Palladium-Catalyzed Carbonylative Synthesis of Six-Membered Heterocycles from Aryl Halides

Abstract

The main achievements on palladium-catalyzed carbonylative synthesis of six-membered heterocycles based on aryl halides as the substrates have been summarized and discussed.

1 Introduction

Six-membered ring system is widely present in many natural products, pharmaceuticals, agrochemicals, and functional materials [1, 2]. Specifically, the oxygen-, nitrogen-, and sulfur-containing six-membered fused ring scaffolds are of great interest for the drug industry. For example, quinolones, pyrimidines, and quinazolines are present in many of the best-selling drugs (Fig. 1a) [3]. In 2009, in the highly cited paper titled Heteroaromatic Rings of the Future, Pitt el al. described a virtual exploratory heterocyclic library based on a learning computer program, which would be a powerful tool in drug discovery [4]. Many fused six-membered heterocyclic scaffolds are found in the library (Fig. 1b). Owing to their great importance for the human beings, the chemists have tried a lot to devise various methods to obtain these heterocyclic compounds. Look at the structures in Fig. 1, one could find that all the compounds contain a carbonyl group (-CO-). These types of carbonyl-incorporated six-membered rings are widely present in numerous other pharmaceutically interesting molecules. In the past decades, catalytic carbonylation reactions have found many applications in the synthesis of such type of six-membered heterocycles [5]. In this chapter, we mainly review the palladium-catalyzed formation of oxygen- and nitrogen-containing rings from organo halides. Some closely related ring formation from non-halide starting materials will also be mentioned.

Fig. 1

Six-membered heterocycles in important drugs/their candidate structures

2 Chromone and Flavonoid Derivatives

Chromones and flavones (flavonoids) are an important class of biologically and pharmacologically interesting heterocycles (Fig. 2) [6–9]. For example, flavones have many activities such as antioxidant, antitumor, antimicrobial, and anti-inflammatory, and they could affect the behavior of some mammalian enzymes [10–16]. In clinical setting, flavonoid drugs have been used in the treatment of cancer, diabetes, cardiovascular disease, neurodegenerative disorders, etc. [17–20]. Although more than 4,000 naturally occurring flavonoids have been reported, chemists are still trying to synthesize more structurally versatile ones to explore their therapeutic applications. Besides the traditional procedures for their synthesis [8, 21], palladium-catalyzed carbonylations have provided a more straightforward route to flavonoid derivatives.

Fig. 2

Structure of chromone and flavonoids

The first synthesis of chromones and flavones using palladium-catalyzed carbonylation reaction was reported in 1990 by Kalinin and coworkers [22]. In their report, 2-iodophenols and two equivalents of alkynes were converted into substituted chromone derivatives catalyzed by 1 mol% of PdCl₂(dppf). However, only five examples were provided and the yields were moderate to good (Scheme 1). One drawback of this earliest procedure is the employment of diethylamine both as the solvent and base. The yields were much lower in other solvents like THF, DMF, benzene, and anisole (46–55%). In 1993, the substrate scope of this reaction was extended under the same reactions by the same group [23].

Scheme 1

First synthesis of chromones and flavones by Pd-catalyzed carbonylation

In 2005, Yang and coworkers developed a PdCl₂/PPh₃-catalyzed carbonylative Sonogashira cross-coupling with the same starting materials at room temperature [24]. The key feature of this reaction was that water was used as the green solvent and the atmospheric pressure of CO. They used this new procedure to synthesis several flavones in good to excellent yields (Scheme 2). By using 4 mol% of Pd(PPh₃)₄ as the catalyst, several 2-ferrocenyl flavones were synthesized in 72–80% yields (Scheme 3) [25]. In their procedure, 4 mol% of CuI was needed as the cocatalyst and with K₂CO₃ as the base.

Scheme 2

Pd-catalyzed carbonylative synthesis of flavones in water

Scheme 3

Carbonylative synthesis of 2-ferrocenyl flavones

In 2009, Awuah and Capretta developed a microwave-assisted synthesis of flavones through one-pot Sonogashira–carbonylation–annulation reaction [26]. Starting from commercially available aryl bromides or iodides and trimethylsilylacetylene, flavones were obtained without isolation of the Sonogashira coupling intermediates. In their procedure, 1.5 mol% of Pd₂(dba)₃ was used as the catalyst, and PA–Ph (1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane) was used as the ligand (Scheme 4).

Scheme 4

Microwave-assisted synthesis of flavones

In 2010, Yang and Alper reported a ligand-free carbonylative synthesis of flavones from 2-iodophenols and alkynes in phosphonium salt ionic liquids [27]. They used 5 mol% of PdCl₂ as the sole catalyst and triethylamine as the base. Under atmospheric CO pressure, 64–96% yields of various substituted flavones were obtained. One drawback of this procedure was that the reaction must be performed at 110°C, and the catalyst loadings were high (5 mol%).

