Dess–Martin Periodinane/Brønsted Acid-Mediated Tandem Oxidation/Cyclization of Homopropargylic Alcohols for Synthesis of Trisubstituted Furans

Abstract

A facile, efficient, and metal-free single-flask procedure for the synthesis of trisubstituted furans from simple readily available homopropargylic alcohols is described. A combination of Dess–Martin periodinane, H₂O, and TsOH·H₂O plays a crucial role in the formation of the trisubstituted furans. The advantages of this method include operational ease, mild reaction conditions, and good functional-group tolerance.

Key words

furans - Dess–Martin oxidation - 5-endo-dig cyclization - Brønsted acids - homopropargylic alcohols

The furan scaffold is well documented to be present in pharmaceuticals,[1] bioactive natural products,[2] and polymers.[3] Moreover, furans are widely recognized to serve as valuable synthetic building blocks for constructing more-advanced motifs in organic synthesis;[4] consequently, numerous methods have been developed for their synthesis.[5] The Feist–Bénary synthesis[6] and the Paal–Knorr condensation[7] are the most frequently used furan-synthesis methods, and many effective approaches for synthesizing functionalized furans have been developed since these methods were first reported. Most existing catalytic furan-synthesis systems involve a cycloisomerization/cyclization strategy based on alkynes or allenes with activation by metals such as Pd(II),[8] Cu(I/II),[9] Zn,[10] Ag (I),[8l] [11] Au(I/III),[8l,12] Rh(I/II),[8l,13] Cr(0), W(0), Ru(II), or Pt(II)[8l] [14] (Scheme [1a]). Compared with well-established transition-metal-catalyzed approaches, transition-metal-free furan syntheses aimed at promoting an intramolecular cyclization event are less well explored. For example, Chong and co-workers reported that the cyclization of β-alkynylated ketones in the presence of 50 mol% of oxalic acid afforded substituted furans (Scheme [1b]).[15] Unfortunately, the poor functional-group tolerance of methods used to synthesize β-alkynylated ketones hinder efficient access to functionalized furans. Liu and co-workers demonstrated a 2-iodoxybenzoic acid (IBX)-mediated synthesis of 3,5-substituted 2-acylfurans from (Z)-alkynylated allylic alcohols by using a tandem oxidation/cyclization process (Scheme [1c]),[16] and base-promoted oxacyclizations of (Z)-alkynylated-allylic alcohols have also recently been reported to afford polysubstituted furans;[17] however, these methods require the synthesis of geometrically defined (Z)-alkene substrates. On the other hand, electrophilic cyclizations of homopropargylic ketones or 4-dimethoxyphosphoryl-substituted allenyl alcohols promoted by a stoichiometric amount of NBS, NIS,[18] I₂,[19] or a Brønsted acid[20] afford the corresponding tri- or tetrasubstituted furans (Scheme [1d]). Although cycloisomerization and cyclization strategies provide noteworthy results, it should be noted that methods for constructing highly functionalized furans normally involve difficult preparations of precursors. Therefore, devising synthetic strategies that provide access to substituted furans under mild conditions from simple and readily available starting materials remains an important objective.

Table 1 Optimizing the Reaction Conditions^a

Entry	H2O (equiv to DMP)	TsOH·H2O (mol%)	Yieldb (%)
			2a	3a b	4a	5a
1	–	–	31	trace	trace	5
2c	–	–	0	74	0	0
3	1	–	6	42	13	0
4	1	5	41	11	2	trace
5	1.5	5	46	3	2	2
6	2	5	63	0	0	2
7	3	5	46	12	7	trace
8	4	5	53	0	0	0
9d	2	5	53	8	4	0
10e	2	5	63	0	0	0
11f	2	10	49	4	5	0
12f	2	20	8	17	7	0

^a Reaction conditions: 1a (0.3 mmol), DMP (0.45 mmol), H₂O, TsOH·H₂O, anhyd CH₂Cl₂, 30 °C, 72 h.

^b Isolated yields.

^c 0.5 h reaction time.

^d 48 h reaction time.

^e 60 h reaction time.

^f 24 h reaction time.

