2017 Publications

Qiu, H.; Deng, Y.; Marichev, K.O.; Doyle, M.P. “Diverse Pathways in Catalytic Reactions of Propargyl Aryldiazoacetates. Selectivity Between Three Reaction Sites” J. Org. Chem. 2017, 82, 1584-1590. (DOI: 10.1021/acs.joc.6b02770)

Three catalyst-dependent divergent reaction pathways for reactions of propargyl aryldiazoacetates are disclosed. Transition metal catalysts including those of rhodium(II), palladium(0 and II), silver(I), mercury(II), copper(I and II), platinum(II) and cationic gold(I) are effective for reactions that proceed through dinitrogen extrusion, carbene/alkyne metathesis, and aromatic substitution to form fused indeno-furanones, and use of tetrakis(acetonitrile)copper(I) provides indeno-furanones in the highest product yields. A Lewis acid catalyzed pathway that forms furan-2-ones is uncovered with FeCl3, ZnBr2 and BF3•Et2O as catalysts that proceed through activation of the aryldiazoacetate ester for arylpropargyl cation dissociation followed by recombination through cation addition to the diazo carbon. Neutral gold catalysts selectively activate the triple bond of propargyl aryldiazoacetates, resulting in the formation of allenic aryldiazoesters that further undergo uncatalyzed rearrangement.

Duan, A.; Yu, P.; Liu, F.; Qiu, H.; Gu, F.L.; Doyle, M.P.; Houk, K.N. “Diazo Esters as Dienophiles in Intramolecular (4+2) Cycloadditions: Computational Explorations of Mechanism” J. Am. Chem. Soc. 2017, 139, 2766–2770. (DOI: 10.1021/jacs.6b12371)

The first experimental examples of Diels–Alder (DA) reactions of diazo compounds as heterodienophiles with dienes have been studied with density functional theory (DFT) using the M06-2X functional. For comparison, the reactivities of diazo esters as dienophiles or 1,3-dipoles with
1,3-dienes in intermolecular model systems have been analyzed by the distortion/interaction model. The 1,3-dipolar cycloaddition is strongly favored for the intermolecular system. The intramolecular example is unique because the tether strongly favors the (4+2) cycloaddition.

Marichev, K.O.; Ramey, J.T.; Arman, H.; Doyle, M.P. “Highly Regio-, Diastereo-, and Enantioselective Rhodium-Catalyzed Intramolecular Cyclopropanation of (Z)-1,3-Dienyl Aryldiazoacetates” Org. Lett. 2017, 19, 1306-1309. (DOI: 10.1021/acs.orglett.6b02965)

Chiral cyclopenta[2,3]-cyclopropa[1,2-c]pyran-4-ones have been synthesized via dirhodium(II)-catalyzed intramolecular cyclopropanation of (Z)-1,3-dienyl aryldiazoacetates. High regio-, diastereo-, and enantiocontrol were achieved using chiral dirhodium 2-phthalimide carboxylates. Preferential addition occurs at the 3,4- rather than the 1,2-double bond with the chiral dirhodium catalysts, although both outcomes occur with other transition metal catalysts.

Deng, Y.; Massey, L.A.; Zavalij, P.Y.; Doyle, M.P. “Catalytic Asymmetric [3+1]-Cycloaddition Reaction of Ylides with Electrophilic Metallo-Enolcarbene Intermediates” Angew. Chem. Int. Ed. 2017, 56, 7479-7483. (DOI: 10.1002/anie.201704069)

The first asymmetric [3+1]-cycloaddition was successfully achieved by copper(I) triflate/double-sidearmed bisoxazoline complex catalyzed reactions of β-triisopropylsilyl-substituted enoldiazo compounds with sulfur ylides. This methodology delivered a series of chiral cyclobutenes in good yields with high enantio- and diastereoselectivities (up to 99% ee, and >20:1 dr). Additionally, the [3+1]-cycloaddition of catalytic metallo-enolcarbenes was successfully extended to reaction with a stable benzylidene dichlororuthenium complex.

Yu, Y.; Humeidi, R.; Alleyn, J.R.; Doyle, M.P. “Catalytic Allylic Oxidation of Cyclic Enamides and 3,4-Dihydro-2H-Pyrans by TBHP” J. Org. Chem. 2017, 82, 10732-10736. (DOI: 10.1021/acs.joc.7b01163)

Allylic oxidation of heteroatom substituted cyclic alkenes by tert-butyl hydroperoxide (70% TBHP in water) using catalytic dirhodium caprolactamate [Rh2(cap)4] forms enone products with a variety of 2-substituted cyclic enamides and 3,4-dihyro-2H-pyrans. These reactions occur under mild reaction conditions, are operationally convenient to execute, and are effective for product formation with as low as 0.25 mol% catalyst loading. With heteroatom stabilization of the intermediate allylic free radical two sites for oxidative product formation are possible, and the selectivity of the oxidative process varies with the heteroatom when R = H. Cyclic enamides produce 4-piperidones in good yields when R = alkyl or aryl, but oxidation of 2H-pyrans also gives alkyl cleavage products. Alternative catalysts for TBHP oxidations show comparable selectivities but give lower product yields.

