Russian Chemical Reviews 69 (3) 201 ± 220 (2000) Naphthyridines. Structure, physicochemical properties and general methods of synthesis V P Litvinov, S V Roman, V D Dyachenko Contents I. Introduction II. Physicochemical properties III. The reactivity of naphthyridines IV. General methods for the synthesis of naphthyridines V. Conclusion Abstract. applica- and properties chemical synthesis, the on Data Data on the synthesis, chemical properties and applica- tions years 15 last the over mainly published naphthyridines of tions of naphthyridines published mainly over the last 15 years are are described systematically and analysed. The bibliography includes described systematically and analysed. The bibliography includes 238 238 references. references. I.Introduction Naphthyridines (pyridopyridines, diazanaphthalenes) represent a group of six isomeric heterocyclic systems containing two fused pyridine rings with different mutual arrangements of nitrogen atoms. They include two groups of compounds � N(1),N(i )- naphthyridines (i=5, 6, 7, 8) 1 ± 4 and N(2),N( j )-naphthyridines ( j=6, 7) 5, 6. N N N N N N 3 1 2 1,5-naphthyridine 1,8-naphthyridine 1,6-naphthyridine N N N N N N 6 4 5 1,7-naphthyridine 2,7-naphthyridine 2,6-naphthyridine The first derivative of the cyclic naphthyridine system was obtained in 1893 by Reissert,1 who proposed this name for the new class of heterocyclic compounds. The first representatives of unsubstituted naphthyridines � 1,5-naphthyridine 1 2 and 1,8- naphthyridine 2 3 �were described only in 1927.Naphthyridines containing nitrogen atoms at positions 1,6 (3),4 1,7 (4),5 and 2,7 (5) 6 were prepared in 1958, and 2,6-naphthyridine (6)7, 8 was synthesised only in 1965. Since then, researchers have shown ever increasing interest in the chemistry of naphthyridines. Indeed, the bibliography of a review 9 published in 1950 included 75 references, while that of a review 10 which appeared in 1970 V P Litvinov N D Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 117913 Moscow, Russian Federation. Fax (7-095) 135 53 28. Tel. (7-095) 135 88 37. S V Roman, V D Dyachenko T G Shevchenko Lugansk State Pedagogical Institute, ul. Oboronnaya 2, 348011 Lugansk, Ukraine. Fax (38-064) 255 33 68.Tel. (38-064) 253 83 94 (V D Dyachenko) Received 16 September 1999 Uspekhi Khimii 69 (3) 218 ± 238 (2000); translated by Z P Bobkova #2000 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2000v069nABEH000559 201 201 202 207 218 comprised 242 references. More recent reviews 11, 12 (1983) present 223 studies. Several reviews dealing with more specific aspects were also published before 1983.13 ± 22 In recent years, the number of publications devoted to various aspects of naphthyridine chemistry has sharply increased. More than 1000 publications have appeared during the last 15 years, 40% of them being patents. This interest in naphthyridine derivatives is due to the excep- tionally broad spectrum of their biological activities.They are used for the diagnostics and therapy of diseases of humans including AIDS; for combating exo- and endo-parasites in agri- culture and in cattle breeding; as preservatives and ingredients of cutting fluids, as ligands in analytical chemistry, etc. This review mainly surveys the data published over the last 15 years; however, earlier fundamental studies are also invoked in the discussion of structures, physicochemical properties and reactiv- ities of naphthyridines. II. Physicochemical properties 1. Structure X-Ray diffraction study was first performed for unsubstituted 1,5- (1) and 2,6-naphthyridines (6).10, 23, 24 It was found that transition from pyridine to naphthyridines is accompanied by shortening and lengthening of C7C bonds approximately equal to that observed on passing from benzene to naphthalene.In addition, the N7C bonds in naphthyridines were found to be shorter than these bonds in pyridine. X-Ray diffraction analysis was also used to determine the structures of several naphthyridine derivatives, 1, 2, 4 and 6.25 ± 37 2. Quantum-chemical calculations Since the 1950s, quantum chemistry methods have been used to elucidate structure ± property relationships in the naphthyridine series.38 ± 57 The intensities of bands in the UV spectra of naph- thyridines have been found to be correlated with the energies of lower unoccupied molecular orbitals;38 ± 40 quantum-chemical calculations have also been used in the 1H and 13C NMR spectroscopy 47 ± 51 and for comparison of the total p-energy and delocalisation energy for naphthyridines and naphthalene.41, 43 Other results include determination of p-electron distribu- tion;43, 44 elucidation of correlations of the total p-electron energy with specific features of electrophilic 43 and nucleophilic 43, 44 substitution and with the hyperfine splitting constants in the EPR spectra.47 In recent years, quantitative structure ± biological activity relationships for 6-[2-(4-arylpiperazino)ethyl]-5,6,7,8-tetrahydro-202 1,6-naphthyridines have been established 53 and complexes of antitumour antibiotics � naphthyridinomycins � with DNA have been studied by molecular modelling methods.54 3.Spectroscopy Spectroscopic techniques (UV, IR, 1H and 13C NMR) are widely used not only to identify naphthyridines but also to elucidate fine points concerning their structures.10, 12 Thus it has been found that the UV spectra of 1,5-, 1,6-, 1,7- and 1,8-naphthyridines 1 ± 4 are fairly similar to one another and contain three separate groups of bands, analogous to the bands displayed in the spectra of quinoline and isoquinoline. However, the spectra of 2,7- and 2,6-naphthyridines 5 and 6 differ both from each other and from the spectra of any other naphthyridines.10, 58 The UV spectra of 4-hydroxy-1,5-naphthyridine 59 and of a large number of substituted 1,8-naphthyridines 60 have been analysed in detail.In order to disclose the influence of substituents on the absorption spectra, UV spectra of 1,8-naphthyridines monosub- stituted at position 2 (Me, Cl, Br, OMe, OEt, SMe, NH2 , OH, SH), position 3 (Me, Cl, Br, NO2, NH2) and position 4 (Me, Cl, Br, OMe, OEt, OH, SH) have been studied.61 Transmission and absorption spectra of 1,8-naphthyridine 2 in the range of 50 000 ± 20 000 cm71 have been investigated in solutions and in various mixed crystals at 4.2 and 300 K.52 The pattern of the band corresponding to the p?p* transition was found to be similar to that observed in the spectrum of the related naphthalene molecule with allowance for perturbations induced by the replacement of carbon by nitrogen. The position of the long-wavelength p?p* band at about 27 000 cm71 complies with the theoretical predictions based on extended HuÈ ckel calcu- lations.The bands at about 31 600 ± 31 900 cm71 were assigned empirically to the second n?p* transition.52 All bands in the IR