CuI-catalyzed amination of Tröger's base halides: a convenient method for synthesis of unsymmetrical Tröger's bases

Abstract

A convenient method for the amination of Tröger's base halides has been developed via copper catalyzed coupling reactions. This reaction proceeds in moderate to good yields. The protocol has been utilized to produce two different classes of Tröger's base derivatives, one bearing identical substituents on both the aryl rings and the other featuring two different substituents on the aryl rings.

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1. Introduction

A simple and convenient method for the construction of C_aryl–N bond is highly desirable in organic chemistry since aryl amines are attractive synthetic targets.¹ Their wide occurrence in a number of biologically active frameworks of pharmaceutical and agrochemical utility has sustained a continuing interest in the development of viable chemical synthesis protocols for C_aryl–N bond formation.² The most often used and industrially feasible pathway for this coupling is still the Ullmann-type reaction.³ Copper-catalyzed carbon–nitrogen bond formation on aryl halides has been studied extensively over the past decade, mostly by using an in situ generated catalyst from a copper source and ligands such as amino acids, diamines, amino alcohols, and diols.⁴ Although more often precious palladium metal derivatives are employed in this process, it would be an enviable approach to employ less expensive metal catalysts such as copper. Added to this, comparatively environmental friendly nature of later led us to study amination reactions of Tröger's base catalyzed by copper.

Tröger's base⁵ (Fig. 1) is a unique V-shape, C₂-symmetric molecule with applications not only in supramolecular chemistry⁶ but also in medicinal chemistry.⁷ The ability to orient recognition sites in a well defined structural framework such as Tröger's base by formation of C_aryl-TB–N bond is an important step in designing specific receptors for various substrates as well as in making of biologically active molecules. As a part of continuing interest of our group in the construction of novel Tröger's base frameworks⁸ for various applications, it has been proposed to construct a variety of aryl as well as heteroaryl amine substituted Tröger's base analogues. Direct synthesis of amino-substituted Tröger's base analogues from the conventional protocols or amination of Tröger's bases is a challenging exercise as most of the concerned reaction protocols involve harsh reaction conditions, tedious extraction and purification procedures which are more often low yielding protocols.^5j The halogen-substituted analogues of Tröger's base, introduced by Wärnmark et al., are particularly important synthetic intermediates because they provide access to many other functional derivatives via metal catalyzed cross coupling reactions such as Kumada, Suzuki–Miyaura, Sonogashira coupling, and Buchwald amination.⁹ To the best of our knowledge most of the synthetic protocols involved the using of expensive Pd catalysts for the coupling of Tröger's base halides. Very few examples involving direct amination of Tröger's base are available in the literature where only mono-substituted Tröger's base analogues were obtained.¹⁰ The above evidences have encouraged us to explore the broader scope of direct amination of Tröger's base halides leading to C_aryl-TB–N bond formation and thereby construction of diverse alkylamino-substituted Tröger's base scaffolds. In this context, the application of Cu(I) catalyzed cross-coupling methodology has been extended to create two different classes of Tröger's base derivatives starting from the corresponding Tröger's base di-halo compounds as outlined in this article.

Fig. 1 Tröger's base, 1.

2. Results and discussions

2.1. Synthesis

Tröger's base dihalides (bromo/iodo) were prepared by the condensation of corresponding anilines with paraformaldehyde in presence of TFA.¹¹ At the outset, the amination of 2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 with morpholine was chosen as a model reaction to screen the various reaction parameters. The screening has been performed in the presence of CuI (20 mol%), proline (40 mol%) and K₂CO₃ (3 eq.) in DMSO at 90 °C under nitrogen atmosphere (entry 1, Table 1). As anticipated, two new spots appeared in TLC monitoring. Work-up followed by purification of the products and analysis by ¹H, ¹³C NMR and ESI mass revealed that the coupled products are mono-aminated compound 5 and di-aminated compound 6 obtained in 18% and 34% yields, respectively (Table 1), along with 13% recovery of the starting material 3. Having successfully identified the coupled products, optimization of reaction conditions has been carried out (Table 1). Increasing the reaction time to 40 h under the same conditions did not alter the product yields greatly (entry 2, Table 1). An increase in the reaction temperature, however, was highly effective in influencing the product formation ratio. When the reaction was conducted at 120 °C, di-substituted (aminated) Tröger's base derivative 6 has been obtained in 68% yield along with trace amounts (<5%) of mono-substituted Tröger's base 5 (entry 3, Table 1) in 12 h. Reaction does not proceed at room temperature (entry 4, Table 1). These observations indicate that the reaction is definitely temperature dependent which played a major role in determining the reaction product profile (either exclusively di-substituted product or both mono- and di-substituted products). The optimized (high temperature) reaction conditions have been extended to 2,8-diiodo-substituted Tröger's base 2 to obtain the di-substituted product 6 in 71% yield (entry 5, Table 1).

