Dichlorocarbene generation

The benzyne adducts prepared from A -methylpyrrole (and A -methylisoindole) are deaminated conveniently by dichlorocarbene generated under phase-transfer conditions (81JOC1025 to give a convenient route to substituted naphthalenes (134) (and anthracenes) (Scheme 49). 

Trimethylpyrazole (336) adds dichlorocarbene generated under basic conditions (CHCla-EtONa) to give 10% of 4-dichloromethyl-3,4,5-trimethylisopyrazole (337 Scheme 28) (bromine also transforms (336) into an isopyrazole (312) Section 4.04.2.1.4(v)). Treatment with sodium ethoxide results in ring expansion of (337) into an ethoxymethyl-pyridazine (338) (B-76MI40402). 

Dichlorocarbene, generated in a variety of ways, was shown to deoxygenate pyridine iV-oxide, being itself oxidized to phosgene. 

Dichlorocarbene, generated by the action of 50 % potassium hydroxide on chloroform, adds to ethyl 1 W-azepine-l-carboxylate to furnish the all /rntu-trishomoazepine 12 in 35% yield280 (see Houben-Weyl, Vol. E 19b, p 1523). Subsequently, and as a result of a careful and detailed study of the addition of dichlorocarbene generated by the thermal decomposition of phenyl(trichloromethyl)mercury, it was deduced that carbene addition takes place sequentially in the order C4 —C5, C2—C3 and C6 — Cl. The intermediary mono- 10 and bis(dichlorocar-bene) 11 adducts have been isolated and characterized. 

The present method utilizes dichlorocarbene generated by the phase-transfer method of Makosza4 and Starks.5 The submitters have routinely realized yields of pure distilled isocyanides in excess of 40%.6 With less sterically hindered primary amines a 1 1 ratio of amine to chloroform gives satisfactory results. Furthermore, by modifying the procedure, methyl and ethyl isocyanides may be prepared directly from the corresponding aqueous amine solutions and bromoform.7 These results are summarized in Table I. 

The addition of dichlorocarbene, generated from chloroform, to alkenes gives dichlorocyclopropanes. The procedures based on lithiated halogen compounds have been less generally used in synthesis. Section D of Scheme 10.9 gives a few examples of addition reactions of carbenes generated by a-elimination. 

The reactions of dichlorocarbene with phosphorus ylides result in the corresponding olefins and phosphines.66-68 In the reaction of dichlorocarbene generated in situ with tributyl- and triphenylmethylenephosphoranes or triphenylethylidenephosphorane, the olefin yield increases as the nucleo-philicity of phosphorus ylide increases. According to,67 the reaction starts from the electrophilic attack of carbene at the a-C atom of phosphorus ylide. Then the intermediately formed betaine (28) (Scheme 14) decomposes to eliminate the phosphine molecule and form dichloroolefin (29). 

Allylic silanes react with dichlorocarbenes, generated from dechlorination of carbon tetrachloride with low valent titanium species, to furnish dichlorocyclopropanes, which in turn get desilylated with CsF in DMF to generate 3-chloro-l,3-butadienes (equation 30)63. 

Compared with the classical procedures, which employ chloroform and dry potassium /ert-butoxide, Makosza s method is several magnitudes superior, in spite of the normally recognized requirements that the dichlorocarbene should be produced under totally anhydrous conditions. Several early reports of the reactions of dichlorocarbene, generated by Makosza s procedure, led to suggestions that the activity of the carbene was considerably greater than that of the classically produced carbenes. This assumption was based on the overall higher yields of dichlorocyclopropanes derived from the reaction with alkenes, and upon the observation that weakly activated alkenes reacted with Makosza carbenes, but not with the classically produced carbenes. A consideration of the mechanism of formation of the carbenes under phase-transfer catalytic conditions exposes the fallacies in the assumptions. 

Phase-transfer catalysed reaction of dichlorocarbene generated from sodium trichloroacetate... 

Diamines react with dichlorocarbene, generated in the presence of ketones, to produce piperazinones [6,7]. The carbene probably reacts initially with the ketone to... 

Amides [41,44], thioamides [41 ] and amidines [45] are converted into nitriles by the reaction with dichlorocarbenes generated by Makosza s procedure (Table 7.16). Under similar conditions, monosubstituted and A.A-disubstituted ureas are converted into cyanamides (Table 7.17) JV,(V -disubstituted ureas produce carbodi-imides in low yield [41,46,47]. /V-Carbamoyl derivatives of dibenzo[/ /]diazepines and the related 10, l l-oxirane derivatives are converted into the corresponding... 

