Synthesis of N-substituted(Thiazol-2-ylidene)pyrazol-5-amine derivatives via condensation of pyrazolylthioureas with ω-bromoacetophenones

Article abstract of DOI:10.1002/jhet.1793

1-Substituted 3-[3-methyl-1H-pyrazol-5-yl]thioureas react with ω-bromoacetophenones forming N-substituted(thiazol-2-ylidene)pyrazol-5- amine derivatives. Rational for these conversations are presented.

Full text of DOI:10.1002/jhet.1793

610
Synthesis of N-Substituted(Thiazol-2-ylidene)pyrazol-5-amine Derivatives
via Condensation of Pyrazolylthioureas with o-Bromoacetophenones
Vol 51
a
a
a
a
b
*
Alaa A. Hassan, Yusria R. Ibrahim, Ashraf A. Aly, Essmat M. El-Sheref, and Alan B. Brown
aChemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt
bChemistry Department, Florida Institute of Technology, 150 W University Boulevard, Melbourne, Florida 32901
*
E-mail: alaahassan2001@yahoo.com
Received May 12, 2012
DOI 10.1002/jhet.1793
Published online 26 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
H3C
S
N
R
R
R'
N
H
N
H
N
H
N
N
O
+
S
Br
H3C
NH
N
R'
1-Substituted 3-[3-methyl-1H-pyrazol-5-yl]thioureas react with o-bromoacetophenones forming N-substituted
(thiazol-2-ylidene)pyrazol-5-amine derivatives. Rational for these conversations are presented.
J. Heterocyclic Chem., 51, 610 (2014).
INTRODUCTION
thiadiazepines [18], and benzobisimidazothiadiazoles [19],
from reactions between hydrazinecarbothioamides and
p-deficient compounds.
Brominated compounds are important intermediates in
organic synthesis because they are amenable to a vast
number of organic reactions involving functional group
transformations [1–4]. a-Haloketones such as phenacyl
halides are among the most versatile intermediates in
organic synthesis: they react with a large number of nucleo-
philes to provide a variety of useful compounds [5].
Phenacyl halides have been used as precursors of various
pharmaceutically important heteroaromatics such as imida-
zoles, selenazoles, and oxazoles [6]. In particular, it is well
known that phenacyl halides are coupled with thioamides
to provide the corresponding thiazoles, in the so-called
Hantzsch synthesis [7].
In the light of these findings, we undertook to investigate
the reactions of phenacyl bromides (5a,c,d) with pyrazo-
lylthioureas 8a–c. As potential nucleophiles, 8a–c offer
the sulfur atom, N1 or N3 of the thiourea structure [20], or
the endocyclic pyrazole-NH. On the other hand, compounds
5 offer the active methylene group and the carbonyl atoms
as electrophilic sites. Thus, several modes of interaction
between pyrazolylthioureas 8a–c and o-bromoacetophenones
5a,c,d may be envisaged.
RESULTS AND DISCUSSION
Pyrazolylthiazoles have been used against cardiovascular
diseases, as selective inhibitors of fibrinogen-mediated
platelet aggregation [8]. Many of these compounds display
antinociceptive activity [9], toxicity towards Caenorhabditis
elegans [10], and phototoxicity against mosquito larvae [11].
The most common route to the synthesis of pyrazo-
lylthiazoles is the reaction of 2-hydrazinothiazoles with
b-diketones [12]. An alternate route to trifluoromethyl-
substituted pyrazolylthiazoles 6a–e and 7a–c has been
explored, involving the reaction of 3(5)-trifluoromethyl-5(3)-
substituted pyrazole-1-thiocarboxamides 3a–e and 4a–e with
phenacyl bromides 5a,b [13] (Scheme 1).
The development of new simple and efficient procedures
for the synthesis of important heterocyclic systems is a part
of our program. We have recently reported different suc-
cessful approaches for the synthesis of oxothiazolidines
[14,15], pyrazolyloxothiazolidines [16], benzimidazoxa-
diazoles, naphthoimidazoxadiazoles, tetrachlorothian-
threnetetraones [17], thiadiazoles, benzothiadiazinediones,
Reaction of pyrazolylthioureas 8a–c with phenacyl bro-
mides 5a,c,d in ethanol at reflux gave, as the sole isolated
products, thiazolylidenepyrazolamines 9a–i (Scheme 2).
The IR spectra of 9a–i showed three absorption bands
at about 3280–3295, 1615–1625, and 1580–1605 cmꢀ1
,
which were assigned to NH, C═N, and Ar—C═C,
respectively.
