One-pot four-component synthesis of 4-hydrazinothiazoles: Novel scaffolds for drug discovery

Article abstract of DOI:10.1016/j.tetlet.2014.08.033

One pot ring synthesis of novel 4-hydrazinothiazoles through sequential four-component route employing carbonyl compounds, aminoguanidine, isothiocyanates, and α-haloketones was accomplished under mild reaction conditions. Base-assisted eliminative aromatization in the [4+1] ring synthesis shed light on interesting leaving group propensities of amine versus hydrazine resulting in the exclusive formation of the title compounds with immense potential as scaffolds for drug discovery. Hydrazone deprotection was effected by acylation which subsequently provided a new set of diacylated molecular systems with a wider scope as chemical handles in the design of thiazolyl drug candidates.

Full text of DOI:10.1016/j.tetlet.2014.08.033

Accepted Manuscript
One-pot four-component synthesis of 4-hydrazinothiazoles: novel scaffolds for
drug discovery
Sarah Titus, Kumaran G. Sreejalekshmi
PII:
S0040-4039(14)01354-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.033
TETL 45000
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 May 2014
8 August 2014
9 August 2014
Please cite this article as: Titus, S., Sreejalekshmi, K.G., One-pot four-component synthesis of 4-hydrazinothiazoles:
novel scaffolds for drug discovery, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.033
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of 4-hydrazinothiazoles: novel scaffolds for drug discovery
Sarah Titus and Kumaran G. Sreejalekshmi*
NH
H NHN NH HNO
2
2
3
Cl
O
1
O
3
Cl
O
R
3
S
NHR
N
S
4
1
2
4
R
R
R
R
Cl
N
R
2
N
6
O
O
NHN
5
DMSO, base, r.t.
HNHN
O
2
R
1
3
R NCS
3
O
Cl
Br
4
R
4

1
Tetrahedron Letters
journal homepage: www.els evier.com
One-pot four-component synthesis of 4-hydrazinothiazoles: novel scaffolds for drug
discovery
Sarah Titusaand Kumaran G. Sreejalekshmia*
aDepartment of Chemistry, Indian Institute of Space Science and Technology, Valiamala Post - 695 547 Thiruvananthapuram, India
ARTICLE INFO
ABSTRACT
Article history:
Received
One pot ring synthesis of novel 4-hydrazinothiazoles through sequential four-component route
employing carbonyl compounds, aminoguanidine, isothiocyanates and α-haloketones was
accomplished under mild reaction conditions. Base-assisted eliminative aromatization in the
[4+1] ring synthesis shed light into interesting leaving group propensities of amine versus
hydrazine resulting in the exclusive formation of the title compounds with immense potential as
scaffolds for drug discovery. Hydrazone deprotection was effected by acylation which
subsequently provided new set of diacylated molecular systems with wider scope as chemical
handles in the design of thiazolyl drug candidates.
Received in revised form
Accepted
Available online
Keywords:
Multicomponent reaction;
Ring synthesis;
Eliminative aromatization;
Drug discovery;
Hydrazone libraries are currently gaining significance as
potential drug discovery portal1 and for dynamic combinatorial
libraries (DCLs)2 based on reversibility of hydrazone
formations.3The functional diversity encompassed by the
azomethine group elaborate the applicability of hydrazones in
various fields including supramolecular chemistry,4 organic
frameworks,5 hole-transporting materials6 and dyes7 among other
applications. Our continued search for novel heterocyclic systems
with promising bioactivities,8 especially members of thiazole
family, coupled with our interest in the development of
combinatorial routes to access these systems9 motivated us to
design novel thiazole derivatives incorporating hydrazone
substituent as potential lead molecules for drug discovery. We
earlier reported on a plethora of C-N-C-S precursors, in solution
phase,9a,10 or anchored to solid support9b suitable for the [4+1]
ring synthesis of substituted thiazoles. We were further motivated
by the fact that despite numerous reports on the synthesis11a and
wide spectrum of bioactivities exhibited by 2-hydrazinothiazoles
A,11b,12 their regioisomersviz; 4-hydrazinothiazoles B (Figure 1)
have barely received mention in the literature. Thus it was of
interest to design a synthetic route to these hitherto unreported
molecular systems possessing a thiazole core with diverse
substituents.
R
S
N
R
R1
S
N
NHN
R2
NHN
R3
R3
R1
R2
B
A
Figure 1. 2-Hydrazinothiazole A is reported widely in literature
whereas 4-hydrazinothiazole B is hitherto unreported.
The versatility of the synthesis opens immense possibilities to
explore reversibility of hydrazone formation for DCL by the
judicious choice of carbonyl component.3b During our several
trials for assessing the dynamicity of hydrazono linkage, we
isolated yet another set of novel biacylated 4-hydrazinothiazoles
and the results of the preliminary investigations are also
discussed.
Following a retrosynthetic analysis (Scheme 1), we envisaged
access to the title compounds through [4+1] ring synthesis
similar to one we reported for 2,4-diaminothiazoles13 by
employing thiocarbamoylguanidines
G
as the C-N-C-S
precursors. The access to G would require a sequential approach,
if performed in a one-pot manner, owing to the binucleophilicity
of aminoguanidine and we have previously reported on an
optimized synthetic route.10 However, unsymmetric substitution
at the amidino carbon which suffers nucleophilic attack by the
carbanion generated at active methylene carbon from α-
haloketones during thiazole ring formation spawned further
curiosity in studying hitherto unexplored cyclization pattern in
these C-N-C-S systems.
In this letter, we report a high-yielding, versatile and simple
one pot method for the rapid synthesis of 4-hydrazinothiazoles B
from carbonyl compounds, aminoguanidine, isothiocyanates and
α-haloketones. It is noteworthy that our protocol allows diversity
multiplication by varying carbonyl compounds, isothiocyanates
and α-haloketones.

