First synthesis of phosphorylated thienopyridines from 2-amino-3- cyanothiophenes and β-ketophosphonates

Article abstract of DOI:10.1080/10426507.2012.700354

In a simple procedure, treatment of 2-amino-3-cyanothiophenes with β-ketophosphonates, under acid catalysis, leads to new 4-amino-5- phosphonothieno[2,3-b]pyridines in good to excellent yields. The structure of obtained products was confirmed by NMR (¹H, ³¹P, ¹³C) and IR spectroscopies, and by mass spectrometry.

Full text of DOI:10.1080/10426507.2012.700354

This article was downloaded by: [Fudan University]
On: 31 May 2013, At: 15:21
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
First Synthesis of Phosphorylated
Thienopyridines from 2-
amino-3-cyanothiophenes and β-
ketophosphonates
Khaoula Khalladi a & Soufiane Touil a
a Laboratory of Heteroatom Organic Chemistry, Department of
Chemistry, Faculty of Sciences of Bizerta , University of Carthage ,
Jarzouna , Tunisia
Accepted author version posted online: 22 Jun 2012.Published
online: 31 May 2013.
To cite this article: Khaoula Khalladi & Soufiane Touil (2013): First Synthesis of Phosphorylated
Thienopyridines from 2-amino-3-cyanothiophenes and β-ketophosphonates, Phosphorus, Sulfur, and
Silicon and the Related Elements, 188:6, 711-718
To link to this article: http://dx.doi.org/10.1080/10426507.2012.700354
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 188:711–718, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.700354
FIRST SYNTHESIS OF PHOSPHORYLATED
THIENOPYRIDINES FROM
2-AMINO-3-CYANOTHIOPHENES AND
β-KETOPHOSPHONATES
Khaoula Khalladi and Soufiane Touil
Laboratory of Heteroatom Organic Chemistry, Department of Chemistry, Faculty
of Sciences of Bizerta, University of Carthage, Jarzouna, Tunisia
GRAPHICAL ABSTRACT
O
H2N
R1
P(R3)2
CN
O
R1
R4
TsOH (cat.)
P(R3)2
+
R4
Toluene, reflux, 72 h
NH2
R2
O
S
R2
N
S
16 examples
up to 97% yield
Abstract In
a simple procedure, treatment of 2-amino-3-cyanothiophenes with β-
ketophosphonates, under acid catalysis, leads to new 4-amino-5-phosphonothieno[2,3-
b]pyridines in good to excellent yields. The structure of obtained products was confirmed by
NMR (1H, 31P, 13C) and IR spectroscopies, and by mass spectrometry.
Keywords Thienopyridines; phosphonothienopyridines; phosphorylated heterocycles; fused
heterocycles; β-ketophosphonates; 2-amino-3-cyanothiophenes
INTRODUCTION
Thienopyridines are very important heterocyclic compounds due to their broad spec-
trum of biological properties including anticancer,1,2 antithrombotic,3,4 anti-inflammatory,5
and antimicrobial6,7 activities. Certain thienopyridine derivatives have also found uses as
anticonvulsants,8 antidepressants,9 and calcium channel modulators.10
Various synthetic procedures for thienopyridines were reported in the literature.11
Among them, the condensation of 2-amino-3-cyanothiophenes with alkyl acetoacetates in
the presence of stannic chloride11,12 is one of the most used methods.
With this in mind, and pursuing our research program concerning the preparation
of new phosphorylated heterocycles with possible biological properties,13 we report here,
Received 11 March 2012; accepted 16 May 2012.
We thank the Tunisian Ministry of Higher Education and Scientific Research for financial support.
Address correspondence to Prof. S. Touil, Laboratory of Heteroatom Organic Chemistry, Department of
Chemistry, Faculty of Sciences of Bizerta, University of Carthage 7021 Jarzouna, Tunisia. E-mail: soufiane.
touil@fsb.rnu.tn
711

712
K. KHALLADI AND S. TOUIL
for the first time, the synthesis of thienopyridine derivatives bearing a phosphonate or a
phosphine oxide group. These phosphorus substituents could regulate important biological
functions and could improve the biological activity of such compounds, in a similar way to
that reported for other pharmaceuticals.14
The target compounds were obtained, in a simple one-pot protocol, from easily made
2-amino-3-cyanothiophenes and β-ketophosphonates, as starting materials.
