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Primary Syntheses of Cinnolines

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Primary Syntheses of Cinnolines CHAPTER 1 Primary Syntheses of Cinnolines The primary synthesis of cinnolines or hydrocinnolines may be done by cyclization of carbocyclic substrates already bearing appropriate substituents; by cyclocondensation of carbocyclic substrates with acyclic synthons that provide one or more of the ring atoms needed to complete the cinnoline system; by similar processing of pyridazine substrates; or by rearrangement, ring expansion, ring contraction, degradation, or modification of suitable derivatives of other hetero- cyclic systems. Typical pre-1972 examples in each category may be found from the cross-references to Simpson’s volume906 (e.g., H 16) or to Singerman’s volume907 (e.g., E 62) that appear at some section headings. Some pre- and post-1972 primary syntheses have also been reviewed elsewhere.903–905,908–916 1.1. FROM A SINGLE CARBOCYCLIC SUBSTRATE (H 3, 6, 16, 46; E 18, 22, 62, 70, 190, 255) Such syntheses are subdivided according to whether the N1–C8a, N1–N2, N2–C3, C3–C4, or C4–C4a bond is formed during the procedure to afford a cinnoline. 1.1.1. By Formation of the N1–C8a Bond This process usually involves cyclization of o-halogeno-a-hydrazonoacetophe- nones or related substrates, as illustrated in the following examples. Using o-Halogeno-a-hydrazonoacetophenones as Substrates a-Ethoxycarbonyl-2,4,5-trifluoro-a-hydrazonoacetophenone (1) gave ethyl 6,7-difluoro-4-oxo-1,4-dihydro-3-cinnolinecarboxylate (2) (dioxane, reflux, Cinnolines and Phthalazines: Supplement II, The Chemistry of Heterocyclic Compounds, Volume 64, by D.J. Brown Copyright # 2005 John Wiley & Sons, Inc. 1 2 Primary Syntheses of Cinnolines 16 h: 70%).414 O O F C CO2Et F CO2Et C ∆ N (−HF) N FF FN NH2 H (1)(2) 2,4-Dichloro-a-ethoxycarbonyl-5-fluoro-a-(p-fluorophenylhydrazono)acetophe- none (3,R¼ C6H4F-p) gave ethyl 7-chloro-6-fluoro-1-p-fluorophenyl-4-oxo- 1,4-dihydro-3-cinnolinecarboxylate (4,R¼ C6H4F-p)(K2CO3, 18-crown-6, 617 Me2NCHO, 100 C, 1 h: 94%); analogs likewise. O O F C CO2Et F CO2Et C K2CO3 or NaH N (−HCl) N Cl Cl Cl N NHR R (3)(4) 2,4-Dichloro-a-ethoxycarbonyl-5-fluoro-a-(methylhydrazono)acetophenone (3, R ¼ Me) gave ethyl 7-chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydro-3-cinnoline- carboxylate (4,R¼ Me) (NaH, dioxane, 10C!90C, 15 min: 93%).414 a-Ethoxalyl-2,3,4,5,6-pentafluoro-a-(p-methoxyphenylhydrazono)acetophenone (5) gave 3-ethoxalyl-5,6,7,8-tetrafluoro-1-p-methoxyphenyl-4(1 H)-cinnoli- 781 none (6) (Et3N, CHCl3,reflux, 4 h: 89%). F O F O F C COCO2Et F COCO2Et C Et3N N (−HF) N FF FN NHC6H4OMe-p F FC6H4OMe-p (5) (6) Also other examples.333,359,765 Using Related Substrates 1-Nitro-2-[2-(phenylhydrazono)acetoacetyl]benzene (7) gave 3-acetyl-1-phenyl- 4(1H)-cinnolinone (8) (Na2CO3, EtOH, H2O, reflux, 1 h: 92%); several analogs likewise.140 O O C Ac Ac C Na2CO3 − NNHPh ( HNO2) N NO2 N Ph (7) (8) From a Single Carbocyclic Substrate 3 2-(2-Fluoro-5-nitrophenyl)-N0,N0-dimethylacetohydrazide (9) gave 