Cycloadditions betaines

Clearly, in the case of (66) two amide tautomers (72) and (73) are possible, but if both hydroxyl protons tautomerize to the nitrogen atoms one amide bond then becomes formally cross-conjugated and its normal resonance stabilization is not developed (c/. 74). Indeed, part of the driving force for the reactions may come from this feature, since once the cycloaddition (of 72 or 73) has occurred the double bond shift results in an intermediate imidic acid which should rapidly tautomerize. In addition, literature precedent suggests that betaines such as (74) may also be present and clearly this opens avenues for alternative mechanistic pathways. 

More recently, Cheeseman and coworkers have investigated cycloaddition reactions of 2,6-dioxypyrazines (80jCS(Pl)1603). 2,6-Dihydroxy-3,5-diphenylpyrazine (77) reacts with electron deficient dienophiles such as iV-phenylmaleimide, diethyl maleate and diethyl fumarate (Scheme 26) to yield adducts of the 3,8-diazabicyclo[3.2.1]octane class such as (78). This reaction is believed to proceed by way of the betaine (79) and has precedent (69AG(E)604) in that photolysis of the bicyclic aziridine (80) generates analogous betaines which have been trapped in cycloaddition reactions. 

A variety of 1-azirines are available (40-90%) from the thermally induced extrusion (>100 °C) of triphenylphosphine oxide from oxazaphospholines (388) (or their acyclic betaine equivalents), which are accessible through 1,3-dipolar cycloaddition of nitrile oxides (389) to alkylidenephosphoranes (390) (66AG(E)1039). Frequently, the isomeric ketenimines (391) are isolated as by-products. The presence of electron withdrawing functionality in either or both of the addition components can influence the course of the reaction. For example, addition of benzonitrile oxide to the phosphorane ester (390 = C02Et) at... 

Trifluoromethyl-substituted diazonium betaines [176]. Synthetic routes to trifluoromethyl-substituted diazo alkanes, such as 2,2,2-trifluorodiazoethane [ 177, 7 78, 179] and alkyl 3,3,3-trifluoro-2-diazopropionates [24], have been developed Rhodium-catalyzed decomposition of 3,3,3-tnfluoro-2-diazopropionates offers a simple preparative route to highly reactive carbene complexes, which have an enormous synthetic potential [24] [3-1-2] Cycloaddition reactions were observed on reaction with nitnles to give 5-alkoxy-4-tnfluoromethyloxazoles [750] (equation 41)... 

Dipolar cycloadditions of dihydropyrimidine-fused mesomeric betaines 389, 391 and 394 with different dipolarophiles afforded 6-oxo-6H-pyrido[l,2-n]pyrimidine-3-carboxylates 390, 392, 393 and 396 (97JOC3109). 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

Dipolar cycloaddition of betaines 492 gave cycloadducts 493, which produced tricyclic compounds 494 on further thermolysis (Scheme 48) <1995H(41)1631>. Heating 9,9-disubstituted yr/ra-(4-hydroxy-2-oxo-2//-pyrido-[2. -//][ 1.3]thiazinium) hydroxides 495 afforded tricyclic compounds 497 as diastereomeric mixtures (Scheme 49) <1995S973>. In the case of the lower homolog (n = 0), a cycloadduct 496 could be also isolated at lower temperature. 

Dipolar cycloaddition of pyrido[2,l-A][l,3]thiazinium betaine 507 (R = Me) with 1-diethylamino-l-propyne afforded cycloadduct 508, from which quinolizin-4-one 509 formed by a rapid cheletropic extrusion of COS (Scheme 53) <1995T6651>. 1,4-Dipolar cycloaddition of 507 and 4-phenyl-l,2,4-triazoline-3,5-dione yielded 511 (via 510) <1995H(41)1631> and 512 <1995T6651>. 

The Diels-Alder cycloaddition potential of fused 4-aryldihydropyrimidine mesomeric betaines has been studied. The cross-conjugated thiazinium betaine 317 underwent 1,4-dipolar cycloaddition with electron-rich dipolaro-philes, and thus 1-diethylaminoprop-l-ine gave the pyrido[l,2-tf]pyrimidine 318 by loss of carbonyl sulfide (Equation 34). Reaction of 317b with 1,1-diethoxyethene resulted in the 8-ethoxy analogue of 318 (R = H) <1997JOC3109>. 

Conjugated heteropentalene mesomeric betaines are electron rich with high-energy HOMO and can be regarded as masked 1,3-dipolarophiles. Their main reactions are electrophilic substitution and cycloaddition reactions with electron-deficient 1,3-dipolarophiles, both were duly discussed in CHEC-II(1996) <1996CHEC-II(8)747>. 

