One-pot synthesis of disubstituted furoxans

Abstract

A one-pot method for the synthesis of disubstituted furoxans and a one-pot method for synthesis of diethyl furoxan dicarboxylate (DFD).

Description

ONE-POT SYNTHESIS OF DISUBSTITUTED FUROXANSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional patent application no. 63 / 651,441, which was filed May 24, 2024, and which is hereby incorporated by reference in its entirety.STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under N00014-19-1-2089 awarded by the Office of Naval Research. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure relates to a one-pot synthesis of furoxans, a starting material used in fields as diverse as drug discovery, energetics, plasticizers, and any application where a furoxan or furazan may be desired. In particular, the disclosure relates to a scalable single- step synthesis of diethyl furoxan di carb oxy late.BACKGROUND

[0004] This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be construed as admissions about what is or is not prior art.

[0005] Diethyl Furoxan Dicarboxylate (DFD) is a common starting material in a variety of research areas, including drug discovery, energetic materials (Russian Chemical Bulletin, 2003, 52, 1822-1828) and general research in the field of 1,3-dipolar cycloadditions (Bulletin Chemical Society of Japan, 1990, 63 (11), 3300-3306; Journal Organic Chemistry, 1983, 48 (18), 3053-3058). As such, numerous investigations have been conducted into the synthesis of this material in the past. The destructive nitration of ethyl acetoacetate is well known. However, destructive nitrations are often very exothermic and difficult to control. Destructive nitration reactions resulting in the production of furoxans proceed via the dimerization of a nitrile oxideintermediate. Other methods of generating the nitrile oxide include basification, microwave photolysis, pH adjustments of chloro-aldoximes, condensation of nitro alkanes, and by elimination of nitrous acid from nitrolic acids. The recent methods of nitrile oxide formation involve the use of potassium iodate (Journal of Chemical Sciences, 2019, 131 (6), 46) as well as Oxone™ / sodium chloride mixtures to generate oximes and subsequently convert them to nitrile oxides. The generation of nitrile oxides for the purpose of synthesizing a furoxan is challenged by the possibility of the formation of an unfavorable dimer: 1,4,2,5-dioxadiazene (Synlett, 2011, 14, 2097-2099). It was suggested that the presence of a large coordinating cation, such as silver (I), could help favor the furoxan dimer (Chemistry of Heterocyclic Compound (NY), 2017, 53, 760-778). A comprehensive overview of nitrile oxide generation can be found in the review by Roscales, Organic Biomolecular Chemistry, 2018, 16 (44), 8446- 8461.

[0006] The preparation of DFD (500 g scale) was reported via the reaction of the hydroximidoyl chloride of ethyl acetate with silver carbonate in THF at room temperature (Organic Process Research Development, 2019, 23 (11), 2527-2531). The major drawback to this preparation is its reliance on large amounts of silver salts, which is less than economic, the need to purify the ethyl 2-chloro-2-(hydroxyamino)acetate before use, and the need to purify the final product by column chromatography at small scales or vacuum distillation at a larger scale.

[0007] It is an object of the present disclosure to provide a scalable, simple, and economical one-pot synthesis of disubstituted furoxans such as diethyl furoxan dicarboxylate with high purity and yield. This and other objects and advantages, as well as inventive features, will be apparent from the detailed description.SUMMARY

[0008] Provided is a one-pot method for the synthesis of a disubstituted furoxan of formula (I):wherein each Ri and R2 is independently selected from the group consisting of (Ci-Ce) alkyl, (C6-C12) aryl, (Cs-Cs) heteroaryl, ar(Ci-Ce)alkyl, (Ci-Ce) alkoxy, COR3, COOR3, nitro, cyano, amine, and halogen, wherein Ri and R2 can be optionally substituted;R3 is hydrogen, (Ci-Ce) alkyl, or (C6-C12) aryl; which method comprises:(i) mixing a compound of formula (II):R^^NO2(II) wherein R is Ri or R2, wherein Ri and R2 are as defined above, with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the disubstituted furoxan of formula (I) is synthesized in the one-pot method.

[0007] In some embodiments, Ri and R2 can be the same.

[0008] Further provided is a method for the synthesis of a diethyl furoxan dicarboxylate (DFD) of formula (III):which method comprises:(i) mixing ethylnitroacetate with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the DFD is synthesized.

