Manganese-Catalyzed β-Alkylation of Secondary Alcohols with Primary Alcohols under Phosphine-Free Conditions

Article abstract of DOI:10.1021/acscatal.8b01960

Manganese(I) complexes bearing a pyridyl-supported pyrazolyl-imidazolyl ligand efficiently catalyzed the direct β-alkylation of secondary alcohols with primary alcohols under phosphine-free conditions. The β-alkylated secondary alcohols were obtained in moderate to good yields with water formed as the byproduct through a borrowing hydrogen pathway. β-Alkylation of cholesterols was also effectively achieved. The present protocol provides a concise atom-economical method for C-C bond formation from primary and secondary alcohols.

Full text of DOI:10.1021/acscatal.8b01960

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Letter
Manganese-Catalyzed #-Alkylation of Secondary Alcohols
with Primary Alcohols under Phosphine-Free Conditions
Tingting Liu, Liandi Wang, Kaikai Wu, and Zhengkun Yu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01960 • Publication Date (Web): 05 Jul 2018
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Manganese-Catalyzed β-Alkylation of Secondary Alcohols
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with Primary Alcohols under Phosphine-Free Conditions
Tingting Liu,†,‡ Liandi Wang,† Kaikai Wu,† and Zhengkun Yu*,†,§
†
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, P. R. China
‡
University of Chinese Academy of Sciences, Beijing 100049, P. R. China
§ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
ABSTRACT: Manganese(I) complexes bearing a pyridylꢀsupported pyrazolylꢀ
imidazolyl ligand efficiently catalyzed the direct βꢀalkylation of secondary alcohols
with primary alcohols under phosphineꢀfree conditions. The βꢀalkylated secondary
alcohols were obtained in moderate to good yields with water formed as the byꢀ
product through a borrowing hydrogen pathway. βꢀAlkylation of cholesterols was also
effectively achieved. The present protocol provides a concise atomꢀeconomical
method for C−C bond formation from primary and secondary alcohols.
KEYWORDS: manganese·alcohols·alkylation·borrowing hydrogen·cholesterols
onstruction of carbon−carbon bonds is of great imporꢀ
achieved much progress in hydrogenation and dehydrogeꢀ
nation reactions.11ꢀ13 Manganese is the third most abundant
metal in the earth’s crust which offers an attractive alternative
to noble metals. In particular, it is capable of existing in
several oxidation states. Milstein and coꢀworkers reported αꢀ
olefination of nitriles,14a dehydrogenative crossꢀcoupling of
alcohols with amines,14b Nꢀformylation of amines with
methanol,15 and deoxygenation of alcohols16 catalyzed by
pincerꢀtype MnꢀPNP complexes. With a manganese complex
as the catalyst, diverse alcohols underwent dehydrogenationꢀ
based processes such as Nꢀalkylation of amines,17 Cꢀalkylation
of ketones,18 dehydrogenation of alcohols to esters,19 and
methanol to H2 and CO2,20 synthesis of pyrroles, quinolines,
1
Ctance in organic synthesis. More and more concern on
the consequence of climate change and dwindling crude oil
reserves results in the search for alternative carbon resources
for the formation of C−C bonds.2 Thus, readily available
alcohols have recently been paid much attention to be utilized
as the electrophiles or alkylating agents to establish C−C
bonds.3 The traditional method to prepare βꢀalkylated alcohols
from secondary alcohols usually requires a multistep process
which involves oxidation of the secondary alcohols, alkylation
with alkyl halides, and reduction of the βꢀalkylated ketones.
The drawbacks of such a protocol include waste generation,
expensive and toxic nobleꢀmetal catalyst, limited availability
of the starting materials. βꢀAlkylation of secondary alcohols
can also be realized by means of hydrogen autotransfer or
borrowing hydrogen which has become an important synthetic
strategy in organic chemistry due to its high efficiency, low
cost, and versatility.4 The operational simplicity, ready
availability of the starting materials from renewable resources,
and generation of water as the only stoichiometric byꢀproduct
make the borrowing hydrogen strategy be atomꢀeconomical,
sustainable, and environmentally benign.5 Direct βꢀalkylation
of secondary alcohols with primary alcohols have been
documented under ruthenium,6 iridium,7 palladium,8 and
copper9 catalysis or under metalꢀfree conditions10 through a
borrowing hydrogen strategy.
