Reactions cyclization

Intramolecular Cyclization Reactions.—Base-induced 1,3-eliminations continue to provide a useful route to cyclopropanes. The dehydrochlorination of 5-chloro-hexan-2-one by sodium hydroxide has been re-examined, and is now believed to yield the corresponding cis- and trons-cyclopropanes in a ratio of 5 95.  

Cyclizations from the erythro- and threo-isomers of (10) proceed stereospecifically to give (11)—(13) as shown. 

The protected cyclopropanone cyanohydrin (15) has been converted into cyclobutanone, which can also be obtained by an identical route from 4-chlorobutanal. Tricyclo[3,2,0,0 ]heptan-6-ones have beat implicated as reaction intermediates in 

Fredlina, A. A. Kamyshova, E. Ts. Chukovskaya, and V. I. Dostovalova, Izvest. Akad. Nauk. 

The substituted indanone (20) has been found to give (21) stereospecifically, and the exo-vinylcyclopropane (23) has been obtained in good yield by neighbouring-group-assisted cyclization of (22). Reductive cyclizations of a -unsaturated ketones 

Intramolecular Cyclization Reactions.— Apart from more routine applications the base-catalysed 1,3-elimination route to cyclopropanes has seen a number of interesting developments during the period of this Report. 

The reaction of o -halogeno-l-(NJV-dialkylamino)cycloalkenes with amines is known to result in a Favorskii-type ring contraction, giving rise to cm-diamino-bicyclo[n,l,0]alkanes, but, under the same conditions, the acyclic analogue (28) yields predominantly acyclic products. However, by employing (28), AgBF, and MejNH in a molar ratio of 1 1 2, cyclization is almost quantitative. Starting from 

The Grignard reagent (29) derived from the ethylene acetal of 4-bromobutan-2-one, previously reported as unavailable, has now been prepared in THF and undergoes cyclization in refluxing solvent. The reaction of myrcene with magnesium results in the complex myrcene-magnesium which, on treatment with acetyl chloride or acetic 

A new facile route to chrysanthemate analogues by 1,5-elimination from 6-bromo-alk-4-enoates and by 1,7-elimination from 8-bromoalka-4,6-dienoates has appeared.  

Matsui, and Y. Takahatake, Tetrahedron Letters, 1976, 4359 K. Kondo, K. Matsui, A. Negishi, S. Dobashi, and Y. Takahatake, Japan. Kokai 7682242 (Chem. Abs., 1976,85,176937). 

Hydrazino-, hyrazono-, and derived quinoxalines are often used for cyclization that may or may not involve annulation of the quinoxaline system. The following examples are classified according to the type of product, initially a few typical azahetarylquinoxalines and then some (annulated) azahetarenoquinoxalines. 

2-Hydrazino-3-methylquinoxaline (247) and phenacyl cyanide gave 2-(3-amino-5-phenylpyrazol-l-yl)-3-methylquinoxaline (248) (EtOH, reflux, 4 h 60% or neat reactants, fused, 5 min 50%) analogs likewise.847 

6-Chloro-2-hydrazinoquinoxaline 4-oxide and acetylacetone gave 6-chloro-2-(3,5-dimethylpyrazol-l-yl)quinoxaline 4-oxide (249) (EtOH, reflux, 2 h 68%) analogs likewise.508 

6-Chloro-2-[l,4-dimethyl(thiosemicarbazido)]quinoxaline 4-oxide (250) with dimethyl acetylenedicarboxylate gave 6-chloro-2- (V-(5-methoxycarbonyl-methylene-3-methyl-4-oxo-2-thioxoimidazolidin-l-yl)-/V-methylamino quinoxa-line 4-oxide (251) (EtOH, reflux, 5 h 54%) a homolog likewise.469 

3-(a-o-Chlorophenylhydrazono-a-hydrazinocarbonylinethyl)-2(l//)-quinoxalinone (252) gave 3-(l -o-chlorophenyl-5-oxo-4,5-dihydro-1,2,4-triazol-3-yl)-2(l//)-quinoxalinone (253) (NaN02, AcOH, H20, 5°C 95°C, 2 h 88% clearly by conversion into an azidocarbonyl intermediate, rearrangement to the isocyanato analog, and a final cyclization).1081 

The results of intramolecular Li-Barbier reactions (cyclization reactions) with 5-bromo-l-cyano-2,2-dimethylpentane and the corresponding 6-bromohexane were rather disappointing [22]. The expected 2,2-dimethylhexanone was formed in only 31% yield  

The formation of cycloheptanone occurred in even lower yield. 

