A Mild Procedure for α , α-Dichlorination of Cyclic Aryl Ketones using Commercial Bleach

Aril cetonas cíclicas α,α-dicloradas foram obtidas pelo tratamento de uma solução metanólica da correspondente cetona com cândida comercial em condições ambiente com rendimentos que variaram de 61 a 92%. A reação ocorre em cetonas contendo tanto grupos doadores quanto retiradores de elétrons, mas parece ser sensível a efeitos estéricos. Além disso, aril-cicloalcanonas com anéis de cinco, seis e sete membros podem ser utilizadas como substrato.


Introduction
Over the last decades, α,α-dichloroketones have been used as substrate in several reactions in synthetic organic chemistry, including important steps in the synthesis of natural products. 1Thus, several methods have been developed for the preparation of α,α-dichloroketones, where the most used is the direct dichlorination of the corresponding ketone.This transformation has been performed with cyclic aryl ketones in a variety of different forms, using: i) Cl 2 in CH 2 Cl 2 2 or in DMF; 3 ii) thionyl chloride in CCl 4 ; 4 iii) thionyl chloride followed treatment with H 2 O 2 ; 5 iv) sulfuryl chloride; 6 v) 2-chloropyridazin-3(2H)-one in CH 2 Cl 2 in the presence of H 2 SO 4 ; 7 vi) manganese(III) acetate in boiling AcOH in the presence of LiCl; 8 vii) FeCl 3 in a mixture of AcOH/H 2 O; 9 and viii) copper(II) chloride in DMF 10 or in acetonitrile. 11In this scenario, we herein present a simple and mild procedure to obtain several α,α-dichloro cyclic aryl ketones using commercial bleach, at room temperature and without the control of the pH, showing the influence of alkyl, electron donating-and electron-withdrawing groups, as well as the ring size of the substrate.Bleach is an inexpensive and environmentally friendly reagent that has a number of applications, including the chlorolactonization of β-and γ-unsaturated carboxylic acids, 12 the oxidation of alcohols, 13 as co-oxidant in TEMPO-catalyzed oxidations, 14 and the dichlorination of dicarbonylic compounds in AcOH/Me 2 CO at 0 °C. 15During the development of this work, a patent by Kumamoto et al., 16 reported the use of bleach for the α,α-dichlorination of a single ketone, namely 5-nitro-1-tetralone, at 50 °C and keeping the pH of the solution around 10.

Results and Discussion
When bleach was added to a methanolic solution of 1-tetralone (1) at room temperature, 2,2-dichloro-1tetralone was obtained in 90% yield (Table 1, entry 1).The reaction is very clean, with no side reactions.Indeed, the NMR of the crude product does not show the presence of any impurity.Furthermore, the haloform reaction, that could be a side reaction, 17 was not observed.Presumably, this transformation occurs by the reaction of the enolate of the ketone with a chloro-containing species in solution, such as chlorine or ClOH.Next, the same protocol was applied to other ketones.Treating tetralones containing an electron-donating substituent in the aromatic ring, such as 2-4 with bleach gave, respectively, the corresponding α,α-dichlorinated products 9-11, in high yields (entries 2-4).The reaction of 7-nitro-1-tetralone (5) led also to the desired product, although in lower yield than the other tetralones (compare entry 5 with entries 1-4).Thus, the presence of an electron-withdrawing group has some influence in the reactivity, which agrees with the result of Kumamoto et al. 16 that performed the chlorination of a similar ketone at 50 °C.The influence of alkyl groups was then investigated.The reaction of 4-methyl-1tetralone (6) with bleach afforded the dichlorinated product in good yield (entry 6).However, when 2-methyl-1-tetralone ( 7) was treated with bleach only 33% of the starting material was converted to the product even after 4 days of reaction time (entry 7).In summary, tetralones can be dichlorinated in an efficient manner.Electrondonating and withdrawing groups are tolerated but the reaction appears to be sensitive to steric effects.
The reactivity of a cyclohexanone was also investigated.When 4-t-butylcyclohexanone was treated with bleach in conditions similar to that presented above, no reaction was observed.The different behavior between the alkyl and the aryl ketones may be explained by the difference of the acidity of the α-hydrogen, where the pKa value of aryl ketones (pK a of 1-tetralone in DMSO: 24.7 18 ) is nearly two units lower than that of the corresponding alkyl ketone (pK a of cyclohexanone in DMSO: 26.4 19 ).
The effect of the ring size was examined for ketones with a five-and a seven-membered ring.The reaction of 1-indanone and of 1-benzosuberone (15 and 16, respectively) with bleach gave the expected dichloro ketones in 61 and 64% yield, respectively (Table 2).Although still good, these yields are clearly lower than that obtained for the six-membered ring ketone 1.

Conclusions
In conclusion, a simple, cheap and efficient method for the preparation of α,α-dichlorinated ketones from readily available cyclic aryl ketones and commercial bleach was developed.This protocol avoids the use of hazardous material and/or difficult procedures.

Experimental
The reactions were carried out using Daclor ® commercial bleach (pH 12, 2.0-2.2% of chlorine).The aryl ketones, besides 7-nitro-1-tetralone, 20 are commercially available.Melting points were determined on a Büchi Melting Point B-545 and are uncorrected.Shimadzu GC-2010 was used to monitor the progress of the reactions. 1H and 13 C NMR spectra were recorded on Bruker spectrometers.IR spectra were measured on a Perkin-Elmer 1750 FT.High resolution mass spectra were performed on a VG Autospec/Fission Instrument and MicroTOF LC from Bruker Daltonics.Although the crude products were often obtained quite pure, analytical pure substances could be obtained by flash chromatography using silica-gel Acros 200-400 Mesh (30% AcOEt in hexanes).

*
Conversion estimated by GC analysis.

Table 1 .
Reaction of 1-Tetralones with Bleach in MeOH