IIIB.7
Methyl 4-(2-(5-phenylisoxazol CDCl 3 )
IV.3. Present Work
decarboxylation of α-keto acid and thus can be used as an suitable alternative to silver/persulphate combination during decarboxylative o-aroylation process.
decarboxylative coupling between 2-phenylbenzothiazole (1, 1 equiv) and phenylglyoxylic acid (a′, 1.2 equiv) was best achieved by using Pd(OAc)2 (10 mol %) and CAN (1.5 equiv) in DMF at 110 oC (see Table IV.3.1). These standardized conditions were used to examine the decarboxylative o-aroylation reactions of a range of directing arenes.
Substrate scope for o-aroylation. Using above standardized conditions, we scrutinized the scope and generality of a decarboxylative coupling reaction with various 2-arylsubstituted benzothiazoles and phenylglyoxylic acid (a′). 2-Phenylbenzothiazole that contained electro- neutral –H (1), electron-donating p-Me (2), p-OMe (3), and p-tBu (4), and electron- withdrawing o-Cl , m-Br, and p-Cl (i.e. 5, 6, and 7) substituents on the 2-phenyl ring coupled efficiently with a' to provide the desired o-aroylated products in moderate to good yields (Scheme IV.3.1). However, no correlation could be ascertained between the effect of substituents on the 2-phenyl ring of the 2-arylbenzothiazole and the yield of the product. m-Br Substituted 2-arylbenzothiazole 6 provided the o-aroylated product 6a′ with the reaction occurring at the less sterically hindered o-site as a result of a favorable cyclopalladation step.
The presence of the strongly electron-withdrawing –CF3 substitient on the benzothiazole ring of 8 provided a comparable yield of 8a′ to that of electro-neutral substrate 1 (Scheme IV.3.1).
2-Phenylbenzoxazole (9), a structural analogue of 2-phenylbenzothiazole (1) provided o- aroylated product 9a′ in low yield (44%), even by using an excess amount of Pd(OAc)2 (15 mol %) and after a prolong reaction time (48 h). Similarly, p-Me substituted 2- phenylbenzoxazole (10) gave a meager yield of 40% under the identical conditions (Scheme IV.3.1). However, for substrate (9) well established oxidants14 such as AgI failed to give the desired product, whereas the use of persulfate (S2O82−) gave comparable yield to that by using CAN. The usefulness of CAN as an oxidizing agent was then successfully applied to directing arene 3,5-diphenylisoxazole (11). 3,5-Diphenylisoxazole (11) with N or O-chelating atoms provided expected o-aroylated product (11a′) but in lower yield (37%). The product yields for these oxygen containing N-directed substrates 9, 10 and 11 are less than those of the sulfur containing N-directed substrates (Scheme IV.3.1). Because of its oxophilic nature, the cerium atom possibly remains bound to oxygen atom of oxygen containing directing arenes, thereby making it unavailable for the oxidative addition and giving lower yields. However, directing arene that contains two nitrogen atoms, as in the case of 2,3-diphenylquinoxaline (12), provided the o-aroylated product (12a′) in good yield (71%) under the optimized reaction conditions. It is worth noting that none of the above-mentioned directing groups have been
Further o-aroylations of directing arenes 1 and 12 were carried out with substituted phenylglyoxylic acids. p-Me Substituted phenylglyoxylic acid b' coupled efficiently with both the directing arenes 1 and 12 to provide their desired products 1b′ and 12b′ in almost identical yields (Scheme IV.3.1). The coupling reaction of p-Cl substituted phenylglyoxylic acid c' with 1 and 12 proceded better than those of p-Me substituted phenylglyoxylic acid b' and provided o-aroylated products 1c′ and 12c′.
Scheme IV.3.1. Substrate scope for decarboxylative o-aroylationa,b
aReaction conditions: directing arenes (0.25 mmol), α-keto acids (0.30 mmol), CAN (0.38 mmol) at 110 oC for 8 h. bIsolated yield. cThe rest is recovered starting materials.
dReactions were performed for 48 h using 15 mol % Pd(OAc)2. eDCE used in lieu of DMF.
Mechanistic studies. When a typical o-aroylation of 1 was carried out in the presence of radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 1 equiv), significant reduction in the product yields (>5 %) were observed along with the detection of TEMPO- ester (A) supports the formation of an aroyl radical (Scheme IV.3.2).
Scheme IV.3.2. Reaction in presence of radical scavenger TEMPO
When the o-aroylation of 1 was carried out in the presence of 1, 1.5, and 2 equiv of oxidant (CAN) under otherwise identical conditions the isolated yields of the product after 12 h were 56%, 68% and 69% respectively. These experiments suggest a minimum requirement of one equiv of oxidant for this transformation, thereby indicating a PdII/PdIII catalytic cycle.17 Taking cues from the above experimental observations, plausible mechanisms can be speculated for this decarboxylative o-aroylation reaction (Scheme IV.3.3).
Pd O N O C
Pd O N O C
COPh
CH3 CH3
III
III
oxidative addition
cyclo- palladation (I)
(II)
Ph O Ph
O 2 CAN
S N H
N CH
N CH
Pd O N O C
Pd O N O C
CH3 CH3
II
II
COPh
Pd O N O C
Pd O N O C
COPh CH3 CH3
III
II
(III) N
CH
Pd N CH
+ N
CCOPh
N CCOPh
OCOCH3
OCOCH3 2
2 O
OH
CO2
(1) (a')
(1)
(1a')
(1a')
Scheme IV.3.3. Proposed mechanism for o-aroylation
For o-aroylation process, the initial cyclopalladation of 2-phenylbenzothiazole (1) leads to the formation of acetate bridged binuclear PdII intermediate I (Scheme IV.3.3). This dimeric PdII complex further undergoes a bimetallic oxidative addition with the in situ generated aroyl radical that is obtained by the action of CAN with phenylglyoxalic acid (a') with concurrent decarboxylation. The proximity of the two Pd-centers might facilitate cooperative redox chemistry; in which both metals participate synergistically to lower the barrier of the redox transformation. The oxidative addition product is a dimeric Pd(III)17 intermediate II.
Although the formation of a monomeric Pd(IV)18 species in the reaction medium via the Pd−Pd cleavage in dimeric Pd(III) intermediate II can not be overrulled. A reductive elimination leads to the o-aroylated product and forms the active dimeric species III.
Intermediate III further releases another o-aroylated product by C−C bond formation and regenerates dinuclear PdII active species II for the next catalytic cycle.
In summary, we have demonstrated the use of the inexpensive terminal oxidant CAN as an efficient substitute for a set of expensive oxidants/additives in the Pd-catalyzed substrate- directed decarboxylative o-aroylation processes. Mechanistic investigations reveal a radical pathway for this process.