Aminophosphine oxides in a pyridine series. Studies on the cleavage of pyridine-2- and pyridine-4-yl-(N-benzylamino)-methyldiphenylphosphine oxides in acidic solutions

Article abstract of DOI:10.1016/j.tet.2006.02.048

The synthesis and reactions of 1-(N-benzylamino)-1-(2-pyridyl)- and 1-(N-benzylamino)-1-(4-pyridyl)-methyldiphenylphosphine oxides are described. It was found that these compounds were exceptionally easy to cleave in aqueous sulfuric acid solutions to form diphenylphosphinic acid and the corresponding N-(pyridylmethyl)-benzylamines. The structure of a single diastereoisomer, that is, the (R)-(+)-1-[N-(α-methylbenzylamino)]-1-(4-pyridyl)-(S)-methyldiphen ylphosphine oxide was determined by X-ray crystallography. The acidic alcoholysis of the selected model chiral pyridine aminophosphine oxides was investigated by means of ³¹P NMR spectroscopy. The cleavage kinetics were also studied. On the basis of the obtained results, a mechanism of the cleavage was formulated.

Full text of DOI:10.1016/j.tet.2006.02.048

Tetrahedron 62 (2006) 4506–4518
Aminophosphine oxides in a pyridine series. Studies on the cleavage
of pyridine-2- and pyridine-4-yl-(N-benzylamino)-
methyldiphenylphosphine oxides in acidic solutions
Waldemar Goldeman,a Tomasz K. Olszewski,a Bogdan Boduszeka,
*
and Wanda Sawka-Dobrowolskab
aDepartment of Organic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wybrzeze Wyspianskiego 27,
50-370 Wrocław, Poland
bDepartment of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wrocław, Poland
Received 27 September 2005; revised 27 January 2006; accepted 16 February 2006
Available online 7 March 2006
Abstract—The synthesis and reactions of 1-(N-benzylamino)-1-(2-pyridyl)- and 1-(N-benzylamino)-1-(4-pyridyl)-methyldiphenyl-
phosphine oxides are described. It was found that these compounds were exceptionally easy to cleave in aqueous sulfuric acid solutions
to form diphenylphosphinic acid and the corresponding N-(pyridylmethyl)-benzylamines. The structure of a single diastereoisomer, that is,
the (R)-(C)-1-[N-(a-methylbenzylamino)]-1-(4-pyridyl)-(S)-methyldiphenylphosphine oxide was determined by X-ray crystallography. The
acidic alcoholysis of the selected model chiral pyridine aminophosphine oxides was investigated by means of 31P NMR spectroscopy.
The cleavage kinetics were also studied. On the basis of the obtained results, a mechanism of the cleavage was formulated.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
observed. Similarly, some oxygen heterocyclic phosphonic
acids, that is, the pyrone-2, chromone-2 and coumarin-4
derivatives of the aminomethylphosphonic acid were
reportedly cleaved in the same manner.7 Interestingly, we
also observed8 that the pyridine aminophosphinic acids
were likewise cleaved by aqueous sulfuric acid to form the
corresponding secondary pyridylamines and arylphos-
phonic acids. The latter cleavage proceeded quickly, even
at room temperature.8 All of these cleavages, which
occurred on pyridine aminophosphonic acids and related
phosphorus compounds, are illustrated in Scheme 1.
Organophosphorus compounds, aminophosphonic acids in
particular, are believed to be stable, durable compounds,
resistant to decomposition in both basic and acidic
solutions. However, there were a few reports describing
the C–P bond cleavage in some functionalized phosphonate
compounds in acidic conditions.1–8 For example, the acid-
catalyzed fragmentation of aromatic a-oxyiminophospho-
nates was reported in the late 1980s.1–3 Recently, an
example of the oxidative cleavage of a C–P bond in
1-amino-1-(3,4-dihydroxyphenyl)-methylphosphonic acid
in low pH was described.4 First of all, we reported5–7 that
certain heterocyclic aminophosphonates were amenable to
definite cleavage in acidic solutions at elevated tempera-
tures. It mainly concerned the pyridine derivatives of
aminomethylphosphonic acid, namely the pyridine-2-yl or
pyridine-4-yl-(N-alkylamino)-methylphosphonic acids5,6
and their esters,5 which are easily cleaved when heated for
a few hours in aqueous sulfuric, or hydrochloric acid at
95 8C. As a result, the formation of secondary N-(pyridyl-
methyl)-alkylamines and phosphoric acid (H3PO4) was
The chemical nature of these cleavage reactions still
remains unclear, despite some attempts to explain it.5–7
Therefore, these reactions became the subject of a more
detailed study in our laboratory.
Particular importance was placed on pyridine amino-
phosphine oxides, which are suitable compounds for
studying the cleavage in acidic conditions due to the
exceptional ease of the C–P bond cleavage. Likewise, the
actual possibility of the synthesis of certain optically active
pyridine aminophosphine oxides with a definite configur-
ation at a-carbon and (or) at phosphorus atom is of great
importance in clarifying the basic questions connected with
the plausible mechanism of these cleavage reactions.
Keywords: Aminophosphine oxides; Pyridine; Acidic solutions.
*
Corresponding author. Tel.: C48 713202917; fax: C48 713284064;
e-mail: bogdan.boduszek@pwr.wroc.pl
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.048

W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
4507
Scheme 1. Cleavage of the pyridine aminophosphonic acids in acidic solutions.
There are two main alternative mechanisms for a C–P bond
breaking in the functionalized phosphonates in acidic
conditions presented in the chemical literature.2
the second one is a metaphosphate-like moiety C. The C is
actually the ‘protonated’ metaphosphate (a phosphiny-
lium,12,13 or phosphacylium cation14,15) and therefore, as a
reactive intermediate, can react with solvent (water) to form a
final product. The B fragment transforms into the amine
(Scheme 2), by incorporating the proton. A driving force to
trigger the cleavage is the presence of a positive charge of
protonated nitrogen in the aminophosphonate A.
The first mechanism is a dissociative-type mechanism
[SN1(P)], which assumes the formation of a monomeric
metaphosphate moiety after the rupture of a C–P bond. The
metaphosphate, as a reactive intermediate, is then trapped
by the solvent to form products in a nucleophilic process.
The second mechanism is an associative-type mechanism
[SN2(P)], which involves a direct nucleophilic attack of a
solvent molecule at phosphorus in the phosphonate prior to
the breaking of a C–P bond. The aforementioned alternative
mechanisms would be taken in consideration for the
cleavage of the pyridine aminophosphonic acids on
the condition that in the considered dissociative mechanism,
the formed species is really ‘protonated’ metaphosphate
moiety C due to the strong acidic conditions. These
mechanisms are shown in Schemes 2 and 3, respectively.
An alternative associative mechanism6 assumes that after
the preceding protonation of an oxygen atom in a
phosphoryl group coincides with an attack of a solvent
molecule at a positively charged phosphorus atom in the
aminophosphonate D (Scheme 3). Further reorganization of
the D gives the final fragmentary products as a result of the
breaking of the C–P bond.
In this paper, we describe in detail the results of our studies
regarding the cleavage of racemic and optically active
pyridine aminophosphine oxides 4a–i in aqueous acidic
solutions. Additionally, the cleavage of aminophosphine
oxides in the presence of some alcohols was explored. Also,
the use of certain optically active aminophosphine oxides
with defined configurations at phosphorus and a-carbon
The proposed dissociative mechanism,5,6 shown in Scheme 2,
relies upon the breaking of a C–P bond in aminophosphonate
A and the formation of two fragmentary products (B, C).
One of the intermediates is an enamine-like moiety B and
Scheme 2. Dissociative mechanism of the cleavage of pyridine aminophosphonic acids.
Scheme 3. Associative mechanism of the cleavage of pyridine aminophosphonic acids.

