Polycyclic phosphonic acid derivatives obtained by a [4+2] cycloaddition strategy using phosphonodienes

Article abstract of DOI:10.1016/j.tet.2012.11.059

A practical route is described for the preparation of 1-phosphono-3(4-di)- substituted-1,3-butadienes based on the Horner-Wadsworth-Emmons (HWE) reaction. Their reactivity in the Diels-Alder (DA) reaction with three selected dienophiles is studied and compared to diethyl 1-phosphono-1,3-butadiene. A particular attention is given to the P-deprotection of cycloadducts from dibenzyl phosphonodienes. New phosphonated bicycles and tricycles have been obtained using this HWE/DA reaction sequence.

Full text of DOI:10.1016/j.tet.2012.11.059

Tetrahedron 69 (2013) 1138e1147
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Polycyclic phosphonic acid derivatives obtained by a [4þ2]
cycloaddition strategy using phosphonodienes
Elise Villemin a, Koen Robeyns a, Raphael Robiette a, Marie-France Herent b,
,
Jacqueline Marchand-Brynaert a
*
a
ꢀ
Universite catholique de Louvain, Institute of Condensed Matter and Nanosciences (ICMN), Molecules, Solids and Reactivity (MOST), Place Louis Pasteur 1, Boîte L4.01.02,
1348 Louvain-la-Neuve, Belgium
b
ꢀ
Universite catholique de Louvain, Louvain Drug Research Institute (LDRI), Avenue Mounier 73, B-1200 Bruxelles, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2012
Received in revised form 14 November 2012
Accepted 16 November 2012
Available online 23 November 2012
A practical route is described for the preparation of 1-phosphono-3(4-di)-substituted-1,3-butadienes
based on the HornereWadswortheEmmons (HWE) reaction. Their reactivity in the DielseAlder (DA)
reaction with three selected dienophiles is studied and compared to diethyl 1-phosphono-1,3-butadiene.
A particular attention is given to the P-deprotection of cycloadducts from dibenzyl phosphonodienes.
New phosphonated bicycles and tricycles have been obtained using this HWE/DA reaction sequence.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1-Phosphonodienes
DielseAlder reaction
Phosphonic acid
HornereWadswortheEmmons reaction
Benzyl deprotection
1. Introduction
easily separable. 1-Phosphono-4-alkyl-1,3-butadienes are mainly
obtained by isomerization of 1-phosphono-alkynes with Pd(0)
Our continuous interest in the DielseAlder (DA) reactions of 1-
phosphono-1,3-butadiene (1a) leads us to consider 3(4)-alkyl-
substituted derivatives to (i) possibly increase the diene reactivity
by conformational and electron-donating effects, and (ii) provide
an entry into cyclic dienes and consequently into unprecedented
polycyclic phosphonated DA cycloadducts.
Different methods are described in the literature for the prep-
aration of 1-phosphono-3-alkyl-1,3-butadienes. Generally they use
multistep synthesis giving low overall yields and/or mixtures of
regioisomers. Phosphochloration reaction,1 modification of phos-
phonoepoxides,2 transformations of phosphonocyclopropenes3 are
the major routes for the preparation of these dienes. Organome-
tallic processes, such as selective reduction of conjugated alkynes
by hydride in the presence of In(III),4 and catalyzed Michae-
liseArbuzov reaction on bromodienes5 are other methods. Lastly,
classical MichaeliseArbuzov reaction followed by acetate elimina-
tion6 and addition of dialkyl phosphite on propargyl alcohols and
alkynes in the presence of Ni(0) or Pd(II) catalyst7,8 lead to mixtures
of 1-phosphonodienes and 2-phosphonodienes, which are not
catalyst9 and HornereWadswortheEmmons (HWE) condensation
of conjugated aldehydes with methylenediphosphonate.10 All
these methods are generally applied to dimethyl and diethyl
phosphonates.
The aim of this work is to propose the same strategy for the
preparation of 3 and/or 4-substituted 1-phosphono-1,3-butadienes,
and to illustrate the reactivity of these dienes in DielseAlder (DA)
cycloadditions with three reactive dienophiles, previously identi-
fied as good partners towards diethyl 1-phosphono-1,3-butadiene
(1a).11 The access to cycloadducts with a free phosphonic acid
group by dibenzyl phosphonate deprotection is also reported. Lastly,
the ability of some ethyl phosphonate cycloadducts to coordinate
metal cations is illustrated.
2. Results and discussion
2.1. Synthesis of dienes 1aef
A limited number of protecting groups of the phosphonate
moiety is reported in the current literature for an easy access to free
phosphonic acid derivatives.12 The most common phosphonate
ester is the diethyl phosphonate, because it is of practical handling
and relative stability. The usual deprotection method13 using
* Corresponding author. Tel.: þ32 10 472746; fax: þ32 10 474168; e-mail address:
Jacqueline.marchand@uclouvain.be (J. Marchand-Brynaert).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.059

E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
1139
trimethylsilyl bromide as SN2 reagent, followed by methanolysis,
was found incompatible with the stability of succinimide de-
rivatives (i.e., DA cycloadducts on maleimides) in our previous
studies.11 Acid hydrolysis of dialkylphosphonates could not be en-
visaged as an alternative method on imide derivatives. The use of 2-
cyanoethyl phosphonate, usually cleaved at pH 10, was discarded.14
The allyl protecting group was avoided,15 because of its possible
reaction as dienophile in the DA cycloaddition of phosphonodienes.
2,2,2-Trichloroethyl and trialkylsilylethyl groups were not envis-
aged because their deprotection conditions (zinc in acetic acid16
and fluoride treatment,17 respectively) are considered too hard.
So, the benzyl group was selected for its soft deprotection by cat-
alytic hydrogenation in neutral conditions.18
Previously, our group has synthesized, in two steps on a multi-
gram scale, diethyl 1-phosphono-1,3-butadiene (1a) via the
MichaeliseArbuzov reaction between triethylphosphite and (E)-
1,4-dichlorobut-2-ene followed by hydrochloride elimination with
a hindered base (DBU).19 The same route cannot be applied for the
preparation of dibenzyl phosphonodienes. Indeed, the Michae-
liseArbuzov reaction between tribenzylphosphite and halogen-
oalkanes was previously reported to be weakly efficient because
of the formation of a by-product, i.e., benzyl halide, which reacts
more easily with tribenzylphosphite than the alkyl halide of
interest.20
Dibenzyl 1-phosphono-1,3-butadiene (1b) was initially pre-
pared from diethyl 1-phosphono-1,3-butadiene (1a) in three
steps.21 Diethyl phosphonate was first dealkylated by an excess of
trimethylsilyl bromide, then the trimethylsilyl groups were
replaced with chlorine atoms by the action of oxalyl chloride and
the formal transesterification was finally achieved with benzyl al-
cohol in the presence of pyridine as a base. This indirect route to-
wards dibenzyl phosphonodienes requires thus the previous
preparation of the corresponding diethyl phosphonodienes. How-
ever, only the diene 1a is easily synthesized with good yields from
(E)-1,4-dichlorobut-2-ene; no general preparation of mono- or di-
substituted phosphonodienes in positions 3 and/or 4 is described
so far.
For the preparation of dibenzyl phosphonodiene 1b, we carried
out the HWE reaction with acrolein and tetrabenzyl methyl-
enediphosphonate prepared from tetrachloromethylenediphos-
phonate using a known procedure.24 The diene 1b (Table 1) was
recovered in moderate yield as a single E-stereosiomer, after puri-
fication by chromatography on silica gel. This one-step synthesis is
more efficient than the transesterification method from diene 1a.
Table 1
Yields of dienes 1aee, E:Z ratio from 1H NMR and energy difference between the s-
cis and s-trans conformers of the (E)-isomer
a
R1
R2
R3
Cmpd
Yields (%)
E:Z
D )
Erel (kcal molꢀ1
H
H
H
H
H
Et
Bn
Et
Et
Bn
Bn
1a
1b
1c
1d
1e
1f
78
51
79
82
19
<5
100:0
100:0
87:13
97:3
87:13
n.d.
3.4
3.3
3.7
3.8
n.d.
n.d.
Me
e(CH2)4e
Me
e(CH2)4e
H
a
B3LYP-D/6-31þG**(THF)/B3LYP/6-31G**; n.d.¼not determined.
The HWE methodology was further exemplified using
two commercially available -unsaturated aldehydes,
a,b
namely methacrylaldehyde and cyclohex-1-encarbaldehyde, for the
preparation of representative 3,(4-di)-substituted 1-phosphono-
1,3-butadienes. In the diethyl phosphonate series, good yields of
purified dienes 1c and 1d were obtained, in the form of two geo-
metrical isomers, non separable by column chromatography
(Scheme 1, Table 1). In the dibenzyl phosphonate series, the yields of
dienes 1e and 1f decreased dramatically. HWE reaction is very
sensitive to steric hindrance; the presence of an alkyl substituent in
position 3/4 of the conjugated aldehyde prevents the attack of bulky
dibenzyl phosphonated anion.
The E:Z ratio of dienes 1 could be experimentally determined
from 1H NMR spectra: the major (or exclusive) isomer E shows the
H-1 and the H-2 protons at 5.42e5.74 ppm and 6.99e7.15 ppm,
respectively, while the very minor isomer Z presents these protons
at 5.72e5.84 ppm and 6.66e6.87 ppm, respectively.
Diethyl 1-phosphono-4-alkenyl-1,3-butadienes were obtained
as intermediates during the preparation of phosphoantigens.10 The
synthesis consists in a HornereWadswortheEmmons (HWE) re-
action between conjugated aldehydes and tetraethyl methyl-
enediphosphonate in the presence of a base, a method generally
applied to the synthesis of simple phosphonated olefins.22 The
convergent synthesis of 1-phosphonodienes by HWE reaction re-
mains to be explored as a general strategy.
Since the concerted DA cycloaddition proceeds from the s-cis
conformer of the diene, we have computed the relative energy of s-
cis and s-trans conformers of E-1aed using DFT methods (Fig. 1).
The nature of the phosphonate ester and the presence of sub-
stituents at C-3/C-4 do not influence significantly the conforma-
tional equilibrium (Table 1).
D
Erel, i.e.,
D
Ecis DEtrans, was found
ꢀ
between 3.3 and 3.8 kcal molꢀ1, suggesting that all these dienes
should have a similar DA reactivity under thermal activation.
HWE reaction was tested in our hands for the preparation of the
reference diene 1a from acrolein and tetraethyl methyl-
enediphosphonate (easily accessible from diethylphosphite and
methylene chloride23) (Scheme 1). Using potassium carbonate as
a base, no reaction was observed but polymerization of acrolein
occurred. The diene 1a was obtained with good yields, as a single E-
stereoisomer, when sodium hydride was used as a base in toluene
solution at room temperature. The same procedure did not work
with ketones, such as methylvinylketone.
R3O
R3O
O
R3O
R3O
2
O
P
P
1
4
3
R1
R1
R2
R2
Fig. 1. s-trans/s-cis equilibrium of (E)-1.
