Regioselective Heteroannelation in 4-Cyanomethyl-3,5- pyridinedicarbonitriles. Synthesis of 6-Alkoxy-3-dialkylamino-1,8-diamino-2,7- naphthyridine-4-carbonitriles

Article abstract of DOI:10.1007/s00706-003-0006-4

The title naphthyridines were found to be the sole products obtained after treatment of 2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles with alkoxides. The starting pyridine derivatives were prepared by amination of the readily available

Full text of DOI:10.1007/s00706-003-0006-4

Monatshefte f€ur Chemie 134, 1045–1052 (2003)
DOI 10.1007/s00706-003-0006-4
Regioselective Heteroannelation
in 4-Cyanomethyl-3,5-pyridinedicarbonitriles.
Synthesis of 6-Alkoxy-3-dialkylamino-1,8-
diamino-2,7-naphthyridine-4-carbonitriles
Anton V. Tverdokhlebov1;ꢀ, Elizaveta V. Resnyanska1,
Andrey A. Tolmachev1, and Alexander V. Zavada2
1
Kiev National Taras Shevchenko University, 01033 Kiev, Ukraine
2
Chernigov State University of Technology, 14027 Chernigov, Ukraine
Received November 4, 2002; accepted November 22, 2002
Published online May 6, 2003 # Springer-Verlag 2003
Summary. The title naphthyridines were found to be the sole products obtained after treatment of
2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles with alkoxides. The starting pyri-
dine derivatives were prepared by amination of the readily available 2-amino-6-chloro-4-cyanomethyl-
3,5-pyridinedicarbonitrile in quantitative yields.
Keywords. Alkoxides; Heterocycles; 2,7-Naphthyridines; Nucleophilic substitutions; Pyridinedicar-
bonitriles.
Introduction
An increasing interest in 2,7-naphthyridine derivatives in recent years has been
caused by isolations of several alkaloids of this structure from the Strychnos plant
family [1, 2]. There are jasmidine [3], jasminine [4], acanthicifoline [5], scaevodi-
merines [6], and neozeylanicine [2, 7] among them. In spite of the fact, that the
structures of these natural compounds are not very complex, the total synthesis has
been reported only for the last one [8]. Hence, synthetic approaches to 2,7-naphthyr-
idines are not yet developed enough. The known methods of their preparation can be
divided into two subgroups. The first one utilizes various derivatives of 4-piperidi-
none as starting materials and, therefore, results in tetrahydro-2,7-naphthyridines
[9–12]. In the second one the key compounds are derivatives of nicotinic acid
suitably substituted at position 4 [13–17]. In addition, a few original and highly
specific approaches to 2,7-naphthyridines have been also reported [18, 19].
ꢀ
Corresponding author. E-mail: atver@mail.univ.kiev.ua

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A. V. Tverdokhlebov et al.
Biological investigations of 2,7-naphthyridines revealed a number of antiarrhytmic, analgesic,
antiinflammatory, antimicrobial, and anxiolytic synthetic drugs [10, 11, 20–23]. Most of them possess
an ester, carboxamide, or carbonitrile group at position 4 of the naphthyridine moiety. This is not
surprising because the alkaloids mentioned above are derivatives of 2,7-naphthyridine-4-carboxylic
acid. Nevertheless, there is a set of biologically active 2,7-naphthyridines with structures unlike those
of the natural products. Mostly, they bear a substituted amino group, such as dimethylamino or
piperazino, at position 1(8) of the naphthyridine nucleus [10, 20, 22]. Thus, the presence of the
carboxyl derived substituent at position 4 as well as the amino group can be formulated as an attribute
of sufficient activity. However, only a single synthesis of a partially hydrogenated 2,7-naphthyridine
possessing both of these groups at the appropriate positions has been described [10]. Moreover, 2,7-
naphthyridines substituted with two amino groups are very rare [16, 23] while derivatives of triamino-
2,7-naphthyridine are hitherto unknown to our knowledge. Noteworthy, to date the 2,7-naphthyridine
system remained the less investigated one among all naphthyridines (for reviews see [24–26]).
