Utilization of MeOH as a C1 Building Block in Tandem Three-Component Coupling Reaction

Article abstract of DOI:10.1021/acs.orglett.7b02105

Ru(II) catalyzed tandem synthesis of α-branched methylated ketones via multicomponent reactions following the hydrogen borrowing process is described. This nonphosphine-based air and moisture stable catalyst efficiently produced various methylated ketones using methanol as a methylating agent. This system was found to be highly effective in three-component coupling between methanol, primary alcohols, and methyl ketones. A proposed catalytic cycle for the α-methylation is supported by DFT calculations as well as kinetic experiments.

Full text of DOI:10.1021/acs.orglett.7b02105

Letter
pubs.acs.org/OrgLett
Utilization of MeOH as a C1 Building Block in Tandem Three-
Component Coupling Reaction
Kaushik Chakrabarti,† Milan Maji,† Dibyajyoti Panja,† Bhaskar Paul,† Sujan Shee,† Gourab Kanti Das,‡
and Sabuj Kundu*,†
†Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India
‡Department of Chemistry, Visva Bharati University, Santiniketan, West Bengal 731235, India
S
* Supporting Information
ABSTRACT: Ru(II) catalyzed tandem synthesis of α-branched methylated
ketones via multicomponent reactions following the hydrogen borrowing process
is described. This nonphosphine-based air and moisture stable catalyst efficiently
produced various methylated ketones using methanol as a methylating agent.
This system was found to be highly effective in three-component coupling
between methanol, primary alcohols, and methyl ketones. A proposed catalytic
cycle for the α-methylation is supported by DFT calculations as well as kinetic
experiments.
ulticomponent reactions (MCRs) are one of the most
the synthesis of similar products in two successive steps using a
Mpowerful tools in synthetic chemistry for the preparation combination of an Ir (2 mol %) and a Rh (10 mol %) catalyst.12
of highly functionalized complex molecular systems.1 They can
Recently, a Ru catalyzed (1 mol %) analogous two-step
sequential reaction using an expensive dpePhos ligand in 48 h
was reported by Seayed et al.13 Although, these are remarkable
advancements, a significantly higher amount of very expensive Ir
and Rh metal-based catalysts, phosphine-based ligands, and
sequential reactions were crucial for the success of this
methodology. In order to develop more efficient and environ-
mentally friendly methods for the synthesis of fine chemicals
using alcohols as coupling partners, a more effective catalytic
system consisting of relatively cheaper metals and ligands is
highly desirable.
In our continued interest to develop effective protocols to
construct new C−C bonds via hydrogen borrowing method-
ology, we report a bifunctional Ru(II)-catalyzed, highly efficient
three-component coupling of methanol, primary alcohols, and
ketones (Scheme 1).
be employed as an extremely economical and efficient synthetic
tactic to generate new bonds in a single step. The methyl groups
can change stereoelectronic properties of molecules which can
alter many biological processes, such as DNA replication,
transcription, nucleosome recognition, etc.2 For example,
thymine and uracil nucleobases differ structurally by only a
methyl group at the 5-position of the pyrimidine ring of
thymine.3 Thus, development of synthetic methodology for the
selective conversion of C−H and N−H bonds to C−CH3 and
N−CH3 bonds is an emerging area of research in synthetic
organic chemistry. The evolution of transition-metal-based
hydrogen borrowing catalysts allows for the use of sustainable
feedstocks such as methanol in C−C and C−N bond formation
reactions which lately has received substantial attention from the
scientific community for broader applicability in green
chemistry.4 However, compared with long chain alcohols,
utilization of methanol is extremely challenging due to its high
dehydrogenation energy.5 Inspired by the pioneering works in
methanol activation by Beller,6 Grutzmacher,7 Milstein,8 and
Krische,5b recently, few examples are reported for the utilization
of methanol as a methylating reagent.9
Scheme 1. Tandem Three-Component Coupling of Two
Alcohols and Ketones
Over the past decades, a variety of protocols for cross-coupling
of alcohols has been developed. Although considerable progress
has been achieved in α-alkylation of carbonyl compounds and β-
alkylation of alcohols,10 catalytic multicomponent reactions
using two different alcohols and ketones remain unexplored. To
the best of our knowledge, in the literature, only one such
example is known for the tandem coupling of ketones, alcohols,
and methanol.11 A three-component one-pot coupling of
methanol, benzyl alcohol, and acetophenone was first described
by the Obora group by employing an Ir-catalyst (10 mol % Ir) at
140 °C.11 At the same time, Donohoe and co-workers described
A Ru(II) complex bearing a phenpy-OH ligand was found to
be highly effective for transfer hydrogenation of ketones and
nitriles as well as β-alkylation of secondary alcohols with primary
alcohols.10h,14 For that reason, to probe the utilization of
methanol as a methylating agent, we started α-methylation of
Received: July 11, 2017
© XXXX American Chemical Society
A
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Letter
a
propiophenone using complex A (Supporting Information (SI)
Table 1). Among these Ru(II) complexes, the phenpy-OH ligand
containing complex E displayed the best performance in the
presence of KOtBu which selectively converted propiophenone
to 2-methyl-1-phenylpropan-1-one (1a) in 99% yields (SI Tables
1 and 2).