PO(OR3)2
PO(OR3)2
O
P
OR3
2.2. [4D2] cycloadditions of dienes 1
1
2
O
H
OR3
R1
R2
R1
R2
4-Phenyl-4H-1,2,4-triazoline-3,5-dione (2) and two N-
substituted maleimides (425 and 626) have been selected as repre-
sentative dienophiles for the DA reactions with dienes 1 (Scheme 2
and Fig. 2). Cycloadducts could be obtained and purified from di-
enes 1aed (Table 2); diene 1e reacted with 2 only and the corre-
sponding cycloadduct could not be purified. Microwave activation
did not improve the yields in all series of experiments.
H
H
3
NaH, toluene,
RT
H
4
1a e
-
Scheme 1. Preparation of 1-phosphono-1,3-butadienes by HornereWadsworthe
Emmons (HWE) reaction.

1140
E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
R
R
O
O
O
R
R
O
O
O
Unsubstituted dienes 1a and 1b reacted similarly (Table 2, en-
P
P
O
O
tries 1e2, 5e6 and 9e10): the nature of the phosphonate ester
(R3¼Et, Bn) has no influence on reactivity. The monosubstituted
diene 1c (R1¼Me) gave bicyclic adducts with moderate yields
(Scheme 2, Table 2, entries 3, 7 and 11), while the disubstituted
diene 1d (R1¼R2¼e(CH2)4e) led to tricyclic adducts with moderate
to low yields (Fig. 2, Table 2, entries 4, 8 and 12). By following the
cycloaddition reactions of diene 1c,d by NMR spectroscopy, it was
clear that the Z-isomers did not react. This observation could par-
tially explain the lower yields of cycloadducts collected with
substituted dienes, combined with purification difficulties.
i
N
N
N
N
N
N
(a)
R
R
O
O
O
1
2
3
(R = H, Me)
OH
OH
R
R
O
O
O
P
O
ii
N
N
1
(b)
+
R
O
O
O
4
5
O
N
O
N
R
R
R
O
O
O
P
The all-cis relative stereochemistry of the cycloadducts 5 and 7
could be determined from typical coupling constant values in 1H
NMR. For cycloadduct 5b as an example, 3J6,P¼21.1 Hz, 3J1,6¼5.8 Hz
O
iii
OR
OR
O
O
P
N
1 +
O
(c)
N
R
O
O
3
and J5,6¼8.9 Hz correspond to dihedral angles of 130ꢁ
6
7
(H6eC6eC1eP), 49ꢁ (H1eC1eC6eH6) and 37ꢁ (H6eC6eC5eH5), re-
spectively. Compounds 5 are thus obtained as racemic mixtures of
single diastereoisomers. In principle, compounds 7 are racemic
mixtures of two diastereoisomers. Despite a lot of experimental
conditions tested, HPLC traces did not reveal peaks splitting. The
separation of diastereoisomers 7 was not possible.
Scheme 2. [4þ2] cycloadditions of dienes 1aec on three representative dienophiles.
Conditions (i) DCE, reflux, 1e1 h 30 min; (ii) neat, 120 ꢁC, 6e8 h; (iii) neat, 140 ꢁC,
6e8 h.
OH
EtO
EtO
2
O
EtO
EtO
O
P
P
O
O
Only the tricycle 3d could be crystallized for single crystal X-ray
diffraction analysis. As shown in Fig. 3, the triazole cycle is planar
N
N
1
ꢁ
ꢁ
N
N
(rms error 0.004 A) making an angle of 44.1(2) with the attached
benzene ring. The heterocyclic six-membered ring is in an enve-
3
4
O
O
lope (E) form (Cremer and Pople: puckering amplitude (Q)¼
ꢁ
0.434(4) A,
q
¼57.3(7)ꢁ,
f
¼54.5(7)ꢁ) with the nitrogen atom at the
3d
5d
junction displaced from the plane on the opposite side of the
phosphorous atom, which is in the axial position. The cyclohexane
O
moiety is in a chair conformation (Cremer and Pople: puckering
ꢁ
amplitude (Q)¼0.586(6) A,
q
¼4.7(6)ꢁ,
f
¼282(8)ꢁ). The rms de-
N
EtO
EtO
O
viations between the different molecules in the asymmetric unit
P
O
ꢁ
ꢁ
(between 0.0955 A and 0.6090 A, see Table 2 in Supplementary
data for more details), means that the molecules display the
same geometrical features. The largest deviations are thus found
around the OCH2CH3 groups attached to the phosphorus atom,
which show disorder in half of the molecules. Looking closely at
the crystal packing one could observe compound 3d to crystallize
as a loose ensemble/dimer of two identical enantiomers, con-
nected by a pseudo-2-fold axis; the driving force for this ar-
rangement is believed to be the optimal shape packing of this pair.
This arrangement is also believed to cause the high Z0¼6 value.
Characteristic bond and angle information are given as
Supplementary data.
O
P
OEt
OEt
O
N
O
7d
Fig. 2. Tricyclic products obtained from diene 1d cycloadditions.
Table 2
Yields of pure cycloadducts 3, 5 and 7
Entry
R1
R2
R3
Cmpd
Yields (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
Et
Bn
Et
Et
Et
Bn
Et
Et
Et
Bn
Et
Et
3a
3b
3c
3d
5a
5b
5c
5d
7a
7b
7c
7d
8311
82
52
Me
e(CH2)4e
H
H
Me
e(CH2)4e
H
H
53
H
H
H
5611d
50
37
45
9
H
H
H
16a,11d
37
10
11
12
Me
e(CH2)4e
34
17
a
Purification problems.
Fig. 3. Ortep representation of the cycloadduct 3d, showing thermal displacement
ellipsoides at the 50% probability level.
Based on the isolated yields of cycloadducts 3, 5, 7, the hetero-
dienophile 2 appeared more reactive than the maleimides 4 and 6.
Cycloadducts 3 were formed within 1 h 30 min by heating 2 and 1
in 1,2-dichloroethane at reflux. Cycloadducts 5 and 7 were obtained
from neat mixtures of 1 with 4 and 6, respectively, maintained at
120 ꢁC and 140 ꢁC during 6e8 h. Under these conditions, compe-
tition with the diene dimerization occured,27 leading to very ar-
duous chromatographic purifications.
By hydrogenation in the presence of Pd/C catalyst, the dibenzyl
phosphonate group of cycloadducts 3b, 5b and 7b was quantita-
tively deprotected, giving access to the phosphonic acid derivatives
8, 9 and 10 (Fig. 4). As expected, the C]C double bond was also
reduced.

E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
1141
OH
HO
HO
2
O
HO
HO
O
P
P
O
O
N
N
1
N
N
3
4
O
O
8
9
O
N
HO
HO
O
P
O
O
P
OH
OH
O
N
O
10
Fig. 4. Phosphonic acid derivatives obtained by hydrogenolysis of dibenzyl phospho-
nate precursors 3b, 5b and 7b.
2.3. Metal coordination study
The dimer-like cycloadducts 7a, 7c and 7d (L) have been tested
for coordination with di- (Ca2þ, Co2þ, Fe2þ, Mg2þ, Ni2þ, Zn2þ) and
trivalent (Eu3þ, Gd3þ, La3þ, Lu3þ) cations (M) in solution, using ESI-
HRMS as the analytical tool according to a procedure described in
precedent works.11 All the complexes identified by ESI-HRMS were
monocharged and possessed the [L:M], i.e., one ligand for one metal
cation, stoichiometry. The coordination sphere of metallic cations
was completed with one or two poorly coordinating counter-
anion(s), that is, one perchlorate anion in the case of divalent metal
and two nitrate anions in the case of trivalent metal. The tables of
identified complexes (experimental and calculated masses, atomic
compositions, and relative abundances) are given in
Supplementary data (Tables 4e6 in Supplementary data S64eS65).
The structures of the coordination complexes are confirmed by the
isotopic distributions, as illustrated in Fig. 5 with the zinc (part A)
and gadolinium (part B) complexes of 7a. The observed patterns are
identical to the calculated ones.
Fig. 5. Experimental (at the top) and theoretical (at the bottom) isotopic distribution
of: part A: [Zn: 7a] coordination complex (with atomic composition:
The ratios of complexes [LM(II)ClO4]þ and [LM(III)(NO3)2]þ
versus the respective free metal salts gave a qualitative idea of the
coordination capacity of the ligands 7. We found the following or-
der: 7a>7c>7d, meaning that the steric hindrance is unfavourable
to the coordination. All the M3þ cations are more efficiently co-
ordinated than M2þ cations, and amongst the M2þ cations, com-
plexes with Zn2þ, Co2þ and Fe2þ are favoured. A possible structure
of [L:M] complex of the ligand 7a with gadolinium is depicted in
Fig. 6.
C
C
30H46O14N2ClP2Zn). Part B: [Gd: 7a] coordination complex (with atomic composition:
30H46O16N4GdP2).
EtO
EtO
P
O
O
O
O
N
N
O
Gd(III)
O
EtO
EtO
2
3. Conclusion
O
P
O
1-Phosphono-3(4-di)-substituted-1,3-butadienes 1aef were
prepared by HornereWadswortheEmmons (HWE) reaction be-
tween dialkyl methylenediphosphonate and
a,
b-unsaturated al-
N
dehydes with good to moderate yields depending on the nature of
the phosphonate ester. Dibenzyl phosphonate dienes (1b, 1e, 1f),
which are the most useful reagents in the context of DA cyclo-
adducts deprotection, were less efficiently synthesized than the
corresponding diethyl phosphonates (1a, 1c, 1d). The HWE reaction
appears sensitive to the steric bulkiness of both partners, the
O
Fig. 6. Postulated structure of [7a: Gd] coordination complex.
diphosphonate anion and the
a
,
b
-unsaturated aldehyde. The in-
tricyclic cycloadducts 3, 5 and 7. In the case of N-substituted mal-
eimide dienophiles, the bicyclic structures present a half-cage
shape due to the all-cis relative stereochemistry of the sub-
stituents, resulting from the cycloaddition mechanism (cis-stereo-
specificity, ortho and endo rules of DA reaction). The novel
stability of benzyl esters under strong basic conditions (NaH) could
also handicap the HWE condensation in the dibenzyl phosphonate
series. DielseAlder (DA) reaction between these dienes 1aee and
reactive dienophiles 2, 4 and 6 gave access to original bicyclic and

1142
E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
phosphonic derivatives 8e10 were obtained in two steps from di-
ene 1b: a DielseAlder reaction followed by the catalytic hydro-
genolysis of dibenzyl phosphonates. The synthesis of pure
phosphonic acids remains a difficult task; in spite of moderate
yields of final products, the use of dibenzyl phosphonodiene seems
to be the best approach. The coordination properties of the ethyl
phosphonates 7 towards M2þ and M3þ cations have been demon-
strated in solution.
(4ꢂ7 mL, R3¼Bn) or ethyl acetate (4ꢂ5 mL, R3¼Et), and the com-
bined organic portions were dried over magnesium sulfate. Filtra-
tion and concentration under reduced pressure gave the crude
diene 1, which is purified by silica gel chromatography with ethyl
acetate.
