A Convenient Procedure for the Synthesis of 2,2,2-Trifluoroethyl Methyl 2-Oxoalkylphosphonates

Article abstract of DOI:10.1080/10426507.2014.978326

(Figure Presented) A convenient and versatile method was developed for the synthesis of 2,2,2-trifluoroethyl methyl 2-oxoalkylphosphonates starting from dimethyl phosphonates by alkaline hydrolysis followed by esterification with 2,2,2-trifluoroethanol using diisopropylcarbodiimide (DIC) in the presence of 4-(dimethylamino)pyridine (DMAP) catalyst following the Steglich protocol.

Full text of DOI:10.1080/10426507.2014.978326

This article was downloaded by: [UQ Library]
On: 17 June 2015, At: 07:30
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
A Convenient Procedure For The Synthesis Of 2,2,2-
Trifluoroethyl Methyl 2-Oxoalkylphosphonates
Katalin Molnára, Julien Behrab, László Takácsa, Mihály Kádára, Zsuzsanna Kardosa & Ferenc
Faiglc
a Sanofi/Chinoin - Prostaglandin Business Unit, Budapest, Hungary
b National Graduate School of Chemistry and Chemical Engineering of Montpellier,
Montpellier, France
c MTA-BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences,
Budapest University of Technology and Economics, Budapest, Hungary
Accepted author version posted online: 14 Nov 2014.
Click for updates
To cite this article: Katalin Molnár, Julien Behra, László Takács, Mihály Kádár, Zsuzsanna Kardos & Ferenc Faigl (2014): A
Convenient Procedure For The Synthesis Of 2,2,2-Trifluoroethyl Methyl 2-Oxoalkylphosphonates, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2014.978326
To link to this article: http://dx.doi.org/10.1080/10426507.2014.978326
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
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. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
Running head: Synthesis of trifluoroethyl methyl phosphonates
A CONVENIENT PROCEDURE FOR THE SYNTHESIS OF 2,2,2-
TRIFLUOROETHYL METHYL 2-OXOALKYLPHOSPHONATES
Katalin Molnár,*a Julien Behra,b László Takács,a Mihály Kádár,a Zsuzsanna Kardos,a
Ferenc Faigl.c
aSanofi / Chinoin - Prostaglandin Business Unit, Budapest, Hungary
bNational Graduate School of Chemistry and Chemical Engineering of Montpellier, Montpellier,
France
cMTA-BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences,
Budapest University of Technology and Economics, Budapest, Hungary
katimolnar88@gmail.com
Abstract: A convenient and versatile method was developed for the synthesis of
2,2,2-trifluoroethyl methyl 2-oxoalkylphosphonates starting from dimethyl phosphonates by
alkaline hydrolysis followed by esterification with 2,2,2-trifluoroethanol using
diisopropylcarbodiimide (DIC) in the presence of 4-(dimethylamino)pyridine (DMAP) catalyst
following the Steglich protocol.
O
O
P
O
O
P
F C
OH
O
O
P
3
H2O
R
R
O
R
O
O
CF
3
O
DMAP/DIC
KOH
O
O H
R=H, Pr, 3-Me-Ph
Keywords: trifluoroethyl ester, mixed phosphonoester, methyl phosphonic acid, 2,2,2-
trifluoroethanol, Steglich protocol
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
INTRODUCTION
Stabilized phosphonates are key compounds in the Horner-Wadsworth-Emmons (HWE) reaction
to form trans double bonds. The work of Still and Gennari1 and later of Jin2 showed that using
bis(2,2,2-trifluoroethyl)phosphonoacetates or 2-oxoalkylphosphonates the stereochemical
outcome of the HWE reaction is reversed and α,β-unsaturated esters or ketones can be prepared
with moderate to good Z stereoselectivity. In order to understand this unexpected effect of the
trifluoroethyl substituents more thoroughly, we wanted to examine the situation when only one
trifluoroethyl group was present. Although many examples can be found for the preparation of
dimethyl- and bis(trifluoroethyl)phosphonates, mixed trifluoroethyl methyl phosphonates are
unknown and therefore elaboration of a simple method for their synthesis was undertaken.
RESULTS AND DISCUSSION
Mixed phosphonates can be conveniently prepared from their readily available dimethyl
analogues using two methods (Scheme 1): (i) activation of the phosphonate moiety by mono
chlorination followed by reaction with trifluoroethanol3 or (ii) partial hydrolysis of a diester
followed by esterification with trifluoroethanol.4 Considering the unpleasant reaction conditions
of chlorination and the stability of 2-oxoalkylphosphonates, partial hydrolysis of the
dimethylester was preferred.
