Synthesis and structures of gold and copper carbene intermediates in catalytic amination of alkynes

Metal carbenes are often proposed as reactive intermediates in the late transition metal-catalysed transformations of alkynes. Owing to their high reactivity, however, isolation and structural characterization of metal carbene intermediates in these transformations has remained unknown. Herein, we report the isolation of two acyclic gold and copper carbene intermediates in either Au(I)- or Cu(I)-catalysed cyclization of N-alkynyl formamidines through five-exo-dig cyclization. X-ray diffraction, 13C NMR spectra data and computational analyses provide evidence for the formation of a gold carbene intermediate with a carbocation-like electronic character. Using the intrinsic bond orbital (IBO) approach, we also evaluate the π-stabilizing effects of organic substituents at the carbene carbon atom in the gold carbene intermediate. Another rare six-membered copper carbene complex is also obtained through 6-endo-dig cyclization. These metal carbenes have proven reactive toward oxidation. The metal-promoted cyclization of N-alkynyl formamidine provides a facile approach to synthesize metal carbene species.

As part of our long-standing interest in the design and synthesis of N-heterocyclic carbenes (NHCs) and abnormal NHC for catalysis, we previously reported the isolation of a rare vinyl silver species through 6-endo-dig cyclization of a formamidine with a s,p-silver-activated terminal alkyne 56 . Herein, we first report the isolation and characterization of gold and copper carbene intermediates, E' (M ¼ Au(I) or Cu(I)), in either Au(I) or Cu(I)-catalysed cyclization oxidation of formamidines with a internal alkyne through 5-exo-dig cyclization (Fig. 1c). In the presence of base, Cu(I)-promoted amination of a formamidine with a terminal alkyne leads to form a 6-membered copper carbene through 6-endo-dig cyclization. The carbene oxidation reaction of these metal carbene species are directly observed. The detailed structural and spectroscopic studies and computational analysis outline the nature of the gold and copper carbenes.

