Formals, aromatic synthesis

This is by far the most used type of primary synthesis for quinoxalines. It usually involves the cyclocondensation of an o-phenylenediamine (or closely related substrate) with a synthon containing an oxalyl [—C(=0)—C(=0)—] or equivalent [e.g., HC(=0)—C=N] grouping. For convenience, discussion of this synthesis is subdivided according to the type of synthon used to produce formally aromatic quinoxalines the formation of similar ring-reduced quinoxalines (mostly from related synthons at a lower oxidation state) is included in each such category. 

The Pictet-Spengler reaction has also seen much use in the synthesis of lavendamycin methyl ester. Both Hibino [31] and Behforouz [32] used it as a key step in their syntheses of this molecule (Fig. 10). In Hibino s synthesis, /i-methyltryptophan ethyl ester 27 was condensed with quinoline aldehyde 28 to give the corresponding lelrahydro- -carbohnc, which was aromatized by heating with palladium on carbon in xylenes, giving /1-carboline 29 in 75% yield. A five-step sequence (which included conversion to the methyl ester for easier comparison with known compounds) yielded bromoquinone 24 in 27% yield for the five steps. This completed Hibino s formal total synthesis of lavendamycin methyl ester, since this was the same intermediate used in Kende s synthesis. 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

The second formal total synthesis by Tsuji employed the carbonylation technique previously explored in several other of his syntheses. As shown in Scheme 1.29, construction of the aromatic residue began with bromination and... 

Bracher, F. and Papke, T. (1996) Polycyclic aromatic alkaloids, XI. A convenient formal total synthesis of the cytotoxic marine alkaloid amphimedine. Liebigs Ann. Chem., 115-116. 

Singh, V. and Samanta, B., Generation of molecular complexity from aromatics a formal total synthesis of coriohn from 6-methylsahgenin, Tetrahedron Lett., 40, 383, 1999. 

Singh, V., Samanta, B., and Kane, V.V., Molecular complexity from aromatics synthesis and photoreaction of endo-tricyclo[5.2.2.0 > ]undecanes. Formal total syntheses of ( )- coriolin. Tetrahedron, 56, 7785, 2000. 

Both the required salts were easily accessible from 19 as described in Section 14.5.3. The viability of this approach has been shown by successful completion of a simple synthesis of (+/-)-0-methyljoubertiamine from 84 [4]. A detailed crystallographic study of conformational effects in an extended series [109,128] of 1-aryl-substituted cyclohexadienyliron complexes had established, as expected, that ortho substituents on the aromatic ring substantially impeded the nucleophile s approach, and could switch the control to predominantly a> control by the aryl group. However, with an o-alkoxy substituent, the conformation with the substituent below the plane of the dienyl system is easily accessible (and characterized in an X-ray structure [128]) opening the way for more ambitious synthetic applications [109]. This conformational effect has been put to use in a formal total synthesis (entry 19) of lycoramine (87) from 88 [106]. Electronic effects from additional donor substituents also flatten the ring and open up the aryl-substituted position [128], effects that will be put to work in ongoing work towards maritidine and crinine. The completed O-methyljoubertiamine and lycoramine syntheses make multiple use of the metal to form both bonds at the aryl-substituted quaternary center, and so can be classified as iterative ( —> f/ V V ) synthetic routes. 

Reduction should result in l,2-dihydro-l,2-diazocine (2) which formally contains a cyclic, conj ugatcd 10 7r-electron system and potentially possesses aromatic character. To date, however, only the synthesis of a dibenzo derivative has been described (see Section 1.2.1.3.). 

Recently, Reinhoudt and Kouwenhoven 53) have reported, in connection with their successful synthesis of monocyclic thiepin 87, that the relatively high stability of 87 is attributed to the presence of the two methoxycarbonyl groups which cause a decrease in the electron density of the 8n-electron system. As a result, the formal anti-aromatic character is reduced. Traynelis and his coworkers 6) have also reported a slight increase in the thermal stability of benzo[6]thiepin when electron-withdrawing groups are present. These conclusions have subsequently been supported by resonance energy calculations on various thiepin derivatives59). Thus, the re-... 

Recently, Curran described a procedure using triethylborane for the synthesis of spirooxindoles and spirodihydroquinolones through intramolecular addition of aryl radicals at the ipso position 4-alkoxy-substituted aromatic rings [15]. The key step for a formal synthesis of the vasopressin inhibitor SR121463A is described in Scheme 5. The initiation was performed with Et3B in an open to air reaction vessel. 

Chemists were using cyanide ion for the synthesis of 1,2-D systems even before the concept of "reactivity inversion" was formally established. Thus, in the classical benzoin condensation, the cyanide-induced coupling of two aromatic aldehydes takes place according to the following mechanism [7] (Scheme 5.6) ... 

IrCl2H(cod)]2 catalyzed the synthesis of substituted quinolines, where the reachon of aniline derivahves, aromatic and alkyl aldehydes efficiently proceeds under an oxygen atmosphere (Scheme 11.34) [46]. The plausible mechanism consists of a Mannich reaction, a Friedel-Craft-type aromahc substituhon, dehydration, and dehydrogenation. This can be recognized as a formal [4+2] cycloaddition of N-aryl imine and enol (Scheme 11.35). 

The intramolecular C-H insertion reaction of phenyldiazoacetates on cyclohexadiene, utilizing the catalyst Rh2(S-DOSP)4, leads to the asymmetric synthesis of diarylacetates (Scheme 8). Utilizing the phenyl di azoacetate 38 and cyclohexadiene, the C-H insertion product 39 was produced in 59% yield and 99% ee. Oxidative aromatization of 39 with DDQ followed by catalytic hydrogenation gave the diarylester 40 in 96% ee. Ester hydrolysis followed by intramolecular Friedel-Crafts gave the tetralone 31 (96% ee) and represents a formal synthesis of sertraline (5). Later studies utilized the catalyst on a pyridine functionalized highly cross-linked polystyrene resin. ... 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

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