Ring transformations of aziridinyl 2-phosphonates: synthesis of 5-phosphono-2-oxazolidinones and 5-phosphono-2-imidazolidinones

Article abstract of DOI:10.1016/j.tet.2007.05.023

Syntheses of 5-phosphono-2-oxazolidinones and 5-phosphono-2-imidazolidinones were achieved from the corresponding 1-vinyl-2-phosphonoaziridines. Regioselective aziridine ring opening employing methyl chloroformate affords 1-amido-2-chloroethylphosphonates

Full text of DOI:10.1016/j.tet.2007.05.023

Tetrahedron 63 (2007) 7679–7689
Ring transformations of aziridinyl 2-phosphonates: synthesis
of 5-phosphono-2-oxazolidinones and 5-phosphono-
2-imidazolidinones
y
*
Bart Vanderhoydonck and Christian V. Stevens
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering,
Ghent University, Coupure Links 653, Gent B-9000, Belgium
Received 9 March 2007; revised 3 May 2007; accepted 4 May 2007
Available online 22 May 2007
Abstract—Syntheses of 5-phosphono-2-oxazolidinones and 5-phosphono-2-imidazolidinones were achieved from the corresponding
1-vinyl-2-phosphonoaziridines. Regioselective aziridine ring opening employing methyl chloroformate affords 1-amido-2-chloroethyl-
phosphonates, which were easily transformed into the corresponding 2-oxazolidinones upon heating in dimethyl sulfoxide. Treatment of
the aziridine ring opening products with ammonia furnishes vinylphosphonates, which undergo a Michael type addition with several amines.
In situ ring closure of the addition products yields the corresponding phosphonylated 2-imidazolidinones.
Ó 2007 Elsevier Ltd. All rights reserved.
R2
N
1. Introduction
R2
NH
P(O)(OR3)2
HCO2NH4, Pd/C, MeOH
or H2, Pd/C, MeOH
OR3
OR3
R1
R1
P
O
The synthesis of azaheterocyclic phosphonates is recently
getting more attention in search of new physiologically ac-
tive compounds because of the mimicking potential of phos-
phonic acids in relation to the corresponding amino acids.1
Because of the important ring strain of aziridines, ring open-
ing reactions are a predominant feature in their chemistry.2,3
Although the reactivity of aziridinyl carboxylates is well
documented,2,3 the ring fission of the corresponding aziri-
dinyl 2-phosphonates 1 is poorly covered in the literature.
Except for their conversion into the corresponding a-amino-
phosphonates 2 by hydrogenolysis (Scheme 1),4,5 ring open-
ing reactions of phosphonylated aziridines have not been
studied in detail. On the other hand, the reactivity of aziri-
dinyl 2-phosphonic acid 3 was studied in the early 1980s.
Treating these aziridines with different nucleophiles, includ-
ing halides, alkoxides, thiolates, and amines, the ring open-
ing was successfully achieved (Scheme 1).6 Because of the
protonation in the corresponding zwitterionic structure 3,
the aziridine ring is activated toward ring fission allowing
the synthesis of 1-amino-2-functionalized ethylphosphonic
acids 4.
2
1
R1 = H, CO2Et, Ts, Boc, Ph
R2 = alkyl, Ph, aryl
R3 = Et
R1, R2, R3 = H
H2
NH3
N
R4XH
R4X
O
OH
O
OH
P
O
P
O
X = NH, O, S
R
4 = H, alkyl, Bn
3
4
Scheme 1. Hydrogenolysis of a-aminophosphonates and ring opening of
aminophosphonic acids by several nucleophiles.
aziridines may allow straightforward synthesis of the corre-
sponding a-amino-phosphonates or may be transformed into
five-membered heterocyclic aminophosphonates.7 Consid-
ering the importance of acyclic and heterocyclic amino-
phosphonates in synthetic, agrochemical, and medicinal
chemistry,8 the potential transformation to phosphonylated
2-oxazolidinones and 2-imidazolidinones from the corre-
sponding aziridines was considered to be worthwhile. In-
deed, the synthesis of phosphonylated 2-oxazolidinones is
very scarcely covered in the literature. 4-Phosphono-9 as
well as 5-phosphono-2-oxazolidinones10 are exclusively
prepared from a-amino-b-hydroxyphosphonates and b-
amino-a-hydroxyphosphonates, respectively, upon reaction
with 1,10-carbonyldiimidazole (CDI) or phosgene. Recently,
a straightforward procedure was reported disclosing the
preparation of oxazolidine-2-thiones 8 from isothiocyano-
methyl phosphonate 6 and several aldehydes 5 (Scheme 2).11
In comparison with aziridinyl 2-carboxylates and their de-
rivatives, which are useful intermediates for the synthesis
of various amine-substituted molecules,2,3 phosphonylated
* Corresponding author. Tel.: +32 9 264 59 57; fax: +32 9 264 62 43; e-mail:
chris.stevens@ugent.be
Present address: Elbion Bioscience N.V., Kapucijnenvoer 33, Leuven
y
B-3000, Belgium.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.023

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B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
S
O
N
R1
O
NaH
or ButOK
O
NH
S
+
SCN
P(O)(OEt)2
R1
H
C
P(O)(OEt)2
R1
P(O)(OEt)2
5
6
7
R1 = But, Pri, Ph, PhCH=CH, 2-furyl
Scheme 2. Preparation of oxazolidine-2-thiones 8 from isothiocyano-methylphosphonate 6 and aldehydes 5.
8
Despite the observation that certain phosphonylated 2-pyrro-
lidinones exhibit antibiotic12 and enzyme-inhibiting acti-
vities,13 the related phosphonylated 2-imidazolidinones are
also poorly investigated. A rare example expounds the
straightforward procedure toward 11 using the reaction of
urea 10 with phosphonylated aldehydes 9 (Scheme 3).14
compounds 17 were isolated in 85–90% purity. Performing
the reaction at room temperature needed 24 h to go to com-
pletion, but led to a more pure reaction product. Finally,
evaluating CH2Cl2 as a solvent at room temperature gave
the best results (Scheme 5).
R1
R1
R1
Cl
O
1.2 equiv. ClCO2Me
P(O)(OEt)2
CH2Cl2, rt, 24 h
OH
P(O)(OR1)2
N
R1
O
N
H
R
HN
HO
NH
P(O)(OEt)2
+
R2OH
H2N
NH2
15
O
O
OMe
P(O)(OR1)2
R2 = H, Me, Et
16
9
10
11
1 = Me, Et, Pri, Bun, Cl(CH2)2, Ph
Scheme 3. Preparation of phosphonylated 2-imidazolidinones 11 from
aldehydes 9 and urea 10.
Cl
O
17a R1 = CH3, 61%
17b R1 = CH2CH3, 56%
17c R1 = (CH2)5, 50%
MeO
R1
N
P(O)(OEt)2
On the other hand, 4-oxo-5-phosphono-2-imidazolidinone
has received considerably more attention,15 especially since
this compound has been abundantly utilized as a Horner–
Wadsworth–Emmons reagent for the introduction of a C-5
unsaturated hydantoin functionality in organic molecules.16
The synthesis of 5-phosphono-2-imidazolones 14 may also
be mentioned here (Scheme 4).
R1
Scheme 5.
After quaternization toward 16, chloride opens the three-
membered ring with complete regioselectivity at C-3. The
observed C-3 regioselectivity is opposite to the one observed
for the reaction of the non-activated aziridinyl 2-carboxyl-
ates with methyl chloroformate.19 The latter undergo nucleo-
philic substitution at C-2, which can be explained by the
enhanced SN2 at the a-position with respect to a carbonyl
group. Hence, the observed regioselectivity for aziridinyl
2-phosphonates might be the result of a less efficient overlap
of the LUMO of the phosphonate functionality with the
LUMO of the carbon nitrogen bond ðsꢁCꢂNÞ so that no com-
bined molecular LUMO, lower in energy than either, is
formed. This, possibly combined with the increased steric
hindrance caused by the tetragonal phosphonate moiety
compared to the trigonal carboxyl group, favors nucleophilic
attack at C-3. The aziridinium-initiated ring opening was
also expanded to other counterattack reagents (Scheme 6).
Thus, reaction of 15 with monomethyl oxalyl chloride suc-
cessfully produced derivatives 18 whereas reaction with
methyl chlorothioformate led to the sulfur containing deriv-
atives 19. Unfortunately, treatment of aziridines 15 with
benzyloxy acetylchloride or methyl 2-bromoacetate led to
complex reaction mixtures. Despite the fact that no forma-
tion of 2-oxazolidinones was observed during the synthesis
b-Enaminophosphonates 12 react with diethyl azodicarb-
oxylate (DEAD) affording functionalized enamines 13, which
undergo cyclocondensation to give 2-imidazolones 14 upon
treatment with sodium hydride.
2. Results and discussion
Recently we reported on the synthesis of electron poor 1-
phosphono-2-aza-1,3-dienes and their aziridination toward
the corresponding 1-vinyl-2-phosphonoaziridines 15 upon
treatment with diazomethane or other diazo compounds.17
In the context of our continuing interest on the synthesis of
heterocyclic aminophosphonates for agrochemical and phar-
maceutical applications,18 the ring transformation of these
aziridines was investigated. Activation of the aziridines to-
ward nucleophilic ring opening was evaluated using methyl
chloroformate as counterattack reagent. Initially aziridines
15 were dissolved in anhydrous acetonitrile/toluene (8:2)
and heated to 80 ꢀC after addition of methyl chloroformate.
After 2 h, TLC analysis revealed complete conversion and
O
EtO2C
CO2Et
CO2Et
NH
N
R1
H2N
N NH
DEAD
NaH
THF
HN
R1
R1
P(O)(OEt)2
THF, reflux
H2N
P(O)(OEt)2
P(O)(OEt)2
14
12
R1 = Ph, (hetero)aryl
13
Scheme 4. Preparation of 5-phosphono-2-imidazolones 14.

