Intramolecular reaction 4+2 annulation

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success of nickel-catalyzed indole synthesis from 2-chloro-fV-allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [122]. Compound 102, easily prepared from 2-bromo-lV-acetylaniline and methyl bromocrotonate, was adopted as the cyclization precursor. Treatment of 102 with Pd(OAc)2 (2 mol%), Ph3P (4 mol%) and NaHCQ3... 

Based on this precedent, Nelson et al. used an intramolecular reaction in the total synthesis of (-)-rhazinilam. In this context, trisubstituted allenes are excellent precursors for a diastereoselective heterocyclic annulation that highlights the usefulness of this reaction in target-oriented synthesis [49]. In this case, the aforementioned catalyst that yielded the best results was [AuPPh3OTf], affording a higher yield and diastereoselectivity than Pd(II). 

A notable eight-membered ring annulation was reported by Echavarren et al. in their study of indoles as substrates for the intramolecular reaction [134]. 

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). 

The rhodium(ii)-catalyzed intramolecular reaction between linked vinyldiazomethanes and pyrroles leads to a novel synthesis of fused tropanes <1996JOC2305>. The reaction occurs by a stepwise [3- -4]-annulation mechanism between a rhodium-stabilized vinylcarbenoid intermediate and the pyrrole rather than by the typical tandem cyclopropanation/Cope rearrangement sequence. The outcome of the reaction is very sensitive to the vinylcarbenoid structure. In particular, the presence of a siloxy substituent on the vinylcarbenoid strongly favors the formation of fused tropanes 1063 or 1064 (Scheme 206) <1996JOC2305>. 

The intramolecular reaction can be extended to the cross-annulation reaction of aryl halides with unsaturated compounds [31,33]. For example, 2-halo-biphenyls react with alkynes to give phenanthrene derivatives [96,97]. By using the method, the analogs of hypericin known as antiviral agent (Eq. 45) [98] and indolocarbazoles (Eq. 46) [99] have been prepared. In these reactions, vinyl-palladium intermediates are involved. 

In 1971, Yamada et al. published their preliminary smdies toward dendrobine (82) 173). Their starting material was the cheap, commercially available arene thymol, and the key step was an intramolecular Robinson annulation also known as Johnson s tandem reaction. After unexpected rearrangements within an ozoifization, their protocol was modified and in 1972 Yamada et al. were able to present the first S3mthesis of ( )-dendrobine (82) 146). 

An additional advantage of the intramolecular protocol stems from the opportunity to prepare easily the required polyfunctional precursors via cobalt carbonyl stabilized propargyl cations. The approach based on the tandem utilization of Co-mediated alkylation and Pauson-Khand annulation was developed in Schreiber s studies to elaborate short pathways for the synthesis of polycyclic compounds. An example of the efficiency of this protocol is the two-step transformation of the acyclic precursor 409 into the tricyclic derivative 410. The cobalt-complexed acetal 409 was first transformed into the cyclooctyne derivative 411 via intramolecular reaction of the in situ generated propargyl cation 409a with the allylsilane moiety. Cyclooctyne 411 underwent smooth cycloaddition in the presence of carbon monoxide to give the target compound 410 with excellent stereoselectivity. 

A simple one-pot synthesis under phase-transfer conditions using two moles of base and one mole of iodine per mol alkene gave geminally substituted cyclopropanes 6. If an ester moiety is incorporated into the starting alkene at a suitable position, an intramolecular reaction may occur resulting in the formation of cyclopropanes 7 with an annulated lactone ring. "... 

Besides the intermolecular versions of this [3+2] annulation, intramolecular reactions are also possible. The first example of this transformation was reported by Oshima as early as 1988 in a synthesis of vinyl cylopentenes [8]. More recently this methodology was applied to the preparation of bicyclo[3.3.0]lactams and lactones... 

An efficient synthetic methodology was developed in which the palladium-mediated intramolecular carbonylative annulation of o-alkynylphenols was employed to construct benzo[l>]furo[3,4-d]furan-l-ones by a tandem reaction. Several densely functionalized alkynyl- phenols were cyclized into their respective substituted benzo[fc]furo[3,4-d]furan-l-ones in good yields under conditions of a combination of PdCljfPPh,), dppp and CsOAc in acetonitrile at 55°C under a balloon pressure of CO. An example is depicted below <01OL1387>. 

