Zwitterion cyclization

D. Further Reactions of the Initial Michael-Type Zwitterions 1. Direct Cyclization... 

Pyridine and dimethyl acetylenedicarboxylate in methanol yield - a mixture of (33) and (34). It is tempting to assume that a zwitterion (30) is first formed and that this then adds a proton followed by a methoxide ion (Michael addition) under the influence of both the positive charge on the ring and the assisting ester group. The resulting structure (31) could then add another molecule of the ester and cyclize, as indicated, to (32). Subsequent aromatization accompanied by loss of one, or the other, substituent at position 3 would lead to the two products, (33) and (34), actually isolated. 

Phenacylpyridinium bromide (155) with aqueous sodium carbonate yields the chloroform soluble zwitterion (156) which, with dimethyl acetylenedicarboxylate in the presence of palladium on charcoal, cyclized to the indolizine (157) in ca. 20% yield. In a similar way the pyrazine (158) gave a mixture of (159) and (160) through loss of the benzoyl group. The last compound was also ob-... 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

The stereochemistry of the ring product (17) was rationalized in terms of the attraction and repulsion between the involved substituents98. The accompanying olefins may be formed via carbene intermediates (arising from a-elimination of S02 from sulfene), and the intermediacy of thiadiazoline dioxide (from sulfene and diazoalkane) explains the formation of the ketazine side-products. Thiadiazoline, on its part, may be formed directly by the cyclization of zwitterion 101. 

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

The steric outcome in the above cyclization can be explained on the basis of either a zwitterionic intermediate or a concerted [7t2s -I- 7t2s] process , depending on the nature of the reactants . Definite predictions are practically impossible as yet. The more stable trans-isomers (i.e. 221a) can be obtained by stirring the isomeric mixture with catalytic amounts of potassium t-butoxide in t-butyl alcohol for several days . 

High stereospecificity is observed when the rotation of the diradical intermediate is slow in comparison with cyclization to cycloadduct or reversion to reactants. With the presence of external heavy atoms, it could facilitate the intersystem crossing (ISC) of the first-formed singlet diradical to the longer-lived triplet counterpart. The triplet diradical will have a chance to undergo rotation before it reverts back to singlet and cyclizes or cleaves to reactants. This then accounts for the reduced stereospecificity. The alternative possibility of a zwitterionic intermediate is considered unlikely because there is no interception of zwitterions by water. 

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

The fused iV-(pynmidin-4-yl)proline derivative 291 undergoes cyclization to the zwitterionic pyrroloimidazopyr-imidine 292 upon treatment with acetic anhydride <1985JHC187> (Equation 49). 

Thermal decomposition of the Meisenheimer zwitterion 88 gave rise to the 2-hydroxy-7-oxa-4-azoniaspiro[3.51-nonane picrate salt 90 by cleavage of the 1,3-dioxolane ring followed by intramolecular cyclization (Scheme 9) <2000RJOC706>. 

Treatment of 2-benzoylpyridine 81 with p-toluene-sulfonamide gave 1-amino-2-benzoylpyridinium tosylate 82 (X = OTs), which was cyclized with formamide in the presence of triethylamine hydrobromide to give 83 (82FRP2486942). The reaction of the perchlorate 82 (X = C104) with urea in polyphosphoric acid afforded 3-hydroxy-l-phenylpyrido[2,l-/][l,2,4]triazinium perchlorate 84. Treatment of this salt with base led to the zwitterionic l-phenylpyrido[2,l-/][l,2,4]triazin-5-ium-3-olate 85 (86JHC375). Pharmaceutical compositions contain 83 (82FRP2486942). 

The oxygen of azole A-ox ides produces a nucleophilic attack to C=S C-atom of a cycloalkanethione forming a zwitterion, which cyclizes and spontaneously decomposes, yielding the product of this sulfur transfer reaction201 (Scheme 16). 

Electrocyclization of 1,4-dienes is an efficient process when a heteroatom with a lone pair of electrons is placed in the 3-position, as in 77 (Scheme 20)38. Photoexcitation of these systems generally results in efficient formation of a C—C bond via 6e conrotatory cyclization to afford the ylide 78. These reactive intermediates can undergo a variety of processes, including H-transfer (via a suprafacial 1,4-H transfer) to 79 or oxidation to 80. In a spectacular example of reaction, and the potential it holds for complex molecule synthesis, Dittami and coworkers found that the zwitterion formed by photolysis of divinyl ether 81 could be efficiently trapped in an intramolecular [3 + 2] cycloaddition by the... 

Full -polarization in diradicals can give rise to zwitterionic products. First examples were studied in detail by Carpenter and coworker who investigated solvent effects on rates and product distribution in Myers-Saito cyclizations.64 Polar solvents and substitution patterns that stabilize either positive or negative charges (or both) favor the zwitterionic products. For example, the presence of a dimethylamino group leads to stabilization of cations and isolation of pyrrolo-quinolines, rather than pyrido-indoles from eneyne-carbodiimides, as reported by Wang and coworkers (Scheme 14).65... 

Another example of a zwitterionic product of a cycloaromatization reaction was given by Kerwin and coworkers. Their skipped (aza)enediynes rearranged to yield (aza)eneyne-allenes that subsequently cyclized under addition of methanol (in a byproduct), which is consistent with a partitioning between a diradical and a zwitterionic reaction pathway (Scheme 15).66... 

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