Site Selectivity in Pd-Catalyzed Reactions of α-Diazo-α-(methoxycarbonyl)acetamides: Effects of Catalysts and Substrate Substitution in the Synthesis of Oxindoles and β-Lactams

The Pd-catalyzed intramolecular carbene C–H insertion of α-diazo-α-(methoxycarbonyl)acetamides to prepare oxindoles as well as β-lactams was studied. In order to identify what factors influence the selectivity of the processes, we explored how the reactions are affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found that, in the synthesis of oxindoles, ((IMes)Pd(NQ))2 can be used as an alternative to Pd2(dba)3 to catalyze the carbene CArsp2–H insertion, although it was less versatile. On the other hand, it was demonstrated that the Csp3–H insertion leading to β-lactams can be effectively promoted by both Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms involved in these transformations was provided by DFT calculations.


Introduction
In recent years, the development of new methodologies for the selective functionalization of unactivated C-H bonds has become a very active area of research [1,2]. As part of this exciting field, the transition metal-catalyzed intramolecular carbene C-H insertion by decomposition of α-diazocarbonyl compounds has emerged as a powerful methodology for the construction of carbocyclic and heterocyclic frameworks [3][4][5][6][7][8]. A number of transition metal complexes have been used as effective catalysts to generate reactive metallacarbenes starting from α-diazocarbonyl compounds [9][10][11][12][13][14][15][16]. Among them, rhodium(II) [17,18], copper(I) [19,20], and more recently ruthenium(II) catalysts [21][22][23][24][25][26][27] have been proven to be especially useful for the development of highly selective carbene C-H insertion methodologies via a variety of reaction modes. Interestingly, palladium, one of the most commonly employed metals in homogeneous catalysis, remains underexploited in this type of carbene C-H insertion processes. Thus, while the effectiveness of palladium complexes in catalyzing carbene C-H insertion reactions from α-diazo carbonyl compounds was demonstrated some time ago [28], their use has been restricted to a couple of examples of insertion into C Ar sp 2 -H bonds [29][30][31]. This fact is highly surprising if we take into account the great success of palladium catalysis in cross-coupling reactions of diazo compounds with organic halides, pseudohalides, or arylboronic acids [32][33][34][35] and with organic halides, pseudohalides, or arylboronic acids [32][33][34][35] and that the palladium-catalyzed cyclopropanation of olefins with diazomethane is a widely used synthetic methodology [36].
The longstanding research on transition metal-catalyzed carbene C-H insertion has generated an extensive literature on the use of dirhodium(II) catalysts to promote the intramolecular C-H insertion of α-diazoacetamides [37,38], as the insertion products, namely β-and γ-lactams as well as 2-oxindoles, are common scaffolds found in numerous natural products. In recent years, some ruthenium(II) catalysts have also been applied to promote this kind of C-H insertion process [21,22,25,[39][40][41][42][43]. It has been shown that the site selectivity of these reactions not only depends on the type of diazocarbonyl compound but also is governed by conformational, steric, as well as electronic factors [44][45][46]. Moreover, some dramatic ligand effects have also been observed. For example, the use of carboxylate and, in particular, carboxamide ligands in dirhodium(II) catalysts has resulted in highly chemo-, regio-and stereoselective transformations [47,48] despite a variety of potentially competitive carbene-mediated processes (Scheme 1). Scheme 1. Typical Rh(II)-catalyzed reactions of α-diazoamides.
As part of our research program on the synthesis of nitrogen heterocycles, we have been exploring different ways to increase the versatility of palladium catalysis in C-C bond-forming reactions [49][50][51], for example, by controlling the ambiphilic character of the organopalladium intermediates in the intramolecular coupling reactions with carbonyl derivatives [52]. Continuing our search for methodologies to enhance the synthetic potential of organopalladium chemistry, we have also investigated the versatility of palladium as a catalyst for the carbene C-H insertion. In this context, we reported that palladium catalysts are able to promote Csp 3 -H insertion of carbenes derived from α-diazoesters to form pyrrolidines through intramolecular Csp 3 -Csp 3 bond formation [53,54].