B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
7681
of compounds 17, an attempt was made to obtain these com-
pounds by refluxing 17 in CH3CN. As expected, only start-
ing material could be recovered. The addition of NaI as
a nucleophilic catalyst, or AgO or LiClO4 as Lewis acids,
did not lead to a better result.
or decomposed when heated in DMSO or diglyme. Some
attention was given to the preparation of vinylphosphonates
such as 23a from the corresponding enamides 17 in order
to evaluate Michael type additions of amines to these sub-
strates. Treating enamine 17a with triethylamine in refluxing
dichloromethane or acetonitrile led to the recovery of start-
ing material. The same outcome was obtained when pyridine
or diisopropylamine was employed as a base. Next, enamide
17a was reacted with ammonia (added as a solution in meth-
anol, 7 N) in dichloromethane. At room temperature, no
elimination was observed and starting material was isolated.
Under reflux, the formation of vinylphosphonate 23a took
place, yet additional amounts of ammonia had to be added
repeatedly to compensate for losses caused by evaporation.
To compensate for this disadvantage, the reaction was exe-
cuted in a sealed vessel. When the elimination was per-
formed in acetonitrile at 80 ꢀC, conversion was finished
after 24 h. The elimination was completed only after 8 h,
however, using toluene at 110 ꢀC (Scheme 8). Hence, vinyl-
phosphonate 23a was isolated in good yield and with high
purity (>95%), and could be further purified utilizing col-
umn chromatography. Employing the same procedure, de-
rivatives 23b and 23c were prepared in comparable yields.
MeO
O
N
Cl
R1
1.2 equiv.
ClCOCO2Me
N
O
P(O)(OEt)2
R1
P(O)(OEt)2
R1
toluene, rt,
32 h
15
R1
1.2 equiv. ClC(S)OMe
CH2Cl2, rt, 32 h
18a R1 = CH3, 61%
18b R1 = CH2CH3, 56%
18c R1 = (CH2)5, 50%
Cl
O
MeS
R1
N
P(O)(OEt)2
19a R1 = CH2CH3, 86%
19b R1 = (CH2)5, 76%
R1
Scheme 6.
It was reasoned, however, that using dipolar solvents could
favor the mesomeric structure 20 of enamides 17 due to
the polarity of the medium. This can be expected to facilitate
the intramolecular substitution leading to the formation of
the corresponding 2-oxazolidinones 22. Performing the re-
action in DMF at 130 ꢀC for 24 h did furnish some promising
results. Two products could be identified in the reaction mix-
ture namely compounds 22 and 23, the latter obviously
formed after elimination of hydrogen chloride with DMF
acting as a base. Therefore, a less basic solvent, namely
DMSO, was evaluated. Indeed, heating enamide 17a in
DMSO at 130 ꢀC for 40 h resulted in the formation of 2-ox-
azolidinone 22a in good yield and high purity after work-up
(Scheme 7). In this case, the elimination product 23a was not
formed. Comparable results were obtained with enamides
17b–c. Further purification using column chromatography
yielded pure 2-oxazolidinones 22 in good yield.
Cl
O
O
NH3 (7N in MeOH)
toluene, 110 °C, 8 h
MeO
R1
N
P(O)(OEt)2
MeO
R1
N
P(O)(OEt)2
R1
R1
17a-c
23a R1 = CH3, 61%
23b R1 = CH2CH3, 54%
23c R1 = (CH2)5, 51%
Scheme 8.
Primary amines were also used to evaluate the substitution
reaction. When enamide 17b was stirred together with
4.0 equiv of propylamine in refluxing acetonitrile, the elim-
ination product 23b was produced (Scheme 9). Next, the
reaction was repeated in refluxing dichloromethane. Rather
surprisingly, the substitution product 24 was formed instead
and isolated in good yield after purification by flash chroma-
tography.
Unfortunately, applying the same conditions to ring-opened
compounds 18 and 19 did not lead to cyclization. Com-
pounds 18 decomposed to a complex mixture whereas
compounds 19 were recovered unchanged after refluxing
in THF, toluene, CH3CN, CH3NO2, CH3NO2/HMPA (9:1)
Cl
O
Cl
O
MeO
R1
N
P(O)(OEt)2
MeO
R1
N
P(O)(OEt)2
O
17
20
R1
R1
MeO
R1
N
P(O)(OEt)2
23a
DMSO
130 °C, 40 h
R1
Cl
H3C
O
O
P(O)(OEt)2
P(O)(OEt)2
N
N
O
O
R1
R1
R1
R1
21
22a R1 = CH3, 83%
22b R1 = CH2CH3, 82%
22c R1 = (CH2)5, 71%
Scheme 7.

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B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
O
evaluated in order to prepare the corresponding b-amino-
phosphonates 25 and 26. Prompted by the promising results
with propylamine, dichloromethane was selected as solvent.
Enamide 23b was stirred together with 4.0 equiv of isobutyl-
amine under reflux and the course of the reaction was fol-
lowed by 31P NMR spectroscopy (Scheme 11). After 4
days, the reaction mixture still contained starting material
and no further conversion was observed. Consequently, an
additional 4.0 equiv of isobutylamine was added. The reac-
tion was stopped after 7 days although a small amount of
starting material (<5%) was still present. After work-up and
purification by means of column chromatography, amine 25
was isolated in moderate yield. Similarly, 12.0 equiv of
allylamine was added to enamide 23b and after 10 days of
reflux the reaction was stopped because of the formation
of unidentified side products. After purification by column
chromatography, amine 26 was isolated, however, only in
poor yield.
MeO
N
P(O)(OEt)2
4 equiv. PrNH2
CH3CN, Δ, 24 h
Cl
O
23b 89%
MeO
N
P(O)(OEt)2
H
N
O
12 equiv. PrNH2
17b
MeO
N
P(O)(OEt)2
CH2Cl2, Δ, 72 h
24 58%
Scheme 9.
Importantly, to drive the reaction to completion, two times
4.0 equiv of propylamine were added during the course of
the reaction. With the spectral data of b-aminophosphonate
24 in hand, it became clear that also in refluxing acetonitrile
amine 24 was formed, however, only in a very small amount.
It was unlikely to believe that only the difference in polarity
of the applied solvents could be responsible for the different
outcome of both reaction set-ups. The hypothesis that instead
of the substitution of the chlorine atom, the elimination of
hydrogen chloride takes place first, followed by a Michael
type addition to vinylphosphonate 23b, was assumed more
plausible. The different outcome when the reaction is per-
formed in acetonitrile should simply be attributed to the
higher boiling point of acetonitrile causing bigger losses of
propylamine (bp 48 ꢀC) during the course of the reaction.
Indeed, even in dichloromethane, additional amounts of pro-
pylamine had to be added in order to complete the reaction.
The fact that a Michael type addition is involved in the prep-
aration of substitution products like amine 24 was further
confirmed when isobutylamine was applied as a nucleophile.
Stirring enamide 17b with 4.0 equiv of isobutylamine under
reflux for 24 h did not result in any reaction and only starting
material was isolated (Scheme 10). However, when 1 equiv
of propylamine was added to the reaction mixture, mainly
b-aminophosphonate 25 was obtained together with small
amounts of amine 24. Apparently, isobutylamine does not
induce elimination, probably because of steric hindrance.
When propylamine is added, vinylphosphonate 23b is
formed, which subsequently undergoes a Michael type addi-
tion by isobutylamine and propylamine resulting in a mixture
of b-aminophosphonates 25 and 24, respectively.
NHR
O
O
RNH2
MeO
N
P(O)(OEt)2
MeO
N
P(O)(OEt)2
CH2Cl2, Δ
25 R = Bui, 49%
26 R = allyl, 23%
23b
Scheme 11.
Guided by the findings that Michael type additions of amines
to vinylphosphonates proceed well in alcoholic solvents,20
the addition was evaluated in methanol. Considering the fac-
ile generation of vinylphosphonates 23 from enamides 17
using ammonia in methanol, it was judged appropriate to
endeavor the preparation of b-aminophosphonates from the
corresponding enamides 17 in one single step, without the
isolation of the intermediate vinylphosphonates 23. How-
ever, when enamide 17a was dissolved in methanol and
reacted with isobutylamine in the presence of ammonia
(sealed vessel, 60 ꢀC), the elimination reaction was observed
to be very slow; after 24 h of stirring, only a trace of elimi-
nation product could be detected. The reaction was repeated,
but this time toluene was applied as solvent and the reaction
mixture was heated to 110 ꢀC (Scheme 12). Following the
reaction with 31P NMR spectroscopy did show the conver-
sion of enamide 17a (w20.8 ppm) into vinylphosphonate
23a (w12.5 ppm). Except for these two signals, three other
signals (w16–17 ppm;w22.3 ppm;w24.3 ppm) appeared in
the 31P NMR spectra. During the course of the reaction,
the signal of vinylphosphonate 23a disappeared in favor
for these new signals. Gradually, the signal with a chemical
shift of 24.3 ppm completely vanished leaving only the sig-
nal with a chemical shift of 22.3 ppm. It was concluded that
H
N
Cl
O
8 equiv. BuiNH2
1 equiv. PrNH2
O
MeO
MeO
N
N
P(O)(OEt)2
MeO
N
P(O)(OEt)2
CH2Cl2, Δ, 7 d
25 51%
17b
H
N
R
O
Cl
N
4 equiv. BuiNH2
CH2Cl2, Δ, 24 h
O
P(O)(OEt)2
24 10%
8 equiv. NH2R
O
MeO
R1
N
P(O)(OEt)2
N
P(O)(OEt)2
NH3 in MeOH (7N)
toluene, 110 °C
R1
No reaction
Scheme 10.
R1
R1
27a R1 = CH3, R = Bui, 25%
27b R1 = CH3, R = allyl, 33%
27c R1 = (CH2)5, R = allyl, 17%
17a R1 = CH3
17c R1 = (CH2)5
Having access to pure vinylphosphonates 23, the Michael
type addition with isobutylamine and allylamine was
Scheme 12.

B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
7683
these signals could be assigned to the corresponding b-ami-
nophosphonate and the 2-imidazolidinone 27a, respectively.
The reaction was stopped when the 2-imidazolidinone 27a
(22.3 ppm) and the side product (w16–17 ppm) were the
only products present in the reaction mixture, at least
according to the 31P NMR spectrum. After work-up, only
small amounts of crude reaction product could be isolated
from which 2-imidazolidinone 27a could not be obtained
completely pure.
