Modification of conditions for the selective preparation of 2-amino-3-cyano-4-phenylpyridines

Article abstract of DOI:10.3998/ark.5550190.0012.223

We herein describe the modification of the experimental conditions for the synthesis of certain 2-amino-4-aryl-3-cyanopyridines from benzaldehyde, malononitrile, ammonium acetate and aminoketones. The outcome of the reaction proved to be highly dependent on the experimental procedure, occasionally giving rise to metaphthalodinitriles. Mechanistical proposals are also reported, in order to explain the observed dependence on the procedure. ARKAT-USA, Inc.

Full text of DOI:10.3998/ark.5550190.0012.223

General Papers
ARKIVOC 2011 (ii) 283-296
Modification of conditions for the selective preparation of
2-amino-3-cyano-4-phenylpyridines
Mónica Álvarez-Pérez* and José Marco-Contelles
Laboratorio de Radicales Libres y Química Computacional, IQOG (CSIC),
C/ Juan de la Cierva 3, 28006 Madrid, Spain
E-mail: maperez@iqfr.csic.es, iqoc21@iqog.csic.es
Abstract
We herein describe the modification of the experimental conditions for the synthesis of certain 2-
amino-4-aryl-3-cyanopyridines from benzaldehyde, malononitrile, ammonium acetate and
aminoketones. The outcome of the reaction proved to be highly dependent on the experimental
procedure, occasionally giving rise to metaphthalodinitriles. Mechanistical proposals are also
reported, in order to explain the observed dependence on the procedure.
Keywords: Heterocycles, pyridines, medicinal chemistry, condensation, bicyclic compounds
Introduction
In the context of a current project developed in our laboratory for the synthesis of biologically
active molecules, 2-amino-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitriles I (Figure 1) were
selected for study as well as 2-aminopyridine- and 2-chloropyridine-3,5-dicarbonitriles.1
Particular interest was focused on the highly functionalized molecules 1-3 (Figure 1).
R2
N
Ph
NC
R1
NC
R
N
N
H2N
H2N
N
I
1 R= CH 2Ph
2 R= CH 2CCH
3 R= Boc
R1= H, alkyl, Ar, etc.
R2= H, alkyl, Bn, etc.
Figure 1. Target 2-amino-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitriles.
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Literature searching shows that very few reports on the preparation of this type of
heterocyclic ring system have been published. Among the few examples, 2-amino-6-methyl-4-
phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile 4 (Figure 2) has recently been
included in a patent dealing with compounds altering the lifespan of eukaryotic organisms.2
Regarding 2-amino-6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile 5 and benzyl 2-
amino-3-cyano-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 6, they have been used as
intermediates in the synthesis of partially restricted linear, tricyclic 5-deaza antifolates.3 Related
tert-butyl 2-amino-4-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate 7 has been
described for the preparation of polysubstituted 2-aminopyrimidines.4
Ph
NC
NC
N
Ph
N
H2N
N
H2N
N
42
53
Ph
O
O
NC
N
N
O
N
O
Ph
H2N
N
H2N
N
63
74
Figure 2. Examples of 2-amino-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitriles reported in
the literature.
As a starting point, a protocol described for the synthesis of certain 2-amino-4-aryl-3-
cyanopyridines was considered.5 The attractiveness of this synthetic choice lies in the fact that it
consists of a one pot procedure, involving the condensation of malononitrile with aromatic
aldehydes and alkyl ketones in the presence of ammonium acetate. To the best of our knowledge,
no N-substituted-4-piperidones have been tested under these conditions (Equation 1). Regarding
our interest in obtaining 2-amino-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitriles,
we decided to study the scope of the above mentioned method.
Ph
R
NC
R
CN
O
N
AcONH4
N
+
+
NC
Ph
O
H2N
N
(1)
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Results and Discussion
Figure 3 shows the piperidones 8-10 selected as the carbonyl partners. Whereas 1-
benzylpiperidin-4-one 8 is commercially available, 1-(prop-2-ynyl)piperidin-4-one 96 and tert-
butyl 4-oxopiperidine-1-carboxylate 107 were synthesized from piperidin-4-one 11 (see
Supporting Information).
O
N
O
N
N
Ph
O
O
O
10
9
8
Figure 3. Selected ketones for the synthesis of 2-amino-4-phenyl-5,6,7,8-tetrahydro-1,6-
naphthyridine-3-carbonitriles.
