Indolyl-5-amines

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

BINOL phosphate (5)-3o (10 mol%, R = 2,4,6- PTj-C Hj) turned out to be the catalyst of choice and gave iV-acetylated 3-indolyl amines 128 bearing a qnatemary stere-ogenic center in excellent yields (94-99%) with high enantioselectivities (73-97% ee). Enamides derived from aryl-methyl ketones as well as indoles with varions substitnents conld be employed. 

The replacement reaetion by poly functional nitrogen-containing derivatives, in particular, makes it possible to introduce multiple RCH2 groups into the same molecule. Thus, the reaction of indole Mannich bases with ammonia y ields bis- and tris-(3-indolyl) amines. Likewise, primary amines, hydrazine, and hydroxylamine can be bis-alkylated by several Mannich bases. 

Convert indole to indolyl-3-methyl-ketone (I) by treating indolyl-Mg-Br (preparation already described) with acetyl-Cl, by treating indole in POCl3 with dimethylacetamide (Vilsmeier reaction), or by reacting indole with diketene (ACS 22,1064(1968)). 15.9 g (1) in 50 ml methanol cool, stir and add dropwise 16 g Br2. Reflux 1 Vi hours on water bath cool, filter, wash with ether and recrystallize-methanol to get 18 g indolyl-3-Br-methyl-ketone (II). Dissolve 11.9 g (II) in 60 ml warm isopropanol and add 11 g 3 8% aqueous DMA (or equimoiar amount other amine) reflux one hour on water bath. Filter (recrystallize-ethanol) to get 8.5 g indolyl-3-dimethylamino-methyl ketone (III). Add 4.6 g (0.02 M) (III) in 30 ml tetrahydrofuran to 2.3 g lithium aluminum hydride in 50 ml tetrahydrofuran, stir one-half hour at room temperature and reflux two hours. Add a little water dropwise and extract the precipitate with acetone. Dry, evaporate in vacuum the combined organic phases to get an oil which will precipitate with ether-petroleum ether to give DMT. (Ill) should be tested for psychedelic activity. Dialkyltryptamines BCSJ 11,221 (1936), BSC 2291 (1966)... 

Padwa has shown that rhodium-catalyzed oxidation of indolyl carbamate 67 employing either Phl(OAc)2 or Phl=0 follows a path similar to that of the D-aUal carbamate (Scheme 17.26) [95]. In principle, indole attack of the putative rhodium-nitrene generates zwitterion 68, which is trapped subsequently by an exogenous nucleophile. Spiro-oxazolidinone products (for example, 69) are isolated as single diastereomers in yields ranging from 50 to 85%. As an intriguing aside, Padwa has found that certain carbamates react with Phl=0 in the absence of any metal catalyst to furnish oxazoHdinone products. This result may have implications for the mechanism of the rhodium-catalyzed process, although it should be noted that control experiments by Espino and Du Bois confirm the essential role of the metal catalyst for C-H amination [57]. 

In summary, protein molecules may contain up to nine amino acids that are readily derivatizable at their side chains aspartic acid, glutamic acid, lysine, arginine, cysteine, histidine, tyrosine, methionine, and tryptophan. These nine residues contain eight principal functional groups with sufficient reactivity for modification reactions primary amines, carboxylates, sulfhydryls (or disulfides), thioethers, imidazolyls, gua-nidinyl groups, and phenolic and indolyl rings. All of these side chain functional groups in addition to the N-terminal a-amino and the C-terminal a-carboxylate form the full complement of polypeptide reactivity within proteins (Fig. 12). 

The methodology described above could be successfully applied for the synthesis of compound 240, containing the core structure of the marine metabolites 225, and 226 starting from N-acetyltryptamine (239). Furthermore, the symmetrical bis(indolyl)nitroethane 236a, as a model structure, could be reduced to the corresponding amine, isolated as its N-acetyl derivative 241 (Scheme 53) [174,177],... 

Since Amadori compounds are secondary amines, the question of the formation and reactivity of /V-nitroso derivatives arises. Accordingly, Pool el al 22 tested those derived from glucose with Ala, Asp, Phe, Gly, Ser, and Try in five strains of S. typhimurium with and without S9. The first three compounds were not mutagenic, the next two showed low but reproducible increases in the number of his+ revertants in TA1535 (without S9), but the last, containing indolyl-nitrosamine-D-fructose-L-tryptophan, was mutagenic in all five strains, with and without S9. When separated, the Try compound was mutagenic in three strains, without S9. 

HO-pyr-T TRYPT AMINE,4-HYDROXY-N,N-TE TRAMETH-YLENE 4-INDOLOL,3-[2-(l-PYRROLIDYL)ETHYL] PYRROLIDINE, l-[2-[3-(4-HYDROXY)INDOLYL]ETHYL] 4-HYDROXY-N,N-TETRA-METHYLENETRYPTAMINE 3-[2-(l-PYRROLIDYL)ETHYL]-4-INDOLOL l-[2-[3-(4-HYDROXY)INDOLYL]ETHYL]PYRROLIDINE 4-HYDROXYPYRROLIDYLTRYPT AMINE ... 

Finally, ortho- 2,2-dibromovinyl)-aniline or -acetanilide can successfully be applied in a sequential cyclizing amination-cross coupling reaction with diethyl phosphonate to furnish the indolyl phosphonic ester 136 or the N-acetyl 2-aryl indole 137 as recently shown by Bisseret and coworkers [ 105] (Scheme 50). This sequence can be also performed with corresponding phenol derivatives furnishing benzofurans. For the N-acetyl 2-aryl indole 137 it can be shown that the Suzuki coupling occurs prior to the intramolecular animation as a consequence of the gradual difference in reactivity between trans-and czs-carbon-bromine bonds. 

Robison, and Robison were the first to prepare 7-azagramine (3-dimethylaminoniethyl-7-azaindole), finding the following procedure to give optimum yields. The azaindole, 10% excess dimethyl-amine hydrochloride, and one molar equivalent of paraformaldehyde are refluxed together in w-butanol for 30 minutes, followed by evaporation under reduced pressure. The residue is extracted with dilute acid, from which the base is precipitated with sodium carbonate. This procedure has been used with only minor variations on a variety of 7-azaindoles. Williamson obtained 7-azagramine in 99% yield on a 0.2-mole scale, compared to 81%. Other 7-azagramines prepared similarly are l-phenyl-4-methyl (72%), ° l-butyl-4-methyl (64%), 6-chloro-4-methyl (60%), 4-methyl (28%), 2-methyl, and 5-methyl (60%). In the case of the last two 4-methyl compounds, it was found that the best yields were obtained with use of a 3 1 molar ratio of dimethylamine hydrochloride and only a 15-minute reflux period. With the 6-chloro-4-methyl isomer, some (6%) of the bis-(7-aza-3-indolyl)methylene by-product was formed. 

Amin Ethyl-(3-indolyl-methyl)-nitro-E16a, 1168 (N-Alkylier.) Benzimidazol 2-Methyl-(l-methyl-2-nitro-ethyl)- E8c, 337 (NH - N — R)... 

Nitro-phenyl)-l -phenyl- E16a, 596 (Hamstoff-Umlager.) 2-(4-Nitro-phenyl)-l -phenyl- X/2, 713 E16a, 609 (Hydrazon-Red.) Naphthalin l-Diazo-4,4-dimethyl-6-nitro-l,4-dihydro- El4b, 1037 (Sulfonylhydrazon/NaO —R A) Propansaure 2-Diazo-3-(3-indolyl)- -methylester E14b, 1103 (Amin + R —O—NO)... 

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