Nucleophilic cleavage of 1-oxo-2,8-disubstituted-2,5,8-triaza-1λ 5-phosphabicyclo[3.3.0]octanes: A new route to eight-and five-membered heterocyclic systems

Article abstract of DOI:10.1039/a903835c

Five 1-oxo-2,8-disubstituted-2,5,8-triaza-1λ ⁵-phosphabicyclo[3.3.0]octanes 1 have been prepared and the nucleophilic cleavage of one of their P-N bonds has been studied. The acid-catalyzed alcoholysis involves in each case the cleavage the P-N(5) bond, yielding the eight-membered monocyclic diamides 2. In the base-catalyzed reaction, the N(2),N(8)-dialkyl substituted substrates 1 yielded the same products 2, while for the N(2),N(8)-diaryl derivatives the exclusive cleavage of the P-N(2) (or P-N(8)) bond was observed yielding the isomeric 1,3,2-diazaphospholidine products 3. Products 2 are stable as N(5) ammonium salts or N(5)-acyl derivatives, but as free bases they rearrange spontaneously to products 3 via the intramolecular N(5)→P nucleophilic attack accompanied with the P-N(2) (or P-N(8)) bond cleavage. The effect of the N(2)-and N(8)-substituents in 2 on the rate of the 2→3 rearrangement, as well as on the product distribution for the unsymmetrically disubstituted substrates has been investigated. The mechanism of the formation of products 3 via the rearrangement and via the direct 1→3 nucleophilic cleavage is discussed in terms of the reactivity of the attacking nucleophile, the electrophilicity of the phosphoryl center, and of the basicity of the departing amine in the P-N bond cleavage step.

Full text of DOI:10.1039/a903835c

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Nucleophilic cleavage of 1-oxo-2,8-disubstituted-2,5,8-triaza-1ꢀ5-
phosphabicyclo[3.3.0]octanes: a new route to eight- and five-
membered heterocyclic systems
Zhengjie He, Susan Laurens, Xavier Y. Mbianda, Agnes M. Modro and Tomasz A. Modro*
Centre for Heteroatom Chemistry, Department of Chemistry, University of Pretoria,
Pretoria 0002, South Africa
Received (in Cambridge, UK) 12th May 1999, Accepted 1st September 1999
Five 1-oxo-2,8-disubstituted-2,5,8-triaza-1λ5-phosphabicyclo[3.3.0]octanes 1 have been prepared and the nucleophilic
cleavage of one of their P–N bonds has been studied. The acid-catalyzed alcoholysis involves in each case the
cleavage of the P–N(5) bond, yielding the eight-membered monocyclic diamides 2. In the base-catalyzed reaction,
the N(2),N(8)-dialkyl substituted substrates 1 yielded the same products 2, while for the N(2),N(8)-diaryl derivatives
the exclusive cleavage of the P–N(2) (or P–N(8)) bond was observed yielding the isomeric 1,3,2-diazaphospholidine
products 3. Products 2 are stable as N(5) ammonium salts or N(5)-acyl derivatives, but as free bases they rearrange
spontaneously to products 3 via the intramolecular N(5)→P nucleophilic attack accompanied with the P–N(2) (or
P–N(8)) bond cleavage. The effect of the N(2)- and N(8)-substituents in 2 on the rate of the 2→3 rearrangement, as
well as on the product distribution for the unsymmetrically disubstituted substrates has been investigated. The
mechanism of the formation of products 3 via the rearrangement and via the direct 1→3 nucleophilic cleavage is
discussed in terms of the reactivity of the attacking nucleophile, the electrophilicity of the phosphoryl center, and
of the basicity of the departing amine in the P–N bond cleavage step.
A bicyclic phosphoric triamide system 1 has recently been
prepared in our laboratory1 and its chemistry is currently
being investigated. The 2,8-diaryl substituted compounds 1 (1,
R = Ar) have already demonstrated interesting chemical
behavior leading to new heterocyclic products containing
nitrogen and phosphorus incorporated in the ring skeleton. For
example, metallation-induced migration of phosphorus from
nitrogen to carbon yields new types of cyclic phosphonic and
phosphinic amides,2 and in the preceding communication we
reported the acidic alcoholysis of the 2,8-diphenyl derivative,
1a (1, R = Ph) (Scheme 1).3 The primary product, the eight-
Since the conversion 2→3 represents a new type of skeletal
rearrangement involving ring contraction, we were interested in
the mechanism of this transformation and the structural effects
on the rate of the reaction. We were also interested in the struc-
tural effects on the regioselective cleavage of the P–N bond in
1 by nucleophilic reagents other than alcohols. Consequently,
we now report the preparation of new substrates 1, the ring-
opening reactions of those products, and the reactivity of
products 2 in their rearrangement to the corresponding
derivatives 3.
Results and discussion
Substrates
Two more substrates 1 (1b, R = 4-MeOC6H4, and 1c, one
R = Ph, one R = 4-MeOC6H4) were prepared before,1 and their
chemistry has now been studied in order to evaluate the elec-
tronic effect of the ring substituents on the regioselectivity of
the P–N bond cleavage in 1 and on the rate of the rearrange-
ment of 2. The unsymmetrically substituted 1c was of particu-
lar interest from the point of view of the selectivity in the 2→3
rearrangement reaction. In order to extend the study on sub-
strates 1 substituted at the 2,8-nitrogen atoms with aliphatic
groups, the synthesis of three additional models was under-
taken: 1d (R = CH2Ph), 1e (R = Et), and 1f (R = Me). Since the
preparation of 1 is based on a sequence of two 1,5-cyclization
reactions (Scheme 3),1 it was necessary to prepare the required
precursors from the common substrate, Cl2P(O)N(CH2CH2-
Cl)2. We have found that the preparation and the isolation of
N-alkyl substituted derivatives 1 were much more difficult than
of those with N-aryl substituents. For 1e, although we suc-
ceeded in arriving at the pure bicyclic product, we were not able
to isolate its immediate precursor, the corresponding 1,3,2-
diazaphospholidine, because the first and the second cycliz-
ations (Scheme 3) proceeded with comparable rates. We were
not able to prepare the simplest N-alkyl member of the group—
1f. Although its precursor (the diazaphospholidine) was pre-
Scheme 1 Reagents and conditions: i, RЈOH, HCl, room temp.
membered cyclic diamide 2a was found to rearrange spon-
taneously to the isomeric diazaphospholidine derivative 3a,
which could also be prepared directly from 1a, via base-
promoted alcoholysis (Scheme 2).3
Scheme 2 Reagents and conditions: i, Benzene, reflux; ii, MeONa–
MeOH, room temp.
J. Chem. Soc., Perkin Trans. 2, 1999, 2589–2596
This journal is © The Royal Society of Chemistry 1999
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introduced at the phosphoryl center in the ring-opening reac-
tion. When 1a was treated with two mole equivalents of
CF3SO3H in CH2Cl2, a white, hygroscopic solid precipitated
out. The product, soluble in acetone, gave rise to a 31P NMR
1
signal of δP (acetone-d6) = 6.6 ppm, and a H NMR spectrum
of the ring ethylene groups analogous to that of 2a (vide infra).
When the product was dissolved in THF containing triethyl-
amine, only the starting 1a was recovered after the work-up. We
interpret this result as evidence for the reversibility of either the
protonation, or the protonation followed by the ring-opening
reaction. The initial, unstable product most likely represents
either the triflate salt of the expected mixed phosphoric–
sulfonic anhydride which undergoes, upon deprotonation,
intramolecular displacement of the triflate ion leading to the
starting material, or, simply, a triflate salt of the protonated 1a.
