Direct Synthesis of Cycloalkanes from Diols and Secondary Alcohols or Ketones Using a Homogeneous Manganese Catalyst

Article abstract of DOI:10.1021/jacs.9b08832

A method for the synthesis of substituted cycloalkanes was developed using diols and secondary alcohols or ketones via a cascade hydrogen borrowing sequence. A non-noble and air-stable manganese catalyst (2 mol %) was used to perform this transformation. Various substituted 1,5-pentanediols (3-4 equiv) and substituted secondary alcohols (1 equiv) were investigated to prepare a collection of substituted cyclohexanes in a diastereoselective fashion. Similarly, cyclopentane, cyclohexane, and cycloheptane rings were constructed from substituted 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol, and sterically hindered ketones following a (4 + 1), (5 + 1), and (6 + 1) strategy, respectively. This reaction provides an atom economic methodology to construct two C-C bonds at a single carbon center generating high-value cycloalkanes from readily available alcohols as feedstock using an earth-abundant metal catalyst.

Full text of DOI:10.1021/jacs.9b08832

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Direct Synthesis of Cycloalkanes from Diols and Secondary Alcohols
or Ketones Using a Homogeneous Manganese Catalyst
‡
‡
Akash Kaithal,†,‡ Lisa-Lou Gracia, Clement Camp, Elsje Alessandra Quadrelli,‡
́
and Walter Leitner*,†,§
†Institut fu
̈
r Technische und Makromolekulare Chemie, RWTH Aachen University, Worringer Weg 2, 52074 Aachen, Germany
‡
́
Laboratory of Chemistry, Catalysis, Polymers and Processes, C2P2 UMR 5265, Universite de Lyon, Institut de Chimie de Lyon,
́
CNRS, Universite Lyon 1, ESCPE Lyon, 43 Bd du 11 Novembre 1918, F-69616 Villeurbanne, France
§Max Planck Institute for Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mu
̈
lheim a.d. Ruhr, Germany
S
* Supporting Information
closing metathesis (RCM) followed by hydrogenation has
generated a significant impact addressing the challenge to
synthesize medium size aliphatic rings.10 Cycloisomerization
followed by hydrogenation can also be considered as a possible
synthetic route.11 However, these strategies require the
dedicated synthesis of very specific starting materials
containing the functional groups in perfect arrangement to
allow for the cyclization step. Developing a straightforward,
sustainable and one-step process to construct the high-value
cycloalkane rings from simple building blocks is therefore an
important challenge for catalysis to open new retrosynthetic
pathways to these important structural units.
We report herein a broadly applicable synthetic route to
cyclopentanes, cyclohexanes, and cycloheptanes from α−ω
diols (n-C5, n-C6, and n-C7, respectively) via coupling with
secondary alcohols or ketones. Alcohols and diols are
ubiquitous starting materials including biomass-derived sub-
strates making them very attractive as cheap sources for the
preparation of essential and challenging building blocks.
Especially C−C bond forming reactions via hydrogen-
borrowing methodologies have gained significant attention
recently.12 For example, metal-catalyzed β-alkylation of
alcohols and α-alkylation of ketones following this principle
are well-established (Scheme 1-A).13 Recently, we reported the
ruthenium and manganese catalyzed selective β-methylation of
alcohols using methanol as a C1 source (Scheme 1-B).14 Based
on this experience, we speculated whether a similar approach
could also be applicable for the preparation of cycloalkane
rings using diols via a double alkylation methodology. Akhtar
and co-workers reported the synthesis of substituted cyclo-
hexanes using sterically hindered 1-(2,3,4,5,6-
pentamethylphenyl)ethanone and diols applying a noble-
metal iridium catalyst.15 However, the reaction was exclusively
restricted to the specific bulky ketone. Gratifyingly, we found
that complex {Mn(CO)2(Br)[HN(C2H4PiPr2)2]}, 1, known as
Mn-MACHO-iPr, acts as a versatile catalyst for the desired
reaction and makes this strategy a potentially very useful
approach for the synthesis of cycloalkanes (Scheme 1-C).
