Article pubs.acs.org/Organometallics
Synthesis and Reactivity of N‑Heterocyclic Carbene Gold(I) and Gold(III) Imidate Complexes and Their Catalytic Activity in 1,5-Enyne Cycloisomerization Jonathan P. Reeds,† Adrian C. Whitwood,† Mark P. Healy,‡,§ and Ian J. S. Fairlamb*,† †
Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
‡
S Supporting Information *
ABSTRACT: The effects of substituting (pseudo)halide for anionic imidate ligands in Au(I) and Au(III) (i.e. [AuBr(NHC)] and [AuBr3(NHC)]) complexes have been investigated. [Au(N-imidate)(NHC)] and [AuBr2(N-imidate)(NHC)] complexes were prepared and the structure and bonding of the complexes examined spectroscopically and crystallographically. The [AuBr2(N-imidate)(NHC)] complexes, in combination with Ag salts, were tested for catalytic activity in the cycloisomerization of 1,5-enynes and found to be more effective than the tribromide analogues (e.g. [AuBr3(NHC)]). Subtle changes to the anionic imidate ligand structure had a pronounced effect on the catalytic activity of the Au(III) complexes.
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INTRODUCTION In recent years there has been great interest in the catalytic properties of gold in synthetic chemistry.1 Au complexes efficiently catalyze the transformation of CC and CC bonds2 in a diverse array of reactions, including nucleophilic substitution,3 hydration,4 cycloaddition,5 rearrangement,6 hydrosilylation,7 polymerization,8 oxidation,9 carbene transfer (C−H functionalization/activation),10 epoxidation,11 hydroamination,12 cycloisomerization,13 and many tandem and domino processes,14 also finding application in the total syntheses of natural products of biological importance.15,16 Au(I) complexes, typically of the type [AuXL], where L is a phosphine17 or N-heterocyclic carbene (NHC)18,19 ligand and X is a weakly coordinating anion20 (usually −OTf or −PF6), have been widely used as catalysts for these reactions. Inorganic Au(III) complexes and related salts, such as AuCl3 and Na[AuCl4], have also been used to carry out similar transformations.6c,21 Generally, less attention has been directed toward the development of organometallic Au(III) catalysts and complexes.22 Key examples include pyridine-derived iminophosphorane (1)23 and o-carboxylate (2)24 precatalysts (Figure 1). This is perhaps surprising, as Au(III) can promote Lewis acid type catalysis.3a,25 Some examples include hydrogenation,26 hydrosilation,27 addition of water and alcohols to triple bonds,28 cycloisomerization,24 and coupling of aldehydes, amines, and terminal alkynes to produce propargyl amines.29 Au(I) and Au(III) oftentimes display distinctive catalytic behavior, proceeding via separate mechanisms to give an eclectic array of products with varying substitution patterns.30 A reaction that has been of interest to us and other groups is the efficient cycloisomerization of 1,5-enynes17,31 mediated by © XXXX American Chemical Society
Figure 1. Pyridine-derived iminophosphorane (1) and o-carboxylate (2) precatalysts.
Au(I) and Au(III) salts. For example, Toste elegantly demonstrated that alkyl- and aryl-substituted 1,5-enynes (3) undergo Au-catalyzed cycloisomerization to afford bicyclo[3.1.0]hexyl ring systems (4) (Scheme 1),17b motifs found embedded in some natural products.32 There have also been three examples of dual-catalyst systems that mediate the nucleophilic substitution of propargyl alcohols with allylsilanes, using a Lewis or Brønsted acid, followed by 1,5-enyne cycloisomerization mediated by an Au(I) catalyst/ Scheme 1. Au(I)-Catalyzed Cycloisomerization of 1,5Enynes (3) To Produce Bicyclo[3.1.0]hex-2-enes (4)
Received: April 12, 2013
A
dx.doi.org/10.1021/om400310z | Organometallics XXXX, XXX, XXX−XXX
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Scheme 2. [1] Concurrent AuCl3-Catalyzed Nucleophilic Substitution and [Au(OTf)(PPh3)]-Catalyzed Cycloisomerization and [2] Equivalent One-Pot Procedure Developed by Our Group
Figure 2. [Au(N-imidate)(NHC)] complexes prepared, including yields.
