Manganese-Catalyzed Regioselective Dehydrogenative C-versus N-Alkylation Enabled by a Solvent Switch: Experiment and Computation

Article abstract of DOI:10.1021/acs.orglett.0c01270

The first base metal-catalyzed regioselective dehydrogenative alkylation of indolines using readily available alcohols as the alkylating reagent is reported. A single air-and moisture-stable manganese catalyst provides access to either C3-or N-alkylated indoles depending on the solvent used. Mechanistic studies indicate that the reaction takes place through a combined acceptorless dehydrogenation and hydrogen autotransfer strategy.

Full text of DOI:10.1021/acs.orglett.0c01270

pubs.acs.org/OrgLett
Letter
Manganese-Catalyzed Regioselective Dehydrogenative C- versus
N‑Alkylation Enabled by a Solvent Switch: Experiment and
Computation
Jannik C. Borghs, Viktoriia Zubar, Luis Miguel Azofra, Jan Sklyaruk, and Magnus Rueping*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01270
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The first base metal-catalyzed regioselective dehy-
drogenative alkylation of indolines using readily available alcohols
as the alkylating reagent is reported. A single air- and moisture-
stable manganese catalyst provides access to either C3- or N-
alkylated indoles depending on the solvent used. Mechanistic
studies indicate that the reaction takes place through a combined
acceptorless dehydrogenation and hydrogen autotransfer strategy.
ndoles represent a prominent and important chemical motif
hydride addition/dehydrogenation sequence via the N-
alkylated product H (Scheme 1). On the basis of our interest
in the area of base metal catalysis,9,11 we decided to investigate
a manganese-catalyzed dehydrogenative alkylation of indolines
using readily available alcohols as alkylating reagents. To the
best of our knowledge, a single base metal complex catalyzing
both the AD of amines and the HA of alcohols in one protocol
is not known. Beyond that, no manganese-catalyzed amine
dehydrogenation has been reported so far. We here describe
the development of a regioselective dehydrogenative alkylation
using a single manganese catalyst and report an interesting
solvent switch that allows a targeted N- versus C-functionaliza-
tion (Scheme 1).
We commenced our investigations with the evaluation of
different Mn complexes as catalysts for the dehydrogenative
coupling of indoline (1a) using benzyl alcohol (2a) in the
presence of a base to give either C3- or N-alkylated indoles 3a
and 4a or N-alkylated indoline 5a as the product (Table 1).
Inspired by our latest results in dehydrogenative coupling
protocols, we initially tested different bifunctional Mn(I)
complexes. Mn-1, which includes a PNN-pyridyl-based
scaffold, remained unreactive in the presence of 60 mol %
KOtBu (Table 1, entry 1). Also, the pyridyl-based PNP
complex Mn-2 provided only trace amounts of 3a (Table 1,
entry 2). Interestingly, the NH-bridged PNP (Macho)
complex Mn-3 showed reactivity and the product 3a was
selectively obtained in moderate yield (Table 1, entry 3).
1
Iin medicinal chemistry and agrochemistry. Several drugs
like oxypertine, bufotenine, or indomethacin include this
heterocyclic scaffold.2 In the past several years, the selective
functionalization of indoles has attracted considerable
attention.3 One of the most common methods for alkylating
indoles at the C3 position is the Lewis acid-catalyzed Friedel−
Crafts reaction using alkyl halides.4 However, due to the
generation of substantial amounts of inorganic salts and the use
of mutagenic (pseudo)haloalkanes, it remains a wasteful and
unsustainable approach. In this regard, abundant alcohols have
emerged as cheap and environmentally benign building blocks
for C−C and C−N bond formation, following acceptorless
dehydrogenation (AD) and hydrogen autotransfer (HA)
reaction strategies.5 However, a lack of regioselectivity is
observed for most of the recent methods that apply the
dehydrogenative coupling protocol for indoles, and these
approaches typically functionalize at the indole C3-6 or N-
position.7 However, accessing both regioisomers with a single
catalyst by omitting noble metals8,9 and additional oxidants
remains challenging,10 and to date, no procedure applying a
