Negishi E. 2002 Handbook of organopalladium chemistry for organic synthesis / 0409 492

Scheme 14 (Continued )

R1 = Me, Boc, OMe; R2 = H, Me, Ph, COOMe, TMS, CH2OTHP;

R3 R4 = (CH2)5, (CH2)2N(Boc)(CH2)2; R3, R4 = Me, (CH2)2CHCH2, (CH2)3Cl

[I] (i) n- or t-BuLi, −78 °C to 0 °C, (ii) BEt3, −78 °C to 0 °C; [II] 10 mol % Pd(PPh3)4, Cl2Pd(PPh3)2, Pd2(dba)3·CHCl3/PPh3, Pd2(dba)3·CHCl3, Pd(OAc)2, Cl2Pd(MeCN)2, THF, 60 °C, 30 min.

Scheme 16

of substituted benzothiophenes or benzofurans, the initial reaction is a Pd-catalyzed coupling between 4-chloro-2,3-disubstituted-2-cyclobutenones and a 2-stannylthiophene or -furan. The product from the Stille cross-coupling with 4-chlorocyclobutenones is an alkylated heterocycle 33, which is not isolated, but the reaction mixture is heated to 100 °C when a rearrangement takes place with formation of the benzannulated heterocycle 34, presumably via a ketene-like intermediate. Relying on the control inherent in the construction of 4-chloro-2,3-disubstituted-2-cyclobutenones, regioisomeric substituted heteroarenes can be prepared. Several annulated heterocyclic systems including 35 and 36 have been prepared by this methodology.[23],[24]

B.i.e. Carbonylation and Acylations

Tin Derivatives. 3-(Tri-n-butylstannyl)furan can be converted into a 3-furyl ketone 37 either by a Stille-type coupling under CO pressure or by acylation with an acid chloride (Scheme 18).[25] When 3-(phenylethyl)-4-(tri-n-butylstannyl)thiophene was allowed to react with benzyl bromide under an atmosphere of CO, formation of the carbonylated product 38 was accompanied by 13% yield of the symmetrical ketone, bis[4-(phenylethyl)thiophen- 3-yl] ketone.[26] In 3,4-bis(tri-n-butylstannyl)furan 39 selective monoacylation can be achieved with acid chlorides. The ketones can subsequently be further carbonylated.[25]

R = Ph, n-Bu, PhCH=CH, n-hexCH=CH

Bn

Bn O

Sn(n-Bu)3

BnBr Bn

[I] 4 mol % Cl2Pd(PPh3)2 or 7 mol % Pd(PPh3)4, THF, CO (30 psi), 50 °C, 2 d; [II] 4 mol % Pd(PPh3) THF, 60 °C, 2 h; [III] 10 mol % Pd(PPh3)4, CO (25−30 psi), THF, 50−60 °C, 2 d; [IV] 4 mol % Cl2Pd(PPh3)2, THF, 65 −80 °C, 8−24 h.

Scheme 18

Zinc Derivatives. 3-Acylindoles are formed by Pd-catalyzed coupling of a 1,2- disubstituted 3-indolylzinc chloride 40 with a number of acid chlorides to give the corresponding ketones (Scheme 19). The method is recommended for the preparation of acid-sensitive 3-acylindoles. The 3-lithio compound was prepared from the 3-bromide and zincated by means of zinc chloride. The palladium catalyst was prepared in situ by treating a suspension of palladium dichloride with n-BuLi.[27]

[II]

N Me

61−74% R = Me, Bn, n-Pr, Ph 33% for R = CH2Cl

[I] (i) t-BuLi, THF, −78 °C, (ii) ZnCl2, THF, −78 °C to r.t.; [II] (i) 10 mol % Cl2Pd(PPh3)2, n-BuLi, r.t.,10 min, (ii) add RCOCl, −35 °C to 0 °C, 2 h.

Scheme 19

B.ii. Halogenoor Triflyloxy-Substituted Five-Membered Ring Systems

B.ii.a. Arylation

Tin Reagents. The N-protected triflyloxy derivative 41 of pyrrolo[2,3-d]pyrimidine when reacted with an arylstannane affords 5-aryl derivatives (Scheme 20).[28] A closely related reaction has been used in the preparation of the 5-substituted -2 -deoxyribo- sylpyrrolo[2,3-d]pyrimidines 42 from the corresponding C-5 triflate.[29]

Stille couplings involving heterocycles have been effected in aqueous solution using a water-soluble catalyst, which was generated in situ from PdCl2 and KOH (Scheme 21). Whereas halogen substituents on tin strongly retard the Stille reaction in organic media, the opposite effect was seen in aqueous media. It would appear that hydrolysis of the RSnCl3 reagent facilitates both solubilization and C — Sn bond activation. Coupling was reported into the 5-position in furan-2-carboxylic acid as well as into the 4-position in pyridine 43.[30]

Zinc Reagents. Negishi coupling between 2-iodofuran and phenylzinc chloride is a good reaction but the same reaction appears to fail when 2-bromofuran is used as reagent (Scheme 22).[31] Coupling between 2,5-dibromothiophene and 2-furylzinc chloride provides the dicoupled product 44 in high yield.[7]