Recent Developments in Naphthyridine Chemistry

ADVANCES I N HFTEROCYCLIC CHFMISTRY VOL 13

Recent Developments in Naphthyridine Chemistry

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. . . . 1.8-Naphthyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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I . Introduction . . . . . . . . . . . . . . . . . . . .

I1 . Syntheses of Naphthyridines

. 111. Electrophilic Substitution Reactions .

IV .

V.

VI . VII . VIII . IX . X.

XI .

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A . Brominations of Hydrohalide Salts of I 7- and B. Gas-Phase Brominntion of 1. 5-Naphthyridine C . Bromination of Oxonaphthyridines . . . . Nucleophilic Substitution Reactions . . . . . A . Transformations of Aminonaphthyridines . . B. The Reissert Reaction . . . . . . . . Reactions on Nitrogen . . . . . . . . . A . N-Alkyl Derivatives . . . . . . . . . B. N-Amino Derivatives. . . . . . . . . C . N-Oxides . . . . . . . . . . . . . . Reduced Naphthyridines. . . . . . . . . 1.8-Naphthyridines as Ligands . . . . . . . I .5-Naphthyridine-l.5-dioxide Complexes . . . Medicinal Uses of Naphthyridines . . . . . Spectroscopic Properties . . . . . . . . . A . Nuclear Magnetic Resonance Spectra . . . B . Vibrational Spectra . . . . . . . . . C . Photoelectron Spectra . . . . . . . . D . Other Spectral Data . . . . . . . . . Electrochemical Studies . . . . . . . . .

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147 148 152 152 154 154 156 161

163 164 164 167

. . . . 168 . . . . 171 . . . . 173 . . . . 178 . . . . 179 . . . . 182 . . . . 182 . . .

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183 183 184 184

1. Introduction The chemistry of naphthyridines was last reviewed in this series in 1970.' Since that time a veritable explosion of publications has occurred emphasizing the chemistry of the naphthyridine metal complexes. their medicinal

147 Copyright (31 ~ x hy 3 ~ c a d c m i ch e > \. liic All rights of reproduction ~n a n y form r c w v c d ISBN IJ- I X12Oh3 1- I

148

[Sec. I1

WILLIAM W. PAUDLER AND ROGER M. SHEETS

application, and the study of the physical properties of these compounds. It is the purpose of this review to update the earlier one. Thus, publications that have appeared since 1970 will be highlighted. The group of six diazanaphthalenes (1-6) that contain a nitrogen atom in each ring are referred to as naphthyridines.

I ,7-

1.8-

(3)

(4)

2.7-

2.6-

(5)

(6)

11. Syntheses of Naphthyridines’ The application of the Skraup reaction, utilizing “sulfo mix,” to the appropriate aminopyridines affords these compounds in variable yields. Recent reaction condition improvements3 in some of these syntheses afford the naphthyridines in up to 90% yields.

.Q N H 2

Skraup reaction

(9)

a (2)

W . Czuba, Khirn. Ge/erot.sikl.Soedin., 3 (1979). Y . Hamada and I . 1. Takeuchi. Chem. Phurm. Bull. 19, 1857 (1971).

SeC. 111

DEVELOPMENTS IN NAPHTHYRIDINE CHEMISTRY

149

It is again' pointed out that no 1,7-naphthyridine is obtained by potential cyclization into the 4-position of 3-aminopyridine, 1,5-naphthyridine (1) being the lone naphthyridine product. Only when the 2-position is blocked by electron-donating groups are 1,7-naphthyridines obtained.' The well-known reaction of 3-aminopyridines ( e g , 10) with ethoxy-

+ EtOCH=C R

Co2Et

C0,Et

&Co2Et

Doatherin,

R

H

(12)

methylene malonic esters in Dowtherm has been reexamined. High yields of the appropriate 0x0 compounds (e.g., 11) along with isomeric 12 are obtained when there is a methyl, ethoxy, or alkylamino group in the 6position. When R is an amino group (e.g., 2,6-diaminopyridine) the 7-amino2-0x0, rather than the 7-amino-4-0x0 isomer, is ~ b t a i n e d . ~An " interesting variant of these cyclization reactions4b involves the reaction of 2-aminopyridine with a-methylacetoacetic ester in the presence of polyphosphoric acid (PPA): 0

Some 1,3-dicarbonyl compounds, when condensed with 2,6-diaminopyridine, afford 2-amino-5,7-disubstituted 1,8-na~hthyridines.~" J . Pomorski, Roc:. Clirni. 48, 321 (1974); J . T. Adams, C. K . Bradsher. D. S. Breslow, S. T. Amore, and C. R. Hauser, J . Am. Chon. SOC.68, 1317 (1946); J . Heinal, H. W . Kehn, E. Dogs. A. Seeger, and C . Herrmann, Eur. J . Mrd. C'lrrni.-Chini. Thw. 549 (1977). 4r E. Eichler. C. S. Rooney. and H. W . R. Williams. J . Hererocycl. Cliern. 13. 41 (1976). 4h E. B. Mullock. R. Searby, and H. Suschitzky, J . C'lier?~. Soc. C 6 , 829 (1970).

150

0

0

II

I1

+ CF3C-CHzCCF3

---+

H2N

NH 2

F3C

2-Aminonicotinaldehydes (13: R

R R

[Sec. I1

WILLIAM W. PAUDLER AND ROGER M. SHEETS

h

= CH,)

R

H

afford 1,8-naphthyridine~~ when

y

+

RJfco2Et

NH,

(15)

(14)

not formed when R

=

CH3

condensed with the appropriate methylene compounds. In the case of 2amino-4,6-dimethylnicotinaldehyde(13), cyanoacetic acid affords the 2-0x01,8-naphthyridine (14) rather than compound 15. The prior conversion of the amino compound to the anil does not alter the course of the reaction.6 An extension of this cyclization involves the condensation of 2-aminonicotinaldehyde with methyl ketones in the presence of alcoholic potassium hydroxide to generate the corresponding 2-substituted 1,8-na~hthyridine.~ RCOCH

K 0I
R

When 4-amino-3-carboxaldehyde derivatives of pyridine are employed, 2-amino-l,6-naphthyridines(16) are obtained.6

(16)

Other activated methylene compounds have been used in the aldehyde cyclizations as well8-' Aminopyridines containing an alkoxycarbonyl J . E. Harper and D. G. Wibberley, J . Chen7. Soc. C 18, 2991 (1971).

'' E. Eichler, C. S. Rooney, and H. W. R. Williams, J . f f e l i w q J c / Clieni. . 13, 43 (1976).

' B. Sreenivasulu and K . Reddy Vijayender, Curr. Sci. 46, 597 (1977). 'I

lo

'I

A. Decormeille, G. Quequiner, and P. Pastour. C. R. Acud. Sci., Ser. C' 3x1 (1975). E. Gudriniece and B. Rigerte, Lutu. P S R Zinat. Akud. Vesri, Kim. Ser., 239, (1974) [CA 81, 3749011 (1974)l. E. M. Hawes, D. K. J . Gorecki, and R. G . Gedir, J . Med. Cl7em. 20, 8 3 8 (1977). D. K. J . Gorecki and E. M. Hawes, J . Med. Climi. 20, 124 (1977).

