Intramolecular C-N bond formation

Microwave-assisted intramolecular C - N bond formations have also been studied. Substituted benzimidazoles were easily prepared from the corresponding M-(2-bromophenyl)imidoformamides by Brian et al. (Scheme 102) [ 104]. The protocol involved the use of a combination of Pd2 (dba)3 and PPha in a mixture of DME and water using NaOH as the base at 160 °C. It was apphca-ble for electron poor, neutral and rich as well as sterically hindered amidines. The fastest reactions were obtained with an electron withdrawing substituent... 

Scheme 2. Pd-catalyzed asymmetric allylic alkylation of 7 is followed by a Pd-catalyzed intramolecular C-N bond formation and a Pd-catalyzed intramolecular Heck-type alkylation in Mori and Shibasaki s total synthesis of lycorane (1995).

Figure 12. Cyclization of the hydrazone 5 intramolecular C-N bond formation of the radical cation.

Intramolecular palladium-catalyzed cyclization reactions have also been used to synthesize pyrazole derivatives. iV-Aryl-iV-(o-bromobenzyl)hydrazines 494 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 495 (Equation 101) <20000L519>. Palladium-catalyzed intramolecular C-N bond formation of iV-acetamino-2-(2-bromo)arylindolines 496, followed by hydrolysis and air oxidation in the presence of aluminium oxide, allowed the preparation of indolo[l,2-3]indazoles 498 via intermediate 497 (Scheme 58) <2002TL3577>. 3-Substituted pyrazoles have been prepared from the intramolecular cyclization of A -tosyl-iV-(l-aryl/ vinyl-1-propyn-3-yl)hydrazine and then exposme of the reaction mixture of the cyclization to potassium /i //-butoxide <1997SL959>. iV-Aryl-iV -(o-bromobenzyl)hydrazines 499 or [A -aryl-A -(t>-bromobenzyl)hydrazinato-A ]-triphenyl-phosphonium bromides 501 participated in a palladium-catalyzed intramolecular amination reaction to give 1-phenyl-l//-indazoles 500 (Scheme 59) <2001TL2937>. 

Scheme 51. Pd-catalyzed intramolecular C-N bond formation in a-carboline synthesis...

Figure 3.11. Cyclization of 1,5-diaminopimelic acid intramolecular C-N bond formation.

Copper and palladium catalysed intramolecular C-N bond formation between an aryl halide and a guanidine moiety affords 2-aminobenzimidazoles. Inexpensive copper salts such as copper iodide (Cul) are generally superior to the use of palladium catalysts [76] (Table 4.12). 

Several examples of cyclizations through intramolecular C-N bond formation catalyzed by hypervalent iodine species have been reported. Antonchick and coworkers developed an efficient organocatalytic method for the preparation of carbazoles through catalytic oxidative C-N bond formation [48]. The best yields of products were obtained in hexafluoro-2-propanol using 2,2 -diiodo-4,4, 6,6 -tetramethylbiphenyl (42) as the catalyst and peracetic acid as the oxidant, as illustrated by a representative example shown in Scheme 4.23. 

It is possible that the mechanism of the Hantzsch pyrrole synthesis commenced with the condensation between the amine and the ketoester. The resulting imine then undergoes an Sn2 replacement reaction with the a-haloketone via the intermediacy of an enamine. The adduct as an enamine ketone then undergoes an intramolecular C-N bond formation to deliver the final pyrrole after extrusion of a molecule of water. 

A number of interesting one-pot or two-pot sequences of Pdarylation processes [14]. For example, a two flask sequence of Negishi coupling followed by intramolecular C—N bond formation has been employed for the synthesis of substituted indolines (Eq. (1.4)) [14a]. Lautens has recently described an elegant one-flask sequence of intermolecular C H bond functionalization followed by intramolecular N-arylation for the preparation of substituted indolines [14b]. As shown below (Eq. (1.5)), the Pd-catalyzed coupling of 2-iodotoluene with 2-bromopropylamine 5 in the presence of norbornene provided indoline 6 in 55% yield. 

