One-pot synthesis of N-chloroacetyl 1-aminoalkyl phosphonates - Precursors of 4-phosphono-β-lactams

Article abstract of DOI:10.1055/s-2005-918440

4-Phosphono-β-lactams are synthesized via a three-step sequence, including final formation of the C3-C4 bond through a phosphorus-stabilized carbanion. The chlorinated precursors can be synthesized via two different methods: a one-pot N-acylation of an aromatic imine followed by addition of a trialkyl phosphite or phosphonylation of a suitable imine followed by N-acylation in a separate reaction step. The former method was preferred because of the ease of the reaction and the good yields obtained. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918440

PAPER
3603
One-Pot Synthesis of N-Chloroacetyl 1-Aminoalkyl Phosphonates – Precursors
of 4-Phosphono-b-Lactams
O
ne PotSynthesis
r
of
N
-Ch
i
loroac
e
s
tyl 1-A
m
t
inoalky
o
l
Phosphona
f
s
Moonen, Christian V. Stevens*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, 9000 Gent, Belgium
Fax +32(9)2646243; E-mail: chris.stevens@UGent.be
Received 13 June 2005; revised 1 July 2005
plied.11 Our preliminary work in this field has been
Abstract: 4-Phosphono-b-lactams are synthesized via a three-step
published and involves ring closure of N-chloroacetyl 1-
sequence, including final formation of the C3–C4 bond through a
phosphorus-stabilized carbanion. The chlorinated precursors can be
synthesized via two different methods: a one-pot N-acylation of an
aminoalkyl phosphonates 9 (Scheme 1).12 Herein, we de-
scribe an enhanced procedure for the synthesis of adducts
aromatic imine followed by addition of a trialkyl phosphite or phos- 9 since the low yields (<30%) previously reported for
phonylation of a suitable imine followed by N-acylation in a sepa-
these compounds prevented the practical use of the proce-
rate reaction step. The former method was preferred because of the
ease of the reaction and the good yields obtained.
dure. This paper further deals with the scope and limita-
tion of this new synthetic approach and the ring closure to
Key words: acylations, addition reactions, b-lactams, aminophos-
4-phosphono-b-lactams 10.
phonates, acyliminium salts
RCOHN
O
RCOHN
O
OH
N
N
During our research in the area of phosphonylated aza-
heterocycles1 we became interested in phosphono-b-lac-
tams because they combine the well known structural fea-
tures of b-lactam enzyme inhibitors with those of
aminophosphonates. Despite their relatively simple struc-
ture, b-lactams show a wide range of pharmacological ac-
tivity because of their ability to inhibiting ‘serine’
enzymes.2 This class of enzyme contains various interest-
ing target enzymes like elastases, b-lactamases, and PBP-
transpeptidases.3 Penicillin and cephalosporin are well
known examples of bicyclic b-lactam antibiotics, inhibit-
ing the PBP-transpeptidase in the bacterial cell wall.4 Also
SO3H
COOH
2
1
O
COOH
(HO)2P
H2N
N
H
P(OH)2
O
NH
O
4
3
HOOC
N
H
P(OH)2
O
5
Figure 1
monocyclic b-lactams, like nocardicins5
1
and
monobactams6 2 appear to possess antibacterial activity
(Figure 1). Aminophosphonates on the other hand are
considered as the structural analogues of amino acids and
therefore usually act as their antagonists, effecting the
physiological activity of the cell. These effects may be an-
tibacterial (e.g. alafosfalin 3), neuroactive (e.g. CGS
19755 4), or pesticidal (e.g. glyphosate 5).7
The N-chloroacetyl 1-aminoalkyl phosphonates 9 were
prepared from the corresponding imines 6 in a two-step
one-pot reaction sequence via the acyliminium salt 7
(Scheme 1). Using the initial reaction conditions [chloro-
acetyl chloride (1.1 equiv) was added to a solution of
imine 6a in anhydrous toluene under a nitrogen atmos-
phere], precipitation of the iminium salts 7 occurred with-
in ten minutes at –40 °C. Triethyl phosphite was then
added and the mixture was refluxed for two hours. After
evaporation of the solvent under reduced pressure, the re-
sulting mixture consisted mainly of the N-chloroacetyl 1-
aminoalkyl phosphonate 9a and 1-phosphonyl vinyl phos-
phate 14, which was formed due to non-regiospecific at-
tack of the trialkyl phosphite (pathway B). The
mechanism of the reaction between chloroacetyl chloride
and trialkyl phosphites was already described by
Brittelli13 and involves a Perkow reaction followed by a
Michaelis–Arbuzov reaction. The ratio of pathway A ver-
sus pathway B was determined to be 1.6 using 31P NMR
Only a limited number of synthetic routes to 3- and 4-
phosphonylated azetidinones are available in the litera-
ture.8 4-Acetoxy-azetidinone and 4-sulfinylazetidinone
were used successfully in a Michaelis–Arbuzov-type re-
action with tricoordinate phosphorus nucleophiles.9
[2+2]-Cycloaddition of a ketene and an imine has proven
useful for the stereoselective construction of the b-lactam
ring, but because of the unstable nature of phospho-
noketenes, it has found only limited application in the syn-
thesis of phosphonylated b-lactams.10 Finally, ring
closure with phosphorus stabilized carbanions through in-
tramolecular nucleophilic substitution has also been ap-
1
spectroscopy (Table 1, entry 1); also the H NMR spec-
SYNTHESIS 2005, No. 20, pp 3603–3612
x
x.
x
x
.
2
0
0
5
trum showed a lot of impurities. From this mixture, the de-
sired N-chloroacetyl 1-aminoalkyl phosphonate 9a could
be obtained in a pure form by column chromatography
(26% yield).
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-918440; Art ID: Z11105SS
© Georg Thieme Verlag Stuttgart · New York

3604
K. Moonen, C. V. Stevens
PAPER
O
Cl
Cl
P(OR3)3
Cl
P(OR3)3
R3
O
O
12
OP(OR3)2
O
P(OR3)2
P(OR3)3
P(OR3)2
O
P(OR3)2
O
O
Cl
P(OR3)3
Cl
R3
Cl
11
14a R = Me
14b R = Et
13
Pathway B
Pathway B
O
R2
O
N
Cl
N
R2
Cl–
Cl
P(OR3)3
Cl
R1
H
R1
H
6
7
Pathway A
Pathway A
O
O
O
R2
Cl–
R2
Cl
R2
N
Cl
N
N
NaH
P(OR3)2
R3
O
R1
P(OR3)2
R1
P
R1
OR3
O
OR3
10
O
8
9
Scheme 1
In the second experiment, a limiting amount of chloro- with an enhanced stabilization of the positively charged
acetyl chloride was used, giving a higher, more favorable transition state. This positive effect was not because of a
ratio (Table 1, entry 2). Also more polar solvents were lower reaction temperature effect (boiling THF versus
evaluated. The reaction failed using acetonitrile (Table 1, boiling toluene in entry 2), since performing the reaction
entry 3) but when THF was used, a beneficial effect could in toluene at 70 °C (entry 5) did not give an improvement
be observed (Table 1, entry 4). This could be explained by compared to entry 2. The conditions used in Table 1, entry
the lack of precipitation of the intermediate salts, together 4 were then repeated using passive air cooling instead of
Table 1 Effect of the Different Reaction Parameters
O
N
Ph
O
Cl
N
Ph
Cl
P(OEt)3
Cl
H
P(OEt)2
O
6a
9a
Entry
ClCH2COCl
P(OEt)3
Ratio 9/14a
1
2
3
4
5
6
7
1.1 equiv, –40 °C, 10 min, toluene
1.0 equiv, –40 °C, 10 min, toluene
1.0 equiv, –40 °C, 10 min, MeCN
1.0 equiv, –40 °C, 10 min, THF
1.0 equiv, –40 °C, 10 min, toluene
1.0 equiv, –40 °C, 10 min, THF
1.0 equiv, –40 °C, 10 min, THF
1.1 equiv, 2 h, D
1.6
2.8
–
1.1 equiv, 2 h, D
1.1 equiv, 2 h, D
1.1 equiv, 2 h, D
6.1
2.1
8.3
13.7
1.1 equiv, 2 h, 70 °C
1.1 equiv, 2 h, D, passive air cooling
1.1 equiv, 2 h, D, passive air cooling
a Ratio 9/14 (pathway A to pathway B) determined by 31P NMR spectroscopy. Vinyl phosphate 14 is the major side product and can be char-
acterized by two doublets around 10.1 and –3.9 ppm for the methyl esters 14a and 7.3 and –6.3 ppm for the ethyl esters 14b with a coupling
constant of 25.5 Hz and 26.7 Hz, respectively.
