Facile synthesis of phosphonates via catalyst-free multicomponent reactions in water

Article abstract of DOI:10.1055/S-0032-1317078

Stable derivatives of phosphonates were prepared using multicomponent reactions of dialkyl acetylenedicarboxylate with l-(6-hydroxy-2-isopropenyl-l- benzofuran-yl)-l-ethanone or 4-hydroxycoumarin in the presence of trimethyl or triphenyl phosphite in wate

Full text of DOI:10.1055/S-0032-1317078

LETTER
▌2397
letter
Facile Synthesis of Phosphonates via Catalyst-Free Multicomponent Reactions
in Water
Synthesis of Phosphonates
Faramarz Rostami-Charati,*a Zinatossadat Hossainib
a
Department of Chemistry, Faculty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran
Fax +98(172)2224060; E-mail: f_rostami_ch@yahoo.com
b
Department of Chemistry, Qaemshahr Branch, Islamic Azad University, P.O. Box 163, Qaemshahr, Iran
Received: 17.06.2012; Accepted after revision: 19.07.2012
ylate with a trivalent phosphorus nucleophile such
Abstract: Stable derivatives of phosphonates were prepared using
as trimethyl phosphite or triphenyl phosphite in the pres-
multicomponent reactions of dialkyl acetylenedicarboxylate
ence of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-
with 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone or
4-hydroxycoumarin in the presence of trimethyl or triphenyl phos-
ethanone15,16 or 4-hydroxycoumarin.
phite in water in good yields.
1-(6-Hydroxy-2-isopropenyl-1-benzofuran-yl)-1-etha-
none (1) has been extracted from the roots of Petasites hy-
bridus. This compound is very soluble in water and has
Key words: phosphonates, triphenyl phosphate, trimethyl phos-
phate, triethyl phosphate
been shown to have potent biological and medicinal prop-
erties.15,16
One powerful tool used to combine economy with envi-
The reaction of 1-(6-hydroxy-2-isopropenyl-1-benzofu-
ronmental concern is to perform organic reactions in wa-
ter in two or more synthetic steps without isolation of any
ran-yl)-1-ethanone (1) and dialkyl acetylenedicarboxylate
2 in the presence of trimethyl phosphite or triphenyl phos-
intermediate, thus reducing time and saving money, ener-
phite 3 produces dialkyl 2-(dialkoxyphosphoryl)succinate
gy, and raw materials.1 Phosphorus-containing organic
4 in good yield (Scheme 1).17
compounds have diverse biological activity and have at-
1
The H NMR spectrum of 4a displayed two singlets at
δ = 2.12 and 2.58 ppm for the methyl protons, two singlets
at δ = 3.72 and 3.84 ppm for the methoxy protons, and two
sets of doublet of doublets for the vicinal methine protons
tracted noteworthy synthetic and pharmacological inter-
est.2,3 Phosphonates have important applications in flame
retardancy,4,5 organic synthesis,6 and biological applica-
tions.3c,7 Furthermore, phosphonates have been used as
substitutes for the corresponding esters and acids of high-
biological activity8,9 and as suitable probes for designing
antibodies on the basis of transition-state models. A large
number of methods has appeared describing novel synthe-
ses of organophosphorus compounds.10–14 Hence, we
describe herein the reaction of dialkyl acetylenedicarbox-
2
at δ = 3.94 and 5.15 ppm, which appeared with JHP and
3JHP values of 20.4 and 11.7 Hz, respectively. The
methoxy groups of the phosphoranyl moiety are diastereo-
topic and show two separate doublets at δ = 2.87 (3 H, d,
3
JHP = 11.2 Hz, MeO) and 3.78 (3 H, d, JHP = 11.2 Hz,
MeO) ppm. The hydroxy proton was observed as a broad
Me
Me
Me
CO2R1
O
Me
O
H2O
(R2O)3P
O
H
+
+
HO
70 °C, 6 h
O
H
HO
H
R1O2C
CO2R1
CO2R1
H
P(OR2)2
O
1
2
3
4
2, 3, 4 R1
R2
Yield (%) of 4
a
b
c
d
e
Me
Et
Me
Me
Me
Ph
87
78
75
72
70
i-Pr
Me
Et
Ph
Scheme 1 Reaction of phosphites, activated acetylenes, and 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone
SYNLETT 2012, 23, 2397–2399
Advanced online publication: 17.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317078; Art ID: ST-2012-D0521-L
© Georg Thieme Verlag Stuttgart · New York

2398
F. Rostami-Charati, Z. Hossaini
LETTER
singlet at δ = 8.22 ppm, which disappeared with addition two separate doublets at δ = 2.92 and 3.72 ppm. The hy-
of D2O. Observation of 3JHH = 12.0 Hz for the vicinal me- droxy proton was observed as a broad singlet at δ = 8.12
thine protons in 4a implies an anti arrangement. Since ppm, which disappeared with addition of D2O. Observa-
3
compound 4a possesses two stereogenic centers, two dia- tion of JHH = 11.7 Hz for the vicinal methine protons in
stereomers with anti HCCH arrangements are possible 6a once again indicates an anti arrangement. Since com-
3
(Figure 1). The observation of JCP = 22.4 Hz for the pound 6a possesses two stereogenic centers, two dia-
CO2Me group and 3JCP = 0 Hz for C of the benzene moiety stereomers with anti HCCH arrangements are possible
is in agreement with the 2R,3S or 2S,3R diastereomer.
