Tautomerism of guanidines studied by 15N NMR: 2-hydrazono-3-phenylquinazolin-4(3H)-ones and related compounds

Article abstract of DOI:10.1039/b907577a

2-Hydrazono-3-phenylquinazolin-4(3H)-ones 11a-i are shown by ¹⁵N NMR to exist in DMSO solution predominantly as the imino tautomers B and not the amino tautomers A. 2-Hydrazino-benzimidazole derivative 12 and 2-hydrazino-4,6-dimethylpyrimidine derivative 13 were found to exist predominantly as the amino tautomers.

Full text of DOI:10.1039/b907577a

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Tautomerism of guanidines studied by 15N NMR:
2-hydrazono-3-phenylquinazolin-4(3H)-ones and related compounds†
Ion Ghiviriga,*a Bahaa El-Dien M. El-Gendy,b,c Peter J. Steeld and Alan R. Katritzky*b
Received 16th April 2009, Accepted 30th June 2009
First published as an Advance Article on the web 11th August 2009
DOI: 10.1039/b907577a
2-Hydrazono-3-phenylquinazolin-4(3H)-ones 11a–i are shown by 15N NMR to exist in DMSO solution
predominantly as the imino tautomers B and not the amino tautomers A. 2-Hydrazino-benzimidazole
derivative 12 and 2-hydrazino-4,6-dimethylpyrimidine derivative 13 were found to exist predominantly
as the amino tautomers.
Introduction
The tautomeric equilibria of heterocycles are of supreme impor-
tance in understanding the function of numerous biologically
important components of living systems.1 Thus the genetic code
could only be deciphered after the dominant structures of the
nucleotide bases were correctly represented. Moreover, it is
now realized that the whole basis of evolution depends on the
occurrence of minor proportions of the less stable nucleotide base
tautomers which cause advantageous genetic mistakes.2
The tautomeric equilibria of heterocycles have been investigated
extensively3–6 and the following major trends are now clear as
illustrated by Fig. 1: (i) most aminohetero-aromatic compounds
exist predominantly in the amino form cf. 1 (and not the imino
form cf. 2) under normal conditions (aqueous solution or the
crystalline state); (ii) under these conditions most (although not
all) hydroxyheteroaromatic compounds exist predominantly in
the tautomeric carbonyl form (for example 2-hydroxypyridine 3
and 4-hydroxypyridine 5 exist as 2-pyridone 4 and 4-pyridone
6 respectively); (iii) mercapto derivatives of 6-membered het-
eroaromatics tend to follow their hydroxy analogs and exist as
thiones, e.g. 8, and not as mercapto derivatives, e.g., 7. In contrast
mercapto derivatives of five-membered heterocyclic rings exist as
mercaptans (following the amino analogs); (iv) methyl groups
and most substituted methyl substituents exist very largely in the
methyl tautomer e.g. 9 and not in the possible methylene tautomer
e.g. 10 which is far less stable.
Fig. 1 Dominant tautomeric forms of amino-, hydroxy-, mercapto-, and
methyl-pyridines.
The present paper discusses the tautomeric equilibrium of
a set of 2-hydrazono-3-phenyl-3H-quinazolin-4-ones 11a–i, all
representatives of a group of compounds of intense current
interest in the development of commercial drugs with analgesic
and anti-inflammatory activity,7–10 as well as the tautomerism of
related 2-hydrazinobenzimidazole 12, and 2-hydrazinopyrimidine
13 derivatives (Fig. 2).
Knowledge of the tautomerism of potential drugs is relevant to
the modeling of their interaction with a receptor since different
tautomers have different affinities for the receptor. It is thus also
important in the tuning of a desired pharmacological activity.
aChemistry Department, University of Florida, Gainesville, FL 32611-7200,
USA. E-mail: ion@chem.ufl.edu; Fax: +1 3528463001; Tel: +1 3528463001
bCenter for Heterocyclic Compounds, Department of Chemistry, Univer-
sity of Florida, Gainesville, FL 32611-7200, USA. E-mail: katritzky@
chem.ufl.edu; Fax: +1 3523929199; Tel: +1 3523920554
cDepartment of Chemistry, Faculty of Science, Benha University, Benha,
Egypt
dChemistry Department, University of Canterbury, Christchurch 8140, New
Zealand. E-mail: peter.steel@canterbury.ac.nz; Fax: +64 3 364 2110;
Tel: +64 3 364 2432
† CCDC reference number 735547. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b907577a
Fig. 2 Compounds under investigation.
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Tautomeric equilibria can depend significantly on the nature of
the medium. There are two major inferences. Firstly, the dielectric
constant of the medium is important and of course this can range
from very low for the vapor phase and nonpolar solvents (favoring
the tautomeric form with the lowest dipole moment) to very high
for certain polar solvents (favoring the form with the highest dipole
moment). The second major effect of the medium is the hydrogen
bonding donor and acceptor ability of the solvent/medium, which
can interact differently with different tautomeric forms. In the
present paper we are dealing with equilibrium positions in DMSO
as a solvent. Given the poor solubility of these compounds in
water, this is probably the best medium to use for comparisons
with biological systems.
The tautomerism of the compounds 11a–i, 12, and 13 under
investigation each involves a guanidine moiety 15. In substituted
guanidines 15a–c (Fig. 5), the most stable tautomer is 15a with the
double bond attached to the nitrogen carrying the most electron-
attracting substituent (e.g. R = NO2, CN, -SO2-C6H4-NH2).11
Fig. 5 Tautomers of disubstituted guanidines.
This can be rationalized by realizing that of the two exchange-
able protons in the common cation (11a–f C in Fig. 3) the hydrogen
attached to the most electronegative nitrogen is the most acidic.
