Manganese Catalyzed α-Alkylation of Nitriles with Primary Alcohols

Article abstract of DOI:10.1021/acscatal.8b02998

The manganese(I) complex bearing a bidentate hydrazone ligand efficiently catalyzes the α-alkylations of nitrile using primary alcohols as alkylating agents. α-Functionalized nitriles were selectively obtained in good to excellent yields. The reaction is environmentally benign, producing water as the sole byproduct. Both benzylic and aliphatic alcohols could be used and functional groups were tolerated.

Full text of DOI:10.1021/acscatal.8b02998

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Article
Manganese Catalyzed #-Alkylation of Nitriles with Primary Alcohols
Akash Jana, Chennayala Bal Reddy, and Biplab Maji
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02998 • Publication Date (Web): 24 Aug 2018
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Manganese Catalyzed α-Alkylation of Nitriles
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with Primary Alcohols
Akash Jana‡, C. Bal Reddy‡, and Biplab Maji*
Department of Chemical Sciences, Indian Institute of Science Education and Research
Kolkata, Mohanpur 741246, India
ABSTRACT. The manganese(I) complex bearing a bidentate hydrazone ligand efficiently
catalyzes the α-alkylations of nitrile using primary alcohols as alkylating agents. α-
Functionalized nitriles were selectively obtained in good to excellent yields. The reaction is
environmentally benign producing water as the sole byproduct. Both benzylic and aliphatic
alcohols could be used and functional groups were tolerated.
KEYWORDS. Homogeneous catalysis, bifunctional ligand, borrowing hydrogen, alcohols,
manganese.
The construction of the carbon-carbon bond is one of the central goals in organic synthesis.1
The search for alternative carbon resources is in demand considering depleting fossils fuels,
climate change, and sustainability.2 In this regard, the use of alcohols as an electrophile have
gained much attention mostly due to their large availability and non-toxic nature.3 α-Alkylated
nitriles are valuable structural motifs for the construction of carboxylic acid derivatives,
amines, ketones, oxazolines and several biologically active molecules.4 Their traditional
synthesis utilizes alkyl halides as alkylating agents in the presence of a stoichiometric amount
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of inorganic bases such as NaH or NaNH2. The major drawbacks of such protocols are the
toxicity of the alkylating agent, production of waste and less selective byproducts. The
alternative α-alkylation reaction using alcohols as an alkylating agent via borrowing hydrogen
strategy represents an atom-economical and environmentally benign protocol producing water
as the sole byproduct.3
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The pioneering work on ruthenium-mediated alkylations of acetonitrile was reported by
Grigg et al.5 Several state-of-the-art nitrile alkylations catalysts are developed based on the
precious noble metals such as iridium,6 rhodium,7 ruthenium,8 and osmium9 (Scheme 1).
However, considering the toxicity, cost and limited availability, the replacement of such metals
with the abundant first-row-transition metals Fe, Mn, Co, Ni has become a highly desirable
strategy to reduce the use of the noble metals in homogeneous catalysis.10 In fact, much
progresses in hydrogen auto-transfer catalysis for the alkylations of carbonyl derivatives and
amines using complexes of base metals have been made.11 During the preparation of this
manuscript, Xiao and Wang et al. have elegantly disclosed PNP-Fe catalyzed alkylations of
nitriles using primary alcohols.12 Despite such advancement, however, to best of our
knowledge, an earth-abundant metal manganese catalyzed α-alkylations of nitrile are not
reported thus far.13
Being the third most abundant transition metal in the earth’s crust, manganese has recently
offered a valuable alternative to the noble metals.14 From the pioneering work on manganese
catalyzed dehydrogenative imine synthesis by Milstein et al.,15 well-defined manganese
complexes have been utilized in a variety of (de)hydrogenation and cascade reactions.16 We
have developed the olefination of methyl heteroarenes using alcohols catalyzed by an in situ
generated manganese complex derived from bi-functional hydrazone pincer ligand.17 The
previous elegant work by Milstein et al. have shown that a PNP-Mn complex catalyzed the
olefination reaction to deliver the α-olefinated nitrile with the liberation of H2 (Scheme 1).18
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Continuing our exploration on manganese catalysis with phosphine-free ligands,13d, 17 we have
recently envisioned that a manganese complex of bidentate hydrazone ligand might exhibit
novel reactivity and selectivity for the alkylations of nitrile using alcohols as alkylating agents.
