3628
K. G. Sreejalekshmi, K. N. Rajasekharan / Tetrahedron Letters 53 (2012) 3627–3629
NH
HN
O2NHN
R1
O
NH
S
RN
C S
N
Br
R1
O2NHN
NH2
O2NHN
NH
3 b
(not isolated)
NHR
DMSO,NaOH
40 min. - 1h.
NHR
S
O
HN
H2N
H2N
N
Et3N
10-30 min.
O2NHN
N
O2NHN
N
R1
R1
R1
O
NHR
NHR
NHR
S
5
S
S
O
H
O
Scheme 2. One pot synthesis of 2,4-diaminothiazoles.
attention owing to their tubulin binding ability3a as well as cyclin
dependent kinase (CDK) inhibitory activity.3b,4 Thus the situation
demands for simplified chemistry and facile one-pot protocols5
amenable to combinatorial synthesis of diversely substituted 2,
4-diaminothiazoles which will generate libraries for structure–
activity relationship (SAR) and clinical studies. The ring synthesis
of 2,4-diaminothiazoles has received only scarce mention in the
literature6–8 (Scheme 1) and there is a further scope to improve
upon the current methods. Interestingly, all the reported methods
make use of the reaction between thiourea derivatives and an
active methylene compound for thiazole ring construction.
In Gewald method, cyanothioureas 1 accessed from cyanamide
and isothiocyanates are utilized as four atom donor precursors. In
their three-component strategy, Masquelin and Obrecht obtained
thioureidothioureas 2, as the condensation product of thiouronium
salts and isothiocyanate. Rajasekharan’s group, developed syn-
thetic routes to diverse thioureas such as amidinothioureas8 3a,
nitroamidinothioureas9 3b, and N-arylthiocarbamoylamidinopy-
razoles10 4. These thioureas are found to undergo base catalyzed
Table 1
4-Amino-2-alkyl/arylamino-5-aroyl/heteroylthiazoles (5a–l)
Product 5
R
R1
Yielda (%)
90
a
CH3
Cl
b
c
d
e
f
89
89
85
90
89
Cl
Cl
CH3
CH3
CH3
Cl
g*
h
90
91
CH3
CH3
cyclizations with
a-haloketones to afford 2,4-diaminothiazoles 5
H
N
in [4+1] thiazole ring construction protocol. Gewald method fol-
lows Thorpe cyclization pathway whereas thioureidothioureas 2
eliminate thiomethyl ketones during cyclization. Reactions of 3
ib
75
83
and 4 with
a-haloketones are found to follow the SN1 pathway
H
N
leading to 5 by the elimination of R2NH and 1-amidinopyrazole,
respectively. We have also reported on a solid phase traceless
method11 which can be adapted to a combinatorial method to ac-
cess these compounds.
However, during our synthetic expeditions to variously substi-
tuted aminothiazoles,12 we have continuously refined the existing
synthetic routes and have now discovered a simple and high yield-
ing route to 4-amino-2-alkyl/arylamino-5-aroyl/heteroylthiazoles.
In this letter, a new one-pot procedure for the fast and convenient
synthesis of 5 is described. The reactions were carried out at room
temperature using commercially available reagents to afford prod-
ucts in very good yield.
j
C2H5
Cl
k
l
90
82
O
O
O
O
a
Yield of pure product.
b
This product was obtained in only 78% yield whereas all others were obtained
in >85% yield (crude).
NMR data available in Ref. 13.
*
The proposed sequential three-component route employs nitro-
guanidine, isothiocyanates, and
a-haloketones in a condensation
followed by base catalyzed cyclization to afford 2,4-diaminothiaz-
oles (Scheme 2). Of the various solvents tried, DMSO was found to
be most suited, whereas DMF was the next preferred solvent. The
optimized reaction, when carried out in DMSO was found to be
complete (monitored by TLC) in 90 min to afford 2,4-diaminothiaz-
oles as the sole product in yield >85% except for compound 5i for
which we obtained 78% yield.
conditions, product yield, and purity. In a typical example, nitro-
guanidine was stirred in DMSO containing an equiv sodium
hydroxide to which an equimolar quantity of phenyl isothiocya-
nate was added and stirred. After further reaction, phenacyl
bromide was added followed by Et3N. Addition of Et3N catalyzes
the reaction as well as quenches the HBr evolved. After a total
reaction period of 1 h, work-up gave 4-amino-5-benzoyl-2-phe-
nylaminothiazole (5a) in 92% crude yield which after simple
crystallization from a 1:1 mixture of methanol and benzene
appeared as yellow shining crystals. Following a general proce-
dure 12 diverse compounds (5a–l) were synthesized (Table 1)
and characterized.14
During the optimization steps, we have isolated the condensa-
tion product of nitroguanidine and isothiocyanate and identified it
as nitroamidinothiourea9 which on the addition of
a-haloketone
underwent base catalyzed ring closure to 2,4-diaminothiazoles
in an SN1 pathway. The new one pot procedure is a tremendous
improvement over the existing methods in terms of reaction
Sreejalekshmi, Kumaran G.
