Phosphorous(v) Lewis acids: Water/base tolerant P3-trimethylated trications

Article abstract of DOI:10.1039/c8cc06564k

The water/base intolerance of the previously reported electrophilic phosphonium cations has been overcome by replacing the labile electron-withdrawing groups generally attached to phosphorus (e.g. -F, -OAr, -CF₃) with methyl groups. Tri-phosphorus(v) tricationic species, accessible in one-pot from commercially available materials, are air and water/base tolerant, yet are sufficiently Lewis acidic for catalysis.

Full text of DOI:10.1039/c8cc06564k

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Phosphorous(V) Lewis acids: water/base tolerant
P3-trimethylated trications†
Cite this: Chem. Commun., 2018,
54, 12467
ab
J. M. Bayne,‡a V. Fasano,
‡
K. M. Szkop, ‡a M. J. Ingleson *b and
a
Received 11th August 2018,
Accepted 12th October 2018
D. W. Stephan
*
DOI: 10.1039/c8cc06564k
rsc.li/chemcomm
The water/base intolerance of the previously reported electrophilic wide variety of Lewis-acid catalyzed transformations,9–13 trace
phosphonium cations has been overcome by replacing the labile water remains problematic as rapid P–F cleavage was observed.14
electron-withdrawing groups generally attached to phosphorus Analogous results were observed by increasing the steric bulk
(e.g. –F, –OAr, –CF3) with methyl groups. Tri-phosphorus(V) tricationic around the phosphorus(V) centre15 or replacing the P–F moiety
species, accessible in one-pot from commercially available materials, with P-OAryl,16 or P-alkyl groups.17 In a related system, the
are air and water/base tolerant, yet are sufficiently Lewis acidic for 1,8-naphthyldiphosphonium dication [(C10H6)(Ph2P)2]2+ (2),
catalysis.
can be stored in air for up to 24 hours without significant
decomposition, addition of H2O to a solution of 2 results in
In the past decade, frustrated Lewis pair (FLP) chemistry rapid degradation.18 On the other hand, [Ph3PCF3]+ (3) is stable
has emerged as a metal-free alternative to transition metal- in the presence of water even at elevated temperature,19 but
catalysed reductions. In these systems, sterically-encumbered undergoes rapid reaction at room temperature in the presence
Lewis acids and Lewis bases in combination enable the activa- of a combination of water and a moderate organic base afford-
tion of sigma bonds of H2 and R3SiH, to generate useful ing the corresponding phosphine oxide (Scheme 1).19 Thus,
reducing agents.1,2 However, water coordination to the Lewis developing EPCs that are active for sigma bond activation but
acid and irreversible O–H activation represents a limitation in stable in the presence of water/base combinations remains a
FLP chemistry using highly electrophilic Lewis acids (e.g. B(C6F5)3). challenge in main group Lewis acid chemistry. In this regard,
This is due to deprotonation forming a hydroxyl-Lewis acid species we envisaged that replacing the –CF3 group in EPCs with a
(e.g. [HOB(C6F5)3]À) and a protonated Lewis base which are a methyl would disfavour hydrolysis and R3PO formation, as
catalytically inactive combination.3 For boranes, the intolerance tetraorgano phosphonium ions are stable in water. For example,
to water/base combinations has been tackled by decreasing the [Bu4P][Cl] has been employed in silane activation via a distinct
Lewis acidity of the borane or by designing Lewis acids with anion coordination mechanism.20,21 However, such a replacement
increased steric bulk around the boron centre thus reducing the
propensity for irreversible water-binding/activation.3 Another
approach to overcome water intolerance in FLP and Lewis acid
chemistry is the use of non-boron based Lewis acids. In this regard,
carbenium and tin(IV) cations, isoelectronic with boranes, are
examples of Lewis acids that are more compatible with water/base
combinations.4–8
Moreover, while highly electrophilic phosphonium cations
(EPCs) such as [(C6F5)3PF]+ (1) have demonstrated reactivity in a
a Department of Chemistry, University of Toronto, M5S 3H6, Canada.
