Propanal in the syntheses of alkyl-substituted 3-cyano-2-piperidone, 3-cyano-2,5,6,7-tetrahydropyrindin-2(1H)-one, and 3-cyanopyridine-2(1H)-thione

Article abstract of DOI:10.1007/s10593-005-0244-y

Condensation of propanal with cyanothioacetamide and morpholine gave 3-cyano-4-ethyl-5-methyl-6-morpholino-2-piperidone, the structure of which was studied by X-ray analysis. Reaction of propanal with cyanothioacetamides and cycloalkanone enamines gave 3-cyano-4-ethyl-2,5,6,7-tetrahydropyrindin-2(1H)-one and 3-cyano-4-ethyl-5,6-hexamethylenepyridine-2(1H)-thione. The latter was used for the preparation of substituted 2-benzyloxycarbonylmethylthiopyridine and 3-amino-2-benzyloxycarbonylthieno[2,3-b]pyridine. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0244-y

Chemistry of Heterocyclic Compounds, Vol. 41, No. 7, 2005
PROPANAL IN THE SYNTHESES OF ALKYL-
SUBSTITUTED 3-CYANO-2-PIPERIDONE, 3-CYANO-
2,5,6,7-TETRAHYDROPYRINDIN-2(1H)-ONE,
AND 3-CYANOPYRIDINE-2(1H)-THIONE
V. D. Dyachenko1 and A. N. Chernega2
Condensation of propanal with cyanothioacetamide and morpholine gave 3-cyano-4-ethyl-5-methyl-6-
morpholino-2-piperidone, the structure of which was studied by X-ray analysis. Reaction of propanal
with
cyanothioacetamides
and
cycloalkanone
enamines
gave
3-cyano-4-ethyl-2,5,6,7-
tetrahydropyrindin-2(1H)-one and 3-cyano-4-ethyl-5,6-hexamethylenepyridine-2(1H)-thione. The latter
was used for the preparation of substituted 2-benzyloxycarbonylmethylthiopyridine and 3-amino-2-
benzyloxycarbonylthieno[2,3-b]pyridine.
Keywords: Michael adduct, 3-cyano-4-ethyl-5,6-hexamethylenepyridine-2(1H)-thione, enamines,
propanal, thieno[2,3-b]pyridine, cyanoacetamide, cyanothioacetamide, 3-cyano-4-ethyl-2,5,6,7-
tetrahydropyrindin-2(1H)-one, condensation.
Alkyl-substituted pyridin-2(1H)-ones show promise in the search for compounds having biological
activity [1, 2]. They represent a novel class of non-nucleosidic anti-AIDS substances [3, 4]. A convenient
method for their synthesis is the formylation of methyl alkyl ketones [5, 6] and cycloalkanones [7] with
subsequent condensation of the products formed with cyanoacetamide.
Continuing the search for potentially biologically active alkyl-substituted pyridine chalcogenones based
on aliphatic aldehydes and cyanoacetic acid chalcogen amides [8, 9] we have studied the reaction of propanal (1)
with cyanoacetamide (2) and morpholine. It was found that the condensation occurred at 20°C in ethanol to give
3-cyano-4-ethyl-5-methyl-6-morpholino-2-piperidone (3). The reaction route very likely includes the formation
of enamine 4 and the substituted acrylamide 5, reaction of which leads to the Michael adduct 6. A regioselective
intramolecular cyclization of the latter gives the substituted piperidone 3. It should be noted that an equimolar
ratio of reagents 1 and 2 gives a yield not exceeding 32% but the introduction of a two-fold excess of the
propanal into this condensation led to an 84% yield of compound 3 and confirmed the proposed reaction
mechanism (Scheme 1).
The structure of compound 3 was proved by X-ray analysis (Table 1 and Fig. 1). The central piperidone
ring N(1)C(1-5) has a half-boat conformation (the modified Cremer-Pople [10] parameters S, θ, and Ψ being 0.82,
30.3°, and 28.7° respectively) and the morpholine ring N(3)C(10-13)O(2) has a chair conformation (S = 1.20,
θ = 0.7°, Ψ = 12.5°), the deviation of the torsional angles in the ring from the ideal value of 60.0° less than 2.8°.
