Synthesis and biological screening of diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates

Article abstract of DOI:10.24820/ark.5550190.p010.534

A three-step synthesis, involving condensation of bromomethyl aryl ketones with urea to afford 2- aminothiazoles, their chloroacetylation and subsequent solvent-free Arbuzov phosphonation has afforded a series of novel diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates 3a-3f in good overall yields; the 4- carboxythiazole analogue 3g was obtained by selective hydrolysis of the corresponding ethyl ester 3f. The phosphonate esters exhibited significant anti-cancer activity (nM - low μM IC₅₀ values) against SH-SY5Y cells and, in one case, 7.6 μM MIC90 anti-TB activity against the virulent M. tuberculosis H₃₇Rv strain; the chloroacetamido precursors all exhibited some antimalarial (PfLDH) activity, three with IC₅₀ values in the range 1.0 - 8.9 μM.

Full text of DOI:10.24820/ark.5550190.p010.534

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Organic Chemistry
Arkivoc 2018, part vii, 110-118
Synthesis and biological screening of
diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates
a
a,b
b,c
c
b,d
Emmanuel O. Olawode,* Roman Tandlich, Earl Prinsloo, Michelle Isaacs, Heinrich Hoppe,
f
g
h
b,e
Ronnett Seldon, Digby F. Warner, Vanessa Steenkamp, and Perry T. Kaye*
a
b
Division of Pharmaceutical Chemistry, Faculty of Pharmacy. Centre for Chemico- and Biomedicinal Research;
c
d
e
Biotechnology Innovation Centre; Department of Biochemistry and Microbiology; and Department of
Chemistry, Rhodes University, Grahamstown, South Africa. Drug Discovery and Development Centre (H3-D),
Department of Chemistry and Molecular Mycobacteriology Research Unit, Department of Pathology and
f
g
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
h
Phytomedicine Unit, Department of Pharmacology, University of Pretoria, Pretoria, South Africa
Email: E.Olawode@ru.ac.za; P.Kaye@ru.ac.za
Received 02-13-2018
Accepted 03-31-2018
Published on line 09-09-2018
Abstract
A three-step synthesis, involving condensation of bromomethyl aryl ketones with urea to afford 2-
aminothiazoles, their chloroacetylation and subsequent solvent-free Arbuzov phosphonation has afforded a
series of novel diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates 3a-3f in good overall yields; the 4-
carboxythiazole analogue 3g was obtained by selective hydrolysis of the corresponding ethyl ester 3f. The
phosphonate esters exhibited significant anti-cancer activity (nM - low µM IC50 values) against SH-SY5Y cells
and, in one case, 7.6 µM MIC90 anti-TB activity against the virulent M. tuberculosis H Rv strain; the
3
7
chloroacetamido precursors all exhibited some antimalarial (PfLDH) activity, three with IC values in the range
5
0
1
.0 - 8.9 µΜ.
Keywords: 2-(2-Chloroacetamido)thiazoles , N-(thiazol-2-yl)carbamoyl]methylphosphonates, synthesis,
biological activities
DOI: https://doi.org/10.24820/ark.5550190.p010.534
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Introduction
The enzyme,1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) regulates a non-mevalonate pathway in
the biosynthesis of isoprenoid-derived compounds in Plasmodium falciparum (Pf), but is not found in
1
,2
humans . This enzyme has been validated as a target for the development of antimalarial drugs capable of
3
-5
selectively inhibiting reduction of 1-deoxy-D-xylulose-5-phosphate 1 in resistant P. falciparum strains . The
4
,5
naturally occurring antibiotic, fosmidomycin [3-(N-formyl-N-hydroxyamino)propylphosphonic acid and its N-
6
,7
acetyl derivative, FR900098 2 , are known to inhibit PfDXR, and various analogues of these compounds have
been prepared. In our own group, research has focussed on the synthesis and antimalarial activity of
8
,9
phosphonated N-aryl- and N-heteroaryl-carboxamides, such as compound 3
phosphoramidate analogues of fosmidomycin.
