In(OTf)₃-catalyzed tandem aza-Piancatelli rearrangement/Michael reaction for the synthesis of 3,4-dihydro-2H-benzo[b][1,4]thiazine and oxazine derivatives

Abstract

Furan-2-yl(phenyl)methanol derivatives undergo smooth aza-Piancatelli rearrangement with 2-aminothiophenol and 2-aminophenol in the presence of 10 mol% In(OTf)₃ in acetonitrile at room temperature to afford the corresponding 3,4-dihydro-2H-benzo[b][1,4]thiazine or oxazine derivatives respectively in good yields with high selectivity in short reaction times. The salient features of this methodology are good yields, high selectivity, low catalyst loading and faster reaction times. The structure of the products was established by nOe studies and X-ray crystallography.

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Introduction

The benzo[b][1,4]oxazine and thiazine structural units are frequently found in various biologically active molecules (Fig. 1).¹ They are known to display aldose reductase inhibitory activity² and potential therapeutic properties.³ In addition to this, benzoxazinones exhibit a diverse range of pharmacological properties such as anti-candida-albicans,⁴ antifungal,⁵ kinase inhibitory,⁶ antagonism to progesterone receptor, antitumor, antiviral, antithrombotic, antimycobacterial, anti-inflammatory, antidiabetic and hypolipidaemic effects.⁷ Furthermore, 2-arylidene-4-aminoalkyl-2H-1,4-benoxazin-(4H)-ones and related compounds were found to exhibit significant CNS (central nervous system) depression.⁸ Thus, benzo[b][1,4]oxazines have been recognized as privileged structures for the generation of drug like libraries in drug-discovery. Consequently, various methods have been devised for the synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine or thiazine derivatives.⁹ Despite the fact that numerous methods are reported for the synthesis of benzo[b][1,4]oxazine derivatives, the development of new methods for generating annulated benzo[b][1,4]oxazine and thiazine derivatives would certainly expand the synthetic utility of the Piancatelli rearrangement in medicinal chemistry.^10–12

Fig. 1 Examples of biologically active benzo[b][1,4]oxazine and thiazine derivatives.

Results and discussion

In continuation of our interest on catalytic application of In(III) salts,¹³ we herein report a novel strategy for the synthesis of cis-3,4-dihydro-2H-benzo[b][1,4]thiazine and oxazine derivatives via a tandem aza-Piancatelli rearrangement/Michael reaction. As a preliminary experiment, we first attempted the reaction of 2-aminothiophenol (1) with furan-2-yl(phenyl)methanol (2) in the presence of 10 mol% In(OTf)₃ in acetonitrile. Interestingly, the reaction proceeded smoothly at room temperature to furnish the corresponding 3,4-dihydro-2H-benzo[b][1,4]thiazine 3a in 86% yield (Scheme 1, Table 1).

Scheme 1 Reaction of 2-aminothiophenol with furan-2-yl(phenyl)methanol.

Table 1 Screening of various acid catalysts and solvents in the formation of product 3a^a

Entry	Acid catalyst	Amount of catalyst	Solvent	Time (h)	Yield (%)^b
a The reaction was performed at 0.5 mmol scale. b Isolated yield. c 20% of cyclopentenone without Michael addition. d With respect to the total weight of the reactants.
a	Montmorillonite K10	67%^d	CH3CN	12.0	45^c
b	Amberlyst-15	67%^d	CH3CN	12.0	70
c	Phosphomolybdic acid	10 mol (%)	CH3CN	2.5	75
d	In(OTf)3	10 mol (%)	THF	8.0	60
e	In(OTf)3	10 mol (%)	DCE	8.0	65
f	In(OTf)3	5 mol (%)	CH3CN	6.0	62
g	In(OTf)3	10 mol (%)	CH3CN	2.0	86
h	InCl3	10 mol (%)	CH3CN	4.0	65
i	InBr3	10 mol (%)	CH3CN	4.0	70
j	CeCl3·7H2O	10 mol (%)	CH3CN	12.0	40
k	Al(OTf)3	10 mol (%)	CH3CN	4.0	72

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In order to optimize the reaction conditions, we performed the above reaction with various acid catalysts such as InCl₃, InBr₃, In(OTf)₃, CeCl₃·7H₂O and Al(OTf)₃. Among these Lewis acids, In(OTf)₃ was found to be more effective than others in terms of reaction time and yields (Table 1). Of the various Brønsted acids like heteropoly acids, K10 clay and ion-exchange resin, i.e. Amberlyst-15^®, used for this reaction, phosphomolybdic acid was found to be superior to other solid acid catalysts (Table 1). Next we examined the effect of various solvents such as 1,2-dichloroethane, tetrahydrofuran and acetonitrile. Of these, acetonitrile appeared to give the best results (Table 1). As seen in Table 1, 10 mol% In(OTf)₃ in acetonitrile is crucial for this conversion.

