Formal allene insertion into amides. Reaction of propargyl magnesium bromide with morpholine amides

Propargyl magnesium bromide rapidly undergoes addition to morpholine amides forming push-pull enaminones – products of allene formal insertion. The scope of the reaction and functional group tolerance are demonstrated on 16 examples, giving rise either to enaminones or 1,3-diketones after instant hydrolysis on silica. Further approaches for direct utilization of crude enaminones are also demonstrated.


Introduction
Recently we have become interested in synthesis of 3-methylbenzo[c]oxepin-5(1H)-ones 1, which we considered as promising building blocks for total synthesis of the rearranged angucyclinone derivatives. 1,2The only description in literature approach to such heterocycles employs addition of propargyl magnesium bromide to phthalides and the following acidic work-up. 3This reaction has intrigued us, because it is a rare example of Grignard mono addition to an ester.
Attempts to reproduce this literature precedent on unsubstituted phthalide however have failed (mostly di-addition product was formed), which have prompted us to search for alternative pathways (Scheme 1).During such studies we attempted addition of the same Grignard reagent to morpholine amides 2, which are known to undergo selective monoaddition providing access to ketone derivatives. 4heme 1. a) Literature precedent and our attempts to reproduce it; b) reaction, developed in this work.
It was discovered that the product of the above reaction was not the expected allenyl ketone 5,6 but enaminone 3 as predominant product.Although its formation could be predicted based on the related literature precedents, 7,8 it was previously undescribed.Extreme ease of such transformation and availability of the starting materials prompted us to study its synthetic potential.Thus, this reaction opens the opportunity to prepare regioselectively enaminones in a single step from cheap morpholine amides and could be regarded as a preparative method.
Synthesis of enaminones is generally performed directly by amine action on 1,3-diketones, 9,10 which are in hand prepared by Claisen condensation of ketone and ester. 11However, in recent years several new methods for synthesis of both 1,3-diketones and enaminones have emerged: reaction of amides (instead of esters) in Claisen condensation; 12,13 addition of organometallic nucleophiles to borylated ketoesters; 14 sulfur extrusion in the Eschenmoser contraction reaction; 15,16 condensation of azaenolate, derived from LDA, to methyl esters; 17 amine addition to ynones; 18,19 as well as some others. 20In comparison to already developed methods, the current protocol is using the more powerful nucleophile and is rather fast, although allows synthesis of enaminones with methyl group only.However, this reaction provides an alternative to aldol-type reactions of acetone, which are known to be problematic. 21age 3 of 14 © AUTHOR(S)

Results and Discussion
Optimization of the reaction conditions was performed on unsubstituted phenyl derivative 2a.There were two key factors found, responsible for reproducibility and feasibility of results: 1) proper stoichiometry of reagents to achieve full conversion of the initial amide as well as to mitigate undesired side-processes (which however occur only in use of great excess of Grignard reagent) and 2) proper quenching and work-up of the reaction mixture.Neither reaction temperature (-78 °C or 0 °C), nor solvent (THF or Et2O) or concentration had much impact on the reaction course.Therefor, the optimal conditions were the use of 1.2 equiv. of propargyl magnesium bromide (titrated with menthol/phenanthroline) 22 at 0 °C in THF, followed by slow quench with water.Enaminone 3a was formed in ca.70% yield based on 1 H NMR but its isolation was complicated with rapid hydrolysis into corresponding diketone 4a (existing mostly in tautomeric enol form in solution according to NMR analysis), which occurs quantitively during silica gel chromatography.Use of the alternative sorbents was also inefficient.The primary product 3a could be isolated by precipitation from acetone with pentane, although with significant material losses.Thus, further scope determination was performed with isolation of 1,3-diketones 4, while enaminones 3 were characterized only in selected cases.
Scheme 2. Substrate scope for the preparation of the aromatic enaminones 3 and diketones 4.
The scope of the reaction was established on differently substituted amides 2 (Scheme 2).The efficiency of the addition to 4-substituted aromatic amides 2b-f was relatively the same.Diketones 4b-f were obtained in 56-82% yields.In most cases, enaminones 3 were also isolated in 21-45% yields after recrystallization.The only exception was nitro derivative 4g, which we were unable to prepare due to the reaction of the nitro group with organometallic reagent.Both m-and o-methoxy derivatives 2h and 2i were participating in the reaction giving rise to 1,3-diketones 4h and 4i in 75% and 68% yield, respectively, meaning that the reaction is, at least in part, tolerant to steric hindrance.Scheme 3. Substrate scope for the preparation of the heteroaromatic, olefinic and aliphatic enaminones 3 and diketones 4.
Later, we studied heteroaromatic derivatives (Scheme 3).Both 2-pyridinyl and 3-pyridinyl amides 2j and 2k participated in the reaction, although we observed some complications during aqueous work-up due to high polarity and water solubility of the products.No matter, both enamines 3j,k and diketone 4k were isolated in pure form, although the yields were low.There was no such problem with thiophene derivative 2lproduct 4l was obtained in 62% yield.
Then, amides 2m-p with olefin and alkyl substituent were examined (Scheme 3).Cinnamyl derivatives 3m and 4m were obtained with the same effectiveness as aryl derivatives.Amides 2n-p with all the primary, secondary and tertiary alkyl groups were able to participate in the reaction, although the yield of secondary and tertiary diketones 4o,p dropped down to ca. 40%, probably due to steric hindrance.