and, more recently,
6
The thiazole scaffold is well represented in medicinal systems. Mjambili et al. have prepared a library of N-
aryl substituted 2-(pyridin-2-yl)thiazol-4-amines and explored their anti-TB and antimalarial activity, and
compounds containing electronegative para substituents were shown to inhibit P. falciparum with sub-
1
1
micromolar IC50 values . The anti-cancer potential of certain thiazole-based compounds has been
investigated, the most active of which, ethyl 2-[3-(diethylamino)propanamido]thiazole-4-carboxylate,
exhibited a GI value of 0.08 μM against the RPMI-8226 leukemia cell line and broad-spectrum activity against
5
0
1
2,13
6
0 tumour cell lines with a GI50 value of 38.3 µΜ
. Jaishree et al. showed that 2-methyl-4-
trifluoromethylthiazole-5-carboxamides exhibited promising anti-parasitic and insecticidal properties, but
1
4
without herbicidal effect.
In this communication, we discuss: (i) the synthesis of
a
series of [N-(thiazol-2-
yl)carbamoylmethylphosphonate esters 3 as fosmidomycin analogues which satisfy the Lipinski “Rule of Five”;
and (ii) screening of these compounds and their synthetic precursors for antimalarial, anti-cancer and anti-
tuberculosis activity.
Result and Discussion
The aminothiazole scaffolds 6a-e were obtained using conventional Hantzsch condensation of the α-bromo
ketones 4a-f with thiourea (Scheme 1). On completion of each of the reactions, the desired product was
1
5-17
precipitated out by pouring the reaction mixture into ice-cold water. The known thiazole derivatives 3a-f
were thus isolated in excellent yields (93–100%; Table 1) and subsequently treated with chloroacetyl chloride
in the presence of triethylamine in dichloromethane, using a modification of the method reported by Xu et
1
8
al. to afford the 2-(2-chloroacetamido)thiazole analogues 7a-f in yields ranging from 54 to 100%. Solvent-
free Arbuzov phosphonation of the 2-(2-chloroacetamido)thiazoles 7a-f was effected by boiling with triethyl
phosphite at 110 ⁰C for 9 h. Excess triethyl phosphite was removed by stirring the crude products with hexane.
Column chromatography afforded the desired phophonate esters 3a-e in 68-98% yield, while treatment of the
carbethoxy analogue 3f with methanolic potassium hydroxide, followed by acidification, permitted selective
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Olawode, E. O. et al.
hydrolysis of the carboxlic ester moiety to give diethyl [(4-carboxythiazol-2-yl)carbamoyl]methylphosphonate
g in 59% yield. The phosphonate esters 3a-g are all new and were fully characterised using 1- and 2-D NMR,
IR and HRMS methods.
3
ᵒ
ᵒ
ᵒ
Reagents and conditions: i) EtOH, 70 C, 1 h; ii) Chloroacetyl chloride, 0 C - rt, 2 h; iii) (EtO) P, 110 C, 9h; and
3
iv) KOH, MeOH, rt, 2h, then 20% HCl.
Scheme 1
Table 1. Yields (%) of the intermediates 6a-f and 7a-f and the diethyl [N-(thiazol-2-yl)carbamoyl]-
methylphosphonates 3a-g.
R
Yield (%)
Ph
6a
6b
6c
6d
6e
6f
-
99
100
93
94
94
100
-
7a
7b
7c
7d
7e
7f
-
54
100
64
64
88
70
-
3a
3b
3c
3d
3e
3f
98
89
68
70
70
87
59
p-ClPh
p-BrPh
p-FPh
p-NO Ph
2
COOEt
COOH
a
a
3g
3
g obtained from hydrolysis of the carbethoxy precursor 3f.
