Bicyclic organophosphorus amides. Nucleophilic cleavage of 1-oxo-2,3- benzo-10-phenyl-4,7,10-triaza-1λ5-phosphabicyclo[5.3.0]decane and its p- anisyl analogues

Article abstract of DOI:10.1039/a904771i

Methanolysis of the title substrates leads to different products depending on the conditions: in the presence of HCl both P-N bonds are broken yielding a non-cyclic phosphonic diester while the MeO^- ion reacts selectively breaking the P-N(Ar) bond and yielding a cyclic, seven-membered phosphonic amidoester.

Full text of DOI:10.1039/a904771i

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656 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 656^657y
Bicyclic Organophosphorus Amides.
Nucleophilic Cleavage of 1-Oxo-2,3-benzo-
10-phenyl-4,7,10-triaza-1k5-phosphabicyclo-
[5.3.0]decane and its -Anisyl Analogues
Zhengjie He and Tomasz A. Modro*
Centre for Heteroatom Chemistry, Department of Chemistry, University of Pretoria, Pretoria
0002, South Africa
Methanolysis of the title substrates leads to different products depending on the conditions: in the presence of
HCl both P^N bonds are broken yielding a non-cyclic phosphonic diester while the MeO ion reacts selectively
breaking the P^N(Ar) bond and yielding a cyclic, seven-membered phosphonic amidoester.
Recently we reported the preparation of a new type of
bicyclic phosphonic diamide 1 via the lithiation-induced
N!C migration of phosphorus in a bicyclic phosphoric
triamide.1 Now we report the nucleophilic cleavage of
the P^N bond(s) in 1 by methanol leading to new cyclic
and non-cyclic phosphonic derivatives. Methanolysis of
Ar
O
N
O
ROH/H+
Ar
P
Ar
P
N
N
N
OMe
Ar
N
+
N
H
H
5
one of the two P^N bonds in
seven-membered 2, or a ten-membered 3 cyclic phosphonic
1 can lead to a
Scheme 2
amidoester (Scheme 1).
of 1, the situation is di¡erent. The most basic atom in
the molecule is the amine nitrogen N(4), protonation of
which does not catalyse the P^N (amide) bond cleavage.
We believe that the reaction involves an associative step
of addition of the MeOH molecule to the conjugate acid
of 1, followed by the proton transfer-assisted cleavage of
the P^N(10) bond in the PV intermediate. The amidoester
2 formed in the ¢rst reaction would be expected to be acti-
vated towards substitution relative to 1 (exchange of one
of the nitrogen substituents at P for the OMe group),
and thus would undergo further methanolysis to the diester
4. The observed selectivity in the ¢rst product-determining
step (formation of 2, but not of 3) can be explained in terms
of the stereoelectronic e¡ects. The PV intermediate with the
N(10) atom occupying the apical position [required for
the ¢rst cleavage of the P^N (Ar) bond] is much less
strained relative to the conformer with the equatorial
location of the N(10) atom because in the latter case the
seven-membered ring has to accommodate the 908
apical^equatorial (as opposed to the 1208 equatorial^
equatorial) bond angle in the tbp structure of the
O
OMe
ArNH
P
N
R
R
N
Ar
O
P
N
N
H
R
2
+ MeOH
O
OMe
N
Ar
P
N
H
N
1
H
N
H
3
Scheme 1
Acid-catalysed alcoholysis of
a
similar bicyclic
phosphotriamidate proceeds with a selective cleavage of
the P^N (bridgehead) bond yielding
a
monocyclic
eight-membered phosphoric diamidoester.2 In the case of
1 we have found that the solvolysis is non-selective and
leads to the cleavage of both P^N bonds, i.e. to the opening
of both heterocyclic rings.
intermediate.
The
proposed
mechanism
for
the
acid-catalysed methanolysis of 1 via the ¢rst cleavage of
Although both amide bonds are broken under those con-
ditions, we think that the P^N(10) bond is cleaved ¢rst
yielding 2, which then undergoes subsequent solvolysis to
4; both steps occurring with comparable rates. In one case
(1a) we were able to isolate small quantities of the inter-
mediate product 2a, identical to that prepared from 1a
under basic conditions (vide infra). The product, when
subjected to the methanolysis under the same conditions
as for 1a, yielded 4a at approximately the same rate as
for the direct formation of 4a. The ¢rst cleavage of the
P^N(Ar), and not the P^N (bridgehead) bond in 1 is in con-
trast with the acid-catalysed solvolysis of its precursor 5,
where the P^N (bridgehead) bond was cleaved selectively,
giving the eight-membered monocyclic product (Scheme 2).2
In the latter case the selectivity was explained in terms of
the greater basicity of the bridgehead nitrogen.2 In the case
the ¢ve-membered ring is shown in Scheme 3.
R
O
Ar
N
N
P
R
H +
MeOH
MeO
1
HO
P
N
H
H
N
H
N
H
+
+
N
Ar
P(O)(OMe)2
–H +
H
N
MeOH/H +
R
2
N
H
NHAr
4a R = H; Ar = Ph
b R = OMe; Ar = 4-MeOC6H4
c R = OMe; Ar = Ph
* To receive any correspondence.
This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).
Scheme 3

