Platinum-(phosphinito-phosphinous acid) complexes as bi-talented catalysts for oxidative fragmentation of piperidinols: An entry to primary amines

Article abstract of DOI:10.1039/c9ra08709e

Platinum-(phosphinito-phosphinous acid) complex catalyzes the oxidative fragmentation of hindered piperidinols according to a hydrogen transfer induced methodology. This catalyst acts successively as both a hydrogen carrier and soft Lewis acid in a one pot-two steps process. This method can be applied to the synthesis of a wide variety of primary amines in a pure form by a simple acid-base extraction without further purification.

Full text of DOI:10.1039/c9ra08709e

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PAPER
Platinum–(phosphinito–phosphinous acid)
complexes as bi-talented catalysts for oxidative
Cite this: RSC Adv., 2019, 9, 37825
fragmentation of piperidinols: an entry to primary
amines†
b
Romain Membrat,a Alexandre Vasseur,
Delphine Moraleda,a Sabine Michaud-
a
a
a
Chevallier,a Alexandre Martinez,
*
Laurent Giordano and Didier Nuel
*
*
Platinum–(phosphinito–phosphinous acid) complex catalyzes the oxidative fragmentation of hindered
piperidinols according to a hydrogen transfer induced methodology. This catalyst acts successively as
both a hydrogen carrier and soft Lewis acid in a one pot – two steps process. This method can be
applied to the synthesis of a wide variety of primary amines in a pure form by a simple acid–base
extraction without further purification.
Received 4th September 2019
Accepted 25th October 2019
DOI: 10.1039/c9ra08709e
rsc.li/rsc-advances
a hydrogen carrier and a Lewis acid in a single chemical system
(Scheme 1(a)).
Introduction
On one hand, we recently reported the Pt(II)-SPO complex-
catalyzed oxidation the N-alkyl-2,2,6,6-tetramethylpiperidin-
4-ols into their corresponding piperidinone derivatives.18 On
the other hand N-alkyl piperidinone motif have been reported
earlier as a source of N-alkyl primary amines.21–26 We hypoth-
esized that the electrophilic features of bisphosphinite met-
allacycle would also promote the double C(sp3)–N bond
cleavage. Combining these two steps with a single catalyst the
whole process would emerge as a readily access to primary
amines (Scheme 1b). Herein we report our results in this
regard.
The terminology “metal-catalyzed hydrogen transfer method-
ology” refers to any chemical process relying on the generation
of a metal hydride from a hydrogen source and its transfer to an
unsaturated hydrogen acceptor.1,2 A substantial number of
consistent versions of this concept have been reported and
implemented with palladium catalysts for alcohols oxidation,3–5
hydrogenation,6,7 C–C,8,9 C–N,10 C-halogen bond formation,11
double bond isomerization,12 cross aldolisation13 or else ami-
nation14 with a view to increasing the molecular complexity. The
critical feature of metal-catalyzed hydrogen transfer method-
ology lays in the design of suitable ligands, able to induce the
formation of a reactive metal hydride intermediate.4,7,15 In this
context, we recently reported that palladium and platinum –
phosphinous acid (PA) complexes can generate active metal
hydrides.16 This property is due to the self-assembled hydrogen
bond negatively charged assisted structure of two PA ligands
(M/PAP complexes, Scheme 1).17 These catalysts allowed there-
fore the anaerobic oxidation of notably reluctant alcohols such
as N-alkyl-(2,2,6,6)-tetramethylpiperidin-4-ols 1.18 In earlier
years, the M/PAP structure proved to be also active as a Lewis
acid toward sterically congested substrates in tandem [2 + 1]
cycloaddition-ring expansion of norbornene derivatives with
propargylic acetates.19 In order to benet from this noteworthy
M/PAP's multiskilling20 we focused our effort on a new hydrogen
transfer induced transformation where the catalyst acts as both
Results and discussion
During our studies on the palladium catalyzed anaerobic
oxidation of N-alkyl-2,2,6,6-tetramethylpiperidin-4-ols18 deriva-
tives, we observed, in the case of 1a, that product 2a was found
only in trace amount along with phorone (2,6-dimethylhepta-
2,5-dien-4-one) 3, which was isolated in 90% yield (Scheme 2).
aAix-Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France. E-mail: didier.
nuel@centrale-marseille.fr
b
´
Universite de Lorraine, CNRS, L2CM, F-54000 Nancy, France
† Electronic supplementary information (ESI) available. See DOI:
Scheme 1 M/PAP complexes as bitalented catalyst.
