Interest in the development of methods for the preparation of chromeno[2,3-b]chromenes is primarily due to the presence of this structural fragment in the composition of many compounds of plant origin possessing antitumor,1 antiplasmodic,2 neuroprotective,3 antiinflammatory, 4 and other types of biological activity. The α-glucosidase inhibitor yunanensin A isolated from plants of the genus Morus,5 the natural antioxidant mongolicin B,6 the phosphodiesterase I inhibitor mesozygin A,7 and mulberrofuran F,8 exhibiting antibacterial activity against vancomycin-resistant enterococci, can be cited as examples (Fig. 1).

Figure 1
figure 1

Biologically active chromeno[2,3-b]chromenes of natural origin.

Full size image

One of the most commonly used methods for the preparation of chromeno[2,3-b]chromenes is the [4+2] cycloaddition with the participation of in situ generated o-quinone methides9 and various dienophiles, including α-chloroacrylonitrile,10 4H-chromenes,11 1,1-bis(morpholino)-ethylene,12 together with the dimerization of 2H-chromenes. 13,14 The synthesis of chromeno[2,3-b]chromene derivatives based on salicylic aldehydes and ketones15 or chromones16 is known. In addition, two examples of the preparation of chromeno[2,3-b]chromenes as a result of the Claisen rearrangement of 2-(aryloxymethyl)-1H-benzo[f]-chromenes, which, in turn, were synthesized from 1H-benzo[f]chromene-2-carbaldehyde in three steps, have been published.17 In this case, the rearrangement itself proceeded under rather harsh conditions with prolonged heating under reflux in N,N-diethylaniline.

In this work, we propose a one-step method for the preparation of polycondensed 7aH,15H-benzo[f]benzo[5,6]-chromeno[2,3-b]chromenes 3a–g from 1H-benzo[f]chromene-2-carbaldehydes 1a–d and 2-naphthols 2a–d (Scheme 1). The reactions were carried out by heating an equimolar mixture of starting compounds 1 and 2 in AcOH under reflux for 8 h in the presence of AcONH4. The yields of 7aH,15H-benzo[f]benzo[5,6]chromeno[2,3-b]chromenes 3a–g varied from 52 to 86%. By studying the reaction of 1H-benzo[f]chromene-2-carbaldehyde 1a with unsubstituted 2-naphthol 2a, it was found that the best yield of product 3a (70%) is achieved when using 2 equiv of AcONH4. In the presence of 1.5 equiv AcONH4, the reaction time increased to 20 h and the yield of chromeno-[2,3-b]chromene 3a was 62%. The reaction did not proceed in the absence of AcONH4. The use of p-TsOH instead of AcONH4 resulted in resinification of the reaction mixture. It should be noted that in the case of 1-substituted aldehydes 1с,d the reaction proceeded diastereoselectively with the formation of trans-isomers 3f,g.

scheme 1

Scheme 1

Apparently, the presence of AcONH4 is necessary for the activation of the carbonyl group of the aldehyde by transforming it into a more electrophilic iminium salt. Subsequent nucleophilic attack by naphthol and deamination lead to the generation of highly reactive 1,2-naphthoquinone 1-methide A which undergoes disrotatory oxa-6π electrocyclization (Scheme 2).

scheme 2

Scheme 2

The reaction of aldehyde 1а with resorcinol (in a ratio of 2:1) in the presence of AcONH4 (2 equiv) led to the symmetric product 4 which was isolated in 52% yield (Scheme 3). Subjecting phloroglucinol to this transformation led to a complex mixture of unidentified compounds, whereas the less nucleophilic hydroquinone, pyrocatechol, and monohydric phenols (4-tert-butyl-, 2-methoxy-, and 3,5-dimethylphenols) were unreactive.