spectra of several substituted 1,5-naph- thyridines have been assigned; the spectrum of 1,5-naphthyridine 1 was compared with the spectrum of 5-substituted quinoline.62 IR spectroscopy was used to study the keto ± enol tautomerism of 4-hydroxy-1,5-naphthyridine in solution and in the solid state; it was found that the keto form predominates in polar solvents and the enol form, in nonpolar solvents.59 Study of the IR and Raman spectra of 1,6- and 1,8-naphthyr- idines permitted the assignment of all 42 fundamental vibrations of these two heterocyclic systems.63 Data on the 1H NMR spectra (chemical shifts and spin ± spin coupling constants) for the naphthyridines 1 ± 4 and 6 can be found in the literature.7, 8, 10, 12, 42, 43, 49 ± 51, 64 ± 77 The chemical shifts observed in the 13C NMR spectra of the naphthyridines 1 ± 6 were compared with those for quinoline and isoquino- line.12, 49 ± 51 The resonance signals in the 1HNMR spectrum of 2-(20-pyridyl)-1,8-naphthyridine were completely assigned using homonuclear 2D NMR spectroscopy.75 The behaviour of derivatives of the isomeric naphthyridines 1 ± 4 under electron impact has been stthe main fragmentation pathways have been identified.10, 78 ± 80 The struc- tures and destruction pathways of the isomeric ions [M7HCN]7.and [M72 HCN]7., resulting from fragmentation of the naph- thyridines 1 ± 4 and benzazines, were studied using collisional activation.81 It was found that the [M72 HCN]7.ions can exist as two isomers, one of them being characteristic of naphthyridines and the other being characteristic of benzazines. High-resolution photoelectron spectra of the naphthyridines 1 ± 6 have been described.82 The ionisation potentials for the n and p orbitals are listed in Table 1. Polarised phosphorescence spectra of 1,5-naphthyridine 1 83 ± 85 and the EPR spectrum of 1,6-naphthyridine 3 were recorded.86 A number of publications deal with the capacity for ionisation (including the pKa values) of the naphthyridines 1 ± 4 and their derivatives.10, 58, 70, 87 ± 91 Table 1. Ionisation potentials (eV) of naphthyridines 1 ± 6.82 Compound 1,5-Naphthyridine 1 1,8-Naphthyridine 2 1,6-Naphthyridine 3 1,7-Naphthyridine 4 2,7-Naphthyridine 5 2,6-Naphthyridine 6 III.The reactivity of naphthyridines Reactions of naphthyridines including electrophilic substitution (bromination, nitration), nucleophilic substitution (amination, metallation), reduction, oxidation, complexation, etc., have been considered fairly comprehensively in reviews. 10, 12 In yet another review, attention is focussed on the reactivity of naphthyridines towards N-nucleophiles.11 Here we survey the data on the reactivity of naphthyridines published over the last 15 years. Electrochemical reduction of the naphthyridines 1 ± 6 has been reported.92, 93 On exposure to UV radiation in the presence of sodium nitrite, 3-amino-1,6-naphthyridine-4(1H)-one eliminates a nitrogen molecule being thus converted into 5-azaindole-3- carboxylic acid.94, 95 Nucleophilic substitution of bromine at position 4 in 3,4-dibromonaphthyridines 7a ± c on treatment with a saturated alcoholic solution of ammonia in an autoclave affords 4-amino-3- bromo-N(1),N(i )-naphthyridines 8a ± c.96 Br N(i ) N 7a ± c i = 5 (a), 6 (b), 7 (c).The naphthyridine derivatives 9a ± c, possessing fungicidal activity, have been synthesised using nucleophilic substitution of the halogen atoms in isomeric halo naphthyridines. These prod- ucts can also be employed for combating exo- and endo-parasites in agriculture and cattle breeding, for wood protection, and as preservatives for paints, varnishes and cutting fluids during metal working.97 XYR N(i) N 9a ± c i = 5 (a), 6 (b), 7 (c); X =O, S, SO, SO2; Y is alkenyl or a single bond; R is cycloalkyl or piperidin-2-yl.In recent years, nucleophilic addition reactions have been widely used for the synthesis of various derivatives of isomeric naphthyridines. For example, nucleophilic addition of indole to 1,5-, 1,6- and 1,8-naphthyridine derivatives in the presence of V P Litvinov, S V Roman, V D Dyachenko n-Orbital 9.20 10.40 1.20 9.20 10.10 0.90 9.50 9.90 0.40 9.30 10.00 0.70 9.35 10.10 0.75 9.40 10.00 0.75 Br NH3, EtOH 4±6 h, 130 ± 150 8C p-Orbital 11.05 11.33 9.07 11.10 8.99 11.14 8.98 8.87 NH2 Br N(i ) N 8a ± c203 Naphthyridines. Structure, physicochemical properties and general methods of synthesis CN N CN N + Hal¡3Hal2 S N S N 25 CHCl3 Ha Hb Hal C C Hc Hal Hal29 27 benzoyl chloride in toluene or DMF yields, depending on the temperature and reactant ratio, hydrogenated mono- (10 ± 12) or bis-(3-indolyl)naphthyridines 13 ± 18.98 ± 100 Hetarylation includes the in situ formation of N-acyl heteroaromatic cations and the addition of nucleophiles to them.Aromatisation of theN-acylated hydrogenated naphthyridine derivatives 13 and 14 on treatment with tetrachloroquinone affords the same compound, naphthyr- idine 19. Hal=Br, I. R N R Bz N CN N I2 R N N R N + 26 I¡3N CHCl3 12 11 10 Bz Bz S N R 28 ICH2 R R HN HN HN R R R N 15 H N 14 H N 13 H R R N R R R R N N NH NH NH Bz Bz Bz 17 18 16 N R R is 3-indolyl.N R 19 X-Ray diffraction analysis has shown that the pyridine nitro- gen atom in the compound 25 has a short non-valence contact with the C=C bond of the cyclohexene fragment. The close arrangement of these reaction sites is favourable for synchronous cyclisation in intermediate 29 involving the Ha, Hb and Hb, Hc systems of protons. The high stereoselectivity of this reaction is apparently due to the synchronism of the action of the donor (i.e. the lone electron pair of the naphthyridine nitrogen atom) on the p-electrons of the cyclohexene double bond and electrophilic rupture of the double bond, which are followed by quaternisation.Thus the Hb and Hc protons occupy trans-positions. This intra- molecular electrophilic quaternisation of the compound 25 can be regarded as synchronous trans-quaternisation with cis-annela- tion.108 Refluxing of N(1),N(i )-naphthyridin-4(1H)-ones 20a ± d in DMSO gives rise to 1-methylthiomethyl naphthyridine deriva- tives 21a ± d, which depress microbial growth.100 ± 103 Similar methylthiomethylation of naphthyridin-2(1H)-ones 22a ± d has resulted in N-substituted N(1),N(i )-naphthyridin-2(1H)-ones 23a ± d.104 2-Cyanomethylthio derivatives 30, prepared by alkylation of the compounds 24 with chloroacetonitrile, cyclise under condi- tions of the Thorpe ± Ziegler reaction to give the corresponding thieno[2,3-b]pyrido[3,2-e]quinuclidines 31, containing a 1,5-naph- thyridine fragment.107 O O R R2 R2 CN N DMSO R1 R1 a b, c D, 8±36 h 24 N N N(i ) N(i ) HN SCH2CN 30 20a ± d 21a ± d CH2SMe R R NH NH2 DMSO N N N(i ) N(i ) D, 8 h CN CN O N O S S N N N 22a ± d H 23a ± d CH2SMe 31 i = 5 (a), 6 (b), 7 (c), 8 (d); R1=H, Me; R2=H, CO2H, CO2Et.R=H, Ph, 4-FC6H4; (a) ClCH2CN, KOH, DMF, 25 8C, 3 h; (b) OH7; (c) H+. Similar