Investigation of the nucleophilic rearrangement of 2-(cyanomethyl)-1,4,6- trimethylpyrimidinium iodide into 4,6-dimethyl-2-methylaminonicotinic acid nitrile

Article abstract of DOI:10.1023/B:COHC.0000033539.37576.76

2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium iodide is rearranged into 4,6-dimethyl-2-methylaminonicotinic acid nitrile by interaction with alcoholic solutions of sodium ethylate, methylamine, and also glycine and β-alanine ethyl esters. This conversion was also observed for the first time for pyrimidinium salts during the process of recording ¹H NMR spectra in CD₃OD solution containing CD₃ONa. After the rearrangement deuterium exchange of the protons of the pyridine ring methyl groups was noted spectrally. It was demonstrated experimentally that for carrying out and completing the recyclization a quantity of nucleophilic reagent must convert the molar equivalent quantity of pyridinium salt.

Full text of DOI:10.1023/B:COHC.0000033539.37576.76

Chemistry of Heterocyclic Compounds, Vol. 40, No. 4, 2004
INVESTIGATION OF THE NUCLEOPHILIC
REARRANGEMENT OF 2-(CYANOMETHYL)-
1,4,6-TRIMETHYLPYRIMIDINIUM IODIDE
INTO 4,6-DIMETHYL-2-METHYLAMINO-
NICOTINIC ACID NITRILE
G. G. Danagulyan, L. G. Sahakyan, and D. A. Tadevosyan
2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium iodide is rearranged into 4,6-dimethyl-2-methylamino-
nicotinic acid nitrile by interaction with alcoholic solutions of sodium ethylate, methylamine, and also
glycine and β-alanine ethyl esters. This conversion was also observed for the first time for pyrimidinium
salts during the process of recording 1H NMR spectra in CD3OD solution containing CD3ONa. After the
rearrangement deuterium exchange of the protons of the pyridine ring methyl groups was noted
spectrally. It was demonstrated experimentally that for carrying out and completing the recyclization a
quantity of nucleophilic reagent must convert the molar equivalent quantity of pyridinium salt.
Keywords: 2-alkylaminonicotinonitrile, pyrimidinium salt, deuterium exchange, Kost–Sagitullin
nucleophilic rearrangement.
The present communication, devoted to the study of the influence of a nitrile group located in the side
chain of a pyrimidinium salt, on the Kost–Sagitullin rearrangement, continues the series of studies on the
recyclization of pyrimidinium salts into 2-alkylaminopyridine derivatives [1-4]. The model for investigation,
2-(cyanomethyl)-1,4,6-trimethylpyridinium iodide (3), was synthesized by the reaction of 2-(carbamoylmethyl)-
4,6-dimethylpyrimidine (1) with P2O5 and subsequent methylation of the obtained nitrile 2 with methyl iodide.
As was shown by our experiments, the introduction of an electron-withdrawing group (nitrile) into the
side chain of a pyrimidinium salt enables the rearrangement to take place. In alcoholic sodium ethylate solution
salt 3 is rearranged in a few minutes into 4,6-dimethyl-2-methylaminonicotinonitrile (4) in close to quantitative
yield. On heating in alcoholic methylamine solution the same recyclization occurs in 72% yield. It is appropriate
to note that under analogous conditions the iodoalkylates of esters and amides of the corresponding substituted
2-pyrimidinylacetic acids are rearranged in an overall yield of 30-55% [3-5].
It is also interesting that isomerization of salt 3 into pyridine 4 was observed by us even under the action
of such amines as glycine and β-alanine ethyl esters. However under these conditions "rearrangement and
transamination" [1], i.e. with the inclusion of an amino acid fragment into the reaction product, was not recorded.
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences (NAN) of the Republic of Armenia,
Erevan 375094; e-mail: gdanag@email.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4,
pp. 560-563, April, 2004. Original article submitted October 26, 2001.
0009-3122/04/4004-0465©2004 Plenum Publishing Corporation
465

