Preparation of sulfonamide herbicide process intermediates

Abstract

Provided are improved methods for preparing chemical precursors of sulfonyl chloride III, which are important intermediates in the preparation of formosan herbicides. Also provided are compounds of formula III, formula VII, and IV, wherein R 1 is C1-C6 alkyl, X is Cl or OH, Y is halogen, OH, or OR 2 , and R 2 It is a C1-C6 alkyl group.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Application Serial No. 62 / 785,353, filed on December 27, 2018, the entire disclosure of which is hereby expressly incorporated by reference.

[0002] The present disclosure includes novel methods, novel compounds, and methods of making such compounds. Such novel methods and compounds are useful intermediates for producing other useful compounds, such as herbicides, such as formosan. Background Art

[0003] Fensulfuron (I), a member of the triazolopyrimidine sulfonamide family, is a commercially available herbicide that provides control of many broadleaf weeds and grass weeds in cereal crops (e.g., wheat crops). The preparation of Fensulfuron has been described, for example, in International PCT Application Publication WO 2002036595A2 and U.S. Patent Application Publication No. 2005 / 0215570A1.

[0004]

[0005] In the conventional process for preparing formosulam (I), the last step may typically involve coupling an amine having formula II with a sulfonyl chloride having formula III:

[0006]

[0007] In such methods, sulfonyl chloride III can be prepared by converting 2-oxo-pyridine IIIa to 2-methoxypyridine IIIc via 3-chloropyridine IIIb. Sulfonyl chloride III can then be prepared by metallization / thiolation of IIIc with a mixture of lithium diisopropylamide (LDA) and elemental sulfur, followed by chloroxidation of the resulting lithium thiolate with chlorine / HCl to provide III.

[0008]

[0009] However, such conventional methods can be expensive, reduce profits, and in some cases may adversely affect the ability to use the produced formosulam in some markets.

[0010] Therefore, there is a need to reduce the production costs of formosulam in an efficient and economical manner. Furthermore, there is a need to be able to prepare formosulam in a manner that allows formosulam to be sold in currently restricted markets. Summary of the invention

[0011] The present disclosure provides various novel compounds and methods for making the same, which allow for novel and more cost-effective methods for preparing chemical precursors of sulfonyl chlorides III shown below by Formula III.

[0012]

[0013] Such compounds can be important intermediates in the preparation of herbicides such as formosan. Specifically, these precursors include compounds having the following formula IV, wherein Y is halogen, OH, or OCH 3 .

[0014]

[0015] Another aspect of the present disclosure includes novel intermediates produced by the described methods, for example, compounds having Formula VII:

[0016] R 1 =C 1 -C 6 alkyl

[0017] In some aspects, a method is provided, comprising: combining acetonitrile, a base, and a compound having Formula V or a compound having Formula VI

[0018]

[0019] To form a compound having formula VII,

[0020]

[0021] Where R 1 It is C 1 -C 6 In some aspects, the method may further include combining the compound of formula VII with at least one of an acid, an alcohol, water, an alkoxide, a dehydrating halogenating agent, or a combination thereof to form a compound of formula IV:

[0022]

[0023] Where Y is halogen, OH, or OR 2 , and R 2 It is C 1 -C 6 In various aspects, the acid may be selected from the group consisting of: 2 SO 4 , HCl, HBr, or HI, and mixtures thereof. In various aspects, the alcohol is C 1 -C6 In various aspects, the alkoxide is C 1 -C 6 Sodium alkoxide or C 1 -C 6 Potassium alkoxide (eg sodium methoxide or potassium methoxide).

[0024] Exemplary dehydrating halogenating agents include SOCl 2 , SOBr 2 POCl 3 POBr 3 、PCl 3 , PBr 3 、PCl 5 , PBr 5 , oxalyl chloride, or a mixture thereof.

[0025] Various aspects also include methods wherein the combining comprises combining the acid and the alcohol simultaneously with the compound of formula VII to provide a compound of formula IV, wherein Y is OR 2 , and R 2 It is C 1 -C 6 alkyl.

[0026] The methods also include aspects wherein the combining comprises simultaneously combining the acid and water with the compound of formula VII to provide the compound of formula IV, wherein Y is OH.

[0027] In some aspects, the method may include sequentially combining an acid that is HCl or HBr and then the alkoxide with the compound of formula VII to provide the compound of formula IV, wherein Y is OR 2 , where R 2 It is C 1 -C 6 alkyl.

