The Mannich-type synthesis of Macroheterocycles with pyrido[2,1- b][1,3,5]thiadiazine Unit Текст научной статьи по специальности «Химические науки»

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DOI: 10.6060/mhc150870d

The Mannich-Type Synthesis of Macroheterocycles with Pyrido[2r1-b][1r3r5]thiadiazine Unit

Victor V. Dotsenko,a@ Elena A. Chigorina,b Elena S. Papaianina, Konstantin A. Frolov,de and Sergey G. Krivokolyskode

c

aKuban State University, 350040 Krasnodar, Russian Federation

hFederal State Unitary Enterprise «Research Institute of Chemical Reactants and Ultrapure Compounds (IREA)», 107076 Moscow, Russian Federation

cUniversity Erlangen-Nuremberg, Institut für Organische Chemie II, 91054 Erlangen, Germany dLugansk State Medical University, 91045 Lugansk, Lugansk People 's Republic eChemEx Lab, Vladimir Dal'Lugansk University, 91034 Lugansk, Lugansk People 's Republic @Corresponding author E-mail: [email protected]

New macrocyclic products containing four pyrido[2,1-b][1,3,5]thiadiazine units linked by methylene bridges and phenylene spacers were synthesized by reaction of morpholinium 3-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-thiolate with aromatic diamines (p-phenylenediamine, benzidine) and excess of HCHO. A rapid solvent-free procedure for synthesis of the starting thiolate was proposed. The structure of the products was confirmed by IR-, solid state NMR 13C data and elemental analysis.

Keywords: Cyanothioacetamide, pyridine-2-thiolates, Guareschi-Thorpe reaction, pyrido[2,1-b][1,3,5]thiadiazines, Mannich reaction, diamines, СР/MAS NMR ^ spectra.

Синтез макрогетероциклов с пиридо[2,1 — Ь][1г3г5]тиадиазиновым фрагментом по реакции Манниха

B. В. Доценко^@ Е. A. Чигорина^ Е. С. Папаянина^ К. A. Фролов,^

C. Г. Кривоколыско^

aКубанский государственный университет, 350040 Краснодар, Российская Федерация

ъФедералъное государственное унитарное предприятие «Государственный ордена Трудового Красного Знамени научно-исследовательский институт химических реактивов и особо чистых химических веществ «ИРЕА», 107076 Москва, Российская Федерация

c Университет Эрлангена-Нюрнберга, Институт органической химии II, 91054 Эрланген, Германия АЛуганский государственный медицинский университет, 91045 Луганск, ЛНР еНИЛ «ХимЭкс», Луганский университет им. Владимира Даля, 91034 Луганск, ЛНР @E-mail: victor_dotsenko@bigmir. net

Новые макроциклические продукты, содержащие четыре пиридо[2,1-Ь][1,3,5]тиадиазиновые субъединицы, связанные метиленовыми мостиками и фениленовыми спейсерами, были синтезированы взаимодействием 4-метил-6-оксо-3-циано-1,6-дигидропиридин-2-тиолата морфолиния с избытком НСНО и ароматическими диаминами (п-фенилендиамином, бензидином). Предложена быстрая solvent-free процедура получения исходного тиолата. Строение продуктов подтверждено данными ИК-спектроскопии, элементного анализа и твердотельными ЯМР 13С-спектрами.

Ключевые слова: Цианотиоацетамид, пиридин-2-тиолаты, реакция Гуарески-Торпа, пиридо[2,1-ь][1,3,5] тиадиазины, реакция Манниха, диамины, СР/MAS ЯМР 13С спектры.

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Макрогетероциклы /Macroheterocycles 2015 5(3) 310-313

1,3,5-Thiadiazines have attracted great attention due to a wide spectrum of biological activity (for reviews on the 1,3,5-thiadiazine chemistry, see[1-4]). Recently we have found that thiolate 1 readily reacts with excess of formaldehyde HCHO and primary amines in boiling DMF to give 7,7'-bis(pyrido[2,1-b][1,3,5]thiadiazinyl)methanes 2[5] (Scheme 1). The linking of two pyridine units by a methylene bridge upon treatment with formaldehyde is known as a general reaction for either pyridin-2(1_ff)-ones, or tautomeric 2-hydroxypyridines with an active C-3 position.[6-8] On the other hand, pyridine-2-thiolates 3 react with HCHO and 1,4-phenylenediamine to form Mannich-type products 4 containing two pyridothiadiazine units linked by phenylene spacer[9] (Scheme 1). The ability of thiolate 1 to form bonds oriented in different directions has prompted us to build macrocyclic ensembles with pyrido[2,1-b][1,3,5]thiadiazine units under Mannich reaction conditions.

