Propargyl-substituted phosphonocarboxylates: Efficient synthesis and application to click chemistry

Article abstract of DOI:10.1055/s-0029-1216982

An efficient pathway for the selective preparation of monopropargyl- substituted phosphonocarboxylate (PC) has been developed via the addition of sodium, acetylenide to ethylidenephosphonate. The reaction works perfectly on multi-gram scales. The synthesi

Full text of DOI:10.1055/s-0029-1216982

PAPER
3579
Propargyl-Substituted Phosphonocarboxylates: Efficient Synthesis and
Application to Click Chemistry
C
lick Chemistry o
l
f
P
ropa
e
rgyl-Substi
g
tuted
P
hosphonoca
I
rboxylate
s
Artyushin,a Sergey N. Osipov,a Gerd-Volker Röschenthaler,b Irina L. Odinets*a
a
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilova str., 119991 Moscow, Russian Federation
Fax +7(499)1355085; E-mail: odinets@ineos.ac.ru
Institute of Inorganic & Physical Chemistry, University of Bremen, Leobener Str., 28334 Bremen, Germany
b
Received 6 March 2009; revised 22 June 2009
Furthermore, it has been found that replacement of one
phosphonate group of N-BPs with a carboxylate moiety
created a new class of pharmacological agents, namely the
phosphonocarboxylates (PCs), that can specifically
Abstract: An efficient pathway for the selective preparation of
monopropargyl-substituted phosphonocarboxylate (PC) has been
developed via the addition of sodium acetylenide to ethylidene-
phosphonate. The reaction works perfectly on multi-gram scales.
The synthesis of the corresponding methyl(propargyl)-, trifluoro- inhibit bone resorption both in vitro and in vivo without
cytotoxic effect on osteoclasts.4b
methyl(propargyl)-, and dipropargyl-substituted derivatives was
elaborated based on direct alkylation of either the correspondingly
substituted phosphonocarboxylates or methylene phosphonocar-
boxylate with excess of propargyl bromide. A series of novel poten-
tially biologically active 1,2,3-triazole-containing phosphono-
carboxylates were synthesized using copper(I)-catalysed 1,3-dipo-
lar cycloaddition of organic azides with propargyl-substituted
phosphonocarboxylates.
O
P
O
P
O
P
OH
OH
OH
H2N
Me
HO
OH
OH
OH
OH
OH
OH
N
P
P
HO
P
HO
N
OH
OH
O
OH
O
O
zoledronate
pamidronate
etidronate
Key words: phosphonocarboxylates, ethylidenephosphonate, alky-
lation, sodium acetylenide, 1,3-dipolar cycloaddition, azides, phos-
phorylated 1,2,3-triazoles
O
O
P
O
OH
OH
OH
P
P
H2N
Cl
Cl
OH
OH
OH
OH
OH
OH
P
P
P
HO
HO
OH
O
clodronate
OH
OH
N
O
O
aledronate
residronate
Bisphosphonates (BPs), being analogues of naturally oc-
curring diphosphates, are the most widely used and effec-
tive antiresorptive agents currently available for the
treatment of malignant hypercalcemia, tumor-associated
Figure 1 Structures of some bisphosphonates used in clinical stu-
dies and medical practice
bone disease, osteoporosis, and Paget’s disease.1,2 BPs are Phosphonic (phosphinic) acids and phosphoamidates
of interest in the context of cancer and immunotherapy, modulating the transition-state analogues or mimics of
and they are also effective against parasites responsible carboxylic acids might act as inhibitors of hydrolytic en-
for sleeping sickness, Chagas’ disease, malaria, leishma- zymes, such as esterases and amidases. Therefore, such
niases, and T. brucei infection.3
compounds may possess antitumor properties [see, for ex-
ample, a review7 concerning the application and creation
of new phosphorus-based chemotherapeutic drugs, in-
cluding the phosphorylacetic acid derivatives, such as
PALA8 (N-phosphonoacetyl-L-aspartic acid)].
All BPs have high affinity for bone mineral as a conse-
quence of their P–C–P backbone structure, which allows
chelation of calcium ions. After successful clinical use of
clodronate and etidronate (Figure 1), bisphosphonates
containing a basic primary amino-nitrogen atom in a side The key features required for high inhibitory potency of
alkyl chain (as in pamidronate and aledronate), were the N-BP and N-PC drug families include the structural
found to be 10- to 100-fold more potent. Moreover, the motif of two geminal phosphonate groups (or a combina-
third generation of BP drugs, containing a nitrogen atom tion of phosphonate and carboxylate moieties respective-
within a heterocyclic ring4 (as in risedronate and zole- ly), which are responsible for interaction with the
dronate), are up to 10,000-fold more potent than etidro- molecular target. For maximal potency, the nitrogen atom
nate in some experimental systems.1 These cyclic nitrogen in the side chain must be a critical distance away from the
bisphosphonates (N-BPs) directly and selectively inhibit P–C–P (or P–C–C) chelating group and in a specific spa-
the activity of osteoclasts – the cells responsible for bone tial configuration. At the same time, the geminal hydroxy
resorption. The detailed inhibitory mechanism of N-BPs group does not influence the ability of these drugs to act
is well documented in the literature.5,6
at the cellular level. Therefore, the purposeful synthesis of
new members of both N-BP and N-PC families, taking
into consideration the dependencies mentioned above, is
of current interest for further development of more potent
drugs.
SYNTHESIS 2009, No. 21, pp 3579–3588
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Advanced online publication: 28.08.2009
DOI: 10.1055/s-0029-1216982; Art ID: T05309SS
© Georg Thieme Verlag Stuttgart · New York

3580
O. I Artyushin et al.
PAPER
Recently,9 we elaborated an efficient, general synthetic stituted phosphonates 2a and 3 using column chromatog-
approach giving the possibility for facile, rapid and cheap raphy is not effective due to the similar Rf values of these
access to a wide range of novel N-BPs as potent drug can- compounds. Therefore, here we want to disclose an effi-
didates based on ‘click’ methodology, namely copper- cient synthetic method for the selective preparation of
catalysed azide–alkyne cycloaddition. The reaction pro- mono-propargyl phosphonate 2a based on the addition of
ceeds regioselectively to give the corresponding 4-regio- sodium acetylenide to readily available ethylidenephos-
isomers exclusively and the capacity of bidentate phonate 4 (Scheme 1).16
phosphorus substrates to form metal-complexes does not
Thus, we have found that the reaction proceeds in anhy-
influence the selectivity of the process in the presence of
drous tetrahydrofuran under mild conditions for several
the copper(I) salts. The method allows the incorporation
hours to afford the desired monopropargyl product 2a in
high yield. Furthermore, the process can also be realized
of two functionalities into the N-BP molecule simulta-
neously, as well as the ability to ligate two N-BPs to each
on multigram scales with excellent results.
another in situ via the one-pot reaction of organic dibro-
In the case of substituted phosphonates 1b and 1c, the cor-
responding monopropargyl derivatives 2b and 2c, respec-
tively, were readily obtained via the ordinary procedure
mides with propargyl-substituted bisphosphonates, gener-
ating both the diazide and copper(I) moiety.
In a continuation of our investigations into biologically
under deprotonation with sodium hydride followed by
active organophosphorus compounds, in this paper we re-
alkylation without any difficulties (Scheme 1).
port the possibility of using an approach based on ‘click’
The alkylation of non-substituted phosphonate 1a by an
methodology for the effective synthesis of a wide range of
excess of propargyl bromide (3.5 equiv) under deprotona-
novel 1,2,3-triazole-modified phosphonocarboxylates (N-
tion with sodium hydride in THF has proven to be a facile
PCs) as potent drug candidates. It should be mentioned
that, despite the great popularity of copper-catalysed
route to disubstituted phosphonate 3a.17 Thus, having the
mono- and dipropargyl-substituted phosphonocarboxy-
lates 2 and 3 in hand, we investigated the possibility of
their utilization in [3+2]-cycloaddition with a variety of
functionalized organic azides under copper(I) catalysis.18
To this end, we used the typical procedure previously de-
scribed by us for regioselective synthesis of the triazole-
substituted N-BPs: alkyne–azide coupling was performed
in water–alcohol media (t-BuOH–H2O) and the copper(I)
catalyst was generated in situ from copper sulfate and so-
dium ascorbate (Scheme 2).
azide–alkyne 1,3-dipolar cycloaddition,10 examples of its
application for the synthesis of triazole-substituted phos-
phonates are limited to a few reports on the cycloaddition
of azidoalkylphosphonates to a variety of alkynes,11 the
creation of a single noncompetitive a-2,3-sialyltrasferase
inhibitor on a steroid base bearing phosphonate moiety,12
and the paper mentioned above on bisphosphonate com-
pounds.9
In order to construct the desired library of triazole-modi-
fied N-PCs, propargyl-substituted phosphonocarboxy-
lates represented suitable starting substrates. According to
our data and similar to those reported in the literature,13
the synthesis of propargyl-substituted phosphonate 2a
based on alkylation of phosphoryl acetic acid ester 1a14 by
propargyl bromide under phase-transfer catalysis condi-
tions or using classical procedures such as potassium in
xylene or deprotonation with sodium hydride (in contrast
to a report15 of a 71% yield of 2a) is accompanied by sub-
stantial amounts of double alkylation (up to 29% of 3).
Moreover, the separation of mono- and dipropargyl sub-
1,3-Dipolar Huisgen cycloaddition of propargyl-contain-
ing phosphonocarboxylates 2a–c with a range of available
azides was found to proceed smoothly at room tempera-
ture (6–8 h) to afford functionalized 1,2,3-triazoles 5a–d,
6a–g and 7a–d in excellent yields (mostly more than
90%) and of high purity after a simple work-up procedure.
Highly functional azides having biologically active resi-
dues such as glucose, adamantyl or azidothimidine, and
phosphorylated azides, which have recently been effi-
ciently synthesized in ionic liquids by us,11 are also good
O
P
O
O
P
O
EtO
EtO
EtO
EtO
+
R = H
OEt
OEt
O
P
O
EtO
EtO
2a
1. NaH, THF
3
OEt
inseparable mixture
2.