[0028] Some aspects include sequentially combining the dehydrating halogenating agent and then the alkoxide with the compound of formula VII to provide the compound of formula IV, wherein Y is OR 2 , and R 2 It is C 1 -C 6 alkyl.

[0029] In some aspects, the combination can include the compound having formula IV, wherein Y is OH, and the dehydrohalogenating agent being thionyl chloride to provide the compound having formula IV, wherein Y is Cl.

[0030] In various aspects, some methods may include aspects in which the combination includes the compound of formula IV wherein Y is a halogen and the alkoxide being sodium methoxide or potassium methoxide to provide the compound of formula IV wherein Y is OCH 3 .

[0031] Various methods also include methods further comprising treating the compound of formula IV (wherein Y is OCH 3 ) is combined with a strong base and sulfur to provide a compound having formula IVb

[0032]

[0033] Some aspects may also include a method further comprising: 2 , HCl and water to provide a compound having formula III

[0034]

[0035] Various compounds may include Where R 1 It is C 1 -C 6 alkyl, and X is Cl or OH. DETAILED DESCRIPTION

[0036] Methods for preparing precursors of sulfonyl chlorides III are described, which are important intermediates in some methods for preparing formolybdate herbicides. Specifically, compounds of formula IV, wherein Y has the formula halogen, OH or OCH 3 , can be prepared by the methods described herein.

[0037]

[0038] Where Y = halogen, OH, or OCH 3 ;

[0039] As shown in Schemes 1 and 2, these methods include the following chemical process steps: (1) converting a compound of formula V or VI to a nitrile of formula VII, and (2) converting VII to a compound of formula IV (wherein Y is halogen, OH or OCH 3 ), and these one or more reactants can be selected from reactants A, B, C, D or E, which include acids (A), alcohols (B), water (C), alcohol salts (D), or dehydrating halogenating agents (E), and combinations thereof.

[0040] Scenario 1:

[0041]

[0042] Where R 1 It is C 1 -C 6 Alkyl, and X is Cl or OH

[0043] Scenario 2:

[0044]

[0045] Where Y is halogen, OH, or OCH 3

[0046] I. Definitions

[0047] As used herein, the term "halo" or "halogen" may be understood to include one or more of F, Cl, Br, and I.

[0048] As used herein, the term "aryl" and derivative terms such as aryloxy are understood to include groups that include monovalent aromatic carbocyclic groups containing 6 to 14 carbon atoms. Aryl groups may include a single ring or multiple fused rings. In some aspects, aryl groups include C 6 -C 10 Aryl. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some aspects, aryl can be phenyl, indanyl, or naphthyl. The term "heteroaryl" and derivative terms such as "heteroaryloxy" refer to a 5- or 6-membered aromatic ring containing one or more heteroatoms (i.e., N, O, or S); these heteroaromatic rings can be fused with other aromatic systems. In some aspects, heteroaryl can be pyridyl, pyrimidinyl, or triazinyl.

[0049] The aryl or heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, amino, halo, hydroxy, nitro, cyano, formyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy, C 1 -C 6 Acyl, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylsulfinyl, C 1 -C 6Alkylsulfonyl, C 1 -C 10 Alkoxycarbonyl, C 1 -C 6 Carbamoyl, hydroxycarbonyl, C 1 -C 6 Alkylcarbonyl, aminocarbonyl, C 1 -C 6 Alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. Preferred substituents include halogen, C 1 -C 4 Alkyl, C 1 -C 10 Alkoxycarbonyl and C 1 -C 4 Halogenated alkyl.

[0050] II. Preparation of Nitrile VII

[0051] For preparing compounds of formula IV (wherein Y is halogen, OH, or OCH 3 ) comprises converting a compound of formula V or VI into a nitrile of formula VII by reaction of V or VI with a lithium anion of acetonitrile (prepared from acetonitrile and a base), as shown in Scheme 3. Bases used in this reaction step include, but are not limited to, organolithium reagents such as n-butyllithium, sec-butyllithium, lithium diisopropylamide (LDA), and lithium or sodium hexamethyldisilazane (LHMDS or NaHMDS). Other bases such as sodium and potassium tert-butoxide (Na-tBuO and K-tBuO), tert-amyl alkoxide may also be used. The reaction of V with lithium acetonitrile has been disclosed in U.S. Pat. No. 8,063,226, the disclosure of which is incorporated herein by reference in its entirety, while the following preparation of VII (X=Cl) using VI has not been previously disclosed.

