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Frustrated Lewis pair catalyzed hydrogenation of amides: halides as active Lewis base in the metal-free hydrogen activation Nikolai Sitte, Markus Bursch, Stefan Grimme, and Jan Henry Hakan Paradies J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12997 • Publication Date (Web): 13 Dec 2018 Downloaded from http://pubs.acs.org on December 13, 2018

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Journal of the American Chemical Society

Frustrated Lewis pair catalyzed hydrogenation of amides: halides as active Lewis base in the metal-free hydrogen activation Nikolai A. Sitte,a Markus Bursch,b Stefan Grimme,b* Jan Paradiesa* a

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

Supporting Information Placeholder ABSTRACT: A method for the metal-free reduction of carbox-

ylic amides using oxalyl chloride as activating agent and hydrogen as final reductant is introduced. The reaction proceeds via the hydrogen splitting by B(2,6-F2-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 a-branched carboxamides.

from H213 and may serve as reduction equivalent in the metalfree reduction of activated carboxamides (Scheme 1). Scheme 1. Metal-free reductions of amides. for sec. amides: R2 = H 1.05 equiv. Tf2O ref. 11 1.1 equiv. 2-fluoropyridine 1.1 equiv. Et3SiH 1.4 equiv. Hantzsch's ester for tert. amides ref. 12 1.1 equiv. Tf2O 2.5 equiv. Hantzsch's ester

O R1

R3

N

R1

R2

The 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 platinum6 or zinc7 and main group Lewis acids, like boronic acids8, 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 this light, frustrated Lewis pairs (FLP) offer a unique catalytic access to borohydrides

this for tert. amides work 1.5 equiv. (COCl)2 80 bar H2, 2 mol% B(2,6-F2-C6H3)3

N

R3

R2

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 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, 13c, 13f, 13g, 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-F2C6H3)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 Table 1. One-pot activation and FLP-catalyzed hydrogenation of amide 6a. X equiv. (COCl) 2 cat. BArF 3/additive (1:1)

O N 6a

entry

Ph

H 2, 70 °C, CDCl 3 – CO – CO2

cat. /mol%

ACS Paragon Plus Environment

add. 4 /mol%

Cl N

H N

Ph

Cl 5 in situ

equiv. (COCl)2

Ph + HCl

Cl 7a

H2 /bar

time /h

yield /%

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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

4 4 4 4 4 4 12 80

18 18 16 18 18 48 28 22

0 40 90 0 85 90 90 99

a

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

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 SI for details). However, in the presence of 20 mol% 2/4 or 3/4 the hydrochloride salt of N-benzyl piperidine (7a) was obtained within 18 h in 40% and 90% yield respectively (entry 2 and 3). These results are surprising, since the base is protonated under the reaction conditions and should no longer engage in the H2activation 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. oxalyl chloride and 80 bar 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 of 20 °C to 60 °C in the presence of a chloride source which assures the availability of free Lewis acid in solution.20 Halides have not yet been considered as Lewis base in borane-mediated H2 activation probably due to two obvious reasons. Firstly, the halide, particularly, chloride and fluoride, forms an irreversible adduct with strong Lewis acids. Secondly, 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 active component in the FLP-catalyzed hydrogenation of olefins19 and in the reduction of carbonyls.21 Systematic studies focusing on the FLP-reactivity in dependence 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 70 °C (Scheme 2). Scheme 2. H2/D2-scrambling using B(2,6-F2-C6H3)3 (3) and halides.

3 + Y X

H 2/D2 –HD CDCl 3

Page 2 of 6 [3–H/D]Y + H/D–X

X = Cl, Y = PPh 4 (8) NBu 4 (9) Y = BMIM X = Cl (10) Br (11) I (12)

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 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: 120 °C). Quantum-chemical 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 support the activity of halides as 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).

