Iridium-catalyzed 1,5-(aryl)aminomethylation of 1,3-enynes by alkenyl-to-allyl 1,4-iridium(I) migration†

A novel multicomponent coupling reaction involving the iridium-catalyzed 1,5-difunctionalization of 1,3-enynes with arylboronic acids and triazinanes is described. A key step in this 1,5-(aryl)aminomethylation reaction is the alkenyl-to-allyl 1,4-iridium(I) migration.


Difunctionalization
reactions, not including (formal) cycloadditions that result in overall annulation, are a diverse family of useful transformations. Although 1,2difunctionalizations of alkenes are the most common, 1 other reaction types such as 1,1-difunctionalization, 2 1,3difunctionalization, 3 and 1,4-difunctionalizations 4 of πunsaturated systems or cyclopropanes are also known. However, to the best of our knowledge, 1,5-difunctionalizations are rare, and are restricted to reactions of vinylcyclopropanes. 5 Addressing this methodological gap could provide new opportunities in synthesis and enable the rapid generation of molecular complexity.
Herein, we report the first example of an iridium-catalyzed multicomponent coupling between 1,3-enynes, arylboronic acids, and triazinanes that results in a novel 1,5functionalization to give 1,3-dienes. The key step in this reaction involves an alkenyl-to-allyl 1,4-iridium(I) migration that enables the functionalization of an otherwise unreactive C-H bond. This overall 1,5-(aryl)aminomethylation 6 reaction introduces nitrogen functionality with the concomitant formation of two new carbon-carbon bonds, thus complementing more well-known hydroaminomethylation and hydroamidomethylation reactions that result in only one new carbon-carbon bond. 7,8 Recently, we reported the enantioselective rhodiumcatalyzed three-component coupling of arylboronic acids, 1,3enynes, and cyclic imines, 9 in which an alkenyl-to-allyl 1,4rhodium(I) migration 10,11 is a key step (Scheme 1A). In seeking to increase the utility of this chemistry in new areas, we questioned whether cyclic imines could be replaced with triazinanes, which are known to produce formaldimines upon heating. 8 Our initial experiments (Table 1) focused on the reaction of 1,3-enyne 2a, triazinane 1a (0.5 equiv), and PhB(OH)2 (1.5 equiv). Although the use of rhodium(I) catalysis under various conditions led only to complex mixtures, we were pleased to observe that heating the three reactants in dioxane at 80 °C for 24 h in the presence of [Ir(cod)Cl]2 (2.5 mol%) and K2CO3 (1.5 equiv) successfully gave a threecomponent coupling product in 14% yield as determined by 1 H NMR analysis (entry 1). 12 Unexpectedly however, the product was 1,3-diene 3a, in which the 1,3-enyne underwent 1,5-(aryl)aminomethylation, in contrast to our previous 1,3difunctionalization using cyclic imines. 9 Variation of the base led to increased yields of 3a (entries 2-4), which was obtained as a mixture of E-and Z-isomers at the methyl-substituted alkene. 13 K3PO4 gave the highest E:Z ratio of 4.3:1 (entry 4). Although changing the solvent to MeCN or THF gave inferior 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins results (entries 5 and 6), the addition of 3 Å molecular sieves was beneficial and gave 3a in 53% NMR yield as a 5.0:1 E/Z mixture (entry 7). 14 With effective conditions in hand, the scope of the reaction with respect to the triazinane was examined in reactions with 1,3-enyne 2a and PhB(OH)2, which gave products 3a-3e and 3g in 52-74% isolated yield (Table 2). Column chromatography partially removed the minor Z-isomer along with unreacted 2a. As well as triazinane 1a, triazinanes containing para-methoxyphenyl or para-fluorophenyl groups reacted successfully to give 1,3-dienes 3b and 3c, respectively. A disubstituted aryl group on the triazinane was tolerated (3d), as was a methoxypyridyl group (3e). Finally, N-alkyltriazinanes were examined. Although 1,3,5-trimethyl-1,3,5-triazinane was ineffective (none of 3f was obtained and unreacted 2a was returned), the corresponding N-isopropyl analogue performed well to give 1,3-diene 3g in 58% yield as a 6.8:1 mixture of E/Z isomers.