RESULTS AND DISCUSSION
The starting 2-amino-3-cyanothiophenes 115 and β-ketophosphonates 216 were easily
prepared according to the reported procedures. Our initial attempts at synthesizing the
desired phosphonothienopyridines involved the coupling of the former reactants in the
presence of stannic chloride as acid catalyst. Unfortunately, the reaction failed and gave only
the starting materials even after refluxing the mixture in toluene for long periods of time. A
great improvement was observed when the reaction was performed with p-toluenesulfonic
acid (TsOH) instead of stannic chloride. Indeed, the condensation of thiophenes 1 with β-
ketophosphonates 2, performed in refluxing toluene, for 72 h, in the presence of a catalytic
amount of TsOH, led to the formation of 4-amino-5-phosphonothieno[2,3-b]pyridines 3
in 62–97% yield (Scheme 1). In order to demonstrate the efficiency and generality of
this protocol, we examined the reactions of various 2-amino-3-cyanothiophenes and β-
ketophosphonates (Table 1). All substrates react to give the corresponding thienopyridines
in good to high yields.
A plausible mechanism for the formation of compounds 3 is depicted in Scheme 2.
The transformation is believed to proceed via a nucleophilic attack of the amino group on
the β-ketophosphonate, giving rise to an imine intermediate. A subsequent intramolecular
cyclization through the nucleophilic attack of the enamine tautomer at the nitrile group,
leads to the final products 3.
The structures of phosphonothienopyridines 3 were established through IR, NMR (1H,
31P, 13C), and mass spectral data. The IR spectra revealed the presence of absorption bands
toward 1250 and 3300 cm−1 corresponding to the P = O and NH2 vibrators, respectively.
1
The H NMR spectrum of each compound 3 showed, in particular, a broad singlet at
4–5 ppm, ascribable to the NH2 protons. The 31P NMR shift recorded for compounds
3 was δ = 20–27 ppm, which is consistent with the phosphoryl chemical shift values.
The 13C NMR spectra display the characteristic signals of all carbons and particularly
those corresponding to the heterocyclic ring. Of particular note is the C–P carbon that
O
H2N
R1
P(R3)2
CN
O
R1
R4
TsOH (cat.)
P(R3)2
+
R4
Toluene, reflux
NH2
R2
O
S
1
R2
N
2
S
3
Scheme 1

FIRST SYNTHESIS OF PHOSPHORYLATED THIENOPYRIDINES
713
Table 1 Synthesis of 4-amino-5-phosphonothieno[2,3-b]pyridines 3
Entry
R1
R2
R3
R4
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(CH2)4
(CH2)4
(CH2)4
(CH2)3
(CH2)3
Ph-CH2
Ph-CH2
Ph-CH2
Ph
CH3
CH3
CH3
CH3
OEt
OMe
Ph
OEt
Ph
Ph
Ph
Ph
H
Ph-CH2
Ph-CH2
Ph
Ph
iPr
CH3
CH3
Ph
CH3
Ph
OEt
OMe
OMe
Ph
OMe
OMe
OMe
OEt
OEt
OEt
OEt
3a
3b
3c
3d
3e
Ph
Ph
CH3
Ph
CH3
Ph
Ph
CH3
Ph
Ph
CH3
91
90
97
68
84
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
91
90
97
68
84
94
96
78
93
62
71
76
72
67
86
79
CH3
CH3
CH3
CH3
H
aIsolated yield.
resonates as a doublet around 90–120 ppm. Such a doublet is characteristic of the coupling
with phosphorus with a 1JCP coupling constant of about 80–130 Hz. The structures of the
compounds 3 were supported additionally by the mass spectra, which showed the correct
molecular ion peaks.
R1
R1
CN
O
CN
R4
O
H
C
H
P(R3)2
TsOH
- H2O
+
NH2
N
C
R4
P(R3)2
R2
R2
O
S
1
S
2
O
P
HN
H
R1
(R3)
C
N
R1
2
O
P (R3)2
R4
N
H
C
R4
C
R2
R2
N
S
S
H
O
H2N
P(R3)2
R1
R4
R2
N
S
3
Scheme 2

714
K. KHALLADI AND S. TOUIL
CONCLUSION
A simple and efficient methodology has been developed for the synthesis of 4-amino-
5-phosphonothieno[2,3-b]pyridines, from easily made 2-amino-3-cyanothiophenes and β-
ketophosphonates. To the best of our knowledge, this is the first synthesis of thienopyridine
derivatives bearing a phosphonate or a phosphine oxide group.
