Synthesis of nicotinic acid derivatives by the reaction of salts of 1-alkyl-4,6-dimethyl-2-pyrimidinylacetic acid esters with amines

Article abstract of DOI:10.1023/A:1017559100450

A study was carried out on the enamine rearrangement of iodoalkylates of the ethyl ester of 4,6-dimethyl-2-pyrimidinylacetic acid to give ethyl esters of 2-alkylamino-4,6-dimethylnicotinic acid, which proceeds upon the action of various amines. The reaction with amines containing an alkyl substituent different from that at the quaternized nitrogen atom of the pyrimidinium salt leads to the formation of products of rearrangement and transamination. In the presence of water, the rearrangement is accompanied by the formation of the ethyl ester of 1,2-dihydro-2-oxo-4,6-dimethylnicotinic acid.

Full text of DOI:10.1023/A:1017559100450

Chemistry of Heterocyclic Compounds, Vol. 37, No. 3, 2001
SYNTHESIS OF NICOTINIC ACID
DERIVATIVES BY THE REACTION
OF SALTS OF 1-ALKYL-4,6-DIMETHYL-
2-PYRIMIDINYLACETIC ACID
ESTERS WITH AMINES
G. G. Danagulyan1, L. G. Saakyan1, and G. A. Panosyan2
A study was carried out on the enamine rearrangement of iodoalkylates of the ethyl ester of
4,6-dimethyl-2-pyrimidinylacetic acid to give ethyl esters of 2-alkylamino-4,6-dimethylnicotinic acid,
which proceeds upon the action of various amines. The reaction with amines containing an alkyl
substituent different from that at the quaternized nitrogen atom of the pyrimidinium salt leads to the
formation of products of rearrangement and transamination. In the presence of water, the
rearrangement is accompanied by the formation of the ethyl ester of 1,2-dihydro-2-oxo-4,6-
dimethylnicotinic acid.
Keywords: amine, iodoalkylates of esters of pyrimidinylacetic acids, pyridone, 2-alkylaminonicotinic
acid derivatives, enamine rearrangement.
Pyridine derivatives are the basis of many natural and synthetic biologically active products, some of
which have found use in medicine and agriculture [1, 2]. These compounds play an important role in the
metabolism of living organisms (vitamins B6 and PP (niacin), and nicotinamide adenine dinucleotide (NAD))
[3]. This clearly lends importance to the search for new methods for the synthesis and functionalization of
pyridine and the development of nonstandard pathways for the introduction of substituents into the pyridine
ring.
In the present work, we studied the enamine rearrangement of pyrimidinium salts, which yields
2-alkylaminopyridine derivatives. These derivatives have not been readily available.
In previous work [4, 5], we reported the transformation of the iodide of ethyl 1,4,6-trimethyl-2-
pyrimidinylacetate (1a) into the ethyl ester of 2-methylamino-4,6-dimethylnicotinic acid (2a), which proceeds in
an ethanolic solution of methylamine. We found that when the reaction is carried out in the presence of amines
containing a substituent different from that at the quaternary pyrimidinium nitrogen atom, the reaction proceeds
through two alternative pathways: 1) with retention of the alkyl group of the pyrimidinium salt in the amine
fragment of the nicotinic acid derivative (isomerizational recyclization) and 2) introduction of the nucleophile
into the rearrangement product leading to 2-alkylaminonicotinates, containing the alkyl group not of the starting
salt but rather of the amine reagent. Thus, the reaction of iodomethylate 1a with ethanolic ethylamine gave
____________________________________________________________________________________________
1
Yerevan Institute of National Economy, Yerevan 375025, Republic of Armenia; e-mail:
ysine@ysine.am. 2 Center for the Study of Molecular Structure, National Academy of Sciences of the Republic
of Armenia, Yerevan 375014, Republic of Armenia. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 3, pp. 351-357, March, 2001. Original article submitted September 21, 1999.
0009-3122/01/3703-0323$25.00©2001 Plenum Publishing Corporation
323