Scheme 3. Double Methylation of Various Ketones
After optimizing the reaction conditions, we turned our
attention to expanding the scope of this methodology by
screening a range of ketones. Different propiophenone
derivatives containing various electron-withdrawing and -donat-
ing substituents at different positions were successfully
methylated in excellent yields using methanol (Scheme 2). A
a
Reaction conditions: ketone (0.41 mmol), KOtBu (1.64 mmol), cat.
E (1.0 mol %), MeOH (3 mL), GC yields. Isolated yields are in
parentheses.
a
Scheme 2. Scope of Monomethylation of Ketones
a
Scheme 4. Scope of Multicomponent Reaction
a
Reaction conditions: ketone (0.37 mmol), KOtBu (1.48 mmol), cat.
E (0.5 mol %), MeOH (3 mL), GC yields. Isolated yields are in
parentheses.
long chain substrate such as butyrophenone was also converted
to 2-methyl-1-phenylbutan-1-one in good yield (Scheme 2, entry
8a). Challenging substrates such as phenylacetone (double
methylation can be possible) and α-tetralone were regioselec-
tively methylated at the α-position in excellent yields (Scheme 2,
entries 9 and 10a).
a
Reaction conditions: ketone (0.41 mmol), alcohol (0.41), KOtBu
Next, a complex E catalyzed one-pot double methylation
reaction of methyl ketones was investigated which is considered
challenging due to poor selectivity. A number of acetophenone
derivatives bearing an electron-withdrawing and -donating
substituent at the different positions were successfully methy-
lated, and the corresponding α-dimethylated ketones were
isolated in excellent yields (Scheme 3, entries 11a−17a).15 2-
Acetylnaphthalene, cyclohexanone, and 3′,4′-(methylenedioxy)-
acetophenone were double methylated effectively by this method
(Scheme 3, entries 18a−20a).
Having successfully tested the potential of complex E in the α-
methylation of ketones, we focused our attention toward catalytic
tandem multicomponent coupling reactions using methanol,
primary alcohols, and methyl ketones. First, acetophenone,
benzyl alcohol, and methanol were tested as model substrates.
Several Ru (II) complexes and bases were again screened, and
complex E in the presence of KOtBu at 110 °C delivered the best
results (SI Table 3).
(1.64 mmol), cat. E (1.0 mol %), MeOH (3 mL), GC yields (isolated
yields). One-pot sequential process. 1.5 mol % cat. E was used.
b
c
naphthylmethanol and 2-thiophenemethanol also proved to be
suitable substrates in this reaction (Scheme 4, entries 25a, 27a,
32a, and 34a). To our delight, complex E displayed significantly
higher reactivity compared to Obora’s system (10 mol % Ir, 15 h,
140 °C).11 One-pot α-methylation using challenging coupling
partners such as 3-acetylpyridine, 1-cyclopropylethanone, 1-
butanol and 1-hexanol revealed moderate reactivity (Scheme 4,
entries 26a, 28a, 35a, and 36a). However, these substrates
required sequential routes probably due to comparable reaction
rates of keto-alcohol coupling and α-methylation reactions.11
Additionally, this protocol worked smoothly with equimolar
amounts of ketones and primary alcohols whereas excess
amounts of coupling partner (either ketones or primary alcohol)
were essential for other systems.11−13
A three-component coupling reaction of methanol with both
the substituted acetophenone and benzyl alcohol having
common functional groups such as −Me, −OMe, and −Br
proceeded smoothly, and the corresponding α-methylated
ketones were selectively formed in good to excellent yields
(Scheme 4, entries 22a−24a and 29a−31a, 33a). Additionally, 2-
acetylnaphthalene and 3′,4′-(methylenedioxy)acetophenone, 1-
Next, the practical relevance of this multicomponent
methylation protocol was extended to gram-scale synthesis of
different substituted ketones (Scheme 5a). Beckmann rearrange-
ment is a remarkably versatile method for the synthesis of various
amides which are used as building blocks in many industrial
processes for the production of numerous valuable com-
pounds.16 Hence a Beckmann rearrangement of these methy-
B
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For a better understanding of the mechanism of α-methylation
of propiophenone, we have performed DFT calculations. The
reaction pathway consists of three key steps: (a) dehydrogen-
ation of methanol, (b) aldol condensation, and (c) hydro-
genation of the CC bond. Two probable pathways (outersphere
and innersphere) are possible for the dehydrogenation and
hydrogenation steps.
