Synthesis of heterocyclic compounds from carboxamides and carboxamide derivatives with halogenated alkanols

Abstract

The present invention provides a process for the synthesis of a plurality of compounds by the reaction of a carboxamide or carboxamide derivative with a plurality of substituted or unsubstituted haloalkanols in a one-step, single vessel reaction mechanism. Preferably, but not exclusively, the reaction is carried out in the absence of any solvent, catalyst, base or any other reagent.

Description

TECHNICAL FIELD

[0001] The present invention relates to a process for the synthesis of heterocyclic compounds by the reaction of carboxamides or carboxamide derivatives with a plurality of 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 a plurality of substituted or unsubstituted haloalkanols in a one-step, single vessel reaction mechanism. BACKGROUND

[0002] Heterocyclic compounds, such as oxazolines, oxazines, dioxazines and dioxazines, play an important role in a plurality of applications in the fields of biomedical chemistry and biomaterials, pharmaceutical product development, polymer chemistry and agrochemistry, to name a few.

[0003] The current processes for the synthesis of these heterocyclic compounds each suffer from one or more of the following disadvantages: use of undesirable organic solvents, use of catalysts, high temperatures, high pressures, low yields and / or selectivity, multi-step reaction mechanisms, and other generally undesirable reaction conditions.

[0004] For example, Oxazolines are five-membered heterocyclic compounds known since the 19thcentury. It is also well known that 2- oxazolines have significant importance in organic synthesis as functional groups as well as protecting groups in hydroxyl, amine and carboxylic acid chemistry, and as ligands in asymmetric catalysis. Furthermore, 2- oxazolines have a wide range and applications in pharmaceutical and polymer chemistry. Recently, 2- oxazoline polymers have emerged as highly efficient macromolecules in the field of targeted drug delivery and drug development in a plurality of therapeutic areas. However, despite the evident importance of this heterocyclic compound, the known methods of synthesis are not entirely desirable.

[0005] In one known method, for example, the synthesis proceeds by reaction of a carboxylic acid with a 1,2-alkanolamine to give the intermediate N-(β-hydroxyethyl)-carboxamide, followed by cyclodehydration. Another known method proceeds by preparing N-(β-haloethyl)-carboxamides, followed by dehalogenation. These procedures proceed through two steps, i.e., formation of the carboxamide, followed by 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 an acyl chloride derivative thereof, with a 1,2-alkanolamine or a 2-haloethanol. On the other hand, the cyclization occurs by cyclodehydration or cyclodehalogenation using a dehydrating agent (including sulfuric acid, aluminum oxide, iron oxide, SOCl2, PPh3 / CCl4, TsCl / Et3N, carbodiimides, PPh3-DEAD, or PPh3-DDQ) or a metal catalyst (including cadmium, organic / inorganic zinc salts, or iron compounds). In addition, the cyclodehalogenation occurs in the presence of a solvent using an inorganic base, such as NaCO3, NaOH, and / or KOH.

[0006] It is therefore an object of the present application to solve at least some of the drawbacks of the methods known to the skilled person for the synthesis of a plurality of heterocyclic compounds from the reaction of a carboxamide or a derivative thereof with a plurality of haloalkanols. SUMMARY

[0007] According to a first aspect of the present application, there is provided a method for the synthesis of a compound of formula (I).

[0008]

[0009] The method comprises reacting a carboxamide or carboxamide derivative of formula (la)

[0010]

[0011] wherein,

[0012] n is 0, 1 or 2;

[0013] 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;

[0014] R 1 selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0015] R 2selected from hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0016] R 3 and R 3’ are independently selected from 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;

[0017] X is selected from hydrogen, NH2OH, SH, NHR 4 ,

[0018] X 1 is selected from NH, O, S, NR 4 , and a direct bond;

[0019] R 4 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0020] Z is silyloxy, mesylate, tosylate, or halogen,

[0021] wherein the method 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 100 °C to about 160 °C to produce a compound of Formula (I).

[0022] According to a second aspect of the present application, there is provided a method for synthesizing a compound of Formula (II)

[0023]

[0024] The method comprises reacting a carboxamide or carboxamide derivative of Formula (IIa) with a substituted alkanol of Formula (IIb)

[0025]

[0026] wherein,

[0027] X is selected from hydrogen, NH2, NHR 4 , OH, and SH;

[0028] X 1 is selected from NH, O, NR 4 , and S;

[0029] R1 selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0030] R 2 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;

[0031] R is selected from the group consisting of hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl,

[0032] Z is a silyloxy group, a methanesulfonic acid group, a p-toluenesulfonic acid group, or a halogen atom selected from the group consisting of Br, CI, I, and F, and

[0033] 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;

[0034] wherein the method 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 100 °C to about 160 °C to produce a compound of formula (II).

[0035] According to a third aspect of the present application, there is provided a method for synthesizing a compound of formula (III)

[0036]

[0037] the method comprising reacting a carboxamide or carboxamide derivative of formula (IIIa) with a substituted alkanol of formula (IIIb)

[0038]

[0039]

[0040] wherein,

[0041] R 1 selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0042] R 2selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0043] R is selected from the group consisting of hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl,

[0044] Z is a silyloxy group, a methanesulfonic acid group, a p-toluenesulfonic acid group, or a halogen atom selected from the group consisting of Br, CI, I, and F, and

[0045] wherein the method comprises providing 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 produce a compound of formula (III).

[0046] According to another aspect of the present application, there is provided a method for synthesizing a compound of formula (IV)

[0047]

[0048] The method comprises reacting a carboxamide or carboxamide derivative of formula (IVa)

[0049]

[0050]

[0051] wherein,

[0052] R 1 selected from the group consisting of hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0053] R 2 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;

[0054] R 3 and R 3’independently selected from 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;

[0055] R is selected from hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl,

[0056] Z is a silyloxy group, a methanesulfonic acid group, a p-toluenesulfonic acid group, or a halogen atom selected from Br, CI, I and F, and

[0057] wherein the method comprises providing 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 produce a compound of formula (IV).

