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Catalytic Radical-Polar Crossover Ritter Reaction Eric E Catalytic Radical-Polar Crossover Ritter Reaction Eric E. Touney‡, Riley E. Cooper‡, Sarah. E. Bredenkamp, David T. George†, and Sergey V. Pronin* Department of Chemistry, University of California, Irvine, California 92697-2025, United States Supporting Information Placeholder Co(II) complex, ABSTRACT: A catalytic radical-polar crossover Ritter R3 R3 R3 silane, oxidant MeCN, H2O R1 R1 AcHN reaction is described. The transformation proceeds under R4 R4 R4 via R3 nuclephilic attack 1 2 acid-free conditions and tolerates a variety of functional R2 R2 & hydrolysis R R R1 R4 groups. The catalyst design overcomes limitations in the 32 examples substitution pattern of starting materials and enables hy- R2 droamidation of a diverse range of alkenes. Formation of Scheme 1. Catalytic radical-polar crossover Ritter reaction. hydrogen contributes to the background consumption of reductant and oxidant and competes with the desired path- polar crossover reactions of alkenes we observed that ap- way, pointing to a mechanistic link between hydrogen plication of acetonitrile as solvent occasionally resulted atom transfer-initiated organic reactions and hydrogen in formation of small amounts of side-products arising evolution catalysis. from apparent Markovnikov addition of acetamide to the carbon-carbon double bond.5,6 The electrophilic interme- diates in this formal Ritter reaction were proposed to arise from direct oxidation of alkyl radicals following the HAT Hydroamidation of alkenes with nitriles in the presence and diffusion from the solvent cage.7 Alternative path- of a strong Brønsted acid, discovered by Ritter, allows for ways involve radical pair collapse to generate the corre- a convenient access to tert-alkylamines and their deriva- 1 sponding alkylcobalt(III) complexes, which undergo oxi- tives from simple precursors. The Ritter reaction is used dation to alkylcobalt(IV) species and subsequent nucleo- in production of tert-octylamine and its higher molecular 2 philic displacement or dissociation to the carbocations weight homologs. Variants of the Ritter reaction have (Scheme 2).8–10 Development of the radical-polar cross- found application in pharmaceutical industry and aca- 3 [CoII] R3 R3 R [CoIII-H] demic research for installation of nitrogen-based func- 1 III R1 R [Co ] 3,4 4 R4 R4 tionalities. The rate-determining protonation of the car- R HAT radical pair 2 R1 R2 bon-carbon double bond necessitates forcing conditions R2 R collapse and application of strong Brønsted acids, which results in cage escape oxidation limited functional group tolerance. Here we demonstrate an acid-free Ritter reaction enabled by cobalt-catalyzed R3 R3 R3 R1 R1 [CoIV] 4 4 4 radical-polar crossover hydroamidation of alkenes. This R oxidation R R transformation takes advantage of hydrogen atom transfer R2 R2 R1 R2 - [CoII] (HAT) followed by oxidation to generate the correspond- ing carbocationic intermediates, accomplishing formal protonation of the carbon-carbon double bond and Scheme 2. Pathways for generation of electrophilic interme- providing excellent tolerance of functional groups diates in HAT-initiated radical-polar crossover reactions. (Scheme 1). We show that catalysis by modified cobalt over variant of the Ritter reaction is appealing because it salen complexes overcomes limitations in the substitution is expected to improve the poor functional group toler- pattern of the alkenes and allows for hydroamidation of a ance associated with the application of strong Brønsted diverse range of substrates. We also present data indicat- acids. Similar benefits were demonstrated in the previous ing that the mechanism of background consumption of re- HAT-initiated hydrofunctionalizations to install nitrogen- ductant and oxidant includes formation of hydrogen, based functionalities, including landmark reports of radi- which competes with the desired pathway, explaining cal hydrohydrazidation and hydroazidation reactions and prior limitations in the substrate scope. more recent radical-polar crossover hydroazolation and During our investigations into HAT-initiated radical- intramolecular hydroamidation methods (Scheme 3).11–16 1 ● Hydrohydrazidation (ref. 11,13) Table 1. Effect of the Catalyst Structure on the Catalytic CO2t-Bu a Me DBAD, 5 mol% [Co], PhSiH Radical-Polar Crossover Ritter Reaction of Alkene 6 3 N CO2t-Bu N 90% H Me Me Me Me AcHN Me AcHN Me ● Hydroazidation (ref. 12,13) 5 mol % catalyst 3 equiv. 