scheme 3

Scheme 3

In the 1H NMR spectra of compounds 3a–e, the diastereotopic methylene protons appear as two separate doublets in the intervals of 4.02–4.06 and 4.17–4.19 ppm with a coupling constant of 17.9–18.1 Hz. The spectra of compounds 3f,g are characterized by the signal of the proton 15-СН in the form of a singlet at 5.63–5.73 ppm. The signal of the acetal proton 7а-СН in the spectra of chromenochromenes 3a–g is found in the 6.65–6.79 ppm region. In the 13С NMR spectra, the methylene (products 3a–е, 4) and acetal (products 3a–g, 4) carbon atoms resonate in the ranges of 30.6–31.4 and 93.3–96.1 ppm, respectively. Based on the established configuration of the previously obtained thiochromeno[3',4':5,6]pyrano[2,3-b]-chromen-6-ones18 as well as the absence of cross peaks corresponding to the interaction of protons 7а-СН and 15-СН in the NOESY spectra of compounds 3f,g, the respective protons were assigned the trans arrangement in relation to each other.

To conclude, we developed a method for the preparation of 7aH,15H-benzo[f]benzo[5,6]chromeno[2,3-b]chromenes based on a heterodomino reaction involving electrophilic substitution in 2-naphthols and oxa-6π electrocyclization with the participation of in situ generated 1,2-naphthoquinone 1-methides.

Experimental

1H and 13C NMR (400 and 100 MHz, respectively) as well as DEPT-135 spectra were registered on a JEOL JNM-ECX400 spectrometer in DMSO-d6 (compounds 3,b,c,f,g, and 4) or CDCl3 (compounds 3a,d,e); the residual solvent signals (DMSO-d6: 2.50 ppm for 1Н nuclei and 39.5 ppm for 13С nuclei; CDCl3: 7.26 ppm for 1Н nuclei and 77.0 ppm for 13С nuclei) served as internal standard. Elemental analysis was performed on a Euro Vector EA-3000 CHNS-analyzer. Melting points were determined by the capillary method on an SRS OptiMelt MPA100 apparatus. Monitoring of the reaction progress and assessment of the purity of synthesized compounds were done by TLC on Merck Silica gel 60 F254 plates, eluent СHCl3, visualization with UV light or by iodine stain.

The starting 1H-benzo[f]chromene-2-carbaldehydes 1a–d were obtained by published methods.18,19

Synthesis of 7a H ,15 H -benzo[ f ]benzo[5,6]chromeno-[2,3- b ]chromenes 3a–g (General method). A mixture of 1H-benzo[f]chromene-2-carbaldehyde 1a–d (1 mmol), 2-naphthol 2a–d (1 mmol), AcONH4 (155 mg, 2 mmol), and AcOH (5 ml) was heated under reflux for 8 h. After cooling the reaction mixture to room temperature, the formed precipitate was filtered off, washed with ice-cold MeOH (2 ml), and recrystallized from AcOH.

7a H ,15 H -Benzo[ f ]benzo[5,6]chromeno[2,3- b ]chromene (3a). Yield 235 mg (70%), colorless crystals, mp 210–211°С (mp 194°С17). 1H NMR spectrum, δ, ppm (J, Hz): 4.03 (1H, d, J = 18.1, CH2); 4.18 (1H, d, J = 18.1, CH2); 6.67 (1H, s, 7a-CH); 7.12 (1H, d, J = 8.9, H Ar); 7.30 (1H, d, J = 8.7, H Ar); 7.36–7.43 (2H, m, H Ar); 7.44 (1H, s, 16-СН); 7.49–7.57 (2H, m, H Ar); 7.67 (1H, d, J = 8.9, H Ar); 7.73 (1H, d, J = 8.9, H Ar); 7.78–7.84 (3H, m, H Ar); 8.05 (1H, d, J = 8.5, H Ar). 13C NMR spectrum, δ, ppm: 31.4 (CH2); 96.0 (7a-CH); 111.2; 114.5; 115.7 (CH); 117.4 (CH); 119.2 (CH); 121.0 (CH); 122.0 (CH); 124.1 (CH); 124.2 (CH); 125.7; 126.9 (3CH); 128.7 (2CH); 128.8 (CH); 129.4; 129.5; 129.6 (CH); 130.0; 132.3; 148.2; 150.9. Found, %: C 85.60; H 4.84. C24H16O2. Calculated, %: C 85.69; H 4.79.

