Mn(0)-mediated chemoselective reduction of aldehydes. Application to the synthesis of α-deuterioalcohols

Article abstract of DOI:10.1021/jo1015618

A mild, simple, safe, chemoselective reduction of different kinds of aldehydes to the corresponding alcohols mediated by the Mn dust/water system is described. In addition to this, the use of D₂O leads to the synthesis of α-deuterated alcohols and constitutes an efficient, inexpensive alternative for the preparation of these compounds.

Full text of DOI:10.1021/jo1015618

pubs.acs.org/joc
SCHEME 1. Usual Reagents for Carbonyl Reductions
Mn(0)-Mediated Chemoselective Reduction of
Aldehydes. Application to the Synthesis of
r-Deuterioalcohols
†
Tania Jimenez, Elisa Barea, J. Enrique Oltra,
‡
†
ꢀ
Juan M. Cuerva, and Jose Justicia*
†
,†
ꢀ
aluminum-based hydrides with good chemoselectivity have
been developed (Scheme 1, path a).3c Nevertheless, despite
their obvious potential interest, their preparation and manip-
ulation is not always simple. Another possibility is the
selective transfer of two electrons and two protons to the
functionality of the aldehyde (Scheme 1, path b). The main
problem with this, however, is the nature of the required SET
reagent, usually Na or Li.3 Within this context, manganese is
a cheap, nontoxic, environmentally benign element, which
has been extensively used in organic reactions as a core-
ducing agent. Nevertheless, its own reactivity has hardly been
explored.4 As proton source for this process we were mainly
interested in water, an inexpensive, innocuous hydrogen
source, because we suspected that its isotopologue, deuterium
oxide, might yield the corresponding R-deuterated alcohols
and thus turn out to be a cheap alternative to other deuter-
ated reduction reagents.5
†Department of Organic Chemistry and ‡Department of
Inorganic Chemistry, Faculty of Sciences, University of
Granada, C. U. Fuentenueva s/n, 18071 Granada, Spain
jjusti@ugr.es
Received August 9, 2010
The main drawback with this approach is that the scarce
studies published concerning the behavior of water on man-
ganese surfaces strongly support a dissociative adsorption
mechanism and the consequent inactivation of the metal
surface.6 Therefore, a water-compatible regenerating agent
able to reactivate the metal surface would be required.
Interestingly, the use of manganese dust is combined in
titanocene(III)-catalyzed transformations with pyridinium-
based hydrochlorides such as 2,4,6-collidinium hydrochlo-
A mild, simple, safe, chemoselective reduction of different
kinds of aldehydes to the corresponding alcohols
mediated by the Mn dust/water system is described. In
addition to this, the use of D2O leads to the synthesis of
R-deuterated alcohols and constitutes an efficient, inexpen-
sive alternative for the preparation of these compounds.
ride (2,4,6-Coll HCl), which are water-compatible additives.7
3
We report here that a simple combination of 2,4,6-collidi-
nium hydrochloride and Mn dust in the presence of water is
able to carry out an efficient, chemoselective8 reduction of
aldehydes to the corresponding alcohols under extremely
safe, mild conditions. It is also important to note that deuterium
The synthesis of alcohols from aldehydes is an essential
process in organic synthesis1 and an important step in the
preparation of natural products.2 Consequently, numerous
chemical methods have been described to accomplish this
basic transformation.3 Nevertheless, many of them are not
chemoselective and also react with ketones and other car-
bonyl compounds or functional groups, thus limiting their
application in polyfunctionalized substrates. Additionally,
many of the chemical reagents normally used to reduce
aldehydes are caustic, expensive, and/or environmentally
unfriendly. Other methods, based on the use of hydrogen
as reducing agent, often present problems because of the
need for high-pressure apparatus to manipulate the gas. To
overcome some of these drawbacks, different boron- and
(4) For a recent review of its properties, activation, and synthetic applica-
ꢀ
´
tions see: Concellon, J. M.; Rodrıguez-Solla, H.; del Amo, V. Chem.;Eur. J.
2008, 14, 10184–10191.
(5) The typical price of D2O (99.90 atom % D, 100 mL) is about h47.70,
while NaBD4 (98 atom % D, 5 g, h176), LiAlD4 (98 atom % D, 5 g, h90.30),
and D2 (99.9 atom % D, 25 L, h221.50) are considerably more expensive.
(6) Flugge, J. C.; Watson, L. M.; Fabian, D. J.; Affrossman, S. Surf. Sci.