Sec. I I ]

151

DEVELOPMENTS I N N A P H T H Y R I D I N E C H E M I S T R Y

group on the carbon adjacent to the amino function (17) react with ethyl acetate to generate the corresponding 2,4-dioxonaphthyridines (

- do

aCo2Et OH

0

+ C H , Cl~O E t

'

NH2

H

(17)

(18)

Cyclizing agents containing an active methylene group (19) react readily with 2-halonicotinic acids (20) to afford 5,7-disubstituted 1,6-naphthyridines (21) after treatment with aqueous a m r n ~ n i a . ' ~

a C O Xz H (20)X

=

c ii ,c oc H ,c o n

+ R -CHz--COzEt

CI. Br, I

+ f7JC02"

CH2C0,Et

(19)

1

I

NH , I1 ,O

a:::oz +-;-61. NH, H,O

R

Et

(21) R

=

Me. 131

The reductive cyclization of appropriately substituted nitropyridines ( e g , 22) affords 1,7-naphthyridines (23).' 2-Cyano-3-pyridyl acetonitrile

(22)

(231

(24)yields the 1,7-naphthyridine (25) when reduced with sodium in ethanol.' W. Czuba and M . Wozniak. Roc:. C%eni.48, 1815 (1974). W. C7uba and M . Wozniak, Zes:. Nrrulc. Unirv,Juyicllon., P r . C'lrem. 20, 61 (1975) [CA 82. S7SX4 ( I W S ) ] . l 4 D. E. Arne5 and W. D. Dodds, J . C'. S. Prrkin I S , 705 (1972). I 5 B. Frydrnan, M. Los. and H. Rapoport. J . Orq. (%em. 36. 450 (1971). l3

152

WILLIAM w. PAUDLER A N D ROGER M. SHEETS

(24)

[Sec. 1II.A

(25)

A rather unique synthetic example based on the well-known pyrrolepyridine carbene insertion reaction involves the following ring expansion.'

111. Electrophilic Substitution Reactions

As already described' the electrophilic substitution reactions in the naphthyridines follow the "pyridine" pattern. Thus, 3-bromo derivatives are formed in all of the 1,X-naphthyridines. In addition, dibromo derivatives are formed with the second bromine at the position p to the other ring nitrogen atom. This pattern prevails when either pyridine or nitrobenzene' is used as a solvent rather than carbon tetrachloride. Bromination of 1,5naphthyridine N-oxide affords the 3,6-dibromo-1,5-naphthyridineas a minor product, apparently through prior de-N-oxygenation. l 8

A. BROMINATIONS OF HYDROHALIDE SALTSOF

1,7- AND 1 ,8-NAPHTHYRIDINES

A means of brominating heterocyclic compounds (treatment of the hydrohalide of an azine with bromine in nitrobenzene) has been developed by Kress'' that gives, in some instances, superior yields to the Eisch bromination. This bromination procedure has now been applied to 1,7- and 1,8-naphthyridine.' In the case of 1,7-naphthyridine hydrobromide, 3bromo-, 5-bromo-, and 3,5-dibromo-l,7-naphthyridine (26, 27, and 28, respectively) are isolated. When an excess (2.5 equiv to 1) of bromine is used,

'' R. Herbert and D. G . Wibberley, J . C'hem. Soc. C 11, 1505 (1969). " H.

C. van der Plas and M. Wozniak, J. Heterocycl. Clzem. 13, 961 (1976)

'" R. A. van Dahm and W. W. Paudler, J . Ory. CIwm. 40, 3068 (1975).

'' T. J. Kress, U.S. Patent 308,389 [CA 82, 73022 (1975)l.

Sec. III.A]

X

=

D ~ ~ V E L O P M E N TI N S NAPHTHYRIDINE CHEMISTRY

Br, CI

(26) I 3 .5",,. I 5",,

(27) X I"<,. W Y , ,

153

(28)45 6",,, 64',,,

the dibromo derivative is obtained in 75% yield. Interestingly, a significant difference in product ratio is observed when the hydrobromide salt is brominated with 1.1 equiv of bromine as compared to the hydrochloride salt reacting under identical conditions. When the hydrochloride salt is used, the products are contaminated with some chloronaphthyridines. A further significant difference between the Eisch and Kress bromination products of 1,7-naphthyridine is that the former procedure does not yield any 3-bromo derivative. Although the Eisch procedure is preferred for the formation of the 5-bromo compound (250/, yield and only traces of the 3,5dibromo compound being formed), the Kress procedure is better for the synthesis of the 35dibromo derivative (45.6% yield). Bromination of 1,8-naphthyridine by the Kress procedure affords a 1:l ratio of the 3-bromo (29) and 3,6-dibromo (30) derivatives when 1.1

H Br

(29) 1 I equiv Br,

32",,

30"

2 5 equiv Br,

< I",,

73",,

(,

equiv of bromine are employed. In contrast, the dibromo compound is obtained in 73?:,, yield when the bromine equivalent is 2.5. The Eisch procedure affords the monobromo compound in a 10:1 ratio over the dibromo derivative. However, the yields are exceedingly low (57()). Thus, the Kress procedure is vastly superior for the dibromination of 1,8-naphthyridine.'4,'9.20 Although little is known about the mechanistic details governing the Eisch or Kress procedures, one possible difference between the two is that, in the former, the starting material may be a quaternary N-bromo derivative, whereas in the latter, it may be a quaternary NH derivative. Presumably, detailed studies of these two mechanisms will offer explanations to account for the difference between these two "electrophilic" bromination reactions.

"'

T. J . Kress and S. M . Conatantino, J . J f c / o r o q ~ c lChwi. . 10, 409 (1973); T. J . Kress and L. L. Moore. ;bid., 153.

154

W I L L I A M w. PAUDLER A N D ROGER M. SHEETS

B. GAS-PHASE BROMINATION OF

[Sec. II1.C

1,5-NAPHTHYRIDINE

When 1,5-naphthyridine mixed with bromine is passed through a glass tube filled with pumice at 500°C, a mixture of 2-bromo-, 2,6-dibromo-, (31, 32, 33, and 34, 2,3,6-tribromo-, and 2,4,6-tribromo-1,5-naphthyridines

mBr wBr

+ Br

Br

+ Br

nr (33)0.5-17,1

(34) 1 2’%, -

respectively) are isolated in the indicated yields. As anticipated bromination under these free radical conditions affords none of the electrophilic bromination products.21

C. BROMINATION OF OXONAPHTHYRIDINES As expected, the bromination of either 2-0x0- or 4-oxonaphthyridines proceeds under much milder conditions than the corresponding parent heterocyclic systems. Thus, the 3-bromo derivatives (35 and 36) are readily

(35) Br2

H O A ~or K R ~ Oi n, H H ~ ’

H ( 1 . 6 . 1.7- or 1,8- isomers)

H (36)

obtained under the conditions indicated in the equation^.'^'^,^^^^^ Th e J. Pomorski and H. J. Hertog, R o c . C/KW.47, 2123 (1973).

*’W. Czuba and M. Woiniak. R e d . Truu. Chiw7. Puy.\-Ba.s 93, 144 (1974) 23

W. Czuba and M. Woiniak, R o c . Chem. 47, 2361 (1973).

SeC. In.c]

DEVELOPMENTS IN NAPHTHYRIDINE CHEMISTRY

I55

corresponding 3-chloro derivatives are obtained when KCIO, in HCI is used as the chlorinating agentz4 The 2-0x0- and 4-oxonaphthyridines are nitrated, affording the corresponding 3-nitro Nitration of 2,5-dioxo derivative 37 affords the 3-nitro derivative 38.'' 0

0

When a competition with potential nitration of a phenyl ring exists, as in compound 39, the site of nitration is dependent upon the reaction condit i o n ~ In . ~the ~ presence of sulfuric acid, initial nitration takes place on the

a

H

24

2s

mo

0

H

E. V . Brown m d S. Mitchell. J . Or<].C ' / / m . 40. 660 (1975). S. Carboni, A. Da Seltimo. D. Bertini. P. L. Ferrarini. 0. LIVI.C. Mori. and I . Tonetti. G u z . Chin/. Ittrl. 102, 2 5 3 (1972).