We have also demonstrated that the carbene CArsp 2 -H functionalization of α-diazo-α-(methoxycarbonyl)acetanilides to give oxindoles can also be promoted by using Pd2(dba)3 as the catalyst [55]. This allowed us to develop a one-pot methodology to prepare 3-(chloroethyl)oxindoles by means of a sequential C-H insertion/alkylation process (Equation (a) in Scheme 2). More recently, we have described the synthesis of β-lactams by Pd(II)-catalyzed carbene Csp 3 -H insertion of α-diazo-α-(methoxycarbonyl)acetamides (Equation (b) in Scheme 2) [56]. As part of our research program on the synthesis of nitrogen heterocycles, we have been exploring different ways to increase the versatility of palladium catalysis in C-C bond-forming reactions [49][50][51], for example, by controlling the ambiphilic character of the organopalladium intermediates in the intramolecular coupling reactions with carbonyl derivatives [52]. Continuing our search for methodologies to enhance the synthetic potential of organopalladium chemistry, we have also investigated the versatility of palladium as a catalyst for the carbene C-H insertion. In this context, we reported that palladium catalysts are able to promote Csp 3 -H insertion of carbenes derived from α-diazoesters to form pyrrolidines through intramolecular Csp 3 -Csp 3 bond formation [53,54].
The aim of the current work was to gain more insight into the Pd-catalyzed carbene insertion reactions of α-diazo-α-(methoxycarbonyl)acetamides leading to oxindoles and β-lactams. In order to ascertain the factors governing the selectivity of the processes, we explored how the reactions are affected by the substituents on α-diazoacetamide and the type of catalyst, using complexes with two oxidation states of Pd and a variety of ligands (Scheme 3). Herein, we present a full account of our experimental and computational studies on the intramolecular insertion of α-diazo-α-(methoxycarbonyl)acetamides using Pd(0) and Pd(II) complexes, focused on identifying differences in the catalyst reactivities and selectivities. Scheme 3. Catalyst and substituent effects in Pd-catalyzed C-H insertion reactions of α-diazo-α-(methoxycarbonyl)acetamides.

Results and Discussion
The oxindole system is a common structural motif in pharmaceuticals and natural products, and the development of efficient procedures for their preparation is, therefore, of considerable interest [57][58][59][60].
Our previous studies on the carbene reactions of α-diazo-α-(methoxycarbonyl)acetanilides showed that, when using palladium catalysts, the C-H insertion giving the oxindole occurs selectively in the CArsp 2 -H rather than the Csp 3 -H bonds (Equation (a) of Scheme 2) [55]. The optimization process with α-diazoacetanilide 1a revealed that the carbene CArsp 2 -H insertion can be selectively promoted by both Pd(0) and Pd(II), the best result being obtained when using Pd2(dba)3 in the presence of Cs2CO3 in dichloroethane at reflux for 96 h, which afforded oxindole 2a in 66% yield (Table 1, entry 1). However, this reaction required a high catalyst loading and long reaction time. All attempts to increase the efficiency of the Pd(0)-catalyzed reaction by adding different phosphine ligands failed, always resulting in a slower reaction rate.
In order to improve the efficiency of the carbene insertion of α-diazoacetanilide 1a, in the present study, we tested some palladium catalysts bearing non-phosphine ligands. (Pd(allyl)Cl)2 was first explored for the insertion/alkylation sequential process (Table 1, entries 2-3), but significant amounts of the starting material were recovered even after 60 h. In contrast, the use of ((IMes)Pd(NQ))2 required a notably shorter reaction time and lower catalyst loading (Table 1, entry 4).
The aim of the current work was to gain more insight into the Pd-catalyzed carbene insertion reactions of α-diazo-α-(methoxycarbonyl)acetamides leading to oxindoles and β-lactams. In order to ascertain the factors governing the selectivity of the processes, we explored how the reactions are affected by the substituents on α-diazoacetamide and the type of catalyst, using complexes with two oxidation states of Pd and a variety of ligands (Scheme 3). Herein, we present a full account of our experimental and computational studies on the intramolecular insertion of α-diazo-α-(methoxycarbonyl)acetamides using Pd(0) and Pd(II) complexes, focused on identifying differences in the catalyst reactivities and selectivities. The aim of the current work was to gain more insight into the Pd-catalyzed carbene insertion reactions of α-diazo-α-(methoxycarbonyl)acetamides leading to oxindoles and β-lactams. In order to ascertain the factors governing the selectivity of the processes, we explored how the reactions are affected by the substituents on α-diazoacetamide and the type of catalyst, using complexes with two oxidation states of Pd and a variety of ligands (Scheme 3). Herein, we present a full account of our experimental and computational studies on the intramolecular insertion of α-diazo-α-(methoxycarbonyl)acetamides using Pd(0) and Pd(II) complexes, focused on identifying differences in the catalyst reactivities and selectivities.

