Synthetic and structural study of 4-phosphacyclohexanones and 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones

Article abstract of DOI:10.1016/j.tet.2012.04.038

The synthesis of bicyclic phosphorus-nitrogen (PN) compounds containing the rigid bicyclo[3.3.1]nonan-9-one framework was attempted using the Mannich condensation reaction of four different phosphorinanone classes with amines and aldehydes. Three different isomers of 4-tert-butyl-2,6-di(methoxycarbonyl)-3,5- bis(p-dimethylaminophenyl)-4-phosphacyclohexanone were obtained from the Michael addition reaction of tert-butylphosphine with 2,4-di(methoxycarbonyl)-1,5- bis(p-dimethylaminophenyl)penta-1,4-dien-3-one. The reaction of the all-equatorial isomer with methylamine and formaldehyde produced the bicyclic PN compound 7-tert-butyl-1,5-di(methoxycarbonyl)-6,8-bis(p-dimethylaminophenyl)-3- methyl-3-aza-7-phosphabicyclo[3.3.1]nonan-9-one. The identical Mannich reaction of the enol tautomer also yielded the same product, as well as the PN compound 4-tert-butyl-6-methoxycarbonyl-5-(p-dimethylaminophenyl)-2-methyl-2-aza-4- phosphacyclohexanone and the E/Z isomers of 3-(p-dimethylaminophenyl)methyl-2- propenoate. The newly synthesised 3-aza-7-phosphabicyclo[3.3.1]nonan-9-one PN compound adopts a chair-chair conformation both in solution and the solid state.

Full text of DOI:10.1016/j.tet.2012.04.038

Tetrahedron 68 (2012) 5109e5116
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic and structural study of 4-phosphacyclohexanones
and 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones
*
Almas I. Zayya, John L. Spencer
School of Chemical and Physical Sciences, Victoria University of Wellington, Kelburn, Wellington 6012, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of bicyclic phosphorusenitrogen (PN) compounds containing the rigid bicyclo[3.3.1]
nonan-9-one framework was attempted using the Mannich condensation reaction of four different
phosphorinanone classes with amines and aldehydes. Three different isomers of 4-tert-butyl-2,6-
di(methoxycarbonyl)-3,5-bis(p-dimethylaminophenyl)-4-phosphacyclohexanone were obtained from
the Michael addition reaction of tert-butylphosphine with 2,4-di(methoxycarbonyl)-1,5-bis(p-dimethy-
laminophenyl)penta-1,4-dien-3-one. The reaction of the all-equatorial isomer with methylamine and
formaldehyde produced the bicyclic PN compound 7-tert-butyl-1,5-di(methoxycarbonyl)-6,8-bis(p-di-
methylaminophenyl)-3-methyl-3-aza-7-phosphabicyclo[3.3.1]nonan-9-one. The identical Mannich re-
action of the enol tautomer also yielded the same product, as well as the PN compound 4-tert-butyl-6-
methoxycarbonyl-5-(p-dimethylaminophenyl)-2-methyl-2-aza-4-phosphacyclohexanone and the E/Z
isomers of 3-(p-dimethylaminophenyl)methyl-2-propenoate. The newly synthesised 3-aza-7-
phosphabicyclo[3.3.1]nonan-9-one PN compound adopts a chairechair conformation both in solution
and the solid state.
Received 17 August 2011
Received in revised form 21 March 2012
Accepted 10 April 2012
Available online 21 April 2012
Keywords:
Bispidinones
Mannich reaction
Phosphorinanones
Michael addition
PN ligands
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
phosphorusenitrogen derivatives (3), which adopt a rigid chaire-
chair conformation both in solution and the solid state, and are
A prominent group of compounds containing the bicyclo[3.3.1]
nonan-9-one framework are the bispidinones (1).1,2 These are
simplified bis-nitrogen derivatives of the natural product sparte-
ine3 (2) with a carbonyl group at the bridging position. Bispidi-
nones were first reported by Mannich and Mohs4 in 1930 and have
since formed an active area of research due to their synthetic
simplicity, potential biological activity5e8 and versatility as che-
lating ligands for transition metals.9e12
preorganised for coordination to transition metals via both donor
atoms.17 A specific example is 1,5-di(methoxycarbonyl)-6,8-bis(p-
dimethylaminophenyl)-3-methyl-7-phenyl-3-aza-7-
phosphabicyclo[3.3.1]nonan-9-one (4).
Our continued interest in developing this novel class of PN
compounds has led us to present here a detailed study on the de-
sign and synthesis of new analogues with different substitution
patterns around the bicyclic backbone.
Bispidinone derivatives, where one nitrogen atom has been
replaced with oxygen,13 sulfur14,15 or selenium16 have attracted
attention for their interesting stereochemical aspects and potential
medicinal properties. Recently we reported the synthesis of
2. Results and discussion
2.1. Phosphorinanone synthesis
The synthesis of the bicyclic PN derivatives consists of
two steps. Firstly a P-Michael18 addition reaction between an ab-un-
saturated carbonyl compound and an aryl- or alkylphosphine (or a
derivative) produces a phosphorinanone (4-phosphacyclohexanone)
* Corresponding author. Tel.: þ64 4 463 5119; fax: þ64 4 463 5241; e-mail address:
john.spencer@vuw.ac.nz (J.L. Spencer).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.038

5110
A.I. Zayya, J.L. Spencer / Tetrahedron 68 (2012) 5109e5116
intermediate. In the second stepthe intermediate iscombined with an
aldehyde and a primary amine in a Mannich19,20 condensation re-
action to give the bicyclic PN compound.
Four different phosphorinanone classes (Fig. 1) were examined
in this work. The six-membered phosphorinanone rings varied in
the substituents at the 2,6- and 3,5-positions with respect to the
carbonyl moiety, as well as different groups on the phosphorus
atom.