Herein, we report on the synthesis of manganese(I)-complexes Mn-L1,2 and their catalytic
activity for the α-alkylations of arylacetonitriles using primary alcohols. The catalyst operates
under low catalyst loading and tolerates several functional groups including iodine, bromine
etc. (Scheme 1). To the best of our knowledge, the first-row-transition metal catalyzed nitrile
alkylation reaction using alcohols as an alkylating agent under phosphine-free conditions is not
reported thus far.
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Scheme 1. State-of-the-art transition metal catalyzed coupling of alcohols with nitriles and this work.
To isolate the manganese complex, the precursor Mn(CO)5Br was reacted with the ligands
L1 and L2 in THF at 90 oC (Scheme 2). Subsequent precipitation by addition of hexane resulted
in the isolation of the complex Mn-L1 and Mn-L2 in 92% and 94% yield, respectively. The
complexes were characterized by NMR, FT-IR and elemental analysis. Up to 1.28 ppm
1
downfield in the H NMR spectrum of Mn-L1 in comparison to the free L1 indicated the
diminished electron density at the ligand because of the coordination to the manganese center.
The 13C{1H} NMR signals at 224.1, 222.9, and 216.8 ppm and IR absorption at 2026, 1935,
1909 cm⁻1 are reminiscent of three carbonyls Mn(CO)3 moiety. Single crystals of Mn-L1
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suitable for X-ray diffraction were obtained by recrystallization in THF (Figure 1).19 The
octahedral complex features bidentate meridional coordination of the potentially tridentate
ligand L1 with the following distances Mn(1)−N(1) (2.03 Å) and Mn(1)−N(3) (2.08 Å). The
other two sites of the quasi-planner plane are occupied by the two-carbonyl ligands. The angles
of N(1)−Mn(1)−C(12) (174°) and N(3)−Mn(1)−C(13) (172°) are in line with the linear
arrangements of the coordinating nitrogen atoms with the carbonyls. The third carbonyl is
linearly oriented trans to the bromide ligand in perpendicular to the manganese plane. The
complex Mn-L2 also shows similar spectroscopic signature (see the SI for details).
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Scheme 2. Synthesis of manganese(I) complexes Mn-L1,2.
Figure 1. The molecular structure of Mn-L1 (50% probability ellipsoids).19
We then explored the catalytic activities of the manganese(I)-complexes Mn-L1,2 for the
alkylations of model substrate benzyl cyanide 1a (Table 1). Thus, heating a solution of 1a in
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the presence of 4-methoxybenzyl alcohol 2a as the alkylating agent, 20 mol% t-BuOK and 2
mol% of Mn-L1 in t-amyl alcohol at 140 oC resulted in the full conversion of 1a and formation
of 90% (GC yield) of the desired product 3a (entry 1). The manganese complex Mn-L2
displayed improved catalytic activity and the product was obtained in 93% GC yield and 88%
isolated yield (entry 2). The reaction under this condition was found to be very selective; in
contrast to the previous PNP-manganese catalyzed reaction,17 the undesired 3-(4-
methoxyphenyl)-2-phenylacrylonitrile 3a’ could not be detected. Control experiments showed
traces of product formation in the absence of the ligand L1 or t-BuOK (entries 3,4). While t-
BuOK loading could be lowered to 5 mol% with a slight decrease in yield, the use of other
bases e.g. t-BuONa, t-BuOLi, Cs2CO3, and KOH were found to be detrimental (entries 5,6).
Other solvents like t-BuOH, toluene, 1,4-dioxane, and THF were also found to be less suitable
(entry 7).
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Table 1. Optimization of the reaction conditions.a
aReaction conditions: Mn-L1,2 (2 mol%), benzyl cyanide 1a (0.2 mmol), alcohol 2a (0.4
o
mmol), t-BuOK (0.04 mmol), and t-AmOH (0.4 mL) were heated at 140 C (oil bath
b
c
temperature) for 24 h under Ar. Yield of the isolated product. (GC yield, conversion).
Determined by GC using mesitylene as an internal standard. dThe catalyst was generated in situ
using an equimolar mixture of Mn(CO)5Br and L1 or L2.
The in situ catalyst generation often enable rapid optimization and is considered to be largely
applicable because of operational simplicity. Gratifyingly, when the in situ generated
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complexes Mn-L1 and Mn-L2 were used as catalysts, the alkylation reactions went in equal
efficiency (Table 1, entries 8,9). Thus, the in situ generated protocol could be adopted for
further study.
