A Highly Active PN3 Manganese Pincer Complex Performing N

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

A Highly Active PN3 Manganese Pincer Complex Performing N‑Alkylation of Amines under Mild Conditions Leonard Homberg,† Alexander Roller,‡ and Kai C. Hultzsch*,† †

University of Vienna, Faculty of Chemistry, Institute of Chemical Catalysis, Währinger Straße 38, 1090 Vienna, Austria University of Vienna, Faculty of Chemistry, X-ray Structure Analysis Center, Währinger Straße 42, 1090 Vienna, Austria

‡

Org. Lett. Downloaded from pubs.acs.org by ALBRIGHT COLG on 04/15/19. For personal use only.

S Supporting Information *

ABSTRACT: A highly active Mn(I) catalyst based on a nonsymmetric PN3-ligand scaffold for the N-alkylation of amines with alcohols utilizing the borrowing hydrogen methodology is reported. A broad range of anilines and the more challenging aliphatic amines were alkylated with primary and secondary alcohols. Moreover, the combination of low catalyst loadings and mild reaction conditions provides high efficiency for this atom-economic transformation.

N

Since 2016, various Mn(I) pincer complexes that utilize metal−ligand cooperation (MLC) in borrowing hydrogen and dehydrogenative condensation processes have been reported in pioneering contributions from Milstein,11 Beller,12 Kempe,13 Kirchner,6d,e,14 Sortais,15 Rueping,16 and others.17 Interestingly, secondary alcohols as substrates were only used in the dehydrogenative synthesis of heterocycles.11g,13a,14a,16b,17d The direct alkylation of amines with secondary alcohols is more prevailing for noble metal catalysts,2 Knoelker type iron complexes,6a,c,f and enzymatic transformations,18 whereas it remains challenging for cobalt catalysts7b and was not reported for manganese-based systems (Figure 2). Most direct alkylations have been reported for anilines, while more nucleophilic benzyl amines pose a challenge for Mn catalysts. Dehydrogenative coupling reactions providing aldimines were reported in the initial work of Milstein11a and

itrogen-containing compounds are of significant importance in many fields of chemistry. Applications range from multiton-scale agrochemicals to fine chemicals and pharmaceuticals.1 In order to meet the insatiable demand, atom-efficient processes utilizing benign starting materials are being sought.2 Over the past four decades, a number of homogeneous catalysts for the N-alkylation using alcohols have been developed,3 with the majority of these catalyst systems being based on precious metals, such as Ru and Ir.4 Recently, the emphasis in catalysis research has shifted in favor of more abundant and cheaper base metals for catalysis,5 in particular, on catalyst systems based on Fe6 and Co.7 Generally, the application of the base metal Mn in catalysis is also highly desirable,8 thanks to its high availability as the third most abundant transition metal after Fe and Ti in the earth’s crust.9 However, Mn-based catalysts for hydrogen transfer and borrowing hydrogen processes, including N-alkylation of amines, have attracted attention only very recently (Figure 1).5,10

Figure 2. Secondary alcohols as substrates for direct N-alkylations.6f,7b Figure 1. Recently developed manganese systems for N-benzylation of anilines.12a,13d © XXXX American Chemical Society

Received: March 6, 2019

A

DOI: 10.1021/acs.orglett.9b00832 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters were further investigated by the groups of Kirchner6d and Kempe.13d In addition, the preparation of amides from benzyl amines and aliphatic alcohols via dehydrogenative coupling was reported recently.11e Many established Mn(I) catalyst systems for borrowing hydrogen reactions are based on a symmetric ligand scaffold, while nonsymmetric variants have been studied less extensively (Figure 3). This shortfall sparked our interest, especially in terms of modular ligand design supporting an MLC mechanism.

temperature to the same species C upon addition of base under identical conditions. Single-crystal X-ray analysis of crystals of complex A obtained from DME at −35 °C revealed that a unit cell consisted of two independent molecules of an octahedral PN3 Mn(I) pincer tricarbonyl cation (Figure 4) as well as