Aliphatic amine derivatives such as amides, carbamates and sulfonamides also participate in Pd - catalyzed intramolecular C-N bond formation. The relative reactivity of these amino nucleophiles toward cyclization has been evaluated in the PdCL-catalyzed cyclization of iV-protected 4-pentenylamines and 5-hexenylamines, and it was found to be urea > carbamate > tosylamide > benzamide. The PdCl2(CH3CN)2-catalyzed dehydrative cyclization of alkenyl urethanes bearing an allylic hydroxyl group has been elegantly applied to the synthesis of chiral piperidine alkaloids. The cyclization reaction occurs with complete stereocontrol in good yields in the presence of 15-20 mol % of catalyst without any reoxidant (eq 16). 

Method A represents a one-pot synthesis of NSBVs 5-1. The dilithio reagent 5-4a was generated in situ from its corresponding 1,4-diiodo compound and t-BuLi (Table 5.1). Reaction of 5-4a with 2.4 equiv of trimethylacetonitrile (t-BuCN) readily afforded the dianion 5-5a [22]. Addition of di-tert-butyl peroxide ((t-BuO)2, 4.0 equiv) as oxidant led to NSBV derivative 5-la via intramolecular C-N bond formation. Decomposition of 5-la was observed when normal work-up procedure and column chromatography using silica gel or alumina were used to purify the product. Finally, the bulb-to-bulb distillation (220 °C, 0.01 kPa) was found to be an... 

LiangJL, Yuan SX, HuangJS, Che CM. Intramolecular C—N bond formation reactions catalyzed by ruthenium porphyrins amidation of sulfamate esters and aziridination of unsaturated sulfonamides. J Org Chem. 2004 69 3610-3619. 

A highly regio- and stereoselective route for the synthesis of racemic 339 and nonracemic 340 substituted tetrahydroquinoxalines used the SN2-type ring opening of activated aziridines with 2-bromoanilines followed by the Pd-catalyzed intramolecular C-N bond formation (Scheme 2.64) (Ghorai et al. 2011). 

J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang, C. Chen, Copper-catalyzed intramolecular C-N bond formation a straight forward synthesis of benzimidazole derivatives in water, J. Org. Chem. 76 (2011) 716-719. 

The Wu group reported a palladium-catalyzed three-component approach to fluorinated indene-fused quinolines 301 using 2-alkynylbromobenzenes 299, 2-alkynylanilines 330, and A-fluorobenzenesulfonimide (NSFI) (Scheme 19.81) [151]. The reaction mechanism proposed includes (1) oxidative addition of 299 to paUa-dium(O) and coordination with the triple-bond of 300 to generate the intermediates 302, (2) formation of vinylpalladium(II) intermediates 303 by the first triple-bond insertion, (3) the second triple bond insertion and an intramolecular C—N bond formation to afford 5/f-indeno[l,2-c]quinoline 304, and (4) electrophilic reaction of NSFI in the presence of a base to give the fluorinated ll//-indeno[l,2-c]quinolines 301. 

As shown in Scheme 24.1, a wide range of substrates have been exploited, and routes involving intermolecular and intramolecular C—N bond formation, as well as tandem C—N bond-forming processes, have been explored. One of the first routes based on an intramolecular construction of the key C—N bond was demonstrated by Wanatabe et al., who showed that A,A-dimethylhydrazones derived from o-chloroarylacetaldehydes 1 underwent cyclization under the action of palladium catalysis to provide the corresponding A-aminoindoles (Scheme 24.1, disconnection D-1 and Scheme 24.2) [16]. 

Routes involving intramolecular C—N bond formation have proved to dominate this area. A number of researchers have reported the cycUzation of appropriately substituted arylhydrazones, as illustrated by Scheme 24.16. Intramolecular coupling of bromo-substituted arylhydrazone 35 using a palladium catalyst derived from biden-tate ligand 36 delivers l//-indazole 37 in good yield [76]. The scope of such a transformation was expanded when it was shown that arylhydrazines such as 38 could also be used. In this case, in situ aromatization occurs following intramolecular N-arylation to yield the desired heterocycle [77]. 

A multitude of similar routes have been reported employing such intramolecular C—N bond formation. A-Tosyl hydrazones have also been established as effective indazole precursors [78] and were utilized in the synthesis of the natural product nigel-licine [79]. 3-Amino- l/f-indazoles were also prepared by similar palladium-catalyzed cyclizations [80]. Generating the appropriate halo-substituted arylhydrazone or aryl-hydrazine in situ has proved a popular tactic and has led to the development of effective one-pot processes [81-85]. 