Results and Discussion
The oxindole system is a common structural motif in pharmaceuticals and natural products, and the development of efficient procedures for their preparation is, therefore, of considerable interest [57][58][59][60].
Our previous studies on the carbene reactions of α-diazo-α-(methoxycarbonyl)acetanilides showed that, when using palladium catalysts, the C-H insertion giving the oxindole occurs selectively in the CArsp 2 -H rather than the Csp 3 -H bonds (Equation (a) of Scheme 2) [55]. The optimization process with α-diazoacetanilide 1a revealed that the carbene CArsp 2 -H insertion can be selectively promoted by both Pd(0) and Pd(II), the best result being obtained when using Pd2(dba)3 in the presence of Cs2CO3 in dichloroethane at reflux for 96 h, which afforded oxindole 2a in 66% yield (Table 1, entry 1). However, this reaction required a high catalyst loading and long reaction time. All attempts to increase the efficiency of the Pd(0)-catalyzed reaction by adding different phosphine ligands failed, always resulting in a slower reaction rate.
In order to improve the efficiency of the carbene insertion of α-diazoacetanilide 1a, in the present study, we tested some palladium catalysts bearing non-phosphine ligands. (Pd(allyl)Cl)2 was first explored for the insertion/alkylation sequential process (Table 1, entries 2-3), but significant amounts of the starting material were recovered even after 60 h. In contrast, the use of ((IMes)Pd(NQ))2 required a notably shorter reaction time and lower catalyst loading (Table 1, entry 4).

Results and Discussion
The oxindole system is a common structural motif in pharmaceuticals and natural products, and the development of efficient procedures for their preparation is, therefore, of considerable interest [57][58][59][60].
Our previous studies on the carbene reactions of α-diazo-α-(methoxycarbonyl)acetanilides showed that, when using palladium catalysts, the C-H insertion giving the oxindole occurs selectively in the C Ar sp 2 -H rather than the Csp 3 -H bonds (Equation (a) of Scheme 2) [55]. The optimization process with α-diazoacetanilide 1a revealed that the carbene C Ar sp 2 -H insertion can be selectively promoted by both Pd(0) and Pd(II), the best result being obtained when using Pd 2 (dba) 3 in the presence of Cs 2 CO 3 in dichloroethane at reflux for 96 h, which afforded oxindole 2a in 66% yield ( Table 1, entry 1). However, this reaction required a high catalyst loading and long reaction time. All attempts to increase the efficiency of the Pd(0)-catalyzed reaction by adding different phosphine ligands failed, always resulting in a slower reaction rate.
As can be seen in Table 2, like Pd2(dba)3, ((IMes)Pd(NQ))2 also selectively promoted the carbene insertion into the arylic C-H bond in substrates having substituents at the nitrogen atom with   3 3 Isolated yield. 4 Catalyst loading: 15%. 5 20% of unreacted 1e was recovered. 6 1 H-NMR analysis of the reaction mixture showed a 1:1 mixture of 1f and 2f. 7 1f was recovered. 8 1 H-NMR analysis of the reaction mixture showed a 1:4.8 mixture of 1h and 2h. 9 Complex reaction mixture. 10 1 H-NMR analysis of the reaction mixture showed a 1:1.5 mixture of 1j and 2j.
As can be seen in Table 2, like Pd2(dba)3, ((IMes)Pd(NQ))2 also selectively promoted the carbene insertion into the arylic C-H bond in substrates having substituents at the nitrogen atom with primary, secondary, as well as tertiary Csp 3 -H bonds. Notably, ((IMes)Pd(NQ))2 was more efficient than Pd2(dba)3 in promoting the insertion of N-alkylacetanilides lacking substituents on the arylic   3 3 Isolated yield. 4 Catalyst loading: 15%. 5 20% of unreacted 1e was recovered. 6 1 H-NMR analysis of the reaction mixture showed a 1:1 mixture of 1f and 2f. 7 1f was recovered. 8 1 H-NMR analysis of the reaction mixture showed a 1:4.8 mixture of 1h and 2h. 9 Complex reaction mixture. 10 1 H-NMR analysis of the reaction mixture showed a 1:1.5 mixture of 1j and 2j.
