Synthesis of benzofurans via an acid catalysed transacetalisation/Fries-type O → C rearrangement/Michael addition/ring-opening aromatisation cascade of β-pyrones

Abstract

An unusual and facile approach for the synthesis of 2-benzofuranyl-3-hydroxyacetones from 6-acetoxy-β-pyrones and phenols is presented. The synthetic sequence involves a cascade transacetalisation, Fries-type O → C rearrangement followed by Michael addition and ring-opening aromatisation. The versatility of this method was further demonstrated via the synthesis of 4,4a-dihydropyrano[3,2-b]benzofuran-3-ones, furo[3,2-c]coumarins, and spiro[benzofuran-2,2′-furan]-4′-ones. The unexpected cascade event would also provide new possible considerations in the β-pyrone-involved organic synthesis.

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Benzofurans are ubiquitous building blocks in many bioactive natural products and primary structural motifs in several pharmaceuticals and molecular electronics.¹ Furthermore, benzofurans are acclaimed privileged scaffolds in drug discovery.² These distinguished features stimulated the development of several efficient and concise strategies for the synthesis of diverse benzofuran derivatives.³ However, owing to the limitations of the conventional approaches, such as the harsh reaction conditions, broad substrate scope and limited functional-group tolerability, there still exists ample scope for exploring new approaches for the synthesis of benzofurans. Herein, we report a new access to benzofurans via a Lewis acid catalysed one-pot cascade process.

Development of novel cascade processes has received great attention owing to their exceptional ability to rapidly assemble intricate molecular scaffolds.⁴ As part of our recent efforts to develop new cascade approaches for the O,S-containing heterocycles, it necessitated us to have rapid and efficient access to 6-aryloxy-β-pyrones of the type 1a.⁵ For this purpose, the Lewis acid catalysed protocols of Grynkiewicz^6a and Feringa^6b were tried with 6-acetoxy-β-pyrone 2a and phenol 3a, but the required product 1a was isolated in low yields, Scheme 1.⁷ A detailed investigation revealed that the formation of a polar compound (on TLC) was responsible for the yield loss. Further study of the reaction under Feringa's conditions revealed that the concentration of the initially formed phenyl ether 1a started diminishing and simultaneous build-up of the unanticipated product 4a was observed. Thus, we have drawn the conclusion at this stage that the unexpected product 4a formed via the intermediacy of 1a. The structure of the unexpected product 4a was deduced from ¹H and ¹³C NMR data and was further confirmed by single-crystal X-ray diffraction analysis (vide infra).⁸ Since the 6-acetoxy-β-pyrone 2a can be accessed from furyl carbinol 5a in two straightforward steps,⁵ this protocol thus represents an unique three-step conversion of furans (of the type 5a) to benzofurans (such as 4a), Scheme 1.⁹

Scheme 1 Unprecedented cascade reaction of 6-acetoxy-β-pyrones and phenols leading to the synthesis of 1-(2-benzofuranyl)-3-hydroxyacetones.

Having realised the significance of benzofurans especially generated under mild Lewis acidic conditions from readily accessible starting compounds, and considering the potential implications of this rearrangement in organic synthesis, we turned to optimising the reaction conditions. Towards this, various Lewis acid and solvent combinations were investigated, and few important results are shown in Table 1.

Table 1 Optimisation of the reaction parameters^a

Entry	Acid (10 mol%)	Solvent	Time (h)	Yield^b (%)
a A 5 mL glass vial was filled with 2a (0.2 mmol), 3a (0.22 mmol), and a solvent (1 mL). A catalyst (0.02 mmol) was then added at 0–5 °C. After stirring at the same temperature for about 30 min, the reaction continued at room temperature until 1a and 2a disappeared (by TLC). b Isolated yield after column chromatography. c 1a exclusively formed. d 20 mol% TMSOTf was employed. e 5 mol% TMSOTf was employed. f 1a and 2a were also recovered. g In the presence of 2,6-di-tert-butyl-4-methylpyridine (1 equiv.).
1	La(OTf)3	DCE	48	74^c
2	SnCl4	DCE	3	50
3	BF3OEt2	DCE	18	55
4	FeCl3	DCE	18	45
5	In(OTf)3	DCE	20	48
6	Zn(OTf)3	DCE	20	45
7	Bi(OTf)3	DCE	20	61
8	AgOTf	DCE	21	40
9	TMSOTf	DCE	20	74
10^d	TMSOTf	DCE	20	47
11^e^,^f	TMSOTf	DCE	30	45
12^g	TMSOTf	DCE	72	—
13	TfOH	DCE	20	63
14	PTSA	DCE	20	51
15	TMSOTf	CH3CN	21	48
16	TMSOTf	Toluene	72	25
17	TMSOTf	THF	72	—

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The reaction catalysed by La(OTf)₃ generated exclusively the 6-phenoxy-β-pyrone 1a even after extended reaction times, thereby establishing a high-yielding method for its selective synthesis (Table 1, entry 1). Most of the Lewis acids employed during the screening otherwise furnished the desired product 4a in varied yields, with TMSOTf giving the best result (entries 2–9). Reaction with higher TMSOTf loading (20 mol%) gave a poor result due to the formation of undesired side products (entry 10). On the other hand, reaction in the presence of 5 mol% TMSOTf was found to be sluggish (entry 11). So, 10 mol% TMSOTf loading was realised to be optimal for this transformation.

