Synthesis of fluorophosphonylated acyclic nucleotide analogues via copper(I)-catalyzed Huisgen 1-3 dipolar cycloaddition

Article abstract of DOI:10.1039/b912724k

Preparation of several acyclonucleosides containing both a difluoromethylphosphonate group and a triazole moiety is described starting from a difluorophosphonosulfide. The key step of the synthesis involves a copper(I)-catalyzed Huisgen 1-3 dipolar cycloa

Full text of DOI:10.1039/b912724k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of fluorophosphonylated acyclic nucleotide analogues
via copper(I)-catalyzed Huisgen 1-3 dipolar cycloaddition†
Sonia Amel Diab, Antje Hienzch, Cyril Lebargy, Ste´phane Guillarme, Emmanuel Pfund and Thierry Lequeux*
Received 29th June 2009, Accepted 27th July 2009
First published as an Advance Article on the web 21st August 2009
DOI: 10.1039/b912724k
Preparation of several acyclonucleosides containing both a difluoromethylphosphonate group and a
triazole moiety is described starting from a difluorophosphonosulfide. The key step of the synthesis
involves a copper(I)-catalyzed Huisgen 1-3 dipolar cycloaddition between difluorophosphonylated
azides and propargylated nucleobases derived from thymine and 2-amino-6-chloropurine.
drugs for psoriasis and related autoimmune diseases, introduction
of a difluoromethylphosphonate group improved their biological
Introduction
Conception of new nucleoside and nucleotide analogues plays
activities. For example, fluorinated phosphonate I was reported as
an important role in medicinal chemistry to develop new drugs
a Purine Nucleoside Phosphorylase (PNP, EC 2.4.2.1) inhibitor
targeting diseases caused by viruses such as HIV, HBV and herpes.1
with an increased activity of 5 to 25 fold compared to its non-
fluorinated analogue.7 Additional studies revealed that confor-
mationally constrained analogue II containing an aromatic ring
also exhibited high PNP inhibitory properties (Fig. 2).8 Recently,
Thymidine Phosphorylase (TP, EC 2.4.2.4), has been identified as
playing a crucial role in angiogenesis and represents a potential
target in cancer drugs discovery.9 To date, few multisubstrate
inhibitors were described and phosphonate III was reported as
a good TP inhibitor. However, due to the difficulties to access
aliphatic and aromatic difluorophosphonates, no example of
specific TPase inhibitors containing a difluoromethylphosphonate
function was reported.
Consequently, a large number of modifications has been made to
both nucleic base and sugar moieties of natural nucleosides.2 For
several decades, particular interest has been devoted to acyclic
nucleotides in which the furanose ring of the nucleoside and the
phosphate function were respectively replaced by an acyclic chain
and a methylene phosphonate group.3 These chemical changes
led to the preparation of many potent marketed antiviral drugs
R
R
including Adefovir dipivoxil (Hepseraꢀ), Cidofovir (Vistideꢀ) and
R
Tenofovir disoproxil fumarate (Vireadꢀ) (Fig. 1).
Fig. 1 Acyclonucleotides as antiviral drugs.
Since the pioneering work of Blackburn4 and Chambers,5
difluoromethylphosphonates are known to be the best isosteric
and isoelectronic phosphate mimics. Thus, many derivatives
containing a difluoromethylphosphonate function were studied as
potential enzyme inhibitors and as useful probes for elucidation of
biochemical processes.6 In the field of acyclic nucleotides as new
Fig. 2 Phosphonylated acyclic nucleosides as NP inhibitors.
In order to introduce a heterocycle to either substitute the
nucleic base or freeze the conformation of an aliphatic spacer,
the “click” chemistry appeared as an attractive approach.10
Triazoles have gained considerable attention in drug discovery,11
bioconjugation,12 carbohydrate chemistry,13 peptidomimetics14
and PET chemistry.15 In the field of nucleic acid chemistry, various
five-membered triazole nucleosides with pronounced biological
activities were developed.16 However, the replacement of the
conventional nucleic base of acyclonucleosides by a triazole moiety
Laboratoire de Chimie Mole´culaire et Thioorganique, ENSICAEN,
Universite´ de Caen Basse-Normandie, UMR-CNRS 6507, FR3038,
6 Bd du Mare´chal Juin, 14050, Caen Cedex, France. E-mail: thierry.
lequeux@ensicaen.fr; Fax: +33 231452865; Tel: +33 231452854
† Electronic supplementary information (ESI) available: Experimental
procedure for compounds 2-4, 6, 7 and 17. NMR spectra for all
compounds. See DOI: 10.1039/b912724k
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or the introduction of this heterocycle in the backbone of an acyclic
nucleoside is less documented,17 and to the best of our knowledge,
none of these modifications has already been mentioned in the case
of fluorophosphonylated nucleoside analogues. In this manuscript,
we report the synthesis of novel 1,2,3-triazole acyclonucleotides
containing a variety of spacers bearing both a difluoromethylphos-
phonate group and a triazole unit. Depending on the target,
this heterocycle is introduced to either mimic a nucleic base or
freeze the conformation of the aliphatic chain. The retrosynthetic
analysis for these compounds is depicted in Scheme 1. The key
step involves a copper(I)-catalyzed Huisgen cycloaddition between
azido difluoromethylphosphonates and terminal alkynes.
Scheme 3 Introduction of the azido group. Reagents and conditions:
(a) TsCl, NEt3, CH2Cl2, r.t., 24 h; (b) NaN3, DMF, r.t., 16 h.
nate function, the copper(I)-catalyzed Huisgen 1,3-dipolar cy-
cloaddition was tested from fluorophosphonylated azides 8-10
and propargyl thymine (T) or 2-amino-6-chloropurine (G6-Cl
)
(1.1 equiv).19 Reactions were conducted in tert-BuOH/H2O (1/1)
in the presence of sodium ascorbate (10 mol%) and copper sulfate
(5 mol%) at room temperature over 16 h to 24 h. Acyclic nucleotide
analogues 11-16 were isolated by flash chromatography in 71-96%
yields (Table 1).
Copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reac-
tions did not require any protection of nucleic bases and toler-
ated the presence of a chlorine atom and/or an amino group
on the nucleobase. As expected in the presence of CuI,20 the
1,4-disubstituted 1,2,3-triazoles were obtained exclusively. The
regioisomers were identified by 2D NMR experiments showing
a correlation between the C-5 triazole carbon atom and both
hydrogen atoms of the methylene group adjacent to the N-1
triazole nitrogen. From propargyl thymine, fluorophosphonylated
triazolonucleosides 11, 13 and 15 containing 2, 3 and 4 carbon
atoms in the spacer were isolated in 87-96% yields (Table 1, entries
1, 3, 5). From propargyl 2-amino-6-chloropurine, cycloaddition
reactions were also efficient and the corresponding adducts 12, 14
and 16 were produced in 71-75% yields (Table 1, entries 2, 4, 6).
In order to access another series of difluorophosphonylated
1,2,3-triazoloacyclonucleosides containing one carbon atom in the
spacer, the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition
reaction was next studied from azides 19 and 22. These azides were
synthesized starting from hydrate 17,21 easily prepared by addition
of the phosphonodifluoromethyl carbanion onto DMF followed
by a careful hydrolysis with HCl 3 N (Scheme 4).
Scheme 1 Retrosynthetic analysis of 1,2,3-triazole difluorophosphony-
lated acyclonucleotides.
Results and discussion
The synthesis of targeted molecules started from hydroxy
difluoromethylphosphonates 2-4 easily available from fluoro-
phosphonylated sulfide 1 following our previous procedures
(Scheme 2).18
Scheme 2 Preparation of difluorophosphonylated hydroxyphosphonates.
Reagents and conditions: (a) tert-BuLi, THF, -78 ◦C, 5 min; (b) 1,2-cyclic
sulfate derived from ethyleneglycol, THF, -78 ◦C, 15 min to give 2;
trimethylene oxide, BF3.Et2O, Et2O, -78 ◦C, 15 min to give 3; THF,
BF3.Et2O, -78 ◦C, 15 min to give 4.
The phosphonodifluoromethyl lithium was first generated at
-78 ◦C by nucleophilic attack of tert-butyllithium onto 1 and
then reacted at low temperature with either 1,2-cyclic sulfate
derived from ethyleneglycol,18b trimethylene oxide or THF,18a to
produce the corresponding fluorinated hydroxyphosphonates 2-4
in moderate to good yields. Transformation of these compounds
into their corresponding azides was then explored (Scheme 3).