In 2011, Li and coworkers reported a Pd–carbene-catalyzed carbonylations of 2-iodophenols. Using 0.5 mol% [PdBr₂(ⁱPr₂-bimy)L] (L=N-phenyl imidazole) as the catalyst and diethylamine as the base, a series of flavones were synthesized in good yields (Scheme 5).

Scheme 5

Pd–NHC-catalyzed carbonylation of 2-iodophenols

Using a new type of palladium–thiourea–dppp complex as the catalyst, Miao and Yang reported a regiospecific carbonylative annulation of 2-iodophenol to form flavones in moderate yields (Scheme 6) [28]. The authors found that significant amount of aurone 3 was observed in all cases (10–20%). Besides, the conversion of 2-iodophenols remained 80–90% even though the reaction time was extended to more than 2 days. To overcome these problems, acetylated 2-iodophenols were used as the substrates to afford the flavonoid products in 70–92% yields. The formation of aurones resulted from the oxidative addition of phenol O–H bond to Pd(0), which could not happen when the hydroxyl was protected by acetyl group.

Scheme 6

Carbonylative annulation of 2-iodophenol acetates with high regioselectivity

The construction of flavones from 2-iodophenols also found many applications in total synthesis. Martin and coworkers reported the total synthesis of luteolin in 2011 (Scheme 7) [29]. Using PdCl₂(PPh₃)₂ as the catalyst, Rixson et al. [30] realized a facile synthesis of some novel anthrapyran-2-ones by the carbonylative cross-coupling between 1-hydroxy-2-iodo-dihydroanthrancene and terminal alkynes. These structures may have been reported with antibacterial or antitumor activities (Scheme 8).

Scheme 7

Carbonylation of 2-iodophenol as key step in total synthesis of luteolin

Scheme 8

Pd-catalyzed carbonylative synthesis of anthrapyran-2-ones

Alper and coworkers reported the first carbonylation reaction with 2-iodophenols and allenes [31]. Using 5 mol% of Pd(OAc)₂/dppb as the catalyst and ⁱPr₂NEt as the base, the reaction favored isomer A in high regioselectivity, especially when terminal allenes (R¹=H) were employed. The regioselectivity resulted from the more favorable OH attacking on the less hindered terminus of the π-allyl palladium intermediate (Scheme 9).

Scheme 9

Pd-catalyzed carbonylation of 2-iodophenols with allenes

Also started from 2-iodophenols and allenes, Grigg and coworkers performed the reaction under atmospheric CO pressure [32]. Using Pd(PPh₃)₄ as the catalyst and K₂CO₃ as the base, various functionalized chroman-4-ones were obtained in good to excellent yields (Scheme 10). Besides, 2-iodoanilines were also converted to quinol-4-ones under the same conditions.

Scheme 10

Chroman-4-ones via Pd-catalyzed carbonylation–allene insertion

In 2000, Kadnikov and Larock reported the carbonylation of 2-iodophenols and internal alkynes (Scheme 11) [33]. A variety of substituted coumarins were synthesized in good yields in the presence of 5 mol% of Pd(OAc)₂ under 1 atm of CO. Owing to the large over amount of alkynes (5 equiv.) and low CO pressure, the insertion of the internal alkyne occurs in preference to the insertion of CO. When asymmetric internal alkynes were used, two regioisomers were obtained in moderate selectivity. In 2014, Zhao, Cai et al. used a highly efficient and reusable PdCl₂(PPh₃)₂/PEG-2000/H₂O system for the carbonylative Sonogashira coupling (Scheme 12) [34]. This system could also been used for the synthesis of flavone under very mild conditions (1 atm CO and 25°C). In 2005, Cao and Xiao performed this reaction using Mo(CO)₆ as the CO source under microwave irradiation, and a series of chromen-2-one derivatives was obtained (Scheme 13) [35].

Scheme 11

Pd-catalyzed synthesis of coumarins from 2-iodophenols and internal alkynes

Scheme 12

Pd-catalyzed carbonylative synthesis of coumarins in aqueous system

Scheme 13

Microwave-promoted carbonylative synthesis of chromen-2-ones using Mo(CO)₆ as CO source

In 2012, Gøgsig, Skrydstrup et al. reported a palladium-catalyzed synthesis of 1,3-diketones through carbonylative α-arylation in a two-chamber reactor using 9-methyl-9H-fluorene-9-carbonyl chloride as the solid CO source [36]. Starting from MOM-protected 2-iodophenol, the ¹³C-labeled 1,3-diketone was obtained in a 90% yield. Subsequent hydrolysis of the ethoxymethyl ether protecting group and dehydrative cyclization formed the 3-methyl-flavone in 99% yield (Scheme 14).