4.2.1. 1-Diethylphosphono-1,3-butadiene (1a). NaH (60%, dispersed
in oil, 28 mg, 0.694 mmol), tetraethyl methylenediphosphonate
(0.20 g, 0.694 mmol) in toluene (4.7 mL) and acrolein (41 mL, 32 mg,
4. Experimental section
0.578 mmol) in toluene (2.3 mL) furnished the title compound as
yellowish oil (86 mg, 78%). The spectral data were in agreement
with the literature.10,19
4.1. Materials and methods
Experiments were performed under an atmosphere of dry ar-
gon. The chemicals purchased from Acros Organic, Alfa Aesar and
SigmaeAldrich were of reagent grade and used without purifica-
tion. TLC analyses were performed on aluminium plates coated
with silica gel Merck 60 F-254 and flash column chromatographies
over silica gel (230e400 mesh). Visualization of TLC plates was
performed under a UV lamp (254 nm), and using p-anisaldehyde or
KMnO4. Analytical grade solvents were used for reactions and
solvents used for column chromatographies were technical sol-
vents distilled before use. Reactions under microwave heating were
conducted in sealed tubes using MicroSYNTH equipment (Mile-
stone Srl). NMR spectra were recorded on a Bruker AVANCE II 300
spectrometer operating at 300 MHz for 1H, 75 MHz for 13C and
121 MHz for 31P and on a Bruker AVANCE II 500 spectrometer op-
erating at 500 MHz for 1H, 125 MHz for 13C and 202 MHz for 31P.
Chemical shifts were reported in parts per million from tetrame-
4.2.2. 1-Dibenzylphosphono-1,3-butadiene (1b). NaH (60% oil dis-
persed, 0.15 g, 3.65 mmol) tetrabenzyl methylenediphosphonate
(1.96 g, 3.65 mmol) in toluene (8 mL), and acrolein (213 mL, 0.17 g,
3.04 mmol) in toluene (8 mL) furnished the title compound as
a yellowish oil (0.49 g, 51%). Rf [silica gel, toluene/ethyl acetate
(5:2)]¼0.6. 1H NMR (300 MHz, CDCl3)
d: 7.33 (m, CH(Ph), 10H), 7.07
(ddd, J2,P¼21.2 Hz, J1,2¼16.9 Hz and J2,3¼10.6 Hz, C(2)eH, 1H),
3
3
3
3
3
6.36 (dt, J3,4a¼17.2 Hz and J2,3¼3J3,4b¼10.3 Hz, C(3)eH, 1H), 5.72
2
3
(dd, J1,P¼19.1 Hz and J1,2¼17.0 Hz, C(1)eH, 1H), 5.50 (d,
3J3,4a¼17.0 Hz, C(4)eHa, 1H), 5.43 (d, J3,4b¼9.9 Hz, C(4)eHb, 1H),
3
5.03 (d, 3JH,P¼8.0 Hz, PO(OCH2Ph)2, 4H). 13C NMR (75 MHz, CDCl3)
d:
149.2 (d, 2J2,P¼5.8 Hz, C(2)), 136.3 (d, 3JC,P¼6.6 Hz, Cq(Ph)), 135.7 (d,
3J3,P¼27.2 Hz, C(3)), 128.6 (s, CH(Ph)), 128.5 (s, CH(Ph)), 128.0 (s,
1
CH(Ph)), 125.3 (s, C(4)), 117.7 (d, J1,P¼190.8 Hz, C(1)), 67.4 (d,
2JC,P¼5.4 Hz, OCH2). For other data, see Ref. 21.
thylsilane as the internal standard (
d
¼0.0 ppm) for the 1H spectra.
4.2.3. 1-Diethylphosphono-3-methyl-1,3-butadiene (1c). NaH (60%,
dispersed in oil, 28 mg, 0.693 mmol), tetraethyl methyl-
enediphosphonate (200 mg, 0.693 mmol) in toluene (4.7 mL) and
The internal standard was deuterated chloroform for the 13C
spectra (
d
¼77.16 ppm). 31P downfield shifts (
d) were expressed with
a positive sign, using 85% H3PO4 in H2O as external standard.
methacrylaldehyde (90%, 54 mL, 41 mg, 0.577 mmol) in toluene
Spectra were reported as follows: chemical shift (
d
ppm), multi-
(2.3 mL) furnished the title compound as a mixture of stereoiso-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet),
coupling constants (Hertz), integration, and assignment. The atom
numbering used for NMR descriptions is given in Scheme 2; the
dienyl protons were assigned as the protons number 1e4 because
this motif was common for all the cycloadducts. Melting points
mers (E:Z¼87:13) not separated by column chromatography, as
a yellow oil (93.3 mg, 79%). Rf [silica gel, ethyl acetate]¼0.5. IR (
n,
cmꢀ1): 3031 (m), 2923 (m), 1623 (w, C]C), 1591 (m, C]C), 1497
(w), 1456 (m, C]C), 1377 (m), 1231 (s, P]O), 1217 (s, P]O), 1014 (s,
PeO), 991 (s, PeO), 735 (s), 696 (s). HRMS (MALDI-TOF, positive
mode) m/z (%) [MþH]: calcd for C9H18O3P: 205.0994, found:
205.0987 (37); [MꢀCH2]CH2]: 177.0644 (19); [Mꢀ2CH2]CH2]:
149.0318 (100); [MꢀCH2]CH2eH2O]: 131.0250 (17).
€
(mp) were determined on a Buchi B-540 apparatus calibrated with
caffeine, vanillin and phenacetin. Infrared spectra (IR) were recor-
ded by transmittance with a Schimadzu FTIR-8400S equipment and
the absorption bands are reported in cmꢀ1. Products were analyzed
as thin films deposited on a SeeZn crystal by evaporation from
CHCl3 solutions. The intensity of peaks was noted by (w), (m) and
(s), respectively, for weak, medium and strong. Mass spectra (MS)
were recorded with a LCQ Finnigan MAT and the masses are re-
ported in Dalton. High Resolution Mass Spectrometry analyses
(MALDI-TOF HRMS) were carried out at the University College
E-Isomer (major): 1H NMR (500 MHz, CDCl3)
d: 7.18 (dd,
3J2,P¼22.0 Hz and 3J1,2¼17.3 Hz, C(2)eH, 1H), 5.68 (t,
2J1,P¼3J1,2¼17.9 Hz, C(1)eH, 1H), 5.34 (m, C(4)eH, 1H), 5.32 (s, C(4)e
H, 1H), 4.12e4.07 (m, PO(OCH2CH3)2, 4H), 1.88 (s, CH3, 3H), 1.34 (t,
3JH,H¼7.1 Hz, PO(OCH2CH3)2, 6H). 13C NMR (125 MHz, CDCl3)
d:
2
3
151.2 (d, J2,P¼5.9 Hz, C(2)), 140.8 (d, J3,P¼23.6 Hz, C(3)), 123.8 (s,
1
2
C(4)), 124.7 (d, J1,P¼189.6 Hz, C(1)), 61.8 (d, JC,P¼5.2 Hz,
3
London using Waters Maldi microMX equipment with an
4-hydroxycinnamic acid matrix.
a-cyano-
PO(OCH2CH3)2), 17.8 (s, CH3), 16.4 (d, JC,P¼6.3 Hz, PO(OCH2CH3)2).
31P NMR (202 MHz, CDCl3)
d: 20.49.
Z-Isomer (minor): 1H NMR (300 MHz, CDCl3)
d: 6.95e6.79 (m,
4.2. General procedure for the preparation of dienes 1
C(4)eH, 1H), 6.66 (dd, 3J2,P¼22.8 Hz and 3J1,2¼17.1 Hz, C(2)eH, 1H),
6.16 (s, C(4)eH, 1H), 5.72 (dd, 2J1,P¼20.4 Hz and 3J1,2¼17.1 Hz, C(1)e
H, 1H), 4.12e4.07 (m, PO(OCH2CH3)2, 4H), 1.88 (s, CH3, 3H), 1.34 (t,
To a suspension of sodium hydride (1.2 equiv) in dry toluene
(6.8 mL/mmol) was added tetraethyl methylenediphosphonate
(R3¼Et) or tetrabenzyl methylenediphosphonate (R3¼Bn)
(1.2 equiv) at room temperature. After about 15 min (end of
gaseous dihydrogen evolution), a solution of aldehyde (acrolein,
methacrylaldehyde or 1-cyclohexen-1-carboxyaldehyde) (1 equiv)
in dry toluene (0.1 mL/mmol of acrolein, 4.0 mL/mmol of meth-
3JH,H¼7.1 Hz, PO(OCH2CH3)2, 6H). 13C NMR (125 MHz, CDCl3)
d:
155.0 (d, 2J2,P¼4.8 Hz, C(2)), 136.4 (s, C(4)), 115.2 (d, 1J1,P¼185.4 Hz,
2
C(1)), 107.8 (s, C(3)), 61.8 (d, JC,P¼5.2 Hz, PO(OCH2CH3)2), 17.8 (s,
CH3), 16.4 (d, JC,P¼6.3 Hz, PO(OCH2CH3)2). 31P NMR (202 MHz,
3
CDCl3) d: 19.82.