After activation of the primary hydroxyl function with a tosylate,
introduction of the azido group was achieved by reaction with
sodium azide in DMF at room temperature. Phosphonodifluo-
romethyl azides 8-10 were isolated in 80-90% yield.
Scheme 4 Preparation of azides 19 and 22. Reagents and conditions:
(a) NaBH4, EtOH, 0 ◦C to r.t., 2 h; (b) 1) Tf2O, pyridine, CH2Cl2, -20 ◦C,
2 h; 2) NaN3, DMF, r.t. 16 h; (c) acetamide, dioxane, reflux 2 h; (d) SOCl2,
CH2Cl2, r.t. 1 h; (e) NaN3, DMF, r.t. 16 h.
Reduction of hydrate 17 with NaBH4 at 0 ◦C afforded the
corresponding alcohol 18 in good yield. No reduction of the
phosphonate ester moiety was observed. This latter was then
To access constrained 1,2,3-triazoloacyclonucleotides contain-
ing different spacer length and the difluoromethylphospho-
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Table 1 Copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition between difluorophosphonylated azides and propargylated nucleobases
Entry
Azide
Alkyne
Time
Product, compound number, yielda
1
8
24 h
11, 87%
2
3
8
9
24 h
24 h
12, 74%
13, 96%
4
5
9
18 h
14, 71%
10
20 h
15, 93%
6
10
16 h
16, 75%
a Isolated yields.
transformed into its corresponding tosylate in 89% yield. However,
the displacement of the tosylate function with NaN3 did not occur
even under refluxing DMF. The corresponding triflate derivative
was prepared and, due to its instability, was directly converted into
azide 19 in 85% overall yield.
As reported for the synthesis of trifluoromethylated azide
from fluoral hemi-acetal,22 preparation of 22 was explored from
the corresponding aldehyde dihydrate. Difluorophosphonylated
hydrate 17 was reacted with acetamide in refluxing dioxane to
lead to the protected hemi-aminal 20 in 69% yield. Chlorination
of the resulting alcohol was then achieved with thionyl chloride
(2 equiv) in dichloromethane in quantitative yield. Compound 21
was directly engaged in the next step without further purification.
The azido group was finally introduced at room temperature
with sodium azide in DMF. Azide 22 was isolated by flash
chromatography in 84% yield.
The 1,3-dipolar cycloaddition reaction was attempted from
propargyl thymine and 2-amino-6-chloropurine under the previ-
ous experimental conditions (Table 2). In all cases, cycloaddition
reactions were faster from propargyl thymine. A total conversion
of 19 and 22 was observed after 12 h under stirring at room
temperature. The corresponding triazoles 23 and 25 were isolated
by flash chromatography in 71 and 62% yields, respectively
(Table 2, entries 1, 3). Reactions were also efficient from propar-
gyl 2-amino-6-chloropurine. Difluorophosphonylated triazoles 24
and 26 containing an acetamido group and one carbon atom in the
spacer were obtained in good yields (Table 2, entries 2, 4). It is ex-
pected that the presence of an acetamido group in 25 and 26 could
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Table 2 Synthesis of difluorophosphonylated 1,2,3-triazole nucleosides containing one carbon atom in the spacer by 1,3-dipolar cycloadditions
Entry
Azide
Alkyne
Time
Product, compound number, yielda
1
19
12 h
23, 71%
2
3
19
22
24 h
24, 79%
12 h
25, 62%
4
22
24 h
26, 69%
a Isolated yields.
play a role in the enzyme binding. Furthermore, this family of
difluorophosphonylated triazoles are important building-blocks
for the synthesis of modified phosphonopeptides.22
Having in hand a large variety of phosphonylated azides the
development of difluorophosphonylated acyclic nucleotide ana-
logues in which conventional pyrimidine nucleobases are replaced
by functionalized 1,2,3-triazoles was also explored (Scheme 5).
Copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction
was realized from azide 10 and methyl propiolate following this
scheme. Copper(I) iodide (10 mol%) was added to a solution of
10 (1 equiv), methyl propiolate (1 equiv) in MeCN/H2O (1/2).
After stirring overnight at room temperature, the reaction reached
completion and triazole 27 was isolated by flash chromatography
in 78% yield. In order to mimic the N-1 nitrogen atom and the C-6
carbonyl group present in conventional purine nucleic bases, the
ester function of 27 was then converted into the amide.
Difluorophosphonylated 1,2,3-triazole acyclonucleotides 28
and 29 bearing an amide function at position 4 were obtained
in good yields by stirring 27 at room temperature for 72 h in
ammonia or methyl amine solution (40% in CH3OH).
Introduction of an amino group onto position 5 of the 1,2,3-
triazoles in order to mimic the N-3 nitrogen atom of purine
nucleobases was attempted. For that matter, copper(I)-catalyzed
1,3-dipolar cycloaddition with 10 and 2-cyanoacetamide was
avoided to prevent the formation of tetrazole derivatives as
mentioned in the literature.23 However, it was shown that the
cycloaddition reaction couldoccur onto the carbon-carbondouble
bond of a ketenimine instead of the nitrile function when CuI
was replaced by a base such as K2CO3 or sodium ethoxide.16p,24
These conditions were applied to the synthesis of 30. Azide 10
(1 equiv) was added to a solution of 2-cyanoacetamide (1.5 equiv)
and potassium hydroxide (1.5 equiv) in H2O/DMF (1/5). After
24 h of stirring at room temperature, triazole 30 functionalized in
Scheme 5 Preparation of difluorophosphonylated acyclonucleotides con-
taining a triazole moiety as nucleobase. Reagents and conditions: (a) methyl
propiolate, CuI, MeCN/H2O (1/2), r.t., 16 h; (b) MeOH/25% aq. NH3,
r.t., 72 h; (c) MeOH/25% aq. MeNH2, r.t., 72 h; (d) 2-cyanoacetamide,
KOH, H2O/DMF (1/5), r.t., 24 h.
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position 5 was isolated by flash chromatography in a modest and
non-optimized 37% yield.
in the EI or ESI mode. IR spectra were recorded on a Perkin-Elmer
ATR IR instrument.
Preparation of tosylate 5
Conclusions
In a 25 mL round bottom flask under N2 atmosphere were
placed the alcohol 2 (0.50 g, 1.92 mmol), tosyl chloride (0.55 g,
2.88 mmol) and anhydrous CH2Cl2 (10 cm3). Triethylamine
(0.40 cm3, 2.88 mmol) was added dropwise and the mixture was
stirred 24 h at room temperature. The solution was hydrolyzed with
1 N aqueous HCl solution (2 cm3) and extracted with CH2Cl2
(2 ¥ 20 cm3). The combined organic layers were successively
washed with saturated aqueous solutions of NaHCO3 (2 ¥ 2 cm3)
and NaCl (2 ¥ 2 cm3) and dried over MgSO4. Solvents were
evaporated under reduced pressure to leave a yellow oil which
was purified by flash column chromatography on silica using ethyl
acetate/pentane (6/4) as eluent to give diisopropyl 1,1-difluoro-
3-(p-toluene-sulfonyl)-propylphosphonate 5 (0.66 g, 83%) as a
colourless oil; nmax(ATR)/cm-1 2985, 2937, 2876, 1598, 1454, 1372,
1267, 1192, 1176, 1145, 1095 and 979; dH(500 MHz, CDCl3) 1.33
(12 H, dd, J 6.2 and 4.2, 2 ¥ (CH3)2CH), 2.37-2.53 (5 H, m,
CH2CF2 and CH3Ph), 4.26 (2 H, t, J 7.2, CH2CH2), 4.79 (2 H,
dsp, J 6.3, 2 ¥ CH(CH3)2), 7.34 (2 H, d, J 8.0, Har) and 7.78 (2 H, d,
J 6.8, Har); dP(202 MHz, CDCl3) 3.96 (1 P, t, J 104.6); dF(470 MHz,
CDCl3) -112.77 (2 F, td, J 18.6 and 104.6); dC(126 MHz, CDCl3)
21.3 (s, PhCH3), 23.9 (2 ¥ d, J 4.9, (CH3)2CH), 24.3 (2 ¥ d, J 3.5,
(CH3)2CH), 33.9 (dt, J 15.0 and 21.0, CF2CH2), 63.2 (dt, J 6.2
and 12.5, CH2O), 74.3 (2 ¥ d, J 7.0, 2 ¥ (CH3)2CH), 118.8 (dt, J
218.8 and 260.7, CF2), 128.2 (2 ¥ s, 2 ¥ Car), 130.2 (2 ¥ s, 2 ¥ Car),
132.9 (s, Car) and 145.37 (s, Car); m/z (ESI) 415.1168 (M + H+.