ethyl ester of 4,6-dimethyl-2-ethylaminonicotinic acid (2b) in 41% yield along with ester 2a and demethylation
product 3. An analogous exchange of the amine fragment was described in our recent work on the reaction of
salt 1a with benzylamine, which gave pyrimidine 3 and enamine rearrangement products 2a and 2c (R = CH2Ph)
[6].
The reaction of iodoethylate 1b with methylamine proved more selective and only pyridine 2a was
isolated in 56% yield, i.e., the rearrangement–transamination product was the sole (or possibly major) product.
The reaction of iodoethylate 1b with ethylamine gave the products of enamine rearrangement 2b and
N-dealkylation 3 as expected.
Me
CO2Et
MeNH2
Me
NHMe
N
2a
Me
N
Me
Me
+
N
Et
_
O
C
O
C
N
Me
_
RNH2
I
+
N
O
OEt
Me
OEt
Me
N
3
C
Me
N
OEt
1b
I
Me
1a
CO2Et
NHR
EtNH2
R = Et
Me
N
2b,c
R = Et, CH2Ph
The steric factor is likely significant in this reaction, as indicated by the high yield and formation of only the
rearrangement–transamination product in the reaction of salt 1b containing an ethyl group with methylamine. In
contrast, when the substituting group is bulkier than the leaving group, both possible enamine rearrangement
products are formed. Furthermore, in a number of cases, the steric factor may completely prevent formation of
the rearrangement–transamination product. Thus, the results of the reaction of salt 1a with diethylamine and of
iodoethylate 1b with tert-butylamine, in which rearrangement–dealkylation products are formed without
rearrangement–transamination products, may be attributed to steric factors.
Me
Me
Me
R1
_
R2R3NH
R
+
N
N
+
Me
I
R
R
N
NHR1
Me
N
Me
N
1
2
3
R = COOEt; a R1 = Me, R2 = R3 = Et; b R1 = Et, R2 = CMe3, R3 = H
The major product in the reaction of aniline with salt 1a is the anilide of 4,6-dimethyl-2-
pyrimidinylacetic acid 4 and only slight recyclization is noted. In this case, the basicity of the base is probably
insufficient for opening of the pyrimidine ring. Analogously, demethylation product 3 was isolated in the
reaction of salt 1a with ethanolamine.
324

TABLE 1. Reaction of Salts 1a and 1b with Amines in Ethanol Solution
Yield, %
Salt,
Time,
h
Amine
Н2О
mmol
2а
2b
2c
3
5
1a
0.9
2
1.5
1
NH3
MeNH2
EtNH2
—
—
25
22
20
20
15
20
25
25
25
25
—
60
18
35
30
—
8
35
—
15
—
—
41
—
—
—
16
—
—
—
—
—
—
—
35
—
—
—
—
—
60
—
15
20
15
60
10
10
50
18
—
—
—
—
—
—
45
17
17
20
—
Et2NH
—
—
—
1 ml
10 drops
2 ml
10 drops
2
PhCH2NH2*
H2N(CH2)2OH
EtNH2
Et2NH
Et2NH
1.5
1.5
1.5
1.5
1.5
1b
1.4
1.4
0.9
Me3CNH2
MeNH2
EtNH2
Me3CNH2
—
—
—
20
25
20
56
—
—
—
44
37
—
—
—
—
20
15
—
—
—
_______
* Data given for reaction of salt with amine (without ethanol).
Me
N
Me
N
CO2Et
NHPh
H2N(CH2)2OH
PhNH2
O
C
N
3
1a
3
+
+
Me
Me
NHPh
Water plays quite an important role in this rearrangement. Thus, the reaction of salt 1a with an ethanol–
water solution of ethylamine gives pyridone 5 as the major product along with the rearrangement products,
pyridines 2a and 2b. We note that when the reaction is carried out in the presence of water, pyridone 5 was also
isolated in the reaction of salt 1a with diethylamine and tert-butylamine.
Me
Me
Me
+
N
CO2Et
+ 2a (8%) + 2b (16%) + 3 (10%)
Et NH2
H2O
_
I
CO2Et
Me
N
Me
O
N
H
5 (45%)
The formation of pyridone 5, as well as the formation of enamine recyclization products 2a-d, may be
attributed to different pathways for the transformation of open form 6. The first step in these rearrangement is
probably nucleophilic attack at the pyrimidine ring with subsequent dissociation of the N(1)–C(6) bond and
transformation of the intermediate into open form 6. Cyclization of 6 leads to formation of a new C–C bond and
conversion to isomerizational recyclization product 2a (pathway A). The formation of a rearrangement product
with transamination due to exchange of the amine group in the enamine fragment (pathway B) or formation of
pyridone 5 through mild, nonpolar hydrolysis in the enamine fragment of intermediate 6 with subsequent
transformation of enol 7 into pyridone 5 (pathway C) are possible directions for the transformation of
intermediate 6.
325

Me
Me
EtN
Me
N
Me
EtHN
Me
Me
CO2Et
+
N
_
Et NH2
– HI
NHMe
I
CO2Et
CO2Et
Me
N
Me
N
N
1a
Me
CO2Et
EtN
Me
EtHN
CO2Et
NHMe
2b
2a
Et NH2
Et NH2
–
Me
NHMe
–
N
H
6
Me
Et NH2
N
–
Me NH2
pathway A
Me
EtHN
CO2Et
–
Me NH2
H2O
Me
Me
NHEt
N
EtN
Me
Me
CO2Et
EtHN
EtN
CO2Et
CO2Et
5
Et NH2
–
Me
N
H
OH
Me
N
H
O
Me
NHEt
N
H
7
pathway B
pathway C

