Substituted ureas based on 2,6-dimethyl-3,5-pyridinedicarboxylic acid azides

Article abstract of DOI:10.1007/s10593-012-1120-1

Under Curtius rearrangement conditions, 2,6-dimethyl-3,5- pyridinedicarboxylic acid azides form the corresponding isocyanates which react in situ with ammonia, primary and secondary amines to form mono-, di-, and trisubstituted ureas. The reaction of the

Full text of DOI:10.1007/s10593-012-1120-1

Chemistry of Heterocyclic Compounds, Vol. 48, No. 8, November, 2012 (Russian Original Vol. 48, No. 8, August, 2012)
SUBSTITUTED UREAS BASED ON 2,6-DIMETHYL-
3,5-PYRIDINEDICARBOXYLIC ACID AZIDES
E. Yu. Nesterova1, A. S. Pugacheva1, and M. V. Voevudsky2*
Under Curtius rearrangement conditions, 2,6-dimethyl-3,5-pyridinedicarboxylic acid azides form the
corresponding isocyanates which react in situ with ammonia, primary and secondary amines to form
mono-, di-, and trisubstituted ureas. The reaction of the 5-ethoxycarbonyl-2,6-dimethylnicotinic acid
azide with imidazole under these conditions gave symmetrical N,N'-bis[5-(ethoxycarbonyl)-2,6-di-
methylpyridin-3-yl]ureas.
Keywords: acylazides, amines, ureas, Curtius rearrangement.
Ureas containing a pyridine fragment possess various pharmacological activities [1-5], including
anticancer activity [1].
We have studied the formation of ureas of the pyridine series by the reaction of the azide of
5-ethoxycarbonyl-2,6-dimethylnicotinic acid (1) and the diazide of 2,6-dimethylpyridine-3,5-dicarboxylic acid
(2) with various amines.
On heating in dry inert solvents (benzene, toluene), the azides 1 and 2 underwent the Curtius
rearrangement to give the corresponding isocyanates 3 and 4, which reacted quantitatively in situ with primary
and secondary amines to give the corresponding ureas 5a-r, 6a-d, 6f,g,j,l-p,r. It should be noted that the
products of the reaction with primary amines 5a-o, 6a-d,f,g,j,l-o have low solubility in most organic solvents,
whereas the trisubstituted ureas 5p,r, 6p,r obtained from secondary amines dissolve well in polar and nonpolar
organic solvents (hexane, benzene, toluene, lower alcohols), which complicates their complete isolation and
purification.
Depending on the amount of ammonia reacting with the isocyanates 3 and 4, formation of different
reaction products was observed. For example, a 20-30-fold excess of aqueous ammonia led to the ureas 5a and
6a, which gave a positive qualitative reaction with p-N,N-dimethylaminobenzaldehyde, characteristic of an
unsubstituted urea group [6]. With a small excess of ammonia in the presence of 2-propanol the basic product of
the reaction was the biuret 7 or a high-melting substance, probably with a polymeric structure. It should be
noted that we did not isolate a urea containing an imidazole fragment when the azide 1 reacted with imidazole.
The product obtained was characterized as the urea 8, the formation of which as the main product of reaction we
also observed on the interaction of azide 1 with tert-butanol [7].
_______
*To whom correspondence should be addressed, e-mail: voevudsky@ukr.net.
1Oles' Gonchar Dnepropetrovsk National University, 72 Gagarin Ave., Dnepropetrovsk 49010, Ukraine; e-mail:
kafedra_vms@mail.ru, anni83@bk.ru.
2Ukrainian State Chemical-technological University, 8 Gagarin Ave., Dnepropetrovsk 49005, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1272-1281, August, 2012.
Original article submitted June 23, 2011; revision submitted September 10, 2012.
0009-3122/12/4808-1187©2012 Springer Science+Business Media New York
1187