H
N
N
O
toluene, Δ, 22 h
O
MeO
N
P(O)(OEt)2
N
P(O)(OEt)2
24
27h 41%
Scheme 14.
Analogous results were obtained when enamides 17a and
17c were treated with allylamine resulting in the isolation
of 2-imidazolidinones 27b and 27c, however, in poor yields.
Compound 27c could also not be obtained completely pure.
With isobutylamine as well as with allylamine, the crude re-
action product only showed one signal assigned to 2-imid-
azolidinones 27a–c. Hence, the side product (w16–17 ppm)
was not recovered. This, together with the minor amounts
of crude reaction product isolated, led to the conclusion
that a water-soluble compound was formed during the reac-
tion, which is subsequently lost during work-up. Possibly, 5-
phosphonylated 2-imidazolidinones 27a–c are converted to
the corresponding phosphonic acids. Prolonged heating in
the presence of ammonium chloride, which is generated by
the elimination reaction, may create a chemical environment
effective to transform the phosphonates into the phosphonic
acids. Trying to avoid the formation of this side product, the
preparation of 5-phosphonylated 2-imidazolidinones 27 was
evaluated in methanol from the corresponding vinylphosph-
onates 23a–c, hence, avoiding the formation of ammonium
chloride in the reaction medium (Scheme 13). Utilizing
31P NMR spectroscopy to monitor the reaction, the forma-
tion of 2-imidazolidinones 27 was established and moreover,
no side product could be detected.
to vinylphosphonate 23b, only a complex reaction mixture
could be isolated in which none of the corresponding addi-
tion product or 2-imidazolidinone 28b could be detected.
Rather remarkably, 2-imidazolidinone 28b was formed when
2-chloro-1-aminophosphonate 17b was applied as starting
material instead. Heating 17b in the presence of hydrazine
monohydrate afforded 1-amino-2-imidazolidinone 28b,
which could be isolated in moderate yield after purification
by flash chromatography (Scheme 15). Noteworthy, no po-
tassium carbonate had to be added to obtain 28b within an
acceptable time span. Applying this procedure on 2-chloro-
1-aminophosphonate 17c led to the formation of 2-imid-
azolidinone 28c in a comparable yield.
H2N
Cl
P(O)(OEt)2
N
O
.
3 equiv. NH2NH2 H2O
O
MeO
R1
N
N
P(O)(OEt)2
MeOH, 60 °C
R1
R1
R1
17b R1 = CH2CH3
17c R1 = (CH2)5
28b R1 = CH2CH3, 44%
28c R1 = (CH2)5, 49%
Scheme 15.
R
N
O
3. Conclusion
6 equiv. NH2R
O
MeO
R1
N
P(O)(OEt)2
N
P(O)(OEt)2
MeOH, 60 °C
K2CO3
R1
In conclusion, the ring opening chemistry of 1-vinyl-2-phos-
phonoaziridines has been evaluated and used for the synthe-
sis of 2-oxazolidinones and 2-imidazolidinones. The ring
opening of the aziridines with methyl chloroformate as
counterattack reagent occurs with complete regioselectivity
at C-3. The resulting 1-amido-2-chloroethylphosphonates
were transformed to the corresponding 2-oxazolidinones by
heating in DMSO. Treatment of the ring-opened products
with ammonia in methanol gave rise to the corresponding vi-
nylphosphonates, by elimination of HCl. These vinylphosph-
onates were easily transformed to the 2-imidazolidinones by
treatment with primary amines in methanol after Michael
type addition followed by cyclization.
R1
R1
23b R1 = CH2CH3
23c R1 = (CH2)5
27c R1 = (CH2)5, R = allyl, 44%
27d R1 = (CH2)5, R = Pr, 41%
27e R1 = CH2CH3, R = Bui, 33%
27f R1 = CH2CH3, R = allyl, 52%
27g R1 = (CH2)5, R = Bn, 44%
Scheme 13.
Of course, ring closure of b-aminophosphonate 24, prepared
from the corresponding vinylphosphonate 17b and propyl-
amine in dichloromethane, was also evaluated (Scheme
14). As could be expected, refluxing b-aminophosphonate
24 in toluene followed by purification afforded the corre-
sponding 2-imidazolidinone 27h.
4. Experimental
While applying different amines in order to prepare several
2-imidazolidinones from the corresponding vinylphospho-
nates, an unexpected chemical behavior of hydrazine was
noticed. As was outlined before, the preparation of several
2-imidazolidinones (27a–c) from the corresponding 2-chlo-
ro-1-aminophosphonates (17a–c) was also possible, how-
ever, this entry was accompanied with the formation of
a (unidentified) side product. When hydrazine was added
4.1. General methods
Flash chromatography was performed on silica gel (Acros,
0.035–0.070 mm). 1H NMR spectra were recorded at
300 MHz. 13C NMR and 31P NMR experiments were ac-
quired at 75 MHz and 121 MHz, respectively. Chemical
shifts (d) are reported in parts per million from TMS as an
internal reference. Coupling constants (J) are given in Hertz.

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B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
IR spectra were recorded with a FTIR spectrometer. Low-
resolution mass spectra (MS) were obtained at 70 eV or
using ES (4000 V). High-resolution mass spectra were
recorded on a Finnigan MAT 95 XP-API-GC-Trap tandem
Mass Spectrometer system. Solvents were dried extensively
over calcium hydride (dichloromethane) or sodium/benzo-
phenone ketyl (toluene) or used as such (methanol).
(6H, m, CH2), 2.13 (4H, m, CH2), 3.73 (3H, s, OCH3),
3.79 (1H, td, J¼11.8 Hz, J¼3.9 Hz, CH2Cl), 3.88 (1H, dt,
J¼11.8 Hz, J¼3.1 Hz, CH2Cl), 4.14 (2H, sextet, J¼
7.0 Hz, P(O)OCH2CH3), 4.15 (2H, sextet, J¼7.0 Hz,
P(O)OCH2CH3), 4.92 (1H, ddd, JHP¼20.1 Hz, J¼11.5 Hz,
J¼2.9 Hz, CHP), 5.66 (1H, s, CH); 13C NMR (75 MHz,
CDCl3) d 16.39 (P(O)OCH2CH3), 16.44 (P(O)OCH2CH3),
26.41 (CH2), 26.57 (CH2), 28.04 (CH2), 28.67 (CH2), 33.43
(CH2), 40.58 (d, JCP¼16.1 Hz, CH2Cl), 53.35 (OCH3),
55.87 (d, JCP¼147.7 Hz, CHP), 62.71 (d, JCP¼6.9 Hz,
P(O)OCH2CH3), 62.76 (d, JCP¼6.9 Hz, P(O)OCH2CH3),
113.95 (CH), 144.96 (Cquat), 156.77 (C]O); 31P NMR
(121 MHz, CDCl3) d 20.56; IR (neat) n 1706 cmꢂ1; MS
m/z 370/368 [M+H+]; HRMS calcd for C15H2735ClNO5P
(M+H+) 368.1388; found 368.1404; Rf (EtOAc/PET
7:3)¼0.33.
4.1.1. General procedure for the ring opening of 2-phos-
phonoaziridines with methyl chloroformate or methyl
chlorothioformate. In a flask of 50 mL, 2-phosphonoaziri-
dine 15a–c (5.0 mmol) was dissolved in 30 mL of anhydrous
dichloromethane and methyl chloroformate (6.0 mmol) (or
methyl chlorothioformate (6.0 mmol) for the preparation
of enamides 19a–b) was added. The flask was fitted with
a calcium chloride tube and stirred at room temperature
for 24 h (the reaction with methyl chlorothioformate needed
48 h of stirring). The solvent was evaporated under reduced
pressure furnishing the crude reaction mixture, which was
purified by flash chromatography (using a mixture of ethyl
acetate and petroleum ether as the eluent) leading to the iso-
lation of enamide 17a–c, 19a–b (50–86%).
4.1.1.4. Diethyl 2-chloro-1-{(2-ethyl-1-butenyl)[(me-
thylsulfanyl)carbonyl]amino}ethylphosphonate 19a. 1H
NMR (300 MHz, CDCl3) d 1.02 (3H, t, J¼7.4 Hz, CH3),
1.09 (3H, t, J¼7.6 Hz, CH3), 1.32 (6H, t, J¼7.0 Hz,
P(O)OCH2CH3), 2.19 (3H, m, CH2), 2.27 (3H, s, SCH3),
2.39 (1H, m, CH2), 3.71 (1H, td, J¼11.5 Hz, J¼3.6 Hz,
CH2Cl), 3.89 (1H, dt, J¼11.8 Hz, J¼3.3 Hz, CH2Cl), 4.13
(2H, quintet, J¼7.1 Hz, P(O)OCH2CH3), 4.15 (2H, quintet,
J¼7.1 Hz, P(O)OCH2CH3), 5.18 (1H, ddd, JHP¼18.7 Hz,
J¼11.2 Hz, J¼2.7 Hz, CHP), 5.77 (1H, s, CH); 13C NMR
(75 MHz, CDCl3) d 11.18 (CH3), 11.95 (CH3), 13.47
(SCH3), 16.28 (d, JCP¼5.8 Hz, P(O)OCH2CH3), 16.35 (d,
JCP¼5.8 Hz, P(O)OCH2CH3), 22.06 (CH2), 25.69 (CH2),
40.27 (d, JCP¼16.1 Hz, CH2Cl), 55.66 (d, JCP¼147.7 Hz,
CHP), 62.64 (d, JCP¼6.9 Hz, P(O)OCH2CH3), 62.78 (d,
JCP¼5.7 Hz, P(O)OCH2CH3), 116.60 (CH), 153.83 (Cquat),
171.74 (C]O); 31P NMR (121 MHz, CDCl3) d 19.74; IR
(neat) n 1664, 1645 cmꢂ1; MS m/z 374/372 [M+H+];
HRMS calcd for C14H2735ClNO4PS (M+H+) 372.1160;
found 372.1171; Rf (EtOAc/PET 1:1)¼0.33.
