Triflic Acid Promoted Decarboxylation of Adamantane-Oxazolidine- 2-One

Article pubs.acs.org/joc Triflic Acid Promoted Decarboxylation of Adamantane-oxazolidine- 2-one: Access to Chiral Amines and Heterocycles † † ‡ Radim Hrdina,*, Marta Larrosa, and Christian Logemann † Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany ‡ Institute of Inorganic and Analytical Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany *S Supporting Information ABSTRACT: We have developed a one-step procedure to a variety of chiral lipophilic and conformationally rigid amines and heterocycles by decarboxylation of adamantane-oxazolidine-2-one. Triflic acid or aluminum triflate promote the addition of diverse nucleophiles to the oxazolidine-2-one moiety accompanied by the release of carbon dioxide. The resulting amine or heterocycle is then protonated/metalated by the catalyst (promotor). Additionally, the starting racemic material, adamantane-oxazolidine-2-one, was resolved into single enantiomers using a chiral auxiliary to access enantio- enriched products and to study the racemization pathway of chiral 1,2-disubstituted adamantane derivatives. ■ INTRODUCTION The reactivity of adamantane oxazolidine-2-ones differs from fl Adamantane based amines (bulky, lipophilic) are synthetically the reactivity of oxazolidin-2-ones with exible alkyl sub- stituents (Figure 2).11 In the case of flexible oxazolidin-2-ones useful building blocks in the preparation of bioactive compounds1 (drug development), ligands (transition metal catalysis), organocatalysts,2 and functional materials as polymers3 and organic frameworks.4 Typically, these adamantane derivatives (diamondoids5 for higher congeners) are used as add-on structures, exploiting the reactivity of an amino group to form an amide bond, thereby increasing the lipophilicity of the target compounds. Monosubstituted adamantane amines, or achiral amines, are generally prepared by undirected C−H oxidation of the adamantane core.6 A number of procedures have been developed to achieve these compounds in an effective way.7 The modular approach to chiral 1,2-disubstituted adamantane derivatives (avoiding the cage opening8) is currently 9 studied in our group employing nitrene insertion methodology Figure 2. Decarboxylation of oxazolidine-2-ones. and C−H activation strategy.10 Herein we describe a one-step procedure to chiral amines (the chirality is embed in the adamantane core) by acid catalyzed decarboxylation of the adamantane-oxazolidine-2-one the decarboxylation reaction leads to aziridines.12 These and subsequent reaction with the nucleophile (Figure 1). aziridines can be further protected on the nitrogen for further Addition of water, Brønstedt acids, heteroatom nucleophiles, functionalization,13 or it may undergo an acid catalyzed opening arenes, nitriles, and carboxylic acids give rise to a variety of reaction,14 where the substitution pattern governs the primary amines or heterocycles in one single step, which can be corresponding regioselectivities.15 In the case of the studied further used as valuable building blocks in the organic synthesis. adamantane derivative, the formation of the aziridine unit is restricted, which enables the addition of nucleophiles on the formal dipole, possessing a partial positive charge on the tertiary carbon and negative charge on the nitrogen. This method minimizes the number of synthetic steps and enables the synthesis of new compounds (Figure 3).16 Figure 1. Synthesis of chiral 1-substituted-adamantane-2 amines. Received: March 27, 2017 Published: April 7, 2017 © 2017 American Chemical Society 4891 DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899 The Journal of Organic Chemistry Article Initial decarboxylation studies were done using arenes as nucleophiles to determine the optimal Brønsted acid and stable solvent. Among a number of screened acids (trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, tetrafluoroboric acid): water-free triflic acid provides the highest conversions and was chosen for further studies. In regards to the tested solvents (hexane, hexafluorohexane, chlorobenzene, α,α,α-trifluoroto- luene, 1,2-dichloroethane, tetrachloroethylene), only 1,3,4- trichlorobenzene and dichloromethane solubilize the solid substrates, do not decompose under strong acidic conditions, and do not react as a substrate with compound 2. In the case of Figure 3. Faster approach to known compounds. Brønsted acid sensitive substrates (ferrocene, methoxyben- ff zene), Al(OTf)3 was found to be an e ective oxophilic Lewis ■ RESULTS AND DISCUSSION acid promoting the decarboxylation of the carbamate moiety and allowing subsequent Friedel−Crafts reaction.19 Each class The starting material 2 was prepared according to the published fi protocol17 from adamantane-1-carbamate 1, and its