Br
R
1a-c
O
P
O
R = Me, CF3
EtO
EtO
CH2O
R = H
65–66%
OEt
R
O
P
O
O
P
O
2b,c
EtO
EtO
EtO
EtO
Na
74%
OEt
OEt
THF, –20 °C
R = H (1a, 2a), F (1b, 2b), Me (1c, 2c)
2a
4
Scheme 1
Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York

PAPER
Click Chemistry of Propargyl-Substituted Phosphonocarboxylates
3581
O
O
P
O
C
OEt
R2N3
EtO
EtO
P
C
O
OEt
OEt
sodium ascorbate (10 mol%)
CuSO4⋅5H2O (20 mol%)
t-BuOH–H2O (4:1)
R1
N
R1
N
OEt
R2
N
5a–d, 6a–g, 7a–d
2a–c
R1 = H: R2 = (EtO)2(O)P(CH2)4 (5a), Ad (5b), GluAc (5c), Azt (5d)
R
1 = F: R2 = 4-FC6H4CH2 (6a), t-BuOC(O)CH2 (6b), t-BuC(O)OCH2 (6c)
(EtO)2(O)P(CH2)3 (6d), Ad (6e), GluAc (6f), Azt (6g)
R
1 = Me: R2 = Bn (7a), t-BuOC(O)CH2 (7b), (EtO)2(O)P(CH2)3 (7c), GluAc (7d)
O
Me
OAc
N
O
O
Azt =
GluAc =
AcO
;
Ad =
;
N
O
OH
OAc
AcO
Scheme 2
partners for propargyl phosphonates 2a–c in these copper- NMR and IR spectroscopy along with HRMS and elemen-
catalysed reactions.
tal analysis data. In this context it should be mentioned
that, according to the NMR data, triazoles 5c, 6f and 7d,
bearing the glucose residue, are formed as diastereomeric
mixtures in 1:1 ratios. Therefore, these compounds exhi-
bit two singlet signals in the 31P spectra, which are further
split into two doublets in the case of fluorine substituted
derivative 6f and the corresponding doubling of signals in
the H, C, and F spectra. Unfortunately, we were un-
able to separate these diastereomers by column chroma-
tography. The corresponding NMR data did not provide
any information concerning the formation of diastereo-
mers in the case of triazoles 5g and 6g, bearing the Azt-
residue.
In a similar manner, copper-catalysed 1,3-dipolar cy-
cloaddition of bispropargyl-substituted phosphonate 3
with azides has been accomplished to afford the corre-
sponding bistriazols 8a and 8b in reasonable yields (52–
62%; Scheme 3).
1
13
19
O
P
O
C
EtO
EtO
O
P
O
C
R2N3
EtO
EtO
OEt
N
OEt
sodium ascorbate (10 mol%)
CuSO4⋅5H2O (20 mol%)
t-BuOH–H2O (4:1)
N
N
N
R1
R1
N
N
3
8a,b
R1 = Bn (8a), CH2C(O)Ot-Bu (8b)
Compounds 5a, 6d and 7c formed from phosphorylated
azides display two signals in the 31P NMR spectra wherein
the singlet at ~30 ppm was assigned to the phosphorus nu-
cleus of the side chain, while the upfield-shifted signal
which occurred as either a singlet or a doublet depending
on the substituent, corresponds to the phosphorus of the
phosphonocarboxylate group.
Scheme 3
Conversely, bistriazoles bearing two phosphonocarboxy-
late moieties could be easily synthesized starting from
diazides and phosphonocarboxylates 2a–c (Scheme 4).
Furthermore, in contrast to bistriazoles 8a and 8b, this re-
action afforded compounds 9a–c in almost quantitative
yields (>94%).
Triazoles of N-PC type can be converted into the corre-
sponding free phosphonic acids via reaction with trimeth-
ylbromosilane in chloroform followed by the treatment of
the intermediate trimethylsilyl esters with aqueous meth-
anol. Subsequent treatment of the phosphonic acids ob-
tained with sodium hydroxide in ethanol resulted in the
free carboxylic acids. The possibility of such total hydro-
Despite their rather high molecular weight, all of the com-
pounds in this series were obtained as colourless or yel-
lowish oils and only azidotymydine derivative 6g
solidified over time. The structures of the phosphorylated
triazoles were unambiguously confirmed by multinuclear
O
P
O
N
EtO
EtO
N3
N
N3
N
OEt
N
N
R
R
P
N
EtO
EtO
R
C
O
OEt
EtO
EtO
P
OEt
O
O
2a–c
9a–c
O
R = H (a, para-isomer), F (b, para-isomer), Me (c, meta-isomer)
Scheme 4 Reaction conditions: sodium ascorbate (10 mol%), CuSO4·5H2O (20 mol%), t-BuOH–H2O (4:1).
Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York

3582
O. I Artyushin et al.
PAPER
O
P
O
P
OEt
OEt
O
P
OH
OH
OH
OH
1. Me3SiBr
10% NaOH/EtOH
R1
R1
2. aq MeOH
C
OH
C
OEt
N
N
R1
N
C
OEt
N
N
N
R2
R2
R2
N
N
N
O
O
O
5b,9c
11a,b
10a,b
R1 = H (5b), Me (9c)
R2 = Ad (5b, 10a, 11a)
Me
N
1,3-C6H4-CH2 (9c, 10b, 11b),
R2 =
X
N N
Y
X = (EtO)2P(O) (9c), (HO)2(O)P (10b, 11b); Y = COOEt (9c, 10b), COOH (11b)
Scheme 5
oration of the solvent under reduced pressure the product was puri-
fied by column chromatography (hexane–acetone, 10:1) to give the
title compound.
lysis of all ester groups is illustrated using compounds 5b
and 9c as representative examples (Scheme 5).
In conclusion, the efficient pathway developed here for
selective preparation of mono-propargyl substituted
phosphonocarboxylates opens a route to the synthesis of a
variety of potentially biologically active phosphonocar-
boxylates modified by either one or two 1,2,3-triazole
rings. The approach gives the possibility for facile, rapid
and cheap creation of a library of novel N-PCs as potent
drug candidates via the ‘click’ methodology. Biological
tests of the compounds obtained as well as the corre-
sponding free phosphonic acids are under current investi-
gation and will be published elsewhere.
Yield: 4.14 g (74%); colourless oil.
1H NMR (200 MHz, CDCl3): d = 1.31, 1.34 and 1.35 (3 × t,
4
3JHH = 6.5 Hz, 9 H, CH3), 2.02 (br t, JHH = 2.0 Hz, 1 H, C≡CH),
2.62–2.97 (m, 2 H, CH and CH2C≡), 3.16 (part of ABX system,
2JHH = 10.5 Hz, 3JPH = 22.2 Hz, 4JHH = 3.9 Hz, 1 H, CH2C≡), 4.05–
4.23 (m, 4 H, POCH2), 4.23 (q, 2 H, COCH2).
13C NMR (50 MHz, CDCl3): d = 14.59 (CH3), 16.80 [d,3JPC = 5.6
2
Hz, P(O)OCH2CH3], 17.60 (d, JPC = 2.5 Hz, PCCH2), 45.64 (d,
2
1JPC = 130.3 Hz, PCH), 62.23 (OCH2), 63.37 (d, JPC = 7.0 Hz,
POCH2), 63.58 (d, 2JPC = 6.5 Hz, POCH2), 70.51 (≡CH), 81.00 (d,
3JPC = 20.6 Hz, C≡CH), 168.25 (d, 2JPC = 5.0 Hz, C=O).
31P NMR (81 MHz, CDCl3): d = 21.36.
Solvents were freshly distilled from respective drying agents before
use. All other reagents were recrystallized or distilled when neces-
sary. Analytical TLCs were performed with Merck silica gel 60 F254
plates. Visualization was accomplished by UV light or spraying by
Ce(SO4)2 solution in H2SO4. Flash chromatography was carried out
using Merck silica gel 60 (230–400 mesh ASTM). Melting points
were determined with an Electrothermal IA9100 Digital Melting
Point Apparatus and are uncorrected. NMR spectra were obtained
on a Bruker DPX-200 spectrometer (1H, 200.13 MHz; 31P, 80.99
MHz; 19F, 188.31 MHz; 13C, 50.32 MHz) and Bruker Avance-300
spectrometer (1H, 300.13 MHz; 31P, 121.49 MHz; 13C, 75.47 MHz)
using residual proton signals of deuterated solvent as an internal
standard (1H, 13C) relative to TMS and H3PO4 (31P) and CFCl3 (19F)
as external standards. HRMS were obtained on a Varian MAT
CH7A instrument using an EI source operating at 70 eV. IR spectra
were recorded in a thin layer or in KBr on a Fourier-spectrometer
Magna-IR750 (Nicolet), resolution 2 cm–1, 128 scans. The purities
of the crude products were estimated by the 1H and 31P NMR spec-
tra.
HRMS: m/z [M+] calcd for C11H19O5P: 262.09701; found:
262.09800.
Propargyl-Substituted Phosphonates 2b and 2c; General Proce-
dure
A solution of the corresponding phosphonate 1b,c (0.1 mol) in THF
(100 mL) was added dropwise to a slurry of NaH (60% in mineral
oil, 4.8 g, 0.12 mol) in THF (100 mL) at 0 °C (ice–water bath). The
mixture was allowed to warm to r.t., stirred for 30 min at ambient
conditions and chilled again to 0 °C. Propargyl bromide (17.9 g,
0.15 mol) was added to this mixture under stirring and after warm-
ing to r.t. the mixture was stirred for another 4 h at 20 °C and left
overnight under ambient conditions. After removing the THF under
reduced pressure, H2O (100 mL) was added to the residue and the
mixture was extracted with Et2O (3 × 100 mL). The combined or-
ganic layers were dried over Na2SO4, the filtrate was evaporated,
and the residue was distilled under reduced pressure to give the de-
sired compound.
Ethyl 2-(Diethoxyphosphoryl)-2-fluoropent-4-ynoate (2b)
Yield: 66%; yellowish liquid; bp 115–116 °C (1 Torr).
The starting a-fluoro-triethylphosphonoacetate (1b),19 triethyl-a-
phosphonopropionate(1c),20
ethyl-2-diethylphosphonoacrylate
2
(4)15 and diethoxyphosphoryl substituted azides18 were obtained ac-
cording to known procedures. Other reactants were purchased from
Aldrich and used without further purification.
19F NMR (188 MHz, CDCl3): d = –179.15 (ddd, JPF = 81.1 Hz,
3JFH = 12.5 Hz, 3JFH = 34.0 Hz).
