Synthesis, spectroscopic, structural and conformational study of some tri-substituted ureas derived from N-methylpiperazine containing phenyl and N-heterocyclic substituents

Article abstract of DOI:10.1016/j.molstruc.2013.01.001

A series of tri-substituted ureas containing an N-methylpiperazine moiety as well as phenyl and N-heterocyclic substituents were synthesized and studied by ¹H, ¹³C NMR and IR spectroscopies. From ¹H and ¹³C NMR data, in CDCl₃ solution at room temperature, a fast inter-conversion of the piperazine ring with the N-CH₃ group in equatorial position can be proposed. Amino-imino tautomerism is observed for both thiazole and benzothiazole derivatives. Moreover, with the exception of the imino form of the thiazole derivative, the aryl substituted N-carbamoyl group rotates freely. IR data show that the compounds adopt a planar trans conformation of the CONH moiety.

Full text of DOI:10.1016/j.molstruc.2013.01.001

Journal of Molecular Structure 1044 (2013) 215–220
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, spectroscopic, structural and conformational study of some
tri-substituted ureas derived from N-methylpiperazine containing phenyl
and N-heterocyclic substituents
I. Iriepa , J. Bellanato b
a,
⇑
a
Departamento de Química Orgánica, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
Instituto de Estructura de la Materia, C.S.I.C., Madrid, Spain
b
g r a p h i c a l a b s t r a c t
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 8 January 2013
A series of tri-substituted ureas containing an N-methylpiperazine moiety as well as phenyl and N-het-
erocyclic substituents were synthesized and studied by H, C NMR and IR spectroscopies. From 1H and
1
13
1
3
3
C NMR data, in CDCl solution at room temperature, a fast inter-conversion of the piperazine ring with
Keywords:
N-methylpiperazine
Ureas
Infrared spectroscopy
NMR spectroscopy
Conformational analysis
Amino–imino tautomerism
the N-CH3 group in equatorial position can be proposed. Amino–imino tautomerism is observed for both
thiazole and benzothiazole derivatives. Moreover, with the exception of the imino form of the thiazole
derivative, the aryl substituted N-carbamoyl group rotates freely. IR data show that the compounds adopt
a planar trans conformation of the ACOANHA moiety.
Ó 2013 Elsevier B.V. All rights reserved.
1
. Introduction
Substituted piperazines are common motifs in a large number
As a result of a continuing effort to develop novel heterocyclic
compounds with potential therapeutic activity, we have designed
and prepared a series of tri-substituted ureas using 4-methyl-
1-piperazine carbonyl chloride and the aromatic compounds ani-
line, aminopyridines, 2-aminobenzothiazole and 2-aminothiazole.
The biological effect of organic compounds is very often
associated with their conformational state. In order to gain deeper
insight into the structure–activity relationships, the conforma-
tional isomerism at the urea group and the amino–imino tautom-
erism in the benzothiazole and thiazole derivatives were studied
using IR and NMR spectroscopies.
of compounds with biological activity. Specifically, N-urea and
N,N -bis-urea piperazine derivatives have interesting therapeutic
indications [1–3]. Furthermore, thiazole and benzothiazole deriva-
tives are widely used in the synthesis of medicinal compounds [4].
0
⇑
Corresponding author. Address: Departamento de Química Orgánica, Univers-
idad de Alcalá de Henares, Ctra. Madrid-Barcelona, Km 33,600, E-28871 Alcalá de
Henares, Madrid, Spain. Tel./fax: +34 91 885 4651.
E-mail address: isabel.iriepa@uah.es (I. Iriepa).
0
022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.01.001

2
16
I. Iriepa, J. Bellanato / Journal of Molecular Structure 1044 (2013) 215–220
ꢀ
1
H
N
solid state (KBr) in the 4000–400 cm
3
and in CDCl solution
1
ꢀ1
3
(ꢁ0.15 M) in the 4000–900 cm region using 0.2 mm NaCl cells.
