Aromatic synthon

A novel use of a chlorofluorocarbon is in the synthesis of a pyrone (30) from 1,1,1-trichlorotrifluoroethane. The key step involves Cu(I) catalysis. Pyrone (30) is a useful CF3 aromatic synthon, as it readily underwent (4 + 2) cycloaddition followed by spontaneous elimination of C02 (85-TL3947). 

The aromatic synthon was obtained by reduction of 3,5-dimethoxyphthalic anhydride (124) to hydroxyphthalide 125. Wittig coupling of the two fragments (125 was first converted to the sodium carboxylate 125a with dimsyl anion) and acid treatment afforded the seco acid 126 as a 1 1 mixture of olefin isomers. 

Difluoronaphthalene [315-52-6] is prepared from 4-fluoro-l-naphthylarnine by the Balz-Schiemann reaction. 1,4-Difluoronaphthalene is used in chemical carcinogenesis studies as a synthon for highly condensed difluoro—polycycHc aromatic hydrocarbons (273). 

Several examples of [5C+1S] cycloaddition reactions have been described involving in all cases a 1,3,5-metalahexatriene carbene complex as the C5-syn-thon and a CO or an isocyanide as the Cl-synthon. Thus,Merlic et al. described the photochemically driven benzannulation of dienylcarbene complexes to produce ortho alkoxyphenol derivatives when the reaction is performed under an atmosphere of CO, or ortho alkoxyanilines when the reaction is thermally performed in the presence of an isonitrile [111] (Scheme 63). In related works, Barluenga et al. carried out analogous reactions under thermal conditions [36a, c, 47a]. Interestingly, the dienylcarbene complexes are obtained in a first step by a [2+2] or a [3S+2C] process (see Sects. 2.3 and 2.5.1). Further reaction of these complexes with CO or an isonitrile leads to highly functionalised aromatic compounds (Scheme 63). 

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. 

Note These synthons will usually give hydroquinoxalines, but some such products may undergo aerial aromatization during the reaction or workup. 1,2-Benzenediamine (129) gave 2-phenyl-3,4-dihydroquinoxaline (130) (AcONa, MeOH, reflux, CH4I, 2 h 55% with unsymmetric analogs of substrate (129), two isomers resulted in each case and the kinetics of such... 

If a target aminodicarboxyl units bears an aryl group in one of its side chains, retrosynthetic analysis indicates that a bromoamide synthon 12, bearing an aliphatic side-chain, should react with a nucleophilic partner carrying the aromatic side chain. In the alternative bromoamide 21, HBr elimination to cinnamic derivatives competes with the desired bromine substitution. 

Disconnection of (2) at the bonds joining the aromatic rings to the aliphatic part of the molecule will need a reagent for the doubly charged synthon (3). 

The O-silylated acyloins such as 1920 c and 1927 are useful synthons for preparation of five-membered aromatic heterocycles such as the substituted imidazole 1925, pyrrole 1926, and furan 1928 [119] (Scheme 12.35). 

Note These synthons will usually give hydroquinoxalines, but some such products may undergo aerial aromatization during the reaction or workup. 

Transmetallation of aiyl halide (VIII) with n-butyl lithium and treating it with readily available and inexpensive 3-ethoxycyclohexen-l-one followed by acid work-up would provide enone (XI) (Scheme 8). Enone (XI) can be then aromatized to phenol (X) or any other biaryl alkyl ether. By using this protocol, 3-ethoxycyclohexen-l-one is a synthon for 3-hydroxyphenyl boronic acid. The bulk price of 3-ethoxycyclohexen-l-one is 85/kg compared to 3500 for the boronic acid, thereby significantly reducing the cost to prepare biaryl (X). 

A one-pot three-step conversion of aryl fluorides to phenols based on a consecutive nucleophilic aromatic substitution/isomerization/hydrolysis sequence has been reported by Levin and Du (Scheme 6.126) [256], The authors discovered that 2-butyn-l-ol can function as a hydroxyl synthon through consecutive SNAr displacement, in situ isomerization to the allenyl ether, and subsequent hydrolysis, to afford phenols rapidly and in good yields. In most cases, excesses of 2-butyn-l-ol (1-2 equivalents) and potassium tert-butoxidc (2-4 equivalents) were required in order to achieve optimum yields. 

All double bonds are perceived as possible dienophile synthons by the notation package. The screening involves only the elimination of all double bonds in aromatic compounds (WLN symbol R ). 

Cyclohexadienones 61 and 64 are readily available from monoprotected hydro-quinones or para-substituted phenols, respectively. Conjugate additions to these symmetrical dienones result in desymmetrization of the prochiral dienone moieties, providing access to multifunctional chiral synthons in two steps from the aromatic precursors (Scheme 7.17) [72]. 

The p-functionalized 2-hydroxyphenyl isocyanide not only contains the isocyanide and the nucleophile within the same molecule, but both functional groups are also arranged in one plane for an intramolecular nucleophilic attack [176]. This arrangement, in addition to the aromaticity of the five-membered ring obtained after cyclization to the carbene ligand, particularly favors the intramolecular nucleophilic attack. In contrast to 2-hydroxyethyl isocyanide, free 2-hydroxyphenyl isocyanide is not stable [177]. The stable 2-trimethylsiloxyphenyl isocyanide [178] can serve as a synthon for 2-hydroxyphenyl isocyanide. Carbene complexes 63 with an NH,0-stabilized NHC ligand can be obtained from the complexes 62 with the... 

A similar reaction of 70 leads to an amino nitrile ylide synthon (36,37), which reacts with a range of aromatic and heteoaromatic aldehydes to give the 2-oxazolines (71), but which fails to react with ahphatic aldehydes, simple ketones, or activated alkenes. 

Similarly, the iminodithiocarbonate 72 serves as a thio nitrile ylide synthon (38). When treated with fluoride ion in the presence of aldehydes and ketones, it gave the alcohols 73 as isolable products that were converted into 74 on treatment with silical gel. Best results were obtained with aromatic aldehydes containing electron-withdrawing groups yields were poorer when electron-donating groups were present and for ketones. 

Given the success of PET switches and sensors of the off-on type (Section 5), there is no fundamental reason why on-off systems cannot grow to be similarly useful. However there is little doubt that off-on systems are more visually appealing. Besides this aesthetic factor, off-on systems and especially the aminoalkyl aromatic family tend to be synthetically more accessible since amine synthons are available in great variety. 

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