2
Tetrahedron Letters
followed by condensation of isothiocyanate 3 and finally base
R3
N
R4
catalyzed cyclization with α-haloketones4 afforded densely
substituted 4-hydrazinothiazoles 5, by elimination of ammonia,
as the sole product (Scheme 2).15 The versatility of the one-pot
protocol was established by synthesizing compounds 5a-g (Table
1) in excellent yield16and were completely characterized.17
R1
R2
H
S
N
NHR3
+
H
N
O
N
O
N
Br
R4
NH2 S
H N
N
G
R1
R2
Table 1. Novel 4-hydrazinothiazole derivatives 5a-gaccessed
via Scheme 2
R1
R2
H
N
R1
R2
R3
R4
Yield(%)a
+
R3NCS
NH2
NH
N
Entry
5a
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-Cl C6H4
4-NO2 C6H4
4-OCH3C6H4
4-OCH3C6H4
4-Cl C6H4
C6H5
94
75
92
85
95
95
95
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
5b
5c
R1
H
N
NH2
NH
O
H2N
+
R2
5d
5e
Scheme 1. Retrosynthesis of 4-hydrazinothiazoles through [4+1]
ring synthesis route.
-(CH2)5-
-(CH2)5-
C6H5
5f
The ring closure step is followed by eliminative aromatization
leading to a thiazole derivative bearing a substituent at the 4th
position of the ring, which largely is decided by the leaving
group propensities of the competing species. In a hypothetical
5g
H
C6H5
aIsolated yield when the reaction was conducted in DMSO at r.t.
We employed acetone, 2-butanone, cyclohexanone and
benzaldehye as carbonyl compounds in the optimized reaction
conducted preferably in dipolar aprotic solvents like DMF or
DMSO. The chemical diversity in the second and fifth positions
of the thiazole ring was achieved by employing phenyl and
substituted phenyl isothiocyanates as well as α-haloketones
respectively. Simple work-up afforded 5a-g as solid products
which were purified by recrystallization. It is worth mentioning
that our protocol encompasses vast scope for diversity
multiplication by varying carbonyl compounds, isothiocyanates
and α-haloketones all of which are commercially available with
varied substituents.
scenario (Figure 2),
a plausible competition during the
aromatization step may expel hydrazone (Path I) or ammonia
(Path II) affording well known 2,4-diaminothiazoles9,13 in the
former case whereas latter would result in novel 4-
hydrazinothiazoles 5.
O
H
R4
S
Path I
1
2
NHR3
Path II
E
R R NNH
2
NHN
R2
N
NH2
R1
Having achieved efficient ring synthesis of novel 4-
hydrazinothiazoles bearing a terminal hydrazone bond, we were
excited to explore further applications17 of these hydrazone
systems. Owing to the significance of dynamicity of the
hydrazono linkage2f-h,18 in DCL, we felt worth exploring
reversibilites of hydrazone formations in our new molecular
systems. The hydrazone linkage survived mild acid hydrolysis as
well as exchange reaction with aminoguanidine salts and the
starting compounds were recovered almost unreacted under our
experimental conditions. This was quite expected and in
agreement with the literature reports3b since electron withdrawing
groups in the hydrazine nitrogen plays a key role in reversing the
hydrazone formation equilibrium. We are further expanding our
studies to impart structural features promoting the reversibility of
E
NH
3
Figure 2. Plausible eliminations in the aromatization step.
We were curious about the cyclization pattern in these C-N-C-
S precursors and in line with our interest in developing protocols
for combinatorial library generation, planned for a one-pot
procedure, notwithstanding the possibilities of ending up with
mixture of products from competitive elimination. The scenario
may further prove intricate since a possible configurational
switching owing to the hydrazone bond can lead to E/Z isomers14
in 5.
R1
O
NH
NHN
NH
NHNH2.HNO3
R1
R2
R2
hydrazone formation and results will be reported summarily
.
2
H2N
H2N
Prompted by the interesting results on hydrazone bond
stability, we next decided to probe the relative reactivities of
nucleophilic centres in our title compounds. To this end, we
performed acylations (Scheme 3) with chloroacetyl chloride in
the presence of Et3N19 in CH3CN under reflux conditions. After
several trials, we accomplished deprotection of hydrazono
substituent when 5, chloroacetyl chloride and Et3N were reacted
in 1:2:1 ratio in refluxing CH3CN for 30 min where upon the
starting material was completely consumed and we isolated
another class of novel thiazole derivatives 6 as the major product.
1
DMSO, Base
R3NCS
S
NH2
NHN
R1
R2
3
R3HN
O
N
G
O
R4
Br
R4
4
S
HN
N
NHR3
O
N
O
Et3N
O
S
N
R4
R1
Cl
(2equiv.)
Et N (1 equiv.)
S
N
R4
R3
Cl
NHR3
N
R2
5a-g
HN
N
HN
HN
O
3
Scheme 2. Sequential multicomponent route to afford 4-
hydrazinothiazoles 5a-g
Cl
CH CN, reflux, 30 min.
3
O
R2
R1
6
5
Cl
To our great excitement, the optimized sequential four-