Our previously reported DFT calculations suggested that the Pd(0)-catalyzed CArsp 2 -H insertion of α-diazo-α-(methoxycarbonyl)acetanilides to give oxindoles proceeds via a genuine stepwise mechanism involving a Pd-mediated 1,5-hydrogen migration from the initially generated pallada(0)carbene complex, followed by a reductive elimination [55]. It was also shown that the complete chemoselectivity of the process, which exclusively produces oxindoles over β-lactams, takes place mainly under kinetic control. We now decided to check the generality of this unprecedented Pd(0)-mediated mechanism using the model Pd(NHC) (NHC = 1,3-bis(phenyl)-imidazil-2-ylidene) catalyst. Figure 1 shows the computed reaction profile for the formation of oxindole 2b', precursor of the experimentally observed oxindole 2b (see Table 2). As expected, based on our previous report [55], the process begins from pallada(0)carbene INT0, formed upon reaction of α-diazoamide 1b and the active catalyst species Pd(NHC). This species evolves into intermediate INT1 in a highly exergonic process (∆GR = -25.3 kcal/mol) through the transition state TS1 with a computed activation barrier of 16.2 kcal/mol, which is fully compatible with the reaction conditions used in the experiment. Closer inspection of TS1 indicates that this reaction step can be viewed as a Pd-mediated 1,5-hydrogen migration, which involves the formal oxidation of the transition metal. The alternative Csp 3 -H activation reaction via TS1', which would involve an analogous Pd-mediated 1,4-hydrogen migration, is not competitive in view of the much higher activation barrier ( G  = 8.2 kcal/mol) computed for this alternative transformation. Therefore, it is once again found that the complete selectivity of the process takes place under kinetic control. The transformation ends with an exergonic (∆GR = -6.8 kcal/mol) reductive elimination reaction that directly transforms INT1 into oxindole 2b' with the concomitant release of the active catalytic species Pd(NHC) through the Regarding the palladium-catalyzed reactions shown in Tables 1 and 2, it should be noted that the formation of β-lactam products, resulting from the possible competitive carbene Csp 3 -H insertion, was not observed. This sharply contrasts with the competition between the carbene C Ar sp 2 -H and Csp 3 -H insertions observed in Rh(II)-promoted processes (see, for instance, Scheme 1(a)) [48].
Our previously reported DFT calculations suggested that the Pd(0)-catalyzed C Ar sp 2 -H insertion of α-diazo-α-(methoxycarbonyl)acetanilides to give oxindoles proceeds via a genuine stepwise mechanism involving a Pd-mediated 1,5-hydrogen migration from the initially generated pallada(0)carbene complex, followed by a reductive elimination [55]. It was also shown that the complete chemoselectivity of the process, which exclusively produces oxindoles over β-lactams, takes place mainly under kinetic control. We now decided to check the generality of this unprecedented Pd(0)-mediated mechanism using the model Pd(NHC) (NHC = 1,3-bis(phenyl)-imidazil-2-ylidene) catalyst. Figure 1 shows the computed reaction profile for the formation of oxindole 2b', precursor of the experimentally observed oxindole 2b (see Table 2). As expected, based on our previous report [55], the process begins from pallada(0)carbene INT0, formed upon reaction of α-diazoamide 1b and the active catalyst species Pd(NHC). This species evolves into intermediate INT1 in a highly exergonic process (∆G R = -25.3 kcal/mol) through the transition state TS1 with a computed activation barrier of 16.2 kcal/mol, which is fully compatible with the reaction conditions used in the experiment. Closer inspection of TS1 indicates that this reaction step can be viewed as a Pd-mediated 1,5-hydrogen migration, which involves the formal oxidation of the transition metal. The alternative Csp 3 -H activation reaction via TS1', which would involve an analogous Pd-mediated 1,4-hydrogen migration, is not competitive in view of the much higher activation barrier (∆G = 8.2 kcal/mol) computed for this alternative transformation. Therefore, it is once again found that the complete selectivity of the process takes place under kinetic control. The transformation ends with an exergonic (∆G R = -6.8 kcal/mol) reductive elimination reaction that directly transforms INT1 into oxindole 2b' with the concomitant release of the active catalytic species Pd(NHC) through the transition state TS2 (with a feasible activation barrier of 18.7 kcal/mol). On the other hand, we have also reported that the intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to form β-lactams can be effectively catalyzed by Pd(II) complexes (Scheme 2(b)) [56]. Due to its ubiquitous presence in the molecular structure of natural products and biologically active compounds, β-lactam synthesis has attracted considerable attention over the years [63][64][65]. To further understand the impact of the electronic nature of the catalyst in the aforementioned insertion reaction, we decided to explore the use of some Pd(0)-precatalysts. Table 3 shows the results of the reactions of diversely substituted N-benzyl-Nt butyl-α-diazoacetamides (5a-5m) when using either Pd2(dba)3 or ((IMes)Pd(NQ))2 as the catalyst and compares them with those previously obtained in the Pd(II)-catalyzed reactions [56].