C16H25F2O6PS requires 415.1156), 373 (98%) and 331 (100).
In summary, we reported the first synthesis of difluoro-
phosphonylated 1,2,3-triazole acyclonucleotide analogues by a
copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction
involving functionalized alkynes and difluoromethylphosphonate
azides easily prepared in few steps starting from the diisopropyl
phosphonodifluoromethyl sulfide 1. From unprotected propar-
gyl thymine and 2-amino-6-chloropurine, conformational con-
strained nucleotide analogues containing both a triazole moiety
and various spacer length were isolated in good yields.
The copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition re-
action was also attempted with highly functionalized secondary
difluorophosphonylated azide 22 and led to the preparation of
acyclonucleotides 25 and 26 in which a protected amino group
was inserted in the spacer. The presence of this could make the
binding to the targeted enzyme by additional hydrogen bonding
easier.
Finally, introduction of functionalized triazoles onto acyclic
nucleotides in order to mimic conventional purine nucleobases
was also explored. The copper(I)-catalyzed Huisgen cycloaddi-
tion with difluorophosphonylated azide 10 and methyl propio-
late followed by amidation reactions afforded 1,4-disubstitued
1,2,3-triazoles 28-29 while the replacement of the copper
source by potassium hydroxide in combination with the use of
2-cyanoacetamide resulted in 1,4,5-trisubstituted 1,2,3-triazole 30
formation in moderate to good yields.
Fully deprotected 1,2,3-triazole acyclonucleotides containing
the difluoromethylphosphonate group in which the triazole unit
is introduced to either substitute the nucleic base or freeze the
conformation are currently studied as nucleoside phosphorylase
inhibitors and their biological evaluations will be reported in due
course.
General procedure for the preparation of azides 8-10
In a 25 mL round bottom flask under N2 atmosphere were
placed the tosylate (1.00 mmol), sodium azide (1.10 mmol) and
anhydrous DMF (5 cm3). The mixture was stirred for 16 h at room
temperature and the DMF was evaporated. The residue was taken
up in Et2O (15 cm3) and the aqueous layer was extracted with Et2O
(2 ¥ 15 cm3). Combined organic layers were washed with water
(5 cm3) and saturated aqueous solution of NaCl (5 cm3), then dried
over MgSO4. Solvents were evaporated under reduced pressure
and crude product was purified by flash column chromatography
on silica using ethyl acetate/pentane (4/6) as eluent to give the
desired azides 8-10 (80-90%) as colourless liquids.
Experimental
General
All commercially available reagents were bought from Aldrich
and used as received. For anhydrous conditions the glassware
was dried in the oven at 120 ◦C and cooled to room temperature
under a continuous nitrogen flow. THF, CH2Cl2, Et2O, CH3CN
were dried at a solvent generator from “Innovative Technologies
Inc.”, which uses an activated alumina column to remove water.
Diisopropyl 3-azido-1,1-difluoropropylphosphonate (8)
BF3-Et2O, DMF and NEt3 were distilled under CaH2 or 4A
(0.27 g, 80%) colourless liquid; nmax(ATR)/cm-1 2983, 2098, 1266
and 980; dH(400 MHz, CDCl3) 1.38 (12 H, dd, J 6.4 and 3.4,
2¥ (CH3)2CH), 2.23-2.48 (2 H, m, CH2CF2), 3.57 (2 H, t, J 7.3,
CH2N3) and 4.85 (2 H, dsp, J 6.4, 2 ¥ CH(CH3)2); dP(162 MHz,
CDCl3) 4.32 (1 P, t, J 105.5); dF(376 MHz, CDCl3) -112.83 (2 F,
td, J 19.1 and 105.5); dC(101 MHz, CDCl3) 24.0 (2 ¥ d, J 4.9,
(CH3)2CH), 24.3 (2 ¥ d, J 3.5, (CH3)2CH), 33.7 (dt, J 14.5 and
20.9, CF2CH2), 44.1 (dt, J 5.8 and 11.6, CH2N3), 74.0 (2 ¥ d, J
7.0, 2 ¥ (CH3)2CH) and 119.0 (dt, J 218.1 and 260.3, CF2); m/z
(ESI) 286.1122 (M + H+. C9H18F2N3O3P requires 286.1132), 244
(100%) and 202 (83).
˚
molecular sieves. Flash column chromatography was realized on
silica gel 60 (40-63 mm) from Merck with air pressure and were
detected by thin layer chromatography, on which the spots were
visualized by UV-irradiation and/or KMnO4 solution. NMR
spectra were recorded on a 250 MHz or 400 MHz apparatus
in deuterated solvent at 25 ◦C. 31P and 19F NMR spectral lines
are with respect to the internal references H3PO4 (capillary) and
CFCl3. All chemical shifts are reported in d parts per million
(ppm) and coupling constants are in hertz (Hz). High-resolution
mass data were recorded on a high-resolution mass spectrometer
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Diisopropyl 4-azido-1,1-difluorobutylphosphonate (9)
product was recrystallized from pentane/ethyl acetate to give (di-
isopropyl) 1,1-difluoro-2-acetamido-2-hydroxyethylphosphonate
20 (0.18 g 69%) as a white solid, mp 129-130 ◦C; dH(400 MHz,
CDCl3) 1.38 (12 H, dd, J 6.8 and 4.0, 2 ¥ (CH3)2CH), 2.04 (3 H, s,
CH3CO), 4.90 (2 H, dsp, J 6.0, 2 ¥ CH(CH3)2), 5.61-5.85 (1 H,
m, CHCF2) and 7.33 (1 H, d, J 9.6, NH); dP(162 MHz, CDCl3)
4.00 (1 P, dd, J 97.2 and 95.6); dF(376 MHz, CDCl3) -119.40 (1
F, ddd, J 9.4, 95.6 and 304.6) and -121.97 (1 F, ddd, J 9.0, 97.2
and 304.6); dC(101 MHz, CDCl3) 22.9 (s, CH3CO), 23.8 (d, J 5.5,
CH3CH), 23.9 (d, J 5.4, CH3CH), 24.5 (d, J 3.5, CH3CH), 24.6
(d, J 3.2, CH3CH), 73.6 (dt, J 14.9 and 28.0, CF2CH), 74.9 (d, J
(0.29 g, 83%) colourless liquid; nmax(ATR)/cm-1 2984, 2940,
2879, 2096, 1454, 1388, 1378, 1266, 1177, 1144, 1102 and 984;
dH(250 MHz, CDCl3) 1.38 (12 H, dd, J 6.2 and 3.7, 2 ¥ (CH3)2CH),
1.75-1.88 (2 H, m, CH2CH2CH2), 1.95-2.25 (2 H, m, CH2CF2),
3.36 (2 H, t, J 6.7, CH2N3) and 4.84 (2 H, dsp, J 6.3, 2 ¥ CH(CH3)2);
dP(101 MHz, CDCl3) 5.19 (1 P, t, J 108.0); dF(235 MHz, CDCl3)
-112.81 (2 F, td, J 19.0 and 108.0); dC(63 MHz, CDCl3) 20.9 (dt,
J 5.0 and 10.1, CF2CH2CH2), 23.9 (2 ¥ d, J 4.9, (CH3)2CH), 24.3
(2 ¥ d, J 3.5, (CH3)2CH), 31.4 (dt, J 14.8 and 21.2, CF2CH2), 51.0
(s, CH2N3), 73.8 (2 ¥ d, J 7.0, 2 ¥ (CH3)2CH) and 120.8 (dt, J 217.8
and 259.6, CF2); m/z (ESI) 300.1288 (M + H+. C10H21F2N3O3P
requires 300.1289), 258 (100%), 216 (28) and 188 (63).
7.2, (CH3)2CH), 75.0 (d, J 6.9, (CH3)2CH), 116.5 (dt, J 205.9 and
+
=
270.4, CF2) and 171.5 (s, C O); m/z (ESI) 304.1134 (M + H .
