Synthesis of Chromones, Annulated with Oxygen-Containing Heterocycles with Two Hetero Atoms at C(7)-C(8) Bond

FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2019, VOLUME 07, ISSUE 01)

Synthesis of chromones, annulated with oxygen-containing heterocycles with two hetero atoms at C(7)-C(8) bond

Tetyana Shokol*, Natalia Gorbulenko, Volodymyr Khilya

Taras Shevchenko National University of Kyiv, Volodymyrska Street, 64/13, Kyiv 01601, Ukraine [email protected]

Keywords: annulation, chromones, 6H-[1,3]dioxolo[4,5-h]chromen-6-one, 2,3-dihydro-7H- [1,4]dioxino[2,3-h]chromen-7-one, 3,4-dihydro-2H,8H-[1,4]dioxepino[2,3-h]chromen-8-one, 2,3- dihydro-1H,7H-chromeno[7,8-b][1,4]oxazin-7-one, 4H,12H-pyrano[2,3-a]phenoxazine-4-one, 9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one. The present review represented the advanced synthetic strategies for chromones annulated at the C(7)-C(8) bond with five-membered, six-membered, and seven-membered oxygen-containing heterocycles with two heteroatoms, such as 6H-[1,3]dioxolo[4,5-h]chromen-6-one, 2,3-dihydro-7H- [1,4]dioxino[2,3-h]chromen-7-one, 3,4-dihydro-2H,8H-[1,4]dioxepino[2,3-h]chromen-8-one, 2,3- dihydro-1H,7H-chromeno[7,8-b][1,4]oxazin-7-one, 4H,12H-pyrano[2,3-a]phenoxazine-4-one and 9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one. The biological activity of naturally occurring and modified synthetic fused hetarenochromones has been also highlighted. ______Introduction Chromone derivatives annulated with oxygen- Angular hetarenochromones are of containing ring with two heteroatoms, such as considerable interest because of their dioxolane and dioxane cycles, were also abundance in natural flavonoids and some isolated from various natural sources. Their alkaloids and promising biological activity O,N-containing analogues remain unobserved [1]. Chromones annulated with oxygen- among natural products. Chromones containing cycle occupy a significant place annulated with oxazole and oxazine cycles, among them. These are first and foremost namely 2-methylchromeno[7,8-d][1,3]оxazol- furo[2,3-h]chromones and pyrano[2,3- 6-оne, chromeno[7,8-d][1,3]оxazol-2,6(3Н)- f]chromones. Their syntheses and biological dіоne, 4Н-chromeno[8,7-d][1,2]оxazol-4-оne activity have been highlited in reviews [1, 2].

121 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2019, VOLUME 07, ISSUE 01) and 3,4-dihydrochromeno[8,7-b][1,4]оxazin- parts of Tephrosia maxima [6-8] and 7,8- 7(2Н)-оne are described in the review [1]. methylenedioxy-4'-methoxyisoflavone 4 from The present mini review is a continuation Indigofera linnaei [9] (Figure 1). of the review [1] and is focused on the O syntheses of chromones annulated at the C(7)- O O O C(8) bond with five-membered, six- O O Pr O O membered, and seven-membered oxygen- containing heterocycles with two heteroatoms, O OH O 1а granulosin such as 6H-[1,3]dioxolo[4,5-h]chromen-6- 2а bausplendin O one, 2,3-dihydro-7H-[1,4]dioxino[2,3- O O h]chromen-7-one, 3,4-dihydro-2H,8H- R2

[1,4]dioxepino[2,3-h]chromen-8-one, 2,3- O R1 dihydro-1H,7H-chromeno[7,8-b][1,4]oxazin- 3a maxima isoflavone А 1 2 R -R =OCH2O 7-one, 4H,12H-pyrano[2,3-a]phenoxazine-4- 3b maxima isoflavone D 1 2 one and 9,10-dihydro-4H,8H-chromeno[8,7- R =R =OMe 4 R1=OMe, R2=H e][1,3]oxazin-4-one. Figure 1. Natural 6H-[1,3]dioxolo[4,5-h]chromen-6- ones 1. Chromones, annulated with heterocycles Two strategies were applied for the containing two oxygen atoms construction of the 6H-[1,3]dioxolo[4,5- This section is dedicated to the progress of h]chromen-6-one system: the formation of the chromones annulated with dioxolane, dioxane dioxolane cycle on the basis of 7,8- and dioxepane rings. dihydroxychromones and the annulation of

