Polycyclic indole derivatives

Iwasawa and co-workers developed a facile method for the construction of polycyclic indole derivatives 190a and 190b by the tungsten(0)-catalyzed reaction of A-(2-(l-alkynyl)phenyl)imine 188 with the electron-rich alkenes 189a and 189b (Scheme 32).42b Photoirradiation of a mixture of imine 188 and ketene silyl acetal 189a with 10mol% of... 

The reaction of vinylindoles containing the vinyl function incorporated in a carbocyclic ring provide access to novel polycyclic indole derivatives. The reaction of 46 with DMAD under forced conditions gave a mixture of Diels-Alder (47), Michael (48), and ene (49) adducts (91LA357). 

In a biomimetic approach toward the synthesis of communesin B (29), Stoltz and coworkers [22] described the IDA reaction of a polycyclic indole derivative 26 and a quinone methide imine formed in situ utilizing conditions previously reported by Corey (Scheme 9) [23]. 

Blechert S, Knier R et al (1995) Domino reactions - new concepts in the synthesis of indole alkaloids and other polycyclic indole derivatives. Synthesis 592-604... 

Oxidative Cyclization and Ring Contraction. An intramolecular cychzation/carboalkoxylation reaction takes place when 2-(penten-l-yl)-indole is treated with Pd2(dba)3 and a stoichiometric amount of copper (II) chloride in methanol under CO (1 atm). The polycyclic indole derivative was obtained in 68% yield, along with the minor C(3)-chlorinated by-product. A het-erobimetaUic Pd/Cu complex was proposed as the active catalyst in this transformation (eq 47). ... 

Chiral polycyclic indoles are ubiquitous and important ring systems found in many bioactive alkaloids and pharmaceuticals. Various methods have been developed for the efficient construction of the polycyclic indole derivatives. Recently, an unprecedented approach to a wide range of diverse, enantioenriched 2,3-dihydro-lH-pyrrolo[l,2-a]indoles 75 was demonstrated by Chen, Xiao, and co-workers. In the presence of 5 mol% Cu(OTf)2 and 5 mol% commercially available bisoxazoline 76 in toluene at 0 °C, the AFC alkylation/N-hemiacetalization cascade reaction of substituted indoles with P,y-unsaturated a-keto esters 74 occurred smoothly to afford products 75 in high yields with excellent diastereo- and enantioselectivity (Table 6.9). 

Table 6.16 Enantioselective synthesis of polycyclic indole derivatives 190 via the in situ formation and migration of spiroindolenine intermediates reported by You.

Recently, the Stanley group reported an asymmetric intramolecular hydroacylation reaction allowing a rapid access to polycyclic indole derivatives. When (5)-MeO-BIPHEP L2 was employed as a chiral ligand, the cyclization product 24, the core structure of natural product yuremamine, could be obtained with moderate to high yields and excellent enantioselec-tivity (Scheme 8.11). 

Nonetheless, this stoichiometric methodology was successfully applied by others for the syntheses of a variety of complex indole derivatives. For instance, Katritzky utilized this chemistry to obtain benzotriazolyl-substituted indoles, valuable intermediates in the synthesis of fused and polycyclic indole-derived structures [244,245]. Shvartsberg used Castro s protocol for the assembly of benz[g]indolediones [246], whereas the synthesis of pharmacologically important 1-aminoindole derivatives was reported by Prikhod ko [247, 248]. 

Iwasawa has reported the gold(III)-catalyzed reaction of N-(o-ethynylphenyl)imi-nes with electron-rich alkenes to form polycyclic indole derivatives [26]. As an example, reaction of N-[l-(l-pentynyl)phenyl]imine 28 and tert-butyl vinyl ether with a catalytic amount of AuBrs in toluene at room temperature led to isolation of the polycyclic indole 29 in 80% yield as a mixture of diastereomers (Scheme 11.3). Conversion of 28 to 29 presumably occurs via initial intramolecular hydroamination to form the gold carbene containing azomethine ylide 30 that undergoes intermo-lecular [3 + 2] cydoaddition with tert-butyl vinyl ether to form the carbene complex 31. 1,2-Migration of the 7t-propyl group to the metal-bound carbon atom coupled with deauration then forms 29. This transformation is also catalyzed efficiently by PtCl2 [26]. 

