And reductive alkylation

Asymmetric Birch reduction and reduction-alkylation in synthesis of natural products 99CC1263. 

Conjugate reductions and reductive alkylations of enones are listed in Section 74 (Alkyls from Alkenes). 

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. 

Because dianion formation appears to be more important when lithium rather than potassium is used, many of the Birch reductions and reduction-alkylations of I and II that have been developed utilize potassium as the reducing metal. Piperylene is added prior to the alkylation reagent to consume any remaining metal and thereby prevent reduction of the alkylation reagent. In the event that the alkylation reagent is unstable to strong bases (e.g. homoallylic and arylethyl halides) LiBr is added to reduce the basicity of the reaction medium. 

Reductive alkylation of ammonia should give primary amines, reductive alkylation of primary amines secondary amines, and reductive alkylation of secondary amines tertiary amines. In reality, secondary and even tertiary amines are almost always present to varying extents since the primary amines formed in the reaction of the carbonyl compounds with ammonia react with the carbonyl compounds to give secondary amines, and the secondary amines similarly afford tertiary amines according to Scheme 128. In addition, secondary amines may be formed, especially at higher temperatures, by additional reactions shown in Scheme 129. Depending on the ratios of the carbonyl compounds to ammonia or amines, different classes of amines predominate. 

The allylic alkylation products represent useful synthons, as exemplified by the reaction sequence outlined in Scheme 10.4. For example, reductive ozonolysis of the allylic alkylation product 15 afforded the y-lactone 16 as a single diastereoisomer. Sequential alkylation with methyl iodide, and reductive alkylation using lithium naphthalenide with allyl iodide furnished the ternary-quaternary substituted y-lactones 17a/17b in 72% overall yield, as a 10 1 mixture of diastereomers favoring 17a [18]. This method provides a versatile approach to the construction of a variety of a-quaternary-/9-ternary stereogenic centers. 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

Metal ammonia reduction of 17a-ethynyl-19-nortestosterone, 52 Metal ammonia reductions and reductive alkylations, 43 Methanol-OD, 212... 

ALKYLATION AND REDUCTIVE ALKYLATION PROCEDURES FOR THE PREPARATION OF SECONDARY AND TERTIARY AMINES... 

Starting from TV-o-Fmoc-aspartic acid a-f-butylester, a wide range of 1,3,4,7-tetrasubstituted perhydro-l,4-diazepine-2,5-diones 3 were synthesized (Fig. 2).28 After deprotection of the aspartic acid amino function and reductive alkylation, a second amino acid was coupled and a second reductive alkylation was carried out. Following fBu cleavage, the thermodynamically favorable coupling of the resulting secondary amine to the side chain of aspartic acid was readily accomplished. 

Chobert, J.-M., Touati, A., Bertrand-Harb, C., Dalgalarrondo, M., Nicolas, M.-G., and Haertle, T. 1990. Ethyl substituted (3-casein. Study of differences between esterified and reductively alkylated (3-casein derivatives. J. Agric. Food Chem. 38, 1321-1326. 

Successive catalytic removal of the benzyl moiety and introduction of the BOC protecting group gave 204. This latter, upon action of TFA and reductive alkylation afforded 12 biologically active compounds 205a-l (Scheme 36) <1999W032487>. 

While this methodology could be extended to more-substituted cyclooctene oxides (Scheme 56, Equation 12), examination of cycloheptene oxide (Scheme 56, Equation 13) revealed the need for considerably longer reaction times, leading to reduced yields due to competing carbenoid-insertion pathways (cycloheptanone formation and reductive alkylation) <2002AGE2376, 2003OBC4293>. 

As with esters, the prevailing view held for many years was that ring reduction of aromatic ketones was not feasible. The first indication that this was incorrect was provided by the reduction of the hydro-phenanthrenone (149 Scheme 29). Further isolated examples of ring reduction in naphthyl ketones and molecules containing such moieties have been reported subsequently, but it is clear that these systems are much more easily reduced than simple benzenoid systems. Optimal procedures for the reduction and reductive alkylation of such systems were first established by Watanabe and Narisada for acetophenone and its methoxy derivatives. ... 

Early studies on the reduction and reductive alkylation of 2-acetylnaphthalenes (184) afforded mixtures of dihydro and tetrahydro derivatives. In one case, the alcohol (188) was the major product. A comprehensive examination of the reductive process and quenching methods has been carried out recent-... 

Schultz, A. G. The asymmetric Birch reduction and reduction-alkylation strategies for synthesis of natural products. Chem. Common. 1999, 1263-1271. 

Oxidation and Reduction.—Alkyl chloroformates (52) react with dimethyl sulphox-ide to give unstable carbonates which lose carbon dioxide to form alkoxydimethyl-sulphonium salts (53). Addition of triethylamine breaks the sulphonium salt down to... 

Tetramic acids are substructures of natural products that show antimicrobial activity. An access to these structures started from Wang resin-bound Fmoc-protected amino acids, which were deprotected and reductively alkylated. These intermediates 111 were transformed into amides, for example with malonic acid monoesters or aryl acetic acids (112 and 114, respectively). Cyclative cleavage was induced with 0.1 M NaOEt at 85 °C and gave substituted tetramic acids 113 and 115 in yields and purities of generally >95% (Scheme 30) [46]. 

The piperidine was prepared from 2-(2-cyanoethyl)-butryraldehyde (470) via ketal 471, which was reduced with lithium aluminum hydride and reductively alkylated with benzaldehyde over 10% palladium on charcoal to 472. Acid hydrolysis led to spontaneous cyclization and formation of enamine 473. Treatment of this enamine with methyl bromoacetate and reduction of the iminium species with sodium borohydride gave the 1-benzyl-3,3-disubstituted piperidine 474 which was debenzylated with palladium charcoal under acidic conditions to give the desired piperidine, 466 (216). 

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