treatment with sodium ethoxide of thioethers 32, prepared by the reaction of 1,2,5,6,7,8-hexahydro-1,6-naphthyr- idine-2-thiones 33 with halo ketones, esters, amides or nitriles, resulted in the synthesis of thieno[2,3-b]-1,6-naphthyridines 34.109 Ph Ph Regioselective alkylation of quinuclidinopyridine-2(1H)-thi- ones 24, containing a 1,5-naphthyridine fragment, with 3-bromo- cyclohexene or allyl bromide in the presence of a base affords the corresponding 2-(cyclohex-2-enylthio)- (25) and 2-allylthio-deriv- atives 26.Halogen-induced quaternisation of these products is a synchronous process yielding salts 27 and 28 with high regio- and stereoselectivity.105 ± 108 CN N CN CN a PriN PriN RCH2Hal EtONa R S N N S SCH2R CN N NH 25 OH7 32 33 Ph Ph Ph R NH2 S 24 HN CN N PriN b R S N N CH2 SCH2CH 26 Br 34 Ph (a) , R =H; (b) CH2=CHCH2Br, R=H, Ph, 4-FC6H4. R=MeCO, PhCO, EtO2C, CONH2, CONHPh, CN, CONHC6H4Me-4, CONHC6H4OMe-4, CONHC6H4COMe-4.204 The reaction of 6,7,8a-trimethyl-1-oxo-3-thio-1,2,3,5,6,7,8,8a- octahydro-2,7-naphthyridine-4-carbonitrile (35) with 4-bromophe- nacyl bromide or N-cyanochloroacetamidine in the presence of a base gives thieno[2,3-c]-2,7-naphthyridines 36.110 Me Me MeN MeN NH2 CN+HalCH2Z KOH DMF Me Me Z S N O S O NH 36 35 Hal=Br, Z=4-BrC6H4CO; Hal=Cl, Z=C(NH2)NCN.Cyclocondensation of 3-ethoxycarbonylmethylthio-2,7-naph- thyridine 37 on heating in anhydrous ethanol in the presence of an equimolar amount of sodium ethoxide affords thienonaphthyr- idine 38. The dihydrochloride of the compound 38 possesses a mutagenic activity.111 Me Me Me Me MeN MeN NH2 CN EtONa 55 ± 60 8C, 2 h CO2Et S Mor Mor SCH2CO2Et N38 N37 Mor is morpholin-1-yl. Treatment of 1-methyl-N(1),N(i )-naphthyridinium iodides 39a,b with liquid ammonia in the presence of potassium perman- ganate gives rise to mixtures of imino (40a,b) and oxo (41a,b) derivatives of dihydronaphthyridines and vicinal methylamino- pyridinecarboxamides 42a,b.112 X NH3 KMnO4 I7 N + Me Y 39a,b X X X CONH2 + + NHMe O NH NMe NMe Y 42a,b Y 41a,b Y 40a,b X=N, Y=CH (a); X=CH, Y =N (b).Unlike compounds 39a,b, 7-methyl-1,7-naphthyridinium iodide 43 and 6-methyl-1,6-naphthyridinium iodide 44 react with liquid ammonia and KMnO4 with ring contraction as the pre- dominant reaction pathway yielding 4-azaindole derivatives 45 ± 48 together with the oxo derivatives of the corresponding dihydronaphthyridines 49 and 50.Study of the 1H NMR spectra showed that on treatment with liquid ammonia in the absence of potassium permanganate, the compounds 43 and 44 are converted into amino derivatives 51 and 52.113 a, b I7 + MeN N O NH2 43 N N NMe + NMe + MeN N O O O 46 45 49 V P Litvinov, S V Roman, V D Dyachenko MeN+ a, b I7 N 44O N MeN + N 50 c 43 MeN N NH2 51 NH2 MeN c 44 N 52 (a) NH3 (liq), KMnO4,733 8C; (b) OH7; (c) NH3 (liq). When 3,6-dinitro-1,8-naphthyridine 53 or 6-R-1-ethyl-3- nitro-1,8-naphthyridin-2(1H)-ones 54 are made to react with a solution of potassium permanganate in liquid ammonia at 7338C, amination proceeds giving rise to the corresponding 4-amino derivatives 55 and 56. The intermediate formation of s-adducts 57 and 58 was detected by 1H NMR spectro- scopy.114, 115 It was also shown that 1-ethyl-3-nitro-1,8-naphthyr- idin-4-one is not aminated under these conditions.115 However, treatment of 1,8-naphthyridine derivatives 59a,b with liquid ammonia at 745 8C affords 4-amino-1,4-dihydro-3,6-dinitro-2- R-1,8-naphthyridines 60a,b.The compound 59c was converted into a mixture of the naphthyridine 60c and isomeric 5-amino-2- ethoxy-3,6-dinitro-5,8-dihydro-1,8-naphthyridine 61.116 NO2 O2N NH3 (liq) 733 8C N N 53 + H NH3NO2 O2N 7 N N 57 R NO2 NH3 (liq) 733 8C O N Et N 54 + H NH3NO2 R KMnO4 7 OH N NEt 58 R=H, NO2. NO2 O2N NH3 (liq) 745 8C R N N 59a ± c O O N +49 NMe NMe+ 48 47 NH NH2 NH2 NO2 O2N KMnO4 N N 55 NH2 R NO2 O N Et N 56Naphthyridines.Structure, physicochemical properties and general methods of synthesis H NH2NO2 O2N R=OH, NH2 R HN N 60a,bH NH2 H NH2 NO2 NO2 O2N O2N R=OEt + OEt N OEt NH HN N60c 61 R=OH (a), NH2 (b), OEt (c). 2-Nitro-N(1),N(i )-naphthyridines 62a ± c undergo replace- ment of the nitro group rather than amination on treatment with a solution of potassium permanganate in liquid ammonia; this gives the corresponding 2-aminonaphthyridines 63a ± c, although their yields are relatively low. These products react with DMSO and trifluoromethanesulfonic anhydride giving rise to S,S- dimethyl-[N(1),N(i )-naphthyridin-2-yl]sulfylimines 64a ± c.115 a b N(i ) N(i ) NH2 NO2 N 63a ± c N 62a ± c N(i ) N SMe2 N 64a ± c i=5 (a), 6 (b), 8 (c); (a) NH3 (liq), KMnO4,733 8C; (b) DMSO, (CF3SO2)2O.The kinetics of N-methylation of benzonaphthyridines 65a ± d with methyl iodide in DMSO have been studied.117 It was shown that the salt 66, formed from the naphthyridine 65b, slowly dimerises in a 10% aqueous solution of DMSO to give compound 67. MeN+ a b N(i ) I7 N N66 65a ± d Me Me MeN+ N 2 I7 Me MeN+ N 67 Me i = 5 (a), 6 (b), 7 (c), 8 (d); (a) i=6, MeI, MeCO2Et, D, 0.5 h; (b) DMSO±H2O (1 : 9), 10 h. The methyl group in benzo[2,3]naphthyridines 65a ± d can be easily modified. Thus refluxing of these compounds with SeO2 in chloro-, 1,2-dichloro- or 1,2,4-trichlorobenzene gives aldehydes 68a ± d, which serve as the starting compounds for the synthesis of diverse functional derivatives of benzonaphthyridines.118 ± 120 Oxidation of the compounds 65a ± d to the aldehydes 68a ± d and further oxidation to the corresponding acids are the key stages of the synthesis of compounds 71 ± 75, which are the aza analogues of the potential antitumour preparation, N-[2-(dimethylamino)- ethyl]acridine-4-carboxamide.118 ± 120 SeO2 N(i ) 65a ± d N 68a ± d CHO O a N(i ) HN 69b COOH b or c N(i ) N 70a,c COOH O d + N(i) N HN 69d COOH i = 5 (a), 6 (b), 7 (c), 8 (d); (a) i=6, NaClO2; (b) i =7,Ag2O; (c) i=5; (d ) i=8, NaClO2.The aldehydes 68a ± d can be oxidised using Ag2O, NaClO2, K2Cr2O7, etc.; oxidation can proceed to different extents depend- ing on the structure of the initial compound and the reagent employed.For instance, oxidation of the aldehyde 68b with NaClO2 involves the central ring and gives oxo acid 69b. The oxidation of the aldehyde 68c with Ag2O affords acid 70c as the only product. The aldehyde 68a is oxidised by Ag2O to 70a but the reaction does not proceed to completion, up to 10% of the starting compound being recovered unchanged. The reaction of the aldehyde 68d with NaClO2 yields a mixture of acids 69d and 70d. The oxo acids 69a ± d are also produced upon oxidation of 68a ± d with NaClO2 in ButOH. Further modification of the acids 69 and 70 includes reactions of the carboxy group with 2-(N,N-dimethylamino)ethylamine and nitration of the benzene ring.Thus compounds 74 and 75 were prepared by oxidation of the methyl group in nitro derivatives 76 followed by modification of the acids 77 and 