Synthesis of 4-hydroxyindole fused isocoumarin derivatives and their fluorescence “Turn-off” sensing of Cu(II) and Fe(III) ions

Abstract

A simple and efficient protocol has been developed for the synthesis of 4-hydroxyindole fused isocoumarins from easily available starting materials. Dihydroxy-indenoindoles, the cyclic hemiaminals of the condensation products of ninhydrin and enamines of 1,3-cyclohexanedione, produced indole fused isocoumarins 11-(aryl/alkyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-diones through an acid catalyzed intramolecular rearrangement. The above isocoumarin derivatives furnished novel 4-hydroxyindole fused isocoumarins 11-(aryl or alkyl)-7-hydroxy-11H-6-oxa-11-aza-benzo[a]fluoren-5-ones through dehydrogenation with Pd/C. The synthesized 4-hydroxyindole fused isocoumarins show fluorescence properties with good quantum yields and fluorescence “Turn-off” sensing of Cu²⁺ and Fe³⁺ ions. Importantly these molecules are found to be chemosensors only for Cu²⁺ ions with respect to UV-Vis spectral change and naked eye colour change in the presence and absence of UV radiation.

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Introduction

α-Pyranone (2H-pyran-2-one), a six-membered oxygen heterocycle, represents an important class of naturally occurring unsaturated lactones. Its benzo derivatives e.g. isocoumarins are found in many natural products and bioactive synthetic compounds.^1,2 This imperative class of naturally occurring lactones has attracted significant attention from chemists due to their varied biological activities.^3–8 Tricyclic isocoumarins A (Fig. 1) isolated from Microdochium bolleyi have shown good antifungal, antibacterial and antialgal activities.⁹ (−)-Cephalosol B is a potent naturally occurring antimicrobial metabolite (Fig. 1).¹⁰ Polyheterocycles like isocoumarin C and isoquinolinone D framework also represent some privileged structures for the development of natural product-inspired compounds of potential biological interest (Fig. 1).^11,12 So development of new and efficient methodology for the synthesis of isocoumarins and their carbo/hetero annulated analogues have attracted great attention of the synthetic as well as medicinal chemists.¹³ Various methodologies for the syntheses of isocoumarins have been reported such as the reaction of o-halobenzoic acids and 1,3-diketones via copper-catalyzed tandem sequential cyclization/addition/deacylation process,¹⁴ iridium-catalyzed oxidative lactonization or intramolecular cyclization reaction of δ-ketoaldehydes,¹⁵ ruthenium-catalyzed aerobic oxidative cyclization of aromatic acids with alkynes,¹⁶ FeCl₃-promoted regioselective annulation of o-(1-alkynyl)benzoates with disulfides,¹⁷ Heck–Matsuda cyclization reaction,¹⁸ 6-endo-dig cyclization of hetero arylesters to alkynes¹⁹ and Pd(II)-mediated cyclization.²⁰

Fig. 1 Some biologically active compounds and natural products containing an isocoumarin analogue.

In the present paper, we wish to report the synthesis of a new class of 4-hydroxyindole fused isocoumarins. These compounds also show diverse kinds of photophysical properties such as fluorescence “Turn-off” sensing of Cu(II) and Fe(III) ions, chemosensing of Cu²⁺ ion and differential fluorescence quantum yields and lifetimes depending upon the solvent polarity. Copper is an essential trace element in the human body which plays a critical role in many biological processes and is also required by the human nervous system.²¹ However, the high levels of copper ion in living cell leads to neurodegenerative diseases.²² Thus, the sensing and recognition of divalent copper ion has attracted considerable attention in recent years²³ and there is a need for development of new fluorescent sensors for detection of copper. To the best of our knowledge suitable isocoumarin based molecules have not been discovered to date for this purpose. In continuation of our research interest in the synthesis of various heterocyclic compounds from ninhydrin,²⁴ we wish to report herein a novel class of potentially bioactive and fluorescence active 4-hydroxyindole fused isocoumarin systems.

Results and discussion

Recently a multicomponent reaction of N-heteroannulations involving enaminones, ninhydrin and acid anhydride or aromatic amines has been reported to produce fused pyrazole derivatives.²⁵ In this reaction the acyclic hemiaminals of C-2 alkylated 1,3-indanediones (1) have been proposed to be an important intermediate (Scheme 1). We became interested to examine whether the above reaction would be fruitful starting from the proposed hemiaminals intermediate 1. Therefore initially a series of enamines of 1,3-cyclohexanedione and dimedone were reacted with ninhydrin in chloroform to isolate cyclic hemiaminals 1 according to the literature procedure.²⁶ Subsequently the intermediate 5-benzyl-4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione 1a (R¹ = –CH₂Ph, R² = H) was heated in acetic anhydride or various acidic media like p-TSA, acetic acid, lactic acid, formic acid and citric acid under conventional refluxing as well as microwave irradiation. The reaction scarcely proceeded to give any fused pyrazole derivatives²⁵ or any other products in these conditions even after prolong refluxing (Table 1, entries 1–6). But when the same reaction was carried out in 8–11 N aqueous H₂SO₄ solution at reflux, a white product was precipitated out from the reaction mixture in low yield after 10 h (Scheme 1, Table 1, entries 7–11). The NMR studies confirmed that the product was not the expected multifunctionalized tetracyclic indeno[1,2-b]indole derivatives²⁵ but a new rearranged product. Eventually, the structure elucidation of the product by single crystal X-ray diffraction study established that a novel indole fused isocoumarin 2a (R¹ = –CH₂Ph, R² = H) has been formed (Fig. 2). The crystal structure of NaBH₄ reduced product of 2a was also determined (Fig. S12, see ESI†). This significant result motivated us to carry out the above reaction at higher acidic condition to achieve better yields. Interestingly, when the acid strength of the reaction medium was increased to about 18 N aqueous H₂SO₄, the yield of the product 2a was enhanced considerably (Table 1, entries 12 and 13). Further the yield of the reaction was improved significantly when melamine sulfonic acid (Table 1, entry 14) and PEG-OSO₃H (Table 1, entry 15) were employed in water under reflux. After performing a series of experiments, we observed that the yield of the product 2a can reach maximum upto 87% without producing any by-product if the reaction was carried out in acetic acid at reflux for 15 min in presence of concentrated H₂SO₄ (Table 1, entry 16).

