A new preparative method for the synthesis of diethyl 1-diazo-2,2,2- trifluoroethylphosphonate via an imino phosphonate

Article abstract of DOI:10.1007/s11172-010-0051-1

A preparative method for the synthesis of diethyl 1-diazo-2,2,2- trifluoroethylphosphonate from trifluoroacetic anhydride and benzyl carbamate via diethyl 1-benzyloxycarbonylimino-2,2,2-trifluoroethylphosphonate is developed. Optimum conditions for the ch

Full text of DOI:10.1007/s11172-010-0051-1

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 107—109, January, 2010
107
A new preparative method for the synthesis
of diethyl 1ꢀdiazoꢀ2,2,2ꢀtrifluoroethylphosphonate via an imino phosphonate
N. M. Karimova, D. V. Vorobyeva, G. T. Shchetnikov, and S. N. Osipov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, Moscow, 119991 Russian Federation.
Fax: +7 (499) 135 6549. Eꢀmail: osipov@ineos.ac.ru
A preparative method for the synthesis of diethyl 1ꢀdiazoꢀ2,2,2ꢀtrifluoroethylphosphonate
from trifluoroacetic anhydride and benzyl carbamate via diethyl 1ꢀbenzyloxycarbonyliminoꢀ
2,2,2ꢀtrifluoroethylphosphonate is developed. Optimum conditions for the chlorination of benꢀ
zyl Nꢀtrifluoroacetylcarbamate with SOCl2—Py to afford the imidoyl chloride, phosphorylaꢀ
tion of the latter under the conditions of the Arbuzov reaction, as well as diazotization of amino
phosphonate with isopropyl nitrite are found.
Key words: trifluoromethylated imidoyl chloride, imino phosphonate, amino phosphonate
and diazophosphonate, Arbuzov reaction.
Scheme 1
Phosphorusꢀcontaining analogs of carboxylic acids are
undoubtedly of interest for the medicinal chemistry.1,2 At
the same time, introduction of fluorine atoms or fluoroꢀ
alkyl residues into the molecules of physiologically active
compounds can significantly influence their biological
properties.3—5 Therefore, the development of universal
building blocks for the synthesis of new fluorineꢀcontainꢀ
ing phosphonates is a topical task.
Earlier we have shown6,7 that copper and rhodium salts
catalyse the insertion of the carbene generated from diꢀ
ethyl 1ꢀdiazoꢀ2,2,2ꢀtrifluoroethylphosphonate (1) into
NH and OH bonds and also cyclopropanation and epoxiꢀ
dation reactions giving the corresponding trifluoromethylꢀ
containing phosphonates (Scheme 1).
The method of synthesis of diazocompound 1, which
we have preliminary published, is based on the use of triꢀ
fluoroacetaldehyde diethyl acetal as the starting comꢀ
pound; it includes several steps requiring purification of
products by column chromatography, that is why this
method is difficult to scale up.8,9
The present work is devoted to the development of
a more convenient alternative approach to the synthesis of
diazophosphonate 1 from commercially available trifluoꢀ
roacetic anhydride and benzyl carbamate (Scheme 2). It is
worth noting that the method envisages the formation of
an intermediate trifluoromethylꢀcontaining imino phosꢀ
phonate 4, having independent interest as the fundamenꢀ
tal synthon for the synthesis of phosphorus analogs of
αꢀaminoꢀαꢀtrifluoromethyl acids.10—12
phonic acids has not been fully disclosed, probably, beꢀ
cause of the low yields (less than 40%) and also because of
the difficulty of the subsequent removal of protecting
groups from the amino function. For the first time, we
have obtained imino phosphonate with orthogonal benzꢀ
yloxycarbonyl (Cbz) and ester protecting groups, which
are the most often used in the chemistry of amino acids
and peptides. Using the standard method,15 we initially
employed PCl5 as the chlorinating agent for the synthesis
Though imino phosphonates of the similar type have
been described earlier,13,14 their synthetic potential as the
universal precursors of the corresponding αꢀamino phosꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 107—109, January, 2010.
1066ꢀ5285/10/5901ꢀ0107 © 2010 Springer Science+Business Media, Inc.

