Introduction

Functionalized quinolines and quinolinones have aroused strong interest of medicinal and pharmaceutical chemistry, on account of their diverse biological properties [1,2,3,4,5] such as, e.g., anti-inflammatory [6, 7], antimicrobial [8, 9], antioxidant [10], or antitumor [11,12,13,14] activity, which qualify them as excellent targets in therapeutic and medicinal research. The classical approaches for the quinoline ring construction involve inter alia Skraup [15] and Doebner–Miller [15, 16] or Pfitzinger [17, 18] methodology. Much attention has been devoted to developing these synthesis methods by using various carbonyl components [19,20,21,22].

The aim of the present work is an application of formyl naphthylamines in the construction of alkyl substituted benzo[h]- or benzo[f]quinolines B and quinoline-2(1H)-ones C via Friedländer condensation (Scheme 1). In this work, we want to shed some light on the mediated by urea/KOH synthesis of quinolines (Friedländer product) and on the specific formation of quinoline-2(1H)-ones (non-Friedländer product) from N-Boc 2-naphthylamine derivatives under basic conditions.

scheme 1

Results and discussion

We began our studies from the synthesis of carbamates 2, 7 (Scheme 2) being key compounds in the construction of the benzoquinoline skeleton. Their synthesis involved the reactions of the aryllithium species, generated from 2, 7 and t-BuLi or BuLi [23,24,25], with DMF and provided to corresponding formyl derivatives 2 and 7 with 60 and 50% yields, respectively. Next, derivative 2 subjected to bromination reaction with NBS in acetonitrile used as a solvent led to bromocarbamate 3 (75%). The subsequent cleavage of the Boc protecting group of 3 by treatment with HClaq afforded desired bromoamine 5 in 92% yield. In turn, the deprotection of N-Boc amine 2, under the same reaction conditions as above, gave aminoaldehyde 4 in good, albeit a bit lower 75% yield (Scheme 2).

scheme 2

On the other hand, attempts to obtain bromocarbamate 8, bromoamine 10, or amine 9 ended in failure (Scheme 2). In all cases, difficult to analyze mixtures were obtained, which did not contain target products 8 or 9 (1H NMR).

In the recent years, the indirect variant of Friedländer reaction has become a very popular wherein both electrophilic and/or nucleophilic components are generated in situ from appropriate primary and/or secondary alcohols [26,27,28]. However, the available in the literature examples often include the use of frequently expensive catalysts, e.g., RuCl2-(DMSO)4 [29,30,31], RhCl(PPh3)3 [32], and IrCl(cod)2 [33]. The alternative approach, described in last years, can be the aerial oxidation of alcohols to appropriate carbonyl compounds carried out with air access and without the use of catalyst [34,35,36,37,38,39].

With the formyl amines 4 and 5 in hand, we focused on the using of primary and secondary alcohols as a source of active carbonyl compounds, able to cyclize with 4 or 5 in the presence of urea and form benzo[h]quinolines 11 via Friedländer annulations [40,41,42,43]. During our earlier studies on the construction of benzo[h]quinazolin-2(1H)-ones from 1-naphthylamine derivatives with the use of urea as a condensing agent, we have observed that heating of the 2-formyl-1-naphthylamine with urea/KOH in alcohol solution can led to the formation of benzo[h]quinoline skeleton. We began our experiments by investigating the reaction of 5 with ethanol, in the presence of 1 equiv. KOH (Table 1, entry 1). Surprisingly, the cyclization process to 11e using these conditions did not take place. With the increase of amount of KOH to 7 equiv., the yield of benzoquinoline 11e was improved but an influence was not spectacular (6%, Table 1, entries 1–3). These results are in partial contrast with those presented in the literature [34].

Table 1 Optimization of reaction conditions
figure b
Full size table

It turned out that the addition of urea had a significant impact on the acceleration as well as the yield of the condensation process (Table 1, entries 4–6). The use of urea and base in the molar ratio 3:7 gave 11e in a satisfactory 45% yield. In this case, a small amount of amino benzoquinazoline 12b (10% yield) was also isolated from post-reaction mixture. The formation of 12b can be an effect of the competing reaction of 5 with urea under basic conditions (similarly to the first stage of the Biginelli reaction) [44,45,46,47]. It is notable that the yield of compound 12b was, to some extent, dependent on an amount of urea (Table 1, entries 4–6). On the other hand, the use of too little amount of KOH (20 mol%, Table 1, entry 7) did not give any reaction product. We found that the reaction worked well not only with EtOH but also with secondary alcohols (i-PrOH). The condensation of 5 with i-PrOH, using urea and KOH in the molar ratio 3:7, led to benzoquinoline 11g with a good yield (60%, Table 1, entry 8). Similarly, as in earlier reactions (Table 1, entries 5, 6), the formation of byproduct 12b (25%) was also observed. The quantity reduction of amount of urea gave better results. The compound 11g was produced in 68% yield as the sole reaction product (Table 1, entries 9, 10). Similarly, as in the case of using ethanol (Table 1, entry 3), the condensation of 5 with i-PrOH performed in the absence of urea was ineffective (Table 1, entry 11), and resulted in obtaining 11g in only 6% yield. Also, the application of other solvents, such as 1,4-dioxane or DCM, was inefficient (Table 1, entries 12, 13). Finally, we conducted the reaction between 5 and i-PrOH under an argon atmosphere (Table 1, entry 14). To our surprise, the cyclization ran with a similar rate and yield like under air conditions (11g, 62% yield, Table 1, entry 14). Increase in the amount of urea led to a little decrease in yield of 11g (60%), but substantial increase in the formation of 12b (33%) (Table 1, entry 15).

