Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 1135 122

CN

OMe

O

CH

O

R

(83) R = H

= (85) (84) R MeO

double-bond bromination takes place. This divergence has been rationalized in terms of increased steric shielding of the double bond and electron density on the aromatic ring152.

Halogen addition to endo- and exo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-ones has been shown to be dependent on the nature of the reagent and the annulation153. The spironaphthopyran 85 has been found to undergo double bromination with remarkable stereoselectivity. The structure of the resulting tetrabromide is in agreement with a mechanism involving initial electrophilic attack at both double bonds from the sides opposite to Ar154. Anomalous bromination of cyclohexylidenecylclohexane has been examined155. Bromination of 3-isopropenyltropolones 86 (R D H, Me, Pri) with Br2 in AcOH leads to furanobromide 87, while NBS gives a different product156.

Although kinetic studies of bromination of methyl (E)-cinnamic acid and methyl (E)-ˇ- styrylphosphonate suggest analogous mechanisms for both reactions, the stereochemistry of the reactions indicates that product-forming steps of different character must be involved157.

Bromine has been reported to add syn to the double bond of the [60]fullerenecyclopentadiene adduct; both bromine atoms in the product 88 point away from the cage158. Epoxidation also occurs from the face away from the cage158.

Br

Br

(88)(89)

cis trans Isomerization of ˛,˛-difluoroolefin 89 in CCl4 by a substoichiometric amount of Br2 has been interpreted as a result of the destabilization of the cyclic bromonium ion in favour of an open carbocation. The latter species is capable of free rotation and of subsequent elimination to afford the trans-isomer of 89. A CF2 group appears to be more effective in promoting isomerization than aryl in stilbenes159.

Micellar effects on alkene bromination have been further studied and strong inhibition (105 106 fold) of the second-order reaction rate constants relative to those in water has been observed. The kinetics and the product distribution suggest that different olefins have different locations at the micellar surface. Kinetics in the presence of added NaBr and n-decane support this hypothesis160. Selective bromination of alkenes using bromine

Br2 and HCl at low temperature; styrene proved inert. A kinetic study with 3- chloropropene showed that the reaction is first-order in both Br2 and HCl. An ionic mechanism has been proposed for polar solvents, whereas a ‘molecular’ mechanism is believed to operate in solvents of low polarity168.

Regioselective (Markovnikov) and stereospecific (anti ) iodochlorination of several alkenes (e.g. 43) and alkynes has been described using polyfstyrene-[4- vinylpyridiniumdichloroiodate(I)]g169. An analogous bromochlorination reagent reacts with substituted styrenes to give products corresponding to those formed by classical methods170. Anti-stereospecific and regioselective iodochlorination of olefins has also been reported using PhCH2NC Me3ICl2 . In methanol, iodomethoxylation competes171. Addition of IN3 to 1-phenylcyclohexene affords the expected Markovnikov product corresponding to the anti-addition mechanism172.

B. Hypohalous Acids and Other XOR-type Reagents

Caesium fluoroxysulphate has been reported to add to alkenes (1-hexene, styrene, cyclohexene and others), furnishing vicinal fluorosulphates. The regioand stereo-selectivity is rather low and may be partially influenced by the solvent; some preference for antiMarkovnikov products and for syn-addition has been observed. The slight predominance of cis-products seems to be consistent with a concerted mechanism173.

The chlorination of ˛,ˇ-unsaturated ketones by Cl2 in MeOH gives mixtures of Markovnikov and anti-Markovnikov methoxychlorides and dichlorides. Significant increase in the proportion of Markovnikov regioisomers was observed in the presence of acid scavengers, such as pyridine. This effect was ascribed to the elimination of the acid-catalysed mechanism, allowing the chlorination to occur via chloronium ion174.

A kinetic model for oxychlorination of olefins has been developed and verified for

or acids occurs solely at the more substituted double bond and gives mixtures of the corresponding products of dichlorination and alkoxyor acyloxy-chlorination (Markovnikovtype), respectively177.

The striking differences observed for the reaction of NBS with allyl alcohol vs crotyl alcohol have been rationalized as follows: with allyl alcohol, formation of the solvated bromonium ion and HOBr are rate-limiting steps. By contrast, with crotyl alcohol, the rate-limiting step appears to be the breakdown of an NBS-crotyl alcohol complex, formed in a fast pre-equilibrium178.