1
The structures of rearrangement products 2a-d were confirmed by their H and 13C NMR spectra,
showing the alkylamino group signals are characteristic for nicotinic acid derivatives, especially the methyl
group doublet in methylamino derivative 2a, methylene group doublet in 2c, and methylene group quartet in the
ethylamino fragment of 2b. The correctness of the signal assignment was also confirmed by double resonance
experiments by suppressing the signal of the proton at the amine nitrogen atom. The rearrangement is indicated
also by the absence of the signal characteristic for the protons of the methylene group of the side chain of salts
1a and 1b in the vicinity of 4.5 ppm.
EXPERIMENTAL
The NMR spectra were taken on a Varian Mercury 300 spectrometer used in the US CRDF RESC 17-5
program framework. Thin-layer chromatography was carried out on Silufol UV-254 plates with development by
iodine vapor and the Ehrlich reagent. Preparative separation was carried out on a column packed with silica gel
L40/100 with 10:1 benzene–ether as the eluent.
Ethyl Ester of 4,6-Dimethyl-2-pyrimidinylacetic Acid (3). Diethyl malonate (137 g, 0.69 mol) was
added dropwise to sodium (14.5 g, 0.63 mol) suspended in toluene and transferred into absolute ether (400 ml).
The mixture was stirred at room temperature for one or two days until the complete disappearance of sodium
and formation of a malonate ester salt. Ether was then distilled off and dry DMF (100 ml) was added. After
complete dissolution of the salt, a solution of 2-chloro-4,6-dimethylpyrimidine (43.5 g, 0.3 mol) in DMF (50 ml)
was added. The reaction mixture was stirred and heated at 120°C with reflux for 15 h. The solvent was distilled
off in vacuum and benzene (200 ml) was added. Acetic acid was added to neutralize the mixture. The solvent
was distilled off the benzene solution and the residue was distilled in vacuum, taking the fraction at 118-121°C
(3 mm). The crystals precipitated upon standing were filtered off, recrystallized from hexane, and dried in the
air to give 23.5 g (40%) of compound 3; mp 65-66°C, Rf 0.5 (3:1 benzene–acetone) (65-66°C (water) [7]).
1
), δ, ppm,
H NMR spectrum (CDCl3
J (Hz): 1.25 (3H, t, J = 7.1, CH2CH3); 2.41 (6H, s, 4- and 6-CH3); 3.78 (2H,
s, CH2); 4.15 (2H, q, J = 7.1, CH2CH3); 7.0 (1H, s, 5-H). Found, %: C 61.98; H 7.35. C10H14N2O2.
Calculated, %: C 61.84; H 7.27.
Iodoalkylates of Ethyl Ester of 4,6-Dimethyl-2-pyrimidinylacetic Acid (1a and 1b). A mixture of
ester 3 (10 g, 0.05 mol) and corresponding alkyl iodide (15 ml) in a sealed glass ampule was heated on a steam
bath. After 10 h, the crystalline precipitate was filtered off (after 40 h in the case of ethyl iodide), washed with a
1
small amount of hexane, and dried in the air. Yield of salt 1a 17 g (98%); mp 134-135°C (acetone). H NMR
), δ, ppm,
spectrum (DMSO-d6
J (Hz): 1.34 (3H, t, CH3CH2O); 2.73 (3H, s, 4-CH3); 2.93 (3H, s, 6-CH3); 4.13
(3H, s, N–CH3); 4.24 (2H, q, J = 7.1, OCH2CH3); 4.5 (2H, s, CH2); 8.14 (1H, s, 5-H). Found, %: C 39.05;
H 4.78. C10H14N2O2·CH3I. Calculated, %: C 39.30; H 5.10.
1
), δ, ppm,
Yield of 1b 19 g (52%); mp 118-119°C (acetone). H NMR spectrum (DMSO-d6
J (Hz): 1.33
(3H, t, J = 7.2, CH3–CH2O); 1.51 (3H, t, J = 7.1, N–CH2CH3); 2.73 (3H, s, 4-CH3); 2.95 (3H, s, 6-CH3), 4.24
(2H, q, J = 7.2, CH3CH2O); 4.49 (2H, s, CH2); 4.63 (2H, q, J = 7.1, N–CH2CH3); 8.17 (1H, s, 5-H). Found, %:
C 40.88; H 5.21. C10H14N2O2·C2H5I. Calculated, %: C 41.16; H 5.47.
Reaction of Pyrimidinium Salts 1a and 1b with Amines (General Method). Pyrimidine salt 1
(0.002 mol) was dissolved in 15% ethanolic methylamine (or 11% ethylamine) (6 ml) and heated in a sealed
ampule on a steam bath. The solvent was then distilled off and the residue was separated on a column packed
with silica gel L40/100 using 10:1 benzene–acetone as the eluent. After completion of the preparatory
separation, the fraction remaining at the start was eluted with acetone to give pyridone 5.
Analogous experiments were carried out in the presence of water. The corresponding amount of water
indicated in Table 1 was added to the starting mixture of the pyrimidinium salt and ethanolic amine.
327

