Synthesis of new aminophosphonothiophene derivatives

Article abstract of DOI:10.1080/10426500307947

The reaction of γ,γ′-diphosphonylketones 1 with active methylenenitriles and sulfur in basic conditions led to the new 5-amino-2-(phosphonomethyl)-3-(phosphonoethyl)thiophenes 2. These compounds were then used in the Horner-Wadsworth-Emmons reaction to gi

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of New Aminophosphonothiophene
Derivatives
Soufiane Touil a & Hedi Zantour a
a Départemente de Chimie, Faculté des Sciences de Tunis , Laboratoire de Synthese
Organique , Tunisia
Published online: 27 Oct 2010.
To cite this article: Soufiane Touil & Hedi Zantour (2003) Synthesis of New Aminophosphonothiophene Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 178:2, 353-360, DOI: 10.1080/10426500307947
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:353–360
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390170462
SYNTHESIS OF NEW
AMINOPHOSPHONOTHIOPHENE DERIVATIVES
Soufiane Touil and Hedi Zantour
Laboratoire de Synthese Organique, De´partemente de Chimie,
Faculte´ des Sciences de Tunis, Tunisia
(Received April 4, 2002)
The reaction of
,
0-diphosphonylketones 1 with active methylenen-
itriles and sulfur in basic conditions led to the new 5-amino-2-
(phosphonomethyl)-3-(phosphonoethyl)thiophenes 2. These compounds
were then used in the Horner-Wadsworth-Emmons reaction to give
5-amino-2-alkenyl-3-(phosphonoethyl)thiophenes 3. The structure of
all obtained products was confirmed by NMR (1H, 31P, 13C) and IR
spectroscopy.
Keywords:
5-Amino-2-alkenyl-3-(phosphonoethyl)thiophenes;
5-
0
amino-2-(phosphonomethyl)-3-(phosphonoethyl)thiophenes;
diphosphonylketones
,
-
INTRODUCTION
In our preceding article,1 we reported the synthesis of
0
,
-
diphosphonylketones and showed that their reaction with phenylhy-
drazine hydrochloride carried out under the Fischer reaction conditions
leads to 2-(phosphonoethyl)3-(phosphonomethyl)indoles.
0
In order to broaden further the application field of
,
-
diphosphonylketones and persuing our research program regarding the
3
synthesis of heterocyclic compounds bearing phosphonyl groups,2 we
now report on the synthesis of the new 5-amino-2-(phosphonomethyl)-
9
3-(phosphonoethyl)thiophenes 2 by a Gewald type condensation4 of
,
0-diphosphonylketones with active methylenenitriles in the pres-
ence of sulfur.
On the other hand, we show that the Horner-Wadsworth-Emmons
(HWE) reaction10–12 of compounds 2 with aldehydes provides a conve-
nient access to 5-amino-2-alkenyl-3-(phosphonoethyl)thiophenes 3.
Address correspondence to Hedi Zantour, Laboratoire de Synthe`se Organique,
De´partement de Chimie, Faculte´ des Sciences de Tunis, 1060, Tunis, Tunisia. E-mail:
soufiane.touil@fsb.rno.tu
353

354
S. Touil and H. Zantour
It is important to note that thiophene derivatives prepared via the
Gewald reaction recently have seen an increasing interest due to the
utility of these heterocycles as a starting point for the synthesis of many
biologically active compounds.8,13–17
RESULTS AND DISCUSSION
Synthesis of 5-Amino-2-(phosphonomethyl)-
3-(phosphonoethyl)thiophenes 2
Recently, we have shown that -ketophosphonates undergo Gewald
condensation to give 2-amino-5-(phosphonomethyl)thiophenes.18 We re-
port here the extension of this reaction to
,
0-diphosphonylketones 1
which leads to a new class of aminophosphonothiophenes. Thus, treat-
ment of compounds 1 with equimolar amounts of active methyleneni-
trile and sulfur using a catalytic amount of diethylamine in ethanol as
solvent and heating the mixture at 50 C for 12–24 h gives the 5-amino-
2-(phosphonomethyl)-3-(phosphonoethyl)thiophenes 2 in 56–78% yield
(Scheme 1).
SCHEME 1
Based on some literature data,4,19 we can propose the reaction
mechanism of Scheme 1 which involves a condensation, catalyzed by