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W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
atoms was studied in order to find the final conclusions
about the proposed mechanism.
2. Results and discussion
2.1. Synthesis of pyridine aminophosphine oxides
The new pyridine aminophosphine oxides were prepared
from pyridinecarboxaldehydes, primary amines and phos-
phine oxides, according to a method described earlier.8
Thus, treatment of the pyridinecarboxaldehydes 1a,b with
benzylamine 2a, or butylamine 2b, followed by the addition
of diphenylphosphine oxide 3a, led to the formation of
racemic 1-(N-alkylamino)-1-(2-pyridyl)- and 1-(N-alkyl-
amino)-1-(4-pyridyl)-methyldiphenylphosphine oxides 4a–d
in high yields (Scheme 4).
Scheme 5. Synthesis of the optically active pyridine aminophosphine
oxides.
butylphenylphosphine oxide10 by resolution of the racemate
with the use of (S)-(C)-mandelic acid, according to a
method described by Drabowicz, et al.11a
Scheme 4. Synthesis of the racemic pyridine aminophosphine oxides.
The most obvious route for the synthesis of optically active
aminophosphine oxides is the addition of enantiomerically
pure P-chiral phosphine oxides to chiral imines, or imines
bearing a chiral auxiliary.9 Thus, diastereomerically pure
pyridine aminophosphine oxides 4e–h were obtained in
a sequence of reactions starting from the corresponding
pyridinecarboxaldehyde 1 and enantiomerically pure
(R)-(C)-a-methylbenzylamine (2c) and (S)-(K)-tert-butyl-
phenylphosphine oxide (3b),11b or (R)-(C)-tert-
butylphenylphosphine (3c),11b respectively (Scheme 5).
For further cleavage studies, one more example of an
optically active aminophosphine oxide, that is, the (C)-1-
[N-(a-methylbenzylamino)]-1-(4-pyridyl)-methyl-phenyl-
methylphosphine oxide (4i), was synthesized (Scheme 5).
The aminophosphine oxide was obtained from pyridine-4-
carboxaldehyde (1b), (R)-(C)-a-methylbenzylamine (2c)
and racemic phenylmethylphosphine oxide 3d.37,39
These reactions proceeded with significant stereoselectivity
and gave a non-equal mixture of two diastereoisomers. The
ratios of the stereoisomers were determined by 31P NMR
spectroscopy and were equal to 60:40 for 4e, 75:25 for 4f,
84:16 for 4g, and 82:18 for 4h. The separation of the major
diastereoisomers was achieved by a simple crystallization
from acetone to give, in each case, the prevailing
diastereoisomer (Scheme 5).
Major diastereoisomers (4e–h) possessed with a S configur-
ation on the tertiary a-carbon atom (in the methine group),
according to the 1H and 31P NMR spectra of the aminopho-
sphine oxides and by comparison with X-ray analysis for the
diastereoisomer 4g (Fig. 1). The predominance in the
formation of the diastereoisomers with a S configuration at
the a-carbon is in agreement with the literature data.9
Optically active phosphine oxides 3b and 3c (S and R
enantiomers), used for the synthesis of aminophosphine
oxides 4h and 4e, were obtained from racemic tert-
Figure 1. Structure of pyridine-4-yl-(N-a-methylbenzylamino)-methyldi-
phenylphosphine oxide 4g.

W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
4509
The single diastereoisomer 4i was isolated from the product
by recrystallization from acetone.
relative quantities of the phosphorus-containing products
and starting materials were estimated from the correspond-
ing integrated 31P NMR signals. In this case, the appearance
of a signal due to phosphinic acid 7 (or 8), together with the
subsequent decay of a signal corresponding to the 4 was
observed. On the basis of 31P NMR data, the rate constants
were calculated. The measured cleavages followed pseudo-
first-order kinetics. It was found that the rate constants were
strongly dependent on the concentration of the sulfuric acid
(entry; 1 and 2, Table 1).
By analogy to the preceding results, the 4i was assigned as
the stereoisomer with a S configuration at the a-carbon. The
configuration at phosphorus was the same as in the case of
4e (see the Sections 2.7 and 4.8.6).
In summary, all of the syntheses were carried out in
dichloromethane solutions at room temperature, in a simple
way, to give the diastereomerically pure pyridine amino-
phosphine oxides 4a–h as crystalline solids in moderate
yields.
The measured cleavages followed pseudo-first-order
kinetics. It was found that the rate constants were
strongly dependent on the concentration of the sulfuric
acid (entry; 1 and 2, Table 1). It was also illustrative that
the 2-pyridyl derivative 4a underwent cleavage 3–4 times
faster than the corresponding 4-pyridyl one (4b). The
runs, which were performed in deuterated solvents and
with the use of deuterated reagents, proved that the
cleavages were considerably faster in solutions of
common, non-deuterated acids. It was also possible to
calculate the kinetic isotope effects in some cases (entry;
4, 6, 8, data for 4f, 4g and 4h, Table 1). All kinetic
results demonstrate that the protonation of pyridine
aminophosphine oxides has a profound effect on the
cleavage of C–P bonds. The kinetic isotope effects
pointed out that the protons were involved on the rate-
determining step of the cleavage. Such values of the
kinetic isotope effects (kH/kDO2, Table 1) rather exclude
an alleged nucleophilic attack of the solvent molecule on
the phosphorus atom in the aminophosphine oxide,
because in such a case kH/kD!1 should be expected
(due to a higher concentration of deuterated phosphorus
species in D2O, in comparison with the concentration of
the corresponding protonated ones in H2O). The obtained
rate constants are summarized in Table 1.
2.2. Cleavage of pyridine aminophosphine oxides 4a–h
The cleavage of pyridine aminophosphine oxides 4a–h
occurred when the solution of these aminophosphine oxides
in aqueous 10% sulfuric acid was heated at 95 8C for 2–10 h.
As a result, there was the formation of the N-(pyridyl-
methyl)-alkylamines 5a–c, 6a–c and diphenylphosphinic
acid 7, or tert-butylphenylphosphinic acid 8, respectively.
Because of a low solubility of the formed phosphinic acids
in the aqueous medium, the acids 7 and 8 separated from the
reaction solution. In turn, amines 5a–c, 6a–c were isolated
by extraction from alkaline reaction mixture. The overall
cleavage of the 4a–h is shown in Scheme 6.
The cleavage of 4a–h also proceeded at room temperature;
however, much slower, requiring a considerable longer
period of time to complete the reaction. It was found,
according to the 31P NMR data, that the pyridine-2
aminophosphine oxides were cleaved 3–4 times faster
than corresponding pyridine-4 compounds.
2.3. Kinetic measurements
For kinetic purposes, the cleavage of the selected amino-
phosphine oxides (4a,b,f,g,h) were run in 50% (v/v)
aqueous methanol solutions, containing a definite quantity
of sulfuric acid. The use of aqueous methanol was to evade
the precipitation of the formed phosphinic acid 7 (or 8),
during kinetic measurements. The reactions were run and
measured in NMR tubes by 31P NMR spectroscopy and the
It is noteworthy that the rate constants were calculated from
estimated 31P NMR integrated signals, and therefore, these
results should not be considered as exact data for mere
kinetic studies. More persuasive arguments for the proposed
mechanism were found during further studies on the
cleavage of optically active pyridine aminophosphine
oxides in methanolic solutions.
Scheme 6. Cleavage of the pyridine aminophosphine oxides in acidic solutions.

