A metal-free tandem ring-opening/ring-closing strategy for the heterocyclic conversion of benzoxazin-4-ones to oxazolines

Abstract

A facile metal-free tandem ring-opening/ring-closing strategy was developed for the synthesis of oxazolines in good to excellent reaction yields under mild reaction conditions. This reaction essentially describes a novel tool for the heterocyclic conversion of benzoxazin-4-ones to 2,5-disubstituted oxazolines directly in one-pot.

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Introduction

In recent years momentous attention has been focused on the development of new synthetic methodologies aiming at the synthesis of novel heterocyclic compounds such as oxazolines, thiazolines, and imidazoline since these scaffolds play a pivotal role in a variety of biological activities¹ and they are also widely used in materials science, bioorganic chemistry, and organometallic chemistry.^2,3 In particular leupyrrin,⁴ an antifungal, bistratamide,⁵ an anticancer and mycobactin T,⁶ a high affinity Fe³⁺-chelating natural product possessing an active oxazoline structural motif have been noted for their biological activities (Fig. 1).

Fig. 1 Example of oxazoline containing products.

Developing new synthetic methodologies towards the construction of N-heterocycles⁷ has always remained a fascinating area for organic chemists due to their high importance in biological studies. In particular, the oxazoline ring could be constructed either by dehydration of amido alcohol or condensation of a nitrile with an amino alcohol.⁸ Conversely, in the recent times several new synthetic methodologies emerged towards the synthesis of oxazolines.⁹ Remarkably, the conversion of N-allylbenzamides to 2,5-disubstituted oxazoline by an α-exo mode cyclization process stands out (Scheme 1). Some esoteric reagents, metal or metal-free catalysts are reported for this transformation. Most prominent amongst them are: Moran et al.^9b reported iodoarene-catalyzed synthesis of oxazolines that involves cyclization of unsaturated amides using selectfluor as the oxidant, while Harned et al.^9d reported iodine(III) promoted synthesis of oxazoline acetates from N-allylamides in the presence of Lewis acids at elevated temperatures. Though the former protocol offered an interesting strategy however was limited in its reagent scope. When m-CPBA or Oxone were used as the oxidants along with iodoarene precatalysts the reaction failed to afford either the resultant oxazoline or the corresponding epoxide.^9b Likewise, synthesis of halo oxazoline derivatives in the presence NBS or NIS required elevated temperatures.^9e Due to these limitations,^9b,d,e there still remains scope to expand the synthetic horizon of accessing oxazoline scaffolds under mild and at ambient temperatures.

Scheme 1 Synthesis of 2,5-disubstituted oxazolines.

Results and discussion

In continuation of our interest in the development of novel synthetic methodologies towards construction of heterocyclic scaffolds,¹⁰ next we planned to synthesize oxazoline heterocycles. We were particularly interested in developing a conceptually new strategy wherein a tandem ring-opening/ring-closing reaction set maybe invoked to realize oxazolines from benzoxazin-4-ones that essentially involves a heterocyclic conversion as the strategic tool. The results are disclosed in this paper.

At the outset, we presumed that benzoxazin-4-one 1a¹¹ onnucleophilic ring-opening reaction with allylamine would lead to the corresponding N-allylbenzamide intermediate 2 in situ which can ring-close to form the oxazoline 2a in presence of an appropriate oxidant via an oxidative cyclization (Scheme 2).

Scheme 2 Synthesis of oxazolines.^{a a}Reaction conditions: 1a (0.44 mol, 1.0 equiv.), allylamine (0.89 mol, 2.0 equiv.), m-CPBA (0.89 mol, 2.0 equiv.), solvent (3 mL).

Checking on this hypothesis, we chose 1a as the test substrate and subjected to tandem ring-opening/ring-closing protocol. As per the plan, the first reaction set i.e. ring-opening of 1a proceeded smoothly with allylamine and the next ring-closing reaction was equally facile with m-CPBA as an oxidant in dichloromethane solvent at 27 °C affording the desired 2,5-substituted oxazoline 2a in good yield (82%, entry 1, Table 1).