Scheme 1. Selected Known Manganese Complex Catalysts
and pyrimidines.21 Hydrogenations of ketones, nitriles, esters,
CO2, and amides have also been realized with manganese
complex catalysts.22,23 Very recently, Kempe, et al. reported
manganeseꢀcatalyzed dehydrogenative alkylation or αꢀolefiꢀ
nation of alkylꢀsubstituted Nꢀheteroarenes with alcohols.24 The
typical phosphineꢀbearing amineꢀbased PNPꢀMnH,14a triazineꢀ
based PNPꢀMnH,21c pyridineꢀbased PNPꢀMnBr,21d and amineꢀ
based PNPꢀMnBr23c complex catalysts have been documented
(Scheme 1).
It has been desired to apply nonꢀnoble metal catalysis in
organic synthesis due to the economic and ecological benefits
as well as different reactivities of the metals. In this regard,
base metals such as iron, cobalt, and nickel have been
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Recently, we have reported versatile pyridylꢀbased NNN,
complexes 1c and 1d could not undergo the same type of
reactions.
CNN and NNP ligands for the construction of ruthenium
complex catalysts for transfer hydrogenation of ketones,
dehydrogenation of Nꢀheterocyclic compounds, synthesis of
pyrrole derivatives, and Oppenauerꢀtype oxidation of
secondary alcohols.25 Among these ruthenium complex
catalysts, Ru(III) complex A exhibited a high catalytic activity
in the βꢀalkylation of secondary alcohols.6b During our
continuous investigation of transitionꢀmetal complex catalysts
bearing a unsymmetrical tridentate ligand, we found that the
transitionꢀmetal complexes bearing a phosphineꢀfree pyridylꢀ
supported 2,6ꢀ(mixed Nꢀheterocycles) ligand can usually
exhibit enhanced catalytic activity and selectivity. Encouraged
by these findings, we envisioned that these ligands might also
be employed to construct manganese complex catalysts.
Herein, we disclose the synthesis of Mn(I)ꢀNN complexes 1
and their catalytic activities in βꢀalkylation of secondary
alcohols with primary alcohols (Scheme 2).
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Complexes 1 were fully characterized by NMR, FTꢀIR, and
elemental analyses, which are consistent with their
compositions. The proton NMR signals of complex 1a was
shifted 0.1ꢀ2.1 ppm downfield as compared with those of the
free ligand L1, suggesting that coordination of the ligand to
manganese diminishes the electron density on the ligand.
Three coordinating carbonyl groups in Mn(CO)3 moiety of
complex 1a were confirmed by the 13C{1H} NMR signals at
225.4, 220.2, and 215.2 ppm. The proton NMR signals of
complex 1b were broadened and its 13C{1H} NMR spectrum
could not be obtained due to the possibility of a dynamic
process.26 The proton NMR spectrum of complex 1c exhibited
one singlet at 4.40 ppm, corresponding to the proton resonance
of Nꢀmethyl group, and other proton resonance signals were
shifted 0.1ꢀ0.5 ppm downfield as compared with those of the
free ligand L2 due to its coordination with the manganese
center. In the 13C{1H} NMR spectrum of 1c, the singlets at
226.6, 221.0, 216.6, and 33.1 ppm revealed the presence of
three coordinating carbonyl groups and Nꢀmethyl, respectively.
The NMR spectra of complex 1d were in accordance with its
composition, and the carbonyl resonance signals appeared at
224.2, 221.3, and 220.8 ppm, respectively. As compared with
the infrared spectrum of ligand L1, the stretching vibrations of
the carbonyls in Mn(CO)3 of complex 1a were assigned at
2025 and 1933 cmꢀ1, respectively, corresponding to two types
of coordinating carbonyls. In a similar manner, two types of
carbonyl stretching vibrations were observed at 2027 and 1909
cmꢀ1, 2024 and 1935 cmꢀ1, and 2025 and 1933 cmꢀ1 for
complexes 1bꢀ1d, respectively.