The outcome of the intramolecular reaction between vinylcar-benoids and furans depends on the structure of the vinylcarbenoid and the position of the tether. In the case of the 2-substituted fiiran 126, the triene 127 is formed exclusively (Scheme 43). Presumably, the additional strain in the intramolecular version favors unraveling of the furan ring to the triene rather than forming the [3+4] annulation product. In contrast, reaction of the 3-substituted furans 128 results in the synthesis of novel tricyclic products 129 that contain two formally anti-Bredt double bonds. " ... 

The structure of the vinylcarbenoid has a major influence on the outcome of intramolecular reactions involving pyrroles. In particular, the presence of a siloxy group on the central carbon favors [3+4] annulation over the formation of side products derived from zwitter-ionic intermediates. This effect is illustrated in the reaction of the 2-substituted pyrroles 130 and 132. Decomposition of the siloxy derivative results in the formation of the [3+4] annulation product 131, whereas the unsubstituted vinyldiazomethane results in the formation... 

In the reaction of allylic ethers with aryl halides, elimination of /t-alkoxy group occurs in some cases. Intramolecular reaction of the glycal 127 afforded the cis-fused pyrano[2,3-c]pyran 129 via deoxypalladation as shown by 128 [74]. On the other hand, ring cleavage of 130 occurs by deoxypalladation to give 132 via 131 [75]. Furthermore, the fcjiy-annulated pyranoside 134 was obtained by domino HR without elimination of the allyl ether group in 133 [76]. 

The Hajos and Wiechert research groups looked at a number of other potential proline based catalysts for their intramolecular Robinson annulation. (. -(-)-Hygrinic acid, Af-methylproline 13, was examined, but only the racemic intermediate ketol product 2 was obtained. In a similar manner, the proline methyl ester 14 also produced the racemic ketol intermediate. No reaction was observed with the piperidine analog 15. The homo-proline analog 16 gave the enantiomeric product. An explanation for this change in selectivity has not been provided yet. Please note that the use of (i )-proline provides the enantiomeric product. 

In contrast to the limited success in achieving direct asymmetric intermolecular Stetter reactions, there have been an abundance of reports detailing highly enantioselective intramolecular Stetter annulations. The first reported example was published by Enders and co-workers in 1996, in which the Ciganek reaction was rendered modestly asymmetric through the use of... 

A concise synthesis of the cytotoxic alkaloids dehydrotylophorine (127) and (+)-tylophorine (128) has been accomplished by a cascade consisting of a cobalt-catalyzed crossed [2 - - 2 - - 2] cyclotrimerization that is followed by an intramolecular ring annulation reaction (Scheme 7.27) [37],... 

Recently, Glorias discovered a Rh(III)-catalyzed coupling of oximes with electron-deficient diazo compounds to give iV-oxides of isoquinoline and pyridine [55]. The reaction proceeds with the liberation of H2O and Nj as by-products. In this reaction, the insertion of Rh-carbene into ortho-C-H bond followed by intramolecular dehydrative annulation plausibly accounts for the generation of Af-oxides (Eqs. (5.107) and (5.108)). The diazo compounds functioned as equivalents of electron-deficient alkynes, enriching the product diversity of isoquinoline and pyridine synthesis. 

Robinson Annulations Asilicagel-absorbedaminoacidsalt(39)-catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 1.12). A tricyclic ring stracture 40 was obtained in 84% yield and up to 97% ee [15]. hitermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]. 

In the presence of an excess of small alkynes the typical [3+2+1 jbenzannulation has to compete with a [2+2+1+lj (two-alkyne) annulation resulting from two consecutive alkyne insertion steps. The selectivity for this variant is increased for an intramolecular reaction. Diynyl-arylcarbene complexes 31 and 32, in which the carbene moiety is tethered by an appropriate spacer to two alkyne functionalities, are formed in a chemoselective Diels-Alder reaction of the more electron-deficient bond in the triyne carbene precursor complexes 35 and 36 with Danishefsky s diene a final thermal two-alkyne annulation affords the steroid skeleton 33. The sequence can be performed as a one-pot procedure in yields of 30%... 

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