A general and practical route to 4,5-disubstituted oxazoles using acid chlorides and isocyanides

Abstract

An efficient and mild method for the synthesis of 4,5-disubstituted oxazoles has been developed. A series of 4,5-disubstituted oxazoles were prepared via [3 + 2] cycloaddition reaction of various isocyanides and acid chlorides in the presence of base. This method serves as an efficient preparation of 5-formyloxazole which might prove to be a synthetically useful intermediate.

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Introduction

Oxazoles represent an important class of five membered heterocycles, occuring as substructural units in a wide variety of biologically active compounds¹ (diazonamide A (1)¹ⁱ and leucamide A (2)^1j), pharmaceuticals² (ostreogrycin-A (3) Fig. 1) and molecular sensors.³ Oxazoles are also popular as valuable precursors in many useful synthetic transformations.⁴ In recent years, 4,5-disubstituted oxazoles have received considerable attention from both synthetic and medicinal chemists, mainly due to their significant therapeutic potential in treating various diseases such as inflammation, cancer and asthma.^5,6 4,5-Disubstituted oxazoles as a class are a potent and selective inhibitor of the stress-activated kinase p38α,⁷ cyclooxygenate-II (COX-II), cyclooxygenase-1 (COX-1) and anti-tumor necrosis factor (anti-TNF).⁸

Fig. 1 Oxazole containing biologically active compounds.

Owing to their medicinal value, a number of synthetic methods have been developed to construct 4,5-disubstituted oxazoles.⁹

Among these methods, the most classical procedure is the cyclocondensation of acetyl chloride and monosubstituted tosyl methyl isocyanides developed by Van Leusen et.al. (Fig. 2 eqn (1)).^10a Later, Yu and Stevens groups reported improved syntheses in ionic liquids and an automated flow reactor system respectively.^10b,c In addition, Miller group devised a new route which involves the regioselective C2 silylation followed by metalation of oxazoles at C5 position (Fig. 2 eqn (2)).^10d

Fig. 2 Scheme depicting previous reports on the synthesis of 4,5-disubstituted oxazoles along with present study.

While all these useful methods provide convenient access to 4,5-disusbtituted oxazoles, there are certain limitations associated with them, such as harsh reaction conditions, multistep synthesis, and difficulties in further functionalization, especially at C5 position of oxazoles. Therefore, development of a mild and efficient approach to 4,5-disubstituted oxazoles is still highly desirable.

Fig. 3 Mechanism of [3 + 2] cycloaddition of acid chloride and isocyanide towards 4,5-disubstituted oxazoles.

Acid chlorides have long been renowned for their reactivity in numerous synthetic transformations, particularly their reactivity in [2 + 2] and [4 + 2] cycloadditions, reductive couplings, SN₂ substitutions as well as both nucleophilic and electrophilic additions. Our current research is focused on the synthesis of various azetidin-2-ones using [2 + 2] cycloaddition reactions of imines with in situ generated ketenes from acid chlorides.¹¹ As a continuation of the same research program which uses acid chlorides as precursors, herein we wish to report an efficient and practical synthesis of 4,5-disubstituted oxazole via [3 + 2] cycloaddition reactions of isocyanides with alkyloxy/aryloxy acid chlorides in the presence of a base (Fig. 2 eqn (3)). This methodology works with broad spectrum of acid chlorides including the ones containing heteroatoms such as oxygen, nitrogen and sulphur. These 4,5-disubstituted oxazoles could in turn be functionalized at C5 position.

