A ONE-POT PROCESS OF PREPARING SUBSTITUTED FLUORINATED HYDRAZINYL THIAZOLE COMPOUNDS

Abstract

ABSTRACT A ONE-POT PROCESS OF PREPARING SUBSTITUTED FLUORINATED HYDRAZINYL THIAZOLE COMPOUNDS 5 10 15 The present invention disclosure is related to a one-pot process of synthesis of substituted fluorinated hydrazinyl thiazole compounds by the green synthesis approach. The process comprises the refluxing and stirring mixture of substituted aromatic aldehyde, semi-thiocarbazide and substituted phenacyl bromides in ethanol using vitamin B1 as catalyst. The present invention disclosure related to substituted fluorinated hydrazinyl thiazole synthesis with a shorter reaction time.

Specification

Description:FIELD OF THE INVENTION
The present invention provides a one-pot process for the preparation of Fluorinated
Hydrazinyl Thiazole Compounds using Vitamin B1.
5
10
15
20
25
30
BACKGROUND OF THE INVENTION
1,3-thiazole derivatives are essential for the development and formulation of a wide
range of therapeutic agents in the pharmaceutical industry. Their inclusion in drug
molecules can improve biological activity, resulting in potent analgesic,
antibacterial, antifungal, anticancer, and anti-inflammatory properties(Gümüş,
Yakan, & Koca, 2019). The FDA has authorized a variety of medications that
contain the thiazole moiety. The agricultural sector benefits from the formulation
of effective pesticides and herbicides that are based on thiazole compounds, which
assist in the enhancement of yields and the protection of crops. As a component in
dyes, pigments, and conducting polymers, 1,3-thiazole is useful in material science
in addition to these applications. Additionally, thiazole derivatives' wide utility and
significance are underscored by their function as ligands in coordination chemistry
and as enzyme inhibitors and probes in biochemical research.
A compound with a thiazole ring and a hydrazine moiety, hydrazinyl thiazole, is an
intriguing combination of two functional groups that exhibit substantial reactivity
and adaptability. The hydrazine group (-NH-NH2) introduces additional reactivity,
allowing for various chemical transformations and interactions, while the presence
of thiazole confers unique electronic properties and stability to the molecule
(Hargrave, Hess, & Oliver, 2002; Tsuji & Ishikawa, 1994).
Hydrazinyl thiazole demonstrates a diverse array of biological and pharmacological
activities. Furthermore, hydrazinyl thiazoles are utilized in the development of
OLEDs and semiconductors, as well as chemosensors. In addition to this halogen
in combination with hydrazinyl and thiazole moieties possess versatile biological
activities. Fluorine and chlorine are the most common substituents in this regard.
Fluorine has a weak ability to form halogen bonds, but its strong C-F bond
facilitates tuning of the physicochemical properties and molecular conformations
of the drug leads. These properties include the change in pKa of neighbouring
3
functionalities, lipophilicity, enhanced membrane permeability, and reduced steric
effect.
Both organic and medicinal chemists are actively involved in the
development and one-pot synthesis of new synthetic procedures for substituted
fluorinated hydrazinyl thiazole as a result of these extensive applications.
5
10
15
20
25
30
There are various patent and non-patent literature that disclosed the synthesis of
substituted hydrazinyl thiazole compounds.
Hasnain Mehmood et al in ACS Omega 2023, 8, 11433−11446 disclosed
fluorophenyl-based thiazoles were synthesized following the Hanztsch method
under reflux in ethanol for 4-5 h.
Sobhi M. Gomha et al in green chemistry letters and reviews, 2024, Vol. 17, Issue.
1, 2380746 disclosed the green synthesis of hydrazono-thiazolones using vitamin
B1 under thermal heating for 3 hr. The prior art does not disclose a one-pot synthesis
of substituted hydrazinyl thiazole compounds.
Rutikesh Gurav et al in Org. Biomol. Chem., 2020,18, 4575-4582 disclosed one
pot synthesis of hydrazinyl thiazole derivatives using Rust derived Fe2O3
nanoparticles as a green catalyst.
Dattatraya G. Raut et al in Journal of Sulfur Chemistry, 2018, Vol 39, Issue 1 page