When 1a was dissolved in CDCl3 containing one mole equiv-
alent of HCl, the 31P NMR spectrum of the solution showed
only a small low-field shift of the signal of the substrate, return-
ing to its usual position upon the addition of Et3N. This result
contrasts sharply with the fast and facile cleavage of the P–N
bond by solutions of HCl in aprotic solvents.7
The amide bond in 1 was found to be resistant to cleavage by
phenols. No reaction was observed when 1a was incubated at
room temperature in a CDCl3 solution containing phenol (or
p-nitrophenol) and 1.1 mole equivalents of HCl. The reaction
with phenol was, however, achieved under conditions of electro-
philic catalysis. A CH2Cl2 solution of 1a containing four mole
equivalents of PhOH and 1.2 mole equivalents of Me3SiCl pro-
duced, after 20 days at room temperature, a crystalline product
(90%) identified as the hydrochloride salt of the expected
phenyl ester. The salt was then deprotonated to the free base 2c,
but the latter product rearranged during isolation. Complete
rearrangement of the neutral ester 2c to the corresponding
product 3c was achieved after four days (Scheme 4). The failure
Scheme 3 Reagents and conditions: i, 2 RNH2, 2 Et3N, CH2Cl2, Ϫ20 ЊC;
ii, MeONa–MeOH, 0 ЊC; iii, NaH, Bu4NBr, benzene, room temp.
pared in a pure state and in large quantities, its further cycliz-
ation to the bicyclic product failed under a variety of conditions
that led only to the recovery of the substrate or to advanced
decomposition. The 2,8-dibenzyl derivative 1d was prepared as
1
a spectroscopically (31P, H NMR) pure compound, but the
yields of the product varied from experiment to experiment,
and we were unsuccessful in preparing crystals of 1d suitable for
X-ray diffraction.
Acid-catalyzed cleavage
All bicyclic compounds 1, when treated with an alcohol
containing one mole equivalent of HCl, underwent quanti-
tative and regiospecific cleavage of the ‘internal’ P–N bond
yielding the hydrochloride salt of the corresponding triaza-
phosphacyclooctane 2, from which the free base 2 could be
obtained upon neutralization. For the N-aromatic substrates
the observed selectivity (the absence of the isomeric products 3)
was expected on the basis of the accepted mechanism of the
acidic cleavage of the amidate P–N bond,4 and can be explained
by the higher basicity of the bridgehead N atom in 1, respon-
sible for the selectivity in the N-protonation pre-equilibrium
step. For 1d and 1e the result of the alcoholysis was more dif-
ficult to predict, as all amide N atoms carry only alkyl substitu-
ents and should not differ much in basicity. Our recent 15N
NMR study of the P–N bonding in cyclic amides demonstrated
however that the endocyclic nitrogen is always more shielded
than the exocyclic N atom.5 According to the data reported by
von Philipsborn and Müller,6 our 15N NMR results suggest that
the N atom incorporated into the ring should also be more
basic; hence the bridgehead N atom in 1 should be more
basic than the two other N atoms, each located in the single
phospholidine ring. It would be however difficult to explain the
observed selectivity for 1d and 1e solely in terms of the
difference in basicity, as it would require a pKa difference of
approximately two units between the bridgehead and the 2,8-N
atoms.† The other, independent factor is of a stereoelectronic
nature. In the penta-coordinate intermediate (or transition
state) of the substitution, the location of the bridgehead N(5)
atom in the apical position (apical departure) allows the mol-
ecule to avoid a disfavored location of other ligands in the
trigonal bipyramid structure. It seems therefore that the select-
ivity of the acidic alcoholysis of all substrates 1 is determined
by the pre-equilibrium protonation step and by stereoelectronic
effects.
Scheme 4 Reagents and conditions: i, PhOH, Me3SiCl, CH2Cl2, 20
days, room temp.; ii, K2CO3, CH2Cl2, 4 days.
to prepare the p-nitrophenyl ester analog of 2c most likely
resulted from the too low nucleophilicity of the p-nitro-
phenolate ion.
Both N-alkyl substituted substrates 1 (1d, 1e) reacted with
the HCl-containing methanol according to the reaction shown
in Scheme 1, yielding the corresponding salts of the products
2d (2, R = CH2Ph, RЈ = Me) and 2e (2, R = Et, RЈ = Me).
The regiospecificity in this case probably results more from
the stereoelectronic effects than from a small difference in the
basicities of the non-equivalent nitrogen atoms.
The monocyclic diamidoesters 2 are perfectly stable in the
form of their ammonium salts or as the N(5)-acyl derivatives.
The stability (and the behavior) of the neutral products 2
depends, however, on the nature of the nucleophilic group
Base-catalyzed cleavage
The mechanism of the base-catalyzed alcoholysis of 1 is much
less clear. As reported in the communication, reaction of 1a
with sodium methoxide in methanol led directly to the diaza-
† Authors thank one of the referees for this comment.
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phospholidine 3a.3 The same behavior was observed for other
N-aryl substrates (1b, 1c), so the products 3a (3, R = Ph;
RЈ = Me), 3b (3, R = Ph; RЈ = Et),3 3d (3, R = 4-MeOC6H4;
RЈ = Me), and 3e, 3f (3, R = one Ph and one 4-MeOC6H4;
RЈ = Me) could be prepared either by direct alcoholysis of 1, or
via the 2→3 rearrangement, which is sufficiently fast for the
preparative purpose (as shown in Scheme 2). The rates of the
direct 1→3 alcoholysis of the N-aryl substituted 1 (the cleavage
of the P–NAr bond), followed by 31P NMR spectroscopy, gave
the following order of decreasing reactivity, as measured by the
approximate half-lives in MeONa–MeOH at room temper-
the 3-substituted 1,3,2λ5-diazaphospholidine system, respect-
ively. The transannular interactions involving nitrogen and a
carbonyl carbon are well known,8 and the N→P interaction in
an eight-membered system was considered in the discussion
of the hydrolysis of some cyclic phosphate aminoesters.9 In all
those cases, however, the ring structure of the substrate remains
intact, and we found no literature precedents of the observed
actual change in the cyclic molecular skeleton. Since the
rearrangement involves the cleavage of one and the formation
of another P–N bond accompanied by the nitrogen–nitrogen
proton transfer, several mechanisms can be envisaged for the
reaction, from fully concerted, to the 1,5-intramolecular nucleo-
philic N(5)→P attack yielding a PV intermediate, followed by
proton transfer and P–N(2) (or P–N(8)) bond cleavage.3 Some
indication of the bond changes occurring in the rearrangement
could be obtained from the molecular parameters of the sub-
strate’s ground state.
Until now, we have not succeeded in preparing crystals of any
of the synthesized compounds 2 suitable for X-ray diffraction;
purification and crystallization led inevitably to the rearrange-
ment into products 3. We have reported, however, the X-ray
structure of the N-benzoyl derivative of 2b (R = Ph; RЈ = Et).3
The structure revealed some features that might be considered
relevant to the 2→3 interconversion. The non-bonded distance
P ؒ ؒ ؒ N(5) is 3.242 Å, shorter than the corresponding sum of
the van der Waals radii (3.40 Å10). Although it could be taken
as an indication of the incipient bonding between N(5) and P
atoms, it is not reflected by any departure of the N(5) center
from trigonal geometry (average C–N(5)–C bond angle is
119.7Њ). The P–N(2) and P–N(8) covalent bonds in the N(5)-
benzoyl 2b are non-equivalent; one (1.651 Å) lies within the
range of 1.61–1.65 Å reported for phosphoramidates,11 the
other (1.688 Å) is closer to the value of 1.77 Å accepted for the
‘pure’ single P–N bond.12 Those differences may, however, stem
₁
ature, for 1b, 1c, and 1a: t = 4, 7, and 10 days, respectively
₂
(krel ≈ 2.5, 1.4, 1.0). The highest reactivity of the N,NЈ-di-p-
anisyl substrate 1b shows that the reaction is accelerated by the
higher basicity of the departing aromatic amine and indicates
the involvement of proton transfer to the leaving group in the
rate-determining step. Substrate 1c gave, as expected, two
isomeric products of methanolysis, 3e and 3f (Scheme 5).
Scheme 5 Reagents and conditons: i, MeONa–MeOH, room temp.
from the difference in the values of the two O᎐P–N–C(Ph)
᎐
torsion angles thus it would be premature to consider the
molecular parameters as an indication of an ‘early stage’13 of
the intramolecular displacement of one of the amide nitrogens
in 2 by the N(5) amine nitrogen atom.
Although only one isomer (3f) was successfully isolated in the
pure state and fully characterized, the product ratio, 3e:3f
(determined by the integration of the 31P NMR signals),
remained greater than one during the course of the reaction, in
agreement with the rate data. A similar preference for the cleav-
age of the P–NAn over the P–NPh bond in a mixed substrate
was also observed in the 2→3 rearrangement (vide infra).
The rates of the 2→3 rearrangement were measured for sub-
strates 2 by means of the 31P NMR spectroscopy. Since for each
pair of compounds 2 and 3 differ significantly in their δP values,
the kinetics of the rearrangement could be followed by measur-
ing the change of the relative intensities of the 31P NMR signals
in the reaction system. The rate data are given in Table 1.