__________________________________________________________________________________________
1
Taras Shevchenko National Pedagogical University, Lugansk 91011, Ukraine, e-mail:
2
dvd_lug@online.lg.ua. Organic Chemistry Institute, Ukraine National Academy of Sciences, Kiev 02094.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1053-1059, July, 2005. Original article
submitted March 12, 2003.
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0009-3122/05/4107-0890©2005 Springer Science+Business Media, Inc.

Scheme 1
Me
H
N
Me
CN
O
N
CN
O
Me
O
2
+
+
CHO
– 2
Me
H2O
H2N
H2N
O
4
5
1
2
Me
Me
N
CN
O
Me
N
CN
O
..
H2N
N
H
O
O
3
6
The N(1) atom has a planar trigonal bond configuration (the sum of valence angles being 357.8(2.9)°) and the
N(3) atom is pyramidal (the sum of the valence angles is 340.0(5)°). As a result of n(N(1))–π(C(1)=O(1))
conjugation the N(1)–C(1) bond length (1.331(3) Å) is markedly shortened when compared with the length
d = 1.45 Å which is typical of a pure N(sp2)–C(sp2) single bond [11]. Thanks to moderately strong
N(1)–H(1)···O(1) intermolecular hydrogen bonding [12] compound 3 forms a centrosymmetric dimer in the crystal
(Fig. 2). The basic geometric parameters for this H bond are: N(1)–H(1) 0.91(2), N(1)···O(1) 2.917(3), O(1)···H(1)
2.02(2) Å with N(1)–H(1)–O(1) 168(1)°.
Fig. 1. General view of molecule 3 with atomic numbering.
891

The introduction of the 1-morpholinocyclopentene (7) into the condensation with propanal (1) and
cyanoacetamide (2) gives 3-cyano-4-ethyl-2,5,6,7-tetrahydropyrindin-2(1H)-one (8). Evidently the reaction
route includes the formation of alkene 5, to which enamine 7 reacts by a Michael addition. The adduct 9 arising
in this way undergoes an intramolecular cyclocondensation to give compound 8.
Me
Me
O
N
CN
O
7
CN
O
..
H2N
1
2
+
N
O
N
H
8
9
The propanal (1) also readily takes part in a condensation with cyanothioacetamide (10) and
1-morpholinocyclooctene (11) to form the Michael adduct 12 in situ. Under these reaction conditions the latter
regioselectively cyclizes to 3-cyano-4-ethyl-5,6-hexamethylenepyridine-2(1H)-thione (13).
N
Me
O
CN
CN
11
1 +
..
H2N
H2N
S
S
N
O
10
12
Ph
O
O
Me
Me
CN
S
CN
S
Cl
O
Ph
N
N
H
O
13
14
Me
NH2
Ph
KOH
O
O
S
N
15
Its structure was confirmed by spectroscopic investigational data and by chemical reactions. Hence the
pyridinethione 13 is regioselectively alkylated by benzyl monochloroacetate in basic medium to the sulfide 14
which can be converted to the corresponding substituted thieno[2,3-b]pyridine 15 using KOH.
892

Fig. 2. Crystal packing of compound 3 (dotted lines indicate the intermolecular hydrogen bonds).
TABLE 1. Basic Bond Lengths (d) and Valence Angles (ω) in the
Compound 3 Molecule
Bond
d, Å
Angle
ω, deg.