C10H20F2NO5P requires 304.1125), 286 (100%) and 244 (12).
Diisopropyl 5-azido-1,1-difluoropentylphosphonate (10)
(0.32 g, 90%) colourless liquid; nmax(ATR)/cm-1 2984, 2939,
2878, 2094, 1456, 1388, 1377, 1266, 1178, 1144, 1103 and 982;
dH(250 MHz, CDCl3) 1.36 (12 H, dd, J 6.2 and 3.6, 2 ¥
(CH3)2CH), 1.55-1.70 (4 H, m, CH2CH2CH2CH2), 1.78-2.15 (2
H, m, CH2CF2), 3.28 (2 H, t, J 6.2, CH2N3) and 4.84 (2 H,
dsp, J 6.3, 2 ¥ CH(CH3)2); dP(101 MHz, CDCl3) 5.49 (1 P, t,
J 109.0); dF(235 MHz, CDCl3) -113.02 (2 F, td, J 20.0 and 109.0);
dC(63 MHz, CDCl3) 18.3 (dt, J 5.0 and 10.1, CF2CH2CH2), 23.8
(2 ¥ d, J 4.9, (CH3)2CH), 24.2 (2 ¥ d, J 3.5, (CH3)2CH), 28.7
(s, CH2CH2N3), 33.5 (dt, J 14.5 and 21.1, CF2CH2), 51.2 (s,
CH2N3), 73.7 (2 ¥ d, J 7.0, 2 ¥ (CH3)2CH) and 120.9 (dt, J 217.3
and 259.4, CF2); m/z (ESI) 314.1436 (M + H+. C11H22F2N3O3P
requires 314.1445), 272 (54%), 244 (10), 230 (9) and 202 (100).
Preparation of azide 19
In a 25 mL round bottom flask under N2 atmosphere were
placed the alcohol 18 (0.13 g, 0.53 mmol), pyridine (2 cm3) and
anhydrous CH2Cl2 (2 cm3). Triflic anhydride (0.14 cm3, 0.79 mmol)
was added dropwise at -20 ◦C and the mixture was stirred for
2 h at this temperature. The solution was poured into cooled
saturated aqueous solution of NaHCO3 (2 cm3). The organic layer
was washed a second time with a saturated aqueous solution
of NaHCO3 (2 cm3). The aqueous layers were extracted with
CH2Cl2 (2 ¥ 15 cm3). Combined organic layers were washed with
a saturated aqueous NaCl solution (2 cm3), dried over MgSO4
and concentrated to give the triflate intermediate (0.19 g, 95%) as
yellow coloured liquid; dH(500 MHz, CDCl3) 1.38 (12 H, dd, J 6.3
and 3.8, 2 ¥ (CH3)2CH), 4.72 (2 H, dt, J 2.9 and 14.0, CH2CF2)
and 4.85 (2 H, dsept, J 6.5, 2 ¥ CH(CH3)2); dP(202 MHz, CDCl3)
1.15 (1 P, t, J 95.6); dF(470 MHz, CDCl3) -121.08 (2 F, td, J 14.0
and 95.6, CF2) and -74.20 (3 F, s, CF3); dC(63 MHz, CDCl3) 23.5
(2 ¥ d, J 5.0, (CH3)2CH), 24.0 (2 ¥ d, J 3.8, (CH3)2CH), 71.3 (dt, J
18.7 and 25.4, CF2CH2), 75.2 (2 ¥ d, J 7.1, 2 ¥ (CH3)2CH), 114.4
(dt, J 213.0 and 264.8, CF2) and 118.4 (q, J 319.6, CF3); m/z (ESI)
379.0394 (M + H+. C9H16F5O6PS requires 379.0404), 337 (95%),
312.9 (14) and 294.9 (20).
In a 25 mL round bottom flask under N2 atmosphere were
placed the obtained triflate (0.50 g, 1.32 mmol), sodium azide
(0.09 g, 1.45 mmol) and anhydrous DMF (13 cm3). The mixture
was stirred for 16 h at room temperature and the DMF was
evaporated. The residue poured in Et2O (30 cm3) and the aqueous
layer was extracted with Et2O (2 ¥ 30 cm3). Combined organic
layers were washed with water (10 cm3) and saturated solution of
NaCl (10 cm3), dried over MgSO4. Solvents were evaporated under
reduced pressure and crude product was purified by flash column
chromatography on silica using ethyl acetate/pentane (4/6) as
eluent to give diisopropyl 2-azido-1,1-difluoroethylphosphonate
19 (0.30, 85%) as a colourless liquid; nmax(ATR)/cm-1 2986,
2940, 2104, 1389, 1378, 1271, 1180, 1144, 1099, 1074 and 987;
dH(400 MHz, CDCl3) 1.39 (12 H, dd, J 6.2 and 3.9, 2 ¥ (CH3)2CH),
3.68 (2 H, dt, J 4.7 and 15.8, CH2CF2) and 4.88 (2 H, dsp,
J 6.3, 2 ¥ CH(CH3)2); dP(162 MHz, CDCl3) 3.02 (1 P, t, J
99.9); dF(376 MHz, CDCl3) -117.01 (2 F, td, J 16.2 and 99.9);
dC(101 MHz, CDCl3) 24.0 (2 ¥ d, J 5.1, (CH3)2CH), 24.4 (2 ¥ d, J
3.5, (CH3)2CH), 52.5 (dt, J 18.5 and 23.4, CF2CH2), 74.7 (2 ¥ d,
J 7.0, 2 ¥ (CH3)2CH) and 117.9 (dt, J 212.8 and 263.4, CF2); m/z
Preparation of alcohol 18
To a solution of difluorophosphonylated hydrate 17 (0.50 g,
1.91 mmol) in absolute ethanol (15 cm3) was added at 0 ◦C
sodium borohydride (0.14 g, 3.82 mmol). After 10 min, the ice bath
was removed and the reaction was stirred at room temperature
for 2 h. The mixture was carefully quenched with a saturated
aqueous NH4Cl solution (2 cm3). Ethanol was removed under
reduced pressure and the resulting aqueous layer was extracted
with CH2Cl2 (3 ¥ 15 cm3). Combined organic layers were washed
with a saturated aqueous NaCl solution (2 ¥ 2 cm3), dried
over MgSO4 and concentrated to give diisopropyl 1,1-difluoro-
2-hydroxyethylphosphonate 18 (0.13 g, 98%) as colourless oil;
n
max(ATR)/cm-1 3560, 2973, 1236 and 989; dH(400 MHz, CDCl3)
1.38 (12 H, dd, J 6.1 and 4.1, 2 ¥ (CH3)2CH), 3.09 (1 H, br s,
OH), 3.95 (2 H, dt, J 7.6 and 14.7, CH2OH) and 4.85 (2 H,
dsp, J 6.3, 2 ¥ CH(CH3)2); dP(162 MHz, CDCl3) 4.54 (1 P, t, J
101.7); dF(376 MHz, CDCl3) -120.76 (2 F, td, J 15.1 and 101.7);
dC(126 MHz, CDCl3) 24.0 (2 ¥ d, J 5.0, (CH3)2CH), 24.4 (2 ¥ d,
J 3.4, (CH3)2CH), 63.1 (dt, J 16.6 and 25.7, CF2CH2), 74.5 (2 ¥
d, J 7.1, 2 ¥ (CH3)2CH) and 118.1 (dt, J 209.3 and 262.9, CF2);
m/z (ESI) 247.0923 (M + H+. C8H17F2O4P requires 247.0911), 205
(100%) and 163 (33).
Preparation of acetamide 20
To a solution of hydrate 17 (0.22 g, 0.84 mmol) in 1,4-dioxane
(3 cm3) was added acetamide (0.05 g, 0.84 mmol). The mixture was
stirred under reflux for 2 h. After solvent evaporation, the crude
4486 | Org. Biomol. Chem., 2009, 7, 4481–4490
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(ESI) 272.0984 (M + H+. C8H16F2N3O3P requires 272.0976), 230
(100%) and 188 (85).