acrylaldehyde
and
1.4
mL/mmol
of
1-cyclohexen-1-
4.2.4. Diethyl-2-cyclohexenylvinylphosphonate (1d). NaH (60%,
dispersed in oil, 87 mg, 2.178 mmol), tetraethyl methyl-
enediphosphonate (1.17 g, 2.178 mmol) in toluene (5.0 mL) and 1-
carboxyaldehyde) was added dropwise to the solution of sodium
salt of tetraalkyl methylenediphosphonate and the mixture was
stirred for two additional hours. After addition of water (2e3 mL/
mmol), the aqueous layer was extracted with dichloromethane
cyclohexen-1-carboxyaldehyde (207
mL, 0.20 g, 1.815 mmol) in
toluene (2.5 mL) furnished the title compound as a mixture of

E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
1143
stereoisomers (E:Z¼97:3), not separated by column chromatogra-
on silica gel. The reaction of 2 and diene 1a, giving the cycloadduct
3a, has been described previously.11a
phy, as a yellowish oil (362 mg, 82%). Rf [silica gel, ethyl acetate]¼
3
0.7. 1H NMR (500 MHz, CDCl3)
d
: 6.99 (dd, J2,P¼22.9 Hz and
3J1,2¼17.4 Hz, C(2)eH, 1H), 6.03 (m, C(4)eH, 1H), 5.42 (t,
2J1,P¼3J1,2¼17.0 Hz, C(1)eH, 1H), 4.00e3.96 (m, PO(OCH2CH3)2, 4H),
2.13e2.06 (m, CH(4)eCH2 or C(3)eCH2, 2H), 2.06e1.98 (m, C(3)e
CH2 or CH(4)eCH2, 2H), 1.63e1.55 (m, CH(4)eCH2eCH2 or C(3)e
CH2eCH2, 2H), 1.55e1.47 (m, C(3)eCH2eCH2 or CH(4)eCH2eCH2,
4.3.1. Dibenzyl 2,3,5,8-tetrahydro-1,3-dioxo-2-phenyl-1H-[1,2,4]tri-
azol-[1,2-a]pyridazin-5-yl-5-phosphonate (3b). Diene 1b (123.0 mg,
0.391 mmol) and 4-phenyl-4H-1,2,4-triazole-3,5-dione 2 (68.5 mg,
0.391 mmol) in 1,2-dichloroethane (1.8 mL) furnished the title
compound as a white solid (156 mg, 82%). Rf [silica gel, ethyl
2H),1.25e1.20 (m, PO(OCH2CH3)2, 6H). 13C NMR (125 MHz, CDCl3)
acetate]¼0.4. Mp (ꢁC): 124.1. 1H NMR (500 MHz, CDCl3)
d: 7.43e7.35
2
3
d:
152.3 (d, J2,P¼6.1 Hz, C(2)), 138.2 (s, C(4)), 135.5 (d,
(m, CH(Ph), 5H), 7.31 (br s, CH(Ph), 10H), 6.05 (ddq, J2,3¼10.1 Hz,
3J3,P¼23.4 Hz, C(3)), 109.2 (d, J1,P¼190.8 Hz, C(1)), 61.6 (d,
2J¼5.2 Hz, PO(OCH2CH3)2), 26.2 (s, CH(4)eCH2 or C(3)eCH2), 23.8
(s, C(3)eCH2 or CH(4)eCH2), 22.0 (s, CH(4)eCH2eCH2 or C(3)e
CH2eCH2), 21.9 (s, C(3)eCH2eCH2 or CH(4)eCH2eCH2), 16.3 (d,
J3,4¼6.0 Hz and J3,4 ¼ J3,P¼ J1,3¼2.4 Hz, C(3)eH, 1H), 5.97 (dddd,
1
3
3
4
4
0
3J2,3¼10.4 Hz, J2,P¼6.9 Hz, J1,2¼3.7 Hz and J2,4¼1.8 Hz, C(2)eH,
4
3
4
3
4
1H), 5.08 (dd, JH,P¼8.0 Hz and JH,H¼1.7 Hz, CH2ePh, 2H), 5.06 (t,
3JH,P¼4JH,H¼8.8 Hz, CH2ePh, 2H), 4.99 (dddt, J1,P¼14.7 Hz,
2
3J¼5.9 Hz, PO(OCH2CH3)2). 31P NMR (202 MHz, CDCl3)
d: 21.97. IR
J1,2¼4.9 Hz, J1,3¼2.3 Hz and J1,4¼ J1,4 ¼1.6 Hz, C(1)eH, 1H), 4.18
2 3 5 4
3
4
5
5
0
, cmꢀ1): 2941 (m), 1632 (s, C]C), 1595 (s, C]C), 1479 (w), 1444
(dddd, J4,4 ¼16.9 Hz, J3,4¼6.0 Hz, J4,P¼2.5 Hz and J2,4¼1.6 Hz,
2 3
0
(n
0
0
(w), 1393 (m), 1246 (s, P]O), 1211 (m, P]O), 1013 (s, PeO), 945 (s,
PeO), 849 (s), 793 (s), 733 (s). HRMS (MALDI-TOF, positive mode)
m/z (%) [MþH]: calcd for C12H22O3P: 245.1307, found: 245.1313
(68); [MꢀCH3]: 230.0955 (64); [MþHꢀCH2]CH2]: 217.1001 (34);
[MþHꢀ2CH2]CH2]: 189.0696 (100); [MþHꢀ2CH2]CH2eH2O]:
171.0580 (10).
C(4)eH, 1H), 3.98 (ddq, J4,4 ¼16.9 Hz, J3,4 ¼2.5 Hz and
4 4 5
J4 ,P¼ J2,4 ¼ J1,4¼1.6 Hz, C(4)eH0, 1H). 13C NMR (125 MHz, CDCl3)
d
:
0
0
153.0 (s, C]O), 151.1 (s, C]O), 135.6 (d, 3JC,P¼5.7 Hz, Cq(Ph)), 131.1
(s, Cq(Ph)),129.1 (s, CH(Ph)), 128.7 (s, CH(Ph)), 128.7 (d, 5JC,P¼1.9 Hz,
CH(Ph)), 128.3 (d, 4JC,P¼5.2 Hz, CH(Ph)), 128.2 (s, CH(Ph)), 128.2 (s,
3
2
CH(Ph)), 125.1 (d, J3,P¼10.0 Hz, C(3)), 118.9 (d, J2,P¼5.2 Hz, C(2)),
2
2
68.7 (d, JC,P¼7.1 Hz, CH2ePh), 68.6 (d, JC,P¼6.4 Hz, CH2ePh), 51.6
1
4
4.2.5. 1-Dibenzyl-3-methyl-1,3-butadiene (1e). NaH (60%, dispersed
in oil, 18 mg, 0.446 mmol), tetrabenzyl methylenediphosphonate
(0.239 g, 0.446 mmol) in toluene (3 mL) and methacrylaldehyde
(d, J1,P¼139.1 Hz, C(1)), 44.2 (d, J4,P¼3.1 Hz, C(4)). 31P NMR
(202 MHz, CDCl3) d: 18.90. IR (n
, cmꢀ1): 3100e2800 (large band, w,
OH), 2000e1665 (w, Ph),1778 (s, C]O),1715 (s, C]O),1693 (s, C]C
(Ph)), 1599 (m, CH]CH), 1502 (s), 1456 (m), 1410 (s), 1298 (m), 1245
(m, P]O), 1138 (m), 1030 (s, PeO), 1007 (s), 993 (s, PeO), 914 (m),
873 (m), 848 (m), 736 (s), 721 (s). HRMS (MALDI-TOF, positive
mode) m/z (%) [MþNa]: calcd for C26H24N3O5PNa: 512.1351, found:
512.1340 (100).
(90%, 34 mL, 0.026 g, 0.371 mmol) in toluene (1,5 mL) afforded the
title compound as a mixture of stereoisomer (E:Z¼87:13), not
separated by column chromatography, as a yellow oil (23 mg, 19%).
Rf [silica gel, toluene/ethyl acetate, 5:2]¼0.3. IR (
n
, cmꢀ1): 2980 (m),
2906 (m), 1626 (w, C]C), 1591 (m, C]C), 1479 (w, C]C), 1442 (m,
C]C), 1392 (m), 1294 (w), 1244 (s, P]O), 1211 (s, P]O), 1163 (m),
1013 (s, PeO), 964 (s, PeO), 854 (s), 829 (m), 752 (s), 696 (s).
HRMS (MALDI-TOF, positive mode) m/z (%) [MþNa]: calcd
4.3.2. Diethyl (1a, 2a, 6, 9)-tetrahydro-8-methyl -4-phenyl-1,2,4]tri-
azolo-[1a, 2-a]-pyridazinyl-6-phosphonate-3,5-dione (3c). 4-Phenyl-
4H-1,2,4-triazole-3,5-dione 2 (0.191 g, 1.09 mmol) and diene 1c
(0.223 g, 1.09 mmol) in 1,2-dichloroethane (5.0 mL) afforded the
for
C
19H21O3PNa: 351.1126, found: 351.1115 (100); [MþH]:
329.1308 (48).
E-Isomer (major): 1H NMR (500 MHz, CDCl3)
d: 7.31e7.37 (m,
title compound as a yellow oil (0.216 g, 52%). Rf [silica gel, ethyl
CH(Ph), 10H), 7.15 (dd, 3J2,P¼22.4 Hz and 3J1,2¼17.3 Hz, C(2)eH, 1H),
acetate]¼0.4. 1H NMR (500 MHz, CDCl3)
d
: 7.53 (dd, JH,H¼8.3 Hz
3
2
3
5.63 (dd, J1,P¼18.9 Hz and J1,2¼17.3 Hz, C(1)eH, 1H), 5.31 (m,
and 4JH,H¼1.2 Hz, CH(Ph), 2H), 7.47 (tt, 3JH,H¼7.9 Hz and 4JH,H¼1.3 Hz,
3
3
4
C(4)eH, 1H), 5.28 (s, C(4)eH0, 1H), 5.05 (d, JH,P¼8.2 Hz,
CH(Ph), 2H), 7.37 (td, JH,H¼7.3 Hz and JH,H¼1.3 Hz, CH(Ph), 1H),
2 5
PO(OCH2Ph)2, 4H), 1.79 (s, CH3, 3H). 13C NMR (125 MHz, CDCl3)
d:
5.80 (br s, C(2)eH, 1H), 4.90 (dddq, J4,4 ¼13.7 Hz, J4,P¼3.9 Hz,
0
153.95 (d, 2J2,P¼6.0 Hz, C(2)), 140.73 (d, 3J3,P¼24.1 Hz, C(3)), 136.29
4J2,4¼2.6 Hz and J4,H¼1.3 Hz, C(4)eH, 1H), 4.23e4.21 (m, C(1)eH,
4
3
(d, JC,P¼11.8 Hz, Cq(Ph)), 128.55 (s, CH(Ph)), 128.37 (s, CH(Ph)),
1H), 4.21e4.11 (m, PO(OCH2CH3)2, 4H), 3.97e3.93 (m, C(4)eH0, 1H),
1.90 (d, 4JH,H¼1.3 Hz, CH3), 1.31 (br t, 3J¼6.9 Hz, PO(OCH2CH3)2, 6H).
127.92 (s, CH(Ph)), 124.03 (s, C(4)), 113.88 (d, 1J1,P¼190.5 Hz, C(1)),
67.33 (d, JC,P¼5.4 Hz, PO(OCH2Ph)2), 17.63 (s, CH3). 31P NMR
13C NMR (125 MHz, CDCl3)
d
: 152.5 (s, C]O),150.5 (s, C]O),131.2 (s,
2
3
(202 MHz, CDCl3)
d
: 21.53.
Cq(Ph)), 131.1 (d, J3,P¼10.1 Hz, C(3)), 129.0 (s, CH(Ph)), 128.0 (s,
Z-Isomer (minor): 1H NMR (500 MHz, CDCl3)
d
: 7.31e7.37 (m,
CH(Ph)), 125.4 (s, CH(Ph)), 113.2 (d, J2,P¼5.1 Hz, C(2)), 63.2 (d,
2
CH(Ph),10H), 6.87 (ddt, 3J2,P¼28.3 Hz, 3J1,2¼17.0 Hz and 4J2,4¼5.7 Hz,
2JC,P¼7.1 Hz, PO(OCH2CH3)2), 63.0 (d, 2J C,P¼6.4 Hz, PO(OCH2CH3)2),
50.7 (d, 1J1,P¼141.1 Hz, C(1)), 47.1 (d, 4J4,P¼2.6 Hz, C(4)), 20.1 (s, CH3),
16.3 (d, 3JC,P¼5.6, PO(OCH2CH3)2), 16.2 (d, 3JC,P¼5.8 Hz,
C(2)eH, 1H), 5.84 (dd, 2J1,P¼20.9 Hz and 3J1,2¼17.1 Hz, C(1)eH, 1H),
2
4
0
6.66 (dd, J4,4 ¼23.2 Hz and J2,4¼1.7 Hz, C(4)eH, 1H), 6.12 (dd,
4J4,H¼2.8 Hz and J2,4¼1.6 Hz, C(4)eH0, 1H), 5.05 (d, JH,P¼8.2 Hz,
PO(OCH2CH3)2). 31P NMR (202 MHz, CDCl3) , cmꢀ1):
d: 18.32. IR (n
4
3
PO(OCH2Ph)2, 4H), 1.79 (s, CH3, 3H). 13C NMR (125 MHz, CDCl3)
d:
2979 (w), 1778 (s, C]O), 1699 (s, C]O), 1599 (w), 1502 (s), 1407 (s),
1286 (s), 1252 (s, P]O), 1161 (m), 1138 (s), 1007 (s, PeO), 951 (s,
PeO), 914 (s), 852 (m), 766 (s), 714 (s), 690 (s) HRMS (MALDI-TOF,
positive mode) m/z (%) [MþNa]: calcd for C17H22N3O5PNa: 402.1195,
found: 402.1182 (100); [MþH]: 380.1349 (14); [MꢀPO(OEt)2]:
242.0930 (45).
