4-(Alkoxyamino)chroman-2-ones were synthesized via a 6-exo-trig cyclization of alkyl radicals obtained from α-bromoesters containing an oxime ether group. In the case of secondary bromides, the best results were achieved using tris(trimethylsilyl)silane as the chain transfer agent and Et3B as the initiator in dichloromethane at room temperature; the corresponding chromanones were produced in 58–70% yield. Low yields of the cyclized compounds were obtained in the case of tertiary alkyl bromides (20–25%). Products of premature reduction of carbon-centered radicals and addition of ethyl radicals to C=N bond were also observed.
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Oxime ethers are useful and versatile compounds in organic synthesis. They are easily prepared and relatively stable to moisture, so that they can be stored during long periods in air.1 Reductive addition of alkyl radicals to oxime ethers is by far the most exploited application of this class of compounds in radical chemistry. Since the first pinacol-type radical cyclization into an oxime ether was reported in 1983,2 many interesting methodologies that involve inter- and intramolecular versions of this transformation have been published.3 , 4 For instance, Naito and coworkers reported the synthesis of 4-(benzyloxyamino) furan-2-ones and 4-(benzyloxyamino)pyran-2-ones from oxime ethers connected with acryloyl and methacryloyl moieties. The synthesis was carried out via tandem intermolecular addition of secondary alkyl radicals to the C=C bond of a carbonyl α,β-unsaturated system, followed by intramolecular addition of the stabilized α-ester radical to the C=N bond, using Et3B and alkyl iodides in a variety of solvents including water.4 c
4-(Alkoxyamino)chroman-2-ones are known as important building blocks of biologically active compounds and are considered privileged molecular moieties present in a variety of natural products.5 With the aim of extending the application of reductive addition of alkyl radicals to oximes, we explored in this work the synthesis of 4-(alkoxyamino)chroman-2-ones from salicylaldehyde oxime ethers connected to α-bromoesters via 6-exo-trig radical cyclization of secondary and tertiary alkyl radicals at the electrophilic carbon atom of C=N–OR group. In order to evaluate the feasibility of this approach, the requisite oxime ethers were obtained in two steps starting from the reaction of salicylaldehyde (1) with O-benzyl- or O-methylhydroxylamine hydrochloride to obtain compounds 2a,b which were reacted with 2-bromoacylbromides 3a–c to provide the oxime ethers 4a–f in yields up to 69% in two steps (Scheme 1).
Scheme 1
In order to establish the most favorable reaction conditions for the 6-exo-trig cyclization to generate 4-(alkoxyamino) chroman-2-ones, we carried out preliminary experiments with compound 4a (Table 1). The reaction with tri(n-butyl)tin hydride (TBTH) and azobisisobutyronitrile (AIBN) in toluene proceeded through the direct reduction of C–Br bond giving rise to compound 6a (91%) as the main product (entry 1).
Due to this unfavorable result, we decided to replace TBTH by a weaker hydrogen donor tris(trimethylsilyl)-silane (TTMSS), retaining AIBN as the initiator (entry 2). In this case, the yield of cyclized product 5a increased, however, the main product as before was the undesired open-chain compound 6a (83%).
In an attempt to improve the yield of compound 5a we carried out a third experiment (entry 3) using Et3B as the initiator, trying to take advantage of its well-known weak Lewis acid character along with the simplification of the experimental procedure, since no heating and deoxygenating processes are needed. The 1H NMR spectrum of the crude mixture after aqueous work-up showed that under these conditions, the desired heterocyclic compound 5a was generated as the main product (yield 58%), in addition to reduction product 6a (37%) and a small amount of openchain product 7a (5%), likely produced by intermolecular addition of ethyl radicals (donated by Et3B) to the C=N bond of the oxime function.
Guided by the results of the preliminary experiments, we synthesized a series of 4-(alkoxyamino)chroman-2-ones 5b–f using TTMSS and Et3B, since these conditions gave rise to a good product ratio 5a : 6a (Table 1, entry 3) and required the simplest experimental procedure.
As shown in Table 2, the cyclization of oximes 4a–d took place with diastereoselectivity favoring the transisomer due to the steric repulsion between the alkyl group tethered to the carbon-centered radical and the oxime ether group NOR1. The assignment of cis/trans configuration to the cyclized products 5a–d was made by NOESY experiments and examining the 3 J HH coupling constants in the 1H NMR spectra (Table 3). The magnitude of coupling constants in trans-isomer showed protons 3-CH and 4-CH in pseudo-equatorial positions.
In the case of oximes 4e,f, the steric hindrance of the tertiary radical precluded the cyclization to proceed in an efficient way, leading to the formation of chromanones 5e,f in only 20–25% yield, and reduced open-chain compounds 6e,f as the major products.
In conclusion, the synthesis of 4-(alkoxyamino)chroman-2-ones via radical cyclization was achieved with reasonably good yields and diastereoselectivity in the case of precursors containing a secondary alkyl bromide and low yields in the case of those containing tertiary alkyl bromides. The experimental protocol to carry out the radical reactions is simple, as is the synthesis of the starting materials.
Experimental
1H and 13C NMR spectra were acquired on a Bruker Avance spectrometer (300 and 75 MHz, respectively) in CDCl3. All chemical shifts are quoted in respect to residual proton signals of CDCl3 (7.28 ppm for 1H nuclei and 77.0 ppm for 13C nuclei). Chemical shifts were assigned with the help of HSQC-edit, HMBC, and COSY experiments. The assignment of cis/trans configuration was made by NOESY experiments (mixing time 300 ms) and examining the 3 J HH coupling constants in the 1H NMR spectra.
High-resolution mass spectra were recorded on an Agilent 6520 q-TOF-MS instrument with orthogonal ESI. GC-MS analyses were performed on an Agilent 6850 series II gas chromatograph coupled to an Agilent 5975B VL mass spectrometer (electron ionization, 70 eV) equipped with split/splitless inlet (split relation 15:1, 260°C), Agilent 6850 series automatic injector, and Agilent HP-5MS column (30 m × 0.25 mm × 0.25 μm); initial oven temperature 80°C for 1 min, then a temperature ramp of 10°C/min to 320°C (hold 3 min); total run time 28 min. Melting points were determined on a Thermo Fisher Scientific IA 9100 apparatus.