EXPERIMENTAL
1
The H, 31P, and 13C NMR spectra were recorded with CDCl3 as the solvent, on a
Bruker-300 spectrometer. The chemical shifts are reported in ppm relative to tetramethyl-
1
silane (TMS) (internal reference) for the H and 13C NMR and relative to 85% H3PO4
(external reference) for the 31P NMR. The coupling constants are reported in hertz. For
the 1H NMR, the multiplicities of signals are indicated by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; qp, quintet; sept, septuplet; and m, multiplet. Sample
1H, 13C, and 31P spectra for 3d and 3c are shown in Figures S1–S6 in the Supplemental
Materials (posted online only).
Mass spectra were determined on a Micromass Quatro Ultima Pt spectrometer, un-
der electrospray ionization (ESI) conditions, or on an Agilent 5975B spectrometer, under
electronic impact (EI) conditions. The IR spectra were recorded on a Nicolet IR200 spec-
trometer. Purification of products was performed by column chromatography using silica
gel 60 (Fluka).
General procedure for the synthesis of 4-amino-5-phosphonothieno[2,3-
b]pyridines 3. A mixture of 2-amino-3-cyanothiophene 1 (0.005 mol), β-ketophosphonate
2 (0.005 mol), and TsOH (0.1 g) in dry toluene (25 mL) was refluxed for 72 h in
Dean–Stark apparatus. The reaction mixture was cooled and extracted with a saturated
sodium bicarbonate solution (30 mL) and then with water (2 × 30 mL). The organic phase
was dried over Na2SO4 and concentrated under vacuum. The crude product was purified
by chromatography on a silica gel column using diethylether as eluent.
3a: Light brown solid; mp = 174–176 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 20.5 ppm; 1H NMR (300 MHz, CDCl3): δ = 1.19 (t, 6H, 3JH-H = 6.0 Hz, CH3–CH2);
3
1.55–2.33 (m, 8H, cyclic H); 2.44 (s, 3H, CH3–C N); 3.98 (qp, 4H, 3JH-H = JP-H = 6.0 Hz,
CH3–CH2); 5.04 (broad s, 2H, NH2); 13C NMR (75.5 MHz, CDCl3): δ = 16.0 (d, 3JCP
=
6.0 Hz, CH3–CH2–O); 21.8 (s, CH2–CH2–C C S); 22.9 (s, CH2 CH2 CH2 C C S);
23.5 (s, CH2–(CH2)3–C C S); 24.0 (s, CH2–C C S); 31.0 (s, CH3–C N); 61.7
1
(d, 2JCP = 6.0 Hz, CH2–O); 104.5 (d, JCP = 104.2 Hz, C–P O); 116.8 (s, C C S);
2
122.3 (s, CH2–C C S); 128.7 (s, CH2–C–S); 130.8 (d, JCP = 23.4 Hz, C–NH2);
148.7 (s, N C S); 162.5 (d, 2JCP = 22.6 Hz, C N); IR (neat): νP = O = 1262 cm−1
;
νNH2 = 3211–3410 cm−1; ESI-MS: m/z = 355.2 ([M+H]+); EI-HRMS: calculated for
C16H23N2O3PS, 354.1167 (M+); found: 354.1164.
3b: Light brown solid; mp = 115–117 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 22.1 ppm; 1H NMR (300 MHz, CDCl3): δ = 1.65–2.39 (m, 8H, cyclic H);
2.23 (s, 3H, CH3–C N); 3.71 (d, 6H, 3JP-H = 12.0 Hz, CH3–O); 4.62 (broad s, 2H,
NH2); 13C NMR (75.5 MHz, CDCl3): δ = 21.2 (s, CH2–CH2–C C S); 22.4 (s,
CH2 CH2 CH2 C C S); 23.2 (s, CH2–(CH2)3–C C S); 23.5 (s, CH2–C C S);
1
30.5 (s, CH3–C N); 52.2 (d, 2JCP = 6.8 Hz, CH3–O); 116.3 (d, JCP = 104.1 Hz,
C–P O); 118.5 (s, C C S); 124.8 (s, CH2–C C S); 130.9 (s, CH2–C–S); 141.1 (d,

FIRST SYNTHESIS OF PHOSPHORYLATED THIENOPYRIDINES
715
2JCP = 19.6 Hz, C–NH2); 144.0 (s, N C S); 163.8 (d, 2JCP = 26.8 Hz, C N); IR (neat):
νP = O = 1234 cm−1; νNH2 = 3211–3432 cm−1; ESI-MS: m/z 327.1 ([M+H]+).