153.95 (d, 2J2,P¼6.0 Hz, C(2)), 140.73 (d, 3J3,P¼24.1 Hz, C(3)), 136.29
3
(d, JC,P¼11.8 Hz, Cq(Ph)), 128.55 (s, CH(Ph)), 128.37 (s, CH(Ph)),
127.92 (s, CH(Ph)), 124.03 (s, C(4)), 113.88 (d, 1J1,P¼190.5 Hz, C(1)),
67.33 (d, JC,P¼5.4 Hz, PO(OCH2Ph)2), 17.63 (s, CH3). 31P NMR
2
(121 MHz, CDCl3) d: 20.85.
4.3. General procedure for the DielseAlder reaction with
N]N dienophile 2
4.3.3. Diethyl-2,3,5,7,8,9,10,10a-octahydro-1,3-dioxo-2-phenyl-1H-
[1,2,4]triazolo[1,2a]cinnolin-5-yl-phosphonate (3d). 4-Phenyl-4H-
1,2,4-triazole-3,5-dione 2 (0.124 g, 0.71 mmol) and diene 1d
(0.174 g, 0.71 mmol) in 1,2-dichloroethane (3.3 mL) afforded the
title compound as white needles (0.158 g, 53%). Rf [silica gel, ethyl
A solution of 4-phenyl-4H-1,2,4-triazole-3,5-dione 2 (1 equiv)
and diene 1b, 1c or 1d (1 equiv), in 1,2-dichloroethane (4.6 mL/
mmol) was stirred under vigourous reflux for 1 h 30 min (R3¼Bn) or
1 h (R3¼Et). The reaction mixture was then concentrated under
reduced pressure and directly purified by column chromatography
acetate]¼0.4. Mp (ꢁC): 103.3e104.4. 1H NMR (500 MHz, CDCl3)
d:
7.52 (br d, 3JH,H¼8.1 Hz, CH(Ph), 1H), 7.46 (br t, 3JH,H¼7.9 Hz, CH(Ph),
3
4
1H), 7.36 (td, JH,H¼7.3 Hz and JH,H¼1.2 Hz, CH(Ph), 2H), 5.77 (dt,

1144
E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
3
3J1,2¼5.4 Hz and J2,P¼4J2,H¼1.7 Hz, C(2)eH, 1H), 4.91 (ddt,
(large band, m, OH), 2945 (m), 2856 (m),1774 (m, C]O),1693 (s, C]
O), 1456 (m), 1402 (s), 1371 (m), 1346 (m), 1252 (s), 1226 (s, P]O),
1080 (s, PeO), 955 (s, PeO), 733 (s), 696 (s). HRMS (MALDI-TOF,
positive mode) m/z (%) [MþNa]: calcd for C28H34NO6PNa: 534.2021,
found: 534.2012 (100); [MþH]: 512.2150 (36).
1J1,P¼14.6 Hz, J1,2¼5.1 Hz and J1,H¼2.5 Hz, C(1)eH, 1H), 4.22 (m,
3
5
PO(OCH2CH3)2, 2H), 4.20 (m, PO(OCH2CH3)2, 2H), 4.17 (dtd,
3JH,4¼14.1 Hz, 4J
¼7.0 Hz and 4J ¼4.1 Hz, C(4), 1H), 3.00 (dq,
H,4
2,4
3
3JH,H¼11.8 Hz and JH,H¼4JH,H¼2.3 Hz, C(4)eCH2, 1H), 2.51 (dt,
2JH,H¼13.8 Hz and JH,H¼1.7 Hz, C(3)eCH2, 1H), 2.08 (dq,
3
3
2JH,H¼13.6 Hz and JH,H¼4JH,H¼6.0 Hz, C(3)eCH2, 1H), 1.91e1.84
4.4.2. Diethyl (1,1a,3,3a,4,7)-hexahydro-2-(6-hydroxyhexyl)-5-
methyl-2H-isoindol-4-phosphonate-1,3-dione (5c). N-(6-Hydroxy-
hexyl)-maleimide 4 (0.185 g, 0.935 mmol) and diene 1c (0.191 g,
0.935 mmol) yielded the title compound as a yellow oil (0.140 g,
37%). Rf [silica gel, ethyl acetate/acetone, 1:1]¼0.4. 1H NMR
(m, C(3)eCH2eCH2, 2H), 1.62 (qd, 2JH,H¼12.1 Hz and
3JH,H¼2.4 Hz, C(4)eCH2eCH2, 1H), 1.55 (qt, JH,H¼13.5 Hz
2
3
2
and JH,H¼2.9 Hz, C(4)eCH2eCH2, 1H), 1.37 (qt, JH,H¼13.4 Hz and
3JH,H¼4JH,H¼4.1 Hz, C(4)eCH2, 1H), 1.34 (t, JH,H¼7.6 Hz,
3
PO(OCH2CH3)2, 3H), 1.33 (t, JH,H¼7.8 Hz, PO(OCH2CH3)2, 3H). 13C
(500 MHz, CDCl3)
d
: 5.64 (dd, 3J2,P¼7.2 Hz, 3J1,2¼6.0 Hz, C(2)eH, 1H),
3
NMR (125 MHz, CDCl3)
d
: 153.4 (s, C]O), 149.2 (s, C]O), 138.5 (d,
4.22e4.05 (m, PO(OCH2CH3)2, 4H), 3.59 (t, 3JH,H¼6.3 Hz, CH2OH, 2H),
3.51e3.43 (m, NCH2, 2H), 3.32 (ddd, 3J6,P¼15.8 Hz, 3J5,6¼9.2 Hz and
3J3,P¼10.1 Hz, C(3)), 131.4 (s, Cq(Ph)), 129.2 (s, CH(Ph)), 128.2 (s,
2
3
3
3
0
CH(Ph)), 125.6 (s, CH(Ph)), 109.8 (d, J2,P¼4.5 Hz, C(2)), 63.4 (d,
J1,6¼6.4 Hz, C(6)eH, 1H), 3.13 (td, J5,6¼ J4 ,5¼8.8 Hz and
2JC,P¼6.3 Hz, PO(OCH2CH3)2), 63.1 (d, JC,P¼7.3 Hz, PO(OCH2CH3)2),
3J4,5¼3.9 Hz, C(5)eH, 1H), 2.87 (dt, J1,P¼22.3 Hz, and
2
3
4
1
2
3J1,2¼3J1,6¼5.3 Hz, C(1)eH, 1H), 2.64 (dt,
J4,4 ¼15.9 Hz,
0
58.6 (d, J4,P¼2.8 Hz, C(4)), 49.5 (d, J1,P¼142.7 Hz, C(1)), 34.0 (d,
5JC,P¼2.1 Hz, C(3)eCH2eCH2), 33.4 (s, C(4)eCH2), 27.2 (d,
4JC,P¼3.4 Hz, C(3)eCH2), 23.8 (s, C(4)eCH2eCH2), 16.6 (d,
3
3
4
2
0
J4,5¼ J4,H¼2.8 Hz, C(4)eH, 1H), 2.26 (dd, J4,4 ¼15.7 Hz and
3
J4 ,5¼8.6 Hz, C(4)eH0,1H),1.80 (s, CH3, 3H),1.54 (tt, JH,H¼7.4 Hz and
0
3JC,P¼5.7 Hz, PO(OCH2CH3)2), 16.5 (d, JC,P¼5.9 Hz, PO(OCH2CH3)2).
3JH,H¼7.0 Hz, NCH2CH2 and CH2CH2O, 4H), 1.40e1.34 (m,
CH2(CH2)2OH, 2H), 1.32 (t, 3JH,H¼7.1 Hz, PO(OCH2CH3)2, 3H), 1.31 (t,
3JH,H¼7.0 Hz, PO(OCH2CH3)2, 3H), 1.30e1.23 (m, N(CH2)2CH2, 2H).
3
31P NMR (202 MHz, CDCl3) , cmꢀ1): 3000e2750 (large
d: 18.00. IR (n
band, w), 1771 (s, C]O), 1703 (s, C]O),1599 (w), 1502 (s), 1408 (s),
1290 (s), 1249 (s, P]O), 1142 (m), 1043 (s, PeO), 955 (s, PeO), 798
(s),767 (s). HRMS (MALDI-TOF, positive mode) m/z (%) [MþNa]:
calcd for C20H26N3O5NaP: 442.1508, found: 442.1507 (71); [MþH]:
420.1665 (19); [MꢀHPO(OEt)2]: 282.1243 (100).
13C NMR (125 MHz, CDCl3)
d
: 179.1 (s, C]O), 176.5 (d, 3JC,P¼4.3 Hz,
C]O), 139.2 (d, 3J3,P¼12.9 Hz, C(3)), 116.9 (d, 2J2,P¼7.1 Hz, C(2)), 62.9
2
(d, JC,P¼6.7 Hz, PO(OCH2CH3)2), 62.2 (s, CH2OH), 61.8 (d,
2JC,P¼7.0 Hz, PO(OCH2CH3)2), 40.5 (d, J6,P¼3.0 Hz, C(6)), 39.3 (d,
2
3J5,P¼10.3 Hz, C(5)), 38.7 (s, NCH2), 34.4 (d, 1J1,P¼147.8 Hz, C(1)), 32.4
(s, CH2CH2OH), 28.3 (s, CH2(CH2)2OH), 27.3 (s, NCH2CH2), 26.2 (s,
4.4. General procedure for DielseAlder reaction with C]C
3
dienophile 4
N(CH2)2CH2), 25.1 (s, CH3), 23.4 (s, C(4)), 16.3 (d, JC,P¼6.3 Hz,
PO(OCH2CH3)2), 16.3 (d, JC,P¼6.6 Hz, PO(OCH2CH3)2). 31P NMR
3
A neat mixture of diene 1b, 1c or 1d (1 equiv) and N-(6-
hydroxyhexyl)maleimide 4 (1 equiv) was vigorously stirred at
120 ꢁC for 6e8 h. The oily mixture was directly purified by column
chromatography on silica gel. The reaction of 4 and diene 1a, giving
the cycloadduct 5a, has been described previously.11d
(202 MHz, CDCl3) d: 26.87. IR (n
, cmꢀ1): 3600e3000 (large band, m,
OH), 2923 (m), 2854 (m), 1776 (w, C]O), 1688 (s, C]O), 1439 (m),
1402 (s), 1369 (m), 1346 (m), 1244 (m, P]O), 1221 (m), 1159 (m),
1016 (s, PeO), 960 (s, PeO), 791 (m), 751 (s), 731 (s). HRMS (MALDI-
TOF, positive mode) m/z (%) [MþNa]: calcd for C19H32NO6PNa:
424.1865, found: 424.1860 (100); [MþH]: 402.2010 (46).