(Figure 1).
A proposed mechanism for the formation of compound 6
is shown in Scheme 3. On the basis of phosphorus nucleo-
philic chemistry,12,19 it is reasonable to presume that com-
pound 6 results from initial addition of the phosphite to
the activated acetylenic compound and following proton-
ation of the reactive 1:1 adduct, attack of the 4-hydroxy-
coumarin 8 to cation 7 to generate ylide 9 which
isomerizes, under the reaction conditions employed, to
ylide 10. Hydrolysis of 10 leads to phosphonate derivative
6.
O
(MeO)2P
H
O
(MeO)2P
H
Ar
CO2Me
H
Ar
CO2Me
H
CO2Me
CO2Me
(2R,3S)-4a or (2S,3R)-4a
(2S,3S)-4a or (2R,3R)-4a
Figure 1 Two diastereomers of 4a with anti arrangement
Under similar conditions, the reaction of 4-hydroxy-
coumarin (5) and dialkyl acetylenedicarboxylate 2 in the
presence of trimethyl phosphite or triphenyl phosphite 3
produced dialkyl 2-(dialkoxyphosphoryl)succinate 6 in
good yield (Scheme 2).18
In conclusion, we found that the reaction of activated acet-
ylenic compounds with trimethyl phosphite or triphenyl
phosphite in the presence of 1-(6-hydroxy-2-isopropenyl-
1-benzofuran-yl)-1-ethanone or 4-hydroxycoumarin leads
to a facile synthesis of some functionalized phosphonates
in water as the solvent without needing a catalyst.
OH CO2R1
O
OH
CO2R1
P(OR2)2
H2O
(R2O)3P
+
+
CO2R1
70 °C, 5 h
Acknowledgment
O
O
CO2R1
O
O
We gratefully acknowledge financial and spiritual support from the
National Endowment for the Elite. Additionally, this work was sup-
ported by the Research Council of Gonbad Kavous University and
Islamic Azad University of Qaemshahr.
5
2
3
6
2, 3, 6
R1
Me
Et
R2
Me
Me
Yield (%) of 6
a
b
85
80
72
68
References and Notes
c
d
Me
Et
Ph
Ph
(1) (a) Mironov, M. A. QSAR Comb. Sci. 2006, 25, 423.
(b) Dömling, A. Chem. Rev. 2006, 106, 17. (c) Ramón, D. J.;
Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602. (d) Orru, R.
V. A.; de Greef, M. Synthesis 2003, 1471.
(2) (a) Sikorski, J. A.; Logusch, E. W. In Handbook of
Organophosphorus Chemistry, Engel, R., Ed.; Marcel
Dekker: New York, 1992, 73. (b) Eto, M. In Handbook of
Organophosphorus Chemistry, Engel, R., Ed.; Marcel
Dekker: New York, 1992, 807–873. (c) Hinkle, P. C.;
McCarty, R. E. Sci. Am. 1978, 238, 104.
