Heteroannulation method

The Bohlmann-Rahtz synthesis of trisubstituted pyridines from /3-aminocrotonates and an ethynyl ketone has found application in the preparation of a variety of heterocycles based on the substituted pyridine motif. Bagley and coworkers have developed a microwave-assisted modification of this one-pot heteroannulation method that is best conducted in dimethyl sulfoxide at 170 °C for 20 min, providing the desired pyridines in 24—94% yield (Scheme 6.227) [406, 407]. Typically, 2 equivalents of the /3-aminocrotonates were employed. 

On the other hand, the Fischer carbene complex 444 was converted to the pyrrole 445 upon treatment with cinnamaldehyde, illustrating an alternative heteroannulation method (Equation 124) <2006CC2271>. 

Ohler, E., A new heteroannulation method to 2-cyclohexenone, mediated hy phosphonate auxiliaries. Synthesis of 4,5,6,7-tetrahydrohenzothiazole derivatives, Monatsh. Chem., 124, 763, 1993. 

Tandem Enlargement of the Six-Membered Ring in Heteroannulated Tetrahydropyridines under the Action of Activated Alkynes - A General Method for the Synthesis of Condensed Azocines 116... 

The chemistry of heteroannulated azocines has not been explored in detail owing to the lack of efficient methods for their synthesis. The exception is azocinoindoles, which have been investigated extensively due to the host of alkaloids with an azocinoindole fragment in their structure. 

TANDEM ENLARGEMENT OF THE SIX-MEMBERED RING IN HETEROANNULATED TETRAHYDROPYRIDINES UNDER THE ACTION OF ACTIVATED ALKYNES - A GENERAL METHOD FOR THE SYNTHESIS OF CONDENSED AZOCINES... 

Mahanty, f. S. De, M. Kundu, N. G. Palladium-catalyzed heteroannulation of vinylic compounds a highly convenient method for the synthesis of N-aryl-l,2,3,4-tetrahy-dro-l-oxoisoquinoline-3-carboxylic adds. 

A very neat method for the synthesis of furanoeremophilanes has been devised which incorporates a so-called bis-heteroannulation process.318 This is achieved by an intramolecular Diels-Alder reaction between an oxazole and an acetylenic grouping and is nicely demonstrated by the synthesis of ligularone (711) and petasalbine (712) (Scheme 67).319 A number of straightforward syntheses of... 

The most popular Pd-catalyzed method for the production of furans and benzofurans involves reactions of alkynols. Acyclic alkynols are converted into furans, while benzene substituted alkynols are transformed into benzofurans. The use of this strategy is widespread for the synthesis of benzofurans however, it is occasionally used for the syntheses of furans. For example, intramolecular alkoxylation of alkyne 189 proceeds via an alkenylpalladium complex and subsequent carbonylation to form furan 190 [156, 157]. In addition, 3 -hydroxyalkyl-benzo[/)J furans were prepared by Bishop et al. via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis [158]. In a related series of experiments, Qing demonstrated that alkynes 191 could be efficiently converted into furans 192 [159]. 

Heteroannulation of alkynes is an efficient method for the preparation of complex heterocycles. Preparation of the preannulation substrate is often accomplished via Sonogashira coupling. Indeed, this protocol has been utilized effectively for the preparation of quinazolinones [107] and benzothioazoles [108]. The reactions have been carried out on substituted iodopyrimidines to provide the desired complex heterocycles. 

Allenylsilanes combine with electron-deficient alkenes or alkynes regio- and stereo-selectively to afford hi ly substituted and functionalized cyclopentenes (Scheme 10). The [3 -i- 2] annulation reaction has been used for heteroannulation approaches to five-membered oxygen and nitrogen heterocycles. One particularly useful application of the method is that readily available tropylium salts can function as allenophiles in a general [3 + 2] annulation route to substituted azulenes (equation 3). ... 

Dieck reported preparation of the tetrahydrocarbazole 337 by heteroannulation of o-iodoaniline with 1,3-cyclohexadiene [137], As a recent example, heteroannulation of the o-iodoaniline derivative 338 with the conjugate dienyl sulfone 339 afforded the vinylogous 2-sulfonylindoline 340, which was converted to the indole derivative 341 by oxidative dehydrogenation [138]. Pd-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumain 342 offers a synthetic method for dihydro-furocoumarins. The dihydrofurocoumarin 343 was obtained by the reaction of 342 with 1-phenylbutadiene in 80% yield. After optimization, the uses of Pd(OAc)2,... 

Intramolecular versions and domino reactions involving appropriately functionalized aryl halides and alkynes offer useful synthetic methods for a variety of heterocycles and carbocycles. Few other methods can compete with these Pd-catalyzed cyclizations in versatility. Numerous reports and a number of excellent reviews covering the carbo- and heteroannulations have been pubhshed [10]. In order to aid understanding of this somewhat complex chemistry, the cyclizations are classified in to three types (Scheme 3.8). 

