Simple unprecedented conversion of phosphine oxides and sulfides to phosphine boranes using sodium borohydride

Article abstract of DOI:10.1039/c1cc14856g

A variety of phosphine oxides and sulfides can be efficiently converted directly to the corresponding phosphine boranes using oxalyl chloride followed by sodium borohydride. Optically active P-stereogenic phosphine oxides can be converted stereospecifically to phosphine boranes with inversion of configuration by treatment with Meerwein's salt followed by sodium borohydride.

Full text of DOI:10.1039/c1cc14856g

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COMMUNICATION
Simple unprecedented conversion of phosphine oxides and sulfides to
phosphine boranes using sodium borohydridew
Kamalraj V. Rajendran and Declan G. Gilheany*
Received 5th August 2011, Accepted 21st September 2011
DOI: 10.1039/c1cc14856g
A variety of phosphine oxides and sulfides can be efficiently
converted directly to the corresponding phosphine boranes using
oxalyl chloride followed by sodium borohydride. Optically active
P-stereogenic phosphine oxides can be converted stereospecifically
to phosphine boranes with inversion of configuration by treatment
with Meerwein’s salt followed by sodium borohydride.
required reduction could not be placed at any point in the
reaction sequence.8 The avoidance of stereochemical control
problems in oxide reductions was emphasised by Buono and
co-workers as one of the advantages of their recent P-stereogenic
phosphine borane synthesis.9
Once formed, the phosphines are relatively reactive (sometimes
violently so) and are often converted to, and stored as, the
corresponding phosphine boranes, from which they are easily
deprotected, with stereocontrol, by a number of methods.2c,d,10
The phosphine boranes are also interesting in their own right,
with respect to both their metal complexation and polymer
chemistry.11,12 Herein, we report our discovery of an easy,
convenient (one pot) and cheap method for the direct conversion,
with or without stereocontrol, of phosphine oxide (or sulfide) to
phosphine borane, by making use of readily available laboratory
reagents. We believe that this is the first report of direct oxide to
borane conversion.12
The reduction of phosphine chalcogenides has been a significant
challenge in phosphorus chemistry for the past four decades.1–4
The process is highly desirable because it provides access to the
corresponding phosphines, which can be put to an extensive
range of uses and also can be converted to other organo-
phosphorus compounds. A very wide variety of all conceivable
reducing agents has been employed but none are problem-
free.1c Although hydride reagents have attracted some recent
attention,2 at present silane reagents are the most commonly
used, both in the laboratory and industrially.4 A significant
point in their favour is that, with care and with much process
development, they can usually be made to stereospecifically
reduce optically active phosphine oxides.4d,5,6 Both silane and
hydride reagents are commonly used in the presence of various
modifiers: silanes are usually used with added tertiary
amine,4d,5 whereas hydrides may require initial treatment with
strong alkylating agent2f and both have been used in the
presence sacrificial phosphine.2j,4g
The first challenge in phosphine oxide reduction is the un-
reactivity of the phosphoryl system due to the high bond strength
of the PO multiple bond.13 With silane reagents this is overcome
by formation of the strong SiO single bond4d,g whereas with
hydride reagents,2d a strong alkylating agent can be used to form
initially a pseudophosphonium species, which is then reduced by
the hydride source. Sodium borohydride would be a first-choice
hydride reagent because of its mild reactivity, ease of use and
relatively low cost. But it requires a fairly reactive substrate and,
indeed, is completely inert to phosphine oxide on its own.2c For
some time, we have been studying chlorophosphonium salts
(CPS)14 because of their possible involvement in our dynamic
resolution of P-stereogenic phosphines under asymmetric Appel
conditions.15,16 One of the methods we have found useful for
CPS generation involves treatment of the corresponding phos-
phine oxide with oxalyl chloride.17 Originally reported by Fukui
and co-workers,18 this method cleanly generates the corres-
ponding chlorophosphonium chloride. It has been used recently
to good effect both by Tanaka and co-workers19 and notably by
Denton and co-workers20 in a catalytic version of the Appel
conditions. One of our interests concerned the reactivity of the
chlorophosphonium species towards hydride reduction18b,19b,21
and we report now that addition of sodium borohydride acts as
both hydride and borane source, giving phosphine borane
directly (Scheme 1).
Despite this very large amount of research, it is still a reality
of organophosphorus chemistry that reduction of a phosphine
oxide will be the likely problem step in an organophosphorus
synthetic sequence. The required silane or hydride reagents
have relatively limited substrate compatibility and aggressive
reaction conditions are often required leading to lowered
yields. Among many, a striking example is provided by
Gladiali and co-workers7 who noted, in one of their diphos-
phane syntheses, that most of the product was lost in the final
low-yielding (45–50%) reduction step. We ourselves have
reported several cases where syntheses failed because the
Centre for Synthesis and Chemical Biology, School of Chemistry and
Chemical Biology, University College Dublin, Belfield, Dublin 4,
Ireland. E-mail: declan.gilheany@ucd.ie; Fax: +353-1-7162127;
Tel: +353-1-7162308
w Electronic supplementary information (ESI) available: Full experi-
mental procedure, and full characterization data for phosphine oxides,
sulfides and boranes; 31P NMR data for all CPS; NMR spectra and
HPLC traces of phosphine boranes. See DOI: 10.1039/c1cc14856g
The methodology was applied to a variety of alkyl and aryl
achiral and racemic phosphine oxides and sulfides, both
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 817–819 817

