1,3-dipolar cycloadditions of the versatile intermediate tetraethyl vinylidenebisphosphonate

Article abstract of DOI:10.1055/s-0033-1338498

The use of tetraethyl vinylidenebisphosphonate as a dipolarophile in 1,3-dipolar cycloaddition reactions was investigated. In particular, the cycloaddition reactions between tetraethyl vinylidenebisphosphonate and azides and nitrile oxides, and of tetraet

Full text of DOI:10.1055/s-0033-1338498

PAPER
▌2397
p1a,p3er-Dipolar Cycloadditions of the Versatile Intermediate Tetraethyl
Vinylidenebisphosphonate
1,3-Dipolar Cycloadditions of Vinylidenebisphosphonate
Mariana Ferrer-Casal, Alejandro P. Barboza, Sergio H. Szajnman,* Juan B. Rodriguez*
Departamento de Química Orgánica and UMYMFOR (CONICET–FCEyN), Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
Fax +54(11)45763346; E-mail: shs@qo.fcen.uba.ar; E-mail: jbr@qo.fcen.uba.ar
Received: 06.05.2013; Accepted after revision: 31.05.2013
lysis.14 The 1-hydroxy-gem-bisphosphonate derivatives
have become the most relevant ones. In addition, 1-ami-
no-1,1-bisphosphonic acids of formula 8 are currently
prepared from cyano derivatives15 or amides,16 while 1-
Abstract: The use of tetraethyl vinylidenebisphosphonate as a di-
polarophile in 1,3-dipolar cycloaddition reactions was investigated.
In particular, the cycloaddition reactions between tetraethyl vinyl-
idenebisphosphonate and azides and nitrile oxides, and of tetraethyl
vinylidenebisphosphonate in the Grigg azomethine 1,3-dipolar cy- (substituted amino)methylene-1,1-bisphosphonates 9 are
clization were studied, affording highly functionalized five-mem-
bered rings containing the bisphosphonic unit. These
straightforward methods allow the preparation of diverse and fairly
complex structures bearing the bisphosphonate moiety, which be-
long to a group of pharmacologically important compounds.
usually synthesized starting from the corresponding
amine (Figure 2).17
O
P
O
P
O
P
OH
OR
OR3
NH2
R2
R1
OH
OH
OR
OR
OR3
O
Key words: bisphosphonates, 1,3-dipolar cycloadditions, azides,
nitrile oxides, Grigg azomethine ylides
OR3
HO
P
P
P
1
2
3
OH
OR
OR3
OH
O
O
O
O
N
OH
CH3
N
O
P
O
P
OH
OH
OH
P
Bisphosphonates 1 are metabolically stable analogues of
naturally occurring pyrophosphates 2 in which a substitut-
ed methylene group replaces the oxygen atom bridge be-
tween the two phosphorus atoms of the pyrophosphate
moiety. Bisphosphonates have become compounds of
pharmacological significance as a result of calcification
studies performed more than 40 years ago.1–3 Pamidronate
(3), alendronate (4), risedronate (5), and ibandronate (6)
(here shown in their acid forms) are representative
bisphosphonates that are FDA-approved drugs for the
long-term treatment and prevention of osteoclast-mediat-
ed bone resorption associated with osteoporosis, hyper-
calcemia, tumor bone metastases, Paget’s disease,
postmenopausal osteoporosis, and other bone diseases
(Figure 1).4–7 Bisphosphonates are not only important
drugs for bone diseases, but also exhibit a wide range of
biological properties such as anticancer action,8 stimula-
tion of γδ T cells,9 antibacterial action,10 herbicidal prop-
erties,11 being potent and selective inhibitors of acid
sphingomyelinase,12 and being antiparasitic agents.13
OH
OH
HO
H2N
OH
OH
P
HO
HO
P
OH
5
4
6
P
O
OH
OH
O
O
Figure 1 General formulae and chemical structures of representative
FDA-approved bisphosphonates clinically employed for long-term
treatment of different bone disorders
O
O
O
O
OH
OH
OEt
OH
H
N
P
P
P
P
P
P
R
R
Y
P
P
OH
OH
OH
OH
OEt
OEt
OH
OH
X
R
H
H
OH
OH
OEt
OH
O
O
O
O
7 X = OH
8 X = NH2
9
10 X = NH
11 X = S
12 X = CH2
13
Figure 2 General formulae of a different class of bisphosphonates
Tetraethyl vinylidenebisphosphonate (13), which is
straightforwardly prepared from commercially available
tetraethyl methylenebisphosphonate,18 is a versatile syn-
thetic intermediate for accessing a variety of compounds
bearing the gem-bisphosphonate moiety found in 10–12,
and others.19 Compound 13 behaves as a highly activated
Michael acceptor, giving rise to 1,4-conjugated adducts,
either with strong nucleophiles such as Grignard re-
agents,19d,e or with very mild ones such as amines19a,b or
mercaptans.20 In connection with this conjugate addition,
13 and other closely related substituted derivatives have
also been used in a number of asymmetric Michael-type
additions employing, mostly, enolate species as nucleo-
philes.21 The use of pericyclic reactions might have great
utility as a synthetic approach to access diverse chemical
structures bearing the bisphosphonic moiety. However,
there are just a few examples where 13 undergoes cyclo-
addition reactions, acting either as a dienophile in Diels–
Because of the pharmacological importance of 1,1-
bisphosphonate derivatives, much attention has been fo-
cused on their syntheses. Prospects in the bisphosphonate
drug area changed substantially since the development of
a reliable and reproducible synthetic approach for obtain-
ing 1-hydroxy-1,1-bisphosphonic acids of formula 7 from
carboxylic acids, which can be converted into 7 by treat-
ment with phosphorous acid and phosphorus trichloride in
the presence of benzenesulfonic acid, followed by hydro-
SYNTHESIS 2013, 45, 2397–2404
Advanced online publication: 10.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338498; Art ID: SS-2013-M0340-OP
© Georg Thieme Verlag Stuttgart · New York

2398
M. Ferrer-Casal et al.
PAPER
Alder reactions,22 or as a dipolarophile in 1,3-dipolar cy- coupling constant (JC–P = 2.0 Hz). Similarly, a slightly
cloadditions.23–25 Therefore, at present, the use of 13 as a more complex azide such as 16, prepared from the known
substrate for cycloaddition reactions is definitely an tosylate 15,29 also gave rise to a 1,2,3-triazole 17 in 68%
under-explored area of research. The role of 13 in conju- yield. In this case, similar diagnostic signals were ob-
gate additions or 1,3-dipolar cycloadditions is summa- served in the 1H and 13C NMR data, indicating that this cy-
rized in Scheme 1.
