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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Org Chem. Author manuscript; available in PMC 2010 August 20.
Published in final edited form as:
PMCID: PMC2924810

Gold(I)-Catalyzed Intramolecular Hydroarylation of Allenes


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Gold(I) complexes react with 4-allenyl arenes in an exo fashion to furnish vinyl-substituted benzocycles. Phosphite gold(I) monocations were found to be optimal, and the catalyst was tolerant of ethers, esters, and pyrroles. Reactions proceeded in unpurified solvent at room temperature.

The Friedel-Crafts reaction has been a part of many successful transformations in organic chemistry.1 The reaction has been accelerated by strong acids and by stoichiometric and catalytic quantities of various metals. Recent developments on the topic of catalytic cycloarylation reactions include the gold-(I)-catalyzed arylation of allenes2,3 by indoles (Widenhoefer4) and pyrroles (Nelson5) and the gold(III)-catalyzed hydroarylation of alkynes reported by He6 (Scheme 1). Hashmi has also shown that intermolecular addition of furans to allenes can be achieved.7 The mechanisms are presumed to proceed by an initiating allene activation by the electrophilic gold(I) cation.

Scheme 1
Recent Gold(I)-Catalyzed Allene Arylations4,5

Related to these first demonstrations is our recent gold(I)-catalyzed cycloisomerization of 1,6-ene-allenes8 (eq 1). The proposed mechanism paralleled the Nelson/Widenhoefer systems with gold(I) acting as an allene activator for intramolecular attack by the alkene to generate an intermediate carbenium ion. Elimination and protodeauration yielded the vinylcyclohexene with variable regiocontrol.

equation image

Arenes exhibit a wide range of π-nucleophilicities as characterized by the Mayr N values,9 which quantify and rank their rates of reaction with a common electrophile. Comparing these values to the allene activations reported in the literature revealed a focus on alkene (N = −1.00 to 1.20) and heteroaromatic (furan/indole/pyrrole; N = 3.60–7.00) nucleophiles (Scheme 2).10

Scheme 2
Representative N Values8 for π-Nucleophiles

Since a number of interesting nucleophiles occupy the spectrum between alkenes and N-heterocycles, we initiated efforts to examine arene-allene cycloisomerizations. One expected benefit was the rearomatization-driven regioselective elimination to products. To develop this concept, we began with the relatively activated dimethoxy substrate 2 and the optimum catalyst for the ene-allene cycloisomerization 3,5-xylyl-BINAP-(AuCl)2/AgBF4. Gratifyingly, the desired vinylated product 3 was obtained, but the rate was slower than desired (>16 h for full conversion).

To improve the reaction rate, a number of alternative catalysts were examined. The best of these was the triphenylphosphite-derived catalyst11 1, which was an easily prepared, colorless, crystalline material that was bench stable for several weeks.12 The less basic phosphite ligand13 generated a catalyst that was significantly more effective (Scheme 3).14 The reaction produces benzocyclic products that are similar to those reported by Ma15 from Brønsted activation of allylic alcohols and by Cook16 utilizing In(III)-mediated atom-transfer cyclization.

Scheme 3
Optimized Conditions with Activated Substrate 2

As shown in Table 1, dichloromethane in combination with the SbF6− counterion was optimum with regard to rate and yield of 3. Under these conditions, the catalyst load could be reduced to 3 mol % with reasonable reaction times and little change in yield.

Table 1
Optimization of Solvent and Silver Counterion for the Conversion of 2 to 3 (Scheme 3)a

Utilizing the standard protocol shown in Scheme 3, a variety of arene nucleophiles were examined (Table 2). Generally speaking, the scope was limited to electron-rich arenes but was tolerant of ethers, acetals, and, not surprisingly, a pyrrole.5 The naphthalene substrate (Mayr parameter9 N = −3.9) was especially well-behaved. Unfortunately, coordinating aromatics such as triazoles, isoxazoles, and oxazoles were not effective, likely due to nonproductive coordination to the gold(I) catalyst. Substrates for this chemistry were obtained from the benzylation of monoallenylmalonate4b with base in THF/DMF.17

Table 2
Au-Catalyzed Cyclohydroarylation of Allenesa

In cases where the arene nucleophile N parameter was sufficiently high, the catalyst loading could be lowered to further increase reaction efficiency (Table 3, entry 7). The catalyst was also tolerant of substitution at the allene terminus and variation of the malonate linker (Scheme 4).