4.1.1.1. Diethyl 2-chloro-1-[(methoxycarbonyl)(2-me-
thyl-1-propenyl)amino]ethylphosphonate 17a. H NMR
1
(200 MHz, CDCl3) d 1.32 (6H, t, J¼7.0 Hz, P(O)OCH2CH3),
1.67 (3H, s, CH3), 1.77 (3H, s, CH3), 3.77 (4H, m, CH2Cl,
OCH3), 3.88 (1H, dt, J¼11.8 Hz, J¼3.3 Hz, CH2Cl), 4.15
(4H, sextet, J¼7.3 Hz, P(O)OCH2CH3), 4.88 (1H, ddd,
JHP¼19.0 Hz, J¼11.5 Hz, J¼3.0 Hz, CHP), 5.68 (1H, s,
CH); 13C NMR (75 MHz, CDCl3) d 16.36 (P(O)OCH2CH3),
16.44 (P(O)OCH2CH3), 18.22 (CH3), 22.42 (CH3), 40.62 (d,
JCP¼16.1 Hz, CH2Cl), 53.45 (OCH3), 56.13 (d, JCP
¼
147.7 Hz, CHP), 62.67 (d, JCP¼6.9 Hz, P(O)OCH2CH3),
62.82 (d, JCP¼6.9 Hz, P(O)OCH2CH3), 117.31 (CH),
138.03 (Cquat), 156.71 (C]O); 31P NMR (121 MHz,
CDCl3) d 20.53; IR (neat) n 1707, 1678 cmꢂ1; MS m/z 330/
328 [M+H+]; HRMS calcd for C12H2335ClNO5P (M+H+)
328.1075; found 328.1081; Rf (EtOAc/PET 9:1)¼0.47.
4.1.1.5. Diethyl 2-chloro-1-{(cyclohexylidenemethyl)
[(methylsulfanyl)carbonyl]amino}ethylphosphonate 19b.
1H NMR (300 MHz, CDCl3) d 1.32 (6H, t, J¼7.0 Hz,
P(O)OCH2CH3), 1.61 (6H, m, CH2), 2.18 (3H, m, CH2),
2.28 (3H, s, SCH3), 2.39 (1H, m, CH2), 3.74 (1H, td, J¼
11.7 Hz, J¼3.8 Hz, CH2Cl), 3.89 (1H, dt, J¼12.1 Hz, J¼
3.3 Hz, CH2Cl), 4.14 (2H, sextet, J¼7.1 Hz, P(O)-
OCH2CH3), 4.15 (2H, sextet, J¼7.4 Hz, P(O)OCH2CH3),
5.20 (1H, ddd, JHP¼20.1 Hz, J¼11.1 Hz, J¼2.9 Hz, CHP),
5.52 (1H, s, CH); 13C NMR (75 MHz, CDCl3) d 13.29
(SCH3), 16.18 (2ꢃP(O)OCH2CH3), 26.09 (CH2), 26.30
(CH2), 27.32 (CH2), 28.59 (CH2), 33.31 (CH2), 40.12 (d,
JCP¼16.1 Hz, CH2Cl), 55.17 (d, JCP¼147.7 Hz, CHP),
62.62 (2C, d, JCP¼3.5 Hz, P(O)OCH2CH3), 114.52 (CH),
150.69 (Cquat), 171.32 (C]O); 31P NMR (121 MHz, CDCl3)
d 19.57; IR (neat) n 1667, 1650 cmꢂ1; MS m/z 386/384
[M+H+]; HRMS calcd for C15H2735ClNO4PS (M+H+)
384.1160; found 384.1172; Rf (EtOAc/PET 6:4)¼0.18.
4.1.1.2. Diethyl 2-chloro-1-[(2-ethyl-1-butenyl)(meth-
oxycarbonyl)amino]ethylphosphonate 17b. 1H NMR
(300 MHz, CDCl3) d 0.94 (3H, t, J¼7.4 Hz, CH3), 1.03 (3H,
t, J¼7.5 Hz, CH3), 1.30 (6H, t, J¼7.0 Hz, P(O)OCH2CH3),
2.11 (4H, quintet, J¼7.4 Hz, CH2), 3.72 (4H, m, OCH3,
CH2Cl), 3.85 (1H, dt, J¼11.8 Hz, J¼2.9 Hz, CH2Cl), 4.13
(4H, sextet, J¼7.0 Hz, P(O)OCH2CH3), 4.86 (1H, ddd,
JHP¼20.0 Hz, J¼11.3 Hz, J¼2.6 Hz, CHP), 5.65 (1H, s,
CH); 13C NMR (75 MHz, CDCl3) d 11.09 (CH3), 12.54
(CH3), 16.40 (P(O)OCH2CH3), 16.46 (P(O)OCH2CH3),
22.16 (CH2), 25.61 (CH2), 40.63 (d, JCP¼16.7 Hz, CH2Cl),
53.30 (OCH3), 56.34 (d, JCP¼148.3 Hz, CHP), 62.64 (d,
JCP¼6.9 Hz, P(O)OCH2CH3), 62.78 (d, JCP¼6.9 Hz,
P(O)OCH2CH3), 116.07 (CH), 148.15 (Cquat), 156.90
(C]O); 31P NMR (121 MHz, CDCl3) d 20.72; IR (neat) n
1709, 1662 cmꢂ1; MS m/z 358/356 [M+H+]; HRMS calcd
for C14H2735ClNO5P (M+H+) 356.1388; found 356.1396;
Rf (EtOAc/PET 9:1)¼0.38.
4.1.2. General procedure for the ring opening of 2-phos-
phonoaziridines with monomethyl oxalyl chloride. In
a flask of 25 mL, phosphonoaziridine 15a–c (2.0 mmol)
was dissolved in 20 mL of anhydrous dichloromethane and
monomethyl oxalyl chloride (2.4 mmol) was added. The re-
action was protected from moisture by a calcium chloride
4.1.1.3. Diethyl 2-chloro-1-[(cyclohexylidenemethyl)
(methoxycarbonyl)amino]ethylphosphonate 17c. 1H
NMR (300 MHz, CDCl3) d 1.32 (3H, t, J¼7.0 Hz, P(O)-
OCH2CH3), 1.33 (3H, t, J¼7.1 Hz, P(O)OCH2CH3), 1.60

B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
7685
tube and the mixture was stirred for 32 h at room tem-
perature. Next, the reaction mixture was extracted with
3ꢃ15 mL of water and dried over magnesium sulfate. The
solvent was evaporated under reduced pressure. The crude
enamide 18a–c was purified by flash chromatography (using
a mixture of ethyl acetate and petroleum ether as the eluent)
furnishing enamide 18a–c (45–56%).
CHP), 63.18 (d, JCP¼5.8 Hz, P(O)OCH2CH3), 63.23 (d,
JCP¼5.8 Hz, P(O)OCH2CH3), 114.98 (CH), 148.98 (Cquat),
162.61 (C]O), 162.87 (C]O); 31P NMR (121 MHz,
CDCl3) d 18.33; IR (neat) n 1749, 1682 cmꢂ1; MS m/z
398/396 [M+H+]; HRMS calcd for C16H2735ClNO6P
(M+H+) 396.1337; found 396.1341; Rf (EtOAc/PET
7:3)¼0.33.
4.1.2.1. Methyl [[2-chloro-1-(diethoxyphosphoryl)-
ethyl](2-methyl-1-propenyl)amino](oxo)acetate 18a. 1H
NMR (300 MHz, CDCl3) d 1.33 (3H, t, J¼7.1 Hz,
P(O)OCH2CH3), 1.34 (3H, t, J¼7.1 Hz, P(O)OCH2CH3),
1.77 (6H, s, CH3), 3.77 (4H, m, OCH3, CH2Cl), 3.95 (1H,
dt, J¼12.1 Hz, J¼3.3 Hz, CH2Cl), 4.17 (2H, quintet, J¼
7.3 Hz, P(O)OCH2CH3), 4.18 (2H, quintet, J¼7.2 Hz,
P(O)OCH2CH3), 5.12 (1H, ddd, JHP¼19.7 Hz, J¼11.4 Hz,
J¼2.9 Hz, CHP), 5.88 (1H, s, CH); 13C NMR (75 MHz,
CDCl3) d 16.37 (2C, d, JCP¼5.8 Hz, P(O)OCH2CH3),
18.60 (CH3), 22.57 (CH3), 39.72 (d, JCP¼13.8 Hz, CH2Cl),
52.47 (OCH3), 53.35 (d, JCP¼150.0 Hz, CHP), 63.16 (d,
JCP¼6.9 Hz, P(O)OCH2CH3), 63.29 (d, JCP¼6.9 Hz, P(O)-
OCH2CH3), 117.89 (CH), 142.63 (Cquat), 162.81 (C]O),
163.09 (C]O); 31P NMR (121 MHz, CDCl3) d 18.42; IR
(neat) n 1749, 1679 cmꢂ1; MS m/z 358/356 [M+H+];
HRMS calcd for C13H2335ClNO6P (M+H+) 356.1024; found
356.1031; Rf (EtOAc/PET 7:3)¼0.24.
4.1.3. General procedure for the preparation of phospho-
nylated 2-oxazolidinones. In a flask of 25 mL, enamide 17
(1.0 mmol) was dissolved in 15 mL of anhydrous dimethyl
sulfoxide (DMSO) and heated to 120–130 ꢀC. After main-
taining this temperature for 40 h, the solvent was distilled
off under high vacuum (50–60 ꢀC/0.10 mmHg) where
upon the residue was dissolved in 20 mL of diethyl ether.
The solution was extracted with brine (3ꢃ10 mL) and dried
over magnesium sulfate. Evaporating the solvent under re-
duced pressure afforded oxazolidinone 22a–c (71–83%, pu-
rity>95%). Further purification might be performed by flash
chromatography using ethyl acetate and petroleum ether as
the eluents (isolated yields: 51–62%).
