X=Y=ZH systems as potential 1,3-dipoles. Part 62:1 1,3-Dipolar cycloaddition reactions of metallo-azomethine ylides derived from α-iminophosphonates

Article abstract of DOI:10.1016/j.tet.2005.08.079

Metallo-azomethine ylides, generated from iminophosphonates in combination with LiBr or AgOAc and bases Et₃N, DBU, t-butyl tetramethylguanidine(BTMG) undergo cycloaddition to give dialkyl pyrrolidine-2-phosphonates along with the corresponding

Full text of DOI:10.1016/j.tet.2005.08.079

Tetrahedron 61 (2005) 10667–10682
X]Y]ZH systems as potential 1,3-dipoles. Part 62:1 1,3-Dipolar
cycloaddition reactions of metallo-azomethine ylides
derived from a-iminophosphonates
a
H. Ali Dondas,a,b Yasar Durust,a,c Ronald Grigg,a, Martin J. Slater
*
and Mohammed Abul Basher Sarkera
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
bDepartment of Chemistry, Faculty of Pharmacy, Mersin University, Yenisehir, 33342, Mersin, Turkey
c
˙
Department of Chemistry, Faculty of Science and Arts, Abant Izzet Baysal University, Bolu, Turkey
Received 23 March 2005; revised 5 August 2005; accepted 19 August 2005
Available online 19 September 2005
Abstract—Metallo-azomethine ylides, generated from iminophosphonates in combination with LiBr or AgOAc and bases Et3N, DBU,
t-butyl tetramethylguanidine(BTMG) undergo cycloaddition to give dialkyl pyrrolidine-2-phosphonates along with the corresponding
Michael adduct in some cases. Cycloadditions with the chiral dipolarophile 5R-(10R,20S,50R-menthyloxy)-2-(5H)-furanone (MOF) afforded
enantiopure cycloadducts.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
group, which becomes conjugated to the putative azo-
methine ylide in the reaction.20 We have shown that a wide
range of such groups are effective in both the 1,2-prototropy
and the metal catalysed protocols for in situ generation of
azomethine ylides.21 A wide range of metal and bases have
been employed to promote the metal catalysed cyclo-
addition, including [Ag(I), Li(I), Zn(II), Mg(II), Mn(II),
Co(II), Sn(IV)],21 Ti(IV),22 Ni(II),1 Cu(I),1 Cu(II)19 and
samarium23 and a range of rare earth24 triflates. However,
LiBr and AgOAc are the most commonly used metal salts,
while DBU and Et3N are the most frequently used bases.19,25
a-Amino phosphonates are an important class of com-
pounds in that they serve as bioisoesters of a-amino acids.2
Moreover when they are incorporated into peptides they
mimick the tetrahedral transition state of peptide hydrolysis
and can thus, be designed to be transition state inhibitors of
specific peptidases or esterases.3
The metal ion catalysed cycloaddition of ester (lactone,
lactam) stabilised azomethine ylides with appropriate
dipolarophiles has been widely developed to access proline
analogues, a-amino acids4 and peptidomimetics.5 This
reaction has been utilised as the key step in the synthesis
of many complex heterocycles.6–8 The metallo-azomethine
ylide cycloaddition has also been exploited in conjunction
with other high yielding core reactions in sequential and
cascade processes, thus, producing more complex hetero-
cycles9–15 with maximum synthetic efficiency. Chiral
versions of these processes have been developed, which
employ chiral dipolarophiles,16 chiral azomethine ylides17
or chiral catalysts.18,19 These processes are dependent on the
presence of an electron withdrawing carbanion stabilising
In this paper, we report the metal catalysed cycloaddition
reactions of a-imino phosphonates with various dipolaro-
philes including chiral menthyloxy furanone with (AgOAc
or LiBr) and a suitable bases [DBU, Et3N, BTMG (t-butyl
tetramethylguanidine)] as outlined in Scheme 1. Scheme 1
affords access to a wide variety of proline analogues and
conformationally constrained a-amino phosphonates.
Moreover, this application of our metal catalysed imine/
metalloazomethine ylide/cycloaddition cascade appeared
ideally suited to the phosphonate, which is a relatively weak
EWG.20 The rate of reaction can be further increased by
employing a stronger base, such as 2-t-butyl 1,1,3,3-
tetramethyl guanidine (BTMG). There is also scope for
the introduction of chirality in the dipole, since phosphorus
can be easily asymmetrically substituted.
Keywords: Cycloaddition; Iminophosphonate metallo-dipole; Azomethine
ylide.
Corresponding author. Tel.: C44 113 343 6501; fax: C44 113 343 6530;
e-mail: r.grigg@chemistry.leeds.ac.uk
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.079

10668
H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
Scheme 1.
2. Synthesis of a-amino phosphonates
(Table 1). The first step involves N-protection of the amino
acids with the N-benzyloxycarbonyl group (Cbz) under
standard Shotten–Baumann conditions. The N-Cbz amino
acids then undergo oxidative decarboxylation upon treat-
ment with lead tetraacetate. The serine analogue was
O-protected prior to this stage with a TBDMS group.
The synthesis of a-amino phosphonates can be achieved in
several ways, for example, addition of phosphites, phos-
phonites and hypophosphorus acids to imines,2,26 reaction
of appropriate phosphorus compounds with N,O-acetals27,28
and alkyl bromides,29 or by alkylation of amino methane-
phosphonate derivatives.30 Such analogues of all the natural
amino acids are known. The simplest a-amino phosphonate,
the glycine analogue, can be obtained in almost quantitative
yield from N-phthalimidomethyl bromide via an Arbuzov
reaction with an appropriate phosphite.29 N-Deprotection
via hydrazinolysis3 gives the a-aminophosphonate in
moderate to excellent yield depending on the phosphite.
Quantitative yields for the hydrogenolysis (Scheme 2) were
obtained in methanol, using 5% Pd on charcoal as the
catalyst. At least 1 equiv of glacial acetic acid, which
remains as an impurity in the amine, is required for this
procedure. The literature method (treatment with NaHCO3
in dry DCM) does not remove the acid completely.
A technical improvement in the N-deprotection (Scheme 2)
was achieved by using p-toluenesulfonic acid as the proton
source. The sodium sulfonate salt can be easily removed
by filtration, after stirring with moist NaHCO3 in DCM,
leaving the pure amine. This method was found to be
unsuitable for the serine derivative 2h, since O-desilylation
occurs during this procedure. Compounds 2a and 2b were
prepared according to the literature procedures.3,29
One of the most efficient syntheses of a-amino phospho-
nates is due to Corcoran and Green.31 The primary
advantage of this method is the use of readily available
natural amino acids as precursors. The four-step procedure
is relatively simple with the final step involving hydro-
genolysis of 1 to 2. The products are obtained in good yield
Table 1. Synthesis of a-aminophosphonates 2a–h
Entry
R1
R2
Product
Yielda
3. Synthesis of a-iminophosphonates
1
2
3
4
5
6
7
8
H
H
Me
Ph
PhCH2
c
—
CH2OH
CH2Osi(Me)2–t-Bu
Me
Ethyl
Me
Me
Me
Me
Me
Me
2ab
2bb
2c
2d
2e
2f
2g
2h
Quant
Quant
Quant
Quant
Quant
Quant
Quant
Quant
Imines 3a–t were synthesised in excellent yield in most
cases by reacting a range of aldehydes with a-aminophos-
phonates 2a–h (Scheme 3). Prior treatment of the
a-aminophosphonate salts with 1 equiv of triethylamine
generated the free amines. Unfortunately, the isolated yield
a Isolated yield.
b Compound 2a and 2b were synthesised according to literature
procedures.3,29
c Product 2f is
.
Scheme 3.
Scheme 2.

H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
10669
Scheme 4.
of pure crystalline arylidene imines was adversely affected
by the presence of the triethylammonium acetate contami-
nant. This became more of a problem with the aliphatic
imines 3i–k, since these products were thick oils and
adequate microanalyses could not be obtained. The aliphatic
imines were also less stable than their arylidene analogues,
and gradually decomposed at rt.
published a related similar case of kinetic acidity impacting
an azomethine ylide cycloadditions.32
The mechanism for the cycloaddition reaction (Scheme 5) is
directly analogous to that proposed by us for imines of
a-amino esters.33 The stereo-specific formation of the syn or
E,E-metallo-dipole (A and/or B), via deprotonation of the
complexed imine, precedes regio- and endo-specific
cycloaddition giving cycloadduct 4.
3.1. Cycloadditions with methyl acrylate
Reaction of phosphonate imine 3a with methyl acrylate in
acetonitrile with AgOAc/DBU afforded cycloadduct 4a
in 61% yield together with a trace Michael adduct 5a
(Scheme 4) (Table 3, entry 1). In contrast, the diethyl
phosphonate 3b with LiBr or AgOAc gave cycloadduct 4b
together with lactam 6. Lactam 6 arises from 5b via
cycloaddition to methyl acrylate to afford 7 followed by
cyclisation to the lactam 6.
Cycloadditions were carried out with a range of imines 3
using methyl acrylate as the dipolarophile (Scheme 4). The
conditions employed, time and yield for the reactions are
collected in Table 3. The reaction times are very much
longer than those required for cycloadditions of the imines
of a-amino esters. This is ascribed to the relatively high pKa
of the a-CH proton in the imino phosphonates.20
To increase the rate of the reaction, 2-t-butyl 1,1,3,3-
tetramethylguanidine (BTMG), a stronger base, was used in
the cycloaddition of the alanine analogue 3c. Contrary to
expectations, a longer reaction time was required and a
lower overall yield was obtained (Table 2). The possible
reaction of the phosphonate and the base was ruled out by
monitoring a mixture of the two compounds over 16 h by 1H
NMR. The most likely explanation is that the imine’s bulky
dimethylphosphonate group impedes efficient deprotonation
by the similarly sterically hindered base. We have recently
The ratio of the bicyclic lactam 6 to the cycloadduct 4b was
found to be 1:1 and 1:2.5 in the lithium and silver salt
catalysed reactions, respectively. These results indicate that
the Michael addition and cycloaddition have comparable
rates in this case. Lactam 6 was isolated and fully
characterised (see Section 6). The tendency of LiBr to
favour Michael addition is well known but it is rare for
silver salts to exhibit this trait.21 In this case it is clearly
related to the comparatively high pKa of the crucial
hydrogen a to the phosphonate (Scheme 6).
Table 2. Synthesis of iminophosphonates 3a–sa
Entry
R1
R2
R3
Product
Yieldb
1
2
3
4
5
6
7
8
H
H
Me
Ph
CH2Ph
2f
CH2OH
CH2OSi(CH3)2t-Bu
Me
Ph
CH2Ph
Me
Me
Me
Ph
CH2Ph
Me
Ph
Me
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Thienyl
2-Naphthyl
2-Naphthyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
4-Nitrophenyl
2-Iodophenyl
2-Pyridyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
Quant
95
57
Ethyl
Me
Me
59
44
—
74
Me
c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
80
94
75
86
94
90
88
91
Quant
79
Quant
Quant
9
10
11
12
13
14
15
16
17
18
19
2-Pyridyl
2-Pyridyl
2-Thienyl
2-Thienyl
2-Thienyl
CH2Ph
a Reaction employed amine (1 mmol), aldehyde (1 mmol) and NEt3 (2 mmol) in dichloromethane at rt for 16 h.
b Isolated yield.
c Iminium ion generated in situ.