Table 1 Screening of reaction conditions^a

Entry	Oxidant	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: oxidant (2 equiv.), solvent (3 mL).b Yields of isolated compounds in the parenthesis.c Decomposition of reaction mixture.
1	m-CPBA	CH2Cl2	10	82 (2a)
2	Oxone	CH2Cl2	4	44 (2a)
3	Oxone	CH2Cl2	6	0^c
4	TBHP (5 M)	CH2Cl2	12	66 (2)
5	TBHP (aq.)	CH2Cl2	12	60 (2)
6	CHP	CH2Cl2	12	64 (2)

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Delighted at accomplishing a single step conversion, next we screened commercially available oxidants such as Oxone, TBHP and CHP in place of m-CPBA which facilitated the second-stage operation during the conversion of 1a to 2a (Table 1). Excepting Oxone (entry 2, Table 1), with TBHP and CHP the reaction did not yield the expected product 2a but rather stopped at the N-allylamide stage 2 (Scheme 2 and entries 4–6 in Table 1). However with Oxone, 2a was obtained in 44% yield or no product depending on the reaction time (entries 2 and 3, Table 1). Optimum product (82%) was obtained when m-CPBA was the oxidant (entry 1, Table 1). Incidentally, it may be recalled that both m-CPBA and Oxone oxidants failed^9b to give the desired products when the starting material was N-allylbenzamide.

Next, the other parameters like optimal oxidant (m-CPBA) amount and the best solvent system for the maximum conversion were explored (Table 2). It was found that the use of 2.5 equiv. of m-CPBA in dichloromethane solvent gave the best result of 2a (90% yield). Varying the amount of m-CPBA to 1.0, 1.5 and 2.0 equiv. resulted in varying yields (40%, 65% and 82% respectively). Optimum yields were obtained in CH₂Cl₂ as the solvent (entry 4, Table 2) and hence it was selected as the solvent of choice for all further investigations. Increasing the reaction temperature or time-line has deleterious effect on the product profile.

Table 2 Optimization of reaction conditions^a

Entry	Oxidant	Equiv.	Solvent	Yield^b (%)
a Reaction conditions: 1a (1.0 equiv.), allylamine (2.0 equiv.), solvent (3 mL).b Yields of isolated compound 2a. DCE = 1,2-dichloroethane.
1	m-CPBA	1.0	CH2Cl2	40
2	m-CPBA	1.5	CH2Cl2	65
3	m-CPBA	2.0	CH2Cl2	82
4	m-CPBA	2.5	CH2Cl2	90
5	m-CPBA	2.5	CHCl3	66
6	m-CPBA	2.5	CH3CN	48
7	m-CPBA	2.5	DCE	72

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Subsequent to optimization of the oxidant equivalents, we then turned our attention to the quantities of allylamine used wherein initially 2 equivalents were employed to affect the transformation of benzoxazinone to allyl amide 2. To rationalise its quantity, we undertook some control experiments. Firstly, in order to facilitate this transformation we planned a sequential investigation of the allylamine equiv. required in combination with an external base (for e.g. Et₃N). The results revealed that with 1.0 and 2.0 equiv. of allylamine in absence of Et₃N 55% and 95% conversion of 1a to 2 respectively has occurred followed by the next conversion of 2 to 2a with 2.5 equiv. of m-CPBA to result in 40% and 90% yields respectively. Surprisingly, when the same experiment was conducted with 1.0 equiv. of allylamine in presence of 1.0 equiv. of Et₃N, a 100% conversion from 1a to 2 was found but no further m-CPBA oxidation was observed suggesting that excess equiv. of allylamine (2.0) plays a dual role as an internal base and as a nucleophile.

After optimizing the reactions, we studied the substrate scope of this protocol. In order to do so, several benzoxazin-4-ones (1b–j, Scheme 3) were prepared from the corresponding amino acids and acid chlorides as per the literature procedure.¹¹

Scheme 3 Synthesis of benzoxazin-4-one.

Subsequently, the thus prepared benzoxazin-4-ones 1b–j were subjected to the facile heterocyclic conversion to afford the corresponding oxazoline derivatives 2b–j in good to excellent yields (61–90%) under the optimized reaction conditions (Scheme 4). All the products are well characterized by their spectral analysis.¹² Presence of various substituent groups on either aryl moieties (as shown in Scheme 3) showed no significant effect on conversion process excepting 1g. Thus several substituent groups, including methyl, substituted aryls (4-methoxy 2b, 4-fluoro 2c, 3,4-dichloro 2d, 4-trifluoromethyl 2e, methyl 2f) groups well tolerated the reaction conditions. Interestingly, the halo-substituted substrates 1h–j also underwent this transformation to afford 2h–j (74–79%).