[0058] According to another aspect of the present application, there is provided a method for synthesizing a compound of formula (V)

[0059]

[0060] The method comprises reacting a hydrazide or a hydrazide derivative of formula (Va) with a substituted alkanol of formula (Vb)

[0061]

[0062] wherein,

[0063] R 1 selected from hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0064] R 2 selected from hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0065] R is selected from hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl,

[0066] Z is a silyloxy group, a methanesulfonic acid group, a p-toluenesulfonic acid group, or a halogen atom selected from Br, CI, I and F, and

[0067] wherein the method comprises providing 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 produce a compound of formula (V).

[0068] According to another aspect of the application, there is provided a method for synthesizing a compound of formula (VI)

[0069]

[0070] The method comprises reacting an N-hydroxycarboxamide or N-hydroxycarboxamide derivative of formula (Via) with a substituted alkanol of formula (VIb)

[0071]

[0072]

[0073] wherein,

[0074] R 1 selected from hydrogen, halogen, nitrile, and optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0075] R 2 selected from hydrogen, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

[0076] R is selected from hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl,

[0077] Z is a silyloxy group, a methanesulfonic acid group, a p-toluenesulfonic acid group, or a halogen atom selected from Br, CI, I and F, and

[0078] wherein the method comprises providing 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 produce a compound of formula (VI).

[0079] In one embodiment, R 1 , R 2 , R 3 and R3’ independently selected from H, optionally substituted hydroxyl, optionally substituted amine, halogen, nitrile, or optionally substituted linear or branched alkyl.

[0080] In one embodiment, R 1 , R 2 , R 3 and R 3’ are independently selected from optionally substituted linear or branched C1-C 10 alkyl.

[0081] In one preferred embodiment, R is selected from optionally substituted linear or branched C1-C 10 alkyl, optionally substituted linear or branched C2-C 10 alkenyl, optionally substituted linear or branched C1-C 10 alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C3-C6 aryl, and optionally substituted C3-C6 heteroaryl.

[0082] In one preferred embodiment, the reaction is carried out in the absence of any solvent, catalyst, base, or other reagent.

[0083] In one embodiment, R is substituted linear or branched C1-C 10 alkyl, said substituted linear or branched C1-C 10 alkyl being substituted with one or more groups selected from halogen, CN or OH.

[0084] In another embodiment, R is substituted linear or branched C2-C 10 alkenyl, said substituted linear or branched C2-C 10 alkenyl being substituted with one or more groups selected from halogen, CN or OH.

[0085] In another embodiment, R is substituted linear or branched C1-C 10 alkoxy, said substituted linear or branched C1-C 10 alkoxy being substituted with one or more groups selected from halogen, CN or OH.

[0086] In yet another embodiment, R is substituted C3-C6 cycloalkyl, substituted C3-C6 heterocycloalkyl, substituted C3-C6 aryl, or substituted C3-C6 heteroaryl, said substituted C3-C6 cycloalkyl, substituted C3-C6 heterocycloalkyl, substituted C3-C6 aryl, or substituted C3-C6 heteroaryl being independently substituted with one or more groups selected from linear or branched C1-C10 alkyl, halogen, NO2, optionally substituted linear or branched C1-C 10 alkyl, halogen, NO2, optionally substituted linear or branched C1-C

[0087] In yet another embodiment, R is substituted C3-C6 aryl, said substituted C3-C6 aryl being substituted with one or more groups selected from the group consisting of halogen, NO2, linear or branched C1-C 10 alkyl, halogen, NO2, optionally substituted linear or branched C1-C 10 alkyl, halogen, NO2, optionally substituted linear or branched C1-C

[0088] In a particularly preferred embodiment, R is a group selected from the group consisting of:

[0089]

[0090]

[0091] In a particularly preferred embodiment, the compound of formula (I) is a compound selected from the group consisting of:

[0092] 2-phenyl-4,5-dihydro oxazole;

[0093] 2-(prop-1 -en-2-yl)-4,5-dihydro oxazole;

[0094] 2-propyl-4,5-dihydro oxazole;

[0095] 2-(chloromethyl)-4,5-dihydro oxazole;

[0096] 2-(4,5-dihydro oxazol-2-yl)acetonitrile;

[0097] 2-isopropyl-4,5-dihydro oxazole;

[0098] 2-(tert-butyl)-4,5-dihydro oxazole;

[0099] 2-butyl-4,5-dihydro oxazole;

[0100] 2-(trichloromethyl)-4,5-dihydro oxazole;

[0101] 2-cyclohexyl-2,5-dihydro oxazole;

[0102] 2-(2-iodophenyl)-4,5-dihydro oxazole;

[0103] 2-(phenoxymethyl)-4,5-dihydro oxazole;

[0104] 2-(thiophen-2-yl)-4,5-dihydro oxazole;

[0105] 2-(2-fluorophenyl)-4,5-dihydro oxazole;

[0106] 2-(2-nitrophenyl)-4,5-dihydro oxazole;

[0107] 2-(2,5-dibromophenyl)-4,5-dihydro oxazole;

[0108] 2-(2-bromo-5-methoxyphenyl)-4,5-dihydro oxazole;

[0109] 2-(2-bromo-4-methylphenyl)-4,5-dihydro oxazole;

[0110] 2-(2-bromo-3-methylphenyl)-4,5-dihydro oxazole;

[0111] 5-methyl-2-phenyl-4,5-dihydro oxazole;

[0112] 2-phenyl-5,6-dihydro-4H-1,3- oxazine;

[0113] 2-(prop-1-en-2-yl)-5,6-dihydro-4H-1,3- oxazine;

[0114] 2-propyl-5,6-dihydro-4H-1,3- oxazine;

[0115] 2-(chloromethyl)-5,6-dihydro-4H-1,3- oxazine;

[0116] 2-isopropyl-5,6-dihydro-4H-1,3- oxazine;

[0117] 2-isobutyl-5,6-dihydro-4H-1,3- oxazine;

[0118] 2-butyl-5,6-dihydro-4H-1,3- oxazine;

[0119] 2-cyclohexyl-5,6-dihydro-4H-1,3- oxazine;

