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AZ9RBAYCAN KIMYA JURNALI № 1 2017
UDC 547.388 + 547.772
SYNTHESIS AND TRANSFORMATIONS OF 3-R-1-CARBAMOIL-5-CHLOROMETHYLPYRAZOLES
R.A.Gadzhily, A.G.Aliyev, A.R.Karayeva, Sh.F.Naghiyeva, L.Y.Gadzhiyeva
Institute of Polymer Materials, NAS of Azerbaijan [email protected] Received 25.02.2016
As a result of the reaction between 3,4-dichloro-2-butene-1-ones and semicarbazide hydrochloride with natrium hydrocarbonate, the hydrazones of ketones are produced. When boiled with the pyridine within surrounding of the dioxan, they are heterocyclized into 3-R-1-carbamoil-5-chIoromethylpyrazoles. When the latter is influenced with binary amines and potassium phenolate, produced are 3-R-1-carbamoil-5 -dialkylamino - and 3 -R-1 -carbamoil-5 -phenoxymethylpyrazoles.
Keywords: semicarbazones of 3,4-dichloro-2-butene-1-ones, heterocyclization, 1-carbamoil-5-chlorine-methylpyrazoles, 1-carbamoil-5-dimethylamino(morpholino)methylpyrazoles, 1-carbamoil-5-phenoxyme-thylpyrazoles.
Introduction
Pyrazole (its derivatives) has a very broad biological reactivity spectrum used against depression, the cold, tumours, diabetes, also as an antioxidant. Additionally, widely used medicines such as amidopyrine, antipyrine, analgene are derivatives of pyrazoles [1, 2]. Also, pyrazole derivatives are used to produce herbicides, substances for paints, luminophores etc. [3]. It has been found out that the heterocyclization of 3,4-b/s-(dimethylamino)-2-butene-1-ones and hydrazine hydrate produces 3-R-5-dimethylaminome-thylpyrazole [4]. N,N-b/'s-(pyrazoles) are produced following the condensation of 2 molecules of 3-aryl-5-dichloromethylpyrazole with hydrazine hydrate. 3-Aryl-5-dichloromethylpyrazole is the result of the heterocyclization of hydrazine hydrate with 3,4,4-trichloro-3-butene-1-ones, the structural analogue of 2-butene-1-ones [5].
Experiments
IQ spectra have been drawn in petrolatum vazeline oil in Fure Protege-460 Nikolet spectrometer and interior and exterior standard HMDS (5 0.05 ppm) solving DMSO-d6 has been drawn on NMR 1H "Tesla" BS-567 (100 MHz) spectrometer. The cleanness of the synthesized compounds have been ensured on the board of Silufol UV-254 with the way of TLX.
The primary 3,4-dichloro-2-butene-1-ones (I a, b) has been produced with the method [6].
Methyl(4-chlorophenyle)-3,4-dichloro-2-butene-1-ones (II a, b). After intensively mixing the blend of 0.2 mol. semicarbazide hydrochloride and 0.2 mol. 3-R-3,4-dixloro-2-butene-1-ones (I a, b) in 40 ml ethanol, the solution of 0.25 mol. NaHCO3 in 50 ml of water is added through the drip funnel. The resulting produce of the reaction after being heated for 3 h under 50-550C is poured into 100 ml of icy water and the produced crystals are filtered and washed until they become pH 7 and then dried. The crystals mixed within 50 ml of methylene chloride are filtered. After vaporizing half of the produce in the water bath, it is made to condense with hexane, filtered and dried. As a result, is obtained (II a, b) with the extract of 63-68%.
3-Methyl(4-chlorophenyle)-1-carbamo-il-5-chloromethylpyrazoles (III a, b). After boiling semicarbazones (II a, b) of 0.05 mol. Ke-tones and 10 ml of pyridine in 20 ml of dioxans with a counter-refrigerator for 8 h and pouring it into water till it becomes pH 3 and acidifies with the hydrochloric acid. Crystals are filtered, washed with water and dried in the vacuum. In the end, the reaction produce is recrystallized in ethanol.
3-Methyl(4-chlorophenyle)-1-carbamo-il-5-dimethylamino(morpholino)methylpyra-zoles (IV a, b; V a, b). After intensively mixing 0.025 mol. pyrazole (III a, b) with 50 ml benzole and 20 ml water and then adding twice as
much 0.05 mol. dimethylamine or morpholine (to catch HCl emitted) with a drip funnel, the produce resulting from the reaction is heated under 30-350C with dimethylamine and under 60-650C with morpholine for 5 h. The produce after cooling down is washed with water with its benzene layer is separated and the liquid part is extracted with ether, to be combined with the extract and dried with MgSO4.
