Reaction between trimethyl phosphite, dimethyl acetylenedicarboxylate and 1,3-dicarbonyl compounds: An efficient method for the synthesis of dimethoxyphosphoryl succinic acid dimethoxy ester derivatives

Article abstract of DOI:10.14233/ajchem.2013.13429

The addition of a phosphorus nucleophile to an acceptor such as alkyne, certainly represents one of the most versatile and powerful tools for the formation of P-C bonds. This offers the possibility to access many diversely functionalized products. In this article, the reaction between trimethyl phosphite and dimethyl acetylenedicarboxylate (DMAD) with 1,3-dicarbonyl compounds such as dimedone, acetyl acetone and diethyl malonate proceeds smoothly to produce stable dimethoxyphosphoryl succinic acid dimethyl ester derivatives (4), (11) and (12) in excellent yields.

Full text of DOI:10.14233/ajchem.2013.13429

Asian Journal of Chemistry; Vol. 25, No. 8 (2013), 4162-4164
http://dx.doi.org/10.14233/ajchem.2013.13429
Reaction Between Trimethyl phosphite, Dimethyl Acetylenedicarboxylate and
1,3-Dicarbonyl Compounds: An Efficient Method for the Synthesis of
Dimethoxyphosphoryl Succinic Acid Dimethoxy Ester Derivatives
*
MARYAM YAZDANIAN and ALI ASADIPOUR
Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
*Corresponding author: Tel: +98 341 3205003; E-mail: aliasadipour@yahoo.com; aliasadipour@kmu.ac.ir
(Received: 30 January 2012;
Accepted: 4 February 2013)
AJC-12918
The addition of a phosphorus nucleophile to an acceptor such as alkyne, certainly represents one of the most versatile and powerful tools
for the formation of P-C bonds. This offers the possibility to access many diversely functionalized products. In this article, the reaction
between trimethyl phosphite and dimethyl acetylenedicarboxylate (DMAD) with 1,3-dicarbonyl compounds such as dimedone, acetyl
acetone and diethyl malonate proceeds smoothly to produce stable dimethoxyphosphoryl succinic acid dimethyl ester derivatives (4), (11)
and (12) in excellent yields.
Key Words: Phosphite, Acetylenedicarboxylate, Dimedone, Phosphoryl succinic acid dimethyl ester.
source such as alcohol, phenol9-11 or NH-acids12. Moreover it
is reported the diastereoselective synthesis of meso-bisphos-
INTRODUCTION
phonates in the presence of 4-nitrophenol13. We described
Phosphorus compounds have emerged to be tremendously
important for many different areas in chemistry and especially
in organic synthesis1. Interest in the preparation of organo-
phosphorus compounds has continued to expand in recent
herein the synthesis of a new series of dimethoxyphosphoryl
succinic acid dimethoxy ester derivatives (4), (11) and (12)
from the reaction of trimethyl phosphite and dimethyl acetylene-
years. This is a direct result of developing applications for
dicarboxylate (DMAD) in the presence of 1,3-dicarbonyl
phosphorus compounds in numerous synthetic procedures as
compounds such as dimedone, acetyl acetone and diethyl
well as an understanding of the role of the element in biological
malonate.
systems. The several classical efforts in regard to applications
EXPERIMENTAL
of organophosphorus compounds-the preparation of insecti-
cides, agricultural chemicals, flame retardants, medicinal
agents and reagents for olefination reactions- continue to be
highly active topics in organophosphorus chemistry2. Organo-
phosphorus compounds are being used as versatile interme-
diates in synthetic chemistry3-5. Especially, the structure of
compounds which a carbon atom is directly bound to a phos-
phorus atom, are synthetic target of interest, not least because
of their value for a variety of industrial, or biological activity
and are useful in chemical synthesis. The physical properties
and chemical reactivity of phosphate esters interlinks many
areas in chemistry and biology. Introduction of a phosphate
monoester into a molecule such as a drug candidate enhances
the water solubility, hence altering its bioavailability6-8. Thus,
a large number of methods have indicated novel synthesis of
organophosphorus compounds. There are many studies on the
reaction between trivalent phosphorus nucleophiles and α,β-
unsaturated carbonyl compounds in the presence of a proton
Most of the chemical compounds were commerically
available and were purchased from Merck company and used
without further purification. Melting points were determined
on an electrothermal 9100 apparatus. The IR spectra were
recorded on a Shimadzu 470 spectrometer. 1H NMR spectra
were appropriately recorded on a BRUKER FT-80 spectrometer.
Elemental analyses were performed by using a Heraeus CHN-
O-rapid analyzer. Their results were found to agree favourably
with the calculated values.
Preparation of compound (4), (11), (12): To a stirred
solution of 1,3-dicarbonyl compound (2 mmol) in 20 mL
diethyl ether was added 2 mL trimethyl phosphite (2 mmol)
and 2 mL dimethyl acetylenedicarboxylate (2 mmol) dropwise
over 15 min at -5 ºC. The reaction mixture was allowed to
room temperature and stirred for 48 h. The solvent was evapo-
rated and the residue was crystallized from ethanol to produce
the pure product.