3c: Light brown solid; mp = 198–199 ◦C; 31P NMR (121.5 MHz, CDCl3):
1
δ = 27.3 ppm; H NMR (300 MHz, CDCl3): δ = 1.63–2.53 (m, 8H, cyclic H); 3.76
(broad s, 2H, NH2); 7.12–7.95 (m, 15H, arom-H); 13C NMR (75.5 MHz, CDCl3):
δ = 22.0 (s, CH2–CH2–C C S); 23.0 (s, CH2 CH2 CH2 C C S); 24.1 (s,
1
CH2–(CH2)3–C C S); 24.6 (s, CH2–C C S); 92.0 (d, JCP = 105.7 Hz, C–P O);
2
114.6 (s, C C S); 127.1 (s, CH2–C C S); 130.9 (s, CH2–C–S); 132.2 (d, JCP
=
33.2 Hz, C–NH2); 156.5 (s, N C S); 161.8 (d, 2JCP = 16.6 Hz, C N); Phenyl carbons:
128.2, 128.5, 128.7, 129.1, 130.1, 131.0, 131.3, 131.7, 133.4, 134.0, 134.8, 138.0; IR
(neat): νP = O = 1262 cm−1; νNH2 = 3211–3410 cm−1; ESI-MS: m/z 481.2 ([M+H]+);
EI-HRMS: calculated for C29H25N2OPS, 480.1425 (M+); found: 480.1426.
3d: Light brown solid; mp = 98–100 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 20.3 ppm; 1H NMR (300 MHz, CDCl3): δ = 1.24 (t, 6H, 3JH-H = 6.0 Hz, CH3–CH2);
3
1.59–2.81 (m, 6H, cyclic H); 2.31 (s, 3H, CH3–C N); 4.10 (qp, 4H, 3JH-H = JP-H
=
6.0 Hz, CH3–CH2); 5.08 (broad s, 2H, NH2); 13C NMR (75.5 MHz, CDCl3): δ = 15.2
(d, 3JCP = 6.0 Hz, CH3–CH2–O); 26.4 (s, CH2–CH2–C C S); 27.4 (s, CH2–C C S);
2
28.6 (s, CH2–(CH2)2–C C S); 30.4 (s, CH3–C N); 61.6 (d, JCP = 6.0 Hz, CH2–O);
1
111.9 (d, JCP = 103.4 Hz, C–P O); 115 (s, C C S); 123.5 (s, CH2–C C S); 128.6
(s, CH2–C--S); 137.0 (d, 2JCP = 21.9 Hz, C–NH2); 143.7 (s, N C S); 165.2 (d, 2JCP
= 25.7 Hz, C N); IR (neat): νP = O = 1262 cm−1; νNH2 = 3215–3422 cm−1; ESI-MS:
m/z 341.1 ([M+H]+).
3e: Light brown solid; mp = 119–120 ◦C; 31P NMR (121.5 MHz, CDCl3):
1
δ = 27.4 ppm; H NMR (300 MHz, CDCl3): δ = 1.05–2.52 (m, 6H, cyclic H); 5.31
(broad s, 2H, NH2); 6.96–7.88 (m, 15H, arom-H); 13C NMR (75.5 MHz, CDCl3): δ = 27.3
(s, CH2–CH2–C C S); 28.4 (s, CH2–C C S); 29.2 (s, CH2–(CH2)2–C C S); 116.2
(s, C C S); 104.8 (d, 1JCP = 100.4 Hz, C--P = O); 127.9 (s, CH2–C = C S); 131.7 (s,
CH2–C–S); 133.3 (d, 2JCP = 36.2 Hz, C–NH2); 141.5 (s, N–C--S); 166.8 (d, 2JCP = 29.4 Hz,
C N); Phenyl carbons: 128.1, 128.2, 128.5, 128.7, 129.1, 130.7, 131.1, 131.3, 131.5,
132.1, 132.6, 137.0; IR (neat): νP = O = 1262 cm−1; νNH2 = 3211–3410 cm−1; ESI-MS:
m/z = 467.3 ([M+H]+).
