Two Copper-Carbenes from One Diazo Compound

Many transition-metal complexes MLn decompose diazo compounds N2=CR1R2 generating metal-carbenes LnM=CR1R2 which transfer the carbene group to other substrates, constituting an important tool in organic synthesis. All previous reports have shown that the CR1R2 fragment at the metal-carbene remains intact from the parent diazo compound. Herein we report the detection and isolation of a monosubstituted copper carbene where the CR1R2 ligand has undergone a modification from the initial diazo reagent. When TpMsCu(THF) (TpMs = hydrotris(3-mesityl)pyrazolylborate ligand) was reacted with N,N-diethyl diazoacetamide [N2=C(H)(CONEt2)], the stable copper carbene TpMsCu=C(H)(NEt2) was isolated, resulting from a decarbonylation process, with carbon monoxide being trapped as TpMsCu(CO). The simultaneous observation of products derived from the intramolecular carbene insertion reaction into C–H bonds demonstrates that the expected TpMsCu=C(H)(CONEt2) complex is also formed. Experimental data, DFT calculations, and microkinetic models allow us to propose that the latter undergoes CO loss en route to the former.


■ INTRODUCTION
More than a century after Buchner postulated the existence of carbene CR 2 groups during the thermal decomposition of ethyl diazoacetate, 1 the catalytic transfer of such moiety from diazo compounds yet constitutes an area of continuous growth. 2,3 Such process consists of the metal-induced decomposition of the diazo reagent in a process in which molecular N 2 is extruded and a metallocarbene intermediate MC is formed (Scheme 1a). 4 This species is electrophilic 5 in nature and reacts with available nucleophiles transferring the carbene group, thus liberating the metal to continue the catalytic cycle. This strategy has been successfully employed in the addition of carbene groups to unsaturated bonds or in its insertion into C−H or other C−X bonds, both intra-and intermolecularly. 6−8 With the appropriate tuning of the carbene substituents and the metal precursor, several metallocarbene complexes have been detected, some of them being isolated and structurally characterized. All metals from groups 8 to 11 are known to catalyze the carbene transfer from diazo compounds (Scheme 1b), and at least one detected/isolated example of a metalcarbene intermediate formed from a diazo compound has been reported for each of them. 8−18 In all cases, the CR 1 R 2 moiety in the initial diazo compound appears unmodified in the subsequent metal-carbene intermediate (Scheme 1b), from where it is further transferred to the nucleophile. From here, it is assumed that the carbene ligand is always transferred without modification. One of the most popular diazo reagents are diazocarbonyl compounds, 4 with a CO group directly bonded to the diazo functionality: the acceptor nature of the −COR group favors the transfer of the carbene group toward the nucleophile.
Herein we report the observation of the unprecedented modification of the carbene unit during the course of a coppercatalyzed transformation. The use of a diazoacetamide compound (Scheme 1c) bearing a CONR 2 substituent leads to the formation of the expected, undetected, hot, highly reactive copper carbene MC E (Scheme 1c) which promotes the intramolecular C−H bond functionalization of the ethyl groups of the amide fragment. In a parallel manner, MC E undergoes the loss of CO en route to the formation of the unexpected, stable and isolable, cold, Fischer carbene complex MC U (Scheme 1c), which has been structurally characterized.

