Phosphorylation of 2-(3-methyl-1,3-diazabuten-1-yl)-3-Ethoxycarbonylthiophenes with phosphorus(III) halides

Article abstract of DOI:10.1002/hc.10002

2-(3-Methyl-1,3-diazabuten-1-yl)-3-ethoxycarbonylthiophenes are phosphorylated with phosphorus(III) halides in basic media at position 5 of the thiophene ring. Up to three heteroaromatic substituents can be introduced one by one at the same phosphorus atom. On this basis, mono-, bis-, and trishetaryl substituted P(III) and P(V) derivatives have been obtained. Phosphorylated 2-(N,N-dimethylformamidino)-3-ethoxycarbonylthiophenes provide a synthetic access to phosphorylated thienopyrimidines.

Full text of DOI:10.1002/hc.10002

Heteroatom Chemistry
Volume 12, Number 7, 2001
Phosphorylation of 2-(3-Methyl-1,3-
diazabuten-1-yl)-3-Ethoxycarbonylthiophenes
with Phosphorus(III) Halides
Alexandr M. Pinchuk, Svetlana A. Kovalyova, Sergey P. Ivonin,
Anatoliy S. Merkulov, Tamara N. Kudrya, Alexandra A.
Chaikovskaya, and Andrey A. Tolmachev
Institute of Organic Chemistry of National Academy of Sciences of Ukraine, Murmanskaya Street,
5, Kiev-94, 02056, Ukraine
Received 3 April 2001; revised 18 June 2001
group, thienylhydrazones are phosphorylated with
ABSTRACT: 2-(3-Methyl-1,3-diazabuten-1-yl)-3-eth-
phosphorus tribromide much more readily [3]. It
oxycarbonylthiophenes are phosphorylated with
might be expected that the electron-donor nature
phosphorus(III) halides in basic media at position
of the N,N-dimethylformamidino substituent in
5 of the thiophene ring. Up to three heteroaromatic
N-(thienyl-2)formamidines would also promote
substituents can be introduced one by one at the
the course of the reaction under mild condi-
same phosphorus atom. On this basis, mono-, bis-,
tions, as in the phosphorylation of N-azolylfor-
and trishetaryl substituted P(III) and P(V) deriva-
mamidines [4]. The present work is focussed on
tives have been obtained. Phosphorylated 2-(N,N-
the phosphorylation of 2-(3-methyl-1,3-diazabuten-
dimethylformamidino)-3-ethoxycarbonylthiophenes
1-yl)-3-ethoxycarbonylthiophenes with phospho-
provide a synthetic access to phosphorylated thienopy-
rus(III) halides with a view to obtain multifunc-
tional phosphorylated thiophenes and to study their
properties.
C
rimidines.
2001 John Wiley & Sons, Inc. Heteroatom
Chem 12:641–651, 2001
INTRODUCTION
RESULTS AND DISCUSSION
It is known that thienyl-2-dichlorophosphine
can be obtained by phosphorylating thiophene
with phosphorus trichloride in the presence
of tin chloride(IV) [1]. However, running the
reaction without the catalyst requires severe con-
ditions, viz. 150–160 C in a sealed vial, even if
phosphorus tribromide, a more reactive phos-
phorylating agent, is used [2]. Because of the
electron-donor effect of the N,N-dimethylhydrazono
The activating effect of the N,N-dimethylamino-
methylidenamino substituent at position 2 of the
thiophene ring in the 2-(3-methyl-1,3-diazabuten-
1-yl)-3-ethoxycarbonylthiophenes (1a–c) has ap-
peared to be so great that despite the presence of
an electron-acceptor group at position 3 of the thio-
phene moiety, the substances are phosphorylated
easily at position 5 of the thiophene ring, when re-
acted with phosphorus(III) halides in benzene in the
presence of triethylamine or in pyridine at room tem-
perature (see Scheme 1). Thus, one, two, or even
three (in the case of phosphorus tribromide) thienyl
substituents may be successively provided at the
Correspondence to: Alexander M. Pinchuk; e-mail: hetfos@
ukrpack.net.
c
2001 John Wiley & Sons, Inc.
641

642 Pinchuk et al.
SCHEME 1
JHP = 9,3 Hz). In the 13C spectrum, resonances of
carbon atoms 2 and 3 also appear as doublets with
chemical shifts C = 127 ppm (JCP = 72.2 Hz) and
C = 139 ppm (JCP = 53.1 Hz), respectively.
same phosphorus atom, depending on the reagent
ratio.
2-(3-Methyl-1,3-diazabuten-1-yl)-3-ethoxycarbo-
nylthiophenes (1a,b) react easily with phosphorus
tribromide and trichloride in the ratio of 1:1 and
2:1, respectively, to give thienyldihalogenophosp-
hines (2a,b, 3a,b) and bisthienylhalogenophos-
phines (4b, 5b), respectively. Tristhienylphosphines
(6a–c) are obtained when compounds 1a–c react
with phosphorus tribromide in the ratio of 3:1. It was
found that the tert-phosphine 6c needs a long period
of heating (up to 50 C) of a mixture to be formed, and
this apparently is connected to an increase of steric
hindrance, if an o-chlorophenyl group is present at
position 4.
The halogenophospines 3a,b, 4b, 5b, 7b, 8b
were characterized by 31P NMR spectroscopy only
(Table 1) and were used in subsequent syntheses
without additional purification.
The dihalogenophosphines 2a,b, 3a,b and the
halogenophosphines 4b, 5b, 7b, 8b react with sec-
ondary amines to afford amidophosphonites 12a,b
and amidophosphinites 13b, 14b (see Scheme 2).