Scheme 5. (a) Gram Scale Multicomponent Reaction; (b)
Beckmann Rearrangement of the Methylated Ketones; (c)
Kinetic Experiments with Possible Intermediates
In the outersphere mechanism,17 the base-mediated activa-
tion18 of the precatalyst E generated the intermediate I1out in
which the hydroxyl hydrogen of methanol remained in a H-
bonded state with the pyridone oxygen (Figure 1). Next,
methanol was dehydrogenated in I1out through a concerted
seven-membered transition state TS1out (18.59 [14.07 kcal/
mol]) resulting in the transfer of hydroxyl hydrogen to the
pyridone oxygen and Cα−H to the Ru center.17b As a result, Ru−
H intermediate I2out (−3.64 [12.02] kcal/mol) was formed.
Afterward, aldol condensation between formaldehyde (gener-
ated from methanol dehydrogenation) and propiophenone
produced the α,β-unsaturated ketone (2-methyl-1-phenylprop-
2-en-1-one). At the final stage of this catalytic cycle, the CC
bond of the α,β-unsaturated ketone was hydrogenated by the
cooperative transfer of the Ru−H and O−H of the 2-
hydroxypyridine ligand scaffold of complex I2out via TS2out
(27.74 [26.07] kcal/mol) and subsequently formed intermediate
I3out (−3.56 [−5.87] kcal/mol). Then I3out was smoothly
converted to I1out which again participated in another catalytic
cycle (Figure 1).
On the other hand, in the innersphere mechanism,19 methoxy-
complex I1in was formed from the precatalyst E in the presence
of base (SI Figure 1). In this molecule, the hydrogen of the 2-
hydroxypyridine unit was H-bonded with the methoxy-oxygen
(SI Figure 1). Next, an acetonitrile molecule was dissociated to
afford the intermediate I2in (20.33 [35.14] kcal/mol) followed
by β-H elimination via a four-membered transition state TS1in
(23.74 [37.79] kcal/mol) generating I3in (19.82 [35.67] kcal/
mol).19b Afterward, aldol condensation took place which
produced the α,β-unsaturated ketone. The CC bond of the
α,β-unsaturated ketone was reduced by the Ru−H (I4in) through
TS2in (54.01 [67.23] kcal/mol) and produced intermediate I5in
which finally resulted in the desired methylated ketone and the
active complex I2in (SI Figure 1). Significantly higher energy
barriers for the dissociation of the CH3CN from I1in and
lated compounds (3a, 6a, 22a, and 23a) was carried out to
expand the applicability of this methodology further which
selectively yielded the corresponding alkylated acetanilide
derivatives efficiently (Scheme 5b).
To understand the mechanism of the α-methylation of
propiophenone using methanol, kinetic experiments were
carried out. Under the optimized conditions, probable
intermediate Q was smoothly transformed to desired product
1a. Following similar reaction conditions, in the presence of
methanol-d4, complex E selectively converted compound Q and
propiophenone to the deuterated products S and T, respectively
(Scheme 5c).
Figure 1. Calculated Gibbs free energies and enthalpies (kcal/mol) for α-methylation of propiophenone following outersphere pathway (Hybrid
functional, B3LYP was used with the LANL2DZ basis set for Ru and 6-31G** basis set for nonmetal elements).
C
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Letter
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tandem three-component coupling of ketones, alcohols, and
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02105.
■
S
General procedure for the α-methylation experiment,
multicomponent reaction, optimization details, DFT
calculations, characterization data and NMR spectra of
the products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sabuj@iitk.ac.in.
ORCID
11162−11171.
Sabuj Kundu: 0000-0002-4227-294X
Notes
(15) Compared to the monomethylation, the double methylation
reaction requuired double the catalyst loading and slightly and elevated
temperature (100 °C).
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful to the Science and Engineering Research Board
(SERB), India and Council of Scientific & Industrial Research
(CSIR) and DST-INSPIRE for financial support. K.C. and B.P.
thank UGC-India, M.M. and S.S. thank CSIR-India, and D.P.
thanks IITK for fellowship.
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