Table 1 Optimization reaction conditions for the amination of Tröger's base dihalide with morpholine^a

Entry	X	Catalyst	Ligand	Base	Temp (°C)	Solvent	Time (h)	Yield% (5/6)^b
a Reaction conditions: Tröger's base (1 mmol), amine (5 mmol), CuI (0.2 mmol, 20 mol%), L-proline (0.4 mmol, 40 mol%), and base (3 mmol) in DMSO under nitrogen except otherwise mentioned.b Isolated yields.c 5–15% of TB 3 was recovered.d Up to 60% of TB 3 was recovered.e 28% of TB 3 was recovered.f 45% of TB 3 was recovered.g 14% of TB 3 was recovered.h 26–63% of TB 3 was recovered. NR: no reaction.
1	Br	CuI	Proline	K2CO3	90	DMSO	24	18/34^c
2	Br	CuI	Proline	K2CO3	90	DMSO	40	13/35^c
3	Br	CuI	Proline	K2CO3	120	DMSO	12	Trace/68^c
4	Br	CuI	Proline	K2CO3	25	DMSO	24	NR
5	I	CuI	Proline	K2CO3	120	DMSO	8	Trace/71^b
6	I	CuI	Proline	K2CO3	120	DMF	24	11/—^d
7	Br	CuI	Proline	K2CO3	82	CH3CN	24	7/—^d
8	Br	CuI	Proline	K2CO3	120	Toluene	24	NR
9	Br	CuI	Proline	K2CO3	120	HMPA	36	NR
10	Br	CuBr	Proline	K2CO3	120	DMSO	24	12/14^e
11	Br	CuCl	Proline	K2CO3	120	DMSO	48	13/trace^f
12	Br	CuOAc	Proline	K2CO3	120	DMSO	24	NR
13	Br	—	Proline	K2CO3	120	DMSO	24	NR
14	Br	CuI (10%)	Proline	K2CO3	90	DMSO	24	13/trace^h
15	Br	CuI (10%)	Proline	K2CO3	120	DMSO	24	9/24^h
16	Br	CuI (10%)	Proline (20%)	K2CO3	120	DMSO	24	10/13^h
17	Br	CuI (5%)	Proline (20%)	K2CO3	90	DMSO	24	8/—^h
18	Br	CuI (5%)	Proline (20%)	K2CO3	120	DMSO	24	8/—^h
19	Br	CuI	NH2CH2CH2OH	K2CO3	90	DMSO	24	9/—^h
20	Br	CuI	NH2CH2CH2OH	K2CO3	120	DMSO	24	10/8^h
21	Br	CuI	CH3NHCH2CH2NHCH3	K2CO3	90	DMSO	24	14/8^h
22	Br	CuI	CH3NHCH2CH2NHCH3	K2CO3	120	DMSO	24	Trace/48^h
23	Br	CuI	Proline	Cs2CO3	90	DMSO	24	17/38^g

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Further, the solvent choice played a major role in progress of the reaction. It has been observed that reaction proceeds more effectively in DMSO compared to DMF, CH₃CN where as in toluene and HMPA no reaction occurred (entries 6–9, Table 1). DMSO serves as a better solvent for this coupling reaction probably due to the high polar nature of DMSO as well as the better solubility of reactants and copper complex compared to the other solvents. An evaluation of the catalyst efficiency has also been made by employing various copper salts such as CuBr, CuCl, and CuOAc as catalysts for the reaction protocol (entries 10–12, Table 1). Among these salts CuBr and CuCl performed modestly as catalysts and corresponding products have been obtained in moderate to low yields. Reaction of Tröger's base 3 with morpholine in presence of CuBr gave both mono- and di-substituted Tröger's bases even when the reaction was carried out at 120 °C. Only mono substituted product formation was observed in the presence of CuCl catalyst and 45% of starting material has been recovered after purification (entry 11, Table 1). No reaction occurred when CuOAc was used as catalyst (entry 12, Table 1). Among all the copper salts screened, the superiority of CuI can perhaps be attributed to its better complexing ability with ligand compared to other copper catalysts. The reaction does not proceed in proline/K₂CO₃ (i.e., absence of catalyst) which clearly illustrates the importance of the catalyst in this reaction (entry 13, Table 1).

The tolerability of the reaction protocol with respect to varying concentrations of catalyst and ligand was investigated next (entries 14–18, Table 1). Catalyst and ligand ratios were reduced to 5 mol% and 20 mol%, respectively; however the yields were lower compared to reactions that employed 20 mol% of CuI and 40 mol% of proline. Other bidentate O,N and N,N ligands such as 2-aminoethanol (entries 19 and 20, Table 1) and N,N′-dimethylethane-1,2-diamine (entries 21 and 22, Table 1) were tested, but these ligands gave inferior results compared to L-proline. 2-Aminoethanol as ligand gave both di- and mono substituted products (10% & 8%, respectively) at 120 °C but only mono substituted product (9%) was obtained at 90 °C. On the other hand N,N-dimethylethane-1,2-diamine as ligand resulted in di-substituted product (48%) at 120 °C along with trace amounts of mono substituted compound while both mono- and di-substituted products (14% & 8%, respectively) were obtained at 90 °C.

The loading ratios of amine and base were also examined. The amination occurs smoothly with 3 equiv. of base and 5 equiv. of morpholine. Even though stoichiometric amount of amine has been found sufficient for progress of the reaction, prolonged reaction times were required for completion of the reaction and the yields were even lower in such cases. Hence, excess (5 equiv.) of morpholine has been utilized to hasten the reaction. Cs₂CO₃ as base (entry 23, Table 1) led to a slightly higher yield of product when compared to K₂CO₃. However, it has not been employed in further reactions due to its higher cost. The extensive survey of reaction parameters described above led to determination of optimal reaction conditions for exclusive di-aminated Tröger's base i.e., Tröger's base (1 mol), CuI (20 mol%), proline (40 mol%), amine (5.0 equiv.), DMSO, 120 °C under nitrogen. However, employing Tröger's base (1 mol), CuI (20 mol%), proline (40 mol%), amine (5.0 equiv.), DMSO, 90 °C under nitrogen gave both mono- and di-aminated Tröger's bases.

