18-Crown-6 as a catalyst in the dialkylation of o-nitrophenacyl derivatives

Prasad, Girija; Hanna, Patrick E.; Noland, Wayl­and E.; Shankar, Viswanathan

doi:10.1021/jo00025a047

Cited by 14 publications

(20 citation statements)

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“…A solution of 43 (6.0 g, 21 mmol) in dry DMSO (20 mL) containing water (0.76 g, 42 mmol) was stirred at 150 °C under an efficient condenser for 3 h.32 Excess solvent was then removed under reduced pressure, the residue was dissolved in CH2C12, and the resulting solution was washed twice with water. Evaporation and chromatography of the residue on silica gel, eluting NMR (CDClg) 8.80 (dd, J = 4.7,1.5 Hz, 1 , H-6), 8.43 (dd, J = 8.3,1.5 Hz, 1 , H-4), 7.48 (dd, J -8.3,4.7 Hz, 1 , H-5), 4.33 (s, 2 H, CH2COO), 4.20 (q, J = 7.1 Hz, 2 H, Cf/üCHg), 1.26 (t, J = 7.1 Hz, 3 H, CHg). Anal.…”

Section: Methodsmentioning

confidence: 99%

“…JV-(4-Methoxyphenyl)-JV-methyl-2-nitrophenylacetamide (19a), mp (aqueous MeOH) 92 ®C: NMR (CDClg) 8 8.05 (d, J = 8.1 Hz, 1 , H-3), 7.53 (t, J = 7.5 Hz, 1 , H-5), 7.40 (t, J = 7.5 Hz, 1 , H-4), 7.22-7.30 (m, 3 , H-6,2',6'), 6.97 (d, J = 8.8 Hz, 2 , H-3',5'), 3.84 (s, 3 H, OCHg), 3.75 (s, 2 H, CH2CO), 12 (dd, J = 7.8,1.3 Hz, 1 , H-3), 8.08 (dd, J = 7.7, 1.5 Hz, 1 , H-6), 8.02 (td, J = 7.7, 1.5 Hz, 1 , H-4), 7.96 (td, J = 7.6,1.3 Hz, 1 , H-5), 7.42 (d, J = 9.0 Hz, 2 H, H-2',6'), 6.90 (d, J = 9.0 Hz, 2 , H-3',5'), NMR ((CD3)2SO) 8 11.01 (s, 1 H, CONH), 8.86 (d, J = 2.4 Hz, 1 , H-2'), 8.64 (d, J = 2.4 Hz, 1 , H-4'), 8.11-8.19 (m, 2 , H-3,6), 7.92-8.08 (m, 4 , H-4,5,5',8'), 7.55-7.73 (m, 2 , H-6',7'), 4.88 (s, 2 H, CH2). Anal.…”

Section: Methodsmentioning

confidence: 99%

“…AT-(4-Methoxyphenyl)-[(2-methyl-6-nitrophenyl)sulfonyl]acetamide (23a), mp (aqueous MeOH) 209-211 ®C: NMR ((CD3)2SO) 8 10.42 (s, 1 H, CONH), 7.78-7.87 (m, 2 H, H-4,5), 7.73 (dd, J = 6.9, 2.2 Hz, 1 , H-3), 7.47 (d, J = 9.0 Hz, 2 H, H-2',6'), 6.92 (d, J = 9.0 Hz, 2 , H-3',5'), 4.56 (s, 2 H, CH2), 3.73 (s, 3 H, OCHg), 2.67 (s, 3 H, CHg). Anal.…”

Section: Methodsmentioning

confidence: 99%

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Relationships between structure and kinetics of cyclization of 2-aminoaryl amides: potential prodrugs of cyclization-activated aromatic mustards