3-Methyl(4-chlorophenyle)-1-carbamoil-5-phenoxymethylpyrazoles (VI a, b). After adding the solution of 0.025 mol KOH 50 ml in water to the mix of 0.02 mol. phenol with 30 ml benzen with a drip funnel, 0.02 mol. 3-methyl(4-chlorophenyle)-1-carbamoil-5-chloromethylpy-razole (III a, b) is also added. The produce after the reaction is heated under 65-700C for 6 h. After it cools down, it is washed with the solution of NaHCO3 in little water. Its part with the benzene is separated and the part in water is extracted, and the produce is mixed with the previous extracts and dried with MgSO4. After removing solvents the remains are distillated in the vacuum.
Results and discussion
Pyrazole derivatives possess a high practical importance. In medical practice, they are used in production of some medications, as well as herbicides, dye items and so on. In order to synthesize new functional derivatives of py-
razole, reaction of 3,4-dichloro-2-butene-1-ones with semicarbazide hydrochloride was studied.
It was identified that during interaction of 3,4-dichloro-2-butene-1-ones (I a, b) and semicarbazide hydrochloride with participation of NaHCO3 in equimolar amount in water environment at 50-550C for 3 h with 56-60% yield, we get semicarbazone of ketones (II a, b). When we boil the latter in dioxane environment with pyridine in double-amount for 8 h or heat in 2% aqueous solution of NaOH at 45-500C for 4 h we get 3 -methyl(4-chlorophenyle)-1 -carbamoil-5 -chloro-methylpyrazoles (III a, b) with 63-68% and 5760% yield accordingly. However, because when we heat semicarbazones in aqueous solution of alkaline we also get resin beside the main product, yield is low. Synthesized pyrazoles (III a, b) are highly active against nucleophilic reagents. So, during their interaction with double amount dimethylamine at 25-300C, with morpholine at 60-650C for 5 h in water-benzole environment we get 3-methyl(4-chlorophenyl)-1-carbamoil-5-dimethylamino(morpholino)methyl-pyrazoles (IV a, b; V a, b) with 65-70% and 6468% yield accordingly. During interaction of pyrazoles (III a, b) with potassium phenolate in water-benzole environment at 65-700C for 6 h we get 3-methyl(4-chlorophenyle)-1-carbamoil-5-phenoxymethylpyrazoles (VI a, b) with 5760% yield (scheme):
R.
O
NH2NHCNH,
O Cl I a, b
R
N
I
\
NR1R2
N
O NH
2
IV a, b; V a, b
HNR1R2
R
N
O'
N
R
NNHC Cl // \
O NH,
Cl
II a, b
NH
III a, b
ÏÏ
N
N
OPh
O nh2
VI a, b
I-VI R=CH3(a), 4-ClC6H4(b); IV R1=R2=(CH3)2; V R1, R2=(CH2)2(CH2)2O.
52
R.A.GADZHILY et al.
The characteristics of the synthesized substances
Substance B.p., 0C Brutto formula Found, % Calculated ,% Yield, % NMR 'H, 5, ppm (J, Hz)
C H N
II a 118-120 C6H9Q2N3O 35.04 34.45 4.50 4.31 20.31 20.09 60 1.76 s (3H,CH3), 3.39 s (2H,CH2Cl), 6.28 s (2H, NH2), 6.89 s (1H,=CH), 9.20 s (1H, NH)
II b 154-156 CnH^NsO 42.64 43.07 3.52 3.27 14.02 13.70 56
III a 218-220 C6H8ClN3O 40.69 41.50 6.80 4.61 23.75 24.21 68 2.10 s (3H, CH3), 3.34 s (2H, CH2Cl), 6.30 s (2H, NH2), 6.70 s (1H, CHpyrazole)
III b 266-268 C11H9Q2N3O 49.61 48.89 3.19 3.34 15.87 15.56 63 3.27 s (2H, CH2Cl), 6.10 s (2H, NH2), 6.65 s (1H, CHpyrazole), 7.15 d (2Hgrom., J 8.1 Hz), 7.85 d (2Harom., 3J 8.2 Hz)
IV a 240-241 C8HMN4O 51.33 52.74 7.98 7.70 31.36 30.77 70 2.05 s (3H,CH3), 2.30 s [6H, N(CH3)2], 3.40 s (2H, CH2N), 6.20 s (2H, NH2), 6.70 s (1H, CHpyrazole)
IV b 257-259 C13H15QN4O 55.37 56.01 5.67 5.39 20.89 20.11 65
V a 253-254 C10H16N4O2 54.69 53.57 7.42 7.14 24.21 25.00 68 2.05 s (3H,CH3), 3.45 t [4H,N(CH2)2, 4J 3 Hz)], 3.60 t [4H, (CH2)2O, 4J 3 Hz], 3.25 s (2H, CH2N), 6.40 s (2H, NH2), 6.60 s (1H, CHpyrazole)
V b 271-273 C^H^Cl^ 55.46 56.51 4.93 4.71 11.04 11.15 64 3.25 t [4H, N(CH2)2 , 4J 3 Hz)], 3.72 t [4H, (CH2)2O, 4J 3 Hz)], 6.45 s (1H, CHpyrazole)
VI a 244-246 C12H13N3O2 61.10 62.34 5.81 5.63 18.70 18.18 57 2.15 s (3H, CH3), 3.40 s (2H, CH2O), 6.30 s (2H, NH2), 6.70 s (1H, CHpyrazole), 7.05-7.60 m (5H, Ph)
VI b 190191/3* C17H14QN3O2 61.05 62.29 4.41 4.28 2.11 12.84 60
Note: II a Cl - 33.09/33.97%; II b Cl - 33.82/34.75%; III a Cl - 20.05/20.47%; III b Cl - 25.64/26.30; IV b Cl -12.43/12.75%; V b Cl - 0.87/11.15%; VI b viscose liquid Cl-11.09/10.84%. *P=3 mm Hg.