156

WILLIAM W. PAUDLER AND ROGER M. SHEETS

[Sec. IV

phenyl ring, whereas in acetic anhydride, nitration occurs exclusively in the naphthyridine rings (42)." Nitrophenyl compounds 40 and 41 can be further nitrated to afford the 3,7-dinitro derivative^.'^

IV. Nucleophilic Substitution Reactions For a detailed account of naphthyridine reactions with nitrogen nucleophiles, see chapter by van der Plas er ul., p. 95 of this volume. The amination of the 1,6-, 1,7-, and L8-naphthyridines (2,3, and 4, respectively) affords the 2-amino derivatives (43), whereas the I .5-isomer yields

(l.6-, l,7-,or 1.8- isomers)

(43) 60 -8O'i,

I

NH,

(44)

the 4-amino-l,5-naphthyridine(44).'' Vastly improved yields of these compounds are obtained when these aminations are done at 50°C rather than at liquid ammonia temperatures.'328 The intermediate adducts in these

*'S. Carboni, A. Da Settimo, D. Bertini, P. L. Ferrarini, 0. Livi, and I . Tonetti. Gnzz. C'hin7. Itul. 104, 499 (1974). *' E. V. Brown and A. C. Plasz, J . H ~ ~ t r r o c y cChem. l. 7, 589 (1970). 28

Y. Hamada and 6Zh382 (1975).

1. Takeuchi, Yuki Gnsri Kaynku Kynkaishi 32, 602 (1974);Z / I . Khim.,

Sec. IV]

DEVELOPMENTS I N N A P H T H Y R I D I N E CHEMISTRY

157

aminations have been identified by NMR spectroscopic analysis. In the 1,X-naphthyridine instances, the 1,a-dihydro structures (45) are the primary adducts. In 1,7-naphthyridine the C-6 (47) and C-8 (48) adducts are ~ b t a i n e d ~ ' . ~in' addition to the formation of the 1,2-dihydro adduct (46). It is of interest that the site of adduct formation in the 1,5- and 1,7-naphthyridines changes to C-4 (48a) and C-8 (48), respectively, when the temperature is increased from -40°C to about 10"C.31

+

The 1,X-naphthyridines react with phenyllithium to afford the corresponding 2-phenyl derivative^.^^ When 1,s-naphthyridine is treated with butyllithium, the 2-butyl derivative is obtained, whereas reaction of dithiane with butyl lithium followed by addition of 1,8-naphthyridine generates bisnaphthyridine 49. An interesting application of the dimethyl sulfoxide-sodium

(49)

hydride methylation to the 1,X-naphthyridines affords dimethyl-1,Xnaphthyridines 50, 51, and 52, r e ~ p e c t i v e l y . 1,6-Naphthyridine, ~~.~~ when

H. C. van der Plas, A. van Veldhuisen. M. Wozniak, and P. Smit, J . Ory. C%ern.43, 1673 (1978). W. Maran, Zesr. Nuuk. Poliietli. Krukow., Chem.. 111 (1979) [CA 93, 71598 (1980)]. 3 ' J. W. H. van Haak, H . C. van der Plas. and B. van Veldhuisen, J . Ory. C'hern. 46,2134(1981). " Y . Hamada and I . Tnkeuchi, C'hem. Plinrm. Bull. 22, 495 (1974). j 3 Y. Hamada and I . Takeuchi, Chrm. Pharni. Bull. 19, 1751 (1971). '')

'"

158

W I L L I A M w. PAUDLER A N D ROGER M . SHEETS

[Sec. IV

treated with DMSO/NaH, is the sole 1,X-naphthyridine that forms a monomethyl derivative (53). Mechanistically, these compounds are formed via CH 3

the addition compound (54) followed by elimination of CH,SO- to form methylene tautomer 55, which then rearranges to the observed products.

[a [d] z-GCH]

__$

~

H

methyl compound

H

(54)

(55)

The “hydroxy” groups in 2-0x0- and 4-0x0- 1,X-naphthyridines and in the corresponding 2,7-naphthyridine derivatives are readily replaced by either

Sec. IV]

159

DEVELOPMENTS I N NAPHTHYRIDINE CHEMISTRY

chlorine34 or bromine’2.22upon treatment with POCl, or POBr,, respectively.’3,22,23,35.36 (PBr, has also been used.) More detailed studies have established that dibromo derivatives (57, 60, 62, and 63) are also formed in these reaction^.^'-^' The second bromine is always introduced at the electrophilic substitution site of the nonoxygenated

N

I

I - I’onI, * N

d H

+

N~

+

Br (57)

N

m Br

(56)

H

(58)

ring. The halogen in the 2-position of 2,4-dihalo-l,X-naphthyridinesundergoes nucleophilic substitution more readily than the halogen at position 4. These type of reactions are exemplified by the following sequences (65-77), 34

W. K. Ensley and M. F. Meyer. Pro(,. Accid. Sci. 32. 109 (1968).

’’ E. Eichler. C . S. Rooney, and H. W. R. Williams, J . Hctcvocxcl. C%m?. 13, 43 (1976).

E. V. Brown and S. Mitchell, J . Ory. Clwii. 40, 660 (1975). W. W. Paudler and T. J . Kress, in “Topics in Heterocyclic Chemistry” ( R . Castle, ed.), p. 109. Wiley (Interscience), New York. 1973. ” W. Czuha and T. Kowalaska. in press. W. W. Paudler and T. J. Kress, J . H r r c v m y l . C‘htwi. 2, 292 (1965). .16

37

’’

160

WILLIAM

w. PAUDLER AND ROGER M. SHEETS

[Sec. IV

X (65) X = OH, HNNH,, NH,

(66)

which introduce hydroxy, hydrazino, and amino groups. As might be expected, tosylhydrazine reacts selectively with the halogen in the 4-position (68) of 3,4-dihalo-1,6-naphthyridines(67).22,145 NHNHTs

(67) X = CI, Br

(68)

In the 3,4-dihalo- L7-naphthyridines (69)22the replacement of the halogens is not selective, in that both halogens are ultimately displaced to form ditosylhydrazine derivative 72. The unusual reactivity of the halogen in the

Nmx mNH

T

?

THNHTs

/

+

'

(69)

N'

N\

(70)

N

(71)

3-position is associated with the fact that intermediate 73 is stabilized by NHNHTs

(72)

(73)

N-7. A series of 4-chloronaphthyridines have been converted to mercapto and amino derivative^.^^'^' Hydrazine reacts with 4-chloro-1,7- and 4-chloro-1,8-naphthyridines (74 and 75) by cleaving the halogenated ring to generate pyrazolylpyridine 1-43 derivatives (76 and 77, re~pectively).~ P. Chien and C. C. Cheng, J . Med. Chem. 11, 164 (1968). R. A. Bowie, J . Ckern. SOC. D 9, 565 (1970). 42 R. A. Bowie, M. J. C . Mullan, and J. F. Unsworth, J . C. S . Perkin 1 8 , 1106 (1972) 4 J R. A. Bowie and B. Wright, J . C. S . Perkin 112, 1109 (1975).

