Umpolung of a hydrogen atom of water by using a hexacoordinated phosphate and its application to deuteride reduction reactions of carbonyl compounds

Article abstract of DOI:10.1021/ja906875d

(Figure Presented) The polarity of a chemical bond is an important factor that determines the reactivity because a reaction of a positively charged atom with a negatively charged atom easily occurs. We report here a method for reversing the polarity of a hydrogen atom of water, which meant conversion of a protic hydrogen (H(δ+)) to a hydridic hydrogen (H(δ-)), by using a hexacoordinated phosphorus species. The method enables a reductive deuteration of carbonyl compounds utilizing inexpensive and easily usable D₂O under mild conditions. The umpolung of a hydrogen atom was achieved by utilizing tautomerization of phosphorus compounds. Classical metal hydrides never have this function, and these results demonstrated the potential utility of nonmetallic compounds for umpolung of a hydrogen atom.

Full text of DOI:10.1021/ja906875d

Published on Web 11/04/2009
Umpolung of a Hydrogen Atom of Water by Using a Hexacoordinated
Phosphate and Its Application to Deuteride Reduction Reactions of Carbonyl
Compounds
Hideaki Miyake, Naokazu Kano,* and Takayuki Kawashima*
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received August 13, 2009; E-mail: takayuki@chem.s.u-tokyo.ac.jp
Umpolung,1 which is a method for reversing polarity, is one of
the most useful methods for organic synthesis. Umpolung of an
isotope of hydrogen in heavy water (D2O or T2O) will provide
deuteride ion (D-) and tritide ion (T-) donors valuable for isotope
labeling,2 which is popular for the study of biomolecules and
reaction mechanisms, because heavy water is cheaper and more
easily usable than other isotope-labeled hydride reagents (LiAlD4,
etc.). However, umpolung of a hydrogen atom is difficult, because
a reaction of a proton source, such as water (Hδ+-OH), with the
product of the umpolung (Hδ--Z) or the reagents used results in
facile conversion to molecular hydrogen. While numerous works
have been reported on the development of isotope-labeling methods
utilizing D2O under strongly acidic conditions, at high temperatures,
or in the presence of transition metal catalysts, the deuterium does
not work as a deuteride ion in those cases.3 Here, we report on the
umpolung of a hydrogen atom of water by using a hexacoordinated
dihydrophosphate as a key species.4 And, we also report the
reductive deuteration of carbonyl compounds by using the umpolung
of D2O under mild conditions without the presence of a transition
metal. To achieve the umpolung, there are two requirements: first,
a proton of water should be exchanged with hydrogens on the
phosphorus of the phosphate anyhow, and second, the P-H groups
of the phosphate should show hydridic reactivity.
the oxygen atoms. Compounds 2a,b can be handled easily in the
air due to their higher stabilities than other reported dihydrophos-
phates.6
Figure 1. ORTEP drawing of 2b with thermal ellipsoid plot (50%
probability).
Table 1. Hydride Reduction of Carbonyl Compounds with 2a
Scheme 1. Synthesis and Reactions of Dihydrophosphates 2a,b
a Isolated yield of alcohol.b Obtained as a mixture with Ph(CH2)3OH
1
(12%). The yields are determined by the H NMR spectroscopy.
To confirm the first requirement for the umpolung, an H-D
(hydrogen-deuterium) exchange reaction of 2a with D2O was
attempted in DMSO-d6 in anticipation of the protic character of an
O-H group in a tautomer of 2a. Although the hydrogen atoms on
the phosphorus atom of 2a were hardly exchanged for the deuterium
atoms in D2O under both basic and neutral conditions, the H-D
exchange proceeded efficiently in the presence of AcOH (1 equiv)
to give 2a-d2 bearing two P-D bonds (95%D) after 0.5 h. The
same reaction in the presence of AcOH (0.03 equiv) in THF also
gave 2a-d2 (98%D) in 81% isolated yield.
The second requirement for the umpolung is hydridic reactivity
of 2a. Compound 2a was subjected to hydride reduction reactions
of aldehydes and a ketone in anticipation of its particular structure,
although a hydrogen atom of a P-H bond rarely behaves as a
hydride.7 The reaction of 2a with 4-phenylbenzaldehyde (1 equiv)
in refluxing THF for 10 h, followed by treatment with aqueous
NH4Cl solution, gave the corresponding alcohol and 1 in good yields
Hydrophosphorane 1,5 which was synthesized from phosphorus
trichloride by a one-step reaction, was successively treated with
lithium naphthalenide (3 equiv), water (excess), and tetraethylam-
monium bromide (1.5 equiv) in one pot to give dihydrophosphate
2a in 46% yield (Scheme 1). Cation exchange of 2a gave 2b in