cloaddition reaction took place (Scheme 2). The
corresponding regioisomer could not be observed. Fron-
tier orbital theory provides strong evidence to assume di-
pole-HO-controlled regiochemistry to yield the molecular
targets 14, 17, and 20 through 19.30
R
1,4-Michael type addition
R
R
S
HN
(EtO)2OP
PO(OEt)2
On the other hand, it has been described that sodium azide
can undergo dipolar 1,3-cycloadditions on reaction with
α,β-unsaturated carbonyl compounds.31 It has also been
reported that when 13 was reacted with sodium azide in
water as solvent, 13 behaved as a Michael acceptor in-
stead of as a dipolarophile, to afford 18.32 There have been
no spectroscopic NMR data available to support the struc-
ture of 18.32 Nevertheless, contrary to what was pub-
lished,32 reaction of 13 with an excess of sodium azide did
not lead to the Michael adduct 18 or to the expected hypo-
thetical cycloaddition product 19, but to 20 instead
(EtO)2OP
(EtO)2OP
PO(OEt)2
R
MgX
PO(OEt)2
R
N
SH
R
NH2
O–
(EtO)2OP
PO(OEt)2
1,3-dipolar cycloaddition
R
13
N
CH2N2
H
O
R´
PO(OEt)2
PO(OEt)2
N
(EtO)2OP
(EtO)2OP
N
R
´R
Scheme 1 Conjugate additions and 1,3-dipolar cycloadditions of 13
1
(Scheme 2). The H NMR spectrum of 20 was in agree-
In this study, we report on the use of tetraethyl vinyli-
denebisphosphonate as a valuable intermediate to access
putatively relevant bisphosphonate derivatives.
ment with the proposed structure. A triplet of triplets
(JH–P = 24.2 Hz and JH–H = 5.2 Hz) centered at δ = 2.76,
assigned to H-2′, clearly indicated the portion of the mol-
ecule that, apparently, underwent conjugate addition
(Scheme 2). Another diagnostic signal was a triplet cen-
tered at δ = 3.81 (JH–P = 26.5 Hz), assigned to H-5, and is
typical in these 4,5-dihydro-1H-1,2,3-triazole rings. The
13C NMR spectra was also very interesting, showing two
different carbon atoms (C-4 and C-2′) bonded to two
phosphorus atoms each. Indeed, two indicative signals
were observed, one of them as a triplet centered at δ = 37.3
(JC–P = 131.7 Hz; C-4), and the other one as a triplet cen-
tered at δ = 85.1 (JC–P = 150.8 Hz; C-2′). The 31P NMR
spectrum also supported the presence of two distinct gem-
bisphosphonic acid units within the molecule showing
two well-differentiated signals at δ = 14.44 and 20.84, re-
spectively. The reaction between 13 and sodium azide
was carried out in different solvents such as methanol,
acetonitrile, and methanol–water (1:1), but afforded, in all
cases, 20 exclusively in excellent yields.
Azide-containing compounds have been widely used in
1,3-dipolar cycloadditions with a number of activated and
non-activated alkenes.26–28 Since we want to access
bisphosphonates with diverse chemical structures, it was
considered that 13 on treatment with alkyl azides would
lead to relatively complex alkyl-4,5-dihydro-1H-1,2,3-tri-
azole-4,4-diyl-gem-bisphosphonates. Indeed, the reaction
between 13 and benzyl azide in acetonitrile at room tem-
perature afforded cycloadduct 14 in 83% yield (Scheme
2). NMR spectroscopy was very helpful to confirm the
formation of 14. In the 1H NMR spectrum, H-5 appeared
as a triplet centered at δ = 3.64, coupled with the two ad-
jacent phosphorus atoms (JH–P = 26.7 Hz). This diagnostic
signal confirmed that 14 was formed. In the 13C NMR
spectrum, the C-4 signal was observed as a triplet centered
at δ = 84.3 (JC–P = 151.2 Hz), while the C-5 signal was ob-
served as a triplet centered at δ = 49.1, but with a smaller
2
N
N
BnN3
1
3
N
4
5
(EtO)2OP
PO(OEt)2
MeCN, r.t., 83%
PO(OEt)2
(EtO)2OP
14
13
O
1'
2''
1''
O
2
N
2'''
1'''
13, MeCN, r.t., 68%
1N
2'
R
3
N
4
5
O
O
PO(OEt)2
15 R = OTs
16 R = N3
(EtO)2OP
17
NaN3, DMF
60 °C, 3 h
1'
N
2
(EtO)2OP
PO(OEt)2
N3
(EtO)2OP
(EtO)2OP
HN
NaN3
N
NaN3 (4 equiv)
H2O, r.t., 92%
13 (1 equiv)
N
N
1
5
2'
3
N
4
13
H2O
PO(OEt)2
(EtO)2OP
PO(OEt)2
(EtO)2OP
18
19
20
Scheme 2 1,3-Dipolar cycloaddition reactions between 13 and various azides
Synthesis 2013, 45, 2397–2404
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,3-Dipolar Cycloadditions of Vinylidenebisphosphonate
2399
To rationalize the formation of 20, the nucleophilicity of the hypothetical 25 and 27 starting from nitro compounds
a compound containing the 4,5-dihydro-1H-1,2,3-triazole (Scheme 4).
unit such as benzotriazole was studied. Reaction of 13
with benzotriazole gave the Michael adduct 21 in 80%
yield (Scheme 3). It was therefore postulated that the for-
mation of 20 resulted after a 1,3-dipolar cycloaddition re-
action occurred first to give 19, which, once produced,
reacted immediately with another molecule of 13 to un-
dergo a Michael-type reaction yielding 20 (Scheme 2).
Competitive reaction studies on 13 reinforced the above
idea. When 13 was treated with a solution containing so-
dium azide (one equivalent) and benzotriazole (one equiv-
alent), only the Michael adduct 21 was formed, while 20
was not detected (Scheme 3). In summary, azides in gen-
eral act, in these systems, as dipolar compounds rather
than as nucleophiles, and the reactions proceed with high
regioselectivity.
(EtO)2OP
(EtO)2OP
PO(OEt)2
3
1
MeNO2, DABCO
CHCl3, r.t., 28%
2
4
5
NO2 PO(OEt)2
13
22
1
(EtO)2OP
3
R
RCH2NO2, DABCO
CHCl3, r.t.
2
23 R = Me
24 R = CO2Et 48%
46%
PO(OEt)2
NO2
(EtO)2OP
(EtO)2OP
1
O
5
25 R = H
26 R = Me 49%
27 R = CO2Et
RCH2NO2, POCl3, Et3N
2
N
3
13
4
CHCl3, r.t.
R
Scheme 4 Conjugate addition versus 1,3-dipolar cycloaddition of ni-
trile oxides by employing nitro compounds as source
3-Substituted 5-dihydroisoxazole derivatives can also be
prepared by employing oximes as a source of nitrile ox-
ides by treatment with (diacetoxyiodo)benzene (DIB) in
the presence of trifluoroacetic acid.38 Oximes 28–30 were
obtained by following standard procedures.39 When a
methanolic solution of 28 in the presence of (diacetoxyio-
do)benzene reacted with 13, the expected 1,3-cycloadduct
31 was produced in a low but reproducible yield of 24%.
The H-4 signal appeared as a triplet (JH–P = 23.7 Hz) cen-
tered at δ = 3.56, while the signal assigned to C-5 was ob-
served as a triplet (JC–P = 157.8 Hz) centered at δ = 81.7,
indicating that a carbon atom is bonded to two phosphorus
atoms and one oxygen atom. The stereochemical course
of the reaction can also be explained by dipole-HO-con-
trolled regiochemistry.30 Unexpectedly, an equivalent
amount of the enol ether 32 was formed, probably via con-
jugate addition of methanol, followed by oxidation. Aro-
matic oximes of benzaldehyde and p-anisaldehyde 29 and
30 gave rise to 1,3-dipolar cycloaddition products 33
(40%) and 34 (23%), respectively, by treatment with di-
acetoxyiodobenzene and 13 in the presence of trifluoro-
acetic acid (Scheme 5).