2-[(Benzyloxyimino)methyl]phenol (2a) and 2-[(methoxyimino) methyl]phenol (2b) were synthesized according to previously reported procedures.4 g, 6 Oxime 2a was obtained as a white solid, mp 62–63°C (MeOH) (mp 62.5–63.0°C (AcOEt–hexane)4 g), and oxime 2b was obtained as a colorless solid, mp 30–32°C (MeOH) (mp ≤ 30°C (cyclohexane–EtOAc)6). The 1H NMR spectra of both compounds were consistent with those reported in literature.
Coupling of oxime ethers with α-bromoesters (General method). A solution of oxime 2a (0.227 g, 1.0 mmol) or 2b (0.151 g, 1.0 mmol), an appropriate α-bromoacyl bromide 3a–c (1.5 mmol), and triethylamine (0.28 ml, 2 mmol) in dichloromethane (3.3 ml) was stirred at 0°C for 2–3 h. The reaction mixture was treated with distilled water and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixtures were purified by column chromatography (silica gel, hexane–CH2Cl2, 4:1) to provide products 4a–f.
2-{[(Benzyloxy)imino]methyl}phenyl 2-bromopropanoate (4a). Yield 0.286 g (79%). Pale-yellow liquid with a (3H, d, J = 6.9, CH3); 4.59 (1H, q, J = 6.9, CHBr); 5.26 (2H, s, OCH2Ph); 7.17 (1H, dd, J = 8.1, J = 1.3, H-6 Ar); 7.24–7.38 (1H, m, H-5 Ar); 7.33–7.51 (6H, m, H-4 Ar, H Ph); 7.85 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.33 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 21.4 (CH3); 39.3 (CHBr); 76.6 (OCH2Ph); 122.4 (C-6 Ar); 124.7 (C-1 Ar); 126.6 (C-5 Ar); 127.9 (C-3 Ar); 128.1 (C-2,6 Ph); 128.3 (C-4 Ph); 128.5 (C-3,5 Ph); 130.8 (C-4 Ar); 137.4 (C-1 Ph); 144.1 (C=N); 148.3 (C-2 Ar); 168.4 (C=O). Found, m/z: 362.0398 [M(79Br)+H]+. C17H17BrNO3. Calculated, m/z: 362.0387.
2-{[(Methoxy)imino]methyl}phenyl 2-bromopropanoate (4b). Yield 0.255 g (89%). Light-yellow liquid. 1H NMR spectrum, δ, ppm (J, Hz): 1.97 (3H, d, J = 6.9, CH3); 3.99 (3H, s, OCH3); 4.65 (1H, q, J = 6.9, CHBr); 7.14 (1H, d, J = 8.1, H-6 Ar); 7.29 (1H, t, J = 7.6, H-5 Ar); 7.42 (1H, t, J = 7.7, H-4 Ar); 7.83 (1H, d, J = 7.8, H-3 Ar); 8.23 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 21.4 (CH3); 39.4 (CHBr); 62.2 (OCH3); 122.4 (C-6 Ar); 124.7 (C-1 Ar); 126.7 (C-5 Ar); 127.7 (C-3 Ar); 130.7 (C-4 Ar); 143.6 (C=N); 148.2 (C-2 Ar); 168.4 (C=O). Mass spectrum, m/z (I rel, %): 285 [M(79Br)]+ (5), 152 (9), 151 (100), 120 (23), 119 (41), 107 (17), 91 (37). Found, m/z: 286.0073 [M(79Br)+H]+. C11H13BrNO3. Calculated, m/z: 286.0074.
2-{[(Benzyloxy)imino]methyl}phenyl 2-bromobutanoate (4c). Yield 0.301 g (80%). Pale-yellow liquid with a pleasant odor. 1H NMR spectrum, δ, ppm (J, Hz): 1.16 (3H, t, J = 7.3, CH2CH3); 2.07–2.34 (2H, m, CH2CH3); 4.41 (1H, dd, J = 7.9, J = 6.5, CHBr); 5.26 (2H, s, OCH2Ph); 7.13–7.18 (1H, m, H-6 Ar); 7.26–7.47 (7H, m, H-4,5, H Ph); 7.88 (1H, dd, J = 7.8, J = 1.5, H-3 Ar); 8.34 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 11.9 (CH2CH3); 28.1 (CH2CH3); 47.1 (CHBr); 76.6 (OCH2Ph); 122.3 (C-6 Ar); 124.7 (C-1 Ar); 126.6 (C-5 Ar); 127.6 (C-3 Ar); 128.0 (C-4 Ph); 128.3 (C-3,5 Ph); 128.5 (C-2,6 Ph); 130.7 (C-4 Ar); 137.4 (C-1 Ph); 143.9 (C=N); 148.3 (C-2 Ar); 167.9 (C=O). Found, m/z: 376.0561 [M(79Br)+H]+. C18H19BrNO3. Calculated, m/z: 376.0543.
2-{[(Methoxy)imino]methyl}phenyl 2-bromobutanoate (4d). Yield 0.267 g (89%). Light-yellow liquid. 1H NMR spectrum, δ, ppm (J, Hz): 1.16 (3H, t, J = 7.3, CH2CH 3); 2.08–2.37 (2H, m, CH 2CH3); 4.00 (3H, s, OCH3); 4.44 (1H, dd, J = 8.0, J = 6,6, CHBr); 7.14 (1H, dd, J = 8.1, J =1.3, H-6 Ar); 7.26–7.33 (1H, m, H-5 Ar); 7.39–7.46 (1H, m, H-4 Ar); 7.86 (1H, dd, J = 7.8, J = 1.8, H-3 Ar); 8.24 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 12.0 (CH2 CH3); 28.1 (CH2CH3); 47.0 (CHBr); 62.2 (OCH3); 122.4 (C-6 Ar); 124.7 (C-1 Ar); 126.7 (C-5 Ar); 127.5 (C-3 Ar); 130.7 (C-4 Ar); 143.4 (C=N); 148.2 (C-2 Ar); 167.9 (C=O). Mass spectrum, m/z (I rel, %): 299 [M(79Br)]+ (4), 152 (9), 151 (100), 120 (19), 119 (35), 91 (24). Found, m/z: 300.0235 [M(79Br)+H]+. C12H15BrNO3. Calculated, m/z: 300.0230.