no 1 to 7, disclosed one pot syntheses of 2-(2-hydrazinyl) thiazole derivatives using
PEG400.
Therefore, there is felt to need for a process for the synthesis of the substituted
Fluorinated Hydrazinyl Thiazole compounds using a green chemistry approach that
utilizes the biodegradable catalyst and requires a shorter reaction time, which
mitigates the drawbacks mentioned herein above or at least provides a useful
alternative.
OBJECTIVE OF THE INVENTION
Some of the objects of the present disclosure, which at least one embodiment herein
satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the
prior art or to at least provide a useful alternative.
4
An objective of the invention is to provide a method for one-pot synthesis of
Fluorinated Hydrazinyl Thiazole Compounds using Vitamin B1 with optimized
reaction conditions.
5
10
15
20
25
Another objective of the invention is to provide for a one-pot synthesis of
Fluorinated Hydrazinyl Thiazole Compounds using Vitamin B1 with a shorter
reaction time.
Another objective of the invention is to provide an efficient method for one-pot
synthesis of Fluorinated Hydrazinyl Thiazole Compounds with high purity and
yield.
SUMMARY OF THE INVENTION
In one aspect the present invention relates to a one-pot process of preparing
substituted fluorinated Hydrazinyl Thiazole Compounds of formula (I)
comprising refluxing and stirring a mixture of substituted aromatic aldehyde
(a), semi-thiocarbazide (b) and substituted phenacyl bromides (c) in an organic
solvent at predetermined temperature using Vitamin B1 (thiamine) to obtained
the reaction mass which further poured into ice-cold water to obtained crude
product. The crude product is recrystallized using hot ethanol to obtain the
substituted fluorinated Hydrazinyl Thiazole Compounds of formula (I).
Br
O
F
F
(a)
NH2
H
S NH
(b)
A
NH2
(R1)n
(c)
O
catalyst
reflux, stirring
F
F
S
NN H
N
(I)
A
(R1)n
Characterized in that, the time required to complete the reaction is 25 to 42
minutes.
DETAILED DESCRIPTION
Embodiments are provided so as to thoroughly and fully convey the scope of the
present disclosure to the person skilled in the art. Numerous details are set forth,
relating to specific components, and methods, to provide a complete understanding
5
5
10
15
20
25
30
of embodiments of the present disclosure. It will be apparent to the person skilled
in the art that the details provided in the embodiments should not be construed to
limit the scope of the present disclosure. In some embodiments, well-known
processes, well-known apparatus structures, and well-known techniques are not
described in detail.
The terminology used, in the present disclosure, is only for the purpose of
explaining a particular embodiment and such terminology shall not be considered
to limit the scope of the present disclosure. As used in the present disclosure, the
forms "a," "an," and "the" may be intended to include the plural forms as well,
unless the context clearly suggests otherwise. The terms "comprises,"
"comprising," "including," and "having," are open-ended transitional phrases and
therefore specify the presence of stated features, integers, steps, operations,
elements, modules, units and/or components, but do not forbid the presence or
addition of one or more other features, integers, steps, operations, elements,
components, and/or groups thereof. The particular order of steps disclosed in the
method and process of the present disclosure is not to be construed as necessarily
requiring their performance as described or illustrated. It is also to be understood
that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the
present disclosure as the aforementioned terms may be only used to distinguish one
element, component, region, layer or section from another component, region, layer
or section. Terms such as first, second, third etc., when used herein do not imply a
specific sequence or order unless clearly suggested by the present disclosure.
Unless otherwise stated, the following terms used in the specification and claims
have the meanings given below.
