Nonbifunctional Outer-Sphere Strategy Achieved Highly Active α-Alkylation of Ketones with Alcohols by N-Heterocyclic Carbene Manganese (NHC-Mn)

Article abstract of DOI:10.1021/acs.orglett.9b03030

The unusual nonbifunctional outer-sphere strategy was successfully utilized in developing an easily accessible N-heterocyclic carbene manganese (NHC-Mn) system for highly active α-alkylation of ketones with alcohols. This system was efficient for a wide range of ketones and alcohols under mild reaction conditions, and also for the green synthesis of quinoline derivatives. The direct outer-sphere mechanism and the high activity of the present system demonstrate the potential of nonbifunctional outer-sphere strategy in catalyst design for acceptorless dehydrogenative transformations.

Full text of DOI:10.1021/acs.orglett.9b03030

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nonbifunctional Outer-Sphere Strategy Achieved Highly Active
α‑Alkylation of Ketones with Alcohols by N‑Heterocyclic Carbene
Manganese (NHC-Mn)
Xiao-Bing Lan,†,§ Zongren Ye,†,§ Ming Huang,† Jiahao Liu,† Yan Liu,*,‡ and Zhuofeng Ke*,†
†School of Materials Science and Engineering, PCFM Lab, Sun Yat-sen University, Guangzhou 510275, People’s Republic of China
‡School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, People’s Republic
of China
S
* Supporting Information
ABSTRACT: The unusual nonbifunctional outer-sphere strategy was
successfully utilized in developing an easily accessible N-heterocyclic
carbene manganese (NHC-Mn) system for highly active α-alkylation of
ketones with alcohols. This system was efficient for a wide range of ketones
and alcohols under mild reaction conditions, and also for the green
synthesis of quinoline derivatives. The direct outer-sphere mechanism and
the high activity of the present system demonstrate the potential of
nonbifunctional outer-sphere strategy in catalyst design for acceptorless
dehydrogenative transformations.
he borrowing hydrogen/hydrogen autotransfer (BH/
HA) has been emerging as a versatile method in
The α-alkylation of ketone via BH/HA has emerged as an
attractive C−C bond formation protocol.1b,e,4,5 With green and
sustainable alcohols as alkylating agents, α-alkylation of ketone
via BH/HA provides advantages, compared to traditional
procedures involving enolates and alkyl halides,6 avoiding the
using of toxic halides and the formation of waste
byproducts.1a−c
The inner-sphere strategy α-alkylation of ketones were
widely studied with precious metals (Scheme 1a) such as
Ru,4b,7 Ir,8 and Rh,9 bearing weak or hemilabile ligands. Later,
T
synthesis. Using nonactivated renewable alcohols as starting
materials, the BH/HA method dehydrogenates the alcohol for
a subsequent reaction with a nucleophile, which is then
followed by hydrogenation with the “borrowed” hydrogen,
showing its merits in sustainability, atomic economy, and
environmentally benign.1
To ensure successful BH/HA, popular strategies (Figure 1)
to develop transition-metal catalysts are (1) designing
Scheme 1. General Strategies To Develop Transition-Metal
Catalysts for α-Alkylation of Ketones with Alcohols
Figure 1. Design strategies for BH/HA catalysts.
bifunctional ligands to achieve a bifunctional outer-sphere
metal−ligand cooperation;2 or (2) designing hemilabile ligands
for inner-sphere mechanism.3 However, the incorporations of
additional functional site(s) or hemilabile arm(s) to the ligands
are usually expensive, air-sensitive, and difficult to synthesize at
a large scale, thus impeding their application. Functional-site
activation or ligand dissociation may also lead to reaction-
conditions-sensitive systems with limited scope. In contrast, a
(3) direct outer-sphere strategy with nonbifunctional ligands is
rare in the development of BH/HA. With straightforward
innocent ligands, the alternative direct outer-sphere strategy
should enlarge the panel of BH/HA catalyst design and
facilitate the combinational screening.