Me
Me
P2O5
N
N
N
CONH2
C
Me
N
Me
N
1
2
MeI
Me
Me
+
N
Me
CN
_
Nu
I
C
N
Me
N
Me
N
NHMe
3
4
Nu = EtONa, MeNH2, H2NCH2COOEt, H2NCH2CH2COOEt
The ease with which the rearrangement of iodide 3 occurs in alcoholic sodium ethylate solution (rapid
process and high yield of reaction product) stimulated us to study the process of converting salt 3 into pyridine 4
in CD3OD solution containing CD3ONa within the dynamics of NMR spectral changes.
It turned out that after adding a small quantity of CD3ONa to a solution of iodide 3 in CD3OD the
1
recyclization product was already formed after 5-10 min. This was indicated by the appearance in the H NMR
spectrum of signals belonging to the protons of the reaction product. In particular there were singlets at 2.17 and
2.26 (4- and 6-CH3), 5.94 (5-H), and 3.15 ppm (N-CH3). However it is necessary to note that the signals of the
protons of the initial salt were retained in the spectrum even on the following day, and the ratio of the intensities
of the signals of both substances were practically unchanged over the course of time.
On adding a large quantity of CD3ONa to the ampul disappearance of the proton signals of salt 3 from
the 1H NMR spectrum was noted already after 5 min, while the signals of the recyclization product protons were
retained. The shape of the spectrum indicated completion of the rearrangement and was confirmed
chromatographically.
We consider that the incomplete conversion described above of the initial salt in the experiment with
CD3ONa (insufficiency of the latter) possibly indicates the formation at the first reaction step of an anhydro form
as a result of fission of proton from the methylene group. Such a deprotonation leads to binding of the CD3O-
alkoxide ion acting as recyclization initiator, and consequently to dying out of the rearrangement. At the same
time the addition of a new portion of CD3ONa (above the equimolar amount) enables completion of the
rearrangement. It was thereby shown that the course of the rearrangement depends on the amount of nucleophilic
reagent. For the progress and the important completion of the recyclization it is necessary that the amount of the
nucleophilic reagent exceeds the molar quantity of the pyrimidinium salt.
On subsequent (after recyclization) recording of the 1H NMR spectra of the same sample we observed a
gradual reduction (in the first 45-60 min) and then complete disappearance of the signals of the methyl group
protons (4- and 6-CH3 of pyridine 4). This is probably linked with basic deuterium exchange of protons. It is
necessary to stress that we recorded no deuterium exchange of the 5-H proton (of the pyridine nucleus) or of the
N-methyl group protons. There are literature data on basic deuterium exchange of protons of pyrimidine and
pyridine nuclei [6]. Previously we noted deuterium exchange for protons in pyrimidine derivatives [7,8] and
considered that it might be an actual process of nucleophilic rearrangement. In the case examined in the present
paper, due to the rapid course of the rearrangement (which was also confirmed by NMR spectra), basic exchange
of protons occurs after completion of the recyclization and consequently does not hinder it and may not compete
with it. It occurs after completion of the rearrangement and consequently is only noticed in the rearrangement
product.
466

