Revisiting the Meerwein-Ponndorf-Verley reduction: A sustainable protocol for transfer hydrogenation of aldehydes and ketones

Article abstract of DOI:10.1039/b913079a

An economical and sustainable transfer hydrogenation for aldehydes and ketones is described. The general protocol is mild, chemo-selective and, importantly, uses neither precious nor non-precious metals and even no ligands. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b913079a

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www.rsc.org/greenchem | Green Chemistry
Revisiting the Meerwein–Ponndorf–Verley reduction: a sustainable protocol
for transfer hydrogenation of aldehydes and ketones
Vivek Polshettiwar* and Rajender S. Varma*
Received 18th May 2009, Accepted 23rd June 2009
First published as an Advance Article on the web 15th July 2009
DOI: 10.1039/b913079a
An economical and sustainable transfer hydrogenation for
aldehydes and ketones is described. The general protocol
is mild, chemo-selective and, importantly, uses neither
precious nor non-precious metals and even no ligands.
Results and discussion
23–27
In view of our ongoing quest for sustainable processes,
we
envisioned a ligand-free catalyst system for transfer hydrogena-
tion of aldehydes and ketones using non-precious iron metal and
preferably a method that is devoid of any metal. Serendipitously,
we have discovered that, using the appropriate conditions, it is
possible to perform transfer hydrogenation reactions without
using any transition-metals and ligands, by simply employing
potassium hydroxide (KOH) (Scheme 1).
Intorduction
The metal-catalyzed transfer hydrogenation of carbonyl com-
pounds known as the Meerwein–Ponndorf–Verley reduction
has received much interest because of the immense number of
1
opportunities that exist to prepare high-value products. This
reaction is also featured in numerous multi-step organic syn-
theses and is arguably the most important catalytic reaction for
1–4
the synthesis of many fine and bulk chemicals. Indeed, in the
last two decades, there have been several hundred publications
in this area. Most of these protocols generally require either a
stoichiometric quantity of hydride donors or precious metals
Scheme 1 Catalyst-free transfer hydrogenation of aldehydes and
ketones.
5–7
and organometallic compounds. Adolfsson et al. developed
8a
an excellent protocol using lithium isopropoxide, which was
recently improved by Ley and coworkers by using a continuous
As an initial stride in the development of our catalyst-free
transfer hydrogenation methodology, we chose to study the
reduction of benzaldehyde as a model reaction. The influence of
different KOH concentrations on the reaction rate was studied.
All the reactions were performed in a 10 mL crimp-sealed thick-
8b
flow method. Catalyst activity is extensively influenced by the
metal as well as ligands and, because of their high activity
and wide applicability, a large percentage of known catalysts
9
10
is based on precious metals such as palladium, rhodium,
11,12
13
14
ruthenium,
iridium and recently gold. However, due to
◦
walled glass tube using 1 mmol of aldehyde at 85 C with 3 mL
their expensive nature, inadequate accessibility, and toxicity of
these often used metals, there is an urgent need to develop less
expensive and easily available catalyst systems for sustainable
isopropanol as a hydrogen source and solvent. The results from
our optimization studies are presented in Table 1.
First, the reaction was conducted with 20 mol% of KOH and
15
hydrogenation protocols.
7
5% conversion was observed within 60 min (entry 1). Further
While a single solution to the problem does not exist, one
of the best ways to overcome this issue could be the use
experiments revealed that even with decreases in the KOH
amount down to 12 mol% (entry 4), a good conversion (75%) was
achieved. However, when the KOH concentration was reduced
to 10 mol% (entry 5), only 65% conversion was observed.
Thus, using 12 mol% as an optimized KOH concentration, the
reaction time was further decreased to 30 min (entry 6). No
reaction (NR) took place in absence of KOH (entry 8). Also, with
16–18
of non-precious metals such as iron.
Since iron is less
expensive and naturally abundant, the resulting protocol will
be economic, benign, and sustainable. Pioneering efforts in this
area have resulted in excellent iron-catalyzed processes and led
19–22
the way to advance this branch of catalysis;
however, the
majority of the reported protocols use exotic iron complexes
and expensive ligands, which overshadows the main objective
of using iron metal as a catalyst. Thus, the development of
a truly sustainable transfer hydrogenation protocol remains a
challenge.
Table 1 Optimization of reaction conditions
Entry
KOH (mol%)
Reaction time/min
Conversion (%)
1
2
3
4
5
6
7
8
20
20
15
12
10
12
12
0
60
120
60
60
60
30
15
120
75
77
74
75
65
75
60
NR
Sustainable Technology Division, National Risk Management Research
Laboratory, U. S. Environmental Protection Agency, MS 443,
Cincinnati, Ohio, 45268, USA.
