Synthesis of functionalized α-CF3-α-aminophosphonates via Cu(I)-catalyzed 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.jfluchem.2009.12.003

A convenient method for the preparation of α-CF₃-α-aminophosphonates bearing alkynyl group at the α-carbon atom has been described. New alkynylphosphonates have been further utilized in the synthesis of functionalized triazole-containing α-CF₃-α-aminophosphonates via copper-catalyzed (3+2)-cycloaddition to different organic azides.

Full text of DOI:10.1016/j.jfluchem.2009.12.003

Journal of Fluorine Chemistry 131 (2010) 378–383
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of functionalized
1,3-dipolar cycloaddition
a
-CF3-a
-aminophosphonates via Cu(I)-catalyzed
Daria V. Vorobyeva a, Natalya M. Karimova a, Tamara P. Vasilyeva a, Sergey N. Osipov a,
,
*
b,**
Grigory T. Shchetnikov a, Irina L. Odinets a, Gerd-V. Ro¨schenthaler
a A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, 119991 Moscow, Russia
b Jacobs University Bremen gGmbH, P.O. Box 750 561, D-28725 Bremen, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient method for the preparation of
a
-CF3-a
-aminophosphonates bearing alkynyl group at the
Received 30 October 2009
Received in revised form 3 December 2009
Accepted 4 December 2009
Available online 16 December 2009
a
-carbon atom has been described. New alkynylphosphonates have been further utilized in the
synthesis of functionalized triazole-containing
(3+2)-cycloaddition to different organic azides.
a
-CF3-
a
-aminophosphonates via copper-catalyzed
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
a
-Aminophosphonates
Organic azides
1,3-Dipolar cycloaddition
1,2,3-Triazoles
1. Introduction
with a biological target or the direction of binding. Therefore, such
approach is very popular in construction of new biologically active
molecules. However, in contrast to the rather well developed
aminophosphonic and aminophosphinic acids area, only limited
During the past three decades a-(fluoromethyl)-substituted a-
amino acids, which can function as highly selective inhibitors of
pyridoxal phosphate dependent enzymes [1], have been attracting
considerable interest as potent low-molecular bioregulators and as
building blocks for the modification of bioactive peptides [2].
representatives of fluorine containing
a-aminophosphonates are
currently known [6–13]. Thus, the synthesis of new fluorinated
a
-
aminophosphonates as potential drug candidates is of current
interest.
Since
a-aminophosphonate derivatives are structural mimics of
a
-amino acids, some of these compounds exhibit very high
On the other hand, 1,2,3-triazole derivatives have displayed an
ample range of application in pharmaceutical and material
sciences [14]. Since Meldal and Sharpless developed Cu(I)-
catalyzed 1,3-dipolar Huisgen cycloaddition reaction of azides
with alkynes [15], the so called ‘‘click chemistry’’ has received
growing interest in the regioselective synthesis of 1,4-disubstitut-
ed 1,2,3-triazoles [16]. The formation of triazoles in this reaction
has represented definitive advances: reliable, effective, benign in
reaction conditions, and high tolerance to many functional groups.
Using this approach, a wide range of compounds with an inert
triazole heterocycle could be prepared being of interest in
medicinal chemistry and material science [17].
Recently, we have elaborated effective synthetic approaches
giving the possibility for facile, rapid, and cheap access to a wide
range of novel nitrogen-bisphosphonates [18a], phosphonocar-
boxylates [18b], triazole-substituted phosphonates [18c], and CF3-
azahistidine analogous [18d] based on ‘‘click’’ methodology.
Herein, we present a convenient synthetic pathway to novel
potency in inhibiting the enzymes that are involved in the
metabolism of the corresponding amino acids. These compounds
have already been found to act as antibacterial agents, neuroactive
compounds, anticancer drugs, and pesticides, with some of them
already being commercialized [3]. For example, Strater and
Lipscomb have reported several L-leucine-phosphonic acid deri-
vatives that are among the most potent low-molecular inhibitors
of leucine aminopeptidase [4]. The altered activity of such an
enzyme has been associated with HIV infections and several
pathological disorders including cancer and cataracts [5].
At the same time, introduction of the fluorine containing group
in a biomolecule may change the ‘‘normal’’ route of its interaction
* Corresponding author. Tel.: +7 495 135 6212; fax: +7 495 135 5085.