■ RESULTS AND DISCUSSION
Reaction of Tp Ms Cu(THF) and N 2 C(H)(CONEt 2 ). Our group has been involved in the area of carbene transfer from diazo compounds, with emphasis on its application to the functionalization of C−H bonds of unmodified alkanes, 6,19 for which the design of very active catalysts precluded the observation of intermediates. However, we recently detected copper-carbene species 20 in solution upon reacting Tp Ms Cu-(THF) (1) and ethyl phenyldiazoacetate (PheDA), which were stable at temperatures below 10°C. After those findings, we aimed to detect copper-carbene intermediates with monosubstituted diazo compounds, which yet remains a challenge, particularly with the most popular catalysts within this field, i.e., rhodium and copper, for which only disubstituted carbene species have been detected or isolated. 11, 13,21 Toward that end we chose Tp Ms Cu(THF) 22 as the copper source, since the Tp Ms ligand provides a high degree of steric protection to the metal center and, when formed, to the carbene ligand. Regarding the diazo reagent, we selected N,N-diethyl diazoacetamide (2), in view of the previously reported 23 intramolecular carbene insertion into the C−H bonds of the ethyl N-substituents in the presence of 1 as the catalyst (Scheme 2a), leading to mixtures of lactams 3 and 4. Olefin 5 was also observed from the catalytic reaction of two molecules of 2. 24 Since heating at 70°C was needed to reach efficient ratios, we reasoned that perhaps the coppercarbene intermediate expected from the reaction of 1 and 2, Tp Ms CuC(H)(CONEt 2 ) (6), could be stable enough at room temperature to be detected. Based on this idea, we started this study carrying out the reaction of Tp Ms Cu(THF) (1) with 5 equiv of N,N-diethyl diazoacetamide (2*), 100% enriched in 13 C at the 13 CN 2 site, in toluene-d 8 (Scheme 2b). Monitoring of the reaction by 13 C{ 1 H} NMR spectroscopy showed the appearance of a resonance centered at 236.6 ppm. This is within the typical region of CuC moieties reported by Hofmann 25 for the complexes [ t Bu 2 P(NSiMe 3 ) 2κ 2 N]CuC(Ar)C(O)R) (235.8−219.0 ppm), by Warren 13 for [β-diketiminate]CuCPh 2 (253.1 ppm), or by our group for complexes Tp x CuC(Ph)(CO 2 Et) (Tp x = Tp iPr2 , Tp*, Tp Ms ; 233.9, 236.8, and 248.5 ppm, respectively). 20 Under these conditions, the resonances for 3, 4, and 5 were also observed, the latter being the major product. The reaction was immediate, and no free diazo compound 2* was observed after 5 min. Successive registration of 13 C{ 1 H} NMR spectra for hours showed no change in the composition of the mixture.
In view of the apparent stability of the species bearing the CuC unit, we repeated the reaction at a bench scale (see Supporting Information (SI) for optimization conditions). When 0.45 g of 1 were reacted with 5 equiv of diazo 2 in toluene at room temperature for 1 h, a yellowish solution was formed from which, after workup, the new compound 7 was isolated as crystalline material in 35% yield. The 1 H NMR spectrum of 7 showed three equivalent pyrazolyl rings, two inequivalent ethyl groups, and a singlet at 8.02 ppm (Scheme 2c), which corresponds to one proton that correlates in the 2D-HSQC experiment with the aforementioned signal at 236.6 ppm (Scheme 2d). In the sample derived from the 13 C-labeled diazo compound, the singlet at 8.02 in the 1 H NMR spectrum split into a doublet with J C−H = 115 Hz (Scheme 2c). Albeit the above data could support the assignment of complex 7 as the pursued Tp Ms CuC(H)(CONEt 2 ), some other experimental data were not in agreement with that proposal: neither the FT-IR spectrum showed the expected absorption for the CO group nor the 13 C{ 1 H} NMR spectrum displayed any resonance within the carbonyl region. We suspected that a decarbonylation process could have occurred, an idea that was confirmed when single crystals of this complex were grown, and the molecular structure determined by X-ray studies showed the formulation Tp Ms CuC(H)(NEt 2 ) (7). 26 As shown in Figure 1, this complex contains the Tp Ms ligand bonded to copper in a κ 3 -fashion, and a carbene ligand with two substituents: a hydrogen and a diethylamido group, the latter resulting from the loss of the CO present in the initial diazo compound. The distance Cu1−C1, 1858(5) Å, is similar to that reported by Warren for [β-diketiminate]CuCPh 2 (1.834(3) Å). 13 Complex 7 constitutes the first example of a metal-carbene complex formed from a diazo compound in which the CR 1 R 2 moiety in the latter is different from that in the former. Additionally, it is also the first example of a monosubstituted copper carbene complex. 27 Further investigation of the 1 H NMR spectrum of the experiment carried out with a 1:5 ratio (excess of diazo is employed since C−H bond insertion also occurs in a catalytic manner to some extent) of 1 and 2* showed that, in addition to 7, another Tp Ms Cu-containing species was formed, both accounting for all detectable Tp Ms Cu cores. Such compound has been identified as Tp Ms Cu(CO) (8) (Scheme 3), as the result of the trapping of carbon monoxide by 1. 22 To gain further information, we have prepared the doubly isotopically enriched N 2 = 13 C(H)( 13 CONEt 2 ) (2**) diazo compound and monitored its reaction with complex 1, observing the resonances of carbene and carbonyl ligands of 7 and 8, respectively (see Supporting Information also). Thus, this observation unambiguously demonstrates the existence of a decarbonylation process.