Scheme 2 Reaction of phosphites, activated acetylenes, and 4-hydroxy-
coumarin
The 1H NMR spectrum of 6a displayed signals for vicinal
methine protons at δ = 3.92 and 5.12 ppm, which ap-
peared as two doublet of doublets with 2JHP and 3JHP val-
ues of 20.4 and 8.7 Hz, respectively. The methoxy groups
of the phosphoranyl moiety are diastereotopic and show
(3) (a) Eto, M. Organic and Biological Chemistry; CRC Press:
Ohio, 1974, 1. (b) Phosphorus and its Compounds; Vol. 2;
O–
O
CO2R1
+
+
(R2O)3P
P(OR2)3
_
C
CHCO2R1
+
H
CO2R1
R1O2C
O
O
O
O
7
8
9
CO2R1
OH CO2R1
OH
O
+
P(OR2)3
_
P(OR2)2
moisture
– R1OH
CO2R1
CO2R1
O
O
O
O
10
6
Scheme 3 Proposed mechanism for the formation of 4
Synlett 2012, 23, 2397–2399
© Georg Thieme Verlag Stuttgart · New York

LETTER
Van Wazer, J. R., Ed.; Interscience Publishers: New York,
Synthesis of Phosphonates
2399
Representative Analytical Data for Compound 4a
1961. (c) Engel, R. Chem. Rev. 1977, 77, 349.
(d) Hildebrand, R. The Role of Phosphonates in Living
Systems; CRC Press: Boca Raton, 1983.
White powder; mp 138–140 °C; yield: 0.81 g (87%). IR
(KBr): νmax = 3225, 1740, 1735, 1724, 1678, 1587, 1128 cm–1.
Anal. Calcd (%) for C21H25O10P (468.39): C, 53.85; H, 5.38.
Found: C, 53.92; H, 5.47. 1H NMR (500 MHz, CDCl3):
(4) Papazoglou, E. S. Handbook of Building Materials for Fire
Protection; Harper, C. A., Ed.; McGraw-Hill: New York,
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(5) Weil, E. D. Kirk-Othmer Encyclopedia of Chemical
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(6) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(7) Freeman, G. A.; Rideout, J. L.; Miller, W. H.; Reardon, J. E.
J. Med. Chem. 1992, 35, 3192.
(8) Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211.
(9) Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997, 53, 13603.
(10) Organic Phosphorus Compounds; Kosolapoff, G. M.;
Maier, L., Eds.; Wiley-Interscience: New York, 1972.
(11) Hudson, H. R. In The Chemistry of Organophosphorus
Compounds: Primary, Secondary and Tertiary Phosphines
and Heterocyclic Organophosphorus(III) Compounds;
Hantely, F. R., Ed.; Wiley: New York, 1990, 386–472.
(12) Engel, R. Synthesis of Carbon–Phosphorus Bonds; CRC
Press: Boca Raton, 1998.
δ = 2.12 (3 H, s, Me), 2.58 (3 H, s, Me), 2.87 (3 H, d 3JHP
=
11.2 Hz, MeO), 3.72 (3 H, s, MeO), 3.78 (3 H, d 3JHP = 11.2
Hz, OMe), 3.84 (3 H, s, MeO), 3.94 (1 H, dd 2JHP = 20.4 Hz,
3JHH = 12.0 Hz, CH), 4.78 (1 H, d, 2J = 3.5 Hz, CH), 5.15
(1 H, dd, 3JHH = 12.0 Hz, 3JHP = 8.7 Hz, CH), 5.30 (1 H, s,
CH), 5.73 (1 H, d, 2J = 3.5 Hz, CH), 7.82 (1 H, s, CH), 8.22
(1 H, s, OH). 13C NMR (125.7 MHz, CDCl3): δ = 18.6 (Me),
27.3 (Me), 44.2 (CH), 48.5 (d, 1JPC = 134.4 Hz, CH), 52.0
(OMe), 52.8 (d, 2JPC = 8.2 Hz, MeO), 53.6 (MeO), 54.6 (d,
2JPC = 8.2 Hz, MeO), 110.8 (d, 3JPC = 5.8 Hz, C), 111.4 (CH),
112.3 (CH2), 117.5 (C), 121.0 (C), 122.4 (CH), 137.5 (C),
154.2 (C), 157.4 (C), 159.2 (C), 167.5 (d, 2JPC = 5.4 Hz,
C=O), 172.6 (d, 3JPC = 22.4 Hz, C=O), 192.8 (C=O). 31
P
NMR (202 MHz, CDCl3): δ = 18.6. MS: m/z (%) = 468 (10)
[M+], 359 (56), 109 (100), 31 (86).