Cyclopropanation of a pyrrole with dichlorocarbene generated from CHCI3 and NaOH. Subsequent rearrangement takes place to give 3-chloropyridine. 

Singlet dichlorocarbene (generated from chloroform by the action of a strong base, such as potassium r r/-butoxide, KOCMe3), reacts with the anion of pyrrole to give an adduct, which then ring expands to give 3-chloropyridine (Scheme 6.11). 

Dichlorocarbene, generated under phase transfer conditions, is reactive enough to insert into an unactivated C-H bond, yet discriminating enough to select for tertiary C-H bonds, as exemplified by the formation of rw-4a-(dichloromethyl)decahydronaphthalene9. 

Surprisingly, there are only a few reports concerning the action of carbenes on azepines. A-ethoxycarbonyl-1//- azepine and dichlorocarbene, generated by the action of 50% potassium hydroxide on chloroform, furnish the trans -trishomoazepine (136 R1 = R2 = Cl) in 35% yield. Under similar conditions the 2,3- and 4,5-homoazepines yield the trans homoazepines (136 R1 = Cl, R2 = H and R1 = H, R2 = C1 respectively). From a careful study of the addition of dichlorocarbene, generated by thermal decomposition of (dichloromethyl)phenylmercury, it is concluded that carbene addition to the 1H-azepine takes place sequentially in the order C-4—C-5, C-2—C-3 and C-6—C-7 (74JOC455). 

For example, methyl 3-phenylbicyclofl.l.0]butane-l-carboxylate (11, R1 = Ph R2 = C02Me) was converted to methyl 2,2-dichloro-3-phenylbicyclo[l.l.l]pentane-l-carboxylate (12, R1 = Ph R2 = C02Me) in 46% yield on reaction with dichlorocarbene generated by thermolysis of sodium trichloroacetate. 3,14... 

The reaction of pyrrole with dichlorocarbene, generated from chloroform and strong base, gives a bicyclic intermediate which can be transformed to either 3-chloropyridine (155) or pyrrole-2-carbaldehyde (156). Indole gives a mixture of 3-chloroquinoline (157) and indole-3-carbaldehyde (158). The optimum conditions involve phase transfer (76S249, 76S798). Benzofuran reacts with dichlorocarbene in hexane solution to give the benzopyran (159), whereas benzothiophene fails to react. 

Systematic studies of the dicyclopropanation of olefinic sugars have been published [194], Dichlorocarbene, generated under phase-transfer catalysis reacts with 2,3-unsaturated pyranosides, such as 161 to yield a single isomer of the expected cyclopropane 162 (Scheme 55). A typical procedure is given in Section IE. The reaction is also possible with an enol... 

Dihalocyclopropanes are generally prepared by the addition of dihalocarbenes to alkenic substrates. As indicated in the introduction, the first synthesis of a dihalocyclopropane was accomplished by Doering and Hoffmann by the addition of dichlorocarbene, generated from chloroform and potassium r-butoxide (Bu OK), to cyclohexene giving dichloronorcarane (1), as shown in equation (l).s... 

The reaction of dihydrobenzothiazepines (1) with dichlorocarbene, generated in situ from chloroform using a phase-transfer catalyst or by thermal decomposition of sodium trichloroacetate, afforded compounds 2 in low yields (18-24%) (Scheme 1). The structure of 2 was postulated on the basis of analytical and spectroscopic data and confirmed by X-ray diffraction (92MI1). 

Reaction of Schiff bases 205 and dichlorocarbene, generated in situ from chloroform with potassium hydroxide, in the presence of benzyltri-ethylammonium chloride at 20°C for 5-12 hours under argon afforded imidazo[l,2-a]pyrimidines 206 and 4//-pyrido[l,2-a]pyrimidin-4-ones 207 in 34-40% and 1-20% yields, respectively (91KGS810). 4/f-Pyrido[l,2-... 

Tetrahydrophosphinine oxide 131 was reacted with dichlorocarbene generated from CHC13 by addition of sodium hydroxide under phase-transfer conditions to give adduct 140 which underwent thermal expansion to give 2,7-dihydrophosphepin oxide 141 <1998JCM210> (Equation 29). 

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