Chloromethylenation

Butyrolactones are prepared by intramolecular reaction of haloallylic 2-alkynoates. The a-chloromethylenebutyrolactone 301 is prepared by the intramolecular reaction of300[150,151]. 4 -Hydroxy-2 -alkenyl 2-alkynoates can be used instead of haloallylic 2-alkynoates, and in this reaction, Pd(II) is regenerated by elimination of the hydroxy group[152]. As a related reaction, the q-(chloromethylene)-7-butyrolactone 304 is obtained from the cinnamyl 2-alkynoate 302 in the presence of LiCl and CuCbflSS]. Isohinokinin (305) has been synthesized by this reaction[l 54]. The reaction is explained by chloro-palladation of the triple bond, followed by intramolecular alkene insertion to generate the alkylpalladium chloride 303. Then PdCb is regenerated by attack of CuCb on the alkylpalladium bond as a key step in the catalytic reaction. 

Hydroxymethylene-isoxazolin-5-ones undergo reaction with SOCI2 to form 4-chloromethylenes, with alcohols they form ethers (62HC(17)1, p. 7) and with amines aminomethylenes are obtained (Scheme 58) (73T4291, 60ZOB600). 

The reaction of enamines derived from cyclohexanone with dichlorocarbene to give the 1 1 adducts is now well established (137-139). The morpholine enamine (113) reacted with dichlorocarbene at —10 to —20° in tetrahydrofuran to give the stable crystalline adduct (201). Thermal decomposition followed by an aqueous work-up gave an a,)3-unsaturated ketone identified as 2-chloromethylene-cyclohexan-l-one (202) (139). 

The reactions of dichlorocarbene with morpholine and piperidine enamines derived from cyclopentanone and cyclohexanone have been reported to lead to ring expanded and a-chloromethylene ketone products (355,356). Similarly a-chloro-a, -unsaturated aldehydes were obtained from aldehyde derived enamines (357). Synthesis of aminocyclopropanes (353,359) could be realized by the addition of diphenyldiazomethane (360) and the methylene iodide-zinc reagent to enamines (367). 

The azidomethyl ether, used to protect phenols and prepared by the displacement of azide on the chloromethylene group, is cleaved reductively with LiAH4 or by hydrogenolysis (Pd-C, H2). It is stable to strong acids, permanganate, and free-radical brominations. ... 

A new synthesis of unsaturated azlactones, which is especially useful in cases where the aldehyde is not readily available, has been developed. The reaction involves the nucleophilic displacement of chlorine in 4-chloromethylene-2-phenyl-5(4Z )-oxazolone (6) by a... 

Curiously, 6-(chloromethyl)-4-methyl-2-methylene-3-phenyl-3-azabicyclo[4.1.0]hept-4-ene-l,5-dicarbonitrile (31), obtained from 4,4-bis(chloromethyl)-2,6-dimethyl-l-phenyl-1,4-dihydro-pyridine-3,5-dicarbonitrile, rearranges via 4-(chloromethyl)-7-methyl-2-methylene-l-phenyl-2, 5-dihydro-l//-azepine-3,6-dicarbonitrile (32) to yield the 4-(chloromethylene)-4,5-dihydro-1//-azepine 33 as the final product.127... 

Note The most common Vilsmeier reagent, (chloromethylene)dimethylammo-nium chloride (ClHC=+NMe2 CU), is usually made in situ from MesNCHO and POCI3, SOCI2, or COCI2. As well as chlorolysis of 0x0 substituents, these reagents are prone to react at other sites in the substrate molecule. 

In isolated examples, reactions of specific amides and thioamides with dihalo-carbenes can take unusual pathways. Thus, for example, using procedure 7.1.1, A,A-dialkylamides are converted into a-chloromethylene derivatives of the amides [48]. The initial step in which the carbene attacks the carbonyl oxygen atom is the same as for the dehydration of the A-alkyl amides, but subsequent steps, for which there is evidence from 2H/ H labelling experiments, lead to the formation of an enamine and further reaction with the carbene (Scheme 7.34). 

In 1981, Appel et al. postulated the transient formation of the (diphenyl-phosphino)(trimethylsilyl)carbene 2e to explain the formation of the phos-phaalkene 4e, in the thermolysis of the P-chloromethylene phosphorane 3e.29 At that time, the authors did not recognize the carbene character of 2e and simply named the intermediate a A5-phosphaalkyne. 

Reaction of 55a with thionyl chloride gave the 3-chloromethylene compound (55b) (62%) and with isopropyl iodide the 3-isopropoxy-methylene derivative (55c) (57%). Hydroxylamine condenses with... 

Reaction of unsaturated 5(4//)-oxazolones with appropriate nucleophiles affords new unsaturated 5(4//)-oxazolone analogues used as intermediates to prepare a variety of interesting compounds. 4-(Chloromethylene)-5(4/i/)-oxazolones react with a variety of nucleophiles. For example, 4-(chloromethylene)-2-phenyl-5(4F/)-oxazolone 395 reacts with imidazole to afford 4-[(imidazol-l-yl)methyl-ene]-2-phenyl-5(4F/)-oxazolone 396. The authors found no evidence for the product derived from carbon-carbon bond formation, that is, 4-[(imidazol-4-yl)methylene]-2-phenyl-5(4//)-oxazolone (Scheme 7.126). 

Heterocyclic amines also react as nucleophiles and, in this context, indole reacts with 404 to yield the unsaturated oxazolone 406, an intermediate in the synthesis of tryptophan (Scheme 7.13It is noteworthy that 406 is the product of carbon-carbon bond formation. Imidazole also reacts with 404 but in this case the product is 396, identical with that obtained from the 4-(chloromethylene) derivative 395. ... 

Chloromethylene)-2-phenyl-5(4H)-oxazolone 394 and 2-(acyloxymethyl-ene)-5(4H)-oxazolone" mainly give a mixture of 2-hetero substituted spirocyclo-propanes. For example, the 2-chloro derivatives 654 and 655 have been isolated and further elaborated to both stereoisomers of l-amino-2-chlorocyclopropanecar-boxylic acid 656 and 657 (Scheme 7.208). 

The reaction of diazomethane with 2-phenyM-(sulfanylmethylene)-5(4//)-oxazolone 665, readily obtained from 4-(chloromethylene)-2-phenyl-5(4//)-oxazo-lone 394, generates the intermediate spirocyclopropane oxazolones 666 and 667, respectively. Both 666 and 667 were independently elaborated to the 2-sulfanyl-1-aminocyclopropanecarboxylic acid derivatives 668 and 669—a novel class of conformationaUy constrained masked cysteines (Scheme 7.210). Representative examples of spirocyclopropane oxazolones are shown in Table 7.47 (Fig. 7.58). 

Diels-Alder reactions of 4-heteromethylene-5(4/7)-oxazolones have been described. ( )-4-(Chloromethylene)-5(4//)-oxazolone 737 reacts with 2,3-dunethyl-butadiene in the presence of ethylaluminum dichloride to afford the cycloadduct 738. The cycloaddition reaction is characterized by high diastereoselectivity and occurs without appreciable isomerization of the dienophile. Further synthetic transformations of 738 yield 1-amino-3,4-dimethyl-6-hydroxy-cyclohex-3-enecar-boxylic acid 739 (Scheme 1.121) Examples of Diels-Alder reactions of acyclic dienes and unsaturated 5(4//)-oxazolones are shown in Table 7.50 (Fig. 7.61). 

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