Synthesis of biologically active pyridoimidazole/imidazobenzothiazole annulated polyheterocycles using cyanuric chloride in water

Abstract

An efficient and mild protocol for rapid access to N-fused polyheterocycles via Pictet–Spengler type 6-endo cyclization using cyanuric chloride in an aqueous reaction medium has been developed. The protocol was successfully applied to a wide range of compounds including aryl/heteroaryl aldehydes (8a–o), ketones (10a–e), an electron-rich metallocene aldehyde (8e) and indoline-2,3-diones (12a–c) using cyanuric chloride (15–20 mol%) with tetra-n-butylammonium bromide (TBAB) (2.0 eq.) as an additive at 80–90 °C to give a good to excellent yield (66–92%) of polyheterocycles. Some of the synthesized compounds were found to exhibit antiplasmodial activity against chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 strains of Plasmodium falciparum.

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Introduction

Research involving reactions in aqueous media, including syntheses of organic heterocycles in water, has been growing tremendously in the past few decades in order to satisfy environmental concerns.¹ Water as a universal solvent has great impact, as it is environmentally acceptable, non-flammable and economical. Organic reactions in water have become exciting and/or essential research endeavors. Indeed, industry prefers to use water as a solvent rather than conventional toxic organic solvents. Although most inorganic reactions can be carried out using water as a solvent, it is not the preferred solvent for organic reactions because of poor solubility of most organic compounds in water.² To overcome the solubility problem, micellar catalysis has been found to be very helpful to allow utilization of aqueous media for carrying out several organic transformations.³

As small organic scaffolds, polyheterocycles are invaluable structural motifs with many applications in the pharmaceutical⁴ and material sciences.⁵ The pyridoimidazole (PI) and imidazobenzothiazole (IBT) substructures are found in several drugs and biologically active molecules.^6,7 For example, the annulated dipyridoimidazoles (Glu-P1 and Glu-P2) (Fig. 1, panels I and II) exhibit anti-cancer activity,⁸ pyridino[1,2-a]imidazo[5,4-b]-indole (Fig. 1, panel III) is a well known anti-hypertensive agent,⁹ and dihydropyrano imidazopyridine (Fig. 1, panel IV) is a potassium-competitive acid blocker used for treatment of gastroesophageal reflux disease.¹⁰ Furthermore, the privileged benzothiazole motif has been recently functionalized by formation of rings (i.e., annulations) with other pharmacophores to prepare pharmaceutically important scaffolds¹¹ such as the arylimidazo-benzothiazole derivative YM-201627 (Fig. 1, panel V) for the treatment of solid tumours.¹² Racemic spirotetrahydro β-carboline-based spiroazepineindole has also been recently shown to exhibit antiplasmodial activity (Fig. 1, panel VI).¹³

Fig. 1 Several biologically active fused polyheterocycles.

In the present work we report the use of privileged PI and IBT structures along with Pictet–Spengler-type cyclizations in aqueous medium to produce a moderate to good yield of biologically relevant polyheterocycles (Fig. 2). The Pictet–Spengler reaction is one of the most powerful strategies for constructing C–C bonds. Previously, the Pictet–Spengler reaction has been performed using strong Brønsted acids such as trifluoroacetic acid (TFA) and methanesulfonic acid, which tend to result in diminished yields, lead to long reaction times, create difficulties in work-up and/or require the use of conventional solvents.^14–16 We chose cyanuric chloride as in our previous work^17,18 and in research reported in the literature¹⁹ it was found to be effective in several transformations. Although there are some reports of the Pictet–Spengler reaction using only water as the medium,²⁰ the use of the combination of water with cyanuric chloride for such transformations has not been reported in the literature. The reaction of cyanuric chloride with water produces HCl and cyanuric acid, which could be useful in carrying out the organic reactions under mild conditions while at the same time producing metal-free, non-volatile and essentially non-toxic side products that should encourage its application in medicinal chemistry.

Fig. 2 Comparison of our Pictet–Spengler cyclisation strategy with previous work. TBAB = tetra-n-butylammonium bromide.

Very recently, Sawant et al. developed a similar cyanuric chloride-promoted Pictet–Spengler cyclisation, but in dimethyl sulfoxide (DMSO) and with limited examples (Fig. 2).²¹ In contrast, we present an extensive polyheterocyclic library with skeletal diversity using a relatively mild and “green” protocol by employing a range of oxo-substrates, such as aryl aldehydes, acetophenones and indoline-2,3-diones. Furthermore, for the first time we focus on using imidazo[1,2-a]benzothiazole as a substrate for such a transformation. It is worth mentioning that compounds bearing pyrido[1,2-a]imidazole annulations have been demonstrated to possess a variety of pharmacological properties.⁹ Therefore, we speculated that this skeleton, upon fusion with aryl quinolone, may generate significant interest regarding its biological activity.²²

Results and discussion

The modified Pictet–Spengler reaction is a two-step process, where an aryl amine and an oxo-substrate first react to give an imine as an intermediate followed by a 6-endo intramolecular cyclization to provide the cyclic product. In the present work the desired aryl amines 6 and 7 (see Scheme 1) were prepared in a mild two-step procedure from 2-amino azines 1 and 2, respectively. Previously, however, synthon 6 was generally synthesized by bromination of 2-nitroacetophenone under harsh conditions.¹⁶ Condensation with 1-(2,2-dibromovinyl)-2-nitrobenzene²³ (3) gives intermediates 4 and 5,²⁴ which upon reduction with Fe powder/acetic acid provides the desired PI substrates 6 and 7 in good yields.

Scheme 1 Synthesis of proposed IP substrates for Pictet–Spengler type cyclization.

The Pictet–Spengler reaction between pyridoimidazole arylamine (6) and benzaldehyde (8a) was further explored to identify the optimal reaction conditions. Several Brønsted acids were evaluated as catalysts at various temperatures in organic and aqueous media (Table 1). Out of all Brønsted acids in different solvents (entries 1–5) screened, cyanuric chloride (20 mol%) in CH₃CN (entry 5) seemed promising, therefore, further refinement was limited to varying the solvents and temperature. Comparison of entries 5 and 7 suggests that increasing the polarity of an aprotic solvent may increase reaction yield, but upon replacing the aprotic solvent, DMSO, with the protic solvent, water, a slight drop in yield was observed (entry 8). Interestingly, further improvement of yield, ease of handling (without inert conditions) and reaction time was found upon using cyanuric chloride (15 mol%) as the reagent, water as the solvent, and a stoichiometric amount of TBAB as an additive (entry 9), which prompted us to further optimise the reaction conditions in aqueous media. Increasing the amount of cyanuric chloride to 20 mol% and of TBAB to 2 eq. was found to be beneficial in terms of reaction yield and time (entry 10). However, a further increase of TBAB to 3 eq. was not of significant benefit (entry 11). Replacing the TBAB with other additives was found to decrease effectiveness (compare entries 10, 12 and 13). A slight increase in cyanuric chloride loading to 30 mol% was also not beneficial (entry 14). As predicted, the reaction did not work at all without cyanuric chloride (entry 15). Thus, a survey of different reaction conditions (compare entries 9, 10, 14) identified 20 mol% cyanuric chloride with 2.0 eq. TBAB to be the optimum conditions (entry 10). The use of p-toluenesulfonic acid (PTSA) in place of cyanuric chloride under otherwise optimized conditions provided the aromatic polycyclic product but the yield was poor (entry 16). To further validate our assumption that we had reached an optimized condition, we ran the same reaction with TBAB (2.0 eq.) in water but with cyanuric acid (20 mol%) in place of cyanuric chloride, which led to the polyheterocycles (9a) in a similar yield but with a prolonged reaction time (entry 17).

