Direct, Chemoselective N‐tert‐Prenylation of Indoles by C ? H Functionalization

Prenylated indole alkaloids have long been targets for total synthesis, possessing a broad range of medicinal properties and intriguing architectures.1 Our interest in this family began with the stephacidin family of indole alkaloids2 during which the fortuitous finding shown in Figure 1A was made. Thus, in 2003, during an attempt to convert N-Boc-tryptophan methyl ester (1) to the C-2 prenylated tryptophan 2 directly using 2-methyl-2-butene via electrophilic palladation3 and olefin capture, we instead observed small amounts (<10%) of a non-polar compound identified as N-tert-prenylated indole 3. Whereas many elegant methods have been invented for accomplishing the direct prenylation of indoles,4–7 no methods currently exist for the direct N-tert-prenylation of indoles (Figure 1B).8 Inspired by our initial findings (Figure 1A), this communication delineates a mild, highly chemoselective, scalable, and one-step route to these biologically relevant motifs via C–H functionalization. Figure 1 Inspiration from a failed campaign in the stephacidin total synthesis (A), currently known direct prenylation modalities (B), and the known route to N-tert-prenyl indoles compared to the C–H functionalization alternative (C). Boc = tert-butoxycarbonyl, ... The only known route to N-tert-prenylated indoles requires a four step sequence, three of which involve non-strategic redox-fluctuations9 (Figure 1C): 1) reduction of the indole to the indoline, 2) propargyl substitution via CuI-catalysis, 3) oxidation back to the indole, 4) and finally Lindlar reduction of the alkyne to the olefin. This chemistry has been successfully incorporated into a number of total syntheses.9 Building off of our initial observations (Figure 1A), we envisioned a direct, one-step procedure to synthesize N-tert-prenylated indoles without the use of pre-functionalized starting materials and superfluous redox steps – well known tenets of C–H functionalization logic.10 Such a strategy would be orthogonal to routes that involve nucleophilic prenylation that in this case would not be applicable.11 Specifically, C–H activation of indoles are known to occur at C-2 or C-3, involving the direct coupling of arenes12 and electron-deficient olefins13 and annulations,2,9,14 even in the presence of free N-H indoles.15 Pd-catalyzed allylic C–H aminations16 have been accomplished; however, there have been only a few reports involving the intermolecular coupling of amines and allylic olefins.17 The fundamental mechanistic insights and reaction designs of Stahl18a and Yu19 were instrumental in transforming our esoteric 2003 observations into a useful method for synthesis. Selected results of extensive optimization with the N-Phth-tryptophan methyl ester 4 are outlined in Table 1. The work of Stahl pointed us to the use of CH3CN as a solvent while research from the Yu lab inspired the use of Cu(OAc)2 and AgOTf in concert. Ultimately, we found that 40 mol% of a Pd source (either 40 mol% Pd(OAc)2 or 20 mol% Pd2dba3•CHCl3) with 30 eq of 2-methyl-2-butene in the presence of Cu(OAc)2 and an AgI source (AgOTf or AgTFA) as the co-oxidants in CH3CN was optimal for this transformation. Table 1 Optimization of the direct indole N-tert-prenylation. With these conditions in hand, the synthetic utility could be immediately demonstrated by applying it to known intermediates in total synthesis (Figure 2). For example, compound 3, an intermediate in the okaramine N synthesis9c requiring the aforementioned four step sequence (50% overall yield), could be obtained in 66% yield on a gram-scale and in a single step with no other regioisomers observed under these conditions. Similarly, N-Cbz-tryptophan methyl ester (6) was converted to 7, an intermediate towards the synthesis of the rufomycins,9b in 61% yield (gram-scale) as compared to 60% over 4 steps. Indole 3-carboxaldehyde (8) was prenylated to give 9 on a gram-scale, an intermediate in a cyclomarin synthesis,9d in 68% yield versus 70% (4-step sequence from indoline). The use of methyl acrylate18a and 3-NO2-pyridine12b,14 (possibly as stabilizing ligands of Pd0) was needed when an electron-withdrawing group was occupied at C-3. The natural product 11, isolated from Aporpium caryae,20 has been synthesized previously starting from indoline9a and indole9e in 60% yield over 5 steps and 34% over 7 steps, respectively. The current approach starts from commercially available methyl indole 3-carboxylate (10) and leads to 11 in a single step