2-Amino-4-aryl-1-arylideneaminoimidazoles and Acylation Products: A Multinuclear (1H, 13C, 15N) NMR Study

Article abstract of DOI:10.1007/s00706-003-0104-3

The structure of 2-amino-4-aryl-1-arylideneaminoimidazoles in DMSO-d ₆ solution was investigated by means of NMR spectroscopic methods (¹H, ¹³C, ¹⁵N). From these data the (E)-configuration at the excocyclic C=N

Full text of DOI:10.1007/s00706-003-0104-3

Monatshefte f€ur Chemie 135, 173–184 (2004)
DOI 10.1007/s00706-003-0104-3
2-Amino-4-aryl-1-arylideneaminoimidazoles
and Acylation Products: A Multinuclear
13
15
(1H, C, N) NMR Study
1;ꢀ
1
2;ꢀ
´ ´ ´
¨ ¨
Zoltan Gyorgydeak , Gyorgy Szabo , and Wolfgang Holzer
1
Department of Organic Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
Department of Pharmaceutical Chemistry, Pharmaziezentrum, University of Vienna, A-1090
Vienna, Austria
2
Received June 26, 2003; accepted (revised) July 14, 2003
Published online January 27, 2004 # Springer-Verlag 2004
Summary. The structure of 2-amino-4-aryl-1-arylideneaminoimidazoles in DMSO-d6 solution was
investigated by means of NMR spectroscopic methods (1H, 13C, 15N). From these data the (E)-
configuration at the excocyclic C¼N bond and a strong preference for the conformer with the imida-
zole H-5 and the N¼CH proton being spatially close (s-trans regarding the N–N bond) can be
concluded. Reaction of the title compounds with acetic anhydride leads to mono and diacylation at
the 2-amino group, whereas treatment with pivalic anhydride exclusively affords the corresponding
monoacyl product. The mono- and diacylation products exhibit similar configurational and conforma-
tional properties as the parent compounds.
Keywords. Heterocycles; 2-Aminoimidazoles; Schiff bases; Acylation; NMR spectroscopy.
Introduction
Guanylhydrazones (GHs) – reaction products of oxo compounds with aminoguani-
dines [1] – are of considerable interest due to various biological activities found with
many representatives [2, 3]. Moreover, such compounds represent valuable synthetic
building blocks for the construction of different nitrogen-containing heterocycles.
Thus, e.g., guanylhydrazones derived from aromatic aldehydes can be transformed
into 3-acylamino-5-aryl-1,4-diacetyl-4,5-dihydro-1,2,4-triazoles [4], N1-(glycopyr-
anosylamino)guanidines into 3-acetylamino-N1-glycopyranosyl-5-methyl-1H-1,
2,4-triazoles [5], and guanylhydrazones of cyclic ketones give 3-acetylamino-1-
cycloalkenyl-5-methyl-1H-1,2,4-triazoles [6]. Many of these reactions proceed
under the influence of hot, excessive acetic anhydride. However, some related gua-
nylhydrazone educts (camphor-GH, isatin-GH, 2,6-dichlorobenzaldehyde-GH, GHs
ꢀ
Corresponding authors. E-mail: gyorgydeak@tigris.klte.hu; holzer@merian.pch.univie.ac.at

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Z. Gyorgydeak et al.
174
derived from (hetero)aryl methyl ketones) show a different reaction behavior and
‘only’ afford the corresponding N,N0-diacetyl derivatives upon treatment with acetic
anhydride [6–9]. In addition to these cyclizations into substituted 1,2,4-triazoles
Beyer et al. have described a straightforward approach to 2-amino-4-aryl-1-arylide-
neaminoimidazoles (1) via reaction of GHs derived from aromatic aldehydes (or
acetophenones) with aryl ꢀ-halogenoalkyl ketones [10] (Scheme 1). It should be
mentioned that compounds 1 are also available via several steps including ring
transformation of 2-amino-3-phenacyl-1,3,4-oxadiazolium halides with appropriate
amines [11]. However, the former method is much more convenient than the
latter and thus it was exclusively employed in the following (for instance, see Refs.
[12–19]). Compounds of type 1 are of considerable interest as in the recent patent
Scheme 1

A Multinuclear (1H, 13C, 15N) NMR Study
175
literature they were claimed to exhibit promising anti-cancer activities [19] (for
instance 1c). Treatment of 1a with refluxing acetic anhydride was described to lead
to the N,N-diacetyl derivative [10], whereas Yamazaki et al. reported the formation of
the monoacetyl product [14] upon ‘acylation’ of 1a (no experimental details given).
It should be emphazised that, in principle, also cyclization into bicyclic systems of
type X should be possible (Scheme 1). In this regard it is refered to a closely related
reaction which smoothly proceeds with related GHs to afford 1,2,4-triazole deriva-
tives [4–6].