Elemental analyses and mass spectra showed that the
elements of H2O and HBr (Mw-99) had been released. In
the electron-impact mass spectra of all the products, loss
of R and R0—C6H4 gives rise to m/z = 178 (C7H6N4S).
This fragment in turn loses the thiazolimine (C3H2N2S)
ring, giving rise to m/z = 81.
1
The H-NMR spectra of 9a–i revealed a thiazole-CH
signal between 7.13 and 7.35 ppm, a pyrazole-CH signal
at 6.01–6.06 ppm, and one pyrazole-NH proton signal for
which the range of chemical shifts is relatively narrow
(12.26–12.97 ppm).
© 2013 HeteroCorporation

May 2014
Synthesis of N-Substituted(Thiazol-2-ylidene)pyrazol-5-amine Derivatives
via Condensation of Pyrazolylthioureas with o-Bromoacetophenones
611
Scheme 1. Previous work, reaction of trifluoromethyl-5(3)-substituted
Scheme 3. Isometric products formed via the intermediate A.
pyrazol-1-thiocarboxamides with phenacyl bromides.
A
S
O
O
i) - H2O
ii) - HBr
S
R
NH2
+
H3C
H2N
N
H
R
CF3
N
N
R
2a-e
1
H3C
N
EtOH
reflux
or
N
N
EtOH, H2SO4
reflux
NH
S
S
N
NH
S
H2N
H2N
N
N
+
N
N
HO
R
R
11
CF3
R'
F3C
i) pyrazole-NH
HA
10
ii) one C=S
HB
3a-e
i) pyrazole-NH
ii) two C=N
iii) thiazole-CH
iv) pyrazole-CH
R'
iii) one C=N
4a-e
iv) pyrazole-CH
v) imidazole-CH
S
R
O
EtOH
reflux
N
HN
EtOH
reflux
Br
R1
R1
5a,b
N
Ph
N
N
N
H3C
S
N
N
S
12
N
N
R
i) triazepine-NH
ii) one C=S
F3C
R'
CF3
R
iii) one C=N
iv) pyrazole-CH
v) triazepine-CH
6a-e
7a-c
2,3,4: a
b
c
d
, R = CH3; , R = CF3; , R = C6H5; , R = p-CH3OC6H4;
e, R = p-ClC6H4
5: a
b
, R1 = C6H5; , R1 = p-CH3OC6H4
6: a, R = CH3, R1 = p-CH3OC6H4; b, R = CF3, R1 = C6H5; c, R = R1 = C6H5;
d, R = p-CH3OC6H4, R1 = C6H5; e, R = p-ClC6H4, R1 = p-CH3OC6H4
7: a
b
c
, R = C6H5; , R = p-CH3OC6H4; , R = p-ClC6H4
Scheme 2. Reaction between pyrazolythioureas 8a–c and phenacyl bromides 5a,c,d.
H3C
O
S
N
Br
R
+
N
N
N
H
H
H
EtOH
reflux
5a,c,d
8a-c
R'
H3C
R
N
N
N
NH
S
R'
9a-i
5: a, R' = H; c, R' = Br; d, R' = C6H5
8: a, R = C6H5; b, R = C6H5CH2; c, R = CH2=CH-CH2
9: a, R = C6H5, R' = H; b, R = C6H5CH2, R' = H; c, R = CH2=CH-CH2, R' = H;
d, R = C6H5, R' = Br; e, R = C6H5CH2, R' = Br; f, R = CH2=CH-CH2, R' = Br;
g, R = R' = C6H5; h, R = C6H5CH2, R' = C6H5; i, R = CH2=CH-CH2, R' = C6H5
Journal of Heterocyclic Chemistry
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A. A. Hassan, Y. R. Ibrahim, A. A. Aly, E. M. El-Sheref, and A. B. Brown
Vol 51
Further support for the structure of 9a–i was provided
Products 10–12 (Scheme 3) might form, if the reaction
proceeds via intermediate A (Fig. 1).
Products 9, 13, and 14 (Scheme 4) might form, if the
reaction proceeds via intermediate B (Fig. 1).
Products 15–17 (Scheme 5) might form, if the reaction
proceeds via intermediate C (Fig. 1).
Products 18–20 (Scheme 6) might form, if the reaction
proceeds via intermediate D (Fig. 1).
7Structures 11, 12, 15, 17, 18, and 20 could be excluded,
by the absence of any C═S carbon from the 13C-NMR data.