3 Barbier-Type Reactions with Other Metals 

It is worth mentioning that the substituted cyclohexanone was also formed from the iodocyanopentane when lithiated with n-butyllithium in diethyl ether. The halogen exchange reaction is obviously much faster than nitrile addition for the organolithium reagent (see also the reaction mentioned on p.96. 

The scope and device application of the 6ji-photoinduced electrocyclization of aromatic systems continue to expand and, as in recent years, the reactions of 

2-diaryl ethenes have again attracted wide interest and attention. Esters (68), readily formed from 2-hydroxy-1,2,2-triphenylethanone and carboxylic acids, undergo efficient photocyclization to the benzofuran (69), which then yields the benzophenanthro[9,10-d]furan (70) by the usual 6ji-oxidative closure process of the cis stilbene moiety. The overall reaction is apparently so convenient that the authors propose the triphenylethanone as a new photolabile protecting group for carboxylic acids. A three-step synthesis of benz[a]acephenanthrene (71) from readily available starting materials has been described by Marcinow and coworkers in which the key procedure is the photocyclization of (72) in benzene solution in the presence of iodine.  

As in recent years, the bir-photocyclization and its reversal of 1,2-diheteroarylethene derivatives has again attracted considerable attention. An ab initio molecular orbital study of the photochromic reactions of these systems has been published, and details of their preswitching dynamics have been reported as have those concerned with the ring-opening dynamics. This year there has been an emphasis on the synthesis of novel systems, particularly those incorporating the dithienylperfluorocyclopentene unit, and in many reports their reversibility and fatigue characteristics are issues that are addressed. Such reports 

Irradiation of the two rigid derivatives (124) and (125) of 2-allylaniline, has been investigated in order to assess the potential of stereoselectivity in the intramolecular cyclization process which yields indole derivatives. Approximately 1 1 mixtures of the cis and trans diastereomeric lilolidines (126) were formed from both (124) and (125), but the latter also gave the cis and trans tetrahydropyrrolo[3,2,l-hi]indole derivatives (127). These cyclizations were carried out at several temperatures to determine whether diastereoselectivity may be entropy dependent, but the only significant effects were observed in the conversion of (125) to (126). Access to indole derivatives such as (128) can be gained by irradiation of toluene solutions of 1,4-quinone monoimines (129).  

The photocyclization reactions of acrylanilides have been researched for a number of years and mediation of the process by a chiral host has now been investigated. Irradiation of toluene solutions of (138) in the presence of the enantiomerically pure chiral lactam (139) produced a significant enantiomeric excess in the formation of the cis and trans cyclization products (140) and (141), respectively, at — 55°C. Under these conditions, the chemical yield is 66%, the respective ratio of (140) to (141) is 1 2.7 and the cis isomer is formed with an ee of 30%, while that of the trans is 57%. These enantiomeric excesses showed different temperature dependences and, whereas the values for (141) increased with reduction in reaction temperature, those for the cis isomer (140) increased to a maximum of 45% at — 15°C but decreased at lower temperatures. Experiments with deuterated compounds showed that the chiral lactam (139) influenced the protonation of the cis and trans forms of the reaction intermediate (142). This type of cyclization has been used to synthesize a variety of previously unknown heterophanes derived from [2.2]paracyclophane. For example, irradiation of 

The influence on the photochromism in dithienylethene systems of replacing the favoured perfluorocylopentene moiety by other cyclic ethene units has attracted the attention of a number of research groups. Dutch workers have shown that the use of the perhydrocyclopentene unit as in (91) has little effect on the photochromic behaviour of (92) but note that in situations where fatigue resistance and thermal stability are critical, the fluorinated moiety would be preferable. The cyclization quantum yield of (93) is reported to increase in the presence of metal ions, and more detailed accounts have been published of the interesting application of the dithienylcyclopentene-tethered jS-cyclodextrins (94) as photoswitchable hosts for meso tetrakis(4-sulfonatophenyl)porphyrin.  