With respect to the fact that no detailed investigations regarding the stereo-
chemistry of 1 are hitherto available and in continuation of our previous investiga-
tions on the structure and reactivity of GHs and related structures [4–9] we here
present NMR (1H, 13C, 15N) studies concerning the determination of structural
features of 2-amino-4-aryl-1-arylideneaminoimidazoles 1 as well as their reaction
products 2 and 3 with aliphatic carboxylic acid anhydrides.
Results and Discussions
Synthesis
Compounds 1 were prepared by ring closure starting from known GHs [9] and
substituted phenacyl bromides using potassium bicarbonate as base (Scheme 1).
Refluxing equimolar amounts of the reactants in methanol afforded products 1. In
the following, the colored, high-melting Schiff bases 1 were heated with an excess
of the appropriate anhydride for 30–50 minutes at 100ꢁC. Whereas reaction of 1
with pivalic anhydride exclusively afforded the monoacyl derivatives 2ꢀ, 2ꢁ, 2ꢂ,
2ꢃ, and 2", treatment with the sterically less hindered acetic anhydride led to
mixtures of N-monoacetyl (2b, 2c, 2e) and the corresponding N,N-diacetyl deriva-
tives (3a, 3b, 3c, 3d, 3e) which was also observed in the reaction with propionic an-
hydride(3ꢀ).PotentialringclosuretobicyclicsystemsoftypeXcouldnotbeobserved.
NMR Spectroscopic Investigations
The NMR data are summarized in Tables 1–4. Full and unambiguous assignment
of 1H and 13C resonances was achieved by combined application of standard NMR
techniques such as NOE difference experiments, 1D-TOCSY, APT, gated decou-
pling, and HMQC. Moreover, selective long-range INEPT experiments [20] were
used for the unequivocal assignment of quaternary carbon atoms and a correspond-
ing two-dimensional version of this technique [21] served for the discrimination of
long-range 13C,1H coupling constants. For the determination and assignment of
15N chemical shifts a sensitivity-enhanced gradient selected gs-HSQC technique
[22–24] and – mainly – gs-HMBC experiments [25] were employed.
1
The H NMR spectra of 2-aminoimidazoles 1 exhibit – besides the signal due
to the NH2 protons between 6.1 and 6.3 ppm – one singlet signal at ꢃ ꢂ 8.0 ppm and
another in the range between ꢃ ¼ 8.5–8.6 ppm. The former can be assigned to the
imidazole H-5 resonance, whereas the latter originates from the N¼CH substruc-
ture. Monoacylation of the 2-amino group (compounds 2) leads to a downfield shift

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Z. Gyorgydeak et al.
176
Table 1. 1H NMR chemical shifts (ꢃ=ppm) of 1–3 in DMSO-d6
No.
Imidazole
H of Ar1
H of Ar2
H of NR1R2
H-5
–N¼CH
H-2,6
H-3,5
H-4
H-2,6
H-3,5
H-4
7.18
1a
1b
1c
1d
1e
2ꢀ
2b
2ꢁ
2c
2ꢂ
2ꢃ
2e
2"
3a
3ꢀ
3b
3c
3d
3e
8.03
7.96
7.96
7.96
8.04
8.50
8.43
8.47
8.42
8.46
8.46
8.47
8.49
8.72
8.71
8.70
8.66
8.64
8.71
8.59
8.55
8.50
8.49
8.50
8.84
8.84
8.83
8.78
8.77
8.76
8.74
8.73
8.97
8.96
8.98
8.89
8.87
8.86
7.94
7.95
7.87
7.25
7.86
7.81
7.87
7.79
7.83
7.77
7.12
7.80
7.74
7.81
7.79
7.81
7.76
7.10
7.75
7.48
7.48
7.73
7.70
7.71
7.71
7.63
7.81
7.78
7.79
7.80
7.82
7.79
7.71
7.73
7.83
7.83
7.82
7.82
7.82
7.75
7.35
7.35
7.34
7.35
7.52
7.41
7.41
7.41
7.41
7.42
7.41
7.58
7.59
7.44
7.44
7.44
7.43
7.43
7.62
6.21 (NH2)
7.55
–
7.19
7.17
7.18
–
6.25 (NH2)
7.05
3.81 (OMe)
3.72 (OMe)
3.82 (OMe)
7.53
6.11 (NH2)
3.87 (OMe)
7.05
6.33 (NH2)
6.21 (NH2)
7.53
7.26
7.26
7.26
7.26
7.26
7.25
–
9.72 (NH), 1.28 (tBu)
10.14 (NH), 2.13 (Me)
9.73 (NH), 1.27 (tBu)
10.09 (NH), 2.13 (Me)
9.70 (NH), 1.30 (tBu)
9.73 (NH), 1.28 (tBu)
10.13 (NH), 2.11 (Me)
9.68 (NH), 1.30 (tBu)
2.28 (Me)
7.61
–
7.61
–
7.10
3.84 (OMe)
3.84 (OMe)
3.74 (OMe)
3.82 (OMe)
3.82 (OMe)
7.54
7.11
3.82 (OMe)
7.08
7.09
–
7.54
7.30
7.29
7.30
7.29
7.29
–
7.53
7.53
2.60 (CH2), 1.03 (Me)
2.28 (Me)
7.61
–
7.09
3.83 (OMe)
3.74 (OMe)
3.83 (OMe)
2.27 (Me)
3.84 (OMe)
7.10
2.29 (Me)
2.26 (Me)
for both imidazole H-5 (ꢃ ꢂ 8.5 ppm) and N¼CH (ꢃ ¼ 8.7–8.8 ppm) signals. Dia-
cylation (compounds 3) results in an additional – albeit small – shift to lower
frequencies (ꢃ ¼ 8.7 and 8.9–9.0 ppm, respectively).
