Reductive alkylation application

D. B. Ramachary, M. Kishor, Org. Biomol. Chem. 2008, 6, 4176-4187. Direct amino acid-catalyzed cascade biomimetic reductive alkylations application to the asymmetric synthesis of Hajos-Parrish ketone analogues. 

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

Application of the reductive alkylation process to the -20-ketone (4) yields the 17a-alkyl derivatives (5a-c). As expected, the presence of the angular 13-methyl group favors the approach of the alkyl iodide from the a-side. ... 

Recent progress of basic and application studies in chitin chemistry was reviewed by Kurita (2001) with emphasis on the controlled modification reactions for the preparation of chitin derivatives. The reactions discussed include hydrolysis of main chain, deacetylation, acylation, M-phthaloylation, tosylation, alkylation, Schiff base formation, reductive alkylation, 0-carboxymethylation, N-carboxyalkylation, silylation, and graft copolymerization. For conducting modification reactions in a facile and controlled manner, some soluble chitin derivatives are convenient. Among soluble precursors, N-phthaloyl chitosan is particularly useful and made possible a series of regioselective and quantitative substitutions that was otherwise difficult. One of the important achievements based on this organosoluble precursor is the synthesis of nonnatural branched polysaccharides that have sugar branches at a specific site of the linear chitin or chitosan backbone [89]. 

Fig. 24 Reductive alkylation mechanism of interaction of kinamycin C with DNA as originally proposed [67], Nucleophilic (DNA) attack can occur on the Michael acceptor 32 through pathway a or b. The same mechanism should be applicable with the revised diazo structures...

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

An application to the asymmetric synthesis of enantiomer-ically pure tram-hexahydroanthracen-9-ones is shown in Scheme 6. It should be possible to carry out a second stereoselective reductive alkylation of the benzoyl group in 22 as was demonstrated in the related hydrofluoren-9-one and... 

We were interested in applications of the high level of stereocontrol associated with the asymmetric Birch reduction-alkylation to problems in acyclic and heterocyclic synthesis. The pivotal disconnection of the six-membered ring is accomplished by utilization of the Baeyer-Villiger oxidation (Scheme 7). Treatment of cyclohexanones 25a and 25b with MCPBA gave caprolactone amides 26a and 26b with complete regiocon-trol. Acid-catalyzed transacylation gave the butyrolactone carboxylic acid 27 from 26a and the bis-lactone 28 from 26b cyclohexanones 31a and 31b afforded the diastereomeric lactones 29 and 30. ... 

A structural requirement for the asymmetric Birch reduction-alkylation is that a substituent must be present at C(2) of the benzoyl moiety to desymmetrize the developing cyclohexa-1,4-diene ring (Scheme 4). However, for certain synthetic applications, it would be desirable to utilize benzoic acid itself. The chemistry of chiral benzamide 12 (X = SiMes) was investigated to provide access to non-racemic 4,4-disubstituted cyclohex-2-en-l-ones 33 (Scheme 8). 9 Alkylation of the enolate obtained from the Birch reduction of 12 (X = SiMes) gave cyclohexa-1,4-dienes 32a-d with diastereoselectivities greater than 100 1 These dienes were efficiently converted in three steps to the chiral cyclohexenones 33a-d. 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

A valuable application of the above-described reduction is the one-step reductive alkylation of amines with carbonyl compounds. ... 

Szardenings, A. K. Burkoth, T. S. Look, G. C. Campbell, D. A. A Reductive Alkylation Procedure Applicable to Both Solution- and Solid-Phase Syntheses of Secondary Amines, J. Org. Chem. 1996, 61, 6720. 

One of the most valuable and widely used applications of C=N bond hydrogenation is in the field of reductive alkylation, in which an aldehyde or ketone is condensed with an amine and reduced in situ with an appropriate catalyst to give a substituted product. This very valuable reaction has most notably been employed for the racemic synthesis of amino acids from a-ketoesters and acids. This type of reduction can be very powerful, as illustrated by the synthesis of tetrahydro-b-carbolines 64 (76% yield) by the reductive coupling of 65 and 66 under conditions of 1 atm of hydrogen and palladium on carbon catalyst277. 

The synthesis of secondary amines from azides is efficient in terms of chemos-electivity [57] and has found valuable applications in the preparation of diamines [58,59], m-alkylaminoboronic esters [60], and in Diels-Alder-based amination reactions [61]. A convenient general route to open-chain polyamines, which play major roles in cellular differentiation and proliferation, has also been developed using the reductive alkylation of aliphatic aminoazides by (co-halogenoalk-yi)dichloroboranes as a key step [62] (Scheme 21). 

The preparation of tertiary amines by reductive alkylation of ammonia appears to find only limited application. Triethylamine and tripropylamine were prepared by hydrogenation of acetaldehyde and propionaldehyde, respectively, in the presence of ammonia over platinum catalyst.38 A high yield (84.1% by GC) of trinonylamine was... 

Hamilton, R. J., Mander, L. N., Sethi, S. P. Improved methods for the reductive alkylation of methoxybenzoic acids and esters. Applications to the synthesis of bicyclic ketones. Tetrahedron 1986, 42, 2881-2892. 

The spectroscopic studies 83,84) afforded chemical applications. The reductive alkylation of dianion 82 gave alkylated products only in the periphery121K This observation confirms the structure So2 suggested by Rabinovitz and Hafner 84b). Contrary to the reductive alkylation of 232 the quench of dianion 82 did not afford any alkylated product at the central atom C-l 1. The alkylated acenaphthylene served as a starting material for the preparation of acephenanthrylene 34z (vide supra)121). 

Elimination, reductive elimination, reductive alkylation, and isomerization reactions have been employed in order to create the fluoroolefin moiety in molecules already containing one or more fluorine atoms. In general, these reactions were developed for a specific purpose and are often not generally applicable to other systems. For example, base catalyzed HF elimination converted 1,2,2-trifluoroethylcyclohexane (107) to the difluoroolefin (108)(50) (Scheme 32). Reductive elimination reactions were employed to prepare the interesting fluoroallene (110) (51)... 

The addition of electrophilic radicals to the nucleophilic double bond of chiral cyclic cnamines can be considered as examples of acyclic stereocontrol as the auxiliary is attached by a single bond. Therefore, the principles that emerge might be applicable to acyclic systems, The reductive alkylation of l-[(2R,5R)-2,5-dimethyl-l-pyrrolidinyl]cyclohexene, employing the tin method, affords four isomeric products with over 90% as selectivity26. The ratio of the c /j-diastereomers is at least 95 5. 

Reductive alkylation. A previously reported A-methylation method for secondary amines with aqueous HCHO, Zn and HOAc is applicable to amino acids. Mono- or dimethy-lation can be controlled by adjustment of pH, reagent stoichiometry, and reaction time. a-Branched amines can be prepared from amines, RCHO and alkyl halides by the action... 

Conversion of pyrylium salts with organolithium and Grignard reagents to pyrans via reductive alkylation or arylation has been enriched by applications of organocopper and other organometallic compounds as well as by photochemical activation. Several new studies with anions of C-acids have been published as well. 

Activated carbon supported palladium catalysts have been widely used in fine organic chemical synthesis. Some of the typical applications are debenzyiation, hydrogenation, reductive alkylation, reductive amination, etc. As an effective synthetic method, debenzyiation has been used commercially in organic synthesis to deprotect various functional groups. 

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