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Clt/ Volume: 3 Sayı/ Issue: 1 Hazran/June: 2015 PİRAZOL TÜREVLERİNİN SENTEZ YÖNTEMLERİ SYNTHESIS METHODS OF PYRAZOLE DERIVATES Adnan Çetin* * Muş Alparslan University, Faculty of Education, Department of Science, 49250, Muş ÖZET Bu derlemede prazollern sentez süreçlern ncelemek hedeflenmştr. Heterosklk bleşklern öneml br sınıfını oluşturan prazoller byoaktf özellklernden dolayı genş br çalışma alanı olarak önem artarak devam etmektedr. Prazoller byolojk aktf çeştllğne sahptr. Bu bleşkler laç araştırmalarında ve tarım ürünler gelştrmesnde kullanılmaktadır. Böylece prazollern sentez çn gelştrlmş metotlar daha öneml hale gelmektedr. Anahtar Kelmeler: Heterosiklik kimya, organik kimya, organik sentez, pirazol. ABSTRACT In this review was aimed to describe process synthesis of pyrazoles. Important classes of heterocyclic compounds forming pyrazoles have continued to grow important because of their wide- spread of study area by biological activity. The pyrazoles have biological activities diversity. These compounds are used in the development of agricultural products and in drug researches. Thus, the methods developed for the synthesis of pyrazoles are becoming more importance. Key Words: Heterocyclic chemistry, organic chemistry, organic synthesis, pyrazole. *Sorumlu Yazar/Corespondng Author: Adnan Çetin, Muş Alparslan University, Faculty of Education, Department of Science, 49250, Muş, E-mail: [email protected] 303 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015. 1. INTRODUCTION 4 3 4 3 Chemistry of heterocyclic compounds is 5 N 2 5 - N 2 one of the most complicated of the organic b N 1 1 chemistry. Chemistry of heterocyclic compounds is interesting for the diversity of its H synthetic procedures and equally theoretical Scheme1. Pyrazole implications for physiological and industrial significance of heterocyclic compounds. In The pyrazole is one of heterocyclic particular, heterocyclic compounds commonly compounds. Firstly pyrazole was obtained from investigate only in themselves but also many decarboxylation pyrazol-3,4,5-tricarboxylic natural products, many drugs, medicines and acid in figure1. Pyrazole was defined for the first dyes. It seems heterocyclic more than one-third time by Buchner in 1889 [2]. of organic compounds. Many alkaloids, vitamins, antibiotics, many synthetic pesticides HOOC COOH and dyes i.e., and so many substances are ISI b N + 3CO2 HOOC closely connected with the life cycle (such as N N H H n u c l e i c a c i d s ) . T h e m o s t i m p o r t a n t "heteroatom" is available nitrogen, oxygen and Figure1. Synthesis of pyrazole sulfur. Pyrazole is a simple aromatic ring an organic compouand of the heterocyclic series by Basic information on their aromatic is characterized five-membered ring structure properties were obtained to compared with which comprises located adjacent two nitrogen benzene derivatives about chemistry of organic atoms and three carbon atoms in scheme1. substances bearing pyrazole group. Since try to Pyrazoles have π-electrons in the heterocycle. N pyrazole, it was based on a structural problem atom attracts ring electrons due to electro with the center present Tautomerism of the N- negativity so that the C (3) and C (5) becomes substituent and resulting from derivatives and partially electropositive and becomes suitable to isomers of the N-substituent. Pyrazole ring can participate in nucleophilic. All of the 1,2-azoles, be represented by different tautomeric pyridine nitrogen and C (4) atoms have been structures in scheme2. Three tautomeric forms focused on the π-electron and moves positive can be written for pyrazole non-substituents. charge as well as other heteroatoms. C (3) and C (5) atom of the π-electron charge can be positive or negative depending on the heterocycle. The b N N highest degree of bond C (3)-N and C (4) - C (5) N H N N was found between atoms. Bond order is the lowest of the heteroatoms. N atom of Scheme2. Tautomeric structures of pyrazole nucleophilic and the steric accessibility can be non-substituents varied by appropriate ring substitution. Although attractive features and powerful Until recently pyrazole was believed advances in the chemistry of pyrazole, The absent in nature. However the first natural interest show on pyrazole and pyrazole pyrazole derivative was isolated by Japanese derivative compounds have been limited up to workers in 1954. Houttuynia cordata was 70s [1]. isolated from 3-n-nonyl pyrazole which s a 304 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015. plant of the family "Piperaceae" Tropical Asia an alternative method suitable for the synthesis [3]. They observed the antimicrobial activity. of some difficult available of N-aryl pyrazoles Another natural pyrazole derivative is Levo-β- (2) in scheme5 [6]. (1-pyrazolyl) alanine [4]. Pyrazolic amino acids R Ar-Br 1.n-BuLi (1 equiv), THF, -78 oC Boc Li 1,3-Dielectrophile N were isolated from watermelon seed (Citrullus or N-N N o Ar-I 2.DBAD, 23 C Ar Boc 4 N HCl or Ar Vulgaris). They are currently the only known 10% H2SO4, Dioxane,reflux 2 1 natural pyrazole derivatives in scheme3. 