Results and discussion

Initially, the synthesis of 4,5-disubstituted oxazole was examined using acetoxyacetyl chloride 1 and methyl 2-isocyanoacetate 2a′ as the model substrate. Our first attempt by treating acetoxyacetyl chloride 1 (0.5 mmol) and methyl 2-isocyanoacetate 2a′ (0.5 mmol) in presence of anhydrous K₂CO₃ (2.0 equiv.) in dry DCM at room temperature was unsuccessful (Table 1 entry-1). Use of different bases such as Cs₂CO₃, Et₃N and DBU in dichloromethane too failed to yield the desired product 1a (Table 1 entries 1–4). However, 20% yield of the product 4,5-disubstituted oxazole 1a was isolated when reaction was performed in anhydrous CH₃CN in the presence of K₂CO₃ (2.0 equiv.) at room temperature under argon atmosphere (Table 1, entry 5). Furthermore, 1a was isolated in 35% yield by using 2.0 equiv. of Et₃N in CH₃CN at room temperature (Table 1, entry-6). The poor performance of the reactions at room temperature, possibly may be due to the polymerization of ketene generated in situ from acid chloride.¹² Therefore, we attempted reaction at lower temperature and a sharp increase in the yield (53%) of 1a was observed when reaction was performed at 0 °C (Table 1, entry 7). To our delight, a much better yield (76%) of 1a was obtained when DBU (2.0 equiv.) was employed as a base (Table 1, entry-8). Notably, the conversion and the yields were affected dramatically by amount of DBU employed, and the best result (95%) was obtained by employing 3.5 equiv. of DBU (Table 1, entry 9). Further increase or decrease in the amount of DBU did not give a better yield (Table 1, entry 10 & 11). Stronger bases such as KOH, NaOMe and KO^tBu were found less effective to promote the reaction (Table 1, entries 12–14) and furnished lower yields of desired 1a. It was plausibly due the enolization of acetate group of the substrate (1) and product (1a) in the presence of strong bases which led to the formation of undesired side products. However, strong bases were equally effective as DBU with substrates containing no acetate group (For details, see ESI†). Furthermore, the cycloaddition reaction of 1 and 2a′ were tried in different solvents such as N,N dimethyl formamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF) and 1,4-dioxane but most of them were found less efficient, resulting 1a in inferior yields (Table 1, entries 15–18). Unsurprisingly, no product was obtained in protic solvents such as MeOH and EtOH (entries 19 & 20).

Table 1 Optimization of reaction conditions^a

Entry	Base/equiv.	Solvent	Temp. °C	Time (h)	Yield^b (%)
a All reactions were carried out on 0.5 mmol of acetoxyacetyl chloride (1), 0.5 mmol of methylisocyanoacetate (2a′).b Isolated yield.
1	K2CO3 (2)	DCM	rt	6	No reaction
2	Cs2CO3 (2)	DCM	rt	6	No reaction
3	Et3N (2)	DCM	rt	6	No reaction
4	DBU (2)	DCM	rt	6	No reaction
5	K2CO3 (2)	CH3CN	rt	6	20%
6	Et3N (2)	CH3CN	rt	6	35%
7	Et3N (2)	CH3CN	0 °C	6	53%
8	DBU (2)	CH3CN	0 °C	6	76%
9	DBU (3.5)	CH3CN	0 °C	4	95%
10	DBU (3.0)	CH3CN	0 °C	4	84%
11	DBU (4.0)	CH3CN	0 °C	4	91%
12	KOH (3.5)	CH3CN	0 °C	4	25%
13	NaOMe (3.5)	CH3CN	0 °C	4	41%
14	t-BuOK (3.5)	CH3CN	0 °C	4	36%
15	DBU (3.5)	DMSO	0 °C	4	45%
16	DBU (3.5)	DMF	0 °C	4	32%
17	DBU (3.5)	THF	0 °C	4	65%
18	DBU (3.5)	1,4-Dioxane	0 °C	4	51%
19	DBU (3.5)	MeOH	0 °C	4	No reaction
20	DBU (3.5)	EtOH	0 °C	4	No reaction

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With optimal conditions in hand (Table 1, entry 9), the scope of the reaction with respect to various acid chlorides and isocyanide components was investigated. Methyl 2-isocyanoacetate effectively reacted with acid chlorides bearing both aliphatic and aromatic groups. Methoxyacetyl chloride 2, phenoxy and benzyloxyacetyl chlorides (3 & 4) also gave corresponding 4,5-disubstituted oxazoles 2a, 3a, and 4a in good yields. Nitrogen containing acid chlorides (PhthNCH₂COCl, 5) on treatment with methyl 2-isocyanoacetate (2a′) produced corresponding oxazole 5a in 92% yield.

Identical yield (91%) of 6a was obtained when thiophenylacetyl chloride (6) was subjected to similar reaction condition. Also worthy of note is the observation that in place of methyl 2-isocyanoacetate (2a′) both ethyl 2-isocyanoacetate (2b′) and tosylmethyl isocyanide (TosMIC, 2c′) readily participated in cycloaddition with various acid chlorides to give corresponding oxazoles (1b, 1c-5b, 1c) in very good yields (Table 2).

Table 2 Substrate scope for 4,5-disubstituted oxazole formation^a,b

a The reaction was carried out with 0.5 mmol of acid chlorides, 0.5 mmol of isocyanides in the presence of DBU (1.75 mmol) in 5 mL of CH₃CN for 4 h.b Isolated yield.

