Cyclization stoichiometric

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

TL2403). Thus, or /io-cyclopalladation of acetanilide 138 gave organo-palladium reagent 139. The or /io-vinylation of 139 afforded enone 140, which was then cyclized to quinoline 141 under acidic conditions. Notice this reaction requires stoichiometric amounts of Pd(OAc)2. 

Larock has developed a new catalyst system for the Pd-catalyzed cyclization of olefinic tosylamides. Whereas typical conditions require either stoichiometric amounts of Pd(II) salts or catalytic amounts of Pd(II) in the presence of benzoquinone as a reoxidant, the new catalyst system utilizes catalytic Pd(OAc)2 under an atmosphere of O2 in DMSO with no additional reoxidant <96JOC3584>. Although o-vinylic tosylamides 76 can be cyclized to Af-tosylindoles 77 using this catalyst system, PdCla/benzoquinone is more effective for such cyclizations. Interestingly, in the case of o-allylic tosylanilides, the cyclization can be modulated to afford either dihydroindole or dihydroquinoline products. In a related approach involving a common 7i-aUyl Pd-intermediate, 2-iodoanilines were coupled with vinylic cyclopropanes or cyclobutanes in the presence of a Pd catalyst to afford dihydroindoles <96T2743>. 

The synthetic route represents a classical ladder polymer synthesis a suitably substituted, open-chain precursor polymer is cyclized to a band structure in a polymer-analogous fashion. The first step here, formation of the polymeric, open-chain precursor structure, is AA-type coupling of a 2,5-dibromo-1,4-dibenzoyl-benzene derivative, by a Yamamoto-type aryl-aryl coupling. The reagent employed for dehalogenation, the nickel(0)/l,5-cyclooctadiene complex (Ni(COD)2), was used in stoichiometric amounts with co-reagents (2,2 -bipyridine and 1,5-cyclooctadiene), in dimethylacetamide or dimethylformamide as solvent. 

In 2007, Womack et al. published the conversion of 2-aUcylcinnamyldehydes to 2-aLkylindanones via a catalytic intramolecular Friedel-Crafts reaction. In the presence of 5-10 mol% FeCls different in situ generated ( )-2-alkylcinnamaldehydes-derived dimethyl acetals cyclized to l-methoxy-2-aIkyl-7//-indenes in good to high yields (Scheme 6) [22]. The transformation corresponds to a formal intramolecular Friedel-Crafts acylation which is achieved with catalytic quantities of Lewis acid. This result is in strong contrast to traditional Friedel-Crafts acylations which require stoichiometric amounts of Lewis acid. 

Whereas the Prins-type cyclizations reported in this and the preceeding chapter were performed using stoichiometric amounts of Fe salts as Lewis acids, a breakthrough in the field of catalysis was reported in 2009 when the first iron-catalyzed Prins- and aza-Prins cyclization was reported. The catalytic system, which is obtained by combining catalytic amounts of an iron salt with trimethylsilyl halides as a halide source, is widely applicable and promotes the construction of substituted six-membered oxa- and aza-cycles (Scheme 33) [44]. 

The catalytic cycle, which is supported by stoichiometric and labeling experiments, is shown in Scheme 38. Loss of 2 equiv. of N2 from 5 affords the active species a. Reaction of a with the 1,6-enyne gives the metallacycle complex b. Subsequently, b reacts with H2 to give the alkenyl hydride complex c or the alkyl hydride complex d. Finally, reductive elimination constructs the C-H bond in the cyclization product and regenerates intermediate a to complete the catalytic cycle. 

Hegedus et al. have thoroughly studied the homogeneous hydroamination of olefins in the presence of transition metal complexes. However, most of these reactions are either promoted or assisted, i.e. are stoichiometric reactions of an amine with a coordinated alkene [98-101] or, if catalytic, give rise to the oxidative hydroamination products, as for example in the cyclization of o-allylanilines to 2-alkylindoles [102, 103], i.e. are relevant to Wacker-type chemistry [104]. 

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

Although the titanium-based methods are typically stoichiometric, catalytic turnover was achieved in one isolated example with trialkoxysilane reducing agents with titanocene catalysts (Scheme 28) [74], This example (as part of a broader study of enal cyclizations [74,75]) was indeed the first process to demonstrate catalysis in a silane-based aldehyde/alkyne reductive coupling and provided important guidance in the development of the nickel-catalyzed processes that are generally more tolerant of functionality and broader in scope. 

Ziegler and Saprong described a stoichiometric cyclization onto an alkyne for the synthesis of the carbocyclic core of entecavir from diacetone glucose. Inverse addition was required to minimize deoxygenation. The highly diastereoselective reaction is tolerant to silylethers [101]. 

Finally, Roy and his group reported the first examples of stoichiometric 8-endo cyclizations for the preparation of aromatic ethers [126]. 

