1 H -Benzo[ de ]cinnolines: an interesting class of heterocycles

1 H -Benzo[ de ]cinnolines, 6 H -dibenzo[ de,g ]cinnolines and 1 H -indeno[6,7,1-def ]cinnolines are an interesting class of heterocyclic compounds related both to perimidines and to indazoles. This review covers the bibliography from their discovery in 1971 to the present days. Synthesis, reactivity and physico-chemical properties are reported in their integrity as well as theoretical calculations. Up to now, there are almost no biological studies.


Introduction
Compared to perimidines 2, [1][2][3] 1H-benzo[de]cinnolines 1 have been much less studied; they have a similar relationship than that between benzimidazoles 4 and indazoles 3 (Figure 1).In the Web of Science (WoS) 4 and ScienceDirect databases, the number of entries on perimidines (2 and derivatives) and benzo[de]cinnolines (1 and derivatives) is very different (Table 1); the same happens for benzimidazoles (4) and indazoles (3).This is partly due to the fact that o-phenylenediamine and 1,8diaminonaphthalene are cheap and convenient starting materials; note however that the difference is much larger in the 2/1 pair than in the 4/3 pair, as a consequence that benzo[de]cinnolines have been reported with different names, such as diazaphenalenes, peridazines, etc.The main contribution to both benzo[de]cinnolines and perimidines came from two groups of the Southern Federal University (Rostov-on-

Synthetic Methodologies
Simple 1H-benzo[de]cinnolines have been prepared by Lacy and Smith, Scheme 1(a) 5 and 1(b), 6 and by Aksenov, Aksenova et al., 7 Scheme 1(c).Using the methods represented in Scheme 1(a), a series of 1H-benzo[de]cinnolines have been prepared (Figure 2) by Mezheritskii et al., [8][9][10][11][12][13]   A totally different method has been reported by Chenoweth et al., 8 (cited in 9 ).A very complex and beautiful reaction, starting from 3,6-dimethyl-1,2,4,5-tetrazine and o-benzyne, allows to prepare compound 20, 4-methyl-6-phenyl-6H-dibenzo[de,g]cinnolin 10 They have prepared a large set of compounds, 20-32, and some dimethyl derivatives starting from 4,5-dimethyl-o-benzyne (Scheme 2).Here appears a first important difference between the two series of benzazoles and naphthoazines (Figure 3).In the case of the benzimidazole 4/perimidine 2 pair there is a perfect similitude, both presenting annular tautomerism of the class called degenerate or autotrope, indicating that both tautomers are identical. 11In the case of indazole 3, annular tautomers, 1H and 2H, are of different energy. 12,13In N-unsubstituted benzo[de]cinnolines 1, the transfer of the proton from N1 to N2 led to a zwitterionic compound (in blue in Figure 3).Analogously of all other compounds of Figure 3, the 1H-benzo[de]cinnoline have also CH tautomers that are much less stable because the aromaticity is totally or partially lost.A recent work 14 where theoretical B3LYP/6-311++G(d,p) calculations 15,16 were carried out using the Gaussian 16 set of programs 17 including general solvent effects (PCM method) 18 resulted in the data depicted in  The fact that the solvation by water leads to values roughly proportional to the gas values allow to discuss only the Erel gas values.
2. The zwitterion 2H although highly unstable compared with the 1H tautomer is still more stable than any CH tautomer.
3. The two most stable CH tautomers are 7H and 9H.The 9aaH-tautomer is very unstable due to the destruction of the aromaticity of two benzene rings.

