Frustrated Lewis Pair Catalyzed Hydrogenation of Amides: Halides as

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Cite This: J. Am. Chem. Soc. 2019, 141, 159−162

Frustrated Lewis Pair Catalyzed Hydrogenation of Amides: Halides as Active Lewis Base in the Metal-Free Hydrogen Activation Nikolai A. Sitte,† Markus Bursch,‡ Stefan Grimme,*,‡ and Jan Paradies*,† †

University of Paderborn, Department of Chemistry, Warburger Strasse 100, D-33098 Paderborn, Germany University of Bonn, Mulliken Center for Theoretical Chemistry, Beringstr. 4, D-53115 Bonn, Germany

J. Am. Chem. Soc. 2019.141:159-162. Downloaded from pubs.acs.org by UNIV OF LOUISIANA AT LAFAYETTE on 01/09/19. For personal use only.

‡

S Supporting Information *

Scheme 1. Metal-Free Reductions of Amides

ABSTRACT: A method for the metal-free reduction of carboxylic amides using oxalyl chloride as an activating agent and hydrogen as the final reductant is introduced. The reaction proceeds via the hydrogen splitting by B(2,6F2-C6H3)3 in combination with chloride as the Lewis base. Density functional theory calculations support the unprecedented role of halides as active Lewis base components in the frustrated Lewis pair mediated hydrogen activation. The reaction displays broad substrate scope for tertiary benzoic acid amides and α-branched carboxamides.

T

he reduction of carboxylic amides is one of the most important key transformations in preparative chemistry on both the laboratory and industrial scale. The development of mild, chemoselective, and robust general methods relying on catalytic reactions is of great importance for the pharmacological industry, since this serves as a platform for the implementation of the structural diversity of amines. Most abundant reductions of carboxamides require strong nucleophilic “ate” hydride donors, such as aluminum or boron reagents. Catalytic processes are highly demanded because of the reduced functional group tolerance, safety issues of these pyrophoric reagents, and byproduct separation. The most desirable reduction of carboxylic amides with molecular hydrogen1 (H2) was reported in 1934 by the use of a heterogeneous Cu/Cr catalyst and required over 990 bar at 250 °C.2 These drastic conditions were improved (10−30 bar, 160 °C) by the application of a bimetallic Pd/Re@graphite3 and a homogeneous ruthenium catalyst.4 Milder amide reductions were realized using stoichiometric hydrosilane based reduction equivalents in combination with metals, e.g. iron,5 platinum,6 or zinc,7 and main group Lewis acids, such as boronic acids,8 B(C6F5)3 (1),9 and electrophilic phosphonium cations.10 Triflic anhydride proved to be a useful, but difficult to handle, carbonyl activation agent for the direct reduction with Hantzsch’s esters11 or silanes,12 with the significant drawback of producing stoichiometric amounts of byproducts. In light of this, frustrated Lewis pairs (FLP) offer a unique catalytic access to borohydrides from H213 and may serve as a reduction equivalent in the metal-free reduction of activated carboxamides (Scheme 1). Here we present the metal-free hydrogenation of carboxamides to amines in excellent yields under mild conditions (50−70 °C, 80 bar), taking advantage of oxalyl chloride as an © 2018 American Chemical Society