91% yield. Compounds 2a,b could also be synthesized by a reaction
of 1 with LiAlH4 followed by the cation exchange reactions in
higher yields (2a: 73%, 2b: 52%). They were characterized by the
NMR and IR spectroscopy, MS, and elemental analysis, and the
structure of 2b was determined by the X-ray crystallographic
analysis which was the first example for a hexacoordinated
dihydrophosphate as far as we know (Figure 1). The anion part of
2b has an octahedral geometry with C2 symmetry around the P1
atom, and the hydrogen atoms are located at the trans positions to
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16622 J. AM. CHEM. SOC. 2009, 131, 16622–16623
10.1021/ja906875d CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
(Table 1, entry 1). The reduction reaction was dramatically
accelerated by the addition of LiCl (1 equiv) or AcOH (5 equiv),
which activated the aldehyde, and consequently the reaction was
completed after 1 h at ambient temperature (entries 2 and 3). This
is remarkable, considering that most hydridic reagents easily
decompose to produce hydrogen gas under acidic conditions. This
reduction method is also applicable to an aliphatic aldehyde (entry
4). In the reduction of an R,ꢀ-unsaturated aldehyde, excess acid
was necessary to prevent consumption of the aldehyde by the side
reaction with the in situ generated conjugate base of 1 (entry 5).
The reduction of a ketone also proceeded in a moderate yield,
although more LiCl and a longer reaction time were necessary (entry
6). Hydrophosphorane 1 was recovered in 75-89% yields (Scheme
1) and is reusable as a precursor of 2a.
tautomerization, and H-D exchange, would be reversible, and
hence treatment of 2a with D2O under an acidic condition would
finally give 2a-d2 by repetition of these processes. While the polarity
of a hydrogen atom of a transition metal hydride can be controlled
by exchanging its ligands,9 this work is significant in terms of
umpolung of a hydrogen atom in one pot only via equilibrium
reactions in addition to its achievement without any metal.
Scheme 2. Plausible Mechanism of H-D Exchange Reaction of 2a
Compound 2a-d2, which had been prepared by the H-D
exchange of 2a with D2O, naturally reduced 4-phenylbenzaldehyde
to give the deuterated alcohol 4-PhC6H4CHDOH (83% yield,
95%D) in the presence of LiCl. The reductive deuteration, even in
the presence of more than 100 equiv of H2O under the same
conditions, also gave the deuterated alcohol (87% yield, 88%D)
showing a deuteride transfer mechanism. This is good evidence
for the umpolung of deuterium of D2O, and it is a clear difference
from other reductive deuterations utilizing D2O such as a reaction
of an anionic carbon atom with a deuteron (D+)3b,c and deuteration
of alkenes or alkynes with a transition metal catalysis.3d,e Further-
more, a one-pot reaction of the H-D exchange and reduction was
successful (Figure 2). The H-D exchange from 2a to 2a-d2 using
D2O and AcOH (1.5 equiv), followed by the addition of
4-PhC6H4CHO in THF, also gave the deuterated alcohol (82% yield,
97%D). This is a promising isotope-labeling method because the
reaction achieves deuteride reduction under mild conditions by
simple procedures, does not need expensive deuteride reagents, and
does not use transition metal reagents that need careful handling.
In summary, we have shown the hexacoordinated dihydrophos-
phate can reduce carbonyl compounds, while the hydrogen atoms
are exchangeable for a proton of water via tautomerization. The
reactivities enabled the umpolung of a deuterium atom of D2O.
This reductive deuteration with D2O without any metal is valuable
for some favorable points such as mild conditions, ease of handling,
and scope of substrates.
Acknowledgment. This work was supported by research grants
from the Global COE program, the Sumitomo Foundation, and
Research Fellowship from the Japan Society for the Promotion of
Science. We thank Tosoh Finechem Corp. and Central Glass Co.,
Ltd. for gifts of alkyllithiums and fluorine compounds, respectively.
Supporting Information Available: Experimental procedures,
spectral data of 1, 2a, 2b, and 2a-d2, and the details of the X-ray
crystallographic analysis of 2b. This material is available free of charge
via the Internet at http://pubs.acs.org.
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1
doublet signal at δP -19.9 (d, JPH ) 223 Hz) in a 31P NMR
spectrum (with coupling) was observed, suggesting the formation
of 4. One of the hydrogen atoms on the phosphorus in 2a migrates
to the oxygen in 4 through the tautomerization, and then it should
be protic and exchangeable. The three processes, protonation,
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