Synthesis of 2,3,4,6-tetrasubstituted pyridines as precursors to bicycles and polycycles

Article abstract of DOI:10.1039/a806439c

Ammonium 1,1,3-tricyano-2-methylprop-2-enide 1a and sodium 2-amino-1,1,3-tricyanoprop-2-enide 1b are treated with H₂S in absolute ethanol to afford 3,4,6-trisubstituted pyridine-2(1H)-thione 3a,b; their structures are confirmed by reaction with

Full text of DOI:10.1039/a806439c

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430 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 430^431y
Synthesis of 2,3,4,6-Tetrasubstituted Pyridines
as Precursors to Bicycles and Polycyclesy
Fathi A. Abu-Shanab*
Chemistry Department, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt
Ammonium 1,1,3-tricyano-2-methylprop-2-enide 1a and sodium 2-amino-1,1,3-tricyanoprop-2-enide 1b are
treated with H2S in absolute ethanol to afford 3,4,6-trisubstituted pyridine-2(1H)-thione 3a,b; their structures
are confirmed by reaction with phenacyl bromide to give 4a,b; also 3a,b reacts with DMFDMA to give 6a,b,
and on treatment of 6a with phenacyl bromide affords 8; reaction of 4b with DMFDMA gave 9 while meth-
ylation of 3a,b by methyl iodide in ethanolic sodium hydroxide gives 10a,b.
R
R
N
Interest in development of e¤cient synthetic approaches for
the preparation of functionalized 3-cyano-2(1H)-pyridine-
thiones is related to their use as versatile precursors in
the preparation of dyes, herbicides, bactericides and other
biologically active compounds.1;3
Generally, it is reported that 3-cyanopyridine-2(1H)-
thiones are prepared by the reaction of 2-cyano-
NC
N
NC
X
COPh
S
N
H
S
5
Me2N
7
PhCOCH2Br
DMFDMA
2 or 3
arylmethylenemalononitriles,4;5
1,4-dioxane
thioacetamide
with
1,3-diketones,6;7 b-enaminoketones,8;9 or bis(methylthio)-
methylene derivatives of malononitrile10 or 1,3-diketones.11
Ammonium 1,1,3-tricyano-2-methylprop-2-enide 1a and
sodium 2-amino-1,1,3-tricyanoprop-2-enide 1b are useful
reagents for the preparation of heterocyclic compounds.12
We now report that the treatment of ammonium
R
R
N
NH2
Mel
NaOH
CN
COPh
S
N
N
H
S
X
4
R
4,5a R = Me, X = NH2
b R = NH2, X = NH2
Me2N
1,1,3-tricyano-2-methylprop-2-enide
2-amino-1,1,3-tricyanoprop-2-enide 1b12 with H2S in
ethanol a¡orded trisubstituted pyridine-2(1H)-thione.
1a
and
sodium
6
6,7a R = Me
CN
a
b R = N=CHNMe2
4b
DMFDMA
1,4-dioxane
The mass spectrum shows molecular ion peaks at m/z
165 ꢀC7H7N3S† and 166 ꢀC6H6N4S† which indicates that
only one molecule of H2S is added. Two modes of
cyclisation may be envisaged, giving 4,5,6- or
3,4,6-trisubstituted products, as outlined in Scheme 1. In
practice only one isomer was isolated in each case, but their
spectra did not enable unequivocal identi¢cation. In their
1H NMR spectra, the signals for the ring protons were
at d ca. 5.9 but the chemical shifts for protons 3 and 5
of pyridin-2-ones are often very similar.13
H2N
N
10
SMe
6a
PhCOCH2Br
a R = Me
b R = NH2
Me
HN
N
N
S
NH2
COPh
COPh
S
N
N
N
Me2N
Me2N
Scheme 2
9
8
R
NC
R
CN
NC
NH2
S
show the disappearance of the cyano group, indicating that
the cyano group is on the same side of the thione group
and thus the products are the thieno[2,3-b]pyridine
derivatives 4a,b.14 For further con¢rmation, the amino
group was protected so that treatment of 2 or 3 with
DMFDMA in boiling dioxane a¡orded pyridine-
2(1H)-thione derivatives 6a,b or 7a,b which by IR show
the absence of the amino group. Further reaction of
pyridine-2(1H)-thione derivative 6a or 7a with phenacyl
bromide and potassium carbonate in ethanol gave
thieno[2,3-b]pyridine derivative 814 the IR spectrum of
which shows the disappearance of the cyano group and
the appearance of an amino group (n 3346, 3175 cm 1). This
also indicates that the cyano group is on the same side of
the thione group. Therefore the pyridine-2(1H)-thione
obtained by the reaction of the salts 1a,b with H2S is
the 3,4,6-trisubstituted pyridine-2(1H)-thione 3. The
tricyclic compound 915 can also be obtained by the reaction
of 4b with DMFDMA in boiling dioxane and its structure
was con¢rmed by 1H NMR which showed the disappear-
ance of the amino groups and mass spectra which showed
a molecular ion peak at m/z 349. Methylation of 3a,b
by methyl iodide in ethanolic sodium hydroxide a¡orded
the corresponding thioethers 10a,b.