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Scheme 2. Relevant Ligands and Their Ru(III) and Mn(I)
Complexes
Treatment of our previously reported pyridylꢀsupported
pyrazolylꢀimidazolyl ligand L1,25e that is, 2ꢀ(3,5ꢀdimethylꢀ
pyrazolꢀ1ꢀyl)ꢀ6ꢀ(benzimidazolꢀ2ꢀyl)pyridine, with Mn(CO)5Br
o
(1 equiv) in THF at 25 C under a nitrogen atmosphere led to
complex 1a in 83% yield (Scheme 3). In a similar fashion,
complex 1b was obtained in 87% yield from the same reaction
in methanol. The Mn−Br bond in 1a was transformed to
Mn−OMe in 1b. Reacting Mn(CO)5Br with the Nꢀmethylated
ligand L2 in methanol only afforded complex 1c (80%), and
the reaction exhibited no solvent effect. For the comparison
study, bidentate ligand L3 without bearing the 3,5ꢀ
dimethylpyrazolꢀ1ꢀyl (Me2pz) moiety was also applied in the
reaction with Mn(CO)5Br in methanol, giving complex 1d in
85% yield. It is noteworthy that stirring a solution of complex
1a in methanol at ambient temperature for 24 h quantitively
gave complex 1b. The Mn−Br bond in 1a was transformed to
Figure 1. Perspective view of complex 1b with thermal ellipsoids
at the 30% probability level.
Single crystals of complex 1b suitable for Xꢀray diffraction
were obtained by slow vapor diffusion of nꢀpentane into a
saturated solution of the complex in CH2Cl2/MeOH (v/v, 1/2)
o
at 4 C. The molecular structure of complex 1b adopts an
octahedral geometry with the metal center coordinated by the
pyridyl and imidazolyl nitrogen atoms of ligand L1 and three
carbonyls, and bonded to the methoxy oxygen atom (Figure 1).
The potentially terdentate ligand L1 actually acts as a
bidentate ligand in complex 1b, forming two coordination
Conditions: L1ꢀL3 (0.5 mmol), Mn(CO)5Br (0.5 mmol), solvent (25 mL),
o
0.1 MPa N2, 25 C, 24 h. (i) Synthesis of 1a: L1, THF, 83% yield; (ii)
Synthesis of 1b: L1, MeOH, 87% yield; (iii) Synthesis of 1c: L2, MeOH,
80% yield; (iv) Synthesis of 1d: L3, MeOH, 85% yield.
bonds of Mn(1)ꢀN(3) (2.13 Å) and Mn(1)ꢀN(4) (2.02 Å)
.
The unsymmetrical coordinating pyridylꢀimidazolyl moiety
occupies the two meridional sites with two carbonyls in a
quasiplanar disposition, and the manganese atom is nearly
situated in such a plane. The methoxy oxygen atom is
Scheme 3. Synthesis of Manganese Complexes
Mn−OMe in 1b by reacting with methanol and release of
hydrogen bromide under the stated conditions, while
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positioned trans to the third carbonyl with a C(18)ꢀMn(1)ꢀO(4)
as 1b > 1d > 1a > 1c (Table 1, entries 2−5). With 1b as the
catalyst, the reaction conditions were further optimized. An
obvious base effect was observed on the alkylation efficiency
with the order tBuOK > tBuONa > KOH > NaOH >> no base
(Table 1, entries 3 and 6−9). Lowering the catalyst loading to
1.0 mol %, varying the base loading to 20ꢀ40 mol %, or
lowering the reaction temperature to 100 °C reduced the
conversion of 2a with deteriorated selectivities of
4a/4a′ (Table 1, entries 10−13). Equivalent base was needed in
the hidden alkylation of alcohol reported by Kempe and
coworkers.21b Under the solventless conditions, the reaction
could not efficiently occur (Table 1, entry 14). The high
catalytic activity of complex 1b is presumably attributed to the
presence of an NH functionality in the ligand and the OMe
ligand attached on the metal center. Methanol may be released
to form a coordinatively unsaturated (16ꢀelectron) Mn(I)
species which thus enhances the interaction between the
substrate and the catalytically active Mn(I) metal center,
accelerating the reaction.
angle of 176°, and bond lengths of Mn(1)ꢀO(4) (2.08 Å) and
Mn(1)ꢀC(18) (1.79 Å), suggesting that the axial carbonyl and
methoxy oxygen atom are almost linearly positioned at the
two sides of the quasiplane. The two coordinating nitrogen
atoms are also nearly linearly arranged with the two equatorial
carbonyls, exhibiting angles of N(3)ꢀMn(1)ꢀC(19) (175°) and
N(4)ꢀMn(1)ꢀC(20) (176°), respectively.
