Dichlorocarbene, addition reactions

Hi) By formation of seven- from six-membered rings The expansion of a di- or a tetra-hydropyran ring fused to a three-membered ring has been used as a synthetic approach to oxepins. Thus the synthesis of oxepin (193) was attempted by thermal dehydrochlorination of a tetrahydropyran (equation 57) obtained from a dichlorocarbene addition reaction (65CI(L)184). Unfortunately the equilibrium appeared to favor the keto tautomer to the apparent exclusion of the enolic oxepin form (193). 

The idea that dichlorocarbene is an intermediate in the basic hydrolysis of chloroform is now one hundred years old. It was first suggested by Geuther in 1862 to explain the formation of carbon monoxide, in addition to formate ions, in the reaction of chloroform (and similarly, bromoform) with alkali. At the end of the last century Nef interpreted several well-known reactions involving chloroform and a base in terms of the intermediate formation of dichlorocarbene. These reactions included the ring expansion of pyrroles to pyridines and of indoles to quinolines, as well as the Hofmann carbylamine test for primary amines and the Reimer-Tiemann formylation of phenols. 

In alkaline solution, the phenol 1 is deprotonated to the phenolate 4, which reacts at the ort/zo-position with dichlorocarbene 3. The initial addition reaction product 5 isomerizes to the aromatic o-dichloromethyl phenolate 6, which under the reaction conditions is hydrolyzed to the o-formyl phenolate." ... 

Claisen rearrangement, 660 conjugate carbonyl addition reaction, 725-726 Curtius rearrangement, 935 cyanohydrin formation, 707 dichlorocarbene formation, 227 Dieckmann cyclization reaction, 892-893... 

The reactive intermediates under some conditions may be the carbenoid a-haloalkyllithium compounds or carbene-lithium halide complexes.158 In the case of the trichloromethyllithium to dichlorocarbene conversion, the equilibrium lies heavily to the side of trichloromethyllithium at — 100°C.159 The addition reaction with alkenes seems to involve dichlorocarbene, however, since the pattern of reactivity toward different alkenes is identical to that observed for the free carbene in the gas phase.160... 

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. 

Carbenes were among the first reactants to be explored in addition reactions. Phenyl (bromodichloromethyl)-mercury has been used to introduce dichlorocarbene, which produced large optical changes at Fermi level transitions [27]. It was recently reported that under certain conditions dichlorocarbene is also able to effect a transition from... 

Acylation of limonene at the disubstituted double bond is favoured by a factor of 2.3 over reaction at the trisubstituted double bond using acetyl hexachloroan-timonate. Mixed alkylcuprate alkylation of tricarbonylcyclohexadienyliron salts has been used to synthesize the a-phellandrene tricarbonyliron complex. Dichlorocarbene addition to limonene in the presence of 1,4-diazabicy-clo[2,2,2]octane is almost 100% stereoselective at the trisubstituted double bond (no yield given) (cf. Vol. 6, p. 31) in contrast to dibromocarbene addition to carvone (Vol. 7, p. 34), dichlorocarbene addition to the carveols is not regio-specific. ... 

Although the gem-dihalocyclopropanes are fairly stable compounds, they can participate — as has been shown in the above sections — in quite a number of chemical transformations. Several reactions between dihalocarbenes and alkenes have been described in which no dihalocyclopropane formation could be observed that these intermediates might have been produced was only inferred from the type of products finally isolated. A typical process of this type is the e/ufo-addition of dihalocarbenes to norbomene and norbomadiene as discussed above. Comparable rearrangements have been observed, when dichlorocarbene additions either lead to aromatic products or when they cycloadd to rather inert aromatic systems. In the latter case a ring-enlargement takes place. A reaction related to the concerted opening of two cyclopropane rings in a bicyclopropyl system as discussed above takes place when dichlorocarbene is added to spiro[2.4]hepta-4,6-diene [227]. 

The ring expansion of furans by dichlorocarbene addition gives unstable 2,3-dichlorochromenes, which are trapped by nucleophilic displacement reactions (Scheme 13).232 233... 

This dominance of sulfur in the reactions with electrophiles is well brought out in the addition of carbenes to the-two monocycles. Tire allylic sulfide (5,6-dihydro-2jF/- thiopyran) only affords the products of reaction at sulfur, while the vinylic sulfide (3,4-dihydro-2f/-thiopyran), in which the alkene is a little more nucleophilic due to the small interaction with the heteroatom, shows dichotomous behaviour. Dichlorocarbene affords the cyclopropane product (78) in 70% yield, but the stabilized ylide (76) is produced from bismethoxycar-bonylmethylide and (75). In fact it is possible that the initial reaction with dichlorocarbene is reaction at sulfur and subsequent rearrangement of this less stabilized ylide. Schemes 6 and 7 illustrate the results and proposed mechanisms (77JOC3365,64JOC2211). 