The examples in Table 3 confirm the generality and functional group tolerance of Pd2(dba)3 and ((IMes)Pd(NQ))2 as catalysts for these insertion processes. Although both Pd(0) and Pd(II) catalysts can be used to promote Csp 3 -H insertion, some significant differences were identified. On the whole, the Pd(II) complexes proved to be more versatile for β-lactam formation despite not always giving the highest yield. In general, the resulting β-lactams were obtained in moderate to good overall yields (53-90%), usually as mixtures of cis and trans isomers, in transformations proceeding with high site selectivity, except when using 5f. In this particular case, the use of Pd(II) catalysts to promote its decomposition resulted in the formation of trans-7f (10-14%), together with major amounts of aldehyde 10. On the other hand, when ((IMes)Pd(NQ))2 was used, a complex reaction mixture was obtained, from which cis-7f (9%), trans-7f (10%), and aldehyde 10 (15%) were isolated, while no cyclization product was obtained in the presence of Pd2(dba)3.
Notably, partial or complete isomerization of the cis β-lactam to the more stable trans isomer took place during the chromatographic purification of the reaction mixtures, which explains the observed differences in cis/trans ratios before and after purification. Relative free energies and bond distances are given in kcal/mol and angstroms, respectively.
On the other hand, we have also reported that the intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to form β-lactams can be effectively catalyzed by Pd(II) complexes (Scheme 2b) [56]. Due to its ubiquitous presence in the molecular structure of natural products and biologically active compounds, β-lactam synthesis has attracted considerable attention over the years [63][64][65]. To further understand the impact of the electronic nature of the catalyst in the aforementioned insertion reaction, we decided to explore the use of some Pd(0)-precatalysts. Table 3 shows the results of the reactions of diversely substituted N-benzyl-N-t butyl-α-diazoacetamides (5a-5m) when using either Pd 2 (dba) 3 or ((IMes)Pd(NQ)) 2 as the catalyst and compares them with those previously obtained in the Pd(II)-catalyzed reactions [56]. Table 3. Palladium-catalyzed cyclization reactions of α-diazoamides 5a-5m 1 .      ) in DCE at reflux for 24 h. 2 Ratios determined by integration of characteristic 1 H-NMR absorptions from the spectrum of the reaction mixture. 3 The majority of reactions were performed twice, while the Buchner:β-lactam:γ-lactam ratio (6/7/8) was essentially the same in the two runs and the cis:trans ratio was quite different due to the partial isomerization of cis β-lactams to the more stable trans isomers during the work-up or even when recording the 1 H-NMR spectra. 4 Yields refer to products isolated by chromatography. 5 4-(Dimethylamino)benzaldehyde (10). 6 Mixture of regioisomers. Table 3 confirm the generality and functional group tolerance of Pd 2 (dba) 3 and ((IMes)Pd(NQ)) 2 as catalysts for these insertion processes. Although both Pd(0) and Pd(II) catalysts can be used to promote Csp 3 -H insertion, some significant differences were identified. On the whole, the Pd(II) complexes proved to be more versatile for β-lactam formation despite not always giving the highest yield. In general, the resulting β-lactams were obtained in moderate to good overall yields (53-90%), usually as mixtures of cis and trans isomers, in transformations proceeding with high site selectivity, except when using 5f. In this particular case, the use of Pd(II) catalysts to promote its decomposition resulted in the formation of trans-7f (10-14%), together with major amounts of aldehyde 10. On the other hand, when ((IMes)Pd(NQ)) 2 was used, a complex reaction mixture was obtained, from which cis-7f (9%), trans-7f (10%), and aldehyde 10 (15%) were isolated, while no cyclization product was obtained in the presence of Pd 2 (dba) 3 .