Structures 12, 13, 130, 15, and 18–20 were also excluded,
because of the presence of pyrazole-NH in the 1H-NMR data
(dH = 12.26–12.97). Finally, structures 10 and 16 could be
excluded on the basis of the thiazole-CH chemical shifts
(dH = 7.13–7.35, consistent with thiazole-H5 as in 9, but not
with thiazole-H4 as in 10 and 16 [21]). Further support for
structures 9 comes from 2D NMR correlation. For example,
in 9b, the benzylic protons in group R give HMBC correla-
tion with thiazole-C4 (immediately ruling out 14b) but not
with thiazole-C5; thiazole-C4 lacks an attached proton, but
thiazole-C5 possesses one, ruling out structures 10b and 16b.
by 13C-NMR spectra, which exhibited signals at dc
162.94–163.69, 148.03–149.22, 105.98–106.66, 94.08–94.62,
and 10.48–10.92 ppm, corresponding to (thiazole-C2),
(pyrazole-C5), (thiazole-C5), (pyrazole-C4), and methyl
group, respectively.
1
The H-NMR spectrum of 9c (R═allyl, R0═H) clearly
showed the presence of an allyl group that resonated at
4.52, 5.03–5.15, and 5.75–5.87 ppm, because of allyl-
CH2N, allyl-CH2═, and allyl-CH═, respectively. The
presence of an allyl group was also evident from the
13C-DEPT-NMR spectrum, which exhibited a positive
signal at 135.91 ppm (allyl-CH═), and negative signals
at 44.86 and 117.82 ppm, because of allyl-CH2N and
allyl-CH2═, respectively.
There are possibilities for the formation of various iso-
mers that would behave very similarly spectroscopically
(Schemes 3–6). It is probable that all products observed
are formed from one of the four labile (1:1) adducts (A–D)
of pyrazolylthioureas 8a–c to o-bromoacetophenones
5a,c,d (Fig. 1).
Scheme 4. Isometric products are formed via intermediate B.
H
N
B
R
N
i) - H2O
ii) - HBr
H3C
H3C
S
N
R
N
N
N
N
NH
S
R'
9
13
i) R-NH
ii) two C=N
i) pyrazole-NH
ii) two C=N
R'
iii) thiazole-CH
iv) pyrazole-CH
iii) pyrazole-CH
iv) thiadiazepine-CH
R
N
R
H
N
N
S
H3C
S
H3C
N
N
N
N
NH
R'
13'
R'
14
i) thiadiazepine-NH
ii) two C=N
iii) pyrazole-CH
v) thiadiazepine-CH
i) pyrazole-NH
ii) two C=N
iii) pyrazole-CH
iv) thiazole-CH
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of N-Substituted(Thiazol-2-ylidene)pyrazol-5-amine Derivatives
via Condensation of Pyrazolylthioureas with o-Bromoacetophenones
613
Scheme 5. Isometric products are formed via intermediate C.
dH = 7.63. Thus, the three signals are assigned as those of
one mono-substituted ring: dH = 7.63, 7.45, and 7.37 are
respectively either H-o0, m0, and p0 or H-o000, m000, and p000.
The attached carbons appear at dC = 126.61, 128.98,
and 127.97, respectively. The non-protonated carbon at
dC = 138.67 gives HMBC correlation with H-m0/m000 at
dH = 7.45, and therefore is assigned as the ipso carbon of
this ring. This carbon also gives HMBC correlation with
the doublet at dH = 7.57, in the p-disubstituted ring; thus,
the doublet is assigned as H-m00. Its attached carbon
appears at dC = 129.09. This connection means that the
mono-substituted phenyl described earlier must be that de-
rived from p-phenylphenacyl bromide, that is, H- and C-o000,
m000, and p000. The remaining protons of the p-disubstituted
ring are the doublet at dH = 7.54, which are assigned as
H-o00, the attached carbon appears at dC = 129.99. The
other two triplets (one 1H and one 2H) are coresonant, at
dH = 7.58; they give COSY correlation with the doublet
at dH = 7.27. Accordingly, the 1H and 2H triplets are
assigned as H-p0 and H-m0 respectively, and the doublet
at dH = 7.27 is assigned as H-o0. Their attached carbons
at dC = 130.29, 126.31, and 129.78 are assigned as C-p0,
m0, and o0, respectively. The assignment of the remaining
non-protonated carbons is somewhat conjectural: it depends
on HMBC correlations in a congested region. The assump-
tion that three-bond correlations are observed leads to the
assignments in Table 2.