The experimental evidence for such tautomerism of guanidines
includes 15N NMR12 and crystal structures.13 When two of the
guanidine nitrogens are part of an aromatic system, the ‘most
aromatic’ tautomer is usually favored. The tautomerism of 2-
aminopyrimidines has been studied extensively; both experimental
data (low temperature IR spectroscopy)14 and semiempirical and
ab initio calculations15,16 confirm the 2-amino tautomer as the
most stable. Spectroscopic studies (UV, IR and 1H NMR) of
N-substituted-2-pyrimidinamine 16 (R = H, NO2) show that
neither the phenyl17 nor the 2,4,6-trinitrophenyl18 is electronegative
enough to shift the equilibrium from the amino form 16a to the
imino form 16b (Fig. 6).
Compounds 11a–i, 12 and 13 could exist in two tautomeric
forms, amino forms A and imino forms B, as shown in Fig. 3 for
11a–f.
Fig. 3 Tautomers A and B of 2-hydrazino-3-phenylquinazolin-4(3H)-
ones 11a–i and their common cation C.
Apparently there has been no previous discussion published
of the tautomerism of 2-hydrazinoquinazolin-4(3H)-ones 11. The
404 hits for substructure 11 in a Beilstein search are depicted in
the presumed amino form 11A and none in the imino form 11B.
However, no supporting evidence such as interatomic distances or
angles from solid state crystallographic data has been provided for
their existence in the amino form A.
The tautomerism of 2-hydrazinopyrimidin-4(3H)-ones 14
(Fig. 4) has not been studied either. Derivatives of 14 are usually
represented in the amino form 14A (308 Beilstein hits). The 18 hits
for the alternative imino 14B form were perhaps due to the fact
that they represent compounds synthesized from uracil.
Fig. 6 Tautomers of 2-pyrimidinamine and of isocytosine.
2-Amino-3H-pyrimidin-4-one 17 (isocytosine), which was stud-
ied extensively, both experimentally19–21 and computationally,22
exists in aqueous solution mainly as 2-amino-3H-pyrimidin-4-one
17a with some 2-amino-1H-pyrimidin-4-one 17b. Calculations
suggest the 2-imino form 17c, not detected experimentally, is 5.6
kcal/mol less stable in aqueous solution than the 2-amino form
17b.
The tautomerism of 2-hydrazinopyrimidine has apparently not
been studied. 2-Quinolylhydrazones 18 (Fig. 7) exist in solution
predominantly in the amino form 18a, although the imino form
was also detected.23–25 In the solid state compounds 18 were found
Fig. 4 Tautomers of 2-hydrazinopyrimidin-4(3H)-ones.
Fig. 7 Tautomeric forms of 2-quinolylhydrazones 18.
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in the amino form when Ar = thienyl or 5-chlorothienyl and in
the imino form when Ar = 5-bromo-2-thienyl.26
We aimed in the present work to identify the tautomeric
preferences of the title compounds 11a–i, 12, 13. The literature
data presented above support both the ‘most aromatic’ amino
form A and the imino form B which has the double bond on
the most electronegative nitrogen. Since the two tautomeric forms
differ in the protonation of two different nitrogens, 15N NMR is
the method of choice as a large difference in the chemical shifts
of the alternative structures is expected. Measurement of the 15
N
chemical shifts at natural abundance is now facile, with the advent
of indirect detection and pulsed field gradients.27,28
Results and discussion
Syntheses
Products 11a–i were prepared eventually by the literature proce-
dure described in Scheme 1.29
Scheme 2 Reagents and conditions: (a) (CH3O)2SO2, 2% ethanolic
sodium hydroxide, rt, 1 h; (b) N2H4·H2O, EtOH, reflux, 20 h; (c) EtOH,
23d, reflux, 7 h.
see Experimental), and with three nitrogens at 187.5, 165.5, and
64.3. The nitrogen at 187.5 ppm was assigned to N1, because it
couples with H8. The nitrogen at 64.3 has the chemical shift of
an amino group and it carries two protons at 5.71. These latter
protons couple with the nitrogen at 165.5 (N3 in 25) and with two
carbons, C4 and another one assigned as C2.
Compound 25 reportedly29 condensed with benzaldehydes to
give the corresponding Schiff’s base 26 (Scheme 2). In our case
25 with p-nitrobenzaldehyde (23d), gave compound 11d instead of
the corresponding 26d. The reaction was much slower than in the
case of 22.
Tautomerism and NMR
1H and 13C chemical shifts were assigned based on the 1H–
1
1H, and one-bond and long-range H–13C couplings, seen in the
gDQCOSY, gHMQC and gHMBC spectra. They are presented in
Tables 1, 2, 4 and 5.
A typical assignment started with identifying the sequence H5–
H8 in the gDQCOSY spectrum. H5 and C4 would then be assigned
by their cross-peak in the gHMBC spectrum. The 1H–13C gHMBC
spectrum of 11b is presented in Fig. 8. Cross-peaks of C4a with
H6 and H8, and of C8a with H5 and H7 reveal these quaternary
carbons. The phenyl protons, H1¢–H3¢ can be assigned from their
intensity and coupling pattern. C5a¢ couples with H2¢.
In 2-hydrazono-3-phenyl-3H-quinazolin-4-ones, 11a–f, H3¢¢,
the singlet on a carbon at ca. 150 ppm couples with C1¢¢¢ and
C5a¢¢¢. Other cross-peaks in the gHMBC spectrum were then used
to complete the assignments on the substituted benzylidene moiety
C1¢¢¢–C5a¢¢¢.
Scheme 1 Reagents and conditions: (a) EtOH, reflux 2 h; (b) n-BuOH,
N2H4·H2O, reflux, 2 h.
Compounds 12 and 13 were prepared by condensing
2-hydrazino-1H-benzimidazole and 2-hydrazino-4,6-dimethyl-
pyrimidine with 4-(dimethylamino)benzaldehyde and 1-methyl-
1H-indole-2,3-dione respectively.
Our initial attempt to prepare compound 22 following the
previously reported procedure7,9,30–34 described in Scheme 2 gave
instead 3-amino-2-anilino-4(3H)-quinazolinone 25. There is a
single literature report29 of 25, in which this compound was
characterized only by melting point and elemental analysis.