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Chloroacetyl 1-Aminoalkyl Phosphonates
3605
intensive cooling with a double jacket water cooler Table 2 Yields of N-Chloroacetyl 1-Aminoalkyl Phosphonates 9
(Table 1, entry 6). Again, the result of the reaction was
improved, probably because of the enhanced removal of
ethyl chloride (bp 12 °C) from the reaction atmosphere.
Starting R1
material
R2
R3
Product
Yield 9
(%)a
6a
6a
6b
6c
6d
6e
6f
Cinnamyl
Bn
Et
9a
9b
9c
9d
46
We had shown previously that phosphite is able to attack
the carbonyl group of acyliminium salts, therefore when
an equimolar amount of phosphite was used the A/B ratio
rose to a level where side product determination via NMR
spectroscopic techniques became almost impossible. Us-
ing these optimal conditions, the desired N-chloroacetyl
1-aminoalkyl phosphonate 9a was obtained in quite a pure
form (purity > 90% from 1H NMR spectrum) after evapo-
ration of the solvent. Even though subsequent column
chromatography resulted in great losses, the yield was al-
most doubled (46%) compared to the initial procedure.12
Furthermore, the obtained reaction mixture had a much
Cinnamyl
Cinnamyl
Cinnamyl
Cinnamyl
Cinnamyl
Bn
Me
Me
Me
Me
Me
Me
Et
55
All
i-Pr
t-Bu
Ph
41
27b
Complex
9e
9f
43
o-Nitro-cinnamyl Bn
Complex
6g
Ph
Bn
Ph
All
Bn
Ph
Bn
Bn
(39)c
0
higher purity and therefore could be used immediately in 6h
Ph
Et
the next step, as will be discussed below.
6i
Furyl
Furyl
Furyl
i-Pr
Me
Me
Me
Me
Me
9g
9h
9i
43
57
35
0
Using the optimal conditions obtained, the method was
extended to other imines. The yields given in Table 2 are
isolated yields after column chromatography. This purifi-
cation step always caused great losses, probably due to the
high affinity of the products towards silica gel. However,
for imines 6a,b,c,e,i,j,k, the products were obtained from
the reaction mixture in high yields and in quite pure form
6j
6k
6l
6m
Myrtenyl
0
a Yield determined after column chromatography.
b Yields: 1,2-adduct, 27%; 1,4-adduct, 7%.
(purity > 90%) after evaporation of the solvent. Surpris-
ingly, the reaction did not work well for imines derived
from benzaldehyde. Several reaction conditions were test-
ed, but in all cases, incomplete conversion of the imines
was observed ( 1H NMR spectroscopy). When a,b-unsat-
urated acyliminium salts 7a–e were treated with trialkyl
phosphite, the 1,4-adduct was expected to form re-
gioselectively as was previously reported by Savignac and
Teulade.17 However, only with a bulky isopropyl group on
the nitrogen could the 1,4-adduct be isolated and then in
only 7% yield (ratio 1,2-addition to 1,4-addition, 4:1).
When the more steric demanding triethyl phosphite was
used, this ratio is slightly higher in favor of the 1,4-prod-
uct. tert-Butyl imine 6d failed to react with the chloro-
acetyl chloride, probably due to steric hindrance, leading
to complex reaction mixtures after the phosphite addition.
Also, when an electron withdrawing group was intro-
duced on the phenyl ring, the reaction failed (imine 6f).
c Yield estimated by 1H NMR spectroscopy without isolation of the
product.
Furthermore, the reaction is not suitable for aliphatic
imines, since an a-proton on the iminium salt is easily
eliminated with the formation of the corresponding N-vi-
nylic amides upon heating (Scheme 2). Anyhow, imine
6m derived from (–)-myrtenal was selected as a non-aro-
matic aldehyde as it had the advantage of not containing
an a-proton. Several reaction conditions were evaluated,
but the desired product could never be isolated. The re-
sulting mixture consisted mainly of vinyl phosphate 14a,
diene 16, formed by elimination of the g-proton, and a
small amount of 1-aminoalkyl phosphonate 17, probably
formed by phosphite addition after deacylation of the imi-
nium salt.
O
O
Cl
Ph
P(OR)3, heat
Cl
Cl
O
N
Ph
N
Ph
N
Cl
Cl
heat
H
H
H
6l
15
7l
O
Bn
N
O
O
Bn
Cl
Bn
H
Cl
HN
1)
N
Cl
P(OMe)2
H
+
+
P(OMe)2
O
2) P(OMe)3
OP(OMe)2
6m
O
16
14a
17
Scheme 2
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

3606
K. Moonen, C. V. Stevens
PAPER
lustrated by the use of LiHMDS as a base; 4-phosphono-
b-lactams 10 are formed typically in one hour at room
temperature while the 4-carboxy-b-lactams are not
formed at all under these conditions: in this case an amide
enolate is formed more readily yielding pyrrolinones via a
Dieckmann-type condensation.21
R2
R2
H
HN
N
45–66%
R1
18
P(OEt)2
O
R1
(i)
6
R1 = PhCH=CH-; R2 = i-Pr
1 = PhCH=CH-; R2 = Bn
R1 = Ph, R2 = Bn
(ii)
30–60%
R
Given the good yields of the final ring closure step, we
were now able to synthesize 4-phosphono-b-lactams 10 in
a three-step sequence. However, the intermediate purifi-
cation of the N-chloroacetyl 1-aminoalkyl phosphonates 9
constituted a major drawback of this pathway, seriously
lowering the overall yield. Therefore, we successfully at-
tempted to use the N-chloroacetyl 1-aminoalkyl phospho-
nates 9, obtained via the acyliminium addition method,
directly in the ring closing reaction without prior chro-
matographic purification. The desired b-lactams 10 were
obtained in reasonable purity (>90%) and with good over-
all yields after simple aqueous work up of the final reac-
tion mixture. Furthermore, they could be obtained in a
pure form by a final chromatographic step with much
smaller losses than the N-chloroacetyl 1-aminoalkyl phos-
phonates 9 because of their lower affinity for silica gel.
O
Cl
R2
N
R1
P(OEt)2
O
9
Scheme 3 Reagents and conditions: (i) P(OEt)2OTMS17 (1 equiv),
CH2Cl2, D, 2 d; (ii) ClCH2COCl (1.5 equiv), pyridine (1 equiv),
CH2Cl2, r.t.
The reverse methodology was also evaluated: starting
with the phosphonylation step, the resulting 1-aminoalkyl
phosphonate 18 was N-acetylated14 in a separate reaction
(Scheme 3). Although addition of dialkyl phosphites to
imines is restricted by the low nucleophilicity of the pre-
dominating s4l5 form,15 the equilibrium can be shifted to-
wards the s3l3 phosphite by deprotonation with a strong
base16 or by silylation of the dialkyl phosphite with
TMSCl.17 By applying the latter method we were able to
convert aromatic imines as well as aliphatic imines to the
corresponding 1-aminoalkyl phosphonates. However,
long reaction times were necessary, generating a growing
amount of side products and therefore leaving up to 15%
of the starting material in the final reaction mixture. Fur-
thermore, subsequent acylation proceeded rather slug-
gishly, due to the reduced nucleophilicity of the nitrogen
atom in 1-aminoalkyl phosphonate 18. Therefore, it was
clear that the acyliminium salt method provided the best
results, probably because the addition of the phosphite to
this acyliminium salt 7 is enhanced by two beneficial ef-
fects: (i) the imine is activated towards nucleophilic attack
and (ii) due to the presence of chloride, it is possible to use
the highly nucleophilic trialkyl phosphite for the addition
reaction followed by an Arbuzov-type dealkylation of the
intermediate phosphonium salt 8. Furthermore, the N-
chloroacetyl 1-aminoalkyl phosphonates 9 can be ob-
tained in much lower reaction times and in a single step.
Table 3 Synthesis of Phosphono-b-lactams 10
10
a
b
c
R1
R2
R3
Yield 10 (%) Yielda
Cinnamyl
Cinnamyl
Cinnamyl
Cinnamyl
Cinnamyl
Furyl
Bn
Et
92
75
62
85
90
55
99
89
92
98% (60%)
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Allyl
i-Pr
Ph
85% (40%)
81% (51%)
d
e
f
Allyl
Bn
62% (25%)
g
h
i
Furyl
Furyl
Ph
Ph
Bn
a Total yield of 4-phosphono-b-lactams 10 (>90% pure) starting from
the corresponding imine 6. The yield after chromatographic separa-
tion is given in parenthesis.