A decrease in the melting points was observed for the compounds 5a-r, 6a-d,f,g,j,l-p,r with increasing
the degree of substitution at the nitrogen atom (Table 1). For example, the monoureas 5b-o are high-melting
substances (mp 170-220°C) in contrast to the ureas 5p-r obtained from secondary amines (mp < 150°C). The
diureas 6b,c,f,g,j,l-o, containing primary amines, decompose at 280-320°C, whereas the diureas 6p,r,
containing the diethylamine and morpholine fragments, have mp < 200°C.
O
O
O
R
N
O
H
N
NHRR1
NCO
Me
Benzene
–N2
N3
R1
EtO
EtO
Me
EtO
Me
O
Me
N
1
Me
N
5a–r
Me
N
3
O
O
O
N
O
H
N
H
N
H
H
N
H
N
NH3, 2-PrOH
N
OEt
EtO
Me
N
OEt
EtO
Me
H
O
O
O
Me
Me
N
Me
N
N
Me
N
Me
Me
8
7
O
O
R
N
R
N
NCO
Me
OCN
H
H
2NHRR1
Benzene
–2N2
N
N
R1
R1
N3
N3
Me
N
O
O
Me
N
2
Me
Me
N
Me
4
6a–d,f,g,j,l–p,r
a–o R = H, a R1 = H, b R1 = Ph, c R1 = 1-naphthyl, d R1 = 2-MeC6H4, e R1 = 3-MeC6H4,
f R1 = 4-MeC6H4, g R1 = 2-MeOC6H4, h R1 = 3-MeOC6H4, i R1 = 4-EtOC6H4, j R1 = 4-HOC6H4,
k R1 = 4-HO-2,6-Me2C6H2, l R1 = 4-BrC6H4, m R1 = Bn, n R1 = c-Hex, o R1 = 2-Py;
p R = R1 = Et, q R+R1 = (CH2)5, r R+R1 = (CH2)2O(CH2)2
In the high-frequency region of the IR spectra of ureas 5a-r, 6a-d,f,g,j,l-p,r, the NH group stretching
bands are observed in the 3350-3270 cm-1 range (Tables 2 and 3). The NH2 group stretching bands at 3450-3400 cm-
1
are observed in the spectra of ureas 5a and 6a. The presence of ester and urea groups in compounds 5a-r is
confirmed by the presence of intense absorption band in the 1760-1720 cm-1 (ethoxycarbonyl fragment) and
1690-1635 cm-1 regions (amide band I). Only the amide band I in the 1700-1640 cm-1 range was observed in the
spectra of diureas 6a-d,f,g,j,l-p,r.
Signals of the non-equivalent methyl groups in the positions 2 and 6 of the pyridine ring with chemical
shifts of 2.36-2.56 and 2.50-2.71 ppm respectively are present in the 1H NMR spectra of ureas 5a-r (Tables 2 and
3). The position of the γ-H proton signal of the pyridine ring (a singlet in the 7.91-8.80 ppm range) depends on
the electronic influence of the β-position substituent (Table 1). In the spectra of the ureas 5b-j,l-o, which contain
an aryl substituent at the nitrogen atom, this signal is shifted by 0.6-0.8 ppm to low field in comparison with the
γ-proton position in the spectrum of the monosubstituted urea 5a. In the spectra of ureas 5k,p-r this signal is
shifted by 0.6-0.7 ppm to high field, which is probably connected to the increased electron density on the
pyridine ring due to the electron-donor substituents in the urea fragment. In the spectra of N,N'-disubstituted
ureas, containing aromatic and pyridine fragments, the NH group proton signals appear as two singlets in the
7.29-9.64 ppm region, which is in agreement with literature data [3, 8, 9]. For N,N,N'-trisubstituted ureas 5p-r,
the NH group proton signal appears in the 7.65-8.25 ppm region, which permits the assignment of the more
high-field NH proton signal in the spectra of N,N'-disubstituted ureas to the NH group attached to the pyridine
ring (Table 2).
1188

