59th Annual Report on Research 2014

The efficient construction of Csp²-Csp³ bonds remains a serious challenge in synthetic organic chemistry. Although remarkable advances have been made recently, these methods are limited by stoichiometric use of main-group organometallics, excess activating agents, poor atom economy and limited substrate scope. For example, the pre-functionalization of one coupling partner as a main-group organometallic nucleophile leads to significant synthetic inefficiencies and waste streams. These problems can be addressed by using simple, readily available olefins and alkynes in sp³-carbon construction. The use of olefins as cross-coupling partners in Csp²-Csp³ coupling requires interrupting the catalytic cycle of the Heck reaction before b-hydride elimination occurs. The work supported by the donors of the ACS-PRF seeks to explore the formation of C-C bonds through novel insertion and coupling technology. During the first year of funding, several important observations were made: 1) alkyl-palladium reduction has been shown to outcompete b-hydride elimination in a reductive-Heck reaction; [1] 2) a formal synthesis of englerin A using the proposed reductive-Heck technology;¹ 3) alkyne insertion has been demonstrated to outcompete b-hydride elimination;[2] 4) the alkyne insertion has been used in the synthesis of tri- and tetra-substituted olefins;^2,[3] and 5) palladium can catalyze iodine transfer reaction over multiple units of unsaturation.[4]In the second year of funding, we have solved some of the many problems we faced in palladium catalysis by switching to iron–our progress on this front is the subject of this report.

During our investigations into the alkyne insertion reaction of primary alkyl palladium species (Scheme 1), we discovered that the pendant alkyne was necessary for facile oxidative addition into the primary iodide.²We are currently investigating the interaction of an alkyne to Pd(0) computationally, but we tried to take advantage of the “alkyne as a ligand” model to facilitate other difficult oxidative addition reactions with palladium. Since CH bonds are ubiquitous in petrochemical feedstocks, we specifically chose to investigate CH oxidative addition to advance this critical area of petrochemical research. We tried for many months to achieve an alkyne directed, palladium-catalyzed CH activation reaction, but we have not been able to realize any transformations as yet. In an attempt to circumvent these difficulties, we moved beyond palladium and eventually found iron to work well in the functionalization of CH bonds.

Since our initial discovery, we have developed a unified strategy for C–H alkylation reactions.[5]^,[6]Our iron-catalyzed conditions can be rapidly tuned to accommodate a range of important electrophiles. The reactions generally proceed in high yields with exceptional regioselectivity on gram scale. The reaction is complete in ≤10 min, and the benzylations can be performed in air with reagent-grade solvent. We are currently investigating the reaction mechanism and expanding the scope of these interesting transformations.

Since alcohols are widely available derivatives of the petrochemicals, we have also been working to establish simple alcohols as electrophiles in cross coupling reactions. This work has focused on the use of powerful Lewis acids to facilitate functionalization with a nucleophile. Based on this work, the use of simple, unactivated alcohols in Friedel-Crafts-type arylations,[7] Ritter reactions, and alcohol additions to alkynes are now possible.[8] Moreover, the dehydrating power of our Fe/Ag system has been demonstrated in Beckmann rearrangement chemistry as well.[9]

Since cross-coupling reactions play a pivotal role in creating value-added products for petrochemicals, we have worked to broaden our work in iron catalysis to include important cross coupling reactions. For example, we recently reported the first iron-catalyzed Csp²-Csp² cross coupling of aryl tosylates and sulfamates with aryl Grignards.[10] Additionally, we have reported an imporanat iron-catalyzed borylation reaction that allows for the conversion of alkyl halides and tosylates into alky boronates.[11] This work was one of the top 10 “Most Read” papers in JACS for July 2014 and was recently highlighted in Org. Proc. Res. Dev. (2014, 18, 1047-1082).

[1] Gao, P.; Cook, S. P. "A Reductive-Heck Approach to the Hydroazulene Ring System: A Formal Synthesis of the Englerins," Org. Lett. 2012, 14, 3340–3343.

[2] Monks, B. M.; Cook, S.P. "Palladium-Catalyzed Alkyne Insertion/Suzuki Reaction of Alkyl Iodides" J. Am. Chem. Soc, 2012, 134, 15297–15300.

[3] Fruchey, E. R.; Monks, B. M.; Patterson, A. M.; Cook, S. P. "Palladium-Catalyzed Alkyne Insertion/Reduction Route to Trisubstituted Olefins" Org. Lett. 2013, 15, 4362–4365.

[4] Monks, B. M.; Cook, S.P. "Palladium-Catalyzed, Intramolecular Iodine-Transfer Reactions in the Presence of b-Hydrogens" Angew. Chem. Int. Ed., 2013, accepted.

[5] Monks, B. M.; Fruchey, E. R.; Cook, S. P. "Iron-Catalyzed C(sp2)–H Alkylation of Carboxamides with Primary Electrophiles," Angew. Chem. Int. Ed., 2014, Early View (DOI: 10.1021/ja505199u).

[6] Fruchey, E. R.; Monks, B. M.; Cook, S. P. "A Unified Strategy for Iron-Catalyzed ortho-Alkylation of Carboxamides," J. Am. Chem. Soc, 2014, ASAP (DOI: 10.1021/ja506823u).

[7] Jefferies, L. R., Cook, S. P. “Iron-Catalyzed Arene Alkylation Reactions with Unactivated Secondary Alcohols,” Org. Lett., 2014, 16, 2026-2029 (DOI: 10.1021/ol500606d).

[8] Jefferies, L. R., Cook, S. P. “Alcohols as Electrophiles: Iron-Catalyzed Ritter Reactions and Benzyl Alcohol Additions to Alkynes,” Tetrahedron, 2014, 70, 4204-4207 (DOI: 10.1016/j.tet.2014.03.072).

[9] Jefferies, L. R., Cook, S. P. “Iron-catalyzed C-N formation in Beckmann rearrangment,” Synlett, 2014, submitted.

[10] Agrawal, T.; Cook, S. P. “Iron-Catalyzed Coupling of Aryl Sulfamates and Aryl/Vinyl Tosylates with Aryl Grignards,” Org. Lett. 2014, ASAP (DOI: 10.1021/ol024344).

[11] Atack, T. C.; Lecker, R. M.; Cook, S. P. "Iron-Catalyzed Borylation of Alkyl Electrophiles," J. Am. Chem. Soc, 2014, 136, 9521-9523 (DOI: 10.1002/anie.201406594).