Isomer 5a exists in the ketone form with normal IR carbonyl
stretches for a ketone at 1707 cmꢀ1 and an ester at 1755 cmꢀ1. The
31P NMR spectrum showed one resonance at 13.0 ppm (Table 1),
while the 1H NMR spectrum of 5a in C6D6 was simple owing to the
presence of a plane of symmetry in the molecule (Table 2). The pairs
of equivalent protons H3/H5 and H2/H6 appeared as doublets of
doublets at 3.59 and 3.97 ppm, respectively, each with JHH coupling
of 12.7 Hz. This large diaxial coupling constant indicates that the
bulky methoxycarbonyl and dimethylaminophenyl groups are in
equatorial positions. Two doublets were observed at 6.62 and
7.21 ppm for the eight aromatic protons in a ratio of 1:1, implying
that both of the aryl rings are rotating freely.
Table 1
31P NMR data of key compoundsa
Compound
d
(ppm)
Solvent
5a
5b
5c
10
11
13.0
6.0
17.5
8.4
CDCl3
CDCl3
CDCl3
C6D6
ꢀ3.5
C6D6
a
All signals are referenced with respect to 85% aqueous H3PO4, 300 MHz.
Table 2
1H NMR data of phosphorinanone isomers 5aeca
Fig. 1. Different phosphorinanone compounds.
Group
5a
5b
5c
H2
H3
H5
3.97 (dd, 12.7 Hz, 5.4 Hz)
3.59 (dd, 12.7 Hz, 5.9 Hz)
3.59 (dd, 12.7 Hz, 5.9 Hz)
e
e
3.90 (m)
3.90 (m)
4.13 (s)
3.78
(dd, 12.6 Hz, 3.2 Hz)
4.42
(dd, 12.6 Hz, 1.0 Hz)
3.58 (s)
The P-Michael addition reaction of dienone 9 with tert-butyl-
phosphine in pyridine at room temperature yielded phosphor-
inanones 5a and 5b in a 2:1 ratio based on isolated yields
(Scheme 1). Most of compound 5a precipitated from the reaction
mixture as a white solid, while isomer 5b remained in solution.
Removal of solvent and several cycles of crystallisation from hot
methanol yielded 5b as air stable fine white needles. The filtrate
still contained small amounts of 5a and 5b plus potentially other
isomers as evident from the signals in the 1H and 31P NMR spectra.
The isolation of the other isomers was not practical as they were
present in very small amounts.
H6
3.97 (dd, 12.7 Hz, 5.4 Hz)
4.28
(d, 5.9 Hz)
3.62 (s)
OMe
NMe2
But
3.51 (s)
3.66 (s)
3.61 (s)
2.90 (s)
2.91 (s)
2.91 (br s)
2.95 (br s)
0.52
(d, 11.6 Hz)
12.84 (s)
0.63 (d, 10.7 Hz)
e
0.96 (d, 11.3 Hz)
13.13 (s)
OH
a
Spectra obtained in CDCl3. Chemical shifts in ppm. Multiplicity and coupling
constants given in parentheses.
Scheme 1. Synthesis of 2,6-diester phosphorinanones.

A.I. Zayya, J.L. Spencer / Tetrahedron 68 (2012) 5109e5116
5111
From previous conformational analysis work on six-membered
phosphacycles,21,22 the bulky tert-butyl group on phosphorus is
expected to occupy an equatorial position in isomer 5a. Quin et al.21
showed that 1-R-phosphorinanes (R¼CH3, C2H5, i-C3H7, C6H5) gave
a single 31P NMR signal at 300 K, but on lowering the temperature,
separate sharp signals for the axial-R and equatorial-R conformers
were observed. However, in the case of 1-tert-butylphosphorinane
only one signal was observed over the entire temperature range
(129e300 K) corresponding to the equatorial conformer. Moreover,
Pringle and co-authors found that the tert-butyl group in 4-tert-
butyl-3,5-diphenyl-4-phosphorinanone also occupied an equato-
rial position.22 The strong preference of the tert-butyl group for the
equatorial position may be attributed to its large size. The 13C NMR
data of 5a is summarised in Table 3.
A coupled HSQC experiment is performed in the absence of
broadband 13C decoupling and with an extended acquisition time
as compared with a regular HSQC. Extraction of 1D traces from the
coupled HSQC spectrum at the carbon frequency allows the ob-
servation of proton multiplets with high resolution nearly equal to
that of a conventional proton spectrum. The resolution is further
enhanced by the increased acquisition time. The primary doublet
1
splitting is due to the large JCH coupling constant as a result of
coupling to 13C nuclei. Residual coupling constants can also be
measured from the 1D traces as second-order effects caused by
strong protoneproton coupling is eliminated. In 1H NMR spectra,
complex coupling patterns result from strongly coupled
1He12Ce12Ce1H spin systems. In the coupled HSQC experiment
these strong couplings are removed and only coupling from
1He13Ce12Ce1H units are observed. Consequently, undistorted
first-order multiplets are restored from which protoneproton and
protonephosphorus coupling constants can be extracted.
Table 3
13C NMR data of phosphorinanone isomers 5aeca
The 1D traces (Fig. 2) from the coupled HSQC spectrum of 5b
showed H5 as a doublet of doublets (JHH¼11.4 Hz, JPH¼6.3 Hz) and
H6 as a doublet with JHH of 12.4 Hz, indicating a diaxial arrange-
ment. Nothing can be said about the configuration at C3 because of
the isolated position of H3, and also as NOE experiments proved
inconclusive. The signals for the eight aromatic protons over-
lapped to give four resonances in a ratio of 3:3:1:1. This suggests
that one of the dimethylaminophenyl rings is rotating freely to
give rise to two signals each integrating for two protons, while the
other group is experiencing restricted rotation resulting in four
resonances integrating for one proton each. Since the orientation
of H5 and H6 is diaxial, the dimethylaminophenyl ring at position
5 is in an equatorial position and would be free to rotate according
to a stereomodel of 5b. By contrast, the other ring on the enol side
of the molecule at position 3 would be restricted in rotation if it
was in an axial position and would give rise to four signals in the
1H NMR spectrum. As this was the case, the H3 proton must
therefore be in an equatorial position while the dimethylamino-
phenyl group is axial. The observation of two signals for the
dimethylaminophenyl groups is consistent with the proposed
structure.
