Novel one-step method for the conversion of isothiocyanates to 2-alkyl(aryl)aminothiazoles

Article abstract of DOI:10.1016/j.tet.2008.09.074

2-Aminothiazole derivatives are widely used structural motifs in medicinal chemistry due to their broad application in drug development. Herein we demonstrate a novel one-step method for the synthesis of 2-aminothiazole derivatives from the corresponding isothiocyanates via thiourea formation followed by cycloisomerisation in an intramolecular thia-Michael fashion. This method is very mild, simple and highly efficient and versatile enough to accommodate various amino substitutions at the C2 position of thiazoles. This methodology is equally well applicable to synthesise various 2-substituted amino-5-thiazolylmethylphosphonate derivatives.

Full text of DOI:10.1016/j.tet.2008.09.074

Tetrahedron 64 (2008) 11074–11080
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel one-step method for the conversion of isothiocyanates
to 2-alkyl(aryl)aminothiazolesq
*
Pradip K. Sasmal , A. Chandrasekhar, S. Sridhar, Javed Iqbal
Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 049, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Aminothiazole derivatives are widely used structural motifs in medicinal chemistry due to their broad
application in drug development. Herein we demonstrate a novel one-step method for the synthesis of
2-aminothiazole derivatives from the corresponding isothiocyanates via thiourea formation followed by
cycloisomerisation in an intramolecular thia-Michael fashion. This method is very mild, simple and
highly efficient and versatile enough to accommodate various amino substitutions at the C2 position of
thiazoles. This methodology is equally well applicable to synthesise various 2-substituted amino-
5-thiazolylmethylphosphonate derivatives.
Received 23 April 2008
Received in revised form
22 September 2008
Accepted 25 September 2008
Available online 7 October 2008
Keywords:
Thiazoles
Ó 2008 Elsevier Ltd. All rights reserved.
Intramolecular thia-Michael reaction
Isothiocyanates
Thiazolylmethylphosphonates
1. Introduction
has reported the synthesis of 2-aminothiazoles from a-bromo ke-
tones using the supported reagents KSCN/SiO2–RNH3OAc/Al2O3.24
Despite these procedures, novel and widely applicable methods for
the synthesis of 2-aminothiazole derivatives are still in demand.
Thiazole derivatives are the prominent players in the pharma-
ceutical research as they possess several biological properties.1–8
Besides, thiazoles are also synthetic intermediates and common
substructures in numerous biologically active natural products.
Typically, 2-aminothiazole derivatives are well known common
motifs in medicinal chemistry due to their broad application in
drug development for the treatment of allergies,9 hypertension,10
inflammation11 and bacterial infections.12 2-Aminothiazole de-
rivatives have also shown high affinity for the NPY5 (neuropeptide
Y5) receptor for the treatment of eating disorders such as obesity
and hyperphagia.13 Besides, aminothiazoles are reported to be CDK
(cyclin dependent kinase) inhibitors14 for the treatment of cancer
2. Results and discussion
Recently, we disclosed an intramolecular thia-Michael strategy25
for the synthesis of thiazole derivatives. As, for example, 1-thio-
benzoylbenzotriazole 1 was converted to thiazole derivative 3
(Scheme 1) by its treatment with ethyl 4-N,N-bis(trimethyl-
silyl)aminobut-2-ynoate 226 in the presence of MeOH in THF without
requiring any base for the final cyclisation.
When this protocol (condition A, Scheme 2) was applied to 1-
thiocarbamoylbenzotriazole 427 the expected 2-aminothiazole 6
was not obtained. After several experiments we realised that
N-desilylation of 2 using 10 equiv of MeOH in THF is very sluggish
in the presence of triethylamine (condition B), whereas unlike thio-
amide (example 3) base is required for the intramolecular cyclisa-
tion of thiourea to aminothiazole derivatives. A combination of
triethylamine and methanol as solvent could balance N-desilylation
of 2 followed by thiourea formation and cyclisation/aromatisation
to produce compound 6 from 4 in 48% yield (condition C). Treat-
ment of 4 with the HCl salt of ethyl 3-aminoprop-1-yn-1-carbox-
ylate 8a28 (Scheme 3) in the presence of Et3N in THF afforded the
desired aminothiazole derivative 6 in 81% isolated yield (condition
D). Conversion of 4 to 6 under various reaction conditions as
mentioned in Scheme 2 has been summarised in Table 1. None of
and 11b-HSD1 (11b-hydroxysteroid dehydrogenase type 1) in-
hibitors15 for the treatment of metabolic disorders. Generally,
2-aminothiazoles are prepared by the Hantzsch method16–18
(condensation of a-halo ketones with monosubstituted thioureas)
or by modified Hantzsch methodologies such as the one reported
by Ochiai’s group, which used mild reaction conditions to generate
2-aminothiazoles via the reaction of in situ generated
a-l
3-iodanyl
ketones with thioureas.19 Aminothiazoles are also prepared by the
reaction of
a-thiocyanato carbonyl compounds with aromatic or
aliphatic amine hydrochlorides.20–23 Recently, Kodomari’s group
q
DRL Publication No. 671.
* Corresponding author. Tel.: þ91 40 2304 5439; fax: þ91 40 2304 5438.
E-mail address: sasmalpk@yahoo.co.in (P.K. Sasmal).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.074

P.K. Sasmal et al. / Tetrahedron 64 (2008) 11074–11080
11075
S
R2
R2
(TMS)2N
2
i
CO2Et
S
CO2Et
Bt
H2N
Cl
Cl
(Boc)2N
MeOH/THF
a: R2 = H
9a-b
10a-b
N
Cl
1
3
b: R2 = CH2CH2Ph
ii
R2
R2
iii
CO2Et
CO2Et
11a-b
O
EtO
HCl·H2N
(Boc)2N
8a-b
O
OEt
S
Thia Michael
S
Scheme 3. Reagents and conditions: (i) (Boc)2O (2.5 equiv), DMAP (1.0 equiv), MeCN,
rt, 12 h; (ii) LDA (1.5 equiv), ethyl chloroformate (1.5 equiv), ether, ꢀ78 ꢁC (1 h) then
ꢀ30 ꢁC, 4 h; (iii) dry HCl, ether, 0 ꢁC, 5 h.
N
H
N
I
II
Cl
Scheme 1. Synthesis of thiazole 3 from 1.
these cyclisation reactions are summarised in Table 2. Amine 8b
also behaved in a similar fashion giving high yield of 2,4,5-
trisubstituted thiazole derivatives (entries 13 and 14). Both alco-
holic functionality (entry 10) and ester group (entries 3 and 14)
were well tolerated in this process.
We next investigated the application of this methodology to
synthesise various 2-substituted amino-5-thiazolylmethyl-
phosphonate derivatives from the corresponding isothiocyanates
and propynylphosphonates as these thiazole appended phos-
phonates will serve as suitable intermediates for further C–C
bond forming reactions. Towards this purpose, we made the HCl
salt of diethyl 3-aminoprop-1-ynylphosphonate (28a)36 and
diethyl 3-amino-5-phenylpent-1-ynylphosphonate (28b)36 fol-
lowing Scheme 4.
these above conditions including condition D produced compound
7 from 5.27 These results demonstrate that benzotriazole carbo-
thioamide system is converted to the thiourea derivatives not
through direct replacement of Bt group rather through the in-
termediacy of the corresponding isothiocyanate29 and in the
presence of base, formation of isothiocyanate is possible only for
compound 4, not for compound 5.
