MoO₂Cl₂(DMF)₂ catalyzed microwave assisted reductive cyclisation of nitroaromatics into dibenzodiazepines

Abstract

The paper describes a gentle and highly efficient protocol for the synthesis of dibenzodiazepines by reductive cyclisation of nitroaniline to dibenzodiazepines under microwave irradiation catalyzed by MoO₂Cl₂(DMF)₂ involving Ph₃P as reducing agent. This synergic approach results in the transformation of nitroaromatics into dibenzodiazepines in high yield and is applicable to the construction of a wide variety of dibenzo(di/ox)azepines and other structurally related heterocycles.

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Introduction

Dibenzodiazepines have attracted considerable attention because of their efficient pharmacological activities.¹ The benzodiazepine nucleus is a well studied traditional pharmacophoric scaffold that has emerged as the core structural unit of a variety of sedatives, hypnotic muscle-relaxants, atypical and potential antipsychotic,² anti-dopaminergic and anti-muscarinic agents,³ compounds displaying H4 receptor affinity⁴ and RXR-antagonist activity drugs.⁵ Since the first reported synthesis of dibenzodiazepine derivatives by Schmutz in 1964–67 (clozapine and loxapine; Fig. 1) limited progress in their synthesis has been made.⁶ Existing routes to dibenzodiazepines generally rely on the preparation of amide⁷ or lactam⁸ intermediates and subsequent functionalization of the heterocyclic scaffold to introduce additional substituents (Scheme 1). Such transformations typically require harsh conditions and purification after each synthetic step, and are characterized by low atom economy and the use of protecting groups.⁹

Fig. 1 Pharmacologically active dibenzodiazepine derivatives.

Scheme 1 Pairs of coupling partners traditionally used for synthesis of dibenzodiazepines. Reagents used: POCl₃, PPA, SOCl₂, RZnCl, Pd/C, SnCl₂, peptide coupling reagents.¹⁴ Coupling of substrates with free NH₂ groups leads to mixtures of products.

Transition metal complexes with metal–oxygen multiple bonds are well known as catalysts for oxo-transfer oxidation reactions and particularly for reduction of organic functional groups.¹⁰ The catalyst MoO₂Cl₂(DMF)₂ has advantages due to its straightforward synthesis (under air, using aqueous media), water solubility and possession of Cl ligands which are prone to hydrolysis and substitution by oxygen ligands.¹¹ The redox ability of dioxomolybdenum reagents has been utilized in designing several useful organic transformations.¹²

Prompted by the above facts and to circumvent the above-mentioned drawbacks we report herein the novel, gentle and highly efficient synthesis of dibenzodiazepines by MoO₂Cl₂(DMF)₂ catalyzed and microwave activated one-step reductive cyclisation of nitroaromatic compounds with Ph₃P as reducing agent in excellent yield (75%) (Scheme 2).

Scheme 2 Proposed microwave synthesis of dibenzo(di)azepines.

The reduction of the dioxomolybdenum(VI) compounds by addition of phosphines like PPh₃ leads to dinuclear m-oxo-bridged complexes. However, oxidation of the oxomolybdenum(V) complexes is restricted by the nature of the ligand and the oxidizing agents.¹³

Result and discussion

In our preliminary investigation encouraged by great progress towards the target molecule, we carried out a one pot reaction with the commercially available compounds 2-nitroaniline 1 and aromatic aldehyde 2a (see Table 6 below) as model reactants by conventional heating methods without any catalyst but no product formation was detected. However when a catalyst was used, product formation occurred in low yield (25–30%). Next we tried triphenylphosphine as reducing agent employed with the catalyst. Conversion of 1 and 2a into 3a was extremely sluggish and both the starting material and product were observed to decompose over several hours under reflux conditions. We envisaged that the efficiency of this modified synthesis could be improved significantly through the use of microwave irradiation methodology.

In order to test the synthesis proposed in Scheme 2 and find the best reaction conditions, 2-nitroaniline 1 and aromatic aldehyde 2a in various solvents with and without catalyst were irradiated with microwaves but the product was only obtained in trace amounts. Our initial studies focused on examining the scope of the catalyst and application of various metal compounds. Commercially available molybdenum oxides such as MoO₂, MoO₃ and MoO₂(acac)₂ showed catalytic activities (40–50% yield, Table 1, entries 1–3). In contrast the catalytic activities of other metal compounds such as Na₂MoO₄ and ReO₂ were very low (Table 1, entries 4 and 5). As far as catalytic activity is concerned MoO₂Cl₂(DMF)₂ was superior to the others (Table 1, entry 6).