C
i) - H2O
ii) - HBr
CH3
S
R
NH
N
H3C
N
HN
N
R
N
N
N
S
R'
15
i) R-NH
R'
16
ii) one C=S
iii) imidazole-CH
iv) pyrazole-CH
i) pyrazole-NH
ii) two C=N
iii) thiazole-CH
iv) pyrazole-CH
S
R
N
H3C
N
R'
N
NH
17
i) pyrazole-NH
ii) one C=N
iii) one C=S
iv) imidazole-CH
v) pyrazole-CH
The formation of thiazolylidenepyrazolamines 9a–i can
be rationalized as in Scheme 7.
The connectivities are illustrated by compound 9g (Fig. 2).
The broad signal at dH = 12.6 (Table 1), detected via integra-
tion, is assigned as NH, and the methyl singlet at dH = 2.30
is assigned as H-3a. The methyl signal gives a weak COSY
correlation to the one-proton singlet at dH = 6.05, which is
assigned as H-4. The attached carbons at dC = 94.62 and
10.87 are assigned as C-4 and C-3a, respectively. Two other
carbon signals give HMBC correlation with H-4: those at
dC = 148.03 (detected only via HMBC) and 140.63. The
former correlates only with H-4, whereas the latter also
correlates with H-3a; they are therefore assigned as C-5 and
C-3 in that order.
CONCLUSION
Cyclo-condensation of pyrazolylthioureas 8a–c with
o-bromo-acetophenones 5a,c,d forms thiazolylidenepyrazol-
amines 9a–i. The reaction between 8a–c and 5a,c,d can
involve attack by four possible sites of compounds 8 (N1,
N3, pyrazol-NH and SH of thioamide group) on the active
methylene and carbonyl group of o-bromoacetophenones.
The thiaheterocyclic N-C-S + C1 mode of cyclization is found
to be favored. Comparison of 1H-NMR and 13C-NMR chem-
ical shifts and 2D NMR correlations for the possible sets of
isomers may serve as a useful supplementary tool in finding
the correct structure of a heterocycle.
The imino carbon C-20 at dC = 163.26 gives HMBC
correlation with the singlet at dH = 7.35, which is assigned
as H-50; the attached carbon at dC = 106.16 is assigned as
C-50. The signal at dC = 140.08 also gives HMBC correla-
tion with H-50; this carbon is assigned as C-40.
EXPERIMENTAL
1
The rest of the H spectrum consists of three phenyl
groups, two mono-substituted, and one p-disubstituted.
Assuming meta coupling constants to be small, these
phenyl groups should give four two-proton (2H) doublets
(H-o0, o00, m00, and o000), two 2H triplets (H-m0 and m000),
and two one-proton (1H) triplets (H-p0 and p000). One triplet
of each type is visible upfield, at dH = 7.45 (2H) and 7.37
(1H); these give COSY correlation with each other, and
the signal at dH = 7.45 correlates with the 2H doublet at
General Procedures. Melting points were determined using
open glass capillaries on a Gallenkamp melting point apparatus
(Weiss-Gallenkamp, Loughborough, UK) and uncorrected. The
IR spectra were recorded from potassium bromide disks with
a Shimadzu 408 (Shimadzu Corporation, Kyoto, Japan). NMR
1
spectra (400 MHz for H, 100 MHz for 13C) were observed in
DMSO-d6 on Bruker AM400 or AV400 spectrometers (Bruker
BioSpin, Karlsruhe, Germany) with tetramethylsilane as the
internal standard. The 13C signals were assigned with the aid of
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614
A. A. Hassan, Y. R. Ibrahim, A. A. Aly, E. M. El-Sheref, and A. B. Brown
Vol 51
Scheme 6. Isometric products are formed via intermediate D.
D
i) - H2O
ii) - HBr
R
HN
S
R
N
S
NH
H3C
N
N
H3C
N
N
N
R'
R'
18
i) R-NH
ii) one C=S
iii) one C=N
iii) pyrazole-CH
iv) imidazole-CH
19
i) R-NH
ii) two C=N
iii) pyrazole-CH
iv) thiadiazepine-CH
R
S
N
HN
HN
R
N
S
N
N
H3C
H3C
N
N
19'
20
R'
R'
i) thiadiazepine-NH
ii) two C=N
i) triazepine-NH
ii) one C=S
iii) pyrazole-CH
iv) thiadiazepine-CH
iii) one C=N
iv) pyrazole-CH
v) triazepine-CH
DEPT 135/90, HMBC, and HMQC experiments. Mass spectra
were recorded on Shimadzu Qp-2010 plus instrument
7.31–7.65 (m, 10H, Ar—CH), 12.68 ppm (s, 1H, pyrazole-NH);
13C-NMR: d 10.92 (CH3), 94.31 (pyrazole-CH), 105.69 (thiazole-
CH), 127.23, 127.46, 128.19, 128.39, 129.21, 129.28 (Ar—CH),
131.44, 135.71 (Ar—C), 140.39 (thiazole-C-4), 142.64 (pyrazole-C-
3), 148.49 (pyrazole-C-5), 162.66 ppm (thiazole-C-2); MS: m/z 332
(M+, 25), 255 (23), 251 (61), 178 (100), 81 (45), 77 (63). Anal.