precatalyst. Toste17b and co-workers reported a Re and Au catalyst combination which can catalyze the nucleophilic substitution−cycloisomerization of 1,3-diphenylprop-2-yn-1-ol and allyltrimethylsilane, and Sanz et al. developed a ptoluenesulfonic acid catalyzed nucleophilic substitution which was followed by a [AuCl(PPh3)]/AgSbF6 catalyzed cycloisomerization.33 Georgy et al. used a combination of AuCl3 followed by [Au(OTf)(PPh3)] to catalyze the reaction of 1phenyloct-2-yn-1-ol (5) and allyltrimethylsilane (6) to generate bicyclo[3.1.0]hexene (8) via the 1,5-enyne 7 (Scheme 2, eq 1).34 In a preliminary study,35 we have reported that [(N,N′-ditert-pentylbutylimidazol-2-ylidene)AuBr2(N-imidate)] complexes alone are active catalysts for a tandem nucleophilic substitution−1,5-enyne cycloisomerization (9 → 10; Scheme 2, eq 2), in which the imidate type affected the catalytic efficacy. On a general note, electron-deficient biocompatible imidate anions are known to ligate to both Au(I) and Au(III),36 an attribute that has been exploited primarily in therapeutic applications.37 For example, Goodgame et al. prepared [Au(Nsucc)(PPh3)],38 and later Bonatti et al. prepared antiinflammatory complexes of the type [Au(N-ptm)(PCy3)] and [Au(N-obs)(PCy3)] (N-ptm is N-phthalimidate; N-obs is N-obenzoic sulfimidate).37c More recently, Berners-Price et al. reported [Au(N-ptm)(PEt3)], trans-[AuBr2(N-ptm)(PEt3)], [Au(N-rib)(PEt3)], and [Au2(N-ptm)2(μ-depe)] (rib is the anion of riboflavin; depe is 1,2-bis(diethylphosphino)ethane).37d Finally, Nolan and co-workers reported the first [Au(N-imidate)(NHC)] complex, [Au(N-obs)(IPr)] (IPr is bis(2,6-diisopropylphenyl)imidazol-2-ylidene), and also [Au(Stgt)(IPr)] (S-tgt is 2,3,4,6-tetra-O-acetyl-1-thio-β-D-pyranosatothiolato anion).37e
It should also be acknowledged that phthalimide has been used in conjunction with Au catalytically. Thus, Cui et al.39 found that the addition of sulfonic acids to alkynes to give vinyl sulfonates could be catalyzed by [Au(NO3)(PPh3)] (2 mol %); added phthalimide (4 mol %) increased product yields from 58 to 74%. The study detailed herein is associated with the comprehensive investigation of the structure and bonding of Au(I) and Au(III) complexes, containing both NHC- and imidate-type ligands. The complexes have then been evaluated in a benchmark Au-catalyzed 1,5-enyne cycloisomerization reaction. The effect of imidate and NHC ligands on catalytic activity, in combination with AgOTf, has been fully scoped.
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RESULTS AND DISCUSSION
A library of [Au(N-imidate)(NHC)] complexes (11−13; Nimidate is N-succinimidate (N-succ), N-tetrafluorosuccinimidate (N-tfs), N-maleimidate (N-mal), N-phthalimidate (Nptm), and N-o-benzoic sulfimidate (N-obs) and NHC is N,N′di-tert-butylbutylimidazol-2-ylidene (ItBu), N,N′-di-tert-pentylbutylimidazol-2-ylidene (I t Pe) and N,N′-bis(2,4,6trimethylphenyl)imidazol-2-ylidene (IMes)) were prepared in order to study the electronic properties of the imidate ligands and as precursors to [AuBr2(N-imidate)(NHC)] complexes (Figure 2). Several types of NHC ligands have been prepared, mainly focusing on the variation of the N substituents. It is interesting to note that tert-butyl groups have been widely used to probe steric and inductive effects, although tert-pentyl groups (prior to our work in the Au field) have not. These alkyl groups are similar electronically, but the tert-pentyl group offers enhanced steric control and directing ability.40 B
dx.doi.org/10.1021/om400310z | Organometallics XXXX, XXX, XXX−XXX
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Scheme 3. Preparation of [Au(N-imidate)(NHC)] Complexes
Figure 3. Molecular structures of 11a,d and 13a. Displacement ellipsoids are shown at the 50% probability level. Hydrogen atoms have been omitted for clarity. Note that only one of the two conformers of 11a is displayed.
