Biphasic glycerol/2-MeTHF, ruthenium-catalysed enantioselective transfer hydrogenation of ketones using sodium hypophosphite as hydrogen donor

Article abstract of DOI:10.1002/ejoc.201300506

Sodium hypophosphite has been used as an efficient hydrogen donor in the transfer hydrogenation of aliphatic and aromatic ketones in the presence of [RuCl₂(p-cymene)]₂ and 2,2′-bipyridine in water. The corresponding alcohols were isolated in moderate to excellent yields (39-95 %). Good chemoselectivity was observed with ester, nitrile and halide functionalities in the ketones not being reduced. An enantioselective version of the reaction using [RuCl(p-cymene){(R,R)-TsDPEN}] as catalyst in a glycerol/2-MeTHF biphasic solvent mixture has been developed and allowed the reduction of (hetero)aromatic ketones with excellent chemo- and enantioselectivities (up to 97 % ee). Sodium hypophosphite has been used in the reduction of ketones in water (nine examples, 40-95 % yield). An original glycerol/2-MeTHF biphasic solvent system has been developed for the enantioselective version of the reaction. This system allows the preparation of aryl alkyl alcohols with up to 97 % ee (22 examples). Copyright

Full text of DOI:10.1002/ejoc.201300506

FULL PAPER
DOI: 10.1002/ejoc.201300506
Biphasic Glycerol/2-MeTHF, Ruthenium-Catalysed Enantioselective Transfer
Hydrogenation of Ketones Using Sodium Hypophosphite as Hydrogen Donor
Carole Guyon,[a] Estelle Métay,[a] Nicolas Duguet,[a] and Marc Lemaire*[a]
Keywords: Reduction / Ketones / Enantioselectivity / Ruthenium
Sodium hypophosphite has been used as an efficient hydro- functionalities in the ketones not being reduced. An enantio-
gen donor in the transfer hydrogenation of aliphatic and aro-
matic ketones in the presence of [RuCl2(p-cymene)]2 and
2,2Ј-bipyridine in water. The corresponding alcohols were
isolated in moderate to excellent yields (39–95%). Good
chemoselectivity was observed with ester, nitrile and halide
selective version of the reaction using [RuCl(p-
cymene){(R,R)-TsDPEN}] as catalyst in a glycerol/2-MeTHF
biphasic solvent mixture has been developed and allowed
the reduction of (hetero)aromatic ketones with excellent
chemo- and enantioselectivities (up to 97% ee).
phoric, air-stable and non-toxic reagents. In our group, ef-
ficient methods using tetramethyldisiloxane associated with
a metal have been developed for the reduction of several
functional groups,[8] but the price of this reagent is one of
the limitations of its use on an industrial scale.
In our search for other reducing agents we have become
interested in sodium hypophosphite[9a] and its derivatives
(i.e., phosphinic acid).[9b] Sodium hypophosphite is an easy-
to-handle solid, stable to air and moisture, available in bulk
quantity and already registered in REACH as a chemical
presenting no obvious toxicity.[10]
Sodium hypophosphite and phosphinic acid are known
as reducing reagents associated with metal catalysts.[9] In
comparison with their large-scale industrial use for electro-
less nickel plating, for example,[11] they have been less
studied for the reduction of functional groups. Sodium hy-
pophosphite derivatives are mainly employed in hetero-
geneous transfer hydrogenation[12] catalysed by Pd/C[13] or
Raney nickel.[14] In contrast, comparatively few examples
of homogeneous catalysis with copper,[15] iron[16] and ruthe-
nium have been reported.[14g,17] Reductions catalysed by Pd/
C are generally not selective,[18c] but activated ketones are
an exception and can be converted into either alcohols[18a]
or alkanes.[18b] Iridium tetrachloride in association with
phosphinic acid or phosphorus acid in water/iPrOH allows
the reduction of cyclic ketones with good diastereoselectivi-
ties (cis/trans ratio = 97:3 for 4-tert-butylcyclohexanone).[19]
A ruthenium-catalysed reduction has also been developed
by using triethylammonium hypophosphite as reductant
and solvent that gives good stereo- and chemoselec-
tivities.[14g,17b] Despite the efficiency of these methods, they
are plagued by the use of water-soluble solvents and the use
of excess triethylamine. To the best of our knowledge, no
enantioselective reduction of prochiral aromatic and linear
aliphatic ketones has been reported by using hypophosphite
derivatives as reductant.
