Nucleophilic attack at carbon

Hydroxylation of azetidine-l-carboxylates 33 with a biocatalyst, Sphingomonas sp. HXN-200, gave the corresponding 3-hydroxyazetidines 34 (Equation 7) 20020L1859 . 

The reaction of 3,3-dichloro-2-methoxyazetidine 35 with lithium aluminium hydride in ether afforded 3-chloro-azetidine 36 (Equation 8). The substitution of the methoxy group by hydride via an azetinium intermediate and subsequent conversion of the geminal dichloro derivative to the monochloroazetidine via a single electron transfer reaction yielded this compound 1998JOC6 . Treatment of 1-benzyl-3-hydroxyazetidine 37 with triphenylphos-phine in carbon tetrachloride yielded l-benzyl-3-chloroazetidine 38 (Equation 9) 2004JOC2703 . 

Alkaline hydrolysis of the saturated salts (62) occurs with loss 

N-acylaziridines occurs on treatment with triphenylphosphine with the formation of the ylides (67), thereby providing a route to a-substituted primary allylic amines via their in situ reactions with aldehydes.The reactions of triphenylphosphine with epoxides in phenolic media provide a new access to the vinyl-phosphonium salts (68). A route to 1-hydroxyalkylphosphonium salts is provided by the reactions of trimethyl- or triethyl-phosphine with aldehydes or ketones in the presence of anhydrous acids. The related 1-trimethylsiloxyalkylphosphonium salts can be isolated in the presence of trimethylsilyl chloride.Further Wittig-products have been isolated from the reaction of 1,2,3-indanetrione with triphenylphosphine, and, in related work, it has been shown that furoin is deoxygenated on heating with triphenylphosphine to form 2-furfuryl(2-furyl)ketone and triphenylphosphine oxide.The structure of the blue product from the reaction of triphenylphosphine with 2,3,5,6-tetracyano-7-oxabicyclo(2,2,1]hepta-2,5-diene has now been shown by X-ray techniques to be the stable ylide (69).  

Here also, for a general theory of nucleophilic reactions of pyrazole-A-oxides in the framework of the donor-acceptor concept see 92H(33)U29 . The most relevant results in this field are those 

Begtrup 92ACS1096,92H(33)l 129,92JCS(Pl)2555,93JCS(P1)625 has shown that azole-A-oxides after O-silylation can be used to activate the 3 and 5 ring positions. 

1 Nucleophilic Attack at Carbon.- The reactions of silyl-aminophosphines with carbon disulphide result in the formation of 

Reactions.—Nucleophilic Attack at Carbon. A number of studies of the kinetics of quaternization of phosphines have been reported, all of which lend support to an earlier suggestion that the transition state for such reactions is reactant-like. From the rates of quaternization of a series of heteroaryldiphenylphosphines (54) with a-bromoacetophenone, it was concluded that the r-excessive heterocyclic substituents are not significantly involved in pj,-d conjugative stabilization of the developing phosphonium centre in the transition state of the reaction. Similarly, there is little evidence of conjugative effects in the transition state for quat nization of 

The competitive elimination (ET) and substitution (iSn2) reactions of cyclohexyl tosylate with triphenylphosphine have been examined. Triphenylphosphine is considered to be representative of neutral weak bases which have good nucleophilic afiinity for carbon, but it is a poor reagent for elimination when compared with anionic weak bases that are also good carbon nucleophiles. The reaction of triphenylphosphine with cyclohexyl bromide occurs with almost complete substitution. Tertiary phosphines react with fluorosulphonyl isocyanate and with isothiocyanates to form the zwitterionic adducts (56) and (57). 

The reaction of triethylphosphine with dimethyl acetylenedicarboxylate in the presence of p-chlorobenzaldehyde is reported to lead to the olefin (58) and the bicyclic lactone (59). In the presence of water, the initial dipolar adduct (60) is hydrolysed, with the formation of dimethyl fumarate and the phosphine oxide.  

Triphenylphosphine reacts with the methyl 2-bromoalkanoates (61) to form either the betaine (62) or the ylide (63), depending on conditions and the nature of the solvent. In the presence of aldehydes, the betaine (62) undergo Wittig reactions via the ylides (63) without the addition of base.  

Treatment of the a-bromovinylphosphonate esters (64) with tri-n-butylphosphine gives the tron -betaines (65). Trimethylphosphine reacts with dichloroacetylene to give the bis-ylide (66).  

Before discussing nucleophilic attack specifically at ring carbon we enumerate five general pathways which have been distinguished for the attack of nucleophiles on heteroaromatic six-membered rings  

Path A Nucleophilic attack at a hydrogen atom of a substituent with subsequent elimination (discussed under the relevant substituent in Section 3.2.3.1). 

Path B Attack at a- or y-ring carbon, with subsequent reaction not involving ring opening (discussed in this section). 

2 Reactions of Phosphines. - 1.2.1 Nucleophilic Attack at Carbon. Treatment of the unsaturated y-lactone (177) with tributylphosphine results in selective relacement of chlorine to form the phosphonium salt (178). Reactions of phosphines with alkynes have continued to attract interest. A palladium-catalysed addition of triphenylphosphine to unactivated terminal alkynes in the presence of methanesulfonic acid provides a route to the vinylphosphonium salts (179). This reaction fails with methyldiphenylphos- 

The heterocyclic rings of (benzo)pyridazine systems are electron deficient and thus susceptible to attack by nucleophiles. However, in the absence of a suitable leaving group this is usually unfavoured due to loss of aromaticity. For example, covalent hydration is not observed, though pseudobase formation can occur with subsequent disproportionation to give, for example, phthalazinones and dihy drophthalazines. 