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The generality of this protocol was then tested (Table 2). A variety of arylacetonitrile reacted
with 2a to deliver the α-alkylated nitriles 3 in good to excellent yields without the formation of
vinyl nitrile or dialkylated product. Both electron-rich (1b-e) and electron-poor (1f-j)
arylacetonitriles were alkylated in good yields. Halogens substituents including bromine (1i)
and iodine (1j) were retained in the products. α-Alkylations of sterically hindered 2-(2-
methoxyphenyl)acetonitrile (1d) and 1-naphthylacetonitrile (1k) were also proceeded
successfully in 71% and 77% yields, respectively.
The scope was also examined with a wide range of primary alcohols. Benzylic alcohols with
varying steric and electronic substituents on the phenyl ring are found to be a viable substrate
for this alkylation reaction. Noticeably, the halide groups, in particular, chlorine (2e), bromine
(2f), and iodine (2g) were retained under the reaction conditions, delivering the products 3s-3u
in 68-71% yields. Similarly, alcohols containing trifluoromethyl (2h), biphenyl (2i), naphthyl
group (2j), coordinating hetero aromatic functional groups such as thiophenyl (2k), and pyridyl
(2l) group could also be utilized for the alkylations reactions. Aliphatic alcohols also underwent
smooth alkylation reactions. The ethylation of 1a,b,h,k proceeded smoothly in 47-88% yields
without the formation of any dialkylated product. Similar reactivities were also observed for
higher alcohols e.g. n-butanol (2n) and n-octanol (2o) and the products 3ah, 3ai were obtained
in 64% and 63% yields, respectively. Even strained cyclopropane methanol (2p) could be used
to deliver the product 3aj in 68% yield. However, methanol (2q) failed to deliver the product
under this condition.
Table 2. The scope of the manganese-catalyzed α-alkylations of nitrile with primary
alcohols.a
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aReaction conditions: Mn-L2 (2 mol%, in situ generated), nitrile 1 (0.2 mmol), alcohol 2 (0.4
mmol), t-BuOK (0.04 mmol), and t-AmOH (0.4 mL) were heated at 140 oC (oil bath
temperature) for 24 h under Ar. The yield of the isolated product. 1.0 mmol of alcohol was
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used.
Mechanistically, to probe the bi-functional behavior of the hydrazone ligand through the
participation of the N-H, we have prepared the N-Me analog (Me-L1) of the ligand L1. The
manganese complex derived from such ligand Me-L1 was found to be inefficient (Scheme 3a;
13% in comparison to 86% with L1) for the alkylation reaction. This indicates an outer sphere
mechanism involving the N-H group of the ligand for the (de)hydrogenation reaction. Kinetic
monitoring of the reaction (see the SI for details) revealed exponential decay of 1a. Whereas
the intermediate aldehyde 2a’ and vinyl nitrile 3a’ remained in low concentration and the latter
disappears after 18 h.
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Deuterium labeling experiment using [α,α-D2]biphenyl methanol (2i-d2) shows 83% D-
incorporation at the β-position of the nitrile group (Scheme 3b). Whereas, deuterium did not
incorporate at the α-position. This indicates a deuteride transfer at the β-position of the
intermediate vinyl nitrile 3w’-d from a manganese deuteride intermediate. The protonation is
then followed at the resulting α-carbanion. A competition experiment revealed a kH/kD = 1.54
which indicates that the dissociation of α-C-H bond in benzylic alcohol is a moderately slow
step.
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The aldol condensation under the reaction condition was found to be fast and a similar rate
was observed for the t-BuOK mediated reaction (Scheme 3c). However, 3a’ did not form in
the absence of t-BuOK. This revealed that the manganese catalyst might not be involved in the
C−C bond formation step and a different mechanism is operative from previously observed by
us13d, 17 and others.16q, 18, 20
Scheme 3. Mechanistic experiments.
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The hydrogenation of the intermediate 3a’ was found to be quantitative when 1a was used
as a hydrogen source under the reaction condition (Scheme 3d). The similar reaction with
deuterium-labeled alcohol 2i-d2 resulted in the formation of the product 3w-d in 88% yield
(Scheme 3e). The 1H NMR analysis of 3w-d revealed exclusive deuterium incorporation at the
β-position. This further indicates the conjugate reduction of 3w’-d by a manganese deuteride
intermediate generated via the dehydrogenation of 2i-d2.