10670
H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
Scheme 5.
Table 3. Cycloaddition reactions of imines 3 with methyl acrylate (MA) to give 4a
Entry
Imine
Metal salt
Solvent
Time (days)b
Product
Yield (%)
1
2
3
4
5
6
7
8
3a
3b
3b
3c
3c
3d
3d
3e
3e
3g
3h
3h
3l
3m
3n
3o
3p
3r
3s
AgOAc
AgOAc
LiBr
AgOAc
AgOAcd
AgOAc
LiBr
AgOAc
LiBr
AgOAc
AgOAc
LiBr
MeCN
MeCN
THF
MeCN
MeCN
MeCN
THF
MeCN
THF
MeCN
MeCN
THF
4
2
3
3
6
7
4
4
4a
4b
4b
4c
4c
4d
4d
4e
4e
4g
4h
4h
4l
4m
4n
4o
4p
4r
4s
61c
47c
44c
73
30d,e
22e
73
20
69
8
12
9
3
4
10
11
12
13
14
15
16
17
18
19
20
5.8
6.8
5.0
2.8
5.0
1.8
1.8
5.0
0.9
1.8
47
AgOAc
AgOAc
AgOAc
LiBr
MeCN
MeCN
MeCN
THF
37f
80c
90
32
75
LiBr
THF
AgOAc
LiBr
LiBr
MeCN
THF
THF
98
64c
79c
3t
4t
a The metal salt (1.5 mol equiv), DBU(1.0 mol equiv), imine (1 mol equiv) and methyl acrylate (1 mol equiv) were reacted at rt using a foil protected flask in
the case of AgOAc.
b The reaction times relate to the disappearance of starting material, which was monitored by TLC.
c Small amount of Michael adduct (!10%) also formed.
d 2-t-Butyl 1,1,3,3-tetramethyl guanidine was used as the base.
e Obtained as a mixture of the imine and cycloadduct (% yield calculated by NMR).
f
Michael adduct 5l (29%) also formed.
Scheme 6.

H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
10671
The cycloadditions of methyl acrylate with the N-(2-
naphthylidene) dimethyl phosphonate imines 3c–e were
relatively straightforward, and gave only the expected
cycloadducts 4c–e whose stereochemistry was established
by 2-D COSY and NOE data (see Section 6).
more pronounced in the phosphonate case compared to the
carboxylate. A further feature of Table 3 is the large amount
of Michael adduct formed from imine 3l (entry 13) but not
from imines 3h, 3o and 3p (Table 3, entries 15–17).
The effect of increasing the electron-withdrawing properties
of the substituents at R1 and R3 (Scheme 8) would be two
fold. Firstly, the basicity of the imine N-atom would
decrease, which would lower the stability of the metal
complexes A and C. Thus, the proportion of species 3 and B
would increase relative to A and C. Secondly, the pKa of the
a-CH proton would decrease; resulting in the species B and
C being favoured relative to 3 and A. Assuming the anion B
reacts to give the Michael adduct, and that the metallo-
dipole C reacts to give cycloadduct only, combining the two
factors could result in an increase in the proportion of
Michael adduct. However, this would be moderated by the
increased stability of the anion. Thus, in considering the
relative rates of the two processes, our results indicate
Michael addition becomes somewhat more competative
and in the case of 3l the rates are approximately the same.
If this were true, it would require only a slight disturbance of
the equilibrium for Michael addition to become the more
prevalent reaction pathway.
The efficiencies of the two metal salts (AgOAc and LiBr) in
the cycloaddition of phosphonate imines follows the same
trend as that observed for imines of a-amino esters. Thus,
imines of phenylglycine have been shown to work better
with Li(I) rather than Ag(I) salts. We have argued that
this preference is a result of steric compression between
the phenyl substituent and the ester moiety caused by the
increase in the angles a and b (Scheme 7) necessary for
chelation of the larger silver ion (the respective ionic radii of
˚
Ag(I) and Li(I) are 1.26 and 0.68 A). This compression is
relieved by the phenyl ring twisting out of plane, which
disrupts resonance stabilisation (higher pKa for the crucial
proton a to the ester) and hinders the cycloaddition.
Generally, the use of electron-withdrawing substituents to
activate the imino phosphonates is very effective in
improving the efficiency of the cycloaddition reaction.
Only when the structure is intrinsically activated are
additional electron-withdrawing substituents either
unnecessary or even detrimental. The trends observed in
this series of reactions should prove useful in the fine tuning
of future cycloadditions.
Scheme 7.
In the case of the phosphonate imines the effect extends to
the phenylalanine analogues (Table 3, entries 8, 9, 17 and
20) and the TBDMS protected serine imine (Table 3, entries
11 and 12).
3.2. Cycloadditions with (R)-5(1R)-menthyloxy-2-(5H)-
furanone 8
The geometries of the phosphonate and carboxylate
metallo-dipoles (Scheme 7) are slightly different. In the
tetrahedral phosphonate the angle b will be closer to 1098
rather than the 1208 angle of the carboxylate dipole. The
tightening of the angles will be compensated for, to some
extent, by the increase in bond lengths to phosphorus,
(which are w20% longer than the corresponding bond
lengths to carbon). However, the results clearly suggest that
the steric compression necessary to accommodate the larger
silver ion and to achieve more appropriate bond angles, is
A second series of cycloadducts was prepared from imines
3b,c and the chiral dipolarophile 8 (Scheme 9). Reaction of
3a,b with 8 occurred over 10–18 h at rt in acetonitrile using
silver acetate-DBU as the catalyst. Enantiopure cyclo-
adducts 9a,b were obtained as single stereoisomers in good
yield (Table 4). The stereochemistry of 9a,b is based on
NOE data (see Section 6) and an X-ray crystal structure5
from our previous related work. Once again the process
Scheme 8.

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H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
Scheme 9.
proceeds via an endo transition state and as expected the
silver azomethine ylide adds to the face of the dipolarophile
8 trans to the O-menthyl group.5 Hence the newly created
stereocentres are 1S, 2R, 4S and 5R (Scheme 9).
of the base to NMM and polymerisation of the resultant
zwitterion. This unwanted side reaction is accompanied by
the appearance of a characteristic deep red colour.34 Use of
DBU in MeCN results in a similar outcome.
The reaction of 3c and NMM, using triethylamine as base
in MeCN or DMSO were also very disapponting. No
cycloadduct was isolated from the reaction carried out in
MeCN after stirring for two weeks, whilst a low yield of 10
was obtained in DMSO after 9 days. This suggest that in
DMSO the Michael addition of the weaker nucleophile
(Et3N) to NMM is accelerated and competes and effectively
suppresses cycloaddition.
4. Variation of the dipolarophile
4.1. N-Methyl maleimide
The AgOAc catalysed reactions of imine 3c with N-methyl-
maleimide (NMM) in MeCN (BTMG as base) or DMSO
(Et3N as base) gave cycloadduct 10 (Scheme 10). Low
yields resulted in both cases (Table 4, entries 3 and 4). The
low yield when BTMG was used is due to Michael addition
4.2. Methyl vinyl ketone (MVK)
The reaction of 3c with (MVK) gave 11 (Scheme 11,
Table 4, entry 5) in poor yield. The mechanism of formation
11 involves stereospecific formation of the syn or E,E-
metallo-dipole followed by regio- and endo- specific
cycloaddition to the dipolarophile. Michael addition of
the cycloadduct to a second molecule of dipolarophile
(Scheme 11) gives 11.
4.3. Thermal iminium ion cycloaddition
Scheme 10.
The dimethyl phosphonate analogue of proline 2f was
Table 4. Cycloaddition of Imines 3b,c with various dipolarophilesa
Entry
Imine
Dipolarophile
Time (h)
Product
Yield (%)
1
2
3b
3c
3c
3c
3c
8
8
18
10
9
3
240
9a
9b
10
10
11
42
58
21
15
25
3b
4c
5
NMM
NMM
MVKd
a Reaction conditions: MeCN, AgOAc (1.5 equiv), DBU (1.0 equiv), 25 8C.
b NEt3 and DMSO used.
c 2-t-Butyl 1,1,3,3-tetramethyl guanidine used as base.
d Methylvinyl ketone.

H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
10673
Scheme 11.
reacted in boiling acetonitrile with thiophene-2-carboxalde-
hyde and NMM. Deprotonation of the intermediate iminium
ion 12 afforded the azomethine ylide (Scheme 12), which
furnished a single cycloadduct 13. The stereochemistry of
13 was assigned on the basis of 1H NMR and NOE data (see
Section 6). The magnitude of the JCH–CP coupling constant
(16 Hz) is characteristic of a cis-relationship between 7-H
and phosphorus. The 15% enhancement of the signal for
3-H (observed on irradiating the signal for 2-H) is consistent
with a cis relationship between these two protons.
By analogy with the cycloaddition of iminium ion derived
from secondary a-amino esters.35 The observed stereo-
selective dipole formation is due to the interaction between
the 1- and 3-substituents of the two dipoles (Scheme 13).35
There is significant out of plane twisting of the thienyl
group, as a consequence of the unfavourable steric
interaction, which disrupts conjugation. This effect is
far greater in Y, due to the size of the dimethyl phospho-
nate ester group, and this dipole is effectively totally
suppressed. It is likely that the endo-transition state of the
cycloaddition to X would also experience the least steric
hindrance.
The cycloaddition is endo-specific and proceeds via the
stereoselective formation of the syn-dipole, where syn and
anti refer to the relative configurations of the 1,3-H/
PO(OMe)2 dipole substituents.
An alternative azaallyl anion cycloaddition approach has
been reported,36 which leads to mixtures of phosphonate
Scheme 12.
Scheme 13.