The examples in
Notably, partial or complete isomerization of the cis β-lactam to the more stable trans isomer took place during the chromatographic purification of the reaction mixtures, which explains the observed differences in cis/trans ratios before and after purification.
The effect of adding phosphine ligands to the Pd(0) catalyst was also explored. However, similarly to the oxindole-forming reactions, the use of Pd 2 (dba) 3 in the presence of phosphine ligands resulted in slower reaction rates. Thus, for example, treatment of 5a with Pd 2 (dba) 3 (10 mol%) in the presence of (o-tolyl) 3 P (20 mol%) under otherwise the same reaction conditions gave a mixture of 6 (12%), cis-7 (22%), and trans-7 (26%) together with some unreacted α-diazoamide (10%) (result not included in the table).
As can be seen in Table 3, the effect of the substituent at the benzyl group on the outcome of the process varied according to its electronic nature as well as its position on the aromatic ring. The introduction of electron-donor groups led to an increased formation of the cycloheptapyrrolone product, especially when using Pd(0) catalysts. The increase was lower when the substituent was located at the ortho-position, probably due to steric interactions. In contrast, the electron-withdrawing groups generally diverted the palladacarbene away from the Buchner reaction in favor of the Csp 3 -H insertion. Similar electronic effects have been observed in related Rh(II)-catalyzed transformations [48]. On the other hand, the use of ((IMes)Pd(NQ)) 2 as the catalyst in the reaction of those substrates bearing electron-withdrawing groups resulted in the formation of minor amounts of the corresponding γ-lactam (8), which arises from the t butyl Csp 3 -H insertion. Notably, the γ-lactams were not observed when using Pd(II) catalysts.
The above results also confirm the significant impact of the electronic nature of the Pd catalyst and ensue electrophilicity of the carbene intermediate in the reaction pathway. Thus, whereas benzylic Csp 3 -H insertion is strongly favored over the Buchner reaction when using Pd(II), an increased cycloheptapyrrolone product formation is usually observed with the more electron-rich Pd(0) complexes. Interestingly, Rh(II)-catalyzed transformations show opposite reactivity trends, in which highly electrophilic Rh(II) complexes favor Buchner reactions over benzylic Csp 3 -H insertion [44][45][46].
Finally, we explored the transition metal-catalyzed decomposition of α-diazoacetamide 11, which bears a (4-pyridinyl)methyl group instead of the N-benzyl substituent ( Table 4). Treatment of 11 with a catalytic amount of ((IMes)Pd(NQ)) 2 under the optimized reaction conditions resulted in the complete decomposition of the material (Table 4, entry 1). When the reaction was performed at lower temperatures (refluxing dichloromethane), 11 was recovered unchanged (Table 4, entry 2). In contrast, the use of Pd(II) catalysts (Table 4, entries 3 and 4) resulted in the formation of β-lactam 12 (cis/trans mixture), with (SIPr)Pd(allyl)Cl affording the highest yield. Interestingly, α-diazoacetamide 11 was recovered unchanged when using the well-known (Rh(OAc) 2 ) 2 catalyst (Table 4, entry 5). Rh(II)-catalyzed transformations [48]. On the other hand, the use of ((IMes)Pd(NQ))2 as the catalyst in the reaction of those substrates bearing electron-withdrawing groups resulted in the formation of minor amounts of the corresponding γ-lactam (8), which arises from the t butyl Csp 3 -H insertion.