The structures of compounds 12b–14b were de-
termined by 31P (Table 1), 1H (Table 2), and 13C
NMR spectroscopy (Table 3). The amidophospho-
nite 12a was characterized by 31P NMR spectroscopy
only (Table 1). Starting from phosphines 6a-c, 10b,
11b and amides 12a,b, 13b, 14b, standard proce-
dures were employed to obtain compounds with
a tetra- and pentacoordinated phosphorus atom,
viz. methylphosphonium salts 15a–c, 19b, 20b,
23b, 24b, oxides 16b, 21b, 25b, thioxides 17a,b,
22b, 26a,b, 27b, and imino derivatives 18a, 28b,
29b (see Scheme 3). The structures of compounds
15–29 were determined by 31P (Table 1) and 1H NMR
spectroscopy (Table 2).
Compounds 1a,b react easily with phenyldibro-
mophosphine and heteroaryldibromophosphines in
the ratio of 1:1 and 2:1, respectively, to give
halogenophosphines 7b, 8b and tert-phosphines 9a,
10b, 11b, respectively.
The structures of compounds 2a,b, 6a–c, 9a,
10b, 11b were determined by 31P (Table 1), 1H
(Table 2), and 13C NMR spectroscopy (Table 3).
1
For example, in the H NMR spectrum of thieny-
ldichlorophosphine (2a) there is no signal of the
proton at the carbon atom 2 of the thiophene ring
and the signal of the proton at the neighboring car-
bon atom 3 appears as a doublet ( H = 7.65 ppm;
In the molecule of tristhienyl(methyl)phos-
phonium iodide(15a) containing no substituents at

TABLE 1 The Experimental Data of Compounds 1–43
P(%)
N(%)
Compound Yield (%)
mp ( C)
Formula
Calcd. Found Calcd. Found
31 Pa
1a
1b
1c
2a
2b
3a
3b
4b
5b
6a
6b
6c
7b
8b
9a
60
98
98
86
70
–
–
–
–
71
82
75
–
–
C10H14N2O2S
C16H18N2O2S
C16H17ClN2O2S
C10H13Cl2N2O2PS
C16H17Cl2N2O2PS
–
–
–
9.47
7.68
–
–
–
–
–
–
9.25
7.81
–
–
–
12.38
9.26
8.32
8.56
6.95
–
–
–
–
11.89
8.99
8.09
–
12.11
9.42
8.48
8.42
6.74
–
–
–
–
12.15
9.22
8.14
–
–
–
–
93–94b
114–115b
69–71b
144.8 (C6H6)
147.3 (C6H6)
131.1 (Py)
134.9 (Py)
53.9 (Py)
44.9 (Py)
43.1 (Py)
56.2 (Py)
59.7 (Py)
67.4 (Py)
60.8 (Py)
52.5 (Py)
64.1 (Py)
146–147b
–
C10H13Br2N2O2PS
C16H17Br2N2O2PS
C32H34ClN4O4PS2
C32H34BrN4O4PS2
–
–
–
–
–
159–160c
230 (dec)c
215–216c
–
C30H39N6O6PS3
C48H51N6O6PS3
C48H48Cl3N6O6PS3
4.38
3.31
2.98
–
4.48
3.03
3.11
–
C
C
22H22ClN2O2PS
22H22BrN2O2PS
–
–
–
–
–
–
70
66
78
–
80–82c
C33H40N5O4PS2
C37H39N4O5PS2
C38H39N4O4PS2
4.65
4.33
4.36
–
4.71
4.15
4.23
–
10.52
7.84
7.88
–
10.23
8.01
7.62
–
10b
11b
12a
12b
13b
14b
15a
15b
15c
16b
17a
17b
18a
19b
20b
21b
22b
23b
24b
25b
26a
26b
27b
28b
29b
30b
31b
32a
33a
34a
35a
36b
37b
38a
39a
40a
41a
42a
43a
199–200c
177–178c
–
41.9 (Py)
C18H29N4O4PS
85.4 (C6H6)
88.9 (C6H6)
28.42 (C6H6)
42.9 (C6H6)
14.2 (C6H6)
2.5 (C6H6)
3.8 (C6H6)
0.04 (C6H6)
13.6 (C6H6)
10.1 (C6H6)
22.8 (C6H6)
4.3 (C6H6)
31.4 (C6H6)
9.9 (C6H6)
44.6 (C6H6)
40.1 (CH3OH)
4.2 (C6H6)
15.5 (C6H6)
68.9 (CHCl3)
63.8 (C6H6)
57.8 (C6H6)
31.5 (CHCl3)
1.4 (C6H6)
63.5 (CHCl3)
57.0 (C6H6)
13.5 (DMSO)
13.7 (DMSO)
5.8 (DMSO)
13.5 (DMSO)
64.7 (C6H6)
64.2 (CH3OH)
13.4 (CHCl3)
2.0 (DMSO)
42.8 (H2O)
13.4 (H2O)
20.8 (H2O)
13.5 (CHCl3)
70
70
68
74
60
84
71
92
90
68
79
71
52
72
40
70
60
77
69
35
50
30
64
50
57
42
34
93
80
70
54
47