Table 1 Screening of catalysts for the synthesis of dibenzodiazepine^a

Entry	Catalyst	Amount (mol%)	Yield^b (%)
a Reaction conditions: nitroaniline 1 (1.0 equiv.), aromatic aldehyde 2a (1.0 equiv.) and catalyst (10 mol%), under microwave irradiation.b Isolated yields.
1	MoO2	10	42
2	MoO3	10	45
3	MoO2(acac)2	10	48
4	Na2MoO4	10	25
5	ReO2	10	32
6	MoO2Cl2(DMF)2	10	60

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The use of H-donor solvents such as toluene and isopropanol allowed the formation of the desired product 3a. Good yields were obtained in both solvents although using isopropanol was less convenient because its low boiling point led to the microwave vial being exposed to high pressure. In order to increase the yield of the desired product further, we focused on the combination of MoO₂Cl₂(DMF)₂ catalyst and a variety of phosphines, using any one of trimethyl, triethyl and triphenyl phosphine under microwave heating. The use of trimethyl and triethyl phosphines led to complex mixtures of 3a with very poor yields. Thus, a homogeneous solution of 1 and 2, Ph₃P (2.4 eq.) and MoO₂Cl₂(DMF)₂ (10 mol%) in toluene was heated at 200 °C using microwave heating for 30 min. With a view to expanding the scope and practical convenience of this dibenzodiazepine synthesis, a variety of solvents and phosphine combinations were studied (Table 2). Herein, we report the development of a new catalytic system based on Ph₃P as reductant and MoO₂Cl₂(DMF)₂ as the catalyst with toluene because of the poor microwave absorption properties of this solvent.

Table 2 Evaluation of the conditions for the MoO₂Cl₂(DMF)₂–PPh₃ mediated conversion of nitroaniline to dibenzodiazepines^a

Entry	Solvent	Phosphine	Temp. (°C)	Time (min)	Yield^b (%)
a Reaction conditions: nitroaniline (1 mmol), aromatic aldehyde (1 mmol), MoO2Cl2(DMF)2 catalyst and different solvents and phosphines.b Isolated yields.
1	1,4-Dioxane	PMe3	200	60	35
2	1,4-Dioxane	PEt3	200	65	44
3	1,4-Dioxane	PPh3	200	55	25
4	Toluene	PMe3	200	40	65
5	Toluene	PEt3	200	42	68
6	Toluene	PPh3	200	30	75
7	Isopropanol	PMe3	200	35	55
8	Isopropanol	PEt3	200	47	62
9	Isopropanol	PPh3	200	50	58

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A temperature of 200 °C was chosen on the basis of previous MW reactions of nitroaniline. In order to optimize the reaction temperature the reaction of 1 and 2a was carried out by using MoO₂Cl₂(DMF)₂ with Ph₃P catalytic system at temperatures ranging from 160 °C to 210 °C with an increment of 10 °C each time. The results are displayed in Table 3.

Table 3 Optimization of temperature with respect to time and yield^a

Entry	Temperature (°C)	Time (min)	Yield^b (%)
a Reaction conditions: nitroaniline (1 mmol), aromatic aldehyde (1 mmol), MoO2Cl2(DMF)2 (10 mol%), Ph3P (2.4 eq.) and toluene solvent.b Isolated yields.
1	160	65	45
2	170	55	50
3	180	48	52
4	190	38	58
5	200	30	75
6	210	40	63

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We observed that the yield of product 3a was improved and the reaction time was shortened as the temperature was increased from 190–200 °C. The yield dropped when the temperature was further increased from 200 °C to 210 °C. Therefore, the most suitable reaction temperature was found to be 200 °C. Moreover screening of the time required for an excellent yield of product (entries 1 and 3, Table 4) showed that at 200 °C the reaction needed irradiation for 30 min to achieve complete conversion but that at longer times side reactions/degradative processes set in. This is derived from the fact that at irradiation times higher than 30 min (Table 4, entry 4 and 5), the yield fell off.

Table 4 Optimization of time with yield at 200 °C^a

Entry	T (°C)	Time (min)	Yield^b (%)
a Reaction conditions: nitroaniline (1 mmol), aromatic aldehyde (1 mmol), MoO2Cl2(DMF)2 (10 mol%), Ph3P (2.4 eq.) and toluene solvent at 200 °C in MW.b Isolated yield.
1	200	20	58
2	200	25	64
3	200	30	75
4	200	35	66
5	200	40	45

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On a comparative point of view, regarding the methodology applied, the dibenzodiazepines were prepared in lower yields (40–45%) using thermal conditions than using microwave irradiation (70–80%). The results are summarised in Table 5. The results in Table 5 clearly show that the reaction was efficiently promoted by MW and the reaction time was strikingly shortened to 30–35 min from 12–15 h.

