Organocatalytic Synthesis of Α‑Triphenylmethylamines from Diarylketimines and Phenols ‡ ‡ Danijel Glavac,̌Nikola Topolovcan,̌ and Matija Gredicaǩ*
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pubs.acs.org/joc Note Organocatalytic Synthesis of α‑Triphenylmethylamines from Diarylketimines and Phenols ‡ ‡ Danijel Glavac,̌Nikola Topolovcan,̌ and Matija Gredicaǩ* Cite This: J. Org. Chem. 2020, 85, 14253−14261 Read Online ACCESS Metrics & More Article Recommendations *sı Supporting Information ABSTRACT: A formal Betti reaction between variously substituted phenols and benzophenone-derived imines to afford α- triphenylmethylamines is reported. The key to the success of this transformation is the in situ generation of the reactive benzophenone iminium species under organocatalytic conditions. Different phenols reacted smoothly, enabling the synthesis of an array of α-triphenylmethylamines, which are highly valued structural motifs in bioactive molecules and chemical sensors. α-Tertiary amines, a class of amines adjacent to a tertiary well-developed and can provide access to α-diarylalkylmethyl- carbon atom, are an attractive structural subunit in bioactive amines,4 methodologies employing additions to benzophe- molecules,1 chemical sensors,2 and molecules used for none-derived imines are few and far between.5 The scarcity of subcellular imaging3 (Scheme 1). The usual strategy for their latter methodologies stems from remarkably low reactivity of preparation is the addition of carbon nucleophiles to ketimines. bis-aromatic ketimines, making arylation of benzophenone It follows that the most efficient approach for the synthesis of imines even more challenging. α-triphenylmethylamines would be the direct C-arylation of A few notable examples of the preparation of α- benzophenone imines, as their parent ketones are either triphenylmethylamines have appeared in the literature, though commercially available or can be prepared by well-known some of them within general studies on imine reactivity Downloaded via RUDJER BOSKOVIC INST on November 6, 2020 at 12:00:47 (UTC). 4b 4c synthetic routes. Although the arylation of alkyl-aryl imines is (Scheme 2). The Harutyunyan group and the Bode group reported 1,2-additions of Grignard reagents to activated See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Scheme 1. α-Tertiary Amines in Bioactive Molecules benzophenone imines. During the development of radical coupling reactions between aryl halides and 2-azaallyl species, Walsh et al. obtained α-triphenylmethylamine motifs in low yields as side products.6 In rhodium-catalyzed reactions, a series of enantioenriched α-triphenylmethylamines were prepared by employing cyclic N-sulfonyl benzophenone- derived imines as reactive electrophiles.7 This concept was extended to a series of palladium-catalyzed transformations,8 as well as to cyclic amides.9 Received: September 15, 2020 Published: October 28, 2020 © 2020 American Chemical Society https://dx.doi.org/10.1021/acs.joc.0c02225 14253 J. Org. Chem. 2020, 85, 14253−14261 The Journal of Organic Chemistry pubs.acs.org/joc Note a Scheme 2. Strategies toward α-Triphenylmethylamines Table 1. Screening of Reaction Conditions entry cat. (mol %) solvent time (h) yield (%) 1 pTsOH (20) toluene 16 77 2 PhCOOH (20) toluene 60 27 3 AcOH toluene 60 67 4H2SO4 (20) toluene 10 50 5 MsOH (20) toluene 12 98 · 6BF3 OEt2 (20) toluene 48 43 7 SnCl2 (20) toluene 24 53 8 Sc(OTf)2 (20) toluene 24 90 9 MsOH (20) o-xylene 24 82 10 MsOH (20) cyclohexane 4 92 11 MsOH (20) heptane 5 70 12 MsOH (10) cyclohexane 16 89b 13 MsOH (5) cyclohexane 48 tracesb 14 MsOH (10) cyclohexane 72 88b,c aReactions were carried out on a 0.2 mmol scale. bp-Chlorophenol (1.5 equiv). c60 °C. entry 4). On the other hand, methanesulfonic acid yielded product 1 in almost a quantitative yield after 12 h (entry 5). In contrast to these elegant examples, to the best of our Next, the catalytic efficiency of various Lewis acids was knowledge, there are no reports on the synthesis of α- investigated. In general, reaction times were significantly · triphenylmethylamines under organocatalytic conditions. The prolonged. BF3 OEt2 (43% yield, 48 h, entry 6) and SnCl2 development of such protocols would add a new dimension to (53% yield, 24 h, entry 7) successfully catalyzed the already existing methods, allowing more versatility in the transformation in moderate yields, while a substantially better preparation of these valuable structural units. yield was obtained by employing Sc(OTf)2 as a catalyst (90% Herein, we report a Brønsted acid-catalyzed formal Betti yield, 24 h, entry 8). reaction, a 1,2-addition of phenols to N-acyl benzophenone- After identifying methanesulfonic acid as the catalyst of ketimines, generated in situ from αN-hydroxy amides. The Betti choice for the transformation, the influence of solvent, reaction is a Mannich-type multicomponent reaction between temperature, and catalyst/reagent loading was investigated. aldehydes, primary amines, and naphthols for the synthesis of By conducting the reaction in o-xylene for 24 h at 80 °C, α-secondary amines, so-called Betti bases.10 Although phenols product 