Group
5a
5b
5c
C1
C2
C3
C5
C6
COO
199.4 (d, 3.4 Hz)
65.4 (d, 15.8 Hz)
42.3 (d, 19.7 Hz)
42.3 (d, 19.7 Hz)
65.4 (d, 15.8 Hz)
168.2 (d, 10.6 Hz)
168.3 (d, 6.2 Hz)
103.8 (d, 9.0 Hz)
35.2 (d, 24.1 Hz)
36.5 (d, 19.1 Hz)
57.3 (d, 17.4 Hz)
172.6 (d, 13.2 Hz)
172.8 (d, 6.7 Hz)
52.4 (s)
52.6 (s)
40.7 (br s)
40.8 (br s)
27.6 (d, 12.3 Hz)
30.2 (d, 21.3 Hz)
169.9 (s)
99.9 (d, 2.8 Hz)
34.5 (d, 13.5 Hz)
34.3 (d, 21.3 Hz)
48.1 (d, 2.0 Hz)
172.6 (d, 6.7 Hz)
173.1 (s)
OMe
52.1 (s)
40.6 (s)
52.0 (s)
NMe2
40.0 (s)
C(CH3)3
C(CH3)3
28.7 (d, 10.1 Hz)
30.9 (d, 20.6 Hz)
29.8 (d, 13.7 Hz)
31.7 (d, 30.9 Hz)
a
Spectra obtained in CDCl3. Chemical shifts in ppm. Multiplicity and coupling
constants given in parentheses.
As a result of ketoeenol tautomerism, phosphorinanone isomer
5b was isolated in the enol form. The IR spectrum showed a broad
enolic OH stretch at 3453 cmꢀ1 and a group of bands at 1644, 1610
and 1519 cmꢀ1 associated with the carbonyl groups. Compound 5b
is asymmetric, as two non-equivalent methoxy and dimethylamino
signals were observed in the 1H NMR spectrum (Table 2). The enolic
proton resonated at 12.84 ppm, while the signals for H5 and H6
overlapped to give a multiplet centred at approximately 3.90 ppm
(Fig. 2). Thus, useful stereochemical information from the magni-
tude of vicinal and phosphorus couplings for H5 and H6 were in-
stead obtained from a coupled HSQC spectrum.23e25
Considering that isomer 5b represents the first example of
a phosphorinanone isolated in the enol form, the orientation of the
tert-butyl group on phosphorus is difficult to determine. Mean-
while, ketoeenol tautomerism has been observed in nitrogen26 and
sulfur27 analogues of the phosphorinanones. Isomer 5b resonated
at 6.0 ppm in the 31P NMR spectrum (Table 1), and the 13C NMR data
is reported in Table 3.
In addition, NMR analysis of the filtrate showed a complete set
of signals corresponding to a second enolic isomer (5c), which
resonated at 17.5 ppm in the 31P NMR spectrum (Table 1). The
dimethylaminophenyl and the methoxycarbonyl groups at posi-
tions 5 and 6 are both equatorial because a large diaxial coupling
constant of 12.7 Hz was observed between H5 and H6 (Table 2). The
H3 proton displayed no phosphorus coupling, resonating as a sin-
glet at 4.13 ppm. Meanwhile, four signals in a ratio of 2:2:2:2 were
observed for the aromatic protons, suggesting free rotation for both
of the dimethylaminophenyl rings. To assign a molecular structure
to the minor enolic isomer 5c, the configuration at C3 is very im-
portant. As free rotation was observed for the aryl groups, the
dimethylaminophenyl group at position 3 must be equatorial. So far
the substituent arrangement in isomer 5c is the same as isomer 5a.
However, since samples containing 5a are very stable in solution
over long periods of time, the possibility of 5c being the enol tau-
tomer of 5a can be ruled out. Consequently, for the enolic isomer 5c
to be different from 5a, the tert-butyl group on phosphorus atom
has to be in an axial position, even though such an arrangement has
not been observed before. The 13C NMR data for 5c is compiled in
Table 3.
Fig. 2. Expanded-scale displays of the 1H NMR spectrum of phosphorinanone isomer
5b (bottom), and 1D traces from a coupled HSQC spectrum of 5b at the frequency of
the corresponding carbon atoms for H5 (top) and H6 (centre), CDCl3, 600 MHz.

5112
A.I. Zayya, J.L. Spencer / Tetrahedron 68 (2012) 5109e5116
Phosphorinanones 6,28 722,29,30 and 831 were prepared by
known literature methods. Mixtures of isomers were obtained for 7
and 8, which were used in the Mannich reactions.
The Mannich reaction of the enol phosphorinanone isomer 5b
with formaldehyde and methylamine in ethanol gave highly un-
expected results (Scheme 3). Removal of ethanol and washing the
resulting yellow residue with diethyl ether several times yielded
the symmetrical PN compound 10 (26%). The ether wash still
contained small amounts of 10. Taking the ether wash to dryness
and washing the residue with hexane successfully separated the
other products. The hexane-insoluble solid was identified as a new
six-membered phosphorusenitrogen compound (11) produced in
low yield (13%) and contaminated with compound 10. Although 11
is air stable, the use of flash column chromatography for its puri-
fication was not successful as it decomposed on the column. It
could, however, be further purified by washing several times with
small volumes of ethyl acetate, which dissolved most of PN com-
pound 10, along with small amounts of 11. The hexane wash con-
tained the E/Z isomers of 3-(p-dimethylaminophenyl)methyl-2-
propenoate (37%) (12), with the E isomer being dominant.
2.2. Synthesis of 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones
The Mannich reaction of isomer 5a with methylamine and
2 equiv of formaldehyde in ethanol produced the bicyclic PN
compound 10 in good yield (Scheme 2). Compound 10 was
obtained as white needles and was air stable.
PN compound 11 was characterised by IR and NMR spectroscopy
and mass spectrometry. Elemental analysis could not be performed
due to contamination with 10, but HRESIMS analysis confirmed the
molecular formula of compound 11. The IR spectrum of 11 showed
Scheme 2. Synthesis of bicyclic PN compound 10.
