Radical addition of tertiary amines

Hoffmann, N., Bertrand, S., Marinkovic F S. and Pesch, J. (2006) Efficient radical addition of tertiary amines to alkenes using photochemical electron transfer. Pure and Applied Chemistry, 78, 2227-2246. 

Bertrand, S., Hoffmann, N., and Pete, J.P. (2000) Highly efficient and stereoselective radical addition of tertiary amines to electron-deficient alkenes-application to the enantioselective synthesis of necine bases. European Journal of Organic Chemistry, 82, 2227—2238. 

Recently, an efficient photocatalytic method has been reported for the radical addition of tertiary amines to electron-deficient double bonds (Scheme 59) [134]. N-methylpyrrolidine was added to the furanone 216. The radical attack occurred specifically anti with respect to the menthyloxy substituent, and the adducts 217 and 218 were isolated in high yields in the presence of sensitizers having electron-rich substituents or in the presence of semiconductors like Ti02-However, the configuration of the chiral center in the a-position of the nitrogen atom could not be controlled. Although the diastereoselectivity was almost the... 

Photoexcited Ti02 can work as a catalyst for radical addition of tertiary amines to electron deficient alkenes. In particular, A-methylpyrrolidine containing a. 

Das, S., Kumar, J.S.D., Shivaramayya, K., and George, M.V., Formation of lactams via photoelectron-transfer catalyzed reactions of N-aUylamines with a,P-unsaturated esters. Tetrahedron, 52,3425,1996. (a) Bertrand, S., Glapski, C, Hoffmann, N., and Pete, J-P., Highly efficient photochemical addition of tertiary amines to electron deficient alkenes. Diastereoselective addition to (5R)-5-menthyloxy-2(5ff]-furanone. Tetrahedron Lett., 40, 3169, 1999 (b) Bertrand, S., Hoflfrnann, N., and Pete, J-P., Stereoselective radical addition of tertiary amines to (5R)-5-menthyloxy-2[5H]-furanone application to the enantioselective synthesis of (-)-isoretronecanol and (-l-)-labumine. Tetrahedron Lett., 40,3173,1999 (c) Farrant, E. and Mann, J., Novel synthesis of the indoUzidine alkaloid skeleton with appropriate functionality and stereochemistry for use as a chiral scaffold, /. Chem. Soc., Perkin Trans. 1,1083,1997. 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

A further example of photochemically induced addition to the enone double bond in (25) has been reported. In this example irradiation using benzophe-none as the radical producing agent in methanol results in a 51% yield of the adduct (26). Pete and his co-workers have reported the sensitized addition of tertiary amines such as (27) to the furanone double bond in (28). The reaction involves electron transfer from the amine to the sensitiser which ultimately... 

The general reaction of tertiary amines with non-initiating peroxy radicals (R02 ), to yield initiating a-amino radicals, is shown in equation (8). These features make Pl2-tertiary amine combinations particularly effective for photocrosslinking in air. Enhanced surface-cure is also expected from addition of tertiary amines to PIi photoinitiators, which may be accompanied by lower crosslink density, resulting from chain transfer to amine. 

Lewis, F.D., Ho, T.I., and Simpson J.T., Photochemical addition of tertiary amines to stilbene. Free radical and electron transfer mechanism for amine oxidation,/. Am. Chem. Soc., 104, 1924, 1982. 

Scheme 55, Eq. 55a) [119]. A plausible mechanism is depicted in Scheme 55 and involves radical addition of the 2-tetrahydrofuryl radical to the aldehyde followed by a rapid reaction of the alkoxyl radical with Et3B. Triethylborane has a crucial role since by reacting with the alkoxyl radical it favors the formation of the condensation product relative to the -fragmentation process (back reaction). A similar reaction with tertiary amines, amides and urea is also possible (Eq. 55b) [120]. 

The 1,4-photoaddition of aliphatic amines with benzene via photoinduced electron transfer was first reported by Bryce-Smith more than 30 years ago [375-378], In the photoreaction of triethylamine with benzene, the proton transfer from the radical cation of triethylamine to the radical anion of benzene is proposed as a probable pathway (Scheme 113). In the case of tertiary amines, the photoaddition is accelerated by the addition of methanol or acetic acid as a proton source. Similar photoaddition of diethyl ether to benzene takes place assisted by trifluoroacetic acid, where methanol is not affective [379], In these photoreactions, a-hydrogen next to the heteroatom moves to the radical anion of benzene as a proton, followed by radical ccoupling to give 1,4-addition products. Similar photoaddition of amines to the benzene ring has been reported by Ohashi et al. [380,381],... 

