Showing papers on "Annulation published in 2007"

Direct synthesis of pyridine derivatives.

Abstract: We describe a single-step conversion of various N-vinyl and N-aryl amides to the corresponding pyridine and quinoline derivatives, respectively. The process involves amide activation with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine followed by π-nucleophile addition to the activated intermediate and annulation. Compatibility of this chemistry with sensitive N-vinyl amides, epimerizable substrates, and a variety of functional groups is noteworthy.

Phosphine-catalyzed [4 + 2] annulation: synthesis of cyclohexenes.

Abstract: Phosphine-catalyzed [4 + 2] annulations of α-alkylallenoates with activated olefins allow the efficient syntheses of cyclohexenes. Hexamethylphosphorous triamide (HMPT)-catalyzed [4 + 2] annulations of α-alkylallenoates with arylidenemalononitriles provided highly functionalized 5,5-dicyano-4,6-disubstituted cyclohex-1-enecarboxylates in excellent yields (77−98%) and moderate to high diastereoselectivities (1:2−12:1). Remarkably, the corresponding triarylphosphine-catalyzed [4 + 2] annulations of α-methylallenoate with arylidenemalononitriles manifested a polarity inversion of the 1,4-dipole synthon, providing 4,4-dicyano-5-substituted cyclohex-1-enecarboxylates in excellent yields (80−93%). The polarity inversion of α-alkylallenoates from one 1,4-dipole to another under phosphine catalysis presumably resulted from a change in the balance of the equilibrium between the phosphonium dienolate and the vinylogous phosphonium ylide intermediate.

Enantioselective, cyclopentene-forming annulations via NHC-catalyzed benzoin-oxy-cope reactions.

Abstract: Chiral N-heterocyclic carbene catalysts generated from triazolium salts promote the cyclopentene-forming annulation of α,β-unsaturated aldehydes and 4-oxoenoates with excellent levels of enantioinduction and preference for the cis-1,3,4-trisubstituted cyclopentene diastereomer. Although the observed products could arise by conjugate additions of catalytically generated homoenolates, our mechanistic and stereochemical investigations strongly support a novel reaction manifold featuring an intermolecular crossed-benzoin reaction and an NHC-catalyzed oxy-Cope rearrangement.

