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 , 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 derivatives about chemistry of organic atoms and three 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 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 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 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. Synthesis of trisubstitute pyrazoles with the ester derivatives (23) when it placed with various reagents in the reaction. Especially 1,5-diaryl-3-methyl pyrazoles (13) were 4-alkyl-1,3,5-triaryl (25) and 5-alkyl-1,3,4- obtained by reaction of 1-aryl butane 1,3-diones triaryl pyrazoles were extensively investigated (12) and aryl hydrazine chloride in reaction as ligands for the estrogen receptor [15-18]. cyclocondensation of 1,3-diketones with Both in the solution and solid phase were hydrazines using alcohol or which is great acetic developed methodologies for the consisting of g r o u p a n a p r o t i c s o l v e n t N , N - synthesis of these compounds in scheme11 [19, dimethylacetamide (DMAc) in scheme9 [13]. 20]. T h e p r o d u c t s w e r e s h o w e d h i g h

R Ar3 O O stereoselectivity and productivity product, O O LiHMDS/THF BBr /CH Cl 1 2 Ar-NHNH2.HCl 3 2 2 N Ar + 1 Ar ! r1 1 3 Ar O Ar Ar N R R THF/DMF 110-120oC Ar 22 23 24 25 R=Me, Et, n-Pr, i-Bu, n-Bu;Ar=Ph, 4-HOC6H4 Me Ar 1 2 3 O O Ar = 4-MeOC6H4; Ar =4-O2NC6H4; Ar =4-HOC6H4

R-C6H4NHNH2.HCl N N ! r Me Ar N + Me N DMA, 10 N HCl Scheme11. Synthesis of tetrasubstitute pyrazole C H R 12 rt, 24 h 6 4 C6H4R 13 Ar=Ph, 4-MeOC6H4 3 R=H, Br, SO2NH2 R =4-MeOC6H4 Symmetrical substituted pyrazole (27) was synthesized in high yield according to I or II the Scheme9. Synthesis of 1,5-diaryl-3-methyl method catalyzed condensation polystyrene pyrazole supported sulfonic acid (PSS) or 12-Tungston phosphoric acid (H3PW12O40) at room 3,5-disubstituted pyrazoles (15-18) were temperature between in aqueous medium synthesized in high yield as a direct result of hydrazines/hydrazide and 2,4-pentadione (26) activated 1,3-diketones (14) with hydrazine derivatives in scheme12 [21, 22].

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R1 Me O O literature which have contain trifluoromethyl Method I or II derivatives. Reagents and reaction conditions + R-NHNH N a e R2 2 2 R N R1 investigated widely effects in the condensation R 26 reaction between fluorine-containing 1,3- 27 Method I: 20% PSSA/H2O, rt, 1-2 min. 1 2 diketones and mono-substituted hydrazines in R =H; R =Me; R=Ph, 4-ClC6H4,MeCO,PhCO,2-Furyl-CO,2-thionyl-CO 1 2 R =Cl; R =Me; R=Ph, 4-ClC6H4,MeCO,2-Furyl-CO,2-thionyl-CO 1 2 scheme14 [24-27]. R =Et; R =Me; R=Ph, 4-ClC6H4,2-Furyl-CO,2-thionyl-CO Method II:H3PW12O40,(1%mole H2O), rt, 6-60 min. 1 2 R =H,Me; R =Me; R=H,Ph, 4-MeC6H4,4-ClC6H4,MeCO R1 R2 Rf R1 O O HO OH N N and/or N wf R2 + RNHNH2 Rf N R2 R1 Scheme12. Synthesis of tetrasubstitute pyrazole R a R H+ Rf: alkyl group containing fluorine -H2O b

R1 2 R1 2 1 R R Rf R H H H O Devery et al. were reported in the literature N 2 N N Rf N Rf N N R2 a new method for synthesis of 1,3,4,5-alkyl/aryl R R R substituted pyrazoles (29, 30) [23]. That method R1 R2 includes synthesis of substituted pyrazole (32) N Rf N with the addition of cerium-catalyzed R 37 substituted hydrazines after cerium ammonium nitrate (CAN), allyl trimethyl silane (31) and Scheme14. Synthesis of fluorine-containing 1,3-diketones (14) interaction. The propantriol pyrazoles pyrazole (PPT) (34) was obtained in 30% yield over 4 steps in scheme 13. PPT was used as A single 3/5 - substituted pyrazole (40) estrogen receptor agonist product or 3/5-substituted mixture of pyrazoles (41) and 3/5-substituted alkoxy pyrazole (42)

R2 R1 R2 R1 were formed depending on reaction conditions O O 1 2 R=4-MeOC6H4; R =Me, R =Allyl CAN, RNHNH2 2 N N R =Me Ph 1 + 1 2 R Ph N Ph N R R =CF3; R =Allyl as a result of condensation reaction β-ketoesters 2 MeCN, Reflux 1 2 R 30 R=Me; R =Me; R =Allyl 28 R 29 (38) and the related hydrazines in scheme15 [28].

