C -H carbonylation

This type of C-H carbonylation is also feasible at C-H bonds in five-membered N-heteroaromatics, such as imidazoles 3 (Scheme 2), thiazoles 5, oxazoles 6, and pyr-azoles 7 [3], Functional group compatibility was extensively studied in the reaction of 3, and it was found that a variety of functional groups, for example ketone, ester, cy-ano, acetal, N, O-acetal, ketal, and silyl groups, were tolerated under the reaction conditions, indicating that C-H carbonylation reactions have now reached a satisfactory level in organic synthesis. The reactivity of the five-membered N-heteroaromatics is significantly affected by the pK, of conjugate acid of the N-heteroaro-... 

Scheme 3. Order of reactivity of five-membered N-heteroaromatics in C-H carbonylation.

In addition to five- and six-membered N-heteroaromatics, other N-heterocyclic compounds have been found to serve as substrates for C-H carbonylation reactions. Benzoimidazole 13 reacted in the same way with CO and olefins in the presence of Ru3(CO)12, but carbonylation occurred at the C-H bond / to the sp2 nitrogen to give 14 (Table 1). The same relationship between reactivity and the pK, values of conjugate acids of heterocycles was also observed in the /8 carbonylation [4],... 

Table 1. Examples of the structural diversity of C-H carbonylation reactions (conditions are different in each reaction).

Although examples are few, C-H carbonylation at C-H bonds d to the sp nitrogen was achieved when N-pyridylindoline 21 was used as the substrate [8]. The reaction is sensitive to solvent polarity. The choice of N,N-dimethylacetoamide as solvent is crucial for the reaction to proceed efficiently. In the y- and c>-carbonylation, only ethylene works effectively as coupling partner. 

A high-throughput procedure using a mass spectrometric labeling strategy for examining applicable substrates in C-H carbonylation catalyzed by Ru3(CO)12 has recently been reported [10],... 

The directing group promoted C-H activation reaction is applicable to sp C-H bonds adjacent to the nitrogen in alkylamines, as shown in Scheme 5. Alkylation occurred when reaction of 25 with CO and ethylene was conducted in the presence of Ru3(CO)12 as catalyst [11], On the other hand, the use of a rhodium complex as catalyst resulted in C-H carbonylation [12],... 

Methyl C-H Methylene C-H Methoxy C-H Carbonyl C-H Aromatic C H Hydroxyl O-H... 

C-H methyl C-H, carbonyl adjacent as (.C=OCH3) C—H methyl, carbonyl adjacent as (.C=0CH3) Ketones... 

The synthesis of l-isochromanones has been accomplished using C—H carbonyl-ation " mediated by Pd(II) in the presence of one atmosphere of carbon monoxide via a hydroxyl-directed C—H activation followed by intra-molecular hydroxyl-trapping of the resulting intermediate (Scheme 3.17). 

The preparation of 1,2-dibenzoic acids catalyzed by Pd(II) can be accomplished via directed C—H carbonylation followed by the in situ hydrolysis of an intermediary cyclic anhydride. Electron-rich substituted benzoic acids performed better overall with respect to yield and rate with the ortAo-directed C—H functionalization occurring more efficiently. Strongly electron-withdrawing groups on the aromatic ring render such substrates difficult with this protocol. 

The reaction of 47 mainly led to the sp C-H carbonylation and formation of 48 (90%) with 5% only of sp C-H bond carbonylation showing that sp C-H bond activation and carbonylation was favoured (Scheme 13). The carbonylation of compound 49 showed that the activation of the cyclopropyl methylene C-H bond was favoured with respect to the methyl one (Scheme 13). 

Palladium-catalyzed double C—H carbonylation of diaryl ethers 86 was developed as an efficient route to xanthones 87 (Scheme 22.20) [42]. The carbonylative cyclization proceeded with the aid of Pd(OAc)2 and K2S2O8 under 1 atm of CO... 

Different to Yu s work which was directed by the carboxy group [45], in 2012, Guan and coworkers described an alkyl amino-directed palladium-catalyzed C-H carbonylation of Af-alkylanilines to synthesize isatoic anhydrides (Scheme 3.22) [46]. Using 5 mol% Pd(OAc)2, 2.2 equiv. of Cu(OAc)2, and 0.2 equiv. of KI, isatoic... 

Scheme 3.21 Pd-catalyzed C-H carbonylation of benzoic and phenylacetic add derivatives.

Scheme 3.22 Pd-catalyzed C-H carbonylation synthesis of isatoic anhydrides.

Besides the cyclic acid anhydrides, the oxaphosphorinanone oxides, which are bioisostere of acid anhydrides and inhibitors of P-lactamase [47], have also been synthesized by palladium-catalyzed C-H carbonylation of phosphonic and phos-phinic acids (Scheme 3.23) [48]. In the presence of 5mol% Pd(OAc)2, l.Sequiv. of PhI(OAc)2, and l.Sequiv. of AgOAc, benzylphosphonic and phosphinic acid derivatives could give the corresponding oxaphosphorinanone oxides in moderate to high yields by incorporation of a carbonyl group. 

In addition, the palladium-catalyzed C-H carbonylation is also useful to construct pyranone derivatives. In 2011, Yu s group reported a Pd(II)-catalyzed ortho-C-H carbonylation reaction of phenethyl alcohol derivatives to give 1-isochromanones by connecting the aryl moiety and alcohol with incorporated carbonyl group (Scheme 3.24) [49]. A wide range of functionahties such as methoxy, fluoro, chloro, and bromo are tolerated under the typical condition and afford various 1-isochromanones in moderate to good yields. The A-protected amino acids are supposed to reduce the rate of Pd(II) reduction in the presence of CO in this work. 

Scheme 3.24 Pd-catalyzed synthesis of oxaphosphorinanone oxides via C-H carbonylation.

In 2013, Shi and coworkers described the first example of phenolic hydroxy group-directed C-H carbonylation to prepare lactones (Scheme 3.25) [50]. Using 5mol% Pd(OAc)2, 10mol% Cu(OAc)2, 2equiv. of Na2C03, and O.Sequiv. of PivOH, dibenzopyranones could be synthesized from 2-arylphenols under an atmospheric pressure of CO and air. The reaction is of wide substrate scope, whereas the steric hindrance and electronic character of phenolic aromatic ring are critical to the yield. 

More recently, Jiang and coworkers used 3-arylquinolin-4(l//)-one as the substrates and realized the construction of 6//-isochromene[4,3-c]-quinolin-6-ones by palladium-catalyzed C-H carbonylation and cyclization (Scheme 3.27) [52]. 

Scheme 3.27 Pd-catalyzed C-H carbonylation to prepare polycyclic heterocyclic compounds.

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