Introduction
The reduction of ketones is widely employed in the re-
search laboratory as well as in industry.[1] Efficient re-
duction systems have been developed by using neutral and
charged hydrides,[2] molecular hydrogen,[3] hydrogen donors
(2-propanol, triethylamine/formic acid, sodium formate),[4]
hydrosilanes[5] and hydrosiloxanes.[5]
Molecular hydrogen remains the most attractive reduct-
ant in terms of both cost and atom economy. However, the
lack of selectivity observed in many cases, the flammability
of the gas and the specialized equipment required has led to
the search for alternatives. Aluminium and boron hydrides
present safety and environmental concerns; they are highly
reactive towards air and moisture, and hence careful
quenching is usually required to avoid any risk of fire. In
addition, the toxicity of the water-soluble solvents used and
one of the byproducts are also a serious limitation.[6]
Reduction performed with alcohols (mainly 2-propanol)
as the hydrogen donor leads to an equilibrium,[4b] and high
dilution is usually preferred to reach high conversions, tri-
ethylammonium formate releases unrecyclable triethyl-
amine, and hydrosilanes can disproportionate to SiH4, a py-
rophoric and toxic gas.[7] Consequently, the development of
new reductive systems that are efficient, selective and cheap
(reaction and treatment) with low environmental impact
and toxicity is highly desirable. Efforts have been directed
towards the use of hydrosiloxanes, which are non-pyro-
[a] Equipe Catalyse Synthèse et Environnement, Institut de Chimie
et Biochimie Moléculaires et Supramoléculaires UMR 5246,
Université Claude Bernard Lyon 1, Bâtiment Curien,
43 boulevard du 11 novembre 1918, 69622 Villeurbanne Cedex,
France
Fax: +33-4-72431408
E-mail: marc.lemaire.chimie@univ-lyon1.fr
Homepage: http://www.icbms.fr/casyen
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300506.
Eur. J. Org. Chem. 2013, 5439–5444
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5439

C. Guyon, E. Métay, N. Duguet, M. Lemaire
FULL PAPER
Herein we report the first reduction of ketones to the As a consequence, a number of ketones were reduced in
corresponding racemic alcohols with sodium hypophos- water in the presence of 2.5 equiv. sodium hypophosphite
phite in a biphasic system using [RuCl2(p-cymene)]2 and with 1 mol-% of [RuCl2(p-cymene)]2 and 2.4 mol-% of 2,2Ј-
2,2Ј-bipyridine. The enantioselective version using the well- bipyridine at 80 °C for 18–24 h.
known Noyori catalyst [RuCl(p-cymene){(R,R)-TsDPEN}]
The reduction of acetophenone derivatives was not sensi-
in a 2-MeTHF/glycerol biphasic solvent mixture is also de- tive to the length of the alkyl chain (Table 2, Entries 1 and
scribed with good chemo- and enantioselectivities.
2). 2-Acetonaphthone was also converted into alcohol 3 in
good yield (Table 2, Entry 3). The reduction was chemose-
lective towards compounds bearing halogen, nitrile and es-
ter groups under these conditions (Table 2, Entries 4–6).
Note that in the case of p-cyanoacetophenone and the ester
derivative, a co-solvent was necessary to reach good yields
and selectivities (Table 2, Entries 5 and 6). Furthermore,
alkyl ketones were also reduced and isolated in yields of 75
and 50% (Table 2, Entries 7 and 8). Finally, benzophenone
was reduced in 39% yield (Table 2, Entry 9).
Results and Discussion
Homogeneous ruthenium catalysts are well known for
the chemoselective reduction of ketones under transfer
hydrogenation conditions.[4] Consequently, we focused our
study on ruthenium species as catalysts. Khai and
Arcelli[14g,17b] successfully used [RuCl2(PPh3)3] for the re-
duction of ketones with a triethylamine/phosphinic acid
mixture. We were interested in a biphasic version of this
reaction with sodium hypophosphite as the reducing agent
in water. The reduction of acetophenone by sodium hypo-
phosphite (5 equiv.) catalysed by [RuCl2(PPh3)3] under bi-
phasic conditions (toluene/water) in the presence of a
phase-transfer catalyst (nBu4NCl) gave a conversion of 20%
(Table 1, Entry 1). The use of water-soluble phosphane li-
gand TPPTS [tris(m-sulfophenyl)phosphane trisodium salt]
with RuCl3·xH2O[20] was also evaluated, but did not lead
to an improvement of the conversion (Table 1, Entry 2). Ni-
trogen ligands were also tested with different RuII and RuIII
precursors. The best conversion observed with RuCl3·xH2O
was 42% when 1,10-phenanthroline was used as ligand
(Table 1, Entry 3). The reduction was less efficient with the
commercially available preformed bipyridine–ruthenium
complex [RuCl2(biPyr)2] (Table 1, Entry 4). Satisfyingly, the
association of 2,2Ј-bipyridine and the p-cymene–Ru com-
plex (1 mol-%) in the absence of toluene and nBu4NCl at
80 °C gave complete conversion of acetophenone (Table 1,
Entry 5).
Table 2. Reduction of ketones.
Table 1. Study of the effect of different ruthenium complexes on
reduction.