H2N
N
S
H
2
NC
R
CN
H2S
–
CN
X +
R
S
CN
S
1
NC
R
NH2
CN
a R = Me, X = NH4
b R = NH2, X = Na
H2N
N
H
3
Scheme 1
Some illustrative reactions designed to con¢rm the
structure, and also to demonstrate the potential usefulness
of the products for further heterocyclic syntheses, are given
in Scheme 2. Thus reaction of pyridines 2 or 3 with
phenacyl bromide and potassium carbonate in ethanol gave
a product that may be formulated as 4 or 5. IR spectra
* E-mail: fathorg82@hotmail.com.
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1999 431
1H, enamine proton), 8.677 (s, 1H, enamine proton). MS (EI): m/z
Experimental
‡
276 (M , 100%) (Anal. Calc.: C, 52.15; H, 5.84; N, 30.43. Found: C,
Mps are uncorrected. IR spectra were recorded on a Perkin-Elmer
1710 FTIR spectrometer as KBr disks. NMR spectra were recorded
on a Bruker AC300 spectrometer at 200 MHz for solutions of CDCl3
and [2H6]dimethyl sulfoxide with tetramethylsilane (TMS) as an
internal standard unless otherwise recorded. Mass spectra were
obtained on Finnigan 4500 (low resolution) spectrometers using elec-
tron impact (EI). The salts, ammonium 1,1,3-tricyano-2-methyl-
prop-2-enide 1a and sodium 2-amino-1,1,3-tricyanoprop-2-enide
1b were prepared according to literature methods.12
Reaction of 1a,b with H2S.öGeneral Method. H2S was passed for
2 h through a solution of salts 1a,b (0.01 mol) in absolute ethanol.
Fine crystals separated and were recovered by ¢ltration and puri¢ed
by recrystallisation from the appropriate solvent.
51.92; H, 6.00; N, 30.56%).
Preparation of Compound 9.öEquimolar amounts of
thieno[2,3-b]pyridine 4b (0.3 g, 0.001 mol) and DMFDMA (0.26 ml,
0.002 mol) in dry dioxane were re£uxed for 2 h. The resultant solid
was recovered by ¢ltration and recrystallised from dioxane, mp
165^167 8C, yield 3 g (85%). dH(DMSO) 3.08 (s, 3H, CH3), 3.11
(s, 3H, CH3), 5.45 (s, 1H, ring proton), 7.46±7.55 (m, 3H, Ar), 7.74
(m, 2H, Ar), 8.36 (s, 1H, CH), 8.55 (s 1H, CH), 8.65 (br exch., 1H,
‡
NH). MS (EI): m/z 349 (M , 60%) (Anal. Calc.: C, 61.87; H, 4.33; N,
20.06. Found: C, 61.69; H, 4.25; N, 21.88%).
Preparation of 4-Substituted 6-Amino-3-cyano-2-methylthio-
pyridine-2(1H)-thione 10a,b.öPyridine-2(1H)-thione 3a,b (0.01 mol)
was dissolved in ethanol (25 ml)^sodium hydroxide (10%, 10 ml)
and treated with methyl iodide [2 ml(excess)] dropwise with stirring
at room temperature. The reaction mixture was left stirring at room
temperature for 2 h and the resultant solid recrystallised from ethanol
as colourless crystals.
6-Amino-3-cyano-4-methylpyridine-2(1H)-thione 3a. Crystallisa-
tion from ethanol, mp 260 8C (decomp.), yield 85%. IR: 3431, 3215
1
(NH2), 2150 cm (CN), dH(DMSO) 2.19 (s, 3H, CH3), 5.95 (s, 1H,
ring proton), 7.25 (br exchangeable, 2H, NH2), 12.25 (br exch., 1H,
‡
NH). MS (EI): m/z 165 (M , 100%) (Calc.: C, 50.9; H, 4.27; N, 25.45.