3.5, (CH3)2CH), 34.8 (dt, J 15.3 and 21.1, CF2CH2), 43.1 (s,
=
CH2NC O), 43.6 (dt, J 6.2 and 12.0, CF2CH2CH2), 74.6 (2 ¥ d,
J 7.1, 2 ¥ (CH3)2CH), 111.6 (s, Car), 119.1 (dt, J 218.0 and 260.5,
=
CF2), 124.5 (s, Car), 140.4 (s, Car), 142.4 (s, Car), 151.2 (s, C O)
Preparation of azide 22
+
=
and 164.4 (s, C O); m/z (ESI) 450.1698 (M + H . C17H26F2N5O5P
To a solution of alcohol 20 (0.20 g, 0.66 mmol) in anhydrous
CH2Cl2 (5 cm3) under N2 atmosphere were added dropwise
SOCl2 (0.10 cm3, 1.32 mmol). The mixture was stirred for 1 h
at room temperature and the solvent was evaporated under
reduced pressure. The residue was solubilised in DMF (2 cm3)
and sodium azide (0.05 g, 0.73 mmol) was added in one portion.
The mixture was stirred for 16 h at room temperature and
the DMF was evaporated. The residue was poured in Et2O
(15 cm3) and the aqueous layer was extracted with Et2O (2 ¥
15 cm3). Combined organic layers were washed with water (5 cm3)
and saturated solution of NaCl (5 cm3), dried over MgSO4.
Solvents were evaporated under reduced pressure and crude
product was purified by flash column chromatography on silica
using ethyl acetate/pentane (4/6) as eluent to give diisopropyl 2-
acetamido-2-azido-1,1-difluoroethylphosphonate 22 (0.22 g, 84%)
as a colourless liquid; dH(500 MHz, CDCl3) 1.40 (12 H, dd, J 6.0
and 3.2, 2 ¥ (CH3)2CH), 2.09 (3 H, s, CH3CO), 4.88 (2 H, dsp, J
6.5, 2 ¥ CH(CH3)2), 5.79-5.95 (1 H, m, CHCF2) and 7.28 (1 H,
d, J 9.2, NHCO); dP(202 MHz, CDCl3) 2.47 (1 P, dd, J 94.9 and
J 98.3); dF(470 MHz, CDCl3) -116.37 (1 F, ddd, J 9.4, 98.8 and
305.9) and -118.62 (1 F, ddd, J 9.4, 94.1 and 305.9); dC(126 MHz,
CDCl3) 23.3 (s, CH3CO), 23.8 (d, J 5.5, CH3CH), 23.9 (d, J 5.5,
CH3CH), 24.4 (d, J 3.3, CH3CH), 24.5 (d, J 3.2, CH3CH), 66.7
(dt, J 15.3 and 28.3, CF2CH), 75.4 (d, J 7.3, (CH3)2CH), 75.5 (d,
requires 450.1718), 408 (84%) and 366 (30).
9-[1-(3-Diisopropoxyphosphono-3,3-difluoro-propyl)-1,2,3-
triazolo-4-methyl]-2-amino-6-chloropurine (12)
(0.38 g, 74%) white solid, mp 115-116 ◦C; nmax(ATR)/cm-1 3460,
3352, 2932, 2854, 1625, 1470, 1272 and 992; dH(400 MHz, CDCl3)
1.33 (12 H, dd, J 6.7 and 3.2, 2 ¥ (CH3)2CH), 2.58-2.80 (2 H, m,
CH2CF2), 4.62 (2 H, t, J 7.4, CH2CH2N), 4.79 (2 H, dsp, J 6.4,
=
2 ¥ CH(CH3)2), 5.34 (2 H, s, CH2NC N), 5.41 (2 H, s, NH2), 7.69
(1 H, s, CH=CCH2) and 7.90 (1 H, s, NCH N); dP(162 MHz,
=
CDCl3) 3.63 (1 P, t, J 103.6); dF(376 MHz, CDCl3) -112.74 (2 F,
td, J 18.7 and 103.6); dC(101 MHz, CDCl3) 24.0 (2 ¥ d, J 4.8,
(CH3)2CH), 24.3 (2 ¥ d, J 3.7, (CH3)2CH), 34.9 (dt, J 15.3 and
=
21.2, CF2CH2), 38.7 (s, CH2NC N), 43.6 (dt, J 6.3 and 11.9,
CF2CH2CH2), 74.6 (2 ¥ d, J 7.2, 2 ¥ (CH3)2CH), 121.6 (dt, J
217.7 and 260.7, CF2), 123.8 (s, Car), 125.3 (s, Car), 142.3 (s, Car),
142.4 (s, Car), 151.6 (s, Car), 153.7 (s, Car) and 159.5 (s, Car); m/z
(ESI) 493.1436 (M + H+. C17H24ClF2N8O3P requires 493.1444),
451 (100%), 409 (37), 381 (10), 296 (5), 254 (23), 212 (88), 194 (11)
and 159 (36).
1-[1-(4-Diisopropoxyphosphono-4,4-difluoro-butyl)-1,2,3-triazolo-
4-methyl]-thymine (13)
J 7.3, (CH3)2CH), 115.9 (dt, J 207.9 and 266.8, CF2) and 170.7
(0.30 g, 96%) white solid, mp 119-120 ◦C; nmax(ATR)/cm-1 3142,
3032, 2979, 2833, 1687, 1652, 1468, 1385, 1278, 1220, 1147, 1104,
1004 and 981; dH(250 MHz, CDCl3) 1.34 (12 H, dd, J 6.2 and
4.3, 2 ¥ (CH3)2CH), 1.88 (3 H, d, J 1.0, CH3), 1.89-2.10 (2 H,
m, CH2CH2CH2), 2.11-2.30 (2 H, m, CH2CF2), 4.41 (2 H, t, J
7.0, CH2CH2N), 4.83 (2 H, dsp, J 6.3, 2 ¥ CH(CH3)2), 4.94 (2
+
=
(s, C O); m/z (ESI) 329.1205 (M + H . C10H19F2N4O4P requires
329.1190), 286 (97%) and 244 (9).
General procedure for the preparation of triazoles 11-16 and 23-26
To a stirred solution of azide (1.00 mmol) in tert-BuOH (2.5 cm3)
and water (2.5 cm3), propargyl nucleobase (1.10 mmol) was added
followed by sodium ascorbate (0.10 mmol) and CuSO4.5H2O
(0.05 mmol). The mixture was stirred for 12-24 h at room
temperature. The organic solvent was removed under reduced
pressure and the residue was poured in CH2Cl2 (10 cm3) and
water (10 cm3). The aqueous layer was extracted with CH2Cl2 (2 ¥
10 cm3) and combined organic layers were washed with saturated
solution of NaCl (5 cm3), dried over MgSO4 and concentrated.
The crude product was purified by flash column chromatography
on silica using CH2Cl2/CH3OH (10/1) as eluent to give the desired
triazoles 11-16 and 23-26 (62-96%) as a white solid.
=
H, s, CH2NCO), 7.33 (1 H, d, J 1.2, CH CCH3), 7.75 (1 H, s,
=
CH CCH2) and 9.31 (1 H, br s, CONHCO); dP(101 MHz, CDCl3)
4.72 (1 P, t, J 106.6); dF(235 MHz, CDCl3) -112.45 (2 F, td, J
19.0 and 106.6); dC(63 MHz, CDCl3) 12.5 (s, CH3), 22.3 (dt, J
5.0 and 10.0, CF2CH2CH2), 23.9 (2 ¥ d, J 4.9, (CH3)2CH), 24.3
(2 ¥ d, J 3.5, (CH3)2CH), 31.3 (dt, J 15.2 and 21.4, CF2CH2),
=
43.2 (s, CH2NC O), 49.9 (s, CH2CH2N), 74.1 (2 ¥ d, J 7.1, 2 ¥
(CH3)2CH), 111.5 (s, Car), 120.5 (dt, J 217.6 and 260.0, CF2), 124.1
=
(s, Car), 140.4 (s, Car), 142.4 (s, Car), 151.5 (s, C O) and 164.7 (s,
+
=
C O); m/z (ESI) 464.1868 (M + H . C18H29F2N5O5P requires
464.1874), 422 (100%) and 380 (72).