It is apparent from the data summarised in Table 2 that, at low concentrations, the phosphonate esters 3a-
c,e,g exhibit encouragingly effective inhibition of the SH-SY5Y cell line with IC50 values in the nanomolar to
1
9,20
very low micromolar range but little, if any, activity against the HeLa cell line
(≥ 95% viability at 20 μM),
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Olawode, E. O. et al.
thus reflecting clear selectivity against the former cell line. Compounds 7a-f, however, exhibit 15-40%
inhibition of the HeLa cells at 20 μM.
Table 2. Bioassay results for compounds 6a-f, 7a-f and 3a-g
H
H
N
NH2
N
N
S
N
OEt
OEt
Cl
N
S
R
P
R
R
S
O
O
O
6
a-f
7a-f
3a-g
Anti-cancer
Antimalarial
Anti-TB
R
SH-SY5Y
IC (µM)
HeLa cells
% Viability
PfLDH
% Viability
MIC90 MIC99
(µM) (µM)
a
IC (μM)
50
5
0
6
6
6
6
6
6
7
7
7
7
7
7
3
3
3
3
3
3
3
a
b
c
d
e
f
a
b
c
d
e
f
a
b
c
d
e
f
Ph
-
-
-
-
-
-
-
-
-
-
-
-
90
98
<100
<100
95
75
80
85
80
85
81
88
83
84
68
18
40
32
16
14
68
115
115
102
102
105
99
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
p-ClPh
p-BrPh
p-FPh
p-NO Ph
COOEt
Ph
p-ClPh
p-BrPh
p-FPh
p-NO Ph
COOEt
Ph
p-ClPh
p-BrPh
p-FPh
p-NO Ph
COOEt
COOH
2
1.86
-
-
8.87
1.04
-
-
-
-
-
-
-
-
60
55
65
2
0.87
0.0018
2.1
> 1 mM
590
> 1 mM
4.6
100
100
100
95
100
<100
<100
100
-
> 20.0
> 20.0
7.62
> 20.0
> 20.0
> 20.0
> 20.0
> 20.0
> 20.0
> 20.0
> 20.0
> 20.0
> 20.0
> 20.0
2
g
102
Controls
Chloroquine
Rifampicin
-
-
0.0143
-
-
-
-
0.0015 0.0016
a
At 20 μM.
The resazurin-based whole-cell PfLDH bioassay was conducted to explore the antimalarial activities of the
crucial intermediates and final compounds using 20 µM as the cut-off concentration before determining IC50
values for compounds with significant levels of inhibition. The results (Table 1) show that the unsubstituted
aminothiazole intermediates 6a-f exhibit low levels of inhibition (66-88% PfLDH viability), whereas the 2-(2-
chloroacetamido)thiazole intermediates 7a-e exhibit significant activity at 20 μM, with IC values of 8.87, 1.86
5
0
and 1.04 μM for compounds 7d, 7a and 7e , respectively.The phosphonate esters 3a-g, which were designed
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Olawode, E. O. et al.
primarily as potential inhibitors of P. falciparum 1-deoxy-1-D-xylulose-5-phosphate reductoisomerase (PfDXR),
unfortunately showed no discernible PfLDH inhibition.
Apart from the para-bromophenyl product 3c, which exhibited an MIC90 value of 7.62 µM, all other
compounds in this series (3) showed little if any inhibitory effect (MIC90 and MIC99 values > 20 µM) on the
1
9
growth of M. tuberculosis H Rv . The relatively high predicted Log P value of 3.87 for compound 3c may
3
7
contribute to its absorption across the lipophilic membrane of M. tuberculosis H Rv, whereas the Log P values
3
7
for the other compounds 3a, 3b, 3d, 3e, 3f and 3g (2.98, 3.62, 3.18, 1.54 and 1.10, respectively) are all lower.