1.230(2)
1.331(3)
1.490(3)
1.136(3)
1.524(3)
1.526(3)
1.534(3)
1.542(3)
1.479(3)
0.91(2)
127.72(17)
117.24(18)
110.82(17)
108.22(16)
114.83(16)
178.2(2)
O(1)−C(1)
N(1)−C(1)
N(1)−C(2)
N(2)−C(6)
C(1)−C(5)
C(2)−C(3)
C(3)−C(4)
C(4)−C(5)
C(5)−C(6)
N(1)−H(1)
C(1)−N(1)−C(2)
N(1)−C(1)−C(5)
N(1)−C(2)−C(3)
C(3)−C(4)−C(5)
C(1)−C(5)−C(4)
N(2)−C(6)−C(5)
C(1)−N(1)−C(2)
C(1)−N(1)−H(1)
C(2)−N(1)−H(1)
127.72(17)
112.6(14)
117.5(13)
EXPERIMENTAL
X-ray Analysis of the Compound 3 Single Crystal with the linear size 0.31 x 0.31 x 0.31 mm was
carried out at room temperature on an Enraf-Nonius CAD-4, four circle, automatic diffractometer (MoKα
irradiation, relative scanning rate 2θ/ω = 1.2, θmax = 25°, spherical segment 0 ≤ h ≤ 7, 0 ≤ k ≤ 16, -18 ≤ l ≤ 18). In
all, 2772 reflections were collected of which 2421 are symmetrically independent (Rint = 0.02). Crystals of 3 are
monoclinic with a = 6.653(2), b = 13.558(1), c = 15.444(2) Å; β = 75.15(1)°; V = 1381.6(5) Å3; M = 251.33; Z =
4; dcalc = 1.21 g/cm3; µ = 0.78 cm-1, F(000) = 544.1, and space group P21/n (N 14). The structure was solved by a
direct method and refined by least squares analysis using the full matrix anisotropic approximation and the
CRYSTALS program package [13]. 1540 Reflections with I > 3(I) were used in the refinement (247 refined
893

parameters, number of reflections per parameter 6.2). All of the hydrogen atoms were revealed in electron
density difference synthesis and included in the refinement with fixed positions and thermal parameters.
Calculation of the absorption in the crystal was carried out using the azimuthal scanning method [14]. The
refinement used the Chebyshev weighting scheme with the five parameters: 0.76, -0.07, 0.53, -0.15, and 0.14.
The final values of the difference factors were R = 0.039 and RW = 0.040, GOF = 1.191. The residual electron
density from Fourier difference synthesis was 0.16 and -0.15 e/Å3. The coordinates of the non-hydrogen atoms
can be obtained from one of the authors (A. N. Chernega).
The IR spectra of the synthesized compounds were recorded on an IRS-29 instrument using vaseline oil.
1H NMR spectra were recorded on Gemini-200 (200 MHz) (compounds 3, 8, 14, 15) and Bruker WP-100 SY
(100 MHz) (compound 13) instruments using DMSO-d6 and TMS internal standard. Mass spectra were taken on
a Kratos MS-890 (70 eV) spectrometer. Melting points were determined on a Koffler block. Monitoring of the
reaction course was carried out by TLC using Silufol UV-254 plates with acetone–hexane (3:5) and revealed
using iodine vapor.
3-Cyano-4-ethyl-5-methyl-6-morpholino-2-piperidone (3). A mixture of propanal 1 (1.46 ml,
20 mmol), cyanoacetamide 2 (0.84 g, 10 mmol), and morpholine (0.87 ml, 10 mmol) was stirred in ethanol
(15 ml) at 20°C for 2 h and left for 1 day. The precipitate formed was filtered off and washed with ethanol and
hexane to give compound 3 (2.11 g, 84%) as colorless crystals; mp 179-180°C (EtOH). IR spectrum, ν, cm-1:
1
3200 (NH), 2247 (C≡N), 1648 (CONH). H NMR spectrum, δ, ppm (J, Hz): 0.93 (3H, t, J = 7.26, CH3); 1.02
(3H, d, J = 6.20, CH3); 1.69 (4H, m, CH2CH3, C(4)H and C(5)H); 2.36 (2H, m, CH2); 2.77 (2H, m, CH2); 3.09 (1H,
m, C(6)H); 3.57 (4H, m, CH2OCH2); 3.80 (1H, d, J = 11.80, C(3)H); 8.23 (1H, br. s, NH). Mass spectrum, m/z
(Irel, %): 251 [M]+ (3), 181 (70), 135 (17), 86 (67), 57 (100), 41 (27). Found, %: C 61.92; H 8.30; N 16.89.
