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SYNTHESIS OF NEW HETEROCYCLIC COMPOUNDSOF TETRAHYDROPYRANS SERIES

Nazym Yelibayeva, Kulzada Bazhykova, Almagul Umbetova

ABSTRACT

A number of new derivatives of tetrahydropyran (oxane), 5,6-dihydro-1,3-oxazine and tetrahydro-1,3-oxazine are synthesized on the basis of reactions of oxymethylation, amidomethylation, aminomethylation of various unsatu-rated compounds. The dependence of the nature of reaction products and their yield on the reaction conditions: a temperature, a ratio of the reagents, reaction duration, a nature of the catalyst and a concentration of the reacting substances and a catalyst is determined. The products obtained are identified and characterized.

Keywords: derivatives of piperidine, tetrahydropyrane (oxane), dihydro-1,3-oxazine, tetrahydro-1,3-oxazine.

Received 22 February 2018Accepted 28 February 2019

Journal of Chemical Technology and Metallurgy, 54, 3, 2019, 488-495

Al-Farabi Kazakh National University 71, Al-Farabi str., 050040, Almaty, KazakhstanE-mail: bazhikova@bk.ru

INTRODUCTION

Salinization, soil erosion and desertification are the most pressing ecological concerns affecting the degrada-tion and loss of productive agricultural land. In addition, several environmental stresses are found to affect crop productivity [1].

Salinity is one of the serious environmental con-straints. It is gradually increasing particularly in arid and semiarid regions of the world due to the mismanagement of the agricultural practices. Nearly 40 % of the world’s surface has salinity problems. The salt stress affects negatively the establishment, the growth and the devel-opment of the plants as well as the biological diversity and the stability of the ecosystems [2].

The derivatives of piperidine, tetrahydropyrane (oxane), 1,3-dioxane, dihydro-1,3-oxazine have a wide spectrum of biological and surface activity and are promising products to be used in medicine, agriculture and industry [3 - 7].

The tetrahydropyranes are structural motifs that are abundantly present in a range of biologically important marine natural products. As such, significant efforts are made to develop efficient and versatile methods of syn-thesis of tetrahydropyrane derivatives. The methods of syntheses of neopeltolide and its analogues, highlighting the synthetic strategies exploited for constructing the

tetrahydropyrane ring are reviewed in ref. [8].Oxazines which have been the object of interest for

the past three decades, still remain less studied. They are heterocyclic compounds containing one nitrogen and one oxygen atom. There are three isomers depending on the relative positions of the heteroatom and the double bonds. 1,2-, 1,3- and 1,4-oxazines are the O-analogues of the three isomeric diazines. Oxazine derivatives are an important class of heterocycles attracting much synthetic interest due to their wide range of biological activities. They have proved within the last few years to be valuable synthetic intermediates having important biological activities like sedative, analgesic, antipyretic, anticonvulsant, antitubercular, antitumour, antimalarial and antimicrobial one [9].

Oxazine heterocycles attract special interest because they constitute an important class of natural and non natural products of useful biological activities.

Despite the evident success these products are intro-duced into production in Kazakhstan with difficulty due to a limited number of commercially available schemes of synthesis and lack of raw materials.

In our opinion, the most promising methods which can be brought to a commercial level are those of oxy-methylation, amidomethylation, aminomethylation of unsaturated hydrocarbons. The latter are products of a thorough processing of hydrocarbon raw materials. The

Nazym Yelibayeva, Kulzada Bazhykova, Almagul Umbetova

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products obtained by these methods are promising plant growth stimulators.

The aim of this investigation is to synthesize new heterocyclic compounds with increased stimulating ac-tivity on the ground of the reactions of oxymethylation, amidomethylation, aminomethylation of unsaturated hydrocarbons.