PO3Et2
NaN3 (1 equiv)
benzotriazole
benzotriazole (1 equiv)
N
N
PO3Et2
21
13
20
+
21
MeCN, r.t., 80%
N
MeCN, r.t., 80%
21/20 = 100:0
Scheme 3 Competition between Michael addition versus 1,3-dipolar
cycloaddition
1,3-Dipolar cycloadditions of 13 with nitrile oxides would
afford bisphosphonates bearing the 4,5-dihydroisoxazole
ring. To date, only a short communication has reported
this type of reaction, by using 13 as a substrate and hy-
droxamic chlorides as the nitrile oxides source.25 These
reactive intermediates can also be prepared in situ from
primary nitro compounds, particularly by dehydration of
these compounds by employing a combination of an acet-
ylating agent and a base.33 The use of a base without an
acetylating agent appeared to be an interesting method to
study this reaction.34 Unfortunately, despite this method
having been described, in our hands, the use of 1,4-diaza-
bicyclo[2.2.2]octane as a base was not satisfactory to al-
low 1,3-dipolar cycloaddition reactions of 13.34 Only
conjugate addition was observed in all cases. For exam-
ple, an interesting case was the use of nitromethane in the
presence of diazabicyclo[2.2.2]octane in chloroform; a
double conjugate addition with 13 gave 22 exclusively
(Scheme 4). This tendency to form 22 when the reaction
is carried out under very mild basic conditions, such as in
the presence of diisopropylamine in tetrahydrofuran, has
been reported previously.35 The use of nitroethane or ethyl
nitroacetate as substrates gave rise to 1,4-conjugate addi-
tion. In these cases, only one molecule of 13 was incorpo-
rated to afford 23 and 24, respectively. On the other hand,
nitrile oxides can also be prepared from nitro derivatives
by treatment with phosphoryl chloride and triethyl-
amine.36,37 Therefore, on treatment with nitroethane, 13
was converted into 26 in 49% yield. In the 1H NMR spec-
trum, the H-4 signal that appeared as a triplet (JH–P = 3.4
Hz) centered at δ = 3.57 confirmed the regioselective for-
mation of 26. This method was not satisfactory to obtain
13, DIB, TFA (cat.)
(EtO)2OP
(EtO)2OP
(EtO)2OP
PO(OEt)2
OCH3
N
H
O
OH
+
N
MeOH, r.t.
R
R
28 R = n-pentyl
29 R = Ph
30 R = 4-MeOC6H4
31 R = n-pentyl 24%
33 R = Ph 40%
34 R = 4-MeOC6H4 23%
32 40%
Scheme 5 1,3-Dipolar cycloaddition of nitrile oxides when employ-
ing oximes as source
The Grigg azomethine ylide cyclization is an interesting
1,3-dipolar cascade cycloaddition reaction where an in
situ imine formation takes place from an aldehyde and an
α-amino acid.40 This imine acts as an azomethine ylide in
the presence of a suitable dipolarophile. When 13 was
treated with an aldehyde and diethyl aminomalonate (35)
in tetrahydrofuran,41 highly functionalized bisphospho-
nates 36–38 with pyrrolidine backbones were produced in
50%, 68%, and 40% yield, respectively (Scheme 6). Once
again, the reactions proceeded with high regioselectivity
as expected.30 Taking 37 as an example, the H NMR
1
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2397–2404

2400
M. Ferrer-Casal et al.
PAPER
1H NMR (500 MHz, CDCl3): δ = 1.36 (t, J = 7.1 Hz, 12 H,
CH2CH3), 4.16 (m, 8 H, CH2CH3), 7.01 (dd, J = 37.8, 33.8 Hz, 2 H,
H-2).
13C NMR (125 MHz, CDCl3): δ = 16.2 (t, J = 3.2 Hz, CH2CH3),
62.6 (t, J = 2.8 Hz, CH2CH3), 132.0 (t, J = 167.0 Hz, C-1), 149.2
(C-2).
31P NMR (202 MHz, CDCl3): δ = 13.07.
NMR data were similar to those previously described.18
spectrum confirmed its chemical structure. Bearing in
mind that a new stereogenic center (C-5) was formed, the
H-5 signal appeared as a doublet of doublets centered at
δ = 4.99, coupled with two distinct phosphorus atoms.
PO(OEt)2
PO(OEt)2
4
5
3
EtO2C
2
EtO2C
O
EtO2C
CO2Et
H
13, THF, r.t., 24 h
+
1N
H
NH2
35
R
R
Tetraethyl (1-Benzyl-4,5-dihydro-1H-1,2,3-triazole-4,4-di-
yl)bisphosphonate (14)
36 R = n-pentyl
37 R = Ph
50%
68%
38 R = 4-MeOC6H4 41%
A soln of 13 (600 mg, 2.0 mmol) in MeCN (5.0 mL) was added
dropwise to a soln of BnN3 (319 mg, 2.4 mmol) in anhyd MeCN (10
mL). The reaction mixture was stirred at r.t. for 24 h. The mixture
was partitioned between CH2Cl2 (30 mL) and aq sat. NaCl (30 mL).
The layers were separated and the organic soln was dried (Na2SO4)
and filtered. The solvent was evaporated and the product was puri-
fied by column chromatography (silica gel, hexane–EtOAc, 1:1);
this afforded pure 14.
Scheme 6 Grigg azomethine ylide 1,3-dipolar cascade cycloaddition
In this article we have described the ability of 13 to behave
as a dipolarophile in 1,3-dipolar cycloaddition reactions.
This approach allowed us to obtain different polyfunc-
tionalized rings bearing a gem-bisphosphonate moiety. In
all cases, we were able to obtain nitrogen-containing
bisphosphonates in specifically substituted five-mem-
bered rings such as triazoles, pyrrolidines, and isoxazoles
with high regioselectivity. In summary, 13, via 1,3-dipo-
lar cycloaddition, could be employed to prepare bisphos-
phonates of diverse chemical structures that could result
in the development of important drugs.
Yield: 370 mg (43%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.31 (t, J = 7.1 Hz, 6 H,
OCH2CH3), 1.34 (t, J = 7.0 Hz, 6 H, OCH2CH3), 3.64 (t, J = 26.7
Hz, 2 H, H-5), 4.21 (m, 8 H, OCH2CH3), 4.90 (s, 2 H, PhCH2), 7.28–
7.38 (m, 5 H, Harom).
13C NMR (125 MHz, CDCl3): δ = 16.30 (q, J = 2.9 Hz, OCH2CH3),
16.33 (q, J = 2.9 Hz, OCH2CH3), 49.3 (PhCH2), 49.1 (t, J = 2.0 Hz,
C-5), 63.9 (t, J = 3.3 Hz, OCH2CH3), 64.2 (t, J = 3.4 Hz,
OCH2CH3), 84.3 (t, J = 151.2 Hz, C-4), 128.1 (C-4′), 128.2 (C-2′),
128.8 (C-3′), 134.9 (C-1′).