E-mail: vivekpol@yahoo.com, varma.rajender@.epa.gov;
Fax: +1 513-569-7677; Tel: +1 513-487-2701
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a
Table 2 Metal catalyst-free transfer hydrogenation of aldehydes
Table 2 (Contd.)
Entry Aldehydes
14
b
b
Entry Aldehydes
1
Product
Yield (%)
75
Product
Yield (%)
70
2
3
76
74
1
1
1
1
5
6
7
8
68
64
62
66
4
5
76
75
a
Reactions were carried out with 1 mmol of aldehydes, 12 mol% of KOH
◦
b
6
7
8
9
72
74
72
in 3 ml of iPrOH at 85 C for 30–45 min, Yield was determined by GC.
◦
an increase in the temperature above 85 C, no effect on
the reaction rate and substrate conversion was noticed; however
below this temperature, conversion was lowered even with
longer reaction times.
After the optimized conditions were established, we investi-
gated the scope and the limitations of this transfer hydrogenation
protocol for a variety of aldehydes (Table 2).
A wide range of aldehydes were successfully reduced to
the respective alcohols in high yields. Substituted aromatic
aldehydes reacted readily and the rates were slightly influenced
by the electronic effects of the substituents on the aryl ring
of the aldehyde. Aldehydes with electron-donating groups
showed less reactivity (entries 9, 10) as compared to substrates
with electron-withdrawing groups (entries 2–7). However, the
location of a particular substitution at the para, ortho, or meta
position (entries 4–6) of the aromatic ring did not hamper the
reactivity. Several functionalized benzaldehydes with reduction-
susceptible functional groups, such as halides (entries 2–6),
alkene (entry 16), alkyne (entry 17) and nitrile (entry 18),
remained unchanged during the reaction, showing high chemo-
selectivity of this protocol. This aspect bodes well for its
application in the total synthesis of drug molecules, wherein
it is possible to reduce carbonyl groups while preserving other
functional groups, which can be used for further elaboration
in synthetic chemistry. Aliphatic cyclohexane aldehyde gave
good yield of the corresponding alcohol (entry 11); however,
in the case of hexanal, a low yield of corresponding alcohol
was observed due to the competitive aldol reaction (entry 12).
The heterocycle-based aldehydes such as thiophene, furan and
pyridine (entries 13–15), extensively used as building-blocks in
drug discovery, also underwent transfer hydrogenation reaction
with high yield, proving the suitability of this protocol for
assembly of bio-molecules.
65
68
1
1
0
1
67
1
1
2
3
10
72
1
314 | Green Chem., 2009, 11, 1313–1316
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a
Despite the wide applications of secondary alcohols in the pro-
duction of high value products and fine chemicals, sustainable
and economical hydrogenation of ketones remains a challenge.
To broaden the scope of this catalyst-free process, we set out
to attempt the transfer hydrogenation of ketones. Although
this catalyst-free system was found to be capable of reducing
ketone carbonyl, reaction conditions optimized for aldehydes
were not suitable for ketones. After several experiments for
hydrogenation of acetophenone as a test reaction, with different
KOH concentrations, reaction temperatures and times, we
observed that heating 1 mmol of acetophenone with 25 mol% of
Table 3 Metal catalyst-free transfer hydrogenation of ketones
b
Entry Ketones
1
Product
Yield (%)
73
2
76
◦
KOH in isopropanol at 85 C resulted in the slow consumption
3
4
75
74
of starting materials; the reaction needed 18 h to achieve good
conversion (73%). Using these optimized reaction conditions,
the results for the transfer hydrogenation of assortment of
ketones are summarized in Table 3.
This methodology is applicable to a wide range of ketones
(
Table 3). Aromatic ketones yielded excellent yields of corre-
sponding alcohols and a variety of functional groups, such
as bromo- (entry 3), chloro- (entry 4), and alkene (entry 6),
were tolerated under these conditions. In the case of aliphatic
cyclodecanone (entry 7), 4-chromanone (entry 8) and flavanone
5
6
82
50
(
entry 10) no reaction (NR) was observed; thiochroma-4-
one (entry 9) produced a modest 20% of the corresponding
alcohol. Notably, heterocyclic 1-(pyridin-4-yl)ethanone (entry
1
1) reacted efficiently with 75% yield.
To eliminate the possibility of any catalytic contamination and
to demonstrate unequivocally that the reaction is indeed metal-
free, we used virgin glassware and stirring bar, semiconductor
grade (99.99% on trace metals basis) potassium hydroxide and
absolute (99.9%) isopropanol in an operation that was devoid of
a metal spatula, and reactions (entries 1 and 2) proceeded well.