Initially, using 1 (2 mol %) in the reaction of a
stoichiometric mixture of 1-phenylethanol 2a and 1,5-
ABSTRACT: A method for the synthesis of substituted
cycloalkanes was developed using diols and secondary
alcohols or ketones via a cascade hydrogen borrowing
sequence. A non-noble and air-stable manganese catalyst
(2 mol %) was used to perform this transformation.
Various substituted 1,5-pentanediols (3−4 equiv) and
substituted secondary alcohols (1 equiv) were investigated
to prepare a collection of substituted cyclohexanes in a
diastereoselective fashion. Similarly, cyclopentane, cyclo-
hexane, and cycloheptane rings were constructed from
substituted 1,4-butanediol, 1,5-pentanediol, and 1,6-
hexanediol, and sterically hindered ketones following a
(4 + 1), (5 + 1), and (6 + 1) strategy, respectively. This
reaction provides an atom economic methodology to
construct two C−C bonds at a single carbon center
generating high-value cycloalkanes from readily available
alcohols as feedstock using an earth-abundant metal
catalyst.
ycloalkanes are ubiquitous structural motifs in natural
1
Cproducts, pharmaceuticals, or materials.
In the past,
substantial efforts have been devoted to the development of
synthetic strategies to build cycloalkane scaffolds.2 Among the
methods to synthesize substituted cyclohexanes one can
mention Diels−Alder cycloaddition (4 + 2) followed by
reduction,1d,3 hydrogenation of aromatic six-membered rings,4
cyclization of dihalides via Wurtz reaction,2b,5 dimerization of
cyclopropanes,6 and Michael reaction on enolizable reagents.7
All these approaches have some drawbacks such as multistep
procedures, poor regio- or stereoselectivity, narrow substrate
scope, or the generation of a stoichiometric amount of
chemical waste. The preparation of substituted cycloheptane
rings is an even bigger challenge. At present, very few organic
syntheses are known to accomplish the formation of seven-
membered rings from noncyclic common chemicals. Simple
cycloheptane derivatives are typically produced via the
reduction of cycloheptanone or cycloheptenes.8 Multistep
procedures for the preparation of substituted cycloheptane-1,3-
diones, which on reduction can produce substituted cyclo-
heptane rings, were reported from 1,2-diketones and ring
expansion of cyclopentanones.9 As a catalytic method, ring
Received: August 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b08832
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Journal of the American Chemical Society
Communication
highlights further the opportunities to use Mn(I) as a proxy for
Ru(II) in pincer frameworks due to the diagonal relationship in
the periodic table.13c,14,16 Varying the diol amount further led
to a maximum of yield and selectivity of 62% 4a at 82%
conversion at a 4:1 ratio (Table 1, entries 3−5). Only minor
amounts of side products stemming from aldol-type reactions
of 1-phenylethanol were observed under these optimized
conditions (see the SI for details).
Scheme 1. Metal-Catalyzed Coupling of Secondary and
Primary Alcohols as Motivation for the Synthetic
Methodology Developed in This Work
Reducing the temperature to 120 °C gave very low
conversion (Table 1, entry 6). Increasing the temperature to
170 °C gave higher conversion of 98% and yield of 74% (Table
1, entry 7) while the selectivity remained virtually constant as
compared to 150 °C. Decreasing the catalyst loading from 2
mol % to 1 mol % diminished the product yield and showed
only 36% product formation at 86% conversion (Table 1, entry
8). Altering the base from KOtBu to Cs2CO3 and NaOtBu also
led to low product formation (Table 1, entries 9 and 10).
Finally, prolonging the reaction time from 24 to 32 h at 2 mol
% catalyst loading with KOtBu resulted in the best catalytic
perfomances with 80% GC yield and 72% isolated yield after
purification by column chromatography (Table 1, entry 11).
Under these optimized conditions, diol 3a could be replaced
with 3-methylpentane-1,5-diol 3b leading to even higher yields
of 4b (92% yield by GC and 81% isolated yield, Table 1, entry
12). The trans-products with both sterically demanding groups
in the equatorial positions are typically the thermodynamically
favored isomers.4d,17 This arrangement was confirmed by
NMR analysis and DFT calculations with a diastereomeric
ratio of 90:10 in favor of the trans-isomer for 4b in the isolated
product (see SI for the assignment of the stereochemistry).
