Facile and efficient synthesis of 4-alkyl derivatives of 3-carbamoyl- and 3,5-dicarbamoylpyridines as nicotinamide mimetics

Article abstract of DOI:10.1055/s-0030-1258264

Nicotinamide plays a key role in many biological processes and, as a consequence, its derivatives could be attractive for the synthesis of biologically active compounds. Here a rapid and efficient way of preparing alkyl derivatives of nicotinamide, precisely, 4-alkyl-3-carbamoylpyridine and 4-alkyl-3,5-dicarbamoylpyridine is reported. The synthetic route developed adopts mild reaction conditions and produces target compounds in higher yields compared with methods described in literature. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258264

PAPER
3835
Facile and Efficient Synthesis of 4-Alkyl Derivatives of 3-Carbamoyl- and
3,5-Dicarbamoylpyridines as Nicotinamide Mimetics
Synthesis of
A
lky
a
l
D
erivativ
r
es of
N
i
b
cotinamide ara Di Rienzo, Paolo Mellini, Silvano Tortorella, Daniela De Vita, Luigi Scipione*
Department of ‘Chimica e Tecnologie del Farmaco’, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
Fax +39(06)49913133; E-mail: luigi.scipione@uniroma1.it
Received 16 July 2010; revised 29 August 2010
Bobbit and Scola.3 The conversion of 3 to the correspond-
ing pure 3-cyano-2,6-dibromo-4-methylpyridine (4) in
75% yield was carried out by treatment with phosphorous
oxybromide; heating to melting point and refluxing for
Abstract: Nicotinamide plays a key role in many biological pro-
cesses and, as a consequence, its derivatives could be attractive for
the synthesis of biologically active compounds. Here a rapid and
efficient way of preparing alkyl derivatives of nicotinamide, pre-
cisely, 4-alkyl-3-carbamoylpyridine and 4-alkyl-3,5-dicarbam- two hours at 190–200 °C. Bobbit and Scola obtained the
oylpyridine is reported. The synthetic route developed adopts mild
2,6-dichloro derivative by reaction with phosphorus oxy-
reaction conditions and produces target compounds in higher yields
compared with methods described in literature.
chloride at high temperature in an autoclave. In our hands,
any attempt to obtain the 2,6-dichloro derivative failed;
instead complex mixtures of polychlorinated compounds
were obtained in which the hydrogens of the 4-methyl
Key words: amides, drugs, hydrogenation, nicotinamide deriva-
tives, nitrile hydrolysis, pyridines
group are substituted by one or more chlorine atoms. The
bromination reaction is more selective than chlorination
Nicotinamide is an essential nutrient, a precursor of nico-
tinamide adenine dinucleotide (NAD) and nicotinamide
adenine dinucleotide phosphate (NADP), and participates
with different roles in many biological processes. Recent-
ly a number of other new biological activities of nicotin-
amide have been described; for example, it is a direct
reaction product and a potent physiological inhibitor of
Sir2 enzymes, a unique class of NAD+-dependent protein
deacetylases (class III Histone/Protein deacetylases).1
Furthermore, pyridine derivatives are substrates or inhib-
itors of transglycosidation reactions catalyzed by Sir2.2 In
this context, it could be of interest to evaluate the title
compounds as NAD and nicotinamide mimetic models
and also as intermediates for the preparation of further de-
rivatives, such as carboxylic acids and esters, to be stud-
ied, for example, as modulator of sirtuine enzyme. The
synthesis of 4-alkyl derivatives of 3-carbamoylpyridine
(Scheme 1) and 3,5-dicarbamoylpyridine (Scheme 2) is
reported here.
and, moreover, bromine is a better leaving group for the
subsequent step. In fact, the hydrogenolysis of 4 was car-
ried out in THF–NH4OH solution simply by adding a re-
ducing metal, such as Zn powder, and boiling the reaction
mixture for two hours. The cyano derivative 5 was then
converted to the corresponding nicotinamide derivative 6
with a selective alkaline hydrolysis accomplished by
treatment with alkaline ion-exchange resin, for example,
Amberlite IRA 410.
