Treatment of 1-chlorocyclobutyl p-tolyl sulfoxides with Grignard reagents such as ethylmagnesium chloride, isopropylmagnesium chloride, and cyclopentylmagnesium chloride in THF at low temperature gave cyclobutylmagnesium carbenoids in high yields. The generated magnesium carbenoids were found to be stable at -78°C for at least 30 minutes. The cyclobutylmagnesium carbenoids reacted with several nucleophiles to give multi-substituted cyclobutanes. The reaction of the cyclobutylmagnesium carbenoids with lithium a-sulfonyl carbanions afforded alkylidenecyclobutanes in moderate to good yields.Although cyclobutane skeletal structures are not widely found in natural products, cyclobutane derivatives are quite interesting compounds. Due to high angular and torsional strain, cyclobutanes are fairly reactive under a variety of conditions and often used as versatile intermediates in organic synthesis. 1 Cyclopropanes are another smallring compounds having inherent ring strain comparable to that of cyclobutanes and have been widely studied in organic chemistry; however, the chemistry of cyclobutanes is not fully investigated even now.We have been interested in the chemistry of cyclopropanes, especially cyclopropylmagnesium carbenoids (cyclopropanes bearing magnesium and chlorine atoms at the same carbon) generated from 1-chlorocyclopropyl p-tolyl sulfoxides with Grignard reagents, and many interesting properties of the carbenoids have been unveiled. 2 In continuation of our interest in the chemistry of small-ring magnesium carbenoids, we recently started to investigate the generation, property, and synthetic uses of cyclobutylmagnesium carbenoids, which delivered quite interesting results. 3 Thus, as shown in Scheme 1, treatment of 1-chlorocyclobutyl p-tolyl sulfoxides 1 with Grignard reagents (R 2 MgCl) in THF at low temperature afforded cyclobutylmagnesium carbenoids 2 in high yields via the sulfoxidemagnesium exchange reaction. 4 The generated cyclobutylmagnesium carbenoids 2 were found to be stable at -78°C for at least 30 minutes. When this reaction was carried out with excess R 2 MgCl, carbenoids 2 were alkylated with the Grignard reagents to give the alkylated cyclobutylmagnesium chloride intermediates 3, which could be trapped with electrophiles to give multi-substituted cyclobutanes 4 in moderate to good yields. Cyclobutylmagnesium carbenoids 2 were proved to be reactive with some alkyllithiums and N-lithioarylamines to give cyclobutanes 5. The reaction of 2 with lithium a-sulfonyl carbanions gave alkylidenecyclobutanes 6 in moderate to good yields. Details of the aforementioned results are reported in this paper. Scheme 1 Synthesis of 1-Chlorocyclobutyl p-Tolyl SulfoxidesThree 1-chlorocyclobutyl p-tolyl sulfoxides 1a-c were selected, which are the precursors for the generation of cyclobutylmagnesium carbenoids 2, and synthesized them as follows (Scheme 2). Alkylation of the two hydroxy groups of known diol 7 5 with 3-phenylpropyl bromide followed by catalytic hydrogenation and oxidation with IBX in DMSO gave cyclob...
Treatment of 1-chlorocyclobutyl p-tolyl sulfoxides with ethylmagnesium chloride at low temperature gave cyclobutylmagnesium carbenoids in over 90% yield. The generated magnesium carbenoids were found to be stable at -78 °C for at least 30 min. The synthesis of multisubstituted cyclobutanes and alkylidenecyclobutanes was realized based on the alkylation of the magnesium carbenoids with Grignard reagent and lithium a-sulfonyl carbanions, respectively.Carbenes and carbenoids are obviously one of the most interesting sets of highly reactive carbon species and are frequently used as versatile intermediates in organic synthesis. 1 Carbenes and carbenoids show a variety of reactions, such as addition into a carbon-carbon double bond to give cyclopropanes, dimerization to give olefins, ylide formation with sulfides. Rearrangement and insertion are other most striking reactions of carbenes and carbenoids. 1 Small-ring carbenes and carbenoids, cyclopropylidenes and cyclobutylidenes, are also quite interesting highly reactive species.Recently, we are interested in the chemistry of much stable cyclopropylidenes, cyclopropylmagnesium carbenoids, and reported their generation, properties, 2 and synthetic uses. 3 In continuation of our investigation for the chemistry of small-ring magnesium carbenoids, we recently started to study for generation, properties, and some synthetic uses of cyclobutylmagnesium carbenoids, and quite interesting results were obtained. Thus, 1-chlorocyclobutyl p-tolyl sulfoxides 1 were treated with a Grignard reagent at low temperature to generate cyclobutylmagnesium carbenoids 2 via the sulfoxide-magnesium exchange reaction (Scheme 1). The generated cyclobutylmagnesium carbenoids 2 were found to be stable at -78°C for at least 30 minutes. Cyclobutylmagnesium carbenoids 2 reacted with the used Grignard reagent to give alkylated cyclobutylmagnesium chloride intermediates 3, which could be trapped with several electrophiles to afford multisubstituted cyclobutanes 4 in moderate to good yields. When cyclobutylmagnesium carbenoids 2 were treated with lithium a-sulfonyl carbanions, alkylidenecyclobutanes 5 were obtained in moderate to good yields. The method presented herein provides a good way for the synthesis of multisubstituted cyclobutanes and alkylidenecyclobutanes. Details of the aforementioned chemistry are reported hereinafter.First of all, two 1-chlorocyclobutyl p-tolyl sulfoxides 1a and 1b were synthesized as the representative examples of aryl 1-chlorocyclobutyl sulfoxide (Scheme 2). Alkylation of the two hydroxy groups followed by catalytic hydrogenation of known diol 6 4 gave a cyclobutanol, which was oxidized with IBX in DMSO to give cyclobutanone 7 in good overall yield. Reductive thiolation of cyclobutanone 7 with 4-methylbenezenethiol under Fyfe's conditions 5 gave cyclobutyl p-tolyl sulfide 8 in good yield. Oxidation followed by chlorination of sulfide 8 gave the desired 1-chlorocyclobutyl p-tolyl sulfoxide 1a in quantitative yield. Scheme 1 L i R 3 R 4 C S O 2 P h R 1 R 1
Synthesis of Multi-Substituted Cyclobutanes and Alkylidenecyclobutanes by the Reaction of Cyclobutylmagnesium Carbenoids with Nucleophiles. -Treatment of 2-chlorocyclobutyl p-tolyl sulfoxides with Grignard reagents at low temperature generates cyclobutylmagnesium carbenoids which can be coupled with a variety of nucleophiles. -(SATOH*, T.; KASUYA, T.; ISHIGAKI, M.; INUMARU, M.; MIYAGAWA, T.; NAKAYA, N.; SUGIYAMA, S.; Synthesis 2011, 3, 397-408, http://dx.doi.org/10.1055/s-0030-1258391 ; Grad. Sch. Chem. Sci. Technol., Sci. Univ. Tokyo, Shinjuku, Tokyo 162, Japan; Eng.) -Mais 18-055
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