The mechanism of the formation of benzoquinolines 11 in the reaction between 5 and primary/secondary alcohols, in the presence of urea/KOH, is not clear, yet. However, based on the literature reports [48, 49] and results mentioned above (Table 1), we suppose that the first step includes the conversion of alcohols into corresponding carbonyl compounds. To obtain the additional information that may help to understand this type of conversion, some variants of reaction based on the condensation of 5 with acetone were checked (Table 2, entries 1–5).

Table 2 Confirmation of reaction conditions
figure c
Full size table

As can be seen from Table 2, the condensation process of 5 with acetone did not take place only in the presence of urea (Table 2, entries 1, 2). The use of 1 equiv. of urea and 25%mol of KOH (Table 2, entry 4) in comparison to reaction without the use of urea (40%, Table 2, entry 3) gave better result in yield of 11g (60%). These observations can confirm that urea anion generated by the action of KOH in polar solvents (alcohols) is an active intermediate can mediate the cyclization process (Table 2, entry 4). Information included in Tables 1 and 2 allow to conclude that urea anion can play dual role acting as additional base and nucleophile [50]. Its nucleophilic activity is strongly visible especially during the reaction of amino ketone 5 with alcohols (urea and KOH excess), where amino benzoquinazoline 12b is produced as side product (Table 1, entries 6, 8, 14, 15).

The probable mechanism for the construction of benzoquinazolines using formylamines and alcohols in the presence of urea was presented below (Scheme 3). We think that the proposed mechanism is not the only one possible for these transformations, and it can operate parallel with, e.g., the classical pathway presented in the literature for Friedländer reaction under basic conditions [51,52,53,54].

scheme 3

Despite the fact that our initial experiments performed under air atmosphere were not efficient (Table 1, entries 1–3), it cannot entirely omit the path involved aerial oxidation of I (Scheme 3, air [O] path) via the formation of appropriate hydroperoxides, and next elimination of H2O2, as it was suggested in the literature [34]. Furthermore, also an alternative oxidation pathways of I to II by, e.g., H2O2 [34, 55,56,57] or the Oppenauer oxidation of I [58,59,60] [relevant notably under anaerobic conditions (argon)], can have an importance. The observed increase in the reaction yields upon the addition of urea, suggest that, it facilitates the formation of quinolines. Our observations suggest that urea or its anion can participate in the oxidation of I to II acting as a hydride acceptor and also has an influence on the reaction between formylamine III and carbonyl component II through, e.g., the hydrogen bonds formation (between urea anion and oxygen atom) activating carbonyl group to nucleophilic attack (Scheme 3, IV, V) [61]. On the other hand, nitrogen atoms of urea anion can also act on the α hydrogens of V or VII through the electronegative pull and the electron density increase at the carbon atom, making easier nucleophilic attack on the carbonyl carbon atom [62].

With the best conditions in hand (Table 1, entry 6, method A, for primary alcohols; entry 10, method B, for secondary alcohols), next we synthesized series of benzoquinoline derivatives 11 (Scheme 4). The cyclization of non-brominated derivative 4 with EtOH or i-PrOH led to the formation of corresponding benzoquinolines 11a and 11b in moderate yields, 40 and 33%, respectively (method A). Beyond these target compounds, just like it was described for the reaction of 5 with ethanol, some amounts of amino derivative 12a (3–8%) and also substrate 4 (10–30%) were achieved. In turn, the reaction of n-propyl alcohol (method A) with 5 gave 3-methylbenzoquinoline (11f) in much better 65% yield. In this case a small quantity of aminobenzoquinazoline 12b (about 4%) was also isolated. Good results were achieved for the reaction between 5 and cyclopentanol (method B), and in effect, the tetracyclic derivative 11h was formed in 64% yield. On the other hand, when unsymmetrical alcohol (sec-butanol) was employed to the condensation with 4 or 5, the reaction proceeded with the formation of mixtures of 2-substituted and 2,3-disubstituted benzoquinolines 11c, 11d and 11i, 11j, however, with a low regioselectivity. (The molar ratios of 11c/11d and 11i/11j were 0.6:1.)

scheme 4

Unexpectedly, condensation reactions of 4 or 5 performed in ethanol, propan-1-ol, or butan-2-ol, provided except 11, also 2-methylbenzoquinoline or 6-bromo-2-methylbenzoquinoline in 1–7% yields. Both 2-methylquinolines were identified by NMR, HRMS spectroscopy, and by comparison of their NMR spectra with the data recorded for products 11b, 11g and also reported in the literature [63, 64]. The formation of unusual products is sometimes observed in Friedländer reaction [65, 66].

In the next step, bromobenzoquinolines 11e, 11f, 11h were subjected to copper(II)-mediated N-formamidation reaction [67]. The couplings of 11e, 11f, 11h with formamide were carried out without the use of ligand, in the presence of CuSO4·5H2O/K2CO3. (Benzo[h]quinolin-6-yl)formamides 13a–13c were obtained in 62–85% yields (Scheme 5). The spectroscopic analysis of coupling products 13 indicated the occurrence the mixture of rotamers in the ratio 2.2:1 (1H NMR).

scheme 5

Obtained values of proton coupling constant of the NHCHO moiety (e.g., for 13c: ~ 10.2 Hz for trans, ~ 1.2 Hz for cis) led to the conclusion that formamide benzoquinolines general exist in the mixture of two rotamers favoring the Z form (Scheme 5).

