Catalytic Amination of β-(Hetero)arylethyl Ethers by Phosphazene

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

Catalytic Amination of β‑(Hetero)arylethyl Ethers by Phosphazene Base t‑Bu-P4 Masanori Shigeno,* Ryutaro Nakamura, Kazutoshi Hayashi, Kanako Nozawa-Kumada, and Yoshinori Kondo* Department of Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai, 980-8578, Japan

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S Supporting Information *

ABSTRACT: We describe the catalytic amination of β(hetero)arylethyl ethers with amines using the organic superbase t-Bu-P4 to obtain β-(hetero)arylethylamines. The reaction has a broad substrate scope and allows the transformations of electron-deficient and electron-neutral β-(hetero)arylethyl ethers with various amines including pyrrole, N-alkylaniline, diphenylamine, aniline, indole, and indoline derivatives. Mechanistic studies indicate a two-reaction pathway of MeOH elimination from the substrate to form a (hetero)arylalkene followed by the hydroamination of the alkene.

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arbon−nitrogen bond formations using readily and widely available amine nucleophiles are of great importance for synthesizing functional molecules in pharmaceuticals, agrochemicals, and material sciences.1 Various strategies available for C−N bond formation include nucleophilic substitution of alkyl (pseudo)halides, transitionmetal-catalyzed cross-coupling, or SNAr reactions of aryl (pseudo)halides, imine reduction, and the nucleophilic addition of carbon-nucleophiles to imine derivatives.1,2 In addition to these approaches, hydroamination of (hetero)aryl alkenes in an anti-Markovnikov fashion has become a powerful tool in organic chemistry, because the protocol allows a highly atom-economic preparation of β-(hetero)arylethylamines, an important scaffold in biologically active molecules (Figure 1a).3,4 The hydroamination of alkenes is catalyzed by transition metals,5 rare earth metals,6 Brønsted bases,7,8 photocatalysts,9 Brønsted acids, and Lewis acids.10 Despite its wide applicability in hydroaminations, however, the compatibility of the alkene functional group in multistep transformations, used for the synthesis of complex or highly functional molecules, is rather low because of its relatively high reactivity under varied reaction conditions.2a,11 In view of the challenge, the development of a novel type of anti-Markovnikov hydroamination using a robust chemical functionality is highly attractive and merits study. We previously reported the substitution reactions of methoxy groups in aryl and heteroaryl substrates by alcohol and amine nucleophiles using the organic superbase t-Bu-P412 as a catalyst (Figure 1, (i)).13,14 In a related study, Bandar and co-workers showed that the hydroalkoxylation of (hetero)aryl alkenes with alcohols proceeds reversibly under t-Bu-P4 catalysis (Figure 1, (ii)).15 Building on our understating of these processes, we report herein the facile catalytic synthesis of β-(hetero)arylethylamines via exchange of the methoxy © XXXX American Chemical Society

Figure 1. β-(Hetero)arylethylamine formations based on antiMarkovnikov addition and t-Bu-P4-catalyzed reactions underlying this study.

Received: July 4, 2019

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DOI: 10.1021/acs.orglett.9b02309 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters group in β-(hetero)arylethyl ethers using t-Bu-P4 (Figure 1c).16 The reaction has a broad substrate scope. Electrondeficient and neutral phenethyl ethers with various substituents such as trifluoromethyl, cyano, halo, and methoxy groups can be efficiently used in the developed amination reaction. Heteroaryl groups such as pyridine and benzothiophene are also compatible with the reaction conditions. Various amine nucleophiles such as pyrrole, indoles, N-alkyl anilines, diphenylamine, aniline, and indolines were successfully used in the reaction. In comparison to the formally similar reactions using β-(hetero)arylethyl (pseudo)halides as electrophiles, the present system is beneficial in avoiding the formation of stoichiometric inorganic salt wastes. Mechanistic studies were carried out to probe the processes of the reaction. The reaction mechanism involves the formation of a (hetero)aryl alkene intermediate in situ by the elimination of methanol from the substrate followed by hydroamination by an amine nucleophile. We began the evaluation of the amination reaction using phenethyl ether 1a bearing a trifluoromethyl moiety as the test substrate and pyrrole 2a as the nucleophile, in the presence of catalyst t-Bu-P4 (Table 1). The reaction conducted at 40 °C

highlights the critical role of t-Bu-P4 in this reaction (Table S1).18 With the optimized conditions in hand, we explored the scope of various β-(hetero)arylethyl ethers under the reaction conditions (Figure 2). Substrate 1b bearing an electron-