[0009] In some embodiments, the DFD can be prepared in a one-pot comprising a single-step method. The sodium nitrite can be added dropwisely to maintain the temperature up to about 5 ° C. The DFD obtained can be in oil form with a purity greater than about 96%. In some embodiments, the work-up process of DFD involves decanting off an aqueous layer from an oily layer that comprises DFD.DETAILED DESCRIPTION

[0010] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the claimed invention is thereby intended.

[0011] The present disclosure is predicated, at least in part, on the discovery that disubstituted furoxans are synthesized via the dimerization of the appropriate nitrile oxide. Reported procedures of preparation of diethyl furoxan dicarboxylate (DFD) involve low-yield destructive nitrations, multiple steps, halogenated solvents, or heavy or precious metals, and do not hold up well for economical scale-up.

[0012] In view of the above, an improved, scalable and economic single-step synthesis of disubstituted furoxans is provided. The method does not require organic solvents such as tetrahydrofuran (THF) or heavy metals (e.g., silver). The method can provide high yields and purity of disubstituted furoxans such as DFD. DFD is a starting material for fields as diverse as drug discovery, energetics, plasticizers, and any application where a furoxan or furazan may be desired.

[0013] Thus, provided is a method for the synthesis of a disubstituted furoxan of formula (I):wherein each Ri and R2 is independently selected from a group consisting of (Ci-Ce) alkyl, (C6-C12) aryl, (Cs-Cs) heteroaryl, ar(Ci-Ce)alkyl, (Ci-Ce) alkoxy, COR3, COOR3, nitro, cyano, amine, and halogen, wherein Ri and R2 can be optionally substituted;R3 is hydrogen, (Ci-Ce) alkyl, or (C6-C12) aryl; which method comprises:(i) mixing a compound of formula (II):R^^NO2(II) wherein R is Ri or R2, wherein Ri and R2 are as defined above, with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the disubstituted furoxan of formula (I) is synthesized in the one-pot method.

[0014] In some embodiments, Ri and R2 can be the same. The method can be a one-pot synthesis of disubstituted furoxans of formula (I). In some embodiments, sodium nitrite is added dropwise to maintain the temperature of the reaction mixture between about 0 °C to about 5 °C.

[0015] Also provided is a method for the synthesis of a diethyl furoxan dicarboxylate (DFD) of formula (III):which method comprises:(i) mixing ethylnitroacetate (ENA) with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the DFD is synthesized.

[0016] The method can be carried out in a one-pot. The DFD obtained can be in the oil form, forming two layers in the reaction mixture. In some embodiments, the DFD is synthesized in a single step. The method can further comprise a work-up procedure for isolating DFD from the reaction mixture by decanting off an aqueous layer from an oily layer that comprises DFD. Thus, DFD can be acquired by direct separation from the aqueous phase.

[0017] The DFD can be synthesized with high purity. The DFD in oil form can have a purity greater than about 96% to about 99%. In some embodiments, the purity of DFD is about 96.5%. In some embodiments, the purity of DFD is about 96.9%. In some embodiments, the purity of DFD is about 97%. In some embodiments, the purity of DFD is about 97.2%. In some embodiments, the purity of DFD is about 97.5%. In some embodiments, the purity of DFD is about 98%. In some embodiments, the purity of DFD is about 98.2%. In some embodiments, the purity of DFD is about 98.5%. In some embodiments, the purity of DFD is about 99%. Thus, the method can avoid tedious work-up and purification steps. The NMR analysis showed no formation of bi-product 1,4,2,5-oxadiazene, no traces of starting material ENA, and no nitrolic acid precursor.