78 formed (Scheme 1). Dipolar 1,3-cycloaddition of various dienophiles to ben- zo[3,4]naphthyridinium ylides 79 ± 81, generated in situ by dehy- drobromination of the corresponding quaternary salts, has been studied; this gives rise to benzo[h]pyrrolonaphthyridines 82 ± 88 (Scheme 2).121 ± 126 The compounds 82 ± 84 exhibit bactericidal activities.124, 125 The dipolar 1,3-cycloaddition of N-dichloromethylides 89 ± 91, generated in situ from the corresponding benzo[h]naph- thyridines 92 ± 94 and dichlorocarbene 127 (produced from CCl3CO2Na on heating or from CHCl3 in the presence of a base and Et3BnN+Cl7), to dimethyl acetylenedicarboxylate is less selective; only the ylide 89 is converted into the corresponding adduct 95 in 52% yield.In the case of 90 and 91, the reaction gives a mixture of dipolar 1,3-addition products 96 and 97 and bisadducts 98 and 99 (Scheme 3). Quaternisation of naphthyr- idines 92 ± 94 128 ± 130 (the compounds 92 and 93 were prepared by the Skraup method 128 and 94 was synthesised by photocyclisation of diazastilbene 131) induced by alkyl, aryl or benzyl halides gave 205 N 70d COOH206 O N a HN 71 69b O N b, a HN 72 a 70c N N 73 N(i ) a 65a ± d N 76a ± d NO2 N(i ) c N 74a ± d CONH(CH2)2NMe2 O NO2 N(i ) d NH 78a ± d COOH (a) KNO3, H2SO4; (b) K2Cr2O7, H2SO4; (c) Me2N(CH2)2NH2; (d ) NaClO2 .quaternary salts 100 ± 102. The salts 101, 102 exhibit bactericidal and fungicidal activities.128 N X7 +NR 100 R=2,4-(NO2)2C6H3, H2C CHCH2, Bn, Me(CH2)9; X=Cl, I. In order to elucidate the influence of the structure of benzo[h]- naphthyridines on their reactivity, charge distributions, excitation energies, and the oscillator strengths for the molecules 92 ± 94 and their amino derivatives have been calculated. The calculation was carried out by a semiempirical self-consistent field method in the Pariser ± Parr ± Pople p-electron approximation with allowance for the configurational interaction between singly excited states and by the HuÈ ckel method.The results are in satisfactory agree- ment with the data of the UV spectra.132 The populations of the atomic p-orbitals, the order of p-bonds and the frequency and oscillator strengths for three electron transitions in the molecules of the naphthyridines 92 ± 94 and their salts 100 ± 102 were also calculated. By comparing the calculated and experimental spectra, correlation coefficients for the relation ncalc=anexp+b were determined. 133 CONH(CH2)2NMe2 NO2 CONH(CH2)2NMe2 CONH(CH2)2NMe2 NO2 N(i ) b N 77a ± d Me O NO2 N(i ) c HN 75a ± d CONH(CH2)2NMe2 N X7 101 102 N + R Scheme 1 NO2 COOH NX7 NR + N + N 7CHR1 79 a N b +N 7 80 CHR1 c N b N + 7 81 CHCO2Et R1=COPh, CO2Et; R2=CN, CO2Et, Ac; O; (b) CH2 CHR2; (c) MeO2CC CCO2Me.(a) O O The formation ofN-ylides of the benzonaphthyridinium series upon dipolar 1,3-addition of benzonaphthyridine N-oxides to dimethyl acetylenedicarboxylate at room temperature has been reported.134 Treatment ofN-oxides 103a,b with POBr3 affords a mixture of 1,5- (1) or 1,8-naphthyridines (2) with their brominated deriva- V P Litvinov, S V Roman, V D Dyachenko Scheme 2 N a N R1 82 N b N R1 83 R2N c N R1 MeO2C CO2Me 84 NN 85 R1N R2 N 86 R1N CO2Me N R1 CO2Me 87 NH N R2 H 88 EtO2CNaphthyridines. Structure, physicochemical properties and general methods of synthesis 92 93 94 tives.A similar mixture of reaction products is also formed when POBr3 reacts with 1,5-naphthyridine bis(N-oxide).135 NO N(i ) 103a,b i = 5 (a), 8 (b). Carboxylic acid derivatives 104 of the pyrrolonaphthyridine series � potential preparations for treatment of degenerative, ischemic, and autoimmune diseases � have been synthesised using intramolecular cyclisation of ethyl (3-ethoxycarbonylnaph- thyridin-4-ylamino)acetates 105 induced by potassium tert-but- oxide in a toluene ±ButOH mixture. 136 N(i ) (a) ButOK, PhMe, ButOH, 20 h. The reaction of naphthyridinecarboxylic acids 106 with gua- nidine in the presence of carbonyldiimidazole in anhydrous THF results in hetaroylguanidines 107, which can be used for the therapy of heart diseases, for surgical operations and organ transplantation, for the diagnostics and treatment of hypertension and proliferative diseases.137 R2 R1 YR4 N(i ) 106 R1, R2=H, Hal, Alk, alkenyl, alkynyl, CN, AlkF; R3, R4=H, Hal, Alk, AlkF, AlkO, Alk2N, CON=C(NH2)2 or none; X=N,Y=C; X = C, Y = N.N N MeO2CC CCO2Me CCl2 + N N 7CCl2 89 N N MeO2CC CCO2Me CCl2 +N N 7 90 CCl2 N N MeO2CC CCO2Me CCl2 +N N 7 91 CCl2 Br Br POBr3 1 or 2+ + N N N(i ) N(i ) CO2Et NHCH2CO2Et HN CO2Et a OH N(i ) N N 105 104 R2 NH2 R1 HN XR3 NH2 XR3 NH2 C(O)N CO2H YR4 N(i ) NH2 107 207 Scheme 3 N N Cl MeO2C CO2Me 95 N N + CO2Me CO2Me N N CO2Me MeO2C Cl CO2Me 98 96 CO2Me N N + CO2Me CO2Me N N CO2Me MeO2C Cl CO2Me 99 97 CO2Me IV.General methods for the synthesis of naphthyridines General synthetic methods used to prepare various types of naphthyridine include the Skraup, Friedlander and some other name reactions; cyclisation, cyclocondensation, dimerisation reactions, etc. 1. The Skraup method and its modifications The Skraup reaction was first employed to synthesise unsaturated 1,5-naphthyridine 1 from 3-aminopyridine in the late 1920s.2, 138, 139 Subsequently this reaction and its modifications have been successfully used to prepare other naphthyridines and their derivatives.9, 10, 12 Recently 1,6-naphthyridine 3 has been prepared by the Skraup method, namely, by heating (135 8C, 48 h) of 4-aminopyridine with glycerol, fuming sulfuric acid and nitrobenzene.140 CH O H2SO4 CHCHO CH2 N N NH2 NH HO H N N N PhNO2 7H2O N 3 HN HN In recent years, a modified Skraup reaction (20% oleum, nitrobenzene, FeSO4 .7H2O, H3BO3) has been used to synthesise fused naphthyridines.Thus 3-aminobenzo[ f ]quinoline 108 was converted in this way into naphtho[2,1-b]-1,5-naphthyridine 109.141 Similarly 2-aminobenzo[h]quinoline 110 was transformed into a mixture of naphthonaphthyridines 111 and 112 (yields 6.8% and 4.5%, respectively), and 3-aminobenzo[g]quinoline 113 gave rise to naphthonaphthyridine 114 (yield 4.2%). The naphtho- naphthyridines 111 and 114 were also prepared from hydro- genated benzoquinolines 115 and 116. Intermediates 117 and 118 were dehydrogenated by treatment with dichlorodicyanoquinone and palladium supported on carbon, respectively.In this case, the overall yields of products were substantially higher.142208 H2N N108 NH2 N 110 N 111 (6.8%) NH2 N 113 NH2 N 115 N 117NH2 N 116 118 A modified Skraup method, namely, the reaction of 4-amino- isoquinoline 119 with methyl vinyl ketone in the presence of As2O5 and concentrated sulfuric acid, was used to prepare 4-methylben- zo[c]-1,5-naphthyridine 120 in 36% yield.143 A similar reaction of 3-aminoquinoline 121 with crotonaldehyde or methyl vinyl ketone results in 2-methyl- (122) or 4-methyl-benzo[ f ]-1,7-naphthyridine 123. Oxidation of the compounds 120, 122 and 123 on treatment with SeO2 in dioxane yields aldehydes 124 ± 126.NH2 a As2O5 N 119 N CH2=CHCHO 130 8C, 5 h N 109 (12.5%) CHCHO CH2 N N N + 112 (4.5%) N CHCHO CH2 N 114 (4.2%) CHCHO CH2 O Cl NC Cl NC N O 111 (24%) CHCHO CH2N Pd/C 114 (20%) N N N SeO2 N N 124 120 CHO Me N121 (a) CH2=CHCOMe; (b) MeCH=CHCHO. 