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This initial success propelled us to investigate the versatility of present method. 5-formyl oxazole 8 which can be considered to be an intermediate of high utility can undergo various reactions such as Grignard, Aldol, Wittig, and reductive amination to give functionalized oxazoles. Similar 5-formyl oxazole have already been used as an advance intermediate in the preparation of biologically active compound which is known to posses CRTH2 receptor activity.¹³ This synthetically important intermediate was easily prepared in two step process from 1c (Scheme 1). The hydrolysis of acetate group of 1c using aqueous sodium bicarbonate solution in MeOH gave intermediate 7 which underwent smooth Swern oxidation to furnish 5-formyl-4-tosyl oxazole 8 in 87% yield.

Scheme 1 synthesis of 5-formyl oxazole from 1c.

Next, in order to expand the scope of the present methodology, we examined the reaction of aryl cyanides (9a, 9b) with methyl 2-isocyanoacetate 2a′ under standard conditions (Scheme 2) to prepare 4,5-disubstituted imidazole 10.¹⁴ But, unfortunately, no desired products (10a,b) were observed. However, when the reaction mixture was refluxed the cyclodimerization of isocyanide takes place to form 11 in 95% yield along with unreacted aryl cyanides (9a,b). The spectral data of 11 is in good agreement with previously reported value.¹⁵

Scheme 2 reaction of aryl cyanides (9a,b) with isocyanide (2a).

The formation of 4,5-disubstituted oxazoles may be explained by two pathways (Fig. 3). In pathway A, initially anionic form of 2a′, undergoes addition on acid chloride 1 give intermediate 13. This intermediate 13 then undergoes enolization, followed by nucleophilic attack on carbene form of 14 leading to the formation of 4,5-disubstituted oxazole 1a. Another possible mechanistic pathway could be via ketene mechanism. The ketene 15 generated in situ from the acid chloride undergoes a [3 + 2] cycloaddition with 12 to yield intermediate 16 which undergoes 1,3 H-shift to give 1a.

Conclusions

In summary, 4,5-disubstituted oxazole construction was achieved in very good yields from readily available acid chlorides and isocyanides under very mild conditions. Moreover, this method was applied to the synthesis of 5-formyl oxazole. Work to exploit the potential of 5-formyl oxazoles for further functionalization to yield valuable intermediates is underway and findings will be disclosed in due course of time. The ready availability of starting materials, broad substrate scope, and operational simplicity makes the present method an attractive option for the synthesis of the oxazole skeleton.

Experimental

General

The reagents, chemicals and solvents were either purchased from commercial suppliers or prepared and purified by standard techniques. Column chromatography was carried out using silica gel 100–200 mesh. Infrared spectra were recorded using a FT-IR spectrophotometer and values reported in cm⁻¹. ¹H and ¹³C NMR spectra were recorded with 300, 400 and 500 MHz NMR instruments with tertramethylsilane (TMS) as an internal standard. High-resolution mass spectra (ESI-HRMS) were recorded on ESI-QTOP mass spectrometer.

Typical experimental procedure for the synthesis of 4,5-disubstituted oxazoles

A solution of acid chlorides (0.5 mmol) in dry CH₃CN (2 mL) was slowly added to a mixture of isocyanides (0.5 mmol) and DBU (1.75 mmol) in dry CH₃CN (4 mL) at 0 °C. The reaction mixture was allowed to stir for additional 4 h at same temperature. The reaction mixture was quenched with water (6 mL) and the mixture was diluted with ethylacetate (10 mL). The organic layer was separated and washed with aqueous NaHCO₃ solution (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulphate and solvent was removed under reduced pressure to produce crude 4,5-disubstituted oxazole, which was on purification using 100–200 mesh silica gel, gave pure 4,5-disubstituted oxazoles in very good yields.

Methyl 5-(acetoxy methyl)-oxazole-4-carboxylate (1a). 95% yield, colourless oil; IR (KBr), 3475, 2957, 1747, 1622, 1517, 1440 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.87 (s, 1H), 5.45 (s, 2H), 3.93 (s, 3H), 2.11 (s, 3H): ¹³C NMR (75 MHz, CDCl₃) δ 170.04, 161.35, 152.23, 150.51, 129.54, 55.11, 52.36, 20.48. HRMS (ESI, Orbitrap): calcd for C₈H₉NO₅ [M + Na], 222.03734; found 222.03728.