[0018] In some embodiments, the solvent used is water. The method does not require any organic solvent. The method can involve the nitrosation of ENA in nitric acid and formation of nitrile oxide simultaneously. The nitric acid can be used in an aqueous solution form. Theconcentration of nitric acid used can be about 25% to about 70%. ENA can be added to the chilled aqueous solution of the nitric acid at a temperature from about 0 °C to about 5 ° C, such as 0 °C to about 5 °C, about 0 °C to 5 °C, or 0 °C to 5 °C. The addition of sodium nitrite is a crucial step. The sodium nitrite can be added dropwise at controlled temperature conditions from about 0 °C to about 5 ° C, such as 0 °C to about 5 °C, about 0 °C to 5 °C, or 0 °C to 5 °C. In some embodiments, the temperature is maintained below about 5 °C until sodium nitrite is added completely. After the addition is completed, the reaction mixture can be heated up to a temperature of about 50 °C to about 90 °C, such as 50 °C to about 90 °C, about 50 °C to 90 °C, or 50 °C to 90 °C. In some embodiments, the reaction mixture is heated at a temperature of about 80 °C. In some embodiments, the reaction mixture is heated at a temperature of about 85 °C. The reaction mixture can be heated for about 15 minutes to about 1 hour, such as 15 minutes to about 1 hour, about 15 minutes to 1 hour, or 15 minutes to 1 hour. The sodium nitrite can be used in an amount of about 0.5 equivalent to about 3.0 equivalent (such as 0.5 equivalent to 3.0 equivalent). In some embodiments, the amount of sodium nitrite is 0.5 equivalent. In some embodiments, the amount of sodium nitrite is 1.0 equivalent. In some embodiments, the amount of sodium nitrite is 1.05 equivalent. In some embodiments, the amount of sodium nitrite is 1.5 equivalent. In some embodiments, the amount of sodium nitrite is 2.0 equivalent. In some embodiments, the amount of sodium nitrite is 2.5 equivalent. In some embodiments, the amount of sodium nitrite is 3.0 equivalent.

[0019] Table 1 shows the summary of reaction variables and acquired yield by direct separation from the reaction mixture.Table 1

[0020] The term "substituted" (e.g., as in "optionally substituted") refers to a functional group in which one or more hydrogen atoms contained therein are replaced by one or more nonhydrogen atoms. The term "functional group" or "substituent" refers to a group that can be or is substituted onto a molecule. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, and carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, azides, hydroxylamines, cyano, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms in various other groups.

[0021] The term " alkyl" refers to substituted or unsubstituted straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms (e.g., C1-C20), 1 to 12 carbons (e.g., C1-C12), 1 to 8 carbon atoms (e.g., Ci-Cs), or, in some embodiments, from 1 to 6 carbon atoms (e.g., Ci-Ce). Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n- octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0022] The term "alkenyl" refers to substituted or unsubstituted straight chain and branched divalent alkenyl and cycloalkenyl groups having from 2 to 20 carbon atoms (e.g., C2-C20), 2 to 12 carbons (e.g., C2-C12), 2 to 8 carbon atoms (e.g., C2-Cs) or, in some embodiments, from 2 to 4 carbon atoms (e.g., C2-C4) and at least one carbon-carbon double bond. Examples ofstraight chain alkenyl groups include those with from 2 to 8 carbon atoms such as -CH=CH-, - CH=CHCH2-, and the like. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)- and the like.

[0023] An alkynyl group is a substituent, which contains an open point of attachment on a carbon atom that would form if a hydrogen atom bonded to a triply bonded carbon is removed from the molecule of an alkyne. The term "hydroxy alkyl" refers to alkyl groups as defined herein and substituted with at least one hydroxyl (-OH) group.

[0024] The term "cycloalkyl" refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, or 6 carbon atoms (e.g., Cs-Ce). Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0025] The term "aryl" refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons (e.g., Ce-Cu) or from 6 to 10 carbon atoms (e.g., Ce-Cio) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be monosubstituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed herein.

[0026] The terms "aralkyl" and "arylalkyl" refer to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0027] The term "heterocyclyl" refers to substituted or unsubstituted aromatic and nonaromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, B, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups can include 3 to 8 carbon atoms (e.g., Cs-Cs), 3 to 6 carbon atoms (e.g., Cs-Ce) or 6 to 8 carbon atoms (e.g., Ce-Cs).

[0028] A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and nonaromatic groups. The term "heteroaryl" represents an aromatic ring comprising at least one hetero atom such as N, S, O, or Se. Heteroaryl in the present disclosure may be any hetero aryl. Heteroaryl includes, but is not limited to, pyrrolidinyl, azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, benzthiazolinyl, benzimidazolinyl groups, or any combination thereof.

[0029] The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can further include double or triple bonds and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0030] The term "amine" refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)s wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines,arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

[0031] The terms "halo," "halogen," and "halide" group, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" group, as used herein, includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl includetrifluorom ethyl, 1,1 -di chloroethyl, 1,2-di chloroethyl, 1, 3 -dibromo-3, 3 -difluoropropyl, perfluorobutyl, -CF(CH3)2 and the like.