10.1039/c9ra08709e
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Under these conditions, the oxidation of 1b to 2b was
complete in 4 hours and the amine 4b was not detected even
under prolonged reaction time like 16 hours at 105 ꢀC (Table
2, entry 1). In this case, we supposed that the relative basicity
of the medium precludes the cleavage process of 2b. Indeed,
in the reaction conditions described in Table 1 (with
complexes 6a, 6b and 6c) no base was added, and catalytic
traces of HCl or AcOH are probably released during the
formation of the [M]–OH active species, which probably
promotes the cleavage of 2b. Thus, once the oxidation reac-
tion under basic conditions is over (typically aer 4 hours), 1
equivalent of HCl or AcOH (Table 2, entries 2 and 4) was
added directly to the mixture.
Results comparable to the reactions done in neutral
medium using 6a, 6b or 6c as catalyst (Table 1, entries 2–4)
were obtained. However, an excess of HCl (5 equiv.) resulted in
a complete deactivation of the catalyst (Table 2, entry 3). In
contrast, the use of an excess of acetic acid (5 equiv.) (Table 2,
entry 5) was shown to be very benecial as quantitative
deprotection of piperidinone 2b was observed aer 16 h at
105 ꢀC. Unfortunately only traces of free amine 4b were
detected probably due to the possible 1,4-addition of the
amine to the MVK 5a (Table 2, entries 2, 4 and 5).27 We then
seek for a less reactive hydrogen acceptor to the addition of
amine. Trans-phenyl-but-3-en-2-one 5b was nally selected as
the H-acceptor as it gives a clean total conversion and 4b was
obtained in a pure form in 88% isolated yield by simple acid–
base extraction without further purication (Table 2, entry 6).
The optimal conditions for the reaction were rened to 105 ꢀC
during 4 hours for the rst step and 5 hours for the second
(Table 2, entry 7).
Scheme
piperidinols.
2 M/PAP complex catalyzed oxidative fragmentation of
We hypothesise that formation of 3 arose through the
cleavage of C–N bonds in the piperidinone 2a leading to
methylamine 4a (not isolated). According to this result, the
development of a one pot oxidative fragmentation of piper-
idinols 1 to deliver primary amines 4 should be possible
(Scheme 1(b)). Thus, a preliminary study was carried out using
N-benzyl-2,2,6,6-tetramethylpiperidin-4-ol 1b in order to isolate
benzylamine 4b (Scheme 2).
The reaction of 1b and electron-poor alkene 5a in the pres-
ence of 5 mol% of Pd/PAP or Pt/PAP complexes 6 in toluene/
water (9/1) at 105 C was examined (Table 1).
ꢀ
The experiment conducted in 4 hours with the catalyst 6a
proved disappointing as the conversion was incomplete and
only 14% of phorone 3 were detected (Table 1, entry 1).
Increasing the reaction time led to complete conversion but the
ring opening remained incomplete affording a mixture of 2b : 3
in a 70 : 30 ratio (Table 1, entry 2). Catalyst 6b also led to
complete conversion with a decreased yield of phorone 3 (Table
1, entry 3). The best ratio of 2b : 3 (64 : 36) was observed with
the platinum complex 6c and improved to 40 : 60 with a longer
reaction time (Table 1, entries 4 and 5) suggesting a sequential
oxidation-opening process. In a previous work, we showed that
treatment of 6c with NaOH afforded a hydroxy-platinum catalyst
6d as active species (see Table 2) for the chemoselective anaer-
obic oxidation of 1b with 5a as H-acceptor and allowed the
oxidation to occur at room temperature. We decided then to try
the reaction in these conditions to obtain the ketone prior to
optimize the ring opening step (Table 2).