These observations encouraged us to develop a direct method
for the conversion of isothiocyanates to 2-aminothiazole de-
rivatives and in that case this protocol will be the shortest possible
route to synthesise this class of compounds.
To test our hypothesis, we initially prepared amine hydro-
chlorides 8 as summarised in Scheme 3. For the synthesis of 8a,
commercially available propargylamine (9a) was first protected
as its Di-Boc derivative 10a by the treatment with excess Boc2O
in MeCN in the presence of DMAP in 95% yield. Compound 10a
was then subjected to C-alkylation with ethyl chloroformate in
the presence of LDA as base to afford ethyl propiolate derivative
11a in 70% yield. Deprotection of N-Boc with ethereal HCl
furnished the corresponding amine salt 8a in 80% yield for sub-
sequent studies. Following a similar protocol, 5-phenylpent-1-yn-
3-amine (9b)30 was converted to the desired amine partner 8b in
45% overall yield. Both 8a and 8b can be stored for several
months in the refrigerator without exposing to moisture but,
they are highly hygroscopic and unstable in solution (H2O and
DMSO) as they are partially converted to their corresponding
vinyl chlorides by the Michael addition of internal HCl to the
propiolate system.31
Treatment of 12a with amine salt 28a led to the smooth for-
mation of the desired compound 29 in 88% yield (Table 3). The
characteristic 1H NMR signal at
d 7.07 as doublet with coupling
4
constant JHP 4.3 Hz and the 13C NMR signal at
d 25.3 as doublet
1
with coupling constant JCP 145.3 Hz confirmed the formation of
thiazolylmethylphosphonate derivative. Reaction of various iso-
thiocyanates with the amino counter parts 28a-b ended up with
good to excellent yields of the corresponding thiazolylmethyl-
phosphonate derivatives and the results are summarised in Table 3.
According to our knowledge, the synthesis of 2-substituted amino-
5-thiazolylmethylphosphonate derivatives has not been reported
in the literature.37
3. Conclusion
In conclusion, we have demonstrated a novel method for the
synthesis of 2-aminothiazole derivatives in one-step from the
corresponding isothiocyanates via thiourea formation followed by
cycloisomerisation in an intramolecular thia-Michael fashion. The
beauty of this method lies in the fact that it is very mild, simple and
highly efficient. This method may find wide application for the
laboratory-scale and combinatorial synthesis of 2,4-disubstituted
and 2,4,5-trisubstituted thiazole libraries. Especially, thiazole
appended phosphonates could be utilised as suitable intermediates
for further C–C bond forming reactions.
Initially, p-chlorophenyl isothiocyanate (12a)32 was reacted
with amine 8a in THF in the presence of triethylamine at room
temperature and according to our expectation we obtained the
corresponding product ethyl 2-(2-(4-chlorophenylamino)thiazol-
5-yl)acetate in 82% yield (entry 1, Table 2). Though, in the literature,
the synthesis of 2-amino-4-thiazolyl acetate derivatives is well
documented, synthesis of 2-amino-5-thiazolyl acetate derivatives
is poorly addressed.14,33–35 Encouraged by our experimental result,
amine 8a was reacted with various isothiocyanates and in all the
cases, reactions were smooth and the corresponding thiazole de-
rivatives were obtained in good to excellent yields. The results of
Table 1
Conversion of 4 and 5 to 6 and 7, respectively
S
Reaction condition
Yield (%)a
Conditions A/B/C/D
S
N
CO2Et
6
NRb
8
45
81
7
N
Bt
N
R
R
4: R = H
5: R = Me
A
B
C
D
NR
NR
NR
NR
6: R = H
7: R = Me
Scheme 2. Reaction conditions, A: 2 (1.5 equiv), THF, MeOH (10 equiv), rt, 24 h; B: 2
(1.5 equiv), THF, Et3N (3.0 equiv), MeOH (10 equiv), rt, 24 h; C: 2 (1.5 equiv), MeOH,
Et3N (3.0 equiv), rt, 24 h; D: 8a (1.5 equiv), THF, Et3N (3.0 equiv), rt, 12 h.
a
Isolated yield.
NR¼no reaction.
b

11076
P.K. Sasmal et al. / Tetrahedron 64 (2008) 11074–11080
R2
O
Table 2
i
Synthesis of thiazole derivatives
10a-b
P OEt
OEt
(Boc)2N
S
N
CO2Et
8a-b, Et3N,
R1 NCS
12
R1HN
13-26
27a-b
ii
THF
R2
R2
O
OEt
OEt
Entry
1
Isothiocyanate
NCS
Amine
Product (% yield)
a: R2 = H
b: R2 = CH2CH2Ph
P
HCl·H2N
Cl
Cl
28a-b
8a
13 (82)
12a
Scheme 4. Reagents and conditions: (i) LDA (1.5 equiv), diethyl chlorophosphate
(1.5 equiv), ether, ꢀ78 ꢁC, 1 h, then ꢀ30 ꢁC, 4 h; (ii) dry HCl, ether, 0 ꢁC, 5 h.
NCS
2
8a
14 (81)
are reported. Mass spectra were recorded with PE Sciex model API
3000 instrument. HRMS spectra were with Waters LCT Premier XE
(Micromass Oa-TOF) instrument. 1H NMR spectra were recorded in
CDCl3 and DMSO-d6 with either Varian Gemini 200 MHz or Varian
Mercury Plus 400 MHz instruments.13C NMR spectra were recorded
in CDCl3 and DMSO-d6 at 50 MHz with Varian Gemini 200 MHz
instrument. Signals due to the solvent (13C NMR) or residual
protonated solvent (1H NMR) served as the internal standard.
The 1H NMR chemical shifts and coupling constants were de-
termined assuming first-order behaviour. Multiplicity is in-
dicated by one or more of the following: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), br (broad); the list of
couplings constants (J) corresponds to the order of the multi-
F3C
12b
t
BuO2C
NCS
3
4
5
8a
8a
8a
15 (81)
16 (75)
17 (88)
12c
NCS
F3CO
Ph
12d
NCS
12e
6
7
8a
8a
18 (75)
19 (65)
NCS
3
plicity assignment. Unless otherwise noted, all ‘J’ refers to JHH
coupling constant. All reported compounds were homogeneous
by thin layer chromatography (TLC) and by NMR.
12f
Cl
NCS
4.2. Di-tert-butyl prop-2-ynylimidodicarbonate (10a)
12g
To a solution of propargylamine (5.0 g, 90.90 mmol) in aceto-
nitrile (50 mL) was added di-tert-butyldicarbonate (49.6 g,
227.27 mmol) followed by DMAP (11.1 g, 90.90 mmol). The reaction
mixture was stirred at room temperature for 16 h and then diluted
with ethyl acetate (300 mL). The organic layer was washed suc-
cessively with water and brine and dried over anhydrous Na2SO4.