Based on these optimized reaction conditions, several
secondary alcohols with different functional groups and varying
steric demands were reacted with 3-methylpentane-1,5-diol 3b
in order to explore the scope of the reaction (see Chart 1).
Replacing the phenyl ring with a naphthyl ring afforded the
corresponding product 4c in 86% GC yield and 83% isolated
yield with a 87:13 diastereomeric ratio. Methyl substitution of
1-phenylethanol in the para- or ortho-position also gave the
cyclohexyl product in high yield with the preferential formation
of the trans-diastereomer (Chart 1, 4d and 4e). Reaction with
the para-methoxy substituted secondary alcohol afforded the
desired product in high yield (78% GC yield), while the ortho-
methoxy substituted derivative showed somewhat lower
selectivity (52% GC yield, see Chart 1, 4f and 4g). The
reaction with 1-(4-chlorophenyl)ethanol showed excellent
conversion but resulted in the formation of a mixture of
products under standard conditions. However, when the
reaction time was decreased to 14 h, the desired cyclohexyl
product 4h was obtained in up to 70% GC yield and 61%
isolated yield with very high selectivity to trans-diastereomer
(Chart 1, entry 4h). Bromo substitution in the para-position of
1-phenylethanol showed a 40% yield to the corresponding
cyclohexyl product 4i after 14 h reaction time. However,
debromination also occurred accounting for another 33% of
cyclization product. Interestingly, heterocyclic-secondary alco-
hol 1-(furan-2-yl)ethan-1-ol also revealed 61% isolated yield to
the cyclohexyl product 4j.
pentanediol 3a in the presence of KOtBu (4 equiv) as a base
gave only 16% yield of 4a. The low yield can be attributed to
the self-condensation of the diol as a side reaction, as
corroborated by the observation of the corresponding lactone
by GC-MS analysis. Increasing the diol-to-alcohol ratio of 2:1
improved the yield of 4a to 47%, along with unreacted starting
material and acetophenone (Table 1, entry 2). Interestingly,
the Mn-catalyst 1 gave a higher yield when compared to the
closely related ruthenium(II) catalyst Ru-MACHO-BH that
leads to 35% of 4a under the same conditions. This example
Table 1. Reaction Optimization for the Synthesis of
a
Substituted Cyclohexanes 4a and 4b
diol
(equiv)
temp
(°C)
conv
b
b
no.
base (equiv)
(%)
yield 4 (%)
1
3a (1)
3a (2)
3a (3)
3a (4)
3a (5)
3a (4)
3a (4)
3a (4)
3a (4)
3a (4)
3a (4)
3b (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
KOtBu (4)
Cs2CO3 (2)
NaOtBu (4)
KOtBu (4)
KOtBu (4)
150
150
150
150
150
120
170
150
150
150
150
150
70
89
>99
82
84
60
98
86
78
69
16
47
60
62
35
10
74
36
2
2
3
4
5
6
7
8
9
c
10
11
12
12
80
d
d
>99
>99
92; 90:10 d.r.
Aliphatic alcohols comprising less acidic β-CH proton than
the benzylic substrates also reacted smoothly. 1-Cyclo-
hexylethanol yielded the desired cyclohexyl product 4k in
good yield. However, in this case, low diastereomeric
selectivity was observed (Chart 1, entry 4k). Small aliphatic
secondary alcohols such as 3-methylbutan-2-ol and isopropyl
a
Reaction conditions: 1-phenylethanol 2a (0.5 mmol), diol 3a or 3b,
Mn-complex 1 (2 mol %), base, and toluene (2 mL) were heated in a
b
closed vessel. Conversion and yield were calculated using GC
c
analysis; mesitylene was used as an internal standard. 1 mol % of the
d
Mn-complex 1 was used. Reaction time: 32 h.
B
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Communication
optimized reaction conditions. The corresponding cyclohexane
products were obtained in very good yields and with fair to
high diastereoselectivity, further confirming the general
efficiency and versatility of this synthetic methodology
(Chart 1).
