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Title:
Overcoming Selectivity Issues in Reversible Catalysis -A Transfer Hydrocyanation Exhibiting High Kinetic Control

Paper sections:

<p>Reversible catalytic reactions such as alkene metathesis 1 and transfer hydrogenation 2 have found a plethora of applications in diverse fields of chemistry. 3,4,5 Given their value to the synthetic practitioner, our group and others have investigated expanding these transformations to include the metathesis of other bonds and the transfer of functionality other than H2. 6,7,8 These reaction paradigms offer numerous advantages aside from their potential applications. For transfer reactions, safer protocols avoiding the use of highly toxic or hazardous reagents can be implemented. One example of such a strategy was reported by our group to achieve transfer hydrocyanation whilst avoiding the use of highly toxic and volatile HCN. 8d These results have subsequently spurred the development of other transfer hydrocyanation strategies that circumvent the use of HCN, 9 as well as opening a new, versatile strategy for the development of other cyanation reactions using relatively non-toxic cyanide sources. 10,11 One fundamental drawback of metathesis and transfer reactions is that, as a result of their inherent reversibility, they operate under thermodynamic control. This often leads to mixtures of products being formed such as in the case for alkene metathesis wherein the ratio of E:Z products is determined by their relative stability (Scheme 1A). 1 In a similar manner, the transfer hydrocyanation reported by our group also leads to mixtures of products, with the reaction of styrene affording an 81:19 mixture of linear and branched products, respectively. 8d This ratio reflects the relative thermodynamic stability of the two isomers and it cannot be manipulated through simple modification of the catalyst system since the selectivity is controlled by the reagents. 12 Scheme 1. Comparison of alkene metathesis and transfer hydrocyanation and the thermodynamic theory underpinning the observed selectivity.</p><p>The reason these reactions operate under thermodynamic control is that they proceed through catalytic intermediates that are close in energy to the products and starting materials of the reaction (Scheme 1B). This leads to an intriguing scenario wherein the barrier to form either product from the catalytic intermediate is roughly the same as the barrier to reform the catalytic intermediate and thus the reaction is reversible. However, if the barrier to form one of the products can be selectively increased over the other one, then a reversible yet kinetically controlled selectivity toward one isomer can occur. This is the case in Z-selective alkene metathesis. 13 Pioneering efforts by the Schrock, Hoveyda and Grubbs' laboratories have led to the development of alkene metathesis catalysts that lead to the selective formation of the thermodynamically less stable Z-alkenes. Critical to this selectivity is the intricate design of the catalysts that lead to a significantly higher kinetic barrier for the formation of the E-alkene. To date, there are no analogous examples of a transfer reaction that have been demonstrated to be reversible and kinetically selective. Instead, most proceed to form the more thermodynamically stable products.</p><p>Inspired by the precedent set by Z-alkene metathesis to obtain a selective reversible metathesis manifold, 13 we sought to develop a protocol that would enable a selective transfer hydrocyanation of styrenes by lowering the barrier for the formation of the branched nitrile isomer (Scheme 1C). This would be complementary to the linear selectivity obtained under thermodynamic control. 8d,9a Based on precedent from the Tolman group and others using HCN for hydrocyanation 14 and our own experiences in this field, we surmised that a branched selective transfer hydrocyanation of styrenes could be achieved by removing the co-catalytic Lewis acid. In the absence of a Lewis acid co-catalyst, selectivity results from a benzylic stabilization effect leading to a markedly lower barrier for both the cleavage and formation of the branched nitrile product when compared to the linear isomer.</p><p>We verified this hypothesis experimentally through the reaction of 2-phenylpropionitrile 1a with 4-tert-butylstyrene 2b and found that a mixture of the starting materials with styrene 2a and branched nitrile 1b was obtained while the linear isomers were not observed (Scheme 2). This confirms that both the oxidative addition and reductive elimination can occur at the benzylic position in the absence of co-catalytic Lewis acid, whereas the formation of the linear product is considerably more challenging. The high barrier to oxidative addition of nonbenzylic nitriles with the Lewis acid free system is also implicated by the lack of reactivity observed between 3-phenylpropionitrile 3a and 4-tert-butylstyrene 2b. Furthermore, hydrocyanation of norbornadiene was not observed upon reaction with 2-phenylpropionitrile 1a. This truly underlines the challenging C-CN reductive elimination at non-benzylic positions without co-catalytic Lewis acid, as norbornadiene is typically a potent acceptor for transfer reactions. 6d,8c-e Collectively, these results show that, in the absence of co-catalytic Lewis acid, the reaction is still reversible yet kinetically controlled toward selective formation and cleavage of the branched isomer, leaving other positions unreacted.</p><p>Next, we considered how to develop a practical, HCN-free transfer hydrocyanation process exhibiting such selectivity. While 2-phenylpropionitrile 1a is a competent HCN donor under the reaction conditions, it is not ideal for use in reversible transfer hydrocyanation as an excess would be required to ensure good conversion of the substrate. Aside from being highly wasteful, this would also present problems with regards to purification and, therefore, an alternative HCN donor had to be devised. Desirable features include being able to form the requisite H-Ni-CN species in the absence of a Lewis acid and it should also ideally form a stable alkene by-product that would be unsusceptible to hydrocyanation itself. We reasoned that malononitrile derivatives bearing an aliphatic group could fulfill these criteria while also being simply synthesized from inexpensive starting materials. 15 It was anticipated that the neighboring nitrile group should lower the barrier for the required oxidative addition 16,17 and the conjugated alkenyl nitrile by-product should be recalcitrant to undergoing hydrocyanation. Gratifyingly, we discovered that malononitriles bearing a secondary aliphatic substituent (4a-4d) afforded the highest yields of product, although those bearing bulkier substituents (4e) failed in the reaction (Scheme 3). A simple isofunctional experiment confirmed that the dehydrocyanation of the reagent is irreversible under the reaction conditions. These results are also supported by comparison of the ground state free energies of the reactants and products in the hydrocyanation of styrene 2a with malononitrile 4a, which suggests that the reaction is distinctly exergonic (ΔG = -12.9 kcal/mol at 298 K, see SI for details). Scheme 2. Experiments to compare relative ease of C-CN oxidative addition/reductive elimination at benzylic and non-benzylic positions.</p>

