Palladium-catalysed intramolecular carbenoid insertion of α-diazo-α-( methoxycarbonyl ) acetanilides for oxindole synthesis

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the reported transition metal-catalysed intramolecular C-H insertions of diazo compounds, the reaction of N-alkyl-N-aryl α-diazoamides has been extensively explored, 12 since the insertion products, namely βand γlactams as well as 2-oxindoles, are common scaffolds found in numerous natural products.The selectivity of these reactions depends not only on the carbenoid and substrate substitution, but is also governed by the catalyst. 13Thus, for instance, the use of Rh(II) carboxylate and, in particular, carboxamide catalysts has resulted in the development of highly chemo-, regio-and stereoselective transformations with a variety of reaction modes. 14On the other hand, more recently, the commercially available [Ru(p-cymene)Cl 2 ] 2 has been used as a catalyst to develop diverse methodologies for oxindole synthesis based on the α-diazoamide carbenoid insertion.
Encouraged by the results of our previous work, we decided to explore the feasibility of palladium as a catalyst to promote the carbenoid C-H insertion from α-diazo-α-(methoxycarbonyl)acetanilides (Scheme 2).In this investigation, we sought to identify differences in the reactivities and selectivities between the palladium catalyst and the transition-metal catalysts mentioned above.α-Diazoamide 1a was chosen as a model substrate for our initial studies (Table 1).In line with the results previously reported for related substrates, 14b-d the Rh(II) acetatecatalysed decomposition of 1a resulted in the intramolecular carbenoid insertion into the benzylic C-H bond to give mainly trans-β-lactam 2a (entry 1).In contrast, treatment of 1a with a catalytic amount of Pd 2 (dba) 3 in toluene at reflux for 72 h afforded oxindole 3a, arising from the arylic C-H bond insertion, in 42% yield (entry 2).While a similar result was obtained when the reaction was carried out in dioxane for 31 h (entry 3), the use of either the more polar CH 3 CN or the high boiling chlorobenzene as the solvent led to the complete decomposition of the material (results not shown in the table).
Note that oxindole 3a was difficult to isolate in pure form due to its well-known tautomeric equilibrium.Pleasingly, we found that when using dichloroethane as the solvent, oxindole 4a was directly obtained (66% yield) from a sequential carbenoid insertion/alkylation process (entry 4).The formation of 4a not only facilitated the isolation of the cyclization product, but also avoided the generation of minor amounts of bisoxindole by-products, 17 which were also observed when using solvents other than DCE.The use of other palladium precatalysts such as Pd(OAc) 2 and Pd(PPh 3 ) 4 resulted in slower reaction rates (entries 5 and 6).Similarly, all our attempts to increase the efficiency of the Pd-catalysed reaction by adding different phosphine ligands met with no success (entries 7-9).Finally, ca.30% of conversion was observed in the absence of the palladium catalyst, giving a 0.2:1 mixture of trans-β-lactam 2a and oxindole 4a, together with unreacted starting material (entry 10). 18These results therefore indicate that Pd 2 (dba) 3 can catalyse the carbenoid C-H insertion of α-diazo-α-(methoxycarbonyl)acetanilides, which chemoselectively proceeds into the arylic C-H bond to give the oxindole 3a. 19The selectivity of the insertion is the opposite of that observed in our previous work with α-diazoesters.
11 Moreover, when using dichloroethane as the solvent, the initially formed oxindole undergoes in situ alkylation 20 to afford 4a.Interestingly, when the reaction was carried out with the base DBU [Pd 2 (dba) 3 (0.1), DBU (1.2) in DCE at reflux], N-benzyl-2-oxindole was obtained (69%) from the demethoxycarbonylation 21 of the initially formed oxindole 3a. 22This result confirms that Cs 2 CO 3 is not necessary for the Pd-catalysed insertion, but is needed for the alkylation process.
In order to assess the scope of this novel Pd-catalysed reaction, we then explored the sequential C-H insertion/alkylation process starting from a variety of αdiazoacetanilides (Scheme 3).Firstly, we investigated the effect of changing the N-alkyl substituent on the course of the two-step sequential process.All the tested N-alkyl substrates were well tolerated under the conditions of the Pd-catalysed reaction.As can be seen in Scheme 3, the insertion occurs selectively into the arylic C-H bond, in the presence of primary, secondary as well as tertiary Csp 3 -H bonds.Oxindoles 4e and 4f, bearing a (methoxycarbonyl)ethyl and a phenyl group, respectively, were also obtained in acceptable yields.Under the optimized reaction conditions, amide 1g, bearing a 2-iodobenzyl substituent at the nitrogen atom, selectively afforded oxindole 4g.Strikingly, no product resulting from the competitive Pd-catalysed coupling of the aryl iodide with the diazo moiety 23 was observed in the reaction mixture.It was also found that the stereoelectronic properties of the substituents on the aniline ring considerably affect the course of the cyclisation reaction.The presence of an orthobromo substituent on the arylic ring resulted in a very slow reaction, probably due to steric interactions.Thus, starting from 1h and after 4 days under the usual reaction conditions, a 1:1 mixture of the starting amide and oxindole 4h (23%) was Please do not adjust margins Please do not adjust margins obtained.Amide 1i, which bears a good electron-donating meta-methoxy group, underwent complete reaction to give oxindole 4i (40%), which was isolated as a 1:3 mixture of regioisomers.On the other hand, amides 1j and 1l, which bear the electron-donating methoxy and electron-withdrawing (methoxycarbonyl) groups, respectively, at the para position afforded oxindoles 4j and 4l also in modest yields, despite complete consumption of the starting material.In contrast, oxindole 4k, which has a fluoro substituent, was obtained in 64% yield.Finally, the N-naphthyl amide 1m underwent selective C-H insertion to give 4m, which was isolated together with the corresponding O-alkylation product.
To further confirm the catalytic role of palladium in the insertion reaction, the thermal decomposition of αdiazoamides 1b (R 1 = H, R = Me) and 1f (R 1 = H, R = Ph) was also evaluated.In the absence of Pd 2 (dba) 3 and under otherwise the same reaction conditions, 1b afforded a 2:1:0.6 mixture of 1b, 4b and β-lactam 2b (Scheme 4). 24When the thermal reaction was run starting from 1f, a 4:1 mixture of the starting material and oxindole 4f was obtained.The recovery of a considerable amount of starting material and, especially, the formation of β-lactams 2a and 2b in the thermal reactions clearly support the essential role of palladium as a catalyst for the oxindole formation.To shed light on the reaction mechanism and selectivity of the Pd-catalysed C-H insertion reaction described above, density functional theory (DFT) calculations were carried out.

