Amide bond formation via C ( sp 3 ) – H bond functionalization and CO insertion † ‡

The importance of amides in chemistry and biology is well recognized and, consequently, a variety of methods have been developed for their synthesis, with notable examples including the Schmidt, Schotten– Baumann and Ugi reactions. These methods are based on the reactions of activated acid derivatives (acid chlorides and anhydrides) or acid/base induced rearrangement reactions. Recently, attention has been devoted to developing new routes to amides that do not require acid or base, but to achieve this goal, relatively expensive starting materials such as aldehydes are required. Metal catalyzed routes enable amides to be generated from starting materials other than carboxylic acids and these reactions are summarized in two excellent review articles. Perhaps the most notable achievement in this regard has been the direct catalytic conversion of alcohols and amines into amides. The synthesis of amides involving transition metal catalyzed C–X (X = H, Br, I etc.) bond functionalization followed by carbonylation with CO has received considerable attention as it has a high atom economy. Seminal research includes the catalytic aminocarbonylation of alk-1-ynes and the application of a homogeneous PdCl2–PPh3 catalytic system for direct oxidative aminocarbonylation using CO and oxygen under basic conditions. The catalytic aminocarbonylation of alkenes using a Co/C catalyst has also been reported, and palladium catalyzed carbonylation reactions of aryl bromides have been used to prepare benzamides from aryl bromides at atmospheric pressure. Other notable developments include transition metal-free alkoxycarbonylation of aryl halides, and the synthesis of amides by the activation of aromatic C–H bonds. Rhodium and ruthenium complexes that catalyze the formation of amides by activating C(sp)– H bonds have also been reported. Palladium–phosphine complexes are widely used to catalyze the formation of carbon–carbon, carbon–nitrogen and carbon–oxygen bonds. Bis-phosphine ligands are particularly useful in these reactions and the influence of the ligand bite-angle on C–C and C–X bond forming cross coupling reactions has been reviewed. The wide bite-angle bis-phosphine, Xantphos, has found a number of important uses. Notably, Huang and co-workers reported the synthesis of esters from alkanes using a PdCl2–Xantphos catalyst in the presence of BuOOBu. Azidocarbonylation reactions may also be catalyzed by a Pd2(dba)3–Xantphos system 18 and intermolecular amidation of aryl halides using Pd(OAc)2–Xantphos has also been reported. Pd-catalyzed direct oxidative carbonylation of allylic C–H bonds with carbon monoxide has also been reported. We found that PdCl2 combined with various bis-phosphines including Xantphos, Nixantphos, ( )-Binapo or (R)-Phanephos catalyze the formation of amides in the absence of acid or base, by the direct functionalization of C(sp)–H bonds with subsequent CO insertion – the outcome of these studies is described herein. The viability of the reaction was explored with toluene 1 and aniline 2 as substrates under CO (50 atm) using various PdCl2-based catalysts due to their excellent performance in carbonylation reactions (Scheme 1, Table 1). High yields of the desired product (compound 3 in Scheme 1) are obtained with the wide bite-angle bis-phosphines, Xantphos, Nixantphos, or (R)-Phanephos and also with ( )-Binapo (Table 1, entries 9–12 and 16–19). The yield of 3 is very low in the absence of a ligand co-catalyst (Table 1, entries 1 and 2) or in the presence of other bis-phosphines and mono-phosphine ligands (Table 1, entries 3–8). The influence of the bis-phosphine bite-angle is apparent (Table 1, entries 3–12), with ligands with bite-angles >901