Scheme 1 Synthesis of indole fused isocoumarin derivatives.

Table 1 Optimization of reaction conditions for the synthesis of 2a from 1a

Entry	Solvent (10 mL)	Acid	Time (h)	Yield (%)
1	Acetic acid	—	10	—
2	H2O	p-TSA	10	Trace
3	H2O	Acetic acid	10	—
4	H2O	Lactic acid	10	—
5	H2O	Formic acid	10	—
6	H2O	Citric acid	10	—
7	H2O	6.5 (N) H2SO4	10	Trace
8	H2O	8.3 (N) H2SO4	10	12
9	H2O	9.3 (N) H2SO4	10	17
10	H2O	10.3 (N) H2SO4	10	23
11	H2O	11.2 (N) H2SO4	10	24
12	H2O	12.0 (N) H2SO4	10	26
13	H2O	13.5 (N) H2SO4	10	26
14	H2O	20 mol% melamine sulfonic acid (MSA)	5	40
15	H2O	PEG6000-OSO3H (20 mol%)	4	50
16	Acetic acid	H2SO4 (0.5 mL)	0.25	87

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Fig. 2 ORTEP diagram of X-ray crystal structure of isocoumarin 2a with atom numbering scheme (CCDC number 940456).

Having prepared 2a successfully, we decided to explore the scope and generality of the reaction in the synthesis of other analogues. Accordingly, a variety of cyclic hemiaminals 1 derived from enamines of commercially available primary amines and 1,3-cyclohexanedione or dimidone were reacted under the optimized conditions (Table 1, entry 16). As evident from Table 2, all the hemiaminals 1 reacted well in the reaction affording the desired products 2a–k and 3a–k in good yields. All the structures of the products were determined by detailed study of the spectroscopic data.

Table 2 Scope of isocoumarins synthesis using different amines and 1,3-cyclohexanones

Entry	R^1	R^2	Product	Time (min)	Yield^a (%)	Melting point (°C)
a Isolated yield.
1		H	2a	15	87	224–226
2		H	2b	15	86	295–297
3		H	2c	20	83	298–300
4		H	2d	18	87	294–296
5		H	2e	35	80	292–294
6		H	2f	25	85	256–258
7		H	2g	18	85	255–257
8		H	2h	25	81	>300
9		H	2i	35	82	300–302
10		H	2j	40	80	>300
11		H	2k	20	86	216–218
12		Me	3a	30	90	252–254
13		Me	3b	30	85	294–296
14		Me	3c	32	83	280–282
15		Me	3d	28	86	>300
16		Me	3e	45	78	255–257
17		Me	3f	34	83	282–284
18		Me	3g	36	82	285–287
19		Me	3h	40	79	280–282
20		Me	3i	40	81	278–280
21		Me	3j	45	78	286–288
22		Me	3k	32	85	270–272

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Formation of isocoumarin ring in products 2 or 3 from adducts 1 can be explained on the basis of the proposed mechanism depicted in Scheme 2. In strong acidic condition, protonation of the carbonyl oxygen in dihydroxy-indenopyrrole 1 generates the oxonium ion 5. Then hydroxyl group of 5 attacks the adjacent carbonyl carbon to generate a hydroxy epoxide intermediate 6 which is subsequently converted to intermediate 7 through protonation of the hydroxyl group. The intermediate 7 then loses water molecule to generate cationic intermediate 8 which provokes the ring expansion through the breaking of the central C–C bond affording an eight-membered lactum intermediate 2 with isocoumarin skeleton. It was not possible to isolate any of the intermediates 5–8 under the reaction conditions (Scheme 2).

Scheme 2 Plausible mechanism for the formation of isocoumarin derivatives 2 or 3.

Finally dehydrogenation of 2 with 10% Pd/C (10 mol% of Pd(0)) in the diphenyl ether at reflux produced 4-hydroxyindole fused isocoumarins 11-(aryl/alkyl)-7-hydroxy-11H-6-oxa-11-aza-benzo[a]fluoren-5-one 9a–f in good yields (Scheme 3, Table 3). All the structures of the aromatized products were determined by detailed analysis of the spectroscopic data. Furthermore, the formation of product 9c was unambiguously confirmed through X-ray crystallographic analysis (Fig. 3). Since palladium is electropositive, the high activity of the catalyst also led to dehalogenation reactions.²⁷ In order to stop the dehalogenation, the reaction was carried out for shorter period of time at low temperature, but the reaction did not produce any satisfactory result. A plausible mechanism of dehalogenation is outlined in Scheme 4. When palladium(0) reacted with compound 2, dehydrogenation took place to produce 9 and palladium dihydride (“PdH₂”). This palladium dihydride (“PdH₂”) species might be responsible for dehalogenation reaction (Scheme 4).²⁸ It should be noted that defluorination did not take place because of high carbon–fluorine (C–F) bond energy. Compounds 3, derived from dimidone, did not aromatize in presence of 10% Pd/C due to the presence of two methyl groups at the same carbon atom of the cyclohexane ring.

Scheme 3 Synthesis of hydroxyindole fused isocoumarins 9.

Table 3 Dehydrogenation using Pd/C to furnish hydroxylindole fused isocoumarin 9

Entry	Isocoumarin (2)	Products (9)	Yield^a (%)	Melting point (°C)
a Isolated yield.
1	2a	9a	79	260–262
2	2b	9b	82	264–266
3	2c	9c	81	280–282
4	2d	9d	82	278–280
5	2e	9a	73	260–262
6	2f	9a	75	260–262
7	2g	9a	75	260–262
8	2h	9a	80	260–262
9	2i	9e	80	262–264
10	2j	9f	81	282–284

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Fig. 3 ORTEP diagram of X-ray crystal structure of hydroxylindole fused isocoumarin 9c with atom numbering scheme (CCDC number 940458).

Scheme 4 The dehalogenation reactions in presence of Pd(0).

