Reductive desulfurization of 3-cyano-2-methylthiopyridines under the action of Raney nickel

Article abstract of DOI:10.1007/s11172-006-0158-6

The action of Raney nickel on substituted 3-cyano-2-methylthiopyridines was studied. Under conditions of catalytic hydrogenation, the reaction yields a mixture containing the aminosulfide resulting from reduction of the nitrile group with retention of the methylthio group, the nitrile resulting from elimination of the methylthio group, and the amine resulting from both reduction of the nitrile group and elimination of the methylthio group. Treatment of 3-cyano-2-methylthiopyridines with a large amount of Raney nickel under desulfurization conditions induces simultaneous elimination of the methylthio group and reduction of the nitrile group to the aminomethyl group. When reductive desulfurization is carried out in methanol or THF, primary amines are formed, while the reactions in isopropyl or ethyl alcohol give secondary or tertiary amines, which are formed upon alkylation of the amino group with alcohols.

Full text of DOI:10.1007/s11172-006-0158-6

2578
Russian Chemical Bulletin, International Edition, Vol. 54, No. 11, pp. 2578—2581, November, 2005
Reductive desulfurization of 3ꢀcyanoꢀ2ꢀmethylthiopyridines
under the action of Raney nickel
A. A. Zubarev, V. K. Zav´yalova,ꢀ and V. P. Litvinov
N. D. Zelinsky Institute of Organic Chemistry, Russian Akademy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7(495) 135 5328. Eꢀmail: zvk@ioc.ac.ru
The action of Raney nickel on substituted 3ꢀcyanoꢀ2ꢀmethylthiopyridines was studied.
Under conditions of catalytic hydrogenation, the reaction yields a mixture containing the
aminosulfide resulting from reduction of the nitrile group with retention of the methylthio
group, the nitrile resulting from elimination of the methylthio group, and the amine resulting
from both reduction of the nitrile group and elimination of the methylthio group. Treatment of
3ꢀcyanoꢀ2ꢀmethylthiopyridines with a large amount of Raney nickel under desulfurization
conditions induces simultaneous elimination of the methylthio group and reduction of the
nitrile group to the aminomethyl group. When reductive desulfurization is carried out in
methanol or THF, primary amines are formed, while the reactions in isopropyl or ethyl alcohol
give secondary or tertiary amines, which are formed upon alkylation of the amino group with
alcohols.
Key words: 3ꢀcyanoꢀ2ꢀmethylthiopyridines; 3ꢀaminomethylpyridines; primary, secondary,
and tertiary amines; Raney nickel; reduction; desulfurization; salts of amines.
Aminoalkyl groups are present in the molecules of
Results and Discussion
many natural biologically active compounds and drugs.1—3
In particular, Nꢀsubstituted 3ꢀaminomethylpyridines posꢀ
sess anticholinesterase activity and exhibit insecticide
properties, similar to those of nicotine and anabasine.4
Compounds of this type are usually prepared from nicoꢀ
tinic acid derivatives.4,5 The use of 3ꢀcyanoꢀ2ꢀmethylꢀ
thiopyridines containing various substituents in the pyriꢀ
dine ring seems to have good prospects for the syntheꢀ
sis of 3ꢀaminomethylpyridines. These starting comꢀ
pounds are readily available and the synthesis of the target
amines includes elimination of the methylthio group
and reduction of the nitrile group to the aminomethyl
group.
Raney nickel is widely used to carry out desulfurizaꢀ
tion of various sulfurꢀcontaining organic compounds.6
The removal of sulfur may be accompanied by the reducꢀ
tion of various functional groups, e.g., nitro and carbonyl
groups. In addition, Raney nickel is used as the catalyst
for hydrogenation of the nitrile group.7
We found that during catalytic hydrogenation of niꢀ
trile 1a under conditions described for nicotinonitrile,5
both reduction of the nitrile group and desulfurization
may take place. According to 1H NMR spectroscopy, the
reaction mixture contains amine 2 resulting from reducꢀ
tion of the nitrile group, nitrile 3 formed upon eliminaꢀ
tion of the MeS group, and amine 4a, the product of
simultaneous reduction of the nitrile and elimination of
the MeS groups. The ratio of the reaction products 2, 3,
and 4a was 5 : 4 : 1. No reduction of the pyridine ring was
detected.
The fact that compounds 2 and 3 are the major reacꢀ
tion products suggests that the nitrile group reduction and
MeS group elimination occur in parallel, while amine 4a
is formed upon the subsequent transformations of 2 and 3
under the reaction conditions.
To increase the yield of 3ꢀaminomethylpyridines conꢀ
taining no methylthio group, we carried out the reaction
of 3ꢀcyanoꢀ2ꢀmethylthiopyridines 1a—e with an excess
of Raney nickel under conditions described for reductive
desulfurization.6
In this case, the action of Raney nickel on substituted
3ꢀcyanoꢀ2ꢀmethylthiopyridines 1a—e results in eliminaꢀ
tion of the MeS group and reduction of the nitrile group
The purpose of this work is to study the action of
Raney nickel on substituted 3ꢀcyanoꢀ2ꢀmethylthiopyriꢀ
dines. The resulting 3ꢀaminomethylpyridines containing
various substituents in the pyridine nucleus may be of
substantial interest both for their biological activities and
as structural blocks in organic synthesis.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2497—2500, November, 2005.
1066ꢀ5285/05/5411ꢀ2578 © 2005 Springer Science+Business Media, Inc.