3f: Light brown solid; mp = 132–134 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 19.9 ppm; 1H NMR (300 MHz, CDCl3): δ = 1.20 (t, 6H, 3JH-H = 6.0 Hz, CH3–CH2);
3.59 (s, 2H, CH2-Ph); 4.06 (qp, 4H, 3JH-H = JP-H = 6.0 Hz, CH3–CH2); 4.37 (broad
3
s, 2H, NH2); 7.04–7.94 (m, 15H, arom-H); 13C NMR (75.5 MHz, CDCl3): δ = 15.2
(d, 3JCP = 6.0 Hz, CH3–CH2–O); 32.6 (s, CH2–C C S); 61.7 (d, 2JCP = 6.8 Hz, CH2–O);
1
113.6 (d, JCP = 122.3 Hz, C–P = O); 124.3 (s, C = C S); 126.0 (s, CH2–C = C S);
2
132.1 (s, CH2–C–S); 132.2 (d, JCP = 18.9 Hz, C–NH2); 143.6 (s, N C S); 160.8 (d,
2JCP = 28.3 Hz, C N); Phenyl carbons: 125.3, 126.7, 126.8, 127.2, 127.5, 127.6, 127.8,
128.0, 128.3, 128.8, 135.5, 138.0; IR (neat): νP = O = 1278 cm−1; νNH2 = 3207–3352 cm−1
;
ESI-MS: m/z = 529.2 ([M+H]+).
3g: Light brown solid; mp = 120–122 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 22.9 ppm; H NMR (300 MHz, CDCl3): δ = 3.59 (d, 6H, 3JP-H = 6.0 Hz, CH3–O);
1
4.37 (s, 2H, CH2-Ph); 5.43 (broad s, 2H, NH2); 7.01–7.89 (m, 15H, arom-H); 13C NMR
(75.5 MHz, CDCl3): δ = 32.9 (s, CH2-Ph); 52.4 (d, 2JCP = 6.8 Hz, CH3–O); 112.9 (d,
1JCP = 118.5 Hz, C–P = O); 122.5 (s, C = C S); 126.2 (s, CH2–C = C S); 129.1 (s,
Ph–C–S); 132.2 (d, 2JCP = 18.8 Hz, C–NH2); 144.1 (s, N C S); 161.2 (d, 2JCP = 24.2 Hz,

716
K. KHALLADI AND S. TOUIL
C N); Phenyl carbons: 124.5, 127.3, 127.4, 127.5, 127.7, 127.8, 127.9, 128.0, 128.2,
128.7, 137.0, 138.3; IR (neat): νP = O = 1272 cm−1; νNH2 = 3211–3342 cm−1; ESI-MS:
m/z = 501.1 ([M+H]+).
3h: Light brown solid; mp = 112–114 ◦C; 31P NMR (121.5 MHz, CDCl3):
1
δ = 22.5 ppm; H NMR (300 MHz, CDCl3): δ = 2.35 (s, 3H, CH3–C N); 3.70 (d,
6H, 3JP-H = 9.0 Hz, CH3–O); 3.89 (s, 2H, CH2-Ph); 4.71 (broad s, 2H, NH2); 7.04–7.89 (m,
10H, arom-H); 13C NMR (75.5 MHz, CDCl3): δ = 28.5 (s, CH3–C N); 32.6 (s, Ph-CH2);
60.8 (d, 2JCP = 5.3 Hz, CH3–O); 112.9 (d, 1JCP = 123.0 Hz, C–P = O); 114.4 (s, C = C S);
125.0 (s, CH2–C = C S); 131.2 (s, Ph-C–S); 132.4 (d, 2JCP = 27.2 Hz, C–NH2); 143.9 (s,
N C S); 160.5 (d, 2JCP = 29.4 Hz, C N); Phenyl carbons: 125.4, 126.5, 127.3, 127.5,
127.8, 128.3, 128.9, 138.0; IR (neat): νP = O = 1245 cm−1; νNH2 = 3219–3460 cm−1
ESI-MS: m/z = 439.1 ([M+H]+).
;
3i: Light brown solid; mp = 138–140 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 27.5 ppm; 1H NMR (300 MHz, CDCl3): δ = 6.18 (broad s, 2H, NH2); 6.96–8.18 (m,
21H, arom-H); 13C NMR (75.5 MHz, CDCl3): δ = 96.1 (d, 1JCP = 110.9 Hz, C–P = O);
124.6 (s, C = C S); 125.3 (s, Ph-C = C S); 128.6 (s, H–C--S); 132.4 (d, 2JCP = 30.2 Hz,
2
C–NH2); 141.7 (s, N C S); 166.4 (d, JCP = 27.9 Hz, C N); Phenyl carbons: 127.3,
127.9, 128.3, 128.5, 128.7, 129.0, 129.1, 129.6, 131.0, 131.1, 131.2, 131.7, 132.2,
133.1, 133.6, 137.0; IR (neat): νP = O = 1276 cm−1; νNH2 = 3211–3345 cm−1; ESI-MS:
m/z = 503.2 ([M+H]+).
