We wish to report that sodium borohydride (NaBH₄) in neat carboxylic acids sequentially reduces the indole double bond and alkylates the nitrogen atom to give N-alkylindolines, e.g., 1 → 2, and that this combination of reagents conveniently alkylates primary and secondary aromatic amines, e.g., 3 → 2 (Scheme I).

Although the reduction of indoles to indolines has received considerable attention,² there is no general, efficient procedure for this transformation. Encouraged by the tendency of the indole ring to protonate at the 3-position^3,4 and by the observations that enamines can be reduced by NaBH₄ in acetic acid-tetrahydrofuran (HOAc-THF)⁵ and sodium cyanoborohydride (NaBH₃CN),⁶ we have examined the behavior of indoles with NaBH₄ in neat carboxylic acids.

Quite unexpectedly, the reaction of indole (1) with NaBH₄ in glacial HOAc gives N-ethylindoline (2) in 86% yield. Likewise, the reactions of indoline (3) and N-ethylindole (4) with NaBH₄-HOAc give 2 in high yield.

This unprecedented reduction-alkylation of indoles and reduction of N-alkylindoles⁷ with NaBH₄ in liquid carboxylic acids appears to be a general transformation (Table I). However, the stronger acid, formic, produces indole dimers and other products in addition to N-methylindoline. Interestingly, the reaction of 1 with NaBH₄ in trifluoroacetic acid (CF₃CO₂H) gives indoline (3), the product of reduction without alkylation, in low yield. The yield of 3 can be increased to 88% when 1 is treated with NaBH₃CN-HOAc (Table I). This latter reaction permits a very convenient synthesis of 3.

We believe that the reaction of 1 → 2 involves 3-protonation of indole,⁴ followed by reduction of the resulting indolenium ion to give 3,⁸ which is subsequently alkylated (vide infra). The reduction of the indoloquinolizidine alkaloid 5 with NaBH₄-CF₃CO₂H proceeds without alkylation (72%) and the deuteration experiments, 5 → 6 and 5 → 7, are in accord with our suggested mechanism.

The combination NaBH₄-RCO₂H also provides for the facile alkylation of a variety of primary and secondary aromatic amines⁹ (e.g., 3 → 2), and the reaction can be controlled to give mono- or dialkylation of primary amines. Thus, aniline with NaBH₄-HOAc at 20°C gives N-ethylaniline, and further reaction at 60°C gives N,N-diethylaniline (Table II).

This alkylation method is extended by our observation that aldehydes and especially ketones are reduced to alcohols relatively slowly by NaBH₄-RCO₂H,¹⁰ so that unsymmetrical tertiary amines can be prepared from primary amines in one flask. Thus, aniline with NaBH₄-HOAc-acetone gives either N-isopropylaniline or N-ethyl-N-isopropylaniline, depending on the temperature (Table II). This versatility is not available with previous methods for reductive amination^6,11 of aldehydes and ketones (H₂,^11a,b HCO₂H,^11c,d NaBH₃CN,^6,11e NaBH₄,^11f,g Fe(CO)₅^11h)

We view the amine alkylation as a stepwise process: (1) reduction of carboxylic acid to aldehyde¹² (or aldehyde equivalent), perhaps via one or more acyloxyborohydride species¹³ and intra- or intermolecular hydride reduction of the carbonyl group; (2) reaction of the aldehyde with amine to form an iminium ion; and (3) hydride reduction¹⁴ of the iminium ion to product amine.

Although amides are side products in some cases, they are very clearly not obligatory intermediates in the alkylation reaction. Thus, N-acetylindoline and N-acetylindole are recovered in 67% and 82% yield, respectively, after treatment with NaBH4-HOAc, under conditions which convert indoline completely into N-ethylindoline. Likewise, it seems unlikely that diborane is the reducing agent in the reaction, since externally generated gaseous diborane bubbled into amine-HOAc gives clean acylation and not alkylation of the amine.¹⁵