Conclusions
The novel diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates (3) were successfully obtained in good
overall yields. Although designed as potential antimalarial agents, these compounds failed to exhibit any
activity against PfLDH, whereas their chloroacetamido precursors (7) all exhibited antimalarial (PfLDH) activity,
three with IC50 values in the range 1.0 - 8.9 μM. The title compounds did, however, exhibit significant and
selective anti-cancer activity (nM - low μM IC50 values) against SH-SY5Y cells and, in one case, 7.6 μM MIC90
anti-TB activity against the virulent M. tuberculosis H Rv strain.
3
7
Experimental Section
General. Reagents were supplied by Sigma-Aldrich and used without further purification. Tetrahydrofuran
(
THF) and methylene chloride were stored over 4 Å molecular sieves. The reaction progress and purity of the
®
compounds were checked by thin layer chromatography (TLC) on pre-coated Merck silica gel G60 F2 plates,
54
and viewed under UV light at 254 and 365 nm. Melting points were recorded, uncorrected, using a Reichert
hot-plate microscope. Nuclear magnetic resonance (NMR) spectra were recorded on Bruker Avance II 600
MHz, Bruker Avance III HD 400 MHz and Bruker Fourier 300 MHz spectrometers. The NMR chemical shifts are
reported in ppm downfield from tetramethylsilane (TMS), and the coupling constants are given in Hertz (Hz).
NMR analyses were carried out in deuterated solvents, such as DMSO-d , CDCl , acetone-d and methanol-d
6
3
6
4
for standard NMR experiments, and the spectra were calibrated using solvent signals [δ : 7.26 ppm for
H
residual CHCl , 2.50 ppm for residual DMSO, 2.05 ppm for residual acetone and 3.31 for residual MeOH; δ :
3
C
7
7.2 ppm (CDCl ), 39.5 ppm (DMSO-d ), 29.8 ppm (acetone-d ) and 49.0 ppm (MeOH-d )]. Infrared (IR) spectra
3
6
6
4
(R)
were obtained using a Perkin Elmer
Spectrum 400 Frontier / FT-IR spectrometer. High-resolution mass
spectra (HRMS) were recorded on a Waters API Q-TOF Ultima spectrometer (University of Stellenbosch,
Stellenbosch, South Africa). NMR spectra for all compounds and the bioassay procedures are provided in the
Supporting Information.
1
o
6-18
The known 2-aminothiazoles (6) were obtained following reported methods.
A mixture of thiourea (1.2
mmol) and 2-bromoacetophenone (1 mmol) in EtOH (2 mL) was stirred at 70 C for 1h. The reaction mixture
was cooled to room temperature, poured into ice-cold water, and the resulting precipitate was filtered and
o
26
o
dried to give the desired compounds: [6a ( 99%) as a white solid, mp 150-152 C (Lit. 149-150 C) ; 6b (100%)
as a white solid, mp 162-165 C (Lit. 163-164 C); 6c (0.236 g, 93%) as a white solid mp 179-181 C (Lit. 180-
o
26
o
o
26
,
o
o
28/22
o
1
81 C); 6d (98%) as a white solid, mp 203.6-204.2 C (Lit.
204.0-204.5 C); 6e (94%) as a bright yellow
285-286 C); 6f (100%) as a white solid, mp 172-174 C (Lit.
o
26,27
o
o
29-31
o
solid, mp 287-288 C (Lit.
172 C).
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The general procedure for the preparation of the known 2-(2-chloroacetamido)thiazoles (7) involved a
18
modification of the procedure reported by Xu and collegues . A solution of 2-amino-4-phenylthiazole 6a
0.530 g, 3 mmol) and Et N (560 µL, 4 mmol) in dichloromethane (15 mL) was cooled to 0-5 ⁰C in an ice-bath
(
3
and stirred for 30 min. 2-Chloroacetyl chloride (578 µL, 6.6 mmol) in dry dichloromethane (1.5 mL) was then
added slowly, and the reaction mixture was allowed to warm to room temperature and stirred until the amine
was completely consumed (ca. 1 h, as monitored by TLC). The reaction mixture was diluted with
dichloromethane and washed successively with water and saturated brine. The organic layer was dried over
anhydrous Na SO , the solvent was removed under reduced pressure and the residue was recrystallised from
2
4
o
18,20,26
o
o
ethanol to give compound 7a (0.413 g, 54%) as light-grey crystals, mp 170-171 C (Lit.
remaining analogues were obtained similarly [7b (100%) as a brown solid, mp 194-195 C (Lit. mp not cited);
c (64%) as a brown solid, mp 241-243 C (Lit. mp not cited); 7d (64%) as a brown solid, mp 135-137 C (Lit.
