Cyclization-methoxycarbonylation

Through the in situ deprotection of A-acyl-2-(trimethylsilyl)ethynylanilines 465 followed by palladium-catalyzed cyclization-methoxycarbonylation, stereoisomeric 4-methoxycarbonylmethylene-3,l-benzoxazine derivatives 466 and 467 were obtained (Equation 51). The (Z)-isomers 466 were consistently found to be the main product, with the exception of the -(methoxycarbonyl)phenyl-substituted compounds (R = H, = C6H4C02Me(/>)), for which a... 

The conversion of 4,5-hexadienoic acids to furanones and of 4,5-hexadienals to furanosides was achieved in a one-pot acetalization-cyclization-methoxycarbonylation procedure (Scheme 21). Trialkylsiloxy substituents in /3-position induce high stereo selectivities. This method was applied in a synthesis of nucleoside analogs bearing a branched difunctional side chain. ]... 

Under oxidative conditions, acyclic [75a,b] and cyclic [75c] 4-yn-l-ols react via a cyclization-methoxycarbonylation pathway to afford ( )-cyclic-P-alkoxyacrylates 2E-[(methoxycarbonyl)methylene]tetrahydrofurans in good yields under mild conditions (Equations 10.37 and 10.38). The stereochemical outcome is entirely consistent with a reaction initiated by intramolecular nucleophilic attack of the hydroxy group on the palladium-coordinated triple bond to generate a vinylpalladiumiodide intermediate that undergoes methoxycarbonylation to afford the P-alkoxyacrylate. The ketopyranose subunit can also be constructed via a palladium-catalyzed oxidative cyclocarbonylation of substituted 5-yn-l-ols, which occurs with excellent stereose-... 

Barrelene was obtained via a double Diels-Alder reaction from a-pyrone with methyl acrylate (H.E. Zimmerman, I969A). The primarily forming bicyclic lactone decarboxylates in the heat, and the resulting cyclohexadiene rapidly undergoes another Diels-Alder cyclization. Standard reactions have then been used to eliminate the methoxycarbonyl groups and to introduce C—C double bonds. Irradiation of barrelene produces semibullvalene and cyclooctatetraene (H.E. Zimmerman. 1969B). 

The intramolecular cyclization of l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5, 6-tetrahydropyridine (140) and l-(3-bromopropyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (143) (89T5269) resulted in the synthesis of quinolizidine ring system 141 and indolizidine ring system 144 in 43% and 72% yields along with the reduced tetrahydropyridines 142 and 145 in 21% and 8% yields, respectively. All the cyclized products appeared to be (ran.s-fused indolizidines or quinolizidines. The (ran.s -fused simple indolizidines are known to be some 2.4 kcal mol more stable than the d.s-fused isomers (68TL6191). In the and-isomer the methoxycarbonyl substituent occupies an equatorial position. 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

It is believed (54IZV47 72JPR353) that in the first stage the intermediate 282 is formed due to the addition of the CH acid to the enamine moiety with subsequent elimination of amine. The enol form of the intermediate 282 undergoes cyclization in two fashions, depending on the nature of substituent X. In the case of the ester (X = OMe) the attack is directed to the cyano group to form substituted 3-methoxycarbonyl-I//-pyridin-2-one (283) or its tautomer (2-hydroxy-3-methoxycarbonylpyridine). With the amide (X = NH2) intramolecular condensation leads to 3-cyano-l//-pyridin-2-one and its hydroxy tautomer (284). 

Substituted perhydropyrido[l,2-c][l,3]oxazines 83 were obtained by the cyclization of l-(/er/-butoxycarbonyl)-2-(2-hydroxyalkyl)piperidines 104 in pyridine on the action of MeS02Cl at room temperature (96CJC2434). Cyclization of c/5-2,6-H- l-(methoxycarbonyl)-2-(2-acetoxyhexyl)-9-methox-ypiperidines 105 and 106 in THF in the presence of KO/-Bu yielded 3-butyl-9-methoxyperhydropyrido[l,2-6 ][l,3]oxazin-l-ones 94. Treatment of l-(/erc-butoxycarbonyl)-2-[2-hydroxy-2,2-di(2-propyl)ethyl]piperidine with NaH in boiling THF yielded 3,3-di(2-propyl)perhydropyrido[l,2-c][l,3] oxazin-l-one (01JA315). 

Cyclization of 1 -(9-fluorenylmethoxycarbonyl)-2-[(A-methoxycarbonyl-methyl)aminocarbonyl)piperidine and 2-(9-fluorenylmethoxycarbonyl) -3-[(A-methoxycarbonylmethyl)aminocarbonyl]-1,2,3,4-tetrahydroisoquino-lines on the action of piperidine in THF yielded 2-(l,4-dioxoperhydropyr-ido[ 1,2-fl]pyrazin-2-y 1)- and 2-( 1,4-dioxo-1,3,4,6,11,11 a-hexahydro-2//-pyr-azino[l,2-i]isoquinolin-2-yl)acetamides, respectively (99MIP11). 

Vinyl radicals can also participate in 6-exo cyclizations. In pioneering work, Stork and his group at Columbia University showed that stereoisomeric vinyl bromides 20 and 21 (see Scheme 3) can be converted to cyclohexene 22.7 The significance of this finding is twofold first, the stereochemistry of the vinyl bromide is inconsequential since both stereoisomers converge upon the same product and second, the radical cyclization process tolerates electrophilic methoxycarbonyl groups. The observation that the stereochemistry of the vinyl bromide is inconsequential is not surprising because the barrier for inversion of most vinyl radicals is very low.8 This important feature of vinyl radical cyclization chemistry is also exemplified in the conversion of vinyl bromide 23 to tricycle 24, the key step in Stork s synthesis of norseychellanone (25) (see Scheme 4).9 As in... 

