Карцев В.Г.Избранные методы с-за и модифик. гетероциклов т.1 , 2003

1,3-Dithiolo[4,5-d]pyrimidines: Synthesis and properties

Neilands O.

Riga Technical University, Department of Chemistry 14/24 Azenes str., Riga, LV-1048 Latvia

e-mail: [e-mail]

Introduction

A novel heterocyclic system, 1,3-dithiolo[4,5-d]pyrimidine 1, has been prepared and characterized. We aimed at synthesizing the derivatives of uracil-fused 1,3-dithiol- 2-selones and their use in preparation of strongly electron-donating tetrathiafulvalenes bearing an uracil function. We proposed that uracil-fused tetrathiafulvalenes will be capable of forming strong intermolecular complementary hydrogen bonds like nucleic acid. In this paper, we will overview the synthesis and properties of dioxoand amino- oxo-1,3-dithiolo[3,4-d]pyrimidines as well as of dioxoand aminooxopyrimido-fused tetrathiafulvalenes.

Synthesis of 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine-2-diethylimmonium salts 3

We synthesized uracil-fused 1,3-dithioles [1–3] from the derivatives of barbituric acid. Reaction of 2-diethylaminothiocarbonylthiobarbituric acid 2 with conc. sulfuric acid (at 60°C) was found to yield target heterocyclic system 3. Upon dilution with conc. HCl and acetone, chloride 3 precipitated as colorless crystals (Scheme 1).

Scheme 1

R'

O

Et

1. H2SO4, 60°C

O

S

S

N

S

Et

N

HN

Et 2. H2O, HX

HN

X

N +

R

N S

O

N

O

S

O

N

S

X−

Et

H

H

1

2

X = HSO4, ClO4, Cl

3

5-Amino-7-oxo(6H)-1,3-dithiolo[4,5-d]pyrimidine-2-diethylimmonium salts

Isocytosine-fused 1,3-dithiole system [4] was synthesized from 5-diethylaminothio- carbonylthio-2-amino(1H,5H)pyrimidine-3,6-dione 4. Cyclisation was performed in conc. sulfuric acid. Upon dilution with aqueous perchlorate, compound 5 was precipitated (in neutral solution) with sodium perchlorate. Solubility of this colorless salt in water is lower than that of salts 3. Salt 5 is well soluble (as a weak base) in dilute acids (Scheme 2).

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Scheme 2

O

Et

O

HN

−

S

N

Et 1. H2SO4, 60°C

HN

S

Et

+

N +

H2N

N

O

S

2. H2O, Na2CO3,

H2N N S

− Et

NaClO4

H

5

ClO4

4

7-Amino-5-oxo(4H)-1,3-dithiolo[4,5-d]pyrimidine-2-diethylimmonium salts

Cytosine-fused 1,3-dithiole system [5] was synthesized from derivatives of 6-amino- uracil, viz. from 5-diethylaminothiocarbonylthio-6-acetylaminouracil 6. Cyclization was performed in conc. sulfuric acid. Upon dilution and neutralization, we precipitated perchlorate 7 with sodium perchlorate. But cyclization of non-acetylated 6-aminouracil derivative gave salts 3 rather than the desired salt (Scheme 3).

Scheme 3

O

Et

HN Ac

S

N Et

1. H2SO4, 60°C

S

Et

HN

N

N +

O N

NH S

2. H2O, Na2CO3,

O N

S

Et

H

NaClO4

H

X

−

Ac

6

7

1,3-Dithiolo[4,5-d]pyrimidine system from 1,3-dithiol derivatives

Reaction of 1,3-dithiol-2-one-4,5-dicarboxamide 8 with strong oxidant, [hydroxyl(tosyloxy)iodo]benzene, followed by the Hoffmann rearrangement yielded colorless 5,7-dioxo- (4H,6H)-1,3-dithiolo[4,5-d]pyrimidin-2-one 9 [6] (Scheme 4).

Scheme 4

O

O

H2N

S

PhI(OH)OTs HN

S

O

O

H2N

DMF

S

N

S

O

H

O

8

9

358	Устные доклады

Reaction of the salts of compound 3 with nucleophiles

Just as NH acids (pKa 3.3, in water) [2], compounds 3 are capable (in the presence of base) of intramolecular salt formation giving betaine 10. Colorless betaine is watersoluble. Salts of 3 react with strong nucleophiles (sulfides and selenides) in aqueous solutions to yield (via disclosure of the dithiol ring) unusual derivatives of 4-thiobar- bituric acid 11. These compounds are unstable, and undergo cyclization under the action of strong acids yielding yellow 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine-2-thione (12, X = S) and red selone 12 (X = Se) [1, 3] (Scheme 5). This selone is an important starting material for further syntheses.

