1-Trifluoromethyl-1-diethoxyphosphoryl carbene: A new synthon for the preparation of CF3-containing α-hydroxy and α-amino phosphonic acid derivatives

Article abstract of DOI:10.1055/s-2006-939704

The first synthesis of diethyl 1-diazo-2,2,2-trifluoroethylphosphonate has been developed starting from readily available compounds. The synthetic utility of this compound is demonstrated via its Rh-catalyzed insertion into O-H and N-H bonds to produce CF₃-substituted α-hydroxy phosphonic and α-amino, phosphonic acid derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939704

LETTER
1355
1-Trifluoromethyl-1-diethoxyphosphoryl Carbene: A New Synthon for the
Preparation of CF3-Containing a-Hydroxy and a-Amino Phosphonic Acid
Derivatives
1
-Trifluo
g
romethyl-1-d
o
iethoxyphos
r
phoryl Carben
D
e
. Titanyuk,a Daria V. Vorob’eva,b Sergej N. Osipov,*b Irina P. Beletskayaa
a
Department of Chemistry, Moscow State University, 119992 Moscow, Leninskie gory 1, Bd.3, Russia
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Vavilov str. 28, Russia
E-mail: osipov@ineos.ac.ru
Received 7 March 2006
results of the initial investigation of its reactivity under
rhodium-catalyzed conditions. Taking into account the
synthetic potential of alkyl-3,3,3-trifluoro-2-diazoprop-
ionate6 (Scheme 1), its nearest carboxylate analogue, we
Abstract: The first synthesis of diethyl 1-diazo-2,2,2-trifluoroeth-
ylphosphonate has been developed starting from readily available
compounds. The synthetic utility of this compound is demonstrated
via its Rh-catalyzed insertion into O–H and N–H bonds to produce
CF3-substituted a-hydroxy phosphonic and a-amino phosphonic believe that 4 will attract considerable attention from both
acid derivatives
synthetic and medicinal chemists.
Key words: diazo compounds, fluorine, aminophosphonates, hy-
droxyphoshonate, insertion reactions
Thus, we found that the diazo compound 4 can be easily
synthesized from a-trifluoromethyl-a-aminophoshonate 3
via diazotization of the latter with isopropyl nitrite in
chloroform under mild conditions (Scheme 2). Despite
The phosphonate (PO32–) moiety is a common structural
the fact that the synthesis of 3 has been described by sev-
eral research teams7 its synthesis is not trivial and includes
multi-step procedures with overall yields around 30%. A
recently published synthesis of the NCbz derivative 2
based on commercially available ethyl trifluoro-
hemiacetal8 has inspired us to utilize this approach for the
synthesis of 3. A slight modification of the described pro-
cedure for the preparation of 2, followed by quantitative
deprotection of the amino function allowed us to increase
the overall yield of 3 up to 74%. For the key diazotisation
step several classical methods have been tested (e.g.
NaNO2/HCl, NaNO2/H2SO4, NaNO2/AcOH), however, in
all cases the yields of the desired compound 4 did not
exceed 28%. The best result was obtained when 3 was
treated with isopropyl nitrite; in this case 4 was synthe-
sized in 67% yield. The product is a stable light-yellow
liquid, which can be distilled under reduced vacuum. Its
synthesis was also successfully performed on a 20 g scale.
fragment present in a wide range of biologically active
compounds. Despite structural and electronic differences
between phosphonate and carboxylic functionalities (in
terms of size, shape, acidity, and geometry) the phospho-
nate functionality is regarded as a bioisostere of the
carboxylic group. Therefore, a-amino and a-hydroxy-
phoshonates are important analogues of the correspond-
ing carboxylic acids, and their synthesis and biological
activity have been a focus of attention in synthetic and
medicinal chemistry.1 Many of them can serve as haptens
in catalytic enzyme antibody generation and as transition
state analogue inhibitors of different proteolytic enzymes
exhibiting a wide spectrum of biological properties in-
cluding antimicrobial, antitumor, antihypertensive, and
antibacterial activities.2 On top of this, the introduction
of fluorine or fluoroalkyl substituents into biological
relevant compounds has become an important tool in the
drug discovery process.3 Special attention is paid to
trifluoromethyl-containing compounds due to the unique
properties of the trifluoromethyl group, such as high
electro-negativity, electron density, steric hindrance, and
hydrophobic character4 that can profoundly improve the
pharmaco-kinetic properties of potential drugs.