Steady state absorption and emission spectra of all the purified compounds 9a–f have been performed in solvents of different polarity. Probe concentration was maintained at 5 × 10⁻⁵ M. UV-Vis absorption spectrum shows structured band with peaks around 380 nm, 339 nm and 311 nm. The emission spectrum shows a structure less band with maximum around 502 nm. The shape and band position of the emission spectra are same regardless of excitation wavelength. Noticeably the molecule displays large Stokes shifted emission of more than ∼100 nm which indicates that the structure of the emitting species and the ground state species are considerably different. The emission maxima for all compounds have been found to shift to longer wavelength with increasing solvent polarity and hydrogen bonding ability (Fig. 4). The most bathochromic emission was found in methanol as solvents. This shifting of emission maxima in protic solvent clearly indicates more stabilization of the emissive species through intermolecular solute solvent intermolecular hydrogen bonding interaction. Concurrently, the measured fluorescence quantum yields (Φ_F) are found to decrease with increasing hydrogen bonding ability of the solvent (see ESI, Table S1†). The high Φ_F values were observed in aprotic solvent, and the lowest were measured in protic polar methanol. The substantial fluorescence quenching of the compounds 9 in protic solvent methanol compared to that of in CH₃CN and DCM might be due to activation of some non-radiative decay channels of molecules 9 through intermolecular hydrogen bonding with the protic solvents.

Fig. 4 (a) UV-Vis absorption spectra and (b) fluorescence emission spectra (λ_ex = nm) of representative compound 9d in different solvents ([9d] = ∼5 × 10⁻⁵ M).

Ground state geometry of 9d has been optimized at B3LYP/6-31+G(d,p) level of theory in methanol solvent. The result shows that the 4-hydroxyindole fused isocoumarin moeity is planar in structure while the phenyl ring at N is perpendicular to the plane of the fused moeity. Further the UV-Vis absorption and emission spectra of 9d have been simulated theoretically in methanol solvent. The calculated excited state energies match well with the experimental values of absorption band positions (Table 4, ESI, Fig. S16†).

Table 4 Excitation energies and oscillator strength calculated at B3LYP/6-31+G(d,p) level of theory in methanol solvent

Excitation energy	Oscillator strength
390.74 nm	0.1734
339.00 nm	0.2633
317.43 nm	0.1345
310.70 nm	0.0149
306.43 nm	0.0002

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Photophysical properties of the ligand 9d, in particular, have been performed in detail in presence of metal ions Ni²⁺, Co²⁺, Zn²⁺, Cu²⁺, Fe³⁺, Cd²⁺, Hg²⁺ and Ca²⁺. Complexation of the ligand 9d with Cu²⁺ and Fe³⁺ ions was accompanied by the change of the colour of the solution from colourless to pink, which was easily observed by the naked-eye (Fig. 5a). This response was selective to Cu²⁺ and Fe³⁺ ions in solution, the colour being more intense in Cu²⁺ than in Fe³⁺. The addition of 10 equiv. of the other cations as their perchlorate salts resulted in no appreciable changes in colour under visible as well as UV-light (Fig. 5b). Interestingly, the molecule 9d in presence of Cu²⁺ ion shows purple colour with UV radiation, but is found to be unchanged with all other metal ion including Fe²⁺ (Fig. 5b).

Fig. 5 Change in color of solution of 9d in acetonitrile in presence of 10 equiv. of each metal ion (a) under visible light (b) under UV light.

UV-Vis spectra of the ligand 9d solution in acetonitrile show no significant change on increasing concentration of metal perchlorate salts of Ni²⁺, Co²⁺, Zn²⁺, Fe³⁺, Cd²⁺, Hg²⁺ and Ca²⁺ (ESI, Fig. S11(a–d)†). However in presence of Cu²⁺ the UV-Vis spectrum of 9d shows appreciable change compared to that in case of free ligand hence indicating ligand–metal interaction. On gradual addition of Cu²⁺ salt an absorption band develops near 500 nm with simultaneous appearance of two isobestic points at 308 nm and 419 nm (Fig. 6). The emission spectra of ligand 9d in acetonitrile shows no change in fluorescence intensity in presence of metal ions Ni²⁺, Co²⁺, Zn²⁺, Cd²⁺, Hg²⁺ and Ca²⁺.²⁹ On the other hand fluorometric titration in presence of Fe³⁺ and Cu²⁺ shows substantial quenching of ligand emission. The extent of fluorescence quenching in Cu²⁺ is significantly higher compared to that in case of Fe³⁺ (Fig. 7). Detection limit of Cu²⁺ by probe 9d has been estimated from fluorescence titration and has been found to be 7.07 × 10⁻⁶ M (ESI, Fig. S15†). Selective complexation of an analyte coupled with the fluorescence properties of a bound chromophore resulted in the development of promising molecular fluorescent probes. Fe³⁺ and Cu²⁺ orientated probes have been developed widely with the use of highly selective copper and iron-chelating molecules such as naturally occurring fluorescent siderophores or synthetic siderophore analogs connected suitably to a light-emitting group.³⁰ It is well known that d-block ions such as Fe³⁺ or Cu²⁺ often open excited state deexcitation pathways via electronic energy transfer (EET) and/or photoinduced electron transfer (PET) involving the metal centre. It is not surprising, therefore, that there are many more examples of “Turn-off” sensors than “Turn-on”.³⁰ In the present case, quenching of fluorescence of the synthetic molecules 9 thus can be treated as fluorescence “Turn-off” sensor selective for Fe³⁺ or Cu²⁺ ions.

Fig. 6 Absorption spectra of 9d ([9d] = 5 × 10⁻⁵ M) on increasing concentration of Cu²⁺ ions.

Fig. 7 (a) Emission spectra (λ_ex = nm) of 9d in acetonitrile in presence of various metal ions. Fluorescence quenching of 9d on gradual addition of (b) Cu²⁺ and (c) Fe³⁺ ions.

Additionally, ¹H NMR titration was carried out by gradual addition of perchlorate salt of Cu²⁺ ions to a DMSO-d₆ solution of 9f. The results show that the intensity of the proton signal corresponding to the hydroxyl group (–OH) at 10.25 ppm, which is the most probable binding site for Cu²⁺ ions, decreases significantly relative to that of other protons upon exposure to Cu²⁺ (Fig. 8). This effect confirms the formation of weak complex between 9f and Cu²⁺ ion. Moreover rapid broadening of the proton signal at 10.25 ppm with gradual addition of Cu²⁺ ions further confirms the fast exchange of –OH protons due to complexation with Cu²⁺ ion.