40

41

Sec. IV.A]

DEVELOPMENTS I N NAPHTHYRIDINE C H E M I S T R Y

161

I

CH 3 (74)

A. TRANSFORMATIONS OF AMINONAPHTHYRIDINES A logical extension of the syntheses of the 1,X-naphthyridines is the application of the Skraup reaction to aminonaphthyridines. When 4-amino1,5-naphthyridine (78) is reacted with glycerol under Skraup reaction conditions, the expected pyrido-l,5-naphthyridine(79) is obtained.44 When

Sk r.i u p

N/

N’

(no)

NH2

H (81)

attempted on 2-amino-1 ,X-naphthyridine (SO), the same reaction affords 2-ox0 derivative 81.44 This facile hydrolysis of 2-amino-1 &naphthyridine has previously been discussed. Under nonhydrolytic conditions, 2-amino-1,S-naphthyridines(82) do, however. undergo the “normal” cyclization reactions with cc-bromo ketones. Thus, imidazo[ 1,2-tr]naphthyridines (83) are readily obtained.45 Y . Hamada. M . Saio. and I . Takeuchi, Yukuguku Zasshi 95, 1492 (1975) J . F. Harper and D. G . Wibbsrley. J . Chrm. Soc. C‘, 2985 (1971).

.24 J5

W I L L I A M w. PAUDLER AND ROGER M. SHEETS

162

I

R

=

[Sec. 1V.A

I

0

alkyl, aryl, or H (821

Ethyl acetoacetate, ethyl ethoxymethylenemalonate, ethyl acetoacetate, and ethyl cyanoacetate afford 2-(ethoxycarbonylvinylamino)-1,8-naphthyridines (84). Some of these compounds have been successfully cyclized to pyrimido [1,2-a]-l,S-naphthyridines(85).45 Me I

Me

I

Similar conversions have been accomplished on 2-amino-7-0x0- 1,8naphthyridines, whereby angular structure 86 is ~ b t a i n e d . ~2-Amino' R

C0,Et

l,S-naphthyridines, following conversion to the corresponding chloro compounds, have been transformed to the 2-azido-1,8-naphthyridines(87), a type of compound that instantly cyclizes into tetrazolo form 88.46-48 '('S. Carboni, A. Da Settmio, and P. L. Ferrarini, Guzz. Chin?.I/u/. 97, 42 (1967). " S. Carboni, A. Da Settimo, and P. L. Ferrarini, J . Hrterocyd. Clwni. 7, 1037 (1070) '* P. L. Ferrarini, Ann. Chim.(Romc,)61, 318 (1971).

Sec. V.B]

163

DEVELOPMFNTS I N N A P H T H Y R I D I N E CHEMISTRY

R

R

The well-known photochemical transformation of a-diazo ketones to ring-contracted derivatives also occurs when 3-amino-4-oxo-1,6-naphthyridine 89 is treated wIth nitrous acid and the r-diazo ketone 90 is photo-

(89)

(90)

(91)

chemically converted to azaindole 91.49 Similar ring-contraction reactions have been observed in the other isomeric 3-amino-4-0x0-1,X-naphthyridines."'

B. THEREISSERT REACTION When 1,6-naphthyridine is reacted with potassium cyanide and with an acyl or aroyl halide, the 5,6-addition product (92) is obtained in poor yields

R( O X

,

RCO

H X

KCN H.0

(92) CH,, C>H,, C,H; X = CN. O H , OMe

R

=

unless diphenylcarbamoyl chloride is used as the acylating agent.' 1.'2 The benzo-1,7-naphthyridine (93) gives the expected addition products (94) resulting from addition to the 7,8-bond of the 1,7-naphthyridine rings3 40

T. Alder and A . Albert. J . C'lrrm. Soc., No. 4. 1794 (1960).

5'

Y . Harnada, I . Takeuchi, nnd M . Matsuoka. C h i . Phurr?~.Bull. 18, 1026 (1970)

'"0. Suss and K . Moller. Ju.sru.v Liehiy.r J m , C'lrenr. 223, 599 (1956).

'' Y . Kobayashi, I . Kumadaki, and H . Sato, C~/reni.P/iurnr. Bull. 17, 2614(1969).

', Y . Hamada. K . Morishita, kind M . Hirota. C / r w . Pharn?. Bull. 26. 350 (1978).

164

W I L L I A M w. PAUDLER A N D ROGER M. SHEETS

(93)

[Sec. V.A

(94) R = Me, Et, Pr

X

=

CN, OH. O M e

V. Reactions on Nitrogen A. N-ALKYLDERIVATIVES The naphthyridines undergo N-alkylation reactions as expected. Thus, N-6 and N-7 are methylated first in 1,6- and in 1,7-naphthyridine, respectively. The quaternary N-methyl salts are oxidized by potassium ferricyanide to afford the N-methyl-a-one derivatives (95-98).54p56 The kinetics of

0

54

Y. Hamada and 1. Takeuchi, Chew.Pllarm. Bull. 19, 1751 (1971).

56

J. W. Bunting and W. G . Meathrel, Can. J . Clzmz. 50, 917 (1972).

'' J. W . Bunting, J . C . S . Perkin 115, 1833 (1974).

Sec. V.A]

DEVELOPMENTS I N NAPHTHYRIDINE C H E M I S T R Y

165

TABLE I SIICOND-ORDER RATli CONSTANTS € O R METHIODIDE F O R M A T I O N IN ACETONI1RII.E AT 24.8 0.1 c 10-4k

Compound

m - l s - l

0.5 11 4.23 0.232 I .66 4.25

Quinoline Isoquinoline 1.5-Naphthyridine 1.6-Naphthyridine 1.8-Naphthyridine

quaternization and the structure of the pseudo bases are a recent addition to the knowledge of these quaternary compounds. Table I lists the second-order rate constants for methiodide formation of a number of naphthyridine~.~' These data clearly show that the additional nitrogen in 1,5-naphthyridine relative to quinoline decreases the charge density on the nitrogen atom being alkylated. The 1,6-naphthyridine alklation rate constant is the sum of the separate constants for reaction at the two nitrogen atoms. The 20times greater rate of alkylation of 1,8-naphthyridine versus that of 1,5naphthyridine may reflect the interaction of the methyl group with the peri-lone pair of electrons in the 1 , 8 - i ~ o m e r . ~ ~ . ~ ~ The di-N-alkyl derivatives of 1,5- and 1,8-naphthyridine have significantly different properties. Diquaternary salt 99 is relatively stable in neutral solution, whereas 100 exists in equilibrium with its pseudo base (101).58*59 A similar pseudo base structure (103) has been identified6' in the 1,8-bridged compound (102).The 1,Snaphthyridinesalt (99) is readily reduced by a oneelectron transfer process to give a fairly stable green radical cation (104).

+ OH N' +I

57

a OH

I

H

R. A. Y. Jones and N . Wagstaff, J . C. S . Clieni. C'omniun., 56 (1969)

D. J. Pokorny and W. W . Paudler, Cun. J . C % m . 51, 576 (1973). 5 y J. W. Bunting and W. G . Meathrel, C ' m . J . C'heni. 52. 962 (1974).

5"

"' J. W. Bunting, J . C. S. Perkin I 1 5 . 1833 (1974).