Entry Ruthenium complex
Ligand
Conv. [%][a]
1
2[b]
3
[RuCl2(PPh3)3]
RuCl3·xH2O
none
20
Ͻ5
42
15–24
98
TPPTS (4.5 mol-%)
1,10-phenanthroline
none
RuCl3·xH2O
4
[RuCl2(biPyr)2]
[RuCl2(p-cymene)]2
5[b,c]
2,2Ј-bipyridine
[a] Conversions were determined by 1H NMR spectroscopy. [b] No
phase-transfer agent or co-solvent was used. [c] 1 mol-% [RuCl2(p-
cymene)]2, 2.4 mol-% 2,2Ј-bipyridine.
[a] Toluene was used as co-solvent ([S] = 2.5 m). [b] 2-MeTHF was
used as co-solvent ([S] = 2 m).
On the basis of these encouraging results, an enantio-
These results indicate that neither a phase-transfer agent selective version of this reaction was explored. To the best
nor a co-solvent is necessary to reach high conversions un- of our knowledge, there is only one report describing an
der these conditions. Additional experiments showed that enantioselective reduction of cyclic ketones with ammo-
the amount of sodium hypophosphite could be reduced nium hypophosphite.[17b] Considering the lack of knowl-
from 5 to 2.5 equiv. without significant loss of conversion. edge on sodium hypophosphite, we considered it of interest
5440
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5439–5444

Enantioselective Transfer Hydrogenation of Ketones
to evaluate its potential in the enantioselective reduction of the reduction of acetophenone; C2-symmetric (R,R)-DPEN
ketones.
(L5) gave a moderate yield with 20% enantiomeric excess.
A recent review[21] on enantiopure bipyridines mentioned Conversely, with Noyori’s ligand (R,R)-TsDPEN (L6), 87%
that the use of these ligands led to relatively poor enantio- ee was reached, but with a poor conversion of 20%. This
meric excesses in the reduction of ketones. Thus, other ni- ligand has successfully been used for the reduction of
trogen ligands were investigated. All the optimized param- ketones in the presence of the same ruthenium complex in
eters (2.5 equiv. of NaH2PO2·H2O at 2.5 m in water, 1 mol- water with sodium formate.[24] Thus, we focused our investi-
% of [RuCl2(p-cymene)]2) were maintained except for the gation on Noyori’s ligand [RuCl(p-cymene){(R,R)-
temperature, which was lowered to obtain a better enantio- TsDPEN}], which gave the best enantioselectivity.
meric excess. First, the nature of the ligand (2.4 mol-%) was
Because of the lack of reactivity of the catalyst in water,
probed (Scheme 1). Oxazoline-based ligands have been re- we considered replacing water by other polar solvents. Data
ported to induce good enantioselectivity in the hydro- concerning the solubility of sodium hypophosphite are only
silylation of ketones[22a] and in the transfer hydrogenation available for water (51.96 wt.-%) and glycols: ethylene glycol
with iPrOH;[22b] however, they were found to be inefficient (33.01 wt.-%), glycerol (32.70 wt.-%) and propylene glycol
in inducing conversion under our conditions (Scheme 1, L1 (9.70 wt.-%) at 25 °C.[25] The optimization was pursued
and L2). The ligand L3 has been used in asymmetric trans- with glycerol, which is considered a green solvent according
fer hydrogenation with formate,[23] but no conversion was to the GSK’s solvent selection guide (Table 3).[26]
observed under our conditions. The reaction performed
A control experiment in the absence of the hypophos-
with cyclohexane-1,2-diamine (L4) gave a modest conver- phite salt did not lead to any conversion (Table 3, Entry 1).
sion of 50% but a poor enantiomeric excess (5%). Finally, This suggests that glycerol does not act as a hydrogen do-
1,2-diphenyl-1,2-ethylenediamine ligands were engaged in nor[27] under these conditions. The concentration of hypo-
phosphite in glycerol did not influence the reaction (33%
conversion in 15–19 h; Table 3, Entries 2 and 3). However,
an increase in the reaction time from 15 to 38 h led to a
conversion of 52% and 88% ee (Table 3, Entry 3). A further
increase in the quantity of sodium hypophosphite from 2.5
to 5 equiv. and its concentration from 2.5 to 5 m did not
significantly improve the conversion after 43 h (Table 3, En-
try 4). When sodium hypophosphite was replaced by its
conjugate acid, the rate of reaction increased, but 3-(1-
phenylethoxy)propane-1,2-diol was also formed as a side-
product (Table 3, Entry 5). The amount of catalyst had a
positive effect on the reaction; an increase in catalyst load-
ing from 2 to 4 mol-% led to an increase in the conversion
from 33 to 56% in 14–15 h (Table 3, Entries 3 and 6). When
the reaction with 4 mol-% catalyst was performed over 86 h,
a conversion of 70% was reached with 90% ee (Table 3,
Entry 6, in parentheses). As the reaction remained slow, the
addition of a co-solvent was considered. In toluene, the re-
action was slower than in its absence (Table 3, Entry 7),
which can be explained by the competition for coordination
to the catalyst between toluene and the substrate. Con-
versely, 2-MeTHF had a positive effect on the reaction; a
Scheme 1. Screening of ligands for the reduction reaction. Conver-
sion calculated by H NMR spectroscopy; ee determined by chiral
GC; *N.D.: not determined.