Inspired by the above results, we extended this process to other substrates. Interestingly, various furan-2-yl(aryl)methanols reacted well with 2-aminothiophenols under the optimized conditions to afford the corresponding cis-fused 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives in excellent yields (entries f and kTable 2). On the other hand, 4-chloro-2-aminothiophenol also participated in this reaction (entries d and i, Table 2). Next we attempted the coupling of 2-aminophenols with furan-2-yl(aryl)methanol derivatives. Though the condensation of furan-2-yl(phenyl)methanol with 5-methyl-2-aminophenol proceeds at room temperature, the reaction requires a relatively long reaction time. The reason may be attributed to the lower reactivity of 2-aminophenol than 2-aminothiophenol (Scheme 2).

Table 2 Synthesis of cis-fused 3,4-dihydro-2H-benzo[b][1,4]thiazine and oxazine scaffolds^a

Entry	Substrate (1)	Arylamine (2)	Product (3)^b	Time (h)	Yield (%)^c
a The reactions were performed at 1 mmol scale. b All the products were characterized by ^1H and ^13C NMR, IR and mass spectroscopy. c Yield refers to pure products after column chromatography.
a				2.0	86
b				3.5	73
c				3.5	78
d				2.5	85
e				3.0	75
f				2.0	87
g				2.5	80
h				2.5	82
i				2.5	88
j				3.5	81
k				2.5	85
l				3.5	78
m				3.5	80

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Scheme 2 Reaction of 5-methyl-2-aminophenol with furan-2-yl(phenyl)methanol.

Next we studied the reactivity of various 2-aminophenols with furan-2-yl(aryl)methanol derivatives. The scope of the reaction is illustrated with respect to various substrates and the results are summarized in Table 2. As seen from Table 2, halogenated 2-aminophenols or 2-aminothiophenols gave comparatively higher yields than methyl-substituted derivatives.

The structure of the compound 3g was characterized by detailed NMR studies including 2-D double quantum filtered correlation spectroscopy (DQFCOSY) and nuclear Overhauser effect spectroscopy (NOESY). The ¹H NMR experiments provided coupling constants of ³J_{H1–H2 (pro-R)} = 4.4, ³J_H1–H4 = 3.1 and ³J_H3–H4 = 10.7 and ³J_{H1–H2 (pro-S)}∼0 Hz. From these coupling values, along with the presence of a nOe correlations, H2(pro-R)/H4 (medium intensity) and H2(pro-S)/H3 (weak intensity), the 5-membered cis-fused ring was found to take a twist conformation. In addition a ω-coupling, ⁴J_{H3–H2(pro-S)} = 1.6 Hz, and nOe correlation between H5/H6 further supports the structure. An energy minimized structure¹⁴ is consistent with the NMR findings which are given in Fig. 2.

Fig. 2 Characteristic nOe's and energy minimized structure of 3g.

Furthermore, the structure of 3e was confirmed by X-ray crystallography† (Fig. 3).¹⁵

Fig. 3 ORTEP diagram of 3e.

Mechanistically, the reaction is expected to proceed via the formation of an oxocarbenium ion from furan-2-yl(phenyl)methanol, likely after activation through In(III). This is followed by attack of 2-aminothiophenol or 2-aminophenol resulting in the formation of an aminal. An acid catalyzed rearrangement of the aminal followed by thia-/oxa-Michael reaction respectively would give the desired product as shown in Scheme 3.

Scheme 3 A plausible reaction pathway.

In the absence of In(OTf)₃, no aza-Piancatelli rearrangement was observed even in refluxing acetonitrile. The effect of various oxidants such as ceric ammonium nitrate, molecular iodine and ferric chloride was studied. The use of 10 mol% of molecular iodine in acetonitrile facilitates the S_N2 substitution of OH rather than aza-Piancatelli rearrangement. Instead of product 3a, the cyclopentenone derivative was formed without the Michael addition when the reaction was performed either by 10 mol% ceric ammonium nitrate or by 10 mol% FeCl₃. Thus the reaction was quite successful only with 10 mol% In(OTf)₃. This method is quite simple and convenient to synthesise a wide range of 3,4-dihydro-2H-benzo[b][1,4]thiazine and oxazine derivatives in a single step process.

