Download (direct link):
2.2. HECK REACTION16
2.2.1. Early Work
In one of the earliest papers with a specific intent to demonstrate the feasibility of palladium-catalyzed reactions on solid supports, Yu et al. showed the production of simple coupled products by the Heck reaction (Scheme l).17 It was noted that the Heck reaction conditions are usually mild, do not require anhydrous or inert atmospheric conditions, and that the reaction is therefore suited to automation. By attaching to Wang18 resin either 4-vinylbenzoic acid or 4-iodobenzoic acid and then subjecting these functionalized supports (1 and 2) to the appropriate coupling partner (either aryl halides/triflates or olefins/phenylacetylene), the reaction was successfully demonstrated in good to excellent yield. The catalyst system varied according to the reagents, but was based around either Pd(OAc)2 with no added phosphine or Pd2(dba)3, and required heating overnight. It had been previously shown that the presence of a phase transfer agent (PTA) allowed
28 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
2.2. HECK REACTION 29
the solution-phase Heck reaction to proceed at mild temperatures,19,20 but in these solid-phase cases the reaction appeared to require heating despite the presence of tetrabutylammonium chloride.
Unsuccessful couplings arose when resin-bound olefin was reacted with aryl triflates (presumably reflecting the lower reactivity observed in solution) and also when resin-bound iodide was reacted with ethyl propionate, where polymerized products were observed. Interestingly, attempts at tran-sesterification as a means to release the products were unsuccessful. The stereochemistry (i.e., cis/trans) of the products was not addressed.
A later report demonstrated similar chemistry under milder conditions.21 The apparently reduced effectiveness of the PTA in the previous work was noted, as was a further report where Pd/M2C03/PTA had been demonstrated to catalyze the Heck reaction in water in excellent yield under mild conditions.22 This chemistry was therefore adapted to the solid phase. After tethering 4-iodobenzoic acid to TentaGel resin, the reaction with ethyl acrylate was examined and found to be successful with the conditions shown in Scheme 2. Initial attempts to run the reaction in neat water failed to convert starting material to product in much more than about 50% yield, but introduction of a DMF-water solvent mixture solved this problem. The chemistry was adapted for the coupling of a number of olefins (generally those with attached electron-withdrawing groups). In contrast to the previous report, where these reactions were shown with reversal of polarity (i.e., the reaction of solution-phase iodides and bromides with resin-bound 4-vinylbenzoic acid), no products were obtained in these reversed cases.
(³) Pd(OAc)2, PPh3 sat. K2C03, Bu4NCI or
Bu4NBr, 9:1 DMF:H20 hq> 37 °Ñ, 4 h
(ii) 0.1 M NaOH
30 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
2.2.2. Indole and Benzofuran Formation
The most widely applied method for indole formation, the Fischer indole synthesis, has been shown on solid support.23 Following a report of the ability of tetramethylguanidine (TMG) to promote palladium-catalyzed coupling and cyclization in the solution-phase one-pot synthesis of 2-un-substituted benzofurans,24 this methodology was used in the synthesis of a number of indoles on solid support with high yields and under mild reaction conditions.25 A pilot solution-phase study to identify effective conditions found a solvent system of TMG-dioxane at 80°C promoted the coupling and cyclization with a mixed catalyst system of PdCl2(PPh3)2 and Cul in 18 h (Scheme 3).
Transfer of these reaction conditions to TentaGel was possible, albeit the conditions involved a slight increase in temperature (Scheme 4). Yields varied from 48 to 95%, with the only observed by-product resulting from incomplete cyclization, implying almost quantitative conversion for the palladium-catalyzed step. The sequence appears to be robust and rapid.
In a follow-up communication,26 similar chemistry was used for the production of 2-substituted benzofurans beginning not with an anthranilic acid derivative, but with a resin-bound ortho-hydroxy aryl iodide 3. In the solid-phase work, depicted in Scheme 5, the relevant carboxylic acid was linked to TentaGel via a Mitsunobu reaction, and after deprotection was seen to undergo smooth Heck coupling and cyclization, giving essentially pure compounds in 40-70% overall yield after cleavage.
In a simple extension of this indole work, Collini and Ellingboe27 introduced an extra element of diversity by using a method originally exemplified in solution.28 This allowed for the synthesis of trisubstituted indoles. The method, shown in Scheme 6, involves the Sonogashira palladium/copper co-catalyzed step to introduce the initial alkyne diversity. After conversion of the aniline group to the trifluoroacetamide, a second palla-