Base-Mediated Meerwein-Ponndorf-Verley Reduction of Aromatic and Heterocyclic Ketones

Article abstract of DOI:10.1021/acs.orglett.9b02342

An experimental protocol to achieve the Meerwein-Ponndorf-Verley (MPV) reduction of ketones under mildly basic conditions is reported. The transformation is tolerant of a range of ketone substrates, including O- and S-containing heterocycles, is scalable, and shows potential to be used as a platform to access enantioenriched products. These studies provide a general method for achieving the reduction of ketones under mildly basic conditions and offer an alternative protocol to more well-known Al-based MPV reduction conditions.

Full text of DOI:10.1021/acs.orglett.9b02342

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Base-Mediated Meerwein−Ponndorf−Verley Reduction of Aromatic
and Heterocyclic Ketones
Timothy B. Boit, Milauni M. Mehta, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: An experimental protocol to achieve the Meer-
wein−Ponndorf−Verley (MPV) reduction of ketones under
mildly basic conditions is reported. The transformation is tolerant
of a range of ketone substrates, including O- and S-containing
heterocycles, is scalable, and shows potential to be used as a
platform to access enantioenriched products. These studies
provide a general method for achieving the reduction of ketones
under mildly basic conditions and offer an alternative protocol to
more well-known Al-based MPV reduction conditions.
experimental5 and computational studies.6 Despite the
he Meerwein−Ponndorf−Verley (MPV) reaction is an
Timportant and powerful tool for the reduction of ketones synthetic utility of the traditional MPV reduction, several
drawbacks exist. These include long reaction times, the need
for a large excess of reducing agent, competing side reactions
such as aldol condensation and the Tishchenko reduction of
aldehydes, and low enantioselectivities in the case of
intermolecular asymmetric variants.1,3 Methodological advan-
ces to address these limitations include the use of additives,7
microwave irradiation,8 and the development of novel
aluminum,9 organoboron,10 and metal alkoxide catalysts (i.e.,
transition11 and lanthanide12).
and aldehydes because of its chemoselectivity, mild reaction
conditions, scalability, and low operational cost.1 Discovered
nearly a century ago,2 the traditional MPV reduction employs
an aluminum alkoxide catalyst generated from a secondary
alcohol (most commonly isopropanol) to achieve the
reversible transfer hydrogenation of carbonyl substrates
(Figure 1).3 This venerable reaction has been featured in the
syntheses of several natural products4 and spurred numerous
A largely unexplored approach to the MPV-type reduction of
carbonyls uses simple alkali metal alkoxides (Figure 1).13,14
This variant of the MPV reaction has several benefits including
its avoidance of metal catalysts, operational simplicity, and
compatibility with heteroatoms known to inhibit metal
catalysis.3,13 Specifically, isopropoxide catalysts generated
from strong alkali bases, such as NaOH13a and KOH13b and
milder bases such as K3PO4,13c have been employed in the
reduction of aldehydes and ketones. Nevertheless, a number of
limitations of the base-mediated MPV reduction remain
unaddressed including a limited scope and the reliance on i-
PrOH as the solvent and hydride source.15 Additionally, no
examples of stereoselective base-mediated MPV reactions exist.
We report the use of a simple potassium alkoxide reductant,
generated in situ from the corresponding alcohol and K3PO4,
for the reduction of a wide range of aromatic ketones. This
methodology is tolerant of heterocycles, is scalable, and shows
potential for the asymmetric reduction of alkyl−aryl ketones.
Figure 1. Traditional MPV reduction of ketones and base-mediated
variant (prior studies).
Received: July 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02342
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Organic Letters
Letter
To initiate our studies, we examined the reduction of
dihydrochalcone (1) using alkyl−alkyl secondary alcohols and
K3PO4, a readily available and mild base (Table 1).16
Table 1. Optimization of Reaction Conditions
a
General conditions unless otherwise stated: substrate 1 (1.0 equiv,
0.10 mmol), K3PO4 (0.50−4.0 equiv), reductant (2.5 equiv), and 1,4-
Figure 2. Scope of the base-mediated MPV reduction of aromatic
ketones. Conditions: substrate (1.0 equiv, 0.10 mmol), K3PO4 (4.0
equiv), reductant (2.5 equiv), and 1,4-dioxane (1.0 M) heated at 120
°C for 16 h in a sealed vial under an atmosphere of N2. Unless
otherwise noted, yields reflect the average of two isolation
experiments. a Yield determined by 1H NMR analysis using