Me 1 CF2R O O 1.CAN/MeCN/rt TMS N + Me N Me Me SO R 1.EtOH, reflux N 2. R-NHNH 2 HO 14 31 2 R or N R=Me,Ph, 4-MeO/HO2CC6H4,2,4- O O 32 i-PrOH,NH4Cl, reflux (2ON)2C6H5 + w1F C N OH 2 OEt 2.NaOH,EtOH N

NHNH2 38 SO R 39 2 O O 40 o 1.POCl3, DMF, 80 C Ar N Ar 2.NH2OH.HCl, TFE, reflux N o Cl3CCOCl3, Et3N, CH2Cl2, 0 C 33 HO PPT OH Ar=4-MeOC6H4 1 CF R1 CN CF2R 34 CN 2

N N 2 Cl R O N N Scheme13. Synthesis of 1,3,4,5- alkyl/aryl R2OH, KF or CsF, DMSO, rt substitute pyrazole and PPT N N SO R SO2R 2 42 41 Most of fluorine or fluorocarbon-containing 1 2 pyrazoles (35) were an area of active researches. w=Me; R =H,F; R =CyPrCH2,cyBu,cyBuCH2,cyHept,cyHex-3-enCH2, (4-Methylene)-cyHexCH2,(2-/-3- Me)cyHex, (4-Ethyl)cyHex,1,2-(Me)2Pr 1 2 These compounds were investigated in the field R=NH2; R =F; R =CyHept,(3-Me)cyHex,(4-Ethyl)cyHex,(4-4-F2)cyHex,cyHeptCH2, 2,2-(Me)2Pr of agricultural chemistry and medicine. Because these compounds were in biological Scheme15. Synthesis of 3/5-substituted alkoxy activity the most frequently cited in the pyrazoles

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3-alkoxy-pyrazole (44) was conducted The substituted pyrazoles (55) were directly for the preparation with a simple obtained by oxidation pyrazolines (54) which method as a result of the condensation reaction formed by the interaction various hydrazines between alkyl acetoacetate (43) with mono with 1,3-diaryl-2-propen-1-one (53) derivatives hydrazine chloride in scheme16 [29, 31]. in scheme19 [38-40].

PhNHNH2 AcOH, reflux, I2 2 OR O R O R R R=Ph, 4-F/ClC6H4, 4-OH-6-Me-2-pyron-3-yl 1 O R OH, reflux, 8h PhI(OAc) Ar=Ph,4-Me/MeO/Cl/O2NC6H4 2-furyl/thionyl,,4-Pyridyl Ph(Het)NHNH2 2 N 1 3 + RNHNH2.HCl N N Ar Het=6-Florobenzothiazol-2-ylhydrazine w O R 3 ! r R N Ar N R AcOH, EtOH, reflux CH2Cl2 2 N Ph(Het) R 53 Ph(Het) 1 2 3 54 55 43 R :Me, Et, Bn, i-Pr, t-Bu R :H, Et R :Me, H R:H R 44 Scheme16. Synthesis of 3-alkoxy-pyrazole Scheme 19. Synthesis of trisubstitute pyrazoles

[3 +2] ring closure reaction was frequently The most of pyrazoline (58) compounds used for synthesizing pyrazole 3-(5) carboxylic were obtained to converting the epoxides (57) acid ester between1, 3-diketoester with which occurred 1,3-diaryl-2-propen-1-one (56) hydrazines. The diethyl oxalates (46) with the by Bhat et al. 3,5-diaryl pyrazoles (59) were enolate of ketone (45) were reported as Claisen synthesized interaction of (58) the with condensation in the literature. The 3 (5)- appropriate hydrazine in scheme20 [41]. carboxylic acid derivatives (48) were O O 6 synthetized by reaction hydrazines with 1,3- 6 1 R 1 R R R H2O2, HO O diketoester (47). Some of these compounds o 0 C R2 R5 R2 R5 3 4 demonstrated significant activity in 3 4 R R R 57 6ي R pharmacology in scheme17 [32-36]. 1 2 3 4 6 R , R , R , R , R =H, OCH3 H2N.NH2.H2O 5 R =H, OCH3,F reflux 4 5 R /R =-OCH2O- R2 CO2Et N NH O O O N NH O 6 1 1 6 1 R 2 OEt RNHNH2 N R =Alkyl, Het(Aryl) R R R 1 CO Et 1 2 R R1 + 9tO R 2 R N R =H, Alkyl,Het(Aryl), heteroatom AcOH R2 R=H, Alkyl, Het(Aryl) O R OH 45 46 47 H SO 2 5 48 R2 R5 2 4 R R 3 4 R3 R4 R R Scheme 17. Synthesis of pyrazol 3 (5)-carboxylic 59 58 acid Scheme20. Synthesis of 3,5-diaryl pyrazoles 3,5-diaryl pyrazoles (50) were easily obtained in high yield by Claisen-Schmidt A series of 3,5-diaryl-1H-pyrazole (61) condensation of chalcone with (1,3-diaryl-2- were synthesized to a way easier and safer rather propen-1-one) (49). The pyrazoline (51) was than high toxic effects of hydrazine hydrate by synthesized using the appropriate reagents. A the interaction with the α-epoxy ketones (59) series of 4-alkyl-1,3,5-triaryl pyrazole (52) using semicarbazide hydrochloride salt (60) in were synthesized with oxidation of compound scheme21 [42].

H (51) in scheme18 [37]. N 1 1 N 1 Ar Ar O 2 2 Ar R R R O EtOH R 40-50 oC O MnO NH2 . HCl Ar3NHNH N 2 N + H2N N 2 N 1.LDA 2 2 2 Ar Ar O H 2 Ar N N Ar1 Ar N 2.RI 1 R 60 9ي DMF, argon Ar3 Ar3 1 Ar3 R 61 49 51 52 50 R1=H, 4-Cl, 4-Me, 4MeO 1 2 Ar =Ph, 4-MeOC6H4 R =H, 2-Cl, 4-Cl, 4-Me, 4MeO, 3-NO2 2 Ar =Ph, 4-MeOC6H4,4-OTBDPSC6H4 3 Ar =Ph, 4-MeOC6H4 R=Me, Et, n-Pr Scheme18. Synthesis of 4-alkyl-1,3,5-triaryl Scheme 21. Synthesis of 3,5-diaryl-1H- pyrazole pyrazoles

308 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015.