2-{[(Benzyloxy)imino]methyl}phenyl 2-bromo-2-methylpropanoate (4e). Yield 0.275 g (73%). Clear yellow liquid. 1H NMR spectrum, δ, ppm (J, Hz): 2.14 (6H, s, CBr(CH3)2); 5.31 (2H, s, OCH2Ph); 7.20 (1H, d, J = 8.1, H-6 Ar); 7.33 (1H, t, J = 7.6, H-5 Ar); 7.39–7.52 (6H, m, H-4 Ar, H Ph); 7.95 (1H, d, J = 7.8, H-3 Ar); 8.42 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 30.6 (C(CH3)2); 55.2 (C(CH3)2); 76.6 (OCH2Ph); 122.3 (C-6 Ar); 124.9 (C-1 Ar); 126.6 (C-5 Ar); 127.5 (C-3 Ar); 128.1 (C-4 Ph); 128.4 (C-3,5 Ph); 128.5 (2C, C-2,6 Ph); 130.8 (C-4 Ar); 137.5 (C-1 Ph); 143.9 (C=N); 148.7 (C-2 Ar); 169.8 (C=O). Found, m/z: 376.0559 [M(79Br)+H]+. C18H19BrNO3. Calculated, m/z: 376.0543.
2-{[(Methoxy)imino]methyl}phenyl 2-bromo-2-methylpropanoate (4f). Yield 0.276 g (92%). Light-yellow liquid. 1H NMR spectrum, δ, ppm (J, Hz): 2.11 (6H, s, CBr(CH3)2); 4.00 (3H, s, OCH3); 7.14 (1H, dd, J = 8.1, J = 1.4, H-6 Ar); 7.29 (1H, t, J = 7.6, H-5 Ar); 7.43 (1H, t, J = 7.7, H-4 Ar); 7.87 (1H, d, J = 7.8, H-3 Ar); 8.26 (1H, s, OCH3). 13C NMR spectrum, δ, ppm: 30.6 (2C, C(CH3)2); 55.1 (C(CH3)2); 62.2 (OCH3); 122.3 (C-6 Ar); 124.8 (C-1 Ar); 126.6 (C-5 Ar); 127.4 (C-3 Ar); 130.7 (C-4 Ar); 143.4 (C=N); 148.5 (C-2 Ar); 169.8 (C=O). Mass spectrum, m/z (I rel, %): 299 [M(79Br)]+ (12), 151 (60), 123 (80), 121 (86), 120 (44), 119 (100), 91 (55). Found, m/z: 300.0236 [M(79Br)+H]+. C12H15BrNO3. Calculated, m/z: 300.0230.
Radical cyclization of compounds 4a–f (General method). A. Experiments using AIBN: a solution of oxime ether 4a (0.181 g, 0.5 mmol), TTMS or TBTH (0.5 mmol), AIBN (0.025 g, 0.15 mmol) in cyclohexane or toluene (20 ml) was deoxygenated for 1 h by bubbling dry argon and stirred at reflux temperature for 6–8 h. The reactions were monitored by TLC and GC-MS until consumption of starting material. After cooling to room temperature, the solution was concentrated under low pressure. In the case of reaction carried out with TBTH, the crude mixture was dissolved in ethyl acetate (5 ml) and treated with a 20% aqueous solution of KF (5 ml) to eliminate brominated organotin by-products. The crude mixtures were analyzed by 1H NMR spectroscopy and GC-MS.
B. Experiments using Et3B: a solution of oxime ether 4a–f (0.5 mmol), TTMS (0.159 ml, 0.5 mmol), and Et3B (1 M in hexane, 0.75 ml, 0.75 mmol) in dichloromethane (20 ml) was stirred at room temperature under air atmosphere for 1–2 h. The reaction mixture was treated with 10% aqueous NaHCO3 solution and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated. The products were preliminarily identified by GC-MS and 1H NMR spectroscopy. Purification by flash column chromatography using silica gel (hexane–AcOEt, 4:1) afforded compounds 5a–f which were characterized by HR-MS and 1H and 13C NMR spectroscopy, except compounds 5c-cis and 5d-cis, which were detected and quantified from the crude mixtures. Compounds 6a–f, 7a,b,d were likewise isolated by chromatography and characterized.
trans- 4-[(Benzyloxy)amino]-3-methylchroman-2-one ( trans- 5a). Yield 0.074 g (52%). 1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, d, J = 7.4, 3-CH3); 3.36 (1H, qd, J = 7.4, J = 2.9, 3-CH); 4.01 (1H, d, J = 2.9, 4-CH); 4.61 (1H, d, J = 11.5, OCH2Ph); 4.70 (1H, d, J = 11.5, OCH2Ph); 7.10 (1H, dd, J = 8.1, J =1.1, H-8); 7.17 (1H, td, J = 7.5, J = 1.1, H-6); 7.27–7.41 (7H, m, H-5,7, H Ph). 13C NMR spectrum, δ, ppm: 14.0 (3-CH3); 38.3 (C-3); 62.6 (C-4); 77.6 (CH2Ph); 116.9 (C-8); 119.4 (C-4a); 124.6 (C-7); 128.1 (C-4 Ph); 128.6 (C-3,5 Ph); 128.7 (C-2,6 Ph); 129.6 (C-5); 130.2 (C-6); 137.0 (C-1 Ph); 151.8 (C-8a); 170.7 (C=O). Found, m/z: 284.1293 [M+H]+. C17H18NO3. Calculated, m/z: 284.1281.