A preliminary trial carried out under the experimental conditions reported for other
aminoketones5 gave rise to the desired 2-amino-6-benzyl-4-phenyl-5,6,7,8-tetrahydro-1,6-
naphthyridine-3-carbonitrile 1 (Figure 1) when mixing malononitrile, benzaldehyde, 8 and
ammonium acetate, albeit in low chemical yield (21%).8 With the aim of improving the yield, we
decided to prepare 2-benzylidenemalononitrile 12 beforehand and add in situ piperidone 8; the
isolated precipitate was then further treated with an AcONH4/ AcOH mixture.9 Surprisingly, 6-
amino-2-benzyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline-5,7-dicarbonitrile 13 (Scheme 1) and
1
not compound 1 was obtained under these conditions. Although the H-NMR spectra are very
similar for both molecules, 13C-NMR was conclusive; in the case of 13, two signals at115.6 and
115.2 ppm and two additional signals at 96.6 and 96.4 ppm account for two nitrile carbons atoms
(CN) and two aromatic carbons bearing the nitrile groups (C-CN) respectively. The mass
spectrum supported the proposed structure, showing a main peak at 365.2 (M+1). The formation
of this product can be rationalized as shown in Scheme 1:10 if ammonium acetate is not present
but piperidone is, both formation of intermediate II and subsequent condensation with
malononitrile take place; due to the reversibility of the initial benzaldehyde-malononitrile
condensation, the presence of malononitrile would be guaranteed even though an excess of this
reagent was not used.
Continuing with our efforts to improve the yield of product 1, an alternative stepwise
protocol5 was considered. Compound 12 was prepared and isolated; then, reaction with 8 and
AcONH4 in toluene was performed. By adding compound 8 and AcONH4 at the same time,
intermediate II formed upon reaction between 12 and 8 evolved to give rise compound 1;
moreover, a better yield of 46% was obtained when following this stepwise protocol.
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CN
O
+
NC
Ph
(a)
Ph
CN
NC
(b), (c)
N
Ph
NC
H2N
Ph
CN
(not isolated)
12
13, 16%
Ph
Ph
NC
HN
NC
NC
II
N
Ph
N
Ph
O
CN
CN
HCN
HNC
N
H2O
Ph
Ph
NC
NC
NC
Ph
N
Ph
NC
HN
NC
CN
CN
Scheme 1. Reaction conditions and mechanism of the formation of compound 13: (a) piperidine
(cat.), toluene, rt; (b) piperidone 8; (c) AcONH4/AcOH reflux.
Besides tetrahydronaphthyridine 1, 2-benzylmalononitrile could be isolated from the crude
mixture in 40% yield. This fact indicates that a side reaction is occuring, consisting of the
reduction of starting 2-benzylidenemalononitrile. Thus, an additional trial to improve the yield of
1 was carried out by doubling the amount of this reagent (Scheme 2). In this way, the yield of
isolated product 1 was increased up to 68%. Further experiments considering larger amounts of
starting 12 were performed, although no significant improvement was achieved.
In a similar fashion, we applied this protocol to the reaction of piperidone 9 with 2
equivalents of 2-benzylidenemalonitrile in the presence of AcONH4 and toluene as solvent. The
formation
of
2-amino-4-phenyl-6-(prop-2-ynyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-
carbonitrile 2 was confirmed and the initial yield of 15% significantly increased to 45% (Scheme
2). On the contrary, derivative 3 (Figure 1) was not detected in the reaction with piperidone 10
even under these optimized conditions.
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Ph
NC
(a)
N
N
Ph
H2N
N
CN
1, 68%
NC
Ph
12 (2 equiv)
Ph
NC
(b)
H2N
N
2, 45%
Scheme 2. Optimized method for the synthesis of compounds 1 and 2. Conditions: (a) piperidone
8, AcONH4, toluene, reflux; (b) piperidone 9, AcONH4, toluene, reflux.
So far, the experiments described just involved N-substituted 4-piperidones, and
consequently, the regioselectivity of the reaction was not an issue. We then decided to study the
outcome of the reaction when using methylalkylketones such as -aminoketone 14 (Scheme 3).
The latter was readily synthesized by a Michael-type reaction of but-3-en-2-one and N-
methylpropargylamine in almost quantitative chemical yield (Scheme 3). Under the improved
experimental conditions above described for 1 and 2, the reaction gave rise to a complex
mixture, from which only compound 15 could be isolated, in poor yield (14%).11 The structure of
this product was confirmed on the basis of its analytical and spectroscopic data as well as by X-
ray diffraction analysis (Figure 4).12 Surprisingly, 2-butanone reacts with 2-
benzylidenemalonitrile to give exclusively 2-amino-5,6-dimethyl-4-phenylnicotinonitrile in 65%
yield.5 Thus, the aminated fragment seems to be playing a role; steric effects might justify the
observed result.
+
N
H
O
(a)
Ph
NC
(b)
N
N
O
H2N
N
14, 99%
15, 14%
Scheme 3. Preparation of -aminoketone 14 and transformation into the unexpected 2-amino-3-
cyanopyridine 15. Conditions: (a) toluene, reflux; (b) reagent 12, AcONH4, toluene, reflux.
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Figure 4. X-ray diffraction analysis of compound 15.