35 C); 7e (0.262 g, 88%) as a yellow solid, mp 174-176 ⁰C (Lit. 175 C); 7f (70%) as a light-brown solid, mp
171-173 C). The
27
o
27
o
28
7
1
2
o
29
o
o
30
o
13-216 C (Lit. 216 C).
General procedure for the preparation of the diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates (3). A
mixture of 2-(2-chloroacetamido)-4-phenylthiazole 7a (0.063 g, 0.25 mmol) and triethyl phosphite (22 μL, 0.13
o
1,2
mmol) in an oven-dried round-bottomed flask was refluxed (ca. 110 C) for 9 h under nitrogen . The reaction
mixture was cooled to room temperature and then stirred 3 times with hexane (3 x 700 μL for 20 min each,
followed each time by decantation of the hexane layer to remove excess triethyl phosphite). The residual
solvent was evaporated under reduced pressure, and the crude product was chromatographed [using silica
gel; eluting with hexane/EtOAc (4:1)] to yield the diethyl [4-phenylthiazol-2-yl)carbamoyl]methylphosphonate.
o
Diethyl [4-phenylthiazol-2-yl)carbamoyl]methylphosphonate (3a). Brown solid (0.087 g, 98%), mp 78-80 C;
+
-1
[
(
7
2
HRMS: m/z calculated for C H N O PS (MH ) 355.0881. Found 355.0876]; ν / cm 1679 (C=O) and 3168
1
5
20
2
4
max
3
3
NH); δ (400 MHz; CDCl ) 10.96 (1H, br s, NH), 7.80 (2H, d, J 8 Hz, ArH), 7.36-7.29 (2H, m, J 7.1-7.4 Hz, ArH),
.01 (1H, s, thiazolyl-H), 4.28-4.21 (4H, m, 2 x OCH ), 3.17 (2H, d, J 24 Hz, PCH ) and 1.39 (6H, t, J 8.0 Hz,
H
3
2
3
2
P,H
2
H,H
2
x CH ); δ (100 MHz; CDCl ) 162.4 (C=O, J 5 Hz), 157.3, 150.2, 134.7, 128.7, 128.0, 126.3, 107.8 (ArC and
3
C
3
C,P
2
1
3
thiazolyl-C), 63.5 (OCH , J 6.4 Hz), 35.9 (PCH , J 131 Hz) and 16.5 (CH , J 5.9 Hz).
2
C,P
2
C,P
3
C,P
Diethyl {N-[4-(4-chlorophenyl)thiazol-2-yl]carbamoyl}methylphosphonate (3b). Brown solid (0.087 g, 89%),
o
35
+
-1
mp 86-89 C; [HRMS: m/z calculated for C H ClN O PS (MH ) 389.0492. Found 389.0488]; ν / cm 1680
15
19
2
4
max
3
3
(
7
6
C=O) and 3169 (NH); δ (400 MHz; CDCl ) 10.99 (1H, br s, NH), 7.72 (2H, d, J 7.8 Hz, ArH), 7.36 (2H, d, J
.8 Hz, ArH), 6.99 (1H, s, thiazolyl-H), 4.27 (4H, m, 2 x OCH ), 3.23 (2H, d, J 21 Hz, PCH ) and 1.40 (6H, t, J
.8 Hz, 2 x CH ); δ (100 MHz; CDCl ) 162.5 (C=O, J 4.7 Hz), 157.5, 149.1, 133.9, 133.2, 129.0, 127.7, 108.1
ArC and thiazolyl-C), 63.7 (OCH , J 6.5 Hz), 35.7 (PCH , J 131 Hz) and 16.6 (CH , J 5.8 Hz).