In particular, 1,7-annulated indole derivatives, such as the prototypical Cilansetron A, display high activity as 5-HT3 receptor antagonists and are being clinically tested for the treatment of symptoms in the gastrointestinal system such as the irritable bowel syndrome (IBS) [26]. To extend our previous synthetic strategy based on the reactivity of hydrazinediido zirconium complexes to annulated polycyclic indole derivatives, we aimed to prepare such hydrazides derived from cyclic hydrazines (B). 

The intra- and intermolecular arylation/carboalkoxylation of unactivated olefins with indoles and related nucleophiles is also effectively catalyzed by the system PdCl2(CH3CN)2 (5 mol %)/CuCl2 (3 equiv) in methanol under CO (1 atm) at room temperature, to give polycyclic indole derivatives in moderate to excellent yields and with excellent regio- and diastereoselectivity (eq 21).3 ... 

Since Larock and Yum s publication, a plethora of modifications and improvements have been reported. The range of starting materials that can be incorporated has been broadened to include o-bromo and o-chloroanilines [151] as well as a range of diversely N-substituted anilines. Ligand- and salt-free versions [152] have been reported as well as examples exploiting solid-phase techniques [153]. Intramolecular versions have also been demonstrated, resulting in polycyclic indole derivatives such as 75 (Scheme 24.48) [154], The procedure has also found application in several elegant natural product syntheses [155-157]. 

A novel three-component coupling reaction for the synthesis of 2-(aminomethyl) indoles and polycyclic indole derivatives from readily available N-protected ethynylanilines, amines, and aldehydes was reported by Ohno, Fujii, and coworkers. This is the first copper catalytic multicomponent construction of an indole ring that produces water as the only by-product. Two C-N bonds and one C-C bond are formed, whereas C(sp)-H bonds of alkynes and C(sp )-H bonds of aldehydes were activated in this reaction [45-48] (Scheme 8.19). 

Scheme 8.19 CuBr catalyzed synthesis of 2-(aminomethyl) indoles and polycyclic indole derivatives from N-protected ethynylanilines, amines, and aldehydes.

In 2008, Chen et al. developed a Ru-catalyzed cascade process combining a CM and an intramolecular hydroarylation (Scheme 5.3) [10]. The approach could transfer co-indol-2-yl alkenes and ot,P-unsaturated compounds into polycyclic indole derivatives 6 in a single step. The combination of two mechanistically distinct transformations relying on a single Grubbs second-generation catalyst 3 (3mol%) makes this reaction remarkably useful. 

Aniline derivatives have been used to synthesize the indoline system. A large variety of indoline alkaloid substructures are available in a very efficient way. Enamine derivatives such as 39 bearing electron withdrawing substituents on the olefinic double bond were transformed in high yields (Scheme 7). Two syn/anti isomers 41 and 42 were isolated. The isomeric ratio of the final products was influenced by a photostationary equilibrium between the substrates 39 and 40. The reaction was applied to the synthesis of a variety of derivatives of the alkaloid aspidospermidine." In this context, the cyclization products 43 were transformed into the polycyclic indole derivatives 44,45, and 46. Polycyclic indolone compounds 48 have been successfully produced by cyclization of enaminone derivatives 47 carrying a quinoline substituentIn these cases and contrary to the examples 41,42, and 43, the products 48 resulted from an oxidation of the cyclization product (also compare the formation of 30 in Scheme 5). 

Scheme 1.39. Synthesis of an indole derivative by a three fold cationic polycyclization.