Results
Isolation of active copper carbene intermediates. First, phenylsubstituted formamidine 1 was initially examined in the amination cyclization (Fig. 2a). In the presence of a stoichiometric amount of IPrCuOTf (IPr ¼ 2,6-bis(diisopropyl-phenyl)imidazol-2-ylidene), 1 underwent 5-exo-dig cyclization to form  a 5-membered vinylcopper species 2 at 10°C in 82% yield, while raising the reaction temperature to 60°C resulted in 6-endo-dig cyclization to afford a 6-membered vinylcopper species 3 in 53% isolated yield. Hydrolysis of either 2 or 3 with HOTf gave the corresponding cyclic formamidinium salt 4 or 5, respectively. In the presence of a catalytic amount of IPrCuOTf and one equivalent of trifluoromethanesulfonic acid (HOTf), the cyclization of the protonated formamidine 1 was required at elevated temperature to achieve a good yield (90%), forming a 5membered product 4. The structures of 4 and 5 were confirmed by X-ray diffraction analysis (see Supplementary Figs 26 and 27).
The Cu-mediated cyclization of formamidine 1 seems to be kinetic versus thermodynamic control reaction. However, attempt to form 3 by heating 2 failed. Vinylcopper species 2 has proven stable only in the solid state at room temperature, and is quite sensitive to oxidation in solution. The formation of a zwitterionic compound 6 was observed from the CDCl 3 solution of 2 on standing 1 week (Fig. 2b). Compound 6 represents a zwitterionic precursor for a kind of hybrid ambidentate NHC ligand decorating the classical imidazol-2-ylidene with an acetylacetonato unit 57 . Further investigation showed 6 can also be directly obtained via cyclization of 1 using a catalytic amount of IPrCuOTf and H 2 O 2 as oxidant at 25°C in 57% isolated yield. When using CuBr.Me 2 S (10 mol%) as catalyst, 6 could be formed in air with a considerable yield (83%). The structure of 6 was confirmed by X-ray crystallography (Fig. 3a), showing it contains a conjugated backbone of alternating single and double bonds of type O1-C2 ¼ C3-C16 ¼ O2 as evidenced by comparison of bond distances within the acac backbone.
The transformation of either vinylcopper species 2 or alkynyl formamidine 1 into 6 is reminiscent of the observation of the carbene oxidation products of both copper (2-furyl)carbene B (M ¼ Cu) 19 and copper pyrazolylcarbene C 24-26 in the Cu-catalysed cyclization of alkynes (Fig. 1b). Based on the observations, the transformation of 2 into 6 would be better described as a copper carbene oxidation reaction (Fig. 2b). The 13 C NMR analysis of 2 exhibits one signal for the carbene carbon at d ¼ 211.4 p.p.m., which is similar to the imidophosphamidato copper a-carbonyl carbene signal at d ¼ 219.0 p.p.m. 32 , upfield of that for the diketiminato copper carbene (d ¼ 253.1 p.p.m.) 31 , and fall into the approximate range of 200-400 p.p.m. established for the very deshielded terminal carbene complexes 58 . It is more deshielded than the carbene signal of IPr moiety in 2 at 181.9 p.p.m. The observation verifies the presence of an electrophilic carbene in 2. Vinylcopper 3 is quite stable in solvent and substantially inert to oxidation. The 3 is colourless, and copper carbene 2 is purple. Similarly, both imidophosphamidato copper a-carbonyl carbenes 30,32 and diketiminato copper carbene complexes 31 are all violet or purple. It indicates that the presence of a b-carbonyl in 2 is crucial for generating a copper carbene intermediate.
After massive attempts to isolate single crystals of 2 failed, we managed to obtain a single crystal of its IPr* counterpart copper carbene 7 suitable for X-ray diffraction analysis (Figs 3b and 4a). Copper carbene 7 was prepared as a wine red solid from the cyclization of 1 in the presence of one equivalent of IPr*CuNTf 2 , which could also catalyse the transformation of 1 into 6. The direct oxidation of 7 to form 6 was also observed in an oxygen atmosphere. In complex 7, the C-O bond distance of 1.207(7) Å is characteristic for a C ¼ O double bond. The imidazol-4-one ring in 7 is essentially planar, indicating charge delocalization. The observation suggests the imidazol-4one ring in 7 could be regarded as a mesoionic imidazolium-4olate (Fig. 4b). The related mesoionic compounds have been known for several decades, and a similar 1,2,3-triazolium-4-olate compound G was reported by Albrecht and co-workers 59 . Therefore, copper complex 7 could be described as a copper carbene complex 7' bearing a mesoionic imidazolium-4-olate ring. The Cu1-C1 bond (1.924 (6)   [ 34 , and longer than those (1.822-1.834 Å) observed for the copper carbenes obtained from either diphenyldiazomethane or a-carbonyl diazo compounds [30][31][32][33] . The imidazolium-4-olate ring in 7 is nearly co-planar with the carbene centre, and the neighbouring phenyl ring is tilted with a slightly contracted bond (1.470(8) Å) between the carbene centre and the C ipso (Ph) carbon.
DFT computation and IBO analysis on gold carbene intermediate. Similar to their copper counterparts, structurally characterized gold carbenes have been mainly prepared by either decomposition of the diazo precursors with various gold sources or carbene transfer from chromium complexes [35][36][37][38][39][40][41][42][43][44][45] . Isolation and structural characterization of gold carbene intermediates generated from the addition of nucleophilic agents to C À C multiple bonds remains very rare. In 2008, the Hammond group 61 reported the spectroscopic detection of a gold carbene/oxonium complex 14 in the gold-mediated cyclization of allenoate and later the Hashmi group 62 isolated the gold carbene intermediates of type 14 and carried out density functional theory (DFT) calculation to study the bonding properties (Fig. 7). Very recently, Mouries-Mansuy, Fensterbank and colleagues 63 isolated and structurally characterized a related gold carbene 15 in the gold-mediated cyclization of pyridyl-allene.
The Au-C bond distance of 1.984(2) Å for 15 with a chloride ligand is shorter than that (2.049(9) Å) for 8, and is in the low range of those known gold carbenes [35][36][37][38][39][40][41][42][43][44][45] (Fig. 7). It should be noted that, in contrast to p-acidic phosphine ligand, the p-donating chloride ligand could increase gold-to-carbon  p bonding, resulting in a short Au-C bond 47 . The gold carbene signal of a related PPh 3 -ligated gold carbene 15a in the 13 C{ 1 H} NMR spectrum appears at d ¼ 203.9 p.p.m. 63 , which is similar to that for 8. Next, we performed DFT calculations to get more insight into the bonding property in 8. All the DFT calculations were performed using Gaussian 09 suite of program. The TPSS functional with Grimme's D3-BJ correction for van der Waals interaction was utilized in combination with the triple-z basis set def2-TZVPP (see Supplementary Methods for more details). The optimized geometry parameters of 8 are in line with the experimental results. Based on the Mayer bond order analysis (Fig. 7), partial single bond for C 2 À C 1 can be formulated in the vinylgold complex 8. Similar bonding scenario was also observed for the related gold complexes 15 (ref. 63) and 14 (ref. 62).