TABLE 1. Physicochemical Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield, %
C
H
N
C11H15N3O3
C17H19N3O3
C21H21N3O3
C18H21N3O3
C18H21N3O3
C18H21N3O3
C18H21N3O4
C18H21N3O4
C19H23N3O4
C17H19N3O4
C19H23N3O4
C17H18BrN3O3
C18H21N3O3
C17H25N3O3
C16H18N4O3
C15H23N3O3
C16H23N3O3
C15H21N3O4
C9H13N5O2
C21H21N5O2
C29H25N5O2
C23H25N5O2
55.75
55.69
65.25
65.16
69.75
69.41
66.15
66.04
66.11
66.04
66.19
66.04
62.75
62.96
62.83
62.96
63.97
63.85
62.09
62.00
63.75
63.85
52.21
52.06
66.15
66.04
64.07
63.93
61.26
61.14
61.65
61.41
6.48
6.37
6.28
6.11
5.68
5.82
6.58
6.47
6.38
6.47
6.61
6.47
6.28
6.16
6.03
6.16
6.56
6.49
5.68
5.81
6.57
6.49
4.48
4.63
6.32
6.47
7.68
7.89
5.48
5.77
7.78
7.90
17.85
17.71
13.35
13.41
11.65
11.56
12.75
12.84
12.95
12.84
12.95
12.84
12.35
12.24
12.13
12.24
11.85
11.76
12.84
12.76
11.89
11.76
10.56
10.71
12.93
12.84
13.31
13.16
17.65
17.82
14.16
14.32
145-147
185-186
180-182
220-221
175-177
178-180
173-175
160-162
198-200
55
99
70
93
95
94
92
96
98
96
85
87
90
88
99
77
67
45
60
95
88
90
5a
5b
5c
5d
5e
5f
5g
5h
5i
272-275
(decomp.)
5j
203-205
215-216
180-182
195-197
193-194
128-130
118-119
110-112
5k
5l
5m
5n
5o
5p
5q
5r
6a
6b
6c
6d
62.77
62.93
58.74
58.62
48.65
48.42
67.31
67.18
73.41
73.25
68.63
68.47
7.48
7.59
6.67
6.89
5.94
5.87
5.49
5.64
5.45
5.30
6.13
6.25
13.59
13.76
13.82
13.67
31.23
31.37
18.53
18.65
250
(subl.)
300-305
(decomp.)
295-300
(decomp.)
320-325
(decomp.)
14.59
14.73
17.41
17.36
C23H25N5O2
C23H25N5O4
C21H21N5O4
C21H19Br2N5O2
C23H25N5O2
C21H33N5O2
C19H19N7O2
C17H29N5O2
C17H25N5O4
68.65
68.47
63.58
63.44
62.03
61.91
47.21
47.30
68.34
68.47
65.19
65.09
60.32
60.47
60.99
60.87
6.38
6.25
5.87
5.79
5.35
5.20
3.72
3.59
6.39
6.25
8.35
8.58
5.16
5.07
8.63
8.71
17.21
17.36
15.87
16.08
17.04
17.19
12.97
13.13
17.49
17.36
18.21
18.07
26.06
25.98
20.68
20.88
280-282
93
85
70
77
80
83
91
65
67
6f
315-320
(decomp.)
310-315
(decomp.)
275-280
(decomp.)
315-320
(decomp.)
280-282
289-291
198-200
205-207
6g
6j
6l
6m
6n
6o
6p
6r
56.32
56.19
7.05
6.93
19.12
19.27
1189