Table 1 Table for the optimisation of the reaction conditions for a Pictet–Spengler reaction^a

Entry	Reagent (mol%)	Additive (eq.)	Solvent	Temp (°C)	Time (h)	Yield^b (%)
a Reaction conditions: substrate 6 (0.5 mmol), substrate 8a (0.5 mmol), reagent (20 mol%), additive (2.0 eq.), solvent (0.64 M) at 90 °C for 1.5 h.b Isolated yield.c Tetramethylammonium iodide.d Reaction without cyanuric chloride.e No reaction. DCM: dichloromethane; THF: tetrahydrofuran.
1	TFA (500)	—	DCM	70	6	34
2	PTSA (20)	—	Toluene	120	5	46
3	CH3COOH	—	Neat	90	5	54
4	CH3SO3H (100)	—	EtOH	90	5	45
5	Cyanuric chloride (20)	—	CH3CN	85	3	56
6	Cyanuric chloride (20)	—	THF	75	3	52
7	Cyanuric chloride (20)	—	DMSO	90	2.0	68
8	Cyanuric chloride (15)	—	H2O	90	3.0	62
9	Cyanuric chloride (15)	TBAB (1.0)	H2O	90	2.0	73
10	Cyanuric chloride (20)	TBAB (2.0)	H2O	90	1.5	82
11	Cyanuric chloride (20)	TBAB (3.0)	H2O	90	1.5	83
12	Cyanuric chloride (20)	TMAI^c (1.0)	H2O	90	2.0	71
13	Cyanuric chloride (20)	Al2O3 (1.0)	H2O	90	2.0	67
14	Cyanuric chloride (30)	TBAB (2.0)	H2O	90	1.5	76
15	—^d	TBAB (2.0)	H2O	90	4	nr^e
16	PTSA (20)	TBAB (2.0)	H2O	90	3	46
17	Cyanuric acid (20)	TBAB (2.0)	H2O	90	3.0	79

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The optimized reaction condition (Table 1, entry 10) was applied to an array of aromatic/heteroaromatic (HetAr) aldehydes appended with various substituents (8a–o, Table 2). Neither steric nor electronic factors had a significant impact on the reaction time and/or yield (products 9a–s). Furthermore, the organometallic and heteroaromatic aldehydes 8e and 8n also participated in a similar way, producing good yields of compounds 9e and 9r, respectively.

Table 2 Scope of the reaction with different aromatic and heteroaromatic aldehydes^a

Entry	Ar/HetAr aldehyde	X	Yield^b (%)
a Reaction conditions: 6 or 7 (0.5 mmol), Ar/HetAr aldehyde (8a–o) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 90 °C for 1.5 h.b Isolated yield.
9a	Benzaldehyde (8a)	H	82
9b	4-Nitrobenzaldehyde (8b)	H	90
9c	4-Flourobenzaldehyde (8c)	H	82
9d	4-Methoxybenzaldehyde (8d)	H	77
9e	Ferrocene aldehyde (8e)	H	75
9f	Benzaldehyde (8a)	CH3	82
9g	4-Nitrobenzaldehyde (8b)	CH3	92
9h	2-Nitrobenzaldehyde (8f)	CH3	77
9i	3-Nitrobenzaldehyde (8g)	CH3	82
9j	4-Cyanobenzaldehyde (8h)	CH3	86
9k	4-Isopropylbenzaldehyde (8i)	CH3	83
9l	4-Bromobenzaldehyde (8j)	CH3	86
9m	4-(N,N-Dimethylamino)benzaldehyde (8k)	CH3	75
9n	4-Methoxybenzaldehyde (8d)	CH3	78
9o	4-Hydroxybenzaldehyde (8l)	CH3	72
9p	3,4,5-Trimethoxybenzaldehyde (8m)	CH3	79
9q	4-Flourobenzaldehyde (8c)	CH3	83
9r	Pyridine-4-aldehyde (8n)	CH3	82
9s	1-Naphthaldehyde (8o)	CH3	87

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Interestingly, less reactive aromatic/HetAr ketone electrophiles also successfully participated in the Pictet–Spengler reaction (Table 3), with slightly improved reaction conditions [15 mol% cyanuric chloride with 2.0 eq. of TBAB at 80 °C in water (compare with Table 1, entry 10)] to produce the high yields (82–88%) of polyheterocycles 11a–f shown in Table 3.

Table 3 Reactions with different aromatic/HetAr ketones^a

Entry	Ar/HetAr ketones	X	Yield^b (%)
a Reaction conditions: 6 or 7 (0.5 mmol), Ar/HetAr ketones (10a–e) (0.5 mmol), cyanuric chloride (15 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 80 °C for 1.5 h.b Isolated yield.
11a	Acetophenone (10a)	H	82
11b	1-(4-Nitrophenyl)ethanone (10b)	H	86
11c	1-(4-Methoxyphenyl)ethanone (10c)	H	82
11d	1-(4-Bromophenyl)ethanone (10d)	H	84
11e	Acetophenone (10a)	CH3	88
11f	1-(Thiophen-2-yl)ethanone (10e)	H	83

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The spirooxindole core has great importance for medicinal chemistry and is found in several natural products such as spirotryprostatins A and B,^25a horsfiline,^25b rhynchophylline,^25c and marcfortine A.^25d Therefore, spirooxiindole-fused azapolycycles were prepared using our method, starting with indole-2,3-dione (12a) and its analogues (12b,c). Cyanuric chloride gave moderate to good yields (66–72%, Table 4) of the spirofused cyclic frameworks 13a–d.

Table 4 Synthesis of spiro-oxyindoles 13a–d via the Pictet–Spengler reaction^a

Entry	Indoline-2,3-dione and analogues	X	R1	Yield^b (%)
a Reaction conditions: 6 or 7 (0.5 mmol), indole-2,3-dione and its analogues (12a–c) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 90 °C for 3.0 h.b Isolated yield.
13a	Indoline-2,3-dione (12a)	H	H	66
13b	1-Ethylindoline-2,3-dione (12b)	H	Et	69
13c	1-Methylindoline-2,3-dione (12c)	CH3	Me	72
13d	1-Ethylindoline-2,3-dione (12b)	CH3	Et	68

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Preparation of tricyclic imidazobenzothiazoles 19 and 20 (Scheme 2), novel substrates for the Pictet–Spengler reaction, was analogous to the preparation of 6 and 7, and carried out under the previously optimized reaction condition (Scheme 1). These substrates were successfully transformed into their respective polycyclic systems 21a–f with good yields as shown in Table 5.

Scheme 2 Synthesis of the proposed tricyclic substrate (19, 20) for Pictet–Spengler cyclisation.

Table 5 Synthesis of IBT polyheterocycles (21a–f) via the Pictet–Spengler reaction^a

Entry	Aryl aldehyde	Y	Yield^b (%)
a Reaction conditions: 19 or 20 (0.5 mmol), aryl aldehyde (8a-b or 8d or 8j) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 90 °C for 2.0 h.b Isolated yield.
21a	Benzaldehyde (8a)	H	76
21b	4-Nitrobenzaldehyde (8b)	H	83
21c	4-Methoxybenzaldehyde (8d)	H	78
21d	4-Nitrobenzaldehyde (8b)	CH3	78
21e	4-Methoxybenzaldehyde (8d)	CH3	76
21f	4-Bromobenzaldehyde (8j)	CH3	78

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In addition, substrate 19 was condensed with different electron-deficient or electron-rich aromatic ketones and 10a–c with cyanuric chloride to obtain their corresponding polyheterocycles 22a–c (Table 6).

Table 6 Synthesis of IBT polyheterocycles (22a–c) using acetophenones^a

Entry	Acetophenones	Yield^b (%)
a Reaction conditions: 19 (0.5 mmol), Ar ketone (10a–c) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 80 °C for 2.0 h.b Isolated yield.
22a	Acetophenone (10a)	76
22b	1-(4-Nitrophenyl)ethanone (10b)	78
22c	1-(4-Methoxyphenyl)ethanone (10c)	74

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A plausible mechanism for the formation of the polyheterocycles is proposed in Fig. 3. The rate-determining step of the Pictet–Spengler reaction is the conversion of the imine intermediate to the cyclised product by a 6-endo intramolecular electrophilic reaction. From research in the literature, we envisage that cyanuric chloride under aqueous conditions releases hydrochloric acid and cyanuric acid.^18,26 The generated HCl as well as cyanuric acid (23a) (entry 17, Table 1) may activate the imine 23b, converting it to the quaternized imine salt 23c to facilitate 6-endo intramolecular cyclisation to provide 23d. When this intermediate 23d is an acetophenone (11a) or indole-2,3-dione (13a), its deprotonation would afford the polycylic product, but when the intermediate is an aromatic aldehyde, its deprotonation and aerial oxidation would lead to the aromatised polyheterocycle (9a).

