A Gold-Catalyzed Three-Component Coupling: Oxidative Oxyarylation of Alkenes

The past decade has seen rapid expansion in the area of homogeneous gold catalysis. The majority of reported methods rely on the π-acidic nature of cationic gold species to activate π-bonds toward nucleophilic attack.¹ On the other hand, the two electron oxidation/reduction cycles typical of other late transition metal catalysts are not commonly encountered in gold catalysis.^1e,2 Recently, a few reports of transformations best explained by Au(I)/(III) redox cycles, including Au-catalyzed oxidative intramolecular heteroarylation reactions, have appeared.³ Different modes of such heteroarylation reactions are accessible by combining two or all three reactant functional groups into a single substrate.⁴ Notably, examples of the fully intermolecular, three-component coupling variant have not previously been reported.^5,6 Herein we disclose a protocol for the three-component gold-catalyzed oxidative oxyarylation of alkenes; alcohols, carboxylic acids and even water are viable nucleophiles in this context.

(1)

(2)

We initially observed this mode of reactivity while studying the related intramolecular aminoarylation.^3b In an attempt to improve the solubility of the arylboronic acid, methanol was used as a co-solvent; however, the expected pyrrolidine 3a was not observed. Instead the alkoxyarylation product 2a was isolated in 38% yield (eq 1). The yield of 2a could be improved to 72% by increasing the temperature and employing 2 equivalents of phenylboronic acid.⁷ While previously reported gold-catalyzed additions of oxygen nucleophiles to alkenes have required temperatures greater than 85 °C,⁸ the oxidative alkoxyarylation proceeds efficiently at 50 °C. Under these conditions, various alkenylamines (1b and 4a-b) participated in the methoxyarylation reaction to afford the adducts of a three component coupling in good yields (eq 2). Moreover, gold-catalyzed reaction of 4b shows excellent chemoselectivity, leaving the more electron-deficient allylic amine unreacted.

In order to probe the scope of the reaction, 5-phthalimidopentene (6) was subjected to the optimized conditions for coupling with various alcohols and phenylboronic acid (Table 1). The expected ethers were obtained in high yield when using several primary alcohols (entries 1, 2, 4 and 6) and secondary alcohols (entries 3, 7 and 8). While neopentyl ether 10 was formed in 91% yield (entry 4), gold-catalyzed reaction with the more sterically encumbered tert-butyl alcohol gave only 33% of tert-butyl ether 11 (entry 5).⁹ Substituting carboxylic acids in place of alcohols afforded the corresponding esters, albeit in slightly lower yield (entries 9-12).

Table 1.

Alkoxy- and acyloxyarylation with various nucleophiles.^a

entry	R	product	yield (%)
1	Me	7	79
2	Et	8	85
3	iPr	9	90
4	(Me)3CCH2	10	91c
5	tBu	11	33b
6		12	85
7		13	85
8		14	88 1:1 d.r.
9	Me(CO)-	15	62
10	Et(CO)-	16	69
11	iPr(CO)-	17	50
12	Ph(CO)-	18	48c

^a100 μmol of alkene, 0.1M in 9:1 MeCN:ROH at 50°C for 14h; 2 equiv PhB(OH)₂, 2 equiv. Selectfluor®. The catalyst and PhB(OH)₂ were added in two portions at t = 0h and 2h.

^bYield determined by ¹H-NMR versus an internal standard (nitrobenzene).

^c10 equiv. ROH used.

The arylboronic acid component of the reaction was also varied with similar success. The gold-catalyzed coupling of alkene 6, methanol and various arylboronic acids gave the expected methyl ethers in good yields (Table 2). The reaction performed well with alkyl-, halo-, carboxymethyl- and formyl-substituted arylboronic acids. Moreover, ortho- (eq 3), meta-(entries 3,6) and para-substituted (entries 1-2,4-5) arylboronic acids were tolerated in the methoxyarylation reaction.

Table 2.

Methoxyarylation with various ArB(OH)₂.^a

entry	R-	product	yield (%)
1	4-Me	19	88
2	4-Br	20	90
3	3-F	21	79
4	4-MeO2C	22	83
5	4-H(CO)	23	82
6	3,5-bis-CF3	24	77

^a100 μmol of alkene, 0.1 M in 9:1 MeCN:MeOH at 50 °C for 14h; 2 equiv. ArB(OH₂), 2 equiv. Selectfluor®. The catalyst and ArB(OH)₂ were added in 2 portions at t = 0 and 2h.

