First synthesis of γ,γ′-diphosphonylketones and their reactivity in the fischer reaction

Article abstract of DOI:10.1080/10426500211716

Two synthetic methods leading to the new γ,γ′-diphosphonylketones 2 and 2′ are reported. The first method involves the base-catalyzed addition of diethylphosphite to diarylideneketones. The second one utilizes the reaction of triethylphosphite and ethoxyd

Full text of DOI:10.1080/10426500211716

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Phosphorus, Sulfur, and Silicon and the Related
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First Synthesis of γ,γ′-Diphosphonylketones and Their
Reactivity in the Fischer Reaction
Soufiane Touil a & Hedi Zantour a
a Département de Chimie, Faculté des Sciences de Tunis , Laboratoire de Synthèse
Organique , Tunisia
Published online: 27 Oct 2010.
To cite this article: Soufiane Touil & Hedi Zantour (2002) First Synthesis of γ,γ′-Diphosphonylketones and Their
Reactivity in the Fischer Reaction, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:5, 1245-1254, DOI:
10.1080/10426500211716
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1245–1254
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290092532
FIRST SYNTHESIS OF
,
0-DIPHOSPHONYLKETONES AND THEIR
REACTIVITY IN THE FISCHER REACTION
Soufiane Touil and Hedi Zantour
Laboratoire de Synthe`se Organique, De´partement de Chimie,
Faculte´ des Sciences de Tunis, Tunisia
(Received November 22, 2001)
Two synthetic methods leading to the new
,
0-diphosphonylketones 2
and 20 are reported. The first method involves the base-catalyzed ad-
dition of diethylphosphite to diarylideneketones. The second one uti-
lizes the0 reaction of triethylphosphite and ethoxydiphenylphosphine
with , -bis(dimethylamino)ketone hydrochlorides. On reaction with
phenylhydrazine hydrochloride, compounds 2 and 20 give the corre-
sponding 2-(phosphonoethyl)3-(phosphonomethyl)indoles 3. The struc-
ture of all obtained products is confirmed by NMR (1H, 31P, 13C) and
IR spectroscopy.
Keywords: Diphosphonylketones; 2-(phosphonoethyl)3-(phosphono-
methyl)indoles
INTRODUCTION
An increasing interest has been paid for several years to the syn-
thesis of -ketophosphonates. Such interest has been stimulated by
their promising applications as antihypertensive,1 herbicide or fungi-
cide agents.2 Some of these compounds exhibit also activity as inhibitors
of matrix-metalloprotease3 and kininogenase.4
With the aim to broaden further the range of -ketophosphonates
and pursuing our research program regarding the synthesis of
8
phosphonylketones,5
we report in the present investigation, two
0
convenient and efficient methods for the synthesis of the new , -
diphosphonylketones from easily accessible diarylideneketones or , -
0
bis(dimethylamino)ketone hydrochlorides.
It is important to note, here, that diphosphorylated compounds
are known for their useful properties ranging from pharmacological
Address correspondence to H. Zantour, Laboratoire de Synthe`se Organique,
De´partement de Chimie, Faculte´ des Sciences de Tunis, 1060 Tunis, Tunisia.
1245

1246
S. Touil and H. Zantour
12
activities9 to the metal-complexing ability.10
For instance, in recent
years, the use of some , -diphosphonylketones as a treatment for os-
teoporosis, has been proposed.13
Furthermore, and in order to explore the synthetic utility of the
0
, -diphosphonylketones synthesized, we show here that their reac-
tion with phenylhydrazine hydrochloride carried out under the Fischer
16
reaction conditions,14
leads to a new class of phosphonoindoles. Our
interest for these compounds is due to the well known interesting bio-
19
logical properties of indol derivatives.17
RESULTS AND DISCUSSION
0
For the synthesis of , -diphosphonylketones, we have used two dif-
ferent approches. The first one involved the base-catalyzed addition of
diethylphosphite to diarylideneketones. The second approach utilizes
the0 reaction of triethylphosphite and ethoxydiphenylphosphine with
, -bis(dimethylamino)ketone hydrochlorides.
Addition of Diethylphosphite to Diarylideneketones 1:
Synthesis of , 0-Diphosphonylketones 2
Treatment of diarylideneketones 1 with a large excess of diethylphos-
phite (10 equivalents), performed at room temperature, for 24 h and in
the presence of a catalytic amount of sodium ethoxide in ethanol, led to
0
the , -diphosphonylketones 2, in good yields (Scheme 1).
SCHEME 1
The reaction was initially carried out with various amounts of di-
ethylphosphite in order to optimize the reaction yield. We have found