Continuing our research on the utility of hetarylacetonitriles in heterocyclic
synthesis [27–34] we have turned our attention to the readily available 2-amino-
6-chloro-4-cyanomethyl-3,5-pyridinedicarbonitrile 1 [35]. Herein a regioselective
heteroannelation observed for its derivatives is reported.
Results and Discussion
A two-step preparation of the pyridine 1 (Scheme 1) from malonodinitrile has been
reported in the sixties [35]. However, since that time nothing has been published on
its chemistry. Compound 1 consists of two unsymmetrical 1,5-dinitrile moieties.
Thus, it would be interesting to investigate their transformation into a pyridine ring
via the well known reaction with alkoxide, which should result in the formation of
a naphthyridine. But first of all, to remove base sensitive chlorine and to introduce
the desirable pharmacophore, the dialkylamino group, compound 1 was converted
into the 2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles 2–8.
The substitution reaction proceeded smoothly in dry dioxane with two equivalents
of amine and gave compounds 2–8 in approximately quantitative yields. Only in
the case of the pyrrolidine derivative 3 some difficulties arose, but they were solved
using one equivalent of pyrrolidine in the presence of triethylamine.
Prolonged refluxing of the pyridinedicarbonitriles 2–8 with an excess of
sodium methoxide or ethoxide in the corresponding alcohol resulted in formation
of 2,7-naphthyridine derivatives to which the structures 9–19 (Scheme 1) or the
isomeric ones like 20–22 (Fig. 1) could be assigned. It should be emphasized that
the reaction gave exclusively one product without detectable amounts of isomers.
Conversion of the pyridines 2–8 into naphthyridines was confirmed by the
1H NMR data. Thus, the characteristic two-proton singlet of the methylene group
of 2–8 at 3.9–4.0 ppm disappeared from the spectra of the naphthyridines, whereas
a one-proton singlet of 5-H at 5.9–6.0 ppm together with the signals from methoxy
or ethoxy residues for derivatives 9–14 and 15–19 were present therein. Two
broadened singlets at 6.2–6.5 and 6.6–7.0 ppm both integrating for two protons
were assigned to the amino groups. Final assignment of the structures 9–19 for the
prepared naphthyridines was made on the basis of a NOESY experiment carried
out for 13. First, it revealed a correlation between the methoxy group signal
at 3.81 ppm and the singlet of 5-H of the naphthyridine ring at 5.97 ppm, thus

Regioselective Heteroannelation
1047
Scheme 1
Fig. 1. Structures of compounds 20–22, isomers to 9–19
excluding structures of type 21 and 22. Second, the correlation between amino
groups signals at 7.00 and 6.44 ppm was observed confirming the structure 13,
while the protons of the piperazine moiety did not give a correlation with the
amino group required for the structure of type 20. Moreover, the 13C NMR spec-
trum of compound 13 was in good agreement with the assigned structure.

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A. V. Tverdokhlebov et al.
It should be noted, that a similar approach has been applied for the synthesis of 1,7- and 2,6-
naphthyridines via alkoxide induced cyclization of 2- and 4-cyano-3-pyridineacetonitriles [36]. In that
case alkoxide also attacked aliphatic, but not aromatic, nitrile. However, there was no alternative direc-
tion for further heterocyclization of the intermediate imidate. Noteworthy, the corresponding benzene
analogue 2-cyano-benzeneacetonitrile has yielded dimeric products under same conditions [37].
The difficulties in preparing 3 should be detailed here. When the reaction was carried out with two
equivalents of pyrrolidine impure 3 was isolated. The impurities obviously were derived from a partial
heterocyclization of 3 induced by the highly nucleophilic pyrrolidine. Indeed, treatment of 3, obtained
using stochiometric amounts of chloropyridine 1, pyrrolidine, and triethylamine, with pyrrolidine
yielded 23 (Scheme 1). The same product was also prepared directly from the pyridine 1 using a
three-fold excess of pyrrolidine and prolonged reaction time. The structure of 23 was confirmed by the
similarity of its spectral data with those of compounds 9–19. Attempts to transform derivatives 2–8 or
1 into naphthyridines like 23 with other amines failed.