Calcd for C19H16N4S: C, 68.65; H, 4.85; N, 16.85; S, 9.65. Found:
C, 68.49; H, 4.91; N, 16.99; S, 9.58.
a
(Shimadzu Corporation, Kyoto, Japan), in EI Mode with 70eV
ionization energy. TLC was performed on analytical Merck 9385
silica aluminum sheets (Kieselgel 60) with Pf254 indicator; TLC’s
were viewed lmax = 254nm. Elemental analyses were carried out
at the Microanalytical Center, Cairo University, Egypt.
Starting materials. Pyrazolylthioureas 8a–c were prepared
according to published procedures [16]. o-Bromoacetophenones
5a,c,d were prepared according to published procedures [22,23].
Procedure: preparation of thiazolylidenepyrazolamines
(Z)-N-(3-Benzyl-4-phenylthiazol-2(3H)-ylidene)-3-methyl-
1H-pyrazol-5-amine (9b).
colorless crystals (230 mg, 64%), mp 296–298ꢁC; IR: NH 3285,
C═N 1620, Ar—C═C 1600, 1580 cmꢀ1 1H-NMR: d 2.19
This compound was obtained as
;
9a–i.
A solution of pyrazolylthioureas 8a–c (0.1 mol) in 10 mL
(s, 3H, CH3), 5.59 (s, 2H, CH2), 6.06 (s, 1H, pyrazole-CH), 7.25
(s, 1H, thiazole-CH), 7.34–7.86 (m, 10H, Ar—CH), 12.54 ppm
(s, 1H, pyrazole-NH); 13C-NMR: d 10.62 (CH3), 42.56 (CH2),
94.31 (pyrazole-CH), 105.98 (thiazole-CH), 126.74, 127.18,
127.96, 128.68, 129.73, 129.97 (Ar—CH), 131.13, 136.68 (Ar—
C), 140.19 (thiazole-C-4), 141.07 (pyrazole-C-3), 148.86
(pyrazole-C-5), 162.64 ppm (thiazole-C-2); MS: m/z 346 (M+,
75), 269 (24), 255 (18), 178 (85), 91 (56), 81 (41), 77 (100).
Anal. Calcd for C20H18N4S: C, 69.34; H, 5.24; N, 16.17; S,
9.26. Found: C, 69.51; H, 5.11; N, 16.38; S, 9.33.
ethanol was added dropwise to (0.1 mol) o-bromoacetophenones 5a,
c,d in 10 mL ethanol, and the reaction mixture was gently refluxed
with stirring for 30 min (for compound 9a), 1 h (for compound 9b),
1.5 h (for compound 9c), 1 h (for compound 9d), 2 h (for compound
9e), 2.25 h (for compound 9f), 2.5 h (for compound 9g), 2.5 h (for
compound 9 h), and 3 h (for compound 9i). The resulting
colorless precipitate was filtered off, washed with ethanol, and
recrystallized from acetonitrile to give pure crystals of 9a–i.
(Z)-N-(3,4-Diphenylthiazol-2(3H)-ylidene)-3-methyl-1H-
pyrazol-5-amine (9a).
colorless crystals (250 mg, 75%), mp 280–282ꢁC; IR: NH 3290,
C═N 1620, Ar—C═C 1605, 1580 cmꢀ1 1H-NMR: d 2.29
(s, 3H, CH3), 6.04 (s, 1H, pyrazole-CH), 7.22 (s, 1H, thiazole-CH),
This compound was obtained as
(Z)-N-(3-Allyl-4-phenylthiazol-2(3H)-ylidene)-3-methyl-1H-
pyrazol-5-amine (9c). This compound was obtained as colorless
crystals (180 mg, 61%), mp 242–244ꢁC; IR: NH 3280, Ali-CH
;
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Synthesis of N-Substituted(Thiazol-2-ylidene)pyrazol-5-amine Derivatives
via Condensation of Pyrazolylthioureas with o-Bromoacetophenones
615
A
B
Table 1
1H-NMR and COSY data for compound 9g.