Figure 4. Molecular structure of cationic species A with thermal ellipsoids set at 50% probability. The anion [MnBr4]2−, a second cationic Mn(I) pincer moiety, and all hydrogen atoms, except for the hydrogen attached to N3a, are omitted for clarity. Selected bond lengths (Å): Mn1A−P1A = 2.2622(13), Mn1A−N1A = 2.049(4), Mn1A−N2A = 2.026(3), Mn1A−C1A = 1.799(5), Mn1A−C2A = 1.861(4), Mn1A−C3A = 1.849(4), P1A−N3A = 1.705(4), C1A− O1A = 1.153(5), C2A−O2A = 1.134(5), C3A−O3A = 1.138(5). Selected angles (deg): N1A−Mn1A−P1A = 159.85(11), N2A− Mn1A−P1A = 81.58(10), N2A−Mn1A−N1A = 78.27(14), C1A− Mn1A−N2A = 177.04(19), C1A−Mn1A−P1A = 96.20(15), C3A− Mn1A−C2A = 166.98(18), C2A−Mn1A−P1A = 96.33(13), C3A− Mn1A−P1A = 94.12(15). See the Supporting Information (SI) for crystallography details.

Figure 3. Selected examples of pincer ligand sets for Mn(I)-catalyzed borrowing hydrogen and dehydrogenative condensation processes.11−16

The group of Ke conducted DFT calculations for Rucatalyzed alcohol dehydrogenation utilizing MLC with different tridentate ligands.19 Thus, we identified the bipyridinebased ligand bpy-6NH-iPrP (Figure 3)20 as a promising candidate for a Mn(I)-based borrowing hydrogen catalyst. Complexation of the PN3-pincer ligand bpy-6NH-iPrP with Mn(CO)5Br was monitored by 31P NMR spectroscopy in various solvents, including toluene, benzene, THF, and DME. The progress of the reaction was accompanied by formation of a dark orange solution. In toluene, partial complex degradation became apparent within 24 h in the form of a dark brown precipitate, possibly due to the poor solubility of the formed intermediates. Complexation in THF-d8 at 25 °C produced a single species A within 2 h (Scheme 1) observed at 98 ppm in

[MnBr4]2− as an unexpected anion, which supports the observation of partial Mn degradation during the complexation. In a separate experiment, crystals of a Mn(II) pincer complex were obtained at room temperature, but this species was found to be catalytically inactive.21 This led to the assumption that Mn(I) is the active species for catalysis and that during the complexation a partial disproportionation of Mn(I) can occur. Due to the degradation process in solution, we performed all reactions with freshly prepared stock solutions with an in situ prepared precatalyst. Thus, all catalyst loadings were determined by the employed amount of Mn(CO)5Br, not taking potential degradation into account. As a starting point, we investigated the N-alkylation of aniline with benzyl alcohol to form N-benzylaniline (1a) as a benchmark reaction (Table 1), with the goal of implementing mild conditions with low catalyst and base additive loadings. Initially, 3 mol % of catalyst and stoichiometric amounts of potassium tert-butoxide as a base were used in toluene at 60 °C, providing 84% conversion in 24 h to a mixture of the desired amine 1a and the imine intermediate 1b in a 98:2 ratio (Table 1, entry 1). Lowering the catalyst loading to 1 mol % in a more concentrated reaction mixture improved the conversion and amine selectivity even as the reaction temperature was lowered to 50 °C (Table 1, entry 3). As the solvent polarity was increased, we found slightly higher activity in ethers like DME, 1,4-dioxane, and THF compared to the commonly used

Scheme 1. Complexation Reaction of Mn(CO)5Br with bpy-6NH-iPrP

the 31P NMR spectrum.21 This species converted within 24 h to two, yet unidentified, new species B and B′ observed at 157 and 149 ppm in a 1:1 ratio. Upon addition of either KH or KOtBu, species A formed a new species C observed at 140 ppm within 5 min at room temperature, which presumably is a dearomatized complex.19 Furthermore, a mixture containing species B and B′ also converged within 5 min at room B