Scheme 14

CO-free carbonylative synthesis of 3-methyl-flavone using two-chamber reactor

All the above carbonylative procedures toward flavones started from expensive iodophenols and terminal alkynes or allenes. In 2012, Wu et al. reported a carbonylative synthesis of flavones from 2-hydroxyacetophenones and aryl bromides (Scheme 15) [37]. This alternative procedure employed only 2 mol% Pd(OAc)₂/dppb as the catalyst and two equivalent UBU as the base, which allowed for the convenient synthesis of various 2-(hetero)aryl-substituted flavones in moderate to good yields. Besides, when 2-propenyl phenol was used as the substrate, 3-methyl-flavone could be obtained in 61% yield.

Scheme 15

Pd-catalyzed synthesis of flavones from 2-hydroxyacetophenones and aryl bromides

In the next year, Wu and coworkers developed a palladium-catalyzed carbonylative synthesis of chromenones from salicylic aldehydes and benzyl chlorides in good to excellent yields (Scheme 16) [38]. Regarding the reaction pathway, the benzyl chloride firstly underwent phenoxycarbonylation with salicylic aldehydes to form 2-formylphenyl 2-phenyl-acetate, which led to the products through intramolecular condensation. 2-Hydroxyacetone could also afford methyl-substituted chromenone but the yield was much lower.

Scheme 16

Carbonylative synthesis of chromenones from salicylic aldehydes and benzyl chlorides

In 2014, Wu and coworkers provided three examples of palladium-catalyzed synthesis of chromenones starting from 2-bromofluorobenzenes and 1,2-diphenylethan-1-one under 50 bar of CO [39]. The combination of carbonylation and nucleophilic substitution afforded the desired product in 30–40% yields (Scheme 17).

Scheme 17

Pd-catalyzed synthesis of chromenones from 2-bromofluorobenzenes

3 Valeralactone, Pyran-2-One, and Their Derivatives

As early as 1980, Cowell and Stille reported the synthesis of γ-lactones by palladium-catalyzed carbonylation of halo alcohols [40] (Fig. 3). In this paper, one example of δ-lactone, 1H-2-benzopyran-3(4H)-one, was also synthesized from (2-(bromomethyl)phenyl)methanol in the presence of 1.6 mol% PdCl₂(PPh₃)₂ (Scheme 18). Owing to the industrial interest as a precursor for various pharmaceuticals and plant protection agents, Lindsell et al. reinvestigated this reaction in 2005 [41]. Although they failed to reproduce Stille’s procedure, they obtained near-quantitative yield of the same product under different reaction conditions. In 2006, Preston et al. patented a palladacycle catalyst to realize this reaction [42]. CO was bubbled through the reaction mixture under mild conditions, and quantitative yield of isochroman-3-one was obtained.

Fig. 3

Structure of six-membered lactones

Scheme 18

Synthesis of γ-lactones by Pd-catalyzed carbonylation

In 1983, Brunet et al. described Co₂(CO)₈-catalyzed SRN₁ carbonylations of the same substrates under sunlamp-irradiated phase-transfer conditions [43]. Two benzolactones were synthesized in excellent yields (Scheme 19). In this procedure, Co₂(CO)₈ was used as both the catalyst and the CO source. When the amines were used instead of alcohols, the corresponding benzolactam was obtained albeit in somewhat lower yields.

Scheme 19

Co₂(CO)₈-catalyzed radical carbonylative synthesis of benzolactones

In 2004, Alterman and coworkers reported a palladium-catalyzed carbonylation of 2-(o-bromophenyl)ethanol using molybdenum hexacarbonyl as the CO source [44]. At high temperature (180°C), isochroman-1-one was obtained in 74% yield (Scheme 20).

Scheme 20

CO-free carbonylative synthesis of isochroman-1-one

In 2007, Alper and coworkers reported an interesting synthesis of highly substituted endocyclic enol lactones (Scheme 21) [45]. In this method, 3 mol% of PdCl₂(PPh₃)₂ and 6 mol% dppp were used as the catalyst, and ionic liquid [bmim][Tf₂N] was used as the reaction medium. Under 200 psi of CO, a series of β-diketones and alkynes were converted to the desired products in reasonably good regioselectivity and yields. More importantly, the system could be recycled five times with only modest loss of its catalytic activity. The authors also proposed a mechanism for this transformation. In the first step, PdCl₂(PPh₃)₂ was reduced to Pd(0) species in the presence of CO. The in situ formed Pd(0)L_n oxidatively added into the enol –OH of the β-diketone to give Pd-hydride intermediate A. Then the alkyne would coordinate to A and CO insertion to form the intermediate B. Next, the alkyne was regioselectively inserted to the Pd–acyl bond to form C, which easily underwent reductive elimination to form D and regenerated Pd(0). D is rearranged through intramolecular cyclization of the vinyl acetate on the activated double bond to give the final product E (Scheme 22).