Received: August 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03030
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the bifunctional outer-sphere strategy was applied in α-
alkylation of ketones with alcohols by Re systems using
PNHP as a bifunctional ligand,10 and by Ru systems with 2-
hydroxypyridine as the functional moiety.11 Interestingly, a Pd
system with nonbifunctional CN ligands was reported, which
probably promoted the α-alkylation of ketones with alcohols
via the outer-sphere mechanism.12
Scheme 2. Activation Free Energies of the Hydrogenation of
α,β-Unsaturated Ketone for C1, Ca, Cb, and Cc
More recently, non-noble transition metals (such as Fe, Co,
or Mn) have received increasing attention, because they are
more eco-friendly and inexpensive, in addition to their
different reactivity, compared with noble metals.13 Although
encouraging developments have been reported very recently,14
the bifunctional outer-sphere strategy is popularly required to
achieve a successful BH/HA C−C bond formation for non-
noble transition metals (Scheme 1b), associated with
sophisticated bifunctional ligands. In 2015, Darcel and co-
̈
workers reported Knolker-type Fe-catalyzed BH/HA alkylation
of ketones with primary alcohols with the assistance of a
carbonyl functional site.14g In 2016, Beller and co-workers
elegantly developed a manganese-catalyzed α-alkylation of
ketones with primary alcohols, using bifunctional PNHP
ligands.15 In 2017, Zhang and co-workers reported the
cobalt-catalyzed α-alkylation using PNHP as bifunctional
ligands.16 In 2018, the Milstein group reported an effective
Mn(I) phosphorus pincer complexes for the α-alkylation of a
range of ketones with alcohols, involving the (de)-
aromatization bifunctional cooperation.17 A phosphine-free
hydrazone-NNN ligand was developed by Maji and co-worker
for bifunctional Mn-catalyzed alkylations of ketones using
primary alcohols.14f Despite the above developments, to the
best of our knowledge, the nonbifunctional outer-sphere
strategy has not yet been applied in the BH/HA C−C bond
formation, although practical non-noble transition-metal
systems with synthetically straightforward, highly tunable,
innocent ligands are desired.18
Encouraged by the theoretical prediction, precatalysts C1−
C3 with nonbifunctional bis-NHC, NHC-pyridine, and
bipyridine ligands, respectively, were prepared.20 Screening
and reaction optimization were performed, using acetophe-
none (1a) and benzyl alcohol (2a) as model substrates, as
listed in Table 1. C1 with strong σ-donating bis-NHC was the
most effective precatalyst (Table 1, entries 1−4) and NaOH
was superior to other bases with 94% yield (Table 1, entries 5−
11). Solvents other than toluene, such as 1,4-dioxane,
dimethylsulfoxide (DMSO), dimethyl acetamide (DMAc),
dimethyl formamide (DMF), and tert-amyl alcohol (t-
AmOH), proved to be inferior (Table 1, entries 12−16).
Other critical parameters, such as the base concentration,
catalyst loading, and temperature, were also examined (see the
SI). The optimal reaction conditions were demonstrated to be
4 mmol of C1 and 0.5 equiv of NaOH at 110 °C for 2 h (Table
1, entry 17). An inert atmosphere seemed to be important
(Table 1, entry 18). Note that there was no reaction in the
absence of a base, and a reaction in the absence of a manganese
complex led to 3aa in only 14% yield (Table 1, entries 19 and
20). It is very exciting that the C1-catalyzed α-alkylation of
ketone proceeds smoothly at 110 °C within 2 h. The reported
bifunctional systems, such as Ca, Cb, and Cc, usually occurred
at higher temperatures (125−140 °C) and over longer times
(18−24 h).14f,15,17
With the optimized reaction conditions, the substrate scope
was next explored. As shown in Scheme 3, it was found that
electron-rich (OMe, Me) and electron-deficient (Cl, F, CF3)
substituted primary alcohols are converted to corresponding
products in good to excellent yields (3ab−3ae, 3ag−3ai). 4-
Bromobenzyl alcohol furnished 3af in moderate yield (57%).
2-Methylbenzyl alcohol gave 3aj in 95%, but more hindered
(2,6-dimethylphenyl)methanol made the transformation some-
what sluggish (3ak, 57%). 2-Naphthylmethanol and redox-
active ferrocenylmethanol reacted with 1a to 3al−3am in high
yields, 92% and 93%, respectively. Heteroaromatic substrates,
such as thiophene and furan-containing alcohols, were also
efficiently applied to the alkylation of 1a, although in moderate
yields (3an−3ao). Aliphatic alcohols, such as 3-phenyl-
propanol and 1-hexanol, were also tolerated (3ap and 3aq).
Subsequently, various substituted ketones were studied with
benzyl alcohol (2a) (Scheme 3). Electron-donating methyl or
methoxy-substituted aryl ketones were well-tolerated, leading
to desired products (3ba and 3ca) in yields of 85% and 93%,
Herein, we report the first implementation of the outer-
sphere strategy in non-noble-metal catalyzed BH/HA C−C
bond formation (Scheme 1c), using a very simple, inexpensive,
tunable bis-NHC-Mn system, which not only promoted highly
active α-alkylation of ketones with alcohols, but also the
̈
Friedlander annulation to form quinoline derivatives.
To begin our design, we investigated the possible advantage
of the outer-sphere strategy by comparing the hydrogenation
ability of the Mn−H species toward α,β-unsaturated ketone,
which is suggested to be the key step in the BH/HA
process.11,18,19 We are keenly interested in comparing the
nonbifunctional bis-NHC-Mn system (C1) for the outer-
sphere strategy18 with previously reported bifunctional
systems, like PNHP-Mn (Ca),15 PNHArP-Mn (Cb),17 and
NNN-Mn (Cc)14f for the bifunctional strategy (Scheme 2).