DOI: 10.1021/acs.orglett.9b00832 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of Reaction Conditions in the NAlkylation of Aniline with Benzyl Alcohola

no.

cat. (mol %)

baseb (equiv)

solventb (mL)

temp (°C)

convc (%)

ratio 1a/1bc

1 2 3 4 5 6 7 8 9 10 11 12 13 14

3 1 1 1 1 1 1 0.5 0.25 0.1 1d 1e 1 g

A (1.0) A (1.0) A (1.0) A (1.0) A (0.5) B (0.5) B (0.4) B (0.5) B (0.5) B (0.5) B(0.5) B(0.5) f B (0.5)

T (1.0) T (1.0) T (0.1) D (0.1) D (0.1) D (0.1) D (0.1) D (0.1) D (0.1) D (0.1) D (0.1) D (0.1) D (0.1) D (0.1)

60 60 50 50 50 50 50 50 50 50 60 60 80 80

84 78 93 99 79 99 81 80 70 55 3 0 0 4

98:2 99:1 99:1 only 1a 99:1 only 1a 98:2 >99:1 >99:1 99:1 90:10

Scheme 2. Screening of Various Amines in the N-Alkylation with Benzyl Alcohola

only 1a

a

General conditions: 1 mmol of aniline, 1 mmol of benzyl alcohol, 1:1 ratio ligand to metal precursor, Ar. bA ≡ KOtBu, B ≡ KH, T ≡ toluene, D ≡ DME. cConversion to 1a and 1b; aniline consumption determined by GC−MS. dNo ligand added. eWithout metal precursor. fNo base added. gWithout catalyst.

a

General conditions: 1.1 mmol of amine, 1 mmol of benzyl alcohol, 0.1 mL of DME, 24 h, 60 °C, Ar. Yields determined by GC−FID with p-xylene as standard. b36 h. c1% N-(4-ethylphenyl)-1-phenylmethanimine, 6% N-benzyl-4-ethylaniline. d100 °C. ePartially racemized ((R)-2l 84% ee (S)-2l 80% ee).

toluene.21 A screening of different bases to investigate lower additive loading provided potassium hydride as being more efficient in substoichiometric ratios,21 though comparatively low base loadings (less than 30 mol %) rendered the system significantly less active.22 The commonly used base KOtBu also provided good activity, but overall KH was more efficient in terms of operating at lower base loadings, lower temperature, and working under almost neat conditions. When the catalyst loading was lowered to 0.1 mol %, a turnover number of 550 was achieved with trace amounts of N-phenylbenzimine (1b) as the only side product (Table 1, entry 10). In the absence of either the metal precursor, the ligand, or the base additive, no or very low conversion was observed (Table 1, entries 11−14). A screening of various other metal precursors showed superior activity of Mn(I) in the N-alkylation reaction.21 Thus, further experiments were conducted with 0.5 mol % catalyst loading and 50 mol % of added base KH at 60 °C in DME as solvent. Different amines were employed in the first part of a substrate screening (Scheme 2), including various substituted anilines as well as more nucleophilic aliphatic amines. Introduction of redox-innocent23 substituents (2a−i) was found to have only a slight effect on the reactivity. Halogenated anilines and toluidines are highly active for N-alkylation with only slight influences from steric hindrance. It was found that hydrogenation of a vinyl group was less favored than the reduction of the imine intermediate, and N-benzyl-4-ethylaniline was only observed as a minor byproduct of 2j. To the best of our knowledge, benzylamine, a potential ammonia surrogate, has not been successfully employed as substrate for amine synthesis using Mn(I) catalysts.6d,11a,12a,13d,17i When used under standard conditions only little activity was observed, but at elevated temperatures excellent yields were