[0120] 2-(2-iodophenyl)-5,6-dihydro-4H-1,3- oxazine;

[0121] 2-(2-bromophenyl)-5,6-dihydro-4H-1,3- oxazine;

[0122] 2-(phenoxymethyl)-5,6-dihydro-4H-1,3- oxazine;

[0123] 2-(furan-2-yl)-5,6-dihydro-4H-1,3- oxazine;

[0124] 2-(thiophen-2-yl)-5,6-dihydro-4H-1,3- oxazine;

[0125] 3-phenyl-5,6-dihydro-1,4,2-dioxazine; and

[0126] 2-phenyl-5,6-dihydro-4H-1,3,4- oxadiazine. BRIEF DESCRIPTION OF DRAWINGS

[0127] The present application will now be described in greater detail, with reference haded to the following non-limiting embodiments and accompanying drawings, in which:

[0128] Figure 1 A reaction mechanism is shown for the proposed synthesis of compounds according to the present application, including simultaneous dehydrohalogenation and cyclodehydration. DETAILED DESCRIPTION

[0129] The present application will now be described in greater detail, with reference haded to the following non-limiting embodiments and accompanying drawings, in which:

[0130] The present application as described below should not be construed as limited to the particular embodiments set forth and other variations and embodiments are intended to be included within the scope of the present application.

[0131] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0132] As used throughout this description and in the claims, the term "comprising" is used in the sense of "including", and the use of the term "comprising" means that other steps, ingredients, components or elements can also be present.

[0133] ​​​​​​​​The terms and expressions employed herein are for descriptive purposes and should not be construed as limiting. The use herein of the terms "comprising", "including", "having", "containing", "including", "involving" and variations thereof, shall be considered as encompassing the items listed thereafter and equivalents thereof as well as additional items.

[0134] In describing the application, the following terms, if present, have the following meanings unless otherwise indicated. It is also to be understood that any portion of the following definitions can be substituted, and each definition is intended to be included within the scope of its use as set forth below. In this regard, the term "substituted" will be defined as set forth below, unless otherwise indicated. It is also to be understood that the terms "group" and "radical" are used interchangeably herein.

[0135] "Alkyl" means a linear or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 10 carbon atoms. More particular are lower alkyl groups having 1 to 8 carbon atoms. Further particular groups have 1 to 6 carbon atoms. Exemplary straight chain alkyl groups include methyl, ethyl, n-propyl, and n-butyl. Branched means one or more alkyl groups, such as methyl, ethyl, propyl, or butyl, are attached to the linear alkyl chain. Exemplary branched groups include iso-propyl and iso-butyl.

[0136] "Alkoxy" means the group -OR x where R x is an alkyl group having the specified number of carbon atoms. Particular alkoxy groups are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, t-butyloxy, sec-butyloxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0137] "Alkylene" means a divalent aliphatic hydrocarbon radical group having the specified number of carbon atoms, specifically 1 to 10 carbon atoms, and more specifically 1 to 8 carbon atoms, which can be linear or branched. The term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)-.

[0138] "Alkenyl" means a monovalent aliphatic hydrocarbon group having the specified number of carbon atoms which is alkenyl unsaturated. Particular alkenyl groups have 2 to 10 carbon atoms, and more specifically 2 to 8 carbon atoms, which can be linear or branched and have at least 1, and specifically 1 to 2, alkenyl unsaturation sites. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-C(CH3)=CH2), and the like.

[0139] "Amino" means the radical -NH2.

[0140] "Aryl" means a monovalent aromatic hydrocarbon group derived by removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Specifically, aryl means a monocyclic or polycyclic aromatic ring structure having the specified number of ring atoms. Specifically, the term includes groups containing 5 to 10 ring members. When the aryl group is a monocyclic ring system, it preferably contains 5 to 8 carbon atoms. Specifically, aryl groups include phenyl and naphthyl. Unless otherwise specified, the terms "phenyl" and "Ph" are used interchangeably herein.

[0141] "Cycloalkyl" means a monocyclic or polycyclic non-aromatic hydrocarbon ring structure having the specified number of ring atoms. Cycloalkyl groups can have 3 to 10 carbon atoms, and specifically 3 to 8 carbon atoms. For example, such cycloalkyl groups include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0142] "Cyano" means the radical -CN.

[0143] "Halo" or "halogen" means fluoro (F), chloro (CI), bromo (Br), and iodo (I).

[0144] "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 with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above described hydrocarbon groups, for example, alkyl, such as heteroalkyl, cycloalkyl, such as heterocycloalkyl; aryl, such as heteroaryl having 1 to 4, and specifically 1, 2, or 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom; and the like.

[0145] "Heteroaryl" means a monocyclic or fused polycyclic aromatic ring structure that includes one or more heteroatoms independently selected from O, N, and S and the specified number of ring atoms. Specifically, the aromatic ring structure can have 5 to 10 ring members. Heteroaryl groups can be, for example, five- or six-membered monocyclic rings or fused bicyclic ring structures formed by the fusion of five- and six-membered rings or two fused six-membered rings, or as another example, two fused five-membered rings. Each ring can include up to four heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will include up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring includes at least one ring nitrogen atom. The nitrogen atoms in 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 nitrogen). Typically, the number of basic nitrogen atoms present in the heteroaryl group, including any amino substituents of the ring, will be fewer than five.

[0146] As used herein, the term "heterocycloalkyl" means a stable monocyclic or polycyclic non-aromatic ring structure that includes one or more heteroatoms independently selected from O, N, and S. The non-aromatic ring structure can have 3 to 10 ring members, and specifically 3 to 8 ring members. A fused heterocyclic system can include carbocyclic rings and need only include one heterocyclic ring. As used herein, the term "heterocycloalkenyl" means a "heterocycloalkyl" in which one bond of the ring is reduced; thus, the ring contains a double bond.

[0147] "Hydroxy" refers to the radical -OH, and "oxo" refers to the radical =0.

[0148] "Substituted" means a group in which one or more hydrogen atoms are each independently replaced by the same or different substituent.