(where appropriate), 13C NMR, and IR spectroscopy and ESIMS studies, and several structures have been characterized by single-crystal X-ray diffraction studies. The novel ItPe ligand 14 exhibits electronic properties similar to those of the ItBu ligand.42 The NMR spectroscopic data of the complexes are consistent with greater electron donation from the tPe group as compared with the tBu group. This is in part reflected in the Au−C carbene carbon chemical shifts, where the following trend is revealed: N-tfs < N-obs < Cl < Nmal ≤ N-succ < N-ptm < Br (with the following ranges: 11a−g, 167.0−172.4 ppm; 12a−g, 167.5−172.3 ppm; 13a−g, 171.9− 176.9 ppm). Less than 0.4 ppm difference was observed among the N-succ (11a−13a), N-mal (11c−13c), and N-ptm (11d−13d) complexes, but an upfield shift of up to 3.9 ppm was observed for the N-tfs (11b−13b) and N-obs (11e−13e) complexes. The related bromide analogues 11g−13g appear downfield relative to the imidate-containing complexes, although the
The preparation of [Au(N-imidate)(NHC)] complexes (11−13) was attempted using a method described for related phosphine Au(I) complexes.38 The reaction of sodium imidates with [AuCl(NHC)] (11f−13f) complexes in an ethanol/water solvent system gave low product yields. Use of neat ethanol gave better yields; however, higher yields (87−96%) were obtained by treatment of the parent [AuCl(NHC)] (11f−13f) complex with the silver salt of the relevant imidate in CH2Cl2 (Scheme 3; yields are shown in Figure 2). In the case of the Ntfs and N-obs ligands the silver salts were prepared in situ, due to the hygroscopic nature of the salts and the sensitivity of tetrafluorosuccinimide and its silver salt to water. A novel NHC ligand, namely N,N′-di-tert-pentylbutylimidazol-2-ylidene (ItPe) (14), was synthesized from the hydrochloride salt (15) by a method similar to that reported.41 This allows a comparison of any subtle electronic and steric effects with those of the related ItBu NHC ligand. All of the Au(I) complexes were fully characterized by 1H NMR, 19F NMR C
dx.doi.org/10.1021/om400310z | Organometallics XXXX, XXX, XXX−XXX
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Table 1. Bond Lengths (Å) of Imidate and NHC Ligands in Au(I) Complexesa imidate ligand entry
a
complex t
b
1
[Au(N-succ)(I Bu)] (11a)
2 3 4 5 6 7 8 9
[Au(N-ptm)(ItBu)] (11d) [Au(N-succ)(IMes)] (13a) [Au(N-ptm)(PPh3)]38 phthalimide51 [AuCl(ItBu)] (11f)19 [AuBr(ItBu)] (11g)19 [AuCl(IMes)] (13f)52 [Au(NTf2)(IMes)] (16)20
NHC ligand
Au−anion
N−C(1)
N−C(2)
CO(1)
CO(2)
Au−C
C−N(1)
C−N(2)
imidazole CC
2.037(4) 2.042(4) 2.029(3) 2.021(2) 2.05(2)
1.372(8) 1.372(8) 1.380(3) 1.378(3) 1.39(1) 1.381
1.371(9) 1.385(7) 1.380(3) 1.372(4) 1.40(1) 1.395
1.233(6) 1.230(13) 1.212(3) 1.212(4) 1.22(1) 1.216
1.207(13) 1.212(6) 1.212(3) 1.217(3) 1.22(1) 1.222
2.005(4) 2.008(4) 1.987(3) 1.965(3)
1.355(8) 1.370(7) 1.361(3) 1.311(3)
1.354(7) 1.353(8) 1.361(3) 1.361(3)
1.340(7) 1.344(6) 1.345(4) 1.347(3)
2.018(3) 1.999(4) 1.999 1.976(3)
1.337 1.358(5)
1.339 1.341(5)
2.2742(7) 2.3994(5) 2.077(3)
Esd values are given in parentheses where known. b11a contains two [Au(N-succ)(ItBu)] conformers.
