Dialkyl Carbonates in the Green Synthesis of Heterocycles

Abstract

This review focuses on the use of dialkyl carbonates (DACs) as green reagents and solvents for the synthesis of several 5- and 6-membered heterocycles including: tetrahydrofuran and furan systems, pyrrolidines, indolines, isoindolines, 1,4-dioxanes, piperidines, and cyclic carbamates. Depending on the heterocycle investigated, the synthetic approach used was different. Tetrahydrofuran systems, pyrrolidines, indolines, isoindoline, and 1,4-dioxanes were synthesized using dimethyl carbonate (DMC) as sacrificial molecule (B_Ac2/B_Al2 mechanism). Cyclic carbamates, namely 1,3-oxazin-2-ones, were prepared employing DACs as carbonylating agents, either by B_Ac2/B_Al2 mechanism or through a double B_Ac2 mechanism. Piperidines were synthetized taking advantage of the anchimeric effect of a new family of dialkyl carbonates, i.e., mustard carbonates. Finally, in the case 5-hydroxymethylfurfural (HMF), DMC has been employed as efficient extracting solvent of this extensively investigated bio-based platform chemical from the reaction mixture. These synthetic approaches demonstrate, once again, the great versatility of DACs and their-yet to be fully explored-potential as green reagents and solvents in the synthesis of heterocycles.

Keywords: cyclization; dialkyl carbonates; green chemistry; green synthesis; heterocycles.

Scheme 1

Syntheses of DMC. Via phosgene (Equation 1); by catalytic oxidative carbonylation of methanol (Equation 2); by CO₂ insertion into oxyrane (Equation 3).

Scheme 2

DMC reactivity according to the HSAB theory.

Scheme 3

Synthesis of 5-membered aliphatic and aromatic heterocycles via DMC chemistry. Reaction conditions: (Equation 1): 1: NaOMe: DMC in 1.0: 2.0: 4.0 molar ratio in ACN, T = 60°C, t = 4 h; (Equation 2): 3: NaOMe: DMC in 1.0: 3.0: 4.0 molar ratio in ACN, T = 70°C, t = 6 h; (Equation 3): 5: NaOMe: DMC in 1.0: 3.0: 4.0 molar ratio in ACN, T = 70°C, t = 24 h; (Equation 4): 7: NaOMe: DMC in 1.0: 2.0: 4.0 molar ratio in ACN, T = 70°C, t = 4 h; (Equation 5): 9: NaOMe: DMC 1.0: 2.0: 4.0 molar ration in ACN, T = 70°C, t = 2 h; (Equation 6): 11: NaOMe: DMC in 1.0: 2.0: 4.0 molar ratio in ACN, T = 70°C, t = 4 h; (Equation 7): 9: DMC: base 1.00: 4.00: 0.05 molar ratio, T = 90°C, t = 8 h; (Equation 8): 11: DMC: DBU 1.0: 8.0: 1.0 molar ratio, T = 90°C, t = 24 h; (Equation 9): Amberlyn 13: tBuOH: DMC in 1.0: 2.0: 30.0 molar ratio, T = 90°C, t = 3 h.

Scheme 4

Cyclisation via phenonium ion. Reaction conditions: 9: DMC 1.0: 60.0 molar ratio, Amberlyst-15 (100% w/w referred to 9), T = 90°C, t = 48 h.

Scheme 5

Conversion of D-fructose 16 into HMF 17. Reaction condition: 16: TEAB: DMC in 1.00: 0.17: 16.80 molar ratio, Ambelyst-15 or BF₃O(Et)₂ (10% w/w referred to D-fructose), T = 90°C, t = 5 h.

Figure 1

Chemical structure of isosorbide and its epimers isomannide and isoidide.

Figure 2

Conversion of D-sorbitol 17 into isosorbide 18 via DMC chemistry.

Scheme 6

Preparation of pyrrolidine 22, indoline 24 and isoindoline 26 via DMC chemistry. Reaction conditions: Equations 1, 3: substrates 21 and 25 (1.0 eq) were reacted with DMC (60.0 eq) and tBuOK (2.0–2.5 eq, at 90°C for 6 h. Equation 2: substrates 23 (1 eq) were reacted with DMC (60 eq) and tBuOK (2.5 eq) or TBD (0.5 eq), at 90°C for 6–21 h.

Scheme 7

Preparation of 2,3-dihydrobenzo[b]-[1,4]dioxine 28 via DMC chemistry. Reaction conditions: 29: DMC: DABCO in 1.00: 8.00: 0.05–1.00, at 90°C for 2–15 h.

Figure 3

Chemical structures of mustard gases and their analog carbonates. Reactivity of nitrogen mustard carbonates in the presence of a nucleophile (NuH) via anchimeric effect.

Scheme 8

Preparation of piperidines via DACs chemistry by reaction of a symmetrical mustard carbonate with a CH₂-acidic compound (Equation 1) or via ring expansion reaction of a pyrrolidine-based carbonate (Equation 2). Reaction conditions of Equation 1: 31: 32 in 1: 1 molar ratio, in ACN, heated in a autoclave to 180°C for 7 h.

Scheme 9

Synthesis of 1,3-oxazin-2-ones via DACs chemistry by reaction of: an amine with a dicarbonate derivative of 1,3-diols (Equation 1), an amine with a 1,3-diol and a dialkyl carbonate (Equation 2), 3-amino-1-propanols with ethylene carbonate (Equation 3); synthesis of an aryl bis(1,3-oxazinan-2-one) (Equation 4). Reaction conditions: Equation 1: 38a-c: 40: tBuOK in 1.0: 1.0: 1.0 molar ratio, at T = 90°C for 2 h; Equation 2: 38a-d: 41: DAC: tBuOK in 1.0: 1.0: 2.0: 3.0 molar ratio, at T = 90°C for 2 h; Equations 3, 4: 42a-f: EC: TBD in 1.0: 1.0: 0.2 molar ratio, at T = 100°C, for 5–97 h.