The 1H NMR spectrum of 10 in C6D6 showed only half of the
signals expected for this PN compound, implying symmetrical po-
sitions for the methoxycarbonyl and dimethylaminophenyl sub-
stituents, and for H6/8 and H2/4. Four broad doublets between 6 and
9 ppm were observed, indicating that the phenyl protons are
magnetically inequivalent as a result of restricted rotation about
the CeC bond. This was confirmed by variable temperature 1H NMR
experiments ranging from 20 to 70 ꢁC. The signals corresponding to
the m-protons between 6 and 7 ppm gradually collapsed and co-
alesced at 60 ꢁC (300 MHz). The 31P NMR spectrum showed a single
peak at 8.4 ppm (Table 1), and the IR spectrum was dominated by
two carbonyl stretches at 1712 and 1733 cmꢀ1 corresponding to the
ketone and ester groups, respectively.
Crystals of PN compound 10 were grown by the slow evapora-
tion of a C6D6 solution. The solid state crystal structure shows
a perfect mirror symmetrical chairechair conformation with the
methoxycarbonyl, dimethylaminophenyl, methyl and tert-butyl
substituents in equatorial sites (Fig. 3). This conformation is
favourable for metal complexation via both donor atoms to form
a complex with a stable tricyclic quasi-adamantane structure. The
equatorial 6,8-dimethylaminophenyl groups are constrained by the
bicyclic framework to be in close proximity to the metal, which
could lead to unusual coordination chemistry. Furthermore, the
X-ray crystal structure also shows the unique out-of-plane pro-
tection that would be provided to coordinated metals by the
dimethylaminophenyl groups.
The crystallographic dimensions of 10 are very similar to the
previously reported phenyl analogue.17 For example, the intra-
molecular distance between the phosphorus and nitrogen donor
ꢀ
atoms is 2.9 A in both PN compounds. This distance is the same as
Fig. 3. ORTEP diagrams of PN compound 10 (30% thermal ellipsoids). Hydrogen atoms
omitted for clarity.
the average NN distance in bispidinone compounds.12

A.I. Zayya, J.L. Spencer / Tetrahedron 68 (2012) 5109e5116
5113
Scheme 3. Mannich reaction of phosphorinanone isomer 5b.
a carbonyl stretch at 1744 cmꢀ1 and an amide stretch at 1655 cmꢀ1
.
to purify the products, including the use of column chromatogra-
phy, and extensive NMR analyses were performed on the mixture of
products, but no reasonable conclusions could be drawn about the
successful synthesis of bicyclic PN compounds in these cases.
Samples containing the two isomers of phosphorinanone 8 were
subjected to typical Mannich reaction conditions. No reaction was
observed between the phosphorinanone isomers and methylamine
and formaldehyde in ethanol over different reaction times. Addi-
tion of either acid or base (as the Mannich reaction can be done
under acidic or basic conditions) resulted only in the isomerisation
of the starting material to the more stable symmetric isomer, pre-
sumably via a reverse Michael reaction. The use of different amines,
aldehydes and solvents was also unsuccessful. The failure of the
Mannich reactions was surprising as analogous bispidinone com-
The phosphorus atom in 11 resonated at -3.5 ppm in the 31P NMR
spectrum in CDCl3 (Table 1). In the 1H NMR spectrum, the axial and
equatorial protons of the CH2 group each appeared as a doublet of
doublets at 2.84 and 3.03 ppm, respectively (JHH¼14.5 Hz). The
phosphorus coupling constants were vastly different between the
two protons; 18.0 Hz for the proton at 3.03 ppm and only 2.6 Hz for
its geminal partner. The protons in positions 5 and 6 were in
a diaxial arrangement with a JHH of 12.8 Hz, indicating that the
methoxycarbonyl and dimethylaminophenyl groups are in equa-
torial positions. The tert-butyl group is expected to occupy an
equatorial position.21,22
The results obtained from the Mannich reaction of 5b are puz-
zling. Firstly, through the use of an asymmetric phosphorinanone,
such as isomer 5b in the Mannich reaction, we hoped to produce an
asymmetric PN compound. As this was not the case, formation of
the symmetric PN compound 10 implies that some sort of iso-
merisation about the stereogenic centres in phosphorinanone 5b
had taken place during the double Mannich reaction.
Similar epimerisation has previously been noted in bispidinone
chemistry whereby the thermodynamically most stable product
forms under double Mannich reaction conditions.32,33 These find-
ings have been rationalised in terms of invoking either a retro-
Michael reaction or a retro-Mannich reaction. Therefore, the for-
mation of PN compound 10 from phosphorinanone 5b under the
double Mannich reaction conditions can also be attributed to the
same reasons as for the nitrogen analogues.
Secondly, formation of compound 11 suggests that a side re-
action occurred under the Mannich conditions, which had not been
observed before. Thirdly, the observation of the E/Z isomers of
compound 12 could be the result of the side reaction, or perhaps
the result of the complete decomposition of phosphorinanone 5b
under such reaction conditions. Consequently, the behaviour of
phosphorinanone isomer 5b under the Mannich conditions used is
very difficult to understand.
The synthesis of bicyclic PN compounds from phosphor-
inanones 6 and 7 was attempted using the Mannich reaction. Many
products were obtained from the reactions, as shown by a plethora
of signals in the 31P NMR spectrum. Varying the amine, aldehyde,
solvent and reaction time gave similar results. All efforts were made
pounds with methyl substituents at the a-positions to the central
carbonyl group have been reported.9,10 Such bispidinones were
prepared by the Mannich condensation reaction with the aldehyde,
ketone and amine components present in the reaction mixture in
a 4:1:2 ratio. However the yields were very low, never exceeding
18%. This suggests that diethyl ketone is not effective as the ketonic
substrate in these syntheses. The methyl groups could be deacti-
vating the a-positions to the carbonyl group, hence disfavouring
a double Mannich reaction. Further support for such a hypothesis
came from work published by Omarov et al.34 They report the
successful condensation of 3,5-diphenylpiperidinone and 2-
methyl-3,5-diphenylpiperidinone to the corresponding bispidi-
none compounds, but 2,6-dimethyl-3,5-diphenylpiperidinone did
not react at all. These observations suggest that a double Mannich
reaction using diethyl ketone can be performed if the synthesis is
carried out in one pot. However, the Mannich reaction is un-
successful when 2,6-dimethyl piperidinones are used as the start-
ing materials. As the results of this work have shown, the same is
true for the isomers of phosphorinanone 8.
