Carbon nucleophiles intramolecular termination reactions

The TT-allylpalladiLim complexes formed as intermediates in the reaction of 1,3-dienes are trapped by soft carbon nucleophiles such as malonate, cyanoacctate, and malononitrile[ 177-179). The reaction of (o-iodophenyl-methyl) malonate (261) with 1,4-cyclohexadiene is terminated by the capture of malonate via Pd migration to form 262. The intramolecular reaction of 263 generates Tr-allylpalladium, which is trapped by malononitrile to give 264. o-[odophenylmalonate (265) adds to 1,4-cyciohexadiene to form a Tr-allylpalladium intermediate via elimination of H—Pd—X and its readdition, which is trapped intramolecularly with malonate to form 266)176]. 

Step 1 of the Edman degradation is the addition of the NH2 group of the N-ter-minal amino acid to the C=N double bond of phenyl isothiocyanate. Step 2 (B —> C) is an intramolecular SN reaction of an S nucleophile on the carboxyl carbon of a pro-tonated amide. It follows the substitution mechanism shown in Figure 6.5. The substitution product C is a heterocyclic derivative of the N-terminal amino acid. The simultaneously formed second reaction product, the oligopeptide D, which has been shortened by one amino acid, is ejected as the leaving group. 

Intramolecular termination by carbon nucleophiles has been achieved with dialkyl malonate moieties. These cascade reactions, developed essentially by Balme, Gore, and colleagues, open an avenue especially to variously substituted methylenecyclopentane derivatives (Scheme 19,and Sect. V.3.4). 

The isomerization of terminal epoxyalkynes into furans catalyzed by RuCl(Tp)(PPh3) (MeCN) inthe presence of Et3N as abase at 80 °C in 1,2-dichloroethaneis explained by a related intramolecular nucleophilic addition of the oxygen atom of the epoxide to the a-carbon atom of a ruthenium vinylidene intermediate, as shovm by deuteration in the 3-position of the furan (Scheme 10.10) [45]. This reaction is specific for terminal alkynes and tolerates a variety of functional groups (ether, ester, acetal, tosylamide, nitrile). 

The intramolecular reactions of the 1,3,8,10-undecatetraene system in [di(2,4-pentadienyl)malonate] 176 with nucleophiles proceeded smoothly to give the five-membered rings. Reaction of nitromethane gave 177, in which the nucleophile is introduced at the terminal carbon [72],... 

The critical feature of the Edman degradation is that it allows the N-terminal amino acid to be removed without cleaving any of the other peptide bonds. Let s see how this occurs. The mechanism of the reaction is shown in Figure 26.3. First the nucleophilic nitrogen of the N-terminal amino acid attacks the electrophilic carbon of phenyl isothiocyanate. When anhydrous HF is added in the next step, the sulfur of the thiourea acts as an intramolecular nucleophile and attacks the carbonyl carbon of the closest peptide bond. II is the intramolecular nature of this step and the formation of a five-membered ring that result in the selective cleavage of only the N-terminal amino acid. The mechanism for this part of the reaction is very similar to that for acid-catalyzed hydrolysis of an amide (see Section 19.5). However, because no water is present, only the sulfur is available to act as a nucleophile. The sulfur is ideally positioned for intramolecular attack at the carbonyl carbon of the N-terminal amino acid, so only this amide bond is broken. 

Terminal perfluoroolefins have two fluorine atoms at the double bond. The carbon atoms of the latter bear a significant positive charge, and the nucleophilic agents easily replace the fluorine atoms at the multiple bond. The reactions of binucleophilic reagents with terminal perfluoroolefins form heterocyclic systems. The first step of the reaction involves a nucleophilic attack at the carbon atom of the double bond, generating a carbanion. The latter is stabilized by elimination of the fluoride ion and formation of a new double bond. Subsequent cyclization by the intramolecular attack of the nucleophilic center at the double bond leads to the formation of a heterocyclic system. For example, when a reaction mixture of hexafluoropropylene and sodium dialkylaminodithiocarbamate in dimethylacetamide is heated with aqueous sodium tetraphenylborate, one obtains the tetraphenylborate salt of 2-dialkylamino-4-trifluoromethyl-4,5-difluoro-l,3-dithiolan-2-yl (78JFC(12)193). This compound is formed by intramolecular cyclization of the S-nucleophilic center. 

Addition of the acetylenic alcohols HC=C(CH2) OH (x = 3,4) to 1 affords a one-pot synthesis of the cyclic carbene complexes (88). The reaction proceeds via initial formation of the vinylidene complexes, followed by an intramolecular attack of the terminal alcohol function on the a carbon [Eq. (84)] (85). Combining the nucleophilicity at the /3 carbon of... 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

The (dienyl)iron cations of type (248) and (265) are susceptible to reaction with nucleophiles. For the (cyclohexadienyl)iron cations, nucleophilic attack always occurs at a terminal carbon, on the face of the ligand opposite to the metal, to afford / -cyclohexadiene products. Typical nucleophiles used are malonate anions, amines, electron-rich aromatics, silyl ketene acetals, enamines, hydrides, and aUyl silanes intramolecular nucleophilic addition is also possible. The addition of highly basic organometaUic nucleophiles (Grignard reagents, organolithiums) is often problematic this may be overcome by replacing one of the iron carbonyl... 

Reaction of iV,A -unsubstituted selenoureas with a 1,2-diaza-l,3-butadiene affords 2-amino-4,5-dihydro-l,3-selenazol-4-ones 81 mainly in the hydrazono form. The reaction proceeds via nucleophilic addition of the selenium atom to the terminal carbon atom of the heterodiene. The subsequent intramolecular nucleophilic attack by the imidic NH at the carboxylate group with the loss of methanol leads to the selenazole ring closure (Scheme 14) <2002EJO2323, 2001SL144>. 

Irradiation of optically pure (l/ ,25 )-(+)-cw-chrysanthemol (22) in the presence of dicyanobenzene as an electron acceptor leads to the formation of (/ )-5-(l-(p-cyanophenyl)-l-methylethyl)-2,2-dimethyloxacyclohex-3-ene (23 Ar = p-cyano-phenyl). The success of this reaction depends upon the relief of ring strain which can be rationalised in terms of nucleophilic attack of the radical cation on the terminal carbon of the vinyl group, and simultaneous replacement of the isopropyl radical as an intramolecular leaving group in an 8 2 reaction. 

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