cis- 4-[(Benzyloxy)amino]-3-methylchroman-2-one ( cis- 5a). Yield 0.008 g (6%). 1H NMR spectrum, δ, ppm (J, Hz): 1.50 (3H, d, J = 7.0, 3-CH3); 2.99 (1H, qd, J = 7.0, J = 5.1, 3-CH); 4.05 (1H, d, J = 5.1, 4-CH); 4.38 (1H, d, J = 11.7) and 4.45 (1H, d, J = 11.6, OCH2Ph); 7.08–7.13 (1H, m, H-8); 7.16–7.21 (1H, m, H-6); 7.30–7.43 (7H, m, H-5,7, H Ph). 13C NMR spectrum, δ, ppm: 11.5 (3-CH3); 37.3 (C-3); 60.6 (C-4); 76.9 (OCH2Ph); 116.8 (C-8); 122.7 (C-4a); 124.2 (C-6); 127.9 (C-4 Ph); 128.3 (C-2,6 Ph); 128.9 (C-3,5 Ph); 129.5 (C-5); 129.9 (C-7); 136.6 (C-1 Ph); 152.1 (C-8a); 170.4 (C=O). Found, m/z: 284.1293 [M+H]+. C17H18NO3. Calculated, m/z: 284.1281.
cis- 4-[(Benzyloxy)amino]-3-methylchroman-2-one ( cis- 5a). Yield 0.008 g (6%). 1H NMR spectrum, δ, ppm (J, Hz): 1.50 (3H, d, J = 7.0, 3-CH3); 2.99 (1H, qd, J = 7.0, J = 5.1, 3-CH); 4.05 (1H, d, J = 5.1, 4-CH); 4.38 (1H, d, J = 11.7) and 4.45 (1H, d, J = 11.6, OCH2Ph); 7.08–7.13 (1H, m, H-8); 7.16–7.21 (1H, m, H-6); 7.30–7.43 (7H, m, H-5,7, H Ph). 13C NMR spectrum, δ, ppm: 11.5 (3-CH3); 37.3 (C-3); 60.6 (C-4); 76.9 (OCH2Ph); 116.8 (C-8); 122.7 (C-4a); 124.2 (C-6); 127.9 (C-4 Ph); 128.3 (C-2,6 Ph); 128.9 (C-3,5 Ph); 129.5 (C-5); 129.9 (C-7); 136.6 (C-1 Ph); 152.1 (C-8a); 170.4 (C=O). Found, m/z: 284.1293 [M+H]+. C17H18NO3. Calculated, m/z: 284.1281.
trans- 4-(Methoxyamino)-3-methylchroman-2-one ( trans- 5b). Yield 0.061 g (59%). 1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, d, J = 7.4, 3-CH3); 3.29 (1H, qd, J = 7.4, J =2.8, 3-CH); 3.50 (3H, s, OCH3); 3.96 (1H, d, J = 2.8, 4-CH); 7.06–7.12 (1H, m, H-8); 7.18 (1H, td, J = 7.4, J = 1.1, H-6); 7.32 (1H, dd, J = 7.4, J = 1.5, H-5); 7.38 (1H, td, J = 7.9, J = 1.7, H-7). 13C NMR spectrum, δ, ppm: 14.1 (3-CH3), 38.3 (C-3); 62.6 (C-4); 63.3 (OCH3); 116.8 (C-8); 119.5 (C-4a); 124.6 (C-6); 129.4 (C-5); 130.2 (C-7); 151.7 (C-8a); 170.7 (C=O). Found, m/z: 208.0966 [M+H]+. C11H14NO3. Calculated, m/z: 208.0968.
cis- 4-(Methoxyamino)-3-methylchroman-2-one ( cis- 5b). Yield 0.008 g (8%). 1H NMR spectrum, δ, ppm (J, Hz): 1.50 (3H, d, J = 6.9, 3-CH3); 2.93–3.01 (1H, m, 3-CH); 3.30 (3H, s, OCH3); 4.01 (1H, d, J = 5.3, 4-CH); 7.09 (1H, d, J = 8.2, H-8); 7.17 (1H, t, J = 7.5, H-6); 7.30–7.38 (2H, m, H-5,7). 13C NMR spectrum, δ, ppm: 11.5 (3-CH3); 37.3 (C-3); 60.8 (C-4); 62.6 (OCH3); 116.8 (C-8); 124.2 (C-6); 128.6 (C-5); 129.9 (C-7); 143.4 (C-4a); 152.3 (C-8a); 170.8 (C=O). Found, m/z: 208.1001 [M+H]+. C11H14NO3. Calculated, m/z: 208.0968.
trans- 4-[(Benzyloxy)amino]-3-ethylchroman-2-one ( trans- 5c). Yield 0.077 g (52%). 1H NMR spectrum, δ, ppm (J, Hz): 1.05 (3H, t, J = 7.5, 3-CH2CH3); 1.47–1.58 (2H, m, 3-CH2CH3); 3.15 (1H, td, J = 7.8, J = 2.1, 3-CH); 4.10 (1H, d, J = 2.1, 4-CH); 4.59 (1H, d, J = 11.5, OCH2Ph); 4.69 (1H, d, J = 11.5, OCH2Ph); 7.08 (1H, dd, J = 8.1, J =1.1, H-8); 7.15 (1H, td, J = 7.5, J = 1.1, H-6); 7.24–7.40 (7H, m, H-5,7, H Ph). 13C NMR spectrum, δ, ppm: 11.8 (3-CH2CH3); 22.1 (3-CH2CH3); 45.7 (C-3); 61.2 (C-4); 77.7 (OCH2Ph); 116.8 (C-8); 119.4 (C-4a); 124.5 (C-6); 128.0 (C-4 Ph); 128.4 (C-3,5 Ph); 128.7 (C-2,6 Ph); 129.6 (C-5); 130.3 (C-7); 137.0 (C-1 Ph); 151.9 (C-8a); 169.7 (C=O). Found, m/z: 298.1444 [M+H]+. C18H20NO3. Calculated, m/z: 298.1438.
cis- 4-[(Benzyloxy)amino]-3-ethylchroman-2-one ( cis- 5c). Yield 0.016 g (11%). 1H NMR spectrum, δ, ppm (J, Hz): 1.12 (3H, t, J = 7.5, 3-CH2CH 3); 1.76–1.88 (2H, m, 3-CH 2CH3); 2.65–2.72 (2H, m, 3-CH); 4.18 (1H, d, J = 4.8, 4-CH); 4.45 (1H, d, J = 11.7) and 4.48 (1H, d, J = 11.7, OCH2Ph); 7.06–7.21 (2H, m, H-6,8); 7.30–7.43 (7H, m, H-5,7, H Ph). Mass spectrum, m/z (I rel, %): 297 [M]+ (3), 265 (6), 175 (30), 119 (20), 91 (100).