** Corresponding author.
E-mail addresses: osipov@ineos.ac.ru (S.N. Osipov),
g.roeschenthaler@jacobs-university.de (G.-V. Ro¨schenthaler).
functionalized
a-CF3-a-aminophosphonates comprising triazole
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.12.003

D.V. Vorobyeva et al. / Journal of Fluorine Chemistry 131 (2010) 378–383
379
moiety as a linker connecting fluorinated
with different functionalities (Fig. 1).
a-aminophosphonate
2. Results and discussions
The synthesis of the starting
a-alkynyl-a-CF3-a-aminopho-
sphonates 2a, 2b was accomplished via the addition of sodium
acetylide or Grignard reagent generated from propargyl bromide,
to the electrophilic imine 1. These reactions proceeded in
anhydrous diethyl ether or tetrahydrofuran under mild conditions
to give the corresponding aminophosphonates in good yields
(Scheme 1).
Even though some fluorinated
a-alkyl(allyl)-substituted a-
aminophosphonates were previously described using the similar
methodology [13a,19,20], to the best of our knowledge the
Scheme 1.
[15], usually in organoaqueous systems. For the synthesis of the
triazolyl-phosphonates 3a–h from ethynyl- or propargyl-substi-
tuted phosphonates 2a,b, the procedure involving in situ genera-
tion of Cu(I) moiety from CuSO4 pentahydrate and sodium
derivatives bearing a-alkynyl group were not described previously.
In a standard procedure for regioselective Cu(I)-catalyzed
alkyne–azide coupling, the catalyst can be either directly intro-
duced as a Cu(I) salt or generated in situ by reduction of Cu(II) salts
Fig. 1.
Scheme 2.
Scheme 3.

380
D.V. Vorobyeva et al. / Journal of Fluorine Chemistry 131 (2010) 378–383
ascorbate in a mixture of tert-butanol/water in a ratio of 1:1 was
the method of choice (Scheme 2).
Thus, acetylene 2a easily reacted with pivaloylmethyl- and
heptadeca-fluoro-decyl azides at room temperature to afford 3,5-
disubstituted triazoles 3a and 3c in good yields over 8 h (entries 1
and 3, Table 1). The reaction of 2a with sugar azide (entry 5, Table
1) required more prolonged reaction time (ca. 12 h) at the same
temperature to yield the corresponding product 3e. However, in
the case of phenyl azide, the best yield of triazole 3g (52% as
determined by the 19F NMR, 38% - isolated) was achieved under
Table 1
Triazole-containing
a-CF3-
a
-aminophosphonatesa.
Entry
RN3
Product
Yieldb (%)
1
89
2
68
3
4
5
92
72
78
6
65
7
PhN3
38
8
PhN3
73
a
Conditions: acetylene (1.0 mmol), azide (1.0 mmol), CuSO4 (5 mol%), sodium ascorbate (30 mol%), H2O–tert-BuOH (1:1), 8–12 h.
b
Yield after column chromatography.

D.V. Vorobyeva et al. / Journal of Fluorine Chemistry 131 (2010) 378–383
381
stirring of reaction mixture at 20 8C for 48 h. The variation of
reaction conditions (excess of phenyl azide and temperature) did
not affect the yield of the product.
was allowed to warm to r.t. within 2 h. The reaction was quenched
with saturated solution of NH4Cl and extracted with Et2O (2Â
25 mL). The combined organic layer was washed with brine
(25 mL), dried over MgSO4 and filtered. The solvent was removed
under reduced pressure and the crude product was purified by
flash chromatography (acetone–hexane). Yield: 59% (solid), m.p.
d 1.44 (m, 6H, 2CH3), 2.88
(br.s, 1H, –CBCH), 4.38 (m, 4H, 2OCH2), 5.19 (dAB, 1H, CH2,
JAB = 12.0 Hz), 5.23 (dAB, 1H, CH2, JAB = 12.0 Hz), 5.65 (d, 1H, NH,
In contrast to ethynylphosphonate 2a, the cycloaddition of
propargyl-containing aminophosphonate 2b to organic azides
proceeded only at 80 8C in the same mixture solvent and lead to
completion for 2 h in all cases to afford the corresponding triazoles
3b, 3d, 3f, and 3h. Such difference in reactivity is apparently
connected with electronic factors (alkynes bearing electron-
withdrawing groups adjacent to the triple bond usually are more
reactive in addition reactions [21]) or with the possible formation
of thermordynamically stable six-membered intermediate copper
complexe via metal coordination on triple and P55O bonds in 2b.