EXPERIMENTAL

Oxymethylation of unsaturated hydrocarbons in acetic acid

Glacial acetic acid of an amount of 200 ml, 3 ml of concentrated sulphuric acid and 0.5 moles of paraform were introduced to a round-bottom flask provided with a mechanical mixer, a reflux condenser and a drop-ping funnel. The content of the flask was heated until paraform dissolution. Then the mixture was cooled to 45oС - 50oС and 0.25 moles of alkene were added drop-wise from the dropping funnel. The temperature of the mixture increased by 10 oС - 15oС during this step. The reaction mixture was heated again to 110oС and left to stand at this temperature for 2 h - 4 h.

After the reaction completion, the acetic acid was distilled under vacuum using a water-jet pump. The resi-due was diluted with 200 ml of water and extracted three times with 50 ml of carbon tetrachloride. The organic layer was washed out with 10 % solution of soda, water and dried over calcined magnesium sulphate. The solvent was distilled, while the product was isolated by distillation under vacuum using an oil pump or by recryctallization.

Amidomethylation of unsaturated hydrocarbonsGlacial acetic acid of an amount of 300 ml and 0.5

moles of N-methylolacetamide were introduced to a round-bottom flask provided with a mechanical mixer and a reflux condenser. The flask was immersed in a bath containing ice and water. Then 0.5 moles of alkene were added to 100 ml of acetic acid at 5oС - 10oС. This step was followed by the addition of 0.5 moles of sulphuric acid. The reaction mass was mixed for 2 h at a room temperature.

On the next day the acetic acid was distilled under the vacuum using a water-jet pump. The residue was diluted with 200 ml of water and the substances left untreated were separated. The aqueous layer was cooled to 5oС - 10oС, then benzene was added and the mixture was neutralized with solid alkali to рН = 10. The aque-

ous layer was separated from the benzene layer and the product was extracted twice with benzene. The mixed benzene layers were dried over calcined sodium sul-phate. The solvent was distilled, while the product was isolated by distillation under vacuum using an oil pump or by recryctallization.

Aminomethylation of unsaturated hydrocarbonsGlacial acetic acid of an amount of 200 ml, 3 ml

of concentrated sulphuric acid, 0.5 moles of paraform and 0.25 moles of primary amine hydrochloride were introduced to a round-bottom flask provided with a me-chanical mixer, a reflux condenser and a dropping funnel. The content of the flask was heated until all paraform was dissolved. Then the mixture was cooled to 45oС - 50oС and 0.25 moles of alkene were added dropwise from the dropping funnel increasing the temperature of the mixture by 10oС - 15oС. After this step the reaction mixture was heated again to 110oС and left to stand at this temperature for 2 h - 4 h. On the reaction comple-tion, the acetic acid was distilled under vacuum using a water-jet pump, the residue was diluted with 200 ml of water and the substances left untreated were separated. The aqueous layer was cooled to 5oС - 10oС and slowly neutralized with solid alkali to рН = 10. The organic layer was extracted three times with 50 ml of carbon tet-rachloride. The mixed extracts were dried over calcined magnesium sulphate. The solvent was distilled and the product was isolated by distillation under vacuum using an oil pump or by recryctallization.

Characterization of the products obtainedThe IR-spectra of the synthesized compounds ob-

tained were recorded on spectrometer Specord 75 IR, while the 1H NMR spectra were recorded on spectrom-eter Bruker DRX400 with an operating frequency of 400 MHz at the temperature of 25oC. СDCl3 was used as a solvent. The chemical shifts of the protons were expressed in δ scale. Gas chromatography was also applied using a mass detector of the brand GS Agilent Technologies 6890N MSD Agilent Technologies 5973N.

