Simple and novel synthesis of 3-(thio)phosphoryl-β-lactams by radical cyclization

Article abstract of DOI:10.1039/c3nj00192j

Radical cyclization of phosphono-acetenamides promoted by manganese(iii) acetate leads exclusively to the formation of 3-phosphoryl-β-lactams. The thiophosphoryl analogues were also prepared using this method. In particular, the presented protocol does not require the use of noble metals, while comparable methods do.

Full text of DOI:10.1039/c3nj00192j

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R1
R2
X
O
X
P
Ph
R1
R2
Mn(OAc)3*H2O 2 eq
AcOH, reflux
P
Ph
tBu
N
tBu
N
O
R1, R2 = alkoxyl, aryl; X = O, S
Radical cyclization of phosphonoꢀacetenamides promoted by manganese (III) acetate leads
exclusively to the formation of 3ꢀphosphorylꢀβꢀlactams.

New Journal of Chemistry
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A simple and novel synthesis of 3ꢀ(thio)phosphorylꢀβꢀlactams by radical
cyclization
Paweł Pundaa, Sławomir Makowiec*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Radical cyclization of phosphonoꢀacetenamides promoted by manganese (III) acetate leads exclusively to
the formation of 3ꢀphosphorylꢀβꢀlactams. The thiophosphoryl analogues were also prepared using this
method. In particular, the presented protocol doesn’t require the use of nobel metals, while comparable
methods do.
10
Modification of the βꢀlactams ring is still the focus of organic
chemists, mainly due to the wellꢀknown antimicrobial activity of
this class of compounds1. However, this is not only the biological
activity of azetidones that attracts attention; βꢀlactams also
exhibit: cholesterol absorption activity2, antiꢀcancer activity3,
literature.
O
P
O
O
O
R1
R2
+
Cl
O
O
O
O
R2
P
R1
O
O
O
P
O
15 muscarinic agonist properties4 or inhibition of human leukocyte
elastase responsible for autoimmune diseases5. In light of the βꢀ
lactam synthon method developed by Ojima, synthetic
application of azetidones have shown increasing importance in
synthetic organic chemistry6. Recently we have focused on the
20 carbamoyl and thiocarbamoyl modification of the azetidone ring
in position 3, based on Meldrum’s acid derivative type of
Staudinger cycloaddition7. As an extension of this topic we have
undertaken attempts to develop a similar method for the
preparation of 3ꢀphosophoryl βꢀlactams. In the chemical
25 literature, three methods can be found for the preparation of 3ꢀ
phosophoryl βꢀlactams: first, the simplest involving direct
metalation of the αꢀposition in 3ꢀunsubstitiuted βꢀlactams
following by reaction with three coordinated phosphorus
electrophiles and oxidation to five coordinated phosphorus.
30 However, this process sometimes leads to a mixture of mono and
diꢀphosphorylated products2c, 8; another promising method is a
Staudinger type cycloaddition of imines with ketenes generated
from the phosphonoꢀacetates activated with CDI9. Despite the
attractive simplicity this method, it is limited only to reaction
35 with Nꢀaryl imines. The last known method for the preparation of
3ꢀphosophoryl βꢀlactams is based on rhodium catalysed
intramolecular CꢀH insertion of carbenes generated from
diazocompounds10. However, the carbene insertion process
usually leads to forming a mixture of five and four membered
40 lactams and selectively 3ꢀphosophoryl βꢀlactams can be obtained
only when specific substituents on nitrogen are present11.
C
O
O
R1
R2
O
O
P
R1
R2
DCC, DMAP
+
ꢀ
O
OH
H
1
R1, R2 = alkoxyl, aryl
[ox]
Ph
O
Ph
P
O
O
O
O
O
O
O
P
Ph
Ph
DMAP
Ph
Ph
H2O
+
Cl
P
+
H
O
O
O
O
O
50
Scheme 1 Attempts for preparation of 5ꢀphosphoryloꢀ2,2ꢀdimethylꢀ1,3ꢀ
dioxaneꢀ4,6ꢀdione 1 a potential source of phosphorylketenes
Hence we undertook a systematical study in the preparation of
55 any 5ꢀphosphorylꢀ2,2ꢀdimethylꢀ1,3ꢀdioxaneꢀ4,6ꢀdione (1);
unfortunately, the reactions with five coordinated phosphorus
electrophiles did not give the desired product, while reaction with
three coordinated derivative means diphenyl chlorophosphine
lead to an unstable compound, which decomposes during
60 purification to phosphine oxide and Meldrum’s acid (Scheme 1).
