Synthesis of heterocyclic compounds from carboxamides and carboxamide derivatives with haloacanols.

Abstract

The present invention provides a method for synthesizing a variety of compounds by the reaction of carboxamides or carboxamide derivatives with a variety of substituted or unsubstituted haloalkanols in a one-step, single-pot reaction scheme. Preferably, but not exclusively, the reaction proceeds in the absence of any solvents, catalysts, bases, or additional reagents.

Description

[Technical Field]

[0001] The present invention relates to a method for the synthesis of heterocyclic compounds by the reaction of carboxamides or carboxamide derivatives with various haloalkanols. In particular, but not exclusively, the present invention relates to the synthesis of compounds of formula (I), (II), (III), (IV), (V) and (VI) by the reaction of carboxamides or carboxamide derivatives with various substituted or unsubstituted haloalkanols in a one-step, single-pot reaction scheme. [Background technology]

[0002] Heterocyclic compounds, such as oxazolines, oxazines, oxadiazines, and dioxazines, play important roles in several applications in areas such as biomedical chemistry and biomaterials, drug development, polymer chemistry, and agricultural chemistry, to name a few.

[0003] Current methods for synthesizing these heterocyclic compounds each suffer from one or more of the following drawbacks: the use of undesirable organic solvents, the use of catalysts, high temperatures, high pressures, low yields and / or selectivities, multi-step reaction mechanisms, and other generally undesirable reaction conditions.

[0004] For example, oxazoline is a five-membered heterocyclic compound that has been known since the 19th century. 2-Oxazoline is also well known for its crucial importance in organic synthesis as a functional group, protecting groups for hydroxyl, amine, and carboxylic acid compounds, and as a ligand in asymmetric catalysis. 2-Oxazoline also has a wide range of applications in pharmaceutical and polymer chemistry. Recently, 2-oxazoline polymers have emerged as efficient macromolecules in the fields of targeted drug delivery and drug development in various therapeutic areas. However, despite the obvious importance of this heterocyclic compound, known synthetic approaches are not entirely satisfactory.

[0005] For example, in one known method, synthesis proceeds via the reaction of a carboxylic acid with a 1,2-alkanolamine to give an intermediate N-(β-hydroxyethyl)-carboxamide, followed by dehydration and cyclization. Another known method proceeds via the preparation of an N-(β-haloethyl)-carboxamide followed by dehydrohalogenation. These processes involve two steps: carboxamide formation and subsequent cyclization. In these methods, the intermediate carboxamide is synthesized from the reaction of a nitrile, a carboxylic acid, a lower alkyl ester of a carboxylic acid, or its acid chloride derivative, with a 1,2-alkanolamine or a 2-haloethanol. Alternatively, cyclization can occur via dehydration cyclization or cyclodehydrohalogenation using dehydrating agents (including sulfuric acid, aluminum oxide, iron oxide, SOCl2, PPh3 / CCl4, TsCl / Et3N, carbodiimides, PPh3-DEAD, or PPh3-DDQ) or metal catalysts (including cadmium, organic / inorganic zinc salts, or iron compounds). Cyclodehydrohalogenation can also occur using inorganic bases such as NaCO3, NaOH, and / or KOH in the presence of a solvent.

[0006] It is therefore an object of the present invention to address at least some of the shortcomings of methods known to those skilled in the art for the synthesis of various heterocyclic compounds from the reaction of carboxamides or derivatives thereof with various haloakanols. Summary of the Invention

[0007] According to a first aspect of the present invention, a compound of formula (I) [ka] Formula (I) The method comprises the steps of: [ka] Formula (Ia) or a carboxamide derivative represented by formula (Ib) [ka] Formula (Ib) with a substituted alkanol of the formula During the ceremony, n is 0, 1 or 2; R is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1 is selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 2 is selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 3 and R 3' are independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; X is hydrogen, NH2, OH, SH, NHR 4 selected from the group consisting of: X 1 , NH, O, S, NR 4 and a direct bond; R 4is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and Z is siloxy, methanesulfonate, para-toluenesulfonate, or halogen; The method comprises the steps of placing a carboxamide or carboxamide derivative and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of about 100° C. to about 160° C. to obtain a compound of formula (I), A method is provided.

[0008] According to a second aspect of the present invention, a compound of formula (II) [ka] Formula (II) The method for synthesizing a compound of formula (IIa) [ka] Formula (IIa) or a carboxamide derivative represented by formula (IIb) [ka] Formula (IIb) with a substituted alkanol of the formula During the ceremony, X is hydrogen, NH2, NHR 4 , OH and SH; X 1 , NH, O, NR 4 and S; R 1 is selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R2 is selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; and R 4 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The method comprises the steps of placing a carboxamide or carboxamide derivative and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of about 100° C. to about 160° C. to obtain a compound of formula (II), A method is provided.

[0009] According to a third aspect of the present invention, a compound of formula (III) [ka] Formula (III) The method comprises the steps of: [ka] Formula (IIIa) or a carboxamide derivative represented by formula (IIIb) [ka] Formula (IIIb) with a substituted alkanol of the formula During the ceremony, R 1 is selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 2 is selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; and The method comprises the steps of placing a carboxamide and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of about 100° C. to about 160° C. to obtain a compound of formula (III), A method is provided.

[0010] According to a further aspect of the present invention, a compound of formula (IV) [ka] Formula (IV) The method comprises the steps of: [ka] Formula (IVa) or a carboxamide derivative represented by formula (IVb) [ka] Formula (IVb) with a substituted alkanol of the formula During the ceremony, R 1 is selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 2 is selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 3 and R 3' are independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; and The method comprises the steps of placing a carboxamide and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of about 100° C. to about 160° C. to obtain a compound of formula (IV), A method is provided.

[0011] According to a further aspect of the present invention, a compound of formula (V) [ka] Formula (V) The method comprises the steps of: [ka] Formula (Va) with a hydrazide or hydrazide derivative represented by formula (Vb) [ka] Formula (Vb) with a substituted alkanol of the formula During the ceremony, R 1 is selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 2 is selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; and The method comprises the steps of placing a carboxamide and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of about 100° C. to about 160° C. to obtain a compound of formula (V), A method is provided.

[0012] According to a further aspect of the present invention, a compound of formula (VI) [ka] Formula (VI) 1. A method for synthesizing a compound of formula (VIa): [ka] Formula (VIa) with an N-hydroxycarboxamide or hydroxycarboxamide derivative of formula (VIb) [ka] Formula (VIb) with a substituted alkanol of the formula During the ceremony, R 1 is selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 2 is selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; and The method comprises the steps of placing a carboxamide and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of about 100° C. to about 160° C. to obtain a compound of formula (VI), A method is provided.

[0013] In one embodiment, R 1 , R 2 , R 3 and R 3' are independently selected from the group consisting of H, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, or optionally substituted straight or branched chain alkyl.

[0014] In one embodiment, R 1 , R 2 , R 3 and R 3' are independently optionally substituted straight or branched chain C-C 10 alkyl.