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H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
analogues of proline and 1-pyrrolidines. The latter are
formed by elimination of the phosphonate moiety.
Compound 2c. Dimethyl N-(benzyloxycarbonyl)-1-amido
ethylphosphonate 1c (1 g, 3.49 mmol) and glacial acetic
acid (0.43 g, 7.16 mmol) were dissolved in methanol
(89 mL) in a 250 mL flask. After the addition of 5%
palladium on charcoal (0.95 g), the flask was evacuated and
the air replaced with hydrogen. The contents of the flask
were then vigorously stirred 16 h at rt. The resulting
suspension was filtered and evaporated under reduced
pressure (!25 8C), to give the crude acetate salt of the
amine 2c in quantitative yield.
5. Summary
The metallo-azomethine ylide cycloaddition route has been
implemented for a-iminophophonates following a previous
single thermal example, which gave a 1:1 mixture of endo
and exo-isomers. The rt metallo-azomethine ylide process is
catalysed by AgOAc/DBU or LiBr/DBU. When methyl
acrylate is employed as dipolarophile the cycloaddition
is slow 0.9–6.8 days and yields range from 8–98%.
The cycloadducts are derived from the corresponding
E,E-metallo-azomethine ylides via endo transition states.
The steric compression necessary to accommodate the
larger Ag(I) ion, and achieve appropriate bond angles, is
more pronounced in the case of the sterically more
demanding phosphonate imines compared to the imines of
a-amino esters. As a result of these factors, in the former
cases, Michael addition competes with cycloaddition in
some cases. The significantly slower rate of cycloaddition,
compared to that of imines of a-amino esters, reflects the
higher pKa of a-proton(s) in the iminophosphonates.
Cycloadditions with R-5(1R)-menthyloxy-2-(5H)-furanone,
NMM and MVK were likewise slow (10 h–10 days) and
yields, in these cases, ranged from 15–58%. The
cycloadducts from the chiral dipolarophile were
enantiopure.
An alternatively procedure was used, in which glacial acetic
acid was replaced by p-toluenesulfonic acid (0.7 g,
3.7 mmol), to give the p-toluenesulfonate salt of the amine
2c. Stirring this salt for 30 min, with damp NaHCO3 (1.2 g)
in dichloromethane (100 mL), resulted in the formation of
crystalline sodium p-toluenesulfonate. The sodium salt was
removed easily by filtration through Celite and the filtrate
was evaporated to give the pure amine 2c (410 mg, 77%).
This method also provided the serine phosphonate analogue
2g via the quantitative removal of both N- and O-protecting
groups of compound 1h.
6.2. General procedure for the preparation of imines
3a–t
The crude acetate salts of a-amino phosphonates 2a–h
(l equiv) in dry dichloromethane were stirred with triethyl-
amine (2 equiv) and anhydrous Na2SO4 (excess) for 1 h,
prior to the addition of the aldehyde (0.9 equiv). After
stirring 16 h, the suspension was filtered and the filtrate was
evaporated under reduced pressure (!25 8C). In the case
of the aryl aldimines, the resulting gum was suspended
in diethyl ether—from which the imine crystallised on
prolonged storage at 0–4 8C. The aliphatic aldimines
were obtained, after heating (w50 8C) under vacuum
(1–5 mmHg) for w5 h, as thick oils contaminated with
trace amounts of acetic acid.
6. Experimental
Melting points were determined on a Koffler hot-stage
apparatus and are uncorrected. Mass spectral data were
obtained from VG 7070 and Autospec instruments operating
at 70 eV. Nuclear magnetic resonance spectra were
recorded on Bruker WM250, QE300 and Bruker AM400
instruments operating at 250, 300 and 400 MHz, respect-
ively. Unless otherwise specified deuteriochloroform was
used as solvent. The following abbreviations are used; s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad; br s, broad singlet; and app, apparent. Microanalyses
were obtained using a Carlo Erba MOD 11016 instrument.
Preparative TLC plates were prepared using silica gel 60 PF
(Merck 7748). Column chromatography was performed
with silica gel 60 (Merck 9385). Chiral HPLC. was
performed on a Chiralcel OD or OG columns (Daicel)
using specified eluants. Petroleum ether refers to the
fraction with bp 40–60 8C. (R)-5(1R)-menthyloxy-2-(5H)-
furanone was purchased from Aldrich and used as
received. Dimethyl N-(phthalimido)methylphosphonate,
diethyl N-(phthalimido)-methylphosphonate, dimethyl
aminomethylphosphonate 2a and diethyl aminomethyl-
phosphonate 2b were synthesised according to literature
procedures.3,29
Where the free base was available the aldehyde (0.95 equiv)
was used in the absence of triethylamine, and the imines
were obtained relatively pure after evaporation of the
solvent.
6.2.1. Dimethyl N-(2-naphthylidene)iminomethyl-phos-
phonate 3a. Dimethyl aminomethylphosphonate 2a3,29
(300 mg, 2.17 mmol) and 2-naphthaldehyde (32 mg,
2.06 mmol) were reacted for 16 h to yield the crude imine
3a (600 mg, quant) as a pale yellow solid, mp 85–86 8C; m/z
(%) 277 (MC, 3), 168 (17), 167 (17), 141 (52), 124 (100)
and 94 (59); d 8.45 (d, 1H, JZ4.7 Hz, CH]N), 8.15–7.25
(m, 7H, naphthyl-H), 4.19 (d, 2H, JP–CHZ17.6 Hz,CH2P),
and 3.84 (d, 6H, JP–OCHZ10.9 Hz, 2!MeOP).
6.2.2. Diethyl N-(2-naphthylidene) imino methylphos-
phonate 3b. Diethyl aminomethyl phosphonate 2b3,29
(1.68 g, 10 mmol) and 2-naphthaldehyde (1.32 g,
8.5 mmol) were reacted for 16 h to yield the product 3b
(95%) as a thick yellow oil, which was purified by
distillation using a mole still, 100–200 8C/1–3 mmHg
(found: C, 59.6; H, 6.95; N, 4.08. C16H20NO3P$H2O
requires: C, 59.50; H, 6.85; N, 4.35%); m/z (%) 306
(MHC, 6), 168 (56), 152 (100), 141 (88) and 125 (97); d
6.1. General procedure for the preparation of a-amino
phosphonates (2c–h)
N-Deprotection of the N-Cbz a-amino phosphonates 1c–h
was achieved by catalytic hydrogenation, using a modifi-
cation of the method of Campbell et al.27

H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
10675
8.46 (d, 1H, JZ4.8 Hz, CH]N), 8.05–8.00 (m, 2H,
naphthyl-H), 7.94–7.84 (m, 3H, naphthyl-H), 7.56–7.50
(m, 2H, naphthyl-H), 4.27–4.12 (m, 6H, 2!CH2OP and
CH2P) and 1.35 (t, 6H, JZ7.1 Hz, MeCH2OP).
cyclohexane carboxaldehyde (284 mg, 2.53 mmol) were
reacted for 16 h to give the product 3h (668 mg, 94%) as a
pale yellow oil. m/z (%) 245 (MCK2, 17), 138 (100), 110
(43) and 95 (24); d 7.59 (t, 1H, JZ4.9 Hz, CH]N), 3.80 (d,
3H, JP–OCHZ10.3 Hz, MeOP), 3.77 (d, 3H, JP–OCH
10.4 Hz, MeOP), 3.63 (dt, 1H, JZ6.3 Hz, JP–CH
Z
Z
6.2.3. Dimethyl N-(2-naphthylidene)imino ethylphospho-
nate 3c. The crude amine salt 2c (0.88 g, 3.5 mmol),
triethylamine (1.l mL, 7.89 mmol) and 2-naphthaldehyde
(496 mg, 3.18 mmol) were reacted for 16 h to give the product
3c (580 mg, 57%), which crystallised from diethyl ether/
petroleum ether as colourless needles, mp 124–125 8C (found:
C, 61.55; H, 6.10; N, 4.65. C15H18NO3P requires: C, 61.79; H,
6.31; N, 4.80%); m/z (%) 291 (MC, 2), 182 (66), 155 (31), 138
(100) and 110 (42); d 8.49 (d, 1H, JZ4.7 Hz, CH]N), 8.00–
7.49 (m, 7H, naphthyl-H), 3.99 (d of quart, 1H, JZ6.8,
13.5 Hz, CHP),3.83(d,6H, JP–OCHZ10.5 Hz, 2!MeOP)and
1.61 (dd, 3H, JZ7.0 Hz, JP–C–CHZ18.2 Hz, Me).
12.7 Hz, CHP), 2.25 (br m, 1H, CHC]N), 1.82–1.60 (m,
Z
5H, cyclohexyl-H), 1.45 (dd, 3H, JZ6.9 Hz, JP–C–CH
8.3 Hz, Me) and 1.38–1.13 (m, 5H, cyclohexyl-H).
6.2.8. Dimethyl N-(cyclohexylidene)-1-imino-1-phenyl
methylphosphonate 3i. The crude amine salt 2d (960 mg,
2.87 mmol), triethylamine (609 mg, 6.0 mmol) and cyclo-
hexane carboxaldehyde (290 mg, 2.58 mmol) were reacted
for 16 h to give the product 3i (75%) a thick brown oil
purified by heating under vacuum (60 8C/1–5 mmHg). m/z
(%) 310 (MHC, 7), 241 (14), 200 (100) and 106 (37); d 7.68
(t, 1H, JZ2.4 Hz, CH]N), 7.57–7.26 (m, 5H, Ar-H), 4.69
(d, 1H, JP–CHZ18.0 Hz, CHP), 3.69 (d, 3H, JP–OCH
Z
6.2.4. Dimethyl N-(2-naphthylidene)-1-imino-1-phenyl
methylphosphonate 3d. The crude amine salt 2d
(963 mg, 2.9 mmol), triethylamine (640 mg, 6.32 mmol)
and 2-naphthaldehyde (399 mg, 2.55 mmol) were reacted
for 16 h to give the product 3d (530 mg, 59%), which was
crystallised from diethyl ether/petroleum ether as colourless
needles, mp 113–116 8C (found: C, 67.70; H, 5.55; N, 3.85.
C20H20NO3P requires: C, 67.98; H, 5.70; N, 3.96%); m/z
(%) 353 (MC, 0.2), 244 (100) and 200 (41); d 8.56 (d, 1H,
JZ4.6 Hz, CH]N), 8.16–7.27 (m, 12H, naphthyl and
Ar-H), 5.05 (d, 1H, JP–CHZ18.4 Hz, CHP), 3.74 (d, 3H,
JP–OCHZ9.8 Hz, MeOP) and 3.71 (d, 3H, JP–OCHZ10.0 Hz,
MeOP).
15.8 Hz, MeOP), 3.66 (d, 3H, JP–OCHZ15.9 Hz, MeOP),
2.36–2.30 (br m, 1H, CHC]N), 1.94–1.62 (m, 5H,
cyclohexyl-H) and 1.45–1.18 (m, 5H, cyclohexyl-H).
6.2.9. Dimethyl N-(cyclohexylidene)-1-imino-2-phenyl
ethylphosphonate 3j. The crude amine salt 2e (900 mg,
2.76 mmol), triethylamine (447 mg, 4.4 mmol) and cyclo-
hexane carboxaldehyde (279 mg, 2.49 mmol) were reacted
for 16 h to give the product 3j (86%) as a thick brown oil
purified by heating under vacuum (60 8C/1–5 mmHg). m/z
(%) 323 (MHC, 3), 255 (34), 232 (31), 214 (100) and 110
(44); d 7.33–7.07 (m, 5H, Ar-H), 7.00 (t, 1H, JZ4.7 Hz,
CH]N), 3.84 (d, 3H, JP–OCHZ12.7 Hz, MeOP), 3.80
(d, 3H, JP–OCHZ12.6 Hz, MeOP), 3.58 (dt, 1H, JZ
2.2 Hz, JP–CHZ11.1 Hz, CHP), 3.32–3.24 (m, 1H, CHPh),
3.11–3.00 (m, 1H, CHPh), 2.41–2.03 (br m, 1H, CHC]N),
1.66–1.52 (m, 5H, cyclohexyl-H) and 1.31–0.97 (m, 5H,
cyclohexyl-H).
6.2.5. Dimethyl N-(2-naphthylidene)-1-imino-2-phenyl-
ethylphosphonate 3e. The crude amine salt 2e (800 mg,
2.76 mmol), triethylamine (680 mg, 2.77 mmol) and
2-naphthaldehyde (431 mg, 2.76 mmol) were reacted for
16 h to give the product 3e (440 mg, 44%), which was
crystallised from diethyl ether/petroleum ether as colourless
needles, mp 72–75 8C (found: C, 65.65; H, 5.65; N, 3.45.
C21H22NO3P$H2O requires: C, 65.45; H, 5.75; N, 3.65%);
m/z (%) 367 (MC, 9), 276 (64), 258 (72), 214 (98) and 167
(100); d 8.05–7.09 (m, 12H, naphthyl and Ar-H), 7.94 (d,
6.2.10. Dimethyl N-(20-naphthylidene)-1-imino-2-{[(t-
butyl)dimethylsilyl]oxy} ethylphosphonate 3k. The
crude acetate salt of the a-aminophosphonate 2h (720 mg,
2.1 mmol), triethylamine (246 mg, 2.4 mmol) and
2-naphthaldehyde (311 mg, 2.0 mmol) were reacted for
16 h. The reaction mixture was filtered, washed with brine
and evaporated under reduced pressure (!25 8C). The
resulting gum was crystallised from petroleum ether to give
the product 3k (737 mg, 80%) as colourless needles, mp 88–
90 8C (found: C, 59.85; H, 7.60; N, 3.30. C21H32NO4PSi
requires: C, 59.85; H, 7.65; N, 3.30%); m/z (%) 406 (MK
Me, 4), 391 (MKMe2, 1), 364 (100), 276 (9), 254 (35) and
167 (57); d 8.41 (d, 1H, JZ3.7 Hz, CH]N), 8.07–8.04 (m,
2H, naphthyl-H), 7.95–7.84 (m, 3H, naphthyl-H), 7.54–7.52
(m, 2H, naphthyl-H), 4.23–4.20 (m, 1H, CHOSi), 4.06 (dt,
1H, JZ4.2 Hz, JCH–PZ10.1 Hz, CHP), 4.03–3.93 (m, 1H,
CHOSi), 3.84 (d, 3H, JCH–OPZ10.3 Hz, MeOP), 3.83 (d,
3H, JCH–OPZ10.4 Hz, MeOP), 0.81 (s, 9H, t-Bu), 0.04 (s,
3H, SiMe) and K0.06 (s, 3H, SiMe).
1H, JZ4.6 Hz, CH]N), 3.95 (dt, 1H, JZ2.2 Hz, JP–CH
Z
11.3 Hz, CHP), 3.96 (d, 3H, JP–OCHZ10.5 Hz, MeOP), 3.85
(d, 3H, JP–OCHZ10.1 Hz, MeOP), 3.42–3.38 (m, 1H,
CH2Ph) and 3.32–3.24 (m, 1H, CH2Ph).
6.2.6. Dimethyl N-(2-naphthylidene)-1-imino-2-hydroxy-
ethylphosphonate 3g. The crude amine 2g (260 mg,
1.54 mmol) and 2-naphthaldehyde (228 mg, 1.46 mmol)
were reacted for 16 h to give the product 3g (330 mg, 74%),
which was crystallised from diethyl ether/petroleum ether as
colourless prisms, mp 113–114 8C (found: C, 58.60; H,
6.10; N, 4.45. C15H18NO4P requires: C, 58.65; H, 5.90; N,
4.60%); m/z (%) 307 (MC, 32), 305 (82), 289 (51), 276 (60),
196 (76), 180 (97) and 154 (100); d 8.47 (d, 1H, JZ4.6 Hz,
CH]N), 8.05–7.50 (m, 7H, naphthyl-H), 4.20–4.13 (m, 2H,
CH2O), 4.05 (dt, 1H, JZ8.l Hz, JP–CHZ12.7 Hz, CHP),
3.82 (d, 3H, JP–OCHZ10.9 Hz, MeOP) and 3.81 (d, 3H,
JP–OCHZ10.4 Hz, MeOP).
6.2.11. Dimethyl N-(40-nitrobenzylidene)-1-imino ethyl-
phosphonate 3l. The amine 2c (577 mg, 3.77 mmol) and
p-nitrobenzaldehyde (5.22 mg, 3.65 mmol) were reacted for
16 h to give the product 3l as a thick dark brown oil (1.04 g,
94% yield) purified by distillation using a mole still, 220 8C/
6.2.7. Dimethyl N-(cyclohexylidene)imino ethylphospho-
nate 3h. The crude amine 2c (410 mg, 2.68 mmol) and