Such 671-electrophotocyclization is commonly observed for a variety of 1-arylbuta-l,3-dienes and is also the basic process for the photochromism of fulgides and fulgimides. The mechanism of these reactions has been subjected to a theoretical investigation using PM3 semiempirical quantum chemistry and MECI Cl methods, and the results are reported to support the mechanism 

Immediately after the commercialization of MALDI-TOF mass spectrometers, several research groups reported on the detection of cyclic oligomers and polymers in their reaction products [26,32,61,79, 85,116-121]. The first systematic study of the role of cyclization reactions in ab polycondensations was performed by Feast et al. [32, 116, 117] and by Dusek et al. [118]. The Feast group studied polycondensations of monomer (e). Formula 11.13, at 240 °C in the melt using Sb203 as transesterification catalyst. It was found the fraction of cycles increased with the conversion, and at long reaction times (40 h) only peaks of cycles were detectable in the mass spectra (up to the technical limit of the mass spectra at 5 kDa). 

Consequently, the limitation of the chain growth (plateau of Mn) was attributed to the influence of ring formation consuming the a functions. Those authors also performed polycondensations in the presence of b2 or bs core monomers and observed that these core monomers did not prevent cyclization. 

Interestingly, Frey et al. [119] reached exactly the same conclusions, although their polycondensations were kinetically controlled, whereas Feast et al. had worked on a thermodynamically controlled system involving cyclization by back-biting . Frey et al. reinvestigated the proton-catalyzed polycondensation of 2,2-bishydroxymethyl propionic acid ((a) in Formula 11.4). It was found that Hult s polyesters (inch the commercial Perstorf products) possess extremely low 

In polycondensations of a2b monomers cyclization competes with chain growth yielding more and more cycles with increasing conversion, and at 100 % conversion all hb polymers necessarily possess a cyclic core. A treeshaped architecture presented in almost all pubhcations and review articles is a fiction, when the hb polymers are prepared with high conversions. 

Cyclization limits the chain growth (see Chap. 7) and reduces the dispersity, when compared with Flory s calculation. For the dispersity cyclization plays an opposite role in two- and three-dimensional polycondensations, because it yields higher dispersities in two-dimensional polycondensations than calculated by Flory (e.g., Ds 3-15 [121, 122]). In fact, the experimentally observed range of dispersities is the same for both, two- and three-dimensional polycondensations. 

Since the intramolecular reactivity often achieves the highest limits of the enzyme reaction rates and even rivals them [9,10], a special attention has been paid to studying its sources. A variety of useful rules and concepts, such as entropy and stereopopulation control, orbital steering, propinquity, and spatiotemporal hypotheses, have been evolved and their scope and limitations critically reviewed [11-13]. While differing from one another in their terms and emphases, they are common in reflecting in their essence a general principle of steric fitness of initial and transition state structures of fast intramolecular reactions. 

Baldwin [14] presented a set of rules which permit prediction of a favorable stereochemical route exo or endo) of the ring-forming reactions. They are based on the stereochemical requirements of transition states for ring closure processes. 

Baldwin s rules have gained a fairly wide acceptance among organic chemists. Regarding the cyclization reactions, in which carbon atoms at single or double 

From 3- x0 to 1-exo From 2 -exo to l-exo 6-endo, 1-endo From 5- X0 to 1-exo From 3-endo to 1-endo 

In actual fact, the angle of attack on the CX bond in addition reactions depends a great deal on the reaction type. Equally essential is the influence of reaction type on the character of rehybridization of the center being attacked occurring in the vicinity of the transition state structure. This may be illustrated by the data of nonempirical (3-21G) calculation [15] on reactions of the hydride ion (XVa), hydrogen atom (XVb) and proton (XVc) additions to the double-bond C(2) atom of propene  

Nitrogen-containing heterocycles are of great importance as they constitute subunits in many natural products and biologically active pharmaceuticals.  