Our proof for the structure of compound 25 is based on its
NMR data. The nitrogen that couples with the ortho protons of the
phenyl ring was at 102.2 ppm and carried the proton at 9.36 ppm.
This proton couples with carbons C1¢ and C5a¢ (for numbering
In
2-[N¢-(2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazono]-3-
phenyl-3H-quinazolin-4-ones 11h,i having a substituent on N1¢¢¢,
the a substituent protons couple with C7a¢¢¢. Carbon C7a¢¢¢
also couples with H6¢¢¢ and H4¢¢¢ which can be discriminated
based on their multiplicity. Other cross-peaks in the gHMBC
spectrum were then used to complete the assignments on the
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Table 1 1H chemical shifts (ppm) in compounds 11a–f, 12, 21, 22 and 24
Position
Compd.
1
5
6
7
8
1¢
2¢
3¢
3¢¢
1¢¢¢
2¢¢¢
3¢¢¢
4¢¢¢
5¢¢¢
11a
11b
11c
11d
11e
11f
12
10.61
10.41
nmb
7.91
7.88
8.00
7.97
7.96
7.94
7.40
7.96
8.50
8.10
7.16
7.11
7.37
7.22
7.22
7.18
7.16
7.35
7.29
7.49
7.69
7.63
7.83
7.72
7.72
7.70
7.16
7.78
7.79
7.84
7.69
7.64
8.04
7.72
7.72
7.70
7.40
7.46
7.88
7.65
7.34
7.31
7.49
7.36
7.36
7.35
—
7.29
7.53
7.47
7.49
7.48
7.61
7.52
7.52
7.50
—
7.50
7.43
7.58
7.40
7.40
7.59
7.44
7.44
7.42
—
7.42
7.29
7.58
8.07
7.87
8.59
8.19
8.16
8.12
8.19
—
7.93
7.68
3.80
8.16
8.11
9.09
7.68
—
7.41
6.64
6.60
8.21
7.86
—
6.74
—
—
7.38
3.37, 1.09a
3.83
—
7.41
6.64
6.65
8.21
7.86
7.43
6.74
—
7.93
7.68
8.38
8.16
8.11
8.31
7.68
—
nm
10.83
10.68
nm
13.03
8.87d
2.50e
—
8.55
2.96
—
—
—
21
22c
24
—
—
—
—
—
—
—
—
—
a CH2 and CH3, correspondingly. b Not measured. c Measured in pyridine-d5 at -30 ◦C. d H1¢¢. e CH3S in position 2.
Table 2 13C chemical shifts (ppm) in compounds 11a–f, 12, 21, 22 and 24
Position
Compd.
2
4
4a
5
6
7
8
8a
1¢
2¢
3¢
5a¢ 3¢¢
1¢¢¢ 2¢¢¢ 3¢¢¢ 4¢¢¢ 5¢¢¢ 5a¢¢¢ Other
11a
11b
152.2 161.3 115.1 128.0 122.6 135.8 116.4 140.6 129.9 129.5 128.7 137.1 153.9 128.5 129.0 130.3 129.0 128.5 135.9 —
150.6 161.3 114.9 128.1 122.1 135.7 116.2 140.8 130.0 129.6 128.6 137.3 154.5 130.3 111.4 149.3 111.4 130.3 122.6 44.4 (CH2), 13.2
(CH3)
nma 160.4 116.0 128.0 124.9 136.4 118.0 139.4 130.0 130.4 130.4 134.2 149.7 160.5 98.6 164.0 107.3 129.4 114.9 56.4 (CH3O-1¢¢¢);
56.3 (CH3O-3¢¢¢)
11c
11d
11e
11f
12
nm
nm
nm
nm
nm
nm
161.2 115.9 128.2 123.0 135.8 116.8 140.3 129.9 129.5 128.6 137.0 151.5 129.2 124.2 148.4 124.2 129.2 142.3 —
161.3 115.4 128.1 122.9 135.8 116.7 140.4 129.9 129.5 128.7 136.9 152.0 128.9 132.9 112.1 132.9 128.9 140.4 119.5 (CN)
161.4 115.3 128.1 122.7 135.8 116.4 140.5 129.9 129.5 128.6 137.0 151.0 149.8 —
150.7 124.3 135.1 131.7 —
—
133.5 112.6 122.7 122.7 112.6 133.5 — 147.0 129.1 112.3 152.1 112.3 129.1 122.2 40.5 (CH3)
—
—
—
21
160.5 116.9 128.1 125.0 136.3 116.4 140.3 129.7 129.6 128.8 140.0 —
163.1 118.7 128.0 122.9 135.4 125.8 150.9 130.2 130.8 130.0 136.0 —
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
22b
24
158.7 161.5 120.3 127.3 126.5 135.6 126.8 148.1 130.1 130.7 130.0 137.0 —
15.7 (CH3)
a Not measured. b Measured in pyridine-d5 at -30 ◦C.
Table 3 15N chemical shifts (ppm) in compounds 11a–f, 12, 21, 22 and 24. Protons which couple to a 15N are given in parentheses
Position
Compd.
1
3
1¢¢
2¢¢
Other
—
78.8 (H2¢¢¢, CH2)
—
11a
11b
11ca
11d
11ea
11f
12
100.4 (H8)
99.7 (H1, H8)
110.5 (H8)
113.9 (H8)
nmb
104.4 (H8)
136.3 (H7,H8)
150.9 (H1, H8)
183.9 (H8, H1¢¢)
230.6 (H8)
151.9 (H1¢)
151.3 (H1¢¢)
156.3 (H1¢)
157.2 (H1¢)
157.1 (H1¢)
156.4 (H1¢)
136.3 (H4,H5)
191.1 (H1, H1¢)
161.4 (H1¢)
180.6 (H1¢)
247.0 (H3¢¢)
247.2 (H3¢¢)
nm
251.7 (H3¢¢)
251.1 (H3¢¢)
251.2 (H3¢¢)
142.9 (H3¢¢)
—
346.0 (H3¢¢ 45)
329.1 (H3¢¢)
318.5 (H3¢¢)
369.2 (H3¢¢)
361.2 (H3¢¢)
354.7 (H3¢¢)
305.1 (H3¢¢, H1¢¢¢)
—
372.9 (H2¢¢¢)
—
318.2 (H1¢¢¢, H3¢¢¢, H4¢¢¢)
55.5 (H2¢¢¢, CH3)
21
—
—
—
22c
24
106.5 (H1¢¢)
—
62.7 (H1¢¢)
—
a Measured at 70 ◦C. b Not measured. c Measured in pyridine-d5 at -30 ◦C.