To investigate the degree of reactivity of the a-positions to the
central carbonyl group in the dimethyl phosphorinanone isomers
of 8, a series of small scale exchange experiments were performed
using different electrophiles and reaction conditions. The only
successful experiment was an H/D exchange in the presence of
NaOMe. In light of these results, it is not surprising that a complex
double Mannich reaction was never observed with 8.

5114
A.I. Zayya, J.L. Spencer / Tetrahedron 68 (2012) 5109e5116
3. Conclusions
4.2. X-ray structure determination
The synthesis of phosphorusenitrogen compounds containing
the 3-aza-7-phosphabicyclo[3.3.1]nonan-9-one framework via the
Mannich reaction proved to be challenging. The nature of the
Diffraction data for 10 were collected using Bruker CCD dif-
ꢀ
fractometers with Mo K
a
radiation (0.71073 A) from a fine-focus
sealed tube with graphite monochromator, using phi and omega
scans. Multi-scan absorption corrections were applied. The struc-
ture was solved by direct methods and full-matrix least squares
refinement, with anisotropic thermal parameters for all non-H
atoms. Hydrogen atoms are in calculated positions and refined
using a riding model with SHELXL defaults. Molecular drawings
were made using ORTEP3.
substituents at the a-positions to the central carbonyl group in the
phosphorinanone compounds had a significant effect on the suc-
cess of the double Mannich reaction. This was demonstrated by the
2,6-diester phosphorinanone system, from which the only PN bi-
cyclic compound was produced. The electron-withdrawing ester
groups enhanced the acidic character of the
resonance stabilised the enol form of the phosphorinanones. The
presence of methyl substituents at the -positions was detrimental
a-CH protons, and also
a
4.3. Synthesis of compounds
to the success of the Mannich reaction, as illustrated by the 2,6-
dimethyl phosphorinanone system. The lack of reactivity can be
attributed to the electron-donating nature of the methyl groups
and their inability to stabilise the enol form of the phosphor-
ianones. The remaining 3,5-diphenyl and 4-phenyl phosphor-
4.3.1. 4-tert-Butyl-2,6-di(methoxycarbonyl)-3,5-bis(p-dimethylami-
nophenyl)-4-phosphacyclohexanones (5aec). Dibenzylideneacetone
derivative 9 (3.6 g, 8.2 mmol) was dissolved in pyridine (30 mL). To
the solution, tert-butylphosphine (1.1 g, 12.3 mmol) was quickly
added. The reaction mixture was stirred at room temperature for 1
inanone systems had no a-substituents, but ascertaining whether
t
the synthesis of any bicyclic PN compounds had been achieved was
still difficult. Overall, these results suggest that a combination of
steric and electronic factors govern the success of a double Mannich
reaction in the different phosphorinanone systems examined in
this work.
The newly synthesised bicyclic PN compound 10 adopted a rigid
chairechair conformation both in solution and the solid state. In
reactions with transition metals this structural feature presets
a bidentate capability and ensures that the nitrogen donor group
remains in close proximity to the metal centre in non-chelating
situations. The coordination chemistry of the novel PN ligand
with transition metals is described elsewhere.35
day in a closed vessel to prevent BuPH2 from escaping. Over time
a white solid precipitated out. The solid was filtered in the air,
washed with diethyl ether then dried in vacuo to give the first batch
of phosphorinanone isomer 5a. The filtrate was reduced to dryness
in vacuo to give a yellow foam. Washing the foam with diethyl ether
yielded a second batch of 5a as a white solid.
The diethyl ether wash was reduced to dryness in vacuo and the
yellow solid was recrystallised from hot methanol in the air to
produce white crystalline fine needles of 5b. The yield can be in-
creased by several cycles of crystallisations of the filtrates from hot
methanol. Sometimes residual 5a co-crystallised with 5b as
off-white spherical aggregates, which could be physically separated
from the needles. The final mother liquor contained small amounts
of 5aec and several other isomers as shown by 1H and 31P NMR
spectra. It was impractical to separate the remaining isomers.
Compound 5a: yield 2.4 g, 55%; decomposition at 200 ꢁC. IR
4. Experimental
4.1. General information
(KBr) nmax 1755, 1707, 1610 and 1520 cmꢀ1
;
1H NMR
d
(500 MHz,
t
All reactions and manipulation of products and reagents were
carried out under an inert nitrogen atmosphere using standard
Schlenk techniques unless otherwise stated. Analytical grade re-
agents and high purity solvents were degassed and purged with
nitrogen gas before use, except for diethyl ether, which was dried
by refluxing over sodium/benzophenone ketyl. NMR spectra were
recorded using a Varian Unity Inova 300 (300 MHz for 1H, 75 MHz
for 13C and 121 MHz for 31P), a Varian Unity Inova 500 (500 MHz
for 1H and 125 MHz for 13C), or a Varian DirectDrive 600 (600 MHz
for 1H and 150 MHz for 13C) spectrometers. The 600 MHz in-
strument was equipped with a Varian inverse-detected triple-
resonance HCN cold probe operating at 25 K. All direct-detected 1H
and 13C chemical shifts were referenced to the residual solvent
peak. NMR samples were prepared under an inert nitrogen at-
mosphere, unless otherwise stated, using C6D6 and CDCl3. All NMR
solvents were degassed before use. Variable temperature NMR
experiments were carried out in C6D6 using Varian Unity Inova
300 MHz NMR spectrometer. Infrared spectra were recorded with
a PerkineElmer Spectrum One FT-IR spectrophotometer using
pressed KBr discs. Microanalyses were performed by The Campbell
Microanalytical Laboratory at Otago University (Dunedin, NZ).
Melting points were recorded on a Gallenkamp Melting Point
Apparatus under vacuum unless otherwise stated. Single crystal X-
ray diffraction data were recorded by the X-ray Crystallography
Laboratory at the University of Canterbury (Christchurch, NZ).
Electrospray ionisation mass spectra were either recorded on a PE
Biosystem Mariner 5158 TOF mass spectrometer at Victoria Uni-
versity, or performed by the GlycoSyn QC laboratory at Industrial
Research Limited (Wellington, NZ) using a Waters Q-TOF Premier
Tandem mass spectrometer.