1H NMR (200 MHz, CDCl3): d = 1.30–1.40 (3 overlapping t, 9 H,
4
CH3), 2.08 (br t, JHH = 1.4 Hz, 1 H, C≡CH), 2.90–3.32 (m, 2 H,
Ethyl 2-(Diethoxyphosphoryl)pent-4-ynoate (2a)
CH2C≡), 4.23 (m, 3JHH = 6.0 Hz, 4 H, POCH2), 4.34 (q, 3JHH = 6.0
To a solution of ethylidenephosphonate 4 (5 g, 21.2 mmol) in anhy-
drous THF (50 mL) a slurry of fresh sodium acetylenide in xylene
(21.2 mmol, 5.65 g of 18% w/w solution) was added dropwise at
–15 °C. The reaction mixture was allowed to warm to r.t. and stirred
overnight. THF was removed under reduced pressure and Et2O (50
mL) and 1 N HCl (50 mL) were added. The organic layer was sep-
arated and the aqueous phase was extracted into Et2O (2 × 50 mL).
The combined organic extracts were dried over Na2SO4. After evap-
Hz, 2 H, COCH2).
13C NMR (50 MHz, CDCl3): d = 14.40 (CH3), 16.67 [d, 3JPC = 5.6
2
2
Hz, P(O)OCH2CH3], 25.15 (dd, JCF = 21.1 Hz, JPC = 3.8 Hz,
2
CH2C≡C), 63.05 (OCH2), 64.86 (d, JPC = 7.0 Hz, POCH2), 65.08
(d, 2JPC = 6.8 Hz, POCH2), 72.65 (≡CH), 76.07 (dd, 3JCF = 17.7 Hz,
3JPC = 3.0 Hz, C≡), 93.80 (dd, JCF = 202.3 Hz, JPC = 162.0 Hz,
1
1
PCF), 166.25 (dd, 2JCF = 23.0 Hz, 2JPC = 3.9 Hz, C=O).
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Click Chemistry of Propargyl-Substituted Phosphonocarboxylates
3583
2
1
31P NMR (81 MHz, CDCl3): d = 12.45 (d, 2JPF = 81.1 Hz).
HRMS: m/z [M+] calcd for C11H18FO5P: 280.08759; found:
23.48 (d, JPC = 3.5 Hz, CH2C=C), 25.03 (d, JPC = 141.9 Hz,
3
1
PCH2), 30.93 (d, JPC = 15.3 Hz, PCCCH2), 45.45 (d, JPC = 129.3
Hz, PCH), 49.68 (CH2N), 61.64 (COCH2), 61.71 (d, 2JPC = 7.0 Hz,
POCH2), 62.98 (d, 2JPC = 4.5 Hz, POCH2), 63.10 (d, 2JPC = 4.0 Hz,
POCH2), 121.99 (=CH), 144.66 (d, 3JPC = 17.1 Hz, C=CH), 168.59
(d, 2JPC = 5.0 Hz, C=O).
280.08830.
Ethyl 2-(Diethoxyphosphoryl)-2-methylpent-4-ynoate (2c)
Yield: 65%; colourless liquid; bp 109–110 °C (1 Torr).
31P NMR (81 MHz, CDCl3): d = 22.60 (s, 1 P, PCH), 32.15 (s, 1 P,
3
1H NMR (200 MHz, CDCl3): d = 1.30 (t, JHH = 6.4 Hz, 3 H,
PCH2).
3
COCH2CH3), 1.33 (t, JHH = 6.8 Hz, 6 H, POCH2CH3), 1.58 (d,
4
3JPH = 16.0 Hz, 3 H, CH3CP), 2.02 (t, JHH = 2.0 Hz, 1 H, C≡CH),
Anal. Calcd for C19H37N3O8P2: C, 45.87; H, 7.50; N, 8.45; P, 12.45.
Found: C, 45.97; H, 7.54; N, 8.31; P, 12.18.
2.55 (HA), and 3.09 (HB) (ABX-system, 2JHH = 18.0 Hz, 3JPH = 8.0
Hz, 4JHH = 2.0 Hz, 2 H, CH2C=), 4.05–4.35 (m, 6 H, OCH2).
Ethyl 3-[1-(1-Adamantyl)-1H-1,2,3-triazol-4-yl]-2-(diethoxy-
13C NMR (50 MHz, CDCl3): d = 14.37 (CH3), 16.72 (d,3JPC = 4.5
phosphoryl)propanoate (5b)
2
Hz, POCH2CH3), 17.57 (d, JPC = 4.5 Hz, CH3CP), 24.85
1
Yield: 95% (crude, 98% purity according to the 31P and H NMR
(CH2C≡C), 47.88 (d, 1JPC = 133.3 Hz, PC), 62.02 (COCH2), 63.22
(d, 2JPC = 7.0 Hz, POCH2), 63.75 (d, 2JPC = 8.6 Hz, POCH2), 71.62
data); yellowish oil.
3
2
(≡CH), 79.42 (d, JPC = 9.6 Hz, C≡), 170.40 (d, JPC = 3.5 Hz,
IR (thin layer): 1735 (C=O), 1550 (C=C), 1452 (triazole), 1249
(P=O), 1024, 1052 (POC, COC), 971 (triazole) cm–1.
C=O).
31P NMR (81 MHz, CDCl3): d = 25.78.
HRMS: m/z [M+] calcd for C12H21O5P: 276.11266; found:
1H NMR (200 MHz, CDCl3): d = 1.21 (t, 3JHH = 7.0 Hz, 3 H, CH3),
1.31 (t, 3JHH = 7.0 Hz, 6 H, CH3CH2OP), 1.78 (s, 6 H, Adm), 2.20
(s, 9 H, Adm), 3.15–3.60 (m, 3 H, CH and CH2C=C), 4.05–4.15 (m,
6 H, OCH2), 7.41 (s, 1 H, =CH).
276.11353.
Ethyl 2-(Diethoxyphosphoryl)-2-(2-propynyl)pent-4-ynoate (3)
Obtained according to the procedure described for the synthesis of
2b,c except using NaH (2.2 equiv) and propargyl bromide (4.5
equiv).
13C NMR (50 MHz, CDCl3): d = 14.52 (CH3), 16.79 (d, 3JPC = 6.0
Hz, CH3CH2OP), 23.64 (CH2C=C), 29.83, 36.31, 43.38 (Adm),
1
45.82 (d, JPC = 129.3 Hz, PCH), 59.72 (NCipso), 61.87 (OCH2),
63.20 (d, 2JPC = 6.0 Hz, POCH2), 63.31 (d, 2JPC = 5.0 Hz, POCH2),
3
118.50 (=CH), 143.92 (d, JPC = 18.1 Hz, C=CH), 169.09 (d,
Yield: 83%; bp 133–135 °C (1 Torr).
2JPC = 4.5 Hz, C=O).
3
1H NMR (200 MHz, CDCl3): d = 1.30 (t, JHH = 7.2 Hz, 3 H,
31P NMR (81 MHz, CDCl3): d = 22.76.
3
COCH2CH3), 1.33 (t, JHH = 7.0 Hz, 6 H, POCH2CH3), 2.06 (t,
4
4JHH = 2.6 Hz, 2 H, C≡CH), 2.98 (d, JHH = 2.6 Hz, 2 H, CH2C=),
Anal. Calcd for C21H34N3O5P: C, 57.39; H, 7.80; N, 9.56; P, 7.05.
Found: C, 57.24; H, 7.94; N, 9.37; P, 7.04.
3.03–3.07 (m, 2 H, CH2C=), 4.10–4.30 (m, 6 H, OCH2).
13C NMR (50 MHz, CDCl3): d = 14.23 (CH3), 16.61 (d, 3JPC = 5.8
Ethyl 2-(Diethoxyphosphoryl)-3-[1-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)-1H-1,2,3-triazol-4-yl]propanoate (5c)
Hz, POCH2CH3), 21.91 (CH2C≡C), 50.93 (d, 1JPC = 133.6 Hz, PC),
2
62.29 (COCH2), 63.55 (d, JPC = 7.0 Hz, POCH2), 71.75 (≡CH),
1
Yield: 95% (crude, 97% purity according to the 31P and H NMR
79.25 (d, 3JPC = 12.3 Hz, C≡), 168.94 (d, 2JPC = 4.5 Hz, C=O).
31P NMR (81 MHz, CDCl3): d = 22.99.
data); colourless oil; mixture of two diastereomers in 1:1 ratio.
IR (KBr): 1759 (C=O), 1558 (C=C), 1458 (triazole), 1231 (P=O),
1040, 1050 (POC, COC), 973 (triazole) cm–1.
1H NMR (200 MHz, CDCl3):
d = 1.12–1.45 [m, 9 H,
CH3CH2OC(O)H and CH3CH2OP], 1.86, 1.88 [2 × s, 1.5 H and 1.5
H, CH3C(O)Glu], 2.04, 2.07, 2.10 [3 × s, 9 H, CH3C(O)Glu], 3.20–
3.60 (m, 3 H, CH2C=C and PCH), 3.95–4.00 (m, 1 H, c-CHO),
4.00–4.05 (m, 1 H, c-CHO), 4.10–4.35 (m, 8 H, OCH2 and
CH2OAc), 5.20–5.25 (m, 1 H, c-CHO), 5.38–5.45 (m, 2 H, c-CHO),
5.75–5.90 (m, 1 H, c-CH), 7.59 and 7.60 (2 × s, 0.5 H and 0.5 H,
C=CH).
Synthesis of Triazoles; General Procedure
The organic azide (2.0 mmol) and acetylene 2 (2.0 mmol) were sus-
pended in H2O–t-BuOH (1:4, 8 mL) and CuSO4·5H2O (5 M, 0.1
mmol, 5 mol%) and sodium ascorbate (0.6 mmol) were added. The
mixture was stirred at r.t. for 6–8 h, at which time TLC (silica, pe-
troleum ether–acetone) indicated complete conversion. The result-
ing solution was concentrated under reduced pressure (rotor
evaporator) and the residue was dissolved in brine (30 mL) and then
extracted with EtOAc (3 × 30 mL). The combined organic layers
were washed with aq NH4OH (5%, 2 × 10 mL), dried over MgSO4,
filtered and the solvent was removed under vacuum to give the
crude product, which was purified by silica gel column chromatog-
raphy if required (hexane–acetone, 10:1→1:10).
13C NMR (50 MHz, CDCl3): d = 14.34 (CH3), 16.70 (d, 3JPC = 5.0
Hz, CH3), 20.39, 20.44, 20.86, 20.99 (4 × s, CH3C=O), 23.63
1
(CH2C=C), 45.44 and 45.75 (2 × d, JPC = 129.5 Hz, PCH), 61.91
(br s, CH2OAc and OCH2), 63.27 (br s, POCH2), 68.07, 70.58,
73.00, 75.22 (4 × s, c-CHO), 85.85 (c-CHGluN), 120.69, 120.52 (2 ×
s, =CH), 145.67 and 145.63 (2 × d, 3JPC = 17.1 Hz, C=CH), 168.51
Ethyl 2-(Diethoxyphosphoryl)-3-{1-[3-(diethoxyphosphor-
yl)butyl]-1H-1,2,3-triazol-4-yl}propanoate (5a)
Yield: 73% (after column chromatography); colorless oil.