Density functional theory (DFT) studies (for detailed
information, see the Supporting Information (SI)) suggest a
significant improvement in the hydrogenation of α,β-
unsaturated ketone for the nonbifunctional outer-sphere
strategy. Hydrogenation transition state C1-TSh in a non-
bifunctional outer-sphere manner has a free energy of only 14.9
kcal mol−1. The low transition-state free energy is mainly due
to the small deformation energy, which indicates the
superiority of the nonbifunctional outer mechanism. The
bifunctional hydrogenation transition states all require one to
overcome relatively higher activation free energies, 22.8, 23.7,
and 26.6 kcal mol−1 for the Ca, Cb, and Cc systems,
respectively.
B
DOI: 10.1021/acs.orglett.9b03030
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Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 3. Scope of α-Alkylation of Ketones with Alcohols
b
catalyst
base
yield
entry
(loading, mol %)
(loading, equiv )
solvent
toluene
(%)
1
2
3
4
5
6
7
8
9
C1 (5)
C2 (5)
C3 (5)
[MnBr(CO)5] (5)
C1 (5)
C1 (5)
C1 (5)
C1 (5)
C1 (5)
KOtBu (0.5)
KOtBu (0.5)
KOtBu (0.5)
KOtBu (0.5)
NaOtBu (0.5)
LiOtBu (0.5)
KOH (0.5)
64
27
31
27
75
trace
81
82
94
49
4
toluene
toluene
toluene
toluene
toluene
toluene
HCsO·H2O (0.5) toluene
NaOH (0.5)
Cs2CO3 (0.5)
K2CO3 (0.5)
NaOH (0.5)
toluene
toluene
toluene
1,4-
dioxane
10
11
12
C1 (5)
C1 (5)
C1 (5)
62
13
14
15
16
17
18
19
20
C1 (5)
C1 (5)
C1 (5)
C1 (5)
C1 (4)
C1 (4)
C1 (4)
−
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
−
DMSO
DMAc
DMF
t-AmOH
toluene
toluene
toluene
toluene
8
25
20
73
95 (91)
79
c
trace
14
a
NaOH (0.5)
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), C1 (4 mol %),
NaOH (50 mol %), toluene (1 mL), at 110 °C for 2 h, isolated yield.
a
Reaction conditions: 1a (0.50 mmol), 2a (0.60 mmol), solvent (1.0
b
mL), at 110 °C for 2 h. Yield determined via gas chromatography
(GC), with 1,4-di-tert-butylbenzene as an internal standard; isolated
yield given in parentheses. Performed in air.
c
ketones with different electronic substituents underwent
smooth annulation reactions delivering the quinolines in yields
of 59%−71% (5aa−5fa). Excitingly, excellent yields observed
when CF3-substituted ketones were utilized (80%−86% yields,
5ga−5ia). These results, together with the results of 3ag−3ai,
3ga−3ia (Scheme 3), indicated that CF3-substituted coupling
partners were well-tolerated. The cross-coupling reactions of 2-
aminobenzyl alcohol with sterically hindered 2-methylaceto-
phenone and 1-acetonaphthone gave satisfactory yields (76%
and 78%), while moderated yield was obtained when using 2,6-
dimethylacetophenone as a substrate (5ja−5la). The use of α-
tetralone as a coupling partner resulted in 5ma in 47% yield.
Heteroaromatic methylketones, such as 2-acetylfuran and 2-
acetylthiophene, reacted with 4a to yield quinolines 5oa and
5pa in 46% and 63% yields, respectively.
Control experiments were performed to shed light on the
mechanism (Scheme 5). The acetophenone and benzaldehyde
gave the α,β-unsaturated ketone smoothly with or without C1
(Scheme 5a) under the optimal conditions, indicating the
involvement of the aldol condensation in our protocol.21 This
enone (3aa′) cannot be reduced without alcohols (Scheme
5b). However, transfer hydrogenation of α,β-unsaturated
ketone could be achieved with 2a or 2g as the hydrogen
sources (see Scheme S2 in the SI). A deuterium labeling
experiment using [α,α-D2]benzyl alcohol (2a−2d) shows
deuterium atoms almost completely distributed in the β-
positions (91% D, Scheme 5c), instead of the α-position
respectively. Electron-withdrawing substituted ketones, such as
F, Cl, and Br, led to a slight decrease in efficiency (3da−3fa;
see Scheme 3). Interestingly, the CF3 substituted ketones gave
corresponding products in high yields (82%−88%, 3ga−3ia).
