Gold-catalyzed alkylation of silyl enol ethers with ortho-alkynylbenzoic acid esters

  1. Haruo Aikawa1,2,
  2. Tetsuro Kaneko1,
  3. Naoki Asao1,3 and
  4. Yoshinori Yamamoto1,3

1Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
2International Advanced Research and Education Organization, Tohoku University, Sendai 980-8578, Japan
3WPI-Advanced Institute for Materials Research, Tohoku University, Sendai 980-8578, Japan

  1. Corresponding author email

This article is part of the Thematic Series "Gold catalysis for organic synthesis".

Guest Editor: F. D. Toste
Beilstein J. Org. Chem. 2011, 7, 648–652. doi:10.3762/bjoc.7.76
Received 01 Apr 2011, Accepted 13 May 2011, Published 20 May 2011

Abstract

Unprecedented alkylation of silyl enol ethers has been developed by the use of ortho-alkynylbenzoic acid alkyl esters as alkylating agents in the presence of a gold catalyst. The reaction probably proceeds through the gold-induced in situ construction of leaving groups and subsequent nucleophilic attack on the silyl enol ethers. The generated leaving compound abstracts a proton to regenerate the silyl enol ether structure.

Keywords: alkylation; gold catalysis; leaving group; silyl enol ether; substitution reaction

Findings

Silyl enol ethers have been widely used in organic synthesis as effective carbon nucleophiles for the construction of carbon frameworks [1-4]. Generally, they react with a variety of electrophiles to give carbonyl compounds as products due to cleavage of the silicon–oxygen bond. For example, the Lewis acid-catalyzed reaction of silyl enol ethers with alkyl halides is well known as one of the most efficient preparative methods for regio-defined α-alkylated ketones (path a in Scheme 1) [5-17]. In contrast, in this paper, we report a gold-catalyzed reaction of silyl enol ethers with ortho-alkynylbenzoic acid esters which leads to the formation of α-alkylated silyl enol ethers (path b).

[1860-5397-7-76-i1]

Scheme 1: Alkylation of silyl enol ethers.

We examined the reactions of silyl enol ether 1a with ortho-alkynylbenzoic acid benzyl esters 2 in the presence of gold catalysts under several reaction conditions and the results are summarized in Table 1 [18-21]. With a cationic gold catalyst, derived from Ph3PAuCl and AgClO4, the reaction of 1a with 2a proceeded at 80 °C over 2 h and the benzylated silyl enol ether 3a was obtained in 35% yield, along with the eliminated isocoumarin 4a and recovered 2a in 32% and 65% yields, respectively (entry 1). On the other hand, no products were obtained from the reaction of 1a with benzyl benzoate (having no alkynyl group at the ortho-position) under similar reaction conditions. These results clearly show that the alkynyl moiety of ester 2a is essential for the formation of 3a. It is well known that concerted pericyclic ene-type reaction of silyl enol ethers with electrophiles, such as aldehydes or ketones, gives functionalized silyl enol ethers without desilylation [22-36]. To the best of our knowledge, however, this is the first example of the introduction of simple alkyl groups through a substitution-type reaction [37-40]. The chemical yield was increased to 55% by use of sterically hindered (o-Tol)3PAuCl as the gold catalyst (entry 2). Besides benzene, (CH2Cl)2 and 1,4-dioxane were also suitable solvents (entries 3 and 4). The use of 5 equiv of 1a improved the chemical yield and 3a was obtained in 72% yield (entry 5). The catalyst derived from AgOTf gave a better yield, although a longer reaction time was required (entry 6). Analogously, the reaction with 2b, with a butyl group at the alkynyl terminus, gave 3a in 75% yield (entry 7). In the current catalyst system using AgOTf, TfOH might be produced during the reactions due to the decomposition of AgOTf with a trace amount of water, which could be present in the reaction medium. However, the alkylation of 1a with 2a did not proceed at all with 5 mol % of TfOH. This result clearly indicates that the gold complex functions as a catalyst in the current transformations.

Table 1: Gold-catalyzed alkylation of silyl enol ethera.

[Graphic 1]
Entry 2 AgX Solvent Conditions Yield (%)b
1c 2a AgClO4 benzene 80 °C, 2 h 35
2 2a AgClO4 benzene 80 °C, 2 h 55
3 2a AgClO4 (CH2Cl)2 80 °C, 2 h 44
4 2a AgClO4 dioxane 100 °C, 2 h 58
5d 2a AgClO4 dioxane 100 °C, 1 h 72
6d 2a AgOTf dioxane 100 °C, 10 h 80
7d 2b AgOTf dioxane 80 °C, 5 h 75

aReaction conditions: 0.25 M solution of 2 was treated with 1a (3 equiv) in the presence of the gold catalyst. bNMR yield using CH2Br2 as an internal standard. cPh3PAuCl was used instead of (o-Tol)3PAuCl. d5 equiv of 1a was used.