Concerning the stereochemistry of compounds 1, diastereomerism at the C¼N
bond as well as the possible preference of specific rotameric forms with respect to
the N–N bond has to be considered (the thus resulting four possible species are
displayed in Fig. 1). In the course of NOE-difference experiments with 1 intensive
NOEs were detected between imidazole H-5 and N¼CH, no through-space inter-
actions emerged between the amino protons and the N¼CH proton. From this
spatial closeness of imidazole H-5 and N¼CH as well as from the complete
absence of an NOE between NH2 and N¼CH the (E)-configuration at the C¼N
double bond and a preferential occurrence of the s-trans conformation can be
concluded (Fig. 1). Similar experiments with monoacylation products 2 (complete
absence of NOEs between NHAc and N¼CH as well as strong through-space

A Multinuclear (1H, 13C, 15N) NMR Study
177
Table 2. 13C NMR chemical shifts (ꢃ=ppm) of 1–3 in DMSO-d6
No.
Imidazole-C
C-2
C of Ar1
C-4
C-5
N¼CH
C-1
C-2,6
C-3,5
C-4
1a
1b
1c
1d
1e
2ꢀ
2b
2ꢁ
2c
2ꢂ
2ꢃ
2e
2"
3a
3ꢀ
3b
3c
3d
3e
149.5
149.7
149.3
149.6
149.2
138.9
138.9
139.0
138.4
138.5
138.9
138.6
138.6
138.0
137.8
138.1
137.7
138.0
137.8
136.6
136.9
136.3
136.6
134.7
137.0
137.0
137.0
136.7
136.7
137.0
135.6
135.6
138.0
138.0
138.1
137.8
138.0
136.7
101.3
101.2
101.2
101.1
102.0
106.7
106.1
106.7
106.3
106.8
106.5
106.9
107.4
108.0
107.9
108.0
108.0
107.8
108.6
146.5
145.2
146.4
146.4
147.0
151.4
150.2
150.3
151.4
151.4
151.0
151.8
151.7
153.6
153.5
152.5
153.4
153.1
153.7
133.8
132.8
126.3
129.3
126.2
133.1
132.0
132.1
125.5
125.6
128.5
125.5
125.5
132.4
132.4
131.3
124.9
127.7
124.8
127.6
129.2
129.3
105.0
129.4
127.7
129.6
129.3
129.8
129.5
105.0
129.9
129.5
128.1
128.0
129.7
130.0
105.3
130.0
128.7
128.9
114.3
153.2
114.3
129.0
129.1
129.2
114.5
114.6
153.2
114.6
114.6
129.1
129.1
129.3
114.7
153.2
114.7
130.5
134.9
161.2
139.6
161.3
131.4
135.9
135.9
161.9
161.9
140.3
162.0
161.9
131.9
131.9
136.5
162.3
140.8
162.3
No.
C of Ar2
C of NR1R2
Other C of Ar1
C-1
C-2,6
C-3,5
C-4
1a
1b
1c
1d
1e
2ꢀ
2b
2ꢁ
2c
2ꢂ
2ꢃ
2e
2"
3a
3ꢀ
3b
3c
3d
3e
134.4
134.4
134.6
134.5
133.6
133.7
133.5
133.6
133.7
133.8
133.7
133.1
133.1
133.0
133.0
132.9
133.1
133.0
132.4
124.1
124.1
124.0
124.0
125.9
124.1
124.2
124.1
124.1
124.1
124.1
126.1
126.0
124.3
124.3
124.3
124.3
124.3
126.2
128.3
128.3
128.3
128.5
131.3
128.6
128.8
128.6
128.6
128.6
128.6
131.6
131.5
128.7
128.7
128.7
128.7
128.7
131.6
126.3
126.3
126.1
126.4
118.9
126.9
127.0
126.9
126.8
126.8
126.9
119.7
119.6
127.4
127.4
127.4
127.3
127.4
120.1
–
–
–
–
–
–
–
55.3 (4-OMe)
60.2 (4-OMe), 56.0 (3,5-OMe)
55.3 (4-OMe)
178.2 (CO), 38.7, 27.1 (tBu)
169.7 (CO), 22.7 (Me)
–
–
178.2 (CO), 38.7, 27.1 (tBu)
169.8 (CO), 22.6 (Me)
–
55.4 (4-OMe)
178.2 (CO), 38.6, 27.1 (tBu)
178.2 (CO), 38.7, 27.1 (tBu)
169.9 (CO), 22.7 (Me)
55.4 (4-OMe)
60.2 (4-OMe), 55.8 (3,5-OMe)
55.4 (4-OMe)
178.1 (CO), 38.6, 27.1 (tBu)
171.7 (CO), 25.2 (Me)
55.4 (4-OMe)
–
175.3 (CO), 30.3, 8.6 (Et)
171.7 (CO), 25.2 (Me)
–
–
171.7 (CO), 25.2 (Me)
55.4 (4-OMe)
171.8 (CO), 25.1 (Me)
60.2 (4-OMe), 55.8 (3,5-OMe)
55.4 (4-OMe)
171.7 (CO), 25.2 (Me)

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Z. Gyorgydeak et al.