Entry 1 contains results of the kinetic runs performed in order
to confirm the unimolecular nature of the rearrangement.
Although a ca. 20% decrease in the value of the first-order rate
constant k1 was observed upon the four-fold decrease of the
substrate’s initial concentration, we believe that the reaction
follows, in principle, first-order kinetics, and that the variations
in the k1 value most likely reflect the changes in the nature of
the reaction medium at the relatively high concentrations of the
substrate. Entry 2 shows the effect of the substituent in the
aromatic ring on the reaction rate. Each of the p-methoxy
groups introduced onto the N–Ar function decelerates the reac-
tion by a factor of about 1.5, making 2f the least reactive in the
series. It has to be noted that the substituent effect on the rate
of the rearrangement for 2a, 2f, and 2g is opposite to that
observed for the cleavage of the corresponding substrates 1a,
1b, and 1c by the MeOϪ ion (vide supra), although both reac-
tions involve nucleophilic attack at the phosphoryl center
(by the N(5) atom and by the MeOϪ ion, respectively), and
cleavage of the same (P–N(2) or P–N(8)) bond. For both reac-
tions we propose a common, associative mechanism, but with
different rate-determining steps for each case. According to our
model, the rate of the rearrangement is determined by the rate
of the N(5)–P bond formation, resulting in the P() intermedi-
ate A, which then undergoes fast proton transfer and product-
determining cleavage of the P–N(2) bond (Scheme 7). For the
Both prepared N-alkyl substrates
1 (1d, 1e) yielded
exclusively in the base-catalyzed methanolysis the eight-
membered cyclic products 2d and 2e, the same as the products
obtained (in the form of the HCl salt) from methanolysis in the
presence of HCl (vide supra). This result suggests that the cleav-
age of the P–N bond by MeOϪ may, in the case of the N-alkyl
substrates 1, follow a mechanism different from that operating
for the N-aryl derivatives, and is driven by the cleavage of the
more strained P–N(5) bond in the bicyclic system 1. The differ-
ence between the N-aryl and N-alkyl substrates was also
observed for their reactivity in the related 2→3 rearrangement
(vide infra).
Rearrangement 2→3
The reported3 rearrangement 2→3 stems from the 1,5-
transannular interaction and results in a net ring contraction
(Scheme 6); the observed spontaneity of the reaction indicates
greater thermodynamic stability of the right-side isomer when I
and II represent the 2,5,8-triaza-1λ5-phosphacyclooctane, and
Scheme 6
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Table 1 Rate data for the rearrangement 2→3
₁
Entry
1
Substrate (δp)
2b (12.2)
Product (δp)
3b (18.5)
Conditions and remarks
k1/10Ϫ5 sϪ1
t /h
₂

Refluxing THF (internal temp. 62 ЊC). Reaction
followed to ca. 85% conversion. [2b]o (M) =
(i) 0.030
(ii) 0.015
(iii) 0.0075
Refluxing THF (internal temp. 62 ЊC). Reaction
followed to ca. 90% conversion. Substrate’s initial
concentration: 0.050 M
CDCl3, room temp. [2a]o = 0.033 M
CDCl3, excess of anhydrous K2CO3, room temp.
[2aؒHCl]o = 0.033 M
CDCl3 and 1.1 mole-equiv. Et3N, room temp.
[2aؒHCl]o = 0.033 M
CDCl3, room temp. Reaction followed to ca. 38%
conversion. [2g]o = 0.022 M
4.8 0.4
4.5 0.2
3.8 0.08
8.9 0.3
3.2 0.1
4.0
4.3
5.1
2.2
6.0
3.2
2
3
2a (12.0)
3a (19.9)
3d (20.1)
3e (19.3), 3f (20.1)
3a (19.9)
3a (19.9)
2f (12.9)
2g (13.8)
6.1 0.2
a
2a (12.0)
ca. 1200
ca. 740
a
a
a
2aؒHCl (12.7)
2aؒHCl (12.7)
2g (13.9)
2e (20.2)
3a (19.9)
ca. 160
ca. 3000
ca. 10
3e (19.3), 3f (20.1)
3gb (26.5)
4
5
Refluxing THF (internal temp. 62 ЊC). Reaction
followed to ca. 55% conversion.c [2e]o = 0.050 M
CDCl3, room temp. Reaction followed to ca. 18%
conversion. [2e]o = 0.050 M
1.9 0.2
a
2e (20.2)
3gb (26.5)
ca. 10500
ca. 960
a
2d (21.9)
2d (21.5)
3hb (27.3)
In MeOH–MeONa from 1d, room temperature;
[1d]o = 0.020 M.
3hb (25.9)
Refluxing THF (internal temp. 62 ЊC). Reaction
0.061 0.020
ca. 320
followed to ca. 60% conversion.d [2d]o = 0.050 M.
a Not enough data points collected to determine a reliable value of k1. Approximate value of the half-life was determined from the [substrate]
vs. time plot. b Not isolated and characterized (see Discussion). c Additional signals appeared in the 31P NMR spectrum at higher conversions.
d Approximate value; additional signals appeared in the 31P NMR spectrum during the course of reaction.
N-alkylation reaction. In an attempt to prepare the N(5)-methyl
derivative of 2a, the free base 2a was treated with NaH in THF,
followed by the addition of an excess of iodomethane. Instead
of the expected N–Me derivative, the rearranged product 3a
was obtained. Since also no N-methylated derivative of 3a was
isolated, we propose that 2a, upon deprotonation, forms a P()
intermediate via the transannular N(5)→P interaction, and that
the intermediate breaks down to 3a during the protonation step
(Scheme 9).
Scheme 7
2a/2f pair of substrates, the less electron-donating phenyl
substituents render the P atom in 2a more electrophilic, thus
making 2a more reactive in the 2→3 rearrangement. For the
base-catalyzed methanolysis of 1, on the other hand, we pro-
pose that the P–O bond formation with a strongly nucleophilic
MeOϪ ion is fast, but the proton-assisted cleavage of the
P–N(2) bond is rate-determining (Scheme 8). The more basic
Scheme 8
Scheme 9 Reagents and conditions: i, NaH, THF, room temp.; ii,
MeOH, room temp.
N-p-anisyl function in 1b makes the intermediate B more
reactive in the second, dissociative step of the reaction.
Entry 3 in Table 1 gives evidence for the base-catalysis in the
rearrangement. The reaction is significantly accelerated when
instead of dissolving the free base of 2a in CDCl3, it was gener-
ated from its hydrochloride salt by adding an excess of base.
After the free base was liberated, the excess of the base
catalyzed the reaction; Et3N (present in the homogeneous solu-
tion) being more effective than the solid K2CO3. The catalysis
may operate by increasing the nucleophilicity of the N(5) nitro-
gen atom (general base catalysis), or via the participation of the
As in refluxing THF (entry 2 in Table 1), entry 3 shows that
substrate 2g is less reactive in the rearrangement than 2a. Entry
4 gives rate data for the N-ethyl substrate, 2e. The reaction is in
this case (as for 2d, entry 5) much less clean than for the N-aryl
substrates; signals additional to those of 2e and 3g appear in
the 31P NMR spectrum at higher conversions. In agreement
with the trend observed for the N-aryl substrates (entry 2), 2e
was found less reactive (by a factor of ca. five) than 2a.
Rearrangement of 2d (entry 5) was very slow and the reaction
did not allow us to isolate and characterize the product 3h. In
the first experiment 1d was used as a precursor for 2d. When
1d was dissolved in MeOH containing MeONa, it solvolyzed
Ϫ
base’s conjugate acid (Et3NHϩ, HCO3 ) in the N(5)→N(2)
proton transfer. The effect of a base on the rearrangement was
also demonstrated in the behavior of 2a in the attempted
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Table 2 Labeling of compounds 1, 2, 3
ide (0.256 g, 1.0 mmol) in ether (20 ml) was added dropwise
with stirring at Ϫ70 ЊC to a solution of benzylamine (0.439 g,
4.1 mmol) in ether (10 ml). The mixture was kept at Ϫ70 ЊC for
2 h, allowed to warm up to room temperature and stirred for
another 140 h. The precipitate (benzylammonium chloride) was
filtered off and washed with ether (20 ml). The combined
etheral solution was washed with water (2 × 20 ml) and cooled
to 0 ЊC (without drying). Two layers separated, which, after
4 days, yielded the crystalline product at the interface of the
layers. Colorless crystals, 0.385 g (97%); mp 83–85 ЊC. δP 17.5;
δH 2.77 (2H, br dt, 2JHP 9.0, 3JHH ca. 6.0, 2 × NH), 3.39 (4H, dt,
1
R
2
R
RЈ
3
R
RЈ
a
b
c
d
e
Ph
a
b
c
d
e
Ph
Ph
Ph
CH2Ph
Et
Me
Et
Ph
Me
Me
a
b
c
d
e
Ph
Ph
Ph
An
Ph (endo)
An (exo)
An (endo)
Ph (exo)
Et
Me
Et
Ph
Me
Me
3
3
3JHP 10.7, JHH 6.6), 3.60 (4H, t, JHH 6.7), 4.06–4.15 (4H, m),
7.22–7.34 (10H, m) (Found: C, 53.75; H, 6.24; N, 10.18.