Fig. 3 Proposed mechanism for synthesis of different polyheterocycles.

Biological activity

Bioevaluation methods.
In vitro assay for evaluation of antimalarial activity. The compounds were evaluated for antimalarial activity against both chloroquininesensitive 3D7 (CQ-S) and chloroquinine-resistant K1 (CQ-R) strains of Plasmodium falciparum using malaria SYBR Green I nucleic acid staining dye-based fluorescence assay as described by Singh et al.²⁷ The stock solution (5 mg mL⁻¹) was prepared in DMSO and test dilutions were prepared in culture medium (RPMI-1640-FBS). Chloroquine was used as a reference drug. The compounds were tested in 96-well plates (in duplicate wells). A parasitized cell suspension (1.0%) containing 0.8% parasitemia was used. The plates were incubated at 37 °C in a CO₂ incubator in an atmosphere of 5% CO₂ and air mixture. After 72 h, 100 mL of lysis buffer containing 2× concentration of SYBR Green-I (Invitrogen) was added to each well and incubated for 1 h at 37 °C. Relative fluorescence units (RFU) of the wells were measured at 485 ± 20 nm excitation and 530 ± 20 nm emission using the fluorescence plate reader (FLUOstar, BMG LabTech). Data were transferred into a graphic programme (EXCEL) and the concentration values corresponding to 50% growth inhibition of the parasite (IC₅₀) were obtained by Logit regression analysis using a pre-programmed Excel spreadsheet.
In vitro assay for evaluation of cytotoxic activity. Cytotoxicity of the compounds was evaluated using a Vero cell line (C 1008; Monkey kidney fibroblast) following the method described by Sashidhara et al.²⁸ The cells were incubated with compound dilutions for 72 h and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used as the reagent for the detection of cytotoxicity. The 50% cytotoxic concentration (CC₅₀) was determined using non-linear regression analysis using a pre-programmed Excel spreadsheet. The Selectivity Index was calculated as SI equals CC₅₀/IC₅₀.

To assess their potential biological activities, subsets of the synthesized compounds were evaluated for their in vitro antimalarial activity against CQ-S 3D7 and CQ-R K1 strains of P. falciparum and their cytotoxicity toward the VERO cell line (Table 7). Compounds 9j, 9l, 9m, 9p, 11a, 11b, 11d, 11f and 13a exhibited low micromolar antiplasmodial activity against both strains, which were comparable to chloroquine for the CQ-resistant organism and were much less active than chloroquine for the CQ-sensitive parasite.

Table 7 In vitro antimalarial activity of compounds against 3D7 and K1 strains of P. falciparum and their cytotoxicity against the VERO cell line

Comp. no.	IC50^a (μM)		CC50^b (μM)
	CQ-S (3D7)	CQ-R (K1)
a IC50 (μM): concentration corresponding to 50% growth inhibition of the parasite.b CC50 (μM): concentration corresponding to 50% toxicity.c ND: not done.d Biological activity of the standard drug chloroquine.
9a	3.40	ND^c	34.54
9b	4.62	ND	66.63
9c	>5.0	ND	104.92
9d	1.24	ND	24.23
9e	2.05	ND	21.94
9f	3.04	ND	37.10
9j	2.83	0.53	43.36
9l	0.99	1.02	31.92
9m	0.75	0.56	25.57
9n	1.07	ND	33.98
9p	0.56	0.67	13.01
9q	1.71	ND	28.47
11a	0.20	0.50	50.17
11b	0.48	0.27	42.16
11d	0.22	0.50	32.28
11f	0.84	0.96	20.92
13a	1.04	1.87	73.02
13b	1.12	ND	80.76
CQ^d	0.005	0.15	125

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Conclusion

In summary, we have developed a mild protocol for the synthesis of annulated polyheterocycles through Pictet–Spengler type 6-endo cyclisation reactions under aqueous conditions. The process is applicable to a variety of aryl/HetAr/metallocene aldehydes, ketones, and indoline-2,3-diones. High yields, mild reaction conditions, operational simplicity and minimum environmental pollution are the key features of our methodology that make it useful for the construction of pharmaceutically important heterocycles, demonstrated by the observation of moderate anti-plasmodial activity in vitro.

Experimental section

General

Melting points are uncorrected and were determined in capillary tubes on a precision melting point apparatus containing silicon oil. Infrared (IR) spectra were recorded on an FTIR spectrophotometer Shimadzu 8201 PC and are reported in terms of frequency of absorption (cm⁻¹). ¹H-NMR and ¹³C-NMR spectra were recorded either on a Bruker DPX-200, a Bruker Advance DRX-300 FT or a Bruker Advance DRX-400 FT spectrometer. Nuclear magnetic resonance (NMR) spectra were recorded on 300 MHz and 400 MHz spectrometers for ¹H-NMR and 50, 75, 100 MHz for ¹³C-NMR in deuterated chloroform (CDCl₃) or deuterated dimethylsulfoxide (DMSO-d₆) with trimethylsilane (TMS) as the internal reference wherever mentioned. Chemical shifts (δ) are reported in parts per million (ppm) for ¹H-NMR and ¹³C-NMR spectra. Coupling constants, J, are reported in hertz (Hz). Multiplicities are reported as follows: singlet (s), broad (br), doublet (d), triplet (t), quartet (q), and multiplet (m). The high-resolution mass spectroscopy (HRMS) spectra were recorded as electrospray ionization (ESI)-HRMS on an Agilent 6520 Q-TOF, LC-MS/MS mass spectrometer. The progress of the reaction was routinely monitored by thin-layer chromatography (TLC) on pre-coated silica gel plates. Column chromatography was performed over silica gel. All the solvents and chemicals were used as procured from the suppliers.

1-(2,2-Dibromovinyl)-2-nitrobenzene (7). To a chilled solution of triphenylphosphine (3.934 g, 15.0 mol) in DCM (40 mL), carbon tetrabromide (CBr₄) (9.948 g, 30 mol) was added in fractions for 15 minutes. To this solution, 2-nitrobenzaldehyde (2.266 g, 15.0 mmol) in DCM (10 mL) was added dropwise (through a dropping funnel) for 15 minutes at 0 °C and the reaction was allowed to run for 4 h at ambient temperature. After completion (monitored by TLC), the reaction mixture was poured into hexane and the precipitated triphenylphosphine oxide was filtered using sintering. This filtrate was concentrated under reduced pressure followed by column chromatography using 60–120 mesh silica gel with CHCl₃ as eluent, to obtain the intermediate 7 as a yellow solid (3.90 g, yield 85%).²³

General procedure 1

Synthesis of intermediates 4, 5, 17 and 18. To a stirred solution of different 2-amino pyridines (1 or 2) (10.0 mmol) or 2-amino benzothiazoles (14 or 15) (10.0 mmol) in dimethylformamide (DMF; 8 mL), NaHCO₃ (40.0 mmol) was added followed by addition of 1-(2,2-dibromovinyl)-2-nitrobenzene (7) (10.0 mmol), and the reaction was allowed to run for 6 h at 120 °C. After completion (monitored by TLC), the reaction mixture was poured into water and extracted with ethyl acetate (40 mL × 4), the organic layer was dried over Na₂SO₄ and evaporated under reduced pressure followed by column chromatography using 60–120 mesh silica gel with 20% ethyl acetate–hexane as eluent to obtain the solid products (4, 5, 17 and 18) with yields of 75–85%.²⁴