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Table 4 1H chemical shifts (ppm) in compounds 11g–i and 13
Position
Compd.
1
5
6
7
8
1¢
2¢
3¢
1¢¢¢
4¢¢¢
5¢¢¢
6¢¢¢
7¢¢¢
11g
11.70
11.76
11.80
10.59d
12.80d
7.99
8.01
8.03
7.27
7.33
7.29
7.75
7.77
7.75
7.75
7.87
7.86
7.45
7.45
7.45
—
7.60
7.60
7.60
—
7.53
7.55
7.55
—
10.42
6.81
7.11
6.94
8.06
7.58
1.97a
—
6.59
7.10
7.12
6.93
7.39
7.19
7.40
7.37
6.63
6.90
6.85
7.04
7.08
11h
3.14a
b
11i
13 (E)c
13 (Z)c
6.86 (CH), 2.40 (CH3)
6.85 (CH), 2.38 (CH3)
3.19a
3.24a
—
—
—
a CH3. b 4.34 (CH2a), 5.83 (CHb), 5.09 (CH2g, H-cis to Hb), 5.12 (CH2g, H-trans to Hb). c At 70 ◦C. d H1¢¢.
Table 5 13C chemical shifts (ppm) in compounds 11g–i, 13 and 29a–c
Position
Compd.
2
4
4a
5
6
7
8
8a
1¢
2¢
3¢
5a¢ 2¢¢¢
3¢¢¢
3a¢¢¢ 4¢¢¢
5¢¢¢
6¢¢¢
7¢¢¢
7a¢¢¢ Other
11g
11h
11i
nma 161.2 116.1 128.0 123.8 136.1 117.2 140.0 129.6 129.9 129.3 137.3 166.8 144.8 118.2 128.0 131.0 131.9 109.0 141.0 21.3 (CH3)
nm 161.2 116.3 128.0 124.1 136.0 117.8 139.8 129.2 129.9 129.9 136.9 164.1 142.2 114.6 129.0 118.8 133.6 109.0 143.2 25.9 (CH3)
nm 161.2 116.3 128.1 123.9 138.0 117.6 140.0 129.6 130.0 128.8 137.0 164.9 nm 117.6 127.7 122.3 131.1 107.5 143.5 41.9 (Ca),
132.8 (Cb),
117.2 (Cg)
13 (E)b
nm 168.6 24.1 115.4 —
nm 168.8 24.0 115.4 —
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
164.6 nm 116.2 125.5 122.7 131.7 107.4 144.5 —
161.9 131.7 120.7 120.1 123.4 130.4 108.6 143.0 —
166.8 134.6 118.9 125.5 120.8 128.1 109.0 140.7 —
158.9 132.2 124.3 118.5 120.6 127.1 109.0 139.6 —
165.1 133.8 118.0 125.2 121.3 128.0 107.5 141.9 —
156.9 130.8 123.4 118.0 120.9 126.8 107.4 140.7 —
166.8 134.8 118.9 126.1 129.4 128.4 108.6 138.5 —
13 (Z)b
29a (E)c
29a (Z)c
29b (E)c
29b (Z)c
29c (E)c
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
a Not measured. b At 70 ◦C. c From ref. 40.
Table 6 15N chemical shifts (ppm) in compounds 11g–i and 13. Protons which couple to a 15N are given in parentheses
Position
Compd.
1
3
1¢¢
2¢¢
1¢¢¢
11g
104.2 (H8)
109.4 (H8)
105.1 (H8)
254.2 (CH3)
156.7 (H1¢)
161.8 (H1¢)
157.5 (H1¢)
nm
nma
nm
nm
nm
377.6 (H1¢¢¢)
133.0 (H1¢¢¢, H7¢¢¢)
11h
nm
131.8 (CH3, H7¢¢¢)
11i
nm
nm
136.2 (CH2a, CHb, H7¢¢¢)
—
—
13 (E)b
13 (Z)b
252.4 (CH3, CH, NH)
164.3 (NH, CH)
340.0 (NH, H7¢¢¢)
133.1 (CH3, H7¢¢¢, H6¢¢¢)
a Not measured. b At 70 ◦C.
substituted indole moiety C1¢¢¢–C7a¢¢¢. In compound 11g, lacking
the substituent on N1¢¢¢, H7¢¢¢ is the proton on a carbon at ca.
110 ppm.
shift of C8, at ca. 117 ppm, further supports this assignment
of tautomerism. Final proof for the imino tautomer comes
1
from the one-bond cross-peak in the H–15N CIGAR spectrum
A sharp signal of the exchangeable proton in compound
11b afforded cross-peaks with C8, C8a, C4a and with another
quaternary carbon, assigned as C2 (Fig. 8). This indicates that this
exchangeable proton is linked to N1, meaning that 11b is present
in DMSO solution mainly as the imino tautomer. The chemical
(Fig. 9) between the exchangeable proton and the nitrogen at
99.7 ppm, which is N1, because it displays a long-range coupling
with H8.
The X-ray structure of compound 11b (Fig. 10) unambiguously
demonstrated the imino tautomer in the solid state.35
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Fig. 8 Expansions of the 1H–13C gHMBC spectrum of compound 11b.
Fig. 9 Expansions of the 1H–15N CIGAR spectrum of compound 11b.
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with nitrogens. In all of these cases, the tautomerism was assigned
based solely on 15N chemical shifts.
