The importance of carbon monoxide as a C-1 unit in organic synthesis can hardly be overemphasized [1]. It is a readily available feedstock that can be easily obtained by steam reforming of light hydrocarbons (including natural gas), partial oxidation of petroleum hydrocarbons, or gasification of coal to give syngas (CO and H₂) [2]. It can be installed into an organic substrate, usually under catalytic conditions, leading to the direct formation of high value-added carbonylated compounds with 100% atom economy (carbonylation reactions) [1].

Here, some examples of carbonylative double cyclization processes for the synthesis of carbonylated fused heterocycles (in particular, starting from suitably functionalized olefinic substrates) are presented.

2. Functionalized Olefinic Substrates

It is well-know that palladium(II)-based catalysts activate unsaturated carbon–carbon bonds towards the attack of a variety of nucleophilic groups (mainly oxygen- or nitrogen-based). The intramolecular version of this reactivity is of particular importance as it allows the construction of heterocyclic derivatives in a straightforward manner and under mild reaction conditions (Pd(II)-catalyzed heterocyclization reactions) ^[3][5]. On the other hand, it is also very well known that Pd(II) catalysts promote many important kinds of carbonylation processes, particularly under oxidative conditions, including cyclization processes in which carbon monoxide is inserted as a carbonyl function inside the newly formed ring (cyclocarbonylation reactions) ^[4][6]. It is therefore not surprising that several important methods have been developed in which a single Pd(II)-based catalytic system promotes, in one synthetic step, the sequential heterocyclization−cyclocarbonylation of suitably functionalized olefinic substrates that carry two nucleophilic moieties placed in appropriate positions to undergo double cyclization. Pioneering studies on this kind of reactivity were conducted by the Semmelhack and Yoshida research groups during the 1980s. In 1984, Semmelhack et al. reported the Pd(II)-promoted stereoselective carbonylative double cyclization of 1-(2-(hydroxymethyl)phenyl)prop-2-en-1-ols to give 3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-ones with a cis junction between the newly formed rings using a stoichiometric amount of Pd(OAc)₂ ^[5][7]. The process started with the intramolecular 6-exo-trig nucleophilic attack of the benzylic hydroxyl group to the double bond, activated by coordination to the Pd(II) center. This led to the formation of a cis-type alkylpalladium intermediate stabilized by chelation of the second hydroxyl group. The final bicyclic product was then formed through CO migratory insertion followed by intramolecular nucleophilic displacement by the hydroxyl, possibly via the formation of a palladacycle followed by reductive elimination (Scheme 1). Interestingly, when an oxidant for Pd(0) such as CuCl₂ was employed to make the process catalytic, the reaction led to the formation of (E)-(2-(3-chloroprop-1-en-1-yl)phenyl)methanol from allylic chlorination (74% yield) ^[5][7]. Later on, however, suitable conditions were elaborated by the Yoshida group for performing the carbonylative double cyclization of 3-hydroxy-4-pentenoic acids to stereoselectively give tetrahydrofuro[3,2-b]furan-2,5-diones with a cis junction between the rings under Pd(II) catalysis (10 mol% PdCl₂ in the presence of 3 equiv of CuCl₂ and 3 equiv of AcONa, in glacial acetic acid as the solvent, at room temperature and under 1 atm of CO) (Scheme 2) ^[6][8]. The process took place through 5-exo-trig cyclization by the intramolecular nucleophilic attack of the carboxylic group to the double bond coordinated to the metal center, stabilized by hydroxyl chelation, to give a cis-type alkylpalladium complex followed by CO insertion and intramolecular nucleophilic displacement, possibly via the formation of a palladacycle followed by reductive elimination (Scheme 2) ^[6][8]. The same research group then published the carbonylative double cyclization of 4-ene-1,3-diols under similar reaction conditions to obtain tetrahydrofuro[3,2-b]furan-2(3H)-ones (Scheme 3) ^[7][9]. Considering that the bicyclic tetrahydrofuro[3,2-b]furan-2(3H)-one substructure is largely found in natural and biologically active molecules, the methods disclosed by Semmelhack and Yoshida for constructing this important core by the carbonylative double cyclization of enediol derivatives have been largely employed as the key step in the semi- or total synthesis of natural products and bioactive compounds. Representative examples are shown in Table 1.