NMR spectra were recorded using a Bruker AM-500 MHz spec-
trometer. High-resolution mass spectra were obtained using a Bruker
micrOTOF-Q II spectrometer, which is a hybrid quadrupole time-
of-flight mass spectrometer with MS/MS capability. Melting points
were determined using a Fisher-Johns apparatus and are uncorrect-
ed. IR spectra were recorded using a Nicolet Magna 550 spectrom-
eter. Column chromatography was performed on silica gel (Merck,
Kieselgel 60, 230–400 mesh). Analytical TLC was performed em-
ploying 0.2 mm coated commercial silica gel plates (Merck, DC-
aluminum sheets, Kieselgel 60 F254).
31P NMR (202 MHz, CDCl3): δ = 14.55.
HRMS (ESI): m/z [M + Na]+ calcd for C17H29N3O6P2Na: 456.1429;
found: 456.1441.
(4-Phenoxyphenoxyethyl) Azide (16)
NaN3 (175.5 mg, 2.7 mmol) was added to a soln of tosylate 15 (350
mg, 0.9 mmol) in anhyd DMF (5 mL) . The reaction mixture was
stirred at 80 °C for 5 h. Then the mixture was allowed to cool to r.t.
and H2O (50 mL) was added. The aqueous phase was extracted with
CH2Cl2 (2 × 20 mL) and the combined organic layers were washed
with aq sat. NaCl (5 × 20 mL) and H2O (2 × 20 mL) and dried
(MgSO4). The solvent was evaporated and the product was purified
by column chromatography (silica gel, hexane); this afforded pure
16.
Tetraethyl Vinylidenebisphosphonate (13)
Tetraethyl 2-Methoxyethylidenebisphosphonate Intermediate
A mixture of paraformaldehyde (3.05 g, 0.1 mol) and Et2NH (2.08
mL, 1.47 g, 20.1 mmol) in MeOH (50 mL) was refluxed for 2 h until
dissolution was complete. Then tetraethyl methylenebisphospho-
nate (5.0 mL, 5.815 g, 20.2 mmol) was added. The reaction mixture
was refluxed for 24 h. The reaction was monitored by 1H NMR until
disappearance of the typical peak of the substrate, a triplet centered
at δ =2.45 (JH–P = 21.0 Hz). The mixture was allowed to reach r.t.,
and the solvent was evaporated. Then MeOH (50 mL) was added
and the solvent was evaporated. The residue was twice redissolved
in toluene (25 mL) and evaporated, to complete elimination of the
remaining MeOH. This afforded the corresponding intermediate
tetraethyl 2-methoxyethylidenebisphosphonate.
Yield: 150 mg (65%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 3.59 (t, J = 5.0 Hz, 2 H, H-2), 4.14
(t, J = 5.0 Hz, 2 H, H-1), 6.90 (d, J = 9.2 Hz, 2 H, H-3′), 6.95 (m, 2
H, Harom), 6.98 (d, J = 9.2 Hz, 2 H, H-2′), 7.05 (tt, J = 7.4, 1.1 Hz, 1
H, H-3′), 7.30 (m, 2 H, Harom).
13C NMR (125 MHz, CDCl3): δ = 50.2 (C-1), 67.5 (C-2), 115.7 (C-
2′′), 117.8 (C-2′), 120.8 (C-3′), 122.6 (C-4′′), 129.6 (C-3′′), 150.8
(C-4′), 154.5 (C-1′), 158.3 (C-1′′).
Tetraethyl {1-[2-(4-Phenoxyphenoxy)ethyl]-4,5-dihydro-1H-
1,2,3-triazole-4,4-diyl}bisphosphonate (17)
1H NMR (500 MHz, CDCl3): δ = 1.34 (t, J = 7.1 Hz, 12 H,
CH2CH3), 2.69 (tt, J = 23.9, 5.4 Hz, 1 H, H-1), 3.37 (s, 3 H, OCH3),
3.89 (dt, J = 16.1, 5.5 Hz, 2 H, H-2), 4.18 (m, 8 H, CH2CH3).
A soln of azide 16 (90 mg, 0.35 mmol) in anhyd MeCN (5.0 mL)
was treated with a soln of 13 (87 mg, 0.29 mmol) in MeCN (3.0 mL)
according to the method for the preparation of 14. The product was
purified by column chromatography (silica gel, EtOAc–i-Pr, 99:1);
this afforded pure 17.
Compound 13
Anhyd toluene (50 mL) was added to this intermediate, and a Dean-
Stark trap was attached to the reaction flask. The reaction mixture
was refluxed for 48 h. The mixture was concentrated and partitioned
between CH2Cl2 (70 mL) and H2O (70 mL). The organic phase was
washed with H2O (2 × 50 mL) and dried (MgSO4), and the solvent
was evaporated. The product was purified by column chromatogra-
phy (silica gel, EtOAc–MeOH, 99:1); this afforded pure 13.
Yield: 131 mg (68%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.31 (t, J = 7.1 Hz, 6 H,
OCH2CH3), 1.32 (t, J = 7.1 Hz, 6 H, OCH2CH3), 3.94 (t, J = 26.8
Hz, 2 H, H-5), 4.08 (t, J = 5.1 Hz, 2 H, H-1′), 4.20 (t, J = 5.0 Hz, 2
H, H-2′), 4.24 (m, 8 H, OCH2CH3), 6.88 (d, J = 9.3 Hz, 2 H, H-2′′),
Yield: 5.785 g (95.5%); colorless oil.
Synthesis 2013, 45, 2397–2404
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,3-Dipolar Cycloadditions of Vinylidenebisphosphonate
2401
6.94 (m, 2 H, Harom), 6.98 (d, J = 9.3 Hz, 2 H, H-3′′), 7.05 (tt, J = 7.4,
1.1 Hz, 1 H, Harom), 7.31 (m, 2 H, Harom).
(MgSO4), and the solvent was evaporated. The product was purified
by column chromatography (silica gel, EtOAc); this afforded pure
22.
13C NMR (125 MHz, CDCl3): δ = 16.3 (q, J = 3.2 Hz, OCH2CH3),
49.3 (C-1′), 50.9 (t, J = 1.9 Hz, C-5), 64.0 9 (t, J = 3.3 Hz,
OCH2CH3), 64.1 9 (t, J = 3.3 Hz, OCH2CH3), 67.0 (C-2′), 84.7 (t,
J = 151.3 Hz, C-4), 115.6 (C-2′′′), 117.7 (C-2′′), 120.8 (C-3′′), 122.6
(C-4′′′), 129.6 (C-3′′′), 150.8 (C-4′′), 154.4 (C-1′′), 158.2 (C-1′′′).
31P NMR (202 MHz, CDCl3): δ = 14.51.
HRMS (ESI): m/z [M + Na]+ calcd for C24H35N3O8P2Na: 578.1797;
Yield: 102 mg (28%); colorless oil; Rf = 0.41 (EtOAc–i-PrOH–
H2O, 8:1.5:0.5).
1H NMR (500 MHz, CDCl3–CD3OD): δ = 1.35 (dt, J = 7.0, 2.9 Hz,
12 H, OCH2CH3), 1.37 (dt, J = 7.0, 2.2 Hz, 12 H, OCH2CH3), 2.28
(m, 2 H, H-1, H-2a, H-4a), 2.42 (dddd, J = 25.2, 22.5, 9.0, 2.8 Hz, 2
H, H-1, H-5), 2.54 (dddt, J = 25.0, 15.0, 10.2, 3.3 Hz, 2 H, H-2b, H-
4b), 5.21 (tt, J = 9.4, 3.6 Hz, 1 H, H-3); 4.18 (m, 16 H, OCH2CH3).