For purposes of interpreting the specification, the following definitions will apply
and whenever appropriate, terms used in the singular will also include the plural
and vice versa.
The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.
The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely
carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one
6
5
10
15
20
25
30
to six carbon atoms, and is attached to the remainder of the molecule by a single
bond, for example (C1-C6) alkyl or (C1-C4) alkyl, representative groups include e.g.,
methyl, ethyl, n-propyl, 1-methyl ethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethyl
ethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl
groups described or claimed herein may be straight-chain or branched.
The term "alkoxy" refers to an alkyl group attached via an oxygen linkage. Non
limiting Examples of such groups include, for example (C1-C6) alkoxy, (C1-C4)
alkoxy, methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the
contrary, all alkoxy groups described or claimed herein may be straight chain or
branched.
The term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded
to an alkyl group as defined above, for example (C1-C6) alkoxy-(C1-C6) alkyl, (C1
C4) alkoxy-(C1-C4) alkyl, -CH2-O-CH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3 and the
like.
The term "hydroxyalkyl" refers to an alkyl group, as defined above that is
substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is
monohydroxyalkyl or dihydroxyalkyl. Non-limiting examples of hydroxyalkyl
include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and the like.
The term "haloalkyl" refers to an alkyl group as defined above that is substituted by
one or more halogen atoms as defined above. For example (C1-C6) haloalkyl or (C1
C4) haloalkyl. Suitably, the haloalkyl may be monohaloalkyl, dihaloalkyl or
polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine,
bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be
substituted with two or more of the same halogen atoms or a combination of
different halogen atoms. Suitably, a polyhaloalkyl is substituted with up to 12
halogen atoms. Non-limiting Examples of a haloalkyl include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A per
haloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms.
7
Unless set forth or recited to the contrary, all haloalkyl groups described or claimed
herein may be straight chain or branched.
5
10
15
20
25
30
Unless otherwise specified, the term "substituted" as used herein refers to a group
or moiety having one or more substituents attached to the structural skeleton of the
group or moiety; such substituents include, but are not limited to hydroxy, halogen,
carboxyl, cyano, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy (C2-C6)
alkenyl, (C2-C6) alkynyl, aryl, aryl (C1-C6) alkyl, (C3-C7) cycloalkyl, heteroaryl,
heterocyclic ring, heterocyclyl (C1-C6) alkyl, heteroaryl (C1-C6) alkyl, -C(O)ORx,
C(O)Rx, -C(S)RX, -C(O)NRxRy, -NRxC(O)NRyRz, -NRxRy, -NRxC(O)Ry, -
S(O)2NRxRy, -ORx, -OC(O)Rx, -OC(O)NRxRy, RxC(O)Ry, -SRX, and -S(O)2Rx;
wherein each occurrence of Rx, Ry and Rz are independently selected from
hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C3-C7) cycloalkyl and aryl.
It is to be understood that the aforementioned "substituted" groups cannot be further
substituted. For example, when the substituent on "substituted alkyl" is "aryl" or
"alkenyl", the aryl or alkenyl cannot be substituted aryl or substituted alkenyl
respectively.
The compounds of the present invention may have one or more chiral centers. The
absolute stereochemistry at each chiral center may be 'R' or 'S'. The compounds of
the invention include all diastereomers and enantiomers and mixtures thereof.
Unless specifically mentioned otherwise, reference to one stereoisomer applies to
any of the possible stereoisomers. Whenever the stereoisomeric composition is
unspecified, it is to be understood that all possible stereoisomers are included.
The term "stereoisomer" refers to a compound made up of the same atoms bonded
by the same bonds but having different three-dimensional structures which are not