The catalytic activities of complexes 1 were evaluated in the
Cꢀalkylation of 1ꢀphenylethanol (2a) with benzyl alcohol (3a)
(Table 1). With 2.1 mol % loading, complexes 1a−1d were
applied as the catalysts for the reaction in the presence of 30
mol % tBuOK as the base in refluxing toluene. In the case of
using complex 1a, 86% conversion was achieved for 2a with a
67/33 selectivity for the target Cꢀalkylation product 4a and Cꢀ
alkylation/dehydrogenation product 4a′ (Table 1, entry 2),
while the reaction proceeded less efficiently without a catalyst
(Table 1, entry 1). The reaction efficiency was remarkably
improved with complex 1b as the catalyst, reaching 96%
conversion for 2a and a 94/6 selectivity for 4a/4a′, and the
corresponding βꢀalkylation product 4a was isolated in 90%
yield (Table 1, entry 3). Under the same conditions, both
complexes 1c and 1d behaved less efficiently to the reaction
than complex 1b as the catalyst (Table 1, entries 4 and 5).
Presence of both the NꢀH functionality and 3,5ꢀ
dimethylpyrazolꢀ1ꢀyl moiety in the ligand (L1) seems to be
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Table 2. Scope of Primary Alcohols (3)a
Table 1. Screening of Reaction Conditionsa
Conversion of
4a:4a'
2ab (%)
(molar ratio)b
Entry
1
Catalyst
Base
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuONa
KOH
83
86
96
84
92
87
80
74
<1
91
90
84
78
66
40:60
67:33
2
1a
1b
1c
3
94:6 (90)c
53:47
4
5
1d
1b
1b
1b
1b
1bd
1b
1b
1b
1b
78:22
6
92:8
7
88:12
8
NaOH
86:14
9
10
11
12
13g
14h
tBuOK
tBuOKe
tBuOKf
tBuOK
tBuOK
65:35
90:10
91:9
aConditions: 2a (2 mmol), 3 (2 mmol), 2.1 mol % 1b, 30 mol % tBuOK, 0.1
MPa N2, toluene (1 mL), 110 oC, 24 h. b4.2 mol % 1b, oꢀxylene (1 mL), 140 oC,
48 h.
88:12
89:11
aConditions: 2a (2 mmol), 3a (2 mmol), catalyst 1 (2.1 mol %), base (30 mol
Under the optimized conditions, the protocol generality was
explored by applying a variety of primary alcohols (Table 2).
Benzyl alcohols (3) bearing an electronꢀdonating methyl,
methoxyl, isopropyl, or 3,4ꢀmethylenedioxy substituent
reacted with 2a to form the target products 4b−4h in good
o
b
%), toluene (1 mL), 0.1 MPa N2, 110 C, 24 h. Determined by GC analysis.
d
e
f
cIsolated yield of 4a given in parentheses. 1.0 mol %. 20 mol %. 40 mol %.
g100 oC. hSolventꢀfree conditions.
crucial to render the formation of complex 1b. The order of
the catalytic activities for these complexes was thus obtained
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yields (78−88%). Methyl group exhibited no obvious steric
bromo, and trifluoromethyl could be tolerant on the aryl group
of 1ꢀarylethanols (2). oꢀ, mꢀ, and pꢀmethyls did not exhibit an
obvious impact on the formation of 5a−5c (81−84%). 2ꢀOMe
and 4ꢀOMe diminished the yields of 5d (62%) and 5e (74%).
3ꢀChloro also led to a relatively low yield for 5f (70%), while
4ꢀchloro facilitated the production of 5g (80%). Unexpectedly,
3ꢀ and 4ꢀBr groups promoted the reactions to yield the target
products 5h and 5i in good yields (83−93%). The strong
electronꢀwithdrawing trifluoromethyl did not favor the
reactions to produce 5j (60%) and 5k (70%). In a similar
fashion, 1ꢀ(2ꢀnaphthyl)ethanol efficiently reacted with 3a to
afford 5l (82%), exhibiting no steric effect. 1ꢀ(2ꢀPyridyl)ꢀ
ethanol and aliphatic secondary alcohols reacted with 3a less
efficiently, giving 5m−5p in 54−61% yields by means of 4.2
mol % 1b as the catalyst under relatively harsh conditions.