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J. CHEM. RESEARCH (S), 1999 657
The crude product was puri®ed by column chromatography (CHCl3±
acetone, 1 : 1). 1a, white solid (0.51 g, 85%); mp 236.4^237.7 8C (from
THF); dP 23.7 (Found: C, 64.61; H, 6.17; N, 14.08. C16H18N3OP
requires C, 64.21; H, 6.06; N, 14.04%). 1b, white solid (0.45 g, 63%);
mp 201.8^203 8C (from CHCl3 acetone, 1:1); dp 23.3 (Found: C,
59.16; H, 6.15; N, 11.50. C18H22N3O3P requires C, 60.16; H, 6.17; N,
11.69%). 1c, white solid (0.39 g, 59%); mp 208.4^209.0 8C (from
CHCl3 acetone, 1 : 1), dP 24.0 (Found: C, 61.80; H, 6.19; N, 12.83.
Unlike the acidic methanolysis, reaction of 1 with sodium
methoxide in methanol proved to be fully regioselective and
yielded the monocyclic seven-membered phosphonic
amidoesters
2
(2a, R ˆ H; Ar ˆ Ph; 2b, R ˆ OMe;
Ar ˆ 4-MeOC6H4; 2c, R ˆ OMe; Ar ˆ Ph) as the exclusive
products. Again, we propose that the observed
regioselectivity is a consequence of the generally accepted
mechanism of the nucleophilic substitution at phosphorus
in cyclic organophosphorus amides and of the relative stab-
ility of the corresponding intermediates. Extensive work by
Hudson and co-workers3 and Hall and Inch4 on the base
hydrolysis of cyclic organophosphorus amidoesters demon-
strated that the rates and products of the reaction can
be explained in terms of an addition^elimination mechanism
in which a PV intermediate can undergo pseudorotation
before the bond breaking product-determining step. As dis-
cussed above for the acidic methanolysis, application of
the mechanism to the reaction of 1 with MeO ion can lead
to two isomeric PV intermediates (A and B) as the direct
C
17H20N3O2P requires C, 62.00; H, 6.12; N, 12.76%).
Acid-catalysed Methanolysis of 1. General Procedure.öA solution
of 1 (1.0 mmol) in methanol (30 ml) containing anhydrous HCl
(2.2 mmol) was kept at room temperature and the reaction progress
was monitored by recording the 31P NMR spectrum of the solution.
When the signal derived from 1 had almost disappeared the solution
was evaporated under reduced pressure. Chloroform (50 ml) was
added, followed by ¢nely powdered K2CO3 (1.6 g). After ¢ltration
(or centrifugation), the chloroform solution was washed with water
(3  5 ml), dried ‰Na2SO4† and evaporated under reduced pressure.
Column chromatography (CHCl3öethyl acetate, 1 : 1, followed by
CHCl3^MeOH, 20 : 1) yielded the following products. From 1a
(reaction time 35 days, 50% conversion after approx. 5 days):
unreacted 1a (5%), 2a (0.02 g, 6%); viscous oil solidifying on standing,
NMR spectra identical to those of 2a obtained in base-catalysed
methanolysis (vide supra), and 4a (0.22 g, 61%); viscous oil; dP 25.7
(Found: C, 59.10; H, 7.30; N, 11.25. C18H26N3O3P requires C, 59.49;
H, 7.21; N, 11.56%). From 1b (reaction time 44 days, 50% conversion
after approx. 10 days): unreacted 1b (15%) and 4b (0.28 g, 67%);
viscous oil; dP 24.9 (Found: C, 56.52; H, 7.20; N, 9.58.
C20H30N3O5P requires C, 56.73; H, 7.14; N, 9.92%). From 1c
(reaction time 43 days, 50% conversion after approx. 7 days):
unreacted 1c (7%) and 4c (0.25 g, 64%); viscous oil; dP 24.8 (Found:
C, 57.59; H, 7.20; N, 10.55. C19H28N3O4P requires C, 58.00; H, 7.17;
N, 10.68%).
precursors of products
2
and
3
(Scheme 4). The
Carom Nbridgehead bond angle in 1, as shown in the X-ray
P
crystal structure, is 107.78.1 Location of the bridgehead
nitrogen in the apical position (intermediate B) involves
contraction of that angle by 17.78, while the equatorial
location of the same atom (intermediate A) results in