[0149] "Sulfo" or "sulfonic acid" refers to the radical, for example, -SO3H. "Thiol" refers to the group -SH.

[0150] As used herein, the term "substituted by one or more" refers to one to four substituents. In one embodiment, it refers to one to three substituents. In another embodiment, it refers to one or two substituents. In yet another embodiment, it refers to one substituent.

[0151] Where a range is mentioned in the present specification, e.g. C 1-10 The recitation of a range of values shall be considered as a disclosure of each individual member of the range.

[0152] The present invention relates generally to a process for the synthesis of heterocyclic compounds by the reaction of carboxamides or carboxamide derivatives with a variety of substituted or unsubstituted halogenated alkanols.

[0153] More specifically, the present invention relates to the synthesis of compounds of formula (I), (II), (III), (IV), (V), and (VI) as described herein by the reaction of carboxamides or carboxamide derivatives with a variety of substituted or unsubstituted halogenated alkanols in a one-step, single vessel reaction mechanism. Preferably, the reaction is carried out in the absence of any solvent, catalyst, base, or any other reagent.

[0154] The inventors of the present invention have developed a one-step, single vessel reaction of carboxamides and carboxamide derivatives with a variety of substituted or unsubstituted halogenated alkanols that unexpectedly produces the desired heterocyclic reaction product in unexpected yields and purity. Thus, without wishing to be bound by any particular theory, the inventors postulate that the reaction undergoes a simultaneous process of dehydrohalogenation plus ring-closing dehydration to produce the desired product. In addition to being a one-step, single vessel reaction, the process of the present invention is advantageously carried out in the absence of any solvent, base, or catalyst. Furthermore, the reaction is carried out at relatively mild temperatures and at relatively low pressures.

[0155] 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) is carried out by microwave heating or thermal heating in a one-step, single vessel reaction. Microwave heating can be applied at a temperature of about 100 °C to about 160 °C for a time of about 10 minutes to about 60 minutes. Thermal heating can be applied at a temperature of about 100 °C to about 160 °C for a time of about 8 hours to about 15 hours.

[0156] The temperature range for microwave heating and thermal heating can 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, most preferably about 130 °C.

[0157] The 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, most preferably about 40 minutes.

[0158] The 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 to about 14 hours, most preferably about 12 hours.

[0159] In one embodiment, the present application provides a method for synthesizing a compound of formula (I)

[0160]

[0161] The method comprises reacting a carboxamide or carboxamide derivative of formula (la) with a substituted alkanol of formula (lb)

[0162]

[0163] In one embodiment, n in the above formula (lb) is selected from 0, 1, or 2.

[0164] In another embodiment, the present application provides a method for synthesizing a compound of formula (II)

[0165]

[0166] The method comprises reacting a carboxamide or carboxamide derivative of formula (IIa) with a substituted alkanol of formula (lib)

[0167]

[0168] In another embodiment, the present application provides a method for synthesizing a compound of formula (III)

[0169]

[0170] The method comprises reacting a carboxamide or carboxamide derivative of formula (IIIa) with a substituted alkanol of formula (IIIb)

[0171]

[0172] In another embodiment, the present application provides a method for synthesizing a compound of formula (IV)

[0173]

[0174] The method comprises reacting a carboxamide or carboxamide derivative of formula (IVa) with a substituted alkanol of formula (IV)

[0175]

[0176] In another embodiment, the present application provides a method for synthesizing a compound of formula (V)

[0177]

[0178] The method comprises reacting a hydrazide or hydrazide derivative of formula (Va) with a substituted alkanol of formula (Vb)

[0179]

[0180] In another embodiment, the present application provides a method for synthesizing a compound of formula (VI)

[0181]

[0182] The method comprises reacting an N-hydroxycarboxamide or N-hydroxycarboxamide derivative of formula (Via) with a substituted alkanol of formula (VIb)

[0183]

[0184]

[0185] Preferably, the method of the present application 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, thereby producing the desired compound in a one-step reaction.

[0186] 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.

[0187] Optionally substituted linear or branched alkyl can be C1-C 10 alkyl, optionally substituted linear or branched alkenyl can be C2-C 10 alkenyl, optionally substituted linear or branched alkoxy can be C1-C 10 alkoxy, optionally substituted cycloalkyl can be C3-C6 cycloalkyl, optionally substituted heterocycloalkyl can be C3-C6 heterocycloalkyl, optionally substituted aryl can be C3-C6 aryl and optionally substituted heteroaryl can be C3-C6 heteroaryl, which, when substituted, can be substituted with one or more occurrences of halogen, CN or OH. The aforementioned carbon number ranges, e.g. C1-C 10 alkyl, are to be understood as representing each member of the range.

[0188] R 1 and R 2 may be 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, optionally substituted aryl and optionally substituted heteroaryl. In one particular embodiment, R 1 and R 2 may be independently selected from the group consisting of optionally substituted linear or branched C1-C 10 alkyl.

[0189] R 3 may be 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.

[0190] R 3 may be 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.

[0191] X can be selected from the group consisting of hydrogen, OH, SH and NHR 4 and X 1 may be correspondingly selected from the group consisting of O, S, NR4 and a direct bond.

[0192] R 4 may be independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0193] Z is a silyloxy group, a methanesulfonic acid group, a p-toluenesulfonic acid group, or a halogen. The halogen atom can be bromine (Br), chlorine (Cl), iodine (I), or fluorine (F).

[0194] Exemplary compounds of the present application can be represented by the chemical structures provided in Table 1 below.

[0195] Table 1. Chemical structures of compounds of the present application.

[0196]

[0197]

[0198]

[0199]

[0200]

[0201] General Synthetic Method

[0202] Carboxamide, hydrazide or N-hydroxycarboxamide (1 eq) and haloalkanol (2 eq) were added to a single reaction vessel. The resulting mixture was heated to 130 °C in a microwave at 100 W power for 40 min. Alternatively, the resulting mixture was heated to 130 °C by heat for 12 h. The progress of the reaction was monitored by thin layer chromatography. The crude compound was purified by silica gel column chromatography in hexane: ethyl acetate solvent mixture. The purified compound was obtained in moderate to excellent yield of about 40% to about 90%.