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W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
Table 1. Rate constants for cleavage of the aminophosphine oxides (4a,b and 4f,g,h) at 20 8C
Entry
Compound
Solvent
Concn of compound Concn of acid
mol LK1
Kinetic parameters
mol LK1
102 kobsd hK1
t1/2, kH/kD
1
2
4a
4b
50% Aqueous methanol
50% Aqueous methanol
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.20
0.20
0.5 (H2SO4)
1.0 (H2SO4)
2.0 (H2SO4)
0.5 (H2SO4)
1.0 (H2SO4)
2.0 (H2SO4)
1.0 (H2SO4)
1.0 (D2SO4)
1.0 (H2SO4)
1.0 (D2SO4)
1.0 (H2SO4)
1.0 (D2SO4)
0.83
6.17
15.08
1.17
1.78
2.78
1.08
0.43
0.95
0.30
0.81
0.34
t1/2aZ11.2 h
t1/2aZ38.9 h
t1/2Z64.2 h
t1/2Z161 h, kH/kDZ2.53
t1/2Z73.0 h
t1/2Z231 h, kH/kDZ3.17
t1/2Z85.3 h
t1/2Z202 h, kH/kDZ2.36
3
4
5
6
7
8
4f
4f
4g
4g
4h
4h
50% Aqueous methanol
50% CH3OD in D2O
50% Aqueous methanol
50% CH3OD in D2O
50% Aqueous methanol
50% CH3OD in D2O
a
1/2
t
was measured for 1 M H2SO4 solution.
2.4. Cleavage of (R)-(D)-1-[N-(a-methylbenzylamino)]-
1-(2-pyridyl)-(S)-methyldiphenylphosphine oxide (4f)
and (R)-(D)-1-[N-(a-methylbenzylamino)]-1-(4-pyridyl)-
(S)-methyldiphenylphosphine oxide (4g) in D2O
It was described14–16 that the heterolytic cleavage of a bond
between phosphorus and a leaving group, occurring on a
chiral center, should lead to the formation of racemic
products, in the case of a dissociative mechanism. Likewise,
the inversion of the configuration at phosphorus should be
observed in the case of a bimolecular, associative
mechanism, that is, the nucleophilic substitution of a
phosphorus atom.15,16
The basic question connected with a mechanism of the
considered cleavage is the formation of a highly reactive
intermediate, that is, the metaphosphate, or its equivalent.
The dissociative mechanism assumes the formation of such
species by a rupture of a C–P bond and the elimination of a
The questions that arise with the mechanism of the present
cleavage could be answered by the use of appropriate
optically active aminophosphine oxides. Therefore, we took
the aminophosphine oxides (4f, 4g) into account for further
studies. The cleavage of 4f and 4g was invoked by D2SO4 in
D2O solutions. The use of D2SO4 should generate an
additional stereogenic center at the a-carbon of the formed
amine due to formation of the CHD group. One might expect
that the cleavage of aminophosphine oxide by the elimination
of phosphorus moiety should lead to racemization at the
a-carbon in the amine due to the formation of a planar, imine-
like intermediate. Such a course of reaction is illustrated in
Scheme 7 for the cleavage of 4f and the formation of the
deuterated amine 5c–d, via the intermediate B.
‘protonated’ metaphosphate (a phosphinylium cation12,13
)
in the first stage of a reaction. In order to find out that the
phosphinylium cation is formed, a trapping agent for it
should be used. Usually, in aqueous solutions, the
corresponding phosphinic acids were formed. If alcohol is
used as a solvent, the corresponding phosphoester should be
obtained. In turn, the final amine may be formed by the
incorporation of a proton to an enamine-like heterocyclic
fragment, or by a bimolecular process, in which, the
attachment of the proton coincides with the departure of the
phosphinylium cation. In this case, the amine would be
formed directly, as a result of the electrophilic substitution
of the phosphorus moiety.
On the other hand, the cleavage might be caused by a direct
nucleophilic attack of the solvent on a phosphorus atom
with a positive charge in the aminophosphine oxide
molecule. Such displacement might be considered a
nucleophilic substitution occurring at phosphorus in the
aminophosphine oxide.
The experiments have demonstrated that the cleavages of 4f
and 4g led to the racemization at the a-carbon (as shown by
1H NMR spectra of the formed amines).
Signals attributed to the CHD groups in the amines 5c–d,
6c–d, with deuterium incorporated can be easily
Scheme 7. Mechanism of the cleavage of aminophosphine oxide 4f in D2SO4 solution.

W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
4511
rationalized by analyzing the corresponding 1H NMR
spectra. The ratios of the formed diastereoisomers were
were established on the basis of their literature data.27–32 A
course of the reaction is shown in Scheme 8.
1
determined from H NMR signals of the CHD groups. A
similar question was exploited by Japanese researchers17
and others18 for some titanium, and chromium complexes of
deuterated benzylamine derivatives, where the proper ratio
of the diastereoisomers with the incorporated deuterium
Due to the steric effects linked with a particular alcohol, the
yield of the phosphoesters should fall in this order: MeOHO
EtOHOi-PrOHOt-BuOH. This is seen in the present case.
1
The formation of the phosphoesters confirms the assumed
dissociative mechanism of the cleavage of the aminopho-
sphine oxide 4a. The formation of the 9a–d and
diphenylphosphinic acid 7, with the amounts corresponding
to the molar ratio of alcohol and water, additionally verifies
this assumption. These results exclude an alternative
associative mechanism, at least in the case of the
aminophosphine oxide 4a.
were calculated from integrated H NMR signals.
These results support a dissociative mechanism, at least in
the case of 4f and 4g, which is connected with the formation
of a phosphinylium species (C, Scheme 7).
The four-coordinate phosphinylium cation C that is
assumed to be formed in the first stage of the fragmentation
of the 4f and 4g is closely associated with the
monomeric metaphosphate (HOPO2), which is well-known.
The metaphosphate and its chemistry is also the subject of
two reviews.19,20 First of all, the metaphosphate, as transient
species, is postulated as the putative intermediate in
biological phosphoryl-transfer reactions20 and in many
fragmentations of organophosphorus compounds.19,20
More convincing proof for the proposed mechanism of the
cleavage should come from the cleavage of the P-chiral
aminophosphine oxide 4e.
2.6. Methanolysisof(D)-1-(N-benzylamino)-1-(4-pyridyl)-
(S)-methyl-t-butylphenyl-(SP)-phosphine oxide (4e)
The phosphinylium species, which is allegedly formed in
the case of the cleavage of a P-chiral aminophosphine
oxide, should lead to the formation of racemic products, that
is, the formation of the racemic methyl phosphoester when
the cleavage is carried out in methanol. On the contrary, if
the product is formed by a bimolecular process (a
nucleophilic substitution at phosphorus), the formed
phosphoester should exhibit optical activity (an inversion
of configuration is expected in this case).
2.5. Cleavage of 1-(N-benzylamino)-1-(2-pyridyl)-
methyldiphenylphosphine oxide (4a) in aqueous
solutions of different alcohols
One of the commonly accepted diagnostic tests for an
involvement of metaphosphate, is phosphorylation of
alcohols, especially hindered alcohols,19–21 or amines.22
The metaphosphate (ROPO2) is considered a strong
electrophile,19 and therefore, it takes place in an aromatic
substitution, coinciding with an activated aromatic ring.23
This criterion was examined in the present work by the
cleavage of the representative aminophosphine oxide 4a, in
aqueous solutions of different alcohols. The formation of
phosphoesters (i.e., the corresponding alkyl esters of
diphenylphosphinic acid, in this case) was expected if the
‘protonated’ metaphosphate (a phosphinylium cation) was
involved in the cleavage.
In order to verify such a hypothesis, the P-chiral,
aminophosphine oxide 4e was cleaved by 1 M sulfuric
acid in methanol.
The projected cleavages were carried out at room
temperature. The reactants were kept for a month to
accomplish the reaction. Surprisingly, the major products
found and isolated from the reaction mixtures were starting
reagents; that is, the phosphine oxide 3c and the imine 11
(see the Scheme 9). The expected phosphoester 10 was
formed in a minimal amount.
The cleavages of 4a were carried out in 50% aqueous
solutions of various alcohols. The solutions containing
methanol, ethanol, isopropanol, or tert-butanol and a
definite amount of sulfuric acid were used. The progress
of the reaction was monitored by 31P NMR spectroscopy.
The solutions were kept for 2 weeks at room temperature to
complete the reaction and then worked-up to isolate the
products. The products were phosphinic alkyl esters 9a–d,
N-(2-pyridylmethyl)-benzylamine (5a) and diphenyl-phos-
phinic acid (7). The structures of the phosphoesters 9a–d
The cleavage was in fact a reverse reaction of the formation
of pyridine aminophosphine oxide 4e. Such a reaction was
observed only in pure methanol, in the presence of sulfuric
acid.
During work-up, the formed products underwent further
transformations. The imine 11 decomposed to aldehyde 1b,
Scheme 8. Cleavage of the pyridine aminophosphine oxide 4a in 50% aqueous alcohols.