Vol. 25, No. 8 (2013)
Synthesis of Dimethoxyphosphoryl Succinic Acid Dimethoxy Ester Derivatives 4163
Me Me
2-(Dimethoxy-phosphoryl)-3-(2-hydroxy-4,4-
dimethyl-6-oxo-cyclohex-1-enyl)succinic acid dimethyl
ester (4): Whitecrystals, m.p. 171. 3 ºC, 0.73 g (91 % yield);
Anal. calcd.: C, 46.83; H, 5.94. Found: C, 48.98; H, 6.42 %.
IR (KBr, νmax, cm-1): 3125-3450 (broad peak, OH), 1780
(C=O), 1630 (C=C), 1230 (P=O), 900 (POCH3); 1H NMR (80
MHz, CDCl3): 1.09 (s, 6H, 2CH3), 2.25 (m, 4H, 2CH2), 3.59
(d, 3H, OCH3(P(OCH3)), 3.64 (s, 3H, OCH3(COOCH3)), 3.67
(s, 3H, OCH3(COOCH3)), 3.80 (d, 3H, OCH3(P(OCH3)), 4.00
O
O
(MeO)3P
, (C2H5)2O
1
O
OH
CO2Me
MeO2C
CO2Me
Me Me
MeO2C
OMe
2
P
3
O
4
OMe
Scheme-I: Synthesis of 2-(dimethoxy-phosphoryl)-3-(2-hydroxy-4,4-
dimethyl-6-oxo-cyclohex-1-enyl)succinic acid dimethyl ester (4)
3
2
(dd, 1H, JHH = 9.00-12.00 Hz, JHP ≈ 20 Hz, CH), 4.40 (dd,
1H, 3JHH = 9.00 -12.00 Hz, 3JHP ≈ 10.00 Hz, CH) ppm.
2-(1-Acetyl-2-hydroxy-propenyl)-3-(dimethoxy-
phosphoryl)succinic acid dimethyl ester (11): Orange crys-
tals, m.p. 97 ºC, 0.64 g (90 % yield);Anal. calcd.: C, 45.86; H,
6.18. Found: C, 44.32; H, 6.01 %. IR (KBr, νmax, cm-1): 3370-
3500 (broad peak, OH), 1720 (C=O), 1650 (C=C), 1259 (P=O),
850 (POCH3); 1H NMR (80 MHz, CDCl3): 2.15 (s, 3H, CH3),
2.25 (s, 3H, CH3), 3.58 (s, 3H, OCH3(P(OCH3)), 3.59 (s, 3H,
OCH3(COOCH3)), 3.70 (s, 3H, OCH3(COOCH3)), 3.80 (s, 3H,
Me
Me
MeO2C
O
OH
H
O
P
H
O
P
O
MeO
MeO
MeO
MeO
CO2Me
Me
Me
HO
CO2Me
H
H
CO2Me
OCH3(P(OCH3)), 4.20 (dd, 1H, 3JHH = 9.00-12.00 Hz, 2JHP
≈
≈
3
20.00 Hz, CH), 4.80 (dd, 1H, JHH = 9.00-12.00 Hz, JHP
3
(2S , 3R) or (2R*, 3S*)
(2S , 3S) or (2R*, 3R*)
10.00 Hz, CH) ppm.
Scheme-II: Diastereomers of 2-(dimethoxy-phosphoryl)-3-(2-hydroxy-4, 4-
dimethyl-6-oxo-cyclohex-1-enyl)succinic acid dimethyl ester (4)
2-(1-Acetyl-2-ethoxy-2-hydroxy-vinyl)-3-(dimethoxy-
phosphoryl)succinic acid dimethyl ester (12) : Orange oil,
0.71 g (86 % yield);Anal. calcd.: C, 45.27; H, 6.38. Found: C,
44.97; H, 6.60 %. IR (KBr, νmax, cm-1): 3300-3620 (broad
peak, OH), 1729 (C=O), 1620 (C=C), 1248 (P=O), 781
(POCH3); 1H NMR (80 MHz, CDCl3): 1.30 (t, 6H, 2CH3), 3.35
(s, 6H, 2OCH3(P(OCH3)), 3.71 (s, 3H, OCH3(COOCH3)), 3.77
(s, 3H, OCH3(COOCH3)), 4.15 (q, 4H, 2CH2), 4.40 (dd, 1H,
well established chemistry of phosphorus nucleophiles4,5, it is
reasonable to assume that compounds (4) result from initial
addition of trimethyl phosphite to the activated dimethyl
acetylenedicarboxylate and subsequent protonation of the
reactive 1:1 adduct by dimedone. Following on, the positively
charged ion (6) is attacked by the anion of the 1,3-dicarbonyl
ion(7) to produce compound (8) that is converted to compound
(9). Then by attack of the oxygen atom of the anion to phos-
phorus cation, to generate compound (10), which is
hydrolyzed to give compound (4). Since the reaction was
carried out under an ordinary atmosphere, the conversion of
compound (10) to (4) is presumably accomplished by the
moisture from the air (Scheme-III). The reaction of trimethyl
phosphite with DMAD in the presence of acetyl acetone and
diethyl malonate gave (11) and (12) in high yields (Scheme-
3JHH = 9.00-12.00 Hz, 2JHP ≈ 20Hz, CH), 5.00 (dd, 1H, 3JHH
9.00-12.00 Hz, 3JHP ≈ 10.00 Hz, CH) ppm.
=
RESULTS AND DISCUSSION
The reaction of trimethyl phosphite (1) and dimethyl
acetylenedicarboxylate (2) in the presence of dimedone (3) as
the proton source/nucleophile leads to 2-(dimethoxy-phos-
phoryl)-3-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-
succinic acid dimethyl ester (4) in 91 % yields (Scheme-I).
The reaction was completed by mixing diethyl ether with
dimedone (3), then respectively trimethyl phosphite and
dimethyl acetylenedicarboxylate (DMAD) were added slowly.
The reaction was complete within 48 h. The structure of
compound as 1:1:1 adducts was deduced from its elemental
3
3
IV). Observation of JHH = 9.00-12.00 Hz and, JHH = 9.00-
12.00 Hz for the vicinal methine protons (11) and (12)
compounds, show the dominance of the anti arrangement and
(2S, 3R) or (2R, 3S) diastereoisomer respectively.
Finally, the reaction of trimethyl phosphite,dimethyl
acetylenedicarboxylate (DMAD) and 1,3-dicarbonyl compounds
such as dimedone, acetyl acetone and diethyl malonate
provides a simple one-pot synthesis of stable dimethoxy-
phosphoryl succinic acid dimethyl esters of potential synthetic
and pharmaceutical interest. The present method carries the
advantage that not only is the reaction performed under neutral
conditions, but also the substances can be used without any
activation or modification.
1
1
analyses, IR and H NMR. The H NMR spectrum of (4) in
CDCl3 exhibited two doublets recognized as arising for the
two methoxy (δ = 3.59 and 3.80 ppm) groups. The two singlets
at (δ = 3.64 and 3.67 ppm) belong to the ester methoxy protons.
Observation of a doublet of doublet at (δ = 4.00 ppm, 3JHH
=
2
3
9.00-12.00 Hz, JHP = 20.00 Hz) and (δ = 4.40 ppm, JHH
=
9.00-12.00 Hz, 3JHP = 10.00 Hz) for the vicinal methine protons
in (4), indicates the dominance of the anti arrangement. Since
compound (4) posses two stereogenic centers, two diastere-
omers with anti HCCH arrangement are possible (Scheme-
II). Although we have not yet established the mechanism of
the reaction between trimethyl phosphite and DMAD in the
presence of dimedone in an experimental manner, a possible
explanation is proposed in Scheme-III. On the basis of the
Conclusion
Dimethoxyphosphoryl succinic acid dimethoxy ester
derivatives (4), (11) and (12) have been synthesized from the
reaction of trimethyl phosphite, dimethyl acetylenedicarboxy-
late and 1,3-dicarbonyl compounds.