C18H24N3POCl2 requires: C, 54.01; H, 6.04; N, 10.58%). The
structure of the product was confirmed independently by X-ray
diffraction.15
Ana
Ph, An
CH2Ph
Et
f
Me
f
An
Me
Me
f
Me
3-(2-Chloroethyl)-2-oxo-2-benzylamino-1-benzyl-1,3,2ꢀ5-
diazaphospholidine. A solution of the above phosphoric tri-
amide (1.119 g, 2.8 mmol) in THF (100 ml) was added drop-
wise with stirring at room temperature to a solution of ButOK
(0.52 g, 4.6 mmol) in THF (100 ml). The mixture was then
stirred at room temperature for 48 h. Water (150 ml) was added
and the solution was extracted with ether (2 × 120 ml). The
etheral solution was dried (MgSO4), evaporated under reduced
pressure and the crude product was purified by column
chromatography (ethanol). The pure product was obtained as a
pale-yellow viscous oil (0.64 g, 63%). δP 25.3; δH 2.98–3.04 (2H,
m, NCH2), 3.16–3.26 (4H, m, 2 × NCH2), 3.51 (1H, t, 3JHH 6.5,
g
Ph, An
g
h
Me
Me
CH2Ph
a An = 4-MeOC6H4.
relatively fast to 2d: after four days the solution contained no 1d
(δP = 47.3), 98% of 2d (δP = 21.9), and 2% of the product with
δP = 27.3; the latter was, by analogy with previous systems, iden-
tified as the rearrangement product 3h. The 2d→3h inter-
conversion was then followed in the usual way, yielding very
slowly the final product with an approximate half-life of 960 h.
In the absence of the base (MeOϪ) the rearrangement was too
slow to allow any rate determination. When 2d (free base) was
subjected to the rearrangement in THF at 62 ЊC, the conversion
to the product with δP = 25.9 (the difference of ∆δP = 1.4 with
respect to the previous experiment was shown to result from the
solvent effect) was accompanied by the formation of significant
quantities of unidentified phosphorus containing products. The
obtained value of k1 = 0.06 × 10Ϫ5 sϪ1 is only approximate, but
it demonstrates much lower reactivity of 2d in the rearrange-
ment as compared with the N,NЈ-diaryl and N,NЈ-diethyl
analogs.
3
one diastereotopic H of CH2Cl), 3.52 (1H, t, JHH 6.5, second
2
3
diastereotopic H of CH2Cl), 3.83 (1H, dd, JHH 14.9, JHP 7.8,
2
3
one diastereotopic H of CH2Ph), 3.97 (2H, dd, JHH 10.7, JHP
6.8, two diastereotopic H’s of CH2Ph), 4.07 (1H, dd, 2JHH 14.8,
3JHP 6.8, one diastereotopic H of CH2Ph), 7.22–7.31 (10H, m,
2 × Ph); δC 42.75 (d, 2JCP 3.6), 44.0 (d, 2JCP 13.1), 45.2 (s), 45.4
(s), 46.7 (d, 2JCP 5.1), 48.5 (d, 2JCP 5.0), 127.1 (s), 127.3 (s), 127.4
3
(s), 128.2 (s), 128.5 (s), 128.6 (s), 137.6 (d, JCP 5.1), 140.0 (d,
3JCP 6.2) (Found: C, 59.04; H, 6.86; N, 10.92. C18H23N3OPCl
requires: C, 59.42; H, 6.37; N, 11.55%).
In conclusion, a new type of the molecular rearrangement
(2→3) is a reasonably well understood process for the N,NЈ-
diaryl substituted substrates (2a, 2b, 2f, 2g). For the N,NЈ-
dialkyl substituted compounds (2d, 2e), the reaction is much
more complex and the structure–reactivity relationship is much
less clear. The chemistry of the latter, as well as of the related
compounds 2 is currently studied in our laboratory.
1-Oxo-2,8-dibenzyl-2,5,8-triaza-1ꢀ5-phosphabicyclo[3.3.0]-
octane 1d. NaH (3.8 g, 158 mmol; large excess) and Bu4NHSO4
(0.1 g, 0.29 mmol) were added to a solution of the above phos-
pholidine in THF (250 ml) and the mixture was stirred at room
temperature for 45 h. The THF solution was decanted and the
residue was washed several times with THF. The combined
THF solution was evaporated under reduced pressure and the
crude product was purified by column chromatography (THF).
Pure 1d was obtained as a slightly greyish viscous oil (0.43 g,
58%). δP 45.7; δH 2.79–3.01 (4H, m, 2 × NCH2), 3.27–3.46 (4H,
Experimental
Solvents and commercially available substrates were purified by
conventional methods. Melting points are uncorrected. For
column chromatography Merck Kieselgel 60 (0.063–0.200 mm)
was used as a stationary phase. Mass spectra were recorded on a
Varian MAT-212 double focusing direct inlet spectrometer at
an ionization potential of 70 eV. NMR spectra were recorded
on a Bruker AC 300 spectrometer in CDCl3, and the chemical
shift values (δ) are given in ppm relative to the solvent (1H,
δ 7.24; 13C, δ 77.0). 31P NMR chemical shifts are given relative
to 85% H3PO4 as external standard. Labeling of compounds 1,
2, 3, together with the numbering of heteroatoms is given in
Table 2.
2
3
m, 2 × NCH2), 4.02 (2H, dd, JHH 15.1, JHP 8.1, 2 H’s of two
2
3
CH2Ph groups), 4.22 (2H, dd, JHH 15.1, JHH 7.4, 2H’s of two
CH2Ph groups), 7.20–7.32 (10H, m); δC 47.9 (d, 2JCP 17.9), 48.5
2
2
(d, JCP 8.2), 50.2 (d, JCP 3.1), 127.2 (s), 128.0 (s), 128.4 (s),
150.1 (s) (Found: C, 61.62; H, 6.98; N, 11.58. C18H22N3OPؒH2O
requires: C, 62.60; H, 7.00; N, 12.17%).
N,N-Bis(2-chloroethyl)-NЈ,NЉ-diethylphosphoric triamide. A
large excess (ca. 10 ml) of Et2NH was distilled off from a 70%
aq. solution, dried and condensed in a flask immersed in ice.
Ether (20 ml) was added and the solution was added dropwise
with stirring to a solution of N,N-bis(2-chloroethyl)phosphor-
amidic dichloride (3.00 g, 11.6 mmol) in ether (20 ml) at
Ϫ80 ЊC. The mixture was kept at Ϫ80 ЊC for 2 h and left over-
night without cooling. Solvent was evaporated under reduced
pressure, the residue was transferred to a Soxhlet apparatus and
extracted with ether for 55 h. The solvent was evaporated from
the extract yielding pure product, 3.09 g (97%); colorless solid,
after recrystallization from ether, mp 69.3–70.5 ЊC. δP 18.5;
δH 1.15 (6H, t, 3JHH 7.1), 2.27 (2H, br s), 2.96 (4H, dq, 3JHH, 3JHP
Preparation of substrates
N,N-Bis(2-chloroethyl)phosphoramidic dichloride. This was
prepared according to the literature procedure.14 The prepar-
ation of 1a, 1b, and 1c has been described before.1
N,N-Bis(2-chloroethyl)-NЈ,NЉ-dibenzylphosphoric triamide.