General procedure 2

Synthesis of intermediates 6, 7, 19 and 20. To a solution of intermediates 4 or 5 or 17 or 18 (10.0 mmol) in acetic acid (10 mL), Fe powder (50.0 mmol) was added. The reaction mixture was heated at 90 °C for 40 minutes. After completion of the reaction (indicated by a change in colour of the reaction mixture from brown to yellow and monitored by TLC), the reaction mixture was filtered through a celite pad followed by neutralisation with 10% sodium bicarbonate solution and extracted with ethyl acetate (40 mL × 3). The combined organic layer was dried over Na₂SO₄, concentrated under reduced pressure and the crude product was purified by column chromatography using 60–120 mesh silica gel with ethyl acetate–hexane (30%) as eluent to get the intermediates 6, 7, 19, and 20 as brown solids (yield 78–84%).
2-(3-Methyl-imidazo[2,1-b]-benzothiazol-6-yl)-phenylamine (7). The title compound was obtained according to general procedure 2 as a brown solid. Yield: 2.17 g, 78%; mp: 140–143 °C; IR (KBr): ν 761, 1215, 1388, 1614, 3020, 3432 cm⁻¹, ¹H-NMR (CDCl₃, 300 MHz): 7.87 (s, 1H), 7.51–7.47 (m, 3H), 7.26 (s, 1H), 7.13 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 7.6 Hz, 2H), 2.47 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 147.7, 146.5, 145.2, 135.0, 130.2, 130.1, 128.5, 127.6, 127.2, 124.4, 117.6, 116.9, 112.4, 107.3, 21.4 ppm; HRMS (ESI) calculated for [M + H]⁺: C₁₆H₁₄N₃S: 280.0908, actual: 280.0917.