To resume, pyridines 2–8 were found to undergo a regioselective heteroannela-
tion under treatment with alkoxide leading to the naphthyridines 9–19. Therefore,
the initial attack of the alkoxide occurs at the aliphatic nitrile, probably because it
is not hindered sterically unlike other ones. Further ring closure involving the
nitrile group at position 3 without participation of 5-CN is less understandable.
It can be explained by either repulsive interaction of dialkylamino and amino groups
in a structure like 20 making its formation unfavorable, or by facilitation of cycli-
zation with 3-CN due to its activation by an intramolecular hydrogen bond with the
neighboring amino group. Of course, the influence of both factors can take place.
Experimental
2-Amino-6-chloro-4-cyanomethyl-3,5-pyridinedicarbonitrile (1) was prepared as reported [35].
Amines were commercially available and were used without additional purification. Dioxane was
dried with sodium. Methanol and ethanol were dried with Mg and Ca, respectively. All mps were
determined in open capillary tubes in Thiele’s apparatus and are uncorrected. IR spectra were obtained
on a Pye Unicam SP 3-300 spectrometer for KBr tablets. 1H NMR spectra were recorded on a Varian
VXR-300 (300MHz) and Mercury 400 (400MHz) spectrometers in DMSO-d6 solutions with Me4Si as
internal standard. 13C and 2D NMR experiments (HSQC, HMBC) were performed on a Bruker Avance
1
500 (500MHz for H and 125 MHz for 13C) spectrometer to assign signals. The purity of all com-
pounds was checked by 1H NMR and for all compounds satisfactory elemental analyses were obtained.
2-Amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles (2, 4–8)
General Procedure
The corresponding amine (10 mmol) was added to 1.1 g of the pyridine 1 (5mmol) in 10cm3 dioxane.
The mixture was boiled to dissolve starting materials and then heated on a water-bath for 1 h. After
cooling the precipitate formed was filtered, thoroughly washed with water to remove amine hydro-
chloride, and dried to give 2 and 4–8. In most cases obtained materials were analytically pure. If
necessary, additional purification could be achieved by recrystallization from dioxane.
2-Amino-4-(cyanomethyl)-6-(diethylamino)-3,5-pyridinedicarbonitrile (2, C13H14N6)
1
Yield 97% (1.23 g), mp 167ꢁC; H NMR: ꢀ ¼ 1.19 (t, 2CH3), 3.64 (q, 2NCH2), 4.00 (s, CH2CN),
7.49 (s, NH2) ppm; 13C NMR: ꢀ ¼ 12.38 (CH3), 19.50 (CH2CN), 45.67 (NCH2), 83.16 (3-C), 84.99

Regioselective Heteroannelation
1049
(5-C), 105.35 (3 or 5-CN), 105.46 (3 or 5-CN), 119.54 (CH2CN), 158.67 (4-C), 160.61 (6-C), 168.42
(2-C) ppm.
2-Amino-4-(cyanomethyl)-6-(4-methyl-1-piperazinyl)-3,5-pyridinedicarbonitrile (4, C14H15N7)
1
Yield 94% (1.32 g), mp 134ꢁC; H NMR: ꢀ ¼ 2.24 (s, CH3), 2.44 (t, 2NCH2), 3.74 (t, 2NCH2), 3.97
(s, CH2CN), 7.51 (s, NH2) ppm; 13C NMR: ꢀ ¼ 19.10 (CH2CN), 46.85 (NCH3), 47.82 (NCH2), 54.82
(NCH2), 83.84 (5-C), 84.46 (3-C), 105.67 (3 or 5-CN), 105.87 (3 or 5-CN), 119.39 (CH2CN), 156.27
(4-C), 160.23 (6-C), 168.67 (2-C) ppm.
2-Amino-4-(cyanomethyl)-6-(1-piperidinyl)-3,5-pyridinedicarbonitrile (5, C14H14N6)
Yield 99% (1.32 g), mp 144ꢁC; 1H NMR: ꢀ ¼ 1.62 (m, 3CH2), 3.73 (t, 2NCH2), 4.02 (s, CH2CN), 7.59
(s, NH2) ppm.