Chart 1. Manganese-Catalyzed Synthesis of Substituted
Cyclohexanes from a Variety of Secondary Alcohols and
Diols
a b
,
Assuming that dehydrogenation of the secondary alcohol is a
crucial step in the reaction sequence (vide infra), ketones 5a
and 5b were also tested in the reaction (see Chart 2).
Chart 2. Manganese-Catalyzed Selective Preparation of
a b
,
Substituted Cycloalkanes from Ketones and Diols
a
Reaction conditions: 1-(methylpolysubstituted-phenyl)-ethanone 5
(0.5 mmol), diol 6 (2 mmol), Mn-complex 1 (5 mg, 2 mol %), KOtBu
(224 mg, 2 mmol), and toluene (2 mL) were heated in a closed vessel.
b
Conversion and yield were calculated using GC analysis. Yields in
parentheses correspond to isolated yields after purification via column
chromatography.
Interestingly, their use yielded selectively the ketone products;
the corresponding alcohol derivatives were not observed.
While the steric hindrance in these substrates reduced the
reactivity to form the six-membered cycle somewhat giving
only 52% yield of product 7d, it proved beneficial for synthesis
of five- and seven-membered cycloalkanes. The reaction of 1,6-
hexanediol with pentamethyl acetophenone 5a led to
formation of the desired seven-membered ring species 7a
with very good yield and high selectivity (78% GC yield and
66% isolated yield). Reaction of methyl substituted 1,6-
hexanediol with 5a also provided to the cycloheptane product
7b with excellent 98% yield. The methyl substitution of the
ketone derivative was reduced from 5a to 1-mesitylethanone
5b without altering the efficiency of the reaction (see
formation of 7c in good yield: 78% by GC, 62% as isolated
yield). The reaction of 5a with 1,4-butanediol gave the five-
membered ring product in 46% yield (Chart 2). In a similar
manner, the reaction of 5b with 1,4-butanediol afforded the
expected cyclopentane derivative with a 39% yield. The
reaction of secondary alcohols with 1,4-butanediol and 1,6-
hexanediol to prepare five- and seven-membered rings revealed
only a mixture of products. Similarly, attempts to prepare four-
membered rings from 1,3-propanediol either with the ketone
a
Reaction conditions: secondary alcohol 2 (0.5 mmol), diol 3 (2
mmol), Mn-complex 1 (5 mg, 2 mol %), KOtBu (224 mg, 2 mmol),
and toluene (2 mL) were heated in a closed vessel. Conversion and
yield were calculated using GC analysis. Yields in parentheses
correspond to isolated yields after purification via column
b
c
d
chromatography. Reaction time: 14 h. 1.5 mmol of diol was used.
e
Three mmol of diol and 4 mmol of KOtBu were used. n.d.: not
determined.
alcohol also confirmed good reactivity and high selectivity to
the trans-diastereomer (Chart 1, entry 4l, 4m). By using
isopropyl alcohol as a substrate two cyclohexyl ring formations
were made possible.
Next, a variety of alkyl and aryl substituted diols were
coupled with a range of secondary alcohols using the same
C
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Journal of the American Chemical Society
Communication
or secondary alcohol did not yet yield synthetically useful
yields.
Scheme 3. Proposed Reaction Sequence and the Role of the
Mn-Catalyst for the Synthesis of Substituted Cycloalkanes
from Diols and Secondary Alcohols
The overall reaction of the new synthetic protocol requires a
complex sequence of several individual transformations to
assemble the cycloalkane rings. Several control experiments
support the assumption that it follows a Guerbet-type de/
rehydrogenation-condensation mechanism. Reactions without
either complex 1 or KOtBu did not show any product
formation which confirmed that the reaction requires both the
manganese complex and the base to achieve the desired
reaction sequence. While the reaction with 1-phenyethanol 2a
resulted in alcohol 4a as product (Table 1, entry 11), the
coupling of sterically more hindered 1-mesitylethanol 8 with
1,5-pentanediol 3a resulted in the selective formation of ketone
9 as product with 37% isolated yield (Scheme 2). This can be
Scheme 2. Control Experiments To Probe Hydrogen
Borrowing as Metal-Catalyzed Step of the Overall Reaction
Sequence
condensation takes place between B and B′ to form the
corresponding enone C. The manganese hydride intermediate
III that originates from β-hydride elimination14b,18b rehy-
drogenates the CO unit of C to the corresponding enol
product D, thereby regenerating the active Mn-species I. Base-
catalyzed allyl isomerization of enol D leads to the
corresponding hydroxy ketone E,19 from which the analogous
sequence starts again whereby intramolecular aldol-condensa-
tion fabricates the cyclic structure. Depending on the steric
hindrance of the ketone moiety, the reaction may stop at
product F or involve another rehydrogenation step to result in
alcohol G as the final product.