The developed metal catalyst-free protocol is superior to
known processes in terms of reactivity and economics of the
entire process. The yield and activity of a recently reported gold
7
8
—
—
NR
NR
14
catalyzed protocol are comparable to the results we obtained
without any metals, thus raising the question, why use expensive
gold metal, when we really don’t need any metal? Although
9
20
28
Beller’s iron-catalyzed procedure is one of the most sustainable
methods to date, it requires toxic phosphine ligands, in contrast
to our ligand-free protocol. Also, most of the other previous
catalytic hydrogenations require metals and the removal of
metal-impurities from the reaction product is extremely difficult
but is a required condition in the production of fine chemicals
because of toxicity concerns. It is always preferable to develop
transition metal-free protocols so that these catalytic systems
leave no remnants of metal within the end product, as metal
contamination is highly regulated by pharmaceutical industry.
Importantly, since no catalyst was used in our system, there is
absolutely no possibility (as confirmed by AES-ICP analysis) of
any transition-metal contamination in the final product, which
will make this a process of first choice for pharmaceutical and
chemical industries.
1
0
1
—
NR
1
75
a
Reactions were carried out with 1 mmol of ketones, 25 mol% of KOH
◦
b
in 3 ml of iPrOH at 85 C, Yield was determined by GC.
Conclusions
In conclusion, we have developed a transfer hydrogenation
protocol which uses neither precious metals nor non-precious
metals and even no ligands. This unprecedented, mild, and
chemo-selective process is highly economical and truly sustain-
able. In the present scenario of world economy and environment,
performing chemistry in a sustainable manner is a key aspect
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and this work may shed light on newer possibilities in transfer-
hydrogenation methods for aldehydes and ketones.
7 J. R. Ruiz and C. Jim e´ nez-Sanchidri a´ n, Curr. Org. Chem., 2007, 11,
1
113–1125.
8
(a) J. Ekstr o¨ m, J. Wettergren and H. Adolfsson, Adv. Synth. Catal.,
2
007, 349, 1609–1613; (b) J. Sedelmeier, S. V. Ley and I. R. Baxendale,
Experimental
Green Chem., 2009, 11, 683–685.
9
K. Prasad, X. Jiang, J. S. Slade, J. Clemens, O. Repi cˇ and T. J.
Blacklock, Adv. Synth. Catal., 2005, 347, 1769–1773 and references
cited there in.
Transfer hydrogenation of aldehydes
1
0 T. Zweifel, J. -V. Naubron, T. B u¨ ttner, T. Ott and H. Gr u¨ tzmacher,
Angew. Chem., Int. Ed., 2008, 47, 3245–3249 and references cited
there in.
1 R. L. Patman, V. M. Williams, J. F. Bower and M. J. Krische, Angew.
Chem., Int. Ed., 2008, 47, 5220–5223.
2 S. Enthaler, R. Jackstell, B. Hagemann, K. Junge, G. Erre and M.
Beller, J. Organomet. Chem., 2006, 691, 4652–4659 and references
cited there in.
The aldehydes (1 mmol) were placed in a 10 mL crimp-
sealed thick-walled glass tube containing 3 mL of isopropanol.
1
2 mol% of KOH (from the stock solution prepared by
1
1
sonicating 0.5 g of KOH in 10 mL isopropanol for 15–20 min)
was then added to the reaction mixture and the sealed tube
◦
was heated in a preheated oil bath at 85 C for 30–45 min, under
continuous stirring. The reaction was monitored by GC-MS and
yield was determined by GC. After completion of the reaction,
isopropanol was evaporated under vacuum and the residue was
dissolved in 2 mL ethyl acetate. It was then washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated
in a vacuum to yield crude product, which was further purified
by column chromatography.
13 X. Wu, J. Liu, X. Li, A. Zanotti-Gerosa, F. Hancock, D. Vinci, J.
Ruan and J. Xiao, Angew. Chem., Int. Ed., 2006, 45, 6718–6722 and
references cited there in.
1
4 F.-Z. Su, L. He, J. Ni, Y. Cao, H.-Y. He and K. -N. Fan, Chem.
Commun., 2008, 3531–3533.
15 F. Studt, F. Abild-Pedersen, T. Bligaard, R. Z. Sørensen, C. H.
Christensen and J. K. Nørskov, Science, 2008, 320, 1320–1322.
1
1
1
6 C. P. Casey and H. Guan, J. Am. Chem. Soc., 2007, 129, 5816–5817.
7 S. Gaillard and J. -L. Renaud, Chem. Sus. Chem., 2008, 1, 505.
8 B. D. Sherry and A. F u¨ rstner, Acc. Chem. Res., 2008, 41, 1500–1511.
Transfer hydrogenation of ketones
19 S. Enthaler, K. Junge and M. Beller, Angew. Chem., Int. Ed., 2008,
7, 3317–3321.