166

WILLIAM W. PAUDLER AND ROGER M. SHEETS

[SeC. V.A

CH, ( 104)

In contrast, the 102 salt does not form a radical6* Methyl bromocyanoacetate reacts with 1,6-naphthyridine to form a stable ylide (105)62and with

(106)

( 107)

tetracyanoethylene to afford 106. When 106 is treated with sodium methoxide it affords the imidazo[ 1,2-a]pyridine derivative ( 107).62 ''I

J . E. Dickeson, I. F. Eckhard, R. Fielden, and L. A. Summers, J . c'. S. Perkin I , 2885 (1973).

'' Y. Kobayashi, P. Kutsuma, K . Morinaga, F. Fujito, and Y. Hanzawa, C'liern. Pliurn7. Bull. 18, 2489 (1970).

Sec. V.B]

DEVELOPMENTS I N NAPHTHYRIDINE CHEMISTRY

B.

167

N-AMINODERIVATIVES

The 1,X-naphthyridines react with 0-mesitylenyl sulfonylhydroxylamine to generate the N-amino compounds (108-11 These compounds are

(109)

readily benzoylated. 1,3-Dipolar c y c l ~ a d d i t i o n shave ~ ~ been accomplished on the 1 3 - and 1,E-naphthyridine N-imides to afford tricyclic derivatives (112 and 113).

Y. Tamura. J . Minamikaw%, Y. Miki. S. Malsugashita. a n d M . Ikeda. 7 i ~ / t ' U / f < , d ! Y J /Ll c / l . 40. 41 11 (1972). I" Y . Tamura. Y . Miki. a n d M . Ikcda. J. H(,/wJcIY/.C'lrcwr. 11, 675 (1974). '' Y . Tamura, Y. Miki. a n d M. Ikeda. J. HC/W(JC.VC/. C'lrcw. 12. I19 (1975). '" Unpublished rcsults from authors' laboratory. h3

168

WILLIAM

w. PAUDLEK AND ROGER M. SHEETS

[Sec. V.C

C. N-OXIDES All of the 1,X-naphthyridines can be N-oxidized. For 1,6- and 1,7-naphthyridine the 6- and 7-oxides are formed initially. No 1,8-naphthyridine di-N-oxide has been The Skraup reaction on 3-aminopyridine N-oxide yields N-oxide 114 in good yield34 or, at 150"C, lS-naphthyridine itself.

0

0(114)

The N-oxidation of 1,6-naphthyridine with hydrogen peroxide in acetic acid forms the 2-0x0 (1 16) and 1-hydroxy-Zoxo derivatives (117), along

with the 6-oxide (115).71 2-Amino-l,5-naphthyridine(118), when treated with hydrogen peroxide and sodium tungstate, forms the 1,5-di-N-oxide (119) in good yield.70

67

68 ''I

7o

7'

E. P. Hart, J . Chem. Soc. 6, 1879 (1954). U. Petrov and B. Sturgeon, J . Cliem. Soc. 4, 1157 (1949). W. W. Paudler. D . J . Pokorny, and S. Cornrich, J . Hererocycl. Chrm. 7, 291 (1970). R. M . Titkova, A. S . Elina, and N. P. Kostyuchenko, Khim. Geterotsik/, Soedin., 1237 ( 1972). T. Takahashi, Y . Hamada, I. Takeuchi, and H. Uchiyarna, Yukuyuku Zusslii 89, 1260 ( 1 969).

Sec. VI.C]

DEVELOPMENTS I N NAPHTHYRIDINE CHEMISTRY

169

0 I

0 (118)

(119)

The Meisenheimer reaction of the 1,X-naphthyridine 1-oxides has been examined in some detai1.72-75Table I1 lists the relative yields of the 2-, 3-, and 4-chloronaphthyridines formed. As the amount of 2-chloronaphthyridine decreases, the 3-chloro and 4-chloro isomers increase in the series 1,7-, 1 5 , 1,8-, and 1,6-naphthyridine. T A B L E II MIIISENHEIMLR RLA(.rio!i PKODIK‘TS t K O M I . X - N A l ~ l l T l i Y R l l > l ’ J F I-OXlll[3

Relative yields ( I > < , ) 1.5-Naphthyridine 1,6-Naphthyridine 1,7-Naphthyridine 1.8-Naphthyridine

42 12 56 36

3 20 3 7

54” 66J2 35J3 5773

The 2-chloro compound may be formed via an intramolecular process, whereas an intermolecular route may be operative in the formation of the 4-chloro c o m p o ~ n d . ’The ~ 3-chloro isomer, however, could be formed through a modified electrophilic substitution process.

72

W. W. Paudler and D. J . Pokorny, J . Ory. C‘heni. 36. 1720 (1971).

’’ D. J . Pokorny and W. W. Paudler, J . Ory. CArni. 37, 3101 (1972). 74 75

E. V. Brown and A. C. Plasz. J . Ory. Chem. 36, 1331 (1971). D. J . Pokorny and W. W. Paudler, J . H e t r r o c j d . C‘l1cvn. 9, 1151 (1972).

170

W I L L I A M w. PAUDLER A N D ROGER M. SHEETS

[Sec. V.C

Phosphorus oxychloride converts 1,6-naphthyridine 1,6-dioxide to a mixture of 2,5-dichloro-, 3,5-dichloro-, 4,5-dichloro-, and 5-chloro- 1,Xnaphthyridines (121, 120, 122, and 123, respectively). The 3,5- and 2,5dichloro isomers are formed as the major products. CI

CI

(121) 347<,

( 120) 422,

0

CI

CI

CI

(122) 157"

(123) 22,

The Reissert reaction with 1,6-naphthyridine-l-oxide (124),as well as with HCN in methanol, forms 2-cyano- 1,6-naphthyridine (1 25).

CN

+I

0

(124

( I 25)

The 1,6-naphthyridine-6-0xide (126) and 1,6-naphthyridine- 1,6-dioxide (127) form the 5-cyano (128) and 2,5-dicyano (130) compounds, respectively, when subjected to Reissert reaction condition^.^^ The 5-0x0 isomer (129) is a by-product in the 6-oxide reaction. Cyano- 1,6-naphthyridines are obtained when the 1,6-di-N-oxide (127) is treated with potassium cyanide in the presence of potassium f e r r i ~ y a n i d e . ~Methanolic ~.~~ potassium cyanide yields the 5-cyano-, 5-carboxamido-, and 2-methoxy-1,6-naphthyridines (128, 131, and 132, respectively) when reacted with 1,6-naphthyridine 1,6-dioxide ( I 27)."

'"Y.Kobayashi, I . Kumadaki, and H. Sato, d . Ory. Clirni. 37, 3588 (1972). " Y.

Hamada, I . Takeuchi, and M . Matsuoka, Chmi. Phutm. Bull. 18, 1026 (1970).

'' Y.Kohayashi, I . Kumndaki, and H . Sato, C'hrm. Phurm. Bull. 18, 861 (1970).