Scheme 5

	O				O
HN	S		Et	−	HN	S	Et
		N +		HO			N +
	N S				−	S
O		X−	Et		O N		Et
	H
	3					10

1.Na2X, H2O

2.HCl

O

Et

O

HN

S N

Et

HCl

HN

S

X

O

N

SH X

DMF

O

N S

H

11

60−70°C

H

X = S, Se

12

We observed an unusual condensation of salts of 3 (or betaine 10) with β-dicarbo- nyls 13 (in the presence of base in DMF at 90°C) yielding yellow 5,7-dioxo(4H,6H)-1,3- dithiolo[4,5-d]pyrimidine-2-ylidene diethylmalonate 14a, isopropylidene malonate 14b, dimedone 14c, and indan-1,3-dione 14d (Scheme 6). These compounds are NH acids and are capable of salt formation [7].

Scheme 6

O

O

O

O

HN

S

Et

+

R

base

HN

S

R

N +

S

S

O

N

−

Et

R

O

N

R

H

3

X

O

H

O

13

14

R = OEt (a); R+R = OCMe2O (b), CH2CMe2CH2 (c),

(d)

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Synthesis and properties of 5,7-dihloro-1,3-dithiolo[4,5-d]pyrimidine-2-thione and selone (15) [8]

Reaction of thione or selone 12 (POCl3, 90–120°C, in the presence of N,N-diethyl- aniline) results in dihloroproducts 15a, b (Scheme 7). Deep yellow thione 15a and deep red-brown selone 15b are important starting materials for further syntheses. Selone 15b readily reacts with N-methylaniline (or thiourea) to afford 7-methylphenylamino-5- chloro-1,3-dithiolo[4,5-d]pyrimidine-2-selone 16 or chloride of 7-isothiuronio-5-chloro- 1,3-dithiolo[4,5-d]pyrimidine-2-selone 17 (Scheme 8).

	O
				S			POCl3		N
HN						X
				S			PhNEt2	Cl
O N
	H 12					X = S (a), Se (b)

		PhNHMe
	Cl	Cl
	N	S
		Se
Cl	N	S
	15b	S
		H2N NH2
		Cl

Scheme 7

Cl

S

X

N S

15

Scheme 8

N Ph
N	S	Se
	S
N
16
NH	2	−
+		Cl
S NH2
N	S	Se
	S
N
17

Cyclization of N-methyl-5-diethylaminothiocarbonylthiobarbituric acid [9]

Aming at synthesizing N-methylsubstituted selone 12, we found out that cyclization of N-methylbarbituric acid derivative 18 yielded a mixture of 4-methyl- and 6-methyl- substituted salts 19, 20. Transformation of these products into selones gave a mixture of 4-methyl- and 6-methylsubstituted selones 21, 22 (Scheme 9). The isomers were separated chromatographically. 4-Methylselone 22 was a major product.

360	Устные доклады

Scheme 9

Et

O S

N Et

O

O

S

1. H2SO4, 60°C

S

Et

S

Et

N

N

+ HN

2. H2O, HClO4

S

N +

S

N +

O

N

O

O

N

Et

O

N

Et

H

H

ClO4−

20

ClO4−

18

19

Na2Se

O

O

N

S

Se

+ HN

S

Se

N

S

S

O

O

N

H

21

22

Transformations of 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine-2-one (9) [6]

Dithiolone 9 containing polarized S–CO bonds can readily react with strong bases. Reaction of compound 9 with sodium methoxide resulted in dimercaptide methylation of which gave 5,6-di(methylthio)uracil 23. Reaction of dimercaptide with nickel salt and tetrabutylammonium chloride resulted in interesting deep colored dithiolene complex 24 (Scheme 10).

Scheme 10

O

O−

4Na+

O

HN

S

O

MeONa N

S −

MeI

HN

SMe

N S

−

S −

+

O

N

SMe

O

N

O

H

H

H

9

23

−

1. NiCl2

O

H

2. Bu4NCl

O

HN

S

S N

Bu4N

+

Ni

S

NH

O

N

S

H

24

O

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Synthesis of isocytosine-fused 1,3-dithiol-2-thione and 2-selone [4]

Diethylimmonium perhlorate 5 easily reacts with sodium sulfide (or sodium selenide) in water to yield 2-amino-5-diethylaminothio(seleno)carbonylthio-6-mercapto(3H)pyrimidin- 4-one 25. This unusual compound is unstable and undergoes cyclisization under the action of strong acids (in DMF or acetic acid) yielding yellow 5-amino-7-oxo(6H)-1,3- dithiolo[4,5-d]pyrimidine-2-thione (26, X = S) or red selone (26, X = Se) (Scheme 11). This selone is a valuable starting material for further syntheses.