RESULTS AND DISCUSSION

Oxymethylation of unsaturated compoundsThe investigation of the reactions of oxymethylation

of unsaturated compounds shows that the nature of the

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reaction products and their yield depend on the reaction conditions: the temperature, the ratio of the reagents, the duration of the reaction, the nature of the catalyst as well as the concentration of the reacting substances and the catalyst. Our precious investigations [11] report that the main products of interaction of liquid aliphatic alkenes-1 with paraform solution in acetic acid in the temperature range (60 - 110oС) are 4-alkyl-1,3-dioxanes (1) (the yields up to 75 %), acetates of 3-alkyloxane-4-ols (2) (the yields 20 - 80 %), and diacetates of alkane-1,3-diols (3) (the yields up to 40 %). These results are obtained by gas chromatography with mass-selective detection (GS Agilent Technologies 6890N MSD Agilent Technologies 5973N). The reaction studied proceeds in correspond-ence with:

R-CH2-CH=CH2 + 2 CH2O HAc, H+

O

OCH2-R

+

O

OCOCH3R

+

OCOCH3

OCOCH3

CH2-R

1 2 3

R-CH2-CH=CH2 + 2 CH2O HAc, H+

O

OCH2-R

+

O

OCOCH3R

+

OCOCH3

OCOCH3

CH2-R

1 2 3

where R = C3H7, C5H11, C7H13

The best catalyst refers to sulphuric acid in an amount of 5 mass % - 10 mass % of loading. The use of phosphoric acid, p-toluenesulphonic acid, cation-exchange resin (KU-2) as catalysts decreases the yield of the target products. Acetic acid does not catalyze the process.

The use of formalin leads to derivatives of 4-R, 4-R’-1,3-dioxane (4) as main products. The yield of the product depends on the nature of the unsaturated compound. Aliphatic alkenes give low yields unlike the alkylaromatic one. The reaction in the latter case follows the equation:

O

Ph

+ 2 CH2O H+

O

O

O

Ph

4

At a molar ratio of α-olefin: formaldehyde of 1:1, the main reaction products refer to diacetates of alkane-1,3-diols and 4-R, 4-R’-1,3-dioxanes. At a ratio of unsatu-rated compound:formaldehyde = 1:3 and above, the main

reaction products are highly boiling fractions – products of a condensation. The latter formation is favored by increase of the temperatures (> 120oC) and the reaction duration (> 6 hours).

It is stated that in the temperature range from 100oC to 110oC the derivatives of 4-R, 4-R’-1,3-dioxane are subjected to recyclization into dihydropyrane derivatives (5) following the equation:

O

OPh

H+

-H2OO

Ph

5

Thus, the optimum conditions of obtaining deriva-tives of 4-R, 4-R’-1,3-dioxane and acetate of 3-R-oxane-4-ols refer to a temperature range from 60oC to 110oC and duration of the reaction up to 4 h. The main reaction products in the temperature range from 60oC to 80oC refer to derivatives of 4-R, 4-R’-1,3-dioxane, while acetates of 3-R-oxane-4-ols are preferably obtained in the temperature range from 90oC to 110oC.

The acetic acid dilution with water increases the yield of the derivatives of 4-R, 4-R’-1,3-dioxane and decreases the yield of the acetates of 3-R-oxane-4-ols.

Amidomethylation of unsaturated compoundsThe investigation of the reaction of amidomethyla-

tion of unsaturated compounds shows that the nature of the reaction products and their yield depend on the reac-tion conditions: the temperature, the ratio of the reagents, the duration of the reaction, the nature of the catalyst as well as the concentration of the reacting substances and the catalyst [12].

Sulphuric acid in a molar amount of loading is the best catalyst. Phosphoric acid, p-toluenesulphonic acid, cation-exchange resin (KU-2) and acetic acid do not catalyze the process.

Aliphatic unsaturated compounds do not undergo reactions of amidomethylation. High yields of deriva-tives of dihydro-1,3-oxazine (6, 7) are observed when using alkylaromatic hydrocarbons.

It is stated that the preliminary formation of N-methylolamides is required to achieve high yields. The reaction considered is described by:

CH2=C-CH3

Ph

+ HO-CH2-NH-C-CH3

OH+

HAc N

OH3C Ph

6

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491

Fig. 1. 1H NMR spectra of compound (4).

Fig. 2. 1H NMR spectra of compound (7).