10676
H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
0.9 mmHg (found: C, 46.85; H, 5.45; N, 9.60. C11H15N2O5P
requires: C, 46.15; H, 5.30; N, 9.80%); m/z (%) 287 (MHC,
4), 177 (96), 138 (100), 131 (67) and 110 (80); d 8.46 (d, 1H,
JZ4.8 Hz, CH]N), 8.28 (d, 2H, JZ8.4 Hz, p-nitrophenyl
3,5-H), 7.96 (d, 2H, JZ8.4 Hz, p-nitrophenyl 2,6-H), 4.03
(d quart, 1H, JZ6.8 Hz, JCH–PZ13.8 Hz, CHP), 3.83 (d,
6H, JCH–OPZ10.3 Hz, 2!MeOP) and 1.61 (dd, 3H, JZ
6.9 Hz, JCH–CPZ18.1 Hz, MeCHP).
214 (51), 209 (95), 195 (40), 182 (31), 118 (33), 110 (37)
and 91 (72); d 8.50 (d, 1H, JZ4.6 Hz, CH]N), 7.99 (d, 1H,
JZ7.8 Hz, pyridyl 3-H), 7.88 (d, 1H, JZ4.7 Hz, pyridyl
6-H), 7.66 (td, 1H, JZ1.4, 7.8 Hz, pyridyl 4-H), 7.23
(apparent t, 1H, JZ6.9 Hz, pyridyl 5-H), 7.15–7.03 (m, 5H,
Ar-H), 3.91 (dt, 1H, JZ2.5, 11.3 Hz, CHP), 3.75 (d, 6H,
JCH–OPZ10.3 Hz, 2!MeOP), 3.34 (ABXY, 1H, JZ2.8,
8.2, 13.8 Hz, CHCP).
6.2.12. Dimethyl N-(20-iodobenzylidene)-1-imino ethyl-
phosphonate 3m. The amine 2c (1.15 g, 7.5 mmol) and
o-iodobenzaldeyde (1.6 g, 6.9 mmol) were reacted for 16 h
to yield a thick colourless oil 3m (1.14 g, 90%), (found: C,
35.95; H, 4.05; N, 4.0. C11H15INO3P requires: C, 36.0; H,
4.10; N, 3.80%); m/z (%) 368 (MHC, 4), 258 (66), 232 (29),
203 (7), 138 (100), 130 (65) and 110 (77); d 8.51 (d, 1H, JZ
4.8 Hz, CH]N), 8.01 (d, 1H, JZ7.6 Hz, o-iodophenyl
3-H), 7.86 (d, 1H, JZ7.8 Hz, o-iodophenyl 6-H), 7.37 (t,
1H, JZ7.4 Hz, o-iodophenyl 4-H), 7.13 (t, 1H, JZ7.5 Hz,
6.2.16. Dimethyl N-(20-thienylidene)-1-imino ethylphos-
phonate 3r. The amine 2c (577 mg, 3.77 mmol) and
thiophene-2-carboxaldehyde (429 mg, 3.83 mmol) were
reacted for 16 h to give the product 3r (780 mg, 79%
yield) as a yellow oil by distillation using a mole still (60–
100 8C/0.3–0.4 mmHg) (found: C, 43.55; H, 5.75; N, 5.60.
C9H14NO3PS requires: C, 43.75; H, 5.70; N, 5.65%); m/z
(%) 248 (MHC, 1), 138 (100), 111 (87), 110 (62), 109 (22)
and 96 (19); d 8.42 (d, 1H, JZ4.3 Hz, CH]N), 7.41 (d, 1H,
JZ5.0 Hz, thienyl 5-H), 7.34 (d, 1H, JZ3.4 Hz, thienyl
3-H), 7.06 (apparent t, 1H, JZ4.3 Hz, thienyl 4-H), 3.90 (d
quart, 1H, JZ7.0 Hz, JCH–PZ14.1 Hz, CHP), 3.79 (d, 6H,
JCH–OPZ10.3 Hz, 2!MeOP) and 1.53 (dd, 3H, JZ7.0 Hz,
JCH–CPZ18.0 Hz, MeCHP).
o-iodophenyl 5-H), 4.03 (d quart, 1H, JZ6.8 Hz, JCH–P
Z
13.5 Hz, CHP), 3.83 (d, 3H, JCH–OPZ10.3 Hz, MeOP), 3.82
(d, 3H, JCH–OPZ10.4 Hz, MeOP) and 1.60 (dd, 3H, JZ
6.8 Hz, JCH–CPZ18.1 Hz, MeCHP).
6.2.13. Dimethyl N-(20-pyridylidene)-1-imino ethylphos-
phonate 3n. The amine 2c (577 mg, 3.77 mmol) and
pyridine-2-carboxaldehyde (399 mg, 3.73 mmol) were
reacted for 16 h to give the product 3n as a thick dark
brown oil (830 mg, 88%), (found: C, 49.45; H, 6.10; N,
11.45. C10H15N2O3P requires: C, 49.60; H, 6.25; N,
11.55%); m/z (%) 243 (MHC, 2), 227 (3), 195 (4), 139
(7), 133 (100), 110 (57) and 92 (89); d 8.67 (d, 1H, JZ
4.3 Hz, CH]N), 8.45 (d, 1H, JZ4.7 Hz, pyridyl 3-H), 8.08
(d, 1H, JZ7.7 Hz, pyridyl 6-H), 7.77 (t, 1H, JZ7.5 Hz,
pyridyl 4-H), 7.36 (t-1H, JZ6.0 Hz, pyridyl 5-H), 4.05 (d
quart, 1H, JZ6.8 Hz, JCH–PZ13.5 Hz, CHP), 3.83 (d, 6H,
JCH–OPZ10.5 Hz, 2!MeOP) and 1.61 (dd, 3H, JZ6.9 Hz,
JCH–CPZ18.1 Hz, MeCHP).
6.2.17. Dimethyl N-(20-thienylidene)-1-imino-1-phenyl
methylphosphonate 3s. The amine 2d (664 mg,
3.09 mmol) and thiophene-2-carboxaldehyde (604 mg,
5.39 mmol) were reacted for 16 h to yield the product 3s
in quantitative yield by distillation using a Kugelrohr
apparatus (40–84 8C/0.3 mmHg) (found: C, 50.95; H, 5.10;
N, 4.25. C15H18NO3PS$H2O requires: C, 51.35; H, 5.55; N,
4.30%); m/z (%) 310 (MHC, 1), 231 (1), 218 (3), 200 (100),
173 (9), 153 (16), 148 (18) and 111 (18); d 8.39 (d, 1H, JZ
4.6 Hz, CH]N), 7.50 (d, 2H, JZ7.4 Hz, Ar 2,6-H), 7.36–
7.18 (m, 5H, Ar-H and thienyl 3,5-H), 6.99 (t, 1H, JZ
4.3 Hz, thienyl 4-H), 4.87 (d, 1H, JCH–PZ18.9 Hz, CHP),
3.66 (d, 3H, JCH–OPZ10.4 Hz, MeOP) and 3.60 (d, 3H,
JCH–OPZ10.6 Hz, MeOP).
6.2.14. Dimethyl N-(20-pyridylidene)-1-imino-1-phenyl
methylphosphonate 3o. The amine 2d (634 mg,
2.95 mmol) and pyridine-2-carboxaldehyde (577 mg,
5.39 mmol) were reacted for 16 h to yield (1.15 g, 91%)
the product 3o, which was crystallised from dichloro-
methane/diethylether as colourless prisms, mp 106–108 8C
(found: C, 59.20; H, 5.35; N, 9.15. C15H17N2O3P requires:
C, 59.20; H, 5.65; N, 9.20%); m/z (%) 305 (MHC, 1), 227
(2), 200 (45), 195 (100), 167 (13), 105 (8) and 92 (50); d
8.56 (d, 1H, JZ4.5 Hz, CH]N), 8.41 (d, 1H, JZ4.8 Hz,
pyridyl 3-H), 8.13 (d, 1H, JZ7.9 Hz, pyridyl 6-H), 7.69 (t,
1H, JZ7.2 Hz, pyridyl 4-H), 7.56 (d, 2H, JZ7.4 Hz, Ar
2,6-H), 7.33–7.21 (m, 4H, Ar-H and pyridyl 5-H), 4.97 (d,
1H, JCH–PZ18.6 Hz, CHP), 3.62 (d, 3H, JCH–OPZ10.7 Hz,
MeOP) and 3.60 (d, 3H, JCH–OPZ10.6 Hz, MeOP).
6.2.18. Dimethyl N-(20thienylidene)-1-imino-2-phenyl
ethylphosphonate 3t. The amine 2e (705 mg, 3.08 mmol)
and thiophene-2-carboxaldehyde (580 mg, 5.17 mmol)
were reacted for 16 h to yield the product 3t in quantitative
yield by distillation using a Kugelrohr apparatus (20–70 8C/
0.09 mmHg) followed by crystallisation from diethyl ether
to afford colourless prisms, mp 68–70 8C, (found: C, 55.95;
H, 5.45; N, 4.45. C15H18NO3PS requires: C, 55.71; H, 5.61;
N, 4.35%); m/z (%) 323 (MC, 5), 232 (56), 214 (100), 200
(20), 123 (20), 110 (47) and 93 (32); d 7.90 (d, 1H, JZ
4.5 Hz, CH]N), 7.39 (d, 1H, JZ5.1 Hz, thienyl 5-H),
7.24–7.12 (m, 6H, Ar-H and thienyl 3-H), 7.0 (dd, 1H, JZ
3.8, 4.9 Hz, thienyl 4-H), 3.84 (d, 4H, JCH–OPZ10.4 Hz,
MeOP and CHP), 3.81 (d, 3H, JCH–OPZ10.6 Hz, MeOP),
3.34 (ABXY, 1H, JZ2.6, 7.9, 13.6 Hz, CHCP) and 3.19
(ABXY, 1H, JZ7.5, 10.8, 13.6 Hz, CHCP).
6.2.15. Dimethyl N-(20-pyridylidene)-1-imino-2-phenyl
ethylphosphonate 3p. The amine 2e (654 mg, 2.85 mmol)
and pyridine-2-carboxaldehyde (554 mg, 5.17 mmol) were
reacted for 16 h to yield the product 3p in quantitative yield,
which was crystallised from diethyl ether/ethyl acetate as
colourless prisms, mp 78–81 8C (found: C, 60.25; H, 5.70;
N, 8.65. C16H19N2O3P requires: C, 60.35; H, 6.0; N,
8.80%); m/z (%) 318 (MC, 1), 287 (1), 240 (1), 227 (100),
6.3. General procedure for the metal catalysed cyclo-
addition reactions
A mixture of the imine 3 (l mol equiv), base (DBU or
BTMG) (l mol equiv), dipolarophile (l mol equiv) and
metal salt (AgOAc or LiBr) (1.5 mol equiv) in an
appropriate solvent (MeCN, THF or toluene) was stirred