The obtained N-chloroacetyl 1-aminoalkyl phosphonates
9 appeared to be excellent substrates for ring closure to 4-
phosphono-b-lactams 10, through an unusual C3–C4
bond formation. When treated with sodium hydride, a
phosphorus-stabilized carbanion19 was formed, which
upon refluxing for two or three hours in THF led to the
four-membered heterocycle. No side products were
formed during this procedure and the 4-phosphono-b-lac-
tams 10 were obtained in excellent yields. This type of
ring closure has already been evaluated for similar car-
boxylates.20 However, for the carboxylates, longer reac-
tion times are necessary (one to several days at room
temperature) and the yields are lower, indicating a differ-
ence between the stabilizing effect of the carboxylate and
phosphonate group towards the anion. This can also be il-
In conclusion, 4-phosphono-b-lactams 10 can be easily
synthesized in excellent yields by intramolecular alkyla-
tion of N-chloroacetyl 1-aminoalkyl phosphonates 9 un-
der basic conditions. For the synthesis of these N-
chloroacetyl 1-aminoalkyl phosphonates, two methodolo-
gies were evaluated, starting from aromatic aldimines.
Phosphonylation of the imine, followed by acylation with
chloroacetyl chloride gave only the desired amides in
moderate yields after an extended reaction time. When the
imines are acylated first, the very reactive intermediate
acyliminium salts are suitable substrates for the addition
of trialkyl phosphites when using the appropriate reaction
conditions due to the short reaction time, the easy work-
up of the reaction, and the satisfying product purity and
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Chloroacetyl 1-Aminoalkyl Phosphonates
3607
reduced pressure and pure N-chloroacetyl 1-aminoalkyl phospho-
nate can be obtained after flash chromatography.
yield; this is the method of choice for the synthesis of the
N-chloroacetyl 1-aminoalkyl phosphonates 9. The ring
closure can be performed on the crude reaction mixture
using sodium hydride to generate the phosphonate-stabi-
lized anion, which shows different properties compared to
the corresponding carboxylate-stabilized anions. The b-
lactams obtained have been submitted for bio-testing and
our investigation is continuing in trying to widen the
scope of the reaction.
Diethyl (2E)-1-[Benzyl(chloroacetyl)amino]-3-phenyl-2-prope-
nylphosphonate (9a)
The reaction was carried out at –40 °C and stirred for 10 min prior
to the addition of trialkyl phosphite.
Rf 0.33 (EtOAc–petroleum ether–MeOH, 78:20:2); yield: 46%.
IR (neat): 1665, 1248, 1050 (br) cm–1.
1H NMR (300 MHz): d = 1.27 (3 H, t, J = 6.9 Hz, CH3), 1.32 (3 H,
t, J = 6.9 Hz, CH3), 3.88 (1 H, d, JAB = 12.7 Hz, CHAHBPh), 3.98 (1
H, d, JAB = 12.7 Hz, CHAHBPh), 4.06–4.23 (4 H, m, OCH2), 4.88 (1
H, d, JAB = 18.2 Hz, CHAHBCl), 5.10 (1 H, d, JAB = 18.2 Hz, CHAH-
BCl), 5.73 (1 H, dd, JH–P = 20.6 Hz, J = 9.2 Hz, CHP), 6.09–6.20 (1
H, m, =CH), 6.77 (1 H, dd, J = 16.0 Hz, JH–P = 2.8 Hz), 7.16–7.32
(10 H, m, Ar-CH).
NMR spectra were recorded at 300 MHz (JEOL ECX300) or at 270
MHz (JEOL EX270) with CDCl3 as solvent (unless otherwise stat-
ed) and TMS as the internal standard. The absolute value of the cou-
pling constants (J) in Hz and assignments of 1H and 13C peaks were
determined using COSY, HSQC, HMBC, and DEPT experiments.
MS spectra were measured with an Agilent 1100 mass spectrometer
using ESI (4000 V) or with a Varian MAT 112 spectrometer using
EI ionization (EI, 70 eV). IR spectra were measured with a Perkin–
Elmer Spectrum One spectrometer. THF and toluene were dried and
distilled over Na (benzophenone ketyl) prior to use. CH2Cl2 was
dried and distilled over CaH. Petroleum ether used has a bp range
30–60 °C.
13C NMR (75 MHz): d = 16.48 (CH3), 16.53 (CH3), 41.61 (CH2Cl),
49.62 (CH2Ph), 54.86 (d, JC–P = 156.3 Hz, CHP), 62.84 (d, JC–P
=
6.4 Hz, OCH2), 63.42 (d, JC–P = 5.8 Hz, OCH2), 119.43 (=CH),
126.03 (Ar-CH), 126.69 (Ar-CH), 127.69 (Ar-CH), 128.25 (Ar-
CH), 128.44 (Ar-CH), 128.62 (Ar-CH), 129.05 (Ar-CH), 135.93
(Ar-Cq), 137.03 (Ar-Cq), 137.15 (d, JC–P = 13.3 Hz, =CH), 167.44
(C=O).
31P NMR (121 MHz): d = 20.99.
Aldimines 6; General Procedure
Aldehyde (50 mmol) was dissolved in anhydrous CH2Cl2 (50 mL)
in a round bottom flask. MgSO4 (3 g) was added together with the
amine (50 mmol). A CaCl2 drying tube was fitted to the flask and
the mixture was stirred overnight at r.t. Then the mixture was fil-
tered to remove the MgSO4 and the solvent removed under reduced
pressure. The aldimines were recovered in a pure form in 92–99%
yield. Spectral data were compared with literature data to confirm
their structure except for 6m.
MS (ESI): m/z (%) = 253 (100), 436 (53) [M + H+], 438 (15), [M +
H+ + 2].
Anal. Calcd for C22H27ClNO4P: C, 60.62; H, 6.24; N, 3.21. Found:
C, 60.52; H, 6.31, N, 3.24.
Dimethyl (2E)-1-[Benzyl(chloroacetyl)amino]-3-phenyl-2-pro-
penylphosphonate (9b)
The reaction was carried out at –40 °C and stirred for 10 min prior
to the addition of trialkyl phosphite.
N-{(E)-[(1R,5S)-6,6-Dimethylbicyclo-[3.1.1]hept-2-en-2-
yl]methylidene}(phenyl)methanamine (6m)
Derived from (–)-myrtenal.
IR (neat): 1634 cm–1.
1H NMR (300 MHz): d = 0.81 (3 H, s, CH3), 1.13 (1 H, d,
J = 9.1 Hz, CHAHB), 1.33 (3 H, s, CH3), 2.10–2.21 (1 H, m, CH),
2.35–2.55 (3 H, m, CH2CH=, CHAHB), 3.05 (1 H, app. t, J = 5.6 Hz,
CHCq=), 4.61 (1 H, JAB = 14.0 Hz, NCHAHB), 4.70 (1 H,
JAB = 14.0 Hz, NCHAHB), 6.03 (1 H, br s, =CH), 7.19–7.33 (5 H, m,
Ar), 7.91 (1 H, s, NCH).
Rf 0.29 (EtOAc–petroleum ether–MeOH, 78:20:2); yield: 55%.
IR (neat): 1661, 1249 cm –1
.
1H NMR (270 MHz): d = 3.79 (3 H, d, JH–P = 10.9 Hz, OCH3), 3.80
(3 H, d, JH–P = 10.6 Hz, OCH3), 3.93 (1 H, d, JAB = 12.5 Hz,
CHAHBCl), 4.01 (1 H, d, JAB = 12.5 Hz, CHAHBCl), 4.87 (1 H, d,
JAB = 18.2 Hz, NCHAHB), 5.05 (1 H, d, JAB = 17.8 Hz, NCHAHB),
5.66 (1 H, dd, JH–P = 20.5 Hz, J = 9.2 Hz, NCHP), 6.18 (1 H, m,
CH=), 6.76 (1 H, dd, Jtrans = 15.7 Hz, J = 3.0 Hz, PhCH=), 7.20–
7.40 (10 H, m, Ar-CH).
13C NMR (75 MHz): d = 21.06 (CH3), 26.04 (CH3), 31.46 (CH2),
32.53 (CH2CH=), 37.74 (Cq), 40.26 (CHCq=), 41.10 (CH), 64.76
(NCH2), 126.87 (Ar-CH), 127.96 (2 × Ar-CH), 128.46 (2 × Ar-
CH), 134.78 (=CH), 139.90 (Ar-C), 148.51 (=Cq), 163.09 (NCH).
13C NMR (68 MHz): d = 41.51 (CH2Cl), 49.78 (NCH2), 53.17 (d,
JC–P = 7.3 Hz, OCH3), 54.00 (d, JC–P = 7.3 Hz, OCH3), 54.74 (d,
JC–P = 157.5 Hz, NCHP), 119.03 (=CH), 125.98, 126.68, 126.99,
127.11, 127.71, 128.44, 128.55, 129.02 (Ar-CH), 135.72, 136.64
MS (ESI): m/z (%) = 240 (100) [M + H+].
(Ar-Cq), 137.32 (d, JC–P = 13.4 Hz, =CHPh), 167.38 (d, JC–P
2.5 Hz, C=O).
31P NMR (109 MHz): d = 23.33.