We recently reported the practical syntheses of highly functionalized homopropargylic alcohols from readily accessible propargylic acetates.[21] In the course of this study, we noted that the Dess–Martin periodinane (DMP) oxidation[22] of homopropargylic alcohols occasionally led to the selective formation of 2,3,5-trisubstituted furans under mild reaction conditions, with old DMP providing better results than fresh DMP. As part of our explorations to derive reliable and more-efficient transition-metal-free furan syntheses and to provide deeper insights into the reaction mechanisms, we describe the successful development of a DMP/Brønsted acid-promoted tandem oxidation/cyclization reaction for the preparation of 2,3,5-trisubstituted furans from homopropargylic alcohols that is both efficient and functional-group-tolerant (Scheme [1e]). To the best of our knowledge, no attention has previously been paid to homopropargylic alcohols as building blocks for 2,3,5-trisubstituted furans under transition-metal-free conditions, despite these reactants being more readily accessible and more easily manipulated than previously reported precursors.

Our initial investigation focused on the DMP/Brønsted acid-promoted tandem oxidation/cyclization reaction of the homopropargylic alcohol 1a (Table [1]).[23] Whereas the DMP oxidation of 1a gave ketone 3a in 74% yield, a prolonged reaction time afforded the 2,3,5-trisubstituted furan 2a in 31% yield along with diketone 5a (Table [1], entries 1 and 2). The formation of 5a is possibly ascribable to the oxidative ring opening of 2a.[24] As a prolonged reaction time led to the decomposition of both 2a and 3a, we next explored decreasing the reactivity of DMP by the addition of H₂O.[22c] Although 1.0 equivalents of H₂O gave 2a in 6% yield, to our delight, the single-flask procedure for the synthesis of the trisubstituted furan was accelerated dramatically when a catalytic amount of p-toluenesulfonic acid monohydrate (TsOH·H₂O) was added, which afforded 2a in 41% yield (entries 3 and 4). Among the loadings of H₂O examined, the use of 2.0 equivalents (relative to DMP) produced the best result, giving 2a in 63% yield (entries 4–8). Note that reproducible outcomes were difficult to achieve when less than 2.0 equivalents of H₂O were used (entries 4 and 5). Reducing the reaction time was found to suppress the formation of 5a (entries 6, 9, and 10). In addition, higher amounts of TsOH·H₂O did not affect the efficiency of this reaction (entries 11 and 12).

With the optimized reaction conditions in hand, we examined the scope of our DMP/Brønsted acid-promoted tandem oxidation/cyclization reaction for the production of trisubstituted furans 2 (Scheme [2]). The method efficiently produced trisubstituted furans bearing a variety of electronically diverse substituents. For example, trisubstituted furans 2b–g were produced irrespective of the electronic nature of the substituent on the propargylic benzene ring (Ar²).

Scheme 1 Synthesis of furans from homopropargylic alcohols and their derivatives

Scheme 2Substrate scope. Reaction conditions: 1 (0.3 mmol), DMP (0.45 mmol), H₂O (2 equiv relative to DMP), TsOH·H₂O (5 mol%), anhyd CH₂Cl₂. ^a The reaction was carried out for 60 h in the absence of TsOH·H₂O. ^b 1i (3.0 mmol) was used.

We next evaluated the influence of the homopropargylic substituent (Ar¹). Whereas the reaction of the 3-methoxy-substituted substrate gave 2h in 61% yield, substrates bearing a 2-methoxyphenyl group at the homopropargylic position reacted efficiently even in the absence of TsOH·H₂O, albeit with prolonged reaction times. Indeed, whereas the reaction of 1i with TsOH·H₂O required 36 hours to afford 2i in 71% yield, 60 h were required in the absence of TsOH·H₂O to give 2i in 70% yield. Moreover, 1i provided 2i in 70% yield in a 3 mmol-scale reaction.

We next examined the effect of the substituent (R) adjacent to the alkyne moiety. Replacing the ethyl group with hexyl group afforded the corresponding product 2n in comparable yield under otherwise identical reaction conditions. In addition, as we had found that 2i could be prepared without the assistance of TsOH·H₂O, we subjected TBSO-substituted substrates 1o and 1p to the furan-synthesis procedure in the absence of TsOH·H₂O; these reactions successfully afforded 2o and 2p, respectively, with the Si–O bond remaining intact.

Scheme 3 TsOH-catalyzed furan synthesis from a mixture of 3a and 4a

To determine whether or not the Brønsted acid-mediated intramolecular cyclization of a homopropargylic ketone proceeds in a catalytic manner, we exposed a mixture of 3a and 4a to a catalytic amount of TsOH·H₂O (Scheme [3]). As expected, the Brønsted acid-catalyzed intramolecular cyclization gave 2a in 72% isolated yield, which suggests that TsOH·H₂O functions as a Brønsted acid that promotes cyclization. Accordingly, an alternative pathway involving a hypervalent iodine species that promotes the cycloisomerization of 3a and 4a to give 2a can be ruled out, because such a system would require excess IBX.[16] It is worth noting that the Brønsted acid-catalyzed synthesis of a furan from an α-alkynylated ketone appears to be unprecedented.