Moreover, polycyclic indole alkaloid-type molecules 225 with a ketopiperazine were prepared by Wang et al. using Ugi-Pictet-Spengler process [68]. Ketocar-boxylic acids 227 were used as bifunctional substrates in Ugi reaction to yield lactams of varying ring sizes (Scheme 41). A diastereomer of hexacyclic indole derivative was crystallized and yielded X-ray diffraction suitable crystal to assign the stereochemistry. 

V-aryl-o-haloanilines can be converted into indole derivatives in a palladium catalysed oxidative addition, C-H activation sequence. The transformation has been utilized extensively in the preparation of polycyclic compounds. In a recent example, leading to the formation of the carbazole ring system, Larock and co-workers demonstrated that the formation of the... 

The majority of published work on aza-ylides concerns their applications in synthesis, and here we report a selection of contributions from this area. The Staudinger reaction is a popular route to aza-ylides and has been used to prepare a series of perfluoroalkyl-tagged aza-Wittig reagents, e.g., (68), which were generated in situ (Scheme 22), and utilised in the synthesis of 3//-quinazolidine-4-ones in a fluorous biphasic system. A method for the preparation of aza-polycyclic compounds derived from pyrrolidine, indolizidine and indole has... 

The Pictet-Spengler reaction has been combined with Ugi multi-component chemistry to construct a number of polycyclic indoles. Isonitrile derivatives prepared from tryptamine (or methyl tryptophanate), a carboxylic acid and formaldehyde condense with aminoacetaldehyde diethyl acetal. A few examples employed substituted aldehydes [352]. 

Carbonyl ylides, most often in the form of isomunchnones (formed by decomposition of diketo diazo compounds in the presence of rhodium (II) acetate, and subsequent cyclization of the intermediate rhodium carbenoid species) are by far the most studied 1,3-dipolar cycloaddition partners for indole derivatives. These cycloadditions have been employed in elegant examples of complex ring construction en route to a number of polycyclic indole-containing natural products. Preliminary work by Pirrung [54, 55] (Scheme 23) on simple intermolecular cycloadditions was followed shortly by the utilization of intramolecular examples by Padwa, Boger and others. 

This review has demonstrated that indole derivatives can participate in [2+2], [3+2], and [2+2+2] cycloaddition reactions with a wide variety of reaction partners to give an astonishing array of polycyclic frameworks. While in many cases these novel ring structures are curiosities with no current utility, several research groups have employed these reactions as key steps in complex natural product syntheses. Not surprisingly, the 2,3-bond of the indole nucleus is the primary site in the majority of these reactions however, notable exceptions exist which provide unique structures that would be difficult to obtain using other methodologies. 

Perez-Castells and coworkers devised a tandem enyne methathesis Diels-Alder reaction strategy for the assembly of polycyclic indole structures [109]. The enyne metathesis reaction using Grubbs s catalyst (311) with the 2-alkynylaniline 310 in the absence of a dienophile proceeded to form the mono- and bis-indole derivatives 313 and 314 (Scheme 66). Testing the hypothesis that a Diels-Alder cycloaddition with an activated diene might be faster than the undesired cross-metathesis reaction which led to the formation of 314, a one-pot reaction with maleic anhydride (312) as the dienophile was conducted. Disappointingly, the above reaction resulted in a... 

In Chap. 2, the author describes a novel synthesis of 2-(aminomethyl)indole by copper-catalyzed domino three-component coupling and cyclization. Two-step construction of polycyclic indoles by combination with palladium-catalyzed C-H functionalization at the indole C-3 position, scope and limitation of the asymmetric three-component indole formation, and synthesis of benzo[e][l, 2]thiazine derivatives and indene-l,l-dicarboxylate, are also presented in this section. 

A wide range of polycyclic pyridoisoindole derivatives can be synthesized by the reaction of arynes with indol-izines and annulated indolizines. Xu and coworkers reported a facile synthesis indolizino[3,4,5-al7]isoindoles 43 by the reaction of arynes with indolizines 41 (Scheme 20) [45]. The reaction was carried out using CsF, in MeCN, at 90 °C,... 

---