Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2017, 82, 11711-11720
Hypervalent Iodine(III)-Mediated Decarboxylative Ritter-Type Amination Leading to the Production of α‑Tertiary Amine Derivatives Kensuke Kiyokawa,* Tomoki Watanabe, Laura Fra, Takumi Kojima, and Satoshi Minakata* Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan S Supporting Information *
ABSTRACT: α-Tertiary amines (ATAs) are attractive structural motifs that are frequently found in biologically active molecules. Therefore, the development of an efficient method for the synthesis of ATAs represents an important research topic in the field of medicinal chemistry as well as organic chemistry. Although the Ritter reaction is a reliable approach for preparing α-tertiary amine derivatives via intermolecular amination reactions, the typical methods suffer from disadvantages such as harsh reaction conditions and the use of strong acids. Because of this, it has been of limited use in the synthesis of ATAs. We report here on the decarboxylative Ritter-type amination of carboxylic acids bearing an α-quaternary carbon center using a combination of PhI(OAc)2 and molecular iodine (I2) to produce the corresponding α-tertiary amine derivatives. This reaction proceeded at ambient temperature on the benchtop with a fluorescent light. Mechanistic investigations suggest that the reaction proceeds via the formation of an alkyl iodide and a higher oxidation state iodine(III) species as key intermediates. Similarly, a stepwise protocol for the Ritter-type amination of alcohols via the formation of oxalic acid monoalkyl esters was also achieved. The present methods represent a useful tool for the synthesis of ATAs that are difficult to prepare by conventional methods.
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methods for preparing α-tertiary amine derivatives, introducing an amino functional group into a tertiary carbon centers, that is, the formation of a C−N bond at a tertiary carbon center, has been recognized as one of the most straightforward approaches1f and has attracted considerable attention in the past decades. In this context, efficient synthetic methods for amination at a tertiary carbon center,3 including radical C−H amination3a,c,d and C−H amination by an imino-λ3-bromane3b and a metal nitrenoid,3f have recently been developed. Most recently, the azidation of tertiary carbon centers4 and the hydroamination of alkenes5 have also emerged as powerful and useful methods. However, despite these advances, novel synthetic strategies for preparing ATAs from readily available starting materials, especially under mild and environmentally benign conditions, continue to be highly desirable in terms of expanding the scope of accessible ATAs. The Ritter reaction, in which nitriles function as a nitrogen source, would be a reliable method for producing amides via an intermolecular amination reaction.6 As the reaction proceeds through the generation of a carbocation intermediate that is trapped by a nitrile, the method could be used in the amination of tertiary carbon centers. The classical Ritter reaction employs alkenes and alcohols as starting materials, and when α-tertiary amine derivatives are being prepared, strong Brønsted/Lewis acids and high temperatures are needed.7 Because of this, its use has remained limited in scope. The Ritter-type C−H amination of a tertiary carbon center has recently emerged as a promising approach for the synthesis of ATAs.8,9 Our group has also
INTRODUCTION α-Tertiary amines (ATAs), which consist of a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen functionality, are attractive structural motifs that are frequently found in biologically active molecules (Figure 1).1 In addition, ATAs are recognized as useful building blocks in drug discovery because sterically demanding tertiary alkyl substituents can improve the lipophilicity and metabolic stability of a drug.2 Therefore, the development of efficient methods for the synthesis of ATAs has been an important research topic in the field of organic synthesis and medicinal chemistry. Among the
Special Issue: Hypervalent Iodine Reagents
Figure 1. Representative biologically active molecules containing an αtertiary amine moiety. © 2017 American Chemical Society
Received: May 16, 2017 Published: June 12, 2017 11711
DOI: 10.1021/acs.joc.7b01202 J. Org. Chem. 2017, 82, 11711−11720
Article
The Journal of Organic Chemistry Scheme 1. Strategies for the Ritter-Type Amination at Tertiary Carbon Centers Using Iodine Oxidants
developed the Ritter-type amination of tertiary C−H bonds using iodic acid (HIO3) as an oxidant, and mechanistic investigations suggest that the reaction proceeds via a unique reaction pathway that involves the formation of tertiary alkyl iodides and the corresponding iodine(III) species as reaction intermediates (Scheme 1).10 On the basis of these results and our ongoing interest in iodine-mediated decarboxylative amination reactions,11 we hypothesized that a method involving a decarboxylative iodination process12 to generate tertiary alkylλ3-iodanes, followed by the Ritter-type amination, would be a useful new approach to producing ATAs from carboxylic acids (Scheme 1).13 Herein, we report on the decarboxylative Rittertype amination of carboxylic acids bearing an α-quaternary carbon center, mediated by a hypervalent iodine(III)/molecular iodine system. The starting carboxylic acids can be readily prepared, and the reaction effectively proceeds at ambient temperature to afford α-tertiary amine derivatives.14 In addition, a series of mechanistic experiments were performed to reveal the reaction pathway.
Table 1. Effect of Oxidant and Reaction Parameters on the Decarboxylative Ritter-Type Aminationa
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RESULTS AND DISCUSSION We began our investigation by examining the decarboxylative Ritter-type amination of 2,2-dimethyl-3-phenylpropanoic acid (1a) using a combination of PhI(OAc)2 and I2 as oxidants.12a After optimizing the reaction parameters, including the amount of oxidants required, temperature, and time, we found that, when 1a was treated with PhI(OAc)2 (2 equiv) and I2 (0.5 equiv) in acetonitrile at ambient temperature for 16 h on the benchtop in the presence of a fluorescent light on the ceiling, the decarboxylative amination proceeded effectively, thus affording the corresponding amide 2a in 79% yield (Table 1, entry 1).15 It is noteworthy that no products derived from oxidation at the benzylic position were detected. Control experiments in the absence of either PhI(OAc)2 or I2 revealed that both reagents are required for this transformation to proceed (entries 2 and 3). Decreasing the amount of PhI(OAc)2 from 2 to 1 equiv resulted in lower yields of 2a (entries 4 and 5). The addition of 1 equiv of iodine did not improve the product yield, and no reaction was observed when a catalytic amount of iodine was used (entries 6 and 7). Investigation of the effect of other hypervalent iodine(III) reagents revealed that PhI(OAc)2 was the most suitable oxidant for this amination, whereas PhIO, PhI(Ot-Bu)2, and PhI(OCOCF3)2 resulted in very low yields (entries 8−10). In addition, simple iodine(V) oxidants such as HIO3 and I2O5 failed to provide 2a, even though they were found to be efficient oxidants in our previous work on tertiary C−H
entry
oxidant (x equiv)
I2 (equiv)
yieldb (%)
1 2 3 4 5 6 7 8c 9c 10c 11c 12c 13c 14c 15d 16e 17c,f
PhI(OAc)2 (2 equiv) none PhI(OAc)2 (2 equiv) PhI(OAc)2 (1.5 equiv) PhI(OAc)2 (1 equiv) PhI(OAc)2 (2 equiv) PhI(OAc)2 (2 equiv) PhIO (2 equiv) PhI(Ot-Bu)2 (2 equiv) PhI(OCOCF3)2 (2 equiv) HIO3 (2 equiv) I2O5 (1 equiv) NIS (1 equiv) t-BuOI (1 equiv) PhI(OAc)2 (2 equiv) PhI(OAc)2 (2 equiv) PhI(OAc)2 (2 equiv)
0.5 0.5 0 0.5 0.5 1.0 0.1 0.5 0.5 0.5 0.5 0.5 0 0 0.5 0.5 0.5
79 0 0 77 64 70 0 23 18 0