Fig. 8 Change in ¹H NMR spectra of 9f upon addition of Cu²⁺ ions, (a) 00 equiv., (b) 0.5 equiv., (c) 1.0 equiv., and (d) 2.0 equiv. in [d₆]-DMSO.

Conclusions

In summary, we have successfully developed a synthetic protocol for constructing novel tetracyclic skeleton of 4-hydroxyindole fused isocumarins. This methodology has the advantages of using easily available reactants and inexpensive catalyst and high yields of the product formation. To the best of our knowledge, this is the first report of synthesis of suitable isocoumarin based fluorescence active molecules with high quantum yields and ability to act as fluorescence “Turn-off” sensor for Cu²⁺ and Fe³⁺ ions. Most importantly the same molecules are found to be chemosensor for Cu²⁺ion only with respect to UV-Vis spectral change and naked eye colour change in presence and absence of UV radiation.

Experimental section

General procedure for the preparation of 2a–k or 3a–k

Concentrated H₂SO₄ (0.5 mL) was added to a solution of dihydroxy-indenopyrroles 1 (500 mg) in acetic acid (10 mL). The reaction mixture was heated at reflux for 15–45 min (as mentioned in Table 2). The initial colorless solution was intensified to red. Then it was poured into ice cold water to obtain solid products. The compounds were purified by crystallization technique using acetone and petroleum ether as mixed solvents.

General procedure for the preparation of 4a,b

The isocoumarin derivatives 2 (500 mg) were dissolved in 2.5 mL of methanol. NaBH₄ (0.3 equiv.) was added in one portion with stirring. A vigorous gas evolution occurs, together with a temperature rise. Stirring was continued for a few minutes (30 min) and then the pH was adjusted to neutrality with addition of dilute aqueous HCl, the mixture was extracted (ethyl acetate) and dried (Na₂SO₄), and the solvent was evaporated. The crude residue was then purified by column chromatography and crystallized by using petroleum ether and ethyl acetate.

General procedure for the preparation of 9a–f

10% Pd/C (97 mg, 0.09 mmol) was added to a stirred solution of 2 (0.9 mmol) in Ph₂O (4 mL). The mixture was heated for 2 h at 250 °C under an inert atmosphere of N₂. After the mixture was cooled to room temperature, the catalyst was removed by filtration on Celite and the filter cake was rinsed several times with EtOAc. Volatiles were removed under reduced pressure and the resulting mixture was loaded onto a silica gel column. Elution of the column with hexanes (for removal of Ph₂O) and then with 1 : 3 hexane–EtOAc provided yellow solid.

11-Benzyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2a). White solid (413 mg, 87%); m.p. 224–226 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.29 (d, J = 8.7 Hz, 1H), 7.48–7.42 (m, 1H), 7.38–7.22 (m, 5H), 7.03 (d, J = 6.9 Hz, 2H), 5.53 (s, 2H), 2.83 (t, J = 6.3 Hz, 2H), 2.53 (t, J = 6.0 Hz, 2H), 2.23–2.15 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.8, 161.6, 145.4, 139.2, 135.2, 134.7, 131.6, 129.9, 129.3, 128.1, 125.7, 125.3, 118.8, 118.0, 112.8, 109.0, 49.2, 38.0, 22.8, 21.5; IR (KBr): [small nu, Greek, macron] 1724 cm⁻¹; anal. calcd for C₂₂H₁₇NO₃: C, 76.95; H, 4.99; N, 4.08% found C, 76.82; H, 4.93; N, 4.00%.

11-Phenyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2b). White solid (408 mg, 86%); m.p. 295–297 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.13 (d, J = 8.1 Hz, 1H), 7.66–7.64 (m, 3H), 7.55–7.52 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 2.59 (t, J = 6.0 Hz, 2H), 2.46 (t, J = 6.0 Hz, 2H), 2.15–2.09 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.9, 161.5, 145.9, 138.9, 136.8, 134.1, 131.4, 130.2, 130.1, 128.2, 128.0, 125.7, 118.7, 118.0, 113.8, 109.2, 38.1, 22.9, 22.1; IR (KBr): [small nu, Greek, macron] 1721 cm⁻¹; anal. calcd for C₂₁H₁₅NO₃: C, 76.58; H, 4.59; N, 4.25% found C, 76.44; H, 4.52; N, 4.19%.

11-p-Tolyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2c). White solid (394 mg, 83%); m.p. 298–300 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.14 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.24–7.08 (m, 4H), 6.44 (d, J = 8.1 Hz, 1H), 2.48 (t, J = 6.0 Hz, 2H), 2.42–2.38 (m, 5H), 2.05–1.96 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.9, 161.7, 145.8, 140.3, 138.9, 134.2, 131.7, 130.8, 130.3, 127.7, 125.8, 125.6, 118.8, 118.3, 113.2, 109.3, 38.2, 23.0, 22.2, 21.3; IR (KBr): [small nu, Greek, macron] 1722 cm⁻¹; anal. calcd for C₂₂H₁₇NO₃: C, 76.95; H, 4.99; N, 4.08% found C, 76.80; H, 4.91; N, 4.03%.

11-(4-Fluorophenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2d). White solid (414 mg, 87%); m.p. 294–296 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.13 (d, J = 7.8 Hz, 1H), 7.35–7.31 (m, 2H), 7.21–7.07 (m, 4H), 6.35 (d, J = 8.1 Hz, 1H), 2.44 (t, J = 6.0 Hz, 2H), 2.38 (t, J = 6.0 Hz, 2H), 2.03–1.97 (m, 2H); ¹³C NMR (75 MHz, CDCl₃, F coupled ¹³C spectra): δ = 191.7, 164.8, 161.6, 161.5, 145.7, 139.4, 135.4, 134.3, 134.2, 132.2, 131.9, 130.0, 129.9, 126.0, 118.5, 117.5, 117.2, 113.9, 109.4, 38.2, 23.0, 22.2; IR (KBr): [small nu, Greek, macron] 1716 cm⁻¹; anal. calcd for C₂₁H₁₄FNO₃: C, 72.62; H, 4.06; N, 4.03% found C, 72.48; H, 3.98; N, 3.97%.