H
3
H,H
H,H
2
3
2
P,H
2
H,H
2
3
C
3
C,P
2
1
3
(
2
C,P
2
C,P
3
C,P
Diethyl {N-[4-(4-bromophenyl)thiazol-2-yl]carbamoyl}methylphosphonate (3c). Brown solid (0.074 g, 68%),
o
79
+
-1
mp 96-98 C; [HRMS: m/z calculated for C H BrN O PS (MH ) 432.9987. Found 432.9979]; ν / cm 1680
1
5
19
2
4
max
3
3
(
8
7
C=O) and 3160 (NH); δ (400 MHz; CDCl ) 11.02 (1H, br s, NH), 7.65 (2H, d, J 8.3 Hz, ArH), 7.51 (2H, d, J
.3 Hz, ArH), 6.98 (1H, s, thiazolyl-H), 4.25 (4H, m, 2 x OCH ), 3.22 (2H, d, J 22 Hz, PCH ) and 1.38 (6H, t, J
.0 Hz, 2 x CH ); δ (100 MHz; CDCl ) 162.4 (C=O, J 4.5 Hz), 157.5, 149.0, 133.6, 131.8, 127.9, 121.9, 108.1
ArC and thiazolyl-C), 63.6 (OCH , J 6.5 Hz), 35.6 (PCH , J 130.6 Hz) and 16.5 (CH , J 6.0 Hz).
H
3
H,H
H,H
2
3
2
P,H
2
H,H
2
3
C
3
C,P
2
1
3
(
2
C,P
2
C,P
3
C,P
Diethyl {N-[4-(4-fluorophenyl)thiazol-2-yl]carbamoyl}methylphosphonate (3d) Brown solid (0.0651 g, 70%),
o
+
-1
mp 72-74 C; [HRMS: m/z calculated for C H FN O PS (MH ) 373.0787. Found 373.0786]; ν / cm 1680
1
5
19
2
4
max
3
4
(
(
C=O) and 3159 (NH); δ (400 MHz; CDCl ) 10.89 (1H, br s, NH), 7.74 (2H, dd, J =8.3 Hz, J 5.6, ArH), 7.06
H
3
H,H
F,H
3
3
2
2H, t, J JH,H 8.4 Hz, ArH), 6.92 (1H, s, thiazolyl-H), 4.20 (4H, m, 2 x OCH ), 3.18 (2H, d, J 21 Hz, PCH ) and
F,H
2
P,H
2
2
3
1
1
.38 (6H, t, J 7.0 Hz, 2 x CH ); δ (100 MHz; CDCl ) 162.8 ( J 247 Hz, ArC), 162.3 (C=O, J 4.6 Hz), 157.3,
H,H
3
C
3
F,C
C,P
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Olawode, E. O. et al.
4
3
2
2
1
3
49.3, 130.9 ( J 2.7 Hz, ArC), 128.0 ( J 8.1 Hz, ArC), 115.6 ( J 22 Hz, ArC), 107.3, 63.5 ( J 6.5 Hz, OCH2),
F,C
F,C
F,C
C,P
1
3
5.6 ( J 131 Hz, PCH ), 16.5 ( J 6.0 Hz, CH3).
