Fluorenones, cyclization

By analogy, thermal cyclization was described also for 6-nitro-2 -hydroxy-biphenyl-2-carboxylic acids, e.g. 14, obtained by other methods. The same product 15 was also formed from lactone 17, prepared by oxidation of fluorenone 16 (Scheme 2). If the reaction was performed in DMF, the corresponding dimethylamide was isolated (82KGS703, 86KGS852, 87KGS314, 89MI1). 

The authors used a synthesis of 9,9-spirobitluorenes 32 which was developed by Clarksen and Gomberg [60] and which includes the addition of biphenyl-2-yl-magnesium iodide to fluorenone and subsequent cyclization with protic acids. To obtain 2,2,, 7,7 -arylated 9,9-spirobifluorenes 33, 9,9-spirobifluorene (32) was tetrabrominated [58] to yield 34 followed by a Suzuki-type aryl-aryl cross-coupling with various oligoaryl and oligoheteroaryl boronic acids to obtain the 2,2, 7,7 -tetraarylated derivatives 33. 

The use of l-iodo-9-fluorenone (59) for cross-coupling with phenylacetylene produced 60, which on treatment with 51 gave the benzannulated enyne-allenes 61 (Scheme 20.14) [43], Thermolysis of 61 in 1,4-CHD at 75 °C promoted the Myers-Saito cyclization reaction, leading to 63 in excellent yields. Again, the benzylic radical center in 62 is a stabilized triarylmethyl radical. 

Although the ketone (416) gives a good yield of the pyran-4-one (417) with acetic acid (Scheme 138), the structurally related deoxybenzoin is converted into the fluorenone derivative (418) (equation 16). In the latter case intramolecular acylation occurs, presumably as a result of a favourable conformation of the carbonyl group. The former ketone cannot adopt such an array and hence is unable to cyclize in this manner (61JA193). 

The dilithio derivative of N-methyl-o-toluamide reacts with aromatic aldehydes and ketones to give hydroxyamides. Thermal cyclization affords 3-phenylisochroman-l-ones (64JOC3514). Spiroannelated isochromanones result when the organolithium compound reacts with fluorenone or alicyclic ketones. 

Interesting possibilities of synthesis arise when elimination leads to cyclic products. Such cyclization is fairly common with aromatic compounds. The mixture of products obtained from diphenylmethane contains about 25 per cent fluorene 2S> (Table 3). Similarly, benzophenone yields about 30 per cent fluorenone 20). The same method can be applied to the synthesis of heterocyclic compounds. Diphenylamine yields up to 30 per cent carbazol 26 di-phenylether about 10 per cent dibenzofurane 16). 

The expedient and regioselective metalation of unprotected biphenyl-2-, -3-, and -4-carboxylic acids has been reported.59 Unprotected biphenyl-2-carboxylic acid has been cleanly metalated with. sex-butyllithium at the position adjacent to the carboxylate and can then be subjected to site-selective electrophilic substitution (Scheme 8). The remote C(2 )-position has been attacked by the superbasic mixture of n-BuLi and t-BuOK (LICKOR) in THF or benzene. The resulting dianion cyclizes to give the fluorenone skeleton. The mechanism of the metalation of homologous compounds, 2-(pyridin-3-yl)benzoic acid derivatives, with strong bases has also been discussed.60... 

The products obtained from esters of anthranilic acid and substituted anthranilic acids are of interest because fluorenones can be prepared from them. From diazotized methyl anthranilate and benzene, 2-carbometh-oxybiphenyl is obtained in 24% yield. Hydrolysis affords 2-biphenylcar-boxylic acid, which can be cyclized to fluorenone. By this procedure, a number of 2- and 3-substituted fluorenones have been prepared.16 Thus, 3-chlorofluorenone was prepared from methyl 4-chloroanthranilate and benzene through the following steps. 

Directed remote metalation (DreM) of biaryl amides and O-carbamates, conceptually based on the complex-induced proximity effect (CIPE) [15] provides, especially in view of their link to transition metal-catalyzed cross coupling regimens [16], general and versatile routes to fluorenones (16 —> 15, Scheme 4) [5,17] and biaryl amides (16 —> 17) [18] whose features are overriding Friedel-Crafts reactivity and yield enhancement in comparison to Suzuki-Miyaura coupling routes for highly hindered biaryls, respectively. Additional features of the O-carbamate DreM result is potential further DoM of 17 with appropriate phenol protection and cyclization to dibenzopyranones [18]. 

