A facile metal-free one-flask synthesis of multi-substituted furans via a BF₃·Et₂O mediated formal [4 + 1] reaction of 3-chloro-3-phenyldiazirines and α,β-alkenyl ketones

Abstract

A facile, efficient and metal free one-flask approach to diversely substituted furans from easily accessible 3-chloro-3-phenyldiazirines and α,β-alkenyl ketones is reported. This protocol integrates three steps of cyclopropanation, Cloke–Wilson rearrangement and elimination of HCl in one-flask to give products in moderate to good yields. It provides a metal and oxidant free approach to multi-substituted furans with the advantages of easy operation, mild reaction conditions and a broad scope of substrates.

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Introduction

Furan is a five-membered oxygenated heteroaromatic which is widely spread in natural products¹ and plays an important role in both pharmaceutical chemistry^2,3 and in synthetic organic chemistry as a useful building block.^2,4–6 Long attracting the interests of chemists, a number of synthetic methods for furan have been developed,^3,7–12 including the cyclodehydration of dicarbonyl compounds through Paal–Knorr synthesis¹³ and Feist–Bénary cyclocondensation.^14,15 Nevertheless, more selective approaches to multi-substituted furans under mild conditions still remain a challenging task.

In the past decades, cyclopropane has been widely used as a three-carbon synthon to access variable chemicals due to the readiness of ring-opening from high angle and torsion strain and tunable reactivity by substituent-controlled C–C bond polarization/cleavage.^16–21 Transition-metal catalyzed intramolecular ring-opening cycloisomerization of cyclopropenyl ketones^22,23 or alkylidene cyclopropyl ketones^24–26 has been proved to be a very successful and reliable approach to furans (Scheme 1A). Early in 2003, Ma and Zhang²² developed a regioselective cycloisomerization of cyclopropenyl ketones using copper(I) or Pd catalysts. Later in 2004, they developed a Pd mediated ring-opening cycloisomerization of 2-methylene- or alkylidene cyclopropyl ketone to di- or tri-substituted furans.²⁴ In 2007, Liang group reported a synthesis of trisubstituted furans via a Cu(I)-catalyzed formal [4 + 1] cycloaddition of α,β-alkynyl ketones with diazoacetates.²⁷ Xu and co-workers further developed a Cu–Pd relay catalysis to access tetra-substituted furans from cyclopropenes.²⁸ These elegant transition-metal catalyzed methods are advantageous in both atom economy and efficiency. However, using alternative non-metal catalysts to promote cycloisomerization is very essential in account of economic, environmental and sustainability requirement. Recently, Wang and coworkers^29–31 have developed I₂/K₂CO₃ or DBU mediated ring opening and cyclization of cyano-substituted cyclopropyl ketones to afford furan derivatives.

Scheme 1 Synthesis of furan from cyclopropanes by literature and this work.

The Cloke–Wilson rearrangement (CWR) reaction has been intensively used to access dihydrofurans from cyclopropyl ketones.^32–37 Besides transition-metal catalysis,^38,39 CWR reaction can also be promoted by Lewis acid,^40,41 photocatalysis,^42–44 and organo-catalysis.^26,32,33 Regrettably, an extra dehydrogenation procedure is a prerequisite to transform dihydrofurans to furans using stoichiometric oxidants such as DDQ.^45,46 To avoid the harmful oxidation procedure, we envisioned that halocyclopropyl ketone is an ideal alternative precursor to perform CWR reaction to deliver halogenated dihydrofuran, which is converted to furan via elimination of HX (Scheme 1B). However, there are few reports making use of this elimination strategy. As an elegant example, Namboothiri's group reported that acidic Al₂O₃ could be used to promote CWR reaction of dibromocyclopropyl ketone followed by elimination to access 3-bromo furans.^47,48