2. The Friedlander reaction in the synthesis of naphthyridines The condensation of vicinal aminopyridinecarbaldehydes 127 with malononitrile in ethanol in the presence of a base (according to the Knoevenagel reaction pattern) furnished 2-amino-3-cyano- N(1),N(i )-naphthyridines 128a ± d; some of them were found to be effective diuretics.144, 145 The condensation of the aldehydes 127 with creatinine in ethylene glycol affords imidazo[4,5-b]- N(1),N(i )-naphthyridines 129a ± d.146 The reaction of the com- pounds 127 with 2-methylcyclohexanone in ButOH in the pres- ence of ButOK (1.5 h, refluxing) followed by dehydrogenation of the products 130a,c,d thus formed (refluxing with Pd/C in Ph2O) gives rise to benzo[b]-N(1),N(i )-naphthyridines 65a,c,d.Using the Friedlander reaction, naphthyridines 131 have been synthesised; they are active components of herbicide formulations.147, 148 Benzo[b]-1,6-naphthyridine 65b has been prepared by condensa- tion of the amino acid salt 132 (obtained from 7-methylisatin 133) CHO N127 i = 5 (a), 6 (b), 7 (c), 8 (d). 127 O NH (a) NH ; (b) Me N V P Litvinov, S V Roman, V D Dyachenko b SeO2 N N CHO N Me N 122 (21%) 125 CHO Me NH2 a SeO2 N N N N 123 (40%) 126 CN CH2(CN)2 NH2 CN NH2 N(i ) CN CN NH NH2 HN N N(i ) 128a ± d N(i ) NMe a NH2 N N(i ) N 129a ± d Pd/C b N N N(i ) N(i ) 65a,c,d Me 130a,c,d Me CO2Et c N CO2Et N(i ) 6 stepsCO2Et HN O N N(i ) 131 N ; (c) EtO2CCH2C(O)CO2Et.O MeNaphthyridines. Structure, physicochemical properties and general methods of synthesis with N-benzylpiperidone (KOH, 0.5 h, <40 8C; refluxing, 20 h) followed by dehydrogenation of the reaction product 134.117 ± 119 CO2K O NBn O KOH O O NH2 HN Me Me 132 133 CO2H N NBn 10% Pd/C Ph2O, D N N Me 65b 134 Me 3. Condensation of aminopyridines with diethyl ethoxymethylidenemalonate As in the previous cases, the use of condensation of amino- pyridines with diethyl ethoxymethylidenemalonate for the syn- thesis of naphthyridines attracts attention because it provides the possibility of synthesising diverse naphthyridines exhibiting a broad range of biological activities.Thus the condensation of substituted aminopyridines 135 with diethyl ethoxymethylidene- malonate 136 and subsequent cyclisation on refluxing of the resulting diesters of N-(pyridyl)aminomethylidenemalonic acids 137 gives derivatives of naphthyridinecarboxylic acids 138, pos- sessing antibacterial activity or serving as intermediates in the synthesis of compounds with this type of activity.130, 149 ± 161 EtO O C CO2Et R1nR1nCO2Et D + EtO RN2 CO2Et R2HN N 135 136 N 137 O7 EtO O R1nH R1n CO2Et CO2Et 7EtOH + RN2 N(i ) NR2 N(i ) 138 n=1, 2; R1=Me, EtO, EtS, F, 4-pyridyl; R2 =H, cyclopropyl.Naphthyridines 138 (R2=H) without substituents at nitro- gen have served as the starting compounds en route to pyra- zolo[3,4-c]naphthyridines 139, which act as modulators of benzodiazepine receptors and possess sedative and antispasmodic activities.162 ± 164 The reactions of chloronaphthyridines 140 with amino acid amides afford compounds 141, which possess anxio- lytic, anticonvulsive, sedative and hypnotic activities, antimicro- bial and analgesic properties; they are capable of reducing blood pressure and are used as pharmaceuticals.165 ± 167 OH Cl R1n R1nCO2Et CO2Et R2=H a b 138 N N N(i ) N(i ) 140 HN NR3 N NR3 R1n R1nO O N 139 HN N(i ) N(i ) n=1, 2; R1=Me, MeO; R2=Ph, pyridyl, quinolyl, isoquinolyl, pyrimidyl, thiazolyl; (a) (COCl)2, MeCN, DMF, from730 to 20 8C; (b) R3NHNH2, xylene, D.209 R4 R5NCH(CH2)mCONR2R3 R1nCO2Et a 140 N N(i ) 141 (a) R2R3NC(O)(CH2)mCH(R4)NHR5; n=1, 2; m=0±2; R1=Hal, Alk, AlkO, NO2, CF3; R2, R3=H, Alk, Ph, Bn; R27R3=(CH2)x (x=4 ± 8); R4=H, Alk, Bn; R5=H, Alk. The condensation of diethyl ethoxymethylidenemalonate 136 with 5-amino-2,3-dihydrofuro[3,2-b]pyridine 142 154 or 7-amino- oxazolo[4,5-b]pyridine 143 168 results in annelated naphthyridines 144 and 145. 2,3-Dihydrofuro[3,2-b]-1,8-naphthyridine 144 shows antibacterial activity.154 O O C(CO2Et)2 136 Ph2O, D N N NH2 HN 142 OH CO2Et O N N 144 CO2Et NH2 NHCH O 136 CO2Et Ph2O, D O NEt2 NEt2 N N N 143 N OH CO2Et N N N O 145 Et2N 4.Condensation of aminopyridinecarboxylic acids and their derivatives with compounds containing an active methylene group The condensn of vicinal aminopyridinecarboxylic acids or esters with ethyl hexanoate 146 in the presence of ButOK under a nitrogen atmosphere gave N(1),N(i )-naphthyridin-2(1H)-ones 147a ± c, exhibiting antiallergic activities.169 OH CO2R Bu N(i ) +BuCH2CO2Et 146 O N NHPh N 147a ± c Ph R=H, Me, Et; i = 5 (a), 7 (b), 8 (c). Naphthyridones 148, which are of interest as pharmacological preparations, have been synthesised by the reaction of vicinal aminopyridinecarbonitriles 149 with diethyl malonate.Alkylation of these products with ethyl monobromoacetate results in N-sub- stituted compounds 150.170 NH2 NH2 CN CO2Et CO2Et b a O N O N NH2 NH N(i ) N(i ) 149 148 CH2CO2Et 150 (a) CH2(CO2Et)2, EtONa; (b) BrCH2CO2Et, BuOH, K2CO3; i =5±8.210 When diethyl malonate is made to react with ethyl 3-amino- picolinate, substituted 1,5-naphthyridine 151 is formed; it is used in the synthesis of potential antimalarial remedies.171 NH2 EtONa +CH2(CO2Et)2 N CO2Et 1,8-Naphthyridine-3-carboxamides 152 � starting com- pounds for the preparation of products with antihypertensive, antiphlogistic and antiaggressive activities � have been synthes- ised from 2-aminonicotinic acid and amido esters 153.The syn- thesis includes the formation of the chloride and a salt of 2-aminonicotinic acid upon the reaction of 153 with POCl3 . The subsequent reaction of these intermediates results in the C-acy- lated product, the condensation of which gives the compound 152.172 CO2H+R2NC(O)CH2CO2Et N 153 NH2 Cl O + POCl3 NR2 N CO2Et NH2 R2=Me2, Et2, Pri2, (CH2)5. 