Synthesis of New Aminophosphonothiophene Derivatives
355
TABLE I 13C NMR for Compounds 2: in ppm (JCP in Hz)
2a
2b
2c
2d
2e
2f
C1
164.2
164.4
163.8
164.1
162.0
163.2
C2 138.3 (6.9) 139.5 (7.1) 140.2 (7.0) 141.3 (6.5)
C3 117.5 (16.0) 117.1 (16.4) 117.8 (15.2) 116.2 (15.5) 116.8 (15.7)
C4 102.8 111.5 101.6 112.0 103.9
143.3 (7.0)
142.5 (6.7)
115.4 (16.9)
113.4
C5 27.3 (142.6) 26.8 (141.4) 33.0 (79.4) 32.6 (78.5) 42.0 (138.8:2e1) 42.8 (138.4:2f1)
43.8 (138.5:2e2) 44.7 (138.0:2f2)
C6
28.7
27.4
29.9
29.4
25.0 (3.6)
24.7 (3.2)
C7 22.2 (145.5) 22.0 (144.3) 31.8 (80.5) 31.5 (79.9) 38.6 (144.5:2e1) 38.8 (144.2:2f1)
38.9 (145.1:2e2) 39.2 (145.9:2f2)
C8 16.0–16.4 13.9–16.3 128.6–133.5 128.4–133.2
15.9–16.2
62.1–63.9
125.7–136.2
114.8 (2e1)
115.2 (2e2)
—
14.0–16.3
61.8–63.0
125.8–135.8
164.7 (2f1)
164.9 (2f2)
61.8–63.0
14.0–16.3
C9 63.2–64.3 61.9–63.2
—
—
114.0
—
—
167.3
C10
C11
—
112.1
—
166.2
C12
C13
—
—
61.9–63.2
13.9–16.3
—
—
61.5
14.1
—
diethylamine, of the active methylenenitrile with the ketone 1. The ob-
tained intermediates I undergo a second base-catalyzed condensation
with sulfur leading to compounds 2.
The 1H, 13C, and 31P NMR data confirm the structures of compounds
2 and are in accordance with some literature data.18 The NH2 protons
show a broad singlet at = 8.2–8.8 ppm. The 13C NMR spectra display
the characteristic signals of all carbons and particularly those corre-
sponding to the thiophene ring (Table I).
In addition, 31P, 1 H, and 13C NMR analysis of compounds 2e–f shows
a mixture of two diastereoisomers in an approximate 1:1 ratio which
was estimated from the 31P NMR spectra (Table II). Indexes 1 and 2
are attributed to the major and minor diastereoisomers respectively.
Synthesis of 5-Amino-2-alkenyl-
3-(phosphonoethyl)thiophenes 3
The presence of the activated phosphonomethyl group on the thiophene
ring of compounds 2 allows them to perform HWE reaction. Thus, treat-
ment of compounds 2 with various aldehydes at room temperature, us-
ing aqueous potassium carbonate as base and THF as solvent, led to