N
Cl (a) R-NH2 / dry pyridine
(b) Na2CO3
2
N
R
Spectra for very dilute CCl
4
solutions were taken in the 4000–
N
N
4
5
ꢀ1
6
2500 cm region with 4 cm quartz cells. The reported wavenum-
bers are estimated to be accurate to within ±3 cm
O
O
ꢀ1
.
1
'
3'
2'
4'
3'
3'
N
1
'
3a'
6
'
2' 4'
3' 5'
2
'
3'
N
5'
N
4'
5'
2'
3. Results and discussion
2'
R:
5'
N1'
4
'
6'
6
'
S
1'
S
7
a'
4
1
'
6'
5'
1'
3.1. Chemistry
7
'
2
3
4
5
The carbamoyl chloride derived from 4-methylpiperazine with
aniline affords the expected urea 1.
Scheme 1. Synthesis of ureas 1–5.
Primary N-heterocyclic aromatic amines react as a nucleophile
with either of its nitrogen atoms, the exocyclic or the endocyclic
sp nitrogen, depending upon the electrophilic centre and the
experimental conditions. Usually, with acyl halides the exocyclic
nitrogen is the main nucleophile [5]. Consequently, the aminopyri-
dines, the 2-aminobenzothiazole and the 2-aminothiazole were
acylated on the exocyclic nitrogen atom obtaining the urea deriv-
atives 2–5. Products of the N-ring acylation have not been isolated.
Compounds 4–5 can undergo tautomerization to give amino (a)
and imino (b) isomers (Scheme 2).
2
. Experimental
.1. General procedure for preparing the ureas 1–5
-Methyl-1-piperazine carbonyl chloride, aniline and
2
2
4
N-heterocyclic amines were purchased from Aldrich and they were
used without further purification. Pyridine was distilled over so-
dium hydroxide pellets.
For the synthesis of the ureas 1–5, we started with the
4
-methyl-1-piperazine carbonyl chloride (Scheme 1). By reaction
of this compound with the corresponding amine in dry pyridine
as solvent, at room temperature, the urea derivative crystallized
as hydrochloride. The hydrochloride was dissolved in water, basi-
3.2. NMR spectra
3.2.1. Spectral analysis and assignments
1
fied with aqueous Na
2
CO
3
(10%) and extracted with CH
2
Cl
2
. The or-
The values of the H NMR chemical shifts with the signal assign-
ganic layer was dried over Na
2
SO and the solvent was removed to
4
ments are listed in Table 1.
afford a residue, which was purified by chromatography column to
3
At 300 MHz in CDCl solution the signals corresponding to the
obtain the corresponding ureas 1–5.
piperazine moiety for compounds 1–4 and 5a appeared as a singlet
at 2.21–2.31 ppm and two multiplets at 2.31–2.43 ppm and 3.45–
3.56 ppm. However, for compound 5b a singlet at 2.26 ppm and
four multiplets at 2.40, 2.30, 3.55 and 3.25 ppm were observed.
The aromatic protons appeared well differentiated in all cases.
The singlet at 2.21–2.31 ppm for compounds 1–4 and 5a has
2.2. NMR spectra
The NMR spectra of compounds 1–5 were recorded on a Varian
UNITY-300 spectrometer.
1
The H NMR spectra of CDCl
3
solutions (about 4% w/v) were ob-
3
been assigned to the N-CH protons according to results in related
tained at 300 MHz using spectral width of 4000 Hz in 24 K memory
and acquisition time of 3.0 s over 64 transients. Resolution
enhancement (LB = ꢀ0.80, GF = 0.60 and GFS = 0.20) was followed
by zero filling into 32 K memory prior to Fourier transformations.
The C NMR spectra were obtained in CDCl solutions (20% w/
3
v) at 75.429 MHz with a spectral width of 16501 Hz in 64 K mem-
ory, acquisition time of 1 s and relaxation delay of 1 s.
compounds [6]. For the assignment of the signals corresponding to
C2, C6, C3 and C5 protons, the electronic, anisotropic and the steric
effects exerted by the urea group have been taken into account.
The signal at 3.45–3.56 ppm has been assigned to H2ax(H2eq),
H6ax(H6eq) and the signal at 2.31–2.43 ppm to H3ax(H3eq),
H5ax(H5eq).