The yield in complex 7 is dramatically affected by temperature, as shown in Figure 2a. The reaction of 1 and 2 (1:5 ratio) has been performed within the −30 to +70°C range, showing an increase in the reaction yield from 2% to 78%, respectively, in 1 h time experiments. The high yield preparation and isolation of 7 is better performed at 70°C (see Supporting Information). We have also monitored the concentration of complex 7 with time at three different temperatures ( Figure 2b) and have found that at 0 or 25°C such concentration remains constant after 24 h. However, at 70°C, a process involving the disappearance of 7 takes place with time in such a way that after 12 h it cannot be detected in solution.
The reactivity of isolated copper carbene 7 has also been investigated. On one hand, no reaction was observed with styrene, tert-butanol, benzene, or cyclohexane from room temperature to 70°C. It seems clear that the loss of the CO  The reactivity observed from the initial mixture of 1 and 2 (1:5 ratio) is rationalized in Scheme 4. The Tp Ms Cu core is generated upon decoordination of THF and reacts with the diazo compound 2 to generate the transient copper carbene 6. This species undergoes either the intermolecular reaction with a second molecule of 2 or the intramolecular insertion of the carbene group into the secondary or primary C−H bonds of the ethyl groups of the NEt 2 fragment, thus yielding lactams 3 and 4, these catalytic cycles taking place at room temperature. Intermediate 6 can alternatively undergo a decarbonylation process which generates the isolable copper carbene 7, a process which occurs, at least, within the −30 to +70°C interval. Evolved CO can be trapped by Tp Ms Cu cores leading to the formation of Tp Ms Cu(CO) (8). At 70°C, coppercarbene 7 originates olefin 9 and carbonyl 8 in a process requiring carbon monoxide. This proposal agrees with the initial observation of the need for heating at 70°C to induce catalysis by 1, 23 since the copper−carbonyl 8 under the reaction conditions in the presence of 2 also generates Tp Ms Cu cores to catalyze the C−H bond functionalization reaction.
The transformation of 6 into 7 somehow resembles the Wolff rearrangement of diazo compounds (Scheme 5a), which originate short-lived ketenes 4,28 which further react with nucleophiles, in a process triggered by light, heating, or silver(I) salts. Grotjahn and co-workers described a ketene iridium complex which undergoes the reversible conversion of the coordinated ketene into a metallocarbene which contains a CO ligand (Scheme 5b). 29 Based on these precedents, it could be possible that copper-carbene 6 undergoes a related rearrangement in the coordination sphere of copper, followed by CO extrusion (Scheme 5c). As mentioned above, the reverse reaction is not observed in our case, at least apparently, as inferred from the experiment carried out with 7 and CO.