1,1-dimethyl- 6-nitro-1,4-dihydrocinnolin-1-ium-3-olate (10)(K2CO3,H2O, reflux, 3 h: 82%); analogs likewise.717 H 2 − O2N C O2NO CO K2CO3 − NHNMe2 ( HF) + N F N Me Me (9) (10) 6-Methoxy-a-p-methoxyphenyl-b-(p-nitrophenylazo)styrene (11) gave 6-methoxy- 4-p-methoxyphenyl-1-p-nitrophenyl-1,2-dihydrocinnoline (12) (AcOH, reflux, 3 h: 90%);639 the identities of this product and analogs made similarly are not fully established; they could be isomeric indole derivatives.639 C6H4OMe-p C6H4OMe-p C CH AcOH N NH MeO N MeO N C6H4NO2-p C6H4NO2-p (11) (12) a-Diazo-a-ethoxycarbonyl-2,4,5-trifluoroacetophenone (13) gave ethyl 6,7- difluoro- 4-oxo-1,4-dihydro-3-cinnolinecarboxylate (14)(Bu3P, dioxane, 20 C ! reflux, 5 h: 60%); analogs likewise.414 O O F C CO2Et F CO2Et C Bu3P N2 N F F F N H (13) (14) Also other examples.324,325 1.1.2. By Formation of the N1–N2 Bond This unusual procedure is represented by the controlled electroreduction of appropriate dinitro alcohols followed by aerial oxidative cyclization under basic conditions; these processes are illustrated in the following examples. 1-(1-Hydroxy-2-nitropropyl)-2-nitrobenzene (15,R¼ Me) gave 3-methylcinno- line (17), via the unisolated intermediate (16,R¼ Me) ([H], pH 5, 0C; then 747 K2CO3#, open to air, 12 h: 59%; for details, see original). 4 Primary Syntheses of Cinnolines In contrast, 1-(a-hydroxy-b-nitrophenethyl)-2-nitrobenzene (15,R¼ Ph) like- wise gave a separable mixture of 3-phenylcinnoline (18) and its 1-oxide (19) (47% and 22%, respectively).747 OH OH C C Me HHCHR [H], pH 5 CHR [O] NO2 NHOH (R = Me) N NO2 NHOH N (15)(16) (17) [O] (R = Ph) Ph Ph + N N N N O (18)(19) 1,4-Dihydrocinnoline (45%), cinnoline (65%), and 3,3-dimethyl-3,4-dihydro- cinnoline (12%) have been made somewhat analogously;64,341,983 also ben- zo[c]cinnoline and its 5-oxide.1035 1.1.3. By Formation of the N2–C3 Bond Several types of substrate may be used for this cyclization, as illustrated by the following broadly classified examples. Using Derivatives of o-Ethylphenylhydrazine as Substrates 3-Benzyloxy-N0,N0-di-tert-butoxycarbonyl-6-(2,2-dimethoxyethyl)-4-methoxy- phenylhydrazine (20) gave either di-tert-butyl 7-benzyloxy-3,6-dimethoxy- 1,2,3,4-tetrahydro-1,2-cinnolinedicarboxylate (21) (TsOH, MeOH, 20C, 16 h: 72%) or di-tert-butyl 7-benzyloxy-6-methoxy-1,2-dihydro-1,2-cinnoli- nedicarboxylate (22) (TsOH, dioxane, 20C, 16 h: 80%).494 MeO OMe TsOH, MeOH N t PhH2CO N CO2Bu t MeO CH2CH(OMe)2 CO2Bu (21) t PhH2CO N-NHCO2Bu CO But MeO 2 TsOH, dioxane (20) N t PhH2CO N CO2Bu t CO2Bu (22) From a Single Carbocyclic Substrate 5 1-Ethyl-1-methoxycarbonylmethyl-2-(o-propylphenylhydrazono)cyclohexane (23) (prepared in situ) gave 4a-ethyl-2-(o-propylphenylhydrazono)-4,4a,5, 6,7,8-hexahydro-3(2H)-cinnolinone (24) (20% H2SO4,reflux, 30 min: 26% after separation from another product); analogs likewise.212 Et Et O H+ CH2CO2Me N NNHC6H4Pr-o N C6H4Pr-o (23) (24) 30-Oxo-5-phenylhydrazono-30,50,70,80,8a0-hexahydrospiro[cyclohexane-1,10(20H)- naphthalene]-20,20,40-tricarbonitrile (25) gave 3-oxo-2-phenyl-2,3,5,6,7,8- hexahydro-4-cinnolinecarbonitrile (26), a