α-C(sp3)-H Arylation of Cyclic Carbonyl Compounds

α-C(sp3)-H arylation is an important type of C-H functionalization. Various biologically significant natural products, chemical intermediates, and drugs have been effectively prepared via C-H functionalization. Cyclic carbonyl compounds comprise of cyclic ketones, enones, lactones, and lactams. The α-C(sp3)-H arylation of these compounds have been exhibited high efficiency in forming C(sp3)-C(sp2) bonds, played a crucial role in organic synthesis, and attracted majority of interests from organic and medicinal communities. This review focused on the most significant advances including methods, mechanism, and applications in total synthesis of natural products in the field of α-C(sp3)-H arylations of cyclic carbonyl compounds in recent years.


Introduction
C-H functionalization is the most powerful method that directly transforms C-H bond to C-R bond (R is any atom except H, such as C, O, N, etc.) (Scheme 1). Since C-H bonds are common in organic compounds, C-H functionalization has an extremely broad space of application. Through direct C-H functionalization, the functionalized substrate [1][2][3][4][5][6][7], drug intermediates [8][9][10], and bioactive natural products with complex structures [11][12][13][14][15] can be successfully synthesized in a highly effective manner. Therefore, it has been regarded as an "eternal theme" in organic chemistry [16,17]. As an important type of C-H functionalization, the α-C(sp 3 )-H arylations of cyclic carbonyl compounds (cyclic ketones, enones, lactones and lactams) are affected by ring tension, steric hindrance, and electronic effect, which have been considered to be a tough issue [18,19]. Considering the important application of the α-C(sp 3 )-H arylations of cyclic carbonyl compounds in organic chemistry, medicinal chemistry, and drug development process. Previous reviews summarized the progress in Pd-catalyzed α-C(sp 3 )-H arylations of carbonyl compounds [20][21][22], the applications of these reactions in the total synthesis of natural products [23], and the enantioselective approaches [24]. This review mainly focused on the conditions, substrates ranges and the application of α-C(sp 3 )-H arylation of cyclic carbonyl compounds in recent years.

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The organopalladium intermediate iii finally converts to α-aryl compound through reductive elimination (path C).
In view of the fact that the α-substituted cyclic carbonyl compounds can form chiral fixed all-carbon quaternary stereocenter by α-arylation, such as compounds 19a-19i, 26a-26g, and 29, which can effectively avoid the racemization of α-aryl compounds and subsequent reduce of optical purity. Moreover, the construction of chiral all-carbon quaternary stereocenter has always been attracted a majority of interests from the field of organic chemistry [52][53][54][55][56][57][58], so it is of great significance to design suitable substrates for such reactions. Hartwig et al. initiated the asymmetric α-arylation of α-fluoroketone 34a under various catalytic systems. The results showed that all the attempts were either low yield (54%) or low ee (72%). They speculated that the enolization of 34a was less effective when using weak base K 3 PO 4 , but α-fluoroketones 34b could be completely enolized in situ by weak base [59]. Based on the systematic screening of the catalytic conditions, Hartwig et al. found that the asymmetric coupling of α-fluoroketones (34b-34c) with different aryl bromides (25b and 35a-35e) could be efficiently realized under the catalysis of TMEDA·PdMe 2 /(S)-Difluorphosto which gave α-arylation product (36a-36f) (Scheme 16) [60].
Direct introduction of N atom into the reaction system can greatly promote the reaction by forming the Pd-N complex stabilizing the intermediate transition state and probably also activating the substrate [69][70][71][72]. Dong et al. found that palladium catalytic system could be combined with pyrrolidine to effectively achieve the α-arylation of cyclopentanones 55a.
Lactones are ubiquitous bioactive precursors of diols and relative analogues. Similar to lactams, conditions that involved strong base are often used to generate the enolates which may decrease the stereo-selectivity of α-arylation. phenolic trifluoromethanesulfonates (68a-68f) at ambient temperature. Intriguingly, some sterical hindered aryl substrates (69b-69e) were well comrpatible (Schemes 28 and 29) [41]. Difficulties of α′-C(sp 3 )-H arylations of cyclic α, β-unsaturated ketones are trifold. Affected by the conjugated system, the dienolates formed from cyclic ketenes are less nucleophilic than the corresponding enolates. In which, cyclic vinylogous ester (3-or β-alkoxyl substituted cyclic α, β-unsaturated ketone) is more electron-rich thereby its dienolate is hardly formed by deprotonation. Furthermore, the dienolates are easy to polymerize with itself, further To overcome the limitation of aryl sources in this reaction, Lautens et al. screened different palladium catalysts, and finally found that products (83a-83f) could be generated with high yield using the Palladium precatalyst Pd-P(tBu) 3 -G2, and α′ arylation could be realized at room temperature (Scheme 31) [82]. The α′-arylation of 3-ethoxy-2-cyclohexenone can also be effectively promoted by using the bulky base [83] or phosphine ligand with large steric hindrance [84].

