New Easy Approach to the Synthesis of 2,5-Disubstituted and 2,4,5-Trisubstituted 1,3-Oxazoles. The Reaction of 1-(Methylthio)acetone with Nitriles

Herrera, Antonio; Martínez‐Álvarez, Roberto; Ramiro, Pedro; Molero, Dolores; Almy, John

doi:10.1021/jo052619v

Cited by 49 publications

(28 citation statements)

References 27 publications

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“…No reaction was seen without catalyst, with dichloro(pyridine-2-carboxylato)gold being superior to other metal salts,including cationic gold and [Ir(cod)Cl] 2 . [1c] 5-Methylthio-oxazole (3aa)w as favored over 4-methylthio-oxazole (3aa' ')inall cases, [18] thus contradicting the predicted outcome if sulfur were acting as a p-donor substituent.…”

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confidence: 68%

Alkynyl Thioethers in Gold‐Catalyzed Annulations To Form Oxazoles

2017

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Non-oxidative,regioselective,and convergent access to densely functionalized oxazoles is realized in af unctionalgroup tolerant manner using alkynyl thioethers.S ulfur-terminated alkynes provideaccess to reactivity previously requiring strong donor-substituted alkynes such as ynamides.Sulfur does not act in an analogous donor fashion in this gold-catalyzed reaction, thus leading to complementary regioselective outcomes and addressing the limitations of using ynamides.Compared to other heteroatom-substituted alkynes,alkynyl thioethers are remarkably little explored in intermolecular late-transition-metal catalysis,d espite being readily accessed and robust. [1,2] Ynamides,i nc ontrast, are privileged substrates:i np-acid catalysis their donor nature aids metalalkyne coordination and affords highly polarized electrophiles,t hus providing the high chemo-and regioselectivity required for the discovery of efficient intermolecular reactions (Scheme 1a). [3,4] As the resulting inclusion of ad onornitrogen atom limits the utility of the products,r etaining the reactivity profile of these transformations whilst accessing more flexible and readily elaborated substitution patterns would be desirable.T he value of sulfur-substituted compounds [5] coupled with progress in C À Ca nd C-heteroatom bond formation from CÀSbonds, [6] renders alkynyl thioethers appealing alternatives to ynamides.I ndeed the ketenethionium pathway (Scheme 1a)f rom alkynyl thioethers has recently been invoked in proton-catalyzed reactions with nitriles [2g,h] and gold-catalyzed reactions with sulfides.[2i]Ynamides enabled the discovery of formal [3+ +2] dipolar cycloadditions with nucleophilic nitrenoids, [7] thus allowing intermolecular access to a-imino gold carbene-type reactivity for heterocycle synthesis (Scheme 1b). [8, 9] Such reactions, which do not depend on ynamides,a re scarce.[8b,h] As trong donor alkyne substituent proved critical in the formation of oxazoles using N-acyl pyridinium N-aminides,aselectron-rich alkynes such as anisole derivatives did not react (Scheme 1b, inset). [8a,b] Oxazoles are valuable synthetic intermediates [10,11] and structural components in bioactive natural products, [12] agrochemicals, [13] ligands, [14] and functional materials.[15]Despite recent advances,asingle modular and convergent route to trisubstituted oxazoles,which provides the structural and functional-group diversity needed across the 2-, 4-, and 5-positions,r emains unrealized. [16] Following our interest in the use of gold catalysis with sulfides [17] we report here on the reactivity of alkynyl thioethers with nucleophilic nitrenoids to prepare oxazoles. Importantly,t he regioselectivity is not consistent with ac ontrolling ketenethionium species.T he sulfur group plays an alternative role in enabling reactivity,t hus proving complementary to donor-enabled approaches.Ther eaction of the alkynyl thioether 1a and aminide 2a (Table 1) showed that conversion into the oxazole 3 was possible at 125 8 8Ci n1 ,2-dichlorobenzene (1,2-DCB;s ee...

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confidence: 68%

Alkynyl Thioethers in Gold‐Catalyzed Annulations To Form Oxazoles

2017

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“…The 1 H, 13 C NMR and DEPT experiments showed the presence of a methyl, four methines and five quaternary carbons. The 1 H and 13 C NMR spectra also indicated the presence of a dihydroxybenzene unit (δ H 7.06 (H-8), 6.81 (H-11), 7.01 (H-12); and δ C 121.2, 112.4, 146.9, 147.4, 116.8, 117.3 (C-7 C-12), and a 2,5-disubstituted 1,3-oxazole (δ H 7.09 (H-4) and δ C 153.6 (C-2), 120.0 (C-4), 162.0 (C-5) [10]. …”

