Gold Catalyzed Decarboxylative Cross-Coupling of Iodoarenes
This report details a decarboxylative cross-coupling of (hetero)aryl carboxylates with iodoarenes in the presence of a gold catalyst (>25 examples, up to 96% yield). Generating an aryl nucleophile via decarboxylation obviates problems associated with transmetalation at a putative gold(III) complex. This reaction is site specific, which overcomes prior limitations associated with gold catalyzed oxidative coupling reactions. The reactivity of the (hetero)aryl carboxylate correlates qualitatively to the field effect parameter (Fortho). Furthermore, each step in a proposed mechanism was observed from isolated gold complexes, supporting a gold catalyzed mechanism.
<!>Scheme 1. Gold Catalyzed Biaryl Formations<!>Table 1. Optimization for Gold Catalyzed Decarboxylative Cross-Coupling<!>Table 2. Substrate Scope of Iodoarene<!>Table 3. Substrate Scope of (hetero)aryl carboxylates
<p>Gold was once thought to have few uses in fine chemical synthesis. 1 Advances in homogeneous gold catalysis demonstrated that gold(I) complexes can promote a wide variety of synthetically relevant transformations. [2][3][4][5] Most employ a gold(I) catalyst as a Lewis acid or π-activator, where gold is thought to formally remain at the +1 oxidation state. The apparent redox stability of gold(I) complexes [6][7][8] contrasts with prominent two electron redox events known for palladium, rhodium, platinum, and iridium complexes. The redox stability of gold(I) complexes has limited development of complementary methods utilizing redox gold catalysts. This work describes a gold catalyzed decarboxylative cross-coupling reaction.</p><p>Pioneering studies demonstrated that gold(I) complexes could participate in oxidative addition with methyl iodide, 9,10 trifluoromethyl iodide, 11,12 aryl diazonium salts, [13][14][15][16][17][18] iodine(III) reagents, [19][20][21][22][23][24][25][26] and other strong oxidants. [27][28][29] Initially Lloyd-Jones and co-workers demonstrated a catalytic oxidative coupling of aryl silanes in the presence of a strong acid and a stoichiometric iodine(III) oxidant (Scheme 1a). 20,21 A limiting feature of this and subsequent work [22][23][24][25][26]30,31 is that the site selectivity of C-H bond activation is governed by an apparent electrophilic aromatic substitution (EAS) mechanism. Patil and coworkers demonstrated a dual gold/photoredox catalyzed cross-coupling with aryl silanes 17 or aryl stannanes, which is thought to occur via a radical mechanism (Scheme 1b). 18 The direct oxidative addition with more standard and less hazardous aryl halide electrophiles (e.g. Ar-I), which is standard for palladium(0), is relatively rare with gold(I). 6,7,[30][31][32][33][34][35][36][37][38] The barrier for the oxidative addition of gold(I) complexes into aryl halides can be decreased through the use of bidentate ligands with a hemilabile site. 6,33,37 Amgoune, Bourissou, and co-workers recently disclosed a gold catalyzed arylation of electron rich indoles and trimethoxybenzene with aryl halides (Scheme 1c). 30,31 This was recently expanded to amination. 38,39 Attempts at expanding this reactivity to more common organometallic reagents have been problematic. In an elegant study, Bower, Russell, and co-workers demonstrated that all three elementary steps in a putative gold(I/III) cross-coupling are viable. 6,32 However, this reactivity was not incorporated into a catalytic method. Additionally, aryl boron reagents were found to be sub-optimal coupling partners, which may be due to a challenging and potentially endothermic transmetalation. 40,41 An alternative to transmetalation would be to utilize decarboxylation.</p><!><p>Our lab has focused on decarboxylative cross-coupling. 42,43 Decarboxylative functionalization reactions are recognized as promising alternatives to traditional cross-couplings because expensive or unstable organometallic reagents can be replaced by readily available benzoic acids . [44][45][46][47][48] Inspired by two reports describing stoichiometric gold(I) mediated decarboxylation, 49,50 we surmised that this elementary step could offer an alternate pathway to gold-aryl complexes, obviating traditional transmetalation. 