As the observed regioselectivity in the previous example was not the one leading to nicotinic
derivatives, we tried to control the regioselectivity by increasing the acidity of the required
proton atoms in the carbonylic reagent. 1,3-dicarbonylic compound 1613 (Figure 5) was then
prepared and tested under the above mentioned optimized conditions. The reaction turned out to
give a high degree of decomposition and no defined products could be detected. At this point, we
decided to follow an alternative synthetic method to prepare 6-amino-5-cyano-2-methyl-4-
phenyl-N-(prop-2-ynyl)nicotinamide 17 as shown in scheme 4. According to this, tert-butyl
acetoacetate was chosen as the 1,3-dicarbonylic compound.14 Under the optimized conditions
previously described, expected tert-butyl 6-amino-5-cyano-2-methyl-4-phenylpyridine-3-
carboxylate 18 was isolated in 41% yield. Removal of the tert-butyl group and subsequent amide
formation with N-propargylamine and EDCI/HOBt provided us with the required nicotinamide
in 29% yield (from starting 18).
N
O
O
16
Figure 5
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Ph
O
NC
N
H2N
N
17
Ph
O
CN
NC
(a)
(b), (c)
O
17, 29%
NC
H2N
N
Ph
12 (2 equiv)
18, 41%
Scheme 4. Alternative way to prepare nicotinamide 17. Conditions: (a) tert-butyl acetoacetate,
AcONH4, toluene, reflux; (b) i) TFA, CH2Cl2, rt, 7 days ii) NaOH 2N; c) EDCI, DIPEA, HOBt,
N-methylpropargylamine, CH2Cl2, 0 ºC to rt, 12h.
For comparison, a trial of preparation of compound 18 in a one-pot fashion was carried out
by mixing malononitrile, benzaldehyde, tert-butyl acetoacetate and ammonium acetate in
methanol. Decomposition was observed in this case too and just a 4% of compound 19 (Figure 6)
could be isolated. On the other hand, an attempt of obtaining compound 18 from the pyrane
precursor 20 (Figure 6)9,14 gave rise to pyridine 21 (Figure 6), which implied a decarboxylation
process taking place. These facts showed again that slight variations of the protocol afforded
quite different compounds.
Ph
O
Ph
O
NC
NC
O
O
H2N
H2N
O
CN
19
20
Ph
NC
H2N
N
21
Figure 6
Conclusions
To sum up, this is the first time that a simple method based on four components is used for the
preparation of 2-amino-3-cyano-4-phenylnicotinic compounds. The previously described
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synthesis of 2-amino-4-aryl-3-cyanopyridines inspired us to prepare the required tetrahydro-1,6-
naphthyridines 1 and 2. A slight modification of the protocol afforded tetrahydroisoquinoline 13
instead of the required 1. Mechanistical explanations for the high dependence on the followed
procedure in the preparation of nicotinic compounds from four components have been provided.
Moreover, unexpected regiochemistry was observed when employing -aminoketone 14. In
order to obtain the desired regiochemistry, tert-butyl acetoacetate was used as the carbonylic
reagent and intermediate 18 was succesfully prepared. Finally, subsequent modification of the
latter afforded nicotinamide 17.
Experimental Section
General. Unless otherwise stated, all reagents were purchased from commercial sources
(Aldrich, Fluka) and used without further purification. Anhydrous toluene was obtained by
passing the solvent through an activated alumina column on a PureSolvTM solvent purification
system (Innovative Technologies, Inc., MA). Flash column chromatography was carried out
using silica gel C60 (230 mesh) as the stationary phase. Analytical thin layer chromatography
was performed on 0.25 mm thick precoated silica gel plates (60F254). Compounds were
visualized under UV light at 254 nm or either staining with a 1% ninhydrin in EtOH solution or
1
13
with cerium molybdate. H NMR and C NMR spectra were recorded at room temperature in
CDCl3 or d6-DMSO, at 300, 400 or 500 MHz and at 75, 100 or 125 MHz, respectively, using
solvent peaks (7.26 (H), 77.2 (C) ppm) as internal reference. The assignment of chemical shifts
1
is based on standard NMR experiments (1H, 13C-DEPT, H,1H-COSY, gHSQC, gHMBC).
Melting points were determined on a microscope type apparatus and are uncorrected. Mass
spectra (EI, ES) were carried out by the mass spectrometry services at CQO (CSIC, Spain), as
well as elemental analysis.
2-Amino-6-benzyl-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile
(1).
AcONH4 (116 mg, 1.5 mmol), dry toluene (3 mL), benzylidenemalononitrile (308 mg, 2 mmol)
and N-benzyl-piperidin-4-one 8 (189 mg, 1 mmol) were mixed and heated under reflux for 4h in
a Dean-Stark system. Solvents were then removed in vacuum and the resulting residue purified
by flash column chromatography (30% ethyl acetate in hexane, then 40% and finally 50%)
yielding the titled compound (231 mg, 68%) as a colorless solid.