activating reagent. The produced amines are furnished as hydrochloride salts, enabling the most convenient isolation by filtration. Mechanistic details support the unparalleled role of chloride as the Lewis base in the frustrated Lewis pair catalyzed hydrogenation.13a,c,f,g,14 We initiated our investigation using the FLP system consisting of B(C6F5)3 (1), B(2,4,6-F3-C6H2)3 (2),15 or B(2,6-F2-C6H3)3 (3)15,16 in combination with 2,6-lutidine (4) and the in situ generated chloroiminium chloride 5 from the reaction of the amide 6a with oxalyl chloride (Table 1).17,18 The hydrogenation of 6a with the FLP 1/4 was not observed because 1 was inhibited by the chloride (entry 1) as evidenced by the 11B NMR resonance at 6.53 ppm (see Supporting Information (SI) for details). However, in the presence of 20 mol % 2/4 or 3/4 the hydrochloride salt of Nbenzyl piperidine (7a) was obtained within 18 h in 40% and 90% yield respectively (entries 2 and 3). These results are surprising, since the base is protonated under the reaction conditions and should no longer engage in the H2-activation event. Control experiments clearly revealed that the borane is necessary for the hydrogenation (entry 4) whereas the Lewis base 2,6-lutidine (4) had essentially no impact on the reaction (entry 5). The catalyst loading could be reduced to 2 mol % using 1.5 equiv of oxalyl chloride and 80 bar of H2 at 70 °C in the absence of a supporting base (entries 6−8). Further studies support chloride operating as a weak Lewis base in the transient19 FLP-mediated H2-activation. In contrast to 1, the boranes 2 and 3 show dynamic 11B NMR spectra in the temperature range 20 to 60 °C in the presence of a chloride Received: December 4, 2018 Published: December 13, 2018 159

DOI: 10.1021/jacs.8b12997 J. Am. Chem. Soc. 2019, 141, 159−162

Communication

Journal of the American Chemical Society

support the activity of halides as an active Lewis base in the heterolytic splitting of H2 in combination with 3. The reaction of 3 with dihydrogen and a halide cation pair [Me4N]X was investigated in chloroform at 50 °C for X = Cl−, Br−, and I−. For all three halides, transition states (TS(X)) for a H2 splitting with 3 were identified in a thermally accessible energy range (Figure 1).

Table 1. One-Pot Activation and FLP-Catalyzed Hydrogenation of Amide 6aa

entry

cat./ mol %

add. 4/ mol %

equiv (COCl)2

1 2 3 4 5 6 7 8

20 (1) 20 (2) 20 (3) 0 20 (3) 10 (3) 5 (3) 2 (3)

20 20 20 20 − − − −

1.0 1.0 1.0 1.0 1.0 1.2 1.5 1.5

H2/bar time/h 4 4 4 4 4 4 12 80

18 18 18 18 18 48 28 22

yield/% 0 40 90 0 85 90 90 99

a

Conditions: 2−20 mol % 3, 0−20 mol % 4, 0.1 mmol of 6a in CDCl3 (0.16 M), 1 to 1.5 equiv of oxalyl chloride (in 0.2 mL CDCl3), 4−80 bar of H2.

source which assures the availability of free Lewis acid in solution.20 Halides have not yet been considered as a Lewis base in borane-mediated H2 activation probably due to two obvious reasons. First, the halide, particularly, chloride and fluoride, forms an irreversible adduct with strong Lewis acids. Second, the basicity of the halide decreases dramatically going from fluoride to iodide. However, very weak Lewis bases, e.g. fluorinated phosphanes or ethers, have been reported as an active component in the FLP-catalyzed hydrogenation of olefins19 and in the reduction of carbonyls.21 Systematic studies focusing on the dependence of FLP-reactivity on the pKa of the conjugate Brønsted acid15a,16a,19a support that chloride should be able to activate H2 (pKa (MeCN): 10.30)22 provided that it does not deactivate the Lewis acid (vide supra). We were able to exclude the amide and the chloroimine, which may arise from nucleophilic ring opening23 as active Lewis bases in the H2 splitting (see SI). Instead we observed the fast isotope scrambling of a H2/D2 mixture by 3 in the presence of the chloride sources 8, 9, and 10 at 50−70 °C (Scheme 2).

Figure 1. Relative Gibbs energy diagram of the H2 splitting reactions. All energies given are in kcal/mol relative to the corresponding separated reactants. A = Me4N+; R = 2,6-F2-C6H3; X = Cl− (green), Br− (red), I− (purple).