The second part of our work was dedicated to the synthesis of alkyl benzoquinolines via standard Friedländer reaction conditions using dicarbonyl compounds, e.g., ethyl acetoacetate, acetylacetone, and ethyl benzoylacetate (Scheme 6). Because of using ethanol as a solvent and the possibility of the course of the competitive condensation process, KOH was replaced with weaker base K2CO3. When amino aldehyde 5 was treated with 1 equiv. of ethyl acetoacetate and 1 equiv. of base in ethanol as a solvent, the desired product 14a was received in moderate 25% yield (Scheme 6). In turn, when the amount of ethyl acetoacetate was increased up to 10 equiv. target benzoquinoline 14a was effectively produced and finally obtained in an excellent 85% yield. Under similar reaction conditions, aminoaldehyde 5 condensed with acetylacetone gave acetylquinoline 14b in 68% yield. The structures of newly synthesized quinolines 14a, 14b were confirmed by NMR spectroscopy analyses. In the 13C NMR spectra of 14a and 14b characteristic signals corresponding to carbon atoms of C=O group of COOMe and Ac substituent were observed at 166.5 and 199.9 ppm, respectively and signals of methyl carbon atoms at 2 position were detected at 26.0 ppm. The obtained NMR chemical shift data are in accordance with the literature ones published for 2,3-disubstituted quinolines [68,69,70] containing ester (166–170 ppm) or acetyl (199–207 ppm) moiety placed at 3 position and methyl group at 2 position (23–26 ppm).

scheme 6

Previously, we have noticed that N-Boc-2-naphthylamine derivatives contrary to N-Boc-1-naphthylamine are ready for cleavage of the Boc protecting group under basic conditions [23,24,25]. This fact has prompted us to extend the presented methodology and use the carbamate 7 in the cyclization reaction, without a prior deprotection (Scheme 6). As we observed, when compound 7 was treated with ethyl acetoacetate (10 equiv.) in the presence of K2CO3 (1 equiv.; Scheme 6, 15 h, 70 °C), similarly as in the case of 5, the target product was not formed. Furthermore, the formation of amine 9 was also not observed. In 1H NMR spectra of post-reaction mixtures indicated only signals belonging to unreacted carbamate 7. The increase in an amount of K2CO3 from 1 to 5 equiv. led, after 40 h to the mixture of 9 and 7 in the molar ratio 0.84:1 (1H NMR). With evidence to support our ideas in hand, we used 5 equiv. of K2CO3 suspended in ethanol to the condensation of 7 with ethyl acetoacetate.

Similarly as for 5 and in accordance with generally accepted course of the Friedländer reaction and commonly available literature reports, from the reaction of 7 with ethyl acetoacetate (Scheme 6), we expected to receive ester 15a. The analysis of 1H and 13C NMR spectra unexpectedly showed no signals which could be assigned to the ester group. Instead, the 1H NMR spectrum has shown the presence of two characteristic signals at 2.68 ppm and 12.52 ppm, which could indicate the occurrence of methyl group and labile hydrogen atom (–OH or –NH). One may wonder about the possibility of the formation of acid 16a via hydrolysis of ester 15a [68]. The formation 2-methylquinoline-3-carboxylic acids under Friedländer reaction conditions is described in literature [71, 72] and their examples were presented in Table 3 (compounds 19 [73], 20 [74]). It is an important to say here, that in each case, it was taken for granted that the formation of compounds 19a, 19b, and 20 is a consequence of the hydrolysis of corresponding ethyl esters produced under Friedländer annulations [71,72,73,74].

Table 3 13C NMR data
Full size table

In the 13C NMR spectrum of the reaction product of 7 and ethyl acetoacetate (Scheme 6), our attention was drawn to two carbon atom signals at 197.1 and 160.4 ppm. Very similar 13C NMR peaks were described for compounds 19a and 19b (19a: 197.3 and 160.4 ppm; 19b: 203.5 and 159.5 ppm) [73]. In turn, in the 13C NMR spectrum of acid 20 the most downfield carbon signal was situated at 169.0 ppm and was assigned to carbon atom of –COOH group [74], which seems more likely. It is known, that typical range of chemical shifts for carbon of –COOH group in aromatic acids is between 159–170 ppm, while for carbons of –CHO or –COR groups they are usually observed above 190 ppm [75,76,77,78]. The comparison of 13C NMR spectroscopic data of the obtained product with compounds 14, 19, and 20 and also with signals from spectra of quinolinones 21 [79, 80] and 22 [79,80,81] (Table 3), led to the conclusion that the reaction of 7 with ethyl acetoacetate (10 equiv.) in the presence of base (5 equiv.) gives benzoquinolinone 17a (30%). To our delight, increase an amount of base up to 10 equiv. allowed to achieve 17a in 85% yield. By contrast, the reaction of 7 with ethyl benzoylacetate led to formation of 17b in 65% yield under the same reaction conditions. In this case, similarly to 17a, the 13C NMR spectrum showed specific peaks located at 194.9 ppm (keton) and 160.8 ppm (lactam) (Table 3). On the other hand when N-Boc derivative 3 (Scheme 2) was treated with ethyl acetoacetate (10 equiv.) in the presence of 10 equiv. K2CO3 in ethanol, desired product was not obtained. After reaction unchanged substrates were only isolated, which prove that 3 under these conditions did not undergo cleavage of protecting group and consequently amine 5, necessary to completion of the reaction is not formed. Besides, the reaction of aminoaldehyde 5 with ethyl acetoacetate (10 equiv.) and K2CO3 (10 equiv.) in ethanol leads to ester 14a as the only product (72%, Scheme 6).

In our opinion, the possible mechanism of the formation of compounds 17 includes 1) in the first step, in situ formation of amine 9 in the presence of base and next 2) the reaction of 9 with ketoester leading to the intermediate 18 [82], which under basic conditions undergoes intramolecular cyclization yielding quinolinones 17 (Scheme 6) [74, 79,80,81, 83]. This transformation to some extent resembles the Niementowski-type cyclization reaction, described in literature [84].

