Tandem cycloaddition–decarboxylation of α-keto acid and isocyanide under oxidant-free conditions towards monosubstituted oxazoles

Abstract

An efficient method, tandem [3 + 2] cycloaddition–decarboxylation of α-keto acid and isocyanide promoted by copper salt, has been developed. Under oxidant-free conditions, a series monosubstituted oxazoles have been constructed. Different from the traditional application of α-oxo acids as acyl surrogates, the elegant approach herein ingeniously avoids consuming excess oxidants.

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Oxazoles are very useful building blocks in organic chemistry because they are essential moieties in many synthetic materials, natural products and medicines.¹ For example, VX-497 and texaline which contain oxazole rings, are used as conventional immunosuppressants^1d and antimycobacterial drugs respectively. As a consequence, increasing attention has been paid to the synthesis of oxazoles and their derivatives.² One of the most important strategy towards oxazoles is [3 + 2] cycloaddition reactions of methyl isocyanides with electrophilic acyl compounds.^3,4 Differently, Lei's group recently developed a silver promoted novel [3 + 2] cycloaddition route of methyl isocyanides and α-oxocarboxylates, where α-oxocarboxylates acted as nucleophiles rather than an electrophilic acyl source.⁵ The α-keto acids and α-oxocarboxylates have received extensive attention in organic chemistry because they could be used as highly effective acyl surrogates for C–Z (Z = C, N, S) bond formation via decarboxylation reactions.^6–16 In 2014, Lei described a synthetic method of 6-acyl phenanthridines through silver catalyzed oxidative decarboxylation–cyclization of α-oxocarboxylates and isocyanides in the presence of excess Na₂S₂O₈.¹¹ The same year, Duan et al. reported a decarboxylative acylfluorination of styrenes with α-oxocarboxylic acids using Selectfluor as oxidant.¹² Mechanically, it was thought that initial decarboxylation of α-keto acids to form “acyl” is crucial among these examples. In addition, it should be noted that the decarboxylation catalyzed by transition metal is a fast oxidative process, and thus excessive oxidants such as persulfate and Selectfluor were necessary, which add the complication and difficulty in separation of products.

In recent years, we have focused on the research of organic reactions catalyzed by transition metal organic complexes¹⁷ and the synthesis of heterocycle compounds using methyl isocyanides as N-donor.¹⁸ On the ongoing interests for construction of heterocycle by using isocyanides, we questioned whether we could find an ideal system, in which α-oxocarboxylic acids or α-oxocarboxylates will be directly involved in reaction as acyl reagents before the release of CO₂. At the same time, we hope that the decarboxylation will be completed automatically, so that the use of oxidants could be avoided. Herein, we disclose our results on tandem [3 + 2] cycloaddition–decarboxylation of isocyanide and α-keto acid in one pot for the synthesis of monosubstituted oxazoles without using any oxidant. This novel method provides a convenient access to 5-aryl oxazoles promoted by copper salt.

Seeking to find a novel efficient, cheap and concise method accords with the concept of green chemistry. Base on this point, inexpensive copper salts were chosen as catalysts for optimizing the reaction conditions. Originally, our investigation started with α-oxo-2-phenylacetic acid 1a and TosMIC 2 to give the corresponding 5-phenyloxazole 3a as the model reaction. Under air atmosphere, the product 3a can be monitored by GC in 60% yield in the presence of (1 mol%) Cu(NO₃)₂ and 1.1 equiv. of KOH at 80 °C in DMF for 12 h (Table 1, entry 1). Then, it was found that low-valent copper salt was more conductive to the tandem reaction (entries 2, 3). In comparison, the yields of 3a were basically the same with CuI or CuCl as catalyst. In addition, copper salt was helpful to the transformation (entry 4, 5). Taken together, CuCl was more ideal because of lower cost. With 1,10-phen as an additive, the yield increased dramatically (entry 6). If the temperature continued to rise, the yields decreased rapidly (entry 7, 8). In addition, both the usage of NaOH as base and the decreasing of temperature to 60 °C need a longer time to 12 hours for getting a good and medium yield, respectively (entries 9, 10). Increasing the amount of CuCl to 5 mol%, reaction time was shortened obviously (entry 11). Interestingly, the equivalent target product can be tested even in the nitrogen flow throughout (entry 12). That was to say, the process of cyclization–decarboxylation was no need for any oxidant. No significant difference was observed when α-oxocarboxylates as substrate in the absence of additional base (entry 13). Therefore, the optimal oxidant-free system under air for this reaction involves CuCl/1,10-phen (1 mol%) and KOH (1.1 eq.) in DMF at 80 °C.

Table 1 Optimization of reaction conditions^a

Entry	Cat (1 mol%)	Additive (1 mol%)	Base (1.1 eq.)	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 1a (0.55 mmol; 83.3 mg), 2 (0.5 mmol; 97.6 mg), catalyst (1 mol%), 1,10-phen (1 mol%, 0.9 mg), base (1.1 eq.), DMF (1 mL), air.b Determined by GC.c 5 mol% catalyst and 5 mol% ligand.d N2 atmosphere.e α-Oxocarboxylates as substrate.f Yield determined by GC, the reactive mixture is difficult to be separated.
1	Cu(NO3)2	—	KOH	80	12		60
2	CuI	—	KOH	80	5		86
3	CuCl	—	KOH	80	5		89
4	—	—	KOH	80	5		42
5	—	—	K2CO3	80	12		26^f
6	CuCl	1,10-Phen	KOH	80	5		96
7	CuCl	1,10-Phen	KOH	120	12		30
8	CuCl	1,10-Phen	KOH	160	12		15
9	CuCl	1,10-Phen	NaOH	80	12		95
10	CuCl	1,10-Phen	KOH	60	12		78
11^c	CuCl	1,10-Phen	KOH	80	1		97
12^d	CuCl	1,10-Phen	KOH	80	5		95
13^e	CuCl	1,10-Phen	—	80	5		98