2
2
(d, JPC = 7.0 Hz, C=O), 168.63 (d, JPC = 5.5 Hz, C=O), 168.97,
169.12, 169.69, 170,21, 170.77 (5 × s, CH3C=O).
IR (thin layer): 1734 (C=O), 1550 (weak, C=C), 1461 (triazole),
1249 (P=O), 1026, 1050 (POC, COC), 964 (triazole) cm–1.
31P NMR (81 MHz, CDCl3): d = 22.35.
Anal. Calcd for C25H38N3O14P: C, 47.24; H, 6.03; N, 6:61; P, 4.87.
Found: C, 47.17; H, 6.15; N, 6.60; P, 4.73.
1H NMR (200 MHz, CDCl3): d = 1.23 (t, 3JHH = 6.0 Hz, 3 H, CH3),
1.32 and 1.35 (2 × t, 3JHH = 6.0 Hz, 12 H, CH3CH2OP), 1.55–1.75
3
3
(m, 4 H, PCCH2CH2), 2.00 (dt, JHH = 6.0 Hz, JPH = 8.0 Hz, 2 H,
PCH2), 3.15–3.60 (m, 3 H, PCH and CH2C=C), 4.00–4.25 (m, 10 H,
OCH2), 4.32 (t, 3JHH = 6.0 Hz, 2 H, CH2N), 7.36 (s, 1 H, =CH).
Ethyl 3-(1-{3-(Hydroxymethyl)-5-[5-methyl-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl]tetrahydrofuran-2-yl}-1H-1,2,3-triazol-
4-yl)-2-(diethoxyphosphoryl)propanoate (5d)
13C NMR (50 MHz, CDCl3): d = 14.24 (CH3), 16.55 and 16.55 (2 ×
Yield: 95% (after column chromatography); colourless oil.
3
2
d, JPC = 5.0 Hz, CH3CH2OP), 19.78 (d, JPC = 5.0 Hz, PCCH2),
Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York

3584
O. I Artyushin et al.
PAPER
31P NMR (81 MHz, CDCl3): d = 12.84 (d, 2JPF = 82.6 Hz).
IR (KBr): 3399 (OH), 1735 (C=O), 1695 (C=O), 1554 (weak,
C=C), 1473 (triazole), 1273, 1239 (P=O), 1045 and 1023 (POC,
COC), 973 (triazole) cm–1.
2
19F NMR (188 MHz, CDCl3): d = –179.74 (ddd, JPF = 82.7 Hz,
3JFH = 13.2 Hz, 3JFH = 39.5 Hz, C=O).
1H NMR (200 MHz, CDCl3): d = 1.22 (t, 3JHH = 7.0 Hz, 3 H, CH3),
1.34 (t, 3JHH = 7.0 Hz, 6 H, CH3CH2OP), 1.90 (s, 3 H, CH3), 2.80–
3.00 (m, 2 H, CH2CH), 3.20–3.60 (m, 2 H, PCH and CHcycl), 3.65–
4.00 (m, 4 H, c-CH2O and CH2C=C), 3.90–4.05 (m, 2 H, CHcycl),
4.10–4.30 (m, 4 H, POCH2 and COOCH2), 4.30–4.40 (m, 1 H,
CHcycl), 5.40–5.50 (m, 1 H, CHcycl), 6.20–6.35 (m, 1 H, CHcycl), 7.59
(s, 1 H, C=CH), 7.64 (s, 1 H, CHcycl), 8.50 (br s, 1 H, NH).
HRMS: m/z [M+] calcd for C17H29FN3O7P: 437.17272; found:
437.17547.
Ethyl 2-(Diethoxyphosphoryl)-1-{[(2,2-dimethyl-1-oxoprop-
oxy)methyl]-1H-1,2,3-triazol-4-yl}-2-fluoropropanoate (6c)
Yield: 83% (after column chromatography); light-yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.23 (s, 9 H, CH3 in t-Bu), 1.30 (t,
3JHH = 7.3 Hz, 3 H, CH3CH2O), 1.42 and 1.43 (two overlapping t,
3JHH = 7.0 Hz, 6 H, CH3CH2OP), 3.60 (HA) and 3.84 (HB) (ABXY
13C NMR (50 MHz, CDCl3): d = 12.87 (CH3), 14.47 (CH3), 16.77
3
(d, JPC = 6.0 Hz, CH3CH2OP), 23.54 (CH2C=C), 38.34 (c-CH2),
1
45.40 (d, JPC = 129.8 Hz, PCH), 59.66 (CHN), 61.64 (CH2OH),
2
3
3
system, JHH = 15.8 Hz, JPH(A) = 8.0 Hz, JPH(B) = 4.3 Hz,
2
62.15 (OCH2), 63.59 (d, JPC = 7.0 Hz, POCH2), 85.73 (CHN),
3JFH(A) = 11.4 Hz, JFH(B) = 39.0 Hz, 2 H, CH2C=C), 4.37–4.28 (m,
3
87.31 (CHCH2OH), 111.35 (=CCH3), 122.73 (CH=C), 137.72
(=CHN), 145.14 (d, 3JPC = 16.6 Hz, C=CH), 151.13 (C=O), 164.82
(C=O), 168.85 (d, 2JPC = 4.5 Hz, C=O).
31P NMR (81 MHz, CDCl3): d = 22.59.
6 H, OCH2), 6.23 (HA) and 6.26 (HB) (AB system, 2JHH = 10.6 Hz,
2 H, NCH2O), 7.77 (s, 1 H, =CH).
13C NMR (75 MHz, CDCl3): d = 13.68 (CH3), 16.11 (d, 3JPC = 5.5
2
Hz, CH3CH2OP), 28.46 (CH3 in t-Bu), 30.14 (d, JCF = 19.2 Hz,
Anal. Calcd for C21H32N5O9P·2H2O: C, 44.60; H, 6.42; N, 12.38; P,
5.48. Found: C, 44.32; H, 6.58; N, 11.59; P, 5.52.
CH2C=C), 38.43 [C(CH3)3], 62.27 (OCH2), 64.15 (d, 2JPC = 7.1 Hz,
POCH2), 64.38 (d, 2JPC = 7.1 Hz, POCH2), 94.02 (dd, 1JPC = 162.5
1
3
Hz, JCF = 197.3 Hz, PCF), 124.18 (=CH), 140.10 (d, JFC = 15.4
2
2
Ethyl 2-(Diethoxyphosphoryl)-2-fluoro-3-[1-(4-fluorobenzyl)-
1H-1,2,3-triazol-4-yl]propanoate (6a)
Hz, C=CH), 166.85 (dd, JPC = 3.3 Hz, JCF = 23.6 Hz, CF-
C=O),177.25 [C(O)O(t-Bu)].
Yield: 83% (after column chromatography); colourless oil.
31P NMR (121 MHz, CDCl3): d = 11.84 (d, 2JPF = 83.1 Hz).
1H NMR (200 MHz, CDCl3): d = 1.19 (t, 3JHH = 7.2 Hz, 3 H, CH3),
19F NMR (282 MHz, CDCl3): d = –178.63 (ddd, JPF = 83.1 Hz,
2
3
1.36 (br t, JHH = 6.8 Hz, 6 H, CH3), 3.53 (HA) and 3.77 (HB)
3JFH = 11.4 Hz, 3JFH = 39.0 Hz).
(ABXY system, 2JHH = 15.8 Hz, 3JPH(A) = 12.6 Hz, 3JPH(B) = 4.8 Hz,
3
3JFH(A) = 12.2 Hz, JFH(B) = 39.0 Hz, 2 H, CH2C=C), 4.10–4.40 (m,
Anal. Calcd for C17H29FN3O7P: C, 46.68; H, 6.68; N, 9.61; P, 7.08.
Found: C, 46.75; H, 6.74; N, 9.61; P, 7.05.
6 H, OCH2), 5.40 (HA) and 5.52 (HB) (AB system, 2JHH = 21.0 Hz,
2 H, CH2Ar), 7.05 (app t, 3JHH = 4JFH = 8.4 Hz, 2 H, ArH), 7.23 (dd,
3JHH = 8.4 Hz, 4JFH = 9.8 Hz, 2 H, ArH), 7.41 (s, 1 H, CH).
Ethyl 2-(Diethoxyphosphoryl)-3-{1-[3-(diethoxyphosphor-
yl)propyl]-1H-1,2,3-triazol-4-yl}-2-fluoropropanoate (6d)
Yield: 60% (after column chromatography); colourless oil.
13C NMR (50 MHz, CDCl3): d = 14.33 (CH3), 16.80 (d, 3JPC = 5.7
2
Hz, CH3CH2OP), 31.02 (d, JCF = 20.3 Hz, CH2C=C), 63.00
(OCH2), 64.84 (d, 2JPC = 7.0 Hz, POCH2), 65.07 (d, 2JPC = 6.7 Hz,
POCH2), 94.89 (dd, 1JPC = 162.9 Hz, 1JCF = 196.9 Hz, PCF), 116.43
(d, 2JCF = 21.8 Hz, CHCFAr), 130.27 (d, 3JCF = 8.4 Hz, CHCHCFAr),
IR (thin layer): 1760, 1742 (C=O), 1550 (w, C=C), 1463 (triazole),
1260, 1236 (P=O), 1200, 1047 and 1025 (POC, COC), 966 (tria-
zole) cm–1.
4
1H NMR (200 MHz, CDCl3): d = 1.26 (t, 3JHH = 6.5 Hz, 3 H, CH3),
1.33 (t, 3JHH = 6.5 Hz, 6 H, CH3CH2OP), 1.39 (t, 3JHH = 7.0 Hz, 6 H,
CH3CH2OP), 1.60–1.77 (m, 2 H, CH2CH2P), 2.10–2.35 (m, 2 H,
131.03 (d, JCF = 3.1 Hz, Cipso), 123.38 (=CH), 140.72 (d,
1
3JCF = 15.1 Hz, C=CH), 163.18 (d, JCF = 247.8 Hz, CFAr), 166.77
(dd, 2JCF = 23.2 Hz, 2JPC = 3.9 Hz, C=O).
2
31P NMR (81 MHz, CDCl3): d = 12.07 (d, 2JPF = 83.0 Hz).