Table 1. Optimization of the Amination Conditions of 1a and 2aa

Entry

Deviation from standard conditions

3aa (%)b

1 2 3 4 5 6 7 8 9

None 40 °C, without 3 Å MS 40 °C 40 °C, 4 Å MS instead of 3 Å MS 40 °C, 5 Å MS instead of 3 Å MS 10 mol % of t-Bu-P4 1,4-dioxane as solvent toluene as solvent Scale-up of the reaction

92 (9)c 61 60 44 43 84 (8)c 90d

a

Standard conditions: 1a (0.20 mmol), 2a (0.40 mmol), t-Bu-P4 (0.04 mmol), 3 Å MS (70 mg), THF (0.3 mL), 60 °C, 12 h. bIsolated yields. cThe yields in parentheses were determined by 1H NMR spectroscopy with 1,1,2-trichloroethane as an internal standard. d1a (1.0 mmol), 2a (2.0 mmol), t-Bu-P4 (0.20 mmol), 5 Å MS (350 mg), THF (1.5 mL), 60 °C, 12 h.

Figure 2. Scope of β-(hetero)arylethyl ethers 1 in catalytic amination reaction.a,b a Reactions were conducted on a 0.2 mmol scale. b Isolated yields. c Reaction was conducted in 1,4-dioxane at 130 °C. d Reaction was conducted in 1,4-dioxane at 110 °C. e Reaction was conducted for 24 h. f Reaction was conducted at 90 °C.

withdrawing cyano group at the para-position afforded product 3ba in 83% yield. Halogen substituents (Cl and Br) are compatible in the reaction and afforded products 3ca and 3da in 87% and 88% yields, respectively. Substitutions at the orthoposition of the phenyl ring with trifluoromethyl, cyano, fluoro, and chloro groups furnished the desired products 3ea−3ha in high yields of 90%, 95%, 73%, and 88%, respectively. The uses of naphthalene (1i) and biphenyl (1j) derivatives also delivered the amination products 3ia and 3ja in excellent yields of 93% and 87%, respectively. The use of electronically neutral phenyl substrate 1k resulted in the formation of the corresponding product 3ka in 79% yield, while the methoxy substitution in substrate 1l gave the product in 73% yield. Electronically rich substrate 1m did not provide the product 3ma.19 Then, the reaction of α-substituted substrate 1n was

afforded the desired product 3aa, albeit in a low NMR yield of 9% (entry 2).17 The reactions were then carried out in the presence of 3 Å molecular sieves to trap the methanol generated in the reaction, which resulted in the formation of 3aa in a much improved yield of 61% (entries 3−5). We were pleased to find an increase in the yield of 3aa to 92% with an increase in the reaction temperature to 60 °C (entry 1). The yield of the product decreased with the use of lower equivalents of t-Bu-P4 (10 mol %, entry 6). The use of dioxane as the reaction solvent afforded 3aa in a high yield of 84%, while toluene gave a lower yield of 8% (entries 7 and 8). When scaling up the reaction to 1.0 mmol, a high yield of 90% was obtained (entry 9). Use of other Brønsted bases was completely ineffective for the formation of 3aa, which B

DOI: 10.1021/acs.orglett.9b02309 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Having explored the scope of the amination reaction, we conducted experiments to gain insights into the mechanism of amination (Figure 4). Substrate 1i was subjected to the

carried out, which resulted in the production of 3na in 67% yield. The amination of 2,2-diphenylethy ether 1o also proceeded to furnish the product 3oa in 57% yield. We next evaluated the scope of heteroaryl substituents in this reaction. 4- and 2-Pyridyl-containing substrates 1p and 1q afforded the products in 87% and 83% yields, respectively, while the use of benzothiophene derivative 1r allowed amination in 87% yield. To broaden the substrate scope in the present catalytic amination, a variety of amine nucleophiles were tested with 1a (Figure 3). N-Methylaniline 2b and its derivatives 2c−2f,

Figure 4. Mechanistic studies. a The yield was determined by 1H NMR spectroscopy with 1,1,2-trichloroethane as an internal standard.

reaction conditions in the absence of the amine nucleophile, which resulted in the formation of the corresponding styrene derivative 4i by the elimination of methanol.15 The reaction of 4i with 2a was carried out, which resulted in the formation of the aminated product 3ia. The use of 4-(trifluoromethyl)benzyl methyl ether 5 in the reaction conditions afforded no amination products, which eliminates the possibility of an SN2 reaction pathway. These reactions clearly indicate the intermediacy of the alkene product. Based on these results, we propose the mechanism described in Figure 5, which involves two distinct processes by t-Bu-P4.

