Quinoxaline: a new directing group for ortho C–H alkenylation / intramolecular ortho C–H cycloamination under open air leading to bioactive polynuclear N-heteroarenes

Abstract

Quinoxaline has been identified as a new directing group for the Pd (or Ru)-catalyzed ortho C–H alkenylation of aniline derivatives and subsequent hypervalent iodine promoted intramolecular ortho C–H cycloamination of the resulting N-arylquinoxalin-2-amine derivatives. This two-step strategy afforded alkenyl substituted benzo[4,5]imidazo[1,2-a]quinoxalines as inhibitors of PDE4. The Pd-catalyzed ortho C–H alkenylation of phenol derivatives was also performed successfully when quinoline was found to be an effective directing group.

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The strategy consisting of directed ortho C–H functionalization followed by converting the directing group into an integral part of the target molecule is of fundamental interest as this may allow easy and quick access to functionalized heteroarenes for their potential applications in organic/medicinal/pharmaceutical chemistry.

While functionalized alkenes¹ have been explored in the discovery of new drugs² e.g. tamoxifen^2a in the past, assembly of polynuclear heteroarene and an alkenyl moiety in the same molecule largely remain underexplored. Their potential applications in medicinal and pharmaceutical chemistry and our interest in bioactive alkenyl substituted heteroarenes³ prompted us to focus on alkenyl substituted benzo[4,5]imidazo[1,2-a]quinoxalines (A, Fig. 1) and their pharmacological evaluation in vitro. Indeed the selection of benzo[4,5]imidazo[1,2-a]quinoxaline ring was inspired by the promising pharmacological properties of structurally related imidazo[1,2-a]quinoxaline based molecules^4,5 e.g. EAPB0203 (B, Fig. 1). The core structure of A i.e. the central polynuclear heterocyclic ring can be realized simply by moving and fusing the benzene ring of 3-methoxy phenyl group with the imidazole ring of B.

Fig. 1 New alkenyl substituted benzo[4,5]imidazo[1,2-a]quinoxalines (A) and a known imidazo[1,2-a]quinoxaline derivative EAPB0203 (B).

Alkenylation is one of the most powerful methods for accessing substituted alkenes⁶ that involved Pd-catalyzed coupling of aryl halides with alkenes (the Mizoroki–Heck reaction).⁷ However, because of drawbacks such as limited availability of expensive aryl halide component, or their cumbersome preparation, direct C–H bond olefination (the Fujiwara–Moritani reaction)⁸ has attracted huge attention as a greener alternative during past several years. While transition metals have been used extensively for the C–H functionalization leading to C–C and C-heteroatom bond formation,⁹ the Pd-catalyzed chelation-directed sp² C–H activation has been found to be a highly effective strategy for this purpose.¹⁰ This approach involves the use of σ-chelating directing groups with a metal center that leads to o-selectivity via in situ generation of conformationally rigid rings. A range of directing groups has been reported to aid C(Ar)–H activation until recently e.g. pyridine,^10a–c imidazoline,^10d pyrazole,^10e oxazoline,^10f,g amide,^10h,i oxime ether,^10j ketones,^10k hydroxyl,^10l,m carboxylic acids,^10n,o 2-pyridylsulfinyl,^10p quinoline^10q etc. However, several of these groups are non-removable and are considered as serious limitations for practical applications of these processes. In our strategy we wondered if any of these groups or a new one could be considered as a pre-installed precursor required for further chemical transformation instead of attempting their removal after the C–H activation step. This strategy appeared to be attractive and economical as it could allow salvaging of directing groups. A retro synthetic analysis of A (Fig. 2) revealed that a quinoxaline moiety could serve the purpose and it was therefore necessary for the quinoxaline moiety to play the role of a directing group in the present case. This prompted us to test quinoxaline as a new directing group for the C–H functionalization with o-selectivity.¹¹ Herein we report our preliminary results on the Pd (or Ru)-catalyzed o-alkenylation of aniline derivatives via C–H activation assisted by quinoxaline (Scheme 1). We also report subsequent conversion of the resulting N-arylquinoxalin-2-amine derivatives (5) to A (or 6) via hypervalent iodine promoted intra-molecular C–H cycloamination reaction¹² under mild and environmental friendly conditions (Scheme 1). To our knowledge the use of this two-step strategy consisting of ortho C–H functionalization followed by intramolecular C–H cycloamination involving quinoxaline moiety leading to alkenyl substituted polynuclear N-heteroarenes e.g. benzo[4,5]imidazo[1,2-a]quinoxalines¹³ is not common in the literature. Moreover, though synthesis of this class of N-heteroarenes has been reported earlier their alkenyl analogues are not known. The effectiveness of quinoline in the o-alkenylation of phenol derivatives via C–H activation under the conditions studied was also examined.