68
81
53
67
112–113b
178–179b
115–116b
113–115d
265 (dec)d
260 (dec)d
279–280c
143–145c
243(dec)c
194–195d
135(dec)e
200–201e
101–102c
177–178c
203–204e
196–197
128–129b
48–50c
C24H33N4O4PS
C36H44N5O4PS2
C26H30N3O3PS
C31H42IN6O6PS3
C49H54IN6O6PS3
C49H51Cl3IN6O6PS3
C48H51N6O7PS3
C30H39N6O6PS4
C48H51N6O6PS4
C37H46N7O6PS3
C39H42IN4O4PS2
C37H47IN5O4PS2
C38H39N4O5PS2
C36H44N5O4PS3
C25H36IN4O4PS
6.14
4.39
6.25
3.65
2.88
2.62
3.26
4.19
3.20
3.81
3.63
3.65
4.26
4.20
4.79
4.86
5.95
6.73
5.77
5.87
4.59
5.28
6.70
4.35
6.00
5.52
4.88
3.54
6.08
6.43
4.71
4.83
5.42
5.13
4.58
6.33
6.11
4.51
5.98
3.22
3.06
2.89
3.33
4.38
3.16
4.09
3.72
3.42
4.11
4.44
4.52
5.07
6.12
6.59
5.89
5.79
4.46
5.43
6.51
4.17
6.19
5.61
4.64
3.46
5.96
6.67
5.09
5.11
5.29
5.27
4.67
6.58
11.10
9.92
8.48
9.90
7.80
7.12
8.84
11.37
8.69
12.07
6.57
8.26
7.71
9.49
8.67
6.59
10.76
12.16
10.44
7.96
10.38
9.55
12.11
11.79
16.27
22.45
22.07
14.42
8.25
8.73
6.39
6.55
7.35
6.96
8.28
8.58
11.23
10.14
8.62
10.11
7.95
6.95
9.12
11.23
8.74
12.15
6.22
8.43
7.66
9.61
8.75
6.52
10.97
12.05
10.59
8.12
10.05
9.49
11.96
7.45
16.04
22.14
22.19
14.55
8.14
8.59
6.25
6.59
7.39
6.82
8.37
8.71
C27H33IN3O3PS
C24H33N4O5PS
C18H29N4O4PS2
C24H33N4O4PS2
C26H30N3O3PS2
C30H37BrN5O4PS
C32H35N4O3PS
C20H23N4O3PS2
C36H21N6O3PS3
C18H9N6O3PS4
C18H12N9O3PS4
C25H19N10O3PS3
183–184c
108–109b
89–90c
69–71b
225–226c
>320c
268–270c
314–315c
228–230c
252–253
177–179c
186–187c
133–135c
148–150c
267–268 f
260 (dec) f
277–278 f
210–212 f
C39H24N9O6PS4
C22H28N3O5PS2
C21H28N3O4PS2
C24H24N3O9PS4
C24H24N3O10PS3
C15H9K3N3O6PS3
C15H9K3N3O6PS4
C22H16K3N4O6PS3
C15H12N3O6PS4
aCompounds within parentheses represent the solvents.
bRecrystallize from octane.
cRecrystallize from i -PrOH.
dPrecipitated from benzene by hexane.
eRecrystallized from an ethylacetate–hexane mixture.
f Precipitated from ethanol by water.

644 Pinchuk et al.
TABLE 2 The 1H Data of Compounds 1–29 ( , ppm; J, Hz)
CH3CH2
O
N
CHN(CH3)2
N(CH3)2
i
No.
CH3 CH2
CH2
O
N
CH
R
(H) or
P
Solvent
1a
1.33 (t, 3H,
JHH = 7.2)
1.03 (t, 3H,
JHH = 7.2)
1.08 (t, 3H,
JHH = 7.2)
0.8 (t, 3H,
JHH = 7.2)
0.67 (t, 3H,
JHH = 7.2)
1.05 (t, 9H,
JHH = 7.2)
0.75 (t, 9H,
JHH = 7.2)
0.62–0.98
(m, 9H)
4.25 (q, 2H,
JHH = 7.2)
4.10 (q, 2H,
JHH = 7.2)
4.13 (q, 2H,
JHH = 7.2)
3.84 (q, 2H,
JHH = 7.2)
3.90 (q, 2H,
JHH = 7.2)
4.17 (q, 6H,
JHH = 7.2)
3.98 (q, 6H,
JHH = 7.2)
3.95–4.22
(m, 6H)
7.65 (s, 1H)
7.69 (s, 1H)
7.67 (s, 1H)
6.87 (s, 1H)
7.20 (s, 1H)
7.68 (s, 3H)
8.04 (s, 3H)
8.01 (br s, 3H)
3.09 (s, 6H)
3.06 (s, 6H)
3.06 (s, 6H)
7.21 (d, 1H,
6.52 (d, 1H, JHH = 3.8)
CDCl3
JHH = 3.8)
1b
1c
2a
2b
6a
6b
6c
7.28–7.35 (m, 5H)
6.48 (s, 1H)
CDCl3
CDCl3
C6D6
C6D6
C6D6
C6D6
C6D6
7.37 (m, 4H)
6.46 (s, 1H)
1.83; 2.26
(s, 6H)
1.93; 2.48
(s, 6H)
1.90; 2.52
(s, 18H)
2.59; 2.15
(s, 18H)
2.01–2.16;
2.59–2.63
(m, 18H)
3.12 (s, 12H)
.57 (d, 1H,
–
–
–
–
–
JHP = 9.3)
7.07–7.06 (m, 3H);
7.32–7.37 (m, 2H)
8.13 (d, 3H,
JHP = 9.6)
6.98–7.18
(m, 15H)
6.78–6.91;
7.11–7.22 (m, 12H)
9a
1.34 (t, 3H,
4.26 (q, 2H,
8.57 (s, 2H)
7.71 (s, 1H)
1.79 (s, 3H, 5 CH3);
1.79 (s, 3H, 2 CH3);