Ethyl 5-(acetoxy methyl)-oxazole-4-carboxylate (1b). 93% yield, brown colour liquid, IR (KBr), 3474, 2956, 1747, 1623, 1517, 1441 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.88 (s, 1H), 5.46 (s, 2H), 4.39 (q, J = 7.1, 14.2 Hz, 2H), 2.11 (s, 3H), 1.39 (t, J = 7.1, 14.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.14, 161.35, 152.23, 150.51, 148.77, 129.81, 77.42, 77.00, 76.57, 55.11, 52.36, 20.48. HRMS (ESI, Orbitrap): calcd for C₉H₁₂NO₅ [M + H]⁺ 214.07100 found 214.07161.

(4-Tosyloxazol-5-yl)methyl acetate (1c). Yield: 91%; white solid, M.P. 85–87 °C; IR (KBr), 3453, 1744, 1595, 1499, 1234 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (d, J = 8.3 Hz, 2H), 7.85 (s, 1H), 7.36 (d, J = 8.3 Hz, 2H), 5.54 (s, 2H), 2.45 (s, 3H), 2.14 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.80, 150.78, 149.52, 145.28, 138.50, 136.16, 129.83, 128.20, 54.51, 21.54, 20.37; HRMS (ESI, Orbitrap): calcd for C₁₃H₁₄NO₅S [M + H]⁺ 296.05872 found 296.05864.

Methyl 5-(methoxymethyl)oxazole-4-carboxylate (2a). Yield: 86%, colourless oil; IR (KBr) 3412, 2956, 1741, 1680, 1517, 1440 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 4.83 (s, 2H), 3.95 (s, 3H), 3.43 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 162.13, 150.41, 129.45, 63.37, 58.75, 52.304; HRMS (ESI, Orbitrap): calcd for C₇H₁₀NO₄ [M + H]⁺ 172.06043 found 172.06054.

Ethyl 5-(methoxymethyl)oxazole-4-carboxylate (2b). Yield: 93%; colourless oil, IR (KBr), 3465, 3128, 1720, 1613, 1376, 1282 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.88 (s, 1H), 4.82 (s, 2H), 4.39 (q, J = 14.2, 7.14 Hz, 2H), 3.42 (s, 3H), 1.40 (t, J = 14.3, 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 161.14, 154.15, 150.21, 129.46, 63.16, 61.11, 58.39, 13.95; HRMS (ESI, Orbitrap): calcd for C₈H₁₁NO₄ [M + Na] 208.05803 found 208.05785.

5-(Methoxymethyl)-4-tosyloxazole (2c). Yield: 90% light brown solid, M.P. 93–95 °C; IR (KBr) 3149, 2928, 1597, 1505, 1325 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 4.88 (s, 1H), 3.46 (s, 2H), 2.44 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 151.60, 150.78, 145.18, 136.54, 129.88, 128.20, 62.74, 58.82, 21.59; HRMS (ESI, Orbitrap): calcd for C₁₂H₁₄NO₄S [M + H]⁺ 268.06435 found 268.06388.

Methyl 5-(phenoxymethyl)oxazole-4-carboxylate (3a). Yield 85%; yellow oil; IR (KBr) 3481, 3132, 1722, 1597, 1493, 1346 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.91 (s, 1H), 7.34–7.28 (m, 2H), 7.02–7.00 (m, 3H), 5.46 (s, 2H), 3.96 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 161.60, 157.65, 153.29, 150.53, 129.48, 121.70, 114.74, 59.46, 52.23; HRMS (ESI, Orbitrap): calcd for C₁₂H₁₂NO₄ [M + H]⁺ 234.07663 found 234.07582.

Ethyl 5-(phenoxymethyl)oxazole-4-carboxylate (3b). Yield: 92%; white solid, M.P. 74–75 °C; IR (KBr) 3390, 3120, 1712, 1629, 1501, 1324, 1196 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 7.30 (dd, J = 11.7, 4.3 Hz, 2H), 7.04–6.97 (m, 3H), 5.46 (s, 2H), 4.43 (q, J = 14.2, 7.1 Hz, 2H), 1.40 (t, J = 14.2, 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 161.12, 157.65, 153.09, 150.45, 129.69, 129.42, 121.62, 114.70, 61.34, 59.49, 14.03; HRMS (ESI, Orbitrap): calcd for C₁₃H₁₄NO₄ [M + H]⁺ 248.09228 found 248.09180.