3
evaluate applications as chemical handles in drug development
and in the design and development of thiazolyl azapeptides.
In summary, we have developed an efficient one-pot four-
component ring synthesis method to access highly substituted
novel 4-hydrazinothiazoles with potential applications in drug
development. The [4+1] ring synthesis revealed interesting
Scheme 3. Deprotection of 5 following acylation to afford 6
Table 2. Diacylated 4-hydrazinothiazole derivatives 6a-c
accessed via Scheme 3
leaving group propensities of hydrazine vs amine in
a
competitive eliminative aromatization. Acylation employing
chloroacetyl chloride facilitated deprotection of hydrazono
linkage and subsequently provided yet another set of novel
diacylated molecular systems bearing the thiazole core which
may have a wider scope in the design of thiazolyl drugs and
azapeptide analogues.
Entry
R3
R4
Yield(%)
6a
C6H5
C6H5
C6H5
4-Cl C6H4
4-OCH3C6H4
C6H5
70
65
82
6b
6c
Supplementary Information
Subsequently we could establish the generality of the protocol
by using differently substituted 5 to isolate products 6a-c(Table
2) bearing two chloroacetyl substituents, one on terminal
hydrazine N and the other on mono substituted amino N at the
second position of the thiazole ring. These novel diacylated
molecular systems are currently under active investigation to
Detailed experimental procedures, characterization data of
new compounds and copies of 1H and 13CNMR spectra are
available as supporting information.
9. (a) Sreejalekshmi, K. G.;Rajasekharan, K. N. Tet.Lett.2012, 53,
3627.(b) Sreejalekshmi, K. G.; Devi, S. K. C.;Rajasekharan, K. N.
Tet.Lett.2006, 47, 6179.
.
Acknowledgments
10. Sreejalekshmi, K. G. Phosphorus, Sulfur Silicon Relat.
Elem.2010, 185, 1830.
We thank IISER,NIIST(Thiruvananthapuram), IIT-M and IIT-
B for recording spectra (NMR and MS). Research support from
IIST in the form of doctoral research fellowship for ST is highly
acknowledged.
11. (a) Manivel,P.; Khan, F. N.Phosphorus, Sulfur Silicon Relat.
Elem.2009, 184, 2910.(b) Holla, B. S.; Malini, K. V.;Rao, B. S.;
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