Reactions of 3-cyano-2-(methylthio)pyridines with butyllithium

Article abstract of DOI:10.1007/s11172-008-0334-y

Reactions of substituted 3-cyano-2-(methylthio)pyridines with butyllithium were studied. The reactions afforded 3-pentanoylpyridines, 2,3-dihydrothieno[2, 3-b]pyridine, or 1-amino-2,7-naphthyridine, depending on the starting substrate and the reaction con

Full text of DOI:10.1007/s11172-008-0334-y

Russian Chemical Bulletin, International Edition, Vol. 57, No. 11, pp. 2349—2352, November, 2008
2349
Reactions of 3ꢀcyanoꢀ2ꢀ(methylthio)pyridines with butyllithium
V. K. Zav´yalova, A. A. Zubarev, and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: zvk@ioc.ac.ru
Reactions of substituted 3ꢀcyanoꢀ2ꢀ(methylthio)pyridines with butyllithium were studied.
The reactions afforded 3ꢀpentanoylpyridines, 2,3ꢀdihydrothieno[2,3ꢀb]pyridine, or 1ꢀaminoꢀ
2,7ꢀnaphthyridine, depending on the starting substrate and the reaction conditions.
Key words: 3ꢀcyanoꢀ2ꢀ(methylthio)pyridines, 3ꢀpentanoylpyridines, butyllithium,
2,3ꢀdihydrothieno[2,3ꢀb]pyridine, 1ꢀaminoꢀ2,7ꢀnaphthyridine.
Apparently, the reaction passes through imine formation
followed by deprotonation of the SMe group, which is
favored by the coordinating properties of both the sulfur
atom and the intermediate iminium anion. The resulting
dianion undergoes intramolecular cyclization into a
dihydrothiophene ring (see Scheme 1). Amine 3 was
characterized in the form of hydrochloride 4. Its structure
The pyridine ring is found in many compounds exhibꢀ
iting various biological activity.1,2 In a search for new
functionalized pyridines, including pyridineꢀ2ꢀthione
derivatives, a study of methods for transformations of the
cyano group in 3ꢀcyanopyridineꢀ2(1H)ꢀthiones is of both
theoretical and practical interest. In the last few years, we
studied the modification of the cyano group in those comꢀ
pounds under the action of butylꢀ and methyllithium,3,4
as well in the presence of such reducing agents5—7 as
lithium aluminum hydride and its derivatives. Substituted
2ꢀalkylthioꢀ3ꢀcyanopyridines were also used in the
reduction reaction. We found that the reaction pathway
substantially depends on both the structure of the starting
reagent and the conditions of the synthesis. These reacꢀ
tions involve not only the cyano group, which can be
reduced in different ways, but also adjacent substituents
such as 4ꢀmethyl and 2ꢀmethylthio groups, probably
because of the basic character of the reagents employed.
In connection with the aforesaid, the use of 3ꢀcyanoꢀ
2ꢀ(methylthio)pyridines in reactions with organometallic
compounds is of interest.
1
was confirmed by IR, H NMR, and mass spectra. The
IR spectrum of compound 3 contains absorption bands
1
at 3360 and 3272 cm–1 (NH2). The H NMR spectrum
shows, apart from the signals for the pyridine and butyl
protons, signals for the protons of the dihydropyridine
ring as a classic AB system: a quartet at δ 3.17 and 3.39
(2J = 11.8 Hz).
In contrast to nitrile 1a, a reaction of 3ꢀcyanoꢀ
4,6ꢀdimethylꢀ2ꢀ(methylthio)pyridine (1b) with butylꢀ
lithium (1 equiv.) is selective only at –20 °C, leading to
the corresponding ketone 2b in 88% yield. At –3 to –5 °C,
the yield of the target ketone 2b does not exceed 35%
because of resinification of the reaction mixture. Such a
decrease in the yield can be due to both steric hindrance
presented by the methyl group in position 4 and side
reactions. To verify the influence of steric hindrance, we
used in a similar reaction 3ꢀcyanoꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ
2ꢀmethylthioꢀ6ꢀphenylpyridine (1c) containing a bulkier
substituent in position 4. The yield of the target ketone 2c
(68%) is only slightly lower than the yield of compound
2a. The structures of compounds 2a—c were proved by
Results and Discussion
We found that the reaction outcome depends on
the structure of 3ꢀcyanoꢀ2ꢀ(methylthio)pyridines and the
reaction conditions. A reaction of 3ꢀcyanoꢀ6ꢀmethylꢀ
2ꢀ(methylthio)pyridine (1a) with butyllithium (1 equiv.)