2.40 (s, 3H, CH3 C6H4);
7.08 (d, 2H, o-C6H4,
JHH = 8.1); 7.45 (d, 2H,
m-C6H4, JHH= 8.1)
2.01(s, 3H, CH3); 5.77 (br s,
1H, CH C(CH3));
CDCl3
JHH = 7.2)
JHH = 7.2)
10b
0.68 (t, 6H,
3.93 (q, 4H,
7.34 (s, 2H)
1.89; 2.51
(s, 12H)
6.99–7.10;
7.34–7.39 (m, 10H)
C6D6
JHH = 7.2)
JHH = 7.2)
6.63 (d, CH C(P),
JHP= 2.7)
11b
12b
0.67 (t, 6H,
JHH = 7.2)
0.73 (t, 3H,
JHH = 7.2)
3.95 (q, 4H,
JHH = 7.2)
3.97 (q, 2H,
JHH = 7.2)
7.22 (s, 2H)
7.46 (s, 1H)
1.79; 2.48
(s, 12H)
1.93; 2.51
(s, 6H)
7.61 (t, 2H, JHH = 7.2);
7.57 (d, 4H, JHH = 7.2)
7.04 (d, 1H, JHH = 8);
7.58 (d, 2H, JHH = 7);
7.10–7.18 (m, 2H)
7.02–7.12 (m, 9H,
C6D6
C6D6
C6H5 C+ C6H5 P)
2.80 (m, 8H); 3.37 (m, 8H)
13b
14b
0.88 (t, 6H,
3.92 (m, 4H,
7.37 (s, 2H)
7.32 (s, 1H)
1.91; 2.52
(s, 6H)
7.24–7.38 (m, 6H);
7.75 (dd, 4H)
0.68 (t, 6H, CH3CH2,
JHH = 7.2); 3.26–3.39
(m, 4H, CH3CH2)
C6D6
C6D6
JHH = 7.2)
JHH = 7.2)
0.73 (t, 3H,
3.99 (q, 2H,
1.89; 2.51
(s, 6H)
aromatic: 7.03–7.22 (m, 6H); 7.14–7.64 (m, 4H);
aliphatic: 2.87 (br s, 4H, CH2N); 3.45 (br s, 4H,
CH2O)
JHH = 7.2)
JHH = 7.2)
15a
15b
15c
16b
17a
17b
18a
1.35 (t, 9H,
JHH = 7.2)
0.93 (t, 9H,
JHH = 6.9)
0.82–0.94
(m, 9H)
0.82 (t, 9H,
JHH = 7.2)
1.31 (t, 9H,
JHH = 6.9)
0.83 (t, 9H,
JHH = 7.2)
0.91 (t, 9H,
JHH = 7.2)
4.30 (q, 6H,
JHH = 7.2)
4.02 (q, 6H,
JHH = 6.9)
3.91–4.05
(m, 6H)
3.93 (q, 6H,
JHH = 7.2)
4.23 (q, 6H,
JHH = 6.9)
3.93 (q, 6H,
JHH = 7.2)
4.03 (q, 6H,
JHH = 7.2)
8.19 (s, 3H)
8.62 (s, 3H)
8.73 (br s, 3H)
7.59 (s, 3H)
7.83 (s, 3H)
7.56 (s, 3H)
3.16; 3.30
(s, 18H)
3.15; 3.43
(s, 18H)
3.17; 3.45
(s, 18H)
3.07; 3.11
(s, 18H)
3.08; 3.12
(s, 18H)
3.08; 3.11
(s, 18H)
1.88; 2.48
(s, 18H)
7.79 (d, 3H,
2.76 (d, 3H, CH3 P,
JHH = 19.2)
CDCl3
CDCl3
CDCl3
CDCl3
CD3OD
CDCl3
C6D6
JHP = 10.5)
6.92 (d, 6H);
0.14 (d, 3H, CH3 P,
JHH = 14)
7.17–7.29 (m, 9H)
6.95–7.19 (m, 12H)
0.23 ( d, 1H, JHP = 14);
0.35 (d, 2H, JHP = 14)
–
7.17–7.26 (m, 15H)
7.61 (d, 3H,
–
–
JHP = 10.2)
7.12–7.22(m, 15H)
7.02 (m, 5H,
o-C6H4
8.51 (d, 3H,
2.15 (s, 3H, CH3);
JHH = 9.3)
7.53 (d, 2H, m-C6H4,
JHH = 7.2)
+CH N)
19b
20b
0.9 (t,6H,
3.98 (q, 4H,
8.28 (s, 2H)
3.11; 3.30
(s, 12H)
6.99 (d, 4H, m-C6H5
7.2–7.4; 7.62–7.8 (m,
11H, o,p-C6H5+
CDCl3
CDCl3
JHH = 7.2)
JHH = 7.2)
JHH = 7.2)
C6H5 P); 0.11 (d, 3H,
CH3 P, J HP = 14.4)
1.22 (t, 6H,CH3CH2);
3.19–3.27 (m, 4H,
0.92 (t, 6H,
4.01 (q, 4H,
8.53 (s, 1H)
3.14; 3.39
(s, 12H)
7.03 (br s, 4H);
7.28–7.39 (m, 6H)
JHH = 7.2)
JHH = 7.2)
CH3CH2); 0.62 (d, 3H,
CH3-P,CH3-P, JHP = 13.5)
21b
22b
23b
0.82 (t, 6H,
JHH = 7.2)
0.91 (t, 6H,
JHH = 7.2)
0.90 (t, 3H,
JHH = 7.2)
3.94 (q, 4H,
JHH = 7.2)
3.94 (q, 4H,
JHH = 7.2)
3.98 (q, 2H,
JHH = 7.2)
7.68 (s, 2H)
7.65 (s, 2H)
7.98 (s, 1H)
3.08; 3.09
(s, 12H)
3.08; 3.09
(s, 12H)
3.13; 3.25
(s, 6H)
6.98–7.2 (m, 15H, C6H5 + C6H5 P)
CDCl3
CDCl3
CDCl3
7.19 (br s, 10H)
0.86 (t, 6H);
2.83–2.94 (m, 4H)
7.19–7.23 (m, 2H);
7.45–7.48 (m, 3H)
2.11 (t, 3H, CH3 P,
JHH = 10.2); 3.18
(m, 8H); 3.75 (m, 8H)
(Continued)

Phosphorylation of 2-(3-Methyl-1,3-diazabuten-1-yl)-3-Ethoxycarbonylthiophenes with Phosphorus(III) Halides 645
TABLE 2 Continued
CH3CH2
CH3 CH2
O
N
CHN(CH3)2
i
No.