trans- 3-Ethyl-4-(methoxyamino)chroman-2-one ( trans- 5d). Yield 0.067 g (61%). 1H NMR spectrum, δ, ppm (J, Hz): 1.01 (3H, t, J = 7.4, 3-CH2CH3); 1.43–1.56 (2H, m, 3-CH2CH3); 3.05 (1H, td, J = 7.8, J = 2.1, 3-CH); 3.45 (3H, s, OCH3); 4.03 (1H, d, J = 2.1, 4-CH); 7.04 (1H, dd, J = 8.1, J = 1.2, H-8); 7.13 (1H, td, J = 7.5, J = 1.2, H-6); 7.27 (1H, dd, J = 7.5, J = 1.7, H-5); 7.34 (1H, td, J = 7.8, J = 1.7, H-7). 13C NMR spectrum, δ, ppm: 11.7 (3-CH2CH3); 22.1 (3-CH2CH3); 45.6 (C-3); 61.2 (C-4); 63.3 (OCH3); 116.7 (C-8); 119.6 (C-4a); 124.5 (C-7); 129.5 (C-5); 130.2 (C-6); 151.9 (C-8a); 169.6 (C=O). Found, m/z: 222.1125 [M+H]+. C12H16NO3. Calculated, m/z: 222.1125.
cis- 3-Ethyl-4-(methoxyamino)chroman-2-one ( cis- 5d). Yield 0.010 g (9%). 1H NMR spectrum, δ, ppm (J, Hz): 1.05 (3H, t, J = 7.5, 3-CH2CH 3); 1.47–1.57 (2H, m, 3-CH 2CH3); 3.09 (1H, td, J = 7.7, J = 2.1, 3-CH); 3.49 (3H, s, OCH3); 4.06 (1H, d, J = 2.1, 4-CH); 7.08 (1H, dd, J = 8.2, J =1.1, H-8); 7.16 (1H, td, J = 7.4, J = 1.2, H-6); 7.30–7.41 (2H, m, H-5,7). Mass spectrum, m/z (I rel, %): 221 [M]+ (2), 176 (12), 175 (100), 147 (21), 133 (27), 119 (20), 91 (53).
4-[(Benzyloxy)amino]-3,3-dimethylchroman-2-one (5e). Yield 0.037 g (25%). 1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, s, 3-CH3); 1.52 (3H, s, 3-CH3); 3.69 (1H, s, 4-CH); 4.29 (1H, d, J = 11.7) and 4.39 (1H, d, J = 11.7, OCH2Ph); 7.06–7.10 (1H, m, H-8); 7.14–7.20 (3H, m, H-6, H Ph); 7.33–7.41 (5H, m, H-5,7, H Ph). 13C NMR spectrum, δ, ppm: 20.8 (3-CH3); 24.8 (3-CH3); 40.4 (C-3); 66.7 (C-4); 76.8 (OCH2Ph); 116.2 (C-8); 122.1 (C-4a); 124.3 (C-6); 127.8 (C-4 Ph); 128.3 (C-3,5 Ph); 128.4 (C-2,6 Ph); 129.7 (C-5); 129.8 (C-7); 136.8 (C-1 Ph); 151.8 (C-8a); 173.1 (C=O). Found, m/z: 298.1447 [M+H]+. C18H20NO3. Calculated, m/z: 298.1438.
4-(Methoxyamino)-3,3-dimethylchroman-2-one (5f). Yield 0.022 g (20%). 1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, s, 3-CH3); 1.52 (3H, s, 3-CH3); 3.24 (3H, s, OCH3); 3.65 (1H, s, 4-CH); 7.05–7.09 (1H, m, H-8); 7.18 (1H, td, J = 7.4, J =1.2, H-6); 7.32–7.37 (2H, m, H-5,7). 13C NMR spectrum, δ, ppm: 20.8 (3-CH3); 24.7 (3-CH3); 40.2 (C-3); 62.6 (C-4); 66.8 (OCH3); 116.2 (C-8); 122.1 (C-4a); 124.4 (C-6); 129.5 (C-5); 129.7 (C-7); 151.8 (C-8a); 173.1 (C=O). Found, m/z: 222.1150 [M+H]+. C12H16NO3. Calculated, m/z: 222.1125.
2-{[(Benzyloxy)imino]methyl}phenyl propionate (6a). Yield 0.052 g (37%). 1H NMR spectrum, δ, ppm (J, Hz): 1.26 (3H, t, J = 7.5, CH2CH 3); 2.60 (2H, q, J = 7.4, CH2CH3); 5.23 (2H, s, OCH2Ph); 7.11 (1H, d, J = 8.1, H-6 Ar); 7.23 – 7.29 (1H, m, H-5 Ar); 7.35 – 7.45 (6H, m, H-4 Ar, H Ph); 7.81 (1H, d, J = 7.8, H-3 Ar); 8.22 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 9.0 (CH2 CH3); 27.6 (CH2CH3); 76.6 (OCH2Ph); 123.0 (C-6 Ar); 124.6 (C-1 Ar); 126.1 (C-5 Ar); 127.8 (C-3 Ar); 128.1 (C-4 Ph); 128.4 (C-2,6); 128.5 (C-3,5); 130.7 (C-4); 137.2 (C-1 Ph); 144.5 (C=N); 148.8 (C-2 Ar); 172.7 (C=O). Mass spectrum, m/z (I rel, %): 283 [M]+ (1), 210 (10), 91 (100).
