**2. Methods Using Palladium-Catalyzed Reactions**

#### *2.1. Carbon–Carbon Bond Formation*

## 2.1.1. Intramolecular Heck Reaction

The intramolecular variant of the Heck reaction consists of the palladium-catalyzed coupling of an aryl or alkenyl halide with an alkene in the same molecule, leading to a carbocyclic or a heterocyclic structure bearing an *endo* or *exo* double bond resulting from β-hydride elimination in the final step. In the category of cross-coupling reactions, this method is probably the most encountered for accessing medium rings. Among the various substrates designed for this reaction, some have been appropriately tethered to afford medium-sized heterocycles (Scheme 1). Generally, in these cases *endo*-trig cyclization is favored, but depending on the substrate structure competing *endo* or *exo* cyclization could be encountered.

**Scheme 1.** Schematic representation of an intramolecular Heck reaction accessing medium-sized heterocycles.

The literature dealing with the synthesis of medium-sized heterocycles by intramolecular Heck cyclization has been covered until 2011, mostly by two reviews published by Majumdar [16,17]. To avoid redundancy, we decided to not discuss the publications having been reported therein in the present review. However, to show the wide diversity of structures obtained by this strategy, selected examples of obtained products (i.e., 8 to 10 membered-sized *O*-, *S*-, *O, S*- or *N*-heterocycles) have been summarized in Table 1, with the corresponding data (reaction conditions, yields, number of examples) extracted from the cited articles. Two more recent examples that were not covered by the reviews mentioned before were also added (Table 1, entries 7 and 14).


**Table 1.** Selected examples of medium-sized heterocycles obtained by intramolecular Heck reaction.


**Table 1.** *Cont.*

<sup>a</sup> The formed bond is indicated in magenta. <sup>b</sup> Number of examples.

#### 2.1.2. Intramolecular Pd-Catalyzed Cyclization of Alkynes

The most encountered reaction in this category is the intramolecular carbopalladation of alkynes, which represents a version of the Heck–Mizoroki reaction using an alkyne instead of an alkene [32–34]. A vinyl–palladium species is generated in this catalytic process and can be trapped by reduction or cross-coupling. In our context, this generally involves an acyclic substrate bearing aryl, vinyl iodide, or bromide, and a triple bond tethered by an appropriate chain, including at least one heteroatom. Placed under Pd catalysis conditions, this type of substrate can afford a medium-sized heterocycle, which includes an *exo* or *endo* double bond with stereo-controlled geometry. A competing direct reduction (or C–C cross-coupling) might be observed, given the difficulty of alkyne intramolecular carbopalladation to form medium-sized rings.

Van der Eycken and Donets reported a regio- and stereoselective reductive cyclocarbopalladation of propargylamides to synthesize 3-benzazepines, which are 7-membered*N*-heterocycles [35]. Then, the authors demonstrated that the method could be extended to the synthesis of the 8-membered ring counterparts, namely benzoazocines. Substrate **1** was placed under microwave-assisted conditions at 110 ◦C, in a mixture of dimethylformamide-water, in the presence of palladium-tetrakis(triphenylphosphine) as the catalyst (Scheme 2). Sodium formate was used as the H-donor for the reduction. The 8-*exo*-dig cyclization via *syn*-addition of the arylpalladium species to the triple bond exclusively provided the desired product **2** in moderate yields, with Z-stereochemistry of the exocyclic double bond.

The same research group applied this methodology to access azocino-[*cd*]indoles [36]. Starting from substrates **3**, the reaction was performed under Pd catalysis conditions, using microwave heating at 110 ◦C, in DMF–water, and led with complete conversion after 15 min to the desired product **4** in good yields (Scheme 3). As in the previous cases, the reaction occurred with total regioselectivity in favor of the 8-*exo*-dig cyclization and with full control of the geometry around the exocyclic double bond.

**Scheme 2.** Synthesis of benzo[*d*]azocines by reductive cyclocarbopalladation of alkynes.

**Scheme 3.** Synthesis of azocino[*cd*]indoles by reductive cyclocarbopalladation of alkynes.

Another application of the method was reported by Majumdar and co-workers, who synthesized dibenzoazocine derivatives [37]. The reaction conditions were similar to those previously reported but performed under conventional heating. The alkynyl group is directly linked to the aromatic ring of substrate **5** and the *ortho*-iodobenzene moiety is placed as a substituent on the amide chain. From this, diverse dibenzoazocine **6** products were obtained in satisfactory yields (Scheme 4).