Figure 3. Scope of amines 2 in the catalytic amination reaction.a,b Reactions were conducted on a 0.2 mmol scale. b Isolated yields. c Reaction was conducted at room temperature for 24 h. d Reaction was conducted at 40 °C. e Reaction was conducted in 1,4-dioxane at 130 °C. f Reaction was conducted at 90 °C.

a

bearing a methyl, methoxy, chloro, and bromo groups on the phenyl ring, formed the desired products in good yields of 71%, 71%, 76%, 79%, and 82%, respectively. N-Ethyl- and Nbenzylanilines 2g and 2h as well as diphenylaniline 2i underwent the amination to afford the yields of 51%, 64%, and 64%, respectively. Amination using aniline 2j also proceeded in 58% yield. The use of indole 2k afforded the corresponding product 3ak in 87% yield. Interestingly, the reaction with 5-methoxytryptamine 2l proceeded chemoselectively at N−H of the indole moiety to afford 3al in 77% yield. Indoline 2m and its derivatives 2n and 2o, bearing methyl and bromo groups at the 5-position, coupled with 1a in high yields, while 2-methylindoline 2p also gave the desired product in 96% yield. Using 3,4-dihydro-2H-1,4-benzoxazine 2q as a substrate, the desired amination product 3aq was obtained in 45% yield. When pyrrolidine 2r was employed, the target product 3ar was furnished in 30% yield.

Figure 5. Proposed mechanism for catalytic amination.

Initially, the E2 elimination of MeOH occurs by the reaction of substrate 1 with t-Bu-P4 to form aryl alkene 4 in a step that can be regarded as the deprotection of the masked alkene. Subsequent deprotonation of 2 occurs to form B, which leads to the hydroamination on 4 to provide 3. C

