Reaction transannular

An important characteristic of medium-sized alicyclic rings is the ease with which transannular reactions arising from proximity of atoms occur (e.g. see 103). In the preferred conformation of the four-carbon bridge in the longifolane (155) and longibornane (156) systems, the proximity of the C-3, C-10 and C-2, C-9 positions, respectively has been responsible for interesting transannular reactions, both of homolytic and heterolytic types. 

The diyne cyclizations discussed so far involve the formation of an aromatic system together with the biradical. Surprisingly, though, a new kind of diyne- to -biradical cyclization has been discovered only recently, where the transannular interaction of two triple bonds in a diazacy- 

The importance of transannular electronic interactions is beautifully shown in a reaction found by S. Misumi, T. Ogawa and T. Kaneda [Eq. (22)], when transannular interaction between a diyne system and an aromatic ring results in completely unusual reactivity [3 a]. 

5-Dimethylcyclo-octa-1,5-diene reacts with boron trifluoride diethyl etherate to give 2,5-dimethylbicyclo[3,3,0]oct-2-ene (60%), whereas l,5-dimethylbicyclo[3,2,l] octan-8-ol (156 R = H 50%) and its tosylate (156 R = Ts 70%) are formed on treatment with perchloric acid-aqueous dioxan and toluene-p-sulphonic acid, respectively. Preliminary results indicate that cis,ci -cyclo-octa-l,5-diene and hydrogen peroxide-mercury(ii) nitrate react to give a transannular peroxide. The boron trifluoride diethyl etherate-benzene catalysed cyclizations of the cyclo-octenyl ester (157 R = COjEt) and ketone (157 R = COMe) to the bicyclo[3,3,l]nonanes (158 R = C02Et) and (158 R = COMe), respectively, have been studied further. Possible intermediates in these reactions were synthesized but no cyclized products were obtained. The mechanism that was finally suggested involves protonation of the 

Cyclo-octa-2,4-dien-l-ol is converted into anti -2,3-epoxycyclo-oct-4-enol (91 %) on treatment with m-chloroperoxybenzoic acid, whereas t-butyl peroxide-VO(acac)2 gives the bicyclic ether (163 78 %). 2,6,6-Trimethylcyclohepta-2,4-dienol is converted into syn-2,3-epoxy-2,6,6-trimethylcyclohept-4-enol (65 %) by m-chloroperoxybenzoic acid and into (164 86%) by t-butyl per oxide-VO(acac)2- As the syn-epoxycyclo-heptenol gave (164) on treatment with VO(acac)2, it was suggested that in the t-butyl peroxide-VO(acac)2 epoxidations the bicyclic ethers were formed via the syn-2,3-epoxides and subsequent transannular S 2 substitution. The nature of the products obtained from reactions of epoxides with lithium diethylamide is solvent dependent. Thus the mono-epoxide of cyclo-octa-1,5-diene gives cyclo-oct-3-enone in benzene or ether and bicyclo[5,l,0]oct-2-en-syn-6-ol in HMPT the exocyclic 

Jitsukawa, K. Koneda, and S. Teranishi, Tetrahedron Letters, 1976, 3157. 

Treatment of cyclo-octa-2,7-dienone with phenylphosphine and hydrogen peroxide gives a mixture of transannular adducts (167 50%). Transannular nitrogen-bridged products are obtained from the reactions of (168) with mercury salts, 1,4-and 1,5-bridged compounds being obtained using mercury(ii) acetate or mercury(ii) chloride. 

Caryophyllane-2,6-a- and -P-oxides have been prepared from (— )-isocaryophyll-ene. Intramolecular epoxide opening has been studied for seven diols prepared by oxidation of the exocyclic double-bond of caryophyllene and isocaryophyllene epoxides.  

SeTen-membered Rings.—Oxymercuration of cycIohept-4-enoI followed by iodide-ion exchange gives the crystalline mercurial (259). Stabilization of 

E ht-membered Rii — The reaction of cyclo-octene with lead tetrachloride to produce rrnns-1,4-dichlorocyclo-octene is discussed, as are the solvolyses of cyclo-oct-3-enol, cyclo-oct-4-enol, and cyclo-oct-4-enylmethyl brosylates 

Cyclo-octene oxide is known to give largely bicyclo[3,3,0]octan-2-ol on cyclization with lithium diethylamide, but this transannular reaetion may be avoided by using bases such as KOBu -DMSO, which give predominantly cyclo-oct-2-enol  

Oxymercuration-demercuration of 5,6-epoxy- and 4,5-epoxy-cyclo-octenes leads largely to CTido-9-oxabicyclo[3.3 l]nonan-2-ol. Cyclo-oct-4-enone and cyclo-oct-2-enone give largely hydroxy-ketones, whereas cyclo-oct-3-enone 