base metal-catalyzed regio- and chemoselective alkylation of
indoles or indolines has been reported. The regioselective
alkylation with a single catalyst is rather challenging as several
reactions involving a hydrogen autotransfer (HA) or accept-
orless dehydrogenation (AD) need to be catalyzed by the same
catalyst in a chemoselective manner: (i) the dehydrogenation
of an alcohol A to provide an aldehyde B, which can either
react with indole D to give the corresponding imine E or react
with indoline C to give the iminium ion G resulting in either a
C- or an N-alkylated product; (ii) the dehydrogenative
aromatization of indoline C to provide indole D; (iii) the
selective 1,4-reduction of E to give the C3-alkylated indole F,
and (iv) the formation of N-alkylated product I through an
isomerization/deprotonation of G or alternatively through a
Received: April 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01270
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Dehydrogenative Alkylation of Indolines
Table 1. Optimization of the Reaction Conditions
yield (%),
entry
catalyst
Mn-1
Mn-2
base
KOtBu
solvent
Tol
3a:4a:5a
1
2
3
4
5
6
7
8
9
2:0:0
7:0:0
56:0:0
10:0:0
8:0:0
63:0:0
5:0:0
47:0:0
98:0:0
80:0:0
7:0:0
49:1:2
29:2:1
0:1:2
0:41:9
19:26:20
0:68:6
0:98:0
−
KOtBu
KOtBu
KOtBu
KOtBu
Cs2CO3
K2CO3
NaH
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Mn-3
Mn-4
Mn-5
Mn-3
Mn-3
Mn-3
Mn-3
Mn-3
Mn-3
Mn-3
Mn-3
Mn-3
Mn-3
Ru-1
b
b
b
b
Surprisingly, the PNP analogue Mn-4 provided only low
conversion (Table 1, entry 4). Furthermore, N-methylated
Mn-5 yielded trace amounts of product, illustrating the
necessity of the NH moiety (Table 1, entry 5).12 To further
optimize the reaction conditions with Mn-3, different bases
and solvents were evaluated (Table 1, entries 6−18). With
cesium bases, such as Cs2CO3 or CsOH·H2O, with toluene as
the solvent, and with 1 mol % catalyst, the yields considerably
increased to 63% and 98% (Table 1, entries 6 and 9,
respectively). Decreasing the temperature by 10 °C reduced
the yield significantly (Table 1, entry 10). The best results
were obtained when 1 mol % Mn-3 was employed with 10 mol
% CsOH·H2O in toluene (Table 1, entry 9). Conversely, with
a chance in the solvent from apolar aprotic, such as toluene or
ethers, to polar protic, such as 2,2,2-trifluoroethanol (TFE), a
complete selectivity switch was observed (Table 1, entries 11−
15). In fact, only N-alkylated indole 4a and indoline 5a were
obtained in the absence of 3a, when TFE was applied (Table 1,
entry 15). Surprisingly, no other polar protic solvents such as
tert-amyl alcohol and hexafluoroisopropanol (HFIP) afforded
equally good results (Table 1, entries 13 and 14, respectively).
Interestingly, switching the metal source from Mn to Ru
resulted in a mixture of all three products (Table 1, entry 16).
Using a mixture of TFE and toluene reduced the amount of
undesired alkylated indoline 5a (Table 1, entry 17). Finally,
increasing the dilution and decreasing the amount of base to
10 mol % and alcohol to 1.5 equiv, we obtained the alkylated
indole 4a in excellent yield and remarkable selectivity (Table 1,
entry 18). In the absence of base, PNP ligand, or Mn-3, no
conversion was observed (Table 1, entries 19−21). With our
optimized conditions in hand, we subsequently explored the
substrate scope for the regioselective coupling of different
indolines and alcohols (Scheme 2).
CsOH·H2O Tol
CsOH·H2O Tol
b,c
10
11
12
13
14
15
16
17
18
19
20
21
CsOH·H2O 1,4-dioxane
CsOH·H2O CPME
CsOH·H2O t-AmOH
CsOH·H2O HFIP
CsOH·H2O TFE
CsOH·H2O TFE
CsOH·H2O 2:1 TFE/Tol
CsOH·H2O 2:1 TFE/Tol
Mn-3
Mn-3
Mn-3
Mn(CO)5Br
−
d
e
−f
−
TFE or Tol
e
e
,g
CsOH·H2O TFE or Tol
CsOH·H2O TFE or Tol
−
−
a
Reaction conditions: 1a (0.2 mmol) and 2a (0.4 mmol) in toluene
(1.0 M) at 135 °C for 20 h under an argon atmosphere. Yields were
determined by GC analysis using ethylbenzene (0.2 mmol) as an
internal standard. Abbreviations: Tol, toluene; CPME, cyclopentyl
methyl ether; t-AmOH, tert-amyl alcohol; HFIP, 1,1,1,3,3,3-
hexafluoro-2-propanol; TFE, 2,2,2-trifluoroethanol. With 1 mol %
Mn. At 125 °C. For a 0.17 M reaction mixture. With 10 mol %
b
c
d
e
f
g
base, 1.5 equiv of benzyl alcohol. With a 36 h reaction time. With 5
mol % Mn.