Scheme 21

Pd-catalyzed carbonylative synthesis of substituted endocyclic enol lactones

Scheme 22

Proposed mechanism for the transformation in Scheme 21

Based on the similar strategy, Wu and Hua described an efficient synthesis of 3,4,7,8-tetrahydro-2H-chromene-2,5(6H)-dione derivatives via a [3+2+1] cyclocarbonylative coupling of 1,3-cyclohexanediones, terminal alkynes, and CO (Scheme 23) [46]. Using 5 mol% Pd(PPh₃)₄ as the catalyst and THF as the solvent, the products were obtained in excellent selectivity. The route for the formation of chromene-2,5-dione derivatives was proposed to involve the similar steps in Scheme 22.

Scheme 23

Pd-catalyzed cyclocarbonylative synthesis of chromene-2,5-dione derivatives

4 Saturated Oxygen-Containing Six-Membered Rings

In 2015, Yang and coworkers [47] described a Pd(II)-catalyzed intramolecular carbonylative cyclization reaction of aryl alkenes and aryl alkenols (Scheme 24). Using 10 mol% of PdCl₂(PPh₃)₂ as the catalyst and 3.5 equiv. of CuCl₂ as the oxidant, chromane derivatives were obtained under atmospheric CO pressure. When external alcohols were added as nucleophiles, α-(chroman-4-yl) acetate esters were obtained in high yields and stereoselectivity. When aryl alkenols were used as the substrates, five-membered lactone rings were constructed by intramolecular alkoxycarbonylation. It was noticeable that the only electron-rich aromatic rings led to the products in good yields. The authors also propose a mechanism to explain the formation of the fused ring products (Scheme 25). At the first step, the allylic alcohol reacted with palladium carbonyl complex to form complex B. Next, a cis-intramolecular nucleopalladation led to an intermediate palladacycle C. The migratory CO insertion led to complex D, which released the product by reductive elimination. The resultant Pd(0) was then reoxidized by CuCl₂.

Scheme 24

Pd-catalyzed intramolecular carbonylative cyclization toward chromanes

Scheme 25

Proposed mechanism for the Pd-catalyzed carbonylative cyclization of aryl alkenols

5 Quinolinone Derivatives

Quinolinone and its derivatives have diverse chemical and pharmacological properties and thus attracted much interest of both synthetic and pharmaceutical chemists [48–53] (Fig. 4). Palladium-catalyzed carbonylative construction of these structures has become a very unique method because it employed some readily available starting materials and CO as the carbonyl source.

Fig. 4

Structure of quinolinones

In 1990, Torii et al. reported an efficient synthesis of 3-substituted 3-(2-haloarylamino)prop-2-enoates catalyzed by 5 mol% Pd(OAc)₂ and 20 mol% PPh₃ under CO pressure (Scheme 26) [54]. When lactone substrates were employed, the desired products were obtained in very good yields.

Scheme 26

First example of carbonylative synthesis of quinolin-4(1H)-ones

Two years later, Kalinin and coworkers synthesized 2-substituted quinolin-4-ones from 2-iodoanilines and terminal alkynes (Scheme 27) [55]. They used 5 mol% PdCl₂(PPh₃)₂ as the catalyst and diethylamine as the solvent. Under 20 bar CO pressure, 61–95% yields of the products were isolated. As a synthetic application, Haddad et al. accomplished convergent synthesis of the key quinolone intermediate for protease inhibitor BILN 2061 by using 1.5 mol% PdCl₂(dppf) as the catalyst [56]. In 2015, Larhed’s group reported a similar carbonylative synthesis of 4-quinolones using Co(CO)₆ as the carbonyl source (Scheme 28) [57]. Under microwave conditions, this method yielded the products after only 20 min of microwave heating at 120°C. Using Pd(OAc)₂/P^tBu₃·HBF₄ as the catalytic system, the reaction could run in a one-pot two-step sequence at room temperature, and some sensitive substituents in the substrates could be well tolerated.

Scheme 27

Carbonylative synthesis of 2-substituted quinolin-4-ones from 2-iodoanilines and terminal alkynes

Scheme 28

Synthesis of 4-quinolones using Mo(CO)₆ as the carbonyl source

In 2005, Alper and coworkers developed an intramolecular carbonylation procedure with recyclable palladium-complexed dendrimers on silica for the synthesis of some fused ring system [58]. In this report, they gave one example of six-membered ring synthesis. Starting from 2′-iodo-[1,1′-biphenyl]-2-amine, 6(5H)-phenanthridinone was obtained in 97% yield catalyzed by G1-palladium dendrimer (Scheme 29).