5. Acylation of a-hetarylacetonitriles with halo-substituted nicotinic and isonicotinic acid chlorides Fused azahetareno-1,7-naphthyridines 154a ± 158a, containing a nitrogen atom in the bridgehead position, were obtained by the reaction of 3-bromoisonicotinic acid chloride 159 with 2-cyano- methyl derivatives of pyridine, 1-methylbenzoimidazole, benzo- 1,3-thiazole, quinoline or 4-methyl-1,3-thiazole followed by cyc- lisation of the resulting C-acylated derivatives on heating to the melting point or on refluxing in N-methyl-2-pyrrolidone (as shown for compound 154a taken as an example).173 N N CN N(i ) O N(i ) 154a,b O 155a,bMeN N CN N(i ) N(i ) O O 158a,b 157a,b i = 7 (a), 6 (b).COCl Br + N CH2CN N 159 OH N CO2Et OH N 151 POCl3 Cl CONR2 O N N 152 H NMe S N CN CN N(i ) O 156a,b SCN CN NH O N Br V P Litvinov, S V Roman, V D Dyachenko CN N 154a HO N Br A similar reaction of 2-cyanomethyl derivatives of hetarenes with 4-chloronicotinoyl chloride yielded annelated azahetareno- 1,6-naphthyridines 154b ± 158b.173 In this case, the intermediate C-acylated derivatives were not isolated because they easily cyclised to give 154b ± 158b.4,6-Dichloronicotinoyl chloride was used as the initial compound in this synthesis.174 The product of interaction of 2-cyanomethylbenzo-1,3-thia- zole with 2-chloronicotinoyl chloride cyclises on refluxing in DMF to give benzothiazolo[3,2-a]-1,8-naphthyridin-4-one deriv- ative 156c.173 COCl N + CH2CN S Cl N S CN NH N OCl CN SN D N H OCl 6. Photocyclisation of aminopyridines with chlorides of ortho-chlorinated hetarenecarboxylic acids The reaction of 3-chlorobenzo[b]thiophene-2-carboxylic acid chloride 160 with 2-, 3- or 4-aminopyridine 161 in benzene in the presence of triethylamine has resulted in the synthesis of amides 162, which undergo photocyclisation (UV irradiation by a medium-pressure mercury lamp, 450 W), giving rise to naphthyr- idines 163.175 Deoxygenation of these products on treatment with POCl3 followed by dechlorination of compounds 164 results in [1]benzothieno-N(1),N(i )-naphthyridines 165a ± d.H2N Cl Et3N + COCl S N 161 160 Cl hn S CONH N 162 N(i ) POCl3 NH S 163 O S N N CN 156c ONaphthyridines. Structure, physicochemical properties and general methods of synthesis N(i ) Pd/C N S 164 Cl i = 5 (a), 6 (b), 7 (c), 8 (d). Similarly, the reaction of chloride 160 with 4-amino-2-methyl- quinoline gave 1-methylbenzo[h][1]benzothieno[2,3-c]-1,6-naph- thyridine 166.176 NH2 a, b, c, d +160 Me N (a) Et3N; (b) hn; (c) POCl3; (d ) Pd/C.Photocyclisation is also one of the stages in the synthesis of naphthothieno-N(1),N(i )-naphthyridines 167a ± c and 168 from the chlorides of vicinal chloronaphthothiophenecarboxylic acids 169a ± c and 170.177 H2N Cl a, b + N COCl 161 S 169a ± c i = 5 (a), 6 (b), 7 (c). Cl NH2 + COCl S N 170 N N S 168 (a) PhH, D, 4 h; (b) hn (Hg lamp, 450 W), 1% MeOH in PhH, 3 h; (c) POCl3, D, 4 h; (d ) 10% Pd/C, KOH, MeOH±PhH (1 : 1), 20 8C, 24 h. 7. Synthesis of naphthyridines fused to a thiophene ring A one-stage procedure has been proposed 178 ± 181 for the prepara- tion of isomeric N(1),N(i )-naphthyridines; the procedure includes Pd(PPh3)4-catalysed cross-coupling of thiopheneboronic acids 171, 172 or 173 containing an ortho-formyl group with o-amino- hetaryl halides 174 ± 176.The cross-coupling products cyclise spontaneously during the reaction to give thiophenonaphthyr- idines 177 ± 185 with all possible types of ring fusion. The effects of the amount of the catalyst, the nature of the base and the reaction time on the yield of the naphthyridines 178 and 181 have been studied.180 N(i ) N S 165a ± d N 174a ± c Me NN S 166 NHR N(i) N 175b,c NH S 167a ± c O R=H: X=Cl (a), Br (b); R=Ac, X=Br (c); (a) Pd(PPh3)4, Na2CO3, DME or DMF. a, b, c, d Me N 176 (a) Pd(PPh3)4, Na2CO3, DME or DMF.When 2-bromo-3-nitropyridine 186 is employed in the cross- coupling with formylthiopheneboronic acids 171 ± 173, thieno- 1,5-naphthyridine 5-oxides 188 ± 190 are produced. However, in this case, cyclisation of the cross-coupling products 191 ± 193 proceeds on treatment with FeSO4 in NH4OH. Isomeric thieno- 1,5-naphthyridine 9-oxides 194 ± 196 are formed upon cross- coupling of the formylboronic acids 171 ± 173 with 3-acetyl- amino-2-bromopyridine oxide 187. 2-Tributylstannyl-3-formyl- thiophene 197 can be used in the cross-coupling with arenyl halides 186 and 187 instead of arylboronic acids. A mixture of N-oxide isomers 190 and 196 is also formed upon oxidation of thienonaphthyridine 179 with m-chloroperbenzoic acid.181 B(OH)2 S CHO 171 OHC B(OH)2 NHR S 172 a X CHO S B(OH)2 173 N 171 N 180 Br N 172 a N 181 S N 173 N 182 Me 171 Me Br 172 a NH2 Me 173 211 S N N 177 S N N 178 S N N 179 S S S N N183 S N N184 S N N 185212N 186 NO 187 (a) Pd(0), Na2CO3, DME or DMF; (b) FeSO4, NH4OH.The reaction of vicinal trimethylstannyl derivatives of tert- butoxycarbonylaminothiophenes 198 and 199 with halo-substi- tuted pyridinecarbaldehydes 200 ± 203 in the presence of PdCl2 , CuO and bis(diphenylphosphino)butane results in fused thieno- naphthyridines of all the possible types.182 N 171 CHO NO2 191 OHC NO2 N 172 a Br NO2 192 OHC N S 173 NO2 193 ON 171 N 194 O NHAc N 172 a Br N 195 O S N 173 N 196 b 186 CHO 193 a 187 196 SnBu3 S 197 NHCO2But SnMe3 S 198 SnMe3 I a NHCO2But S CHO 199 N 200 S S N b N 188 O S N S b N 189 OS N b N 190 O S S 190 S N N S N N 198 I CHO a 199 N 201 198 CHO Br a 199 N 202 198 CHO a Br 199 N 203 (a) PdCl2, CuO, Ph2P(CH2)4PPh2.The photoelectron spectra of all the thienonaphthyridine isomers have been analysed using semiempirical methods for the calculation of the ionisation energies of molecular orbitals.183, 184 Cross-coupling catalysed by zerovalent palladium complexes has been employed to obtain other annelated naphthyridines.Thus the reaction of bromoaminopyridine 176 with 2-formylphe- nylboronic acid provided 9-methylbenzo[c]-1,8-naphthyridine 204.178 B(OH)2 176, Pd(PPh3)4 Na2CO3, (MeOCH2)2 CHO Cross-coupling of o-bromoacetanilides 205 with trimethyl- stannylpyridyl ketones 206 in the presence of PdCl2 and CuO in DMF affords benzo[c]-2,7-naphthyridines 207.185 Benzo[c]-2,7- naphthyridines 208 were prepared by refluxing 2-tert-butoxycar- bonylaminophenylboronic acid 209 with substituted iodonicotin- aldehydes 210 in the presence of Pd(PPh3)4 and K2CO3 in a mixture of ethanol and toluene.186 NHAc SnMe3COR2 Br+ R3 N 206 R1 205 R1=H, Me, OMe; R2=H, Me; R3=H, OMe. I B(OH)2 + NHCO2But N 210 209 R=F, Cl, CONPri2 . V P Litvinov, S V Roman, V D henko S N N S N N S N N S N NS N N S N NMe PdCl2, CuO DMF N CHO Pd(PPh3)4 K2CO3 R N N204 R1 N R3 R2207 N R N 208Naphthyridines.Structure, physicochemical properties and general methods of synthesis 8. b-Enaminocarbonyl compounds in the synthesis of naphthyridines b-Enaminocarbonyl compounds have long been used successfully in the synthesis of isomeric naphthyridines. Thus pyridone 211, prepared by the reaction of b-enamino ketone 212 with 4,4- dicyano-3-aminobut-2-enenitrile 213, cyclises to give substituted 1,2,7,8-tetrahydro-1,8-naphthyridin-2-one 214. On treatment with concentrated hydrochloric acid at 100 8C, compound 214 undergoes disproportionation giving rise to a mixture of hexahy- dro (215) and dihydro derivatives of 1,8-naphthyridin-2-ones 216.187, 188 CN H2N + PhCOCH CHNR1R2 212 CN NCCH2 213 Ph NH2 Ph NH2 CN CN conc.HCl CN 100 8C O O NH NH HN 214 211 Ph NH2 NH2 H Ph CN CN+ O N O NH NH NH 216 215 The reaction of 4-dialkylaminopyridones 217, containing a b-enaminoamide fragment, with N-methylcyanoacetamide (218) is accompanied by replacement of the endocyclic amino group