[0052] Scenario 3:

[0053]

[0054] Where R 1 It is C 1 -C 6 Alkyl and X is Cl or OH;

[0055] Compound VI can be prepared by the following method as described in International PCT Patent Application Publication No. WO 2002053518.

[0056]

[0057] The process step of preparing VII can be carried out in a solvent such as, but not limited to, ether solvents like THF (tetrahydrofuran), DME (1,2-dimethoxyethane), 2-methyl-THF, diethyl ether, dioxane, and mixtures thereof, and mixtures of these solvents with hydrocarbon solvents such as pentane, hexane, cyclohexane, toluene, etc. The temperature range for carrying out this process step can be in the range of about 25°C to about -80°C, about 0°C to about -80°C, about 25°C to about -70°C, or about 0°C to about -70°C, and the reaction can be carried out in a time period of about 1 hour to about 72 hours, about 1 hour to about 48 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, about 1 hour to about 6 hours, or about 1 / 2 hour to about 2 hours.

[0058] From about 1.0 to about 1.5, from about 1.0 to 1.4, from about 1.0 to 1.3, from about 1.0 to 1.2, or from about 1.0 to 1.1 molar equivalents of base can be used in the process to prepare VII.

[0059] III. Preparation of pyridine IV

[0060] The second step of the process for preparing a compound of formula IV comprises reacting a compound of formula VII (wherein R 1 It is C 1 -C 6 alkyl and X is Cl or OH) is converted to a compound having formula IV by treatment with a reactant or combination of reactants, as shown in Scheme 4. The reactant or combination of reactants used may preferably include a reactant that promotes the cyclization of the nitrile VII to the pyridine IV.

[0061] Solution 4:

[0062]

[0063] Where Y is halogen, OH, or OCH 3

[0064] Table 1 below lists a number of reactants that can be used for the transformations shown in Scheme 4. Reactants A (acids) or E (dehydrohalogenating agents) readily promote the cyclization of VII to IV, however, reactants B, C, or D, alone or in combination, do not readily promote the cyclization of VII to IV. However, when reactants B, C, or D are used in combination with reactants A or B, either simultaneously (mixed together before addition to VII) or sequentially (added separately to VII), then cyclization of nitrile VII to pyridine IV will occur.

[0065] Table 1 : Description of reactants AE

[0066]

[0067] In one aspect of proceeding in a simultaneous manner, a mixture containing an acid and an alcohol can be combined with compound VII to provide compound IV, wherein X is Cl or OH, R 1 It is C 1 -C 6 Alkyl, and R 2 It is C 1 -C 6 This aspect is demonstrated by the following reaction:

[0068]

[0069] In another aspect of proceeding in a simultaneous manner, a mixture containing an acid and water can be combined with compound VII to provide compound IV, wherein X is Cl or OH, and R 1 It is C 1 -C 6 This aspect is demonstrated by the following reaction:

[0070]

[0071] In aspects proceeding in a sequential manner, anhydrous acid HY (Y is Cl or Br) can be combined with compound VII to provide compound IV (wherein Y is Cl or Br), which can then be reacted with alkoxide MOR 2 (M is Na or K) to provide compound IV, wherein R 2 It is C 1 -C 6 This aspect is demonstrated by the following reaction:

[0072]

[0073] In another aspect of the sequential method, the dehydrating halogenating agent (SOY 2 , POY 3 , PY 3 , or PY 5 ) can be combined with compound VII to provide compound IV (wherein Y is Cl or Br), which can then be further reacted with an alkoxide MOR 2 (M is Na or K) to provide compound IV, wherein R 2 It is C 1 -C 6 This aspect is demonstrated by the following reaction:

[0074]

[0075] Solvents that may be suitable for preparing substituted pyridines of Formula IV from compounds of Formula VII include, but are not limited to, acetonitrile (ACN), N,N-dimethylformamide (DMF), dichloromethane (DCM), 1,2-dichloroethane (DCE), tetrahydrofuran (THF), 2-methyl-THF, dioxane, cyclopentyl methyl ether, toluene, one or more xylenes, methanol, or ethanol, and mixtures thereof.