the γ-pyron ring to benzodioxole derivatives. 1.1. 6H-[1,3]dioxolo[4,5-h]chromen-6-ones The first one was realized in the The system with an annulated dioxolane synthesis of bausplendin 2a and its analogues cycle to the chromone nucleus at the C(7)- 2b,c, which were synthesized from the C(8) bond occurs in some natural flavonoids, corresponding 7,8-dihydroxyflavones by such as granulosin 1a from the bark of alkylation with diiodomethane [5], Galipea granulosa [3, 4], bausplendin 2a dibromomethane [10] or methylene sulfate from Bauhinia shlendens [5], maxima [11] in DMSO [5], DMF [10] or acetone [11] isoflavones A (3a) and D (3b) from aerial in the presence of an inorganic base: Na2CO3

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[5], K2CO3 [11] or KF [10] (Scheme 1).

о OH а. CH2I2, Na2CO3, DMSO, 8.5 h, 50-60 С O b. CH Br , KF, DMF, 1.5 h, 120оС O 1 HO O R1 2 2 O R c. methylene sulfate, K2CO3, acetone,20 h, 

R2 R2 O R3 O R3 2а [5] 1 2 3 2b R =4-HOC6H4, R =H, R =OH [10] 2с R1=Ph, R2=H, OMe, R3=H [11]

Scheme 1. The synthesis of bausplendin 2a and its analogues 2b,c

7,8-Methylenedioxyisoflavones and their completed in 36 [12] and 15 hours [8], thiazole analogues of formula 5, were respectively. When DMF [8, 14, 15] or its prepared via the alkylation of the mixture with acetone [13] has been used as a corresponding 7,8-dihydroxychromones by solvent, the reaction time was reduced to 1,5- diiodo [12, 13] and dibromomethane [8, 14, 2 h and yield of target products was increased

15] in the presence of K2CO3. When heated in (Scheme 2). acetone or dioxane, the reaction was

OH O O HO O R а. CH2I2, K2CO3, acetone, 36 h,  O R [12, 13]], or Het(Ar) Het(Ar) b. CH2Br2, K2CO3, DMF, 1.5-2 h O or dioxane, 15 h, 80-90оС O [8, 14, 15] 5

R=H, Me, CF3; Het(Ar)= Ph, 4-FC6H4, 4-ClC6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3, O O N Me N , , , Me S S O O

Scheme 2. The synthesis of 7,8-methylenedioxyisoflavones and their thiazole analogues 5

Alkylation of the natural chromone retusin evolution of HCI gas ceased (5 min) resulted 6, with α-dichlorodiphenylmethane upon in the diphenylmethylene derivative 7 [16] heating in an oil bath to 210oC until the (Scheme 3).

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Ph Ph OH Ph Cl Ph O HO O Cl O O

OMe 210oC, 5 min OMe O O 6 7 Scheme 3. Alkylation of the natural chromone retusin 6 with α-dichlorodiphenylmethane

Granulosin 1a and its analogues 1b-e, all 2'-hydroxy-3',4'-methylendioxy)acetophenone of which exhibit toxicity to the brine shrimp 8 with two equivalents of sodium ethoxide in Artemia salina, have been prepared from ethanol afforded the enolate which, on 2',3',4'-trihydroxyacetophenone using a reaction with a series of ethyl carboxylate second approach. The first step of the esters gave mixtures of the corresponding synthesis involved the formation of the enols 9 and their cyclic derivatives 10, benzodioxole derivative 8 via the according to NMR spectroscopy. Treatment of regioselective acetalisation of 2',3',4'- these mixtures with a mixture of acetic and trihydroxyacetophenone (Scheme 4) using 1 sulfuric acids afforded 7,8- equivalent of bromochloromethane in the methylenedioxychromones 1a-e in 58-85% presence of cesium carbonate. Treatment of yields [4].