In general, conjugated heterocyclic mesomeric betaines are associated with 1,3-dipoles and cross-conjugated heterocyclic mesomeric betaines are associated with 1,4-dipoles. The dipolar cycloaddition reactions of both types of heterocyclic mesomeric betaines have been widely investigated and its use for the preparation of a diverse variety of heterocyclic compounds was duly covered in CHEC-II(1996) <1996CHEC-II(8)747>. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

The third cycloaddition substrate explored the feasibility of a vinyl nitro functionality as an activated dipolarophile (98, Scheme 1.9c). Preparation of nitroalkene oxidopyridinium betaine 98 began with silylenol ether 92, which was treated with methoxydioxolane in the presence of Lewis acid catalyst, TrC104, to afford keto dioxolane 93 in 58 % yield [47]. Ketone 93 then underwent a-nitration by treatment with /-BuONCL and KOt-Bu to provide nitro ketone 84 (91 %), which was then converted to the nitroalkene functionality via reduction under Luche conditions to... 

Each of the 3-oxidopyridinium betaine substrates 83, 91, and 98 were extensively investigated for their potential to engage in intramolecular dipolar cycloaddition (Scheme 1.10). Heating a solution of ene-nitrile 83 in variety of solvents failed to effect the desired intramolecular [3+2] dipolar cycloaddition to form the bridged pyrrolidine 100, as tricyclic oxidopyridinium betaine 103 was the only... 

Despite the lack of success in the attempts at intramolecular cycloaddition with substrates 83 and 91, a moderately promising outcome was observed for the nitroalkene substrate (98, Scheme 1.10c). Heating a dilute solution of oxido-pyridinium betaine 98 in toluene to 120 °C produced a 20 % conversion to a 4 1 mixture of two cycloadducts (110 and 112), in which the major cycloadduct was identified as 110. While initially very encouraging, it became apparent that the dipolar cycloaddition reaction proceeded to no greater than 20 % conversion, an outcome independent of choice of reaction solvent. Further investigation, however, revealed that the reaction had reached thermodynamic equilibrium at 20 % conversion, a fact verified by resubmission of the purified major cycloadduct 110 to the reaction conditions to reestablish the same equilibrium mixture at 20 % conversion. 

Scheme 1.13 Intramolecular dipolar cycloaddition of nitroalkene oxidoisoquinolinium betaine 123...

Scheme 1.15 Intramolecular dipolar cycloaddition of ene-nitrile oxidoisoquinolinium betaine 131...

When ene-nitrile oxidoisoquinolium betaine 131 was heated as a dilute solution in toluene to 120 °C (Scheme 1.15), near quantitative conversion to the cycloadduct 133, resulting from the undesired regioselectivity, was observed. While the near complete conversion to cycloadduct 133 of oxidoisoquinolinium betaine 131 indeed demonstrated complete avoidance of the conjugate addition pathway in favor of cycloaddition, initial production of undesired isomeric cycloadduct 133 (instead of 136) was disappointing. Notably, cycloadduct 133 is expected to be less kinetically favored based on frontier molecular orbital (FMO) analysis (assuming dipole HOMO-controlled cycloaddition) of the putative transition state. This result stands in contrast to the cycloaddition of nitroalkene oxidoisoquinolinium betaine... 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

The ring expansion reaction of diaryl cyclopropenones and cyclopropene thiones occurring with pyridinium, sulfonium, and phosphonium enolate betaine 427268-270) is related to 1,3-dipolar cycloadditions. This process results in formation of 2-pyrones 428 by loss of pyridine (or sulfide or phosphine) and insertion of the remaining fragment C=C-0 to the C1(2)/C3 bond of the cyclopropenone ... 

There is mechanistic evidence to show that this formal (3 + 3) cycloaddition starts with attack of betaine-C at CI<2 of the three-ring (429) and leads to 2-pyrone formation either by a concerted process (429 — 428) or stepwise via cyclobutenone and 0-acyl vinylketene intermediates (430/431) depending on the leaving group ... 

The (3 + 3) cycloaddition principle has been extended to the heterocyclic betaines 448 representing aza analogues of ylides 427. The betaines 448 combined with diphenyl cyclopropenone and its thione268 to yield the condensed heteroaromatic systems 449 ... 

A more complex cycloaddition type is observed when diphenyl cyclopropenone and its thio analogue are reacted with the pyrylium betaine 451276 and the products obtained were assigned structures 450 and 452, respectively. 

In another example (Scheme 8), the intramolecular cycloaddition of an azido functionality onto an enone group afforded bicyclic derivatives with bridgehead iV atoms. The cyclopentenone derivative 28 afforded the indolizidinone 30 through the proposed compound 29 which might react through a diradical intermediate or through a betaine intermediate <2002TL5385>. 

The betainic imidazo[l,2- 7][l,2,4]triazinium-olate 107 was found to react as a 1,3-dipole in 1,3-dipolar cycloaddition with ynamines to yield a bridged skeletone 108 <1999T13703> as shown in Scheme 15. This cycloadduct 108 underwent subsequent rearrangement upon heating, and resulted in formation of a fused eight-membered heterocycle 109. With acetylenes other than ynamines, the transformation was found to proceed slowly and in bad yields. The fact that ynamines were used successfully, as well as theoretical considerations (cf. Section 11.17.2) in this chapter, indicated that these Diels-Alder reactions are of inverse electron demand. 

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