Concentration and purification over silica gel (100–200 mesh) us-
ing 10% ethyl acetate in petroleum ether as eluent afforded 10a
(22 g, 95% yield) as an oil. Rf¼0.56 (10% ethyl acetate in petroleum
N
NCS
Cl
8
8a
20 (71)
O
12h
NCS
12i
9
8a
8a
21 (93)
22 (70)
HO
NCS
10
12j
ether); 1H NMR (400 MHz, CDCl3):
d
4.35 (d, J¼2.5 Hz, 2H), 2.18 (t,
J¼2.5 Hz, 1H), 1.53 (s, 18H); 13C NMR (50 MHz, CDCl3):
d 151.0, 82.2,
NCS
11
12
8a
8a
23 (86)
24 (72)
79.1, 70.2, 35.2, 27.4; IR (neat): 2980, 1794, 1751, 1369, 1231,
1150 cmꢀ1; MS (ES): m/z 256.1 (Mþ1); HRMS m/z found 278.1380,
calcd for C13H21NO4Na 278.1368.
12k
NCS
N
12l
4.3. Di-tert-butyl 5-phenylpent-1-yn-3-ylimidodi-
carbonate (10b)
13
14
12a
8b
8b
25 (82)
26 (83)
Following a similar procedure as mentioned in 10a, compound
10b was obtained in 85% yield as an oil. Rf¼0.62 (10% ethyl acetate
NCS
MeO2C
12m
Table 3
Synthesis of thiazole derivatives
4. Experimental
4.1. General
O
OEt
OEt
S
N
P
28a-b, Et3N,
R1HN
29-35
R1 NCS
12
THF
R2
All reactions were carried out under inert atmosphere. All sol-
vents were distilled prior to use. Anhydrous solvents were distilled
by following standard protocols. Low temperature baths were ice/
water (0 ꢁC) and CO2(s)/acetone (ꢀ78 ꢁC). Reaction temperatures
refer to that of the bath. Melting points (mp) were recorded with
Buchi Melting Point B-540 instrument and are uncorrected. IR
spectra were recorded either neat or as KBr pallet with a Shimadzu
IR-Prestige-21 instrument and only diagnostic and/or intense peaks
Entry
Isothiocyanate
Amine
Product (% yield)
1
2
3
4
5
6
7
12a
12f
12i
28a
28a
28a
28a
28a
28b
28b
29 (88)
30 (66)
31 (63)
32 (70)
33 (81)
34 (82)
35 (85)
12l
12m
12a
12m

P.K. Sasmal et al. / Tetrahedron 64 (2008) 11074–11080
11077
in petroleum ether); 1H NMR (400 MHz, DMSO-d6):
d
7.31–7.27 (m,
1192 cmꢀ1. MS (ES): m/z 232.3; HRMS m/z found 232.1328, calcd for
2H), 7.21–7.17 (m, 3H), 4.84–4.80 (m, 1H), 3.33–3.32 (m, 1H), 2.67–
C14H18NO2 232.1338.
2.55 (m, 2H), 2.22–2.06 (m, 2H), 1.44 (s, 18H); 13C NMR (50 MHz,
CDCl3):
d
151.9, 140.7, 128.3, 125.9, 82.8, 81.7, 71.7, 47.6, 35.8, 32.4,
4.8. Di-tert-butyl 3-(diethoxyphosphoryl)prop-2-
ynylimidodicarbonate (27a)
27.9; IR (neat): 2980, 2934,1746,1705,1369,1140 cmꢀ1; MS (ES): m/z
360.3 (Mþ1); HRMS m/z found 398.1734, calcd for C21H29NO4K
398.1734.
To a solution of diisopropyl amine (6.6 mL, 47.06 mmol) in
diethylether (20 mL) was added nBuLi (1.6 M in hexane, 18.8 mL,
47.06 mmol) drop wise at ꢀ78 ꢁC. The reaction mixture was placed
in an ice water bath and stirred at 0 ꢁC for 1 h. Then the reaction
mixture was cooled to ꢀ78 ꢁC and a solution of 10a (8.0 g,
31.37 mmol) in diethylether (80 mL) was added drop wise and
continued stirring for additional 1 h. Then was added diethyl
chlorophosphate (6.8 mL, 47.06 mmol) drop wise and continued
stirring at ꢀ78 ꢁC for 1 h. The reaction mixture was allowed to
warm up to ꢀ30 ꢁC over a period of 3 h and quenched with satu-
rated sodium sulfate solution followed by water and stirred at room
temperature for 30 min. The organic layer was separated, washed
successively with water, brine and dried over anhydrous Na2SO4
and rotary evaporated. The residue was purified on silica gel (100–
200 mesh) using 10% ethyl acetate in petroleum ether as eluent to
afford 27a (9.8 g, 80% yield) as an oil. Rf¼0.48 (10% ethyl acetate in
4.4. Ethyl 4-(bis(tert-butoxycarbonyl)amino)but-
2-ynoate (11a)
A solution of diisopropyl amine (6.6 mL, 47.06 mmol) in dieth-
ylether (20 mL) was cooled to ꢀ78 ꢁC and to it was added nBuLi
(1.6 M in hexane,18.8 mL, 47.06 mmol) drop wise and stirred at 0 ꢁC
for 1 h. Then the reaction mixture was cooled to ꢀ78 ꢁC and a so-
lution of 10a (8.0 g, 31.37 mmol) in diethylether (80 mL) was added
drop wise and continued stirring for additional 1 h. Then ethyl
chloroformate (4.5 mL, 47.06 mmol) was added drop wise and
stirred for 1 h at the same temperature. The reaction mixture was
warmed up to ꢀ30 ꢁC over a period of 3 h and then quenched by the
addition of saturated sodium sulfate solution followed by water and
stirred at room temperature for 30 min. The organic layer was
separated, washed successively with water, brine and dried over
anhydrous Na2SO4. Concentration and purification over silica gel
(100–200 mesh) using 10% ethyl acetate in petroleum ether as el-
uent afforded 11a (7.2 g, 70% yield) as an oil. Rf¼0.52 (10% ethyl
petroleum ether); 1H NMR (400 MHz, DMSO-d6):
d 4.47 (d,
4JHP¼3.8 Hz, 2H), 4.07–4.03 (m, 4H), 1.46 (s, 18H), 1.26 (t, J¼6.9 Hz,
6H); 13C NMR (50 MHz, CDCl3):
d
150.9, 96.5 (d, 2JCP¼50.7 Hz), 83.5,
2
3
74.3 (d, 1JCP¼294.8 Hz), 63.0 (d, JCP¼5.3 Hz), 35.9 (d, JCP¼4.2 Hz),
3
acetate in petroleum ether); 1H NMR (400 MHz, CDCl3):
d 4.50 (s,
27.8, 15.9 (d, JCP¼7.9 Hz); IR (neat): 2982, 2214, 1755, 1728, 1369,
1261, 1148 cmꢀ1; MS (ES): m/z 409.3 (Mþ1); HRMS m/z found
2H), 4.22 (q, J¼7.0 Hz, 2H), 1.53 (s, 18H), 1.30 (t, J¼7.0 Hz, 3H); 13C
414.1672, calcd for C13H14N2O2SCl 414.1658.
NMR (50 MHz, CDCl3): d 153.0, 151.0, 83.4, 74.4, 70.7, 61.8, 35.6, 27.9,
13.9; IR (neat): 2982, 2936, 2239, 1717, 1369, 1250, 1148 cmꢀ1; MS
(ES): m/z 350.1 (Mþ1); HRMS m/z found 350.1580, calcd for
C16H25NO6Na 350.1580.
