Catalyst‐Free Deaminative Functionalizations of Primary Amines by Photoinduced Single‐Electron Transfer

Abstract The use of pyridinium‐activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst‐free conditions is described. By taking advantage of the visible light absorptivity of electron donor–acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et3N, photoinduced single‐electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.

Visible light photochemistry in organic synthesis has witnessed asurge in research activity over the last decade. [1] This is largely due to agrowing appreciation of the synthetic utility of photoredox catalysts,w hich, upon photoexcitation, function as single-electron or energy transfer catalysts to provide access to free-radical intermediates. [2] An alternative strategy, that circumvents the need for catalysis,i sd irect photoexcitation of as ubstrate,w hich has classically been performed using UV light. [3] However,r ecent developments have taken advantage of the visible light absorptivity of specific functional groups that act as photoactive handles to enable photoinduced electron transfer (PET). [4] Although direct photoexcitation is possible with an umber of different functional groups, [5] such reactions more commonly take advantage of electron donor-acceptor (EDA) complexes,w hose absorption spectra display ab athochromic shift relative to their constituent parts,t hus enabling photoexcitation with visible light. [6] These strategies have enabled the development of abroad range of radical transformations that proceed through visible light-mediated PET under catalyst-free conditions.However, such reactions are typically limited to the generation of perfluoroalkyl or stabilized alkyl radicals. [5,7,8] Access to nonstabilized alkyl radicals under such conditions is considerably more challenging, [9,10] with only asingle report by Melchiorre and co-workers that generates secondary alkyl radicals by direct photoexcitation of 4-alkyl-1,4-dihydropyridine derivatives. [11] We sought an alternative functional group that could act as av ersatile photoactive handle for catalyst-free generation of non-stabilized carbon-centered radicals.O ne possibility was Katritzky N-alkylpyridinium salts 1,w hich are easily prepared from primary amines 2 by reaction with 2,4,6-triphenylpyrylium 3,a re air and moisture stable,a nd allow selective deaminative transformations of abundant amino groups (Scheme 1A). [12] While these redox active amines have recently been applied to an umber of radicalmediated transformations,t hey usually rely on catalysis to promote single-electron transfer (SET)-induced deamination. [13,14] We recently reported ac atalyst-free deaminative borylation reaction that proceeds through EDAcomplex formation between 1 and bis(catecholato)diboron (B 2 cat 2 )( Scheme 1B). [15] Subsequent PET and fragmentation provided efficient access to non-stabilized alkyl radicals that were intercepted by the diboron reagent. We reasoned that the 2,4,6-triphenylpyridinium moiety in 1 could be complexed with other electron-donors to generate EDAc omplex 4, [16] thus providing ap hotoactive handle capable of generating non-stabilized alkyl radicals for application in adiverse range of C À CorC À Xbond forming reactions (Scheme 1B). Herein, we report that Katritzky pyridinium salts are versatile substrates for photoinduced deaminative functionalizations of primary amines under catalyst-free conditions. Our investigations began by studying the use of pyridiniums 1 in Giese reactions with electron-deficient alkenes ( Table 1). Such reactions are well-developed using photocatalysis,but there are few reports of photoinduced reactions under catalyst-free conditions. [17] Given the overall transformation is reductive,astoichiometric reductant was required. We selected Hantzsch ester (5)a st his would act as areductant but could also function as an electron-donor to form the key EDAc omplex with 1. [10c,d] Gratifyingly,i rradiation (l max = 450 nm) of am ixture of 4-aminopiperidinederived pyridinium 1a,Hantzsch ester,and methyl acrylate in DMA yielded the desired Giese adduct 6 in 77 %y ield ( Table 1). Control experiments confirmed the necessity of light and 5 for successful reaction, and alternative reductants, such as Et 3 N, gave no desired product. [18] These optimized conditions were subsequently applied to abroad range of Michael acceptors (Table 1). Giese products from reactions with substituted acrylates (7), acrylonitrile (8), methyl vinyl ketone (9), N-phenylacrylamide (10), and phenyl vinyl sulfone (11)w ere formed in good to excellent yields. Aldehydes were tolerated (12)(13)(14), although the substituted enals methacrolein (13)a nd tiglic aldehyde (14)r equired higher temperatures for successful reaction. Interestingly, vinyl silanes and boronic esters were also suitable substrates, providing products 15 and 16,respectively,albeit in low yield. Finally,m ethyl propiolate underwent the Giese reaction to give alkene product 17 as amixture of E and Z isomers.
With respect to the pyridinium salts,avariety of cyclic (18 and 19)a nd acyclic ( 20)s econdary alkyl substrates reacted efficiently.The Giese product from a g-amino alcohol-derived pyridinium could be cyclized by treatment with acid to generate lactone 21.A lternatively, t-butyl acrylate could be used in place of methyl acrylate to inhibit lactonization, allowing isolation of norephedrine-derived alcohol 22.P harmaceutical and natural product derivatives were also readily accessed, as exemplified by the formation of product 23,from the anti-arrhythmic drug mexiletine,and 24,from the steroid tigogenin.