The direct syntheses of A -aryl-azacycloalkanes, 4,5-dihydrophazine derivatives and pyrazoles by double alkylation of hydrazine derivatives with alkyl 

12 Solvent Controlled Mono- and Bis-allylation of Active Methylene Compounds 

Hydrazinophthalazines with dicarbonyl synthones usually give (unfused) heterocyclylphthalazines but with monocarbonyl synthons usually give (fused) 

1-Hydrazinophthalazine (135, R = H) with acetylacetone gave l-(3,5-dimethyl-pyrazol-l-yl)phthalazine (134) (reactants, EtOH, reflux, 2h 1,4-dihydrazinophthalazine (135, R = NHNH2) gave l,4-bis(3,5-dimethyl-pyrazol-l-yl)phthalazine (136) (neat reactants, 95°C, 1 h 80% note improved yield) and analogs were made similarly.  

1-Hydrazinophthalazine (137) with acetonylacetone gave l-[(2,5-dimethylpyr-rol-l-yl)amino]phthalazine (138) (substrate, AcOH synthonj slowly 65°C 3h 15%) analogs likewise.  

1-Hydrazinophthalazine (141) with o-formylbenzoic acid (142) gave an unseparated mixture of two intermediates (substrate HCl, synthon, H2O, reflux, 30 min 93%) that gave 3-(o-carboxyphenyl)-l,2,4-triazolo[3,4-a]phthalazine (143) (mixture, EtOH, 20 C, 2 weeks %) mechanistic details are dis- 

1-Hydrazinophthalazine (144) with ethyl 3-benzoylpyruvate gave 3-phenyl-4//-[l,2,4]triazino[3,4-fl]phthalazin-4-one (145) (EtOH, reflux, 30 min 32%) analogs likewise.  

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Stork-Eschenmoser Hypothesis- Olefin Geometry is preserved in the cyclization reaction, i.e. trans olefin leads to a trans fused ring jucntion A. Eschenmoser HCA 1955, 38, 1890 G. Stork JAGS 1955, 77, 5068... 

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

First the protected oligopeptide is coupled with polymer-bound nitrophenol by DCC. N"-Deblocking leads then to simultaneous cycliiation and detachment of the product from the polymer (M. Fridkin, 1965). Recent work indicates that high dilution in liquid-phase cycli-zation is only necessary, if the cyclization reaction is sterically hindered. Working at low temperatures and moderate dilution with moderately activated acid derivatives is the method of choice for the formation of macrocyclic lactams (R.F. Nutt, 1980). 

The cyclization reactions discussed here either involve the intramolecular reaction of a donor group D with an acceptor group A or a cyclizing dimerization of two molecules with two terminal acceptors and two donors. A polymerization reaction will always compete with cyclization. For macrolides see p. 146 and p. 319 — 329. 

Dimethyl acetylenedicarboxylate (DMAD) (125) is a very special alkyne and undergoes interesting cyclotrimerization and co-cyclization reactions of its own using the poorly soluble polymeric palladacyclopentadiene complex (TCPC) 75 and its diazadiene stabilized complex 123 as precursors of Pd(0) catalysts, Cyclotrimerization of DMAD is catalyzed by 123[60], In addition to the hexa-substituted benzene 126, the cyclooctatetraene derivative 127 was obtained by the co-cyclization of trimethylsilylpropargyl alcohol with an excess of DMAD (125)[6l], Co-cyclization is possible with various alkenes. The naphthalene-tetracarboxylate 129 was obtained by the reaction of methoxyallene (128) with an excess of DMAD using the catalyst 123[62],... 

Probably first obtained by Hantzsch and Arapides (105) by condensation of a,/3-dichlorether with barium thiocyanate, and identified by its pyridine-like odor, thiazole was first prepared in 1889 by G. Popp (104) with a yield of 10% by the reduction in boiling ethanol of thiazol-2-yldiazonium sulfate resulting from the diazotization of 2-aminothiazole. prepared the year before by Traumann (103). The unique cyclization reaction affording directly the thiazole molecule was described in 1914 by Gabriel and Bachstez (106). They applied the method of cyclization, developed by Gabriel (107, 108), to the diethylacetal of 2-formylamino-ethanal and obtained thiazole with a yield of 62% - Thiazole was also formed in the course of a study on the ease of decarboxylation of the three possible monocarboxylic acids derived from it (109). On the other... 

Several 4-amino-2,5-disubstituted thiazoles (257) have been obtained recently (702, 756, 776, 814, 820) by a ring cyclization reaction of halogeno compounds with cyanamide derivatives (263) according to the general Scheme 135. 