General procedure 3

Synthesis of 6-phenyl-5,6b,11-triaza-benzo[a]fluorenes (9a–s). To a solution of Pictet–Spengler substrate (6 or 7) (0.96 mmol) in water (1.5 mL), each one of the desired aromatic aldehydes (8a–o) (1 eq.) was added followed by addition of tetra-n-butylammonium bromide (2.0 eq.). The reaction mixture was stirred for 15 minutes followed by addition of cyanuric chloride (0.19 mmol, 20 mol%) at 90 °C. The reaction was allowed to run for 1.5 h. After completion (monitored by TLC), the reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure and the crude product was purified by column chromatography using 60–120 mesh silica gel with 3% MeOH–CHCl₃ as eluent to obtain good to excellent yields of the Pictet–Spengler products 9a–s.
6-Phenyl-5,6b,11-triaza-benzo[a]fluorene (9a). The title compound was obtained according to general procedure 3 using substrate 6 as an off-white solid. Yield: 0.23 g, 82%; mp: 214–217 °C; IR (KBr): ν 1386, 1489, 3023 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz): δ 8.81 (d, J = 7.9 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 6.9 Hz, 1H), 7.95 (d, J = 9.1, 1H), 7.82 (t, J = 7.1, 1H), 7.73 (br, 3H), 7.66–7.61 (m, 3H), 7.54 (t, J = 7.5, 1H), 6.80 (t, J = 6.8, 1H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 149.6, 148.2, 147.2, 145.0, 138.2, 129.9, 129.6, 129.5, 129.3, 128.9, 128.7, 127.1, 126.5, 122.6, 121.4, 120.3, 117.9, 112.0 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₀H₁₄N₃: 296.1183, actual: 296.1178.
6-(4-Nitro-phenyl)-5,6b,11-triaza-benzo[a]fluorene (9b). The title compound was obtained according to general procedure 6 as a pale-yellow solid. Yield: 0.29 g, 90%; mp: >250 °C; IR (KBr): ν 1384, 1600, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.83 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 8.4 Hz, 2H), 8.30 (d, J = 7.8 Hz, 1H), 8.04–7.96 (m, 4H), 7.86–7.75 (m, 2H), 7.61 (t, J = 7.8, 1H), 6.89 (t, J = 6.9, 1H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 149.9, 148.7, 147.8, 145.5, 145.0, 144.7, 139.4, 130.4, 130.3, 129.8, 129.4, 127.4, 126.8, 124.6, 122.9, 118.5, 112.7 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₀H₁₃N₄O₂: 341.1039, actual: 341.1032.
6-(4-Flouro-phenyl)-5,6b,11-triaza-benzo[a]fluorene (9c). The title compound was obtained according to general procedure 6 as a brown solid. Yield: 0.24 g, 82%; mp: 209–212 °C; IR (KBr): ν 1384, 1612, 3021 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.81 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H), 8.07 (d, J = 5.7, 1H), 7.96 (d, J = 8.1, 1H), 7.80–7.74 (m, 4H), 7.57 (t, J = 7.5, 1H), 7.37 (t, J = 7.8, 2H), 6.84 (t, J = 5.1, 1H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 161.1, 149.7, 147.3, 147.0, 144.9, 134.4, 130.8, 130.7, 130.0, 129.5, 129.0, 126.9, 126.7, 122.6, 121.3, 118.0, 116.6, 116.2, 112.1 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₀H₁₃FN₃: 314.1094, actual: 314.1116.
6-(4-Methoxy-phenyl)-5,6b,11-triaza-benzo[a]fluorene (9d). The title compound was obtained according to general procedure 3 as an off-white solid. Yield: 0.24 g, 77%; mp: 224–227 °C; IR (KBr): ν 1384, 1610, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.82 (d, J = 7.5 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.20 (d, J = 6.7, 1H), 7.97 (d, J = 9.0, 1H),7.81–7.68 (m, 4H), 7.58 (t, J = 7.8, 1H), 7.19 (d, J = 8.0, 2H), 6.85 (t, J = 6.7, 1H), 3.97 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 160.8, 149.7, 148.2, 147.4, 145.2, 130.7, 130.2, 130.0, 129.6, 128.9, 127.3, 126.5, 122.7, 121.4, 120.6, 118.1, 114.8, 112.0 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₂₁N₂O₄: 365.1501, actual: 365.1501.
6-(Ferrocenyl)-5,6b,11-triaza-benzo[a]fluorene (9e). The title compound was obtained according to general procedure 3 as a black solid. Yield: 0.28 g, 75%; mp: 216–219 °C; IR (KBr): ν 1384, 1640, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.75 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 6.6 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.81 (t, J = 7.4 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.0 Hz, 1H), 6.81 (t, J = 6.6 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 4.47 (s, 5H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 149.2, 146.3, 145.2, 139.2, 129.5, 129.4, 128.5, 127.8, 126.1, 122.5, 122.0, 121.3, 117.7, 111.3, 87.2, 70.6, 70.3, 68.7, ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₄H₁₈FeN₃: 404.0850, actual: 404.0844.
6-(Phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9f). The title compound was obtained according to general procedure 3 as an orange solid. Yield: 0.24 g, 82%; mp: 217–220 °C; IR (KBr): ν 1384, 1485, 1652, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.78 (d, J = 6.4 Hz, 1H), 8.29 (d, J = 6.2 Hz, 1H), 7.90 (d, J = 5.7, 1H), 7.78–7.62 (m, 8H), 6.61 (d, J = 5.8, 1H), 2.47 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 150.3, 148.0, 147.7, 145.1, 141.7, 138.5, 129.6, 129.4, 128.9, 126.4, 126.3, 122.8, 121.6, 120.4, 116.3, 114.8, 21.8 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₆N₃: 310.1344, actual: 310.1339.
6-(4-Nitro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9g). The title compound was obtained according to general procedure 3 as a yellow solid. Yield: 0.31 g, 92%; mp: >250 °C; IR (KBr): ν 1384, 1653, 2924 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz): δ 8.79 (d, J = 7.8 Hz, 1H), 8.52 (d, J = 8.4 Hz, 2H), 8.27 (d, J = 8.2, 1H), 7.98 (d, J = 8.4, 2H), 7.88 (d, J = 7.0, 1H), 7.83 (t, J = 7.2, 1H), 7.76 (t, J = 7.5, 1H), 7.69 (s, 1H), 6.68 (d, J = 7.0, 1H), 2.50 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): compound is too insoluble to record a carbon NMR spectrum; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₅N₄O₂: 355.1195, actual: 355.1193.
6-(2-Nitro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9h). The title compound was obtained according to general procedure 3 as a yellow solid. Yield: 0.26 g, 77%; mp: >250 °C; IR (KBr): ν 1389, 1648, 3021 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz): δ 8.80 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.4 Hz, 1H), 7.83–7.66 (m, 5H), 7.53 (d, J = 7.0, 1H), 6.62 (d, J = 6.9, 1H), 2.48 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 150.4, 148.2, 147.1, 144.7, 144.2, 143.3, 134.7, 132.9, 131.8, 131.3, 129.5, 129.0, 127.4, 125.5, 125.3, 122.8, 121.6, 120.8, 116.2, 21.9 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₅N₄O₂: 355.1195, actual: 355.1236.
6-(3-Nitro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9i). The title compound was obtained according to general procedure 3 as a yellow solid. Yield: 0.28 g, 82%; mp: >250 °C; IR (KBr): ν 1389, 1648, 3021 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.80 (d, J = 7.8 Hz, 1H), 8.67 (s, 1H), 8.50 (d, J = 7.9 Hz, 1H), 8.28 (d, J = 8.1, 1H), 8.14 (d, J = 7.1, 1H), 7.90–7.72 (m, 5H), 6.69 (d, J = 7.0, 1H), 2.51 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 150.4, 148.7, 147.9, 145.0, 144.8, 142.4, 140.1, 135.1, 130.4, 129.5, 129.3, 127.1, 125.6, 124.5, 124.3, 122.9, 121.5, 119.9, 116.6, 115.5, 21.9 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₅N₄O₂: 355.1195, actual: 355.1237.
6-(4-Cyano-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9j). The title compound was obtained according to general procedure 3 as a beige solid. Yield: 0.27 g, 86%; mp: >250 °C; IR (KBr): ν 1384, 1650, 2265, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.78 (d, J = 7.4 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.96–7.67 (m, 8H), 6.67 (d, J = 6.4, 1H), 2.49 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 150.5, 148.1, 145.5, 145.1, 143.0, 142.2, 133.1, 130.0, 129.7, 129.2, 127.1, 125.8, 122.8, 121.7, 120.0, 118.5, 116.7, 115.3, 113.6, 21.9 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₂H₁₅N₄: 335.1297, actual: 335.1294.
6-(4-Isopropyl-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9k). The title compound was obtained according to general procedure 3 as a beige solid. Yield: 0.28 g, 83%; mp: 237–240 °C; IR (KBr): ν 1386, 1655, 3019 cm⁻¹, ¹H-NMR (CDCl₃, 300 MHz): δ 8.75 (d, J = 7.2 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 6.9 Hz, 1H), 7.77–7.62 (m, 5H), 7.48 (d, J = 7.7, 2H), 6.60 (d, J = 6.60, 1H), 3.10–3.01 (m, 1H), 2.45 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 153.2, 150.6, 150.3, 148.2, 147.7, 145.3, 141.7, 136.0, 129.7, 128.9, 128.8, 127.4, 126.5, 126.4, 122.8, 121.6, 120.5, 116.3, 114.8, 31.8, 24.1, 21.9 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₄H₂₂N₃: 352.1814, actual: 352.1839.
6-(4-Bromo-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9l). The title compound was obtained according to general procedure 3 as a white solid. Yield: 0.32 g, 86%; mp: 218–221 °C; IR (KBr): ν 1384, 1651, 3023 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.80 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 7.0 Hz, 1H), 7.82–7.63 (m, 7H), 6.70 (d, J = 7.2, 1H), 2.52 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 150.5, 150.1, 148.1, 147.6, 145.1, 141.5, 135.8, 129.5, 128.7, 127.3, 126.3, 126.2, 122.6, 121.4, 120.4, 116.1, 114.6, 21.7 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₅BrN₃: 388.0449, actual: 388.0468.
6-(4-N,N-Dimethylamino-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9m). The title compound was obtained according to general procedure 3 as a yellow solid. Yield: 0.25 g, 75%; mp: 235–238 °C; IR (KBr): ν 1384, 1610, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.77 (d, J = 7.6 Hz, 1H), 8.30–8.23 (m, 2H), 7.79–7.61 (m, 5H), 6.95 (d, J = 8.2 Hz, 2H), 6.66 (d, J = 6.3 Hz, 1H), 3.11 (s, 6H), 2.50 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 151.3, 150.1, 148.7, 147.6, 145.3, 141.4, 131.0, 129.9, 128.9, 128.6, 126.6, 125.9, 122.6, 121.3, 120.7, 116.1, 114.5, 112.5, 40.5, 21.8 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₂₁N₄: 353.1766, actual: 353.1760.
6-(4-Methoxy-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9n). The title compound was obtained according to general procedure 3 as a brown solid. Yield: 0.25 g, 78%; mp: >250 °C; IR (KBr): ν 1215, 1390, 1507, 1609, 3020 cm⁻¹; ¹H-NMR (CDCl3, 300 MHz): δ 8.64 (d, J = 7.5 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.75–7.64 (m, 4H), 7.46 (s, 1H), 7.12 (d, J = 8.5, 2H), 6.87 (d, J = 8.5, 1H), 6.06 (d, J = 8.5, 1H), 3.94 (s, 3H), 2.38 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 160.9, 157.6, 150.5, 146.5, 144.2, 134.9, 133.1, 131.2, 131.0, 129.2, 128.3, 127.1, 126.5, 124.2, 123.9, 122.1, 120.8, 116.2, 114.4, 55.7, 21.0 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₂H₁₈N₃O: 340.1540, actual: 340.1543.
4-(9-Methyl-5,6b,11-triaza-benzo[a]fluoren-6-yl)-phenol (9o). The title compound was obtained according to general procedure 3 as a white solid. Yield: 0.22 g, 72%; mp: >250 °C; IR (KBr): ν 1384, 1650, 3019, 3416 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 10.78 (s, 1H), 9.44 (d, J = 9.0 Hz, 1H), 8.94 (d, J = 6.0 Hz, 2H), 8.59–8.51 (m, 3H), 8.42 (d, J = 9.0, 2H), 7.85 (d, J = 6.0, 2H), 7.77 (d, J = 9.0, 1H), 3.31 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): compound is too insoluble to record a carbon NMR spectrum; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₆N₃O: 326.1293, actual: 326.1329.
6-(3,4,5-Trimethoxy-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9p). The title compound was obtained according to general procedure 3 as a beige solid. Yield: 0.30 g, 79%; mp: 212–214 °C; IR (KBr): ν 1215, 1325, 1385, 1464, 1586, 1651, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.78 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.78–7.68 (m, 3H), 6.91 (s, 2H), 6.67 (d, J = 6.6, 1H), 3.96 (s, 3H), 3.90 (s, 6H), 2.50 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 154.2, 153.4, 150.3, 147.7, 145.0, 141.8, 139.1, 133.9, 129.6, 128.8, 126.5, 122.7, 121.6, 120.2, 116.3, 114.8, 105.8, 61.2, 56.5, 21.9 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₄H₂₂N₃O₃: 400.1661, actual: 400.1652.
6-(4-Flouro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9q). The title compound was obtained according to general procedure 3 as a beige solid. Yield: 0.26 g, 83%; mp: 175–177 °C; IR (KBr) 1504, 1653, 3026 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.79 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 6.9 Hz, 1H), 7.83–7.71 (m, 5H), 7.38 (t, J = 8.4, 2H), 6.67 (d, J = 6.3, 1H), 2.51 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 150.3, 147.6, 146.8, 145.0, 142.0, 136.3, 134.5, 130.9, 130.8, 144.7, 141.9, 129.5, 128.9, 126.8, 125.7, 123.5, 122.6, 121.5, 119.6, 116.2, 115.0, 21.7 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₅FN₃: 328.1250, actual: 328.1244.
6-(4-Pyridyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9r). The title compound was obtained according to general procedure 3 as a brown solid. Yield: 0.24 g, 82%; mp: 217–219 °C; IR (KBr): ν 1384, 1653, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.91 (d, J = 5.2 Hz, 2H), 8.74 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.80–7.68 (m, 4H), 7.61 (s, 1H), 6.61 (d, J = 7.0, 1H), 2.45 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 150.7, 150.1, 147.7, 146.2, 144.8, 144.7, 141.9, 129.5, 128.9, 126.8, 125.7, 123.5, 122.6, 121.5, 119.6, 116.2, 115.0, 21.7 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₀H₁₅N₄: 311.1297, actual: 311.1266.
6-(1-Naphthyl)-9-methyl-5,6b,11-triaza-benzo[a]fluorene (9s). The title compound was obtained according to general procedure 3 as a beige solid. Yield: 0.30 g, 87%; mp: 239–241 °C; IR (KBr): ν 1387, 1504, 1653, 3026 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.85 (d, J = 7.0 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.84–7.69 (m, 4H), 7.64 (s, 1H), 7.55 (t, J = 7.1, 1H), 7.43 (d, J = 8.1, 1H), 7.34 (t, J = 7.2, 1H), 7.11 (d, J = 6.9, 1H), 6.37 (d, J = 6.6, 1H), 2.40 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 150.2, 146.6, 145.2, 141.7, 135.3, 133.7, 131.3, 129.8, 129.6, 128.8, 128.6, 127.3, 127.0, 126.6, 125.9, 124.8, 122.7, 121.7, 116.1, 114.8, 21.7 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₅H₁₈N₃: 360.1501, actual: 360.1492.