–
Me
N
Me
OCD3
OCD3
Me
Me
+
Me
Me
–
–
OCD3
N
–
N
N
CD3ONa
I
CN
CN
H
–NaI
–CD3OH
Me
CD3O
Me
N
Me
N
CN
H
–
3
OCD3
Me
Me
CN
H
CN
4
–
–
OCD3
Me
N
NMe
Me
N
NMe
–
EXPERIMENTAL
The 1H NMR spectra were obtained on a Varian Mercury 300 (300 MHz) spectrometer in the Center for
Investigation of Molecular Structure, National Academy of Sciences (NAN) of Armenia (program US CRDF
RESC 17-5). The mass spectra were recorded on a chromato-mass spectrometer (HP 6890 Series Gas
Chromatograph, HP 5973 Mass Selective Detector), obtained with grant AR1-991 US CRDF. Silufol UV 254
plates were used for TLC, visualizing with iodine vapor and Ehrlich's reagent. Preparative separation was carried
out by column chromatography on silica gel (Silicagel L 5/40 µm).
2-(Cyanomethyl)-4,6-dimethylpyrimidine (2). A mixture of amide 1 [5] (10.0 g, 0.06 mol) and P2O5
(7.1 g, 0.05 mol) was carefully heated for 10-15 min until homogeneous. After cooling the reaction mixture was
transferred to a sublimation apparatus and sublimed at 85-100°C (3-5 mm Hg). Nitrile 2 (2.9 g, 33%) was
1
obtained having mp 75-77°C, Rf 0.47 (Silufol UV 254, benzene–acetone, 3:1). H NMR spectrum (CDCl3),
δ, ppm: 2.48 (6H, s, 4- and 6-CH3); 3.99 (2H, s, CH2); 6.98 (1H, s, 5-H). Found, %: C 65.59; H 6.45; N 28.39.
C8H9N3. Calculated, %: C 65.29; H 6.16; N 28.55.
2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium Iodide (3). A solution of nitrile 2 (1.47 g, 0.01 mol) in
MeI (5 ml, 11.36 g, 8-fold excess) was heated in a sealed glass ampul at 90-100°C for 10 h. The resulting solid
was filtered off, washed with a small quantity of hexane, and air dried. Salt 3 (1.76 g, 61%) was obtained having
mp 158-160°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 2.78 (3H, s, 4 or 6-CH3); 2.85 (3H, s, 6 or 4-CH3); 4.08
(3H, s, N-CH3); 5.03 (2H, s, CH2); 8.19 (1H, s, 5-H).
Rearrangement of 2-(Cyanomethyl)-1,4,6-trimethylpyrimidinium Iodide (3) into 4,6-Dimethyl-2-
methylaminonicotinonitrile (4). A. Iodide 3 (0.6 g, 2.0 mmol) was dissolved in an alcoholic solution of sodium
ethylate [sodium (0.06 g, 2.7 mmol) in EtOH (10 ml)] and the solution was left at room temperature for 30 min.
After neutralizing with an alcoholic solution of HCl, the precipitated salt was filtered off. A portion of the
solvent was removed, the precipitated solid was filtered off, and washed with hexane. The yield of pyridine 4
was 0.3 g (90%) of mp 216-217°C, Rf 0.3 (benzene–acetone, 3:1). 1H NMR spectrum (CDCl3), δ, ppm: 2.21 (3H,
s, 4 or 6-CH3); 2.25 (3H, s, 6 or 4-CH3); 3.1 (3H, s, N-CH3); 3.6 (1H, s, NH); 5.71 (1H, s, 5-H). Mass spectrum,
m/z (Irel, %): 162 (7), 161 (100 ) [M]+, 121 (13), 120 (21), 119 (20), 108 (9), 105 (9), 94 (10), 93 (12), 81 (10), 80
(47), 79 (9), 66 (15), 55 (18), 53 (12). Found, %: C 67.34; H 6.59; N 25.98. C9H11N3. Calculated, %: C 67.06; H
6.87; N 26.07.
B. A solution of iodide 3 (0.5 g, 1.7 mmol) in 15% ethanolic methylamine solution (5 ml) was heated in
a sealed ampul at 90-100°C for 10 h. The resulting solid was filtered off, dried, and recrystallized from hexane–
acetone, 5:1. The yield of pyridine 4 was 0.16 g (58%). After removing the solvent from the filtrate and
separation of the residue on a column (silicagel L 5/40, benzene–acetone 3:1), further compound 4 (0.04 g, 14%)
and pyrimidine 2 (0.025 g, 10%) were obtained. Mass spectrum, m/z 161.
467

C. A mixture of iodide 3 (0.6 g, 2 mmol) and an alcoholic solution (10 ml) of aminoacid ethyl ester
(6-8 mmol) was heated for 15 h at 90-100°C in a sealed glass ampule. The ethanol was removed, and the residue
was washed with hot hexane. After distilling off the hexane the residue was put onto a column (silicagel,
acetone–benzene, 2 : 1). Pyridine 4 (0.08 g, 52%) was obtained. Pyrimidine 2 was also isolated (with glycine
ester 0.04 g (14%), with β-alanine ester 0.06 g (21%)).
The work was carried out within the framework of scientific theme 00-405b of the Ministry of Science
and Education of the Armenian Republic, and also jointly with Prof. A. R. Katritzky (University of Florida)
grant No. ACH-006 98/ AC1-955 of the National Fund for Science and Advanced Technology of Armenia
(NFSAT) and the US Civil Research and Development Fund (USCRDF).
The authors are grateful to A. G. Panosyan for assistance in carrying out the spectral investigations.
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