**Scheme 4.** Synthesis of dibenzoazocines by reductive cyclocarbopalladation of alkynes.

Anderson and co-workers reported the reductive Pd-catalyzed cyclization of bromoenynamides and used ethanol as the hydride source [38]. The transformation afforded 2-amido exocyclic dienes with a ring size of 5 to 8. The example leading to the 8-membered ring product diazocane 8 is depicted in Scheme 5. The competing direct reduction of **7** was observed in this case, however, the corresponding product **9** was minor in the mixture with the desired heterocycle (the ratio **8**/**9** was 8:2).

**Scheme 5.** Pd-catalyzed reductive cyclization of bromoenynamides.

The synthesis of sulfur-containing heterocycles via palladium-catalyzed reactions is a less-common method than for the other heterocycles, because sulfur species are known to deactivate the Pd catalyst and make the reaction difficult. Our group was interested in this aspect, and since 2014 has published several papers dealing with the use of intramolecular carbopalladation of propargyl or alkynyl sulfides to access 5- and 6-membered *S*-heterocycles [39–41]. Then, we decided to extend the method to more challenging compounds, such as the medium-sized rings, and focused on *N*,*S*-heterocycles as target compounds. We first developed the synthesis of benzimidazole-fused thiazocine **11** and thiazonine **12** via the 8- or 9-*exo*-dig reductive Pd-catalyzed cyclization, respectively, starting from 2-sulfanylated benzimidazole derivative **10** (Scheme 6) [42]. Ammonium or sodium formate was used as the reducing agent. The direct reduction of **10** was a competitive reaction, however the resulting side product was minor and could be removed by column chromatography and the desired cyclic products isolated in satisfactory yields. By varying the substituents on the substrate; R<sup>1</sup> (alkyl, aryl, heteroaryl) on the triple bond; or X, X', Y on the aromatics, the scope of the reaction was demonstrated to be broad.

**Scheme 6.** Pd-catalyzed reductive cyclization to access thiazocine and thiazonine derivatives.

During the same study, when we attempted to extend the method to access 10-membered rings, the major product obtained was the one resulting from the reduction of substrate **13** (isolated in 49% yield). However, the crude mixture also contained two inseparable cyclic products, thiazecine **14** and of thiazaundecine **15**, at a ratio **14**/**15** of 1:1 and with a combined yield of 24% (Scheme 7). This represents a rare example of competing processes between 10-*exo* and 11-*endo* cyclocarbopalladation of alkynes.

**Scheme 7.** Pd-catalyzed reductive cyclization to access thiazecine and thiazaundecine derivatives.

We also attempted to trap the vinyl-palladium intermediate by a Suzuki–Miyaura coupling instead of the reduction to produce benzimidazole-fused thiazocines bearing a stereo-defined tetrasubstituted exocyclic double bond; however, the yield was very low [43].

A nice transformation based on the intramolecular *exo*-dig cyclization strategy was described in 2002 by Grigg and co-workers [44]. The cyclocarbopalladation is followed by an allene insertion and final capture of the resulting π-allyl palladium(II) species by a secondary amine nucleophile. The authors explored the possibility of forming an eight-membered ring using this methodology; therefore, one example was achieved starting from substrate **16**, affording the desired tetrahydro-2-benzoxocine **17** and the acyclic product **18** resulting from the direct coupling in a 1:1.4 mixture, with a 43% combined yield (Scheme 8).

**Scheme 8.** Pd-catalyzed cyclization–allenylation–amination to access tetrahydro-2-benzoxocine.

In 2013, Mukherjee and co-workers described intramolecular Sonogashira cross-coupling using judiciously substituted sugars to access medium-sized *O,S*-heterocycles [25]. Various sugar-based *O*-propargyl derivatives were prepared, including propargyl ethers derived from 1,2,5,6-di-*O*-acetonideα-D-glucofuranose and 1,2,3,4-di-*O*-acetonide-α-D-galactopyranoside (Scheme 9). The reaction was performed with a heterogeneous palladium catalyst and copper iodide as the co-catalyst. Heterocyclic products with nine to eleven atoms and containing an endocyclic triple bond were obtained with good yields.

**Scheme 9.** Intramolecular Sonogashira reaction to access medium-sized *O,S*-heterocycles.

#### *2.2. Carbon–Heteroatom Bond Formation*

#### 2.2.1. C–N Bond Formation

Palladium-catalysis is extensively used in C–N bond formation [45,46]. Many reactions belonging to this category are applicable in an intramolecular version, leading to various N-heterocycles. In the examples highlighted hereafter, an intramolecular Pd-catalyzed amination was used to access medium-sized *N*-heterocycles.

