Anti‐Markovnikov Hydrofunctionalization of Olefins Mediated by Rhodium–Porphyrin Complexes (2004)

A rationally designed mechanistic approach to anti-Markovnikov olefin hydrofunctionalization and its application to the synthesis of heterocycles are described. Porphyrin–rhodium complexes have been shown to exhibit remarkable reactivity and selectivity for each step of the proposed catalytic cycle (see scheme). A critical step of this reaction sequence is a new, facile, and remarkably general carbon–heteroatom bond-forming reductive elimination. We envisaged a three-step catalytic cycle for intramolecular anti-Markovnikov olefin hydrofunctionalization involving: a) olefin insertion into a [Rh]H bond, b) intramolecular functionalization of the resulting σ-alkyl adduct, and c) protonation of the resulting [RhI]− species to regenerate the starting [Rh]-H complex (Scheme 1). We anticipated that the regioselectivity of the reaction would be dictated by the olefin-insertion step, which should favor the less-substituted metal σ-alkyl species6 and thereby selectively provide the anti-Markovnikov product. We report herein that (TPP)Rh-H (TPP=tetraphenylporphyrin) efficiently mediates each step of this postulated catalytic cycle to afford heterocyclic products with extremely high (>97 %) anti-Markovnikov regioselectivity. The functionalization step serves as a rare and unusually general example of direct C(sp3)–heteroatom bond-forming reductive elimination.7, 8 Rhodium–porphyrin-mediated olefin hydrofunctionalization. The first step of the process involves a reversible olefin insertion into (TPP)Rh-H to produce a σ-alkyl rhodium complex (Scheme 1, step a).9 As summarized in Table 1, the desired reaction proceeded efficiently (within 1 h at 25 °C) to afford a variety of stable rhodium–alkyl products.10 This transformation was highly regioselective, and in all cases the less-substituted metal–alkyl species was the only insertion product observed by 1H NMR spectroscopy.10 Furthermore, yields remained excellent in the presence of a diverse array of functional groups, including alcohols, aldehydes, carboxylic acids, sulfonamides, and nitroalkanes (Table 1, entries 1–5). This extraordinary functional-group tolerance is particularly notable because the insertion mechanism involves reactive RhII radicals as intermediates.9, 11 Entry Substrate Product Yield [%][b] 1 0 0 88 2 0 0 74 3 0 0 91 4 0 0 76 5 0 0 83 The second step involves reaction of the σ-alkyl–rhodium species with an internal nucleophile (Nu; Scheme 1, step b). CNu bond-forming reductive elimination reactions are extremely rare, particularly when the α carbon atom is sp3 hybridized and/or β hydrogen atoms are present.6, 7, 12 We note several previous examples of this transformation that involve methyl–rhodium–porphyrin complexes (e.g., Nu=PPh312a or RhI12b). Initial investigations focused on the intramolecular cyclization of (TPP)Rh(CH2)4OH to produce THF (Table 2, entries 1-3). The pendant alcohol was not sufficiently nucleophilic to cleave the Rh–alkyl bond under neutral conditions. However, the addition of base led to rapid CO bond-forming reductive elimination. THF was produced in 78 % yield under optimized conditions ([D6]DMSO, NMe4OH (3 equiv); Table 2, entry 3). The only other organic product identified was 3-buten-1-ol, which is readily recycled under the hydrofunctionalization conditions. The Rh–porphyrin complex was converted into [(TPP)RhI]− quantitatively. The cyclization of β-hydroxyalkyl–RhIII derivatives to produce epoxides also proceeded in high yield (>97 %; Table 2, entry 5).13 However, attempts to prepare four- and six-membered oxygen heterocycles by using this methodology were unsuccessful. Instead the corresponding olefins were the only organic products formed (Table 2, entries 6 and 7).14 Entry Substrate Solvent Base Yield [%] A B 1[b] 0 C6D6 KOtBu 29 71 2[b] 0 [D6]DMSO KOtBu 60 40 3[c] 0 [D6]DMSO NMe4OH 78 22 4[c] 0 [D6]DMSO NMe4OH 70 30 5[b,d] 0 C6D6 KOtBu >97 <3 6[c,e] 0 [D6]DMSO NMe4OH <3 >97 7[c] 0 [D6]DMSO NMe4OH <3 >97 Several pieces of evidence suggest that these unusual reductive eliminations, which involve the formation of a CO bond, proceed by an SN2 mechanism. First, the furan/olefin product ratio increased dramatically upon changing the solvent from C6D6 to [D6]DMSO (Table 2, entries 1 and 2). Furthermore, modification