A series of 1,3,5-trisubstituted pyrazole The required substituted pyrazoles were (65) was synthesized with the interaction of a synthesized to interaction of with various mild base which pyrazoline (63) intermediate of hydrazines of chiral oxazolidines and product by condensation the appropriate tetrahydropiranyloxy ynones under the hydrazines and α-enone (62) including a leaving appropriate reaction conditions. Silva et al were group in scheme22 [43]. worked a series of compounds based on Bt Ph including these structures at the synthesis R2 N various pyrazole derivatives (72, 74, 75, 77, 78) Bt Ph R1 N NaOEt using equivalent formyl groups such as w1 R O n-BuLi/R2I or 64 t-BuOK a l k o x y m e t h y l e n e , a m i n o m e t h y l a n d 62 dimethylaminomethylene [49-52]. A series of Ph Ph Bt R2 3,4-diaryl-5-methyl pyrazole (80, 81) was used RNHNH2 NaOEt/EtOH N N for the synthesis that previously obtained NaOEt/EtOH R1 N reflux R1 N reflux R R method based on chromen-4-one (79). Some of 63 65 the compounds were synthesized. These Bt=Benzotriazolyl 2 1 R =H, R=Me or Ph; R =i-Pr, Ph, 4-MeC6H4, 3-Pyridyl compounds were tried about inhibition of cell 2 1 1 R =H, R=Me or Ph; R =i-Pr, Ph, 4-MeC6H4, R=Me; R =4-MeC6H4 2 1 proliferation R =n-Bu or Allyl or Bn; R=Ph; R =4-MeC6H4

O Scheme22. Synthesis of 1,3,5-trisubstitute NH2NH2.H2O MeOH, reflux

O N NH N NH OH pyrazoles O 71 OH 72 H H N N N O N O HO The yield of less trisubstituted pyrazoles HO NH NH NH N DDQ 2 2 N AcOH N (67) were prepared with reacting α,β-chalcone O O 1,4-Dioxane Ar Ar of ditosylate (66) and an appropriate hydrazine 73 74 75 1 Ar =Ph, 4-MeC6H4, 4-MeOC6H4,4-FC6H4,4-ClC6H4,4-BrC6H4, in scheme 23 [44].

R RHN R R X RNHNH H H2N-NH2 O O OTs 2 O NH N N N N N DMF,reflux 1,2-Shift O Ar O NH Ar1 H2N-HN Ar HN 1 2 1 ! r Ar 1 2 Ar Ar Ar N Ar EtOH,reflux -TsOH 1 HO -H O O OTs Ar 2 H NNH X Ar -TsOH OTs H Ar2 2 2 Ar2 66 Ar2 Ar O Ar O O 1 2 67 O Ar Ar =Ph;Ar = 4-Me/MeO/BrC6H4,2-thionyl-3-Me-2-thionyl 80 1 2 MeOH Ar =4-MeC6H4;Ar =4-MeC6H4,2-thionyl-3/5-Me-2-thionyl 1 2 reflux Ar =4-MeC6H4;Ar =Ph,4-MeC6H4,2-thionyl-3-Me-2-thionyl O Ar1=4-ClC H ;Ar2=Ph,4-MeC H ,2-thionyl-3/5-Me-2-thionyl 6 4 6 4 O Ar Ar R=Ph, CO(S)NH2 OBn O Ar Ar NHNH2 O X N X O 79 NH O Ar O Scheme23. Synthesis of 1,4,5-trisubstitute O Ar Ar 81 Ar=Ph, 4-2ONC6H4, 4-MeOC6H4,4-FC6H4,4-ClC6H4,4-MeC6H4;X=HO-6BnOCH3 pyrazoles

1 O R R2 R2 X=O; R1=H,Ph NH2NH2.H2O 2 R =2/3/4-Cl,4-Br/NO2,2,4/3,4-Cl2 R1 1 1,3- and 1,5-substituted pyrazoles (69,70) prydine R1 X=S; R =H,Ph R2 R2=4-Cl/Br,3-Cl,4-NO ,2,4-Cl O OH N NH 2 2 OH HN N were synthesized as the result of condensation 82 83

Ynones (68) and substituted hydrazines in scheme 21 [45-48]. Scheme25. Synthesis of 3,4-diaryl-5-methyl pyrazoles Ar1 O 2 Ar NHNH2 1 ! r1 N + N Ar =Ph, 4-MeO/ ClC6H4 Ar1 2 d.HCl-MeOH N N Ar =Ph, 4-Me/ O2NC6H4 A series of 4-substituted pyrazole (85) were 68 Ar2 Ar2 synthesized based on a aryl hydrazines of 2- 69 70 formula glycol (84) any solvent. The yield of the Scheme24. Synthesis of 1,3- and 1,5- reaction products were compared with done disubstituted pyrazoles separately of the results obtained under thermal

309 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015. conditions and microwave radiation in appropriate reaction conditions. The obtained scheme26 [54]. pyrazoles were exhibited pharmacologic activity in scheme29 [57-59].