1
3
Concerning compound 5b, the singlet at 2.26 ppm corresponds
3
to the N-CH protons. The signals corresponding to the C2, C6, C3
2.3. IR spectra
and C5 protons have been assigned according to the reported val-
ues for related compounds [6].
The IR spectra of compounds 1–5 were recorded on a Perkin–El-
mer FTIR 1725X spectrophotometer, assisted by a computer, in the
It can be noted that the spectra of the compounds studied
showed only a signal for H2ax and H2eq, H6ax and H6eq, H3ax
H
Y
N
N
Y
N
C
O
N
N
X
N
N
O
X
4
a amino form
4b imino form
H
Y
X
N
N
N
C
O
N
Y
N
O
X
5a amino form
5
b imino form
X = N Y = S
X = S Y = NH
X = NH Y = S
Scheme 2. Tautomers for benzothiazole (4) and thiazole (5) derivatives.

I. Iriepa, J. Bellanato / Journal of Molecular Structure 1044 (2013) 215–220
217
Table 1
1
3
H NMR chemical shifts (d, ppm) for compounds 1–5 in CDCl .
1
2
3
4
5
Amino (5a)
Imino (5b)
H2ax(H2eq) (m)
H6ax(H6eq) (m)
H3ax(H3eq) (m)
H5ax(H5eq) (m)
3.50
3.50
2.43
2.43
2.31
6.35
7.31 (dd)
7.26 (m)
7.01 (tt)
7.26 (m)
7.31 (dd)
–
3.49
3.49
2.37
2.37
2.31
7.74
8.38 (d)
–
7.89 (ddd)
7.14 (dd)
8.14 (dd)
–
3.45
3.45
2.31
2.31
2.21
7.81
–
7.92 (d)
7.54 (dd)
6.83 (dd)
8.07 (d)
–
3.56
3.56
2.34
2.34
2.24
11
–
–
7.72 (d)
7.34 (t)
7.22 (t)
7.53 (d)
3.55
3.55
2.39
2.39
2.28
nd
3.55
3.25
2.30
2.40
2.26
nd
NACH
3
(s)
NH (brs)
0
0
0
0
0
0
H2
H3
H4
H5
H6
H7
–
–
–
–
7.28 (d)
6.81 (d)
–
6.87 (d)
6.41 (d)
–
–
–
Abbreviations: brs, broad singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets of doublets; m, multiplet; nd, not determined; s, singlet; t, triplet; tt, triplet of
triplets.
Table 2
3.2.3. Amino–imino tautomerism
Amino derivatives of N-heterocyclic compounds can exist in the
amino or imino form. Previously published data of the literature
1
3C chemical shifts (d, ppm) for compounds 1–5 in CDCl
3
.
1
2
3
4
5
[
9,10] confirm the importance of the heterocyclic moiety and of
Amino (5a)
Imino (5b)
the medium on the tautomeric ratio of this type of compounds.
Pyridine derivatives (e.g. compound 2 and 3) do not exhibit any
imino form even when strong electron-withdrawing groups are
bonded to the exocyclic nitrogen. On the contrary, the N-heterocy-
clic five-membered ring (e.g. compounds 4 and 5) is more prone to
transform itself in a non-aromatic form than the six-membered
one. This fact may be related to the relative stabilization by the res-
onance energy, which is higher for six- than for five-membered
heterocycles [9].
Taking into account the above considerations we have investi-
gated, by means of IR and NMR spectroscopies, the amino/imino
equilibria for 2-aminothiazole derivative 5 and its benzo analog 4
(Scheme 2).