Taking advantage of the fact that the highly reactive halocarbenes (RCX) derived from the easily available 3-halodiazirines (RCN₂X) upon the loss of N₂ readily take part in [2 + 1] cycloaddition with alkenes to give halogenated cyclopropanes,^49–52 we design a formal [4 + 1] approach to furans using this cyclopropanation method to obtain the required halocyclopropyl ketone precursors (Scheme 1C). Firstly, photolysis or thermolysis of 3-halo-3-phenyldiazirine 1 in the presence of α,β-alkenyl ketone 2 gives the halocyclopropyl ketone 3, which is then subjected to a tandem CWR–elimination reaction sequence to afford the furan 4. We further succeeded in using the same Lewis acid to promote both the CWR and the elimination reactions to facilitate the reaction procedure. As a result, we herein report a one-flask metal-free synthetic approach to a diversity of di-, tri- or tetra-substituted furans from a series of 3-halo-3-phenyldiazirines and α,β-alkenyl ketones via cylopropanation and BF₃·Et₂O mediated CWR–elimination reactions.

Results and discussions

Initially, the synthesis of halocyclopropyl ketones was investigated (Scheme 2). Photolysis or thermolysis of 3-chloro-3-(4-chlorophenyl)diazirine (1a) was used to generate phenylchlorocarbene (PhCCl) in situ, which rapidly reacted with chalcone (2a) to give the halocyclopropyl ketone diastereomers (3a/3a′). After an optimization of solvents and temperatures (for details, please see Table S1†), either photolysis at room temperature or thermolysis at 80 °C in 1,2-dichloroethane (DCE) gave the halocyclopropyl ketones (3a/3a′) in highest yield with similar diastereoselectivity.

Scheme 2 Synthesis of halo-cyclopropyl ketone 3a/3a′.

Next, the transformation of halocyclopropyl ketone 3a (major isomer) to furan 4a was investigated and selected results are summarized in Table 1 (for more details, see Table S2†). Lewis acid promoters FeCl₃·6H₂O, TiCl₄ and FeCl₂·4H₂O were the most efficient catalysts for this conversion (0.08–0.5 h), while BF₃·Et₂O, AlCl₃, SnCl₄ and Sc(OTf)₃ promoted the reaction less efficiently (15–45 h). Delightfully, furan 4a was obtained in excellent yields (85–98%) in the presence of these seven catalysts (entries 1–7). On the contrary, BiCl₃ couldn't complete this transformation in 72 h and gave 4a in lower yield (entry 8). No reaction could take place in the absence of a Lewis acid (entry 9). Brønsted acid para-toluene sulfonic acid (PTSA) could also mediate this reaction to give 4a in 90% yield in 36 h (entry 10). Therefore, among these promoters, BF₃·Et₂O and FeCl₂·4H₂O showed the best catalytic activity to give nearly quantitative yields of 4a. It is also noted that the halocyclopropyl ketone diastereomer 3a′ was similarly converted to 4a in the nearly quantitative yield as 3a in the presence of either BF₃·Et₂O or FeCl₂·4H₂O (entries 12–13). Therefore, there is no need to separate two diastereomers 3a/3a′ for the transformation to 4a. We then succeeded in implementing these reaction steps in one-flask (for details, please see Table S3†) with BF₃·Et₂O (1 eq.) as the best catalyst, which was added into the flask after the completion of cyclopropanation to avoid side reactions. This one-flask protocol gave 4a in an overall yield of 68%.

Table 1 Screening of Lewis acids for 4a^a

Entry	Lewis acid	Time, h	Yield,^b %
a Reagents and conditions: halocyclopropyl ketone 3a (0.06 mmol), Lewis acid (0.06 mmol, 1 eq.) in 5 mL DCE was heated at 80 °C in a 38 mL reaction tube equipped with a condenser until the reaction was completed by TLC monitoring. NR = no reaction. RSM = recovery of starting material.b Isolated yield.c Yield is based on consumed halocyclopropyl ketone. RSM was 16%.d 0.2 eq. LA was used.e 3a′ was used instead of 3a.
1	TiCl4	0.16	86
2	FeCl2·4H2O	0.5	96
3	FeCl3·6H2O	0.08	86
4	BF3·Et2O	15	98
5	AlCl3	17	90
6	SnCl4	21	87
7	Sc(OTf)3	45	86
8	BiCl3	72	68^c
9	None	24	NR
10	PTSA	36	90
11^d	FeCl2·4H2O	1	97
12^e	BF3·Et2O	16	98
13^d^,^e	FeCl2·4H2O	1	97

