Stereospecific Radical Bromination of β-Aryl Alcohols with Thiourea Additives Through A Serendipitous Discovery of A 1,2-Aryl Migration

Abstract

The development of new protocols for stereospecific and stereoselective halogenation transformations by mild reaction conditions is a highly desirable research target for the chemical and pharmaceutical industries. Following the straightforward methodology for directly transforming a wide scope of alcohols to alkyl bromides and chlorides using substoichiometric amounts of thioureas and N-halo succinimides (NXS) as a halogen source in a single step, we noticed that in apolar solvents bromination of chiral secondary alcohols did not produce the expected racemates. In this study, the stereochemical aspects of the bromination reaction were examined. Surprisingly, bromination of (±)-threo- or (±)-erythro-3-phenyl-2-butanols revealed a single diastereomeric brominated product with retention of configuration. The scope of these reactions was expanded on several β-aryl alcohols. During these studies, an unexpected stereospecific 1,2-migration of the phenyl group was shown to take place. The proposed mechanism of the 1,2-phenyl migration involves the formation of a spiro[2,5]octadienyl radical, which is then attacked by a bromide radical at any of the two cyclopropyl positions anti to the phenyl position, leading to products that retain the stereoisomeric configuration of the starting material.

Keywords: Alcohols; Halogenation; Radical aryl migration; Stereoselectivity; Thiourea.

Scheme 1

Top: A general scope for direct halogenation of alcohols mediated by NXS (X=Cl, Br) as a halogen source and a thiourea additive. Middle: Stereoselectivity in brominations of chiral alcohols. Bottom: Stereospecific bromination of alcohols following radical 1,2‐aryl migration.

Scheme 2

Synthesis of 3‐phenyl‐2‐butanol diastereomers and their elimination products. Reaction conditions: (i) PhMgBr (1.5 equiv), CuI (5 mol %), THF, 0 °C, 1 h; (ii) MsCl (1.2 equiv), pyridine (1.2 equiv), DCM, 0 °C‐RT, 12 h; (iii) KOH (1.2 equiv), MeOH‐DCM (3 : 1), reflux, 3 h.

Scheme 3

Stereoselective bromination pathways of (±)‐erythro‐2  a and subsequent elimination.

Scheme 4

Transformation of (±)‐erythro‐3‐phenyl‐2‐butanol to the corresponding bromoalkane stereoisomers under three different reaction conditions.

Scheme 5

Synthesis of (±)‐erythro‐3‐phenyl‐2‐bromobutane derivatives, (±)‐erythro ‐5  a‐h. Yields are referred to as isolated products. Diastereomeric ratios (dr) were determined by GC‐MS analysis.

Scheme 6

Synthesis of (±)‐threo‐3‐phenyl‐2‐bromobutane, (±)‐threo ‐5  a–d, 5  g, 5  i and 5  j. Yields and dr were determined as in Scheme 4.

Scheme 7

Bromination of (±)‐erythro‐2‐phenyl‐3‐pentanol, (±)‐erythro ‐6. Reaction conditions: (i) NBS (2.3 equiv), PMTU (0.3 equiv), DCE, RT, 4 h; (ii) KOH (1.2 equiv), MeOH‐DCM (3 : 1), reflux, 3 h.

Scheme 8

Bromination mechanism involving a spiro[2,5]octadienyl radical intermediate.

Scheme 9

Reduction of 1,1‐diphenyl‐2‐propanone and subsequent bromination to afford sequential radical 1,2‐phenyl migration and bromination. Reaction conditions: (i) 1,1‐diphenyl‐2‐propanone (9.5 mmol), (S)‐B‐methyl‐oxazaborolidine (0.1 equiv); BH₃‐Me₂S complex (11 equiv), dry THF, N₂, 50 °C, 1.5 h (chiral) or; 1,1‐diphenyl‐2‐propanone (0.95 mmol), LiAlH₄ (1.75 equiv), dry THF, N₂, 0 °C, 2 h (racemate) in 93–94 % yield for both conditions; (ii) (rac)11 or (R)‐11 (0.47 mmol), NBS (2.3 equiv.), PMTU (0.3 equiv), DCE, RT, 6 h.

Scheme 10

Stereoselective Lewis base‐catalyzed reaction of diphenyl oxirane with trialkyl aluminum and subsequent bromination. Reaction conditions: (i) (2R,3S)‐2,3‐diphenyl oxirane (0.51 mmol), AlEt₃ (2 equiv), AsPh₃ (10 mol‐%), RT, 24 h and (ii) (±)‐threo‐14 (0.35 mmol), NBS (2.3 equiv.), PMTU (0.3 equiv), DCE, RT, 6 h.

Scheme 11

Bromination of 17 and 18 to develop enantioselective bromination methodologies. Reaction conditions: NBS (2.3 equiv.), PMTU (0.3 equiv), DCE, RT, 6 h.