Metal-free sequential reaction via a propargylation, annulation and isomerization sequence for the one-pot synthesis of 2,3-disubstituted benzofurans

Abstract

A metal-free one-pot synthesis of 2,3-disubstituted benzofurans is described, which allows for the reactions to be performed under ambient conditions with readily accessible propargyl alcohols and general phenols, including phenols substituted with an electron withdrawing group or a nitrogen-containing group.

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Benzofuran derivatives are ubiquitous in both natural products and artificial compounds with interesting biological activities and photochromic properties.¹ Particularly, the 2,3-disubstituted benzofurans are widely distributed in bioactive structures.² The common strategies for the synthesis of 2,3-disubstituted benzofurans relied mainly on metal-catalyzed intra/intermolecular annulations, in which the pre-prepared ortho-alkynylated phenol derivatives, ortho-hydroxybenzophenones, ortho-hydroxy-α-arylstyrenes, or ortho-disubstituted halogenated arenes were used as the substrates.^3,4 For the reason that metal-based protocols have inherent restrictions, including costly metal catalysts, fastidious reaction installations, troublesome metal residue in the synthetic products and difficulties in the disposal of metal waste, metal-free intramolecular annulations of ortho-alkynylated phenol derivatives have also been disclosed.⁵ Although the above strategies are synthetically viable, they suffered from some limitations such as multistep syntheses, inaccessible starting materials, tedious procedures, or requirement for using metals, frequently, noble metals as catalysts. Therefore, the development of mild, convenient, highly selective and atom economic methods to afford substituted benzofurans is still highly desirable. Recently, a few elegant methodologies have been reported, enabling the single-step synthesis of substituted benzofurans from readily available phenols with β-keto esters, internal alkynes, or olefins.⁶ Nevertheless, all these methods require the use of metals or their salts as catalysts for the annulation reactions.

A sequential reaction, incorporating two or more different transformations in a facile “one-pot” operation, holds great promise for the rapid buildup of molecular complexity and diversity.⁷ In contrast to traditional “step-by-step” operations, such transformations allow for reactions to be carried out with readily accessible starting materials in a single reaction vessel without purification between steps, and hence efficiently improve atom economy and lower energy and raw materials consumption.⁸ Accordingly, Chen et al. reported a one-pot synthetic method of benzofurans from phenols with propargyl acetates catalyzed by InCl₃,^9a and Tian et al. disclosed a similar method from phenols with benzylic propargylic sulfonamides catalyzed by ZnCl₂.^9b

However, these methods require the use of metals as catalysts and pre-prepared acetates or sulfonamides as substrates in addition to the use of different solvents between steps for the former and the requirement of heating for the latter. To the best of our knowledge, there is only one example that involved the one-pot synthesis of 2,3-disubstituted benzofurans via a sequential reaction from phenols and readily accessible propargyl alcohols,¹⁰ but it still requires the use of transition metals as catalysts, and heating in sealed tubes is necessary for the annulation reactions. To expand the concept of sequential reaction for the rapid buildup of polysubstituted benzofurans, we here report a metal-free one-pot synthesis of 2,3-disubstituted benzofurans from phenols and secondary propargyl alcohols. Our method represents the first example of metal-free one-pot synthesis for such transformations, allowing for the reactions to be performed at room temperature in the ambient atmosphere without any metal catalysts while it holds the advantages of the above method (Scheme 1).

Scheme 1 One-pot sequential synthesis of benzofurans from commercial phenols.

Our studies began with the propargylation between phenol 1a and propargyl alcohol 2a, with screening of various Brønsted acids in different solvents. As shown in Table 1, several strong Brønsted acids efficiently catalyzed the propargylation to yield 3a in common solvent at room temperature. However, solvents with large polarity strongly inhibited this reaction when the acidity of Brønsted acid was decreased (entries 5 & 6 vs. 4 & 7), which was possibly attributed to that the catalytic species of the propargylation, protons, were bound by the solvents when the acidity of Brønsted acid was not strong enough, since these solvents can be looked as Lewis bases, and are strong H-bond acceptors. Thus, Brønsted acid–solvent matching was very important toward the propargylation. Among the tested Brønsted acid systems, 4-toluenesulphonic acid monohydrate–dichloromethane (TsOH/DCM) was proved to be most efficient (entry 8), and organic weak acid, e.g., acetic acid, chloroacetic acid, and benzoic acid, was incapable of catalyzing this transformation (results not shown).

