Catalytic one-pot synthesis of 4-( hetero ) aryl substituted 5-( 2-oxoethyl ) oxazol-2 ( 3 H )-ones by coupling – isomerization – elimination ( CIE ) sequence † ‡

Oxazol-2(3H)-one is an interesting derivative of the parent oxazole. While the aromatic structure is formally negated by the presence of an amide carbonyl group, the amide resonance retains it (Fig. 1). As a consequence, the N-proton is strongly acidified (pKa = 15.0) in comparison to the saturated oxazolidin-2-one (pKa = 20.9) or the structurally related open-chain ethyl carbamate (pKa = 24.6). 2 The structural motif of oxazol-2(3H)-one is not only present in muscazone (A), a toxic, psychoactive ingredient of amanita muscaria, i.e. fly agaric, but also in highly active herbicides against broadleaf and narrowleaf weeds plaguing rice fields, such as compound B, which does not affect the growth of the crop (Fig. 2). Chiral oxazolidin-2-ones have found broad application as Evans’ auxiliaries in enantioselective syntheses, such as asymmetric aldol additions, Diels–Alder reactions, 1,3-dipolar cycloadditions, and radical reactions, and as protected 1,2amino alcohols in the synthesis of biologically active compounds. Furthermore they have reached particular attention as building blocks in natural product synthesis. Oxazolidinones and oxazolones can also be found in the core of a series of antimicrobial active ingredients. For instance, the antibiotic linezolid (zyvoxid® by Pfizer) was found to be active against multiresistant Gram positive bacteria (Fig. 3). Inter-


Introduction
Oxazol-2(3H)-one is an interesting derivative of the parent oxazole. While the aromatic structure is formally negated by the presence of an amide carbonyl group, the amide resonance retains it (Fig. 1). 1 As a consequence, the N-proton is strongly acidified ( pK a = 15.0) in comparison to the saturated oxazolidin-2-one ( pK a = 20.9) or the structurally related open-chain ethyl carbamate ( pK a = 24.6). 2 The structural motif of oxazol-2(3H)-one is not only present in muscazone (A), a toxic, psychoactive ingredient of amanita muscaria, 3 i.e. fly agaric, but also in highly active herbicides against broadleaf and narrowleaf weeds plaguing rice fields, such as compound B, which does not affect the growth of the crop (Fig. 2). 4 Chiral oxazolidin-2-ones have found broad application as Evans' auxiliaries in enantioselective syntheses, 5 such as asymmetric aldol additions, Diels-Alder reactions, 1,3-dipolar cycloadditions, and radical reactions, 6 and as protected 1,2amino alcohols in the synthesis of biologically active compounds. 7 Furthermore they have reached particular attention as building blocks in natural product synthesis. 8 Oxazolidinones and oxazolones can also be found in the core of a series of antimicrobial active ingredients. 9 For instance, the antibiotic linezolid (zyvoxid® by Pfizer) was found to be active against multiresistant Gram positive bacteria (Fig. 3). 10 Inter-   estingly, linezolid does not act as a classical peptide transferase inhibitor but rather binds to the 23S portion of the 50S subunit of tRNA and affects an early stage of translation. 11 Combretoxazolones are oxazolinones that were recognized as analogues of combretastatin A-4 (Fig. 3), a biologically active constituent of several anticancer agents. Similar activity found against the same cancer cell lines is attributed to the configurational fixation of the Z-configured double bond in the heterocyclic congeners (Fig. 3). 12 Finally, oxazol-2-ones in their own right have become valuable synthetic building blocks for multiple transformations. 13 From N-acyl oxazol-2-ones 14 over activation and displacements with oxygen, nitrogen, and carbon nucleophiles to give oxazoles, 15 they span the range to Diels-Alder reactions with inverse electron demand, since oxazol-2-ones can be regarded as electron rich dienophiles. 16 The classical syntheses of oxazoles predominantly rely on carbonyl condensation and some famous name reactions have paved the way to this important class of five-membered heterocycles. 17,18 Recently, we reported an efficient three-component amidation-coupling-cyclization-isomerization (ACCI) of specifically 2,5-disubstituted oxazoles, which proceeds via an intramolecular Michael-type addition after the activating formation of an ynone by Sonogashira coupling (Scheme 1). 19 By employing the heterocyclization concept and by addressing the methylene carbonyl functionality in the product for a Fischer indole synthesis a novel three-component synthesis of deep-blue luminescent 5-(3-indolyl)oxazoles could be successfully disclosed. 20 Later a related strategy was reported by Wachenfeldt and co-workers who took advantage of a solventfree amidation of N-benzyl propargylamines under microwave irradiation furnishing trisubstituted oxazoles with concomitant, aromatizing cleavage of the benzyl group in good to excellent yield. 21 Although classical syntheses 22 and recent contributions on Au(I)-, [23][24][25][26] Pd(II)-, 27 and Lewis acid 28 and ionic liquid 29 catalyzed cycloisomerization syntheses of structurally related oxazolidinones have been reported, the catalyzed, diversity-oriented formation of oxazol-2-ones has remained unexplored.
