Palladium-catalyzed N1-selective allylation of indoles with allylic alcohols promoted by titanium tetraisopropoxide

2020-02-29 12:41:33

 


Chieh-Yu Chang, Yu-Huan Lin and Yen-Ku Wu


Indoles are prevailing structural motifs in natural products,  pharmaceutical agents, and organic optoelectronic materials. Given their significance, the selective functionalization of this privileged scaffold continues to be the essence of many synthetic studies.1 In particular, extensive efforts have been undertaken to develop methods for the selective allylic alkylation of indole nucleophiles at N1 and C3 sites.2 The formation of C3-allylated products from simple indoles is generally favored due to the high reactivity of the C3 position toward electrophiles.3 On the other hand, it has been reported that the reaction courses of indolates,  an ambient nucleophile, are strongly dependent on the choice of counter cations and polarity of solvents; for instance, the reaction at N1 was shown to be facilitated with less covalently coordinated metal ions and in a polar medium.4 However, such conventional transformations necessitate the employment of strong bases, thus restricting their scope due to the incompatibility of base-sensitive functional groups.

 

Catalysis by transition metal complexes has emerged as an indispensible approach for the C3-allylation of indoles.5 Despite the poor capability of the hydroxyl group to serve as a leaving group,6 a number of catalytic systems have been devised for the direct allylation of indoles with allylic alcohols; most notably, excellent C3 selectivity had been observed in each of these cases (Scheme 1a).7 Nevertheless, catalytic protocols for the N1-selective allylation of indoles remain rare. Bandini and Umani-Ronchi showed the Pd-catalyzed alkylation of indoles with allylic carbonates could occur at the N1 site by judiciously selecting bases and solvents, however the reaction scope had not been broadly studied (Scheme 1b).8 Recent advances by Stanley and Hartwig were achieved upon strategic installation of an electron-withdrawing substituent to the indole nucleus, which tempers the C3-nucleophilicity as well as increasing N–H acidity (Scheme 1c).9 Other ingenious methods exploiting the N-substitution of indolines or aryl hydrazines require additional transformations to accomplish the formal N1-allylation of indoles.10 Therefore, a general N1-allylation of indoles by catalysis still represents a formidable challenge. It is also worth noting that the N1-selective condensation of indoles and allylic alcohols had been an unsolved problem. Here we report a Pd(0)/Ti(IV)- based tactic that directly addresses this gap in organic synthesis, and present a simple, high-yielding route to a wide variety of N-allylated indoles (Scheme 1d).

 

Palladium-catalyzed titanium(IV)-assisted catalytic allylations with underivatized allyl alcohols had been first developed by Miura and co-workers using phenols as the substrates.11 Later Yang12 and Wu13 showed analogous Pd(0)/Ti(IV) systems could be applied to the allylations of anilines  and nitroalkanes,  respectively. At the outset of this project, we sought to examine the capacity of these published conditions for the allylation of an  electron-rich  indole as a test substrate (Table 1). While the yields of the catalytic allylation were modest with 50 mol% of Ti(Oi-Pr)4  in the presence  of different amounts of DBU, we observed an exclusive  formation  of N1-allylated product 2a along with unconsumed 5-methoxy- indole (1a) (entries 1 and 2). The complete selectivity favoring the N1 – over the C3-allylation was unprecedented with allylic alcohols as the allyl source; the corresponding N1,C3-bisallylated product was not detected even with the excess alcohol. Prompted by this intriguing find, we set out to optimize this reaction by systematically varying the molar ratio of titanium tetraisoprop- oxide and DBU. Increasing the equivalent of Ti(Oi-Pr)4 besteaded the reaction efficiency, but such beneficial effects  reached  a plateau at the level of 150 mol% Ti(Oi-Pr)4 (cf. entries 4 and 5). Further surveys on the loading of DBU showed 50 mol%  is optimal to ensure efficient transformations (entries 6 and 7). The allylation with other bases including Hu¨nig’s base, triethyl- amine, pyridine, and 1,4-diazabicyclo[2.2.2]octane (DABCO) was also studied but gave inferior results than the one with DBU.  In lieu of Ti(Oi-Pr)4, a few Lewis acids (AlCl3, Sc(OTf)3, and ZnI2) were examined; however, the desired N1-allylation product  was not generated under those conditions. In  consideration  of  cost  and practicality, we examined the reaction of 5-methoxyindole with only 1.1 equiv. of b-methallyl alcohol and were delighted to see it still gave 2a in good yield (entry 8). We also performed control experiments which verified the requisite role of both the Ti(IV) reagent and the palladium catalyst (entries 9 and 10).