6,40,41 Presented herein is a gold catalyzed decarboxylative cross-coupling reaction between iodoarenes and (hetero)aryl carboxylates (Scheme 1e). This work represents the first site-specific gold catalyzed cross-coupling with standard coupling partners and the first gold catalyzed decarboxylative coupling of (hetero)aryl carboxylates. Initial trials were inspired by Amgoune and Bourissou, who recommended MeDalphos as a ligand. 30,31 The use of sodium carboxylate 1a (M = Na) with NaOTf did not produce any detectible biaryl (Table 1, entry 1). Excitingly, using AgOTf afforded cross-coupled product 3a along with protodecarboxylation product 4 (entry 2). 51 Switching from a sodium carboxylate to a silver carboxylate (entry 3) and decreasing the loading of AgOTf dramatically improved the yield (entry 4). Changing the limiting reagent to iodoarene 2a significantly diminished the yield (entry 5).</p><!><p>a Reactions conducted with benzoate 1a (0.1 mmol), iodoarene 2a (0.5-1.0 mmol), in 1,2-dichlorobenzene (0.5 M, DCB), with 5 mol % [Au]. b Yield determined by 19 F NMR analysis. All yields reflect the average of duplicate trials. c Reactions conducted neat in iodoarene 2a. d  A variety of precatalysts were screened and it was discovered that Buchwald style phosphine ligands performed well under neat conditions (entries 6-11). 52 The quantity of iodoarene was decreased from 10 equiv to 5 equiv (entries 12-13). The t BuXPhos ligand outperformed the t BuJohnphos ligand under these conditions. Next, the counterion on the precatalyst was evaluated (entries 14-16). With LAuCl or LAuI complexes, in the absence of silver trifluoromethanesulfonate, significant homocoupling of benzoate 1a was observed. The optimal precatalyst was LAuNTf2 (entry 17). A further reduction in the iodoarene to 3 equiv was tolerated but decreased the selectivity (entry 18). The reaction was conducted in a new vial with a new stir bar to avoid possible contamination, 53 which did not significantly affect the yield (entry 19). In the absence of gold, small amounts of product were observed along with significant protodecarboxylation (entry 20, see SI for additional trials and control experiments).</p><p>The substrate scope of the iodoarene was investigated (Table 2). Substrate 3a was isolated in excellent yield (86%). Iodobenzene (3b), 4-iodoanisole (3c), and 4-iodobenzotrifluoride (3d) afforded product, covering the traditional Hammett series (4-OMe, σp = -0.27; 4-CF3, σp = 0.54). Iodoanisole gave an improved yield at 120 °C, while iodobenzotrifluoride required heating to 160 °C. This matches prior observations demonstrating that oxidative addition at gold(I) is faster with electron rich substrates (vide infra). 31,33 Iodoarenes with meta substituents gave acceptable yields (3e-3h). The reaction tolerated ortho groups (3i-3k). Chemoselectivity was observed for oxidative addition in the presence of aryl chlorides (3j) and aryl bromides (3h, 3k). Iodonaphthalene (3l) also worked well.</p><!><p>Yield determined by 19 F NMR. Yield in parenthesis is the isolated yield. All values are the average of duplicate reactions. Reaction conducted at a 120 °C, b 160 °C, c in 1,2-dichlorobenzene. See SI.</p><p>A competition experiment was conducted between 4-iodoanisole (2c) and 4-iodobenzotrifluoride (2d, Table 2 bottom). The reaction afforded biaryl 3c as the major product with a 3c:3d ratio of 3.3:1. A similar competition experiment with stoichiometric MeDalphosAuSbF6, afforded gold(III) complexes with a ratio of 6.7:1. 31 The inversion of reactivity, relative to oxidative addition at palladium(0), 54 is a potential hallmark of gold oxidative addition. 27,31,33 The substrate scope with respect to the aryl carboxylate was investigated (Table 3). It is well recognized in the area of palladium, copper, and silver decarboxylative cross-coupling that substrates with polarizing ortho substituents are particularly reactive. [44][45][46][47][48] Hoover and co-workers correlated the field effect parameter (Fortho) to reactivity for silver mediated protodecarboxylation. 