Notably, the γ-lactams were not observed when using Pd(II) catalysts. The above results also confirm the significant impact of the electronic nature of the Pd catalyst and ensue electrophilicity of the carbene intermediate in the reaction pathway. Thus, whereas benzylic Csp 3 -H insertion is strongly favored over the Buchner reaction when using Pd(II), an increased cycloheptapyrrolone product formation is usually observed with the more electron-rich Pd(0) complexes. Interestingly, Rh(II)-catalyzed transformations show opposite reactivity trends, in which highly electrophilic Rh(II) complexes favor Buchner reactions over benzylic Csp 3 -H insertion [44][45][46].
Finally, we explored the transition metal-catalyzed decomposition of α-diazoacetamide 11, which bears a (4-pyridinyl)methyl group instead of the N-benzyl substituent ( Table 4). Treatment of 11 with a catalytic amount of ((IMes)Pd(NQ))2 under the optimized reaction conditions resulted in the complete decomposition of the material (Table 4, entry 1). When the reaction was performed at lower temperatures (refluxing dichloromethane), 11 was recovered unchanged (Table 4, entry 2). In contrast, the use of Pd(II) catalysts (Table 4, entries 3 and 4) resulted in the formation of β-lactam 12 (cis/trans mixture), with (SIPr)Pd(allyl)Cl affording the highest yield. Interestingly, α-diazoacetamide 11 was recovered unchanged when using the well-known (Rh(OAc)2)2 catalyst (Table 4, entry 5). In our previous work on the synthesis of β-lactams, we studied computationally the Pd(II)-catalyzed insertion reaction of α-diazo-α-(methoxycarbonyl)acetamides [56]. According to our DFT calculations, this insertion reaction also occurs stepwise and involves an unprecedented Pd(II)-promoted Mannich-type reaction through a pallada(II)carbene-induced zwitterionic In our previous work on the synthesis of β-lactams, we studied computationally the Pd(II)-catalyzed insertion reaction of α-diazo-α-(methoxycarbonyl)acetamides [56]. According to our DFT calculations, this insertion reaction also occurs stepwise and involves an unprecedented Pd(II)-promoted Mannich-type reaction through a pallada(II)carbene-induced zwitterionic intermediate. To shed light on the reaction mechanism and the influence of the Pd(0) catalyst on the selectivity of the C-H insertion described above, DFT calculations were also carried out. To this end, the process involving 5a in the presence of the model Pd(NHC) (NHC = 1,3-bis(phenyl)-imidazil-2-ylidene) catalyst was explored. Figure 2 shows the computed reaction profile for the transformation of the initially formed pallada(0)carbene intermediate INT0 into the observed β-lactams cis-7a and trans-7a. Similar to the reaction profile computed for the formation of oxindoles discussed above (Figure 1), the initial INT0 readily evolves into the corresponding five-membered pallada(II)cycle INT1 via the transition state TS1 in a highly exergonic transformation (∆G R ≈ -40 kcal/mol). Once again, this saddle point is associated with a 1,4-hydrogen migration reaction mediated by the transition metal fragment, thus confirming the generality of this type of C-H insertion reaction. Then, species INT1 is transformed into the final β-lactam through a reductive elimination reaction via TS2, which releases the active catalyst able to enter into a new catalytic cycle. Interestingly, the computed cis/trans activation barrier differences for either the initial 1,4-H migration (∆G = 1.3 kcal/mol) or for the subsequent elimination reaction (∆G = 0.2 kcal/mol) indicates that the formation of the cis-7a β-lactam should be only slightly favored over the formation of its trans counterpart, which nicely matches the experimental findings (see Table 3, entry 2). elimination reaction ( G  = 0.2 kcal/mol) indicates that the formation of the cis-7a β-lactam should be only slightly favored over the formation of its trans counterpart, which nicely matches the experimental findings (see Table 3, entry 2).

General Information
All commercially available reagents were used without further purification. 1 H-and 13 C-NMR spectra were recorded using Me4Si as the internal standard with a Varian Mercury 400 instrument (Oxford, United Kingdom). Chemical shifts are reported in ppm downfield (δ) from Me4Si for 1 H and 13 C-NMR. TLC was carried out on SiO2 (silica gel 60 F254, Merck), and the spots were located with Computed reaction profile for the transformation of pallada(0)carbene INT0 into β-lactams cis-7a and trans-7a: Relative free energies and bond distances are given in kcal/mol and angstroms, respectively.