[0076] In some aspects, one or more of the reactants can be used as a solvent in the preparation of the substituted pyridine having Formula IV.

[0077] The preparation of a compound of formula IV from a compound of formula VII can be carried out at a temperature of at least about 0° C., at least about 10° C., at least about 20° C., at least about 25° C., at least about 30° C., at least about 40° C., at least about 50° C., at least about 60° C., at least about 70° C., at least about 80° C., at least about 90° C., or at least about 100° C. In some aspects, the preparation of a compound of formula IV from a compound of formula VII can be carried out at a temperature of about 0° C. to about 50° C., about 10° C. to about 50° C., about 25° C. to about 50° C., about 25° C. to about 60° C., about 25° C. to about 70° C., about 25° C. to about 80° C., about 25° C. to about 90° C., about 25° C. to about 100° C., about 25° C. to about 125° C., or about 25° C. to about 150° C.

[0078] IV. Preparation of 2-alkoxy-4-(trifluoromethyl)pyridine-3-sulfonyl halide IIId

[0079] Using previously disclosed methods, compounds of formula IV can then be converted to sulfonyl halides of formula IIId, wherein R 2 It is C 1 -C 6 alkyl, and Y is C1 or Br. This transformation is shown in Scheme 5 and involves treating compound IV with a strong base and sulfur, and then treating with a hydrohalic acid HY, a halogen Y 2 The unisolated lithium-sulfur intermediate is treated with a mixture of , and water (wherein Y is Cl or Br) to provide a compound having formula IIId, wherein Y is Cl or Br, and R 2 It is C 1 -C 6 alkyl.

[0080] Solution 5:

[0081]

[0082] In one aspect of preparing a compound of Formula IIId, Y 2 It is Cl 2 (chlorine; Y = Cl), the hydrohalic acid HY is HCl, and R2 Yes CH 3 (eg a compound of formula III).

[0083] In another aspect of preparing the compound of formula IIId, a water-immiscible co-solvent may be included. This co-solvent may be selected from dichloromethane, 1,2-dichloroethane, chlorobenzene, or 1,2-dichlorobenzene, or a mixture thereof.

[0084] In another aspect of preparing compounds of formula IIId, a phase transfer catalyst may be included in the preparation. Suitable phase transfer catalysts may include tetraalkylammonium halides such as, for example, methyltributylammonium chloride.

[0085] IV. Isolation / Purification

[0086] After preparing the compound with formula IV and VII by the method described herein, the product can be isolated by using standard separation and purification techniques. For example, the crude product can be separated using standard methods as described herein and purified by crystallization using a single solvent or a mixture of two or more solvents. In addition, the crude product can be purified by washing it with a single component, a two component or a three component solvent mixture or stirring it in a single component, a two component or a three component solvent mixture. In one aspect, the crude product can be purified by stirring it in an aqueous alcohol solvent mixture.

[0087] The crude product may also be purified by dissolving it in one solvent to form a solution, and then adding a second solvent to the solution to cause the product to crystallize out from the mixture of the two solvents.

[0088] The crude product can also be purified by distillation under vacuum.

[0089] The following examples are presented to illustrate various aspects of the methods and compositions described herein.

[0090] Examples

[0091] Example 1a. Preparation of 2,2,4-trichloro-4-ethoxy-1,1,1-trifluorobutane

[0092]

[0093] 1,1,1-trichloro-2,2,2-trifluoroethane (41.60 g, 220.02 mmol) and n-1-(vinyloxy)butane (9.8 g, 97.84 mmol) were charged into a three-neck 100 mL round-bottom flask. The mixture was heated to 45 ° C, followed by the addition of azobisisobutyronitrile (AIBN) (0.186 g, 1.13 mmol; dissolved immediately). The reaction mixture was heated at 45 ° C for 10 min and then the temperature was heated to 50 ° C. The reaction mixture was heated for 4 h, after which the NMR of the aliquot indicated a conversion of about 50%. Additional AIBN (0.28 g) and 1,1,1-trichloro-2,2,2-trifluoroethane (17 g) were added and stirring was continued at 50 ° C overnight. Excess starting material was removed by distillation to give the desired product (17 g, 60% yield) as a clear light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ5.97 (dd, J=7.7, 2.4 Hz, 1H), 3.95 (dt, J=9.3, 6.4 Hz, 1H), 3.56 (dt, J=9.3, 6.5 Hz, 1H), 3.12 (dd, J=15.2, 7.7 Hz, 1H), 3.01 (dd, J=15.2, 2.4 Hz, 1H), 1.71-1.57 (m, 2H), 1.50-1.32 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ 126.14, 123.33, 120.53, 93.42, 81.70, 81.35, 71.04, 49.98, 30.80, 19.14, 13.61.