Conclusions

In summary, we have demonstrated a novel strategy for the synthesis of 3,4-dihydro-2H-benzo[b][1,4]thiazine and oxazine derivatives via a tandem aza-Piancatelli/Michael reaction between furan-2-yl(phenyl)methanols and 2-aminothiophenols and 2-aminophenols respectively. This is the first report on the synthesis of annulated 3,4-dihydro-2H-benzo[b][1,4]thiazine and oxazine derivatives by means of aza-Piancatelli rearrangement.

Experimental

General

The solvents were dried according to a standard literature procedure. The reactions were performed in oven-dried round bottom flasks under a nitrogen atmosphere. Glass syringes were used to transfer the solvent. The products were purified by column chromatography on silica gel of 60–120 mesh. Thin layer chromatography plates were visualized by the ultraviolet light and/or by exposure to iodine vapours and/or by exposure to acidic methanolic solution of p-anisaldehyde followed by heating (<1 min) on a hot plate (∼250 °C). Organic solutions were concentrated on rotary evaporator at 35–40 °C. IR spectra were recorded on FT-IR spectrometer. ¹H and ¹³C NMR spectra were recorded in CDCl₃ using 300 or 500 MHz NMR spectrometers. The chemical shifts (δ) were reported in parts per million (ppm) with respect to TMS as an internal standard. The coupling constants (J) are quoted in Hertz (Hz). Mass spectra were recorded on mass spectrometer by Electrospray ionization (ESI) technique.

Typical procedure: A mixture of furan-2-yl(phenyl)methanol (1, 1.2 mmol), 2-aminophenol or 2-aminothiophenol (2, 1 mmol) and In(OTf)₃ (56 mg, 10 mol%) in acetonitrile (4 mL) was stirred at room temperature for a specified time as required to complete the reaction (see Table 1). After complete conversion, as indicated by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, concentrated in vacuo and purified by column chromatography on silica gel (Merck, 60–120 mesh, ethyl acetate–hexane, 3 : 7) to afford the pure 3,4-dihydro-2H-benzo[b][1,4]oxazine or thiazine derivative.

3a: IR (neat): ν_max 3880, 3020, 2923, 2853, 1743, 1591, 1485, 1260, 1154, 1074, 749 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 2.61 (d, 1H, J = 19.4 Hz), 2.87 (dd, 1H, J = 7.0, 19.0 Hz), 3.72 (d, 1H, J = 10 Hz), 3.81 (t, 1H, J = 5.0 Hz), 4.17–4.26 (m, 1H), 4.31–4.40 (brs, 1H), 6.53 (d, 1H, J = 8.0 Hz), 6.70 (t, 1H, J = 8.0 Hz), 6.97 (t, 1H, J = 7.0 Hz), 7.09 (d, 3H, J = 7.0 Hz), 7.30 (t, 1H, J = 7.0 Hz), 7.36 (t, 2H, J = 8.0 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 35.3, 44.8, 59.8, 60.1, 115.3, 115.5, 118.5, 126.4, 127.5, 127.6, 128.9, 129.0, 135.8, 139, 212.9; ESI-MS: m/z 282 (M+H); HRMS calcd for C₁₇H₁₆NOS: 282.0947, found: 282.0944.

3b: Solid, m.p. 163–165 °C; IR (neat): ν_max 3390, 3053, 2915, 2857, 1753, 1642, 1527, 1463, 1295, 1241, 1121, 1038, 759 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.24 (s, 3H), 2.65 (dd, 1H, J = 4.5, 18.8 Hz), 2.76–2.86 (m, 1H), 3.35 (d, 1H, J = 10.5 Hz), 3.75 (dd, 1H, J = 3.0, 11.3 Hz), 4.34 (t, 1H, J = 3.0 Hz), 4.64–4.71 (m, 1H), 6.67–6.80 (m, 2H), 7.04 (dd, 1H, J = 1.5, 7.5 Hz), 7.24–7.31 (m, 2H), 7.33–7.45 (m, 2H), 7.56 (dd, 1H, J = 2.3, 6.0 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 20.3, 46.1, 56.6, 56.9, 69.7, 116.5, 117.9, 122.9, 127.7, 128.8, 128.9, 129.5, 135.6, 136.3, 137.8, 142.9, 161.7, 212.3; ESI-MS: m/z 280 (M+H).