OH O O 1. NaOEt, BrCH Cl O HO OH 2 OH EtOH O OH Cs CO , 2 3 2. RCO2Et R DMF O O 9 O OH 8 + O O O O R OH AcOH, H2SO4 O O R

58-85 % O 10 O 1а-е R=Pr (a), Me (b), Et (c), i-Pr (d), PhCH (e) 2

Scheme 4. The synthesis of Granulosin 1a and its analogues 1b-e

Cyclization of chalcones 11, obtained from 7,8-methylenedioxyflavones 13 [9, 17, 18] acetophenone 8 and benzaldehydes, in TFA (Scheme 5). Finally, the flavone 13b was also resulted in 7,8-methylenedioxyflavanones 12, prepared in 95% yield by simply heating which on oxidation with I2 in DMSO gave chalcone 11b under reflux in DMSO

124 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2019, VOLUME 07, ISSUE 01) containing a crystal of I2 [9].

O O CF COOH, O I , DMSO, O OH 3 2 O 2 h,  O O Ar 45 min,  O Ar Ar

O 12a-d O O 11a-d 13a-d I2, DMSO, 45 min, 

Ar = 2-MeOC H (a), (b)4-MeOC H (b), 3,4-(MeO) C H (c), 3,4,5-(MeO) C H (d) 6 4 6 4 2 6 3 3 6 2

Scheme 5. Oxidative cyclization of chalcones 11 This new series of chalcones 11, readily available plant metabolite from dill flavanones 12 and flavones 13 have been and parsley seeds [19] (Scheme 6). The assessed for their effect on proliferation, reaction sequence involved an efficient cytotoxic potential and apoptosis in human conversion of the key intermediate epoxide 16 leukemia cells. Among the tested compounds, into the respective β-ketoaldehyde 17 the chalcone series showed the best activity followed by its Cu(I)-mediated cyclization and chalcone 11a showed a significant effect into the target 7,8-methylenedioxyisoflavone on down-regulation of cancer cell 14 and its 5-unsubstituted derivative 15, proliferation and viability in three different obtained due to the instability of the 5-OMe leukemia cell lines (K562, Jurkat, U937) [17]. group under experimental conditions (overall A mixture of 7,8- yield 22%). The latter compound 15 was methylenedioxyisoflavones 14 and 15 (13:10 successfully isolated from the reaction ratio, respectively) was obtained starting with mixture via chromatography. O O 5 stages O O Br OMe NaOH, H2O2 EtOH, 57 h MeO MeO OMe , 20-30oC OMe OMe O

BF -Et O O 3 2 O CH Cl O Br 2 2 O Br O O 3 h, 20оС MeO inert MeO atmosphere OMe O OMe O OMe OMe 16 17 OMe OMe

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2-Picolinic acid, O O Cu(I)I, K CO , O 2 3 O O O DMF, 8 h, + 135-140î Ñ MeO MeO OMe O O OMe OMe 15 OMe 14 OMe

Scheme 6. The synthesis of 7,8-methylenedioxyisoflavones 14 and 15 from epoxides 16

7,8-Methylenedioxyisoflavones and their and borontrifluoride-diethyletherate, followed homoanalogs can also be obtained via by methanesulfonylchloride addition and formylation of deoxybenzoines and their heating at 90°-100° for 2 h [20]. 2’-Hydroxy- homo-analogs followed by the γ-pyron ring dihydrochalcone 20 was subjected to closure, as shown in Scheme 7. Thus, 4-(6- cyclization by treatment with N,N- oxo-6H-[1,3]dioxolo[4,5-h]chromen-7- dimethylformamide diethyl acetal to give yl)benzoic acid 18, patented as useful for homoisoflavone 21, which on reduction and treating vascular diseases, was obtained from deracemization resulted in homoisoflavonone, deoxybenzoine 19 upon treatment with DMF isolated from Chlorophytum Inornatum [21].

O 1. DMF, BF3-Et2O, O O OH 50oC O O 2. methanesulfonylchloride, 90-100 oC O OH O OH

19 O 18 O

EtO O O O N O O HCO NH , Pd/C O O O OH EtO 2 4 THF / MeOH PhMe, 10 h,  50oC inert atmosphere O O O 20 21

OMe OMe OMe

Scheme 7. The synthesis of 7,8-methylenedioxyisoflavones and their homoanalogs via formylation of deoxybenzoines and their homo-analogs

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Synthesis of 5-hydroxy-2-methyl-7,8- methoxy-7,8-methylenedioxy-4'- methylenedioxy-4'-methoxyisoflavone 22 by methoxyisoflavone 23 using the second the first approach and its conversion to 5- strategy is reported in [22] (Scheme 8).