Scheme 29

Recyclable carbonylation palladium catalyst for the phenanthridinone synthesis

In 2007, Alper’s group synthesized a series of methylene-2,3-dihydro-1H-quinolin-4-ones through the carbonylative cross-coupling between o-iodoanilines and allenes in ionic liquid. They used only 2 mol% Pd₂(dba)₃·CHCl₃ and dppb as the catalyst, and both terminal and internal allenes were applicable as the substrates (Scheme 30). Under relatively mild conditions (5 bar of CO and 90°C), up to 82% yield of the products was obtained. When the asymmetric enteral allenes were used, two region isomers were isolated in a ca. 2:1 to 7:1 ratio. Notably, cyclononene could be incorporated into the dihydro-1H-quinolin-4-one ring system.

Scheme 30

Pd-catalyzed carbonylative cross-coupling between o-iodoanilines and allenes

Quinazolinones are another important class of six-membered heterocyclic compounds containing two isolated nitrogen atoms. Until now, many methods had been reported for their synthesis [59–61]. As early as in 1987, Tilley and coworkers reported a carbonylative synthesis of pyrido[2,1-b]quinazoline derivatives starting from N-(2-bromophenyl)pyridine-2-amines (Scheme 31) [62]. The authors proposed that this reaction initialized with the oxidation of N-(2-bromophenyl)pyridine-2-amine onto Pd(0) to form the aryl-palladium bond. Then CO insertion and nucleophilic attack by the pyridine nitrogen afforded the desired product.

Scheme 31

Pd-catalyzed aminocarbonylation of N-(2-bromophenyl)pyridin-2-amines

Inherently, 2-aminopyridine (pK _a = 6.86) exists s as a mixture of tautomeric amino and imino isomers with the predominance of the amino form over the imino form (1000:1). By utilization of this unique tautomerization nature of 2-aminopyridine, several syntheses of nitrogen heterocycles were reported through carbonylation. In 2014, Wu, Beller and their coworkers reported a synthesis of quinazolinones by carbonylation/nucleophilic aromatic substitution sequence [63]. Started from 2-bromofluorobenzene and 2-aminopyridines, they obtained both linear and angular fused quinazolinones using Pd(OAc)₂/n-BuPAd₂ as the catalytic system (Scheme 32). In this regio-switchable procedure toward two isomers, the basicity difference between Et₃N (pK _a = 10.8) and DBU (pK _a = 12) played a key role. In 2015, Xu and Alper updated Torii’s procedure (Scheme 33) reaction by using Pd(OAc)₂ and DIBPP as the catalytic system [64]. Under their optimized conditions, nine examples of pyrido[2,1-b]quinazolin-11-ones and six examples of dipyrido[1,2-a:2,3:b]pyrimidin-5-ones were synthesized through Pd/DIBPP-catalyzed dearomatizing carbonylation. It was notable that the starting materials could be prepared from Pd-catalyzed amination of the 1,2-dibromides without isolation.

Scheme 32

Regio-switchable procedure toward linear and angular fused quinazolinones

Scheme 33

Pd-catalyzed dearomatizing carbonylation to form quinazolin-11-ones and pyrimidin-5-ones

In 1999, Cacchi et al. described a one-pot process synthesis of 6-aryl-11H-indolo[3,2-c]quinolines through a straightforward palladium-catalyzed carbonylative cyclization of o-(o′-aminophenylethynyl)trifluoroacetanilide with aryl iodides [65]. In this procedure, 2-(2-aminophenyl)-3-aroyl-1H-indol was formed as the primary product, which underwent intramolecular condensation to form the six-membered ring system (Scheme 34).

Scheme 34

One-pot process synthesis of 6-aryl-11H-indolo[3,2-c]quinolones

The above strategy was also employed in the carbonylative synthesis of 3-substituted 4-aroylisoquinolines by Dai and Larock [66]. In the presence of 5 mol% of Pd(PPh₃)₄ as the catalyst and 5 equiv. of K₂CO₃ as the base, 2-(1-alkynyl)benzaldimines were cyclized to the desired products in moderate to good yields (Scheme 35). In the first step of the reaction, aroylpalladium complexes (A) were formed from aryl bromides or iodides by sequential oxidative addition and CO insertion. Then the aroylpalladium(II) species coordinate to the alkynes, and subsequent nucleophilic attack from the imine nitrogen produced the intermediate C. Primary product D was then released from C by reductive elimination and further deprotection of the tertiary butyl group in the presence of base to give the final products.