achieved.24 The sterically more demanding 1-phenylethylamine provided average conversions.25 We then began to investigate different benzyl alcohols in the N-alkylation of aniline (Scheme 3). We expected a stronger influence of the substituents on the rate of the dehydrogenation step in the borrowing hydrogen cycle. Redox-innocent substituents23 in the meta and para position of the benzyl alcohol were readily tolerated and provided good to excellent yields (3a, 3c, 3f). A significant effect was induced by fluorine substituents in the ortho and para positions, providing only low conversion under standard conditions. However, when the reaction was performed at 80 °C for 48 h, good yields were obtained (3e, 3g). Interestingly, 2-chlorobenzyl alcohol provided good yields merely by extending the reaction time (3d). Methyl-substituted benzyl alcohols required prolonged reaction times (3h−j), suggesting that the +I methyl substituents reduce activity compared to benzyl alcohol. Nonactivated linear alcohols showed decent activity as alkylating substrates, although methanol remained a challenging substrate under the standard conditions (3l−q). 1-(2Hydroxyethyl)piperidine provided only a low yield at standard conditions, but with elevated temperature slightly increased yields were obtained (3k). In order to implement a broad substrate scope, we also investigated secondary alcohols which have only been reported as substrates in Mn(I)-catalyzed dehydrogenative synthesis of nitrogen heterocycles,11g,13a,14a,16b,17d but to the best of our knowledge, not in the N-alkylation of amines. Only very low activity was observed under standard conditions, but at slightly elevated temperatures N-isopropylaniline was obtained from C

DOI: 10.1021/acs.orglett.9b00832 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

2k and 2l, a fair conversion to the desired secondary amine was observed with a good 9:1 amine to imine ratio (Scheme 5).

Scheme 3. Screening of Various Alcohols in the NAlkylation of Anilinea

Scheme 5. Exemplary Preparation of Cinacalcet

In summary, we have established a new Mn(I)-based catalyst system utilizing a bipyridine-based PN 3 -pincer ligand bpy-6NH-iPrP with high activity toward N-alkylation of different amines with alcohols. We were able to reduce the additive loading to a half equivalent while using low catalyst loadings unprecedented in Mn(I) borrowing hydrogen catalysis. Mild reaction conditions could be implemented for the alkylation of anilines, which allows reactions to be performed with temperature-sensitive compounds at 60 °C instead of 80 °C. The overall milder approach was also implemented successfully when using different benzyl alcohols as alkylating agents with the only exemption of fluorinated substrates. More nucleophilic aliphatic amines and challenging secondary alcohols were also successfully employed as substrates. The catalytic system not only works under mild conditions but, moreover, tolerates higher temperatures when necessary for challenging substrates. Introducing benzylamine as a high-yielding substrate provides amination with an ammonia surrogate after subsequent hydrogenolysis.

a

General conditions: 1.1 mmol of aniline, 1 mmol of alcohol, 0.1 mL of DME, 24 h, 60 °C, Ar. Yields determined by GC−FID with pxylene as standard. b36 h. c48 h. d80 °C. e100 °C.

aniline and 2-propanol in good yield (3r). Nonsymmetrical secondary alcohols, such as 2-butanol and 1-phenylethanol, were also successfully employed as alkylating agents (3s, 3t), though in the latter case, the phenyl group in α-position of the alcohol seems to obstruct the reaction by its steric hindrance and more forcing conditions were required to obtain fair yields. Cyclohexanol was also successfully converted at elevated temperatures, providing an average yield (3u). Aside from screening different substrates, the mild conditions were successfully applied in a gram scale Nbenzylation of aniline with benzyl alcohol. Since the benchmark reaction showed already high productivity at lower catalyst loading (Table 1, entry 9) and slightly lower additive loading (Table 1, entry 7), we were able to obtain 1a in excellent isolated yield (Scheme 4). Since the more challenging benzylamine substrates (Scheme 2, 2k, 2l) were successfully employed, the synthesis of cinacalcet (4) (Mimpara, Sensipar) was chosen as an exemplary application. With the nonoptimized conditions of

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00832. Experimental details, optimization of catalytic reaction conditions, NMR spectroscopic data of bpy-6NH-iPrP, complex A and N-alkylated anlines, and crystallographic data (PDF) Accession Codes

CCDC 1900349−1900350 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Scheme 4. Gram-Scale N-Alkylation of Aniline with Benzyl Alcohol

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kai C. Hultzsch: 0000-0002-5298-035X Notes

The authors declare no competing financial interest. D

DOI: 10.1021/acs.orglett.9b00832 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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ACKNOWLEDGMENTS We express our gratitude to Dr. Agnieszka J. Nawara-Hultzsch and Ms. Natalie Hofmann for assistance in product isolation and characterization.