Diphosphonylketones
1247
TABLE I 31P in ppm and % of Diastereoisomers for Compounds 2
2a1
2a2
2b1
2b2
2c1
2c2
2d1
2d2
2e1
2e2
31P
% dias
28.4
52
28.3
48
27.5
59
26.8
41
26.5
55
26.1
45
29.5
54
26.6
46
29.2
53
29.1
47
that the use of 10 equivalents of diethylphosphite gave the best result
(80–92% yield).
1
Compounds 2 were characterized on the basis of their 31P, H, and
13C NMR data, which indicate that they are obtained as a mixture of
two diastereoisomers. The major will be designated by index 1 and the
minor by index 2. The relative proportions of these diastereoisomers
were estimated from the 31P NMR spectra where a singlet for each
diastereoisomer is present (Table I).
2-2 Reaction of Triethylphosphite and
Ethoxydiphenylphosphine with
,
0-bis(dimethylamino)ketone Hydrochlorides 10:
0
Synthesis of , -Diphosphonylketones 20
It is well known that -(dialkylamino)ketone hydrochlorides react
21
with phosphites under reflux to yield -ketophosphonates.6,20
We
0
show here that the extension of this reaction to , -bis(dimethyl-
amino)ketone hydrochlorides 10 leads to the formation of , -
0
diphosphonylketones 20 (Scheme 2).
SCHEME 2
The reaction was achieved by heating under reflux for 6 h a mixture
of 10 in excess phosphite (5 equivalents).
The structures of compounds 20 have been unambiguously charac-
terised from their IR and NMR (1H, 31P, 13C) spectral data.

1248

Diphosphonylketones
1249
TABLE III 13C NMR for Compounds 20: in ppm (JCP in Hz)
20a
207.9(14.6)
40.4
27.8(129.8)
—
20b
208.8(12.1)
42.7
30.1(78.5)
—
20c
215.0(13.2)
43.8
24.3(144.5)
36.2
20d
208.0(12.9)
44.5
24.1(143.4)
35.2(5.5)
24.2
20e
209.1(11.6)
42.9
25.3(58.2)
37.1(5.2)
21.8
127.8–135.3
—
C1
C2
C3
C4
C5
C6
C7
—
—
—
61.8(6.4)
16.1(4.6)
127.8–135.5
—
61.0(6.2)
15.9(6.3)
60.5(6.4)
15.4(6.4)
0
Reaction of , -Diphosphonylketones 2 and 20 with
Phenylhydrazine Hydrochloride: Synthesis of
2-(Phosphonoethyl)3-(phosphonomethyl)indoles 3
In connection with our interest in the synthesis of heterocyclic com-
23
pounds bearing phosphoryl groups,22
we report here the indoliza-
16
0
tion according to Fischer14
of the , -diphosphonylketones 2 and 20
which leads to a new class of phosphorylated indoles. Thus, treatment of
compounds 2 and 20 with an equimolar amount of phenylhydrazine hy-
drochloride, using ethanol as solvent and heating the mixture under re-
flux for 12 h gives the 2-(phosphonoethyl)3-(phosphonomethyl)indoles
3 in good yields (Scheme 3).
SCHEME 3
The 1H, 13C, and 31P NMR data confirm the structures of compounds
3 and are in accordance with some literature data.16 The N H proton
shows a broad singlet at = 8.8–9.2 ppm. The 13C NMR spectra display

1250
S. Touil and H. Zantour
TABLE IV 13C NMR for Compounds 3: in ppm (JCP in Hz)
3a
3b
3c
3d
3e
C1
C2
C3
C4
C5
138.5
139.1
139.5
138.8
136.9(16.0)
103.8(7.5)
112.0–135.7 111.5–131.8
27.5(78.8)
138.3
136.2(16.2)
104.0(7.8)
136.7(16.4)
102.5(8.2)
112.5–135.2
137.0(15.9)
103.4(8.5)
111.8–144.2
137.4(15.5)
104.2(8.0)
109.1–142.0
44.9(138.5; 3a1) 41.8(140.5; 3b1) 41.3(139.4; 3c1)
45.3(138.3; 3a2) 42.5(140.1; 3b2) 41.5(139.0; 3c2)
23.8(143.5)
C6
C7
32.6(4.0)
32.0(3.7)
31.7(3.9)
33.9(3.0)
25.6(80.3)
32.2(3.5)
21.0(144.7)
40.8(144.1; 3a1) 39.8(145.5; 3b1) 39.5(142.2; 3c1)
42.5(146.7; 3a2) 40.1(146.2; 3b2) 39.7(143.0; 3c2)
C8
C9
C10
15.9–16.5
62.0–63.3
112.5–135.2
15.5–16.3
61.8–63.2
111.8–144.2
15.7–16.5
62.0–63.4
109.1–142.0
112.0–135.7
16.0–16.3
61.9–62.2
—
—
—
the characteristic signals of all carbons and particularly those corre-
sponding to the indole ring (Table IV).
In addition, 31P, 1 H, and 13C NMR analysis of compounds 3a–c shows,
0
similar to the corresponding , -diphosphonylketones (2a–c), a mix-
ture of two diastereoisomers in an approximate 1:1 ratio which was
estimated from the 31P NMR spectra (Table V). Indexes 1 and 2 are
attributed to the major and minor diastereoisomers respectively.
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
TABLE V 31P in ppm and % of Diastereoisomers for Compounds 3
3a1
27.9
27.4
51
3a2
27.6
27.5
49
3b1
28.6
28.2
55
3b2
28.5
28.4
45
3c1
27.5
27.1
52
3c2
27.3
27.2
48
3d
31.0
30.6
—
3e
28.3
28.1
—
P1
P2
% dias