C5
C3
C6
C2
54.68
54.68
44.07
44.07
46.17
154.71
138.72
119.75
128.77
–
54.54
54.54
43.95
43.95
45.99
154.88
–
143.20
136.39
–
54.48
54.48
43.85
43.85
45.92
153.90
–
152.62
113.28
–
54.44
54.44
43.95
43.95
45.89
163.68
–
54.99
54.99
44.63
44.63
46.18
166.00
–
161.16
–
–
138.33
112.55
–
–
–
55.47
54.77
46.88
42.80
46.36
170.05
–
150.70
–
–
136.00
112.70
–
–
–
NACH
C@O
3
0
C1
0
0
C2
155.14
–
C3
0
C3a
145.63
118.07
125.99
123.20
121.43
130.91
0
C4
123.02
128.77
119.75
–
127.58
123.39
141.09
–
137.81
118.02
146.97
–
0
C5
0
C6
0
C7
0
C7a
–
–
–
With respect to the prototopic tautomerism in aminobenzo-
thiazoles, some authors reported that the displacement to lower
1
3
0
values of C chemical shifts for C4 (C4 in compound 4) upon pass-
ing from the amino to the imino tautomer, enables the detection
and relative quantification of the imino tautomers of the heterocy-
cles [11,12].
and H3eq and H5ax and H5eq, suggesting a conformational
dynamics of the piperazine ring, which is fast enough on the
NMR time-scale to give one average signal.
The aromatic protons have been assigned in agreement with the
Furthermore, for 2-aminobenzothiazole derivatives the C3a
(C3a in compound 4) chemical shift of 151–153 ppm is character-
istic of a carbon atom vicinal to an sp nitrogen bearing a lone pair
amino form). On the contrary, values of 137–138 ppm are typical
for a C3a (C3a in compound 4) bound to an NAH group (imine
form) [13].
data of the literature [7,8].
0
For the assignment of 13C NMR chemical shifts (Table 2), substi-
2
tuent, electronic effects and the values for related compounds [6]
have been taken into consideration.
(
0
3
.2.2. Conformational study
As said above, from the H and 13C NMR data in CDCl
at room temperature a fast inter-conversion of the piperazine chair
ring with an equatorial position of the N-CH group can be pro-
posed. This is evidenced by the H NMR spectra where the N-CH
1
With respect to the tautomeric process, compounds 4 and 5 can
be represented by imidol type, amino and imino tautomers.
Two configurations Z and E can be proposed for the imidol type
tautomer and each configuration may have four preferred
conformers. In the case of the amino tautomer, four preferred con-
formers for each trans and cis conformation of the ACOANHA
structure are possible.
For the imino tautomer two configurations Z and E are expected,
which can exchange by isomerization at the exocyclic nitrogen of
the amino thiazole moiety. At the same time, each configuration
may have several conformers obtained by rotation around the
N1ACO and the CNACO single bonds. Four preferred conformers
I, II, V and VI) for the (Z)-isomer and three preferred conformers
III, IV and VII) for the (E)-isomer are shown in Scheme 3.
Examination of conformers and isomers for the imino form of
compounds 4 and 5 suggests that the (E)-isomer is the most stable
due to the formation of an intra-molecular hydrogen bond (III, IV
and VII).
3
solution
3
1
3
1
H chemical shifts of compounds 1–4, 5a and 5b of 2.21–
.31 ppm have the same values as those found in equatorial N-
2
13
CH
3
substituted piperazines. Besides, the N-CH
3
C chemical shifts
of 45.89–46.368 ppm are in agreement with previously reported
values in related compounds with an equatorial disposition of this
group [6].
3
For compounds 1–4 and 5a in CDCl solution the existence of
free rotation of the carbamoyl group around the N1ACO bond is
deduced. This conclusion is based on the equivalence of the H2ax
and H6ax, the H2eq and H6eq, the H3ax and H5ax and the H3eq
and H5eq and also on the equivalence of C2 and C6, and of C3
and C5. On the contrary, for compound 5b a restricted rotation
around the N1ACO bond is proposed due to the non-equivalence
of the mentioned carbons and protons of the piperazine ring.