Scheme 35

Pd-catalyzed carbonylative cyclization of 2-(1-alkynyl)benzaldimines to form 3-substituted 4-aroylisoquinolines

In 2000, Larksarp and Alper disclosed a catalyst system comprising Pd(OAc)₂-dppf for the cyclocarbonylation of o-iodoanilines with heterocumulenes at 70–100°C for 12–24 h to give the corresponding 4(3H)-quinazolinone derivatives in good to excellent yields (Scheme 36) [67, 68]. Heterocumulenes such as isocyanates, carbodiimides, and ketenimines could be used in their procedures to prepare different substituted products.

Scheme 36

Cyclocarbonylation of o-iodoanilines with various heterocumulenes

Based on these earlier works of their own group, Zeng and Alper later reported a highly practical and efficient method for the synthesis of 2-heteroquinazolin-4(3H)-ones through palladium-catalyzed tandem reaction [69] in good to excellent yields (Scheme 37). Using the same catalytic system, the authors developed a domino process for the synthesis of quinazolino[3,2-a]quinazolinones (Scheme 38) [70]. The starting carbodiimides were efficiently prepared by metathesis reactions of the corresponding isocyanates with N-(o-iodoaryl)triphenyliminophosphoranes. It was noteworthy that five new bonds and two fused heterocycles were formed in a single step. Less bulky alkyl amines led very good yields and steric hindrance in the amines decreased the yields. When N,N′-dimethylethylenediamine was used as the amine, the desired product with a nine-membered ring structure was not observed.

Scheme 37

Pd-catalyzed tandem reaction to synthesize 2-heteroquinazolin-4(3H)-ones

Scheme 38

Pd-catalyzed tandem reaction to synthesize quinazolino[3,2-a]quinazolinones

In 2008, Zheng and Alper developed a palladium-catalyzed cyclocarbonylation of 2-iodoanilines with imidoyl chlorides under 500 psi of CO [71]. The reaction was believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones in 63–91% yields (Scheme 39).

Scheme 39

Pd-catalyzed cyclocarbonylation of 2-iodoanilines with imidoyl chlorides

In 2013, Wu, Beller, and their coworkers developed a novel palladium-catalyzed four-component carbonylative coupling system for the selective construction of 4(3H)-quinazolinones in a one-pot fashion [72]. Starting from 2-bromoanilines, trimethyl orthoformate, and amines under 10 bar of CO, the desired products were isolated in good yields catalyzed by 2 mol% of Pd(OAc)₂ and n-BuPAd₂. Notably, the process tolerated the presence of various reactive functional groups and was very selective for quinazolinones (Scheme 40).

Scheme 40

Pd-catalyzed four-component carbonylative coupling to form 4(3H)-quinazolinones

Later on, Wu’s group reported the synthesis of quinazolinones from 1-bromo-2-fluorobenzenes and amidines with 2 mol% of Pd(OAc)₂ and 6 mol% n-BuPAd₂ as the catalyst (Scheme 41) [39]. The reaction was believed to initialize from the aminocarbonylation to form the N-(amino(phenyl)methylene)-2-fluorobenzamide intermediate. The nucleophilic substitution and rearrangement led to the final products. As an evidence, 1,2-diphenylquinazolin-4(1H)-one was obtained in 70% yield when N-phenylbenzimidazole hydrochloride was used as the amidine.

Scheme 41

Pd-catalyzed quinazolinones synthesis from 1-bromo-2-fluorobenzenes and amidines

In the same year, Wu, Beller, and their coworkers reported a domino synthesis of quinazolinediones through a double carbonylation process. Starting from commercially available 2-bromobenzonitriles and 2-bromoanilines series, 20 examples of isoindolo[1,2-b]quinazoline-10,12-dione structures were synthesized in the presence of Pd(OAc)₂ and P^tBu₃·HBF₄ as the catalyst (Scheme 42). After determination of the final product by X-ray crystalline structure and the validation of 2-phenyl-3-iminoisoindolin-1-one as the isomerization intermediate, the authors proposed a two-sequential aminocarbonylation reaction pathway in Scheme 42.

Scheme 42

Synthesis of isoindolo[1,2-b]quinazoline-10,12-diones through double carbonylation

In Zeng and Alper 2008 [73] (Scheme 43), a wide variety of substituted isoquinolin-1(2H)-ones was synthesized in reasonable to good yields by the palladium-catalyzed cyclization of diethyl(2-iodoaryl)malonates with imidoyl chlorides and carbon monoxide in tetrahydrofuran. A palladium-catalyzed carbonylation–decarboxylation process may be involved in the one-step synthesis of the isoquinolin-1(2H)-ones. Later on, Okuro and Alper reported a palladium-catalyzed intermolecular cyclocarbonylation of 2-iodoanilines with diethyl ethoxycarbonylbutendienoate [74]. By the similar procedure involving Michael addition and subsequent carbonylation, 2,3,3-triethoxycarbonyl-2,3-dihydro-4(1H)-quinolinone derivatives were obtained in moderate to good yields (Scheme 44).