[0203] The compound was characterized by FT-IR, NMR 1 H and 13 C) spectroscopy, and / or mass spectrometry.

[0204] Experimental Data

[0205] 2-phenyl-4,5-dihydro oxazole (1)

[0206] Yellow viscous liquid, yield = 90%. FTIR: (adsorbed on KBr, v 最大 , cm -1) : 3065.31 (C-H, Ar), 2960.16 (C-H, CH2), 2929.34 (C-H, CH2), 1719.19 (C=N), 1449.89 (C=C, Ar), 1271.43 (C-N), 1105.60 (C-O), 707.43 (C-H, Ar). NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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. 13 C-NMR (100 MHz, CDC13, 25°C): δ = 167.10 (C2), 133.43 (C9), 129.91 (C7), 129.61 (C6), 128.60 (C8), 64.36 (C5), 28.90 (C4) ppm.

[0207] 2-(prop-1 -en-2-yl)-4,5-dihydro oxazole (2)

[0208] Colorless liquid, yield 76.59%; NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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, CDC13, 25°C): δ = 167.26 (C2), 135.10 (C6), 126.40 (C7), 64.20 (C5), 28.90 (C4), 18.53 (C8) ppm.

[0209] 2-propyl-4,5-dihydro oxazole (3)

[0210] Yellow liquid, yield 39.66%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25°C) 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 CNMR (100 MHz, DMSO-d6, 25°C) δ = 173.29 (C), 63.73 (CH2), 36.14 (CH2), 28.84 (CH2), 18.53 (CH2), 13.74 (CH3) ppm.

[0211] 2-(chloromethyl)-4,5-dihydro oxazole (4)

[0212] Pale yellow liquid, yield 45.07%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2958.56 (C-H, CH2), 2922.89 (C-H, CH2), 2853.57 (CH, CH2), 1740.75 (C=N), 1265.00 (C-H), 1129.78 (C-O). NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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, CDC13, 25°C): δ = 166.83 (C2), 65.28 (C5), 41.07 (C6), 29.91 (C4) ppm.

[0213] 2-(4,5-dihydro oxazol-2-yl)acetonitrile (5)

[0214] Colorless liquid, yield 28.4%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2967.76 (C-H, CH2), 2929.11 (C-H, CH2), 2264.39 (nitrile), 1745.61 (C=N), 1192.30 (C-O). NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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, CDC13, 25°C): δ = 162.80 (C2), 112.91 (C7), 65.72 (C5), 27.89 (C4), 24.63 (C6) ppm.

[0215] 2-isopropyl-4,5-dihydro Oxazole (6)

[0216] Yellow liquid (350 mg); NMR: 1 H-NMR (400 MHz, DMSO-d6, 25 °C) 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 °C) δ = 176.7, 63.6, 33.9, 28.9, 18.9 ppm.

[0217] 2-(tert-Butyl)-4,5-dihydro Oxazole (7)

[0218] Pale yellow liquid, yield 68.80%; NMR: 1 H-NMR (400 MHz, CDCl3, 25 °C): 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 °C) δ = 178.18 (C), 63.71 (CH2), 38.94 (C), 29.04 (CH2), 27.22 (CH3) 3 ppm.

[0219] 2-Butyl-4,5-dihydro Oxazole (8)

[0220] Yellow liquid, yield 50.22%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25 °C) 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 °C) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7.

[0221] 2-(Trichloromethyl)-4,5-dihydro Oxazole (9)

[0222] Yellow liquid, yield 37.30%; NMR: 1H-NMR (400 MHz, DMSO-d6, 25 °C) 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 °C) δ = 161.7, 89.5, 67.9, 26.9 ppm.

[0223] 2-cyclohexyl-2,5-dihydro oxazole (10)

[0224] Yellow liquid, yield 66.73%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25 °C) 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 °C) δ = 175.63 (C), 63.51 (CH2), 43.08 (CH2), 29.06 (C), 29.03 (CH2)2, 25.78 (CH2), 25.44 (CH2)2 ppm.

[0225] 2-(2-iodophenyl)-4,5-dihydro oxazole (11)

[0226] Colorless liquid, yield 58.80%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2926.14 (C-H, CH2), 2892.53 (C-H, CH2), 1729.85 (C=N), 1289.37 (C-O), 1248.91 (C-O), 1089.39 (C-N), 1045.30 (C-N), 741.17 (C-H, Ar). NMR: 1 H-NMR (400 MHz, DMSO-d6, 25 °C) 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. 13C-NMR (400 MHz, DMSO-d6, 25°C) δ = 165.9, 141.5, 134.4, 133.1, 131.3, 129.8, 128.1, 64.9, 28.5 ppm.

[0227] 2-(Phenoxymethyl)-4,5-dihydro oxazole (12)

[0228] Colorless liquid, yield 48%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25°C) 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°C) 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.

[0229] 2-(Thiophen-2-yl)-4,5-dihydro oxazole (13)

[0230] Yellow liquid, yield 80.24%; NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 7.84 (dd, J = 3.7 Hz, 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 (1, J = 6.2 Hz, 2H), 3.61 (t, J = 6.2 Hz, 2H) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): δ = 161.7, 134.1, 133.0, 133.1, 127.9, 64.3, 28.6 ppm.

[0231] 2-(2-Fluorophenyl)-4,5-dihydro oxazole (14)

[0232] Colorless liquid, yield 60.23%; NMR: 1H-NMR (400 MHz, CDC13, 25°C): δ = 7.95 (dt, J = 7.6 Hz, 1.8 Hz, 1 H), 7.52 (m, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 7.13 (t, J = 9.6 Hz, 1 H), 4.63 (t, J = 6.1 Hz, 2 H), 3.63 (t, J = 6.1 Hz, 2 H) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): 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.