Both OH- and NH-insertion reactions of metallocar-
benoid intermediates derived from their corresponding
diazo compounds have found widespread use in the syn-
thesis of biologically active compounds including the
construction of bicyclic b-lactams,9a a-amino and a-hy-
droxy acids,9b peptides,9c–e and depsipeptides6j etc. We
examined the reactivity of diazophosphonate 4 in such
transformations under rhodium-catalyzed conditions.
Among the range of fluorination methods available the
building block strategy represents the most attractive
route for the incorporation of fluorinated moieties into or-
ganic molecules. In this context, along with our interest in
new fluorinated building blocks,5 we wish to disclose a
convenient method for the preparation of novel trifluoro-
methyl-containing a-diazophosphonate 4 as well as the
Thus, we found that 4 readily reacts with different alco-
hols and carboxylic acids under reflux in anhydrous ben-
zene (5–10 h) in the presence of catalytic amounts (2–3
mol%) of Rh2(OAc)4 to afford regioselectively the corre-
sponding OH-insertion products 5 in good yields
(Scheme 3, Table 1). The nature of the substituents does
not significantly affect the outcome of the process. In the
case of NBoc-protected phenylalanine (Table 1, entry 6)
SYNLETT 2006, No. 9, pp 1355–1358
0
1.
0
6.
2
0
0
6
Advanced online publication: 26.04.2006
DOI: 10.1055/s-2006-939704; Art ID: G08606ST
© Georg Thieme Verlag Stuttgart · New York

1356
I. D. Titanyuk et al.
LETTER
O
CF3
F3C
F3C CO2R
XR1
R1
CO2R
N
ref. 6b
RO
R1
O
OSiMe3
X = S, O, NR1
ref. 6c,g
ref. 6a,d
R1
XR1
R1
C
N
CF3
R1
Y
CO2R
R1YH
F3C
CO2R
F3C
ref. 6f,i
CO2R
Y = O, NH, NR2
ref. 6e,g
N2
O
O
R1
NH2
Ar
H
O
CF3
Ar
O
Ar
CF3
O
O
R1
N
H
CO2R
O
S
R1
OH
O
O
CO2R
Ar
ref. 6g
ref. 6h
O
S
CF3
RO2C
F3C
R1
CO2R
ref. 6j
ref. 6k
Scheme 1 Synthetic transformations of alkyl-3,3,3-trifluoro-2-diazopropionate.6
O
P
O
P
Diazophosphonate 4 demonstrates comparable reactivity
in reactions with different amino compounds under
analogous reaction conditions yielding the corresponding
OEt
OEt
OEt
OEt
F3C
OH
OEt
F3C
F3C
a, b
c
NH2
NHCbz
a-trifluoromethyl-a-aminophosphonate derivatives
6
2
(Scheme 4, Table 2). Attempts to induce diastereoselec-
tivity in the reaction of 4 with (1R)-menthyl carbamate
proved to be unsuccessful; the insertion product 6e (entry
5, Table 2) was isolated as a mixture of diastereomers in a
1:1 ratio.
1
3
O
OEt
OEt
F3C
P
d
N2
4
O
P
O
P
Scheme 2 Synthesis of diethyl 1-diazo-2,2,2-trifluoroethyl-phos-
phonate. Reagents and conditions: a) CbzNH2, CH2Cl2, Et3N, 5 Å
MS, r.t., 14 d, 88%; b) i) (CF3CO)2O, py, ii) HP(O)(OEt)2, Me3SiCl,
–20 °C, 84%; c) H2, Pd/C, MeOH, r.t, 12 h, 100%; d) i-PrONO,
CHCl3, 30 min, 67%.