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A plausible mechanism is depicted in Scheme 4. The manganese complex A generated by
the base-mediated salt elimination of the pre-catalyst Mn-L1 dehydrogenates the primary
alcohol 2a in a moderately slow step. The intermediacy of a manganese-alkoxy complex B, as
isolated by Milstein,16p Liu,16o us,17 and Yu,13e is proposed. The fast t-BuOK or A mediated
aldol condensation of the liberated aldehyde 2a’ with the nitrile 1a generates the vinyl nitrile
3a’. Facile outer-sphere hydrogenation of 3a’ then yields the desired product 3a and closes the
catalytic cycle. In such a process the manganese complex C transfers the hydride at the β-
position of the vinyl nitrile 3a’.
Scheme 4. Proposed mechanism.
In conclusion, we have presented the first example of a base-metal catalyzed α-alkylations
of nitrile using primary alcohols as alkylating agents under phosphine-free condition. The
protocol provides a useful method for the selective synthesis of α-branched nitriles in an
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environmentally benign manner. The novel bifunctional hydrazone ligand enables the switch
in the reaction mode to hydrogen-borrowing versus previously reported acceptorless
dehydrogenative coupling. The homogeneous catalysis with earth-abundant transition metals
is a valuable option to save rare noble-metal resources. We believe the developed procedure
will set forth further development in base-metal catalysis.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, analytical data and NMR spectra of
compounds and complexes, X-ray crystallographic analysis for Mn-L1. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: bm@iiserkol.ac.in
Author Contributions
‡These authors contributed equally.
Funding Sources
This research was supported by IISER Kolkata (Start-up grant) and SERB
(ECR/2016/001654).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The financial support from IISER Kolkata (Start-up grant) and SERB (ECR/2016/001654) is
gratefully acknowledged. A.J. thanks CSIR and C. B. R. thanks SERB (PDF/2017/000362)
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for fellowship. This work is dedicated to Professor Hisashi Yamamoto on the occasion of his
75th birthday.
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REFERENCES
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(1) Rygus, J. P. G.; Crudden, C. M. Enantiospecific and Iterative Suzuki–Miyaura Cross-
Couplings. J. Am. Chem. Soc. 2017, 139, 18124-18137.
(2) Poliakoff, M.; Fitzpatrick, J. M.; Farren, T. R.; Anastas, P. T. Green Chemistry: Science
and Politics of Change. Science 2002, 297, 807.
(3) (a) Hamid, S. A. M. H.; Slatford, P. A.; Williams, J. M. Borrowing Hydrogen in the
Activation of Alcohols. Adv. Synth. Catal. 2007, 349, 1555-1575. (b) Dobereiner, G. E.;
Crabtree, R. H. Dehydrogenation as a Substrate-Activating Strategy in Homogeneous
Transition-Metal Catalysis. Chem. Rev. 2010, 110, 681-703. (c) Obora, Y. C-Alkylation by
Hydrogen Autotransfer Reactions. Top. Curr. Chem. 2016, 374, 1-29. (d) Yang, Q.; Wang, Q.;
Yu, Z. Substitution of Alcohols by N-nucleophiles via Transition Metal-Catalyzed
Dehydrogenation. Chem. Soc. Rev. 2015, 44, 2305-2329. (e) Fei, H.; Zhuqing, L.; Zhengkun,
Y. C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed
Dehydrogenation. Angew. Chem. Int. Ed. 2016, 55, 862-875.
(4) (a) Kulp, S. S.; McGee, M. J. Oxidative Decyanation of Benzyl and Benzhydryl Cyanides.
A Simplified Procedure. J. Org. Chem. 1983, 48, 4097-4098. (b) Grundmann, C., Houben-
Weyl: Methoden der organischen Chemie. 4th ed.; Thieme: Stuttgart, 1985; Vol. E5. (c)
Hartmann, R. W.; Batzl, C. Aromatase Inhibitors. Synthesis and Evaluation of Mammary
Tumor Inhibiting Activity of 3-Alkylated 3-(4-Aminophenyl)piperidine-2,6-diones. J. Med.
Chem. 1986, 29, 1362-1369. (d) Im, D. S.; Cheong, C. S.; Lee, S. H.; Youn, B. H.; Kim, S. C.
