Letter pubs.acs.org/acscatalysis
Deoxygenative Hydrogenation of Amides Catalyzed by a Well-Defined Iridium Pincer Complex Ming-Lei Yuan,† Jian-Hua Xie,† Shou-Fei Zhu,† and Qi-Lin Zhou*,†,‡ †
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
‡
S Supporting Information *
ABSTRACT: The iridium-catalyzed highly chemoselective hydrogenation of amides to amines has been developed. Using a well-defined iridium catalyst bearing a P(O)C(O)P pincer ligand combined with B(C6F5)3, the C−O cleavage products are formed under mild reaction conditions. The reaction provides a new method for the preparation of amines from amides in good yield with high selectivity. KEYWORDS: amide, deoxygenative hydrogenation, boron Lewis acid, iridium pincer complex, homogeneous catalysis
A
found that using boron Lewis acids such as B(C6F5)3 or BCl3 to activate the amide bond, the reaction could be achieved with high selectivity by using well-defined iridium catalysts 6, which bear a P(O)C(O)P pincer ligand (Scheme 1). Specifically,
s a common functional group, amides have always attracted the attention of organic chemists.1 One of the most important conversions of amides is deoxygenative reduction of amides to corresponding amines.2 Traditionally, a stoichiometric amount or an excess of a reducing hydride reagent such as LiAlH4, boranes,2 or silanes3 is used for this transformation. However, owing to the hazardous nature of these reagents, the difficult workup procedures, and the high level of residual waste, the use of this method for industrial applications is problematic. Catalytic deoxygenative reduction of amides with hydrogen would be an efficient method for the preparation of amines.4 However, the hydrogenation of amides is much more challenging than the hydrogenation of other carboxylic derivatives because of the high stability of amides and the difficulty in achieving selectivity between deoxygenative hydrogenation (C−O cleavage) and deaminative hydrogenation (C−N cleavage). Several heterogeneous catalysts have been developed for the deoxygenative hydrogenation of amides, and bimetallic catalysts show particularly good conversions and high selectivity. However, heterogeneous catalysts generally require harsh conditions and have a narrow substrate scope and limited functional group tolerance. For example, in reactions of aromatic amides, the aromatic rings are generally hydrogenated along with the amide group.5 Homogeneous catalysts can also be used to hydrogenate amides with tunable selectivity under relatively mild conditions. Remarkable progress in deaminative hydrogenation of amides with homogeneous catalysts has been achieved;6 however, deoxygenative hydrogenation of amides remains a challenge. Only one type of catalyst, a ruthenium complex with a triphos ligand, has been reported to show good selectivity for deoxygenative hydrogenation of amides.7 Recently, we developed several iridium and ruthenium catalysts for the hydrogenation of esters to alcohols under mild reaction conditions.8 In this study, as part of our ongoing work on catalytic hydrogenation of carboxylic derivatives, we investigated the deoxygenative hydrogenation of amides and © XXXX American Chemical Society
Scheme 1. Iridium-Catalyzed Highly Chemoselective Hydrogenation of Amides to Amines
various amines 2 were prepared in high yield with excellent selectivity by means of efficient catalytic deoxygenative hydrogenation of amides 1. We herein report the novel highly selective iridium-catalyzed hydrogenation of amides to amines in the presence of boron Lewis acids. Received: April 8, 2016 Revised: May 4, 2016
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ACS Catalysis Initially, iridium pincer complexes 4−69 (Scheme 1) were tested for the catalytic hydrogenation of N-phenylacetamide (1a) under 50 atm H2 at 120 °C in toluene (Table 1). Inspired by a
reaction was changed to 1 mmol scale, no significant change was observed in both yield and selectivity (entry 14). Although frustrated Lewis pairs were recently shown to catalyze hydrogenation of polarized double bonds,14 neither B(C6F5)3 itself nor the combination with P(O)C(O)P-phosphine ligand (or the amine product 2a) was active for the hydrogenation of 1a (see Table S1 in SI). Under the optimal reaction conditions, the substrate scope of this iridium-catalyzed hydrogenation of amides was investigated (Table 2). The hydrogenation of acetanil derivatives with various N-aryl moieties (1a−n) smoothly gave the desired deoxygenative products in high isolated yields (73−91%) with excellent selectivities (2/3 = 12:1−45:1) (entries 1−14). The steric and electronic properties of the substituents on the benzene ring of the amides have little influence on either the yield or the selectivity of the reaction. The hydrogenation of N-(naphthalen-1-yl)acetamide (1m) was slow, owing to its poor solubility in toluene (entry 13). N-Aniline amides with various acyl moieties (1o−v) underwent the deoxygenative hydrogenation reaction in good to excellent isolated yields (70−96%) with excellent selectivities (2/3 = 8:1−49:1) (entries 15−22). However, the yield with an amide with a bulky isobutyryl group (1q) was lower (entry 17), and full conversion of amides with an aromatic acyl group (1u) or an aromatic heterocycle (1t and 1v) required a catalyst loading of 5 mol % (entries 20−22). Note that substrates bearing a heteroatom such as N, O, or S in either the benzene ring or the acyl group (1k, 1l, 