4.9. Di-tert-butyl 1-(diethoxyphosphoryl)-5-phenylpent-1-
yn-3-ylimidodicarbonate (27b)
Following a similar procedure as mentioned in 27a, compound
27b was obtained in 60% yield as an oil. Rf¼0.58 (10% ethyl acetate
4.5. Ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-phenylhex-2-
ynoate (11b)
in petroleum ether); 1H NMR (400 MHz, DMSO-d6):
d 7.32–7.28 (m,
2H), 7.22–7.18 (m, 3H), 5.09–5.04 (m, 1H), 4.10–4.02 (m, 4H), 2.67–
Following a similar procedure as mentioned in 11a, compound
11b was obtained in 72% yield as an oil. Rf¼0.57 (10% ethyl acetate in
2.52 (m, 2H), 2.34–2.10 (m, 2H), 1.45 (s, 18H), 1.27 (t, J¼7.0 Hz, 6H);
13C NMR (50 MHz, CDCl3):
d 151.3, 140.1, 128.4, 128.2, 126.2, 98.5 (d,
petroleum ether); 1H NMR (400 MHz, DMSO-d6):
d 7.31–7.28 (m,
1
2
2JCP¼50.7 Hz), 83.5, 80.0 (d, JCP¼293.3 Hz), 63.1 (d, JCP¼5.3 Hz),
47.6 (d, 3JCP¼4.2 Hz), 35.1, 32.2, 27.9, 16.0 (d, 3JCP¼7.2 Hz); IR (neat):
2982, 2208, 1746, 1709, 1369, 1263, 1140, 1026 cmꢀ1; MS (ES): m/z
513.4 (Mþ1); HRMS m/z found 518.2292, calcd for C25H38NO7NaP
518.2284.
2H), 7.22–7.18 (m, 3H), 5.08 (t, J¼7.8 Hz, 1H), 4.18 (q, J¼7.2 Hz, 2H),
2.66–2.52 (m, 2H), 2.26–2.15 (m, 2H), 1.45 (s, 18H), 1.22 (t, J¼7.2 Hz,
3H); 13C NMR (50 MHz, CDCl3):
d 153.3, 151.4, 140.3, 128.5, 128.3,
126.2, 85.5, 83.4, 75.7, 61.9, 47.4, 35.4, 32.3, 28.0, 14.0; IR (neat):
2980, 2241, 1748, 1715, 1369, 1248, 1138 cmꢀ1; MS (ES): m/z 432.3
(Mþ1); HRMS m/z found 454.2265, calcd for C24H33NO6Na
454.2206.
4.10. Diethyl 3-aminoprop-1-ynylphosphonate
hydrochloride (28a)
4.6. Ethyl 4-aminobut-2-ynoate hydrochloride (8a)
Following a similar procedure as mentioned in 8a, 28a was
obtained in 90% yield. 1H NMR (400 MHz, DMSO-d6):
d 8.74 (br s,
3H), 4.18–3.90 (m, 6H), 1.29 (t, J¼6.8 Hz, 6H); 13C NMR (50 MHz,
To an ice-cooled ethereal HCl solution (40 mL) was added 11a
(4 g, 12.23 mmol) and stirred at room temperature for 1 h. Sepa-
rated solid was filtered, washed with ether and dried under vacuum
to afford 8a (1.6 g, 80% yield) as an off white solid (highly hygro-
DMSO-d6):
d
93.9 (d, 2JCP¼50.0 Hz), 75.8 (d, 1JCP¼287.3 Hz), 63.2 (d,
2JCP¼5.7 Hz), 28.3 (d, JCP¼4.6 Hz), 15.9 (d, JCP¼7.2 Hz); IR (neat):
3418, 2984, 1620, 1396, 1240, 1022 cmꢀ1. MS (ES): m/z 192.1; HRMS
m/z found 192.0781, calcd for C7H15NO3P 192.0790.
3
3
scopic). 1H NMR (400 MHz, DMSO-d6):
d 8.82 (br s, 3H), 4.22 (q,
J¼7.2 Hz, 2H), 3.98 (s, 2H), 1.23 (t, J¼7.2 Hz, 3H); IR (neat): 3200–
2800 (br), 2984, 2253, 1721, 1369, 1258, 748 cmꢀ1. MS (ES): m/z
127.9; HRMS m/z found 128.0711, calcd for C6H10NO2 128.0712.
4.11. Diethyl 3-amino-5-phenylpent-1-ynylphosphonate
hydrochloride (28b)
4.7. Ethyl 4-amino-6-phenylhex-2-ynoate hydrochloride (8b)
Following a similar procedure as mentioned in 8a, 28b was
obtained in 80% yield. 1H NMR (400 MHz, DMSO-d6):
d 8.94 (br s,
Following a similar procedure as mentioned in 8a, compound 8b
3H), 7.35–7.31 (m, 2H), 7.25–7.21 (m, 3H), 4.31–4.17 (m, 1H), 4.16–
4.12 (m, 4H), 2.82–2.68 (m, 2H), 2.22–2.11 (m,1H), 2.10–2.04 (m,1H),
was obtained in 74% yield. 1H NMR (400 MHz, DMSO-d6):
d 8.95 (br
s, 3H), 7.34–7.28 (m, 2H), 7.27–7.16 (m, 3H), 4.33–4.30 (m, 1H), 4.20
(q, J¼7.1 Hz, 2H), 2.83–2.52 (m, 2H), 2.25–1.98 (m, 2H), 1.24 (t,
J¼7.1 Hz, 3H); IR (neat): 3200–2800, 2932, 1726, 1699, 1499, 1223,
1.31 (t, J¼7.0 Hz, 6H); 13C NMR (50 MHz, DMSO-d6):
d 139.8, 128.5,
128.1, 126.3, 95.5 (d, 2JCP¼48.4 Hz), 76.6 (d, 1JCP¼284.2 Hz), 63.3 (d,
2JCP¼5.7 Hz), 41.5 (d, 3JCP¼4.2 Hz), 33.6, 30.8,15.9 (d, 3JCP¼6.8 Hz); IR

11078
P.K. Sasmal et al. / Tetrahedron 64 (2008) 11074–11080
(neat): 3399, 3026–2629 (br), 2214, 1722, 1603, 1371, 1240,
1022 cmꢀ1. MS (ES): m/z 296.1; HRMS m/z found 296.1407, calcd for
C15H23NO3P 296.1416.
2H), 7.64–7.60 (m, 4H), 7.45–7.41 (m, 2H), 7.32–7.30 (m, H), 7.08 (s,
1H), 4.12 (q, J¼7.1 Hz, 2H), 3.81 (s, 2H), 1.21 (t, J¼7.1 Hz, 3H); 13C
NMR (50 MHz, CDCl3): d 170.1, 163.4, 140.7, 139.9, 137.5, 132.6, 128.8,
127.0, 126.6, 125.9, 118.6, 117.1, 60.6, 31.9, 14.0; IR (KBr): 3300–2600
(br), 3244, 2940, 1740, 1609, 1558, 1456, 1439, 1161 cmꢀ1; MS (ES):
m/z 339 (Mþ1); HRMS m/z found 339.1174, calcd for C19H19N2O2S
339.1167.
4.12. General procedure for thiazole formation
The isothiocyanate (1.0 mmol) was dissolved in THF (0.2 M)
under an inert atmosphere. To the solution at room temperature
was added amine salt (1.5 equiv) followed by Et3N (3.0 equiv). The
reaction mixture was stirred for 12 h (24 h, for the phosphonate
derivatives) and by this time, both starting material and the in-
termediate thiourea were disappeared, as checked by TLC. The re-
action mixture was diluted with ethyl acetate and the organic layer
was successively washed with water and brine and dried (Na2SO4).