OEt
OEt
OEt
OEt
ROH
F3C
F3C
Rh2(OAc)4
N2
NHR
6a–f
4
Scheme 4
phosphorylated depsipeptide 5f was isolated as a mixture
of diastereomers in approximately a 1:1 ratio. Compound
5e (Table 1, entry 5) has proved to be hydrolytically
unstable; under standard purification by column chroma-
tography it loses the trifluoroacetic group to give the cor-
responding 2-hydroxy-3,3,3-trifluoroethylphosphonate.
In conclusion we have developed a simple preparative
pathway to new diethyl-1-diazo-2,2,2-trifluoroethylphos-
phonate (4);10 this is the first example of an a-trifluoro-
methylated a-diazo-phosphonate. The synthetic utility of
this compound was demonstrated via its Rh-catalyzed in-
sertion into OH and NH bonds to produce CF3-substituted
a-hydroxy phosphonic and a-amino phosphonic acid
derivatives.11
O
P
O
P
OEt
OEt
OEt
OEt
ROH
F3C
F3C
Rh2(OAc)4
N2
OR
5a–g
Acknowledgment
4
This work was supported by Russian Foundation of Basic Research
(grant N 04-03-32644).
Scheme 3
Synlett 2006, No. 9, 1355–1358 © Thieme Stuttgart · New York

LETTER
1-Trifluoromethyl-1-diethoxyphosphoryl Carbene
1357
Table 1 Reaction of 4 with Alcohols and Carboxylic Acids
Table 2 Reaction of 4 with NH2-Functionalized Compounds
Entry ROH
Product
Yield
(%)a
Entry
1
RNH2
Product
Yield
(%)a
O
O
P
OEt
OEt
OEt
OEt
O
F3C
P
F3C
1
2
MeOH
EtOH
88
93
BocNH2
59
OMe
N
H
O
P
O
O
P
OEt
OEt
F3C
F3C
OEt
OEt
O
F3C
OEt
O
2
3
CbzNH2
62
64
N
H
Ph
OEt
P
3
4
5
PhC(O)OH
MeC(O)OH
CF3C(O)OH
64
OEt
Ph
O
O
P
O
O
OEt
OEt
F3C
PhSO2NH2
O
P
N
H
OEt
SO2Ph
F3C
84
OEt
CH3
O
OEt
OEt
F
O
O
F3C
P
4
5
C6F5NH2
63
N
H
F
O
P
OEt
F3C
F
F
86b
OEt
CF3
F
O
O
O
O
O
P
OEt
F3C
OEt
O
Ph
O
MenthOC(O)NH2
50b
O
P
N
H
OEt
OEt
6
7
BocPheOH
PhOH
62
78
O
N
H
O
CF3
O
P
a Isolated yield given after column chromatography.
b Diastereomeric mixture in a 1:1 ratio.
OEt
OEt
F3C
OPh
a Isolated yield given after column chromatography.
b Yield determined by 1H NMR spectroscopy.
(3) (a) Filler, R.; Kobayashi, Y.; Yagupolski, L. M. In
Organofluorine Compounds in Medicinal Chemistry and
Biomedicinal Applications; Elsevier Science: Amsterdam,
1993. (b) Ojima, I.; McCarthy, J.; Welch, J. T. Biomedicinal
Frontiers of Fluorine Chemistry, ACS Symposium Series
639; ACS: Washington, D.C., 1996.
(4) Banks, R. E.; Tatlow, J. C.; Smart, B. E. In Organofluorine
Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994.
References and Notes
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F. In Comprehensive Organic Functional Group
(5) (a) Osipov, S. N.; Kolomiets, A. F.; Fokin, A. V. Russ.
Chem. Rev. 1992, 61, 798; and references cited therein.