CH2P), 3.55 (HA) and 3.79 (HB) (ABXY system, JHH = 16.0 Hz,
3
3
3
3JPH(A) = 8.0 Hz, JPH(B) = 4.0 Hz, JFH(A) = 13.2 Hz, JFH(B) = 39.5
Hz, 2 H, CH2C=C), 4.00–4.45 (2 m, 4 H + 6 H, POCH2 + COCH2),
4.43 (t, 3JHH = 6.5 Hz, 2 H, CH2N), 7.53 (s, 1 H, =CH).
2
19F NMR (188 MHz, CDCl3): d = –179.00 (ddd, JPF = 83.0 Hz,
3JFH = 12.2 Hz, 3JFH = 38.9 Hz, 1 F, PCF), –113.38 (m, 1 F, CAr-F).
HRMS: m/z [M+] calcd for C18H24F2N3O5P: 431.14217; found:
431.14112.
13C NMR (50 MHz, CDCl3): d = 14.14 (CH3), 16.57 (d, 3JPC = 6.0
Hz, CH3), 22.44 (d, 1JPC = 142.4 Hz, PCH2), 23.85 (PCCH2), 30.70
2
3
(d, JCF = 20.6 Hz, CH2C=C), 50.02 (d, JPC = 16.1 Hz, CH2N),
61.87 (d, 2JPC = 6.5 Hz, POCH2), 62.65 (OCH2), 64.56 (d, 2JPC = 7.0
Ethyl 3-[1-(2-tert-Butoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl]-2-
(diethoxyphosphoryl)-2-fluoropropanoate (6b)
2
Hz, POCH2), 64.76 (d, JPC = 7.0 Hz, POCH2), 94.62 (dd,
1
Yield: 97% (crude, 99% purity according to the 31P and H NMR
1JPC = 162.5 Hz, JCF = 197.3 Hz), 123.75 (=CH), 139.75 (d,
1
data); light-yellow oil.
3JCF = 15.0 Hz, C=CH), 166.32 (dd, JPC = 4.0 Hz, 2JCF = 23.1 Hz,
2
3
1H NMR (200 MHz, CDCl3): d = 1.26 (t, JHH = 6.4 Hz, 3 H,
C=O).
CH3CH2O), 1.39 (t, 3JHH = 7.0 Hz, 6 H, CH3CH2OP), 1.48 (s, 9 H,
CH3 of t-Bu), 3.59 (HA) and 3.83 (HB) (ABXY system, 2JHH = 16.0
31P NMR (81 MHz, CDCl3): d = 31.03 (s, 1 P, PCH2), 12.77 (d,
2JPF = 82.6 Hz, 1 P, PCF).
3
3
3
Hz, JPH(A) = 8.0 Hz, JPH(B) = 6.0 Hz, JFH(A) = 13.2 Hz,
3JFH(B) = 39.5 Hz, 2 H, CH2C=C), 4.20–4.40 (m, 6 H, OCH2), 4.95
(HA) and 5.07 (HB) (AB system, 2JHH = 26.0 Hz, 2 H, CH2CO), 7.61
(s, 1 H, =CH).
2
19F NMR (188 MHz, CDCl3): d = –180.17 (ddd, JPF = 82.6 Hz,
3JFH = 13.2 Hz, 3JFH = 39.5 Hz).
HRMS: m/z [M+] calcd for C18H34FN3O8P2: 501.18052; found:
501.17839.
13C NMR (50 MHz, CDCl3): d = 14.37 (CH3), 16.82 (d, 3JPC = 5.5
2
Hz, CH3CH2OP), 28.33 (CH3 in t-Bu), 31.02 (d, JCF = 20.6 Hz,
CH2C=C), 51.94 (OC in t-Bu), 63.03 (OCH2), 64.86 (d, 2JPC = 7.0
Ethyl 3-[1-(1-Adamantyl)-1H-1,2,3-triazol-4-yl]-2-(diethoxy-
phosphoryl)-2-fluoropropanoate (6e)
2
Hz, POCH2), 65.07 (d, JPC = 7.0 Hz, POCH2), 84.10 (CH2CO),
Yield: 94% (crude, >98% purity according to the 31P and 1H NMR
data); yellowish oil.
1
94.88 (dd, 1JPC = 163.0 Hz, JCF = 196.8 Hz, PCF), 124.90 (=CH),
3
140.42 (d, JFC = 15.0 Hz, C=CH), 165.56 (C=O), 166.65 (dd,
2JPC = 4.0 Hz, 2JCF = 23.7 Hz, CFC=O).
Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York

PAPER
Click Chemistry of Propargyl-Substituted Phosphonocarboxylates
3585
IR (thin layer): 1761, 1741 (C=O), 1550 (w, C=C), 1453 (triazole),
1265, 1236 (P=O), 1052, 1037, 1021 (POC, COC), 979 (triazole)
cm–1.
CH3), 2.86 (br, 1 H, OH), 2.90–3.00 (m, 2 H, c-CH2), 3.35–3.37 (m,
1 H, CH2C=C), 3.50–3.90 (m, 2 H, CH2OH and CH2C=C), 3.92–
4.20 (m, 1 H, CH2OH), 4.20–4.35 (m, 6 H, POCH2 and COOCH2),
4.35–4.45 (m, 1 H, CHcycl), 5.35–5.45 (m, 1 H, CHcycl), 6.19–6.26
(m, 1 H, CHcycl), 7.44 (s, 1 H, C=CH), 7.64 (s, 1 H, CHcycl), 8.60 (br
s, 1 H, NH).
1H NMR (200 MHz, CDCl3): d = 1.22 (t, 3JHH = 7.0 Hz, 3 H, CH3),
1.38 (t, 3JHH = 7.0 Hz, 6 H, CH3CH2OP), 1.78 (2 × br s, 6 H and 9 H,
2
Adm), 3.55 (HA) and 3.81 (HB) (ABXY system, JHH = 16.0 Hz,
3
3
3
3JPH(A) = 8.0 Hz, JPH(B) = 4.0 Hz, JFH(A) = 11.6 Hz, JFH(B) = 39.5
13C NMR (50 MHz, CDCl3): d = 12.87 (CH3), 14.43 (CH3CH2OC),
3
2
Hz, 2 H, CH2C=C), 4.15–4.40 (m, 6 H, OCH2), 7.52 (s, 1 H, =CH).
16.84 (d, JPC = 6.0 Hz, CH3CH2OP), 30.86 (d, JCF = 20.1 Hz,
CH2C=C), 38.2 (c-CH2), 59.79 (CHN), 61.72 (CH2OH), 63.21
(OCH2), 65.07 (d, 2JPC = 7.0 Hz, POCH2), 65.33 (d, 2JPC = 7.0 Hz,
POCH2), 85.73 (CHN), 87.68 (CHCH2OH), 94.78 (dd, 1JPC = 163.0
13C NMR (50 MHz, CDCl3): d = 14.40 (CH3), 16.82 (d, 3JPC = 6.0
Hz, CH3CH2OP), 29.81, 36.28, 43.32 (Adm), 31.20 (d, 2JCF = 20.1
2
Hz, CH2C=C), 59.88 (NCipso), 62.90 (OCH2), 64.78 (d, JPC = 7.0
1
Hz, JCF = 196.7 Hz, PCF), 111.44 (=CCH3), 123.95 (CH=C),
2
Hz, POCH2), 65.02 (d, JPC = 6.5 Hz, POCH2), 95.09 (dd,
137.84 (=CHN), 140.37 (d, 3JCF = 14.6 Hz, C=CH), 151.05 (C=O),
1
1JPC = 162.5 Hz, JCF = 196.8 Hz, PCF), 119.7 (=CH), 139.15 (d,
164.68 (C=O), 166.68 (dd, 2JCF = 23.1 Hz, 2JPC = 3.5 Hz).
3JFC = 15.6 Hz, C=CH), 166.76 (dd, 2JPC = 4.0 Hz, 2JCF = 23.1 Hz,
C=O).
31P NMR (81 MHz, CDCl3): d = 13.16 (d, 2JPF = 82.6 Hz).
2
31P NMR (81 MHz, CDCl3): d = 12.41 (d, 2JPF = 83.4 Hz).
19F NMR (188 MHz, CDCl3): d = –179.11 (ddd, JPF = 82.6 Hz,
3JFH = 11.3 Hz, 3JFH = 37.6 Hz).
19F NMR (188 MHz, CDCl3): d = –179.74 (ddd, JPF = 83.4 Hz,
2
3JFH = 11.3 Hz, 3JFH = 39.4 Hz).
Anal. Calcd for C21H31FN5O9P: C, 46.07; H, 5.70; N, 12.79. Found:
C, 45.88; H, 5.64; N, 12.59.
MS (EI): m/z (%) = 458 (100) [M + H]+, 457 (2) [M]+, 135 (100)
[Adm].
Ethyl 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-(diethoxyphosphor-
Anal. Calcd for C21H33FN3O5P: C, 55.13; H, 7.27; N, 9.19; P, 6.77.
Found: C, 55.04; H, 7.18; N, 9.11; P, 6.59.
yl)-2-methylpropanoate (7a)
1
Yield: 80% (crude, 97% purity according to the 31P and H NMR
data); yellowish oil.
Ethyl 2-(Diethoxyphosphoryl)-3-[1-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)-1H-1,2,3-triazol-4-yl]-2-fluoropropanoate (6f)
Yield: 80% (after column chromatography); colourless oil; mixture
of two diastereomers in 1:1 ratio.
1H NMR (200 MHz, CDCl3): d = 1.23 (t, 3JHH = 7.0 Hz, 3 H, CH3),
1.36 and 1.37 (two overlapping t, 3JHH = 7.0 Hz, 6 H, CH3CH2OP),
1.84, 2.00, 2.04, 2.07 (4 × s, 12 H, CH3C=O), 3.52 (HA) and 3.77
(HB) (ABXY system, 2JHH = 16.0 Hz, 3JPH(A) = 8.0 Hz, 3JPH(B) = 6.0
Hz, 3JFH(A) = 11.5 Hz, 3JFH(B) = 38.0 Hz, 2 H, CH2C=C), 3.90–4.00
(m, 1 H, c-CHO), 4.00–4.05 (m, 1 H, c-CHO), 4.10–4.35 (m, 8 H,
OCH2 and CH2OH), 5.15–5.25 (m, 1 H, c-CHO), 5.30–5.45 (m,
1 H, c-CHO), 5.75–5.85 (m, 1 H, c-CH), 7.66 (s, 1 H, C=CH).
IR (thin layer): 1729 (C=O), 1548 (w, C=C), 1498 (triazole), 1266,
1245, 1226 (P=O), 1198, 1049, 1024 (POC, COC), 969 (triazole)
cm–1.