The salts 7 and 8 were obtained by condensing cyanoacet-
amide with acetaldehyde in the presence of piperidine4
and propionaldehyde in the presence of ammonia, respec-
tively (Scheme 2). Also in this case, the conversion of 7
and 8 to the corresponding dibromo derivatives 9a,b was
conducted successfully in good yields, avoiding polychlo-
rination products, by treatment with phosphorous oxybro-
mide, by heating to melting point and refluxing for one
hour at 170 °C. Hydrogenolysis of 9a,b proceeded in
good yields in the presence of Pd/CaCO3 by simply bub-
bling H2 through the reaction mixture at room temperature
and atmospheric pressure to afford 4-methylpyridine-3,5-
dicarbonitrile (10a) and 4-ethyl-1,2-dihydropiridine-3,5-
dicarbonitrile (10b).
For the synthesis of 3-carbamoyl-4-methylpyridine (6),
the corresponding 3-cyano-4-methylpyridine (5) was cho-
sen as the starting material (Scheme 1). This nitrile was
prepared in two steps, from 3-cyano-2,6-dihydroxy-4-
methylpyridine (3), modifying the procedure described by
O
NC
NC
NC
H2N
c
a
b
N
Br
N
Br
N
HO
N
OH
3
4
5
6
Scheme 1 Reagents and conditions: (a) POBr3, 190 °C; (b) Zn, NH4OH–THF; (c) 10% aq NaOH, IRA 410.
SYNTHESIS 2010, No. 22, pp 3835–3838
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.09.2010
DOI: 10.1055/s-0030-1258264; Art ID: P11510SS
© Georg Thieme Verlag Stuttgart · New York

3836
B. Di Rienzo et al.
PAPER
R
O
O
NC
HO
CN
O–
CN
NC
a
+
NC
2
+
N
NH2
H
e
c
d
N
N
H
H
R
R
N
7
10a
NC
Br
CN
Br
H2NOC
CONH2
N
d
c
e
R
O
NC
CN
O
9a,b
11a,b
b
NC
CN
+
+
2
NC
NH4
NH2
H
HO
N
O–
N
H
8
a: R = Me
b: R = Et
10b
Scheme 2 Reagents and conditions: (a) piperidine–MeOH; (b) aq 25% NH3; (c) POBr3, 190 °C; (d) H2, Pd/CaCO3, EtOH–benzene (1:1);
(e) 10% aq NaOH, IRA 410.
13C NMR (CDCl3): d = 155.7, 144.3, 143.1, 128.2, 114.6, 114.0,
Selective hydrolysis of the cyano group in 10a,b with
20.7.
Amberlite IRA 410 resin caused also the oxidation of 1,2-
dihydropyridine, generating amide derivatives 11a,b. It is Anal. Calcd for C7H4Br2N2: C, 30.47; H, 1.46; N, 10.15. Found: C,
1
30.07; H, 1.73; N, 9.78.
noteworthy that H NMR spectra of solutions of 10b in
DMSO-d6 shelved at room temperature in air, showed the
progressive oxidation to the corresponding 4-ethylpyri-
dine-3,5-dicarbonitrile.
4-Methylpyridine-3-carbonitrile (5)
To the nitrile 4 (1.00 g, 3.6 mmol) dissolved in anhyd THF (25 mL)
were added Zn powder (5 g) and 15% aq NH3 (100 mL) and the sus-
pension was refluxed for 4 h. The reaction mixture was cooled to
r.t., the Zn residue was filtered off, and the solution was extracted
Chemical reagents and solvents used in this study were purchased
from Sigma-Aldrich Chemical Co. and were of analytical grade.
with CHCl3 (7 × 100 mL). The combined organic layers were dried
(Na2SO4) and evaporated under reduced pressure to give a crude
Melting points were determined on a Tottoli apparatus and are un-
residue that was purified by silica gel column chromatography
corrected. IR spectra were registered on neat compounds on a
Perkin-Elmer Spectrum-One spectrophotometer equipped with an
(CHCl3–EtOAc, 6:4 v/v) to give (0.34 g, 2.9 mmol, 80%) 5; mp 44–
46 °C.
IR (neat): 2227, 1593 cm–1.
1H NMR (CDCl3): d = 8.90 (s, 1 H, H-2), 8.69 (d, J = 5.1 Hz, 1 H,
H-6), 7.52 (d, J = 5.1 Hz, 1 H, H-5), 2.50 (s, 3 H, CH3).
ATR detector; band frequencies are reported in wavenumber (cm–1).