Atwell

Sykes²,

O’Connor³

et al. 1994

J. Med. Chem.

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2-Nitroaryl amides of general structure I are proposed as bioreducible prodrugs, capable of releasing cytotoxic aminoaniline mustards V on bioactivation by spontaneous cyclization of the resulting 2-aminoarylamides II via a tetrahedral intermediate, III. This concept allows separate optimization of the substituent effects influencing nitro-group reduction and mustard reactivity. A series of model 2-aminoaryl amides has been synthesized, and their rates of cyclization have been studied; these varied by a factor of more than 50,000-fold (kobs from 0.00040 to 21 min-1) at pH 2.4. For three compounds studied in detail, the rates were linearly dependent of pH, indicating that no change in the mechanism of the rate-determining step occurs over the pH range studied. The nucleophilicity of the amino group had a modest influence on the kinetics of cyclization, with electron-withdrawing groups slowing the rate. The geometry of the compound was also important, with structure-activity relationships indicating that the rate of cyclization is greatly enhanced by the preorganization of the molecule. In contrast, 4-substitution on the leaving aniline by a variety of groups had little effect on the cyclization reaction. These results are consistent with the rate-determining step being formation of the tetrahedral intermediate. These model studies suggest that the phenyldimethylacetamide system could be developed as a prodrug system for the bioreductively-triggered release of amines. Further substantial rate enhancements appear possible by alterations in the geometry of the system, whereas substitution of electron-withdrawing groups (required to raise the nitro-group reduction potential into the appropriate range) has only relatively modest retardation effects on rates of cyclization. More rigid systems may also be useful; a nitronaphthaleneacetamide analogue cyclized spontaneously during nitro-group reduction, suggesting a very short half-life for the reduced intermediate (amine or hydroxylamine).

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Relationships between structure and kinetics of cyclization of 2-aminoaryl amides: potential prodrugs of cyclization-activated aromatic mustards

Atwell

Sykes²,

O’Connor³

et al. 1994

J. Med. Chem.

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“…Treatment of the acid with methanol under Fischer esterification conditions gave methyl (5-methoxy-2-nitrophenyl)acetate 6a,7 (13), which was subjected to a onepot α,α-dimethylation in dry THF according to the protocol reported by Prasad and co-workers. 8 Treatment of 13 with 2.2 equiv of MeI and t BuOK in the presence of 18-Crown-6 resulted in the formation of a ca. 1.4:1 mixture of the target methyl 2-(5-methoxy-2-nitrophenyl)-2-methylpropionate 8 (14) and the α-monomethylated compound methyl 2-(5-methoxy-2-nitrophenyl)propionate 8,9 (15).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…A slightly yellowish microcrystalline solid: mp, 63−64°C; lit., 8 Synthesis of N-Homopiperonyl-2-methyl-2-(5-methoxy-2-nitrophenyl)propionamide (19). A mixture of amine 8 (1.28 g, 7.8 mmol), acid 9 (1.56 g, 6.5 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 980 mg, 7.2 mmol), 1-ethyl-3-(3-dimethylamonopropyl)-carbodiimide hydrochloride (EDC·HCl, 7.2 mmol), 1,8-bis(N,Ndimethylamino)naphthalene (PS, 710 mg, 3.3 mmol), and DMF (20 mL) was heated at 70°C for 5 h. The reaction mixture was poured into cold H 2 O (50 mL) and extracted with EtOAc (3 × 50 mL).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Total Synthesis of 4,5-Didehydroguadiscine: A Potent Melanogenesis Inhibitor from the Brazilian Medicinal Herb, Hornschuchia obliqua

et al. 2015

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The first total synthesis of the 7,7-dimethylaporphinoid, 4,5-didehydroguadiscine (6), originally isolated from the stems and roots of Hornschuchia oblique (Annonaceae), was achieved by the condensation of homopiperonylamine (7) with an α,α-dimethylphenylacetic acid derivative (8) and subsequent Pschorr reaction of the resulting benzylisoquinoline intermediate (22). The reported (13)C NMR data were partially revised on the basis of the analysis of HMBC spectra measured under different conditions. The melanogenesis inhibitory activity (IC50 = 4.7 μM) of 6 was 40 times stronger than that of arbutin (174 μM), which was used as reference standard. Furthermore, 6 was the most potent natural melanogenesis inhibitor within this class of compounds.

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18-Crown-6

Charles

Berkner

2001

Encyclopedia of Reagents for Organic Synthesis

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18-Crown-6 as a catalyst in the dialkylation of o-nitrophenacyl derivatives

Cited by 14 publications

References 0 publications

Relationships between structure and kinetics of cyclization of 2-aminoaryl amides: potential prodrugs of cyclization-activated aromatic mustards

Relationships between structure and kinetics of cyclization of 2-aminoaryl amides: potential prodrugs of cyclization-activated aromatic mustards

Total Synthesis of 4,5-Didehydroguadiscine: A Potent Melanogenesis Inhibitor from the Brazilian Medicinal Herb, Hornschuchia obliqua

18-Crown-6

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