1H NMR (200 MHz, CDCl3): d = 1.14 (t, JHH = 7.0 Hz, 3 H,
3
3
CH3CH2OC), 1.30, 1.31 (two overlapping t, JHH = 7.0 Hz, 6 H,
CH3CH2OP), 1.38 (d, 3JPH = 16.6 Hz, 3 H, CH3CP), 3.06 (HA) and
2
3
3.55 (HB) (ABX system, JHH = 14.4 Hz, JPH = 8.4 Hz, 2 H,
CH2C=), 4.18–4.05 (m, 6 H, OCH2), 5.45 (s, 2 H, CH2Ph), 7.40–
7.30 and 7.24–7.16 (2 × m, 5 H, Ar), 7.21 (s, 1 H, =CH).
13C NMR (50 MHz, CDCl3): d = 14.37 (CH3), 16,80 (d, 3JPC = 5.7
Hz, CH3), 17.50 (d, 2JPC = 4.7 Hz, CH3CP), 30.53 (d, 2JPC = 2.9 Hz,
1
CH2C=C), 49.24 (d, JPC = 137.2 Hz, PC), 54.32 (CH2Ph), 63.25
13C NMR (50 MHz, CDCl3): d = 14.17 (CH3), 16.64 (d, 3JPC = 5.5
Hz, CH3), 20.23, 20.28, 20.73, 20.75, 20.86 (5 × s, CH3C=O), 30.70
and 63.53 (2 × d, 2JPC = 7.1 Hz, POCH2), 123.16 (=CH), 128.27 (o-
C6H5), 128.98 (p-C6H5), 129,39 (m-C6H5), 135.25 (ipso-C6H5),
143.57 (d, 3JPC = 17.3 Hz, C=CH), 171.24 [d, 2JPC = 3.6 Hz, C(O)].
2
(d, JCF = 20.6 Hz, CH2C=C), 61.90 (OCH2), 62.83 and 62.88
(CH2OH), 64.73 (d, 2JPC = 7.0 Hz, POCH2), 64.92 (d, 2JPC = 6.5 Hz,
POCH2), 68.07, 70.53, 70.60, 72.99, 75.05 (5 × s, c-CHO), 85.66 (s,
c-CHON), 94.63 (dd, 1JPC = 162.5 Hz, 1JCF = 198.3 Hz), 94.80 (dd,
1JPC = 163.0 Hz, 1JCF = 197.8 Hz), 121.94 and 122.29 (2 × s, =CH),
31P NMR (81 MHz, CDCl3): d = 26.61.
MS (EI): m/z (%) = 409 (8) [M+].
3
3
Anal. Calcd for C19H28N3O5P: C, 55.74; H, 6.89; P, 7.57; N, 10.26.
Found: C, 55.86; H, 7.00; N, 10.11; P, 7.60.
140.72 (dd, JPC = 9.6 Hz, JCF = 15.6 Hz, C=CH), 166.35 (dd,
2JPC = 3.0 Hz, JCF = 23.1 Hz, C=O), 168.93, 169.07, 169.65,
2
170.14, 170.70 (5 × s, CH3C=O).
Ethyl 3-[1-(2-tert-Butoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl]-2-
(diethoxyphosphoryl)-2-methylpropanoate (7b)
Yield: 65% (after column chromatography); colourless oil.
31P NMR (81 MHz, CDCl3): d = 13.03, 13.00 (2 × d, JPF = 82.6
2
Hz).
19F NMR (188 MHz, CDCl3): d = –179.90, –180.01 (2 × ddd,
3
1H NMR (200 MHz, CDCl3): d = 1.27 (t, JHH = 7.0 Hz, 3 H,
2JPF = 82.6 Hz, 3JFH = 11.3 Hz, 3JFH = 38.0 Hz).
3
CH3CH2OC), 1.35 (t, JHH = 6.8 Hz, 6 H, CH3CH2OP), 1.43 (d,
Anal. Calcd for C25H37FN3O14P: C, 45.94; H, 5.71; N, 6.43; P, 4.74.
Found: C, 45.84; H, 5.75; N, 6.28; P, 4.67.
3JPH = 16.0 Hz, 3 H, CH3CP), 1.47 (s, 9 H, t-Bu), 3.14 (HA) and 3.64
2
3
(HB) (ABX system, JHH = 14.0 Hz, JPH = 8.0 Hz, 2 H, CH2C=),
4.17 (q, 3JHH = 7.0 Hz, 2 H, OCH2), 4.20 (quint, 3JHH = 6.8 Hz, 4 H,
POCH2), 5.01 (s, 2 H, CH2CO), 7.46 (s, 1 H, =CH).
Ethyl 3-(1-{3-(Hydroxymethyl)-5-[5-methyl-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl]tetrahydrofuran-2-yl}-1H-1,2,3-triazol-
4-yl)-2-(diethoxyphosphoryl)-2-fluoropropanoate (6g)
13C NMR (50 MHz, CDCl3): d = 14.20 (CH3), 16.63 (d, 3JPC = 5.5
Hz, CH3CH2OP), 17.23 (d, 2JPC = 5.0 Hz, CH3CP), 28.06 (CH3 in t-
Yield: 91% (crude, 99% purity according to the 31P and H NMR
1
3
1
Bu), 30.25 (d, JPC = 2.0 Hz, PCCH2), 48.95 (d, JPC = 132.8 Hz,
PC), 51.60 (OC in t-Bu), 61.77 (OCH2), 63.07 and 63.37 (2 × d,
2JPC = 7.0 Hz, POCH2), 83.46 (NCH2CO), 124.65 (=CH), 142.94
(d, 3JPC = 17.6 Hz, C=CH), 165.64 [C(O)tBu], 170.96 [d, 2JPC = 3.5
Hz, C(O)].
data); mp 125 °C (dec.).
IR (KBr): 3338 (OH), 1745, 1692, 1661 (C=O), 1552 (w, C=C),
1470 (triazole), 1278, 1265 (P=O), 1043, 1015 (POC, COC), 978
(triazole) cm–1.
3
1H NMR (200 MHz, CDCl3): d = 1.27 (t, JHH = 7.0 Hz, 3 H,
31P NMR (81 MHz, CDCl3): d = 26.35.
CH3CH2OC), 1.40 (t, 3JHH = 7.0 Hz, 6 H, CH3CH2OP), 1.95 (s, 3 H,
Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York

3586
O. I Artyushin et al.
PAPER
HRMS: m/z [M+] calcd for C18H32N3O7P: 433.19779; found:
433.19786.
13C NMR (50 MHz, CDCl3): d = 14.28 (CH3), 16.64 (d, 3JPC = 6.0
Hz, POCH2CH3), 28.54 (br s, CH2C=C), 53.51 (d, 1JPC = 132.8 Hz,
PC), 54.10 (CH2Ph), 62.15 (OCH2), 63.16 (d, JPC = 7.0 Hz,
2
Ethyl 2-(Diethoxyphosphoryl)-3-{1-[3-(diethoxyphosphor-
yl)propyl]-1H-1,2,3-triazol-4-yl}-2-methylpropanoate (7c)
Yield: 55% (after column chromatography); colourless oil.
POCH2), 124.43 (=CH), 128.21 (o-CPh), 128.77 (p-CPh), 129.26 (m-
CPh), 135.55 (ipso-CPh), 143.48 (d, 3JPC = 10.5 Hz, C=CH), 170.10
(d, 2JPC = 3.5 Hz, C=O).
IR (thin layer): 1730 (C=O), 1555 (w, C=C), 1463 (triazole), 1240
(P=O), 1197, 1049, 1025 (POC, COC), 966 (triazole) cm–1.
31P NMR (81 MHz, CDCl3): d = 24.32.
HRMS: m/z [M+] calcd for C28H35N6O5P: 566.24066, found:
1H NMR (200 MHz, CDCl3): d = 1.24–1.38 (m, 15 H, CH3), 1.41
566.23909.
3
(d, JPH = 16.0 Hz, 3 H, CH3CP), 1.60–1.80 (m, 2 H, CH2CH2P),
2.09–2.30 (m, 2 H, PCH2), 3.12 (HA) and 3.64 (HB) (ABX system,
Ethyl 3-[1-(2-tert-Butoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl]-2-
{[1-(2-tert-butoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl]methyl}-2-
(diethoxyphosphoryl)propanoate (8b)
2JHH = 14.0 Hz, 3JPH = 8.0 Hz, 2 H, CH2C=), 4.10 (q, 3JHH = 7.0 Hz,
3
2 H, OCH2), 4.20 (quint, JHH = 6.8 Hz, 8 H, POCH2), 4.41 (t,
3JHH = 7.0 Hz, 2 H, CH2N), 7.37 (s, 1 H, =CH).
Yield: 52% (after column chromatography); colourless oil.
13C NMR (50 MHz, CDCl3): d = 14.43 (CH3), 16.80 (d,3JPC = 6.0
IR (KBr): 1750 (C=O), 1549 (w, C=C), 1467 (triazole), 1238
(P=O), 1158, 1052, 1024 (POC, COC), 970 (triazole) cm–1.
2
1
Hz), 17.49 (d, JPC = 4.5 Hz, CH3CP), 22.79 (d, JPC = 143.4 Hz,
2
2
PCH2), 24.04 (d, JPC = 4.5 Hz, PCCH2), 30.42 (d, JPC = 2.5 Hz,
3
1H NMR (200 MHz, CDCl3): d = 1.28 (t, JHH = 7.0 Hz, 6 H,
CH2C=C), 49.16 (d, 1JPC = 132.3 Hz, PC), 50.16 (d, 3JPC = 15.0 Hz,
CH3CH2OP), 1.29 (t, 3JHH = 7.0 Hz, 3 H, CH3), 1.46 (s, 18 H, CH3
2
CH2N), 61.95 (OCH2), 62.12 and 63.50 (2 × d, JPC = 6.5 Hz,
3
in t-Bu), 3.40 (s, 2 H, CH2C=C), 3.44 (d, JPH = 4.0 Hz, 2 H,
2
POCH2), 63.27 (d, JPC = 7.0 Hz, POCH2), 123.41 (=CH), 143.18
CH2C=C), 4.00–4.16 (m, 4 H, POCH2), 4.20 (q, 3JHH = 7.0 Hz, 2 H,
OCH2), 4.95 (HA) and 5.05 (HB) (AB system, 2JHH = 18.0 Hz, 4 H,
CH2CO), 7.79 (s, 2 H, =CH).
(d, 3JPC = 17.0 Hz, C=CH), 171.25 (d, 2JPC = 3.5 Hz, C=O).