In both 2-hydrazono-3-phenyl-3H-quinazolin-4-ones 11a–f
and in the 2-[N¢-(2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazono]-
3-phenyl-3H-quinazolin-4-ones 11g–i, N1 displayed a cross-peak
with H8 in the CIGAR spectrum. The range of chemical shifts
for N1 was 100–114 ppm (Tables 3 and 6). In the first series,
the chemical shift of N1¢¢ was detected through the coupling
between N1¢¢ and H3¢¢. The values for N1¢¢ chemical shifts were
247–251 ppm. These chemical shifts identify the imino form as
the prevalent tautomer in solution for compounds 11a–i. The N1
chemical shift is expected to depend mainly on the position of
the tautomeric equilibrium, and could be used to estimate this
position, if values in the two tautomers are known.
When the guanidine is part of a more aromatic structure, the
amino form would prevail. This is demonstrated by compounds
12 and 13. In 12, rapid exchange of the proton between N1 and
N3 (numbering relative to the aminoguanidine moiety, as in 11a–i)
produced an AA¢XX¢ pattern for the signals of H5–H8. The NH
protons were in fast exchange with the residual water in DMSO-d6,
and did not produce a separate signal. The chemical shift of N1,
N3 was revealed by coupling with H5, H8; cross-peaks with H3¢¢
revealed N1¢¢ and N2¢¢. The chemical shifts in the pair N1¢¢, N2¢¢,
(142.9, 305.1) were closer to the values in 27 (133, 328) than to the
values in 28 (238,384), indicating that compound 12 is present in
DMSO solution predominantly in the amino form. The chemical
shift of the azole nitrogen cannot be used for the assignment of the
tautomerism, at least in the presence of fast exchange. The value in
12, 136.3 ppm, is closer to the value for N1 in 1-methyl-2-amino-
benzimidazole (134.6 ppm), than to their average (N3 is at 191.9
ppm), which would suggest that 12 is in the imino form. However,
in 1-methyl-benzimidazole N1 and N3 are at 143.8 and 243.9 ppm,
correspondingly, while in benzimidazole, the equivalent nitrogens
are at 143.2 ppm.38
Fig. 10 X-ray structure of 11b.
There is one more long-range cross-peak of the exchangeable
proton in the H–15N CIGAR spectrum of 11b, with one of the
nitrogens three bonds away, which was assigned as N3 (151.3 ppm),
because it also couples with H1¢.
1
N1¢¢ and N2¢¢ both couple with H3¢¢ only, therefore, they
could not be discriminated based on their couplings with protons.
Their chemical shifts, 329.1 and 247.2 ppm, are different enough
however to allow for the assignment based on chemical shifts
seen in related compounds. Particularly interesting is the example
presented in Fig. 11, from the work of Bedford, Taylor and Webb,36
of heterocycles that have the same sequence of nitrogen atoms as in
aminoguanidines, in the amino form in 27, and in the imino form
in 28. Based on the 15N chemical shifts in compound 28, the signal
at 247.2 ppm was assigned to N1¢¢, and the signal at 329.1 ppm to
N2¢¢.
Compound 13 did ◦not dissolve in DMSO-d6 at room tempera-
ture, but it did at 70 C. About 30 minutes after dissolution, the
proton spectrum of 13 displayed the signals of two compounds,
in a ratio 2:1. 1H–13C correlations indicated that both compounds
contain the 4,6-dimethylpyrimidine and the 1,3-dihydro-indole-
2-one moieties. After one day, the sample consisted entirely of
what was initially the minor compound. Correlations to the methyl
protons identified the pyrimidine nitrogens at 254.2 and 252.4 ppm
in the initially major and minor compounds, correspondingly
(Table 6). These values are comparable to the one in 2-amino-4,6-
dimethylpyrimidine, at 242 ppm,39 indicating that both isomers
are in the amino form. Further evidence comes in the case of
the initially minor compound, which displayed a sharp signal for
the exchangeable proton at 12.80. This proton is on the nitrogen
at 164.3, and displays long-range couplings with the nitrogens
at 252.4 and 340.0 ppm. Being both the amino tautomers, these
two isomers have to differ in the configuration of the C3¢¢¢=N2¢¢
double bond. The sharp, deshielded signal of the NH proton in the
initially minor compound suggests an intramolecular hydrogen
bond, possible only in the Z isomer. Some of the signals in
the other isomer, E, are broadened, particularly H4¢¢¢ and the
pyrimidine CH. This has to do with restricted rotation. The bonds
to be considered as having partial double bond character are
C2–N1¢¢ and N1¢¢–N2¢¢. Restricted rotation about C2-N1¢¢ would
produce broadening of the signals of the methyl groups in the
Fig. 11 15N chemical shifts in related heterocycles from ref. 36.
The heterocycles in Fig. 11 demonstrate that the chemical
shifts of N1 and N1¢¢ are good reporters of the amino–imino
tautomerism of 2-hydrazono-3-phenyl-3H-quinazolin-4-ones, as
a difference of ca. 100 ppm is to be expected in the two tautomers.
The value of 99.7 ppm for N1 in 11b is in the range found for N1
in a series of 2,3-dihydro-1H-quinazolin-4-ones, 92–100 ppm; in a
series of quinazolin-4(3H)-ones N1 was at 253–270 ppm. In both
series, N3 was at 140–190 ppm.37
Of all the compounds taken into this study, 11a and 11b were the
only ones in which the signal of the exchangeable proton was sharp
1
enough to afford cross-peaks in the H–13C gHMBC spectrum.
Cross-peaks with C4a, C8 and C8a identified the imino tautomer.
A cross-peak with C3¢¢¢ would have been a proof for the amino
tautomer. For all of the other compounds, exchange with water or
between tautomeric forms broadens the signal of the exchangeable
proton too much for it to display any couplings with carbons or
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4,6-dimethylpyrimidine moiety, but not of the pyrimidine CH or
of H4¢¢¢. Broadening of these latter signals is due to restricted
rotation about the N1¢¢–N2¢¢ bond (Fig. 12). The assignment of
the Z and E isomers was also confirmed by 13C chemical shifts, as
described further on.