Bromomethoxylations (NBS/MeOH) of conformationally mobile hydroxyor methoxycyclohexenes and dihydropyrans suggest that the inductive effect of the substituent governs the regiochemistry, as with 96, whereas the steric hindrance (if present) controls the stereoselectivity (97)179. In the latter case, however, the possibility of isomerization at the anomeric centre has not been taken into account. It has also been found that compounds with strong steric hindrance, exercised by an axial substituent, may prefer a reversal of the regiochemistry of the nucleophile attack to avoid the interaction of incoming nucleophile with the axial substituent179.

Substantial amounts of anti-Markovnikov products have been found for bromination of non-symmetrically substituted olefins RCHDCH2 in methanol, particularly with bulky R groups (R D But and Pri)109. Mechanistic studies of a novel regiospecific hydroxybromination, employing CBr4, O2 and RO (R D Me, Pri, But) as reagents, suggest that both radical and carbanionic intermediates are involved180.

A dramatic effect of the presence of NBS upon the bromination of ˛,ˇ-unsaturated ketones with bromine in MeOH has been observed. While in the absence of NBS mostly dibromides are formed, bromination in its presence has been found to afford anti-Markovnikov methoxy-bromides as the major products, e.g. CH2DCHCOMe !

MeOCH2CH(Br)COMe181. It has been suggested that NBS removes acid, thereby causing a change from an acid-catalysed mechanism to a bromonium ion-type reaction.

Bromination of cinnamic acid with NBS in aq. MeOH gives 2-bromo-3-methoxy-3- phenyl propionic acid, PhCH(OMe)CHBrCO2H. At moderately high [HC ] the reaction is second-order and independent of [HC ], whereas at low [HC ] the rate increases with decrease in [HC ]. Succinimide inhibits the reaction182.

Bromide or chloride anions can now be oxidized to XC by p-nitrobenzenesulphonyl peroxide. The positive halogen thus formed reacts with olefins via halonium ions183. Similarly, PhSeC can be generated from PhSeSePh184.

Bromination of (Z)-2-methyl-3-alkenal acetal 98 with NBS in DMSO under irradiation affords selectively bromohydrin 99. The reaction is assumed to proceed via a bromoradical (generated by irradiation of NBS) that reacts with DMSO to give a yellow intermediate (possibly BrO SMe2) which may further react either with olefin to give the adduct 99 or with water, furnishing hypobromous acid185.

Hypobromous (HOBr) and hypoiodous (IOH) acids can be generated from NaBrO3 and H5IO6, respectively, by reduction with NaHSO3 in MeCN/H2O. Markovnikov orientation and anti-stereochemistry has been observed on addition of these reagents to a variety of olefins186.

Regio- (Markovnikov) and stereo-specific (anti ) incorporation of MeCN (a Ritter-type reaction) has been observed upon bromination of a series of olefins, carried out in this solvent187. The degree of this incorporation depends on the olefin structure and on the initial reagent concentrations and ratios. Thus, when performed at low initial concentrations and with the initial Br2/alkene ratio 2, this reaction can be used preparatively187.

A methyl substituent at a double bond of benzobicyclootadienes has a pronounced effect upon the course of addition of hypoiodous acid. While the unsubstituted derivative 80 has been known to give solely rearranged products, the stabilization of the transient carbocation by the methyl group prevents the rearrangement to some extent188.

Nitrosonium ion was found to promote iodination of cyclohexene; when AcOH was used as solvent, the trans-iodo acetoxy derivative was formed in a good yield. Solvolysis of the latter, followed by saponification, led to a cis-diol so that this method can serve as an alternative to the ‘wet-Prevost’´ reaction. The NOC cation is believed to promote the formation of ‘some positive iodine species’ (equation 1). Oxidation by oxygen leads to the regeneration of iodine and NOC from nitrosyl chloride189.

A stereospecific addition of But OI to ˇ-methylstyrene was observed in the presence of BF3, yielding Markovnikov products. This result contrasts with the non-stereospecific addition of ButOCl and ButOBr. It has been suggested that the bridging in the intermediate chloronium and bromonium ion derived from PhCHDCHMe is not as symmetrical as in the iodonium ion. Consequently, charge develops on the benzylic carbon in the first two cases, and rotation occurs about the C C bond190. By contrast, a radical mechanism is assumed in the absence of BF3 as anti-Markovnikov products are formed (both in the dark and upon UV irradiation)190.

Reactions of But OI/BF3, AcOI, ICl or IBr with 1,3-butadiene give mixtures of Markovnikov 1,2- and 1,4-addition products; no anti-Markovnikov 1,2-products have been detected. A radical mechanism was observed for ButOI. Greater 1,4-addition occurs with reagents containing an anion of lower basicity (ICl and IBr). These results have been interpreted as reflecting the charge density and ion-pair stability191.