Concentration and chromatographic purification afforded the de-
sired thiazole derivatives.
4.18. Ethyl 2-(2-(benzylamino)thiazol-5-yl)acetate (18)
Rf¼0.48 (40% ethyl acetate in petroleum ether); mp 86–88 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
7.93 (t, J¼5.9 Hz,1H), 7.34–7.29 (m,
4H), 7.27–7.21 (m, 1H), 6.80 (s, 1H), 4.40 (d, J¼5.9 Hz, 2H), 4.07 (q,
J¼7.0 Hz, 2H), 3.66 (s, 2H), 1.18 (t, J¼7.0 Hz, 3H); 13C NMR (50 MHz,
CDCl3):
d 170.2, 168.7, 139.2, 137.2, 128.1, 127.3, 126.7, 116.2, 60.4,
47.4, 32.1, 14.0; IR (KBr): 3180, 2984, 1738, 1578, 1173, 1208 cmꢀ1
;
MS (ES): m/z 276.7 (Mþ1); HRMS m/z found 277.1016, calcd for
4.13. Ethyl 2-(2-(4-chlorophenylamino)thiazol-5-yl)-
acetate (13)
C14H17N2O2S 277.1011.
Rf¼0.62 (40% ethyl acetate in petroleum ether); mp 111–113 ꢁC;
4.19. Ethyl 2-(2-(4-chlorophenethylamino)thiazol-5-
yl)acetate (19)
1H NMR (400 MHz, DMSO-d6):
d
10.20 (br s, 1H), 7.63 (d, J¼8.8 Hz,
2H), 7.32 (d, J¼8.8 Hz, 2H), 7.07 (s, 1H), 4.12 (q, J¼7.1 Hz, 2H), 3.80 (s,
2H), 1.20 (t, J¼7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 170.0, 163.1,
Rf¼0.12 (40% ethyl acetate in petroleum ether); mp 88–90 ꢁC; 1H
140.0, 137.3,128.6, 124.1,118.9,118.1, 60.6, 31.9, 14.0; IR (KBr): 3446–
2771 (br), 3246, 3190, 2980, 1736, 1614, 1495, 1186, 1165 cmꢀ1; MS
(ES): m/z 296.7 (Mþ1); HRMS m/z found 297.0449, calcd for
C13H14N2O2SCl 297.0465.
NMR (400 MHz, CDCl3):
d
7.28 (d, J¼8.5 Hz, 2H), 7.15 (d, J¼8.5 Hz,
2H), 6.90 (t, 4JHH¼1.1 Hz, 1H), 4.95 (br s, 1H), 4.19 (q, J¼7.1 Hz, 2H),
3.65 (d, 4JHH¼1.1 Hz, 2H), 3.55–3.48 (m, 2H), 2.92 (t, J¼7.0 Hz, 2H),
1.28 (t, J¼7.1 Hz, 3H); IR (KBr): 3204, 2994, 1746, 1557, 1146 cmꢀ1
MS (ES): m/z 325.1 (Mþ1).
;
4.14. Ethyl 2-(2-(4-chloro-2-(trifluoromethyl)phenyl-
amino)thiazol-5-yl)acetate (14)
4.20. Ethyl 2-(2-((2-(4-chlorophenyl)-5-methyloxazol-
4-yl)methylamino)thiazol-5-yl)acetate (20)
Rf¼0.70 (40% ethyl acetate in petroleum ether); mp 68–70 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
10.56 (br s, 1H), 8.23 (d, J¼2.9 Hz,
Rf¼0.24 (40% ethyl acetate in petroleum ether); mp 146–148 ꢁC;
1H), 7.82 (dd, J¼2.7 & 9.0 Hz, 1H), 7.60 (d, J¼8.8 Hz, 1H), 7.14 (s, 1H),
1H NMR (400 MHz, DMSO-d6):
d
7.91 (d, J¼8.8 Hz, 2H), 7.83 (t,
4
4.12 (q, J¼7.1 Hz, 2H), 3.83 (d, JHH¼1.0 Hz, 2H), 1.21 (t, J¼7.1 Hz,
3H); 13C NMR (50 MHz, CDCl3):
d 169.9, 162.6, 140.3, 137.4, 131.9,
J¼5.4 Hz, 1H), 7.57 (d, J¼8.8 Hz, 2H), 6.83 (s, 1H), 4.28 (d, J¼5.4 Hz,
125.9 (q, 1JCF¼30.5 Hz), 121.2, 119.8, 115.0, 114.9, 60.6, 31.8, 13.9; IR
(KBr): 3248, 2920, 1734, 1570, 1337, 1180, 1134, 1028 cmꢀ1; MS (ES):
m/z 364.9 (Mþ1); HRMS m/z found 365.0344, calcd for
C14H13N2O2F3SCl 365.0338.
2H), 4.07 (q, J¼7.0 Hz, 2H), 3.67 (s, 2H), 2.41 (s, 3H), 1.18 (t, J¼7.0 Hz,
3H); 13C NMR (50 MHz, CDCl3):
d 170.1, 168.1, 157.4, 145.9, 137.1,
134.7, 133.4, 129.1, 127.1, 125.7, 116.4, 60.4, 38.2, 32.1, 14.0, 10.1; IR
(KBr): 3165.2, 2974, 1738, 1570, 1369, 1184, 1092 cmꢀ1 MS (ES): m/z
392.0 (Mþ1); HRMS m/z found 392.0835, calcd for C18H19N3O3SCl
392.0836.
4.15. tert-Butyl 4-(5-(2-ethoxy-2-oxoethyl)thiazol-2-
ylamino)benzoate (15)
4.21. Ethyl 2-(2-(isopropylamino)thiazol-5-yl)acetate (21)
Rf¼0.52 (40% ethyl acetate in petroleum ether); 1H NMR
(200 MHz, DMSO-d6):
d
10.49 (br s, 1H), 7.83 (d, J¼8.9 Hz, 2H), 7.68
Rf¼0.45 (40% ethyl acetate in petroleum ether); 1H NMR
(d, 8.9 Hz, 2H), 7.13 (s, 1H), 4.11 (q, J¼7.1 Hz, 2H), 3.84 (s, 2H), 1.53 (s,
9H), 1.20 (t, J¼7.1 Hz, 3H); IR (neat): 3329, 2978, 1738, 1705, 1605,
1292, 1159, 1115 cmꢀ1; MS (ES): m/z 363.2 (Mþ1).
(400 MHz, DMSO-d6):
d
7.27 (d, J¼7.3 Hz, 1H), 6.78 (s, 1H), 4.11 (q,
J¼7.0 Hz, 2H), 3.76–3.68 (m, 1H), 3.65 (s, 2H), 1.19 (t, J¼7.0 Hz, 3H),
1.14 (d, J¼6.3 Hz, 6H); 13C NMR (50 MHz, CDCl3):
d 170.1, 168.0,
137.3,115.4, 60.4, 45.8, 32.2, 22.3,14.0; IR (neat): 3369.6, 2972,1736,
1537, 1171 cmꢀ1; MS (ES): m/z 229 (Mþ1); HRMS m/z found
229.1006, calcd for C10H17N2O2S 229.1011.