178
Table 3. Selected 13C,1H spin coupling constants (J=Hz) of 1–3 in DMSO-d6
No.
Imidazole-C
3J(C2,H5)
2J(C4,H5)
3J(C4,Ph2,6)
1J(C5,H5)
1J(N ¼ CH)
1a
1b
1c
1d
1e
2ꢀ
2b
2ꢁ
2c
2ꢂ
2ꢃ
2e
2"
3a
3ꢀ
3b
3c
3d
3e
7.5
7.5
7.6
7.3
7.5
8.0
8.4
7.9
7.2
8.0
7.6
8.0
8.1
8.3
8.3
8.1
8.3
8.1
8.3
6.7
6.6
4.2
4.4
193.6
193.6
193.2
193.5
194.1
193.8
194.2
193.9
193.5
193.5
193.9
194.6
193.7
195.5
195.3
195.6
195.1
195.2
195.6
165.4
166.8
163.9
165.2
163.9
165.7
167.2
167.3
164.5
164.2
166.0
164.6
164.1
166.5
166.7
168.2
165.4
167.4
165.4
6.7
a
4.5
a
a
6.8
6.5
6.5
6.3
6.4
6.4
6.1
6.4
4.4
4.6
4.4
4.6
4.6
a
4.0
4.3
4.6
4.6
4.5
6.5
a
6.4
a
6.5
a
4.5
a
6.8
4.4
Imidazole-C
No. 3J(¼NCH,Ph2,6) Other couplings
1a
1b
1c
1d
1e
4.8
4.6
–
–
4.6
a
1J(4-OMe) ¼ 144.8
1J(4-OMe) ¼ 144.5, J(3,5-OMe) ¼ 144.7
1
4.4
1J(4-OMe) ¼ 144.8
3
2ꢀ 4.7
1J(Me) ¼ 126.8, J(CH3,CH3) ¼ 4.7
2b
2ꢁ
2c
2ꢂ
2ꢃ
4.6
4.4
4.5
4.6
5.1
1J(Me) ¼ 128.5
1J(Me) ¼ 126.9, J(CH3,CH3) ¼ 4.7
3
1J(4-OMe) ¼ 144.9, J(Me) ¼ 128.2
1
1J(4-OMe) ¼ 144.9, J(Me) ¼ 126.8, J(CH3,CH3) ¼ 4.7
1
3
1J(4-OMe) ¼ 144.8, J(3,5-OMe) ¼ 144.7, J(Me) ¼ 126.7,
1
1
3J(CH3,CH3) ¼ 4.7
a
2e
2"
3a
1J(4-OMe) ¼ 144.8
1
3
4.6
4.8
1J(4-OMe) ¼ 144.9, J(Me) ¼ 126.8, J(CH3,CH3) ¼ 4.7
1J(Me) ¼ 130.4, J(CO,Me) ¼ 6.6
2
2
1
2
3ꢀ 4.6
1J(CH2) ¼ 129.3, J(CH2,CH3) ¼ 4.4, J(Me) ¼ 128.3, J(CH3,CH2) ¼ 4.4
2
3b
3c
3d
4.5
4.5
5.2
1J(Me) ¼ 130.5, J(CO,Me) ¼ 6.7
1J(Me) ¼ 130.4, J(CO,Me) ¼ 6.7, J(4-OMe) ¼ 145.0
2
1
1J(4-OMe) ¼ 144.8, J(3,5-OMe) ¼ 144.8, J(Me) ¼ 130.4,
1
1
2J(CO,Me) ¼ 6.6
2
1
3e
4.4
1J(Me) ¼ 130.5, J(CO,Me) ¼ 6.7, J(4-OMe) ¼ 145.0
a
not unequivocally determined

A Multinuclear (1H, 13C, 15N) NMR Study
179
Table 4. 15N NMR chemical shifts (ꢃ=ppm)a of 1–3 in DMSO-d6
No.