details). Initially, the dehydrogenative C3-alkylation was
investigated (Scheme 2a). Subjecting unsubstituted indoline
1a to the standard conditions using simple benzylic alcohols
furnished alkylated indoles 3a−c in good yields. Electron-
donating and electron-withdrawing groups on the aromatic
ring, regardless of their position, were tolerated, and the
desired products 3d−g were obtained in good yields,
demonstrating that the steric hindrance of the substituents
has no significant effect on the yield. Likewise, an alcohol
bearing a heterocycle such as pyridine could also be used as the
coupling partner (3h). Primary aliphatic alcohols were also
successfully applied as alkylating reagents, affording the
Notably, all indoline starting materials were synthesized by a
novel Mn-3-catalyzed hydrogenation protocol starting from
the corresponding indoles (see the Supporting Information for
B
https://dx.doi.org/10.1021/acs.orglett.0c01270
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Manganese-Catalyzed Dehydrogenative C3- and N-Alkylation of Indolines
a
All yields refer to the isolated products. Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), CsOH·H2O (0.3 mmol), and Mn-3 (1 mol %) in
b
toluene (0.5 mL) at 135 °C for 20 h. All yields refer to the isolated products. Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), CsOH·H2O
c
d
(0.03 mmol), and Mn-3 (3 mol %) in toluene (0.6 mL) and TFE (1.2 mL) at 135 °C for 36 h. Reaction on a 1 mmol scale. With a 48 h reaction
e
f
time and 4 mol % Mn-3. With 0.3 mL of i-PrOH. N-Bu indoline observed as the byproduct.
corresponding indoles 3i−l in good yields. Gratifyingly,
secondary alcohols such as norbonyl or isopropyl alcohol,
which are less prone to undergoing condensation and
hydrogenations,6i,13 were also used as suitable coupling
partners, and the corresponding indoles 3m and 3n were
obtained in moderate to good yields. To demonstrate the
general applicability of the reaction, benzyl alcohol (2a) was
coupled with a variety of substituted indolines providing the
desired products 3o−r in good to excellent yields.
Next, we investigated the substrate scope for the
dehydrogenative N-alkylation of indolines (Scheme 2b).
Under the optimized reaction conditions, several benzylic
alcohols were converted into the corresponding products 4a−c
in good yields. Electron-rich or electron-deficient alcohols were
tolerated as well and used efficiently as coupling partners to
give 4d−g in high yields. Notably, heterocyclic alcohols
bearing pyridine or thiophene moieties were successfully
employed as alkylating reagents (4h and 4i). In addition, this
transformation could be further extended to halide- and
methoxide-substituted indolines, and the corresponding N-
benzyl-substituted indoles 4j−l were obtained in good yields.
Moreover, also aliphatic alcohols appeared to be suitable
coupling partners. As such, N-butyl indole was converted,
although in a lower yield (4m). However, N-alkylated indoline
4n could be also obtained as the main product, indicating an
impeded dehydrogenation of the alkylated indoline or
isomerization of the corresponding enamine intermediate. To
better understand the reactions, several experiments were
performed to investigate the formation of related intermediates
and the mechanism in general (Scheme 3). The catalytic
indoline dehydrogenation occurs in toluene, providing indole
in quantitative yield (Scheme 3a).
However, minor conversion was observed when TFE was
added as a co-solvent. Interestingly, N-benzyl indoline could
not be dehydrogenated under the optimized conditions,
indicating an alternative mechanism for the N-alkylation
(Scheme 3b). Moreover, we anticipated aldehydes and ketones
to be crucial intermediates.