[0233] 2-(2-nitrophenyl)-4,5-dihydro oxazole (15)

[0234] yellowish liquid, yield 59.16 %: NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 7.95 (dd, J = 7.8 Hz, 1.3 Hz, 1 H), 7.77 (dd, J = 7.5 Hz, 1.7 Hz, 1 H), 7.70 (dt, J = 7.5 Hz, 1.4 Hz, 1 H), 7.66 (dt, J = 7.6 Hz, 1.7 Hz, 1 H), 4.64 (t, J = 6.2 Hz, 2 H), 3.60 (t, J = 6.2 Hz, 2 H) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): δ = 165.1, 148.2, 133.2, 132.1, 130.0, 127.3, 124.1, 65.5, 27.8 ppm.

[0235] 2-(2,5-dibromophenyl)-4,5-dihydro oxazole (16)

[0236] white solid, yield 80.10 %; NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 7.96 (d, J = 2.4 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.46 (dd, J = 8.5 Hz, 2.4 Hz, 1 H), 4.64 (t, J = 6.1 Hz, 2 H), 3.64 (t, J = 6.1 Hz, 2 H) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): δ = 164.3, 135.9, 134.4133.0, 121.2, 120.7, 65.1, 28.2 ppm.

[0237] 2-(2-bromo-5-methoxyphenyl)-4,5-dihydro oxazole (17)

[0238] yellowish liquid, yield 85.10%; NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 7.52 (d, J = 8.8 Hz, 1 H), 7.36 (d, J = 3.0 Hz, 1 H), 6.89 (dd, J = 9.0, 3.2 Hz, 1 H), 4.62 (t, J = 6.1 Hz, 2 H), 3.80 (s, 3 H), 3.63 (t, J = 6.1 Hz, 2 H)) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): 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.

[0239] 2-(2-bromo-4-methylphenyl)-4,5-dihydro oxazole (18)

[0240] yellowish liquid, yield 85.55%; NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 7.79 (d, J = 8.0 Hz, 1 H), 7.50 (s, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 4.62 (t, J = 6.2 Hz, 2 H), 3.64 (t, J = 6.10, 2 H), 2.37 (s, 3 H) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): 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.

[0241] 2-(2-bromo-3-methylphenyl)-4,5-dihydro oxazole (19)

[0242] yellowish liquid, yield 78.52%; NMR: 1H-NMR (400 MHz, CDC13, 25°C): δ = 7.53 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 7.5 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 4.64 (t, J = 6.2 Hz, 2 H), 3.64 (t, J = 6.2 Hz, 2 H), 2.46 (s, 3 H) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): 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.

[0243] 5-methyl-2-phenyl-4,5-dihydro oxazole (20)

[0244] Yellow liquid, yield 51.10% major: NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 8.08-8.04 (m, 2 H, 7-H), 7.58-7.52 (m, 1 H, 9-H), 7.45-7.41 (m, 2 H, 8-H), 5.35-5.27 (m, 1 H, 5-H), 3.60-3.53 (m, 2 H, 4-H), 1.47 (d, J = 6.3 Hz, 3 H, 5-CH3) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): 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. minor: NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 8.08-8.04 (m, 2 H, 7-H), 7.58-7.52 (m, 1 H, 9-H), 7.45-7.41 (m, 2 H, 8-H), 4.53-4.42 (m, 2 H, 4-H), 4.38-4.29 (m, 1 H, 5-H), 1.76 (d, J = 6.7 Hz, 3 H, 5-CH3) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): 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.

[0245] 2-phenyl-5,6-dihydro-4H-1,3- oxazine (21)

[0246] Colorless liquid, yield = 60%. FTIR: (absorbed on KBr, v 最大 , cm -1 ): 3063.22 (C-H, Ar), 2962.84 (C-H, CH2), 2867.63 (C-H, CH2), 1717.02 (C=N), 1451.19 (C=C, Ar), 1269.43 (C-N), 1110.18 (C-O), 705.43 (CH, Ar). NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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. 13 C-NMR (100 MHz, CDC13, 25°C): 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.

[0247] 2-(prop-1 -en-2-yl)-5,6-dihydro-4H-1,3- oxazine (22)

[0248] Colorless liquid, yield 38.48%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2960.69 (C-H, CH2), 2927.17 (C-H, CH2), 2857.59 (C-H, CH2), 1716.86 (C=N), 1156.02 (C-H). NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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. 13C-NMR (100 MHz, CDC13, 25°C): δ = 167.28 (C2), 136.27 (C7), 125.77 (C8), 62.49 (C6), 31.87 (C5), 29.47 (C4), 18.38 (C9) ppm.

[0249] 2-propyl-5,6-dihydro-4H-1,3- oxazine (23)

[0250] Pale yellow liquid, yield 64.85%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2963.76 (C-H, CH2), 2933.67 (C-H, CH2), 2875.46 (CH, CH2), 1734.70 (C=N), 1172.56 (C-H). NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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, CDC13, 25°C): 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.

[0251] 2-(chloromethyl)-5,6-dihydro-4H-1,3- oxazine (24)

[0252] Pale yellow liquid, yield 64.85%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2964.19 (C-H, CH2), 1736.12 (C=N), 1279.20 (CH), 1109.41 (C-O). NMR: 1H-NMR (400 MHz, CDC13, 25°C): 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, CDC13, 25°C): δ = 167.14 (C2), 63.92 (C6), 31.45 (C5), 29.05 (C4), 25.67 (C7) ppm.

[0253] 2-Isopropyl-5,6-dihydro-4H-1,3-

[0254] Yellow liquid, yield 62%; NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 4.18 (t, J = 5.34 Hz, 2H), 3.44 (t, J = 6.72 Hz, 2H), 2.57-2.50 (m, 1H), 2.20-2.13 (m, 2H), 1.15 (d, J = 7.03 Hz, 6H) ppm. 13 C-NMR (100 MHz, DMSO-d6, 25°C) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7. MS (ESI) m / z: 510.5 [M+H] + .

[0255] 2-Isopropyl-5,6-dihydro-4H-1,3-

[0256] Yellow liquid, yield 62%; NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ = 4.20 (t, J = 5.59 Hz, 2H), 3.45 (t, J = 6.45 Hz, 2H), 2.20-2.15 (m, 4H), 2.13-2.05 (m, 1H), 0.95 (d, J = 6.60 Hz, 6H) ppm. 13 C-NMR (100 MHz, DMSO-d6, 25°C) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7 ppm.