Table 2 Optimization of the sequencea
Table 1 Feasibility of the oxidation/C–N bond cleavage tandem
sequence of 1ba
Entry
H-acceptor
Acid (equiv.)
t (h)
2b : 3 : 4b ratiob (%)
1
2
3
4
5
6
7
5a
5a
5a
5a
5a
5b
5b
—
16
16
16
16
16
16
5
100 : 0 : 0
HCl (1)
HCl (5)
AcOH (1)
AcOH (5)
AcOH (5)
AcOH (5)
82 : 18 : NDc
100 : 0 : 0
Entry
Cat.
t (h)
1b : 2b : 3 ratiob (%)
72 : 28 : NDc
0 : 100 : NDc
0 : 100 : 100
0 : 100 : 100
1
2
3
4
5
6a
6a
6b
6c
6c
4
16
16
16
72
14 : 71 : 14
0 : 70 : 30
0 : 78 : 22
0 : 64 : 36
0 : 40 : 60
a
All reactions were carried out with 1 mmol of 1b in toluene/H2O 9/1 at
105 ꢀC, 4 h. 1/5b/6c ¼ 1/2/0.05 and then addition of acid (5 equiv.),
All reactions were carried out with 1 mmol of 1b in toluene/H2O 9/1 at 105 ꢀC. Determined by 1H NMR spectroscopy. 4b is detected in
a
b
c
105 ꢀC. 1b/5a/cat. 6 ¼ 1/2/0.05. b Determined by 1H NMR spectroscopy. trace amounts.
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Scheme 5 Complementary experiments.
amine 4q although in lower yield (38%). Interestingly, the
method could be utilized on a large scale (4 grams) as 4b was
obtained in 86% yield through simple acid–base extraction. In
addition, treatment of the organic phase with ammonia (14 M
in MeOH) allowed the recovery of 2,2,6,6-tetramethylpiperidin-
4-one 2 in quantitative yield.30
It should be stressed that amino-ester (see 1r) could be
directly involved in a three steps one pot process oxidation–
fragmentation–cyclization reaction to give the corresponding
pure lactam 7 in 98% isolated yield without further purication
(Scheme 4).
Complementary experiments were performed in order to
elucidate the oxidative fragmentation mechanism of piper-
idinone 2 into primary amines 4. A E1CB type mechanism
involving the enolate form of product 2 can be ruled out because
this ring opening process was unsuccessful under basic condi-
tions (Table 2, entry 1) and required the addition of acetic acid
to occur (Table 2, entries 5–7). In order to get insights into this
mechanism, we decided to compare the reactivity of two
different substrates N-benzyl-2,6-diphenylpiperidin-4-ol 1s and
N-benzyl-2,6-dimethyl-3,5-diphenylpiperidin-4-ol 1t. Aer reac-
tions under our optimized conditions 1s gave a mixture of
2s : 4b in a 38 : 62 ratio while the reaction involving 1t stopped
Scheme 3 Scope of the process.
Having established the feasibility of the oxidation-opening
sequence,
we
synthesized
various
N-alkyl-2,2,6,6-
tetramethylpiperidin-4-ols 1b–q to extend its applicability.28,29
Under optimized conditions, the conversion of 1 proceeded
cleanly and the amines 4 were obtained in good to excellent
yields without chromatography (Scheme 3). All benzylic amines
were obtained in very good yields whatever is the substitution
on the phenyl ring (Scheme 3, 4b–4j). The electronic features of
the functional groups within the phenyl moiety have no major
inuence on the outcome of the reaction (compare for instance
4d with 4i). Allylic amines are also efficiently produced
(compounds 4k and 4l) as well as aliphatic amines (4m, 4n). The
obtention of product 4p stressed the already presumed neces-
sity of the activation of the protective group by a ketone func-
tion. Even a congested piperidinol (1q) was able to deliver
Table 3 Control experiments to elucidate the role of the metal in the
fragmentation stepa
Entry
Added acid
Equiv.
3b (%)
1
2
3
4
5
6
7
8
HCl
AcOH
1
1
0.05
1
1
0.05
0.05
0.05
—
—
BF3$Et2O
BF3$Et2O
Sc(OTf)3
PtCl2
<5
>90
29
—
<5
>90
[PtCl(dppp)]+
6c
a
All reactions were carried out with 1 mmol of 2b in toluene/H2O 9/1 at
105 ꢀC. b Determined by 1H NMR spectroscopy.
Scheme 4 Application to three steps-one pot oxidation–fragmenta-
tion–cyclization.