expanding the angle by 12.398. It seems that the
seven-membered ring in the substrate molecule accommo-
dates the latter angular change in preference to the possible
contraction, particularly in view of the restrictions existing
already due to the 2,3-benzo substituent.
Base-catalysed Methanolysis of 1. General Procedure.öA solution
of 1 (1.0 mmol) in methanol (15 ml) containing sodium methoxide
(3.0 mmol) was kept at 50^55 8C and the progress of the reaction
was monitored by 31P NMR spectroscopy. The reaction was stopped
at 60±80% conversion, since further incubation led to the formation
of some unidenti®ed, phosphorus-containing products. Finely
powdered NH4Cl (6.0 mmol) was added to the solution, the solvent
was evaporated under reduced pressure, chloroform (50 ml) was
added and the solution was washed with water and dried (Na2SO4†.
After evaporation of the solvent the crude product was puri®ed by
column chromatography (CHCl3±AcOEt, 1 : 1). The following prod-
ucts were obtained. From 1a (reaction time 42 days, 50% conversion
after approx. 36 days): unreacted 1a (38%) and 2a (0.11 g, 34%);
colourless needles, mp 125.4^126.8 8C (from THF±hexane, 1 : 2);
dP 27.9 (Found: C, 61.52; H, 6.85; N, 12.48. C17H22N3O2P requires
C, 61.62; H, 6.69; N, 12.68%). From 1b (reaction time 35 days, 50%
conversion after approx. 27 days): unreacted 1b (22%) and 2b (0.08 g,
21%); viscous oil; dP 27.7 (Found: C, 58.01; H, 6.95; N,10.66.
C19H26N3O4P requires C, 58.30; H, 6.70; N, 10.74%). From 1c
(reaction time 35 days, 50% conversion after approx. 25 days):
unreacted 1c (23%) and 2c (0.15 g, 42%); viscous oil; dP 27.8 (Found:
C, 59.58; H, 7.01; N, 11.50. C18H24N3O3P requires C, 59.82; H, 6.69;
N, 11.63%).
Under the basic conditions of the methanolysis, the prod-
ucts 2 are stable and do not undergo further reaction. This
behaviour is in agreement with the known resistance of
the tertiary, non-strained phosphoramidates to undergo
base-catalysed cleavage.5
R
OMe
Ar
O–
R
N
P
MeO–
MeO
1
–O
P
N
N
H
N
N
N
H
Ar
B
A
H +
H +
3
2
Scheme 4
Experimental
Financial assistance from the University of Pretoria and
the Foundation for Research Development is gratefully
acknowledged.
NMR spectra were recorded on a Bruker AC 300 spectrometer in
CDCl3 and d values are relative to SiMe4 (1H, 13C) or 85%
H3PO4
(
31P). 13C NMR spectra were proton-decoupled, but the
proton-coupled spectra gave the expected patterns of signals. Proton
and 13C NMR spectra were in full agreement with the indicated struc-
tures for all the prepared compounds. For column chromatography
Merck Kieselgel 60 (0.063^0.200 mm) was used as a stationary phase.
Elemental analyses (C, H, N) were performed at the Chemistry
Department, University of Cape Town. Solvents and commercially
available reagents were puri¢ed by conventional methods immediate-
ly before use. Bicyclic substrates 1 were prepared from the corre-
sponding bicyclic triamidates 5.1
General Procedure for the Preparation of 1.öA solution of BuLi
(10.0 mmol, 1.6 M solution in hexane) was added by means of a syr-
inge to a stirred and cooled to 78 8C solution of 5 (0.2 mmol) in
anhydrous THF (100 ml) under an atmosphere of dry nitrogen.
The solution was stirred at 78 8C for 1 h, warmed to room
temperature and stirred for an additional 5 h. Methanol (1±2 ml)
was added, followed by CHCl3 (100 ml), the solution was washed
with water, dried (Na2SO4) and evaporated under reduced pressure.
Received, 15th June 1999; Accepted, 19th July 1999
Paper E/9/04771I
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