Evidently, the coupling of indoline and benzaldehyde
afforded a mixture of C3- and N-alkylated products in toluene,
suggesting that the initial dehydrogenation of indoline is
critical for the regioselectivity (Scheme 3c). However, upon
addition of TFE, both high conversion and regioselectivity
were observed and the N-alkylated indole 4a was obtained
along with traces of indoline 5a. To further prove the necessity
of indole as an intermediate for the C3-alkylation, we carried
out the alkylation reaction with benzylalcohol (2a). Indeed,
when the reaction was performed in toluene, C3-alkylated
indole 3a was provided as the sole product, highlighting
flexibility of the developed procedure. Importantly, upon
addition of TFE, only traces of the product were observed
(Scheme 3c). To further understand the mechanism of the N-
C
https://dx.doi.org/10.1021/acs.orglett.0c01270
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 3. Mechanistic Studies for the Divergent Alkylation
of Indoline
Figure 1. Proposed mechanism for the divergent dehydrogenative
alkylation of indolines involving acceptorless dehydrogenation (AD)
and hydrogen autotransfer (HA). The proton abstraction by OH−
leading to the aromatized 1-butyl-1H-indole (4m) has been
computed as a barrierless process.
a
With 10 mol % CsOH·H2O.
alkylation, we performed a control reaction to exclude a base-
catalyzed isomerization/deprotonation of the iminium inter-
mediate. Thus, indolium triflate salt 4a-OTf was reacted with
CsOH·H2O (Scheme 3d). However, only traces of product 4a
were formed. This result implies that the Mn catalyst is
involved in the process that would occur via an imine
hydrogenation, indoline dehydrogenation sequence. On the
basis of these results, we propose the following reaction
mechanism for the regioselective dehydrogenative alkylation of
indolines (Figure 1).
Initially, Mn-3 reacts with CsOH to generate the active Mn
catalyst, which subsequently dehydrogenates the alcohol to the
corresponding aldehyde. In toluene, the catalyst additionally
converts indoline 1a to indole 1a′ and releases hydrogen gas in
an acceptorless dehydrogenation (AD) manner. Next, 1a′ and
the aldehyde react to form intermediate 6, which is then
transformed to the final product 3 by the Mn−H2 species
[hydrogen autotransfer (HA)]. In contrast, no dehydrogen-
ation of indoline 1a occurs in the presence of TFE. Thus, the
N-alkylation pathway occurs via the formation of indolinium
species 7.
The corresponding and more stable enamine 5 can be
observed as a side product. Upon the release of hydrogen gas,
the Mn* catalyst is regenerated again. The final product 4 is
then provided by isomerization/deprotonation of 7. To
understand this process, we conducted computational studies
to shed light on the mechanism for the N-alkylation. Under
basic conditions, an indolinium cation is formed. For the
specific case of 1-butyl-3H-indol-1-inium (see Figure 2), the
18-electron Mn−H2 species (A) acts as the hydride-borrowing
catalyst. The free activation barrier for the hydride transfer
from Mn to C1 has been calculated as 17.7 kcal mol−1
Figure 2. Reaction mechanism for the isomerization of 1-
butylideneindolin-1-inium into 1-butyl-3H-indol-1-inium via Mn-
catalyzed hydride borrowing. Free energy results (1 atm, 135 °C,
kcal mol−1) are shown at the PBE0/SVP level of theory with TFE (ε
= 26.726) as the solvent. R refers to C2H5.
[TS(AB)] under 1 atm and 135 °C in TFE. Thus, 1-
butylindoline is formed (B, −8.3 kcal mol−1) with the Mn(I)
species being oxidized into a Mn(II) species. State C (−8.8
kcal mol−1) represents a conformational minimum with the
hydride on C2 (five-membered ring) ready to be transferred
back to the Mn catalyst. This process, characterized by
TS(CA), shows a free activation barrier of 13.7 kcal mol−1
(22.5 kcal mol−1 relative to C) and represents the rate-limiting
D
https://dx.doi.org/10.1021/acs.orglett.0c01270
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
step of this cycle. Thus, the 1-butyl-3H-indol-1-inium cation is
produced, and the 18-electron Mn−H2 species is regenerated.
To rationalize the influence of TFE on the remarkable
selectivity switch, we conducted further solvent screenings (see
the Supporting Information). It was found that no other
solvents with a lower or higher pKa compared to that of TFE
(12.37) could provide similar conversion and selectivity. TFE
has been shown to accelerate condensation reactions through
hydrogen-bonding activation,14 indicating that the fast
condensation of indoline and the aldehyde is key for the
selective N-alkylation reaction. Furthermore, recent computa-
tional studies by Poater showed that polar protic solvents help
to facilitate the β-hydride elimination during an acceptorless
alcohol dehydrogenation process (AAD).15
In summary, we have developed a new base metal-catalyzed
regioselective dehydrogenative alkylation of indolines with
readily available alcohols by applying a single manganese
catalyst. This catalyst can catalyze the dehydrogenation of both
alcohols and indolines as well as the selective 1,2- and 1,4-
reduction of imines using either acceptorless dehydrogenation
(AD) and hydrogen autotransfer (HA) pathways or both
processes. Additionally, we demonstrate that the selective N-
or C-alkylation can be achieved by an interesting solvent
polarity and acidity switch.