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Scheme 6 Plausible pathway for cascade oxidation fragmentation by M/PAP catalysts.
at the oxidized product 2t (Scheme 5).31 Since 2t is present as
According to these results, a possible pathway for the
a single diastereomer, in which the methyl and phenyl sequence is proposed in Scheme 6. First, in basic conditions
substituents are all in equatorial position the absence of frag- (NaOH, Scheme 6, 1), the Pt/PAP catalyst acted as a hydrogen
mentation suggests the requirement of an anti-relationship carrier to promote the oxidation of 1 to 2 according to our
between the H at C2 and the nitrogen atom (Scheme 5).32
previously reported mechanism.18 Thereaer, a one pot minor
For these reasons, we suggest that an Hofmann type degra- modication of the experimental conditions (AcOH, Scheme 6,
dation could proceed via the anti-deprotonation of an amino– 2) switched Pt/PAP's properties and triggered the ring opening
platinum complex.33,34 At this stage of the study, elucidating the process. A mechanism involving a Pt(II) cationic species 6f
role of the metal in the fragmentation has been found to be playing the role of Lewis acid is suggested and can be compared
crucial. M/PAP moiety has been chosen because of its supposed to a Hofmann degradation.34 It appeared that the combined
Lewis acid activity.19 To support this assumption, reactions with effect of both Lewis and Brønsted acid is crucial for the reaction
2b were performed in an acidic medium adding either Brønsted outcome. The pathway can be described as follows: (i) the
or Lewis acid (Table 3).
nitrogen atom coordinates to the Lewis acid (complex 8), thus
AcOH or HCl (1 equiv.) were inefficient for the aminone C–N promoting the ring opening (complex 9), (ii) the Brønsted acid
bond cleavage process (Table 3, entries 1 and 2). A stoichio- allows the Pt–N cleavage and the resulting protonated amine 4
metric amount of BF3$ Et2O allowed a complete conversion is carried away in the aqueous layer. In this phase transfer
(Table 3, entry 4). However, a catalytic amount of BF3$ Et2O led mechanism, the bi-talented nature of the Pt/PAP structure was
to a low conversion (Table 3, entry 3). The produced primary clearly highlighted.
amine probably easily coordinates BF3 thus rendering it inef-
fective for further ring opening. As a result, the yield of amine
matches the amount of BF3 used (5%). This also maintains the
Conclusions
amine in the organic phase and we were unable to isolate it in
pure form. Other Lewis acids such as scandium triate (Table 3,
M/PAP complexes can be used as unique catalyst to carry out
oxidation of N-alkyl-2,2,6,6-tetramethylpiperidin-4-ols
1
through hydrogen transfer methodology followed by C(sp3)–N
bond cleavage in a single operation. The self-assembled nega-
tively charged structure of the ligand may ease the abstracting
hydrogen step from 1 while the metal cationic centre may
promote the formation of amino–platinum complex species
from 2 responsible fora Hofmann-type degradation so as to
entry 5) gave poorer results even when used in stoichiometric
quantities. PtCl2 also known as a so Lewis35 acid did not gave
a better result (3 was not detected) (Table 3, entry 6). A cationic
platinum complex [PtCl(dppp)][PF6], in which the covalent
dppp ligand mimic the supramolecular bisphosphinite chelate
structure, was also inefficient (Table 3, entry 7). All these results
tend to show that the PAP ligand provides the right Lewis acid
character to our platinum catalyst 6c (Table 3, entry 8) which is
consistent with a Hofmann type fragmentation.
afford
a
primary
amine
4.
As
N-alkyl-2,2,6,6-
tetramethylpiperidin-4-ols are easily accessible from the cheap
2,2,6,6-tetramethylpiperidin-4-ol,28 this cascade reaction
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sequence provides an interesting entry to aliphatic primary 15 G.-J. ten Brink, I. W. C. E. Arends and R. A. Sheldon, Adv.
amines merely isolated aer simple acid–base extraction. Synth. Catal., 2002, 344, 355–369.
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2,2,6,6-tetramethylpiperidin-4-ol by reacting with ammonia and and L. Giordano, ChemCatChem, 2017, 9, 728–732.
the method is practicable on a large scale (see ESI†). The 17 P. M. Castro, H. Gulyas, J. Benet-Buchholz, C. Bo, Z. Freixa
´
proposed mechanism for this sequence clearly shows the mul-
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
´
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This work was supported by Ministere de l'Enseignement
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