Ring construction

The use of carbonyl groups to set the polarity of bond disconnections in ret-rosynthetic analysis is useful for the construction of rings as well. If a carbon electrophile and a carbon nucleophile are connected by a carbon chain, they can react with each other to form a carbon-carbon bond. This is an absolutely normal type of carbon-carbon bond-forming process, but the fact that the carbon nucleophile and carbon electrophile are connected by a chain means that the new carbon-carbon bond closes up the ends of the chain, forming a ring. 

For example, the Claisen reaction is a reaction of an ester enolate with an ester to produce a /3 ketoester. We learned this reaction earlier. 

If both ester groups are in the same molecule and are connected by a chain, then a Claisen-type reaction between the a position of one ester and the carbonyl 

Likewise reactions with 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane give the corresponding cyclobutyl-, cyclopentyl-, and cyclohexyl-1, 1 -dicarboxy lates. 

The yields of these reactions are not the same, however, and reactions which produce three-, five-, and six-membered rings are generally more effective. Use of 1,6-dibromohexane fails to give the cycloheptyl product. 

Among many Lewis acid-promoted cycloadditions Diels-Alder reactions have been most widely investigated to date. Simple silicon Lewis acids such as la do not, unfortunately, catalyze the standard Diels-Alder reaction of acrylate and cyclopenta-diene. Accordingly, silicon Lewis acids are generally not very suitable for the related cycloaddition reaction. Few reports on silicon Lewis acid-promoted cycloaddition reactions are thus shown herein. 

In 1988, Gassman et al. described ionic Diels-Alder addition of vinyl ortho ethyl ester 25 to a series of 1,3-dienes in the presence of la (Sch. 20) [51]. This concept came from their previous report that allylic cations are powerful Diels-Alder dieno-philes toward 1,3-dienes. When an attempt was made to clarify the nature of the intermediate 27 by trapping with trimethylsilyl cyanide, 24 % 28 was accompanied by 25 % adduct 26. 

Ic-catalyzed Diels-Alder reaction between N,A-dimethylacrylamide and activated cyclic dienes was reported by Ghosez. Non-catalyzed thermal reaction or use of Eu(fod)3 resulted in exo-preference, whereas complete stereochemical divergence was observed with Ic under mild conditions (Sch. 21). 

Compound 7 was evaluated as a Diels-Alder catalyst instead of silyl triflate (Sch. 22). As expected from Si NMR measurement, substantial rate acceleration was observed in the Diels-Alder reaction of methyl acrylate with a variety of dienes. 

Diels-Alder reaction of Ic with cationic species formed from chromones or pyr-ones was reported by Akiba et al. (Sch. 23) [53]. The cationic intermediates react with a range of 1,3-dienes to furnish the corresponding cycloadducts in moderate to good yields. 

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Remarkably few examples of this type of ring construction are available. The cobalt carbonyl hydride catalyzed hydroformylation of A/,A/ -diallylcarbamates has provided 3-pyrrolidinones (Scheme 61a) (81JOC4433). The pyrrole synthesis shown in Scheme 61b depends on Michael addition of ethyl a-lithioisocyanoacetate to ethyl a-isocyanocrotonate (77LA1174). 

Although widely applied in functional group modification in a variety of heterocyclic systems, phosphorus ylides have only been employed sparingly in heterocyclic ring construction with two or more heteroatoms in the nucleus. Their potential is shown in the applications illustrated below. 

The discovery of palladium trimethylenemethane (TMM) cycloadditions by Trost and Chan over two decades ago constitutes one of the significant advancements in ring-construction methodology [1]. In their seminal work it was shown that in the presence of a palladium(O) catalyst, 2-[(trimethylsilyl)methyl]-2-propen-l-yl acetate (1) generates a TMM-Pd intermediate (2) that serves as the all-carbon 1,3-di-pole. It was further demonstrated that (2) could be efficiently trapped by an electron-deficient olefin to give a methylenecyclopentane via a [3-1-2] cycloaddition (Eq. 1). 

The Balz-Schiemann reaction continues to attract attention, with much of it generated by the interest in fluoroquinolones, e.g., (7), which is a potential antibacterial. Two approaches to its synthesis are possible—introduction of fluorine prior to or post ring construction. Decomposition of the tetrafluoroborate salt was unsuccessful, whereas the PF6 salt (8) gave only a poor yield (84JMC292). A more successful approach was the introduction of F into the pyridine nucleus prior to formation of the 1,8-naphthyridine ring (84JHC673). A comparison of decomposition media showed that cyclohexane was the best with regard to yield and time. 

