Development of a redox-free Mitsunobu reaction exploiting phosphine oxides as precursors to dioxyphosphoranes

Article abstract of DOI:10.1039/c4cc02171a

The development of the first redox-free protocol for the Mitsunobu reaction is described. This has been achieved by exploiting triphenylphosphine oxide-the unwanted by-product in the conventional Mitsunobu reaction-as the precursor to the active P(v) coupling reagent. Multinuclear NMR studies are consistent with hydroxyl activation via an alkoxyphosphonium salt.

Full text of DOI:10.1039/c4cc02171a

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Development of a redox-free Mitsunobu reaction
exploiting phosphine oxides as precursors to
dioxyphosphoranes†
Cite this: Chem. Commun., 2014,
50, 7340
Received 24th March 2014,
Accepted 16th May 2014
Xiaoping Tang,a Charlotte Chapman,a Matthew Whitingb and Ross Denton*a
DOI: 10.1039/c4cc02171a
www.rsc.org/chemcomm
The development of the first redox-free protocol for the Mitsunobu bipyridyl-tagged phosphine reagents,4 fluorous phosphines,5
reaction is described. This has been achieved by exploiting tetraaryl phosphonium salts incorporating phosphines,6
triphenylphosphine oxide – the unwanted by-product in the conven- rasta resins,7 a ‘‘waste as catalyst strategy’’8 and ‘‘impurity
tional Mitsunobu reaction – as the precursor to the active P(V) coupling annihilation’’ methods.9
reagent. Multinuclear NMR studies are consistent with hydroxyl
More recently the requirement for both a stoichiometric
oxidant and phosphine in the Mitsunobu coupling and other
phosphorus-mediated reactions has begun to be addressed.10
activation via an alkoxyphosphonium salt.
Bimolecular nucleophilic substitution reactions of alcohols are In a pioneering study, Toy described a Mitsunobu system that
fundamentally important transformations in chemical synthesis. employed substoichiometric DEAD and an iodine(III)-based terminal
During the last sixty years phosphorus(V) compounds have emerged oxidant.11 More recently still Taniguchi has demonstrated an
as widely used activating agents for nucleophilic coupling reactions impressive catalytic variant that exploits molecular oxygen as the
through a process originally described by Mukaiyama as ‘‘redox terminal oxidant.12 The necessity for an oxidant in the Mitsunobu
dehydration’’,1 the most familiar of these protocols being the 1967 procedure is a consequence of the fact that phosphorus(V) reagents
Mitsunobu reaction2 (Scheme 1).
have been accessed almost exclusively in an oxidative sense
Although this powerful protocol has been widely employed from phosphine precursors e.g. triphenylphosphine and DEAD
in chemical synthesis it suffers from low atom economy. (Scheme 1). A corollary of this conventional approach is that any
Furthermore, the diazodicarboxylate oxidants are toxic, high phosphorus recycling or indeed catalysis13,14 of such reactions
energy compounds and the derived hydrazine and phosphine must be achieved through the addition of a terminal reductant.15
oxide by-products can complicate product isolation. To this end
In contemplating a method to improve the Mitsunobu reaction
many creative strategies have been developed to aid purification. For and eliminate hydrazine by-products we were attracted to a concep-
example, tagged3 or polymeric phosphine and diazodicarboxylate tually distinct alternative in which the active phosphorus(V) reagent
reagents have emerged. Notable work in this area includes would be accessed from a phosphorus(V) precursor,16 specifically
triphenylphosphine oxide – the unwanted by-product from the
redox-based protocol (Scheme 2).17
Such a protocol was attractive since it would: (a) eliminate
the need for an oxidant; (b) eliminate competing side reactions
such as alkylation of the hydrazinedicarboxylate; and (c) result
Scheme 1 The 1967 Mitsunobu protocol based on the DEAD–PPh3
combination.
a School of Chemistry, University Park, University of Nottingham, Nottingham, UK.
E-mail: ross.denton@nottingham.ac.uk; Tel: +44 (0)1159514194
b GlaxoSmithKline, Gunnels Wood Road, Stevenage, UK
† Electronic supplementary information (ESI) available: Details of Mitsunobu
Scheme 2 This work: a redox-free Mitsunobu process which relies upon
generation of the active P(V) reagent from triphenylphosphine oxide.
coupling procedure and full experimental supporting information. See DOI:
10.1039/c4cc02171a
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Table 1 Redox-free Mitsunobu reactions using phosphorane 3a
Scheme 3 Synthesis of the Ishikawa phosphorane 3 from triphenylphos-
phine oxide.
Entry Product
Yield e.e. Entry Product
73%
Yield (%)
70
in no net phosphorus waste. To the best of our knowledge this
approach has only been investigated to date by Jenkins, whose