[0032] The terms "optionally substituted" and "optional substituents" are used to describe groups, which are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents can be the same or different. The terms "independently" "independently are" and "independently selected from" mean that the groups in question may be the same or different. Certain of the defined groups or substituents can occur more than once in the structure, and upon such occurrence each group or substituent shall be defined independently of the other.

[0033] The disclosure provides an economical, scalable, one-pot synthesis of DFD in which the product is extracted directly from the reaction vessel in high purity and high yield. The method requires one temperature-controlled addition, followed by an extraction after a moderately elevated temperature stir. The method can replace other past multi-step, lower- yield syntheses using only commodity chemicals, requiring no toxic or organic solvents or heavy metals.

[0034] It will be appreciated by persons skilled in the art that the present disclosure is not limited by what has been particularly shown and described herein above. Rather the scope of the present disclosure includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications which would occur to persons skilled in the art upon reading the specification and which are not in the prior art.

[0035] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference.EXAMPLES

[0036] The following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention in any way.All chemicals were used as purchased from Ambeed, Sigma Aldrich, or Fischer Scientific without further purification.

[0037] Ethylnitroacetate (ENA) was investigated via several routes to produce DFD. The first investigated was destructive nitration. The reaction of ENA in strong nitrating conditions (100% nitric acid or mixed acids) did not yield DFD in an easily isolatable amount. To produce the nitrolic acid (HNO2) of ethyl acetate nitrosation of ENA was carried out (Scheme 1).Scheme 1Nitrosation of ENA and subsequent elimination of HNO2 to produce DFD

[0038] Next, rather than nitrosate ethylnitroacetate to its corresponding nitrolic acid and subsequently producing the nitrile oxide for dimerization, the nitrosation in 26% nitric acid, such that the nitrosation and nitrile oxide formation conditions could be met simultaneously, was attempted.

[0039] The slow addition of a concentrated sodium nitrite solution to a slurry of ENA in 26% nitric acid, followed by heating to 50 °C overnight, resulted in the formation of a slightly yellow oil that settled to the bottom of the reaction vessel once stirring was ceased. Analysis of this oil by H and13C NMR showed the formation of DFD with no 1,4,2,5-oxadiazene biproduct, noethylnitroacetate, and no nitrolic acid precursor. This route was optimized. The ideal heating profile for this reaction is to keep the temperature below 5 °C during the addition of nitrite, ramp the temperature up to 80 °C over 20 minutes, and stir at 80 °C for 30 minutes. This temperature profile is most easily controlled by running the reaction in an EasyMax™ 102 by Mettler Toledo (100 ml reaction vessel). The reaction can be nearly quantitative when run perfectly at this temperature profile (see Table 1).

[0040] It was found that DFD does not separate as well from water when there is too much nitric acid in the reaction mixture. Lower concentrations of nitric acid resulted in greater amounts of DFD separating from the aqueous phase after completion of the reaction. When the ideal nitric acid concentration and sodium nitrite equivalents were run at 144 g ENA scale, the lack of perfect thermal control resulted in significantly lower reaction yield (77.5% vs 98.5% with EasyMax™ control). The EasyMax™ reported a maximum difference in temperature between the cooling jacket and reaction vessel of 6.5 °K during the 20-minute nitrite addition, indicating that while there was an exotherm, it was not too extreme. The initial addition of the nitrite solution shot the reaction temperature up from 0 °C to 0.8 °C, where the largest difference in temperature between the jacket and reactor was recorded. After stabilizing, the reaction oscillated tightly around 0.2 °C during the remainder of the addition. This was a much lower exotherm than was expected and was easily controlled by the EasyMax™. This exotherm was not as easily controlled using only an ice bath (the temperature oscillated between 3 and 5 °C). Better thermal control, comparable to that of EasyMax™, would result in high yields of DFD on larger scales.