11-(2-Chlorophenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2e). White solid (381 mg, 80%); m.p. 292–294 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.22 (d, J = 8.1 Hz, 1H), 7.77–7.73 (m, 1H), 7.70–7.58 (m, 3H), 7.34–7.29 (m, 1H), 7.26–7.17 (m, 1H), 6.37 (d, J = 8.1 Hz, 1H), 2.63–2.45 (m, 4H), 2.23–2.05 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.8, 161.5, 145.7, 139.0, 134.6, 134.5, 133.4, 131.7, 131.6, 130.9, 130.5, 130.0, 128.7, 125.9, 118.1, 117.8, 113.6, 109.7, 38.1, 22.9, 21.8; IR (KBr): [small nu, Greek, macron] 1726 cm⁻¹; anal. calcd for C₂₁H₁₄ClNO₃: C, 69.33; H, 3.88; N, 3.85% found C, 69.21; H, 3.80; N, 3.78%.

11-(3-Chlorophenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2f). White solid (405 mg, 85%); m.p. 256–258 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.31 (d, J = 8.1 Hz, 1H), 7.67–7.60 (m, 2H), 7.50 (s, 1H), 7.43–7.35 (m, 2H), 7.30–7.26 (m, 1H), 6.54 (d, J = 8.1 Hz, 1H), 2.63 (t, J = 6 Hz, 2H), 2.55 (t, J = 6 Hz, 2H), 2.20–2.11 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.6, 161.8, 145.4, 139.5, 136.9, 135.4, 134.8, 130.4, 130.2, 129.5, 128.8, 128.3, 127.6, 124.7, 118.5, 117.7, 113.6, 109.4, 38.1, 22.3, 21.8; IR (KBr): [small nu, Greek, macron] 1720 cm⁻¹; anal. calcd for C₂₁H₁₄ClNO₃: C, 69.33; H, 3.88; N, 3.85% found C, 69.19; H, 3.81; N, 3.79%.

11-(4-Chlorophenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2g). White solid (405 mg, 85%); m.p. 255–257 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.25 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 9.3 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.26–7.21 (m, 1H), 6.54 (d, J = 7.8 Hz, 1H), 2.62–2.50 (m, 4H), 2.18–2.10 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.0, 160.8, 145.2, 138.5, 135.5, 134.6, 133.9, 131.0, 129.9, 129.3, 128.8, 125.5, 118.0, 117.5, 113.1, 108.9, 37.5, 22.3, 21.5; IR (KBr): [small nu, Greek, macron] 1718 cm⁻¹; anal. calcd for C₂₁H₁₄ClNO₃: C, 69.33; H, 3.88; N, 3.85% found C, 69.46; H, 3.79; N, 3.78%.

11-(4-Bromophenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2h). White solid (388 mg, 81%); m.p. >300 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.30 (d, J = 6.6 Hz, 1H), 7.81–7.79 (m, 2H), 7.40–7.28 (m, 4H), 6.58 (d, J = 7.8 Hz, 1H), 2.77–2.55 (m, 4H), 2.16–2.09 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.0, 160.7, 145.1, 138.9, 135.1, 133.9, 132.9, 131.0, 129.3, 129.0, 125.5, 123.6, 118.0, 117.4, 113.0, 108.7, 37.5, 22.3, 21.5; IR (KBr): [small nu, Greek, macron] 1723 cm⁻¹; anal. calcd for C₂₁H₁₄BrNO₃: C, 61.78; H, 3.46; N, 3.43% found C, 61.90; H, 3.37; N, 3.36%.

11-(3-Methoxyphenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2i). White solid (390 mg, 82%); m.p. 300–302 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.30 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 8.7 Hz, 1H), 7.37–7.34 (m, 1H), 7.28–7.26 (m, 1H), 7.21–7.17 (m, 1H), 7.05–7.02 (m, 2H), 6.61 (d, J = 8.1 Hz, 1H), 3.92 (s, 3H), 2.65 (t, J = 6 Hz, 2H), 2.55 (t, J = 6 Hz, 2H), 2.17–2.11 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.6, 161.4, 160.2, 145.6, 139.4, 137.9, 134.3, 131.8, 130.9, 130.1, 127.1, 125.9, 120.0, 118.8, 118.6, 116.0, 113.5, 109.2, 55.7, 38.2, 23.0, 22.2; IR (KBr): [small nu, Greek, macron] 1724 cm⁻¹; anal. calcd for C₂₂H₁₇NO₄: C, 73.53; H, 4.77; N, 3.90% found C, 73.40; H, 4.71; N, 3.82%.

11-(4-Methoxyphenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2j). White solid (381 mg, 80%); m.p. >300 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.25 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 9.0 Hz, 2H), 7.37–7.18 (m, 2H), 7.13 (d, J = 9.0 Hz, 2H), 6.57 (d, J = 7.8 Hz, 1H), 3.95 (s, 3H), 2.60 (t, J = 6.0 Hz, 2H), 2.51 (t, J = 6 Hz, 2H), 2.16–2.08 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.7, 161.5, 160.4, 145.9, 139.4, 134.1, 131.5, 130.1, 129.2, 129.0, 125.9, 125.6, 118.6, 118.1, 115.1, 109.1, 55.5, 38.1, 22.9, 22.0; IR (KBr): [small nu, Greek, macron] 1720 cm⁻¹; anal. calcd for C₂₂H₁₇NO₄: C, 73.53; H, 4.77; N, 3.90% found C, 73.43; H, 4.70; N, 3.80%.

11-(4-Nitrophenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (2k). White solid (410 mg, 86%); m.p. 216–218 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.53 (d, J = 6.9 Hz, 2H), 8.31 (d, J = 8.2 Hz, 1H), 7.75–7.72 (m, 2H), 7.35–7.26 (m, 2H), 6.28 (d, J = 8.1 Hz, 1H), 2.63–2.55 (m, 4H), 2.17–2.12 (m, 2H); IR (KBr): [small nu, Greek, macron] 1717 cm⁻¹; anal. calcd for C₂₁H₁₄N₂O₅: C, 67.38; H, 3.77; N, 7.48% found 67.53; H, 3.69; N, 7.40%.