Mp 193-195 ºC. IR (KBr): 3457, 3342, 3221, 2937, 2819, 2764, 2220, 1627, 1564, 1496, 1456,
1430, 1365, 1247 cm-1.1H NMR (CDCl3, 400 MHz):  = 7.42-7.34 (m, 3H, ArH), 7.25-7.12 (m,
7H, ArH), 5.19 (br s, 2H, NH2), 3.47 (s, 2H, NCH2CCH), 3.23 (s, 2H, CCCH2N), 2.81 (t, J = 6.0
Hz, 2H, CH2CH2N), 2.62 (t, J = 6.0 Hz, 2H, CH2CH2N) ppm. 13C NMR (CDCl3, 100 MHz):  =
159.4, 157.9, 153.0, 137.8, 135.1 (C), 129.3, 129.1, 128.9, 128.4, 128.0, 127.3 (CH), 119.0,
116.6, 90.0 (C), 62.3, 54.0, 49.1, 33.1 ppm. MS (ES): m/z (%) = 341.2/342.3/343.2 [M+1]+.
Anal. Calcd for C22H20N4: C, 77.62; H, 5.92; N, 16.46; found C, 77.48; H, 6.05; N, 16.22.
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2-Amino-4-phenyl-6-(prop-2-ynyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile (2).
Procedure as above described for compound 1. Starting from 137 mg (1 mmol) of 9, 130 mg
(45%) of the titled compound were obtained after flash column chromatography (30% ethyl
acetate in hexane, then 40%, 50% and finally 60%) as a yellowish solid.
Mp 163-165 ºC. IR (KBr): 3418, 3302, 3180, 2911, 2818, 2787, 2211, 1641, 1561, 1464, 1435,
1376, 1253, 1142, 734, 702, 662, 638 cm-1. 1H NMR (CDCl3, 300 MHz):  = 7.53-7.33 (m, 3H,
ArH), 7.29-7.11 (m, 2H, ArH), 5.18 (br s, 2H, NH2), 3.32 (br s, 2H, NCH2CCH), 3.25 (br s, 2H,
NCCCH2N), 2.98-2.86 (m, 2H, CH2CH2N), 2.86-2.74 (m, 2H, CH2CH2N), 2.16 (s, 1H, CCH)
ppm. 13C NMR (CDCl3, 75 MHz):  = 158.7, 157.8, 153.2, 135.1 (C), 129.4, 129.0, 128.0 (CH),
118.6, 116.5, 90.2, 78.1 (C), 73.8 (CH), 51.8, 49.0, 46.6, 33.2 (CH2) ppm. MS (ES): m/z (%) =
289.2/290.3/291.3 [M+1]+. Anal. Calcd for C18H16N4: C, 74.98; H, 5.59; N, 19.43. Found: C,
74.79; H, 5.46; N, 19.24.
N-Propargyl-piperidin-4-one (9).6 A suspension of 4-piperidone hydrochloride 11 (172 mg, 1
mmol) in THF (12 mL) was treated with DIPEA (0.17 mL, 1 mmol) and tBuNH2 (0.26 mL, 2.5
mmol). The mixture was cooled in an ice-bath and then propargyl bromide (0.09 mL, 1 mmol)
was carefully added. The reaction was kept overnight while reaching rt. The precipitate was
filtered off and washed with Et2O (6×10 mL), the filtrate concentrated and the resulting residue
purified by flash column chromatography. The product (106 mg, 77%) was obtained as a
yellowish oil.
1H NMR (CDCl3, 300 MHz):  = 3.41 (d, J = 2.4 Hz, 2H, CH2CCH), 2.84 (t, J = 6.2 Hz, 4H,
2×CH2CH2N), 2.46 (t, J = 6.2 Hz, 4H, 2×CH2CH2N), 2.27 (t, J = 2.4 Hz, 1H, CH2CCH) ppm.
tert-Butyl-4-oxopiperidin-N-carboxylate (10).7 A suspension of reagent 11 (1.72 g, 10 mmol)
in CHCl3 (20 mL) was treated at 0 ºC with K2CO3 (2.76 g, 20 mmol), Boc2O (2.25 g, 10.3 mmol)
and NEt3 (1.39 mL, 10 mmol). The stirring was kept overnight while reaching rt. Water (20 mL)
and CH2Cl2 (40 mL) were then added, layers separated and the organic fraction was further
washed with water (2×40 mL), HCl 1N (3×40 mL) and NaOH 1N (3×40 mL). Solvents were
removed in vacuo to give 10 as a colorless solid (1.89 g, 95%), m.p. 68-70 ºC (lit. 72 ºC).
6-Amino-2-benzyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline-5,7-dicarbonitrile
(13).
A
solution of benzaldehyde (0.1 mL, 1 mmol) in dry toluene (2.5 mL) under argon was treated with
malononitrile (66.1 mL, 1 mmol) and then piperidine (0.01 mL, 0.1 mmol) was slowly added.
The solution gradually became cloudy while a brownish oil appeared. After 12h of stirring at rt,
piperidone 8 (147.6 mg, 0.78 mmol) and further piperidine (0.01 mL, 0.1 mmol) were added.