2-{[(Methoxy)imino]methyl}phenyl propionate (6b). Yield 0.027 g (26%). 1H NMR spectrum, δ, ppm (J, Hz): 1.29 (3H, t, J = 7.5, CH2CH3); 2.65 (2H, q, J = 7.5, CH2CH 3); 3.98 (3H, s, OCH3); 7.11 (1H, dd, J = 8.1, J = 1.2, H-6 Ar); 7.25 (1H, td, J = 7.5, J = 1.2, H-5 Ar); 7.40 (1H, td, J = 7.8, J = 1.7, H-4 Ar); 7.79 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.12 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 9.0 (CH2CH3); 27.6 (CH2CH3); 62.1 (OCH3); 123.0 (C-6 Ar); 124.5 (C-1 Ar); 126.1 (C-5 Ar); 127.7 (C-3 Ar); 130.6 (C-4 Ar); 144.04 (C=N); 148.7 (C-2 Ar); 172.7 (C=O). Found, m/z: 230.0798 [M+Na]+. C11H13NO3Na. Calculated, m/z: 230.0788.
2-{[(Benzyloxy)imino]methyl}phenyl butyrate (6c). Yield 0.046 g (31%). 1H NMR spectrum, δ, ppm (J, Hz): 1.06 (3H, t, J = 7.4, (CH2)2CH3); 1.76–1.85 (2H, m, CH2CH2CH3); 2.56 (2H, t, J = 7.4, CH2CH2CH3); 5.25 (2H, s, OCH2Ph), 7.12 (1H, d, J = 8.1, H-6 Ar); 7.26 (2H, t, J = 7.5, H-5 Ar); 7.36–7.45 (6H, m, H-4 Ar, H Ph); 7.83 (1H, d, J = 7.8, H-3 Ar); 8.24 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 13.7 (CH2)2CH3); 18.3 (CH2CH2CH3); 36.0 (CH2CH2CH3); 76.5 (OCH2Ph); 123.0 (C-6 Ar); 124.6 (C-1 Ar); 126.1 (C-5 Ar); 127.6 (C-3 Ar); 128.0 (C-4 Ph); 128.4 (C-2,6 Ph); 128.5 (C-3,5 Ph); 130.6 (C-4 Ar); 137.3 (C-1 Ph); 144.4 (C=N); 148.8 (C-2 Ar); 171.8 (C=O). Found, m/z: 298.1453 [M+H]+. C18H20NO3. Calculated, m/z: 298.1438.
2-{[(Methoxy)imino]methyl}phenyl butyrate (6d). Yield 0.028 g (25%). 1H NMR spectrum, δ, ppm (J, Hz): 1.07 (3H, t, J = 7.4, (CH2)2CH 3); 1.78–1.88 (2H, m, CH2CH 2CH3); 2.61 (2H, t, J = 7.4, CH 2CH2CH3); 3.99 (3H, s, OCH3); 7.09–7.13 (1H, m, H-6 Ar); 7.23–7.29 (1H, m, H-5 Ar); 7.38–7.44 (1H, m, H-4 Ar); 7.81 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.13 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 13.7 ((CH2)2 CH3); 18.3 (CH2 CH2CH3); 36.1 (CH2CH2CH3), 62.2 (OCH3); 123.0 (C-6 Ar); 124.5 (C-1 Ar); 126.1 (C-5 Ar); 127.5 (C-3 Ar); 130.6 (C-4 Ar), 143.9 (C=N); 148.7 (C-2 Ar); 171.8 (C=O). Found, m/z: 244.0955 [M+Na]+. C12H15NNaO3. Calculated, m/z: 244.0944.
2-{[(Benzyloxy)imino]methyl}phenyl isobutyrate (6e). Yield 0.10 g (69%). 1H NMR spectrum, δ, ppm (J, Hz): 1.36 (6H, d, J = 6.8, CH(CH 3)2); 2.85 (1H, hept, J = 6.8, CH(CH3)2); 5.25 (2H, s, OCH2Ph), 7.10 (1H, d, J = 8.1, H-6 Ar); 7.26 (1H, t, J = 7.5, H-5 Ar); 7.35–7.47 (6H, m, H-4 Ar, H Ph), 7.87 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.24 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 18.9 (2C, CH(CH3)2); 34.2 (CH(CH3)2); 76.6 (OCH2Ph); 122.9
(C-6 Ar); 124.6 (C-1 Ar); 126.1 (C-5 Ar); 127.3 (C-3 Ar); 128.1 (C-4 Ph); 128.4 (C-3,5 Ph); 128.5 (C-2,6 Ph); 130.7 (C-4 Ar); 137.3 (C-1 Ph); 144.1 (C=N); 148.9 (C-2 Ar); 175.2 (C=O). Found, m/z: 298.1454 [M+H]+. C18H20NO3. Calculated, m/z: 298.1438.
4-(Methoxyamino)-3,3-dimethylchroman-2-one (5f). Yield 0.022 g (20%). 1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, s, 3-CH3); 1.52 (3H, s, 3-CH3); 3.24 (3H, s, OCH3); 3.65 (1H, s, 4-CH); 7.05–7.09 (1H, m, H-8); 7.18 (1H, td, J = 7.4, J =1.2, H-6); 7.32–7.37 (2H, m, H-5,7). 13C NMR spectrum, δ, ppm: 20.8 (3-CH3); 24.7 (3-CH3); 40.2 (C-3); 62.6 (C-4); 66.8 (OCH3); 116.2 (C-8); 122.1 (C-4a); 124.4 (C-6); 129.5 (C-5); 129.7 (C-7); 151.8 (C-8a); 173.1 (C=O). Found, m/z: 222.1150 [M+H]+. C12H16NO3. Calculated, m/z: 222.1125.
2-{[(Benzyloxy)imino]methyl}phenyl propionate (6a). Yield 0.052 g (37%). 1H NMR spectrum, δ, ppm (J, Hz): 1.26 (3H, t, J = 7.5, CH2CH3); 2.60 (2H, q, J = 7.4, CH2CH3); 5.23 (2H, s, OCH2Ph); 7.11 (1H, d, J = 8.1, H-6 Ar); 7.23 – 7.29 (1H, m, H-5 Ar); 7.35 – 7.45 (6H, m, H-4 Ar, H Ph); 7.81 (1H, d, J = 7.8, H-3 Ar); 8.22 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 9.0 (CH2CH3); 27.6 (CH2CH3); 76.6 (OCH2Ph); 123.0 (C-6 Ar); 124.6 (C-1 Ar); 126.1 (C-5 Ar); 127.8 (C-3 Ar); 128.1 (C-4 Ph); 128.4 (C-2,6); 128.5 (C-3,5); 130.7 (C-4); 137.2 (C-1 Ph); 144.5 (C=N); 148.8 (C-2 Ar); 172.7 (C=O). Mass spectrum, m/z (I rel, %): 283 [M]+ (1), 210 (10), 91 (100).