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DOI: 10.1021/acs.orglett.9b00832 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters (13) (a) Deibl, N.; Kempe, R. Manganese-Catalyzed Multicomponent Synthesis of Pyrimidines from Alcohols and Amidines. Angew. Chem., Int. Ed. 2017, 56, 1663−1666. (b) 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. (c) Zhang, G.; Irrgang, T.; Dietel, T.; Kallmeier, F.; Kempe, R. Manganese-Catalyzed Dehydrogenative Alkylation or α-Olefination of Alkyl-Substituted NHeteroarenes with Alcohols. Angew. Chem., Int. Ed. 2018, 57, 9131−9135. (d) Fertig, R.; Irrgang, T.; Freitag, F.; Zander, J.; Kempe, R. Manganese-Catalyzed and Base-Switchable Synthesis of Amines or Imines via Borrowing Hydrogen or Dehydrogenative Condensation. ACS Catal. 2018, 8, 8525−8530. (14) (a) Mastalir, M.; Glatz, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K. Sustainable Synthesis of Quinolines and Pyrimidines Catalyzed by Manganese PNP Pincer Complexes. J. Am. Chem. Soc. 2016, 138, 15543−15546. (b) 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. (15) Bruneau-Voisine, A.; Wang, D.; Dorcet, V.; Roisnel, T.; Darcel, C.; Sortais, J.-B. Mono-N-methylation of anilines with methanol catalyzed by a manganese pincer-complex. J. Catal. 2017, 347, 57−62. (16) (a) Jang, Y. K.; Krückel, 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. (b) 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. (c) Sklyaruk, J.; Borghs, J. C.; El-Sepelgy, O.; Rueping, M. Catalytic C1 Alkylation with Methanol and Isotope-Labeled Methanol. Angew. Chem., Int. Ed. 2019, 58, 775−779. (d) ElSepelgy, O.; Matador, E.; Brzozowska, A.; Rueping, M. C-Alkylation of Secondary Alcohols by Primary Alcohols through ManganeseCatalyzed Double Hydrogen Autotransfer. ChemSusChem 2018, DOI: 10.1002/cssc.201801660. (17) Selected examples: (a) Fu, S.; Shao, Z.; Wang, Y.; Liu, Q. Manganese-Catalyzed Upgrading of Ethanol into 1-Butanol. J. Am. Chem. Soc. 2017, 139, 11941−11948. (b) 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. (c) 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, 360, 3233−3238. (d) Das, K.; Mondal, A.; Srimani, D. Phosphine free Mn-complex catalysed dehydrogenative C-C and C-heteroatom bond formation: a sustainable approach to synthesize quinoxaline, pyrazine, benzothiazole and quinoline derivatives. Chem. Commun. 2018, 54, 10582−10585. (e) Landge, V. G.; Mondal, A.; Kumar, V.; Nandakumar, A.; Balaraman, E. Manganese Catalyzed N-Alkylation of Amines with Alcohols: Ligand Enabled Selectivity. Org. Biomol. Chem. 2018, 16, 8175−8180. (f) 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. (g) 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. (h) Jana, A.; Reddy, C. B.; Maji, B. Manganese Catalyzed α-Alkylation of Nitriles with Primary Alcohols. ACS Catal. 2018, 8, 9226−9231. (i) Reed-Berendt, B. G.; Morrill, L. C. Manganese-Catalyzed N-Alkylation of Sulfonamides Using Alcohols. J. Org. Chem. 2019, 84, 3715−3724. (18) (a) Montgomery, S. L.; Mangas-Sanchez, J.; Thompson, M. P.; Aleku, G. A.; Dominguez, B.; Turner, N. J. Direct Alkylation of Amines with Primary and Secondary Alcohols through Biocatalytic Hydrogen Borrowing. Angew. Chem., Int. Ed. 2017, 56, 10491−10494. (b) Thompson, M. P.; Turner, N. J. Two-Enzyme Hydrogen-