Conclusion

In summary, we presented the method for the synthesis of alkyl benzoquinolines via KOH/urea-mediated indirect Friedländer reaction of amino naphthalene aldehydes with aliphatic alcohols. We have found that under aerial as well as inert atmosphere the method involving the use of urea may be employed and lead to desired benzoquinolines with good yields. In addition, we have briefly discussed the different behavior of 1- and 2-naphthylamine derivatives during the condensation with dicarbonyl compounds containing active methylene moiety. In result either benzo[h]quinoline or benzo[f]quinolinone derivatives were obtained in also good yields as the major products. In copper(II) catalyzed N-aryl formamidation reaction, several formamide benzoquinolines have been also synthesized. There is no doubt that new formamide benzoquinolines may constitute excellent starting material to further modifications.

Experimental

Melting points were determined on a Boetius hot stage apparatus. 1H, 13C NMR spectra were recorded on a Bruker Avance III spectrometer at 600 MHz and 150 MHz. The residual CDCl3 or DMSO-d6 signal was used for reference (CDCl3 at 7.26 ppm or DMSO-d6 at 2.54 ppm for 1H NMR and CDCl3 at 77.0 ppm or DMSO-d6 at 39.0 ppm for 13C NMR). IR spectra were recorded on a Nicolet Nexus FT-IR spectrometer. LC/HRMS analyses were performed using an Agilent Technologies HPLC 1290 coupled to an Agilent Technologies 6550 Accurate Mass Q-TOF LC–MS mass spectrometer equipped with a JetStream Technology ion source housed in the Department of Pathophysiology, Medical University of Lublin, Poland. Internal mass calibration was enabled; reference ions of m/z = 121.0509 and 922.0098 were used. The analytical thin layer chromatography tests (TLC) were carried out on Sigma-Aldrich (Supelco) silica gel plates (Kiselgel 60 F254, layer thickness 0.2 mm) and the spots were visualized using UV lamp. The flash column chromatography purifications were performed on Fluka silica gel (Silica gel 60, 0.040–0.063 mm). t-Butyllithium or butyllithium solutions (Aldrich) were each time titrated before use [85]. All reactions with organolithium compounds were performed under an argon atmosphere using standard Schlenk technique. Diethyl ether was distilled from sodium benzophenone ketyl prior to use. Commercially available solvents and reagents: N,N-dimethylformamide (DMF), N-bromosuccinimide (NBS), EtOH, PrOH, i-PrOH, butan-2-ol, cyclopentanol, urea, acetylacetone, ethyl acetoacetate, ethyl benzoylacetate, CuSO4·5H2O, and formamide were purchased from Sigma-Aldrich and were used without further purification. N-Boc-2-naphthylamine (1) and tert-butyl (1-bromonaphthalen-2-yl)carbamate (6) were prepared by a procedure similar to that in the literature [23,24,25].

General procedure for the preparation of 1-formylnaphthalene and 2-formylnaphthalene carbamates 2 and 7

Under argon, to a solution of N-Boc 1-naphthylamine (1, 2.1 mmol) or tert-butyl (1-bromonaphthalen-2-yl)carbamate (6, 1.55 mmol) in 20 cm3 dry Et2O at -20 °C, t-BuLi solution in pentane or BuLi solution in hexanes (2.2 equiv.) was added dropwise. The reaction mixture was stirred at this temperature for 2 h. Next, a solution of DMF (1 equiv.) at − 20 °C was added dropwise and whole was further stirred for 2 h (− 20 °C). After this time to the reaction mixture 20 cm3 saturated solution of NH4Cl was added. The water layer was separated and extracted subsequently with Et2O (3 × 20 cm3). The organic phase was dried over MgSO4 and concentrated to dryness. The crude material was separated by flash chromatography.

tert-Butyl (2-formylnaphthalen-1-yl)carbamate (2, C16H18NO3)

Beige solid (342 mg, 60% yield); Rf = 0.16 (hex/AcOEt, 10:1); m.p.: 123–125 °C; IR (KBr): \(\bar{\nu }\) = 3275, 2999, 2983, 2968, 2870, 1720, 1690 cm−1; 1H NMR (CDCl3): δ = 10.27 (s, 1H, CHO), 8.22–8.05 (m, 2H, NH, Ar–H), 7.87 (d, J = 7.8 Hz, 1H, Ar–H), 7.84–7.78 (m, 2H, Ar–H), 7.66–7.56 (m, 2H, Ar–H), 1.53 (s, 9H, Boc–Me) ppm; 13C NMR (CDCl3): δ = 192.4, 154.5, 138.0, 137.0, 129.3, 128.9, 128.4, 126.9, 126.6, 126.0, 125.7, 125.2, 81.7, 28.4 ppm.

tert-Butyl (1-formylnaphthalen-2-yl)carbamate (7, C16H18NO3)

Lemon solid (210 mg, 50% yield); Rf = 0.44 (PE/AcOEt, 10:1); m.p.: 107–109 °C; IR (KBr): \(\bar{\nu }\) = 3433, 2983, 2935, 1723, 1650 cm−1; 1H NMR (CDCl3): δ = 11.54 (br s, 1H, NH), 11.01 (br s, 1H, CHO), 8.73 (d, J = 9.3 Hz, 1H, Ar–H), 8.43 (d, J = 8.6 Hz, 1H, Ar–H), 8.02 (d, J = 9.3 Hz, 1H, Ar–H), 7.83 (d, J = 8.0 Hz, 1H, Ar–H), 7.64–7.58 (m, 1H, Ar–H), 7.48–7.42 (m, 1H, Ar–H), 1.57 (s, 9H, Boc–Me) ppm; 13C NMR (CDCl3): δ = 192.2, 153.2, 143.8, 137.5, 134.0, 129.5, 129.0 (2C), 124.9, 119.7, 118.2, 112.0, 81.4, 28.4 ppm.