Having successfully screened and established the reaction conditions, the generality of the method was investigated by elaborating the same reaction protocol for the construction of various other aminated Tröger's base analogues. Reaction of 2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 with cycloalkyl amines such as piperidine 7, pyrrolidine 8, 2-(piperazin-1-yl)benzo[d]thiazole 9a, 1-(2-fluorophenyl)piperazine 9b, 1-(2-methoxyphenyl)piperazine 9c, tert-butyl piperazine-1-carboxylate 9d, 4-benzylpiperidine 9e, and 1-tosylpiperazine 9f has been carried out at both 90 °C and 120 °C (Table 2). Products 10(a–g) and 11(a–b) have been obtained in moderate to good yields (Table 2). Reaction of Tröger's base 3 with piperidine and pyrrolidine at 90 °C in DMSO gave both mono- (10a: 14% and 10b: 18%) and di-substituted compounds (11a: 22% and 11b: 28%) whereas at 120 °C gave di-substituted compounds 11a & 11b in 63% and 72%, respectively along with trace amounts of mono-substituted Tröger's bases 10a & 10b, respectively. However, the coupling of 3 with 9(a–e) gave only mono-substituted Tröger's base analogues 10(c–g) at both 90 °C and 120 °C, probably due to steric crowding of the substituted amine in the resulting compound due to V-shaped geometry of Tröger's base molecule. Highly electron deficient substrate 1-tosylpiperazine 9f was also employed in the reaction with Tröger's base 3. As anticipated the reaction did not proceed at all in this case (Table 2).

Table 2 Synthesis of cycloalkylamino substituted Tröger's base analogues^a

Amine (RH)	Product		Yield (m/d^b at 90 °C), yield (m/d^b at 120 °C)
a Reaction conditions: TB 3 (1 mmol), CuI (0.2 mmol, 20 mol%), proline (0.4 mmol, 40 mol%), amine (5 mmol), K2CO3 (3 mmol) in DMSO at 90 °C or 120 °C.b m: monosubstituted, d: disubstituted.c NO-not obtained. 18–44% of unconverted TB 3 has been recovered in above reactions.
			14/22, trace/63
			18/28, trace/72
		NO^c	19/—, 24/—
		NO	12/—, 12/—
		NO	18/—, 25/—
		NO	14/—, 16/—
		NO	16/—, 23/—

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All the products were confirmed by NMR and mass spectral analysis. In the ¹H NMR spectrum of symmetrical Tröger's base analogues (di-substituted), the diazocine unit protons have exhibited a classic Tröger's base ¹H NMR pattern. However, in mono-substituted Tröger's base analogues lack of symmetry led to different ¹H NMR pattern which has been explained and assignment of protons confirmed by 2D NMR studies.¹²

2.2. NMR correlation studies

Structural features of the mono-substituted (unsymmetrical) compounds were established by the extensive two dimensional NMR experimental studies. Assignment of all protons was made by COSY experiments, and confirmed by NOESY. Herein the NOESY NMR correlation of compound 5 (also see ESI†) has been illustrated.

From the interpretation of NOESY NMR spectrum of compound 5 (Fig. 2), it was observed that the aromatic proton signals appeared at δ 7.25 (H-20), δ 7.04 (H-18), δ 7.03 (H-9), δ 7.00 (H-21), δ 6.78 (H-10), and δ 6.40 (H-6) ppm. The methylene protons of morpholine moiety observed as two triplets at δ 3.80 (H-2, 2′) and δ 3.03 (H-3, 3′) ppm. The diazocine protons (H_a, H_b, H_c, and H_d) having geminal coupling (J², H_a with H_b and H_c with H_d) and appeared as four individual doublets at δ 4.65 (H_a), δ 4.08 (H_b), δ 4.61 (H_c), and δ 4.07 (H_d) ppm integrating for one proton each. Methylene bridge protons (–NCH₂N–) H_e and H_f also coupled with each other possessing geminal (J²) and long range couplings (J⁴) with H_a and H_c and appeared as two individual doublets at δ 4.29 (H_e), δ 4.24 (H_f) ppm (being the molecule asymmetric).

Fig. 2 NOE correlations and assignment of ¹H NMR chemical shifts of compound 5.

The proton at δ 6.40 (H-6) has NOE with protons at δ 3.03 (H-3′), δ 4.08 (H_b), and δ 4.65 (H_a) ppm. The proton at δ 4.08 ppm (H_b) also has a correlation with proton at δ 7.00 ppm (H-21). The proton at δ 6.78 ppm (H-10) has NOE with proton at δ 3.03 ppm (H-3). The proton at δ 7.04 ppm (H-18) has NOE with the protons at δ 4.61 (H_c), and δ 4.07 (H_d) ppm. The proton at δ 4.07 ppm (H_d) also has a NOE with proton at δ 6.78 ppm (H-9). All the NOE observations are in agreement with the assigned structure (Fig. 2). A similar NMR pattern has been observed for other unsymmetrical Tröger's base analogues.

2.3. Synthesis of unsymmetrical Tröger's base analogues

Interestingly, the monosubstituted product allows an active halide site for further functionalization. Amination of the mono aminated analogues 5, 10b and 10g with morpholine, piperidine or pyrrolidine under the optimized reaction conditions at 90 °C gave the di-substituted Tröger's base derivatives 6, 12 and 13 in upto 65% yield (Scheme 1). Thus, di-substituted Tröger's base analogues are accessible from the corresponding mono-substituted Tröger's base analogues opening up a window for construction of unsymmetrical aminated derivatives (different amines on two aromatic rings) of Tröger's base.