[0015] In a preferred embodiment, R is an optionally substituted straight or branched chain C-C 10 Alkyl, optionally substituted straight or branched chain C-C 10 Alkenyl, optionally substituted straight or branched chain C1-C 10It is selected from the group consisting of alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C3-C6 aryl, and optionally substituted C3-C6 heteroaryl.

[0016] In a preferred embodiment, the reaction proceeds in the absence of any solvents, catalysts, bases or other reagents.

[0017] In one embodiment, R is a substituted straight or branched chain C-C alkyl group substituted with one or more groups selected from the group consisting of halogen, CN, or OH. 10 It is alkyl.

[0018] In another embodiment, R is a substituted straight or branched chain C-C alkyl group substituted with one or more groups selected from the group consisting of halogen, CN, or OH. 10 It is alkenyl.

[0019] In another embodiment, R is a substituted straight or branched chain C-C alkyl group substituted with one or more groups selected from the group consisting of halogen, CN, or OH. 10 It is an alkoxy.

[0020] In yet another embodiment, R is independently a straight or branched chain C-C 10 Alkoxy, halogen, NO2, optionally substituted straight or branched chain C1-C 10 and substituted C3-C6 cycloalkyl, substituted C3-C6 heterocycloalkyl, substituted C3-C6 aryl, or substituted C3-C6 heteroaryl, each of which is substituted with one or more groups selected from the group consisting of alkyl.

[0021] In yet another embodiment, R is halogen, NO, a straight or branched chain C-C 10 Alkoxy, optionally substituted straight or branched chain C1-C 10 and substituted C3-C6 aryl, substituted with one or more groups selected from the group consisting of alkyl.

[0022] In a particularly preferred embodiment, R is: [ka] is a group selected from the group consisting of:

[0023] In a particularly preferred embodiment, the compound of formula (I) is: 2-phenyl-4,5-dihydrooxazole; 2-(prop-1-en-2-yl)-4,5-dihydrooxazole; 2-Propyl-4,5-dihydrooxazole; 2-(chloromethyl)-4,5-dihydrooxazole; 2-(4,5-dihydrooxazol-2-yl)acetonitrile; 2-Isopropyl-4,5-dihydrooxazole; 2-(tert-butyl)-4,5-dihydrooxazole; 2-butyl-4,5-dihydrooxazole; 2-(trichloromethyl)-4,5-dihydrooxazole; 2-Cyclohexyl-2,5-dihydrooxazole; 2-(2-iodophenyl)-4,5-dihydrooxazole; 2-(phenoxymethyl)-4,5-dihydrooxazole; 2-(thiophen-2-yl)-4,5-dihydrooxazole; 2-(2-fluorophenyl)-4,5-dihydrooxazole; 2-(2-nitrophenyl)-4,5-dihydrooxazole; 2-(2,5-dibromophenyl)-4,5-dihydrooxazole; 2-(2-bromo-5-methoxyphenyl)-4,5-dihydrooxazole; 2-(2-bromo-4-methylphenyl)-4,5-dihydrooxazole; 2-(2-bromo-3-methylphenyl)-4,5-dihydrooxazole; 5-methyl-2-phenyl-4,5-dihydrooxazole; 2-phenyl-5,6-dihydro-4H-1,3-oxazine; 2-(prop-1-en-2-yl)-5,6-dihydro-4H-1,3-oxazine; 2-Propyl-5,6-dihydro-4H-1,3-oxazine; 2-(chloromethyl)-5,6-dihydro-4H-1,3-oxazine; 2-Isopropyl-5,6-dihydro-4H-1,3-oxazine; 2-Isobutyl-5,6-dihydro-4H-1,3-oxazine; 2-Butyl-5,6-dihydro-4H-1,3-oxazine; 2-Cyclohexyl-5,6-dihydro-4H-1,3-oxazine; 2-(2-iodophenyl)-5,6-dihydro-4H-1,3-oxazine; 2-(2-bromophenyl)-5,6-dihydro-4H-1,3-oxazine; 2-(phenoxymethyl)-5,6-dihydro-4H-1,3-oxazine; 2-(furan-2-yl)-5,6-dihydro-4H-1,3-oxazine; 2-(thiophen-2-yl)-5,6-dihydro-4H-1,3-oxazine; 3-phenyl-5,6-dihydro-1,4,2-dioxazine; and 2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine The compound is selected from the group consisting of: [Brief explanation of the drawings]

[0024] The invention will now be described in more detail with reference to the following non-limiting embodiments and figures.

[0025] [Figure 1] A proposed reaction mechanism involving simultaneous dehydrohalogenation and cyclodehydration is shown for compounds synthesized according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which some non-limiting embodiments of the invention are shown.

[0027] The invention described below should not be construed as limited to the particular embodiments disclosed, as slight modifications and other embodiments are intended to be included within the scope of the invention.

[0028] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0029] As used in this application throughout this specification and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly indicates otherwise.

[0030] The terms and phrases used herein are for purposes of description and should not be regarded as limiting. As used herein, the use of the terms "comprising," "containing," "having," "including," and variations thereof, is meant to encompass the items listed thereafter and equivalents thereof, as well as additional items.

[0031] When describing the present invention, the following terms, if present, have the following meanings, unless otherwise stated. It should also be understood that, as described herein, any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within their scope as provided below. In this regard, unless otherwise stated, the term "substituted" shall be defined as provided below. It should further be understood that the terms "group" and "radical" can be considered interchangeable as used herein.

[0032] "Alkyl" means a straight or branched chain aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 10 carbon atoms. More particular are lower alkyls having 1 to 8 carbon atoms. Even more particular groups have 1 to 6 carbon atoms. Exemplary straight chain groups include methyl, ethyl, n-propyl, and n-butyl. Branched means that one or more alkyl groups, such as methyl, ethyl, propyl, or butyl, are attached to a straight chain alkyl group. Exemplary branched groups include isopropyl and iso-butyl.

[0033] "Alkoxy" is -OR x refers to a group, wherein R x is alkyl having the specified number of carbon atoms. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0034] "Alkylene" refers to a divalent alkene radical group having the specified number of carbon atoms, particularly 1 to 10 carbon atoms, and more particularly 1 to 8 carbon atoms, which may be straight or branched. This term is exemplified by groups such as methylene (-CH-), ethylene (-CH-CH-), or -CH(CH)-.

[0035] "Alkenyl" refers to a monovalent olefinically unsaturated hydrocarbon group having the specified number of carbon atoms. Particular alkenyls have from 2 to 10 carbon atoms, more particularly from 2 to 8 carbon atoms, can be straight or branched, and have at least one, and especially two or two, sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH), n-propenyl (-CHCH=CH), isopropenyl (-C(CH)=CH), and the like.

[0036] "Amino" refers to the radical -NH2.

[0037] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from one carbon atom of a parent aromatic ring system. In particular, aryl refers to a monocyclic or polycyclic aromatic ring structure having the specified number of ring atoms. Specifically, it includes groups containing 5 to 10 ring members. When an aryl group is a monocyclic ring system, it preferably contains 5 to 8 carbon atoms. In particular, aryl groups include phenyl and naphthyl. The terms "phenyl" and "Ph" are used interchangeably herein unless otherwise specified.