ACKNOWLEDGMENTS
■
This work was financially supported by the King Abdullah
University of Science and Technology (KAUST), Saudi
Arabia, Office of Sponsored Research (FCC/1/1974). We
thank KAUST Supercomputing Laboratory for use of the
supercomputer Shaheen II and providing the computational
resources.
REFERENCES
■
(1) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(b) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970. (c) Somei, M.; Yamada, F. Simple indole alkaloids and
those with a non-rearranged monoterpenoid unit. Nat. Prod. Rep.
2005, 22, 73−103.
(2) Sravanthi, T. V.; Manju, S. L. Indoles - A promising scaffold for
drug development. Eur. J. Pharm. Sci. 2016, 91, 1−10.
(3) Selected examples: (a) Bandini, M.; Eichholzer, A. Catalytic
Functionalization of Indoles in a New Dimension. Angew. Chem., Int.
Ed. 2009, 48, 9608−9644. (b) Leitch, J. A.; Bhonoah, Y.; Frost, C. G.
Beyond C2 and C3: Transition-Metal-Catalyzed C−H Functionaliza-
tion of Indole. ACS Catal. 2017, 7, 5618−5627. (c) Chen, J.; Wu, J.
Transition-Metal-Free C3 Arylation of Indoles with Aryl Halides.
Angew. Chem., Int. Ed. 2017, 56, 3951−3955. (d) Hu, Y.-C.; Ji, D.-W.;
Zhao, C.-Y.; Zheng, H.; Chen, Q.-A. Catalytic Prenylation and
Reverse Prenylation of Indoles with Isoprene: Regioselectivity
Manipulation through Choice of Metal Hydride. Angew. Chem., Int.
Ed. 2019, 58, 5438−5442.
(4) (a) Bandini, M.; Umani-Ronchi, A. Catalytic Asymmetric Friedel-
Crafts Alkylations; Wiley-VCH: Weinheim, Germany, 2009. (b) Ruep-
ing, M.; Nachtsheim, B. J. A review of new developments in the
Friedel−Crafts alkylation − From green chemistry to asymmetric
catalysis. Beilstein J. Org. Chem. 2010, 6, 6.
(5) Selected reviews: (a) Irrgang, T.; Kempe, R. 3d-Metal Catalyzed
N- and C-Alkylation Reactions via Borrowing Hydrogen or Hydrogen
Autotransfer. Chem. Rev. 2019, 119, 2524−2549. (b) Crabtree, R. H.
Homogeneous Transition Metal Catalysis of Acceptorless Dehydro-
genative Alcohol Oxidation: Applications in Hydrogen Storage and to
Heterocycle Synthesis. Chem. Rev. 2017, 117, 9228−9246. (c) Yang,
Q.; Wang, Q.; Yu, Z. Substitution of alcohols by N-nucleophiles via
transition metal-catalyzed dehydrogenation. Chem. Soc. Rev. 2015, 44,
2305−2329. (d) Huang, F.; Liu, Z.; Yu, Z. C-Alkylation of Ketones
and Related Compounds by Alcohols: Transition-Metal-Catalyzed
Dehydrogenation. Angew. Chem., Int. Ed. 2016, 55, 862−875.
(e) Gunanathan, C.; Milstein, D. Applications of acceptorless
dehydrogenation and related transformations in chemical synthesis.
Science 2013, 341, 1229712. (f) Choi, J.; MacArthur, A. H. R.;
Brookhart, M.; Goldman, A. S. Dehydrogenation and Related
Reactions Catalyzed by Iridium Pincer Complexes. Chem. Rev.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01270.
Experimental data, including characterization data for all
new compounds, NMR spectra, and computational
details (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Magnus Rueping − Institute of Organic Chemistry, RWTH
Aachen University, 52074 Aachen, Germany; KAUST Catalysis
Center (KCC), KAUST, Thuwal 23955-6900, Saudi Arabia;
orcid.org/0000-0003-4580-5227;
Email: magnus.rueping@kaust.edu.sa
Authors
Jannik C. Borghs − Institute of Organic Chemistry, RWTH
Aachen University, 52074 Aachen, Germany
́
2011, 111, 1761−1779. (g) Guillena, G.; Ramon, D. J.; Yus, M.