tert-Butyl (4-bromo-2-formylnaphthalen-1-yl)carbamate (3, C16H17BrNO3)

To a solution of the appropriate carbamate 2 (2.5 mmol) in 15 cm3 acetonitrile at 0 °C, a solution of NBS (3.0 mmol) in 10 cm3 acetonitrile was added dropwise. Next, the resulting mixture was allowed to warm to ambient temperature. The reaction was continued under these conditions until TLC analysis of the reaction mixture indicated the absence of starting material 2 (4–6 h). After the reaction acetonitrile was removed under reduced pressure and the bromo derivative 3 was separated by flash chromatography. Yellow solid (657 mg, 75% yield); Rf = 0.32 (hex/AcOEt, 5:1); m.p.: 165–168 °C; IR (KBr): \(\bar{\nu }\) = 3354, 2969, 2935, 2852, 1701, 1684 cm−1; 1H NMR (CDCl3): δ = 10.19 (s, 1H, CHO), 8.30–8.26 (m, 1H, Ar–H), 8.16–8.10 (m, 2H, Ar–H), 7.87 (s, 1H, NH), 7.75 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H, Ar–H), 7.66 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H, Ar–H), 1.52 (s, 9H, Boc–Me) ppm; 13C NMR (CDCl3): δ = 190.6, 154.3, 137.5, 135.2, 130.7, 130.3, 129.0, 128.0, 127.7, 126.8, 125.4, 121.1, 82.1, 28.3 ppm.

Procedure for the preparation of amino aldehydes 4, 5

To a mixture of HClaq (0.5 M) and 1,4-dioxane in the ratio 2:3 (v/v) at room temperature, aldehyde (2 or 3, 1.6 mmol) was added. The resulting mixture was then heated at 60 °C (oil bath) for about 3–4 h, until TLC analysis indicated the completion of the reaction. Then all the volatile materials were removed under reduced pressure and 15 cm3 water was added to residue. The mixture was adjusted to pH 7–8 with saturated NaHCO3 and extracted with chloroform (3 × 20 cm3). The combined extracts were dried over MgSO4 and then concentrated. A crude residue was subjected to column chromatography to give amines 4 and 5.

1-Aminonaphthalene-2-carbaldehyde (4) [86]

Yellow solid (205 mg, 75% yield); Rf = 0.3 (hex/AcOEt, 5:1); m.p.: 99–101 °C (lit. [86], 97–100 °C).

1-Amino-4-bromonaphthalene-2-carbaldehyde (5, C11H9BrNO)

Yellow solid (368 mg, 92% yield); Rf = 0.32 (hex/AcOEt, 5:1); m.p.: 165–168 °C; IR (KBr): \(\bar{\nu }\) = 3306, 2751, 1637 cm−1; 1H NMR (CDCl3): δ = 9.89 (s, 1H, CHO), 8.22–8.19 (m, 1H, Ar–H), 7.93 (d, J = 8.4 Hz, 1H, Ar–H), 7.76 (s, 1H, Ar–H), 7.75–7.71 (m, 1H, Ar–H), 7.60–7.55 (m, 1H, Ar–H), 7.36 (s, 2H, NH2) ppm; 13C NMR (CDCl3): δ = 192.5, 148.7, 134.9, 132.9, 130.9, 128.3, 126.5, 124.1, 122.3, 113.3, 108.4 ppm.

General procedure for the preparation of benzoquinolines 11

The reaction was carried out in the open air conditions (vessels with air supply). To a mixture of amino aldehyde (4 or 5, 0.2 mmol) and KOH (7 equiv. in case of the reaction with primary alcohols or 1 equiv. with secondary alcohols) in 10 cm3 of appropriate alcohol, urea was added (3 equiv. for reaction with primary alcohols or 1 equiv. with secondary alcohols). The whole mixture was stirred and heated at 75 °C (oil bath) until TLC analysis indicated the absence of substrate 4 or 5. After the reaction was completed, alcohol was removed under reduced pressure and 15 cm3 water was added to residue. The mixture was adjusted to pH 7–8 with 0.5 M HCl and then extracted with DCM (3 × 20 cm3). The combined extracts were dried over MgSO4 and concentrated, and a crude mixture was purified by flash chromatography to give desired benzoquinoline 11.

Benzo[h]quinoline (11a) [87]

Light orange solid (14 mg, 40% yield); Rf = 0.54 (hex/AcOEt, 5:1); m.p.: 46–47 °C (lit. [88], 49–51 °C).

2-Methylbenzo[h]quinoline (11b) [89, 90]

Light orange solid (11 mg, 33% yield); Rf = 0.68 (hex/AcOEt, 5:1); m.p.: 38–39 °C (lit. [90], 47–48 °C).

Mixture of 2-ethylbenzo[h]quinoline (11c) [91] and 2,3-dimethylbenzo[h]quinoline (11d) [92, 93]

Light yellow solid (36 mg, 38% yield (11c) and 60% yield (11d); Rf = 0.6 (for both compounds; hex/AcOEt, 5:1).

6-Bromobenzo[h]quinoline (11e) [94, 95]

Beige solid (23 mg, 45% yield); Rf = 0.84 (hex/AcOEt, 1:1); m.p.: 105–107 °C (lit. [95], 109–111.5 °C).

