Desulfonylation of Indoles and 7-Azaindoles Using Sodium tert-Butoxide

Abstract

A mild method for the desulfonylation of N-indoles and N-azaindoles is described. Deprotection is carried out under basic conditions, using sodium tert-butoxide in dioxane. Several functionalized indoles and 7-azaindoles were efficiently deprotected by this method, which is mild enough to be used to deprotect compounds including functions that are known to be sensitive to acidic or basic conditions. Indoles and related structures are found in many active pharmaceutical molecules. [1][2][3][4][5] The NH group needs to be protected during synthetic pathways by a suitable group that can easily be removed at the end of the synthesis. The benzenesulfonyl group is one of the blocking groups commonly used to protect amines, because the resultant sulfonamides are more robust, confer crystallinity, and facilitate isolation. This group also modifies the polarity of the protected compound by withdrawing electrons. The methods for its deprotection are well known: dissolving metal reductions (Li or Na) in ammonia, HMPA, or alcohol; 6,7 sodium naphthalene 8 or anthracene, 9 Na-Hg, 10 Bu 3 SnH, 11,12 mischmetal with TiCl 4 , 13 SmI 2 , 14 Mg/ MeOH, 15,16 alkali metals in silica gel; 17 severe acidic conditions with H 2 SO 4 , 18 AcOH-HClO 4 , 19 48% HBr with PhOH and 30% HBr in AcOH, 20 KF on alumina under microwaves; 21 or basic conditions such as NaOH and KOH, 22,23 K 2 CO 3 in a acetonitrile, 24,25 Cs 2 CO 3 in THFMeOH, 26 n-Bu 4 NF in refluxing THF. [27][28][29] Most of these methods are effective in a number of cases, but are not compatible with other groups. We tried several of the methods described in the literature, but none of them gave satisfactory results.In a previous study, we were interested in the synthesis of compound 2. Treating 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1) in the presence of K 2 CO 3 refluxing in a MeOH-H 2 O mixture 30 or using an aqueous solution of NaOH reflux in EtOH 31 led to degradation products. Moreover, observed desulfonylation instead of introduction of an amine into position 2 during attempted Buchwald-type coupling of 2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 3 with aryl or alkylamines.This unexpected result has led us to develop a new and mild method to cleave the benzenesulfonyl moiety from protected indoles and related structures using sodium tertbutoxide. In order to determine the optimum stoichiometry, we carried out a series of experiments with 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1).The amount of sodium tert-butoxide and the heating method (sealed tube or flask) were studied. The best results were obtained with the addition of 1.5 equivalents of sodium tert-butoxide and heating in a sealed tube at 80°C for three hours. Under these conditions, the derivative 2 was isolated with 92% yield.Under these new optimized conditions, 32 a variety of substituted indoles and azaindoles was subjected to N-desulfonylation with NaOt-Bu in dioxane. The results are shown in Table 1.The desulfonylation of unsubstituted N-sulfonyl-7-aza...

Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

“…When the reaction was carried out with N -sulfonyl-protected 4-bromo-7-azaindole 1b only the desulfonated product (Table 2, entry 2) was obtained. It is worth mentioning that the N -sulfonyl protected 7-azaindole 1b was efficiently deprotected under basic conditions in dioxane [57]. The optimized reaction conditions worked well with benzamide ( 2a ) (Table 2, entry 3) and phenylsulfonamide ( 2b ) (Table 2, entry 4) to obtained a good yield.…”

Transition-Metal-Free and Visible-Light-Mediated Desulfonylation and Dehalogenation Reactions: Hantzsch Ester Anion as Electron and Hydrogen Atom Donor

“…19 F NMR (377 MHz, CDCl 3 ) δ −58.0. GC/MS EI m/z 332 (M + + 1, 2), 331 (M + , 15), 190 (81), 162 (11), 95 (20), 92 (11), 78 (11), 77 (100), 69 (16), 66 (12), 65 (11), 51 (61), 50 (16). HRMS (ESI-TOF + ) m/ z: [M + H] + calcd for C 14 H 13 F 3 NO 3 S 332.0563; found 332.0572.…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 6.99 (d, J = 8.5 Hz, 2H), 6.54 (d, J = 8.4 Hz, 2H), 3.51 (s br, 1H), 2.80 (s, 3H), 2.24 (s, 3H). 13 (13), 91 (41), 89 (10), 79 (12), 78 (15), 77 (26), 65 (25), 63 (16), 60 (12), 53 (11), 52 (18), 51 (26), 50 (16).…”

“…13 C NMR{ 1 H} (101 MHz, CDCl 3 ) δ 147.0, 140.1, 126.0, 112.2, 33.8, 31.6, 31.0. GC/MS EI m/z 164 (M + + 1, 3), 163 (M + , 28), 149 (11), 148 (100), 133 (16), 120 (21), 108 (12), 107 (13), 91 (13), 77 (16), 65 (12), 50 (3).…”

“…Likewise, many methods using strong bases or nucleophiles are well known, such as NaOH or KOH in MeOH, 13,14 KOH in tetrahydrofuran (THF)/H 2 O mixture, 15 NaO t Bu in dioxane, 16 thioglycolate in dimethylformamide (DMF), 17 Cs 2 CO 3 in THF/MeOH, 18 PhMe 2 SiLi in THF, 19 sodium bis(2-methoxyethoxy)aluminum hydride in benzene or toluene as solvents 20 and n-Bu 4 NF 21 in dry THF. Despite the large number of N-desulfonylation methodologies in basic media, only a few are useful in industries because long-time reactions and high temperatures are required to obtain the corresponding desulfonylated products.…”