Indeed, the copper coordination on triple bond is well described in
Ref. [8g] while phosphoryl compounds are also inclined to form
strong copper complexes [22].
99–100 8C. 1H NMR (CDCl3, 300 MHz):
3JH-P = 9.0 Hz), 7.43 (br.s, 5H, Ph). 19F NMR (CDCl3, 282 MHz):
d
5.45. 31P NMR (CDCl3, 121 MHz):
16H19F3NO5P: C, 48.86; H, 4.87; N, 3.56. Found: C, 48.94; H,
d 14.62. Anal. Calcd for
C
4.81; N, 3.60.
4.1.2. Diethyl[(1-{[(benzyloxy)carbonyl]amino}-1-
trifluoromethyl)but-3-yne-1-yl] phosphonate (2b)
Functionalized triazoles 3 derived from propargylphosphonates
2b can be regarded as phosphoryl analogous of azahistidine—
important histidine surrogate [23]. For efficient use of such
compounds in peptide synthesis, an easy access to orthogonally
protected derivatives is strongly required. To demonstrate a
possibility of selective removing of protecting groups N-pivaloyl-
methyl derivative 3b was selected as the most suitable precursor.
Therefore, we have found that the pivaloylmethyl group can be
selectively removed under basic conditions for 45 min at room
temperature in methanol to afford NH-triazole 4 in good yield.
Classical Pd-catalyzed hydrogenation in methanol was successful-
ly applied for deprotection of amino function of 3b. Final acidolysis
of phosphonate group accomplished by the treatment of triazole 5
with trimethylsilylbromide in chloroform followed by hydrolysis
of the intermediate silyl ester, yielded the free aminophosphonic
acid 6 as HBr salt (Scheme 3).
Allenylmagnesiumbromide (solution in Et2O, 22.0 mmol) was
added dropwise to a stirred solution of an imine 1 [20b]
(10.0 mmol) in dry Et2O (25 mL) at À78 8C. After 3 h at À78 8C
the reaction mixture was allowed to warm to r.t. within 2 h. The
reaction was quenched with saturated solution of NH4Cl and
extracted with Et2O (2Â 25 mL). The combined organic layer was
washed with brine (25 mL), dried over MgSO4 and filtered. The
solvent was removed under reduced pressure and the crude
product was purified by flash chromatography (acetone–hexane).
Yield: 57% (solid), m.p., 88–89 8C. 1H NMR (CDCl3, 300 MHz):
d 1.42
(t, 6H, 2CH3, 3JH-H = 7.1 Hz), 2.13 (s, 1H, –CBCH), 3.31 and 3.46 (t, 1H
3
and 1H, CH2, JH-H = 14.6 Hz), 4.32 (m, 4H, 2OCH2), 5.17 (m, 2H,
3
CH2,), 5.96 (d, 1H, NH, JH-P = 9.3 Hz), 7.40 (m, 5H, Ph). 19F NMR
3
(CDCl3, 282 MHz):
121 MHz):
d
6.70 (d, JF-P = 4.1 Hz). 31P NMR (CDCl3,
3
d
15.42 (d, JP-F = 4.1 Hz).
4.2. General procedure for the synthesis of triazoles 3a–h
3. Conclusion
To a solution of the corresponding acetylene 2a, 2b (1.0 mmol)
in the mixture of t-BuOH-H2O (3 ml) was added a solution of
corresponding azide (1.0 mmol) in the mixture of t-BuOH-H2O
(2 ml), sodium ascorbate (0.3 mmol) and 0.5 M copper sulfate
pentahydrate (0.05 mmol). The reaction mixture was stirred at
room temperature for about 8–12 h (in the case of 2b at 80 8C, 2 h)
until the completion of the reaction monitored by TLC. After
evaporation of the solvent under reduced pressure, water was
added to a residue and the aqueous layer was extracted twice with
ethyl acetate (20 ml). The organic layer was dried over MgSO4 and
evaporated. The residue was purified by silica gel column
chromatography using EtOAc-hexane as an eluent.