13C NMR (125 MHz, CDCl3–CD3OD): δ = 16.1 (m, OCH2CH3),
29.9 (t, J = 4.4 Hz, C-2, C-4), 33.2 (t, J = 135.0 Hz, C-1, C-5), 63.0
(t, J = 6.2 Hz, OCH2CH3), 63.3 (d, J = 6.8 Hz, OCH2CH3), 84.8 (C-
3).
found: 578.1772.
Tetraethyl {1-[2,2-Bis(diethoxyphosphoryl)ethyl]-4,5-dihydro-
1H-1,2,3-triazole-4,4-diyl}bisphosphonate (20)
A soln of NaN3 (260 mg, 4.0 mmol) in H2O (10 mL) was treated
dropwise with a soln of compound 13 (300 mg, 1.0 mmol) in H2O
(5.0 mL). The reaction mixture was stirred at r.t. for 30 min. The
mixture was extracted with CH2Cl2 (3 × 30 mL). The combined or-
ganic phases were dried (MgSO4), and the solvent was evaporated.
The product was purified by column chromatography (silica gel,
CH2Cl2–MeOH, 99:1); this afforded pure 20.
31P NMR (202 MHz, CDCl3–CD3OD): δ = 21.20, 21.62.
HRMS (ESI): m/z [M + Na]+ calcd for C21H47O14NP4Na: 684.1845;
found: 684.1847.
Tetraethyl (3-Nitrobutane-1,1-diyl)bisphosphonate (23)
A soln of EtNO2 (167 mg, 2.5 mmol) and DABCO (56 mg, 0.5
mmol) in anhyd CHCl3 (5 mL) was treated with a soln of compound
13 (300 mg, 1.0 mmol) in CHCl3 (2.0 mL) under an argon atmo-
sphere, as reported for the preparation of compound 22. After the
usual reaction workup, the residue was purified by column chroma-
tography (silica gel, EtOAc); this afforded pure 23.
Yield: 306 mg (92%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.32 (t, J = 7.4 Hz, 12 H,
OCH2CH3), 1.34 (t, J = 7.6 Hz, 12 H, OCH2CH3), 2.76 (tt, J = 24.2,
5.2 Hz, 1 H, H-2′), 3.80 (t, J = 26.5 Hz, 2 H, H-5), 4.17 (dt, J = 10.3,
5.6 Hz, 2 H, H-1′), 4.22 (m, 16 H, OCH2CH3).
13C NMR (125 MHz, CDCl3): δ = 16.3 (m, OCH2CH3), 37.3 (t,
J = 131.7 Hz, C-2′), 46.4 (t, J = 3.2 Hz, C-1′), 49.9 (br s, C-5), 62.9
(d, J = 6.7 Hz, OCH2CH3), 63.0 (d, J = 6.5 Hz, OCH2CH3), 64.0 (p,
J = 3.2 Hz, OCH2CH3), 85.1 (t, J = 150.8 Hz, C-4).
31P NMR (202 MHz, CDCl3): δ = 14.44, 20.84.
HRMS (ESI): m/z [M + Na]+ calcd for C20H45N3O12P4Na: 666.1846;
Yield: 175 mg (46%); colorless oil; Rf = 0.60 (EtOAc–i-PrOH–
H2O, 8:1.5:0.5).
1H NMR (500 MHz, CDCl3–CD3OD): δ = 1.367 (dt, J = 7.1, 1.4 Hz,
6 H, OCH2CH3), 1.367 (dt, J = 7.1, 1.4 Hz, 6 H, OCH2CH3), 1.59
(d, J = 6.9 Hz, 1 H, H-4), 2.20 (dddd, J = 23.1, 15.0, 9.4, 3.9 Hz, 1
H, H-2a), 2.43 (dddd, J = 24.8, 22.9, 9.4, 3.9 Hz, 1 H, H-1), 2.61
(ddddd, J = 26.4, 15.2, 13.6, 9.8, 3.8 Hz, 1 H, H-2b), 4.19 (m, 8 H,
OCH2CH3), 4.99 (ddq, J = 9.9, 6.7, 3.6 Hz, 1 H, H-3).
found: 666.1878.
13C NMR (125 MHz, CDCl3–CD3OD): δ = 15.85 (d, J = 3.9 Hz,
OCH2CH3), 15.90 (d, J = 3.9 Hz, OCH2CH3), 19.5 (C-4), 30.6 (t,
J = 4.9 Hz, C-2), 33.3 (t, J = 134.5 Hz, C-1), 62.9 (t, J = 6.9 Hz,
OCH2CH3), 63.2 (dd, J = 8.8, 6.9 Hz, OCH2CH3), 81.3 (dd, 10.8,
3.9 Hz, C-3).
31P NMR (202 MHz, CDCl3–CD3OD): δ = 21.24, 21.88.
HRMS (ESI): m/z [M + H]+ calcd for C12H28O8NP2: 376.1290;
Tetraethyl [2-(1H-Benzo[d][1,2,3]triazol-1-yl)ethane-1,1-di-
yl]bisphosphonate (21)
Benzotriazole (119 mg, 1 mmol) was added to a soln of 13 (100 mg,
0.33 mmol) in anhyd MeCN (5 mL). The reaction mixture was
stirred at r.t. overnight. The mixture was partitioned between H2O
(20 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted
with CH2Cl2 (2 × 20 mL) and the combined organic layers were
washed with aq sat. NaCl (2 × 20 mL) and dried (MgSO4), before
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, EtOAc); this afforded pure 21.
found: 376.1292.
Ethyl 4,4-Bis(diethoxyphosphoryl)-2-nitrobutanoate (24)
A soln of ethyl nitroacetate (332 mg, 2.5 mmol) and DABCO (56
mg, 0.5 mmol) in anhyd CHCl3 (5.0 mL) was treated with a soln of
13 (300 mg, 1.0 mmol) in CHCl3 (2.0 mL) according to the method
described for the preparation of compound 22. The product was pu-
rified by column chromatography (silica gel, EtOAc); this afforded
pure 24.
Yield: 90 mg (65%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.165 (t, J = 7.0 Hz, 6 H,
OCH2CH3), 1.170 (t, J = 7.0 Hz, 6 H, OCH2CH3), 3.51 (tt, J = 23.0,
6.9 Hz, 1 H, H-1), 4.10 (m, 8 H, OCH2CH3), 5.21 (ddd, J = 14.2,
12.9, 7.0 Hz, 2 H, H-2), 7.34 (dist t, J = 7.7 Hz, 1 H, H-5′), 7.47 (dist
t, J = 7.7 Hz, 1 H, H-4′), 7.66 (dd, J = 8.5, 0.8 Hz, 1 H, H-3′), 8.03
(dd, J = 8.4, 0.8 Hz, 1 H, H-6′).