CH2
O
N
CH
N(CH3)2
R
(H) or
P
Solvent
24b
0.88 (t, 3H,
JHH = 7.2)
3.87 (q, 2H,
8.12 (s, 1H)
3.15; 3.28
(s, 6H)
aromatic: 7.02 (br s, 2H, ); 7.24–7.38(m, 3H); 7.63–7.92
(m, 5H); aliphatic: 3.00–3.12(m, 4H, CH2N);
3.77(br s, 4H, CH2O); 2.22 (d, 3H, CH3 P,
J HP = 13.5)
CDCl3
JHH = 7.2)
25b
26a
26b
27b
0.69 (t, 3H,
JHH = 7.2)
1.34 (t, 3H,
JHH = 7.2)
0.86 (t, 3H,
JHH = 7.2)
0.80 (t, 3H,
JHH = 7.2)
3.93 (q, 2H,
JHH = 7.2)
4.26 (q, 2H,
JHH = 7.2)
3.93 (q, 2H,
JHH = 7.2)
3.90 (q, 2H,
JHH = 7.2)
7.33 (s, 1H)
7.71 (s, 1H)
7.77 (s, 1H)
7.87 (s, 1H)
1.91; 2.47
(s, 6H)
–
7.16 (br s, 3H);
7.82 (d, 2H, JHH = 8.7)
7.73 (d, 1H)
2.89 (m, 8H); 3.59 (m, 8H)
CD3OD
CDCl3
CDCl3
CDCl3
3.13 (m, 14H, CH2N+NCH3);
3.66 (m, 8H, CH2O)
2.95 (m, 8H, CH2N);
3.51 (m, 8H, CH2O)
JHP = 12
3.74 (s, 6H)
3.69 (s, 6H)
7.35 (br s, 5H)
aromatic: 6.89–6.92 (m, 2H); 7.13–7.53 (m, 8H);
aliphatic: 2.78–3.00 (m, 4H, CH2N); 3.16 (br s, 4H, CH2O)
CH2O)
28b
29b
0.86 (t, 3H,
JHH = 7.2)
3.92 (q, 2H,
7.73 (s, 1H)
7.78 (s, 1H)
3.08; 3.11
(s, 6H)
7.28–7.32
(m, 5H)
aromatic: 6.60 (d, 2H,
JHH = 8.7); 7.15 (d, 2H,
JHH = 8.7); aliphatic:
2.92 (br s, 8H, CH2N);
3.48 (br s, 8H, CH2O)
CDCl3
CDCl3
JHH = 7.2)
0.81 (t, 3H,
JHH = 7.2)
3.91 (q, 2H,
3.07 (t, 6H)
aromatic: 6.68–7.57 (m, 15H); aliphatic: 2.95 (br, s, 4H, CH2N);
3.8 (br, s, 4H, CH2O)
JHH = 7.2)
atom in the methylphosphonium salts 15b, 19b,
20b, 23b, 24b (R = C6H5) and 15c (R = 2-ClC6H4)
exhibit signals that are shifted to a stronger field
(Table 2); for instance, the corresponding chemical
shift for methylphosphonium iodide 15b reaches the
value H = 0.14 ppm (JHP = 14.7 Hz). In this case,
position 3 of the thiophene rings (R = H), the signal
of protons of the methyl group at the phosphorus
atom gives rise to a 1H NMR peak in the normal re-
gion, which appears as a doublet with the chemical
shift H = 2.73 ppm (JHP = 19 Hz). At the same time,
the protons of the methyl groups at the phosphorus
TABLE 3 The 13C Data of Compounds 2a, 6b, 12b ( , ppm; J, Hz)
Carbon No.
2
3
4
5
6
126.68 (d, JCP = 72.2)
150.58 (d, JCP = 30.2)
126.14 (d, JCP = 27.9)
125.02 (d, JCP = 4.2)
140.11 (d, JCP = 4.7)
168.07 (s)
125.75 (d, JCP = 19.5)
145.31 (d, JCP = 17.5)
124.98 (s)
139.26 (s)
166.03 (s)
138.71 (d, JCP = 53.1)
116.16 (d, JCP = 11.1)
161.19 (s)
173.08 (s)
7
8
9
58.59 (s)
13.12 (s)
154.01 (s)
63.24 (s)
17.47 (s)
158.48 (s)
60.66 (s)
14.74 ((d, JCP = 24.7)
154.68 (s)
10
11
12
13
14
15
16
33.03 (s); 38.25 (s)
38.10 (s)
167.35 (s)
132.47 (s)
131.03 (s)
23.65 (s); 32.58 (s)
141.7 (s)
–
–
–
–
–
–
130.59 (s)
–
130.78 (s)
127.68 (s)
–
–
50.53 (d, JCP = 14.2)
68.44 (d, JCP = 6.5)

646 Pinchuk et al.
group as compared to the “crown-like” pattern, and
the corresponding resonance will therefore occur at
a weaker field. Besides, such a configuration allows
for three possibilities for the mutual arrangement of
chlorine atoms in the o-chlorophenyl groups lying
on the same side of the plane as the methyl group,
two of the three variants being identical as regards
the disposition of the chlorine atoms relative to the
1
methyl group. Thus, in the H NMR spectrum, the
P CH3 group should resonate in the form of two
signals, with their integral intensities related as 2:1.
This is the case for compound 15c: the methyl group
1
at the phosphorus atom shows the H resonance as
two doublets with the chemical shifts H = 0.35 ppm
(JHP = 14.7 Hz) and H = 0.23 ppm (JHP = 14.7 Hz)
and the integral intensity ratio equal to 2:1.
Steric hindrance caused by aryl groups at po-
sition 4 of the thiophene rings also exert an effect
on the reactivity of phosphines 6b,c. So, unlike the
phosphine 6a, the phosphines 6b,c do not react with
aryl azides, probably, due to increasing steric hin-
drance at the phosphorus atom.