55 Here, products 3m -3v could be isolated in good to excellent yield and these results qualitatively correlate to the field effect parameter. Less activated substrates required elevated temperatures and/or increased catalyst loading (3v -3y). It is particularly exciting that substrates 3x and 3y can be isolated in any yield given the scope limitations of other decarboxylative cross-coupling reactions. 43,48,56 Substrates with an ortho C-H bond did not afford product with palladium catalyzed reactions 42,43,56 and a chlorine substituent (3y) is not considered to be particularly polarizing. A substrate with an orthomethoxy was not activated enough to provide an acceptable yield (3z, Fortho = 0.29). Activated pyridine carboxylates afforded products 3aa and 3bb. Pyridines are particularly challenging substrates in traditional cross-coupling reactions. [57][58][59] It is conceivable that the observed cross-coupling reaction could proceed via protodecarboxylation 51,55 and subsequent C-H bond activation. 60 This concern is valid because product 4 was observed and since carboxylates facilitate C-H bond activation. 60 A reaction with 1,3-difluorobenzene (4) and excess silver benzoate 1o afforded a negligible quantity of product 3a (Scheme 2a). The majority of compound 4 was detected after the reaction, with the mass loss being attributed to volatility. As such, a protodecarboxylation and C-H bond activation sequence is unlikely.</p><!><p>Yield determined by 19 F NMR. Yield in parenthesis is the isolated yield. All values are the average of duplicate reactions. Reaction conducted a in 1,2-dichlorobenzene at 0.1 M, b in 1,2-dichlorobenzene at 0.17 M, c at 180 °C, d at 180 °C using 10 mol % [Au]. See SI. Fortho = field effect parameter.</p><p>A tentative mechanism was supported by monitoring various elementary steps with isolated complexes (Scheme 2). Benzoate 1a' underwent salt metathesis, yielding complex Au1 (Scheme 2b). Gold(I)-aryl complex Au2 could be isolated via thermolysis of complex Au1 (Au2 crustal structure shown, Scheme 2b), indicating that gold mediated decarboxylation is viable. 49,50 Heating complex Au2 in neat iodoarene provided some biaryl (Scheme 2c). The majority of complex Au2 remained unreacted, even after 24 h. However, when AgOTf was used with complex Au2, product 3a was observed in high yield (Scheme 2c). This suggests that silver is needed to either promote oxidative addition or reductive elimination en route to product 3a. Tetracoordinate gold(III) complexes can be stable and halide abstraction can trigger reductive elimination. 12,27 While minimal product 3a was formed from complex Au2 (Scheme 2c) in the absence of silver, using stoichiometric t BuXPhosAuNTf2 with carboxylate 1a' did produce product 3a (21%) as well as complex Au2 (36%, Scheme 2d). Potentially, t BuXPhosAuNTf2 can abstract iodide from a putative gold(III) complex, while complex Au2 does not. To test this hypothesis, complex Au2 was subjected to the reaction conditions with added t BuXPhosAuNTf2 (Scheme 2e) and product 3a was observed. These results demonstrate that silver is not required and the most likely role for AgOTf is to promote halogen abstraction prior to reductive elimination from an Au(III) complex. 12,27 A reversible and endothermic oxidative addition is also possible and would complicate the isolation of Au(III) complex.  In conclusion, we report the first gold catalyzed decarboxylative cross-coupling. This work expands on recent progress regarding gold(I) oxidative addition. Decarboxylation overcomes site selectivity limitations associated with prior gold catalyzed arylations. The scope of the aryl carboxylate correlates qualitatively with the field effect parameter and preliminary studies indicate that all steps in a catalytic cycle can occur at gold. A more comprehensive mechanistic study will be reported in due course.</p>