Manganese complex-catalysed α-alkylation of ketones with secondary alcohols enables the synthesis of β-branched carbonyl compounds

Article abstract of DOI:10.1039/d0cc01460e

Herein, β-branched carbonyl compounds were synthesised via the α-alkylation of ketones with secondary alcohols under "borrowing hydrogen"catalysis. A wide range of secondary alcohols, including various cyclic, acyclic, symmetrical, and unsymmetrical alcohols, have been successfully applied under the developed reaction conditions. A manganese(i) complex bearing a phosphine-free multifunctional ligand catalysed the reaction and produced water as the sole byproduct.

Full text of DOI:10.1039/d0cc01460e

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DOI: 10.1039/D0CC01460E
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Manganese Catalysed α-Alkylation of Ketones with Secondary
Alcohols Enables the Synthesis of β-Branched Carbonyl Compounds
Satyadeep Waiba,† Sayan K. Jana,† Ayan Jati, Akash Jana, Biplab Maji*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Herein, β-branched carbonyl compounds were synthesised via the by earth-abundant metals for such type of catalytic
α-alkylation of ketones with secondary alcohols under “borrowing transformations is highly attractive in terms of toxicity, cost, and
hydrogen” catalysis. A wide range of secondary alcohols, including sustainability.6 In this regard, the only base metal-catalysed
various cyclic, acyclic, symmetrical, and unsymmetrical alcohols, such a reaction was reported by the Sundararaju group using
has been successfully applied under the developed reaction [Cp*Co(N,O)I] ((N,O) = quinolin-8-olate) as a catalyst (Scheme
conditions. A manganese(I) complex bearing a phosphine-free 1Bb).3b However, the recent European Com-mission’s list of
multifunctional ligand catalysed the reaction and produced water critical raw materials (CRMs) suggested that except cobalt, all
as the sole byproduct.
first-row transition metals exceed the economic importance
threshold while their abundance is below the supply risk
threshold.7 In this regards, lately, well-defined manganese(I)
complexes have emerged as an attractive noble metal replacer
in sustainable (de)hydrogenation reactions and other organic
transformations.8 Manganese is the third abundant transition
metal in the earth’s crust (after iron and titanium) and is less
toxic than its higher analogs. Not long ago, selective α-
alkylations of ketones was achieved by using Mn(I) catalysis by
Beller,2h Rueping,2l Sortais,2m and our group2k. Alkylations of
esters and amides with primary alcohols were also disclosed
under manganese catalysis.9 We have also reported the
alkylations of nitriles using a well-defined phosphine-free
manganese complex.10 However, to the best of our knowledge,
manganese catalysed alkylations of methyl ketones with
secondary alcohols to form β-branch molecular structures are
not developed thus far.
The development of catalytic methods for the construction of
C–C bonds is one of the central goals in organic synthesis. The
delicacy of “borrowing hydrogen” (BH) catalysis lies in the fact
that it utilizes alcohol as an alternative carbon source for such
process under eco-friendly conditions avoiding substrate
prefunctionalizations, organohalides, cryogenic temperature
etc.1 In this process, alcohols get activated by dehydrogenation
for a reaction with a nucleophile, which is then followed by
hydrogenation of the resulting unsaturated intermediate by the
“borrowed hydrogen”, thereby making the whole process atom
economical, and benign.
In the recent past, the BH catalysis has widely been applied for
the α-alkylation of ketones with primary alcohols (Scheme
1A).1i, 1j, 2 On the other hand, the use of secondary alcohols
under BH catalysis to generate β-branched molecular
architecture is limited (Scheme 1B).3 Commonly, the β-
branched ketones were made in the presence of lithium bases
by using secondary alkyl halide as an electrophile and
unavoidably produces a large amount of waste.4 In a pioneering
work, Donohoe and coworkers have reported the α-alkylation
of ketones with secondary alcohols leading to β-branched
products using [Cp*IrCl2]2 (Cp* = (C5(CH3)5) as a catalyst
(Scheme 1Ba).3a The steric factor of the used carbonyl substrate
was exploited to limit the self-condensation of the carbonyl
substrate used and the ketone derived during the reaction from
the secondary alcohol.3a, 5 The replacement of precious metals
Scheme 1. Alkylation of ketones
a. Department of Chemical Sciences, Indian Institute of Science Education and
Research Kolkata, Mohanpur 741246, India.
Multifunctional ligand design is an integral part of synthetic
chemistry to augment the bond activation processes during the
catalytic cycle.2d In this regard, most of the BH catalysis with
† Authors contributed equally.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Mn-cat (2 mol%), t-BuOK (0.2
base metals rely on the metal-ligand bifunctional cooperation
for the alcohol (de)hydrogenation. We recently reported the
synthesis of (1 + n)-membered cycloalkanes from methyl
ketones and 1,n-diols by using an Mn(I)-catalyst Mn2 bearing a
hybrid ligand.11 We have exhibited that in addition to
protonation/deprotonation bifunctionality in picolylamine
fragment, a hemilabile thiophene sidearm that coordinates the
manganese site with a relatively elongated Mn–S bond is
instrumental for the success of the catalyst. In continuation of
our recent effort in developing phosphine-free manganese
catalysis for the (de)hydrogenation reaction,2k, 10-12 herein, we
report the catalytic efficiency of Mn2 for the α-alkylation of
ketones with secondary alcohols leading to the β-functionalised
products with the elimination of water as the sole byproduct
(Scheme 1Bc).