interchangeable. The three-dimensional structures are called configurations. As
used herein, the term "enantiomer" refers to two stereoisomers whose molecules are
non-super imposable mirror images of one another. The term "chiral center" refers
to a carbon atom to which four different groups are attached. As used herein, the
term "diastereomers" refers to stereoisomers which are not enantiomers. The terms
"racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers.
8
5
10
15
20
A "tautomer" refers to a compound that undergoes rapid proton shifts from one atom
of the compound to another atom of the compound. Some of the compounds
described herein may exist as tautomers with different points of attachment of
hydrogen. The individual tautomers as well as mixture thereof are encompassed
with compounds of Formula (I).
The present invention describes a one-pot process of preparation of fluorinated
hydrazinyl thiazole compounds and pharmaceutically acceptable salts thereof
wherein in the process the fluorinated hydrazinyl thiazole compounds utilize a
green synthesis approach using a biodegradable catalyst.
In one embodiment, a one-pot process of preparing substituted fluorinated
Hydrazinyl Thiazole Compounds (I) comprising:
F
F
S
N
N
N
A (R1)n
H
(I)
Refluxing and stirring a mixture of substituted aromatic aldehyde (a), semi
thiocarbazide (b) and substituted phenacyl bromides (c) in an organic solvent
at a predetermined temperature using Vitamin B1 (thiamine) to obtain the
reaction mass which further poured into ice-cold water to obtained crude
product. The crude product is recrystallized using hot ethanol to obtain the
substituted fluorinated Hydrazinyl Thiazole Compounds of formula (I):
Br
O
F
F
(a)
NH2
H
S NH
(b)
A
NH2
(R1)n
(c)
O
catalyst
reflux, stirring
F
F
NN H
S
N
A
(I)
(R1)n
wherein ring A is phenyl or naphthyl; R1 is halogen, nitro, hydroxy, substituted
and unsubstituted (C1-C3) alkyl, substituted and unsubstituted (C1-C3)
haloalkyl, substituted and unsubstituted (C1-C3) alkoxy, substituted and
unsubstituted (C1-C3) haloalkoxy, phenyl, 'n' is integer ranging from 0 to 3,
both inclusive.
9
In another embodiment, a one-pot process of preparing substituted fluorinated
Hydrazinyl Thiazole Compounds, wherein the time required to complete the
reaction is 25 to 42 minutes.
In another embodiment, a one-pot process of preparing substituted fluorinated
5
10
15
20
25
30
Hydrazinyl Thiazole Compounds, wherein substituted aromatic aldehyde,
semi-thiocarbazide and substituted phenacyl bromides are present in the molar
ratio 1:1:1.
In another embodiment, a one-pot process of preparing substituted fluorinated
hydrazinyl thiazole compounds, wherein the quantity of Vitamin B1 is 10 molar
equivalents.
In another embodiment, a one-pot process of preparing substituted fluorinated
Hydrazinyl Thiazole Compounds, wherein predetermine temperature is 75 to
79℃, more preferably 78℃.
In another embodiment, a one-pot process of preparing substituted fluorinated
hydrazinyl thiazole compounds, wherein stirring is performed for 25 to 42 minutes
In another embodiment, a one-pot process of preparing substituted fluorinated
Hydrazinyl Thiazole Compounds, wherein the organic solvent used is ethanol.
In another embodiment, a one-pot process of preparing substituted fluorinated
Hydrazinyl Thiazole Compounds, wherein the organic solvent used is ethanol
present in the range of 4 ml to 6 ml, more preferably 5 ml.
In another embodiment, a one-pot process of preparing substituted fluorinated
Hydrazinyl Thiazole Compounds, wherein the purity of compounds is 67 to
84%.
The foregoing description of the embodiments has been provided for purposes of
illustration and is not intended to limit the scope of the present disclosure.
Individual components of a particular embodiment are generally not limited to that
particular embodiment, but, are interchangeable. Such variations are not to be
regarded as a departure from the present disclosure, and all such modifications are
considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments
which are set forth for illustration purposes only and not to be construed for limiting
10
11