31P NMR (81 MHz, CDCl3): d = 26.17 (s, 1 P, PCH), 30.87 (s, 1 P,
PCH2).
MS (EI): m/z (%) = 497 (8) [M]+.
13C NMR (50 MHz, CDCl3): d = 14.31 (CH3), 16.72 (d, 3JPC = 6.0
Hz, POCH2CH3), 28.29 (CH3 in t-Bu), 51.76 (CO in t-Bu), 53.4 (d,
2
1JPC = 132.8 Hz, PC), 62.26 (OCH2), 63.40 (d, JPC = 7.0 Hz,
Anal. Calcd for C19H37N3O8P2: C, 45.87; H, 7.50; N, 8.45; P, 12.45.
Found: C, 45.79; H, 7.57; N, 8.37; P, 12.12.
POCH2), 83.75 (CH2CO), 125.90 (=CH), 143.33 (d, 3JPC = 11.0 Hz,
C=CH), 165.74 (CH2CO), 170.39 (d, 2JPC = 4.0 Hz, C=O).
Ethyl 2-(Diethoxyphosphoryl)-3-[1-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)-1H-1,2,3-triazol-4-yl]-2-methylpropanoate
(7d)
Yield: 91% (after column chromatography); colourless oil; mixture
of two diastereomers in 1:1 ratio.
31P NMR (81 MHz, CDCl3): d = 22.54.
Anal. Calcd for C26H43N6O9P: C, 50.81; H, 7.05; N, 13.67; P, 5.04.
Found: C, 50.81; H, 7.07; N, 13.61; P, 4.98.
Diethyl 2,2¢-(1,1¢-{1,4-Phenylenebismethylenebis[2-diethoxy-
phosphoryl-3-(1H-1,2,3-triazol-4-yl)]})bispropanoate (9a)
Yield: 83% (after column chromatography); colourless oil.
IR (KBr): 1759 (C=O), 1556 (w, C=C), 1463 (triazole), 1234
(P=O), 1098, 1041 (POC, COC), 963 (triazole) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.22–1.45 (m, 12 H, CH3CH2O
and PCCH3), 1.84, 1.87, 2.03, 2.07, 2.09, 2.10 (6 × s, 12 H,
CH3C=O), 3.03–3.20 (m, 1 H, CH2C=C), 3.58–3.71 (m, 1 H,
CH2C=C), 3.95–4.05 (m, 1 H, c-CHO), 4.10–4.40 (m, 9 H, OCH2
and c-CHO), 5.15–5.20 (m, 1 H, c-CHO), 5.38–5.45 (m, 1 H, c-
CHO), 5.78–5.90 (m, 1 H, c-CH), 7.57 (s, 1 H, C=CH).
IR (thin layer): 1733 (C=O), 1552 (C=C), 1460 (triazole), 1254
(P=O), 1223, 1048, 1025 (POC, COC), 972 (triazole) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.17 (t, 3JHH = 7.0 Hz, 6 H, CH3),
3
1.33 (t, JHH = 7.0 Hz, 12 H, CH3), 3.15–3.60 (m, 6 H, PCH and
CH2C=C), 4.05–4.25 (m, 12 H, OCH2), 5.46 (s, 4 H, CH2Ar), 7.21
(s, 4 H, Ar), 7.29 (s, 2 H, C=CH).
13C NMR (50 MHz, CDCl3): d = 14.27 (CH3), 16.71 (d, 3JPC = 5.0
13C NMR (50 MHz, CDCl3): d = 14.29 (CH3), 16.63 (d, 3JPC = 6.0
3
Hz, POCH2CH3), 17.11 (d, JPC = 5.0 Hz, CH3CP), 20.22, 20.25,
2
Hz, POCH2CH3), 23.59 (d, JPC = 3.0 Hz, CH2C=C), 45.5 (d,
20.76, 20.87 (4 × s, CH3C=O), 30.19 (d, 2JPC = 9.1 Hz, CH2C=C),
1JPC = 129.8 Hz, PCH), 53.65 (CH2Ar), 61.74 (CH2O), 63.09 (d,
1
1
48.89 (d, JPC = 132.8 Hz, PC), 49.10 (d, JPC = 131.8 Hz, PC),
61.85 (CH2OH and OCH2), 63.34 (POCH2), 68.09, 70.51, 70.63,
72.87, 75.01 (c-CHO), 85.64 (c-OCHN), 121.62 (=CH), 143.59 and
2
2JPC = 4.0 Hz, POCH2), 63.22 (d, JPC = 3.5 Hz, POCH2), 122.24
(=CH), 128.77 (CArH), 135.80 (ipso-CAr), 145.23 (d, 3JPC = 17.1 Hz,
C=CH), 168.68 (d, 2JPC = 5.0 Hz, C=O).
3
2
143.94 (2 × d, JPC = 10.0 Hz, C=CH), 168.97 (d, JPC = 8.6 Hz,
C=O), 169.65, 170.08, 170.64, 170.88 (4 × s, CH3C=O).
31P NMR (81 MHz, CDCl3): d = 22.54.
31P NMR (81 MHz, CDCl3): d = 26.25, 26.16.
MS (ESI): m/z = 650 [M + H]+.
Anal. Calcd. for C30H46N6O10P2: C, 50.56; H, 6.51; N, 11.79; P,
8.69. Found: C, 50.68; H, 6.61; N, 11.64; P, 8.42.
Anal. Calcd for C26H40N3O14P: C, 48.07; H, 6.21; N, 6.47; P, 4.77.
Found: C, 48.09; H, 6.18; N, 6.37; P, 4.76.
Diethyl 2,2¢-(1,1¢-{1,4-Phenylenebismethylenebis[2-fluoro-2-di-
ethoxyphosphoryl-3-(1H-1,2,3-triazol-4-yl)]})bispropanoate
(9b)
Ethyl 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-[(1-benzyl-1H-1,2,3-
triazol-4-yl)methyl]-2-(diethoxyphosphoryl)propanoate (8a)
Yield: 62% (after column chromatography); colourless oil.
1H NMR (200 MHz, CDCl3): d = 1.13 (t, 3JHH = 6.9 Hz, 6 H, CH3),
1.16 (t,3JHH = 7.0 Hz, 3 H, CH3), 3.30 (s, 2 H, CH2C=C), 3.37 (d,
3JPH = 2.0 Hz, 2 H, CH2C=C), 3.95 (q, 3JHH = 7.0 Hz, 4 H, CH2OP),
4.13 (q, 3JHH = 6.9 Hz, 2 H, CH2O), 5.41 (s, 4 H, CH2Ph), 7.05–7.20
(m, 10 H, Ph), 7.60 (s, 2 H, =CH).
Yield: 85% (after column chromatography); yellowish oil.
1H NMR (300 MHz, CDCl3): d = 1.16 (t, 3JHH = 7.1 Hz, 6 H, CH3),
1.33 (t, 3JHH = 7.1 Hz, 12 H, CH3CH2OP), 3.48 (HA) and 3.73 (HB)
2
3
3
(ABXY system, JHH = 15.8 Hz, JPH(A) = 8.0 Hz, JPH(B) = 6.1 Hz,
3JFH(A) = 11.9 Hz, JFH(B) = 39.3 Hz, 4 H, CH2C=C), 4.16–4.26 (m,
3
12 H, OCH2), 5.37 (HA) and 5.48 (HB) (AB system, 2JHH = 15.1 Hz,
2 H), 7.19 (s, 4 H, ArH), 7.39 (s, 2 H, C=CH).
13C NMR (50 MHz, CDCl3): d = 14.21 (CH3), 16.68 (d, 3JPC = 6.0
2
Hz, CH3CH2OP), 30.85 (d, JCF = 20.0 Hz, CH2C=C), 53.65
Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York

PAPER
Click Chemistry of Propargyl-Substituted Phosphonocarboxylates
3587
(CH2Ph), 62.82 (s, OCH2), 64.91 (d, 2JPC = 7.0 Hz, POCH2), 64.70
(d, 2JPC = 7.5 Hz, POCH2), 94.75 (dd, 1JPC = 162.5 Hz, 1JCF = 197.3
Hz, PC), 123.64 (C=CH), 128.74 (CArH), 135.76 (ipso-CAr), 140.34
Diethyl 2,2¢-(1,1¢-{1,3-Phenylenebismethylenebis[2-methyl-2-
dihydroxyphosphoryl-3-(1H-1,2,3-triazol-4-yl)]})bispro-
panoate (10b)
3
2
2
(d, JCF = 15.6 Hz, C=CH), 166.48 (dd, JCF = 23.0 Hz, JPC = 3.5
Yield: 78%; white solid; mp 108 °C (dec.).
Hz, C=O).
IR (KBr): 3398–2200 (br, H2O), 1720 (C=O), 1599 (C=C), 1465
(triazole), 1272, 1222 (P=O), 1145, 1014 (COC), 937 (triazole)
cm–1.
31P NMR (121 MHz, CDCl3): d = 11.89 (d, 2JPF = 91.7 Hz).
19F NMR (282 MHz, CDCl3): d = –178.27 (ddd, JPF = 91.7 Hz,
2
3JFH = 11.9 Hz, 3JFH = 39.3 Hz).
1H NMR (400 MHz, D2O): d = 0.88, 0.87 (2 × t, 3JHH = 7.0 Hz, 6 H,
3
CH3), 1.20 (d, JPH = 15.4 Hz, 6 H, CH3CP), 2.88 (HA) and 3.51
Anal. Calcd for C30H44F2N6O10P2: C, 48.14; H, 5.92; N, 11.23; P,
8.27. Found: C, 48.17; H, 5.97; N, 11.27; P, 8.15.
2
3
3
(HB) (ABX system, JHH = 14.5 Hz, JPH(A) = 7.1 Hz, JPH(B) = 7.7
Hz, 4 H, CH2C=C), 3.87–3.96 (m, 4 H, OCH2), 5.46 (AB system,
3
2JHH = 15.0 Hz, 4 H, CH2Ph), 7.08 (d, JHH = 7.6 Hz, 1 H, ArH),
Diethyl 2,2¢-(1,1¢-{1,3-Phenylenebismethylenebis[2-methyl-2-
diethoxyphosphoryl-3-(1H-1,2,3-triazol-4-yl)]})bispropanoate
(9c)
3
7.23 (d, JHH = 7.6 Hz, 1 H, ArH), 7.24 (s, 1 H, ArH), 7.33 (t,
3JHH = 7.6 Hz, 1 H, ArH), 7.70 and 7.71 (2 × s, 2 H, C=CH).
Yield: 75% (after column chromatography); colourless oil.