The 7,7-dihalobicycloheptene route appears easily adaptable to the synthesis of 6n 5 atom cyclopropa[c]heteroarenes 61 as the three-membered ring is suitably located and the requisite precursors—the dichlorocarbene addition products of, for example, 2,5-dihydrofuran—are easily accessible. Unfortunately, treatment of halides 59 with r-BuOK fails to provide any evidence for sought after 61. Dehydrochlorination does occur but the strained 1,3-bridged cyclopropenes 60 ring expand to carbene or add a nucleophile faster than rearrangement and loss of a second molar equivalent of HCl. The precise outcome of these reactions is very dependent upon the nature of the ring system as the detailed studies show . ... 

Dichlorocarbene addition to aikenes. Dehmiow and LisseP have examined the reaction variables in the generation of dichlorocarbene by PTC. Optimal conditions include use of 4 molar excess each of CHCI3 and 50% aqueous NaOH, 1 mole % of catalyst, and efficient stirring. The reaction should be conducted initially at 0-5°, then at 20° for 1-2 hours, and finally at 50° for 2-4 hours. Most quaternary ammonium salts are suitable as catalysts the anions should be chloride or hydrogen sulfate. From the point of cost/efficiency, the most useful are benzyltriethylammonium chloride, tetra-n-butylammonium chloride, Aliquat 336, and tri-n-propylamine. The reaction rate is strongly dependent on the nucleophilicity of the alkene. 

Since dibromocarbene is more susceptible to hydrolysis than dichlorocarbene, dibro-mocarbene addition by the PTC method often gives the expected adducts in lower yields than those of the dichlorocarbene addition. Use of excess tribromomethane , execution of the reaction at ambient or lower temperature and addition of a small amount of alcohol have been recommended to improve the yields. Diiodocarbene has also been generated by PTC procedures and has been added to alkenes . However, the CHl3/r-BuOK method appears to be superior . It has also been pointed out that the Cl2 adducts are sometimes rather unstable when they are prepared by the PTC method, probably due to contamination of some sensitive byproducts . 

It was found that alkylidenemalononitriles 41 undergo 1,1-dichlorocyclopropane (223) formation by reaction with trichloroacetic acid. This reaction is presumed not to involve a dichlorocarbene addition, but instead a trichloromethylated carbanionic intermediate (equation 64) Substitution of one of the cyano groups by another EWG such as an ester... 

Reaction of piperidone 145 with dichlorocarbene under phase-transfer catalysis conditions affords a mixture of 146 and 147 in 85-90% yields (80JOC1513, 80TL119) with the ratio determined by the catalyst (80JOC1513). The reaction presumably occurs via dichlorocarbene addition onto the carbonyl group of 145 followed by rearrangement with ring contraction. 

As an additional reaction of the aromatic system the ring expansion with dichlorocarbene may be mentioned T. Hatsui, H. Ushijima, A. Mori and H. Takeshita, Tetrahedron Lett, 42, 6855 (2001). 

Attempted 1,4-cycloaddition of dichlorocarbene with 1,3-diphenylisobenzofuran was unsuccessful (Houben-Weyl, Vol.E19b, pi562). The formation of 8,8-dichloro-2-(2-phenylethyl)-2,3-dihydro-l,3-methano-l//-isoindole-l-carbonit ile (31) by the reaction of chloroform with isoindole derivative 30 under phase-transfer catalysis conditions has probably been misinterpreted as 1,4-addition of dichlorocarbene.This reaction may involve the Michael addition of trichloromethyl anion to isoindole followed by the cyclization of the adduct. 

Esters of allylic and homoallylic alcohols undergo addition of dichlorocarbene, the reactions are conveniently carried out by the chloroform/base/phase-transfer catalyst method. Some products of this type are specified in Table 17. 

The enamine structure, which is formed in situ (by means of the trichloromethyl anion, the precursor of dichlorocarbene), may undergo further addition of dichlorocarbene. The reaction of A -methylpyridinium iodide with chloroform under phase-transfer catalytic conditions exemplifies this case, forming 16 and 17 (see Houben-Weyl, Vol. E19b, p 1557). 

The double elimination of 1,1-dichlorocyclopropanes with potassium tert-butoxide to give cycloproparenes is an important variant of the reaction discussed in Section 5.2.2.1.2.3. When a six-membered ring fused to the cyclopropane contains a double bond, the elimination is accompanied by isomerization of the new double bonds to give an aromatic ring (Table 7). The reaction is illustrated by the synthesis of bicyclo[4.1.0]hepta-l,3,5-triene (l//-cyclo-propabenzene, 3) in two steps from cyclohexa-1,4-diene (1), the first step being dichlorocarbene addition to the diene to give 7,7-dichlorobicyclo[4.1.0]hept-3-ene... 

The dibromocyclopropanes are frequently preferred to their less reactive dichlorides, although the latter are often prepared in higher yields from dichlorocarbene additions to alkenes. Di-fluorocyclopropanes are not useful precursors to cyclopropylidenes with reactions leading to alkylated cyclopropenes and alkynes. ... 

---