1n, 1s, 1t, and 1v) required an additional equivalent of B(C6F5)3 for full conversion. (entries 11, 12, 14, 19, 20, and 22). Hydrogenation of lactams was also evaluated under the standard reaction conditions. Lactams with a six- or seven-membered ring (1w and 1x) were suitable substrates, affording full conversion, high yield, and excellent selectivity (entries 23 and 24). However, lactam 25, which has a fivemembered ring, gave a low yield, although the selectivity was excellent (entry 25). The secondary amides containing functional group such as methyl 4-acetamidobenzoate and N-(4-nitrophenyl)acetamide were also hydrogenated, and the desired amine products were obtained in low yield.15 Primary amides such as benzamide and butyramide were tested under optimized conditions, but no reaction occurred. To gain insight into the mechanism of this deoxygenative hydrogenation reaction of amides, we performed a deuteration reaction of N-(p-tolyl)acetamide (1d) (Scheme 2). Deuterium incorporation at the α-CH2 position was high (>95%) in product 2d, whereas there was almost no deuterium incorporated in the β-CH3 group, which suggests that an imine might be a key intermediate in the reaction (Scheme 2a). This hypothesis was further supported by the fact that N-(p-tolyl)ethanimine prepared independently could be hydrogenated with catalyst 6b under the same reaction conditions used for 1d just without adding B(C6F5)3 (Scheme 2b). No interaction between the iridium hydride complexes and B(C6F5)3 indicated that B(C6F5)3 only react as Lewis acid in this catalytic system (Scheme 2c).16 On the basis of the aforementioned experiments we propose the following mechanism for the iridium-catalyzed deoxygenative hydrogenation of amides17 (Scheme 3). First, the chloride atom of 6b is exchanged for NaBArF, and subsequent hydrogenation generates active cationic catalyst A (step a). Electron-deficient B(C6F5)3 (LA) facilitates transformation of the amide group of the substrate from a neutral state to a zwitterionic state (B),18 which is protonated by A to form
Table 1. Iridium-Catalyzed Hydrogenation of 1a
entrya
Ir
additive
Lewis acid
conv. (%)b
yield (%)b
selectivity (2a/3a)b
1 2 3 4 5 6 7 8 9c 10 11 12 13 14f
4a 4b 4c 5a 5b 5b 6a 6b 6b 6b 6b 6b 6b 6b
− − − − − NaBArF NaBArF NaBArF NaBArF NaBArF NaBArF NaBArF NaBArF NaBArF
B(C6F5)3 B(C6F5)3 B(C6F5)3 B(C6F5)3 B(C6F5)3 B(C6F5)3 B(C6F5)3 B(C6F5)3 B(C6F5)3 B(C6H5)3 BEt3d BF3·OEt2 BCl3e B(C6F5)3
0 0 0 40 8 60 92 92 94 2 70 0 63 91
− − − 37 7.8 59 88 89 (85) 90 (86) 2 62 0 63 91 (89)
− − − 12:1 50:1 48:1 20:1 32:1 30:1 100:0 17:1 − 100:0 31:1
a
Reaction conditions: 0.1 mmol 1a, 2 mol % [Ir], 2 mol % additive, 0.1 mmol Lewis acid, 0.5 mL toluene, 50 atm H2, 120 °C, 24 h. b Conversions, yields, and selectivities were determined by GC analysis using triphenylamine as an internal standard; isolated yields are given in parentheses. c36 h. dBEt3 using as 1 M solution in n-hexane. e BCl3 using as 1 M solution in n-heptane. fUsing 1 mmol 1a.
report on the use of Lewis acids as activators for nucleophilic additions of amides, we added one equivalent of B(C6F5)3 in an attempt to facilitate the deoxygenative hydrogenation.10 Although complexes 4a−c failed to catalyze the hydrogenation of 1a (entries 1−3), PCP-Ir(III) dihydride complex 5a was active, giving deoxygenative product N-ethylaniline 2a in 37% yield with 12:1 C−O/C−N selectivity (2a/3a) (entry 4). Chloroiridium hydride complex 5b also catalyzed the hydrogenation of 1a, but with low conversion and yield (entry 5). Noting that the counterion of iridium catalysts has been reported to strongly influence both the activity and the selectivity of catalysts in hydrogenation reactions,11 we introduced 2% mol NaBArF (BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) to provide an anion for exchange with the chloride anion of 5b.12 As expected, the addition of NaBArF significantly improved the yield and selectivity of the reaction (entry 6). P(O)C(O)P−Ir(III) complexes 6a and 6b exhibited much higher activity than 5b in the presence of both B(C6F5)3 and NaBArF (entries 7 and 8), with 6b giving the best performance (92% conversion, 85% isolated yield, 2a/3a = 32:1). Other boron Lewis acids such as BEt3, BPh3, BF3·OEt2, and BCl3 were also examined. Reactions in the presence of BEt3 or BCl3 gave the desired deoxygenative product 2a, but the conversion and yield were lower than those with B(C6F5)3 (entries 11 and 13). However, neither BPh3 nor BF3·OEt2 showed activity in the reaction (entries 10 and 12). When the reaction time was increased to 36 h, only a little improvement in the yield was achieved with a slight drop in selectivity (entry 9).13 Further experimental studies on the additives, hydrogen pressure, solvents, and temperature failed to improve the reaction outcome (see Tables S1−S3 in SI). When the 3666
DOI: 10.1021/acscatal.6b01019 ACS Catal. 2016, 6, 3665−3669
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ACS Catalysis Table 2. Iridium-Catalyzed Hydrogenation of Amides: The Substrate Scope
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ACS Catalysis Table 2. continued
Reaction conditions: 0.1 mmol amide, 2 mol % 6b, 2 mol % NaBArF, 0.1 mmol B(C6F5)3, 0.5 mL toluene, 50 atm H2, 120 °C, 24 h. Conversions, yields, and selectivities were determined by GC analysis using triphenylamine as an internal standard; isolated yields are given in parentheses. c0.2 mmol B(C6F5)3. d36 h. e5 mol % 6b, 5 mol % NaBArF.