All investigated reactions are endergonic giving rise to the observed transient formation of a borohydride upon H2 splitting at the given reaction conditions as evidenced by the NMR experiments. The observed trend of energetically higher lying transition states in the order Cl < Br < I is reflected by the increased demand of heating upon using Br and I salts. The bond length of the split hydrogen molecule in the TS increases from Cl over Br to I as bases. The value computed for the most active system of about 0.8 Å is similar to that observed in typical P···B FLP systems and points to an early TS.25 The substrate scope of the metal-free hydrogenation of amides was explored (Table 2). Benzoic amides bearing cyclic and acyclic alkyl chains, heterocycles, or aromatic substituents were hydrogenated in excellent yields (7a−k). Notably, small N-Me substituted amides as well as amides bearing steric encumbrance in the αposition (6m) were reduced in excellent yields. Highly reactive aromatic compounds, e.g. the diphenylamine 6l and the indole 6n, decomposed under the reaction conditions. However, electron-rich compounds such as indoline 6o or the lactam 6p cleanly underwent reduction in high yields. Benzoic amides derived from primary amides were cleanly activated, but the corresponding chloro imines were not susceptible to FLPcatalyzed hydrogenation.26 Nonetheless, the protocol enables the reduction of amides derived from aliphatic carbonic acids (6q−6aa). The acetyl derivatives 7q and 7r were obtained in low yields.27 However, the formyl and branched amides 6s− 6aa were converted to the corresponding N-methyl amines 7s−v and α-branched amines 7w−7aa in high to excellent yields. Furthermore, we investigated the functional group tolerance of the reaction. Esters, ethers, nitro, cyano, or thiophenyl groups were well tolerated (7ab−ag, 67−99%). Amides bearing reactive multiple bonds as in the acrylate 6ai,

Scheme 2. H2/D2-Scrambling Using B(2,6-F2-C6H3)3 (3) and Halides

HD was unmistakably identified by its 1H NMR resonance at 4.43 ppm with the characteristic coupling constant of 1JHD = 43 Hz. The three chloride sources 8, 9, and 10 featured identical performance in the H/D exchange supporting the role of the chloride as an active Lewis base. Importantly, the BMIM bromide and iodide salts 11 and 12 also displayed activity in the H/D scrambling; however, elevated temperatures were required (11, 70 °C; 12, 90 °C). Quantumchemical investigations at the PW6B95-D3(BJ, ATM) + COSMO-RS (CHCl3)/def2-QZVP//PBEh-3c + COSMO(CHCl3)24 level of theory (see SI for further details) strongly 160

DOI: 10.1021/jacs.8b12997 J. Am. Chem. Soc. 2019, 141, 159−162

Communication

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of silyl ether 6am and of the carbamate 6an in 65% and 70% yield, respectively. In summary, we developed the FLP-catalyzed hydrogenation of carboxylic amides with the aid of oxalyl chloride as a deoxygenating agent. Mechanistic and quantum-mechanical investigations strongly support the role of halides in the FLPmediated H2-activation. The reaction displays broad generality and high functional group tolerance, providing access to tertiary amines in the presence of hydride sensitive functional groups.

Table 2. Substrate Scope for the FLP-Catalyzed Reduction of Amidesa

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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/jacs.8b12997. Synthetic procedures, NMR spectroscopic data, and quantum-mechanical details (PDF) Structures as coordinates (XYZ)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Stefan Grimme: 0000-0002-5844-4371 Jan Paradies: 0000-0002-3698-668X Funding

German Science Foundation (DFG) and Gottfried Wilhelm Leibniz prize to S.G. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The German science foundation (DFG) and the Fonds der Chemischen Industrie (FCI) are gratefully acknowledged for financial support (PA 1562/6-1 and Gottfried Wilhelm Leibniz prize to S.G.) and for a stipend to N.A.S.

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REFERENCES

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