Found: C, 50.77; H, 4.15; N, 25.34%).
6-Amino-3-cyano-4-methyl-2-methylthiopyridine-2(1H)-thione 10a.
Mp 218^220 8C, yield 1.43 g (80%). IR: nmax 3340, 3310 (NH2),
4,6-Diamino-3-cyanopyridine-2(1H)-thione 3b. Crystallisation
from ethanol, mp 310^312 8C, yield 65%. IR: 3346, 3215 (NH2),
1
2165 cm (CN), dH(DMSO) 2.22 (s, 3H, CH3), 2.5 (s, 3H, CH3), 6.1
(s, 1H, ring proton), 6.97 (br exch., 2H, NH2). MS (EI): m/z 179
1
2155 cm (CN), dH(DMSO) 5.29 (s, 1H, ring proton), 6.54 (br
exch., 2H, NH2), 6.69 (br exch., 2H, NH2), 11.19 (s, exch., 1H, NH).
‡
(M , 100%) (Anal. Calc.: C, 53.62; H, 5.07; N, 23.46. Found: C,
53.77; H, 5.17; N, 23.28%).
‡
MS (EI): m/z 166 (M , 100%) (Calc.: C, 43.37; H, 3.64; N, 33.74.
Found: C, 43.16; H, 3.42; N, 33.52%).
4,6-Diamino-3-cyano-2-methylthiopyridine-2(1H)-thione 10b. Mp
153^155 8C, yield 1.4 g (77%). IR: nmax 3430, 3320, 3205 (NH2),
2150 (CN), 1618, 1573 (CˆN, CˆC† cm 1, dH(DMSO) 2.45 (s, 3H,
SCH3), 3.46 (br exch., 2H, NH2), 5.46 (s, 1H, ring proton), 6.23 (br
Preparation of Thieno[2,3-b]pyridines 4a,b and 8).öGeneral
Method. An equimolar mixture of pyridine-2(1H)-thione 3a,b or
6a (0.01 mol), phenacyl bromide (1.99 g, 0.01 mol) and potassium
carbonate in absolute ethanol were re£uxed for 2 h. After cooling
the mixture was diluted with water and the solid obtained recovered
by ¢ltration and puri¢ed by recrystallisation from the appropriate
solvent.
3,6-Diamino-2-benzoyl-4-methylthieno[2,3-b]pyridine 4a. Crystal-
lisation from ethanol, mp 280^282 8C, yield 2.4 g (86%). IR: nmax
3460, 3325, 3160 (NH2), 1630 (CO) cm 1. dH(DMSO) 2.61 (s, 1H,
CH3), 6.27 (s, 1H, ring proton), 6.84 (br exch., 2H, NH2), 7.49±7.53
(m, 3H, Ar), 7.67±7.73 (m, 2H, Ar), 8.00 (br exch., 2H, NH2). MS
‡
exch., 1H, NH2). MS (EI): m/z 180 (M , 100%) (Anal. Calc.: C,
46.65; H, 4.48; N, 31.11. Found: C, 46.44; H, 4.60; N, 30.96%).
Received, 17th August 1998; Accepted, 29th March 1999
Paper E/8/06439C
References
‡
(EI): m/z 283 (M , 70%) (Anal. Calc.: C, 63.59; H, 4.63; N, 14.84.
Found: C, 63.28; H, 4.33; N, 14.57%).
1
V. P. Litvino, L. A. Rodinovskaya, Yu. A. Sharanin, A. M.
Shestopalov and A. Senning, Sulfur Rep., 1992, 13, 155.
A. M. Shestopalov, V. K. Promomenkov, Yu. A. Sharanin, L.
A. Rodinovskaya and S. Yu. Sharanin, Zh. Org. Khim., 1984,
20, 1517.
A. M. Shestopalov, V. K. Promomenkov, Yu. A. Sharanin and
A. M. Shestopalov, Enaminocarbonyl Compounds in Synthesis
of 3-cyano-2(1H)-pyridinethiones, in Itogi Nauki i Techniki,
Ser. Organicheskaya Khimiya, ed. Kabachnie, VINITI,
Moscow, 1989, vol. 17, pp. 72^156 and references therein.
G. E. Elgemeier, M. M. Sallam, M. S. Sherif and M. H.
Elnagdi, Heterocycles, 1985, 23, 3107.