108
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Karimova et al.
Scheme 2
at lower temperatures though the reaction rate noticeꢀ
ably decreases.
The reduction of a double bond with sodium boroꢀ
hydride with the subsequent removal of the Cbzꢀprotecꢀ
tion by catalytic hydrogenolysis leads to αꢀamino phosꢀ
phonate 6 in almost quantitative yield. During preparaꢀ
tion of the present work, an article16 devoted to the alterꢀ
native twoꢀstep method for the synthesis of amino phosꢀ
phonate 6 based on the reaction of trifluoroacetonitrile
with diethyl phosphite in the presence of pyridine folꢀ
lowed by reduction of a nonsubstituted intermediate imiꢀ
ne with a BH3•SMe2 complex has been published. From
our point of view, the necessity of a special equipment
(autoclave) when working with gaseous trifluoroacetoniꢀ
trile is an essential disadvantage of this method.
Diazotization of αꢀamino phosphonate 6 was carried
out using the method which has previously been develꢀ
oped,6 viz., the addition of an equimolar amount of isoꢀ
propyl nitrite to a solution of 6 in ether at room temperaꢀ
ture. After addition of approximately half of isopropyl niꢀ
trite, the exothermic reaction started; the remaning nitrite
was added at a rate providing mild boiling of the reaction
mixture. As the result, the target diazo compound 1 was
obtained after vacuum distillation in 80% yield.
In conclusion, it is worth noting that we have develꢀ
oped a new convenient approach to the synthesis of diethyl
1ꢀdiazoꢀ2,2,2ꢀtrifluoroethylphosphonate — the universal
synthon for the simultaneuos introduction of trifluoromeꢀ
thyl and phosphoryl groups into bioactive molecules. High
yields of the intermediate products in the developed synꢀ
thetic sequence excluding the use of chromatographic puꢀ
rification allow largeꢀscale preparation of the final diazo
compound.
of imidoyl chloride 3. In this case, a number of admixtures
is formed as the result of the Cbzꢀgroup destruction (benꢀ
zyl chloride is identified in the reaction mixture), and this
decreases the yield of 3 to 30—40%. Milder chlorinating
agent (thionyl chloride in pyridine), which totally elimiꢀ
nates the destruction mentioned, has been found as the
result of optimization. For example, chlorination carried
out at room temperature with a molar ratio of reagents
CbzNHC(O)CF3 : SOCl2 : Py = 1 : 3 : 1.5 occurs without
formation of byꢀproducts and yields 95% of imidoyl chloꢀ
ride 3 after 24 h .
Experimental
Reactions of Nꢀacylated αꢀtrifluoromethylꢀimidoyl
chlorides with trivalent phosphorus derivatives have been
investigated earlier,14 but their regularities are not wellꢀ
studied, and this often leads to unpredictable results. The
Arbuzov reaction leading to imino phosphonate is the main
direction in the case of trialkyl phosphites.
It has been established that imidoyl chloride 3 reꢀ
acts with triethyl phosphite even at room temperature
leading along with the Arbuzov reaction product 4 to
several byꢀproducts (19F and 31Р NMR data), which
could not be identified. We successed in minimizing
the formation of byꢀproducts and preparing NꢀCbzꢀimiꢀ
no phosphonate 4 in a yield of up to 90%. The best reꢀ
sult was obtained when triethyl phosphite was slowly
added to a concentrated ethereal solution of imidoyl chloꢀ
ride 3 at –10 °С with vigorous stirring of the reaction
mixture: the reaction is fully completed in 2 h. It is interꢀ
esting to note that because of the high electrophilicity
of imidoyl chloride 3, the Arbuzov reaction occurs even
NMR spectra were recorded using a Bruker AVꢀ300 specꢀ
trometer at 300 MHz for 1H, 282 MHz for 19F (CF3CO2H) and
121.5 MHz for 31H (H3PO4), respectively. All solvents used for
the reaction were dried by standard methods. Monitoring of the
reactions was carried out using TLC on plates with silica gel
Merck 60 F254
1ꢀBenzyloxycarbonyliminoꢀ2,2,2ꢀtrifluoroacetimidoyl chloꢀ
ride (3). SOCl2 (35.7 g, 0.3 mol) was added dropwise to a mixture
of benzyl Nꢀtrifluoroacetylcarbamate (24.7 g, 0.1 mol) and anꢀ
hydrous pyridine (11.8 g, 0.15 mol) with intensive stirring at 0 °С.
After 24 h at 20 °С, the reaction mixture was concentrated
in vacuo, the product was extracted with anhydrous ether
(5×50 mL), ether was evaporated, the residue was distilled. Imiꢀ
doyl chloride 3 (25.2 g, 95%) was obtained, b.p. 73—74 °C
(0.8 Torr). 1H NMR spectrum (CDCl3): δ 5.43 (s, 2 H, OCH2);
7.49 (br.s, 5 H, Ph). 19F NMR spectrum (CDCl3,): δ 5.21
(s, CF3).
Diethyl 1ꢀbenzyloxycarbonyliminoꢀ2,2,2ꢀtrifluoroethylphosꢀ
phonate (4). A solution of triethyl phosphite (9.9 g, 60 mmol) in
anhydrous ether (30 mL) was added dropwise for 2 h to a soluꢀ
tion of imidoyl chloride 3 (15.9 g, 60 mmol) in anhydrous ether