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 row 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, 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). Table 2. Substrate scope for the FLP-catalyzed reduction of amides.a


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Journal of the American Chemical Society 1.5 equiv. (COCl) 2 2 mol% B(2,6-F 2-C6H 3)3

O R2

N R1 R3 6a-ao

H 2 (80 bar), CHCl 3 40-70 °C – CO, – CO2

Products from benzoyl derivatives n = 5 (7a), 99% N Ph 4 (7b), 90% (CH 2)n 6 (7c), 97% nHex

R2

N O

H N R1 R 3 Cl 7a-an

Ph

Me 2N

7d, 97%

Ph cHex N Ph Ph N Ph Me R R = Me (7f), 90% 7h, 81% R = Me (7i), 73%b Et (7j), 85%b nHex (7g), 83% iPr, (7k), 73%b Ph (7l), 15% b Ph

N

7n, 0%

Ph

7e, 95%

N R

N

+ HCl

N

Ph

N

Ph

7m, 81%

Me

7p, 78%

7o, 65%c

from acetyl derivatives from cyclohexyl and pivaloyl derivatives Me nHex N N Me N Me N Me nHex c,d c,d 7q, 33% 7r, 26% 7w, 82% 7x, 45% from formyl derivatives Me Me Me Et Me Bn Me N N N N Me Me Et Me Me 7t, 94% 7y, 71% 7z, 76% 7s, 92% Me iPr Me Me N N N Me iPr Me Me 7u, 87% 7v, 94% 7aa, 76% functionalized derivatives R EtO N N N Ph O Me OMe R R = H (7ac), 91% R = NO 2 (7ae), 99% 7ab, 67%c OMe (7ad), 95% CN (7af), 99% N

N S

Ph

7ag, 96%

O O

7ah, 89%

N Ph Me 7aj, 87%b

7ak, 97%

Ph

7al, 76% (69% ee)b 62% (93% ee)b,e

7ai, 84%

N Et

Ph

ASSOCIATED CONTENT

N

acid sensitive groups MeO 2C TBDPSO N

Ph

Cl

7am, 65%

Ph N N Et

Ph

tBuO

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 a-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, the allyl amine 6aj or in the alkyne 6ak remained unchanged and the amines 7aj-ak were isolated in high to excellent yields. Even substrates bearing acid-sensitive groups were reduced in good yields. The proline derivative 7al was obtained in 65% yield in the presence of 1.0 equiv. of 2,6-di-tbu-pyridine with marginally diminished enantiomeric purity of 93% ee (without base 76%, 69% ee). The TBDPS- and even the Boc group were stable under the reaction conditions and enabled the reduction 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.

Ph

N O 7an, 70%e

The Supporting Information is available free of charge on the ACS Publications website: synthetic procedures, NMRspectroscopic data, quantum-mechanical details and structures as coordinates.xyz.

AUTHOR INFORMATION Corresponding Author

a

reactions were typically performed with 1 equiv. amide in CHCl3 (0.16 M), 2 mol% 3, 1.5 equiv .(COCl)2, 80 bar at 40-70 °C for 22h; b 5 mol% 3; c 20 mol% 3; d performed on NMR-scale; e in the presence of 1.0 equiv. 2,6-di-tBu-pyridine (7al) or 2,6lutidine (7an, 7ao); • denotes former position of the carbonyl group.

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 a-position (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

[email protected] [email protected] Funding Sources

German Science Foundation (DFG) and Gottfried Wilhelm Leibniz prize to SG. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT 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 SG) and for a stipend to N. Sitte.

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Journal of the American Chemical Society

25.

26.

Type between Three Atoms. J. Chem. Phys. 1943, 11, 299–300; (j) Muto, Y., Force between Nonpolar Molecules. Proc. Phys. Math. Soc. Jpn. 1943, 17, 629–631. Grimme, S.; Kruse, H.; Goerigk, L.; Erker, G., The Mechanism of Dihydrogen Activation by Frustrated Lewis Pairs Revisited. Angew. Chem. Int. Ed. 2010, 49, 1402-1405. The corresponding chloroimine is not protonated under the reaction conditions so that it remains unreactive to hydride addition. The calculated pKa of a chloro imine is ca. 5, whereas the pKa of of HCl is

27.

9.92 (exptl. 10.3, see SI for details). The chloro imin is not active as Lewis base in the H2-splitting with 3. Result of the high propensity of enamine formation of the corresponding chloro iminium chlorides and subsequent polymerization. Accordingly, aliphatic carboxamindes and lactones were not compatible with the reaction conditions.



Page 6 of 6

Insert Table of Contents artwork here O R1

N R2

R3

1.5 equiv. (COCl) 2 80 bar H 2 2 mol% B(2,6-F 2-C6H 3)3 R1 50-70 °C CHCl 3 – CO – CO2

N

R 3 • HCl

R2 39 examples up to 99% yield


6

Frustrated Lewis pair catalyzed hydrogenation of amides: halides as

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