3j: Light brown solid; mp = 114–116 ◦C; 31P NMR (121.5 MHz, CDCl3):
1
δ = 22.5 ppm; H NMR (300 MHz, CDCl3): δ = 2.03 (s, 3H, CH3–C C); 2.38 (s, 3H,
CH3–C N); 3.60 (d, 6H, 3JP-H = 9.0 Hz, CH3–O); 3.78 (s, 2H, CH2-Ph); 4.98 (broad
s, 2H, NH2); 6.95–7.72 (m, 5H, arom-H); 13C NMR (75.5 MHz, CDCl3): δ = 20.6 (s,
CH3–C C); 29.0 (s, CH3–C N); 32.6 (s, Ph-CH2); 55.2 (d, 2JCP = 6.8 Hz, CH3–O);
1
116.6 (d, JCP = 122.6 Hz, C–P = O); 120.2 (s, C = C S); 125.0 (s, CH3–C = C S);
2
131.1 (s, CH2–C–S); 140.1 (d, JCP = 21.1 Hz, C–NH2); 141.9 (s, N C S); 163.9
2
(d, JCP = 34.7 Hz, C N); Phenyl carbons: 124.3, 126.6, 127.8, 143.9; IR (neat):
νP = O = 1271 cm−1; νNH2 = 3211–3340 cm−1; ESI-MS: m/z = 377.0 ([M+H]+).
3k: Light brown solid; mp = 118–119 ◦C; 31P NMR (121.5 MHz, CDCl3):
1
δ = 22.9 ppm; H NMR (300 MHz, CDCl3): δ = 2.47 (s, 3H, CH3–C C); 3.65 (d,
6H, 3JP-H = 9.0 Hz, CH3–O); 3.92 (s, 2H, CH2-Ph); 4.78 (broad s, 2H, NH2); 7.03–7.91 (m,
10H, arom-H); 13C NMR (75.5 MHz, CDCl3): δ = 11.9 (s, CH3–C C); 35.5 (s, Ph-CH2);
52.1 (d, 2JCP = 6.8 Hz, CH3–O); 110.6 (d, 1JCP = 132.1 Hz, C–P = O); 120.1 (s, C = C S);
125.1 (s, CH3–C = C S); 130.4 (s, CH2–C–S); 137.7 (d, 2JCP = 33.2 Hz, C–NH2); 139.9
(s, N C S); 159.8 (d, 2JCP = 33.2 Hz, C N); Phenyl carbons: 124.3, 126.8, 127.2, 127.7,
128.0, 129.1, 132.7, 143.8; IR (neat): νP = O = 1272 cm−1; νNH2 = 3219–3340 cm−1
ESI-MS: m/z = 439.2 ([M+H]+).
;
3l: Light brown solid; mp = 85–87 ◦C; 31P NMR (121.5 MHz, CDCl3): δ = 23.1 ppm;
1H NMR (300 MHz, CDCl3): δ = 2.34 (s, 3H, CH3–C C); 3.55 (d, 6H, 3JP-H = 11.4 Hz,
CH3–O); 5.33 (broad s, 2H, NH2); 6.91–7.79 (m, 10H, arom-H); 13C NMR (75.5 MHz,
CDCl3): δ = 14.1 (s, CH3–C C); 53.2 (d, 2JCP = 6.0 Hz, CH3–O); 116.5 (d, 1JCP = 80.8 Hz,
C–P = O); 121.2 (s, C = C S); 125.3 (s, CH3–C = C S); 130.5 (s, Ph-C–S); 133.6
2
(d, 2JCP = 27.2 Hz, C–NH2); 138.4 (s, N C S); 161.9 (d, JCP = 24.9 Hz, C N);
Phenyl carbons: 123.0, 128.3, 128.6, 128.7, 128.9, 129.2, 133.1, 137.1; IR (neat):
νP = O = 1273 cm−1; νNH2 = 3217–3340 cm−1; ESI-MS: m/z = 425.1 ([M+H]+); EI-
HRMS: calculated for C22H21N2O3PS, 424.1010 (M+); found: 424.1014.

