Synthetic transformation

The efficiency of a synthetic transformation is normally expressed as a percent yield or percentage of the theo retical yield Theoretical yield IS the amount of prod uct that could be formed if the reaction proceeded to completion and did not lead to any products other than those given in the equation... 

It IS convenient in synthetic transformations involving more than one step simply to list all the reagents with a single arrow Individual syn thetic steps are indicated by number Numbering the in dividual steps is essential so as to avoid the implication that everything is added to the reaction mixture at the same time... 

Show how each of the following compounds could be prepared from 3 pentanone In most cases more than one synthetic transformation will be necessary... 

The reaction proceeds in good yield (86%) and the product is a useful one in fur ther synthetic transformations of the type to be described in Section 21 7... 

Reactive halogen compounds, alkyl haUdes, and activated alkenes give quaternary pyridinium salts, such as (12). Oxidation with peracids gives pyridine Akoxides, such as pyridine AJ-oxide itself [694-59-7] (13), which are useful for further synthetic transformations (11). 

Dimethylaminopyridine [1122-58-3] (DMAP) (24) has emerged as the preferred catalyst for a variety of synthetic transformations under mild conditions, particularly acylations, alkylations, silylations, esterifications, polymeri2ations, and rearrangements (100). POLYDMAP resin [1122-58-3], a polymeric version of DMAP, is available, and is as effective as DMAP as a catalyst for acylation reactions. Furthermore, it can be recycled without regeneration more than 20 times with very Htde loss in activity. POLYDMAP is a trademark of Reilly Industries, Inc. 

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves and by the addition of hydrogen cyanide to silyl enol ethers. Silylated cyanohydrins have proved to be quite useful in a variety of synthetic transformations, including the regiospecific protection of p-quinones, as intermediates in an efficient synthesis of a-aminomethyl alcohols, and for the preparation of ketone cyanohydrins themselves.The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as... 

The reactions of fluorinated esters and amides to form, respectively, enol ethers [47] and enamines [4S] give high yields and are interesting synthetic transformations (equations 34 and 35) (Table 12)... 

Suggest a suitable series of reactions for carrying out each of the following synthetic transformations ... 

Asymmetric Diels-Alder reactions using a dienophile containing a chiral auxiliary were developed more than 20 years ago. Although the auxiliary-based Diels-Alder reaction is still important, it has two drawbacks - additional steps are necessary, first to introduce the chiral auxiliary into the starting material, and then to remove it after the reaction. At least an equimolar amount of the chiral auxiliary is, moreover, necessary. After the discovery that Lewis acids catalyze the Diels-Alder reaction, the introduction of chirality into such catalysts has been investigated. The Diels-Alder reaction utilizing a chiral Lewis acid is truly a practical synthetic transformation, not only because the products obtained are synthetically useful, but also because a catalytic amount of the chiral component can, in theory, produce a huge amount of the chiral product. 

The required nitrite esters 1 can easily be obtained by reaction of an appropriate alcohol with nitrosyl chloride (NOCl). The 3-nitroso alcohols 2 formed by the Barton reaction are useful intermediates for further synthetic transformations, and might for example be converted into carbonyl compounds or amines. The most important application for the Barton reaction is its use for the transformation of a non-activated C-H group into a functional group. This has for example been applied for the functionalisation of the non-activated methyl groups C-18 and C-19 in the synthesis of certain steroids. ... 

The a-bromo or a-chloro carboxylic acids 2 are versatile intermediates for further synthetic transformations. For example they can be converted into a-hydroxy carboxylic acids by reaction with water by reaction with cyanide a-cyanocarboxylic acids 7 are obtained, which can be further converted to... 

The Michael addition1, a well known key synthetic transformation, has recently emerged as an important method for stereoselective C — C bond formation2-369"371. Two developments have contributed to a great extent ... 

Few methodologies have either the diversity of synthetic transformations or the high level of product selectivity as catalytic reactions with the intermediate involvement of metal carbenes [ 1-5]. They provide synthetic opportunities that are clearly demonstrated in the preparation of the antidepressant sertraline (1)... 

Decarboxylation reactions performed on activated or aromatic carboxylic acids, e.g., /1-keto acids, is a well-known synthetic transformation. However, the reaction has also been applied on other systems, e.g., N-carboxythiopyri-dones, N-acyloxyphthalimides and by thermolysis of peresters [104-106]. 

Biocatalysts usually require mild reaction conditions for an optimal activity (physiologic temperature and pH) and, in general, they show high activity, chemo- and enantioselectivity. Furthermore, when using enzymes, many functional group protections and/or activations can be avoided, allowing shorter synthetic transformations. The use of enzymes is therefore very attractive from an environmental and economic point of view. 

From the above discussion it is evident that adaptation of oxythallation to the development of useful synthetic transformations rests largely on the degree of control which can be exerted on the decomposition pathway of the intermediate RTlXj derivative. The results obtained by Freppel et al., for... 

Martin, Padron, and coworkers have reported on the scope and limitations of the use of iron(lll) halides as effective catalysts in the coupling of alkenes or acetylenes with aldehydes to achieve a wide variety of useful synthetic transformations. All these reactions are shown in Scheme 10, which serves as a guide through the aliphatic C-C bond formation section [27]. 

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

Another examination involves a synthesis of thienobenzazepines based on the formation of key intermediate 6 prepared according to the method of McDowell and Wisowaty (Scheme 6.2). ° Selective reduction of this intermediate using zinc dust in 28-30% ammonia solution afforded the benzoic acid 7, which upon subsequent Curtius rearrangement and aluminum trichloride-mediated cyclization furnished the oxo-azepine 8. While this synthetic approach gave the tricycle in a few synthetic transformations, many of the same concerns as above exist when considering large scale preparation of 8 the use of large amounts of zinc, sodium azide, and aluminum trichloride. 

A New Improved Synthesis of Tricycle Thienobenzazepines Apphcation of chemistry recently developed by Knochel" combined with the well-described halogen dance (HD) reaction, allowed preparation of our key intermediate A in only three synthetic transformations (Scheme 6.4). In this respect, treatment of 2-bromo-5-methylthiophene with hthium diisopropylamide followed by dimethylformamide afforded aldehyde 11 in good yield, lodo-magnesium exchange with conunercial 4-iodo-3-nitro anisole followed by reaction with 11 afforded the thiophene catbinol 12. Dehydroxylation of 12 provided our key intermediate A which presented the requisite functionality to examine our approach to the construction of the seven-member ring system. 

In summary, we have described a novel and efficient synthesis of thienobenzazepine derivatives in which the key transformation includes a telescoped process involving a selective intro reduction followed by palladium-mediated intramolecular amidation. The process developed is quite amenable for preparative scale (multi-gram) and presents significant advantage to those reported previously with respect to overall yield (e.g., 50% vs. 17% overall yield), total number of synthetic transformations (4 vs. 9), and reagents and/or conditions that are suitable for large-scale synthesis. 

These reactions accomplish the same overall synthetic transformation as the acylation of ester enolates, but use desulfurization rather than decarboxylation to remove the anion-stabilizing group. Dimethyl sulfone can be subjected to similar reaction sequences.232... 

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