2.3- Dihydrofuran, Heck coupling

Scheme 3 Asymmetric Heck coupling of 3,4-dihydrofuran and iodobenzene in the presence of Pd complexes 9-12 giving a mixture of regio and stereo isomers a) 2(R)-phenyl-2,3-dihydrofuran, b) 2(R)-phenyl-2,5-dihydrofuran c) 2(S)-phenyl-2,3-dihydrofuran d) 2(S)-phenyl-2,5-dihydrofuran.

The phosphine-thiazole ligand 149 has been shown to promote asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates <07ASC2595>. Microwave irradiation of a mixture of 2,3-dihydrofuran (6 equiv.), aryl triflates (1 equiv.) and DIPEA (3 equiv.) in THF in the presence of Pd2(dba)3 (3 mol%) and the ligand 149 (6 mol%) at 120 °C provides 2-aryl-2,5-dihydrofurans 150 in high enantioselectivity. Other phosphine-thiazole ligands have also been evaluated, and ligand 149 proves to be the best in terms of enantioselectivity. 

Scheme 3-49 Ligand-induced asymmetric Heck coupling of 2,3-dihydrofuran [205-207],...

Table 5. Yields obtained for Matsuda Heck coupling between the p-methoxyphenyl diazonium salt and 2, 3-dihydrofurane using Pd2(dba)s.CHCl3 or [Pyr]2[PdCU] as catalyst (1 % mol) in microemulsions I, II, IE and IV formed with bnPyrNTf2 (on line (a) of Figure 8) at 27°C. Standard deviation on yields was around 2%.

In 1996, the first examples of intermolecular microwave-assisted Heck reactions were published [85]. Among these, the successful coupling of iodoben-zene with 2,3-dihydrofuran in only 6 min was reported (Scheme 75). Interestingly, thermal heating procedures (125-150 °C) resulted in the formation of complex product mixtures affording less than 20% of the expected 2-phenyl-2,3-dihydrofuran. The authors hypothesize that this difference is the result of well-known advantages of microwave irradiation, e.g., elimination of wall effects and low thermal gradients in the reaction mixture. 

Larhed et al. investigated enantioselective Heck reactions with 2,3-dihydrofuran as alkene [86]. In the coupling with phenyl triflate, conditions previously reported by Pfaltz [87] were attempted under microwave irradiation. Interestingly, the catalytic system Pd2(dba)3/(4S)-4-t-butyl-2-[2-(diphenylphosphanyl)phenyl]-4,5-dihydro-l,3-oxazole, identified by the Swiss team, was found suitable for high-temperature microwave-assisted enantioselective Heck reactions (Scheme 76). Using a proton sponge as a base and benzene as a solvent gave the best conversions (Scheme 76). At tempera-... 

Reactions of aryllead triacetates with olefins (Heck-type reactions) proceed similarly but do not require Cul as co-catalyst. From the numerous reported reactions, that of phenyllead triacetate with 2,3-dihydrofuran is mentioned as a typical example. This affords the C-C coupling product 27 in 68% yield, together with 10% of the homocoupling product (Equation (ll)).47... 

Using NMR the same authors have identified several intermediates in the asymmetric Heck arylation of dihydrofuran [23, 24]. Reaction of the Binap salt, 30, with 2,3-dihydrofuran below 233 K gave salt 31 as the single species (see Figure 1.8). A parallel reaction between 30 and [2- H] 2,3-dihydrofuran confirmed the structure. At 243 K, 31 slowly decomposed to form 32 and 32 with concomitant release of the coupling product 33 (91% ee). 

As mentioned previously, the partially reduced forms of five membered heteroaromatic systems might act as olefins in insertion reactions. This behaviour is characteristic particularly of dihydrofuranes. The olefin insertion and the following / hydride elimination should in principle lead to a trisubstituted olefin, which is rarely observed, however. Typical products of this reaction are 2-aryl-2,3-dihydrofuranes. A characteristic example of such a reaction is presented in 6.54. The coupling of 4-iodoanisole and dihydrofurane led to the formation of the chiral 2-anisyl-2,3-dihydrofurane in excellent yield.83 The shift of the double bond, which leads to the creation of a new centre of chirality in the molecule, opens up the way for enantioselective transformations. Both intermolecular and intramolecular variants of the asymmetric Heck reaction have been studied extensively.84... 