followed by cyclisation to give 2,7-naphthyridine 219.189 O NR2R3 NMe PriONa NH2 PriOH CN+NCCH2CONHMe 218 O R1 O R1 N 217 Me N 219 Me R1=Ph, 4-ClC6H4, 4-MeOC6H4; R2=Et, Ph, CH2Ph, CH2CH(OEt)2; R3=H, CH2CH2OCH2CH2. One approach to the construction of fused 1,6-naphthyridines 220 includes the reaction of 4-amino-2,6-dioxo-1,2,5,6-tetrahy- dro-3-pyridinecarbonitrile 221 with cyclic b-enamino ketones 222. The pyridinedione 221 reacts with 3-dimethylamino-1-phenyl- propan-1-one to give 1,5,6,7-tetrahydro-1,6-naphthyridine-5,7- dione 223.190 ± 192 OH NH2 HN O CN CN O + N CHMor (CH2)n O O 222 HN (CH2)n 221 220 n=1±3.221+PhCOCH2CH2NMe2 NH Ph NH2 CN CN Ph Me2N D 7Me2NH O O O NH HN O223 213 Enamino amides 226 and 227, containing a b-enaminocar- bonyl fragment, are promising starting compounds in the syn- thesis of hydrogenated naphthyridines 224 and 225.193 ± 204 Study of the kinetics of these reactions demonstrated that the rate of cyclisation of the compounds 226 is much higher than that for the amidine 227, due to the more pronounced delocalisation of the positive charge in the amidine system compared to the enamine system.195, 203, 204 AlkNH D 7Me2NH CON C(Alk)NMe2 O CN CN NAlk 226 NAlk 224 NMe2 CN NC D 7Me2NH O O NH NMe NMe225 N 227 9.Cyclisation of 1,5-dinitriles and 1,5-amino(amido)nitriles of the pyridine series Acid hydrolysis of 3- or 4-cyanopyridylacetonitriles or their reaction with sodium ethoxide affords isomeric amino derivatives of naphthyridines 228a ± c and 229a ± c. The 1,6-naphthyridines 228d,e have been prepared by hydrolysis of 2-cyanomethylnicoti- nonitriles.144, 205 R NH2 a N(i ) N CH(R)CN 228a ± c Br CN R N OEt b N(i ) N 229a ± c NH2 R=H: i=6, 7;R=Me, i=6; (a) HBr; (b) EtONa. R R N N NH2 a CN N CN 228d,e Br R=H, 4-FC6H4; (a) 30% HBr ± AcOH.2-Cyanophenyl- (230a) or 2-cyano-3-pyridylacetonitriles 230b react with methyl crotonate to give adducts 231a,b. Subsequent acid-catalysed cyclisation of compounds 231a,b gives rise to the corresponding pyrido- and benzo[c]-1,8-naphthyridines 232a,b� potential means for treating heart weakness, stenocardia and hypertension.206, 207 CH2CN 5% MeONa ±MeOH +MeCH CHCO2Me CN X 230a,b Me Me HBr X X O Br N NH CN CN CO2Me 231a,b 232a,b X=CH (a), N (b).214 O R1 NH a R2 CN CN O O R1 R1 b N NH R2 OMe R2 CN CN235 233 O R1 c N R2 CN236 R1, R2=H, Me, Ph; (a) CH2(CN)2; (b) NCCH2CO2Me; (c) NCCH2CONH2; (d ) HX, X=Cl, Br; (e) MeONa, MeOH, X =OMe; ( f ) HBr; (g) OH7, H2O orRO7, ROH.The methoxy group in 5-cyano-6-methoxy-3,4-dihydro- 2(1H)-pyridones 233 is replaced by malononitrile, methyl cya- noacetate or cyanoacetamide. The intermediates 234 ± 236 cyclise in acid or basic media to give 3,4-dihydro-1,6-naphthyridin- 2(1H)-ones 237 ± 239 (Scheme 4).208, 209 Cyclisation of piperidone 240 yields 1,6-naphthyridine mono- hydrate 241. An X-ray diffraction study showed that the C(2)7N(1) bond (1.362A) is longer than these bonds in other cyclic amides due to less efficient conjugation with the carbonyl group.210 CN CN HN H2N 1 O HN NC HBr N NC Me 240 Me Br241 Dinitriles 242 have been used to perform regioselective syn- thesis of 7-amino-8-cyano-1,6-naphthyridines 243.144, 211, 212 X R2 MeOH or AcOH ± HBr CN R1 R1 HN CN 242 R1, R2=Me, Et; X=Br, OMe.Naphthyridinediones 244 and 245 have been synthesised using reactions of 3-amino-4,4-dicyanobut-2-enenitrile (213) with a-diketone monophenylhydrazones. Cyclisation of intermediate dinitriles 246 and 247 was performed on treatment with a mixture of AcOH and HCl.213 CN H2N AcONH4 CN NCCH2 213 O R1 CN R2 CN 234 R1 H O f R2 OMe CN R1 H O g R2 NH2 CN O 2R2 N N NH2 CN 243 V P Litvinov, S V Roman, V D Dyachenko Scheme 4 O O R1 R1 NH NH NH d or e CN CN + R2 R2 CN X X H2N NH2 CN N 237b N 237a O O R1 NH NH CO2Me CO2Me + R2 Br NH2 Br H2N N 238a N 238b O NH CN O HN H2N239 O O PhNHN NH PhNHN NH c a CN Me CN Me O HO 246 CN CN N 244 NH2 PhNHN NH2 N PhNHN CN N c b Me CN Me O O 247 CN CN NH 245 (a) PhNHN=C(Ac)CO2Et; (b) PhNHN=C(Ac)CN; (c) AcOH, HCl.Enamino nitriles of 2,7-naphthyridinone(or -thione) 248 have been synthesised by cyclisation of amido(or thioamido) nitriles 249, which are prepared from enamine 250 or substituted malo- nonitrile 251.214, 215 CN NC PhNCX CH2(CN)2 Mor Me N Me Me Me251 Mor X Me N 250 Me PhNCX CH2(CN)2 NHPh Me Me NMeNaphthyridines. Structure, physicochemical properties and general methods of synthesis CN NC CN X Me NH NHPh Me MeMeN NPh Me Me N X 249 CN Me NH2 MeMeN NPh 248 X X=O, S.On treatment with sodium ethoxide in ethanol, 1-methyl-2- dicyanomethylidenepiperidine-3-carbanilides 252 cyclise to give partially hydrogenated 1,6-naphthyridin-5(6H)-ones 253.216 O O NAr NHAr EtONa, EtOH CN NH2 Me N Me N CN CN 253 252 Ar=Ph, 4-ClC6H4, 3-MeC6H4. Ammonolysis of enamines 254, obtained from 1-aryl-3-(2,2- dicyanovinyl)-4-piperidones affords 2-amino-6-aryl-3-cyano- 5,6,7,8-tetrahydro-1,6-naphthyridines 255, employed in the syn- thesis of pteridines 256.211 CN NH3 4-R1C6H4N MeOH CN NR22254 NH2 . HCl HN CN 4-R1C6H4N NMe2 EtONa, DMF N NH2 255 NH2 N 4-R1C6H4N N N NH2 256 R1=Me, Et; R22 =(CH2)4. 10.Thorpe dimerisation of cyanopicolines Dimerisation of 2-methylnicotinonitrile (257) induced by potas- sium tert-butoxide and including intramolecular addition of the imine to the nitrile at the cyclisation stage gives rise to 5-amino-7- (2-methyl-3-pyridyl)-1,6-naphthyridine (258).130 N CNH CN ButOK N Me N 257 Me N NH2 N N N 258 Me 215 8-Amino-1,7-, 1-amino-2,6- and 1-amino-2,7-naphthyridines 259 ± 261, possessing efficient bactericidal and fungicidal activ- ities, were prepared from the corresponding cyanopicolines in a similar way.144 Me NH2 N N N(i ) N N N 259, 260 261 Me NH2 i=6, 7. 11. Condensation of piperidones with cyanoacet(or thioacet)amides The condensation of cyanothioacetamide 262 with the sodium salt of 2-formyl-3-quinuclidone 263 in ethanol in the presence of AcOH has resulted in the synthesis of 1,5-naphthyridine-2(1H)- thione 24a.106 CN N CHONa N NCCH2C(S)NH2 262 S O NH 24a 263 Cyanothioacetamide 262 condenses with 2-arylmethylidene- 3-oxoquinuclidines 264 in the presence of piperidine to yield relatively stable salts 265; in an acid medium, these products are converted into 3,4-dihydro-1,5-naphthyridinethiones 266.Upon refluxing in an HCl ± EtOH mixture, the compounds 266 are transformed into naphthyridinethiones 24, which are also formed directly on refluxing the salts 265 in an ethanolic solution of HCl. R H R CN N N 10% HCl PiH+ 262 Pi O S7 HN 265 264 R CN N 24 HCl EtOH S HN 266 R=H, Ph, 4-FC6H4; Pi is piperidine.The partially hydrogenated 1,6-naphthyridinethione 33 has been synthesised by the reaction of 3,5-bis(phenylmethylidene)-1- isopropyl-4-piperidone 267 and the amide 262.107 Ph Ph CN PriN PriN 262 S O HN33 267 Ph Ph The reaction of the salt 268 with the amide 262 in ethanol in the presence of AcOH follows the Knoevenagel reaction