(b) Osipov, S. N.; Golubev, A. G.; Sewald, N.; Kolomiets,
A. F.; Fokin, A. V.; Burger, K. Synlett 1995, 1269.
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Kolomiets, A. F.; Fokin, A. V.; Burger, K. J. Org. Chem.
1996, 61, 7521. (d) Osipov, S. N.; Artyushin, O. I.;
Kolomiets, A. F. Mendeleev Commun. 2000, 5, 192.
(e) Kobel’kova, N. M.; Osipov, S. N.; Kolomiets, A. F. Russ.
Chem. Bull. 2002, 7, 1298.
(6) (a) Shi, G.; Xu, Y. Chem. Commun. 1989, 607. (b) Shi, G.;
Xu, Y. J. Org. Chem. 1990, 55, 3383. (c) Shi, G.; Xu, Y.;
Xu, M. Tetrahedron 1991, 47, 1629. (d) Shi, G.; Xu, Y.;
Xu, M. J. Fluorine Chem. 1991, 52, 149. (e) Shi, G.; Cao,
Z.; Cai, W. Tetrahedron 1995, 51, 5011. (f) Paulini, K.;
Reissig, H.-U. J. Prakt. Chem./Chem.-Ztg. 1995, 337, 55.
(g) Osipov, S. N.; Sewald, N.; Burger, K.; Kolomiets, A. F.;
Fokin, A. V. Tetrahedron Lett. 1996, 37, 615. (h) Jiang, B.;
Transformations, Vol. 4; Katritzky, A. R.; Meth-Kohn, O.;
Rees, C. W., Eds.; Elsevier Science: Oxford UK, 1995,
Chap. 4, 10.
(2) (a) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med.
Chem. 1986, 29, 29; and references cited therein.
(b) Kafarski, P.; Lejcazk, B. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 193. (c) Bird, J.; De Mello, R. C.;
Harper, H. P.; Hunter, D. J.; Karran, E. H.; Markwell, E. R.;
Miles-Williams, A. J.; Rahman, S. S.; Ward, R. W. J. Med.
Chem. 1994, 37, 158. (d) McLeod, D. A.; Brinkworth, R. I.;
Ashley, J. A.; Janda, K. D.; Wirsching, P. Bioorg. Med.
Chem. Lett. 1991, 1, 653. (e) Hirschmann, R.; Smith, A. B.
III; Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.; Yager, K.
M.; Sprengeler, P. A.; Benkovic, S. J. Science (Washington,
D.C.) 1994, 265, 234. (f) Grembecka, J.; Mucha, A.;
Cierpicki, T.; Kafarski, P. J. Med. Chem. 2003, 46, 2641.
Synlett 2006, No. 9, 1355–1358 © Thieme Stuttgart · New York

1358
I. D. Titanyuk et al.
LETTER
Zhang, Z.; Luo, Z. Org. Lett. 2002, 4, 2453. (i) Mueller, P.;
Grass, S.; Shahi, S. P.; Bernardinelli, G. Tetrahedron 2004,
60, 4755. (j) Vorob’eva, D. V.; Titanyuk, I. D.; Beletskaya,
I. P.; Osipov, S. N. Mendeleev Commun. 2005, 6, 222.
(k) Zhu, S.; Xing, C.; Zhu, S. Tetrahedron 2006, 62, 829.
J = 7.0 Hz), 3.65 (s, 3 H), 3.78–3.9 (m, 1 H), 4.20–4.30 (m,
4 H). 31P NMR (CDCl3): d = 11.8 (app. q, J = 8.9 Hz). 19
F
NMR (CDCl3): d = 6.7 (app. t, J = 8.5 Hz). Anal. Calcd for
C7H14F3O4P: C, 33.61; H, 5.64. Found: C, 33.75; H, 5.75.