Ethyl Ester of 4,6-Dimethyl-2-methylaminonicotinic Acid (2a); mp 39-40°C (39-40°C [4, 5]), Rf 0.5
1
), δ, ppm,
(10:1 benzene–acetone). H NMR spectrum (CDCl3
J (Hz): 1.39 (3H, t, J = 7.2, CH2CH3); 2.38 and
2.43 (6H, s, 4-CH3 and 6-CH3); 3.04 (3H, d, J = 5.1, NCH3); 4.33 (2H, q, J = 7.2, CH2CH3); 6.23 (1H, s, 5-H);
13
), δ, ppm: 14.37 (OCH
7.77 (1H, s, NH). C NMR spectrum (CDCl3
2CH3), 23.59 (4-CH3), 24.66 (6-CH3), 28.22
(N–CH3), 60.47 (OCH2), 104.04 (C(4)), 114.69 (C(5)), 150.97 (C(6)), 159.61 (C(2)), 160.77 (C(3)), 169.13 (C=O).
Found, %: C 63.69; H 7.97; N 13.31. C11H16N2O2. Calculated, %: C 63.44; H 7.74; N 13.45.
Ethyl Ester of 2-Ethylamino-4,6-dimethylnicotinic acid (2b) was obtained as an oil, Rf 0.65 (10:1
1
), δ, ppm,
benzene–acetone). H NMR spectrum (CDCl3
J (Hz): 1.23 (3H, t, J = 7.2, NHCH2CH3); 1.39 (3H, t,
J = 7.1, OCH2CH3); 2.35 and 2.44 (6H, s, 4-CH3 and 6-CH3); 3.51 (2H, dq, 1J = 7.2, 2J = 5.0, NHCH2CH3); 4.34
13
), δ, ppm: 14.31
(2H, q, J = 7.1, OCH2CH3); 6.23 (1H, s, 5-H); 7.73 (1H, s, NH). C NMR spectrum (CDCl3
(NHCH2CH3), 14.89 (OCH2CH3), 23.58 (4-CH3), 24.62 (6-CH3), 35.99 (N–CH2), 60.42 (OCH2), 103.74 (C(4)),
114.66 (C(5)), 151.08 (C(6)), 159.01 (C(2)), 160.87 (C(3)), 169.18 (C=O). Found, %: C 64.68; H 8.01; N 12.81.
C12H18N2O2. Calculated, %: C 64.84; H 8.16; N 12.60.
Reaction of Salt 1a with Aniline. Aniline (5 ml) was added to salt 1a (1 g, 0.003 mol) and heated at
95-100°C in a sealed ampule for 40 h. The reaction mixture was then treated as in the general method described
above. The residue was separated on a column packed with silica gel L40/100 using 5:1 benzene–acetone as the
eluent to give 0.36 g (50%) of anilide 4 and 0.065 g (8%) 2d.
Anilide of 4,6-Dimethyl-2-pyrimidinylacetic Acid (4); mp 109-110°C, Rf 0.3 (3:1 benzene–acetone).
1
), δ, ppm,
H NMR spectrum (CDCl3
J (Hz): 2.53 (6H, s, 4-CH3 and 6-CH3); 4.03 (2H, s, CH2); 6.97 (1H, s,
5-H); 7.09 (1H, dd, 1J = 7.2, 2J = 1.9, 4'-H); 7.31 (2H, m, 3'-H); 7.57 (2H, dd, 1J = 7.8, 2J = 1.9, 2'-H); 10.29 (1H,
br. s, NH).
Ethyl Ester of 4,6-Dimethyl-2-phenylaminonicotinic Acid (2d), Rf 0.56 (3:1 benzene–acetone).
1
), δ, ppm: 1.39 (3H, t, OCH
H NMR spectrum (CDCl3
2CH3); 2.25 (3H, s, 4(6)-CH3); 2.31 (3H, s, 6(4)-CH3);
4.38 (2H, q, OCH2CH3); 5.95 (1H, s, 5-H); 7.31 (5H, m, Ph).
The spectra of 2c and 5 were described in our previous work [6, 8].
This work was carried out within the framework of Science Theme 96-559 of the Ministry of Science
and Education of the Republic of Armenia and a joint grant ACH-006 98/AC1-955 of the National Fund for
Science and Advanced Technology of Armenia (NFSAT) and Civilian Research and Development Fund of the
USA (US CRDF).
The authors thank Prof. Alan Katritzky of the University of Florida for support and a discussion of these
results.
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