FIRST SYNTHESIS OF PHOSPHORYLATED THIENOPYRIDINES
717
3m: Light brown solid; mp = 189–191 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 21.9 ppm; 1H NMR (300 MHz, CDCl3): δ = 1.34 (t, 6H, 3JH-H = 6.0 Hz, CH3–CH2);
3
2.21 (s, 3H, CH3–C N); 2.31 (s, 3H, CH3–C C); 4.16 (qp, 4H, 3JH-H = JP-H = 6.0 Hz,
CH3–CH2); 5.56 (broad s, 2H, NH2); 6.63–7.49 (m, 5H, arom-H); 13C NMR (75.5 MHz,
3
CDCl3): δ = 14.2 (s, CH3–C C); 16.2 (d, JCP = 6.0 Hz, CH3–CH2–O); 31.3 (s,
CH3–C N); 62.6 (d, 2JCP = 6.0 Hz, CH2–O); 111.5 (d, 1JCP = 114.7 Hz, C–P = O); 121.1
2
(s, C = C S); 126.0 (s, CH3–C = C S); 128.6 (s, Ph-C–S); 130.0 (d, JCP = 28.7 Hz,
2
C–NH2); 138.4 (s, N C S); 161.8 (d, JCP = 29.4 Hz, C N); Phenyl carbons: 126.2,
127.0, 129.2, 135.5; IR (neat): νP = O = 1262 cm−1; νNH2 = 3215–3367 cm−1; ESI-MS:
m/z = 391.3 ([M+H]+).
3n: Light brown solid; mp = 150–152 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 20.0 ppm; 1H NMR (300 MHz, CDCl3): δ = 0.79 (d, 6H, 3JH-H = 6.0 Hz, (CH3)2CH);
1.17 (t, 6H, 3JH-H = 6.0 Hz, CH3–CH2); 2.19 (s, 3H, CH3–C C); 3.55 (sept, 1H,
3
3JH-H = 6.0 Hz, (CH3)2CH); 4.02 (qp, 4H, 3JH-H = JP-H = 6.0 Hz, CH3–CH2); 5.32
(broad s, 2H, NH2); 6.99–8.01 (m, 5H, arom-H); 13C NMR (75.5 MHz, CDCl3): δ = 12.6 (s,
CH3–C C);16.3(d, 3JCP =6.8Hz, CH3–CH2–O); 22.3(s, (CH3)2CH); 26.5(s, (CH3)2CH);
62.5 (d, 2JCP = 6.8 Hz, CH2–O); 114.1 (d, 1JCP = 128.3 Hz, C–P = O); 125.2 (s, C = C S);
127.2 (s, CH3–C C S); 131.5 (s, CH C S); 137.2 (d, 2JCP = 26.4 Hz, C NH2); 140.9
(s, N C S); 160.3 (d, 2JCP = 27.2 Hz, C N); Phenyl carbons: 127.7, 128.5, 133.0, 143.2;
IR (neat): νP = O = 1277 cm−1; νNH2 = 3220–3343 cm−1; ESI-MS: m/z = 419.2 ([M+H]+).
3o: Light brown solid; mp = 155–156 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 19.9 ppm; 1H NMR (300 MHz, CDCl3): δ = 1.06 (t, 6H, 3JH-H = 6.0 Hz, CH3–CH2);
3
2.12 (s, 3H, CH3–C C); 2.36 (s, 3H, CH3–C S); 3.93 (qp, 4H, 3JH-H = JP-H = 6.0 Hz,
CH3–CH2); 5.31 (broad s, 2H, NH2); 6.92–7.95 (m, 5H, arom-H); 13C NMR (75.5 MHz,
3
CDCl3): δ = 12.3 (s, CH3–C S); 13.0 (s, CH3–C C); 16.0 (d, JCP = 6.0 Hz,
1
CH3–CH2–O); 62.5 (d, 2JCP = 6.8 Hz, CH2–O); 105.7 (d, JCP = 113.2 Hz, C–P = O);
120.1 (s, C = C S); 127.6 (s, CH3–C = C S); 131.2 (s, CH3–C–S); 136.7 (d,
2JCP = 39.2 Hz, C–NH2); 138.5 (s, N C S); 160.3 (d, 2JCP = 38.5 Hz, C N); Phenyl car-
bons: 125.2, 128.5, 129.0, 137.5; IR (neat): νP = O = 1271 cm−1; νNH2 = 3217–3340 cm−1
ESI-MS: m/z = 391.1 ([M+H]+).
