Fabio Arico

Green synthesis of dimethyl isosorbide.

In the last twenty years, new categories of solvents have been investigated in order to deal with safety and environmental issues; that is, water, supercritical fluids, ionic liquids, solvents derived from CO2 [1b, 4] or from renewables. The advantage of using solvents derived from renewables is that natural products are present in large amounts, although only a small fraction (ca. 4 %) is used for this purpose. d-sorbitol is a good example of biofeedstock and has several applications in food and non-food industries. Besides, its cyclic derivate, isosorbide, is widely used in the pharmaceutical and hygiene industries. The methyl derivative of isosorbide, dimethyl isosorbide (DMI), is also extensively used in cosmetics and as a thinning agent. Furthermore, due to its renewable starting materials and high boiling point (246 8C), DMI is also a suitable substitute of the more toxic currently used solvents, such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), and dimethylacetamide (DMAc). However, currently DMI is synthesized by common methylation reactions, which employ dimethyl sulfate (DMS) or methyl halides. Herein, it is reported an improved green synthesis of DMI by reaction of isosorbide with dimethyl carbonate (DMC) as reagent and solvent, in the presence of a base at reflux temperature of 90 8C. (Scheme 1). DMC, nowadays produced by a clean and halogen-free process, is an environmentally benign substitute of phosgene, DMS, and methyl halides and it is a well-known nontoxic solvent and reagent. 10] In general DMC, as a methylating agent (bimolecular, base-catalyzed, alkyl cleavage, nucleophilic substitution, BAl2, mechanism) [4c] requires temperatures higher than 150 8C in the presence of a base. However, we previously reported that under similar conditions the reaction of hard alkoxides and DMC gave exclusively the transesterified methylcarbonates derivatives (via BAc2 mechanism), also at high temperatures. On the contrary, other softer nucleophiles such as anilines, phenols and methylene-active compounds were easily methylated by DMC via a BAl2 mechanism. [4, 12] Methyl ethers of primary alcohols can be obtained through two steps: a BAc2 transesterification followed by the decarboxylation of the resulting methylcarbonate. However, methylation of secondary alcohols was never obtained quantitatively due to the formation of elimination products. On the other hand, this is not the case in the present work; the secondary hydroxyls groups of isosorbide are efficiently methylated at reflux temperature (90 8C) by reaction with DMC in the presence of a range of bases (Table 1). This is quite surprising, especially in consideration of all the possible products that could be formed by reacting isosorbide with DMC, which include three classes of compounds (Figure 1): carboxymethyl derivates (MC-1, MC-2, dicarboxymethyl isosorbide (DC)), carboxymethyl methyl derivates (MCE-1, MCE-2), and methyl derivates (MMI-1, MMI-2 and DMI). In particular, it was possible to isolate all these isosorbide derivatives as pure compounds except MMI-2 and MC-2 due to their low amount in the reaction mixture. The isolated compounds were identified by GS–MS analysis and NMR spectroscopy (see the Experimental Section). Table 1 shows that the reaction of isosorbide with DMC in the presence of weak bases (entries 1–2), which led mostly to the formation of carboxymethylated products MC-1, MC-2, and DC. However, reactions conducted in the presence of a strong base led to the formation of DMI with yields up to 40 % (Table 1, entries 3–4). Increasing the amount of base (Table 1, entries 5–6), enhanced the yield of DMI. Quantitative conversion to DMI could be achieved using 3 equivalents of sodium methoxide. It is also interesting to point out that the methyl carboxymethyl derivative of isosorbide MCE-1 was formed in higher yields compared to MCE-2 (Table 1, entries 3–5). This result shows that the OH in endo position is more reactive towards methylation compared to the OH in exo position. Scheme 1. Synthesis of dimethyl isosorbide.

Reaction of the Ambident Electrophile Dimethyl Carbonate with the Ambident Nucleophile Phenylhydrazine

To explore the ambident electrophilic reactivity of dimethyl carbonate (DMC), reactions with the ambident nucleophile phenylhydrazine were investigated. When a Brönsted base was used, selective carboxymethylation occurred at N-1, after that several other compounds were produced selectively utilizing various conditions. Formation of these compounds was explained by using the Hard-Soft Acid-Base (HSAB) theory. Catalysis by some metal salts altered the reactivity of phenylhydrazine, which effected selective carboxymethylation at N-2 of phenylhydrazine instead.

Synthesis of Five-Membered Cyclic Ethers by Reaction of 1,4-Diols with Dimethyl Carbonate

The reaction of 1,4-diols with dimethyl carbonate in the presence of a base led to selective and high-yielding syntheses of related five-membered cyclic ethers. This synthetic pathway has the potential for a wide range of applications. Distinctive cyclic ethers and industrially relevant compounds were synthesized in quantitative yield. The reaction mechanism for the cyclization was investigated. Notably, the chirality of the starting material was maintained. DFT calculations indicated that the formation of five-membered cyclic ethers was energetically the most favorable pathway. Typically, the selectivity exhibited by these systems could be rationalized on the basis of hard-soft acid-base theory. Such principles were applicable as far as computed energy barriers were concerned, but in practice cyclization reactions were shown to be entropically driven.