R1O h OR1 N 1 OR 1 RHNNH2 R =Me,Et,Bn O HN O RHNNH2, THF, rt or.و CHO R=H,Ph, 2-EtC6H4,3,4-ClC6H4,4-MeOC6H4 1 R O OR1 OH OR1 RHNNH2 (HX), Et3N,MeOH,THF,rt 84 85 N R 2.DMFDMA, reflux N Scheme26. Synthesis of 4-substituted pyrazoles n O n=1,2 n R=Me,Et,Bn,Ph - -2 93 86 x=2Cl veya Cr2O4 Firstly 1,3-cyclo alkanedione (88) was obtained with react dimethyl formamide dimethyl acetal (DMFDMA) (86) and β- Scheme29. Synthesis of fused cyclohexanone enamindione (87) in one step under microwave pyrazoles radiation. Then a series of 4,5-fused of cycloalkonoes that 1-substituted pyrazoles (89) Longhi et al were synthesized a series of 5- was conducted hydrazine and the obtained (het)-aryl-NH pyrazoles (97) with reaction product in scheme27 [55]. h y d r a z i n e s u l f a t e ( 9 5 ) a n d β - dimethylaminovinyl ketone (94) using as O O O N catalyst p-toluene sulfonic acid (96) solid phase Me OMe RHNNH2,H2O N + N any solvent conditions in scheme30 [60]. Me OMe AcOH n b O n O n R 87 88 89 R2 86 96 O n=1,2; R=H, t-Bu, cyklohexzyl, Ph, 2,4-Me2C6H3, 3,5-Me2C6H3 Me PTSA R1 + H2NNH2.H2SO4 R1 N N b Me R2 Scheme27. Synthesis of 4,5-fused of 95 R 94 97 cycloalkonoes 1-substituted pyrazoles 2 1 R =H; R =Ph, 4-Me/F/Cl/Br/O2NC6H4,3-MeOC6H4,2-furyl,2-thionyl 2 1 R =MeOC6H4; R =Me 1 2 R /R =-(CH2)3C(O)- Fused of cyclopentanone 1-substituted pyrazoles (91, 92) were synthesized to Scheme30. Synthesis of 5-(het)-aryl-NH condensation reaction of the enamindione (90) pyrazoles with various hydrazines in solvent and appropriate conditions, changing the product Persson and Nielsen were developed an formed itself and stereoisomer mentioned effective method of interaction the hydrazines depending on the molecular size of hidrazine of compound (100) which obtained product and the reaction temperature in scheme28 [56]. from Weinreb amides (98) and ethyl propionate (99) in the appropriate solvent and temperature N O for the synthesis of pyrazole-3-carboxylate N N R wHNNH2, MeOH (101) in scheme31 [61]. N N + R R=Ph,Bu,Me,Et CO Et O O 2 O CO Et OMe 2 90 w1 NaHMDS,THF RHNNH2,CDCl3 91 92 N + OEt R1 OMe R1 N N N Me -78 oC - -40 oC 100 oC Me R 98 99 100 101 Scheme28. Synthesis of fused pyrazoles 1 R=Me or Ph; R =Me, Ph(CH2)2,Ph, 2,4-Cl2C6H3

The pyrazole products (93) were Scheme31. Synthesis of pyrazole-3-carboxylate synthesized in excellent yield with ring closure cycloalkyl 1,3-dione with various mono Giacomelli et al were synthesized by β-keto substituted of hydrazines in a single step esters and the β-keto amide derivatives (103)

310 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015. which obtained as a result of ring opening They were synthesized directly a serial 4-acyl interaction of various alcohols and , pyrazole-5-carboxylate (111) products from acylation derivatives of acid chloride as known unsymmetrical of enaminodiketoester (110) in Meldrum's acid (102). A series of 1,5- scheme35 [67, 68]. O O O O O substituted 4-pyrazole of ester and amide EtOH, reflux or R1 1 OEt R1 OEt rt, 1h R N derivatives (105) were obtained by interaction EtO2C O -HNMe2 O N Me2N NHNHR hydrazines of compound (104) in scheme32 R wHNNH2 R=t-Bu, CO2Me 1 [62]. 110 R =Ph, 4-MeO/Cl/F/O2NC6H4, 2-thionyl, CCl3, CF3 111

O Scheme35. Synthesis of 4-acyl pyrazole-5- 2 OH R2OH XR2 XR XR2 or O O NMe R1 2 carboxylate pyrazole O RNH2 DMFDMA wHNNH2 N N R1 O O O O 1 R R1 R 102 103 104 105 Thio-, silyl-and halo pyrazoles were used as Scheme32. Synthesis of 1,5-substituted 4- a building block in heterocyclic chemistry due pyrazole ester and amide to easy replacement by carbon or heteroatomic substitutions. The pyrazole was synthesized A series of 4-substituted pyrazole (107) primary by reaction with hydrazines as synthon were synthesized in high yield by condensation of α-oxoketen S-S-acetal [69]. According that of the interaction various hydrazines and α- method the pyrazole was obtained by ethoxycarbonyl-β-Enaminones (106) with condensation a hydrazine and 2-tiohydanto catalytic amount of p-TsOH in suitable solvent (imidazolidyne 2,4-dione) (114) in the suitable medium. The obtained pyrazole products were solvent for the synthesis of methylsulfanyl- used as histamine analogs in scheme33 [63-65]. imidazo [4,5-c] pyrazole (201) in scheme36 [70]. Br 1 NH2 O R CO Et n-BuLi 2 H Zn 2 SCH3 S Zn/BrCH2CO2Et (R CO) wHNNH2 N R1-CN HN O 2 1 O R OEt N O H CS R2 3 THF, reflux, 1h 3h, rt TsOH N 1.CS2, EtONa H3CS N 1 2 1 RNHNH R OEt O R MeOH HN N R EtOH, rt 1 2 1 reflux R HN N R N R R N 1 106 107 2.CH I, MeOH, rt R = Ph, Me,Ph, sec-Bu S 3 EtOH, piperidine, reflux 2 S 1 R = Me, Ph, sec-Bu, i-Pr, CF3 R /R=H, Ph 114 113 12و R=H, Ph Scheme33. Synthesis of 4-substituted pyrazole Scheme36. Synthesis of methylsulfanyl-imidazo [4,5-c] pyrazole Flores et al were synthesized β- alkoxyvinyl trichloro methyl ketone (108) as Peruncheralathan et al were synthesized 1- starting products then alkoxycarbonyl pyrazole aryl-3-(methylthio)-4,5-substituted/cyclic derivative (109) was synthesized in good yields p y r a z o l e s ( 1 1 7 ) a n d 1 - a r y l - 3 , 4 - to interaction with hydrazine hydrochloride or substituted/cyclic-5-(methylthio)-pyrazoles phenyl hydrazine in medium suitable solvent in (120) as a result of condensation of aryl scheme34 [66]. hydrazines with β-oxoditioesters (115) and α-