In the course of our studies on three-component couplingaddition-cyclocondensation synthesis 30 of N-Boc 2-substituted 4-iodopyrroles from acid chlorides and N-Boc protected propargyl carbamates, 31 we discovered by serendipity that oxazol-2-ones were formed when 1-aryl substituted N-Boc protected propargyl carbamates were used as starting materials (Scheme 2). Important to notice is that oxazol-2-ones were already obtained upon aqueous workup of the ynone intermediate, indicating that sodium iodide was not involved in the cyclization. In addition, trifluoroacetic acid could also catalyze the cyclization-elimination reaction. Here, we report the optimization of this unprecedented formation of oxazol-2-ones and the methodological development of their synthesis by coupling-isomerization-elimination (CIE).

Results and discussion
Encouraged by the serendipitous finding of oxazol-2-ones (Scheme 2) we first set out to optimize the overall sequence with respect to catalytic acid, solvent, reaction temperature, and time. As a model reaction 4-methoxybenzoylchloride (1a) and tert-butyl(1-phenylprop-2-yn-1-yl) carbamate (2a) were chosen as reaction partners. For ynone formation the standard conditions were employed (Scheme 3). 32 However, we were never able to isolate the corresponding ynone with this peculiar substitution pattern (vide infra). First, the effect of various Brønsted acids on the isomerization-elimination was investigated at room temperature for 1 h (Table 1).
It could be shown that the addition of t BuOH as a cosolvent as under 4-iodopyrrole formation conditions was not required for PTSA monohydrate ( pK a ≈ 0.7) as an acid ( Table 1, entries 1 and 2). A slightly increased acidity by changing the acid component to trifluoroacetic acid ( pK a ≈ 0.2) did not increase the yield (Table 1, entry 3), whereas stronger acids, such as methane sulfonic acid ( pK a ≈ −1.9) and concentrated hydrochloric acid, even diminished the yields of oxazolone 3a (Table 1, entries 4 and 5). Weaker acetic acid and water were not efficient proton sources for the isomerization-elimination (Table 1, entries 6 and 7).
Further on, the solvent, reaction temperature, and reaction time were screened maintaining PTSA monohydrate as a catalyst for the product forming step ( Table 2).
As a solvent best suitable for both the coupling and the isomerization-elimination steps THF gave higher yields ( Table 2, entries 1-11) than 1,4-dioxane and dichloromethane ( Table 2, entries 12 and 13). Performing the coupling step with carefully dried triethylamine (distillation from Na/benzophenone) as a base and thereby minimizing the water concentration gave comparable yields (  [4][5][6]. For the sake of practicability the employment of peculiarly dried triethylamine is therefore not necessary. Complete conversion can be achieved after 30 min at room temperature (entry 7) whereas the addition of 2 equiv. of triethylamine does not improve the yield (entries 8 and 9). Further reduction of the reaction time results in lower yields (entries 10 and 11). Increasing the reaction temperature to 50°C gave already lower yields (Table 2, entry 6). In summary, the optimal conditions of the coupling-isomerization-elimination sequence are given under entry 7. With these conditions in hand, the methodological scope and limitation study was performed with various acid chlorides 1 and 1-aryl substituted N-Boc protected propargyl carbamates 2 25,33,34 to give 4-substituted 5-(2-oxoethyl) oxazol-2(3H)-ones 3 in moderate to good yields (Scheme 4, Table 3).