OH O Me2SO4 HO O methylene sulfate O O K2CO3

KOH, EtOH, H O, acetone Ar 2 о Ar  30 h 45-50 С, N2 atm. OH O OH O

Ar= 4-MeOC6H4 22

O O O O KOH, O O O O OH HCO2Et EtOH, H2O, Na -10oC  2 h Ar Ar Ar 3 days N2 atm. OMe O OMe O OMe O 23

Scheme 8. The synthesis of 7,8-methylenedioxyisoflavones 22 and 23

1.2. 2,3-Dihydro-7H-[1,4]dioxino[2,3- This system is the basis of the molecules of h]chromen-7-ones scutellasprostins A, B, C 24a-c [23] and xanthocercines A and B 25a,b [24] - Annulation of the 1,4-dioxane heterocycle flavolignans isolated from the plants to the chromone system at C(7)-C(8) bond Scutellaria prostrata and Xanthocercis leads to the formation of 2,3-dihydro-7H- zambesia, respectively (Figure 2). [1,4]dioxino[2,3-h]chromen-7-ones.

OMe OMe HO OH R2 HO OH R1 O R O O O O O

24а-c OH O 25a,b O OMe scutellasprostin A R1=R2=H B R1=OH, R2=H xanthocercine A R=MeO C R1=R2=OH B R=H

Figure 2. Natural 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-ones

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Synthesis of these compounds and their isoflavones in the presence of silver oxide analogues was realized by oxidative coupling [23-25] or horsradish peroxidase [26] of the coniferyl or synapic alcohol with the (Scheme 9). corresponding natural flavones and

OMe OMe HO HO OH R2 OH R1 O R1 Ag O, OH + 2 O O HO O 2 acetone, benzene, R 50-60оС

24 R3 O R3 O R3=H, OH R1=R2=H; R1=OH, R2=H; R1=R2=OH OMe HO OMe HO OH OH R Ag2O, + R O OH MeOH, benzene, HO O 20 h, room.t. O O OMe OMe 25 R=H, OMe O O OMe OMe

Scheme 9. The synthesis of natural 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-ones Synthetic analogues of xanthocercin with hetaryl analogues via the alkylation with 1,2- unsubstituted dioxane ring 26, were prepared dibromoethane in dioxane or DMF in the from 7,8-dihydroxyisoflavones and their 3- presence of K2CO3 [8, 14, 15] (Scheme 10).

OH O Br HO O R Br O O R

Het(Ar) K2CO3, DMF, 1.5-2 h Het(Ar) î O or dioxane, 15 h, 80-90 Ñ O 26 R=H, Me, CF3; Het(Ar)= Ph, 4-FC6H4, 4-ClC6H4, O O N Me N , , , Me S S O O Scheme 10. The synthesis of 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-ones via the alkylation of 7,8- dihydroxychromones with 1,2-dibromoethane Upon alkylation of 7,8-dihydroxyflavone 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen- with 2-chloromethyloxirane 3-hydroxymethyl- 7-one 27 [27] was obtained, while the reaction

128 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2019, VOLUME 07, ISSUE 01) with ethyl 2,3-dibromopropanoate resulted in series of amides 30a-f in 40-73% yields [28] a mixture of the regio isomers 28 and 29, (Scheme 11). In the spasmolysis test, 30b which was separated by fractional showed significant antagonistic effect towards crystallisation. Selective group transformation the acetylcholine agonists, barium chloride in compound 29 using various and histamine [28]. ethylenediamine derivatives is furnished in a

O OH O HO O Ph Cl O O Ph

K2CO3, acetone, 30 min, 100оС O O 27

EtO O

Br OH EtO Br O HO O Ph O O Ph O

K2CO3, acetone, 30 min,  O 28 8 % O R1 1 2 N R + R NH OEt 2 N R NH2 O O O O O O Ph EtOH O O Ph 2 h, 80oC

