Synthetic approach route

The first synthetic route for isocyanates was reported in 1848 (10,11)- Subsequent efforts by Hofmann, Curtius, and Hentschel pioneered alternative synthetic approaches (12). These efforts highlighted the phosgene—amine approach. Staudinger presented the stmctural similarities between isocyanates and ketenes and stimulated interest in this class of compounds (13). However, it was not until 1945, when the world was pressed for an alternative to natural mbber, that synthetic routes to isocyanates became an area of great importance. Several excellent review articles covering the synthesis and chemistry of isocyanates have been presented (1 9). 

ISlew Synthetic Approaches. There have been a number of efforts to prepare quinolines by routes quite different from the traditional methods. In one, the cyclization of 3-ariiino-3-phenyl-2-alkerLiniines (18) using alkah metals leads to modest yields of various 4-arylaminoqurnolines (54). Because this stmcture is found in many natural products and few syntheses of it exist, the method merits further investigation. 

The previously described penem syntheses from 6-APA-derived starting materials have been inefficient in the sense that the C(2) and C(3) atoms of the penam are lost during the sequence. Scheme 71 shows a route in which C(2) and C(3) of the penam become C(2) and C(3) of the penem (79CC665). The major product of this sequence is the (55) enantiomer. A related synthetic approach, starting with the natural product clavulanic acid, has been described (79CC663). 

In Pedersen s first full paper on the synthesis of macrocyclic polyethers, he reported the synthesis of thirty-three macrocycles having a variety of ring sizes and substituents. These compounds were prepared by a variety of routes and Pedersen offered a scheme in which he generalized the synthetic approaches he used. He designated the four principal methods V , W , X , and Y . The methods are diseussed individually. 

Ring-fluonnated aromatics have found wide applications in pharmaceuticals, crop protection chemicals, polymer intermediates, liquid crystals, etc [10] Routes based on aromatic amines represent one of the major synthetic approaches to these compounds The scope and the techniques have been sufficiently described in reviews [//, I2 and monographs [13, 14, fi] Therefore, only reactions and techniques published after 1971 are discussed... 

There have been a number of different synthetic approaches to substituted PTV derivatives proposed in the last decade. Almost all focus on the aromatic ring as the site for substitution. Some effort has been made to apply the traditional base-catalyzed dehydrohalogenation route to PTV and its substituted analogs. The methodology, however, is not as successful for PTV as it is for PPV and its derivatives because of the great tendency for the poly(u-chloro thiophene) precursor spontaneously to eliminate at room temperature. Swager and co-workers attempted this route to synthesize a PTV derivative substituted with a crown ether with potential applications as a sensory material (Scheme 1-26) [123]. The synthesis employs a Fager condensation [124] in its initial step to yield diol 78. Treatment with a ditosylate yields a crown ether-functionalized thiophene diester 79. This may be elaborated to dichloride 81, but pure material could not be isolated and the dichloride monomer had to be polymerized in situ. The polymer isolated... 

The known, in many cases very special, synthetic approaches to azocines often proceed via valence isomerization of appropriate precursor molecules. In this section these routes are classified by the last step in the reaction cascade. The synthesis and chemistry of azocines has been described in several excellent reviews,9-11 so that the treatment here is systematic and rather concise. 

Another limitation of the traditional Cu-mediated cyclooligomerization reaction is generation of differentially substituted PDMs. In the above case, the substitution pattern in the starting o-diethynylbenzene must be maintained on each and every benzene moiety in the oligomeric mixture of PDMs that is produced. Thus, it is impossible to prepare less symmetric systems like 100 via this route. With the intramolecular synthetic approach, however, it should be possi-... 

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. 

The cis-2,3-diaryl-2,3-dihydro-l,4-benzoxathiin is a very unique structural motif. Other than scattered reports in the literature on the formation of this scaffold, there was no effective asymmetric synthesis for it [6]. We explored two major synthetic approaches to realize the key chiral as-diaryl dihydrobenzoxathiin scaffold, as shown in Scheme 5.3. One was the quinone ketal route in which the quinone ketal 13 and the chiral mercaptol alcohol 14 were the key intermediates. The other approach was the stereo- and enantioselective reduction of the diaryl benzoxathiin 16. The key mercaptol alcohol 14 and the diaryl benzoxathiin 16 were both envisioned to be prepared from the key, common iodoketone intermediate 15. 