4•BF4 N TsN3, 6 mol% [Co], PhSiH3 3 3 equiv. Me2PhSiH Ph 90% Ph Me O O 5 equiv. H2O, MeCN O O O O 4:1 mixture of 7 and 8 ● Intramolecular hydroamidation (ref. 15) see table for yield Me Ph Ph 1 mol% 3, 4•BF , (Me SiH) O Me Me Me Me Me Me H 4 2 2 Ph N 6 7 8 Ts 99% Ph N Ts catalyst 5 0% ● Hydroazolation (ref. 16) catalyst 3 Me N 34% BTA, 20 mol% 5, 4•BF4, PhSiH3 Ph Ph N PhCH3; 76% N R1 R1 R2 R2 Me BF N N 1 2 4 9: 40% N N 3 (R = Ph, R = H) Co 1 2 5 (R = R = Me) 4•BF4 Co t-Bu O O t-Bu t-Bu O O t-Bu Me N Me F t-Bu t-Bu t-Bu t-Bu N N Co Scheme 3. Examples of relevant hydrofunctionalizations. 10: 43% t-Bu O O t-Bu Our initial optimization efforts allowed for efficient conversion of dihydrocarvone to the corresponding hy- t-Bu t-Bu droamidation product in the presence of catalyst 5 (Scheme 4). At the same time, we observed significant R R Me Me Me 11 (R = Ph): 51% 5 mol % 5, 4•OTf O O N N 12 (R = c-Hex): 52% PhSiHMe 2 56% from Co limonene t-Bu O O t-Bu MeCN, H2O 77% Me Me NHAc NHAc Me Me Me t-Bu t-Bu Scheme 4. Initial studies in the catalytic radical-polar cross- over Ritter reaction. R R 13 (R = 1-Naphth): 60% limitations in the substitution pattern at the carbon-carbon N N 14 (R = c-Hex): 68% double bond with only 1,1-disubstituted alkenes showing t-Bu Co t-Bu optimal performance. As a corollary, these limitations O O could be leveraged to achieve selective Ritter reactions of t-Bu t-Bu differentially substituted polyenes, such as limonene. No- tably, similar challenges were previously associated with O O other relevant radical-polar crossover hydrofunctionali- zations and also highlighted in a recent study of HAT- 15: 76% 15,17 N N initiated hydroamidation of alkenes. Here we over- Co come these limitations using catalyst design and relate the MeO O O OMe substrate intolerance to competing hydrogen evolution. t-Bu t-Bu To address the identified limitations in the scope of al- ayields and ratios were determined by 1H NMR analysis. kenes, we focused our efforts on substrates that appeared Isolated yield with catalyst 15 was 76%. inert towards reaction conditions that successfully en- gaged 1,1-disubstituted alkenes in the HAT-initiated Rit- unsubstituted ethylenediamine motif. Increased reaction ter reaction. Thus, attempted hydroamidation of fully sub- times, additional amounts of the oxidant and reductant, stituted alkene 6 in the presence of catalyst 5 did not in- and changes in the order of addition did not lead to im- 18 duce any significant reactivity of the substrate (Table 1). proved outcomes. Subsequent modifications in the salen Application of complexes 3 and 9, commonly employed ligand were more fruitful and produced several instruc- in other HAT-initiated reactions, produced a mixture of tive trends. Thus, application of complexes containing o- amides 7 and 8, but returned the majority of material in substituted aromatic motifs in the ethylenediamine-de- the form of starting alkene 6. Similar outcome was ob- rived fragment delivered improved yields of products 7 served in the presence of complex 10, which contained and 8, as seen in the cases of catalysts 11 and 12. 2 Table 2. Preliminary Substrate Scope of the Catalytic Radical-Polar Crossover Ritter Reactiona Me Me Me Me Me Me Me Me 2 R3 5–10 mol % 15 or 23 3 2 AcHN 1 R AcHN 1 4•OTf or 4•BF4, PhSiHMe2 Me R1 AcHN OAc AcHN OTBS 4 AcHN R R4 Me MeCN, H2O R2 R1 R2 16 (77%, C2:C1 1.3:1)b,c,d 17 (69%, C2:C1 1.4:1)b,c,d 24 (61%)e,f 25 (64%)c,e Me Me Me Me Me Me Me Me Me Me Me Me Me 2 Me AcHN 8 O AcHN AcHN AcHN OTBS AcHN OBOM AcHN OBn Me O Me 18 (63%, C2:C8 4:1)b,c,d 19 (67%)b,c 20 (52%, d. r. 4:1)b,c,d 26 (79%e,f, 63%f,g) 27 (74%e,f, 46%d,f,g) 28 (73%c,e, 68%d,f,g) OAc Me Me Me Me Me Me Me Me O AcO OAc NHBoc Me Me AcHN O O AcHN OAc AcHN OAc AcHN O O 22 29 (83%e,f, 70%d,f,g) 30 (79%e,f, 43%d,f,g) 31 (74%)c,e Me O catalyst 3: 34% Me Me Me Me Me Me AcHN O O AcHN O AcHN Me catalyst 5: 49% 32 (56%)c,e 33 (80%)e,f 34 (69%)e,f catalyst 15: 77% Me OH Me Me Me Me Me Me Me Br AcHN AcHN Ph AcHN OH Ph O O 35 (60%)e,f 36 (72%)e,f 37 (70%)e,f O O Me Me Me MeO N N OMe Me Me MeO Co H AcHN N NHBoc AcHN N MeO O O OMe Me Me H H t-Bu t-Bu AcHN O 23: 84% 38 (73%)c,e 39 (65%)c,e 40 (53%)c,e NHAc NHAc Me Me TBSO Me Me HO Me Me Me AcHN Me Me Me Me AcHN AcHN MeO OMe AcHN H Me OTBS Me Me 41 (72%)c,e 42 (64%)c,e,h 43 (55%)e,f 44 (58%)e,f 45 (49%, d.
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