4.16. Ethyl 2-(2-(4-(trifluoromethoxy)phenylamino)thiazol-
5-yl)acetate (16)
Rf¼0.64 (40% ethyl acetate in petroleum ether); 1H NMR
(400 MHz, DMSO-d6):
d
10.26 (br s, 1H), 7.70 (d, J¼9.0 Hz, 2H), 7.28
4.22. Ethyl 2-(2-(3-hydroxypropylamino)thiazol-5-yl)-
acetate (22)
(d, J¼9.0 Hz, 2H), 7.07 (s, 1H), 4.11 (q, J¼7.1 Hz, 2H), 3.81 (s, 2H), 1.21
(t, J¼7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 170.0, 163.2, 141.7,
141.7, 140.3, 137.3, 121.7, 119.0, 117.7, 60.6, 31.9, 14.0; IR (neat): 3244,
3206, 2957, 1740, 1225, 1667 cmꢀ1; MS (ES): m/z 347 (Mþ1); HRMS
m/z found 347.0674, calcd for C14H14N2O3F3S 347.0677.
Rf¼0.23 (60% ethyl acetate in petroleum ether); 1H NMR
(400 MHz, DMSO-d6):
d
7.37 (t, J¼5.3 Hz,1H), 6.79 (s, 1H), 4.55–4.44
4
(br s, 1H), 4.08 (q, J¼7.1 Hz, 2H), 3.66 (d, JHH¼0.9 Hz, 2H), 3.45 (t,
J¼6.3 Hz, 2H), 3.24–3.19 (m, 2H), 1.70–1.64 (m, 2H), 1.19 (t, J¼7.1 Hz,
4.17. Ethyl 2-(2-(biphenyl-4-ylamino)thiazol-5-yl)acetate (17)
3H); 13C NMR (50 MHz, CDCl3):
d 170.8, 170.5, 136.6, 116.4, 61.2,
59.3, 42.4, 32.8, 32.1, 14.0; IR (neat): 3291, 1732, 1545, 1369,
1153 cmꢀ1; MS (ES): m/z 245.5 (Mþ1). HRMS m/z found 245.0958,
calcd for C10H17N2O3S 245.0960.
Rf¼0.55 (40% ethyl acetate in petroleum ether); mp 146–148 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
10.18 (br s, 1H), 7.69 (d, J¼8.6 Hz,

P.K. Sasmal et al. / Tetrahedron 64 (2008) 11074–11080
11079
4.23. Ethyl 2-(2-(cyclohexylamino)thiazol-5-yl)acetate (23)
4.28. Diethyl (2-(benzylamino)thiazol-5-yl)-
methylphosphonate (30)
Rf¼0.42 (40% ethyl acetate in petroleum ether); mp 103–104 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
7.32 (d, J¼7.3 Hz, 1H), 6.76 (s, 1H),
Rf¼0.42 (40% ethyl acetate in petroleum ether); 1H NMR
4.08 (q, J¼7.9 Hz, 2H), 3.64 (d, 4JHH¼1.0 Hz, 2H), 3.42–3.38 (m, 1H),
(400 MHz, DMSO-d6):
d
7.90 (t, J¼5.8 Hz, 1H), 7.34–7.26 (m, 3H),
1.92–1.89 (m, 2H), 1.71–1.67 (m, 2H), 1.57–1.54 (m, 2H), 1.19 (t,
7.25–7.21 (m, 2H), 6.78 (d, 4JHP¼4.6 Hz, 1H), 4.39 (d, J¼5.9 Hz, 2H),
J¼7.9 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d
170.2, 167.9, 137.1, 115.3,
4.00–3.93 (m, 4H), 3.21 (dd, JHH¼0.9, JHP¼20.0 Hz, 2H), 1.19 (t,
4
2
60.4, 52.9, 32.3, 32.1, 25.3, 24.4, 14.0; IR (neat): 3370, 3200, 2930,
1736, 1529, 1177, 1161, 1130 cmꢀ1; MS (ES): m/z 269.8 (Mþ1); HRMS
m/z found 269.1331, calcd for C13H21N2O2S 269.1324.
J¼7.0 Hz, 6H); 13C NMR (50 MHz, CDCl3):
d 170.2, 139.1, 137.4 (d,
3JCP¼3.8 Hz), 128.5, 127.5, 127.4, 113.7 (d, JCP¼11.0 Hz), 62.3 (d,
2
2JCP¼6.5 Hz), 49.6, 25.1 (d, 1JCP¼145.3 Hz), 16.3 (d, JCP¼6.1 Hz); IR
3
(neat): 3267, 2981, 2930, 1667, 1537, 1236, 1024 cmꢀ1; MS (ES): m/z
341.2 (Mþ1); HRMS m/z found 341.1075, calcd for C15H22N2O3PS
341.1089.
4.24. Ethyl 2-(2-(pyridin-3-ylamino)thiazol-5-yl)acetate (24)
Rf¼0.12 (40% ethyl acetate in petroleum ether); mp 131–132 ꢁC;
4.29. Diethyl (2-(isopropylamino)thiazol-5-yl)-
methylphosphonate (31)
1H NMR (400 MHz, DMSO-d6):
d
10.30 (br s, 1H), 8.72 (d, J¼2.0 Hz,
1H), 8.16–8.13 (m, 2H), 7.33–7.29 (m, 1H), 7.10 (s, 1H), 4.12 (q,
Rf¼0.40 (40% ethyl acetate in petroleum ether); 1H NMR
J¼7.1 Hz, 2H), 3.82 (s, 2H), 1.18 (t, J¼7.1 Hz, 3H); 13C NMR (50 MHz,
(400 MHz, DMSO-d6):
d
7.24 (d, J¼7.3 Hz, 1H), 6.77 (d, 4JHP¼4.3 Hz,
CDCl3):
d 170.0, 163.0, 141.6, 138.6, 137.8, 137.4, 123.6, 123.1, 119.4,
1H), 4.02–3.95 (m, 4H), 3.74–3.69 (m, 1H), 3.21 (d, 2JHP¼20.0 Hz, H),
60.6, 31.9, 14.0; IR (neat): 3277, 3200, 2992, 2745, 1732, 1541, 1518,
1429, 1180 cmꢀ1; MS (ES): m/z 263.7 (Mþ1); HRMS m/z found
264.0796, calcd for C12H14N3O2S 264.0807.
1.21 (t, J¼7.1 Hz, 6H), 1.14 (d, J¼6.5 Hz, 6H); 13C NMR (50 MHz,
CDCl3):
d
169.6, 136.9 (d, 2JCP¼11.0 Hz), 113.2 (d, 2JCP¼11.0 Hz), 62.3
2
1
(d, JCP¼6.8 Hz), 47.9, 25.2 (d, JCP¼145.3 Hz), 22.6, 16.3 (d,
3JCP¼5.7 Hz); IR (neat): 3266, 2967, 2932, 2874, 1726, 1531, 1261,
1026 cmꢀ1; HRMS m/z found 293.1088, calcd for C11H22N2O3PS
293.1089.