the scope of the disclosure. The following experiments can be scaled up to an
industrial/commercial scale and the results obtained can be extrapolated to an
industrial scale.

Examples 5
Table 1. Synthesis of Fluorinated Hydrazinyl Thiazole Compounds using Vit. B1.
Example Compounds Time
(min)
Yield
(%)
Melting
Points
(oC)
1
S
N N H
N
F F
30 80 178-180
2
S
N
F
H N
N
F F
F
F
F

28 84 176-178
3 S
N N H
N
F F
Br

35 82 198-200
4 S
N N H
N
F
F

25 83 210-212
5 S
N N H
N
F F
29 78 200-202
12

6
S
N
NH
N
F
F
NO2

36 69 220-222
7 S
N N H
N
F F
O
F
F
F

42 67 180-182
8 S
N N H
N
F F
F

40 72 218-220
9 S
N N H
N
F F
O

25 70 198-200
10 S
N N H
N
F F
F
F
F

36 73 214-216

Example 1: (Z)-2-(2-(3,5-difluoro benzylidene) hydrazinyl)-4-(p-tolyl) thiazole.
S
N N H
N
F F
A one-pot synthesis was carried out by refluxing and stirring a mixture of
5
10
15
20
25
substituted 3,5-difluoro benzaldehyde (1 mmol), semi-thiocarbazide (1 mmol),
and 4-methyl-phenacyl bromide in 5 ml ethanol at 78oC stirring then added 10
mol % of Vitamin-B1 as a catalyst. The Progress of the reaction was monitored
using TLC. After completion of the reaction mass was poured on cold water to
obtain a crude product later on product was purified by crystallization in hot
ethanol.
IR(KBr)(νmax/cm-1): 3060.21, 2912.75, 1680.94, 1578.92, 1308.82, 1115.93,
1017.45; 1H NMR (500 MHz, DMSO-d6) δ: 2.31(S, 3H), 7.20-7.26 (m, 3H),
7.29(S, 1H), 7.35 (t, 2H), 7.75 (d, 2H), 8.00(S, 1H) and 12.39 (S,1H); 13C (125
MHz, DMSO- d6) NMR δ = 20.70, 101.78, 103.28, 104.14,107.20, 108.68,
108.90, 125.37, 129.09; HRMS: Calcd. For C17H13F2N3S: 329.0798; found
330.0877[M +H] +.
Examples 2 to 10 were prepared by following a similar procedure as described
in Example 1 using 3,5-difluoro benzaldehyde (1 mmol), semi-thiocarbazide (1
mmol), and appropriate substituted phenacyl bromide.
Example 2:(Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-fluoro-3-(trifluoromethyl)
phenyl) thiazol-2-yl) hydrazine.
F
F
H
N
N
S
F
F
N
F
F
IR(KBr)(νmax/cm-1): 3088.53, 2966.38, 1613.37, 1569.29, 1303.82,1119.20,
1054.68; 1H NMR (500 MHz, DMSO- d6) δ : 7.21 (t, 1H), 7.32 (d, 2H), 7.54 (t,
1H), 7.99 (s, 1H), 8.17 (d, 2H), 12.48 (s, 1H); 13C NMR (125, MHz, DMSO-d6)
δ = 104.14, 104.34, 104.55, 105.92, 108.88, 108.93, 109.04, 109.09, 116.75,
116.90, 117.63, 117.80, 121.58, 123.75, 123.88, 123.92, 131.59, 131.62,
131.75, 131.82, 138.10, 138.18, 138.26, 138.84, 147.94, 161.66, 161.76, 163.61,
163.72, 168.30; HRMS: Calcd. For C17H9F6N3S: 401.0421; found 402.0498 [M
+H] +.
Example 3: (Z)-1-(3,5-difluorobenzylidene)-2-(4-(2-bromophenyl) thiazol-2
yl) hydrazine.
13
S
Br
N N H
N
F
5
F
IR(KBr)(νmax/cm-1): 3045.93, 2880.71, 1582.40, 1304.21, 1114.89, 1015.23,
665.97; 1H NMR (500 MHz, DMSO-d6) δ: 7.22-7.26 (m, 1H), 7.35-7.40 (m,
3H), 7.49 (s, 1H), 7.50-7.53 (m, 1H), 7.86 (t, 1H), 8.02-8.05 (m, 1H), 8.04 (s,
1H), 12.52 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 92.91, 104.12,
104.33,104.54, 105.88, 108.87, 108.92, 109.03, 109.09, 109.30, 121.61,
122.14, 124.43, 126.61, 128.17,130.23, 130.38, 130.59, 130.85, 130.99,
135.66, 136.77, 138.15, 138.23, 138.31, 138.75, 138.78,138.81, 139.86,
146.01, 148.84, 161.67, 161.78, 163.63, 163.73, 166.91, 168.07; HRMS:
10
15
20
Calcd. For C16H10BrF2N3S: 392.9747; found 393.9819 [M+H] + & 395.9800
[M+2] +
Example 4: (Z)-1-(3,5-difluorobenzylidene)-2-(4-(naphthalen-2-yl) thiazol-2
yl) hydrazine.
S
N N H
N
F
F
IR(KBr)(νmax/cm-1): 3050.90, 2883.82, 1564.58, 1109.82, 1047.43, 1014.50;
1H NMR (500 MHz, DMSO-d6) δ: 7.22 (t, 1H), 7.35 (d, 2H), 7.36 (s, 3H), 7.51
7.90 (m 3H), 7.91-7.99 (m, 2H), 8.1-8.04 (m,1H), 8.39 (d, 1H), 12.56 (s, 1H); 13C