[0041] DFD acquired by direct separation from the aqueous phase was highly pure. Directly extracted DFD had a lower bound purity of 85.4% by 'H quantitative NMR against a 2-4-6- trimethoxy-l,3,5-triazene (TMT) standard. After desiccation over P2O5 overnight, the lower bound purity rose to 96.9%. The highest purity DFD was the as separated oil from the 7.194 g ENA EasyMax reaction, with a purity of 98.2% (Table 1). The primary impurities in the DFD were initially thought to be water. However, no water peak was ever observed in the quantitative1H NMR spectra. The most likely candidate for the primary impurity was NOx gases. The first indicator of this was that freshly separated DFD smelled like NOx gases and would slowly lose mass when left on a scale. This, paired with the desiccator clouding with orange gas and the DFD changing colors from a dark yellow to a slight yellow as purityincreased, further pointed at NOx gases being the primary impurity. The final indicator was that 1,3,5-trimethoxybenzene, the initial standard chosen for the quantitative 'H NMK turned deep blue when added to an NMR tube with DFD that still had NOx gases present, indicating a likely nitrosation.

[0042] The method of producing DFD described above offers a variety of improvements over previously reported methods: i) The precursor, ethylnitroacetate, is more economical than that of the reported starting material, ethyl 2-chloro-2-(hydroxyamino)acetate. Ethylnitroacetate can be used without any purification, while ethyl 2-chloro-2-(hydroxyamino)acetate needs to be filtered before being used to remove impurities. The use of sodium nitrite is cheaper than silver carbonate. ii) The replacement of THF as reaction solvent with water. It makes the method economical and environmentally friendly. It makes isolation of DFD simpler and safer due to the lack of all flammable solvents being used. The DFD can be isolated by separating directly from the aqueous phase and needs only to sit in a desiccator after separation. The reported largest scale synthesis of DFD requires a tedious multi-step process, such as the filtration of silver carbonate followed by evaporation of the THF solvent and subsequent purification via vacuum distillation or column chromatography. iii) The production of DFD in high yield (e.g., 98.5%) and high purity (e.g., 98.2%).Overall, the method of DFD synthesis can significantly reduce the cost, trivialize work-up and purification, remove the need for heavy or precious metals while maintaining the single-step, one-pot approach, and does not require any organic solvents or involve uncontrollable exotherms.

[0043] Examples:Preparation of DFD at the 5 g scale

[0044] 6.00 ml (7.194 g, 54.0 mmol) of ethylnitroacetate (ENA) was added to a chilled solution of 50 ml water and 10 ml of 68% nitric acid at 0 °C in a 100 mL Mettler Toledo EasyMax™ reactor. 7.1 ml (3.92 g, 56.8 mmol, 1.05 equivalents) of 8.0 M aqueous sodium nitrite (NaNCE) was added dropwise over 20 minutes using a Mettler-Toledo dosing unit. The solution wasthen ramped to 80 °C over 20 minutes and, subsequently, stirred at this temperature for 30 minutes. The solution was then cooled back down to 10 °C, and the stirring stopped. The reaction was transferred to a separatory funnel and allowed to stand for 30 minutes. The DFD layer at the bottom was separated and left to sit in a desiccator over P2O5 until no water droplets remained and the color had dulled to a faint yellow. 6.128 g DFD were obtained this way (98.5% yield, 98.2% pure).Preparation of DFD at the 100 g Scale

[0045] 0.200 L of 68% nitric acid and 1.15 L water were chilled to 0 - 5 °C in a 3 -L round bottom flask. Once cold, 0.120 L (144 g, 1.08 mol) ENA was added, and the solution temperature was allowed to equilibrate. 135 ml of 8 M NaNO? (74.6 g, 1.08 mol, 1.0 equivalents) was added over 16.5 minutes such that the temperature of the reaction did not exceed 5 °C. The solution was heated to 80 °C and held for 30 minutes, after which it was cooled to room temperature. The magnetic stirrer was removed, and the solution was allowed to settle. The top layer of water was mostly decanted off, and the oil layer and remaining aqueous layer were transferred to a separatory funnel. After allowing it to settle, the oil layer was separated and left to dry. 90.44 g of DFD was collected as a yellow oil (72.7 %, 97.2% pure). The collected aqueous portions were collected and extracted with 3x200 ml diethyl ether, dried over magnesium sulfate, and evaporated to yield an additional 5.987 g of DFD (unknown purity) for a total reaction yield of 77.5 %.

[0046] Those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above. The implementations should not be limited to the particular limitations described. Other implementations may be possible. While the inventions have been illustrated and described in detail in the drawings and foregoing description, the same is to be considered illustrative and not restrictive in character, it being understood that only certain embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected.Enumerated Embodiments:The following list of enumerated embodiments presents claims with multiply dependent claims depending from multiply dependent claims for presentation in those jurisdictions where such dependencies are allowed as well as additional claims, which may be pursued during the examination of the application or a divisional thereof.