11-Benzyl-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3a). White solid (429 mg, 90%); m.p. 252–254 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.15 (d, J = 8.1 Hz, 1H), 7.35–7.13 (m, 6H), 6.94 (d, J = 7.2 Hz, 2H), 5.45 (s, 2H), 2.60 (s, 2H), 2.28 (s, 2H), 1.03 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.2, 161.6, 144.3, 139.1, 135.2, 134.8, 131.7, 129.9, 129.4, 128.1, 125.7, 125.1, 118.8, 118.0, 113.1, 107.9, 52.0, 49.1, 35.5, 35.0, 28.5; IR (KBr): [small nu, Greek, macron] 1715 cm⁻¹; anal. calcd for C₂₄H₂₁NO₃: C, 77.61; H, 5.70; N, 3.77% found C, 77.75; H, 5.63; N, 3.71%.

9,9-Dimethyl-11-phenyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3b). White solid (405 mg, 85%); m.p. 294–296 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.40 (d, J = 7.5 Hz, 1H), 7.89–7.86 (m, 3H), 7.71–7.68 (m, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.38–7.35 (m, 1H), 6.66 (d, J = 8.1 Hz, 1H), 2.66 (s, 2H), 2.56 (s, 2H), 1.28 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.4, 161.5, 144.8, 138.9, 136.8, 134.2, 131.5, 130.3, 130.3, 130.2, 128.1, 125.7, 118.7, 118.1, 114.1, 108.2, 52.2, 36.0, 35.1, 28.4; IR (KBr): [small nu, Greek, macron] 1722 cm⁻¹; anal. calcd for C₂₃H₁₉NO₃: C, 77.29; H, 5.36; N, 3.92% found C, 77.42; H, 5.28; N, 3.83%.

9,9-Dimethyl-11-p-tolyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3c). White solid (396 mg, 83%); m.p. 280–282 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.34 (d, J = 6.3 Hz, 1H), 7.45–7.26 (m, 6H), 6.55 (d, J = 7.8 Hz, 1H), 2.65–2.41 (m, 7H), 1.09 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.39, 161.6, 144.7, 140.4, 138.1, 134.2, 131.8, 130.9, 130.3, 127.7, 125.8, 125.6, 118.7, 118.3, 113.6, 108.3, 52.3, 36.1, 35.1, 28.4, 21.4; IR (KBr): [small nu, Greek, macron] 1725 cm⁻¹; anal. calcd for C₂₄H₂₁NO₃: C, 77.61; H, 5.70; N, 3.77% found C, 77.47; H, 5.61; N, 3.69%.

11-(4-Fluorophenyl)-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3d). White solid (410 mg, 86%); m.p. >300 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.2 (d, J = 7.8 Hz, 1H), 7.53–7.49 (m, 2H), 7.39–7.17 (m, 4H), 6.49 (d, J = 8.1 Hz, 1H), 2.45 (s, 2H), 2.37 (s, 2H), 1.09 (s, 6H); ¹³C NMR (75 MHz, CDCl₃, F coupled ¹³C spectra): δ = 191.4, 164.8, 161.6, 161.6, 144.9, 138.6, 134.3, 132.8, 131.7, 130.1, 130.0, 125.9, 124.7, 118.5, 118.1, 117.6, 117.3, 113.9, 108.4, 52.1, 36.0, 35.1, 28.4; IR (KBr): [small nu, Greek, macron] 1724 cm⁻¹; anal. calcd for C₂₃H₁₈FNO₃: C, 73.59; H, 4.83; N, 3.73% found C, 73.70; H, 4.75; N, 3.66%.

11-(2-Chlorophenyl)-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3e). White solid (373 mg, 78%); m.p. 255–257 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.30 (d, J = 6.9 Hz, 1H), 7.72–7.59 (m, 3H), 7.37–7.23 (m, 3H), 6.36 (d, J = 7.8 Hz, 1H), 2.45 (s, 2H), 2.33 (s, 2H), 1.11 (s, 3H), 1.09 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.6, 161.6, 145.0, 138.8, 134.7, 134.5, 133.2, 131.9, 131.5, 130.9, 130.6, 130.1, 128.9, 126.0, 118.0, 117.9, 113.9, 108.5, 52.1, 35.7, 35.2, 29.3, 27.4; IR (KBr): [small nu, Greek, macron] 1721 cm⁻¹; anal. calcd for C₂₃H₁₈ClNO₃: C, 70.50; H, 4.63; N, 3.57% found C, 70.36; H, 4.56; N, 3.51%.

11-(3-Chlorophenyl)-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3f). White solid (397 mg, 83%); m.p. 282–284 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.17 (d, J = 7.8 Hz, 1H), 7.66–7.62 (m, 2H), 7.51–7.49 (m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 2.47 (s, 2H), 2.35 (s, 2H), 1.09 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.4, 161.3, 144.9, 138.8, 137.9, 135.8, 134.3, 131.5, 131.4, 130.5, 129.8, 128.3, 126.8, 125.8, 118.6, 117.8, 113.9, 108.3, 52.0, 35.9, 35.2, 28.3; IR (KBr): [small nu, Greek, macron] 1719 cm⁻¹; anal. calcd for C₂₃H₁₈ClNO₃: C, 70.50; H, 4.63; N, 3.57% found C, 70.39; H, 4.56; N, 3.51%.

11-(4-Chlorophenyl)-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3g). White solid (392 mg, 82%); m.p. 285–287 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.27 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.46–7.33 (m, 3H), 7.27 (t, J = 7.8 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 2.46 (s, 2H), 2.40 (s, 2H), 1.10 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.3, 161.4, 144.6, 138.9, 136.4, 136.2, 135.4, 131.9, 130.6, 130.0, 129.4, 126.0, 118.5, 118.4, 114.2, 108.3, 52.2, 36.1, 35.2, 28.4; IR (KBr): [small nu, Greek, macron] 1722 cm⁻¹; anal. calcd for C₂₃H₁₈ClNO₃: C, 70.50; H, 4.63; N, 3.57% found C, 70.64; H, 4.56; N, 3.51%.

11-(4-Bromophenyl)-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3h). White solid (379 mg, 79%); m.p. 280–282 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.24 (d, J = 8.1 Hz, 1H), 7.81–7.78 (dd, J₁ = 2.1 Hz, J₂ = 6.6 Hz, 2H), 7.39–7.32 (m, 3H), 7.24 (t, J = 8.2 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 2.44 (s, 2H), 2.36 (s, 2H), 1.08 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 190.8, 161.4, 144.2, 138.7, 135.5, 133.9, 133.2, 131.3, 129.5, 129.3, 125.5, 123.9, 118.1, 117.9, 113.8, 108.4, 51.7, 35.7, 34.7, 28.0; IR (KBr): [small nu, Greek, macron] 1720 cm⁻¹; anal. calcd for C₂₃H₁₈BrNO₃: C, 63.32; H, 4.16; N, 3.21% found C, 63.47; H, 4.07; N, 3.16%.