After 6h, the precipitate was collected by filtration, washed with cold toluene (6×5 mL) and
dried under vacuum. AcONH4 (107 mg, 1.39 mmol) was dissolved in AcOH (1.7 mL) while
heating. The previously obtained precipitate was then added and the mixture refluxed for 10h.
After this time, TLC showed the formation of a sole product. Solvent was partially removed in
vacuum and the resulting oil was treated with sat. NaHCO3 (20 mL) and extracted with ethyl
acetate (3×20 mL). The organic fractions were dried (MgSO4) and concentrated, giving rise to a
colorless solid (45.5 mg, 16% from starting ketone).
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1H NMR (CDCl3, 400 MHz):  = 7.42-7.36 (m, 3H, ArH), 7.24-7.11 (m, 7H, ArH), 5.02 (br s,
2H, NH2), 3.45 (s, 2H, NCH2Ph), 3.16 (s, 2H, CCH2N), 2.95 (t, J = 5.9 Hz, 2H, CH2CH2N), 2.59
13
(t, J = 6.0 Hz, 2H, CH2CH2N) ppm. C NMR (CDCl3, 100 MHz):  = 150.2, 148.7, 144.9,
137.4, 135.8 (C), 129.3, 129.1, 129.0, 128.5, 128.2, 127.4 (CH), 124.4, 115.6, 115.2, 96.6, 96.4
(C), 62.2, 54.5, 48.3, 29.6 (CH2) ppm. MS (ES): m/z (%) = 365.2/366.3 [M+1]+.
4-(N-Methyl-N-propargylamino)-butan-2-one (14). N-Methylprop-2-yn-1-amine (1.7 mL, 20
mmol) and toluene (20 mL) were charged in a flask fitted with a reflux condenser under argon.
But-3-en-2-one (2.3 mL, 28 mmol) was dropwise added at rt and the mixture heated at reflux for
4h. HCl 1N was then added up to pH=1 and after addition of Et2O (20 mL), layers were
separated, the aqueous one being treated with further Et2O (2×20 mL). The aqueous fractions
were basified to pH=8 and extracted with CH2Cl2 (3×50 mL), the organic fractions dried
(MgSO4), filtrated and concentrated. The resulting brown oil (2.63 g, 94%) was used without
further purification.
1
IR (KBr): 3286, 2946, 2098, 1712, 1358, 1165 cm-1. H NMR (CDCl3, 300 MHz):  = 3.32 (d,
J = 2.4 Hz, 2H, CH2CCH), 2.72 (t, J = 7.0 Hz, 2H, CH2CH2N), 2.58 (t, J = 7.0 Hz, 2H,
CH2CH2N), 2.29 (s, 3H, CH3N), 2.21 (t, J = 2.4 Hz, 1H, CH2CCH), 2.16 (s, 3H, CH3CO) ppm.
13C NMR (CDCl3, 75 MHz):  = 207.5, 78.2 (C), 73.3 (CH), 50.0, 45.5, 41.8, 41.6 (CH3,
3×CH2), 29.9 (CH3) ppm. EM (ES): m/z (%) = 140.2/141.2 [M+1]+.
2-Amino-6-(2-(methyl(prop-2-ynyl)amino)ethyl)-4-phenylnicotinonitrile (15). AcONH4 (115
mg, 1.5 mmol), dry toluene (3 mL), 2-benzylidenemalononitrile 12 (308 mg, 2 mmol) and 4-(N-
methyl-N-propargylamino)-butan-2-one 14 (137 mg, 1 mmol) were mixed and heated under
reflux for 4h in a Dean-Stark system. Solvents were then removed in vacuum and the resulting
residue purified by flash column chromatography (30% ethyl acetate in hexane, then 40%, 50%
and finally 60%) yielding the titled compound (42 mg, 14%) as a brown oil, that crystallized as a
yellowish solid (from ethyl acetate).
1
Mp 114-116 ºC. IR (KBr): 3437, 3306, 3181, 2214, 1648, 1577, 1556, 1047 cm-1. H NMR
(CDCl3, 400 MHz):  = 7.59-7.54 (m, 2H, ArH), 7.52-7.46 (m, 3H, ArH), 6.67 (s, 1H, CHCN),
5.34 (br s, 2H, NH2), 3.41 (d, J = 2.3 Hz, 2H, NCH2CCH), 2.84 (s, 4H, CH2CH2N), 2.37 (s, 3H,
13
CH3N), 2.24 (t, J = 2.3 Hz, 1H, NCH2CCH) ppm. C NMR (CDCl3, 100 MHz):  = 164.2,
160.3, 154.7, 136.8 (C), 129.9, 129.0, 128.3 (CH), 117.2 (C), 113.8 (CH), 87.7, 78.5 (C), 73.5
(CH), 54.8, 45.7 (CH2), 41.9 (CH3), 36.8 (CH2) ppm. MS (EI): m/z (%) = 290.2/291.2/292.2
[M]+. Anal. Calcd for C18H18N4: C, 74.46; H, 6.25; N, 19.30. Found: C, 74.19; H, 5.98; N, 19.43.