4.4.1. Dibenzyl 2,3,3a,4,7,7a-hexahydro-2-(6-hydroxyhexyl)-1,3-
dioxo-1H-isoindol-4-yl-4-phosphonate (5b). N-(6-Hydroxyhexyl)-
maleimide 4 (189 mg, 0.957 mmol) and diene 1b (301 mg,
0.957 mmol) yielded the title compound as a yellow oil (246 mg,
4.4.3. Preparation of diethyl-1a,3a,4,5,5a,6,7,8,9,9a-decahydro-2-(6-
hydroxyhexyl)-1,3-dioxo-1H-benzo[e]isoindol-4-yl-4-phosphonate
(5d). N-(6-Hydroxyhexyl)-maleimide (80.7 mg, 0.409 mmol) 4 and
diene 1d (100 mg, 0.409 mmol) yielded the title compound as
50%). Rf [silica gel, ethyl acetate]¼0.4. 1H NMR (500 MHz, CDCl3)
d:
7.27e7.35 (m, CH(Ph), 5H), 6.03 (dtd, 3J2,3¼9.1 Hz,
a pale yellow oil (81.7 mg, 45%). Rf [silica gel, ethyl acetate/acetone,
3
4
4
3
J3,4 ¼ J3,H¼4.8 Hz, J3,P¼1.3 Hz, C(3)eH, 1H), 5.97 (tdd,
1:2]¼0.4. 1H NMR (500 MHz, CDCl3)
d
: 5.59 (td, J2,P¼3J1,2¼4.3 Hz,
0
3J2,3¼3J2,P¼9.3 Hz, J1,2¼4.9 Hz and J2,4¼1.5 Hz, C(2)eH, 1H), 5.08
4J2,H¼1.7 Hz, C(2)eH, 1H), 4.60e4.24 (m, PO(OCH2CH3)2, 4H), 3.59
3
4
3
2
3
3
(dd, JH,P¼9.3 Hz and JH,H¼7.7 Hz, CH2Ph, 1H), 5.05 (dd,
(t, JH,H¼6.5 Hz, CH2OH, 2H), 3.42 (t, JH,H¼7.1 Hz, NCH2, 2H), 3.35
(ddd, 3J6,P¼13.5 Hz, 3J5,6¼8.0 Hz and 3J1,6¼6.1 Hz, C(6)eH, 1H), 3.11
3JH,P¼11.8 Hz and JH,H¼11.7 Hz, CH2Ph, 1H), 4.99 (dd, JH,P¼9.4 Hz
2
3
2
3
3
2
and JH,H¼7.8 Hz, CH2Ph, 1H), 4.90 (dd, JH,P¼11.8 Hz and
2JH,H¼11.7 Hz, CH2Ph, 1H), 3.57 (t, 3JH,H¼6.5 Hz, CH2OH, 2H), 3.42 (q,
(t, J4,5¼3J5,6¼8.5 Hz, C(5)eH, 1H), 2.80 (dt, J1,P¼24.4 Hz and
3J1,2¼3J1,6¼5.0 Hz, C(1)eH, 1H), 2.34 (t, J4,H¼11.7 Hz, C(4)eH, 1H),
3
3JH,H¼6.9 Hz, NCH2, 2H), 3.40 (ddd, J6,P¼21.1 Hz, J5,6¼8.7 Hz and
2.24e2.19 (m, C(3)eCH2, 1H), 2.13e2.05 (m, C(3)e(CH2)2CH2, 2H),
1.88e1.79 (m, C(4)eCH2, 2H), 1.66e1.57 (m, C(3)eCH2, 1H), 1.52 (tt,
3
3
3
3
3
0
J1,6¼5.8 Hz, C(6)eH, 1H), 3.08 (ddd, J4 ,5¼ J5,6¼8.9 Hz and
3J4,5¼3.7 Hz, C(5)eH, 1H), 2.91 (dt, 2J1,P¼23.3 Hz, 3J1,2¼3J1,6¼5.4 Hz,
3JH,H¼7.2 Hz and JH,H¼7.3 Hz, C(3)eCH2CH2, NCH2CH2 and
3
2
C(1)eH, 1H), 2.69 (m, C(4)eH, 1H), 2.20 (dddt, J4,4 ¼13.8 Hz,
CH2CH2OH, 6H), 1.4e1.33 (m, N(CH2)2CH2, 2H), 1.32 (t, 3JH,H¼7.1 Hz,
0
J4 ,5¼8.4 Hz, 3J3,4 ¼4.4 Hz and J4 ,P¼ J2,4 ¼1.9 Hz, C(4)eH , 1H), 1.51
PO(OCH2CH3)2, 3H), 1.31 (t, JH,H¼7.1 Hz, PO(OCH2CH3)2, 3H),
3
4
4
3
0
0
0
0
0
(tt, 3JH,H¼7.0 Hz and 3JH,H¼6.3 Hz, NCH2CH2 or CH2CH2OH, 2H), 1.50
1.27e1.23 (m, CH2(CH2)2OH and CH2CH2OH, 4H). 13C NMR
(tt, 3JH,H¼6.9 Hz and 3JH,H¼6.4 Hz, CH2CH2OH or NCH2CH2, 2H), 1.31
(125 MHz, CDCl3)
d
: 177.0 (s, C]O), 176.2 (d, JC,P¼4.3 Hz, C]O),
3
3
3
2
(quint., JH,H¼7.3, N(CH2)2CH2 or CH2(CH2)2O, 2H), 1.23 (quint.,
144.8 (d, J3,P¼12.8 Hz, C(3)), 114.0 (d, J2,P¼6.7 Hz, C(2)), 63.0 (d,
3JH,H¼7.3, CH2(CH2)2O or N(CH2)2CH2, 2H). 13C NMR (125 MHz,
2JC,P¼6.7 Hz, PO(OCH2CH3)2), 62.3 (s, CH2OH), 61.9 (d, 2JC,P¼6.9 Hz,
3
2
3
CDCl3)
d
: 179.1 (s, C]O), 176.5 (d, JC,P¼4.3 Hz, C]O), 136.5 (d,
PO(OCH2CH3)2), 42.5 (d, J5,P¼10.2 Hz, C(5)), 41.2 (d, J6,P¼2.9 Hz,
C(6)), 38.5 (s, NCH2), 37.0 (s, C(4)), 33.9 (d, 1J1,P¼148.4 Hz, C(1)), 32.5
(s, NCH2CH2 or CH2CH2OH), 31.6 (s, C(3)eCH2CH2 or C(4)CH2CH2),
27.5 (s, NCH2CH2 or CH2CH2OH), 26.3 (s, C(3)eCH2CH2 or C(4)e
CH2CH2), 26.00 (s, C(4)eCH2), 25.2 (s, N(CH2)2CH2 or CH2(CH2)2OH),
23.7 (s, N(CH2)2CH2 or CH2(CH2)2OH or C(4)), 23.7 (s, C(4) or,
N(CH2)2CH2 or CH2(CH2)2OH), 16.5 (d, 3JC,P¼6.3 Hz, PO(OCH2CH3)2),
3JC,P¼5.8 Hz, Cq(Ph)), 136.2 (d, JC,P¼6.0 Hz, Cq(Ph)), 130.5 (d,
3
3J3,P¼13.1 Hz, C(3)), 128.6 (s, CH(Ph)), 128.43 (s, CH(Ph)), 128.4 (s,
2
CH(Ph)), 128.3 (s, CH(Ph)), 128.2 (s, CH(Ph)), 124.6 (d, J2,P¼6.8 Hz,
C(2)), 68.6 (d, 2JC,P¼6.6 Hz, CH2Ph), 67.6 (d, 2JC,P¼6.8 Hz, CH2Ph), 62.4
2
3
(s, CH2OH), 40.7 (d, J6,P¼3.1 Hz, C(6)), 39.1 (d, J5,P¼11.0 Hz, C(5)),
38.9 (s, NCH2), 34.4 (d,1J1,P¼148.7 Hz, C(1)), 32.5 (s, CH2CH2OH), 27.5
(s, NCH2CH2), 26.3 (s, CH2(CH2)2OH), 25.1 (s, N(CH2)2CH2), 23.4 (s,
16.4 (d, 3JC,P¼6.4 Hz, PO(OCH2CH3)2). 31P NMR (202 MHz, CDCl3)
d:
C(4)). 31P NMR (202 MHz, CDCl3)
d
: 27.46. IR (
n
, cmꢀ1): 3500e3100
27.03. IR (n
, cmꢀ1): 3800e3000 (large band, w, OH), 3000e2800

E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
1145
(large band, m), 1776 (w, C]O), 1699 (s, C]O), 1439 (m), 1402 (m),
1369 (m), 1346 (m), 1238 (m, P]O), 1163 (m), 1051 (s), 1028 (s,
PeO), 959 (s, PeO), 794 (m), 721 (s). HRMS (MALDI-TOF, positive
mode) m/z (%) [MþNa]: calcd for C22H36NO6PNa: 464.2178, found:
464.2197 (100)); [MþH]: 442.2416 (29).
27.1 (s, N(CH2)2CH2), 26.0 (s, CH3), 23.3 (s, C(4)), 16.4 (d,
3
3JC,P¼5.9 Hz, PO(OCH2CH3)2), 16.2 (d, JC,P¼6.6 Hz, PO(OCH2CH3)2).
31P NMR (202 MHz, CDCl3) , cmꢀ1): 2982 (m), 2974
d: 26.71. IR (n
(m), 1774 (m, C]O), 1693 (s, C]O), 1431 (m), 1402 (s), 1348 (m),
1246 (s, P]O), 1221 (s, P]O), 1053 (s), 1018 (m, PeO), 959 (s, PeO),
793 (s), 743 (s). HRMS (MALDI-TOF, positive mode) m/z (%) [MþNa]:
calcd for C32H50N2O10P2Na: 707.2838, found: 707.2828 (100);
[MþH]: 685.2965 (28).