Synthesis of 3ꢀaminomethylpyridines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2579
Scheme 1
Comꢀ
pound
1a, 4a, 5a, 6a
1b, 4b, 5b, 6b
R1 = R3 R2
Comꢀ
R1 + R2 R3
i. H2 (200 atm), Raney Ni (125 g mol–1 nitrile), EtOH, 130 °C.
ii. Raney Ni (1.25 kg mol–1 nitrile), MeOH or THF, ∆.
iii. Raney Ni (1.25 kg mol–1 nitrile), EtOH, ∆.
pound
1c, 4c
1d, 5c
1e, 4d
Me
Ph
H
H
(CH2)3
(CH2)4
(CH2)5
H
H
H
iv. Raney Ni (1.25 kg mol–1 nitrile), PriOH, ∆.
to give the aminomethyl group. The synthesis was carried
out by refluxing compounds 1a—e with a suspension of a
large amount of Raney nickel in an organic solvent. It was
found that the structure of the reaction products depends
appreciably on the nature of the solvent used. The reacꢀ
tion carried out in methanol or tetrahydrofuran gives priꢀ
mary amines 4a—d. When ethanol is used as the solvent,
tertiary amines 5a—c are formed, and in isopropyl alcoꢀ
hol, the reaction gives secondary amines 6a,b. The IR
spectra of the resulting compounds exhibit no band for
the nitrile group but contain an N—H absorption band
(except for compounds 5a—c) at 3330—3450 cm–1
.
Amines 4—6 are colorless liquids or lowꢀmelting comꢀ
pounds, which were characterized as salts. 4,6ꢀDiphenylꢀ
substituted amines 4b, 5b, and 6b were isolated as hydroꢀ
chlorides by treatment with a saturated solution of HCl in
ether.
Amines 4a,c,d and 6a, whose hydrochlorides are highly
hygroscopic, were isolated as oxalates by treatment with a
saturated solution of oxalic acid in ether.
The structure of compounds 5a,c, 7a—c, and 8a—d
was confirmed by 1H NMR data. The 1H NMR spectra of
all compounds exhibit a signal for methylene group proꢀ
tons in the region of 3.4—4.4 ppm and no signal for the
MeS group; the signal of H(2) is a singlet located in a
lower field (δ 8.0—9.4) than the other signals for the
pyridine ring protons. In addition, the spectra of comꢀ
pounds 5a,c contain signals for two ethyl groups as a
triplet at δ 0.93—0.95 and a quartet at δ 2.4—2.9; the
spectra of compounds 7c and 8d show isopropyl group
signals as doublets at δ 1.15—1.30 and a sextet at δ 3.2—3.4.
The characteristics of compounds 5a,c, 7a—c, and 8a—d
are summarized in Tables 1 and 2.
Scheme 2
Thus, we demonstrated that treatment of substituted
3ꢀcyanoꢀ2ꢀmethylthiopyridines with Raney nickel under
conditions of catalytic hydrogenation induces eliminaꢀ
tion of the methylthio group and reduction of the nitrile
group to the aminomethyl group. Under catalytic hydroꢀ
genation conditions, the reaction affords a mixture of
three possible products: the aminosulfide resulting from
the reduction of the nitrile group, the nitrile formed upon
7a—c: R1 = R3 = Ph, R2 = H, R4 = R5 = H (a), Et (b),
R4 = H, R5 = Pri (c)
8a—d: R2 = R4 = H, R5 = H (a—c), Pri (d), R1 = R3 = Me (a, d),
R1 + R2 = (CH2)3 (b), (CH2)5 (c)