These unpublished and unsatisfactory attempts for preparation of
5ꢀphosphoryloꢀ2,2ꢀdimethylꢀ1,3ꢀdioxaneꢀ4,6ꢀdione forced us to
search a new strategy for the synthesis of 3ꢀphosophoryl βꢀ
lactams. On the other hand, an alternative to the typical
65 Staudinger method of construction a βꢀlactam ring involves the
oxidation and radical cyclization of derivatives of acetyl
acetenamides12. However, to the best of our knowledge, this type
of reactions was never tested for the preparation of 3ꢀphosphoryl
βꢀlactams from phosphonoacetenamides, which due to different
70 position of the ketolꢀenol equilibrium, may cause problems
during oxidation.
In the light of our own experience7 it seemed obvious that a
convenient alternative approach for the synthesis of 3ꢀ
phosophoryl βꢀlactams should assume the use of 5ꢀphosphorylꢀ
45 2,2ꢀdimethylꢀ1,3ꢀdioxaneꢀ4,6ꢀdiones as a source for thermal
generation of phosphoryloketenes and subsequently their
cycloaddition to aldimines. However, no example of preparation
and reactivity of phosphoryl Meldrum’s acid is known in the
In this paper we wish to report the application of the
manganese (III) acetate as a reagent for the cyclization of
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[journal], [year], [vol], 00–00 | 1

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phosphonoꢀacetatenamides to βꢀlactams. The key substrate 3 was
obtained in the classic carbodiimide coupling of phosphonoacetic
acids with enolizable imine (Scheme 2).
cyclization of phosphonoꢀacetenamides 3 we decided to apply our
method to other models. The oxidation and subsequent
cyclization of 1,3ꢀneopentylidene 2ꢀ[methyl(2ꢀphenylpropꢀ1ꢀ
enyl)amino]ꢀ2ꢀoxoethylphosphonate (3b) leads to a high yield of
In the first experiment we oxidized diethyl 2ꢀ[methyl(2ꢀ
5
phenylpropꢀ1ꢀenyl)amino]ꢀ2ꢀoxoethylphosphonate (3a) in acetic 30 3ꢀphosophoryl βꢀlactam (Entry 7, Table 1), whereas introduction
acid with Mn(OAc)3•2H2O added in small portions to determine
the minimum required amount of oxidizer, leaving other
conditions the same as those optimal for oxidation of acetyl
acetenamides12. However, in the case of 3a we observed the rate
of one aryl group instead of alkoxyl results in a significant
decrease in yield. It should be noted that in the case of 4c, an
additional stereocenter is introduced into the molecule, causing
the formation of two pair of enantiomers, all with trans
10 of oxidation indicated as a manganese (III) colour disappearance 35 configuration in the βꢀlactam ring (H3 –H4 coupling constants
was much slower, and the yield obtained was low (Entry 1, Table
1). The next two experiments were performed with gradually
increased temperature using the theoretically required amount of
oxidizer (Entries 2, 4, Table 1) to give a significant increase in
2.4 and 2.5 Hz respectively) whereas models with achiral
phosphorus 4a, b, f gave only one pair of enantiomers. Substrates
with two PꢀC bond proved to be inert; even using a large excess
of oxidizer and prolonged time of reaction did not allow us to
15 yield. On the other hand, we decided to check if it is possible to 40 obtain cyclized product; in the reaction mixture, unreacted
replace rather expensive manganese oxidizer with CAN.
Unfortunately, using only CAN or a system with small amount of
Mn(OAc)3•2H2O with equimolar amount of CAN for
regeneration of Mn3+ allows to obtaining only low yields of the
20 desired product (Entries 5, 6, Table 1).
starting material 3d, e was still observed (Entries 9, 10, Table 1).