2-Amino-4-(cyanomethyl)-6-[4-(2-methoxyphenyl)-1-piperazinyl]-3,5-pyridinedicarbonitrile
(6, C20H19N7O)
Yield 95% (1.77 g), mp 172ꢁC; 1H NMR: ꢀ ¼ 3.06 (t, 2NCH2), 3.81 (s, OCH3), 3.91 (t, 2NCH2), 4.02
(s, CH2CN), 6.55–6.97 (m, C6H4), 7.26 (s, NH2) ppm.
2-Amino-4-(cyanomethyl)-6-(4-morpholinyl)-3,5-pyridinedicarbonitrile (7, C13H12N6O)
Yield 98% (1.31 g), mp 201ꢁC; 1H NMR: ꢀ ¼ 3.70 (t, 2NCH2), 3.78 (t, 2OCH2), 3.94 (s, CH2CN), 7.33
(s, NH2) ppm.
2-Amino-6-(butylethylamino)-4-(cyanomethyl)-3,5-pyridinedicarbonitrile (8, C15H18N6)
1
Yield 96% (1.36 g), mp 153ꢁC; H NMR: ꢀ ¼ 0.94 (t, CH3), 1.20 (t, CH3), 1.35 (m, CH2), 1.61
(m, CH2), 3.57 (t, NCH2), 3.68 (q, NCH2), 3.94 (s, CH2CN), 7.33 (s, NH2) ppm.
2-Amino-4-(cyanomethyl)-6-(1-pyrrolidinyl)-3,5-pyridinedicarbonitrile (3, C13H12N6)
Pyrrolidine (0.36 g, 5 mmol) and 0.7cm3 of triethylamine (5mmol) were added to 1.1g of 1 (5 mmol)
in 10cm3 of dioxane. The mixture was boiled to dissolve starting materials, then heated on a water-
1
bath for 40 min and elaborated as above to yield 1.1 g (87%) of 3, mp 185ꢁC; H NMR: ꢀ ¼ 1.93
(t, CH2CH2), 3.70 (t, 2NCH2), 3.94 (s, CH2CN), 7.31 (s, NH2) ppm.
6-Alkoxy-3-dialkylamino-1,8-diamino-2,7-naphthyridine-4-carbonitriles (9–19)
General Procedure
Na (0.23 g, 0.01 mol) was dissolved in 30cm3 of the corresponding alcohol and then 4 mmol of the
pyridine 2–8 were added. The mixture was refluxed for 3 days. After cooling the precipitate formed
was filtered, washed with H2O, and recrystallized from an appropriate solvent to yield the 1st portion of
the target naphthyridines 9–19. The alcoholic mother liquor was evaporated to dryness in vacuo, the
residue was treated with H2O, filtered, and recrystallized to give the 2nd portion of 9–19.
1,8-Diamino-3-(diethylamino)-6-methoxy-2,7-naphthyridine-4-carbonitrile (9, C14H18N6O)
Yield 81% (0.93 g, from ethanol), mp 167ꢁC; 1H NMR: ꢀ ¼ 1.21 (t, 2CH3), 3.66 (q, 2NCH2), 3.81 (s,
OCH3), 5.95 (s, 5-H), 6.33 (s, NH2), 6.79 (s, NH2) ppm.

1050
A. V. Tverdokhlebov et al.
1,8-Diamino-6-methoxy-3-(1-pyrrolidinyl)-2,7-naphthyridine-4-carbonitrile acetate
(10 ꢂ CH3COOH, C14H16N6O ꢂ C2H4O2)
Yield 78% (1.07 g, from AcOH), mp 232ꢁC; 1H NMR: ꢀ ¼ 1.90 (m, CH2CH2, AcOH), 3.70 (t, 2NCH2),
3.81 (s, OCH3), 5.93 (s, 5-H), 6.33 (s, NH2), 6.80 (s, NH2), 11.86 (s, AcOH) ppm.
