Anionic cyclizations, annulation reactions

Enders and coworkers reported studies in which the RAMP and SAMP chiral auxiliaries were employed in the aza-annulation process (Scheme 39).1,4 Condensation of 179 with RAMP provided a route to the optically active enamino hydrazone 473, which was then metalated with nBuLi to generate the corresponding anion. Aza-annulation of 473 with 474 produced intermediate 475, which could be cyclized slowly (2 d) at 60 °C to give 476. Alternatively, heterocycle formation could be facilitated by an increase in reaction temperature (toluene, heat). Removal of the chiral auxiliary gave 477 in 50-52% overall yield from 179 in >99 1 enantiomeric purity. Substituents on the aromatic ring did not have a measureable effect on the yield of the aza-annulation reaction. 

This reaction has been extended to the Michael Addition on a,)0-unsaturated nitrile by temporarily chelating the Grignard reagent to y-hydroxy unsaturated nitrile. An alternative route involving a free-radical )0-alkylation of nonactivated carbon atoms and subsequent anionic cyclization has been developed as a complementary route of the Robinson annulation. In addition, this reaction has been modified to occur under antibody catalysis" or with the combination of a lithium enolate with aluminum tris(2,6-diphenylphenoxide). Further modifications include the Robinson annulation in supercritical C02, the reaction promoted by K2CO3 under ultrasound,and the solid-supported reaction under microwave irradiation. ... 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

The a-oxoketene dithioacetal 6.40 is derived from indoxyl (l,2-dihydroindol-3-one), a heterocyclic carbonyl precursor, and its reaction with simple allyl anions will also yield the corresponding Jl-annulation product. Thus when 6.40 was reacted with allyl anions 65 the corresponding carbinol acetals 66 formed insitu underwent smooth BF3.Et20 assisted cyclization to afford the corresponding carbazoles 67 in high yields <99T11563>. 

If the moeity adding to the aryne carries a suitably placed electrophilic center, cyclization with the initially formed anion can occur as observed in the synthesis of dibenzothiophene (60).92 Of wider synthetic import in this context is enolate addition to arynes. Here, after the initial ring closure many types of products can be formed (Scheme ll).35 However, with some substrates, a particular reaction course can predominate 93 94 for example, reaction of cyclodecanone with bromobenzene provides an efficient method for benzo-annulation and ring expansion. Similarly, high yields of benzocyclobutenols can be obtained from the monoketals of ot-diketones.9s... 

Cyclopentenes are commonly formed in the reaction of the appropriate alkynyliodonium salts with enolate anions. Various alkynyliodonium tetrafluo-roborates interact with / -dicarbonyl enolates to give products of cyclopentene annulation in 50-90% yield [121]. Several examples of such annulations are shown in Scheme 59. The carbene cyclization can also occur when the long alkyl... 

A brief exploration of annulations with nitro-free fluoro arene 37—readily prepared from ( )-methyl 3-methoxyacrylate (36) by a Michael addition elimination strategy with 2-(2-fluorophenyl)acetonitrile (35)—again revealed that direct SNAr cyclization was impeded under all conditions. Extended conjugation may have contributed however, the necessity for the conjugated sp2-hybridized aryl-propene anion to couple intramolecularly with another sp2-hybridized carbon atom imposed a highly strained reaction trajectory (Scheme 9). 

Similar a,a -annulations were achieved from reaction of oc,/ -unsaturated acid chlorides with cyclic ketone enamines which afforded bicyclo[3.3.1]nonane-2,9-diones41,60 65 or bicyclo[4.3.1]decanones66. In this reaction, 7V-acylation of the enamine 109 occurs as the first step giving 110, followed by a [3,3] sigmatropic rearrangement to a ketene intermediate (111). Ketene 111 subsequently cyclized via 112 to a bicyclic immonium salt (113) which after hydrolysis gave the corresponding dione 11463. If there is an axially oriented electrophilic substituent at C-4 of the enamine (for example, R = COPh) the enolate anion 115 may cyclize to an adamantane derivative 116 (equation 20). 

On the other hand, carbonylation via a one-electron reduction system by reducing metals can also lead to useful transformations [Scheme 4-33]. The first example in Scheme 4-34 shows that a zinc reduction system of pent-4-enyl iodide undergoes dual annulations, a [4-f1] radical annulation with CO and a [3-f2] anion annulation with alkenes, to give a bicyclo[3.3.0]octanol, in which four C-C bonds are produced [59]. An extension of the present strategy to the construction of bicyclo[3.2.1]octanol skeletons has also been successful with a system in which 6-endo cyclization is favored over 5-exo cyclization. In these two reactions three C-C bonds were created by radical reactions and one by anionic reaction. 

Aromatic Annulation. 7-Methoxy-3-(phenylsulfonyl)-l(3Y/)-isobenzofuranone (1) can be deprotonated at —78 °C with either lithium diisopropylamide or lithium ferf-butoxide to form a soluble yellow anion which can be utilized as an effective nucleophile in the Michael reaction. The initial anionic adduct cyclizes with concomitant elimination of benzenesulfinic acid to yield a 1,4-dihydroxynaphthalene which is unambiguously disubstituted at the 2- and 3-positions (eq l). ... 

Scheme 8.63. A representation of the Robinson annulation process. The initial addition of the enolate anion to the a,P-imsaturated ketone represents a Michael reaction. Subsequent cyclization with loss of water is an aldol reaction.

The capnellane (109) has been synthesized, using two dififerent annulation procedures (Scheme 11). The a/b ring junction was formed through consecutive Michael and ene-type reactions by addition of a lithium cuprate to 3-methyl-cyclopent-2-enone and trapping of the enolate anion that is thus formed as the enol acetate (110). Lewis-acid-induced cyclization then formed the ketone (111). 

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