3-Amino-8-azabicyclo octane

Monochloramine is also used in organic synthesis for preparation of amines, substituted hydrazines, etc. For example, reaction of NH2CI with 3-azabicyclo [3.3.0]octane [5661-03-0] yields A/-amino-3-azabicyclo[3.3.0]octane [54528-00-6] a pharmaceutical intermediate (38). 

To a suspension containing 4.86 parts of 4-methylbenzenesulfonyl urethane (MP 80° to 82°C) and 36 parts of anhydrous toluene there are rapidly added 2.5 parts of N-amino-3-azabicyclo(3.3.0)octane (BP/18 mm = 86°C). The reaction mixture is heated under reflux for 1 hour. The resulting ciear solution crystallizes on cooling. The crystals are filtered, washed with 2 parts of toluene, then recrystallized from anhydrous ethanol. There are obtained 3.8 parts of the desired product, MP 180° to 182°C. 

Another route to the formation of piperidine heterocycles is cyclization via reductive animation utilizing various hydride sources. The scheme below depicts a bis reductive animation, using sodium triacetoxyborohydride as the hydride source, to generate exo-178 and endo-179 azabicyclo[3.2.1]octane amino acids in moderate yields <06JOC8467>. 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

As an example of non-enzymatic catalyst using oxazaborolidines [10], Corey and his associates have described an efficient synthesis of (-i-)-l(S),5(R),8(S)-8-phenyl-2-azabicyclo[3.3.0]octan-8-ol (2.) and its enantiomer. The B-methyloxazaborolidine derivatives (3) of these amino alcohols are excellent catalysts -or chemzymes- for the enantioselective reduction of a variety of achiral ketones to chiral secondary alcohols [11]. 

Important improvement in the in vitro activity was obtained when the central proline was replaced by thiaproline (thiaPRO) to give compound 66, suggesting that modification of the central amino acid (of the proline type) could be of importance in modulating the PEP inhibitory activity, Eq. (25) [76]. In fact, replacement of the proline moiety of63 - 66 by non-natural amino acids derived from 2-perhydroindole or from 2-azabicyclo[2.2.2]octane and modulation of the side chain by replacement of the terminal phenyl ring by a dicyclopropyl-carbinyl moiety afforded derivatives such as 67 and 68 with improved activities (IC50 between 10 and 20 nM), Eq. (26). 

Cavalleri et al. (219) studied the cycloaddition of thioisomiinchnones with 5-amino-4-methylene-l,2,3-triazolines. The resulting cycloadducts afford 2-pyridones with Raney Ni or 8-thia-6-azabicyclo[3.2.1]octanes with acid. Kato has continued his extensive exploration of cycloaddition studies of mesoionic heterocycles with atypical dipolarophiles. Thus, whereas thioisomiinchnone (320) gave a complex mixture with 6,6-dimethylfulvene (119), it reacted with 2-tert-butyl-6,6-dimethylfulvene to afford 321 in 17% yield (151,152). The cycloaddition of 320 with benzocyclobutadiene was much cleaner to give 322 in 70% yield (114). 

The cephalosporins, discovered in the 1950s, are produced by various species of the mold Cephalosporium. Cephalosporin C (9.46) is the prototype of these antibiotics, and its structure shows a close similarity to the penam stmcture. The 5-thia-l-azabicyclo[4.2.0] octane ring system is therefore called the cepham ring. The parent compound carries the aminoadipate side chain, which can be cleaved to supply the 7-amino-cephalosporanic acid. This amine can easily be acylated and thus forms the basis of many useful derivatives. The 3-acetoxymethyl substiment is also amenable to modifications. 

The preparation of a chiral bicyclic hydrazine, (15,35,5S)-2-amino-3-methoxymethyl-2-azabi-cyclo[3.3.0]octane (SAMBO, 3), was reported32 in 1990. (12 S, 31 S,51 5 )-2-Azabicyclo[3.3.0]-octane-3-carboxylic acid was resolved into its enantiomers. The (lS ,35,55)-enantiomer was converted to the chiral hydrazine 3 in six steps, utilizing Hofmann degradation, which is also employed in the preparation of SAMP. 