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In searching for an alternative to methyl triflate, we settled
on triethyloxonium tetrafluoroborate (Meerwein’s salt), which
had previously been used to convert phosphine oxides to
alkoxyphosphonium salts.24 We found that it could convert
(S)-methylphenylo-tolylphosphine oxide (of 93% ee) cleanly in
DCM to the ethoxyphosphonium salt, as judged by 31P NM R
(d 71.9 ppm). Subsequent treatment with sodium borohydride
yielded, stereospecifically, the corresponding inverted phos-
phine borane, again in reasonable yield (entry 3). The methyl
analogue behaved similarly (entry 4) as did several other
enantioenriched phosphine oxides (entries 5–10).
Scheme 1 One-pot reduction of phosphine oxides and sulfides using
oxalyl chloride and NaBH4.
tertiary and secondary, shown in Chart 1w. In each case,
reaction with oxalyl chloride was followed by 31P NMR and
all the compounds showed rapid and clean conversion to a
single species with a 31P chemical shift, which, by analogy with
the known triphenyl case14 (64.4 ppm) we assign to the derived
chlorophosphonium salt (CPS). The shifts are mostly in the
ranges 57–65 ppm for triarylcases, 67–72 ppm for diarylmethyl
cases rising to 90–100 ppm with greater alkyl substitution
(ESI–Table A). Subsequent in situ treatment of the CPS with
sodium borohydride in diglyme resulted in clean conversion to
phosphine borane, all reactions at room temperature. Note also
that the phosphine sulfides are converted via the same CPS.
We also studied an enantiomerically enriched P-stereogenic
case, (S)-methylphenylo-tolylphosphine oxide (of 93% ee).
Disappointingly, this gave racemic phosphine borane under
a variety of reaction conditions.22 It was our strong suspicion
that this racemisation was induced by the presence of the
chloride counter ion of the chlorophosphonium salt. Therefore
we considered how we could generate a pseudophosphonium
salt with a non-nucleophilic counter-ion, in order to stop any
racemisation process. This caused us to re-consider alkylation
of the PO bond,23 in particular the work of Imamoto and
co-workers.2d They had shown that stereospecific reduction
could be effected by initial treatment at room temperature with
methyl triflate, followed by LAH reduction at low temperature
of the alkoxyphosphonium triflate that was formed. Since the
sodium borohydride method had worked so well for us, we
were encouraged to use it instead as the reductant and we were
gratified to find that it worked in reasonable yield with the
expected inversion and the same optical purity, both at low
and ambient temperatures (Table 1, entries 1/2).
In all of the experiments reported in Table 1, a small but
noticeable amount of phosphine oxide with the same ee as the
starting material was recovered after reduction was complete,
accounting for the reduced yield of phosphine borane. This
may result from hydrolysis of the alkoxyphosphonium salt by
adventitious water, although it is surprising that this would
occur with full retention of configuration. However the most
significant point in this regard is that sodium borohydride,