General procedure 4

Synthesis of 5,6-dihydro-5,6b,11-triaza-benzo[a]fluorene (11a–f). To a solution of Pictet–Spengler substrate (6 or 7) (0.96 mmol) in water (1.5 mL), each one of the desired acetophenones (10a–e) (1.0 eq.) was added followed by addition of TBAB (2.0 eq.). The reaction mixture was stirred for 15 minutes followed by addition of cyanuric chloride (0.14 mmol, 15 mol%) at 80 °C. The reaction was allowed to run for 1.5 h. After completion (monitored by TLC), the reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine solution and dried over anhydrous Na₂SO₄. The crude product was purified by column chromatography using 60–120 mesh silica gel with 1% MeOH–CHCl₃ as eluent to obtain a good to excellent yield of the Pictet–Spengler products 11a–f.
6-Methyl-6-(phenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]fluorene (11a). The title compound was obtained according to general procedure 4 as a gray solid. Yield: 0.24 g, 82%; mp: 245–247 °C; IR (KBr): ν 1384, 1620, 3019, 3412 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 7.96 (d, J = 7.1 Hz, 1H), 7.65–7.59 (m, 3H), 7.37 (br, 3H), 7.20 (d, J = 6.4, 1H), 7.08 (br, 2H), 6.82 (t, J = 7.1, 1H), 6.52 (d, J = 5.9, 2H), 4.25 (s, 1H), 2.04 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 145.8, 143.9, 141.7, 139.2, 137.4, 129.1, 128.9, 128.2, 126.9, 124.4, 123.3, 123.0, 120.3, 118.0, 116.9, 115.0, 114.1, 113.0, 112.4, 58.8, 25.7 ppm; HRMS (EI) calculated for [M + H]⁺: C₂₁H₁₈N₃: 312.1501, actual: 312.1507.
6-Methyl-6-(4-nitro-phenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]fluorene (11b). The title compound was obtained according to general procedure 4 as a gray solid. Yield: 0.29 g, 86%; mp: >250 °C; IR (KBr): ν 1384, 1622, 3019, 3409 cm⁻¹; ¹HNMR (CDCl₃, 300 MHz): δ 8.23 (d, J = 9.0 Hz, 2H), 7.97 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 8.2, 2H), 7.68 (d, J = 9.2, 1H), 7.24 (d, J = 7.2, 1H), 7.16–7.09 (m, 2H), 6.89 (t, J = 7.2, 1H), 6.61 (t, J = 8.2, 2H), 4.27 (s, 1H), 2.16 (s, 3H) ppm; ¹³C-NMR (CDCl₃ + deuterated methanol (CD₃OD), 50 MHz): δ 157.4, 151.7, 150.9, 147.6, 142.9, 133.9, 132.5, 129.4, 129.1, 128.9, 127.2, 124.2, 121.9, 121.7, 119.9, 117.9, 117.6, 63.3, 30.9 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₇N₄O₂: 357.1352, actual: 357.1360.
6-Methyl-6-(4-methoxy-phenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]fluorene (11c). The title compound was obtained according to general procedure 4 as a gray solid. Yield: 0.26 g, 82%; mp: 248–251 °C; IR (KBr): ν 1217, 1384, 1622, 3019, 3409 cm⁻¹, ¹H-NMR (CDCl₃, 300 MHz): δ 7.96 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 7.0, 2H), 7.21 (d, J = 6.4, 1H), 7.09 (d, J = 7.0, 2H), 6.90 (d, J = 7.0, 2H), 6.82 (t, J = 7.0, 1H), 6.54 (t, J = 6.5, 2H), 4.15 (s, 1H), 3.79 (s, 3H), 2.00 (s, 3H) ppm; ¹³C-NMR (CDCl₃ + CD₃OD, 50 MHz): δ 163.6, 149.8, 147.7, 143.6, 141.6, 141.4, 136.1, 133.9, 132.7, 129.6, 128.7, 127.8, 127.0, 125.4, 121.2, 120.9, 119.1, 118.6, 117.8, 117.5, 62.6, 59.9, 27.2 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₂H₂₀N₃O: 342.1606, actual: 342.1617.
6-Methyl-6-(4-bromo-phenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]fluorene (11d). The title compound was obtained according to general procedure 4 as a brown solid. Yield: 0.31 g, 84%; mp: >250 °C; IR (KBr): ν 1384, 1650, 3019, 3412 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.03 (d, J = 6.7 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.50 (br, 3H), 7.28 (br, 3H), 7.13 (t, J = 6.7, 1H), 6.84 (t, J = 7.7, 1H), 6.75 (t, J = 6.7, 1H), 6.60 (d, J = 8.6, 1H), 4.50 (s, 1H), 2.07 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): compound is insoluble and a carbon NMR spectrum could not be recorded; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₇BrN₃: 390.0606, actual: 390.0608.
6-Methyl-6-(phenyl)-5,6-dihydro-9-methyl-5,6b,11-triaza-benzo[a]fluorene (11e). The title compound was obtained according to general procedure 4 as a brown solid. Yield: 0.27 g, 88%; mp: 210–213 °C; IR (KBr): ν 1384, 1651, 3019, 3411 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz): δ 7.93 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.7 Hz, 2H), 7.37–7.28 (m, 4H), 7.07 (d, J = 7.1, 2H), 6.81 (t, J = 7.1, 1H), 6.51 (d, J = 8.2, 1H), 6.34 (d, J = 6.6, 1H), 4.24 (s, 1H), 2.29 (s, 3H), 2.03 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 100 MHz): δ 146.4, 144.2, 141.6, 137.3, 135.3, 128.8, 128.1, 126.9, 122.8, 122.5, 119.8, 117.9, 115.5, 114.8, 112.9, 58.8, 25.8, 21.2 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₂H₂₀N₃: 326.1657, actual: 326.1672.
6-Methyl-6-(2-thiophenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]fluorene (11f). The title compound was obtained according to general procedure 4 as a yellow solid. Yield: 0.25 g, 83%; mp: 187–189 °C; IR (KBr): ν 1384, 1653, 3019, 3408 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 7.98 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 6.4 Hz, 1H), 7.35 (d, J = 4.6 Hz, 1H), 7.17–7.08 (m, 3H), 7.02 (br, 1H), 6.88 (t, J = 7.2, 1H), 6.60 (d, J = 7.5, 2H), 4.43 (s, 1H), 2.09 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 100 MHz): δ 150.1, 146.2, 141.2, 137.4, 129.0, 127.3, 126.5, 124.8, 124.4, 123.3, 122.9, 119.8, 118.5, 117.1, 115.6, 113.3, 112.4, 59.9, 27.4 ppm; HRMS (ESI) calculated for [M + H]⁺: C₁₉H₁₆N₃S: 318.1065, actual: 318.1080.

