2016 Publications

Sha, Q.; Arman, H.; Doyle, M.P. “Asymmetric Synthesis of 1H-Pyrrol-3(2H)-ones from 2,3-Diketoesters by Combination of Aldol Condensation with Benzilic Acid Rearrangement” Chem. Commun. 2016, 52, 108-111. (DOI: 10.1039/C5CC07780J)

A highly efficient two-step protocol for the asymmetric synthesis of 1H-pyrrol-3(2H)-one derivatives from conveniently accessed 2,3-diketoesters has been developed. The aldol products were obtained in moderate to good yields with up to 89/11 d.r. and 99% ee. Benzylic acid rearrangement of the major diastereoisomer produced 1H-pyrrol-3(2H)-ones in good yields without loss of enantioselectivity.

Cheng, Q.-Q.; Yedoyan, J.; Arman, H.; Doyle, M.P. “Copper-Catalyzed Divergent Addition Reactions of Enoldiazoacetamides with Nitrones” J. Am. Chem. Soc. 2016, 138, 44-47. (DOI: 10.1021/jacs.5b10860)

This manuscript describes for the first time the use of easily accessible and highly efficient copper(I) catalysts that as the tetrafluoroborate salt with a chiral BOX ligand produce [3 + 3]-cycloaddition products in the highest yields (all > 90%) and enantioselectivities (all > 93% ee) yet observed for cycloaddition reactions of vinyldiazo compounds, and with copper(I) triflate directs the same reactants to Mukaiyama-Mannich products in which the diazo functionality is retained. These accessible and highly efficient copper catalysts exhibit their unique advantages by switching the reaction pathway between Mannich addition and [3+3]-cycloaddition.

Qiu, H.; Srinivas, H.; Zavalij, P.; Doyle, M.P. “Unprecedented Intramolecular [4+2]-Cycloaddition Between a 1,3-Diene and a Diazo Ester” J. Am. Chem. Soc. 2016, 138, 1808-1811. (DOI: 10.1021/jacs.5b12877)

This manuscript describes for the first time the [4+2]-cycloaddition reaction between the N=N of a diazo functional group and a diene. This transformation has not been previously observed with diazo compounds which normally react with alkenes and one C=C of dienes by [3+2]-cyclization, even though their isoelectronic allenes and ketenes are well known to undergo [4+2]-cycloaddition.

Cheng, Q.-Q.; Yedoyan, J.; Arman, H.; Doyle, M.P. “Dirhodium(II)-Catalyzed Annulation of Enoldiazoacetamides with α-Diazoketones: An Efficient and Highly Selective Approach to Fused and Bridged Ring Systems” Angew. Chem. Int. Ed. 2016, 55, 5573-5576. (inside cover, pg 5350) (DOI: 10.1002/anie.201601260)

A new synthetic methodology is reported through which two diazocarbonyl compounds undergo dinitrogen extrusion with the same catalyst to form two reactive chemical intermediates that combine by [3+2]-cycloaddition to furnish unique benzoxa[3.2.1]octane scaffolds in high yield. Furthermore, the cyclopropane-fused benzoxa[3.2.1]octane products are readily transformed into benzoxa[3.3.1]nonane and hexahydronaphthofuran derivatives with exact stereocontrol. All three ring systems are important skeletons of numerous biologically active natural products.

Doyle, M.P.; Deng, Y.; Qiu, H.; Srinivas, H. “Chiral Dirhodium(II) Catalysts for Selective Metal Carbene Reactions” Curr. Org. Chem. 2016, 20, 61-81. (DOI: 10.2174/1385272819666150714182732)

Dirhodium(II) catalysts have proven effectiveness in controlling selectivity in metal carbene reactions of diazocarbonyl compounds. Over the years many dirhodium(II) paddlewheel derivatives with chiral ligands have been advanced, but three structural classes have emerged as being most effective for inducing high stereocontrol: chiral dirhodium carboxamidates derived from cyclic chiral carboxamides and chiral dirhodium carboxylic acids derived from sybstituted chiral prolinates or from phthalimide-protected α-amino acids. This review focuses on describing which of these classes of chiral dirhodium(II) catalysts have provided the highest levels of stereocontrol in intramolecular and intermolecular reactions of diazoacetates, diazoacetoacetates and diazomalonates, vinyl- and aryldiazoacetates, and enoldiazoacetates. Assessment is taken from published results that compare catalyst results for cyclopropanation, cyclopropenation, C-H insertion, ylide formation and reactions, as well as cycloaddition reactions, especially [3+3]- and [4+3]-cycloaddition.