6-Bromo-3-methylbenzo[h]quinoline (11f, C14H11BrN)

Yellow solid (35 mg, 65% yield); Rf = 0.64 (hex/AcOEt, 5:1); m.p.: 114–115 °C; IR (KBr): \(\bar{\nu }\) = 2924, 2852, 1595 cm−1; 1H NMR (CDCl3): δ = 9.31–9.27 (m, 1H, Ar–H), 8.84 (d, J = 2.0 Hz, 1H, Ar–H), 8.34–8.29 (m, 1H, Ar–H), 7.99 (s, 1H, Ar–H), 7.86–7.84 (m, 1H, Ar–H), 7.79–7.75 (m, 2H, Ar–H), 2.56 (s, 3H, Me) ppm; 13C NMR (CDCl3): δ = 150.9, 144.1, 134.3, 132.7, 132.2, 131.7, 128.8, 128.7, 128.0, 127.6, 126.6, 124.6, 122.7, 18.8 ppm.

6-Bromo-2-methylbenzo[h]quinoline (11g) [96]

Light yellow solid (35 mg, 68% yield); Rf = 0.62 (hex/AcOEt, 5:1); m.p.: 92–94 °C (lit. [96], 101–103 °C).

5-Bromo-9,10-dihydro-8H-benzo[h]cyclopenta[b]quinoline (11h, C16H13BrN)

Yellow solid (38 mg, 64% yield); Rf = 0.45 (hex/AcOEt, 5:1); m.p.: 105–107 °C; IR (KBr): \(\bar{\nu }\) = 3030, 2959, 2920, 2855, 1596 cm−1; 1H NMR (CDCl3): δ = 9.37–9.31 (m, 1H, Ar–H), 8.32–8.26 (m, 1H, Ar–H), 7.98 (s, 1H, Ar–H), 7.83–7.81 (m, 1H, Ar–H), 7.76–7.72 (m, 2H, Ar–H), 3.26–3.21 (m, 2H, CH2), 3.15–3.11 (m, 2H, CH2), 2.30–2.21 (m, 2H, CH2) ppm; 13C NMR (CDCl3): δ = 167.0, 145.0, 136.9, 132.7, 131.7, 129.9, 129.2, 128.6, 127.6, 127.4, 125.6, 124.7, 121.2, 35.0, 30.8, 23.8 ppm.

Mixture of 6-bromo-2-ethylbenzo[h]quinoline (11i, C15H13BrN) and 6-bromo-2,3-dimethylbenzo[h]quinoline (11j, C15H13BrN)

Yellow solid (43 mg, 30% yield (11i) and 54% yield (11j)); Rf = 0.78 (for both compounds; hex/AcOEt, 1:1); 1H NMR (CDCl3): δ = 9.44–9.40 (m, 1H, Ar–H), 9.36–9.32 (m, 1H, Ar–H), 8.34-8.27 (m, 2H, Ar–H, Ar–H), 8.01 (s, 1H, Ar–H), 7.98-7.96 (m, 1H, Ar–H), 7.96 (s, 1H, Ar–H), 7.80–7.72 (m, 5H, 3Ar–H, 2Ar–H), 7.40 (d, J = 8.5 Hz, 1H, Ar–H), 3.09 (q, J = 7.6 Hz, 2H, CH2), 2.76 (s, 3H, Me), 2.48 (s, 3H, Me), 1.49 (t, J = 7.6 Hz, 3H, CH2Me) ppm; 13C NMR (CDCl3): δ = 163.2, 158.0, 145.4, 143.6, 135.2, 134.7, 132.7, 132.5, 132.1, 131.7, 131.3, 128.9, 128.8, 128.5, 128.5, 127.7, 127.6, 127.4, 125.6, 125.0, 124.9, 124.6, 124.6, 121.9, 121.4, 121.3, 32.3, 23.9, 19.6, 13.7 ppm.

Benzo[h]quinazolin-2-amine (12a, C12H10N3)

White solid (1.2–3 mg, 3–8% yield); Rf = 0.07 (hex/AcOEt, 5:1); m.p.: 194–196 °C; IR (KBr): \(\bar{\nu }\) = 3336, 3184, 2926, 2854, 1651 cm−1; 1H NMR (CDCl3): δ = 9.06 (d, J = 8.0 Hz, 1H, Ar–H), 8.97 (s, 1H, Ar–H), 7.86–7.82 (m, 1H, Ar–H), 7.73–7.69 (m, 1H, Ar–H), 7.68–7.63 (m, 1H, Ar–H), 7.55 (s, 2H, Ar–H), 5.28 (s, 2H, NH2) ppm; 1H NMR (DMSO-d6): δ = 9.05 (s, 1H), 8.91 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.77–7.71 (m, 1H), 7.69–7.63 (m, 2H), 7.58–7.54 (m, 1H), 6.93 (s, 2H, NH2) ppm; 13C NMR (CDCl3): δ = 161.1, 160.7, 152.6, 136.1, 130.0, 129.4, 128.0, 126.8, 124.8, 124.2, 123.6, 117.5 ppm.

6-Bromobenzo[h]quinazolin-2-amine (12b, C12H9BrN3)

Light orange solid (2.2–14 mg, 4–25% yield); Rf = 0.5 (hex/AcOEt, 1:1); m.p.: 223–225 °C; IR (KBr): \(\bar{\nu }\) = 3479, 3285, 3166, 2925, 2853, 1623, 1606 cm−1; 1H NMR (DMSO-d6): δ = 9.06 (s, 1H, Ar–H), 9.00 (d, J = 8.0 Hz, 1H, Ar–H), 8.16 (d, J = 8.2 Hz, 1H, Ar–H), 8.13 (s, 1H, Ar–H), 7.92–7.88 (m, 1H, Ar–H), 7.80–7.75 (m, 1H, Ar–H), 7.13 (s, 2H, NH2) ppm; 13C NMR (DMSO-d6): δ = 161.8, 160.4, 151.1, 133.3, 130.9, 129.9, 127.7, 127.3, 126.8, 124.4, 116.5, 114.6 ppm.