In conclusion, we have developed an efficient and versatile
synthetic strategy to prepare substituted cycloalkanes via
catalytic coupling of diols and secondary alcohols/ketones
using an earth-abundant and air-stable manganese pincer
complex. Various aromatic and aliphatic secondary alcohols
were coupled with several substituted 1,5-pentanediols to
generate substituted cyclohexane rings with very good to high
yield and moderate to high diastereoselectivity. Notably, the
same methodology allows the catalytic synthesis of cyclo-
heptane and cyclopentane rings by variation of the carbon
chain in the diol component, reaching high to excellent yields
for challenging cycloheptane derivatives. The reaction principle
is atom economic producing only water as stoichiometric
byproduct. Presently, however, an excess diol is required due
to formation of intramolecular side products such as lactones.
Further optimization to suppress this path would be facilitated
by a more detailed understanding of the complex reaction
network and the factors controlling the rates of the individual
steps. While the Mn-catalyst affects primarily the de- and
rehydrogenations steps, the base mediates probably the C−C
bond formation and isomerization. Given the significant
rationalized assuming that ketone 5b is formed from 8 as
intermediate, but the CO group in the product cannot be
rehydrogenated due to steric hindrance. To verify the
hypothesis, the reaction of acetophenone 10 with 3b was
performed. Indeed, the alcohol product 4b was obtained in
90% GC yield with a 86:14 diastereomeric ratio (Scheme 2),
very similar to that obtained when starting from the alcohol 2a
(Table 1, entry 12). Reacting deuterium-labeled 1-phenyl-
ethanol (1 equiv) 2ad with 3b (4 equiv) gave product 4bd with
only very low deuterium content, confirming large degrees of
H/D scrambling in agreement with a hydrogen borrowing
mechanism (Scheme 2).
On the basis of these experimental data and literature
precedence,18 a plausible reaction sequence illustrating the role
of the Mn-catalyst and the base is proposed in Scheme 3 (a
more detailed representation is given in the SI). In the
presence of KOtBu, complex 1 is converted to the amido
complex I,18b,c a type of Mn(I) complexes that is well-known
for its activity in hydrogen-transfer reactions.18a,b The
formation was also verified by 31P NMR in the present case
(see the SI). Dehydrogenation occurs via reaction of I with
secondary alcohol A or diol A′ to Mn-alkoxy amino complexes
II and II′ followed by β-hydride elimination to give ketone B
and aldehyde B′, respectively. In the presence of base, aldol-
D
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Communication
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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/jacs.9b08832.
■
S
Detailed description of synthetic protocol, full analytical
data, and additional information regarding mechanistic
proposal (PDF)
AUTHOR INFORMATION
Corresponding Author
*walter.leitner@cec.mpg.de
■
ORCID
́
Clement Camp: 0000-0001-8528-0731
Walter Leitner: 0000-0001-6100-9656
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The studies were performed as part of our activities in the
framework of the “Fuel Science Center” funded by the
Deutsche Forschungsgemeinschaft (DFG, German Research
Foundation) under Germany’s Excellence Strategy − Ex-
zellenzcluster 2186, The Fuel Science Center“ ID: 390919832.
A.K. thanks the Erasmus Mundus Action 1 Programme
(FPA2013- 0037) “SINCHEM” for a stipend. We are thankful
to David A. Kuß for performing the DFT calculation. We
gratefully acknowledge the CPE Lyon, its sustainable develop-
ment chair, CNRS, and University of Lyon 1 for the support,
the experimental infrastructure, and the internship of L.-L.G.
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E. 1.1 - Stabilized Nucleophiles with Electron Deficient Alkenes and
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