Mori-Ban reaction

Recently, Cook s group described their Mori-Ban indole synthesis of substrate 10, easily assembled from 9 [23]. The intramolecular cyclization gave a 1 1 mixture of indole 11 and exo-3-methylene-indoline 12, which was readily converted to 11 upon treatment with acid. By changing the base from K2CO3 to Ag2C03, the Mori-Ban reaction gave exo-3-methylene-indoline 12 exclusively in 90% yield. 

Three representative examples of intramolecualar Heck reaction are shown below. The first one is the Mori-Ban reaction the second is an intramolecualar Heck reaction taking place on the indole ring and the third one is an intramolecualar heteroaryl Heck reaction connecting two aromatic rings. 

The Mori-Ban reaction has been widely used in drug discovery and development. In the process synthesis of a selective PPARy modulator by Merck, the enamine was cyclized to afford the indole core. ... 

Mori-Ban reaction refers to a synthesis of indole derivatives by an intramolecular Heck reaction of o-halo-aniline with pendant olefin catalyzed by a low-valent metal complex Pd and Ni. The preferred ortho-haXogcn is bromine or iodine (chlorine has very low reactivity under this case). More often, the o-iodo-iV-allylaniline is more reactive than corresponding o-bromo-and o-chloro-substrate. Also, it has been found that the catalyst can be deactivated under the reaction. Therefore, a periodic provision of fresh catalyst normally gives higher overall yields than that using the same total amount of catalyst with one addition. In the past three decades, the Mori-Ban reaction has been improved and applied to variety of organic synthesis. 

As the first application of Heck reaction in making heterocyclic compounds — namely indole derivatives, the Mori-Ban reaction has been widely used in variety synthesis of indoles. In a program to synthesize CC-1065 analogs, Sundberg prepared indole 19 from o-bromo-JV-allylaniline 18 in an excellent yield using the Jeffrey s conditions. Silver carbonate and sodium carbonate were less effective than triethylamine. 

Macor and co-workers explored the Mori-Ban reaction to synthesize several antimigraine analogs of Sumatriptan and homo-tryptamines as potent and selective serotonin reuptake inhibitors.The second bromine on substrate 25 was not significantly deleterious to the reaction although a small amount of the 7-bromoindole 26 might be sacrificed at the end of the reaction to consume the active palladium catalyst. This approach to 7-bromoindole 26 can provide a general method accessing 7-bromoindoles, which then could be further manipulated for the synthesis of more complex 7-substituted indoles. 

The Mori-Ban reaction also has been expanded to synthesize 3-... 

In the total synthesis of clavicipitic acid and aurantioclavine, Jia and co-workers have successfully prepared the key intermediate 56 via a Mori-Ban reaction by direct coupling of 3-nitro-2-iodoaniline with (5)-2-iV,A(-di-rer/-butoxycarbonyl-5-oxopentane under standard Pd-catalyzed indole synthesis conditions, yielding the optically pure 4-nitrotryptophan derivative 56 in 80% yield. ... 

Cook and colleagues improved Mori-Ban reaction and developed the general approach to the total synthesis of 9-methoxy-substituted indole alkaloids/ The intermediate 57 was successfully synthesized via the modified method and provided a key material 58 for preparations of mitragynine, as well as 9-methoxygeissoschizol and 9-methoxy- b-methylgeissoschizol. 

Employing Jefferey s ligandless conditions, Larock and Babu (87TL5291) synthesized quinolines and other nitrogen-containing heterocycles via the intramolcular Heck reaction strategy as exemplified by reaction 144 145. This reaction is similar to the Mori-Ban indole... 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success of nickel-catalyzed indole synthesis from 2-chloro-fV-allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [122]. Compound 102, easily prepared from 2-bromo-lV-acetylaniline and methyl bromocrotonate, was adopted as the cyclization precursor. Treatment of 102 with Pd(OAc)2 (2 mol%), Ph3P (4 mol%) and NaHCQ3... 

The application of Heck cyclizations to the synthesis of indoles, indolines, and oxindoles was discovered independently by Mori-Ban s [296-298], and Heck s groups [299]. These investigators found that Pd can effect the cyclization of o-halo-lV-allylanilines to indoles under Heck conditions [300], The cyclization of o-halo-/V-allylanilines to indojes is a general and efficient methodology, especially with the Larock improvements where he cyclized o-halo-W-allylanilines and o-halo-N-acryloylanilides into indoles and oxindoles [301]. For example, the conversion of 279 to 280 can be performed at lower temperature, shorter reaction time, and with less catalyst to give 3-methylindole (280) in 97% yield. Larock s improved conditions, which have been widely adopted, are catalytic (2%) Pd(OAc)2, n-Bu4NCl, DMF, base (usually... 

The incredibly powerful and versatile Heck coupling reaction has found enormous utility in the indole ring synthesis and in the elaboration of this important heterocycle. Due to the enormity of this topic, the section is divided into Heck reactions of indoles, the synthesis of the indole ring as developed by Hegedus, Mori-Ban, and Heck, and the Larock indole ring synthesis. 

While the intramolecular Heck reaction has been widely used to synthesize indoles and benzofurans, not many applications have been found in the preparation of benzothiophenes because of the thiophilicity of the Pd(ll) species. Pleixats and coworkers treated iodophenylsulfide 276, obtained from o-iodoaniline and crotyl bromide in two steps, with Pd(Ph,P)4 and EtjN in refluxing acetonitrile to form the intramolecular Heck cychzation product 277 [175]. The mechanism is akin to that of the Mori-Ban indole synthesis (see page 27). In another case, the intramolecular Heck cyclization of enamidone 278 with a pendant thienylbromide moiety furnished the 6-endo-trig product, indolizine 279, in 63% yield, along with the debrominated enamidone 280 in 37% yield [179]. 

Palladium-Catalyzed Cross-Coupling Reactions 2.1 Mori-Ban Indole Synthesis... 

The Mori-Ban indole synthesis [5-12], the intramolecular version of the Heck reaction as applied to the synthesis of indoles, is not a cross-coupling reaction per se, but it is covered here due to its importance in assembling the indole core. 

The Mori-Ban indole synthesis is referred to the intramolecular version of the Heck reaction applied to synthesis indoles. The cyclization of o-halo-A-allylanilines to indoles is a general and efficient methodology. For... 

Thankfully, some of the conventional and modem indole synthesis methods do apply to make azaindoles. They include the Larock reaction, Mori-Ban indole synthesis, Bartoli indole synthesis, Batcho-Leimgmber indole synthesis, and Cadogan-Sundberg indole synthesis. 

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