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Subsequent work was to evaluate the scopes and limitations of cyclization–decarboxylation reaction of TosMIC 2 with a variety of substituted α-oxocarboxylic acids under the optimal condition (Table 1, entry 5). α-Oxo-2-phenylacetic acids with electron-donating groups in the meta and para position, such as both methyl and methoxy, performed well to the desired products in excellent yields (Table 2, entries 2–5). As well, the combination of CuCl and 1,10-phen was amenable to substrates bearing halogen groups (F, Cl, Br, I) and electron-deficient (–NO₂), providing the satisfactory C-5 substituted oxazoles (3f–k) with good yields (entries 6–11). Furthermore, the space steric hindrance employing substituents at ortho position of α-oxo-2-phenylacetic acids showed a slight influence on the formation of corresponding oxazoles (3e, 3j). It is noteworthy that α-keto acid containing thienyl ring or naphthalene ring, due to its general reactivity, was monitored moderate yield of target product (3l, 3m) even lengthening the time to 12 hours and complicated mixture was detected by GC after a longer time (entries 12, 13). Whereas, aliphatic ketonic acid was inert to the conversion even extending the reaction to 24 h (Table 2, entry 14).

Table 2 Synthesis of monosubstituted oxazoles^a

Entry		R	Time (h)	Yield^b (%)
a Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol; 97.6 mg), CuCl (1 mol%; 1.3 mg), 1,10-phen (1 mol%, 0.9 mg), KOH (0.55 mmol; 25.3 mg), DMF (1 mL), 80 °C, air.b Determined by GC; isolated yield in parenthese.
1	1a	C6H5–	5	3a	96 (91)
2	1b	4-CH3C6H4–	8	3b	98 (94)
3	1c	4-CH3OC6H4–	10	3c	98 (92)
4	1d	3-CH3OC6H4–	10	3d	96 (94)
5	1e	2-CH3OC6H4–	10	3e	71 (65)
6	1f	4-FC6H4–	8	3f	89 (82)
7	1g	4-BrC6H4–	6	3g	95 (88)
8	1h	4-IC6H4–	8	3h	82 (76)
9	1i	4-ClC6H4–	4	3i	99 (93)
10	1j	2-ClC6H4–	12	3j	97 (91)
11	1k	4-NO2C6H4–	6	3k	94 (83)
12	1l	1-Nathphyl	12	3l	53 (46)
13	1m	2-Thienyl	12	3m	50 (45)
14	1n	CH3	12	3n	0

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According to the reports of relative literatures, most of reactions with α-keto acids as acyl surrogates underwent through a radical process. To further verify the possibility, 2.0 equiv. of TEMPO (excellent free radical trapping species) was added into the mixture of 1a and 2 under standard condition and the formation of 3a wasn't obviously inhibited, supervised in 80% yield by GC (Scheme 1).

Scheme 1 Control experiment.

The fact showed that our reaction hadn't experienced the radical mechanism. In addition, as noted during optimizing condition, the reaction didn't need any additional oxidant (Table 1, entry 9) and the copper catalyst played an indispensable role in reaction (Table 1, entry 4). All of which pointed out a novel reaction pathway involving Cu(I)-promoted might be involved. A tentative tandem reaction mechanism for the construction of monosubstituted oxazoles is described in Scheme 2. In the presence of CuCl/1,10-phen and KOH, α-oxocarboxylates II metalled by copper experience [3 + 2] cycloaddition with cuprioisocyanide III^18d,19 activated similarly by copper to generate the intermediate IV. Subsequently, decarboxylation of IV followed by leaving of tosylate anion afford the aromatized oxazole products 3.

Scheme 2 A plausible mechanism of the tandem cyclization–decarboxylation reaction.

In summary, we have disclosed an efficient and practical method for construction of monosubstituted oxazoles through tandem [3 + 2] cycloaddition–decarboxylation of isocyanide and α-keto acid reaction in one pot. Using inexpensive CuCl/1,10-phen as catalyst, we provide an elegant access to 5-aryl oxazoles under oxidant free mild condition. The method has found a novel application way for α-oxocarboxylic acids as acyl surrogates.

Experimental section

General procedure for the synthesis of 3a

To a 5 mL round bottom flask, the mixture of α-oxo-2-phenylacetic acid 1a (0.55 mmol, 83.3 mg) and KOH (0.55 mmol, 25.3 mg) in DMF (1 mL), was stirred at room temperature for 1 h. After 1a was consumed traced by TLC, TosMIC 2 (0.5 mmol, 97.6 mg) and CuCl (1 mol%, 1.3 mg)/1,10-phenanthroline (1 mol%, 0.9 mg) was added. The vial was stirring in oil bath at 80 °C for another 5 hours in air atmosphere, and monitored by TLC. Followed by TosMIC (2) was exhausted completely, the reaction was cooled down to room temperature and quenched in (10 mL) saturated NaCl solution then extracted with EtOAc (3 × 10 mL). Organic layers was combined and solvent was evaporated, then the residue was purified by flash column chromatography (petroleum ether : ethyl acetate = 9 : 1) to get 5-phenyloxazole 3a as yellow liquid.

Acknowledgements

Financial support for this research provided by the NSFC (Grant 21402112) is greatly acknowledged.

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra16031j

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