Phosphine 6b, phosphine thioxide 17a, imino-
phospine 18a, and diamidothiophosphonate 26b re-
act with formamide or hydrazine when heated to
give phosphorylated thienopyrimidones 30b, 31b,
32a–34a by means of heterocyclization with partic-
ipation of amidine and ethoxycarbonyl groups. 3-
Aminothienopyrimidone (33a) reacts easily with a
substituted benzaldehyde to give a Shiffs base, as, for
example, 35a (see Scheme 4). Unsymmetrical phos-
phines 9a, 10b, 11b by heating in formamide, do not
react to form thienopyrimidones; this, apparently, is
connected with their lower thermal stability.
SCHEME 2
the shift of the signal of the methyl group is evi-
dently due to the symmetric screening of its pro-
tons by three phenyl groups, which are located in
the “ortho” position to the phosphorus atom. In our
opinion, the phenyl rings and the methyl group at
the phosphorusatom are positioned on the same side
of the conventional plane passing through the phos-
phorus atom perpendicular to the P CH3 bond. This
conjecture is consistent with potential energy val-
ues computed by the molecular mechanics method
(MM+) for the starting trisphosphine molecule 6b
with varied mutual arrangement of the lone elec-
tron pair of the phosphorus atom and the phenyl
rings. As seen from the calculated data, the “crown-
like” configuration of the phenyl rings relative to
the lone electron pair is, on the average, 20–30%
more energetically preferable than other configura-
tions (see Fig. 1). With regard to the fact that the
alkylation of tertiary phosphines is not accompanied
by inversion at the phosphorus atom [5], one can ex-
pect that the “crown-like” configuration will be re-
tained on alkylation. In the molecule of the more
sterically hindered methylposphonium iodide (15c)
(R = 2-ClC6H4), the arrangement of all o-chloro-
phenyl rings on the same side of the plane is ham-
pered. In this case, the calculations suggest that the
most energetically preferable configuration involves
the disposition of the methyl group at the phos-
phorus atom and with only two o-chlorophenyl sub-
stituents on the same side of the plane. This arrange-
ment will result in lesser screening of the methyl
The amidothiophosphonate 26b, phosphine
thioxide 17a, and imino derivative 18a un-
der acidic hydrolysis conditions give derivatives
of 5-(N-formyl)aminothiophenes 36b, 38a, 39a.
The compound 26b, on heating with aqueous-
alcoholic alkali, leads to phosphorylated 5-amino-4-
ethoxycarbonylthiophene (37b), whereas phosphine
6a, phosphine thioxide 17a, and the imino deriva-
tive 18a under the same conditions are hydrolized
with participation of both ethoxycarbonyl and ami-
dine groups, giving phosphorylated derivatives of
5-amino-4-thiophenecarboxylic acid (40a–43a) (see
Scheme 5). The structures of compounds obtained
as shown in Schemes 4 and 5 were determined by
1
31P (Table 1) and H NMR spectroscopy (Tables 4
and 5).
EXPERIMENTAL
All manipulations with moisture-sensitive com-
pounds were performed under an atmosphere of dry

Phosphorylation of 2-(3-Methyl-1,3-diazabuten-1-yl)-3-Ethoxycarbonylthiophenes with Phosphorus(III) Halides 647
SCHEME 3
argon, standard Shlenk techniques being used. Sol-
vents were purified by conventional procedures. The
31P, 1 H, and 13C NMR spectra were recorded on a Var-
ian VXR-300 spectrometer (121, 300, and 75 MHz
respectively). Chemical shifts are reported relative
to internal tetramethylsilane (1H, 13C) or to external
85% H3PO4 (31P).
General Procedure for Synthesis
of (2-Thienyl)dibromophosphines (3a,b)
The solution of each compound 1a,b (0.013 mol)
in pyridine (25 ml) was cooled to 10 C, and phos-
phorus tribromide (0.013 mol) was added drop-
wise. The reaction mixture was stirred at 25 C for
1.5 h and then evaporated to dryness in vacuo. The
residue was dissolved in benzene, followed by ad-
dition of triethylamine (0.015 mol), filtration of the
mixture, and evaporation of the filtrate to dryness in
vacuo. The products 3a,b were used without further
purification.
General Procedure for Synthesis
of (2-Thienyl)dichlorophosphines (2a,b)
The solutions of the corresponding compounds 1a,b
(0.013 mol) in pyridine (25 ml) were cooled to 10 C,
and phosphorus trichloride (0.02 mol) was added
dropwise. Each reaction mixture was stirred at 25 C
for 2.5 h and then evaporated to dryness in vacuo.
The residue was dissolved in benzene (25 ml), fol-
lowed by addition of triethylamine (0.015 mol), fil-
tration of the mixture, and evaporation of the filtrate
to dryness in vacuo.
General Procedure for Synthesis of
Bis-[3-phenyl-4-ethoxycarbonyl-5-(1-methyl-1,3-
diazabuten-1-yl)-thienyl]halogenophosphines
(4b, 5b)
A solution of the compound 1b (0.01 mol) in pyri-
dine (20 ml) was cooled to 10 C, and phosphorus

648 Pinchuk et al.
General Procedure for Synthesis
of the Tertiary Phosphines 6a,b
A solution of each compound 1a,b (0.01 mol) in
pyridine (20 ml) was cooled to 10 C and stirred,
and phosphorus tribromide (0.0033 mol) was added
dropwise. The mixture was stirred at 25 C for 28 h.
Then it was diluted with benzene (10 ml), filtered,
and evaporated to dryness in vacuo.
Tris-[3-(2-chlorophenyl)-4-ethoxycarbonyl-5-(1-
methyl-1,3-diazabuten-1-yl)-thienyl]phosphine
(6c)
A solution of 1c (0.01 mol) in pyridine (20 ml) was
cooled to 10 C and stirred, and phosphorus tribro-
mide (0.0033 mol) was added dropwise. The mixture
was stirred at 50 C for 40 h. Then it was diluted with
benzene (10 ml), filtered, and evaporated to dryness
in vacuo.