4.1.3.1. Diethyl 3-(2-methyl-1-propenyl)-2-oxo-1,3-ox-
azolidin-4-ylphosphonate 22a. 1H NMR (300 MHz,
CDCl3) d 1.34 (3H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.35
(3H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.71 (3H, s, CH3), 1.79
(3H, s, CH3), 4.06 (1H, ddd, JHP¼8.7 Hz, J¼7.3 Hz, J¼
1.9 Hz, CHP), 4.16 (2H, quintet, J¼7.2 Hz, P(O)OCH2CH3),
4.18 (2H, quintet, J¼7.1 Hz, P(O)OCH2CH3), 4.52 (2H, m,
OCH2), 5.69 (1H, t, J¼1.4 Hz, CH); 13C NMR (75 MHz,
CDCl3) d 16.48 (P(O)OCH2CH3), 16.56 (P(O)OCH2CH3),
18.27 (CH3), 22.36 (CH3), 54.07 (d, JCP¼163.8 Hz, CHP),
62.82 (OCH2), 62.94 (d, JCP¼13.8 Hz, P(O)OCH2CH3),
63.18 (d, JCP¼8.1 Hz, P(O)OCH2CH3), 117.39 (CH),
135.67 (Cquat), 156.11 (C]O); 31P NMR (121 MHz,
CDCl3) d 19.93; IR (neat) n 1766 cmꢂ1; MS m/z 278
[M+H+]; HRMS calcd for C11H20NO5P (M+H+) 278.1152;
found 278.1153; Rf (EtOAc/PET 9:1)¼0.18.
4.1.2.2. Methyl [[2-chloro-1-(diethoxyphosphoryl)-
ethyl](2-ethyl-1-butenyl)amino](oxo)acetate 18b. 1H
NMR (300 MHz, CDCl3) d 0.97 (3H, t, J¼7.5 Hz, CH3),
1.01 (3H, t, J¼7.5 Hz, CH3), 1.34 (3H, t, J¼7.1 Hz,
P(O)OCH2CH3), 1.35 (3H, t, J¼7.3 Hz, P(O)OCH2CH3),
2.11 (3H, m, CH2), 2.40 (1H, m, CH2), 3.73 (1H, td,
J¼11.8 Hz, J¼3.8 Hz, CH2Cl), 3.78 (3H, s, OCH3), 3.94
(1H, dt, J¼12.1 Hz, J¼3.3 Hz, CH2Cl), 4.18 (4H, quintet,
J¼7.2 Hz, P(O)OCH2CH3), 5.15 (1H, ddd, JHP¼20.1 Hz,
J¼11.3 Hz, J¼2.9 Hz, CHP), 5.89 (1H, s, CH); 13C NMR
(75 MHz, CDCl3) d 11.40 (CH3), 12.47 (CH3), 16.14 (d,
JCP¼5.8 Hz, P(O)OCH2CH3), 16.21 (d, JCP¼4.6 Hz,
P(O)OCH2CH3), 21.51 (CH2), 25.41 (CH2), 39.58 (d, JCP
¼
4.1.3.2. Diethyl 3-(2-ethyl-1-butenyl)-2-oxo-1,3-oxazo-
lidin-4-ylphosphonate 22b. H NMR (300 MHz, CDCl3)
1
13.8 Hz, CH2Cl), 52.07 (OCH3), 53.43 (d, JCP¼147.7 Hz,
CHP), 62.95 (d, JCP¼5.8 Hz, P(O)OCH2CH3), 63.03 (d,
JCP¼5.8 Hz, P(O)OCH2CH3), 116.84 (CH), 152.06 (Cquat),
162.52 (d, JCP¼2.3 Hz, C]O), 162.69 (C]O); 31P NMR
d 1.04 (3H, t, J¼7.7 Hz, CH3), 1.07 (3H, t, J¼7.7 Hz,
CH3), 1.34 (3H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.35 (3H, t,
J¼7.0 Hz, P(O)OCH2CH3), 2.14 (4H, q, J¼7.5 Hz, CH2),
4.04 (1H, ddd, JHP¼8.3 Hz, J¼6.8 Hz, J¼1.9 Hz, CHP),
4.16 (2H, quintet, J¼7.2 Hz, P(O)OCH2CH3), 4.18 (2H,
quintet, J¼7.0 Hz, P(O)OCH2CH3), 4.52 (2H, m, OCH2),
5.66 (1H, s, CH); 13C NMR (75 MHz, CDCl3) d 11.61
(CH3), 12.30 (CH3), 16.51 (P(O)OCH2CH3), 16.59 (P(O)-
(121 MHz, CDCl3) d 18.48; IR (neat) n 1749, 1678 cmꢂ1
;
MS m/z 386/384 [M+H+]; HRMS calcd for C15H2735ClNO6P
(M+H+) 384.1337; found 384.1353; Rf (EtOAc/PET 1:1)¼
0.16.
4.1.2.3. Methyl [[2-chloro-1-(diethoxyphosphoryl)-
ethyl] (cyclohexylidenemethyl)amino](oxo)acetate 18c.
1H NMR (300 MHz, CDCl3) d 1.33 (3H, t, J¼7.1 Hz,
P(O)OCH2CH3), 1.34 (3H, t, J¼7.0 Hz, P(O)OCH2CH3),
1.55 (6H, m, CH2), 2.06 (2H, m, CH2), 2.20 (1H, m, CH2),
2.39 (1H, m, CH2), 3.77 (4H, m, OCH3, CH2Cl), 3.94 (1H,
dq, J¼12.1 Hz, J¼3.0 Hz, CH2Cl), 4.17 (2H, quintet,
J¼7.3 Hz, P(O)OCH2CH3), 4.18 (2H, quintet, J¼7.2 Hz,
P(O)OCH2CH3), 5.15 (1H, ddd, JHP¼19.8 Hz, J¼11.3 Hz,
J¼2.7 Hz, CHP), 5.87 (1H, s, CH); 13C NMR (75 MHz,
CDCl3) d 16.33 (d, JCP¼4.6 Hz, P(O)OCH2CH3), 16.40 (d,
JCP¼5.8 Hz, P(O)OCH2CH3), 26.06 (CH2), 26.96 (CH2),
OCH2CH3), 22.90 (CH2), 25.99 (CH2), 54.49 (d, JCP
¼
162.7 Hz, CHP), 62.77 (d, JCP¼3.5 Hz, OCH2), 63.02 (d,
JCP¼6.9 Hz, P(O)OCH2CH3), 63.16 (d, JCP¼6.9 Hz,
P(O)OCH2CH3), 116.15 (CH), 146.26 (Cquat), 156.43 (d,
JCP¼4.6 Hz, C]O); 31P NMR (121 MHz, CDCl3) d 20.13;
IR (neat) n 1769 cmꢂ1; MS m/z 306 [M+H+]; HRMS calcd
for C13H24NO5P (M+H+) 306.1465; found 306.1480; Rf
(EtOAc/PET 9:1)¼0.25.
4.1.3.3. Diethyl 3-(cyclohexylidenemethyl)-2-oxo-1,3-
oxazolidin-4-ylphosphonate 22c. 1H NMR (300 MHz,
CDCl3) d 1.35 (6H, t, J¼7.4 Hz, P(O)OCH2CH3), 1.57
27.89 (CH2), 28.51 (CH2), 33.58 (CH2), 39.72 (d, JCP
¼
(6H, m, CH2), 2.15 (4H, m, CH2), 4.05 (1H, ddd, JHP
¼
13.8 Hz, CH2Cl), 52.42 (OCH3), 53.39 (d, JCP¼145.4 Hz,
8.7 Hz, J¼6.9 Hz, J¼1.8 Hz, CHP), 4.20 (4H, m,

7686
B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
P(O)OCH2CH3), 4.51 (2H, m, OCH2), 5.64 (1H, s, CH); 13
C
(300 MHz, CDCl3) d 1.33 (6H, t, J¼7.1 Hz, P(O)OCH2CH3),
1.54 (6H, m, CH2), 2.11 (4H, m, CH2), 3.73 (3H, s, OCH3),
4.09 (2H, octet, J¼7.1 Hz, P(O)OCH2CH3), 4.12 (2H, octet,
J¼7.1 Hz, P(O)OCH2CH3), 5.76 (1H, s, CH), 5.88 (1H, d,
JHP¼38.2 Hz, CH2), 6.13 (1H, d, JHP¼13.2 Hz, CH2); 13C
NMR (75 MHz, CDCl3) d 16.25 (P(O)OCH2CH3), 16.35
(P(O)OCH2CH3), 26.32 (2ꢃCH2), 27.72 (CH2), 28.12
NMR (75 MHz, CDCl3) d 16.51 (P(O)OCH2CH3), 16.59
(P(O)OCH2CH3), 26.30 (CH2), 26.74 (CH2), 27.80 (CH2),
28.76 (CH2), 33.12 (CH2), 54.38 (d, JCP¼163.8 Hz, CHP),
62.71 (d, JCP¼2.3 Hz, OCH2), 63.07 (d, JCP¼6.9 Hz, P(O)-
OCH2CH3), 63.16 (d, JCP¼8.1 Hz, P(O)OCH2CH3), 114.29
(CH), 142.78 (Cquat), 156.35 (d, JCP¼4.6 Hz, C]O); 31P
NMR (121 MHz, CDCl3) d 20.03; IR (neat) n 1767 cmꢂ1
;
(CH2), 33.02 (CH2), 53.16 (OCH3), 62.34 (2C, d, JCP
5.8 Hz, P(O)OCH2CH3), 118.60 (CH), 128.08 (d, JCP
¼
¼
MS m/z 318 [M+H+]; HRMS calcd for C14H24NO5P
(M+H+) 318.1465; found 318.1468; Rf (EtOAc/PET
7:3)¼0.14.
21.9 Hz, CH2), 139.03 (d, JCP¼206.5 Hz, CP), 141.19
(Cquat), 155.06 (C]O); 31P NMR (121 MHz, CDCl3)
d 12.73; IR (neat) n 1721 cmꢂ1; MS m/z 332 [M+H+];
HRMS calcd for C15H26NO5P (M+H+) 332.1621; found
332.1627; Rf (EtOAc/PET 1:1)¼0.11.
4.1.4. General procedure for the preparation of vinyl-
phosphonates 23a–c. In a sealed vessel, enamide 17a–c
(5.0 mmol) was dissolved in 20 mL of toluene and 5.7 mL
of ammonia (40 mmol) (7 M in MeOH) was added. The re-
action mixture was heated in an oil bath of 120 ꢀC for 8 h af-
ter which the reaction mixture was extracted using 30 mL of
dichloromethane and 3ꢃ40 mL of water. The organic layer
was dried over magnesium sulfate, which was subsequently
filtered off and the solvent was evaporated under reduced
pressure. Vinylphosphonate 23a–c (72–83%, purity>95%)
was obtained, which might be further purified by flash chro-
matography using a mixture of ethyl acetate and petroleum
ether as the eluent (isolated yields: 51–61%).