Acidity and basicity
Figure 6 compares indazoles and benzo [de]cinnolines in what acidity and basicity are concerned.The anions are similar but the cations are different, the most stable protonated form of 6c is the C-protonated 8cH + (in red) and not the N2-protonated 6cH + (in blue).
In the cited work, 20 the structures of the twelve more stable cations were calculated.The 1,7H cation, 8cH + (in red), is the most stable both in the gas-phase and in water; the cation 6cH + occupies the 8 th place in order of stability.Here also there is a linear relationship between water and gas-phase stabilities: Erel water = (0.88±0.05)Erel gas, n = 12, R 2 = 0.964.Remember that 8cH + is the structure found experimentally (Scheme 1 and section 3.3).The different structures of 3H + and 8cH + prevent a comparison between the basicity of indazoles 3 and that of 1H-benzo[de]cinnolines 1. © ARKAT USA, Inc B3LYP/6-31G(d,p) calculations were carried out on some of the cations of compound 38, Figure 7. 13 The presence of the fourth ring in 1-ethyl-3-methyl-1H-indeno[6,7,1-def]cinnoline (38) modifies the preferred protonation site that now took place at carbon C6 (red).
Here again protonation on N2 leading to 38H + -H2 (blue) is highly disfavored.The structure of cation 38H + -H6 was established by 1 H NMR using the spectra in CF3CO2H and CF3CO2D. 133.Reactivity 3.3.1.On nitrogen atoms.Besides protonation (Section 3.2), we have reported in Scheme 1 an example of N-methylation, Scheme1(a), and two others of protonation, Scheme 1(b).According to Lacy et al., 6 protonation of 6a and 6c does not afford the cations 6aH + and 6cH + but structures protonated at C7, 8aH + and 8cH + , based on the 1 H NMR spectrum in CF3CO2H (Figure 8).Dorofeenko et al. demonstrated using 1 H NMR in CF3CO2H that 6-methoxy-1H-benzo[de]cinnoline 13 and its N-methyl derivative protonate on C7.21 Page 207 © ARKAT USA, Inc  (10) with methyl and propyl iodides as well as with benzyl chloride in alkaline medium leads to the formation of the corresponding both N-substituted (11, 39, 40) and 9-substituted cinnoline derivatives (41, 42) and also to the dimerization product (43) of the initial compound that corresponds to the formation of a N1-C9 bond (Scheme 3). 22IR and 1 H NMR spectra were used to establish the structures; remember that protonation takes place at C7 while the alkylation occurs at C9.

Nitration. Benzo[de]
cinnolines could be dissected into aniline or better 1-naphthylamine and a pyridine, 46 (Figure 10); the pyridine suppressed the electrophilic aromatic substitution 23 while aniline is nitrated in neutral conditions at ortho and para positions. 24,251-Naphthylamine is nitrated in position 4 (para). 26Isoquinoline is nitrated in positions 5 and 8. 27 This oversimplified model suggests that the nitration of benzo[de]cinnolines should occur predominantly at positions 7 and 9 and then 4. In the experimental Page 208 © ARKAT USA, Inc results reported below in Scheme 4 all the starting benzo[de]cinnolines have the position 6 protected.Positions 4, 5 and 8 will never be attacked by electrophilic reagents in the absence of donor substituents in position 6 or 7.The second paper 29 is much richer in results (Scheme 5) because nitration (61-64) competes with the oxidation of the C6C7 bond (38, 44, 63 and 64) and with the dimerization of the compound 10 to afford 43 (Scheme 5).
The last paper of the Mezheritskii group, 30 besides Schemes 6 and 7 results it reports theoretical calculations (Section 7).Starting from 59, five compounds are formed, 65 (oxidation and mononitration), 66 (loss of the acyl group and mononitration), 67 (loss of the acyl group and dinitration), 68 (dinitration) and 69 (loss of the acyl group and dinitration).The dihydro derivative 69 arises from the electrophilic addition of nitric acid to a double bond of 65 (Scheme 6).© ARKAT USA, Inc The results summarized in Scheme 7 39 are an extension to molecules having either H or different groups on N1 instead of an acetyl group, R = H (10), Me (11), Et (12), Pr (39), Bn (40)  The structure of 80 was first deduced from its 1 H NMR spectrum and afterwards definitely established by X-ray crystallography (Figure 11).The structure has not been deposited in the CSD.When position 1 is unsubstituted (N1H) acylation occurs in that position, Scheme 9; 32 in that way 1acyl derivatives 50, 59, 84 and 85 were prepared.