SeC. VI]

DEVELOPMtNTS IN NAPHTHYRIDINE CHEMISTRY CN

i

CONHz I

0

CN I

0-

(127)

171

0-

R

=

R ' = H or C N

VI. Reduced Naphthyridines Tetrahydro- (133) and r,wn.s-decahydronaphthyridines (134) can be selectively prepared from the parent ring systems by reduction in the presence of either platinum oxide or palladium or by reduction with sodium in ethanol or amyl a l ~ o h o l . ~ ' -Hydrogenation ~" in acetic acid with platinum catalyst affords a cis- and trurwdecahydro mixture (I35 and 134).*'

K . Miyaki. J . Phcrrrn. Soc. Jpn. 62. 26 (1942). D/.sch. <'/7cm Gc'r. 74 I 1 15 (1941) W. L. F. Armarego. J . Chtwf.SOC.C' 5. 377 (1967). " 2 N . Ikekawa. C h m . P / i u m . Bid/. 6, 408 (195X). "'J. Pomorski. Arch. fr7f/?fi~r~~J/. Tlfer.E.Y/I.19. 261 (1971). 79

"'E. Ochini and K . Miyaki, Bcr

"'

W I L L I A M w. PAUDLER AND ROGER M. SHEETS

172

134

[Sec. VI

+

Lithium aluminum hydride converts 0 x 0 compounds 136 and 137 to 5,6,7,8-tetrahydronaphthyridines138 and 139, r e ~ p e c t i v e l y .Butyllithium ~~

adds to the pyridine ring in 0 x 0 compound 140 to form 141.85An interesting photochemical cyclization (142 -+ 143) generates a tetrahydro-l,8-naphthyridine.86An oxidative cyclization involving substituted piperidones (such as 144) affords octahydronaphthyridines of general structure ( 145).871,2,3,4tetrahydro-2,6-naphthyridine(148) is obtained as shown in the transfor-

S. Yoshinobu, Chew. Pharm. Bull. 8,427 (1960). J . Artus, J . J . Bonet, and A. E. Pena, J . C. S. Chon. Commun., 579 (1973) M . Ogata and H . Matsumoto, Cheni. Pharm. Bull. 20,2264 (1972). *’H . Moehrle and F. Specks, Arch. Plzurm. (Weinheim. G r r . ) 308, 499 (1975).

84

” J.

Sec. VII]

DEVELOPMENTS I N N A P H T H Y R I D I N ECHEMISTRY

173

mations 146 + 147 + 148. Catalytic reduction of 2,6-naphthyridine itself affords the same tetrahydro isomer."

VII. 1,SNaphthyridines as Ligands The availability of 1,8-naphthyridine and its alkyl derivatives has spawned a veritable explosion of studies aimed at examining the behavior of this ring system as a ligand. Much of this work has been done by Hendricker and co-workers, initially caused by the availability of 1,g-naphthyridine synthesized by Kress and Paudler.

" F.

Alhaique, F. M . Riccieri, and L. Campanella, Arirr. Chini. (Rome)62, 239 (1972)

174

WILLIAM

w. PAUDLER A N D ROGER M . SHEETS

[Sec. VII

Metal ion complexes with 1,8-naphthyridine could be conceived as possessing any or all of the following structures (a, h, or c):

(4

(b)

The monodentate behavior exemplified by II could also involve an equilibrium between the structure shown and the corresponding species where M is bonded to N,. Among the first complexes studied were the Fe(I1) perchlorates (149)"9.'" and the corresponding Mn(II), Ni(II), Cu(II), Zn(II), Pd(II), and Cd(lI)"'

(a) 4Fe+2(C104)*

(149)

The X-ray crystallographic structure of the Fe(I1) complex showed that the 1,8-naphthyridine was part of an eight-coordinate Fe(I1) complex in which one of the l&naphthyridines is more tightly bonded than the other three."' In solution the complex dissociates into a tris-l,8-naphthyridineP Fe(I1) species. The Mossbauer "Fe spectrum of the Fe(l1) complex has shown that it has the largest quadrupole splitting (4.49 mm/sec) thus far encountered for any Fe(l1) specie^.^^*‘)^ These unique eight-coordinate complexes of the first-row transition metal ions maintain the four-membered chelate ring even in solution, where they dissociate into the tris-complex species."- ''

89

D. G . Hendricker and R. L. Bodner, Nucl. C%em.Lett. 6 , 187 (1970). A. Clearfield, P. Sing, and I . Bernal, J . C . S . Cheni. C'omniun., 389 (1970). 91 J. M. Epstein, J . C. Dewan, D. L. Kepert, and 0. H. White, J . C'. S. Dal/nn, 1949 (1974). 9 2 R. L. Bodner and D. G. Hendricker, Nucl. Chem. Lett. 6,421 (1970). " E. Konig, R. Ritker, E. Lindner, and I . P. Lorenz, Chem. Phys. Let/. 13, 70 (1972). 9 4 M . A . Cavanough, U. M. Coppo, C. J. Alexander, and M . L. Good, Inory. Chem. IS, 2615 (1976). " E. Dittmer, C. J. Alexander, and M. L. Good, J . Coord. C'lreni. 2, 69 (1972). " D. G . Blight and D. L. Wispert. Inory. Cheni. 11, 1556 (1972). " I . Bertini and D. Gatteschi, Inorg. Chem. 12, 2740 (1973).

Sec. VII]

DEVELOPMENTS I N N A P H T H Y R I D I N E CHEMISTRY

175

A binuclear complex of 4-methyl-1 &naphthyridine (150) has been preIts structure, as determined by X-ray diffraction, shows two nearly equivalent copper atoms in a pseudotetrahedral environment bridged by one chlorine and two 4-methyl- 1 &naphthyridine rings.

2.078 A

2.024 8,

CH 3 (150)

The difference of about 0.14 A observed in the Cu-N distance (2.162.02 A) at one of the copper sites has been attributed to the steric requirements of the bridged structure.'0n The alkaline earths, Mg, Ca, Sr, and Ba, also form four-membered chelate systems with I&naphthyridine and its 2.7-dimethyl derivative (lSI).'" When dissolved in polar media the complexes show 3-ion conductance.

solid state (151) M = Mg. Ca, Sr, Be

Sonic 10 (lS2), and possibly 12, coordinate complexes have been described,' ". and some of their infrared spectra have been analyzed.lO"

'"'

(152) M

=

La-Pr

'"D. Gatteschi, C. Mcalli, and L. Saccani. Irrory. Clrcwr. 15, 2774 (1976). ")

A. Emad and K . Emerson. I m r y . Chrnr. 11. 2288 (1972). Emerson, A. Eniad, R. W. Brookes. and R. L. Martin, Inory. Chrr77. 12. 978 (1973). R. L. Bodner and D . G . Hendricker, Irrory. C%rnr.9, 1255 (1970). D. G . Hcndrickcr and R. J . Foster. J . Inory. Nucl. C ' / 7 ~ 7 ,34, 1949 (1972). R. J . Fobter, R. L. Bodiicr, and D. G. Hendricker, J . Iriory. Nucl. C/?w7.34, 3795 (1972J. B. Hutchinson and A. Sunderland, I n o r y . Chm7. 11, 1948 (1972).

"'" K. "" I"'

In3 '04

176

W I L L I A M w. PAUDLER A N D ROGER M. SHEETS

[Sec. VII

Ten-coordinate complexes using 2,7-dimethyl- 1,8-naphthyridine (1 53) have been synthesized as well.'02

( H 3 C m C H l 2

(153) M = Y, La-Yb

lntensily colored (near 450 nm) complexes involving Ruthenium (154) and 1,8-naphthyridine and its more basic derivative, 2,7-dimethyl-1,8-naphthyridine, have recently been d e ~ c r i b e d . ' ~The ' highly colored nature of these complexes has been ascribed to metal-to-ligand charge transfer transitions.

(154)

The metal carbonyls lend themselves to complexation with 1,S-naphthyridines in a manner where they behave as both mono and bidentate ligands of general structures 155-157,'06 depending on the number of carbonyl ligands.

(155)

( 156)

M

=

Cr, Mo, W

One example of a seven-coordinate complex (158) involving three coordinated bidentatenaphthyridines and one perchlorate bonded to the metal through one of its oxygen atoms has also been prepared."