3c: Solid, m.p. 136–138 °C; IR (neat): ν_max 3396, 3027, 2924, 2856, 1742, 1602, 1498, 1287, 1121, 1016, 755 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 2.70 (dd, 1H, J = 4.7, 19.1 Hz), 2.90 (d, 1H, J = 19.1 Hz), 3.47 (d, 1H, J = 10.3 Hz), 4.00–4.08 (m, 1H), 4.19–4.28 (brs, 1H), 4.62 (t, 1H, J = 3.9 Hz), 6.58 (d, 1H, J = 2.4 Hz), 6.65 (dd, 1H, J = 2.4, 7.9 Hz), 6.80 (d, 1H, J = 8.7 Hz), 7.09 (d, 2H, J = 7.2 Hz), 7.31 (t, 1H, J = 7.2 Hz), 7.37 (t, 2H, J = 7.9 Hz); ¹³C NMR (125 MHz, CDCl₃): δ 45.4, 58.2, 58.5, 70.5, 114.5, 118.2, 118.4, 127.1, 127.7, 128.8, 129.1, 131.1, 135.4, 140.6, 212.1; ESI-MS: m/z 300 (M+H); HRMS calcd for C₁₇H₁₅NO₂Cl: 300.07858, found: 300.07855.

3d: IR (neat): ν_max 3402, 2951, 2894, 1736, 1582, 1526, 1322, 1239, 1165, 1073, 895, 754 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.61 (d, 1H, J = 18.8 Hz), 2.90 (dd, 1H, J = 6.8, 18.8 Hz), 3.69 (d, 1H, J = 9.8 Hz), 3.77 (t, 1H, J = 4.5 Hz), 4.18–4.30 (m, 1H), 4.46 (d, 1H, J = 4.5 Hz), 6.53 (d, 1H, J = 2.3 Hz), 6.67 (dd, 1H, J = 2.3, 8.3 Hz), 7.01 (d, 1H, J = 8.3 Hz), 7.05–7.13 (m, 2H), 7.28–7.43 (m, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 34.9, 44.6, 59.6, 60.3, 113.4, 114.8, 118.4, 127.6, 128.5, 128.9, 129.1, 131.7, 135.5, 140, 212.4; ESI-MS: m/z 316 (M+H).

3e: Solid, m.p. 119–121 °C; IR (KBr): ν_max 3388, 2922, 2841, 1889, 1739, 1608, 1249, 1026, 826, 747 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.68 (dd, 1H, J = 4.5, 18.8 Hz), 2.89 (d, 1H, J = 18.8 Hz), 3.47 (d, 1H, J = 10.5 Hz), 3.80 (s, 3H), 4.01 (dd, 1H, J = 2.3, 10.5 Hz), 4.65 (t, 1H, J = 3.7 Hz), 6.61 (dd, 1H, J = 1.5, 7.5 Hz), 6.72 (dd, 1H, J = 1.5, 7.5 Hz), 6.72 (dd, 1H, J = 1.5, 7.5 Hz), 6.81–6.95 (m, 4H), 7.03 (d, 2H, J = 9.1 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 45.3, 55.2, 57.3, 58.6, 70.3, 114.4, 115.1, 117.1, 118.6, 122.4, 127.5, 129.8, 130.1, 142.1, 158.9, 213.1; ESI-MS: m/z 297 (M+H); HRMS calcd for C₁₈H₁₈NO₃: 296.1281, found: 296.1276.

3f: IR (KBr): ν_max 3373, 2923, 2853, 1735, 1587, 1463, 1248, 1178, 1026, 753 cm⁻¹; ¹H NMR (500 MH_z, CDCl₃): δ 2.61 (d, 1H, J = 18.6 Hz), 2.87 (dd, 1H, J = 6.5, 18.6 Hz), 3.68 (d, 1H, J = 10.3 Hz), 3.75–3.84 (m, 1H), 3.80 (s, 3H), 4.16–4.23 (m, 1H), 4.37 (brs, 1H), 6.55 (d, 1H, J = 8.4 Hz), 6.71 (t, 1H, J = 7.5 Hz), 6.91 (d, 1H, J = 8.4 Hz), 6.98 (t, 1H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 7.10 (d, 1H, J = 7.5 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 45.3, 55.2, 57.3, 58.5, 70.2, 114.4, 115.1, 117.1, 118.6, 122.4, 127.5, 129.8, 130.1, 142.0, 158.9, 213.2; ESI-MS: m/z 310 (M+H).