1
Table 3. Optimization of the reaction conditions using glycerol as protic solvent.[a]
Entry Ru. [mol-%] NaH2PO2·H2O [equiv.] c in glycerol [m]
Additive
Time [h] Conv. [%][b] (conv. [%], ee [%][c])
1
2
3
4
5
6
7
8
2
2
2
2
2
4
4
4
0
–
0.71
2.5
5
2.5
2.5
2.5
2.5
–
–
–
–
36
19
15 (38)
43
17
14 (86)
14
0
33
2.5
2.5
5
2.5
2.5
2.5
2.5
33 (52, 88)
53
H3PO2 (2.5 equiv.)
–
toluene ([S] = 2 m)
61[d]
56 (70, 90)
40
82 (90, 96)
2-MeTHF ([S] = 2 m) 16 (24)
[a] Reagents and conditions: acetophenone, NaH2PO2·H2O, glycerol, [RuCl(p-cymene){(R,R)-TsDPEN}], 40 °C. [b] Conversions were
determined by 1H NMR analysis of the reaction mixture. [c] Conversions and ees determined after the period of time given in parentheses
in the preceding column. The ees were determined by chiral GC. [d] Two products were obtained: 1-phenylethanol (49%) and 3-(1-
phenylethoxy)propane-1,2-diol (12%).
Eur. J. Org. Chem. 2013, 5439–5444
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5441

C. Guyon, E. Métay, N. Duguet, M. Lemaire
FULL PAPER
conversion of 82% was noted along with an enantiomeric halide, nitro,[28] ester, nitrile and ether functional groups
excess of 96% in 16 h (Table 3, Entry 8). An increase in the were not affected by the reducing agent, while retaining
reaction time to 24 h gave a conversion of 90% with 96% high levels of chiral induction (82–94% ee).
ee (Table 3, Entry 8). To the best of our knowledge, this
The reduction of other ketone derivatives was also inves-
biphasic system, glycerol/2-MeTHF, has not been employed tigated (Scheme 3). The reduction of 2-acetonaphthone
previously. Such solvent systems could be advantageously gave 3 with a comparable conversion and ee (80% yield,
used in other sensitive reactions requiring the separation of 96% ee) as acetophenone. Ketones bearing heterocycles
the product from other chemical partners. This is in accord such as benzo[b]furan and benzo[b]thiophene led to prod-
with the need to decrease the environmental impact of pro- ucts 18 and 19 in isolated yields of 98 and 28% and enantio-
cesses.
meric excesses of 83 and 97%, respectively. The reduction
By using these optimized conditions, acetophenone was of 2,6-diacetylpyridine afforded the corresponding diol 20
converted into the corresponding (R)-alcohol 1 in 73% in 45% yield and 66% de. The major diastereoisomer was
yield and 96% ee (Scheme 2). Then the scope and limita- isolated with Ͼ95% ee in favour of the (R,R) enantiomer.
tions of the reaction were investigated. Acetophenones Heteroaromatic ketones bearing a free N–H bond (pyrrole
bearing an electron-donating group at the para position led and indole) were also tested, but with no conversion, which
to the corresponding alcohols 10 and 11 with excellent confirms the previous observation that protic functional
enantioselectivities (91–92% ee), although in low yields. groups are deleterious to the reaction (Scheme 2, products
Similarly, acetophenone derivatives bearing an electron- 12 and 15).
withdrawing group also led to the products 5, 6, 16 and 17
with the same levels of enantioselectivity (82–94% ee) but
improved isolated yields (65–97%). Within this group of
compounds, the nitrile 5 was obtained in the lowest yield
(65%) and with ee (85%), probably due to the potential
ligand effect of the nitrogen atom. Bromoacetophenones
were also readily converted into their corresponding
alcohols 4, 13 and 14 with no obvious effect due to the
position of the substituent on the aromatic ring. Finally,
compounds bearing protic functionalities such as phenol 12
and carboxylic acid 15 afforded low or no conversions.
Overall, this method proved to be highly chemoselective as
Scheme 3. Enantioselective reduction of ketones. [a] The amount
of catalyst, reductive reagent and glycerol were doubled; 81% of
the initial mass was recovered after extraction. Isolated yields, ee
determined by GC or HPLC; configurations were determined by
comparison of the measured [α]D values with the literature data;
*not isolated, conversion calculated on the reaction mixture, N.D.:
not determined.
Substituents on the alkyl chain were next investigated.
