Chloroform dichlorocarbene generation

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. 

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. 

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). 

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). 

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. 

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-... 

CUorofttlvene. The reaction of cyclopentadiene (I) with dichlorocarbene (generated from chloroform and potassium t-butoxide) gives 6-chk>rofulvcnc (2) as the major product (10% yield) chlorobenzene (3) is also formed (1-2% yield). 

Benzocyclopropene. ° Benzocyclopropene (3) can be prepared conveniently in two steps. 1,4-Cyclohexadiene (I) is treated with dichlorocarbene (generated from chloroform and potassium (-butoxide) to give 7,7-dichlorobicyclo[4.1.0]heptene-3 (2) in 41 % yield. This intermediate is then treated with potassium i-butoxide and D VTSO... 

The conditions involving dichlorocarbene generated from chloroform and thallium ethoxide give the best chemoselectivity, yields and reproducibility (Scheme 162, e Scheme 16S, c Scheme 166, e Scheme 186, b Scheme 188, a Scheme 189, The reactions are usually carried out at... 

Surprisingly, with dichlorocarbene generated by another method (ther-mocatalytic decomposition of sodium trichloroacetate instead of alkaline hydrolysis of chloroform under phase-transfer catalysis conditions) N-(p-R-benzylidene)-feH-butylamines 55 (R = H, Cl) give 3,3-dichloroazetidi-... 

The high yield of hexachlorocyclopropane is noteworthy for with dichlorocarbene generated from either ethyl trichloroacetate or chloroform the yield is only 0.2-1 %. 

An interesting result is given in a paper provided by this group on the reaction of benzaldehyde with dichlorocarbene generated in situ from chloroform and solid NaOH under sonication in the presence of PTC [43]. Normally a-hydroxybenzoic acid is the additional product in this reaction [44], but under sonication, benzoic... 

A mixture of the monoadducts 14 and 15, one of which rearranged, was formed from 1-phenyl-buta-1,2-diene and dichlorocarbene generated from ethyl trichloroacetate/sodium methoxide. Under the conditions of the chloroform/base/phase-transfer catalyst or thermolysis of sodium trichloroacetate methods, dichlorocarbene reacts further with the rearranged product to give 16. ... 

The reaction of allyl alcohol with dichlorocarbene, generated from bromodichloro-methyl(phenyl)mercury/heat or chloroform/base/phase-transfer catalyst, does not afford the corresponding cyclopropane derivative. In the first case, allyl chloride, allyl formate and chloroform were formed and in the second case, tris(allyloxy)ethane (20%), l,l-dichloro-2-... 

Cyclic allylic alcohols fairly easily cycloadd dichlorocarbene, particularly if generated under chloroform/base/phase-transfer catalyst conditions. Five- and six-membered-ring allylic alcohols form a mixture of cis- and fran.v-isomers, while those of larger rings form only the trans-isomer. In contrast with the phase-transfer catalysis method, dichlorocarbene generated from bromodichloromethyl(phenyl)mercury did not add to cyclohex-3-en-1 -ol, while cyclonon-3-en-l-ol yielded exo-10,10-dichlorobicyclo[7.1.0]decan-2-ol (28 /o), which could not be purified. Examples of dichlorocarbene adducts to cyclic allylic alcohols are presented in Table 19. 

Allyl 2-methylprop-l-enyl sulfide yielded two products 6 and 7 with dichlorocarbene generated from chloroform/base/phase-transfer catalyst. ... 

V-Acyl-1,2-dihydroisoquinolines, another example of nonaromatic nitrogen heterocycles, readily undergo addition of dichlorocarbene generated by the chloroform/base/phase-transfer catalyst method to give tricyclic products and 13. " ... 

Dichlorocarbene, generated from chloroform/potassium fert-butoxide, undergoes addition to a series of tertiary allylamines (and amides).If the dichlorocarbene was produced by the trichloromethyl(phenyl)mercury method, apart from the 1,1-dichlorocyclopropane derivatives, other products were isolated (see Houben-Weyl, Vol. 4/3, p 180). 

The reaction of dichlorocarbene (generated by ultrasonic irradiation of a mechanically stirred mixture of chloroform and powdered sodium hydroxide, 40°C, 4 hours) with 2-vinyl-pyridine gave 3-chloroindolizine (23) in 13% yield, via the corresponding A -pyridinium ylide. ... 

Aryl-l-aryltelluroethenes underwent addition of dichlorocarbene, generated under solid-liquid phase-transfer catalytic conditions (chloroform/base/catalyst) to afford relatively stable... 

Vinyl, allyl and homoallyl derivatives of germanium and tin also form the corresponding cyclopropanes with dichlorocarbene generated by the chloroform/potassium /er/-butoxide or bromodichloromethyl(phenyl)mercury methods (Table 23). ... 

The lack of trichloromethyl anion adducts to acrylates in these processes is possibly due to relatively tight, poorly lipophilic ion pairs Me4N CCI3 which cannot penetrate the organic phase thus, they reside in the interfacial region where the hydrated trichloromethyl anions have low activity. Consequently, dichlorocarbene reacts with acrylates to form 1,1-dichlorocy-clopropanes 2. ( )-A -tert-Butyl but-2-enamide forms the cyclopropane 3 on reaction with dichlorocarbene, generated from chloroform/base/phase-transfer catalyst, with tetramethylam-monium chloride as the catalyst. ... 

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