3g: Solid, m.p. 127–129 °C; IR (neat): ν_max 3396, 3013, 2925, 1743, 1612, 1514, 1460, 1296, 1251, 1123, 1028, 757 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 2.23 (s, 3H), 2.62 (dd, 1H, J = 4.4, 18.7 Hz), 2.83 (d, 1H, J = 18.7 Hz), 3.42 (d, 1H, J = 10.7 Hz), 3.77 (s, 3H), 3.93 (dd, 1H, J = 2.2, 11.0 Hz), 4.59 (t, 1H, J = 3.1 Hz), 6.49 (d, 1H, J = 8.8 Hz), 6.64 (d, 1H, J = 7.7 Hz), 6.69 (s, 1H), 6.88 (d, 2H, J = 7.7 Hz), 6.98 (d, 2H, J = 8.8 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 20.5, 45.5, 55.3, 56.9, 58.7, 70.5, 114.5, 115.3, m117.6, 122.9, 127.3, 127.6, 128.6, 129.8, 124.1, 142.1, 159, 213; ESI-MS: m/z 310 (M+H); HRMS calcd for C₁₉H₂₀NO₃: 310.1437, found: 310.1436.

3h: IR (neat): ν_max 3385, 2925, 2853, 1744, 1606, 1250, 1126, 1029, 757 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.68 (dd, 1H, J = 4.5, 19.1 Hz), 2.87 (d, 1H, J = 19.1 Hz), 3.41 (d, 1H, J = 10.5 Hz), 3.79 (s, 3H), 3.99 (dd, 1H, J = 3.0, 10.7 Hz), 4.13–4.42 (brs, 1H), 4.60 (t, 1H, J = 3.7 Hz), 6.58 (d, 1H, J = 2.3 Hz), 6.60–6.70 (m, 1H), 6.78 (d, 1H, J = 8.5 Hz), 6.90 (d, 2H, J = 8.7 Hz), 7.01 (d, 2H, J = 8.7 Hz); ESI-MS: m/z 330 (M+H); HRMS calcd for C₁₈H₁₇NO₃Cl: 330.0891, found: 330.0893.

3i: IR (neat): ν_max 3406, 2957, 2875, 1754, 1593, 1536, 1373, 1257, 1215, 1064, 849, 764 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.31 (t, 1H, J = 7.5 Hz), 2.68 (dd, 1H, J = 3.7, 18.8 Hz), 2.88 (d, 1H, J = 18.8 Hz), 3.42 (d, 1H, J = 10.6 Hz), 3.80 (s, 3H), 3.99 (d, 1H, J = 10.6 Hz), 4.60 (brs, 1H), 6.58 (s, 1H), 6.64 (d, 1H, J = 8.3 Hz), 6.79 (d, 1H, J = 9.0 Hz), 6.90 (d, 2H, J = 8.3 Hz), 7.01 (d, 2H, J = 8.3 Hz); ESI-MS: m/z 346 (M+H).

3j: Solid, m.p. 138–140 °C; IR (KBr): ν_max 3433, 3026, 2918, 1739, 1603, 1305, 1216, 1119, 838, 732 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.70 (dd, 1H, J = 4.5, 18.8 Hz), 2.92 (d, 1H, J = 18.1 Hz), 3.53 (d, 1H, J = 10.5 Hz), 4.03 (d, 1H, J = 10.6 Hz), 4.09–4.21 (brs, 1H), 4.65 (t, 1H, J = 3.8 Hz), 6.64 (dd, 1H, J = 1.5, 7.5 Hz), 6.74 (dd, 1H, J = 1.5, 7.5 Hz), 6.82–6.93 (m, 2H), 7.08 (d, 4H, J = 6.8 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 45.4, 57.3, 58.7, 70.2, 115.2, 115.8, 116, 117.2, 118.8, 122.5, 129.9, 130.3, 130.4, 131.3, 142, 160.5, 163.8, 212.5; ESI-MS: m/z 284 (M+H); HRMS calcd for C₁₇H₁₅NO₂F: 284.1081, found: 284.1079.