H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
10677
for the time shown in Tables 2 and 3. To compensate for loss
by evaporation, 2–3 equiv of the lower boiling dipolar-
ophiles (e.g., methyl-acrylate, -propiolate and -vinyl ketone)
were used. The reaction mixture was filtered, and quenched
by the addition of saturated ammonium chloride. The
organic layer was separated and the aqueous layer extracted
twice with diethyl ether. The combined organic layers were
then washed with brine, dried (anhyd. Na2SO4) and the
solvent removed under reduced pressure. The residue was
purified by flash column chromatography. Yields are
collected in Tables 2 and 3.
8.9, 12.9 Hz, 4-Ha), 2.10 (dt, 1H, JZ4.5, 12.5 Hz, 6-Ha) and
1.19–1.13 (m, 6H, 2!MeCH2OP).
6.3.4. Dimethyl c-4-methoxycarbonyl-2-methyl-c-5-(20-
naphthyl)pyrrolidine-r-2-phosphonate 4c. Work-up
followed by flash chromatography eluting with a diethyl
ether/ethyl acetate afforded the product 4c, which was
crystallised from ether/hexane as colourless prisms, mp
113–114 8C (found: C, 60.30; H, 6.65; N, 3.75.
C19H24NO5P requires: C, 60.47; H, 6.40; N, 3.71%); m/z
(%) 377 (MC, 2), 291 (39), 267 (46), 208 (100), 181 (90)
and 140 (63); d 7.83–7.74 (m, 4H, naphthyl-H), 7.51–7.40
(m, 3H, naphthyl-H), 4.97 (d, 1H, JZ9.4 Hz, 5-H), 3.99 (d,
6.3.1. Dimethyl c-4-methoxycarbonyl-c-5-(20-naphthyl)
pyrrolidine-r-phosphonate 4a. Work-up followed by flash
chromatography eluting with 10:1 v/v ethyl acetate/ethanol
afforded the product 4a as a pale brown gum (contaminated
with a trace amount of Michael adduct 5a); d 7.92–7.68 (m,
4H, naphthyl-H), 7.49–7.39 (m, 3H, naphthyl-H), 4.63 (d, 1H,
JZ10.2 Hz, 5-H), 3.96 (d, 3H, JP–OCHZ17.1 Hz, MeOP),
3.92 (d, 3H, JP–OCHZl7.0 Hz, MeOP), 3.66 (br s, 1H, NH),
3.56 (m, 1H, 2-H), 3.39 (q, 1H, JZ9.2 Hz, 4-H), 3.00 (s, 3H,
MeOC), 2.63 (m, 1H, 3-Hb) and 2.31 (m, 1H, 3-Ha).
3H, JP–OCHZ10.1 Hz, MeOP), 3.88 (d, 3H, JP–OCH
Z
10.4 Hz, MeOP), 3.59 (apparent dt, 1H, JZ8.7, 9.4 Hz,
4-H), 3.02 (s, 3H, MeOC), 2.92 (ABXY and br s, 2H, JZ9.3,
13.0, 15.6 Hz, 3-Hb and NH), 1.92 (ABXY, 1H, JZ2.0, 8.1,
13.0 Hz, 3-Ha) and 1.51 (d, 3H, JP–C–CHZ15.7 Hz, 2-Me).
6.3.2. Diethyl c-4-methoxycarbonyl-c-5-(20-naphthyl)
pyrrolidine-r-phosphonate 4b. Work-up followed by
flash chromatography eluting with 10:1 v/v ethyl acetate/
ethanol afforded several fractions containing different
amounts of cycloadduct 4b and Michael adduct 5b (Scheme
4). The best sample of cycloadduct (contaminated with only
a small amount of Michael adduct 5b) was analysed by 1H
NMR and mass spectroscopy; m/z (%) 390 (MC, 36), 330
(28), 254 (100), 194 (67), 167 (78) and 127 (62); d 7.87–
7.75 (m, 4H, naphthyl-H), 7.52–7.41 (m, 3H, naphthyl-H),
4.68 (d, 1H, JZ9.1 Hz, 5-H), 4.42–4.23 (m, 4H, CH2OP),
3.55 (ABX, 1H, JZ4.8, 6.7, 11.1 Hz, 2-H), 3.43 (q, 1H, JZ
8.5 Hz, 4-H), 3.05 (s, 3H, MeOC), 2.70–2.63 (m, 4H, CH2
and NH2) and 1.5–1.28 (m, 6H, MeCH2OP). The lithium
bromide-catalysed reaction afforded fractions containing
different amounts of lactam 6 and cycloadduct 4b. A sample
consisting of a 2:1 mixture of lactam 6 and cycloadduct 4b
NOE data:
Signal irradiated
Enhancement (%)
3-Ha
3-Hb
4-H
5-H
3-Ha
3-Hb
4-H
—
19
4
25
—
—
—
8
—
4
9
—
—
—
11
5-H
—
6.3.5. Dimethyl c-4-methoxycarbonyl-2-phenyl-c-5-(20-
naphthyl)pyrrolidine-r-2-phosphonate 4d. Work-up
followed by flash chromatography eluting with 10:1 v/v
ethyl acetate/ethanol afforded the product 4d, which was
crystallised from diethyl ether/petroleum ether as colourless
plates, mp 120–121 8C (found: C, 65.60; H, 5.70; N, 3.10.
C24H26NO5P requires: C, 65.59; H, 5.96; N, 3.18%); m/z
(%) 439 (MC, 0.1), 408 (0.5), 330 (57), 270 (100) and 243
(85); d 7.84–7.32 (m, 12H, naphthyl and Ar-H), 4.68 (t, 1H,
JZ8.l Hz, 5-H), 3.79 (d, 3H, JP–OCHZ10.5 Hz, MeOP),
3.72 (d, 3H, JP–OCHZ10.4 Hz, MeOP), 3.27 (m, 3H, 3-Hb,
4-H and NH), 3.02 (s, 3H, MeOC) and 2.76 (ABXY, 1H,
JZ13, 7.3, 12.7 Hz, 3-Ha).
1
was analysed by H NMR and mass spectroscopy; m/z 445
(MC, 33), 389 (34), 308 (100) and 254 (45); d 5.25 (d,1H,
JZl0.0 Hz, 2-H).
6.3.3. Diethyl 1-aza-c-2-(20-naphthyl)-c-3-methoxy-
carbonyl-8-oxobicyclo[3.3.0]octane-r-5-phosphonate 6.
Work-up followed by flash chromatography eluting with
10:1 v/v ethyl acetate/methanol afforded three fractions
containing different mixtures of the lactam 6 and the
cycloadduct 4b. The fraction containing the most lactam
(3.5:1 by 1H NMR) was subjected to a further column
chromatography purification step. Elution with 5:1 v/v ethyl
1
acetate/methanol afforded a thick yellow oil (4:1 by H
NMR), which crystallised from diethyl ether as colourless
prisms, mp 103–104 8C; m/z (%) 445 (MC, 7), 384 (42), 308
(100), 276 (35), 248 (64), 206 (31), 180 (32), 116 (18), 55
(45); HRMS of (MKPO(OEt)2): found 308.128, calcd
308.129; d 7.82–7.70 (m, 4H, naphthyl-H), 7.47–7.41 (m,
3H, naphthyl-H), 5.41 (d, 1H, JZ8.6 Hz, 2-H), 4.14–3.95
(m, 5H, 2!CH2OP and 3-H), 3.74 (s, 3H, MeOC), 3.08
(ABXY, 1H, JZ8.8, 12.7, 16.8 Hz, 7-Hb), 2.85 (ABXY,1H,
JZ7.5, 10.2, 13.2 Hz, 4-Hb), 2.79 (dt, 1H, JZ8.7, 12.7 Hz,
6-Hb), 2.52 (dd, 1H, JZ9.2, 16.7 Hz, 7-Ha), 2.20 (dt, JZ
NOE data:
Signal irradiated
Enhancement (%)
3-Ha
3-Hb
4-H
5-H
—
3-Ha
3-Hb
4-H
—
16
4
26
—
—
—
8
—
—
10
9
—
5-H
—