The derivatives with medium or bulky alkyl chains were ba-
rely reduced to products 2 and 21 (16 and 0% conversion,
respectively). Methyl benzoylformate underwent moderate
conversion, and the corresponding hydroxy ester 23 was ob-
tained in an isolated yield of 55% with a modest induction
of 66% ee. The trifluoromethyl derivative 22 was obtained
with complete conversion, but the enantiomeric excess was
low (22%), and the absolute configuration was attributed
Scheme 2. Enantioselective reduction of acetophenone derivatives.
to (R) by comparison of the measured [α]D value with the
Isolated yields, ee determined by chiral GC or HPLC; configura-
literature data. Thus, the face that was attacked is the oppo-
tions were determined by comparison of the measured [α]D values
site to that of other ketones because of the inversion of
priority due to the presence of the CF3 group. The loss of
with the literature data; *not isolated, conversion calculated on the
reaction mixture, N.D.: not determined.
5442
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5439–5444

Enantioselective Transfer Hydrogenation of Ketones
at 254 nm, vacuum degasser) with a chiral column Chiralcel OJ-H
column 0.46ϫ25 cm (Daicel Chemical Ind., Ltd.).
enantiomeric induction with CF3 compared with CH3 has
previously been observed in the reduction with [RuCl(p-
cymene){(R,R)-TsDPEN}] and has been attributed to an
Procedure for the Reduction with [RuCl2(p-cymene)]2 and 2,2Ј-Bipyr-
attack at the opposite side due to a poor size differentiation idine: In a sealed tube under argon, [RuCl2(p-cymene)]2 (15.3 mg,
between CF3 and the phenyl core.[29] Finally, dialkyl
ketones underwent moderate conversion and with low en-
antiomeric excess (Scheme 3, products 7 and 8). This can
0.025 mmol, 1 mol-%), 2,2Ј-bipyridine (9.4 mg, 0.06 mmol,
2.4 mol-%) and sodium hypophosphite monohydrate (662 mg,
6.25 mmol, 2.5 equiv.) were introduced as solids. The ketone
(2.5 mmol, 1 equiv.) followed by water (2.5 mL, [NaH2PO2·H2O] in
be attributed to the lack of C(sp2)–H/π attractive interac-
water = 2.5 m) were then added, and the tube was sealed. The reac-
tions that normally operate between an η6-arene ligand and
tion mixture was stirred at 1200 rpm and heated at 80 °C. After
aromatic ketones in the transition state.[30]
24 h, the tube was cooled to room temperature, depressurized and
an aliquot was taken for 1H NMR analysis to check the conversion
of the starting material. The reaction mixture was diluted by ad-
ditional water (10 mL) and extracted with either pentane or
CH2Cl2. The combined organic extracts were dried with Na2SO4,
Conclusions
filtered, and concentrated under reduced pressure. The crude mate-
We have developed a general method for the reduction
rial was purified by flash column chromatography on silica gel by
of ketones by using sodium hypophosphite as an efficient
using a gradient of pentane or cyclohexane/ethyl acetate (1:0 to
hydrogen donor. The transfer hydrogenation of aliphatic
7:3). After concentration, alcohols were obtained as an oil or solid.
and aromatic ketones has been achieved by using an
[RuCl2(p-cymene)]2/2,2Ј-bipyridine system in water, and the
corresponding alcohols were isolated in moderate to excel-
lent yields (39–95%). Encouraged by these results, we devel-
oped an enantioselective version of the reaction by using
[RuCl(p-cymene){(R,R)-TsDPEN}] in a biphasic glycerol/2-
MeTHF solvent mixture. The original conditions allowed
The products were characterized by NMR spectroscopy (full spec-
troscopic data are given in the Supporting Information).
Procedure for the Reduction with [RuCl(p-cymene){(R,R)-
TsDPEN}]: NaH2PO2·H2O (265 mg, 2.5 mmol, 2.5 equiv.) and
glycerol (1 mL) were added to a Schlenk tube. The tube was flushed
with argon and, with slow stirring, preformed [RuCl(p-
cymene){(R,R)-TsDPEN}] (25.2 mg, 0.04 mmol, 4 mol-%),
a
the reduction of (hetero)aromatic ketones with excellent
enantioselectivities (up to 97% ee). The reactions were con-
ducted by using biosourced non-toxic solvents and a cheap
reducing agent, sodium hypophosphite, which has been reg-
istered in REACH with no obvious toxicity. For these
reasons, we believe this reductive system could be of great
interest in the context of green chemistry and could be par-
ticularly attractive for industrial applications. Current in-
vestigations are focused upon expanding the scope of the
reaction to a variety of functional groups.
ketone (1 mmol, 1 equiv.) and 2-MeTHF (0.5 mL) were quickly
added. The reaction mixture was then fluid, and the stirring rate
was increased to allow good agitation. The tube was placed in an
oil bath preheated to 40 °C, and the reaction mixture was then
stirred at 40 °C for 24 h. The subsequent treatment was similar to
that described in the previous procedure. The products were char-
acterized by NMR spectroscopy and the ees determined by chiral
GC or HPLC (full spectroscopic and chromatographic data are
given in the Supporting Information). Configurations were deter-
mined by comparison of the measured [α]D values with the litera-
ture data.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data, NMR spectra, GC and HPLC analyses.