3-Bromo-7a H ,15 H -benzo[ f ]benzo[5,6]chromeno[2,3- b ]-chromene (3b). Yield 280 mg (67%), colorless crystals, mp 233–234°С. 1H NMR spectrum, δ, ppm (J, Hz): 4.06 (1H, d, J = 17.9, CH2); 4.19 (1H, d, J = 17.9, CH2); 6.79 (1H, s, 7a-CH); 7.05 (1H, d, J = 8.7, H Ar); 7.35 (1H, d, J = 8.5, H Ar); 7.38–7.42 (1H, m, H Ar); 7.55–7.59 (1H, m, H Ar); 7.64 (1H, d, J = 8.5, H Ar); 7.70–7.75 (2H, m, 16-СН, H Ar); 7.83–7.89 (3H, m, H Ar); 8.16–8.21 (2H, m, H Ar). 13C NMR spectrum, δ, ppm: 31.1 (CH2); 95.5 (7a-CH); 112.0; 115.2 (CH); 115.4; 117.9; 118.8 (CH); 119.1 (CH); 122.8 (CH); 124.5 (CH); 124.6 (CH); 127.5 (CH); 127.9; 128.1; 128.9 (2CH); 129.2 (CH); 129.4; 130.3 (CH); 130.8 (CH); 131.3; 132.3; 148.2; 150.7. Found, %: C 69.45; H 3.61. C24H15BrO2. Calculated, %: C 69.41; H 3.64.

3-Trityl-7a H ,15 H -benzo[ f ]benzo[5,6]chromeno[2,3- b ]-chromene (3c). Yield 300 mg (52%), light-yellow crystals, mp 185–186°С. 1H NMR spectrum, δ, ppm (J, Hz): 4.03 (1H, d, J = 18.1, CH2); 4.18 (1H, d, J = 18.1, CH2); 6.76 (1H, s, 7a-CH); 7.05 (1H, d, J = 9.0, H Ar); 7.15–7.31 (17H, m, H Ar); 7.39 (1H, t, J = 7.4, H Ar); 7.55 (1H, t, J = 7.1, H Ar); 7.61 (1H, s, 16-СН); 7.65 (1H, d, J = 1.8, H-4); 7.68 (1H, d, J = 8.9, H Ar); 7.72 (1H, d, J = 9.0, H Ar); 7.83 (1H, d, J = 7.8, H Ar); 7.86 (1H, d, J = 8.5, H Ar); 8.09 (1H, d, J = 9.0, H Ar). 13C NMR spectrum, δ, ppm: 31.2 (CH2); 64.9 (CPh3); 95.6 (7a-CH); 111.6; 115.4 (CH); 115.5; 117.6 (CH); 119.2 (CH); 121.3 (CH); 122.8 (CH); 124.5 (CH); 126.6 (3CH Ph); 127.5 (2CH); 127.6; 128.4 (6CH Ph); 128.8 (CH); 128.9 (2CH); 129.3; 129.4; 130.3 (CH); 131.1 (6CH Ph); 131.5 (CH); 132.4; 142.9; 146.7 (3C Ph); 148.1; 150.8. Found, %: C 89.31; H 5.19. C43H30O2. Calculated, %: C 89.25; H 5.23.