Interestingly, the reaction in the presence of a proton sponge such as 2,6-di-tert-butyl-4-methylpyridine completely inhibited the product formation, indicating most likely that catalytic amounts of TfOH generated in situ might be promoting this process (entry 12). However, despite repeated attempts, TfOH furnished the required product in lower yields when compared to TMSOTf (entry 13). Among few other Brønsted acids employed, PTSA generated 4a in satisfactory yield (entry 14). So, TMSOTf was identified as the catalyst of choice for this study considering its mild nature and ease of handling. Brief solvent screening with TMSOTf offered no further improvement in the yield (Table 1, entries 15–17).

With the optimised reaction conditions in hand, the scope of the reaction was subsequently investigated, and the representative results are presented in Table 2. Since the 6-benzoyloxy-β-pyrones (2b and 2g) afforded the respective products (4b, 4d, 4l, and 4m) consistently in low yields under the optimised conditions, acetates of β-pyrones were preferred over benzoates during this study.

Table 2 Substrate scope^a,b

a A 5 mL glass vial was filled with 2 (0.2 mmol), 3 (0.22 mmol), and DCE (1 mL). TMSOTf (0.02 mmol) was then introduced at 0–5 °C. After stirring at the same temperature for 30 min, the reaction continued at room temperature until 1 and 2 disappeared (by TLC). b Isolated yield after column chromatography. c Structure confirmed by single crystal X-ray diffraction analysis, see the ESI for details.¹⁰

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A variety of 6-acetoxy-β-pyrones (2c–2f, 2h–2j) and phenols (3b–3e) conveniently generated the respective benzofurans 4b–4x in good to excellent yields.¹¹ A range of possible substitution patterns on the pyrones were considered that provided 2-benzofuranyl propanones possessing 1°, 2° and 3°-alcoholic centres. Notably, chiral hydroxyacetones such as 4g–4j and 4t can be easily assembled by employing this strategy. In particular, isolation of alcohols 4j and 4t in 98% and 93% ee, respectively, indicates the involvement of a non-racemising process during the transformation which in turn signifies the mildness of the reaction conditions.

Interestingly, the reaction of the pyrone 2a with halogenated phenols 3f–3h generated only the 4,4a-dihydropyrano[3,2-b]benzofurans 4y, 4z, and 4aa. Even prolonged reaction times did not yield the expected 2-benzofuranyl-3-hydroxyacetones. This result has two-fold significance; it not only provided mechanistic insights into the conversion of 2 to 4, but also provided a new entry for the synthesis of pyrano[3,2-b]benzofuran-3-ones.¹²

Apart from phenols, strikingly, enol such as 4-hydroxycoumarin 3i also proved to be a distinctive reactive partner in producing furocoumarins 4ab–4ad in one simple step from 6-acetoxy-β-pyrones, Scheme 2. Furocoumarins are part of several bioactive natural products and medicinally interesting compounds.¹³ Most of the synthetic approaches have focused on the construction of coumestans. Only a few methods have been described for the synthesis of furo[3,2-c]coumarins.¹⁴ In this regard, our approach depicted herein provides an unprecedented access for the synthesis of 2-alkylated furo[3,2-c]coumarins.

Scheme 2 Unprecedented approach for the synthesis of furo[3,2-c]coumarins and a few representative bioactive furocoumarins.

Based on the experimental observations, a plausible mechanism has been proposed in Scheme 3.¹⁵ The cascade process begins with an acid catalysed transacetalisation⁶ followed by an unusual Fries-type O → C rearrangement¹⁶ which leads to the formation of a neutral but unstable intermediate 6a in a highly regio- and chemoselective manner.¹⁷ Subsequently, 6a undergoes aromatisation and concomitant oxa-Michael addition to form intermediate 4a′. Furthermore, acid-induced ring-opening aromatisation of 4a′ affords the 2-benzofuranyl-3-hydroxyacetone 4a.

Scheme 3 Plausible mechanism.

To further illustrate the generality and synthetic utility of this methodology, we considered an elaboration, Scheme 4. We intended to exploit the presence of alcohol functionality in the side chain in an intramolecular haloetherification reaction which would potentially generate spiro[benzofuran-2,2′-furan]-4′-ones.¹⁸ Accordingly, reaction of the keto-alcohols 4a, 4b and 4l with NBS at room temperature conveniently furnished the respective 5,5-spiroketals 4ae–4ag in excellent yields, thereby establishing a mere two-step unprecedented access from readily accessible 6-acetoxy-β-pyrones. The relative stereochemistry of 4ae–4ag was assigned based on the X-ray crystal analysis of 4ag.¹⁹ Prevalence of several bioactive natural products possessing the 5,5-spiroketal scaffold renders this an attractive strategy for their easy synthesis, Scheme 4.²⁰

Scheme 4 An unusual two-step synthetic approach for spiro[benzofuran-2,2′-furan]-4′-ones from β-pyrones.

Finally, scalability and practicality of the cascade process were verified by conducting gram scale reactions of 2a.⁸

In conclusion, we have described a cascade event of β-pyrones and phenols, originating out of serendipity, leading to the synthesis of 2-benzofuranyl-3-hydroxyacetones. The versatility of this strategy lies in its ability to establish unprecedented access for medicinally significant scaffolds such as 4,4a-dihydropyrano[3,2-b]benzofuran-3-ones, furo[3,2-c]coumarins, and spiro[benzofuran-2,2′-furan]-4′-ones in a short and efficient manner. Efforts to extend these methods for the total synthesis of natural products are in progress and will be communicated in due course.

We thank the DST (SR/FT/CS-156/2011) and IISER Mohali for funding. We also thank NMR, mass, and departmental X-ray facilities at IISER Mohali. S. K. B. thanks IISER Mohali for a research fellowship and J. M. thanks DST, Govt. of India, for the INSPIRE fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1437901 and 1441109. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6cc01016d

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