Positive results in the cyclization of phosphonoꢀacetenamides has
raised the question of whether 3ꢀthiophosophoryl βꢀlactams can
also be obtained by this radical cyclization. However, it is clear
45 that oxidative cyclization of thiophosphonoꢀacetenamides may
suffer from desulfurization caused by the oxidizing reagent13.
Fortunately, oxidation of O,Oꢀethyl 2ꢀ[methyl(2ꢀphenylpropꢀ1ꢀ
enyl)amino]ꢀ2ꢀoxoethylphosphonothioate 3f with Mn (III) allows
obtaining the desired 3ꢀthiophosophorylꢀβꢀlactam (4f) with 15%
50 yield; moreover, in this case 1ꢀ[3ꢀ(diethoxyphosphorothioyl)ꢀ1ꢀ
tertꢀbutylꢀ4ꢀoxoazetidinꢀ2ꢀyl]ꢀ1ꢀphenylethyl acetate (5f) with
15% yield, as a mixture of two pairs of enantiomers with a 1:2
ratio was also formed, indicating that carbocation formed after
the second oxidation has two potential ways of reaction, the first
55 with abstraction of proton, and the second, less common, leading
to the formation of acetoxy derivative of βꢀlactam.
Ph
O
O
X
P
X
P
Ph
R1
R2
R1
R2
DCC, DMAP
+
OH
N
tBu
N
tBu
2
3
Mn(OAc)3*H2O 2 eq
AcOH, reflux
R1, R2 = alkoxyl, aryl; X = O, S
R1
R2
X
R1
R2
X
OAc
Ph
P
P
Ph
Generally, for the presented method, several factors which
have a negative influence on the yield can be demonstrated.
Firstly, phosphono or phosphino substituted acetic acid are less
60 prone to enolization than their alkoxycarbonyl or acetyl
analogues, while it is well known that enolic form is necessary
for effective radical formation during manganese (III) acetate
+
N
N
tBu
O
tBu
O
5
4
(1S, 2'R, 3'R),
(1R, 2'S, 3'S),
(1R, 2'R, 3'R),
(1S, 2'S, 3'S)
(3R, 4R),
(3S, 4S)
oxidation12c, 14
.
Scheme 2 Synthesis of 3ꢀ(dialkoxyphosphoryl)ꢀβꢀlactams
25
Knowing the optimal condition for the oxidation and
65 Table 1 Cyclization of phosphonoacetenamides 3 with Mn(OAc)3•2H2O
Entry
1
2
2, 3, 4
R1
R2
X
O
O
O
O
O
O
O
O
O
O
S
Temp (°C)
70
Time (min)
Mn(OAc)3•2H2O (eq)
Yieldd (%) 4:5
22 : 0
42 : 0
30 : 0
50 : 0
4 : 0
a
a
a
a
a
a
b
c
d
e
f
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
25
10
10
10
10
10
10
10
10
120
15
15
1.2
2
1.2
2
ꢀ
0.1
2
2
2
6
2
90
3
119
119
119
119
119
119
119
119
119
119
4
5a
6b
7
11 : 0
70 : 0
34 : 0
0
OCH2C(CH3)2CH2O
8
9
MeO
tꢀBu
nꢀBu
EtO
Ph
Ph
nꢀBu
EtO
EtO
10c
11
12
0
15 : 15
7 : 0
f
EtO
S
4
a 2 eq of CAN was used, instead of Mn(OAc)3.
b 2 eq of CAN was added
c Mn(OAc)3.was added in three 2 eq portions, each after decolorization
d isolated yields
2
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50 Notes and references
Additionally, introduction of alkyl or aryl substituents on a
a
Department of Organic Chemistry, Faculty of Chemistry, Gdańsk
phosphorus atom causes a decrease in electrophilicity of the
radical, which results in the lower yield in the cyclization step
where electron rich πꢀbond is attacked.
University of Technology, Narutowicza 11/12, 80ꢀ233 Gdańsk, Poland.