A solution of N,N-bis(2-chloroethyl)phosphoramidic dichlor-
J. Chem. Soc., Perkin Trans. 2, 1999, 2589–2596
2593

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7.2, 8.8), 3.40 (4H, dt, 3JHH, 3JHP 6.7, 10.7), 3.63 (4H, t, 3JHH 6.5)
(Found: C, 34.55; H, 7.35; N, 15.18. C8H20Cl2N3OP requires: C,
34.80; H, 7.30; N, 15.22%).
containing one mole equivalent of anhydrous HCl (ca. 0.1 M
solution) was kept at room temperature until the 31P NMR
spectrum of a sample of the reaction mixture showed the
complete disappearance of 1 (30 min–24 h). For slower
reactions the acidity of the solution (pH = 4–5) was adjusted by
the occasional addition of small volumes of alcoholic HCl.
Alcohol was removed under reduced pressure and the hydro-
chloride salt (2ؒHCl) was isolated and characterized. The salts
were then converted to the free bases 2 or to other derivatives of
2, as described for individual products.
3-(2-Chloroethyl)-2-oxo-2-ethylamino-1-ethyl-1,3,2ꢀ5-diaza-
phospholidine. This compound was never isolated and char-
acterized, but its formation and disappearance during the
preparation of 1e could be followed by 31P NMR spectroscopy;
δP (benzene) = 24.0.
1-Oxo-2,8-diethyl-2,5,8-triaza-1ꢀ5-phosphabicyclo[3.3.0]-
octane 1e. A mixture of the phosphoric triamide described
above (1.00 g, 3.6 mmol), NaH (prewashed with benzene, 0.400
g, 16.6 mmol) and Bu4NBr (0.27 g, 0.18 mmol) was stirred in
benzene (100 ml) at room temperature for two days; the reac-
tion progress was monitored by recording directly the 31P NMR
spectra of samples of the solution. An additional amount of
NaH (0.400 g) was added and the stirring was continued for
another two days. The 31P NMR spectrum demonstrated full
conversion and formation of a single phosphorus-containing
product. The benzene solution was decanted, the residue was
washed several times with benzene and the combined benzene
solution was evaporated under reduced pressure. The crude
product (viscous oil, 0.886 g, >100%) was purified by bulb-to-
bulb distillation (oven temp. 200 ЊC/0.06 mmHg) yielding 0.475
g (65%) of the almost pure product; second bulb-to-bulb distil-
lation (oven temp. 150–200 ЊC/0.07 mmHg) afforded pure 1e
(0.400 g, 58%) as a colorless viscous oil. δP 45.5; δH 1.08 (6H, t,
3JHH 7.2), 2.65–2.90 (6H, m), 2.90–3.16 (2H, m), 3.24–3.42 (4H,
m); δC 14.6 (s), 40.5 (s), 47.6 (d, 2JCP 17.7), 48.5 (d, 2JCP 8.1); MS,
m/z 203 (Mϩ, 51%), 188 (Mϩ Ϫ CH3, 70), 147 (Mϩ Ϫ 2C2H4,
29), 146 (Mϩ Ϫ C2H4 Ϫ C2H5, 39), 99 (100) (Found: C, 43.43;
H, 9.11; N, 18.99. C8H18N3OPؒH2O requires: C, 44.08; H, 9.11;
N, 18.76%).
1-Oxo-1-methoxy-2,8-diphenyl-2,5,8-triaza-1ꢀ5-phospha-
cyclooctane 2a. Hydrochloride salt. Reaction time 24 h (100%).
Purified by crystallization from CHCl3–hexane; colorless
crystals, mp 119.8–122.0 ЊC (decomp.). δP 12.7; δH 3.20–3.55
(4H, m), 3.36 (3H, d, 3JHP 11.2), 4.01 (4H, m), 7.19–7.46 (10H,
m), 10.40 (2H, br d, NH2 ); δC 45.5 (s), 46.5 (d, JCP 5.1), 54.0
(d, 2JCP 5.2), 126.6 (s), 126.8 (s), 129.7 (s), 142.2 (s) (Found: C,
55.28; H, 6.45; N, 11.30. C17H23ClN3O2P requires: C, 55.51;
H, 6.30; N, 11.42%).
ϩ
2
Free base 2a. Anhydrous K2CO3 (0.69 g, 5.0 mmol) was
added to a solution of 2aؒHCl (0.180 g, 0.50 mmol) in CHCl3
(20 ml) and the mixture was stirred vigorously at room temper-
ature for 24 h. After filtration (or centrifugation) the solution
was washed three times with water (5 ml each), dried (Na2SO4)
and evaporated under reduced pressure. 2a was obtained as a
white solid (0.166 g, 100%), mp 91.5–92.7 ЊC. δP 13.6; δH 1.84
3
3
(1H, br s), 2.73 (2H, ddd, JHP 6.7, JHH 14.7, 3.0), 3.03 (2H,
ddd, 3JHP 7.0, 3JHH 14.6, 3.4), 3.50 (3H, d, 3JHP 11.3), 3.68 (4H,
2
m), 7.05–7.10 (10H, m); δC 47.4 (s), 51.7 (d, JCP 4.7), 53.3
(d, 2JCP 5.1), 123.5 (d, JCP 3.1), 124.1 (s), 129.3 (s), 143.2 (d, JCP
4.5).
N-Benzoyl-2a. Described before;3 δH 3.40–3.50 (2H, m), 3.55
(3H, d, 3JHP 11.3), 3.50–3.65 (1H, m), 3.70–3.85 (3H, m), 4.00–
4.15 (1H, m), 4.15–4.30 (1H, m), 7.10–7.43 (15H, m); δC 41.6
(s), 49.0 (s), 49.5 (s), 49.7 (s), 53.5 (d, 2JCP 5.5), 129.4 (s), 130.0
(s), 136.3 (s), 142.4 (s), 143.8 (s), 172.5 (s); MS m/z 435 (Mϩ,
2%), 330 (Mϩ Ϫ PhCO, 1.4), 317 (91), 235 (21), 214 (99), 119
(100), 105 (90), 77 (57).
N,N-Bis(2-chloroethyl)-NЈ,NЉ-dimethylphosphoric triamide.
A solution of N,N-bis(2-chloroethyl)phosphoramidic dichlor-
ide (1.00 g, 3.90 mmol) in ether (5 ml) was added dropwise with
stirring at Ϫ80 ЊC to a solution of methylamine (7.2 ml, 160
mmol) in ether (10 ml). The mixture was stirred for 2 h at
Ϫ80 ЊC and allowed to warm up to room temperature. The
solvent and the excess of methylamine was evaporated under
reduced pressure, the residue was transferred to a Soxhlet
apparatus and extracted with ether for 22 h. The product was
obtained as white crystals (0.856 g, 89%), mp 92.1–93.7 ЊC.
N-Acetyl-2a. Obtained by acetylation of 2a with Ac2O in
pyridine. White solid (74%), mp 144.5–145.9 ЊC (from benzene).
δP 12.0; δH 1.90 (3H, s), 3.49 (3H, d, 3JHP 11.3), 3.35–4.08 (8H,
m), 7.29–7.41 (10H, m); δC 21.9 (s), 45.9 (s), 48.3 (s), 49.1 (d,
2JCP 8.5), 49.3 (d, 2JCP 8.5), 53.4 (d, 2JCP 5.5), 123.7 (s), 125.0 (s),
2
129.4 (s), 143.8 (d, JCP 4.7), 171.3 (s); MS m/z 374 (Mϩ ϩ 1,
3
3
1%), 373 (Mϩ, 4), 255 (89), 214 (99), 119 (100), 106 (74) (Found:
C, 61.10; H, 6.63; N, 11.05. C19H24N3O3P requires: C, 61.11; H,
6.47; N, 11.25%).
δP 20.7; δH 2.31 (2H, br s), 2.59 (6H, dd, JHP 12.1, JHH 5.8),
3.40 (4H, dt, 3JHP 10.6, 3JHH 6.5), 3.62 (4H, t, 3JHH 6.5); δC 26.4
(s), 42.2 (s), 49.0 (d, 3JCP 5.0); the 1H-coupled spectrum showed
the expected patterns of q, t, t, for the NMe, NCH2, and CH2Cl
groups, respectively.