Scheme 4 Scope of cyclization of different benzoxazin-4-ones under metal free conditions.^{a a}Yields of the isolated compounds in the parenthesis.

After showcasing the substrate scope of this protocol, we wanted to investigate the role of the ortho amide group in this unique oxidative-heterocyclic conversion.¹³ Hence we prepared a set of compounds, starting from anthranilic acid, to conduct some control experiments (Scheme 5). Thus, compound 3 (ref. 14) was prepared by the coupling of anthranilic acid with allylamine according to the literature procedure.¹⁵ Compound 3 itself on reaction with m-CPBA resulted in the nitro compound 4 (ref. 9d) (56%) rather than the target oxazoline product. Next, compound 3 on treatment with MeI under K₂CO₃ conditions provided the N-alkylated product 5 (ref. 16) (70%) which on subsequent m-CPBA oxidation resulted in a mixture of products rather than the expected oxazoline product. In the next experiment, compound 3 was N-acylated¹⁵ with but-3-enoic acid to afford the diamide 6 (78%) which on m-CPBA oxidation under optimized conditions furnished the corresponding oxazoline 7 (ref. 12) (60%). These experiments conclusively prove that the presence of ortho amidic moiety plays an important role in the m-CPBA oxidation, unlike literature reports where unsubstituted aryl amides failed to yield the oxazoline derivatives.^9b

Scheme 5 Some control experiments.^{a a}Reaction conditions: (a) allylamine, EDCl, DMAP, CH₂Cl₂, 0 °C to rt, 12 h, 72%; (b) m-CPBA, CH₂Cl, rt, 8 h; (c) Mel, K₂CO₃, CH₃CN, reflux, 8 h, 70%; (d) but-3-enoic acid, EDCl, DMAP, CH₂Cl₂, 0 °C to rt, 12 h, 78%.

On the basis of these results, a plausible mechanism is proposed (Scheme 6). Firstly, the regioselective addition of amine nucleophile on benzoxazinone 1a affords a ring-opened intermediate 2 which on tautomerization of ortho amidic group facilitates the H-bonding with C=O of m-CPBA increasing the electrophilic character of m-CPBA on electron rich olefin to result in the corresponding epoxide intermediate A followed by the cyclization of epoxy amide to oxazoline derivative.

Scheme 6 Plausible mechanism.

Following our efforts towards one-pot (nucleophilic ring opening of benzoxazin-4-one followed by intramolecular oxidative cyclization) synthesis of heterocyclic scaffold, oxazolines; we were intrigued to know if such a methodology could be extrapolated to access the halo oxazoline derivative which is considered a privileged structure. Interestingly, NBS promoted synthesis of oxazolines was previously reported^9e via oxidative cyclization of N-allylbenzamides albeit at elevated temperatures. However, herein when NBS/NIS and molecular I₂ were tried under the optimized reaction conditions with 1a as the starting material, the corresponding bromo/iodo oxazoline derivatives were obtained at ambient temperatures in good to high yields (Scheme 7). The conversion of 1a to the iodo oxazoline 8a in one-pot under molecular I₂ promoted cyclization is perhaps the most promising reaction for its subsequent exploitation. This reaction follows the same mechanistic pathway as reported in literature.^9e

Scheme 7 Synthesis of halo derived oxazolines using NIS/NBS/I₂.^{a a}Reaction conditions: 1a (1.0 equiv.), allylamine (2.0 equiv.), NIS/NBS/I₂ (2.0 equiv.), solvent (3 mL). ^bYields of the isolated compounds in the parenthesis.

Conclusion

In conclusion, a facile one-pot heterocyclic conversion of benzoxazin-4-ones to oxazolines involving a tandem ring-opening and ring-closing strategy in the presence of allylamine and m-CPBA was successfully demonstrated under metal-free conditions. More importantly, the one-pot conversion of benzoxazinone to the iodo oxazoline derivative under allylamine/molecular I₂ promoted cyclization is notable. Likewise, NIS or NBS under similar conditions gave the corresponding halo oxazoline derivatives.¹² Application of this strategy towards accessing a library of compounds is underway.

Experimental section

Unless otherwise noted, commercial chemicals were used without any further purification. Solvents were dried and distilled prior to use by the usual methods. The starting materials (1a–j) were prepared according to reported method.¹¹ Melting points are uncorrected. ¹H NMR spectra were recorded at 300, 400 and 500 MHz in CDCl₃ unless otherwise stated. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl₃: 7.26 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), and coupling constants (Hz). ¹³C NMR was recorded at 75, 100 and 125 MHz in CDCl₃ unless otherwise stated with complete proton decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent as the internal standard (CDCl₃: 77.4 ppm). Mass spectrometry (m/z) was performed in ESI mode. High-resolution mass spectra for all the new compounds were collected on Micromass Q-Tof instrument (ESI). Infrared (IR) spectra ν_max are reported in cm⁻¹.