=
Anal. Calcd for C17H21N: C, 85.30; H, 8.84; N, 5.85. Found: C,
85.26; H, 8.81; N, 5.92.
MS (EI, 70 eV): m/z (%) = 91 (100), 116 (18), 207 (12), 209 (25),
299 (39), 301 (14).
N-Chloroacetyl Aminophosphonates 9; Typical Procedure
A solution of the desired imine (5 mmol) in THF (10 mL) was
stirred in a round bottom flask under a nitrogen atmosphere at the
temperature given. Then, chloroacetyl chloride (0.57 g, 5 mmol)
was added dropwise using a syringe. The mixture was stirred at the
temperature given for the appropriate time before trimethyl or tri-
ethyl phosphite (5 mmol) was added. The resulting mixture was
heated very fast and refluxed for a further 2 h using an air cooler.
CAUTION: during this reaction, MeCl is liberated from the reac-
tion mixture. Therefore, the reaction should be performed in a prop-
erly working fume hood. Finally, the solvent is removed under
Anal. Calcd for C20H23ClNO4P: C, 58.90; H, 5.68; N, 3.43. Found:
C, 58.67; H, 5.71; N, 3.41.
Dimethyl (2E)-1-[Allyl(chloroacetyl)amino]-3-phenyl-2-prope-
nylphosphonate (9c)
The reaction was carried out at –20 °C and stirred for 20 min prior
to the addition of trialkyl phosphite.
Rf 0.21 (EtOAc–MeOH, 99:1); yield: 41%.
IR (neat): 1663, 1251, 1033 (br) cm–1.
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

3608
K. Moonen, C. V. Stevens
PAPER
1H NMR (300 MHz): d = 3.789 (3 H, d, JH–P = 10.7 Hz, OCH3),
3.791 (3 H, d, JH–P = 10.7 Hz, OCH3), 4.08 (1 H, d, JAB = 12.7 Hz,
CHAHBCl), 4.16 (1 H, d, JAB = 12.4 Hz, CHAHBCl), 4.19–4.44 (2 H,
Dimethyl (2E)-1-[(Chloroacetyl)anilino]-3-phenyl-2-propenyl-
phosphonate (9e)
The reaction was carried out at 0 °C and stirred for 10 min prior to
the addition of trialkyl phosphite.
m, NCH2), 5.19–5.29 (2 H, m, =CH2), 5.67 (1 H, dd, JH–P
=
21.1 Hz, J = 8.9 Hz, CHP), 5.83–5.94 (1 H, m, CH2CH=), 6.27 (1
H, ddd, Jtrans = 15.7 Hz, JH–P = 8.8 Hz, J = 8.8 Hz, =CHCHP), 6.79
(1 H, dd, Jtrans = 15.7 Hz, JH–P = 2.8 Hz, =CHPh), 7.28–7.39 (5 H,
m, Ar-CH).
13C NMR (75 MHz): d = 41.41 (CH2Cl), 48.48 (NCH2), 53.22 (d,
JC–P = 6.9 Hz, OCH3), 53.79 (d, JC–P = 6.4 Hz, OCH3), 53.84 (d,
JC–P = 159.9 Hz, CHP), 117.38 (=CH2), 119.13 (HC =CHPh),
126.71 (2 × Ar-CH), 128.51 (Ar-CH), 128.69 (2 × Ar-CH), 134.05
(=CH), 135.82 (Ar-Cq), 136.99 (d, JC–P = 12.7 Hz, =CHPh), 167.13
(C=O).
Mp 90–93 °C; Rf 0.25 (EtOAc–petroleum ether, 4:1); yield: 43%.
IR (KBr): 1677, 1663, 1259, 1047, 1023 cm–1.
1H NMR (300 MHz): d = 3.77 (3 H, d, JH–P = 10.7 Hz, OCH3), 3.78
(3 H, d, JH–P = 11.0 Hz, OCH3), 3.82 (2 H, s, CH2Cl), 5.59 (1 H, dd,
JH–P = 19.4 Hz, J = 9.8 Hz, CHP), 6.09 (1 H, Jtrans = 15.8 Hz,
J = 9.7 Hz, JH–P = 6.3 Hz, =CH), 66.76 (1 H, Jtrans = 15.8 Hz, JH–P
3.0 Hz, =CH), 7.22–7.51 (10 H, m, Ar-CH).
13C NMR (75 MHz): d = 42.09 (CH2Cl), 52.89 (d, JC–P = 8.1 Hz,
OCH3), 53.98 (d, JC–P = 6.9 Hz, OCH3), 57.70 (d, JC–P = 158.0 Hz,
CHP), 119.34 (d, JC–P = 2.3 Hz, =CH), 126.82, 128.50, 128.64,
=
31P NMR (121 MHz): d = 23.64.
129.56, 129.72, 129.86 (Ar-CH), 135.82 (Ar-Cq), 137.24 (d, JC–P
13.9 Hz, =CHPh), 138.49 (Ar-Cq), 166.02 (d, JC–P = 2.3 Hz, C=O).
31P NMR (121 MHz): d = 23.57.
=
MS (ESI): m/z (%) = 225 (100), 248 (18), 358 (13) [M + H+], 360
(4) [M + H+ + 2].
Anal. Calcd for C16H21ClNO4P: C, 53.71; H, 5.92; N, 3.92. Found:
C, 53.82; H, 5.94; N, 3.94.
MS (ESI): m/z (%) = 225 (100), 284 (34), 394 (31) [M + H+], 396
(11) [M + H+ + 2].
Dimethyl (2E)-1-[(Chloroacetyl)(isopropyl)amino]-3-phenyl-2-
propenylphosphonate (9d)
1,2-Adduct
Anal. Calcd for C19H21ClNO4P: C, 57.95; H, 5.37; N, 3.56. Found:
C, 57.78; H, 5.39; N, 3.57.
Dimethyl [Allyl(chloroacetyl)amino](2-furyl)methylphospho-
nate (9g)
The reaction was carried out at 0 °C and stirred for 10 min prior to
the addition of trialkyl phosphite.
The reaction was carried out at –20 °C and stirred for 10 min prior
to the addition of trialkyl phosphite.
Rf 0.10 (EtOAc–petroleum ether, 4:1); yield: 27%.
IR (neat): 1651, 1250, 1055 (br) cm–1.
1H NMR (300 MHz): d = 1.26 (3 H, d, J = 6.5 Hz, CH3), 1.39 (3 H,
d, J = 6.5 Hz, CH3), 3.71 (3 H, d, JH–P = 11.0 Hz, OCH3), 3.89 (3 H,
d, JH–P = 11.0 Hz, OCH3), 4.09–4.27 (4 H, m, CHP, CH, CH2),
6.47–6.60 (2 H, m, HC=CH), 7.23–7.41 (5 H, m, Ar-CH).
Rf 0.42 (EtOAc–petroleum ether, 1:4); yield: 43%.
IR (neat): 1665 (br), 1251, 1041 (br) cm–1.
1H NMR (300 MHz): d = 3.73 (3 H, d, JH–P = 10.7 Hz, OCH3), 3.83
(3 H, d, JH–P = 10.7 Hz, OCH3), 4.07 (1 H, d, JAB = 12.7 Hz,
CHAHBCl), 4.11–4.19 (1 H, m, CHAHBN), 4.17 (1 H, d, JAB = 12.7
Hz, CHAHBCl), 4.37–4.45 (1 H, m, CHAHBN), 4.91–5.01 (2 H, m,
=CH2), 5.30–5.43 (1 H, m, CH =CH2), 6.38 (1 H, s (br), CH=), 6.41
(1 H, d, JH–P = 26.4 Hz, CHP), 6.70 (1 H, d, J = 3.0 Hz, =CHCq),
7.42 (1 H, d, J = 1.7 Hz, =CHO).
13C NMR (75 MHz): d = 41.37 (CH2Cl), 47.34 (d, JC–P = 162.7 Hz,
CHP), 47.88 (CH2N), 53.63 (d, JC–P = 8.1 Hz, OCH3), 53.80 (d,
JC–P = 6.9 Hz, OCH3), 110.94 (=CH), 112.81 (d, JC–P = 3.5 Hz,
=CHCq), 116.31 (=CH2), 133.12 (CH =CH2), 143.49 (=CHO),
145.54 (d, JC–P = 10.4 Hz, =Cq), 167.25 (d, JC–P = 3.5 Hz, C=O).
13C NMR (75 MHz): d = 21.03 (CH3), 21.62 (CH3), 41.57 (CH2Cl),
50.90 (NCH), 52.30 (d, JC–P = 6.9 Hz, OCH3), 54.86 (d, JC–P
=
161.0 Hz, CHP), 54.91 (d, JC–P = 5.8 Hz, OCH3), 121.82 (=CH),
126.80 (2 × Ar-CH), 128.19 (Ar-CH), 128.66 (2 × Ar-CH), 133.97
(d, JC–P = 12.1 Hz, =CHPh), 136.29 (Ar-Cq), 165.97 (C=O).