C13H21N3O2. Calculated, %: C 62.13; H 8.42; N 16.72.
3-Cyano-4-ethyl-2,5,6,7-tetrahydropyrindin-2(1H)-one (8). A mixture of propanal 1 (0.73 ml,
10 mmol), cyanoacetamide 2 (0.84 g, 10 mmol), and 1-morpholinocyclopentene 7 (1.53 g, 10 mmol) was stirred
in ethanol (15 ml) at 20°C for 1 h and left for 1 day. The precipitate formed was filtered off and washed with
ethanol and hexane to give compound 8 (1.39 g, 74%) as colorless flakes with mp 185-187°C (EtOH) and
1
fluorescing with a blue light upon UV irradiation. IR spectrum, ν, cm-1: 2214 (C≡N), 1644 (CONH). H NMR
spectrum, δ, ppm (J, Hz): 1.20 (3H, t, J = 7.62, CH3); 2.10 (2H, m, CH2); 2.59 (2H, t, J = 7.78, CH2); 2.71 (2H, t,
J = 7.62, CH2); 2.79 (2H, t, J = 7.88, CH2CH3); 12.47 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 188 [M]+
(100), 187 (90), 159 (36), 77 (10). Found, %: C 70.04; H 6.52; N 15.03. C11H12N2O. Calculated, %: C 70.19;
H 6.43; N 14.88.
3-Cyano-4-ethyl-5,6-hexamethylenepyridine-2(1H)-thione (13). A mixture of propanal 1 (0.73 ml,
10 mmol), cyanothioacetamide (1.0 g, 10 mmol), and 1-morpholinocyclooctene 11 (1.95 g, 10 mmol) was stirred
in ethanol (15 mol) for 1 h at 20°C and left for one day. The precipitate was separated and washed with ethanol
and hexane to give compound 13 (1.85 g, 75%) as bright-yellow crystals; mp 234°C (EtOH, sublimation occurs
1
at 150°C). IR spectrum, ν, cm-1: 2224 (C≡N). H NMR spectrum, δ, ppm (J, Hz): 1.16 (3H, t, J = 7.60, CH3);
1.36-1.61 (6H, m, (CH2)3); 2.43-2.98 (8H, m, (CH2)4); 13.77 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 246
[M]+ (100), 245 (9), 230(27), 217 (50), 203 (46), 178 (14), 91 (15), 77 (13), 41 (25). Found, %: C 68.12; H 7.20;
N 11.42. C14H18N2S. Calculated, %: C 68.25; H 7.36; N 11.37.
2-Benzyloxycarbonylmethylthio-3-cyano-4-ethyl-5,6-hexamethylenepyridine (14). Aqueous KOH
solution (10%, 5.6 ml, 10 mmol) and benzyl monochloroacetate (1.85 g, 10 mmol) were added successively with
stirring to a solution of the pyridinethione 13 (2.46 g, 10 mmol) in DMF (10 ml) and the product was stirred for
4 h. The reaction mixture was diluted with water (15 ml) and filtered to give a precipitate which was washed
with water, ethanol, and hexane to give compound 14 (2.96 g, 72%) as yellow crystals; mp 97-98°C (EtOH).
IR spectrum, ν, cm-1: 2220 (C≡N), 1694 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.23 (3H, t, J = 7.12, CH3);
1.33 (4H, m, (CH2)2); 1.64 (4H, m, (CH2)2); 2.81 (6H, m, (CH2)3); 4.03 (2H, s, SCH2); 5.09 (2H, s, OCH2); 7.28
(5H, m, C6H5). Mass spectrum, m/z (Irel, %): 394 [M]+ (18), 259 (100), 246 (11), 91 (58), 77 (4), 65 (10).
Found, %: C 69.84; H 6.72; N 6.95. C23H26N2O2S. Calculated, %: C 70.02; H 6.64; N 7.10.