N-1
N-3
CH¼N
NR1R2
1a
1b
1c
1d
1e
2ꢀ
2b
2ꢁ
2c
2ꢂ
2ꢃ
2e
2"
3a
3ꢀ
3b
3c
3d
3e
ꢃ 191.9
ꢃ 191.7
ꢃ 192.2
ꢃ 192.2
ꢃ 191.9
ꢃ 173.6
ꢃ 176.1
ꢃ 173.7
ꢃ 175.6
ꢃ 173.3
ꢃ 173.7
ꢃ 175.3
ꢃ 172.8
ꢃ 172.5
ꢃ 172.5
ꢃ 172.7
ꢃ 172.5
ꢃ 173.2
ꢃ 171.9
ꢃ 179.5
ꢃ 179.1
ꢃ 178.5
ꢃ 179.5
ꢃ 179.2
ꢃ 76.0
ꢃ 74.4
ꢃ 81.7
ꢃ 77.9
ꢃ 82.2
ꢃ 72.7
ꢃ 73.0
ꢃ 71.7
ꢃ 80.2
ꢃ 78.8
ꢃ 75.2
ꢃ 80.4
ꢃ 79.2
ꢃ 79.9
ꢃ 79.8
ꢃ 79.1
ꢃ 86.3
ꢃ 81.3
ꢃ 86.2
ꢃ 329.3
ꢃ 329.4
ꢃ 330.0
ꢃ 328.8
ꢃ 329.6
ꢃ 271.0
ꢃ 261.4
ꢃ 270.9
ꢃ 261.4
ꢃ 270.9
ꢃ 270.9
ꢃ 261.5
ꢃ 271.1
ꢃ 134.6
b
ꢃ 134.6
b
ꢃ 135.0
ꢃ 134.7
b
ꢃ 135.3
ꢃ 128.7
ꢃ 128.5
ꢃ 128.0
ꢃ 129.5
ꢃ 129.1
ꢃ 129.6
ꢃ 208.0
b
ꢃ 207.4
ꢃ 207.6
ꢃ 207.6
ꢃ 207.8
a
b
error margins ꢄ 1.56 ppm; not unequivocally determined
Fig. 1. Configurational and conformational assignment in 1 via a strong NOE between imidazole
H-5 and N¼CH (preference of the s-trans-(E) form)
interactions beetween imidazole H-5 and N¼CH) and with N,N-diacyl derivatives
3 also reveal the corresponding s-trans-(E) forms to be highly probable for these
compounds. It should be mentioned that similar steric situations were found
recently with somewhat related structures [26].
The 13C NMR chemical shifts of compounds 1–3 are displayed in Table 2,
whereas selected 13C,1H spin coupling constants are given in Table 3. The obtained
data exhibit a high degree of consistency, particularly within the 1-arylideneami-
noimidazole system. Switching from parent compounds 1 to the corresponding
monoacyl derivatives 2 leads to a marked upfield shift (approximately 10 ppm)
for the imidazole C-2 resonance. In contrast, the imidazole C-5 signal receives a
downfield shift (ꢂ5 ppm), whereas the position of the imidazole C-4 line is nearly

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Z. Gyorgydeak et al.
180
unaffected. Attachment of a second acyl group at the excocyclic 2-amino function
(2 ! 3) has only little influence. In diacyl derivatives 3 the imidazole C-2 and C-4
resonances are very close or – accidentally – isochronous. For this reason, the
corresponding coupling constant 2J(C4,H5) could not be unequivocally determined
in all cases. The characteristic 13C,1H spin coupling constants in the 1-arylidene-
aminoimidazole system are nearly of the same size with structures 1, 2, and 3 and
thus they remain unaffected upon acylation. The 15N NMR chemicals shifts of
compounds 1–3 (Table 4) represent a valuable set of data as very little is known
regarding nitrogen-15 NMR spectroscopy of such (and related) type of compounds.
A comparison between structures 1, 2, and 3 reveals the imidazole N-3 resonance
to be most sensitive upon acylation of the 2-amino function, even the introduction
of a second acetyl group (2 ! 3) leads to an additional, distinct downfield shift.
1H Coupled INEPT spectra of 1d and 3a show only a small splitting (ꢂ3 Hz) for
the CH¼N signal. This finding supports the above assignment of the (E)-config-
uration at the C¼N bond as it is known that in such systems the trans-position of
the nitrogen’s lone-pair and the geminally coupled H-atom leads to a small (posi-
2
tive) J coupling constant, whereas a cis-position (and thus (Z)-configuration)
should result in a considerably larger (ꢂ10–16 Hz), negative geminal coupling,
as observed in (Z)-aldoximes or in different heterocyclic systems [27–29].