The X-ray structure of 11b (Fig. 10) shows the E configuration
of the C3¢¢¢=N2¢¢ double bond. Since this is the expected config-
uration of hydrazones of aldehydes40 it is reasonable to assume it
for all of the compounds 11a–f.
The C2 =N1¢¢ double bond is in the E configuration in 11b.
The same configuration is expected for all of 11a–i, because the
2-hydrazono-3-phenyl-3H-quinazolin-4-one moiety is common to
all of these compounds. The Z configuration would be higher in
energy due to the steric hindrance between the phenyl in position 3
and N2¢¢. Besides, there is a hydrogen bond between H1 and N2¢¢,
which stabilizes the E form.
Conclusions
15N NMR is a powerful technique for the elucidation of tau-
tomerism involving protonation of a nitrogen atom, since a large
chemical shift difference, ca. 100 ppm, is expected for that nitrogen
between the two tautomeric forms. 15N chemical shifts can be
measured by indirect detection, through coupling of the nitrogen
reporter of tautomerism with non-exchangeable protons 2 or 3
bonds away. On typical samples of 15–30 mg, at natural abundance
of 15N, the total experiment time was a couple of hours.
2-(2-Substituted-methylenehydrazinyl)-3-phenylquinazolin-
4(3H)-ones (11a–i) in DMSO solution were found to be
predominantly in the imino form, following the tautomeric
preferences of the aminoguanidines.
2-Hydrazino-3-phenyl-3H-quinazolin-4-one (22) itself is in the
amino form, demonstrating that the terminal nitrogen in the
hydrazine moiety has to be involved in a double bond for the
imino form to prevail.
When the 3,4-dihydro-4-oxo-3-phenylquinazolin-2-yl moiety of
11a–i is replaced by a more aromatic one, as benzimidazol-2-yl
in 12 or 4,6-dimethylpyrimidin-2-yl in 13, the amino tautomer
dominates the equilibrium in DMSO solution.
Fig. 12 Isomers/rotamers of compound 13.
Discrimination between compounds 22 and 25 was possible
1
only based on the 15N NMR data. The H–15N correlations are
presented in the experimental part for 25 and in Table 3 for
22. N1 was identified in both compounds by its cross-peak with
H8 in the CIGAR-gHMBC spectrum. Chemical shift values for
N1 of 183.9 ppm in 22 and 188.0 ppm in 25 demonstrate that
these compounds are both present in solution predominantly as
the amino tautomer. This is to be expected for 25, in which the
exocyclic guanidine nitrogen does not carry another nitrogen. The
preference for the amino tautomer of 22 is surprising, considering
that its derivatives 11a–i prefer the imino form, and can be
explained by the greater electronegativity of N2¢¢ in the latter
compounds. The substituents on N1¢¢ could be used to control the
tautomeric equilibrium of 2-hydrazino-3-substituted-quinazolin-
4(3H)-ones and related compounds, in order to fine tune their
pharmacological and optical properties.
Experimental
General
Melting points were determined on a capillary point apparatus
equipped with a digital thermometer.
The NMR spectra were recorded on a Varian Inova instrument,
=
Stereochemistry of the C N bonds
1
operating at 500 MHz for H, 125 MHz for 13C and 50 MHz
for 15N, equipped with a three channel, 5 mm, indirect detection
probe, with z-axis gradients. The solvent was DMSO-d6, and
the temperature was 25 ◦C, unless specified otherwise. The
=
The barrier to rotation about a C N bond is smaller than that
about a C C bond, and decreases with the electronegativity
of the substituents on the N atom. In hydrazones, often the E
and Z forms equilibrate in a matter of hours or days.40 NOe
experiments when both forms were available identified the isomers
and demonstrated that 13C chemical shifts can be diagnostic for the
=
1
chemical shifts for H and 13C were referenced to the residual
1
solvent signal, 2.50 ppm for H and 39.5 ppm for 13C, on the
tetramethylsilane scale. The chemical shifts for 15N were referenced
to N = 10.1328898, corresponding to 0 for neat ammonia. On
the N scale the frequency of protons in tetramethylsilane is
100.0000000 MHz. For conversion to the neat nitromethane scale,
subtract 381.7 ppm.27
=
stereochemistry. Particularly, carbons alpha to the C N carbons
are shifted upfield when syn to the vicinal nitrogen, relative to the
situation when they are anti. This is the gamma effect and it is due
to steric compression.
The E–Z pairs of the related isatin guanylhydrazones41 29a
and 29b (Table 5) display 13C chemical shift differences of ca.
6 ppm in positions 2¢¢¢, 3a¢¢¢ and 4¢¢¢. The 13C chemical shifts of
these positions in 11g–i demonstrate the E configuration for the
C3¢¢¢=N2¢¢ double bond in these compounds. The chemical shifts
of the same positions in 13 (E) and 13 (Z) confirm the assignment.
1H spectra were acquired in one transient, with a 90◦ pulse, no
relaxation delay and an acquisition time of 5 s, over a spectral
window from 16 to -2 ppm. The FID was zero-filled to 131072
points prior to Fourier transform.
Typically, 1H–13C gHMBC spectra were acquired in 2048 points
in f2, on a spectral window from 6.5 to 11 ppm, and 1 s relaxation
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delay. In f1, 256 increments were acquired in 1 transient over
a spectral window from 110 to 170 ppm, then the corresponding
FID’s were zero-filled twice prior to the second Fourier transform.
1H–15N CIGAR-gHMBC spectra were acquired with a pulse
sequence optimized for 15N, as decribed in ref. 42. 2048 points were
acquired in f2, over a spectral window typically from 6.5 to 11 ppm,
with 1 s relaxation delay. 1024 increments were acquired in f1, on
a spectral window from 0 to 400 ppm, and the corresponding FID
was zero-filled twice prior to Fourier transform. The accordion
(E)-2-((E)-(4-Nitrobenzylidene)hydrazono)-3-phenyl-2,3-dihy-
droquinazolin-4(1H)-one (11d). The precipitate formed was col-
lected and crystallized from n-butanol to give ye◦llow microcrystals
(97%), m.p. 275.0–277.0 ◦C [Lit. m.p. 260–262 C].7 Anal. Calcd.
for C21H15N5O3·1/3 H2O (391.39): C, 64.44; H, 4.03; N, 17.89.