4164 Yazdanian et al.
Asian J. Chem.
O
O
Me
(MeO)3P
MeO2C
Me
(MeO)3P
MeO2C
(MeO)3P
3
MeO2C
CO2Me
CCO2Me
CHCO2Me
+
1
2
5
6
Me Me
O
Me Me
O
Me Me
7
O
O
O
Me
Me
O
O
O
CO2Me
CO2Me
P(OMe)3
CO2Me
MeO2C
MeO2C
MeO2C
P(OMe)3
Me Me
O
P(OMe)3
8
9
Me Me
O
O
OH
moisture
P(OMe)3
CO2Me
OMe
MeO2C
MeO2C
- CH OH
3
CO2Me
P
O
OMe
4
10
Scheme-III: A possible mechanism for synthesis of 2-(dimethoxy-phosphoryl)-3-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)succinic
acid dimethyl ester (4)
3. R.R. Holmes, Acc. Chem. Res., 37, 746 (2004).
OEt OEt
OH
Me Me
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O
O
OH
CO2Me
OMe
CO2Me
MeO2C
MeO2C
OMe
OMe
P
P
O
O
OMe
11
12
Scheme-IV: Structures of 2-(1-acetyl-2-hydroxy-propenyl)-3-(dimethoxy-
phosphoryl)succinic acid dimethyl ester (11)and 2-(1-acetyl-2-
ethoxy-2-hydroxy-vinyl)-3-(dimethoxy-phosphoryl)succinic acid
dimethyl ester (12)
ACKNOWLEDGEMENTS
The authors are so grateful for kind cooperation of Prof.
IssaYavari (Department of Chemistry, Tarbiat Modarres Uni-
versity, Tehran, Iran) and to theVice-Chancellor for Research
of Kerman University of Medical Sciences for financial support.
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