General Procedure for Synthesis
of [3-Phenyl-4-ethoxycarbonyl-5-(1-methyl-1,3-
diazabuten-1-yl)-thienyl]phenylhalogenophos-
phines (7b, 8b)
FIGURE 1 The spatial structure of the central moiety of the
phosphine 6b molecule corresponding to the potential energy
minimum. (Calculated by the MM+ method).
trichloride (0.005 mol) or phosphorus tribromide
(0.005 mol) was added dropwise. The reaction mix-
ture was stirred at 25 C for 5 days (in the case of
phosphorus trichloride) and for 20 h (in the case
of phosphorus tribromide). Then it was evaporated
to dryness in vacuo. The residue was dissolved in
benzene, followed by addition of triethylamine (0.02
mol), filtration of the mixture, and evaporation of the
filtrate to dryness in vacuo. The products were used
without further purification.
A solution of the compound 1b (0.01 mol) in pyri-
dine (20 ml) was cooled to 10 C and stirred, and
phenyldichlorophosphine (0.01 mol) or phenyldibro-
mophosphine (0.01 mol) was added dropwise. The
reaction mixture was stirred at 25 C for 5 days (in
the case of phenyldichlorophosphine) and for 20 h
(in the case of phenyldibromophosphine). Then it
was evaporated to dryness in vacuo. The residue
was dissolved in benzene, followed by addition of
triethylamine (0.011 mol), filtration of the mixture,
SCHEME 4

Phosphorylation of 2-(3-Methyl-1,3-diazabuten-1-yl)-3-Ethoxycarbonylthiophenes with Phosphorus(III) Halides 649
SCHEME 5
and evaporation of the filtrate to dryness in vacuo.
The compounds 7b, 8b were used without further
purification.
General Procedure for Synthesis of the
Amidophosphonites 12a,b
A solution of each compound 2a,b (0.01 mol) or 3a,b
(0.01 mol) in benzene (25 ml) was cooled to 10 C and
stirred; then morpholine (0.04 mol) was added drop-
wise. The mixture was stirred at 25 C for 1 h and
then filtered. The filtrate was evaporated to dryness
in vacuo. The compound 12a was used without fur-
ther purification.
General Procedure for Synthesis
of the Tertiary Phosphines 9a, 10b, 11b
A solution of each compound 1a,b (0.01 mol) in
pyridine (20 ml) was cooled to 10 C and stirred,
and the corresponding [1-(4-methylphenyl)-2,5-
dimethylpirrolyl-3]- (0.005 mol), (2-methylfuryl-5)-
(0.005 mol), or phenyldibromophosphine (0.005
mol) was added dropwise. The mixture was stirred
at 25 C for 28 h. Then it was diluted with benzene
(10 ml), filtered, and evaporated to dryness in vacuo.
General Procedure for Synthesis of the
Amidophosphinites 13b, 14b
A solution of each compound 4b, 5b (0.01 mol) or
7b, 8b (0.01 mol) in benzene (25 ml) was cooled to
TABLE 4 The 1H Data of Compounds 30–35 ( , ppm; J, Hz)
i
No.
30b
31b
R 0
8.28 (br s, 1H)
N
CH N
R
P
Solvent
CDCl3
7.23 (s, 1H)
8.19 (s, 1H)
7.45–7.51 (m, 5H)
3.04 (m, 8H, CH2 N);
3.57 (m, 8H, CH2 O)
–
12.51 (br s, 1H)
6.93 (d, 2H, JHH = 7);
7.21 (m, 3H)
DMSO-d6
32a
33a
34a
35a
12.7–12.9 (3H)
7.74 (s, 6H)
8.30 (s, 3H)
9.28 (s, 3H)
9.28 (s, 3H)
9.89 (s, 3H)
7.95 (d, 3H, , JHP = 10.5)
7.52 (d, 3H, JHP = 10.5)
7.56 (d, 3H, JHP = 9.3)
7.72 (d, 3H, JHP = 10.5)
–
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
–
2.53 (s, 3H, CH3)
–
7.73 (m, 10H, NH2 + C6H4)
6.79 (d, 6H, JHH = 8.1);
7.49 (d, 6H, JHH = 8.1);
8.25 (s, 1H, N N CH);
11.3 (s, 3H)

650 Pinchuk et al.
TABLE 5 The 1H Data of Compounds 36–43: (ppm), J (Hz)
NHR 0
i
No.
OCH2CH3 or OH
NH
R 0
R
P
Solvent
36b 0.73 (t, 3H, CH3CH2,
JHH = 7.2); 3.91
(q, 2H, CH3CH2,
JHH = 7.2)
11.45 (s, 1H) 8.61 (s, 1H)
7.23 (m, 2H);
7.36 (m, 3H)
2.98 (m, 8H, CH2 N);
3.6 (m, 8H, CH2 O)
CDCl3
37b 0.72 (t, 3H, CH3CH2,
JHH = 7.2); 3.86
(q, 2H, CH3CH2,
JHH = 7.2)
6.52 (s, 2H)
7.24 (m, 2H);
7.36 (m, 3H)
2.89 (m, 8H, CH2 N);
3.56 (m, 8H, CH2 O)
CDCl3
38a 1.10 (t, 9H, CH3CH2,
JHH = 6.9); 4.36
(q, 6H, CH3CH2,
JHH = 6.9)
3.20 (s, 3H) 8.60 (s, 3H)
7.84 (d, 3H,
–
–
CDCl3
JHP = 10.8)
39a 1.31 (t, 9H, CH3CH2,
JHH = 7.2); 4.38
(q, 6H, CH3CH2,
JHH = 7.2)
–
8.74 (s, 3H)
8.09 (d, 3H,
DMSO-d6
JHP = 12.0)
40a
41a
42a
–
–
–
–
–
–
8.21 (br s, 3H)
7.72 (br s, 3H)
8.20 (s, 3H)
–
D2O
D2O
D2O
–
2.56 (s, 3H, CH3);
7.20–7.30 (m, 4H, C6H4)
–
43a
7.30–8.50 (9H, NH2 + COOH)
7.21 (d, 3H,
DMSO-d6
JHP = 12.3)
10 C and stirred, and then morpholine (0.02 mol)
or diethylamine (0.02 mol) respectively was added
dropwise. The mixture was stirred at 25 C for 1 h and
then filtered. The filtrate was evaporated to dryness
in vacuo.
was added. After the reaction mixture had been
stirred for 4 h, the organic layer was separated,
washed with water twice, dried over sodium sulfate,
and evaporated in vacuo.