;
3p: Light brown solid; mp = 113–115 ◦C; 31P NMR (121.5 MHz, CDCl3):
δ = 19.7 ppm; 1H NMR (300 MHz, CDCl3): δ = 1.28 (t, 6H, 3JH-H = 6.0 Hz, CH3–CH2);
3
2.09 (s, 3H, CH3–C C); 2.23 (s, 3H, CH3–C N); 4.08 (qp, 4H, 3JH-H = JP-H = 6.0 Hz,
CH3–CH2); 5.16 (broad s, 2H, NH2); 7.70 (s, 1H, arom-H); 13C NMR (75.5 MHz, CDCl3):
δ = 14.2 (s, CH3–C C); 15.3 (d, 3JCP = 6.8 Hz, CH3–CH2–O); 30.4 (s, CH3–C N); 61.6
1
(d, 2JCP = 6.8 Hz, CH2–O); 115.1 (d, JCP = 113.2 Hz, C–P = O); 124.3 (s, C = C S);
127.2 (s, CH3–C = C S); 128.8 (s, H C S); 132.4 (d, 2JCP = 23.3 Hz, C--NH2);
143.7 (s, N C S); 162.2 (d, 2JCP = 26.4 Hz, C N); IR (neat): νP = O = 1266 cm−1
νNH2 = 3235–3338 cm−1; ESI-MS: m/z = 315.2 ([M+H]+).
;
REFERENCES
1. Pevet, I.; Brule´, C.; Tizot, A.; Gohier, A.; Cruzalegui, F.; Boutin, J. A.; Goldstein, S. Bioorg.
Med. Chem. 2011, 19, 2517-2528.
2. Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.; Sugano, Y. Bioorg. Med. Chem. Lett.
2004, 14, 3411-3414.

718
K. KHALLADI AND S. TOUIL
3. Jakobowski, J. A.; Smith, G.; Sall, D. Annu. Rep. Med. Chem.; Bristol, J. A. (Ed.), Vol. 27;
Academic: New York, 1992; p. 99.
4. Angiolillo, D. J.; Bates, E. R.; Bass, T. A. Am. Heart J. 2008, 156, 16-22.
5. Kuncha, M.; Boyapati, S.; Vegi Ganga, M. N.; Sistla, R.; Banda, N.; Akkinepally, R. R.; Prakash,
V. D. Eur. J. Pharmacol. 2012, 678, 48-54.
6. Bakhite, E. A.; Abdel-Rahman, A. E.; Mohamed, O. S.; Thabet, E. A. Bull. Korean Chem. Soc.
2002, 23, 1709-1714.
7. Malicorne, G.; Bompart, J.; Giral, L.; Despaux, E. Eur. J. Med. Chem. 1991, 26, 3-11.
8. Fischer, U.; Schneider, F.; Widmer, U. (Hofman La Roche and Co.). Eur. Pat. 183998, 1986;
Chem. Abstr. 1987, 107, 134200.
9. New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer, F.; Van der Mealen, C. P.;
Cipollina, J. A. J. Med. Chem. 1989, 32, 1147-1156.
10. Holland, D. R.; Wikel, J. H. (Eli Lilly and Co.). U.S. Pat. 4902694, 1990; Chem. Abstr. 1990,
113, 34706.
11. Litvinov, V. P.; Dotsenko, V. V.; Krivokolysko, S. G. Adv. Heterocycl. Chem. 2007, 93, 117-178.
12. Veronese, A. C.; Callegari, R.; Morelli, C. F. Tetrahedron 1995, 51, 12277-12284.
13. Chebil, E.; Chamakhi, M.; Touil, S. J. Sulfur Chem. 2011, 32, 249-256; (b) Said, N.; Touil, S.;
Ben Akacha, A.; Efrit, M. L. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 2726-2733;
(c) Ben Gaied, L.; Touil, S.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181,
601-608; (d) Touil, S.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 353-360;
(e) Said, N.; Touil, S.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1891-
1899; (f) Touil, S.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 131, 183-189; (g)
Touil, S.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 1998, 134, 493-502; (h) Touil, S.;
Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 1245-1254; (i) Said, N.; Touil,
S.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179, 2487-2496.
14. Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899-931; (b) Kafarski,
P.; Lejezak, B. Phosphorus & Sulfur 1991, 63, 193-215; (c) Hoagland, R. E. In: H. G. Culter
(Ed.), Biologically Active Natural Products; ACS Symposium Series 380. American Chemical
Society: Washington, DC, 1988; p. 182; (d) Toy, A. D. F.; Walsh, E. N. In: Phosphorus Chemistry
in Everyday Living; American Chemical Society: Washington, DC, 1987; (e) Engel, R. In:
Handbook of Organophosphorus Chemistry; Marcel Dekker Inc.: New York, 1992.
15. Gewald, K.; Schinke, E.; Boettcher, H. Chem. Ber. 1966, 99, 94-100.
16. Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2931-2932; (b) Mathey,
F.; Savignac, P. Tetrahedron 1978, 34, 649-654.