(158)

A variant of this complex is bis[(l,S-naphthyridine)niercury(I)]diperchlorate (159).'07In this instance, the 1,8-naphthyridine behaves largely in a unidentate fashion, as shown by the fact that the N,-Hg bond distance is los lo' I"'

R. J . Glaniewicz and D. J . Hendricker, J . Am. Clicw. Soc. 99, 6581 (1977). T. E. Reed and D. G . Hendricker, J . Coord. Chmi. 2, 83 (1972). J . C. Dewan. D. L. Kepert, and A. H . White, J. C. S. Dalton, 4901 (1975).

Sec. VII]

DEVELOPMENTS I N N A P H T H Y R I D I N E C H E M I S T R Y

177

2.78 A, whereas the N 2 - Hg distance is 2.03 A. The Hg-Hg bond in this compound is extremely short. The 1,8-naphthyridine nickel complex, [Ni,( I ,8-naphthyridine),Br2]+ PF,-, also has a very short metal-metal bond length. However, all four of the naphthyridines are bridge-bonded and each metal atom is coordinated in a square-planar array by four nitrogen atoms.'08 The platinum 1 &naphthyridine complex (160) in the solid state shows square-planar coordination about platinum with the naphthyridine behaving essentially as a monodentate heterocycle.'"9 ~

Et,P-

PEt, (160)

The solution proton N M R spectrum of the compound shows the naphthyridine protons to be equivalent at -3O'C or higher. Thus, under these conditions the complex shows fluxional behavior as exemplified by the following:

a=a I

I

11' (CI)

Pt(CI)

'"' D. Gatteschi, C. Mealli, and L. Saccari, J . An?. C'heni. SOC.95,2736 (1973) '(''

K . R. Dixon, fnory. C/iem. 16, 261 (1977).

178

WILLIAM W. PAUDLllR AND ROGER M. SHEETS

[SeC. VIII

Similar fluxional behavior has been observed for dimethyl gold complexes of 2,7-dimethyl-l &naphthyridine.' l o In methylene chloride or chloroform the intermolecular exchange is rapid on the N M R time scale at ambient temperatures, whereas below 200 K, the exchange is sufficiently slow to give two different sets of proton signals. Thus. the equilibrium that exists can be described by the following equation:

H3 c

m=QQ

H3C-Au

I

CH3

1

H 3c

X

H,C-Au

CH3

I

CH3

-X

CH 3

A detailed study of the infrared spectra of a number of 1,8-naphthyridinemetal complexes has established that the M-N stretching vibrations decrease consistently when the complexes containing a four-membered ring are compared with similar complexes in which the ligand is cr,a'-bipyridine. Thus, this technique lends itself admirably to the structure determination of these complexes.Io4*'I ' The reactions of l&naphthyridine with tris(dipiva1oylmethanato)lanthanide to form the appropriate complexes are exothermic.

VIII. 1,5-Naphthyridine-1,5-dioxideComplexes The title compound forms coordination compounds with Cu(I1) chloride, bromide, and nitrate. The postulated structure of these compounds is 161.'13

L

Cl,'

c u\

0

A . Schmidbaur and K . C. Dosh, J . Am. Clre~vr.SOL..95, 4855 (1973).

'lo I'

'Iz

' B. Hutchinson, A. Sunderland, M. Neal, and S . Olbricht, Spcvtrochinl. Acru 29,2001 (1973). D. R. Dakternieks, J . Inorg. N u d . Cliem. 38, 141 (1976). H. W. Richardson, J . R. Wasson, W. E. Halfield, and E. V. Brown, Inorg. C'lrmi. 15, 916 (1976).

Sec. 1x1

179

DEVELOPMENTS I N N A P H T H Y R I D I N E C H E M I S T R Y

IX. Medicinal Uses of Naphthyridines A large number of 4-0XO derivatives of the 1,s-naphthyridine ring system have been synthesized and screened for their antibacterial activity. In general, the active compounds are similar to the 1,Snaphthyridine derivative nalidixic acid.' 14- l 7 The following 7-substituted compounds have shown some antibacterial 18--122.

R' R'

= =

R ' = R ' = H"' Et, R' = CCI,. HO. C 0 2 H , R' H , R' = H. R' = -CH CH

R'

=

Et or binyl. R'

R1 =

C702R3

R'

R'

=

= Et1l5

n

N-NH""

Other 1,8-naphthyridines have demonstrated antithrombic activity(l62)' 2 3 and tranquilizer, muscle relaxant, and hypnotic properties ( 163),'24as well as anticonvulsant behavior (163124and 16412').Some other derivatives (165)

S. Carhoni, A . Da Settimo. D. Bertini, P. L. Ferrarini, 0. Livi, and I . Tonetti. Furniuco, E d &I. 28, 722 (1973). 115 S. Carhoni, A . Da Settimo. D. Bertini. P. L. Ferrarini. 0. Livi, and I Tonetti, Furniuco, Ed. Sci. 30, 185 ( 1975). ' I h E. M. Hawes. K . W. Hindmarsh. N. W . Hnmon. and B. J . A . Parkes, c'crn. J . Pharr17. Sri. 10. 45 (1975). C. Cotrel, C . Crisan. C. Jeanmart. and M. N . Messer, U.S. Patent 4,220,646 (l976j. ' I H S. Nishigaki, N. Mimshima, and K. Senga. Chrni. Phurni. Bull. 24, 1658 (1976). ' I " S. Nishigaki. M. Ichiha, S. Fukazawa. M. Kanahori. K. Shinomura, F. Yoneda. and K . Sengn, Uirtri. P h u m . Bull. 23. 3170 (1975). Dainippon Pharmaceutical Co. Ltd., J p i . Kokui T o k k ~ oKolio 81 46,811 (1981). 1 2 ' Dainippon Pharmaceutical Co. Ltd.. ./pi, Kokui Tokkvo Ko/io 81 05,484 (1981) [C'A 95, 42143 (l98lj]. "' Dainippon Pharmaceutical Co. Ltd.. Jpri. Kokui T o k k j o K O ~ C81J 05,485 (1981) [ ( ' A 95. 43 144 (198 I )] 1 2 3 1. Tonetti. D. Bertini. P. L. Ferrarini. 0. Livi, and M . Del Tacca, Furniuco, Ed. Sci. 31, 175 (1976). Chinese Academy of Medical Sciences. Shanghai. Yuo Hsueli Hsueh Pao 1.5, 630 (1980). I25 s c . arboni. A. Da Settimo, D. Bertini, P. L. Ferrarini, 0. Livi, and I . Tonetti, Furtnuco. Ed. Sci. 30, 237 (1975). 'I4

180

W I L L I A M w. P A U D L E R A N D ROGER M. SHEETS

[Sec. IX

0

i

C=0

R

have the property of inhibiting secretion of acid stomach.'26 A number of 4-amino-substituted lS-naphthyridines have been shown to have no significant antimalarial activity.' 2 7 Derivatives 166 and 167, however, have some antitubercular and antidysentery activity.' 2 8 0

The benzo-1,5-naphthyridine (168) has shown significant activity against chloroquine-resistant strains of Plasmodium fulciparum.' 24 0 x 0 derivatives

lZb

"*

A . A . Santilli and A. C. Scotese, European Patent Appl. 18,735 (1980) [CA 94, 175095 ( 1 98 I )] . J . F. Pilot and E. L. Stogryn, U S . NTIS, A D Rep. ADA023974, 49 (1975); Got:. Rep. Announce. Index ( U . S . )16, 66 (1976). R. M. Titkova, A. S. Elina, E. N. Padeiskaya, and L. M. Polukhina, Khini. Furtvi. Zh. 9, 10 (1975).