Experimental Section
General: All reagents were obtained from commercial sources and
used as received. [RuCl(p-cymene){(R,R)-TsDPEN}], 2,2Ј-bipyr-
idine and H3PO2 (50% w/w in H2O) were purchased from Sigma
Aldrich®. [RuCl2(p-cymene)]2 was purchased from Strem Chemi-
cals Inc. and NaH2PO2·H2O from Acros Organics. All reactions
were performed under argon. Silica gel (40–63 micron) was used
for column chromatography. Thin layer chromatography was per-
formed on precoated silica gel 60-F 254 plates. UV light and phos-
phomolybdic acid were used for analysis of the TLC plates. All
compounds were characterized by spectroscopic data. The NMR
spectra were recorded with a Bruker ALS or DRX 300 instrument
(1H: 300 MHz: 13C: 75 MHz), chemical shifts are expressed in ppm,
J values are given in Hz; CDCl3 was used as solvent and internal
standard (δ = 7.26 ppm in 1H and δ = 77.16 ppm in 13C). The peak
patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br. broad. Chiral GC was performed on a
Shimadzu gas chromatograph GC-14A coupled with an integrator
Shimadzu C-R6A Chromatopac by using an Rt®-βDEXm capillary
column (30.0 mϫ0.25 mmϫ0.25 μm) purchased from Restek
Chromatography Products and an FID (flame ionisation detector).
N2 gas was used as a carrier at 1.75 kg/cm2. Chiral HPLC was
performed with a Perkin Elmer Series 200 (pump, UV/VIS detector
Acknowledgments
The authors warmly thank the Région Rhone-Alpes for their fin-
ancial support and F. Albrieux, C. Duchamp and N. Henriques
from the Centre Commun de Spectrométrie de Masse (ICBMS
UMR-5246) for their assistance and access to the Mass Spectrome-
try facilities.
[1] J. Magano, J. R. Dunetz, Org. Process Res. Dev. 2012, 16, 1156–
1184.
[2] J. Seyden-Penne, Reduction by the Alumino- and Borohydrides
in Organic Synthesis 2nd ed., Wiley-VCH, New York, 1997.
[3] a) R. Noyori, T. Ohkuma, Angew. Chem. 2001, 113, 40; Angew.
Chem. Int. Ed. 2001, 40, 40–73; b) for a recent example, see:
K. E. Jolley, A. Zanotti-Gerosa, F. Hancock, A. Dyke, D. M.
Grainger, J. A. Medlock, H. G. Nedden, J. J. M. Le Paih, S. J.
Roseblade, A. Seger, V. Sivakumar, I. Prokes, D. J. Morris, M.
Wills, Adv. Synth. Catal. 2012, 354, 2545–2555.
[4] a) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97–
102; b) J.-E. Bäckvall, J. Organomet. Chem. 2002, 652, 105–
111; c) S. Gladiali, E. Alberico, Chem. Soc. Rev. 2006, 35, 226–
ˇ
236; d) J. Václavík, P. Kacˇer, M. Kuzma, L. Cervený, Molecules
2011, 16, 5460–5495; for reviews on aqueous-phase transfer hy-
Eur. J. Org. Chem. 2013, 5439–5444
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5443

C. Guyon, E. Métay, N. Duguet, M. Lemaire
FULL PAPER
drogenation, see: e) X. Wu, J. Xiao, Chem. Commun. 2007,
2449–2466; f) C. Wang, X. Wu, J. Xiao, Chem. Asian J. 2008,
3, 1750–1770; g) A. Robertson, T. Matsumoto, S. Ogo, Dalton
Trans. 2011, 40, 10304–10310.
T. Van Es, J. Chem. Soc. C 1966, 531–532; for oxime to carb-
onyl compound, see: d) D. Monti, P. Gramatica, G. Speranza,
S. Tagliapietra, P. Manitto, Synth. Commun. 1986, 16, 803–807;
for nitrile to aldehyde, see: e) O. G. Backeberg, B. Staskun, J.
Chem. Soc. 1962, 3961–3963; f) B. Staskun, T. S. van Es, S. Afr.
J. Chem. 2008, 61, 144–156; g) B. T. Khai, A. Arcelli, J. Org.
Chem. 1989, 54, 949–953; for reductive desulfurization, see: h)
M. Node, K. Nishide, Y. Shigeta, K. Obata, H. Shiraki, H.
Kunishige, Tetrahedron 1997, 53, 12883–12894.
[5] G. L. Larson, J. L. Fry in Ionic and organometallic-catalysed
organosilane reductions, Wiley, Hoboken, NJ, 2009.