The nitrogen-containing functional groups in 1a-b, 4a-b, and 6 are not required for successful oxyarylation. Simple alkenes lacking these functionalities proved to be suitable substrates for alkoxy- and acyloxyarylation under our optimized conditions. The expected ethers were obtained in good yields when alkenes such as 1-octene and 1-bromo-2-(3-buten-1-yl)benzene were reacted with several combinations of alcohols and arylboronic acids (Table 3). Acetate esters were isolated in attenuated but synthetically useful yields from simple alkenes when using acetic acid as the nucleophile (entries 2, 7).

Table 3.

Alkoxy- and acyloxyarylation of simple alkenes.^a

entry			R1	R2	product	yield (%)
1				4-Br	25	69
2			Me	2-CO2Me	26	78
3			Me(CO)	4-Br	27	51b
4		n = 5		4-Br	28	76
5		n = 5	(Me)3CCH2	4-Br	29	73
6		n = 9	(Me)3CCH2	H	30	66
7		n = 5	Me(CO)	4-Br	31	53b

^a100 μmol of alkene, 0.1 M in 9:1 MeCN:R¹OH at 50 °C for 14h; 2 equiv. ArB(OH₂), 2 equiv. Selectfluor®. The catalyst and ArB(OH)₂ were added in 2 portions at t = 0 and 2h.

^bOnly 5 equiv R¹OH used, 0.1 M in MeCN.

Using water as a nucleophile would allow for the formation of alcohols directly via hydroxyarylation, circumventing the requirement for protective groups for installation of the alcohol functionality.¹⁰ We were pleased to find that simply replacing the alcohol in our protocol with water cleanly effected the formation of the desired hydroxyarylation products. A variety of terminal alkenes and arylboronic acids were subjected to these conditions, furnishing the expected products in good yield (Table 4). Various functional groups, including ether (entry 2), ester (entry 3), amide (entry 1), cyano (entry 2), nitro (entry 3) and arylhalide (entries 5-7), were well-tolerated.

Table 4.

Scope of hydroxyarylation reaction.^a

entry	product		yield (%)
1		32	88b
2		33	85c
3		34	67d
4		35	76
5		36	73
6		37	72
7		R = 3-F, 38	83
8		R = 4-Me, 39	71

^aAt 0.1 M alkene in MeCN, 10 equiv. H₂O, catalyst (2.5 mol%/addition) and ArB(OH)₂ (1 equiv./addition) were added in 2 portions each, at t = 0h and 1h.

^bIsolated as a 1.2:1 mixture of diastereomers.

^c3 portions of catalyst (2.5 mol%/addition) and ArB(OH)₂ (1 equiv./addition).

^dUsing (4-CF₃C₆H₄)₃PAuBr as catalyst, 2 portions of 5 mol% each.

The ability to use either alcohols or water as nucleophiles in the gold-catalyzed three-component coupling provides access to a greater diversity of products. Moreover, the hydroxyarylation reaction offers the opportunity of forming an additional C-O bond to the resulting alcohol. For example, methoxyarylation of 6 with boronic acid 40 furnished methyl ether 41 in 85% yield. Using water as a nucleophile, 42 was formed in 87% yield from gold-catalyzed hydroxyarylation followed by in situ lactone formation of the resulting alcohol (eq 3).

(3)

At present, we proffer a catalytic cycle for the gold-catalyzed oxyarylation of alkenes that is analogous to the mechanism proposed for the related intramolecular aminoarylation reaction.^3b Initial oxidation of the gold(I) bromide is thought to provide a cationic gold(III) species capable of activating the alkene toward nucleophilic attack. Oxyauration of the π-bond is then followed by C-C bond formation, without prior transmetallation of the aryl group from boron to gold (Figure 1).

Figure 1.

Proposed catalytic cycle for alkene hydroxyarylation.

Reaction of monodeuterated alkene d₁-6 stereospecifically produced d₁-42 with stereochemistry consistent with initial syn-hydroxyauration followed by invertive C-C bond formation. The stereochemical course of the hydroxyarylation is consistent with our earlier observations from the gold-catalyzed intramolecular aminoarylation (eq 4).^3b

(4)

In conclusion, we have demonstrated the gold-catalyzed three-component coupling reaction of alkenes, arylboronic acids and several types of oxygen nucleophiles, including alcohols, carboxylic acids and water. It is notable that the latter effectively participates as a nucleophile in these reactions, especially given difficulties associated with transition metal-catalyzed hydration of alkenes.¹¹ This method represents the first fully intermolecular alkene heteroarylation reaction and stands as one of the few examples of gold-catalyzed multicomponent couplings.¹²