Annulation processes

The syntheses of stemodin and stemodinone, structural relatives of aphidicolin, were accomplished using the A/B double annulation and B/C spiro annulation processes developed for the assembly of aphidicolin. 

We have also been able to generate carbocycles by annulation processes. For example, the reaction of halobiaryls and 1 atm of CO in the presence of a Pd catalyst affords excellent yields of fluorenones (Scheme 15).16... 

Scheme 1.19. Cationic domino ring-enlargement/annulation process for the synthesis of bicyclo[3.2.0]heptanes.

Rychnovsky and coworkers very recently described a so-far unknown domino Michael addition/2 -oxonia Cope/aldol-type reaction to give tetrahydropyran rings [475]. The transformation has as its origin an annulation process (see Section 2.1) which was discovered by the same group. 

Pyrano[3,2 ]indolizines such as 120 can be prepared from the reaction of N-( 1 -benzotriazolylmethyl)indolines with 3,4-dihydro-2//-pyran under acidic or Lewis-acidic conditions (Equation 26) <2001T4933>, and a simpler analogue 122 is the end product of an annulation process starting from the enamine 121 and ethyl acrylate <1996H(43)1391> (Scheme 34). Pyrano[4,3-/]indolizinetriones, for example, 124, result from the hydrolysis of protected 2,3-dihydro-l//-indolizincdioncs 123 (Equation 27) <2000H(53)771>. 

The mechanism for the Mori-Ban indole formation is representative of many Pd-catalyzed pyrrole annulation processes [123], Reduction of Pd(OAc)2 by PPh3 generates Pd(0) species accompanied by triphenylphosphine oxide and acetic anhydride. 

The radical carboazidation of alkenes has been achieved in water using triethylborane as initiator [118]. This efficient process is complete in one hour at room temperature in an open to air reaction vessel (Scheme 54, Eq. 54a). These new tin-free carboazidation conditions are environmentally friendly and allow to run reactions with an excess of either the alkene or the radical precursor. They are also suitable for simple radical azidation of alkyl iodides as well as for more complex cascade reactions involving annulation processes (Eq. 54b). In both reactions (Eq. 54a and 54b), an excess of triethylborane (3 equivalents) is required to obtain a good yield. This may be an indication that the chain process, more precisely the reaction between the phenylsul-fonyl radical and Et3B, is not efficient. 

The allenylsilanes are excellent nucleophiles and they can react with a variety of electrophilic species in annulation processes that provide access to diverse products. Allenylsilane 112 (Eq. 13.36) reacts with tropylium fluoroborate 111 to provide azu-lene 113 [35]. The reaction is slow and it is necessary to use an acid scavenger so as to inhibit protiodesilylation by the fluoroboric acid that is generated during the course of the annulation. The excess tropylium salt abstracts a hydride from the reaction intermediate leading to the azulene. There are relatively few direct methods for the synthesis of azulenes. 

This annulation process was of considerable value in early approaches to steroid synthesis. The structural relationship of the bicyclic product obtained here to the male sex hormone testosterone is immediately apparent. Further, the non-conjugated carbonyl is now activating the adjacent carbon that subsequently features in building up the third ring system. 

Hudlicky and Barbieri (178) developed a simple two-step strategy to generate vinyl oxiranes, and then rearrange the vinyl oxirane to form functionalized dihydrofurans in a formal [2- -3]-annulation process. Both pyrolysis and ring opening with TMSI have been used to initiate the rearrangement process (Scheme 4.90). 

In spite of its formal similarity to the above mentioned annulation processes, the reaction shown in 4.37. includes a unique migration step. Oxidative insertion of the palladium into the phenyl-iodine bond is followed by the migration of the palladium onto the more electron rich indole ring. The 2-indolylpalladium complex than carbopalladates the pendant alkync moiety and the process ends by the formal activation of a C-H bond of the phenyl substituent and subsequent reductive elimination, furnishing the pentacyclic product.48 The same strategy has been utilised in the preparation of the indoloindolone framework from /V-bcnzoyl-3-(o-iodophcnyl)-indolc in an oxidative addition - palladium migration - C-H activation sequence.49... 