2 R R1 oxoketen thioacetals (118) in scheme37 [71- O OR wHNNH .HCl R=Me, Et 2 N RO C 1 73]. Cl3C R1 2 N R =H,Me, Ph,2-furyl, 2-thionyl MeOH or EtOH R2=H, Me; R1/R2=-(CH )- 2 o 2 R 25 C, reflux R 2 O R 1 1 2 2 R R R 108 1 R 109 R ! rHNNH 2 SMe Raney-Ni N N t-BuOK, t-BuOH N EtOH,reflux, 4-5 h N MeS SMe reflux, 10 h Ar 1 Ar R =Ph,4-ClC6H4,4-MeOC6H4,3-Py,Me 115 2 Scheme34. Synthesis of alkoxycarbonyl 116 7 R =H, Ph 11 1 2 2 R /R =-(CH ) - S 2 R 2 4 MeS R Ar=Ph,4-FC H 2 ArHNNH Raney-Ni 6 4 pyrazole MeS R 2 N 1 N 1 R EtOH,reflux, 4 h N R EtOH,reflux, 4-5 h N 1 O R Ar Ar 118 120 Martins et al proposed reaction mechanism 119 about how the reaction occurs in synthesis. Scheme37. Synthesis of substituted pyrazoles

311 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015.

OTMS R1 1,3-dipolar cycloaddition reaction is used 3 1.TMSC(MgBr)N2 R O THF,-78 oC, 1,5 h OH R3C CR4 R2 one of the widely synthetic instruments for R1 TMS 1 2 N w R R2 THF, reflux, 1 h N R4 2.H2O obtaining substituted pyrazoles [74]. The 1,3- N2 H 124 dipolar are used three main classes as [CNN] 122 123 1 R =Ph, 4-ClC6H4, 4-MeOC6H4, PhCH2CH2, t-Bu R2=H,Me synton including diazoalkanes, nitrile imines 3 4 3 4 R =R =CO2Me; R =H; R =CO2Et and azomethine imines in scheme38.

1 2 Scheme40. Synthesis of di-and tri-substituted w1 R2 R R X Z (1,3-Dipoller) pyrazoles X Z X Z Y Y Y

N N C N N C (Diazoalkanlar) Jiang et al were synthesized carbonyl and ethoxy carbonyl pyrazoles (127) by 1,3-dipolar C N N C N N (Nitriliminler) cyclo addition of molecules between alkinolate or alkinone (125) and cyclic or acyclic α-diazo C N N C N N (Azometin iminler) carbonyl (126) compounds using catalysis InCl3 in water at room temperature in scheme41 [78]. Scheme38. 1,3-dipolar classes O R1 R3 O Me Me 2 InCl R R3 3 O N 1,3-dipolar cyclo addition was carried out R1 + b O H2O, rt H effectively with alkynes the electron-rich of O R2 125 126 127 1 R =H, MeCH(OH)C6H4, 3/4-MeOC6H4, PhCH2CH2, 4-FC6H4 diazo compounds under thermal conditions. But R2=Me, Et 3 diazo compounds are potentially explosive and R =H, CO2Et toxic due to natural processing and preparation is hazardous. These problems were overcome Scheme41. Synthesis of carbonyl and ethoxy by used a method for multiplication of aryl carbonyl pyrazoles diazomethane from suitable tosyl hydrazone derivatives. Thus, for preparation of 3,5-aryl Recently alkynes were begun a broad pyrazoles from aromatic aldehydes (121) were workspace for the synthesis of pyrazole. Qi et al used as a functional in one step in scheme39 [75, synthesized a series of 3,5-disubstituted 76]. pyrazole (130) as a result of cyclo addition diazo

N-Vinilimadazol Ar carbonyl (128) of compounds a series of alkyne or 2 O 1.TsNHNH2 N R MeCN,rt R1 (129) in the reaction medium. They worked how N N ! r H R1 N affects yield alkyl and aryl alkynes and aryl 2.NaOH H Ar H 121 alkynes by adding Zn(OTf)2 any solvent at a R1 R1=H certain temperature. They were determined that R2=2,2(Bisalcoholatecarbonyl)cyclopropyl R=Me, Bn alkyne gave better yields in scheme42 [79].

R1 Scheme39. Synthesis of 3,5-aryl pyrazoles N2 OR2 method 1-2 1 O N + R b H O OR2 128 129 130 method I method II Di-and tri-substituted pyrazoles (124) o o n-BuLi, THF, -78 C, CuCN.6LiCl Zn(OTf)2, NEt3, 100 C, 8 h 1 rt, 2-4 h R =Me3Si, EtCH2, EtOCH2, Et(CH2)3, AllylOCH2, 5-AllylOCH2, PhCOOCH , Ph,4-MeC H ,4-BrC H were synthesized with [3 +2] cycloaddition 1 2 6 4 6 4 R =H,MeC6H4, 3FC6H4, 3,5-(CF)3C6H4, NC(CH2)3, R2=Et 2-(6-MeO)N, 4-N-Morfoline(CH)2 between derivatives of dimethyl acetylene R2=Bn, t-Bu, Et dicarboxylate or ethyl propylate (122) and 2- diazo-2-(trimethylsilyl) ethanol (123) in Scheme42. Synthesis of carbonyl and scheme40 [77]. ethoxycarbonyl pyrazole