Scheme 11

Et

O X

O

N Et

O

S

Et Na2X

S

S

HN

HN

HCl

HN

N +

X

S

Et

HCl

H2N N

SH

DMF

H2N

N

S

H2N N

−

ClO

5

4

25

X = S, Se

26

Synthesis of dioxoand aminooxopyrimidotetrathiafulvalenes

We have performed the cross coupling of two 1,3-dithiol-2-selones (12 and 27) aiming at preparation of tetrathiafulvalene (TTF) system fused with uracil or isocytosine. A best coupling agent was found to triphenylphosphine. Starting selone has been trimethylsilylated due to its poor solubility in benzene to give disubstituted 4,6-dioxo(3H,5H)py- rimido-TTFs 28a–d [10–13]. As NH acids, TTFs 28 are capable of salt formation. Tetrabutylammonium salts 29 are being used for purification of poor-soluble TTF 31. Oxidation of salts 29 with iodine leads to insoluble deep green betaine cation radicals 30 [13, 14] (Scheme 12). The structure of TTFs 28 was confirmed by XRD [12] and mass spectra [15]. These compounds were used to synthesize oligoribonucleotides [16, 17] and H-bonded complexes [18]. Betaines 30a, d exhibit unusually high electroconductivity in pellets [13, 19].

										Scheme 12
		OSiMe3			R	S		O
							Se				R
			S		R S				S	S
	i	N					27	HN
12				Se
			S			1. Ph3P			S	S R
	Me3SiO	N						O N
						2. EtOH
								H

i: BTSA, benzene, reflux	28a−d

362	Устные доклады

O

+	−		S		S	R
Bu4N OH	HN
28		−	S		S
AcOH	O					R
		N
	Bu4N+		29a−d
		I	NH2NH2
		2	Bu4NOH
		O
						R
	HN		S	·	S
		−
			S	+	S
	O	N				R

30a,d

R = Me (a), SMe (b); R+R = SCH2CH2S (c), OCH2CH2O (d)

Cross coupling of selone 26 with disubstituted 1,3-dithiol-2-selones resulted in disubstituted 4-amino-6-oxo(5H)pyrimidoTTFs 31a, b. Low-soluble selones were purified upon oxidation with insoluble betaine cation radicals 32a, b followed by reduction [19, 20] (Scheme 13). Betaines possess unusually high electroconductivity (single-component organic conductors [13, 19]). The chemical and electrophysical properties of dioxoand aminooxopyrimidoTTFs have been reviewed in [21, 22].

Scheme 13

O

O

R

N

S

S

S

1. Silylation

N

Se

2. 27a, b, Ph3P

S

H2N

N S

H2N N

S

R

H

H

31

26

DMF,

NH2NH2·OH

Et3N, I2

O

R

S

·

S

N

−

S

+ S

R = Me (a); R+R = OCH2CH2O (b)

H2N

N

R

32

References

1.Tilika V.Zh., Khodorkovskii V.Yu., Neiland O.Ya., USSR Inventor's Certificate 1 738 810.

2.Neiland O.Ya., Zagorskaya N.N., Khim. Geterotsikl. Soedin. 1992 (3) 416.

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3.Neiland O.Ya., Khodorkovskii V.Yu., Tilika V.Zh., Khim. Geterotsikl. Soedin. 1992 (12) 1667.

4.Neiland O.Ya., Adamsone B.Ya., Raiskuma I.K., Khim. Geterotsikl. Soedin. 1992

(8) 1117.

5.Neilands O., unpublished results.

6.Neiland O.Ya., Valters R.A., Pukitis G.G., Tilika V.Zh., Edzina A.S.,

Khim. Geterotsikl. Soedin. 1992 (9) 1270.

7.Neilands O., unpublished results.

8.Neiland O.Ya., Valters R.A., Beljakov S.V., Khim. Geterotsikl. Soedin. 2002 (1) 87.

9.Neiland O.Ya., Adamsone B.Ya., Dureja R.Ya., Gudele I.Ya., Zagorskaya N.N.,

Khim. Geterotsikl. Soedin. 1993 (11) 1526.

10.Neiland O.Ya., Tilika V.Zh., Edzina A.S., Khim. Geterotsikl. Soedin.1992 (8) 1122.

11.Neiland O.Ya., Tilika V.Zh., Edzina A.S., Khim. Geterotsikl. Soedin. 1994 (9) 1285.

12.Neilands O., Belyakov S., Tilika V., Edzina A., Chemical Commun. 1995 (3) 325.

13.Balodis K., Khasanov S., Chong C., Maesato M., Yamochi H., Saito G., Neilands O.,

Synthetic Metals, 2003 (in press).

14.Neiland O.Ya., Tilika V.Zh., Supe A.A., Edzhinya A.S., Khim. Geterotsikl. Soedin. 1996 (1) 123.