The structures of the 5-substituted 2-oxoethyl oxazol-2(3H)ones 3 were unambiguously assigned by 1 H and 13 C NMR and IR spectroscopy, mass spectrometry, and combustion analysis or high resolution mass spectrometry. Most characteristically, the methylene protons between the ketone and the oxazol-2 (3H)-one appear as singlets at δ 3.90-3.95 for aliphatic substituents R 1 and at δ 4.15-4.54 for (hetero)aryl substituents R 1 in the 1 H NMR spectra. The corresponding resonances of the methylene carbon nuclei can be found in the 13 C NMR spectra between δ 35.0 and 40.3. The ketone carbon nuclei appear between δ 188.0 and 209.8 depending on the nature of the (hetero)aromatic or (cyclo)aliphatic substituent. The oxazolone carbonyl nuclei can be detected at higher field in a very narrow range around δ 155. In the proton spectra at lower field the heterocyclic NH-amide protons appear as broad signals between δ 11.0 and 11.3. In the IR spectra the two distinct carbonyl stretching vibrations can be assigned for the methylene ketones appearing between 1694 and 1661 cm −1 and for the oxazol-2-ones in a range from 1753 to 1736 cm −1 typical for oxazol-2(3H)-one. 35 The structure was additionally corroborated by an X-ray structure analysis of 5-substituted 2-oxoethyl oxazol-2(3H)-one 3r indicating the formation of unsymmetrical dimers by amide hydrogen bonding in the solid state (Fig. 4). 36 The presented one-pot coupling-isomerization-elimination (CIE) synthesis of 4-substituted 5-(2-oxoethyl) oxazol-2(3H)ones 3 can be performed with a broad range of (hetero)aroyl chlorides ranging from electron rich (Table 3, entries 1, 3, 4, 6, 7, 18-22) over electroneutral (Table 3, entries 5 and 8) to electron deficient (Table 3, entries 2, 9-13), heterocyclic ( Table 3, Table 1 Optimization of the acid in the coupling-isomerization-elimination synthesis (CIE) of the 5-(2-oxoethyl) oxazol-2(3H)-one 3a a a All reactions were performed on a 1.0 mmol scale at concentrations c 0 (1a) = c 0 (2a) = 0.2 m, the isomerization-elimination step was performed at room temp for 1 h. b 2.0 equiv. of acid were added in the isomerization-elimination step. c Isolated yields after chromatography on silica gel. d 37% aqueous solution. e Impure product. Scheme 4 General procedure for the coupling-isomerization-elimination synthesis of oxazole-2(3H)-ones 3. entries 14 and 23) and even certain (cyclo)aliphatic acid chlorides (Table 3, entries [15][16][17]. The substitution pattern of N-Boc protected 1-(hetero)aryl propargyl carbamates 2 also allows for the implementation of electron releasing and withdrawing substituents as well as heteroaromatic substituents, however, an ortho-substituent apparently hampers the cycloisomerization (Table 3, entry 21). As a consequence of the elusiveness of the ynone coupling product and the subsequent acid mediated isomerizationelimination to furnish 4-substituted 5-(2-oxoethyl) oxazol-2 (3H)-ones 3 we reasoned that in case of a strict absence of an acid the tert-butyl group will be kept intact and thereby the corresponding 2-tert-butoxy oxazole derivative should be accessible. Indeed, upon reacting p-methoxy benzoyl chloride (1a) and N-Boc protected 1-phenyl propargyl carbamate (2a) under modified Sonogashira coupling conditions 32 and upon basic aqueous workup and chromatography on silica gel the 2-tertbutoxy oxazole 5 was obtained in 71% yield (Scheme 5).
Mechanistically, this observation can be interpreted as a consequence of a steric interaction of the tert-butyl carbamate with the 1-aryl moiety which is present in the N-Boc substituted 1-aryl substituted propargyl carbamate. Thus, the oxygen atom of the carbamate immediately undergoes a Michael-type on the triple bond of the ynone that is formed by the crosscoupling reaction, resulting in the observed cyclization. In the absence of 1-aryl substitution the ynone becomes persistent to spontaneous Michael addition, as supported by the consecutive transformation to 4-iodo pyrroles. 31 Hence, the acid in this novel one-pot CIE synthesis of 4-substituted 5-(2-oxoethyl) oxazol-2(3H)-ones cannot be attributed to the cycloisomerization, but rather to induce tert-butyl cleavage. Table 3 One-pot coupling-isomerization-elimination (CIE) synthesis of 4-substituted 5-(2-oxoethyl) oxazol-2(3H)-ones 3 a

Conclusion
Here, we have unraveled and developed an unusual couplingisomerization-elimination synthesis of 4-substituted 5-(2oxoethyl) oxazol-2(3H)-ones, a subclass of side-chain functionalized oxazol-2(3H)-one derivatives. The substitution pattern at the two diversity points, i.e. the acid chloride and the N-Boc protected 1-aryl substituted propargyl carbamate is fairly broad and allows electronically diverse decoration of the title compound class by a straightforward one-pot protocol. The isolation of a 5-substituted 2-oxoethyl 2-tert-butoxy oxazole product as a consequence of strict absence of acid not only elucidates the overall mechanistic rationale but also sets the stage for further developing one-pot methodologies with this intermediate. Further studies directed to develop propargyl amide and carbamate based one-pot sequences initiated by crosscoupling are currently underway.