André M. Beauchemin

Photocatalytic Generation of N‐Centered Hydrazonyl Radicals: A Strategy for Hydroamination of β,γ‐Unsaturated Hydrazones

A visible-light photocatalytic generation of N-centered hydrazonyl radicals has been accomplished for the first time. This approach allows efficient intramolecular addition of hydrazonyl radical to terminal alkenes, thus providing hydroamination and oxyamination products in good yields. Importantly, the protocol involves deprotonation of an N-H bond and photocatalytic oxidation to an N-centered radical, thus obviating the need to prepare photolabile amine precursors or the stoichiometric use of oxidizing reagents.

Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes†

Nitrogen-containing functional groups are ubiquitous in natural products and pharmaceuticals. The hydroamination of unactivated alkenes and alkynes is an attractive approach for the synthesis of such molecules, but it is underdeveloped and remains challenging, especially for intermolecular reactions. Most recent progress has been accomplished using transition-metal catalysis, or strong acids with less basic nitrogen nucleophiles, but often procedures are limited to specific substrate classes and functional-group compatibility is either limited or yet undefined. A conceptually different approach to the functionalization of alkenes and alkynes in intramolecular reactions is the Cope-type hydroamination (also referred to as reverse-Cope cyclization). 6] While this strategy has received some attention (particularly in the formation of fiveand six-membered heterocycles), fundamental limitations have precluded its application in synthesis and in more challenging intermolecular reactions. Notably, the nitrogen atom is usually substituted to increase reactivity, but this severely limits the reaction scope, leading to the formation of amine oxides, which are less versatile synthetic intermediates and less stable products. Consequently, the intermolecular process is energetically unfavorable (Scheme 1). To expand the use of this concerted hydroamination strategy, we sought a solution to this requirement for nitrogen substitution (R’, R’’= alkyl). Herein, we report that heating (unsubstituted) aqueous hydroxylamine with alkynes and alkenes affords the intermolecular hydroamination products under mild conditions and in the absence of a metal catalyst. We also present experimental and theoretical evidence which suggest that the reduced reactivity of less substituted hydroxylamines is associated with a difficult intramolecular proton-transfer step rather than a difficult hydroamination step (Scheme 2). Thus, the presence of alcohols or water in our reaction conditions is crucial to mediate a facile, bimolecular proton transfer of the amine oxide intermediate.

Total Synthesis of (+)-Azaspiracid-1. An Exhibition of the Intricacies of Complex Molecule Synthesis

The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual fragments were synthesized by catalytic enantioselective processes: A hetero-Diels-Alder reaction to afford the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by aldol and sulfone anion methodologies. All ketalization events to form the nonacyclic target were accomplished under equilibrating conditions utilizing the imbedded configurations of the molecule to adopt one favored conformation. A final fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-aldehyde completed the convergent synthesis of (+)-azaspiracid-1.

Hydrazides as tunable reagents for alkene hydroamination and aminocarbonylation.

Benzoic hydrazides (R = Ph), which are remarkably bench and thermally stable reagents (often up to 230 degrees C), afford intramolecular hydroamination products upon heating at high temperatures (120-235 degrees C). A concerted Cope-type hydroamination event, followed by a hydrazide-mediated proton transfer step of the hydrazinium ylide intermediate, is proposed and supported by DFT calculations. In contrast, a simple modification of the reagent structure (R = Ot-Bu or NH(2)) favors the formation of aminocarbonylation products at 200 degrees C, and the latter reaction is shown to be stereospecific.

A catalytic tethering strategy: simple aldehydes catalyze intermolecular alkene hydroaminations.

Herein we describe a catalytic tethering strategy in which simple aldehyde precatalysts enable, through temporary intramolecularity, room-temperature intermolecular hydroamination reactivity and the synthesis of vicinal diamines. The catalyst allows the formation of a mixed aminal from an allylic amine and a hydroxylamine, resulting in a facile intramolecular hydroamination event. The promising enantioselectivities obtained with a chiral aldehyde also highlight the potential of this catalytic tethering approach in asymmetric catalysis and demonstrate that efficient enantioinduction relying only on temporary intramolecularity is possible.

Intermolecular cope-type hydroamination of alkenes and alkynes using hydroxylamines.

