Unusually mild and efficient synthesis of functionalized spiro-substituted 1,2,3,4-tetrahydro-nicotinamides by the michael reaction

Full text of DOI:10.1007/s10593-011-0854-5

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
UNUSUALLY MILD AND EFFICIENT
SYNTHESIS OF FUNCTIONALIZED
SPIRO-SUBSTITUTED 1,2,3,4-TETRAHYDRO-
NICOTINAMIDES BY THE MICHAEL REACTION
V. D. Dyachenko1* and I. E. Dyachenko1
Keywords: acetoacetanilide, ethyl acetoacetate, 1,2,3,4-tetrahydronicotinamides, cyclopentylidene-
cyanoacetamides, cyclohexylidenecyanoacetamides, Michael reaction.
The use of chalcogen amides of cyanoacetic acid in the synthesis of nicotinic acid nitriles by means of
the Michael reaction is well known [1–3]. On the other hand, the transformation of the nitrile group as a
substituent in the pyridine ring into an amide [4], ester [5], or acid group [6] requires relatively rigorous
conditions, similar to most reactions of nitriles [7].
We have found that cyclopentylidenecyanoacetamide 1a and cyclohexylidenecyanoacetamide 1b react
under conditions of the Michael reaction with acetoacetanilide 2a or ethyl acetoacetate 2b to give functionalized
spiro-substituted 1,2,3,4-tetrahydronicotinamides 3a,b in good yields.
The mechanism for the transformation of the nitrile group into an amide group, the scope of this reac-
tion, and the chemical and biological properties of products 3a,b are under investigation.
O
(
)
n
(
)
n
NH
O
O
R
+
R
NH2
NH2
EtOH,
20 oC
NC
1a,b
Me
O
Me
N
O
O
H
2a,b
3a,b
1, 3 а n = 1, b n = 2; 2, 3 a R = PhNH, b R = EtO
1
The IR spectra were taken on a Perkin-Elmer FIR Spectrum One for KBr pellets. The H NMR spectra
were taken on a Bruker DR-500 spectrometer at 500 MHz in DMSO-d6 solution with TMS as internal standard.
The 13C NMR spectrum for product 3a was taken on a Varian VXR-300 spectrometer at 75 MHz in DMSO-d6
with TMS as internal standard. The mass spectrum of product 3b was obtained on a Kratos MS-890 mass
_______
*To whom correspondence should be addressed, e-mail: chem@luguniv.ua.
1Taras Shevchenko Lugansk State University, 2 Oboronnaya St., Lugansk 91011, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 1106–1108, July, 2011. Original
article submitted May 11, 2011.
0009-3122/11/4707-0911©2011 Springer Science+Business Media, Inc.
911

spectrometer with direct sample inlet into the ion source. The course of the reactions and purity of the products
were monitored by thin-layer chromatography on Silufol UV-254 plates using 3:5 acetone–hexane as the eluent
with detection by iodine vapor and UV irradiation. The melting points were determined on a Kofler hot bench.
6-Methyl-2-oxo-5-phenylcarbamoyl-1,2,3,4-tetrahydrospiro[pyridine-4,1'-cyclopentane]-3-carbox-
amide (3a). Piperidine (1.2 ml, 12 mmol) was added to a stirred solution of cyclopentylidenecyanoacetamide
(1a) (1.5 g, 10 mmol) and acetoacetamide 2a (1.77 g, 10 mmol) in absolute ethanol (20 ml) at 20°C, stirred for
2 h, and left for 48 h. The precipitate formed was filtered off and washed with ethanol and hexane to give 2.0 g
1
(61%) carboxamide 3a; mp 258–260°C. IR spectrum, , cm–1: 3188–3415 (NH, NH2), 1785 (CONH). H NMR
spectrum, , ppm (J, Hz): 1.22–1.78 (8H, m, 4CH2); 1.82 (3H, s, CH3); 2.98 (1H, s, H-3); 6.96 (1H, t, J = 7.4,
H Ph); 7.80 (1H, br. s, NH2); 7.22 (2H, t, J = 7.4, H Ph); 7.34 (1H, br. s, NH2); 7.54 (2H, d, J = 7.8, H Ph); 9.36
(1H, br. s, NH); 9.44 (1H, br. s, NH). 13C NMR spectrum, , ppm: 17.32, 23.33, 33.14, 38.39, 47.11, 57.21,
119.92, 123.93, 129.20, 131.15, 139.35, 167.38, 167.85, 169.71. Found, %: C 65.89; H 6.33; N 12.72.
C18H21N3O3. Calculated, %: C 66.04; H 6.47; N 12.84.
5-Ethoxycarbonyl-6-methyl-2-oxo-1,2,3,4-tetrahydrospiro[pyridine-4,1'-cyclohexane]-3-carbox-
amide (3b) was obtained analogously to compound 3a using cyclohexylidenecyanoacetamide (1b) (1.76 g,
10 mmol) and ethyl acetoacetate 2b (1.27 ml, 10 mmol). The yield of carboxamide 3b was 2.12 g (72%);
1
mp 236–239°C. IR spectrum, , cm–1: 3192–3445 (NH, NH2), 1714 (C=O), 1678 (CONH). H NMR spectrum,
, ppm (J, Hz): 1.13 (2H, m, CH2); 1.24 (3H, t, J = 6.2, CH2CH3); 1.33–1.49 (4H, m, 2CH2); 1.52–1.74 (4H, m,
2CH2); 1.81 (3H, s, CH3); 3.49 (1H, s, H-3); 4.12 (2H, q, J = 6.2, CH2CH3); 6.82 (1H, br. s) and 7.29 (1H, br. s,
NH2); 9.34 (1H, br. s, NH). Electron-impact mass spectrum, m/z (Irel, %): 295 [M+1]+ (5), 294 [M]+ (31), 277
[M–NH3]+ (6), 250 (76), 248 (68), 209 (64), 208 (100), 204 (38), 180 (42), 176 (30), 123 (40), 91 (20), 79 (16),
77 (18), 67 (16), 65 (14), 55 (19), 42 (46). Found, %: C 61.14; H 7.41; N 9.39. C15H22N2O4. Calculated, %:
C 61.21; H 7.53; N 9.52.
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