5-(Phenoxymethyl)-4-tosyloxazole (3c). Yield: 87%; brown solid, 122–124 °C; IR (KBr) 3146, 1593, 1493, 1324, 1230, 1148 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J = 8.3 Hz, 2H), 7.86 (s, 1H), 7.34 (d, J = 7.5 Hz, 3H), 7.03 (d, J = 8.5 Hz, 2H), 5.51 (s, 2H), 2.43 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.53, 151.05, 150.39, 145.33, 138.42, 136.20, 130.29, 129.91, 129.64, 129.36, 128.28, 122.02, 115.00, 59.01, 21.64; HRMS (ESI, Orbitrap): calcd for C₁₇H₁₆NO₄S [M + H]⁺ 330.37824 found 330.07960.

Methyl 5-(benzyloxymethyl)oxazole-4-carboxylate (4a). Yield 92%, colourless oil, IR (KBr), 3468, 1744, 1595, 1499, 1234 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (s, 1H), 7.34–7.19 (m, 5H), 4.92 (s, 2H), 4.62 (s, 2H), 3.91 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 161.73, 154.63, 150.33, 137.11, 128.41, 127.97, 127.83, 72.99, 61.07, 52.22; HRMS (ESI, Orbitrap): calcd for C₁₃H₁₄NO₄ [M + H]⁺ 248.09173 found 248.09154.

Ethyl 5-(benzyloxymethyl)oxazole-4-carboxylate (4b). Yield 95%, yellow oil; IR (KBr) 3452, 1738, 1720, 1613, 1518, 1375 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.88 (s, 1H), 7.35–7.26 (m, 5H), 4.92 (s, 2H), 4.61 (s, 2H), 4.38 (q, J = 14.3, 7.1 Hz, 2H), 1.38 (t, J = 14.3, 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 161.32, 154.33, 150.28, 136.99, 128.37, 127.91, 127.77, 72.94, 61.28, 61.15, 14.11; HRMS (ESI, Orbitrap): calcd for C₁₄H₁₆NO₄ [M + H]⁺ 262.10346 found 262.10737.

5-(Benzyloxymethyl)-4-tosyloxazole (4c). Yield 87%, brown sticky solid, 64–65 °C; IR (KBr) 3157, 2922, 1600, 1503, 1331 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 8.3 Hz, 2H), 7.82 (s, 1H), 7.40–7.29 (m, 7H), 4.98 (s, 2H), 4.65 (s, 2H), 2.42 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.74, 150.70, 145.08, 138.10, 136.96, 136.51, 129.80, 128.39, 128.28, 128.14, 127.96, 127.82, 73.15, 60.62, 21.55; HRMS (ESI, Orbitrap): calcd for C₁₈H₁₈NO₄S [M + H]⁺ 344.09118 found 344.09535.

Methyl 5-((1,3-dioxoisoindolin-2-yl)methyl)oxazole-4-carboxylate (5a). Yield: 92%; brown solid; 139–141 °C; IR (KBr) 3465, 1713, 1509, 1422, 1282, 1088, 1053 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.91–7.88 (m, 2H), 7.81–7.75 (m, 3H), 5.32 (s, 2H), 3.98 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.19, 161.60, 152.32, 149.81, 134.34, 131.78, 123.64, 52.35, 32.61; HRMS (ESI, Orbitrap): calcd for C₁₄H₁₁N₂O₅ [M + H]⁺ 287.06625 found 287.06361.

Ethyl 5-((1,3-dioxoisoindolin-2-yl) methyl)oxazole-4-carboxylate (5b). Yield: 91%; brown solid; 114–116 °C; IR (KBr) 3464, 1712, 1511, 1396, 1184, 1050 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.92–7.90 (m, 2H), 7.79–7.77 (m, 3H), 5.33 (s, 2H), 4.46 (q, J = 14.3, 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.22, 161.42, 152.12, 149.78, 134.34, 131.79, 123.64, 61.54, 32.66, 14.26; HRMS (ESI, Orbitrap): calcd for C₁₅H₁₃N₂O₅ [M + H]⁺ 301.08080 found 301.08079.

