Chloroacetoxylation

An increased chloride ion concentration in the palladium-catalyzed oxidation of 1,3-cyclohexadiene resulted in a highly stereo- and regioselective 1,4-chloroacetoxylation35. The product selectivity was also high. Thus, palladium-catalyzed chloroacetoxylation afforded an 89% isolated yield of chloroacetate 29 which was >98% cis (Scheme 5). Only 1-2% of diacetate was observed in the crude product. 

The chloroacetoxylation is a quite general reaction and works well with a number of conjugated dienes. Some additional examples are given in Scheme 6 and in equations 15 and 16. The reaction is highly syn stereoselective for a number of cyclic dienes tried. Also, for acyclic dienes the reaction leads to a 1,4 syn addition and the reaction takes place with good stereospecificity (94 -96% syn). Thus (Zi,.E)-dienes give the R R isomer whereas (E,Z)-dienes produce the R S isomer (equations 15 and 16). The reaction has also been extended to include other carboxylic acids than acetic acid (chloroacyloxylation)33d. 

The chloroacetoxylation reaction is synthetically useful since the chloride can be substituted with either retention [Pd(0)-catalyzed reaction] or inversion (Sjv2 reaction) by a number of nucleophiles. In this way both the cis and trans isomers are accessible and have been prepared from a number of allylic acetates (Schemes 5 and 6). In a subsequent reaction the allylic acetate can be substituted by employing a copper- or palladium-catalyzed reaction. The latter reactions are stereo specific. 

Amino alkenols have been prepared by palladium-catalyzed chloroacetoxylation and allylic amination of 1,3-dienes. 1,4-Acetoxychlorination is stereospecific and cyclic dienes give an overall cis- 1,4-addition12. Acetoxychlorination of 6-acetoxy-l,3-cycloheptadiene afforded only one isomer as shown in equation 8. Sequential substitution of the allylic chloro group can occur with either retention or inversion, thereby allowing complete control of the 1,4-relative stereochemistry (equation 9). 

While the process works for a great number of conjugated dienes, a few, such as 1,3-cyclopentadiene and those acyclic dienes that have an oxygen substituenl in an allylic position, did not give a chloroacetoxylation product.23 Control of the 1,4-relative stereochemistry and preparation of compounds analogous to the title compounds also work for acyclic dienes,23 5 This process was used to obtain remote stereocontrol in acyclic systems and applied to the synthesis of a pheromone.5... 

Nystrom, J. E. Rein, T. Backvall, J. E. 1,4-Functionalization of 1,3-dienes via Pd-cata-lyzed chloroacetoxylation and allylic animation l-acetoxy-4-diethylamino-2-butene and l-acetoxy-4-benzylamino-2-butene. Org. Synth. 1993, Coll. Vol. VIII, 9-13. 

Palladium, benzylchlorobis(triphenylphosphine)-, trans-, 67, 86 Palladium-catalyzed aryl-aryl coupling, 66, 70 PALLADIUM-CATALYZED ALLYLIC AMINATION, 67,105 PALLADIUM-CATALYZED CHLOROACETOXYLATION, 67, 105 PALLADIUM-CATALYZED COUPLING OF ACID CHLORIDES WITH ORGANOTIN REAGENTS, 67, 86 PALLADIUM-CATALYZED COUPLING OF ARYL HALIDES, 66, 67 PALLADIUM-CATALYZED syn-ADDITION OF CARBOXYLIC ACIDS,... 

A,-Chloro-4-alkenylamines in 4 M sulfuric acid in acetic acid or TV-chloro-iV-methylamines in 1 M sulfuric acid undergo regioselective and stereoselective cyclization involving initial anti-chloroacetoxylation or am/-chlorohydroxylation of the double bond depending on the temperature of basification, /5-acetoxy (at —15 °C to 20 =C) or /5-hydroxy (at 50 °C) amines were obtained103. 

Scheme 8-22 cis- and imns-Annulation via Pd-catalyzed 1,4-chloroacetoxylation and raetallo-ene reaction. 

The chloroacetoxylation proceeds via the same type of intermediate as that involved in the palladium-catalyzed 1,4-diacetoxylation, i.e. via a 4-acetoxy-l,2,3-(jr-allyl)palladium intermediate (cf. Scheme 8-7). The high selectivity for iinsymmetrical product formation (usually >98%) is remarkable. Since chloride is the stronger nucleophile of the two amions present (CI and AcO ), the 4-chloro-l,2,3-( r-allyl)palladium intermediate 60 is initially formed. However, the chloride in the 4-position is rapidly exchanged for acetate to give a more stable, jr-allyl intermediate 61, which leads to product. The presence of intermediate 60 was confiimed by its trapping by a faster oxidant (isoamyl nitrate) than benzoqiiinone (BQ), which furnished l,4-dichloroalk-2-ene [78,84], In the case of cyclohexa-1,3-diene, this product was c -1,4-dichlorocyclohex-2-ene [84]. 

The chloroacetoxylation approach was also used for the stereoselective synthesis of tropine and pseudotropine employing a sulfonamide as nucleophile [80]. By the same approach, scopine and pseudoscopine were synthesized (Scheme 8-23) [81]. 

Chloroacetoxylation of 6-benzyloxycyclohepta-1,3-diene was highly diastereoselective and produced only the diastereoisomer 65 shown. Transformation of the chloroacetate 65 to 66 was realized by a Pd(0)-catalyzed substitution of the chloride by a sulfonamide, which occurs with retention of configuration. Reaction of the allylic chloride with the sulfonamide... 

An S 2 copper-catalyzed nucleophilic substitution of the chloride in a cyclic chloroacetate by butylmagnesium bromide was employed in a synthesis toward perhydrohistrionicotoxin [Eq.(47)] [79]. Histrionicotoxins are found in South American dart-poison frogs of the Dendrobatid family. Palladium-catalyzed chloroacetoxylation of 2-substituted diene 68 gave a highly regio- and stereoselective 1,4-addition product where the chloride ends up in the 1-position. Copper-catalyzed reaction of the chloroacetate 69 with butylmagnesium... 

A stereocontrolled synthesis of polyfused ring systems utilizing the chloroacetoxylation approach is shown in Scheme 8-26 [95]. Sequential ally lie substitution of the chloroacetates afforded key intermediate 75. Subsequent palladium-catalyzed tandem metalloene/Heck insertion reactions gave polyfused ring systems 76 and 77. 

Additional examples where chloroacetates from acyclic dienes have been used include the synthesis of pentadienylamines [96], dienesulfones [97], c-methylenecyclopentenones [98], marine natural products [99], and the carpenter bee pheromone [82]. Some additional Synthetic applications of the chloroacetoxylation of cyclic dienes are given in Refs. [100-104]. Chloroacetoxylation was also used to prepare a number of starting materials for the intramolecular reactions discussed in this chapter. 

Procedure A 1s very effective for a range of acyclic and cyclic conjugated dienes. The major side reaction in the chloroacetoxylation Is Diels-Alder addition of p-benzoquinone to the diene. The purpose of the pentane phase 1s to ensure a low concentration of diene In the acetic acid phase, which depresses the Diels-Alder reaction. The reaction can also be performed without the pentane phase with slow addition of the diene using a syringe pump. 

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