Scheme 1 Synthesis of di-substituted (symmetrical and unsymmetrical) Tröger's base analogues from mono-substituted Tröger's base analogues.

The C–N coupling protocol could be extended to methylene bridge substituted Tröger's base analogues (Scheme 2). Coupling of N,N-dimethylamino-crowned bromo Tröger's base analogue 14 with morpholine under the optimized reaction conditions at 90 °C gave the mono- and di-substituted Tröger's base analogues 15 and 16 in 17% and 23% yields, respectively, along with the 23% recovery of starting material 14. N,N-Dimethylamino-crowned bromo Tröger's base analogue was prepared by the classic Vilsmeier–Haack reaction of compound 3 using DMF and POCl₃.¹³

Scheme 2 Amination of N,N-dimethylamino-crowned Tröger's base analogue.

The copper-catalyzed C–N coupling protocol has also been examined with diverse amines replacing the cyclic aliphatic amines with other amines such as imidazole, triazole, diphenylamine, aniline, 2,8-diazabicyclo-[4,3,0]nonane, N-methylaniline, (Scheme 3). However, these aminations have not been successful under various reaction conditions. In all the cases unconverted Tröger's base dihalide has been recovered.

Scheme 3 Reaction of Tröger's base 3 with amines.

With an aim to broaden the scope of the method the reaction has also been carried out with aliphatic amines such as diethylamine and diisopropylamine (Scheme 4). About 5% of mono-substituted product was obtained in case of reaction of Tröger's base 3 with diethylamine whereas reaction didn't proceed at all with diisopropylamine.

Scheme 4 Reaction of Tröger's base 3 with diethyl amine.

3. Conclusions

In summary, the scope of copper-catalyzed C–N couplings has been expanded substantially on Tröger's base substrate. A convenient and efficient Ullmann type copper catalyzed amination method has been developed for the direct amination of halogen substituted Tröger's base analogues. Current method provides convenient direct access to aminated Tröger's base analogues bearing either identical substituents on both the aryl rings or two different substituents on the aryl rings. It is an efficient tool for construction of sophisticated libraries of Tröger's bases; adding substantially to the pool of molecules available for supramolecular applications (such as molecular recognition) as well as biologically important molecules.

4. Experimental section

4.1. General methods

All the starting materials were obtained from commercial sources and used without further purification. All reactions were carried out in anhydrous conditions. Organic layers were dried over anhydrous Na₂SO₄. TLC analyses were performed on glass plates coated with silica gel 60 F254. Plates were visualized using UV light (254 nm) and/or iodine. Column chromatography was performed on silica gel (60 × 120 mesh) on a glass column. Melting points (mp) were determined in capillary tubes and are uncorrected. ¹H and ¹³C NMR spectra (300, 400, 500, and 75 MHz, respectively) were recorded using TMS as an internal standard (0 ppm). Mass (ESI) data were recorded on quadruple mass spectrometry. HRMS data were obtained by the ESI ionization sources. IR spectra were recorded on a FTIR spectrometer as KBr pellets or neat.

4.2. General procedure for the amination of Tröger's base dihalides

To the solution of Tröger's base dihalide (2 or 3) (1 mmol) in DMSO, CuI (20 mol%), proline (40 mol%) and K₂CO₃ (3 mmol) were added under nitrogen atmosphere at room temperature. Then amine (5 mmol) was added to the reaction mixture and reaction was stirred at the indicated temperature (90 °C or 120 °C) for 12–24 h. After completion of the reaction (monitored by TLC or after indicated reaction time), the reaction mixture was allowed to reach room temperature. The cooled mixture was partitioned between water (20 mL) and chloroform (30 mL). The organic layer was separated, and the aqueous layer was extracted with chloroform (2 × 30 mL). The combined organic layers were washed with brine and dried over Na₂SO₄. Solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel to afford the desired product.

Note: yields of the products have been given at both the temperatures.

Synthesis of (±)-4-(8-bromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)morpholine (5). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (378 mg, 1 mmol), morpholine (435 mg, 5 mmol), K₂CO₃ (414 mg, 3 mmol), CuI (38 mg, 0.2 mmol) and proline (46 mg, 0.4 mmol) in 4 mL of DMSO was heated at 90 °C for 24 h under nitrogen atmosphere. The crude compound was loaded on a silica gel column; compound 5 was eluted in 15% EtOAc in hexane as a white solid and compound 6 was eluted in 25% EtOAc in hexane as light brown solid. Yield: 18%; mp: 87–88 °C; ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.24 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 7.0 (d, J = 8.7 Hz, 1H), 6.77 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 6.40 (d, J = 2.8 Hz, 1H), 4.65 (d, J = 16.6 Hz, 1H), 4.61 (d, J = 16.8 Hz, 1H), 4.30 (d, J = 12.8 Hz, 1.3 Hz, 1H), 4.24 (d, J = 12.8 Hz, 1.3 Hz, 1H), 4.08 (d, J = 16.8 Hz, 1H), 4.06 (d, J = 16.8 Hz, 1H), 3.81 (t, J = 4.73 Hz, 4H), 3.03 (t, J = 4.4 Hz, 4H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ ppm: 148.1, 147.2, 140.2, 133.3, 130.13, 129.8, 127.9, 126.7, 125.6, 116.5, 113.3, 66.9, 66.8, 58.9, 58.2, 49.7; MS (ESI) m/z (%): 386 ([M + H], 100); HRMS (ESI): calcd for C₁₉H₂₀BrN₃O 386.08739, found 386.08732.

