Cyclization acetylenic

The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

Subsequent dehydrohalogenation afforded exclusively the desired (Z)-olefin of the PGI2 methyl ester. Conversion to the sodium salt was achieved by treatment with sodium hydroxide. The sodium salt is crystalline and, when protected from atmospheric moisture and carbon dioxide, is indefinitely stable. A variation of this synthesis started with a C-5 acetylenic PGF derivative and used a mercury salt cataly2ed cyclization reaction (219). Although natural PGI has not been identified, the syntheses of both (6R)- and (65)-PGl2, [62777-90-6] and [62770-60-7], respectively, have been described, as has that of PGI3 (104,216). 

Reactions of acetylene and iron carbonyls can yield benzene derivatives, quinones, cyclopentadienes, and a variety of heterocycHc compounds. The cyclization reaction is useful for preparing substituted benzenes. The reaction of / fZ-butylacetylene in the presence of Co2(CO)g as the catalyst yields l,2,4-tri-/ f2 butylbenzene (142). The reaction of Fe(CO) and diphenylacetylene yields no less than seven different species. A cyclobutadiene derivative [31811 -56-0] is the most important (143—145). 

The cyclization of 6-aminouracils with three-carbon fragments such as a,B- unsaturated carbonyl compounds, /3-dicarbonyl compounds, acetylenic esters, etc., is dealt with as a [3+3] reaction (see Section 2.15.5.7.2). Reactions with alkoxymethylenemalonates and related compounds are regarded as proceeding through [6 + 0 (y)] cyclizations (see Section 2.15.5.4.2). 

This stereoelectronic requirement would lead to a large distortion of the normal geometry of a five-membered ring and introduce strain. It is this distortion and strain that disfavor the 5-endo-trig cyclization. In contrast, 5-endo-dig cychzation is feasible because the acetylenic system provides an orbital that is available for a nearly planar mode of approach. 

In agreement with these analyses, it was found that conqiound S was unreactive toward base-catalyzed cyclization to 6, even though the double bond would be expected to be reactive toward nucleophilic conjugate addition. On the other hand the acetylene 7 is readily cyclized to 8 ... 

More importantly, Peet and coworkers reported the reaction of o-nitroaniline 35 with acetylene dicarboxylate 32 to provide fumarate 36. Subsequent cyclization proved difficult under thermal conditions and only a 35% yield of quinolone 37 was isolated. Use of PPA for the cyclization improved the yield of 37 significantly. Using this modification allowed enamino-ester formation with a nitro-group attached to the arylamine. 

An elegant synthesis of both isothiazole and 3-methylisothiazole has been reported by Wille and his co-workers.This depends on the cyclization with liquid ammonia of the cis form of the addition product 14 which is obtained from the appropriate acetylenic carbonyl... 

Reversible interaction of the carbonyl group with an azine lone-pair (cf. 245) should facilitate substitution adjacent to the heteroatom by the anion of a )3-hydroxyethyl ketone. A similar cyclic intermediate (246) is presumably responsible for the cyclization of acetylene dicarboxylic esters with azines. Similar cyclic intermediates... 

Another type of cyclization leading to acetylenylpyrazoles is the interaction between a-acetylenic and -diacetylenic ketones and nitrogen-containing binucleophiles. 

It is known that the ability of nitrotolane to cyclize depends on electronic factors (69MI2) hence l,3-dimethyl-4-nitro-5-phenylethynylpyrazole, whose acetylene group is in the most electron-accepting position of the pyrazole ring, i.e., favorable for nucleophilic addition, was introduced into the reaction of cyclization. Thus,... 

The results obtained, i.e., agreement between the directions of cyclization and acetylenic cyclocondensation of iodazolecarboxylic acids and much shorter duration of the first reaction, confirm the assumption of the two-stage mechanism of cyclocondensation (66JOC4071 69JA6464). 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

Hydrazides of vicinal acetylene-substituted derivatives of benzoic and azole carboxylic acids are important intermediate compounds because they can be used for cyclization via both a- and /3-carbon atoms of a multiple bond involving both amine and amide nitrogen atoms (Scheme 131). Besides, the hydrazides of aromatic and heteroaromatic acids are convenient substrates for testing the proposed easy formation of a five-membered ring condensed with a benzene nucleus and the six-membered one condensed with five-membered azoles. 

The effect of the nature of the substituent at the acetylene bond is not so noticeable. Substitution reduces the C-3 activity due to polarization effects and steric factors. As aresult, in the cyclization with hydrazines and hydroxylamines an increase in the content of 5-substituted pyrazoles and isoxazoles is observed (81UK1252). As mentioned above, nonsymmetiic nitrogen-containing binucleophiles H2N—YH (Y = O, NMe, NPh) react with l-heteroalk-l-en-3-ynes in two alternative pathways by functions H2N and YH. 

The third synthetic scheme is employed when the phenylthio substituent is in the a-position of the lactone function, which interferes with the cyclization (90JOC5894). Acetylenic ketone 194 (95% yield) is readily transformed to the acetal 195 (with potassium carbonate in methanol) however, under the above conditions neither its hydrolysis nor cyclization to the spiroketal occurs. The spirocyclic pyrone 197 is formed in quantitative yield on treatment of 195 with p-toluenesulfonic acid in a 4 1 THF-H2O mixture at reflux for 12 h. 

The aminobutynones 342 contain a push-pull system with a strongly electron-withdrawing carbonyl group therefore, they show electrophilic properties. Cyclizations with their participation proceed differently from those with ynamines (91UK103 00UK642) and acetylenic ketones (73UK511). 

Among various other ways of cyclizing 3-aminopropan-l-ol to a tetrahydro-1,3-oxazine derivative, an interesting reagent is acetylene under pressure ... 

A number of other reagents cyclize 3-propanolamines to 5,6-dihydro-1,3-4/f-oxazines, These reagents are acetylenic ethers (which act as... 

The palladium-catalyzed reaction of o-iodoanilides with terminal acetylenic carbinols provides a facile route to the synthesis of quinolines using readily available starting materials (93TL1625). When o-iodoanilide 126 was stirred with acetylenic carbinol 127 in the presence of bis-triphenyl phosphine palladium(ll) chloride in triethylamine at room temperature for 24 h, the substituted alkynol 128 was obtained in 65% yield. On cyclization of 128 with sodium ethoxide in ethanol, 2-substituted quinoline 129 was obtained in excellent yield. 

It is evident that in this ring transformation the C-3-C-4 bond in the pyridine ring has undergone fission. This bond breaking very probable occurs in the covalent o-adduct at C-4. After ring opening the imino-acetylene derivative is formed it is in equilibrium with the iminoketenimine, in which cyclization easily occurs (Scheme 45). 

Alternatively, hydration of the acetylenes in cold concentrated sulfuric acid, or with mercury(II) sulfate in formic acid, yields 1-aryl-3,4-dihydro-5//-2-benzazepin-5-ones which are isolated as their methylsulfonate salts.79 If, however, acetylene 4 is stirred with pyrrolidine at room temperature then cyclization is accompanied by amination to give 8-chloro-l-(2-chlorophenyl)-4-(pyrrolidin-l-yl)-3i/-2-benzazepine (5) in high yield. 

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