NH₄PF₆-promoted cyclodehydration of α-amino carbonyl compounds: efficient synthesis of pyrrolo[3,2,1-ij]quinoline and indole derivatives

Abstract

NH₄PF₆ is an inexpensive, safe, and low-toxicity inorganic salt; it was found to promote the cyclodehydration of α-amino carbonyl compounds in the absence of metal reagents. This simple cyclodehydration strategy enables highly atom-economic formation of pyrrolo[3,2,1-ij]quinoline and indole derivatives, which are significant pharmacophores.

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Pyrrolo[3,2,1-ij]quinolines¹ and indoles² are important structural units, and are found in numerous pharmaceuticals and natural products. Extensive studies have demonstrated that pyrrolo[3,2,1-ij]quinolines are lead candidates for fungicides active against rice blast disease,^1d and in potential treatments for asthma,^1e epilepsy, and obesity.^1f In addition, it has been reported in numerous patents that pyrrolo[3,2,1-ij]quinoline is a promising skeleton in drug development.³ Considerable efforts have been devoted to the synthesis of pyrroloquinolines.^4–12 Early reported methods generally suffer from drawbacks such as harsh reaction conditions, limited substrate scope or low yields.⁴ In the past decade, synthetic methodologies including Michael-type annulations,⁵ free radical cyclizations,⁶ sigmatropic rearrangements⁷ and multicomponent reactions⁸ have been used for pyrroloquinolines synthesis, albeit with narrow substrate scope. Broader substrate scope can be achieved by transition metal-catalyzed reaction. For instance, palladium- or copper-catalyzed intramolecular cyclization of 8-alkynylated tetrahydroquinolines,^9,10 indium-catalyzed intramolecular Friedel–Crafts annulations of modificated indoles,¹¹ and zirconium-catalyzed cycloaddition of tetrahydroquinoline hydrazines with internal alkynes.¹² However, these substrates require complicated pre-functionalization. The development of efficient synthetic methods for pyrrolo[3,2,1-ij]quinolines preparation is therefore urgent.

Indoles, because of their wide-ranging biological activity, continue to promote numerous researchers to focus on efficient synthetic methodologies.^2a,13 Among indole synthesis, an intriguing approach would start from an ortho-unsubstituted anilines or mono-substituted arene, followed by direct cyclization with C–C or C–N bond formation to a C–H bond.^13b This type of approach includes Fischer indole synthesis,¹⁴ Bischler indole synthesis,¹⁵ Hemetsberger indole synthesis,¹⁶ Nenitzescu indole synthesis,¹⁷ Bartoli indole synthesis¹⁸ and et al. We hypothesized that the Bischler reaction¹⁵ would provide a suitable pathway for the preparation of pyrrolo[3,2,1-ij]quinolines and indoles, because the sole by-product is water, and α-amino carbonyl compounds are readily prepared.¹⁹ An improved Bischler reaction involves a microwave-assisted approach, which allows one-pot synthesis of 2-arylindoles under solvent-free and metal-free conditions, albeit with moderate yields.²⁰ Metal catalysts such as rhodium carbenoids,²¹ cationic iridium complexes,²² Ru₃(CO)₁₂ (ref. 23) and Zn(TfO)₂ (ref. 24) give efficient indole synthesis via the Bischler reaction. However, most of these metal reagents are expensive, which has limited synthetic applications. Recently, a modified Bischler reaction was developed for the preparation of N-aryl-2,3-disubstituted indoles, although expensive and unstable arynes are used as reaction partners.²⁵ Based on previous reports of Bischler indole synthesis,^15,20–25 we strive to use eco-friendly reagents to synthesize pyrrolo[3,2,1-ij]quinolines and indoles via the Bischler reaction; this will contribute to sustainable development in chemistry (Scheme 1). Here, we report a NH₄PF₆-promoted efficient method for the synthesis of pyrrolo[3,2,1-ij]quinolines and indoles by cyclodehydration of α-amino carbonyl compounds in the absence of metals.

Scheme 1 Green synthesis of pyrrolo[3,2,1-ij]quinolines.