First, we had to develop fast and scalable synthesis of thiolate 1. The compound 1 could be obtained by reaction of cyanothioacetamide 5 with either ethyl-3-morpholinocro-tonate 6, or 3-morpholinocrotonanilide,[1011] cycloalkylidene cyanothioacetamide with ethyl acetoacetate in the presence of morpholine,[12] or by ternary Guareschi-Thorpe condensation of cyanothioacetamide 5 with morpholine and aceto-acetic ester (EtOH, 20 °C, 24 h)[13] (Scheme 2). The highest yield of salt 1 (87 %) was achieved when p-aminocrotonate 6 was reacted with thioamide 5; however, this synthesis includes an additional step in which aminocrotonate 6 has to be prepared.

From the practical point of view, the Guareschi-Thorpe ternary condensation seems to be the most effective and convenient approach. However, when we had attempted to prepare thiolate 1 by the reported procedure[13] under carefully controlled conditions, the yield was only 43 % instead of reported 78 %. These results have prompted us to find an alternative procedure, which would combines one-pot approach, reproducibility, gram-scalability and rapidity. The problem was successfully solved by refusing to use any solvent. Thus, when cyanothioacetamide 5, ethyl acetoacetate and morpholine were slowly melted until an exothermic reaction had completed and the melt was treated with acetone, thiolate 1 was obtained in 66 % yield. When thioamide 5, ethyl acetoacetate and morpholine were vigorously stirred at the ambient temperature, the mixture had solidified within 10-15 min to obtain thiolate 1 in 55 % yield. The highest yield (76 %) was achieved when thioamide 5 was fused with beforehand prepared mixture of AcCH 2CO2Et and morpholine (Scheme 3)§. Obviously the reaction proceeds via the formation of p-aminocrotonate 6 in situ, followed by the Guareschi-Thorpe cyclization. The proposed solvent-free procedure could be easily scaled up to produce tens of grams of pure thiolate 1 in reasonable yields.

After developing fast and scalable synthesis of thiolate 1, we have attempted to prepare macrocyclic compounds by the Mannich reaction of thiolate 1 with HCHO excess and aromatic diamines. Thus, when thiolate 1 was treated with 0.5 eq. of 1,4-phenylenediamine (or benzidine) and HCHO

ch,

CH,

CH,

o

CN

s

M

MorH+

rnh2

hcho

DMF

67-87%

NC

S'

V

I

Mor = morpholine R 1,4-H2N-C6H4-NH2

\ 7

CN

O

AT

/y® HCHO, EtOH

XX-3

o

N S

V i

R

n H

NMMH+

24-56% NMM = N-methylmorpholine

NC S-

N

^s cn N >= N,

O

Ar

Ref. [5]

Refs. [6-8]

Scheme 1.

NCCH2C(S)NH2 (5) morpholine, EtOH + 20 °C, 24 h

MeC(0)CH2C02Et

^N. O

Q

+

NH.

2 Refs. [10,11]

Me. ^^ .NHPh EtOH, X „CN

20 °C, 24 h

N. O

+

+

NH,

76-81%

Ref. [12] NC' XSNH2

n = 0, 1 R = EtO, NHPh

Scheme 2.

Макрогетер0цикJlbl /Macroheterocycles 2015 8(3) 310-313

311

Synthesis of Macroheterocycles with Pyridothiadiazine Unit

Me

rV

H

Û

CN

fusing

EtO"% h NH, -

Scheme 3.

NH,

DMF

O N S H MorH

HCHO

n x—S CN

7a n=1; b n=2.

Scheme 4.

in hot DMF, amorphous solids were obtained for which we have assigned the structure 7a,b (Scheme 4)1

The compounds 7a,b are beige powders which are insoluble in any common organic solvents, including DMF, DMSO, acetone, CHCl3 and TFA. Therefore we have failed to characterize the compounds by LCMS and NMR 'H /13C spectroscopy. In order to confirm the structure, solid state CP/MAS 13C NMR experiments have been performed (Figure 1)#. IR spectra of the obtained products are similar to those of compounds 2 and show the absorption bands of C=C (v 1650-1645 cm-1) and conjugated C^N (v 2205 cm-1). No absorption bands of N-H or O-H bands were observed.

In the CP/MAS 13C NMR spectra two peaks at 5=18-29 ppm corresponding to CH3 and methylene bridge carbons were observed, while resonance peaks of SCH2NCH2N carbon atoms were observed at 5=52-65 ppm. Elemental analysis data do not contradict the proposed structures.*

Notes and References

§ Morpholinium 3-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-thiolate (1). Method A. A mixture of cyanothioacetamide 5 (1.88 g, 18.77 mmol), ethyl acetoacetate (2.5 ml, 19.73 mmol) and

<D 00 Ö CM

I

o o «? CD CO CO o „ od J

5 8 S \

CNI CN

' ' I.........I.........I "

130 125 120

Chemical Shift (ppm) CNJ

tri CT>

CO

m

CO

m

co m

V

K/VAMJWVS^

I.........I.........I.........I.........I.....

180

160

140

120 100 Chemical Shift (ppm)

80

60

40

20

Figure 1. NMR CP/MAS 13C spectrum (101 MHz, ns = 256, 10 kHz) of compound 7a.