The use of a-thiophenyl enones (106 Scheme 12) allows the preparation of phenols such as (107) from cyclic ketones (18).30 The same product can also be obtained by normal Robinson annulation of methyl vinyl ketone (30) and the p-keto sulfoxide (lOS).30 Acceptors other than a, 3-unsaturated carbonyls have been used in both the Michael reaction and the Robinson annulation process. For example, nu-... 

As with Michael additions to activated alkenes, the initial adducts with activated alkynes can be trapped by various processes. An aldol reaction can occur if a carbonyl is properly situated in the starting material (Scheme 71).123 However, the use of methyl ethynyl ketone (509) and its homologs in the Robinson annulation process to give cyclohexadienones (510 equation 110) usually proceeds in poor... 

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

Ill. N. Naz, T. H. Al-Tel, Y. Al-Abed, and W. Voelter, Palladium-cobalt-mediated double annulation process a new strategy to chiral and poly substituted bis-cyclopentanoids on carbohydrate precursors, J. Org. Chem., 61 (1996) 3250-3255. 

It appears that, apart from such specialized methods of synthesis that have been developed as part of an overall effort to prepare analogues of artemisinin (9), the most popular and effective general methods for preparing the ring systems described involve the cyclization of a ring component that contains [6 + 0] ring atoms or the insertion of a one atom unit in a [5 + 1] annulation process. These general methods have found wide use, notably in the preparation of triazine-based compounds. 

A further thought to bear in mind is that an enamine reaction, particularly an annulation process involving a bidentate reagent, rarely gives a single pure product mixtures are usually obtained and, hopefully, the desired product is the one in excess and/or can readily be separated from the rest. For example, in the reaction between methyl vinyl ketone (MVK) with 1-A-pyrrolidinylcyclohexene to give A1,8a-2-octalone... 

The stereochemical course of the annulation process has been determined by reaction of acryloyl chloride with the morpholine enamine of 4-f-butyl-2-methylcyclohexanone. The bicyclic dione was obtained in 76% yield as a 4 1 mixture of two isomers (Scheme 150). X-ray analysis of the main isomer showed that reaction had occurred by axial attack from the same side as the C-2 methyl group. In order for regeneration of the enamine system to occur under conditions of stereoelectronic control, the intermediate ketene-iminium salt presumably adopts a twist conformation. Cyclization of the ketene... 

The stereochemical outcome of this new annulation process can be rationalized by assuming the transition state structure 10. The synclinal arrangement of the respective hydrogen atoms exclusively gives the all-cw-annulation product 9a. 

Related palladium-catalyzed ring closures permit simple and selective either cis or trans annulation processes via an almost 100% stereospecific C—O C— Pd C—C transfer. The diastereoselectivity... 

No doubt the Diels-Alder reaction will lend itself to further extensions of scope and selectivity. Nevertheless, the current state of the art and the pivotal applications of Diels-Alder adducts (XXX) for the efficient chemo-, regio- and stereo-selective syntheses of complex structures, e.g. via annulation processes (a, b) and/or cleavage reactions (c, d, e) speak for themselves (Scheme 6). An adequate treatise would vastly exceed the limits of this chapter. 

As illustrated with the above example, a notable feature of this annulation method is its stereoselectivity. As in the earlier version of the method, the overall annulation process can be viewed as accomplishing the effective suprafacial exo cycloaddition of a substituted carbene to the conjugated diene (Scheme 11). However, the generality of this stereochemical control does not appear to be as impressive as in the previous oxyanion-based strategy. Thus, whereas rearrangement of the (vinylcyclopropyl)methyl sul-fones derived from ( )-l,3-pen iene affords almost exclusively the predicted tra/is-substimt cy-clopentene, annulation employing (Z)-l,3-pentadiene produces a mixture of cyclopentenes in which the expected cu-substituted isomer is the minor product ( heme 13). 

New ring-opening methods for phenylthio-substituted cyclopropylcarbinols generate intermediates with various possibilities for further transformation an example is shown in equation lOS " An overall [3 -I- 3]-annulation process is offered by combination of the Trost route to 2-vinylcyclobutanones and an alkoxy-accelerated rearrangement (equation 109). ... 

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