a b
The boron Lewis acid then promotes dehydration of D to produce imine intermediate E and Ir(H)2 (step d). Finally, reduction of E by Ir(H)2 yields the amine product and regenerates catalyst A (step e). In summary, we report a novel highly efficient iridiumcatalyzed hydrogenation of amides to amines. Well-defined iridium complexes bearing a P(O)C(O)P pincer ligand combined with boron Lewis acids showed high activity and good to excellent selectivity for deoxygenative hydrogenation of aromatic and aliphatic amides, as well as lactams. This method shows higher chemoselectivity than the previously reported method and gives a new strategy to improve the reactivity and control the selectivity in the hydrogenation of amides by adding boron Lewis acid as activator. Further studies to elucidate the detailed mechanism and to enhance the activity and selectivity of the catalysts are underway in our laboratory.20
Scheme 2. Control Experiments: (a) Deuterium Labeling Study; (b) Catalytic Hydrogenation of N-(p-Tolyl)ethanimine; (c) Interaction between Ir Complexes and B(C6F5)3
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b01019. Experimental procedures and analytical data of the products (PDF)
Scheme 3. Proposed Mechanism
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China, the National Basic Research Program of China (2012CB821600), and the “111” project (B06005) of the Ministry of Education of China for financial support.
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REFERENCES
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intermediate C via heterocleavage of the coordinated H2 molecule (step b).19 Hydrogenation of C by the Ir(H)2 complex affords hemiaminal intermediate D and regenerates catalyst A.3d 3668
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(11) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897−2899. (b) Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 12886−12891. (12) (a) Findlater, M.; Cartwright-Sykes, A.; White, P. S.; Schauer, C. K.; Brookhart, M. J. Am. Chem. Soc. 2011, 133, 12274−12284. (b) Findlater, M.; Schultz, K. M.; Bernskoetter, W. H.; CartwrightSykes, A.; Heinekey, D. M.; Brookhart, M. Inorg. Chem. 2012, 51, 4672−4678. (13) The product N-ethylaniline (2a) could not convert to N-phenylacetamide (1a) with one equivalent H2O under the reaction conditions in 24 h. (14) Stephan, D. W.; Erker, G. Angew. Chem., Int. Ed. 2015, 54, 6400−6441. (15) In the hydrogenation of 4-acetamidobenzoate, the deoxygenative reduction product, methyl 4-(ethylamino)benzoate was obtained in 15% yield; the main byproduct was the ester reduction product, N-(4-(hydroxymethyl)phenyl)acetamide (80%). (16) B(C6F5)3 is known to be able to abstract hydrides from some organometallic species; for ref see: Yang, X.; Stern, C. L.; Marks, T. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 1375−1377 The chloroiridium hydride complex 6b and its corresponding iridium dihydride complexes reacted with B(C6F5)3 in toluene-d8 at 120 °C for 4 h, and no change was observed in both 1H and 31P NMR spectra.. (17) For the mechanism study of the ruthenium-catalyzed hydrogenation of amides, see ref 7b. (18) When heating the mixture of N-phenylacetamide and one equivalent B(C6F5)3 mixed in toluene-d8 at 120 °C for 10 h, server rotational isomers of the boron-amide adduct were observed by carefully checking the NMR spectrum. (19) For other iridium-catalyzed hydrogenation involving heterocleavage of the coordinated H2, see: (a) Dobereiner, G. E.; Nova, A.; Schley, N. D.; Hazari, N.; Miller, S. J.; Eisenstein, O.; Crabtree, R. H. J. Am. Chem. Soc. 2011, 133, 7547−7562. (b) Manas, M. G.; Graeupner, J.; Allen, L. J.; Dobereiner, G. E.; Rippy, K. C.; Hazari, N.; Crabtree, R. H. Organometallics 2013, 32, 4501−4506. (20) Using catalytic amount of B(C6F5)3 was tested. When 10 mol% B(C6F5)3 and 20 mol% scavengers to remove the formed water was used in the iridium-catalyzed hydrogenation of N-phenylacetamide (1a), moderate conversion (31−64%) and selectivity (4:1−30:1) were achieved. For details, see SI, Table S4.
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