4.25. Ethyl 2-(2-(4-chlorophenylamino)-4-phenethylthiazol-
5-yl)acetate (25)
4.30. Diethyl (2-(pyridin-3-ylamino)thiazol-5-yl)-
methylphosphonate (32)
Rf¼0.63 (30% ethyl acetate in petroleum ether); mp 186–188 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
12.44 (br s, 1H), 7.56 (d, J¼7.9 Hz,
2H), 7.29 (d, J¼7.9 Hz, 2H), 7.27–7.18 (m, 5H), 3.86 (q, J¼7.1 Hz, 2H),
3.34 (s, 2H), 2.87–2.83 (m, 2H), 2.75–2.71 (m, 2H), 1.00 (t, J¼7.1 Hz,
Rf¼0.15 (80% ethyl acetate in petroleum ether); mp 120–122 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
10.30 (br s, 1H), 8.73 (d, J¼2.2 Hz,
3H); 13C NMR (50 MHz, CDCl3):
d 168.5, 161.0, 140.1, 135.4, 134.1,
1H), 8.16–8.13 (m, 2H), 7.34–7.31 (m, 1H), 7.08 (d, 4JHP¼4.3 Hz, 1H),
130.0, 129.7, 128.5, 128.4, 127.1, 126.4, 120.2, 61.4, 35.3, 29.4, 26.3,
4.05–3.98 (m, 4H), 3.37 (d, 2JHP¼20.1 Hz, 2H), 1.23 (t, J¼7.0 Hz, 6H);
14.0; IR (KBr): 3335, 2907, 1707, 1493, 1474, 1368, 1215, 700 cmꢀ1
;
13C NMR (50 MHz, CDCl3):
d
164.1 (d, JCP¼1.9 Hz), 142.0, 139.1,
4
MS (ES): m/z 401.2 (Mþ1); HRMS m/z found 401.1096, calcd for
3
2
138.1, 137.9 (d, JCP¼11.4 Hz), 124.3, 123.8, 116.2 (d, JCP¼11.3 Hz),
C21H22N2O2SCl 401.1091.
2
3
62.7 (d, JCP¼7.2 Hz), 25.2 (d, 1JCP¼145.4 Hz), 16.3 (d, JCP¼5.7 Hz);
IR (KBr): 3252, 3181, 3053, 3015, 2988, 2903, 1614, 1543, 1522, 1422,
1223, 1024 cmꢀ1; MS (ES): m/z 328.1 (Mþ1); HRMS m/z found
328.0883, calcd for C13H19N3O3SP 328.0885.
4.26. Methyl 4-(5-(2-ethoxy-2-oxoethyl)-4-phenethylthiazol-
2-ylamino)benzoate (26)
4.31. Methyl 4-(5-((diethoxyphosphoryl)methyl)thiazol-2-
ylamino)benzoate (33)
Rf¼0.60 (40% ethyl acetate in petroleum ether); mp 160–162 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
12.49 (br s, 1H), 8.05 (d, J¼8.6 Hz,
Rf¼0.44 (60% ethyl acetate in petroleum ether); mp 177–179 ꢁC;
2H), 7.39 (d, J¼8.6 Hz, 2H), 7.32–7.29 (m, 2H), 7.24–7.19 (m, 2H),
3.89 (s, 3H), 3.83 (q, J¼7.1 Hz, 2H), 3.36 (s, 2H), 2.87–2.84 (m, 2H),
2.76–2.72 (m, 2H), 0.96 (t, J¼7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3):
1HNMR(400 MHz,DMSO-d6):
d
10.51 (brs,1H), 7.89(d, J¼8.9 Hz, 2H),
7.70(d, J¼8.9 Hz,2H), 7.13(d, 4JHP¼4.3 Hz,1H),4.05–3.98(m, 4H),3.81
(s, 3H), 3.39 (dd, 4JHH¼0.8 Hz, 2JHP¼20.0 Hz, 2H),1.23 (t, J¼7.1 Hz, 6H);
d
168.5, 166.0, 160.9, 140.1, 139.6, 130.9, 130.7, 128.8, 128.5, 128.4,
13C NMR (50 MHz, CDCl3):
(d, JCP¼11.0 Hz), 131.1, 122.8, 116.5 (d, JCP¼11.0 Hz), 116.0, 62.7 (d,
d
166.8,163.7 (d, 4JCP¼2.3 Hz), 144.8,137.8
127.4, 126.4, 120.0, 61.4, 52.4, 35.3, 29.4, 26.3, 14.0; IR (KBr): 3067,
2934, 1724, 1479, 1288, 1182 cmꢀ1; MS (ES): m/z 425.2 (Mþ1);
HRMS m/z found 425.1531, calcd for C23H25N2O4S 425.1535.
3
2
1
3
2JCP¼6.8 Hz), 51.8, 25.2 (d, JCP¼145.3 Hz), 16.3 (d, JCP¼5.7 Hz); IR
(KBr): 3267, 3069, 1715, 1607, 1518, 1283, 1229 cmꢀ1; MS (ES): m/z
385.3 (Mþ1); HRMS m/z found 385.0968, calcd for C16H22N2O5PS
385.0987.
4.27. Diethyl (2-(4-chlorophenylamino)thiazol-5-yl)-
methylphosphonate (29)
4.32. Diethyl (2-(4-chlorophenylamino)-4-phenethylthiazol-
5-yl)methylphosphonate (34)
Rf¼0.14 (60% ethyl acetate in petroleum ether); mp 177–179 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
10.22 (br s, 1H), 7.61 (d, J¼9.2 Hz,
2H), 7.34 (d, J¼9.2 Hz, 2H), 7.07 (d, 4JHP¼4.3 Hz, 1H), 4.07–4.02 (m,
Rf¼0.18 (60% ethyl acetate in petroleum ether); mp 88–90 ꢁC; 1H
4H), 3.38 (dd, 4JHH¼0.8 Hz, 2JHP¼20.0 Hz, 2H), 1.24 (t, J¼7.1 Hz, 6H);
NMR (400 MHz, DMSO-d6):
d
10.12 (br s, 1H), 7.60 (d, J¼9.0 Hz, 2H),
4
13C NMR (50 MHz, CDCl3):
d
164.5 (d, JCP¼1.9 Hz), 139.2, 137.7 (d,
7.32 (d, J¼9.0 Hz, 2H), 7.30–7.23 (m, 4H), 7.20–7.16 (m, 1H), 4.02–
2
2
3JCP¼11.0 Hz), 129.2, 127.2, 119.1, 115.7 (d, JCP¼11.0 Hz), 62.6 (d,
2JCP¼6.4 Hz), 25.3 (d, 1JCP¼145.3 Hz), 16.4 (d, 3JCP¼5.7 Hz); IR (KBr):
3265, 3101, 3069, 1612, 1541, 1522, 1242, 1034 cmꢀ1; MS (ES): m/z
361.0 (Mþ1); HRMS m/z found 361.0560, calcd for C14H19N2O3PSCl
361.0543.
3.94 (m, 4H), 3.15 (d, JHP¼20.1 Hz, 2H), 2.95–2.91 (m, 2H), 2.82–
2.78 (m, 2H), 1.20 (t, J¼7.0 Hz, 6H); 13C NMR (50 MHz, CDCl3):
d
162.2,149.3 (d, 4JCP¼11.3 Hz),141.6,139.3,129.1,128.4,128.3,127.0,
2
2
125.9, 119.0, 109.2 (d, JCP¼11.4 Hz), 62.5 (d, JCP¼6.8 Hz), 35.4 (d,
4JCP¼2.6 Hz), 31.1, 24.3 (d, JCP¼145.3 Hz), 16.4 (d, JCP¼5.7 Hz); IR
1
3

11080
P.K. Sasmal et al. / Tetrahedron 64 (2008) 11074–11080
(KBr): 3264, 3067, 1616, 1531, 1491, 1314, 1229 cmꢀ1; MS (ES): m/z
465.1 (Mþ1); HRMS m/z found 465.1164, calcd for C22H27N2O3PSCl
465.1169.