The natural product was synthesized together with its 8-hydroxy isomer (160) via the cyclization of 4-methyl-2-(3-hydroxyphenyl) nicotinic acid (90). A11 four ring C monohydroxylated onychines have been prepared by a different, unambiguous route and their mass, UV, and H-NMR spectra discussed in detail, showing that the base- and aluminum chloride-induced bathochromic shifts are useful criteria for the location of phenol functions on the benzene ring of aza-fluorenones (97). 

Cyclopropanols undergo facile reaction with photoexcited aryl ketones such as benzophenone and fluorenone. Irradiation of fluorenone (14) and 1-phenylcyclopropanol gives a 78% yield of the coupling product 15. Spiro product 16, obtained from 1,2,2-trimethylcyclopropanol, may be derived from the y-hydroxy ketone by a further intramolecular cyclization reaction of this initial coupling adduct. 

An interesting extension of palladium-catalyzed arylation of directing-group containing arenes by aryl iodides has been recently described by Cheng [74], The arylation of aldoxime ethers under standard conditions (Pd(OAc)2 catalyst, CF3C02H solvent, stoichiometric Ag+ source at elevated T) affords fluorenones by tandem o-ary I at ion/pal ladium-catalyzed cyclization pathway (Scheme 20). 

Padwa and co-workers also used this methodology to synthesize the aza-fluorenone alkaloid onychine 570 (Scheme 4.26). The sulfoxide 565 was prepared from 2-(2-butenyl)benzoic acid in four steps. Generation of the thionium ion 566 under standard Pummerer reaction conditions was followed by cyclization to isomunchnone 567 and then to cycloadduct 568, which loses water to form a-pyridone 569. Subsequent manipulation involving deoxygenation and debenzyla-tion completed the synthesis. 

This carbamoyl transfer was used to synthesize the fluorenone dengibsin (6) from the key intermediate 4. An anionic rearrangement provides 5. Methylation and desilylation provides an amide that cyclizes to a fluorenone that on dealkylation with BCI3 provides 6. 

Isotope effects have also been applied to intramolecular homolytic aromatic substitution. Denney and Klemchuk (1958b) cyclized three biphenyl derivatives deuteriated in the 2 -position and substituted in the 2-position by a group suitable for homolytic intramolecular substitution. 2-(Phenyl-2 -d)-benzaldehyde heated with di-t-butyl peroxide gave a mixture of fluorenone and fluorenone-d (10) corresponding to an isotope... 

Other reactions such as alkane dehydrogenation [159, 160], decarbonylation reactions [161], cyclization of alkynoic acids [162,163], three-component coupling reactions of boronic acids, allenes and imines [164], fluorenone synthesis by sequential reactions of 2-bromobenzaldehydes with arylboronic acids [165], and hydrosilylation reactions [166, 167] using cyclometalation compounds as their catalysts have also been reported. 

The first account of the indeno[2,l-a]fluorene core in the literature dates to 1939 when Weizmann investigated polycyclic structures and their potential carcinogenic properties [23]. Intramolecular Friedel-Crafts acylation of 3,6-diphenylphthalic anhydride (113) in refluxing CS2 afforded fluorenone carboxylic acid 114 (Scheme 33). Acid chloride formation and subsequent cyclization in concentrated sulfuric acid generated the parent indeno[2,l-a]fluorene dione 115 in 5% yield with respect to 113. This was reaffirmed by Deuschel in 1951 where 115 is obtained in 72% under the same conditions [26]. 

Two relevant examples for categories A and D are presented (Schemes 26.9 and 26.10). Reaction of A,A-diethyl 2-biphenyl carboxamide 39 with i-BuLi/TMEDA (1.1 equiv) at-78°C followed by the addition of an electrophile affords C3-substituted derivatives 40 (DoM process, CIPE mechanism). In contrast, cyclization to give fluorenone 45 occurs with EDA at 0°C-rt (84%, DreM process) [ 1 34]. When an excess of LDA (4 equiv) and TMSCl (4 equiv) are premixed in THE at -78°C prior to addition of A,A-diethyl 2-biphenyl carboxamide 39 (ISQ conditions), the 3-trimethylsilyl derivative 42 is formed exclusively (65%). 

The LDA metalation is proposed to proceed via initial amide base complexation and equilibrium formation of the 3-lithio anion 41, whose fast reaction with an in situ electrophile (TMSCl) to afford the 3-trimethylsilylated product 42 prevents its equilibration with the 2 -lithio anion 43. In the absence of TMSCl, the 3-lithio anion undergoes equilibration with 43, which cyclizes to a stable tetrahedral carbinolamine oxide which, upon hydrolysis, affords fluorenone 45. 

Figure 1.19 Synthesis of fluorenones from oxime ethers and aryl iodides by palladium-catalyzed dual C-H activation and Heck cyclization reported by Cheng [74].

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