Intermolecular Methoxycarbonylation of Terminal Alkynes Catalyzed by Palladium(II) Bis(oxazoline) Complexes

Abstract

The b-methoxyacrylate system is a common structure present in biologically active natural products such as dihydrokawain [1a] (and related six-membered lactones [1b-e] ), tetronic acids [2a] (and related five-membered lactones [2b-e] ), and bmethoxyacrylate antibiotics. [3] Transition-metal-catalyzed reactions of unsaturated systems has recently been widely used for the construction of a variety of carbo-and heterocycles.[4] Palladium-catalyzed carbonylation of alkynes has provided several kinds of transformation. [5] In general, the intermolecular addition of alcohols to alkynes is more difficult to accomplish than the intramolecular process, thus requiring a stronger p Lewis acid catalyst.[6] Although many examples of the intramolecular oxycarbonylation of 4-alkynols, [7] 4-alkynones, [8] and propargyl acetates [9] have been reported, the intermolecular reaction is extremely rare. Tamaru and co-workers reported the palladium-catalyzed carbonylation of 4-alkyl-or 4-aryl-3-butyn-1-ols, in which MeOH attacked the C4 position of the alkyne to afford methoxycarbonylated five-membered lactones (Scheme 1).[5a]The reaction of the terminal alkyne was not described.The intermolecular methoxycarbonylation of terminal alkynes is a synthetically valuable method for the direct conversion of terminal alkyne units into b-methoxyacrylate units. To our knowledge, there is no precedent for the intermolecular methoxycarbonylation of a simple terminal alkyne. Recently, we reported the ligand-controlled tandem carbonylative cyclization of propargyl acetates with 1,4-diyne [10a] and 1,5-diyne structures. [10b] In the absence of the bis(oxazoline) ligand (box), the second triple bond did not react. However, the use of the box ligand caused a significant change to the course of the reaction, and tandem carbonylative cyclization occurred as a result of insertion at the second triple bond. Although box ligands are among the most popular classes of chiral ligands in asymmetric chemistry, examples of the box ligand changing the course of the reaction are rare. [10,11] We believe that the box ligand enhances the p-electrophilicity of Pd II complexes, and thus promotes coordination of the second triple bond to Pd II , leading to the tandem reaction. We hypothesize that {(box)-Pd II } complexes should strongly activate the alkyne, so that the intermolecular methoxycarbonylation of alkynes can be realized. Consequently, we report the [(Phbox)Pd(tfa) 2 ]-catalyzed intermolecular methoxycarbonylation of alkyne 1 (Phbox = 2,2-isopropylidenebis(4-phenyl-2-oxazoline); tfa = trifluoroacetate; Table 1).Initially, the carbonylation of 1 a was performed under the conditions reported by Tamaru and co-workers. However, methoxyacrylate 2 a was not obtained, but instead the acetylene carboxylate [5b] (32 %) and maleate derivatives [5n] (20 %) were afforded, together with an unidentified mixture.[12] The reaction conditions were therefore changed to those used for our previously reported Pd II

Synthesis of β‐Methoxyacrylate Natural Products Based on Box‐PdII‐Catalyzed Intermolecular Methoxycarbonylation of Alkynoles

“…Although the use of [(CH 3 CN) 2 PdCl 2 ] resulted in increased yields of β‐methoxyacrylate 2a (12 %) and six‐membered lactone 3a (12 %), 5a was also produced in 19 % yield. As mentioned previously,7c,d, 9, 10 the phosphine ligand seemed to be ineffective for reactions of this type, that is, the [Pd(tfa) 2 ] complex of ( S )‐BINAP gave 7a (20 %), and [(Ph 3 P) 2 PdCl 2 ] did not show catalytic activity. Bipyridine‐PdCl 2 complex and (−)‐sparteine‐[Pd(tfa) 2 ] complex also gave no reaction.…”

“…The reaction conditions were then changed to those used for our previously reported Pd II / p ‐benzoquinone catalytic system (Scheme ) 5–7. 9 The reaction of 1a with [Pd(tfa) 2 ] (5 mol %) and p ‐benzoquinone (2 equiv) in the absence of the ligand in methanol under a carbon monoxide atmosphere (balloon) afforded acetylene carboxylate derivative4d 7a (37 %) and maleate derivative 5a (19 %) with a small amount of 2a (8 %). Although the use of [(CH 3 CN) 2 PdCl 2 ] resulted in increased yields of β‐methoxyacrylate 2a (12 %) and six‐membered lactone 3a (12 %), 5a was also produced in 19 % yield.…”

“…The β‐methoxyacrylate 2 should be produced via Path A, because the reaction of simple terminal alkynes without hydroxyl groups proceeded well 9. The triple bond of 1 coordinates to box‐Pd II , and intermediate A1 undergoes nucleophilic attack by MeOH to produce the vinyl palladium intermediate A2 .…”

“…Although the intermolecular methoxycarbonylation of terminal alkynes is considered to be a useful method for the direct conversion of terminal alkyne units to β‐methoxyacrylate units, the intermolecular addition of alcohols to alkynes is more difficult to accomplish than the intramolecular process,5–7 requiring stronger π‐Lewis acid catalysts 8. In our preliminary communication, we reported the intermolecular methoxycarbonylation of terminal alkynes catalyzed by palladium(II) bisoxazoline (box) complexes (Scheme ) 9. The box ligand enhances the π electrophilicity of Pd II complexes,7c,d, 9, 10 which leads to effective activation of the triple bond.…”

“…In our preliminary communication, we reported the intermolecular methoxycarbonylation of terminal alkynes catalyzed by palladium(II) bisoxazoline (box) complexes (Scheme ) 9. The box ligand enhances the π electrophilicity of Pd II complexes,7c,d, 9, 10 which leads to effective activation of the triple bond. Herein, we report the direct conversion of homopropargyl and propargyl alcohols to β‐methoxyacrylates, and its application to the synthesis of natural products containing 4‐methoxyfuran‐2‐one, acyclic β‐methoxyacrylate, and 4‐methoxy‐2‐pyrone structures (Scheme ).…”