General procedure 5

Synthesis of spirooxyindoles (13a–d). To a solution of Pictet–Spengler substrate (6 or 7) (0.96 mmol) in water (1.5 mL), indoline-2,3-dione or N-substituted indoline-2,3-dione (1.0 eq.) was added followed by addition of TBAB (2.0 eq.). The reaction mixture was stirred for 15 minutes followed by addition of cyanuric chloride (0.19 mmol, 20 mol%) at 90 °C. The reaction was allowed to run for 3.0 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into water and was extracted with ethyl acetate (20 mL × 5). The combined organic layers were washed with saturated brine solution and dried over anhydrous Na₂SO₄. The crude product was purified by column chromatography using 60–120 mesh silica gel with 3% MeOH–CHCl₃ as eluent to obtain a good yield of the Pictet–Spengler product (13a–d).
6-Spiro-indol-2(1H)-one-5,6-dihydro-5,6b,11-triaza-benzo[a]fluorine (13a). The title compound was obtained according to general procedure 5 as a yellow solid. Yield: 0.21 g, 66%; mp: 244–246 °C; IR (KBr): ν 1384, 1639, 1724, 3019, 3417 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 10.50 (s, 1H), 7.83 (s, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.29–7.21 (m, 2H), 7.10 (t, J = 7.5, 1H), 6.98 (br, 4H), 6.65 (t, J = 7.5, 1H), 6.58 (t, J = 6.8, 1H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 180.4, 151.2, 147.9, 146.3, 144.8, 143.8, 135.3, 134.8, 133.7, 130.7, 129.4, 127.9, 127.7, 127.1, 121.9, 119.5, 119.3, 118.5, 118.0, 117.7, 115.6, 68.2 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₁H₁₅N₄O: 339.1246, actual: 339.1247.
6-Spiro-indol-2(N-ethyl)-one-5,6-dihydro-5,6b,11-triaza-benzo[a]fluorine (13b). The title compound was obtained according to general procedure 5 as a yellow solid. Yield: 0.24 g, 69%; mp: 228–230 °C; IR (KBr): ν 1384, 1611, 1721, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 7.95 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.43–7.38 (m, 2H), 7.12–7.00 (m, 4H), 6.88 (m, 2H), 6.61 (d, J = 7.8 Hz, 1H), 6.52 (t, J = 6.7 Hz, 1H), 4.55 (s, 1H), 3.94–3.73 (m, 2H), 1.37 (t, J = 7.1, 3H) ppm; ¹³C-NMR (CDCl₃, 50 MHz): δ 173.5, 146.8, 141.5, 141.4, 140.4, 130.8, 129.0, 126.2, 124.3, 123.9, 123.0, 122.5, 118.8, 117.5, 115.5, 113.2, 113.0, 112.6, 109.0, 63.3, 35.1, 12.7 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₁₉N₄O: 367.1559, actual: 367.1552.
6-Spiro-indol-2(N-methyl)-one-5,6-dihydro-9-methyl-5,6b,11-triaza-benzo[a]fluorine (13c). The title compound was obtained according to general procedure 5 as a yellow solid. Yield: 0.25 g, 72%; mp: >250 °C; IR (KBr): ν 1385, 1617, 1719, 3020 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 7.92 (d, J = 7.3 Hz, 1H), 7.42–7.35 (m, 3H), 7.07 (br, 2H), 6.99 (d, J = 7.7 Hz, 1H), 6.87 (t, J = 7.3, 1H), 6.69 (d, J = 6.8 Hz, 1H), 6.60 (d, J = 6.9 Hz, 1H), 6.35 (d, J = 6.9 Hz, 1H), 4.68 (s, 1H), 3.26 (s, 3H), 2.29 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 174.2, 147.1, 142.6, 141.3, 139.9, 136.0, 131.0, 129.1, 129.0, 126.0, 124.2, 123.2, 121.9, 119.1, 115.9, 115.6, 113.3, 112.4, 109.0, 63.4, 26.6, 21.3 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₁₉N₄O: 367.1559, actual: 367.1550.
6-Spiro-indol-2(N-ethyl)-one-5,6-dihydro-9-methyl-5,6b,11-triaza-benzo[a]fluorine (13d). The title compound was obtained according to general procedure 5 as a yellow solid. Yield: 0.24 g, 68%; mp: 232–234 °C; IR (KBr): ν 1386, 1622, 1718, 3020 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 7.91 (d, J = 7.3 Hz, 1H), 7.41–7.35 (m, 3H), 7.07–6.98 (m, 3H), 6.86 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 6.7 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.34 (d, J = 6.4 Hz, 1H), 4.65 (s, 1H), 3.90–3.72 (m, 2H), 2.28 (s, 3H), 1.35 (t, J = 6.9 Hz, 1H), ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 173.6, 147.3, 141.4, 140.1, 135.4, 130.7, 129.4, 128.8, 126.1, 123.8, 123.0, 121.7, 118.7, 116.0, 115.7, 115.2, 113.2, 112.5, 109.0, 63.4, 35.0, 21.2, 12.7 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₄H₂₁N₄O: 381.1715, actual: 381.1719.