N-Tosyl-2a. Obtained from 2a, TsCl and pyridine in CH2Cl2
and purified by column chromatography (MeOH–CH2Cl2,
1:1). Colorless solid (51%), mp 69–70 ЊC. δP 11.7; δH 2.38 (3H,
3-(2-Chloroethyl)-2-oxo-2-methylamino-1-methyl-1,3,2ꢀ5-
diazaphospholidine. A solution of MeONa prepared from 0.750
g Na (32 mmol) in MeOH (37 ml) was added dropwise with
stirring at 0–5 ЊC to a solution of the above phosphoric tri-
amide (1.00 g, 4.0 mmol) in MeOH (25 ml). After 1 h the mix-
ture was allowed to warm up to room temperature and was
stirred for further 70 h. Methanol was removed under reduced
pressure and the crude product was purified by column chrom-
atography (EtOH). Viscous oil (0.428 g, 50%); δP 27.2; δH 2.41
(3H, dd, 3JHP 12.5, 3JHH 5.6, exocyclic NMe), 2.57 (3H, d, 3JHP
9.7, endocyclic NMe), 3.09–3.28 (4H, m), 3.57 (1H, t, 3JHH 6.6,
3
s), 3.19 (2H, m), 3.48 (3H, d, JHP 11.1), 3.45–3.51 (2H, m),
3.76–3.94 (4H, m), 7.13–7.64 (14H, m); δC 21.5 (s), 47.9 (s), 51.9
2
(d, JCP 4.9), 125.5 (s), 126.3 (s), 127.1 (s), 129.3 (s), 129.8 (s),
130.8 (s), 135.9 (s), 146.5 (d, JCP 6.0) (Found: C, 56.84; H, 6.23;
N, 8.13. C24H28N3O4PS requires: C, 56.23; H, 5.85; N, 8.19%).
1-Oxo-1-ethoxy-2,8-diphenyl-2,5,8-triaza-1ꢀ5-phosphacyclo-
octane 2b. Hydrochloride salt. Prepared as for 2a. Colorless
crystals (100%), mp 114.8–116.8 ЊC (from acetone–hexane).
3
δP 11.2; δH 0.90 (3H, t, JHH 7.3), 3.34 (4H, m), 3.72 (2H, dq,
3
3JHP 14.6, JHH 7.3), 4.01 (4H, m), 7.18–7.45 (10H, m); δC 15.8
3
one H of CH2Cl), 3.58 (1H, t, JHH 6.5, one H of CH2Cl); MS
(d, 3JCP 5.9), 45.5 (s), 48.4 (d, 2JCP 4.7), 63.7 (d, 3JCP 5.9), 126.5
(s), 127.0 (s), 129.6 (s), 142.4 (s) (Found: C, 56.18; H, 6.73; N,
10.90. C18H25ClN3OP requires: C, 56.62; H, 6.60; N, 11.00%).
Free base 2b. Prepared as for 2a. Colorless crystals (100%),
mp 93.0–93.9 ЊC (from ether–hexane). δP 12.2; δH 1.10 (3H, t,
m/z 213, 211 (Mϩ, 5%, 15%), 162 (Mϩ Ϫ CH2Cl, 100), 133
(Mϩ Ϫ CH2Cl Ϫ NMe, 99), 119 (Mϩ Ϫ CH2Cl Ϫ NMe Ϫ CH2,
56).
General procedure for the acidic alcoholysis of 1-oxo-2,8-
3
3
3JHH 7.2), 1.76 (1H, br s), 2.73 (2H, ddd, JHP 6.7, JHH 14.5,
disubstituted-2,5,8-triaza-1ꢀ5-phosphabicyclo[3.3.0]octanes 1
3.1), 3.03 (2H, ddd, 3JHP 7.0, 3JHH 14.7, 3.4), 3.73 (4H, m), 3.92
(2H, dq, JHP 14.1, JHH 7.2), 7.07–7.42 (10H, m); δC 15.7 (d,
3
3
A solution of 1 (0.33–1.23 mmol) in an alcohol (5–20 ml)
2594
J. Chem. Soc., Perkin Trans. 2, 1999, 2589–2596

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3JCP 6.4), 47.5 (s), 51.7 (d, 2JCP 4.7), 62.9 (d, 2JCP 5.3), 122.5 (s),
123.6 (s), 124.0 (s), 143.4 (d, JCP 3.5) (Found: C, 62.81; H,
1-Oxo-1-methoxy-2,8-diethyl-2,5,8-triaza-1ꢀ5-phosphacyclo-
octane 2e. Hydrochloride salt. Prepared as for 2a; reaction time
3
7.19; N, 12.29. C18H24N3OP requires: C, 62.60; H, 7.00; N,
12.17%).
30 min. Colorless, hygroscopic crystals (98%). δP 18.8; δH 1.12
3
3
(6H, t, JHH 7.0), 3.08–3.39 (12H, m), 3.64 (3H, d, JHP 11.2);
N-Benzoyl-2b. Described before;3 δH 1.08 (3H, t, JHH 7.1),
δC 14.5 (s), 42.2 (d, 2JCP 2.6), 43.2 (d, 2JCP 4.8), 45.3 (s).
3
3.35–3.50 (2H, m), 3.50–4.30 (8H, m), 7.00–7.50 (15H, m);
δC 15.8 (d, 3JCP 6.9), 46.1 (s), 48.2 (s), 49.2 (s), 49.6 (s), 63.0 (d,
2JCP 5.1), 123.0 (s), 125.6 (s), 128.1 (s), 129.3 (s), 136.3 (s), 142.4
(s), 143.8 (s), 144.2 (s), 172.0 (s); MS m/z 405 (Mϩ Ϫ C2H5O,
6%), 331 (100), 300 (30), 228 (50), 119 (42), 105 (63).
Picrate salt, 2eؒPicH. 2eؒHCl (0.067 g, 0.246 mmol) was dis-
solved in EtOH (0.5 ml) and the solution was added to a solu-
tion of picric acid (0.070 g, 0.307 mmol) in EtOH (1.25 ml). The
solution was heated at 60 ЊC for 10 min and cooled. The pre-
cipitate was filtered off, washed with EtOH and dried. Yellow
crystals (0.100 g, 81%), mp 144 ЊC. δP (D2O) 21.1; δH (D2O)
3
1-Oxo-1-methoxy-2,8-di(4-methoxyphenyl)-2,5,8-triaza-1ꢀ5-
phosphacyclooctane 2f. Hydrochloride salt. Prepared as for 2a.
Needles (100%), mp 155.1–156.6 ЊC (decomp.) (from CHCl3–
1.08 (6H, t, JHP 7.1), 3.00–3.22 (4H, m), 3.39–3.50 (8H, m),
3
3.73 (3H, d, JHP 11.4), 8.90 (2H, s) (Found: C, 38.70; H,
5.51; N, 17.90. C15H25N6O9P requires: C, 38.80; H, 5.43; N,
18.06%).
3
benzene, 1:1). δP 12.9; δH 3.15–3.45 (4H, m), 3.31 (3H, d, JHP
3
Free base 2e. 1e (0.175 g, 0.86 mmol) was dissolved in MeOH
(20 ml), a solution of MeONa (1.3 mole-equiv.) in MeOH (20
ml) was added and the solution was kept at room temperature,
with the 31P NMR spectra recorded periodically (substrate’s
11.0), 3.76 (6H, s), 3.94 (4H, m), 6.84 (4H, d, JHH 6.8), 7.38
ϩ
(4H, d, 3JHH 6.7), 9.99 (2H, br s, NH2 ); δC 45.3 (s), 49.1 (d, 2JCP
2
5.1), 54.0 (d, JCP 5.9), 55.5 (s), 114.8 (s), 129.0 (s), 134.9 (s),
158.3 (s) (Found: C, 53.52; H, 6.45; N, 9.87. C19H27ClN3O4P
requires: C, 53.34; H, 6.36; N, 9.82%).
₁
signal at δP 47.7 being replaced by the signal at δP 22.7), t ca.
₂

65 h. After 13 days (ca. 4.8 half-lives) the solution was neutral-
ized with the required volume of 0.73 M methanolic HCl and
evaporated under reduced pressure. The residue was extracted
with CHCl3 (4 × 20 ml) and the combined CHCl3 solution was
evaporated under reduced pressure yielding 2e (0.180 g, 89%) as
a viscous oil. δP 19.9; δH 1.13 (6H, t, 3JHH 7.0), 3.05–3.32 (12H,
Free base 2f. Prepared as for 2a. Oil (93%); δP 12.9; δH 2.37
3
3
(1H, br s), 2.77 (2H, ddd, JHP 6.5, JHH 14.6, 3.3), 2.98 (2H,
ddd, 3JHP 6.8, 3JHH 14.5, 3.5), 3.42 (3H, d, 3JHP 11.3), 3.63 (4H,
m), 3.78 (6H, s), 6.85 (4H, m), 7.31 (4H, m); δC 46.6 (s), 51.8 (d,
2JCP 4.3), 53.4 (d, 2JCP 5.9), 55.5 (s), 114.5 (s), 129.0 (s), 134.9 (s),
158.3 (s).