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W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
Scheme 9. Cleavage of the pyridine aminophosphine oxide 4e in pure methanol.
which partially reacted with phosphine oxide 3c to give the
pyridine hydroxyphosphine oxide 12, as a final, stable
product (see the Scheme 9).
aminophosphine oxide 4i, which ended up being more
suitable for the isolation of the corresponding phosphoester.
The aminophosphine oxide 4i comprised the methyl and
phenyl groups at phosphorus, which should not offer such
steric obstacles responsible for the pathway B.
In this case, there are two competitive reactions, shown in
the Scheme 9, relying upon the site of an attack of an
electrophile in the aminophosphine oxide 4e. If a proton
attacks the a-carbon, it should lead to methyl ester 10
(pathway A, Scheme 9) via the elimination of metaphos-
phate-like moiety. In the second case, while the proton
attacks the phosphorus atom (pathway B, Scheme 9), such a
process should give the phosphine oxide 3c by the
elimination of the imine 11 (see the Scheme 10).
2.7. Methanolysis of the (D)-1-[N-(a-methylbenzyl-
amino)]-1-(4-pyridyl)-methyl-phenylmethylphosphine
oxide (4i)
The optically active aminophosphine oxide 4i, {[a]20
D
C33.0 (c 1.0, CHCl3)} was cleaved in the methanolic
solution of sulfuric acid. Likewise, as in the previous case,
the phosphine oxide 3d37,39 and methyl phosphoester
13,40,41 together with the corresponding amine 6c and
aldehyde 1b, were isolated from the reaction mixture (see
the Scheme 11).
It was assumed15,16 that the heterolytic bond cleavage
between phosphorus and carbon would lead to the
formation of the products with a retained configuration.
It happened in the considered case, where the substitution
at phosphorus caused the formation of t-butylphenyl-
phosphine oxide 3c, with the retained configuration. Such
a pathway seems to be preferable for the pyridine
aminophosphine oxides with a bulky group at phos-
phorus, demonstrating a large steric effect, as for
example, the tert-butyl group.
The ester 13 and phosphine oxide 3d were formed roughly
in a molar ratio equal to 1:1.
After the separation of the ester 13 and phosphine oxide 3d,
the corresponding optical rotations of the 3d and 13 were
measured. Phosphine oxide 3d showed the optical activity
{[a]20D C26.0 (c 0.4, CHCl3)}, likewise as did the ester 13,
The expected methyl t-butylphenylphosphinate (10)11a,33–36
was also formed, but the quantity was very low. Due to the
small amount of ester, isolation and the measurement of the
optical activity of 10 was hard to realize. In order to avoid
such difficulties, we turned to another optically active
which has the optical activity {[a]20 C20.0 (c 0.4,
D
CHCl3)}. The formation of the optically active ester 13
indicates that the cleavage of 4i is
a complex
process, having among other things a bimolecular character
(Scheme 11).
Scheme 10. Substitution at phosphorus in 4e (pathway B).

W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
4513
with the retention of the configuration at phosphorus. In the
case of 4i, the corresponding phosphoester 13 was also
formed, with the inversion of the configuration.
The t-butylphosphine oxide (3c) was formed in an action of
the proton on the phosphorus atom in the hindered
aminophosphine oxide 4e, accompanied by the elimination
of the corresponding aldimine.
The formation of methyl phosphoester 13 with the inversion
of the configuration at phosphorus indicates that, in the case
of 4i, the cleavage had a bimolecular character, and a
prospective formation of the metaphosphate-like moiety
was doubtful. However, a partial loss of the optical activity
of the formed ester suggested that the dissociative
mechanism was possible to some extent.
Scheme 11. Cleavage of the pyridine aminophosphine oxide 4i in pure
methanol.
The results showed that the presented cleavages of the
pyridine aminophosphine oxides have had diversified
mechanisms depending on the chemical nature of the
groups attached to phosphorus.
In the transition state (Scheme 11), methanol is displacing
the enamine-like moiety in the 4i, which is attached to a
phosphorus atom, in the bimolecular process. However, the
decrease of the optical activity of the ester indicates that a
partial racemization of the product also occurred during the
cleavage. The enantiomerically pure (C)-(RP)-methyl
phenylmethylphosphinate40,41 (13) has the specific rotation:
4. Experimental
4.1. General
[a]20 C45.2 (c 3.7, MeOH).41
D
1H and 31P NMR spectra were measured on a Bruker
Avance 300 MHz spectrometer using TMS as an internal
standard. IR spectra were recorded on a Perkin Elmer 1600
FTIR spectrophotometer. GC/MS analyses were determined
on a Hewlett Packard 5890 II gas chromatograph (HP-5,
25 m capillary column) with a Hewlett Packard mass
spectrometer 5971 A (EI, 70 eV) and on a Finnigan TSQ
700 instrument (electrospray ionization on mode: ESIC
Q1MS). Optical rotations were measured at 589 nm using
an Optical Activity Ltd. Model AA-5 automatic polari-
meter. Melting points were determined using an Electro-
thermal 9200 apparatus and a Boetius hot-stage apparatus
and were uncorrected. Elemental analyses were done in the
Laboratory of Instrumental Analysis in the Institute. Thin-
layer chromatography analyses were performed on silica gel
60 precoated plates (Merck). Reagents used were obtained
Aminophosphine oxides possessing aliphatic, or more basic
groups at phosphorus (4e, 4i) are more preferential for the
bimolecular process, involving an attack of the proton on the
a-carbon and the simultaneous formation of the phospho-
ester by an interaction of methanol with a positively charged
phosphine oxide moiety. In turn, the corresponding
phosphine oxide (3c or 3d) is formed in a parallel process,
involving an attack of the proton at phosphorus.
Examining the cleavage of amino-diphenylphosphine
oxides 4a, 4f and 4g, possessing electron-withdrawing
groups at phosphorus, it looks that the monomolecular,
dissociative mechanism is preferable there.
´
from the Sigma–Aldrich Company (Poznan, Poland).
Solvents were of commercial quality and purchased from
a local supplier (POCh Gliwice, Poland).
3. Conclusions
A series of racemic and optically active pyridine
aminophosphine oxides were prepared by the addition of
the phosphine oxides to chiral and achiral pyridine
aldimines. The obtained pyridine aminophosphine
oxides were easily cleaved in acidic solutions to form
the corresponding N-(pyridylmethyl)-benzylamines and
aryl(alkyl)phosphinic acids. The cleavage of pyridine
aminophosphine oxides was studied in different solutions,
containing water, deuterium oxide and various alcohols,
respectively. The obtained results demonstrated that the
cleavage was a dissociative process and proceeded via a
phosphinylium cation stage, in the case of the pyridine
aminodiphenylphosphine oxides 4a and 4b. In the case of
aminophosphine oxides 4e and 4i, possessing bulky groups
at phosphorus, the cleavage in methanol underwent by two
parallel, different ways. It was found that the main products
were initial t-butyl- and methylphenylphosphine oxides,
Racemic methylphenylphosphine oxide 3d37 was prepared
from ethyl methylphosphinate38 according to the procedure
described in.39
Resolution of the racemic t-butylphosphine oxide was done
by the method described by Drabowicz et al.11a
4.2. Procedure for preparation of racemic pyridine
aminophosphine oxides 4a–d
To a solution of pyridine aldehyde (1a or 1b; 1.07 g,
10 mmol) in dichloromethane (25 mL) benzylamine (2a;
1.07 g, 10 mmol), or butylamine (2b; 0.73 g, 10 mmol) was
added, respectively, and a mixture was left for 24 h at room
temperature. After this, anhydrous sodium sulfate (5 g) was
added, followed by addition of diphenylphosphine oxide