It should be noted that the Grob fragmentation reaction and the reductive cyclization (homoallylation) discussed in this section involve the same oxanickellacyclopentane 66 as a common intermediate (Scheme 17). The reversibility of these C - C bond cleavage reaction and C - C bond formation reaction is also supported by the isolation and characterization (by X-ray analysis) of an oxanickellacyclopentane-like 66 (without a tether), which is prepared from a stoichiometric amount of Ni(cod)2, a diene, an aldehyde, and a monodentate phosphine ligand [41]. 

All of the reactions described above use anionic alkyl metal complexes as stoichiometric reductants. Cationic zirconium catalyst 58 was shown to re-ductively cyclize a variety of 1,5-dienes to give both mono- and bicyclic silane products when H3SiPh was employed as the stoichiometric reductant (Scheme 10) [32]. Poor yields due to competing polymerization processes were observed when less substituted dienes were employed. It is likely that... 

Other metal hydrogen donors can be used in place of silanes. For instance, cyclization of substituted 1,5- and 1,6-dienes in the presence of Cp 2SmTHF, using a borohydride as the stoichiometric reductant, has been reported other... 

Cationic palladium complex 121 reductively coupled enynes (Eq. 20) using trichlorosilane as the stoichiometric reductant [71]. This combination of catalyst and silane afforded silylated methylenecyclopentanes such as 122 in good yield from enynes such as 123. Attempts to develop an enantioselective version of this reaction were not successful [71]. When enediyne 124 was cyclized in the presence of trichlorosilane, the reaction favored enyne cycli-zation 126 by a 3 1 ratio over diyne cyclization to 125 (Eq. 21). In contrast, when the more electron-rich dichloromethylsilane was used as the reductant, diyne cyclization product 125 was preferred in a ratio of 4 1 [71]. Selectivities of up to 10 1 for enyne cyclization were observed, depending on the substrate employed [72],... 

Rhodium and rhodium-cobalt based catalysts using silanes as the stoichiometric reductant were initially reported in 1992 to reductively couple enyne substrate (Eq. 30) [90,91]. Further investigation showed this reaction to be an effective method for the cyclization of enyne substrates 129 to... 

A few stoichiometric reactions that formed aromatic carbon nitrogen bonds in the presence of stoichiometric amounts of Pd(PPh3)4 had been reported by Boger and co-workers (Equation (3)).24-26 In the absence of base, the palladium(0) was apparently not regenerated. Pd(PPh3)4 failed to catalyze these reactions when used in a 1 mol.% quantity, but it did induce cyclization in good yield when it was used in stoichiometric amounts 24-26... 

Dialkylindolines and 1,3-dialkylindoles are formed in poor yield (<10%) from the reaction of ethyl- or phenymagnesium bromide with 2-chloro-N-methyl-N-allylaniline in the presence of catalytic quantities of (bistriphenylphosphine)nickel dichloride.72 In a modification of this procedure, the allyl derivatives can be converted by stoichiometric amounts of tetrakis(triphenylphosphine)nickel into 1,3-dialkylindoles in moderate yield72 (Scheme 43) an initial process of oxidative addition and ensuing cyclization of arylnickel intermediates is thought to occur. In contrast to the nickel system,72 it has proved possible to achieve the indole synthesis by means of catalytic quantities of palladium acetate.73 It is preferable to use... 

Silyl enol ethers of alkenyl methyl ketones can be efficiently cyclized to cyclopentenones and cyclohexenones by treating them with stoichiometric amounts of palladium acetate244 an example indicating the elaboration of this approach to the synthesis of a reduced benzoxepinone derivative, and the suggested244 mechanism of the reaction, are depicted in Scheme 174. 

A series of benzo[fc]benzo[2,3-cfjthiophen-6,9-diones 12 has been prepared in modest yields by palladium mediated cyclization of the precursors 13. However, the necessity to use stoichiometric amounts of the palladium source precludes cost effective preparation of the targets. The required substrates 13 may be constructed by palladium catalyzed reactions between the appropriate phenols with 2,3-dimethylbenzoquinone <06SC3319>. 

Treatment of p-methoxyphenylethylamine with a stoichiometric amount of Cu(OAc)2 and in the presence of a catalytic amount of Pd(OAc)2 produced a 3,4-diarylpyrrole via an unexpected three-component cyclization process <06JACS12046>. Another three-... 

For example, a dienyl aldehyde reductively cyclizes in the presence of an Ni(0)/PPh3 complex and triethylsilane to give homoallylic cyclopropentanol with high regio- and stereoselectivities, while bishomoallylic cyclopropentanol is obtained as major product under the conditions using stoichiometric Ni(0)-diene complexes (Scheme 85). 

Alkynyl enals cyclize on treatment with a stoichiometric amount of Ni(COD)2/TMEDA complex to give nickel enolates such as 193,436>436a These metallacycles react with electrophiles including methyl iodide and benzaldehyde to yield cyclopentenol derivatives (Scheme 91). 

The use of organomagnesium reagents as terminal reductants in zirconocene-catalyzed diene reductive cyclization permits derivatization of the resulting bis(magnesiomethyl)cycloalkanes. However, the use of other stoichiometric reductants is likely to afford catalytic systems that exhibit complementary selectivity profiles. Molander reports the... 

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