Major limitations in scaling up reactions arise from the use of corrosive acids and metal pollution, therefore we focused on using inorganic salts that are eco-friendly, readily post-treated, and compatible with functional groups to achieve the cyclodehydration of α-amino carbonyl compounds. We reasoned that ammonium salts would promote cyclodehydration because the NH₄⁺ cation can activate the carbonyl group.^26,27 Based on this supposition, we used the cyclodehydration of 1a as the model reaction. NH₄Cl, NH₄OAc, and NH₄PF₆ were used to explore the reaction in CH₃CN at 110 °C (Table 1, entries 1–3). As expected, the reaction occurred in the presence of NH₄Cl or NH₄OAc, giving the desired products in 8% and 10% yields, respectively (Table 1, entries 1 and 2). Under the NH₄PF₆-promoted reaction conditions, the yield increased to 56% (Table 1, entry 3). We then attempted to improve the reactivity by using the more soluble (n-Bu)₄NPF₆. However, only a 12% yield was obtained (Table 1, entry 4). We speculated that the PF₆⁻ anion may be crucial for the reaction, therefore we investigated KPF₆ and AgPF₆ in the reaction, respectively. No target product was obtained in the reaction with KPF₆ or AgPF₆ (Table 1, entries 5 and 6). In terms of the solvent effect, 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) significantly enhanced the reactivity of NH₄PF₆, affording the target product in 95% yield (Table 1, entry 11). HFIP, as a strong polar solvent, may help to dissolve NH₄PF₆, leading to amplifying the reactivity. In contrast, other solvents, e.g., toluene, DCE, and DMF, did not affect the reaction (Table 1, entries 7–9); while EtOH gave a rather low yield (Table 1, entry 10). To further test the effect of HFIP, the reaction with NH₄Cl or NH₄OAc in HFIP was conducted, respectively; to our delight, both yields were enhanced to 75% (Table 1, entries 12 and 13). It was showed that addition of 2 equiv. of H₂O would slightly decrease the yield to 87% (Table 1, entry 14). We next reduced the NH₄PF₆ loading and lowered the reaction temperature, respectively. Decreasing the NH₄PF₆ loading gave a lower yield (Table 1, entry 15), and the yield at 90 °C decreased to 69% (Table 1, entry 16). Several Lewis acids (FeCl₃, ZnCl₂, AlCl₃, and AgOTf) and Brønsted acids (HCl, H₂SO₄, AcOH, F₃CCOOH, TsOH, and HPF₆) were evaluated (see the ESI†). In comparison with NH₄PF₆, these reagents showed poor reactivity and gave low yields. Control reactions, in the absence of NH₄PF₆, were conducted in CH₃CN and HFIP, respectively. No reaction occurred in CH₃CN, which suggested that ammonium salts were crucial for the reaction (Table 1, entries 1–3 and 17); interestingly, a 48% yield was obtained in HFIP without NH₄PF₆ (Table 1, entry 18), which demonstrated that the unique solvent effect of HFIP may decrease the reaction energy barrier, thus facilitating the cyclodehydration under 110 °C. Moreover, HFIP can act as an acid to promote the reaction. Finally, we found that a combination of NH₄PF₆ as the promoter and HFIP as the solvent, at 110 °C, gave the best yield.

Table 1 Screening of optimal conditions^a

Entry	Additive	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), additive (0.4 mmol, 2 equiv.) in solvent (2 mL) at 110 °C for 24 h.b Isolated yields.c H2O (2 equiv.) was added.d NH4PF6 (0.2 mmol, 1 equiv.).e At 90 °C.
1	NH4Cl	CH3CN	8
2	NH4OAc	CH3CN	10
3	NH4PF6	CH3CN	56
4	(n-Bu)4NPF6	CH3CN	12
5	KPF6	CH3CN	0
6	AgPF6	CH3CN	0
7	NH4PF6	Toluene	Trace
8	NH4PF6	DCE	Trace
9	NH4PF6	DMF	0
10	NH4PF6	EtOH	24
11	NH4PF6	HFIP	95
12	NH4Cl	HFIP	75
13	NH4OAc	HFIP	75
14^c	NH4PF6	HFIP	87
15^d	NH4PF6	HFIP	72
16^e	NH4PF6	HFIP	69
17	—	CH3CN	0
18	—	HFIP	48

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With this new Bischler reaction procedure in hand, the scope of α-amino carbonyl compounds tolerated was investigated (Table 2). Substituents such as Me, MeO, Br, Cl, F, CN, and CF₃ groups on the aromatic ring of the 1-arylethanone moiety are tolerated well under the standard conditions (products 2b–2i); for example, substrate 1b, which has a methyl group, gave a high yield of 2b (92%). The presence of a MeO group on substrate 1c was tolerated, providing the corresponding product 2c in 78% yield. Halo-substituted substrates also gave good yields, these are synthetically useful for further modifications, because of the diverse reactivities of halo groups (products 2d–2g). These results showed that different halo-substituted substrates had similar reactivity (products 2d–2g). For example, the para- and meta-fluoro-substituted substrates almost had the same yields (products 2f and 2g). Reactions of substrates with electron-withdrawing groups such as cyano and trifluoromethyl were also carried out, affording the corresponding products 2h and 2i in 53% and 78% yields, respectively. A difluoro-substituted substrate had better reactivity, giving the desired product 2j in 92% yield. Despite the steric hindrance effect of the naphthalene, substrate 1k underwent cyclodehydration smoothly to afford the target product 2k in 72% yield. The benzofuran moiety, which is a useful pharmacophore, was tolerated, providing the corresponding product 2l in 72% yield. An alkyl ketone showed excellent reactivity in the reaction, affording the desired product 2m in 92%. An α-amino ester performed smoothly under the optimal conditions (product 2n), enabling further modifications that are important for the preparation of diverse pyrrolo[3,2,1-ij]quinolines. Substituted tetrahydroquinolines were also investigated to test the scope (products 2o–2q). 2-Methyl and 6-methyl substituted tetrahydroquinolines proceeded smoothly to give the target product in good yields (products 2o and 2p). To our delight, substrate 1q with two methyl group at the 2-position of tetrahydroquinoline also performed well, giving the target product in 76% yield (product 2q).