894

3-Amino-2-benzyloxycarbonyl-4-ethyl-5,6-hexamethylenethieno[2,3-b]pyridine (15). Aqueous KOH
solution (10%, 5.6 ml, 10 mmol) was added to a solution of compound 14 (3.94 g, 10 mmol) in DMF (10 ml)
with stirring and then stirred for 5 h. The reaction mixture was treated with ethanol (10 ml) and filtered to give a
precipitate which was washed with ethanol and hexane to give compound 15 (3.51 g, 89%) as opaque flakes;
1
mp 184-185°C (EtOH). IR spectrum, ν, cm-1: 3240, 3318, 3492 (NH2), 1718 (C=O), 1646 (δ NH2). H NMR
spectrum, δ, ppm (J, Hz): 1.28 (3H, t, J = 7.11, CH3); 1.50 (4H, m, (CH2)2); 1.73 (4H, m, (CH2)2); 2.97 (6H, m,
(CH2)3); 5.30 (2H, s, OCH2); 6.76 (2H, br. s, NH2); 7.35 (5H, m, C6H5). Mass spectrum, m/z (Irel, %): 394 [M]+
(70), 285 (33), 260 (12), 91 [PhCH2]+ (100), 77 (3), 65 (9). Found, %: C 70.14; H 6.51; H 7.19. C23H26N2O2S.
Calculated, %: C 70.02; H 6.64; N 7.10.
REFERENCES
1.
A. T. Soldatenkov, N. M. Kolyadina, and I. V. Shendrik, Basic Organic Chemistry of Medicinal
Compounds [in Russian], Khimiya, Moscow (2001).
2.
3.
V. D. Dyachenko, Doctorial Dissertation in Chemical Sciences, Moscow (1998).
J. S. Wai, T. M. Williams, D. L. Bamberger, T. E. Fisher, J. M. Hoffman, R. J. Hudcosky,
S. C. Mactough, C. S. Rooney, and W. S. Saari, J. Med. Chem., 36, 249 (1993); Chem. Abstr., 118,
124358 (1993).
4.
5.
M. A. Wallace, D. C. Dean, R. L. Ellsworth, and D. C. Melitto, J. Labell. Compounds Radiopharm., 38,
155 (1996); Ref. Zh. Khim., 13O123 (1996).
W. S. Saari, J. M. Hoffman, J. S. Wai, T. E. Fisher, C. S. Rooney, A. M. Smith, C. M. Thomas,
M. E. Goldman, J. A. O∋Brien, J. H. Nunberg, J. C. Quintero, W. A. Schleit, E. A. Emini, A. M. Stern,
and P. S. Anderson, J. Med. Chem., 34, 2922 (1991).
6.
I. N. Houpis, A. Molina, J. Lynch, R. A. Reamer, R. P. Volante, and P. J. Reider, J. Org. Chem., 58,
3176 (1993).
7.
8.
L. A. Rodinovskaya, Doctorial Dissertation in Chemical Sciences, Moscow (1994).
V. D. Dyachenko, V. N. Nesterov, S. G. Krivokolysko, and V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim.,
196 (1997).
9.
10.
11.
12.
13.
V. D. Dyachenko, S. G. Krivokolysko, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 1094 (1996).
N. S. Zefirov and V. A. Palyulin, Dokl. Akad. Nauk, 252, 111 (1980).
M. Burke-Laing and M. Laing, Acta Crystallogr., B32, 3216 (1976).
L. N. Kuleshova and P. M. Zorkii, Acta Crystallogr., B37, 1363 (1981).
D. J. Watkin, C. K. Prout, J. R. Carruthers, and P. W. Betteridge, CRYSTALS, Issue 10, Chemical
Crystallography Laboratory, Oxford University (1996).
14.
15.
A. C. T. North, D. C. Phillips, F. Scott, and F. S. Mathews, Acta Crystallogr., A24, 351 (1968).
J. R. Carruthers and D. J. Watkin, Acta Crystallogr., A35, 698 (1979).
895