Rh‐Catalyzed Transannulation of Pyridotriazoles with Alkynes and Nitriles

Abstract: Transition-metal-catalyzed annulations are widely used in the synthesis of heterocyclic compounds.[1] One of the most efficient methods for the construction of five-membered oxygen-containing heterocycles involves the annulation of diazocarbonyl compounds with alkynes and nitriles. Thus, Davies et al.[2] and Padwa et al.[3] have employed this method[4] for the synthesis of furans (X = CH), and Helquist et al.[5] for the preparation of oxazoles (X = N) [Eq. (1)]. In contrast, analogous transformations of α-imino diazo compounds, which may lead to the formation of pyrrole and imidazole rings, are unknown. Herein we report an efficient, direct, Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles that leads to indolizines (X= CH) and imidazopyridines (X = N), respectively [Eq. (2)]. (1) (2) It has been shown that 2-pyridyl diazo compounds 1[6] transform into their cyclic triazole form 2[7] upon storage [Eq. (3)], and it is also known that some of these cyclic triazoles can still undergo transformations that are characteristic of diazo compounds.[8] This phenomenon has been attributed to the closed/open form equilibrium of N-fused triazoles in solution,[9] which can produce trace to significant amounts of 1. The position of this equilibrium depends on the temperature and the substitution pattern of the triazole.[9b] Thus, introduction of a halogen substituent at C7 (R1 = Cl) shifts the equilibrium to the left, which has been explained in terms of nonbonding repulsion between the lone pair of the halogen and that of the nitrogen in the peri position.[10] (3) To evaluate the feasibility of using triazoles as precursors of Rh carbenoids we investigated the reaction of triazoles 3a and 3b with triethylsilane in the presence of a catalytic amount of rhodium(II) acetate, which is a method developed by Doyle and coworkers[11] for the efficient trapping of Rh carbenoids [Eq. (4)]. Not surprisingly, pyridotriazoles 3a and 3b behave differently under these reaction conditions. Thus, while the 7-H derivative 3a remains unaffected, the 7-chloro-substituted compound 3b is smoothly converted into 4, which is the product of carbenoid insertion into the Si–H bond. These experiments clearly indicate that 7-halo-substituted pyridotriazoles can indeed serve as convenient precursors of Rh carbenoids. (4) Next, to test our hypothesis regarding the annulation of α-imino diazo compounds with alkynes to form a pyrrole ring, we treated triazole 3b with phenylacetylene in the presence of rhodium(II) acetate. This reaction proceeded smoothly to produce a mixture of cyclopropene 5 and indolizine 6a with yields of 68% and 28% of isolated product, respectively [Eq. (5)]. Surprisingly, cyclopropene 5 does not undergo further isomerization into indolizine 6a under these reaction conditions.[12] The ratio of these products remained constant throughout the course of the reaction, thereby suggesting an independent path for the formation of 6a. (5) We found, however, that the selectivity of the transannulation (6 over 5) could be dramatically improved by using rhodium(II) heptafluorobutyrate as catalyst.[13] Thus, transannulation of 3b with a series of aryl and alkenyl alkynes[14] proceeded highly chemoselectively (90:10 to 95:5 vs. cyclopropene) to produce indolizines 6[15] in good yields (Table 1). Electron-rich, electron-deficient, and sterically hindered aryl alkynes were nearly equally effective in this reaction. Table 1 Rhodium(II)-catalyzed transannulation of triazole 3b with alkynes. Inspired by the successful formation of an N-fused pyrrole ring from the transannulation of triazoles with alkynes, we examined the formation of an N-fused imidazole ring in the reaction of 3 with nitriles and found that pyridotriazoles 3 react smoothly with a variety of aryl, alkyl, and alkenyl nitriles in the presence of Rh2(OAc)4 (1 mol%) in toluene at 60°C (Table 2) to afford N-fused imidazopyridines 7 in reasonable to high yields. Table 2 Rhodium(II)-catalyzed transannulation of triazoles with nitriles. Both 3-carbomethoxy-(Table 2, entries 1–9) and 3-aryl-(Table 2, entry 10) pyridotriazoles are equally efficient in this reaction. Moreover, 7-bromo-(Table 2, entry 11) and even 7-methoxy-substituted (Table 2, entry 12) triazoles proved to be good substrates for this transannulation reaction. We propose the following mechanism for this novel Rh-catalyzed transformation (Scheme 1). First, pyridotriazole 3 undergoes closed/open form equilibrium[9] to produce small amounts of diazo compound 1 which, upon reaction with rhodium(II) carboxylate, generates the Rh-carbenoid species I. A direct nucleophilic attack[18] of alkyne or nitrile 8 on species I produces ylide species II, according to path A, which then cyclizes to form 6 or 7 via cyclic zwitterion III. Alternatively (path B), [2+2] cycloaddition of I and 8 leads to metallacyclobutene IV, which can also be formed by cyclization of II.[19] Rhodacycle IV then undergoes metathesis to produce Rh carbenoid V which, upon 6π-electrocyclization and subsequent reductive elimination, furnishes product 6 or 7. [2+1] Cycloaddition of I with 8 (path C) accounts for the formation of cyclopropene 5 in the presence of rhodium(II) acetate [see Eq. (5)]. As discussed above, 5 does not transform into heterocycle 6 under these reaction conditions.[12] Scheme 1 Plausible mechanisms for the Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles. Y=N, CR″. In summary, we have developed an efficient Rh-catalyzed transannulation of pyridotriazoles for the formation of pyrrolo- and imidazopyridines, which are important fused heterocyclic scaffolds.[20] We have also demonstrated that some of these pyridotriazoles can serve as stable[13] and convenient[21] precursors of Rh carbenoids.

Synthesis and properties of 2,3,6,7-tetraarylbenzo[1,2-b:4,5-b']difurans as hole-transporting material.

Abstract: A new zinc-based annulation method produced regioselectively a variety of 2,3,6,7-tetraarylbenzo[1,2-b:4,5-b‘]difurans in good yields. The organic electroluminescent devices using these tetraarylbe...

Synthesis and cellular profiling of diverse organosilicon small molecules.

Abstract: Small-molecule synthesis coupled with cellular profiling using multidimensional screening can be used to assess the impact of varying stereochemical and appendage contexts on biological activity. In this communication, we describe the synthesis and cellular profiling of chiral organosilicon small molecules derived from a crotylsilane annulation pathway. We considered that incorporating a main-group element, such as silicon, within the chiral environment of a more complex product could provide new structures where the distinctive chemical properties of silicon may contribute to new biological activity. The annulation of various indole-2,3-dione (isatin) reagents with functionalized crotylsilanes provides efficient access to spiro-oxindole structures for biological evaluation. The modular placement of aryl iodide functional groups in the isatin component can be used in appending processes for further substitution, such as conversion of the aryl iodide to various amido functionalities using the Buchwald amid...

C-2/c-3 annulation and C-2 alkylation of indoles with 2-alkoxycyclopropanoate esters.

