A New and Efficient Synthesis of Substituted 2-Hydroxymethyl-2-methyl-2H-chromenes

Abstract

S y n t h e s i s o f S u b s t i t u t e d 2 -H y d r o x y m e t h y l -2 -m e t h y l -2 H -c h r o m e n e sAbstract: A new and efficient three step procedure for the synthesis of functionalized 2H-chromenes 1 is described, starting from commercially available salicylaldehydes 2 and 2-methylpropenylmagnesium chloride 3, which involves catalytic acid-mediated intramolecular cyclization of phenolic epoxide 5 as the key step.Synthesis of Substituted 2-Hydroxymethyl-2-methyl-2H-chromenes 2H-Chromenes are key heterocyclic units in many natural and biologically polyoxygenated active compounds. 1 Moreover, they are widely employed as useful intermediates in the synthesis of medicinal agents such as cordiachromene, 2 potassium channel activating drugs 3 and a range of tannins. 4 A common building block for the synthesis of such structures is 2-hydroxymethyl-2-methylchromene 1 (Scheme 1). Scheme 1Although several methods have been reported in literature 5 for the construction of such various 2,2-dialkylchromene skeletons, only few direct preparations of 2-functionalized chromenes have been described. 2,6 We herein report a new and facile route to diverse 2-hydroxymethyl-2-methylchromenes 1, starting from commercially available salicylaldehydes 2, which involves the cyclization of 5, a nucleophilic epoxide opening reaction as the key step. The synthetic strategy requires the preparation of epoxides 5, whose aryl ether-forming reaction provides chromenemethanols 1 via a (6-exo) mode of cyclization, followed by an intramolecular dehydratation reaction (Scheme 2).Preparation of epoxide 5 is outlined in Scheme 3. The treatment of salicylaldehydes 2 with an excess of 2-methylpropenylmagnesium chloride 3 in THF afforded the corresponding homoallylic alcohols 4 in good to excellent yields (Table 1). For the preparation of key epoxides 5, homoallylic alcohols 4 were subjected to standard epoxidation with m-CPBA in CH 2 Cl 2 . The reaction was carried out at 0 °C for 4 hours. Purified by column chromatography on silica, the corresponding epoxides 5a-d were obtained in a 70-75% yield. It will be noteworthy that in the case of compounds 4e,f, m-CPBA epoxidation leads to epoxides 5e,f in only 20-30% yields. These low yields are due to the instability of compounds 5e,f on silica. To improve these yields, phenolic groups of compounds 2e,f were protected by the TBS group, 7 then allylmetallation and epoxidation reactions were successful (Table 1, entries 7 and 8). Subsequent O-silyldeprotection of 5g,h with TBAF 7 gave corresponding phenolic epoxides 5e,f in quantitative yields. These epoxides were, then, immediately used in the next step without further purification. (3), THF, -20°C. ii) m-CPBA, CH 2 Cl 2 , 0 °C. Scheme 3 Reagents and conditions i) CH 2 =C(CH 3 )CH 2 MgClIn the last step (Scheme 4), the crucial cyclization of epoxides 5a-e with AlCl 3 (2 equiv) in THF at 0 °C did not give the expected chromanemethanols 1a-e but instead bicyclic compounds 7a-e. The naphthalene derivative 5f leads, under these conditions, to the expec...

New flavonoids from the Saudi Arabian plant Retama raetam which stimulates secretion of insulin and inhibits α-glucosidase

“…The benzo-fused furanofuran unit in 6 is hitherto unknown in natural-product flavones and isoflavones, although it is present in the hexahydrofuranobenzofurans (+)-panacene (from the sea hare Aplysia brasiliana), 22 platypodantherone (from Platypodanthera melissaefolia), 23 and (+)-gynunone (from Gynura elliptica). 24 The motif is seen fused to coumarin in compounds from Aegle marmelos 25 and Peucedanum praeruptorum, 26 and to xanthones in psorofebrin and related compounds from Psorospermum febrifugum. 27 In all cases, the two furans are cis-fused, as in 6.…”

“…However, amongst compounds with Me and OH at the equivalent of C-3′′, two examples have the same relative configuration as 6 (with Me cis to the ringjunction-H). 25,26 Two others have the opposite configuration (Me trans to ring-junction-H), although one lacks the OH. 24,27 The positive-ion HRESIMS of 7 contained a peak for Table 2) contained eighteen discrete resonances, with two of the methine signals representing two equivalent carbons each.…”

2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile propan-2-one monosolvate

“…For the synthesis of chromene compounds, see: Coujon et al (2002). For the bioactivity of chromene compounds see: Kaye & Nocanda (2002).…”

Copper‐based Schiff Base Complex Immobilized on Core‐shell Fe3O4@SiO2 as a magnetically recyclable and highly efficient nanocatalyst for green synthesis of 2‐amino‐4H‐chromene derivatives

“…[13,[16][17][18][19][20][21][22][23][24][25] Among different nitrogen-based ligands, Schiff-Base ligands supported on magnetic nanoparticles immobilize in excellent state through the coordination to a variety of transition metals with improved catalytic activity and stability. [26][27][28][29][30][31] This is because the ligands containing N-donors exhibit a high performance by a stable hosting a range of metal cations and as a result, these materials become excellent candidates in catalysis design as well as analytical, industrial and medicinal applications. [32][33][34][35][36] In comparison, the Cu-based catalysts have offered excellent alternatives to other noble-metalbased catalysts due to their interesting features including low price, facile separation and high catalytic performance.…”