N-Methyl-N-propargylacetoacetamide (16).13 tert-Butyl acetoacetate (0.75 mL, 4.5 mmol) was
diluted in toluene (5 mL) and N-methyl-N-propargylamine (0.34 mL, 4.1 mmol) added. The
mixture was refluxed for 14h and then diluted in Et2O (20 mL) after cooling. HCl 1N (10 mL)
was then added and layers separated. The organic layer was treated with further HCl 1N (2×20
mL), the aqueous fractions combined, extracted once with Et2O (20 mL) and basified with NaOH
50%. When reaching pH=7-8, the aqueous fraction was extracted with ethyl acetate (3×150 mL).
The organic fractions were separately dried (Na2SO4) and filtered. The first organic fraction
(obtained in Et2O) showed a mixture of product and starting material and was purified by flash
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column chromatography (10% ethyl acetate in hexane to 60%), giving rise to 85 mg of a
yellowish oil; the second one (360 mg of a dark brownish oil, obtained in ethyl acetate) was used
without further purification. Total yield: 71%.
Mixture of rotamers.1H NMR (CDCl3, 300 MHz):  = 4.21 (d, J = 2.4 Hz, 2H, CH2CCH of
major rotamer), 4.00 (d, J = 2.3 Hz, 2H, CH2CCH of minor rotamer), 3.59 (s, 2H, CH2CO of
minor rotamer), 3.53 (s, 2H, CH2CO of major rotamer), 3.02 (s, 3H, CH3N of major rotamer),
3.00 (s, 3H, CH3N of minor rotamer), 2.32 (t, J = 2.4 Hz, 1H, CCH of minor rotamer), 2.26 (s,
3H, CH3CO of minor rotamer), 2.25 (s, 3H, CH3CO of major rotamer), 2.22 (t, J = 2.5 Hz, 1H,
CCH of major rotamer) ppm.
6-Amino-5-cyano-2-methyl-4-phenyl-N-(prop-2-ynyl)nicotinamide (17). Compound 18 (193
mg, 0.62 mmol) was treated under argon at rt with CH2Cl2 (13 mL) and TFA (0.95 mL). After 7
days, solvents were removed in vacuum and the residue was basified with NaOH 2N (50 mL).
CHCl3 (30 mL) was added until the observed solid was dissolved and layers were then separated.
The aqueous layer was extracted with CHCl3 (2×20 mL). The organic fractions were washed
once with NaOH 2N (5 mL) and with water (10 mL). The collected aqueous fractions were then
acidified (pH 3-4) by adding HCl conc. to pH=3-4 and extracted with isopropanol-CHCl3 1:3
(3×30mL). The organic fractions were dried over MgSO4 and solvents were evaporated to yield
6-amino-5-cyano-2-methyl-4-phenylpyridine-3-carboxylic acid (116 mg, 74%), which was used
without further purification.
1
Colorless solid. Mp 228-230 ºC. H NMR (DMSO-d6, 300 MHz):  = 7.51-7.44 (m, 3H, ArH),
7.38-7.29 (m, 2H, ArH), 7.20 (br s, 2H, NH2), 2.40 (s, 3H, CH3) ppm. EM (EI): m/z (%) =
253.0/254.0/255.0 [M]+; 236.0/237.0 [M-17]+.
To a mixture of 6-amino-5-cyano-2-methyl-4-phenylpyridine-3-carboxylic acid (50.6 mg, 0.20
mmol) in CH2Cl2 (0.5 mL) at 0 ºC, EDCI (38.3 mg, 0.20 mmol), DIPEA (40 µl, 0.24 mmol), N-
propargylamine (15 µl, 0.24 mmol) and HOBt (27 mg, 0.20 mmol) were added. Stirring was kept
overnight while the mixture reached rt. Water (10 mL) and further CH2Cl2 (15 mL) were then
added. Layers were separated and the organic layer was washed with water (5 mL) and sat.
NaHCO3 (3×10 mL) and dried (MgSO4). Solvents were removed in vacuum and the resulting
residue was purified by flash column chromatography (1% to 2.5% MeOH in CH2Cl2) to yield
the titled compound 17 (22.4 mg, 39%) as a white-off solid.
Mp 178-180 ºC. IR (KBr): 3393, 3332, 3288, 3178, 2219, 1665, 1641, 1561, 1290, 1252, 761,
706, 648, 529 cm-1. 1H NMR (DMSO-d6, 300 MHz):  = 8.61 (t, J = 5.4 Hz, 1H, NH), 7.47-7.39
(m, 3H, ArH), 7.38-7.30 (m, 2H, ArH), 7.06 (s, 2H, NH2), 3.72 (dd, J = 5.4, 2.1 Hz, 2H, NCH2),
13
3.00 (t, J = 2.1 Hz, 1H, CCH), 2.30 (s, 3H, CH3) ppm. C NMR (DMSO-d6, 75 MHz):  =
166.3, 159.6, 158.7, 152.0, 135.4 (C), 129.0, 128.3, 128.2 (CH), 122.0, 116.4, 86.6, 80.2 (C),
73.0 (CH), 28.0 (CH2), 22.6 (CH3) ppm. EM (EI): m/z (%) = 290.1/291.1 [M]+;
236.1/237.1/238.1 [M-54]+. Anal. Calcd for C17H14N4O: C, 70.33; H, 4.86; N, 19.30. Found: C,
70.11; H, 4.91; N, 19.54.