312 Макрогетероциmbl /Macroheterocycles 2015 8(3) 310-313

morpholine (1.7 ml, 19.5 mmol) was stirred at 20 °C. A slightly exothermic reaction was observed and the solution was solidified within 10 minutes. Acetone (15 ml) was added and thereafter the obtained slurry was filtered off, washed with acetone and dried at 60 °C. The product 1 (2.59 g, 55 %) was obtained as a beige powder, m.p. 224-227 °C (Lit.: 226-228 °C,[10,11] 224-226 °C[13]). IR v cm-1: 2205 s (C=N); 1640 s (NHC(O)). 1H NMR ([D6]DMSO) SH ppm: 2.00 (3H, s, CH3); 3.12 (4H, m, (CH2)2N); 3.76 (4H, m, (CH2)2O); 5.40 (1H, s, H-5); 8.69 (2H, br.s, H2N+); 10.40 (1H, br.s, NH). Found, %: C, 52.36; H, 6.00; N, 16.(51. C11H15N3O2S. Calculated, %: C, 52.16; H, 5.97; N, 16.59. Method B. A mixture of cyanothioacetamide 5 (1.52 g, 15.17 mmol), ethyl acetoacetate (2.1 ml, 16.57 mmol) and morpholine (1.5 ml, 17.22 mmol) was stirred at 20 °C until the starting material dissolved, then it was slowly heated until an exothermic reaction began. Heating was immediately discontinued and acetone (20-25 ml) was added to the red melt under vigorous stirring. The melt was solidified immediately, the precipitate was ground, filtered off and washed with acetone to give thiolate 1 (2.54 g, 66 %) which was identical to the sample obtained by Method A.

MethodC. To a mixture of ethyl acetoacetate (5.0 ml, 39.46 mmol) and morpholine (3.8 ml, 43.62 mmol), formic acid (8-10 drops) was added; the mixture was stirred at 30-40 °C for 20 min, then cyanothioacetamide 5 (3.90 g, 38.95 mmol) was added. The formed red solution was slowly heated until an exothermic reaction began (2-3 min). Heating was immediately discontinued and acetone (50 ml) was added to the red melt under vigorous stirring. The melt had solidified immediately, the precipitate was ground, filtered off and washed with acetone to give thiolate 1 (7.46 g, 76 %) as beige powder.

1 The reaction of thiolate 1 with p-phenylenediamine (benzidine) andHCHO. Thiolate 1 (465 mg, 1.82 mmol) and the corresponding diamine (0.92-0.93 mmol, 101 mg of p-phenylenediamine or 175 mg of benzidine) were dissolved in hot DMF (5 ml) and then excess HCHO (37 % aq. soln., 1.5 ml) was added. The product had separated almost immediately. The mixture was gently boiled for 1-3 min under vigorous stirring, allowed to cool, the precipitated solid was filtered off and washed with EtOH and acetone. The product 7a was obtained as a heavy beige powder (333 mg, 72.5 %), m.p. > 300 °C. IR v cm-1: 2205 s (C=N), 1640 m (C=O). 13C NMR CP/MAS SC ppm: 20.9 (CH,); 27.6 (methylene bridge CH2); 56.8 (SCH2N); 64.6 (NCH2N); 95.43 (C-9); 122.0 (C=N); 123.0 (C-7); 127.0 (CH of the phenylene spacer); 143.8 (C-8); 148.3 (C-N phenylene); 154.9 (C-9a); 160.6 (C=0). Found, %: C, 59.83; H, 4.19; N, 16.88. C50H40N12O4S4. Calculated, %: C, 59.98; H, 4.03; N, 16.79.

The product 7b was obtained as a sand-coloured powder (459 mg, 86.5 %), m.p. > 300 °C. IR v cm-1: 2205 s (C=N); 1650 m (C=O). 13C NMR CP/MAS SC ppm: 18.3 (CH3); 28.8 (methylene bridge CH2); 51.9 (SCH2N); 59.0 (NCH2N); 110.8 (C-9); 117.6 (C=N); 117.9 (C benzidine); 123.4 (C-7); 125.9 (C benzidine); 128.2 (C benzidine); 144.1 (C-8); 148.3 (C-N benzidine); 151.6 (C-9a); 161.5 (C=0). Found, %: C, 64.43; H, 4.30; N, 14.70. C62H48N12O4S4. Calculated, %: C, 64.56; H, 4.19; N, 14.57

62 48 12 44 ' ' J J J J

# The solid state CP/MAS 13C NMR spectra were recorded on a Bruker Avance II 400 spectrometer (101 MHz, ns=256, 10 kHz). 1H NMR spectra of thiolate 1 were recorded on Bruker DRX-500 spectrometer (500 MHz) in [L>6]DMSO with TMS as an internal standard. IR spectra were taken in Nujol mulls on an IKS-29 (LOMO, USSR) spectrometer. Elemental analysis was performed on Carlo Erba Strumentazione 1106 device.

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Received 20.08.2015 Accepted 20.10.2015

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