3,5,6-Triamino-2-benzoylthieno[2,3-b]pyridine 4b. Crystallisation
from ethanol, mp 240^242 8C, yield 2.3 g (82%). IR: nmax 3390,
3150 (NH2), 1637 (CO) cm 1. dH(DMSO) 5.66 (s, 1H, ring proton),
6.5 (br exch., 2H, NH2), 6.45 (br exch., 1H, NH2), 7.45±7.51 (m, 3H,
Ar), 7.64±7.69 (m, 2H, Ar), 8.36 (br exch., 1H, NH2). MS (EI): m/z
2
3
‡
284 (M , 30%) (Anal. Calc.: C, 59.14; H, 4.26; N, 19.72. Found: C,
58.86; H, 4.39; N, 19.50%).
3-Amino-6-(N,N-dimethylformimdyl)-4-methylthieno[2,3-b]pyridi-
ne 8. Crystallisation from ethanol, mp 167^169 8C, yield 2.7 g (80%).
IR: nmax 3346, 3175 (NH2), 1632 (CO) cm 1. dH(DMSO) 2.64 (s, 1H,
CH3), 3.05 (s, 3H, NCH3), 3.18 (s, 3H, NCH3), 6.3 (s, 1H, ring
proton), 6.5 (br exch., 2H, NH2), 7.48±7.55 (m, 3H, Ar), 7.67±7.73
4
5
F. M. A. Galil, M. M. Sallam, M. S. Sherif and M. H. Elnagdi,
Liebigs Ann. Chem., 1986, 1639.
‡
(m, 2H, Ar), 8.4 (s, 1H, enamine proton). MS (EI): m/z 338 (M ,
30%) (Anal. Calc.: C, 63.88; H, 5.37; N, 16.57. Found: C, 63.67;
H, 5.42; N, 16.65%).
Preparation of Pyridine-2(1H)-thiones 6a,b.öPyridine-2(1H)-
thione 3a,b (0.01 mol) and DMFDMA in dry dioxane were re£uxed
for 2 h. The solvent was then evaporated and the resulting solid col-
lected by ¢ltration and recrystallised from ethanol.
3-Cyano-6-(N,N-dimethylformimdyl)-4-methylpyridine-2(1H)-thi-
one 6a. Mp 186^188 8C, yield 1.7 g (76%). IR: nmax 2150 cm
(CN), dH(DMSO) 2.26 (s, 3H, CH3), 3.04 (s, 3H, NCH3), 3.16 (s, 3H,
NCH3), 6.42 (s, 1H, ring proton) 8.32 (s, 1H, enamine proton), 12.69
6
7
8
U. Schmidt and H. Kubitzek, Chem. Ber., 1960, 93, 1559.
H. Vieweg, S. Leistner and G. Wagner, Pharmazie, 1986, 41.
F. A. Abu-Shanab, A. D. Redhouse, J. R. Thompson and B. J.
Wake¢eld, Synthesis, 1995, 557.
F. A. Abu-Shanab, F. A. Ali and B. J. Wake¢eld, Synthesis,
1995, 923.
9
10 D. Briel, S. Dumke, G. Wagner and B. Olk, J. Chem. Res.,
1991, (S) 178; (M) 1841.
11 F. A. Abu-Shanab, M. H. Elnagdi, F. A. Ali and B. J.
Wake¢eld, J. Chem. Soc., Perkin Trans. 1, 1994, 1449.
12 A. W. Erian, Chem. Rev., 1993, 93, 1991 and references
therein.
13 D. H. Williams and I. Fleming, Spectroscopic Methods in
Organic Chemistry, McGraw-Hill, London, 4th edn., 1987.
14 K. Gewald, Chimia, 1980, 34, 101 and references therein.
15 H. Sliwa, D. Blondeau and R. Rydzkowsk, J. Heterocycl.
Chem., 1983, 20, 1613.
1
‡
(br exch., 1H, NH). MS (EI): m/z 220 (M , 100%) (Anal. Calc.: C,
54.53; H, 5.50; N, 25.45. Found: C, 54.66; H, 5.34; N, 25.26%).
3-Cyano-4,6-bis(N,N-dimethylformimdyl)pyridine-2(1H)-thione 6b.
1
Mp 160^162 8C, yield 2.2 g (80%). IR: nmax 2160 cm
(CN),
dH(DMSO) 3.005 (s, 3H, NCH3), 3.013 (s, 3H, NCH3), 3.102 (s,
3H, NCH3), 3.131 (s, 3H, NCH3) 6.273 (s, 1H, ring proton), 8.184 (s,