Nucleophilic functional

In the first mechanism (equation 74) the nucleophile function attacks the aromatic ring in an ipso-type displacement involving a Meisenheimer complex intermediate243,244, and leads to the rearranged product after expulsion of sulfinate anion (X-). This mechanism should be favoured by the presence of an electron-withdrawing substituent in conjugation with the anion. The second mechanism (equation 75) involves a direct displacement of sulfinate anion (X ) by Y-, without involvement of the aromatic n electrons. 

Several other nucleophilic functional groups can be induced to participate in iodocyclization reactions. t-Butyl carbonate esters cyclize to diol carbonates.79... 

Other nucleophilic functional groups can participate in iodocyclization. Amides usually react at oxygen, generating imino lactones that are hydrolyzed to lactones.88... 

Compounds in which a carbonyl or other nucleophilic functional group is close to a carbenoid carbon can react to give ylide intermediate.221 One example is the formation of carbonyl ylides that go on to react by 1,3-dipolar addition. Both intramolecular and intermolecular cycloadditions have been observed. 

Scheme 6/1.75. Pd-catalyzed transformation of organic halides or triflates with alkynes or allenes containing a nucleophilic functionality.

When the alkynyl substrate possesses a nucleophilic functionality, intramolecular solvomercuration reactions can sometimes be observed. These reactions, which result in the formation of a heterocycle, have been used in the total synthesis of natural products. For example, reaction of 114 with Hg(OAc)2 affords the benzofuran derivative 115, which is an important intermediate for the synthesis of various neolignans (Equation (42)).154 155... 

Generally speaking imidazole is the nucleophilic functional group, and many of the chiral surfactants are histidine derivatives (Brown and Bunton, 1974 Brown et al., 1981). In other cases mixed systems have been used, e.g. an inert cationic surfactant plus a chiral amphiphilic histidine or hydroxa-... 

Ring closure with formation of heterocyclic derivatives may occur when a nucleophilic function is present in the starting alkene and it is suitably placed for cyclization [30-43]. Both kind of the mechanistic pathways shown in path a of Scheme 3 and in Scheme 4 may operate, as exemplified by Schemes 5-6 (Y = O, NR). Clearly, only in the first case carbon monoxide is incorporated into the heterocyclic ring (cyclocarbonylation). 

Anodic nucleophilic functionalization of an a-carbon turned out to be particularly efficient for the fluorination of organic sulfides. The introduction of one or two fluorine atoms at the a-carbon was reported in several papers for sulfides bearing EWGs = CN, COMe, COPh, CF3, COzEt, CONEt2, PO(OEt)2) (Scheme 18) [75-78], Two systems are mainly used as the supporting electrolyte and fluorine source at a time namely, EtsN-SHF and Etr NF. 

The other nucleophilic functionalities (OH, CO2H, CH2OH, CONH2) are fully preserved from alkylation and/or transesterification reactions. 

As shown in Figure 4.1, the initial step of the conversion of an ylide into a carbene complex is an electrophilic attack at the ylide. Reactions of this type will, therefore, occur more readily with increasing nucleophilicity of the ylide and increasing electrophilicity of the metal complex L M. Complexes which efficiently catalyze the decomposition of even weakly nucleophilic ylides can easily react with other nucleophiles also, such as amines or thiols. This has to be taken into account if reactions with substrates containing such strongly nucleophilic functional groups are to be performed. 

The use of functionalized isocyanides containing both the isocyanide function and the nucleophile in the same molecule leads to complexes with heterocyclic carbene ligands via a 1,2-addition across the C=N triple bond. Complexes with functionalized isocyanide ligands can be generated in template reactions or a nucleophile functionalized isocyanide can be reacted directly with a suitable metal complex. 

The nucleophiles that are used for synthetic purposes include water, alcohols, carboxylate ions, hydroperoxides, amines, and nitriles. After the addition step is complete, the mercury is usually reductively removed by sodium borohydride. The net result is the addition of hydrogen and the nucleophile to the alkene. The regioselectivity is excellent and is in the same sense as is observed for proton-initiated additions.16 Scheme 4.1 includes examples of these reactions. Electrophilic attack by mercuric ion can affect cyclization by intramolecular capture of a nucleophilic functional group, as illustrated by entries 9-11. Inclusion of triethylboron in the reduction has been found to improve yields (entry 9).17... 