2580
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005
Zubarev et al.
Table 1. Characteristics of compounds 5a,c, 7a—c, and 8a—d
Comꢀ
pound
Mol.
weight
Yield**
(%)
M.p.
/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
5a
5c
7a
7b
7c
8a
8b
8c
8d
192
218
43.2
60.8
50.9
57
*
74.83
74.95
77.05
77.01
72.77
72.84
74.80
74.88
74.48
74.43
45.51
45.57
47.52
47.56
50.52
50.56
50.29
50.28
10.55
14.49
14.57
12.70
12.83
9.35
9.44
7.86
7.94
8.21
8.27
8.81
8.86
8.49
8.53
7.85
7.86
7.86
7.82
C12H20N2
10.48
10.18
10.16
5.86
5.77
7.25
7.14
6.89
6.84
5.18
5.10
5.01
4.91
5.78
5.66
6.42
6.19
*
C14H22N2
296.5
352.5
338.5
316
224—228
198—201
213—216
183—186
176—178
169—172
173—177
C18H16N2•HCl
C22H24N2•HCl
C21H22N2•HCl
C8H12N2•2 H2C2O4
C9H12N2•2 H2C2O4
75.8
36.5
54.3
53.7
47.7
328
356
C11H16N2•2 H2C2O4
C11H18N2•2 H2C2O4
358
* Liquid.
** The yields of salts 7, 8 are based on the starting nitriles 1.
Table 2. Spectroscopic characteristics of compounds 5a,s, 7a—s, and 8a—d
Comꢀ
pound
IR*,
ν/cm—1
1H NMR
(δ, J/Hz)
5a
5c
7a
7b
—
0.94 (t, 6 H, 2 CH2CH3, J = 6.7); 2.28 (s, 3 H, Me(4)); 2.37 (s, 3 H, Me(6)); 2.40 (q, 4 H,
2 CH2CH3, J = 6.7); 3.42 (s, 2 H, CH2NEt2); 6.99 (s, 1 H, H(5)); 8.18 (s, 1 H, H(2))
1.04 (t, 6 H, 2 CH2CH3, J = 6.7); 1.78 (m, 4 H, CH2); 2.49 (q, 4 H, 2 CH2CH3, J = 6.7);
2.76 (m, 4 H, CH2); 3.43 (s, 2 H, CH2NEt2); 7.14 (s, 1 H, H(5)); 8.01 (s, 1 H, H(2))
4.09 (m, 2 H, CH2NH2); 7.50—7.60 (m, 8 H, 4ꢀPh: H(2), H(6) + 6ꢀPh: H(3), H(5));
8.00 (s, 1 H, H(5)); 8.19 (m, 2 H, 6ꢀPh: H(2), H(6)); 9.14 (s, 1 H, H(2))
0.95 (m, 6 H, 2 CH2CH3); 2.89 (m, 4 H, 2 CH2CH3); 4.43 (s, 2 H, CH2NEt2);
7.50—7.62 (m, 8 H, 4ꢀPh: H(2), H(6) + 6ꢀPh: H(3), H(5)); 8.02 (s, 1 H, H(5)); 8.21
(m, 2 H, 6ꢀPh: H(2), H(6)); 9.40 (s, 1 H, H(2))
—
3448 (NH2)
—
7c
3356 (NH)
1.14 (d, 6 H, CH(CH3)2, J = 6.8); 3.18 (m, 1 H, CH); 4.21 (s, 2 H, CH2NHPri);
7.55—7.70 (m, 8 H, 4ꢀPh: H(2), H(6) + 6ꢀPh: H(3), H(5)); 7.86 (s, 1 H, H(5)); 8.24 (m,
2 H, 6ꢀPh: H(2), H(6)); 9.41 (s, 1 H, H(2))
8a
8b
8c
8d
3408 (NH2)
3387 (NH2)
3374 (NH2)
3328 (NH)
2.32 (s, 3 H, Me(4)); 2.41 (s, 3 H, Me(6)); 4.11 (s, 2 H, CH2NH2); 7.15 (s, 1 H, H(5));
8.38 (s, 1 H, H(2))
2.18 (m, 2 H, CH2(2)); 2.39 (m, 4 H, CH2); 4.12 (s, 1 H, CH2NH2); 7.41 (s, 1 H, H(4));
8.25 (s, 1 H, H(2))
1.54 (m, 4 H, CH2); 1.96 (m, 2 H, CH2(2)); 2.53 (m, 4 H, CH2); 4.09 (s, 2 H, CH2NH2);
7.21 (s, 1 H, H(4)); 8.13 (s, 1 H, H(2))
1.28 (d, 6 H, CH(CH3)2, J = 6.8); 2.34 (s, 3 H, Me(4)); 2.42 (s, 3 H, Me(6)); 3.42
(m, 1 H, CH); 4.15 (s, 2 H, CH2NHPri); 7.18 (s, 1 H, H(5)); 8.43 (s, 1 H, H(2))
* IR spectra were recorded for free amines.
abstraction of the MeS group, and the amine produced by
both processes taking place simultaneously. The lastꢀmenꢀ
tioned amines are formed as the only products when subꢀ
stituted 3ꢀcyanoꢀ2ꢀmethylthiopyridines are treated with
excess Raney nickel under desulfurization reaction conꢀ
ditions. The reactions in methanol or tetrahydrofuran yield