E-mail: dstephan@chem.utoronto.ca
b School of Chemistry, University of Manchester, M13 9PL, UK.
E-mail: michael.ingleson@manchester.ac.uk
† Electronic supplementary information (ESI) available: Synthetic and spectral
details are deposited. CCDC 1861575 and 1861576. For ESI and crystallographic
Scheme 1 Examples of EPCs and their relative stability towards water/
data in CIF or other electronic format see DOI: 10.1039/c8cc06564k
base.
‡ Authors contributed equally to this work.
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of an electron withdrawing group by methyl is also expected to and [MeC(CH2PMePh2)3][OTf]3 ([7][OTf]3) in yields of 88% and
reduce Lewis acidity. Thus, we proposed to compensate for this 96%, respectively. Single crystals of [6][OTf]3 and [7][OTf]3 were
shortcoming by the inclusion of multiple positive charges. obtained and characterized by X-ray diffraction studies, further
Herein, we report that P3-trimethylated phosphonium trica- confirming their formulation (Fig. 1). Notably, the trication [7]3+
tions are readily prepared, provide water/base stability, and shows an interesting arrangement in the solid state, assuming
are effective and highly robust Lewis acid catalysts for pseudo-C3 symmetry, with all the methyl groups orientated in
reduction chemistry. In this regard, while polycationic phos- the same direction. One of the three triflate counterions
phonium based polymers and oligomers have found applica- occupies the putative electrophilic pocket. While the P–O(OTf)
tions in material science and biology, as ionic liquids,22 metal contacts are longer than the sum of the van der Waals radii,
scavengers,23 antibacterial agents,24 and dendrimers,25 their short contacts are seen between the triflate anion and the CH2
utility in FLP chemistry and Lewis acid catalysis remains protons of the cation. This hydrogen bonding network is
unexplored.
reminiscent of urea-based organocatalysts, where short anion-H
The commercially available triphosphine ligands PhP(CH2CH2- contacts are also observed.26
PPh2)2 (4) and MeC(CH2PPh2)3 (5) were treated with an excess of
Both [6][OTf]3 and [7][OTf]3 can be synthesized on a gram
MeOTf (methyl trifluoromethanesulfonate, 6–10 equiv.) in CH2Cl2 scale and stored as solids for months in air and/or dissolved in
at room temperature (Scheme 2). In both cases, after 10–15 minutes non-purified MeCN without observable degradation even at
a white solid precipitated from the solution. The reaction was elevated temperature (100 1C). These trications were also stable
left stirring at room temperature for 12 hours to ensure in the presence of an excess (10 equiv.) of water and aniline,
complete conversion, after which time solvent removal and with no phosphine oxide formation observed after 24 hours
pentane washing gave the desired P3-trimethylated phos- at 100 1C in MeCN.
phonium trications [PhPMe(CH2CH2PMePh2)2][OTf]3 ([6][OTf]3)
While the field of EPC-catalysed transformation has grown
significantly in the last 5 years, transformations have been
limited to reactions that do not employ strongly donating
substrates or generate strongly donating products, including
water. Moreover, reactions generally required strict air- and
moisture-free conditions, limiting further applications. Given
the tolerance of the trications to the presence of air, moisture,
and moisture/base combinations, the catalytic reactivity for
reductive amination of carbonyl compounds with primary
amines was probed. In this strategy, the corresponding imine
is formed and reduced in situ without purification, thus providing
reactivity in the presence of water (generated as a by-product). Such
reductive aminations using H2 or hydrosilanes as reductants
mediated by boranes and tin cations have been reported in the
past 2 years.27–31 However, to the best of our knowledge, there
are no reports of phosphorus(V) reductive amination catalysts.