General procedure for the synthesis of N-(2-(5-(hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)benzamide, 2a

Allylamine (0.067 mL, 0.89 mmol, 2 equiv.) and 2-phenyl-4H-benzo[d][1,3]oxazin-4-one 1a (0.1 g, 0.44 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (3 mL) and the mixture was stirred for 1 h at room temperature under nitrogen. Then, aqueous m-CPBA (0.192 g, 1.12 mmol) was added by portion to the reaction mixture and allowed to stir for another 8 h at same temperature. Then, 30% aq. KOH solution (3 mL) was added and the mixture was extracted with CH₂Cl₂ (2 × 5 mL). The organic layers were combined and dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash chromatography (2.4 : 7.6 EtOAc/petroleum ether) to provide 2a as a white solid (0.11 g, 90%); mp 159–161 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 12.92 (1H, s), 8.97 (1H, d, J = 8.5 Hz), 8.08 (2H, dt, J = 7.0, 1.5 Hz), 7.92 (1H, dd, J = 7.7, 1.5 Hz), 7.57–7.47 (4H, m), 7.12 (1H, td, J = 7.7, 1.0 Hz), 4.86–4.79 (1H, m), 4.25 (1H, dd, J = 14.4, 9.9 Hz), 4.03 (1H, dd, J = 14.6, 7.6 Hz), 3.93 (1H, ddd, J = 12.2, 5.3, 3.3 Hz), 3.76 (1H, dt, J = 11.7, 5.3 Hz); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 166.1, 164.2, 140.3, 135.3, 132.8, 131.7, 129.2, 128.6, 127.7, 122.4, 120.0, 113.3, 78.7, 64.0, 56.1; IR(neat) 3478, 2930, 2866, 1664, 1642, 1624, 1588, 1546, 1446, 1354, 1304, 1256, 1058, 757, 712 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₇H₁₇N₂O₃ 297.1233, found 297.1230.

N-(2-(5-(Hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)-4-methoxybenzamide, 2b

This compound was prepared according to the representative procedure for 2a using allylamine and 2-(4-methoxyphenyl)-4H-benzo[d][1,3]oxazin-4-one 1b giving 2b as a white solid (0.12 g, 87%); mp 163–166 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 12.80 (1H, s), 8.94 (1H, d, J = 8.4 Hz), 8.04 (2H, dt, J = 8.9, 1.9 Hz), 7.90 (1H, dd, J = 7.9, 1.5 Hz), 7.51 (1H, td, J = 8.6, 1.5 Hz), 7.08 (1H, td, J = 8.5, 0.9 Hz), 6.98 (2H, dt, J = 8.9, 2.8 Hz), 4.86–4.78 (1H, m), 4.25 (1H, dd, J = 14.5, 9.9 Hz), 4.03 (1H, dd, J = 14.5, 7.5 Hz), 3.92 (1H, dd, J = 12.2, 3.1 Hz), 3.88 (3H, s), 3.75 (1H, dd, J = 12.3, 5.5 Hz); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 165.7, 164.2, 162.4, 140.5, 132.8, 129.5, 129.2, 127.6, 122.1, 119.9, 113.8, 113.1, 78.6, 64.2, 56.1, 55.4; IR(neat) 3438, 2928, 1637, 1614, 1512, 1445, 1329, 1258, 1177, 1026, 841, 757, 680 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₈H₁₉N₂O₄ 327.1339, found 327.1341.