in 83% yield (gram-scale). Figure 2 Scalable, one-step routes to previously employed N-tert-prenyl indole intermediates. As delineated in Table 1, this mild reaction exhibits broad functional group tolerance. For example, tryptophan derivatives with various protecting groups can be prenylated (Table 2, 13a–i). Peptides containing tryptophan also undergo prenylation (13a, 13h), including a tripeptide (13b). The presence of amides, particularly at the tryptophan nitrogen (13d, 13h), reduces the reactivity, possibly due to ligation of the amides onto electrophilic PdII. However, a sterically hindered amide substrate does lead to an increased yield (13e) compared to other amide substrates. A tryptamine derivative (13j) is also prenylated, albeit in lower yield, but starting material can be recovered. Free alcohol, acid, and protected phenols substrates are well tolerated under the reaction conditions (13i, 13k, and 13m respectively). Halogenated substrates (13f–g), including those incorporated in the indole ring (13l) work well, and are not oxidatively cleaved under these conditions. Table 2 Scope of N-tert-prenylation. To gain insight into the mechanism of this transformation, we studied the interactions that Pd may have with both the indole and the olefin. We initially believed that the indole was being palladated at C-2, thus providing proximal delivery of the prenyl group to nitrogen.3,13 When a methyl group occupied the C-2 position, there was less than 5% conversion to the desired product (Figure 3A). However, when deuterium was placed on C-2 (16), we found that the deuterium was fully incorporated in product 17. We also found that 1,1,1-d3-3-methyl-2-butene reacted at the same rate as its protio isomer with PdII, consistent with Bercaw’s mechanistic studies of allylic C–H activation (the C-H activation step is not rate-determining).21 Figure 3 Mechanistic probe experiments (A), and postulated mechanism (B). Based on these results, we have proposed the following mechanism (Figure 3B). First, C–H activation of the olefin with PdII gives intermediate 18. The palladated olefin reacts with indole in three possible modes. The first involves direct coordination of the indole nitrogen to Pd leading to 19. Alternatively, indole palladation at C-3 takes place to give 20 which rearranges to the product by a metallo-Clasien rearrangement.22 Finally, a Wacker-type mechanism (21) may also be operative.16a All three intermediates are plausible, although intermediate 20 may explain the regioselectivity more convincingly. The Pd0 species then undergoes oxidation with AgI and CuII to close the cycle. In order to rule out initial allylic oxidation of the olefin to prenyl acetate a control experiment was performed using prenyl acetate in place of 2-methyl-2-butene (following Method A). The reaction did not provide the desired product, but rather produced 22 in ca. 10% yield (tentative assignment). The use of cis-butene substituted for 2-methyl-2-butene did afford desired products in decent yield (23, 24). This method is obviously not without limitations. For example, terminal olefins provided only enamine products. Lowering the loading of palladium to 10–20% or reducing the equivalents of olefin added (5 equiv.) led to diminished yields (<30%). With regard to indole substrate scope, substitution at C–3 is required, diketopiperazine ring systems give lower yields of product, and pyrroles are too reactive under these conditions. While the current method is by no means atom-economic, it is direct, scalable, and selective even on complex substrates. It compares favorably to the only other method known for the synthesis of these compounds.23 Finally, our attempts to utilize prenyl acetate (or similar derivatives) in concert with various transition metals has not led to indole N-tert-prenylation.24 In conclusion, a simplified, redox-conserving route to N-tert-prenylated indoles using PdII-mediated C–H functionalization has been developed. Contrary to the known reactivity of indoles, prenylation occurs exclusively at N-1. Although substitution at C-2 hindered reactivity and the use of stoichiometric AgI and CuII salts are required, this method is amenable to gram-scale synthesis using a variety of indoles, including formal syntheses of a number of natural products and the synthesis of antifungal natural product 11 in a single step. The high level of chemoselectivity exhibited in this reaction bodes well for further applications in both the early and advanced stages of prenylated indole total synthesis endeavors.