Remote Nucleophilic Allylation by Allylrhodium Chain Walking

: Metal migration through a carbon chain is a versatile method for achieving remote functionalization. However, almost all known examples involve the overall net migration of alkylmetal species. Here, we report that allylrhodium species obtained from hydrorhodation of 1,3-dienes undergo chain walking toward esters, amides, or (hetero)arenes over distances of up to eight methylene units. The final, more highly conjugated allylrhodium species undergo nucleophilic allylation with aldehydes and an imine to give Z -homoallylic alcohols and amines, respectively. EP/M50810X/1 and EP/K504348/1]; the Basque Country government; the Leverhulme Trust [grant number RPG-2016-341]; and GlaxoSmithKline. Allylrhodium species obtained from hydrorhodation of 1,3-dienes undergo chain walking toward esters, amides, or (hetero)arenes over distances of up to eight methylene units. The final, more highly conjugated allylrhodium species undergo nucleophilic allylation with aldehydes and an imine to give Z -homoallylic alcohols and amines, respectively.

Remote functionalization reactions are those in which an initial interaction of a functional group with a reagent or catalyst leads to eventual reaction at a distal site. [1] Although achieving high efficiency and selectivity in such processes is often challenging, developments in this area can facilitate the activation of otherwise unreactive C-H and C-C bonds, thus providing powerful new tools for synthesis. Of the available methods for remote functionalization, metal migration through a carbon chain, or "chain walking", is particularly versatile as it dispenses with the need for complex directing groups (Scheme 1A). [1g-i, 2 , 3 ] However, most known metal chain walking reactions effectively result in the overall net migration of alkylmetal species (Scheme 1A). Chain walking of organometallics beyond simple alkylmetals, such as allylmetal species (Scheme 1B), could dramatically expand the scope of remote functionalizations, but to our knowledge, there are such few examples. [4] During our studies of enantioselective nucleophilic allylations of imines, [4b,5] we discovered the first examples of allylrhodium chain walking (Scheme 1C). [4b] These reactions employ δtrifluoroboryl α,β-unsaturated esters as precursors to allylrhodium species A. Chain walking of A towards the ester is proposed to occur via a 1,3-diene-ligated rhodium hydride B to give the more highly conjugated, and presumably thermodynamically more stable allylrhodium species C, which then reacts with the imine in a highly diastereo-and enantioselective nucleophilic allylation. [4b] To increase the synthetic utility of allylrhodium chain walking, we wondered whether migration could be accomplished through more than just one methylene carbon. This goal was expected to be challenging because rhodium must participate in a greater number of steps before the final allylrhodium species is formed, Scheme 1. Metal chain walking. and in principle, any of the intermediate allylrhodium species can react with the electrophile to give complex mixtures of products. Herein, we describe remote nucleophilic allylations of aldehydes and an imine, in which allylrhodium chain walking occurs through up to eight methylene units (Scheme 1D).
For this study, the use of allylrhodium precursors that are simpler to prepare than allyltrifluoroborates was desirable. We therefore considered generating allylrhodium species by the hydrorhodation of 1,3-dienes, as described by Kimura and coworkers in related reductive nucleophilic allylations. [ 6 ] Accordingly, substrate 1a was reacted with benzaldehyde (1.2 equiv) in the presence of [Rh(cod)OH]2 (5 mol%) and Et3B (2.0 equiv) in THF at 50 °C for 16 h. [6] Pleasingly, this reaction gave homoallylic alcohol 2a, which was isolated as a single diastereomer in 60% yield [Eq. (1) and Table 1, entry 1]. [7] The use of Et3SiH in place of Et3B gave no reaction.
A possible catalytic cycle is shown in Scheme 2. First, the reaction of [Rh(cod)OH]2 with Et3B generates the ethylrhodium species 3, which undergoes β-hydride elimination to give Scheme 2. Proposed catalytic cycle. rhodium hydride 4. Hydrorhodation of 1,3-diene 1a with 4 then provides allylrhodium species 5A, which undergoes σ-π-σ isomerization to give 5B. [8] β-Hydride elimination of 5B gives a rhodium hydride coordinated to benzyl sorbate (as in 6). Hydrorhodation of the alkene distal to the ester gives allylrhodium species 7, resulting in an overall 1,4-hydrogen shift from the carbon adjacent to the carbonyl group, to the methylene carbon adjacent to the methyl group. Allylrhodium species 7 then reacts with benzaldehyde in a nucleophilic allylation through conformation 8, in which the ethyl group occupies a pseudoaxial position to minimize unfavorable nonbonding interactions with the cyclooctadiene ligand. Reaction of the resulting rhodium alkoxide 9 with Et3B or Et2BOH gives 10 (which upon workup gives the product 2a) and regenerates the ethylrhodium species 3.