Due to the advances in the field made independently by Buchwald and Hartwig, the Pd-catalyzed *N*-arylation is used for the synthesis of a wide range of acyclic or cyclic nitrogen-containing compounds; however, few examples are described for obtaining medium-sized *N*-heterocycles.

An unprecedented intramolecular Buchwald–Hartwig amidation enabling the formation of medium-sized *N*-polyheterocycles was described by Zhu and co-workers [47]. The method consisted of a Pd-catalyzed domino reaction involving an intramolecular *N*-arylation, a C–H activation, and an aryl-aryl bond-formation, which led to *N*-polyheterocycle **22** with 8–11 and 13-membered rings (Scheme 10). The optimal catalytic reaction conditions were PdCl2(dppf) and KOAc in DMSO, but the authors also showed that starting from the substrate **21** with the ether tether, the ligand-free

transformation using only Pd(OAc)2 was possible, probably due to an internal Pd coordination in a catalytic intermediate.

**Scheme 10.** Synthesis of medium-sized *N-*polyheterocycles by a Pd-catalyzed intramolecular *N*-arylation–C–H activation–aryl–aryl bond-forming domino reaction.

Chattopadhyay and co-workers reported the synthesis of sugar-fused 8-membered *N*,*O*-heterocycles (Scheme 11) [48]. Starting from D-glucose, the suitable substrates **23** were functionalized with both an aryl halide and a secondary amine. Using classic conditions for the palladium-catalyzed *N*-arylation with Pd2(dba)3 as the precatalyst source and racemic (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) (BINAP) as the ligand, the substrates were converted with good yields into the corresponding benzoxazocine **24**.

**Scheme 11.** Synthesis of benzoxazocines by intramolecular Pd-catalyzed *N*-arylation.

Piersanti and co-workers also used intramolecular N-arylation for the synthesis of a nine-membered *N*-heterocycle, the natural product (–)-epi-indolactam V. Starting from the appropriate precursor **25** derived from tryptophan, it was difficult for the reaction to succeed, and after many tested reaction conditions the best result was obtained using a palladacycle precatalyst based on XPhos phosphine ligand, NaOtBu as the base, and dioxane as the solvent (Scheme 12) [49]. The reaction could be accelerated using microwaves and by increasing the temperature. The initial experiment on the diastereomeric 1:1 mixture of precursors **25a** and **b** showed that the intramolecular *N*-arylation using these conditions was highly stereospecific, revealing the importance of a favored conformational preorganization induced by the stereocenters on the efficiency of the cyclization. Indeed, diastereoisomer **25a** was transformed into the desired heterocycle **26a**, while diastereoisomer **25b** furnished only traces of the corresponding heterocycle **26b**, along with the side product **27** resulting from reductive dehalogenation. Then, under the same conditions, the bromotryptophan dipeptide derivative **25a** was converted into the desired product **26a**, which was transformed in two steps into the natural product (-)-epi-indolactam V, with 81% overall yield.

A very well-documented study in the synthesis of cyclohexane-fused 1,5-diazocin-6-one was reported by Fülöp and co-workers using a Pd(II)-catalyzed oxidative intramolecular *cis*-aminopalladation reaction [50]. Starting from tosyl-protected *trans*-*N*-allyl-2- aminocyclohexanecarboxamides **28**, the optimization of the reaction conditions allowed a highly regioselective formation of the medium-sized heterocycles **29** via an 8-*endo*-trig cyclization, with relatively good yields (Scheme 13). Interestingly, this regioselectivity was enhanced by the solvent, allowing reduction of the amount of cyclohexane-fused pyrimidin-4-one product 30. On the other hand, this regioselectivity was observed only when the *trans* substrate was used, whereas the *cis*-isomer gave only the six-membered ring product.

**Scheme 12.** Synthesis of 9-membered *N*-heterocycle by intramolecular Pd-catalyzed *N*-arylation.

**Scheme 13.** Synthesis of 8-membered *N*,*N*-heterocycles by Pd-catalyzed oxidative *cis*-aminopalladation.

An interesting method to synthesize eight-membered *N*-heterocycles was reported by Ohno and co-workers, using as cyclization precursors bromoallene bearing a chain functionalized with a nitrogen nucleophile (Scheme 14) [51]. First, achiral bromoallene **31** attached to a sulfonamide group was prepared and converted under Pd catalysis in the presence of methanol into benzazocine **32** in good yield. A small amount of the side product **32** was formed, corresponding to the β-elimination product. Then, applied to an enantiopure substrate **33**, the reaction took place regio- and stereo-selectively, leading to the optically active diazocine **34** in 63% yield.