13C NMR (75 MHz, D2O): d = 12.83 (CH3), 17.40 (d, 2JPC = 4.5 Hz,
1
CH3CP), 28.82 (CH2C=C), 48.97 (d, JPC = 168.3 Hz, PC), 53.83
IR (thin layer): 1728 (C=O), 1613 (Ar), 1548 (C=C), 1462 (tria-
zole), 1267, 1243 (P=O), 1049, 1023 (POC, COC), 969 (triazole)
cm–1.
(CH2Ph), 62.21 (OCH2), 125.17 (C=CH), 127.36 (ArC-2), 128.38
(ArC-4,6), 129.67 (ArC-5), 134.87 (ipso-C-1,3), 142.32 (d,
3JPC = 22.7 Hz, C=CH), 172.94 (d, 2JPC = 5.1 Hz, C=O).
31P NMR (121 MHz, DMSO-d6): d = 19.93.
1H NMR (200 MHz, CDCl3): d = 1.19 (t, 3JHH = 7.0 Hz, 6 H, CH3),
1.33 (t, 3JHH = 7.0 Hz, 12 H, CH3CH2OP), 1.42 (d, 3JPH = 16.0 Hz,
2
6 H, CH3CP), 3.10 (HA) and 3.59 (HB) (ABX system, JHH = 16.0
Anal. Calcd for C24H34N6O10P2·3H2O: C, 42.23; H, 5.91; N, 12.31;
P, 9.08. Found: C, 42.21; H, 5.97; N, 12.07; P, 8.76.
Hz, 3JPH(A) = 8.0 Hz, 3JPH(B) = 9.0 Hz, 2 H, CH2C=C), 4.05–4.25 (m,
16 H, OCH2), 5.50 (s, 4 H, CH2Ph), 7.17 (br s, 1 H, ArH), 7.28 (s,
2 H, C=CH), 7.20–7.40 (m, 3 H, ArH).
3-[1-(1-Adamantyl)-1H-1,2,3-triazol-4-yl]-2-(dihydroxyphos-
phoryl)propane Acid (11a)
13C NMR (50 MHz, CDCl3): d = 14.24 (CH3), 16.68 (d, 3JPC = 6.0
Hz, CH3CH2OP), 17.40 (d, JPC = 4.5 Hz, CH3CP), 30.38
A solution of NaOH (23 mg, 0.57 mmol) in a mixture of EtOH (2
mL) and H2O (1 mL) was added to a solution of the phosphonate
10a (373 mg, 1 mmol) in EtOH (1 mL) at r.t. After stirring over 24
h under ambient conditions, the mix ture was evaporated to dryness,
then 1N HCl was added (to pH ~1) and the mixture was washed with
CHCl3 (2 × 5 mL). The aqueous phase was evaporated to dryness
and MeCN (20 mL) was added to the solid residue. The precipitate
(NaCl) was filtered off, washed by MeCN (2 × 5 mL) and the fil-
trate was evaporated to a volume of ~1 mL. Et2O (15 mL) was add-
ed and the solvents were decanted from the yellowish oil
precipitated from the solution and the residue was dried in vacuo to
give 11a.
2
1
(CH2C=C), 48.97 (d, JPC = 132.8 Hz, PC), 53.61 (CH2Ph), 61.76
(OCH2), 63.08 (d, 2JPC = 7.0 Hz, POCH2), 123.33 (C=CH), 127.36
(ArC-2), 128.01 (ArC-4,6), 129.91 (ArC-5), 136.37 (ipso-ArC-1,3),
143.32 (d, 3JPC = 17.0 Hz), 170.98 (d, 2JPC = 3.5 Hz, C=O).
31P NMR (81 MHz, CDCl3): d = 26.41.
Anal. Calcd for C32H50N6O10P2: C, 51.89; H, 6.80; N, 11.35; P, 8.36.
Found: C, 51.97; H, 6.98; N, 11.21; P, 8.15.
Ethyl (1H-1,2,3-Triazol-4-yl)-2-(dihydroxyphosphoryl)pro-
panoates 10a and 10b; General Procedure
A solution of a two-fold excess of TMS-Br (10 mmol) in CHCl3 (2
mL), was added dropwise to a solution of the corresponding phos-
phonate 5b (4 mmol) or 9c (2 mmol) in CHCl3 (2 mL). The reaction
mixture was allowed to stir at r.t. for 3 d, then solvent was removed
under reduced pressure and the residue was dissolved in 75%
MeOH (1 mL). To this solution Et2O (20 mL) was added and the
mixture was kept under ambient conditions overnight. The solvents
were decanted and the residue was dried in vacuo to give a white
foam.
Yield: 285 mg (80%); white hydroscopic solid; mp 80 °C (dec.).
IR (KBr): 3423, 3140, 2912, 2855, 1725 (C=O), 1598 (C=C), 1453
(triazole), 1215, 1181 (P=O), 1156, 1105, 985, 939 (triazole) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.76 (s, 6 H, Adm), 2.16, 2.20,
2.21 (3 × s, 9 H, Adm), 2.99–3.05 (m, 1 H, CH), 3.12–3.20 (m, 2 H,
CH2C=C), 7.93 (s, 1 H, =CH).
13C NMR (75 MHz, DMSO-d6): d = 23.81 (CH-CH2), 29.11
(CHAdm), 35.56, 42.50 (CH2-Adm), 46.95 (d, 1JPC = 122.4 Hz, PCH),
3
58.87 (NCipso), 118.97 (=CH), 144.38 (d, JPC = 18.1 Hz, C=CH),
Ethyl 3-[1-(1-Adamantyl)-1H-1,2,3-triazol-4-yl]-2-(dihydroxy-
phosphoryl)propanoate (10a)
Yield: 84%; white solid; mp 206–207 °C (dec.).
170.78 (d, 2JPC = 4.9 Hz, C=O).
31P NMR (121 MHz, DMSO-d6): d = 17.00.
Anal. Calcd for C15H22N3O5P·4H2O: C, 42.15; H, 7.08; N, 9.83; P,
7.25. Found: C, 42.27; H, 6.83; N, 10.09; P, 6.88.
IR (KBr): 2908 (CH), 1725 (C=O), 1453 (triazole), 1240 and 1224
(P=O), 1173, 1161, 1138, 1072 (COC), 978 (triazole) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.10 (t, JHH = 7.1 Hz, 3 H,
CH3), 1.76 (s, 6 H, Adm), 2.16 (s, 6 H, Adm), 2.20 (s, 3 H, Adm),
3.00–3.21 (two overlapping m, 1 H and 2 H, CH and CH2C=C),
4.00–4.07 (q, J = 7.1 Hz, 4 H, OCH2), 7.93 (s, 1 H, =CH).
3
2,2¢-(1,1¢-{1,3-Phenylenebismethylenebis[2-methyl-2-dihydroxy-
phosphoryl-3-(1H-1,2,3-triazol-4-yl)]})bispropane Acid (11b)
1
Obtained according to the above procedure. According to the H
and 13C NMR data the compound was isolated as a strong solvate
with 0.5 EtOH.
13C NMR (75 MHz, DMSO-d6): d = 14.24 (CH3), 23.82 (CHCH2),
1
29.11 (CHAdm), 35.57, 42.49 (CH2-Adm), 47.10 (d, JPC = 82.5 Hz,
Yield: 78%; off-white solid; mp 112 °C (dec.).
PCH), 58.85 (NCipso), 60.39 (OCH2), 118.99 (=CH), 144.04 (d,
1H NMR (300 MHz, D2O): d = 1.19 and 1.21 (2 × d, 3JPH = 14.1 Hz,
6 H, CH3CP), 2.89–2.97 (m, 2 H, CH2C=C), 3.44–3.57 (m, 1 H,
CH2C=C), 3.82–3.94 (m, 1 H, CH2C=C), 5.49 (AB system,
2JHH = 15.0 Hz, 2 H, CH2Ph), 5.51 (s, 2 H, CH2Ph), 6.99–7.04 (m,
3JPC = 18.1 Hz, C=CH), 169.54 (d, 2JPC = 5.5 Hz, C=O).
31P NMR (121 MHz, DMSO-d6): d = 16.15.
Anal. Calcd for C17H26N3O5P: C, 53.26; H, 6.84; N, 10.96; P, 8.08.
Found: C, 52.93; H, 7.01; N, 10.41; P, 7.88.
3
1 H, ArH), 7.18–7.26 (m, 2 H, ArH), 7.34 (t, JHH = 7.6 Hz, 1 H,
Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York

3588
O. I Artyushin et al.
PAPER
(5) (a) Rogers, M. J. Curr. Pharm. Des. 2003, 9, 2643.
ArH), 7.70 (d, 4JHH = 6.8 Hz, 1 H, C=CH), 7.84 (d, 4JHH = 4.1 Hz,
1 H, C=CH).
(b) Sato, M.; Grasser, W.; Endo, N.; Akins, R.; Simmons,
H.; Thompson, D. D.; Golub, E.; Rodan, G. A. J. Clin.
Invest. 1991, 88, 2095. (c) Masarachia, P.; Weinreb, M.;
Balena, R.; Rodan, G. A. Bone 1996, 19, 281. (d) Dunford,
J. E.; Thompson, K.; Coxon, F. P.; Luckman, S. P.; Hahn, F.
M.; Poulter, C. D.; Ebetino, F. H.; Rogers, M. J.
J. Pharmacol. Exp. Ther. 2001, 296, 235.
31P NMR (121 MHz, D2O): d = 20.27, 19.95 (2 × s, 1:1 ratio).
Anal. Calcd for C20H24N6O10P2·0.5EtOH·2H2O: C, 41.12; H, 5.09;
N, 13.70; P, 10.10. Found: C, 39.87; H, 4.82; N, 13.56; P, 11.88.
Acknowledgment
(6) (a) van Beek, E. R.; Lowik, C.; van der Pluijm, G.;
Papalous, S. E. J. Bone Miner. Res. 1999, 14, 722.
(b) Coxon, F. P.; Helfrich, M. H.; Van’t, H. o. f. R.; Sebti, S.;
Ralston, S. H.; Hamilton, A. D.; Rogers, M. J. J. Bone
Miner. Res. 2000, 15, 1467. (c) Graham, R.; Russell, G.
Pediatrics 2007, 119, S150.
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG No.: 436 RUS 113/905/0-1) and the Russian Foundation of
Basic Research (Grant No.: 06-03-04003).
(7) Engel, R. Handbook of Organophosphorus Chemistry;
Marcel Dekker: New York, 1992, Chap. 11.
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Synthesis 2009, No. 21, 3579–3588 © Thieme Stuttgart · New York