The development of the Cope-type hydroamination as a method for the metal- and acid-free intermolecular hydroamination of hydroxylamines with alkenes and alkynes is described. Aqueous hydroxylamine reacts efficiently with alkynes in a Markovnikov fashion to give oximes and with strained alkenes to give N-alkylhydroxylamines, while unstrained alkenes are more challenging. N-Alkylhydroxylamines also display similar reactivity with strained alkenes and give modest to good yields with vinylarenes. Electron-rich vinylarenes lead to branched products while electron-deficient vinylarenes give linear products. A beneficial additive effect is observed with sodium cyanoborohydride, the extent of which is dependent on the structure of the hydroxylamine. The reaction conditions are found to be compatible with common protecting groups, free OH and NH bonds, as well as bromoarenes. Both experimental and theoretical results suggest the proton transfer step of the N-oxide intermediate is of vital importance in the intermolecular reactions of alkenes. Details are disclosed concerning optimization, reaction scope, limitations, and theoretical analysis by DFT, which includes a detailed molecular orbital description for the concerted hydroamination process and an exhaustive set of calculated potential energy surfaces for the reactions of various alkenes, alkynes, and hydroxylamines.

Catalysis through temporary intramolecularity: mechanistic investigations on aldehyde-catalyzed Cope-type hydroamination lead to the discovery of a more efficient tethering catalyst.

Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.

Synthesis of Pyridines and Pyrazines Using an Intramolecular Hydroamination-Based Reaction Sequence†

The prevalence and diversity of aromatic nitrogen heterocycles found in natural products and used in medicinal chemistry continues to fuel the development of new methods and strategies for their syntheses. Recently, advances in amination chemistry (e.g., C H insertions, metal-catalyzed annulations, Buchwald–Hartwig cross-couplings, oxidative aminations, hydroaminations) have enabled routes to diverse aromatic ring systems and offer excellent potential for broad applicability in heterocycle synthesis. Specifically, several hydroamination routes to access unsaturated nitrogen functional groups are emerging. The hydroamination of alkynes using amines (and equivalents thereof) affords enamines or imines reliably, and alkene “hydroiminiumation” reactivity of imines recently reported by Bertrand et al. are representative examples. However, hydroamination routes to aromatic nitrogen heterocycles are rare and have so far been mostly limited to five-membered ring systems. Analogously, metalcatalyzed alkyne annulations have been thoroughly studied, such as indole formation from o-alkynylanilines or isoquinoline formation from o-alkynylbenzaldimines, but reports of such cyclizations to form pyridines or pyrazines are rare. Herein we report a simple acid-catalyzed hydroamination/ isomerization/aromatization sequence leading to pyridines and pyrazines from simple acyclic alkynyl oxime (LG = OH) precursors [Eq. (1)].

The Tandem Cope-Type Hydroamination/[2,3]-Rearrangement Sequence: A Strategy to Favor the Formation of Intermolecular Hydroamination Products and Enable Difficult Cyclizations

The tandem hydroamination/Meisenheimer rearrangement sequence was developed to address the issue of unfavorable reaction thermodynamics for intermolecular reactions of alkenes and to improve the scope of Cope-type hydroaminations. This tandem sequence allows intermolecular reactions of N-alkyl-N-methallylhydroxyl-amines to be energetically more favorable: the N-oxide intermediate formed via Cope-type hydroamination, which can revert to the starting materials via a Cope elimination, can form a more stable neutral product via a [2,3]-Meisenheimer rearrangement. This tandem sequence also leads to increased efficiency in intramolecular systems as illustrated by syntheses of two alkaloids (coniine and norreticuline) featuring difficult hydroamination key steps.

A Tunable Route for the Synthesis of Azomethine Imines and β-Aminocarbonyl Compounds from Alkenes

Cyclic azomethine imines possessing a β-aminocarbonyl motif are accessed from simple alkene and hydrazone starting materials. A thermal, concerted alkene aminocarbonylation pathway involving an imino-isocyanate intermediate is proposed and supported by DFT calculations. A notable feature of the process is the steric shielding present in the dipoles formed, which allows for facile purification of the products by chromatography or crystallization. In addition, a fluorenone-derived reagent is reported, which provides reactivity with several alkene classes and allows for mild derivatization of the dipoles into β-aminoamides, β-aminoesters, and β-amino acids.