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Recently β-chloro acryl amide were at 1,3-cyclo addition reaction with nitriles reported systematic work dipolarofilic on imines in scheme45 [85]. behavior oxidation levels of sulfide and sulfate against phenyl azomethane, trimethylsilyl N Ar1 Ar2 N azomethane, diazomethane and diazoethane in 2 SO p-Tol SO2p-Tol 1 Ar1 O Ar N Ar2 scheme43 [80]. N O NH H NH R1 Cl N R1 1.DBU,DCM,rt R2 N O O 2 HN 2. 25% TFA, DCM Ar 2 H 9tN3, DMC HN R N R2 N Rink R3 N N Rink 138

CONHR 1 CONHR R =H,Me,Bn,i-Bu 132 2 1 137 R =CONHCHR CONH2 1 2 R=Me, Bu, Bn, Ar Ar =Ph,4-Me,/4-MeO/F/Br/O2N/CF3/NCC6H4,1-Naftyl,4-Biphenyl,2-Furyl O R N 1 1 2 3 -R SOCl R =Ph, Bu, Bn, Tol Ar =Ph,4-Me,/4-MeO/F/Cl/Br/O2N/i-PrC6H4 2 3 R N R1S(O)n R R CN2 R2=H, Me, Ph NHR H 3 n=1 CONHR R =H, TMS Cl S / l 1 131 O R Scheme45. Synthesis of 1,3-diaryl pyrazole

2 H 2 2 R N 2 R N R N R N 3 R3 N R N R3 N N H -Cl H CONHR CONHR 1 CONHR S 1 The tetra substituted pyrazole (141) was Cl SR SR1 R S CONHR R1 133 obtained in high yield by 1,3-dipolar cycloaddition α-bromocinnamaldehyde (139) Scheme43. Synthesis of the substituted pyrazole with C-aryl-N-phenyl nitrile imines (140) in scheme46 [86]. Nitrile imines were obtained by interacted Ph Ar a base and hydrazonoyl halide in the reaction O Cl H Et3N + N H N medium. Last decade 1,3-cyclo alkenes Ph H Ar b Ph N DCM Br O Ph participate of nitrile imines were used for the 140 synthesis of substituted pyrazole [81]. This 139 141 Ar=Ph,4-Cl,/4-MeOC6H4,3-O2NC6H4,2,6-Cl2C6H3 methods that rimonabant, the cannabinoid type- 1 COX-2 of selective inhibitors were applied for Scheme46. Synthesis of tetra substituted pyrazole the synthesis of stereo-selective in the solid phase [82, 83]. In addition reaction (135) was Synthesis of pyrazole (144) was reported synthesized between nitrile imines and aryl both the catalyst and without the catalyst 1,3- acetaldehyde with gummy piperazine (134). cyclo addition reactions taking place between Then 1,4-diaryl pyrazole-3-carboxylate (136) C-carboxymethyl-N-aryl (143) and C-aryl-N- was synthesized directly separated from the aryl nitrile imines (142) in scheme47 [87]. resin acidic medium in scheme44 [84]. O 1 1 Cl ROC R Cl R H N X N R 1 2 N Ar COR Ar N 2 N O Ar1 Ar 3% TFA N Ag CO or Et N b N 2 3 3 N N N NH O 1 DCM, rt N Sc(OTf)3 Ar EtN3, CHCl3 + reflux, 16 h Ar2 o 134 N X dioxane, 80 C 1 Ar =Ph, 4-Me,/Cl/Br/O2NC6H4 136 2 Ar =3-MeOC6H4, 4-IC6H4 143 R=OEt, Me X=OBn, NHPh 2 135 2 1 R w R =CO2Me,Ph 144 142 Scheme44. Synthesis of 1,4-diaryl pyrazole-3- carboxylate Scheme47. Synthesis of 4 - and 5-substituted pyrazole Vinyl sulphones polymer supported (137) were used stereo selective dipolarophile for N-phenyl-5-substituted-3- dimethoxy derivatives a series of 1,3-diaryl pyrazole (138) phosphone pyrazoles (146) were obtained in

313 Çetn,A. Muş Alparslan Unversty Journal of Scence, 3 (1), 303-321, 2015. low yield with1,3-dipolar cycloaddition of Synthesis of novel pyrazoles (154) were nitrile imines and monosubstituted alkynes conducted with reacting substituted using phosphonate groups (145) instead of furopyrazoles (153) and sydone (142) with three carboxylate groups for preparation of Withasomnine that occur naturally in scheme51 compounds having pharmacological activity in [92]. scheme48 [88]. O TMS Ar h BPin PO3Me2 Me2O3P Me2O3P BPin NaHCO3 TMS 1. Ar-I, Pd AcOEt N N R PDC, DMF, rt N t h-NH-N=C(Br)PO3Me2 N N N N N N R N R reflux N 2.TBAF/THF 145 N Ph Ph Ph 152 153 154 146 Ar=Ph,Withasomnine Ar=4-HOC6H4,4'-HidroxyWithasomnine Ar=4-MeOC6H4,4'-Methoxywithasomnine Scheme48. Synthesis of N-phenyl-5-substituted- 3- dimethoxy phosphone Scheme51. Synthesis of substituted pyrazoles