General procedure for the preparation of formamide derivatives of benzoquinoline 13 via copper-mediated N-formamidation

Benzoquinoline 11e or 11f or 11h (0.18 mmol), CuSO4·5H2O (2.5 equiv.) and K2CO3 (5 equiv.) suspended in 15 cm3 formamide was heated with magnetic stirring at 140 °C (oil bath) for about 25 h until TLC analysis indicated the absence of starting benzoquinoline. After cooling to the reaction mixture, 20–30 cm3 water with ice was added and allowed to stand for 30 min. After this time mixture was extracted with DCM. The combined extracts were dried over MgSO4 and concentrated to give crude product 13 which was next subjected to flash chromatography.

N-(Benzo[h]quinolin-6-yl)formamide (13a, C14H11N2O)

White solid (27 mg, 70% yield); Rf = 0.42 (hex/AcOEt, 1:2); m.p.: 214–216 °C; IR (KBr): \(\bar{\nu }\) = 3434, 3228, 3044, 2928, 2890, 1683, 1658 cm−1; 1H NMR (DMSO-d6; mixture of rotamers in the ratio 2.2:1*): δ = 10.61 (d, J = 10.0 Hz, NH*), 10.44 (br s, 1H, NH), 9.33–9.23 (m, 2H, Ar–H, Ar–H*), 8.99–8.90 (m, 2H, Ar–H, Ar–H*), 8.73 (d, J = 10.0 Hz, 1H, CHO*), 8.59 (s, 1H, CHO), 8.42 (s, 1H, Ar–H), 8.40–8.34 (m, 2H, Ar–H, Ar–H*), 8.31–8.23 (m, 2H, Ar–H, Ar–H*), 7.87–7.78 (m, 5H, 2Ar–H, 3Ar–H*), 7.70–7.63 (m, 2H, Ar–H, Ar–H*) ppm; 13C NMR (DMSO-d6): δ = 163.8, 160.6, 148.5, 148.4, 143.4, 135.6, 135.5, 131.5, 131.4, 131.3, 128.4, 128.4, 127.6, 127.2, 125.8, 124.3, 124.1, 122.9, 122.6, 121.9, 116.8, 115.8 ppm.

N-(3-Methylbenzo[h]quinolin-6-yl)formamide (13b, C15H13N2O)

White solid (35 mg, 85% yield); Rf = 0.24 (hex/AcOEt, 1:1); m.p.: 221–223 °C; IR (KBr): \(\bar{\nu }\) = 3435, 3193, 3101, 2948, 2919, 2876, 1701 cm−1; 1H NMR (DMSO-d6; mixture of rotamers in the ratio 2.2:1*): δ = 10.58 (d, J = 10.1 Hz, 1H, NH*), 10.40 (br. s, 1H, NH), 9.27–9.19 (m, 2H, Ar–H, Ar–H*), 8.83–8.77 (m, 2H, Ar–H, Ar–H*), 8.70 (d, J = 10.1 Hz, 1H, CHO*), 8.57 (br. s, 1H, CHO), 8.33 (br. s, 1H, Ar–H), 8.29–8.24 (m, 1H, Ar–H), 8.24–8.19 (m, 1H, Ar–H*), 8.16–8.10 (m, 2H, Ar–H, Ar–H*), 7.83–7.76 (m, 4H,  2Ar–H, 2Ar–H*), 7.70 (br. s, 1H, Ar–H*), 2.51 (s, 6H, Me, Me*) ppm; 13C NMR (DMSO-d6): δ = 163.9, 160.6, 149.8, 149.7, 142.0, 141.4, 134.7, 134.6, 132.6, 132.0, 131.5, 131.4, 131.3, 128.1, 128.0, 127.9, 127.5, 127.2, 125.7, 125.5, 124.1, 123.9, 122.8, 121.9, 116.7, 115.7, 18.0 ppm.

N-(9,10-Dihydro-8H-benzo[h]cyclopenta[b]quinolin-5-yl)formamide (13c, C17H15N2O)

Light yellow solid (28 mg, 62% yield); Rf = 0.32 (hex/AcOEt, 1:1); m.p.: 247–249 °C; IR (KBr): \(\bar{\nu }\) = 3433, 3232, 2959, 1687, 1663 cm−1; 1H NMR (DMSO-d6; mixture of rotamers in the ratio 2.2:1*): δ = 10.52 (d, J = 10.2 Hz, 1H, NH*), 10.35 (br s, 1H, NH), 9.26–9.20 (m, 2H, Ar–H, Ar–H*), 8.66 (d, J = 10.2 Hz, 1H, CHO*), 8.55 (d, J = 1.2 Hz, 1H, CHO), 8.30 (br. s, 1H, Ar–H), 8.24–8.20 (m, 1H, Ar–H), 8.20–8.16 (m, 1H, Ar–H*), 8.11 (br. s, 2H, Ar–H*, Ar–H), 7.79–7.74 (m, 4H, 2Ar–H, 2Ar–H*), 7.72 (br. s, 1H, Ar–H*), 3.18–3.13 (m, 4H, 2Ar–H, 2Ar–H*), 3.13–3.07 (m, 4H, 2Ar–H, 2Ar–H*), 2.23–2.14 (m, 4H, 2Ar–H, 2Ar–H*) ppm; 13C NMR (DMSO-d6): δ = 165.5, 165.4, 163.8, 160.5, 141.0, 142.8, 142.3, 136.5, 131.5, 131.4, 131.3, 130.2, 128.1, 127.7, 127.6, 127.2, 127.1, 126.8, 124.4, 124.3, 124.1, 124.0, 122.7, 121.8, 117.7, 116.7, 34.0, 30.0, 23.1 ppm.