To probe the reactivity of the trications as Lewis acid catalysts
in reductive amination reactions, [6][OTf]3 and [7][OTf]3 were
dissolved in ‘‘wet’’ MeCN. The reaction between benzaldehyde
and aniline (1 : 1.2), in the presence of 5 mol% of [6][OTf]3 or
[7][OTf]3 and 1.2 equiv. of PhMe2SiH yielded a significant amount
of imine after 18 h at room temperature. This was similar to that
previously reported for the borane-catalysed reaction.32 However,
heating the reaction mixtures to 100 1C in a sealed tube for
5 hours resulted in formation of the desired N-benzyl-aniline
using both [6][OTf]3 and [7][OTf]3. A control experiment without
catalyst showed no reactivity under identical conditions
(Table 1, entries 1–3). Notably, replacing the trications with
[Ph3PMe][OTf] as the catalyst at 15 mol% to provide comparable
[R4P]+ content, resulted in 58% conversion after 5 h. Longer
reaction times were required for comparable conversion (Table 1,
entry 4). Similarly, using 7.5 mol% [Ph2PMe(CH2)3MePPh2][OTf]2 as
the catalyst resulted in 20% conversion after 5 h and 41% after
24 h. It is worth noting that the decrease in reactivity compared to
[Ph3PMe][OTf] may be a result of increased electron density around
the P centre due to the alkyl linker. This reactivity highlights the
Scheme 2 Synthesis of P3-trimethylated phosphonium trications.
Fig. 1 POV-ray depictions of the trications of [6]3+ (top, hydrogen atoms
and triflate counterions omitted for clarity) and [7]3+ (bottom); hydrogen
atoms selected triflate counterions, and co-crystallized solvent molecules
omitted for clarity C: black, P: orange, O: red, S: yellow, F: purple.
12468 | Chem. Commun., 2018, 54, 12467--12470
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Table 1 Reductive aminations using P(V) Lewis acids catalystsa
between 5 and 24 hours. Notably, ester groups were not reduced
under these reaction conditions, in contrast to previous obser-
vations in the B(C6F5)3-catalysed reductive amination of
similar substrates.15 However, aliphatic aldehydes and ketones
proved to be challenging substrates for this reaction. Several
functional groups on the aniline component were also compa-
tible (Scheme 3, bottom). The tolerance to –CF3 groups is
noteworthy as previously EPCs have been shown to activate
the C–F bonds of trifluorotoluene and fluoroadamantane.9 When
aniline was replaced with the more basic amine t-butylamine, the
reductive amination with benzaldehyde and PhMe2SiH using
[7][OTf]3 was unsuccessful due to catalyst decomposition. A
complex 31P{1H} NMR spectrum was observed; among the pro-
ducts, the phosphine oxide was evident, however other by-products
were not identified. It is interesting to note that the tricationic
Lewis acids can be recycled multiple times for the reductive
amination of benzaldehyde with aniline using PhMe2SiH as
reductant in the presence of the initial 5 mol% of [7][OTf]3,
although gradual diminishing in reactivity is observed (Scheme 4).
Probing the mechanism of these reductive aminations
prompted a series of control experiments. Under anhydrous
conditions, isolated N-benzylidene-aniline was reduced to some
extent (B20% conversion) in the presence of PhMe2SiH in
CH3CN and 5 mol% of [7][OTf]3 upon heating to 100 1C for
5 hours. The formation of BnN(SiMe2Ph)Ph was confirmed by
Entry
Catalyst
T (h)
Yieldb (%)
1
2
3
4
5
None
5 mol% [6][OTf]3
5 mol% [7][OTf]3
15 mol% [Ph3PMe][OTf]
7.5 mol% [Ph2PMe(CH2)3MePPh2][OTf]2
18
5
5
5
5
0
82
93
58
20
a
Reaction conditions: 1.0 equiv. of aldehyde, 1.2 equiv. of amine,
b
1.2 equiv. of silane and the catalyst, ‘‘wet’’ MeCN as the solvent. Based
on 1H-NMR spectroscopy using mesitylene as an internal standard.