**Scheme 14.** Synthesis of 8-membered *N*-heterocycles by Pd-catalyzed cyclizations of bromoallenes.

In 1998, Larock's group reported the synthesis of azepines containing an exocyclic double-bond by heteroannulation of allenes starting from amines or tosylamide derivative **35** attached to an aryl iodide moiety (Scheme 15) [52]. The Pd catalysis conditions allowed the insertion of the *mono*- or *di*-substituted allene **36** after the oxidative addition, generating a π-allylpalladium species. Then, a regioselective intramolecular attack at the non-substituted carbon of the π-allyl system by the *N*-nucleophile furnished the eight- or nine-membered ring. Products **37** or **38** were obtained in good yields as a mixture of *E*/*Z* isomers, with the *E*-isomer being the major one.

**Scheme 15.** Synthesis of 8- or 9-membered *N*-heterocycles by Pd-catalyzed heteroannulation of 1,2-dienes.

Another strategy was employed by Alper and Lu, who used palladium-complexed dendrimers supported on silica as catalysts to obtained 8-membered *N*,*O* and *N,S*-heterocycles by intramolecular carbonylation of aniline derivatives (Scheme 16) [53]. This recyclable source of palladium (**G1**-Pd) allowed in a first step the insertion of the carbon monoxide on various **39a** 2-((2-halobenzyl)oxy)anilines or the thioether analogue **39b**. Then, the intramolecular attack of the aniline nitrogen on the allylpalladium intermediate and C–N bond formation by reductive elimination furnished the desired 8-membered *N*,*O* or *N,S*-heterocycle **40** with excellent yields. This methodology allowed either strongly electron-withdrawing or electron-donating substituents on the anilines.

**Scheme 16.** Synthesis of 8-membered *N*-heterocycles by Pd-catalyzed intramolecular carbonylation.

#### 2.2.2. C–O Bond Formation

Alcaide and co-workers developed a Pd-catalyzed intramolecular C–O bond formation by reacting 2-azetidinone-tethered allendiols with allyl bromide or lithium bromide, leading to azetidinone-fused 8 and 9-membered *O*-heterocycles [54]. Starting from enantiopure γ,δ-allendiols **41**, the 8-*endo* cyclization took place with total chemo- and regioselectivity via the attack of the primary hydroxy group to the terminal allene carbon, leading to oxocine **42** or **43**, depending on the reaction conditions **A** or **B** (Scheme 17). When ε,ζ-allendiols **44** were used as substrates, 2-azetidinone-fused dioxonines **45** were

p

obtained via the 9-*endo* cyclization, under conditions A. Plausible mechanistic hypotheses were given by the authors and DFT studies have been performed to understand the experimental results.

**Scheme 17.** Synthesis of medium-sized *O*-heterocycles by Pd-catalyzed cyclization of allendiols.

## 2.2.3. C–S Bond Formation

Very recently, Werz and co-workers described the first example of Pd-catalyzed intramolecular cyanosulfenylation of a triple bond and applied this method to the synthesis of two medium-sized heterocycles **47**, one oxathiocin and one oxathionin (Scheme 18) [55]. Mechanistically, the sequence consists of a thiopalladation–cyanide transfer cascade.

**Scheme 18.** Synthesis of medium-sized *O,S*-heterocycles by Pd-catalyzed cyanosulfenylation.

#### *2.3. Cyclization of Bromoallenes*

Ohno, Tanaka, and co-workers described an original synthetic method to construct medium-sized rings consisting of the Pd-catalyzed cyclization of bromoallenes judiciously attached to a nucleophile, such as **48** [51]. In this section, we treated this case separately, as the three types of intramolecular bond formations are described (i.e., C–C, C–N, and C–O) by using a carbon, nitrogen, or an oxygen nucleophile, respectively, to attack the allene moiety (Scheme 19). The reaction took place in the presence of a Pd(0) catalyst and in methanol as the solvent. In this process, bromoallenes act as allyl dication equivalents and the intramolecular nucleophilic attack takes place exclusively at the central carbon. Interestingly, bromoallene **48** has a *N*- or an *O*-nucleophile with eight-membered rings, in which the double bond is of *cis*-geometry (product **49**), while those having a *C-*nucleophile give the corresponding *trans*-rings (products **50**).

**Scheme 19.** Synthesis of 8-membered heterocycles by Pd-catalyzed cyclization of bromoallenes.