1 was isolated in 82% yield (entry 9). Significant can be used in the Betti reaction, 2-naphthols are preferred improvements in terms of reaction times were observed when nucleophiles because of their higher reactivity in comparison to cyclohexane (92% yield, 4 h, entry 10) and heptane (70% standard phenol derivatives, especially in rare examples yield, 5 h, entry 11) were used as solvents, respectively. The describing the formation of α-diarylalkylmethylamine prod- reaction maintained its effectiveness when the amount of p- ucts.11 In recent years, a number of methodologies were chlorophenol was lowered to 1.5 equiv, accompanied by 10 developed where reactive imine species were formed in situ mol % catalyst loading (89% yield, 16 h, entry 12). A further from their stable precursors, 3-hydroxyisoindolinones, and decrease in catalyst loading to 5 mol % resulted only in traces utilized in various transformations.12 On the basis of reported of the product, even after 48 h (entry 13). Finally, performing strategies, we reasoned that benzophenone-derived iminium the reaction under entry 11 parameters at 60 °C prolonged its species generated in this way might act as highly reactive time to 72 h (entry 14). Hence, the chosen reaction conditions electrophiles for poor nucleophiles, such as phenols, and for the formal Betti reaction include diarylketimine precursor enable 1,2-addition of aryl rings in a formal Betti reaction. (1.0 equiv), phenol (1.5 equiv), and methanesulfonic acid (10 We started our investigations by combining 3-phenyl 3- mol %) in cyclohexane at 80 °C. hydroxyisoindolinone 32 with p-chlorophenol in the presence With the optimized reaction conditions in hand (in terms of of various Brønsted and Lewis acids (Table 1). the ratio between the catalyst and reagent loading and Our initial attempt with p-toluenesulfonic acid in toluene at obtained yield), we turned our attention to investigate the 80 °C led to the desired product 1 within 16 h (77% yield, substrate scope and reaction limitations (Table 2). entry 1). Employing carboxylic acids as catalysts substantially The reaction maintained its effectiveness upon changing the prolonged reaction time; after 60 h, product 1 was isolated in halogen atom in the para position of the phenol to alkyl groups 27% (benzoic acid, entry 2) and 67% (acetic acid, entry 3) (2−5). In order to investigate the regioselectivity of the yield, respectively. By using a catalytic amount of sulfuric acid, reaction, m-cresol was employed as a nucleophile. Under the the reaction was completed within 10 h, though decomposition same reaction conditions, products 6 and 6′ were isolated in products were observed along with the product (50% yield, 81% yield as an inseparable mixture of ortho (6)vspara (6′) 14254 https://dx.doi.org/10.1021/acs.joc.0c02225 J. Org. Chem. 2020, 85, 14253−14261 The Journal of Organic Chemistry pubs.acs.org/joc Note a Table 2. Substrate Scope I: Phenols aReactions were carried out on a 0.2 mmol scale. bInseparable mixture of ortho and para addition products with respect to the hydroxy group. Ratio determined by 1H NMR. c2-(tert-Butyl)-4-methoxyphenol (5.0 equiv), pTsOH (20 mol %), 48 h. dSesamol (1.5 equiv), pTsOH (20 mol %), 16 h. addition products (with respect to the hydroxy group) in a 3:1 yield). Under the standard reaction conditions, the reaction ratio. The ratio between two regioisomers did not significantly with 1-naphthol resulted in an almost quantitative yield of change when the reaction was performed at 60 °C or at 100 product 14. °C, respectively (see Supporting Information for details). The Reactions with different dihydroxybenzenes were inves- introduction of activating and deactivating groups in the para tigated next. Employing catechol as a nucleophile resulted in position had little or no influence on product yield or the the addition through the para position with respect to one of reaction course (7−10, > 80% yield). In comparison to p- the hydroxy groups, generating more favorable 1,2,5-trisub- chlorophenol, the reaction with p-bromophenol resulted in a stituted product 15 in 75% yield. In reactions with quinol and significantly lower yield (11, 60% yield); however, the reaction resorcinol, products 16 and 17 were isolated in low yields did not lose its effectiveness when performed on a 1.0 g scale. (34% and 50% yield, respectively). Since starting isoindolinone Under the same conditions, the reaction with 2,4-disubstituted alcohol 32 was completely consumed in both reactions, this phenol afforded a complex reaction mixture in which product observation can be attributed to problems encountered during 12 was not detected. The reason most likely lies in the cleavage the isolation of products. By conducting the reaction with of aryl-methyl ethers with methanesulfonic acid under elevated orcinol, the addition occurred almost exclusively through temperatures.13 By switching the catalyst to p-toluenesulfonic carbon positioned between two hydroxy groups, with only acid and by increasing the amount of phenol to 5.0 equiv, traces of the other regioisomer visible in the NMR spectra (18, product 12 was obtained in 81% yield.