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. 2023 Aug 1;13(16):10751–10755. doi: 10.1021/acscatal.3c02461

Gold(I)-Catalyzed Intermolecular Aryloxyvinylation with Acetylene Gas

Tania Medina-Gil 1,2, Anna Sadurní 1,2, L Anders Hammarback 1,2, Antonio M Echavarren 1,2,*
PMCID: PMC10442918  PMID: 37614519

Abstract

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Acetylene gas is an important feedstock for chemical production, although it is underutilized in organic synthesis. We have developed an intermolecular gold(I)-catalyzed alkyne/alkene reaction of o-allylphenols with acetylene gas that gives rise to chromanes by a stereospecific aryloxycyclization through the nucleophilic regioselective opening of cyclopropyl gold(I)-carbene intermediates. The synthetic application of this method was demonstrated in the late-stage functionalization of the natural product lapachol.

Keywords: gold catalysis, acetylene, aryloxycyclization, chromanes, enantioselective catalysis

Acetylene is one of the most important feedstocks in chemical industry due to its ready availability and high reactivity.1,2 Acetylene can be produced by several well-established methods such as the reaction of calcium carbide with water2 or the partial combustion of hydrocarbons.3 The importance of acetylene-based chemistry is best illustrated by its remarkable production market that reached 1.9 million tones in 2020 and is expected to continue growing until 2030.2 Despite this, so far, chemical applications of acetylene have been mainly limited to noncatalyzed vinylation reactions4 or hydrochlorination processes,5 whereas its use in catalytic reactions has been less explored.2,6−8

Homogeneous gold(I) complexes are highly efficient catalysts for the electrophilic activation of alkynes.9 Although gold(I)-catalyzed cyclizations of 1,n-enynes,9 such as the alkoxycyclizations by intramolecular alkyne/alkene reactions (Scheme 1a),10 have been widely explored, broad scope intermolecular reactions between alkynes and alkenes are less common.11−13 Besides the possible polymerization of the alkenes,14 the main hurdle is that products of intermolecular reactions of alkynes with alkenes are also alkenes, which can react further with the alkyne leading to the formation of oligomers. Indeed, we recently reported that acetylene gas reacts with trans-stilbene in the presence of gold(I) catalysts to form (Z,Z)-1,3-dienes, along with oligomers that result from the formal insertion of C2 units (Scheme 1b, pathway 1).15 By using a NHC-gold(I) catalyst, biscyclopropyl products were also obtained, which was applied to the first total synthesis of the sesquiterpene waitziacuminone in a single step.15 (Scheme 1b, pathway 2).

Scheme 1. (a) Gold(I)-Catalyzed Alkoxycyclization by Intramolecular Alkyne/Alkene Reaction9,10 and (b) Activation of Acetylene Gas15.

Scheme 1

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Although alkoxycyclizations of 1,n-enynes are well-known (Scheme 1a),10,16 the intermolecular version has not yet been developed. We reasoned that using acetylene gas as an intermolecular in the gold(I)-catalyzed reaction with an alkene would give rise to products with a terminal vinyl group, which are less reactive in subsequent reactions with acetylene, thus minimizing the problem of oligomerization. Here, we report the realization of this concept by developing an intermolecular alkyne/alkene gold(I)-catalyzed reaction from o-allylphenols 1 and acetylene gas that gives rise stereospecifically to chromanes 2 (Scheme 2). In this aryloxyvinylation reaction, the initial acetylene gold(I) complex is the electrophile that reacts with the alkene to form cyclopropyl gold(I)-carbene IntA, which reacts regioselectively with the phenol at C-3 of the allyl chain to form a 6-membered ring. The resulting chromanes are important heterocyclic scaffolds present in a wide variety of natural products, agrochemical, and pharmaceutical compounds,17 such as α-tocopherol,18 (+)-catechin,19 deguelin,20 and cromakalim.21

Scheme 2. Aryloxyvinylation by Gold(I)-Catalyzed Intermolecular Alkyne/Alkene Reaction.

Scheme 2

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The reaction of 2-cinnamyl phenol (1a) with acetylene gas in the presence of commercially available JohnPhosAuCl (A) as a catalyst and NaBArF4 as a halide scavenger gave the desired vinylated chromane 2a in 78% yield (Table 1, entry 1). Gold(I) catalysts B, C, and D led to 2a in lower yields (Table 1, entries 2–4). Using CHCl3 instead of CH2Cl2 as solvent with catalyst A improved the yield of 2a to 89% (Table 1, entry 5). Aromatic solvents gave comparable yields, toluene being the best one, providing 2a in 81% yield (Table 1, entry 6). Changing NaBArF4 to AgSbF6 as a chloride abstractor led to a drop of the yield (49%) (Table 1, entry 7). Finally, 2a was obtained in 91% yield by increasing the concentration (Table 1, entry 9).22

Table 1. Gold(I)-Catalyzed Reaction of 1a with Acetylene Gas to Form Chromane 2aa.