Deng, Y.; Doyle. M.P. “Versatile Donor-Acceptor Cyclopropenes in Metal Carbene Transformations” Isr. J. Chem. 2016, 56, 399-408. (DOI: 10.1002/ijch.201500083)

Select transition metal compounds catalyze metal vinylcarbene formation from cyclopropenes, and their documented reactions include both intermolecular and intramolecular C-H insertion and cyclopropanation, as well as [3+3]-cycloaddition. Although known to undergo carbene-like transformations for decades, the uses of cyclopropenes as reactive alternatives to diazo compounds under mild conditions has been limited. However, recently developed donor-acceptor cyclopropenes that are conveniently accessed from enoldiazoacetates and enoldiazoacetamides are effective metallo-vinylcarbene precursors. They provide entry to highly stereoselective metal carbene transformations under reaction conditions that are milder than those required for dinitrogen extrusion from diazo compounds.

Deng, Y.; Yglesias, M.V.; Arman, H.; Doyle, M.P. “Catalytic Asymmetric Synthesis of Cyclopentyl β-Amino Esters by [3+2]-Cycloaddition of Enecarbamates with Electrophilic Metalloenolcarbene Intermediates” Angew. Chem. Int. Ed. 2016, 55, 10108-10112. (DOI: 10.1002/anie.201605438)

Chiral cyclopentyl β-amino esters are formed catalytically by [3+2]-cycloaddition reactions of enecarbamates with electrophilic metalloenolcarbenes in high yield with up to 98% ee and excellent diastereocontrol. Use of β-TBSO-substituted enoldiazoacetates with the chiral dirhodium catalyst Rh2(S-TCPTTL)4 and trans-β-arylvinylcarbamates are optimal for this transformation that occurs with hydrogen bond association between the vinylcarbamate and the intermediate metalloenolcarbene. Reductive conversion of the protected amino-esters forms highly functionalized cyclopentyl β-amino acids and 3-aminocyclopentanones.

Jing, C.; Cheng, Q.-Q.; Deng, Y.; Arman, H.; Doyle, M.P. “Highly Regio- and Enantioselective Formal [3+2]-Annulation of Indoles with Electrophilic Enol Carbene Intermediates” Org. Lett. 2016, 18, 4550-4553. (DOI: 10.1021/acs.orglett.6b02192)


Chiral cyclopentane-fused indolines are synthesized with high regio- and enantiocontrol by formal [3+2]-annulation reactions of indoles and electrophilic enol carbenes. High enantioselectivity and exclusive regiocontrol occurred with enoldiazoacetamides using a less sterically encumbered prolinate-ligated dirhodium(II) catalyst in reactions with N-substituted indoles without substituents at the 2- or 3-positions via a selective vinylogous addition process. In this transformation, donor–acceptor cyclopropenes generated from enoldiazoacetamides serve as the carbene precursors to form metal carbene intermediates.

Marichev, K.O.; Qiu, H.; Offield, A.C.; Arman, H.; Doyle, M.P. “Catalyst-free Rearrangement of Allenyl Aryldiazoacetates into 1,5-Dihydro-4H-pyrazol-4-ones” J. Org. Chem. 2016, 81, 9235-9246. (DOI: 10.1021/acs.joc.6b01833)


Phenylpropargyl diazoacetates exist in equilibrium with 1-phenyl-1,2-dien-1-yl diazoacetate – allenes that are rapidly formed at room temperature through 1,3-acyloxy migration catalyzed by gold(I) or gold(III) compounds, and these catalysts react solely with the π-donor rather than with the diazo group. The product allene of the aryldiazoacetates undergoes rearrangement that is not catalyzed by gold in which the terminal nitrogen of the diazo functional group adds to the central carbon of the allene initiating a sequence of bond forming reactions resulting in the production of 1,5-dihydro-4H-pyrazol-4-ones in good yields. These 1,5-dihydro-4H-pyrazol-4-ones undergo intramolecular 1,3-acyl migration to form an equilibrium mixture and can quantitatively transfer the acyl group to an external nucleophile with formation of 4-hydroxypyrazoles. Reactions of phenylpropargyl phenyldiazoacetates catalyzed by cationic gold complexes are initiated at the diazo functional group to form a gold carbene whose subsequent cascade process (intramolecular addition then aromatic substitution) results in the formation of a product that is uniquely characteristic of this pathway.