The action of nucleophilic reagents with isoxazoles can take a number of courses involving (i) nucleophilic addition to the ring (ii) nucleophilic replacement of a substituent and (iii) deprotonation. Other processes such as thermal or photochemical reactions may precede reaction with a nucleophile (see Section 4.16.3.1.2). 

Nucleophilic replacement of hydrogen on an isoxazole is unknown and replacement of substituents is discussed in Section 4.16.3.3. In this series it is difficult to identify reactions involving addition to the ring as, in many instances, they are rapidly followed by elimination or ring cleavage sequences. 

Similar instability is found for 3-unsubstituted 2,1-benzisoxazole in the presence of base, ring opening to anthranilic acid derivatives occurring readily (see Section 4.16.3.1.6). 

Sodium borohydride and 3-isoxazolium salts with a 3-unsubstituted position also give isoxazolines, as do the 3-substituted 5-unsubstituted derivatives. With the latter group, further reduction occurs to the isoxazolidines (74CPB70). 

Addition of Grignard reagents and organolithium compounds to the pyridazine ring proceeds as a nucleophilic attack at one of the electron-deficient positions to give initially 

4- addition products which rearrange to 1,2-dihydro products. 3-Methoxy-6-phenyl-pyridazine reacts with r-butylmagnesium chloride to give 4-/-butyl-3-methoxy-6-phenyl- 

5- double bond of 3,6-dimethoxypyridazine to give 4-substituted 4,5-dihydropyridazine derivatives. 

Phenyllithium in ether adds to pyridazine and 6-substituted pyridazines at position 3. By using TMEDA, addition at position 4 is strongly promoted (78RTC116). 

The addition of phenyllithium to 6-arylpyridazin-3(2H)-one takes place at position 6 to give 6-aryl-3-oxo-6-phenyl-l,2,3,4-tetrahydropyridazine and the reaction of 6-aryl-2,4-diphenylpyridazin-3 (2FT) - one with phenyllithium or phenylmagnesium bromide affords 6-aryl-2,3,4,6-pentaphenyl-l,2,3,4-tetrahydropyridazine (80S457). 

The K-region -oxirans (63) and (64), of interest in studies of chemical carcinogenesis, have been prepared by cyclization with TDAP of the dialdehydes obtained by oxidative cleavage of the parent hydrocarbons.54 

The reaction of the phospholen (65) with aromatic acid chlorides in the presence of triethylamine, followed by addition of DaO, gives a ready route to aromatic [1-2H]-aldehydes with 100% incorporation of deuterium.55 

Ring opening of diphenylthiiren 1,1-dioxide5 8 and diphenylcyclopropenone6 occurs on reaction with tertiary phosphines to form the betaines (69) and the keten phosphoranes (70), respectively. Tertiary phosphines react with the thione (71) to form mainly the betaine (72).60 

Hamada and T. Takizawa, Chem. and Pharm. Bull. Japan), 1975, 23, 2933. 

The iV-propargylaminophosphines (78) readily rearrange to give the azabuta-dienylphosphine (79) via intramolecular nucleophilic attack of phosphorus at the terminal acetylenic carbon. Full details have now appeared of the reactions of 2 -1,2,3-diazaphosphole derivatives (80) with alkyl halides, giving 2,3-disub-stituted indoles as the major product. Several examples of the attack of phosphines at carbon of a, -unsaturated carbonyl compounds have been described. The betaine (81) is the active intermediate in the triphenylphosphine-induced polymerization of maleic anhydride. Phosphines also catalyse the 

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Nucleophilic Attack at Carbon or Hydrogen. Only the strongest of nucleophiles (eg, —NH2) can replace a hydrogen in pyridine. However, N-oxides and quaternary salts rapidly undergo addition, followed by subsequent transformations (12). 

In these solvents at sufficiently low Br2 concentration (< 10-3 m) the kinetics are first order both in the olefin and in Br2 and the main solvent effect consists of an electrophilic solvation of the departing Br ion. A nucleophilic assistance by hydroxylic solvents has also been recognized recently (ref. 26) (Scheme 10). So far, return during the olefin bromination in methanol had been admitted only for alkylideneadamantanes, and was ascribed to steric inhibition to nucleophilic attack at carbons of the bromonium ion (ref. 26). 

D. Coenzyme A.—Succinyl phosphate (42) reacts rapidly and non-enzymatically with CoA in the pH range 3—8 to yield succinyl CoA (43). This reaction is dependent on the presence of a suitably situated free carboxy-group as such nucleophilic attack at carbon is not known with other acyl phosphates. Moreover, maleyl phosphate reacts rapidly with CoA while fumaryl phosphate fails to react under the same conditions. Hence the formation of a cyclic intermediate (44) from succinyl phosphate is... 

Displacement of a halogen atom of the imidazole ring of a tricyclic 5 6 5 angular system via nucleophilic attack at carbon has been used to incorporate amines, the trifluoromethyl group, or ethers as illustrated for the reaction of 69 with methoxide to give 70 (Equation 10) <2004BML1291>. However, the authors do not comment on the yields obtained in these reactions. 

Nucleophilic Attack at Carbon, Sulfur, or Hydrogen Attached to Carbon 528... 

Nucleophilic attack at carbon, sulfur, or hydrogen attached to carbon is well documented in CHEC(1984) <1984CHEC(6)513> and in CHEC-II(1996) <1996CHEC-II(4)355>. No recent work has been reported. 

A close comparison between intramolecular proton transfer and intramolecular nucleophilic attack at carbon is provided by the varying amounts of olefins [46] which accompany the ring-closure reactions of 0--OC6H4O(CH2) 4Br [1] to the corresponding catechol polymethylene ethers [2] (Illuminati etal., 1975). 

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