(
(

2
18
I. Iriepa, J. Bellanato / Journal of Molecular Structure 1044 (2013) 215–220
N
O
N
O
N
N
N-CO bond rotation
N
N
S
S
N
N
H
H
(Z)-isomer (conformer V)
(
Z)-isomer (conformer VI)
N1-CO bond rotation
N1-CO bond rotation
H
S
N
N-CO bond rotation
H
N
N
N
N
N
N
S
O
N
(
Z)-isomer (conformer I)
O
(
Z)-isomer (conformer II)
inversion at N atom
inversion at N atom
N
S
N
N
S
H
N
N
N
N
O
N-CO bond rotation
H
N
O
(
E)-isomer (conformer III)
4b, 5b
(E)-isomer (conformer IV)
N1-CO bond rotation
N
O
N
H
N
N
(
E)-isomer (conformer VII)
S
Scheme 3. Conformers and isomers for imino forms of compounds 4 and 5.
3
.2.3.1. Compound 4. Regarding the identification of the preferred
amino–imino tautomers in CDCl solution for 2-aminobenzothia-
zole derivative 4, the C NMR analysis could give evidence by clo-
the E configuration is the preferred for the imino tautomer in
solution.
3
1
3
The chemical shift values of the 13C and H signals for the piper-
azine moiety in compound 4 are similar in magnitude to those of
the compounds 1–3 (Tables 1 and 2). The values are characteristic
of a piperazine ring where the nitrogen atom does not take part in
a hydrogen bond [6]; therefore, the conformers III and VII are
predominant.
1
0
0
sely looking at C3a and C4 chemical shifts. This compound
presented for C3a a chemical shift value of 145.63 ppm, which is
in between the characteristic values for the amino and the imino
forms (see above), in agreement with a fast inter-conversion
between the amino and imino forms. Besides, the chemical shift
0
0
value of C4 (118.07 ppm) is lower than the value found in related
The amino–imino tautomerization is also observed by the
1
13
compounds (ca. 120 ppm), in which the amino tautomer
dominates over the imino form [14,15]. The decrease in the d value
indicates the presence of the imino tautomer.
broadening of the H and C NMR signals as this exchange process
lead to average signals at room temperature [19]. Moreover, the
broadening and chemical shifts also indicate
conversion between the amino and imino forms.
a fast inter-
Furthermore, the proton migration from the urea group to the
0
nitrogen atom in position 3 of the thiazole fragment in compound
4
, as a result of amino–imino tautomerism, was also confirmed in
3.2.3.2. Compound 5. For compound 5 only one form could be iso-
1
0
the H NMR spectrum by the presence of resonance from the N3
proton of the thiazole moiety at high chemical shift (d = 11 ppm).
According to the data of the literature [16–18], the high value of
lated by chromatography column which is characterized as the
0
amino tautomer (5a), mainly because the H4 resonates at
0
7.28 ppm and H5 resonates at 6.81 ppm, with a coupling constant
this signal and the results in the
luted CCl solution (see below) suggest the formation of an intra-
molecular hydrogen bond (Scheme 3). These results confirm that
m
NAH infrared region in very di-
of 3.2 Hz (the vicinal coupling constants of 2-aminothiazoles are
4
generally in the range 3.1–3.8 Hz [7]). The spectrum in CDCl
3
ob-
tained after several days, presented new signals along with those

I. Iriepa, J. Bellanato / Journal of Molecular Structure 1044 (2013) 215–220
219
(
(
A)
N
N
S
N
N
H
S
N
N
N
N
3
N
O
O
'
3'
H
4
b, 5b
4c, 5c
B)
N
N
N
N
S
S
N
N
3'
N
O
O
H
H
3'
4
d, 5d
4e, 5e
0
Scheme 4. Proton exchange between the N3 atom and the carbonyl oxygen in compounds 4b and 5b. (A) Tautomerism and (B) single bond-no bond resonance.
ꢀ
1
of the amino form. Two of the new signals appear at 6.81 ppm and
at 6.41 ppm with a coupling constant of 5 Hz, which are assigned
to H4 and H5 , respectively. Given that the vicinal coupling con-
stants of 2-aminothiazolidines (imino forms) are in the range
probably NHꢂ ꢂ ꢂN since the
(KBr) did not practically change in CDCl
the case of compound 3 results in the
m
(C@O) at 1650 cm
in the solid
solution (1655 cm 1). In
(C@O) region also suggest
the presence of NHꢂ ꢂ ꢂN intermolecular hydrogen bonding in the
ꢀ
3
0
0
m
5
.4–5.0 Hz [7], the presence of the imino form (5b) is deduced.