Chemoenzymatic Synthesis of Optically Active 2-Phenyl-2-(1H-1,2,4-triazol-1-
11
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ylmethyl)hexanenitrile. Tetrahedron. 2000, 56, 1309-1314. (e) Hikaru, T.; Kazunori, Y.;
Katsuhiro, I.; Hiroki, T.; Shun-Ichi, M. Transition-Metal-Based Lewis Acid and Base
Ambiphilic Catalysts of Iridium Hydride Complexes: Multicomponent Synthesis of
Glutarimides. Angew. Chem. Int. Ed. 2003, 42, 3302-3304. (f) Fleming, F. F.; Yao, L.;
Ravikumar, P. C.; Funk, L.; Shook, B. C. Nitrile-Containing Pharmaceuticals: Efficacious
Roles of the Nitrile Pharmacophore. J. Med. Chem. 2010, 53, 7902-7917.
10
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55
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(5) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. Oxidation of Alcohols
by Transition Metal Complexes Part V. Selective Catalytic Monoalkylation of
Arylacetonitriles by Alcohols. Tetrahedron Lett. 1981, 22, 4107-4110.
(6) (a) Löfberg, C.; Grigg, R.; Whittaker, M. A.; Keep, A.; Derrick, A. Efficient Solvent-Free
Selective Monoalkylation of Arylacetonitriles with Mono-, Bis-, and Tris-primary Alcohols
Catalyzed by a Cp*Ir Complex. J. Org. Chem. 2006, 71, 8023-8027. (b) Anxionnat, B.; Gomez
Pardo, D.; Ricci, G.; Cossy, J. Monoalkylation of Acetonitrile by Primary Alcohols Catalyzed
by Iridium Complexes. Org. Lett. 2011, 13, 4084-4087. (c) Sawaguchi, T.; Obora, Y. Iridium-
Catalyzed α-Alkylation of Acetonitrile with Primary and Secondary Alcohols. Chem, Lett.
2011, 40, 1055-1057. (d) Morita, M.; Obora, Y.; Ishii, Y. Alkylation of Active Methylene
Compounds with Alcohols Catalyzed by an Iridium Complex. Chem. Commun. 2007, 2850-
2852.
(7) (a) Feng, L.; Xiaoyuan, Z.; Nana, W. Direct Coupling of Arylacetonitriles and Primary
Alcohols to α-Alkylated Arylacetamides with Complete Atom Economy Catalyzed by a
Rhodium Complex–Triphenylphosphine–Potassium Hydroxide System. Adv. Synth. Catal.
2015, 357, 1405-1415. (b) Junjun, L.; Yuxuan, L.; Weijun, T.; Dong, X.; Chaoqun, L.;
Jianliang, X.; Chao, W. Atmosphere-Controlled Chemoselectivity: Rhodium-Catalyzed
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ACS Catalysis
1
2
3
4
Alkylation and Olefination of Alkylnitriles with Alcohols. Chem. Eur. J. 2017, 23, 14445-
5
6
14449.
7
8
9
(8) (a) Motokura, K.; Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. A
Ruthenium-Grafted Hydrotalcite as a Multifunctional Catalyst for Direct α-Alkylation of
Nitriles with Primary Alcohols. J. Am. Chem. Soc. 2004, 126, 5662-5663. (b) Motokura, K.;
Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Jitsukawa, K.; Kaneda, K. Environmentally
Friendly One-Pot Synthesis of α-Alkylated Nitriles Using Hydrotalcite-Supported Metal
Species as Multifunctional Solid Catalysts. Chem. Eur. J. 2006, 12, 8228-8239. (c) Cheung, H.
W.; Li, J.; Zheng, W.; Zhou, Z.; Chiu, Y. H.; Lin, Z.; Lau, C. P. Dialkylamino Cyclopentadienyl
Ruthenium(ii) Complex-Catalyzed α-Alkylation of Arylacetonitriles with Primary Alcohols.
Dalton Trans. 2010, 39, 265-274. (d) Kuwahara, T.; Fukuyama, T.; Ryu, I. Synthesis of
Alkylated Nitriles by [RuHCl(CO)(PPh3)3]-Catalyzed Alkylation of Acetonitrile Using
Primary Alcohols. Chem, Lett. 2013, 42, 1163-1165. (e) Thiyagarajan, S.; Gunanathan, C.
Facile Ruthenium(II)-Catalyzed α-Alkylation of Arylmethyl Nitriles Using Alcohols Enabled
by Metal–Ligand Cooperation. ACS Catal. 2017, 7, 5483-5490.