Synthesis of dialkyl ethers by decarboxylation of dialkyl carbonates

The decarboxylation reaction of dialkyl carbonates to give their related ethers was investigated. The reaction was carried out at atmospheric pressure and in the presence of hydrotalcite or basic alumina as catalysts without any solvent. The influence of several reaction parameters on the selectivity was studied (e.g. temperature, amount of catalyst, substrate concentration, solvent). The stability of the catalyst was also investigated. The experimental data for the decarboxylation confirmed that this reaction is complicated by competitive processes, such as dismutation and, in one case, pyrolysis. The results obtained show that in the presence of hydrotalcite as a catalyst, symmetrical dialkyl ethers can be synthesised with yields up to 80%. Dissymmetrical ethers (i.e.methyl alkyl ethers) can be produced with yields up to 80% at high temperature (250 °C). The catalyst proved to be fully recyclable in all cases studied, except for the carbonate containing n-octyl moiety.

Reaction of dialkyl carbonates with alcohols: Defining a scale of the best leaving and entering groups*

A series of dialkyl and methyl alkyl carbonates has been synthesized and their reactivity investigated. The behavior of preferential leaving and entering groups for the newly synthesized carbonates has been accurately investigated. Both experimental and computational studies agreed that the scale of leaving groups follows the trend: PhCH2O–, MeO– ≥ EtO–, CH3(CH2)2O–, CH3(CH2)7O– > (CH3)2CHO– > (CH3)3CO–. Accordingly, the scale of the entering group has the same trend, with t-butoxide being the worst entering group. A preliminary attempt to rationalize the nucleofugality trends, limited to the (CH3)3CO– and CH3O– groups, has indicated that a likely origin of the observed trends lies in the different entropic contributions and solvation effects.

Insight into the Hard−Soft Acid−Base Properties of Differently Substituted Phenylhydrazines in Reactions with Dimethyl Carbonate†

Following the preliminary studies on the reactivity of the ambident nucleophile phenylhydrazine with dimethyl carbonate, investigations involving para-substituted phenylhydrazines were carried out in order to probe differences in the reactivity within this class of nucleophile. Phenylhydrazines substituted by electron withdrawing or donating substituents showed an increase in reactivity of the phenylhydrazine toward dimethyl carbonate. Under the basic conditions used, all phenylhydrazines displayed hard nucleophilicity, signifying that para-substitution on the phenyl ring has little effect on the hard-soft behavior of this class of nucleophile. This conclusion fits well within the results previously obtained using other para-substituted nucleophiles, i.e., phenols.

5-Membered N-heterocyclic compounds by dimethyl carbonate chemistry

Aliphatic and aromatic 1,4-bifunctional compounds bearing a primary alcoholic function and an amine can be efficiently cyclised with dimethyl carbonates in the presence of a base to achieve 5-membered N-heterocyclic compounds. This novel synthetic pathway is quantitative, one-pot and green as it does not involve the use of chlorine solvents or reagent.

Synthesis of five- and six-membered heterocycles by dimethyl carbonate with catalytic amounts of nitrogen bicyclic bases

A catalytic amount of a nitrogen bicyclic base, i.e., DABCO, DBU or TBD, is effective for the one-pot synthesis of heterocycles from 1,4-, 1,5-diols and 1,4-bifunctional compounds via dimethyl carbonate chemistry under neat conditions. Nitrogen bicyclic bases that were previously shown to have enhanced the reactivity of DMC in methoxycarbonylation reaction by a BAc2 mechanism are herein used for the first time as efficient catalysts for cyclization reactions encompassing both BAc2 and BAl2 pathways. This synthesis procedure was also applied to a large scale synthesis of cyclic sugars, isosorbide and isomannide, starting from D-sorbitol and D-mannitol, respectively. The resulting anhydro sugar alcohols were obtained as pure crystalline compounds that did not require any further purification or crystallization.

Cyclization reaction of amines with dialkyl carbonates to yield 1,3-oxazinan-2-ones*

A number of six-membered cyclic carbamates (oxazinanones) were synthesized from the reaction of a primary amine or hydrazine with a dicarbonate derivative of 1,3-diols in a one-pot reaction, in good yield, short time span, and in the absence of a solvent. The reaction proceeds in two steps: an intermolecular reaction to give a linear intermediate and an intramolecular cyclization to yield the cyclic carbamate. This is the first example of a carbonate reacting selectively and sequentially, firstly at the carbonyl center to form a linear carbamate and then as a leaving group to yield a cyclic carbamate.

Phosgene-free carbamoylation of aniline via dimethyl carbonate

The synthesis of N-phenylcarbamate from aniline and dimethyl carbonate (DMC) in the presence of homogeneous, supported heterogeneous, and heterogeneous catalysts was investigated in batch conditions. First, a selection of homogeneous catalysts was studied and their reactivity in the same reaction conditions was compared to zinc acetate, a catalyst extensively used for this reaction. Then the best homogeneous catalysts were supported on silica or alumina, and the resulting heterogeneous supported catalysts were tested for the carbamoylation of aniline. Finally, several heterogeneous catalysts were investigated. Zinc carbonate basic was shown to be the best catalyst, giving quantitative conversion and selectivity for the N-phenylcarbamate. Its catalytic activity was fully investigated taking into account substrate concentration, amount of catalysts, and temperature influence. Zinc carbonate was also shown to be recyclable, once it was recovered from the reaction mixture and calcinated.