The addition of pseudohalogens IX (X = NCO, N3, or NO3) to cyclo-octa-1,5-diene gives monocyclic 1,2-products, but Ij-MeOH gives (262 X = Y = 1), whose chair conformation is confirmed by n.m.r. spectroscopy. Similarly, 5-methoxycyclo-octene gives (262 X = H, Y = I) with I -MeOH whereas the O 

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Onium ions of small and large heterocyclics are usually produced by electrophilic attack on a heteroatom. In three- and four-membered rings nucleophilic attack on an adjacent carbon follows immediately, in most cases, and ring opening stabilizes the molecule. In large rings the onium ion behaves as would its acyclic analog, except where aromaticity or transannular reactions come into play (each with its electronic and steric pre-conditions). A wide diversity of reactions is observed. 

Anions of small heterocyclics are little known. They seem to be involved in some elimination reactions of oxetan-2-ones (80JA3620). Anions of large heterocycles often resemble their acyclic counterparts. However, anion formation can adjust the number of electrons in suitable systems so as to make a system conform to the Hiickel rule, and render it aromatic if flat geometry can be attained. Examples are found in Chapter 5.20. Anion formation in selected large heterocycles can also initiate transannular reactions (see also Section 5.02.7 below). 

Large ring heterocyclic radicals are not particularly well known as a class. Their behavior often resembles that of their alicyclic counterparts, except for transannular reactions, such as the intramolecular cyclization of 1-azacyclononan-l-yl (Scheme 1) (72CJCH67). As is the case with alicyclic ethers, oxepane in the reaction with r-butoxy radical suffers abstraction of a hydrogen atom from the 2-position in the first reaction step (Scheme 2) (76TL439). 

Nucleophilic attack on ring atoms of large heterocycles is largely confined to saturated systems, saturated parts of partially unsaturated systems, and to carbonyl functions and the like. These reactions are not fundamentally different from those of corresponding acyclic systems, except for transannular reactions. 

The homolysis of tertiary hypochlorites for the production of oxy radicals is well known." The ease with which secondary hypohalites decompose to ketones has hampered the application of hypohalites for transannular reactions. However the tendency for the base-catalyzed heterolytic decomposition decreases as one passes from hypochlorites to hypobromites tohypoidites. Therefore the suitability of hypohalites for functionalization at the angular positions in steroids should increase in the same order. Since hypoidites (or iodine) do not react readily with ketones or carbon-carbon double bonds under neutral conditions hypoiodite reactions are more generally applicable than hypochlorite or hypobromite decompositions. 

Reaction of dibromocyclopropane (39) with hot quinoline gives 1-ethoxy-cyclohepta-l,3,5-triene (37) in 32% yield. Dihalocyclopropanes prepai ed from larger ring enol ethers do not react with hot pyridine but afford products with hot quinoline formed by transannular reactions. 

Dell C. P. Cycloaddition in Synthesis Contemporary Organic Synthesis 1997 4 87 Keywords natural products, metal catalyzed, asymmetric reactions, Ionic reactions, transannular reactions, tethered reactions, tandem reactions, benzo-qulnones, quinodimethanes, hefero-Dlels-Alder reactions... 

An illustration of the plethora of reactions that may occur is afforded by the transformation of caryophyllene oxide by Botrytis cinerea. Although most of the reactions were hydrox-ylations or epoxidations, two involved transannular reactions (a) between the C4-epoxide oxygen and Cy and (b) between the C4-epoxide and C13 with formation of a caryolane (Figure 7.47) (Duran et al. 1999). 

The Hofmann degradation is the most well-known C—N bond cleavage reaction, and its value to structural elucidation of alkaloids has been demonstrated (76). Hofmann degradation of tetrahydroberberine methohy-droxide (1) led to two products base A (2), the C-14—N bond cleavage product, and base B (3), the C-6—N bond cleavage product (Scheme 2) (17,18). The former was the major product when 1 was heated under reduced pressure, but the latter, the thermodynamically controlled product, predominated when the reaction was carried out at atmospheric pressure or in an alkaline medium because base A recyclized back to the starting quaternary base through the transannular reaction. In fact, 2 was heated in aqueous alcohol to afford 1. The mechanism of this recyclization reaction was discussed by Kirby et al. (19). 

A well-known characteristic of medium-sized rings (8- to 11-membered) is their ability to undergo facile transannular reactions. Cere et al. found that acid-catalyzed transannular cyclizations of 8-10-membered 7,5-unsaturated cyclic sulfides yield fused bicyclic sulfonium salts independently of the geometry of the double bond <1998J(P2)977>. 

In type A reactions one electron is removed from one of the two double bonds to form a cation radical, and allylic substitution and oxidative addition take place as the following reactions. On the other hand, in type B reactions the initial electron transfer from the double bond is accompanied by a transannular reaction between the two double bonds. 