4.5. General procedure for the DielseAlder reaction with bis-
maleimide 6
A neat mixture of pure diene 1b, 1c or 1d (2 equiv) and mal-
eimide 6 (1 equiv) was vigorously stirred at 140 ꢁC for 6e8 h. The
oily mixture was directly purified by column chromatography. The
reaction of 6 and diene 1a, giving the cycloadduct 7a, has been
described previously.11d
4.5.3. Diethyl-1a,3a,4,5,5a,6,7,8,9,9a-decahydro-2-(hexyl)-bis-1,3-
dioxo-1H-1,3dioxo-1H-benzoisoindol-4-yl-4-phosphonate (7d). N,N-
Hexamethylen-bis-maleimide 6 (0.226 g, 0.819 mmol) and diene
1d (0.452 g, 1.637 mmol) yielded the title compound as a yellow oil
(0.105 g, 17%), after column chromatography [silica gel: ethyl ace-
tate: acetone: 1:1 then ethyl/acetone: 1:1þ5% MeOH]. Rf [silica gel,
ethyl acetate/acetone, 1:1þ5% MeOH]¼0.4. 1H NMR (500 MHz,
4.5.1. Dibenzyl (1,1a,3,3a,4,7)-hexahydro-2-(hexyl)-bis-2H-isoindol-
4-phosphonate-1,3-dione (7b). N,N-Hexamethylene-bis-maleimide
6 (99 mg, 0.358 mmol) and diene 1b (225 mg, 0.358 mmol) yielded
the title compound as a yellow oil (119 mg, 37%). Rf [silica gel, ethyl
CDCl3) d: 5.64e5.55 (m, C(2)eH), 4.29e4.16 (m, PO(OCH2CH3)2, 2H),
4.16e4.09 (m, PO(OCH2CH3)2, 2H), 3.40 (t, 3JH,H¼7.2 Hz, NCH2, 2H),
3
3
3.36 (m, J6,P¼14.0 Hz and J1,6¼6.8 Hz, C(6)eH, 1H), 3.12 (t,
acetate/acetone (1:1)]¼0.5. 1H NMR (500 MHz, CDCl3)
d: 7.34e7.27
3J4,5¼3J5,6¼8.4 Hz, C(5)eH, 1H), 2.81 (d, 3J1,P¼24.3 Hz, C(1)eH, 1H),
3
(m, CH(Ph), 20H), 6.05e5.99 (m, C(3)eH, 2H), 5.98 (ddd,
2.35 (t, J4,H¼7.5 Hz, C(4)eH, 1H), 2.25e2.19 (m, C(3)eCH2, 1H),
3
4
3J2,3¼9.1 Hz, J1,2¼4.8 Hz and J2,4¼1.4 Hz, C(2)eH, 2H), 5.11 (dd,
2.18e2.10 (m, C(4)eCH2CH2, 2H), 2.09e2.04 (m, C(3)eCH2, 1H), 1.85
2JH,P¼11.8 Hz and 2JH,H¼7.6 Hz, CH2Ph, 2H), 5.07 (dd, 2J¼11.8 Hz and
(t, JH,H¼10.7 Hz, C(4)eCH2, 2H), 1.68e1.57 (m, C(3)eCH2CH2, 2H),
3
2J¼9.5 Hz, CH2Ph, 2H), 4.98 (dd, JH,P¼11.7 Hz and JH,H¼9.4 Hz,
1.56e1.43 (m, NCH2CH2, 2H), 1.33 (t, JH,H¼7.1 Hz, PO(OCH2CH3)2,
2
2
3
2
2
3
CH2Ph, 2H), 4.89 (dd, JH,P¼11.8 Hz and JH,H¼7.9 Hz, CH2Ph, 2H),
3.41 (dddd, 3J6,P¼15.6 Hz, 3J5,6¼9.3 Hz, 3J1,6¼6.0 Hz and 4J4,6¼1.2 Hz,
C(6)eH, 2H), 3.36 (dt, 3JH,H¼7.3 Hz and 3JH,H¼3.7 Hz, NCH2, 4H), 3.10
2H), 1.30 (t, JH,H¼7.1 Hz, PO(OCH2CH3)2, 2H), 1.26e1.22 (m,
N(CH2)2CH2, 2H). 13C NMR (125 MHz, CDCl3)
d: 176.9 (s, C]O), 176.2
3
3
(d, JC,P¼4.0 Hz, C]O), 144.7 (d, J3,P¼12.9 Hz, C(3)), 114.1 (d,
3
3
4
2
(ddd, J4 ,5¼ J5,6¼9.0 Hz and J5,P¼3.5 Hz, C(5)eH, 2H), 2.91 (dt,
2J2,P¼6.1 Hz, C(2)), 63.0 (d, JC,P¼6.6 Hz, PO(OCH2CH3)2), 61.8 (d,
0
2J1,P¼23.2 Hz, J1,2¼3J1,6¼5.2 Hz, C(1)eH, 2H), 2.69 (ddd,
2J¼6.8 Hz, PO(OCH2CH3)2), 42.4 (d, J5,P¼9.8 Hz, C(5)), 41.2 (d,
3
3
2
3
3
5
J4,4 ¼15.7 Hz and J4,5¼ J3,4¼ J4,P¼3.5 Hz, C(4)eH, 2H), 2.23e2.17
2J6,P¼3.0 Hz, C(6)), 38.5 (s, NCH2), 37.0 (s, C(4)), 34.0 (d,
1J1,P¼148.0 Hz, C(1)), 31.7 (s, C(3)eCH2), 27.4 (s, NCH2CH2, 26.3 (s,
N(CH2)2CH2), 26.1 (s, C(4)eCH2CH2), 23.8 (s, C(3)eCH23CH2 or C(4)e
CH2), 23.8 (s, C(4)eCH2 or C(3)eCH2CH2), 16.5 (d, JC,P¼6.5 Hz,
0
(m, C(4)eH0, 2H), 1.45 (tt, 3JH,H¼6.2 Hz and 3JH,H¼6.1 Hz, NCH2CH2,
4H), 1.19e1.16 (m, N(CH2)2CH2, 4H). 13C NMR (125 MHz, CDCl3)
d:
179.0 (s, C]O), 176.5 (d, 3JC,P¼4.4 Hz, C]O), 136.6 (d, 3JC,P¼5.8 Hz,
Cq(Ph)), 136.3 (d, 3JC,P¼6.0 Hz, Cq(Ph)), 130.5 (d, 3J3,P¼13.1 Hz, C(3)),
128.6 (s, CH(Ph)), 128.4 (d, 4JC,P¼2.3 Hz, CH(Ph)), 128.3 (s, CH(Ph)),
128.2 (s, CH(Ph)), 124.7 (d, 2J2,P¼6.8 Hz, C(2)), 68.6 (d, 2JC,P¼6.0 Hz,
PO(OCH2CH3)2), 16.4 (d, JC,P¼6.8 Hz, PO(OCH2CH3)2). 31P NMR
3
(202 MHz, CDCl3) d: 26.87. IR (n
, cmꢀ1): 3000e2800 (large band, w),
1771 (m, C]O), 1694 (s, C]O), 1437 (m), 1398 (m), 1366 (s), 1220
(m, P]O), 1163 (m), 1016 (s, PeO), 957 (s, PeO), 908 (s), 793 (m),
723 (s). HRMS (MALDI-TOF, positive mode) m/z (%) [MþNa]: calcd
for C38H58N2O10P2Na: 787.3464, found: 787.3448 (100); [MþH]:
765.36 (14).
2
2
CH2Ph), 67.5 (d, JC,P¼6.8 Hz, CH2Ph), 40.8 (d, J6,P¼3.4 Hz, C(6)),
39.1 (d, J5,P¼11.1 Hz, C(5)), 38.9 (s, NCH2), 34.5 (d, 1J1,P¼148.7 Hz,
3
C(1)), 27.4 (s, NCH2CH2), 26.3 (s, N(CH2)2CH2), 23.4 (s, C(4)). 31P
NMR (202 MHz, CDCl3) d: 27.42. IR (n
, cmꢀ1): 1776 (w, C]O), 1699
(s, C]O), 1498 (w), 1438 (w), 1402 (m), 1265 (m, P]O), 1151 (w),
1036 (s, PeO), 1024 (s), 997 (s, PeO), 906 (s), 725 (s), 702 (s). HRMS
(MALDI-TOF, positive mode) m/z (%) [MþH]: calcd for
4.6. General procedure for the catalytic hydrogenation
C
50H55N2O10P2: 905.3332, found: 905.3323 (100).
A mixture of dibenzyl phosphono-cycloadduct 3b, 5b or 7b
(1 equiv), Pd/C (10%, 0.1 equiv) and tetrahydrofurane (2 mL/
0.1 mmol) was stirred at room temperature overnight under 1 atm
of H2. The reaction mixture was then filtered over a CeliteÓ pad and
rinced with a CH2Cl2/MeOH (1:1) solution (10 mL/0.1 mmol). The
solvent was removed under reduced pressure.
4.5.2. Diethyl (1,1a,3,3a,4,7)-hexahydro-2-(hexyl)-bis-2H-isoindol-4-
phosphonate-1,3-dione (7c). N,N-Hexamethylene-bis-maleimide 6
(98.4 mg, 0.356 mmol) and diene 1c (145.2 mg, 0.711 mmol) yiel-
ded the title compound as a yellow oil (83.62 mg, 34%), after col-
umn chromatography [silica gel: CH3CN then CH3CNþmethanol
gradient (1e10%)]. Rf [silica gel, CH3CNþ10% MeOH]¼0.2. 1H NMR
4.6.1. Hexahydro-1,3-dioxo-2-phenyl-1H-[1,2,4]triazol-[1,2-a]pyr-
idazin-5-yl-5-phosphonic acid (8). Reduction of the cycloadduct 3b
(215.0 mg, 0.439 mmol) yielded the title compound as a white
3
(500 MHz, CDCl3)
d
: 5.64 (t, J1,2¼3J2,P¼6.4 Hz, C(2)eH, 2H),
4.23e4.13 (m PO(OCH2CH3)2, 4H), 4.13e4.10 (m PO(OCH2CH3)2,
3
3
4H), 3.44 (t, JH,H¼6.4 Hz, NCH2, 4H), 3.32 (ddd, J6,P¼16.2 Hz,
powder (136.0 mg, 100%). 1H NMR (500 MHz, D2O)
d: 7.58e7.50 (m,
3J5,6¼9.1 Hz and 3J1,6¼6.0 Hz, C(6)eH, 2H), 3.12 (td,
CH(Ph), 3H), 7.42 (dd, JH,H¼7.1 Hz and JH,H¼1.4 Hz, CH(Ph), 2H),
3
4
3
3
3
2
3
0
0
J4 ,5¼ J5,6¼8.7 Hz and J4,5¼3.0 Hz, C(5)eH, 2H), 2.87 (dt,
4.48 (dd, J4,4 ¼11.1 Hz and J3,4¼5.6 Hz, C(4)eH, 1H), 4.05 (d,
1J1,P¼23.6 Hz and J1,6¼3J1,2¼5.3 Hz, C(1)eH, 2H), 2.64 (dd,
J1,P¼10.3 Hz, C(1)eH, 1H), 3.27 (td, J4,4 ¼ J3,4¼12.0 Hz and
3
1
3
2
3
0
J4,4 ¼15.9 Hz and J4,H¼2.3 Hz, C(4)eH, 2H), 2.25 (dd, 2J4,4 ¼15.6 Hz
J3 ,4¼3.5 Hz, C(4)eH,1H), 2.29e2.24 (m, C(3)eH, 2H), 2.11e1.97 (m,
2
3
0
0
0
3
and J4 ,H¼8.7 Hz, C(4)eH0, 2H), 1.79 (s, CH3, 3H), 1.52 (tt,
C(2)eH,1H),1.89e1.86 (m, C(2)eH0,1H). 13C NMR (125 MHz, MeOD)
0
3JH,H¼5.5 Hz and 3JH,H¼4.7 Hz, NCH2CH2, 2H), 1.32 (t, 3JH,H¼6.8 Hz,
d
: 154.8 (s, C]O),152.9 (s, C]O),132.8 (s, Cq(Ph)),130.0 (s, CH(Ph)),
3
1
PO(OCH2CH3)2, 6H), 1.31 (t, JH,H¼7.0 Hz, PO(OCH2CH3)2, 6H),
129.4 (s, CH(Ph)), 127.4 (s, CH(Ph)), 51.5 (d, J1,P¼146.4 Hz, C(1)),
1.28e1.20 (m, N(CH2)2CH2, 4H). 13C NMR (125 MHz, CDCl3)
d: 178.8
45.4 (s, C(4)), 24.1 (s, C(2)), 20.26 (s, C(3)). 31P NMR (121 MHz,
3
(s, C]O), 176.4 (s, C]O), 138.9 (d, J3,P¼12.5 Hz, C(3)), 116.8 (d,
MeOD) d: 19.46. IR (n
, cmꢀ1): 3421e3061 (large band, m, OH), 2926
2J2,P¼6.8 Hz, C(2)), 62.6 (d, JC,P¼3.6 Hz, PO(OCH2CH3)2), 61.5 (d,
(m), 2839 (w), 1759 (m, C]O), 1693 (s, C]O), 1502 (m), 1416 (m),
1300 (m),1151 (m, P]O),1065 (w, PeO), 920 (w, PeO), 766 (m), 690
(s). MS (ESI, negative mode) m/z (%)642.98 (14) [2MꢀHeNa],
2
2JC,P¼5.6 Hz, PO(OCH2CH3)2), 40.4 (s, C(6)), 39.1 (d, J5,P¼9.9 Hz,
3
C(5)), 38.5 (s, NCH2), 34.3 (d, 1J1,P¼147.5 Hz, C(1)), 28.0 (s, NCH2CH2),

1146
E. Villemin et al. / Tetrahedron 69 (2013) 1138e1147
620.76 (38) [2Mꢀ2H], 310.12, 280.13 (100) [MꢀH]; MS (ESI, positive
mode) m/z (%)¼333.98 (100) [MþNa], 311.96 (35) [MþH]. HRMS
(MALDI-TOF, negative mode) m/z (%) [MꢀH]: calcd: for
4.8. Crystal data
Compound 3d was crystallized from diethyl ether. Crystal di-
C
12H13N3O5P 310.0593, found: 310.0595 (100).