in ether at –3 to –5 °C selectively gives, on treatment
with dilute HCl, the corresponding 3ꢀpentanoylpyridine
2a in high yield (Scheme 1). With an excess of butyllithium
(BuLi : 1a = 2—3 : 1) or in boiling ether, a small amount
of dihydrothienopyridine 3 is detected (1H NMR data).
The high yield of compound 3 was achieved by reflux of
pyridine 1a in ether with a threefold excess of butyllithium.
1
IR and H NMR spectroscopy and mass spectrometry.
The IR spectra of ketones 2a—c show an absorption band
at 1656—1672 cm–1 (C=O); the 1H NMR spectra exhibit
a system of signals for the butyl substituent.
In the case of 4,6ꢀdimethyl derivative 2a, the reaction
at the cyano group is probably accompanied by deprotoꢀ
nation of the 4ꢀmethyl group. This parallel process is
favored by the coordinating properties of the cyano group,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2303—2306, November, 2008.
1066ꢀ5285/08/5711ꢀ2349 © 2008 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Zav´yalova et al.
Scheme 1
i or ii
i. –3 to –5 °C (1a,c); ii. –20 °C (1b);
1,2: R = Me, R = H (a); R = R = Me (b); R = Ph, R = 4ꢀMeOC H (c).
1
2
1
2
1
2
6
4
Table 1. Characteristics of compounds 2a—c, 3, 5
Comꢀ
pounds
Molecular
weight
Yield
(%)
M.p./°С
(solvent)
Found
Calculated
Molecular
formula
(%)
C
H
N
2a
2b
2c
3
223
237
391
222
356
87
65—67
64.35
64.54
65.62
65.78
73.41
73.63
64.59
64.82
60.48
60.64
7.78
7.67
8.18
8.07
6.50
6.44
8.27
8.16
5.73
5.65
6.20
6.27
5.78
5.90
3.45
C12H17NOS
C13H19NOS
C24H25NO2S
C12H18N2S
C18H20N4S2
(C6H14
Oil
)
88.5
68
227—230
(EtOH)
Oil*
3.58
74
12.44
12.60
15.58
15.72
5
17
223—226
(Me2CO)
* For hydrochloride 4, m.p. 206—209 °C.
1H NMR spectrum shows no signal for the butyl substituꢀ
ent; yet it exhibits a broadened singlet at δ 6.20 (2 H,
NH2), five singlets at δ 2.07—2.75 (3 H each, CH3), and
three singlets at δ 6.78—6.98 for the protons of the
heteroaromatic rings.
Interestingly, the 6ꢀmethyl group remains inert in these
reactions in the presence of both the 4ꢀmethyl and SMe
group, although the latter is much less reactive. The fact
which initiates further substitution and polycondensation
reactions. This is confirmed by isolation from the reacꢀ
tion mixture of a small amount of substituted 1ꢀaminoꢀ
2,7ꢀnaphthyridine 5. Its structure was proved by IR and
1H NMR spectroscopy and mass spectrometry. The
IR spectrum of compound 5 contains no signals for the
carbonyl or cyano group; instead, the absorption bands
appear at 3436, 3284, and 1636 cm–1 (δ(NH2)). The

Reactions of 3ꢀcyanoꢀ2ꢀ(methylthio)pyridines with BuLi Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2351
Table 2. Spectroscopic characteristics of compounds 2a—c, 3, and 5
Comꢀ
pound
IR
ν/cm–1
MS
m/z, (I(%))
1H NMR
(δ, J/Hz)
2a
2b
2c
1672 (C=O)
1656 (C=O)
1668 (C=O)
223 (19.6) [М]+, 208 (35.4),
194 (30.2), 190 (32.6), 166
(100), 138 (20.1), 92 (27.4).