[0038] "Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic hydrocarbyl ring structure having the specified number of ring atoms. Cycloalkyls can have from 3 to 10 carbon atoms, particularly from 3 to 8 carbon atoms. Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0039] "Cyano" refers to the radical -CN.

[0040] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0041] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocycloalkyl; aryl, e.g., heteroaryl, etc., having 1 to 4, particularly 1, 2, or 3, heteroatoms, more typically 1 or 2, e.g., 1 heteroatom.

[0042] "Heteroaryl" refers to a monocyclic or fused polycyclic aromatic structure containing one or more heteroatoms independently selected from O, N, and S, and having a specified number of ring atoms. In particular, aromatic ring structures contain 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings, or fused 5- or 6-membered rings, or two fused 6-membered rings, or, as a further example, fused bicyclic ring structures formed from two fused 5-membered rings. Each ring can contain up to four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to four heteroatoms, more typically up to three heteroatoms, and more usually up to two, e.g., one heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms on the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in the heteroaryl ring, including any amino group substituents on the ring, is less than five.

[0043] As used herein, the term "heterocycloalkyl" refers to a stable, monocyclic or polycyclic, non-aromatic ring structure containing one or more heteroatoms independently selected from O, N, and S. The non-aromatic ring structure may contain 3 to 10 ring members, particularly 3 to 8 ring members. A fused heterocyclic ring system may contain carbocyclic rings and need only contain one heterocyclic ring. As used herein, the term "heterocycloalkenyl" refers to a "heterocycloalkyl" in which one bond in the ring has been reduced, thus the ring contains a double bond.

[0044] "Hydroxyl" refers to the radical --OH, while "oxo" refers to the radical =O.

[0045] "Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0046] "Sulfo" or "sulfonic acid" refers to a radical such as -SO3H. "Thiol" refers to the group -SH.

[0047] As used herein, the term "substituted with one or more" refers to one to four substituents. In one embodiment, it refers to one to three substituents. In a further embodiment, it refers to one or two substituents. In yet a further embodiment, it refers to one substituent.

[0048] When referring to ranges herein (e.g., C 1-10 alkyl), recitation of ranges should be considered to represent each member of the range.

[0049] The present invention relates broadly to a method for the synthesis of heterocyclic compounds by the reaction of carboxamides or carboxamide derivatives with various substituted or unsubstituted haloalkanols.

[0050] More specifically, the present invention relates to the synthesis of compounds of formulas (I), (II), (III), (IV), (V), and (VI) described herein by the reaction of carboxamides or carboxamide derivatives with various substituted or unsubstituted haloalkanols in a one-step, single-pot reaction scheme. Preferably, the reaction proceeds in the absence of any solvent, catalyst, base, or additional reagents.

[0051] The present inventors have surprisingly developed a one-step, single-pot reaction of carboxamides and carboxamide derivatives with various substituted or unsubstituted haloalkanols that affords the desired heterocyclic reaction products in unexpected yields and purities. While not wishing to be bound by any theory, the present inventors hypothesize that the reaction proceeds via the simultaneous processes of dehydrohalogenation followed by dehydrative cyclization to produce the desired products. In addition to being a one-step, single-pot reaction, the present method advantageously proceeds in the absence of solvents, bases, or catalysts. Furthermore, the reaction proceeds at relatively mild temperatures and relatively low pressures.

[0052] In one embodiment, for example, the reaction of a carboxamide or carboxamide derivative (e.g., a hydrazide or N-hydroxycarboxamide) with a haloalkanol (e.g., 2-bromoethanol, 2-chloroethanol, 2-iodoethanol, 3-bromopropanol, or 1-bromo-2-propanol) proceeds in a one-step, single-pot reaction by microwave heating or thermal heating. Microwave heating can be applied at a temperature of about 100°C to about 160°C for a time period of about 10 minutes to about 60 hours. Thermal heating can be applied at a temperature of about 100°C to about 160°C for a time period of about 8 hours to about 15 hours.

[0053] The temperature range for microwave heating and thermal heating may suitably be about 100°C to about 160°C, preferably about 110°C to about 150°C, more preferably about 120°C to about 140°C, and most preferably about 130°C.

[0054] Heating can be applied by microwave heating for about 10 minutes to about 60 minutes, preferably about 20 minutes to about 50 minutes, more preferably about 30 minutes to about 40 minutes, and most preferably about 40 minutes.

[0055] Heating can be applied by thermal heating for about 8 hours to about 20 hours, preferably about 9 hours to about 18 hours, more preferably about 10 hours to about 16 hours, more preferably about 10 hours to about 14 hours, and most preferably about 12 hours.

[0056] In one embodiment, the present invention provides a compound of formula (I) [ka] Formula (I) The present invention provides a method for synthesizing a compound represented by the formula:

[0057] The method comprises reacting a compound of formula (Ia) [ka] Formula (Ia) or a carboxamide derivative represented by formula (Ib) [ka] Formula (Ib) with a substituted alkanol of the formula:

[0058] In one embodiment, n in the above formula (Ib) is selected from 0, 1 or 2.

[0059] In another embodiment, the present invention provides a compound of formula (II) [ka] Formula (II) The present invention provides a method for synthesizing a compound represented by the formula:

[0060] The method comprises reacting a compound of formula (IIa) [ka] Formula (IIa) or a carboxamide derivative represented by formula (IIb) [ka] Formula (IIb) with a substituted alkanol of the formula:

[0061] In another embodiment, the present invention provides a compound of formula (III) [ka] Formula (III) The present invention provides a method for synthesizing a compound represented by the formula:

[0062] The method comprises reacting a compound of formula (IIIa) [ka] Formula (IIIa) or a carboxamide derivative represented by formula (IIIb) [ka] Formula (IIIb) with a substituted alkanol of the formula:

[0063] In another embodiment, the present invention provides a compound of formula (IV) [ka] Formula (IV) The present invention provides a method for synthesizing a compound represented by the formula:

[0064] The method comprises reacting a compound of formula (IVa) [ka] Formula (IVa) or a carboxamide derivative represented by formula (IVb) [ka] Formula (IVb) with a substituted alkanol of the formula:

[0065] In another embodiment, the present invention provides a compound of formula (V) [ka] Formula (V) The present invention provides a method for synthesizing a compound represented by the formula:

[0066] The method comprises reacting a compound represented by formula (Va) [ka] Formula (Va) with a hydrazide or hydrazide derivative represented by formula (Vb) [ka] Formula (Vb) with a substituted alkanol of the formula:

[0067] In another embodiment, the present invention provides a compound of formula (VI) [ka] Formula (VI) The present invention provides a method for synthesizing a compound represented by the formula:

[0068] The method comprises reacting a compound of formula (VIa) [ka] Formula (VIa) with an N-hydroxycarboxamide or hydroxycarboxamide derivative of formula (VIb) [ka] Formula (VIb) with a substituted alkanol of the formula:

[0069] Preferably, the method of the present invention comprises providing a carboxamide or carboxamide derivative and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of about 110° C. to about 150° C. to obtain the desired compound in a single reaction step.