A convenient method for the preparation of new
a-CF3-a-
aminophosphonates bearing alkynyl group at the -carbon atom
a
has been developed. New alkynylphosphonates 2a, 2b have been
further used in the synthesis of functionalized triazole-containing
-CF3-a-aminophosphonates via copper-catalyzed (3+2)-cycload-
dition to different organic azides. To demonstrate a potential of
compounds 3 for the possible application in peptide chemistry, the
efficient procedures for selective removing of protective groups
were also elaborated.
a
4. Experimental
4.1. General methods
4.2.1. {4-[2-{[(Benzyloxy)carbonyl]amino}-2-(diethoxyphosphoryl)-
3,3,3-trifluoropropyl]-1H-1,2,3-triazole-1-yl} pivalate (3a)
All solvents used in reactions were freshly distilled from
appropriate drying agents before use. All other reagents were
recrystallized or distilled as necessary. Reactions were performed
under an atmosphere of dry nitrogen. Analytical TLC was
performed with Merck silica gel 60 F254 plates. Visualization
was accomplished by UV light or spraying by Ce(SO4)2, solution in
5% H2SO4. Flash chromatography was carried out using Merck
silica gel 60 (230–400 mesh ASTM). NMR spectra were obtained on
a Bruker AV-300 spectrometer operating at 300 MHz, respectively
(TMS) for 1H; 282 MHz for 19F (CF3COOH); 121 MHz for 31P
(H3PO4).
Yield: 89% (solid), m.p. 87–88 8C. 1H NMR (CDCl3, 300 MHz):
d
1.19 (s, 9H, 3CH3), 1.29 (m, 6H, 2CH3), 4.17 (m, 4H, 2OCH2), 5.10 (m,
3
2H, CH2), 6.25 (s, 2H, OCH2), 6.43 (d, 1H, NH, JH-P = 8.0 Hz), 7.37
(br.s, 5H, Ph), 8.02 (s, 1H, CH-triazole). 19F NMR (CDCl3, 282 MHz):
d
6.44. 31P NMR (CDCl3, 121 MHz): 13.55 (d, 3JP-H = 7.21 Hz). Anal.
d
Calcd for C22H30F3N4O7P: C, 48.03; H, 5.45; N, 10.19. Found: C,
48.09; H, 5.44; N, 10.11.
4.2.2. {4-[2-{[(Benzyloxy)carbonyl]amino}-2-(diethoxyphosphoryl)-
3,3,3-trifluoropropyl]-1H-1,2,3-triazole-1-yl}methyl pivalate (3b)
Yield: 68% (solid), m.p. 83–84 8C. 1H NMR (CDCl3, 300 MHz):
d
3
1.22 (s, 9H, 3CH3), 1.33 (q, 6H, 2CH3, JH-H = 7.3 Hz), 3.81 (m, 2H,
CH2), 4.20 (m, 4H, 2OCH2), 5.19 (s, 2H, OCH2), 5.98 (d, 1H, NH, 3JH-
P = 8.9 Hz), 6.18 (dAB, 1H, CH2, JAB = 10.7 Hz), 6.23 (dAB, 1H, CH2,
4.1.1. Diethyl[(1-{[(benzyloxy)carbonyl]amino}-1-
trifluoromethyl)prop-2-yne-1-yl] phosphonate (2a)
Sodium acetylide (18% slurry in xylene; 11.0 mmol) was added
dropwise to a stirred solution of imine 1 [20b] (10.0 mmol) in dry
THF (25 mL) at À40 8C. After 8 h at À40 8C the reaction mixture
JAB = 10.7 Hz), 7.42 (m, 5H, Ph), 7.68 (s, 1H, CH-triazole). 19F NMR
3
(CDCl3, 282 MHz):
121 MHz):
d
8.23 (d, JF-P = 3.4 Hz). 31P NMR (CDCl3,
d
15.62 (d, 3JP-F = 3.1 Hz). Anal. Calcd for

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D.V. Vorobyeva et al. / Journal of Fluorine Chemistry 131 (2010) 378–383
C23H32F3N4O7P: C, 48.96; H, 5.67; N, 9.93. Found: C, 48.81; H, 5.59;
N, 9.85.
8.23 (s, 1H, CH-triazole). 19F NMR (CDCl3, 282 MHz):
31P NMR (CDCl3, 121 MHz):
13.76. Anal. Calcd for
d 6.72.
d
C22H24F3N4O5P: C, 51.57; H, 4.72; N, 10.93. Found: C, 52.26;
H, 4.78; N, 10.57.