Sec. 1x1

DEVELOPMENTS I N N A P H T H Y R I D I N E CHEMISTRY

NH

R

=

181

-CH,-N

(168)

169, 170, and 171 have some insecticidal activity against Nephotethix

(170)

(16%

(1711

cincticeps and Museu derno~tica.'~~ N-oxides 172, 173 and 174 have some

(1721

( 173)

(174)

general antibacterial activity.' 30 In combination with /l-blocking agents, the tetrahydro- 1,6-naphthyridine (175) has some curative power in cardiac insufficiencies and infarction. 3'

P

(175)

lZy I3O

13'

I . Takeuchi and Y . Hamada. Clretn. Plfarm. Bull. 24, 1813 (1976). T. Takahnsi, Y. Hamada. 1. Takeuchi, and H. Uchiyama, Yukuyoku Zasshi 89, 1260 (1969). A. G . Sandox, Jpn. Kokai Tokkyo Kobo 80/8S, 519 (1980).

182

WILLIAM

w. PAUDLER A N D ROGER M . SHEETS

[Sec. X.A

X. Spectroscopic Properties

A. NUCLEARMAGNETIC RESONANCE SPECTRA The proton NMR spectra for the various naphthyridines have already been listed in Volume 2 of this series.' The 13C spectra either have since been reported or have since been obtained in the authors' laboratory.' 3 2 , 1 3 3 The data, along with the 13Cchemical shifts for quinoline and isoquinoline, are as follows (6 ppm, with respect to TMS at 0 ppm): 128.3

136.0

121.5

126.8

129'7

\

130. I

149.0 N

126.8

1203

127.9

153.1

130.5

150.9

I 19.9

140.4

152.6 150.0

119.6

138.0

125.0 138.9

120.0

137.0 125.5

I45

152.0

153.0 153.0

These chemical shifts are linearly dependent upon the total charge density on the carbons as calculated by self-consistent molecular orbital approximations. A. C . Boicelli, R. Daniel, A. Mangini, L. Lunazzi, and G . Placucci, J . C. S. Perkin I t , 1024 (1973). 1 3 3 The data for the 1.6- and 1,7-naphthyridines were obtained in the author's laboratory in saturated CH,CN solution with TMS as an external reference, 132

Sec. X.C]

DEVELOPMENTS I N NAPHTHYRIDINE CHEMISTRY

183

The 'H-NMR spectra of some of the n a p h t h y r i d i n e ~ ' ~ ~partially ~'~' oriented in liquid crystalline solvents have been obtained. Except in 1,snaphthyridine, in which X-ray diffraction analysis has shown that the two rings are not totally coplanar, the naphthyridines have a hydrogen-tohydrogen ratio identical to that of the corresponding hydrogens in pyridine. Thus, "fusion" of the pyridine rings to generate these naphthyridines does not affect the bond distances significantly.

B. VIBRATIONAL SPECTRA The use of infrared and Raman spectra of 1,6- and 1,s-naphthyridine has allowed the assignment of all 42 fundamental vibrations of these two ring systems. 37 A transferable valence force field has been developed and applied to the calculation of the out-of-plane vibrations of 1,5-, 1,6- 1,7-, l&, and 2,7-naphthyridines. 38

'

C. PHOTOELECTRON SPECTRA The high-resolution Me 584 photoelectron spectra of all of the naphthyridines have been r e ~ 0 r t e d . IIn~ ~the 1,s- and 1,s-naphthyridines, the first ionization involves an n-orbital, whereas in the other naphthyridines the n-orbital is involved. The observed potentials (eV) for n- and n-orbitals are 15naphthyridine: n : 9.20, 10.40, 1.20 n : 11.05 1,6-naphthyridine: n : 9.50, 9.90,0.40 n: 9.07, 11.10 1,7-naphthyridine: n : 9.30, 10.00, 0.70 n : 8.99, 11.14 1,s-naphthyridine: n : 9.20, 10.10, 0.90 n : 11.33 2,6-naphthyridine: n : 9.40, 10.00, 0.60 n : 8.87 2,7-naphthyridine: n : 9.35, 10.10,0.75 n : 8.98 C. L. Khetrapal and A. C. Kunwar, M u / . C'ryst. Liy. C I: ~.S/. 15, 363 (1972). C. L. Khetrapal. A. Saupe. and A. C. Kunwar, Mol. C r y s / . Liy. Cryst. 17, 121 (1972). 1 3 6 R. Daniel, L. Lunazzi, and C. A. Veracini, J . C. S. Perkin I I , 19 (1976). 1 3 ' J . T. Carrano and S. C. Wait, Jr.. J . Mol. Spec/rosc. 46, 401 (1973). 1 3 8 P. J . Chappeil and J . G . Ross, J . Mol. Spectrosc. 83, 192 (1977). D. M. W. Van den Ham and D. Van der Meer, Chern. Phys. Lcrr. 447 (1972). 134

135

184

WILLIAM w. PAUDLER AND ROGER M. SHEETS D.

[Sec. XI

OTHERSPECTRAL DATA

The polarized phosphorescence spectra of 1,5-naphthyridine and its d, isomer in durene and in durene-d,, mixed crystals have been obtained at 4°K. The lowest singlet state is at 27123 and 27200 cm- I , whereas the corresponding triplet state is at 23215 and 23288 cm-' for the proto and deutero compounds, respectively. The phosphorescence lifetime in durene crystals is 0.23 sec.140 The polarized spectra (4°K) of 1,5-naphthyridine and its d , isomer in naphthalene have also been examined. There is a difference between the spectra in naphthalene and in durene attributable to a decrease in the strong vibronic coupling that is considered to exist between the n + n* state and the higher n + n* states.',' The EPR spectrum of 1,6-naphthyridine in its lowest triplet state has been observed for solid solutions in single crystals of durene. The nuclear hyperfine structure allows an estimate of 0.14 to be made for the spin density on the nitrogen atom in the 1 - p o ~ i t i o n . l ~ ~

XI. Electrochemical Studies The 1,5-, 1,6-, 1,7-, 1,8-, 2,6-, and 2,7-naphthyridines have been electrochemically reduced to afford radicals that decay by a slow shift of hydrogen from nitrogen to carbon. 1 4 3 The resulting radicals dimerize readily. In acid media the first reduction step produces a radical-cation that is relatively stable in the 1,7- and 2,6-naphthyridines, whereas in 2,7-naphthyridine, the species is stable for a few minutes only. All of these radical-cations undergo a hydrogen shift from nitrogen to carbon to form unstable radicals that react with original cation radicals to form dimers. The process is an acid- or base-catalyzed first-order r e a ~ t i 0 n . l ~ ~ See chapter by van der Plas and co-workers, p. 95 of this volume, for a detailed discussion of these types of reactions.

G . Fischer, Chem. Phys. Left. 21, 305 (1973). A. D. Jordon, G. Fischer, and I . G. Ross, J . Mol. Spectrosc. 87, 345 (1981). 14' R. Bramley and B. J. McCool, Mol. Phys. 659 (1974). L. Roullier and E. Laviron, Elecfrochim. Acfa, 421 (1976). 144 L. Roullier and E. Laviron, Electrochim. Acta, 773 (1978). I4O

14'