The NAH proton signal was not clearly visible but the results in
the NAH infrared region (see below) indicate the formation of
an intramolecular hydrogen bond as in compound 4 (Scheme 3).
solid state.
Compounds 4 and 5, besides the
m(NAH) of the urea amide
ꢀ
1
m
group in the amino tautomer at 3431–3438 cm
and 3447–
ꢀ
1
3452 cm in CDCl
3
and CCl
4
, respectively, presented a complex
and broad absorption centered at ca. 3172 cm in CDCl
1
ꢀ1
The H NMR results in CDCl
3
solution show that the exchange tau-
3
and at
ꢀ1
tomerism process in compound 5 is slow.
3164–3171 cm in CCl
8,22,23] the low frequency absorption is attributable to the intra-
molecularly bonded NH group of the imino tautomer (see Scheme
). In both cases the proportion of the imino tautomer, as revealed
by the intensity ratio of the amino/imino (NAH) absorptions, is
greater in the more polar CDCl solvent than in CCl . In compound
in CCl an increase of the imino tautomer with the corresponding
decreasing of the amino tautomer was observed with time
3 days). Moreover, the proportion of the imino tautomer is also
greater in the aminothiazole 5 than in the aminobenzobenzothiaz-
ole derivative 4, in the solid and in CCl and CDCl solutions.
The (C@O) band of compounds 4 and 5 appeared, in CDCl
solution, in the expected region at 1665–1660 cm and the band
4
. In agreement with the literature data
[
0
3
.2.3.3. Proton exchange between nitrogen atom N3 and the carbonyl
3
oxygen. Another prototropy can also be considered for the imino
forms of compounds 4 and 5 (4b and 5b, conformers III and VII).
If the NAH bond is shorter than the Oꢂ ꢂ ꢂH (Scheme 4A), two
tautomers can be proposed by intramolecular exchange of the
m
3
4
5
4
0
hydrogen between N3 and the carbonyl oxygen. On the other
(
hand, if the proton of the Oꢂ ꢂ ꢂHAN intramolecular bond would
be situated just in the middle, the system would show single
bond-no bond resonance with two mesomeric forms [17,20]
4
3
m
3
(Scheme 4B). In our working conditions, IR spectra do not present
ꢀ1
OH bands. Therefore, the imidol type tautomers (4c, 5c) and mes-
omeric forms (4d, 5d, 4e, 5e) can be excluded.
ꢀ1
amide II at ca. 1535 cm
.
In compound 4, the three characteristic bands of the benzothi-
azole ring in the 1600–1500 cm region (‘‘thiazole I’’, aromatic
ꢀ1
m
3
.3. IR spectra
(C@C) and ‘‘thiazole II’’ [8,23]) appeared at 1599 (m), 1560 (sh)
ꢀ
1
and ca. 1535 cm (overlapped by the Amide II band).
According to the results in the (NAH) region, a medium band at
In the
m(NAH) region, the infrared spectrum of the phenyl deriv-
m
ꢀ1
ative 1 in CDCl
3
and in very dilute CCl solution showed a main
4
1620 cm in CDCl solution in compound 4 is tentatively assigned
3
ꢀ
1
sharp band at 3462 and 3470 cm , respectively, which is assigned
to a planar trans conformation of the ACOANHA structure, accord-
ing to literature data for tri-substituted ureas [21]. Moreover, a
to the coupled O@CAN@C system of the imino structure 4b [9]. In
ꢀ1
compound 5 the band at ca. 1590 cm may have the same origin
ꢀ1
0
0
whereas the shoulder at ca. 1550 cm is assigned to
the imino structure.
m(C4 @C5 ) of
ꢀ1
very weak band in CCl
4
at 3410 cm is tentatively assigned to a
small proportion of the cis conformation. In the pyridyl derivatives
2
3
and 3 the corresponding
462 in CDCl and 3448 and 3452 in CCl
Compounds 1–3 presented in CDCl in the double bond region a
strong band at 1655–1660 cm attributed to the urea (C@O)
m
(NAH) band appeared at 3455 and
3
4
, respectively.