Abstract: The annulation reaction between various indoles and 2-alkoxycyclopropanoate esters is reported. Both high efficiency and complete stereochemical control were observed in some cases with this annulation process. A single stereocenter on the cyclopropane controls the diastereoselective formation of up to four new stereocenters. A different reaction course was observed with 3-substituted indole substrates, and an intervening C-3 to C-2-migration process arose that gives synthetically useful C-2 alkylation indole products.

Phosphine-catalyzed intramolecular formal [3+2] cycloaddition for highly diastereoselective synthesis of bicyclo[n.3.0] compounds.

Abstract: Ylides have been widely applied in constructing small-ring compounds such as epoxides, cyclopropanes, and aziridines. Recently, several ylide cyclizations that go beyond the formation of three-membered rings have also been developed. Lu and co-workers demonstrated in a number of elegant studies that phosphines are good catalysts for the construction of cyclopentenes. Krische and co-workers developed the first intramolecular variant of the cycloaddition. Catalytic asymmetric [3+2] cycloadditions have been reported by both Zhang and Fu, with their respective coworkers. Recently, Aggarwal and co-workers documented an elegant protocol for the asymmetric synthesis of epoxideand aziridine-fused heterocycles through a sulfur ylide route. In a previous study on ylide chemistry, we reported a tandem ylide Michael addition–elimination–substitution reaction for the controllable synthesis of 2H-chromenes 2a and 4H-chromenes 2a’ (Scheme 1). To further extend the reaction scope, 3a was synthesized and subjected to the reaction. However, the desired compound 4a’was obtained in only 15% yield under the same conditions. To improve the yield, other potential catalysts such as PPh3 and 1,4diazabicyclo[2.2.2]octane (DABCO) were tested instead of THT. When triphenylphosphine was used, the bicyclic compound 4a was, unexpectedly, isolated as the sole product in 30% yield with excellent diastereoselectivity (Scheme 1). Herein, we wish to report the preliminary results of this cyclization. Further studies showed that the desired product was not observed in the absence of PPh3. In the presence of PPh3 (20 mol%) with Na2CO3 as a base, bromide 3b afforded the corresponding benzobicyclo[4.3.0] compounds (4b/4b’) in 95% yield with excellent diastereoselectivity (entry 1, Table 1). To study the generality of the current reaction,

Copper(I)-Mediated and Microwave-Assisted Caryl−Ocarboxylic Coupling: Synthesis of Benzopyranones and Isolamellarin Alkaloids

Abstract: A simple and highly effective C−Ocarboxylic coupling reaction catalyzed by copper(I) salts has been developed to synthesize benzopyranones. The reaction of various 2-halobiarylcarboxylic acids was examined using microwave irradiation. A new class of pyrroloisoquinoline alkaloid, isolamellarin, was synthesized based on the annulation of dihydroisoquinoline with aryl pyruvates under basic condition and Cu-mediated/MW-assisted C−Ocarboxylic lactonization.

Highly efficient route to fused polycyclic aromatics via palladium-catalyzed aryne annulation by aryl halides.

Abstract: Polycyclic aromatic and heteroaromatic hydrocarbons have been synthesized in high yield by two different processes involving the Pd-catalyzed annulation of arynes. The first process involves a Pd-catalyzed annulation of arynes by 2-halobiaryls and related vinylic halides. The second process utilizes a Pd-catalyzed double annulation of arynes by simple aryl halides. Both processes appear to involve the catalytic, stepwise coupling of two very reactive substrates, an aryne and an organopalladium species, to generate excellent yields of cross-coupled products.

Rapid Access to Polyprenylated Phloroglucinols via Alkylative Dearomatization−Annulation: Total Synthesis of (±)-Clusianone1

Abstract: A concise approach to the bicyclo[3.3.1]nonane framework of the polyprenylated phloroglucinol natural products utilizing a tandem alkylative dearomatization−annulation sequence is described. Syntheses of (±)-clusianone and a complex adamantane framework have been achieved using the developed methodology.

Friedländer Synthesis of Quinolines Using a Lewis Acid‐Surfactant‐Combined Catalyst in Water

Abstract: In water, Friedlander annulation using Lewis acid-surfactant-combined catalyst provides a mild and efficient route for the synthesis of quinolines. Employing a catalytic amount of scandium tris(dodecyl sulfate) [Sc(O3SOC12H25)3], various polysubstituted and polycyclic quinolines were obtained in exellent yields.