Experimental
¨
Melting points were determined on a Boetius-type hot-stage microscope and are uncorrected. MS
1
spectra were obtained on a Shimadzu QP 1000 spectrometer (EI, 70eV). H and 13C NMR spectra
1
were recorded on a Varian Unityplus 300 spectrometer (300MHz for H, 75.4MHz for 13C) from
DMSO-d6 solutions (approximately 0.2 M) at 28ꢁC. The solvent signal was used as an internal standard
which was related to TMS with ꢃ ¼ 2.49ppm (1H) and ꢃ ¼ 39.5ppm (13C). The digital resolutions were
1
0.25 for the H NMR spectra, 0.5 for the broadband decoupled 13C NMR spectra, and 0.33Hz=data
point for the gated decoupled 13C NMR spectra. All 15N NMR spectra were obtained at 300 K on a
Bruker Avance 500 spectrometer (50.69MHz for 15N) equipped with a 5 mm broadband observe probe
using gradient-selected inverse techniques (sensitivity enhanced gs-HSQC and gs-HMBC) and, occa-
sionally, the INEPT sequence. HMBC Spectra were acquired as 4096ꢅ 256 data matrices (10 ppm for
1H and 400 ppm for 15N) with 24 transients accumulated per t1 increment; the delay for the evolution of
the 15N,1H long-range coupling was set to 83 ms (optimized for J ¼ 6 Hz). Processing was performed
using zero-filling to 1K data points in the F1 dimension and sine multiplication in both dimensions.
1
HSQC Spectra were recorded as 1024ꢅ 64 data matrices (3 ppm for H and 50ppm for 15N) with 8
transients per t1 increment and were optimized to a 1J(15N,1H) coupling constant of 90Hz. Processing
was performed in the echo-antiecho mode using squared sine window functions in both dimensions.
Referencing of the 15N NMR spectra was performed against external nitromethane (coaxial capillary).
Elemental analyses (C, H, N) were performed by Microanalytical Laboratory, Department of Physical
Chemistry, University of Vienna; the results for the novel compounds agreed satisfactorily (ꢄ0.4%)
with the calculated values. Compounds 1b and 3c have a registry number in Chemical Abstracts,
however, no references and thus no data are available.
General Method for the Preparation of Compounds 1a–1e
A solution of 3 mmol of the appropriate guanylhydrazone in 7 cm3 of methanol was treated with
300 mg of KHCO3 (3mmol) and 3 mmol of the corresponding phenacyl bromide. The resulting
suspension was refluxed for 3 h, cooled, and then diluted with ꢂ80cm3 of H2O. The precipitation

A Multinuclear (1H, 13C, 15N) NMR Study
181
of the reaction product was promoted by sonication. The products were filtered, crystallized from the
solvents given below, and dried in vacuo.
(E)-4-Phenyl-N1-(phenylmethylene)-1H-imidazole-1,2-diamine (1a)
Yield: 90%; mp 201–204ꢁC (EtOH) (Ref. [18] 200–203ꢁC, Refs. [10, 11] 213ꢁC); MS (180ꢁC): m=z
(%) ¼ 262 (Mþꢆ, 10), 223 (16), 158 (51), 131 (11), 117 (33), 105 (100), 104 (17), 103 (14), 90 (18), 89
(20), 85 (11), 77 (81), 51 (40), 50 (12).
(E)-N1-[(4-Chlorophenyl)methylene]-4-phenyl-1H-imidazole-1,2-diamine (1b, C16H13ClN4)
Yield: 86%; mp 230–234ꢁC (DMF-H2O); MS (180ꢁC): m=z (%) ¼ 296=298 (Mþꢆ, 9=3), 158 (100),
131 (17), 117 (55), 104 (22), 89 (21), 77 (21), 75 (11), 51 (11), 43 (11).
(E)-N1-[(4-Methoxyphenyl)methylene]-4-phenyl-1H-imidazole-1,2-diamine (1c)
Yield: 83%; mp 192–195ꢁC (DMF-H2O) (Ref. [16] 197–198ꢁC); MS (175ꢁC): m=z (%) ¼ 292 (Mþꢆ
,
14), 159 (14), 158 (100), 134 (12), 131 (14), 117 (48), 105 (14), 104 (21), 89 (10), 77 (33), 73 (23), 51
(14), 44 (25), 42 (12).
(E)-4-Phenyl-N1-[(3,4,5-trimethoxyphenyl)methylene]-1H-imidazole-1,2-diamine
(1d, C19H20N4O3)
Yield: 47%; mp 193–194ꢁC (MeOH-Et2O-hexane); MS (190ꢁC): m=z (%) ¼ 352 (Mþꢆ, 16), 158 (100),
131 (10), 117 (34), 105 (24), 104 (12), 77 (22), 44 (11).