31P NMR (121 MHz): d = 25.86.
MS (ESI): m/z (%) = 225 (100), 360 (14) [M + H+], 362 (4) [M +
H+ + 2].
Anal. Calcd for C16H23ClNO4P: C, 53.41; H, 6.44; N, 3.89. Found:
C, 53.28; H, 6.46; N, 3.91.
31P NMR (121 MHz): d = 20.77.
MS (ESI): m/z (%) = 189 (100), 322 (26) [M + H+], 324 (9) [M +
1,4-Adduct
H+ + 2].
Rf 0.19 ( EtOAc–petroleum ether, 4:1); yield: 7%.
IR (neat): 1668, 1647, 1252, 1032 cm–1.
Anal. Calcd for C12H17ClNO5P: C, 44.80; H, 5.33; N, 4.35. Found:
C, 44.64; H, 5.34; N, 4.35.
1H NMR (300 MHz): d = 1.10 (3 H, d, J = 8.3 Hz, CH3), 1.12 (3 H,
d, J = 7.2 Hz, CH3), 3.07 (3 H, d, JH–P = 10.7 Hz, OCH3), 3.72 (3 H,
d, JH–P = 10.7 Hz, OCH3), 3.99 (1 H, dd, JH–P = 24.9 Hz, J = 9.2 Hz,
CHP), 4.10 (2 H, s, CH2Cl), 4.35–4.75 (1 H, m, CHN), 5.95–6.07 (1
H, m, =CH), 6.24 (1 H, dd, Jtrans = 13.8 Hz, JH–P = 4.1 Hz, =CHN),
7.30–7.40 (5 H, m, Ar-CH).
Dimethyl [Benzyl(chloroacetyl)amino](2-furyl)methylphospho-
nate (9h)
The reaction was carried out at 0 °C and stirred for 10 min prior to
the addition of trialkyl phosphite.
Rf 0.26 (EtOAc–petroleum ether, 7:3); yield: 57%.
IR (neat): 1651, 1252, 1057, 1043 cm–1.
1H NMR (300 MHz): d = 3.72 (3 H, d, JH–P = 10.7 Hz, OCH3), 3.82
(1 H, d, JAB = 12.8 Hz, CHAHBCl), 3.85 (3 H, d, JH–P = 10.9 Hz,
OCH3), 3.94 (1 H, d, JAB = 12.8 Hz, CHAHBCl), 4.78 (1 H, d,
JAB = 18.0 Hz, CHAHBN), 5.13 (1 H, d, JAB = 18.0 Hz, CHAHBN),
13C NMR (75 MHz): d = 19.89 (CH3), 20.00 (CH3), 42.32 (CH2Cl),
46.07 (d, JC–P = 146.5 Hz, CHP), 46.94 (CHN), 53.25 (d, JC–P
=
6.9 Hz, OCH3), 53.83 (d, JC–P = 6.9 Hz, OCH3), 127.93, 128.73,
128.82, 129.12 (Ar-CH, =CH), 134.31 (Ar-Cq), 165.71 (C=O).
31P NMR (121 MHz): d = 26.61.
MS (ESI): m/z (%) = 250 (23), 284 (15), 360 (100) [M + H+], 362
6.24 (1 H, dd, J = 2.9 Hz, J = 2.1 Hz, =CH), 6.55 (1 H, d, JH–P =
(34) [M + H+ + 2].
22.8 Hz, CHP), 6.68 (1 H, d, J = 3.3 Hz, =CHCq), 6.83 (2 H, app. d,
J = ca. 6.6 Hz, Ar-CH), 7.14–7.28 (3 H, m, Ar-CH), 7.31 (1 H, d,
J = 1.1 Hz, =CHO).
Anal. Calcd for C16H23ClNO4P: C, 53.41; H, 6.44; N, 3.89. Found:
C, 53.32; H, 6.45; N, 3.91.
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Chloroacetyl 1-Aminoalkyl Phosphonates
3609
13C NMR (75 MHz): d = 41.71 (CH2Cl), 48.00 (d, JC–P = 162.7 Hz,
CHP), 49.16 (CH2N), 53.71 (d, JC–P = 6.9 Hz, OCH3), 54.05 (d,
JC–P = 5.8 Hz, OCH3), 111.02 (=CH), 113.29 (d, JC–P = 3.5 Hz,
=CHCq), 125.25 (2 × Ar-CH), 127.35 (Ar-CH), 128.83 (2 × Ar-
CH), 136.83 (Ar-Cq), 143.62 (=CHO), 145.42 (d, JC–P = 9.2 Hz,
=Cq), 167.79 (C=O).
Rf 0.35 (EtOAc); yield: 9%.
IR (neat): 3318, 1677, 1244, 1060, 1033 cm–1.
1H NMR (300 MHz): d = 0.90 (3 H, s, CH3, major), 0.93 (3 H, s,
CH3, minor), 1.19–1.26 (2 × 1 H, m, CHAHB), 1.31 (2 × 3 H, s,
CH3), 2.08–2.15 (2 × 1 H, m, CH), 2.18 (2 × 1 H, br s, NH), 2.31–
2.50 (2 × 4 H, m, CHAHB, CH2CH=, CHCq=), 3.46 (1 H, d, JH–P
=
31P NMR (121 MHz): d = 20.84.
21.2 Hz, CHP, minor), 3.49 (1 H, d, JH–P = 20.9 Hz, CHP, major),
3.60 (1 H, d, JAB = 13.2 Hz, CHAHBN, minor), 3.63 (1 H, d,
JAB = 13.2 Hz, CHAHBN, major), 3.70 (2 × 3 H, d, JH–P = 10.5 Hz,
OCH3), 3.77 (2 × 3 H, d, JH–P = 10.5 Hz, OCH3), 3.86 (2 × 1 H, d,
JAB = 13.2 Hz, CHAHBN), 5.56 (2 × H, br s, =CH), 7.21–7.41 (2 × 5
H, m, Ar-CH).
MS (ESI): m/z (%) = 189 (15), 372 (100) [M + H+], 374 (25), [M +
H+ + 2].
Anal. Calcd for C16H19ClNO5P: C, 51.69; H, 5.15; N, 3.77. Found:
C, 51.52; H, 5.16; N, 3.79.
Dimethyl [(Chloroacetyl)anilino](2-furyl)methyl Phosphonate
(9i)
The reaction was carried out at 0 °C and stirred for 10 min prior to
the addition of trialkyl phosphite.
13C NMR (75 MHz): d = 21.07 (CH3, major), 21.54 (CH3, minor),
26.26 (CH3, minor), 26.37 (CH3, major), 31.62 (CH2CH=, minor),
31.68 (CH2CH=, major), 32.06 (CH2), 37.85 (Cq, minor), 38.34 (Cq,
major), 40.67 (CH, minor), 40.84 (CH, major), 42,95
(CHCq=, major), 43,35 (CHCq=, minor), 51,36 (d, JC–P = 13.9 Hz,
CH2N, major), 51,61 (d, JC–P = 13.9 Hz, CH2N, minor), 52.69 (d,
JC–P = 6.9 Hz, OCH3, major), 52.78 (d, JC–P = 6.9 Hz, OCH3, mi-
nor), 53.44 (d, JC–P = 6.9 Hz, OCH3, major), 53.51 (d, JC–P = 6.9 Hz,
OCH3, minor), 59.56 (d, JC–P = 156.9 Hz, CHP, minor), 60,00 (d,
JC–P = 156.9 Hz, CHP, major), 123.05 (d, JC–P = 13.8 Hz, =CH, mi-
nor), 123.50 (d, JC–P = 13.8 Hz, =CH, major), 127.09 (Ar-CH),
128.33 (Ar-CH), 128.37 (3 × Ar-CH), 139.61 (Ar-Cq), 142.16 (d,
JC–P = 5.8 Hz, =Cq), 142.34 (d, JC–P = 5.8 Hz, =Cq).
Rf 0.24 (EtOAc–petroleum ether, 7:3); yield: 35%.
IR (neat): 1677, 1238 (br), 1035 (br) cm–1.
1H NMR (300 MHz): d = 3.73 (3 H, d, JH–P = 3.7 Hz, OCH3), 3.81
(3 H, d, JH–P = 11.0 Hz, OCH3), 3.81 (2 H, s, CH2Cl), 6.26–6.28 (1
H, m, =CH), 6.35–6.36 (1 H, m, =CHCqO), 6.57 (1 H, d, JH–P
=
22.6 Hz, CHP), 7.28–7.39 (6 H, m, Ar-CH, =CHO).
13C NMR (75 MHz): d = 42.23 (CH2Cl), 50.46 (d, JC–P = 163.8 Hz,
CHP), 53.28 (d, JC–P = 8.1 Hz, OCH3), 53.96 (d, JC–P = 5.8 Hz,
OCH3), 110.82 (=CH), 113.47 (d, JC–P = 2.3 Hz, =CHCqO), 129.23
(Ar-CH), 129.44 (Ar-CH), 137.63 (Ar-Cq), 143.23 (=CHO), 145.32
(d, JC–P = 9.2 Hz, =CO), 166.32 (C=O).