Borrowing Amination of Alcohols Enabled by a Cofactor-Switched Alcohol Dehydrogenase. ChemCatChem 2017, 9, 3833−3836. (19) (a) Hou, C.; Zhang, Z.; Zhao, C.; Ke, Z. DFT Study of Acceptorless Alcohol Dehydrogenation Mediated by Ruthenium Pincer Complexes: Ligand Tautomerization Governing Metal Ligand Cooperation. Inorg. Chem. 2016, 55, 6539−6551. (b) Goncalves, T. P.; Huang, K. W. Metal-Ligand Cooperative Reactivity in the (Pseudo)-Dearomatized PNx(P) Systems: The Influence of the Zwitterionic Form in Dearomatized Pincer Complexes. J. Am. Chem. Soc. 2017, 139, 13442−13449. (20) (a) Ligands related to bpy-6NH-iPrP with tert-butyl, phenyl, and adamantyl substituents on phosphorous have been used for the synthesis of Ru- and Co-based complexes; see: Huang, K.-W.; Chen, T.; He, L.; Gong, D.; Jia, W.; Yao, L. Phospho-Amino Pincer-Type Ligands and Catalytic Metal Complexes Thereof. US 2012/0323007, 2012. (b) Chen, T.; Li, H.; Qu, S.; Zheng, B.; He, L.; Lai, Z.; Wang, Z.-X.; Huang, K.-W. Hydrogenation of Esters Catalyzed by Ruthenium PN3-Pincer Complexes Containing an Aminophosphine Arm. Organometallics 2014, 33, 4152−4155. (c) Li, H.; Wang, Y.; Lai, Z.; Huang, K.-W. Selective Catalytic Hydrogenation of Arenols by a Well-Defined Complex of Ruthenium and Phosphorus−Nitrogen PN3−Pincer Ligand Containing a Phenanthroline Backbone. ACS Catal. 2017, 7, 4446−4450. (d) Zhao, J.; Chen, H.; Li, W.; Jia, X.; Zhang, X.; Gong, D. Polymerization of Isoprene Promoted by Aminophosphine(ory)-Fused Bipyridine Cobalt Complexes: Precise Control of Molecular Weight and cis-1,4-alt-3,4 Sequence. Inorg. Chem. 2018, 57, 4088−4097. (21) See the Supporting Information. (22) It is unclear at present why near-stoichiometric amounts of base are necessary to achieve catalytic turnover. Besides formation of the dearomatized catalyst species C, the base also appears necessary to complete the reduction cycle, as lower base loadings favor formation of the imine product (see Table S8). Also note that previous manganese-based catalyst systems for the N-alkylation of anilines have employed 0.2−1 equiv of base (see refs 12a,12c, 13d, 15, and 17e), whereas base-free manganese-based catalyst systems resulted in dehydrogenative coupling of the amine with the alcohol exclusively (see refs 6d and 11a). (23) Substituted phenols were insoluble under the given reaction conditions and therefore showed no reaction. Reactions with cyano and nitro substituents as well as carbonyl moieties are part of our ongoing research. (24) Attempts to utilize secondary amines, such as N-methylaniline, morpholine, or piperidine, have been unsuccessful so far. (25) Partial racemization of the stereocenter of (R)- and (S)phenylethylamine was observed during the reaction, indicating that slow dehydrogenation/hydrogenation of the amine does occur under these conditions.

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DOI: 10.1021/acs.orglett.9b00832 Org. Lett. XXXX, XXX, XXX−XXX