Iodoalkoxylation of glycals has been found to furnish anti-addition products exclusively192. The product distribution is not affected by the electronegativity of the 5- substituent; steric factors appear to affect only the trans-diaxial opening of the intermediate iodonium ion192.

Addition of IN3 to 1-phenylcyclohexene affords the expected Markovnikov product corresponding to the anti-mechanism. Although further chemical transformations of the product seemed to be in conflict with the proposed structure, extensive 15N NMR experiments finally convinced the authors that the original structure was correct172,193. Iodination of cyclohexene promoted by silver isocyanate was used to prepare the corresponding trans-iodocyanate194.

The addition of astatine to ethylene in aqueous solutions forms the expected adduct, CH2At CH2OH, at various pH values195. Monovalent AtC was found to exist in a hydrated form (AtOH2)C .

C. Neighbouring Group Participation

Semiempirical MO methods have been employed to determine the reaction surface for intramolecular bromoetherification reactions. Bromonium ions have not been identified as intermediates; instead, the additions involve the formation of a weak olefin/BrC - complex, which is subsequently captured by a proximate nucleophile196.

Systematic investigation of the stereoand regio-control of electrophilic additions to cyclohexene systems (steroids in particular) by neighbouring groups allowed formulating certain principles, which govern the reactivities toward representative electrophiles,

namely BrC , IC , PhSeX, Hg2C, Tl3C and Pd2C197 . The conclusions that have been arrived at are in full agreement with those previously derived for HOBr and can be summarized as

follows. Stringent stereoelectronic control, resulting normally in the formation of diaxial products (as with cholesteryl acetate 100 and other compounds), can be suppressed, and the regiochemistry of the addition reversed by a neighbouring group in those structures in which the electronic (Markovnikov) effect favours this reaction course. Diequatorial adducts are then formed preferentially, provided the spacer between the neighbouring group and the double bond allows for the formation of at least a five-membered ring, as with 101 (R D H, Me, Ph, NH2, NHBn etc.) and 102. However, when the spacer is shorter, as with 103, exclusive formation of diaxial products is observed again. It has been suggested that while electrophilic additions to cyclohexenes normally proceed predominantly via cyclic ‘onium’ intermediates, neighbouring group intervention can result in the dominance of ‘open’ species, stabilized by the interaction with the neighbouring group. This would parallel the well known stabilization of the ‘open’ intermediates by the aromatic ring in additions to styrenes197. This reversion can thus be achieved only with cyclohexene systems containing a non-symmetrically substituted double bond having inherent tendency towards SN1-like or a borderline mechanism of cleavage of the halonium ion. With ‘symmetrical’ double bonds, where the preference for the SN2-like mechanism is strong, the presence of a neighbouring group alone does not suffice to override the stringent stereoelectronic control. Finally, intervention of a neighbouring group residing on the less hindered face of the double bond, as in 104 and 105, can alter the overall stereochemistry. These observations show that the introduction of a neighbouring group can control the course of electrophilic additions not only to aliphatic olefins and sets the limits for this type of control in highly biased and discriminating cyclohexene systems197.

Remarkable differences have been observed in the reactivity of iodonium reagents generated in different ways (I2 C AgC , TlC , Ce4C , Cu2C , Bi3C or KI)197. It appears that AgC and TlC salts are the best promoters, while reagents generated in situ by mixing iodine with Bi3C or Cu2C are much less reactive and can discriminate between diand tri-substituted CDC bonds. Silver(I)-mediated iodocyclizations of olefinic alcohols are followed by subsequent solvolysis, with an overall retention of configuration, employing a push pull mechanism (106 ! 109)197. This stereospecific, Koenigs Knorr-type reaction can occur readily with the iodo intermediates (such as 107) arising from electrophilic exo-Trig ring closure, regardless of the size of the ring initially formed. By contrast, the solvolysis is highly disfavoured for the heterocycles formed in a 5-endo-Trig fashion (110), as the corresponding transition state would be too strained. However, if a sixmembered heterocycle 111 is being formed as the result of a 6-endo-Trig cyclization, the subsequent solvolysis becomes possible197.

The same effects have been found to operate in the Tl(III)-mediated hydroxycyclization: as expected, 106 is readily cyclized to 109, employing analogous 5(O)n-exo-Trig cycliza-

tion and Tl3C as an electrophile198. For further comments, see the section on Tl(III) as an electrophile197,198.

A silver-free alternative to the Woodward Prevost´ synthesis of cis-1,2-diols has been reported199,200. An efficient preparation of 18O-labelled epoxides has been developed (112 ! 113), based on the silver(I)-mediated I2 addition carried out in the presence of

H218O201,202.

