4- Aryl-2,3-dihydropyrroles

In these Heck reactions some degree of enantioselectivity (up to 83% ee) is achieved in the presence of (/ )-BINAP, although the yields of Heck products are often very low in the highest degree of enantioselectivity (e.g., 19% isolated yield at 83% ee) [93]. An example of a tandem Heck reaction is shown below involving the arylation of dihydropyrrole 132 with 1-naphthyl triflate (133) [92]. Complete chirality transfer is observed for the arylation of 134 to 135. 

With regard to the Pd-catalyzed arylation of dihydropyrroles presented in Section 2.5, it is noteworthy that the readily available 2,5-dihydropyrroles 197 can be smoothly isomerized to 2,3-dihydropyrroles 198 under the influence of Pd [144],... 

Scheme 6.86 Typical 2-aryl-2,5-dihydropyrrole derivatives prepared with the asymmetric [3 + 2] cycloaddition between buta-2,3-dienoic acid ethyl ester and various DPP-protected (hetero)aromatic imines catalyzed by phosphinothiourea 75.

Alkynyl azomethine ylides containing an aryl bridge have been shown to undergo cyclization. Thus, tautomerization of imine (137) afforded an azomethine ylide which cyclized to give two diastereomeric dihydropyrroles and traces of aromatized product (Scheme 42).56 The activated cyclic ylide (138), generated via the desilylation route, underwent cyclization to afford dihydropyrrole (139) in 42% yield.67b The structure of (139) is closely related to erythramine. The structurally related non-stabilized azomethine ylide (140) did not cyclize, tautomerizing to the corresponding enamine instead. 

A method was proposed [196] for the production of 4-phosphazenyl-2,3-dihydropyrrol-2-ones and 5-phosphazenyl-2-pyridones from p-(N-acylphosphazenyl)enamines of dimethyl acetylenedicarboxylate. The authors of [197] examined the chemoselective cycloaddition of C-aryl-N-phenyl nitrones at the 1,2 double bond of allenylphosphonates, leading to a mixture of adducts possessing pyrrolidine and isoxazolidine structures. 

Most of the important general methods for forming 1H-1,2,3-triazole derivatives involve the thermal 1,3-dipolar cycloaddition of hydrazoic acid or organic azides to suitable dipolarophiles (69CRV345,74AHC(16)33). For example, the cycloaddition of aryl azides to l-alkyl-2,5-dihydropyrroles gives pyrrolo[3,4-rf][l,2,3]triazoIes (equation 34) (80JHC267). 

The methods described for arylation of dihydrofurans (see above) have also been applied to 2,3-dihydropyrroles such as 63 [55], with similar patterns of re-gio- and enantioselectivity being observed. Thus little or no ee was obtained when using aryl iodides, but aryl triflates gave mixtures of 2-aryl-2,3-dihydro-pyrroles 64 and 2-aryl-2,5-dihydropyrroles 65, with the former predominating and the kinetic resolution process again being in effect, as evidenced by another inverse relationship between the ee of 64 and the 64 65 ratio (Scheme 16). The reaction was also successfully extended to vinyl triflates, which gave even better ee s than obtained for the dihydrofurans [50]. 

An example of a reaction with 2,5-dihydropyrroles has also been recently disclosed [56]. Arylation of 66 using 1-naphthyl triflate and an (i )-BINAP/ Pd(OAc)2/z-Pr2NEt system in DMF gave the 3-arylation product 67 (Scheme 17) with moderate yield and ee. It was found that the addition of excess acetate served to suppress formation of the undesired 2-arylation product (which was formed after initial isomerization of the double bond in 66), and this was conveniently achieved by adding TlOAc, with the thalHum cation acting as a co-catalyst. Unfortunately, attempts to carry out this reaction with other aryl triflates or with aryl iodides were unsuccessful. 

The application of ligand 102 has successfully been extended to derivatiza-tions of nitrogen containing substrates. Arylation of the 2,3-dihydropyrrole 63 with phenyl triflate catalyzed by the 102-palladium complex [R=C(CH3)3] produced the single isomer 65 with 88% yield and in 85% ee [81]. 