11-(3-Methoxyphenyl)-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3i). White solid (387 mg, 81%); m.p. 278–280 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.10 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.17–7.08 (m, 3H), 6.97 (d, J = 7.8 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 3.92 (s, 3H), 2.42 (d, J = 6.3 Hz, 2H), 2.23 (d, J = 2.7 Hz, 2H), 1.03 (s, 3H), 1.00 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.3, 161.5, 160.9, 144.7, 138.7, 137.7, 134.2, 131.4, 131.3, 130.9, 125.6, 119.9, 118.8, 117.9, 116.2, 113.9, 113.5, 108.0, 55.7, 52.0, 35.8, 35.0, 28.6, 28.0; IR (KBr): [small nu, Greek, macron] 1721 cm⁻¹; anal. calcd for C₂₄H₂₁NO₄: C, 74.40; H, 5.46; N, 3.62% found C, 74.52; H, 5.38; N, 3.55%.

11-(4-Methoxyphenyl)-9,9-dimethyl-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3j). White solid (373 mg, 78%); m.p. 286–288 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.22 (d, J = 8.1 Hz, 1H), 7.40–7.28 (m, 3H), 7.21–7.12 (m, 3H), 6.55 (d, J = 7.8 Hz, 1H), 3.97 (s, 3H), 2.45 (s, 2H), 2.35 (s, 2H), 1.07 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.4, 161.6, 160.6, 145.1, 138.8, 134.3, 131.6, 130.6, 130.3, 129.2, 129.2, 125.7, 118.7, 118.1, 115.4, 108.1, 55.7, 52.2, 36.0, 35.1, 28.4; IR (KBr): [small nu, Greek, macron] 1726 cm⁻¹; anal. calcd for C₂₄H₂₁NO₄: C, 74.40; H, 5.46; N, 3.62% found C, 74.27; H, 5.37; N, 3.55%.

9,9-Dimethyl-11-(4-nitrophenyl)-8,9,10,11-tetrahydro-6-oxa-11-aza-benzo[a]fluorine-5,7-dione (3k). White solid (407 mg, 85%); m.p. 270–272 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.54 (d, J = 8.7 Hz, 2H), 8.31 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 6.3 Hz, 2H), 7.26 (t, J = 4.8 Hz, 1H), 7.26–7.24 (m, 1H), 6.48 (d, J = 7.8 Hz, 1H), 2.47 (s, 2H), 2.42 (s, 2H), 1.10 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ = 191.4, 161.6, 152.5, 144.5, 135.2, 134.4, 131.9, 129.2, 126.2, 125.5, 124.8, 123.1, 118.3, 118.2, 113.3, 108.5, 51.8, 36.1, 35.2, 28.2; IR (KBr): [small nu, Greek, macron] 1727 cm⁻¹; anal. calcd for C₂₃H₁₈N₂O₅: C, 68.65; H, 4.51; N, 6.96% found C, 68.76; H, 4.44; N, 6.91%.

11-Benzyl-7-hydroxy-8,9,10,11-tetrahydro-7H-6-oxa-11-aza-benzo[a]fluoren-5-one (4a). White solid (377 mg, 75%); m.p. 150–152 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.33 (d, J = 8.4 Hz, 1H), 7.50–7.44 (m, 1H), 7.38 (m, 5H), 7.02 (d, J = 6.9 Hz, 2H), 5.42 (s, 2H), 5.13 (t, J = 4.2 Hz, 1H), 2.70–2.48 (m, 2H), 2.13–1.85 (m, 4H); ¹³C NMR (75 MHz, CDCl₃): δ = 162.6, 140.4, 136.5, 134.7, 134.2, 131.1, 129.1, 127.7, 125.4, 124.6, 118.4, 117.6, 111.6, 108.7, 61.1, 48.5, 31.4, 21.6, 18.5; IR (KBr): [small nu, Greek, macron] 3491, 1695 cm⁻¹; anal. calcd for C₂₂H₁₉NO₃: C, 76.50; H, 5.54; N, 4.06% found C, 76.37; H, 5.49; N, 3.99%.

7-Hydroxy-11-p-tolyl-8,9,10,11-tetrahydro-7H-6-oxa-11-aza-benzo[a]fluoren-5-one (4b). White solid (362 mg, 72%); m.p. 170–172 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.32–8.29 (dd, J₁ = 3.0 Hz, J₂ = 8.1 Hz, 1H), 7.36–7.20 (m, 6H), 6.61 (d, J = 8.1 Hz, 1H), 5.14 (t, J = 4.2 Hz, 1H), 2.50 (s, 3H), 2.69–2.44 (m, 2H), 2.11–1.84 (m, 4H); ¹³C NMR (75 MHz, CDCl₃): δ = 162.5, 139.3, 135.2, 135.0, 134.2, 131.8, 131.3, 130.5, 130.4, 128.0, 127.9, 124.6, 118.5, 117.5, 108.8, 61.2, 31.6, 22.3, 21.3, 18.5; IR (KBr): [small nu, Greek, macron] 3499, 1700 cm⁻¹; anal. calcd for C₂₂H₁₉NO₃: C, 76.50; H, 5.54; N, 4.06% found C, 76.35; H, 5.48; N, 3.99%.

11-Benzyl-7-hydroxy-11H-6-oxa-11-aza-benzo[a]fluoren-5-one (9a). Yellow solid (242 mg, 79%); m.p. 260–262 °C; ¹H NMR (300 MHz, DMSO-d₆): δ = 10.18 (bs, 1H), 8.29 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.27–7.04 (m, 7H), 6.57 (d, J = 5.7 Hz, 1H), 5.90 (s, 2H); ¹³C NMR (75 MHz, DMSO-d₆): δ = 161.6, 151.5, 139.5, 137.9, 135.4, 131.4, 130.5, 129.0, 127.4, 126.9, 126.6, 125.9, 125.9, 120.9, 118.7, 115.3, 106.1, 105.0, 101.4, 48.1; IR (KBr): [small nu, Greek, macron] 3297, 1686 cm⁻¹; anal. calcd for C₂₂H₁₅NO₃: C, 77.41; H, 4.43; N, 4.10% found C, 77.54; H, 4.36; N, 4.05%; HRMS (ESI-TOF) m/z calcd: 342.1130 [M + H]; found: 342.1124.