1H and 13C NMR spectra were acquired on a Bruker Avance 400
spectrometer operating at 400 and 100 MHz, respectively. Chemi-
cal shift values, unless otherwise stated, are reported as d (ppm) rel-
atively to TMS as internal reference; coupling constants are given
in Hz. Yields of all reactions refer to the purified products.
13C NMR (CDCl3): d = 152.6, 152.4, 150.7, 124.8, 115.8, 110.8,
20.0.
2,6-Dihydroxy-4-methylpyridine-3-carbonitrile (3)
This compound was prepared according to Bobbit and Scola;3
mp 295–300 °C.
Anal. Calcd for C7H6N2: C, 71.17; H, 5.12; N, 23.71. Found: C,
70.93; H, 5.26; N, 23.78.
IR (neat): 2223, 1597 cm–1.
4-Methylpyridine-3-carboxamide (6)
To 4-methylpyridine-3-carbonitrile (5; 0.50 g, 4.2 mmol) dispersed
in freshly degassed H2O (25 mL) was added anionic exchange resin
IRA 410 (1.0 g) previously conditioned as follows: IRA 410 (1 g)
was suspended in 10% aq NaOH (15 mL) and stirred at r.t. for 90
min, after this time the resin was filtered and washed with degassed
H2O until the pH of washings was nearly 7. The suspension contain-
ing 6 and IRA 410 was refluxed for 1 h and then the resin was fil-
tered off and washed with boiling water (2 × 10 mL). The combined
aqueous portions were lyophilized to give pure 6 (0.49 g, 3.6 mmol,
86%); mp 159–161 °C (Lit.3 mp 167–167.5 °C).
1H NMR (DMSO-d6): d = 5.57 (s, 1 H, H-5), 2.21 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 162.3, 161.5, 160.8, 117.6, 93.2, 89.5,
21.1.
Anal. Calcd for C7H6N2O2: C, 56.00; H, 4.03; N, 18.66. Found: C,
55.87; H, 4.39; N, 18.27.
2,6-Dibromo-4-methylpyridine-3-carbonitrile (4)
A mixture of 3 (2.00 g, 13.3 mmol) and POBr3 (7.64 g, 26.6 mmol)
was heated in a sand bath and maintained at 190 °C for 2 h. The re-
action mixture was then cooled to r.t. and quenched by the addition
of ice. The obtained suspension was extracted with CHCl3 (4 × 50
mL). The combined organic extracts were dried (Na2SO4) and evap-
orated under reduced pressure. The solid residue was purified by sil-
ica gel column chromatography (eluent: CHCl3) to give pure 4 (2.77
g, 10.0 mmol, 75%); mp 137–140 °C.
IR (neat): 3304, 1667, 1598 cm–1.
1H NMR (DMSO-d6): d = 10.3 (s, 1 H, NH), 8.45 (d, J = 4.9 Hz, 1
H, H-6), 7.92 (br s, 1 H, NHa), 7.56 (br s, 1 H, NHb), 7.27 (d, J = 4.9
Hz, 1 H, H-5), 2.37 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 163.7, 159.9, 119.3, 82.4, 44.29, 22.71,
22.09, 19.9.
IR (neat): 2230, 1560 cm–1.
1H NMR (CDCl3): d = 7.48 (s, 1 H, H-2), 1.26 (s, 3 H, CH3).
Anal. Calcd for C7H8N2O: C, 61.75; H, 5.92; N, 20.58. Found: C,
62.04; H, 6.02; N, 19.97.
Synthesis 2010, No. 22, 3835–3838 © Thieme Stuttgart · New York

PAPER
Synthesis of Alkyl Derivatives of Nicotinamide
3837
Piperidinium 3,5-Dicyano-4-methyl-6-hydroxypyridin-2-olate
(7)
4-Methylpyridine-3,5-dicarbonitrile (10a)
2,6-Dibromo-4-methylpyridine-3, 5-dicarbonitrile (9a; 1.47 g, 4.9
mmol) was dissolved in a 1:1 mixture of EtOH and benzene (50 mL)
in a two-necked round-bottomed flask. Pd/CaCO3 (1 g) was then
added and H2 was bubbled through the reaction mixture. The mix-
ture was slowly stirred and maintained under H2 atmosphere, the
product formation was monitored by means of silica gel TLC
(EtOAc–CHCl3, 6:4 v/v). After 3 days, the catalyst was removed by
filtration and the solvent evaporated under reduced pressure. The
remaining thick oil was treated with sat. aq NaHCO3 (15 mL) and
the obtained suspension was extracted with CHCl3 (3 × 20 mL). The
combined organic layers were dried (Na2SO4) and evaporated under
reduced pressure to give a yellow solid that was purified on silica
gel column chromatography (EtOAc–CHCl3, 6:4 v/v) to afford pure
10a (0.51 g, 3.6 mmol, 73%); mp 80–82 °C (Lit.5 mp 84–85 °C).