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W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
(3a; 2.02 g, 10 mmol). The whole mixture was left for 24 h
and filtered. Filtrate was evaporated to dryness and an oily
residue was kept at 60 8C for 2 h to finish up the reaction.
Solidified products were crystallized from acetone (25 mL);
(4-pyridyl derivatives), or from a mixture of toluene and
hexane (1:1 v/v, 25 mL); (2-pyridyl derivatives). After
cooling separated crystals were filtered off, washed with
hexane and dried to give the racemic pyridine aminophos-
phine oxides 4a–d.
4-pyridyl derivative, the product 4g was crystallized from a
mixture of methylene chloride and hexane (1:1, v/v), while
in the case of 2-pyridyl derivative 4f, the crude product was
treated first with warm acetone (5 mL) in order to remove an
unsoluble by-product (the 1-hydroxy-1-(2-pyridyl)-methyl-
diphenyl-phosphine oxide). The filtrate was evaporated to
dryness and the residue was recrystallized from methylene
chloride and hexane (1:1, v/v).
The remaining mother solution was evaporated to give a
product, composed with two stereoisomers, in which the R,R
stereoisomer was predominant over of the S,R one.
4.2.1. Compound 4a. White solid, 3.50 g, yield 88%, mp
120–122 8C, lit.8 102–104 8C. Spectroscopic data consistent
with that reported.8
4.3.1. Compound 4e. White solid, 1.36 g, yield 36%, mp
162–165 8C. 1H NMR; dH (CDCl3; 300 MHz): 8.55 (2H, d,
JZ5.9 Hz, 2,6-PyH); 7.60 (2H, m, 3,5-PyH); 7.50–6.86
(10H, m, ArH); 4.05 (1H, d, JZ7.6 Hz, CH–P); 3.62 (1H, d,
JZ13.4 Hz, NCH2); 3.22 (1H, d, JZ13.4 Hz, NCH2); 2.22
(1H, br s, NH), 0.79 (9H, d, JZ14.6 Hz, t-Bu). 31P NMR; dP
(CDCl3; 121.5 MHz): 50.15 (s). IR, nmax (KBr): 3350; 3259
(NH); 3028; 2961; 2868; 1593; 1495; 1437; 1165 (P]O);
4.2.2. Compound 4b. White solid, 2.87 g, yield 72%, mp
158–160 8C, lit.8 148–149 8C. Spectroscopic data consistent
with that reported.8
4.2.3. Compound 4c. White solid, 2.95 g, yield 81%, mp
100–102 8C. 1H NMR; dH (CDCl3; 300 MHz): 8.37 (1H, d,
JZ4.8 Hz, 6-PyH); 7.84–7.08 (13H, m, PyH, ArH); 4.72
(1H, d, JZ13.3 Hz, CH–P); 2.59–2.43 (2H, m, NCH2); 1.41
(2H, m, CH2); 1.23 (2H, m, CH2); 0.81 (3H, t, JZ7.3 Hz,
CH3). 31P NMR; dP (CDCl3; 121.5 MHz): 29.62 (s). IR, nmax
(KBr): 3387 (NH); 3039; 2916; 2806; 1578; 1471; 1428;
1146 (P]O); 1108; 1037; 990; 831; 744; 733 (P–C); 690;
634; 611; 549; 511 cmK1. Anal. Calcd for C22H25N2OP,
requires C, 72.51; H, 6.92; N, 7.69; P, 8.45. Found: C,
72.21; H, 6.98; N, 7.54; P, 8.43%.
1105; 818; 743 (P–C); 699; 640; 554; 490 cmK1. [a]20
D
C2.1 (c 0.7, CHCl3). Anal. Calcd for C23H27N2OP, requires
C, 72.99; H, 7.19; N, 7.40; P, 8.18. Found: C, 72.81; H, 7.28;
N, 7.25; P, 8.22%.
4.3.2. Compound 4f. White solid, 1.73 g, yield 42%, mp
135–137 8C. 1H NMR; dH (CDCl3; 300 MHz): 8.34 (1H, d,
JZ4.8 Hz, 6-PyH); 7.95–7.87 (4H, m, PyH, ArH); 7.55–
7.40 (9H, m, ArH); 7.20–7.15 (2H, m, ArH); 7.13–7.05 (3H,
m, ArH); 4.76 (1H, d, JZ13.5 Hz, CH–P); 3.51 (1H, q,
JZ6.5 Hz, CH); 3.23 (1H, br s, NH); 1.30 (3H, d,
JZ6.5 Hz, CH3). 31P NMR; dP (CDCl3; 121.5 MHz):
31.37 (s). IR, nmax (KBr): 3439 (NH); 3053; 3005; 2926;
2875; 2808; 1601; 1584; 1566; 1470; 1447; 1437; 1431;
1375; 1309; 1262; 1186 (P]O); 1119; 1101; 1067; 1048;
1038; 1030; 993; 912; 831; 747; 738 (P–C); 722 (P–C); 693;
639; 606; 555; 515; 487 cmK1. [a]20D C29 (c 1.0, CHCl3).
Anal. Calcd for C25H23N2OP, requires N, 6.79; P, 7.51.
Found: N, 6.49; P, 7.28%.
4.2.4. Compound 4d. White solid, 3.13 g, yield 86%, mp
145–147 8C. 1H NMR; dH (CDCl3; 300 MHz): 8.43 (2H, d,
JZ5.9 Hz, 2,6-PyH); 7.85 (2H, m, 3,5-PyH); 7.62–7.21
(10H, m, ArH); 4.56 (1H, d, JZ12.7 Hz, CH–P); 2.53–2.41
(2H, m, NCH2); 1.40 (2H, m, CH2); 1.23 (2H, m, CH2); 0.83
(3H, t, JZ7.3 Hz, CH3). 31P NMR; dP (CDCl3; 121.5 MHz):
30.52 (s). IR, nmax (KBr): 3297 (NH); 3046; 3006; 2973;
2808; 1582; 1493; 1455; 1326; 1154 (P]O); 1112; 987;
835; 772; 732 (P–C); 681; 641; 558; 512; 491 cmK1. Anal.
Calcd for C22H25N2OP, requires C, 72.51; H, 6.92; N, 7.69;
P, 8.45. Found: C, 72.31; H, 7.08; N, 7.55; P, 8.52%.
4.3.3. Compound 4g. White solid, 2.02 g, yield 49%, mp
174–176 8C. 1H NMR; dH (CDCl3; 300 MHz): 8.39 (2H, d,
JZ4.7 Hz, 2,6-PyH); 7.96 (2H, dd, JZ4.7, 3.1 Hz, 3,5-
PyH); 7.64–7.02 (15H, m, ArH); 4.61 (1H, d, JZ11.2 Hz,
CH–P); 3.62 (1H, q, JZ6.4 Hz, CH); 2.59 (1H, br s, NH);
1.29 (3H, d, JZ6.4 Hz, CH3). 31P NMR; dP (CDCl3;
121.5 MHz): 32.22 (s). IR, nmax (KBr): 3337 (NH); 3057;
3026; 2973; 2848; 2808; 1590; 1560; 1494; 1469; 1451;
1436; 1378; 1326; 1176 (P]O); 1121; 1102; 1070; 1025;
991; 833; 795; 773; 742 (P–C); 723 (P–C); 691; 639; 603;
559; 531; 514; 495 cmK1. [a]20D C79 (c 1.0, CHCl3). Anal.
Calcd for C25H23N2OP, requires N, 6.79; P, 7.51. Found: N,
6.60; P, 7.77%.
4.3. Procedure for preparation of optically active
pyridine aminophosphine oxides 4e–h
To a solution of pyridine aldehyde (1a or 1b; 1.07 g,
10 mmol) in dichloromethane (25 mL) benzylamine (2a;
1.07 g, 10 mmol), or (R)-(C)-a-methylbenzylamine (2c;
1.21 g, 10 mmol) was added, respectively, and a mixture
was left for 48 h at room temperature. Then, the solution
was dried (anh. Na2SO4), filtered, and diphenylphosphine
oxide (3a; 2.02 g, 10 mmol), or (S)-(K)-tert-butylphenyl-
phosphine oxide11 3b, 1.82 g, 10 mmol, [a]20 K24.8
D
(c 1.0, CHCl3), or (R)-(C)-tert-butylphenylphosphine11 3c,
1.82 g, 10 mmol, [a]20 C24.6 (c 1.0, CHCl3) was added,
D
respectively. The formed solution was left for 24 h and
evaporated to dryness to give an oily residue, which was
kept for 2 h at 60 8C. After this, the oil turned to a whitish
solid. The solid was dissolved in warm acetone (25 mL) and
the solution was kept at room temperature for several hours.
The product crystallized out from the solution. The product
was collected by filtration and dried. If necessary, the
crystallization from acetone was repeated. In the case of
4.3.4. Compound 4h. White solid, 2.12 g, yield 54%, mp
210–212 8C. 1H NMR; dH (CDCl3; 300 MHz): 8.21 (2H, d,
JZ5.9 Hz, 2,6-PyH); 7.44 (2H, d, JZ5.9 Hz, 1.7 Hz, 3,5-
PyH); 7.20–7.05 (10H, m, ArH); 4.51 (1H, d, JZ8.3 Hz,
CH–P); 3.43 (1H, q, JZ6.4 Hz, CH); 2.65 (1H, br s, NH);
1.31 (9H, d, JZ15.0 Hz, t-Bu); 1.24 (3H, d, JZ6.4 Hz,
CH3). 31P NMR; dP (CDCl3; 121.5 MHz): 48.97 (s). IR, nmax
(KBr): 3351 (NH); 3064; 2967; 2868; 1592; 1557; 1459;