DFT Studies and Microkinetic Model. Given the unexpected formation of 7, we further explored the process with DFT studies (B3LYP-D3 optimizations in solution; see details in the Supporting Information) and microkinetic simulations. Computational results are summarized in Figure  3, showing the free energy profile for the conversion from the starting Tp Ms Cu(THF) complex (1) to compound 7. The initial steps follow the usual mechanism up to the formation of metal-carbene 6, with the highest barrier corresponding to nitrogen extrusion (17.3 kcal/mol −1 ). Species such as metalcarbene 6 have been previously shown to be very reactive toward homocoupling or C−H activation. 19,23,24 The novelty in this system is the availability of an alternative low energy The lack of observation of the reverse pathway when reacting complex 7 and CO at 70°C is due to the more favorable path of formation of olefin 9 and carbonyl adduct 8 (see below). Further calculations were carried out for the case where the toluene solvent is replaced by dichloromethane, also reproducing the experimental observation of pyrrolidinone (3) and azetidinone (4). The detailed computational results for these cases are given in the Supporting Information. The formation of 9 has also been investigated. Several paths previously reported for such carbene coupling have been discarded based on their high energy barriers: (a) direct interaction of two molecules of 7; 24 (b) carbene C(H)NEt 2 dissociation and reaction with 7; 24 and (c) coupling of two dissociated carbene units 30 (see Supporting Information). At variance with that, we have found an accessible route which involves two molecules of 7 and one of CO. The simplified mechanism for the formation of olefin 9 is depicted in Figure  3b. The mechanism starts with one molecule of the metalcarbene 7 adding a molecule of CO to form the abovementioned intermediate INTDCO2 which further reacts with a second molecule of 7. The formation of the olefin 9 must overcome a barrier of 23.1 kcal/mol. Thus, albeit olefin 9 is more stable than metal-carbene 7, its formation involves a higher barrier (see Supporting Information for further details).
The third possible product from the interaction between the precursor 1 and N,N-diethyl diazoacetamide is olefin 5, which is also experimentally observed. We also computed the mechanism of its formation from 6, which is detailed in the Supporting Information. The key result is that the free energy barrier for CC bond formation leading to 5 is 8.9 kcal/mol. This value is significantly lower than the 13.8 kcal/mol reported above for decarbonylation, which from a simplistic view would indicate that decarbonylation should not take place. However, for convoluted mechanisms such as the one present here, it is better to translate the computed free energy barriers to rate constants and use those to estimate reaction times through microkinetic modeling. 31 We performed such microkinetic modeling with additional energy adjustment 32 (see Supporting Information for details), and we obtained the results shown in Figure 4. The agreement between calculations and experimental data (displayed in Figure 2) is certainly remarkable, and this strongly supports the validity of our mechanistic proposal.

■ CONCLUSION
We herein report the first example of the modification of a carbene group during its metal-catalyzed transfer from a diazo functionality, a discovery that should result in further consideration from the community involved in this area. From now on, the belief that the carbene moiety remains undisturbed in this type of processes must be reconsidered when analyzing reaction outcomes, particularly in those catalytic systems which either seem deactivated or require anomalous heating. Additionally, the chemistry of these isolated metal-carbenes is yet to be developed and could find important applications as surrogates of well-known midtransition metal Fischer carbene complexes ■ EXPERIMENTAL SECTION Synthesis and Characterization of Complexes 7 and 7*. In a 250 mL Schlenk flask, Tp Ms Cu(THF) (1, 0.450 g, 0.64 mmol) was dissolved in 75 mL of toluene, and a solution of 2-diazo-N,Ndiethylacetamide (2, 0.451 g, 3.2 mmol) in the same solvent (37 mL) was added via canula. The mixture was stirred at 70°C for 1 h before the volatiles were removed under reduced pressure. The residue was washed with dry acetone (5 mL) and cold Et 2 O (3 × 5 mL) and dried under vacuum, to afford 0.35 g of a yellow solid corresponding, according to NMR studies, to a mixture of complexes 7 and 8 (yields of 47% and 10% referred to initial 1). Crystallization from a mixture of toluene/hexane (4:4 mL) at −30°C led to the isolation of complex