Ligandless conditions

Employing Jefferey s ligandless conditions, Larock and Babu (87TL5291) synthesized quinolines and other nitrogen-containing heterocycles via the intramolcular Heck reaction strategy as exemplified by reaction 144 145. This reaction is similar to the Mori-Ban indole... 

Overman s group [71,72] enlisted an intramolecular Heck reaction to form a quaternary center in their efforts toward ( )-gelsemine. When the cyclization precursor 70 was submitted to the ligandless conditions [Pd2(dba)3, Et3N] in the weakly coordinating solvent toluene, the quaternary center was formed as a 9 1 ratio of diastereomers (72 71 = 89 11). Addition of a silver salt in polar solvent THF completely reversed the sense of asymmetric induction in the cyclization reaction (72 71 = 3 97). 

The major improvement compared to the Rh(I) catalysts was the ability of the Cu(I)/RB (OR )2 system to also carboxylate alkenyl-boronic esters in very good yield, under similar conditions. Interestingly, the system functioned better under ligandless conditions, producing the corresponding unsaturated carboxylic acids in good yields. 

As shown in Scheme 45, DMSB can undergo polymerization or dimerization in the presence of similar platinum catalysts in good to excellent yields. The course of the reaction is apparently linked to the presence or absence of phosphine ligands platinum complexes that include added phosphines lead to dimerization, whereas polymerization usually occurred under ligandless conditions. Divinyltetramethyldisiloxane also serves as a ligand for the platinum-catalyzed dimerization of SCBs and disilacyclobutanes as reported by Chu and Frye <1993JOM(446)183>. 

Bromo- and iodoimidazoles are useful intermediates for further functionalization. 4(5)-Aryl- I //-imidazoles 57 can be efficiently and selectively prepared by palladium-catalyzed Suzuki-Miyaura reaction of commercially available 4(5)-bromo-l//-imidazole 56 with arylboronic acids under phase-transfer conditions, which then underwent highly selective palladium-catalyzed and copper(I) iodide mediated direct C-2-arylation with a variety of aryl bromides and iodides under base-free and ligandless conditions to produce 2,4(5)-diaryl-l//-imidazoles 58 in modest to good yields <07JOC8543>. A new procedure for the synthesis of a series of substituted 2-phenylhistamines 60 utilizing a microwave-promoted Suzuki... 

The coupling reaction is believed to proceed via an activated hypervalent organostannate intermediate prepared in situ by adding a fluoride source. Comparison between PPhj, P(/-Pr)3, and AsPhj, in conjunction with Pd2dba3, showed that the highest yields in the desired products are obtained under ligandless conditions. 

T. Jeffery, Tetrahedron Lett., 1985, 26, 2667 J. Chem. Soc., Chem. Common., 1984, 1287 and R. Larock and B. E. Baker, Tetrahedron Lett., 1988, 29, 905. These reaction parameters are sometimes referred to as Jeffery s ligandless conditions. ... 

Equations 12.45103 and 12.46104 show two examples of intramolecular Heck olefination. In the first case, under Jeffrey s ligandless conditions, the Pd catalyst also acts to isomerize a C=C bond to give a final product that has the C=N bond in conjugation with the aromatic ring. The second example demonstrates how the Heck reaction can cause alkynes as well as alkenes to undergo 1,2-insertion. The transformation is also a nice application of tandem Pd-catalyzed reactions to create a rather complex ring system. 

Under ligandless conditions, 3-thiophenetrifluoroborate (23) was treated with 2-bro-mopyridine and 3-broniopyridine in the presence of 1% palladium acetate to afford the coupled thiophenes 121a and 121b in 60 and 68% yield, respectively [84],... 

It was discovered, however, that the ligandless conditions were highly dependent on the heteroaryl halide substrate [84], For example, 5-acetyl-2-bromothiophene reacted with the thiophene in the presence of PdfOAcij to furnish the desired product in 84% yield, but efficient coupling with the more electron-rich 2-bromothiophene required the use of PdidppfjCIj. Other heterocyles were coupled to 23, but these also required the use of Pd(dppf)Cl2 as shown in the table below. 

Under ligandless conditions PdCl2 catalyzed the hydrogenolysis of several 4-substituted aryl chlorides in alkaline aqueous solutions using NaH2P02 as reductant (Scheme 3.40) [275]. In case of certain ortho-substituted substrates, such as 2-chlorophenolate and 2-chloroaniline, strong chelation in the intermediate palladacycle completely inhibited the reaction. On the other hand, in case of 2-chlorobenzoic acid addition of iodide led to 86 % yield of benzoic acid. 

Scheme 34 Direct C3-arylation of NH-free indoles under ligandless conditions.

Cyclization of the quinoxaline chloride 50 to prepare pyrrolo[2,3-f ]quinoxaline under usual conditions is slow and the yield is low, because the aminoquinoxa-lines are strong chelating agents and poison Pd catalysts. However, the locked Pd catalyst is released and the reaction proceeds smoothly under Jeffery s ligandless conditions to give the pyrrolo[2,3- ]quinoxaline 51 in 67 % yield [38]. 

Interestingly, HR of < -bromobenzaldehyde (93) with acrylate gave the doubly substituted product 94 and the expected product 95 under Jeffery s ligandless conditions [60]. Eormation of 94 is explained by the following mechanism. Insertion of acrylate to 93, followed by oxidative addition of aldehyde generates 96. The palladacycle 97 is formed by decarbonylation, and its reductive elimination gives 98. The final product 94 is obtained by HR of 98 with acrylate. 

The Stille reactions with aryldiazonium tetrafluoroborates are performed under the ligandless conditions in the presence of simple palladium-complexes, Pd(OAc)2 or Pd(dba)2. For example, phenyltri-n-butylstannane (184) was reacted with 4-tolyl diazonium tetrafluoroborate (185) to afford 4-methylbiphenyl (139) in 59% yield [107], Scheme 26. 

Aminations of pyridyl systems, as well as related heteroaromaties (e.g., bromopyrimidines), have been achieved in moderate-to-good 3delds under ligandless conditions using Cu powder in the presence of CsOAc in DMSO. Both iodides and bromides serve equally well both primary and secondary amines can be used and the procedure is insensitive to both air and moisture. 

In the quest for coordinatively unsaturated palladium catalysts, the more radical approach uses ligandless conditions [165, 166] following the work pioneered by Beletskaya [38b, 167]. However, the mechanism of cross-coupling reactions under these conditions is not known [168]. 

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