[6] P. A. Fail, R. E. Chapin, C. J. Price, J. J. Heindel, Reprod. Tox-
icol. 1998, 12, 1–18.
[7] S. C. Berk, S. L. Buchwald, J. Org. Chem. 1993, 58, 3221.
[8] For recent examples, see: a) L. Pehlivan, E. Métay, S. Laval,
W. Dayoub, P. Demonchaux, G. Mignani, M. Lemaire, Tetra-
[15] For nitro compound to amine, see: M. A. Mailhe, M. Murat,
Bull. Soc. Chim. Fr. 1910, 7, 952–956.
hedron Lett. 2010, 51, 1939–1941; b) L. Pehlivan, E. Métay, S. [16] a) For nitro compound to amine, see: H. M. Meshram, Y. S. S.
Laval, W. Dayoub, P. Demonchaux, G. Mignani, M. Lemaire,
Tetrahedron 2011, 67, 1971–1976; c) Y. Shi, W. Dayoub, G.-R.
Chen, M. Lemaire, Tetrahedron Lett. 2011, 52, 1281–1283; d)
L. Pehlivan, E. Métay, O. Boyron, P. Demonchaux, G. Mig-
nani, M. Lemaire, Eur. J. Org. Chem. 2011, 4687–4692; e) L.
Pehlivan, E. Métay, S. Laval, W. Dayoub, D. Delbrayelle, G.
Mignani, M. Lemaire, Eur. J. Org. Chem. 2011, 7400–7406; f)
L. Pehlivan, E. Métay, D. Delbrayelle, G. Mignani, M. Le-
maire, Tetrahedron 2012, 68, 3151–3155; g) L. Pehlivan, E.
Métay, D. Delbrayelle, G. Mignani, M. Lemaire, Eur. J. Org.
Chem. 2012, 4689–4693.
Ganesh, K. C. Sekhar, J. S. Yadav, Synlett 2000, 993–994; b)
for sulfoxide to sulfide, see: H. M. Meshram, Y. S. S. Ganesh,
K. Ramesh Babu, B. Eeshwaraiah, J. S. Yadav, Indian J. Chem.
2005, 44B, 193–195.
[17] For alkene to alkane, see: a) O. A. Karpeiskaya, A. A. Belyi,
M. E. Vol’pin, Bull. Acad. Sci USSR, Cl. Sci. Chim. 1985,
1554; Izv. Akad. Nauk Kaz. SSR, Ser. Khim. 1985, 1693; for
ketone to alcohol, see: b) B. Th. Khai, A. Arcelli, Tetrahedron
Lett. 1996, 37, 6599–6602.
[18] a) S. K. Boyer, J. Bach, J. McKenna Jr., E. Jagdmann, J. Org.
Chem. 1985, 50, 3408–3411; b) V. J. Demopoulos, Synth. Com-
mun. 1989, 19, 2585–2594; c) A. F. Brigas, C. S. C. Fonseca,
R. A. W. Johnstone, J. Mol. Catal. A 2006, 246, 100–108.
[19] H. B. Henbest, T. R. B. Mitchell, J. Chem. Soc. C 1970, 785–
791.
[20] For the reduction of aldehydes, see: a) J. M. Grosselin, C.
Mercier, G. Allmang, F. Grass, Organometallics 1991, 10, 2126–
2133; b) N. C. Kokkinos, A. Lazaridou, N. Nikolaou, G. Papa-
dogianakis, N. Psaroudakis, A. K. Chatzigakis, C. E. Papado-
poulos, Appl. Catal. A 2009, 363, 129–134; for the reduction of
ketones, see: c) J. M. Tukacs, D. Király, A. Strádi, G. Novod-
arszki, Z. Eke, G. Dibó, T. Kégl, L. T. Mika, Green Chem.
2012, 14, 2057–2065.
[21] G. Chelucci, R. P. Thummel, Chem. Rev. 2002, 102, 3129–3170.
[22] a) H. Nishiyama, M. Kondo, T. Nakamura, K. Itoh, Organo-
metallics 1991, 10, 500–508; b) D. Cuervo, M. P. Gamasa, J.
Gimeno, Chem. Eur. J. 2004, 10, 425–432.
[23] Y. Xing, J.-S. Chen, Z.-R. Dong, Y.-Y. Li, J.-X. Gao, Tetrahe-
dron Lett. 2006, 47, 4501–4503.
[24] X. Wu, X. Li, W. Hems, F. King, J. Xiao, Org. Biomol. Chem.
2004, 2, 1818–1821.
[25] a) V. Alishoglu, G. Nedzhefoglu, Russ. J. Inorg. Chem. 1998,
43, 1609–1610; Zh. Neorg. Khim. 1998, 43, 1732–1733; b) C. R.
Hammonds, CRC Handbook of Chemistry and Physics (Ed.: D.