[0257] 2-Isopropyl-5,6-dihydro-4H-1,3-

[0258] Colorless liquid, yield 48%; NMR: 1 ​​​​​​H-NMR (400 MHz, CDC13, 25°C): δ = 4.20 (t, J = 6.10 Hz, 2H), 3.45 (t, J = 6.61 Hz, 2H), 2.30 (t, J = 7.85 Hz, 2H), 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°C) δ = 173.4, 63.6, 33.8, 28.8, 27.0, 22.2, 13.7 ppm.

[0259] 2-cyclohexyl-5,6-dihydro-4H-1,3- oxazine (28)

[0260] Yellow liquid, yield 43%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25°C) 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°C) 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.

[0261] 2-(2-iodophenyl)-5,6-dihydro-4H-1,3- oxazine (29)

[0262] Colorless liquid, yield 43.02%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2958.04 (C-H, CH2), 2921.01 (C-H, CH2), 2851.10 (C-H, CH2), 1726.65 (C=N), 1286.84 (C-O), 1246.07 (C-O), 1127.08 (C-N), 1102.66 (C-N), 739.24 (C-H, Ar). NMR: 1H-NMR (400MHz, CDCl3, 25°C): δ=7.98 (d, J=7.8Hz, 1H), 7.77 (dd, J=7.7Hz, 1H), 7.42-7.38 (m, 1H), 7.17-7.13 (m, 1H), 4.47 (t, J=6.00Hz, 2H), 3.51-3.47 (m, 1H), 2.33 (p, J=6.2Hz, 2H)ppm. 13 C-NMR (100MHz, CDCl3, 25℃): δ=166.43, 141.33, 135.25, 132.75, 130.98, 128.00, 93.97, 68.45, 30.63, 29.60ppm.

[0263] 2-(2-Bromophenyl)-5,6-dihydro-4H-1,3- Oxazine (30)

[0264] Yellow oil, yield 72%; FTIR: (adsorbed on KBr, v 最大 , 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 (400MHz, CDCl3, 25°C): δ=7.77 (d, J=7.35Hz, 1H, 9-H), 7.65 (d, J=7.35Hz, 1H, 12-H), 4.24 (m, 2 H, 10-H, 11-H), 4.48 (t, J=5.96Hz, 2H, 6-H), 3.56 (t, J=6.47Hz, 2H, 4-H), 2.35-2.28 (m, 2H, 5-H)ppm. 13 C-NMR (100MHz, 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.

[0265] 2-(Phenoxymethyl)-5,6-dihydro-4H-1,3- Oxazine (31)

[0266] Yellow liquid, yield 48%; NMR: 1H-NMR (400 MHz, DMSO-d6, 25°C) 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°C) 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.

[0267] 2-(Phenoxymethyl)-5,6-dihydro-4H-1,3- oxazine (32)

[0268] Yellow liquid, yield 46%; NMR: 1 H-NMR (400 MHz, DMSO-d6, 25°C) 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; 13 C-NMR (100 MHz, DMSO-d6, 25°C) 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.

[0269] 2-(Thiophen-2-yl)-5,6-dihydro-4H-1,3- oxazine (33)

[0270] Brown oil: 506 mg, yield 77%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2966.06 (C-H, CH2), 2923.78 (C-H, CH2), 1707.17 (C=N), 1257.56 (C-O), 1220.60 (C-O), 1095.48 (C-N), 747.31-721.26 (C-H, Ar). NMR: 1H-NMR (400 MHz, CDC13, 25°C): δ = 7.81 (d, 1 H, J = 2.34 Hz, 10-H), 7.56 (d, J = 2.34 Hz, 1 H, 8-H), 7.10 (t, J = 6.35 Hz, 2 H, 9-H), 4.44 (t, J = 6.03 Hz, 2 H, 6-H), 3.53 (t, J = 6.03 Hz, 2 H, 4-H), 2.33-2.26 (m, 2 H, 5-H) ppm. 13 C-NMR (100 MHz, CDC13, 25°C): 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.

[0271] 3-phenyl-5,6-dihydro-1,4,2-dioxazin-4-yl (34)

[0272] Colorless liquid; yield: 72.27%; FTIR: (absorbed on KBr, v 最大 , cm -1 ): 2957.91 (C-H, CH2), 2926.66 (C-H, CH2), 1718.47 (C=N), 1451.55 (C-H, Ar), 1264.74 (C-O), 1109.85 (C-O), 707.72 (C-H, Ar). NMR: 1 H-NMR (400 MHz, CDC13, 25°C): δ 8.06 (d, J = 8.0 Hz, 2 H, 8-H), 7.56 (t, J = 7.5 Hz, 1 H, 10-H), 7.4 (t, J = 7.8 Hz, 2 H, 9-H), 4.61 (t, J = 6.1 Hz, 2 H, 5-H), 3.63 (t, J = 6.1 Hz, 2 H, 6-H), ppm; 13 C-NMR (100 MHz, CDC13, 25°C): δ = 166.06 (C3), 133.29 (C10), 129.76 (C8), 129.65 (C7), 128.47 (C9), 64.24 (C5), 28.85 (C6) ppm.

[0273] 2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl (35)

[0274] Colorless liquid, yield: 65.00%; FTIR: (absorbed on KBr, v 最大 , cm -1) : 3461.01 (C-H), 2955.46 (C-H, CH2), 2928.29 (C-H, CH2), 1718.26 (C=N), 1264.13 (C-N), 1109.71 (C-O), 708.33 (C-H, Ar); NMR: 1 H-NMR (400 MHz, CDC13, 25°C): 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; 13 C-NMR (100 MHz, CDC13, 25°C): δ = 166.11 (C2), 133.33 (C10), 129.80 (C8), 129.69 (C7), 128.51 (C9), 64.28 (C6), 28.87 (C5) ppm.