NMR spectroscopy
Regarding NMR spectroscopy, most publications report 1 H and 13 C data but only as peak lists without assignment of the signals.For simple molecules, experimental 1 H NMR data, chemical shifts and coupling constants, are reported in Table 3. Table 3. 1 H NMR chemical shifts (δ, ppm) and 1 H-1 H coupling constants (Hz)  * Also reported in ref. 5 but probably with a lower field apparatus (not given) than that used more recently (200 MHz).These values will be compared with the calculated chemical shifts (Section 6).Like most recent papers, the experimental part contains 1 H NMR [9][10][11][12][13]30,31,[37][38][39]44 and 13 C NMR 11,37,43 data. 15 N NMR data re however still scarce 37 (see Section 7).

Mass Spectrometry
In most cases, only the molecular ion is given, in some others just a list of fragments 13,37 while in other cases, the fragmentation mechanisms are discussed. 10-12

X-Ray Crystallography
A search in the Cambridge Structural Database 40 affords seven X-ray structures having the skeleton of 1Hbenzo[de]cinnolines.In Figure 12 we have shown all of them with the correlation of the compound numbers with the Cambridge Structural Database Refcodes.
FOSLAC 83 13 GETLIB (toluene) 43 11 GETLIB (toluene) 43 11 HIPPIF 36 29 HIPPOL 37 29 HUDTOR 20 14 XOTJUO 99 44 YEBHOF 91 43  11 In compound 99, the acenaphthene skeleton is almost planar whereas the heterocycle is somewhat distorted due to the proximity of the phenyl and the COCF3 moiety. 44The tricyclic system of 91 approaches planar configuration but the N1-ethyl and C9trifluoroactyl groups deviate from the corresponding ring planes. 43age 215 © ARKAT USA, Inc  Concerning 15 N-shifts, the only experimental data are those of reference 37 -they are consistent with the calculated values for 7a assuming that the reported data use ammonia as reference compound; we have transformed them to nitromethane reference by subtracting 380.2 ppm (Figure 13).Pozharskii and Malysheva calculated with the Hückel approximation, HMO, the electronic properties of some derivatives including 1 and 2 in 1970. 38Much later, in 2018, B3LYP/6-311++G(d,p) calculations were carried out on the complexes of HNO3 hydrogen bonded (HB) to different positions of compound 12 39 (Figure 14).The minimum has a bifurcated HB to N1 and C3.There is no evidence that these calculations would be useful to discuss the positions of nitration.Compound 1 together with other aza derivatives of phenalene, including perimidine 2, have been calculated with the (RO)B3LYP method, where RO stands for restricted open-shell, with the aim of designing stable radical molecular materials. 39inally, there are two papers by Tsoungas et al. in 2018 and 2021. 40,41on the aromaticity of 1Hbenzo[de]cinnolines and related heterocycles based on NICS calculations, compound 1 being the most aromatic. 43In the cited work of Tsoungas et al., 44 they analyzed the MEP to indicate that the reactivity of electrophiles towards 1 will occur at positions 3, 6 and 9, which is not the case.

Biological Properties
Actually there are no medicinal papers reporting biological properties of 1H-benzo[de]cinnolines.The only publication is due to Baell and Holloway, where a large series of substructures are included in the Supporting Information 42 Amongst these substructures, there is compound 1 with the code number 350 and the name naphth_a.mino_C(2).Since cinnolines belong to a class of heterocyclic compounds with rich pharmaceutical properties, 43 those of 1H-benzo[de]cinnolines deserve to be explored.

Figure 9 .
Figure 9. Structures of the oxidation products.

4 Figure 13 .
Figure13.Calculated for 7a and experimental15 N chemical shifts of 49 and 53 (δ, ppm).For the 7-nitro group of 53 there are two values in reference,37 one in the main text and the other in the experimental part.

Table 1 .
Number of references cited in the literature who isolated the intermediate hydrazones linking 5 to 6.

Me 7 Figure 8 .
Results of the protonation of benzo[de]cinnolines 6c and 6a.

Table 2
reports UV data of simple compounds.Page 213© ARKAT USA, Inc