4.2.3. Diethyl{1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-
[(1-(heptadeca-fluoro-decyl)-1H-1,2,3-triazole-4-
yl)]ethyl}phosphonate (3c)
4.2.8. Diethyl{1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-[(1-
Yield: 85% (solid), m.p. 85–86 8C. 1H NMR (CDCl3, 300 MHz):
d
phenyl-1H-1,2,3-triazole-4-yl)methyl]ethyl}phosphonate (3h)
1.28 (m, 6H, 2CH3), 2.85 (m, 2H, CH2), 4.18 (m, 4H, 2OCH2), 4.69 (t,
2H, CH2, 3JH-H = 6.0 Hz), 5.16 (dAB, 1H, CH2, JAB = 12.0 Hz), 5.07 (dAB
1H, CH2, JAB = 12.0 Hz), 6.46 (d, 1H, NH, 3JH-P = 8.0 Hz), 7.37 (s, 5H,
Ph), 7.86 (s, 1H, CH-triazole). 19F NMR (CDCl3, 282 MHz):
Yield: 73% (oil). 1H NMR (CDCl3, 300 MHz):
d
1.21 (t, 3H, CH3,
3
,
3JH-H = 7.2 Hz), 1,26 (t, 3H, CH3, JH-H = 7.2 Hz), 3.84 (m, 2H, CH2),
4.16 (m, 4H, 2OCH2), 5.09 (dAB, 1H, CH2, JAB = 9.1 Hz), 5.16 (dAB, 1H,
CH2, JAB = 9.1 Hz), 5.96 (d, 1H, NH, 3JH-P = 8.6 Hz), 7.30 (m, 6H, Ph),
d
À50.76
(br.s, 2F, CF2), À48.01 (br.s, 2F, CF2), À47.36 (br.s, 2F, CF2), À46.53
(br.s, 6F, 3CF2), À38.83 (m, 2F, CF2), À5.39 (s, 3F, CF3), 6.52 (s, 3F,
7.47 (t, 2H, Ph, 3JH-H = 7.8 Hz), 7.59 (d, 2H, Ph, 3JH-H = 7.0 Hz), 7.81
(s, 1H, CH-triazole). 19F NMR (CDCl3, 282 MHz):
d
15.51 (d, JF-
3
CF3). 31P NMR (CDCl3, 121 MHz):
d
13.70. Anal. Calcd for
P = 3.4 Hz). 31P NMR (CDCl3, 121 MHz):
d 8.04 (d, JP-F = 3.4 Hz).
3
C
26H23F20N4O5P: C, 35.40; H, 2.61; N, 6.35. Found: C, 35.28; H,
Anal. Calcd for C23H26F3N4O5P: C, 52.50; H, 4.94; N, 10.64. Found:
C, 52.55; H, 5.31; N, 10.48.
2.45; N, 6.30.
4.2.4. Diethyl{1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-[(1-
(heptadeca-fluoro-decyl)-1H-1,2,3-triazole-4-yl)methyl]ethyl}
phosphonate (3d)
4.2.9. Diethyl[1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-
(1H-1,2,3-triazole-4-yl methyl)ethyl]phosphonate (4)
To a solution of 3b (0.2 mmol) in MeOH (3.6 ml), was added
NaOH (1M aq solution, 3.6 ml). The reaction mixture was stirred
at r.t. for 45 min and subsequently neutralized with 1N HCl
(5 ml), diluted with H2O (20 ml), and was extracted with ethyl
acetate (3Â 15 ml). The organic layer was dried over MgSO4 and
evaporated. The residue was purified by silica gel column
Yield: 92% (oil). 1H NMR (CDCl3, 300 MHz):
d 1.31 (t, 3H, CH3,
3
3JH-H = 7.1 Hz), 1.35 (t, 3H, CH3, JH-H = 7.1 Hz), 2.79 (m, 2H, CH2),
3
3.83 (m, 2H, CH2), 4.19 (m, 4H, 2OCH2), 4.57 (t, 2H, CH2, JH-
H = 7.5 Hz), 5.14 (dAB, 1H, CH2, JAB = 12.0 Hz), 5.22 (dAB, 1H, CH2,
3
JAB = 12.0 Hz), 5.94 (d, 1H, NH, JH-P = 8.5 Hz), 7.34 (s, 1H, CH-
triazole), 7.42 (m, 5H, Ph). 19F NMR (CDCl3, 282 MHz):
d
À48.46 (m,
chromatography using acetone-hexane as an eluent. Yield:
75%. 1H NMR (CDCl3, 300 MHz):
d
1.36 (q, 6H, 2CH3, JH-
3
2F, CF2), À45.78 (br.s, 2F, CF2), À45.07 (br.s, 2F, CF2), À44.01 (br.s,
3
3
6F, 3CF2), À36.50 (t, 2F, CF2, JF-F = 13.4 Hz), À3.09 (t, 3F, CF3, JF-
H = 8.1 Hz), 3.70 (m, 2H, CH2), 4.15 (m, 2H, OCH2), 5.12 (m, 2H,
F = 10.1 Hz), 7.94 (s, 3F, CF3). 31P NMR (CDCl3, 121 MHz):
d
15.62.