Sydnone (147) was stable meso-ionic Alkynes with metal of activity lead to compounds relatively as dipolar type formation of the pyrazoles result of cyclization azomethine imine. These compounds were 5-exo/endo-dig to participate nucleophilic readily obtained by dehydrating cyclo of N- nitrogen derivatives intramolecular. Synthesis substituted-N-nitroso amino acids with reagents of 3 (5)-3,5- and 3,4,5- substituted pyrazoles such as acetic anhydride. 3,5-disubstituted- (155) were reported in the literature in pyrazole (148) was comprised due to extraction scheme52 [93]. of carbon dioxide by 1,3-dipolar cycloaddition Boc Boc HN NH with acetylenes in scheme49 [89, 90]. CuLi L (20 mole %) R2 1 2 1 R R2 R1 2 R R CaCO R R1 3 TFA NBoc I THF, 80 oC NBoc DCM, rt NH O CO2R NHBoc N N 3 3 w R 3 O CO R L= Me NH HN Me R Boc R3 2 R=Bn,Et,t-Bu,CHPh 155 N 2 1 N NC R =H,n-Pr,n-Bu,Bn,Ph,TIPSOCH2 NC 2 1 2 N Ar=C6H4p-OEt R =H,Et; R /R =-(CH2)3- b chlorobenzene 3 R =n-Pr,n-Pent,n-Oct,CO2Et,CH2CH2OBn,-(CH2)-Cl,Ph Ar reflux, 48 h Ar 147 148 Scheme52. Synthesis of 3 (5)-, 3,5- and 3,4,5- Scheme49. Synthesis of 3,5-disubstituted- substituted pyrazoles pyrazole The 1,3,5-trisubstituted pyrazoles (157) Hedge et al used unsymmetric α, β- were synthesized with 5-endo-dig ring closure acetylenic phenones (150) including 5-nitro from alkynyl nitroso amines (156) using a as dipolarophiles at the 1,3-dipolar catalyst at room temperature [94]. The obtained cycloaddition with N-aryl sydonone (149) for yields were quite high and even two products the synthesis of a series of 1-aryl-3-(5-nitro-2- were observed quantitatively in scheme53. furyl)-4-arylpyrazoles (151). The similar 2 O R NO 10% AgNO 2 b 3 R2 R N SiO (20 mole %) N N 2 N PCl ,CHCl 3 results were made using substituting R3 3 3 R R1 CHCl3 or DCM 60 oC,2 h 1 o 1 R 3 20 C, 6-8 h R furan in scheme50 [91]. 156 R 157

NO2 R1=i-Bu,Ph R2=Pr,Bn,Allyl -Ag O X Ag O R3=Bu,Ph,(CH3)2OTBDPS h O NO O N X 2 2 O N xylene R O N R2 N 2 2 + N R N R N reflux N N N R3 R3 R2 150 X= O; S 1 1 R1=H,Me,MeO R1 R R 1 Ag R R2=H,Me,MeO,Cl 3 H H 1 R Ag 149 R Ag 151 Scheme50. Synthesis of 1-aryl-3-(5-nitro-2- Scheme53. Synthesis of 1,3,5-trisubstituted furyl)-4-arylpyrazoles pyrazole

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Propargyl N-sulfonyl hydrazones (158) heterocyclic chemistry [100]. were used for the synthesis 1,3- and 1,5- Ar O disubstituted pyrazoles (159) in the medium RNHNH2 1 N 1 a veya b Ar R w + N silver (II) catalyst and the reaction was carried R1 Ar I R out at high productivity to interaction with 163 o a)CO (1atm),PdCl2(PPh3)2, rt b)Mo(CO)6,Pd(OAc)2,CuI,Pt-Bu3,Cs2CO3, 80 C, 18 h various hydrazones as catalyst together %5 mol R=H,Me R=H,Me,Ph 1 1 R =n-C6H3,4-MeC6H4 R =Ph,4-MeO/ClC6H4,Bn,3-Thionyl/pyridyl,CH2O Ar=Ph,4-Me/MeOC H ,2-Thionyl Ar=Ph,4-Me/ClC H ,3-pyridyl AgSbF6 with dry dichloromethane in the 6 4 6 4 reaction medium in scheme54 [95]. Scheme56. Synthesis of 3,5-diaryl pyrazole R2 2 2 Ag 2 Ag AgSbF6 R R R 3 R 3 R Ag H N 1 H b 1 3 R R3 R R N N DCM, rt N N 1 -Ag Adib et al synthesized dialkyl 5- N R 3-12 h N R1 Ts Ts 159 Ts Ts 158 R1=H,Me (alkylamino)-1-arylpyrazole-3,4-dicarboxylate R2=H,Me,Ph 3 R =Alkenyl,aryl,PhCH=CH,4-MeOC6H4CH=CH (164) in good yield according to the multi- component reaction at room temperature in Scheme54. Synthesis of 1,3- and 1,5- scheme 57 [101]. disubstituted pyrazoles O RO2C CO2R acetone 1 + RO C CO R + R N C 2 2 ArNNH NHPh 1 N rt, 36 h R HN b Ar Multi-component reaction was reactions 164 leading to the formation simultaneously of the -CO -PhNH2 CO2R Ar CO2R H CO R N O 2 desired a combinations of two or more building CH 1 RO2C C PhHNN R N N H C CO2R C CO2R O NHPh N O R1HN block. For example, 3,5-disubstituted pyrazole PhHN RO2C CO R N C 2 C R=Me Ar NHPh N (162) were synthesized to react using catalyst at N R=Me, Et R R R1=t-Bu,1,1,3,3-tetramethylbuthyl the appropriate temperature acid chloride (160), Ar=Ph,Tol alkyne (161) and hydrazines which three components in a single step in scheme55 [96, Scheme57. Synthesis of dialkyl 5-(alkylamino)- 98]. 1-arylpyrazole-3,4-dicarboxylate

1 R2 1 R 1. PdCl2(PPH3)2/CuI R O Et3N,THF N 1 N 2 veya R2 veya R Recently a series of 1-aryl-4,5-disubstituted + R N N N 1 R2 R Cl 2.RNHNH2 b H R R 161 pyrazole (165) was obtained only one product 160 162 R=Me R=Ar 1 R =Ph,2-Furyl,4-MeC6H4,4-2ONC6H4,2-Thionyl,cyclohexyl using catalyst together 1,3-diimides and 2 R =Ph,4-MeC6H4,2-napthyl,hexyl R=H hydrazine or its derivatives in scheme 58 [102].