Dihydropyrroles and indoles. The salt reacts with tosylamide anions to provide five-membered heterocycles via carbene intermediates. When a nucleofugal group (methoxy is sufficient) is present at the bond insertion point, automatic elimination gives a pyrrole as the product. Insertion into an aryl C-H bond leads to an indole. 

Ibuka et al. observed that under the catalysis of Pd(PPh3)4 (4-20 mol%), optically active 2,3-allenyl amines 20 can be cyclized in the presence of aryl halides in DMF (Scheme 8). The chirality of the allene moiety was smoothly transferred into the final products, i.e., 2,5-dihydropyrrole [8]. 

Azomethine ylides can also be trapped by aryl trifluoromethyl alkynes. When l-t-butyl-2-cyano-aziridine was used, a pyrrole was formed by elimination of hydrogen cyanide <94S287>. Use of aziridine-2-carboxylate esters with this dipolarophile gave regioisomeric mixtures of dihydropyrroles which could be converted to pyrroles by oxidation with ddq (Equation (60)). 

Two further examples for arylation reactions catalyzed by phosphinooxazoline-palla-dium complexes are shown in Scheme 31 with the formation of 129 and 131 as nitrogen-containing substrates arylation of the 2,3-dihydropyrrole 63 with phenyl triflate catalyzed by the palladium complex 120 (R = CMcs) gave the single isomer 65 in 88% yield and with 85% ee.[ i... 

While 2,3-dihydrofuran (1) was the initial test substrate of choice for the intermolecular asymmetric Mizoroki-Heck reaction, the reaction was also applied to 2,3-dihydropyrrole 12, which shows similar patterns of both regio- and stereoselectivity to 2,3-dihydrofuran (1) [16], The intermolecular Mizoroki-Heck reaction with substituted 2,3-dihydropynole 12 and aryl triflates 13 gave mixtures of the 2-aryl-2,3-dihyropym)les 14 and the 2-aryl-2,5-dihydropyrroles 15, with the 2,3-product being the major product formed with a 74% ee (Scheme 11.9). 

The alkenyl triflate 8 was reacted with the 2,3-dihydropyirole 12 and the product 16 was formed exclusively in 95% yield and with a greater than 99% ee (Scheme 11.9). Sonesson et al. [17] reported the arylation of 2,5-dihydropyrrole 17 with naphthyl triflate 18 using (1 )-B1NAP (5) and Pd(OAc)2 to give the 3-naphthyl product 19 in 34% yield and 58% ee (Scheme 11.10). 

Sonesson, C., Larhed, M., Nyquist, C. and Hallberg, A. (1996) Regiochemical control and suppression of double bond isomerisation in the Heck arylation of l-(methoxycarbonyl)-2,5-dihydropyrrole. J. Org. Chem., 61, 4756-63. 

Danger and co-workers used an acid-catalyzed Dimroth rearrangement to prepare. /V-aryl-5-alkylildene-2,5-dihydropyrrol-2-ones. These eompounds are potent inhibitors of serine proteases, and are important intermediates in synthesis of y-laetams and tetramie aeid antibiotics such as pukeleimid A. Treatment of fiiran 100 in THF with and without the presence of lithium chloride gave the eorresponding a,P-unsaturated ketone 101 in 56% and 12% yield, respeetively, illustrating the importance of the acid catalyst for this system. 

A new class of chiral bifunctional thiourea catalysts derived from trans-2-amino-l-(diphenylphosphino)cyclohexane was developed by Jacobsen and Fang in order to be applied to a highly enantioselective synthesis of a wide range of 2-aryl-2,5-dihydropyrrole derivatives. This strategy was based on a [3-1-2] cycloaddition between an A-phosphinoyl imine and an allene in the presence of TEA and water as additives. High yields combined with excellent enantioselectivities of up to 98% ee were observed in all cases of substrates, as shown in Scheme 6.19. 

Jacobsen and Fang have synthesized a new family of diphenylpho-sphinoyl imines (217) and used them in the highly enantioselective imine-allene [3 + 2] cycloaddition raction leading to substituted 2-aryl-2,5-dihydropyrroles (218) (Scheme 16) ... 

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