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492

O

Ph

+ CH3CONHCH2OH H+

N

O

O

Ph

7

Aminomethylation of unsaturated compoundsThe investigation of the interactions of alkenes with

an aminomethylating reagent obtained by the reaction of methylamine hydrochloride with formalin shows that the nature of the reaction products (8, 9) and their yield depend on the nature of the alkene, the concentration of the aqueous solution of formaldehyde as well as the reaction conditions: the temperature, the ratio of the reagents and the amount of the catalyst [13].

The investigation shows that the reaction proceeds only with α-methylstyrene derivatives participation. The latter is described by:

Ph CCH3

H+

NN

OPh CH3

CH3

+

CH3

PhR R

8 9

CH R + 2 CH2O + CH3NH2 HCl

Ph CCH3

H+

NN

OPh CH3

CH3

+

CH3

PhR R

8 9

CH R + 2 CH2O + CH3NH2 HCl

The aliphatic alkenes do not react.The reaction proceeds in presence of formalin of

a concentration higher than 35 %. Homogenization with formalin is not observed when the formaldehyde amount is low.

The yield of the reaction products is affected by the ratio of the reagents and the amount of the catalyst. The best results are observed at a ratio styrene derivative: methylamine hydrochloride: sulphuric acid: formalde-hyde = 1:1:1:2:1. The optimum reaction conditions are: a temperature range of 90oC - 95oC, reaction time of 6 h.

The investigation of the reaction of aminomethylation of α-methylstyrene in acetic acid shows that acetates of 4-phenyloxane-4-ol (10) and 4-phenyldihydropyrane (11) form alongside with 4-phenyl-1,4-dimethyl-1,3-tetrahy-drooxazine (8). The reaction proceeding is described by:

H2C CH3

+ CH2O + CH3NH2*HCl+ H2SO4

CH3COOHO

N O

O

H3C

OH3CH3C

+O

+

108 11

H2C CH3

+ CH2O + CH3NH2*HCl+ H2SO4

CH3COOHO

N O

O

H3C

OH3CH3C

+O

+

108 11

Thus, the reaction of aminomethylation in acetic acid is accompanied by a reaction of oxymethylation.

2

O34 10

9O

6`

5 O67

8

1`2`3`

4`5`

2

N3 4109

O1

5 O67

8

1`2`3`

4`5`

6`

4 7

H1H

j

i

H HH

h gH Hf e

HH

c

d

H Hba

H

H H HHH

HH

HH

hg f e

d

cba

Compounds 4 and 7 are new ones among those syn-thesized. They are obtained in the form of white crystals of melting temperatures of 59oC (4) and 76oC (7). The func-tional composition of 8a-phenylhexahydropyrano[4,3-d][1,3]dioxine (4) and 8a-phenylhexa-hydropyrano[3,4-e][1,3]oxazine (7) is suggested on the ground of IR-spec-troscopic analysis. The characteristic absorption band of the phenyl group is observed in the IR-spectrum of (4) and (7) at 3055 cm-1 and 3077 cm-1. Absorption bands referring to C-H bonds stretching vibrations are recorded in the range of 2800 cm-1 - 3000 cm-1. The absorption band at 1642 cm-1 is attributed to N=C bond (7).

The structure of the synthesized compounds is iden-tified by 1H NMR- and 13C NMR-spectroscopy. The 1H NMR-spectra of compounds (4) and (7) are recorded in deuterated chloroform. They include the corresponding number of the proton signals. Multiplets of five phenyl protons with chemical shifts of 7.27 ppm - 7.21 ppm and 7.30 ppm - 7.16 ppm, respectively, are the lowest field signals of the protons of the synthesized compounds. Signals of two protons at C2 in the form of two doublets of centers at 4.72 ppm and 4.61ppm appear in the spec-trum of compound 4 on further shifting to the higher field area. They are absent in the spectrum of compound 7. But one proton of the latter appears at C2 in the form of a singlet with a chemical shift at 6.87 ppm. The signals at 2.90 ppm (4) in the form of a multiplet are referred to the protons at C10. The signals of the same proton in case of compound (7) are approximately in the same field (2.78 ppm) but in the form of a quintet. One of the protons at C4 appears in the form of a doublet with a

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Fig. 3. 13C NMR spectra of compound (4).