Section: Resultsmentioning

confidence: 99%

“…The ester was afforded by 3,4-dihydroxybenzoic acid and aminoisopropanol. After carbonyl nucleophilic addition with azyl, dehydration, and dehydrogenation reactions, compound 1 could be created [10]. Tyrosine could be transformed to dopa by the enzyme tyrosine hydroxylase.…”

Section: Resultsmentioning

confidence: 99%

The biosynthetic products of Chinese insect medicine, Aspongopus chinensis

et al. 2012

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“…[11] Pyrimidines are an important class of compounds which includes numerous natural, pharmaceutical, and functional materials. [11] Pyrimidines are an important class of compounds which includes numerous natural, pharmaceutical, and functional materials.…”

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“…[11] Pyrimidines are an important class of compounds which includes numerous natural, pharmaceutical, and functional materials. [11,14] In spite of the importance of these reactions, no spectroscopic confirmation of the postulated intermediates or kinetic data on the reaction have been reported. [11,14] In spite of the importance of these reactions, no spectroscopic confirmation of the postulated intermediates or kinetic data on the reaction have been reported.…”

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confidence: 99%

Real‐Time Monitoring of Organic Reactions with Two‐Dimensional Ultrafast TOCSY NMR Spectroscopy

Herrera¹,

Fernández-Valle²,

Martínez‐Álvarez³

et al. 2009

Angew Chem Int Ed

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Multidimensional nuclear magnetic resonance plays a number of essential roles in present day spectroscopy. It is also an integral part of the image formation protocol in magnetic resonance imaging (MRI).[1] Traditional two-dimensional experiments are intrinsically time consuming, because many t 1 increments have to be acquired to obtain twodimensional spectra with adequate digital resolution in the indirect dimension.[2] Proposals for accelerating multidimensional NMR spectroscopy include non-Fourier transform schemes, [3] the acquisition of multiple NMR spectra in a single experiment, [4] and "single scan" multidimensional NMR spectroscopy, also called ultrafast NMR spectroscopy (UF NMR), have been introduced. The latter methodology was inspired by echo planar imaging (EPI) [5] and was developed by Frydman et al. [6] It permits the collection of complete multidimensional NMR data sets within a single continuous acquisition. This new methodology is compatible with existing standard (TOCSY, HSQC, MRI) and recently described combined multidimensional pulse sequences, [7] and it can be implemented with conventional hardware. This attractive feature enables ultrafast NMR to examine dynamic processes, that is, organic reactions and their mechanisms as they happen in real time.[8] Figure 1 shows the schematic of the two-dimensional UF-TOCSY sequence used.[9] The sequence uses a continuous spatial encoding [10] which was implemented by pairs of RF pulses which excite/store spins over the full length, L, of the sample. The sample was swept over intervals t 1 max /2 whereas AE G e external gradients were applied. The offsets of such pulses were thus chirped over a AE gG e L/2 span, and their amplitudes calibrated as effective p/2 nutations by setting gB 1 as a function of 0.25 [(2 gG e L/t 1 max )] 1/2 .We focused our attention on one-pot syntheses of pyrimidines and similar heterocyclic compounds, which we had previously developed. [11] Pyrimidines are an important class of compounds which includes numerous natural, pharmaceutical, and functional materials.[12] Elegant new procedures have been described [13] and revealed decisive information on the mechanistic details of the reaction between carbonyl compounds and strong electrophiles such as trifluoromethanesulfonic acid anhydride (Tf 2 O). [11,14] In spite of the importance of these reactions, no spectroscopic confirmation of the postulated intermediates or kinetic data on the reaction have been reported.Using a medium field 500 MHz spectrometer, we have now applied UF NMR methodology to monitor the reaction between aliphatic ketones and Tf 2 O in the presence of nitriles. We have determined how the signals of the starting and final products evolve as they happen, in real time and attempted to detect the presence of intermediates. We chose a symmetric aliphatic ketone, 3-pentanone (1), as the model compound to react with a two-fold amount of Tf 2 O in [D 3 ]acetonitrile, which served as both a co-reactant and solvent.Scheme 1 shows the previously proposed reaction mec...

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New Easy Approach to the Synthesis of 2,5-Disubstituted and 2,4,5-Trisubstituted 1,3-Oxazoles. The Reaction of 1-(Methylthio)acetone with Nitriles

Cited by 49 publications

References 27 publications

Alkynyl Thioethers in Gold‐Catalyzed Annulations To Form Oxazoles

Alkynyl Thioethers in Gold‐Catalyzed Annulations To Form Oxazoles

The biosynthetic products of Chinese insect medicine, Aspongopus chinensis

Real‐Time Monitoring of Organic Reactions with Two‐Dimensional Ultrafast TOCSY NMR Spectroscopy

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