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To this end, the reaction profile involving the simplest substrate 1b and the model palladium(0) catalyst Pd(PMe 3 ) 2 (thus resembling the reaction conditions gathered in Table 1, entry 6) was explored (Figure 1).As previously reported for the process involving the strongly related α-diazoesters, Please do not adjust margins

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To understand the selectivity of the insertion, the formation of the possible β-lactam 2b was also computed.As shown in Figure 1, the corresponding pathway leading to βlactam 2b is rather similar to that computed for oxindole 3b, i.e.Pd-mediated 1,4-H migration via TS1-B followed by reductive elimination through TS2-B.From the data in Figure 1, it becomes evident that both reaction steps are associated with much higher activation barriers than those computed for the pathway involving TS1-A and TS1-B.In particular, the rather high barrier computed for the reductive elimination via TS2-B (∆G ≠ = 42.8 kcal/mol) makes this step unfeasible.
Therefore, it can be concluded that the complete selectivity of the process, which exclusively produces oxindoles over βlactams, takes place mainly under kinetic control.
In summary, we have shown that palladium catalysis constitutes an useful alternative to promote the carbenoid C-H insertion of α-diazo-α-(methoxycarbonyl)acetanilides, which selectively occurs into the arylic C(sp 2 )-H bond rather than the C(sp 3 )-H bonds.Moreover, when using DCE as the solvent, the insertion is followed by alkylation to give 3-(chloroethyl)oxindoles.Although the carbenoid insertion into the arylic C-H bond starting from α-diazo-α-(alkoxycarbonyl)acetanilides can also be promoted by rhodium(II) perfluorocarboxamides, 14c-d these catalysts are not commercially produced.Thus, considering the ready availability of Pd 2 (dba) 3 in particular, the present process would complement the existing methodologies based on the use of Rh as well as Ru catalysts.We gratefully acknowledge financial support for this work from MINECO-FEDER (Projects CTQ2013-44303-P, CTQ2014-51912-REDC, CTQ2015-64937-R and CTQ2016-78205-P).

a
All reactions were conducted with 1a (0.2 mmol, 0.2 M). b Isolated yield.c Minor amounts of the cis-β-lactam (<10%) were also formed.d Small amounts of the bisoxindole dimer (≈ 5%) were also formed, see the ESI.e 1 H NMR ratio, yields were not quantified.f Complex mixture with less than 10% of 4a.
11 the reaction begins with intermediate INT0, the initial Pd(0)-carbene complex formed upon reaction of Pd(PMe 3 ) 2 with 1b.This species evolves to the Pd(II)-complex INT1-A through TS1-A with a low activation barrier of 12.3 kcal/mol in a highly exergonic transformation (ΔG R = -16.4kcal/mol).As clearly depicted in Figure1, this step can be viewed as a Pd-mediated 1,5-H migration from the C(aryl)-H moiety to the carbenoid carbon atom, thus resulting in the formal oxidation of the transition metal.This transformation strongly resembles the one we recently described for the Pd(0)-catalysed Csp 3 -H insertion reactions of carbenoids derived from α-diazoesters, 11 therefore suggesting a general reaction mechanism that does not depend upon the nature of the initial substrate.The process ends up with the conversion of the readily formed Pd(II)-complex INT1-A into oxindole 3b (which in the presence of DCE and Cs 2 CO 3 evolves into the observed alkylated oxindole 4b).This highly exergonic INT1-A → 3b transformation (ΔG R = -23.8kcal/mol) can be viewed as a reductive elimination reaction (via TS2-A, ∆G ≠ = 24.1 kcal/mol) which releases the active catalyst Pd(PMe 3 ) 2 .This journal is © The Royal Society of Chemistry 20xx