10678
H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
6.3.6. Dimethyl c-4-methoxycarbonyl-2-benzyl-c-5-(20-
naphthyl)pyrrolidine-r-2-phosphonate 4e. Work-up
followed by flash chromatography eluting with 10:1 v/v
ethyl acetate/ethanol afforded the product 4e, which
crystallised from hexane as colourless prisms, mp 122–
123 8C (found: C, 66.40; H, 6.05; N, 3.15. C25H28NO5P
requires: C, 66.20; H, 6.20; N, 3.10%); m/z (%) 453 (MC,
0.2), 422 (0.8), 362 (51), 343 (61), 284 (86), 257 (49) and 91
(100); d 7.77–7.70 (m, 4H, naphthyl), 7.46–7.28 (m, 8H,
naphthyl and Ar-H), 4.64 (d, 1H, JZ9.2 Hz, 5-H), 3.87
NOE data:
Signal irradiated
Enhancement (%)
2-H(downfield) 3-Ha
3-Hb
4-H
5-H
2-H(upfield)
3-Ha
3-Hb
4-H
5-H
16
11
—
—
—
—
—
11
3
—
22
—
—
—
—
9
—
—
10
1
—
—
10
—
—
(d, 3H, JP–OCHZ10.2 Hz, MeOP), 3.86 (d, 3H, JP–OCH
Z
6.3.9. Dimethyl 2-methy1-c-4-methoxycarbony1-c-40-
nitrophenyl) pyrrolidine-r-2-phosphonate 4l. Work-up
followed by flash chromatography, eluting with a gradient
from diethyl ether to 1:1 v/v ethyl acetate/methanol,
afforded four fractions containing different mixtures of the
cycloadduct 4l and the Michael adduct 5l. The two fractions
containing the most cycloadduct were subjected to a further
column chromatography purification step. Elution with 10:1
v/v ethyl acetate/methanol afforded the pure cycloadduct,
which was crystallised from ethyl acetate/diethyl ether as
yellow prisms, mp 156–158 8C (found: C, 48.30; H, 5.65; N,
7.45. C15H21N2O7P requires: C, 48.40; H, 5.70; N, 7.55%);
m/z (%) 357 (MKMe, 2), 341 (2), 286 (1), 263 (100), 203
(38) 0and 176 (33); d 8.14 (d, 2H, JZ8.7 Hz, p-nitr0ophenyl
30, 5 -H), 7.59 (d, 2H, JZ8.7 Hz, p-nitrophenyl 2 , 60-H),
4.93 (d, 1H, JZ9.7 Hz, 5-H), 3.92 (d, 3H, JCH–OPZ10.3 Hz,
MeOP), 3.85 (d, 3H, JCH–OPZ10.5 Hz, MeOP), 3.60 (dt,
1H, JZ8.2, 9.7 Hz, 4-H), 3.19 (s, 3H, MeOC), 2.83 (ABXY,
1H, JZ10.2, 13.1 Hz, JCH–OPZ15.4 Hz, 3-Hb), 2.09 (br s,
1H, NH), 1.95 (ABXY, 1H, JCH–OPZ1.6 Hz, JZ7.9,
13.0 Hz, 3-Ha) and 1.48 (d, 3H, JCH–OPZ15.5 Hz, 2-Me).
10.3 Hz, MeOP), 3.22 (ABX, 1H, JZ10.1, 13.7 Hz, CHPh),
3.13–2.91 (m, 3H, CHPh, 4-H and 3-Ha), 3.26–2.97 (m, 4H,
CH2Ph, 4-H and 3-Hb), 2.94 (s, 3H, MeOC), 2.34 (br s, 1H,
NH) and 2.23–2.12 (m, 1H, 3-Ha).
6.3.7. Dimethyl 2-hydroxymethyl-c-4-methoxycarbonyl-
c-5-(20-naphthyl)pyrrolidine-r-2-phosphonate 4g. Work-
up followed by flash chromatography eluting with 5:1
v/v ethyl acetate/ethanol afforded the product 4g as a
colourless oil. m/z (%) 362 (MHC, 47), 310 (43), 265
(27), 167 (38) and 83 (100); d 7.97–7.68 (m, 4H,
naphthyl), 7.58–7.37 (m, 3H, naphthyl and Ar-H), 4.62
(d, 1H, JZ10.2 Hz, 5-H), 4.05 (d, 3H, JP–OCH
Z
10.2 Hz, MeOP), 3.86 (d, 4H, JP–OCHZ10.2 Hz, MeOP
and CHOH), 3.71–3.66 (m, 1H, CHOH), 3.59–3.42 (m,
1H, 4-H) 3.05 (s, 3H, MeOC), 2.97–2.76 (m, 1H, 3-Hb)
and 2.00–1.85 (m, 1H, 3-Ha).
6.3.8. Dimethyl 2-{[(t-buty1)dimethylsilyl]oxy} methyl-c-
4-methoxycarbonyl-c-5-(20-naphthyl)pyrrolidine-r-2
phosphonate 4h. Work-up followed by flash chromato-
graphy (the column was pre-washed with chloroform/
triethylamine to prevent cleavage of the OTBDMS group)
eluting with diethyl ether afforded the product 4h as a
brown gum (found: C, 57.65; H, 7.20; N, 2.85.
C25H38NO6PSi requires: C, 59.15; H, 7.20; N, 2.75%);
HRMS found 507.223, calcd 507.221; m/z (%) 507
(MC, 2), 476 (5), 448 (20), 389 (35), 362 (95), 340
(95), 216 (13), 170 (100), 156 (94) and 127 (5); d 7.84
(s, 1H, naphthyl-H), 7.80–7.77 (m, 2H, naphthyl-H),
7.75 (d, 1H, JZ8.7 Hz, naphthyl-H), 7.52 (dd, 1H, JZ
1.7, 8.5 Hz, naphthyl-H), 7.45–7.40 (m, 2H, naphthyl
6.3.10. Dimethyl N-(40-nitrobenzylidene)-1-imino-1-
methyl-3methoxycarbonylpropylphosphonate 5l. The
two fractions, which contained the most Michael adduct
(described in Section 6) were combined and subjected to a
further column chromatography purification step. Elution
with an ethyl acetate/methanol gradient afforded the product
5l as a thick brown oil, (found: C, 46.10; H, 5.45; N, 7.10.
C15H21N2O7P$H2O requires: C, 46.15; H, 5.95; N, 7.20%);
m/z (%) 373 (MC, 2), 359 (2), 341 (10), 263 (100), 224 (27),
203 (54), 176 (18) and 151 (82); d 8.46 (d, 1H, JZ5.2 Hz,
CH]N), 8.28 (d, 2H, JZ8.7 Hz, p-nitrophenyl 30, 50-H),
7.95 (d, 2H, JZ8.6 Hz, p-nitrophenyl 20, 60-H), 3.79 (d, 3H,
JCH–OPZ10.4 Hz, MeOP), 3.78 (d, 3H, JCH–OPZ10.4 Hz,
MeOP), 3.64 (s, 3H, MeOC), 2.58–2.16 (m, 4H, 2!CH2
and 1.56 (d, 3H, JCH–OPZ15.5 Hz, MeCP).
H), 5.06 (d, 1H, JZ9.8 Hz, 5-H), 3.94 (d, 3H, JCH–OP
10.3 Hz, MeOP), 3.90 (ABX, 1H, JZl0.4 Hz, JCH–CP
21.5 Hz, CHOSi), 3.89 (d, 3H, JCH–OPZ10.4 Hz,
MeOP), 3.80 (ABX, 1H, JCH–CPZ9.2, 10.5 Hz,
CHOSi), 3.63 (dt, 1H, JZ8.8, 9.5 Hz, 4-H), 2.99 (s,
Z
Z
6.3.11. Dimethyl 2-methyl-c-4-methoxycarbonyl-c-5-(20-
iodophenyl)pyrrolidine-r-2-phosphonate 4m. Work up
followed by flash chromatography eluting with 5:1 v/v ethyl
acetate/methanol afforded the product 4m, which crystal-
lised from dichloromethane as colourless prisms, mp 121–
123 8C (found: C, 39.55; H, 4.40; N, 3.0. C15H21INO5P
requires: C, 39.75; H, 4.65; N, 3.10%); m/z (%) 452 (MK1,
0.2), 344 (100), 284 (27), 257 (40) and 216 (53); d 7.78 (d,
1H, JZ7.8 Hz, 0o-iodophenyl 30-H), 7.58 (d, 1H, JZ7.8 Hz,
o-iodophenyl 6 -H), 7.30 (t, 1H, JZ6.4 Hz, o-iodophenyl
40-H), 6.94 (t, 1H, JZ7.6 Hz, o-iodophenyl 50-H), 4.98
(d, 1H, JZ9.2 Hz, 5-H), 4.00 (d, 3H, JCH–OPZ10.0 Hz,
MeOP), 3.86 (d, 3H, JCH–OPZ10.4 Hz, MeOP), 3.68 (dt,
1H, JZ8.1, 8.5 Hz, 4-H), 3.10 (s, 3H, MeOC), 2.86 (ABXY,
3H, MeOC), 2.94 (ABXY, 1H, JZ8.9, 13.4 Hz, JCH–OP
Z
17.2 Hz, 3-Hb), 2.08 (ABXY, 1H, JCH–OPZ2.8 Hz, JZ8.6,
13.3 Hz, 3-Ha), 0.94 (s, 9H, t-BuSi) and 0.12 (s, 6H, 2!
MeSi).