4-Fluoro-N-(2-(5-(hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)benzamide, 2c

This compound was prepared according to the representative procedure for 2a using allylamine and 2-(4-fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one 1c giving 2c as white solid (0.10 g, 84%); mp 139–142 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 12.90 (1H, s), 8.92 (1H, dd, J = 8.5, 1.0 Hz), 8.12–8.06 (2H, m), 7.93 (1H, dd, J = 7.9, 1.5 Hz), 7.53 (1H, td, J = 8.6, 1.5 Hz), 7.20–7.09 (3H, m), 4.87–4.80 (1H, m), 4.25 (1H, dd, J = 14.4, 9.9 Hz), 4.04 (1H, dd, J = 14.4, 7.6 Hz), 3.94 (1H, dd, J = 12.3, 3.0 Hz), 3.76 (1H, dd, J = 12.3, 5.3 Hz); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 165.0, 164.3, 163.9, 140.2, 132.9, 130.0, 129.3, 122.5, 119.9, 115.7, 115.5, 113.3, 78.7, 63.9, 56.0; IR(neat) 3428, 3250, 2923, 2853, 1666, 1623, 1547, 1448, 1326, 1298, 1231, 1162, 1053, 886, 847, 750, 670 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₇H₁₆N₂O₃F 315.1139, found 315.1141.

3,4-Dichloro-N-(2-(5-(hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)benzamide, 2d

This compound was prepared according to the representative procedure for 2a using allylamine and 2-(3,4-dichlorophenyl)-4H-benzo[d][1,3]oxazin-4-one 1d giving 2d as a white solid (0.088 g, 80%); mp 165–168 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 13.03 (1H, s), 8.88 (1H, dd, J = 8.5, 0.9 Hz), 8.19 (1H, d, J = 2.0 Hz), 7.91 (2H, td, J = 9.4, 1.5 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.53 (1H, td, J = 8.9, 1.7 Hz), 7.13 (1H, td, J = 8.4, 1.1 Hz), 4.89–4.80 (1H, m), 4.27 (1H, dd, J = 14.5, 9.9 Hz), 4.06 (1H, dd, J = 14.6, 7.7 Hz), 3.96 (1H, dd, J = 12.3, 3.1 Hz), 3.77 (1H, dd, J = 12.3, 5.3 Hz); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 164.4, 163.7139.8, 136.0, 135.0, 133.0, 132.9, 130.6, 130.0, 129.3, 126.9, 122.8, 119.9, 113.3, 78.8, 63.9, 55.9; IR(neat) 3419, 2924, 2861, 1663, 1629, 1589, 1550, 1450, 1321, 1257, 1112, 1058, 1031, 891, 832, 750, 676 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₇H₁₅N₂O₃Cl₂ 365.0454, found 365.0464.

N-(2-(5-(Hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)-4-(trifluoromethyl)benzamide, 2e

This compound was prepared according to the representative procedure for 2a using allylamine and 2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-one 1e giving 2e as yellow solid (0.093 g, 78%); mp 146–148 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 13.07 (1H, s), 8.93 (1H, dd, J = 8.3, 0.7 Hz), 8.18 (1H, d, J = 8.0 Hz), 7.93 (1H, dd, J = 7.9, 1.5 Hz), 7.76 (2H, d, J = 8.2 Hz), 7.54 (1H, td, J = 8.6, 1.5 Hz), 7.14 (1H, td, J = 7.9, 1.0 Hz), 4.87–4.80 (1H, m), 4.25 (1H, dd, J = 14.4, 9.9 Hz), 4.04 (1H, dd, J = 14.6, 7.7 Hz), 3.95 (1H, dd, J = 12.3, 3.2 Hz), 3.77 (1H, dd, J = 12.3, 5.3 Hz); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 164.7, 164.3, 139.8, 138.5, 133.1, 132.9, 132.6, 129.0, 128.1, 125.6, 122.8, 120.0, 113.4, 78.8, 63.9, 56.0; IR(neat) 3426, 2924, 2853, 1657, 1630, 1582, 1552, 1453, 1341, 1254, 1167, 1112, 1061, 997, 971, 856, 761, 693 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₈H₁₆O₃N₂F₃ 365.1107, found 365.1117.

N-(2-(5-(Hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)acetamide, 2f

This compound was prepared according to the representative procedure for 2a using allylamine and 2-methyl-4H-benzo[d][1,3]oxazin-4-one 1f giving 2f as a yellow solid (0.118 g, 85%); mp 116–119 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 12.08 (1H, s), 8.70 (1H, d, J = 8.3 Hz), 7.87 (1H, dd, J = 7.9, 1.5 Hz), 7.45 (1H, td, J = 8.6, 1.5 Hz), 7.06 (1H, td, J = 8.0, 1.0 Hz), 4.82–4.75 (1H, m), 4.19 (1H, dd, J = 14.6, 10.0 Hz), 3.94 (2H, J = 14.6, 7.6 Hz), 3.73 (1H, dd, J = 12.3, 5.4 Hz), 2.21 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 169.4, 163.9, 140.0, 132.6, 129.1, 122.1, 119.7, 112.6, 78.5, 63.9, 56.1, 25.4; IR(neat) 3393, 2927, 1637, 1535, 1448, 1367, 1305, 1250, 1061, 769, 676 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₂H₁₅N₂O₃ 235.1077, found 235.1075.