[0070] In one embodiment, R is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0071] Optionally substituted straight or branched chain alkyl is C1-C 10 The optionally substituted straight or branched chain alkenyl may be alkyl and may be C-C 10 The optionally substituted straight or branched chain alkoxy may be alkenyl, and may be C-C 10The optionally substituted cycloalkyl can be C3-C6 cycloalkyl, the optionally substituted heterocycloalkyl can be C3-C6 heterocycloalkyl, the optionally substituted aryl can be C3-C6 aryl, the optionally substituted heteroaryl can be C3-C6 heteroaryl, and when substituted, the groups may be substituted with one or more occurrences of halogen, CN, or OH. 10 Alkyl should be understood to represent each member of the range.

[0072] R 1 and R 2 is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl. 1 and R 2 are independently optionally substituted straight or branched chain C-C 10 It may be selected from alkyl.

[0073] R 3 are independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0074] R 3'are independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0075] X is hydrogen, OH, SH and NHR 4 and X may be selected from the group consisting of 1 O, S, NR 4 and a direct bond.

[0076] R 4 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0077] Z is siloxyl, methanesulfonate, para-toluenesulfonate or halogen. The halogen atom can be bromine (Br), chlorine (Cl), iodine (I) or fluorine (F).

[0078] Exemplary compounds of the present invention can be represented by the chemical structures shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0079] General synthesis method A carboxamide, hydrazide, or N-hydroxycarboxamide (1 equivalent) and a haloalkanol (2 equivalents) were added to a single reaction vessel. The resulting mixture was heated to 130°C for 40 minutes at 100 W in a microwave. Alternatively, the resulting mixture was heated to 130°C for 12 hours by thermal heating. The reaction progress was monitored by thin-layer chromatography. The crude compound was purified by silica gel column chromatography in a hexane:ethyl acetate mixture. Pure compounds were obtained in moderate to excellent yields ranging from approximately 40% to approximately 90%.

[0080] The compound was analyzed by FT-IR, NMR ( 1 H and 13 C) Characterized by spectroscopy and / or mass spectrometry.

[0081] Experimental data

[0082] 2-Phenyl-4,5-dihydrooxazole(1) Yellow viscous liquid, 90% yield; FTIR: (adsorbed on KBr, ν max , cm -1 ): 3065.31 (CH, Ar), 2960.16 (CH, CH2), 2929.34 (CH, CH2), 1719.19 (C=N), 1449.89 (C=C, Ar), 1271.43 (CN), 1105.60 (CO), 707.43 (CH, Ar). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 8.07 (d, J = 7.9 Hz, 2H, 7-H), 7.58 (t, J = 7.5 Hz, 1H, 9-H), 7.46 (t, J = 7.8 Hz, 2H, 8-H), 4.63 (t, J = 6.2 Hz, 2H, 5-H), 3.65 (t, J = 6.2 Hz, 2H, 4-H) ppm. 13C-NMR (100 MHz, CDCl3, 25℃): δ = 167.10 (C2), 133.43 (C9), 129.91 (C7), 129.61 (C6), 128.60 (C8), 64.36 (C5), 28.90 (C4) ppm.

[0083] 2-(プロパ-1-エン-2-イル)-4,5-ジヒドロオキサゾール(2) Colorless liquid, yield 76.59%; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 6.10 (s, 1H, 7-Ha), 5.54 (p, J = 1.56 Hz, 1H, 7-Hb), 4.38 (t, J = 6.12 Hz, 2H, 5-H), 3.48 (t, J = 6.12 Hz, 2H, 4-H), 1.89 (t, J = 1.26 Hz, 3H, 8-H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 167.26 (C2), 135.10 (C6), 126.40 (C7), 64.20 (C5), 28.90 (C4), 18.53 (C8) ppm.

[0084] 2-プロピル-4,5-ジヒドロオキサゾール(3) Yellow liquid, yield 39.66%; NMR: 1 H-NMR (400MHz, DMSO-d6, 25℃) δ 4.38 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 6.1 Hz, 2H), 2.33 (t, J =7.4 Hz, 2H), 1.67 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6, 25℃) δ = 173.29 (C), 63.73 (CH2), 36.14 (CH2), 28.84 (CH2), 18.53 (CH2), 13.74 (CH3) ppm.

[0085] 2-(chloromethyl)-4,5-dihydrooxazole (4) Light yellow liquid, 45.07% yield; FTIR: (adsorbed on KBr, ν max , cm -1 ): 2958.56 (CH, CH2), 2922.89 (CH, CH2), 2853.57 (CH, CH2), 1740.75 (C=N), 1265.00 (CH), 1129.78 (CO). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 4.48 (dt, J = 6.4, 1.3 Hz, 2H, 5-H), 3.87 (s, 2H, 6-H), 3.53 (t, J = 6.2 Hz, 2H, 4-H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 166.83 (C2), 65.28 (C5), 41.07 (C6), 29.91 (C4) ppm.

[0086] 2-(4,5-dihydrooxazol-2-yl)acetonitrile (5) Colorless liquid, 28.4% yield; FTIR: (adsorbed on KBr, ν max , cm -1 ): 2967.76 (CH, CH2), 2929.11 (CH, CH2), 2264.39 (nitrile), 1745.61 (C=N), 1192.30 (CO). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 4.47 (t, J = 6.0 Hz, 2H, 5-H), 3.52 (s, 2H, 6-H), 3.51 (t, J = 6.0 Hz, 2H, 4-H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 162.80 (C2), 112.91 (C7), 65.72 (C5), 27.89 (C4), 24.63 (C6) ppm.

[0087] 2-Isopropyl-4,5-dihydrooxazole (6) Yellow liquid (350 mg); NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ 4.35 (t, J = 6.25 Hz, 2H), 3.49 (t, J = 6.83 Hz, 2H), 2.60 - 2.53 (m, 1H), 1.17 (d, J = 7.06 Hz, 6H). 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 176.7, 63.6, 33.9, 28.9, 18.9 ppm.

[0088] 2-(tert-ブチル)-4,5-ジヒドロオキサゾール(7) Light yellow liquid, yield 68.80%; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 4.35 (t, J = 6.0 Hz, 2H), 3.49 (t, J = 6.0 Hz, 2H), 1.20 (s, 9H) ppm. 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 178.18 (C), 63.71 (CH2), 38.94 (C), 29.04 (CH2), 27.22 (CH3)3ppm.

[0089] 2-ブチル-4,5-ジヒドロオキサゾール(8) Yellow liquid, yield 50.22%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 4.36 (t, J = 6.16 Hz, 2H), 3.49 (t, J = 6.33 Hz, 2H), 2.33 (t, J = 7.88 Hz, 2H), 1.65 - 1.57 (m, 2H), 1.39 - 1.30 (m, 2H), 0.90 (t, J = 7.50 Hz, 3H). 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7.

[0090] 2-(trichloromethyl)-4,5-dihydrooxazole (9) Yellow liquid, 37.30% yield; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 4.65 (t, J = 5.68 Hz, 2H), 3.60 (t, J = 5.52 Hz, 2H). 13 C-NMR (100 MHz, DMSO d6, 25℃) δ = 161.7, 89.5, 67.9, 26.9 ppm.

