Alkylation annulation

Table 4.3 gives some examples of the dehydrative alkylation-annulation of bis-sulfones. 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

Methyl ketones are important intermediates for the synthesis of methyl alkyl carbinols, annulation reagents, and cyclic compounds. A common synthetic method for the preparation of methyl ketones is the alkylation of acetone derivatives, but the method suffers limitations such as low yields and lack of regioselectivity. Preparation of methyl ketones from olefins and acetylenes using mercury compounds is a better method. For example, hydration of terminal acetylenes using HgSO gives methyl ketones cleanly. Oxymercuration of 1-olefins and subsequent oxidation with chromic oxide is... 

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst." ... 

Helquist and coworkers60 have developed a six-membered ring annulation via a conjugate addition of aryllithium generated by metal-halogen exchange and subsequent intramolecular alkylation. This is illustrated in equation 71. 

Note One or more alkyl groups on quinoxaline may become involved in annulation or other cyclization reactions. 

This section contains alkylations of ketones and protected ketones, ketone transpositions and annulations, ring expansions and ring openings and dimerizations. Conjugate reductions and Michael alkylations of enone are listed in Section 74 (Alkyls from Alkenes). 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Although 1,3,2-diazaphospholenium cations are usually prepared from neutral NHPs or 1,3,2-diazaphospholes via Lewis-acid induced substituent abstraction or A-alkylation, respectively (cf. Sect. 3.1.2), the group of Cowley was the first to describe a direct conversion of a-diimines into cationic heterocycles by means of a reaction that can be described as capture of a P(I) cation by diazabutadiene via [4+1] cycloaddition [31] (Scheme 4). The P(I) moiety is either generated by reduction of phosphorus trihalides with tin dichloride in the presence of the diimine [31] or, even more simply, by spontaneous disproportionation of phosphorus triiodide in the presence of the diimine [32], The reaction is of particular value as it provides a straightforward access to annulated heterocyclic ring systems. Thus, the tricyclic structure of 11 is readily assembled by addition of a P(I) moiety to an acenaphthene-diimine [31], and the pyrido-annulated cationic NHP 12 is generated by action of appropriate... 

One representative of the oxazolo[4,5-/][ 1,6]naphthyridine system, viz. the ester 62, is produced in four steps by annulation of 2-(dicthy lam ino)oxazolo[4,5- pyridine (Scheme 20). Whether the final product exists mainly as the hydroxy tautomer or as the 9//-6-one cannot be deduced from the spectral data presented alkylation occurs either at the oxygen or at N-9, and gives either 63 or 64 <1993SC2931>. 

The first approach to oxa-[3 + 3] annulation precursor 8 would rely on late-stage oxidation of the cyclohexanone motif in 10 to the diketone, and 10 can be accessed through a sequence of 1,4-conjugate addition of a Me-nucleophile followed by trapping with a homoallyl electrophile 9 to set the A-ring stereochemistry (Scheme 8.1). Unfortunately, while the addition of Me2CuLi proceeded smoothly, no alkylation using iodide 9 was observed instead, only a mixture of 2,3-dimethylcyclohexanones and recovered iodide were isolated. 

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

Fused pyrazole compounds have been prepared from A-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from IV-bromoalkyl pyrazoles 57 and aryl iodides 58. 

Two sequential lithiations and treatments with different bifunctional electrophiles make possible one-pot syntheses of relatively complex molecules. Thus, in the [1+2+2] annulation depicted in Scheme 69, alkylation of 1-benzylbenzotriazole 399 with 2-bromoacetaldehyde diethyl acetal to give intermediate 426 is followed by alkylation with W-benzylideneaniline to produce derivative 427. Following treatment with formic acid causes cyclization to ethoxypyrrolidine 428 that subsequently eliminates ethanol and benzotriazole to give pyrrole 429 <1997JHC1379>. 

Workers at Merck recently reported three variants for pyridine formation in conjunction with the synthesis of COX-2-Specific inhibitor 8 (Scheme 1). Acid catalyzed annulation (path a) was achieved in 72% with 2 equivalents of methanesulfonic acid and four equivalents of 2-chloro-3-aminoacrolein. Base-promoted annulation between 7 and 2,3-dichloroacrolein provided 8 in 58% yield. Finally, base-promoted annulation with 2-chloro-iV,jV-dimethyl-armnotrimethinium hexafluorophosphate afforded 8 in 97% yield . Other alkylation-based strategies for pyridine formation include the work of Manna <00BMC1883> and Parra <00S273>. 

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