(±)-2,8-Dimorpholino-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (6). Yield: 34% (at 120 °C: 68%); mp: 258–259 °C; ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.06 (d, J = 8.7 Hz, 2H), 6.77 (dd, J = 8.7 Hz, 2.7 Hz, 2H), 6.42 (d, J = 2.7 Hz, 2H), 4.64 (d, J = 16.6 Hz, 2H), 4.30 (s, 2H), 4.07 (d, J = 16.6 Hz, 2H), 3.80 (t, J = 4.7 Hz, 4H), 3.03 (t, J = 4.7 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 147.9, 140.7, 128.4, 125.7, 115.9, 113.5, 67.3, 66.9, 58.9, 49.8; MS (ESI) m/z (%): 393 ([M + H], 100); HRMS (ESI): calcd for C₂₃H₂₈N₄O₂ 393.23106, found 393.22948.

Synthesis of (±)-2-bromo-8-(piperidin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (10a). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (378 mg, 1 mmol), piperidine (425 mg, 5 mmol), K₂CO₃ (414 mg, 3 mmol), CuI (38 mg, 0.2 mmol) and proline (46 mg, 0.4 mmol) in 4 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 10a was eluted in 15% EtOAc in hexane as a light brown solid and compound 11a was eluted in 25% EtOAc in hexane as a light brown solid. Yield: 14%; mp: 147–148 °C; ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.25 (dd, J = 2.3 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.80 (dd, J = 8.7 Hz, J = 2.7, 1H), 6.42 (d, J = 2.7 Hz, 1H), 4.64 (d, J = 16.5 Hz, 1H), 4.60 (d, J = 16.6 Hz, 1H), 4.30 (dd, J = 1.2 Hz, 12.5 Hz, 1H), 4.25 (d, J = 12.7 Hz, 1H), 4.22 (d, J = 12.7 Hz, 1H), 4.07 (d, J = 16.6 Hz, 1H), 3.01 (t, J = 5.5 Hz, 4H), 1.69–1.63 (m, 4H), 1.54–1.49 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 149.1, 147.2, 139.3, 130.2, 129.7, 127.6, 126.6, 125.3, 116.9, 114.1, 66.9, 59.1, 58.2, 51.1, 25.9, 24.2; MS (ESI) m/z (%): 384 ([M + H], 100); HRMS (ESI): calcd for C₂₀H₂₂BrN₃ 384.10699, found 384.10810.

(±)-2,8-Di(piperidin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (11a). Yield: 22% (at 120 °C: 63%); mp: 167–168 °C; ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.01 (d, J = 9.1 Hz, 2H), 6.79 (dd, J = 3.0 Hz, 9.1 Hz, 2H), 6.43 (d, J = 2.3 Hz, 2H), 4.62 (d, J = 16.6 Hz, 2H), 4.29 (s, 2H), 4.05 (d, J = 16.6 Hz, 2H), 3.00 (t, J = 5.3 Hz, 8H), 1.73–1.46 (m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 148.9, 140.0, 128.1, 125.2, 116.7, 114.2, 67.2, 58.8, 51.2, 25.9, 24.1; MS (ESI) m/z (%): 389 ([M + H], 100); HRMS (ESI): calcd for C₂₅H₃₂N₄ 389.26997, found 389.27085.

Synthesis of (±)-2-bromo-8-(pyrrolidin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (10b). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (378 mg, 1 mmol), pyrrolidine (355 mg, 5 mmol), K₂CO₃ (414 mg, 3 mmol), CuI (38 mg, 0.2 mmol) and proline (46 mg, 0.4 mmol) in 4 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 10b was eluted in 15% EtOAc in hexane as light brown solid and compound 11b was eluted in 25% EtOAc in hexane as a light brown solid. Yield: 18%; mp: 175–176 °C; ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.24 (dd, J = 8.5 Hz, 2.1 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 7.00 (dd, J = 8.5 Hz, 2.1 Hz, 2H), 6.44 (dd, J = 8.5 Hz, 2.1 Hz, 1H), 6.04 (d, J = 2.1 Hz, 1H), 4.67 (d, J = 16.5 Hz, 1H), 4.59 (d, J = 16.5 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 4.24 (d, J = 12.7 Hz, 1H), 4.08 (t, J = 12.8 Hz, 2H), 3.18 (t, J = 17.8 Hz, 4H), 1.94 (quin, J = 12.8 Hz, 3.2 Hz, 4H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ ppm: 149.2, 147.3, 139.4, 130.3, 129.8, 126.7, 125.9, 116.9, 114.1, 66.9, 59.086, 58.2, 51.1, 25.9, 24.2; MS (ESI) m/z (%): 371 ([M + H], 100); HRMS (ESI): calcd for C₁₉H₂₀BrN₃ 370.09227, found 370.09134.