Table 2 NH₄PF₆-promoted synthesis of pyrrolo[3,2,1-ij]quinolines^a

a Reaction conditions: 1 (0.2 mmol), NH₄PF₆ (0.4 mmol, 2 equiv.) in HFIP (2 mL) at 110 °C for 24 h.

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Having demonstrated the efficiency of NH₄PF₆ in the synthesis of pyrrolo[3,2,1-ij]quinolines, we investigated whether this approach was generally applicable to the synthesis of indoles. A wide range of α-amino carbonyl compounds 3 (Table 3, products 4a–4p) were subjected to the optimal conditions. The cyclodehydration of 3a in HFIP gave product 4a in 93% yield. Substituents such as Me, MeO, Cl, Br, and CF₃ were compatible with the optimal conditions, providing the corresponding products 4b–4f in moderate to high yields. Importantly, chlorinated and bromated arenes on α-amino carbonyl compounds 3 were well tolerated, facilitating possible further modifications at the halogenated positions (4d and 4e). Cyclodehydration of the difluoro-substituted substrate 3g proceeded smoothly to afford the expected product 4g in 73% yield. Substrate 3h, which has a benzofuran motif, also underwent cyclodehydration to yield the corresponding product 4h in 47% yield. The poor yield resulted from partial decomposition and low conversion rate of substrate 3h. It is worth noting that a yield of 71% was obtained in the reaction of substrate 3i, which has an ester group. To further test the scope of this protocol, compounds with Me, MeO, Cl, and Br substituents on the aromatic ring of aniline were evaluated for the reaction; and the corresponding products were obtained in yields of 65–87% (4j–4n). Finally, the effect of protecting group on nitrogen atom was examined. Benzyl protected aniline gave a good yield of 85% (product 4o). Unfortunately, unprotected aniline 3p was decomposed under standard conditions, only a large amounts of N-methylaniline was observed on GC-MS (product 4p).

Table 3 NH₄PF₆-promoted synthesis of indoles^a

a Reaction conditions: 1 (0.2 mmol), NH₄PF₆ (0.4 mmol, 2 equiv.) in HFIP (2 mL) at 110 °C for 24 h.

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To test their potential in large scale synthesis, the reactions of 1a and 3a were conducted at 0.502 g (2 mmol) and 0.45 g (2 mmol) scales, respectively, giving 2a and 4a in 85% and 84% yields, respectively (Scheme 2). Additionally, HFIP is readily recovered by distillation, because its boiling point is 59 °C. These results suggest that the newly established reaction system has potential for industrial applications.

Scheme 2 Reaction scale up.

According to the classical Bischler reaction mechanism¹⁵ and the present results, possible reaction pathways were illustrated as showed in Scheme 3. The role of NH₄⁺ may activate the carbonyl that facilitates the Friedel–Crafts cyclization to produce an intermediate A and NH₃·H₂O.^26,27 The intermediate A undergoes a dehydration process to give an intermediate C, followed by a deprotonation route to afford the target product (Path 1). Alternatively, the present reaction may involve an acid-promoted process, because NH₄PF₆ may be subjected to a hydrolytic reaction under the standard conditions, resulting in in situ formation of HPF₆, which is likely to promote the cyclization to afford intermediate B (Path 2). The role of HFIP can be concluded on two aspects: firstly, HFIP can improve the reactivity of ammonium salts; secondly, HFIP is serving as an polar, acidic solvent that promotes the reaction itself.

Scheme 3 Possible reaction pathways.

In summary, we discovered that an inorganic salt, NH₄PF₆, efficiently promotes the Bischler reaction in HFIP. The new strategy provides a convenient and efficient route for the preparation of pyrrolo[3,2,1-ij]quinolines and indoles, without using metal reagents, which were required in previous methods.^21–24 Moreover, the reaction can be scaled up under conventional means, and have better yields than those in microwave-assisted method.²⁰ The simple post-treatment and easy recovery of HFIP help to protect the environment.

Acknowledgements

We gratefully acknowledge the NSFC (no. 21202121 and 21272178) and Wenzhou University (no. wzucy034) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed condition screening table, experimental details, and ¹H and ¹³C NMR spectra of the products. See DOI: 10.1039/c4ra11168k

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