Fig. 2 Retrosynthetic analysis of compound A.

Scheme 1 Pd-catalyzed ortho C–H functionalization followed by intramolecular C–H cycloamination under open air leading to alkenyl substituted N-heteroarenes (6).

Having prepared the required starting materials (3a–g) according to the reported methods¹⁴ (see ESI†) we began our study with the coupling of 3a with ethyl acrylate (4a) under various conditions (Table 1). The reaction was initially performed in the presence of a Pd-catalyst, Cu(OAc)₂, trifluoroacetic acid (TFA), in CH₃CN at 60 °C for 12 h under open air. The use of Pd(PPh₃)₄, Pd(dba)₃, and Pd(PPh₃)₂Cl₂ did not afford good yields of 5a (entries 1–3, Table 1). However, a dramatic increase in yield of 5a was observed when Pd(OAc)₂ was used (entry 4, Table 1). The change of oxidants e.g. the use of K₂S₂O₈ and CuCl₂ in place of Cu(OAc)₂ was discouraging (entries 5 & 6, Table 1) and CuCl₂ acted as an inhibitor. While some progress of reaction was observed when no oxidant was used (perhaps assisted by aerial oxygen) the yield of 5a was low (entry 7, Table 1). The use of other solvents such as 1,4-dioxane, DMF, DCE (1,2-dichloroethane), EtOH and toluene in place of CH₃CN was also ineffective (entries 8–12, Table 1) except 1,4-dioxane. The role of Pd(OAc)₂ and TFA was confirmed by performing the reaction in the absence of these reagents where no or poor yield of 5a was observed (entries 13 & 14, Table 1). Indeed, TFA was better compared to other additives e.g. PivOH and CH₃COOH (entries 15 & 16, Table 1). The decrease of reaction temperature from 60 °C decreased the product yield (entry 17, Table 1) whereas increase of temperature (e.g. to 80 °C) resulted quick evaporation of TFA (bp 72.4 °C). Moreover, a longer reaction time was also found to be less effective (entry 18, Table 1). Notably, the present quinoxaline directed ortho C–H alkenylation proceeded well in the presence of a Ru(II) catalyst (vide infra). However, requirement of sealed tube in this case prompted us to proceed with Pd(II)-catalyzed method and the conditions of entry 4 appeared to be optimal.

Table 1 Effect of conditions on the reaction of 3a with 4a^a

Entry	Catalyst	Additive/oxidant	Solvent	% Yield^b
a All the reactions are carried out using 3a (1 mmol), alkene 4a (1.5 mmol), a Pd-catalyst (5 mol%), an oxidant (1.5 mmol) and an additive (1.2 mmol) in a solvent (2.5 mL) at 60 °C for 12 h under open air.b Isolated yield.c No oxidant.d No catalyst.e No additive.f Performed at 40 °C.g Reaction time was 24 h.
1	Pd(PPh3)4	TFA/Cu(OAc)2	CH3CN	26
2	Pd(dba)3	TFA/Cu(OAc)2	CH3CN	35
3	Pd(PPh3)2Cl2	TFA/Cu(OAc)2	CH3CN	52
4	Pd(OAc)2	TFA/Cu(OAc)2	CH3CN	84
5	Pd(OAc)2	TFA/K2S2O8	CH3CN	22
6	Pd(OAc)2	TFA/CuCl2	CH3CN	0
7	Pd(OAc)2	TFA/—	CH3CN	30^c
8	Pd(OAc)2	TFA/Cu(OAc)2	1,4-Dioxane	82
9	Pd(OAc)2	TFA/Cu(OAc)2	DMF	10
10	Pd(OAc)2	TFA/Cu(OAc)2	DCE	48
11	Pd(OAc)2	TFA/Cu(OAc)2	EtOH	0
12	Pd(OAc)2	TFA/Cu(OAc)2	Toluene	72
13	—	TFA/Cu(OAc)2	CH3CN	0^d
14	Pd(OAc)2	—/Cu(OAc)2	CH3CN	28^e
15	Pd(OAc)2	PivOH/Cu(OAc)2	CH3CN	Trace
16	Pd(OAc)2	AcOH/Cu(OAc)2	CH3CN	19
17	Pd(OAc)2	TFA/Cu(OAc)2	CH3CN	45^f
18	Pd(OAc)2	TFA/Cu(OAc)2	CH3CN	80^g