3-(Adamantan-1-yl)-7a H ,15 H -benzo[ f ]benzo[5,6]chromeno[2,3- b ]chromene (3d). Yield 320 mg (68%), lightyellow crystals, mp 185–186°С. 1H NMR spectrum, δ, ppm (J, Hz): 1.76–1.84 (6H, m, CH2 Ad); 2.01 (6H, br. s, CH2 Ad); 2.14 (3H, br. s, CH Ad); 4.03 (1H, d, J = 17.9, CH2); 4.17 (1H, d, J = 17.9, CH2); 6.66 (1H, s, 7a-CH); 7.12 (1H, d, J = 8.9, H Ar); 7.27 (1H, d, J = 8.9, H Ar); 7.38–7.43 (2H, m, 16-СН, H Ar); 7.53–7.57 (1H, m, H Ar); 7.61 (1H, dd, J = 8.9, J = 1.6, H Ar); 7.65–7.68 (2H, m, H Ar); 7.71 (1H, d, J = 8.9, H Ar); 7.79 (1H, d, J = 8.2, H Ar); 7.82 (1H, d, J = 8.5, H Ar); 8.00 (1H, d, J = 8.9, H Ar). 13C NMR spectrum, δ, ppm: 29.0 (3CH Ad); 31.4 (CH2); 36.2 (C Ad); 36.9 (3CH2 Ad); 43.2 (3CH2 Ad); 96.1 (7a-CH); 111.0; 114.6; 115.8 (CH); 117.1 (CH); 119.2 (CH); 120.8 (CH); 122.0 (CH); 123.7 (CH); 124.0 (CH); 125.1 (CH); 125.4; 126.9 (CH); 127.6; 128.7 (2CH); 129.5; 129.6 (CH); 130.0; 132.3; 147.1; 147.8; 150.9. Found, %: C 86.82; H 6.35. C34H30O2. Calculated, %: C 86.78; H 6.43.

12-(Adamantan-1-yl)-7a H ,15 H -benzo[ f ]benzo[5,6]-chromeno[2,3- b ]chromene (3e). Yield 353 mg (75%), lightyellow crystals, mp 209–210°С. 1H NMR spectrum, δ, ppm (J, Hz): 1.77–1.85 (6H, m, CH2 Ad); 2.02 (6H, br. s, CH2 Ad); 2.14 (3H, br. s, CH Ad); 4.02 (1H, d, J = 18.1, CH2); 4.17 (1H, d, J = 18.1, CH2); 6.65 (1H, s, 7a-CH); 7.09 (1H, d, J = 8.9, H Ar); 7.30 (1H, d, J = 8.9, H Ar); 7.36–7.40 (1H, m, H Ar); 7.43 (1H, s, 16-СН); 7.49–7.53 (1H, m, H Ar); 7.63–7.67 (3H, m, H Ar); 7.73 (1H, d, J = 8.9, H Ar); 7.77–7.80 (2H, m, H Ar); 8.05 (1H, d, J = 8.7, H Ar). 13C NMR spectrum, δ, ppm: 29.0 (3CH Ad); 31.4 (CH2); 36.2 (C Ad); 36.9 (3CH2 Ad); 43.2 (3CH2 Ad); 96.0 (7a-CH); 111.3; 114.3; 115.5 (CH); 117.4 (CH); 119.0 (CH); 121.1 (CH); 121.8 (CH); 123.8 (CH); 124.1 (CH); 125.1 (CH); 125.9; 126.9 (CH); 128.7 (2CH); 129.4; 129.5 (CH, C); 130.0; 130.4; 147.0; 148.2; 150.4. Found, %: C 86.85; H 6.37. C34H30O2. Calculated, %: C 86.78; H 6.43.

trans -15-(4-Methoxyphenyl)-7a H ,15 H -benzo[ f ]benzo-[5,6]chromeno[2,3- b ]chromene (3f). Yield 330 mg (75%), colorless crystals, mp 243–244°С. 1H NMR spectrum, δ, ppm (J, Hz): 3.65 (3H, s, OCH3); 5.63 (1H, s, 15-CH); 6.55 (1H, s, 7a-CH); 6.84 (2H, d, J = 8.7, H Ar); 7.15 (1H, d, J = 8.9, H Ar); 7.20 (2H, d, J = 8.7, H Ar); 7.24 (1H, d, J = 8.9, H Ar); 7.29–7.33 (1H, m, H Ar); 7.36–7.42 (2H, m, H Ar); 7.52–7.58 (2H, m, H Ar); 7.78–7.87 (4H, m, H Ar); 8.02 (1H, s, 16-СН); 8.25 (1H, d, J = 8.5, H Ar). 13C NMR spectrum, δ, ppm: 45.5 (15-CH); 55.6 (OCH3); 93.3 (7a-CH); 111.7; 114.7 (2CH); 115.4 (CH); 116.3; 117.4 (CH); 119.2 (CH); 121.9 (CH); 123.6 (CH); 124.4 (CH); 124.9 (CH); 127.5 (CH); 127.7 (CH); 129.1 (2CH); 129.4 (2CH); 129.6; 129.7; 129.9; 130.0; 130.3 (2CH); 132.1; 134.0; 147.7; 150.8; 158.8. Found, %: C 84.06; H 4.96. C31H22O3. Calculated, %: C 84.14; H 5.01.