(2.037(4) and 2.042(4) Å) is slightly longer (statistically significant) by 0.016(6) and 0.021(6) Å than that for 13a (2.021(2) Å). The Au−N bond is significantly shorter in these complexes (up to 0.012(5) Å) than in [Au(NTf2)(IMes)] (16), due to the greater electron withdrawing ability of N-triflyl groups. Phthalimide has bond lengths in the range of those for [Au(N-ptm)(PPh3)] and 13d, highlighting the similarity (and isolobal relationship) between the Au(I) center and a proton. The Au−anion bond lengths in the ItBu complexes 11a,d (2.040(4) and 2.029(3), respectively) are significantly shorter than those in the analogous chloride (11f) and bromide (11g) complexes (2.2742(7) and 2.3994(5) Å, respectively); however, they are similar to those in the cyanide (2.009(7) and 2.043(6) Å), acetate (2.040(2) Å), and nitrate (2.012(3) Å) complexes reported by Baker.19 The bond lengths observed for the NHC ligands are also similar; complex 13a has a shorter Au−C bond than 11a (by 0.040(7) to 0.043(7) Å) and 11d (by 0.022(6) Å), consistent with similar complexes.53 Complexes 11a,d share bond lengths with the analogous Au(I) complex 11g. The complexes are stable in air and solution (although after several weeks in solution, hydrolysis and colloidal Au are noted). Treatment of [Au(N-tfs)(ItPe)] (12b) with [(nBu)4N] Br (1 equiv) results in partial exchange of N-tfs and Br anions; a similar situation occurs with [Au(N-succ)(IMes)] (13a) and LiBr. Interestingly, the [Au(N-mal)(NHC)] complexes 11c and 12c can undergo dimerization by a [π2S + π2S] cycloaddition in the solid state (Scheme 4). This has been reported for neutral
chloride analogues 11f−13f appear upfield. This upfield shift in the electron-deficient complexes is seen in other types of Au(I) complexes38 and is speculated to be due to the polarization of the NHC ligand by the more electron-deficient Au(I) atom. The imidazole proton and carbene carbon signals are similar to those reported by Baker (complexes 14 and 15).19 These similarities confirm the validity of imidate anions as pseudohalide ligands and are in keeping with other trends reported for metal imidate complexes.43 The imidate ligand carbonyl bond stretching frequencies are 53−78 cm−1 lower than those for the free imides, suggesting increased electron density on the imidate nitrogen in the complexes,44 as observed in other imidate metal complexes.45 A degree of ionic character46 is associated with the metal−imidate bond, resulting in a shift of electron density from the Au−N into the N−C bond (reducing the CO bond order). The stretching frequencies reflect the NMR spectroscopic data, allowing the following trend to be established: N-succ < N-mal < N-ptm < N-obs < N-tfs (with the following ranges: 11a−e, 1645−1704 cm−1; 12a−e, 1644−1704 cm−1; 13a−e, 1648− 1705 cm−1). The range is up to 60 cm−1, with the higher frequencies reflecting the increased imidate electron-withdrawing capacity, which largely reflects the pKa values of the parent imides: N-obs (1.6)47 < N-tfs (2.1 est.)48 < N-ptm (8.3)47 < N-mal (9.5)49 < N-succ (9.7).50 The pKa of N-tfs does not fit the pattern exactly, although this is an estimated value. The pKa was estimated by comparison of the pKa of succinimide to those of pyrrolidinium (11.31) and 3,3,4,4tetrafluoropyrrolidinium (4.05) ions. The NHC ligands have little effect on the carbonyl stretching frequencies of the imidate ligands (99
3 4 5
1
AgOTf
1
35
95
6 7
a
Conditions: 0.5 M 4-phenyl-1-hexen-5-yne (24) in CH2Cl2, 3 h. Note that AuCl3 was used as a benchmark catalyst. bConversion determined by GC analysis (cross-checked with 1H NMR spectroscopic analysis) of the crude reaction mixture (the percent conversion quoted is an average of two runs, taking into account the percent loss of 24).
8 9
conversn (%)b
entry
complex
32
10
87
11
81
11
94
12
53
13
83
14
34
15
35
16
95
17
[AuBr2(N-tfs) (ItPe)] (19c) [AuBr2(N-mal) (ItPe)] (19d) [AuBr2(N-ptm) (ItPe)] (19e) [AuBr2(N-obs) (ItPe)] (19f) [AuBr3(ItPe)] (19g) [AuBr2(N-succ) (IMes)] (20a) [AuBr2(N-mal) (IMes)] (20b) [AuBr2(N-ptm) (IMes)] (20c) [AuBr3(IMes)] (20d)
conversn (%)b 89 99 18 95 32 51 18 51 3
a
Conditions: 0.5 M solution of 4-phenyl-1-hexen-5-yne (24) in CH2Cl2, 1 mol % Au catalyst, 1 mol % AgOTf, 3 h, 25 °C. b Conversion determined by GC analysis (cross-checked with 1H NMR spectroscopic analysis) of the crude reaction mixture (the percent conversion quoted is an average of two runs, taking into account the percent loss of 24).