1,3-Dielectrophile: O O O O O O Me Me Me N I H Me Me H N (CH2)8CH3 Me Cl(Br) Me Me Ar-Br=2-MeC6H4, 3-MeOC6H4, 4-F3CCH4, 2,3,5-MeC6H2, C6F5, 2-(6-Me)pridyl, 3-(6-Cl)pridyl Ar-I= 2-ClC6H4, 4-FC6H4, 2,3-F2C6H3 b N Scheme5. Synthesis of N-aryl pyrazoles N N H 1,3-diketones, β-ketoesters and 2,4- CH2CH(NH2)COOH diketoester condensation with hydrazines were widely used in the preparation N-substituent and Scheme3. Examples of naturally occurring n o n N - s u b s t i t u e n t - 3 , 5 - a n d 3 , 4 , 5 - pyrazoles alkyl/(het)aryl pyrazoles, alkoxy pyrazoles and pyrazole of carboxylic esters, respectively. 3- 2. SYNTHESIS OF PYRAZOLES and 5-positions in the various alkyl (4) and aryl (5) bearing the substituent simple pyrazoles 3 - and 5-positions in the various alkyl or could occur in that condensed effectively aryl substituents including the 1,3-dicarbonyl hydrazines with 1,3-diketones (3) in scheme6 (I), α, β-unsaturated carbonyl compounds (II, [7-10]. III) and β-enaminones or related compounds R-NHNH2 a (IV) such as 1,3 positions two electrophilic 3 1 R 2 R 3 R O O R carbon feature with a triple carbon units that act a b 1 as a pair of nucleophile containing a suitable b R R2 N R1 R2 N 3 N R b cyclocondensation with hydrazine for the R R preparation of pyrazole to functional C-3 and C- 3 5 H2NHN-R 5 is used a very common method in scheme4 [5]. 4 Scheme6. Synthesis of tetra substitute pyrazoles O O O O O 1 3 1 1 3 1 3 1 1 2 3 R X w1 R2 R R R1 Elguero et al. proposed the general R2 I II III IV mechanism following loss consecutively two R-NHNH2 molecules of water intermediate step which R2 R1 N involved to form 3,5-dihydroxy pyrazolidine in 1 or/for 2 N R N R N the reaction of asymmetric 1,3-diketones with R R monosübstitüent hydrazine. Formation two N-C Scheme4. Synthesis of substitute pyrazole bonds at carbonyl amine considered reversible whereas observed not reversible part of Recently a study of conducted, one-pot dehydration kinetically controlled step. Two approach based on cyclocondensation of 3,5-dihydroxy pyrazolidine were in balance and compounds 1,3-di electrophilic with aryl then these compounds showed that the product hydrazine Bis-Boc protected (1) was shown as formed two different pyrazole (6,7) in scheme7 305 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015. 1 1 R R1 R R1 R2 w1 HO H without using any solvent with a catalytic OH OH OH N O O N N 2 N + H 2 H + 2 N R 2 + N R N R N R amount of acid at room temperature. A single R R R R R-NHNH2 product (21) or a tautomeric mixture were 2 R1 R2 R HO obtained unsymmetrical with 1,3-diketones (19) OH N N 1 2 H N N R N R N R1 R R in scheme10 [14]. R 7 6 1 R2 R N N 1 R2 Scheme7. Synthesis of disubstitute pyrazoles R N N + H H 1 2 1 2 NH2NH2, H Ar=Ph, R =R =Me; R =R =t-Bu 15 1 2 O O 16 R =Me; R =CO2Et 1 2 R=Me, t-Bu,CO Et ; R2 =Me, t-Bu, Ph R =Me; R =Ph 2 1 2 1 Ar=4-MeC H ; R =Me; R =Me w R2 6 4 Enol ketone form (10) was synthesized 1 R2 R 14 + ArNH2NH2, H + mainly quickly effective in a single step by N N 1 R2 R N N Heller and Natarajan. 1,3-diketones were not Ar Ar 17 18 isolate but they were converted to 3,5-, 1,3,5-, 3,4,5-substituted pyrazoles (11) by adding to the Me Ph Me O O RCONHNH N medium suitable hydrazine in scheme8 [12]. 2 HO N H+, 120 oC N aMe Ph R=Me, Ph O Ph N H 19 R 20 21 2 O R R3 OLi O O LiHMDS toluene R-NHNH2 1 w1 3 N R + R 2 3 o 2 R Scheme10. Synthesis of 3,5-disubstitute 2 R Cl 0 C, 2 min. R AcOH,EtOH,THF N R reflux, 5 min. 8 9 10 R pyrazole 11 2 1 3 R=H R =H R or R = n-C5H11 4-Br/MeO/H2N/NC/EtO2CC6H4,2,6-(MeO)2C6H3,4-pridyl,2-thionyl 2 1 3 R =n-Pr or Ph, R =4ClC6H4, R =4-MeOC6H4 2 1 3 R=Me, R =H, R =Ph, R =4-MeC6H4 1 3 R =4-BrC6H4, R =4-MeOC6H4 2 1 3 1,3-diketo structure of product (24) were R=Ph, R =H, R =4-O2NC6H4, R =4-MeOC6H4 obtained by interacting ketone derivatives (22) Scheme8.