10
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12
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14
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16
17
18
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20
21
22
23
24
25
26
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54
55
56
57
58
59
60
(9) Buil, M. L.; Esteruelas, M. A.; Herrero, J.; Izquierdo, S.; Pastor, I. M.; Yus, M. Osmium
Catalyst for the Borrowing Hydrogen Methodology: α-Alkylation of Arylacetonitriles and
Methyl Ketones. ACS Catal. 2013, 3, 2072-2075.
(10) (a) Bullock, R. M., Catalysis without Precious Metals. Wiley-VCH: Weinheim, 2010;
(b) Crabtree, R. H. Homogeneous Transition Metal Catalysis of Acceptorless Dehydrogenative
Alcohol Oxidation: Applications in Hydrogen Storage and to Heterocycle Synthesis. Chem.
Rev. 2017, 117, 9228-9246.
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Page 14 of 19
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2
3
4
5
6
7
8
9
(11) (a) Deibl, N.; Kempe, R. General and Mild Cobalt-Catalyzed C-Alkylation of
Unactivated Amides and Esters with Alcohols. J. Am. Chem. Soc. 2016, 138, 10786-10789. (b)
Zhang, G.; Wu, J.; Zeng, H.; Zhang, S.; Yin, Z.; Zheng, S. Cobalt-Catalyzed α-Alkylation of
Ketones with Primary Alcohols. Org. Lett. 2017, 19, 1080-1083. (c) Rösler, S.; Ertl, M.;
Irrgang, T.; Kempe, R. Cobalt-Catalyzed Alkylation of Aromatic Amines by Alcohols. Angew.
Chem. Int. Ed. 2015, 54, 15046-15050. (d) Yin, Z.; Zeng, H.; Wu, J.; Zheng, S.; Zhang, G.
Cobalt-Catalyzed Synthesis of Aromatic, Aliphatic, and Cyclic Secondary Amines via a
"Hydrogen-Borrowing" Strategy. ACS Catal. 2016, 6, 6546-6550. (e) Zhang, G.; Yin, Z.;
Zheng, S. Cobalt-Catalyzed N-Alkylation of Amines with Alcohols. Org. Lett. 2016, 18, 300-
303. (f) Yan, T.; Feringa, B. L.; Barta, K. Iron Catalysed Direct Alkylation of Amines with
Alcohols. Nat. Commun. 2014, 5, 5602. (g) Rawlings, A. J.; Diorazio, L. J.; Wills, M. C–N
Bond Formation between Alcohols and Amines Using an Iron Cyclopentadienone Catalyst.
Org. Lett. 2015, 17, 1086-1089. (h) Balaraman, E.; Nandakumar, A.; Jaiswal, G.; Sahoo, M.
K. Iron-Catalyzed Dehydrogenation Reactions and their Applications in Sustainable Energy
and Catalysis. Catal. Sci. Technol. 2017, 7, 3177-3195. (i) Vellakkaran, M.; Singh, K.;
Banerjee, D. An Efficient and Selective Nickel-Catalyzed Direct N-Alkylation of Anilines with
Alcohols. ACS Catal. 2017, 7, 8152-8158.
10
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53
54
55
56
57
58
59
60
(12) Ma, W.; Cui, S.; Sun, H.; Tang, W.; Xue, D.; Li, C.; Fan, J.; Xiao, J.; Wang, C. Iron-
Catalyzed Alkylation of Nitriles with Alcohols. Chem. Eur. J. 2018, doi:
10.1002/chem.201803762.
(13) (a) Pena-Lopez, M.; Piehl, P.; Elangovan, S.; Neumann, H.; Beller, M. Manganese-
Catalyzed Hydrogen-Autotransfer C-C Bond Formation: α-Alkylation of Ketones with Primary
Alcohols. Angew. Chem. Int. Ed. 2016, 55, 14967-14971. (b) Elangovan, S.; Neumann, J.;
Sortais, J.-B.; Junge, K.; Darcel, C.; Beller, M. Efficient and Selective N-Alkylation of Amines
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1
2
3
4
5
6
7
8
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with Alcohols Catalyzed by Manganese Pincer Complexes. Nat. Commun. 2016, 7, 12641. (c)
Mastalir, M.; Glatz, M.; Gorgas, N.; Stöger, B.; Pittenauer, E.; Allmaier, G.; Veiros, L. F.;
Kirchner, K. Divergent Coupling of Alcohols and Amines Catalyzed by Isoelectronic Hydride
MnI and FeII PNP Pincer Complexes. Chem. Eur. J. 2016, 22, 12316-12320. (d) Barman, M.