Fig. 4. 13C NMR spectra of compound (7).

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chemical shift 3.72 ppm and 2J = 12.42 Hz (coupling with Hg) and 3J = 7.69 Hz (coupling with 10H) (4). 8Ha and 8Hb protons are a doublet of a triplet with a chemical shift at 2.29 ppm and 2.04 ppm, respectively.

The 13C NMR spectra of compounds (4) and (7)

show an appropriate number of carbon signals (Figs. 3, 4). The signals of the carbon atoms of the benzene ring refer to chemical shifts in the ranges of 126,99 ppm - 128,40 ppm and 127,08 ppm - 128,43 ppm, respectively. The signals of carbon atoms C2 and C4

Chemical shift of protons δ (ppm), multiplicity and J in Hz Com-pound

2Hj 2Hi 4Hh 4Hg 5Hf 5He

4 4.72 d 2J=12.42

4.61 d 2J=12.42

3.72 dd 2J=12.42 3J=7.69

3.53 m

3.46 dd 2J=10.38 3J=5.61

3.26 dd 2J=12.36 3J=9.07

7 6.87 s

3.58 m

3.58 m

3.52 m

3.29 dd 2J=12.35 3J=8.29

Com-pound

7Hd 7Hc 8Hb 8Ha 10H H-Ph (5 proton)

4 3.53 m

3.62 dt 2J=12.44 3J=6.26

2.04 dt 2J=12.47 3J=6.26

2.29 dt 2J=12.44 3J=6.26

2.90 m

7.27-7.21 m

7 3.65 m

3.58 m

2.07 dt 2J=12.41 3J=5.00

2.33 dt 2J=12.40 3J=5.03

2.78 q 3J=8.15 3J=8.13

7.30-7.16 m

Table 1. Chemical shifts of protons of the compounds (4 and 7).

Chemical shift of carbons, δ (ppm), multiplicity and J in Hz Com-pound

C2 C4 C5 C7 C8 C9

4 89,62 s 2J=11

73,01 2J=6

64,3 2J=3

66,06 2J=8

68,61 2J=10

40,66 d 2J=4

7 75,39 2J=6

40,07 2J=4

68,61 2J=3

67,10 2J=8

68,61 2J=10

40,07 2J=4

Com-pound

C10 Car

2,6 Car 3,5 Car

4 C ar1

4 36,58 2J=11

126,99 dd 2J=17 2J=13

128,40 dd 2J=14 3J=16

127,4 2J=15

144,64 2J=12

7 49,41 2J=3

127,08 dd 2J=17 2J=15

128,43 dd 2J=16 3J=14

127,50 2J=15

144,17 2J=12.3

Table 2. Chemical shifts of carbons of the compounds (4 and 7).

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495

have different chemical shifts for compounds (4) and (7). The C2 signals are at 89.62 ppm for compound 4, while at 75.39 ppm for compound 7. The signals of the C4 atom are at 73.01 ppm for compound 4 and at 40.07 ppm for compound 7 (Table 2).

CONCLUSIONSDerivatives of tetrahydropyrane (oxane), 5,6-di-

hydro-1,3-oxazine and tetrahydro-1,3-oxazine are synthesized by oxymethylation, amidomethylation and aminomethylation reactions. The nature of the re-action products and their yield depend on the reaction conditions: the temperature, the ratio of the reagents, the duration of the reaction, the nature of the catalyst as well as the concentration of the reacting substances and the catalyst.

Overal 11 compounds are synthesized. Compounds 4 and 7 are new among them. Their structure is identi-fied by IR- and NMR-spectroscopy. These compounds are sent for bioscreening for determination of their biological activity.

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