31P NMR (121 MHz): d = 26.60 (major), 26.87 (minor).
MS (ESI): m/z (%) = 240 (100), 350 (14) [M+ + H].
31P NMR (121 MHz): d = 20.55.
Phosphono-b-lactams 10; Typical Procedure
A NaH emulsion in mineral oil (0.24 g, 6 mmol) was washed with
petroleum ether (3 × 10 mL) to remove the oil and then anhydrous
THF (15 mL) was added. The N-chloroacetyl 1-aminoalkyl phos-
phonate (5 mmol) in THF (5 mL) was then added dropwise, a CaCl2
tube was attached, and the reaction was refluxed for 2 h or 3 h. After
cooling, the mixture was poured into H2O (25 mL) and extracted
with Et2O (20 mL). The remaining aqueous phase was then washed
with Et2O (2 × 10 mL). The combined organic phases were dried
with MgSO4 and after filtration the solvent was removed under re-
duced pressure.
MS (ESI): m/z (%) = 358 (100) [M + H+]), 360 (33, [M + H+ + 2].
Anal. Calcd for C15H17ClNO5P: C, 50.36; H, 4.79; N, 3.92. Found:
C, 50.24; H, 4.81; N, 3.93.
N-Benzyl-2-chloro-N-{[(1R,5R)-6,6-dimethylbicyclo-
[3.1.1]hept-3-en-2-ylidene]methyl} Acetamide (16)
Formed as an undesired side-product when the reaction was carried
out at 20 °C and stirred for 45 min prior to the addition of trialkyl
phosphite.
Rf 0.80 (EtOAc–petroleum ether, 2:3); yield: 44%.
IR (neat): 1671, 1639 cm–1.
Diethyl 1-Benzyl-4-oxo-2-[(E)-2-phenylethenyl]-2-azetidinyl-
phosphonate (10a)
1H NMR (300 MHz): d = 0.62 (3 H, s, CH3), 1.24 (3 H, s, CH3), 1.34
(1 H, d, J = 8.5 Hz, CHAHB), 2.31 (1 H, ddd, J = 6.6 Hz, J = 5.8 Hz,
J = 5.5 Hz, CHCH=), 2.45 (1 H, ddd, J = 8.8 Hz, J = 5.5 Hz, J = 5.5
Hz, CHAHB), 2.63 (1 H, dd, J = 5.5 Hz, J = 5.8 Hz, CHCq=), 4.00 (1
H, d, JAB = 13.2 Hz, CHAHBCl), 4.09 (1 H, d, JAB = 13.2 Hz,
CHAHBCl), 4.54 (1 H, d, JAB = 14.1 Hz, CHAHBN), 4.66 (1 H, d,
JAB = 14.1 Hz, CHAHBN), 5.82 (1 H, s, =CHN), 5.99 (1 H, d,
J = 8.5 Hz, =CHCq), 6.43 (1 H, dd, J = 8.5 Hz, J = 6.6 Hz,
=CHCH), 7.22–7.33 (5 H, m, Ar-CH).
13C NMR (75 MHz): d = 22.03 (CH3), 25.88 (CH3), 35.96 (CH2),
41.97 (CH2Cl), 43.27 (CHCH=), 44.66 (CHCq=), 44.80 (Cq), 51.91
(CH2N), 119.69 (=CHN), 123.70 (=CHCq), 127.51 (Ar-CH),
128.36 (2 × Ar-CH), 128.88 (2 × Ar-CH), 136.56 (Ar-Cq), 140.99
(=CHCH), 145.93 (=Cq), 166.36 (C=O).
Rf 0.31 (EtOAc–petroleum ether–MeOH, 80:20:2); yield: 92%.
IR (neat): 1760, 1249, 1050, 1024 cm–1.
1H NMR (300 MHz): d = 1.31 (6 H, t, J = 7.2 Hz, CH3), 3.07 (1 H,
dd, JAB = 14.6 Hz, JH–P = 5.8 Hz, CHAHBCO), 3.47 (1 H, dd,
JAB = 14.6 Hz, JH–P = 8.3 Hz, CHAHBCO), 4.04–4.24 (4 H, m,
OCH2), 4.39 (1 H, d, JAB = 15.1 Hz, CHAHBPh), 4,77 (1 H, d,
JAB = 15.1 Hz, CHAHBPh), 6,19 (1 H, dd, Jtrans = 16.2 Hz, JH–P = 8.3
Hz, =CH), 6.50 (1 H, dd, Jtrans = 16.2 Hz, JH–P = 3.6 Hz, =CHPh),
7.07–7.44 (10 H, m, Ar-CH).
13C NMR (75 MHz): d = 16.58 (CH3), 45.81 (CH2Ph), 47.81
(CH2CO), 59.47 (d, JC–P = 166.7 Hz, PCq), 63.13 (d, JC–P = 7.5 Hz,
OCH2), 63.43 (d, JC–P = 6.9 Hz, OCH2), 123.07 (d, JC–P = 6.3 Hz,
=CH), 126.57 (Ar-CH), 127.68 (Ar-CH), 128.35 (Ar-CH), 128.61
(Ar-CH), 128.94 (Ar-CH), 132.34 (d, JC–P = 9.2 Hz, =CHPh),
135.60 (Ar-Cq), 136.96 (Ar-Cq), 166.21 (d, JC–P = 7.5 Hz, C=O).
MS (ESI): m/z (%) = 316 (100) [M + H+], 318 (31) [M + H+ + 2].
31P NMR (121 MHz): d = 21.70.
MS (ESI): m/z (%) = 400 (100) [M + H+].
Dimethyl (Benzylamino)[(1R,5S)-6,6-dimethylbicyc-
lo[3.1.1]hept-2-en-2-yl]methylphosphonate (17)
A minor side product recovered as an inseparable mixture of two di-
astereomers in a 1:1.2 ratio when the reaction was carried out at
20 °C and stirred for 45 min prior to the addition of trialkyl phos-
phite.
Anal. Calcd for C22H26NO4P: C, 66.15; H, 5.56; N, 3.51. Found: C,
66.07; H, 5.58; N, 3.50.
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

3610
K. Moonen, C. V. Stevens
PAPER
Dimethyl 1-Benzyl-4-oxo-2-[(E)-2-phenylethenyl]-2-azetidi-
nylphosphonate (10b)
134.33 (d, JC–P = 9.2 Hz, =CHPh), 135.66 (Ar-Cq), 165.39 (d, JC–P =
8.1 Hz, C=O).
Mp 115–117 °C; Rf 0.24 (EtOAc–petroleum ether–MeOH,
78:20:2); yield: 75%.
IR (KBr): 1754, 1252, 1056, 1022 cm–1.
1H NMR (300 MHz): d = 3.08 (1 H, dd, CHAHBCO, JAB = 14.6 Hz,
31P NMR (121 MHz): d = 24.75.
MS (ESI): m/z (%) = 324 (100) [M + H+].
Anal. Calcd for C16H22NO4P: C, 59.44; H, 6.86; N, 4.33. Found: C,
59.55; H, 6.89, N, 4.30.
JH–P = 5.8 Hz), 3.47 (1 H, dd, CHAHBCO, JAB = 14.6 Hz, JH–P
8.3 Hz), 3.75 (3 H, d, JH–P = 10.5 Hz, OCH3), 3.76 (3 H, d, JH–P
=
=
Dimethyl 4-Oxo-1-phenyl-2-[(E)-2-phenylethenyl]-2-azetidi-
nylphosphonate (10e)
Rf 0.21 (EtOAc); yield: 90%.
IR (neat): 1760, 1253, 1059, 1032 cm–1.
10.5 Hz, OCH3), 4.39 (1 H, d, JAB = 15.3 Hz, CHAHBPh), 4.74 (1 H,
d, JAB = 15.3 Hz, CHAHBPh), 6.18 (1 H, dd, Jtrans = 16.2 Hz, JH–P
=
8.5 Hz, =CH), 6.52 (1 H, dd, Jtrans = 16.2 Hz, JH–P = 3.3 Hz,
=CHPh), 7.08–7.44 (10 H, m, Ar-CH).