1975, 49, 61–76.
€
(7) (a) Gansauer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed.
1998, 37, 101–103. (b) Gansauer, A.; Lauterbach, T.; Bluhm, H.; Noltenmeyer,
€
€
M. Angew. Chem., Int. Ed. 1999, 38, 2909–2910. (c) Gansauer, A.; Ndene, N.;
Lauterbach, T.; Justicia, J.; Winkler, I.; Muck-Lichtenfeld, C.; Grimme, S.
€
€
Tetrahedron 2008, 64, 11839–11845. (d) Gansauer, A.; Fleckhaus, A.;
Lafont, M. A.; Okkel, A.; Kotsis, K.; Anoop, A.; Neese, F. J. Am. Chem.
(1) (a) Comprehensive Organic Synthesis, 1st ed.; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 8. (b) Smith, M. B.; March,
J. March’s Advanced Organic Chemistry, 6th ed.; Wiley: New York, 2007,
p 1786.
ꢀ
Soc. 2009, 131, 16989–16999. (e) Estevez, R. E.; Oller-Lopez, J. L.; Robles,
R.; Melgarejo, C. R.; Gansauer, A.; Cuerva, J. M.; Oltra, J. E. Org. Lett.
ꢀ
€
~
2006, 8, 5433–5436. (f) Cuerva, J. M.; Campana, A. G.; Justicia, J.; Rosales,
(2) (a) Kidwai, M.; Motshra, P.; Mohan, R.; Biswas, S. Bioorg. Med.
Chem. Lett. 2005, 15, 915–917. (b) Kidwai, M.; Saxena, S.; Mohan, R.;
Venkataramanan, R. J. Chem. Soc., Perkin Trans. 1 2002, 1845–1846.
(3) (a) Greeves, N. Comprehensive Organic Synthesis, 1st ed.; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 8,
pp 1-24. (b) Larock, R. C. Comprehensive Organic Transformations, 2nd
ed.; VCH: New York, 1999. (c) Kidwai, M.; Bansal, V.; Saxena, A.; Shankar,
R.; Mozumdar, S. Tetrahedron Lett. 2006, 47, 4161–4165. and references
cited therein.
ꢀ
A.; Oller-Lopez, J. L.; Robles, R.; Cardenas, D. J.; Bunuel, E.; Oltra, J. E.
Angew. Chem., Int. Ed. 2006, 45, 5522–5526. (g) Gansauer, A.; Fan, C.-A.;
ꢀ
~
€
Piestert, F. J. Am. Chem. Soc. 2008, 130, 6916–6917. (h) Paradas, M.;
ꢀ
~
ꢀ
ꢀ
Campana, A. G.; Estevez, R. E.; Alvarez de Cienfuegos, L.; Jimenez, T.;
Robles, R.; Cuerva, J. M.; Oltra, J. E. J. Org. Chem. 2009, 74, 3616–3619.
(8) For an overview concerning the importance of chemoselectivity in
organic chemistry see: Afagh, N. A.; Yudin, A. K. Angew. Chem., Int. Ed.
2010, 459, 262–310.
7022 J. Org. Chem. 2010, 75, 7022–7025
Published on Web 09/16/2010
DOI: 10.1021/jo1015618
r
2010 American Chemical Society

ꢀ
Jimenez et al.
JOCNote
TABLE 1. Reduction of 1 with a Mn Dust/Water System in the
Presence of Different Ammonium and Pyridium Salts
were efficiently reduced and no traces of the corresponding
pinacol coupling products were detected. This suggests that
the quantity of the corresponding ketyl radical in solu-
tion was very low.14 Interestingly, the E stereochemistry of
geranial (7) and farnesal (8) (entries 5 and 6) was completely
preserved. When aliphatic, aromatic, and R,β-unsaturated
ketones 11-13 (entries 9-11) were submitted to the same
reaction conditions, on the other hand, no reduction prod-
ucts were observed. Consequently ketoaldehyde 15 (entry
13) afforded good yields of the corresponding ketoalcohol
35. The only exception was tert-butyl cyclohexanone 14
(entry 12), which gave low quantities of cis-cyclohexanol
34 (20%). This could be related to the strain associated with
this functionalized cyclohexane ring. In fact it is known that
cyclohexanone is reduced by sodium borohydride 355 times
faster than di-n-hexyl ketone.15 Interestingly, other com-
pounds that are prone to react with the typical hydride-based
reduction reagents,3 such as esters (entry 14), amides (entry
15), nitriles (entry 21), primary halides and mesilates (entry
16 and 22), or epoxides (entry 19), do not react under these
conditions. Bearing in mind the presence of water and a
entry
additive
hydrogen source
solvent
yield
1
2
3
4
5
6
7
8
2,4,6-Coll HCl
3
H2O
H2O
H2O
H2O
H2O
H2O
H2O
D2O
THF
THF
THF
THF
THF
THF
THF
THF
81%
12%
50%
11%
traces
traces
traces
81%a
2,4,6-Coll HBF4
3
2,6-Lut HCl
3
Py HCl
3
Et3N HCl
3
NH4Cl
PPTS
2,4,6-Coll DCl13
3
a70% of deuterium incorporation.