One‐Pot Three‐Component Catalytic Synthesis of Fully Substituted Pyrroles from Readily Available Propargylic Alcohols, 1,3‐Dicarbonyl Compounds and Primary Amines

Abstract: A simple and highly efficient method for the preparation of fully substituted pyrroles, from readily accessible secondary propargylic alcohols, 1,3-dicarbonyl compounds and primary amines, has been developed. The one-pot multicomponent reaction, which is catalysed by the system [Ru(eta(3)-2-C(3)H(4)Me)(CO)(dppf)][SbF(6)]/CF(3)CO(2)H (dppf: 1,1'-bis(diphenylphosphanyl)ferrocene), involves initial propargylation of the 1,3-dicarbonyl compound promoted by CF(3)CO(2)H and subsequent condensation between the resulting gamma-keto alkyne and the primary amine to afford a propargylated beta-enamino ester or ketone, which undergoes a ruthenium-catalysed 5-exo-dig annulation to form the final pyrrole.

Silica supported perchloric acid: A mild and highly efficient heterogeneous catalyst for the synthesis of poly-substituted quinolines via Friedländer hetero-annulation ☆

Abstract: Silica supported perchloric acid (HClO4-SiO2) is found to be a heterogeneous recyclable catalyst for the rapid and efficient synthesis of various poly-substituted quinolines in the Friedlander condensation of 2-aminoarylketones with carbonyl compounds and β-keto esters at ambient temperature. The catalyst can be reused at least three times.

Formal synthesis of (-)-aphanorphine using sequential photomediated radical reactions of dithiocarbamates

Abstract: Aphanorphine (1), an alkaloid isolated from the freshwater blue-green alga Aphanizomenon flos-aquae, has attracted considerable attention from the synthetic community owing to its structural similarity to natural and non-natural analgesics such as morphine, eptazocine, and pentazocine (Scheme 1). Approaches to aphanorphine developed to date have all relied on the formation of the B or C ring to complete theC-norbenzomorphan skeleton, typically exploiting the rigidity of the bridged tricyclic 3-benzazepine structure to set the second stereocenter from a preexisting quaternary benzylic stereocenter at C1, or from an abranched amine at C4. In this communication we present a complementary strategy for the synthesis of aphanorphine which is characterized by the late-stage incorporation of the aromatic A ring, and formation of the pyrrolidine C ring through a novel carbon–carbon bondforming reaction. We have recently reported a new method for the generation of carbamoyl (aminoacyl) radicals from dithiocarbamate precursors, and their subsequent intramolecular addition—dithiocarbamate group-transfer reactions with alkenes. Application of this methodology to the synthesis of the core 6-azabicyclo[3.2.1]octane ring system of aphanorphine was envisaged based upon a regioselective 5-exo-trig cyclization of carbamoyl radical 2 followed by dithiocarbamate group transfer to give the functionalized bicyclic lactam 3 (Scheme 1). It was further envisaged that the dithiocarbamate group in 3 would provide a handle for phenol annulation. Critical to the success of such an approach is the ability of carbamoyl radicals generated from dithiocarbamate precursors to undergo potentially difficult cyclizations onto unactivated alkenes. 4] Previous work by Quirante, Bonjoch, et al. had shown that a-amino radicals undergo analogous cyclizations onto alkenes carrying electron-withdrawing groups at C9a (aphanorphine numbering); however, unactivated alkenes did not undergo cyclization. The effect of a further alkene substituent at C1, which may also disfavor 5-exo-trig cyclization, was not evaluated. An asymmetric synthesis of the requisite secondary cyclohexenylamine is outlined in Scheme 2 and relies on Ellman6s sulfinamide auxiliary to set the amino-substituted stereocenter destined to be C4 of aphanorphine. 8] Condensation of enantiomerically pure (R)-tert-butanesulfinamide (5) with commercially available cis-4-heptenal gave the expected (E)-sulfinimine 6 (Scheme 2). Addition of 2methylallylmagnesium chloride gave rise to sulfinamide 7 in excellent yield as a 83:17 mixture of diastereoisomers. The configuration of the major stereoisomer 7 was predicted to be R on the basis of the Ellman model and was ultimately proven through a formal synthesis of ( )-aphanorphine. Separation of the two diastereomers could not be achieved at this stage, and so the mixture was carried through the following steps. Following N-methylation of 7, 1,7-diene 8 was subjected to ring-closing metathesis using the Grubbs second-generation catalyst, which furnished the trisubstituted alkene 9 in excellent yield. Finally removal of the sulfinyl auxiliary under acidic conditions gave the hydrochloride salt 10. At this stage, a single recrystallization of 10 gave enantiomerically pure material. Scheme 1. Analgesics structurally related to aphanorphine and a retrosynthesis of ( )-aphanorphine (1).