1190

1191

1192

Substitution of ester group by urea in compounds 6a-d,f,g,j,l-p,r leads to an upfield shift by 0.09-0.16
ppm of the methyl group proton signals at the positions 2 and 6 of the pyridine ring; the signal of the γ-proton
on the pyridine ring is shifted upfield by 0.1-0.3 ppm due to the presence of aryl substituents in the compounds
6a-d,f,g,j,l, and by 0.4-0.6 ppm in the case of compounds 6p,r containing a diethylamine and morpholine
fragment, respectively. The signals of the protons of the NH groups are also shifted upfield by 0.1-0.4 ppm, in
comparison with the positions of these protons in the spectra of the corresponding monoureas 5a-d,f,g,j,l-p,r.
It should be noted that in compounds 5o and 6o, obtained with 2-aminopyridine, the proton signal of
one of the urea NH groups is strongly shifted downfield and appears at 11.10 and 10.89 ppm, respectively. This
may be connected to the formation of intramolecular hydrogen bond between the nitrogen atom of the pyridine
ring substituent and the proton of the NH group of the urea group, analogous to the hydrogen bond in
N,N'-dipyridylureas [2], which leads to a considerable downfield shift of one of the NH group signals.
Ureas with different degrees of substitution at the nitrogen atom have different disintegration patterns
under the influence of electron impact [10]. The most characteristic for N,N'-disubstituted aryl-containing ureas
is the formation of the corresponding isocyanate and amine fragments, capable of forming the particular urea
(paths 1 and 2). In N,N,N'-trisubstituted ureas decomposition proceeds with the formation of N,N-disubstituted
isocyanate fragments (path 3).
+ ·
O
NH2
Me
Path 1
R1NCO
+ ·
and
EtO
Me
B (m,o)
N
+
A
R1
+·
R
N
O
H
N
R1
EtO
Me
+ ·
O
O
NCO
Path 2
Path 3
N
Me
NHRR1
+ ·
EtO
Me
and
M (m,o–q)
D (m,o,q)
N
Me
C
+
+
R
;
N
R1
Me
N
F
CH2
O
E
In the mass spectra of N,N'-disubstituted ureas 5m,o and 8 (Table 4), molecular ion peaks with intensity
12-15% are present, the fragmentation of which is linked to decomposition of the urea fragment (paths 1 and 2)
in agreement with [10, 11]. The main direction of decomposition in the case of compounds 5m and 8 is the
formation of the ion of the ethyl ester of 5-amino-2,6-dimethylnicotinic acid (A, m/z 194), which exhibits the
strongest peak in the spectra of these compounds, whereas in the spectra of compound 5o the 2-aminopyridine
peak (Do, m/z 94, path 2) is the strongest. Apparently this is connected to the charge localization on the amino
group nitrogen atom, which in better stabilized by resonance at the α-position of the pyridine nucleus, rather
than in the β-position. The peaks of the benzylisocyanate ion (Bm, m/z 133) and 2-pyridylisocyanate ion (Bo, m/z
120) are present in the spectra of these compounds with intensities of 29 and 23% respectively. In the spectra of
compound 5m, the subsequent fragmentation of the ion Bm probably leads to the appearance of the intense ion
peak of the resonance stabilized benzyl ion R1m (m/z 91, 70%). In the spectrum of compound 5o, the pyridinium
cation peak intensity R1 (m/z 78, 33%) is lower by almost a half (Table 4).
o
1193

TABLE 4. Mass Spectra of Ureas 5m,o-q and 8
m/z (Irel, %)
[М]+•
Compound
B
R1
D
E
A 194
(100) 133 (29) 91 (70)
C 220
F 106
327 (15)
314 (15)
293 (7)
(19)
(4)
107 (26)
94 (100)
—
—
—
(40)
—
5m
5o
5p
5q
8
(32)
—
120 (23) 78 (32)
—
—
—
—
—
—
—
100 (100) (26)
305 (20)
414 (12)
—
(12)
84 (16) 112 (100)
—
(100)
(30) 194 (100)
—
(12)
In the mass spectra of the N,N,N'-trisubstituted ureas 5p,q, there are molecular ion peaks with intensities
of 7 and 20%, respectively, the fragmentation of which most probably leads to the formation of disubstituted
isocyanate ions E(p,q) (path 3), which appear in the spectra as the peaks Ep (m/z 100) and Eq (m/z 112) with
intensities of 100% (Table 4). The 2,6-dimethylpyridine fragment F (m/z 106) is present in the spectra of ureas
5m,p and 8 as peaks of medium and low intensity.
Therefore, the azides of 2,6-dimethylpyridine-3,5-dicarboxylic acid and its monoethyl ester react with
primary amines, secondary amines and ammonia under the conditions of Curtius rearrangement, to give the
corresponding ureas, decomposition of which under electron impact is in agreement with the generally accepted
disintegration scheme for this class of compounds.
EXPERIMENTAL
1
IR spectra of KBr pellets were recorded with a Specord 75IR spectrometer. H NMR spectra were
recorded on a Varian VXR-300 (300 MHz) spectrometer in a 4:1 mixture of DMSO-d6 and CCl4 with TMS as
internal standard. Chromato-mass spectrometry was carried out on a Varian 1200L gas chromatograph with a
mass spectrometer as detector (0.25 mm×50 m column with SE-30 stationary phase (polymethylsiloxane + 5%
phenylsiloxane), helium carrier gas, evaporator temperature 300°C, EI ionization 70 eV). Elemental analysis
was carried out with a Vario EL III instrument (Elementar). Melting points were determined in open capillary
with an apparatus for melting point determination (PTP). The course of reactions and the purity of the reaction
products were monitored by TLC on Sorbfil PTSKh-AF-A plates with iodine vapor visualization.
The 5-ethoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid azide (1) was synthesized by a known
method [12], and the 2,6-dimethylpyridine-3,5-dicarboxylic acid diazide (2) by method [7].
Ethyl 5-[(Aminocarbonyl)amino]-2,6-dimethylnicotinate (5a). 35% Aqueous ammonia (15 ml) was
added to monoazide 1(1.5 g, 6 mmol), and the mixture was refluxed for 30 min. The precipitate which formed
on cooling was filtered off, washed with a small amount of water, and crystallized from 2-PrOH.
Ureas 5b-r (General Method). A mixture of monoazide 1(1.99 g, 8 mmol) and the corresponding
amine (9 mmol) in dry benzene (10 ml) was refluxed for 1 h. The solution was cooled, the precipitate was
filtered off and crystallized from 2-PrOH. Compounds 5p-r were isolated by evaporating benzene from the
reaction mixture in vacuum with subsequent recrystallization of the residue from 2-PrOH.
Diureas 6a-d,f,g,j,l-p,r (General Method). A mixture of diazide 2 (1.96 g, 8 mmol) and the
corresponding amine (18 mmol) in dry benzene (10 ml) was refluxed for 1 h. The solution was cooled, the
precipitate was filtered off and crystallized from EtOH. Compounds 6p,r were isolated by evaporation of the
benzene from the reaction mixture in vacuum and subsequent recrystallization of the residue from 2-PrOH.
Ethyl
5-({[({[5-(Ethoxycarbonyl)-2,6-dimethylpyridin-3-yl]amino}carbonyl)amino]carbonyl}-
amino)-2,6-dimethylnicotinate (7). Dry benzene (50 ml) and a solution of 35% aqueous ammonia (2.5 ml) in
1194