N-(2-(5-(Hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)acrylamide, 2g

This compound was prepared according to the representative procedure for 2a using allylamine and 2-vinyl-4H-benzo[d][1,3]oxazin-4-one 1g giving 2g as yellow solid (0.066 g, 48%); mp 138.7 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 12.37 (1H, s), 8.83 (1H, dd, J = 8.3, 0.7 Hz), 7.89 (1H, dd, J = 7.9, 1.6 Hz), 7.49 (2H, td, J = 8.6, 1.5 Hz), 7.09 (1H, td, J = 8.2, 1.0 Hz), 6.42 (1H, dd, J = 17.0, 1.2 Hz), 6.31 (1H, dd, J = 17.0, 10.2 Hz), 5.76 (1H, dd, J = 10.2, 1.2 Hz), 4.83–4.77 (1H, m), 4.20 (1H, dd, J = 14.6, 10.0 Hz), 3.95 (2H, dd, J = 14.6, 7.6 Hz), 3.74 (1H, dd, J = 12.3, 5.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 164.4, 164.0, 139.9, 132.7, 129.2, 126.8, 122.4, 119.9, 113.0, 78.6, 63.9, 58.1; IR(neat) 3450, 2922, 2852, 1637, 1462, 1219, 768 cm⁻¹; HRMS m/z calcd for [M + Na]⁺ C₁₃H₁₄N₂O₃Na⁺ 269.0896, found 269.0893.

N-(4-Chloro-2-(5-(hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)benzamide, 2h

This compound was prepared according to the representative procedure for 2a using allylamine and 6-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 1h giving 2h as a white solid (0.098 g, 78%); mp 176–178 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 12.84 (1H, s), 8.93 (1H, d, J = 9.0 Hz), 8.04 (2H, dd, J = 8.1, 1.2 Hz), 7.88 (1H, d, J = 2.5 Hz), 7.58–7.43 (4H, m), 4.88–4.79 (1H, m), 4.26 (1H, dd, J = 14.7, 10.0 Hz), 4.06 (1H, dd, J = 14.7, 7.8 Hz), 3.95 (1H, dd, J = 12.3, 3.1 Hz), 3.76 (1H, dd, J = 12.3, 5.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 166.1, 163.3, 138.8, 134.8, 132.5, 131.9, 128.9, 128.6, 127.7, 127.4, 121.4, 114.6, 79.0, 63.8, 56.1; IR(neat) 3443, 2924, 2853, 1638, 1614, 1528, 1307, 1232, 1106, 1054, 826, 704 cm⁻¹; HRMS m/z calcd for [M + Na]⁺ C₁₇H₁₅ClN₂O₃Na⁺ 353.0663, found 353.0657.

N-(2-(5-(Hydroxymethyl)-4,5-dihydrooxazol-2-yl)-4-iodophenyl)benzamide, 2i

This compound was prepared according to the representative procedure for 2a using allylamine and 6-iodo-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 1i giving 2i as a yellow solid (0.88 g, 74%); mp 135–138 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 12.86 (1H, s), 8.76 (1H, d, J = 9.0 Hz), 8.23 (1H, d, J = 2.1 Hz) 8.05 (2H, dt, J = 7.0, 1.5 Hz), 7.80 (1H, dd, J = 9.0, 2.1 Hz), 7.58–7.46 (3H, m), 4.86–4.80 (1H, m), 4.26 (1H, dd, J = 14.6, 9.9 Hz), 4.06 (1H, dd, J = 14.6, 7.7 Hz), 3.95 (1H, d, J = 11.9 Hz), 3.76 (1H, dt, J = 12.2, 4.4 Hz); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 166.1, 164.2, 140.2, 135.2, 132.8, 131.7, 129.2, 128.6, 127.7, 122.4, 120.0, 113.3, 78.7, 64.0, 56.1; IR(neat) 3438, 2923, 2853, 1668, 1621, 1570, 1521, 1310, 1229, 1058, 775, 700, 567 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₇H₁₆IN₂O₃⁺ 423.0200, found 423.0217.