1-(Diethoxyphosphoryl)-2,2,2-trifluoroethyl N-(tert-
Butoxycarbonyl)-1-phenylalaninate (5f) Yield: 62%; oil;
dr 1:1. 1H NMR (CDCl3): d = 1.35–1.45 (m, 6 H), 1.45 (s, 9
H), 3.10 (ddd, 1 H, J = 4.1, 6.4, 14.0 Hz), 3.28 (app. dt, 1 H,
J = 5.5, 14.0 Hz), 4.20–4.37 (m, 4 H), 4.78 (m, 1 H), 4.98 (m,
1 H), 5.68–5.83 (m, 1 H), 7.20–7.30 (m, 2 H), 7.30–7.41 (m,
3 H). 31P NMR (CDCl3): d = 8.7 (app. q, J = 7.4 Hz), 9.3
(app. q, J = 7.4 Hz). 19F NMR (CDCl3): d = 7.63 (app. t,
J = 7.3 Hz), 7.84 (app. t, J = 7.3 Hz). Anal. Calcd for
C20H29F3NO7P: C, 49.70; H, 6.00; N 2.90. Found: C, 49.51;
H, 6.21; N 2.75.
Diethyl (2,2,2-Trifluoro-1-phenoxyethyl)phosphonate
(5g) Yield: 78%; oil. 1H NMR (CDCl3): d = 1.40 (t, 6 H,
J = 7.1 Hz), 4.20–4.40 (m, 4 H), 4.88–5.00 (m, 1 H), 7.05–
7.15 (m, 3 H), 7.40–7.50 (m, 2 H). 31P NMR (CDCl3): d =
10.6 (app. q, J = 8.9 Hz). 19F NMR (CDCl3): d = 7.10 (app.
t, J = 8.2 Hz). Anal. Calcd for C12H16F3O4P: C, 46.16; H,
5.17. Found: C, 46.27; H, 5.21.
(7) (a) Sinitsa, A. D.; Onisko, P. P.; Kim, T. V.; Kiseleva, E. I.;
Pirozhenko, V. V. J. Gen. Chem. USSR 1986, 52, 2372.
(b) Flynn, A. G.; Beight, D. W.; Bohme, E. H. W.; Metcalf,
B. W. Tetrahedron Lett. 1985, 26, 285. (c) Vaubaillon, D.;
Giraud, V.; Rabiller, C.; Gruss, U.; Haas, A.; Haegele, G.
Phosphorus, Sulfur Silicon Relat. Elem. 1997, 126, 177.
(8) (a) Ingrassia, L.; Mulliez, M. Synthesis 1999, 1731. (b) De
Medina, P.; Ingrassia, L. S.; Mulliez, M. E. J. Org. Chem.
2003, 68, 8424.
(9) (a) Yates, P. J. Am. Chem. Soc. 1952, 74, 5376. (b) Ye, T.;
McKervey, A. Chem. Rev. 1994, 94, 1091; and references
cited therein. (c) Aller, E.; Buck, R. T.; Drysdale, M. J.;
Ferris, L.; Haigh, D.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 1996, 2879. (d) Ferris, L.; Haigh, D.; Moody, C. J.
J. Chem. Soc., Perkin Trans. 1 1996, 2885. (e) Moody, C.
J.; Ferris, L.; Haigh, D.; Swann, E. Chem. Commun. 1997,
2391.
(10) Diethyl (1-Diazo-2,2,2-trifluoroethyl)phosphonate (4)
The reaction was conducted in a 500 mL flask equipped with
a condenser, a funnel, and magnetic stirrer. i-PrONO (9.5 g,
0.106 mol) was added to a vigorously stirred solution of
aminophosphonate (19.6 g, 0.083 mol) in CHCl3 (300 mL).
After the addition of approximately 1.0 g of i-PrONO an
exothermic reaction began; the rest of the nitrite was added
dropwise providing a mild refluxing reaction mixture for 20
min. After stirring for an additional 40 min (the temperature
was reduced to r.t.) the solvent was removed under reduced
pressure and the residue was distilled in vacuo to afford 13.7
g (67%) of diazo compound 4 as light yellow liquid. Bp 47–
50 °C (1 Torr). IR (KBr): 2160, 1150 cm–1. 1H NMR
(CDCl3): d = 1.40 (t, 6 H, J = 7.1 Hz), 4.15–4.30 (m, 4 H).