Table 1 Propargylations between 1a and 2a catalyzed by Brønsted acid

Entry^a	Acid	Solvent	Yield^b
a Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), acid (0.1 mmol) and solvent (4 mL). Ar = p-CH3O–C6H4. TFA: trifluoroacetic acid. TsOH: 4-toluenesulphonic acid monohydrate. DCE: 1,2-dichloroethane. DCM: dichloromethane. DMF: N,N-dimethylformamide. NR: no reaction.b The product was isolated by chromatographic purification on silica column.
1	HClO4	DCE	74%
2	HClO4	Dioxane	76%
3	HClO4	CH3CN	83%
4	TFA	CH3CN	89%
5	TFA	DMF	NR
6	TFA	Dioxane	NR
7	TFA	DCM	94%
8	TsOH	DCM	99%

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To investigate the annulation process of ortho-propargyl phenols, several bases were screened by taking the reaction of 3a to yield benzofuran 4aa in various solvent (Table 2). The results demonstrated that the relatively weak bases, such as tertiary amines (results not shown), carbonates (entry 1), or hydroxides (entry 2), were incapable of promoting the annulation of 3a at room temperature, whereas t-BuOK was suitable (entries 3, 4, 8 & 9). When t-BuOK was used as base, the choice of solvent was also important (entries 3–9). The solvents with weak acidity (entries 5, 6 & 10) or with large dipole moment (entries 6 & 7) were unsuitable, while the common halogenated solvents (except chloroform) and ether solvents were workable (entries 3, 4, 8 & 9). Among the tested base catalytic systems, t-BuOK/DCM and t-BuOK/dioxane were efficient (entries 3 & 9).

Table 2 Annulations of ortho-propargyl phenol 3a promoted by base

Entry^a	Base	Solvent	Yield^b
a Reaction conditions: 3a (0.5 mmol), base (1 mmol) and solvent (4 mL). THF: tetrahydrofuran.b The product was isolated by chromatographic purification on silica column.c 3a was totally transformed, but no target product (4aa) was generated, as monitored by thin-layer chromatography (TLC).
1	K2CO3	DCE	Trace
2	NaOH	DCM	Trace
3	t-BuOK	DCM	93%
4	t-BuOK	DCE	66%
5	t-BuOK	CHCl3	NR
6	t-BuOK	CH3CN	0^c
7	t-BuOK	DMF	NR
8	t-BuOK	THF	67%
9	t-BuOK	Dioxane	99%
10	t-BuOK	MeOH	Trace

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After the optimized conditions for the two steps were established, we focused on the screening of an appropriate combination of Brønsted acid catalyst, base, and solvent that enables the propargylation and the following annulation to occur efficiently through a one-pot operation. Some representative results are summarized in Table 3. A screening of base amount showed that it was necessary to employ 2 equiv. or more of t-BuOK for the annulation (entries 2–4 vs. 1). When TsOH was used in the first step, it was better to add 2.5 equiv. of t-BuOK in the following step because 0.2 equiv. of water from monohydrate TsOH could transform a certain amount of t-BuOK to KOH and thus reduce the efficacy of t-BuOK. Based on an overall consideration of the investigated parameters, we could establish the optimized conditions for the one-pot synthesis of benzofuran 4aa from phenol 1a and propargyl alcohol 2a, i.e., 1a and 2a in the presence of 20 mol% of TsOH catalyst at room temperature in DCM for 2 h, then t-BuOK (2.5 equiv.) was recharged in situ and the reaction mixture was stirred at room temperature for an additional 5 h. Under these conditions, 4aa could be isolated in 90% yield (entry 3).

Table 3 One-pot sequential synthesis of benzofuran 4aa from phenol 1a with propargyl alcohol 2a

Entry^a	Solvent 1	Solvent 2	Acid	t-BuOK	Yield^b
a Reaction conditions: unless noted otherwise, the mixture of 1a (1.0 mmol), 2a (0.5 mmol), acid (0.1 mmol) and DCM (4 mL) was stirred at room temperature for 2 h, then indicated amount of base was added to it, and the reaction mixture was stirred at room temperature for 5 h.b The product was isolated by chromatographic purification on silica column.c After the completion of the first step, the solvent (DCM) was removed via rotary evaporation, and the residual was diluted with 4 mL of dioxane, followed by the addition of t-BuOK (1 mmol).
1	DCM	DCM	TFA	1.2 equiv.	Trace
2	DCM	DCM	TFA	2.2 equiv.	62%
3	DCM	DCM	TsOH	2.5 equiv.	90%
4^c	DCM	Dioxane	TFA	2.0 equiv.	81%

