Heck 5- 2,3-dihydrofuran

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-... 

Scheme 7.2 Heck reactions of dihydrofuran with aryl or alkenyl triflates with R)-BITIANP.

Scheme 7.5 Heck reactions of dihydrofuran with phenyl- or cyclohexenyl-triflates with (benzo)thiophene-containing phosphinooxazoline ligands.

In 2004, Molander et al. developed another type of chiral sulfur-containing ligands for the intermolecular Heck reaction. Thus, their corresponding novel cyclopropane-based phosphorus/sulfur palladium complexes proved to be active as catalysts for the reaction between phenyltriflate and dihydrofuran, providing at high temperature a mixture of the expected product and its iso-merised analogue (Scheme 7.7). The major isomer C was obtained with a maximum enantioseleetivity of 63% ee. 

Scheme 7.7 Heck reaction of dihydrofuran with phenyltriflate with cyclopropane-based phosphorus/sulfur ligands.

Scheme 7.8 Heck reactions of dihydrofuran with aryltriflate with S/P-ferrocenyl ligand.

A novel phosphinito dipeptido ligand series were prepared, and fully characterized. These ligands readily form metal complexes with Pd(H) and Pt(II) precursors. The Pd(II) complexes were investigated for their suitability in asymmetric Heck reaction using 3,4-dihydrofuran as a substrate. 

Pd complexes 9-12 were tested for their catalytic behavior in the asymmetric Heck reaction involving the phenylation of 2,3-dihydrofuran (Scheme 3). The results are summarized in Table 2. The two isomeric products of 2-phenyl-2,5-dihydrofuran are formed with varying yields from 80% to 0%. The obtained ee s are high. Complex 12 is shown to be catalytically inactive. The lack of catalysis in complex 12 is rationalized by differences in the steric requirements between the diphenylphosphinites 1-3 (cone angle >140°) and the more sterically hindered cyclohexyl-phosphinite 4 (cone angle >170°) and the resulting stereochemistry on the Pd center. The ligands in complex 12 adopt a... 

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.

General procedure for the Heck reaction. A mixture of iodobenzene (5 mol equ.), diisopropylethylamine (3 mol equ.), 2,3-dihydrofuran (1 mol eq.), and the complexes 9-12 (3 mol %) in degassed benzene was stirred at 70 °C. The progress of the reaction was monitored by GC. Upon completion, the mixture was filtered through basic alumina (58 mesh, Aldrich) to remove Pd and the products were identified using GCMS. 

A short five-step synthesis of a bifuran, namely ( )-2,2 -bis(diphenylphosphino)-3,3 -binaphtho[2,l-I>]furan (BINAPFu) from naphthofuranone via a low-valent titanium-mediated dimerization was reported. The newly developed resolution procedure for phosphines was utilized to provide the optically active bidentate phosphine ligands (BINAPFu), which consistently outperforms BINAP in the asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate . Another way in which a benzofuranone can be converted into benzo[7 ]furan is by treatment of the former with 1-BU2AIH at -78°C followed by an acidic work up <00TL5803>. 

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). 

Regio- and enantioselective Heck reactions of 2 3-dihydrofuran with aryl and alkenyl triflates in the presence of the chiral ligand (R)-BITIANP provides 2-substituted 23-dihydro-furans with complete regioselectivity, high enantioselectivity (86-96% ee) and good yields (76-93%) <99CC1811>. A catalytic oxyselenylation-deselenylation reaction of alkenes offers a stereoselective one-pot conversion of alkenes into 2 -dihydrofurans <99EF0797>. 

The catalytic asymmetric arylation (Heck reaction) of 2,3-dihydrofuran to give (/J)-2,3-di-hydro-2-phenylfuran which, upon Jones oxidation, yields (/ )- 2 (for assignment, see p 439)80. 

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. 

Asymmetric Heck-type ary lotion.1 A catalyst prepared in situ from Pd(OAc)2 and (R)-BINAP effects a highly enantioselective arylation of 2,3-dihydrofuran with aryl triflates with diisopropylethylamine as base and benzene as solvent. Two products (2 and 3) are formed with opposite configurations. The highly enantioselective formation of the major product (2) is ascribed to a kinetic resolution step which converts the enantiomer of 2 into 3. 

These cationic conditions are also used for intermolecular Heck olefinations in which the chiral centers are generated via double-bond migration. The synthesis of 2-aryl-2,3-dihydrofurans 17 is a good example (Scheme 9) [26]. 

As p-hydride elimination is reversible, hydropalladation with the opposite regiochemistry provides a mechanism for forming regioisomers of the alkene. This allows the most stable alkene that is accessible by the hydropalladation-dehydropalladation sequence to dominate. The only restriction is that all of these processes are syn. The migration can be prevented by the addition of bases like silver carbonate, which effectively removes the hydrogen halide from the palladium complex as soon as it is formed. This synthesis of a complex trans dihydrofuran involves the Heck reaction followed by alkene isomerization and then a Heck reaction without migration to preserve the stereochemistry. 

In an interesting example of the first asymmetric Heck reaction,6 using sulfoxides as chiral auxiliaries, Carretero et al.145 have recently used a new chiral sulfoxide, obtained by the DAG methodology. The palladium-catalyzed arylations of 4-arylsulfinyl-2,3-dihydrofurans 102 have shown that the stereochemical outcome of the reaction is highly dependent on the substitution of the sulfoxide. Thus, independently of electronic substitution of the aryl iodide, different aryl sulfoxides... 

A palladium-mediated annulation of Y-( o-bromoary l)pyrroles across strained alkenes led to the formation of pyrrolo[l,2-a]quinolines <07OL1761>. An intramolecular Heck reaction involving tethered iodoarenes produced an entry to pyrrolo[2,3-t/][2]benzazepin-7-ones, analogues of the pyrrole natural product latonduines <07T867>. A Heck reaction of a 3-iodopyrrole with a 2,3-dihydrofuran provided pyrrole deoxyribonucleosides <07T12747>. 

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. 

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