[0275] The above description of certain illustrative embodiments of the application has been presented for the purpose of illustration and description. It is not intended to be exhaustive or to limit the application to the precise form disclosed, and many modifications and variations are possible in light of the above teachings. It is intended that the scope of the application be limited not with this detailed description, but rather by the claims appended hereto.

Claims

1. A method for synthesizing a compound of formula (II) The method comprises reacting a carboxamide or carboxamide derivative of formula (IIa) with a substituted alkanol of formula (IIb) in, X is selected from NH2, NHR 4 and OH; X 1 Selected from NH, O and NR 4 ; R 1 selected from hydrogen and optionally substituted linear or branched C1-C 10 alkyl; R 2 selected from hydrogen and optionally substituted linear or branched C1-C 10 alkyl; R is selected from hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, Z is a silyloxy group, a methanesulfonyl group, a p-toluenesulfonyl group, or a halogen atom selected from Br, Cl, I and F, R 4 is optionally substituted alkyl; and The method comprises providing the carboxamide or carboxamide derivative and the 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 produce the compound of formula (II).

2. A method for synthesizing a compound of formula (III) The method comprises reacting a carboxamide or carboxamide derivative of formula (IIIa) with a substituted alkanol of formula (IIIb) in, R 1 selected from hydrogen and optionally substituted linear or branched C1-C 10 alkyl; R 2 is selected from hydrogen and optionally substituted alkyl; R is selected from hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, Z is a silyloxy group, a methanesulfonyl group, a p-toluenesulfonyl group, or a halogen atom selected from Br, Cl, I, and F, and The method comprises providing the carboxamide and the 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 produce the compound of formula (III).

3. A method for synthesizing a compound of formula (IV) The method comprises reacting a carboxamide or carboxamide derivative of formula (IVa) with a substituted alkanol of formula (IVb) in, R 1 selected from hydrogen and optionally substituted linear or branched C1-C 10 alkyl; R 2 is selected from hydrogen and optionally substituted alkyl; R 3 and R 3’ are independently selected from hydrogen and optionally substituted alkyl; R is selected from hydrogen, optionally substituted linear or branched alkyl, optionally substituted linear or branched alkenyl, optionally substituted linear or branched alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, Z is a silyloxy group, a methanesulfonyl group, a p-toluenesulfonyl group, or a halogen atom selected from Br, Cl, I, and F, and The method comprises providing the carboxamide and the 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 produce the compound of formula (IV).

4. The method according to any one of the preceding claims, wherein R is selected from an optionally substituted linear or branched C1-C 10 Alkyl, optionally substituted linear or branched C2-C 10 Alkenyl, optionally substituted linear or branched C1-C 10 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C3-C6 aryl, and optionally substituted C3-C6 heteroaryl.

5. The process according to any one of claims 1 to 3, wherein the reaction is carried out in the absence of any solvent, catalyst, base or other reagent.

6. The method according to any one of claims 1 to 3, wherein R is a substituted linear or branched C1-C 10 Alkyl, the substituted linear or branched C1-C 10 The alkyl group is substituted with one or more groups selected from halogen, CN or OH.

7. The method according to any one of claims 1 to 3, wherein R is a substituted linear or branched C2-C 10 Alkenyl, the substituted linear or branched C2-C 10 The alkenyl group is substituted with one or more groups selected from halogen, CN or OH.

8. The method according to any one of claims 1 to 3, wherein R is a substituted linear or branched C1-C 10 Alkoxy, the substituted linear or branched C1-C 10 The alkoxy group is substituted with one or more groups selected from halogen, CN or OH.

9. The method according to any one of claims 1 to 3, wherein R is a substituted C3-C6 cycloalkyl, a substituted C3-C6 heterocycloalkyl, a substituted C3-C6 aryl, or a substituted C3-C6 heteroaryl, wherein the substituted C3-C6 cycloalkyl, the substituted C3-C6 heterocycloalkyl, the substituted C3-C6 aryl, or the substituted C3-C6 heteroaryl is independently substituted by one or more groups selected from linear or branched C1-C6 10 Alkoxy, halogen, NO2, optionally substituted linear or branched C1-C 10 Alkyl groups are substituted.

10. The method according to any one of claims 1 to 3, wherein R is a substituted C3-C6 aryl group, wherein the substituted C3-C6 aryl group is substituted with one or more halogens, NO2, linear or branched C1-C6 aryl groups. 10 Alkoxy, optionally substituted linear or branched C1-C 10 Alkyl groups are substituted.

11. The method according to any one of claims 1 to 3, wherein R is a group selected from:

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

13. The method according to claim 2, wherein the compound of formula (III) is a compound selected from the group consisting of: 2-phenyl-4,5-dihydro azole; 2-(Propan-1-en-2-yl)-4,5-dihydro azole; 2-propyl-4,5-dihydro azole; 2-(Chloromethyl)-4,5-dihydro azole; 2-(4,5-dihydro oxazol-2-yl)acetonitrile; 2-Isopropyl-4,5-dihydro azole; 2-(tert-Butyl)-4,5-dihydro azole; 2-Butyl-4,5-dihydro azole; 2-(Trichloromethyl)-4,5-dihydro azole; 2-Cyclohexyl-2,5-dihydro azole; 2-(2-iodophenyl)-4,5-dihydro azole; 2-(Phenoxymethyl)-4,5-dihydro azole; 2-(Thien-2-yl)-4,5-dihydro azole; 2-(2-Fluorophenyl)-4,5-dihydro azole; 2-(2-nitrophenyl)-4,5-dihydro azole; 2-(2,5-dibromophenyl)-4,5-dihydro azole; 2-(2-bromo-5-methoxyphenyl)-4,5-dihydro azole; 2-(2-bromo-4-methylphenyl)-4,5-dihydro azole; 2-(2-bromo-3-methylphenyl)-4,5-dihydro azoles; and 5-Methyl-2-phenyl-4,5-dihydro Azoles.

14. The method according to claim 3, wherein the compound of formula (IV) is a compound selected from the group consisting of: 2-phenyl-5,6-dihydro-4H-1,3- oxazine; 2-(Propan-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.

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