We started our investigation by carrying out the alkylation of
2,3,4,5,6-pentamethyl acetophenone 1a with cyclohexanol 2a
as the model substrates (Table 1). Treatment of 1a and 2a in the
catalytic system of Mn2 (2 mol%) and t-BuOK (1 equiv.) in
toluene as solvent at 140 oC for 24h gave the desired alkylated
product 3aa in 85% isolated yield, and no other side products
were observed (Table 1, entry 1). Previously reported catalyst
Mn1, which displayed high catalytic activities for the α-
alkylations of nitriles,10 was found to be ineffective for this
reaction giving the product 3aa in less than 10% yield (entry 2).
The manganese catalyst Mn3 with a furan sidearm instead of
thiophene performs poorly, delivering 3aa in 25% yield, thereby
stressing the need of soft donor in the ligand backbone (entry
3). No product was observed when Mn4 was used as a catalyst
(entry 4), highlighting the importance of the NH proton for
catalytic activity, vide infra. Manganese precursor MnBr(CO)5
did not catalyze the reaction (entry 5), which further validates
the need for a proper ligand design for efficient catalysis.
Further, the effect of other bases and solvents were tested, and,
in all cases, they were found to be less effective (entries 6,7).
Controlled reactions demonstrated the importance of catalyst
and base in the reaction as the reaction could not be
reproduced in the absence of either of them (entry 8).
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mmol) under Ar at 140 oC in toluene (0.05 mL) for 24 h. Isolated yields.
DOI: 10.1039/D0CC01460E
With the optimised conditions in hand, we next proceeded to
determine the scope of this manganese catalysed C–C bond
formation reaction, and the results are summarised in Table 2.
The cyclic secondary alcohols with different ring sizes were
found to be viable coupling partners delivering the desired
products 3aa-3ac in high yields. Interestingly, the 4-substituted
cyclohexanols 2d-f were found to impart high cis-
diastereoselectivities in the products 3ad-3af, which were
obtained in 76-89% yield. An equatorial attack of the
intermediate manganese hydride to the exocyclic enone species
can explain the observed diastereoselectivity. Unsymmetrical
cyclic alcohols such as 1-tetralol 2g, 1-indanol 2i, and their
derivatives 2h,l also proceeded smoothly under the reaction
condition delivering the desired products 3ag-3al in 64-90%
yields. The NMR analysis revealed cis-diastereoselectivity in the
product 3ak and 3al.
The scope of acyclic secondary alcohol was then examined. 1-
Phenylethan-1-ol 2m and their derivatives 2n and 2p with
electron-donating substituents underwent smooth α-alkylation
reaction delivering the β-branched products 3am, 3an and 3ap
in 93-90% yields. Gratifyingly, the reaction of 1a with 2n could
Table 2: Reaction Scopea
Table 1: Optimization Studiesa
aReaction conditions: Table 1, entry 1.b5.26 mmol scale.
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be performed in gram scale, and the product 3an was isolated position. This points out a deuteride transfer at the β-position
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in high yield (1.48 g, 87%). It thus highlights the synthetic utility of the intermediate chalcone speciesDOfrI:o1m0.10a39/mD0aCnCg0a1n4e6s0eE
and practicality of the protocol. Aryl alkyl secondary alcohols deuteride intermediate. The calculated primary kinetic isotope
with halogen substituents 2o, 2q and 2r also produced the effect kH/kD = 2.14 from a parallel experiment suggests that the
desired products 3ao,3aq and 3ar in good to moderate yields dehydrogenation step might be the rate-determining step. The
with the retention of the halo group, which leaves the room for intermediacy of the chalcone was further probed by the
further functionalizations. Alcohol bearing a p-(phenylethynyl) reaction between 1a and 2-adamantanol (2zb). The steric factor
2s selectively yielded the desired product in 30% yield where imparted due to the bulky adamantyl group slowed down the
the triple bond remains intact. Similarly, α-methyl-2- hydrogenation step and allowed the isolation of the
naphthalenemethanol 2t could also be used as a coupling unsaturated product 3azb’ in 47% yield (Scheme 2c). To know
partner. We then shifted our focus towards aryl alkyl secondary the electronic influence of the aryl alkyl secondary alcohol
alcohols bearing heteroaromatic rings. Secondary alcohols with substituents on the reaction outcome, the Hammett correlation
2-, 3-pyridyl (2u,v), 2-thiophenyl (2w), and 2-furyl (2x) groups study was performed (Scheme 2d).14 We observed a linear
were found to be viable coupling partners delivering the desired correlation with a slope –0.84, which suggests that in the
products 3au-3ax in 60-93% yields. It was found that the transition state, electrons are flowing away, which is stabilised
reaction is equally tolerable to aliphatic secondary alcohols with by electron-donating substituents. Further, an Eyring analysis
different chain lengths delivering the desired alkylated products was carried out to predict the type of mechanism involved. We
3ay-3aza in 56-86% yields.