R1 R2 Scheme55. Synthesis of 3,5-disubstituted 10 mole% Ti(dpma) (NMe2)2 + 4 R2 or R HN RNHNH2 pyrazole pyridine, 150 oC 3 10-20 mole% Ti(dpm) (NMe2)2 R NH2 1 N 3 R R N 2 4 b + o R -NH R toluene, 100 C 2 R R4N C 3 R1 -H2NR 3,5-diaryl pyrazole (163) was synthesized 165

1 2 by reacting using a catalyst four components in R =H, R =Ph, R=H,Me,t-Bu,C6H11,Bn,Ph,4-MeC6H4,4-MeOC6H4,4-NCOC6H4,4-MeO2CC6H one step terminal coupling alkynes, methyl hydrazine, the aryl iodide and carbon monoxide Scheme58. Synthesis of 1-aryl-4,5-disubstituted i.e. in scheme 56 [98]. It was reported that the pyrazole reaction takes place with use the hexane carbonyl molybdenum instead of carbon The strategies developed for pyrazole monoxide in the multi-component reaction compounds which are considerable because of [99]. Particularly it was the subject for multi- indicate the potential biological activity component reaction to isocyanate-based in the pyrazole carboxylic acid and derivatives.

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R1 R2 For example, high-functional derivatives of 2 b R Cu(OAc)2 N o R1 14-24 h, 110-120 C N N + CO R pyrazole-4-carboxylic acid (167) were H 2 CO R R3 3 1 3 2 R R :Ph,4-FC6H4 R :Me,Ph,CO2Me,Et,i-Pr 2 synthesized in good yields with the addition the 169 R :Me,H R:Me,Bn,t-Bu -Cuo

AcO OAc OAc Huisgen of isoelectronic of the product which Cu R2 R2 Cu N R2 N 1 R1 R CO2R N R1 N 3 obtained from the reaction of dialkyl N R -HOAc Cu R3 3 H CO2R N R azodicarboxylate, 4-substituted allenoates CO2R (166) and triphenyl phosphine [103]. The Scheme61. Synthesis of tetra substituted reaction mechanism was proposed a cyclization pyrazole-4-carboxylate containing a carbon-nitrogen migration of carbonyl group alkoxy, double bond Tetra substituted pyrazole-4-ol (170) was isomerization and the elimination of triphenyl obtained from the reaction 3,6-diaryl-1,2,4,5- phosphide oxide in scheme 59. and thioethanone in THF at room temperature in scheme62 [106].

PPh 1 2 3 R CO2Et R 1 Ar R OEt N CO R O Ar CO2R 2 O - O Ar b Ph P 2 O N RO 3 R RO2C R1 b N N O + Ph KOH/solvent S N N RO2C N N Ph N H OR RO C N N N OR 2 S HN 2 DME,rt, 3h EtO R THF S N OH Ph P CO R Ph P Ph 166 3 2 3 Ar Ar O O OR Ar=Ph, 4-BrC H ,2-Pyridyl R=Et, i-Pr 6 4 R=Me,Et,(CH2)2OH R1=Me,Ar O Ar Ar solvent=MeOH,EtOH,OH(CH2)2OH H H O R2=H,Ph RO S OEt N N N S OEt OEt OEt RO C O N 2 RO RO2C RO2C RO C O Ph 2 N Ar Ar 1 PPh Ph N H N N PPh3 R N 3 1 R1 N R N -PhP=O R1 N 170 R2 CO2R 2 CO R R2 CO2R R 2 R2 CO2R 167 Scheme62. Synthesis of tetra substituted pyrazole-4-ol Scheme59. The mechanism proposed for the reaction of tetra substituted pyrazoles Dragovich et al were proposed a new procedure for the preparation 1-substituted-5- Substituted pyrazol-4-carboxylates (168) hydroxypyrazole (171) which including ester were obtained to addition hydrazonoyl chloride groups at the 3,4-position. These compounds isoelectronic to intermediate product including were prepared in three steps including coupling from acetylenic esters and triphenyl phosphine methyl malonyl chloride and monosubstituted [104]. Then the expected pyrazole was occurred benzyl carbezide. 5-hydroxy-3-pyrazole ring closure with release of the triphenyl carboxylate was observed to occurring reaction phosphine in scheme60. that introduce intermolecular to the carbonyl carbon of an amide part of oxalyl and a 2 2 Cl H R O2C R O2C 2 Ar CO R2 CO2R 1 Ar 2 N R Ph P methylene carbon part of malonyl in scheme63 R1 Ar N Ph 3 N Ph3P,MeCN N R1 N 1 b N N Ph R Ph3P -PPh3 [107]. rt, 2-5 h PPh3 1 2 Ph Ph R CO2R 168 MeO O O 1.H2,Pd/C R1=H,CO Et; R2=Me,Et; Ar=Ph,4-Me/ClC H O O o 2 6 4 1 o EtOAc, 23 C H R 1,4-dioxane, 100 C O MeO OMe / bz N N + Cl OMe N H R1 2. ClC(O)CO2 O N N OH i-Pr2NEt, DCM N 0-23 oC R1 H Cbz Scheme60. Synthesis of tetra substituted pyrazole 1 171 R =(CH2)2CH(CH3)2,CH2C6H11,Ph

OC(O)CO2Me OMe O Me Me O O O O O O O O Recently important and effective a method H N O N HO OMe 1 OMe MeO O R HN HN O N O was reported in the literature that contained an N O O 1 1 R oxidative bond formation C-C/N-N from OMe R nitriles and the enamine for the synthesis of tetra substituted pyrazole-4-carboxylate (169) in Scheme63. Synthesis of 5-hydroxy-3-pyrazole scheme61 [105]. carboxylate

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