Deng, Y.; Cheng, Q.-Q.; Doyle, M.P. “Asymmetric [3+3] Cycloaddition for Heterocycle Synthesis” Synlett 2017, 28, 1695-1706. (DOI: 10.1055/s-0036-1588453)

Asymmetric syntheses of six-membered ring heterocycles are important research targets not only in synthetic organic chemistry but also in pharmaceuticals. The [3+3]-cycloaddition methodology is a complimentary strategy to [4+2]-cycloaddition for the synthesis of heterocyclic compounds. Recent progress in [3+3]-cycloaddition processes provides powerful asymmetric methodologies for the construction of six-membered ring heterocycles with one to three heteroatoms in the ring. In this Account, synthetic efforts during the past five years towards the synthesis of enantioenriched six-membered ring heterocycles through asymmetric [3+3]-cycloaddition are reported. Asymmetric organocatalysis uses chiral amines, thioureas, phosphoric acids, or NHC catalysis to achieve high enantiocontrol. Transition metal catalysts used as chiral Lewis acids to activate a dipolar species is an alternative approach. The most recent advance, chiral transition metal catalyzed reactions of enoldiazo compounds, has contributed versatile and highly selective synthesis of six-membered heterocyclic compounds.

Cheng, Q.-Q.; Lankelma, M.; Wherritt, D.; Arman, H.; Doyle, M.P. “Divergent Rhodium-Catalyzed Cyclization Reactions of Enoldiazoacetamides with Nitrosoarenes” J. Am. Chem. Soc. 2017, 139, 9839-9842. (DOI: 10.1021/jacs.7b05840)

The first cyclization reactions of enoldiazo compounds with nitrosoarenes have been developed. Under the catalysis of rhodium(II) octanoate, [3+2]-cyclization between enoldiazoacetamides and nitrosoarenes occurred through cleavages of the enol double bond and the amide bond, thus furnishing fully substituted 5-isoxazolone derivatives. Upon changing the catalyst to rhodium(II) caprolactamate, the reaction pathway switched to an unprecedented formal [5+1]-cyclization that provided multifunctionalized 1,3-oxazin-4-ones with near exclusivity under otherwise identical conditions. Mechanistic studies uncovered distinct catalytic activities and reaction intermediates, which plausibly rationalized the novel reactivity and catalyst-controlled chemodivergence. Furthermore, a mechanism-inspired enantioselective rhodium-catalyzed reaction of γ-substituted enoldiazoacetamide with nitrosobenzene produced highly enantioenriched heterocycle-linked trialkylamine.

Cheng, Q.-Q.; Deng, Y.; Lankelma, M.; Doyle, M.P. “Cycloaddition Reactions of Enoldiazo Compounds” Chem. Soc. Rev. 2017, 46, 5425-5443. (DOI: 10.1039/c7cs00324b)

Enoldiazo esters and amides have proven to be versatile reagents for cycloaddition reactions that allow highly efficient construction of various carbocycles and heterocycles. Their versatility is exemplified by (1) [2+n]-cycloadditions (n = 3, 4) by the enol silyl ether units of enoldiazo compounds with retention of the diazo functionality to furnish α-cyclic-α-diazo compounds that are themselves subject to further transformations of the diazo functional group; (2) [3+n]-cycloadditions (n= 1−5) by metallo-enolcarbenes formed by catalytic dinitrogen extrusion from enoldiazo compounds; (3) [2+n]-cycloadditions (n = 3, 4) by donor−acceptor cyclopropenes generated in situ from enoldiazo compounds that produce cyclopropane-fused ring systems. The role of dirhodium(II) and the emergence of copper(I) catalysts are described, as are the different outcomes of reactions initiated with these catalysts. This comprehensive review on cycloaddition reactions of enoldiazo compounds, with emphasis on methodology development, mechanistic insight, and catalyst-controlled chemodivergence, aims to provide inspiration for future discoveries in the field and to catalyze the application of enoldiazo reagents by the wider synthetic community

Deng, Y.; Massey, L.A.; Rodriguez Núñez, Y.A.; Arman, H.; Doyle, M.P. “Catalytic Divergent [3+3]- and [3+2]-Cycloaddition by Discrimination Between Diazo Compounds” Angew. Chem. Int. Ed. 2017, 57, 12292–12296. (DOI:10.1002/anie.201706639)

Highly selective divergent cycloaddition reactions of enoldiazo compounds and α-diazocarboximides catalyzed by copper(I) or dirhodium(II) have been developed. With tetrakis(acetonitrile)copper(I) tetrafluoroborate as the catalyst epoxypyrrolo[1,2-a]azepine derivatives were prepared in good yields and excellent diastereoselectivities through the first reported [3+3]-cycloaddition of a carbonyl ylide. Use of Rh2(pfb)4 or Rh2(esp)2 directs the reactants to regioselective [3+2]-cycloaddition generating cyclopenta[2,3]pyrrolo[2,1-b]oxazoles with good yields and excellent diastereoselectivities.

Marichev, K.O.; Garcia, E.C.; Bhowmick, K.C.; Wherritt, D.J.; Arman, H.; and Doyle, M.P. “Highly selective acylation of polyamines and aminoglycosides by 5-acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones” Chem. Sci. 2017, 8, 7152–7159. (DOI: 10.1039/C7SC03184J)

5-Acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones, accessible from arylpropargyl phenyldiazoacetates, are highly selective acyl transfer reagents for di- and polyamines, as well as aminoalcohols and aminothiols. As reagents with a carbon-based leaving group, they have been applied for benzoyl transfer with a broad selection of substrates containing aliphatic amino- in combination with other competing nucleophilic functional groups. The substrate scope and levels of selectivity for direct benzoyl transfer exceed those of known benzoylating reagents. With exceptional selectivity for acylation between primary amines bound to primary and secondary carbons, these new reagents have been used in direct site-selective monobenzoylation of aminoglycoside antibiotics.