Internal Alkynes. Several applications of the Larock synthesis of indoles have been published where heterocycles are used as substrate. f " In the Larock method for indol construction, Pd-catalyzed heteroannulation of internal alkynes using ort/to-iodoanilines are used. Similarly, Pd-catalyzed heteroannulation of internal alkynes using ortho-amino-iodopyridine substrates produces azaindoles (Scheme 103). The method provides a convenient access to a structurally diverse range of 5-, 6-, and 7-azaindoles, 304, 305, and... 

The volume commences with an account of The Larock Reaction in the Synthesis of Heterocyclic Compounds by Mercedes Alvarez and colleagues at the University of Barcelona, Barcelona, Spain. This palladium-catalyzed heteroannulation of 2-iodoanihnes and substituted alkynes is now often the method of choice for the preparation of many heterocyclic derivatives since it can provide both excellent regioselectivity and high yields. This is followed by a chapter entided HeHcal Phosphorus Derivatives Synthesis and Applications by David Virieux and colleagues at the Ecole Nationale Superieure de Chimie de MontpeUier, Montpellier, France. This review surveys helical structures based on organophosphorus derivatives and describes the synthesis of heterocycHc derivatives and their applications, particularly the specificity introduced by the presence of phosphorus. 

Since Watanabe s synthesis of 4(3H)-quinazolinones in 1993 via transition-metal catalyzed reductive N-heterocychzation [ 181 ], several catalytic methods for quinazoline synthesis have been developed [182-186]. For example, palladium-catalyzed cyclocarbonylations of halides with appropriate reactants provided regioselective synthesis of 4(3H)-quinazolinone derivatives [182] and indoloquinazolines [184]. Also selenium-catalyzed reductive N-heterocyclization to quinazolinones has been developed by Sonoda et al. [183]. Copper-catalyzed heteroannulation with alkynes has been developed as highly region- and stereoselective route to 2-(2-arylvinyl)-l,2,3,4-tetrahydroquinazolin-4-ones 64 by Kimdu et al. [ 185] (Scheme 12). Recently, condensation of anthranylamide with various aldehydes to 4-quinazotinones has been found to give excellent yields in the presence of cupric chloride [186]. 

Larock heteroannulation reaction was further extended and an intramolecular Larock indole synthesis of 2-chloroanilines bearing tethered acetylenes 106 was developed for the elaboration of a variety of polycyclic indole skeletons 107, for example, in 108-112. This intramolecular indolization method unveiled an unusual >sy -anidopalladation pathway of a tethered alkyne. The major side product is the dechlorinated starting material as a result of a reductive process. 

Hosseini-Sarvaria (2011b) reported the synthesis of quinoline derivatives (60) by the condensation of 2-aminoaryl ketones (58) with methylene carbonyl compounds (59) catalyzed by nanoflake ZnO as a reusable heterogeneous catalyst under solvent-free conditions involving Friedlander heteroannulation (Scheme 9.14). The employed catalyst was synthesized from zinc acetate dihydrate and urea. It constitutes a simple, environmentally benign, and cost-effective method for the synthesis of quinolines. Tamaddon and Moradi (2013) reported the application of nano-ZnO as a reusable heterogeneous catalyst for the synthesis of Biginelli dihydropyrimidines... 

The heteroannulation catalyzed by silver salts of alkynols or alkynoic acids is considerably enhanced by the presence of a propargylic C-O bond. This method allows for rapid access to highly functionalized heterocycles, such as a-methylene oxolanes or oxanes and y-methylene pentanolactones (Dalla and Pale 1999). 

Ring Closure Reactions Palladium(II) complexes (PdCl2L2, L=P, CN), covalently immobilized onto SBA-15 silica by a postsynthetic method, were used as catalysts in the Larock synthesis of indoles [86]. The reaction consisted of the heteroannulation of 2-iodoaniline and 2-bromoaniline with triethyl(phenylethynyl)silane showing high activities and selectivities to 3-phenyl-lH-indole 26 (Scheme 17). 

Since it was first reported in 1991, the Larock indole synthesis has become one of the most attractive and practical methods for the preparation of 2,3-disubstituted indoles (Scheme 24.46, disconnection D-1). In the seminal publication, Larock and Yum described the palladium-catalyzed heteroannulation of internal alkynes such as 71 with o-iodoanilines to generate substituted indoles such as 73 in excellent yield (Scheme 24.47) [149]. Unsymmetrical alkynes could be regioselectively incorporated, with the more sterically hindered group of the alkyne resulting at the 2-position of the indole. Trimethylsilyl-substituted alkynes were found to be particularly effective, affording the corresponding 2-silylated products such as 73 in exemplary yields. 

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