20 C. Bolm, J. Legros, J. Le Paih and L. Zani, Chem. Rev., 2004, 104,
217–6254.
1 A. Correa, O. Garc ´ı a Manche n˜ o and C. Bolm, Chem. Soc. Rev., 2008,
7, 1108–1117.
2 R. M. Bullock, Angew. Chem., Int. Ed., 2007, 46, 7360–7367.
4
The ketones (1 mmol) were placed in a 10 mL crimp-sealed thick-
walled glass tube containing 3 mL of isopropanol. 25 mol% of
KOH (from the stock solution prepared by sonicating 0.5 g of
KOH in 10 mL isopropanol for 15–20 min) was then added to the
reaction mixture and the sealed tube was heated in a preheated
6
2
2
3
23 (a) V. Polshettiwar and R. S. Varma, Chem. Soc. Rev., 2008, 37,
◦
1546–1557; (b) V. Polshettiwar and R. S. Varma, Acc. Chem. Res.,
oil bath at 85 C for 18–24 h, under continuous stirring. After
2
008, 41, 629–639; (c) V. Polshettiwar and R. S. Varma, Pure Appl.
completion of the reaction, product workup similar to aldehydes
was followed.
Chem., 2008, 80, 777–790; (d) V. Polshettiwar and R. S. Varma, Curr.
Opin. Drug Discov. Dev., 2007, 10, 723; (e) V. Polshettiwar, M. N.
Nadagouda and R. S. Varma, Aust. J. Chem., 2009, 62, 16–26.
4 (a) V. Polshettiwar and R. S. Varma, J. Org. Chem., 2008, 73, 7417–
2
2
Acknowledgements
7
7
2
419; (b) V. Polshettiwar and R. S. Varma, J. Org. Chem., 2007, 72,
420–7422; (c) V. Polshettiwar and R. S. Varma, Tetrahedron Lett.,
008, 49, 397–400; (d) V. Polshettiwar and R. S. Varma, Tetrahedron
VP thanks the U.S. Environmental Protection Agency, Cincin-
nati and Oak Ridge Institute for Science and Education for a
research fellowship.
Lett., 2007, 48, 8735–8738; (e) V. Polshettiwar and R. S. Varma,
Tetrahedron Lett., 2007, 48, 5649–5652; (f) V. Polshettiwar and R. S.
Varma, Tetrahedron Lett., 2007, 48, 7343–7346.
5 (a) V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2008, 49,
7
165–7167; (b) V. Polshettiwar and R. S. Varma, Tetrahedron, 2008,
4, 4637–4643; (c) V. Polshettiwar and R. S. Varma, Tetrahedron
References
6
1
(a) C. F. de Grauw, J. A. Peters, H. van Bekkum and J. Huskens,
Synthesis, 1994, 1007–1017; (b) G. Brieger and T. J. Nestrick, Chem.
Rev., 1974, 74, 567–580.
G. W. Kabalka, R. S. Varma, Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, vol. 8,
pp 363.
W. S. Knowles, Angew. Chem., Int. Ed., 2002, 41, 1998–2007.
C. Wang, X. Wu and J. Xiao, Chem.–Asian J., 2008, 3, 1750–1770.
S. Gladiali, G. Mestroni, in Transition Metals for Organic Synthesis,
ed. M. Beller and C. Bolm, 2nd edn, Wiley-VCH, Weinheim, 2004,
pp 145.
Lett., 2008, 49, 879–883; (d) V. Polshettiwar and R. S. Varma,
Tetrahedron Lett., 2008, 49, 2661–2664.
26 (a) V. Polshettiwar, M. N. Nadagouda and R. S. Varma, Chem.
Commun., 2008, 6318–6320; (b) V. Polshettiwar, B. Baruwati and
R. S. Varma, ACS Nano, 2009, 3, 728–736; (c) M. N. Nadagouda, V.
Polshettiwar and R. S. Varma, J. Mater. Chem., 2009, 19, 2026–2031.
27 (a) V. Polshettiwar and R. S. Varma, Chem.–Eur. J., 2009, 15, 1582–
1586; (b) V. Polshettiwar and R. S. Varma, Org. Biomol. Chem., 2009,
7, 37–40; (c) V. Polshettiwar, B. Baruwati and R. S. Varma, Chem.
Commun., 2009, 1837–1839; (d) V. Polshettiwar, B. Baruwati and R. S.
Varma, Green Chem., 2009, 11, 127–131.
2
3
4
5
6
R. A. W. Johnstone, A. H. Wilby and I. D. Entwistle, Chem. Rev.,
28 S. Enthaler, B. Hagemann, G. Erre, K. Junge and M. Beller, Chem.–
Asian J., 2006, 1, 598–604.
1
985, 85, 129–170.
1
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