CDCl3): 0.63 (d, JPH¼10.7 Hz, 9H, Bu), 2.91 (s, 12H, NMe2), 3.51 (s,
6H, OMe), 3.59 (dd, JPH¼12.7 Hz, JHH¼5.9 Hz, 2H, PCH), 3.97 (dd,
JPH¼12.7 Hz, JHH¼5.4 Hz, 2H, PCCH), 6.62 (d, JHH¼8.5 Hz, 4H, m-H),
7.21 (d, JHH¼8.5 Hz, 4H, o-H); 13C NMR
d (125 MHz, CDCl3): 28.7
(d, JPC¼10.1 Hz, CMe3), 30.9 (d, JPC¼20.6 Hz, CMe3), 40.6 (s, NMe2),
42.3 (d, JPC¼19.7 Hz, PCH), 52.1 (s, OMe), 65.4 (d, JPC¼16.1 Hz,
PCCH), 112.7 (s, m-C6H4), 127.7 (d, JPC¼8.2 Hz, C6H4), 129.9
(d, JPC¼8.2 Hz, o-C6H4), 149.6 (s, p-C6H4), 168.2 (d, JPC¼10.6 Hz,
COO), 199.4 (d, JPC¼3.4 Hz, CO); 31P NMR
d (121 MHz; CDCl3): 13.0;
HRMS calcd for C29H40N2O5P [MþH]þ: m/z¼527.2675; found:
527.2661; Anal. Calcd for C29H39N2O5P: C, 66.1; H, 7.5; N, 5.3; found:
C, 66.2; H, 7.7; N, 5.4.
Compound 5b: yield 0.64 g, 15%; decomposition at 170 ꢁC. IR
(KBr) nmax 3453, 1735, 1644, 1610 and 1519 cmꢀ1
;
1H NMR
t
d
(600 MHz, CDCl3): 0.52 (d, JPH¼11.6 Hz, 9H, Bu), 2.91 (br s, 6H,
NMe2), 2.95 (br s, 6H, NMe2), 3.62 (s, 3H, OMe), 3.66 (s, 3H, OMe),
3.90 (m, 2H, PCH/PCCH), 4.28 (d, JPH¼5.9 Hz,1H, PCH), 6.51 (br s,1H,
m-C6H4), 6.74 (br s, 3H, m-C6H4), 6.91 (br s, 1H, o-C6H4), 7.40 (br s,
3H, o-C6H4), 12.84 (s, 1H, OH); 13C NMR
d (150 MHz, CDCl3): 27.6 (d,
JPC¼12.3 Hz, CMe3), 30.2 (d, JPC¼21.3 Hz, CMe3), 35.2 (d,
JPC¼24.1 Hz, PCH), 36.5 (d, JPC¼19.1 Hz, PCH), 40.7 (br s, NMe2), 40.8
(br s, NMe2), 52.4 (s, OMe), 52.6 (s, OMe), 57.3 (d, JPC¼17.4 Hz,
PCCH), 103.8 (d, JPC¼9.0 Hz, C]COH), 112.0 (br s, m-C6H4), 112.5 (br
s, m-C6H4), 113.7 (br s, m-C6H4), 127.1 (br s, C6H4), 128.5 (br s, C6H4),
128.9 (br s, o-C6H4), 130.6 (br s, o-C6H4), 149.1 (br s, p-C6H4), 149.7
(br s, p-C6H4), 168.3 (d, JPC¼6.2 Hz, C]COH), 172.6 (d, JPC¼13.2 Hz,
COO), 172.8 (d, JPC¼6.7 Hz, COO); 31P NMR
d (121 MHz; CDCl3): 6.0;
HRMS calcd for C29H40N2O5P [MþH]þ: m/z¼527.2675; found:
527.2677; Anal. Calcd for C29H39N2O5P: C, 66.1; H, 7.5; N, 5.3; found:
C, 66.3; H, 7.6; N, 5.4.

A.I. Zayya, J.L. Spencer / Tetrahedron 68 (2012) 5109e5116
5115
Compound 5c: this phosphorinanone isomer was not isolated.
4.3.4. 4-tert-Butyl-6-methoxycarbonyl-5-(p-dimethylaminophenyl)-
2-methyl-2-aza-4-phosphacyclohexanone (11). Melting point and
elemental analysis data could not be obtained due to contamina-
tion with compound 10. IR (KBr) nmax 1744, 1655, 1612, 1520, 1351
t
1H NMR
d
(600 MHz, CDCl3): 0.96 (d, JPH¼11.3 Hz, 9H, Bu), 2.90
(s, 12H, NMe2), 3.58 (s, 3H, OMe), 3.61 (s, 3H, OMe), 3.78 (dd,
JHH¼12.6 Hz, JPH¼3.2 Hz, 1H, PCH), 4.13 (s, 1H, PCH), 4.42 (dd,
JHH¼12.6 Hz, JPH¼1.0 Hz, 1H, PCCH), 6.57 (d, JHH¼8.8 Hz, 2H,
m-C6H4), 6.72 (m, 2H, m-C6H4), 7.13 (d, JHH¼8.7 Hz, 2H, o-C6H4),
and 1164 cmꢀ1
;
1H NMR
d
(500 MHz, C6D6): 0.79 (d, JPH¼11.5 Hz,
9H, tBu), 2.45 (s, 6H, NMe2), 2.68 (s, 3H, NMe), 2.84 (dd,
JHH¼14.5 Hz, JPH¼2.6 Hz, 1H, CH2), 3.03 (dd, JPH¼18.0 Hz,
JHH¼14.5 Hz, 1H, CH2), 3.32 (s, 3H, OMe), 3.67 (dd, JHH¼12.8 Hz,
JPH¼7.2 Hz, 1H, PCH), 3.90 (dd, JHH¼12.8 Hz, JPH¼5.3 Hz, 1H, PCCH),
6.55 (d, JHH¼8.8 Hz, 2H, m-H), 7.32 (d, JHH¼8.8 Hz, 2H, o-H); 13C
7.24 (m, 2H, o-C6H4), 13.13 (s, 1H, OH); 13C NMR
d (150 MHz,
CDCl3): 29.8 (d, JPC¼13.7 Hz, CMe3), 31.7 (d, JPC¼30.9 Hz, CMe3),
34.3 (d, JPC¼21.3 Hz, PCH), 34.5 (d, JPC¼13.5 Hz, PCH), 40.0 (s,
NMe2), 52.0 (s, OMe), 48.1 (d, JPC¼2.0 Hz, PCCH), 99.9 (d,
JPC¼2.8 Hz, C]COH), 112.0 (s, m-C6H4), 126.0 (d, JPC¼6.7 Hz,
C6H4), 130.8 (d, JPC¼11.8 Hz, C6H4), 128.4 (d, JPC¼5.9 Hz, o-C6H4),
128.7 (d, JPC¼5.9 Hz, o-C6H4), 148.7 (m, p-C6H4), 169.9 (s, C]
COH), 172.6 (d, JPC¼6.7 Hz, COO), 173.1 (s, COO); 31P NMR
NMR
d
(150 MHz, C6D6): 27.4 (d, JPC¼13.0 Hz, CMe3), 29.2 (d,
JPC¼18.7 Hz, CMe3), 36.6 (s, NMe), 39.2 (d, JPC¼17.3 Hz, PCH), 40.0
(s, NMe2), 43.3 (d, JPC¼27.8 Hz, CH2), 51.7 (s, OMe), 57.6 (d,
JPC¼8.6 Hz, PCHC), 112.9 (s, m-C6H4), 129.0 (d, JPC¼13.4 Hz, C6H4),
130.0 (d, JPC¼8.6 Hz, o-C6H4), 149.5 (d, JPC¼1.9 Hz, p-C6H4), 167.6 (s,
d
(121 MHz; CDCl3): 17.5.