correlation between the electronegativity of the imidate ligand and the rate at which the bromide ligand is abstracted. In the case of the tribromide and succinimidate complexes, bromide extraction occurs immediately on mixing in solution, which is observable by the precipitation of silver(I) bromide. Complexes containing more electron-withdrawing imidates are activated more slowly, with gradual precipitation seen using phthalimidate and maleimidate and no observable formation with tetrafluorosuccinimidate and o-benzoic sulfimidate complexes. This results in low product conversions when the catalyst is added to the reaction solution without prior formation of the active catalyst for the electron-withdrawing imidate systems (Table 5). However, when the catalyst and AgOTf were mixed
very similar results. The N-succ and tribromide Au(III) complexes (18a,g and 19a,g) exhibit low catalytic activity, giving approximately 30% conversion. The N-ptm complex 18e gave a higher conversion at 53%, possibly due to the formation of more electropositive Au(III) complexes that are able to activate the alkyne more effectively. The N-mal Au(III) complexes (18d and 19d) give more than 90% conversion. This outcome is quite surprising, considering the electronic similarity to the N-ptm ligand. The N-tfs (18b and 19b), N-dbs (18c and 19c), and N-obs (18f and 19f) Au(III) complexes give high conversions, of 87 and 95%, 81 and 89%, and 83 and 95%, respectively, presumably due to the greater acidity of the activated catalysts. It is interesting to note that the IMes-substituted Au(III) complexes (20) do not follow the trend seen for 18 and 19. The N-succ, N-mal, and N-ptm complexes (20a−c, respectively) all give similar conversions of 51, 18, and 51%, respectively; note that 20b (N-mal) is the least active. Quite remarkably the tribromide Au(III) catalyst (20d) exhibited less than 5% conversion (to 25), showing that the imidate ligands do exhibit a catalytic effect.
Table 5. Effect of Active Catalyst Preformation for [AuBr2(N-imidate)(ItPe)] Complexes in the Cycloisomerization of 4-Phenyl-1-hexen-5-yne (24)a conversn (%)b entry
complex
no preformation
preformation
1 2 3
[AuBr2(N-succ)(ItPe)] (19a) [AuBr2(N-tfs)(ItPe)] (19c) [AuBr2(N-ptm)(ItPe)] (19e)
29 3 31
35 89 18
a
Conditions: 0.5 M solution of 4-phenyl-1-hexen-5-yne (24) in CH2Cl2, 1 mol % Au catalyst, 1 mol % AgOTf, 3 h, 25 °C. b Conversion determined by GC analysis (cross-checked with 1H NMR spectroscopic analysis) of the crude reaction mixture (the percent conversion quoted is an average of two runs, taking into account the percent loss of 24).
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CONCLUSION The preparation of a library of [Au(N-imidate)(NHC)] (11− 13) and [AuBr2(N-imidate)(NHC)] complexes (18−20) in high yield has been achieved. Comprehensive analysis shows that the spectroscopic characteristics of the Au complexes are determined by the electronic properties of the NHC and imidate ligands. The Au(III) complexes (18−20) exhibit good catalytic activity in the cycloisomerization of 4-phenyl-1-hexen5-yne (24). The ItBu and ItPe Au(III) complexes exhibit similar spectroscopic properties and catalytic activities, whereas IMes complexes exhibited poor stability and low catalytic activity. A significant effect of the structure of the imidate ligand on catalytic activity was observed, with more electronegative
in CH2Cl2 and the solvent was removed in vacuo, redissolution in the reaction solvent resulted in immediate precipitation of AgBr. In order to ensure reliable results, this catalyst preactivation step was carried out before each test. The remaining [AuBr2(N-imidate)(NHC)] complexes (18− 20) were tested against the 1,5-enyne cycloisomerization reaction, at 1 mol % Au and AgOTf loading, at 25 °C over 3 h (Table 6). The results show that there is a significant effect of the nature of the imidate ligand on the catalytic activity of ItBu and ItPe Au(III) complexes. These sets of complexes (18 and 19) give J
dx.doi.org/10.1021/om400310z | Organometallics XXXX, XXX, XXX−XXX
Organometallics
Article
[MNa]+), 476.2 (100%, [MH]+), 420.1 (4%, [M − tBu + 2H]+), 405.1 (31%), 349.1 (8%), 293.0 (3%). ESI + -HRMS: calcd for C15H25AuN3O2 ([MH]+) 476.1607, found 476.1596. Mp: 230 °C dec. Complete procedures and full characterization data for the AuI complexes can be found in the Supporting Information. Representative Procedure for the Synthesis of a AuIII Complex Containing NHC and Imidate Ligands: [AuBr2(Nsucc)(ItBu)] (18a). [Au(N-succ)(ItBu)] (11a; 28.5 mg, 59.9 μmol, 1 equiv) was dissolved in dichloromethane (1 mL), bromine (10.5 mg, 65.9 μmol, 1.1 equiv) was added, and the brown solution was stirred for 1 h at room temperature. The solution was reduced in vacuo to