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Under the optimized conditions for the one-pot process, we examined the substrate scope of this methodology. The results, summarized in Table 4, demonstrated the generality of this method. Sequential reactions of common phenols bearing alkyl, alkoxy or aryl with phenylacetylene-derived α-aryl propargyl alcohols smoothly afforded the expected benzofuran 4 mostly in good to very good yields (entries 1–21), which is comparable to that of the literature method.¹⁰ In all these transformations, the corresponding benzopyran derivatives were not isolated. Furthermore, this protocol gave acceptable yields with deactivated phenols (entries 22 & 23). In comparison, the yield of benzofuran 4gc from 4-chlorophenol (1g) was only 14% by using the literature method (entry 23).¹⁰ Generally, electron donating groups (EDGs) on both phenols and propargyl alcohols were favorable to the sequential reaction, whereas electron withdrawing groups (EWGs) unfavorable because an EWG on a phenol reduced the phenol's nucleophilicity and that on the aromatic ring, Ar of 2 decreased the stability of the corresponding carbocation. Both effects were unfavorable to the propargylation of the phenol. Relatively, an EWG on phenol 1 influenced the propargylation more than that on the aromatic ring, Ar of 2. For example, the substitution at the aromatic ring, Ar of 2 with an EWG (2e) only slightly decreased the yields of benzofuran 4 and the reactions could be achieved at room temperature (entries 5 & 18), but when a phenol substituted with an EWG (1g) was employed as a substrate, it was necessary to elevate the reaction temperature to 40 °C and the yields were lower (entries 22 & 23). In addition, the reactions of alkylacetylene-derived α-aryl propargyl alcohols (R² = alkyl) were more difficult and required higher reaction temperatures than that of the arylacetylene-derived counterparts (entries 27 and 28 vs. 1–21). Gratifyingly, phenols substituted with an amido or an alkoxyformamido were workable (entries 24–27), which is very interesting because using such substrates helps to conveniently introduce nitrogen-containing groups into the products, which makes the method useful in the field of medicinal chemistry. For comparison, two experiments parallel to entries 26 and 27 were conducted by using the literature method,¹⁰ but the reactions were messy and unidentifiable mixtures were observed instead. Therefore, our method selectively afforded the target products in yields that were comparable to the above method, whereas showed more generality of substrates than it.

Table 4 Substrate scope of the one-pot synthesis of benzofuran 4 from phenol 1 with propargyl alcohol 2

Entry^a	1 (R^1)	2 (R^2, Ar)	T1/T2 (h)	4	Yield^b
a Reaction conditions: unless noted otherwise, the mixture of 1 (1.0 mmol), 2 (0.5 mmol), TsOH·H2O (0.1 mmol) and DCM (4 mL) was stirred at room temperature until 2 had disappeared as monitored by TLC, then t-BuOK (1.25 mmol) was recharged in situ and the reaction mixture was continually stirred at room temperature until the new component that generated at the first stage had fully transformed as monitored by TLC.b Isolated yield after silica-gel column chromatography.c The reaction was conducted at 40 °C in the whole process.d Phenol 1i was dissolved in acetonitrile (1 mL) and then added to the reaction mixture.e The mixture of 1i (1.0 mmol), 2f (0.5 mmol), triflic acid (0.1 mmol) was dissolved in THF (4 mL) instead of DCM, and stirred at room temperature until 2f had disappeared as monitored by TLC, then the solvent was evaporated. To the residue were added DMF (4 mL) and NaOH (1.25 mmol). The reaction mixture was stirred at 60 °C until the new component that generated at the first stage had fully transformed as monitored by TLC.f At the stage of annulation, the reaction temperature was elevated to 40 °C.
1	1a (4-t-Bu)	2a (Ph, 4-MeO-C6H4)	2/5	4aa	90%
2	1a	2b (Ph, 4-Me-C6H4)	10/10	4ab	74%
3	1a	2c (Ph, Ph)	5/6	4ac (ref. 10)	79%
4	1a	2d (Ph, 1-naphthyl)	3/5	4ad	86%
5	1a	2e (Ph, 4-Br-C6H4)	10/7	4ae (ref. 10)	63%
6	1b (4-MeO)	2a	8/9	4ba	80%
7	1b	2b	5/10	4bb	75%
8	1b	2c	4/7	4bc (ref. 10)	74%
9	1c: 2-naphthalenol	2a	4/7	4ca	70%
10	1c	2b	4/7	4cb (ref. 3e)	80%
11	1c	2c	4/6	4cc (ref. 10)	81%
12	1c	2d	6/10	4cd	73%
13	1d (4-Me)	2a	5/6	4da	72%
14	1d	2b	6/9	4db	75%
15	1d	2c	8/6	4dc (ref. 10)	74%
16	1e (3,5-diMe)	2b	4/7	4eb	70%
17	1e	2c	3/8	4ec	70%
18	1e	2e	11/9	4ee	60%
19	1f (4-Ph)	2a	7/11	4fa	77%
20	1f	2b	5/5	4fb	70%
21	1f	2c	4/6	4fc (ref. 10)	68%
22^c	1g (4-Cl)	2a	16/11	4ga	45%
23^c	1g	2c	12/11	4gc (ref. 10)	55%
24^c	1h (4-AcNH)	2a	9/13	4ha	49%
25^c	1h	2c	15/11	4hc	50%
26^d	1i (4-BocNH)	2a	18/20	4ia	52%
27^e	1i	2f (n-C4H9, 4-MeO-C6H4)	24/14	4if	56%
28^f	1c	2f	9/12	4cf	51%