4. Conclusions
3
ꢀ1
m
Reaction of 4-methyl-1-piperazine carbonyl chloride with ani-
line gives the urea 1. The reaction with primary N-heterocyclic
amines yields the ureas 2–5 where the acylation takes place at
the exocyclic nitrogen.
Amino–imino tautomerism is observed by means of NMR and IR
spectroscopies for both benzothiazole and thiazole derivatives (4
and 5). NMR results reveal that the tautomeric equilibrium in com-
pound 5 is slower than in compound 4. Moreover, the IR spectra in
our working conditions show that the proportion of the imino tau-
ꢀ1
vibration, and a second band at 1627–1522 cm assigned to the
Amide II band.
Moreover, results for compound 1 in the
sented in CDCl solution a broad weak band at ca. 3355 cm
which decreased on dilution and is assigned to intermolecular
m(NAH) region pre-
ꢀ1
3
ꢀ1
NHꢂ ꢂ ꢂO bonding, as the
in the solid (KBr) to 1658 cm in CDCl
The spectrum of the oily compound 2 showed a broad band at
m(C@O) band was shifted from 1635 cm
ꢀ1
3
.
ꢀ1
ꢀ1
3
284 cm , which shifted to 3313 cm in CDCl
dilution and disappearing in very dilute CCl solution. This band
is attributed to the presence of intermolecular hydrogen bonding,
3
, decreasing with
tomer is greater in the more polar CDCl
also greater in the solid and in CCl and CDCl
nothiazole 5 with respect to the benzoaminothiazole derivative 4.
3
4
solvent than in CCl and
4
4
3
solution for the ami-

2
20
I. Iriepa, J. Bellanato / Journal of Molecular Structure 1044 (2013) 215–220
1H and 13C NMR data for compounds 1–4, 5a and 5b show that,
in CDCl solution at room temperature, a fast inter-conversion of
[8] C. Avendaño, M.T. Ramos, J. Elguero, M.L. Jimeno, J. Bellanato, F. Florencio, Can.
J. Chem. (1988) 1467.
3
[
9] M. Annese, A.B. Corradi, L. Forlani, C. Rizzoli, P. Sgarabotto, J. Chem. Soc. Perkin
Trans. 2 (1994) 615.
the piperazine ring with the N-CH
3
group in equatorial position
can be proposed.
In compounds 1–4 and 5a in CDCl
group rotates freely around the N1ACO bond.
[10] L. Forlani, E. Mezzina, C. Boga, M. Forconi, Eur. J. Org. Chem. (2001) 2779.
[
[
11] R. Faure, J. Elguero, J. Vincent, Org. Magn. Resonance 11 (1978) 617.
12] A. Molinos-Gómez, X. Vidal, M. Maymó, D. Velasco, J. Martorell, F. López-
Calahorra, Tetrahedron 61 (2005) 9075. and references cited therein.
13] Z. García-Hernández, A. Flores-Parra, J.M. Grevy, A. Ramos-Organillo, R.
Contreras, Polyhedron 25 (2006) 1662.
3
solution the carbamoyl
[
[
Acknowledgment
14] I. Iriepa, F.J. Villasante, E. Gálvez, J. Bellanato, A. Martín, P. Gómez-Sal, New J.
Chem. 28 (2004) 618.
We would like to thank to A.I. Madrid for the synthesis of the
compounds.
[15] I. Iriepa, J. Bellanato, J. Mol. Struct. 1006 (2011) 508.
[
16] I.A. Tolmacheva, E.V. Igosheva, V.V. Grishko, O.S. Zhukova, G.K. Gerasimiva,
Russ. J. Bioorg. Chem. 36 (2010) 377.
[
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Sierra, B. Paz-Michel, H. Noth, A. Flores-Parra, R. Contreras, Eur. J. Org. Chem.
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[
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