356
S. Touil and H. Zantour
TABLE II 31P in ppm and % of Diastereoisomers for
Compounds 2
2a
28.1
28.2
—
2b
28.5
28.7
—
2c
31.4
31.5
—
2d
31.6
31.8
—
2e1
27.1
28.1
58
2e2
27.4 27.0
27.5 27.4
42
2f1
2f2
27.2
27.3
47
P1
P2
% dias
53
the 5-amino-2-alkenyl-3-(phosphonoethyl)thiophenes 3 in moderate to
good yields (Scheme 2).
SCHEME 2
The reaction was found to be highly stereoselective. Indeed, com-
pounds 3d–f where a mixture of Z and E isomers is possible, have ex-
clusively the E configuration. This was evidenced by the absence of sig-
nal doubling in the 31P (Table III), 13C (Table IV) and 1H NMR spectra.
3
The E configuration was assigned on the basis of JH
constant values (16.1–16.8 Hz).
coupling
C
C H
EXPERIMENTAL SECTION
1H, 31P, and 13C NMR spectra were recorded with CDCl3 as solvent,
on a Bruker-300 spectrometer. The chemical shifts are reported in ppm
relative to TMS (internal reference) for 1H and 13C NMR and relative to
TABLE III 31P in ppm for Compounds 3
3a
27.8
3b
28.0
3c
31.1
3d
31.5
3e
30.8
3f
27.3
31P

Synthesis of New Aminophosphonothiophene Derivatives
357
TABLE IV 13C NMR for Compounds 3: in ppm (JCP in Hz)
3a
3b
3c
3d
3e
3f
C1 163.6
164.0
163.2
162.7
163.8
164.1
C2 144.0
144.3
144.9
145.5
145.8
144.7
C3 118.9 (15.5) 118.3 (15.7) 119.2 (15.0) 118.8 (15.2) 119.1 (15.0) 119.4 (15.3)
C4 102.0
C5 137.5
C6 116.0
C7 29.1
113.2
137.1
115.7
28.0
101.2
137.3
115.8
30.1
101.5
138.4
125.6
30.4
113.8
141.9
126.4
29.5
101.8
142.5
126.8
28.4
C8 22.8 (144.2) 22.4 (143.6) 32.2 (78.5)
32.5 (79.7)
31.9 (79.0)
22.1 (144.6)
C9 16.1 (6.5)
C10 61.4 (6.3)
16.0 (6.5)
61.2 (6.2)
—
166.3
61.8
128.4–133.5 128.2–133.2 128.1–136.3 16.0 (6.7)
—
—
—
61.2 (6.3)
C11
—
—
112.8
—
27.0
112.6
—
128.1–136.3 128.0–134.6
C12 112.5
167.1
61.2
14.9
112.8
—
—
C13
C14
—
—
15.2
—
—
85% H3PO4 (external reference) for 31P NMR. The coupling constants
1
are reported in Hz. For the H NMR, the multiplicities of signals are
indicated by the following abbreviations: s: singlet, d: doublet, t: triplet,
q: quartet, qp: quintet, m: multiplet.
IR spectra were recorded in CHCl3, on a Perkin Elmer Paragon 1000
PC spectrometer.
The progress of the reactions was controlled by TLC.
Purification of products was performed by column chromatography
using silica gel 60 (Fluka).
0
Synthesis of , -Diphosphonylketones 1
The starting , 0-diphosphonylketones 1 were synthesized as described
in our preceding article.1
Synthesis of 5-Amino-2-(phosphonomethyl)-
3-(phosphonoethyl)thiophenes 2
To a mixture of
,
0-diphosphonylketone (0.01 mmol), active methyle-
nenitrile (0.01 mmol) and sulfur (0.011 mmol, 0.35 g) in ethanol (40 mL),
was added dropwise with stirring a solution of 1 mL of diethylamine in
10 mL of ethanol. The reaction mixture was then stirred at 50 C for the