1-[1-(3-Diisopropoxyphosphono-3,3-difluoro-propyl)-1,2,3-
triazolo-4-methyl]-thymine (11)
9-[1-(4-Diisopropoxyphosphono-4,4-difluoro-butyl)-1,2,3-triazolo-
4-methyl]-2-amino-6-chloropurine (14)
(0.47 g, 79%) white solid, mp 112-113 ◦C; nmax(ATR)/cm-1 3501,
2984, 1673, 1467, 1377, 1258 and 992; dH(400 MHz, CDCl3) 1.38
(12 H, dd, J 6.4 and 3.1, 2 ¥ (CH3)2CH), 1.89 (3 H, d, J 1.1, CH3),
2.60-2.85 (2 H, m, CH2CF2), 4.65 (2 H, t, J 7.5, CH2N), 4.87 (2
H, dsp, J 6.3, 2 ¥ CH(CH3)2), 4.95 (2 H, s, CH2NCO), 7.32 (1 H,
(0.34 g, 71%) white solid, mp 123-124 ◦C; nmax(ATR)/cm-1 3465,
3345, 2942, 2856, 1628, 1471, 1276 and 1000; dH(250 MHz, CDCl3)
1.25 (12 H, dd, J 6.2 and 3.8, 2 ¥ (CH3)2CH), 1.90-2.07 (2 H,
m, CH2CF2), 2.08-2.20 (2 H, m, CH2CH2CH2), 4.35 (2 H, t, J
7.0, CH2CH2N), 4.72 (2 H, dsp, J 6.3, 2 ¥ CH(CH3)2), 5.51 (2
=
=
d, J 1.1, CH=CCH3), 7.79 (1 H, s, CH CCH2) and 9.09 (1 H,
H, s, CH2NC N), 5.60 (2 H, s, NH2), 7.72 (1 H, s, CH=CCH2)
=
br s, NH); dP(162 MHz, CDCl3) 3.77 (1 P, t, J 103.9); dF(376 MHz
CDCl3) -113.01 (2 F, td, J 18.8 and 103.9); dC(126 MHz, CDCl3)
12.6 (s, CH3), 24.0 (2 ¥ d, J 4.7, (CH3)2CH), 24.4 (2 ¥ d, J
and 8.31 (1 H, s, NCH N); dP(101 MHz, CDCl3) 4.40 (1 P, t, J
106.6); dF(235 MHz CDCl3) -112.33 (2 F, td, J 19.2 and 106.6);
dC(63 MHz, CDCl3) 22.3 (dt, J 4.9 and 9.5, CF2CH2CH2), 23.8
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©

View Article Online
(2 ¥ d, J 4.8, (CH3)2CH), 24.2 (2 ¥ d, J 3.6, (CH3)2CH), 31.0 (dt, J
15.3 and 21.4, CF2CH2), 39.1 (s, CH2NC N), 49.8 (s, CH2CH2N),
F, td, J 16.0 and 98.0); dC(63 MHz, CDCl3) 12.4 (s, CH3), 23.8
(2 ¥ d, J 5.0, (CH3)2CH), 24.2 (2 ¥ d, J 3.8, (CH3)2CH), 42.9 (s,
CH2NC O), 51.7 (dt, J 15.6 and 22.0, CF2CH2), 75.1 (2 ¥ d, J
=
=
74.0 (2 ¥ d, J 7.1, 2 ¥ (CH3)2CH), 119.6 (dt, J 217.3 and 259.8,
CF2), 123.7 (s, Car), 126.3 (s, Car), 129.6 (s, Car), 131.9 (s, Car), 145.4
(s, Car), 151.1 (s, Car) and 156.6 (s, Car); m/z (ESI) 507.1570 (M +
H+. C18H26ClF2N8O3P requires 507.1591), 465 (68%), 423 (27), 395
(9), 310 (55) and 268 (15).
7.5, 2 ¥ (CH3)2CH), 111.4 (s, Car), 115.8 (dt, J 214.2 and 264.8,
=
CF2), 125.9 (s, Car), 140.3 (s, Car), 142.7 (s, Car), 151.4 (s, C O)
+
=
and 164.7 (s, C O); m/z (ESI) 436.1579 (M + H . C16H25F2N5O5P
requires 436.1561), 394 (100%), 352 (47) and 324 (2).
1-[1-(5-Diisopropoxyphosphono-5,5-difluoro-pentyl)-1,2,3-
triazolo-4-methyl]-thymine (15)
9-[1-(2-Diisopropoxyphosphono-2,2-difluoro-ethyl)-1,2,3-triazolo-
4-methyl]-2-amino-6-chloropurine (24)
(0.46 g, 93%) white solid, mp 99-100 ◦C; nmax(ATR)/cm-1 3143,
3027, 2984, 2935, 2826, 1684, 1651, 1467, 1387, 1271, 1147, 1102
and 978; dH(250 MHz, CDCl3) 1.35 (12 H, dd, J 6.2 and 3.1, 2 ¥
(CH3)2CH), 1.48-1.70 (2 H, m, CH2CH2CH2), 1.88 (3 H, d, J 1.1,
CH3), 1.89-2.03 (4 H, m, CH2CF2 and CH2CH2N), 4.34 (2 H, t,
J 7.1, CH2CH2N), 4.82 (2 H, dsp, J 6.2, 2 ¥ CH(CH3)2), 4.94 (2
H, s, CH2NCO), 7.33 (1 H, d, J 1.1, CH=CCH3), 7.71 (1 H, s,
CH=CCH2) and 9.26 (1 H, s, NH); dP(162 MHz, CDCl3) 5.21 (1
P, t, J 108.0); dF(376 MHz CDCl3) -112.90 (2 F, td, J 20.0 and
108.0); dC(101 MHz, CDCl3) 12.4 (s, CH3), 18.2 (dt, J 5.0 and
9.7, CF2CH2CH2), 23.9 (2 ¥ d, J 4.8, (CH3)2CH), 24.3 (2 ¥ d, J
3.5, (CH3)2CH), 29.9 (s, CH2CH2N), 33.4 (dt, J 14.5 and 21.1,
(0.28 g, 79%) white solid, mp 111-112 ◦C; nmax(ATR)/cm-1 3451,
3350, 2935, 2847, 1623, 1461, 1265 and 986; dH(400 MHz, CDCl3)
1.27 (12 H, dd, J 6.3 and 2.9, 2 ¥ (CH3)2CH), 4.81 (2 H, dsp, J
6.2, 2 ¥ CH(CH3)2), 4.92 (2 H, dt, J 3.5 and 16.2, CH2CF2), 5.34
=
(2 H, s, CH2NC N), 5.57 (2 H, s, NH2), 7.81 (1 H, s, CH=CCH2)
=
and 7.90 (1 H, s, NCH N); dP(202 MHz, CDCl3) 1.84 (1 P, t,
J 97.4); dF(470 MHz CDCl3) -117.02 (2 F, td, J 15.6 and 97.4);
dC(101 MHz, CDCl3) 23.8 (2 ¥ d, J 4.8, (CH3)2CH), 24.1 (2 ¥ d,
=
J 3.6, (CH3)2CH), 38.6 (s, CH2NC N), 52.0 (dt, J 15.6 and 23.5,
CF2CH2), 75.2 (2 ¥ d, J 7.1, 2 ¥ (CH3)2CH), 115.8 (dt, J 214.0 and
264.9, CF2), 125.0 (2 ¥ s, 2 ¥ Car), 142.3 (s, Car), 142.6 (s, Car), 151.4
(s, Car), 153.7 (s, Car) and 159.6 (s, Car); m/z (ESI) 479.1294 (M +
H+. C16H22ClF2N8O3P requires 479.1287), 437 (75%) and 395 (26).
=
CF2CH2), 43.2 (s, CH2NC O), 50.3 (s, CH2CH2N), 73.8 (2 ¥ d,
J 7.1, 2 ¥ (CH3)2CH), 111.4 (s, Car), 120.5 (dt, J 217.4 and 259.5,
=
CF2), 124.2 (s, Car), 140.4 (s, Car), 142.3 (s, Car), 151.5 (s, C O)
1-[1-(2-Diisopropoxyphosphono-2,2-difluoro-ethyl)-2-acetamido-
1,2,3-triazolo-4-methyl]-thymine (25)
+
=
and 164.7 (s, C O); m/z (ESI) 478.2025 (M + H . C19H31F2N5O5P
requires 478.2031), 436 (100%) and 394.1 (83).