[0047] EE1. A method for the synthesis of a diethyl furoxan dicarboxylate (DFD) of formula (III):which method comprises:(i) mixing ethylnitroacetate with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the DFD is synthesized.EE2. The method of EE1, wherein the method is a one-pot method.EE3. The method of EE1, wherein the DFD is in oil form.EE4. The method of any one of EE1-EE3, wherein the method further comprises isolating DFD from the reaction mixture by decanting off an aqueous layer from an oily layer that comprises DFD.EE5. The method of EE1 or EE2, wherein the sodium nitrite is added dropwisely.EE6. The method of any one of EE1-EE5, wherein a purity of DFD in oil form is greater than about 96%.EE7. A one-pot method for the synthesis of a disubstituted furoxan of formula (I):wherein each Ri and R2 is independently selected from the group consisting of (Ci-Ce) alkyl, (C6-C12) aryl, (Cs-Cs) heteroaryl, ar(Ci-Ce)alkyl, (Ci-Ce) alkoxy, COR3, COOR3, nitro, cyano, amine, and halogen, wherein Ri and R2 can be optionally substituted;R3 is hydrogen, (Ci-Ce) alkyl, or (C6-C12) aryl; which method comprises:(i) mixing a compound of formula (II):R^^NO2(II) wherein R is Ri or R2, wherein Ri and R2 are as defined above, with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the disubstituted furoxan of formula (I) is synthesized in the one-pot method.EE8. The method of EE7, wherein Ri and R2 is the same.EE9. The method of EE8, wherein the sodium nitrite is added dropwisely.

[0048] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0049] The term "about," when referring to a number or a numerical value or range (including, for example, whole numbers, fractions, and percentages), means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error) and thus the numerical value or range can vary between 1% and 15% of the stated number or numerical range (e.g., + / - 5 % to 15% of the recited value, such as within 10%, within 5%, or within 1% of a stated value or stated limit of a range) provided that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result).

[0050] The term "substantially" can allow for a degree of variability in a value or range, for example, within 90%, within 95%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more of a stated value or of a stated limit of a range.

[0051] The terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. In addition, the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid the reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that particular section. The terms "including" and "having" are defined as comprising (i.e., open language).

[0052] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference.

[0053] It is intended that the scope of the present methods and apparatuses be defined by the following claims. However, it must be understood that this disclosure may be practiced otherwise than is specifically explained and illustrated without departing from its spirit or scope. It should be understood by those skilled in the art that various alternatives to the embodiments described herein may be employed in practicing the claims without departing from the spirit and scope as defined in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for the synthesis of a diethyl furoxan dicarboxylate (DFD) of formula (III):which method comprises:(i) mixing ethylnitroacetate with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the DFD is synthesized.

2. The method of claim 1, wherein the method is a one-pot method.

3. The method of claim 1, wherein the DFD is in oil form.

4. The method of any one of claims 1-3, wherein the method further comprises isolating DFD from the reaction mixture by decanting off an aqueous layer from an oily layer that comprises DFD.

5. The method of claim 1 or 2, wherein the sodium nitrite is added dropwisely.

6. The method of any one of claims 1-5, wherein a purity of DFD in oil form is greater than about 96%.

7. A one-pot method for the synthesis of a disubstituted furoxan of formula (I):wherein each Ri and R2 is independently selected from the group consisting of (Ci-Ce) alkyl, (C6-C12) aryl, (Cs-Cs) heteroaryl, ar(Ci-Ce)alkyl, (Ci-Ce) alkoxy, COR3, COOR3, nitro, cyano, amine, and halogen, wherein Ri and R2 can be optionally substituted;R3 is hydrogen, (Ci-Ce) alkyl, or (C6-C12) aryl; which method comprises:(i) mixing a compound of formula (II):R^^NO2(II) wherein R is Ri or R2, wherein Ri and R2 are as defined above, with an aqueous solution of nitric acid at 0 °C to obtain a reaction mixture; and(ii) adding sodium nitrite to the reaction mixture at a temperature from about 0 °C to about 5 °C followed by heating the reaction mixture, whereupon the disubstituted furoxan of formula (I) is synthesized in the one-pot method.

8. The method of claim 7, wherein Ri and R2 is the same.

9. The method of claim 7, wherein the sodium nitrite is added dropwisely.

Images