Deng, Y.; Jing, C.; Arman, H.; Doyle, M.P. “Reactivity and Selectivity in Catalytic Reactions of Enoldiazoacetamides. Assessment of Metal Carbenes as Intermediates” Organometal. 2016, 35, 3413-3420. (DOI: 10.1021/acs.organomet.6b00648)

Catalyst effectiveness for metal carbene formation and reactions has been surveyed using N-(tert-butyl)-3-[(tert-butyldimethylsilyl)oxy]-2-diazo-N-(4-chlorobenzyl)but-3-enamide in the formation of the products from both intramolecular C-H insertion and aromatic cycloaddition. Both products are indicators of metal carbene intermediates, and this system provides a means to assess catalysts for metal carbene formation. Donor-acceptor cyclopropene production from the reactant enoldiazoacetamide has been monitored to assess its formation, and the independently formed cyclopropene has also been used to assess metal carbene formation. Catalysts of rhodium(II), copper(I), silver(I), Pd(II), cationic Au(I), and Zn(II) convert the enoldiazoacetamide to the donor-acceptor cyclopropene which serves as the resting state for the intermediate metal carbene, and both the enoldiazoacetamide and its derivative cyclopropene give the same ratios of insertion to cycloaddition products. Catalysts of copper(II) and Ru(II) do not give the cyclopropene as an observable intermediate, and the product ratio from insertion/cycloaddition varies when the reactant is the enoldiazoacetate from that with its derivative cyclopropene. The variation of product ratio with the metal carbene precursor in copper(II) catalyzed reactions is dependent on the catalyst ligand, the solvent, and substituents of the benzyl group of the reactant. [Ru(p-cymene)Cl2]2 formed the products from a metal carbene intermediate with the reactant enoldiazoacetamide catalytically, but with an enoldiazoacetate formed a η3-allyl ruthenium complex stoichiometrically.

Deng, Y.; Pei, C.; Arman, H.; Dong, K.; Xu, X.; Doyle, M.P. “Syntheses of Tetrahydropyridazine and Tetrahydro-1,2-diazepine Scaffolds through Cycloaddition Reactions of Azoalkenes with Enol Diazoacetates” Org. Lett. 2016, 18, 5884–5887. (DOI: 10.1021/acs.orglett.6b02965)

Catalyst-dependent [4+2]-cycloaddition reactions of azoalkenes from α-halohydrazones with enoldiazoacetates have been developed. A [4+2]-cycloaddition of enoldiazoacetates with in situ formed azoalkenes produces tetrahydropyridazinyl-substituted diazoacetates promoted by only Cs2CO3. In contrast, donor-acceptor cyclopropenes, which are formed in situ from enoldiazoacetates by Rh2(OAc)4 catalyzed dinitrogen extrusion, undergo [4+2]-cycloaddition with azoalkenes yielding bicyclo[4.1.0]-tetrahydropyridazines. These stable cycloaddition products undergo subsequent one-step transformations to form 6-alkylidene-tetrahydropyridazines and 4,5,6,7-tetrahydro-1,2-diazepine derivatives in good yields.

Cheng, Q.-Q.; Doyle, M.P. “The Selection of Catalysts for Metal Carbene Transformations” in Adv. Organometal. Chem., Vol. 66 Perez, P. J., Ed., Elsevier Limited. Oxford, United Kingdom, 2016. Chapter 1, pg. 1-26. (DOI:10.1016/bs.adomc.2016.07.002)

A selective survey of the literature since 2013 that includes novel catalytic strategies and transformations involving electrophilic metal carbene intermediates is presented. This review is organized according to donor and acceptor substituents of the carbene precursor and provides an overview of the rapidly expanding field of electrophilic metal carbene generation and reactions. New developments in catalyst and ligand design, the expanded uses of diazo compounds, and the profusion of transformations are presented. The rapid expansion in applications of electrophilic metal carbenes from cyclopropanation and C−H insertion to cycloaddition and reactions of carbene-generated ylides are among the highlighted developments that are discussed.