4.1.5. Experimental procedure for the preparation of di-
ethyl 1-[(2-ethyl-1-butenyl)(methoxycarbonyl)amino]-2-
(propylamino)ethylphosphonate 24. In a flask of 25 mL,
0.35 g of 2-chloro-1-aminophosphonate 17b (1.0 mmol)
and 0.24 g of propylamine (4.0 mmol) were dissolved in
10 mL of dichloromethane. The reaction mixture was heated
under reflux for 72 h (to compensate for the loss of propyl-
amine by evaporation, 0.24 g of propylamine (4.0 mmol)
was added to the reaction mixture after 24 and 48 h). Next,
the reaction mixture was extracted with 10 mL of dichloro-
methane and 3ꢃ10 mL of 0.1 M sodium bicarbonate after
which the organic layer was dried over magnesium sulfate.
Filtering off the drying agent and evaporating the solvent
under reduced pressure afforded 0.32 g of crude reaction
mixture from which 0.22 g of 2-propylamino-1-amino-
phosphonate 24 (58%) was isolated upon purification by
flash chromatography.
4.1.4.1. Diethyl 1-[(methoxycarbonyl)(2-methyl-1-
propenyl)amino]vinylphosphonate 23a. 1H NMR
(300 MHz, CDCl3) d 1.31 (3H, t, J¼7.0 Hz, P(O)OCH2CH3),
1.32 (3H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.62 (3H, d,
J¼0.8 Hz, CH3), 1.73 (3H, d, J¼1.4 Hz, CH3), 3.74 (3H, s,
OCH3), 4.08 (2H, octet, J¼7.2 Hz, P(O)OCH2CH3), 4.11
(2H, octet, J¼7.3 Hz, P(O)OCH2CH3), 5.82 (1H, s, CH),
5.90 (1H, d, JHP¼38.2 Hz, CH2), 6.16 (1H, d, JHP¼13.5 Hz,
CH2); 13C NMR (75 MHz, CDCl3) d 16.28 (P(O)OCH2CH3),
16.38 (P(O)OCH2CH3), 17.78 (CH3), 22.30 (CH3), 53.29
(OCH3), 62.39 (2C, d, JCP¼4.6 Hz, P(O)OCH2CH3),
121.66 (CH), 128.63 (d, JCP¼23.1 Hz, CH2), 134.15 (Cquat),
138.38 (d, JCP¼205.4 Hz, CP), 155.04 (C]O); 31P NMR
(121 MHz, CDCl3) d 12.76; IR (neat) n 1721 cmꢂ1; MS m/
z 292 [M+H+]; HRMS calcd for C12H22NO5P (M+H+)
292.1308; found 292.1312; Rf (EtOAc/PET 7:3)¼0.21.
1H NMR (300 MHz, CDCl3) d 0.90 (3H, d, J¼7.4 Hz, CH3),
0.97 (3H, d, J¼7.3 Hz, CH3), 1.04 (3H, t, J¼7.4 Hz, CH3),
1.31 (6H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.46 (2H, sextet, J¼
7.2 Hz, CH2), 2.07 (4H, m, CH2), 2.49 (1H, dt, J¼11.5 Hz,
J¼7.1 Hz, NCH2), 2.61 (1H, dt, J¼11.3 Hz, J¼7.1 Hz,
NCH2), 2.96 (2H, m, NCH2), 3.70 (3H, s, OCH3), 4.12
(2H, quintet, J¼7.2 Hz, P(O)OCH2CH3), 4.14 (2H, quintet,
J¼7.1 Hz, P(O)OCH2CH3), 4.85 (1H, m, CHP), 5.71 (1H, s
CH); 13C NMR (75 MHz, CDCl3) d 10.88 (CH3), 11.72
(CH3), 12.44 (CH3), 16.38 (P(O)OCH2CH3), 16.44 (P(O)-
OCH2CH3), 21.99 (CH2), 23.15 (CH2), 25.48 (CH2), 46.44
(NCH2), 50.79 (NCH2), 52.92 (d, JCP¼148.8 Hz, CHP),
53.06 (OCH3), 62.15 (2C, d, JCP¼6.9 Hz, P(O)OCH2CH3),
117.07 (CH), 145.89 (Cquat), 156.87 (C]O); 31P NMR
(121 MHz, CDCl3) d 24.39; IR (neat) n 1705 cmꢂ1; MS
m/z 379 [M+H+]; HRMS calcd for C17H35N2O5P (M+H+)
379.2356; found 379.2372; Rf (EtOAc/PET 9:1)¼0.10.
4.1.4.2. Diethyl 1-[(2-ethyl-1-butenyl)(methoxycarbo-
nyl)amino]vinylphosphonate 23b. 1H NMR (300 MHz,
CDCl3) d 0.96 (3H, t, J¼7.5 Hz, CH3), 1.04 (3H, t,
J¼7.4 Hz, CH3), 1.32 (6H, t, J¼7.1 Hz, P(O)OCH2CH3),
2.08 (2H, q, J¼7.4 Hz, CH2), 2.09 (2H, q, J¼7.1 Hz, CH2),
3.73 (3H, s, OCH3), 4.09 (2H, octet, J¼7.1 Hz, P(O)-
OCH2CH3), 4.12 (2H, octet, J¼7.2 Hz, P(O)OCH2CH3),
5.80 (1H, s, CH), 5.90 (1H, d, JHP¼38.2 Hz, CH2), 6.14
(1H, d, JHP¼13.2 Hz, CH2); 13C NMR (75 MHz, CDCl3)
d 11.31 (CH3), 12.31 (CH3), 16.30 (P(O)OCH2CH3), 16.39
(P(O)OCH2CH3), 22.10 (CH2), 25.98 (CH2), 53.20 (OCH3),
62.39 (2C, d, JCP¼5.8 Hz, P(O)OCH2CH3), 120.50 (CH),
128.15 (d, JCP¼21.9 Hz, CH2), 138.86 (d, JCP¼205.4 Hz,
4.1.6. Experimental procedure for the preparation of di-
ethyl 1-[(2-ethyl-1-butenyl)(methoxycarbonyl)amino]-2-
(isobutylamino)ethylphosphonate 25. In
a flask of
25 mL, 0.32 g of vinylphosphonate 23b (1.0 mmol) and
0.29 g of isobutylamine (4.0 mmol) were dissolved in
10 mL of dichloromethane and the reaction mixture was
heated under reflux for 7 days. After 4 days, 0.29 g of iso-
butylamine (4.0 mmol) was added to compensate the loss of
amine by evaporation. The work-up performed was identical
to that for derivative 24 and afforded 0.36 g of crude reaction
mixture. Purification by flash chromatography yielded
0.19 g of 2-isobutylamino-1-aminophosphonate 25 (49%).
31
CP), 144.66 (Cquat), 155.21 (C]O); P NMR (121 MHz,
CDCl3) d 12.84; IR (neat) n 1722 cmꢂ1; MS m/z 320
[M+H+]; HRMS calcd for C14H26NO5P (M+H+) 320.1621;
found 320.1633; Rf (EtOAc/PET 7:3)¼0.27.
4.1.4.3. Diethyl 1-[(cyclohexylidenemethyl)(methoxy-
carbonyl)amino]vinylphosphonate 23c. 1H NMR

B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
7687
1H NMR (300 MHz, CDCl3) d 0.88 (3H, d, J¼6.6 Hz, CH3),
0.89 (3H, d, J¼6.9 Hz, CH3), 0.96 (3H, t, J¼7.3 Hz, CH3),
1.04 (3H, t, J¼7.4 Hz, CH3), 1.31 (6H, t, J¼7.0 Hz,
P(O)OCH2CH3), 1.69 (1H, nonnet, J¼6.6 Hz, CH), 2.07
(4H, m, CH2), 2.34 (1H, dd, J¼11.3 Hz, J¼6.6 Hz,
NCH2), 2.45 (1H, dd, J¼11.3 Hz, J¼6.9 Hz, NCH2), 2.95
(2H, m, NCH2), 3.70 (3H, s, OCH3), 4.12 (2H, quintet,
J¼7.2 Hz, P(O)OCH2CH3), 4.14 (2H, quintet, J¼7.1 Hz,
P(O)OCH2CH3), 4.84 (1H, m, CHP), 5.71 (1H, s, CH);
13C NMR (75 MHz, CDCl3) d 10.92 (CH3), 12.47 (CH3),
16.39 (P(O)OCH2CH3), 16.47 (P(O)OCH2CH3), 20.59
(CH3), 20.67 (CH3), 22.04 (CH), 25.52 (CH2), 28.48
(CH2), 46.76 (NCH2), 53.00 (d, JCP¼147.7 Hz, CHP),
53.06 (NCH2), 57.05 (OCH3), 62.18 (2ꢃP(O)OCH2CH3),
117.16 (CH), 145.86 (Cquat), 156.89 (C]O); 31P NMR
(121 MHz, CDCl3) d 24.51; IR (neat) n 1706 cmꢂ1; MS m/
z 393 [M+H+]; HRMS calcd for C18H37N2O5P (M+H+)
393.2513; found 393.2530; Rf (EtOAc/PET 6:4)¼0.14.
The crude reaction mixture was purified by flash chromato-
graphy affording 2-imidazolidinone 27a–f (33–44%).