NMR (125, MHz, DMSO-d6) δ :104.27, 105.06, 108.85, 108.90, 109.01, 109.06,
123.93, 124.16, 125.53, 126.06, 126.46, 126.56, 126.69, 127.19, 127.57,
127.60, 127.78, 128.15, 128.19, 128.28, 131.93, 132.45, 132.49, 132.60,
133.17, 138.29, 138.69, 150.41, 161.67, 161.78, 163.63,163.73, 166.84,
168.04; HRMS: Calcd. For C20H13F2N3S; 365.0798, found 366.0870 [M +H] +.
Example 5: (Z)-4-([1,1'-biphenyl]-4-yl)-2-(2-(3,5-difluorobenzylidene)
hydrazinyl) thiazole.
14
5
S
N N H
N
F
F
IR(KBr)(νmax/cm-1): 3060.40, 2881.13, 1678.75, 1564.19, 1340.67, 1116.75,
1052.43; 1H NMR (500 MHz, DMSO-d6) δ: 7.23 (t 1H), 7.35-7.38 (m, 3H) ,
7.45 (t, 1H), 7.47 (t, 2H), 7.70-7.73 (m, 4H), 7.96 (d, 2H), 8.03 (s, 1H), 12.47
(s ,1H); 13C NMR (125 MHz, DMSO-d6) δ:104.27, 104.49, 108.83, 108.88,
109.04, 126.12, 126.49, 126.87, 127.50, 128.98, 133.67, 138.24, 138.32,
138.54, 139.14, 139.64, 161.67,161.78, 163.63, 163.74, 167.98; HRMS:
Calcd. For C22H15F2N3S; 391.0955, found 392.1020 [M +H] +.
10
15
20
Example 6: (Z)-1-(3,5-difluorobenzylidene)-2-(4-(3-nitrophenyl) thiazol-2-yl)
hydrazine.
S
N
N
NH
NO2
F
F
IR(KBr)(νmax/cm-1): 2993.43, 2813.08, 1577.45, 1309.38, 1118.88, 1015.72;
1H NMR (500MHz, DMSO-d6) δ: 7.25 (t 1H), 7.36-7.38 (m 2H), 7.71 (t 2H),
8.02 (s 1H), 8.15 (t 1H), 8.31 (d 1H), 8.67 (t 1H), 12.56 (s 1H); 13C NMR (125
MHz, DMSO-d6) δ:104.17, 104.38, 107.02, 108.90, 108.95, 109.11, 119.95,
122.10, 130.27, 131.58, 136.05, 138.15, 138.23, 138.90, 148.29, 161.65, 161.75,
163.60, 163.71, 168.29; HRMS: Calcd. For C16H10F2N4O2S; 360.0493, found
361.0567 [M +H] +.
Example 7: (Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-(trifluoromethoxy)
phenyl) thiazol-2-yl) hydrazine.
15
S
O
F
F
F
N N H
N
F
IR(KBr)(νmax/cm-1):3060.35,
5
2843.99,
1566.69,
F
1310.86,
1250.02,
1107.90,1044.86; 1H NMR (500 MHz, DMSO-d6) δ: 7.23-7.26 (m, 1H), 7.35
7.37 (m, 2H), 7.40-7.42 (m, 2H), 7.47 (s, 1H), 7.96-7.99 (m, 2H), 8.02 (s, 1H),
12.48 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 104.55, 104.76, 104,97, 105.81,
109.30, 109.35, 109.46, 109.51, 119.56, 121.60, 121.79, 127.75, 134.30,
138.63, 138.71, 138.78, 139.11, 148.06, 149.70, 162.12, 162.23, 164.08,
164.18, 168.60; HRMS: Calcd. For C17H10F5N3OS; 399.0465, found 400.0544 [M
+H] +.
10
15
20
Example 8: (Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-fluorophenyl) thiazol-2
yl) hydrazine.
S
N
F
N N H
F
F
IR(KBr)(νmax/cm-1): 3048.62, 2851.32, 1553.84, 1306.56, 1114.60, 1053.74;
1H NMR (500 MHz, DMSO-d6) δ: 7.23 (t 3H), 7.35 (d 3H), 7.88 (q 2H), 8.01
(s 1H), 12.43 (s 1H); 13C NMR(125-MHz, DMSOd6) δ: 104.01, 104.05,
104.26, 104.47, 108.81, 108.86, 108.98, 109.03, 115.38, 115.55, 127.48,
127.55, 131.18, 138.28, 160.68, 161.76, 162.62, 163.61, 163.72, 168.01;
HRMS: Calcd. For C16H10F3N3S; 333.0548, found 334.0622 [M +H] +.
Example 9: (Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-methoxyphenyl) thiazol
2-yl) hydrazine.
16
S
O
N N H
N
F
5
F
IR(KBr)(νmax/cm-1): 3055.16, 2833.12, 1559.01, 1296.78, 1113.12, 1021.90 ;
1H NMR(500 MHz, DMSO-d6) δ: 3.79 (s 3H), 6.98 (t 2H), 7.24 (t 2H), 7.34
7.37 (m 2H), 7.79 (t 2H), 8.01 (s 1H),12.40 (s 1H); 13C NMR (125,MHz,
DMSO-d6) δ: 55.59, 102.57, 104.46, 104.67, 104.88, 109.24, 109.29,
109.40, 109.45, 114.46, 127.33, 127.90, 138.81, 138.89, 169.31, 162.12,
162.23, 164.08, 164.19, 168.26; HRMS: Calcd. For C17H13F2N3OS; 345.0747,
found 346.0815[M +H] +.
10
15
20
Example10:(Z)-1-(3,5-difluoro benzylidene)-2-(4-(4-(trifluoromethyl) phenyl)
thiazol-2-yl) hydrazine.
S
F
F
F
N N H
N
F
F
IR(KBr)(νmax/cm-1): 3066.47, 2855.49, 1568.20, 1307.30, 1108.19, 1050.98;