Acidic hydrolysis needs harsh conditions and yields the fully hydrolyzed product.4,5 Mono
dealkylation can be performed in alkaline medium where the difference of an order of magnitude
in the rate of hydrolysis of mono and diesters enables partial hydrolysis.4,5 Best results were
obtained with KOH in water at 50 °C. No organic solvent was needed because of the water
solubility of the dimethyl phosphonates studied (1). Solubility in water of the dimethyl ester 1a
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
was considerable explaining the lower yield of the monoester 2a. Work-up was adjusted to the
different solubilities of monoesters 2 (see in the Supplement). Conditions and results of
hydrolysis are summarized in Table 1.
The next step was the alkylation of the mono phosphonic acids (2). Trifluoroethanol is a weak
nucleophile therefore it was not surprising that direct esterification in the presence of H2SO4, the
use of Mitsunobu reaction6 and base catalyzed alkylation with trifluoroethyl mesylate or tosylate
were all unsuccessful. Even with trifluoroethyl triflate only traces of the product was formed.
Activation of the monoester (2) with carbamide derivatives as in Kampe’s procedure7 was
promising. Satisfying results were achieved by following Steglich’s protocol8, which is
frequently used for preparing carboxylic acid esters with hindered alcohols. The monoester (2)
was dissolved in dichloromethane and activated with a carbamide derivative (DCC or DIC) and
esterification was catalyzed by DMAP. Results are summarized in Table 2.
EXPERIMENTAL
General procedure for the synthesis of trifluoroethyl methyl phosphonates 3a-c
Esterification. To the solution of 2-oxoalkylphosphonic acid monomethyl esters 2a-c (30 mmol)
in 20 mL DCM 2.93 g (24 mmol) DMAP and 2.62 mL (36 mmol) trifluoroethanol were added
under nitrogen atmosphere. The reaction mixture was cooled to -10 °C and 5.57 mL (36 mmol)
DIC was added, then it was let to warm up overnight. Reaction was quenched by 46 mL 1 M
HCl. After stirring for 20 minutes, the reaction mixture was cooled to 0 °C. Precipitation was
filtered off and washed with EtOAc. The phases were separated, the aqueous phase was extracted
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
with EtOAc. The combined organic phases were washed with 1 M NaHCO3 and brine, dried
over Na2SO4 and evaporated. The crude product was purified by silica gel column
chromatography giving the title compound as yellowish liquids.
1
13
31
Supplemental data are available online with synthetic details and H, C and P NMR data of
compounds 1a-c, 2a-c, and 3a-c and HRMS data of 3a-c.
CONCLUSIONS
A two-step procedure was worked out for the preparation of novel, mixed, trifluoroethyl methyl
-oxoalkylphosphonates. Our procedure using alkaline hydrolysis and a carbamide derivative
activated esterification is mild and can be generally used even with less nucleophilic alcohols.
Investigation of the stereochemistry in HWE reactions of mixed ester phosphonates is in
progress.
ACKNOWLEDGEMENTS
We thank the financial support of Sanofi-Chinoin and Varga József Foundation.
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
REFERENCES
1. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
2. Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725.
3. Iorga, B., Carmichael, D.; Savignac, P. C. R. Acad. Sci. Paris, Série IIc, Chimie : Chemistry
3, 2000, 821.
4. Greene, T. W.; Wuts, P. G. M. Protective groups in organic synthesis, 3rd ed.; Wiley & Sons:
New York, 1999, pp 660.
5. Cox, J. R. JR.; Ramsay, O. B. Chem. Rev., 1964, 64, 317.
6. a, Campbell, D. A. J. Org. Chem. 1992, 57, 6331; b, Mitsunobu, O. Synthesis 1981, 1, 1.
7. Kampe, W. Chem. Ber., 1965, 98, 1031.
8. Neises. B.; Steglich, W. Org. Synth., 1985, 63, 183.
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
O
P
COCl2
or PCl5
O
P
CF3CH2OH /
N(CH2CH3)3
O
O
R
R
R
O
O
O
O
Cl
1
a: R = H
b: R = Pr
c: R = 3-Me-Ph
O
P
O
CF3CH2OH /
DIC / DMAP
O
P
O
KOH / H2O
R
O
O
OH
CF
3
2
3
Scheme 1
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 1. Partial hydrolysis of dimethyl -oxophosphonates 1a-c
Compound
R
H
Reaction time (h) Yield (%)
5
6
73
89
93
2a
2b
2c
Pr
3-Me-Ph
24
Table 2. Synthesis of mixed esters 3a-c
Compound
R
H
Purity (%)*
Yield (%)
73
89
93
38
42
36
3a
3b
3c
Pr
3-Me-Ph
* Determined by 1H NMR
7
ACCEPTED MANUSCRIPT