The kinetics of the reaction of 3-azabicyclo[3.3.0]octane with chloramine have been studied in the pH range 8-13.25 Two competitive bimolecular reactions lead to the formation of A -amino and A-eh loro derivatives, by reaction between neutral species in the former case and by reaction between chloramine and protonated aza compound in the latter case. 

Dansyl amino acids (li ,3R,5R)-2-Azabicyclo-[3,3,0]-octane-3-carboxylic acid 115... 

The oxidation of A-amino-3-azabicyclo[3.3.0]octane with chloramine follows a second-order rate law and exhibits specific acid catalysis. The nature of the product is pH dependent in strongly alkaline solutions, the product is 3,4-diazabicyclo[4.3.0]non-2-ene. A mechanism involving a nitrene insertion (Scheme 8) has been suggested.154... 

A solution of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-l,4-benzoxazine-8-carboxylic acid in tetrahydrofuran and dimethylformamide is cooled to below 0°C and triethylamine is added under stirring thereto. Further, ethyl chlorocarbonate is added and the mixture is stirred at room temperature. To the resultant mixture is added 3-amino-8-azabicyclo[3.2.1]octane and the mixture stirred. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off to give 6-chloro-3,4-dihydro-4-methyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-3-oxo-2H-l,4-benzoxazine-8-carboxamide. 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

Hydrogenation of p-aminobcnzoic acid to a mixture of cis- and fran.s-4-aminocy-clohexanecarboxylic acid was successful with the use of a Rh-Pd-C catalyst (10% Rh-0.1% Pd) in water at room temperature and a low hydrogen pressure (eq. 11,65).222 The cis isomer of the amino acid was further converted to 3-isoquinuclidone (2-azabicyclo[2.2.2]octan-3-one] (23) by heating in boiling Dowtherm A (258°C). 

Ifenprodil (= l-Methyl-2-hydroxy-2-(4-hydroxyphenyl) ethyl-1 -(4-benzyl-piperidine)] -(aryl piperidine) [at(/o-3-(Indol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane] (indolotropane) [Kynurenic acid (= 4-Hydroxy-2-quinolinecarboxylic acid)] (quinoline carboxylic acid) [Memantine (= 1-Amino-3,5 dimethyladamantane)] (amino adamantane, amino cyclic aliphatic) [Methadone (= 6-Dimethylamino-4,4-diphenyl-3-heptanone)] (aryl tertiary amine) [em/o-3-(l -Methylindol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane(indolotropane) exo- 3-( 1 -Methylindol-2-yl)-8-methyl-8-... 

Preparation of 3-amino-2-((3-pyridinyl)methyl)-l-azabicyclo[2.2.2]octane... 

Martens, J., Luebben, S. (1S,3S,5S)-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane SAMBO, a new chiral auxiliary. Liebigs Ann. Chem. 1990, 949-952. 

Wilken, J., Thorey, C., Groger, H., Haase, D., Saak, W., Pohl, S., Muzart, J., Martens, J. Utilization of industrial waste materials. Part 11. Synthesis of new, chiral P-sec-amino alcohols. Diastereodivergent addition of Grignard reagents to a-amino aldehydes based on the (all-R)-2-azabicyclo[3.3.0]octane system. Liebigs Ann. Chem. 1997, 2133-2146. 

Aside fixtm offering proof of the 6-hydroxyl group, these oxo compounds are examples of a widely sought structural unit. They are lactams derived from l-azabicyclo[3,2,l]octane. By Bredt s Rule, resonance interaction between the free electron pair of the nitrogen and the carbonyl group should be at a minimum. As a consequence, the compounds should behave as amino ketones rather than lactams. To a considerable extent, this expectation has been verified. The carbonyl absorption in the infrared more nearly resembles 6,7-methylenedioxy-... 

Plants in the Solanaceae family produce a variety of alkaloids, some of them having a considerable therapeutic importance. One such group of alkaloids possesses a tropane nucleus. Tropane alkaloids are structurally related natural products having in common the azabicyclo[3.2.1]octane structure and therefore the systematic name for tropane is 8-methyl-8 azabicyclo[3.2.1]octane (Fig. 1). The majority of these alkaloids are esters between organic acids and hydroxytropanes. 3a-Hydroxytropane, called tropine, is the amino alcohol most frequently encountered. In addition, its 3 (3-isomer (pseudotropine), the di- (3,6- 3,7- or 6,7-) and trihydroxylated... 

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