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cat. PdCI2(PPh3)2, Cul TMG/dioxane, 80 °Ñ, 18 h
2.2. HECK REACTION 31
TMG/dioxane NHAc PdCI2(PPh3)2 Cul, 90 °Ñ, 18 h
dium-catalyzed step, in which there is included the vinyl triflate of a second element of diversity, allows for limited functionality at the Ç-position also. The nitrogen may be alkylated using NaH and the appropriate organohalide. The method allows for the production of complex indoles such as 4, with a
R= ^NE12 ^NH2
°H II I
PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
I cat. PdCI2(PPh3)2, Cul Et2NH, DMF, 2 h
2 (ii) (CF3C0)20, pyr CH2CI2, 2 h
R OTf, cat. Pd(PPh3)4
K2C03, DMF, 24 h
D1 (i) R3X, NaH, DMF, 4 h
(ii) TFA, CH2CI2, 2 h
number of other examples being given of successful syntheses in low to good overall yields.
The indole pharmacophore has attracted further attention in the work of Zhang et al. (see also below, Scheme 10), who used the route developed by Larock29 for the heteroannulation of internal alkynes with o-iodoanilines (Scheme 7).30 The cyclization proceeded well on the solid phase. In the case of unsymmetrical alkynes, the predominant species was the expected one with the more sterically demanding group in the 2-position.
In a useful extension to this chemistry, the coupling of the starting iodoaniline with trimethylsilylalkynes was found to give the silylated species 5, which can bp a useful precursor to either 2-unsubstituted indoles or 2-halogenated derivatives as shown in Scheme 8. These could then be taken on further with standard organometallic coupling reactions.
2.2. HECK REACTION 33
NH LiCI or Bu4NCI, base, PPh3
2 cat. Pd(OAc)2/PPh3 DMF, 80 °Ñ, 12 h
In another investigation featuring the indole nucleus, the related 2-oxin-dole pharmacophore was shown to be easily derived using the synthesis shown in Scheme 9, involving an ø´ãàòî³åñè¿àã Heck reaction to close the second ring.31 The resin-bound iodoaniline 6 was derivatized first with a reductive alkylation, followed by coupling with an a,(3-unsaturated acyl chloride. This established a substrate for the pivotal Heck reaction, using 30 mol % Pd(OAc)2 at 100°C in DMF. Cleavage (TFA) and product analysis showed that, save for acryloyl chloride cases (R2 = H), yields and purities were good. In all cases more (E) double bond isomer was produced than (Z). No special washing conditions were needed after the palladium coupling step, and no problems with palladium black deposition were observed.
Zhang et al.32 constructed compounds with either an indole or benzofuran nucleus in a similar way using the support-bound intramolecular Heck reaction. Their strategy was based on cyclization of 7V-allyl-substituted <?r^<9-haloanilines to indoles in solution.33,34 Having found that orthoiodides underwent the solution-phase coupling with greater ease than the corresponding ortho-bromides, they set about applying their chosen reaction conditions to the solid phase (Scheme 10). It was noted that the presence of tetrabutylammonium chloride and water appeared to help the solution-phase reactions.
If the allyl nitrogen were unalkylated, the reaction went in lower yield (60%) than its solution-phase counterpart (80%), and a variety of unidenti-
34 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
30 mol% Pd(OAc)2 Ag2C03, PPh3, DMF
100 °Ñ, 16h
fied products were formed. It has been shown that TFA can induce the dimerization of indole 3-acetic acid and its methyl ester.35 To avoid this possible complication, the same reaction was attempted but with an allyl N-alkylated material (the alkylation was performed on resin), with the desired indole 7 being formed in 88% yield after 24 h at 80°C, using PdCl2(PPh3)2 as the catalyst. No exocyclic double bonds were observed. This implies that the initial (5-hydrido elimination product was subject to a further addition (by PdH) to give a new G-adduct which could effect double