Entry	Conditions	Substrate	Product	Yield (%)	Refs.
1	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 41 h			63	[8][10]
2	PdCl2(MeCN)2, (10 mol%), CuCl2 (2.4 equiv), CO (1 atm), THF, 25 °C, 24 h			65	[9][11]
3	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 8 h			85	[10][12]
4	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (4 equiv), CO (1 atm), AcOH, 25 °C, 24 h			93	[11][13]
5	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 33 h			38	[12][14]
6	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 15 h			>80	[13][15]
7	Pd(OAc)2 (1.5 equiv), CO (1.1 atm), THF, 23 °C, 4 h			87	[14][16]
8	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 15 h			81	[15][17]
9	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C			63	[16][18]
10	PdCl2, CuCl, AcONa, CO, AcOH			33	[17][19]
11	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 10 h			85	[18][20]
12	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 23 °C, 24 h			75	[19][21]
13	Pd(OAc)2 (1.5 equiv), N-methylmorpholine (3 equiv), CO, THF, 25 °C, 15 h			58	[20][22]
14	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 20 h			65	[21][23]
15	Pd(OAc)2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 15 h			63, 70	[22][23][24,25]
16	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 24 h			33	[24][26]
17	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 24 h			87	[25][27]
18	PdCl2 (10 mol%), CuCl2 (3 equiv), AcONa (3 equiv), CO (1 atm), AcOH, 25 °C, 12 h			61	[26][28]
19	PdCl2(MeCN)2 (10 mol%), CuCl2 (5 equiv), AcOLi (5 equiv), [Fe(CO)5] (0.5 equiv), AcOH, 60 °C, 1 h			47	[27][29]
20	PdCl2(MeCN)2 (10 mol%), Cu(OAc)2 (4 equiv), LiCl (4 equiv), [Fe(CO)5] (0.25 equiv), AcOH, 60 °C, 15 min			67	[28][30]
21	PdCl2(MeCN)2 (10 mol%), CuCl2 (4 equiv), AcOLi (4 equiv), [Fe(CO)5] (0.3 equiv), AcOH, 60 °C, 30 min			75	[29][31]