General Procedure for Synthesis
of the Phosphine Thioxides 17a,b, the
Amidothiophosphinates 22b, 27b, and the
Amidothiophosphonates 26a,b
General Procedure for Synthesis of the
Methylphosphonium Iodides 15a–c, 19b,
20b, 23b, 24b
To a solution of each compound 6a,b, 12a,b, 13b,
14b (0.01 mol) in benzene (20 ml), sulfur (0.01 mol)
was added. The mixture was refluxed for 1h. Then it
was evaporated to dryness in vacuo.
To a solution of each compound 6a–c, 11b–14b
(0.005 mol) in benzene (10 ml), methyl iodide (0.02
mol) was added. The reaction mixture was refluxed
for 4 h. Compounds 23b, 24b precipitated. The so-
lution was decanted. The product 24b is sufficiently
pure and does not need further purification.
General Procedure for Synthesis
of the Iminophosphine 18a, the
Amidoiminophosphonate 28b, and the
Amidothiophosphinate 29b
General Procedure for Synthesis of the
Phosphine Oxides 16b, 21b and the
Amidophosphonate 25b
To a solution of each compound 6a, 12b, 14b (0.01
mol) in benzene (20 ml), a solution of the corre-
sponding aryl azide (0.01 mol) in benzene (20 ml)
was added. The mixture was refluxed for 1h. Then it
was evaporated to dryness in vacuo.
To a stirred and cooled to 10 C solution of each com-
pound 6b, 11b, 12b (0.01 mol) in benzene (20 ml), a
30% aqueous solution of hydrogen peroxide (5 ml)

Phosphorylation of 2-(3-Methyl-1,3-diazabuten-1-yl)-3-Ethoxycarbonylthiophenes with Phosphorus(III) Halides 651
General Procedure for Synthesis of the
Thienopyrimidones 30b, 31b, 32a
General Procedure for Synthesis of the
2-(N-formyl)-3-ethoxycarbonylthiophenes
(36b, 38a, 39a)
A suspension of each compound 6b, 17a, 26b (0.01
mol) in formamide (10 ml) was heated on an oil bath
at 145–150 C for 1 h. After the mixture had been
cooled, the product was precipitated by addition of
water. Then it was filtered off and washed with water.
To a solution of each compound 17a, 18a, 26b (0.01
mol) in ethanol (40 ml), hydrochloric acid 10% (4 ml)
was added. The mixture was refluxed for 1 h. After
the mixture had cooled, the precipitate was filtered
off.
General Procedure for Synthesis
of the 3-Aminothienopyrimidones 33a, 34a
General Procedure for Synthesis of the
2-Amino-3-carboxythiophenes (40a–42a)
To a solution of each compound 17a, 18a (0.01 mol)
in ethanol (30 ml), hydrazine 99% (0.03 mol) was
added. The mixture was refluxed for 5 h. The reaction
mixture was diluted with water, and the precipitated
solid was filtered off.
To a solution of the corresponding compound 6a,
17a, 18a (0.01 mol) in ethanol (30 ml), potassium
hydroxide (0.03 mol) was added. The mixture was
refluxed for 5 h. After it had cooled, the precipitate
was filtered off.
Tris-{3-[1-(4-hydroxyphenyl)methylideneamino]-
4-oxo-3, 4-dihydrothieno[2,3-d]pyrimidin-6-yl}
phosphine thioxide (35a)
Tris-[(5-amino-4-carboxy)thienyl-2]phosphine
Thioxide (43a)
To a suspension of compound 17a (0.01 mol) in pyri-
dine (5 ml), 4-hydroxybenzaldehyde (0.03 mol) and
one drop of piperidine were added. The mixture was
stirred at 80 C for 0.5 h. During this time a precipitate
dissolved. Then pyridine was eveporated to dryness
in vacuo. The product was washed with hot hexane
(30 ml).
To a solution of salt 42a (0.01 mol) in water (5 ml),
10% hydrochloric acid (0.04 mol) was added. The
precipitate was filtered off.
REFERENCES
[1] Bentov M.; David L.; Bergmann, E. D. J Chem Soc
1964, 12, 4750–4752.
[2] Tolmachev, A. A.; Ivonin, S. P.; Pinchuk, A. M. Het-
eroatom Chem 1995, 6(5), 407–412.
[3] Tolmachev, A. A.; Ivonin, S. P.; Charchenko, A. V.;
Kozlov, E. S. Zh Obshch Khim (Russ) 1993, 63, 222–
224.
[4] Tolmachev, A. A.; Oshovskii, G. V.; Merkulov, A. S.;
Pinchuk, A. M Khim Geterotsikl Soed 1996, 9, 1288–
1289.
[(3-Phenyl-4-ethoxycarbonyl-5-aminothienyl)]
dimorpholidothiophosphonate (37b)
To a suspension of compound 26b (0.01 mol) in
iso-propyl alcohol (30 ml), a solution of potassium
hydroxide (0.05 mol) in water (5 ml) was added. The
mixture was refluxed for 6 h. After it had cooled, the
precipitate was filtered off.
[5] Hudson, R. F.; Green, M. Angew Chem 1963, 75, 47–56.