1H NMR (300 MHz): d = 3.20 (1 H, dd, JAB = 15.3 Hz, JH–P
5.8 Hz, CHAHB), 3.63 (1 H, dd, JAB = 15.3 Hz, JH–P = 8.0 Hz,
CHAHB), 3.74 (3 H, d, JH–P = 10.7 Hz, OCH3), 3.82 (3 H, d, JH–P
11.6 Hz, OCH3), 6.59 (1 H, dd, Jtrans = 16.2 Hz, JH–P = 9.4 Hz,
=CH), 6.84 (1 H, dd, Jtrans = 16.2 Hz, JH–P = 2.8 Hz, =CHPh), 7.11
(1 H, td, J = 7.4 Hz, J = 1.1 Hz, p-PhN), 7.24–7.39 (7 H, m, Ar-
CH), 7.80 (2 H, d, J = 8.0 Hz, o-PhN).
13C NMR (75 MHz): d = 49.42 (CH2), 53.51 (d, JC–P = 6.9 Hz,
OCH3), 54.43 (d, JC–P = 6.9 Hz, OCH3), 59.82 (d, JC–P = 168.5 Hz,
PCq), 118.08 (2 × o-PhN), 122.21 (d, JC–P = 6.9 Hz, =CH), 124.45
(p-PhN), 126.80 (2 × Ar-CH), 128.65 (ArCH), 128.71 (2 × Ar-CH),
129.06 (2 × Ar-CH), 134.25 (d, JC–P = 9.2 Hz, =CHPh), 135.38 (Ar-
Cq), 137.40 (Ar-Cq), 163.41 (d, JC–P = 8.1 Hz, C=O).
=
13C NMR (75 MHz): d = 45.84 (CH2Ph), 47.87 (CH2CO), 53.52,
53.62, 53.85, 53.94 (OCH3), 59.34 (d, JC–P = 167.3 Hz, CqP),
122.74 (d, JC–P = 6.9 Hz, =CH), 126,58 (2 × Ar-CH), 127,70 (Ar-
CH), 128.41 (Ar-CH), 128.56 (2 × Ar-CH), 128.92 (2 × Ar-CH)
128.94 (2 × Ar-CH), 134.20 (d, JC–P = 9.2 Hz, =CHPh), 135.40 (Ar-
Cq), 136.70 (Ar-Cq), 166.06 (d, JC–P = 6.9 Hz, C=O).
31P NMR (121 MHz): d = 24.01.
MS (ESI): m/z (%) = 372 (100), [M + H+].
=
Anal. Calcd for C20H22NO4P: C, 64.68; H, 5.97; N, 3.77. Found: C,
64.78; H, 5.99; N, 3.79.
Dimethyl 1-Allyl-4-oxo-2-[(E)-2-phenylethenyl]-2-azetidinyl-
phosphonate (10c)
Rf 0.23 (EtOAc); yield: 62%.
IR (neat): 1760, 1253, 1053, 1031 cm–1.
31P NMR (121 MHz): d = 24.19.
MS (ESI): m/z (%) = 358 (100) [M + H+].
Anal. Calcd for C19H20NO4P: C, 63.86; H, 5.64; N, 3.92. Found: C,
63.72; H, 5.67; N, 3.91.
1H NMR (300 MHz): d = 3.07 (1 H, dd, JAB = 14.6 Hz, JH–P
=
5.8 Hz, CHAHBC=O), 3.44 (1 H, dd, JAB = 14.6 Hz, JH–P = 8.0 Hz,
CHAHBC=O), 3.83 (3 H, d, JH–P = 10.5 Hz, OCH3), 3.85 (3 H, d,
JH–P = 10.5 Hz, OCH3), 3.88–4.12 (2 H, m, CH2N), 5.24 (1 H, dd,
Jcis = 10.2 Hz, J = 1.1 Hz, =CHAHB), 5.31 (1 H, dd, Jtrans = 17.1 Hz,
J = 1.4 Hz, =CHAHB), 6.03–5.91 (1 H, m, CH =CH2), 6.47 (1 H, dd,
Jtrans = 16.2 Hz, JH–P = 8.3 Hz, =CH), 6.79 (1 H, dd, Jtrans = 16.2 Hz,
JH–P = 3.6 Hz, =CHPh), 7.27–7.42 (5 H, m, Ar-CH).
Dimethyl 1-Allyl-2-(2-furyl)-4-oxo-2-azetidinylphosphonate
(10f)
Rf 0.20 (EtOAc–petroleum ether, 4:1); yield: 55%.
IR (neat): 1764, 1645, 1260, 1055, 1036 cm–1.
1H NMR (300 MHz): d = 3.46 (1 H, dd, JAB = 14.7 Hz, JH–P
=
13C NMR (75 MHz): d = 44.97 (CH2N), 47.85 (CH2C=O), 53.79 (d,
JC–P = 7.5 Hz, OCH3), 54.07 (d, JC–P = 6.9 Hz, OCH3), 58.88 (d,
JC–P = 167.3 Hz, PCq), 118.35 (=CH2), 123.02 (d, JC–P = 6.9 Hz,
=CH), 126.81 (2 × Ar-CH), 128.68 (Ar-CH), 128.84 (2 × Ar-CH),
132.57 (CH =CH2), 134.18 (d, JC–P = 9.2 Hz, =CHPh), 135.62 (d,
JC–P = 1.7 Hz, Ar-Cq), 165.97 (d, JC–P = 7.5 Hz, C=O).
31P NMR (121 MHz): d = 24.23.
MS (ESI): m/z (%) = 322 (100) [M + H+].
7.8 Hz, CHAHBC=O), 3.53 (1 H, dd, JAB = 14.7 Hz, JH–P = 6.1 Hz,
CHAHBC=O), 3.79 (3 H, d, JH–P = 10.7 Hz, OCH3), 3.79–3.86 (1 H,
m, CHAHBN), 3.86 (3 H, d, JH–P = 10.7 Hz, OCH3), 3.95 (1 H, dd,
JAB = 16.0 Hz, J = 5.8 Hz, CHAHBN), 5.06 (1 H, dd, Jcis = 10.2 Hz,
J = 1.4 Hz, =CHAHB), 5.12 (1 H, dd, Jtrans = 17.1 Hz, J = 1.4 Hz,
=CHAHB), 5.76–5.63 (1 H, m, CH =CH2), 6.40–6.42 (1 H, m, =CH),
6.69–6.70 (1 H, m, =CHCq), 7.46–7.47 (1 H, m, =CHO).
13C NMR (75 MHz): d = 44.33 (CH2N), 46.14 (d, JC–P = 2.3 Hz,
CH2), 53.71 (d, JC–P = 6.9 Hz, OCH3), 54.12 (d, JC–P = 5.8 Hz,
OCH3), 54.64 (d, JC–P = 174.2 Hz, PCq), 111.03 (CH =CH), 111.76
(d, JC–P = 2.3 Hz, CH =Cq), 117.78 (=CH2), 131.66 (CH =CH2),
143.35 (=CHO), 147.28 (d, JC–P = 18.5 Hz, OC =CH), 166.03 (d,
JC–P = 8.1 Hz, C=O).
Anal. Calcd for C16H20NO4P: C, 59.81; H, 6.27; N, 4.36. Found: C,
59.59; H, 6.30; N, 4.38.
Dimethyl 1-Isopropyl-4-oxo-2-[(E)-2-phenylethenyl]-2-azetidi-
nylphosphonate (10d)
Rf 0.22 (EtOAc); yield: 85%.
IR (neat): 1752, 1252, 1055, 1031 cm–1.
31P NMR (121 MHz): d = 22.06.
MS (ESI): m/z (%) = 203 (100), 286 (24) [M + H+].
Anal. Calcd for C12H16NO5P: C, 50.53; H, 5.65; N, 4.91. Found: C,
50.39; H, 5.69; N, 4.93.
1H NMR (300 MHz): d = 1.43 (3 H, d, J = 6.9 Hz, CH3), 1,45 (3 H,
d, J = 6.9 Hz, CH3), 2.96 (1 H, dd, JAB = 14.6 Hz, JH–P = 5.5 Hz,
CHAHB), 3.32 (1 H, dd, JAB = 14.6 Hz, JH–P = 7.7 Hz, CHAHB), 3.59
(1 H, septet, J = 6.9 Hz, CH), 3.81 (3 H, d, JH–P = 9.1 Hz, OCH3),
3.85 (3 H, d, JH–P = 9.4 Hz, OCH3), 6.43 (1 H, dd, Jtrans = 16.2 Hz,
JH–P = 10.2 Hz, =CH), 6.84 (1 H, dd, Jtrans = 16.1 Hz, JH–P = 3.0 Hz,
=CHPh), 7.26–7.42 (5 H, m, Ar-CH).
13C NMR (75 MHz): d = 20.87 (CH3), 22.14 (CH3), 47.13 (CH2),
47.49 (CH), 53.83 (d, JC–P = 7.2 Hz, OCH3), 53.92 (d, JC–P = 7.2 Hz,
OCH3), 58.06 (d, JC–P = 167.9 Hz, Cq), 123.41 (d, JC–P = 8.1 Hz,
=CH), 126.79 (2 × Ar-CH), 128.70 (Ar-CH), 128.86 (2 × Ar-CH),
Dimethyl-1-benzyl-2-(2-furyl)-4-oxo-2-azetidinylphosphonate
(10g)
Rf 0.29 (EtOAc–petroleum ether, 4:1); yield: 99%.