13C NMR (CDCl3): d = 15.9, 63.6, 118.6 (m), 124.1 (dq,
Diethyl {1-[(tert-Butoxycarbonyl)amino]-2,2,2-
trifluoroethy}phosphonate (6a) Yield: 59%; white
crystals; mp 81.5–82.5 °C. 1H NMR (CDCl3): d = 1.41 (t, 6
H, J = 8.1 Hz), 1.52 (s, 9 H), 4.20–4.30 (m, 4 H), 4.65–4.80
(m, 1 H), 5.20 (m, 1 H). 31P NMR (CDCl3): d = 13.6 (app. q,
J = 6 Hz). 19F NMR (CDCl3): d = 8.05 (app. t, J = 7.5 Hz).
Anal. Calcd for C11H21F3NO5P: C, 39.41; H, 6.31; N, 4.18.
Found: C, 39.47; H, 6.31; N, 4.15.
Diethyl {1-[(Phenylsulfonyl)amino]-2,2,2-
trifluoroethyl}phosphonate (6c) Yield: 64%; white solid;
mp 115–117 °C. 1H NMR (CDCl3): d = 1.33 (t, 3 H, J = 7.1
Hz), 1.39 (t, 3 H, J = 7.1 Hz), 4.10–4.30 (m, 4 H), 4.35–4.57
(m, 1 H), 7.05–7.15 (m, 1 H), 7.30–7.65 (m, 3 H), 7.92–7.97
(m, 2 H). 31P NMR (CDCl3): d = 12.3 (app. q, J = 7.4 Hz).
19F NMR (CDCl3): d = 8.03 (app. t, J = 8.0 Hz). Anal. Calcd
for C12H17F3NO5PS: C, 38.40; H, 4.57; N, 3.73. Found: C,
38.21; H, 4.44; N, 3.67.
J
C-F = 271.0 Hz, JC-P = 12.1 Hz). 31P NMR (CDCl3): d =
9.23. 19F NMR (CDCl3): d = 23.0.
(11) OH- and NH-Insertion; General Procedure A solution of
diazo compound 4 (1.1 mmol) in anhydrous benzene (3 mL)
was added to a solution of the hydroxy or amino compound
(1.0 mmol) and dirhodium tetraacetate (2 mol%) in benzene
(10 mL). The reaction mixture was stirred under reflux for 4
h. After evaporation of the solvent under reduced pressure
the crude product was purified by column chromatography
on silica gel (EtOAc–hexanes).
Diethyl {1-[(Pentafluorophenyl)amino]-2,2,2-
trifluoroethyl}phosphonate (6d) Yield: 63%; white solid;
mp 55–56 °C. 1H NMR (CDCl3): d = 1.40 (dt, 6 H,
J = 0.7, 7.1 Hz), 4.20–4.38 (m, 4 H), 4.38–4.50 (m, 1 H).
31P NMR (CDCl3): d = 13.2 (app. q, J = 7.4 Hz). 19F NMR
(CDCl3): d = 8.06 (app. t, J = 7.8 Hz, 3 F), –78.0 (d, J = 21.8
Hz, 2 F), –85.2 (dt, J = 5.8, 21.8 Hz, 2 F), –88.9 (t, J = 21.8
Hz, 1 F). Anal. Calcd for C12H12F8NO3P: C, 35.93; H, 3.01;
N, 3.49. Found: C, 36.25; H, 3.22; N, 3.47.
Diethyl (2,2,2-Trifluoro-1-methoxyethyl)phosphonate
(5a) Yield: 88%; oil. 1H NMR (CDCl3): d = 1.38 (t, 6 H,
Synlett 2006, No. 9, 1355–1358 © Thieme Stuttgart · New York