[0091] 2-Cyclohexyl-2,5-dihydrooxazole (10) Yellow liquid, 66.73% yield; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 4.35 (t, J = 6.1 Hz, 2H), 3.48 (t, J = 6.1 Hz, 2H), 2.36 - 2.28 (tt, J = 11.2, 3.6 Hz, 1H), 1.90 (m, 2H), 1.73 (m, 2H), 1.62 (m, 1H), 1.44 (q, J = 12.0 Hz, 2H), 1.32-1.18 (m, 3H) ppm; 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 175.63 (C), 63.51 (CH2), 43.08 (CH2), 29.06 (C), 29.03 (CH2)2, 25.78 (CH2), 25.44 (CH2)2ppm.

[0092] 2-(2-iodophenyl)-4,5-dihydrooxazole (11) Colorless liquid, 58.80% yield; FTIR: (adsorbed on KBr, ν max , cm -1): 2926.14 (CH, CH2), 2892.53 (CH, CH2), 1729.85 (C=N), 1289.37 (CO), 1248.91 (CO), 1089.39 (CN), 1045.30 (CN), 741.17 (CH, Ar). NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 8.00 (dd, J = 8.10, 1.42 Hz, 1H), 7.87 (dd, J = 7.99 Hz, 1.62 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.19 - 7.15 (m, 1H), 4.64 (t, J = 6.17 Hz, 2H), 3.65 (t, J = 6.37 Hz, 2H) ppm. 13 C-NMR (400 MHz, DMSO-d6, 25℃) δ = 165.9, 141.5, 134.4, 133.1, 131.3, 129.8, 128.1, 64.9, 28.5 ppm.

[0093] 2-(フェノキシメチル)-4,5-ジヒドロオキサゾール(12) Colorless liquid, yield 48%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 7.31 (t, J = 8.0 Hz, 2H), 7.01 (tt, J = 7.4, 1.4 Hz, 1H), 6.93 (td, J = 7.8, 1.4 Hz, 2H), 4.68 (s, 2H), 4.51 (t, J = 6.1 Hz, 2H), 3.52 (t, J = 6.1 Hz, 2H) ppm; 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 168.60 (C), 157.71 (C), 129.65 (CH), 121.92 (CH), 114.71 (CH), 65.15 (CH2), 64.37 (CH2), 28.31 (CH2) ppm.

[0094] 2-(チオフェン-2-イル)-4,5-ジヒドロオキサゾール(13) Yellow liquid, 80.24% yield; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.84 (dd, J = 3.7Hz, 1.2 Hz, 1H), 7.59 (dd, J = 5.0 Hz, 1.2 Hz, 1H), 7.11 (dd, J = 5.0 Hz, 5.0 Hz, 1H), 4.59 (t, J = 6.2 Hz, 2H), 3.61 (t, J = 6.2 Hz, 2H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 161.7, 134.1, 133.0, 133.1, 127.9, 64.3, 28.6 ppm.

[0095] 2-(2-fluorophenyl)-4,5-dihydrooxazole (14) Colorless liquid, yield 60.23%; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.95 (dt, J = 7.6Hz, 1.8 Hz, 1H), 7.52 (m, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 9.6 Hz, 1H), 4.63 (t, J = 6.1 Hz, 2H), 3.63 (t, J = 6.1 Hz, 2H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 163.8, 163.7, 160.8, 134.9, 134.8, 132.2, 124.1, 124.0, 118.2, 118.1, 117.2, 117.0, 64.5, 28.5 ppm.

[0096] 2-(2-nitrophenyl)-4,5-dihydrooxazole (15) Light yellow liquid, yield 59.16%; NMR: 1H-NMR (400 MHz, CDCl3, 25℃): δ = 7.95 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 7.77 (dd, J = 7.5 Hz, 1.7 Hz, 1H), 7.70 (dt, J = 7.5 Hz, 1.4 Hz, 1H), 7.66 (dt, J = 7.6 Hz, 1.7 Hz, 1H), 4.64 (t, J = 6.2 Hz, 2H), 3.60 (t, J = 6.2 Hz, 2H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 165.1, 148.2, 133.2, 132.1, 130.0, 127.3, 124.1, 65.5, 27.8 ppm.

[0097] 2-(2,5-Dibromophenyl)-4,5-dihydrooxazole (16) White solid, 80.10% yield; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.96 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 4.64 (t, J = 6.1 Hz, 2H), 3.64 (t, J = 6.1 Hz, 2H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 164.3, 135.9, 134.4 133.0, 121.2, 120.7, 65.1, 28.2 ppm.

[0098] 2-(2-Bromo-5-methoxyphenyl)-4,5-dihydrooxazole (17) Light yellow liquid, yield 85.10%; NMR: 1H-NMR (400 MHz, CDCl3, 25℃): δ = 7.52 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 3.0 Hz, 1H), 6.89 (dd, J = 9.0, 3.2 Hz, 1H), 4.62 (t, J = 6.1 Hz, 2H), 3.80 (s, 3H), 3.63 (t, J = 6.1 Hz, 2H) ) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 165.43 (C), 158.66 (C), 135.25 (CH), 132.08 (C), 119.36 (CH), 116.73 (CH), 112.22 (C), 64.85 (CH2), 55.76 (CH2), 28.55 (CH3) ppm.

[0099] 2-(2-ブロモ-4-メチルフェニル)-4,5-ジヒドロオキサゾール(18) Light yellow liquid, yield 85.55%; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.79 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.62 (t, J = 6.2 Hz, 2H), 3.64 (t, J = 6.10, 2H), 2.37 (s, 3H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 165.47 (C), 144.23 (C), 135.27 (CH), 131.89 (CH), 128.23 (CH), 128.18 (C), 122.25 (C), 64.70 (CH2), 28.67 (CH3), 21.27 (CH3) ppm.

[0100] 2-(2-ブロモ-3-メチルフェニル)-4,5-ジヒドロオキサゾール(19) Light yellow liquid, yield 78.52%; NMR: 1H-NMR (400 MHz, CDCl3, 25℃): δ = 7.53 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 4.64 (t, J = 6.2 Hz, 2H), 3.64 (t, J = 6.2 Hz, 2H), 2.46 (s, 3H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 166.75 (C), 140.03 (C), 133.62 (CH), 133.39 (C), 128.36 (CH), 127.04 (CH), 123.43 (C), 64.88 (CH2), 28.54 (CH2), 23.93 (CH3) ppm.