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entry [Au(I)] (mol %) solvent yield (%)b
1 A (6) CH2Cl2 78
2 B (6) CH2Cl2 71
3 C (6) CH2Cl2 53
4 D (6) CH2Cl2 50
5 A (6) CHCl3 89
6 A (6) toluene 81
7c A (6) CHCl3 49
8 A (4) CHCl3 69
9d A (6) CHCl3 91
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a

Reactions were carried out using 0.10 mmol scale of substrate 1a at 0.2 M concentration.

b

Yields determined by 1H NMR using 1,1,2,2-tetrachloroethane as internal standard.

c

AgSbF6 instead of NaBArF4.

d

0.4 M concentration.

graphic file with name cs3c02461_0006.jpg

The optimized reaction conditions were applied to the synthesis of a variety of 3-vinyl chromane derivates 2a–w (Scheme 3). First, the influence of the substituents on the phenol ring was investigated. Substrates with electron-donating groups gave the corresponding products 2b–d, 2h, and 2j–l in moderate to good yields, whereas 2i could only be isolated in 29% yield. An allyl phenol with a Br substituent in the para-position led to chromane 2e in good yield, whereas substitution with more strongly electron-withdrawing ester or CF3 groups led to 2f and 2g in 20% and 33% yield, respectively, presumably because of the decreased nucleophilicity of the corresponding phenols. Substrates with different substituents on the phenyl ring of the cinnamyl chain led to products 2m–t in gold yields, except for 2p and 2r with a p-CF3 or o-Br, which were isolated in 21% and 30% yields, respectively (Scheme 3). Other o-allyl phenols with different substituents at the alkene gave chromanes 2u–w in 37–74% yields.

Scheme 3. Synthesis of Chromanes 2 by Gold(I)-Catalyzed Aryloxyvinylation of o-Allylphenols 1 with Acetylene Gas.

Scheme 3

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48 h reaction time.

0 °C for 3 h.

1:1 mixture of stereoisomers

The observed anti-stereochemistry and excusive 6-endo-trig regioselectivity is identical to that found in similar formation of chromanes by halocyclization of the same substrates.23 However, in our case, the cyclization is induced by the addition of acetylene as a C2 equiv of the halonium electrophile.

Since o-allylphenols are ubiquitous in nature, this aryloxyvinylation could be used for the late-stage modification of this class of natural products.24 As a preliminary demonstration of this concept, we have applied this new reaction to the natural product lapachol (3), a derivate of vitamin K,25 leading to 3-vinyl-α-lapachone 4 in 50% yield (Scheme 4a). Vinyl chromane 2d was converted into 2x by Suzuki cross-coupling with bromobenzene (Scheme 4b). The vinyl group provides a versatile handle for diversification. Thus, 2a led to 5 by Wacker oxidation, whereas reaction with mCPBA gave 6 (Scheme 4c). Furthermore, metathesis of 2a with methyl acrylate afforded 7, and the hydroboration with HBpin provided 8. A monocationic catalyst generated in situ from JosiPhos-type digold(I) complex (R,SP)-E12d proved to be highly active leading to 2a, 2d, 2e, and 2m (Scheme 4d). Although the achieved enantioselectivities are still moderate, these are the first examples of enantioselective activation of acetylene in gold(I) catalysis.

Scheme 4. (a) Vinylation of Lapachol (3); (b) Derivatization of 2d; (c) Derivatization of 2a; (d) Enantioselective Aryloxycyclization.

Scheme 4

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In summary, we have developed a gold(I)-catalyzed intermolecular reaction between acetylene gas and readily available o-allylphenols as a novel approach for the synthesis of 3-vinylchromanes. This stereoselective intermolecular aryloxyvinylation leads to chromanes in moderate to excellent yields, showing good functional group tolerance. The applicability of this method was demonstrated by the late-stage functionalization of the natural product lapachol (3) and with the diversification at the aryl or vinyl of the resulting chromanes. This new methodology combines the use of common feedstock reagents such as acetylene gas and phenols with the employment of gold(I) catalysis to obtain scaffolds widely abundant in natural products and pharmacologically active compounds.

Acknowledgments

We thank the MCIN/AEI/10.13039/501100011033 (PID2019-104815GB-I00 and CEX2019-000925-S), the European Research Council (Advanced Grant 835080), the AGAUR (2021 SGR 01256), and CERCA Program/Generalitat de Catalunya for financial support. T.M. thanks the MCIN/AEI for a FPI predoctoral fellowship (PRE2020-092105), A.S. thanks the European Union (H2020 MSCA-COFUND 801474 Postdoctoral Fellowship, GA 801474), L.A.H. thanks the European Union (Horizon 2020 Marie Skłodowska-Curie Postdoctoral Fellowship, H2020-MSCA-IF-2020 under Grant Agreement No. 101029012-GASGOLD). We also thank ICIQ X-ray diffraction, NMR, and mass spectrometry units.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.3c02461.

  • Experimental procedures, characterization data, NMR data, UPC2 and HPLC traces, computational details, and X-ray data (PDF)

The authors declare no competing financial interest.

Supplementary Material

cs3c02461_si_001.pdf (6.8MB, pdf)

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  22. See Supporting Information for additional details.
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Supplementary Materials

cs3c02461_si_001.pdf (6.8MB, pdf)

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