DOI: 10.1021/acs.orglett.9b02309 Org. Lett. XXXX, XXX, XXX−XXX

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(b) Rappoport, Z., Ed. The Chemistry of Anilines, Parts 1 and 2; John Wiley & Sons: New York, 2007. (2) (a) Smith, M. B. March’s Advanced Organic Chemistry, 6th ed.; John Wiley & Sons, Inc.: New York, 2007. (b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27. (c) Bhunia, S.; Pawar, G. G.; Kumar, S. V.; Jiang, Y.; Ma, D. Angew. Chem., Int. Ed. 2017, 56, 16136. (d) Terrier, F. Modern Nucleophilic Aromatic Substitution; John Wiley & Sons, Inc.: Weinheim, 2013. (3) (a) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem. Rev. 2015, 115, 2596. (b) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (c) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (4) (a) Li, J. J.; Corey, E. J. Drug Discovery: Practices, Processes, and Perspectives; Wiley: NJ, 2013. (b) Lednicer, D. Strategies for Organic Drug Synthesis and Design, 2nd ed.; John Wiley & Sons, Inc.: New York, 2008. (c) Silverman, R. B.; Holladay, M. W. The Organic Chemistry of Drug Design and Drug Action, 3rd ed.; San Diego, 2014. (5) (a) Munro-Leighton, C.; Delp, S. A.; Alsop, N. M.; Blue, E. D.; Gunnoe, T. B. Chem. Commun. 2008, 111. (b) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702. (c) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608. (6) (a) Germain, S.; Schulz, E.; Hannedouche, J. ChemCatChem 2014, 6, 2065. (b) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. (c) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584. (7) For the reactions using alkaline-earth metal bases, see: (a) Brinkmann, C.; Barrett, A. G. M.; Hill, M. S.; Procopiou, P. A. J. Am. Chem. Soc. 2012, 134, 2193. (b) Liu, B.; Roisnel, T.; Carpentier, J.-F.; Sarazin, Y. Angew. Chem., Int. Ed. 2012, 51, 4943. (c) Barrett, A. G. M.; Brinkmann, C.; Crimmin, M. R.; Hill, M. S.; Hunt, P.; Procopiou, P. A. J. Am. Chem. Soc. 2009, 131, 12906. (d) Zhang, X.; Emge, T. J.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2012, 51, 394. (8) For the reactions using alkali metal bases, see: (a) Germain, S.; Lecoq, M.; Schulz, E.; Hannedouche, J. ChemCatChem 2017, 9, 1749. (b) Horrillo-Martínez, P.; Hultzsch, K. C.; Gil, A.; Branchadell, V. Eur. J. Org. Chem. 2007, 2007, 3311. (c) Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.; Bçttcher, H.; Beller, M. Chem. - Eur. J. 2004, 10, 746. (d) Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157. (e) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193. (f) Hamana, H.; Iwasaki, F.; Nagashima, H.; Hattori, K.; Hagiwara, T.; Narita, T. Bull. Chem. Soc. Jpn. 1992, 65, 1109. For a review, see: (g) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795. (9) (a) Nguyen, T. M.; Manohar, N.; Nicewicz, D. A. Angew. Chem., Int. Ed. 2014, 53, 6198. (b) Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 9588. (10) (a) Ghasemi, M. H.; Kowsari, E.; Shafiee, A. Tetrahedron Lett. 2016, 57, 1150. (b) Abou-Shehada, S.; Teasdale, M. C.; Bull, S. D.; Wade, C. E.; Williams, J. M. J. ChemSusChem 2015, 8, 1083. (c) Bhanushali, M. J.; Nandurkar, N. S.; Bhor, M. D.; Bhanage, B. M. Catal. Commun. 2008, 9, 425. (11) Hartwig, J. F. Organotransition Metal Chemistry. From Bonding to Catalysis; University Science Books: Sausalito, CA, 2010. (12) (a) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl. 1987, 26, 1167. (b) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.; Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; von Schnering, H. G.; Walz, L. Liebigs Ann. 1996, 1996, 1055. (13) (a) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y. Chem. - Eur. J. 2019, 25, 6077. (b) Shigeno, M.; Hayashi, K.; NozawaKumada, K.; Kondo, Y. Org. Lett. 2019, 21, 5505. For our related tBu-P4 catalyzed reactions, see: (c) Araki, Y.; Kobayashi, K.; Yonemoto, M.; Kondo, Y. Org. Biomol. Chem. 2011, 9, 78. (d) Hirono, Y.; Kobayashi, K.; Yonemoto, M.; Kondo, Y. Chem. Commun. 2010, 46, 7623. (e) Naka, H.; Koseki, D.; Kondo, Y. Adv. Synth. Catal. 2008,

To further reveal the catalytic features of t-Bu-P4 in the current system, the following experiment were conducted. A catalytic amount of Brønsted bases other than t-Bu-P4 were employed in the MeOH-elimination reaction from the substrate 1i and the hydroamination of 2a on 4i (Tables S3 and S4). In both the investigations, the yields of the corresponding products (4i in the former; 3ia in the latter) were much lower than those obtained by using t-Bu-P4 (Figure 4).20,21 The results clearly displayed the validity of t-Bu-P4 as a reactive catalyst in both the processes. In summary, the amination reactions of β-(hetero)arylethyl ethers with various amines under t-Bu-P4 catalysis were reported. The optimized reaction conditions were applicable to a wide range of β-(hetero)arylethyl ether substrates with varied electronic properties and deliver excellent yields. The mechanistic analysis indicated that the reaction proceeds through two pathways, which includes the initial formation of the (hetero)arylalkene by the elimination of MeOH followed by its hydroamination with an amine.

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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/acs.orglett.9b02309. Effects of organic or inorganic bases in the reaction of 1a and 2a (Table S1); reactions of substrates containing a leaving group other than methoxy group (Table S2); effects of organic or inorganic bases in the MeOHelimination from 1i (Table S3); effects of organic or inorganic bases in the hydroamination of 4i and 2a (Table S4); preparations of 1a, 1n, 1o, 7, 8, and 9; experimental procedures and spectra data for obtained products; and 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Masanori Shigeno: 0000-0002-9640-8283 Kanako Nozawa-Kumada: 0000-0001-8054-5323 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grant Number 19H03346 (Y.K.), JSPS KAKENHI Grant Number 17K15419 (M.S.), JSPS KAKENHI Grant Number 19K06967 (M.S.), Grand for Basic Science Research Projects from The Sumitomo Foundation (M.S.), Yamaguchi Educational and Scholarship Foundation (M.S.), NIPPON SHOKUBAI Award in Synthetic Organic Chemistry, Japan (M.S.), and also the Platform Project for Supporting Drug Discovery and Life Science Research funded by Japan Agency for Medical Research and Development (AMED) (M.S., K.N.K., and Y.K.).