[0101] 5-メチル-2-フェニル-4,5-ジヒドロオキサゾール(20) Yellow liquid, yield 51.10% メジャー: NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 8.08-8.04 (m, 2H, 7-H), 7.58- 7.52 (m, 1H, 9-H), 7.45-7.41 (m, 2H, 8-H), 5.35-5.27 (m, 1H, 5-H), 3.60-3.53 (m, 2H, 4-H), 1.47 (d, J = 6.3 Hz, 3H, 5-CH3) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 165.95 (C2), 133.18 (C9), 130.08 (C6), 129.71 (C7), 128.44 (C8), 69.80 (C5), 35.50 (C4), 18.78 (5-CH3) ppm. MANA: NMR: 1H-NMR (400 MHz, CDCl3, 25℃): δ = 8.08-8.04 (m, 2H, 7-H), 7.58-7.52 (m, 1H, 9-H), 7.45-7.41 (m, 2H, 8-H), 4.53-4.42 (m, 2H, 4-H), 4.38-4.29 (m, 1H, 5-H), 1.76 (d, J = 6.7 Hz, 3H, 5-CH3) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 165.72 (C2), 133.31 (C9), 130.08 (C6), 129.78 (C7), 128.51 (C8), 69.29 (C4), 44.88 (C5), 22.61 (5-CH3) ppm.

[0102] 2-フェニル-5,6-ジヒドロ-4H-1,3-オキサジン(21) Colorless liquid, yield 60%; FTIR: (KBr adsorption, ν max , cm -1 ): 3063.22 (CH, Ar), 2962.84 (CH, CH2), 2867.63 (CH, CH2), 1717.02 (C=N), 1451.19 (C=C, Ar), 1269.43 (CN), 1110.18 (CO), 705.43 (CH, Ar). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.95 (d, J = 8.0 Hz, 2H, 8-H), 7.47 (t, J = 7.6 Hz, 1H, 10-H), 7.34 (t, J = 7.7 Hz, 2H, 9-H), 4.37 (t, J = 6.0 Hz, 2H, 6-H), 3.45 (t, J = 6.6 Hz, 2H, 4-H), 2.21 (m, 2H, 5-H) ppm. 13C-NMR (100 MHz, CDCl3, 25℃): δ = 166.18 (C2), 132.97 (C10), 129.93 (C7), 129.47 (C8), 128.32 (C9), 62.58 (C6), 31.75 (C5), 29.45 (C4) ppm.

[0103] 2-(プロパ-1-エン-2-イル)-5,6-ジヒドロ-4H-1,3-オキサジン(22) Colorless liquid, yield 38.48%; FTIR: (KBr adsorption, ν max , cm -1 ): 2960.69 (CH, CH2), 2927.17 (CH, CH2), 2857.59 (CH, CH2), 1716.86 (C=N), 1156.02 (CH). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 6.09 (s, 1H, 8-Ha), 5.56 (p, J = 1.6 Hz, 1H, 8-Hb), 4.27 (t, J = 6.0 Hz, 2H, 6-H), 3.47 (t, J = 6.6 Hz, 2H, 4-H), 2.22 (m, 2H, 5-H), 1.93 (t, J = 1.2 Hz, 3H, 9-H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 167.28 (C2), 136.27 (C7), 125.77 (C8), 62.49 (C6), 31.87 (C5), 29.47 (C4), 18.38 (C9) ppm.

[0104] 2-プロピル-5,6-ジヒドロ-4H-1,3-オキサジン(23) Light yellow liquid, yield 64.85%; FTIR: (KBr adsorption, ν max , cm -1 ): 2963.76 (CH, CH2), 2933.67 (CH, CH2), 2875.46 (CH, CH2), 1734.70 (C=N), 1172.56 (CH). NMR: 1H-NMR (400 MHz, CDCl3, 25℃): δ = 4.20 (dt, J = 6.1, 1.8 Hz, 2H, 6-H), 3.45 (dt, J = 6.6, 1.8 Hz, 2H, 4-H), 2.29 (dt, J = 7.3, 1.8 Hz, 2H, 7-H), 2.17 (dt, J = 6.2, 1.8 Hz, 2H, 5-H), 1.65 (dq, J = 7.4, 1.8 Hz, 2H, 8-H), 0.95 (dt, J = 7.4, 1.8 Hz, 3H, 9-H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 173.51 (C), 68.32 (C), 61.97 (CH2), 36.16 (CH2), 31.81 (CH2), 29.44 (CH2), 18.49 (CH2), 13.71 (CH3) ppm.

[0105] 2-(クロロメチル)-5,6-ジヒドロ-4H-1,3-オキサジン(24) Light yellow liquid, yield 37.75%; FTIR: (KBr adsorption, ν max , cm -1 ): 2964.19 (CH, CH2), 1736.12 (C=N), 1279.20 (CH), 1109.41 (CO). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 4.31 (q, J = 5.7 Hz, 2H, 6-H), 3.82 (s, 2H, 7-H), 3.46 (t, J = 6.5 Hz, 2H, 4-H) 2.20 (t, J = 6.5 Hz, 2H, 5-H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 167.14 (C2), 63.92 (C6), 31.45 (C5), 29.05 (C4), 25.67 (C7) ppm.

[0106] 2-イソプロピル-5,6-ジヒドロ-4H-1,3-オキサジン(25) Yellow liquid, yield 62%; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 4.18 (t, J = 5.34 Hz, 2H), 3.44 (t, J = 6.72 Hz, 2H), 2.57 - 2.50 (m, 1 H), 2.20 - 2.13 (m, 2H), 1.15 (d, J = 7.03 Hz, 6H) ppm. 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7. MS (ESI) m / z: 510.5 [M+H] + .

[0107] 2-イソブチル-5,6-ジヒドロ-4H-1,3-オキサジン(26) Yellow liquid, yield 59%; NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 4.20 (t, J = 5.59 Hz, 2H), 3.45 (t, J = 6.45 Hz, 2H), 2.20 - 2.15 (m, 4 H), 2.13 - 2.05 (m, 1H), 0.95 (d, J = 6.60 Hz, 6H) ppm. 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7 ppm.

[0108] 2-ブチル-5,6-ジヒドロ-4H-1,3-オキサジン(27) Colorless liquid, yield 48%; NMR: 1H-NMR (400 MHz, CDCl3, 25℃): δ = 4.20 (t, J = 6.10 Hz, 2H), 3.45 (t, J = 6.61 Hz, 2H), 2.30 (t, J = 7.85 Hz, 2 H), 2.18 - 2.15 (m, 2H), 1.64 - 1.56 (m, 2H), 1.37 - 1.29 (m, 2H), 0.91 (t, J = 7.10 Hz, 3H) ppm. 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7 ppm.

[0109] 2-シクロヘキシル-5,6-ジヒドロ-4H-1,3-オキサジン(28) Yellow liquid, yield 43%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 4.17 (t, J = 6.0 Hz, 2H), 3.43 (t, J = 6.6 Hz, 2H), 2.31 - 2.24 (tt, J = 11.3, 3.7 Hz, 1H), 2.1 (p, J = 6.4 Hz, 2H), 1.87 (m, 2H), 1.72 (m, 2H), 1.62 (m, 1H), 1.41 (m, 2H), 1.31 - 1.18 (m, 4H) ppm; 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ = 175.92 (C), 61.84 (CH2), 43.18 (CH), 31.81 (CH2), 29.48 (CH2), 29.05 (CH2), 25.78 (CH2), 25.46 (CH2) ppm.