2-{[(Methoxy)imino]methyl}phenyl propionate (6b). Yield 0.027 g (26%). 1H NMR spectrum, δ, ppm (J, Hz): 1.29 (3H, t, J = 7.5, CH2CH3); 2.65 (2H, q, J = 7.5, CH2CH3); 3.98 (3H, s, OCH3); 7.11 (1H, dd, J = 8.1, J = 1.2, H-6 Ar); 7.25 (1H, td, J = 7.5, J = 1.2, H-5 Ar); 7.40 (1H, td, J = 7.8, J = 1.7, H-4 Ar); 7.79 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.12 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 9.0 (CH2 CH3); 27.6 (CH2CH3); 62.1 (OCH3); 123.0 (C-6 Ar); 124.5 (C-1 Ar); 126.1 (C-5 Ar); 127.7 (C-3 Ar); 130.6 (C-4 Ar); 144.04 (C=N); 148.7 (C-2 Ar); 172.7 (C=O). Found, m/z: 230.0798 [M+Na]+. C11H13NO3Na. Calculated, m/z: 230.0788.
2-{[(Benzyloxy)imino]methyl}phenyl butyrate (6c). Yield 0.046 g (31%). 1H NMR spectrum, δ, ppm (J, Hz): 1.06 (3H, t, J = 7.4, (CH2)2CH3); 1.76–1.85 (2H, m, CH2CH2CH3); 2.56 (2H, t, J = 7.4, CH2CH2CH3); 5.25 (2H, s, OCH2Ph), 7.12 (1H, d, J = 8.1, H-6 Ar); 7.26 (2H, t, J = 7.5, H-5 Ar); 7.36–7.45 (6H, m, H-4 Ar, H Ph); 7.83 (1H, d, J = 7.8, H-3 Ar); 8.24 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 13.7 (CH2)2CH3); 18.3 (CH2CH2CH3); 36.0 (CH2CH2CH3); 76.5 (OCH2Ph); 123.0 (C-6 Ar); 124.6 (C-1 Ar); 126.1 (C-5 Ar); 127.6 (C-3 Ar); 128.0 (C-4 Ph); 128.4 (C-2,6 Ph); 128.5 (C-3,5 Ph); 130.6 (C-4 Ar); 137.3 (C-1 Ph); 144.4 (C=N); 148.8 (C-2 Ar); 171.8 (C=O). Found, m/z: 298.1453 [M+H]+. C18H20NO3. Calculated, m/z: 298.1438.
2-{[(Methoxy)imino]methyl}phenyl butyrate (6d). Yield 0.028 g (25%). 1H NMR spectrum, δ, ppm (J, Hz): 1.07 (3H, t, J = 7.4, (CH2)2CH 3); 1.78–1.88 (2H, m, CH2CH2CH3); 2.61 (2H, t, J = 7.4, CH 2CH2CH3); 3.99 (3H, s, OCH3); 7.09–7.13 (1H, m, H-6 Ar); 7.23–7.29 (1H, m, H-5 Ar); 7.38–7.44 (1H, m, H-4 Ar); 7.81 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.13 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 13.7 ((CH2)2 CH3); 18.3 (CH 2 CH2CH3); 36.1 (CH2CH2CH3), 62.2 (OCH3); 123.0 (C-6 Ar); 124.5 (C-1 Ar); 126.1 (C-5 Ar); 127.5 (C-3 Ar); 130.6 (C-4 Ar), 143.9 (C=N); 148.7 (C-2 Ar); 171.8 (C=O). Found, m/z: 244.0955 [M+Na]+. C12H15NNaO3. Calculated, m/z: 244.0944.
2-{[(Benzyloxy)imino]methyl}phenyl isobutyrate (6e). Yield 0.10 g (69%). 1H NMR spectrum, δ, ppm (J, Hz): 1.36 (6H, d, J = 6.8, CH(CH3)2); 2.85 (1H, hept, J = 6.8, CH(CH3)2); 5.25 (2H, s, OCH2Ph), 7.10 (1H, d, J = 8.1, H-6 Ar); 7.26 (1H, t, J = 7.5, H-5 Ar); 7.35–7.47 (6H, m, H-4 Ar, H Ph), 7.87 (1H, dd, J = 7.8, J = 1.7, H-3 Ar); 8.24 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 18.9 (2C, CH(CH3)2); 34.2 (CH(CH3)2); 76.6 (OCH2Ph); 122.9 (C-6 Ar); 124.6 (C-1 Ar); 126.1 (C-5 Ar); 127.3 (C-3 Ar); 128.1 (C-4 Ph); 128.4 (C-3,5 Ph); 128.5 (C-2,6 Ph); 130.7 (C-4 Ar); 137.3 (C-1 Ph); 144.1 (C=N); 148.9 (C-2 Ar); 175.2 (C=O). Found, m/z: 298.1454 [M+H]+. C18H20NO3. Calculated, m/z: 298.1438.
2-{[(Methoxy)imino]methyl}phenyl isobutyrate (6f). Yield 0.08 g (74%). 1H NMR spectrum, δ, ppm (J, Hz): 1.35 (6H, d, J = 7.0, CH(CH 3 )2); 2.86 (1H, hept, J = 7.0, CH(CH3)2); 3.97 (3H, s, OCH3); 7.07 (1H, dd, J = 8.1, J = 1.2, H-6 Ar); 7.23 (1H, t, J = 7.3, H-5 Ar); 7.35–7.41 (1H, m, H-4 Ar); 7.82 (1H, dd, J = 7.8, J = 1.8, H-3 Ar); 8.12 (1H, s, HC=N). 13C NMR spectrum, δ, ppm: 18.9 (2C, CH(CH3)2); 34.1 (CH(CH3)2); 62.1 (OCH3); 123.0 (C-6 Ar); 124.8 (C-1 Ar); 126.0 (C-5 Ar); 127.2 (C-3 Ar); 130.6 (C-4 Ar); 143.6 (C=N); 148.5 (C-2 Ar); 169.8 (C=O). Mass spectrum, m/z (I rel, %): 221 [M]+ (7), 152 (11), 151 (100), 120 (24), 119 (38), 91 (39).