(0.18 g, 62%) white solid, mp 121-122 ◦C; nmax(ATR)/cm-1 3256,
2985, 2115, 1678, 1531, 1377, 1257, 1097 and 991; dH(400 MHz,
CDCl3) 1.35 (12 H, dd, J 6.4 and 2.3, 2 ¥ (CH3)2CH), 1.89 (3 H, d, J
9-[1-(5-Diisopropoxyphosphono-5,5-difluoro-pentyl)-1,2,3-
triazolo-4-methyl]-2-amino-6-chloropurine (16)
=
1.2, CH3C C), 1.99 (3 H, s, CH3CO), 4.49 (2 H, s, CH2NCO), 4.85
(0.33 g, 75%) white solid, mp 105-106 ◦C; nmax(ATR)/cm-1 3470,
3357, 2940, 2852, 1619, 1479, 1270 and 1004; dH(400 MHz, CDCl3)
1.29 (12 H, dd, J 6.5 and 3.2, 2 ¥ (CH3)2CH), 1.45-1.64 (2 H, m,
CH2CH2CH2), 1.83-2.10 (4 H, m, CH2CF2 and CH2CH2N), 4.28
(2 H, t, J 7.0, CH2CH2N), 4.76 (2 H, dsp, J 6.1, 2 ¥ CH(CH3)2),
(2 H, dsp, J 6.4, 2 ¥ CH(CH3)2), 5.74-5.90 (1 H, m, CHCF2), 7.22
(1 H, d, J 1.2, CH=CCH3), 7.53 (1 H, s, CH=CCH2), 7.56 (1 H, s,
CHNHCO) and 9.80 (1 H, s, CONHCO); dP(162 MHz, CDCl3)
2.50 (1 P, dd, J 96.9 and 97.5); dF(376 MHz CDCl3) -116.31 (1
F, ddd, J 8.0, 97.5 and 304.9) and -119.64 (1 F, ddd, J 12.8, 96.9
and 304.9); dC(101 MHz, CDCl3) 12.7 (s, CH3), 23.3 (s, CH3CO),
23.9 (2 ¥ d, J 5.2, (CH3)2CH), 24.4 (2 ¥ d, J 3.3, (CH3)2CH), 36.9
=
5.31 (2 H, s, CH2NC N), 5.59 (2 H, s, NH2), 7.61 (1 H, s,
=
CH=CCH2) and 7.89 (1 H, br s, NCH N); dP(162 MHz, CDCl3)
=
4.96 (1 P, t, J 107.7); dF(376 MHz CDCl3) -112.71 (2 F, td, J
19.6 and 107.7); dC(101 MHz, CDCl3) 18.2 (dt, J 4.8 and 10.2,
CF2CH2CH2), 23.9 (2 ¥ d, J 4.7, (CH3)2CH), 24.2 (2 ¥ d, J
3.5, (CH3)2CH), 29.9 (s, CH2CH2N), 33.2 (dt, J 15.6 and 21.8,
(s, CH2NC O), 66.8 (dt, J 15.3 and 27.9, CF2CH), 75.4 (2 ¥ d,
J 7.1, 2 ¥ (CH3)2CH), 111.8 (s, Car), 118.4 (dt, J 211.7 and 267.2,
CF2), 124.5 (s, Car), 138.6 (s, Car), 140.0 (s, Car), 150.7 (s, Car),
+
=
=
164.2 (s, C O) and 170.7 (s, C O); m/z (ESI) 493.1785 (M + H .
C18H27F2N6O6P requires 493.1776), 451 (100%), 286 (94), 244 (9)
and 208 (7).
=
CF2CH2), 50.2 (s, CH2CH2N), 53.6 (s, CH2NC N), 73.8 (2 ¥ d,
J 7.1, 2 ¥ (CH3)2CH), 128.0 (dt, J 181.9 and 260.0, CF2), 129.7
(s, Car), 142.4 (s, Car), 151.3 (s, Car), 153.3 (s, Car) and 159.6 (s,
Car); m/z (ESI) 521.1906 (M + H+. C19H28ClF2N8O3P requires
521.1896), 479 (65%), 437 (100), 409 (45) and 324 (23).
9-[1-(2-Diisopropoxyphosphono-2,2-difluoro-ethyl)-2-acetamido-
1,2,3-triazolo-4-methyl]-2-amino-6-chloropurine (26)
(0.33 g, 69%), white solid, mp 126-127 ◦C; nmax(ATR)/cm-1 3461,
3336, 2929, 2850, 1615, 1468, 1271 and 1000; dH(400 MHz, CDCl3)
1.29 (12 H, dd, J 6.3 and 2.0, 2 ¥ (CH3)2CH), 2.06 (3 H, s,
1-[1-(2-Diisopropoxyphosphono-2,2-difluoro-ethyl)-1,2,3-triazolo-
4-methyl]-thymine (23)
(0.34 g, 71%) white solid, mp 138-139 ◦C; nmax(ATR)/cm-1 3199,
3066, 2988, 2939, 1691, 1676, 1466, 1380, 1310, 1244, 1218, 1180,
1138, 1097, 1060, 1045 and 996; dH(250 MHz, CDCl3) 1.31 (12
H, dd, J 6.1 and 3.3, 2 ¥ (CH3)2CH), 1.83 (3 H, d, J 1.1, CH3),
4.87 (2 H, dsp, J 6.1, 2 ¥ CH(CH3)2), 4.94 (2 H, dt, J 2.9 and 15.8,
CH3C C), 4.76 (2 H, dsp, J 6.3, 2 ¥ CH(CH3)2), 5.37 (2 H, s,
=
=
CH2NC N), 5.46 (2 H, s, NH2), 6.83-7.01 (1 H, m, CHCF2),
=
7.98 (2 H, s, CH=CCH2 and NCH N) and 8.16 (1 H, s, NH);
dP(162 MHz, CDCl3) 1.16 (1 P, dd, J 97.7 and 93.9); dF(376 MHz
CDCl3) -116.14 (1 F, ddd, J 8.3, 93.9 and 306.1) and -120.63
(1 F, ddd, J 14.7, 97.7 and 306.1); dC(101 MHz, CDCl3) 23.1
(s, CH3CO), 23.8 (2 ¥ d, J 5.2, (CH3)2CH), 24.1 (2 ¥ d, J 3.7,
=
CH2CF2), 4.99 (2 H, s, CH2NCO), 7.32 (1 H, d, J 1.1, CH CCH3),
=
7.91 (1 H, s, CH CCH2) and 10.05 (1 H, br s, NH); dP(101 MHz,
=
CDCl3) 0.00 (1 P, t, J 98.0); dF(235 MHz CDCl3) -117.28 (2
(CH3)2CH), 38.6 (s, CH2NC N), 65.1 (dt, J 18.7 and 28.0,
4488 | Org. Biomol. Chem., 2009, 7, 4481–4490
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CF2CH), 75.8 (2 ¥ d, J 7.2, 2 ¥ (CH3)2CH), 115.3 (dt, J 211.0
and 270.5, CF2), 124.3 (s, Car), 125.2 (s, Car), 142.0 (s, Car), 142.5
(s, Car), 151.6 (s, Car), 153.8 (s, Car), 159.6 (s, Car) and 170.3 (s,
Car); m/z (ESI) 536.1497 (M + H+. C18H25ClF2N9O4P requires
536.1497), 477 (3%), 286 (1) and 251 (100).