[0094] Example 1b. Preparation of (E)-5-ethoxy-3-hydroxy-3-(trifluoromethyl)pent-4-enenitrile

[0095]

[0096] 50mL 1,2-dimethoxyethane (DME) was loaded into a 125mL three-necked reactor equipped with a magnetic stirring bar and a nitrogen inlet, stirring was started, and cooled to -72°C by a dry ice / isopropanol bath. 12.49mL (7.98 grams) of 2.5 moles of n-butyl lithium solution (23.11wt%) in hexane were added to the cooled mixture and allowed to rebalance to -72°C. 1.282 grams (1.631mL) of acetonitrile were measured and 90 minutes were allowed to form anions completely. In a separate vial, 5g of compound Va was diluted with 10mL DME and the mixture was measured via a syringe. The mixture was stirred at -72°C for 1h, and then the bath was removed to allow the mixture to warm to room temperature. With H 2 SO 4The mixture was quenched with a solution (1.677 grams of 97wt% sulfuric acid in 5mL deionized water). Toluene (100mL) was then added to the mixture and stirred. The biphasic mixture was transferred to a 500mL separatory funnel and the aqueous phase was discharged. The aqueous phase was extracted twice with 20mL of partial toluene. The organic solution was dried over magnesium sulfate, filtered and concentrated to a brown translucent oil. 1H NMR (400MHz, chloroform-d) δ 6.88 (d, J = 12.7Hz, 1H), 4.89 (d, J = 12.7Hz, 1H), 3.84 (q, J = 7.0Hz, 2H), 2.92 (d, J = 16.7Hz, 1H), 2.78 (d, J = 16.6Hz, 1H), 2.36 (s, 1H), 1.33 (t, J = 7.0Hz, 3H).

[0097] Example 1c. Preparation of (E)-3-chloro-5-ethoxy-3-(trifluoromethyl)pent-4-enenitrile

[0098]

[0099] A 50mL three-necked round bottom flask was equipped with a magnetic stirring bar, a thermocouple sleeve, a nitrogen supply, a diaphragm, and a 1 / 8th inch compression fitting. 12mL of anhydrous DME was added through the diaphragm after the container was inerted. The reactor was immersed in an IPA-dry ice bath, and the internal temperature of the reactor was allowed to reach -73°C. Using a gas-tight syringe, 1.17g of 2.5 molar n-butyl lithium solution in hexane was injected through the diaphragm. 0.172 grams of acetonitrile was added in a similar manner, producing a dark yellow and clear solution in the reactor. Exothermic heat was noted after acetonitrile was added, and for larger volumes, a syringe pump should be used. The mixture was allowed to stir for 30 minutes to ensure complete anion formation. 0.172 grams of 2,2,4-trichloro-4-ethoxy-1,1,1-trifluorobutane was added in a separate vial and then diluted with 3mL of anhydrous DME. 2,2,4-trichloro-4-ethoxy-1,1,1-trifluorobutane solution was drawn into a 5mL syringe and loaded by a syringe pump at a rate of 0.15mL / min through a 1 / 8 inch line. The color changed from yellow and clear to dark brown / opaque. The initial temperature was -71.5°C, and the final temperature after the addition of 2,2,4-trichloro-4-ethoxy-1,1,1-trifluorobutane was -68.9°C. The mixture was stirred at about -72°C for 30min, and then the bath was removed to allow the mixture to warm to 0°C. The mixture was then quenched with 1.11 grams of saturated aqueous ammonium chloride solution by adding it to the reactor at 0°C. The ammonium chloride-quenched mixture was allowed to stand overnight before analysis. The quenched reaction mixture was absorbed in toluene and washed with deionized water in a separatory funnel. Analysis of the crude material by NMR showed the presence of the desired product.