We next examined the substrate generality with several types of silyl enol ethers 1 and esters 2 (Table 2). Treatment of five-membered silyl enol ether, cyclopentenyloxytrimethylsilane (1b), with 2b in the presence of the gold catalyst gave the corresponding benzylated product 3b in 61% yield (entry 1). It is worth mentioning that benzo-fused silyl enol ether 1c is suitable for this transformation as shown in entries 2 and 3, whereas it cannot be used for ene-reaction due to the lack of a hydrogen atom at the α’-position. Not only cyclic silyl enol ethers but also an acyclic silyl enol ether underwent the reaction. Thus, 1d reacted stereoselectively with 2a to yield E-3e. Interestingly, the formation of the isomeric Z-3e was not detected at all (entry 4) [41]. The reaction of 1a with allyl ester 2d proceeded smoothly and the corresponding allylated product 3f was obtained in 70% yield (entry 5) [42].

Table 2: Gold-catalyzed alkylation of silyl enol ethera.

[Graphic 2]
Entry 1 2 R1 R2 3 Yield (%)b
1c 1b [Graphic 3] 2b Bn Bu 3b 61
2 1c [Graphic 4] 2b Bn Bu 3c 70
3d 1c [Graphic 4] 2c [Graphic 5] Ph 3d 60e
4c,f 1d [Graphic 6] 2a Bn Ph 3e 61
5 1a [Graphic 8] 2d [Graphic 7] Ph 3f 70

aReaction conditions: 0.25 M solution of 2 was treated with 1 (5 equiv) in the presence of the gold catalyst. bNMR yield using CH2Br2 as an internal standard. c10 mol % of the catalyst was used. d3 equiv of 1 was used. eYield of isolated product. fAgOTf was used instead of AgClO4.

A plausible mechanism for the gold-catalyzed alkylation of silyl enol ethers is shown in Scheme 2. The gold catalyst enhances the electrophilicity of the alkynyl moiety of 2, leading to the formation of a cationic intermediate 6 via the intramolecular nucleophilic attack of the carbonyl oxygen on the alkyne as shown in 5. Due to the high leaving ability of the isocoumarin moiety of 6, the silyl enol ether 1 attacks the R group to give the intermediate 7 together with the gold complex 8 as a leaving compound [43-46]. In the case of ordinary substitution reactions with alkyl halides (path a in Scheme 1), generated halide ions would attack the silyl group, due to their strong affinities with the silicon atom, and cleave the silicon–oxygen bond of 7. However, in the present reaction system, intermediate 8 would prefer to act as a base and abstract a proton, Ha, from the α-position rather than attack the silyl group as a nucleophile, probably due to steric and electronic reasons. For these reasons, deprotonation of 7 occurs to give the product 3 together with 4 as a final leaving compound.

[1860-5397-7-76-i2]

Scheme 2: Plausible mechanism for the alkylation of silyl enol ether.

On the other hand, in the case of reactions with silyl enol ethers having a proton, Hb, at the α’-position, compound 9 might be produced through the deprotonation of Hb by 8. However, such products were not obtained in any of the examples studied. These results imply that isomerism from 9 to 3 would occur during the reaction. Thus, compound 1e was prepared according to a known procedure and treated with the gold catalyst at 100 °C for 2 h (Scheme 3). As expected, the isomerization of the double bond occurred and 3a was obtained in 80% yield. This result shows that the indirect pathway from 7 to 3 via deprotonation of Hb is also possible. In addition, it was found that the reaction of 1f, having no hydrogen at the α-position, proceeded smoothly and α,α-dialkyl silyl enol ether 3g was obtained in good yield (Scheme 4). Obviously, this result supports the possibility of the indirect pathway.

[1860-5397-7-76-i3]

Scheme 3: Gold-catalyzed isomerism of silyl enol ether.

[1860-5397-7-76-i4]

Scheme 4: Gold-catalyzed alkylation of tetra-substituted silyl enol ether.

In conclusion, we have developed an unprecedented alkylation method for silyl enol ethers, using a gold catalyst and ortho-alkynylbenzoic acid esters as alkylating agents. The reaction probably proceeds through the gold-induced in situ construction of a leaving group and subsequent nucleophilic attack on the silyl enol ether. Unlike ordinary leaving groups, such as halide ions, the generated leaving compound 8 acts as a base and abstracts a proton to regenerate the silyl enol ether structure. The current protocol can also be used with substrates having no hydrogen at the α-position, such as 1f. Further studies to elucidate the mechanism of this reaction and to extend the scope of synthetic utility are underway.

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