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Unfortunately, neither the propargyl alcohols containing a strongly EWG on the benzene ring, such as nitro, nor the α-alkyl propargyl alcohols gave the expected products,¹¹ which indicated that the α-aromatic rings of propargyl alcohols played an extremely important role in stabilizing the carbocation and initiating the propargylation step.

To establish the mechanism of the metal-free annulation of ortho-propargyl phenol 3, we envisioned two possible pathways (Scheme 2). Path A, an ionic mechanism, consists of an isomerization of 3a catalyzed by t-BuOK to form allene 3a2 and an intramolecular annulation via nucleophilic addition of phenolate anion to allenyl carbon. Alternatively, path B, a radical mechanism, is also conceivable, which consists of a radical annulation (3b1 to 3b2), one time of intermolecular proton transfer (3b3 + 3a → 3b4 + 3b1) and two intramolecular isomerizations (3b2 to 3b3 & 3b4 to 4aa). In principle, path A seems to be reasonable because (1) the connection of two aryl groups and an alkynyl group makes the methine proton of 3a rather acidic, and (2) it has been known for the catalytic isomerization of propargyl to allenyl by t-BuOK.¹² A typical feature of path A lies in that two times of intermolecular proton transfer (3a1 to 3a2 & 3a3 to 4aa) are involved, while for path B, there are one time of intermolecular and two times of intramolecular proton transfer instead. To this end, a hydrogen–deuterium exchange experiment was performed (eqn (1)).¹³ The result indicated that as high as 96.5% of product (4aa + D-4aa) retained one H atom at the benzylic position against the hydrogen–deuterium exchange, which is consistent with path B, i.e., one H atom at the benzylic position of 4aa is difficult to be exchanged with a deuterium atom in which intramolecular proton transfer is involved and the other one is possible to be done in which intermolecular proton transfer is involved. By the addition of 2 equiv. of t-BuOK to the CDCl₃ solution of 3a overnight, the ¹H NMR signal of methine proton remained unchangeable, and that of hydroxyl was totally disappeared, whereas that of CHCl₃ largely increased (eqn (2)). This result indicated that the acidity of the methine proton of 3a was weaker than that of CHCl₃, and implied that the catalytic isomerization of 3a to allene 3a2 by t-BuOK via deprotonation–protonation was difficult under the reaction conditions (Scheme 2, path A).¹⁴ Furthermore, the para-propargyl substituted counterpart 3b failed to isomerize to allene 3c even with more amount of base and at higher temperature (eqn (3)), which disapproves of the pathway from 3a to 3a2. To further validate the mechanism of radical annulation, extra control experiments were conducted (eqn (4) & (5)). The results demonstrated that (1) under inert atmosphere, the annulation step was remarkably sluggish,¹¹ and (2) under aerobic atmosphere, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, a radical scavenger) greatly inhibited this step. Therefore, path B is more appropriate than path A.

Scheme 2 Possible mechanisms for the metal-free annulation of ortho-propargyl phenol 3.

In conclusion, a metal-free one-pot synthesis of 2,3-disubstituted benzofurans from phenols and secondary propargyl alcohols is described. The transformations are high yielding, atom-efficient, and environmentally benign in terms of the substrates and reagents being used and the water as the only by-product. The control experiments support the transformations undergo the sequence of propargylation, radical annulation and isomerization.

Acknowledgements

We are grateful to Prof. Fa-Jun Nan and Dr Min Gu (Shanghai Institute of Materia Medica, CAS, China) for help with HRMS analysis. The authors thank the financial support from the National Natural Science Foundation of China (no. 20971105) and the Fundamental Research Funds for the Central Universities (XDJK2012B011).

Notes and references

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13. Protic solvents inhibited the annulation of ortho-propargyl phenol 3 (Table 2, entry 10). In the presence of MeOD, the amount of t-BuOK was increased to 7 equivalents in order to promote the annulation.
14. The solvent environment of chloroform is close to that of dichloromethane, while the annulation of 3a was unsuccessful in the former solvent (Table 2, entry 5).

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, ¹H and ¹³C NMR spectra for products, and HRMS spectra for new compounds. See DOI: 10.1039/c4ra05503a

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