Synthesis of 3ꢀaminomethylpyridines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 11, November, 2005 2581
Salts 7, 8. Amines 4—6 were dissolved in 10 mL of ether, the
solution was mixed with 20 mL of a saturated ether solution of
HCl or oxalic acid, and the precipitate was filtered off to give
salts 7 and 8 as colorless crystals in 85—95% yields.
primary amines, and those in isopropyl or ethyl alcohol,
secondary or tertiary amines due to alkylation of the amino
group with alcohols.
Experimental
This work was performed with the financial support of
the Russian Foundation for Basic Research (Project
No 05ꢀ03ꢀ32031).
The melting points were determined on a Koeffler hot stage.
IR spectra were recorded on a Specord Mꢀ80 spectrophotomꢀ
eter in KBr pellets, 1H NMR spectra were run on a Bruker
ACꢀ200 instrument (200 МHz) in DMSOꢀd6. The solvent signal
was used as the internal standard (δH = 2.50). Elemental analyꢀ
sis was carried out on a Perkin—Elmer 2400 instrument.
3ꢀCyanoꢀ2ꢀmethylthiopyridines 1a—e were prepared by a known
procedure.8
Hydrogenation. Freshly prepared Raney nickel (prepared by
treatment of a suspension of 0.5 g of a Ni/Al alloy in H2O with
NaOH) was added to a solution of nitrile 1a (0.35 g, 2 mmol) in
EtOH (20 mL), and the mixture was hydrogenated in an autoꢀ
clave at 130 °C and a hydrogen pressure of 200 atm. The lightꢀ
green solution was filtered off from the catalyst, and the solvent
was evaporated to give 0.25 g of a lightꢀgreen liquid containing,
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according to H NMR data, compounds 2, 3, and 4a in 5 : 4 : 1
ratio.
3ꢀ(Aminomethyl)pyridines (4—6). Freshly prepared Raney
nickel (prepared by treatment of a suspension of 5 g of a Ni/Al
alloy in H2O with NaOH) was added to a solution of nitrile
1a—e (2 mmol) in the desired solvent (30 mL). The mixture was
refluxed for 5 h and cooled. Nickel was filtered off and the
solvent was evaporated to give amines 4—6 as colorless liquids
or lowꢀmelting compounds in 45—85% yields.
Received June 2, 2005;
in revised form September 6, 2005