Indoles paraformaldehyde reaction

The formation of a nitroethene electrophile in situ, is believed to be involved in the reaction between an indole, paraformaldehyde and ethyl nitroacetate, giving precursors for tryptophans. ... 

During the course of the author s efforts directed toward the development of useful transformations of allenic compounds [66-77], the author found that the reaction of A -tosylated 2-ethynylaniline 1 with paraformaldehyde 2 and diisopropylamine 3 in dioxane in the presence of copper(l) bromide (Crabbe conditions) [78] afforded a 2-(aminomethyl)indole derivative 7 in 92% yield (Scheme 2) without forming the expected [2-(A -tosylamino)phenyl]allene. This reaction can be rationalized by Mannich-type MCR followed by indole formation through intramolecular hydroamination toward the activated alkyne moiety of a plausible intermediate 6. This is the first example of three-component indole formation without producing stoichiometric amount of salts as byproducts. 

Next, the author examined the scope of the 2-(aminomethyl)indole formation with various symmetrical secondary amines (Table 2) under the optimized conditions (Table 1, entry 4). The reaction of 2-ethynylaniline la with bulky diisopropylamine 3a (1.1 equiv) and paraformaldehyde 2a (2 equiv) in the presence of CuBr (1 mol.%) gave the expected indole derivatives 7a in 81% yield (entry 1). Pyrrolidine 3c also showed efficient conversion into the corresponding indoles 7c (entry 3). The use of volatile diethylamine 3d successfully afforded 7d, although 2 equiv of Et2NH were needed (entry 4). Secondary amines containing removable allyl and benzyl groups 3e and 3f, respectively, were also acceptable as amine components when the reactions were conducted with a prolonged reaction time (entries 5 and 6). ... 

Calindol (13), which contains a 2-(aminomethyl)indole motif, is a positive modulator of the human Ca " receptor showing a calcimimetic activity [1-3]. This compound could be easily synthesized using this domino three-component indole formation (Scheme 4). As the author expected, the reaction of 2-ethynylaniline la with paraformaldehyde 2a and l-(l-naphthyl)ethylamine 11 in presence of CuBr directly produced a protected calindol 12. The allyl and tosyl groups on the nitrogen atoms of 12 were easily removed by successive treatment with Pd(PPh3)4 (2 mol.%)/NDMBA and TBAF [14] to give calindol 13 in 90% yield over 2 steps. 

The mixture of ethynylaniline li (0.19 mmol), paraformaldehyde 2d (2 equiv.), and amino ester 3 (1.2 equiv.) in dioxane was stirred with CuX (5 mol%) under microwave irradiation (300 W). After indole formation was complete on TLC, the reaction mixture was treated with MsOH at 80 °C for 30 min... 

All reactions were conducted with ethynylaniline 1, paraformaldehyde (2 equiv), and secondary amine 2 (1.1 equiv) in the presence of Cul (2.5 mol%) in 1,4-dioxane at 170 °C for 20-40 min under microwave irradiation. After the indole ftnmation was completed (monitored by TLC), MeONa (6 equiv) was added and the mixture was heated at 170 °C for 20 min under microwave irradiation Isolated yields... 

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