H3C
N
R
Br
H
1H-NMR (DMSO-d6):
COSY
Assignment
N
NH
S
Ar
H3C
R
H
N
12.6 (b; 1H)
N—H
H-o0000
H-m , p0
H-m00
H-o00
N
H
NH
S
N
H
Ar
N
7.63 (d, J = 7.9; 2H)
7.58 (t, J = 7.4; 3H)
7.57 (d, J = 6.7; 2H)
7.54 (d, J = 7.0; 2H)
7.45 (t, J = 7.6; 2H)
7.37 (t, J = 7.2; 1H)
7.35 (s, 1H)
7.27 (d, J = 8.2; 2H)
6.05 (s, 1H)
2.30 (s, 3H)
7.58–7.54, 7.45
O
7.27
7.63
Br
R
O
7.63, 7.37
7.45
H-m000
H-p000
H-50
H
N
Br
S
NH
Ar
H3C
7.58–7.54
2.30
6.05
H-o0
NH
N
H-4
H-3a
O
C
D
H3C
N
H3C
S
S
Table 2
R
HSQC and HMBC data for compound 9g.
R
H
N
N
H
N
N
N
N
H
13C-NMR
H
NH
H
Ar
(DMSO-d6)
HSQC
HMBC
Assignment
Ar
Br
Br
163.26
148.03
140.63
140.08
138.67
134.88
130.29
129.99
129.78
129.09
128.98
128.78
128.19
127.97
126.61
7.35
6.05
6.05, 2.30
7.63, 7.35
7.58–7.57, 7.45
7.54
C-20
C-5
O
O
C-3
C-400
C-i000
C-i00
A-D, Ar=
R'
Figure 1. Four labile (1:1) adducts (A–D).
7.58
7.54
7.27
7.57
7.45
7.58
7.57
7.27
7.45
7.54
7.58
7.63
7.63
C-p0
C-o00
C-o0
C-m00
C-m000
C-i000
C-p
p'''
i'''
o'
p'
o''
p''
m'''
m'
7.37
7.63
C-p000
C-o000
7.63–7.58, 7.37,
7.27
o'''
i'
126.31
106.16
94.62
7.58
7.35
6.05
2.30
C-m0
C-50
C-4
m''
N
S
7.45
2.30
5
N
10.87
C-3a
i''
5'
4
4'
NH
255 (51), 219 (33), 178 (100), 95 (18), 83 (21), 81 (45), 77
(78), 41 (19). Anal. Calcd for C16H16N4S: C, 64.84; H,
5.44; N, 18.90; S, 10.82. Found: C, 64.91; H, 5.26; N,
19.03; S, 10.68.
2'
N
3a
3
(Z)-N-[4-(4-Bromophenyl)-3-phenylthiazol-2(3H)-ylidene]-
3-methyl-1H-pyrazol-5-amine (9d).
This compound was
Figure 2. The structure of compound 9g.
obtained as colorless crystals (260 mg, 63%), mp 274–276ꢁC; IR:
NH 3295, Ali-CH 2950, C═N 1620, Ar—C═C 1600,
1580cmꢀ1; 1H-NMR: d 2.31 (s, 3H, CH3), 6.05 (s, 1H, pyrazole-
CH), 7.31 (s, 1H, thiazole-CH), 7.22–7.64 (m, 9H, Ar—CH),
12.97 ppm (s, 1H, pyrazole-NH); 13C-NMR: d 10.64 (CH3), 94.16
(pyrazole-CH), 106.31 (thiazole-CH), 126.12, 127.22, 128.40,
129.72, 134.13 (Ar—CH), 136.14, 141.42 (Ar—C), 140.01
(thiazole-C-4), 141.06 (pyrazole-C-3), 149.06 (pyrazole-C-5),
163.69 ppm (thiazole-C-2); MS: m/z 412/410 (M+, 23), 332 (100),
331 (79), 255 (45), 178 (71), 156 (47), 81 (36), 77 (51). Anal.
Calcd for C19H15BrN4S: C, 55.48; H, 3.68; N, 13.62; S, 7.80.
Found: C, 55.56; H, 3.76; N, 13.56; S, 7.99.