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tert-Butyl 6-amino-5-cyano-2-methyl-4-phenylpyridine-3-carboxylate (18). AcONH4 (116
mg, 1.5 mmol), dry toluene (3 mL), benzylidenemalononitrile (308.3 mg, 2 mmol) and tert-butyl
acetoacetate (0.17 mL, 1 mmol) were mixed and heated under reflux for 4h in a Dean-stark
system. Solvents were then removed in vacuum and the resulting residue purified by flash
column chromatography (5% ethyl acetate in hexane, then 10%, 20% and finally 30%) yielding
the titled compound (126 mg, 41%) as a colorless solid.
Mp 215-217 ºC. IR (KBr): 3399, 3331, 3149, 3064, 3002, 2972, 2931, 2220, 1703, 1660, 1552,
1498, 1476, 1447, 1367, 1299, 1257, 1150, 1076, 865, 844, 811, 798, 759, 742, 699, 563 cm-1.
1H NMR (CDCl3, 400 MHz):  = 7.48-7.43 (m, 3H, ArHmeta, ArHpara), 7.38-7.32 (m, 2H,
ArHortho), 5.41 (br s, 2H, NH2), 2.50 (s, 3H, CH3), 1.18 [s, 9H, C(CH3)3] ppm. 13C NMR (CDCl3,
100 MHz):  = 166.5, 160.2, 158.8, 153.5, 135.9 (C), 129.5, 128.7, 128.2 (CH), 121.8, 116.1,
89.1, 82.4 (C), 27.6, 23.5 (CH3) ppm. EM (IE): m/z (%) = 309.2/310.2 [M]+;
253.2/254.1/252.1/255.1 [M-57]+; 236.2/ 235.1/ 237.1/238.1 [M-73]+. Anal. Calcd for
C18H19N3O2: C, 69.88; H, 6.19; N, 13.58. Found: C, 69.75; H, 6.08; N, 13.43.
tert-Butyl 5-amino-4,6-dicyano-3-methylbiphenyl-2-carboxylate (19). MeOH (30 mL),
toluene (30 mL), tert-butyl acetoacetate (6.63 mL, 40 mmol), benzaldehyde (4.06 mL, 40 mmol),
malononitrile (2.52 mL, 40 mmol) and AcONH4 (3.24 g, 42 mmol) were mixed and heated under
reflux for 24h. Solvents were then removed in vacuum and then toluene (30 mL) and water (3
mL) were added to continue refluxing for additional 24h. The reaction was concentrated and the
residue partially purified by re-precipitation in CH2Cl2-CHCl3-hexane. The observed brown oil
was discarded and the resulting fraction was concentrated and purified by flash column
chromatography (5% hexane in CH2Cl2) to yield pure compound (570 mg, 4%) as a colorless
solid.
Mp 200-202 ºC. IR (KBr): 3461, 3352, 3248, 2976, 2226, 2218, 1725, 1645, 1563, 1371, 1307,
1
1283, 1216, 1148, 843, 753, 701 cm-1. H NMR (CDCl3, 400 MHz):  = 7.52-7.38 (m, 3H,
ArHmeta, ArHpara), 7.37-7.31 (m, 2H, ArHortho), 5.35 (br s, 2H, NH2), 2.55 (s, 3H, CH3), 1.15 [s,
13
9H, C(CH3)3] ppm. C NMR (CDCl3, 100 MHz):  = 165.7, 151.8, 148.3, 145.3, 136.3 (C),
129.5, 128.6, 128.6 (CH), 127.0, 115.1, 115.1, 97.5, 96.0, 82.8 (C), 27.6, 19.4 (CH3) ppm.
EM (ES): m/z (%) = 356.3/357.2/358.3 [M+23]+; 334.2/335.2 [M+1]+; 278.2/279.3/280.2 [M-
57+2]+; 260.2/ 261.2/ 262.0 [M-73]+. Anal. Calcd for C20H19N3O2: C, 72.05; H, 5.74; N, 12.60.
Found: C, 71.87; H, 5.91; N, 12.85.
tert-Butyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (20).15 A solution of
benzaldehyde (4.06 mL, 40 mmol) in dry toluene (100 mL) under argon was treated with
malononitrile (2.52 mL, 40 mmol) and then piperidine (0.40 mL, 4 mmol) was slowly added.
The solution became gradually cloudy while a brownish oil appeared. After 12h of stirring at rt,
tert-butyl acetoacetate (6.63 mL, 40 mmol) and further piperidine (0.1 mL, 1 mmol) were added.