CH2), 5.67 (br.s, 1H, CH-triazole), 6.08 (d, 1H, NH, 3JH-H = 10.0 Hz),
7.35 (br.s, 5H, Ph), 7.58 (br.s, 1H, CH-triazole). 19F NMR (CDCl3,
Anal. Calcd for C27H25F20N4O5P: C, 36.19; H, 2.79; N, 6.25. Found: C,
36.35; H, 2.73; N, 6.21.
3
282 MHz):
121 MHz):
d
d
7.37, 8.23 (d, JF-P = 3.4 Hz). 31P NMR (CDCl3,
3
15.52 (d, JP-F = 2.9 Hz).
4.2.5. Diethyl{1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-
[(1-(2,3,4,6-tetra-O-acetyl-
4-yl)]ethyl}phosphonate (3e)
Yield: 78% (cristal in oil), mixture of diastereomers 1:1. 1H NMR
(CDCl3, 300 MHz): 1.27 (br.s, 6H, 2CH3), 1.86 (s, 3H, CH3), 2.07 (t,
b
-
D
-glucopiranozyl)-1H-1,2,3-triazole-
4.2.10. {4-[2-Amino-2-(diethoxyphosphoryl)-3,3,3-trifluoropropyl]-
1H-1,2,3-triazole-1-yl}methyl pivalate (5)
To
a solution of Cbz-protected aminophosphonate 3b
d
(1.6 mmol) in methanol (20 ml) 10% Pd/C (5 mol%) was added
and slow stream of hydrogen was bubbled at room temperature.
When TLC indicated no starting material (about 3 h), mixture
was filtered and the solvent was removed under reduced
pressure. The residue was purified by silica gel column
chromatography using acetone–hexane as an eluent. Yield:
3
9H, 3CH3, JH-H = 6.0 Hz), 4.18 (m, 7H, 2OCH2, CH2, CH), 5.11 (m,
2H, CH2), 5.30 (m, 2H, CH, CH), 5.45 (m, 1H, CH), 5.88 (d, 1H, NH,
3
3JH-P = 10.0 Hz), 6.39 (t, 1H, CH, JH-H = 10.0 Hz), 7.35 (s, 5H, Ph),
8.09 (s, 1H, CH-triazole). 19F NMR (CDCl3, 282 MHz):
d
6.14 and
13.42. Anal. Calcd for
30H38F3N4O14P: C, 47.00; H, 5.00; N, 7.31. Found: C, 47.43; H,
5.00; N, 6.92.
6.64. 31P NMR (CDCl3, 121 MHz):
d
C
80% (oil). 1H NMR (CDCl3, 300 MHz):
d
1.23 (s, 9H, 3CH3), 1,35 (q,
3
6H, 2CH3, JH-H = 6.5 Hz), 2.07 (br.s, 1H, NH), 3.39 (d, 2H, CH2,
3JH-H = 10.7 Hz), 4.28 (m, 4H, 2OCH2), 6.21 (d, 1H, CH2,
JAB = 10.6 Hz), 6.25 (d, 1H, CH2, JAB = 10.6 Hz), 7.77 (s, 1H, CH-
4.2.6. Diethyl{1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-[(1-
(2,3,4,6-tetra-O-acetyl- -glucopiranozyl)-1H-1,2,3-triazole-4-
b
-D
triazole). 19F NMR (CDCl3, 282 MHz):
d
5.57 (d, 3JF-P = 4.2 Hz). 31
d 18.23. Anal. Calcd for C15H26F3N4O5P:
P
yl)methyl]ethyl}phosphonate (3f)
NMR (CDCl3, 121 MHz):
Yield: 65% (solid), m.p. 61–67 8C, mixture of diastereomers 1:1.