0.95 (t, 3 H, Meꢀδ, J = 7.5); 1.40 (m, 2 H, C(3)H2);
1.71 (m, 2 H, C(2)H2); 2.51 (s, 3 H, SMe);
2.56 (s, 3 H, Me(6)); 2.89 (t, 2 H, C(1)H2, J = 7.3);
6.90 (d, 1 H, H(5), J = 7.4); 7.95 (d, 1 H, H(4), J = 7.4)
236 (2.8) [М–1]+, 221 (61.4),
178 (100), 164 (26.4), 118
(26.3), 106 (64.6), 95 (77.8).
0.94 (t, 3 H, Meꢀδ, J = 7.5); 1.40 (m, 2 H, C(3)H2);
1.64 (m, 2 H, C(2)H2); 2.14 (s, 3 H, SMe);
2.46 (s, 3 H, Me(4)); 2.51 (s, 3 H, Me(6));
2.57 (t, 2 H, C(1)H2, J = 7.3); 6.69 (s, 1 H, H(5))
375 (100), 331 (53.5), 242
(15.9), 128 (28.1), 101 (31.9),
80 (38.9).
0.76 (t, 3 H, Meꢀδ, J = 7.5); 1.22 (m, 2 H,
C(3)H2), 1.53 (m, 2 H, C(2)H2); 2.60 (m, 2 H, C(1)H2);
2.77 (s, 3 H, SMe); 3.89 (s, 3 H, OMe); 7.05 (d, 2 H,
H(2)+H(6), MeOC6H4, J = 8.5); 7.40—7.51 (m, 6 H;
H(3)+H(5), MeOC6H4; H(3), H(4), H(5), Ph; H(5),
Py); 8.10 (m, 2 H, Ph, H(2)+H(6))
3
5
3360 (NH2)
3272 (NH2)
222 (9.7) [М]+, 207 (20.1),
165 (100), 150 (13.3), 138
(48.6), 132 (14.2), 119 (17.1),
92 (11.5).
0.87 (m, 3 H, Meꢀδ); 1.28 (m, 4 H, C(2)H2 + C(3)H2);
1.80 (m, 4 H, C(1)H2 + NH2); 2.46 (s, 3 H, Me); 3.17
(d, 1 H, Heq(2), J = 11.8); 3.39 (d, 1 H, Hаx(2), J = 11.8);
6.82 (d, 1 H, H(5), J = 7.3); 7.25 (d, 1 H, H(4), J = 7.3)
3436 (NH2)
3284 (NH2)
1636 (δ NH2)
356 (4.1) [М]+, 341 (100),
323 (6.3), 307 (6.5), 295 (6.3),
153 (6.3), 110 (8.3), 99 (22.2).
2.07 (s, 3 H, Me(6´); 2.48 (s, 3 H, SMe(2´));
2.50 (s, 3 H, Me(4´)); 2.56 (s, 3 H, Me(6));
6.20 (br.s, 2 H, NH2); 6.78 (s, 1 H, H(5´));
6.79 (s, 1 H, H(4)); 6.98 (s, 1 H, H(5))
Scheme 2

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Zav´yalova et al.
yield of amine 3 was 0.5 g (73.5%), a light brown oil. The oil was
dissolved in CH2Cl2 (15 mL) and precipitated with an excess of
a solution of HCl in ether. The precipitate of hydrochloride 4
(0.53 g, 91%) was filtered off.
that the reactions described above occur at the last two
substituents can be explained by intramolecular stabilizaꢀ
tion of the reaction intermediates via coordination to the
cyano group or products of its modification.8
1ꢀAminoꢀ3ꢀ[4,6ꢀdimethylꢀ2ꢀ(methylthio)pyridinꢀ3ꢀyl]ꢀ
6ꢀmethylꢀ8ꢀmethylthioꢀ2,7ꢀnaphthyridine (5). An ethereal soluꢀ
tion of BuLi (3.8 mL, 6.5 mmol; c = 0.11 g mL–1) was added
dropwise at –3 to –5 °C for 10 min to a solution of nitrile 1b
(1.1 g, 6 mmol) in ether (25 mL). The solution was stirred at
–3 to –5 °C for 1 h. Then 3% aqueous HCl (15 mL) was added.