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Communications 5698 www.angewandte.org that adding Et 3 Nt ot he reaction mixture and increasing the reaction temperature to 60 8 8Ch ad ad ramatic effect on the outcome of the reaction and enabled the isolation of adduct 28,a lbeit in low yield. Switching from benzyl acrylate to the more activated alkene methyl 2-phenylacrylate provided further improvements and enabled isolation of product 29 in 47 %yield. Despite the yield being moderate,this result is notable as it is ar are example of ap hotoinduced Giese reaction of an on-stabilized primary alkyl radical under mild and catalyst-free conditions.W ith these new conditions, ar ange of non-benzylic primary alkyl pyridiniums reacted to give the Giese products (29-35)inmoderate to good yields. Furthermore,t he functional group tolerance of the methodology was highlighted by generating products bearing primary sulfonamide (31), pyridine (32), thiophene (33), and silyl ether (35)moieties.
To shed light on the mechanism of this catalyst-free Giese reaction, we analyzed the reaction components by UV/Vis absorption spectroscopy.D MA solutions of secondary alkyl pyridinium 36 and Hantzsch ester (5)w ere both found to absorb in the visible region (> 400 nm) ( Figure 1A). However,amixture of 36 and 5 displayed asignificant red-shift in absorbance,c onfirming formation of the postulated EDA complex. As imilar shift was observed with am ixture of primary alkyl pyridinium 37 and 5 ( Figure 1B). Interestingly, am ixture of 37, 5,a nd Et 3 Ns howed af urther bathochromic shift, suggesting the formation of at ernary EDAc omplex, which could contribute to the enhanced reactivity observed with primary alkyl pyridiniums upon addition of Et 3 N. The formation of alkyl radical intermediates was confirmed by ar adical clock experiment with cyclopropylmethyl pyridinium 38,d uring which ring-opening occurred to give alkene 39 as the only observable product ( Figure 1C).
During our UV/Vis absorbance studies of pyridinium 36 we found that it also forms an EDAc omplex with Et 3 N ( Figure 1A). Thus,w ew ere curious as to whether these photoinduced reactions could be performed with Et 3 Ni n place of Hantzsch ester.While the Giese reaction proceeded with low yield, the allylation reaction proceeded smoothly to generate 50 in 71 %when using 6.0 equiv of Et 3 Ninplace of Hantzsch ester (Scheme 2). [18] An identical result was also obtained when Et 3 Nw as replaced by iPr 2 NEt. This result is intriguing given that these conditions are very similar to the photoredox-catalyzed conditions recently reported by Liu and co-workers,w hich differ only by the use of an iridium photocatalyst. [14c] We also investigated other addition-elimination reactions with unsaturated sulfone reagents and found that alkynylation and vinylation reactions also proceeded

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Communications under our catalyst-free conditions,g enerating alkyne 71 and alkene 72 in good yields.Again, these conditions are similar to previously reported photoredox-catalyzed protocols by Gryko and co-workers but proceed efficiently in the absence of aphotocatalyst. [14b] Finally,wefound that by replacing the unsaturated sulfones with other sulfur-based reagents,u nder otherwise identical conditions,h igh yielding hydrodeamination and deaminative thioetherification reactions were also possible,p roviding good yields of N-Boc-piperidine 73 and thioether 74,respectively.
In conclusion, we have described the development of ag eneral catalyst-free deaminative protocol for the generation of non-stabilized alkyl radicals,p roceeding through visible light photoexcitation of EDAc omplexes of N-alkylpyridinium salts.The radicals were shown to undergo arange of transformations,i ncluding Giese,a llylation, vinylation, alkynylation, HAT, and thioetherification reactions.The mild conditions,h igh functional group tolerance and ease of synthesis of the pyridinium substrates make this au seful catalyst-free approach to alkyl radical formation. [a] General conditions: Pyridinium(1.0 equiv), allyl sulfone (3.0 equiv), and 5 (1.5 equiv) in DMA (0.4 m)at408 8Cfor 16 h. Yields are of isolated products after flash column chromatography. [b] Isolated after acetyl protection of the alcohol. [c] Reactionsperformed at 60 8 8Cwith 5 (2.5 equiv) and Et 3 N(3.0 equiv).