route and affords adduct 269, which recyclises when refluxed in ethanol in the presence of a catalytic amount of piperidine, giving rise to the the 2,naphthyridine 35. The compound 35 is the product of a cascade type reaction comprising acidic cleavage according to Claisen, the Michael intramolecular addition, the interaction between the thioamide and ester groups and dehydrogenation.110216 ONa O Me 262 AcOH, EtOH Me Me N 268 Me O N EtO Me Me Me MeN CN EtO2C Me CSNH2 Me MeN Me O HN 35 The cyclocondensation of piperidone 270 with cyanoaceta- mide in the presence of diethylamine gives 1,6-naphthyridinone 271, which reacts with POCl3 to give chloro derivative 272.217 The compound 272 was also prepared by condensation of enamine 273 with ethoxymethylidenemalononitrile followed by cyclisation of intermediate 274.217 CHONa NCCH2CONH2 Et2NH, H2O MeN Me Me O 270 CN MeN Me Me O NH 271 CN Mor CN EtO THF, N2 Me Me Me Me Me N 273 Refluxing of 1,3-dicarbonyl compounds 275 with cyanoacet- amide in ethanol in the presence of piperidine gives 2,7-naphthyr- idine derivatives 276, used as components of formulations for treatment of diseases of blood circulation organs.218 CN O NCCH2CONH2 EtOH, Pi RN COMe 275 R=H, Alk, Ph, Ac, Bn, 4-pyridyl.12. Cyclocondensation of piperidones with aminopyrimidines When aminopyrimidines 277 are heated (100 8C, 3 h) with the salts of isomeric hydroxymethylidenepiperidones 278 and 279 in 85% orthophosphoric acid, substituted tetrahydropyrimido- [4,5-b]-1,6- (280a,b) 219 and -1,7-naphthyridines 281a,b are formed; 220 they are potential antitumour remedies. O C(CN)CSNH2 Me EtOH, Pi Me Me N 269CSNH2 CN Me MeN CN 7H2 Me S O NH CN S CN POCl3 MeN Me Me Cl N 272 Mor CN HCl (gas) 272 PriOH CN 274 Me N O NH RN 276 Me V P Litvinov, S V Roman, V D Dyachenko ONa BnN OH O N BnN 278 OH R N ONa N 280a,b N O BnN R H2N O N 277a,b 279 NH BnN R N N 281a,b R=NH2 (a), OH (b).Refluxing of aminopyrimidines 277a,b and 282 with methyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride 283 in gla- cial acetic acid provided the synthesis of pyrimido[4,5-c]-2,7- naphthyridin-6-ones 284a,b and 285. The compounds 284b and 285 present in concentrations of 1075 and 261076 mol litre71, respectively, inhibit in vitro the growth of malignant leukemia cells by 50%. 221 NBn O HN 277a,b AcOH O R N N 284a,b NH2 NBn. HCl N O NBn NH2 H2N NH2 283 CO2Me N N 282 AcOH O H2N N N 285 H A similar condensation of the aminopyridine 277a with hydrogenated 3-formylpyridine 286 in the presence of HCl in ethanol results in tetrahydropyrimido[4,5-c]-2,7-naphthyridine 287 mixed with its 7-benzoyl derivative.219, 222 NH O NCOPh 277a, HCl HN D N H2N N 287 CHO 286 13.Other general methods for the synthesis of naphthyridines Below we present the syntheses of naphthyridines starting from pyridine derivatives containing an amino (or protected amino) group and a carbonyl group or its synthetic equivalent in vicinal positions. Cyclisation is accomplished by treatment with basic or acidic reagents. CO2Et EtONa, EtOH R R O N NH N(i ) NH2 288 289 R=H, Me; i=5±8.O C(O)NH2 EtONa, EtOH NH Me Me N C Ph N(i ) 291 CPh 290Naphthyridines. Structure, physicochemical properties and general methods of synthesis O C(O)NH2 TsOH NH N(i ) N CH2CH(OMe)2 293 292 CH(OH)CH2CO2But b a R1 R1 O N NH N(i ) NHCOBut 294 295 c R1 Cl N N(i ) R1 N XC6H4OCH(Me)CO2R2-4 N(i ) 296 i=6±8; R1=H, Me, Cl; R2=Alk; X=O, S; (a) 3M HCl; (b) POCl3, D; (c) 4-HXC6H4OCH(Me)CO2R2, K2CO3 or NaH, DMSO. Me Me OHPh Cl Cl Me c a, b N N X CH(OEt)2 NHCOBut 297 299 Me Ph Cl N N 301 O O O O CHO OHPh Ph e d Me a, b N N N OH OH X CH(OEt)2 NHCOBut NH 298 300 CHO CHO Ph Ph f N N OH OMe N HN 302 (a) BunLi; (b) (EtO)2CHCOPh; (c) HCl; (d) H2SO4; (e) MeOH, H3PO4; ( f ) diazabicycloundecene, dioxane, D.Cyclisation of ethyl aminopyridineacrylates 288 in ethanol in the presence of sodium ethoxide has served as a route to N(1),N(i )-naphthyridin-2(1H)-ones 289.223 Cyclisation of ethy- nylpyridinecarboxamides 290 under similar conditions yields 1,6-, 1,7-, 2,6- and 2,7-naphthyridones 291.224 Naphthyridones 292 were prepared by refluxing vicinal (2,2-dimethoxyethyl)pyridine- carboxamides 293 with toluene-p-sulfonic acid in benzene.224 N(1),N(i )-Naphthyridin-2(1H)-ones 294, prepared by refluxing vicinal 2-tert-butoxycarbonyl-1-hydroxyaminopyridines 295 in dioxane in the presence of 3M HCl, have been used to obtain naphthyridine derivatives 296, which possess herbicidal and fungicidal properties and are efficient for the protection of cotton, soy-bean and sugar-cane crops.225, 226 Intramolecular cyclisation of substituted tert-butoxycarbonylaminopyridines 297 and 298, synthesised from compounds 299 and 300 via a two-stage proce- dure, gives 1,7- (301) and 1,6-naphthyridines 302.227 2-(3-Cyanopropyl-oxy or -thio)pyridine-3-carbonitriles 303 undergo an intramolecular nucleophilic rearrangement, similar to the Smiles rearrangement, being thus converted into fused 1,6- naphthyridines 304.228 ± 230 A similar cyclisation of 2-pyridinecar- bonitrile 305 gives rise to dihydrofuro[3,2-f ]-1,7-naphthyridine 306.231N R X(CH2)3CN ButOK CN 303 R X N 7R CN CN H X R N N N7 X N R N 304 NH2 X=S, R=H; X=O, R=Me.O(CH2)3CN ButOK CN N 305 Substituted 1,2,4-triazines decompose on thermolysis with nitrogen evolution.Thermolysis of compounds 307 and 308, having an ethynyl substituent in the side chain, yields substituted naphthyridines 309 232 and 310.233 N NH(CH2)3C CH MeO2C MeO2C N N 307 CONH(CH2)2C CH F3C NN N Ph 308 N-Hydroxyethyl-substituted 1,6- (311) and 2,7-naphthyri- dones 312 were prepared by refluxing the pyranopyridine isomers 313 and 314 with ethanolamine.234 Ph N H2NCH2CH2OH O 313 O Ph H2NCH2CH2OH O N 314 O The synthetic routes to 1,8- (315) and 1,6-naphthyridones 316 and 317 and annelated systems 318 and 319 make use of the reactions of pyrans 320 and 321 with malononitrile or its deriva- tives. The reactions are carried out in ethanol in the presence of piperidine (Scheme 5).235 ± 237 217 7 N R X(CH2)2CHCN CNX7 N N CN CH X N R N NHO N N 306 NH2 HN N MeO2C D 7N2 MeO2C 309 HN O D F3C 7N2 N Ph 310 Ph N N(CH2)2OH 311 O Ph N N(CH2)2OH 312 O218 R1 NC CO2Et Me H2N O 320 R1=2-ClC6H4, 4-ClC6H4, 4-MeC6H4; (a) NCCH2CONH2; (b) CH2(CN)2; (c) R2CH=C(CN)2; R2=Alk, Ar.Me CN a O 321 NHNC HNO318 CH2 CN 321 O NH2 (a) NCCH2CONH2 . 3-Acetyl-2-cyanomethylidenepyridine 322 and 3-acetyl-4-cya- nomethylidenepyridine 323 cyclise on heating (130 8C, 30 ± 45 min) in 85% orthophosphoric acid to give 1,6- (324) and 2,7-naphthyridinone derivatives 325 (Scheme 6).238 Me Me Me O H3PO4 CN Me NPh R1 322 R1 CNO H3PO4 Me SMe Me NR2 323 R1=CN, CO2Et; R2=Ph, 4-MeOC6H4.V. Conclusion The data surveyed here demonstrate that general and facile methods for the synthesis of diverse substituted naphthyridines are now available. 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