CO), 169.7 (d, JPC¼9.1 Hz, COO); 31P NMR
d
(121 MHz; C6D6): ꢀ3.5;
4.3.2. 7-tert-Butyl-1,5-di(methoxycarbonyl)-6,8-bis(p-dimethylami-
nophenyl)-3-methyl-3-aza-7-phosphabicyclo[3.3.1]nonan-9-one
(10). Phosphorinanone isomer 5a (1.7 g, 3.2 mmol), methylamine
(0.30 mL, 3.2 mmol) and formaldehyde (0.51 mL, 6.3 mmol) were
combined in absolute ethanol (30 mL). The reaction mixture was
heated under reflux for one day. Colourless needles crystallised out
of the yellow reaction mixture as it cooled to room temperature.
The needles were filtered in the air, washed with cold ethanol and
dried in vacuo (1.83 g, 75%); decomposition at 200 ꢁC. IR (KBr) nmax
HRMS calcd for C19H30N2O3P [MþH]þ: m/z¼365.1994; found:
365.1997.
Supplementary data
CCDC 839378 contains the supplementary crystallographic data
for compound 10. This information can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB2 1EZ, UK; e-mail: deposit@ccdc.cam.sc.uk. Supplemen-
tary data related to this article can be found online at doi:10.1016/
j.tet.2012.04.038.
1733, 1712, 1612, 1521, 1360 and 1264 cmꢀ1 1H NMR
; d (300 MHz,
C6D6): 0.86 (d, JPH¼9.8 Hz, 9H, tBu), 2.30 (s, 3H, NMe), 2.48 (s, 12H,
NMe2), 2.91 (d, JHH¼12.0 Hz, 2H, CH2), 3.44 (s, 6H, OMe), 3.56 (d,
JHH¼12.5 Hz, 2H, CH2), 4.44 (d, JPH¼5.4 Hz, 2H, PCH), 6.32 (br d,
JHH¼7.8 Hz, 2H, m-H), 6.69 (br d, JHH¼6.7 Hz, 2H, m-H), 7.27 (br d,
JHH¼8.1 Hz, 2H, o-H), 8.17 (br d, JHH¼8.6 Hz, 2H, o-H); 13C NMR
References and notes
d
(75 MHz, C6D6): 28.1 (d, JPC¼13.4 Hz, CMe3), 31.4 (d, JPC¼27.5 Hz,
1. Jeyaraman, R.; Avila, S. Chem. Rev. 1981, 81, 149e174.
2. Breuning, M.; Steiner, M. Synthesis 2008, 18, 2841e2867.
3. Clemo, G. R.; Raper, R. J. Chem. Soc. 1933, 644e645.
4. Mannich, C.; Mohs, P. Chem. Ber. 1930, B63, 608e612.
5. Brandt, W.; Drosihn, S.; Haurand, M.; Holzgrabe, U.; Nachtsheim, C. Arch. Pharm.
Pharm. Med. Chem. 1996, 329, 311e323.
CMe3), 39.9 (s, NMe2), 43.0 (d, JPC¼28.4 Hz, PCH), 44.1 (s, NMe), 51.6
(s, OMe), 60.7 (s, CH2), 65.8 (d, JPC¼1.4 Hz, PCHC), 112.2 (br s,
m-C6H4), 112.4 (br d, JPC¼1.3 Hz, m-C6H4), 132.1 (br d, JPC¼3.4 Hz,
C6H4), 133.1 (br d, JPC¼1.8 Hz, o-C6H4), 133.4 (br d, JPC¼2.0 Hz,
o-C6H4), 149.7 (d, JPC¼1.7 Hz, p-C6H4), 169.7 (d, JPC¼2.2 Hz, COO),
€
6. Kogel, B.; Christoph, T.; Friderichs, E.; Hennies, H. H.; Matthiesen, T.; Schneider,
205.2 (d, JPC¼2.5 Hz, CO); 31P NMR
d (121 MHz; C6D6): 8.4; HRMS
J.; Holzgrabe, U. CNS Drug Rev. 1998, 4, 54e70.
7. Siener, T.; Cambareri, A.; Kuhl, U.; Englberger, W.; Haurand, M.; Kogel, B.;
€
calcd for C32H45N3O5P [MþH]þ: m/z¼582.3096; found: 582.3086;
Anal. Calcd for C32H44N3O5P: C, 66.1; H, 7.6; N, 7.2; found: C, 65.7; H,
7.6; N, 7.0.