13C NMR (125 MHz, CDCl3): δ = 16.07 (d, J = 2.3 Hz, OCH2CH3),
16.12 (d, J = 2.3 Hz, OCH2CH3), 38.2 (t, J = 131.9 Hz, C-1), 44.2
(t, J = 3.3 Hz, C-2), 62.9 (d, J = 6.7 Hz, OCH2CH3), 63.3 (d, J = 6.7
Hz, OCH2CH3), 109.9 (C-3′), 119.8 (C-6′), 123.9 (C-5′), 127.3 (C-
4′), 133.5 (C-2′), 145.6 (C-1′).
Yield: 202 mg (48%); colorless oil: Rf = 0.68 (EtOAc–i-PrOH–
H2O, 8:1.5:0.5).
1H NMR (500 MHz, CDCl3): δ = 1.30 (dt, J = 7.1, 1.1 Hz, 3 H,
C(O)OCH2CH3), 1.339 (dt, J = 7.1, 1.6 Hz, 6 H, POCH2CH3), 1.341
(dt, J = 7.1, 1.2 Hz, 6 H, POCH2CH3), 2.44 (ddddd, J = 23.8, 22.7,
9.1, 5.2, 1.1 Hz, 1 H, H-1), 2.65 (m, 1 H, H-2a), 2.82 (m, 1 H, H-2a),
4.19 (m, 8 H, OCH2CH3), 4.277 (dq, J = 7.1, 2.8 Hz, 1 H,
C(O)OCH2aCH3), 4.279 (dq, J = 7.1, 2.8 Hz, 1 H, C(O)OCH2bCH3),
5.74 (dd, J = 9.6, 5.1 Hz, 1 H, H-1).
13C NMR (125 MHz, CDCl3): δ = 13.8 (C(O)OCH2CH3), 16.24 (d,
J = 5.9 Hz, POCH2CH3), 16.27 (d, J = 5.9 Hz, POCH2CH3), 26.8 (t,
J = 4.4 Hz, C-3), 33.4 (t, J = 133.5 Hz, C-4), 63.0 (dd, J = 6.6, 4.1
Hz, C(O)OCH2CH3), 63.25 (d, J = 1.8 Hz, POCH2CH3), 63.31
(POCH2CH3), 86.02 (dd, 10.3, 5.2 Hz, C-2), 164.1 (C-1).
31P NMR (202 MHz, CDCl3): δ = 19.18.
Octaethyl (3-Nitropentane-1,1,5,5-tetrayl)tetrakis(phospho-
nate) (22)
Compound 13 (300 mg, 1.0 mmol) in CHCl3 (2.0 mL) was added to
a soln of MeNO2 (152 mg, 2.5 mmol) in the presence of DABCO
(56 mg, 0.5 mmol) in anhyd CHCl3 (5.0 mL) under an argon atmo-
sphere. The reaction mixture was stirred at r.t. for 24 h. The mixture
was partitioned between Et2O (30 mL) and aq sat. NaCl (30 mL).
The organic layer was washed with brine (2 × 30 mL) and dried
31P NMR (202 MHz, CDCl3): δ = 20.72, 21.08.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2397–2404

2402
M. Ferrer-Casal et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C14H30O10NP2: 434.1345;
found: 434.1597.
Tetraethyl (3-Phenyl-4,5-dihydroisoxazole-5,5-diyl)bisphos-
phonate (33)
A soln of 13 (200 mg, 0.67 mmol) in MeOH (1 mL) was added
dropwise to a soln of DIB (259 mg, 0.80 mmol), benzaldehyde ox-
ime (97 mg, 0.80 mmol), and TFA (15 μL, 0.20 mmol) in MeOH (2
mL) under an argon atmosphere. The reaction mixture was stirred
at r.t. for 1 h. The solvent was evaporated and the residue was puri-
fied by column chromatography (silica gel, CH2Cl2–MeOH, 98:2);
this afforded pure 33.
Tetraethyl (3-Methyl-4,5-dihydroisoxazole-5,5-diyl)bisphos-
phonate (26)
POCl3 (675 mg, 5.6 mmol) in CHCl3 (1.0 mL) was added dropwise
to a soln of 13 (600 mg, 2.0 mmol), EtNO2 (390 mg, 5.2 mmol), and
Et3N (565 mg, 5.6 mmol) in anhyd CHCl3 (10 mL) at 0 °C under an
argon atmosphere. The reaction mixture was stirred at r.t. for 3 d.
The reaction was quenched by the addition of cold H2O (20 mL).
The organic phase was washed with 10% aq HCl (2 × 20 mL), 5%
aq NaOH (2 × 20 mL), and brine (3 × 20 mL). The organic layer
was dried (MgSO4) and the solvent was evaporated. The residue
was purified by column chromatography (silica gel, CH2Cl2–
MeOH, 99:1); this afforded pure 26.
Yield: 112 mg (40%); yellowish oil; Rf = 0.52 (CH2Cl2–MeOH,
9:1).
1H NMR (500 MHz, CDCl3): δ = 1.34 (t, J = 6.9 Hz, 6 H,
OCH2CH3), 1.35 (t, J = 7.0 Hz, 6 H, OCH2CH3), 3.99 (t, J = 23.4
Hz, 2 H, H-4), 4.31 (m, 8 H, OCH2bCH3), 7.43 m, 3 H, Harom), 7.67
(dd, J = 8.0, 1.5 Hz, 2 H, H-2′, H-6′).
13C NMR (125 MHz, CDCl3): δ = 16.3 (q, J = 3.2 Hz, OCH2CH3),
42.3 (t, J = 2.1 Hz, C-4), 64.1 (t, J = 3.4 Hz, OCH2CH3), 64.4 (t,
J = 3.3 Hz, OCH2CH3), 83.1 (t, J = 157.1 Hz, C-5), 126.9 (C-2′),
127.9 (C-1′), 128.7 (C-3′), 130.6 (C-4′), 156.0 (t, J = 4.3 Hz, C-3).
Yield: 350 mg (49%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.35 (t, J = 7.1 Hz, 12 H,
OCH2CH3), 2.02 (s, 3 H, CH3 at C-3), 3.57 (t, J = 23.4 Hz, 2 H, H-
5), 4.27 (m, 8 H, OCH2CH3).
13C NMR (125 MHz, CDCl3): δ = 16.4 (q, J = 2.9 Hz, OCH2CH3),
19.9 (CH3 at C-3), 45.9 (C-5), 64.2 (t, J = 3.3 Hz, OCH2CH3), 64.5
(t, J = 3.4 Hz, OCH2CH3), 82.0 (t, J = 158.5 Hz, C-4), 154.9 (C-3).
31P NMR (202 MHz, CDCl3): δ = 14.51.
HRMS (ESI): m/z [M + Na]+ calcd for C17H27O7NP2Na: 442.1161;
found: 442.1153.
31P NMR (202 MHz, CDCl3): δ = 14.81.
HRMS (ESI): m/z [M + Na]+ calcd for C12H25O7NP2Na: 380.1004;
found: 380.1005.
Tetraethyl [3-(4-Methoxyphenyl)-4,5-dihydroisoxazole-5,5-di-
yl]bisphosphonate (34)
The same method as that used for the preparation of compound 33
was followed; a soln of DIB (322.9 mg, 0.80 mmol), anisaldehyde
oxime (121 mg, 0.80 mmol), and TFA (15 μL, 0.20 mmol) in
MeOH (2 mL) was reacted with a soln of 13 (200 mg, 0.67mmol) in
MeOH (1 mL). After the usual workup, the product was purified by
column chromatography (silica gel, CH2Cl2–MeOH, 98:2); this af-
forded pure 34.