(±)-2,8-Di(pyrrolidin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (11b). Yield: 28% (at 120 °C: 72%); mp: 229–230 °C; ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.01 (d, J = 8.7 Hz, 2H), 6.42 (dd, J = 8.7 Hz, 2.6 Hz, 2H), 6.05 (d, J = 2.7 Hz, 2H), 4.64 (d, J = 16.5 Hz, 2H), 4.32 (s, 2H), 4.06 (d, J = 16.5 Hz, 2H), 3.16 (t, J = 6.6 Hz, 4H), 1.93 (quin, J = 3.4 Hz, 6.6 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 145.0, 136.5, 128.5, 125.5, 111.4, 108.7, 67.7, 59.0, 47.7, 25.3; MS (ESI) m/z (%): 361 ([M + H], 100); HRMS (ESI): calcd for C₂₃H₂₈N₄ 361.23942, found 361.23867.

Synthesis of (±)-2-(4-(8-bromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)piperazin-1-yl)benzo[d]thiazole (10c). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (189 mg, 0.5 mmol), 2-(piperazin-1-yl)benzo[d]thiazole 9a (548 mg, 2.5 mmol), K₂CO₃ (207 mg, 1.5 mmol), CuI (19 mg, 0.1 mmol) and proline (23 mg, 0.2 mmol) in 3 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 10c was eluted in 25% EtOAc in hexane as a light brown foam. Yield: 19% (at 120 °C, yield 24%); ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.92 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.48 (td, J = 7.9 Hz, 0.8 Hz, 1H), 7.37 (td, J = 7.9 Hz, 0.6 Hz, 1H), 7.28–7.25 (m, 1H), 7.08 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.87 (dd, J = 2.6 Hz, 1H), 6.51 (d, J = 1.9 Hz, 1H), 4.68 (d, J = 16.5 Hz, 1H), 4.63 (d, J = 16.8 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 4.26 (d, J = 12.7 Hz, 1H), 4.12 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.5 Hz, 1H), 3.65 (t, J = 5.2 Hz, 4H), 3.30 (t, J = 5.2 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 163.8, 152.7, 148.0, 140.2, 130.4, 130.1, 129.8, 127.9, 127.7, 127.5, 126.725, 126.4, 125.7, 124.0, 123.9, 120.6, 116.7, 114.0, 66.9, 59.0, 58.3, 50.1, 49.6; MS (ESI) m/z (%): 518 ([M + H], 100); HRMS (ESI): calcd for C₂₆H₂₄BrN₅S 518.10086, found 518.10232.

(±)-2-Bromo-8-(4-(2-fluorophenyl)piperazin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (10d). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (149 mg, 0.39 mmol), 1-(2-fluorophenyl)piperazine 9b (354 mg, 1.97 mmol), K₂CO₃ (163 mg, 1.18 mmol), CuI (15 mg, 0.08 mmol) and proline (18 mg, 0.16 mmol) in 3 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 10d was eluted in 25% EtOAc in hexane as a light brown solid. Yield: 12% (at 120 °C, yield 12%); mp: 92–93 °C; ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.28–7.24 (m, 1H), 7.09–6.93 (m, 7H), 6.84 (dd, J = 2.7, 8.7 Hz, 1H), 6.47 (d, J = 2.7 Hz, 1H), 4.67 (d, J = 16.5 Hz, 1H), 4.62 (d, J = 16.8 Hz, 1H), 4.28 (dd, J = 0.9, 12.85 Hz, 2H), 4.09 (dd, J = 4.4, 16.6 Hz, 2H), 3.24 (t, J = 6.4 Hz, 4H), 3.19 (t, J = 6.1 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 156.7, 154.7, 148.2, 147.2, 141.0, 139.9, 130.2, 130.1, 129.7, 129.6, 127.7, 126.6, 125.5, 123.1, 120.9, 118.1, 116.4, 113.7, 111.2, 66.9, 58.9, 58.1, 55.3, 50.7, 49.8; MS (ESI) m/z (%): 479 ([M + H], 100); HRMS (ESI): calcd for C₂₅H₂₄BrFN₄ 479.12411, found 479.12353.

(±)-2-Bromo-8-(4-(2-methoxyphenyl)piperazin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (10e). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (201 mg, 0.53 mmol), 1-(2-methoxyphenyl)piperazine 9c (511 mg, 2.5 mmol), K₂CO₃ (220 mg, 1.59 mmol), CuI (20 mg, 0.11 mmol) and proline (24 mg, 0.21 mmol) in 4 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 10e was eluted in 25% EtOAc in hexane as a white solid. Yield: 18% (at 120 °C, yield 25%); mp: 90–91 °C; ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.28–7.24 (m, 1H), 7.07–6.82 (m, 8H), 6.47 (d, J = 2.7 Hz, 1H), 4.67 (d, J = 16.6 Hz, 1H), 4.62 (d, J = 16.9 Hz, 1H), 4.28 (ddd, J = 1.2, 12.8 Hz, 2H), 4.09 (d, J = 17.3 Hz, 2H), 3.87 (s, 3H), 3.26 (t, J = 5.3 Hz, 4H), 3.18 (t, J = 5.3 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 152.2, 148.2, 147.2, 141.0, 139.9, 130.2, 130.1, 129.7, 129.6, 127.7, 126.6, 125.5, 123.1, 120.9, 118.1, 116.4, 113.7, 111.2, 66.9, 58.9, 58.1, 55.3, 50.7, 49.8; MS (ESI) m/z (%): 491 ([M + H], 100); HRMS (ESI): calcd for C₂₆H₂₇BrN₄O 491.14410, found 491.14200.

