Copper(II) Chloride-Copper(II) Oxide1,2

CuCl2-CuO
(CuCl2)

[7447-39-4]  · Cl2Cu  · Copper(II) Chloride-Copper(II) Oxide  · (MW 134.45) (CuO)

[1317-38-0]  · CuO  · Copper(II) Chloride-Copper(II) Oxide  · (MW 79.54)

(carbonyl deprotection reagent; allows transformation of thioacetals, a-heterosubstituted sulfides, and selenoacetals to aldehydes or ketones)

Solubility: sol aq acetone, alcohols, THF, MeCN.

Form Supplied in: both components are commercially available solids.

Introduction.

The combination reagent CuCl2-CuO, originally introduced by Mukaiyama for the hydrolysis of 1,3-dithiane derivatives to carbonyl compounds,3 also proved to be valuable for the hydrolysis of a-heterosubstituted sulfides and vinyl sulfides to carbonyl compounds.1 It provides an interesting alternative to other methods.1,2,4 The reaction occurs under mild conditions; the presence of copper oxide prevents the medium from becoming too acidic.1 It delivers disulfides5,6 as byproducts besides the desired carbonyl compounds.

The reactions are usually carried out in wet acetone (1%) or in aqueous or anhydrous alcohols (usually MeOH or EtOH)3 at 20 °C or at reflux temperature. In the latter case, the alcohol can be involved in the transformation6,7 (see eq 10). A higher percentage (10%) of water proved, in one specific case, important in order to avoid side reactions (eq 2).8 Acetonitrile, as well as THF, can be used as solvent but proved, at least in one case, less efficient.3

Transformation of Thioacetals and Selenoacetals to Aldehydes or Ketones.

The reaction has been successfully achieved with cyclic thioacetals such as 1,3-dithiolanes,9 1,3-dithianes (eq 1),3,10-12 a,a-bis(alkylthio)alkanes,13 a,a-bis(phenylthio)alkanes,14 and 1,5-dihydro-2,4-benzodithiepins (eq 2).8 The nature of the protecting group does not seem to affect the rate of the reaction, which is usually fast (20 °C or reflux, 0.5-2 h). It has been performed on several functionalized thioacetals including b,g-unsaturated,13 g-keto,15 and a-hydroxy derivatives.15

This reaction, coupled with the transformation of cyclic O,O-acetals to the corresponding 1,3-dithianes (1,3-Propanedithiol, Boron Trifluoride Etherate, CH2Cl2, 0 °C), has been used to deprotect cleanly d-keto acetals to d-keto aldehydes without affecting the chiral center a to the aldehyde group (eq 3).12

Selenoacetals derived from both the methylseleno and phenylseleno series,16 including functionalized examples,15,17,18 have been readily transformed to the corresponding aldehydes or ketones with CuCl2-CuO (eq 4). These conditions proved as effective as those involving seleninic acid.16

Transformation of Other a-Heterosubstituted Sulfides to Carbonyl Compounds.

a-Chloro sulfides are efficiently transformed to aldehydes19-21 and ketones22-24 on reaction with CuCl2-CuO (eq 5). This includes the synthesis of polyfunctionalized carbonyl compounds such as a-diketones,23,25 a-keto aldehydes,20 and b-keto esters.26 Particularly interesting is the one-pot transformation of ketones to a-diketones (eq 5),23,25 which takes advantage of the in situ oxidation of intermediate a-thioketones to a-thio-a-chloro ketones by CuCl2.25

2-Phenylthiotetrahydropyrans and 2,2-bis(alkylthio)tetrahydropyrans have been transformed, on reaction with CuCl2-CuO, to 2-hydroxytetrahydropyrans27 and to the corresponding six-membered lactones,28 respectively (eqs 6 and 7). The latter strategy proved better by far in producing the six-membered lactones than the one implying oxidation of initially formed 2-hydroxytetrahydropyrans with Jones' reagent.

Transformation of Vinyl Sulfides and Related Derivatives.

CuCl2-CuO also promotes the transformation of vinyl sulfides and related derivatives to aldehydes or ketones.1 The reaction takes another course with 3-methylthio-29 and 3-hydroxy-1-thio-1-alkenes,5,30 which lead instead to a,b-unsaturated aldehydes and ketones (eq 8). The intermediate formation of a b-hydroxycarbonyl compound is not observed, and the entire conjugated system is involved in the transformation.

1-Alkoxy-3-thioalkyl-1-alkenes, which bear the thio substituent at the allylic position, have also been successfully transformed to a,b-unsaturated aldehydes and ketones using the same reagent (eq 9).31 The reaction is easier with those derivatives that produce aldehydes rather than ketones, as in these cases the reaction mixture does not require heating.31

Ketene thioacetals are usually transformed into esters, provided that the reaction is performed in alcohols, and 1,1-bis(methylthio)allenes are converted to a,b-unsaturated esters (eq 10).6

Finally, CuCl2-CuO in alcohol promotes the transformation of thioisoxazoles to aldehydes32 and of alkyl dithioesters to methyl or ethyl esters.7,14,33 The former reaction requires an additional reduction step (1. Al/Hg; 2. CuCl2-CuO). Remarkably, this reagent allows the synthesis of b-hydroxy esters bearing a chiral a-carbon without affecting the a-chiral center and without the loss of water, which would have produced the corresponding a,b-unsaturated ester.7

Synthetic Uses.

The transformation of thioacetals to their corresponding carbonyl compounds is valuable in synthesis. It allows the formation of carbonyl compounds via acyl anion equivalents using 1-metallo-1,1-dithioalkanes (eqs 1 and 2).1 Other important examples include the aldol condensation involving metallo-dithioesters,7 which exhibits very high facial stereoselectivity (>99:1) and high simple diastereoselectivity (95:5), and the version of the thio-Claisen rearrangement which allows the very stereoselective synthesis of (E)-trisubstituted double bonds (eq 11).14 It is therefore important that the conditions involved for the transformation of the thio moiety to the carbonyl compound do not interfere with the other functional groups present in the molecule.

Chemoselectivity.

Even under the mild conditions used in carbonyl group generation, CuCl2-CuO deprotects THP (eq 1)11 and ethoxyethyl (eq 2)34 ether-protected alcohols and leads to diols from benzylidenedioxy compounds (eq 2).34 This feature has been successfully applied to the direct synthesis of the dioxaspiro[5.5]undecanes shown in eq 2. It allows, under suitable conditions, the concomitant acetalization of ketones.33 However, this reagent does not promote (a) cyclization of 1,4-diketones to a-enones from g-keto-a,a-bis(thio)alkanes;14 (b) the retro-aldol reaction of the intermediate b-hydroxy ketone shown in eq 2 (provided that 10% water is used instead of 1%), which would have produced the (4S,6R) rather than the expected (4S,6S) stereoisomer;8,34 (c) epimerization at the a-position of an aldehyde,12 a ketone,12 an ester,7 or a dithio ester;7 (d) the (Z) to (E) or (E) to (Z) isomerization of C=C double bonds (eq 11);14 or (e) conjugation of the C=C double bond in b,g-unsaturated aldehydes21 and ketones.35

Related Reagents.

Copper(II) Chloride.


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Alain Krief

Facultés Universitaires Notre Dame de la Paix, Namur, Belgium



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