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REFERENCES

(1) (a) Ricci, A. Amino Group Chemistry. From Synthesis to the Life Sciences; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2008. D

DOI: 10.1021/acs.orglett.9b02309 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 350, 1901. (f) Ueno, M.; Yonemoto, M.; Hashimoto, M.; Wheatley, A. E. H.; Naka, H.; Kondo, Y. Chem. Commun. 2007, 2264. (g) Imahori, T.; Hori, C.; Kondo, Y. Adv. Synth. Catal. 2004, 346, 1090. (h) Imahori, T.; Kondo, Y. J. Am. Chem. Soc. 2003, 125, 8082. (14) For the recent studies by other groups, see: (a) Kondoh, A.; Koda, K.; Terada, M. Org. Lett. 2019, 21, 2277. (b) Jardel, D.; Davies, C.; Peruch, F.; Massip, S.; Bibal, B. Adv. Synth. Catal. 2016, 358, 1110. (c) Okusu, S.; Hirano, K.; Tokunaga, E.; Shibata, N. ChemistryOpen 2015, 4, 581. (d) Du, G.-F.; Wang, Y.; Gu, C.-Z.; Dai, B.; He, L. RSC Adv. 2015, 5, 35421. (e) Punirun, T.; Soorukram, D.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Eur. J. Org. Chem. 2014, 2014, 4162. (15) (a) Luo, C.; Bandar, J. S. J. Am. Chem. Soc. 2018, 140, 3547. (b) Luo, C.; Bandar, J. S. Synlett 2018, 29, 2218. (c) Puleo, T. R.; Strong, A. J.; Bandar, J. S. J. Am. Chem. Soc. 2019, 141, 1467. (16) β-(Hetero)arylethyl ethers are usually stable and rather unreactive, and a limited number of their catalytic transformations were achieved by using transition metals with prefunctionalized carbon nucleophiles (Grignard and organoboron reagents); see: (a) Luo, S.; Yu, D.-G.; Zhu, R.-Y.; Wang, X.; Wang, L.; Shi, Z.-J. Chem. Commun. 2013, 49, 7794. (b) Ogiwara, Y.; Kochi, T.; Kakiuchi, F. Org. Lett. 2011, 13, 3254. (17) Even when the reaction time was prolonged to 72 h, 3aa was formed in a low NMR yield of 17% (results not shown). (18) Substrates having a leaving group other than methoxy group were also tested (Table S2). Reaction of the substrate bearing an ethoxy group took place in 65% yield. The substrate having a (tertbutyldimethylsilyl)oxy group afforded 3aa in an NMR yield of 7%, while those containing acetate or benzoate groups did not. (19) In the reaction of 1m, 4-methoxystyrene was formed in 4% yield with recovery of 1m (96%). When 4-methoxystyrene was subjected to the reaction conditions, 3ma was obtained in 12% yield with its recovery (80%). Thus, in the amination of 1m, neither MeOH elimination nor hydroamination, noted in Figure 5, efficiently occurs. (20) A stoichiometric amount of Brønsted bases were previously used for the MeOH-elimination from β-arylethyl ethers; see: (a) Margot, C.; Rizzolio, M.; Schlosser, M. Tetrahedron 1990, 46, 2411. (b) Barlow, J. W.; McHugh, A. P.; Woods, O.; Walsh, J. J. Eur. J. Med. Chem. 2011, 46, 1545. Also see the related studies about the MeOH-elimination from α,α-dimethoxy-β-phenylethane derivatives: (c) Deagostino, A.; Prandi, C.; Venturello, P. Tetrahedron 1996, 52, 1433. (21) Recently, Bandar and co-workers reported that KO-t-Bu catalyzes the reversible addition of MeOH on (hetero)arylalkene in DMSO as t-Bu-P4; see ref 15c.

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DOI: 10.1021/acs.orglett.9b02309 Org. Lett. XXXX, XXX, XXX−XXX