K.; Jana, A.; Maji, B. Phosphine-Free NNN-Manganese Complex Catalyzed α-Alkylation of
Ketones with Primary Alcohols and Friedländer Quinoline Synthesis. Adv. Synth. Catal. 2018,
doi:10.1002/adsc.201800380. (e) Liu, T.; Wang, L.; Wu, K.; Yu, Z. Manganese-Catalyzed β-
Alkylation of Secondary Alcohols with Primary Alcohols under Phosphine-Free Conditions.
ACS Catal. 2018, 8, 7201-7207.
10
11
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48
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58
59
60
(14) (a) Maji, B.; Barman, M. K. Recent Developments of Manganese Complexes for
Catalytic Hydrogenation and Dehydrogenation Reactions. Synthesis 2017, 49, 3377-3393. (b)
Garbe, M.; Junge, K.; Beller, M. Homogeneous Catalysis by Manganese-Based Pincer
Complexes. Eur. J. Org. Chem. 2017, 2017, 4344-4362. (c) Fabian, K.; Rhett, K. Manganese
Complexes for (De)Hydrogenation Catalysis: A Comparison to Cobalt and Iron Catalysts.
Angew. Chem. Int. Ed. 2018, 57, 46-60. (d) Gorgas, N.; Kirchner, K. Isoelectronic Manganese
and Iron Hydrogenation/Dehydrogenation Catalysts: Similarities and Divergences. Acc. Chem.
Res. 2018, 51, 1558-1569. (e) Valyaev, D. A.; Lavigne, G.; Lugan, N. Manganese
Organometallic Compounds in Homogeneous Catalysis: Past, Present, and Prospects. Coord.
Chem. Rev. 2016, 308, 191-235.
(15) Mukherjee, A.; Nerush, A.; Leitus, G.; Shimon, L. J. W.; Ben David, Y.; Espinosa
Jalapa, N. A.; Milstein, D. Manganese-Catalyzed Environmentally Benign Dehydrogenative
Coupling of Alcohols and Amines to Form Aldimines and H2: A Catalytic and Mechanistic
Study. J. Am. Chem. Soc. 2016, 138, 4298-4301.
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8
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(16) (a) Elangovan, S.; Topf, C.; Fischer, S.; Jiao, H.; Spannenberg, A.; Baumann, W.;
Ludwig, R.; Junge, K.; Beller, M. Selective Catalytic Hydrogenations of Nitriles, Ketones, and
Aldehydes by Well-Defined Manganese Pincer Complexes. J. Am. Chem. Soc. 2016, 138,
8809-8814. (b) Kallmeier, F.; Irrgang, T.; Dietel, T.; Kempe, R. Highly Active and Selective
Manganese C=O Bond Hydrogenation Catalysts: The Importance of the Multidentate Ligand,
the Ancillary Ligands, and the Oxidation State. Angew. Chem. Int. Ed. 2016, 55, 11806-11809.
(c) Widegren, M. B.; Harkness, G. J.; Slawin, A. M. Z.; Cordes, D. B.; Clarke, M. L. A Highly
Active Manganese Catalyst for Enantioselective Ketone and Ester Hydrogenation. Angew.
Chem. Int. Ed. 2017, 56, 5825-5828. (d) Espinosa-Jalapa, N. A.; Nerush, A.; Shimon, L. J. W.;
Leitus, G.; Avram, L.; Ben-David, Y.; Milstein, D. Manganese-Catalyzed Hydrogenation of
Esters to Alcohols. Chem. Eur. J. 2017, 23, 5934-5938. (e) Putten, R. v.; Uslamin, E. A.; Garbe,
M.; Liu, C.; Gonzalez-de-Castro, A.; Lutz, M.; Junge, K.; Hensen, E. J. M.; Beller, M.; Lefort,
L.; Pidko, E. A. Non-Pincer-Type Manganese Complexes as Efficient Catalysts for the
Hydrogenation of Esters. Angew. Chem. Int. Ed. 2017, 56, 7531-7534. (f) Dubey, A.; Nencini,
L.; Fayzullin, R. R.; Nervi, C.; Khusnutdinova, J. R. Bio-Inspired Mn(I) Complexes for the
Hydrogenation of CO2 to Formate and Formamide. ACS Catal. 2017, 7, 3864-3868. (g) Kar,
S.; Goeppert, A.; Kothandaraman, J.; Prakash, G. K. S. Manganese-Catalyzed Sequential
Hydrogenation of CO2 to Methanol via Formamide. ACS Catal. 2017, 7, 6347-6351. (h)
Bruneau-Voisine, A.; Wang, D.; Dorcet, V.; Roisnel, T.; Darcel, C.; Sortais, J.-B. Transfer
Hydrogenation of Carbonyl Derivatives Catalyzed by an Inexpensive Phosphine-Free
Manganese Precatalyst. Org. Lett. 2017, 19, 3656-3659. (i) Wang, D.; Bruneau-Voisine, A.;
Sortais, J.-B. Practical (Asymmetric) Transfer Hydrogenation of Ketones Catalyzed by
Manganese with (Chiral) Diamines Ligands. Catal. Commun. 2018, 105, 31-36. (j) Nguyen,
D. H.; Trivelli, X.; Capet, F.; Paul, J.-F.; Dumeignil, F.; Gauvin, R. M. Manganese Pincer
10
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Complexes for the Base-Free, Acceptorless Dehydrogenative Coupling of Alcohols to Esters:
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Development, Scope, and Understanding. ACS Catal. 2017, 7, 2022-2032. (k) Daw, P.;
Chakraborty, S.; Leitus, G.; Diskin-Posner, Y.; Ben-David, Y.; Milstein, D. Selective N-
Formylation of Amines with H2 and CO2 Catalyzed by Cobalt Pincer Complexes. ACS Catal.