8. Wang, W.-L.; Yao, D.-Y.; Gu, M.; Fan, M.-Z.; Li, J.-Y.; Xing, Y.-C.; Nan, F.-J. Bioorg.
Med. Chem. Lett. 2005, 15, 5284.
9. Hargrave, K. D.; Hess, F. K.; Oliver, J. T. J. Med. Chem. 1983, 26, 1158.
10. Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.; Taylor, D. J. J.; Connoly, C.
J. C.; Doherty, A. M.; Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batly, B. L.;
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S. Bioorg. Med. Chem. Lett. 2005, 15, 1409.
4.33. Methyl 4-(5-((diethoxyphosphoryl)methyl)-4-
phenethylthiazol-2-ylamino)benzoate (35)
Rf¼0.50 (50% ethyl acetate in petroleum ether); mp 168–170 ꢁC;
1H NMR (400 MHz, DMSO-d6):
d
10.45 (br s, 1H), 7.89 (d, J¼9.0 Hz,
2H), 7.68 (d, J¼9.0 Hz, 2H), 7.30–7.24 (m, 4H), 7.20–7.16 (m, 1H),
14. Mortlock, A. PCT Int. Appl. 2004, WO2004058752.
3
3
15. Nilsson, C.; Dreifeldt, C. PCT Int. Appl. 2004, WO2004112782.
16. Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20, 3118.
17. Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473.
18. Varma, R. S. Pure Appl. Chem. 2001, 73, 193.
19. Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen, D.-W. J. Org. Chem.
2003, 68, 7887 and references cited therein.
20. Baily, N.; Dean, A. W.; Judd, D. B.; Middlemiss, D.; Storer, R.; Watson, S. P. Bioorg.
Med. Chem. Lett. 1996, 6, 1409.
21. Kearney, P. C.; Fernandez, M. J. Org. Chem. 1998, 63, 196.
22. Rudolp, J. Tetrahedron 2000, 56, 3161.
23. Schantl, J. G.; Lagoja, I. M. Synth. Commun. 1998, 28, 1451.
24. Kodomari, M.; Aoyama, T.; Suzuki, Y. Tetrahedron Lett. 2002, 43, 1717.
25. Sasmal, P. K.; Sridhar, S.; Iqbal, J. Tetrahedron Lett. 2006, 47, 8661.
26. Corriu, R. J. P.; Bolin, G.; Iqbal, J.; Moreau, J. J. E.; Vernhel, C. Tetrahedron 1993,
49, 4603.
3.99 (dq, JHH¼7.0 Hz, JHP¼14.0 Hz, 4H), 3.81 (s, 3H), 3.19 (d,
2JHP¼20.0 Hz, 2H), 2.97–2.94 (m, 2H), 2.86–2.82 (m, 2H), 1.21 (t,
J¼7.0 Hz, 6H); 13C NMR (50 MHz, CDCl3):
d 166.8, 161.0 (d,
3JCP¼2.2 Hz), 149.4 (d, 4JCP¼11.3 Hz), 145.1, 141.5, 130.9, 128.3, 128.2,
125.8, 122.2, 115.9,109.7 (d, 2JCP¼11.7 Hz), 62.5 (d, 2JCP¼7.2 Hz), 51.7,
4
1
35.2 (d, JCP¼2.3 Hz), 31.0, 24.1 (d, JCP¼145.3 Hz), 16.3 (d,
3JCP¼5.7 Hz); IR (KBr): 3264, 3075, 1715, 1605, 1524, 1433, 1281,
1254, 1175, 1028 cmꢀ1; MS (ES): m/z 489.3 (Mþ1); HRMS m/z found
489.1618, calcd for C24H30N2O5PS 489.1613.
Acknowledgements
27. Katritzky, A. R.; Ledoux, S.; Witek, R. M.; Nair, S. K. J. Org. Chem. 2004, 69, 2976.
28. Maclnnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1987, 1077.
29. This observation was also reported by Katritzky’s group; see Ref. 27.
30. Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593.
We thank Dr. Reddy’s Laboratories Ltd. for the support and en-
couragement. Help from the analytical department in the form of
spectral data is also appreciated.
31. In DMSO-d6 solution of 8a, the appearance of 1H NMR signal at
d
6.65 and 3.90
and 13C NMR signal at
d 120.2 (]CH) indicated that most probably 8a partially
and predominantly converted to 8a0. This conversion took place slowly in dilute
solution whereas increased with time and concentration. In DMSO-d6 (0.01 M
concentration), 8a/8a0 after 5 min, 10.6:1; after 5 h, 3.3:1; after 1 day, 2.9:1 and
after 7 days, 1.5:1. When the concentration was 0.1 M in DMSO-d6, 8a/8a0 was 1.
8:1 after 5 min.
Supplementary data
1H NMR and 13C NMR spectra of compounds 13, 20, 22, 25, 26,
28b, 32, 33, 34 and 35 are available as Supplementary data (20
pages). Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.09.074.
Cl
CO2Et
H
CO2Et
HCl·H2N
8a
HCl·H2N
References and notes
8a'
1. Metzger, J. V. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon: New York, NY, 1984; Vol. 6, pp 235–332.
2. Miwatashi, S.; Arikawa, Y.; Kotani, E.; Miyamoto, M.; Naruo, K.-I.; Kimura, H.;
Tanaka, T.; Asahi, S.; Ohkawa, S. J. Med. Chem. 2005, 48, 5966.
3. Papadopoulou, C.; Geronikaki, A.; Hadjipavlou-Litina, D. IL Farmaco 2005, 60,
969 and references cited therein.
32. Isothiocyanates are either commercially available or were prepared from the
corresponding amines by the treatment of thiophosgene in dichloromethane in
the presence of pyridine.
33. Westphal, G.; Wasicki, H. Z. Chem. 1968, 8, 337.
34. Sawhney, S. N.; Dhindsa, G. S.; Singh, S. P. Indian J. Chem., Sect. B 1983, 22, 1044.
35. Reddy, G. J.; Rao, K. S.; Jayaveera, K. N.; Sailaja, S.; Reddanna, P.; Reddy, D. B.
Indian J. Chem., Sect. B 2006, 45, 2143.
4. Kumar, Y.; Green, R.; Borysko, K. Z.; Wise, D. S.; Wotring, L. L.; Townsend, L. B.
J. Med. Chem. 1993, 36, 3843.
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6. Pereira, R.; Gaudon, C.; Iglesias, B.; Germain, P.; Gronemeyer, H.; de Lera, A. R.
Bioorg. Med. Chem. Lett. 2006, 16, 49.
36. Unlike their ester counter parts 8a and 8b, the solution stability of phosphonate
salts 28a and 28b were longer enough to record their both 1H and 13C NMR
spectra.
7. Tsuruni, Y.; Ueda, H.; Hayashi, K.; Takase, S.; Nishikawa, M.; Kiyoto, S.; Okuhara,
M. J. Antibiot. 1995, 48, 1066.
37. The synthesis of diisopropyl(2-amino-4-methylthiazol-5-yl)methylphosphonate
was reported, see: Penz, G.; Zbiral, E. Chem. Ber. 1985, 118, 4131.