Table 5 MoO₂Cl₂(DMF)₂, catalysed and microwave activated synthesis of dibenzodiazepines 3(a–j)^a

Product	MP °C	Time		Yield^b
		MW (min)	Thermal (h)	MW (%)	Thermal (%)
a Reaction conditions: nitroaniline (1 mmol), aromatic aldehydes (1 mmol), MoO2Cl2(DMF)2 (10 mol%), Ph3P (2.4 eq.) and toluene solvent.b Isolated yield.
3a	138	31	12	72	42
3b	144	30	14	74	44
3c	152	30	13	73	40
3d	128	32	12	75	42
3e	120	31	14	78	45
3f	158	33	13	80	43
3g	148	34	15	76	44
3h	136	32	12	75	42
3i	132	35	13	77	41
3j	146	34	15	78	40

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This observation clearly indicates the existence of a non-thermal microwave effect. It is thus assumed that the microwave synergy plays a significant role in the reaction and it combines with the specific effect of the electromagnetic field of the microwaves in decreasing the activation energy of the reaction by stabilising the polar activated complex of the reaction, to provide excellent yields and reducing reaction time from hours to minutes.

Mechanistically, microwave activated synthesis of dibenzodiazepines and reductive cyclization of nitroaromatics via intramolecular cyclization can be achieved by employing a catalytic system (Scheme 3). The structural assignments of the new compounds are based on chemical and spectroscopic evidence. In order to have accurate data for comparison to hand, we explored the scope of our proposed reaction where nitroaniline was reacted with a range of commercially available aromatic aldehydes under the optimised conditions. The results are listed in Table 6.

Scheme 3 Possible mechanism for the synthesis of dibenzodiazepines in the catalytic system.

Table 6 Scope of variation of aromatic aldehydes for the synthesis of dibenzodiazepines^a

Entry	Products	Substrate 2				Time (min)	Yield (%)	MP (°C)
		R^1	R^2	R^3	R^4
a Reaction condition: nitroaniline (1 mmol), aromatic aldehydes (1 mmol), MoO2Cl2(DMF)2 (10 mol%), Ph3P (2.4 eq.) and toluene solvent at 200 °C in MW.
1	3a	H	H	H	H	30	75	138
2	3b	H	H	H	Cl	31	74	144
3	3c	H	H	H	NO2	30	73	152
4	3d	H	H	H	OCH3	32	75	128
5	3e	H	H	OCH3	OCH3	31	78	120
6	3f	H	H	NO2	Cl	33	80	158
7	3g	H	H	NO2	NO2	34	76	148
8	3h	H	H	H	CH3	32	75	136
9	3i	H	H	CH3	CH3	35	77	132
10	3j	H	H	Cl	Cl	34	78	146

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Conclusion

The advantages of microwave heating to effect a wide variety of organic reactions are now well established.¹⁵ Key advantages of modern scientific microwave apparatus are the ability to control reaction conditions, precisely monitoring temperatures, pressure and reaction time. The microwave reactor “Monowave 300” (manufactured by Anton-paar Pvt. Ltd.) was used for irradiation reactions. The instrument uses a maximum of 850 W magnetron output power (2.45 GHz). The temperature was recorded using IR temperature sensor. The irradiation experiments were performed in temperature control mode. Care was taken to ensure efficient stirring in all experiments. In summary we devised a mild, convenient and efficient protocol for the synthesis of dibenzodiazepines from easily available and cost effective starting materials. The simple experimental procedure is convenient and environmentally benign.

Experimental section

Materials

All chemicals were reagent grade, were purchased from Aldrich and Alfa Aesar and were used without purification. NMR spectra were recorded on a BRUKER AVANCE II-400FT Spectrometer (400 for ¹H NMR, 100 MHz for ¹³C) using CDCl₃ as solvent and TMS as an internal reference. Mass spectra were recorded on a JEOL SX-102 (FAB) mass spectrometer at 70 eV. Elemental analyses were carried out in a Coleman automatic carbon, hydrogen, oxygen, chlorine and nitrogen analyzer. All the reactions were monitored by TLC using 40 pre-coated sheets of silica gel G/UV-254 of 0.25 mm thickness (Merck 60F254). Melting points were determined by the open glass capillary method and were uncorrected.

Method

Herein, for the microwave assisted synthesis of dibenzodiazepines 3(a–j), a mixture of 2-nitroaniline 1 (1 mmol), various aromatic aldehydes 2(a–j) (1 mmol), Ph₃P (2.4 equivalents), 10% mol of MoO₂Cl₂(DMF)₂ and toluene (3 ml) was irradiated with microwaves at 200 °C for 30–35 minutes. After completion of the reaction (indicated by TLC solvent system, 3 : 1 ratio of ethyl acetate : hexane), the reaction mixture was filtered and allowed to stand for 1.5 hours to remove the solvent. The mixture was dissolved in H₂O (100 ml) and the product was extracted with EtOAc (3 × 50 ml), washed with brine (3 × 20 ml) and dried over MgSO₄. The solvent was removed by distillation under reduced pressure. The remaining residue was purified by flash column chromatography to obtain analytically pure 3(a–j). All products were characterized by comparison of their MP, ¹H NMR spectra with those of authentic samples.⁴

Acknowledgements

We gratefully acknowledge the financial support from the University Grants Commission and CSIR. Authors are also thankful to SAIF, Punjab University Chandigarh for providing all the spectroscopic and analytical data.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra11089g

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