Having established proof of principle, the scope with respect to the diene was investigated ( Table 1). One of two sets of conditions were employed. Method A used 2.0 equivalents of Et3B in THF at 50 °C, whereas method B used 3.0 equivalents of Et3B in dioxane at 80 °C. Method B was used for reactions that did not proceed in high conversion with method A. Pleasingly, a range of dienes reacted successfully with benzaldehyde to give products of chain walking-nucleophilic allylation 2 in up to 65% yield. These reactions also gave complex mixtures of other products in ca. 20% yield, which were tentatively identified as nucleophilic allylation products resulting from various intermediate allylrhodium species. [ 9 ] The complexity of the reactions prevented determination of the diastereoselectivities by 1 H NMR analysis, but with a few exceptions (entries 7-9), the products 2 were isolated as single diastereomers. In addition to chain walking through one carbon (entries 1 and 2), walking through two carbons (entries [3][4][5][6][7][8] and three carbons is possible (entries 10 and 11). As well as terminal dienes (R 2 = H, entries 1, 3, and 10), the process is compatible with internal dienes with various alkyl groups at R 2 (entries 2, 4, 6-8, and 11). However, Table 1. Scope of the 1,3-diene. [a] entry diene method product yield (%) [b] walking through one carbon:  [c] 8 1h B 2g 43 (9:1 d.r.) [c] 9 1i B 2h 23 (3:1 d.r.) [d,e] walking through three carbons: [a] Reactions were conducted with 0.30 mmol of 1.
[b] Yield of isolated product. Unless stated otherwise, the products were isolated as single diastereomers. [c] Conducted with 0.24 mmol of 1i. [d] Isolated as a mixture of inseparable diastereomers in the ratio indicated in parentheses.
[e] The reaction time was 40 h. diene 1e, which contains a 1-chlorobutyl group, only returned unchanged starting materials (entry 5). [ 10 ] Methyl and phenyl esters are also tolerated (entries 7 and 8). An amide also promotes chain walking, but with lower efficiency (entry 9). Chain walking over greater distances is possible, as shown by the reaction of diene 1l, which contains eight methylene units between the diene and the ester [Eq. (2)].
(3)]. The product of chain walking towards the ester (2k) was isolated in 15% yield, while product 12, resulting from chain walking towards the phenyl group, was obtained in 31% yield.
The discovery that arenes also promote allylrhodium chain walking significantly increases the possibilities of this chemistry, and this aspect was explored further in the reaction of dienes 13a-13g with benzaldehyde (Scheme 4). As expected, the phenyl-terminated diene 13a reacted successfully to give 14a in 50% yield. [7] Other arenes that bring about chain walking include 2-naphthyl (14b), 2-fluorophenyl (14c), and 3-methoxyphenyl groups (14d). Pleasingly, heteroarenes such as 2-pyridyl (14e), 2-furyl (14f), and 2-thienyl (14g) groups are also effective. An advantageous feature of these reactions is that the stereochemistry of the starting dienes appears inconsequential, which removes the need to prepare the substrates in high stereoisomeric purity. For example, the reaction of diene (3E,5Z)-13a with benzaldehyde gave results that are comparable with its (E,E)-counterpart [Eq. (4), compare with Scheme 4]. A mixture of all four possible stereoisomers of 13a can also be used with similar efficiency [Eq. (5)].
The reaction of benzaldehyde with the doubly deuteriumlabeled diene [D]2-13a gave homoallylic alcohol [D]2-14a in ≤87% purity, in which one deuterium atom was transferred to the homoallylic methylene carbon, with no evidence of deuteration at other sites [Eq. (6)]. This overall 1,4-deuterium shift is consistent with the mechanism shown in Scheme 2 (see the Supporting Information for details).
In conclusion, we have reported the rhodium-catalyzed reductive nucleophilic allylation of aldehydes or an imine with 1,3-dienes, in which carbon-carbon bond formation occurs at a site remote from the initiation site by the overall net migration of allylrhodium species. This study illustrates the potential utility of allylmetal chain walking in remote C-H functionalization, which complements much more well-known alkylmetal chain walking processes. Compared with our previous work (Scheme 1C), [4b] we have shown that chain walking can proceed through greater distances (up to eight methylene units). Furthermore, an expanded range of functional groups was shown to promote chain walking, which includes esters, amides, and (hetero)arenes. Our future work will include the development of enantioselective variants of this process. [11] Received: ((will be filled in by the editorial staff)) Published online on ((will be filled in by the editorial staff))