unlike LAH, does not react with this reformed phosphine oxide,
so that there is no risk of its direct non-specific reduction,
which sometimes leads to erosion of ee with LAH. We will
report subsequently on the optimisation of this stereospecific
reduction and on the mechanism of the borohydride
reduction/boronation of the CPS for which both stepwise
and concerted versions can be written.
In conclusion, we have found a convenient method for
conversion of a wide range of tertiary and secondary, phosphine
oxides and sulfides directly to phosphine borane in excellent
yield. The method has significant advantages over the other
common reduction methods (other hydrides and silanes):
milder conditions, easier to handle reagents and significantly
expanded substrate scope. In addition, preliminary studies
suggest that a similar methodology can be developed for
stereospecific reduction of optically enriched P-stereogenic
Table
P-stereogenic phosphine oxides
1
Stereospecific reduction/boronationa of optically active
% ee A % ee B
Alkylating agent Yield (%)b (config)c (config)c
#
R
1
2
3
4
5
6
7
8
9
o-tolyld,e
o-tolyld
o-tolyl
o-tolyl
o-anisyl
o-anisyl
o-biphenylyl [Et3O]BF4
mesityl
tert-butyl
MeOTf
MeOTf
[Et3O]BF4
[Me3O]BF4
[Et3O]BF4
[Me3O]BF4
62
73
76
71
67
71
68
67
63
68
93 (S)
93 (S)
93 (S)
93 (S)
95 (R)
95 (R)
81 (S)
44f
93 (S)
93 (S)
93 (S)
93 (S)
95 (R)
95 (R)
81 (S)
44f,g
[Et3O]BF4
[Et3O]BF4
[Et3O]BF4
53 (R)
46 (S)
53 (R)
46 (S)
10 tert-butyl
a
Unless otherwise specified the addition of alkylating agent (in DCM)
and NaBH4 (in diglyme) was carried at room temperature followed by
b
c
refluxing; isolated yield; by CSP HPLC, configuration determined
d
e
as described in SI; in DME solvent NaBH4 was added at À78 1C;
f
g
configuration not assigned; % ee measured by conversion to
corresponding phosphine oxide.
Chart 1 Oxides and sulfides converted according to Scheme 1.
818 Chem. Commun., 2012, 48, 817–819
c
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phosphine oxides. A significant advantage of the latter is that
sodium borohydride will not reduce any of the oxide regenerated
as side-product, which is not the case if, e.g. LAH is used. This
holds out promise of being a mild and reliable stereospecific
variant. We think therefore that together these two borohydride
methods may prove to be the method of choice for this once
recalcitrant reaction.
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We thank sincerely Science Foundation Ireland (SFI) for
funding this chemistry under Grant RFP/08/CHE1251. We
are also grateful to UCD Centre for Synthesis and Chemical
Biology (CSCB) and the UCD School of Chemistry and
Chemical Biology for access to their extensive analysis facilities
and to Celtic Catalysts Ltd. and Luka Senica for gifting
enantioenriched phosphine oxides. DGG also thanks University
College Dublin for a President’s Research Fellowship, held
partly in Stanford University in the Laboratory of Professor
James Collman.
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c
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Chem. Commun., 2012, 48, 817–819 819