(E)-4-(4-Bromophenyl)-N1-[(4-methoxyphenyl)methylene]-1H-imidazole-1,2-diamine
(1e, C17H15BrN4O)
Yield: 82%; mp 220–224ꢁC (DMF-H2O); MS (220ꢁC): m=z (%) ¼ 370=372 (Mþꢆ, 21=19), 237=239
(12=12), 236=238 (75=76), 183=185 (48=44), 182=184 (12=13), 158 (13), 157 (100), 155 (18), 135
(26), 134 (37), 133 (18), 117 (14), 107 (11), 104 (15), 103 (18), 102 (21), 92 (22), 91 (19), 90 (18), 89
(18), 82 (11), 80 (12), 79 (12), 78 (10), 77 (54), 76 (34), 75 (31), 64 (19), 63 (19), 56 (11), 51 (31), 50
(25), 44 (21), 43 (21).
General Method for the Preparation of Compounds 2 and 3
Educt 1 (1 mmol) was mixed with 3 cm3 of acetic anhydride, 3 cm3 of propionic anhydride, or 1 cm3 of
pivalic anhydride (plus a catalytic amount of 4-pyrrolidinopyridine). Under stirring, the mixture was
heated at 100ꢁC for 30–50min. Then the volatile components were distilled off in vacuo and the
residue was subjected to column chromatography (silica gel, eluent: EtOAc:n-hexane¼ 5:1) and=or it
was directly crystallized from the solvents given below.
(E)-2,2-Dimethyl-N-[4-phenyl-1-[(phenylmethylene)amino]-1H-imidazol-2-yl]propanamide
(2ꢀ, C21H22N4O)
Yield: 52%; mp 256–257ꢁC (MeOH); MS (185ꢁC): m=z (%) ¼ 346 (Mþꢆ, 22), 290 (20), 289 (100),
243 (14), 186 (35), 185 (62), 159 (23), 158 (48), 131 (11), 118 (14), 117 (27), 104 (38), 103 (11), 77
(36), 57 (68), 51 (11), 41 (22).

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Z. Gyorgydeak et al.
182
(E)-N-[1-[[(4-Chlorophenyl)methylene]amino]-4-phenyl-1H-imidazol-2-yl]acetamide
(2b, C18H15ClN4O)
Yield: 60%; mp 228–229ꢁC (EtOH-EtOAc). MS (200ꢁC): m=z (%) ¼ 338=340 (Mþꢆ, 12=4), 296=298
(11=3), 159 (56), 158 (100), 131 (13), 117 (36), 104 (20), 89 (14), 77 (18), 43 (27).
(E)-2,2-Dimethyl-N-[1-[[(4-chlorophenyl)methylene]amino]-4-phenyl-1H-imidazol-2-
yl]propanamide (2ꢁ, C21H21ClN4O)
Yield: 67%; mp 270–273ꢁC (EtOAc); MS (195ꢁC): m=z (%) ¼ 380=382 (Mþꢆ, 5=2), 323=325 (35=11),
243 (12), 186 (26), 185 (58) 159 (27), 158 (45), 131 (11), 129 (11), 118 (12), 117 (32), 111 (17), 104 (36),
103 (13), 89 (17), 85 (11), 77 (18), 75 (13), 57 (100), 56 (12), 55 (17), 44 (14), 43 (19), 41 (30).
(E)-N-[1-[[(4-Methoxyphenyl)methylene]amino]-4-phenyl-1H-imidazol-2-yl]acetamide
(2c, C19H18N4O2)
Yield: 36%; mp 180–181ꢁC (EtOAc); MS (250ꢁC): m=z (%) ¼ 334 (Mþꢆ, 26), 292 (11), 159 (75), 158
(100), 134 (15), 131 (11), 117 (33), 104 (14), 77 (22), 43 (51).
(E)-2,2-Dimethyl-N-[1-[[(4-methoxyphenyl)methylene]amino]-4-phenyl-1H-imidazol-2-
yl]propanamide (2ꢂ, C22H24N4O2)
Yield: 55%; mp 205–207ꢁC (EtOAc-hexane); MS (220ꢁC): m=z (%) ¼ 376 (Mþꢆ, 17), 320 (21), 319
(100), 243 (38), 187 (12), 186 (90), 185 (29), 159 (38), 158 (61), 134 (45), 118 (14), 117 (28), 106 (15),
104 (21), 92 (13), 91 (12), 77 (40), 57 (69), 41 (27).
(E)-2,2-Dimethyl-N-[4-phenyl-1-[[(3,4,5-trimethoxyphenyl)methylene]amino]-1H-imidazol-2-
yl]propanamide (2ꢃ, C24H28N4O4)
Yield: 57%; mp 247–248ꢁC (EtOAc-hexane); MS (215ꢁC): m=z (%) ¼ 436 (Mþꢆ, 3), 379 (15), 243
(39), 186 (57), 185 (11), 167 (13), 159 (39), 158 (48), 117 (26), 104 (19), 77 (20), 57 (100), 56 (16), 43
(29), 41 (26).