O 30 29 44 % O R1=R2=H(a), Me (b), Et (c); R1=H, R2=Me (d), Et (e), i-Pr (f)

Scheme 11. The synthesis of 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-ones with substituted dioxine ring

An alternative way to the 2,3-dihydro-7H- chlorides followed by rearrangement into β- [1,4]dioxino [2,3-h]chromene-7-one system is diketones 32 and their cyclization in an acidic the construction of γ-pyron ring based on medium produced 9-(het)aryl-2,3-dihydro-7H- benzodioxane derivatives. [1,4]dioxino[2.3-h]chromen-7-ones 33, which Acetylation of 5-hydroxy-6- were tested for the ability to activate the cystic acetylbenzodioxane 31 with (het)aroyl ﬁbrosis transmembrane conductance regulator

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(CFTR) of both wild type CFTR and a mutant in some human subjects [29] (Scheme 12). CFTR (G551D-CFTR) that causes cystic ﬁbrosis

O O R O H SO O O O 2 4 , AcOH,  O O R O OH R Cl O O KOH, Py O OH 40oC Py, 0-20oC R 33 O 31 O O 32 O O R=Ph, 2-FC H , 4-MeOC H , 4-FC H , 3-FC H , 4-IC H , pyridin-4-yl 6 4 6 4 6 4 6 4 6 4

Scheme 12. The synthesis of 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-ones starting from 5-hydroxy-6- acetylbenzodioxane

Condensation of 3-hydroxymethyl-5- derivative 34, which was further modified by hydroxy-6-acetylbenzodioxane with N,N- the hydroxyl group into compounds 35, dimethylformamide dimethylacetal and patented as useful for the treatment of subsequent cyclization in the presence of depressive disorders [30, 31] (Scheme 13). sulfuric acid results in 2-hydroxymethyl

OH DMF-DMA, OH OH xylene, N , 120oC, H SO O 2 2 4 O 45 min O H O, O OH 2 O OH N O O o N2, 120 C, 45 min F O 34 O O

OTs N N H HN TsCl, Py O O O O o O O DMSO N2, 20 C

O O 35

Scheme 13. The synthesis of 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-ones starting from 3-hydroxymethyl- 5-hydroxy-6-acetylbenzodioxane

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1.3. 3,4-Dihydro-2H,8H-[1,4]dioxepino[2,3- with benzodioxane, benzodioxepane and h]chromen-8-ones thiazole substituents with 1,3- Annulation of dioxepane cycle to dibromopropane in DMF (1,5-2 h) or dioxane chromone system was carried out using the (22 h), products of the dioxepane cycle same starting 7,8-dihydroxychromones, on the annulation to the chromone nucleus, namely basis of which chromones condensed with 3,4-dihydro-2H,8H-[1,4]dioxepino[2,3- dioxolane and dioxane cycles were h]chromen-8-ones 36 were formed [8, 14, 15] synthesized. (Scheme 14). Thus, upon the alkylation of 7,8- dihydroxyisoflavones and their analogues

OH O HO O R Br Br O O R

K CO , DMF,  1.5-2 h Het(Ar) 2 3 Het(Ar) or dioxane, 22 h, 80-90оС O O 36

R=H, Me, CF3; Het(Ar)= Ph, 4-FC6H4, 4-ClC6H4, O O N Me N Me , , , S S O O Scheme 14. The synthesis of 3,4-dihydro-2H,8H-[1,4]dioxepino[2,3-h]chromen-8-ones

2. Chromones, annulated with 7-one. 8-Nitro-7-(2-oxopropoxy)chromone 37 (benz)oxazine cycles has been selectively reduced to the amine, 2,3-Dihydro-1H,7H-chromeno[7,8- which spontaneously cyclizes into 2-methyl- b][1,4]oxazine-7-one is an aзаanalogue of 2,3-dihydro-1H,7H-chromeno[7,8- 2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromene- b][1,4]oxazin-7-one 38 [32] (Scheme 15).