of the nucleophile from a primary to a secondary alkoxide (Table 2, entries 3 and 4) led to a significant decrease in the ratio of the cyclic product to the 3-buten-1-ol. Both results are indicative of competing SN2 and E2 reactions, whereby the SN2 transition state is favored in more polar solvents15 and with less sterically hindered nucleophiles. Han has also shown that the cyclization of (TPP)Rh(CDH)CH(CH)3OH (a deuterated analogue of the substrate in Table 2, entry 5) produces [D1]propylene oxide with 100 % inversion of stereochemistry at the α carbon atom.13 This experiment clearly implicates an SN2 mechanism that proceeds by backside attack at the carbon atom bonded to Rh (as opposed to precoordination of the alkoxide to the Rh center).7 Importantly, the proposed mechanism is consistent with that of a closely related RhIII/RhI alkyl-exchange reaction, which proceeds through an SN2 pathway.12b As summarized in Tables 2 and 3, C(sp3)–Nu reductive elimination is extremely general in this system and could be applied to the formation of the CO, CN, and CC bonds of a diverse range of cyclic compounds. Once again, the only organic products observed were the desired heterocycle (or carbocycle in the case of Table 3, entry 4) and the corresponding olefin. The Rh complex was quantitatively converted into [(TPP)RhI]−. For example, α-, β-, and γ-substituted Rh–alkyl intermediates with pendant alcohol groups underwent cyclization to produce the corresponding tetrahydrofurans within 1 h at 25 °C (Table 3, entries 1–3). A phenol-substituted rhodium complex underwent facile cyclization at room temperature to give 2,3-dihydro-2-methylbenzofuran (Table 3, entry 5). The modest yield (53 %) observed for this system is probably due to the SN2 mechanism, which requires nucleophilic attack at a sterically hindered tertiary carbon center. Finally, the CC bonds of cyclopentane (Table 3, entry 4) and CN bonds of pyrrolidine derivatives (Table 3, entries 6–8) were also constructed readily by using this methodology. Although harsher conditions (70 °C, 12 h) were required relative to the analogous CO bond-forming reactions, the yields and SN2/E2 product ratios remained excellent. Entry Substrate Product Yield [%] 1[b] 0 0 73 2[b] 0 0 >95 3[b] 0 0 >95 4[c] 0 0 69 5[b,d] 0 0 53 6[c] 0 0 83 7[c] 0 0 92 8[c] 0 0 >95 The final step of the catalytic cycle involves protonation of [(TPP)RhI]− to regenerate the (TPP)Rh-H catalyst (Scheme 1, step c). Nelson and Dimagno recently reported that the pKa value of (TPP)Rh-H is approximately 11;12a therefore, as expected, the addition of excess trifluoroacetic acid to the crude reaction mixtures resulted in quantitative regeneration of (TPP)Rh-H.16 This transformation completes the proposed catalytic cycle and makes it possible to recycle the expensive rhodium porphyrin. In summary, we have developed and implemented a new, rational mechanistic approach to the design of catalysts for the anti-Markovnikov hydrofunctionalization of olefins. We have shown that (TPP)Rh-H mediates each step of the proposed catalytic cycle with high selectivity, and have demonstrated a new and remarkably general carbon–heteroatom bond-forming reductive elimination reaction. The reactions described herein do not yet constitute a working catalytic cycle. Preliminary attempts to carry out these transformations under catalytic conditions (e.g., with several phenol-based substrates and a variety of weak bases) have thus far been hampered by the incompatibility of step a with the polar solvents required for steps b and c. However, the reactions as performed do allow for the facile recycling of the valuable porphyrin–Rh-H complex. Additionally, we anticipate that the design principles presented herein will serve as a valuable foundation for the development of a new generation of regioselective olefin-hydrofunctionalization catalysts. Current efforts in our laboratories are aimed at improving these systems in terms of catalytic turnover through modification of the solvent system, as well as by steric or electronic perturbation of the porphyrin ligands. Efforts to circumvent reaction-medium limitations through the use of solid-supported Rh catalyst systems are also in progress. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2004/z51941_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.