3
2
m), 3.64 (3H, d, JHP 11.1); δC 14.4 (s), 42.1 (d, JCP 2.7), 43.0
2
(d, JCP 4.8), 44.8 (s) (Found: C, 45.60; H, 9.82; N, 17.51.
1-Oxo-1-methoxy-2-phenyl-8-(4-methoxyphenyl)-2,5,8-triaza-
1ꢀ5-phosphacyclooctane 2g. Hydrochloride salt. Prepared as
for 2a. Highly insoluble crystals (100%), mp 129.1–132.0 ЊC.
δP 12.7; δH 3.15–3.50 (4H, m), 3.32 (3H, d, 3JHP 11.2), 3.76 (3H,
s), 3.97 (4H, m), 6.85 (2H, d, 3JHH 6.7), 7.17–7.43 (7H, m), 10.00
C9H22N3O2P requires: C, 45.94; H, 9.43; N, 17.86%).
Reaction of 1a with trifluoromethanesulfonic acid
1a (0.100 g, 0.33 mmol) was dissolved in CH2Cl2 (5 ml) and the
solution was cooled to Ϫ50 ЊC. A suspension of CF3SO3H
(0.100 g, 0.66 mmol) in CH2Cl2 (3 ml) was then added dropwise
with stirring. The mixture was stirred at Ϫ50 ЊC for 1 h, and at
room temperature for 2 h. White precipitate was formed and
the 31P NMR spectrum of the solution showed the complete
disappearance of 1a. The precipitate was collected; white,
highly hygroscopic solid (0.100 g, 51%), soluble in acetone;
δP [(CD3)2CO] 6.6. The solid (0.100 g) was dissolved in THF (10
ml) containing Et3N (0.070 g) and the solution was stirred at
room temperature. 31P NMR spectroscopy showed the gradual
disappearance of the signal at ca. 6.0 and the appearance of a
signal at δP 32.2, confirmed to be the signal of 1a by the addi-
tion of an authentic sample. After 6 h the reaction was com-
plete; the solvent was evaporated under reduced pressure, the
residue was dissolved in CHCl3, washed with water and dried
(Na2SO4). After evaporation of the solvent the white solid
product (0.030 g, 30%) was purified by crystallization from
THF–hexane (1:1) yielding pure 1a, mp 150.0–151.2 ЊC (lit.1
2
2
(2H, br s); δC 45.4 (s), 45.5 (s), 48.7 (d, JCP 5.1), 49.0 (d, JCP
2
3
5.1), 54.0 (d, JCP 5.6), 114.8 (s), 126.4 (s), 126.7 (d, JCP 2.5),
129.2 (s), 129.6 (s), 134.7 (s), 142.4 (s), 158.4 (s) (Found: C,
53.83; H, 6.53; N, 10.36. C18H25ClN3O3P requires: C, 54.34; H,
6.33; N, 10.56%).
Free base 2g. Prepared as for 2a. Oil (93%). δP 13.8; δH 1.97
3
(1H, br s), 2.74 (2H, m), 3.02 (2H, m), 3.46 (3H, d, JHP 11.3),
3.69 (4H, m), 3.77 (3H, s), 6.63–7.41 (9H, m); δC 47.1 (s), 47.7
2
2
2
(s), 51.8 (d, JCP 3.4), 53.0 (d, JCP 5.9), 53.2 (d, JCP 5.2), 55.5
2
3
(s), 114.5 (s), 122.9 (d, JCP 3.1), 123.8 (s), 127.1 (d, JCP 2.4),
129.3 (s), 136.2 (s), 143.3 (d, 3JCP 3.5), 157.2 (s).
Alternative preparation of hydrochloric salts 2bؒHCl, 2fؒHCl,
2gؒHCl; general procedure
To a solution of 1 (0.33 mmol) in MeOH (5 ml), Me3SiCl (0.039
g, 0.36 mmol) was added and the reaction mixture was stirred at
room temperature for 4 h (full conversion was demonstrated by
31P NMR spectroscopy). The solution was evaporated under
reduced pressure yielding the corresponding 2ؒHCl (100%).
The products were sufficiently pure not to require further
purification.
1
mp 148.0–149.5 ЊC); δP 33.5; H NMR spectrum identical to
that of an authentic sample of 1a.
Reaction of 1a with phenol
1-Oxo-1-methoxy-2,8-dibenzyl-2,5,8-triaza-1ꢀ5-phospha-
cyclooctane 2d. Hydrochloride salt. Prepared as for 2a; reaction
time 20 h. White solid (96%), purified by crystallization from
CHCl3–benzene (1:1), mp 250.4–256.0 ЊC. δP 18.7; δH 2.90–
3.01 (2H, m), 3.10–3.18 (2H, m), 3.25–3.45 (4H, m), 3.68 (3H,
Hydrochloride salt. A solution of 1a (0.200 g, 0.67 mmol),
phenol (freshly distilled, 0.248 g, 2.64 mmol) and trimethyl-
chlorosilane (0.086 g, 0.80 mmol) in CH2Cl2 (15 ml) was kept at
room temperature for 20 days. The solvent and volatile prod-
ucts were removed under reduced pressure, the residue was
dissolved in CH2Cl2 (10 ml) and the product was precipitated
by the dropwise addition of ether (30 ml) with stirring. The
dissolving–precipitation procedure was repeated several times
until 2cؒHCl (0.285 g, 89%) was obtained as a white solid, mp
87.0–92.0 ЊC. The 31P NMR spectrum indicated that the purity
of the product was ca. 90% and further purifications did not
improve the quality of the product. δP 7.0; δH 3.20–3.80 (6H,
m), 4.09 (2H, m), 6.68–7.47 (15H, m), 10.01 (2H, br d); δC 45.3
3
3
2
d, JHP 11.2), 4.33 (2H, dd, JHP 9.5, JHH 15.2, two H’s of the
3
2
CH2Ph groups), 4.43 (2H, dd, JHP 11.2, JHH 15.2, two H’s of
the CH2Ph groups), 7.24–7.40 (10H, m), 9.98 (2H, br s) (Found:
C, 57.94; H, 7.10; N, 10.07. C19H27ClN3O3P requires: C, 57.65;
H, 6.87; N, 10.61%).
Free base 2d. Prepared as for 2a. Oil (69%). δP 21.3; δH 1.98
(1H, br s), 2.52–2.61 (2H, m), 2.66–2.77 (2H, m), 2.90–3.08
3
3
2
(4H, m), 3.66 (3H, d, JHP 10.9), 4.14 (2H, dd, JHP 8.1, JHH
15.3, two H’s of the CH2Ph groups), 4.32 (2H, dd, 3JHP 9.4, 2JHH
15.4, two H’s of the CH2Ph groups), 7.22–7.39 (10H, m).
2
2
(s), 48.8 (d, JCP 4.4), 120.2 (d, JCP 4.4), 124.7 (s), 126.9 (s),
2
127.6 (s), 129.4 (s), 129.7 (s), 142.0 (s), 150.8 (d, JCP 5.8)
J. Chem. Soc., Perkin Trans. 2, 1999, 2589–2596
2595

View Article Online
(Found: C, 58.17; H, 6.03; N, 9.56. C22H25ClN3O2PؒH2O
requires: C, 58.99; H, 6.03; N, 9.36%).
Base-catalyzed methanolysis of 1-oxo-2,8-dibenzyl-2,5,8-triaza-
1ꢀ5-phosphabicyclo[3.3.0]octane 1d
The reaction was monitored by 31P NMR spectroscopy which
showed the disappearance of 1d (δP 47.3) and the formation of
a new product (δP 21.9), which, in turn, gave way to the final
product (δP 27.3), accepted as the rearrangement product 3h.