The experiment was carried out with (i )-(-)-2[l-(methoxycarbonyl)ethyl]benzene-diazonium chloride (6.80). The product, methyl 3-methyl-3-//-indazole-3-carboxylate (6.81), was racemic. With regard to the inconclusive H/D exchange experiments one therefore has to conclude that the cyclization of the diazo-methylene intermediate 6.75 is faster than the rate of deuterium incorporation. 

Bicychc pyrazinones foimd in several natural products were synthesized via Michael addition of heterocyclic amines to nitro olefin followed by reduction/cyclization of the nitro group of the adduct [20] (Scheme 5). Further elaboration of the C-6 methoxycarbonyl group in pyrazinone to the n-propyl guanidine group could result in the synthesis of indoloperamine. 

Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous la cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-A-p-toluenesulfonylanilide to N-tosylindole <06CL1122>. 

In the authors opinion, the nitrosonium cations A are chlorinated by TiCl4(LA) and undergo cyclization with one of the methoxycarbonyl groups to give buty-rolactones (151). This process can be accompanied by ortho-cyclization giving rise to oximes (152) as by-products. 

Aminal reduction (NaBH3CN, 2 M HC1, EtOH) of the C-5-methoxycarbonyl pyrroloimidazole 52a or its enantiomer 52b resulted solely in lactamization to pyrrolopyrazines 53a and 53b, respectively the C-5-ethoxycarbonyl pyrroloimidazole 52c similarly cyclized to 53c (Equation 5) <1996TL1711, 1997TL1647>. 

Whereas methyl 5-(3-methyl[l,2,4]thiadiazolyl)diazoacetate 56 shows no tendency to cyclize to 7-methoxycarbonyl-3-methyl[l,2,3]triazolo[3,4-A][l,2,4]thiadiazole 57, the 5-(l-diazoalkyl)substituted [l,3,4]thiadiazoles 58 are in equilibrium with the fused bicyclic form, the [l,2,3]triazolo[5,l-A]][l,3,4]thiadiazoles 59 <1988BSB795, 1992JHG713>. The latter ring-closed form 59 prevails in the solid state as indicated by infrared (IR KBr disk). The chain/ring equilibrium of the diazoimine/triazole forms is shifted toward the open-chain diazo form 58 by raising the temperature and by using less polar solvents (Equations 8 and 9). 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

Diethyl N-(4-Aminophenyl)aminomethylenemalonate (167, R = H) was reacted with N, Af -bis(methoxycarbonyl)-5-methylisothiourea in the presence of p-toluenesulfonic acid in boiling methanol for 4 hr to afford the guanidine derivative (1590) in 50% yield. The guanidine (1590) was oxidized in chloroform with lead tetraacetate to the quinoline diimine (1591), which cyclized to 1592. After methanolysis, the 2-(methoxycarbon-ylamino)benzimidazole derivative (1593) was obtained in 41% yield [86JCR(S)161]. 

Intramolecular alkoxycarbonylation of alkynols is parallel to what has been described for alkenols except that functionalization of the triplebond produces a double bond. No lactone formation is observed in the Pd(II)-catalyzed oxidative cyclization-carbonylation of alkynes. Instead [(methoxycarbonyl)methylene]tetrahydrofurans are selectively formed [134, 135]. Moreover, starting from an enynol, furan-2-acetic ester is obtained resulting from a final aromatization step [136]. 

Cyclization by amidomercuration has been reported (391). Reaction of N-methoxycarbonyl-6-aminohept-l-ene (211) with mercuric acetate gave the organomercurial (212). Reductive coupling of 212 with l-decen-3-one in the usual way gave the cis and trans isomers (213). Successive treatment of 213 with ethanedithiol, Raney nickel, and ethanolic hydrogen chloride afforded ( )-sole-nopsin A (Id, 2 parts) and its isomer (Ic, 3 parts), which were separable by preparative gas chromatography (GC) (Scheme 5) (391). 

Dihydrothieno[3,4-Z ]thiophene (131) was prepared by two methods. In the first (Scheme 8), chloromethylation of methyl thiophene-2-carboxylate (132) forms methyl 2,3-bischloromethyl-thiophene-5-carboxylate (133) (85%) cyclization of 133 with sodium sulfide in methanol yields (66%) methyl 4,6-dihydrothieno[3,4-i]-thiophene-2-carboxylate (134). Peroxide oxidation of 134 gives 2-methoxycarbonyl-4,6-dihydrothieno[3,4-h]thiophene 5,5-dioxide (135) and hydrolysis of 134 followed by metaperiodate oxidation furnishes the sulfoxide (91). Thienothiophene (131) was produced by hydrolysis and decarboxylation of 134. As indicated above, the sulfoxide (91) was used for the synthesis of thieno[3,4-6]thiophene (3). 

The bicyclic system has also been prepared by annulation of a pyrimidine ring onto an existing thiazine (Scheme 97) the cyclization fails with acetamidine or d -methylthiourea <1996JHC235>. Alternatively, a pyrimidine ring is formed by reaction of guanidine with the lactim ether formed by 0-methylation of a 2-methoxycarbonyl-l,4-thiazin-2-one (Scheme 98)<1997JME2502>. 

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