Dichloromethyl ketones

Dioxanes and dioxolanes, derived from alkyl and aryl aldehydes, react with dichlorocarbene specifically at the C-2 position, with no evidence of reaction at C-4 or C-5 (Scheme 7.2). The yields are variable, but provide a convenient route to dichloromethyl ketones [13, 14], The rate of insertion into the C-H bond correlates with the electronic character of the 2-aryl substituent and is also influenced by... 

The reaction of ethyl thiophen-2-carboxylate with triphenylphosphine-CCI4 gave (159), which upon acidic hydrolysis afforded the dichloromethyl ketone. 2-Thenoyl chloride reacts with some piperazine derivatives. Trimethylsilyldiazomethane has been used as a safe reagent in the Arndt-Eistert reaction for the transformation of 2-thenoyl chloride into benzyl 2-thienylacetate. ... 

Dichloromethyl ketones. Dichlorocarbene generated by the Makosza technique reacts with acetals of type 1 to form ketals of dichloromethyl ketones (2). The same reaction is observed with dibromocarbene. The R group of 1 can be hydrogen, alkyl, or aryl. ... 

After the umpolung of an aldehyde group by conversion to a l,3 dithian-2-ide anion (p. 17) it can be combined with a carbonyl group (D. Seebach, 1969, 1979 B.-T. GrO-bel, 1977 B). Analogous reagents are tosylmethyl isocyanide (TosMIC), which can be applied in the nucleophilic formylation of ketones (O.H. Oldenziel, 1974), and dichloromethyl lithium (G. KObrich, 1969 P. Blumbergs, 1972 H. Taguchi, 1973),... 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

Treatment of a-dichloromethyl phenyl sulfoxide with lithium diisopropylamide in THF gave monolithiated derivative 122, which upon further treatment with aldehyde afforded the )S-hydroxy-a-dichlorosulfoxide 123. Thermolysis of 123 gave dichloroketone 124, by extruding benzenesulfenic acid as shown below . Similarly, in the reaction of lithio-a-fluoromethyl phenyl sulfoxide and aldehyde, fluoromethyl ketone 126 was obtained, after thermolysis of the hydroxy intermediate 125. Diethylphosphorylmethyl methyl sulfoxide was shown by Miko/ajczyk and coworkers to be lithiated with n-BuLi to intermediate 127, which upon treatment with carbonyl compounds afforded the corresponding a, -unsaturated sulfoxides 128 in good yields. 

Another useful reagent for introduction of the carbonyl carbon is dichloromethyl methyl ether. In the presence of a hindered alkoxide base, it is deprotonated and acts as a nucleophile toward boron. Rearrangement then ensues with migration of two boron substituents. Oxidation gives a ketone. 

Alkyl- or aryl-dibenzothiophenes are conveniently prepared from the 2-arylthio-cyclohexanones, which are readily cyclized and dehydrogenated to yield the respective 1-, 2-, 3- or 4-substituted dibenzothiophenes (382 equation 9 Section 3.15.2.3.2). More complex polycyclic systems are available, using suitable aryenethiols, such as naph-thalenethiols, and 2-bromo-l-tetralone to synthesize the appropriate 2-arylthio ketones. Diaryl sulfides can be converted to dibenzothiophene derivatives in satisfactory yields by photolysis in the presence of iodine (equation 10) (75S532). Several alkyldibenzothiophenes with substituents in the 2- and/or 3-positions were prepared in satisfactory yield by the condensation of dichloromethyl methyl ether with substituted allylbenzo[6]thiophenes (equation 11) (74JCS(P1)1744). 

Acylation of the keto acid (637) leads to the isobenzopyrylium salt (638) (77CHE1183). However, the isobenzopyrylium salt (639), a potential intermediate for the synthesis of analogues of berberine alkaloids, results from the formylation of the substituted ketone or the isochromanone (640) using dichloromethyl butyl ether (Scheme 251) (81CHE221). A second product, the 5-oxoniachrysene (641), is formed and this compound may also be obtained by reaction of the isobenzopyrylium salt with phosphorus pentachloride and then with triethylamine. The intermediacy of a cyclic vinyl ether is proposed. 

Chiral ketones.3 Asymmetric hydroboration of a prochiral alkene with monoisocampheylborane followed by a second hydroboration of a nonprochiral alkene provides a chiral mixed trialkylborane. This product reacts with acetaldehyde with elimination of a-pinene to give a chiral borinic acid ester in 73-100% ee. Treatment of this intermediate with a,a-dichloromethyl methyl ether (2,120 5, 200-203) and lithium triethylcarboxide followed by oxidation results in an optically active ketone in 60-90% ee. 

Migration of tertiary alkyl groups in the dichloromethyl methyl ether reaction does however mean that ketones cannot be synthesized using thexylborane and the approach adopted in the carbonylation and cyanidation processes. In order to obtain ketones by this route, boranes bearing chloro or alkoxy groups, i.e. groups of very low migratory aptitude, have to be used as substrates (Equation B3.17). 

Another 1,2-silyl migration from C to C was found during the reaction of an a-silyl cyclopropyllithium 42 with dichloromethyl methyl ether 43 to give the silyl ketone 44 (equation 36)87. 

Asymmetric hydroboration 2171 of prochiral alkenes with monoisopinocampheyl-borane in the molar ratio of 1 1, followed by a second hydroboration of non-prochiral alkenes with the intermediate dialkylboranes, provides the chiral mixed trialkylbo-ranes. Treatment of these trialkylboranes with acetaldehyde results in the selective, facile elimination of the 3-pinanyl group, providing the corresponding chiral borinic acid esters with high enantiomeric purities. The reaction of these intermediates with base and dichloromethyl methyl ether provides the chiral ketones (Eq. 130)2l8>. A simple synthesis of secondary homoallylic alcohols with excellent enantiomeric purities via B-allyldiisopinocampheylborane has been also reported 219),... 

Unsaturated ketones are known to react with dichloromethyl phenyl sulfoxide to give adducts which produced fully substituted furans in high yields after treatment with trifluoroacetic anhydride and Nal, as illustrated in the following scheme. Trisubstituted... 

The total synthesis of the tricyclic sesquiterpene (+)-P-copaene was accomplished by E. Wenkert and co-workers. The required bicyclic starting material was prepared in three steps from carvacrol. In the first step, carvacrol was subjected to typical Reimer-Tiemann conditions. The abnormal Reimer-Tiemann product, 6-dichloromethyl-3-isopropyl-6-methyl-cyclohexa-2,4-dienone, was obtained, and upon treatment with sodium carbonate in DMSO, cyclization occurred to afford a bicyclic halo ketone. The double bonds were then hydrogenated in the presence of Pd(C) catalyst. 

Chiral boronic esters react with organolithium reagents to form diorganylalkoxyboranes (borinic esters). Subsequent reaction with the anion of dichloromethyl methyl ether then yields chiral ketones by rearrangement of both of the groups on boron (Scheme 42). No racemization is observed in this sequence and alkyl-, aryl- or alkynyl-lithium reagents can be used. 

---