IR (neat): 1754, 1261 cm–1.
1H NMR (270 MHz): d = 3.48 (1 H, dd, JAB = 14,5 Hz, JH–P
=
7.9 Hz, CHAHBC=O), 3.56 (1 H, dd, JAB = 14.5 Hz, JH–P = 5.9 Hz,
CHAHBC=O), 3.68 (6 H, d, JH–P = 10.9 Hz, OCH3), 4.42 (2 H, s,
CH2Ph), 6,28 (1 H, t, J = 1,7 Hz, =CH), 6.59 (1 H, dd, J = 1,7 Hz,
J = 1.0 Hz, =CH), 7.15–7.21 (5 H, m, Ar-CH), 7.30 (1 H, s, =CHO).
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of N-Chloroacetyl 1-Aminoalkyl Phosphonates
3611
13C NMR (68 MHz): d = 45.89 (CH2Ph), 46.07 (CH2), 53.54 (d,
JC–P = 8.6 Hz, OCH3), 53.84 (d, JC–P = 7.3 Hz, OCH3), 54.75 (d,
JC–P = 173.4 Hz, NCqP), 110.83 (=CH), 111.93 (=CH), 127.24,
128.19 (2 C), 128.44 (2 C) (Ar-CH), 135.83 (Ar-Cq), 143.34
N-Benzyl-2-chloro-N-(2-methyl-1-propenyl)acetamide (15)
A solution of imine 6l (0.81 g, 5 mmol) in THF (10 mL) was stirred
in a round bottom flask under a nitrogen atmosphere at r.t. Then
chloroacetyl chloride (0.57 g, 5 mmol) was added dropwise using a
syringe. The mixture was stirred for 30 min at r.t. and then refluxed
for a further 2 h. Finally, the solvent is removed under reduced pres-
sure and the enamide can be recovered as white crystals.
(=CHO), 146.79 (d, JC–P = 19.5 Hz, =CqO), 166.21 (d, JC–P
=
8.6 Hz, C=O).
31P NMR (109 MHz): d = 21.36
Mp 96–97 °C; yield: 89%.
IR (KBr): 1661 (br) cm–1.
MS (EI, 70 eV): m/z (%) = 337 (6), 231 (21), 228 (17), 227 (100),
203 (14), 173 (12), 94 (10), 93 (10), 91 (59), 65 (9).
Anal. Calcd for C16H18NO5P: C, 57.31; H, 5.41; N, 4.18. Found: C,
57.43; H, 5.39; N, 4.19.
1H NMR (300 MHz, CDCl3): d = 1.40 (3 H, d, J = 1.2 Hz, CH3),
1.68 (3 H, d, J = 1.2 Hz, CH3), 4.03 (2 H, s, CH2Cl), 4.61 (2 H, s,
CH2N), 5.79–5.81 (1 H, m, =CH), 7.25–7.31 (5 H, m, Ar-CH).
Dimethyl-1-phenyl-2-(2-furyl)-4-oxo-2-azetidinylphosphonate
(10h)
Rf 0.26 (EtOAc–petroleum ether, 4:1); yield: 89%.
IR (neat): 1762, 1260 cm–1.
13C NMR (75 MHz, CDCl3): d = 17.34 (CH3), 21.74 (CH3), 42.23
(CH2Cl), 51.37 (CH2N), 121.98 (=CH), 127.49 (Ar-H), 128.39
(2 × Ar-CH), 128.80 (2 × Ar-CH), 136.41 Ar-Cq), 138.73 (=Cq),
166.42 (C=O).
1H NMR (270 MHz): d = 3.60 (1 H, dd, JAB = 9.2 Hz, JH–P = 2.6 Hz,
CHAHBC=O), 3.65 (1 H, dd, JAB = 9.2 Hz, JH–P = 4.3 Hz, CHAH-
MS (ESI): m/z (%) = 238 (100) [M + H+], 240 (39) [M + H+ + 2].
BC=O), 3.74 (3 H, d, JH–P = 10.6 Hz, OCH3), 3.80 (3 H, d, JH–P
=
Acknowledgment
10.9 Hz, OCH3), 6.39 (1 H, dd, J = 1.7 Hz, J = 2.0 Hz, =CH), 6.88
(1 H, d, J = 3.3 Hz, =CH), 7.03–7.08 (1 H, Ar-CH), 7.23–7.34 (2 H,
m, Ar-CH), 7.42 (1 H, d, J = 1.0 Hz, =CHO), 7.64 (1 H, m, Ar-CH),
7.66 (1 H, m, Ar-CH).
Kristof Moonen wishes to thank the Fund for Scientific Research,
Flanders (FWO–Vlaanderen) for financial support.
13C NMR (68 MHz): d = 47.56 (d, JC–P = 2.4 Hz, CH2C=O), 53.66
(d, JC–P = 7.3 Hz, OCH3), 54.52 (d, JC–P = 7.3 Hz, OCH3), 55.91 (d,
JC–P = 172.1 Hz, NCqP), 110.91 (=CH), 112.54 (=CH), 117.79 (2
C), 124.49, 128.91 (2 C, Ar-CH), 137.36 (Ar-Cq), 143.66 (=CHO),
146.44 (d, JC–P = 20.8 Hz, =CqO), 163.77 (d, JC–P = 7.4 Hz, C=O).
References
(1) (a) Ghelfi, F.; Stevens, C. V.; Laureyn, I.; Van Meenen, E.;
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2003, 59, 1147. (b) Vanderhoydonck, B.; Stevens, C. V.
Synthesis 2004, 722.
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Georgopapadakou, N. H.; Koster, W. H.; Liu, W. C.; Parker,
W. L.; Principe, P. A.; Rathnum, M. L.; Slusarchyk, W. A.;
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(8) For a review on phosphonylated aza-heterocycles see:
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31P NMR (109 MHz): d = 21.80.
MS (EI, 70 eV): m/z (%) = 322 (3), 205 (20), 204 (66), 203 (40), 174
(100), 173 (61), 171 (95), 120 (11), 110 (30), 96 (37), 95 (43), 94
(35), 77 (62).
Anal. Calcd for C15H16NO5P: C, 56.08; H, 5.02; N, 4.36. Found: C,
56.24; H, 5.05; N, 4.37.
Dimethyl-1-benzyl-4-oxo-2-phenyl-2-azetidinylphosphonate
(10i)
Rf 0.23 (EtOAc–petroleum ether, 7:3); yield: 92%.
IR (neat): 1759, 1251 cm–1.
1H NMR (270 MHz): d = 3.24 (1 H, dd, JAB = 14.8 Hz, JH–P
6.3 Hz, CHAHBC=O), 3.60 (3 H, d, JH–P = 9.6 Hz, OCH3), 3.63 (1 H,
dd, JAB = 14.8 Hz, JH–P = 6.3 Hz, CHAHBC=O), 3.64 (3 H, d, JH–P
=
=
9.6 Hz, OCH3), 4.60 (1 H, d, JAB = 15.5 Hz, NCHAHB), 4.74 (1 H,
d, JAB = 15.5 Hz, NCHAHB), 7.17–7.41 (10 H, m, Ar-CH).
13C NMR (68 MHz): d = 47.04 (NCH2), 48.52 (CH2C=O), 53.53 (d,
JC–P = 7.3 Hz, OCH3), 53.95 (d, JC–P = 6.1 Hz, OCH3), 61.28 (d,
JC–P = 163.5 Hz, Cq), 127.17, 127.24, 127.42, 128.35, 128.43 (2 C),
128.50 (2 C, Ar-CH), 135.50 (d, JC–P = 8.6 Hz, Ar-Cq), 136.55 (Ar-
Cq), 167.19 (C=O, JC–P = 7.3 Hz).
31P NMR (109 MHz): d = 23.84.
MS (EI, 70 eV): m/z (%) = 346 (5), 240 (27), 236 (100), 103 (15),
92 (16), 91 (76), 77 (12), 65 (12).
Anal. Calcd for C18H20NO4P: C, 62.60; H, 5.84; N, 4.06. Found: C,
62.48; H, 5.81; N, 4.04.
Dimethyl 1-(Dimethoxyphosphonyl)ethenylphosphate (14a)
and Diethyl 1-(Diethoxyphosphonyl)ethenylphosphate (14b)
Both were found as side products in the reaction of imines with
chloroacetyl chloride and trialkyl phosphite. Their spectral data
were in accordance with earlier published results.14
Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York

3612
K. Moonen, C. V. Stevens
PAPER
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Synthesis 2005, No. 20, 3603–3612 © Thieme Stuttgart · New York