oxide can be used as a hydrogen atom source instead of water
to yield the corresponding R-deuterated alcohols.
Initially we studied the reduction reaction of decanal (1)
(1 mmol), a prototypical aldehyde, using different ammo-
nium and piridynium salts (2 mmol), Mn dust (8 mmol),9 and
water (10 mmol)10 in THF11 (Table 1, entries 1-7). The best
€
Bronsted acid, it is worth noting that acidic labile groups,
such as epoxides and O-MEM functionalities, also afford
good yields of the corresponding alcohols (entries 19 and 22).
Although hydrogen gas is also generated by the reaction of
2,4,6-collidinium hydrochloride and Mn dust, this reducing
agent is unable to react with the C-C multiple bonds present
in aldehydes 19, 20, and 22 (entries 17, 18, and 20). This
excellent chemical profile may contribute to a precise control
over the individual reactivity of functional groups within a
complex molecular architecture, allowing the use of less
protective groups, which constitutes an important objective
in modern organic chemistry.16
As mentioned above, the substitution of D2O for water
may allow the preparation of R-deuterated alcohols, consti-
tuting an efficient and inexpensive alternative to known
processes for the preparation of this kind of compound.5,12
To check the synthetic usefulness of our reaction in the
synthesis of these compounds we submitted a set of alde-
hydes to our reduction conditions in the presence of D2O.
The results are set out in Table 3.
To our satisfaction, the results obtained in the reduction of
aldehydes 3, 8-10, 18, 19, and 21 with D2O as the deuterium
source were on the whole fairly good. The yields were slightly
lower than those obtained with water as the hydrogen source.
The formation of nondeuterated alcohols was probably due
to the presence of adventitious water in the solvent or to a
hydrogen atom transfer from THF. Thus, when aldehyde 1
was reduced in deuterated THF in the presence of D2O, com-
plete deuterium incorporation was observed (99% D incor-
poration).17 In any case, these reaction conditions constitute
a useful procedure for the preparation of R-deuterated
alcohols of different kinds.
results were obtained with 2,4,6-Coll HCl as regenerating
3
agent for the Mn surface. The success of this additive is related
in some cases to the very low solubility of the other additives in
THF (entries 4-6) and, apparently, with the nature of the
counteranion in the manganese(II) salt generated (entries 2
and 7). 2,6-Lutidine hydrochloride (2,6-Lut HCl), which is
3
slightly less soluble than 2,4,6-Coll HCl, also triggered the
3
reaction, but produced somewhat lower yields (see entry 3).
As we expected, the substitution of water and 2,4,6-Coll HCl
3
for their deuterium analogues afforded a good yield of
1-deuteriodecanol (2d) with a high incorporation of deute-
rium (Table 1, entry 8).12 This result also reflects unequivo-
cally that the hydrogen atom required in the reduction pro-
cess comes from water.
Using these optimized conditions we extended our study
to the reduction of different carbonyl compounds to deter-
mine their scope and chemoselectivity. To this end we sub-
mitted different types of aldehyde and ketones to the reduc-
tion reaction. The results are set out in Table 2.
Different kinds of aldehydes (aliphatic, aromatic, and R,β-
unsaturated) were reduced under these conditions to give
moderate-to-good yields. In entries 1-4 aromatic aldehydes
(9) Although strictly only 1 equiv of Mn dust is required, we found that 8
equiv gives better, more reliable results (see the S.I.). Interestingly, the excess
of Mn dust and Coll HCl could be reused up to four times with excellent
3
results.
(10) Methanol and ethanol can also be used but with lower yields (52%
and 34%, respectively).
(11) The reaction was also tried in other common solvents such as
acetone, DMF, acetonitrile, benzene, and hexane but the reaction did not
take place. The reaction took place in other polar solvents such as MeOH
(52%) or EtOH (34%), but with lower yields.