4.1.8.1. Diethyl 3-(cyclohexylidenemethyl)-2-oxo-1-
propyl-4-imidazolidinylphosphonate 27d (potassium
carbonate was added after 4 days of heating). H NMR
1
(300 MHz, CDCl3) d 0.91 (3H, d, J¼7.4 Hz, CH3), 1.32
(3H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.33 (3H, t, J¼7.0 Hz,
P(O)OCH2CH3), 1.56 (8H, m, CH2), 2.20 (4H, m, CH2),
3.15 (1H, dt, J¼13.6 Hz, J¼7.0 Hz, NCH2), 3.20 (1H, dt,
J¼13.6 Hz, J¼7.3 Hz, NCH2), 3.58 (2H, m, NCH2), 3.86
(1H, m, CHP), 4.12 (4H, m, P(O)OCH2CH3), 5.54 (1H, s
CH); 13C NMR (75 MHz, CDCl3) d 11.20 (CH3), 16.53
(P(O)OCH2CH3), 16.60 (P(O)OCH2CH3), 20.80 (CH2),
26.48 (CH2), 26.94 (CH2), 27.95 (CH2), 29.02 (CH2),
33.23 (CH2), 43.78 (NCH2), 45.83 (NCH2), 52.26 (d, JCP
¼
165.0 Hz, CHP), 62.61 (d, JCP¼6.9 Hz, P(O)OCH2CH3),
62.74 (d, JCP¼6.9 Hz, P(O)OCH2CH3), 116.81 (CH),
139.89 (Cquat), 158.92 (d, JCP¼6.9 Hz, C]O); 31P NMR
(121 MHz, CDCl3) d 22.42; IR (neat) n 1716 cmꢂ1; MS
m/z 359 [M+H+]; HRMS calcd for C17H31N2O4P (M+H+)
359.2094; found 359.2095; Rf (EtOAc/PET 9:1)¼0.11.
4.1.7. Experimental procedure for the preparation of
diethyl 2-(allylamino)-1-[(2-ethyl-1-butenyl)(methoxy-
carbonyl)amino]ethylphosphonate 26. Following the
procedure for the preparation of derivative 25 with 0.32 g
of vinylphosphonate 23b (1.0 mmol) and 0.68 g of allyl-
amine (12 mmol) afforded 0.33 g of crude reaction mixture
(reflux, 10 days) from which 0.09 g of 2-allylamino-1-
aminophosphonate 26 (23%) was isolated by flash chroma-
tography.
4.1.8.2. Diethyl 3-(2-ethyl-1-butenyl)-1-isobutyl-2-
oxo-4-imidazolidinylphosphonate 27e (potassium car-
bonate was added after 8 days of heating). 1H NMR
(300 MHz, CDCl3) d 0.91 (3H, d, J¼6.6 Hz, CH3), 0.92
(3H, d, J¼6.6 Hz, CH3), 1.02 (3H, t, J¼7.5 Hz, CH3), 1.06
(3H, t, J¼7.5 Hz, CH3), 1.32 (6H, t, J¼7.1 Hz, P(O)-
OCH2CH3), 1.86 (1H, nonnet, J¼6.8 Hz, CH), 2.14 (4H,
m, CH2), 2.98 (1H, dd, J¼13.7 Hz, J¼7.4 Hz, NCH2),
3.04 (1H, dd, J¼13.6 Hz, J¼7.5 Hz, NCH2), 3.59 (2H, m,
NCH2), 3.86 (1H, ddd, JHP¼9.6 Hz, J¼7.1 Hz, J¼1.5 Hz,
CHP), 4.13 (4H, m, P(O)OCH2CH3), 5.56 (1H, d,
J¼0.8 Hz, CH); 13C NMR (75 MHz, CDCl3) d 11.78
(CH3), 12.54 (CH3), 16.53 (P(O)OCH2CH3), 16.60
(P(O)OCH2CH3), 19.98 (CH3), 20.09 (CH3), 22.93 (CH2),
26.03 (CH2), 27.00 (CH), 44.50 (NCH2), 51.97 (NCH2),
52.35 (d, JCP¼165.0 Hz, CHP), 62.58 (d, JCP¼4.6 Hz,
P(O)OCH2CH3), 62.67 (d, JCP¼4.6 Hz, P(O)OCH2CH3),
118.63 (CH), 143.38 (Cquat), 159.20 (d, JCP¼5.8 Hz,
C]O); 31P NMR (121 MHz, CDCl3) d 22.51; IR (neat) n
1716 cmꢂ1; MS m/z 361 [M+H+]; HRMS calcd for
C17H33N2O4P (M+H+) 361.2251; found 361.2259; Rf
(EtOAc/PET 8:2)¼0.15.
1H NMR (300 MHz, CDCl3) d 0.96 (3H, t, J¼7.4 Hz, CH3),
1.04 (3H, t, J¼7.6 Hz, CH3), 1.31 (6H, t, J¼7.1 Hz,
P(O)OCH2CH3), 1.76 (1H, s, NH), 2.07 (4H, m, CH2), 2.96
(2H, m, NCH2), 3.19 (1H, dd, J¼13.9 Hz, J¼6.1 Hz,
NCH2), 3.29 (1H, dd, J¼13.8 Hz, J¼5.8 Hz, NCH2), 3.70
(3H, s, OCH3), 4.12 (2H, quintet, J¼7.2 Hz, P(O)-
OCH2CH3), 4.14 (2H, quintet, J¼7.1 Hz, P(O)OCH2CH3),
4.80 (1H, m, CHP), 5.09 (1H, d, J¼10.4 Hz, CH2), 5.17
(1H, dd, J¼17.1 Hz, J¼1.4 Hz, CH2), 5.72 (1H, s, CH),
5.85 (1H, ddt, J¼16.8 Hz, J¼10.4 Hz, J¼6.0 Hz, CH); 13C
NMR (75 MHz, CDCl3) d 10.97 (CH3), 12.54 (CH3), 16.45
(P(O)OCH2CH3), 16.53 (P(O)OCH2CH3), 22.09 (CH2),
25.55 (CH2), 45.80 (NCH2), 51.49 (NCH2), 53.05 (d, JCP
¼
147.7 Hz, CHP), 53.17 (OCH3), 62.29 (2ꢃP(O)OCH2CH3),
116.32 (CH2), 117.15 (CH), 136.46 (CH), 146.06 (Cquat),
156.93 (C]O); 31P NMR (121 MHz, CDCl3) d 24.18; IR
(neat) n 1705 cmꢂ1; MS m/z 377 [M+H+]; HRMS calcd for
C17H33N2O5P (M+H+) 377.2200; found 377.2217; Rf
(EtOAc/PET 8:2)¼0.19.
4.1.8.3. Diethyl 1-benzyl-3-(cyclohexylidenemethyl)-2-
oxo-4-imidazolidinylphosphonate 27g (potassium car-
bonate was added after 14 days of heating). H NMR
1
4.1.8. General procedure for the preparation of 2-imid-
azolidinones 27d,e,g from vinylphosphonates 23b–c. In
a sealed vessel, vinylphosphonate 23b–c (1.0 mmol) and the
appropriate amine (6.0 mmol) were dissolved in 10 mL of
methanol and the reaction mixture was heated in an oil bath
of 50–60 ꢀC. After 4–14 days of heating (a sample from the
reaction mixture showed a w1:1 ratio of addition product
(w24.6 ppm) vs ring closed product 27 (w23.5 ppm), all start-
ing material (w13.3 ppm) was consumed; determined by
31P NMR), potassium carbonate (1.0 mmol) was added and
the reaction was heated for an additional 2 days until ring clo-
surewas complete. The solvent was evaporated under reduced
pressure and the residue was extracted with 10 mL of
dichloromethane and was washed with 3ꢃ10 mL of water.
(300 MHz, CDCl3) d 1.27 (3H, t, J¼7.1 Hz, P(O)-
OCH2CH3), 1.30 (3H, t, J¼6.9 Hz, P(O)OCH2CH3), 1.61
(6H, m, CH2), 2.21 (4H, m, CH2), 3.46 (2H, m, NCH2),
3.83 (1H, ddd, JHP¼9.8 Hz, J¼7.3 Hz, J¼1.1 Hz, CHP),
4.07 (4H, m, P(O)OCH2CH3), 4.35 (1H, d, J¼14.8 Hz,
CH2), 4.44 (1H, d, J¼14.8 Hz, CH2), 5.56 (1H, d,
J¼0.8 Hz, CH), 7.32 (5H, m, CH); 13C NMR (75 MHz,
CDCl3) d 16.51 (P(O)OCH2CH3), 16.59 (P(O)OCH2CH3),
26.53 (CH2), 27.00 (CH2), 27.99 (CH2), 29.11 (CH2),
33.28 (CH2), 43.32 (NCH2), 48.39 (NCH2), 52.15 (d, JCP
¼
166.1 Hz, CHP), 62.64 (d, JCP¼9.2 Hz, P(O)OCH2CH3),
62.74 (d, JCP¼6.9 Hz, P(O)OCH2CH3), 116.66 (CH),
127.66 (CH), 128.31 (2ꢃCH), 128.72 (2ꢃCH), 136.73
(Cquat), 140.43 (Cquat), 158.75 (d, JCP¼6.9 Hz, C]O); 31P

7688
B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
NMR (121 MHz, CDCl3) d 22.10; IR (neat) n 1716 cmꢂ1
;
affording 0.20 g of crude reaction mixture. Purification
by flash chromatography led to the isolation of 0.08 g of
2-imidazolidinone 27h (41%).
MS m/z 407 [M+H+]; HRMS calcd for C21H31N2O4P
(M+H+) 407.2094; found 407.2102; Rf (EtOAc/PET
8:2)¼0.15.
1H NMR (300 MHz, CDCl3) d 0.91 (3H, t, J¼7.4 Hz, CH3),
1.02 (3H, t, J¼7.7 Hz, CH3), 1.05 (3H, t, J¼7.4 Hz, CH3),
1.32 (6H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.54 (2H, sextet, J¼
7.3 Hz, CH2), 2.12 (4H, m, CH2), 3.16 (1H, dt, J¼13.7 Hz,
J¼7.1 Hz, NCH2), 3.20 (1H, dt, J¼13.7 Hz, J¼7.1 Hz,
NCH2), 3.59 (2H, m, NCH2), 3.86 (1H, m, CHP), 4.15
(4H, m, P(O)OCH2CH3), 5.56 (1H, s CH); 13C NMR
(75 MHz, CDCl3) d 11.23 (CH3), 11.81 (CH3), 12.57 (CH3),
16.54 (P(O)OCH2CH3), 16.62 (P(O)OCH2CH3), 20.85
(CH2), 22.93 (CH2), 26.03 (CH2), 43.87 (NCH2), 45.87
4.1.9. General procedure for the preparation of diethyl 1-
allyl-2-oxo-4-imidazolidinylphosphonates 27b,f. Follow-
ing the procedure for the preparation of 2-imidazolidinones
27, vinylphosphonate 23a,b (1.0 mmol) and 0.34 g of allyl-
amine (6.0 mmol) were heated for 6 days (a sample from the
reaction mixture showed that ring closure was complete; de-
termined by 31P NMR). After work-up, the crude reaction
mixture was purified by flash chromatography affording 2-
imidazolidinone 27b,c,f (44–52%).