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To expand the generality and scope of this methodology a range of substrates e.g. 3a–f carrying substituents such as MeO, Me, F, Cl and Br on the N-phenyl ring were employed (Table 2). The other coupling partner e.g. 4a–c generally included Me, Et or t-Bu ester of acrylic acid. The reaction proceeded well in all these cases affording the corresponding desired product 5a–n in good to acceptable yield. To test the effectiveness of quinoxaline moiety towards Ru(II)-catalyzed o-alkenylation of 3 the coupling of 3a–b with 4a–c was performed under reported conditions¹⁵ when the desired product 5a–e was obtained almost in the same yields (Scheme 2) as observed in case of Pd-catalyzed reaction. Notably, the Ru(II)-catalyzed o-alkenylation of 3 was carried out in a sealed tube as the reaction did not proceed well when performed in an open reaction vessel.

Table 2 Synthesis of alkenyl substituted N-arylquinoxalin-2-amine derivatives (5)^a

Entry	Substrate (3)	Alkene (4)	Product (5)	Yield^b (%)
	R^1, R^2, R^4=	R^3=	R^1, R^2, R^4, R^3=
a All the reactions are carried out using compound 3 (1 mmol), alkene 4 (1.5 mmol), Pd(OAc)2 (5 mol%), Cu(OAc)2 (1.5 mmol) and TFA (1.2 mmol) in CH3CN (2.5 mL) at 60 °C, under air.b Isolated yield.
1	3a	4a	5a	84
	Cl, OCH3, H	Et	Cl, OCH3, H, Et
2	3a	4b	5b	82
		Me	Cl, OCH3, H, Me
3	3a	4c	5c	67
		t-Bu	Cl, OCH3, H, t-Bu
4	3b	4a	5d	75
	Cl, CH3, H		Cl, CH3, H, Et
5	3b	4b	5e	80
			Cl, CH3, H, Me
6	3b	4c	5f	62
			Cl, CH3, H, t-Bu
7	3c	4a	5g	77
	Cl, Cl, H		Cl, Cl, H, Et
8	3c	4b	5h	71
			Cl, Cl, H, Me
9	3c	4c	5i	59
			Cl, Cl, H, t-Bu
10	3d	4a	5j	78
	Cl, Br, H		Cl, Br, H, Et
11	3d	4b	5k	74
			Cl, Br, H, Me
12	3e	4a	5l	79
	Cl, F, H		Cl, F, H, Et
13	3e	4c	5m	74
			Cl, F, H, t-Bu
14	3f	4b	5n	55
	Cl, H, OCH3		Cl, H, OCH3, Me
15	3a	Et	5a	84
	Cl, OCH3, H	4a	Cl, OCH3, H, Et

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Scheme 2 Ru-catalyzed direct ortho C–H alkenylation of 3a–b.

We then focused on the Pd-catalyzed ortho C–H alkenylation of a phenol derivative 3g that was coupled with the alkene 4a–c under the conditions of entry 4 of Table 1. The reaction proceeded smoothly affording the corresponding alkenyl substituted analogs 5o–q (Scheme 3). Notably, quinoline was found to be an effective directing group in these cases. While alkenylation of phenol derivatives are known in the literature¹⁶ the use of quinoline moiety as a directing group for this purpose has not been explored earlier. Thus the present strategy of ortho C–H alkenylation of phenol is of further interest.

Scheme 3 Pd-catalyzed ortho C–H alkenylation of a phenol derivative 3g.