role of the three proximal P(V)-centres in enhancing Lewis acidity,
as was suggested by the solid state structure of [7][OTf]3, although
conclusive evidence of silane activation (both experimentally and
computationally) were not accessible. However, this phenomenon
is conceptually related to the activation of carbonyl substrates using
¨
dicationic antimony-based Lewis acids reported by Gabbaı and
co-workers.33
The Gutmann–Beckett method was used to assess the Lewis
acidity of [7]3+ ([7][OTf]3 : Et3PO 1 : 1, in CD3CN) and showed a
small downfield shift of the signal of Et3PO by 31P NMR
spectroscopy (Dd = 4.1 ppm), suggesting a weak interaction with
Et3PO, although this is comparable to [(C6F5)3POC6F5][B(C6F5)4]
([8][B(C6F5)4]) which contains strongly electron-withdrawing
substituents around the phosphorus centre.14 Moreover, the
Gutmann–Beckett test with [Ph3PMe][OTf] (in a 3 : 1 ratio of
phosphonium to Et3PO) showed a slightly smaller chemical
shift change of Et3PO by 31P NMR spectroscopy (Dd = 3.8 ppm).
The ability to promote reductive aminations was then further
explored with other substrates in the presence of 5 mol% of
[7][OTf]3 (Scheme 3). It is noteworthy that all reactions were
completed in air, with ‘‘wet’’ and untreated reagent-grade solvent.
Several functional groups on the benzaldehyde were tolerated, with
good conversion obtained after heating the reaction mixture for
1
in situ H/29Si NMR spectra and GC-MS analysis. However, we
note the significant decrease in reactivity (cf. Table 1, entry 3).
This infers a role for H2O, possibly as the nucleophile attacking
the Lewis acid activated silane, R3Si–H–[PR4]+ species. It is
noteworthy that repeating the standard reaction (Table 1, entry 3)
in the presence of the non-nucleophilic base PMes3 (Mes = 2,4,6-
trimethylphenyl, 5 mol%) slowed reductive amination, affording
the desired amine in only 17% after heating for 5 hours at 100 1C.
Moreover, a similar decrease in reactivity was observed for the
corresponding reaction of 2-pyridinecarboxaldehyde yielding the
desired product in 43% after heating for 5 hours at 100 1C. These
results suggest that the presence of an exogenous base deproto-
nates a Lewis acid–water adduct (e.g. [R4P–OH2]+ or [R3Si–OH2]+
adducts). This suggests protonation of the imine enables more
rapid reduction, although the fact that the chemistry proceeds in
anhydrous solvents (albeit more slowly) indicates that reduction via
an imine silylation process also occurs. It is noteworthy that
previous reports have described mechanisms involving both Lewis
acid and Brønsted acid activation of the reductant followed by
silylation or protonation of the imine.27,30,32,34–37
The facile methylation of commercially available triphosphine
ligands affords air and water tolerant EPCs with non-coordinating
Scheme 3 Reductive amination substrate scope. For reaction conditions
see Table 1. Yields based on 1H NMR spectroscopy using mesitylene as an
internal standard. * 24 hours.
Scheme 4 Recycling experiment of the reductive amination with [7][OTf]3.
For reaction conditions see Table 1. Yields based on 1H-NMR spectra using
mesitylene as an internal standard.
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12 J. M. Bayne and D. W. Stephan, Chem. Soc. Rev., 2016, 45, 765–774.
13 D. W. Stephan, Angew. Chem., Int. Ed., 2017, 56, 5984–5992.
triflate anions. The unprecedented (for EPCs) water/aniline toler-
ance of these phosphonium trications allow them to be employed as
Lewis acid catalysts for the one-pot reductive amination of benz-
aldehydes with arylamines using hydrosilanes as the reductant.
We are grateful to the Royal Society of Chemistry for a
Research Mobility Grant (V. F.) and the University of Manchester
for financial support. J. M. B. is grateful for funding from the
Vanier Graduate Scholarship program. K. M. S. thanks NSERC for
the award of NSERC PGS-D fellowship. D. W. S. acknowledges the
financial support of the NSERC of Canada and the award of a
Canada Research Chair. M. J. I. acknowledges the EPSRC (grant
numbers EP/K03099X/1 and EP/M023346/1) for financial support.
´
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Conflicts of interest
The authors declare no conflicts of interest.
24 T. J. Cuthbert, B. Hisey, T. D. Harrison, J. F. Trant, E. R. Gillies and
P. J. Ragogna, Angew. Chem., Int. Ed., 2018, 57, 12707–12710.
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12470 | Chem. Commun., 2018, 54, 12467--12470
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