Viktoriia Zubar − Institute of Organic Chemistry, RWTH
Aachen University, 52074 Aachen, Germany; KAUST Catalysis
Center (KCC), KAUST, Thuwal 23955-6900, Saudi Arabia
Luis Miguel Azofra − CIDIA-FEAM (Unidad Asociada al
Hydrogen Autotransfer in the N-Alkylation of Amines and Related
Compounds using Alcohols and Amines as Electrophiles. Chem. Rev.
2010, 110, 1611−1641.
(6) (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. Pd-
Catalyzed C3-Selective Allylation of Indoles with Allyl Alcohols
Promoted by Triethylborane. J. Am. Chem. Soc. 2005, 127, 4592−
4593. (b) Whitney, S.; Grigg, R.; Derrick, A.; Keep, A. [Cp*IrCl2]2-
Catalyzed Indirect Functionalization of Alcohols: Novel Strategies for
the Synthesis of Substituted Indoles. Org. Lett. 2007, 9, 3299−3302.
(c) Hikawa, H.; Suzuki, H.; Azumaya, I. Au(III)/TPPMS-Catalyzed
Benzylation of Indoles with Benzylic Alcohols in Water. J. Org. Chem.
2013, 78, 12128−12135. (d) Siddiki, S. M. A. H.; Kon, K.; Shimizu,
K.-I. General and Selective C-3 Alkylation of Indoles with Primary
Alcohols by a Reusable Pt Nanocluster Catalyst. Chem. - Eur. J. 2013,
́
Consejo Superior de Investigaciones Cientificas, CSIC, avalada
por el Instituto de Ciencia de Materiales de Sevilla, Universidad
de Sevilla), Instituto de Estudios Ambientales y Recursos
Naturales (i-UNAT), Universidad de Las Palmas de Gran
Canaria (ULPGC), 35017 Las Palmas de Gran Canaria,
Spain; orcid.org/0000-0003-4974-1670
Jan Sklyaruk − Institute of Organic Chemistry, RWTH Aachen
University, 52074 Aachen, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01270
́
19, 14416−14419. (e) Cano, R.; Yus, M.; Ramon, D. J. Environ-
mentally friendly and regioselective C3-alkylation of indoles with
alcohols through a hydrogen autotransfer strategy. Tetrahedron Lett.
2013, 54, 3394−3397. (f) Putra, A. E.; Takigawa, K.; Tanaka, H.; Ito,
Y.; Oe, Y.; Ohta, T. Regioselective Synthesis of 3-Alkylindoles
Notes
The authors declare no competing financial interest.
E
https://dx.doi.org/10.1021/acs.orglett.0c01270
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Mediated by Zinc Triflate. Eur. J. Org. Chem. 2013, 2013, 6344−6354.
(g) Bartolucci, S.; Mari, M.; Bedini, A.; Piersanti, G.; Spadoni, G.
Iridium-Catalyzed Direct Synthesis of Tryptamine Derivatives from
Indoles: Exploiting N-Protected β-Amino Alcohols as Alkylating
Agents. J. Org. Chem. 2015, 80, 3217−3222. (h) Weiss, M.; Peters, R.
Catalytic Direct Dehydrogenative Cross-Couplings of C−H (Pro)-
Nucleophiles and Allylic Alcohols without an Additional Oxidant.
ACS Catal. 2015, 5, 310−316. (i) Di Gregorio, G.; Mari, M.;
Bartoccini, F.; Piersanti, G. Iron-Catalyzed Direct C3-Benzylation of
Indoles with Benzyl Alcohols through Borrowing Hydrogen. J. Org.
Chem. 2017, 82, 8769−8775. (j) Polidano, K.; Allen, B. D. W.;
Williams, J. M. J.; Morrill, L. C. Iron-Catalyzed Methylation Using the
Borrowing Hydrogen Approach. ACS Catal. 2018, 8, 6440−6445.
(k) Motokura, K.; Nakagiri, N.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
Nucleophilic Substitution Reactions of Alcohols with Use of
Montmorillonite Catalysts as Solid Brønsted Acids. J. Org. Chem.