hexamethylbenzene as an external standard. b Reaction heated at 80
°C for 16 h.
dioxane (1.0 M) heated at 80−120 °C for 16 h in a sealed vial under
1
an atmosphere of N2. Yields determined by H NMR analysis using
1,3,5-trimethoxybenzene as an external standard.
Subjecting 1 to catalytic K3PO4 using isopropanol or 3-
pentanol (3, 2.5 equiv) in 1,4-dioxane at 80 °C provided none
of the desired alcohol product 2 (entries 1 and 2).16−18 Owing
to the potential reversibility of the reaction,1a−c,16 we turned to
the use of aryl−alkyl reductants to bias the reaction
equilibrium. Importantly, this class of alcohols enabled greater
control of the redox properties of the reductant. We evaluated
alcohol 4 and the more electron-rich derivative 5 as
reductants,19 anticipating that the stability of the respective
aryl ketone and doubly vinylogous amide byproducts would
drive the forward reaction to yield 2. Gratifyingly, the use of
2.5 equiv of 4 or 5 provided 2 in 40% and 61% yield,
respectively (entries 3 and 4). Employing reductant 5 at 120
°C furnished desired product 2 in 92% yield (entry 5). Finally,
alcohol 2 was obtained in near-quantitative yield by utilizing
excess base (entry 6).
mediated MPV reductions of heterocyclic ketones have been
previously reported (Figure 3).20 Benzofuran- and dibenzofur-
With optimized conditions in hand, we examined a range of
aryl ketone substrates in the reduction (Figure 2). Linear and
α-branched substrates smoothly underwent reduction, giving
rise to alcohols 2 and 6−8 in good yields. Of note, steric bulk
on the alkyl substituent of the ketone was tolerated, as shown
by the successful reduction of tert-butyl phenyl ketone to
furnish alcohol 8 in 83% yield. The reduction of α-tetralone to
give α-tetralol (9) in 86% yield demonstrates competence of a
cyclic ketone substrate in this transformation. Notably, we
found that electron-rich aromatic ketones and those highly
decorated with heteroatom substituents underwent facile
reduction, as demonstrated by the formation of alcohols 10
and 11 in 81% and 87% yield, respectively. Finally, both
electron-rich and electron-deficient benzophenone derivatives
were suitable substrates, as shown by the production of alcohol
products 12 and 13 in good yields.
Figure 3. Scope of the base-mediated MPV reduction of
heteroaromatic ketones. Conditions: substrate (1.0 equiv, 0.10
mmol), K3PO4 (4.0 equiv), reductant (2.5 equiv), and 1,4-dioxane
(1.0 M) heated at 120 °C for 16 h in a sealed vial under an
atmosphere of N2. Unless otherwise noted, yields reflect the average
of two isolation experiments. a Yield determined by 1H NMR analysis
using hexamethylbenzene as an external standard. b Reaction heated at
130 °C for 16 h.
We next set out to evaluate the reactivity of a number of
heterocyclic ketone substrates, as only a few examples of base-
B
DOI: 10.1021/acs.orglett.9b02342
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Letter
an-containing ketones underwent reduction to provide
alcohols 14 and 15 in 73% and 76% yield, respectively.
Benzodioxole and benzodioxane moieties were also well
tolerated, as seen by the formation of alcohols 16 and 17 in
good yields. Lastly, ketones bearing thiophenes were
successfully employed, as judged by the formation of
benzothiophene 18 and tetrahydrobenzothiophene 19 in
70% and 73% yield, respectively.21
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02342.
■
S
Experimental details and compound characterization
data (PDF)
As a demonstration of the utility of the base-mediated MPV
reduction of ketones, we performed the additional studies
shown in Figure 4. In the first, we performed a gram-scale
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: neilgarg@chem.ucla.edu.
ORCID
Milauni M. Mehta: 0000-0002-4597-2829
Neil K. Garg: 0000-0002-7793-2629
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (R01-GM117016 to
N.K.G.), the California Tobacco-Related Disease Research
Program (28DT-0006 to T.B.B.), the Trueblood Family
(N.K.G.), and the University of California, Los Angeles, for
financial support. Colleen Hui (UCLA) is acknowledged for
assistance in performing trace metal analysis. Dr. Junyong Kim
is acknowledged for experimental assistance. We thank the
Nelson laboratory (UCLA) for use of instrumentation. These
studies were supported by shared instrumentation grants from
the NSF (CHE-1048804) and the NIH NCRR
(S10RR025631).
Figure 4. Gram-scale reduction and stereochemical transfer studies
demonstrating the synthetic utility of the base-mediated MPV
reduction. Conditions: substrate (1.0 equiv), K3PO4 (4.0 equiv),
reductant (2.5 equiv), and 1,4-dioxane (1.0 M) heated at the
indicated temperature and time in a sealed vial under an atmosphere
of N2.
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