Cycloaddition ester

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

A key intermediate, 163, which possesses all but one chiral center of (+ )-brefeldin, has been prepared by the enantiocontrolled cycloaddition of the chiral fi,/3-unsaturated ester 162 to 154[107], Synthesis of phyllocladane skeleton 165 has been carried out by the Pd-catalyzed cycloaddition of the unsaturated diester 164 and cobalt-catalyzed cycloaddition of alkynes as key reactions[108]. Intramolecular cycloaddition to the vinylsulfone in 166 proceeds smoothly to give a mixture of the trans and cis isomers in a ratio of 2.4 1[109], Diastereocontrolled cycloaddition of the hindered vinylsulfone 167 affords a single stereoisomeric adduct, 168, which is used for the synthesis of the spirocarbocyclic ring of ginkgolide[l 10],... 

Vinylboranes are interesting dienophiles in the Diels-Alder reaction. Alkenylboronic esters show moderate reactivity and give mixtures of exo and endo adducts with cyclopentadiene and 1,3-cyclohexadiene (441). Dichloroalkenylboranes are more reactive and dialkylalkenylboranes react even at room temperature (442—444). Dialkylalkenylboranes are omniphilic dienophiles insensitive to diene substitution (444). In situ formation of vinyl-boranes by transmetaHation of bromodialkylboranes with vinyl tri alkyl tin compounds makes possible a one-pot reaction, avoiding isolation of the intermediate vinylboranes (443). Other cycloadditions of alkenyl- and alkynylboranes are known (445). 

Methacryhc acid and its ester derivatives are Ctfjy -unsaturated carbonyl compounds and exhibit the reactivity typical of this class of compounds, ie, Michael and Michael-type conjugate addition reactions and a variety of cycloaddition and related reactions. Although less reactive than the corresponding acrylates as the result of the electron-donating effect and the steric hindrance of the a-methyl group, methacrylates readily undergo a wide variety of reactions and are valuable intermediates in many synthetic procedures. 

From Diazo Compounds via 1,3-Dipolar Cycloaddition. This method has been utilized widely in heterocychc chemistry. Pyrazohne (57) has been synthesized by reaction of ethyl diazoacetate (58) with a,P-unsaturated ester in the presence of pyridine (eq. 12) (42). 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

A newer method for the preparation of nitronic esters, namely utilizing the (9-trimethyl-silyl ester, has been reported and these are prepared by the reaction of alkylnitro compounds and (V,(V-bis(trimethylsilyl)acetamide. These nitronic esters also undergo cycloaddition with alkenes to produce isoxazolidines (equation 54) (74MIP41601, 74DOK109, 78ACS(B)ll8). 

Chlorination of sodium cyanodithioformate gives 3,4-dichloro-5-cyanoisothiazole (227), probably via the isothiazolodithiine (226) (72AHC(l4)l). The thienoisothiazole (228) undergoes cycloaddition with alkynic esters to give adducts such as compound (229), which... 

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... 

Isothiazole-4,5-dicarboxylic acid, 3-phenyl-dimethyl ester synthesis, S, 150 Isothiazole-5-glyoxylic acid ethyl ester reduction, 6, 156 Isothiazole-4-mercurioacetate reactions, 6, 164 Isothiazole-5-mercurioacetate reactions, 6, 164 Isothiazoles, 6, I3I-I75 acidity, 6, 141 alkylation, 6, 148 aromaticity, S, 32 6, 144-145 basicity, 6, I4I biological activity, 6, 175 boiling points, 6, I43-I44, 144 bond fixation, 6, 145 bond orders, 6, I32-I34 calculated, 6, 133 bromination, S, 58 6, 147 charge densities, 6, 132-134 cycloaddition reactions, 6, 152 desulfurization, S, 75 6, 152 deuteration, S, 70... 

Another triflate ester that recently has found growing application in organic synthesis is commercially available trimethylsilylmethyl trifluoromethanesul fonate. This powerful alkylating reagent can be used for the synthesis of various methylides by an alkylation-desilylation sequence A representative example is the generation and subsequent trapping by 1,3-dipolar cycloaddition of indolium methanides from the corresponding indole derivatives and trimethylsilylmethyl trifluoromethanesulfonate [108] (equation 54)... 

A more conventional cycloaddition occurs with activated acetylenes, however, the intermediate cyclobutene adducts undergo rearrangement to give insertion of two carbon atoms into the enamine chain (55). Thus the enamine (16) reacted with methyl propiolate to give the dienamino ester (73), presumably via the cycloaddition product (65a). 

Enamino ketones and esters also react with dimethyl acetylenedicarboxylate (67). Again cycloaddition appears to occur and the unstable cyclobutene intermediates rearrange to give insertion of two carbon atoms. 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

Enamines have been observed to act both as dienophiles (46-48) and dienes (47,49) (dienamines in this case) in one-step, Diels-Alder type of 1,4 cycloadditions with acrylate esters and their vinylogs. This is illustrated by the reaction between l-(N-pyrrolidino)cyclohexene (34) and methyl t/-a i-2,4-pentadienoate (35), where the enamine acts as the dienophile to give the adduct 36 (47). In a competitive type of reaction, however, the... 

Azides can use enamines as dipolarophiles for ],3 cycloadditions to form triazolines. These azides can be formate ester azides (186), phenyl azides (187-195), arylsulfony] azides (191-193,196), or benzoylazides (197,198). For example, the reaction between phenyl azide (138) and the piperidine enamine of propionaldehyde (139) gives 1 -phenyl-4-methy l-5-( 1 -piperidino)-4,5-dihydro-l,2,3-triazole (140), exclusively, in a 53% yield (190). None of the isomeric l-phenyl-5-methyl product was formed. This indicates that the... 

TosMIC reagents. For example, glyoxylic acid ethyl ester undergoes cycloaddition with (2-naphthyl) tosylmethyl isonitrile (17) to produce oxazole 18 in good yield. ... 

An example of this methodology was its use in the synthesis of vitamin Be, pyridoxine 12. Cycloaddition of oxazole 9, prepared from ethyl A-acetylalanate and P2O5, with maleic anhydride initially gave 10. Upon exposure to acidic ethanol, the oxabicyclooctane system fragments to afford pyridine 11. Reduction of the ester substituents with LiAlIU generated the desired product 12. 

Intramolecular cycloadditions of 4/f-pyrido[l,2-n]pyrimidin-4-ones 235 (R = H, Me Ph) and MeNHOH HCl gave tetracyclic isoxazolo derivatives 237. In the case of 235 (R = Me) a minor epimer 238 was also isolated (00JCR(S)414). Similar reaction of 235 (R = H, Me, Ph) and sarcosine ethyl ester HCl afforded an isomeric mixture of epimeric tetracyclic pyrrolo derivatives 239 and 240. In the reaction of 235 (R = H) and PhCHjNHCHjCOOEt only one product 241 was obtained. 

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