Found: C, 64.66; H, 3.85; N, 17.67.
4-((E)-((E)-(4-Oxo-3-phenyl-3,4-dihydroquinazolin-2(1H)-yli-
dene)hydrazono)methyl)benzonitrile
(11e). The
precipitate
formed was collected and crystallized from n-butanol to give pale
yellow microcrystals (90%), m.p. 312–314 ◦C. Anal. Calcd. for
C22H15N5O (365.40): C, 72.32; H, 4.14; N, 19.17. Found: C, 72.07;
H, 3.99; N, 19.03.
1
delay was optimized for a value of H–15N coupling constants
between 3 and 10 Hz. The number of transients per increment was
between 4 and 64, depending on the concentration of the sample.
Total experiment time was in most cases, ca. 2 h.
(E)-3-Phenyl-2-((E)-(pyridin-3-ylmethylene)hydrazono)-2,3-di-
hydroquinazolin-4(1H)-one (11f). The precipitate formed was
collected and crystallized from n-butanol to give white crystals
(97%), m.p. 216.0–217.0 ◦C. Anal. Calcd. for C20H15N5O.H2O
(359.39): C, 66.84; H, 4.77; N, 19.49. Found: C, 67.04; H, 4.56;
N, 19.38.
Preparation of 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-
one (21). Anthranilic acid (1.37 g, 0.01 mol) and phenylisoth-
iocyanate (1.35 g, 0.01 mol) were refluxed in 50 mL ethanol
for 2 hours. The solid obtained was filtered off and purified by
crystallization from DMF: white microcrystals (2.03 g, 80%), m.p.
◦
313–315 ◦C [Lit. m.p. 300 C].29 Anal. Calcd. for C14H10N2OS
(E)-2-((E)-(5-Methyl-2-oxoindolin-3-ylidene)hydrazono)-3-
phenyl-2,3-dihydroquinazolin-4(1H)-one (11g). The product was
crystallized fro◦m n-butanol to give pale yellow needles (96%),
m.p. 348–350 C [Lit. m.p. not reported].43 Anal. Calcd. for
C23H17N5O2.H2O (413.44): C, 66.82; H, 4.63; N, 16.94. Found:
C, 66.66; H, 4.50; N, 16.88.
(254.31): C, 66.12; H, 3.96; N, 11.02. Found: C, 66.11; H, 3.78; N,
10.94.
Preparation of 2-hydrazino-3-phenylquinazolin-4(3H)-one (22).
A mixture of 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
21 (0.25 g, 1 mmol) and hydrazine hydrate (99%, 0.05 g, 10 mmol)
was refluxed in butanol for 3 h. After the reaction was cooled
down, a white precipitate was separated. This precipitate was
recrystallized from n-butanol to give the desired product in 79%
yield (0.2◦0 g, 0.8 mmol). White needles, m.p. 193–195 ◦C [Lit. m.p.
202–203 C].29 Anal. Calcd. for C14H12N4O (252.28): C, 66.65; H,
4.79; N, 22.21. Found: C, 66.27; H, 4.70; N, 21.96.
(E)-2-((E)-(5-Bromo-1-methyl-2-oxoindolin-3-ylidene)hydra-
zono)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (11h). The pro-
duct was crystallized from EtOH to give orange needles (95%),
m.p. 363–365 ◦C. Anal. Calcd. for C23H16BrN5O2 (474.32): C,
58.24; H, 3.40; N, 14.77. Found: C, 57.98; H, 3.35; N, 14.60.
(E)-2-((E)-(1-Allyl-2-oxoindolin-3-ylidene)hydrazono)-3-phenyl-
2,3-dihydroquinazolin-4(1H)-one (11i). The product was crys-
tallized from EtOH to give yellow needles (84%), m.p. 242–
244 C. Anal. Calcd. for C25H19N5O2.H2O (474.32): C, 68.33; H,
4.82; N, 15.94. Found: C, 68.79; H, 4.58; N, 15.94.
General procedure for preparing compounds 11a–i
2-Hydrazinyl-3-phenylquinazolin-4(3H)-one 22 (0.25 g, 1 mmol)
was heated under reflux in ethanol (25 mL) for 15 min. to 1 h
with 1 mmol of the corresponding aldehyde or ketone 23a–i.
The precipitate formed was collected and crystallized from the
appropriate solvent to give the desired products in quantitative
yields.
◦
4-[(2-(1H-Benzimidazol-2-yl)hydrazono)methyl]-N,N-dimethyl-
aniline (12). 2-Hydrazinyl-1H-benzoimidazole (0.074 g,
0.5 mmol) was heated under reflux in ethanol (25 mL) with
4-(dimethylamino)benzaldehyde (0.075 g, 0.5 mmol) for 3 h. The
precipitate formed was collected and crystallized from EtOH
to gi◦ve brown microcrystals (50%), m.p. 262–264 ◦C [Lit. m.p.
245 C].44 HRMS (ESI) calcd. for C16H17N5 (MH)+ 280.1557,
found 280.1557.
(E)-2-((E)-Benzylidenehydrazono)-3-phenyl-2,3-dihydroquin
-azolin-4(1H)-one (11a). The product was crystallized from
EtO◦H to give white needles (98%), m.p. 215–217 ◦C [Lit. m.p.
218 C].29 Anal. Calcd. for C21H16N4O (340.39): C, 74.10; H, 4.74;
N, 16.46. Found: C, 74.21; H, 4.63; N, 16.46.
3-[2-(4,6-Dimethylpyrimidin-2-yl)hydrazono]-1-methylindolin-
2-one (13). 2-Hydrazinyl-4,6-dimethylpyrimidine (0.069 g,
0.5 mmol) was heated under reflux in ethanol (25 mL) with
1-methyl-1H-indole-2,3-dione (0.08 g, 0.5 mmol) for 1 h. The
precipitate formed was collected and purified by column chro-
matography using ethyl acetane/hexanes (1:3) as an eluent system.