Diphosphonylketones
1251
relative to TMS (internal reference) for 1H and 13C NMR and relative to
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.
Purification of products was performed by column chromatography
using silica gel 60 (Fluka).
Synthesis of Compounds 1 and 10
The starting diarylideneketones 124 and bis(dimethylamino)ketone
hydrochlorides 1025 were prepared according to reported procedures.
Synthesis of , 0-Diphosphonylketones 2
To a mixture of diarylideneketone (0.01 mol) and diethylphosphite
(0.1 mol), was added dropwise with stirring, a solution of 0.025 g of
sodium in 0.5 mL of absolute ethanol. The reaction mixture was then
stirred at room temperature for an additional 24 h. The excess of di-
ethylphosphite was removed under reduced pressure then CHCl3 (100
mL) was added. The organic phase was washed with water (2 50 mL),
dried over MgSO4 and concentrated in vacuo. The obtained residue was
chromatographed on silica gel column using a mixture of ether and hex-
ane 3/1 as eluent.
2a: Oil; Yield = 92%; 1H NMR: = 1.02–1.30 (m; 12H; CH3 CH2 O);
2.93–3.23 (m; 4H; CH2 C O); 3.60–3.73 (m; 2H; CH P O); 3.83–4.13
(m; 8H; CH3 CH2 O); 7.10–7.32 (m; 10H; H arom.); IR:
O = 1715
C
1
1
cm
;
O = 1262 cm
.
P
2b: Oil; Yield = 86%; 1H NMR: = 1.06–1.25 (m, 12H; CH3 CH2 O);
2.82–3.14 (m; 4H; CH2 C O); 3.23–3.35 (m; 2H; CH P O); 3.80–
4.12 (m; 8H; CH3 CH2 O); 6.79–7.34 (m; 6H; H arom.); IR:
1
1
O = 1721 cm
;
O = 1272 cm
.
C
P
2c: Oil; Yield = 80%; 1H NMR: = 1.03–1.24 (m, 12H; CH3 CH2 O);
2.98–3.27 (m; 4H; CH2 C O); 3.40–3.54 (m; 2H; CH P O); 3.89–
4.16 (m; 8H; CH3 CH2 O); 6.30–7.27 (m; 6H; H arom.); IR:
1
1
O = 1720 cm
;
O = 1270 cm
.
C
P
2d: Oil; Yield = 87%; 1H NMR: = 0.84–1.28 (m; 12H; CH3 CH2 O);
1.45–3.40 (m; 6H; cyclic H); 3.45–3.72 (m; 2H; CH P O); 3.82–4.15 (m;
1
8H; CH3 CH2 O); 6.80–7.91 (m; 10H; H arom.); IR:
O = 1741 cm
;
C
1
O = 1260 cm
.
P
2e: Oil; Yield = 81%; 1H NMR: = 0.87–1.33 (m; 12H; CH3 CH2 O);
1.37–3.26 (m; 8H; cyclic H); 3.63–3.72 (m; 2H; CH P O); 4.03–4.23