Structure of synthesized ketones' semi-carbazones and pyrazoles were identified with iQ and NMR 1H spectroscopic methods.
Following characteristic [7] absorption lines of semicarbazones (II a, b) of 3,4-dichloro-2-butene-1-ones in IQ spectrum are observed, v, cm-1: 3395-3423 (CONHNH2), 3245-3290 (CONHNH2), 3100-3185 (=CHpyrazole), 1670-1685 (C=O), 1550-1574 (C=N), 705-745 (C-Cl). When we synthesize pyrazoles (III a, b) from semicarbazones (II a, b) substance is not observed in spectrum of synthesized pyrazoles (III a, b) because hydrogen atom belonging to 3395-3423 cm-1 (CONHNH2) group participates in heterocyclization reaction. 705-745 cm-1 (C-Cl) absorption line belonging to chlore atom in substance IV-VI (a, b) IQ spectrum disappears and additionally absorption lines belonging to 1120-1235 cm-1 (C-O-C), and (VI a, b) of 1230-1270 cm-1 (C-O-Ph) are observed.
In compounds II-VI NMR 1H spectra singlet of CH3, CH2 and N(CH3)2 groups, singlet of pyrazole core, multiplet of phenyl protons and doublet of chlorophenyl group protons, doublet signals are observed (scheme).
Thus, since in molecule of synthesized pyrazoles III( a, b) N- and O-keep agile chlore atom against nucleophilic reagents we can use them as prospective synthons during organic synthesis to get new derivatives of pyrazoles.
References
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3-R-1-KARBAMOiL-5-XLORMETiLPiRAZOLLARIN SiNTEZi УЭ CEVRiLMOLORi
R.O.Hacili, 0.H.0liyev, A.R.Qarayeva, §.F.Nagiyeva, L.Y.Haciyeva
3,4-Dixlor-2-buten-1-onlann semikarbazid hidroxloridla natrium hidrokarbonatin i§tirakinda qar§iliqli tasiri naticasinda ketonlann hidrazonlari alinir. Onlari piridinla dioksan mühitinda qaynatdiqda 3-R-1-karbamoil-5-xlormetilpirazollara heterotsikilla§irlar. Axirincilara ikili aminlar va kalium fenolyatla tasir etdikda 3-R-1-karbamoil-5-dialkilamino- va 3-R-1-karbamoil-5-fenoksimetilpirazollar alinir.
Agar sözlar: 3,4-dixlor-2-buten-1-onlarm semikarbazonlari, heterotsikiÜ3§m3, 1-karbamoil-5-xlormetilpirazollar, 1-karbamoil-5-dimetilamino(morfolino)metilpirazollar, 1-karbamoil-5-fenoksimetilpirazollar.
СИНТЕЗ И ПРЕВРАЩЕНИЯ 3-Я-1-КАРБАМОИЛ-5-ХЛОРМЕТИЛПИРАЗОЛОВ
Р.А.Гаджилы, А.Г.Алиев, А.Р.Караева, Ш.Ф.Нагиева, Л.Я.Гаджиева
В результате реакции 3,4-дихлор-2-бутен-1-онов с гидрохлоридом семикарбазида в присутствии гидрокарбоната натрия получены гидразоны кетонов. Кипячение последних с пиридином в среде диоксана способствовало их гетероциклизации в 3-Я-1-карбамоил-5-хлорметилпиразолы, взаимодействием которых с вторичными аминами и фенолятом калия синтезированы 3-Я-1-карбамоил-5-диалкиламино- и 3-Я-1-карбамоил-5-феноксиметилпиразолы.
Ключевые слова: семикарбазоны 3,4-дихлор-2-бутен-1-онов, гетероциклизация, 1-карбамоил-5-хлорметил-пиразолы, 1-карбамоил-5-диметиламино(морфолино)метилпиразолы, 1-карбамоил-5-феноксиметилпиразолы.