detailed studies on the Hendrickson reagent (Ph3POPPh3Á2OTf)
indicated that the latter could function in analogy to the
Mitsunobu system for esterification of primary alcohols. How-
ever, critically, in the case of secondary alcohols the ester
products were obtained with retention of configuration18
In this communication we describe the successful implementa-
tion of redox-free Mitsunobu inversion reactions in which the active
phosphorus(V) reagent is obtained from triphenylphosphine oxide.
The approach taken (Scheme 2) was contingent upon accessing
1
499 : 1
7
8
9
e.r.
70%
2
3
499 : 1
e.r.
72
50
90%
96 : 4
e.r.
the required dioxyphosphorane – of which many are known19–22
–
from triphenylphosphine oxide. While this was unprecedented at
the time of our study we reasoned that the established conversion
of phosphine oxides into chlorophosphonium salts23,24 would
provide a means to access the required dioxyphosphoranes follow-
ing addition of the appropriate alkoxides. Gratifying this proved to
be the case and several dioxyphosphoranes25 were obtained
through this protocol (Scheme 3) including dioxyphosphorane 3
(31P d = À58.2, 2JC–P J = 6.0, 19F d = À74.3, 2JF–F, J = 9.0 CDCl3), which
was originally described by Ishikawa and is known to promote a
wide range of Mitsunobu-type coupling reactions.22
4
5
79%
76%
10
11
27
30
While these studies were instructive and guided our choice
of phosphorane the stereochemical outcome of intermolecular
coupling reactions using 3 remained unknown.26 A further
attractive feature of 3 was the presence of the CF3 groups which
allowed us to calculate the molarity of stock solutions of the
reagent using 19F NMR.27
6
a
For each entry the isolated yield after chromatography is reported.
With this protocol in hand we carried out a multinuclear
Having developed a new method to access the Ishikawa
dioxyphosphorane we next developed a Mitsunobu-type alcohol
inversion protocol using reagent 3 and ethyl acetate as solvent NMR study in order to gain further insight into the course of
(Table 1). the reaction. We were particularly interested in establishing
The redox-free coupling reactions took place with inversion whether or exchange of one of the trifluoroalkoxy ligands
of configuration with both non-activated (entries 1 and 2) at phosphorus would occur in the presence of the alcohol alone
as well as an activated secondary alcohol (entry 3 and 4). The to generate a mixed dioxyphosphorane of general structure
process depicted in entry 1 was equally efficient on 15 mmol Ph3P(OCH2CF3)(OR) as originally proposed by Ishikawa.
scale (with respect to the alcohol) and, in this case, 86% of
The results we obtained (Scheme 4) indicated that this was not
triphenylphosphine oxide was recovered for reuse in subsequent the case with (S)-2-octanol. Thus a 0.25 M solution of 3 in ethyl
coupling reactions. Furthermore, we determined that the stereo- acetate remained unchanged upon addition of one equivalent of the
chemical outcome of the reaction was independent of the order alcohol. However, upon addition of benzoic acid the 31P resonance
of addition of the alcohol and carboxylic acid.
at À59.6 ppm was replaced by a new signal at 53.4 ppm which
Additional secondary alcohols underwent esterification in corresponds to the indicated alkoxyphosphonium salt with a
good yield (entries 5 and 6). Acetic acid could also be employed carboxylate counteranion. The structure of this intermediate is
in place of the aromatic carboxylic acids (entry 9); however, the corroborated by the presence of a single peak in the 19F NMR,
isolated yield in this case was moderate. Finally, menthol which corresponds to trifluoroethanol and rules out the formation
underwent esterification with inversion of configuration albeit of a ‘‘mixed’’ dioxyphosphorane of the type Ph3P(OCH2CF3)(OR).
in low yield (entries 10 and 11).
The former species then underwent slow Arbuzov collapse to
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Scheme 4 Multinuclear NMR study.
the afford ester product with inversion of configuration with
concomitant generation of triphenylphosphine oxide.
In summary we have developed for the first time a redox-free
approach to Mitsunobu inversion reactions that relies upon acces-
sing the Ishikawa phosphorane 3 from triphenylphosphine oxide.
This new protocol eliminates the need for diazo-based
oxidants and, given that reagent 3 is also known to promote
C–N, C–S and other cyclodehydration reactions,22 opens up a
wide range of other useful Mitsunobu-type reactions that will
not require the addition of an external oxidant. Furthermore,
since triphenylphosphine oxide is used to prepare the coupling
reagent no net phosphorus waste is generated.
Notes and references
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