[0110] 2-(2-ヨードフェニル)-5,6-ジヒドロ-4H-1,3-オキサジン(29) Colorless liquid, yield 43.02%; FTIR: (KBr adsorption, ν max , cm -1): 2958.04 (CH, CH2), 2921.01 (CH, CH2), 2851.10 (CH, CH2), 1726.65 (C=N), 1286.84 (CO), 1246.07 (CO), 1127.08 (CN), 1102.66 (CN), 739.24 (CH, Ar). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.98 (d, J = 7.8 Hz, 1H), 7.77 (dd, J = 7.7 Hz, 1H), 7.42-7.38 (m, 1H), 7.17-7.13 (m, 1H), 4.47 (t, J = 6.00 Hz, 2H), 3.51-3.47 (m, 1H), 2.33 (p, J = 6.2 Hz, 2H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 166.43, 141.33, 135.25, 132.75, 130.98, 128.00, 93.97, 68.45, 30.63, 29.60 ppm.

[0111] 2-(2-ブロモフェニル)-5,6-ジヒドロ-4H-1,3-オキサジン(30) Yellow oil, yield 72%; FTIR: (KBr adsorption, ν max , cm -1 ): 2962.17 (CH, CH2), 2865.22 (CH, CH2), 1729.85 (C=N), 1289.68 (CO), 1246.47 (CO), 1109 (CN), 743.31 (CH, Ar). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.77 (d, J = 7.35 Hz, 1H, 9-H), 7.65 (d, J = 7.35 Hz, 1H, 12-H), 4.24 (m, 2H, 10-H, 11-H), 4.48 (t, J = 5.96 Hz, 2H, 6-H), 3.56 (t, J = 6.47 Hz, 2H, 4-H), 2.35-2.28 (m, 2H, 5-H) ppm.13 C-NMR (100 MHz, CDCl3, 25℃): δ = 166.43 (C2), 134.69 (C7), 132.99 (C9), 132.53 (C12), 131.68 (C10), 127.56 (C11), 121.88 (C8), 68.60 (C-4), 63.69 (C-6), 33.10 (C-5) ppm.

[0112] 2-(フェノキシメチル)-5,6-ジヒドロ-4H-1,3-オキサジン(31) Yellow liquid, yield 48%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 7.29 (t, J = 8.0 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 4.64 (s, 2H), 4.33 (t, J = 6.0 Hz, 2H), 3.35 (t, J = 6.5 Hz, 2H), 2.17 (m, 2H) ppm; 13 C-NMR (100 MHz, DMSO-d6, 25℃) δ 169.0 (C), 157.88 (C), 129.71 (CH), 121.94 (CH), 114.67 (CH), 65.36 (CH2), 63.06 (CH2), 31.55 (CH2), 29.12 (CH2) ppm.

[0113] 2-(フェノキシメチル)-5,6-ジヒドロ-4H-1,3-オキサジン(32) Yellow liquid, yield 46%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25℃) δ = 7.57 (dd, J = 1.8, 0.9 Hz, 1H), 7.18 (dd, J = 3.5, 0.9 Hz, 1H), 6.50 (dd, J = 3.5, 1.8 Hz, 1H), 4.44 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.29 (m, 2H) ppm; 13C-NMR (100 MHz, DMSO-d6, 25℃) δ = 158.56 (C), 146.51 (CH), 144.51 (C), 118.21 (CH), 111.95 (CH), 62.67 (CH2), 31.84 (CH2), 29.29 (CH2) ppm.

[0114] 2-(Thiophen-2-yl)-5,6-dihydro-4H-1,3-oxazine (33) Brown oil: 506 mg, 77% yield; FTIR: (adsorbed on KBr, ν max , cm -1 ): 2966.06 (CH, CH2), 2923.78 (CH, CH2), 1707.17 (C=N), 1257.56 (CO), 1220.60 (CO), 1095.48 (CN), 747.31-721.26 (CH, Ar). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ = 7.81 (d, 1H, J = 2.34 10-H), 7.56 (d, J = 2.34 Hz, 1H, 8-H), 7.10 (t, J = 6.35 Hz, 2H, 9-H), 4.44 (t, J = 6.03 Hz, 2H, 6-H), 3.53 (t, J = 6.03 Hz, 2H, 4-H), 2.33-2.26 (m, 2H, 5-H) ppm. 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 162.31 (C2), 133.91 (C8), 133.81 (C7), 132.89 (C9), 128.14 (C10), 68.59 (C4), 63.13 (C6), 33.09 (C5) ppm.

[0115] 3-Phenyl-5,6-dihydro-1,4,2-dioxazine (34) Colorless liquid; Yield: 72.27%; FTIR: (adsorbed on KBr, ν max , cm -1): 2957.91 (CH, CH2), 2926.66 (CH, CH2), 1718.47 (C=N), 1451.55 (CH, Ar), 1264.74 (CO), 1109.85 (CO), 707.72 (CH, Ar). NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ 8.06 (d, J = 8.0 Hz, 2H, 8-H), 7.56 (t, J = 7.5 Hz, 1H, 10-H), 7.4 (t, J = 7.8 Hz, 2H, 9-H), 4.61 (t, J = 6.1 Hz, 2H, 5-H), 3.63 (t, J = 6.1 Hz, 2H, 6-H), ppm; 13 C-NMR (100 MHz, CDCl3, 25℃): δ = 166.06 (C3), 133.29 (C10), 129.76 (C8), 129.65 (C7), 128.47 (C9), 64.24 (C5), 28.85 (C6) ppm.

[0116] 2-フェニル-5,6-ジヒドロ-4H-1,3,4-オキサジアジン(35) Colorless liquid, yield: 65.00%; FTIR: (KBr adsorption, ν max , cm -1 ): 3461.01 (CH), 2955.46 (CH, CH2), 2928.29 (CH, CH2), 1718.26 (C=N), 1264.13 (CN), 1109.71 (CO), 708.33 (CH, Ar); NMR: 1 H-NMR (400 MHz, CDCl3, 25℃): δ 8.06 (d, J = 8.0 Hz, 2H, 8-H), 7.56 (t, J = 7.5 Hz, 1H, 10-H), 7.4 (t, J = 7.7 Hz, 2H, 9-H), 4.61 (t, J = 6.1 Hz, 2H, 6-H), 3.63 (t, J = 6.1 Hz, 2H, 5-H) ppm; 13C-NMR (100 MHz, CDCl3, 25℃): δ = 166.11 (C2), 133.33 (C10), 129.80 (C8), 129.69 (C7), 128.51 (C9), 64.28 (C6), 28.87 (C5) ppm.

[0117] The above description of some exemplary embodiments of this invention is intended to show how the invention can be made and practiced. Those skilled in the art will recognize that various details and substituents can be modified to arrive at further embodiments, many of which remain within the scope of this invention.