Substituents larger than hydrogen atoms cannot generally occupy intraannular positions. We have seen about transannular reactions which are special distinctive feature of medium-sized rings. The transannular reactions do not occur at the carbon atom of the chain and they also do not involve the neighbouring atoms. They take place between atoms on opposite sides of the ring. 

Transannular reactions have also been described in cyclooctane series. For example, cyclooctane oxide combines with formic acid to form two glycols by such reaction. 

Another characteristic feature of such transannular reactions is their stereospecificity. Thus if the starting material is a certain spatial stereoisomer, the product will also be a certain stereoisomer and not a mixture of isomers. This is because of the spatial form of the ring. 

Dimethyl tricyclo[4.2.2.02 -5]deca-3,7-diene-9,10-dicarboxylate adds bromine and iodine only to the less hindered double bond to give the syn 1,2-addition product of the cyclobutene moiety79. The product composition from this compound depends on the temperature and the solvent. At high temperatures, the 1,2-addition predominates over the transannular reaction, but this predominance is small in a solvent like chloroform and is lost in a protic solvent such as acetic acid (equation 47). 

A transannular reaction involving a through-space interaction has been observed also when bromine was added to homohypostrophene (40). The bromination proceeds straightforwardly by 1,4-addition to give exclusively the dibromo adduct 41 (equation 49)80. 

Elimination of HI, which in the presence of an excess of IN3 can form hydrazoic acid, followed by its addition to the vinyl azides can give an intermediate triazide 75. The same compound could arise directly by substitution of one iodine atom by an azido group. The intermediate 75 has been considered to undergo a transannular reaction with homolytic cleavage of the weak C—I bond to form the radical 76, which loses a nitrogen atom to a radical 77. Combination of the two radicals leads to the 2-tetrazene 74 (equation 77). 

The larger (Z,Z)-l,5-cyclononadiene (169) reacts141 stereoselectively with PhSeCl in AcOH to give the substituted hydrindan 170 (equation 138). In consideration of the anti addition mode of selenenyl reagents to double bonds, the transannular reactions of 169 have been rationalized on the basis of the two reaction intermediates, 171 or 172, which are liable to place the PhSe- and AcO- groups in a cis- 1,4-relationship and trans to the bridgehead hydrogen (equation 139). The preferential formation of 170 has thus been attributed to the fact that the pathway via 172 should involve a boat transition state. 

Depending upon substituents, transannular interactions in the [2.2]paracyclophane system are characterized by the steric or electronic effects of one aromatic nucleus on the physicochemical behavior of the other aromatic ring. The transannular reactions themselves, of course, are very dependent upon molecular geometry. 

Medium ring compounds are flexible, and a knowledge of their predominant conformations should help to predict the course of reactions in these molecules (276). MM calculations proved to be useful in this respect as well, especially for transannular reactions of sesquiterpenes (10a,277,278). 

On the contrary, a-lithiated epoxides have found wide application in syntheses . The existence of this type of intermediate as well as its carbenoid character became obvious from a transannular reaction of cyclooctene oxide 89 observed by Cope and coworkers. Thus, deuterium-labeling studies revealed that the lithiated epoxide 90 is formed upon treatment of the oxirane 89 with bases like lithium diethylamide. Then, a transannular C—H insertion occurs and the bicyclic carbinol 92 forms after protonation (equation 51). This result can be interpreted as a C—H insertion reaction of the lithium carbenoid 90 itself. On the other hand, this transformation could proceed via the a-alkoxy carbene 91. In both cases, the release of strain due to the opening of the oxirane ring is a significant driving force of the reaction. 

FIG. 10. Precursors, electrophilic intermediates, and products of transannular reactions of septanoses. 

Racemic argemonine (5) has been synthesized from the readily available tetrahydro-6,12-methanodibenz[c,/Iazocine (74) (120-122) through a sequence involving a Stevens rearrangement and in an overall yield of 53% from 74 (Scheme 11) (123). Hofmann degradation of 74 furnished the cxo-methylene compound 75 (120,122). An oxidative ring expansion of 75 afforded ketone 76, which was then reduced to secondary alcohol 77. A transannular reaction, effected by acetic acid-acetic anhydride, resulted in the formation of the tetra-... 

The synthesis of a new class of compounds possessing the general structure 4,4,8,8-tetraalkyl-2,3 6,7-dibenzo-9-azabicyclo[3.3.1]nonane-l,5-diol (84) deserves mention since the basic skeleton is analogous to that of the pavines (Scheme 12) (124-129). Oxidation of a series of indeno[2,l-a]indenes 82 with chromic acid yielded dibenzocyclooctanediones 83. Treatment of these diketones with various amines resulted in a transannular reaction to afford species 84 in good yields. 

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