(12) For some selected examples of the synthesis of 1-deuterioalcohols
see: (a) Midland, M. M.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc.
1977, 99, 5211–5213. (b) Midland, M. M.; Greer, S.; Tramontano, A.; Zderic,
S. A. J. Am. Chem. Soc. 1979, 101, 2352–2355. (c) Corey, E. J.; Link, J. O.
Tetrahedron Lett. 1989, 30, 6275–6278. (d) Keck, G. E.; Krishnamurthy, D.
J. Org. Chem. 1996, 61, 7638–7639. (e) Junk, T.; Catallo, W. J. Chem. Soc.
Rev. 1997, 26, 401–406. (f) Morelli, C. F.; Cairoli, P.; Marigolo, T.; Speranza,
G.; Manitto, P. Tetrahedron: Asymmetry 2009, 20, 351–354.
(14) (a) Handa, Y.; Inanaga, J. Tetrahedron Lett. 1987, 28, 5717–5718.
€
(b) Gansauer, A. Chem. Commun. 1997, 457–458. (c) Gansauer, A.; Bauer, D.
J. Org. Chem. 1998, 63, 2070–2071. (d) Gansauer, A.; Bauer, D. Eur. J. Org.
€
€
Chem. 1998, 2673–2676. (e) Hirao, T.; Hatano, B.; Asahara, M.; Muguruma,
Y.; Ogawa, A. Tetrahedron Lett. 1998, 39, 5247–5248. (f) Dunlap, M. S.;
€
Nicholas, K. M. J. Organomet. Chem. 2001, 630, 125–131. (g) Gansauer, A.;
Moschioni, M.; Bauer, D. Eur. J. Org. Chem. 1998, 1923–1927.
(15) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, 1st
ed.; Wiley-Interscience: New York, 1994; pp 731-732.
(13) Coll DCl was prepared from commercial 2,4,6-collidine and DCl 7
3
N in D2O.
(16) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404–408.
J. Org. Chem. Vol. 75, No. 20, 2010 7023

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JOCNote
TABLE 2. Reduction of Aldehydes 3-10, Ketones 11-14, and Polyfunctionalyzed Aldehydes 15-25 with a Mn Dust/Water System under the Optimized
Reaction Conditions
aYield based on recovered starting material.
Although other similar aldehyde/ketone chemoselective
reductions with a metal in aqueous media have been described,18
they are based on the difference between the reduction
potentials of both functional groups. In fact, single electron
transfer (SET) reactions could provide monosubstituted
hydroxy radical intermediates or dianionic species adsorbed
on the manganese surface, which can subsequently lead to
the corresponding alcohols via a reaction with hydrogen
atom donors or proton sources. The absence of pinacol
coupling products or their corresponding Michael adducts
with methyl acrylate, which could not be detected in this
reaction, suggests that free ketyl radicals are not involved in
this transformation. Moreover, the chemoselectivity observed
in this reaction is apparently incompatible with a selectivity
based only on reduction potentials, bearing in mind that aro-
matic ketones are not reduced by this protocol.19 It would seem
that the higher steric hindrance of ketones compared to
(17) The deuterium incorporation of 99% in THF-d8 suggests that THF is
also donating hydrogen atoms under the described conditions, although less
efficiently than water, taking into account the molar relationship. In fact,
control experiments showed that in the absence of water THF is also able to
promote the reaction albeit in lower yield and higher reaction times
(18) (a) Hazarika, M. J.; Barua, N. C. Tetrahedron Lett. 1989, 30, 6567–
6570. (b) Wang, W.-B.; Shi, L.-L.; Huang, Y.-Z. Tetrahedron Lett. 1990, 31,
1185–1186. (c) Baruah, R. N. Tetrahedron Lett. 1992, 33, 5417–5418.
(d) Bordoloi, M.; Sharma, R. P.; Chakraborty, V. Synth. Commun. 1999,
29, 2501–2506. (e) Desai, D. G.; Swami, S. S.; Nandurdikar, R. S. Synth.
Commun. 2002, 32, 931–933.
7024 J. Org. Chem. Vol. 75, No. 20, 2010

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Jimenez et al.