W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
4515
1437; 1162 (P]O); 1105; 822; 752 (P–C); 698; 642; 557;
4.5.2. Amines 5a–c, 6a–c. The remained filtrate was
alkalized with an excess of aqueous sodium bicarbonate
solution and extracted with methylene chloride (25 mL).
Evaporation of the extract gave the crude amines 5a–c and
6a–c, which were characterized as oxalate salts. The
oxalates were obtained by a following way; the crude
amine dissolved in acetone (5 mL) and oxalic acid
[(COOH)2$2H2O (0.25 g, 2 mmol)] in acetone (5 mL) was
added and the mixture refrigerated. The separated precipi-
tate was filtered, washed with acetone and dried on air.
492 cmK1. [a]20 C121.8 (c 1.0, CHCl3). Anal. Calcd for
D
C24H29N2OP, requires N, 7.14; P, 7.89. Found: N, 7.01; P,
7.87%.
4.4. Procedure for preparation of optically active
pyridine aminophosphine oxide 4i
To a solution of pyridine-4-carboxaldehyde (1b; 250 mg,
2.34 mmol) in dichloromethane (25 mL) (R)-(C)-a-
methylbenzylamine 2c (280 mg, 2.34 mmol) was added
and a mixture was left for 48 h at room temperature. Then,
the mixture was dried (anh. Na2SO4), filtered, and the
racemic methylphenylphosphine oxide 3d (330 mg,
2.35 mmol) was added. The solution was refluxed for 4 h
and left for 24 h. After evaporation of the solvent, an oily
product was obtained (840 mg). The product was dissolved
in warm acetone (10 mL) and refrigerated. After several
hours, white crystals separated out, which were then
collected by filtration and dried on air. The obtained
product was a pure stereoisomer 4i, according to the NMR
data.
The spectroscopic data for N-(pyridylmethyl)-benzyl(bu-
tyl)amines 5a,b and 6a,b are consistent with those
reported.5,8 The amines 5c and 6c are new compounds and
their spectroscopic data are given below.
4.5.2.1. N-(2-Pyridyl-methyl)-(R)-(D)-a-methylbenzyl
amine 5c. Compound 5c oxalate; white solid, 229 mg, yield
76%, mp 135–137 8C. H NMR; dH (D2O; 300 MHz): 8.46
1
(1H, d, JZ4.5 Hz, 6-PyH); 7.79 (1H, dt, JZ1.65, 7.8 Hz,
4-PyH); 7.44–7.28 (7H, m, PyH, ArH); 4.43 (1H, q,
JZ6.9 Hz, CHCH3); 4.20 (1H, d, JZ14.3 Hz, NCH2); 4.05
(1H, d, JZ14.3 Hz, NCH2); 1.64 (3H, d, JZ6.9 Hz, CH3).
[a]20D C9.0 (c 1.0, H2O).
4.4.1. Compound 4i. White solid, 252 mg, yield 31%, mp
138–140 8C. 1H NMR; dH (CDCl3; 300 MHz): 8.41 (2H, d,
JZ4.3 Hz, 2,6-PyH); 7.53–7.53–7.40 (5H, m, PyH, ArH);
7.19–6.95 (8H, m, ArH); 4.06 (1H, d, JZ13.5 Hz, CH–P);
3.48 (1H, q, JZ6.45 Hz, CH); 1.86 (1H, br s, NH); 1.59
(3H, d, JZ15.3 Hz, P–CH3); 1.17 (3H, d, JZ6.45 Hz, CH3).
31P NMR; dP (CDCl3; 121.5 MHz): 39.11 (s). IR, nmax
(KBr): 3265 (NH); 3051; 2955; 2810; 1588; 1437; 1160
For GC/MS analysis, a sample of oxalate (50 mg) was
treated with 10% aqueous solution of Na2CO3 (3 mL),
extracted with 5 mL CH2Cl2, the extract dried (anh.
Na2SO4) and evaporated to give the free amine 5c, as an
oil (31 mg). GC/MS (HP-5 column, 25 m, temperature
program; 100/6/290): tR (retention time)Z10.41 min; m/z
(EI, 70 eV): 212 (0.1, MC), 211 (1, MK1), 197 (18), 180
(3), 135 (5), 120 (76), 105 (19), 93 (100), 92 (28), 79 (8), 77
(10), 65 (10), 51 (5%).
(P]O); 1105; 820; 751 (P–C); 695; 641; 552 cmK1. [a]20
D
C33.0 (c 1.0, CHCl3). Anal. Calcd for C21H23N2OP,
requires C, 71.98; H, 6.62; N, 8.00; P, 8.84. Found: C,
71.81; H, 6.75; N, 7.88; P, 8.72%.
4.5.2.2. N-(4-Pyridyl-methyl)-(R)-(D)-a-methylbenzyl
amine 6c. Compound 6c oxalate; white solid, 208 mg, yield
69%, mp 178–181 8C. H NMR; dH (D2O; 300 MHz): 7.80
1
4.5. Cleavage of pyridine aminophosphine oxides 4a–h
and isolation of the products
(2H, d, JZ6.7 Hz, 2,6-PyH); 7.62 (2H, d, JZ6.7 Hz, 3,5-
PyH); 7.36 (5H, br s, ArH); 4.44 (1H, q, JZ6.9 Hz, CHCH3);
4.37 (1H, d, JZ14.8 Hz, NCH2); 4.15 (1H, d, JZ14.8 Hz,
A sample of pyridine aminophosphine oxide 4a–h
(1.0 mmol) was dissolved in 10% aqueous H2SO4 solution
(10 mL) and heated at 95–100 8C for 2 h for 2-pyridyl
derivatives, or 10 h for 4-pyridyl derivatives. The reaction
mixture was allowed to stand at room temperature for 24 h
in order to separate the phosphinic acids (7 or 8). Crystals of
the phosphinic acids were collected by filtration and dried
on air. Yield of the 7: 67–90% diphenylphosphinic acid 7 is
a known, commercial compound and its data are given
elsewhere.
NCH2); 1.62 (3H, d, JZ6.9 Hz, CH3). [a]20 C4.0
D
(c 1.0, H2O).
For GC/MS analysis, a sample of oxalate (50 mg) was
treated with 10% aqueous solution of Na2CO3 (3 mL),
extracted with 5 mL CH2Cl2, the extract dried (anh.
Na2SO4) and evaporated to give the free amine 6c, as an
oil (28 mg). GC/MS (HP-5 column, 25 m, temperature
program; 100/25/290): tR (retention time)Z7.49 min; m/z
(EI, 70 eV): 212 (1, MC), 211 (1, MK1), 197 (100), 135
(13), 105 (33), 92 (64), 79 (14), 77 (18), 65 (23), 51 (9%).
4.5.1. t-Butylphenylphosphinic acid 8. Crystalline solid,
yield 131–143 mg, 66–72% (depending from the experi-
ment), mp 157–158 8C, lit.24 154–156 8C, lit.26 155–157 8C.
1H NMR; dH (CDCl3; 300 MHz): 7.75–7.69 (2H, m, ArH);
7.49–7.43 (1H, m, ArH); 7.39–7.33 (2H, m, ArH); 5.67 (br
s, 1H, POH); 1.03 (9H, d, JZ15.7 Hz, t-Bu). 31P NMR; dP
(CDCl3; 121.5 MHz): 54.178 (s). 31P NMR; dP (DMSO;
121.5 MHz): 49.883 (s).
4.6. Kinetic measurements
Solutions of samples of the corresponding pyridine
aminophosphine oxides (c 0.1 mLK1) in aqueous 50%
methanol, containing an appropriate quantity of H2SO4 (the
0.5, 1.0 and 2.0 m LK1 H2SO4 solutions) in NMR tubes
were prepared and thermostated at 20 8C for a desired period
of time (1, 2, 4, 8, 16 h, respectively). The 31P NMR spectra
were consecutively recorded. The kinetic runs in D2O/
MeOD with use of D2SO4 were done similarly. The use of
Spectroscopical and physico-chemical data of the t-butyl-
phenylphosphinic acid 8 were in agreement with the
literature data.24–26