3k: Solid, m.p. 140–142 °C; IR (KBr): ν_max 3432, 2924, 2854, 1738, 1590, 1506, 1310, 1219, 1156, 1095, 840, 737 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.64 (d, 1H, J = 19.3 Hz), 2.40 (dd, 1H, J = 6.6, 19.2 Hz), 3.75 (d, 1H, J = 10.4 Hz), 3.82 (t, 1H, J = 5.3 Hz), 4.15–4.26 (m, 1H), 4.35 (brs, 1H), 6.57 (d, 1H, J = 7.9 Hz), 6.73 (t, 1H, J = 7.5 Hz), 7.00 (t, 1H, J = 7.3 Hz), 7.08 (d, 4H, J = 6.9 Hz), 7.12 (d, 1H, J = 1.1 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 35.2, 44.7, 59.4, 59.9, 115.4, 115.6, 115.8, 116.1, 118.6, 126.5, 127.6, 130.5, 130.6, 131.4, 138.9, 160.6, 163.8, 212.5; ESI-MS: m/z 300 (M+H); HRMS calcd for C₁₇H₁₅NOSF: 300.0852, found: 300.0851.

3l: IR (neat): ν_max 3396, 2923, 2855, 1741, 1597, 1509, 1293, 1229, 1155, 1020, 808, 758 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 2.25 (s, 3H), 2.68 (dd, 1H, J = 4.9, 19.8 Hz), 2.90 (d, 1H, J = 19.8 Hz), 3.51 (d, 1H, J = 10.8 Hz), 3.99 (d, 1H, J = 7.9 Hz), 4.65 (t, 1H, J = 2.9 Hz), 6.55 (d, 1H, J = 7.9 Hz), 6.67 (d, 1H, J = 7.9 Hz), 6.72 (s, 1H), 7.07 (d, 4H, J = 6.9 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 20.5, 45.5, 56.9, 58.8, 70.4, 115.3, 115.8, 116.1, 117.7, 123, 128.8, 130.3, 130.4, 131.3, 163.9, 212.6; ESI-MS: m/z 298 (M+H).

3m: IR (KBr): ν_max 3405, 3076, 2974, 1739, 1582, 1563, 1540. 1387, 1274, 1106, 1172, 1037, 964, 860, 752 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 2.67 (dd, 1H, J = 4.5, 18.8 Hz), 2.87 (d, 1H, J = 19.6 Hz), 3.44 (d, 1H, J = 10.5 Hz), 3.98 (dd, 1H, J = 3.0, 10.5 Hz), 4.22–4.50 (brs, 1H), 4.56 (t, 1H, , J = 3.0 Hz), 6.56 (d, 1H, J = 2.3 Hz), 6.63 (dd, 1H, J = 2.3, 8.3 Hz), 6.78 (d, 1H, J = 9.1 Hz), 7.04 (d, 4H, J = 6.8 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 45.2, 57.5, 58.3, 70.3, 114.5, 115.8, 116.1, 118.2, 118.3, 127.1, 130.3, 130.4, 131, 140.5, 160.5, 163.8, 212.2; ESI-MS: m/z 318 (M+H). HRMS calcd for C₁₇H₁₃FClNO₂: (M+H): 318.1008; found: 318.1014.

Acknowledgements

GNL thanks CSIR, New Delhi for the award of a fellowship.

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14. Energy-minimized structure was deduced using the INSIGHT-II, Discover model on SGI workstation, Version 2.98; Biosym molecular simulation, San Diego, CA, 1995.
15. The crystal (C₁₈H₁₇NO₃, M = 295.33, colorless block, 0.21 × 0.18 × 0.08 mm³) belongs to the orthorhombic crystal system, space group is Pbcn (No. 60), a = 18.360(3), b = 10.7617(18), c = 15.277(3) Å, V = 3018.5(9) ų, Z = 8, D_c = 1.300 g cm⁻³, F₀₀₀ = 1248, CCD Area Detector, Mo-Kα radiation, λ = 0.71073 Å, T = 294(2)K, 2θ_max = 50.0°, 27253 reflections collected, 2661 unique (R_int = 0.0281). Final GooF = 1.053, R₁ = 0.0341, wR₂ = 0.0898, R indices based on 2219 reflections with I >2σ(I) (refinement on F²), 204 parameters, 0 restraints. μ = 0.089 mm⁻¹. CCDC 890425 contains supplementary Crystallographic data for the structure†.

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Footnote

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c2ra21591h

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