1
2290, C═N 1615, Ar—C═C 1605, 1585 cmꢀ1; H-NMR: d 2.31
(s, 3H, CH3), 4.52 (br, 2H, allyl-CH2N), 5.03–5.15 (m,
2H, allyl-CH2═), 5.75–5.87 (m, 1H, allyl-CH═), 6.04 (s, 1H,
pyrazole-CH), 7.13 (s, 1H, thiazole-CH), 7.01–7.47 (m, 5H,
Ar—CH), 12.45 ppm (s, 1H, pyrazole-NH); 13C-NMR: d 10.59
(CH3), 44.86 (allyl-CH2N), 94.14 (pyrazole-CH), 106.11
(thiazole-CH), 117.82 (allyl-CH2═), 127.41, 128.02, 129.21
(Ar—CH), 135.91 (allyl-CH═), 136.11 (Ar—C), 140.06
(thiazole-C-4), 141.13 (pyrazole-C-3), 149.06 (pyrazole-C-5),
162.98 ppm (thiazole-C-2); MS: m/z 296 (M+, 24), 296 (24),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

616
A. A. Hassan, Y. R. Ibrahim, A. A. Aly, E. M. El-Sheref, and A. B. Brown
Vol 51
Scheme 7. Rationalize for the formation of thiazolylidenepyrazolamines
9a–i.
(thiazole-CH), 117.86 (allyl-CH2═), 128.12, 129.33 (Ar—CH),
135.86 (allyl-CH═), 131.23, 136.02 (Ar—C), 139.51 (thiazole-
C-4), 140.02 (pyrazole-C-3), 148.88 (pyrazole-C-5), 162.98 ppm
(thiazole-C-2); MS: m/z 376/374 (M+, 24), 332 (43), 255 (25),
178 (75), 154 (66), 81 (87), 77 (100). Anal. Calcd for
C16H15BrN4S: C, 51.21; H, 4.03; N, 14.93; S, 8.54. Found: C,
51.38; H, 4.19; N, 15.01; S, 8.43.
H3C
O
S
N
Br
R
+
N
H
N
H
N
H
(Z)-N-[4-(biphenyl-4-yl)-3-phenylthiazol-2(3H)-ylidene]-3-
methyl-1H-pyrazol-5-amine (9g). This compound was obtained
as colorless crystals (280 mg, 69%), mp 316–318ꢁC; IR: NH
EtOH
reflux
8a-c
R'
5a,c,d
1
3290, Ar—H 3100, C═N 1620, Ar—C═C 1600cmꢀ1; H-NMR
R'
and 13C-NMR (see Tables 1 and 2); MS: m/z 408 (M+, 20), 331
(23), 254 (56), 251 (61), 178 (46), 81 (41), 77 (100). Anal. Calcd
for C25H20N4S: C, 73.50; H, 4.93; N, 13.71; S, 7.85. Found: C,
73.39; H, 5.11; N, 13.66; S, 7.81.
H3C
N
R
O
S
NH
Br
(Z)-N-[3-Benzyl-4-(biphenyl-4-yl)thiazol-2(3H)-ylidene]-3-
N
H
N
methyl-1H-pyrazol-5-amine (9h).
This compound was
H
B
obtained as colorless crystals (270 mg, 64%), mp 340–
342ꢁC; IR: NH 3285, C═N 1615, Ar—C═C 1600,
1585 cmꢀ1 1H-NMR: d 2.23 (s, 3H, CH3), 5.56 (s, 2H,
;
R
N
CH2), 6.01 (s, 1H, pyrazole-CH), 7.22 (s, 1H, thiazole-CH),
R'
OH
7.21–7.46 (m, 14H, Ar—CH), 12.38 ppm (s, 1H, pyrazole-
H
Br
NH); 13C-NMR:
d 10.62 (CH3), 42.51 (CH2), 94.08
N
(pyrazole-CH), 106.29 (thiazole-CH), 126.22, 126.54,
127.28, 128.26, 128.41, 128.82, 129.43, 129.87 (Ar—CH),
130.23, 135.18 136.13 (Ar—C), 140.04 (thiazole-C-4),
141.28 (pyrazole-C-3), 149.04 (pyrazole-C-5), 163.33 ppm
(thiazole-C-2); MS: m/z 422 (M+, 75), 331 (22), 254 (23),
178 (56), 91 (16), 81 (100), 77 (78). Anal. Calcd for
C26H22N4S: C, 73.90; H, 5.25; N, 13.26; S, 7.59. Found:
C, 74.06; H, 5.11; N, 13.38; S, 7.67.
