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Home > Formal [4 + 1] Cycloaddition of o-Aminobenzyl Chlorides with Isocyanides: Synthesis of 2-Amino-3-Substituted Indoles
Formal [4 + 1] Cycloaddition of o-Aminobenzyl Chlorides with Isocyanides: Synthesis of 2-Amino-3-Substituted Indoles
Formal [4 + 1] Cycloaddition of o-Aminobenzyl Chlorides with Isocyanides: Synthesis of 2-Amino-3-Substituted Indoles
Jacobus A. W. Jong, Xu Bao, Qian Wang, and Jieping Zhu
Introduction
2-Aminoindole is an important structural motif found frequently in natural products and pharmaceuticals. Cryptotackieine[1,2] and perophoramidine[3] are repre- sentative indoloquinoline alkaloids that contain such a structural subunit. While many powerful reactions have been developed for the synthesis of indoles,[4] synthetic methods allowing efficient construction of 2- aminoindoles remained limited.[5–11] Listed in Scheme 1 are some of the recently developed method- ologies including 1) Pd-catalyzed Buchwald– Hartwig N-arylation of 2-haloindoles with anilines (Sche- me 1,a);[12,13] 2) Pd-catalyzed heteroannulation of N- alkynyl-2-haloanilides with amines (Scheme 1,b);[14] 3) Pd-catalyzed coupling of ynamides and o-iodoanilines (Scheme 1,c);[15] 4) Pd-catalyzed domino N-arylation followed by base-promoted cyclization; copper-catalyzed reaction of substituted N-(2- halophenyl)-2,2,2-trifluoroacetamides with alkyl 2-cya- noacetate or malononitrile (Scheme 1,e);[17] 6) gold- catalyzed intermolecular reaction of azides with ynamides (Scheme 1,f).[18,19] In spite of these significant achievements, the development of practical and cost-effective methods are still highly demanding. Indeed, most of the recently developed 2-aminoindole syn- thesis relied on the expensive transition metals.
Isocyanide, by virtue of its carbene-like reactivity, has been widely used as a key component in the development of novel multicomponent reactions.[20–26] The capability of isocyanide to under- go an α-addition with both an electrophile and a nucleophile also made it an ideal one carbon synthon[27–29] that has been extensively exploited in a broad range of cycloaddition reactions including [4 +
1],[30,31] [3 + 1],[32 – 34] [5 + 1],[35 – 40] and [2 + 2 + 1][41,42]cycloaddition reactions, and radical addition processes.[43] More relevant to the present topic, a number of valuable synthetic methodologies have also been developed for the synthesis of indoles using aryliso- cyanides as starting materials.
Our group has a long-term interest in isocyanide chemistry[45–52] and has reported an AlCl3-catalyzed formal [4 + 1] cycloaddition of 2-cyano-1-azadienes with isocyanides for the synthesis of 2-amino-5- cyanopyrroles.[53] As a continuation of this research program, we report herein a novel synthesis of 2- aminoindoles 3 by a base-promoted (NaHCO3) reac- tion of N-tosyl-2-aminobenzyl chlorides 1 with isocyanides 2 (Scheme 1,g). While isocyanide-based formal [4+ 1] cycloadditions have been employed for the syn- thesis of diverse heterocycles,[30] its application to the synthesis of indoles was, to the best of our knowledge, unprecedented. We note that Xiao and co-workers have reported an elegant synthesis of 2-acylindoles by reaction of 1 with sulfur ylides.
Results and Discussion
Our initial efforts to find suitable reaction conditions were pursued using tBuNC (2a) and N-{2-[chloro- (phenyl)methyl]phenyl}-4-methylbenzene-1-sulfon- amide (1a) as testing substrates (Table 1). The con- ditions were optimized by varying systematically the bases, the solvents, the temperature, and the reaction time. Key observations are summarized as follows: 1) NaHCO3 was a base of choice among those screened (Cs2CO3, NaOH, MeONa, NaHCO3, Na2CO3, K2CO3, Et3N, DBU, Entries 1 – 8). In the absence of base, the reaction gave the desired product with much lower yield (Entry 9); 2) Using NaHCO3 as base, CH2Cl2 turned out to be the best solvent (Entries 4, 10 – 14); 3) Reaction was best performed at room temperature (Entries 4 vs. 15). The structure of 3a was confirmed by X-ray crystallographic analysis. It is very stable and can be stored at room temperature for months without degradation.