1252
S. Touil and H. Zantour
(m; 8H; CH3 CH2 O); 6.91–7.86 (m; 10H; H arom.); IR:
=
C
O
1
1
1712 cm
;
O = 1271 cm
.
P
Synthesis of , 0-Diphosphonylketones 20
A mixture of
0-bis(dimethylamino)ketone hydrochloride (0.02 mol)
,
and phosphite (0.1 mol) was heated under reflux for 6 h. After cool-
ing, the excess of phosphite was removed under reduced pressure then
CHCl3 (100 mL) was added. The organic phase was washed with water
(2 50 mL), dried over MgSO4 and concentrated in vacuo. The obtained
residue was chromatographed on silica gel column using a mixture of
ether and hexane 3/1 as eluent.
20a: Oil; Yield = 78%; 31P NMR: = 29.2; 1H NMR: = 1.19
(t; 12H; 3JHH = 6.4; CH3 CH2 O); 1.80–3.18 (m; 8H; CH2 CH2 C O);
3
3
1
3.96 (qp; 8H; JHH = JPH = 6.4; CH3 CH2 O); IR:
O = 1720 cm
;
C
1
O = 1260 cm
.
P
20b: Oil; Yield = 71%; 31P NMR: = 30.8; 1H NMR: = 1.75–3.20
(m; 8H; CH2 CH2 C O); 7.12–7.95 (m, 20H, H arom.); IR:
=
C
O
1
1
1718 cm
;
O = 1270 cm
.
P
20c: Oil; Yield = 82%; 31P NMR: = 31.5; H NMR: = 0.90 (t; 12H;
1
3JHH = 7.0; CH3 CH2 O); 1.25–2.47 (m; 10H; cyclic H and CH2 P O);
3
3
1
3.65 (qp; 8H; JHH = JPH = 7.0; CH3 CH2 O); IR:
O = 1743 cm
;
C
1
O = 1262 cm
.
P
20d: Oil; Yield = 90%; 31P NMR: = 31.8; H NMR: = 0.82 (t; 12H;
1
3JHH = 7.1; CH3 CH2 O); 1.18–2.44 (m; 12H; cyclic H and CH2 P O);
3
3
1
3.59 (qp; 8H; JHH = JPH = 7.1; CH3 CH2 O); IR:
O = 1714 cm
;
C
1
O = 1263 cm
.
P
20e: Oil; Yield = 83%; 31P NMR: = 30.7; 1H NMR: = 1.10–2.87
(m; 12H; cyclic H and CH2 P O); 7.12–7.90 (m; 20H; H arom.); IR:
1
1
O = 1712 cm
;
O = 1269 cm
.
C
P
Synthesis of 2-(Phosphonoethyl)3-(phosphonomethyl)-
indoles 3
0
A mixture of , -diphosphonylketone (0.005 mol) and phenylhydrazine
hydrochloride (0.005 mol) in 30 mL of absolute ethanol, was heated
under reflux for 12 h. After removal of ethanol under reduced pressure,
the residue was diluted with water (50 mL) and extracted with CHCl3 (2
25 mL). The organic phase was dried over MgSO4 and concentrated in
vacuo. The obtained residue was chromatographed on silica gel column
using EtOAc as eluent.
3a: m.p. C = 108; Yield = 71%; 1H NMR: = 0.85–1.27 (m; 12H;
CH3 CH2 O); 2.80–3.24 (m; 2H; CH2 C C); 3.42–3.71 (m; 2H; CH