The most general pathways to thiazoles bearing such groups as alkyl, aryl, aralkyl, and alkenyl, substituted or not by functional groups, are the cyclization reactions described in Chapter II. A certain number of indirect methods also exist, though only a few examples of each are given here. Others are discussed in the following chapters, with the more important references cited here. 

This first-stage polymer is then introduced into the application environment, where the final cyclization reaction occurs. 

Reactions. In addition to the usual reactions of primary hydroxyl groups and of double bonds, i j -butenediol undergoes a number of cyclization reactions. 

R = H) undergoes a variety of enzyme-catalyzed free-radical intramolecular cyclization reactions, followed by late-stage oxidations, eliminations, rearrangements, and O- and N-alkylations. Working from this generalization as an organizing principle, the majority of known AmaryUidaceae alkaloids can be divided into eight stmctural classes (47). 

Other types of cyclization reactions have been demonstrated (95). 

The aminophenols are chemically reactive, undergoing reactions involving both the aromatic amino group and the phenoHc hydroxyl moiety, as weU as substitution on the benzene ring. Oxidation leads to the formation of highly colored polymeric quinoid stmctures. 2-Aminophenol undergoes a variety of cyclization reactions. 

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). 

Tb allium (ITT) ttifluoroacetate promotes olefin cyclization reactions and intramolecular coupling reactions (32,33). 

Thiophene [110-02-1] and a number of its derivatives are significant in fine chemical industries as intermediates to many products for pharmaceutical, agrochemical, dyestuffs, and electronic appHcations. This article concentrates on the industrial, commercial, and economic aspects of the production and apphcations of thiophene and thiophene derivatives and details the main synthetic schemes to the parent ring system and simple alkyl and aryl derivatives. Functionalization of the ring and the synthesis of some functional derivatives that result, not from the parent ring system, but by direct ring cyclization reactions are also considered. Many good reviews on the chemistry of thiophene and thiophene derivatives are available (1 7). 

Electrophilic substitution of thiophene occurs largely at the 2-position and the reactivity of the ring is greater than that of benzene. 3-Substituted derivatives are generally prepared by indirect means or through ring cyclization reactions. 

Other photoiaduced cyclization reactions can occur by conrotatory bond formation to give the 9 P,10 P-antiisomers, isopyrocalciferol2 [474-70-4] (23) or isopyrocalciferol [10346-44-8] (24) (Fig. 5), whereas thermal cychzation at >100°C leads to the two 9,10-syn isomers, (9a,10 a)-pyrocalciferol (27)... 

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). 

Ammonium acetate and sodium methoxide are effective catalysts for the ammonolysis of soybean oil (49). Polyfunctional amines and amino alcohols such as ethylenediamine, ethanolamine, and diethanolamine react to give useful intermediates. Ethylenediamine can form either a monoamide or a diamide depending on the mole ratio of reactants. With an equimolar ratio of reactants and a temperature of >250° C, a cyclization reaction occurs to give imidazolines with ethylenediamine (48) ... 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

Cyclization reactions effected by intramolecular attack of the heteroatom on a nitrile group provide a useful source of 2-amino heterocycles. Some illustrative examples are depicted in Scheme 16. 

A 1 1 adduct from diphenylsulfilimine and a benzoylacetylene underwent an intramolecular cyclization reaction to give an isoxazole in good yield (equation 40). Similarly, the 1 1 adduct from iodoazide and chalcone gave 3,5-diphenylisoxazole (equation 41). These two approaches to regiospecific isoxazole synthesis are of little practical significance. Additional examples of the (OCCCN) reaction are given in equations (42) and (43). 

Appropriately substituted selenides can undergo cyclization reactions via a group transfer process. 

Intramolecular addition reactions are quite common when radicals are generated in molecules with unsaturation in a sterically favorable position. Cyclization reactions based on intramolecular addition of radical intermediates have become synthetically useful, and several specific cases will be considered in Section 10.3.4 of Part B. 

Divergence of Enzymatic and Biomimetic Chemical Cyclization Reactions.297... 

The cyclization reaction could also be carried out before the reduction of the nitro group. The resulting nitro alcohols were then converted toPGEi and l5-epi- and 11,15-epi-PGEi s. 

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