(18) General Procedure for the Preparation of Compounds 6
To a magnetically stirred solution of dialkyl
(13) (a) Yavari, I.; Hossaini, Z.; Alizadeh, A. Monatsh. Chem.
2006, 137, 1083. (b) Yavari, I.; Mohtat, B.; Zare, H.
Mendeleev Commun. 2006, 15, 102. (c) Alizadeh, A.;
Yavari, I. Mendeleev Commun. 2005, 14, 154. (d) Yavari, I.;
Alizadeh, A. Synthesis 2004, 237. (e) Yavari, I.; Alizadeh,
A.; Anary-Abbasinejad, M. Tetradhedron Lett. 2003, 44,
2877. (f) Yavari, I.; Anary-Abbasinejad, M.; Hossaini, Z.
Org. Biomol. Chem. 2003, 1, 560.
(14) Yavari, I.; Hossaini, Z.; Karimi, E. Monatsh. Chem. 2007,
138, 1267.
(15) Khaleghi, F.; Bin Din, L.; Rostami Charati, F.; Yaacob, W.
A.; Khalilzadeh, M. A.; Skelton, B.; Makha, M. Phytochem.
Lett. 2011, 4, 254.
acetylenedicarboxylate 2 (2 mmol) and 4-hydroxycoumarin
(5, 2 mmol) in H2O was added trimethyl or triphenyl
phosphite 3 (2 mmol). The reaction mixture was then stirred
for 5 h. After completion of reaction (monitored by TLC),
the mixture was purified by silica gel column chromatog-
raphy (Merck 230–400 mesh) using n-hexane–EtOAc as
eluent to give compound 6.
Representative Analytical Data for Compound 6a
Colorless crystals; mp 185–187 °C; yield 0.70 g (85%). IR
(KBr): νmax = 3235, 1754, 1740, 1732 cm–1. Anal. Calcd (%)
for C17H19O10P (414.30): C, 49.28; H, 4.62. Found: C, 49.36;
H, 4.74. 1H NMR (500 MHz, CDCl3): δ = 2.92 (3 H, d, 3JHP
= 11.2 Hz, MeO), 3.65 (3 H, s, MeO), 3.72 (3 H, d, 3JHP
=
(16) Khaleghi, F.; Bin Din, L.; Jantan, I.; Yaacob, W. A.;
Khalilzadeh, M. A. Tetrahedron Lett. 2011, 52, 7182.
(17) General Procedure for the Preparation of Compounds 4
To a magnetically stirred solution of dialkyl
11.2 Hz, OMe), 3.85 (3 H, s, MeO), 3.92 (1 H, dd, 2JHP
=
20.4 Hz, 3JHH = 11.7 Hz, CH), 5.12 (1 H, dd, 3JHH = 11.7 Hz,
3JHP = 8.7 Hz, CH), 6.95–7.92 (4 H, m, 4 CH), 8.12 (1 H, s,
OH). 13C NMR (125.7 MHz, CDCl3): δ = 43.8 (CH), 48.2 (d,
1JPC = 134.4 Hz, CH), 51.8 (OMe), 52.3 (d, 2JPC = 8.2 Hz,
MeO), 53.4 (MeO), 54.0 (d, 2JPC = 8.2 Hz, MeO), 115.4 (C),
122.4 (CH), 123.8 (C), 125.4 (CH), 126.8 (CH), 127.5 (C),
132.6 (CH), 149.6 (C), 165.2 (C=O), 167.5 (d, 2JPC = 5.4 Hz,
C=O), 172.6 (d, 3JPC = 21.5 Hz, C=O). 31P NMR (202 MHz,
CDCl3): δ = 18.6. MS: m/z (%) = 414 (20) [M+], 252 (48),
162 (86), 31 (100).
acetylenedicarboxylate 2 (2 mmol) and 1-(6-hydroxy-2-
isopropenyl-1-benzofuran-yl)-1-ethanone (1, 2 mmol) in
H2O was added trimethyl or triphenyl phosphite 3 (2 mmol).
The reaction mixture was stirred for 6 h, and, after
completion of reaction (monitored by TLC), the mixture was
purified by silica gel column chromatography (Merck 230–
400 mesh) using n-hexane–EtOAc as eluent to give
compound 4.
(19) Cadogan, J. I. G. Organophosphorus Reagents in Organic
Synthesis; Academic Press: New York, 1977.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2397–2399