358
S. Touil and H. Zantour
time tr. The ethanol was removed under reduced pressure then CHCl3
(100 mL) was added. The organic phase was washed with 5% aqueous
HCl solution (2 50 mL), dried over MgSO4, and concentrated in vacuo.
The obtained residue was chromatographed on silica gel column using
a mixture of ethanol and petroleum ether 9/1 as eluent.
1
3
2a: Oil; Yield = 74%; tr = 12 h; H NMR: = 1.30 (t; 6H; JHH = 7.0;
3
CH3 CH2 O); 1.42 (t; 6H; JHH = 6.9; CH3 CH2 O); 1.92–3.60 (m;
3
3
6H; CH2 P O and CH2 CH2 P O); 3.96 (qp; 4H; JHH = JPH = 6.9;
3
3
CH3 CH2 O); 4.16 (qp; 4H; JHH = JPH = 7.0; CH3 CH2 O); 8.27
1
1
(broad s; 2H; NH2); IR:
O = 1260 cm
;
CN = 2214 cm
;
P
1
= 3281–3390 cm
.
NH2
2b: Oil; Yield = 69%; tr = 24 h; 1H NMR: = 1.12–1.45 (m; 15H;
CH3 CH2 O); 1.88–3.52 (m; 6H; CH2 P O and CH2 CH2 P O);
3.98–4.20 (m; 10H; CH3 CH2 O); 8.45 (broad s; 2H; NH2); IR:
1
1
1
O = 1268 cm
;
CO Et = 1670 cm
;
= 3377–3484 cm
.
P
NH2
2
1
2c: m.p. 110 C; Yield = 62%; tr = 12 h; H NMR: = 1.87–3.31 (m;
6H; CH2 P O and CH2 CH2 P O); 6.90–7.87 (m; 20H; H arom.);
1
1
8.34 (broad s; 2H; NH2); IR:
O = 1265 cm
;
CN = 2201 cm
;
P
1
= 3276–3388 cm
.
NH2
2d: m.p. 118 C; Yield = 56%; tr = 24 h; 1H NMR: = 1.32 (t;
3
3H; JHH = 7.3; CH3 CH2 O); 1.90–3.48 (m; 6H; CH2 P O and
3
CH2 CH2 P O); 4.27 (q; 2H; JHH = 7.3; CH3 CH2 O); 7.02–7.93
1
(m; 20H; H arom.); 8.52 (broad s; 2H; NH2); IR
O = 1273 cm
;
P
1
1
CO Et = 1672 cm
;
= 3372–3480 cm
.
NH2
2
2e: Oil; Yield = 78%; tr = 12 h; 1H NMR: = 0.90–1.28 (m; 12 H;
CH3 CH2 O); 2.78–3.40 (m; 2H; CH2 C C); 3.51–3.74 (m; 2H;
CH P O); 3.85–4.19 (m; 8H; CH3 CH2 O); 6.80–7.43 (m; 10H; H
1
1
arom.); 8.60 (broad s; 2H; NH2); IR:
O = 1262 cm
;
CN = 2220 cm
;
P
1
= 3289–3394 cm
.
NH2
2f: Oil; Yield = 70%; tr = 24 h; 1H NMR: = 0.92–1.35 (m; 15 H;
CH3 CH2 O); 2.86–3.44 (m; 2H; CH2 C C); 3.60–3.81 (m; 2H;
CH P O); 3.92–4.26 (m; 10H; CH3 CH2 O); 6.87–7.49 (m; 10H;
1
H arom.); 8.82 (broad s; 2H; NH2); IR:
O = 1274 cm
;
=
P
CO2Et
1
1
1667 cm
;
= 3380–3486 cm
.
NH2
Synthesis of 5-Amino-2-alkenyl-
3-(phosphonoethyl)thiophenes 3
To a mixture of 5-amino-2-(phosphonomethyl)-3-(phosphonoethyl)-
thiophenes 2 (0.005 mmol) and aldehyde (0.006 mmol) in THF (25 mL),
was added dropwise with stirring, a 6 M aqueous K2CO3 solution (2 mL).
The reaction mixture was then stirred at room temperature for an ad-
ditional 24 h. It was then diluted with water (50 mL) and extracted