 

With the optimized condition in hand, we then explored the scope of N-unprotected indole substrates (Table 2). Indoles of diverse steric and electronic properties were reacted smoothly to give N1-allylated products in good to excellent yields. The broad functional group compatibility of this method is evident in exhibiting tolerance to halo, ester, cyano, nitro, allyl, tertiary amino, and formyl substituents (see 2e–g, 2h, 2i, 2j, 2n, 2o, 2q, respectively). Moreover, the exclusive N1-allylation of tryptophol showcased innocence of the primary hydroxyl group in the  transformation (see 2p); such high level of selectivity, bypassing uses of protecting groups, would be hard to achieve with conventional N-allylation protocols involving the use of strong bases and allyl halides.14 In the cases of 2-substituted indoles, a minor amount of the corresponding N1,C3-bisallylated indoles were concomitantly formed with the expected products (see 2l and 2m);15 the results were attributed to the enhanced nucleo- philicity of the C3 cite by the C2-electron-donating substituent. The favorable N1-allylation of a highly sophisticated indole, namely reserpine,16 further testified the applicability of this method (see 2s). The reactions with a few representative allyl alcohols also delivered allylated products in excellent N1-selectivity (see 2t–w). In the case with crotyl alcohol, the branched product 2u was formed as the major component in a mixture of inseparable isomeric N-allylated indoles. On the other hand, the allylation with cinnamyl alcohol proceeded cleanly to afford linear allylated indole 2v as the sole product. The reason behind the observed branched/linear selectivity with crotyl and cinnamyl alcohol is still obscure and deserves further investigation. The reaction between indole and a cyclic allylic alcohol was relatively sluggish giving 2w in modest yield.17 Unfortunately, prenyl alcohol was not compatible with the standard reaction conditions. A few common heterocycles (pyrole, carbazole, indazole  and  phenothiazine)  were  subjected  to  the catalytic allylation; to our delight, the corresponding N-allylated products 3a–d were uneventfully produced in synthetically useful yields (Table 3).

 

A plausible reaction mechanism for the synthesis of 2 from indoles is illustrated in Scheme 2. We envisioned that titanium tetraisopropoxide serves a dual purpose of activating allyl alcohols toward the generation of a palladium p-allyl inter-  mediate and functioning as a latent base for the deprotonation of indoles  (for a related mechanistic discussion, please see ref. 11). Nevertheless, further computational studies are demanded to fully rationalize the exceptional N1-selectivity with this catalytic system.

 

To further showcase the versatility of our method, we sought to tackle the total synthesis of N-(40-hydroxyprenyl)-cyclo(alanyl- tryptophyl) (6), recently isolated from the culture extract of Eurotium cristatum, an endophytic fungus obtained from the marine alga Sargassum thunbergii.18 While the bio-medicinal profile of 6 is yet to be explored, several indole diketopiperazine alkaloids were shown to display antibacterial and nematicidal activities.19 Our synthesis commenced with a known amide bond formation20 between commercially available L-tryptophan methyl ester hydrochloride and N-Boc-L-alanine using 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide (EDC) as the coupling reagent (Scheme 3). The chemoselective allylation of masked dipeptide 4, a delicate substrate bearing amide N–H groups and epimerizable a-centers, provided 2x in good yield. Subsequent to the allylation was a cross metathesis between the allyl indole and b-methallyl alcohol, thus setting up the prenyl unit at the indole nitrogen (see 5).21 Finally, a two-step process involving sequential removal of the Boc group22 and construction of the diketopiperazine core23 was successfully executed resulting in the first total synthesis of N-(40-hydroxyprenyl)-cyclo(alanyltryptophyl) (6).  The  spectral  data  of  the  synthetic  N-(40-hydroxyprenyl)- cyclo(alanyltryptophyl) were found to be in good agreement with those of the natural product reported in the literature.

 

In summary, we have developed a general method for the selective N-allylation of indoles. We conceived that the prospects of implementing the late-stage N-allylation of complex indole substrates are enlightened by the current work. Studies directed toward gaining mechanistic insights into the regioselectivity are currently underway, and the results will be detailed in due course. We thank the Young Scholar Fellowship Program by the Ministry of Science and Technology in Taiwan (MOST107-2636-M-009-003) for financial support of this work.

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CAS No.:11072-92-7 MDL No.:MFCD22666053

MF:C51H42O3Pt MW:897.9554

89-55-4

2-Methoxy-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

Catalog No.:AA0093H5

CAS No.:1107625-56-8 MDL No.:MFCD22544055

MF:C12H17N3O3 MW:251.2817

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