2007, 72, 6006−6015.
Methanol. Angew. Chem., Int. Ed. 2019, 58, 775−779. (e) Matador,
E.; Brzozowska, A.; El-Sepelgy, O.; Rueping, M. C-Alkylation of
Secondary Alcohols with Primary Alcohols through Manganese
Catalyzed Double Hydrogen Autotransfer. ChemSusChem 2019, 12,
3099−3102. (f) Jang, Y. K.; Kruckel, T.; Rueping, M.; El-Sepelgy, O.
̈
Sustainable Alkylation of Unactivated Esters and Amides with
Alcohols Enabled by Manganese Catalysis. Org. Lett. 2018, 20,
7779−7783. (g) Zubar, V.; Lebedev, Y.; Azofra, L. M.; Cavallo, L.; El-
Sepelgy, O.; Rueping, M. Hydrogenation of CO2 -Derived Carbonates
and Polycarbonates to Methanol and Diols by Metal-Ligand
Cooperative Manganese Catalysis. Angew. Chem., Int. Ed. 2018, 57,
13439−13443. (h) Wang, C.; Maity, B.; Cavallo, L.; Rueping, M.
Manganese catalyzed regioselective C-H alkylation of heteroarenes:
Experiment and Computation. Org. Lett. 2018, 20, 3105−3108.
(i) Wang, C.; Rueping, M. Rhenium and Manganese-Catalyzed
Selective Alkenylation of Indoles. ChemCatChem 2018, 10, 2681−
2685. (j) Brzozowska, A.; Azofra, L. M.; Zubar, V.; Atodiresei, I.;
Cavallo, L.; Rueping, M.; El-Sepelgy, O. Highly Chemo- and
Stereoselective Transfer Semihydrogenation of Alkynes Catalyzed
by a Stable, Well-defined Manganese(II) Complex. ACS Catal. 2018,
8, 4103−4109. (k) Wang, C.; Wang, A.; Rueping, M. Manganese
catalyzed C-H functionalizations involving an unexpected heteroaryl-
shift. Angew. Chem., Int. Ed. 2017, 56, 9935−9938.
̈
(7) (a) Bahn, S.; Imm, S.; Mevius, K.; Neubert, L.; Tillack, A.;
Williams, J. M. J.; Beller, M. Selective ruthenium-catalyzed N-
alkylation of indoles by using alcohols. Chem. - Eur. J. 2010, 16,
3590−3593. (b) Siddiki, S. M. A. H.; Kon, K.; Shimizu, K.-I. Selective
N-alkylation of indoles with primary alcohols using a Pt/HBEA
catalyst. Green Chem. 2015, 17, 173−177. (c) Wang, Z.; Zeng, H.; Li,
C.-J. Dearomatization−Rearomatization Strategy for Reductive Cross-
Coupling of Indoles with Ketones in Water. Org. Lett. 2019, 21,
2302−2306. (d) De Angelis, F.; Grasso, M.; Nicoletti, R. N-Alkylation
of Indole with Secondary Alcohols. Synthesis 1977, 1977, 335−336.
(8) (a) Bullock, R. M. Catalysis without Precious Metals; Wiley-VCH:
Weinheim, Germany, 2010. (b) Plietker, B. Iron Catalysis in Organic
Chemistry: Reactions and Applications, 2nd ed.; Wiley-VCH;
Weinheim, Germany, 2008.
(9) For recent reviews, see: (a) Gorgas, N.; Kirchner, K.
Isoelectronic Manganese and Iron Hydrogenation/Dehydrogenation
Catalysts: Similarities and Divergences. Acc. Chem. Res. 2018, 51,
1558−1569. (b) Filonenko, G. A.; van Putten, R.; Hensen, E. J. M.;
Pidko, E. A. Catalytic (de)hydrogenation promoted by non-precious
metals − Co, Fe and Mn: recent advances in an emerging field. Chem.
Soc. Rev. 2018, 47, 1459−1483. (c) Kallmeier, F.; Kempe, R.
