Palladium‐Catalyzed C–C Ring Closure in α‐Chloromethylimines: Synthesis of 1H‐Indoles

Abstract

The C‐C ring closure of α‐chloromethyl alkyl or aryl N‐aryl imines catalyzed with 1 to 10 % Pd(OAc)2/P(p‐tolyl)3 afford efficiently 2‐aryl‐ and 2‐alkyl‐1H‐indoles. The heterocyclization reaction involves the initial formation of [2‐(arylimino)ethyl]palladium(II) chloride complexes with subsequent C‐H activation of the aromatic amine ring. Readily or commercially available α‐chloromethyl‐aryl or ‐alkyl ketones are used as the precursors. Functionalized indoles at the benzene ring are obtained when the imines are derived from substituted anilines.

Straightforward Synthesis of α-Chloromethylketimines Catalyzed by Gold(I). A Clean Way to Building Blocks

“…Eluent 50:1 n-hexane/AcOEt; 156 mg as a thick colorless oil; isolated yield of 68%. NMR data were consistent with literature values: 5 1 H NMR (500 MHz, CDCl 3 ) δ 7.75 (s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.06−6.96 (m, 2H), 6.22−6.09 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 1.63 (p, J = 7.6 Hz, 2H), 1.35−1.14 (m, 12H), 0.81 (t, J = 6.8 Hz, 3H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 140. 2, 136.0, 129.0, 121.0, 119.9, 119.7, 110.4, 99.6, 32.0, 29.6, 29.5, 29.4, 29.3, 28.4, 22.8, 14.2. General Reduction of Chloroimine to β-Chloroamine (8).…”

“…First, crude chloroimines 3aa , 3ba , and 3ea were directly subjected to palladium-catalyzed cyclization to afford indoles 7 (Table ). The results obtained with this selection of chloroimines show the power of this methodology for preparing indoles presenting bulky or aliphatic substituents, arduous to synthesize through other pathways such as condensation or cross-coupling …”

“…Thus, these species are used in situ in the presence of large amounts of starting materials and side products that complicate subsequent transformations. 5,6,8,9 The synthetic routes for α-chloroketimines described so far cannot be considered general or satisfactory in any instance. Therefore, the design of a general and clean way to prepare these versatile building blocks is necessary.…”

“…1 The reduction of these compounds provides β-haloamino derivatives, 2 the main entrance route for the synthesis of aziridines, 3 substances with interesting biological properties that are widely used as synthetic intermediates. 4 In addition, halogenated imines can be subjected to in situ cyclization to afford indoles, 5 piperidines, and other nitrogen-containing heterocycles. 6 Two strategies have been applied for the synthesis of halogenated ketimines: the electrophilic halogenation 7 of the corresponding imine in a process similar to the halogenation of ketones and the condensation of a monohalogenated ketone with an amine (Scheme 1).…”

“…For this reason, they have never been properly characterized by NMR. Thus, these species are used in situ in the presence of large amounts of starting materials and side products that complicate subsequent transformations. ,,, …”