1H NMR (500 MHz, DMSO d6) δ: 7.22 (t, 1H), 7.34 (d, 2H), 7.60 (s, 1H), 7.74
(d, 2H), 8.01(s, 1H) 8.04 (t, 2H), 12.49 (s, 1H); 13C NMR(125 MHz, DMSO
d6) δ:104.09,104.29,104.50,107.03,108.84,108.89,109.00, 109.05, 123.26,
125.42, 125.53, 125.57, 125.60, 125.63, 126.05, 127.50, 127.75,
138.12,138.20,138.28,138.77,149.12,161.65, 161.75, 163.60, 163.71, 168.21;
HRMS: Calcd. For C17H10F5N3S; 383.0516, found 384.0595 [M+H].
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages
including, but not limited to, the realization of a one-pot process for substituted
17
fluorinated Hydrazinyl Thiazole Compounds using vitamin B1 (Thiamine) as
the catalyst which:
➢ is a simple, reliable, reproducible, and efficient method for the synthesis
of substituted fluorinated Hydrazinyl Thiazole Compounds.
5
10
15
20
25
30
➢ Sustainable synthesis with shorter reaction time.
➢ Eco-friendly, biodegradable catalyst.
➢ Green methodology for the synthesis of substituted fluorinated
Hydrazinyl Thiazole Compounds.
➢ Industry feasible.
The embodiments herein and the various features and advantageous details thereof
are explained with reference to the non-limiting embodiments in the following
description. Descriptions of well-known components and processing techniques are
omitted so as to not unnecessarily obscure the embodiments herein. The examples
used herein are intended merely to facilitate an understanding of ways in which the
embodiments herein may be practiced and to further enable those of skill in the art
to practice the embodiments herein. Accordingly, the examples should not be
construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveals the general
nature of the embodiments herein that others can, by applying current knowledge,
readily modify and/or adapt for various applications such specific embodiments
without departing from the generic concept, and, therefore, such adaptations and
modifications should and are intended to be comprehended within the meaning and
range of equivalents of the disclosed embodiments. It is to be understood that the
phraseology or terminology employed herein is for the purpose of description and
not of limitation. Therefore, while the embodiments herein have been described in
terms of preferred embodiments, those skilled in the art will recognize that the
embodiments herein can be practiced with modification within the spirit and scope
of the embodiments as described herein.
The use of the expression "at least" or "at least one" suggests the use of one or more
elements or ingredients or quantities, as the use may be in the embodiment of the
disclosure to achieve one or more of the desired objects or results.
18
5
10
15
20
25
30
Any discussion of documents, acts, materials, devices, articles or the like that has
been included in this specification is solely for the purpose of providing a context
for the disclosure. It is not to be taken as an admission that any or all of these matters
form a part of the prior art base or were common general knowledge in the field
relevant to the disclosure as it existed anywhere before the priority date of this
application.
The numerical values mentioned for the various physical parameters, dimensions
or quantities are only approximations and it is envisaged that the values
higher/lower than the numerical values assigned to the parameters, dimensions or
quantities fall within the scope of the disclosure, unless there is a statement in the
specification specific to the contrary.
While considerable emphasis has been placed herein on the components and
component parts of the preferred embodiments, it will be appreciated that many