As the program continued to move forward the team once again faced the need to evaluate the synthetic approach to taranabant, this time with regard to implementation on scales in excess of 100kg and for potential manufacturing purposes. Despite the significant advancements outlined in Section 9.1, a route analysis indicated a number of issues and shortcomings still to be addressed, as outlined below (Table 9.3). 

Diene (VI) was reacted with aniline in methanol in the presence of sodium carbonate to yield N-pheny1-3,4-dimethylenepyrrolidine. However, the purified yield was poor (-20%). The alternate route was a more direct method to prepare the monomer (III) without the side reactions on elimination that could take place in the first synthetic approach. Nevertheless, due to the poor yield, all the monomer (III) used for this work was prepared via the first route. The alternative method does have applicability in the preparation of substituted N-phenyl derivatives as these could be less volatile and more difficult to recover by sublimation. 

Parker, Raphael, and Wilkinson have investigated a synthetic approach to tropinone (124), which they call the acetylenic route (78). Reaction of hexa-1,5-diyne-l,6-dicarboxylate (145) with methylamine yields the pyrrolidine derivative (146), which by catalytic hydrogenation affords the diester 147 (79,50). 

Development of new synthetic routes to optically active (3-lactam derivatives is still an attractive problem in organic chemistry. As a synthetic approach to penicillin derivatives, photocyclization of oe-oxoamides 76 to (3-lactams has long been studied 41, 42). This reaction (Scheme 6), however, results in a complex mixture of racemic cis-and trans-isomers of (3-lactams 72 and of oxazolidin-4-ones 73, since the reaction proceeds via a zwitterionic intermediate 7143>. Of these isomers, only the optically... 

The many efforts of synthesizing the thiepin system described in Section 2 have revealed that extremely mild conditions have to be employed for the construction of the thiepin skeleton in order to avoid thermal sulfur extrusion from the resulting thiepins. This is an especially important prerequisite for the synthetic designs aimed at obtaining simple (thermolabile) thiepin derivatives. In our own study in this field we have previously developed new versatile routes for the synthesis of the thiepin skeleton. In this section we summarize our synthetic approaches to the relatively simple thiepin derivatives. 

Thus, the synthetic route via dilithiosilane 62 should be noted as an alternative synthetic approach to the heavy ketones. To date, the isolation of silanetellone 60 as stable crystals has not been achieved yet, though 60 was found to be stable in solution at ambient temperature. 

There are natural targets whose syntheses have important practical applications. For example, paclitaxel (marketed as Taxol by Bristol-Myers Squibb) is an anticancer compound originally isolated from the bark of a species of yew tree, but for a long time it seemed that natural sources would not be sufficient to meet the need. Consequently, many chemists developed synthetic approaches to paclitaxel from readily available materials, although these are not yet fully practical for manufacturing. The quest continues, and a semisynthetic route has been developed starting with a compound isolated from yew needles that can be harvested without destroying the tree. An alternative approach has employed plantcell cultures in bioreactors to produce paclitaxel from yew needles (see Chapter 7 for discussion of related matters). 

In terms of economical synthetic approaches to indoles, the synthesis of this heterocycle from anilines and trialkylammonium chlorides was effected in an aqueous medium (H20-dioxane) at 180°C in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)chloride <00TL1811>. Muchowski devised a novel synthetic route to indole-4-carboxaldehydes and 4-acetylindoles 86 via hydrolytic cleavage of W-alkyl-5-aminoisoquinolinium salts 85 to homophthaldehyde derivatives upon heating in a two phase alkyl acetate-water system containing an excess of a 2 1 sodium bisulfite-sodium sulfite mixture <00JHC1293>. 

The synthetic approaches to ort/zo-substituted iodoterphenyl reagents, which are used as starting materials for many of the compounds in this review, are due largely to the work of Hart, Liming, and co-workers.25,93 These routes allow the incorporation of new functionalities into the 1-position with relative ease. Lithiation and subsequent reaction with elec-... 

Synthetic approaches to the hitherto described stable germanimines are summarized in Scheme 20 (for reviews see Refs. 3, 4, 5b, 6, 7, and 119) and new routes are described next. 

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