[0100] Example 2a. Preparation of 2-chloro-4-(trifluoromethyl)pyridine

[0101]

[0102] In a 35 mL vial with a septum cap and a magnetic stir bar was added 1 gram of (E)-5-ethoxy-3-hydroxy-3-(trifluoromethyl)pent-4-enenitrile in toluene followed by 2 g of neat thionyl chloride. The mixture was placed under nitrogen. The mixture was clear and orange. The vial and its contents were heated to 50° C. for 12 hours while stirring. After 12 hours of heating, the mixture was stirred by 1 H-NMR and 19 The contents of the vials were analyzed by F-NMR spectroscopy. The expected product standards were included in 19 F-NMR analysis was used for comparison. 1 H-NMR analysis showed some impurities in the reaction mixture, and 19 F-NMR analysis showed conversion of the cyclized precursor to the desired 2-chloro-4-(trifluoromethyl)pyridine. Non-optimized yield of crude material: about 60%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.58 (d, J = 5.0 Hz, 1H), 7.57 (s, 1H), 7.48-7.41 (m, 1H).

[0103] Example 2b. Preparation of 2-methoxy-4-(trifluoromethyl)pyridine

[0104]

[0105] Example 2c. Preparation of 2-hydroxy-4-(trifluoromethyl)pyridine

[0106]

[0107] The compositions and methods of the claims are not limited by the scope of the specific compositions and methods described herein (which are intended as illustrations of several aspects of the claims), and any compositions and methods that are functionally equivalent are intended to fall within the scope of the present claims. Various modifications to these compositions and methods, in addition to those shown and described herein, are also intended to fall within the scope of the appended claims. Further, although only certain representative composition materials and method steps disclosed herein are specifically described, other combinations of these composition materials and method steps are intended to fall within the scope of the appended claims even if not specifically described. Therefore, a combination of steps, elements, components or elements may be explicitly mentioned herein; however, other combinations of steps, elements, components and elements are included even if not explicitly stated. As used herein, the term "comprising" and its variations are used synonymously with the term "including" and its variations, and are open, non-limiting terms. Although the terms "comprising" and "including" have been used herein to describe various aspects, the terms "consisting essentially of" and "consisting of" may also be used instead of "comprising" and "including" to provide more specific aspects of the present invention and are also disclosed.

Claims

1. A method comprising: Acetonitrile, a base, and a compound having formula VI are reacted To form a compound having formula VII, Where R 1 is C1-C6 alkyl, and X is Cl.

2. The method of claim 1, further comprising: The compound of formula VII is reacted with at least one of the following as a reactant: a) an acid selected from HCl, HBr, HI or a mixture thereof; b) a dehydrating halogenating agent, wherein the dehydrating halogenating agent is selected from SOCl2, SOBr2, POCl3, POBr3, PCl3, PBr3, PCl5, PBr5, oxalyl chloride or a mixture thereof; or c) a combination of said acid and said dehydrating halogenating agent, To form a compound having formula IV: wherein Y is a halogen.

3. The method of claim 2, wherein: In the case where the acid is selected, the method further comprises: adding at least one of the following: a) alcohol, wherein the alcohol is selected from C1-C6 alcohol; b) water; or c) combinations thereof, Simultaneously react with the reactant of claim 2 to form a compound having the formula Where R 2 It is a C1-C6 alkyl group.

4. The method of claim 3, wherein: The alcohol is methanol.

5. The method of claim 2, wherein: In the case where the acid is selected, the method further comprises: reacting the alkoxide with the reactant of claim 2 sequentially to form a compound having the formula Where R 2 is a C1-C6 alkyl group, The alkoxide is selected from sodium C1-C6 alkoxide, potassium C1-C6 alkoxide or a combination thereof.

6. The method of claim 5, wherein: The alkoxide is sodium methoxide or potassium methoxide.

7. The method of claim 2, wherein: In the case where the dehydrating halogenating agent is selected, the method further comprises: reacting the alkoxide with the reactant of claim 2 sequentially to form a compound having the formula Where R 2 is a C1-C6 alkyl group, The alkoxide is selected from sodium C1-C6 alkoxide or potassium C1-C6 alkoxide.

8. The method of claim 2, wherein: The dehydrohalogenating agent is thionyl chloride to provide the compound of formula IV, wherein Y is Cl.

9. The method of claim 7, wherein: The sequential reaction involves the alkoxide as sodium methoxide or potassium methoxide to provide a compound having the formula 10. A compound having the following structure: Where R 1 is C1-C6 alkyl, and X is Cl.

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