Fax: 48ꢀ58ꢀ347ꢀ2694; Tel: 48ꢀ58ꢀ347ꢀ1724; Eꢀmail: mak@pg.gda.pl
† Electronic Supplementary Information (ESI) available: [Experimental
55 procedures for the preparation of compounds 3aꢀf, 4aꢀf, 5f and 6a and
their spectroscopic characterization]. See DOI: 10.1039/b000000x/
5
O
O
EtO
EtO
EtO
EtO
EtO
EtO
O
EtO
EtO
O
P
P
P
P
Ph
tBu
Ph
tBu
Mn3+
-H+
Mn3+
1
(a) T. J. Dougherty, M. J. Pucci, Antibiotic Discovery and
Development, Springer, 2012. DOI: 10.1007/978ꢀ1ꢀ4614ꢀ
1400ꢀ1; (b) R. B. Morin, M. Gorman, Chemistry and Biology
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N
N
N
N
O
O
O
tBu
O
tBu
4a
6a
60
65
Scheme 3 Subsequent oxidation of 4a
2
On the other hand, in all reactions, acetophenone as a byꢀ
10 product was observed, meaning oxidative cleavage of πꢀbond15
competes with radical formation and causes the decomposition of
the substrate. The last observed drawback is due to the
subsequent oxidation of already formed 3ꢀphosphoryl βꢀlactam.
We observed in an independent experiment that heating of 4a
15 within 2 h with 4 eq of Mn(OAc)3•2H2O leads to approx. 13%
conversion of 4a into 6a through, intramolecular aromatic radical
substitution (Scheme 3).
In summary, we have described the method for preparing 3ꢀ
phosphoryl βꢀlactams and 3ꢀthiophosphoryl βꢀlactams‡ based on
20 the use of radical cyclization of phosphonoꢀacetenamides. The
method is simple, convenient and does not require the use of
noble metals as in comparable literature methods that are known.
The obtained yields are moderate, and depends on substitution on
the phosphorus atom. Among tested oxidizers, the best results
25 was obtained with Mn(OAc)3•2H2O.
70
3
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75
4
5
80
6
7
Experimental
85
Typical procedure for the preparation of diethyl 1ꢀtertꢀbutylꢀ2ꢀ
oxoꢀ4ꢀ(1ꢀphenylvinyl)azetidinꢀ3ꢀylphosphonate (4a): To a stirred
mixture of diethyl 2ꢀ[methyl(2ꢀphenylpropꢀ1ꢀenyl)amino]ꢀ2ꢀ
30 oxoethylphosphonate (3a) (1 mmol, 0.367g ) in acetic acid (10
mL) at reflux, was added Mn(OAc)3•2H2O (2 mmol, 0.535 g).
After 10 min., reaction mixture was cooled and poured into 50mL
of ice water, and extracted with CH2Cl2 (5x20 mL). Organic layer
was washed with aqueous 5 % NaHCO3 (3x10mL), dried with
35 MgSO4 and concentrated. The residue was subject to column
chromatography over silica gel using hexanes/EtOAc (1:1) as
eluent to give 4a with 50% yield. 1H NMR (200 MHz, CDCl3): δ
(ppm) 1.24 (3 H, t, J = 6.9 Hz), 1.30 (3 H, t, J = 6.9 Hz), 1.38 (9
H, s), 3.23 (1 H, dd, JPH = 13.9 Hz, JHH = 2.4 Hz), 4.04ꢀ4.23 (4 H,
40 m), 4.66 (1 H, dd, JPH = 9.2 Hz, JHH = 2.4 Hz), 5.51 (1 H, s), 5.59
(1 H, s), 7.33ꢀ7.49 (5 H, m). 13C NMR (50 MHz, CDCl3): δ
(ppm) 16.7 (d, J2 = 3.1 Hz), 16.8 (d, J2 = 3.2 Hz), 28.3, 54.2 (d, J1
= 29.3 Hz), 55.8 (d, J2 = 2.2 Hz), 56.7, 62.8 (d, J2 = 6.5 Hz), 63.2
(d, J2 = 6.1 Hz), 115.8, 127.1, 128.7, 129.0, 139.2, 148.3 (d, J3 =
45 2.8 Hz), 162.6 (d, J2 = 6.3 Hz). HRMS (ESI): m/z [M + Na]+
calcd for C19H28NO4PNa: 388.1654; found: 388.1665.
K. Janikowska, N. Pawelska, S. Makowiec, Synthesis, 2011,
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8
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95
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Acknowledgments
We thank the Gdańsk University of Technology for financial
support (DS 020334 T. 001).
This journal is © The Royal Society of Chemistry [year]
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