Synlett 2023; 34(13): 1626-1630
DOI: 10.1055/a-2047-9765
letter

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

Miki Murakami
a   Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
,
Megumi Miyazaki
b   Department of Applied Chemistry and Bioscience, Chitose Institute of Science and Technology, Bibi 65-758, Chitose, Hokkaido 066-8655, Japan
,
Mayo Ishibashi
c   Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
,
Mizuki Oda
b   Department of Applied Chemistry and Bioscience, Chitose Institute of Science and Technology, Bibi 65-758, Chitose, Hokkaido 066-8655, Japan
,
Karin Takekuma
b   Department of Applied Chemistry and Bioscience, Chitose Institute of Science and Technology, Bibi 65-758, Chitose, Hokkaido 066-8655, Japan
,
Yoshikazu Horino
b   Department of Applied Chemistry and Bioscience, Chitose Institute of Science and Technology, Bibi 65-758, Chitose, Hokkaido 066-8655, Japan
› Author Affiliations
 


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.


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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 Conditionsa

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 2bg were produced irrespective of the electronic nature of the substituent on the propargylic benzene ring (Ar2).

Zoom Image
Scheme 1 Synthesis of furans from homopropargylic alcohols and their derivatives
Zoom Image
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.

Zoom Image
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 Acida

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.

Zoom Image
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.

Zoom Image
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.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information


Corresponding Author

Yoshikazu Horino
Department of Applied Chemistry and Bioscience, Chitose Institute of Science and Technology
Bibi 65-758, Chitose, Hokkaido 066-8655
Japan   

Publication History

Received: 16 February 2023

Accepted after revision: 06 March 2023

Accepted Manuscript online:
06 March 2023

Article published online:
20 March 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


Zoom Image
Scheme 1 Synthesis of furans from homopropargylic alcohols and their derivatives
Zoom Image
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.
Zoom Image
Scheme 3 TsOH-catalyzed furan synthesis from a mixture of 3a and 4a
Zoom Image
Scheme 4Plausible reaction pathway
Zoom Image
Scheme 5 Oxidative ring-opening reaction of 2a