7-Hydroxy-11-phenyl-11H-6-oxa-11-aza-benzo[a]fluoren-5-one (9b). Yellow solid (329 mg, 82%); m.p. 264–266 °C; ¹H NMR (300 MHz, DMSO-d₆): δ = 10.26 (bs, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.67–7.44 (m, 7H), 7.11–7.05 (m, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.59 (t, J = 4.2 Hz, 1H), 6.46 (t, J = 4.8 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ = 161.4, 151.4, 140.1, 137.7, 135.7, 134.8, 131.3, 130.3, 130.2, 129.4, 128.6, 126.9, 126.7, 119.9, 118.6, 115.9, 106.4, 105.4, 101.4; IR (KBr): [small nu, Greek, macron] 3285, 1680 cm⁻¹; anal. calcd for C₂₁H₁₃NO₃: C, 77.05; H, 4.00; N, 4.28% found C, 77.20; H, 3.93; N, 4.22%; HRMS (ESI-TOF) m/z calcd: 328.0974 [M + H]; found: 328.1272.

7-Hydroxy-11-p-tolyl-11H-6-oxa-11-aza-benzo[a]fluoren-5-one (9c). Yellow solid (249 mg, 81%); m.p. 280–282 °C; ¹H NMR (300 MHz, DMSO-d₆): δ = 10.18 (bs, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.55–7.53 (m, 1H), 7.48–7.35 (m, 5H), 7.00 (t, J = 8.1 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 3.26 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆): δ = 161.4, 151.3, 140.2, 138.9, 135.5, 135.0, 134.8, 131.2, 130.7, 130.3, 128.3, 126.8, 126.6, 119.9, 118.6, 115.8, 106.2, 105.2, 101.4, 20.9; IR (KBr): [small nu, Greek, macron] 3290, 1682 cm⁻¹; anal. calcd for C₂₂H₁₅NO₃: C, 77.41; H, 4.43; N, 4.10% found C, 77.30; H, 4.37; N, 4.05%; HRMS (ESI-TOF) m/z calcd: 342.1130 [M + H]; found: 342.1246.

11-(4-Fluorophenyl)-7-hydroxy-11H-6-oxa-11-aza-benzo[a]fluoren-5-one (9d). Yellow solid (255 mg, 82%); m.p. 278–280 °C; ¹H NMR (300 MHz, DMSO-d₆): δ = 10.43 (bs, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.66–7.38 (m, 6H), 7.14 (t, J = 8.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆, F coupled ¹³C spectra): δ = 163.7, 161.4, 160.4, 151.4, 140.3, 135.7, 134.9, 134.0, 131.3, 130.9, 130.8, 130.1, 126.9, 126.8, 119.8, 118.6, 117.3, 117.0, 115.9, 106.3, 105.5, 101.2; IR (KBr): [small nu, Greek, macron] 3296, 1686 cm⁻¹; anal. calcd for C₂₁H₁₂FNO₃: C, 73.04; H, 3.50; N, 4.06% found C, 72.90; H, 3.44; N, 4.00%.

7-Hydroxy-11-(3-methoxyphenyl)-11H-6-oxa-11-aza-benzo[a]fluoren-5-one (9e). Yellow solid (257 mg, 80%); m.p. 262–264 °C; ¹H NMR (300 MHz, DMSO-d₆): δ = 10.24 (bs, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.66–7.45 (m, 3H), 7.23–7.05 (m, 4H), 6.87 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 3.80 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆): δ = 161.4, 160.5, 151.3, 140.1, 138.8, 135.7, 134.9, 131.2, 131.0, 130.2, 126.9, 126.7, 120.5, 120.0, 118.6, 115.8, 115.3, 114.0, 106.3, 105.4, 101.5, 55.6; IR (KBr): [small nu, Greek, macron] 3293, 1687 cm⁻¹; anal. calcd for C₂₂H₁₅NO₄: C, 73.94; H, 4.23; N, 3.92% found C, 73.85; H, 4.16; N, 3.86%.

7-Hydroxy-11-(4-methoxyphenyl)-11H-6-oxa-11-aza-benzo[a]fluoren-5-one (9f). Yellow solid (260 mg, 81%); m.p. 282–284 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.43–8.40 (dd, J₁ = 1.2 Hz, J₂ = 8.1 Hz, 1H), 7.49–7.37 (m, 4H), 7.17–7.10 (m, 3H), 6.92 (d, J = 8.1 Hz, 1H), 6.68–6.61 (m, 2H), 6.04 (s, 1H), 3.95 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ = 161.9, 159.9, 149.1, 140.0, 138.7, 134.4, 131.9, 130.6, 130.2, 129.7, 126.5, 126.5, 120.1, 119.0, 116.4, 115.0, 105.8, 105.7, 102.8, 55.5; IR (KBr): [small nu, Greek, macron] 3289, 1681 cm⁻¹; anal. calcd for C₂₂H₁₅NO₄: C, 73.94; H, 4.23; N, 3.92% found C, 73.83; H, 4.17; N, 3.85%; HRMS (ESI-TOF) m/z calcd: 358.1079 [M + H]; found: 358.1073.

Acknowledgements

S.P. and S.M. thank CSIR and A. K. thanks UGC, New Delhi, India, for offering Senior Research Fellowship (SRF). D. D. acknowledges UGC for Dr D. S. Kothari Postdoctoral Fellowship. The financial assistance of CSIR, New Delhi is gratefully acknowledged [Major Research Project, no. 02(0007)/11/EMR-II]. Crystallography was performed at the DST-FIST, India-funded Single Crystal Diffractometer Facility at the Department of Chemistry, University of Calcutta.

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Footnote

† Electronic supplementary information (ESI) available: ¹H, ¹³C data of compounds 2, 3, 4 and 9 and crystallographic data for 9a, 9f. CCDC 940456–940459 and 940478. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra01060h

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