Claims

1. Formula (II) 【Chemistry 1】 Formula (II) The method for synthesizing a compound of formula (IIa) 【Chemistry 2】 Formula (IIa) with a carboxamide represented by formula (IIb) 【Transformation 3】 Formula (IIb) with a substituted alkanol of the formula During the ceremony, X is NH 2 , NHR 4 and OH; X 1 , NH, O and NR 4 selected from the group consisting of: R 1 is hydrogen and optionally substituted straight or branched chain C 1 -C 10 selected from the group consisting of alkyl; R 2 is hydrogen and optionally substituted straight or branched chain C 1 -C 10 selected from the group consisting of alkyl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; R 4 is optionally substituted aryl; and The method comprises the steps of placing a carboxamide and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of 100°C to 160°C to obtain a compound of formula (II), method.

2. Formula (III) 【Chemistry 4】 Formula (III) The method comprises the steps of: 【Transformation 5】 Formula (IIIa) with a carboxamide represented by formula (IIIb) 【Transformation 6】 Formula (IIIb) with a substituted alkanol of the formula During the ceremony, R 1 is hydrogen and optionally substituted straight or branched chain C 1 -C 10 selected from the group consisting of alkyl; R 2 is hydrogen and optionally substituted straight or branched chain C 1 -C 10 selected from the group consisting of alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; and The method comprises the steps of placing a carboxamide and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of 100°C to 160°C to obtain a compound of formula (III), method.

3. Formula (IV) 【Transformation 7】 Formula (IV) The method comprises the steps of: 【Transformation 8】 Formula (IVa) with a carboxamide represented by formula (IVb) 【Chemistry 9】 Formula (IVb) with a substituted alkanol of the formula During the ceremony, R 1 is hydrogen and optionally substituted straight or branched chain C 1 -C 10 selected from the group consisting of alkyl; R 2 is hydrogen and optionally substituted straight or branched chain C 1 -C 10 selected from the group consisting of alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl; R 3 and R 3' is independently selected from the group consisting of hydrogen and optionally substituted alkyl; R is selected from the group consisting of hydrogen, optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, optionally substituted straight or branched chain alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Z is siloxyl, methanesulfonate, para-toluenesulfonate, or a halogen atom selected from the group consisting of Br, Cl, I, and F; and The method comprises the steps of placing a carboxamide and a substituted alkanol in a single reaction vessel to form a reaction mixture, and heating the reaction mixture at a temperature of 100°C to 160°C to obtain a compound of formula (IV), method.

4. R is an optionally substituted straight or branched chain C 1 -C 10 Alkyl, optionally substituted straight or branched chain C 2 -C 10 Alkenyl, optionally substituted straight or branched chain C 1 -C 10 Alkoxy, optionally substituted C 3 -C 6 Cycloalkyl, optionally substituted C 3 -C 6 Heterocycloalkyl, optionally substituted C 3 -C 6 Aryl and optionally substituted C 3 -C 6 The method of any one of claims 1 to 3, wherein the aryl is selected from the group consisting of heteroaryl.

5. 4. The method of any one of claims 1 to 3, wherein the reaction proceeds in the absence of any solvent, catalyst, base or other reagent.

6. R is a substituted straight or branched chain C substituted with one or more groups selected from the group consisting of halogen, CN, or OH. 1 -C 10 The method according to any one of claims 1 to 3, wherein the alkyl is alkyl.

7. R is a substituted straight or branched chain C substituted with one or more groups selected from the group consisting of halogen, CN, or OH. 2 -C 10 The method according to any one of claims 1 to 3, wherein the alkyl group is alkenyl.

8. R is a substituted straight or branched chain C substituted with one or more groups selected from the group consisting of halogen, CN, or OH. 1 -C 10 The method according to any one of claims 1 to 3, wherein the alkyl group is alkoxy.

9. R is independently a straight or branched chain C 1 -C 10 Alkoxy, halogen, NO 2 , optionally substituted straight or branched chain C 1 -C 10 substituted with one or more groups selected from the group consisting of alkyl, 3 -C 6 Cycloalkyl, substituted C 3 -C 6 Heterocycloalkyl, substituted C 3 -C 6 Aryl or substituted C 3 -C 6 The method according to any one of claims 1 to 3, wherein the aryl is heteroaryl.

10. R is halogen, NO 2 , linear or branched chain C 1 -C 10 Alkoxy, optionally substituted straight or branched chain C 1 -C 10 substituted with one or more groups selected from the group consisting of alkyl, 3 -C 6 The method according to any one of claims 1 to 3, wherein the aryl is aryl.

11. R: 【Chemistry 10】 The method according to any one of claims 1 to 3, wherein the group is selected from the group consisting of:

12. The compound of formula (II) is 3-phenyl-5,6-dihydro-1,4,2-dioxazine; and 2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine 2. The method of claim 1, wherein the compound is selected from the group consisting of:

13. The compound of formula (III) is 2-phenyl-4,5-dihydrooxazole; 2-(prop-1-en-2-yl)-4,5-dihydrooxazole; 2-propyl-4,5-dihydrooxazole; 2-(chloromethyl)-4,5-dihydrooxazole; 2-(4,5-dihydrooxazol-2-yl)acetonitrile; 2-Isopropyl-4,5-dihydrooxazole; 2-(tert-butyl)-4,5-dihydrooxazole; 2-butyl-4,5-dihydrooxazole; 2-(trichloromethyl)-4,5-dihydrooxazole; 2-Cyclohexyl-2,5-dihydrooxazole; 2-(2-iodophenyl)-4,5-dihydrooxazole; 2-(phenoxymethyl)-4,5-dihydrooxazole; 2-(thiophen-2-yl)-4,5-dihydrooxazole; 2-(2-fluorophenyl)-4,5-dihydrooxazole; 2-(2-nitrophenyl)-4,5-dihydrooxazole; 2-(2,5-dibromophenyl)-4,5-dihydrooxazole; 2-(2-bromo-5-methoxyphenyl)-4,5-dihydrooxazole; 2-(2-bromo-4-methylphenyl)-4,5-dihydrooxazole; 2-(2-bromo-3-methylphenyl)-4,5-dihydrooxazole; and 5-methyl-2-phenyl-4,5-dihydrooxazole 3. The method of claim 2, wherein the compound is selected from the group consisting of:

14. The compound of formula (IV) is 2-phenyl-5,6-dihydro-4H-1,3-oxazine; 2-(prop-1-en-2-yl)-5,6-dihydro-4H-1,3-oxazine; 2-Propyl-5,6-dihydro-4H-1,3-oxazine; 2-(chloromethyl)-5,6-dihydro-4H-1,3-oxazine; 2-Isopropyl-5,6-dihydro-4H-1,3-oxazine; 2-Isobutyl-5,6-dihydro-4H-1,3-oxazine; 2-butyl-5,6-dihydro-4H-1,3-oxazine; 2-Cyclohexyl-5,6-dihydro-4H-1,3-oxazine; 2-(2-iodophenyl)-5,6-dihydro-4H-1,3-oxazine; 2-(2-bromophenyl)-5,6-dihydro-4H-1,3-oxazine; 2-(phenoxymethyl)-5,6-dihydro-4H-1,3-oxazine; 2-(furan-2-yl)-5,6-dihydro-4H-1,3-oxazine; and 2-(thiophen-2-yl)-5,6-dihydro-4H-1,3-oxazine; 4. The method of claim 3, wherein the compound is selected from the group consisting of:

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