
ester 3a (0.4 g, 2 mmol) in Et2O (20 mL), while maintaining the
reaction temperature at 0 °C. The resulting light green solution
was stirred at the same temperature for 2.5 h and 10% HCl
(15 mL) was added dropwise. The organic layer was separated,
washed with water, dried over MgSO4, and concentrated to give
alcohol 4 (0.34 g, 99%) as colorless crystals.
2ꢀ(2ꢀAlkylthioꢀ6ꢀmethylpyridinꢀ3ꢀylmethylene)propanediꢀ
nitriles (5a,b). A drop of Et3N was added to a solution of aldeꢀ
hyde 2a or 2b (2 mmol) and malononitrile (0.13 g, 2 mmol) in
EtOH (5 mL). The resulting mixture was stirred at room temꢀ
perature for 12 h. The precipitate that formed was filtered off
and recrystallized from hexane to give ylidenes 5a or 5b, respecꢀ
tively, as yellow crystalline powders. The characteristics of comꢀ
pounds 5a,b are given in Tables 1 and 2.
B. A 1 M solution of BMAP (9 mL, 9 mmol) in Et2O was
added dropwise for 20 min to a stirred boiling solution of niꢀ
trile 1 (0.5 g, 3 mmol) in Et2O (25 mL). The resulting red
solution was refluxed with stirring for 3 h and cooled and 10%
HCl (10 mL) was added dropwise. The organic layer was sepaꢀ

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Zubarev et al.
Methyl
[2ꢀcyanoꢀ3ꢀ(6ꢀmethylꢀ2ꢀmethylthiopyridinꢀ3ꢀ
3. I. Stibor, M. Janda, and J. Srogl, Z. Chem., 1970, 10, 342.
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5. T. Abe, T. Haga, S. Negi, Y. Morita, K. Takayanagi, and
K. Hamamuza, Tetrahedron, 2001, 57, 2701.
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Chem. Soc. Jpn, 1989, 62, 3038.
8. C. Buehler and D. Pearson, Survey of Organic Syntheses,
WileyꢀInterscience, New York—London—Sydney—
Toronto, 1970.
yl)]propꢀ2ꢀenoate (6). A drop of Et3N was added to a solution of
aldehyde 2a (0.33 g, 2 mmol) and methyl cyanoacetate (0.2 g,
2 mmol) in EtOH (5 mL). The resulting mixture was refluxed
with stirring for 1 h and cooled. The precipitate that formed was
filtered off and washed with hexane to give ylidene 6 (0.35 g,
69%) as a light orange crystalline powder.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
32031).
9. Z. Weglinski, Pr. Nauk. Akad. Ekon. im. Oskara Langego
Wroclawiu, 1985, 313, 141; Chem. Abstrs, 1987, 106, 84355n.
10. L. A. Rodinovskaya, Yu. A. Sharanin, A. M. Shestopalov,
and V. P. Litvinov, Khim. Geterotsikl. Soedin., 1988, 805
[Chem. Heterocycl. Compd., 1988 (Engl. Transl.)].
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Received April 26, 2005;
in revised form May 20, 2005