A mixture of cyanoacetamide (5.98 g, 71.0 mmol), piperidine
(12.17 g, 143.0 mmol) and MeOH (45 mL) was heated until com-
plete dissolution. The obtained solution was cooled to r.t. and acet-
aldehyde (1.56 g, 35.50 mmol) was then added, maintaining the
mixture for 24 h under vigorous stirring. The volume of the ob-
tained suspension was halved under reduced pressure and the white
precipitate was collected, washed with EtOAc (3 × 10 mL), and
dried under reduced pressure to give pure 7 (6.49 g, 24.9 mmol,
70%); mp 245–247 °C.
IR (neat): 3143, 2197, 1655 cm–1.
1H NMR (DMSO-d6): d = 3.00 (m, 4 H, 2 CH2), 2.17 (s, 3 H, CH3),
1.63 (m, 4 H, 2 CH2), 1.55 (m, 2 H, CH2).
13C NMR (DMSO-d6): d = 163.7, 159.9, 119.3, 82.4, 44.29, 22.71,
22.09, 19.9.
IR (neat): 3076, 2193, 1632 cm–1.
1H NMR (DMSO-d6): d = 9.05 (s, 2 H, H-2,6), 2.62 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 156.4, 155.6, 115.8, 111.8, 20.1.
Anal. Calcd for C13H16N4O2: C, 59.99; H, 6.20; N, 21.52. Found: C,
59.53; H, 6.07; N, 20.37.
Anal. Calcd for C8H5N3: C, 67.12; H, 3.52; N, 29.35. Found: C,
67.41; H, 3.46; N, 29.15.
Ammonium 3,5-Dicyano-4-ethyl-6-hydroxypyridin-2-olate (8)
This compound was prepared according to the procedure described
by Lukes and Kuthan.4 Cyanocetamide (6.02 g, 71.4 mmol) was
suspended in H2O (40 mL), then 25% aq NH3 (2 mL) and propional-
dehyde (2.14 g, 37.0 mmol) were added. The mixture was stirred for
20 h at r.t. The obtained white precipitate was collected by filtration,
washed with small portions of cold MeOH, and dried under reduced
pressure to give pure 8 (5.34 g, 25.9 mmol, 70%); mp >300 °C.
IR (neat): 3165, 2210, 1666 cm–1.
1H NMR (DMSO-d6): d = 2.45 (q, J = 7.6 Hz, 2 H, CH2), 1.13 (t,
J = 7.6 Hz, 3 H, CH3).
4-Ethyl-1,2-dihydropyridine-3,5-dicarbonitrile (10b)
Product 10b (0.41 g, 2.6 mmol, 67%) was prepared from 9b (1.23
g, 3.9 mmol) following the same procedure as described for 10a;
mp 155–160 °C (Lit.6 mp 182–187 °C).
IR (neat): 3313, 2250, 1633 cm–1.
1H NMR (DMSO-d6): d = 8.38 (br s, 1 H, NH), 7.55 (s, 1 H, H-6),
4.10 (s, 2 H, H-2 + H-2¢), 2.30 (q, J = 7.5 Hz, 2 H, CH2), 1.08 (t,
J = 7.5 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 153.2, 152.9, 118.1, 115.1, 83.6, 77.6,
41.7, 27.1, 13.4.
13C NMR (DMSO-d6): d = 165.9, 164.2, 118.9, 81.3, 27.4, 14.0.
Anal. Calcd for C9H10N4O2: C, 52.42; H, 4.89; N, 27.17. Found: C,
51.97; H, 5.06; N, 26.85.
Anal. Calcd for C9H9N3: C, 67.90; H, 5.70; N, 26.40. Found: C,
66.46; H, 6.23; N, 26.01.