The importance of amides in chemistry and biology is well recognized and, consequently, a variety of methods have been developed for their synthesis, 1 with notable examples including the Schmidt, Schotten-Baumann and Ugi reactions. 2 These methods are based on the reactions of activated acid derivatives (acid chlorides and anhydrides) or acid/base induced rearrangement reactions. Recently, attention has been devoted to developing new routes to amides that do not require acid or base, but to achieve this goal, relatively expensive starting materials such as aldehydes are required. Metal catalyzed routes enable amides to be generated from starting materials other than carboxylic acids and these reactions are summarized in two excellent review articles. 3,4 Perhaps the most notable achievement in this regard has been the direct catalytic conversion of alcohols and amines into amides. 5 The synthesis of amides involving transition metal catalyzed C-X (X = H, Br, I etc.) bond functionalization followed by carbonylation with CO has received considerable attention as it has a high atom economy. 6 Seminal research includes the catalytic aminocarbonylation of alk-1-ynes 7 and the application of a homogeneous PdCl 2 -PPh 3 catalytic system for direct oxidative aminocarbonylation using CO and oxygen under basic conditions. 8 The catalytic aminocarbonylation of alkenes using a Co/C catalyst has also been reported, 9 and palladium catalyzed carbonylation reactions of aryl bromides have been used to prepare benzamides from aryl bromides at atmospheric pressure. 10 Other notable developments include transition metal-free alkoxycarbonylation of aryl halides, 11 and the synthesis of amides by the activation of aromatic C-H bonds. 12 Rhodium 13 and ruthenium 14 complexes that catalyze the formation of amides by activating C(sp 2 )-H bonds have also been reported.
Palladium-phosphine complexes are widely used to catalyze the formation of carbon-carbon, carbon-nitrogen and carbon-oxygen bonds. 15 Bis-phosphine ligands are particularly useful in these reactions and the influence of the ligand bite-angle on C-C and C-X bond forming cross coupling reactions has been reviewed. 16 The wide bite-angle bis-phosphine, Xantphos, has found a number of important uses. Notably, Huang and co-workers reported the synthesis of esters from alkanes using a PdCl 2 -Xantphos catalyst in the presence of t BuOO t Bu. 17 Azidocarbonylation reactions may also be catalyzed by a Pd 2 (dba) 3 -Xantphos system 18 and intermolecular amidation of aryl halides using Pd(OAc) 2 -Xantphos has also been reported. 19 Pd-catalyzed direct oxidative carbonylation of allylic C-H bonds with carbon monoxide has also been reported. 20 We found that PdCl 2 combined with various bis-phosphines including Xantphos, Nixantphos, (AE)-Binapo or (R)-Phanephos catalyze the formation of amides in the absence of acid or base, by the direct functionalization of C(sp 3 )-H bonds with subsequent CO insertion -the outcome of these studies is described herein.
The viability of the reaction was explored with toluene 1 and aniline 2 as substrates under CO (50 atm) using various PdCl 2 -based catalysts due to their excellent performance in carbonylation reactions (Scheme 1, Table 1). 21 High yields of the desired product (compound 3 in Scheme 1) are obtained with the wide bite-angle bis-phosphines, Xantphos, Nixantphos, or (R)-Phanephos and also with (AE)-Binapo ( Under standard conditions toluene was replaced by toluene-d 8 and after 2 hours the yield of the desired product is 7% (compared to 18% for toluene -r H /r D = 2.6) suggesting that the C(sp 3 )-H bond cleavage step occurs before the rate-limiting step or might be involved in the rate-limiting step of this transformation. Hence, the yield of the desired product should be related to the C(sp 3 )-H bond dissociation energies. The substrate scope of the reaction was explored under optimized conditions (CO 50 atm, 125 1C) using 5 mol% of PdCl 2 with Xantphos or (R)-Phanephos and DTBP as the oxidant (Table 2). Products resulting from carbonylation of C(sp 2 )-H (aromatic) bonds are not observed ( Table 2, entry 1). Cyclohexane reacts in the presence of DTBP to afford the corresponding amide in reasonable yield ( Table 2, entries 4 and 5), albeit lower than the yield of the product obtained with toluene ( Table 2, entries 6 and 7), presumably due to the higher bond dissociation energy of the C-H bond in cyclohexane compared to toluene. 27 With diphenylmethane the main product is 1,3-diphenylurea, presumably due to steric hindrance. Presumably the yield of the branched product is higher than the linear product using ethylbenzene as the substrate for the same reason ( Table 2, entries 2  and 3). Moreover, electron withdrawing -F and -Cl substituents in the para-position favor the reaction; however, for the carbonylation of toluene, ethylbenzene and cyclohexane, the ligand (R)-Phanephos is superior to Xantphos, whereas for substrates with electron withdrawing -F and -Cl substituents in the para-position, Xanthphos is superior (Table 2, entries 2-11). These combined data confirm that the yield of the desired product is related, at least in part, to the C(sp 3 )-H bond dissociation energies. The PdCl 2 -Xantphos catalyst tolerates anilines with electron withdrawing or donating substituents (Scheme 2 and Table 3), although electron withdrawing groups are more favorable for this reaction. The system is, unfortunately, inactive with alkylamines.

View Article Online
The full mechanistic details of this transformation have not been determined, however, in the presence of the radical scavenger TEMPO the reaction is completely suppressed, indicative of a radical process, 28 which is similar to the one proposed by Huang and co-workers for the formation of esters from alkanes and alcohols using a similar catalytic system. A plausible reaction mechanism is shown in Scheme 3. In the presence of a ligand, sequential oxidation of the Pd(0) bis-phosphine catalyst generated in situ with the anilino and benzyl radicals produced in the presence of DTBP leads to the formation of intermediate (B). Subsequent insertion of CO gives intermediate (C) which can undergo reductive elimination to afford the final product. The concentration of aniline strongly influences the yield of the product, i.e. at high concentrations the yield of 1,3-diphenylurea is increased (see ESI ‡), presumably because the aniline can more easily react with itself and CO to form 1,3-diphenylurea.
ESI-MS was used to analyze the reaction and a peak that may be tentatively assigned to [(Xantphos)PdCH 2 Ph] + (Fig. S1, ESI ‡) was observed. This species could be derived from either B or C (see ESI ‡ for further details).
In summary, a convenient and efficient method for the synthesis of amides via Pd-catalyzed oxidative carbonylation of C-H bonds with CO has been devised. The method represents a practical and efficient approach for the synthesis of substituted phenyl amides from simple alkanes. This work was supported by the EPFL and the Swiss National Science Foundation.