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W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
different concentrations of H2SO4, (or D2SO4) was allowed
to calculate the pseudo-first-order rate constants (kobsd). The
rate constants were determined by plotting the dependence
of log(aKx) on time (where the ‘a’ is a relative quantity of
the starting aminophosphine oxide and the ‘aKx’ represents
a relative quantity of unreacted aminophosphine oxide).
dissolved in 10 mL aqueous-alcoholic solutions (1:1, v/v),
containing 0.98 g (10 mmol) H2SO4. The particular sol-
utions contained methanol, ethanol, iso-propanol and tert-
butanol, respectively. The solutions were kept for 2 weeks at
room temperature. Progress of the reaction was monitored
by 31P NMR spectroscopy. The formed diphenylphosphinic
acid (7) crystallized partially in the reaction mixtures. The
mixtures were filtered to remove the acid 7 and treated with
an excess of aqueous 5% NaHCO3 solution. An oily product
separated, which was extracted with dichloromethane
(25 mL). The extract was dried (anhydrous Na2SO4),
filtered and evaporated to give an oil (0.22–0.28 g), which
was a mixture of N-(2-pyridylmethyl)-benzylamine 5a and
corresponding alkyl phosphoester 9a–d. Separation of the
esters and amines was done as follows; the whole mixture
was treated with 1 M aqueous HCl (10 mL) and extracted
with dichloromethane (25 mL). After drying (anh. Na2SO4),
the extract was evaporated to give the ester (9a–d), as an
oily product, solidified after several hours.
4.7. Cleavage of optically active pyridine aminophos-
phine oxides 4f and 4g in D2O/D2SO4 solution
A sample of optically active pyridine aminophosphine oxide
(4f or 4g, 0.412 g, 1.0 mmol) was dissolved in 10% D2SO4/
D2O solution (10 mL) and heated at 95–100 8C for 3 h. The
reaction mixture was allowed to stand at room temperature
for 24 h in order to separate the phosphinic acid 7. Crystals
of the phosphinic acid 7 were collected by filtration and
dried on air. Yield of the 7 was 93% in the case of 4f, and
82% in the case of 4g.
The remaining filtrate was alkalized with an excess of
aqueous sodium bicarbonate solution and extracted with
methylene chloride (25 mL). Evaporation of the extract
gave the deuterated amines 5c–d (181 mg) and 6c–d
(170 mg), as thick oils, which were transformed to the
corresponding oxalate salts, likewise as described in the
preceding case. The oxalates were equimolar mixtures of
S,R and R,R stereoisomers of the corresponding amines
(according to the NMR data).
The formed amine 5a was isolated from the remaining
acidic solutions by subsequent alkalization with aqueous
NaHCO3 and extraction with methylene chloride as
described in Section 4.5.2. Yield of the 5a exceeded 90%.
4.8.1. Methyl ester 9a. A whitish solid, yield 75 mg (27%),
mp 52–55 8C, lit.30 55–57 8C, lit.31 50 8C, lit.32 56–58 8C.
1H NMR; dH (CDCl3; 300 MHz): 7.77–7.70 (4H, m, ArH);
7.43–7.37 (6H, m, ArH); 3.71–3.67 (3H, d, JZ10.1 Hz,
OCH3). 31P NMR; dP (CDCl3; 121.5 MHz): 34.908 (s).
4.7.1. Mixture of S,R and R,R stereoisomers of
deuterated N-(2-pyridylmethyl)-(R)-(D)-a-methyl-
benzylamine 5c–d. Oxalate; white solid, yield 233 mg,
4.8.2. Ethyl ester 9b. A colorless oil, yield: 35 mg (14%),
1
lit.29 oil. H NMR; dH (CDCl3; 300 MHz): 7.77–7.70 (4H,
1
(77%). H NMR; dH (D2O; 300 MHz): 8.46 (1H, d, JZ
4.8 Hz, 6-PyH); 7.79 (1H, dt, JZ1.5, 7.8 Hz, 4-PyH); 7.40–
7.28 (7H, m, PyH, ArH); 4.43 (1H, q, JZ6.9 Hz, CHCH3);
4.17 (0.5H, br t, JZnot determined, NCHD); 4.05 (0.5H, br
t, JZnot determined, NCHD); 1.64 (3H, d, JZ6.9 Hz,
CH3).
m, ArH); 7.41–7.35 (6H, m, ArH); 4.08–3.98 (2H, m,
OCH2), 1.29 (3H, t, JZ7.1 Hz, CH3). 31P NMR; dP (CDCl3;
121.5 MHz): 33.058 (s).
4.8.3. iso-Propyl ester 9c. White solid, yield: 18 mg (7%),
1
mp 99–101 8C, lit.27 97–99 8C, lit.29 100.6–101.5 8C. H
Free amine; GC/MS (HP-5 column, 25 m, temperature
program; 100/6/290): tRZ10.38 min; m/z (EI, 70 eV): 213
(0.1, MC), 212 (0.4, MK1), 198 (16), 136 (5), 120 (81), 105
(18), 94 (100), 93 (37), 79 (8), 77 (10), 66 (10), 51 (5%).
NMR; dH (CDCl3; 300 MHz): 7.77–7.70 (4H, m, ArH);
7.40–7.35 (6H, m, ArH); 4.66–4.55 (1H, m, OCH), 1.27
(6H, d, JZ6.2 Hz, CH3). 31P NMR; dP (CDCl3;
121.5 MHz): 31.397 (s).
4.7.2. Mixture of S,R and R,R stereoisomers of
deuterated N-(4-pyridylmethyl)-(R)-(D)-a-methyl-
benzylamine 6c–d. Oxalate: white solid, yield 215 mg,
4.8.4. tert-Butyl ester 9d. White solid, yield: 14 mg (5%),
mp 108–110 8C, lit.28 111.5–112 8C. lit.29 108.6–109.6 8C.
1H NMR; dH (CDCl3; 300 MHz): 7.75–7.68 (4H, m, ArH);
1
(71%). H NMR; dH (D2O; 300 MHz): 7.84 (2H, d, JZ
7.39–7.30 (6H, m, ArH); 1.26 (9H, d, JZ2.0 Hz, CH3). 31
NMR; dP (CDCl3; 121.5 MHz): 32.582 (s).
P
6.0 Hz, 2,6-PyH); 7.64 (2H, d, JZ6.0 Hz, 3,5-PyH); 7.36
(5H, br s, ArH); 4.45 (1H, q, JZ6.8 Hz, CHCH3); 4.38
(0.5H, br t, JZnot determined, NCHD); 4.17 (0.5H, br t,
JZnot determined, NCHD); 1.63 (3H, d, JZ6.8 Hz, CH3).
4.8.5. Cleavage of 4e in the presence of methanol. A
sample of optically active the pyridine-4-methyl-(N-
benzylamino)-tert-butylphenyl-phosphine oxide (4e)
(0.38 g, 1.0 mmol), was dissolved in methanol (10 mL),
containing 0.98 g (10 mmol) H2SO4. The solution was
refluxed for 5 h, cooled and left for 2 weeks. After this, the
solvent (methanol) was evaporated, the resulting oil was
dissolved in water (10 mL) and heated at 60 8C for 5 h,
cooled and extracted with methylene chloride (50 mL). The
extract was dried (anh. Na2SO4), filtered and evaporated to
give an oil, which solidified after several hours. The
obtained product was mainly the (R)-(C)-tert-butylphenyl-
phosphine oxide 3c, mixed with a small quantity of the
Free amine; GC/MS (HP-5 column, 25 m, temperature
program; 100/25/290): tRZ7.49 min; m/z (EI, 70 eV): 213
(1, MC), 212 (1, MK1), 199 (29), 198 (100), 197 (20), 136
(9), 105 (19), 93 (32), 79 (7), 77 (10), 66 (9), 51 (4%).
4.8. Cleavage of 4a in the presence of 50% aqueous
alcohols
Samples of the pyridine-2-methyl-(N-benzylamino)-
diphenylphosphine oxide (4a) (0.40 g, 1.0 mmol), were