R. Lide), 73rd ed., 1992–1993, 4-100, No. s382; c) S. R. Palit,
J. Am. Chem. Soc. 1947, 69, 3120–3129.
[26] R. K. Henderson, C. Jiménez-González, D. J. C. Constable,
S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P.
Binks, A. D. Curzons, Green Chem. 2011, 13, 854–862.
[9] a) J. O. Saunders, “Sodium Hypophosphite” in Encyclopedia of
Reagents for Organic Chemistry (Ed.: L. A. Paquette), Wiley,
New York, 1995, vol. 7, p. 4587; b) V. V. Popik, “Hypophos-
phorous Acid” in Encyclopedia of Reagents for Organic Chemis-
try (Ed.: L. A. Paquette), Wiley, Chichester, 1995, vol. 4, pp.
2790–2792.
[10] Information on the REACH registration can be found on
http://echa.europa.eu, search for chemicals: sodium hypophos-
phite.
[11] K. H. Krishnan, S. John, K. N. Srinivasan, J. Praveen, M.
Ganesan, P. M. Kavimani, Metall. Mater. Trans. A 2006, 37,
1917–1926.
[12] R. A. W. Johnstone, A. H. Wilby, Chem. Rev. 1985, 85, 129–
170.
[13] a) For alkynes to alkenes, see: B. T. Khai, A. Arcelli, Chem.
Ber. 1993, 126, 2265–2268; b) for alkene to alkane, see: R. Sala,
G. Doria, C. Passarotti, Tetrahedron Lett. 1984, 25, 4565–4568;
c) for nitro to amine, see: I. D. Entwistle, A. E. Jackson,
R. A. W. Johnstone, R. P. Telford, J. Chem. Soc. Perkin Trans.
1 1977, 443–444; d) for nitro aromatic to aromatic hydroxyl-
amine, see: I. D. Entwistle, T. Gilkerson, R. A. W. Johnstone,
R. P. Telford, Tetrahedron 1978, 34, 213–215; e) for α,β-unsatu-
rated nitroalkenes to oximes, see: R. S. Varma, M. Varma,
G. W. Kabalka, Synth. Commun. 1986, 16, 91–96; f) for imine
to amine, see: P. Battistoni, P. Bruni, G. Fava, Synthesis 1979,
220–221; g) for deoxygenation of heteroaromatic N-oxide, see:
R. Balicki, L. Kaczmarek, Gazz. Chim. Ital. 1994, 124, 385–
386; h) for carboxylic acid to aldehyde, see: L. J. Gooβen, K.
Ghosh, Chem. Commun. 2002, 836–837; i) for hydrogenolysis [27] For selected examples, see: a) A. Wolfson, C. Dugly, Y. Shot-
of C–O bonds, see: D. V. Davydov, I. P. Beletskaya, Russ.
Chem. Bull. 1993, 42, 573–576; Izv. Akad. Nauk Kaz. SSR, Ser.
Khim. 1993, 607–609; j) for halide to alkane, see: C. A. Mar-
ques, M. Selva, P. Tundo, J. Chem. Soc. Perkin Trans. 1 1993,
529–533; k) for quinones to hydroquinones, see: I. D. Entwistle,
R. A. W. Johnstone, R. P. Telford, J. Chem. Res. Synop. 1977,
117; l) for deprotection, see: J. Li, S. Wang, G. A. Crispino, K.
Tenhuisen, A. Singh, J. A. Grosso, Tetrahedron Lett. 2003, 44,
4041–4043.
land, D. Tavor, Tetrahedron Lett. 2009, 50, 5951–5953; b) A.
Azua, J. A. Mata, E. Peris, Organometallics 2011, 30, 5532–
5536.
[28] For the reduction of aromatic nitro and halide groups by so-
dium hypophosphite in the presence of Pd/C, see: M. Baron,
E. Métay, F. Popowycz, M. Lemaire, Green Chem. 2013, 15,
1006–1015.
[29] S. V. Slungård, T.-A. Krakeli, T. H. K. Thvedt, E. Fuglseth, E.
Sundby, B. H. Hoff, Tetrahedron 2011, 67, 5642–5650.
[30] For mechanistic studies on the Noyori catalyst, see: a) M. Ya-
makawa, I. Yamada, R. Noyori, Angew. Chem. 2001, 113, 2900;
Angew. Chem. Int. Ed. 2001, 40, 2818–2821.
[14] a) For nitro to amine, see: E. A. Parfenov, L. D. Smirnov,
Chem. Heterocycl. Compd. (N.Y.) 1992, 28, 274–278; for α,β-
insaturated nitroalkenes to carbonyl compounds, see: b) D.
Monti, P. Gramatica, G. Speranza, P. Manito, Tetrahedron
Lett. 1983, 24, 417–418; for oxime to amine, see: c) B. Staskun,
Received: April 8, 2013
Published Online: July 2, 2013
5444
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5439–5444