N-(5-Fluoro-2-(5-(hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)benzamide, 2j

This compound was prepared according to the representative procedure for 2a using allylamine and 7-fluoro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 1j giving 2j as a white solid (0.099 g, 79%); mp 158–161 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 13.07 (1H, s), 8.78 (1H, dd, J = 12.1, 2.5 Hz), 8.07 (2H, dd, J = 8.0, 1.1 Hz), 7.91 (1H, dd, J = 8.8, 6.4 Hz), 7.58–7.47 (2H, m), 6.81 (1H, td, J = 7.5, 2.5 Hz), 4.86–4.79 (1H, m), 4.25 (1H, dd, J = 14.5, 9.9 Hz), 3.99 (1H, dd, J = 14.5, 7.7 Hz), 3.76 (1H, dd, J = 12.2, 5.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 166.3, 163.8, 163.7, 142.2, 134.8, 131.9, 131.1, 128.6, 127.7, 109.4, 107.3, 78.7, 63.9, 56.0; IR(neat) 3499, 3440, 2923, 2853, 1666, 1643, 1539, 1429, 1297, 1270, 1161, 1099, 1055, 979, 873, 712, 668 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₇H₁₆O₃N₂F 315.11395, found 315.11442.

N-Allyl-2-(but-3-enamido)benzamide, 6

To a solution of N-allyl-2-aminobenzamide 3 (0.2 g, 1.13 mmol) in CH₂Cl₂ (5 mL) at 0 °C were successively added DMAP (0.07 g, 0.57 mmol), but-3-enoic acid (0.09 g, 1.13 mmol) and EDCI (0.30 g, 1.59 mmol) portion wise. After 12 h, the reaction mixture was hydrolyzed with water and extracted with CH₂Cl₂. The combined organic extracts were successively washed with a 1 M aqueous solution of hydrochloric acid, a saturated aqueous solution of NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (1.5 : 8.5 EtOAc/petroleum ether) to provide 6 as a white solid (0.21 g, 78%); mp 123–125 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 11.03 (1H, br.s), 8.58 (1H, dd, J = 8.8, 1.0 Hz), 7.49–7.44 (2H, m), 7.07 (1H, td, J = 7.7, 1.0 Hz), 6.33 (1H, m), 6.09–6.00 (1H, m), 5.98–5.89 (1H, m), 5.32–5.26 (3H, m), 5.23 (1H, dq, J = 10.2, 1.3 Hz), 4.06 (2H, tt, J = 5.6, 1.5 Hz), 3.20 (2H, dt, J = 7.1, 1.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 169.8, 168.7, 139.4, 133.5, 132.6, 130.7, 126.3, 122.8, 121.7, 120.4, 119.7, 117.1, 43.3, 42.3; HRMS m/z calcd for [M + Na]⁺ C₁₄H₁₆N₂O₂Na 267.1104, found 267.1095.

N-(2-(5-(Hydroxymethyl)-4,5-dihydrooxazol-2-yl)phenyl)but-3-enamide, 7

To a solution of N-allyl-2-(but-3-enamido)benzamide 6 (0.1 g, 0.40 mmol) in CH₃Cl (5 mL) at 0 °C was added aqueous m-CPBA (0.21 g, 1.22 mmol) by portion and allowed to stir at room temperature. After complete consumption of 7 (after 8 h, monitored by tlc) 30% aq. KOH solution (3 mL) was added and the mixture was extracted with CH₂Cl₂ (2 × 5 mL). The organic layers were combined and dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography (2 : 8 EtOAc/petroleum ether) to provide 7 as a white solid (0.06 g, 60%); mp 116–118 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 12.13 (1H, br.s), 8.72 (1H, d, J = 8.5 Hz), 7.87 (1H, dd, J = 7.9, 1.5 Hz), 7.49–7.43 (1H, m), 7.07 (1H, t, J = 7.6 Hz), 6.10–5.98 (1H, m), 5.30–5.23 (2H, m), 4.82–4.75 (1H, m), 4.18 (1H, dd, J = 14.8, 10.0 Hz), 3.95 (1H, dd, J = 14.6, 7.6 Hz), 3.91 (1H, dd, J = 12.2, 3.2 Hz), 3.74 (1H, dd, J = 12.2, 5.4 Hz), 3.22 (2H, d, J = 7.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 170.2, 163.8, 139.9, 132.6, 131.0, 129.1, 122.3119.8, 119.2, 112.9, 78.6, 64.0, 56.1, 43.6; HRMS m/z calcd for [M + H]⁺ C₁₄H₁₇N₂O₃ 261.1233, found 261.1225.