synthesis of nucleophiles requires speci c reaction conditions (acid and was optimized to lower the loading of the dirhodium catalyst solvent) and is described separately (Figure 4). (Scheme 1). By changing the solvent from dichloromethane to One of the most important class of compounds are adamantane-1-halogen-2-amines. These derivatives can be a 20 21 Scheme 1. Improved Synthesis of Starting Material 2 used for highly useful coupling and substitution reactions. For their synthesis, corresponding salts were used as precursors toward generating water-free halic acids. The 1-iodo, bromo, and chloro derivatives were prepared following the same protocol (Scheme 2). Upon mixing with TfOH, the use of KI, KBr, and NaCl provides the corresponding HX acids, which exchange with the triflate substituent in the position 1 of the adamantane core aChanges to original protocol highlighted in red. after the decarboxylation step. A 2:1 ratio of triflic acid to salt was found to achieve the highest isolated yields. This protocol 1,2-dichloroethane and increasing the reaction temperature to cannot be used for the introduction of fluorine as a substituent, 70 °C, the cyclic carbamate 2 was prepared with a comparable due to the low nucleophilicity of HF. Preparation of the 1- yield, but with a significant decrease in catalyst loading.18 fluoro derivative 3d was optimized separately mimicking the Figure 4. Scope of the method (isolated yields of derivatives 3 upon neutralization and purification step). 4892 DOI: 10.1021/acs.joc.7b00711 J. Org. Chem. 2017, 82, 4891−4899 The Journal of Organic Chemistry Article Scheme 2. Synthesis of 1-Halogen-2-amines and 1-Azide-2- Scheme 5. Synthesis of Heterocycles (Amidine) amines Of particular importance is the application of this method 24 Balz−Schiemann reaction.22 The addition of an excess of the toward the formation of oxazolines, given their utility as − HBF4 Et2O complex in CH2Cl2 provides the desired ligands in transition metal catalysis (Scheme 6). Direct addition compound in 41% yield. The azide derivative 3e was prepared following the same protocol by generating 1.5 equiv of HN3 Scheme 6. Synthesis of Heterocycles (Oxazolines) from NaN3 (excess of HN3 leads to undesired formation of bis azide derivative). Introduction of ether, thioether, and phosphine moieties at the position next to the amino group on the adamantane is desirable for the development of new bidenatate ligands and organocatalysts.23 Conversion to the products is observed (Scheme 3) by using triflic acid; however, in the case of the of acid and a subsequent condensation reaction does not Scheme 3. Synthesis of 1-(O,S,P)-Aryl-2-amines provide the desired compounds. Starting material 2 is first acylated and then subjected to the triflic acid promoted decarboxylation step. The reaction does not proceed using Al(OTf)3 as the catalyst or promotor. Compound 3a was acetylated to 3a-Ac, which was tested in the palladium catalyzed coupling reaction with 1,3-benzoxazole using the procedure developed by Hierso et al.25 The coupling reaction proceeded in 69% yield (Scheme 7) demonstrating the phenolic derivatives, side reactions occur. Therefore, triflic acid applicability of our method toward the preparation of was replaced with the less acidic p-toluenesulfonic acid, which derivatives with heterocycles in the position next to the does not degrade the starting nucleophile. The phosphine amine group on the adamantane framework. derivative oxidizes upon exposure to air and is characterized as phosphine oxide 3i. Scheme 7. Postfunctionalization/Coupling of 1,3- C−C bond formation in position 1 of the adamantane Benzoxazole 4 and 1-Iodo-2-acetamido Adamantane 3a-Ac skeleton was performed through decarboxylative Friedel− Crafts reaction (Scheme 4). Electron-rich substrates provide Scheme 4. Synthesis of 1-Aryl-2-amines Generally, the decarboxylation/nucleophile addition method is practical for electron-rich systems, which are stable in acidic conditions. The method is not applicable for carbamates derived from adamantane-2-ol 2′. In this case, the formation of fl 1-amino-2-phenyl-adamantane was not observed (Figure 5). products in good yields using tri ic acid (3j, 3k) or Al(OTf)3 (3l, 3m, 3k) as the catalyst. Compound 3j was prepared from the enantiopure (S)-2 in 87% yield and with measurable unexpected loss of enantiopurity (86% ee). Starting material 2 was N-benzylated to attempt an intramolecular variant of this reaction to form piperidine derivatives 3o and 3p. In both cases the reaction proceeds very ° slowly using Al(OTf)3 as the promotor at 140 C. Further Figure 5. Limits of the method. increasing of the temperature leads to undesired side reactions. The utilization of triflic acid leads to cleavage of the

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