General procedure 6

Synthesis of 6-(phenyl)-(11-S)-5,6b,12-triaza-benzo[a]fluorenes (21a–f). To a solution of Pictet–Spengler substrate (19 or 20) (0.96 mmol) in water (1.5 mL), each one of the desired aromatic aldehydes (1.0 eq.) was added followed by addition of TBAB (2.0 eq.). The reaction mixture was stirred for 15 minutes followed by addition of cyanuric chloride (0.15 mmol, 20 mol%) at 90 °C. The reaction was allowed to run for 2.0 h. After completion (monitored by TLC), the reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure and the crude product was purified by column chromatography using 60–120 mesh silica gel using 30% ethyl acetate–hexane as eluent to obtain a good yield of the Pictet–Spengler products (21a–f).
6-(Phenyl)-(11-S)-5,6b,12-triaza-benzo[a]fluorine (21a). The title compound was obtained according to general procedure 6 as an orange solid. Yield: 0.19 g, 76%; mp: 175–177 °C; IR (KBr): ν 1384, 1653, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.67 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.78–7.59 (m, 8H), 7.25 (s, 1H), 7.01 (t, J = 7.9, 1H), 5.96 (d, J = 8.4, 1H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 158.0, 150.8, 146.9, 144.4, 140.8, 133.4, 129.8, 129.7, 129.5, 129.3, 129.2, 128.6, 126.9, 126.3, 124.9, 124.0, 122.2, 121.0, 116.5 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₂H₁₄N₃S: 352.0908, actual: 352.0926.
6-(4-Nitro-phenyl)-(11-S)-5,6b,12-triaza-benzo[a]fluorene (21b). The title compound was obtained according to general procedure 6 as a brown solid. Yield: 0.24 g, 83%; mp: 175–177 °C; IR (KBr): ν 1348, 1521, 1654, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.68 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 8.1 Hz, 2H), 8.26 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.81–7.71 (m, 3H), 7.33 (t, J = 7.4, 1H), 7.09 (t, J = 8.5, 1H), 6.15 (d, J = 8.6 Hz, 1H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 158.5, 151.4, 148.6, 146.8, 144.5, 139.1, 133.0, 131.1, 129.6, 129.0, 127.6, 129.3, 125.3, 124.5, 124.2, 123.4, 122.3, 121.1, 119.8, 115.8 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₂H₁₃N₄O₂S: 397.0759, actual: 397.0805.
6-(4-Methoxy-phenyl)-(11-S)-5,6b,12-triaza-benzo[a]fluorene (21c). The title compound was obtained according to general procedure 6 as a brown solid. Yield: 0.22 g, 78%; mp: 173–175 °C; IR (KBr): ν 1348, 1521, 1654, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.63 (d, J = 7.2 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.73–7.66 (br, 5H), 7.25 (s, 1H), 7.11–6.85 (m, 3H), 6.20 (d, J = 8.2, 1H), 3.93 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 100 MHz): δ 161.0, 148.9, 148.3, 146.7, 141.7, 132.0, 131.9, 131.1, 130.8, 130.5, 128.2, 127.5, 126.4, 125.5, 124.5, 123.7, 114.5, 113.1, 110.1, 55.8 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₁₆N₃OS: 382.1014, actual: 382.1063.
6-(4-Nitro-phenyl)-7-methyl-(11-S)-5,6b,12-triaza-benzo[a]fluorene (21d). The title compound was obtained according to general procedure 6 as an orange solid. Yield: 0.24 g, 79%; mp: >250 °C; IR (KBr): ν 1384, 1653, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.66 (d, J = 7.7 Hz, 1H), 8.47 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.79–7.69 (m, 2H), 7.51 (s, 1H), 6.87 (d, J = 8.3, 1H), 5.98 (d, J = 8.5, 1H), 2.40 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 158.3, 151.0, 148.6, 146.7, 144.3, 143.8, 135.6, 131.0, 130.8, 129.4, 128.8, 127.4, 127.2, 124.5, 124.1, 123.3, 122.2, 121.0, 115.3, 21.1 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₁₅N₄O₂S: 411.0916, actual: 411.0919.
6-(4-Methoxy-phenyl)-7-methyl-(11-S)-5,6b,12-triaza-benzo[a]fluorene (21e). The title compound was obtained according to general procedure 6 as a brown solid. Yield: 0.23 g, 79%; mp: >250 °C; IR (KBr): ν 1387, 1647, 3022 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.64 (d, J = 7.5 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.75–7.60 (m, 4H), 7.46 (s, 1H), 7.11 (d, J = 8.5, 2H), 6.87 (d, J = 8.5, 1H), 6.05 (d, J = 8.5, 1H), 3.94 (s, 3H), 2.37 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 100 MHz): δ 160.9, 157.7, 150.5, 146.5, 144.2, 134.9, 133.1, 131.2, 131.1, 129.2, 128.3, 127.1, 126.5, 124.2, 123.9, 122.1, 120.8, 116.2, 114.4, 55.7, 21.0 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₄H₁₈N₃OS: 396.1171, actual: 396.1171.
6-(4-Bromo-phenyl)-7-methyl-(11-S)-5,6b,12-triaza-benzo[a]fluorene (21f). The title compound was obtained according to general procedure 6 as a beige solid. Yield: 0.25 g, 78%; mp: >250 °C; IR (KBr): ν 1384, 1645, 3019 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 8.65 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.75–7.66 (m, 4H), 7.63 (d, J = 7.7, 2H), 7.49 (s, 1H), 6.92 (d, J = 8.4, 1H), 6.01 (d, J = 8.4, 1H), 2.40 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 100 MHz): δ 158.1, 150.9, 148.0, 145.4, 144.4, 139.6, 135.4, 132.3, 131.6, 131.2, 129.5, 128.7, 127.3, 127.0, 124.3, 124.1, 124.0, 122.2, 121.0, 115.9, 21.3 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₁₅BrN₃S: 444.0170, actual: 444.0236.

General procedure 7

Synthesis of 6-(phenyl)-5,6-dihydro-(11-S)-5,6b,12-triaza-benzo[a]fluorines (22a–c). To a solution of Pictet–Spengler substrate (19 or 20) (0.96 mmol) in water (1.5 mL), each one of the acetophenones (10a–c) (1.0 eq.) was added followed by addition of TBAB (2.0 eq.). The reaction mixture was stirred for 15 minutes followed by addition of cyanuric chloride (0.15 mmol, 20 mol%) at 80 °C. The reaction was allowed to run for 2.0 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine solution and dried over anhydrous Na₂SO₄. The crude product was purified by column chromatography using 60–120 mesh silica gel with 30% ethyl acetate–hexane as eluent to get a good yield of the Pictet–Spengler product 22a–c.
6-Methyl-6-(phenyl)-5,6-dihydro-(11-S)-5,6b,12-triaza-benzo[a]fluorine (22a). The title compound was obtained according to general procedure 7 as a brown solid. Yield: 0.20 g, 76%; mp: 236–238 °C; IR (KBr): ν 1384, 1653, 3021, 3407 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): δ 7.80 (d, J = 7.4 Hz, 1H), 7.63 (t, J = 7.8 Hz, 3H), 7.41–7.31 (m, 3H), 7.16 (t, J = 7.1, 1H), 7.04–6.94 (m, 2H), 6.80 (d, J = 7.3, 1H), 6.47 (d, J = 8.0, 2H), 4.08 (s, 1H), 2.10 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 149.7, 145.9, 140.2, 140.0, 132.3, 130.3, 130.1, 130.0, 129.3, 128.4, 128.2, 128.0, 126.9, 125.8, 124.1, 122.0, 118.0, 114.3, 112.5, 59.9, 32.1 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₁₈N₃S: 368.1221, actual: 368.1269.
6-Methyl-6-(4-nitro-phenyl)-5,6-dihydro-(11-S)-5,6b,12-triaza-benzo[a]fluorine (22b). The title compound was obtained according to general procedure 7 as a brown solid. Yield: 0.24 g, 78%; mp: >250 °C; IR (KBr): ν 1384, 1653, 3019, 3409 cm⁻¹; ¹H-NMR (CDCl₃, 300 MHz): 8.26 (d, J = 7.9 Hz, 2H), 7.81–7.76 (m, 3H), 7.65 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 7.5, 1H), 7.07 (t, J = 6.3, 2H), 6.84 (t, J = 7.3, 1H), 6.50 (t, J = 6.7, 2H), 4.04 (s, 1H), 2.22 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 152.2, 151.7, 147.3, 140.4, 139.6, 131.9, 130.1, 128.5, 127.7, 126.1, 125.9, 124.5, 122.3, 122.1, 121.0, 118.9, 118.4, 113.6, 112.5, 59.6, 32.0 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₃H₁₇N₄O₂S: 413.1072, actual: 413.1128.
6-Methyl-6-(4-methoxy-phenyl)-5,6-dihydro-(11-S)-5,6b,12-triaza-benzo[a]fluorine (22c). The title compound was obtained according to general procedure 7 as a brown solid. Yield: 0.22 g, 74%; mp: 246–247 °C; IR (KBr): ν 1384, 1653, 3019, 3407 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz): δ 7.78 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.15 (t, J = 7.2, 1H), 7.02 (t, J = 7.7, 2H), 6.89 (d, J = 8.3, 1H), 6.77 (t, J = 7.8, 1H), 6.54 (d, J = 8.3, 1H), 6.44 (d, J = 8.4, 1H), 3.77 (s, 3H), 2.06 (s, 3H) ppm; ¹³C-NMR (CDCl₃, 75 MHz): δ 159.4, 149.6, 140.1, 138.3, 132.3, 130.3, 130.1, 130.0, 129.8, 128.1, 128.0, 125.9, 124.1, 121.9, 117.8, 115.8, 114.5, 112.4, 59.4, 55.4, 32.0 ppm; HRMS (ESI) calculated for [M + H]⁺: C₂₄H₂₀N₃OS: 398.1327, actual: 398.1380.

Acknowledgements

Two of the authors AKP and RS are thankful to CSIR, New Delhi for Senior Research Fellowships (SRFs). We also thank SAIF division, CSIR-CDRI for the analytical facilities. The CDRI communication number is 8715.

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra03415e

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