Tetraethyl (3-Pentyl-4,5-dihydroisoxazole-5,5-diyl)bisphospho-
nate (31) and Tetraethyl (2-Methoxyethene-1,1-diyl)bisphos-
phonate (32)
A soln of 13 (200 mg, 0.67 mmol) in MeOH (2.0 mL) was added
dropwise to a soln of (diacetoxyiodo)benzene (DIB; 259 mg, 0.80
mmol), hexanal oxime (92 mg, 0.80 mmol), and TFA (15 μL, 0.20
mmol) in MeOH (2 mL) under an argon atmosphere. The reaction
mixture was stirred at r.t. for 1 h. The solvent was evaporated and
the residue was purified by column chromatography (silica gel,
CH2Cl2–MeOH, 98:2); this afforded pure 31 and 32.
Yield: 70 mg (23%); yellowish oil; Rf = 0.45 (CH2Cl2–MeOH, 9:1).
1H NMR (500 MHz, CDCl3): δ = 1.33 (t, J = 6.9 Hz, 6 H,
OCH2CH3), 1.35 (t, J = 6.9 Hz, 6 H, OCH2CH3), 3.85 (s, 3 H,
OCH3), 3.97 (t, J = 23.4 Hz, 2 H, H-4), 4.31 (m, 8 H, OCH2bCH3),
6.93 (d, J = 8.7 Hz, 2 H, H-3′, H-5′), 7.61 (d, J = 8.6 Hz, 2 H, H-2′,
H-4′).
13C NMR (125 MHz, CDCl3): δ = 16.4 (q, J = 3.0 Hz, OCH2CH3),
42.6 (t, J = 2.2 Hz, C-4), 55.3 (OCH3), 64.2 (t, J = 3.4 Hz,
OCH2CH3), 64.5 (t, J = 3.3 Hz, OCH2CH3), 82.9 (t, J = 157.1 Hz,
C-5), 114.2 (C-3′), 120.4 (C-1′), 128.6 (C-2′), 155.6 (t, J = 4.3 Hz,
C-3), 161.5 (C-4′).
Compound 31
Yield: 67 mg (24%); colorless oil; Rf = 0.38 (CH2Cl2–MeOH, 9:1).
1H NMR (500 MHz, CDCl3): δ = 0.90 (t, J = 7.0 Hz, 3 H, H-5′), 1.35
(t, J = 7.2 Hz, 12 H, OCH2CH3), 1.37 (m, 4 H, H-3′, H-4′), 1.58 (p,
J = 7.4 Hz, H-2′), 2.36 (t, J = 7.6 Hz, H-1′), 3.56 (t, J = 23.7 Hz, 2
H, H-4), 4.26 (m, 8 H, OCH2CH3).
13C NMR (125 MHz, CDCl3): δ = 13.8 (C-5′), 16.33 (q, J = 3.3 Hz,
OCH2CH3), 22.1 (C-4′), 25.8 (C-2′), 26.7 (C-3′), 31.1 (C-1′), 44.4
(t, J = 2.1 Hz, C-4), 64.1 (t, J = 3.4 Hz, OCH2CH3), 64.4 (t, J = 3.3
Hz, OCH2CH3), 81.7 (t, J = 157.8 Hz, C-5), 158.4 (t, J = 4.2, C-3).
31P NMR (202 MHz, CDCl3): δ = 14.67.
HRMS (ESI): m/z [M + H]+ calcd for C18H30O8NP2: 450.1448;
found: 450.1457.
31P NMR (202 MHz, CDCl3): δ = 14.94.
HRMS (ESI): m/z [M + H]+ calcd for C16H34NO7P2: 414.1811;
found: 414.1794.
Diethyl (±)-4,4-Bis(diethoxyphosphoryl)-5-pentylpyrrolidine-
2,2-dicarboxylate (36)
A soln of hexanal (80 mg, 0.80 mmol) and 35 (44 mg, 0.25 mmol)
in anhyd THF (4 mL) was treated with a soln of 13 (44 mg, 0.25
mmol) in THF (1.0 mL) under an argon atmosphere. The reaction
mixture was stirred at r.t. for 7 d. The solvent was evaporated and
the product was purified by column chromatography (silica gel,
EtOAc); this afforded pure 36.
Compound 32
Yield: 89 mg (40%); colorless oil; Rf = 0.32 (CH2Cl2–MeOH, 9:1).
1H NMR (500 MHz, CDCl3): δ = 1.33 (m, 12 H, OCH2CH3), 4.01
(s, 3 H, OCH3), 4.11 (m, 8 H, OCH2CH3), 7.62 (dd, J = 33.4, 13.1
Hz, 1 H, H-2).
13C NMR (125 MHz, CDCl3): δ = 16.1 (t, J = 5.9 Hz, OCH2CH3),
62.0 (d, J = 5.0 Hz, OCH2CH3), 62.1 (d, J = 4.4 Hz, OCH2CH3),
63.3 (OCH3), 93.7 (ddd, J = 180.7, 173.6, 2.6 Hz, C-1), 174.2 (dd,
J = 16.1, 4.4 Hz, C-2).
31P NMR (202 MHz, CDCl3): δ = 12.29 (d, J = 31.7 Hz), 17.95 (d,
J = 30.2 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C11H25O7P2: 331.1076; found:
Yield: 72 mg (50%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H, H-5′), 1.27
(t, J = 7.1 Hz, 6 H, C(O)OCH2CH3), 1.33 (t, J = 7.1 Hz, 3 H,
POCH2CH3), 1.34 (t, J = 7.1 Hz, 9 H, POCH2CH3), 2.13 (m, 1 H,
H-1′a), 3.98 (ddd, J = 20.9, 15.1, 9.1 Hz, 1 H, H-3a), 3.25 (dt,
J = 20.5, 15.2 Hz, 1 H, H-3b), 3.48 (ddt, J = 22.9, 10.4, 2.2 Hz, 1 H,
H-5).
13C NMR (125 MHz, CDCl3): δ = 13.96 (C(O)OCH2CH3), 13.97
(C(O)OCH2CH3), 14.1 (C-5′), 16.34 (d, J = 4.6 Hz, POCH2CH3),
16.37 (d, J = 4.5 Hz, POCH2CH3), 16.44 (d, J = 4.5 Hz,
331.1082.
Synthesis 2013, 45, 2397–2404
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,3-Dipolar Cycloadditions of Vinylidenebisphosphonate
2403
POCH2CH3), 22.5 (C-4′), 28.4 (C-2′), 31.1 (d, J = 3.2 Hz, C-1′),
31.7 (C-4′), 38.7 (dd, J = 4.2, 2.4 Hz, C-3), 50.9 (t, J = 134.5 Hz, C-
4), 62.0 (OCH2CH3), 62.1 (OCH2CH3), 62.4 (d, J = 6.4 Hz,
OCH2CH3), 62.6 (d, J = 6.1 Hz, OCH2CH3), 63.1 (d, J = 6.1 Hz,
OCH2CH3), 63.4 (d, J = 5.9 Hz, OCH2CH3), 65.5 (d, J = 2.7 Hz, C-
5), 72.4 (dd, J = 7.2, 2.0 Hz, C-2), 169.2 (CO), 170.6 (CO).