1ꢀDiazoꢀ2,2,2ꢀtrifluoroethylphosphonate
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
109
(30 mL) with vigorous stirring at –10°С . The reaction mixture
was stirred at –10 °С for 1 h, and kept at +5 °С for 24 h. Ether
was evaporated, the residue was fractionated. Imino phosphoꢀ
nate 4 (19.8 g, 90%) was obtained, b.p. 141 °С (1 Torr). 1H NMR
δ 23.00 (s, CF3). 31P NMR spectrum (CDCl3): δ 9.23 (s, 1 Р).
13С NMR spectrum (CDCl3, δ, J/Hz): 15.90 (СН3—СН2),
63.6 (СН2—СН3), 118.60 (m, С—С—СF3), 124.10 (d.q, 1JC,F
= 271.0 Hz, 1JC,P = 12.1 Hz).
=
3
spectrum (CDCl3, δ): 1.37 (t, 6 H, 2 CH3, JH,H = 7.0 Hz);
4.19—4.30 (m, 4 H, 2 OCH2); 5.37 (s, 2 H, OCH2); 7.40—7.46
(m, 5 H, Ph). 19F NMR spectrum (CDCl3): δ 8.15 (s, CF3).
31P NMR spectrum (CDCl3): δ –4.56.
References
1. S. C. Field, Tetrahedron, 1999, 55, 12237.
Diethyl 1ꢀbenzyloxycarbonylaminoꢀ2,2,2ꢀtrifluoroethylphosꢀ
phonate (5). A mixture of imino phosphonate 4 (18.3 g, 50 mmol)
and sodium borohydride (2.8 g, 75 mmol) in anhydrous ether
was refluxed with stirring in an argon atmosphere for 1.5 h, then
cooled to 0°С and 1 М HCl (50 mL) was added portionwise. The
layers were separated, the aqueous phase was extracted with
ether (3 × 30 mL), the combined ethereal extracts were dried
with magnesium sulphate. Amino phosphonate 5 (17.3 g, 94%)
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of lowꢀmelting crystals, m.p. 53—55 °С. 1H NMR spectrum
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2 OCH2); 4.69—4.82 (m, 1 H, CH); 5.19 (d, 1 H, OCH2,
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3
8.21 (d, CF3, JF,P = 6.9 Hz). 31P NMR spectrum (CDCl3, δ):
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genolysis with hydrogen in the presence of 10% Pd/C (5 mol%)
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3
1.35 (t, 6 H, 2 CH3, JH,H = 7.0 Hz); 2.75 (br.s, 2 Н, NH2),
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3.57—3.67 (m, 1 Н, СН); 4.23—4.28 (m, 4 H, 2 OCH2).
19F NMR spectrum (CDCl3, δ, J/Hz): 6.19 (d, CF3, 3JF,P = 7.1 Hz).
31P NMR spectrum (CDCl3, δ, J/Hz): 16.43 (q, 3JP,F = 7.1 Hz).
Diethyl 1ꢀdiazoꢀ2,2,2ꢀtrifluoroethylphosphonate (1) was synꢀ
thesized from compound 6 using the known procedure.6 Freshly
obtained isopropyl nitrite (9.5 g, 0.106 mol) was added to a soluꢀ
tion of amino phosphonate 6 (19.6 g, 0.083 mol) in chloroform
(300 mL) with vigorous stirring. As the reaction is exothermic,
the addition was carried out so that uniform boiling of the reacꢀ
tion mixture was provided. The reaction mixture was stirred for
40 min, after this time the temperature of the reaction mixture
decreased to room temperature. The solvent was removed
in vacuo, the residue was distilled. Diazo compound 1 (16.4 g,
80%) was obtained as lightꢀyellow liquid, b.p. 47—50 °C (1 Torr).
IRꢀspectrum (KBr), ν/cm–1: 2160 (C=N2); 1150 (P=O). 1H NMR
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3
spectrum (CDCl3, δ): 1.40 (t, 6 H, СН3, JН,Н = 7.1 Hz),
4.21—4.27 (m, 4 H, ОСН2). 19F NMR spectrum (CDCl3):
Received June 11, 2009