The trialkyloxonium salts are powerful alkylating agents. Trimethyl- and triethyloxonium tetrafluoroborates, in particular, have been widely employed for methylation and ethylation of sensitive or weakly nucleophilic functional groups. Alkylations of over 50 such functional groups have been reported in the literature. Examples include amides,4,7,13 16 lac-... 

Highly Lewis basic and nucleophilic functional groups are not compatible with zinc carbenoids. The methylation or ylide formation of heteroatoms is one of the most important side reactions of these reagents. For example, amines, thioethers and phosphines readily react with the zinc reagents to generate ammonium salts", sulfonium" and phosphonium ylides" ". Terminal alkynes generally lead to a large number of by-products". ... 

The second chemical principle of interest here is that many biochemical reactions involve interactions between nucleophiles (functional groups rich in electrons and capable of donating them) and electrophiles (electron-deficient functional groups that seek electrons). Nucleophiles combine with, and give up electrons to, electrophiles. Common nucleophiles and electrophiles are listed in Figure 6-21. Note that a carbon atom can act as either a nucleophile or an electrophile, depending on which bonds and functional groups surround it. 

Under these conditions, other nucleophilic functional groups may also be alkylated, which limits the range of compounds accessible by this methodology. Moreover, volatile alkylating agents are often highly toxic and therefore problematic to handle. 

The identity of the heteroatom present in a target molecule dictates the identity of the nucleophilic atom (Z) to be used in an electrophilic heteroatom cyclization reaction of the type shown in Scheme 1. However, successful application of this strategy to the synthesis of specific target molecules also requires selection of appropriate combinations of nucleophilic functionality (Z-R) and activating electrophile. Therefore, major subdivisions within this chapter are based on the identity of the heteroatom, although comparisons between results observed for the different heteroatoms will be made. 

Some unusual nucleophile functional groups that have been utilized in cyclofunctionalizations to form bridged ring systems include cyclic hemiacetals (equation 18)73 and epoxides (equation 19).87 The cyclizations in equation (20) involve a cyclic enol ether as the reactive ir-system and have been used in syn-... 

An interesting example of the apparent dependence of stereoselectivity on the rate of breakdown of the initial cyclization intermediate has been observed in cyclizations with isoxazolines as the nucleophilic functionality (equation 48 and Table 14).141 The stereochemistry of products from cyclizations to form tetrahydrofuran products varies significantly upon changing the 3-substituent of the isoxazoline ring (Table 14, entries 1-3). The exact factors controlling these variations have not been determined, but the stereoselectivity may be synthetically useful. Particularly noteworthy is the high selectivity for the less... 

The cyclofunctionalization of cycloalkenyl systems where the chain containing the nucleophilic functionality is attached at one end of the double bond leads to spirocyclic structures. Cyclizations of cyclic and acyclic enol ethers to generate spiroacetals are shown in equations (66)168 and (67).169 These reactions generate the thermodynamically more stable products based on anomeric and steric factors.170 Spiroacetal products have also been obtained using isoxazolines as the nucleophilic functionality (cf. Table 14).l4lb Studies of steric and stereoelectronic control in selenoetherification reactions which form spirocyclic tetrahydrofurans have been reported.38 An interesting example of stereoelectronic control in the formation of a spirocyclic lactone has been reported in a recent mevinolin synthesis (equation 68).171... 

Several examples of intramolecular solvomercuration of arylalkynes have been reported (equations 81 to 83).200 The mercury moiety can be removed by protiodemetallation or converted to a variety of other functional groups. The use of a methyl ether as the nucleophilic functionality is noteworthy, as is the change in the regioselectivity (equation 82 versus equation 83). A bromocyclization related to equation (83) using a phenylethynylbenzoate ester also gives an isocoumarin derivative via 6-endo cyclization.201 Palladium-catalyzed cyclizations of 3,y-alkynic ketones or 2-methyl-3-alkyn-l-ols to form substituted furans are discussed in Chapter 1.4, Section 3.1.3 in this volume. 

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