(±)-tert-Butyl-4-((5S)-8-bromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)piperazine-1-carboxylate (10f). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (215 mg, 0.57 mmol), tert-butyl piperazine-1-carboxylate 9d (529 mg, 2.84 mmol), K₂CO₃ (235 mg, 1.7 mmol), CuI (22 mg, 0.11 mmol) and proline (26 mg, 0.23 mmol) in 5 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 10f was eluted in 25% EtOAc in hexane as a white solid. Yield: 14% (at 120 °C, yield 16%); mp: 219–220 °C; ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.24 (d, J = 2.3 Hz, 1H), 7.06–6.98 (m, 3H), 6.79 (dd, J = 2.7, 8.8 Hz, 1H), 6.42 (d, J = 2.6 Hz, 1H), 4.63 (t, J = 16.2 Hz, 2H), 4.26 (dd, J = 11.9 Hz, 2H), 4.07 (d, J = 16.9 Hz, 2H), 3.52 (t, J = 4.9 Hz, 4H), 2.99 (t, J = 4.9 Hz, 4H), 1.47 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 154.6, 148.0, 147.1, 140.4, 130.3, 130.1, 129.7, 127.9, 126.6, 125.5, 116.9, 116.4, 114.3, 79.8, 66.9, 58.9, 58.2, 49.8, 43.6, 28.4; IR (neat, cm⁻¹): 2970, 2924, 1690, 1243, 1159, 823; MS (ESI) m/z (%): 485 ([M + H], 100); HRMS (ESI): calcd for C₂₄H₂₉BrN₄O₂ 485.15467, found 485.15274.

(±)-2-(4-Benzylpiperidin-1-yl)-8-bromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (10g). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (200 mg, 0.53 mmol), 4-benzylpiperidine 9e (463 mg, 2.64 mmol), K₂CO₃ (219 mg, 1.59 mmol), CuI (20 mg, 0.1 mmol) and proline (24 mg, 0.21 mmol) in 4 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 10g was eluted in 25% EtOAc in hexane as a white solid. Yield: 16% (at 120 °C, yield 23%); mp: 158–159 °C; ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.31–7.23 (m, 3H), 7.19 (tt, J = 2.1, 7.5 Hz, 1H), 7.16–7.13 (m, 2H), 7.03 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 2.7, 8.5 Hz, 2H), 6.78 (dd, J = 2.7, 8.8 Hz, 1H), 6.40 (d, J = 2.60 Hz, 1H), 4.64 (d, J = 16.5 Hz, 1H), 4.60 (d, J = 16.6 Hz, 1H), 4.29 (dd, J = 1.2, 12.7 Hz, 1H), 4.23 (dd, J = 1.2, 12.7 Hz, 1H), 4.06 (d, J = 16.6 Hz, 2H), 3.52–3.45 (m, 2H), 2.55 (d, J = 7.9 Hz, 2H), 2.52 (dt, J = 2.4, 12.1 Hz, 2H), 1.73–1.67 (m, 2H), 1.64–1.56 (m, 1H), 1.40–1.31 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 147.2, 140.4, 130.2, 129.7, 129.1, 128.2, 127.7, 126.7, 125.9, 125.4, 117.0, 116.4, 114.2, 77.3, 77.0, 76.7, 66.9, 59.0, 58.2, 43.1, 37.7, 32.0; MS (ESI) m/z (%): 474 ([M + H], 100); HRMS (ESI): calcd for C₂₇H₂₈BrN₃ 474.15394, found 474.15202.

(±)-2-(Piperidin-1-yl)-8-(pyrrolidin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (12). A mixture of (±)-2-bromo-8-(pyrrolidin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 10b (105 mg, 0.28 mmol), piperidine 7 (121 mg, 1.42 mmol), K₂CO₃ (118 mg, 0.85 mmol), CuI (11 mg, 0.06 mmol) and proline (13 mg, 0.11 mmol) in 3 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 12 was eluted in 25% EtOAc in hexane as a white solid. Yield: 57%; mp: 200–201 °C; ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.01 (d, J = 8.7 Hz, 2H), 6.78 (dd, J = 2.7, 8.7 Hz, 1H), 6.44 (dd, J = 2.7, 7.1 Hz, 2H), 6.06 (d, J = 2.7 Hz, 1H), 4.65 (d, J = 16.5 Hz, 1H), 4.62 (d, J = 16.5 Hz, 1H), 4.30 (s, 2H), 4.06 (t, J = 15.6 Hz, 2H), 3.18 (t, J = 6.5 Hz, 4H), 2.99 (t, J = 5.5 Hz, 4H), 1.93 (quintet, J = 3.2 Hz, 4H), 1.65 (quintet, J = 5.6 Hz, 4H), 1.51 (quintet, J = 5.6 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 148.9, 145.0, 140.1, 136.3, 128.4, 128.1, 125.5, 125.2, 116.9, 114.4, 111.3, 108.4, 67.4, 58.8, 51.3, 47.6, 25.8, 25.3, 24.1; MS (ESI) m/z (%): 375 ([M + H], 100); HRMS (ESI): calcd for C₂₄H₃₁N₄ 375.25432, found 375.25496.