ture for 72 h. The solvents were removed and the residue
was purified by flash column chromatography on silica using
CH2Cl2/CH3OH (97/3) as eluent to give 1-((diisopropyl)-1,1-
difluoropentylphosphonyl)-4-methyl-carbamoyl-1,2,3-triazole 29
(128 mg, 85%) as a white solid, mp 111-112 ◦C; nmax(ATR)/cm-1
3342, 3118, 2983, 1654, 1583, 1263, 1011 and 984; dH(400 MHz,
CD3OD) 1.35 (6 H, d, J 6.3, (CH3)2CH), 1.37 (6 H, d, J 6.3,
(CH3)2CH), 1.50-1.64 (2 H, m, CH2CH2CH2), 1.96-2.18 (4 H,
m, CF2CH2 and CH2CH2N), 2.93 (3 H, s, NCH3), 4.50 (2 H,
t, J 6.9, CH2CH2N), 4.80 (2 H, dsept, J 6.3, 2 ¥ (CH3)2CH),
Preparation of triazole 27
To a solution of azide 10 (765 mg, 2.45 mmol) in a MeCN/H2O
1/2 mixture (16 cm3) was added methyl propiolate (0.220 cm3,
2.45 mmol) and copper(I) iodide (46.7 mg, 0.245 mmol). The
solution was stirred overnight at room temperature. H2O (2 cm3)
was added and the mixture was extracted with Et2O (3 ¥
10 cm3). Combined organic layers were dried over MgSO4 and
concentrated. The crude product was purified by flash column
chromatography on silica using pentane/ethyl acetate (6/4) as
eluent to yield 1-((diisopropyl)-1,1-difluoropentylphosphonyl)-4-
methoxycarbonyl-1,2,3-triazole 27 (758 mg, 78%) as a white solid,
mp 65-66 ◦C; nmax(ATR)/cm-1 3123, 2979, 1723, 1541, 1267, 1238,
1222, 1175, 1000 and 976; dH(400 MHz, CDCl3) 1.34 (6 H, d, J
6.3, (CH3)2CH), 1.36 (6 H, d, J 6.3, (CH3)2CH), 1.54-1.77 (2 H, m,
CH2CH2CH2), 1.96-2.21 (4 H, m, CH2CF2 and CH2CH2N), 3.89
(3 H, s, OCH3), 4.43 (2 H, t, J 7.1, CH2CH2N), 4.81 (2 H, dsept,
=
8.37 (1 H, s, CH C); dP(202 MHz, CD3OD) 5.40 (1 P, t, J
111.2); dF(470 MHz CD3OD) -114.00 (2 F, td, J 20.0 and 111.1);
dC(101 MHz, CD3OD) 9.1 (dt, J 5.0 and 10.1, CF2CH2CH2), 14.5
(d, J 4.6, (CH3)2CH), 14.8 (d, J 3.8, (CH3)2CH), 16.6 (s, NCH3),
21.2 (s, CH2CH2N), 24.8 (dt, J 14.6 and 21.1, CF2CH2), 41.5 (s,
CH2CH2N), 66.1 (2 ¥ d, J 7.1, 2 ¥ (CH3)2CH), 111.9 (dt, J 219.2
=
and 258.3, CF2), 117.4 (s, Car), 134.5 (s, Car) and 153.5 (s, C O);
m/z (ESI) 398.1836 (M + H+. C15H28F2N4O4P requires 398.1816).
Preparation of triazole 30
Azide 10 (233 mg, 0.744 mmol) in DMF (1 cm3) was added
to a solution of 2-cyanoacetamide (93.7 mg, 1.12 mmol) and
KOH (62.5 mg, 1.12 mmol) in H2O/DMF 1/5 (1.2 cm3). After
24 h of stirring at room temperature, the reaction mixture
was filtered through Celite and the filtrate was evaporated
to dryness. The residue was taken up in CH3OH (10 cm3)
and neutralized with a Dowex 50 resin, filtered and con-
centrated. The crude product was purified by flash column
chromatography on silica using CH2Cl2/CH3OH (90/10) as
eluent to give 1-((diisopropyl)-1,1-difluoropentylphosphonyl)-4-
carbamoyl-5-amino-1,2,3-triazole 30 (112 mg, 37%) as a white
solid, mp 130-131 ◦C; nmax(ATR)/cm-1 3425, 3193, 3089, 2983,
1651, 1621, 1574, 1466, 1377, 1265, 1180, 1143 and 983;
dH(400 MHz, CD3OD) 1.35 (6 H, d, J 6.3, (CH3)2CH), 1.37 (6
H, d, J 6.3, (CH3)2CH), 1.55-1.65 (2 H, m, CH2CH2CH2), 1.91 (2
H, quint, J 7.0, CF2CH2), 2.00-2.17 (2 H, m, CH2CH2N), 4.20 (2
H, t, J 7.0, CH2CH2N), 4.81 (2 H, dsept, J 6.3, 2 ¥ (CH3)2CH)
and 4.87 (2 H, s, NH2); dP(202 MHz, CD3OD) 5.50 (1 P, t, J
111.2); dF(470 MHz, CD3OD) -114.00 (2 F, td, J 20.0 and 111.1);
dC(101 MHz, CD3OD) 19.2 (dt, J 5.4 and 10.1, CF2CH2CH2),
24.0 (d, J 4.6, (CH3)2CH), 24.4 (d, J 3.8, (CH3)2CH), 29.2
(s, CH2CH2N), 34.5 (dt, J 14.2 and 21.1, CF2CH2), 46.6 (s,
CH2CH2N), 75.7 (2 ¥ d, J 7.1, 2 ¥ (CH3)2CH), 123.0 (dt, J 219.1
=
J 6.3, 2 ¥ CH(CH3)2) and 8.09 (1 H, s, CH C); dP(202 MHz,
CDCl3) 5.1 (1 P, t, J 108.0); dF(470 MHz, CDCl3) -112.80 (2
F, td, J 20.1 and 108.2); dC(101 MHz, CDCl3) 18.2 (dt, J 4.9
and 10.0, CF2CH2CH2), 23.9 (d, J 4.2, (CH3)2CH), 24.3 (d, J
4.0, (CH3)2CH), 29.9 (s, CH2CH2N), 33.3 (dt, J 14.3 and 21.2,
CF2CH2), 50.5 (s, CH2CH2N), 52.4 (s, CH3O), 73.9 (2 ¥ d, J 7.1,
2 ¥ (CH3)2CH), 120.2 (dt, J 217.2 and 259.1, CF2), 127.7 (s, Car),
+
=
140.2 (s, Car) and 161.3 (s, C O); m/z (ESI) 398.1673 (M + H .
C15H27F2N3O5P requires 398.1656).
Preparation of amide 28
Compound 27 (260 mg, 0.655 mmol) was stirred in a CH3OH/25%
aqueous NH3 solution 1/1 (5 cm3) at room temperature for 72 h.
The solvents were removed and the residue was purified by flash
column chromatography on silica using CH2Cl2/CH3OH (97/3)
as eluent to give 1-((diisopropyl)-1,1-difluoropentylphosphonyl)-
4-carbamoyl-1,2,3-triazole 28 (192 mg, 77%) as a white solid, mp
100-101 ◦C; nmax(ATR)/cm-1 3425, 3194, 3089, 2983, 1651, 1621,
1574, 1466, 1388, 1378, 1268 and 983; dH(400 MHz, CD3OD)
1.35 (6 H, d, J 6.1, (CH3)2CH), 1.36 (6 H, d, J 6.1, (CH3)2CH),
1.42-1.63 (2 H, m, CH2CH2CH2), 1.88-2.20 (4 H, m, CH2CF2
and CH2CH2N), 4.50 (2 H, t, J 7.0, CH2N), 4.72-4.90 (2 H,
=
and 258.2, CF2), 146.4 (2 ¥ s, 2 ¥ Car) and 167.0 (s, C O); m/z
(ESI) 398.1771 (M + H+. C14H27F2N5O4P requires 398.1769).
=
m, 2 ¥ (CH3)2CH) and 8.38 (1 H, s, CH C); dP(202 MHz,
CD3OD) 5.10 (1 P, t, J 111.2); dF(470 MHz, CD3OD) -113.70
(2 F, td, J 20.0 and 111.1); dC(101 MHz, CD3OD) 9.2 (dt, J
5.2 and 9.8, CF2CH2CH2), 14.5 (d, J 4.7, (CH3)2CH), 14.8 (d,
J 3.6, (CH3)2CH), 21.2 (s, CH2CH2N), 24.8 (dt, J 14.5 and 21.2,
CF2CH2), 41.6 (s, CH2CH2N), 66.2 (2 ¥ d, J 7.1, 2 ¥ (CH3)2CH),
Acknowledgements
This work has been performed within the Interregional Organic
Chemistry Network (CRUNCh network). The “Ministe`re de la
Recherche” and the European ERASMUS program (grant to
A. H. from Chemnitz University, Germany) are gratefully thanked
for their financial support.
112.5 (dt, J 220.1 and 258.3, CF2), 118.0 (s, Car), 134.3 (s, Car) and
+
=
155.2 (s, C O); m/z (ESI) 383.1658 (M + H . C14H26F2N4O4P
requires 383.1660).
References
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Compound 27 (151 mg, 0.380 mmol) was stirred in a CH3OH/40%
aqueous MeNH2 solution 1/1 (3 cm3) at room tempera-
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4490 | Org. Biomol. Chem., 2009, 7, 4481–4490
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