1,8-Diamino-6-methoxy-3-(4-methyl-1-piperazinyl)-2,7-naphthyridine-4-carbonitrile
(11, C15H19N7O)
1
Yield 74% (0.93 g, from i-PrOH), mp 143ꢁC; H NMR: ꢀ ¼ 2.24 (s, NCH3), 2.40 (t, 2NCH2), 3.75
(t, 2NCH2), 3.81 (s, OCH3), 5.94 (s, 5-H), 6.41 (s, NH2), 6.94 (s, NH2) ppm; 13C NMR: ꢀ ¼ 46.85
(NCH3), 47.82 (NCH2), 53.85 (OCH3), 54.43 (NCH2), 74.15 (4-C), 85.98 (5-C), 92.51 (8a-C), 119.98
(CN), 151.71 (4a-C), 157.98 (3-C), 158.38 (8-C), 160.34 (6-C), 163.10 (1-C) ppm.
1,8-Diamino-6-methoxy-3-(1-piperidinyl)-2,7-naphthyridine-4-carbonitrile (12, C15H18N6O)
1
Yield 85% (1g, from i-PrOH), mp 129ꢁC; H NMR: ꢀ ¼ 1.62 (m, 3CH2), 3.73 (t, 2NCH2), 3.82
(s, OCH3), 5.95 (s, 5-H), 6.34 (s, NH2), 6.85 (s, NH2) ppm.
1,8-Diamino-6-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2,7-naphthyridine-4-carbonitrile
(13, C21H23N7O2)
Yield 82% (1.33 g, from ethanol), mp 181ꢁC; 1H NMR: ꢀ ¼ 3.06 (t, 2NCH2), 3.81 (s, OCH3), 3.82 (s,
OCH3), 3.91 (t, 2NCH2), 5.97 (s, 5-H), 6.44 (s, NH2), 6.55–6.97 (m, C6H4), 7.00 (s, NH2) ppm; 13C
NMR: ꢀ ¼ 47.06 (NCH2), 50.19 (NCH2), 53.15 (OCH3), 55.30 (OCH3), 69.40 (4-C), 86.22 (5-C),
92.33 (8a-C), 111.92 (30-CPh), 118.17 (60-CPh), 119.62 (CN), 120.79 (50-CPh), 122.68 (40-CPh), 140.77
(10-CPh), 150.91 (20-CPh), 151.99 (4a-C), 158.18 (3-C), 158.51 (8-C), 159.93 (6-C), 163.86 (1-C) ppm.
1,8-Diamino-6-methoxy-3-(4-morpholinyl)-2,7-naphthyridine-4-carbonitrile (14, C14H16N6O2)
1
Yield 68% (0.82 g, from toluene), mp 243ꢁC; H NMR: ꢀ ¼ 3.69 (t, 2NCH2), 3.72 (t, 2OCH2), 3.82
(s, OCH3), 5.95 (s, 5-H), 6.44 (s, NH2), 7.00 (s, NH2), ppm.
1,8-Diamino-6-ethoxy-3-(4-morpholinyl)-2,7-naphthyridine-4-carbonitrile (15, C15H18N6O2)
1
Yield 65% (0.82 g, from toluene), mp 157ꢁC; H NMR: ꢀ ¼ 1.33 (t, CH3), 3.69 (t, 2NCH2), 3.72
(t, 2OCH2), 4.26 (q, OCH2), 5.96 (s, 5-H), 6.25 (s, NH2), 6.87 (s, NH2) ppm; 13C NMR: ꢀ ¼ 14.73
(CH3), 49.20 (NCH2), 61.56 (OCH2), 66.45 (OCH2), 68.70 (4-C), 85.95 (5-C), 95.51 (8a-C), 119.37
(CN), 153.50 (4a-C), 158.28 (3-C), 160.18 (8-C), 160.23 (6-C), 163.50 (1-C) ppm.