The resulting twoꢀphase system was vigorously stirred without
cooling for 30 min. The organic layer was separated, washed
with water, dried over MgSO4, and concentrated. The yield of
ketone 2b was 0.49 g (35%). The aqueous layer was alkalified
with NaOH and the product was extracted with CHCl3. The
organic layer was dried over MgSO4 and concentrated. The dark
brown resinous residue was triturated with acetone (5 mL),
filtered off, and washed with acetone. The yield of amine 5
was 0.19 g (17%), a light gray powder.
To sum up, we demonstrated that the reactions of
3ꢀcyanoꢀ2ꢀ(methylthio)pyridines with butyllithium give
various products, depending on the reaction conditions.
A lowꢀtemperature reaction at an equimolar reagent—
substrate ratio yields 2ꢀmethylthioꢀ3ꢀpentanoylpyridines.
With an increase in the temperature and in the amount
of butyllithium, intraꢀ and intermolecular condensation
processes lead to 2,3ꢀdihydrothieno[2,3ꢀb]pyridines and
1ꢀaminoꢀ2,7ꢀnaphthyridines.
Experimental
Melting points were determined on a Kofler hot stage. IR
spectra were recorded on a Specord Mꢀ80 spectrophotometer
(in KBr pellets). 1H NMR spectra were recorded on a Bruker
WMꢀ250 spectrometer (250.13 MHz) in CDCl3. The signal of
the solvent (δH 7.25) served as the internal standard. Mass specꢀ
tra were measured on a Finnigan MAT INCOSꢀ50 instrument
(ionizing energy 70 eV).
This work was financially supported in part by the
Presidium of the Russian Academy of Sciences (Program
Pꢀ8, 2008).
References
Synthesis of 6ꢀmethylꢀ2ꢀmethylthioꢀ3ꢀpentanoylpyridine (2a)
and 4ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀmethylꢀ2ꢀmethylthioꢀ3ꢀpentanoylꢀ
pyridine (2c) (general procedure). An ethereal solution of BuLi
(3.8 mL, 6.5 mmol; c = 0.11 g mL–1) was added dropwise at
–3 to –5 °C for 10 min to a solution of nitrile 1a,c (6 mmol) in
ether (25 mL). The solution was stirred at –3 to –5 °C for 1 h.
Then 3% aqueous HCl (15 mL) was added. The resulting twoꢀ
phase system was vigorously stirred without cooling for 30 min.
The organic layer was separated, washed with water, dried over
MgSO4, and concentrated. The product was crystallized from
70% aqueous ethanol. The yields of ketones 2a and 2c as yellow
crystals were 1.18 g (87%) and 1.59 g (68%), respectively.
4,6ꢀDimethylꢀ2ꢀmethylthioꢀ3ꢀpentanoylpyridine (2b) was
obtained analogously from nitrile 1b (1.1 g, 6 mmol) at –20 °C.
The yield was 1.25 g (88%).
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3ꢀAminoꢀ3ꢀbutylꢀ6ꢀmethylꢀ2,3ꢀdihydrothieno[2,3ꢀb]pyridine
(3). An ethereal solution of BuLi (5.2 mL, 9 mmol; c = 0.11 g mL–1
)
was added to ether (25 mL). Then nitrile 1a (0.5 g, 3 mmol) was
added in portions at –3 to –5 °C for 10 min. The resulting
solution was stirred without cooling for 30 min, heated to
boiling, and refluxed with stirring for 30 min. On cooling, 5%
aqueous HCl (20 mL) was added and the mixture was stirred
without cooling for 30 min. The organic layer was separated,
washed with water, dried over MgSO4, and concentrated. The
yield of ketone 2a was 0.1 g (15%). The aqueous layer was
alkalified with NaOH and the product was extracted with CHCl3.
The organic layer was dried over MgSO4 and concentrated. The
Received April 1, 2008;
in revised form July 3, 2008