According to the proposed mechanism (Scheme 4), the reaction appeared to proceed¹⁷ via (i) in situ generation of highly electrophilic Pd(II) cationic species E-1 in TFA, (ii) stabilization of E-1 by the quinoxaline/quinoline nitrogen aided by the C-2 arylamine/aryloxy moiety (via + M effect) in E-2, (iii) generation of E-3 via σ-bond formation between the “Pd” center and the proximate ortho C-aryl following a C(aryl)–H activation, (iv) alkene coordination with E-3 to give E-4, (v) syn addition via 1,2-migratory insertion to afford E-5, that undergoes (vi) β-hydride elimination to give 5 and the Pd⁰ species, and (vii) finally, oxidation of Pd⁰ to Pd^II by Cu(OAc)₂ to complete the catalytic cycle. The Cu(OAc)₂ is regenerated from the reduced copper species i.e. CuOAc by the aerial oxygen. A similar 6-membered ruthenacycle (like E-3, Scheme 4) generated in situ from [Ru(OAc)L]⁺[SbF₆]⁻ (L = p-cymene) species and 3 can be proposed¹⁵ for the Ru(II)-catalyzed alkenylation of 3 that on coordinative insertion of alkene 4 followed by β-hydride elimination could afford the product 5 (see ESI†).

Scheme 4 The plausible reaction mechanism.

The intramolecular C–H cycloamination of 5 was performed by using a hypervalent iodine(III) reagent¹⁸ such as PIDA [phenyliodine diacetate or PhI(OAc)₂] at room temperature (Scheme 5) to afford alkenyl substituted benzo[4,5]imidazo[1,2-a]quinoxalines^19a (6) in good to excellent yields. The Br, Cl, F and alkenyl ester^19b substituents remained intact during this mild and selective oxidative cyclization. The reaction seemed to involve an initial activation of the aniline nitrogen of 5 by PIDA that facilitated a nucleophilic attack by the proximate quinoxaline nitrogen atom on the aniline ring of F-1 affording the cyclic intermediate F-2 (Scheme 5). Deprotonation followed by aromatization of F-2 afforded product 6.

Scheme 5 Synthesis of 6a–d via intramolecular C–H cycloamination under open air.

Due to the reported PDE4 (phosphodiesterase type 4) inhibitory activities of related imidazo[1,2-a]quinoxalines⁵ the compounds 6a–d were tested for their PDE4 inhibition. Notably, inhibitors of PDE4 are known to be generally useful for the treatment of chronic obstructive pulmonary disease (COPD) and asthma.²⁰ All these compounds showed promising inhibition of PDE4B [e.g. 6a (69.77 ± 9.69%), 6b (42.15 ± 1.23%) 6c (60.66 ± 3.93%), 6d (79.50 ± 1.12%)] when tested in vitro²¹ at 30 μM. In a dose response study the compound 6d showed dose depended inhibition of PDE4B with IC₅₀ ∼ 2.3 μM (comparable to rolipram's IC₅₀ ∼ 1.0 μM) (Fig. 3) indicating potential medicinal value of this class of heterocycles.

Fig. 3 Dose dependent inhibition of PDE4B by compound 6d.

In conclusion, we have developed a two-step strategy for accessing new chemical entities based on alkenyl substituted benzo[4,5]imidazo[1,2-a]quinoxaline framework via C–H activation methods. The strategy involved use of a quinoxaline moiety as a new directing group for the Pd (or Ru)-catalyzed ortho C–H alkenylation of aniline derivatives and subsequent hypervalent iodine(III)-promoted intramolecular ortho C–H cycloamination of the resulting N-arylquinoxalin-2-amine derivatives. Both the steps were performed under open air and mild conditions. All these alkenyl substituted benzo[4,5]imidazo[1,2-a]quinoxalines were identified as inhibitors of PDE4 indicating their potential medicinal importance. The Pd-catalyzed ortho C–H alkenylation of phenol derivatives was also performed successfully when quinoline was found to be an effective directing group. Overall, our efforts on exploration of new C–H activation strategies for Med Chem purpose would be of further interest.

Acknowledgements

RS thank CSIR, New Delhi, India for a research fellowship. The authors thank management of DRILS and CSIR [Grant 02(0127)/13/EMR-II] for support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, copies of the ¹H and ¹³C NMR spectra. See DOI: 10.1039/c5ra14671b

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