2-{1-[(Benzyloxy)amino]propyl}phenyl propionate (7a). Yield 0.008 g (5%). 1H NMR spectrum, δ, ppm (J, Hz): 1.01 (3H, t, J = 7.2, CHCH2CH 3); 1.15 (3H, t, J = 7.5, COCH2CH 3); 2.02–2.16 (1H, m, CHCH 2CH3); 2.30–2.53 (2H, m, COCH 2CH3); 2.56–2.70 (1H, m, CHCH 2CH3); 4.60 (1H, d, J = 10.2) and 4.65 (1H, d, J = 10.3, OCH2Ph); 5.51 (1H, dd, J = 9.7, J = 5.4, CHNH); 6.91 (1H, t, J = 7.5, H-5 Ar); 7.00 (1H, d, J = 8.0, H-6 Ar); 7.21–7.40 (7H, m, H-3,4 Ar, H Ph); 8.86 (1H, s, NH). 13C NMR spectrum, δ, ppm: 8.8 (COCH2 CH3); 11.3 (CHCH2 CH3); 22.3 (CHCH2CH3); 25.5 (COCH2CH3); 57.2 (CHNH); 79.1 (OCH2Ph); 117.7 (C-6 Ar); 119.7 (C-5 Ar); 125.1 (C-1 Ar); 126.9 (C-3 Ar); 128.7 (C-4 Ph); 128.9 (C-2,6 Ph); 129.0 (C-3,5 Ph); 129.8 (C-4 Ar); 134.0 (C-1 Ph); 156.0 (C-2 Ar); 178.1 (C=O). Found, m/z: 336.1587 [M+Na]+. C19H23NNaO3. Calculated, m/z: 336.1570.
2-[1-(Methoxyamino)propyl]phenyl propionate (7b). Yield 0.008 g (7%). 1H NMR spectrum, δ, ppm (J, Hz): 0.99 (3H, t, J = 7.2, CHCH2CH 3); 1.19 (3H, t, J = 7.4, COCH2CH 3); 1.96–2.11 (1H, m) and 2.55–2.69 (1H, m, CHCH 2CH3); 2.34–2.50 (2H, m, COCH 2CH3); 3.57 (3H, s, OCH3); 5.42 (1H, dd, J = 9.7, J = 5.6, CHNH); 6.88 (1H, t, J = 7.6, H-5 Ar); 6.95 (1H, d, J = 8.2, H-6 Ar); 7.22 (1H, t, J = 7.6, H-4 Ar); 7.33 (1H, d, J = 7.6, H-3 Ar); 8.80 (1H, s, NH). 13C NMR spectrum, δ, ppm: 8.8 (COCH2 CH3); 11.3 (CHCH2 CH3); 22.1 (CHCH2CH3); 25.3 (COCH2CH3); 56.6 (CHNH); 65.2 (OCH3); 117.7 (C-6 Ar); 119.6 (C-5 Ar); 125.2 (C-1 Ar); 126.9 (C-3 Ar); 129.6 (C-4 Ar); 155.7 (C-2 Ar); 177.6 (C=O). Found, m/z: 260.1272 [M+Na]+. C13H19NNaO3. Calculated, m/z: 260.1257.
2-[1-(Methoxyamino)propyl]phenyl butyrate (7d). Yield 0.007 g (5.5%). 1H NMR spectrum, δ, ppm (J, Hz): 0.98 (3H, t, J = 7.4, CH2CH2CH 3); 0.99 (3H, t, J = 7.3, CHCH2CH 3); 1.72 (2H, hept, J = 7.3, CH2CH 2CH3); 1.96–2.11 (1H, m, CHCH 2CH3); 2.32–2.46 (2H, m, CH2CH2CH3); 2.51–2.64 (1H, m, CHCH 2CH3); 3.57 (3H, s, OCH3); 5.44 (1H, dd, J = 9.6, J = 5.5, CHNH); 6.87 (1H, td, J = 7.5, J = 1.3, H-5 Ar); 6.95 (1H, dd, J = 8.2, J = 1.3, H-6 Ar); 7.22 (1H, ddd, J = 8.2, J = 7.3, J = 1.7, H-4 Ar); 7.33 (1H, dd, J = 7.3, J = 1.7, H-3 Ar); 8.77 (1H, s, NH). 13C NMR spectrum, δ, ppm: 11.2 (CHCH2CH3); 13.8 (CH2CH2CH3); 18.0 (CH2CH2CH3); 22.1 (CHCH2CH3); 33.7 (CH2CH2CH3); 56.5 (CHNH); 65.2 (OCH3); 117.7 (C-6 Ar); 119.6 (C-5 Ar); 125.2 (C-1 Ar); 126.9 (C-3 Ar); 129.6 (C-4 Ar); 155.7 (C-2 Ar); 176.8 (C=O). Found, m/z: 274.1424 [M+Na]+. C14H21NNaO3. Calculated, m/z: 274.1414.
The authors thank Pontificia Universidad Javeriana (PUJ) and COLCIENCIAS for the financial support through the projects ID 5564 and 120365843351. John Díaz thanks PUJ for the teaching assistantship.
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Published in Khimiya Geterotsiklicheskikh Soedinenii, 2016, 52(3), 177–182
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Bejarano, C.A., Díaz, J.E. & Loaiza, A.E. Synthesis of 4-(alkoxyamino)chroman-2-ones via 6-exo-trig cyclization of carbon-centered radicals into oxime ethers. Chem Heterocycl Comp 52, 177–182 (2016). https://doi.org/10.1007/s10593-016-1857-z
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DOI: https://doi.org/10.1007/s10593-016-1857-z