Scheme 3. Development of novel HCN donors for regioselective transfer hydrocyanation.
<p>Following further optimization of the reaction conditions, the applicability of this HCN-free, branched-selective transfer hydrocyanation was examined (Scheme 4). A variety of functional groups were well tolerated in the reaction including both electron donating and electron withdrawing moieties. Besides the high branched selectivity of this new reaction, which is complementary to previous HCN transfer protocols, 8d,9a we were also interested to see if it exhibits greater functional group tolerance, given that the current reaction conditions do not require co-catalytic Lewis acid. Indeed, substrates possessing acidic protons (1r-1w) or a Boc-protected amine (1v) were well tolerated. Finally, vinylheteroarenes were also investigated and several common heterocyclic cores (1x-1z) were found to successfully undergo transfer hydrocyanation with high selectivity. Scheme 4. Substrate scope for the regioselective, HCN-free transfer hydrocyanation. a,b a Yields are given for isolated and purified material. Reactions were conducted on a 0.5 mmol scale. b Regioselectivity was determined by 1 H NMR analysis of the crude reaction mixture. c Aldehyde 1k was also isolated in 33% yield.</p><p>Interestingly, during the course of studying vinylheteroarenes as substrates in the reaction, a complete switch in regioselectivity was observed with 2-vinylpyridine 5 (Scheme 5). In this case, exquisite selectivity for the linear isomer 6 was observed. This is most likely due to a directing group effect by the N atom of the pyridine, lowering the otherwise inaccessible energy barrier for C-CN reductive elimination at non-benzylic positions. 18 To further probe this coordinating effect, reaction of 6-methyl-2-vinylpyridine 7 was attempted and this was found to afford a mixture of both the linear (8) and branched (9) isomers, with the latter preferred. This lack of selectivity likely arises from the methyl group interfering with the ligation of the pyridine ring to the metal catalyst, allowing for the normal benzylic stabilization-controlled selectivity to compete with the directing group effect. Excitingly, even simple, unprotected alcohols (e.g. 10) afforded the linear product 11, suggesting that alcohols can also act as directing groups. a Yields are given for isolated and purified material. Reactions were conducted on a 0.5 mmol scale. b Regioselectivity was determined by 1 H NMR analysis of the crude reaction mixture.</p><p>Having found that directing groups could be used to control the selectivity of the reaction, we recognized that this provided an opportunity to explore less well-documented directing group effects. 19 In particular, we were attracted to vinylsilanes as we reasoned that the silyl groups ability to stabilize both αanions and β-cations could provide another mechanism to lower the energy barrier for reductive elimination through inductive effects (Scheme 5). Accordingly, phenyldimethylvinyl silane 12 afforded the linear nitrile product 13 in high yields and selectivity, possibly hinting at the build-up of a positive charge at the β-position to the silicon during the C-CN reductive elimination.</p><p>Finally, to further illustrate the value of this reversible and selective reaction, we used this new protocol to resolve the mixture of linear and branched isomers (l:b = 81:19) obtained upon transfer hydrocyanation of styrene 2a using our previous, thermodynamically controlled protocol (Scheme 6). 8d By using an excess of commercially available 4-methoxystyrene, selective dehydrocyanation of the branched isomer 1a was achieved while the linear isomer 3a could be recovered quantitatively with exquisite linear purity. In this manner, the linear nitrile can be obtained in high regiopurity through successive transfer hydrocyanations. This process is analogous to the resolution of a mixture of E-and Z-alkenes by Z-selective ethenolysis to afford enrichment of the E-alkene content. 