JOCNote
TABLE 3. Synthesis of R-Deuterated Alcohols via the Reduction of
Aldehydes 3, 6, 8-10, 18, 19, and 21 with Mn Dust/D2O
SCHEME 2. Mechanistic Proposal for the Reduction of Alde-
hydes by the Mn Dust/H2O System
R,β-unsaturated) to afford good-to-excellent yields of alco-
hols and almost complete chemoselectivity. Ketones and
other groups, normally reactive toward typical hydride-
based reduction reagents, do not react under these condi-
tions, providing a satisfactory, mild alternative for the
reduction of aldehydes, which may well be of interest in
the synthesis of polyfunctionalized substrates. Additionally,
the use of D2O instead of water allows the synthesis of
R-deuterated alcohols, thus constituting an efficient and
inexpensive alternative to the processes currently used for
the preparation of these kinds of compounds. At the mo-
ment, we are working in the determination of the mechan-
istic aspects of this reaction.
Experimental Section
General Procedure for the Reduction of Aldehydes in the
Presence of Water/D2O. Completely deoxygenated THF (20 mL)
was added to a mixture of Coll HCl (2 mmol) and Mn dust (Acros,
3
317442500) (8 mmol) under an Ar atmosphere. A solution of
aldehyde (1 mmol) and water or D2O (10 mmol) in 1 mL of THF
was then added. The almost neutral mixture (pH 6) was stirred
for 8-10 h at rt. AcOEt was added and the organic layer was
washed with a saturated solution of acidic KHSO4 (pH 1)23
before being dried with anhyd Na2SO4 and the solvent removed.
The residue was submitted to flash chromatography (EtOAc/
hexane) to give the corresponding alcohol. Products 2, 26-45,
26d, 31d-33d, 38d-39d, and 41d were purified by flash chro-
matography on silica gel (hexane: EtOAc) and characterized
by spectroscopic techniques.24 The yields obtained are reported
in Tables 1-3.
aldehydes may prevent an efficient η2-type interaction between
the carbonyl group and the metal surface.20,21 Therefore, we
propose that the experimental results are better explained by a
double reduction process of the corresponding aldehyde by η2-
interaction between the carbonyl group and the Mn surface,
followed by two protonation steps (see Scheme 2).22
In conclusion, a mild, selective, safe, and economic meth-
od for the reduction of aldehydes to alcohols based on a Mn/
water system is described. This method allows the reduc-
tion of aldehydes of different kinds (aliphatic, aromatic,
Acknowledgment. We thank the Spanish MICINN
(project CTQ2008-06790) and the Regional Government of
Andalucıa (projects P09-FQM-4571 and P07-FQM-3213)
´
for financial support. T.J. and E.B. thank the Spanish
MICINN for FPU fellowship and a “Ramon y Cajal”
contract. J.J. thanks the University of Granada for his
(19) In a competitive experiment with a mixture of decanal (1) and
benzaldehyde (3) we obtained a 1:2 relationship of the corresponding
alcohols 2 and 26. Bearing in mind the reported reduction potentials of
benzaldehyde (-0.85 V vs SCE) and aliphatic aldehydes (-1.5 to -1.9 V vs
SCE), chemoselectivity cannot be exclusively based on the difference between
such reduction potentials: Joyce-Pruden, C.; Pross, J. K.; Li, Y. J. Org.
Chem. 1992, 57, 5087–5091.
ꢀ
“Reincorporacion de Doctores” contract. Finally we thank
Dr. J. Trout of the University of Granada Scientific Transla-
tion Service for revising our English text.
Supporting Information Available: General experimental
details, synthesis of aldehydes 17 and 23-25, and 1H NMR and
13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) (a) Huang, Y.-H.; Gladysz, J. J. Chem. Educ. 1988, 65, 298–303.
(b) Adams, R. D.; Chen, G.; Chen, L.; Wu, W.; Yin, J. J. Am. Chem. Soc.
1991, 113, 9406–9408.
(21) It is known that metal hydrides are generated on transition metal
surfaces from their interaction with water molecules and they could poten-
tially be used in reduction reactions. This possibility remains unexplored,
however, probably owing to their fleeting existence. Nevertheless, this
posible mechanism cannot be completely ruled out: Thiel, P. A.; Madey,
T. E. Surf. Sci. Rep. 1987, 7, 211–385.
(23) Owing to the acid workup is only required to remove the 2,4,6-
collidine obtained during the process, other acid solutions with different pH
values or even water can also be used for the workup of this reaction.
(24) All new compounds are fully described in the Supporting
Information.
(22) Thepossible deuterium atom in the hydroxyl group is removed by aqueous
workup of the reaction or by D/H exchange with environmental humidity.
J. Org. Chem. Vol. 75, No. 20, 2010 7025