C, 41.86; H, 6.09; N, 13.02. Found: C, 41.84; H, 5.91; N, 12.94.
3
1H NMR (CDCl3, 300 MHz):
d
1.26 and 1.34 (t, 6H, 2CH3, JH-
3
H = 7.1 Hz), 1.88 (s, 6H, 2CH3), 2.06 (d, 9H, 3CH3, JH-H = 3.2 Hz),
2.13 (d, 9H, 3CH3, 3JH-H = 3.9 Hz), 3.86 (m, 4H, 2CH2), 4.09 (m, 14H,
4OCH2, 2CH2, 2CH), 5.26 (m, 6H, 2CH2, 2CH), 5.44 (m, 4H, 2CH,
4.2.11. {1-Amino-1-[(1-{[(2,2-dimethylpropanoyl)oxy]methyl}-1H-
1,2,3-triazole-4-yl)methyl]-2,2,2-trifluoroethyl}phosphonic acid
hydrobromide (6)
3
2CH), 5.83 (m, 3H, 2CH, NH), 5.96 (d, 1H, NH, JH-P = 8.2 Hz), 7.45
To a solution of aminophosphonate 5 (0.20 mmol) in dry
chloroform (5 ml) was added SiMe3Br (0.80 mmol). The reaction
mixture was kept at room temperature 72 h. Then, the volatiles
were evaporated under reduced pressure. The residue was
dissolved in ethanol (10 ml) and after 20 min at room temperature
the solvent was evaporated under reduced pressure. This
manipulation was repeated three times, then the residue was
treated with ether to afford a solid product. Yield: 85% (solid), m.p.
(m, 10H, Ph), 7.59 and 7.70 (s, 1H, CH-triazole). 19F NMR (CDCl3,
282 MHz):
(CDCl3, 121 MHz):
d
8.08 (d, 3JF-P = 3.0 Hz), 8.33 (d, 3JF-P = 3.1 Hz). 31P NMR
3
d
15.51 (t, JP-F = 4.0 Hz). Anal. Calcd for
C
31H40F3N4O14P: C, 47.72; H, 5.13; N, 7.18. Found: C, 47.38; H,
5.08; N, 7.00.
4.2.7. Diethyl{1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-[(1-
phenyl-1H-1,2,3-triazole-4-yl)]ethyl}phosphonate (3g)
58–60 8C. 1H NMR (D2O, 300 MHz):
2H, CH2), 6.23 (s, 2H, CH2),8.01 (s, 1H, CH-triazole). 19F NMR
(CDCl3, 282 MHz): 4.28. Anal.
7.25. 31P NMR (CDCl3, 121 MHz):
Calcd for C11H19F3N4O5PBr: C, 29.03; H, 4.29; N, 12.31. Found: C,
29.61; H, 4.59; N, 11.84.
d 1.05 (s, 9H, 3CH3), 3.48 (m,
Yield: 38% (oil). 1H NMR (CDCl3, 300 MHz):
d
1.26 (m, 6H, 2CH3),
4.16 (m, 4H, 2OCH2), 5.09 (dAB, 1H, CH2, JAB = 12.0 Hz), 5.17 (dAB
,
d
d
3
1H, CH2, JAB = 12.0 Hz), 6.53 (d, 1H, NH, JH-P = 8.0 Hz), 7.36
3
(br.s, 5H, Ph), 7.51 (m, 3H, Ph), 7.76 (d, 2H, Ph, JH-H = 8.0 Hz),

D.V. Vorobyeva et al. / Journal of Fluorine Chemistry 131 (2010) 378–383
383
(b) V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, Angew. Chem. Int. Ed.
41 (2002) 2596–2599;
Acknowledgments
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This work was supported by Deutsche Forschungsgemeinschaft
(RO 362/37-1) and Russian Foundation of Basic Research (grant No.
06-03-04003).
(b) D. Fournier, R. Hoogenboom, U.S. Schubert, Chem. Soc. Rev. 36 (2007) 1369–
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