S
H3C
NH
N
21
i) - H2O
ii) - HBr
R
R'
N
N
(Z)-N-[3-Allyl-4-(biphenyl-4-yl)thiazol-2(3H)-ylidene]-3-
methyl-1H-pyrazol-5-amine (9i).
obtained as colorless crystals (220 mg, 59%), mp 280–282ꢁC;
IR: NH 3285, C═N 1620, Ar—C═C 1600, 1585 cmꢀ1 1H-
This compound was
S
H3C
NH
N
;
9a-i
NMR: d 2.26 (s, 3H, CH3), 4.51 (br, 2H, allyl-CH2N), 5.01–
5.18 (m, 2H, allyl-CH2═), 5.65–5.77 (m, 1H, allyl-CH═), 6.06
(s, 1H, pyrazole-CH), 7.20 (s, 1H, thiazole-CH), 7.11–7.57
(m, 9H, Ar—CH), 12.26 ppm (s, 1H, pyrazole-NH); 13C-NMR:
d 10.66 (CH3), 44.85 (allyl-CH2N), 94.44 (pyrazole-CH),
106.11 (thiazole-CH), 116.89 (allyl-CH2═), 127.44, 128.12,
129.21, 129.39, 131.46 (Ar—CH), 135.77 (allyl-CH═), 132.36,
136.11 (Ar—C), 140.11 (thiazole-C-4), 141.53 (pyrazole-C-3),
148.86 (pyrazole-C-5), 162.98 ppm (thiazole-C-2); MS: m/z
372 (M+, 33), 331 (26), 295 (48), 219 (24), 178 (100), 96 (18),
81 (52), 77 (42), 41 (23). Anal. Calcd for C22H20N4S: C,
70.94; H, 5.41; N, 15.04; S, 8.61. Found: C, 71.05; H, 5.33; N,
15.13; S, 8.46.
(Z)-N-[3-Benzyl-4-(4-bromophenyl)thiazol-2(3H)-ylidene]-
3-methyl-1H-pyrazol-5-amine (9e). This compound was
obtained as colorless crystals (240 mg, 56%), mp 289–291ꢁC; IR:
NH 3290, C═N 1615, Ar—C═C 1605, 1585 cmꢀ1 1H-NMR: d
;
2.30 (s, 3H, CH3), 5.48 (s, 2H, CH2), 6.03 (s, 1H, pyrazole-CH),
7.29 (s, 1H, thiazole-CH), 7.04–7.87 (m, 9H, Ar—CH),
12.42 ppm (s, 1H, pyrazole-NH); 13C-NMR: d 10.48 (CH3),
42.44 (CH2), 94.11 (pyrazole-CH), 106.66 (thiazole-CH),
126.25, 127.18, 128.31, 129.13, 130.77 (Ar—CH), 131.44,
135.68 (Ar—C), 140.02 (thiazole-C-4), 140.93 (pyrazole-C-3),
149.22 (pyrazole-C-5), 162.96 ppm (thiazole-C-2); MS: m/z
426/424 (M+, 33), 332 (27), 255 (56), 187 (100), 178 (25),
91 (55), 81 (23), 77 (63). Anal. Calcd for C20H17BrN4S: C,
56.48; H, 4.03; N, 13.17; S, 7.54. Found: C, 56.51; H, 4.18;
N, 13.36; S, 7.39.
Acknowledgments. Purchase of the AV-400 NMR spectrometer
was assisted by the National Science Foundation (CHE 03-42251).
(Z)-N-[3-Allyl-4-(4-bromophenyl)thiazol-2(3H)-ylidene]-3-
methyl-1H-pyrazol-5-amine (9f). This compound was obtained
as colorless crystals (200 mg, 53%), mp 250–252ꢁC; IR: NH
REFERENCES AND NOTES
3285, C═N 1620, Ar—C═C 1600 cmꢀ1 1H-NMR: d 2.22
;
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(s, 3H, CH3), 4.51 (br, 2H, allyl-CH2N), 5.11–5.16 (m, 2H,
allyl-CH2═), 5.55–5.77 (m, 1H, allyl-CH═), 6.01 (s, 1H,
pyrazole-CH), 7.15 (s, 1H, thiazole-CH), 7.22–7.44 (m, 4H,
Ar—CH), 12.27 ppm (s, 1H, pyrazole-NH); 13C-NMR: d 10.71
(CH3), 44.82 (allyl-CH2N), 94.33 (pyrazole-CH), 105.98
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of N-Substituted(Thiazol-2-ylidene)pyrazol-5-amine Derivatives
via Condensation of Pyrazolylthioureas with o-Bromoacetophenones
617
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