N-(2-(5-(Bromomethyl)-4,5-dihydrooxazol-2-yl)phenyl)benzamide, 8b

Allylamine (0.067 mL, 0.89 mmol, 2 equiv.) and 2-phenyl-4H-benzo[d][1,3]oxazin-4-one 1a (0.1 g, 0.44 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (3 mL) and the mixture was stirred for 2 h at room temperature under N₂. Then, NBS (0.19 g, 1.07 mmol, 2.5 equiv.) was added to the reaction mixture and allowed to stir for another 4 h at same temperature. After completion of reaction the reaction mixture was diluted with CH₂Cl₂ (3 mL) and quenched with saturated aqueous Na₂SO₃. The aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL), and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, concentrated and purified by column chromatography (1.4 : 8.6 EtOAc/petroleum ether) to provide 8b as a yellow solid (0.1 g, 72%); mp 105–108 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 12.80 (1H, s), 8.97 (1H, dd, J = 8.4, 1.1 Hz), 8.10–8.05 (2H, m), 7.91 (1H, dd, J = 7.8, 1.5 Hz), 7.58–7.47 (4H, m), 7.13 (1H, td, J = 8.0, 1.1 Hz), 4.98–4.90 (1H, m), 4.34 (1H, dd, J = 15.0, 9.6 Hz), 4.09 (1H, dd, J = 15.0, 6.6 Hz), 3.59 (1H, dd, J = 10.7, 4.7 Hz), 3.54 (1H, dd, J = 10.7, 6.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 166.1, 164.0, 140.2, 135.2, 133.0, 131.7, 129.3, 128.6, 127.7, 122.5, 120.0, 113.1, 76.5, 59.0, 33.2; IR (neat) 3456, 3010, 2925, 2865, 1665, 1622, 1585, 1444, 1307, 1233, 1053, 757, 703, 679, 648 cm⁻¹; HRMS m/z calcd for [M + H]⁺ C₁₇ H₁₆N₂O₂Br 359.0389, found 359.0392.

N-(2-(5-(Iodomethyl)-4,5-dihydrooxazol-2-yl)phenyl)benzamide, 8a

(a) This compound was prepared according to the representative procedure for 8b using allylamine (0.067 mL, 0.89 mmol, 2 equiv.) and 2-phenyl-4H-benzo[d][1,3]oxazin-4-one 1a (0.1 g, 0.44 mmol, 1 equiv.) and NIS (0.23 g, 1.02 mmol, 2.5 equiv.) giving 8a as a pale yellow solid (0.14 g, 86%).

(b) The compound 8a was prepared in another way according to the representative procedure for 8b using allylamine (0.067 mL, 0.89 mmol, 2 equiv.) and 2-phenyl-4H-benzo[d][1,3]oxazin-4-one 1a (0.1 g, 0.44 mmol, 1 equiv.) and I₂ (0.27 g, 2.5 equiv.) giving 8a as a white solid (0.15 g, 92%); mp 106–109 °C; ¹H NMR (500 MHz, CDCl₃) δ (ppm) 12.80 (1H, s), 8.97 (1H, dd, J = 8.5, 1.0 Hz), 8.10–8.05 (2H, m), 7.91 (1H, dd, J = 7.9, 1.6 Hz), 7.58–7.47 (4H, m), 7.13 (1H, td, J = 8.3, 1.2 Hz), 4.85–4.77 (1H, m), 4.33 (1H, dd, J = 14.9, 9.4 Hz), 3.97 (1H, dd, J = 14.9, 6.7 Hz), 3.41 (1H, dd, J = 10.3, 4.5 Hz), 3.34 (1H, dd, J = 10.3, 7.3 Hz); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 166.0, 163.9, 140.3, 135.2, 132.9, 131.6, 129.3, 128.6, 127.7, 122.4, 120.0, 113.2, 76.8, 60.5, 7.1; IR(neat) 3458, 2923, 2854, 1665, 1630, 1583, 1444, 1306, 1233, 1052, 879, 702, 678, 536 cm⁻¹; HRMS m/z calcd C₁₇H₁₆O₂N₂I 407.0251, found 407.02465.

Acknowledgements

R. N., M. B. and J. R. thank CSIR New Delhi for research fellowship. This research work financially supported by the CSIR New Delhi (BSC 0116).

References and Notes

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra23013f

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