Interestingly, using the appropriate enantiopure ligand, a kinetic resolution of (±)-pent-4-ene-1,3-diols was possible with the formation of the corresponding bicyclic lactone in noracemic form. This was exemplified by the Pd(OAc)₂-catalyzed carbonylation of (±)-pent-4-ene-1,3-diol performed in the presence of an enantiopure bis(oxazoline) ligand and p-benzoquinone as an external oxidant to give (3aR,6aR)-tetrahydrofuro[3,2-b]furan-2(3H)-one in 29% yield and 62% ee (Scheme 4) ^[30][32]. More recently, the kinetic resolution of (±)-pent-4-ene-1,3-diols to give nonracemic tetrahydrofuro[3,2-b]furan-2(3H)-ones [2-(S,S) up to 80% ee, 2-(R,R) up to 57% ee] has been realized under similar conditions [4 mol% of Pd(OAc)₂, 12 mol% of 2,6-bis[(4R)-4-phenyl-2-oxazolinyl]pyridine as enantiopure ligand, 0.5 equiv of p-benzoquinone, and 10 equiv AcOH] using an ionic liquid as the solvent (such as 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [Bmim][NTf₂], 10 equiv), as shown in SchemeScheme 5 5 ^[31][33]. Interestingly, the Gracza group reported that the use of iron pentacarbonyl as an in situ liquid CO source may lead to improved results (significantly shorter reaction times, in particular) in the Pd(II)-catalyzed carbonylative double cyclization of enediols with a terminal double bond, as shown in SchemeScheme 6 6 ^[27][32][33][29,34,35]. The same research group recently reported their reaction under flow conditions using a continuous microflow system, as shown in SchemeScheme 7 7 ^[29][34][31,36]. The carbonylative double cyclization process of enediols has also been reported to occur with 4-ene-1,2-diol derivatives. In this case, after the initial 5-exo-trig O-cyclization, in the cyclocarbonylation it is the free hydroxyl at C-2 that acts as internal nucleophile, with the formation of a 6-membered ring. This is illustrated by the formation of 8-((tert-butyldimethylsilyl)oxy)-2,6-dioxabicyclo[3.2.1]octan-3-one from 3-((tert-butyldimethylsilyl)oxy)pent-4-ene-1,2-diol, as shown in SchemeScheme 8 8 ^[35][37]. The nucleophilic group undergoing initial heterocyclization can also be nitrogen-based. Thus, as early as 1985 the Tamaru and Yoshida group found that the Pd(II)-catalyzed carbonylative double cyclization of the N-protected 5-aminopent-1-en-3-ols yielded N-protected 6-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-2-ones, using the same conditions employed for 4-penten-1,3-diols ^[36][38]. Among the protective groups tested, the –CO₂Me group turned out as the most suitable, as exemplified in SchemeScheme 9 9 ^[37][39]. As predicted, owing to the higher degrees of freedom of the alkyl chain, N-protected 6-aminohex-1-en-3-ols were significantly less reactive, and relatively good results were usually observed with P = CONHPh, as shown in SchemeScheme 10 10 ^[37][39]. Later on, Jäger et al. reported the carbonylation of benzyl ((2R,3S)-2,3-dihydroxypent-4-en-1-yl)carbamate (Scheme 11a) as a key step in the synthesis of novel 1,4-iminoglycitol derivatives as potential glycosidase inhibitors ^[38][40]. On the other hand, the PdCl₂-catalyzed carbonylation of benzyl ((2S,3S)-2,3-dihydroxypent-4-en-1-yl)carbamate gave benzyl (3aR,6S,6aS)-6-hydroxy-2-oxohexahydro-4H-furo[3,2-b]pyrrole-4-carboxylate in a 14% yield (Scheme 11b) ^[39][41]. Kinetic resolution of N-protected 5-aminopent-1-en-3-ols in the Pd(II)-catalyzed carbonylative double cyclization has been reported by Gracza et al. Thus, using enantiopure bisoxazoline ligands, nonracemic hexahydro-2H-furo[3,2-b]pyrrol-2-ones could be obtained as in SchemeScheme 12 12 ^[40][42]. The gaseous CO-free conditions elaborated by the Gracza group for the carbonylation of 4-ene-1,3-diols, involving the use of liquid [Fe(CO)₅] as an in situ CO source (Scheme 6), have also been successfully employed by the same research team in the Pd(II)-catalyzed carboylative double cyclization of N-protected 5-aminopent-1-en-3-ols, as in SchemeScheme 13 13 ^[32][34]. An interesting carbonylative double cyclization process has recently been developed by the Li group ^[41][43]. It involved the reaction of N-(2-aminoethyl)pent-4-enamide or N-(2-hydroxyethyl)pent-4-enamide derivatives with CO (1 atm) in the presence of PdCl₂ as a catalyst (1 mol%) and p-benzoquinone as an oxidant (1.2 equiv) (Scheme 14). As shown in Scheme 14, the initial 5-exo-trig N-cyclization was followed by CO insertion and intramolecular nucleophilic displacement via the formation of an 8-membered ring palladacycle followed by reduction elimination ^[41][43]. A general approach leading to carbonylative double cyclization is the intramolecular Pauson–Khand reaction starting from suitable diene or enyne substrates. Since several excellent reviews have been published on this reaction ^[42][43][44][44,45,46], even in the most recent literature ^[45][46][47][47,48,49], this process will not be treated here; however, a particularly striking example in SchemeScheme 15 15 gives the reader an idea of the powerfulness of this synthetic method for constructing complex carbonylated polycyclic compounds ^[48][50].