Substitution of the Dimethylamino Group in Gramines and One-Pot Cyclization to Tetrahydro-β-carbolines Using a Triazine-Based Activating Agent

Abstract

A new method for the substitution of 3-[(dimethylamino)­methyl]­indoles (gramines) with malonate-based nucleophiles was developed using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) as the activating agent for the dimethylamino group. The reaction was completed in 1.5–6 h at room temperature in the presence of a tert-amine base and lithium salt. CDMT afforded superior results to methyl iodide, a common activating agent for the dimethylamino group in Mannich bases, particularly in the reactions of 1-substituted gramines. The reactivity of the possible intermediates, bis­(indol-3-ylmethyl)­dimethylammonium salts, was examined to obtain mechanistic insights on the reaction. This substitution method with CDMT enabled the sequential transformation of gramines: substitution with (N-alkylidene)­aminomalonates followed by the Pictet–Spengler reaction under acidic conditions afforded 1,2,3,4-tetrahydro-β-carboline derivatives in one pot.

Transition-Metal-Free Base-Promoted Deaminative Coupling of Gramines with Aminomaleimides

“…Based on the results of this control experiment and previous studies, a plausible reaction mechanism was determined, as shown in Scheme . First, the elimination of dimethylamine from gramine 1a via the base generates the highly reactive 3-methyleneindolenine A . , Simultaneously, the deprotonation of 2a results in the formation of intermediate B in the presence of the base . Intermediates B and C are resonant structures .…”

“…This coupling, which is known as the Somei–Kametani reaction, is widely used in the total synthesis of natural products . Subsequently, other activating reagents have been developed for this transformation . However, there has been significantly less research conducted on the deaminative coupling of gramines with sp 2 carbon nucleophiles than with sp 3 carbon nucleophiles.…”

Rapid and efficient syntheses of tryptophans using a continuous-flow quaternization–substitution reaction of gramines with a chiral nucleophilic glycine equivalent

“…to 8a ) was employed.c1.5 M KOH solution in MeOH (2.2 eq. to ( S )- 2 ) was added.dTotal unidentified by-products.eCDMT 32 was employed for the activation of 8a .fEthyl propiolate 33 was employed for the activation of 8a .…”

“…Substitution reactions of 8a with ( S )- 2 in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) 32 and ethyl propiolate, 33 as activating agents of 8a , were also carried out for comparison and they resulted in lower yields of 3a even after a longer reaction time (entries 6 and 7). From these results, the one-pot preparation of 3a through the quaternization–substitution reaction of 8a with ( S )- 2 appears to be the most useful method in a batch process.…”

“…To a mixture of ( S )- 2 (331 mg, 0.55 mmol) and 8a (115 mg, 0.66 mmol) in THF (0.3 mL) and MeCN (2.4 mL) was added CDMT 32 (96.6 mg, 0.66 mmol) at 25 °C and the mixture was stirred at the same temperature for 30 min under N 2 . The reaction mixture was treated with AcOH (2 mL) and subjected to HPLC analysis.…”