have found that ΔH# = +74.3±5.1 kJ mol–1 and ΔS# = –150.2±12.3
Then, we have tried to examine the scope of the ketone J mol–1 K–1 suggesting the involvement of the associative
coupling partner. As demonstrated earlier by the Donohoe and pathway (Scheme 2e).
coworkers,3a, 5 the use of ortho disubstituted methyl ketones,
which can sterically block the undesired Aldol condensation and
transfer hydrogenation reaction, was found to be necessary for
the success of this process. Gratifyingly, 2,4,6-trimethyl
acetophenone 1b was found to display similar reactivity and
selectivity as 1a giving the desired products 3bb and 3bn in 82%
and 80% yields, respectively. Similarly, 2,3,5,6-tetramethyl
acetophenone 1c delivered the desired alkylated product 3cn in
81% yield. However, 2-acetylnapthalene failed to give the
desired product in practically useful yield under these
conditions.
Various experimental studies to probe the probable reaction
mechanism was then performed (Scheme 2). Initially, the
0.2
0.1
0
p-Me
importance of the M-L bifunctional activation of the ligand was
examined. It is conceived that the N−H bifunctionality in the
ligand takes part via a base-mediated dehydrohalogenation to
facilitate the alcohol dehydrogenation. Along this direction, the
manganese complex Mn4 derived from the N-Me analog of the
ligand failed to catalyze the reaction of 1a with 2a (Table 1,
entry 4). Previously, we have delineated the role of hemilabile
thiophene arm for the success of Mn2 in (n + 1) annulation
reaction with 1,n-diols (n = 4-6).11 To examine the importance
of hemilabile coordination of the soft S-donor atom for the
alkylation reaction with secondary alcohols, we have performed
the reaction of 1a with 2a using Mn3 as a catalyst. Supporting
our hypothesis, the complex Mn3 with the furan side arm
lacking the polarizable soft donor atom performed poorly, and
only 25% of 3aa was obtained (Table 1, entry 3). Further, when
the Mn2 catalysed reaction was performed in the presence of
exogenous Lewis bases (pyridine, 4-picoline), the yield of 3aa
was substantially lowered, further supporting the engagement
of the hemilabile of the thiophene arm (Scheme 2a).13
log(kX/kH) = −0.844σ − 0.017
R² = 0.952
H
σ
H
-0.2
-0.1
0
0.1
0.2
0.3
0.4
-0.1
-0.2
-0.3
-0.4
m-OMe
m-Cl
p-Br
0.0023
-14.8
0.00235
0.0024
0.00245
0.0025
ln(k/T) = −8937.7 615.9(1/T) + 5.6994 1.49
-15.2
-15.6
-16
R² = 0.981
ΔH# = 74.31±5.1 kJ
ΔS# = −150.2±12.3 J
-16.4
-16.8
1/T
Scheme 2: Mechanistic Studies
Based on the above experiments and previous reports,11
a
plausible mechanism is proposed (Scheme 3). In the presence
of t-BuOK, Mn2 generates the active imido intermediate I,
which reacts with the secondary alcohol to give the
intermediate II. The hemilabile thiophene arm facilitates the
alcohol dehydrogenation to releases the ketone 4a and the
manganese hydride species III. The aldol condensation of 1a
Deuterium labeling experiment indicated the involvement of BH
catalysis. The reaction of 1-phenylethan-1-d-1-ol 2m-D (92% D)
with 1a delivered the product 3am-D in 44% yield (Scheme 2b).
1H NMR analysis of the product showed 85% D incorporation at
β-position of the carbonyl group and 13% D incorporation at α-
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then subsequently reduced by III giving the desired saturated
product 3aa and continuing the catalytic cycle.
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Scheme 3: Proposed Mechanism
In conclusion, we have demonstrated that a manganese(I)
complex bearing a phosphine-free ligand catalysed the α-
alkylation of ketones with secondary alcohols for the synthesis
of diverse β-functionalised carbonyl compounds. Preliminary
mechanistic studies indicated the involvement of “borrowing
hydrogen” catalysis and delineated the role of the
multifunctionality of the ligand backbone for the success of such
catalysis. Water is produced as the sole byproduct of such a
reaction. We hope that this report paves a way towards further
development of molecular catalysts using earth-abundant
transition metal catalysts for the synthesis of complex
molecular architecture from simple building blocks.
The author acknowledges IISER Kolkata (ARF) and SERB
(ECR/2016/001654) for financial support. S.W., A.J., A.J. thanks
CSIR, and S.K.J. thanks IISER Kolkata for fellowship.
Conflicts of interest
There are no conflicts to declare.
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