mensions
0.27ꢂ0.12ꢂ0.08
(colourless),
monoclinic
Cc,
a¼8.03210(17) A, b¼47.3353(8) A, c¼32.9636(9) A,
¼96.786(2)ꢁ,
ꢁ
ꢁ
ꢁ
b
3
ꢁ
V¼12445.0(5) A , Z¼24, Z ¼6, rcalcd¼1.343 g cmꢀ3, 2
q
¼50.48ꢁ,
0
4.6.2. Hexahydro-2-(6-hydroxyhexyl)-1,3-dioxo-1H-isoindol-4-yl-4-
phosphonic acid (9). Reduction of the cycloadduct 5b (80.16 mg,
0.157 mmol) yielded the title compound as a colourless oil
m
(MoK
a
)¼0.169 cmꢀ1, Rigaku Ultra X 18 rotating anode, Zr filter,
Mar345 image plate, T¼150 K, 35,522 measured reflections, 20,068
unique. Data (224 images Df¼0.7ꢁ) were integrated with the
chrysalis software and corrected for absorption by SADABS. The
structure was twinned (180ꢁ rotation around the c*) and was re-
fined accordingly (twin fraction 68/32%).
(52.24 mg, 100%). 1H NMR (500 MHz, D2O)
d
: 3.56 (t, 3JH,H¼6.5 Hz,
3
CH2OH, 2H), 3.49 (t, JH,H¼7.1 Hz, NCH2, 2H), 3.48e3.44 (m,
3
3
3
J5,6¼7.7 Hz, C(6)eH, 1H), 3.09 (ddd, 3J5,6¼ J4,5¼ J4 ,5¼7.3 Hz, C(5)e
0
H,1H), 2.31e2.31 (m, C(1)eH,1H), 2.04e1.98 (m, C(2)eH or C(3)eH,
2H), 1.97e1.91 (m, C(3)eH or C(2)eH, 2H), 1.53e1.47 (m,
CH2CH2OH, NCH2CH2, N(CH2)2CH2 and CH2(CH2)2OH, 8H),
1.39e1.30 (m, C(4)eH, 1H), 1.30e1.22 (m, C(4)eH0, 1H). 13C NMR
The structure was solved by direct methods (SHELXS) and re-
fined by full-matrix least squares on jF2j (SHELXL).33 Non-hydrogen
atoms were anisotropically refined and the hydrogen atoms were
placed on calculated positions with temperature factors fixed at 1.2
times Ueq of the parent atoms and 1.5 times Ueq for methyl groups,
(125 MHz, MeOH d) d: 181.3 (s, C]O), 181.1 (s, C]O), 62.8 (s,
3
CH2OH), 42.3 (d, J6,P¼9.5 Hz, C(6)), 41.9 (s, C(5)), 39.5 (s, NCH2),
33.4 (s, CH2CH2OH), 28.6 (s, NCH2CH2), 27.7 (s, N(CH2)2CH2 or
CH2(CH2)2OH), 27.1 (d, 1J1,P¼164.0 Hz, C(1)), 26.4 (s, CH2(CH2)2OH
N(CH2)2CH2), 26.0 (s, C(4)), 22.5 (s, C(3)), 21.8 (d,
R1¼0.0554 (for 16,375 with I>2
s
(I)),
u
R2¼0.1093,
u
R2 (all data)¼
ꢁꢀ3
0.1195, max/min. residual electron density 0.367/ꢀ0.295 e A
.
2J2,P¼13.6 Hz, C(2)). 31P NMR (121 MHz, MeOH d)
d: 27.02. IR (n,
4.9. ESI-HRMS
cmꢀ1): 3607e3148 (large band, m, OH), 2931 (m), 2866 (m), 1767
(m, C]O), 1693 (s, C]O), 1437 (m), 1405 (m), 1344 (m), 1250 (w),
1221 (w), 1163 (m, P]O),1061 (w, PeO), 978 (w), 920 (w, PeO), 866
(w). MS (ESI, positive mode) m/z (%)¼688.82 (100) [2MþNa],
666.83 (23) [2MþH], 356.14 (45) [MþNa], 334.13 (17) [MþH]; MS
(ESI, negative mode) m/z (%)¼687.00 (100) [2MꢀHþNa], 665.11
(38) [2M], 332.13 (84) [MꢀH]. HRMS (MALDI-TOF, positive mode)
ESI-HRMS analyses were performed with a LTQ-Orbitrap XL
hybrid mass spectrometer (Thermo Fisher Scientific, Bremen, Ger-
many). Data were acquired in the positive ion mode, using a full-
scan MS with a mass range of 200e2000 m/z. The orbitrap operated
at 30,000 resolution [FWHM (full width at half maximum) defini-
tion]. All experimental data were acquired, along with a daily ex-
ternal calibration prior to the data acquisition. The appropriate
tuning of the electrospray ion source was done to ensure the
preservation of the complexes formed in the solution, but to avoid
the detection of adducts formed during the ESI process.34 The fol-
lowing electrospray inlet conditions were applied: flow rate,
m/z (%) [MþNa]: calcd for
C14H24NO6PNa: 356.1239, found:
356.1226 (97); [MþH]: 334.1404 (87); [MꢀH2O] 316.1297 (100).
4.6.3. Hexahydro-2-(hexyl)-bis-2H-isoindol-4-phosphonic acid-1,3-
dione (10). Reduction of the cycloadduct 7b (48.7 mg,
0.053 mmol) yielded the title compound as a colourless oil
200 m
L minꢀ1; spray voltage, 5 kV; sheath gas (N2) flow rate, 20 a.u.;
3
(28.9 mg, 100%). 1H NMR (500 MHz, D2O)
d
: 3.49 (t, JH,H¼7.1 Hz,
auxiliary gas (N2) flow rate, 20 a.u.; capillary temperature, 275 ꢁC;
capillary voltage, 45 V; and tube lens, 80 V. The salts, which were
purchased from Aldrich, Alpha, or Acros, were of the highest quality
available and vacuum dried at room temperature over P2O5 prior to
use. Ethanol from Fisher (absolute) was used for the MS experi-
ments. For all experiments, the concentration of the ligand was
approximately 0.5 mM with 5 equiv of cation.
3
3
3
0
NCH2, 4H), 3.46 (dt, J5,6¼7.8 Hz and J4,5¼ J4 ,5¼3.9 Hz, C(5)eH,
2H), 3.09 (q, J5,6¼3J1,6¼3J6,P¼7.3 Hz, C(6)eH, 2H), 2.15 (ddt,
3
2J1,P¼23.7 Hz, 3J 1,6¼13.3 Hz and 3J1,2¼4.4 Hz, C(1)eH, 2H), 2.02 (tt,
3JH,H¼6.2 Hz and JH,H¼6.3 Hz, NCH2CH2, 4H), 1.98 (ddt,
3
3J2,P¼13.6 Hz and J1,2¼4.6 Hz, C(2)eH, 2H), 1.55e1.50 (m, C(3)eH,
3
2H), 1.50e1.44 (m, C(4)eH, 2H), 1.40e1.31 (m, C(4)eH0, 2H),
1.30e1.26 (m, N(CH2)2CH2, 4H). 13C NMR (125 MHz, MeOD)
d: 181.9
(s, C]O), 181.6 (s, C]O), 42.6 (d, 2J6,P¼11.6 Hz, C(6)), 42.4 (s, C(5)),
39.3 (s, NCH2), 28.1 (s, NCH2CH2), 27.6 (d, 1J1,P¼138.9 Hz, C(1)), 27.1
(s, N(CH2)2CH2), 26.2 (d, 3J3,P¼4.3 Hz; C(3)), 23.0 (s, C(4)), 22.00 (d,
Acknowledgements
This work was supported by the Fonds de la Recherche Scien-
tifique (F.R.S.-FNRS, Belgium), and the Universite catholique de
2J2,P¼12.8 Hz, C(2)). 31P NMR (121 MHz, MeOD)
d: 24.62. IR (n,
ꢀ
cmꢀ1): 3545e3231 (large band, m, OH), 2933 (m), 2862 (w), 1769
(m, C]O),1697 (s, C]O),1441 (m),1404 (m),1342 (m),1161 (m, P]
O), 1061 (m, PeO), 912 (m, PeO), 868 (w). MS (ESI, negative mode)
m/z (%)¼547.10 (100) [MꢀH], 529.12 (15) [MꢀH2O]. HRMS (MALDI-
TOF negative mode) m/z (%) [MꢀH] calcd for C22H33N2O10P2:
547.1610, found: 547.1620 (100); [MꢀHꢀHPO(OH)2]: 465.1773 (14).
ꢀ
Louvain through the ARC program (Action de Recherche Concertee)
number 08/13-009 and the Project FRFC Nꢁ2.4502.05. R.R. and
ꢀ
J.M.B. are Chercheurs Qualifies of the F.R.S.-FNRS.
Supplementary data
NMR spectra of compounds 1bee, 3bed, 5bed, 7bed and 8e10,
crystal data, and HRMS-ESI analysis of complexes with M2þ and
M3þ are given as Supplementary data. Supplementary data related
to this article can be found online at http://dx.doi.org/10.1016/
j.tet.2012.11.059.
4.7. Computational details
Calculations have been performed using the Jaguar 7.5 pseu-
dospectral program package.28 All species have been fully opti-
mized. Geometry optimization was carried out using the well
established B3LYP hybrid density functional29 as implemented in
Jaguar with the standard split valence polarized 6-31G** basis.30
Energies were obtained by single point energy calculations at
the B3LYP-D level of theory (thus including an approximation
correction for dispersion31) using the larger 6-31þG** basis, using
ORCA package.32 Solvation effects were estimated using the
conductor-like screening model (COSMO) as implemented in ORCA,
using the parameters appropriate for THF.
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