2,6-Dibromo-4-methylpyridine-3,5-dicarbonitrile (9a)
A mixture of 7 (2.00 g, 7.7 mmol) and POBr3 (4.41 g, 15.4 mmol)
was carefully heated in a sand bath at 170 °C and maintained under
stirring at this temperature for 1 h. After cooling to r.t., the reaction
was quenched by the addition of ice and the obtained suspension
was extracted with CHCl3 (5 × 50 mL). The combined organic ex-
tracts were collected, dried (Na2SO4), and evaporated under vacuum
to give a crude residue from which pure 9a (1.96 g, 6.50 mmol,
84%) was obtained by silica gel column chromatography (eluent:
CHCl3); mp 152–155 °C.
4-Methylpyridine-3,5-dicarboxamide (11a)
Product 11a (0.36 g, 2.0 mmol, 77%) was obtained from 10a (0.37
g, 2.6 mmol) using the same procedure as described for 6;
mp 240 °C.
IR (neat): 3340, 3188, 1660, 1573 cm–1.
1H NMR (DMSO-d6): d = 8.51 (s, 2 H, H-2), 8.01 (br s, 2 H, NHa),
7.67 (br s, 2 H, NHb), 2.39 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 164.9, 153.8, 142.8, 138.0, 17.9.
Anal. Calcd for C8H9N3O2: C, 53.63; H, 5.06; N, 23.45. Found: C,
53.11; H, 5.39; N, 22.85.
IR (neat): 2237, 1543 cm–1.
1H NMR (CDCl3): d = 2.81 (s, 3 H, CH3).
13C NMR (CDCl3): d = 156.8, 146.6, 115.0, 112.4, 21.1.
4-Ethylpyridine-3,5-dicarboxamide (11b)
Product 11b (0.37 g, 1.9 mmol, 95%) was obtained from 10b (0.32
g, 2.0 mmol) using the same procedure as described for 6; mp
>300 °C.
Anal. Calcd for C9H5Br2N3: C, 34.32; H, 1.60; N, 13.34. Found: C,
34.98; H, 1.46; N, 13.92.
IR (neat): 3346, 3185, 1677, 1623 cm–1.
2,6-Dibromo-4-ethylpyridine-3,5-dicarbonitrile (9b)
Product 9b (2.24 g, 7.1 mmol, 73%) was obtained from salt 8 (2.00
g, 9.7 mmol) following the same procedure as described for com-
pound 9a; mp 122–124 °C.
1H NMR (DMSO-d6): d = 8.48 (s, 2 H, H-2), 8.03 (br s, 2 H, NHa),
7.64 (br s, 2 H, NHb), 2.85 (q, J = 7.6 Hz, 2 H, CH2), 1.13 (t, J = 7.6
Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 169.9, 148.4, 148.3, 133.8, 22.9, 15.8.
IR (neat): 2236, 1539 cm–1.
1H NMR (acetone-d6): d = 3.13 (q, J = 7.8 Hz, 2 H, CH2), 1.38 (t,
J = 7.8 Hz, 3 H, CH3).
Anal. Calcd for C9H11N3O2: C, 55.95; H, 5.74; N, 21.75. Found: C,
55.66; H, 5.96; N, 21.67.
13C NMR (acetone-d6): d = 164.8, 146.8, 114.1, 113.2, 28.7, 13.9.
Acknowledgment
Anal. Calcd for C9H5Br2N3: C, 34.32; H, 1.60; N, 13.34. Found: C,
34.98; H, 1.46; N, 13.92.
This work was financially supported by Sapienza University of
Rome.
Synthesis 2010, No. 22, 3835–3838 © Thieme Stuttgart · New York

3838
B. Di Rienzo et al.
PAPER
(4) Lukes, R.; Kuthan, J. Collect. Czech. Chem. Commun. 1960,
25, 2173.
(5) Kuthan, J.; Musil, L.; Kohoutova, A. Collect. Czech. Chem.
Commun. 1971, 36, 3992.
(6) Kuthan, J.; Prochazkova, J.; Janeckova, E. Collect. Czech.
Chem. Commun. 1968, 33, 3558.
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(2) Jackson, M. D.; Schmidt, M. T.; Oppenheimer, N. J.; Denu,
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(3) Bobbit, J. M.; Scola, D. A. J. Org. Chem. 1960, 25, 560.
Synthesis 2010, No. 22, 3835–3838 © Thieme Stuttgart · New York