The sharp yellow needle crystals were pure enough for elemental
analysis. This compound was obtained in 71% yield and had m.p.
191–193 ◦C. Anal. Calcd. for C15H15N5O·1/4 H2O (285.83): C,
63.03; H, 5.47; N, 24.50. Found: C, 63.32; H, 5.39; N, 24.10.
(E)-2-((E)-(4-(Diethylamino)benzylidene)hydrazono)-3-phenyl-
2,3-dihydroquinazolin-4(1H)-one (11b). The solid obtained was
crystallized from DCM/hexanes to give the desired product
as yellow needles (97%), m.p. 202–204 ◦C. Anal. Calcd. for
C25H25N5O (411.51): C, 72.97; H, 6.12; N, 17.02. Found: C, 72.81;
H, 6.12; N, 17.11.
(E)-2-((E)-(2,4-Dimethoxybenzylidene)hydrazono)-3-phenyl-
2,3-dihydroquinazolin-4(1H)-one (11c). The solid obtained was
filtered off and crystallized from n-butanol to give yellow micro-
crystals (98%), m.p. 257–259 ◦C. Anal. Calcd. for C23H20N4O3
(400.44): C, 68.99; H, 5.03; N, 13.99. Found: C, 68.73; H, 5.02; N,
13.79.
Preparation of 2-(methylsulfanyl)-3-phenyl-4(3H)-quinazolinone
(24). This compound was prepared according to the lit-
erature method.35 The solid obtained was crystallized from
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dichloromethane/diethyl ether to give compound 24 as colorless
10 V. Alagarsamy, V. R. Solomon and S. Murugesan, Arzneim.- Forsch.,
2008, 58, 174–181.
11 I. D. Cunningham, N. C. Wan and B. G. Cox, J. Chem. Soc., Perkin
Trans 2, 1994, 8, 1849–1853, and references therein.
12 G. R. Bedford, P. J. Taylor and G. A. Webb, Magn. Reson. Chem., 1995,
33, 383–388.
◦
needles (75%), m.p. 118–120 ◦C [Lit. m.p. 124–126 C].7 Anal.
Calcd. for C15H12N2OS (268.34): C, 67.14; H, 4.51; N, 10.44.
Found: C, 67.36; H, 4.50; N, 10.46.
13 J. G. Palenic, Acta Cryst. A, 1965, 19, 47–56.
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20 P. Buehlmann, M. Badertscher and W. Simon, Tetrahedron, 1993, 49,
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Preparation of 3-amino-2-anilino-4(3H)-quinazolinone (25)
This compound was prepared according to the litera-
ture method.29 The solid obtained was crystallized from
dichloromethane/hexanes to afford compound◦ 25 as colorless
21 A. Kaito, M. Hatano, T. Ueda and S. Shibuya, Bull. Chem. Soc. Jpn,
◦
prisms (80%), m.p. 153–155 C [Lit. m.p. 151 C].29 1H NMR
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22 D. Casanova, S. Gusarov, A. Kovalenko and T. Ziegler, J. Chem. Theory
Comput., 2007, 3, 458–476.
(500 MHz, DMSO-d6) d 9.37 (s, 1H, H1¢¢), 8.00 (dd, J = 7.9,
1.3 Hz, 1H, H5), 7.93 (dd, J = 8.7, 1.1 Hz, 2H, H1¢), 7.65 (ddd,
J = 8.5 Hz, 7.2, 1.7, 1H, H7), 7.39 (d, J = 8.1 Hz, 1H, H8),
7.36 (t, J = 8.0 Hz, 2H, H2¢), 7.23 (ddd, J = 8.0, 7.9, 1.1 Hz,
1H, H6), 7.07 (tt, J = 7.4, 1.0 Hz, 1H, H3¢), 5.72 (s, 2H, H2¢¢).
13C NMR (125 MHz, DMSO-d6) d 161.7 (C4), 148.7 (C2), 148.4
(C8a), 139.3 (C5a’), 134.9 (C7), 129.3 (C2¢), 126.8 (C5), 125.8
(C8), 123.6 (C3¢), 123.4 (C6), 121.2 (C1¢), 118.3 (C4a). 15N NMR
(50 MHz, DMSO-d6) d 188.0 (N1), 164.4 (N3), 101.9 (N1¢¢), 64.1
(N2¢¢). Anal. Calcd. for C14H12N4O (252.28): C, 66.65; H, 4.79; N,
22.21. Found: C, 66.45; H, 4.73; N, 22.34.
23 M. F. Zady and J. L. Wong, J. Org. Chem., 1976, 41, 2491–2495.
24 J. L. Wong and M. F. Zady, J. Org. Chem., 1975, 40, 2512–2516.
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27 R. Marek and A. Lycka, Current Organic Chemistry, 2002, 6, 35–66.
28 G. E. Martin and C. E. Hadden, J. Nat. Prod., 2000, 63, 543–585.
29 M. A. Badawy, S. A. L. Abdel-Hady, Y. A. Ibrahim and A. M. Kadry,
J. Heterocycl. Chem., 1985, 22, 1535–1536.
30 V. Alagarsamy, R. Giridhar and M. R. Yadav, Bioorg. Med. Chem.
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32 V. Alagarsamy, M. R. Yadav and R. Giridhar, Arzneim.- Forsch., 2006,
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Acknowledgements
33 V. Alagarsamy, R. Giridhar and M. R. Yadav, J. Pharm. Pharmacol.,
2006, 58, 1249–1255.
34 V. Alagarsamy, V. R. Solomon, P. Parthiban, K. Dhanabal, S. Muruge-
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709–715.
The authors thank Geoffrey Jameson and Shane Telfer, Massey
University, for collection of the X-ray data.
35 Summary of X-ray details† for 11d: C25H25N5O, FW 411.50, or-
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3
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