1,8-Diamino-3-(butylethylamino)-6-ethoxy-2,7-naphthyridine-4-carbonitrile (16, C17H24N6O)
Yield 79% (1.04 g, from ethanol), mp 148ꢁC; 1H NMR: ꢀ ¼ 0.97 (t, CH3), 1.23 (t, CH3), 1.35 (m, CH3,
CH2), 1.67 (m, CH2), 3.59 (t, NCH2), 3.68 (q, NCH2), 4.25 (q, 2OCH2), 5.99 (s, 5-H), 6.07 (s, NH2),
6.54 (s, NH2) ppm.
1,8-Diamino-6-ethoxy-3-(1-pyrrolidinyl)-2,7-naphthyridine-4-carbonitrile (17, C15H18N6O)
1
Yield 86% (1g, from ethanol), mp 178ꢁC; H NMR: ꢀ ¼ 1.31 (t, CH3), 1.92 (m, CH2CH2), 3.69 (m,
2NCH2), 4.23 (q, OCH2), 5.91 (s, 5-H), 6.27 (s, NH2), 6.78 (s, NH2) ppm; 13C NMR: ꢀ ¼ 14.07 (CH3),

Regioselective Heteroannelation
1051
25.71 (CH2CH2), 51.20 (NCH2), 62.42 (OCH2), 75.48 (4-C), 84.94 (5-C), 93.51 (8a-C), 119.99 (CN),
150.50 (4a-C), 156.94 (3-C), 159.57 (6-C), 160.18 (8-C), 164.50 (1-C) ppm.
1,8-Diamino-3-(diethylamino)-6-ethoxy-2,7-naphthyridine-4-carbonitrile (18, C15H20N6O)
1
Yield 85% (1.02 g, from ethanol), mp 145ꢁC; H NMR: ꢀ ¼ 1.21 (t, 2CH3), 1.31 (t, CH3), 3.66
(q, 2NCH2), 4.24 (q, 2OCH2), 5.94 (s, 5-H), 6.23 (s, NH2), 6.74 (s, NH2) ppm.
1,8-Diamino-6-ethoxy-3-(1-piperidinyl)-2,7-naphthyridine-4-carbonitrile (19, C16H20N6O)
1
Yield 77% (0.96 g, from i-PrOH), mp 143ꢁC; H NMR: ꢀ ¼ 1.33 (t, CH3), 1.65 (m, 3CH2), 3.73
(t, 2NCH2), 4.24 (q, 2OCH2), 5.96 (s, 5-H), 6.11 (s, NH2), 6.64 (s, NH2) ppm.
1,8-Diamino-3,6-bis(1-pyrrolidinyl)-2,7-naphthyridine-4-carbonitrile (23, C17H21N7)
Method A. Pyrrolidine (0.85 g, 12 mmol) was added to 0.87 g of 1 (4mmol) in 20cm3 of dioxane and
the mixture was refluxed for 3 h. The solvent was removed in vacuo, the residue was treated with H2O,
filtered, and recrystallized from ethanol to give 0.80g (62%) of 23, mp 231ꢁC; 1H NMR: ꢀ ¼ 1.93 (m,
2CH2CH2), 3.41 (t, 2NCH2), 3.68 (t, 2NCH2), 5.58 (s, 5-H), 5.87 (s, NH2), 6.54 (s, NH2) ppm;
13C NMR: ꢀ ¼ 25.82 (2CH2CH2), 50.71 (NCH2), 51.21 (NCH2), 70.33 (4-C), 86.76 (5-C), 98.53
(8a-C), 119.49 (CN), 153.66 (3-C), 153.98 (4a-C), 155.16 (6-C), 160.26 (8-C), 165.57 (1-C) ppm.
Method B. Pyrrolidine (0.31 g, 4.4 mmol) was added to 1 g of 3 (4 mmol) in 20cm3 of dioxane, the
mixture was refluxed for 3 h, and then elaborated as in method A to give 0.98g (76%) of 23.
Acknowledgements
We wish to thank Prof. H. Neunhoeffer, K. Runzheimer, and E. Blyumin (Darmstadt Technical Uni-
versity, Germany) for performing 2D NMR experiments and the Enamine Ltd. for financial support of
this work.
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