trans -15-(Thiophen-3-yl)-7a H ,15 H -benzo[ f ]benzo[5,6]-chromeno[2,3- b ]chromene (3g). Yield 360 mg (86%), colorless crystals, mp 212–213°С. 1H NMR spectrum, δ, ppm (J, Hz): 5.73 (1H, s, 15-CH); 6.63 (1H, s, 7a-CH); 7.04 (1H, br. s, H thiophene); 7.13 (1H, d, J = 8.9, H Ar); 7.17 (1H, d, J = 4.8, H thiophene); 7.26 (1H, d, J = 8.9, H Ar); 7.31–7.35 (1H, m, H Ar); 7.39–7.44 (2H, m, H Ar); 7.51 (H, dd, J = 4.8, J = 3.0, H thiophene); 7.55–7.59 (1H, m, H Ar); 7.62 (1H, d, J = 8.5, H Ar); 7.81–7.88 (4H, m, H Ar); 7.98 (1H, s, 16-СН); 8.23 (1H, d, J = 8.5, H Ar). 13C NMR spectrum, δ, ppm: 42.1 (15-CH); 93.5 (7a-CH); 111.7; 115.9 (CH); 117.0; 117.4 (CH); 119.2 (CH); 121.9 (CH); 123.4 (2CH); 124.4 (CH); 124.9 (CH); 127.5 (2CH); 127.7 (CH); 128.2 (CH); 128.7; 129.1 (2CH); 129.6; 129.8; 130.0; 130.3 (CH); 130.4 (CH); 132.0; 143.0; 147.8; 150.3. Found, %: C 80.42; H 4.31; S 7.55. C28H18O2S. Calculated, %: C 80.36; H 4.34; S 7.66.

7a H ,10a H ,18 H ,22 H -Benzo[5,6]chromeno[2,3- b ]benzo-[5',6']chromeno[3',2':5,6]pyrano[3,2- g ]chromene (4). A mixture of 1H-benzo[f]chromene-2-carbaldehyde 1a (210 mg, 1 mmol), resorcinol (55 mg, 0.5 mmol), AcONH4 (155 mg, 2 mmol), and AcOH (5 ml) was heated under reflux for 4 h. After cooling the reaction mixture to room temperature, the formed precipitate was filtered off and recrystallized from AcOH. Yield 255 mg (52%), colorless crystals, mp 303–304°С. 1H NMR spectrum, δ, ppm (J, Hz): 3.93 (2H, d, J = 18.1, CH2); 4.06 (2H, d, J = 18.1, CH2); 6.62 (2H, s, 7a,10a-CH); 6.75 (1H, s, H Ar); 6.80 (2H, s, 19,21-СН); 7.05 (2H, d, J = 8.7, H Ar); 7.08 (1H, s, H Ar); 7.36–7.40 (2H, m, H Ar); 7.51–7.55 (2H, m, H Ar); 7.72 (2H, d, J = 9.1, H Ar); 7.82–7.86 (4H, m, H Ar). 13C NMR spectrum, δ, ppm: 30.6 (2CH2); 95.5 (7a,10a-CH); 114.1; 115.3; 119.1; 122.9; 124.5; 124.8; 125.7; 127.4; 128.9; 132.3; 150.7; 150.8. Not all signals can be detected due to poor solubility in most organic solvents and low intensity of signals of carbon atoms in the 13C NMR spectrum. Found, %: C 82.51; H 4.53. C34H22O4. Calculated, %: C 82.58; H 4.48.