reaction said to involve attack by NH at the carbonyl group and loss of cycloalkylidenemalononitrile as shown 954 [HN(CH2)5, EtOH, 35 C, 1 h: 18%]; analogs likewise. NC CN CN O O (CH2)5NH, EtOH N CN N Ph H N N Ph (25)(26) Also other examples.233,383 Using Derivatives of 2-Ethylazo- or 2-Ethylazoxybenzene 2-Carboxymethyl-40-methoxyazobenzene (27) gave 2-p-methoxyphenyl-3(2H)- 83 cinnolinone (28) (ClOCCOCl, CH2Cl2,20C, 15 min: 95%). CH CO H 2 2 (COCl)2 O − N ( H2O) N N C6H4OMe-p N C6H4OMe-p (27) (28) 2-Propionyl-NNO-azoxybenzene (29) gave 3-methoxy-3-methyl-2-phenyl-2, 3-dihydro-4(1H)-cinnolinone (31), possibly via the intermediate (30)(MeONa, MeOH, 20C, 4 h: 22% after separation from another product).741 − O O O C Me Me Me C MeONa, MeOH ? H2 − + OMe ( H2O) N (+MeOH) N N NPh N Ph N Ph H O (29) (30) (31) Also other examples.83,722 6 Primary Syntheses of Cinnolines Using Derivatives of o-Ethylphenyltriazene as Substrates 4-Methoxy-2-(3,3-tetramethylenetriazeno)acetophenone (32) was converted into the sodium salt of ethyl 2-[4-methoxy-2-(3,3-tetramethylenetriaz-1- eno)benzoyl]acetate (33) [NaH, OC(OEt)2, THF, reflux; substrate# during 8 h: crude] and thence into ethyl 7-methoxy-4-oxo-1,4-dihydro-3-cinnoline- carboxylate (34) with loss of pyrrolidine (neat F3CCO2H, 0 C, 12 h: 83% overall).387 OO C C OC(OEt)2 F3CCO2H CH3 CH2CO2Et N N MeON N(CH ) MeO N 2 4 N(CH2)4 (32)(33) O CO2Et N MeO N H (34) o-(3,3-Diethyltriaz-1-eno)phenylacetylene (35,R¼ H) gave cinnoline (36, R ¼ H) (C6H4Cl2-o, 200 C, sealed, 12 h: 99%; the stoichiometry is unclear).817,819 R C R CH 200 °C + EtN CHMe (?) N N N NEt2 N (35)(36) 3-Chloro-6-(3,3-diethyltriaz-1-eno)phenylacetylene (35,R¼ Cl) likewise gave 6-chlorocinnoline (36,R¼ Cl) (96%)816,817,819 and other 6-substituted ana- logs were made similarly.817,819 1.1.4. By Formation of the C3–C4 Bond Although several procedures within this category have been reported, none has been developed to any extent. However, the following examples may point toward useful general syntheses. From a Single Carbocyclic Substrate 7 o-(Nitromethylenehydrazino)benzaldehyde (37) gave 3-nitrocinnoline (38) 370 (1,4-diazabicyclo[2.2.2]octane, H2O, 60 C, 3 h: 86%). CHO NO2 CHNO2 − N ( H2O) N N N H (37) (38) 3-Chloro-6-(methyl-ONN-azoxy)benzophenone (39) gave 6-chloro-4-phenylcin- 11 noline 2-oxide (40) (KOH, H2O, EtOH, reflux, 10 min: 72%). Ph Ph Cl CO Cl HO− CH3 N N N N O O (39)(40) N0-Benzylidene-o-trifluoromethylphenylhydrazine (41) gave 3-phenyl-4-cinno- linamine (42) [NaN(SiMe3)2 (4 equiv), THF (tetrahydrofuran), À78 ! 20C, 4 h: 68%); several substituted-phenyl analogs were made similarly, and a mechanism was proposed.93 NH2 CF3 Ph CHPh (Me3Si)2NNa N N N N H (41)(42) 1-Bromo-3-methoxalyl-4-(a-methoxycarbonyl-a-triphenylphosphoranylidene- methylazo)benzene (43) gave dimethyl 6-bromo-3,4-cinnolinedicarboxylate (44) (PhMe, reflux, 48 h: 46%);43 several related processes have been reported, but all gave unsatisfactory yields.26,43,515 MeO2C CO2Me PPh CO 3 Br CO Me Br ∆ 2 C CO2Me − N ( Ph3PO) N N N (43) (44) 1.1.5.
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