C,P
2
C,P
Diethyl {N-[4-(4-nitrophenyl)thiazol-2-yl]carbamoyl}methylphosphonate (3e). Brown solid (0.070 g, 70%), mp
o
+
-1
8
8-90 C; [HRMS: m/z calculated for C H N O SP (MH ) 400.0732. Found 400.0717]; ν / cm 1683 (C=O)
1
5
19
3
6
max
3
3
and 3165 (NH); δ (400 MHz; acetone-d ) 10.84 (1H, br s, NH), 8.25 (2H, d, J 8.8 Hz ArH), 8.10 (2H, d, J
.8 Hz, ArH), 7.66 (1H, s, thiazolyl-H), 4.24 (4H, m, 2 x OCH ), 3.38 (2H, d, J 22 Hz, PCH ) and 1.83 (6H, t, J
.1 Hz, 2 x CH ); δ (100 MHz; acetone-d ) 164.2 (C=O, J 5.7 Hz), 159.0, 148.2, 147.8, 141.4, 127.5, 124.7,
12.6 (ArC and thiazolyl-C), 63.5 (OCH , J 6.2 Hz), 35.9 (PCH , J 130.1 Hz) and 16.7 (CH , J 6.0 Hz).
H
6
H,H
H,H
2
3
8
7
1
2
P,H
2
H,H
2
3
C
6
C,P
2
1
3
2
C,P
2
C,P
3
C,P
Diethyl [N-(4-carbethoxythiazol-2-yl)carbamoyl]methylphosphonate (3f). Brown solid (0.154 g, 87%), mp 74-
o
+
-1
7
1
7
5 C; [HRMS: m/z calculated for C H N O PS (MH ) 351.0780. Found 351.0773]; ν / cm 1683 (NC=O),
1
2
20
2
6
max
3
721 (OC=O) and 3165 (NH); δ (400 MHz; CDCl ) 11.08 (1H, br s, NH), 7.78 (1H, s, thiazolyl-H), 4.36 (2H, q, J
.0 Hz, OCH ), 4.32-4.15 (4H, m, 2 x OCH ), 3.25 (2H, d, J 22 Hz, PCH ) and 1.45-1.33 (9H, overlapping m,
H
3
H,H
2
2
2
P,H
2
1
3
2
CH ); δ (100 MHz; CDCl ) C NMR (101 MHz, CDCl ) δ 163.4 (NC=O, d, J 5.2 Hz), 161.7 (OC=O), 158.0,
3
C
3
3
C,P
2
1
1
(
42.0, 122.3 (ArC and thiazolyl-C), 63.4 (OCH , d, J 6.4 Hz), 61.5 (OCH ), 35.7 (PCH2, d, J 132 Hz), 16.5
2
C,P
2
C,P
3
CH , J 5.9 Hz) and 14.4 (CH3).
3
C,P
Diethyl [N-(4-carboxythiazol-2-yl)carbamoyl]methylphosphonate (3g).
A
solution of diethyl [(4-
carbethoxythiazol-2-yl)carbamoyl]methylphosphonate 3f (0.088 g, 0.25 mm) and KOH (0.093 g, 0.5 mmol) in
3
1
MeOH (2 mL) was stirred at room temperature for 2 h. Addition of 20% HCl (2 mL) gave the desired product
+
3
3
g as a brown viscous oil (0.0478 g, 59%); [HRMS: m/z calculated for C H N O PS (MH ) 323.0467. Found
1
0 16 2 6
-
1
23.0456]; νmax / cm 1697 (C=O), 2508-3586 (br, COOH) and 3183 (NH); δ (400 MHz; CDCl ) 11.26 (br s,
H
3
2
COOH), 11.02 (1H, br s, NH), 7.97 (1H, s, thiazolyl-H), 4.38 (4H, m, 2 x OCH ), 3.43 (2H, d, J 21 Hz, PCH ) and
2
P,H
2
1
.56-1.49 (6H, m, CH ); δ (100 MHz; CDCl ) 168.2 (COOH), 163.5 (C=O), 158.1, 142.1, 122.4 (thiazolyl-C), 63.5
3
C
3
(
OCH ), 35.8 (CH ) and 16.5 (CH ).
2
2
3
Acknowledgements
The authors thank Rhodes University for financial support and a bursary (E.O.O.) and the South African
Medical Research Council (SAMRC) for support with funds from National Treasury under its Economic
Competitiveness and Support Package.
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