The convergent approach comprises, among other reaction steps, a regio-specific intermolecular benzannulation reaction between the alkyne 88 and the chromium carbene complex 89 for AB ring construction (Scheme 43). It is noteworthy that the regioselectivity of this reaction is attributed to the bulky TBDMS ether in the alkyne a-substituent, that dictates the incorporation of the large substituent ortho to the phenol. Another curiosity is the fact that the reaction failed to provide 90 in the absence of acetic anhydride. 

Keywords chiral lanthanoid complexes, rare earth complexes, carbocyclic ring construction via intramolecular Diels-Alder reaction... 

By starting with enantiomerically enriched IpcBHCl, it is possible to construct chiral cyclic ketones. For example, stepwise hydroboration of 1-allylcyclohexene and ring construction provides /ran.v-1-decalone in greater than 99% e.e.19... 

In contrast to the Johnson s D —> A-ring construction approach, Brown devised an A —> D-ring construction approach [22]. Starting from Wieland-Miescher ketone (30), a common source of the A, B-rings in the de novo synthesis of steroids, the C-ring was introduced via hydrazone allylation, ozonolysis, aldol condensation, and olefin isomerization (31 > 32). The D-ring was assembled by a reductive alkylation... 

At this point, we had exerted an immense amount of effort to overcome a number of difficult transformations and their unprecedented challenges (1) oxidation at C3 and C3a, (2) reduction at C8a, and (3) homologation at C5a. We learned to truly respect the unique structural topology that ABD-tricycle 2 possesses. What remained for the total synthesis was the C-ring construction, which posed serious challenge of its own. 

Carbene complexes are versatile intermediates in ring construction [47], The insertion of alkoxycarbenechromium complexes 93 into cyclobutenediones 63 leads to the ring-expanded cyclopentenediones 94 as shown in Scheme 33 [48]. 

If ammonium thiocyanate is used, the ammonium ion can itself provide a nitrogen atom for heterocyclic ring construction. Such nitrogen and sulfur transfer is the basis of an elegant synthesis of isothiazoles (15) from 3-chloropropenals (16).18... 

All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often one pot , ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction. 

Resin bound dipeptides have been used in the parallel synthesis of 3,4,7-trisubstituted 4,5,8,9-tetrahydro-3//-imidazo l, 2-a l, 3,5 triazcpinc-2(7//)-thioncs and Af-alkyl-4,5,7,8-tetrahydro-3//-imidazo[ 1,2-a][l, 3,5]triazepin-2-amines by ring construction methodology <06JCOl27>. 

This chapter deals with [2 + 2]cycloadditions of various chromophors to an olefinic double bond with formation of a four-membered ring, with reactions proceeding as well in an intermolecular as in an intramolecular pattern. Due to the variety of the starting materials available (ketones, enones, olefins, imines, thioketones, etc.. . .), due to the diversity of products obtained, and last but not least, due to the fact that cyclobutanes and oxetanes are not accessible by such a simple one-step transformation in a non-photo-chemical reaction, the [2+2]photocycloaddition has become equivalent to the (thermal) Diels-Alder reaction in importance as for ring construction in organic synthesis. 

One of the most common approaches to pyrazine ring construction is the condensation of diaminoethane and 1,2-dicarbonyI compounds such as 206 to provide pyrazines 207 after aromatization. Aromatization was accomplished by treating the dihydropyrazines with manganese dioxide in the presence of potassium hydroxide <00JCS(P1)381>. The N-protected 1,2-dicarbonyl compounds 206 were prepared from L-amino acids by initial conversion into diazoketones followed by oxidation to the glyoxal. 

F. Ring-Construction by Intramolecular C-H Insertion of (Phenylthio)carbenes... 

The metal-catalyzed [5 + 2]-cycloaddition reaction of VCPs and 7t-systems provides a new concept for seven-membered ring construction that has been significantly advanced over the last decade in the areas of catalyst development, chemo-, diastereo-, and enantioselectivity, substrate scope, and applications to total synthesis. 

This chapter focuses on cycloaddition reactions in which at least two new cr-bonds are formed between allene derivatives and other unsaturated organic molecules. Intramole-cular cycloaddition reactions are also described. The reactions are categorized according to assembly modes, such as [m + n]-cycloaddition, where the variables m and n simply denote the number of atoms that each component contributes to the ring construction. Some electrocyclic reactions of allene derivatives are also included. 

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