2-PrOH (12 ml) were added to monoazide 1 (5.0 g, 20 mmol). The mixture was refluxed for 1 h, the precipitate
was filtered off, dried in air, and recrystallized from 2-PrOH. Yield 3.0 g (65%); mp 197-199°C. IR spectrum, ν,
1
cm-1: 3310, 3140 (νNH), 1740 (νCO), 1635 (νNHCO), 1550 (δNH), 1455 (δCCH). H NMR spectrum, δ, ppm (J, Hz):
1.31 (6H, t, J = 6.9, 2CH2CH3);, 2.43 (6H, s, 2,2'-CH3); 2.61 (6H, s, 6.6'-CH3), 4.35 (4H, q, J = 6.9, 2CH2CH3); 8.60
(2H, s, H-4,4'); 8.72 (2H, s, 2NH); 9.13 (1H, s, NH). Found, %: C 57.91; H 6.08; N 15.18. C22H27N5O6.
Calculated, %: C 57.76; H 5.95; N 15.31.
Ethyl 5-[({[5-(Ethoxycarbonyl)-2,6-dimethylpyridin-3-yl]amino}carbonyl)amino]-2,6-dimethyl-
nicotinate (8). Benzene (25 ml) and imidazole (0.83 g, 12 mmol) were added to monoazide 1 (3 g, 12 mmol).
The mixture was refluxed for 1 h. The solution was evaporated, the mixture formed was washed with water, the
precipitate was filtered off, washed with water, and crystallized from 2-PrOH. Yield 0.97 g (39%); mp
1
230-232°C. IR spectrum, ν, cm-1: 3300 (νNH), 1710 (νCO), 1550 (δNH), 1455 (δCCH). H NMR spectrum, δ, ppm
(J, Hz): 1.30 (6H, t, J = 7.0, 2CH2CH3); 2.52 (6H, s, 2,2'-CH3); 2.70 (6H, s, 6,6'-CH3); 4.08-4.76 (4H, m,
2CH2CH3); 8.64 (2H, s, H-4,4'); 9.26 (2H, s, 2NH). Found, %: C 61.01; H 6.43; N 13.44. C21H26N4O5.
Calculated, %: C 60.86; H 6.32; N 13.52.
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1195