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With this optimized one-flask conditions in hand, we investigated the scope of para-substituted phenylchlorodiazirines 1 (Table 2). Unsubstituted (R = H) or substituted phenylchlorodiazirines with either electron-donating (R = Me, OMe) or slightly electron withdrawing (R = F, Cl) groups on the phenyl ring gave furans (4a–4e) in good yields (57–71%). However, the cyclopropyl ketones with strong electron-withdrawing substituents such as CF₃ or CN (3f, 3g) need to be heated in n-octane at 120 °C to give furans in reasonable yields (4f 43%; 4g 42%) due to lower ring opening reactivity for less polarization character of C–C bond. This conversion could also be driven by the powerful FeCl₃·6H₂O and gave furans in better yields (4f 57%; 4g 53%). However, the reaction of 3-benzyl-3-chloro-diazirine (PhCH₂CClN₂) and chalcone couldn't afford the expected furan. The scope of chalcones were also investigated: chalcones with substituents on either phenyl ring gave furans (5a–5i; 5m–5t) in good yields (70–80%), no matter they are electron-withdrawing or electron-donating. This one-flask strategy can also be applied to the naphthyl, thiophenyl or pyridinyl substituted chalcones to afford furans (5j–5l, 5u) with moderate to good yields (40–78%).

Table 2 Scope of substrates^a,b

a Reagents and conditions (method A): 3-aryl-3-chlorodiazirine 1 (0.2 mmol), alkenyl ketone 2 (0.2 mmol) in 5 mL DCE was heated at 80 °C in a 38 mL reaction tube with a condenser until the reaction was completed (usually 2 h). BF₃·Et₂O (0.2 mmol, 1 eq.) was added in and kept on heating to complete the transformation.b Isolated yield of one-flask reaction.c Reacted at 120 °C in n-octane and BF₃·Et₂O (5 eq.) was used.

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We further extended this one-flask reaction to a wide range of alkenyl ketones with alkyl groups, and the corresponding furans were obtained in moderate to good yields (Table 3). Alkenyl ketones substituted with a methyl group at R₁, R₂ or R₃ position gave trisubstituted furans 6a–6c in good yields (60–67%). Methyl vinyl ketone (MVK) gave 2-methyl-5-phenyl furan 6d in 45% yield. Notably, this protocol enabled an astonishing access to tetra-substituted furans with structural complexity (6e, 6f). For example, 2-benzylidenecyclohexan-1-one gave tetra-substituted furan 6f with a fused ring in good yield (50%). This protocol can also be applied to α,β-unsaturated aldehydes, e.g., cinnamaldehyde was used to synthesize 2,3-disubstituted furan 6g in 29% yield. Bis(2-phenylvinyl) ketone gave furan 6h in 42% yield, exemplifying the functional group tolerance for another sensitive C=C double bond. Step-by-step analysis of these two-stage reactions (Table S5†) reveals that the lower yields were owing to the poor cyclopropanation reactivity because of less electronic richness (6d, 6g) or steric hindrance (6e) of the C=C double bond, in which a considerable amount of carbene dimer was often generated as side product. Therefore, this one-flask protocol can use a variety of α,β-unsaturated carbonyl substrates to synthesize 2,3- or 2,5-disubstituted, 2,3,5-trisubstituted and even 2,3,4,5-tetrasubstituted furans with moderate to good yields.