Other Metal Catalyzed α-C(sp 3 )-H Arylations of Cyclic Carbonyl Compounds
In 2011, MacMillan et al. reported a Cu(I)-catalyzed α-arylation of enol silyl ether based on δ-lactone 91. The authors speculated that the highly active Cu(III) species in situ formed by the oxidation and insertion of diaryl iodonium salt promoted the reaction, which further underwent the oxidative addition and reductive elimination with enol silyl ether to furnish the final products (92a-92c) (Scheme 35) [92]. The corresponding enolates of carbonyl compounds are easily oxidized by oxidants, such as Cu(II), Fe(III) and so on, to form the α-radicals, which can couple with aryl radicals to give α-arylated products. Baran  (150 mol%), and the corresponding α-arylated products (95a-95d) were obtained in moderate yields (Scheme 36) [93][94][95]. With the method, they further completed the asymmetric syntheses of natural products (+)-hapalindole Q, (+)-welwitindolinone A, (+)-fischerindoles I, and (+)-ambiguine H starting from the α-arylated products (95a-95d). Later, Li et al. group reported a Fe(III)-catalyzed arylation of 3-substituted oxindoles (96a-96f). They believed that the arylation was realized through the addition of free radical in situ generated by Fe(III) or molecular oxygen at C3 position to aryl groups. Moreover, this method was well suitable for preparation of C3-arylated products with largely steric hinderance like 97a-97f (Scheme 37) [96].
Umpolung reactions have been developed as unconventional methods for the synthesis of biologically active target molecules, although the umpolung arylation of cyclic enamines have been much less investigated. Miyata et al. first developed of an efficient umpolung reaction by polarity inversion at the β-position of N-alkoxyenamines 101, which allowed α-arylation of various cyclic ketones 100 under mild conditions (Scheme 39) [22].

Transition-Metal-Free α-C(sp )-H Arylations of Cyclic Carbonyl Compounds
Benzyne has high electrophilicity and is easily attacked by nucleophiles to form arylated products. As early as 1966, Ueda et al. reported the α-arylation through the intermediate of benzyne [98]. In the total synthesis of lycorane, they treated the intermediate 107a with lithium piperidine to form the intermediate 107a′, which underwent intramolecular addition to form the α-arylated product 108 (Scheme 40). Later, the benzyne-based arylation was applied to α-arylation of lactam [99], asymmetric α-arylation of cyclic ketone in the presence of organic small molecular amines [100]. However, the biggest problem of this method is the regioselectivity of addition to benzyne, which is difficult to apply in multiple substituted aromatic substrates.
Photo-initiated S RN 1 aromatization is an effective method for arylation of carbonyl compounds, which was first applied to the total synthesis of cephalotaxinone by semmelhack et al. [79]. Recently, Xia et al. reported the visible-lightpromoted the 3-position arylation of 3-substituted oxindoles. They proved that the reaction followed the S RN 1 pathway through the activation of aryl iodide. The method has the advantages of wide substrate compatibility (111a-111f), high yield (68-85%), and easy operation (Scheme 41) [101].
Jørgensen et al. first reported the α-arylation of cyclic 1,3-diketone 112a by using phase transfer catalyst (PTC) through the nucleophilic aromatic substitution (S N Ar) reaction with electron deficient benzene 113a (Scheme 42, A) [102]. Later they found quinine could also promote such transformation when using 1,4-quinone 113b as aryl source

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could be obtained in good yields. They also proved that the reaction was realized by the addition of oxindole anion to nitrobenzene [105]. Anyang et al. reported a α-arylation of cyclic α-nitroketone 118 with various diaryl iodonium salts which are environmental friendly, easy to prepare, and stable. α-Arylated products (119a-119j) were obtained in moderate to high yields (Scheme 44) [106].

Conclusion
In recent years, α-C(sp 3 )-H arylation of cyclic carbonyl compounds has made a great progress, which provides many simple and effective methods for syntheses of molecules for biological tool, active natural products, and drugs, etc., such as 3-aryl 3-fluoroindoles, etc.. However, most of the asymmetric methods are limited to transition metal catalytic systems, problems such as how to realize green procedures and relatively small range of substrates remains to investigate. For example, Ni(0) catalyst is highly toxic, aryl halides with ortho hindered substituent have low compatibility in palladium catalytic system [107], asymmetric α-arylation of amino acids, and control of α-C(sp 3 )-H arylation through free radical process, etc., need to be solved.
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