Holzgrabe, U. J. Med. Chem. 2000, 43, 3746e3751.
8. Holzgrabe, U.; Brandt, W. J. Med. Chem. 2003, 46, 1383e1389.
9. Black, D. S.; Deacon, G. B.; Rose, M. Tetrahedron 1995, 51, 2055e2076.
ꢁ
10. Gogoll, A.; Grennberg, H.; Axen, A. Organometallics 1997, 16, 1167e1178.
ꢁ
11. Gogoll, A.; Grennberg, H.; Axen, A. Organometallics 1998, 17, 5248e5253.
4.3.3. Mannich reaction of phosphorinanone isomer 5b. Phosphori-
nanone isomer 5b (1.0 g, 1.9 mmol), methylamine (0.16 mL,
1.9 mmol) and formaldehyde (0.28 mL, 3.8 mmol) were combined
in absolute ethanol (100 mL). The reaction mixture was heated
under reflux for 1 day. Large colourless crystals of 10 crystallised
out of the yellow reaction mixture as it cooled to room temper-
ature. The crystals were filtered, washed with ethanol and dried
in the air. All solvent was removed from the filtrate to give
a yellow solid. Washing the solid with ethanol removed most of
the yellow colouration to leave behind 10 as a white solid. Taking
the filtrate to dryness again and washing the resulting yellow
solid with diethyl ether gave another batch of compound 10
bringing the total yield to 0.29 g, 26%. The yields calculated from
this reaction are based on the number of moles of phosphor-
inanone 5b.
The diethyl ether filtrate was taken to dryness and the
resulting yellow residue was washed with hexane. This success-
fully separated the other products from this reaction. The
hexane-insoluble white solid was identified as PN compound 11
but the solid was contaminated with 10. The white solid was
further purified by washing with small volumes of ethyl acetate
to give up to 90% pure sample of compound 11 (0.09 g, 13%). The
hexane wash contained the E/Z isomers of compound 12 (0.27 g,
37%, E/Z 9:1).
12. Comba, P.; Kerscher, M.; Schiek, W. Prog. Inorg. Chem. 2007, 55, 613e704.
13. Arjunan, P.; Berlin, K. D.; Barnes, C. L.; van der Helm, D. J. Org. Chem. 1981, 46,
3196e3204.
14. Bailey, B. R.; Berlin, K. D.; Holt, E. M.; Scherlag, B. J.; Lazzara, R.; Brachmann, J.;
van der Helm, D.; Powell, D. R.; Pantaleo, N. S.; Ruenitz, P. C. J. Med. Chem. 1984,
27, 758e767.
15. Yu, V. K.; Praliev, K. D.; Fomicheva, E. E.; Mukhasheva, R. D.; Klepikova, S. G.
Chem. Heterocycl. Compd. 2006, 42, 512e519.
16. Thompson, M. D.; Smith, G. S.; Berlin, K. D.; Holt, E. M.; Scherlag, B. J.; van
der Helm, D.; Muchmore, S. W.; Fidelis, K. A. J. Med. Chem. 1987, 30,
780e788.
17. Zayya, A. I.; Vagana, R.; Nelson, M. R. M.; Spencer, J. L. Tetrahedron Lett. 2012, 53,
923e926.
18. Enders, D.; Saint-Dizier, A.; Lannou, M.; Lenzen, A. Eur. J. Org. Chem. 2006,
29e49.
19. Tramontini, M.; Angilini, L. Tetrahedron 1990, 46, 1791e1837.
20. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044e1070.
21. Featherman, S. I.; Quin, L. D. J. Am. Chem. Soc. 1975, 97, 4349e4356.
22. Doherty, R.; Haddow, M. F.; Harrison, Z. A.; Orpen, A. G.; Pringle, P. G.; Turner,
A.; Wingad, R. L. Dalton Trans. 2006, 36, 4310e4320.
23. Simova, S. Magn. Reson. Chem. 1998, 36, 505e510.
24. Reynold, W. F.; McLean, S.; Tay, L.; Yu, M.; Enriquez, R. G.; Estwick, D. M.;
Pascoe, K. O. Magn. Reson. Chem. 1997, 35, 455e462.
25. Leon, I.; Enriquez, R. G.; McLean, S.; Reynold, W. F.; Yu, M. Magn. Reson. Chem.
1998, 36, S111eS117.
26. Fernandez, M. J.; Casares, J. M.; Galvez, E.; Bellantato, J. J. Heterocycl. Chem. 1993,
30, 815e817.
27. Chen, C. H.; Reynolds, G. A.; Cossar, B. C. J. Org. Chem. 1981, 46, 2752e2757.
28. Snider, T. E.; Morris, D. L.; Srivastava, K. C.; Berlin, K. D. Org. Synth. 1988, 6,
932e935.

5116
A.I. Zayya, J.L. Spencer / Tetrahedron 68 (2012) 5109e5116
29. Rampal, J. B.; Macdonell, G. D.; Edasery, J. P.; Berlin, K. D.; Rahman, A.; van der
Helm, D.; Pietrusiewicz, K. M. J. Org. Chem. 1981, 46, 1156e1165.
30. Rampal, J. B.; Satyamurthy, N.; Bowen, J. M.; Purdie, N.; Berlin, K. D. J. Am. Chem.
Soc. 1981, 103, 7602e7609.
32. Scheiber, P.; Nemes, P. Liebigs Ann. Chem. 1994, 1033e1036.
33. Harrison, J. R.; O’Brien, P.; Porter, D. W.; Smith, N. M. J. Chem. Soc., Perkin Trans. 1
1999, 3623e3631.
34. Azerbaev, N. I.; Omarov, T. T.; Gubasheva, A. S.; Al’Mukhanova, K. A.; Bai-
salbaeva, S. A. Vestn. Akad. Nauk Kaz. SSR 1975, 2, 47e50.
35. Zayya, A. I.; Spencer, J. L. Organometallics 2012, 31, 2841e2853.
31. Rampal, J. B.; Berlin, K. D.; Edasery, J. P.; Satyamurthy, N.; van der Helm, D. J. Org.
Chem. 1981, 46, 1166e1172.