Sterically hindered 2-methylacetophenone, 1-acetonaphthone,
and 2,6-dimethylacetophenone were compatible, generating
3ja, 3ka, and 3la in yields of 90%, 87%, and 94%, respectively.
A cyclic substrate 3m with a secondary α-carbon atom was also
functionalized to afford product 3ma in 89% yield.
Heterocyclic ketones containing pyridine, thiophene, and
furyl moieties also showed reactivities (38%−52%, 3na−3pa).
More challenging bulky coupling partners were also compatible
(3lj, 3lk, and 3jk; 91%, 55%, and 54%, respectively). The
reactions are more sensitive to the steric hindrance of benzyl
alcohols. For example, 2,6-dimethylacetophenone successfully
coupled with benzyl alcohol and sterically demanding 2-
methylbenzyl alcohol, leading to 94% and 91% yields,
respectively (3la, 3lj). However, moderate yields were
obtained when (2,6-dimethylphenyl)methanol was used (3ak,
3lk, and 3jk).
Subsequently, we were motivated to investigate the
applicability of C1 for the α-alkylation of ketones to the
̈
syntheses of quinoline derivatives via the Friedlander
annulation reaction. As shown in Scheme 4, various aryl
C
DOI: 10.1021/acs.orglett.9b03030
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a
Based on the above results and literature prece-
dents,14f,18,21,22 a direct outer-sphere mechanism is presented
in Scheme 6. The catalytic cycle involves three major stages:
̈
Scheme 4. Scope of the Friedlander Quinoline Synthesis
Scheme 6. Plausible Reaction Mechanism
a
Reaction conditions: 1 (0.5 mmol), 4a (0.6 mmol), C1 (4 mol %),
NaOH (50 mol %), toluene (1 mL), at 110 °C for 2 h, isolated yield.
(1) the dehydrogenation of alcohol, (2) the aldol con-
densation, and (3) the hydrogenation of α,β-unsaturated
ketone. Density functional theory (DFT) investigation (see
Figure S1 in the SI) suggests that the reactive intermediate C1-
1 promotes the hydride elimination through transition state
C1-TSd (12.2 kcal/mol) via an outer-sphere manner without
the dissociation of CO ligands,18 liberating an aldehyde and
the [Mn−H] species. The enone then could be reduced by the
[Mn−H] species through transition state C1-TSh (14.9 kcal/
mol). Note that the hydride elimination step could be
facilitated by an extra protic molecule (byproduct H2O).18
However, unlike the room-temperature N-alkylation, the C-
alkylation required higher temperature, probably because of
the weak coordination ability of ketones, compared to amines.
We further evaluated the reaction in protic solvent t-AmOH
(Table S1 in the SI), which is inferior to toluene. These results
indicated that, besides the protic property, the solubility and
dielectric constant of the solvent will also influence the kinetics
and thermodynamics of the reaction. The formation of [Mn−
H] species was confirmed by 1H NMR spectroscopy (1H NMR
= −6.48 ppm; see the SI).
a
Scheme 5. Control Experiments
In summary, we have successfully utilized the unusual
nonbifunctional outer-sphere strategy in developing an efficient
manganese-catalyzed direct α-alkylation of ketones with
alcohols through BH/HA method. This protocol is not only
effective for the C−C bond formation between a variety of
ketones and alcohols, but also is applicable in the catalytic
a
Isolated yields.
̈
Friedlander annulation reactions. This easily accessible and
(Scheme 5d). These results imply the possibility of a different
pathway from the previously observed prevalence of an NH-
assisted bifunctional outer-sphere mechanism.15 It also
indicates that the dehydrogenation of deuteride should be
suppressed. A parallel experiment revealed a kH/kD value of
1.56 (see Scheme 5e), indicating that the dissociation of the α-
C−H bond in benzylic alcohol may not be involved in the rate-
determining step. The hydrogenation step or the aldol
condensation step might be the slowest step in our reaction
conditions.
phosphine-free system shows advantages of the nonbifunc-
tional outer-sphere strategy in catalyst design for acceptorless
dehydrogenative transformations.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03030.
■
S
D
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(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kezhf3@mail.sysu.edu.cn (Z. Ke).
*E-mail: yanliu@gdut.edu.cn (Y. Liu).
ORCID
Xiao-Bing Lan: 0000-0001-5301-069X
Ming Huang: 0000-0001-8597-8259
Yan Liu: 0000-0002-3864-1992
Zhuofeng Ke: 0000-0001-9064-8051
Author Contributions
§These authors contributed equally (X.-B.L. (exp.), Z.Y.
(comput.)).
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (Nos. 21973113,
21673301, 21977019), the Guangdong Natural Science Funds
for Distinguished Young Scholar (No. 2015A030306027), the
Tip-top Youth Talents of Guangdong Special Support Program
(No. 20153100042090537), and the Fundamental Research
Funds for the Central Universities.
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