Workentin et al. have recently reported the results of an extensive laser flash photolysis investigation of the reactions of the cation radicals of 9-phenyl- and 9,10-diphenylanthracene (PA and DPA, respectively) with amines. Primary amines react with both cation radicals via nucleophilic addition with rate constants which reflect both the amine basicity and a steric requirement for bond formation. Steric effects are more pronounced for addition of DPA " vs. PA ", presumably due to the presence of substituents at both the 9- and 10-position. Tertiary amines and anilines react with PA " and DPA " via electron transfer with rate constants which correlate with amine ionization potentials. Rate constants for nucleophilic addition of primary amines are faster in acetonitrile than in acetonitrile/water solution. The rate-retarding effect of water is attributed to an equilibrium between the fiee amine (reactive) and hydrated amine (unreactive). The beneficial effect of water on preparative ET-sen itized photoamination may reflect its role as a catalyst for the proton transfer processes which follow C-N bond formation (Scheme 2). Hydration of the amine also should render it less reactive in primary and secondary electron transfer processes which can compete with the formation of the arene cation radical. 

The failure of tertiary (AI,IV-dimethylaminoalkyl)arenes and stilbenes to undergo intramolecular addition may reflect structural differences between inter- vs. intramolecular exciplexes. Polar solvents are generally required for the observation of in-termolecular addition reactions of tertiary amine exciplexes. Equilibration between solvent-separated and radical ion pairs may be necessary in order to achieve an appropriate reaction trajectory for a-C-H proton transfer. In the case of intramolecular exciplexes with short chain linkers, electron transfer in polar solvents may occur in extended geometries which are inappropriate for proton transfer and chain folding may not compete effectively with exciplex decay. The exceptions to these generalizations, benzene and styrene, form more localized anion radicals which undergo both inter- and intramolecular reactions with tertiary amine cation radicals in nonpolar solvents. 

The [Ir(ppy)2bpy] complex photo-catalyses inter- and intramolecular C-H functionalisation reactions of tertiary amines under the visible light irradiation. Oxygen behaves as a chemical switch, triggering different reaction pathways and leading to different products from the same starting material. In anaerobic conditions, the intermolecular addition of iV,iV-dimethyl-anilines to electron-deficient alkenes yields y-amino nitriles. Aerobic conditions, on the other hand, favour a radical addition/ cyclisation reaction, leading to tetrahydroquinoline derivatives. The intramolecular version of the radical addition produces unexpectedly indole-3-carboxaldehyde derivatives. ... 

The RX substrate must not contain a flexible P C-H bond so that the metal-alkyl species resulting from its oxidative addition be prevented from undergoing p-elimi-nation before the insertion step (which would result in an overall dehydrohalogena-tion of RX). Thus, the R group must be a vinyl, aryl (the p position is not flexible in these groups) or benzyl radical. The reaction is carried out upon heating RX (organic halide or triflate) with the alkene, a catalytic amount of Pd and an excess of tertiary amine in acetonitrile. 

Single-electron oxidation of tertiary amines is controllable by photoredox catalysis delivering nucleophilic a-aminoalkyl radicals (Scheme 3.11). The recent findings in this area illuminate a nice addition to the above iminium ion chemistry. 

Due to the nucleophilicity of a-aminoaUcyl radical, it is supposed to add to electron-deficient alkenes. This assumption was first achieved by Nishibayashi [50] and Reiser [51] in early 2012 (Scheme 3.12). They reported visible-Ught-mediated addition of a-aminoalkyl radicals derived from tertiary amines to Michael acceptors (unsaturated esters and vinyl ketones). Also, radical addition to acrylate derivatives was later accomplished (Scheme 3.12) [52]. As a follow-up work, Nishibayashi et al. developed visible-light-promoted radical C(sp )-H amination of benzocyclic tertiary amines using di-terr-butyl azodicarboxylate as nitrogen source (Scheme 3.12) [53]. In 2013, Yu et al. found that AA -dimethylaniline derivatives could react with A-aryl- and A-benzyhnaleimides to give tetrahydroquinoline products with air as oxidant (Scheme 3.12) [54]. Unfortunately, the other olefins, such as furan-2,5-dione, diethyl maleate, methyl acrylate, and l-phenylprop-2-en-l-one, fail to undergo this transformation. The mechanistic... 

In addition to the facile reaction of tertiary amines with PIf, which competes effectively with deactivation by O2, the resulting a-amino radicals are known to react with O2 by a radical chain... 

Mechanistic details were also discussed for the reaction of enamineones such as 78 (Scheme 13). After photochemical exdtation, single electron transfer took place. This transfer occurred in an intramolecular way leading to intermediate N or in an intermolecular way (in the presence of tertiary amines) leading to the radical ion pair O. After release of chloride, the latter intermediate yields the pyridyl radical P. Addition of the radical moiety to the enamineone double bond and loss of hydrogen led to the final product 79. Hydrogen abstraction from a solvent molecule or addition with a solvent molecule (e.g., benzene) of P led to side products such as 80. The same produd could also result from the reaction of intermediate N. Under the described reaction conditions, 80 could not be isolated since under photochemical electrocyclization, it was transformed into 79 and 81. 

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