20 Scheme 6. Resolution of a regioisomeric mixture by selective dehydrocyanation.</p><p>a Catalyst loadings are calculated with respect to the amount of the branched isomer in the regioisomeric mixture. b The yield is given with respect to the amount of the linear isomer in the initial regioisomeric mixture.</p><p>Preliminary deuterium labeling studies resulted in a statistical distribution of deuterium at both the branched and linear positions (Scheme 7). This suggests that a rapid pre-equilibrium has been reached and that the barrier for hydride insertion/β-hydride elimination is likely to be insignificant compared to the barrier for C-CN reductive elimination. Thus, a rapid scrambling of the hydrogens at the branched and linear positions can occur. This result further verifies that selectivity in our reaction likely arises from the insurmountable barrier for C-CN reductive elimination at the linear position in the absence of co-catalytic Lewis acid. Scheme 7. Labeling studies and proposed catalytic cycle. This observation, combined with the results shown in Scheme 2 and 3, allow us to understand the origins of the branched selectivity (Scheme 7). Irreversible dehydrocyanation of the malononitrile generates the corresponding H-Ni-CN intermediate. Rapid and reversible alkene insertion into the H-Ni bond allows for an equilibrium to be established between the branched and the linear alkyl nickel intermediates. Finally, reversible reductive elimination to form the desired branched isomer occurs with high kinetic control over formation of the linear isomer.</p><p>In conclusion, we have discovered a HCN-free transfer hydrocyanation manifold that exhibits high kinetic selectivity for the thermodynamically less stable, branched isomer but, significantly, also remains reversible. Key to this selectivity is the lower barrier for C-CN oxidative addition and reductive elimination at the benzylic position in the absence of co-catalytic Lewis acid. This manifold was exploited to achieve a highly selective transfer hydrocyanation of styrenes by using a novel design of HCN donor. To date, no other transfer reactions have been demonstrated to be both kinetically selective and reversible. Extending this concept could have enormous potential in organic synthesis as it opens new strategies to both selectively functionalize multiple bonds and, through the reverse reaction, selectively defunctionalize complex molecules.</p>

Corresponding Author
<p>bill.morandi@org.chem.ethz.ch</p>

Notes
<p>A patent application for transfer hydrocyanation has been filed (US2019031602 (A1)).</p>
Typically, reversible catalytic reactions operate under thermodynamic control and thus establishing a selective catalytic system poses a considerable challenge. In this manuscript, we report a reversible yet kinetically selective transfer hydrocyanation protocol. Selectivity is achieved by exploiting the lower barrier for C-CN oxidative addition and reductive elimination at benzylic positions in the absence of co-catalytic Lewis acid. The design of a novel type of HCN donor was crucial to realizing this practical, branched-selective, HCN-free transfer hydrocyanation. The synthetically useful resolution of a mixture of branched and linear nitrile isomers was also demonstrated to underline the value of reversible and selective transfer reactions. In a broader context, this work demonstrates that high kinetic selectivity can be achieved in reversible transfer reactions, thus opening new horizons for their synthetic applications.