W. Goldeman et al. / Tetrahedron 62 (2006) 4506–4518
4517
methyl ester of tert-butylphenylphosphinic acid (10).
Additional purification of the obtained product by crystal-
lization from hexane–diethyl ether gave the pure (R)-(C)-
tert-butylphenylphosphine oxide (3c)11a,b. White solid,
(2H, m, ArH); 7.42–7.36 (3H, m, ArH); 1.67–1.61 (3H, dd,
JZ13.9, 3.8 Hz, PCH3). 31P NMR; dP (CDCl3; 121.5 MHz):
21.747 (s).
yield 54 mg (29%), mp 69–72 8C, lit.11b 72–74 8C. [a]20
The remaining aqueous layer was made alkaline by adding
an excess of aqueous sodium bicarbonate solution and
extracted twice with chloroform (2!25 mL). The extract
was dried (anh. Na2SO4), filtered and evaporated to give an
oil (45 mg), which was a mixture of amine 6c and aldehyde
1b and traces of other not identified products, according to
NMR data.
D
C23.5 (c 1.0, CHCl3), lit.11a [a]20D C14.6 (c 1.68, MeOH).
1H NMR; dH (CDCl3; 300 MHz): 7.62–6.11 (1H, d,
JZ453.2 Hz, P–H); 7.55–7.32 (5H, m, ArH); 1.01–0.95
(9H, d, JZ16.6 Hz, t-Bu). 31P NMR; dP (CDCl3;
121.5 MHz): 51.764 (s). Evaporation of mother liquid
gave an oily product, partially solidified (18 mg), which
was composed with the phosphine oxide 3c and methyl ester
10, in a ratio 2:1, approximately. The NMR spectrum
(CDCl3) of the crude product showed the dublet of the OMe
group at 3.69–3.65 ppm (JZ10.45 Hz), which was consist-
Supplementary data are deposited with the Cambridge
Crystallographic Data Centre as a supplementary publication
numbers CCDC 283498 (CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK; e-mail; deposit@ccdc.cam.ac.uk).
ent with the literature data11a,33–36
.
The remaining aqueous layer was made alkaline by adding
of an excess of aqueous sodium bicarbonate solution and
extraction with chloroform (50 mL). The extract was dried
(anh. Na2SO4), filtered and evaporated to give an oil,
solidified after short time (0.21 g). Recrystallization of the
product from acetone gave a white crystalline solid, which
was the pyridine hydroxyphosphine oxide 12, as a
diastereomeric mixture. 12; white solid, yield 120 mg
(42%), mpZ172–175 8C. 1H NMR; dH (DMSO;
300 MHz): 8.25 (2H, d, JZ4.9 Hz, 2,6-PyH); 7.71 (2H,
m, 3,5-PyH); 7.39–7.19 (5H, m, ArH); 6.70–6.45 (1H, m,
CHOH); 5.52–5.41 (1H, m, CH–P); 1.14–0.92 (9H, m,
t-Bu). 31P NMR; dP (CDCl3; 121.5 MHz): 44.848 (s),
44.565 (s) in a ratio 1:1.25. IR, nmax (KBr): 3409; 3207;
3081; 2973; 2868; 1597; 1475; 1436; 1415;1149 (P]O);
1107; 833; 747; 715; 697; 610; 572; 551; 517 cmK1. MS;
(ESICQ1MS): 291.0 (43, MCC1), 313.1 (100, MCC1C
Na). Anal. Calcd for C16H20NO2P, requires N, 4.84; P,
10.71. Found: N, 4.67; P, 10.59.
The X-ray diffraction measurements were performed in
Department of Chemistry, University of Wroclaw, on a
Kuma KM4 CCD four circle diffractometer, equipped with
an Oxford Cryosystem Cooler, using graphite monochro-
mated Mo Ka radiation.
The structure of 4g was solved by direct methods using
SHELXS-9742 and refined on S2 by full-matrix least-squares
methods using SHELXL-97.43 Non-hydrogen atoms were
refined with anisotropic thermal parameters. During the
refinement, an extinction and absorption correction was
applied. The correction for the absorption was done using
the empirical method included in the SHELXA program
from the SHELXL-9743 package. The XP package44 was
used to generate the molecular drawings.
The absolute configuration of the molecule 4g was assigned
as (S,R) with reference to the known R configuration of the
(C)-a-methylbenzylamino moiety.
4.8.6. Cleavage of 4i in the presence of methanol. A
sample of optically active (C)-1-[N-(a-methylbenzyl-
amino)]-1-(4-pyridyl)-methyl-phenyl-methylphosphine
oxide (4i) (108 mg, 0.31 mmol), was dissolved in methanol
(5 mL), containing 0.49 g (5 mmol) H2SO4. The solution
was refluxed for 3 h, cooled, left for 24 h and the solvent
(methanol) was evaporated. The resulting oil was dissolved
in water (5 mL) and extracted twice with methylene
chloride (2!25 mL). The combined extracts were dried
(anh. Na2SO4), filtered and evaporated to give an oil
(47 mg). According to NMR data, the product was a mixture
composed with methylphenylphosphine oxide (3d) and
methyl phenylmethylphosphinate (13), in a ratio w1:1.
Separation of the mixture for individual products was done
by column chromatography (silica gel, eluent; pure acetone)
to afford the products: (C)-(R)P methyl phenylmethyl-
phosphinate (13), as a colorless oil.40 Rf 0.88, yield 22 mg
(0.13 mmol), [a]20 C20.0 (c 0.4, CHCl3), lit.41 [a]20
Acknowledgements
This research was supported by an internal grant from the
Faculty of Chemistry, Wroclaw University of Technology.
We thank Mr. Rafał Kowalczyk for measuring the optical
rotations, Mr. Rafał Kozicki for measuring the NMR
´´
spectra, Mrs. Elz˙bieta Mroz for recording the IR spectra,
Dr. Andrzej Nosal for determining the GC/MS analyses and
Mrs. Czesława Andrzejewska for performing the elemental
analyses in the Institute.
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