(E)-N-[4-(4-Bromophenyl)-1-[[(4-methoxyphenyl)methylene]amino]-
1H-imidazol-2-yl]acetamide (2e, C19H17BrN4O2)
Yield: 7%; mp 213–218ꢁC; MS (205ꢁC): m=z (%) ¼ 412=414 (Mþꢆ, 3=3), 239 (27), 238 (28), 237
(29), 236 (26), 185 (21), 183 (16), 158 (21), 157 (41), 135 (16), 134 (27), 133 (17), 121 (53), 117 (11),
107 (11), 104 (13), 103 (11), 102 (15), 92 (18), 91 (16), 89 (11), 83 (11), 78 (11), 77 (54), 76 (19), 75
(15), 64 (14), 63 (12), 57 (30), 56 (10), 51 (21), 50 (14), 45 (12), 44 (19), 43 (100), 41 (12).
(E)-2,2-Dimethyl-N-[4-(4-bromophenyl)-1-[[(4-methoxyphenyl)methylene]amino]-
1H-imidazol-2-yl]propanamide (2", C22H23BrN4O2)
Yield: 60%; mp 276–277ꢁC (dioxane); MS (250ꢁC): m=z (%) ¼ 454=456 (Mþꢆ, 2=2), 397=399 (9=9),
264 (11), 157 (15), 134 (34), 107 (12), 92 (13), 77 (29), 57 (100), 44 (11), 41 (24).
(E)-N-Acetyl-N-[4-phenyl-1-[(phenylmethylene)amino]-1H-imidazol-2-yl]acetamide (3a)
Yield: 45%; mp 201–202ꢁC (toluene) (Ref. [10] 206ꢁC); MS (160ꢁC): m=z (%) ¼ 346 (Mþꢆ, 2), 304
(11), 201 (21), 160 (11), 159 (100), 158 (65), 131 (16), 117 (43), 104 (31), 103 (18), 91 (14), 89 (16),
77 (44), 76 (11), 51 (20), 43 (95).

A Multinuclear (1H, 13C, 15N) NMR Study
183
(E)-N-(1-Oxopropyl)-N-[4-phenyl-1-[(phenylmethylene)amino]-1H-imidazol-
2-yl]propanamide (3ꢀ, C22H22N4O2)
Yield: 43%; mp 197–203ꢁC (EtOH); MS (190ꢁC): m=z (%) ¼ 374 (Mþꢆ, 2), 215 (22), 186 (12), 185
(17), 159 (100), 158 (43), 131 (11), 117 (29), 104 (22), 103 (12), 89 (13), 77 (37), 57 (70), 51 (14), 43
(10).
(E)-N-Acetyl-N-[1-[[(4-chlorophenyl)methylene]amino]-4-phenyl-1H-imidazol-
2-yl]acetamide (3b, C20H17ClN4O2)
Yield: 18%; mp 206–211ꢁC (EtOH); MS (200ꢁC): m=z (%) ¼ 380=382 (Mþꢆ, 4=1), 338=340 (13=4),
201 (24), 159 (100), 158 (61), 117 (34), 104 (14), 103 (11), 89 (11), 77 (11), 43 (48).
(E)-N-Acetyl-N-[1-[[(4-methoxyphenyl)methylene]amino]-4-phenyl-1H-imidazol-
2-yl]acetamide (3c, C21H20N4O3)
Yield: 22%; mp 165–170ꢁC (EtOAc); MS (190ꢁC): m=z (%) ¼ 376 (Mþꢆ, 1), 201 (28), 160 (11), 159
(100), 158 (40), 134 (16), 133 (10), 121 (24), 117 (26), 104 (15), 103 (11), 77 (36), 51 (11), 43 (83).
(E)-N-Acetyl-N-[4-phenyl-1-[[(3,4,5-trimethoxyphenyl)methylene]amino]-1H-imidazol-2-
yl]acetamide (3d, C23H24N4O5)
Yield: 65%; mp 166–170ꢁC (EtOAc-hexane); MS (190ꢁC): m=z (%) ¼ 436 (Mþꢆ, 3), 201 (35), 160
(12), 159 (100), 158 (38), 117 (18), 43 (40).
(E)-N-Acetyl-N-[4-(4-bromophenyl)-1-[[(4-methoxyphenyl)methylene]amino]-
1H-imidazol-2-yl]acetamide (3e, C21H19BrN4O3)
Yield: 48%; mp 208–210ꢁC (EtOAc); MS (210ꢁC): m=z (%) ¼ 454=456 (Mþꢆ, 4=4), 279=281 (19=18),
239 (50), 238 (24), 237 (53), 236 (19), 185 (20), 183 (22), 157 (35), 135 (17), 134 (32), 133 (24), 121
(25), 102 (11), 92 (18), 91 (11), 77 (36), 76 (15), 75 (12), 64 (11), 51 (11), 43 (100).
Acknowledgments
The authors thank Dr. L. Jirovetz for recording the mass spectra and Mrs. V. Kꢀoder for chromatographic
separations.
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