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NO2 NH O O CO Et H /Pd/C O O CO Et O 2 2 2 EtOH

O O 37 38

Scheme 15. The synthesis of 2-methyl-2,3-dihydro-1H,7H-chromeno[7,8-b][1,4]oxazin-7-one 38

Its 2-oxo analogue 39 was obtained upon 2,7-diones 41, synthesized on the basis of 7- cyclization of 7-hydroxy-8- hydroxy-8-aminochromones 42 and pulvinic chloroacetylaminochromone 40 in the acid dilactone, were tested for antimicrobial presence of AcOK [32] (Scheme 16). 2,3- activity [33] (Scheme 16). Dihydro-1H,7H-chromeno[7,8-b][1,4]oxazin-

Cl O

O NH NH

HO O CO2Et AcOK O O CO2Et

EtOH, 1 h,  O O 40 39

O O Ph O O O Ph NH NH 2 O Ph HO O Ph O O O OH

R AcOH, 3-4 h  R or 12 h, room. t. O O 42 41 R=H, Me

Scheme 16. The synthesis of 2,3-dihydro-1H,7H-chromeno[7,8-b][1,4]oxazin-2,7-diones 39 and 41

The interaction of 7-hydroxy-8- the benzoxazine ring to the chromone nucleus aminochromone 42 with a number of ortho- and formation of 4H,12H-pyrano[2,3- nitrochlorobenzenes resulted in annulation of a]phenoxazine-4-ones 43 [34] (Scheme 17) .

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R NO2 R2 1 NH2 R NH O N R HO O 2 AcONa O O + Cl R1 EtOAc 2h, reflux NO O 2 O 42 R=Cl, NO ; R1=H, Me, Cl; R2=H, Me 43 2

Scheme 17. The synthesis of 4H,12H-pyrano[2,3-a]phenoxazine-4-ones 43

Upon the interaction of 7- one nucleus took place leading to the hydroxychromones 44 with amines and the annulation of the 3,4-dihydro-1,3-oxazine ring excess (2 equiv.) of formalin under the to the chromone core and the formation of Mannich reaction conditions simultaneous C- 9,10-dihydro-4H,8H-chromeno[8,7- and O-aminomethylation of the benzopyran-4- e][1,3]oxazin-4-ones 45 [35-41] (Scheme 18).

R N R-NH2, 1 1 HO O R CH2O (excess) O O R

R3 R2 R2 O O 44 45

1 3 R =H, Me, CF3; R =H, Me, Et, Pr;

2 R =Ph, 2-FC6H4, 2-MeOC6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3, Me N N O S N N N ; ; ; ; ; N Ph S O S N Me O CO2Me Ph

R=Pr, i-Pr, MeO(CH2)3, MeO(CH2)2, 2-MeOC6H4(CH2)2, Ph(CH2)3, cyclopropyl, sulfolan-3-yl, pycolyl-4, 4-MeOC6H4,

(CH ) O N 2 n (CH ) X 2 n n=1, 2; X=O,S N

CH2COOH, (CH2)2COOH, CH(Alk)CO2Me Alk=Me, CHMe , CH CHMe , CH Ph, CH(Me)Et 2 2 2 2

Scheme 18. The synthesis of 9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-ones 45

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As a substrate, natural flavones [35], the product 45 in a satisfactory yield, while isoflavones [36, 37], their synthetic analogues the reaction with o-substituted anilines have [37-39] and 3-hetaryl derivatives [40] were not resulted in the desired polycyclic system used. Primary aliphatic [36, 37], aromatic [36]. [36], heterocyclic amines [35], amino acids The reaction with amino acids and [40] and their esters [39], amino alcohols [41] their esters was carried out in aqueous- and alkaloids [38] served as an amine alcoholic solution without a catalyst with the component. excess (2 equiv.) of amino acid. While the For the first time, the 45 system was interaction of isoflavones with amino acid obtained in 31% yield from 7-hydroxyflavone esters runs smoothly and derivatives 45 [39] and 2-amino-4-phenylthiazole, when boiling form in high yields, the reaction products of in acetic acid with an excess of 40% formalin 7-hydroxy-3-hetarylchromones and amino and paraform followed by ammonia treatment, acids depend on the type of heterocycle and after removal of the solvent [35]. amino acid [40]. 9,10-Dihydro-4H,8H- The reaction of isoflavones with amines chromeno[8,7-e][1,3]oxazin-4-ones 45 were was carried out by refluxing in propanol-2 in synthesized from glycine and 3- the presence of a catalytic amount of N,N- azolylchromones, except 3- dimethylaminopyridine (DMAP). With isoxazolylchromone [40]. In this case, the aliphatic amines, as well as benzyl- or Mannich base 46 was isolated (Figure 3). The hetarylalkylamines and alkaloid lupine reaction with β-alanine is similar to the derivative, 9,10-dihydro-4H,8H- reaction with glycine, while proline did not chromeno[8,7-e][1,3]oxazin-4-ones 45 are participate in the reaction and bis(6-ethyl-3- formed in 65-84% yields. In the case of hetaryl-7-hydroxychromon-8-yl)methanes 47 aromatic amines, p-methoxyaniline formed were isolated 47 [40] (Figure 3).