Indazolones can be prepared by a related route utilizing a key intramolecular C—N bond formation [88,89], o-Halobenzohydrazides such as 40 were shown to undergo cyclization via the action of an L-proline-derived copper catalyst, yielding indazolone products such as 41 in excellent yield (Scheme 24.18) [88],... 

Palladium- and copper-catalyzed C—N bond formations can also be utilized effectively in the synthesis of quinolones. As in the synthesis of indazoles, intramolecular cyclizations have proved an efficient route. Battistuzzi et al. described such a route via cyclization of o-bromocinnamamide 43 [93]. The same palladium diacetate catalytic conditions were also found to be effective for an initial intermolecular Heck process, and thus 4-substituted 2-quinolones could be produced (Scheme 24.20). A brief mechanistic investigation confirmed that the Heck reaction occurred before the intramolecular C—N bond formation. 

Another route to 4-quinolones, which also exploits the use of o-haloarylketone substrates is illustrated in Scheme 24.22. Zhao and Xu reported a strategy employing a tandem C—N bond formation to construct the quinolone framework [96]. Mechanistic studies suggested that the reaction proceeded via conjugate addition product 47, which could then undergo intramolecular C—N bond formation under the action of palladium catalysis. A variety of 2-substituted 4-quinolones could be accessed with this methodoiogy, as shown in Scheme 24.22. Jones et al. have also reported a related process based on copper-catalyzed amidation [97]. 

Ruthenium-Catalyzed Heterocycle Synthesis via Intramolecular C-N Bond Formation Based on C-H Bond Activation... 

Under ruthenium-catalyzed ortho-C-H activation and intramolecular C-N bond formation, the condensation of iminophosphoranes (in situ generated from acyl azides and triphenylphosphine) with internal alkynes afforded a variety of isoquinolinone derivatives (Eq. (7.43)) [53]. The regioselective insertion of unsymmetrical alkynes led to an (aryl)C-N bond formation. Thiophene and indole-based acyl azides were also compatible for this transformation. A domino reaction sequence via coordination of ruthenium with Af-atom of iminophosphoranes, ort/zo-cyclometalation, alkyne insertion, protonation, and reductive elimination was proposed for the catalytic cycle. Based on and NMR experiments, the involvement of benzamide during the reaction process was ruled out. 

Alkylative cyclization is one of the important methods in organic synthesis for the construction of cyclic structures. According to this concept, any intramolecular one-step C—N bond formation (V-alkylation) can be termed as C—N alkylative cyclization. Based on the general mechanistic pathways, such reactions are mainly of two kinds. In the first case, intramolecular C-N bond formation takes place by replacement of a leaving group X and the cyclization can occur via both Sjvl and Sjv2 pathways (Figure 40.13). 

The 1,2-amino acids 150, 153, and 156 are widely used as chiral starting materials for stereoselective synthesis of aziridines 152, 155, and 158. The A-activated amines 151, 154, and 157 undergo intramolecular C—N bond formation to afford chiral aziridines. The reactions can be conducted easily on a multigram scale with good overall yields (Scheme 40.30). 

Synthesis of benzoxazines through aziridine ring opening followed by intramolecular C—N bond formation was reported by Sekar and co-workers. " In this approach, a domino ring opening of A -Ts aziridines 332 with o-iodo-phenols 333 followed by copper-catalyzed intramolecular C(aryl)-N(amide) bond formation in the presence of ethyl-enediamine ligand has been established to afford the resultant product 334 in excellent yield (Scheme 40.73). The trans selectivity was confirmed by H NMR spectroscopy and single crystal X-ray analysis. 

Using orf/io-gem-dihalovinylanilines as substrates, the Lautens group developed a series of methods for the synthesis of 2-substituted indoles by Pd-catalyzed cascade reactions. For examples, intramolecular C-N bond formation and subsequent Suzuki-Miyara coupling reaction of orf/io-gem-dihalovinylanilines with boric reagents provided 2-substituted indoles 9, azaindole 10a and thienopyrroles 10b (Scheme 3) [26-28]. In the latter two cases, orf/io-gem-dichlorovinylanilines were... 

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