Scheme 4. Reaction of alternative amide derivatives 2q,r.
We further briefly examined reactivity of other substituted amides, namely diethyl benzamide 2q and pyrrolidine benzamide 2r (Scheme 4).In both cases, the formation of enaminone product 3 was observed.Based on NMR analysis of the reaction mixture, the yield of diethylamino derivative 3q was low.A number of by-products, as well as unreacted starting material were observed.After chromatography 31% of diketone 4a was isolated.In contrast, enaminone 3r was obtained in high yield, which allowed its isolation by recrystallization (35% isolated yield).Overall yield of the Grignard addition in this case could be estimated as 68%, based on isolated 1,3-diketone 4a.Such results are in accordance with literature data on the amides reactivity. 4,7heme 5. Chemical transformations of crude enaminones 3, prepared via the discovered reaction.

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© AUTHOR(S) Taken into account, that we experienced some problems upon isolation of the primary formed enaminones 3 and that they are often used directly after preparation, their utilization in the next step without purification was envisioned (Scheme 5).It was demonstrated on three conceptually different reactions: 1) condensation to form aromatic ring, 23 2) recently discovered Corey-Chaykovsky reaction-based furan synthesis 19 and 3) reaction with bisnucleophile such as phenyl hydrazine.Amide 2d was converted via the reaction of crude enaminone with 4-oxo-4H-chromene-3-carbaldehyde into the trisubstituted benzene derivative 5 in 56% on 2 steps.Reaction of the crude enaminone 3a with dimethylsulfonium ylide resulted in isolation of 2-methyl-4-phenylfuran 6 in 42% yield, based on 2a.Cinnamyl morpholine amide 2m was converted into pyrazole derivative 7 in 59% on 2 steps.

Conclusions
In summary, we have serendipitously discovered original interaction pathway of Grignard reagents with amides.Differently substituted morpholine amides react with propargyl magnesium bromide giving rise to βenaminones -products of formal allene insertion.The discovered reaction provides preparative access to various 1,3-diketones, which are obtained after spontaneous hydrolysis, or, if enaminone is used crude as it is, to various valuable heterocyclic or aromatic compounds.This approach is operationally simple and cheap alternative to already known methods.

Experimental Section
General.All reactions were performed in round-bottom flasks fitted with rubber septa.Reactions sensitive to air and/or moisture were performed under a positive pressure of argon.Air-and moisture-sensitive liquids were transferred by syringe.Analytical thin-layer chromatography (TLC) was performed using aluminum plates pre-coated with silica gel (silica gel 60 F254, Sorbfil).TLC plates were visualized by exposure to 254 nm ultraviolet light (UV) or were stained by submersion in acidic ethanolic solution of vanillin followed by brief heating (vanillin) or submersion in aqueous potassium permanganate solution followed by extensive washing with water (KMnO4).Flash-column chromatography was carried out on silica gel (60 Å, 230-400 mesh, Merck).All solvents for chromatography and extractions were technical grade and distilled prior use.All reagents were obtained from commercial suppliers and were used without further purification.Et2O and THF were stored over sodium benzophenone ketyl and were distilled directly prior use.Nuclear magnetic resonance spectra were recorded using Bruker Fourier 300, Bruker Avance 800 instruments at indicated temperature.Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances), coupling constant (J) in Hertz, integration.Proton chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to residual protium in the NMR solvents (CHCl3, δ 7.26 ppm).Carbon chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to the carbon resonances of the NMR solvents (CDCl3, δ 77.16 ppm).High-resolution mass spectra were recorded on a Bruker micrOTOF-Q II mass spectrometer using electrospray ionization (ESI-TOF).Melting points were determined on Kofler melting point apparatus and are uncorrected.