The intrinsic bond orbital (IBO) analysis is a novel method to analyse chemical bonding. The IBOs mainly depict occupied orbitals in an intuitive way, assigning proportionally the electrons in the doubly occupied IBOs to the individual atoms and allowing quantitative interpretation of chemical bonding. Quite recently, using DFT and the IBO approach, Hashmi, Kästner and colleagues 49,50 evaluated the p-stabilizing effects of organic substituents at the carbene carbon atom in several recently isolated and characterized gold carbene complexes, and the observations by the IBO method are consistent with the previously proposed bonding scenario for the gold carbene species. Therefore, we further carried out the IBO approach to study the p-stabilizing effects of organic substituents in gold intermediate 8.
As depicted in Fig. 8, we identified a strong p-stabilization in 8, which is mainly achieved through the p system of the imidazolium-4-olate ring attached to C 1 (Fig. 8d). Additionally, small contribution from the phenyl ring attached to C 1 was also identified. The phenyl ring is polarized towards C 1 (Fig. 8b), forming the delocalized p bonding with C 1 . In addition, the IBO of coordinative bond between the lone pair of carbene C 1 and the gold atom was identified (Fig. 8a)   mainly located at C 1 . The IBO representing the filled d orbital at gold aligned for p backbonding was also identified but it is largely located at gold atom up to 96.8% (Fig. 8c), suggesting little contribution to stabilize carbenic C 1 . Therefore, gold carbene intermediate 8 should be better described as gold-and heteroatom-stabilized carbocation 8 00 (Fig. 5). Very recently, we isolated a related vinylgold complex 16 prepared by reacting IPrAuOTf with a formamidine bearing a terminal alkyne moiety 56 , which could undergo protodeauration to afford a bis(hydroxyimidazol)ium salt ( Supplementary Fig. 22). Different from gold carbene 8, 16 is quite stable in air, while treatment of 16 with excess H 2 O 2 resulted in complex reaction mixtures without clear product identified. We also reported a PPh 3 counterpart of 16, which is prone to undergo aurophilicity to form a vinyl gem-digold species 64 . The observations suggest besides the imidazolium-4-olate ring, a phenyl substituent bonding to the carbenic carbon, is also important to stabilize gold carbene 8. The differences in reactivity between gold species 8 and 16 may possibly imply the gradation in character from carbene to vinylgold species.
Isolation of six-member copper carbene species. In a stoichiometric AgOTf-promoted cyclization of formamidine 17 bearing a terminal alkyne, we previously revealed that presence of a base can preclude the protonation of imino moiety by HOTf, thus changing cyclization fashion 56 . Moreover, Hashmi et al. 65,66 also reported that addition of a base can slow down the protodemetallation to conserve organometal species.
The observations inspired us to investigate the influence of base in the copper-promoted amidiniumation of 17. Delightfully, treatment of 17 with CuBr.Me 2 S in the presence of N( i Pr) 2 Et as a base afforded a 6-membered vinylcopper species 18 as a yellow solid in a 6-endo-dig cyclization fashion (Fig. 9). Treatment of 18 with AgOTf in the presence of PPh 3 resulted in the formation of a divinylcopper species 19 as a yellow solid, the structure of which was confirmed by X-ray crystallography (Fig. 10). The Cu-C bond (1.870(9) Å) in 19 is shorter than that (1.924(6) Å) for copper carbene 7. In addition, the Cu-C distance in 19 is shorter than those for IPrCuCl (1.953(8) Å) 67 , and the related (IPr 2 Cu) þ BF 4 À (1.926(19) Å, 1.938(18) Å) 68 , and similar to those for either mesoionic NHC imidazol-5-ylidene copper complex (1.871(7) Å) 69 , or abnormal NHC triazol-5ylidene copper complex (1.876 (4) Å) 69 . In the 13 69 . Interestingly, similar to the five-membered copper carbene complex 2, 18 is also found to be reactive towards oxidation in solution. A zwitterionic oxo-adduct 20 was isolated from the DCE solution of 18 on stirring for 1 day, indicating that vinylcopper species 18 is more like a copper carbene complex 18', which also contains a b-carbonyl. Therefore, we speculate that the reason why the six-membered vinylcopper 3 does not react as a copper carbene is largely because of the presence of an a-carbonyl instead of a b-carbonyl in 2 and 18. Zwitterionic compound 20 is known as a zwitterionic precursor for an aminoacrylamido carbene 70 .

Discussion
We have developed both Au(I)-and Cu(I)-catalysed cyclization oxidation of N-propiolic formamidines through 5-exo-dig cyclization. Key gold and copper carbene intermediates are isolated from the stoichiometric reaction, which were fully characterized. X-ray diffraction analysis and 13 C NMR spectra data provide evidence for the formation of a gold carbene intermediate with a carbocation-like electronic character. Using DFT and the IBO approach, we evaluated the p-stabilizing effects of organic substituents at the carbene carbon atom in the gold carbene complex 8. In the presence of base, Cu(I)-promoted amidiniumation of the formamidine with a terminal alkyne leads to form a six-membered copper carbene through 6-endo-dig cyclization. The generation of these gold and copper carbene complexes is attributed to the presence of a b-carbonyl group, and their oxidation reactions are directly observed. The metalpromoted cyclization reaction of N-alkynyl formamidines also provides a facile approach to synthesize metal carbene species, and our future efforts are directed at synthesizing other metal species by using the facile method.

Methods
General. Unless otherwise stated, all reactions and manipulations were performed using standard Schlenk techniques. All solvents were purified by distillation using standard methods. Commercially available reagents were used without further purification. NMR spectra were recorded by using a Bruker 400 MHz spectrometer.