H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
10679
1H, JZ7.5, 13.2 Hz, JCH–OPZ16.1 Hz, 3-Hb), 2.01–1.93 (br
s, 1H, NH), 1.94 (ABXY, 1H, JZ3.1, 8.8, 13.3 Hz, 3-Ha)
and 1.52 (d, 3H, JCH–OPZ15.6 Hz, 2-Me).
v/v ethyl acetate/methanol afforded the product 4p as a pale
brown gum; HRMS of MKPO(OMe)2, found, 313.095,
calcd 313.095; m/z (%) 402 (MK2, 2), 373 (2), 343 (2), 313
(100), 295 (27), 281 (22), 263 (14), 235 (48), 227 (4 1), 208
(66) and 91 (60); d 8.41 (d, 10H, JZ5.2 Hz, pyridyl 60-H),
7.66–7.58 (m, 2H, pyridyl 3 , 40-H), 70.36–7.28 (m, 5H,
phenyl-H), 7.12–7.07 (m, 1H, pyridyl 5 -H), 4.64 (d, 1H,
JZ9.l Hz, 5-H), 3.81 (d, 3H, JCH–OPZ10.0 Hz, MeOP),
3.76 (d, 3H, JCH–OPZ10.6 Hz, MeOP), 3.18 (5, 3H, MeOC),
3.17 (ABX, 1H, JZ9.8, 13.7 Hz, CHPh), 3.07–2.88 (m, 3H,
CHPh, 3-Hb and 4-H), 2.58 (br s, 1H, NH) and 2.76 (m, 1H,
3-Ha).
6.3.12. Dimethyl N-(20-iodobenzylidene)-1-imino-1-
methyl-3-methoxycarbonyl propylphosphonate 5m. The
Michael adduct 5m was observed in the crude reaction
1
mixture and as a minor component (w8% by H NMR) in
fractions of the cycloadduct 4m; d 8.52 (d, 1H, JZ4.6 Hz,
CH]N), 7.95 (d, 1H, JZ8.l Hz, o-iodophenyl 30-H),
7.85 (d, 1H, JZ8.6 Hz, o-iodophenyl 60-H), 7.36 (t, 1H,
JZ8.l Hz, o-iodophenyl 40-H), 7.11 (t, 1H, JZ8.6 Hz,
o-iodophenyl 50-H), 3.81 (d, 3H, JCH–OPZ10.2 Hz, MeOP),
3.79 (d, 3H, JCH–OPZ10.1 Hz, MeOP), 3.63 (s, 3H, MeOC),
6.3.16. Dimethyl 2-methyl-c-4-methoxycarbonyl-c-5-(20-
thienyl)pyrrolidine-r-2-phosphonate 4r. Work-up fol-
lowed by flash chromatography eluting with 10:1 v/v ethyl
acetate/methanol afforded the product 4r, which crystallised
from ethyl acetate–ether as colourless prisms, mp 86–88 8C
(found: C, 46.70; H, 5.85; N, 3.90. C13H20NO5P requires: C,
46.85; H, 6.05; N, 4.20%); m/z (%) 331 (MK2, 3), 302 (7),
286 (4), 272 (2), 224 (100), 192 (34), 164 (44), 137 0(44)
and 96 (38); d 7.17 (dd, 1H, JZ1.0, 5.0 Hz, thienyl 5 -H),
6.95–6.92 (m, 2H, thienyl 30, 40-H), 5.13 (d, 1H, JZ9.6 Hz,
5-H), 3.99 (d, 3H, JCH–OPZ10.1 Hz, MeOP), 3.84 (d, 3H,
JCH–OPZ10.4 Hz, MeOP), 3.51 (dt, 1H, JZ8.2, 9.5 Hz,
4-H), 3.33 (s, 3H, MeOC), 2.85 (ABXY, 1H, JZ10.0,
13.1 Hz, JCH–OPZ15.6 Hz, 3-Hb), 2.31, (br s, 1H, NH), 1.92
(ABXY, 1H, JZ1.2, 7.8, 12.8 Hz, 3-Ha) and 1.46 (d, 3H,
JCH–OPZ15.6 Hz, 2-Me).
2.61–2.12 (m, 4H, 2!CH2) and 1.57 (d, 3H, JCH–OP
14.7 Hz, MeCP).
Z
6.3.13. Dimethyl 2-methy1-c-4-methoxycarbonyl-c-5-(20-
pyridyl)pyrrolidine-r-2-phosphonate 4n. Work-up fol-
lowed by flash chromatography eluting with a gradient
from ethyl acetate to 3:2 v/v ethyl acetate/methanol
afforded the product 4n as a dark brown gum; HRMS of
MKPO(OMe)2; found 219.113, calcd 219.113; m/z (%) 326
(MK2, 10), 311 (3), 297 (2), 283 (3), 267 (5), 253 (2), 233
(53), 219 (100), 187 (32), 159 (43), 132 (53) and 79 (42); d
8.49 (d, 1H, JZ5.l Hz, pyridyl 60-H), 7.66 (dt, 1H, JZ1.7,
7.6 Hz, pyridyl 40-H), 7.57 (d, 1H, JZ7.6 Hz, pyridyl 30-H),
7.15 (ABX, 1H, JZ1.2, 5.5, 7.1 Hz, pyridyl 50-H), 4.91 (d,
1H, JZ9.4 Hz, 5-H), 3.88 (d, 3H, JCH–OPZ10.3 Hz,
MeOP), 3.87 (d, 3H, JCH–OPZ10.4 Hz, MeOP), 3.61 (dt,
1H, JZ8.4, 9.1 Hz, 4-H), 3.25 (s, 3H, MeOC), 2.79 (ABXY,
1H, JZ9.3, 13.0 Hz, JCH–OPZ15.5 Hz, 3-Hb), 2.58 (br s,
1H, NH), 2.01 (ABXY, 1H, JCH–OPZ2.3 Hz, JZ8.0,
12.9 Hz, 3-Ha) and 1.48 (d, 3H, JCH–OPZ15.7 Hz, 2-Me).
6.3.17. Dimethyl 2-phenyl-c-4-methoxycarbonyl-c-5-(20-
thienyl)pyrrolidine-r-2-phosphonate 4s. Work-up fol-
lowed by flash chromatography eluting with diethyl ether/
ethyl acetate afforded the product 4s, which crystallised
from dichloromethane/diethyl ether as colourless prisms,
mp 114–115 8C (found: C, 54.55; H, 5.55; N, 3.30.
C18H22NO5PS requires: C, 54.65; H, 5.60; N, 3.55%); m/z
(%) 395 (MC, 0.1), 364 (2), 309 (3), 286 (100), 254 (13),
226 (34), 199 (30), 96 (44) and 77 (59); d 7.62 (dd, 2H, JZ
1.9, 7.5 Hz, phenyl 20, 60-H), 7.40 (t, 2H, JZ7.6 Hz, phenyl
30, 50-H), 7.31 (t, 1H, JZ6.9 Hz, phenyl 40-H), 7.20 (dd, 1H,
JZ1.9, 4.4 Hz, thienyl 50-H), 6.96–6.93 (m, 2H, thienyl 30,
6.3.14. Dimethyl 2-phenyl-c-4-methoxycarbonyl-c-5-(20-
pyridyl)pyrrolidine-r-2-phosphonate 4o. Work-up fol-
lowed by flash chromatography (the column was pre-
washed with with 2% v/v concd ammonia in ether (4 mL of
33% w/w aqueous ammonia in 250 mL of ether) to aid the
separation) eluting with a gradient from 1:1 v/v ether/ethyl
acetate to 5:1 v/v ethyl acetate/methanol afforded a dark
brown gum. Crystallisation from diethyl ether/ethyl acetate
gave 4o as colourless prisms, mp 129–130 8C, (found: C,
58.20; H, 5.90; N, 7.0. C19H23N2O5P requires: C, 58.45; H,
5.95; N, 7.20%); m/z (%) 391 (MHC, 1), 359 (1), 329 (1),
313 (2), 281 (100), 249 (16), 221 (37) and 195 (28); d 8.55
(d, 1H, JZ4.6 Hz, p0yridyl 60-H), 7.74 (dd, 2H, JZ1.8,
7.4 Hz, phenyl 20, 6 -H), 7.65 (dt, 1H, JZ1.6, 7.7 Hz,
pyridyl 40-H), 7.42–7.29 (m, 4H, phenyl-H and pyridyl
30-H), 7.17 (dd, 1H, JZ5.3, 7.1 Hz, pyridyl 50-H), 4.58
(d, 1H, JZ9.7 Hz, 5-H), 3.82 (d, 3H, JCH–OPZ10.3 Hz,
MeOP), 3.55 (d, 3H, JCH–OPZ10.0 Hz, MeOP), 3.18 (s, 3H,
MeOC), 3.16 (dt, 1H, JZ7.3, 9.7 Hz, 4-H), 2.97 (dt, 1H, JZ
9.8, 13.0 Hz, JCH–OPZ12.9 Hz, 3-Hb) and 2.76 (ABXY, 1H,
JZ1.1, 7.4, 12.5 Hz, 3-Ha).
40-H), 4.82 (d, 1H, JZ9.0 Hz, 5-H), 3.74 (d, 3H, JCH–OP
Z
10.4 Hz, MeOP), 3.74 (d, 3H, JCH–OPZ10.3 Hz, MeOP),
3.30 (s, 3H, MeOC), 3.15–2.98 (m, 3H, NH, 3-Hb and 4-H)
and 2.72–2.62 (m, 1H, 3-Ha).
6.3.18. Dimethyl N-(20-thienylidene)-1-imino-1-phenyl-
3-methoxycarbonyl propylphosphonate 5s. The Michael
adduct 5s was observed in the crude reaction mixture and as
a minor component (a 3:1:1 ratio of cycloadduct 4s, imine
and 5s by 1H NMR, respectively), in a fraction obtained via
chromatography. Due to the very small proportions
involved, a pure sample of the Michael adduct could not
1
be obtained, but a couple of the characteristic H NMR
resonances could be assigned as follows: 8.70 (d, 1H,
JZ4.1 Hz, CHN), 3.60 (s, 3H, MeOC).
6.3.15. Dimethyl 2-benzyl-c-4-methoxycarbonyl-c-5-(20-
pyridyl)pyrrolidine-r-2-phosphonate 4p. Work-up fol-
lowed by flash chromatography (the column was pre-
washed with with 2% v/v concd ammonia in ether (4 mL of
33% w/w aqueous ammonia in 250 mL of ether) to aid the
separation) eluting with a gradient from ethyl acetate to 1:1
6.3.19. Dimethyl 2-benzyl-c-4-methoxycarbonyl-c-5-(20-
thienyl)pyrrolidine-r-2-phosphonate 4t. Work-up fol-
lowed by flash chromatography eluting with a diethyl
ether/ethyl acetate afforded the product 4t, which crystal-
lised from dichloromethane/diethyl ether as colourless