After 6h, the precipitate was collected by filtration, washed with cold toluene (6×20 mL) and
dried under vacuum, to yield the titled compound (9.68 g, 78%) as a light pink solid.
1H NMR (CDCl3, 300 MHz):  = 7.34-7.26 (m, 2H, ArH), 7.25-7.16 (m, 3H, ArH), 4.46 (br s,
2H, NH2), 4.38 (s, 1H, CHPh), 2.34 (s, 3H, CH3), 1.24 [s, 9H, C(CH3)3] ppm.
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2-Amino-6-methyl-4-phenylnicotinonitrile (21).5 AcONH4 (19.3 g, 250 mmol) was dissolved
in AcOH (315 mL) while heating. Compound 20 (7.8 g, 25 mmol) was then added and the
mixture refluxed for 16h. Solvent was partially removed in vacuum and the resulting oil was
treated with sat. NaHCO3 (1000 mL) to pH=6-7. A yellowish solid precipitated and was
collected by filtration, washed with water (6×100 mL) and re-dissolved in ethyl acetate (50 mL).
The aqueous layer was treated with HCl 1N to pH=2-3 and extracted with ethyl acetate to
confirm that no compounds were recovered from the aqueous layer. The re-dissolved precipitate
was washed with water (2×20 mL) and sat. NaCl (2×20 mL), dried (MgSO4) and concentrated.
The resulting crude was purified by re-precipitation in CHCl3-hexane (50:5). Yellowish solid
(345 mg, 6.6 %).
1H NMR (DMSO-d6, 300 MHz):  = 7.60-7.40 (m, 5H, Ph), 6.82 (br s, 2H, NH2), 6.56 (s, 1H,
CHCCH3), 2.32 (s, 3H, CH3) ppm.
Acknowledgements
JMC thanks MICINN (SAF2006-08764-C02-01), Comunidad de Madrid (S/SAL-0275-2006),
and Instituto de Salud Carlos III [Retic RENEVAS (RD06/0026/1002)] for support.
References and Notes
1. Samadi, A.; Marco-Contelles, J.; Soriano, E.; Álvarez-Pérez, M.; Chioua, M.; Romero, A.;
González-Lafuente, L.; Gandía, L.; Roda, J. M.; G. López, M.; Villarroya, M.; García, A.
G.; de los Ríos, C. Bioorg. Med. Chem. 2010, 18, 5861.
2. Goldfarb, D. S. U.S. Pat. Appl. Publ.163 545, 2009.
3. Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2002, 45, 5173.
4. Benderitter, P.; Xavier de Araujo Junior; J.; Schmitt, M.; Bourguignon, J.-J. Tetrahedron
2007, 63, 12465.
5. (a) Kambe, S.; Saito, K.; Sakurai, A.; Midorikawa, H. Synthesis 1980, 366. (b) Mantri, M.;
de Graaf, O.; van Veldhoven, J.; Göblyös, A.; von F. D. Künzel, J. K.; Mulder-Krieger, T.;
Link, R.; de Vries, H.; Beukers, M. W.; Brussee, J.; Jzerman, A. P. J. Med. Chem. 2008, 51,
4449.
6. Papin, C.; Doisneau, G.; Beau, J.-M. Chem.-Eur J. 2009, 15, 53.
7. Vitnik, V. D. Synthetic Comm. 2009, 39, 1457.
8. TLC analysis showed many spots along the TLC plate, most part of which did not give rise
to defined compounds after isolation.
9. This procedure has been used in our group to prepare pyrane derivatives that can be
transformed into pyridines under reflux in the presence of AcONH4/AcOH: Marco, J. L.; de
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los Ríos, C.; Carreiras, M. C.; Baños, J. E.; Badía, A.; Vivas, N. M. Bioorg. Med. Chem.
2001, 9, 727.
10. This mechanism is in accordance with the one proposed by Tu in a related type of reaction.
See: Tu, S.; Jiang, B.; Zhang, Y.; Jia, R.; Zhang, J.; Yao, C.; Shi, F. Org. Biomol. Chem.
2007, 5, 355.
11. In general, we have observed some degree of decomposition when using the described
method, especially in its one-pot version. This degree of decomposition accounts for the
observed low yields. Decomposition was critical in this example and the yield of compound
15 could not be increased.
12. This analysis has been carried out by Mr. César Pastor, SIDI, Facultad de Ciencias, UAM,
Madrid, Spain. Single-crystal data and CIF file of compound 15 (CCDC 763716) have been
deposited at the Cambridge Crystallographic Data Centre and can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44) 1123-336-033; or email:
deposit@ccdc.ac.uk).
13. Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379.
14. Kuthan, J. Adv. Heterocyclic Chem. 1995, 62, 20. Ethyl acetoacetate has been previously
used in our group to produce substituted pyridines. See ref. 9.
15. Srivastava, S.; Batra, S.; Bhaduri, A. P. Indian J. Chem, Sect. B 1996, 35B, 602.
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