H Et Et N COOH OH OH HO O O O N O O O Het Het O 47 N N 46 Het= ; Me CO Me N O 2 Ph

Figure 3. Structures of Mannich reaction products 46 and 47

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In the case of 3-azinylchromones, (3- hydroalkyl)-9,10-dihydro-4H,8H- pyridyl- and 3-quinolylchromones) complex chromeno[8,7-e][1,3]-oxazin-4-ones 45 mixtures of unidentifiable products were and/or the tautomeric 7-hydroxy-8-(1,3- obtained [40]. oxazepan-3-ylmethyl)-4H-chromen-4-ones 48 An attempt of receiving a linear system [41] (Scheme 19). The ratio of these isomeric to 45 from 8-substituted-7- tautomers was dependent on solvent polarity, hydroxychromones and glycine under above electronic effects of aryl substituents in the mentioned conditions [40] failed. isoflavone and the structure of the amino The aminomethylation of 7- alcohol. NMR studies confirmed the hydroxyisoflavones with 2-aminoethanol, 3- interconversion of tautomeric forms. amino-1-propanol, 4-amino-1-butanol and 5- amino-1-pentanol in the presence of excess formaldehyde led principally to 9-(2-

CH2(CH2)nOH (CH2)n N O N

a or b O O R1 O R1 or c HO 44 R3 R3

O O R2 R2 45 48 R1=H, Me, CF ; R2=F, OMe; R3=H, OMe 3 O (a) HOCH2(CH2)nNH2, where n = 1-4, CH2O, EtOH or i-PrOH, DMAP, 80 C, 4–6 h; (b) bis(1,3-oxazolidin-3-yl)methan, dioxane, 100 OC, 2-4 h; (c) 3-butoxymethyl-1,3-oxazolidin, dioxane, 100 OC, 2-4 h.

Scheme 19. Aminomethylation of 7-hydroxyisoflavones with aminoalcohols 6-Hydroxymethyl-9,10-dihydro-4H,8H- R N chromeno[8,7-e][1,3]oxazin-4-ones 49 O O Ph (Figure 4), synthesized from natural flavone HO chrysin, fluoroanilines and an excess (12 OH O equiv.) of formalin in MeOH were patented as 49 useful in treating hyperuricemia [42] (Figure R = 4-FC H , 2,4-F C H , 4-CF C H 6 4 2 6 3 3 6 4 4). Figure 4. Structures of Mannich reaction products 49

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In recent years, with the rapid development excellent thermal properties was synthesized of biobased materials, using renewable from daidzein, paraformaldehide and phenolic or amine derivatives to replace the furfurylamine by using a microwave-assisted petroleum-based raw materials for the heating method in DMSO or PEG 400 as a synthesis of benzoxazine monomers has solvent.[43]. The benzoxazine monomer 50 attracted considerable attention. A biobased synthesis is shown in Scheme 20. benzoxazine resin (Dz-f) demonstrating

O O

H2N N HO O (1 equiv.) O O

CH2O (1 equiv.)

O DMSO or PEG400, OH o O 120 C, O Microwave reactor 50 N O

Scheme 20. The synthesis of the biobased benzoxazine resin (Dz-f) monomer 50

Conclusions the new methods of their syntheses opens up broad prospects in order to create new highly Further search for natural substances and effective materials for medicine and creating new ones among angular agriculture. hetarenochomones as well as development of

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