10680
H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
prisms, mp 105–107 8C (found: C, 55.80; H, 5.75; N, 3.20.
C19H24NO5PS requires: C, 55.75; H, 5.90; N, 3.40%); m/z
(%) 407 (MK2, 0.3), 378 (3), 318 (100), 299 (49), 286 (49),
286 (59), 258 (17), 240 (38), 213 (34) and 91 (87); d 7.340–
7.25 (m, 5H, phenyl-H), 7.11 (d, 10 H, JZ4.8 Hz, thienyl 5 -
H), 6.88–6.83 (m, 2H, thienyl 3 , 40-H), 4.72 (d, 1H, JZ
9.l Hz, 5-H), 3.85 (d, 3H, JCH–OPZ10.4 Hz, MeOP), 3.81
(d, 3H, JCH–OPZ10.9 Hz, MeOP), 3.24 (s, 3H, MeOC), 3.18
(ABX, 1H, JZ10.3, 13.8 Hz, CHPh), 3.02–2.89 (m, 3H,
CHPh, 3-Hb and 4-H), 2.52–2.49 (br s, 1H, NH) and 2.16–
2.06 (m, 1H, 3-Ha).
NOE data:
Signal irradiated
Enhancement (%)
1-H
2-H
4-H
5-H
8-H
MenthOCH
1-H
2-H
4-H
5-H
8-H
—
11
—
7
10
—
5
—
—
—
6
—
8
9
4
—
—
—
—
6
—
12
—
—
—
—
—
—
3
—
6.3.22. Dimethyl 1S,2S,4S,5R,8R-2-methyl-4-(20-
naphthyl)-3-aza-6-oxo-7-oxa-8-(10R,20S,50R-menthyl-
oxy)-bicyclo[3.3.0]octane-2-phosphonate 9b. Work-up
followed by flash chromatography eluting with a diethyl
ether/ethylacetate gradient afforded the product (97% de)
(diastereomeric excess was determined by chiral HPLC
using a Chiralcel OG column (Daicel) eluting with 9.5:0.5
v/v hexane/isopropanol, detecting at a wavelength of
254 nm. The retention times of the two diasteroisomers
were 11.55 (1.48%) and 15.29 (98.52%) min), which
crystallised from diethyl ether/petroleum ether as colourless
needles, mp 154–157 8C (found: C, 65.95; H, 7.9; N, 2.45.
C29H40NO6P requires C, 65.75; H, 7.6; N, 2.65%); m/z (%)
529 (MC, 0.6), 419 (100), 252 (24), 207 (39) and 181 (33); d
7.86–7.79 (m, 4H, naphthyl-H), 7.46–7.42 (m, 3H,
naphthyl-H), 6.21 (s, 1H, 8-H), 4.96 (d, 1H, JZ8.0 Hz,
4-H), 4.02 (d, 3H, JP–OCHZ10.2 Hz, MeOP), 3.89 (d, 3H,
JP–OCHZ10.6 Hz, MeOP), 3.57 (t, 1H, JZ8.2 Hz, 5-H),
3.53 (dt, 1H, JZ4.1, 10.6 Hz, menthyl-OCH), 2.89–2.86
(m, 1H, 1-H), 2.23 (br d, 1H, JZ12.5 Hz, menthyl-H), 2.13
(br s, 1H, NH), 2.02 (m, 1H, menthyl-H), 1.69–1.63 (m, 3H,
menthyl-H), 1.58 (d, 3H, JP–C–CHZ14.7 Hz, 2-Me), 1.52–
1.39 (m, 2H, menthyl-H), 1.26–1.16 (m, 2H, menthyl-H),
1.00–0.86 (m, 1H, menthyl-H), 0.96 (d, 3H, JZ6.4 Hz, Me),
0.83 and 0.69 (2!d, 2!3H, JZ6.9 Hz, CHMe2).
6.3.20. Dimethyl N-(20-thienylidene)-1-imino-1-benzyl-3-
methoxycarbonyl propylphosphonate 5t. The Michael
adduct 5t was observed in the crude reaction mixture and as
a major component (a 1.2:1 ratio of Michael adduct to
cycloadduct by 1H NMR, respectively), in a fraction
obtained via chromatography. Due to the very small
proportions involved, a pure sample of the Michael adduct
could not be obtained, but a couple of the characteristic
1H NMR resonances could be assigned as follows; d 8.25
(d, 1H, JZ4.6 Hz, CH]N), 3.64 (s, 3H, MeOC).
6.3.21. Diethyl 1S,2S,4S,5R,8R-4-(20naphthyl)-3-aza-6-
oxo-7-oxa-8-(10R,20S,50R-menthyloxy)-bicyclo[3.3.0]-
octane-2-phosphonate 9a. Work-up followed by flash
chromatography eluting with a gradient from ethyl acetate
to 5:1 v/v ethyl acetate/methanol afforded the product,
which crystallised from diethyl ether as colourless needles,
mp 206–207 8C (found: C, 66.10; H, 7.60; N, 2.60.
C30H42NO6P requires: C, 66.30; H, 7.80; N, 2.60%); m/z
(%) 543 (MC, 6), 405 (25), 305 (16), 238 (10), 221 (15), 194
(100), 167 (42) and 139 (16); d 7.82–7.79 (m, 4H, naphthyl-
H)., 7.45–7.43 (m, 3H, naphthyl-H), 6.24 (d, 1H, JZ1.5 Hz,
8-H), 4.56 (d, 1H, JZ8.1 Hz, 4-H), 4.34 (m, 2H, CH2OP),
4.26 (quin., 2H, JZ7.1 Hz, CH2OP), 3.60 (dd, 1H, JZ7.4,
9.7 Hz, 2_H), 3.53 (dt, 1H, JZ4.1, 10.6 Hz, menthyl-OCH),
3.48 (t, 1H, JZ8.3 Hz, 5-H), 3.13 (m, 1H, 1-H), 2.39 (br s,
1H, NH), 2.29 (d, 1H, JZ12.4 Hz, 0menthyl 60-H), 2.05 (d
quart, 1H,0JZ2.3, 6.8 Hz, menthyl 2 -H), 1.68–1.60 (m, 2H,
menthyl 2 -H), 1.44 (t, 3H, JZ7.1 Hz, MeCH2OP), 1.40 (t,
5H, JZ7.1 Hz, MeCH2OP and menthyl 20-H), 1.19 (m, 1H,
menthyl-H), 0.96 (d, 5H, JZ6.5 Hz, menthyl-Me and 2!
menthyl-H), 0.84 (d, 3H, JZ7.1 Hz, menthyl-Me) and 0.70
(d, 3H, JZ6.9 Hz, menthyl-Me).
NOE data:
Signal irradiated
Enhancement (%)
1-H
5-H
4-H
8-H
1-H
5-H
4-H
8-H
—
2
—
4
5
—
3
—
—
—
3
—
—
—
11
—
6.3.23. Dimethyl c-4-(20naphthyl)-t-2,7-dimethyl-c-6,8-
dioxo-3,7-diazabicyclo[3.3.0]octane-r-2-phosphonate 10.
Work-up followed by flash chromatography eluting with
10:1 v/v ethyl acetate/methanol afforded the product 13,

H. A. Dondas et al. / Tetrahedron 61 (2005) 10667–10682
10681
which crystallised from ethyl acetate as colourless prisms,
NOE data:
mp 179–180 8C (found: C, 57.55; H, 5.45; N, 6.7.
C20H23N2O5P$H2O requires C, 57.15; H, 6.0; N, 6.7%);
m/z (%) 402 (MC, 2), 387 (2), 293 (8), 234 (8), 207 (20), 181
(66), 165 (25) and 140 (45); 7.84–7.74 (m, 4H, naphthyl-H),
7.49–7.45 (m, 3H, naphthyl-H), 4.96 (d, 1H, JZ7.5 Hz,
4-H), 3.97 (d, 3H, JCH–OPZ10.3 Hz, MeOP), 3.89 (d, 3H,
JCH–OPZ10.9 Hz, MeOP), 3.59 (t, 1H, JZ7.7 Hz, 5-H),
3.20 (dd, 1H, JCH–CPZ4.0, 7.8 Hz, 1-H), 2.91 (s, 3H,
Signal
irradiated
Enhancement (%)
2-H 3-H 7-H 10-Ha 10-Hb 11-Ha 11-Hb Thienyl-
30-H
2-H
7-H
9-H
10-Ha
10-Hb
11-Ha
11-Hb
—
2
—
1
—
—
2
—
—
—
—
—
—
—
—
20
3
—
—
—
21
—
—
4
—
—
—
5
—
—
22
—
—
—
—
5
—
—
—
—
—
2
—
—
—
—
1
—
—
—
—
—
N-Me), 2.25–2.10 (br s, 1H, NH) and 1.69 (d, 3H, JCH–OP
14.7 Hz, 2-Me).
Z
22
—
—
—
6.3.24. Dimethyl N-(40-but-2-onyl)-2-methyl-c-4-acetyl-
c-5-(20-napthyl)pyrrolidine-r-2-phosphonate 11. Work-
up followed by flash chromatography eluting with a diethyl
ether/ethyl acetate afforded the product 11 as a thick brown
oil; m/z (%) 389 (MKMeC]O, 2), 375 (14), 347 (1), 331
(86), 299 (18), 284 (22), 223 (43), 208 (26), 194 (19), 172
(97), 155 (100) and 127 (94); 7.86–7.69 (m, 5H, naphthyl-H),
7.46–7.38 (m, 2H, naphthyl-H), 4.58 (d, 1H, JZ9.7 Hz, 5-H),
3.86 (d, 6H, JCH–OPZ10.3 Hz, 2!MeOP), 3.51 (dt, 1H, JZ
7.7, 9.2 Hz, 4-H), 2.68–2.56 (m, 1H, 3-Hb), 2.2–1.66 (m, 5H,
2!CH2 and 3-Ha), 1.83 (s, 3H, MeC]O), 1.81 (s, 3H,
MeC]O) and 1.50 (d, 3H, JCH–OPZ15.3 Hz, 2-Me).
Acknowledgements
¨ ˙
We thank Leeds University, Mersin University, TUBITAK
(Turkish Scientific and Research Council), the Royal
Society, the Commonwealth Commision UK and the British
Council for providing financial support.
References and notes
6.3.25. Dimethyl t-1,5-diaza-t-4,6-dioxo-5-methyl-t-2(20-
thienyl)-tricyclo[3.3.3.0.0]undecane-r-8-phosphonate 13.
The amine 2f (172 mg, 0.96 mmol), thiophene-2-carbox-
aldehyde (102 mg, 0.91 mmol) and anhydrous sodium
sulphate (excess) were stirred 16 h in acetonitrile at rt.
The dipolarophile, N-methyl maleimide (101 mg,
0.91 mmol), was added to the mixture and the flask was
then flushed with nitrogen and left to reflux 16 h. The
reaction mixture was filtered, washed with dichloromethane
and evaporated under reduced pressure. Flash chromatog-
raphy eluting with from ethyl acetate to 5:1 v/v ethyl
acetate/methanol afforded the product 13, which crystallised
from ethyl acetate/diethyl ether as yellow prisms, mp 176–
178 8C (found: C, 50.25; H, 5.5; N, 7.2. C16H21N2O5PS
requires C, 50.0; H, 5.5; N, 7.3%); m/z (%) 384 (MC, 1), 275
(100), 216 (6), 190 (21), 162 (12), 109 (12) and 79 (15); d
7.39–7.38 (m, 1H, thienyl 50-H), 7.208–7.27 (m, 1H, thienyl
30-H), 7.00–6.98 (m, 1H, thienyl 4 -H), 5.37 (d, 1H, JZ
7.6 Hz, 2-H), 3.92 (d, 3H, JCH–OPZ10.0 Hz, MeOP), 3.83
(d, 4H, JCH–OPZ10.5 Hz, MeOP and 3-H), 3.64 (dt, 1H, JZ
8.0 Hz, JCH–CPZ16.0 Hz, 7-H), 3.05 (ABXY, 1H, JZ4.6,
8.0, 9.7 Hz, 11-Hb), 2.92 (s, 3H, NMe), 2.58 (dt, 1H, JZ7.7,
9.8 Hz, 11-Ha) 2.39 (t, 1H, JZ7.3 Hz, 9-Hb), 2.34 (t, 1H JZ
7.3 Hz, 9-Ha), 1.95–1.88 (m, 1H, 10-Hb) and 1.70–1.66 (m,
1H, 10-Ha).
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