With the optimal reaction conditions in hand, the scope of this novel 2-amino-3-substituted indole syn- thesis was examined. The o-aminobenzyl chlorides 1 and isocyanides 2 used in this study were listed in Figure 1. As shown in Scheme 2, the reaction of tBuNC (2a), BuNC (2b), 4-methoxyphenylisocyanide (2c), and 2,6-dimethylphenylisocyanide (2d) with N-{2-[chloro- (phenyl)methyl]phenyl}-4-methylbenzene-1-sulfon- amide (1a) afforded the corresponding 2-amino-3- phenylindoles (3a, 3b, 3c, 3d) in moderate to good yields. Functionalized isocyanides such as methyl α- isocyanoacetate (2e) and α-isocyanocarboxamides (2f, 2g)[55] participated in the reaction to afford the corresponding products (3e – 3g). It is interesting to note that in the case of 2f and 2g, the competitive formation of oxazole was not observed.[56,57] The 2- alkyl substituted o-aminobenzyl chlorides 1b and 1c reacted with alkyl, aryl, and functionalized isocyanides to provide the corresponding 2-amino-3-alkyl substi- tuted indoles (3h – 3j) in good yields. Chloro- and nitro-substituted N-tosyl-o-aminobenzyl chlorides 1d and 1e reacted with tBuNC (2a) to give the indoles 3k and 3l in 83 % and 67 % yield, respectively. The N-(p- nitrophenyl)sulfonyl and N-(o-nitrophenyl)sulfonyl pro- tected o-aminobenzyl chlorides 1f and 1g participated in the reaction to furnish the 2-aminoindoles 3m – 3o in good to excellent yields. The cyclic carbamate of type 1i (Figure 1) is also known to be a suitable precursor of aza-ortho-xylylene and has been success- fully used in the synthesis of complex natural prod- uct.[58] However, no reaction occurred when 1i and 2a was treated under standard reaction conditions due to the high stability of 1i. Heating the mixture led only to the decomposition of the reactants.
Interestingly, the reaction of N-[2-(chloromethyl)- phenyl]-4-methylbenzene-1-sulfonamide (1h) with tBuNC (2a) under the standard conditions afforded, after 1 h, compound 3p in 66 % yield resulting most probably from the nucleophilic attack of the so formed 2-aminoindole to the second molecule of 1h (Scheme 3). Finally, the indole N-Nos group of 3m can be easily removed to provide the indole N-unpro- tected product 3q in 72 % yield (Scheme 3).
A possible reaction pathway accounting for the formation of 2-aminoindole 3 is depicted in Scheme 4. The reaction was thought to be initiated by the base- promoted elimination of HCl from N-(ortho-chloro- methyl)aryl amide 1 leading to the aza-ortho-xylylene intermediate A.[59,60] Nucleophilic addition of the isocyanide to the benzylic carbon of A would afford the nitrilium intermediate B which underwent a facile cyclization to furnish the cyclic amidine C. Tautomeri- zation of the later would deliver then the 2-amino- indole 3.
Conclusion
In summary, we described herein the first examples of NaHCO3-promoted formal [4 + 1] cycloaddition be- tween isocyanides and N-(ortho-chloromethyl)aryl amides. The reaction proceeded at room temperature to afford the 2-aminoindoles in good to high yields. Mild conditions, high yields, and simple experimental procedures characterized the present indole synthesis.
Experimental Section
General Procedure
To a solution of the N-arylsulfonyl o-aminobenzyl chloride 1 (0.1 mmol, 1.0 equiv.) in CH2Cl2 (1.5 mL) were added NaHCO3 (42 mg, 0.5 mmol, 5.0 equiv.) and the isocyanide 2 (3.0 equiv.). The resulting mixture was stirred at room temperature until the completion of the reaction. The solution was diluted with CH2Cl2 and washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel to give the 2-aminoindole 3.
Acknowledgements
We thank EPFL (Switzerland) and the Swiss National Science Foundation (SNSF 20020-155973) for financial support. We thank Dr. F.-T. Farzaneh and Dr. Rosario Scopelliti for the X-ray structural analysis of compound 3a. J. A. W. J. is an exchange Master student from the Vrije Universiteit Amsterdam, Netherlands.
Author Contribution Statement
J. A. W. J., X. B., Q. W., and J. Z. conceived and designed the experiments. J. A. W. J., X. B. carried out the experiments. J. A. W. J., X. B., Q. W., and J. Z. interpreted the results and co-wrote the manuscript.
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