A range of different arylboronic acids with varying steric and electronic properties are tolerated in this process, as shown by their reactions with 1,3-enyne 2a and either triazinane 1a or 1b (Table 3). For example, 1,5-(aryl)aminomethylation Table 3 Scope of the boronic acid a a Reactions were conducted with 0.30 mmol of 2a and 100 mg of 3 Å molecular sieves. The E:Z ratios quoted after the yields are of a mixture of inseparable isomers obtained after purification. PMP = para-methoxyphenyl. b Range of E:Z ratios of the crude mixtures as determined by 1 H NMR analysis. products were successfully obtained from reactions of arylboronic acids containing para-(3h, 3k, and 3l), meta-(3m and 3n), or ortho-substituents (3i and 3o). However, the yield of 3o was only 16%, presumably because of steric hindrance. Attempted reactions using 1-phenylvinylboronic acid in place of arylboronic acids were unsuccessful, and only starting 1,3enyne 2a was recovered.
Finally, we investigated a range of 1,3-enynes in reactions with PhB(OH)2 and either triazinane 1a or 1b (Table 4). As well as a phenethyl group (3q and 3r; see also Tables 2 and 3), various other aliphatic substitutents at the alkynyl position R 3 are tolerated, including primary (3p, 3s, 3u, and 3v) and secondary (3t) alkyl groups with functional groups such as a silyl ether (3p) or a ketone (3u and 3v). When the substituent R 2 (trans-to the alkyne) was modified from a methyl group to a hydrogen atom (3q), the yield decreased but the stereoisomeric ratio increased. However, replacing this group with a phenyl group resulted in a higher yield at the expense of a lower stereoisomeric ratio (3r and 3s). The presence of a methyl group cis-to the alkyne in the 1,3-enyne is essential for the reaction to proceed, as shown by the failure to provide any three-component coupling product from a 1,3-enyne without this structure feature. 15 Table 4 Scope of the 1,3-enyne a a Reactions were conducted with 0.30 mmol of 2 and 100 mg of 3 Å molecular sieves. The E:Z ratios quoted after the yields are of a mixture of inseparable isomers obtained after purification. PMP = para-methoxyphenyl b Range of ratios of geometric isomers of the crude mixtures as determined by 1 H NMR analysis.
A possible catalytic cycle for these reactions is shown in Scheme 2. After the formation of iridium complex 4, which could have chloride, hydroxide, or phosphate counterions from the species present in the reaction, 16 transmetalation of 4 with the arylboronic acid gives aryliridium species 5. Coordination of 5 with the 1,3-enyne 2, followed by migratory insertion with the alkyne leads to alkenyliridium species 6, which can undergo an alkenyl-to-allyl 1,4-iridium(I) migration 9 to give allyliridium species 7. Although allylation of formaldimine 8 (derived from cracking of triazinane 1) could occur with 7 through a chairlike conformation 9 to give 1,3-difunctionalized product 10, 9 this mode of addition was not observed. Instead, 7 can undergo interconversion with allyliridium species 11 through a σ-π-σ isomerization. Now, allylation of 8 with 11 through a chairlike conformation 12, in which the trisubstituted alkene occupies a pseudoequatorial position, gives the iridium amide 13. Protonolysis of 13 releases the product 3 (major stereoisomer) and regenerates the active iridium complex 4. The formation of the minor stereoisomer of 3 can be explained by allylation through an alternative conformation 14, in which the trisubstituted alkene occupies a pseudoaxial position. This stereochemical model is consistent with the decreasing ratios of geometric isomers observed when R 2 changes from hydrogen to methyl to phenyl (see Table 4), as increasing the steric effect of this substituent will disfavor allylation through 12 because of increasing unfavorable non-bonding interactions of R 2 with the pseudoequatorial trisubstituted alkene. The formation of 1,5difunctionalized products 3 rather than 1,3-difunctionalized Scheme 2 Possible catalytic cycle 4 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins products 10 results from the imine employed, as cyclic imines give 1,3-difunctionalized products under similar conditions. 9 However, the reasons for this selectivity, which likely arises from energy differences between 9 and 12/14, are currently not clear.
In conclusion, we have developed a novel iridium-catalyzed three-component coupling reaction of 1,3-enynes with arylboronic acids and formaldimines derived from triazinanes, to give multisubstituted 1,3-dienes. Key to the success of this reaction is an alkenyl-to-allyl 1,4-iridium(I) migration. This 1,5-(aryl)aminomethylation reaction complements more well-known hydroaminomethylation and hydroamidomethylation reactions 7,8 by forming two, rather one new carbon-carbon bond. Further work is ongoing in our laboratory to increase the scope of catalytic 1,4-metal migrations.

Conflicts of interest
There are no conflicts to declare.