Scheme 43

Pd-catalyzed carbonylative cyclization of diethyl(2-iodoaryl)malonates with imidoyl chlorides

Scheme 44

Pd-catalyzed carbonylative synthesis of 2,3,3-triethoxycarbonyl-2,3-dihydro-4(1H)-quinolinone

In 2008, Broggini’s group [75] reported a carbonylative synthesis of 4-[(methoxycarbonyl) methyl]-3,4-dihydroisoquinolin-1-ones from N-allylamides of 2-iodobenzoic acids under high pressure of CO (Scheme 45). The reaction stared with the oxidative addition of aryl iodides with in situ generated Pd(0). The following intramolecular carbopalladation gave (σ-alkyl)Pd complexes, which underwent CO insertion and nucleophilic attack by MeOH to form the final products.

Scheme 45

Pd-catalyzed coupling between N-allylamides of 2-iodobenzoic acids

In 2001, Kang and Kim reported a reaction between γ-allenic sulfonamides and aryl iodides in the presence of Pd(PPh₃)₄ (5 mol%) to form 3-aroyl-2- or 3-pyrrolines [76]. When started from δ-allenic sulfonamides, this procedure afforded two examples of piperidine-substituted enones in moderate yields (Scheme 46).

Scheme 46

Pd(PPh₃)₄-catalyzed carbonylative coupling between γ-allenic sulfonamides and aryl iodides

In 2008, Alper’s group developed an efficient and simple synthesis of biologically fused ring isoquinolines by utilizing a palladium-catalyzed carboxamidation reaction and aldol condensation reaction cascade protocol (Scheme 47) [77]. The first step of the reaction was the oxidative addition of the aryl iodides with Pd(0) to give aryl-palladium species, and then CO insertion formed aroylpalladium complex which was then attacked by the amide nitrogen to give the imide intermediate. Finally, the intramolecular condensation led to the final product.

Scheme 47

Pd-catalyzed carbonylative synthesis of fused ring isoquinolines

Larock’s group developed a palladium-catalyzed synthesis of 3,4-disubstituted 2-quinolones through the annulation of alkynes and N-substituted o-iodoanilines under 1 atm of CO [78, 79]. The best results were obtained using alkoxycarbonyl, p-tolylsulfonyl, and trifluoroacetyl substituents. The nitrogen protection groups were lost during the course of the reaction resulting in the formation of N-unsubstituted 2-quinolones in moderate to good yields (Scheme 48).

Scheme 48

Pd-catalyzed synthesis of 3,4-disubstituted 2-quinolones from alkynes and N-substituted o-iodoanilines

In Tadd and Willis (2009) [80], palladium-catalyzed intermolecular aminocarbonylation/intramolecular amidation cascade sequences can be used to convert a range of 2-(2-haloalkenyl)aryl halide substrates efficiently and selectively to the corresponding 2-quinolones. Delaying the introduction of the CO atmosphere allows amination/carbonylation sequence and the preparation of an isoquinoline (Scheme 49).

Scheme 49

Pd-catalyzed intermolecular cascade sequences to the 2-quinolones

In 1996, Cacchi, Marinelli et al. reported a palladium-catalyzed reaction of o-iodoaniline with unsaturated halides or triflates [81]. In the presence of K₂CO₃ and catalytic amounts of Pd(PPh₃)₄ under an atmosphere of carbon monoxide, 2-aryl- and 2-vinyl-4H-3,1-benzoxazin-4-ones were obtained in good to high yields (Scheme 50). It was noteworthy that when R was androsta-3,5-dienes, the corresponding products were also obtained in 68–78% yields.

Scheme 50

Pd-catalyzed carbonylative synthesis of 4H-3,1-benzoxazin-4-ones from 2-iodoanilines and aryl halides and triflates

In 1999, Larksarp and Alper [82] reported a one-pot carbonylative regioselective synthesis of 2-substituted-4H-3,1-benzoxazin-4-ones from o-iodoanilines and acid chlorides (Scheme 51). In the presence of Pd(OAc)₂ and diisopropylethylamine, the desired products were obtained in good to excellent yields. The reaction was believed to proceed via in situ amide formation from an o-iodoaniline and an acid chloride, followed by oxidative addition to Pd(0), CO insertion, and intramolecular cyclization to form the 2-substituted-4H-3,1-benzoxazin-4-one derivatives. In 2010, Salvadori et al. [83] realized the same reaction using Pd/C as the heterogeneous catalyst under microwave dielectric heating conditions (Scheme 52).