31P NMR (202 MHz, CDCl3): δ = 24.17 (d, J = 16.8 Hz), 24.29 (d,
J = 16.8 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C23H46O10NP2: 558.2597;
(d, J = 7.0 Hz, OCH2CH3), 63.09 (d, J = 6.9 Hz, OCH2CH3), 65.9
(d, J = 4.3 Hz, C-5), 71.0 (dd, J = 6.8, 1.9 Hz, C-2), 112.5 (C-3′),
128.8 (d, J = 4.9 Hz, C-1′), 130.3 (C-2′), 159.2 (C-4′), 169.0 (CO),
171.1 (CO).
31P NMR (202 MHz, CDCl3): δ = 22.85 (d, J = 13.7 Hz), 23.84 (d,
J = 13.7 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C25H41O11NP2Na: 616.2053;
found: 616.2066.
found: 558.2602.
Acknowledgment
Diethyl (±)-4,4-Bis(diethoxyphosphoryl)-5-phenylpyrrolidine-
2,2-dicarboxylate (37)
This work was supported by grants from the National Research
Council of Argentina (PIP 1888), ANPCyT (PICT 2008 #1690),
and the Universidad de Buenos Aires (200201001003801) to
J.B.R., and from Bunge & Born Foundation to S.H.S.
A soln of benzaldehyde (310 mg, 3.0 mmol) and 35 (117 mg, 0.67
mmol) in anhyd THF (4 mL) was treated with a soln of 13 (200 mg,
0.67 mmol) in THF (1.0 mL) under an argon atmosphere. The reac-
tion mixture was stirred at r.t. for 24 h. The solvent was evaporated
and the product was purified by column chromatography (silica gel,
EtOAc); this afforded pure 37.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are experimental procedures for the preparation of oximes 28–30,
copies of 1H, 13C, and 31P NMR spectra for all the compounds syn-
Yield: 257 mg (68%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.07 (t, J = 7.1 Hz, 3 H,
C(O)OCH2CH3), 1.09 (t, J = 7.1 Hz, 3 H, C(O)OCH2CH3), 1.29 (dt,
J = 12.2, 7.1 Hz, 6 H, POCH2CH3), 1.34 (t, J = 7.1 Hz, 6 H,
POCH2CH3), 3.23 (dd, J = 19.3, 15.2 Hz, 1 H, H-3a), 3.32 (ddd,
J = 22.1, 15.0, 10.4 Hz, 1 H, H-3b), 3.69 (ddt, J = 14.3, 9.6, 7.2 Hz,
1 H, C(O)OCH2aCH3), 3.85 (ddd, J = 14.3, 9.6, 7.2 Hz, 1 H,
C(O)OCH2bCH3), 3.92 (p, J = 7.3 Hz, 2 H, C(O)OCH2CH3), 4.10–
4.31 (m. 8 H, POCH2CH3), 4.99 (dd, J = 30.0, 13.1 Hz, 1 H, H-5),
7.27 (m, 3 H, Ph), 7.67 (m, 2 H, Ph).
13C NMR (125 MHz, CDCl3): δ = 14.01 (C(O)OCH2CH3), 14.02
(C(O)OCH2CH3), 16.1 (dd, J = 6.3, 0.8 Hz, POCH2CH3), 16.4 (dd,
J = 5.8, 1.5 Hz, POCH2CH3), 38.3 (t, J = 3.8 Hz, C-3), 51.7 (t,
J = 136.4 Hz, C-4), 62.1 (OCH2CH3), 62.2 (d, J = 7.3 Hz,
OCH2CH3), 62.7 (d, J = 7.2 Hz, OCH2CH3), 63.1 (d, J = 7.0 Hz,
OCH2CH3), 63.2 (d, J = 7.0 Hz, OCH2CH3), 66.3 (d, J = 4.3 Hz, C-
5), 71.0 (dd, J = 6.9, 1.9 Hz, C-2), 127.1 (C-2′), 127.7 (C-4′), 129.1
(C-3′), 136.6 (d, J = 4.7 Hz, C-1′), 169 (CO), 171.0 (CO).
thesized, and selected 2D-NMR data.SnuIpgforpi
o
nmitSartnuIfp
o
oirgmnirtat
References
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31P NMR (202 MHz, CDCl3): δ = 22.76 (d, J = 13.6 Hz), 23.68 (d,
J = 13.6 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C24H40O10NP2: 564.2122;
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found: 564.2133.
Diethyl (±)-4,4-Bis(diethoxyphosphoryl)-5-(4-methoxyphe-
nyl)pyrrolidine-2,2-dicarboxylate (38)
A soln of anisaldehyde (224 mg, 1.6 mmol) and 35 (58 mg, 0.25
mmol) in anhyd THF (4 mL) was treated with a soln of 13 (100 mg,
0.33 mmol) in THF (1.0 mL) under an argon atmosphere. The reac-
tion mixture was stirred at r.t. for 24 h. The solvent was evaporated
and the product was purified by column chromatography (silica gel,
EtOAc); this afforded pure 39.
Yield: 81 mg (41%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.10 (t, J = 7.1 Hz, 3 H,
C(O)OCH2CH3), 1.14 (t, J = 7.1 Hz, 3 H, C(O)OCH2CH3), 1.29 (dt,
J = 10.9, 7.1 Hz, 6 H, POCH2CH3), 1.34 (dt, J = 7.1, 1.0 Hz, 6 H,
POCH2CH3), 3.21 (dd, J = 19.3, 15.2 Hz, 1 H, H-3a), 3.31 (ddd,
J = 22.0, 15.2, 10.2 Hz, 1 H, H-3b), 3.72 (ddt, J = 14.1, 9.6, 7.2 Hz,
1 H, C(O)OCH2aCH3), 3.79 (s, 3 H, OCH3), 3.85 (ddt, J = 14.2,
10.2, 7.1 Hz, 1 H, C(O)OCH2bCH3), 3.94 (p, J = 7.3 Hz, 1 H,
C(O)OCH2dCH3), 3.96 (p, J = 7.3 Hz, 1 H, C(O)OCH2dCH3), 4.11–
4.31 (m, 8 H, POCH2CH3), 4.95 (dd, J = 30.0, 13.0 Hz, 1 H, H-5),
6.82 (d, J = 8.9 Hz, 2 H, H-3′), 7.59 (d, J = 8.7 Hz, 2 H, H-2′).
13C NMR (125 MHz, CDCl3): δ = 14.02 (C(O)OCH2CH3), 14.03
(C(O)OCH2CH3), 16.2 (d, J = 6.2 Hz, POCH2CH3), 16.4 (d, J = 5.2,
POCH2CH3), 38.2 (t, J = 3.8 Hz, C-3), 51.6 (dd, J = 137.8, 134.9
Hz, C-4), 55.2 (OCH3), 62.07 (OCH2CH3), 62.08 (OCH2CH3), 62.3
(d, J = 7.2 Hz, OCH2CH3), 62.6 (d, J = 7.3 Hz, OCH2CH3), 63.06
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2397–2404

2404
M. Ferrer-Casal et al.
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© Georg Thieme Verlag Stuttgart · New York