General procedure for the preparation of bromobenzoquinolines 14

To a mixture of the amino aldehyde 5 (0.2 mmol) and K2CO3 (1 equiv.) in 20 cm3 ethanol ethyl acetoacetate or acetylacetone (10 equiv.) was added. The whole being then heated at 70 °C (oil bath) until TLC analysis of the reaction mixture indicated the absence of starting material 5 (~ 25 h). The precipitated crude product 14a or 14b was filtered from the solution, washed with 10 cm3 water, air-dried, and next purified by flash chromatography or crystallization.

Ethyl 6-bromo-2-methylbenzo[h]quinoline-3-carboxylate (14a, C17H15BrNO2)

White solid (58 mg, 85% yield); Rf = 0.75 (DCM/PE, 10:1); m.p.: 145–147 °C; IR (KBr): \(\bar{\nu }\) = 3004, 2981, 2927, 1726, 1608 cm−1; 1H NMR (CDCl3): δ = 9.44–9.40 (m, 1H, Ar–H), 8.65 (s, 1H, Ar–H), 8.36–8.31 (m, 1H, Ar–H), 8.08 (s, 1H, Ar–H), 7.85–7.78 (m, 2H, Ar–H), 4.47 (q, J = 7.1 Hz, 2H, CH2), 3.09 (s, 3H, Me), 1.47 (t, J = 7.1 Hz, 3H, Me) ppm; 13C NMR (CDCl3): δ = 166.5, 158.5, 146.7, 138.3, 133.1, 131.8, 130.1, 128.6, 128.2, 127.7, 125.6, 124.8, 124.3, 122.5, 61.6, 25.9, 14.5 ppm.

1-(6-Bromo-2-methylbenzo[h]quinolin-3-yl)ethanone (14b, C16H13BrNO)

White solid (43 mg, 68% yield); crystallization (PE/DCM, 4:1); m.p.: 188–189 °C; IR (KBr): \(\bar{\nu }\) = 2995, 2972, 2927, 1682, 1592 cm−1; 1H NMR (CDCl3): δ = 9.40–9.37 (m, 1H, Ar–H), 8.38 (s, 1H, Ar–H), 8.35–8.32 (m, 1H, Ar–H), 8.07 (s, 1H, Ar–H), 7.85–7.78 (m, 2H, Ar–H), 3.00 (s, 3H, Me), 2.73 (s, 3H, Me) ppm; 13C NMR (CDCl3): δ = 199.9, 157.4, 146.4, 136.5, 133.0, 131.9, 131.8, 130.1, 128.5, 128.2, 127.7, 125.6, 124.1, 122.6, 29.5, 26.0 ppm.

General procedure for the preparation of benzo[f]quinolin-3(4H)-ones 17

To a mixture of the carbamate 7 (0.4 mmol) and K2CO3 (10 equiv.) in 10 cm3 ethanol ethyl acetoacetate or ethyl benzoylacetate (10 equiv.) was added. The resulting mixture was then heated at 70 °C (oil bath), until TLC analysis indicated the completion of the condensation process (~ 15 h). The precipitated solid was filtered from the solution, washed with 10 cm3 water, air-dried, and next purified by flash chromatography to give product 17.

2-Acetylbenzo[f]quinolin-3(4H)-one (17a, C15H12NO2)

Light yellow solid (81 mg, 85% yield); Rf = 0.26 (hex/AcOEt, 1:2); decomposition above 300 °C; IR (KBr): \(\bar{\nu }\) = 3003, 2928, 2797, 1682, 1628, 1561 cm−1; 1H NMR (DMSO-d6): δ = 12.52 (s, 1H, NH), 9.17 (s, 1H, Ar–H), 8.54 (d, J = 8.4 Hz, 1H, Ar–H), 8.15 (d, J = 9.0 Hz, 1H, Ar–H), 7.98 (d, J = 7.8 Hz, 1H, Ar–H), 7.75–7.68 (m, 1H, Ar–H), 7.59–7.55 (m, 1H, Ar–H), 7.52 (d, J = 9.0 Hz, 1H, Ar–H), 2.68 (s, 3H, Me) ppm; 13C NMR (DMSO-d6): δ = 197.1, 160.4, 140.9, 137.9, 134.6, 129.7, 129.0, 128.8, 128.6, 127.8, 125.5, 121.6, 115.8, 111.7, 30.6 ppm.

2-Benzoylbenzo[f]quinolin-3(4H)-one (17b, C20H14NO2)

Yellow solid (78 mg, 65% yield); Rf = 0.46 (AcOEt); decomposition above 300 °C; IR (KBr): \(\bar{\nu }\) = 3010, 2928, 2866, 2797, 1662, 1629 cm−1; 1H NMR (DMSO-d6): δ = 8.94 (s, 1H, Ar–H), 8.53 (d, J = 8.4 Hz, 1H, Ar–H), 8.08 (d, J = 8.4 Hz, 1H, Ar–H), 7.96 (d, J = 8.0 Hz, 1H, Ar–H), 7.89–7.85 (m, 2H, Ar–H), 7.67–7.62 (m, 2H, Ar–H), 7.55–7.49 (m, 4H, Ar–H) ppm; 13C NMR (DMSO-d6): δ = 194.9, 160.8, 141.1, 137.0, 135.6, 133.2, 132.8, 130.6, 129.8, 129.3, 128.8, 128.5, 128.0, 125.0, 121.7, 117.5, 112.1 ppm.