Benzyloxycarbonyl indole

Madclung synthesis, 27-30 Mannich alkylation, 106, 119 7-mcthoxyindole, procedure for, 8 6-methoxyindole-3-carboxaldehyde, procedure for, 115 116 methyl 4-[5-(benzyloxycarbonyl)indol-3-yl]methyl-3-methoxy-benzoate, procedure for, 108... 

Ring-opening reactions with 3-alkylaziridine esters 36 take a similar course. The reactions are in practically all cases regio- and stereospecific with attack at C-3. An important difference is that the aziridine ring needs to be activated by an electron-withdrawing substituent, such as a tosyl or a benzyloxycarbonyl group. In addition, for benzenethiol, indole, and DMF, catalysis with BF3 was necessary (Scheme 22) [31]. 

A variant on the traditional method is to use a phenylhydroxylamine instead of a phenylhydrazine. For example, A-(benzyloxycarbonyl)-phenylhydroxylamine can be reacted with methyl propynoate to give an adduct that spontaneously undergoes a [3,3]-sigmatropic shift and eventually yields l-(benzyloxycarbonyl)-3-(methoxycarbonyl)indole (Scheme 7.15). 

Dibenzylamino)indol-l-ylmagnesium bromide l-(Benzyloxycarbonyl)pyrrolidine-2-carbony] chloride 44 [7]... 

A 7-substituted 3,4,6,7-tetrahydro-2//-pyrido[2,l-h][l,3]oxazine was formed as by-product the alkylation of methyl 2-(benzyloxycarbonyl-6-oxo-l-phenylsulfonyl)indol-2-yl)-2-azabicyclo[2,2,2]octane-6-enrfo-car-boxylate with 3-iodopropanol from a 3-substituted l-(3-hydroxypropyl)-2,3-dihydropyridinium intermediate (90JOC6028). 

To HCl-H-D-(l-naphthyl)Ala-OMe (17 190 mg, 0.715 mmol) in DMF (3mL) at 0°C was added NMM (80 pL, 0.73 mmol), followed by CDI (116 mg, 0.715 mmol). After 1 h, l-(benzyloxycarbonyl)-2-(indol-3-ylmethyl )hydrazine[321 (18 210mg, 0.711 mmol) was added, and the mixture was warmed to rt and stirred for 16 h. The mixture was poured into EtOAc and then washed sequentially with H20, sat. NaHC03, and brine, dried (Na2S04), and the solvent removed under reduced pressure. Column chromatography (20% EtOAc/hexane) of the residue afforded a foam yield 256mg (65%). 

S, 5.S )-2-(2-Aminopropyl)-5-[(benzyloxycarbonyl)amino]-6-(indol-3-yl)-4-oxohexanoic Add Hydrochloride Salt (22, R1 = 3-methylindolyl R2=2-NH2Pr) and (2R/S,5S)-5-[(Benzyloxy-carbonyl)amino]-2-(2-guanidylpropyl)-6-(indol-3-yl)-4-oxohexanoic Add Hydrochloride Salt (22,... 

S)-3-[(Benzyloxycarbonyl)amino]-4-(indol-3-yl)-2-oxobutyl Chloride (19, R1 = 3-Methylindolyl) ... 

R/S,5S)-5-[(Benzyloxycarbonyl)amino]-2-(2-cyanoethyl)-6-(indol-3-yl)-4-oxohexanoic Acid (22,... 

During synthetic studies on the antitumour antibiotic CC-1065, ready access was required to a series of 6-substituted indole-3-carboxylates. The following example illustrates the successful general strategy that was developed reaction of the N-Cbz derivative of N-(3-methylphenyl)hydroxylamine with methyl propiolate in nitromethane as solvent and in the presence of Hunig s base gave methyl l-benzyloxycarbonyl-6-methylindole-3-carboxylate directly in 89% yield. 

The first procedure is the selective protection of an amine in the presence of an indole-NH group or an alcohol.14 Indole-NH (pKa = 17) shows a similar acidity to that of alcohols (pKa = 18). In the next step the benzyloxycarbonyl (CBZ) protected compound 26 is treated with di-fcrt-butyldicarbonate (B0C)20 and DMAP to form 27. Tert-butylchloroformate is unstable and therefore cannot be used for the preparation of BOC derivatives. Conversion of 10 with (B0C)20 in the presence of DMAP would lead to the double BOC protected compound 28. 

Quinazolin-2-one was obtained quantitatively by fusing 2-aminobenzaldehyde with urea (10 min at 150°C).76,91 Similarly, 2-amino-3-formylpyridine and urea (15 min at 160°C) gave an excellent yield of pyrido[2,3-d]pyrimidin-2-one (see 3).92 Finally, as an example from jt-excessive chemistry, 2-amino-indole-3-aldehyde was converted to its 2-benzyloxycarbonyl derivative, which benzylamine quantitatively converted to 3-benzyl-9f/-pyrimidino-[4,5- >]indol-2-one (87)93... 

Typical procedure. Methyl (1aS,8R,8aS,8bR)-1,1a,2,8,8a,8b-hexahydro-7-benzYloxY-8-(benzYloxYcarbonyl)oxymethyl-l-tert-butyloxycarbonyl-8-formylazirino[2, 3 3,4] pyrrolo-[1,2a]indole-5-carboxylate 917 [659] CDI (150 mg, 0.925 mmol) was added to a solution of alcohol 916 (385 mg, 0.779 mmol) in acetonitrile (12 mL), and the reaction mixture was stirred for 3.5 h. Benzyl alcohol (600 gL, 5.80 mmol) and DMAP (60.0 mg, 0.491 mmol) were added, and the reaction mixture was heated at 63 °C for 3.0 h. The solvent was then removed, and the residue was submitted to flash chromatography (column prepared with dichloromethane eluent 10-25% EtOAc/ hexanes) to give a pale-yellow foam of 917 containing traces of an impurity (349 mg, 71%). This material was suitable for further experiments. A sample of 917 was purified by radial chromatography (EtOAc/dichloromethane, 3 97) for characterization purposes [a] D = +36.0 (c = 0.540, chloroform). 

Fluoride ion, crown ether phase-transferred into acetonitrile solution, apparently assists the deprotonation of the indole ring of tryptophan facilitating protection of nitrogen by benzyloxycarbonyl or 2,4-dichlorobenzyloxycarbonyl groups. 

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