embodiments can be made and that many changes can be made in the preferred
embodiments without departing from the principles of the disclosure. These and
other changes in the preferred embodiment as well as other embodiments of the
disclosure will be apparent to those skilled in the art from the disclosure herein,
whereby it is to be distinctly understood that the foregoing descriptive matter is to
be interpreted merely as illustrative of the disclosure and not as a limitation. , Claims:We claim:
1. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds (I) comprising:
F
F
5
10
S
N
N
H
N
A (R1)n
(I)
Refluxing and stirring a mixture of substituted aromatic aldehyde (a),
semi-thiocarbazide (b) and substituted phenacyl bromides (c) in an
organic solvent at a predetermined temperature using Vitamin B1
(thiamine) to obtain the reaction mass which further poured into ice-cold
water to obtained crude product; The crude product is recrystallized
using hot ethanol to obtain the substituted fluorinated Hydrazinyl
Thiazole Compounds of formula (I).
Br
O
F
F
NH2
H
S NH
A
O
catalyst
reflux, stirring
F
F
NH2
(R1)n
S
NN H
N
A
(a)
(b)
(c)
(I)
Characterized in that, the time required to complete the reaction is 25 to
42 minutes;
15
20
wherein ring A is phenyl or naphthyl; R1 is halogen, nitro, hydroxy,
substituted
and unsubstituted (C1-C3) alkyl, substituted and
unsubstituted (C1-C3) haloalkyl, substituted and unsubstituted (C1-C3)
alkoxy, substituted and unsubstituted (C1-C3) haloalkoxy and phenyl, 'n'
is integer ranging from 0 to 3, both inclusive.
2. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds as claimed in claim 1, wherein substituted
aromatic aldehyde, semi-thiocarbazide, and substituted phenacyl
bromides are present in the molar ratio 1:1:1.
(R1)n
20
3. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds as claimed in claim 1, wherein the quantity of
Vitamin B1 is 10 molar equivalents.
5
10
15
20
25
30
4. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds as claimed in claim 1, wherein predetermine
temperature is 75 to 79℃.
5. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds as claimed in claim 1, wherein stirring is
performed for 25 to 42 minutes.
6. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds as claimed in claim 1, wherein the organic solvent
used is ethanol.
7. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds as claimed in claim 1, wherein the organic solvent
used is ethanol present in the range of 4 ml to 6 ml.
8. A one-pot process of preparing substituted fluorinated Hydrazinyl
Thiazole Compounds as claimed in claim 1, wherein compounds are
selected from
(Z)-2-(2-(3,5-difluoro benzylidene) hydrazinyl)-4-(p-tolyl) thiazole;
(Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-fluoro-3 (trifluoromethyl)
phenyl) thiazol-2-yl) hydrazine;
(Z)-1-(3,5-difluorobenzylidene)-2-(4-(2-bromophenyl) thiazol-2-yl)
hydrazine;
(Z)-1-(3,5-difluorobenzylidene)-2-(4-(naphthalen-2-yl) thiazol-2-yl)
hydrazine;
(Z)-4-([1,1'-biphenyl]-4-yl)-2-(2-(3,5-difluorobenzylidene) hydrazinyl)
thiazole;
(Z)-1-(3,5-difluorobenzylidene)-2-(4-(3-nitrophenyl) thiazol-2-yl)
hydrazine;
(Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-(trifluoromethoxy) phenyl)
thiazol-2-yl) hydrazine;
21
22

(Z)-1-(3,5-difluoro benzylidene)-2-(4-(4-fluorophenyl) thiazol-2-yl)
hydrazine; (4h)
(Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-methoxyphenyl) thiazol-2-yl)
hydrazine; and
(Z)-1-(3,5-difluorobenzylidene)-2-(4-(4-(trifluoromethyl) phenyl) 5
thiazol-2-yl) hydrazine;
Or pharmaceutically acceptable salts thereof.

Documents