2017, 7, 2500-2504. (l) Kallmeier, F.; Dudziec, B.; Irrgang, T.; Kempe, R. Manganese-
Catalyzed Sustainable Synthesis of Pyrroles from Alcohols and Amino Alcohols. Angew.
Chem. Int. Ed. 2017, 56, 7261-7265. (m) Mastalir, M.; Pittenauer, E.; Allmaier, G.; Kirchner,
K. Manganese-Catalyzed Aminomethylation of Aromatic Compounds with Methanol as a
Sustainable C1 Building Block. J. Am. Chem. Soc. 2017, 139, 8812-8815. (n) Mondal, A.;
Subaramanian, M.; Nandakumar, A.; Balaraman, E. Manganese-Catalyzed Direct Conversion
of Ester to Amide with Liberation of H2. Org. Lett. 2018, 20, 3381-3384. (o) Fu, S.; Shao, Z.;
Wang, Y.; Liu, Q. Manganese-Catalyzed Upgrading of Ethanol into 1-Butanol. J. Am. Chem.
Soc. 2017, 139, 11941-11948. (p) Das, U. K.; Ben-David, Y.; Diskin-Posner, Y.; Milstein, D.
N-Substituted Hydrazones by Manganese-Catalyzed Coupling of Alcohols with Hydrazine:
Borrowing Hydrogen and Acceptorless Dehydrogenation in One System. Angew. Chem. Int.
Ed. 2018, 57, 2179-2182. (q) Zhang, G.; Irrgang, T.; Dietel, T.; Kallmeier, F.; Kempe, R.
Manganese-Catalyzed Dehydrogenative Alkylation or α-Olefination of Alkyl-Substituted N-
Heteroarenes with Alcohols. Angew. Chem. Int. Ed. 2018, 57, 9131-9135. (r) Das, K.; Mondal,
A.; Srimani, D. Selective Synthesis of 2-Substituted and 1,2-Disubstituted Benzimidazoles
Directly from Aromatic Diamines and Alcohols Catalyzed by Molecularly Defined
Nonphosphine Manganese(I) Complex. J. Org. Chem. 2018, 83, 9553-9560.
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(17) Barman, M. K.; Waiba, S.; Maji, B. Manganese-Catalyzed Direct Olefination of Methyl-
Substituted Heteroarenes with Primary Alcohols. Angew. Chem. Int. Ed. 2018, 57, 9126-9130.
(18) Chakraborty, S.; Das, U. K.; Ben-David, Y.; Milstein, D. Manganese Catalyzed α-
Olefination of Nitriles by Primary Alcohols. J. Am. Chem. Soc. 2017, 139, 11710-11713.
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(19) CCDC-1857433 Contain the Supplementary Crystallographic Data.
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(20) Schlepphorst, C.; Maji, B.; Glorius, F. Ruthenium-NHC Catalyzed α-Alkylation of
Methylene Ketones Provides Branched Products through Borrowing Hydrogen Strategy. ACS
Catal. 2016, 6, 4184-4188.
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BRIEFS. The first example of non-pincer manganese(I)-complex catalyzed α-alkylation of
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nitriles with primary alcohols is reported.
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SYNOPSIS.
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