Kinetic studies of HOCl addition to allylacetic acid revealed the acceleration of lactonization by salts of weak acids (to an extent proportional to their concentration). This effect was attributed to the conversion of HOCl to a more reactive chlorinating agent (a mixed anhydride of HOCl). Non-dissociated allylacetic acid undergoes chlorolactonization approximately 3 times more slowly than its Na salt203.

Other halogenation studies have included the stereoand regio-control by neighbouring groups of additions in both aliphatic and alicyclic series. Allylic oxygen has been shown to have a decisive effect on the stereochemistry of closing up tetrahydrofuran rings via iodo-etherification. Other chiral centres in the substrate appear to have generally little overall influence204. A new model for homoallylic chiral induction in iodo-etherification has been proposed on the basis of semi-empirical MO calculation and experimental results205. The electrophile-mediated intramolecular cyclization of hept-2- enitols was found to conform to the Hehre model for electrophilic additions to alkenes bearing an allylic oxygen206.

In 1992, one group of investigators207 claimed that the stereochemistry of the cyclization of homoallylic alcohols, such as 114, by means of I2/CF3CO2Ag, formally corresponds to syn-addition(!), affording 116. By contrast, PhSeCl exhibited the expected anti-addition. The same dichotomy was reported for several other model compounds. It was noticed that the iodination reaction proceeded well only in MeCN (at temperatures as low as 40 °C) and the products were stable under the reaction conditions. No explanation for the unusual outcome of iodocyclization has been offered207. These results were soon disproved by another team208, who demonstrated that the structural assignment by the former group was incorrect. The second group have shown that, e.g., 115 gave a 60:40 mixture of iodocyclization products 117 and 118, both of which correspond to the expected, clean anti-addition208. In a letter to this reviewer, the senior author of the first group admitted a systematic mistake in structure determination, associated with the technique of NOE experiments.

This correction was later confirmed by yet another group208,209: the corresponding 5(O)n-endo-Trig cyclization of a number of related hydroxyalkenes has been demonstrated to occur via an ordinary anti-addition to the double bond with a very high diastereoselectivity209. Meticulous investigation of the NOE effects proved crucial in determining the product structure. A variation on the same theme gave rise to the trans- annulated tetrahydrofuranes, again via the 5(O)n-endo-Trig iodoetherification (119 ! 120)210,211. In this case, strictly anhydrous conditions are required in order to prevent the opening of the iodonium ion by water210.

Another claim for the syn-addition (this time for BrC and OH) across a double bond has been made212. This unusual outcome has been observed for bromolactonization of 121 employing a mixture of Me3SiBr, Me2SO and an amine as the source of BrC . The mechanism is believed to involve the sulphonium ion 122 as an intermediate arising by

trapping of the initially formed bromonium ion by Me2SO. The sulphonium group is then replaced by the carboxyl in the subsequent step, to give the cis-bromolactone 123212.

The stereochemistry of iodoetherification of N-substituted 3-aminopent-4-en-1-ols (124 ! 125 or 126) correlates well with the electronic effects of the N-substituent. Increasing the electron-withdrawing effect results in the increase of cis-isomer 125. It has been suggested that the sterically less favoured conformer 127 is responsible for the formation of the cis-product 125, whereas the trans-isomer 126 arises from the more favoured conformer 128. The latter conformer should be more reactive toward electrophiles only if there is sufficient donation from the C N to -orbitals, which can occur with N-substituents of relatively low electron-withdrawing effect, such as MeCO. More electron-withdrawing substituents (e.g. CF3SO2) render 128 less reactive than the energetically less favoured 127 which, in turn, is activated toward electrophilic attack due to the nN donation, thus changing dramatically the stereochemical outcome213. Stereoselective iodoetherification has been reported for N-alkenyl-N-(2- hydroxyalkyl)anilines214.

The small differences observed in the reaction rates of ω-alkenyl glycosides 129 and 130 with NBS (2.39 ð 10 4 s 1 and 6.3 ð 10 5 s 1, respectively)215 may suggest that when the reaction is carried out with a 1:1:1 mixture of NBS, 129 and 130, the recovered starting material, should be a 1:2:6 mixture of 129 and 130. In sharp contrast to this expectation, a 23:1 ratio has been found! The authors argue that this result clearly demonstrates the reversibility of the bromonium ion formation: although 132 is obviously generated under the reaction conditions, its consumption to give the corresponding products is apparently slower than that of 131. Hence, 132 serves as a brominating agent for