Manganese Complexes for (De)Hydrogenation Catalysis: A Compar-
ison to Cobalt and Iron Catalysts. Angew. Chem., Int. Ed. 2018, 57,
46−60. (d) Zell, T.; Langer, R. From Ruthenium to Iron and
Manganese-A Mechanistic View on Challenges and Design Principles
of Base-Metal Hydrogenation Catalysts. ChemCatChem 2018, 10,
1930−1940. (e) Maji, B.; Barman, M. K. Recent Developments of
Manganese Complexes for Catalytic Hydrogenation and Dehydrogen-
ation Reactions. Synthesis 2017, 49, 3377−3393. (f) Garbe, M.; Junge,
K.; Beller, M. Homogeneous Catalysis by Manganese-Based Pincer
Complexes. Eur. J. Org. Chem. 2017, 2017, 4344−4362. (g) Liu, W.;
Ackermann, L. Manganese-Catalyzed C−H Activation. ACS Catal.
2016, 6, 3743−3752. (h) Mukherjee, A.; Milstein, D. Homogeneous
Catalysis by Cobalt and Manganese Pincer Complexes. ACS Catal.
2018, 8, 11435−11469. (i) Valyaev, D. A.; Lavigne, G.; Lugan, N.
Manganese organometallic compounds in homogeneous catalysis:
Past, present, and prospects. Coord. Chem. Rev. 2016, 308, 191−235.
(10) Jiang, X.; Tang, W.; Xue, D.; Xiao, J.; Wang, C. Divergent
Dehydrogenative Coupling of Indolines with Alcohols. ACS Catal.
2017, 7, 1831−1835.
(12) For reviews of metal−ligand cooperative catalysis, see:
(a) Khusnutdinova, R.; Milstein, D. Metal−Ligand Cooperation.
Angew. Chem., Int. Ed. 2015, 54, 12236−12273. (b) Luca, O. R.;
Crabtree, R. H. Redox-active ligands in catalysis. Chem. Soc. Rev.
2013, 42, 1440−1459. (c) Lyaskovskyy, V.; de Bruin, B. Redox Non-
Innocent Ligands: Versatile New Tools to Control Catalytic
Reactions. ACS Catal. 2012, 2, 270−279.
(13) (a) Akhtar, W. M.; Cheong, C. B.; Frost, J. R.; Christensen, K.
E.; Stevenson, N. G.; Donohoe, T. J. Hydrogen Borrowing Catalysis
with Secondary Alcohols: A New Route for the Generation of β-
Branched Carbonyl Compounds. J. Am. Chem. Soc. 2017, 139, 2577−
2580. (b) Thiyagarajan, S.; Gunanathan, C. Catalytic Cross-Coupling
of Secondary Alcohols. J. Am. Chem. Soc. 2019, 141, 3822−3827.
(14) (a) Berkessel, A.; Adrio, J. A.; Huttenhain, D.; Neudorfl, J. M. J.
̈
̈
Am. Chem. Soc. 2006, 128, 8421−8426. (b) Shuklov, I. A.; Dubrovina,
̈
N. V.; Borner, A. Fluorinated Alcohols as Solvents, Cosolvents and
Additives in Homogeneous Catalysis. Synthesis 2007, 2007, 2925−
2943.
(15) Masdemont, J.; Luque-Urrutia, J. A.; Gimferrer, M.; Milstein,
D.; Poater, A. Mechanism of Coupling of Alcohols and Amines To
Generate Aldimines and H2 by a Pincer Manganese Catalyst. ACS
Catal. 2019, 9, 1662−1669.
(11) (a) Borghs, J. C.; Tran, M. A.; Sklyaruk, J.; Rueping, M.; El-
Sepelgy, O. Sustainable Alkylation of Nitriles with Alcohols by
Manganese Catalysis. J. Org. Chem. 2019, 84, 7927−7935. (b) Borghs,
J. C.; Azofra, L. M.; Biberger, T.; Linnenberg, O.; Cavallo, L.;
Rueping, M.; El-Sepelgy, O. Manganese Catalyzed Multicomponent
Synthesis of Pyrroles via Acceptorless Dehydrogenation Hydrogen
Autotransfer Catalysis: Experiment and Computation. ChemSusChem
2019, 12, 3083−3088. (c) Borghs, J. C.; Lebedev, Y.; Rueping, M.; El-
Sepelgy, O. Sustainable Manganese Catalyzed Solvent-free Synthesis
of Pyrroles from 1,4-Diols and Primary Amines. Org. Lett. 2019, 21,
70−74. (d) Sklyaruk, J.; Borghs, J. C.; El-Sepelgy, O.; Rueping, M.
Catalytic C1-Alkylation with Methanol and Isotope Labelled
F
https://dx.doi.org/10.1021/acs.orglett.0c01270
Org. Lett. XXXX, XXX, XXX−XXX