Scheme 51

Pd-catalyzed carbonylative coupling with o-iodoanilines and acid chlorides

Scheme 52

Pd/C-catalyzed carbonylative synthesis of 4H-3,1-benzoxazin-4-ones

Ács et al. transformed 2-iodoanilines to the corresponding 2-aryl-benzo[d][1,3]oxazin-4-one derivatives via double carbon monoxide insertion (Scheme 53) [84]. This reaction required a high CO pressure (100 bar).

Scheme 53

Pd-catalyzed double carbon monoxide insertion of 2-iodoanilines

In 2011, Wu et al. described an alternative synthesis of 2-arylbenzoxazinones from commercially available 2-bromoanilines and aryl bromides (Scheme 54) [85]. The first step was the chemoselective aminocarbonylation of the aryl bromides to form the N-aroyl-2-bromoaniline intermediate. The second CO insertion into the aryl-palladium bond furnished the final product. In 2014, Li and Wu reported a palladium-catalyzed carbonylative synthesis of benzoxazinones from N-(ortho-bromoaryl)amides using paraformaldehyde as the carbonyl source [86]. Under this CO-free conditions, various substituted benzoxazinones were obtained in good yields under optimized conditions (Scheme 55). Using ¹³C-labeled paraformaldehyde, 4-¹³C-labeled benzoxazinone derivative was obtained, which has many important applications in pharmaceutical and biological topics.

Scheme 54

Pd-catalyzed synthesis of 2-arylbenzoxazinones from 2-bromoanilines and ArBr

Scheme 55

Pd-catalyzed carbonylative synthesis of benzoxazinones using paraformaldehyde as CO source

In 2015, Konishi et al. reported a synthesis of 4H-3,1-benzoxazin-4-one derivatives from N-(ortho-iodoaryl)amides by using phenyl formate as the CO source (Scheme 56) [87]. Under basic conditions, phenyl formate decomposed to phenol and carbon monoxide. The authors proposed that the reaction proceeded through the phenoxycarbonylation of the aryl iodide intermediates and basic condensation of the intermediates led to the desired products in moderate to good yield.

Scheme 56

Carbonylative synthesis of 4H-3,1-benzoxazin-4-ones using phenyl formate as CO source

6 Other Six-Membered Heterocycles

Palladium-catalyzed carbonylation of C–X bonds has also found some application in some other six-membered heterocycle synthesis. In 1999, Xiao and Alper reported a regioselective heteroannulation of 2-iodothiophenols with allene CO pressure in the presence of palladium catalyst to form various thiochroman-4-one derivatives (Scheme 57) [88]. In 2008, the same group reported a novel synthesis of another type of sulfur-containing heterocycles, 3-substituted-3,4-dihydro-2H-1,3-benzothiazin-2-ones, by palladium-catalyzed carbonylation reaction of 2-substituted-2,3-dihydro-1,2-benzisothiazoles in pyridine (Scheme 58) [89]. The authors suggested that the reaction is initialized with the oxidation of S–N bonds with Pd(0) and then CO insertion into the S–Pd bonds or N–Pd bonds to form the product-releasing intermediates. Finally, the reductive elimination gave the products.

Scheme 57

Pd-catalyzed carbonylative synthesis of thiochroman-4-one derivatives

Scheme 58

Pd-catalyzed carbonylation reaction of 2-substituted-2,3-dihydro-1,2-benzisothiazoles

In 2001, Brown et al. gave an example of carbonylative synthesis of chromane derivative from 1-iodo-2-((3-methylbut-3-en-1-yl)oxy)benzene in the presence of two equivalents of silane (Scheme 59) [90].

Scheme 59

Reductive carbonylation to form 2-(4-methylchromen-4-yl)acetaldehyde

In 2012, Ryu’s group gave several examples of the synthesis of functionalized δ-lactam and δ-lactones through Pd/light-accelerated atom-transfer carbonylation reactions (Scheme 60) [91]. These three-component coupling reactions involved a hybrid organometallic-radical pathway and showed the potential of the utilization of alkyl halides in carbonylative heterocycle synthesis.

Scheme 60

Pd/light-accelerated atom-transfer carbonylation reactions to form lactams and lactones

7 Summary

Palladium-catalyzed synthesis of heterocycles from carbon–halide bonds in the presence of CO has been applied in many types of six-membered heterocyclic compounds. The combination of amino- or alkoxycarbonylation with various intramolecular condensations, nucleophilic substitutions, or further carbonylation reactions was effective for the construction of various carbonyl-derived six-membered rings and fused ring system. We believe that the combination of carbonylation with other types of intramolecular reaction would be a useful tool for the synthesis of more advanced heterocyclic compounds.