Just by adding a tert-butoxy radical precursor, alkylamines react with aryl halides to give α-arylalkylamines. The reaction proceeds through chemoselective homolytic aromatic substitution of the halogen atom (Br or Cl) by an α-aminoalkyl radical.
In the presence of a tert-butoxy radical precursor, the reaction of alkylamines with aryl halides was found to give α-arylated alkylamines through homolytic aromatic substitution of the halogen atoms.
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- 1For reviews, see: a) Free Radicals in Organic Chemistry (Eds.: J. Fossey, D. Lefort, J. Sorba), John Wiley and Sons, Chichester, 1995, chap. 14, pp. 166–180;
- 2For selected examples, see: a) , , , and , Tetrahedron Lett., 1971, 12, 59–62;
- 3 and , Org. Biomol. Chem., 2014, 12, 7469–7473.
- 4For reviews on HAS with a halogen leaving group, see: a) , Chem. Rev., 1979, 79, 323–330;
- 5For example, the reaction of bromobenzene (6.2 equiv.) with cyclohexane (5 equiv.) in the presence of tBuOOtBu (1 equiv.) gives a mixture of cyclohexylbenzene and bromo(cyclohexyl)benzenes (1:5). and , J. Am. Chem. Soc., 1966, 88, 5222–5228.
- 6Several research groups have recently reported the α-arylation of heteroatom-containing aliphatic compounds with heteroaryl halides under photoredox catalysis. Although an HAS mechanism is considered to be operative, it is not clarified how the elimination of the halogen atom proceeds. The reaction requires a rather complicated photoredox system and the scope of aryl halides is limited to heteroaryl chlorides containing more than two heteroatoms on the aromatic ring: a) , , , Org. Lett. 2013, 15, 5390–5393;
- 7α-Arylation of secondary alkylamines is achieved e.g., through acylation of a secondary amine, deprotonation by butyllithium, transmetalation of the resulting α-(acylamino)alkyllithium with ZnCl2, the Negishi coupling with a heteroaryl halide, and deacylation: a) , , , and , J. Am. Chem. Soc., 2006, 128, 3538–3539;
- 8The reaction of 1a with a reduced amount (2 equiv.) of 4a resulted in a much lower yield (19 %, 5aa:5′aa = 84:16) with a low conversion (28 %) of 1a under the conditions of entry 1 of Table 1.
- 9 and , Tetrahedron Lett., 1966, 7, 6163–6168.
- 10Aryl halides substituted with an electron-donating group such as 4-bromoanisole did not participate in the α-arylation at all.
- 11The use of tBuON=NOtBu (1 equiv.) at 120 °C in the reaction of 4-chlorobenzonitrile (1′a) with N-methylpyrrolidine (4a: 10 equiv.) scored a lower yield of 5aa and 5′aa (64 %, 88:12), probably because supply of tBuO· through homolysis is too fast and thus mismatches with other steps.
- 12Facility in generating the corresponding radical from pyrrolidine compared with structurally similar compounds is discussed on the basis of stereoelectronic effects of the lone pair on the nitrogen atom: a) , , and , J. Am. Chem. Soc., 1981, 103, 619–623;
- 13The reaction of butylamine or diethylamine (10 equiv.) with 4-bromobenzonitrile (1a: 1 equiv.) in the presence of tBuON=NOtBu (1 equiv.) at 60 °C for 24 h gave no α-arylated products with no consumption of 1a.
- 14, and , J. Chem. Soc., Chem. Commun., 1986, 207–208.
- 15The possibility that the halogen atom (X) undergoes elimination in a form of X– after single-electron reduction of cyclohexadienyl radical II by α-aminoalkyl radical I, giving α-arylation products 5 and iminium salts III, cannot be excluded. A similar mechanism has been proposed in the reduction of alkyl halides into alkanes by using α-aminoalkyl radicals: a) , , , , Chem. Phys. Lett. 2011, 511, 156–158;