(NCH2), 52.42 (d, JCP¼165.0 Hz, CHP), 62.56 (d, JCP
6.9 Hz, P(O)OCH2CH3), 62.74 (d, JCP¼6.9 Hz, P(O)-
OCH2CH3), 118.63 (CH), 143.39 (Cquat), 159.06 (d, JCP
¼
4.1.9.1. Diethyl 1-allyl-3-(2-methyl-1-propenyl)-2-oxo-
4-imidazolidinylphosphonate 27b. 1H NMR (300 MHz,
CDCl3) d 1.32 (6H, t, J¼7.0 Hz, P(O)OCH2CH3), 1.70
(3H, d, J¼1.1 Hz, CH3), 1.76 (3H, d, J¼1.1 Hz, CH3),
3.56 (2H, m, NCH2), 3.83 (2H, m, NCH2), 3.89 (1H, ddd,
JHP¼9.7 Hz, J¼6.8 Hz, J¼1.2 Hz, CHP), 4.12 (4H, m,
P(O)OCH2CH3), 5.20 (1H, dq, J¼10.0 Hz, J¼1.3 Hz,
CH2), 5.24 (1H, dq, J¼16.9 Hz, J¼1.5 Hz, CH2), 5.62
(1H, sextet, J¼1.3 Hz, CH), 5.75 (1H, ddt, J¼17.1 Hz,
J¼9.9 Hz, J¼6.1 Hz, CH); 13C NMR (75 MHz, CDCl3)
d 16.56 (2ꢃP(O)OCH2CH3), 18.50 (CH3), 22.42 (CH3),
43.58 (NCH2), 47.02 (NCH2), 51.89 (d, JCP¼166.1 Hz,
CHP), 62.61 (d, JCP¼6.9 Hz, P(O)OCH2CH3), 62.81 (d,
JCP¼6.9 Hz, P(O)OCH2CH3), 118.17 (CH2), 119.68 (CH),
132.93 (CH), 133.21 (Cquat), 158.57 (C]O); 31P NMR
(121 MHz, CDCl3) d 22.27; IR (neat) n 1716 cmꢂ1; MS m/
z 317 [M+H+]; HRMS calcd for C14H25N2O5P (M+H+)
317.1625; found 317.1632; Rf (EtOAc/PET 8:2)¼0.13.
¼
4.6 Hz, C]O); 31P NMR (121 MHz, CDCl3) d 22.63; IR
(neat) n 1714 cmꢂ1; MS m/z 347 [M+H+]; HRMS calcd
for C16H31N2O4P (M+H+) 347.2094; found 347.2105; Rf
(EtOAc/PET 8:2)¼0.14.
4.1.11. Experimental procedure for the preparation of di-
ethyl 1-amino-3-(2-ethyl-1-butenyl)-2-oxo-4-imidazolidi-
nylphosphonate 28b. In a sealed vessel, 0.35 g of 2-chloro-
1-aminophosphonate 17b (1.0 mmol) and 0.15 g of hydr-
azine monohydrate (3.0 mmol) were dissolved in 10 mL of
methanol. The reaction mixture was heated in an oil bath
of 60 ꢀC for 4 days after which the solvent was evaporated
under reduced pressure affording 0.31 g of crude reaction
mixture. Purification by flash chromatography led to the iso-
lation of 0.14 g of 2-imidazolidinone 28b (44%).
1H NMR (300 MHz, CDCl3) d 1.03 (3H, t, J¼7.7 Hz, CH3),
1.06 (3H, t, J¼7.4 Hz, CH3), 1.33 (6H, t, J¼7.1 Hz,
P(O)OCH2CH3), 2.14 (4H, m, CH2), 3.68 (4H, m, NCH2,
NH2), 3.81 (1H, dd, JHP¼9.3 Hz, J¼6.0 Hz, CHP), 4.19
(4H, m, P(O)OCH2CH3), 5.55 (1H, d, J¼0.8 Hz, CH); 13C
NMR (75 MHz, CDCl3) d 11.76 (CH3), 12.44 (CH3), 16.51
(P(O)OCH2CH3), 16.59 (P(O)OCH2CH3), 22.93 (CH2),
25.95 (CH2), 48.59 (NCH2), 51.34 (d, JCP¼166.1 Hz,
CHP), 62.62 (d, JCP¼6.9 Hz, P(O)OCH2CH3), 62.87 (d,
JCP¼6.9 Hz, P(O)OCH2CH3), 117.92 (CH), 144.77 (Cquat),
160.75 (d, JCP¼4.6 Hz, C]O); 31P NMR (121 MHz,
4.1.9.2. Diethyl 1-allyl-3-(2-ethyl-1-butenyl)-2-oxo-4-
imidazolidinylphosphonate 27f. 1H NMR (300 MHz,
CDCl3) d 1.03 (3H, t, J¼7.5 Hz, CH3), 1.06 (3H, t,
J¼7.4 Hz, CH3), 1.32 (6H, t, J¼7.0 Hz, P(O)OCH2CH3),
2.14 (4H, m, CH2), 3.56 (2H, m, NCH2), 3.83 (2H, m,
NCH2), 3.86 (1H, ddd, JHP¼9.6 Hz, J¼6.7 Hz, J¼1.2 Hz,
CHP), 4.12 (4H, m, P(O)OCH2CH3), 5.20 (1H, dq,
J¼10.0 Hz, J¼1.5 Hz, CH2), 5.24 (1H, dq, J¼17.1 Hz,
J¼1.5 Hz, CH2), 5.56 (1H, d, J¼0.8 Hz, CH), 5.75 (1H,
ddt, J¼17.2 Hz, J¼10.0 Hz, J¼6.1 Hz, CH); 13C NMR
(75 MHz, CDCl3) d 11.80 (CH3), 12.56 (CH3), 16.53
(P(O)OCH2CH3), 16.60 (P(O)OCH2CH3), 22.94 (CH2),
CDCl3) d 21.84; IR (neat) n 3327, 3211, 1723 cmꢂ1
;
MS m/z 320 [M+H+]; HRMS calcd for C13H26N3O4P
(M+H+) 320.1734; found 320.1746; Rf (EtOAc/MeOH
8:2)¼0.20.
26.01 (CH2), 43.57 (NCH2), 47.06 (NCH2), 52.35 (d, JCP
¼
165.0 Hz, CHP), 62.55 (d, JCP¼6.9 Hz, P(O)OCH2CH3),
62.74 (d, JCP¼6.9 Hz, P(O)OCH2CH3), 118.12 (CH2),
118.49 (CH), 132.96 (CH), 143.68 (Cquat), 158.67 (d,
JCP¼6.9 Hz, C]O); 31P NMR (121 MHz, CDCl3) d 22.45;
IR (neat) n 1718 cmꢂ1; MS m/z 345 [M+H+]; HRMS calcd
for C16H29N2O4P (M+H+) 345.1938; found 345.1940; Rf
(EtOAc/PET 9:1)¼0.13.
4.1.12. Experimental procedure for the preparation of di-
ethyl 1-amino-3-(cyclohexylidenemethyl)-2-oxo-4-imid-
azolidinylphosphonate 28c. Applying the procedure for
the preparation of 2-imidazolidinone 28b on 0.37 g of
2-chloro-1-aminophosphonate 17c led to 0.32 g of crude
reaction mixture from which 0.16 g of 2-imidazolidinone
28c (49%) was isolated.
4.1.10. Experimental procedure for the preparation of
diethyl 3-(2-ethyl-1-butenyl)-2-oxo-1-propyl-4-imidazo-
lidinylphosphonate 27h by ring closure of 2-propyl-
amino-1-aminophosphonate 24. In a flask of 25 mL,
1H NMR (300 MHz, CDCl3) d 1.33 (6H, t, J¼7.2 Hz,
P(O)OCH2CH3), 1.57 (6H, m, CH2), 2.16 (4H, m, CH2),
3.62 (2H, m, NCH2), 3.81 (1H, dd, JHP¼9.5 Hz, J¼6.4 Hz,
CHP), 3.94 (2H, s, NH2), 4.15 (4H, m, P(O)OCH2CH3),
5.54 (1H, s, CH); 13C NMR (75 MHz, CDCl3) d 16.54
(P(O)OCH2CH3), 16.62 (P(O)OCH2CH3), 26.41 (CH2),
0.22 g
of
2-propylamino-1-aminophosphonate
24
(0.58 mmol) was dissolved in 5 mL of anhydrous toluene.
The reaction mixture was heated under reflux for 22 h where
upon the solvent was evaporated under reduced pressure

B. Vanderhoydonck, C. V. Stevens / Tetrahedron 63 (2007) 7679–7689
7689
R.; Hofman, S.; Panunzio, M. Tetrahedron Lett. 1994, 35,
8045–8048.
26.93 (CH2), 27.92 (CH2), 28.96 (CH2), 33.17 (CH2), 48.58
(NCH2), 51.26 (d, JCP¼166.1 Hz, CHP), 62.65 (d, JCP
6.9 Hz, P(O)OCH2CH3), 62.88 (d, JCP¼6.9 Hz, P(O)-
OCH2CH3), 116.12 (CH), 141.30 (Cquat), 160.67 (d, JCP
¼
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5.8 Hz, C]O); 31P NMR (121 MHz, CDCl3) d 21.68; IR
(neat) n 3326, 3211, 1724 cmꢂ1; MS m/z 332 [M+H+];
HRMS calcd for C14H26N3O4P (M+H+) 332.1734; found
332.1747; Rf (EtOAc/MeOH 9:1)¼0.16.
Acknowledgements
This work was supported by the Belgian IWT (Instituut voor
de Aanmoediging van Innovatie door Wetenschap en
Technologie in Vlaanderen; Institute for the Promotion of
Innovation by Science and Technology in Flanders).
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