After four days the 31P NMR spectrum revealed complete dis-
appearance of 1d, and the presence of 2d (98%), together with
Free base. The reaction was repeated starting with 1a (0.100
g, 0.33 mmol), phenol (0.124 g, 1.32 mmol) and Me3SiCl (0.043
g, 0.40 mmol) in CH2Cl2 (15 ml) and after 20 days a large excess
of finely powdered K2CO3 (2.30 g, 17.2 mmol) was added to the
reaction mixture. After four days of vigorous stirring, the mix-
ture was filtered and the filtrate was washed with water and
dried (Na2SO4). The solvent was removed under reduced pres-
sure and the crude product (viscous oil) was purified by column
chromatography (petroleum ether–AcOEt, 2:1) followed by
crystallization from THF–hexane, yielding pure 3c (0.078 g,
60% based on 1a), needles, mp 112.0–114.1 ЊC. δP 14.8; δH 3.00–
3.10 (2H, m), 3.25–3.42 (4H, m), 3.45–3.65 (2H, m), 4.44 (1H,
br s), 6.59–7.35 (15H, m); δC 41.7 (s), 42.8 (d, 2JCP 13.0), 43.1 (d,
2JCP 14.4), 44.5 (d, 2JCP 4.6), 113.0 (s), 116.2 (d, 2JCP 4.7), 117.6
2% of 3h. The 2d→3h rearrangement was then followed by 31
P
NMR spectroscopy yielding the approximate half-life of 2d as
₁
t = 960 h.
₂

1-Oxo-1-methoxy-2,8-diethyl-2,5,8-triaza-1ꢀ5-phosphacyclo-
octane 2e. Reaction time 13 days. Crude 2e (99%, δP 19.9) was
treated with benzoyl chloride in pyridine, yielding N-benzoyl-2e,
oil (45%), δP 20.0; δH 1.14 (6H, t, 3JHH 6.9), 3.08–3.38 (12H, m),
3
3.62 (3H, d, JHP 11.1), 7.35 (5H, br s) (Found: C, 56.90; H,
2
(s), 121.2 (d, JCP 3.4), 122.0 (s), 125.1 (s), 129.3 (s) 129.6 (s)
(Found: C, 67.40; H, 6.50; N, 10.34. C22H24N3O2P requires: C,
67.14; H, 6.15; N, 10.68%).
7.80; N, 12.16. C16H26N3O3P requires: C, 57.05; H, 7.72; N,
12.38%).
Rate measurements for the 2→3 rearrangement
Base-catalyzed methanolysis of 1-oxo-2,8-disubstituted-2,5,8-
triaza-1ꢀ5-phosphabicyclo[3.3.0]octanes 1
Specific conditions used in measuring the rates of the
rearrangement are given in Table 1. At selected intervals sam-
General procedure. A solution of 1 (1.0 mmol) and MeONa
(3.0 mmol) in MeOH (20 ml) was kept at room temperature
while the reaction progress was monitored by 31P NMR spec-
troscopy. When 1 had disappeared, the solution was neutralized
with methanolic HCl, filtered and evaporated under reduced
pressure. The crude product was purified as indicated for indi-
vidual products. The following products were obtained.
ples of the reaction mixtures were placed in NMR tubes and 31
P
NMR spectra were recorded. First-order rate constants were
then calculated as k1 = ln[(A ϩ B)/A]/t, where A and B repre-
sent the 31P NMR integrals of the signals of 2 and 3, respect-
ively. For the rearrangement of 2e and 2d, where signals due to
2 and 3 were accompanied by additional (minor) signals, the
latter were ignored in the calculations.
3-[2-(Phenylamino)ethyl]-2-oxo-2-methoxy-1-phenyl-1,3,2ꢀ5-
diazaphospholidine 3a. Described before,3 but prepared again in
a state of higher purity; reaction time 28 h, purified by column
chromatography (AcOEt–petroleum ether, 1:1), followed by
crystallization from THF–hexane, mp 115.0–116.0 ЊC (56%). δP
19.9; δH 3.43 (6H, m), 3.61 (3H, d, 3JHP 12.3), 3.63 (2H, m), 4.45
Acknowledgements
Financial assistance from the University of Pretoria and
the Foundation for Research Development is gratefully
acknowledged.
2
(1H, br s), 6.62–7.32 (10H, m); δC 41.6 (s), 43.2 (d, JCP 14.3),
43.3 (d, 2JCP 12.8), 44.4 (d, 2JCP 4.6), 54.3 (d, 2JCP 7.8), 112.8 (s),
115.7 (s), 117.4 (s), 121.7 (s), 123.5 (s), 129.3 (s), 129.4 (s), 137.6
(d, 2JCP 5.2) (Found: C, 61.52; H, 6.80; N, 12.55. C17H22N3O2P
requires: C, 61.62; H, 6.69; N, 12.68%).
References
1 H. Wan and T. A. Modro, Synthesis, 1996, 1227.
2 S. A. Bourne, Z. He, T. A. Modro and P. H. van Rooyen, Chem.
Commun., 1999, 853.
3 X. Y. Mbianda, T. A. Modro and P. H. van Rooyen, Chem.
Commun., 1998, 741.
4 J. Rahil and P. Haake, J. Am. Chem. Soc., 1981, 103, 1723 and
references cited therein.
5 A. M. Modro, T. A. Modro, P. Bernatowicz, W. Schilf and
L. Stefaniak, Magn. Reson. Chem., 1997, 35, 774.
6 W. von Philipsborn and R. Müller, Angew. Chem., Int. Ed. Engl.,
1986, 25, 383.
7 M. J. P. Harger, J. Chem. Soc., Perkin Trans. 1, 1975, 514. See also:
B. Krzyzanowska and W. J. Stec, Synthesis, 1982, 270.
8 Conformational Analysis of Medium-Sized Heterocycles, ed. R. S.
Glass, VCH, New York, 1988, ch. 3.8.
3-{2-[(4-Methoxyphenyl)amino]ethyl}-2-oxo-2-methoxy-1-(4-
methoxyphenyl)-1,3,2ꢀ5-diazaphospholidine 3d. Reaction time
25 days, purified by crystallization from THF–hexane, mp
120.5–121.6 ЊC (60%). δP 20.1; δH 3.30 (6H, m), 3.57 (3H, d, 3JHP
12.3), 3.66 (2H, m), 3.75 (3H, s), 6.60–7.10 (8H, m); δC 42.8 (s),
43.6 (d, 2JCP 13.3), 43.8 (d, 2JCP 14.6), 44.6 (d, 2JCP 4.4), 54.1 (d,
2JCP 7.7), 55.6 (s), 55.8 (s), 114.3 (s), 114.8 (s), 114.9 (s), 117.5
(d, 2JCP 4.5), 134.6 (s), 142.1 (s), 152.2 (s), 154.9 (s) (Found: C,
58.45; H, 6.72; N, 10.76. C19H26N3O4P requires: C, 58.30; H,
6.70; N, 10.74%).
9 R. K. Sharma and R. Vaidyanathaswamy, J. Org. Chem., 1982, 47,
1741.
10 D. E. C. Corbridge, Phosphorus. An Outline of its Chemistry,
Biochemistry and Technology, Elsevier, Amsterdam, 1990, p. 50.
11 M. P. du Plessis, T. A. Modro and L. R. Nassimbeni, J. Org. Chem.,
1982, 47, 2313.
3-[2-(Phenylamino)ethyl]-2-oxo-2-methoxy-1-(4-methoxy-
phenyl)-1,3,2ꢀ5-diazaphospholidine 3f. Reaction time 42 days,
two products separated by fractional crystallization from
THF–hexane; 3f (32%), colorless crystals, mp 109.7–110.4 ЊC.
12 D. W. J. Cruickshank, Acta Crystallogr., 1964, 17, 671.
13 H. B. Bürgi, Angew. Chem., Int. Ed. Engl., 1975, 14, 460.
14 S. Bauermeister, A. M. Modro, T. A. Modro and A. Zwierzak, Can.
J. Chem., 1991, 69, 811.
3
δP 20.1; δH 3.34 (6H, m), 3.58 (3H, d, JHP 13.8), 3.66 (2H, m),
2
3.76 (3H, s), 6.63–7.19 (9H, m); δC 41.7 (s), 43.4 (d, JCP 12.8),
43.8 (d, 2JCP 14.2), 44.5 (d, 2JCP 4.5), 54.2 (d, 2JCP 7.7), 55.6 (s),
2
15 Unpublished result from this laboratory.
112.9 (s), 114.8 (s), 117.6 (s), 118.0 (s), 129.3 (s), 134.6 (d, JCP
5.4) (Found: C, 59.99; H, 6.81; N, 11.70. C18H24N3O3P requires:
C, 59.82; H, 6.69; N, 11.63%).
Paper 9/03835C
2596
J. Chem. Soc., Perkin Trans. 2, 1999, 2589–2596