We next evaluated the effect of the Brønsted acid (Table [2]). Among the sulfonic acids examined, TsOH·H₂O proved to be ideal for forming trisubstituted furans in a single-flask procedure. For example, 2c was obtained in 73% yield when the reaction was performed in the presence of DMP and a catalytic amount of TsOH·H₂O (Table [1], entry 1). Conversely, a significantly lower yield of 2c was observed when MeSO₃H, CF₃SO₃H, or 10-camphorsulfonic acid (10-CSA) was used instead of TsOH·H₂O (entries 2–4).

Table 2 Effect of the Brønsted Acid^a

entry	Brønsted acid	Yieldb (%) of 2c
1	TsOH·H2O	73
2	MeSO3H	11
3	CF3SO3H	11
4	10-CSA	20

^a Reaction conditions: 1c (0.3 mmol), DMP (0.45 mmol), H₂O (2 equiv relative to DMP), Brønsted acid (5 mol%), anhyd CH₂Cl₂, 30 °C, 60 h.

^b Isolated yield.

Scheme 4Plausible reaction pathway

We propose that the reaction proceeds through the activation of both the alkyne and ketone by TsOH, followed by intramolecular cyclization (Scheme [4]). The water present in the reaction mixture partially deactivates the DMP, with the homopropargyl ketone and furan partially decomposing in the absence of water. In fact, we observed that 2a partially decomposes under DMP-oxidation conditions (Scheme [5]). On the other hand, whereas the addition of water leads to slower alcohol oxidation, the decomposition of 2 and 3 is also inhibited due to the lower activity of the DMP and the lower concentration of the homopropargylic ketone 3. Additionally, the decomposition of furan 2 is also restrained. Together, these effects are believed to be responsible for the efficient syntheses of trisubstituted furans.

Scheme 5 Oxidative ring-opening reaction of 2a

In conclusion, we have developed a facile, efficient, and metal-free single-flask procedure for synthesizing 2,3,5-trisubstituted furans from easily accessible homopropargylic alcohols. The reaction proceeds through alcohol oxidation followed by a 5-endo-dig cyclization, in which the added H₂O and TsOH·H₂O play crucial roles.

Conflict of Interest

The authors declare no conflict of interest.

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• 23 5-Ethyl-3-(2-methoxyphenyl)-2-phenylfuran (2b); Typical Procedure Homopropargylic alcohol 1b (0.3 mmol) and TsOH·H₂O (5 mol%) were dissolved in anhyd CH₂Cl₂ (3 mL) under argon in a 10 mL vial equipped with a magnetic stirrer bar and a septum. Distilled H₂O (0.9 mmol) and Dess–Martin periodinane (0.6 mmol) were successively added to the stirred solution at ambient temperature. The septum was replaced with a screw cap under argon, and the resulting mixture (0.1 M) was stirred in an oil bath at 30 °C for 60 h until the reaction was complete (TLC). The reaction was quenched with sat. aq NaHCO₃ (1 mL) and Na₂S₂O₃ (1 mL), and the resulting mixture was stirred for 30 min. The separated aqueous layer was extracted with CHCl₃, and the combined organic layers were washed with brine, dried (MgSO₄), and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel) to give a colorless oil; yield: 60.1 mg (72%), R_f = 0.59 (EtOAc–hexane, 3:7). ¹H NMR (400 MHz, CDCl₃): δ = 7.51 (dd, J = 1.2, 8.4 Hz, 2 H), 7.41–7.28 (m, 4 H), 7.22 (tt, J = 1.2, 7.6 Hz, 1 H), 7.03 (d, J = 7.2 Hz, 2 H), 6.20 (t, J = 1.2 Hz, 1 H), 3.77 (s, 3 H), 2.83 (dq, J = 1.2, 7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.7, 156.5, 147.4, 132.1, 131.5, 128.8, 128.2, 126.7, 125.3, 123.9, 120.8, 119.0, 111.3, 109.6, 55.5, 21.6, 12.2. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₁₉O₂: 279.1385; found: 279.1391.

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Publikationsverlauf

Eingereicht: 16. Februar 2023

Angenommen nach Revision: 06. März 2023

Accepted Manuscript online:
06. März 2023

Artikel online veröffentlicht:
20. März 2023