Table 3 Scope of alkyl substituted alkenyl ketones^a,b

a Reagents and conditions: using method A as above unless specified.b Isolated yield of one-flask reaction.c 1a (0.2 mmol) was reacted with 2 eq. alkenyl ketone (0.4 mmol).d Two equivalents of alkenyl ketone were used and reactions were performed at 60 °C in both stages.

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To probe the mechanism of these reactions, β-methyl chalcone was subjected to this one-flask reaction (Scheme 3A). Unlike the α-methyl chalcone, the CWR–elimination reaction of the cyclopropyl ketone promoted by BF₃ gave a complicated mixture without any furan product, indicating the necessity of a β-hydrogen. Reactivities of other 3-halo-3-phenyldiazirines (X = Br, F) were also studied (Scheme 3B). 3-Bromo-3-phenyldiazirine (1ab) gave bromocyclopropyl ketone 3ab/3ab′ in 2 h (72%), which gave furan 4a in 95% yield in 17 h with the similar reactivity as 3a/3a′ (X = Cl). It indicates that BF₃ is supposed to bind with the oxygen in carbonyl group instead of halogen to promote the CWR reaction, leading to no significant difference in the reactivities between 3a and 3ab (Scheme 4, path a). On the other hand, 3-fluoro-3-phenyldiazirine (1ac) gave the cyclopropyl ketone 3ac (59%) much slower (48 h) owing to the less electrophilicity and stability of phenylfluorocarbene (PhCF).^53,54 Moreover, 3ac is quite ready to give furan 4a in 90% yield with excellent reactivity (2 h). This efficient transformation is supposed to be attributed to a different pathway because of the high affinity between BF₃ and fluorine (vide infra).

Scheme 3 Control experiments.

Scheme 4 Plausible mechanism.

Based on these experiments and literature,^34,47,55 a plausible mechanism is proposed in Scheme 4. Upon thermolysis or photolysis, 3-halo-3-phenyldiazirine (1) generates electrophilic singlet phenylhalocarbene (PhCX) with the loss of nitrogen (N₂).^51,56 The PhCX carbene reacts rapidly with α,β-alkenyl ketone (2) to afford halocyclopropyl ketone (3) via a [2 + 1] cycloaddition. Subsequent addition of BF₃·Et₂O catalyzes the CWR rearrangement of chloro- or bromocyclopropyl ketone 3a/3ab by complexing with the carbonyl oxygen in 3 (path a) to facilitate the heterolytic cleavage of this donor–acceptor cyclopropane to give the key zwitterion intermediate I. Then, an intramolecular cyclization of I by nucleophilic attack of oxyanion to carbocation gives dihydrofuran II, which is converted to furan 4 after the loss of HX with the aid of BF₃. In the case of fluorocyclopropyl ketone 3ac, the ring-opening might be driven by the loss of tetrafluoroborate (BF₄⁻) and proceeds through a cyclopropyl carbocation mechanism in a similar intramolecular cyclization mode (path b).

Conclusions

In conclusion, we have developed a facile one-flask approach to the di-, tri- and even tetra-substituted furans in moderate to good yields from readily available starting materials using inexpensive boron trifluoride as catalyst. This metal and oxidant free method involves the cyclopropanation of α,β-alkenyl ketones with phenylchlorocarbene, BF₃ mediated ring-opening cycloisomerization (Cloke–Wilson rearrangement) and elimination of HCl to give the multi-substituted furans. This method has the advantages of simple operation, mild reaction conditions and a broad scope of substrates, which provides a concise approach to diversified biologically and synthetically useful furans. We believe it will benefit the discovery of new application of furan derivatives.

Author contributions

Z. Zhang: most of the experimental work and writing of ESI.† A. Huang & L. Ma: methodology and discussion. J. Xu: manuscript revision and discussion. M. Zhang: conceptualization, funding acquisition, supervision, and writing, review, and editing of the manuscript.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 21861002, 21462003) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See https://doi.org/10.1039/d2ra01472f

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