Scheme 4
Variation in Linker/Allene Substitution
Table 3
Control Experimentsa Using 2 to Test for Ag+ or H+ Background Catalysis

To ensure that the above transformations were indeed proceeding by gold catalysis, a series of control experiments were carried out. Interestingly, 3 was obtained from 2 using stoichiometric amounts of silver but only at higher temperature and longer reaction times (Table 3). Catalytic quantities of triflic acid (5 mol %), HNTf2 (1 mol %), or HBF4 (1 and 5 mol %) did not produce 3, ruling out the possibility of a Brønsted pathway. As expected, leaving out the halide abstraction agent did not provide an active catalyst, reinforcing the notion of a P(OPh)3Au+ active catalyst.

With less activated aryl rings, such as the 4-tert-Bu substrate 20, a major byproduct was allene hydration to methyl ketone 21 (eq 2). The N value of ~ −4.0 for a tert-butylphenyl group likely represents the lower limit for sufficient π-nucleophilicity to add to the Au+-activated allene. More electron-deficient arenes (NO2Ar, BrAr, IAr, etc.) were cleanly converted to the methyl ketone with no trace of cycloisomerized product. A related transformation was recently reported.18

equation image

Attempts to minimize the allene hydration by using anhydrous CH2Cl2 and adding4ÅMS only led to low conversions (<30%, 72 h). We speculate that the adventitious water acts as a proton shuttle to modulate the rearomatization and protodeauration steps of the mechanism.19

In summary, a highly electrophilic phosphite gold(I) catalyst has been applied to the intramolecular allene hydroarylation reaction, producing vinylbenzocycles in good to excellent yields. The catalyst is tolerant of trace water and oxygen, it is bench-stable, and it can be utilized in air with unpurified commercial solvent.

Experimental Section

Representative Cycloisomerization Procedure

To a 5mL vial charged with a stirbar, 1 (27.2 mg, 0.05 mmol, 1.0 equiv), and AgSbF6 (24.0 mg, 0.07 mmol, 1.4 equiv) was added dichloromethane (1.0 mL) by syringe, at which point a white-gray suspension formed. After 2 min, 2 (168 mg, 0.5 mmol, 10 equiv) was added by pipet. The suspension turned deep green within 20 min. After 6 h, the reaction was loaded directly onto a silica flash column and purified with 1:7 ethyl acetate/hexanes. Yield: 85% of 3 as a clear oil. 1H NMR (400 MHz, CDCl3): δ 6.23 (s, 2H), 5.74 (m, 1H), 4.90 (d, 1H, J = 10.4 Hz), 4.68 (d, 1H, J = 17.2 Hz), 3.77 (s, 3H), 3.70 (s, 3H), 3.66 (s, 3H), 3.64 (s, 3H), 3.34 (d, 1H, J = 16 Hz), 2.99 (d, 1H, J = 16.4 Hz), 2.48 (m, 1H), 2.29 (m, 1H). 13C (100 MHz): δ 171.8, 171.7, 159.1, 158.6, 141.3, 135.8, 113.3, 104.3, 97.1, 55.3, 55.2, 52.6, 52.4, 35.4, 35.0, 34.3. HRMS-ESI+: 357.131 calcd for C18H22O6 + Na, found 357.131.

Supplementary Material

Gold(I)Cat SI


Support from the National Institute of General Medicine (GM-60578) is greatly appreciated.


Supporting Information Available: Experimental procedures, 1H, 13C, and HRMS data for all new compounds. This material is available free of charge via the Internet at


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