15.Garin J., Orduna J., Neilands O., Tilika V., Rapid Communications in Mass Spectrometry 1996 10 16.

16.Neilands O., Liepinsh V., Chimia 1997 (7) 392.

17.Neilands O., Liepinsh V., Turovska B., Organic Letters 1999 1 (13) 2065.

18.Goldenberg L.M., Neilands O., J. Electroanalyt. Chem. 1999 463 212.

19.Neilands O., Tilika V., Sudmale I., Grigorjeva I., Edzina A., Fonavs E., Muzikante I., Advanced Materials for Optics and Electronics, 1997 7 39.

20.Neilands O., Tilika V., Celmina Z., Edzina A., Phosphorus Sulfur Silicon Relat. Elem. 1994 95/96 511.

21.Neilands O., Mol. Cryst. Liq. Cryst. 2001 355 331.

22.Neilands O., NATO Science Series IIMathematics, Physics and Chemistry “Molecular Low Dimensional and Nanostructured Materials for Advanced Applications”, Amsterdam: Kluwer, 2002, p. 181.

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Синтез и химические свойства оксазолидин-4,5-дионов

Некрасов Д.Д.

Пермский госуниверситет 614600, Пермь, ул. Букирева, 15

Оксазолидин-4,5-дионы активно изучаются с конца 50-х годов прошлого века. Наличие в структуре этих соединений двух гетероатомов в значительной степени отличает их химические свойства от свойств других гетероаналогов (тетрагидро- фуран-2,3-дионов, пирролидин-2,3-дионов).

Преобладающее количество методов синтеза оксазолидин-4,5-дионов 1 и 2 основано на реакции оксалилхлорида с различными амидами или имидами в присутствии акцепторов хлористого водорода. Значительно реже для синтеза оксазолидиндионов используются мочевины и основания Шиффа. Конденсированные оксазолидин-4,5-дионы 3 и 4 получают взаимодействием фенилэтиламидов с оксалилхлоридом или орто-аминотиопроизводных пиридина с эфирами β-галоген- α,γ-дикетокислот, соответственно.

					R'''		O
									X R
	R	R	R'			N	R'			O
							O
								N
O	N R'	O	N R''				O		N
						R				O
			R''						S	O
O	O	O							R''
			O	R'		3
	1		2						4

Наиболее характерными для оксазолидин-4,5-дионов являются реакции дециклизации, рециклизации и деструкции оксазолидинового цикла. Некоторые 2-метиленоксазолидин-4,5-дионы 2 могут использоваться в синтезе замещенных ацетилизоцианатов, а конденсированные оксазолидиндионы 3 в синтезе дегидроизохинолинов. Приводятся литературные данные об использовании замещенных оксазолидиндионов в синтезе биологически активных соединений.

Работа выполнена при финансовой поддержке РФФИ (грант № 01-03-32641).

Доклад сделан по материалам обзора, полный текст которого опубликован: в кн. "Избранные методы синтеза и модификации гетероциклов", под ред.

Карцева В.Г., М.: IBS PRESS, 2003, т. 2, с. 396.

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Превращения производных кумарина как метод построения новых гетероциклических систем

Никитченко В.М.1, Горобец Н.Ю.1, Борисов А.В.1, Коваленко С.Н.2, Силин А.В.2, Чуев В.П.3

1Харьковский национальный университет им. В.Н. Каразина 61077, Украина, Харьков, пл. Свободы, 4 2Национальный фармацевтический университет Украины 61002, Харьков, ул. Пушкинская, 53 3ЗАО "ВладМиВа"

308011, Белгород, ул. Садовая, 118

В продолжение нашей предыдущей работы [1] мы изучили несколько новых превращений кумаринового и 2-иминокумаринового цикла в другие гетероциклические системы.

Особый интерес для построения новых гетероциклических систем представляют некоторые реакции внутримолекулярного нуклеофильного замещения в иминокумаринах 1, такие как, например, описанный в литературе [2] способ получения хромено[2,3-c]пиразол-3(2H)-она 2a (схема 1).

Схема 1

	O	Ar	O
	N N
R		H3NOH+Cl−	N R'
	H	R
O	NH	EtOH	O N
1			2a R' = H

Однако данный метод не позволяет получать N-замещенные продукты. Нами был предложен простой способ получения N-замещенных хроменопиразолонов 2b с использованием внутримолекулярного нуклеофильного замещения другого типа (схема 2). В этом случае реакция протекает через образование N-замещенных 2-иминокумаринов 3, которые под действием уксусного ангидрида циклизуются в соединения 2 с выходами 60–80%.

Схема 2

	O					O
	NH2	+	R'		AcOH	NH2
R			HN
				NH2	R
O	NH				O	N
					3	HN R'

366	Устные доклады