Next, the substrate scope was extended to cyclic secondary
alcohols. Thus, the reactions of cyclopentanol 6 with benzyl
alcohols were explored (Scheme 4). In order to reach double
Cꢀalkylation, 2 equiv of benzyl alcohol was applied in the
presence of 4.2 mol % catalyst. To our delight, cyclopentanol
impact on the yields of 4b−4d (84−85%), while methoxyl,
isopropyl, and 3,4ꢀmethylenedioxy demonstrated various
electronic/steric effects on the product yields of 4e−4h
(78−88%). The orthoꢀsubstituents such as 2ꢀF and 2ꢀCl on the
aryl group of the benzyl alcohol substrate showed negative
electronic/steric effects, resulting in products 4i (53%) and 4j
(68%), whereas the mꢀ and pꢀCl, and pꢀBrꢀsubstituted benzyl
alcohols reacted well with 2a to afford the target products
4k−4m in 78−82% yields. An obvious substituent effect was
revealed on the reactivity of the chloroꢀsubstituted benzyl
alcohols. 2ꢀNaphthylmethanol efficiently underwent the
reaction with 2a, forming 4n in 90% yield without showing a
steric effect. With a higher catalyst loading (4.2 mol %) and
longer reaction time (48 h) at a higher temperature (140 °C),
2ꢀ and 4ꢀpyridylmethanols also reacted with 2a to give 4o and
4p in 54−60% yields. In these cases, the catalyst might be
partially deactivated by the coordination of the pyridyl atom to
the metal center of the catalyst. Middleꢀchain aliphatic
primary alcohols exhibited reactivities lower than those of the
benzyl alcohols, and their reactions with 2a were conducted
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6 efficiently reacted with benzyl alcohols, affording the diꢀ(βꢀ
alkylated) secondary alcohol products, that is, 2,5ꢀ
dibenzylcyclopentanols 7, in 77−83% yields. However,
cyclohexanol, 1,2,3,4ꢀtetrahydroꢀnaphthalenꢀ1ꢀol, and 2,3ꢀ
dihydroꢀ1Hꢀindenꢀ1ꢀol could not effectively react with benzyl
alcohols under the stated conditions. The substrate scope was
further extended to potentially useful cyclic secondary
alcohols. In a similar manner, cholesterol and its derivative
Table 3. Scope of Secondary Alcohols (2)a
Scheme 4. Reactions of Cyclopentanol with Benzylic Alcohols
aConditions: 2a (2 mmol), 3 (2 mmol), 2.1 mol % 1b, 30 mol % tBuOK, 0.1
MPa N2, toluene (1 mL), 110 oC, 24 h. b4.2 mol % 1b, oꢀxylene (1 mL), 140 oC,
48 h.
under the relatively harsh conditions, forming the target
products 4q−4s in 53−61% yields. These results have revealed
that benzyl alcohols are more reactive than aliphatic primary
alcohols in the βꢀalkylation of secondary alcohols.
Then, the reactions of benzyl alcohol (3a) with structurally
diverse secondary alcohols were investigated (Table 3).
Various functional groups such as methyl, methoxyl, chloro,
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were employed to react with benzyl alcohols to access Cꢀ
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This methodology was further applied for oneꢀpot synthesis
of flavan derivatives from simple alcohols.27 Under the
standard conditions, secondary alcohol 2a was reacted with 2ꢀ
bromobenzyl alcohol (3t). The intermediate alcohol was not
isolated, and then directly subjected to the copper(I) catalysis,
resulting in 2ꢀphenylchroman (10) in 30% yield (Scheme 5).
Scheme 5. One-Pot Synthesis of Flavan Derivative 10
In summary, we have developed efficient manganeseꢀ
catalyzed direct βꢀalkylation of secondary alcohols with
primary alcohols under phosphineꢀfree conditions. The present
protocol offers a concise strategy to construct transitionꢀmetal
complex catalysts from readily available phosphineꢀfree
ligands, and provides a useful alkylation method for secondary
alcohols and cholesterol derivatives.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
Internet http://pubs.acs.org.
Experimental materials and procedures
Analytical data and NMR spectra of compounds and complexes
Xꢀray crystallographic analysis for 1b
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: zkyu@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of
China (21672209) for support of this research.
(11) (a) Balaraman, E.; Nandakumar, A.; Jaiswal, G.; Sahoo, M. K.
IronꢀCatalyzed Dehydrogenation Reactions and Their Applications in
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