A similar procedure was employed in the asymmetric Heck-type coupling of iodonium salt 81 with 2,3-dihydrofuran (Scheme 38) [65]. When carried out in the presence of the chiral bidentate ligand (R)-BINAP, this reaction afforded optically active (up to 78% ee) coupling product 82 in moderate yield. 

The selectivity of the Heck reaction shows up with unsymmetrical dienes, leading to initial coupling at the less-substituted alkene and then nucleophile addition at the other end (equation 65). The intramolecular Heck reaction also is efficient, leading in equation (66) to dihydrofurans. 

A Heck-type coupling of 2,3-dihydrofuran with a secondary chloroacetamide produced the two double bond isomers in about 2 1 ratio <03TL5751>. A palladium-catalyzed Heck-type coupling between the heterocyclic iodide shown below and 2,3-dihydrofuran was used as Ae key step in the synthesis of C-nucleosides. Conditions were optimized to include AgjCOj to prevent double migration and thereby obtain a good yield of the desired 2,5-dihydrofuran products <03JMC1449>. 

Vinylation of heteroaryl triflates also possible. Vinyl halides can be coupled to alkenes to form dienes. " The reaction of dihydrofurans with vinyl triilates and a palladium catalyst leads to a nonconjugated diene, 33. This example illustrates that the product is formed by an elimination step, as with the Heck reaction (13-10), and double bond migration can occur resulting in allylic rearrangement. 

Fu and coworkers have utilized their very successful catalytic mixture of Pd2(dba)3/P(t-Bu)3/Cy2NMe to effect the Heck couphng between the 3-chlorothiophene 261 and 2,3-dihydrofuran at room temperature to furnish 2-thienyl-2,3-dihydrofuran 262 in 87% yield [174]. The coupling proceeded as expected, but olefin isomerization occurred. 

As with N,N ligands, P,S ligands have not received much attention in the area of the Mizoroki-Heck reaction. However, there are a couple of reported examples. Kang et al. [53] applied the pseudo-C2-symmetric P,S-hybrid ferrocenyl ligand 85 to the phenylation of 2,3-dihydrofuran (1). However, low conversions (<37%) and low enantiomeric excesses (<34%) were achieved. Molander et al [54] applied cyclopropane-based P,S ligands 86 and 87 to the same reaction. Excellent conversions (np to 99%) and moderate enantiomeric excesses (up to 60%) were obtained. 

Two new fluorous chiral 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl (BINAP Table 15.1, entries 11 and 12) ligands were synthesized and their efficiency was demonstrated in an asymmetric Mizoroki-Heck reaction (Scheme 15.8) [74-76]. Aryl triflates 38 were coupled with 2,3-dihydrofuran (39) to (i )-40 in up to 93% ee. Either pure fluorous solvents or mixtures of fluorous and nonfluorous solvents were applied. Ligand 34 was compared with conventional BINAP, with the fluorous ligand giving lower reaction rates and a similar level of enantioselectivity in 24-77 h reaction time [74, 75]. The catalyst could not be recovered by reverse-phase silica gel chromatography due to its oxidation. 

Miura and coworkers reported the first palladium catalyzed intermolecular carbonylative Heck reaction of aryl iodides and five membered olefins in the presence of carbon monoxide (Scheme 1.28) [99]. The expected 2,5-dihydrofuran product was not observed in the carbonylative coupling of 4-iodoanisole and 2,3-dihydrofuran as depicted in Scheme 1.28. Instead, isomerization of the double bond via reinsertion of the palladium(II) hydride followed by another ]S-hydride elimination formed the vinyl ether exclusively. 

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