2-((4-Tosyloxazol-5-yl)methyl)isoindoline-1,3-dione (5c). Yield: 87%; white solid, 204–206 °C; IR (KBr) 3426, 1721, 1596, 1392, 1150, 1035 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d, J = 8.3 Hz, 2H), 7.90 (dd, J = 5.5, 3.1 Hz, 2H), 7.77 (dd, J = 5.5, 3.1 Hz, 2H), 7.72 (s, 1H), 7.39 (d, J = 8.1 Hz, 2H), 5.43 (s, 2H), 2.44 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.07, 150.42, 145.28, 136.27, 134.42, 131.72, 129.94, 128.57, 123.72, 32.01, 21.72; HRMS (ESI, Orbitrap): calcd for C₁₉H₁₅N₂O₅S [M + H]⁺ 383.06962 found 383.06999.

Methyl 5-((phenylthio)methyl)oxazole-4-carboxylate (6a). Yield: 91%; yellow oil; IR (KBr) 3058, 1727, 1609, 1521, 1354, 1048, 955 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.78 (s, 1H), 7.40–7.34 (m, 2H), 7.31–7.23 (m, 3H), 4.45 (s, 2H), 3.80 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 161.79, 155.46, 149.77, 133.42, 132.17, 129.05, 127.88, 52.14, 29.26; HRMS (ESI, Orbitrap): calcd for C₁₂H₁₁NO₃SNa [M + Na]⁺ 272.03519 found 272.03560.

Ethyl 5-((phenylthio)methyl)oxazole-4-carboxylate (6b). Yield: 93%; yellow oil; IR (KBr) 2923, 1718, 1608, 1374, 1315, 1045 cm⁻¹; ¹H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.39–7.35 (m, 2H), 7.27–7.24 (m, 3H), 4.46 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl3) δ 159.03, 149.66, 132.08, 129.03, 127.82, 61.26, 29.25, 14.22; HRMS (ESI, Orbitrap): calcd for C₁₃H₁₄NO₃S [M + H]⁺ 264.06889 found 268.0637.

5-((Phenylthio)methyl)-4-tosyloxazole (6c). Yield: 83%; brown solid, 86–88 °C; IR (KBr) 2922, 1587, 1404, 1323, 1145, 1093 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 8.3 Hz, 2H), 7.71 (s, 1H), 7.42–7.39 (m, 2H), 7.34–7.28 (m, 5H), 4.54 (s, 2H), 2.42 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 152.76, 150.23, 145.12, 136.55, 136.36, 133.39, 132.14, 130.03, 129.89, 129.27, 128.30, 128.01, 28.85, 21.74; HRMS (ESI, Orbitrap): calcd for C₁₇H₁₅NO₃S₂ [M + H]⁺ 346.05661 found 346.05525.

(4-Tosyloxazol-5-yl)methanol (7). Yield: 89%; brown sticky solid, IR (KBr) 23 541, 1593, 1506, 1323, 1030 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) 7.92 (d, J = 8.3 Hz, 2H), 7.81 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 4.99 (s, 2H), 3.35 (bs, 1H), 2.43 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 154.83, 150.27, 145.51, 136.99, 136.18, 130.07, 128.19, 54.64, 21.72; HRMS (ESI, Orbitrap): calcd for C₁₁H₁₁NO₄SNa [M + Na]⁺ 276.03010 found 276.03018.

4-Tosyloxazole-5-carbaldehyde (8). Yield: 87%; brown semi solid; IR (KBr) 3412, 2922, 1691, 1608, 1457, 1151 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 10.44 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.97 (s, 1H), 7.41 (d, J = 8.1 Hz, 2H), 2.47 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.29, 153.00, 130.36, 128.94, 126.42, 114.80, 22.51; HRMS (ESI, Orbitrap): calcd for C₁₁H₁₉NO₄SNa [M + Na]⁺ 274.01445 found 274.01449.

Methyl 1-(2-methoxy-2-oxoethyl)-1H-imidazole-4-carboxylate (11). Yield: 95%; white solid; 141–143 °C; IR (KBR) 3462, 1716, 1533, 1342, 1180, 1031 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.63 (s, 1H), 7.52 (s, 1H), 4.75 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) 167.24, 163.02, 138.78, 133.86, 126.25, 53.01, 51.65, 48.12; HRMS (ESI, Orbitrap): calcd for C₈H₁₁N₂O₄ [M + H]⁺ 199.07133 found 199.07139.

Acknowledgements

The authors thank the Department of Science and Technology (DST) New Delhi, India, for financial support. The authors are grateful to the Director, CSIR-IICT for providing the necessary infrastructure. D. K. T. is grateful to Dr P. M. Chincholkar for his valuable suggestions.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra07668d

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