(±)-2-(4-Benzylpiperidin-1-yl)-8-(pyrrolidin-1-yl)-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (13). A mixture of (±)-2-(4-benzylpiperidin-1-yl)-8-bromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 10g (150 mg, 0.32 mmol), pyrrolidine 8 (113 mg, 1.61 mmol), K₂CO₃ (134 mg, 0.97 mmol), CuI (13 mg, 0.06 mmol) and proline (15 mg, 0.13 mmol) in 5 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 13 was eluted in 25% EtOAc in hexane as a white solid. Yield: 40%; mp: 141–143 °C; ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.30–7.24 (m, 2H), 7.22–7.12 (m, 3H), 6.99 (dd, J = 1.1, 8.7 Hz, 2H), 6.75 (dd, J = 2.7 Hz, 1H), 6.44 (d, J = 2.69 Hz, 1H), 6.43–6.39 (m, 1H), 6.05 (d, J = 2.69 Hz, 1H), 4.64 (d, J = 16.5 Hz, 1H), 4.61 (d, J = 16.5 Hz, 1H), 4.33–4.26 (m, 2H), 4.05 (m, 2H), 3.50–3.44 (m, 2H), 3.17 (t, J = 6.5 Hz, 4H), 2.55 (d, J = 7.1 Hz, 2H), 2.50 (dt, J = 2.8, 12.1 Hz, 2H), 1.93 (quin, J = 3.3, 6.5 Hz, 4H), 1.73–1.55 (m, 3H), 1.45–1.24 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 148.5, 144.9, 140.4, 140.2, 136.5, 130.8, 129.0, 128.8, 128.5, 128.1, 125.7, 125.5, 125.2, 116.8, 114.4, 111.3, 108.4, 67.4, 58.9, 50.7, 50.4, 47.6, 43.1, 37.7, 32.1, 25.3; MS (ESI) m/z (%): 465 ([M + H], 100); HRMS (ESI): calcd for C₃₁H₃₆N₄ 465.30127, found 465.30078.

Synthesis of (±)-2-bromo-N,N-dimethyl-8-morpholino-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocin-13-amine (15). A mixture of (±)-(2,8-dibromo-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazocin-13-yl)-dimethyl-amine 14 (211 mg, 0.5 mmol), morpholine (218 mg, 2.5 mmol), K₂CO₃ (207 mg, 1.5 mmol), CuI (19 mg, 0.1 mmol) and proline (23 mg, 0.2 mmol) in 3 mL of DMSO was heated at 90 °C for 24 h. The crude compound was loaded on a silica gel column; compound 15 was eluted in 15% EtOAc in hexane as a light brown solid and compound 16 was eluted in 25% EtOAc in hexane as light brown foam. Yield: 17%; mp: 90–91 °C; ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.29–7.21 (m, 1H), 7.07 (d, J = 2.3 Hz, 1H), 7.05–6.94 (m, 2H), 6.78 (qd, J = 2.3 Hz, 1H), 6.42 (dd, J = 2.3 Hz, 1H), 4.67–4.52 (m, 2H), 4.19–4.10 (m, 1H), 3.87–3.77 (m, 6H), 3.08–3.01 (m, 4H), 2.41 (s, 3H), 2.40 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 147.9, 143.8, 130.0, 129.9, 129.2, 128.2, 127.1, 126.9, 126.0, 125.8, 116.1, 115.9, 115.7, 113.2, 112.9, 90.0, 66.9, 66.8, 59.5, 58.9, 51.8, 51.0, 49.7, 41.3, 41.1; MS (ESI) m/z (%) ([M + H], 100): 430; HRMS (ESI): calcd for C₂₁H₂₅BrN₄O 429.12845, found 429.12832.

(±)-N,N-Dimethyl-2,8-dimorpholino-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocin-13-amine (16). Yield: 23%; ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.06–6.95 (m, 2H), 6.80–6.69 (m, 2H),6.45–6.39 (m, 2H), 4.57 (d, J = 16.1 Hz, 1H), 4.53 (d, J = 16.0 Hz, 1H), 4.11 (d, J = 16.8 Hz, 1H), 3.85–3.74 (m, 10H), 3.07–2.96 (m, 8H), 2.40 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ ppm: 147.7, 147.5, 141.7, 137.5, 128.9, 128.9, 128.8, 126.0, 125.9, 125.8, 115.8, 115.6, 113.5, 113.1, 90.6, 67.0, 66.9, 59.7, 51.8, 49.9, 41.5, 29.6; MS (ESI) m/z (%) ([M + H], 100): 436; HRMS (ESI): calcd for C₂₅H₃₄N₅O₂ 436.27070, found 436.27188.

(±)-8-Bromo-N,N-diethyl-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocin-2-amine (17). A mixture of (±)-2,8-dibromo-6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine 3 (114 mg, 0.3 mmol), diethylamine (78 μL, 0.75 mmol), K₂CO₃ (125 mg, 0.90 mmol), CuI (12 mg, 0.06 mmol) and proline (14 mg, 0.12 mmol) in 3 mL of DMSO was heated at 120 °C for 24 h. The crude compound was loaded on a silica gel column; compound 15 was eluted in 10% EtOAc in hexane as a light brown foam. Yield: 5%; ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.28–7.23 (m, 1H), 7.06–6.96 (m, 3H), 6.56 (dd, J = 2.2, 8.3 Hz, 1H), 6.18–6.14 (m, 1H), 4.65 (d, J = 16.5 Hz, 1H), 4.59 (d, J = 16.8 Hz, 1H), 4.27 (dd, J = 12.1 Hz, 2H), 4.07 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.6 Hz, 1H), 3.25 (q, J = 7.0 Hz, 4H), 1.09 (t, J = 7.0 Hz, 6H); MS (ESI) m/z (%) ([M + H], 100): 374; HRMS (ESI): calcd for C₁₉H₂₃BrN₃ 372.10699, found 372.10824.

Acknowledgements

We would like to thank Director, CSIR-IICT for facilities. MBR, PGR and MS would also like to thank CSIR, New Delhi for fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra21437a

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