Diphosphonylketones
1253
P O); 3.82–4.18 (m; 8H; CH3 CH2 O); 6.84–7.40 (m; 14H; H arom.);
1
1
8.83 (broad s; 1H; N H); IR:
O = 1268 cm
;
NH = 3466 cm
.
P
3b: m.p. C = 114; Yield = 67%; 1H NMR: = 0.92–1.29 (m; 12H;
CH3 CH2 O); 2.37–2.65 (m; 2H; CH2 C C); 3.30–3.58 (m; 2H; CH
P O); 3.79–4.10 (m; 8H; CH3 CH2 O); 6.98–7.90 (m; 10H; H arom.);
1
1
8.80 (broad s; 1H; N H); IR:
O = 1260 cm
;
NH = 3450 cm
.
P
3c: m.p. C = 110; Yield = 62%; 1H NMR: = 0.90–1.25 (m; 12H;
CH3 CH2 O); 2.54–2.78 (m; 2H; CH2 C C); 3.41–3.67 (m; 2H; CH
P O); 3.87–4.15 (m; 8H; CH3 CH2 O); 6.42–7.50 (m; 10H; H arom.);
1
1
8.92 (broad s; 1H; N H); IR:
O = 1265 cm
;
NH = 3462 cm
.
P
3d: m.p. C = 98; Yield = 53%; 1H NMR: = 1.90–3.24 (m; 6H;
CH2 P O and CH2 CH2 P O); 6.85–7.88 (m; 24H; H arom.); 9.12
1
1
(broad s; 1H; N H); IR:
O = 1268 cm
;
NH = 3446 cm
.
P
1
3
3e: m.p. C = 85; Yield = 57%; H NMR: = 1.16 (t; 6H; JHH = 7.0;
3
CH3 CH2 O); 1.35 (t; 6H; JHH = 6.8; CH3 CH2 O); 1.96–3.51
(m; 6H; CH2 P O and CH2 CH2 P O); 3.95 (qp; 4H;
3JHH = JPH = 6.8; CH3 CH2 O); 4.08 (qp; 4H; JHH = JPH = 7.0;
3
3
3
CH3 CH2 O); 6.82–7.50 (m; 4H; H arom.); 9.18 (broad s; 1H; N H);
1
1
IR:
O = 1265 cm
;
NH = 3452 cm
.
P
REFERENCES
[1] D. S. Karanewsky and T. Dejneka, Eur. Pat. Appl. EP 87-104477 870326, 1987; U. S.
Appl. 844635, 1986; Chem. Abstr., 109, 129685 (1988).
[2] I. Mori, G. Iwasaki, A. Scheidegger, S. Koizumi, K. Hayakawa, and J. Mano, PCT
Int. Appl. WO 92-JP485 920417; Chem. Abstr., 118, 124547 (1993).
[3] H. C. E. Kluender, G. H. H. H. Benz, D. R. Britelli, W. H. Bullock, K. J. Combs, B. R.
Dixon, S. Schneider, J. E. Wood, M. C. Vanzandt, D. J. Wolanin, and S. M. Wilhelm,
U.S. Pat. Appl. US 95-539409 951106; Chem. Abstr., 129, 161412 (1998).
[4] M. Szelke, D. M. Evans, and D. M. Jones, PCT Int. Appl. WO 94-GB1887 940831;
Chem. Abstr., 123, 257409 (1995).
[5] S. Barkallah, M. Boukraa, H. Zantour, and B. Baccar, Phosphorus, Sulfur and
Silicon, 108, 51 (1996).
[6] S. Touil, E. Kremp, B. Baccar, and H. Zantour, J. Soc. Chim. Tunisie, 4, 85 (1997).
[7] S. Barkallah, M. Boukraa, H. M’rabet, and H. Zantour, Synth. Commun., 29, 1911
(1999).
[8] S. Touil and H. Zantour, Phosphorus, Sulfur and Silicon, in press (2001).
[9] F. Hartley, The Chemistry of Organophosphorus Compounds (John Wiley & Sons,
New York, 1996), vol. 4.
[10] E. N. Rizkalla, Rev. Inorg. Chem., 5, 223 (1983).
[11] A. W. Herlinger, J. R. Ferraro, R. Chiarizia, and E. P. Horwitz, Polyhedron, 16, 1843
(1997).
[12] H. J. Cristau and D. Virieux, Tetrahedron Lett., 40, 703 (1999).
[13] Y. Isomura, S. Sakamoto, and T. Abe, Jpn. Pat. Appl. JP 87-271433 871026; Chem.
Abstr., 111, 174388 (1989).
[14] B. Robinson, Chem. Rev., 63, 373 (1963).

1254
S. Touil and H. Zantour
[15] B. Robinson, Chem. Rev., 69, 227 (1969).
[16] J. P. Haelters, B. Corbel, and G. Sturtz, Phosphorus and Sulfur, 37, 41 (1988).
[17] F. Kogl, A. J. Haagen-Smit, and H. Erxleben, Z. Physiol. Chem., 228, 90 (1934).
[18] G. Lal and W. K. Anderson, Tetrahedron., 56, 2583 (2000).
[19] H. Takayama, M. Kurihara, M. Kitajima, I. M. Said, and N. Aimi, Tetrahedron, 56,
3145 (2000).
[20] T. C. Myers, R. G. Harvey, and E. V. Jensen, J. Am. Chem. Soc., 77, 3101 (1955).
[21] B. E. Ivanov, V. F. Zheltukhin, and T. G. Vavilov, Izv. Acad. Nauk SSSR, Ser. Khim,
6, 1285 (1967).
[22] S. Touil, M. T. Ben Dhia, H. Zantour, and B. Baccar, Phosphorus, Sulfur and Silicon,
119, 295 (1996).
[23] S. Touil and H. Zantour, Phosphorus, Sulfur and Silicon, 134, 493 (1998).
[24] C. R. Conard and M. A. Dolliver, Org. Synth. Coll., 2, 167 (1959).
[25] F. F. Blicke and F. J. McCarty, J. Org. Chem., 24, 1069 (1959).