Synthesis of New Aminophosphonothiophene Derivatives
359
with CHCl3 (2 50 mL). The organic phase was dried over MgSO4 and
concentrated in vacuo. The obtained residue was chromatographed on
silica gel column using a mixture of ethanol and petroleum ether 9/2 as
eluent.
3
3a: Oil; Yield = 62%; 1H NMR:
= 1.26 (t; 6H; JHH = 7.0;
CH3 CH2 O); 1.86–3.05 (m; 4H; CH2 CH2 P O); 4.01 (qp; 4H;
3JHH = JPH = 7.0; CH3 CH2 O); 5.68–6.44 (m; 3H; CH2 CH); 8.11
3
1
1
(broad s; 2H; NH2); IR:
O = 1262 cm
;
CN = 2212 cm
;
P
1
= 3270–3378 cm
.
NH2
3b: Oil; Yield = 57%; 1H NMR:
= 1.22 (t; 6H; JHH = 7.0;
3
3
CH3 CH2 O); 1.30 (t; 3H; JHH = 7.2; CH3 CH2 O); 1.82–2.98 (m;
3
3
4H; CH2 CH2 P O); 3.97 (qp; 4H; JHH = JPH = 7.0; CH3 CH2 O);
3
4.25 (q; 2H; JHH = 7.2; CH3 CH2 O); 5.53–6.39 (m; 3H; CH2 CH);
1
1
8.20 (broad s; 2H; NH2); IR:
O = 1265 cm
;
CO Et = 1668 cm
;
P
2
1
= 3384–3492 cm
.
NH2
3c: m.p. = 74 C; Yield = 52%; 1H NMR: = 1.79–3.15 (m; 4H;
CH2 CH2 P O); 5.60–6.41 (m; 3H; CH2 CH); 7.10–7.94 (m; 10H; H
1
1
arom.); 8.17 (broad s; 2H; NH2); IR
O = 1268 cm
;
CN = 2208 cm
;
P
1
= 3283–3395 cm
.
NH2
3d: m.p. 81 C; Yield = 66%; 1H NMR: = 1.74–3.20 (m; 4H;
3
CH2 CH2 P O); 1.91 (d; 3H; JHH = 5.2; CH3 CH CH); 6.33–6.48
(m; 1H; CH3 CH CH); 6.50 (d; 1H; 3JHH = 16.8; CH3 CH CH); 7.04–
1
7.87 (m; 10H; H arom.); 8.08 (broad s; 2H; NH2); IR:
O = 1265 cm
;
P
1
1
CN = 2215 cm
;
= 3290–3396 cm
.
NH2
1
3
3e: m.p. 105 C; Yield = 70%; H NMR: = 1.28 (t; 3H; JHH = 7.3;
CH3 CH2 O); 1.77–3.12 (m; 4H; CH2 CH2 P O); 4.21 (q; 2H;
3JHH = 7.3; CH3 CH2 O); 7.06–7.90 (m; 15H; H arom.); 7.14 (d; 1H;
3JHH = 16.1; Ph CH CH); 7.21 (d; 1H; JHH = 16.1; Ph CH CH);
3
1
1
8.24 (broad s; 2H; NH2); IR:
O = 1270 cm
;
CO Et = 1671 cm
;
P
2
1
= 3376–3483 cm
.
NH2
3f: Oil; Yield = 79%; 1H NMR:
= 1.23 (t; 6H; JHH = 7.0;
3
CH3 CH2 O); 1.80–3.02 (m; 4H; CH2 CH2 P O); 3.99 (qp;
3
3
3
4H; JHH = JPH = 7.0; CH3 CH2 O); 7.02 (d; 1H; JHH = 16.3;
3
Ph CH CH); 7.11 (d; 1H; JHH = 16.3; Ph CH CH); 7.30–7.54
1
(m; 5H; H arom.); 8.15 (broad s; 2H; NH2); IR:
O = 1266 cm
;
P
1
1
CN = 2211 cm
;
= 3281–3387 cm
.
NH2
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