An efficient methodology to substituted furans via oxidation of functionalized α-diazo-β-ketoacetates

Abstract

DMDO oxidation of functionalized α-diazo-β-ketoacetates, formed by zinc triflate catalyzed Mukaiyama-aldol condensation of methyl diazoacetoacetate with aldehydes, occurred in quantitative yield to form dihydrofuranols that undergo acid catalyzed dehydration under mild conditions to generate 3-methoxyfuran-2-carboxylates in good yield.

1. Introduction

The vicinal tricarbonyl (VTC) moiety is an important functional unit in organic synthesis. This is mainly due to the highly electrophilic nature of the central carbonyl carbon, which can undergo bond formation with a variety of nucleophiles.¹ The first VTC compound was synthesized in 1890,² and since then there have been a large number of methods developed for their preparation.³ In what have been insightful contributions to the and coworkers demonstrated multiple applications of the VTC system in the synthesis of β-lactams,⁴ alkaloids,⁵ pyrroles,⁶ and indolizidines.⁷

In one application Wasserman used VTC compounds in a novel synthetic route directed to the synthesis of substituted furans (Scheme 1, eq. 1),⁸ an important class of compounds due to their abundance in natural products and biologically relevantmolecules. In this methodology, the VTC unit was prepared by oxidation of phosphorus ylides that were synthesized from enolates of acyl phosphoranylidine carboxylates. Subsequent dehydreation using PTSA yielded 3-hydroxy-furan-2-carboxylates in moderate yields. Herein, we report an improved approach for the synthesis of substituted furans that utilize the oxidation of functionalized α-diazo-β-acetoacetates, formed by zinc triflate catalyzed Mukaiyama-aldol condensation of alkyl diazoacetoacetates with aldehydes,⁹ to generate VTC systems using dimethyldioxirane (DMDO) (Scheme 1, eq. 2). The advantages of this procedure are the ease of preparation andhandling of the diazoacetoacetate reactants, quantitative oxidation under neutral conditions, and the conversion of the VTC compounds to alkoxy-furans under mild conditions.

Scheme 1.

2. Result and Discussion

Our synthesis begins with commercially available aldehydes A and methyl α-diazoacetoacetate B that is easily prepared by diazo transfer to methyl acetoacetate.¹⁰ α-Diazoacetoacetates that include B are stable under a wide range of conditions.¹¹ TBSO-functionalized α-diazo-β-ketodicarbonyl compounds 1 were obtained by a convenient one-pot Mukaiyama-aldol reaction of aldehydes A and methyl α-diazoacetoacetate B in high yield (Scheme 2).⁹ The TBSO-functionalized condensation products (1) were easily hydrolyzed with 4N HCl in THF to form the corresponding alcohol products 2 in high yields (Table 1).

Scheme 2.

Table 1.

Hydrolysis of Compounds 1 via Scheme 2^a

Entry	R	Product	Yield (%)b
1	n-heptyl	2a	90
2	t-butyl	2b	90
3	C6H5	2c	95
4	2-NO2C6H4	2d	91
5	4-NO2C6H4	2e	92
6	4-ClC6H4	2f	88
7	3,5-(CH3)2C6H3	2g	93
8	2,4,6-(CH3)3C6H2	2h	85
9	2-napthyl	2i	95

^aReaction performed in THF at room temperature using 4N HCl for hydrolysis.

^bIsolated yield.

With a variety of functionalized α-diazo-β-ketodicarbonyl 2 in hand, we next sought to oxidize the diazo group to a carbonyl group. We initially began with t-butyl hypochlorite as an oxidant, since several reports have shown t-butyl hypochlorite can generate VTC compounds from α-diazo-β-dicarbonyl compoiuunds.¹² In our hands, however, the use of t-butyl hypochlorite afforded the desired product in moderate yield along with other unidentified by-products. As Saba reported that α-diazo-β-dicarbonyl compounds were oxidized to VTC derivatives using dimethyldioxirane (DMDO) in high yield,¹³ we subjected diazo substrates 2 to DMDO.¹⁴ This process resulted in the quantitative oxidation of the full range of diazo compounds 2. The oxidized compounds 3 are in equilibrium with dihydrofuranols 4 (Table 2) and existed as a mixture of diastereomers. The diastereomer ratios of 4, obtained from their ¹H NMR spectra, were approximately 1:2 for most of the compounds. Compound 4h had the highest dr ratio (1:5.6) due to the steric effect mesityl group. Compounds 4 were easily isolated by evaporation of acetone and taken to the next step without further purification.

Table 2.

Oxidation of α-diazoacetoacetates 2 to a vicinal tricarbonyl with DMDO.^a

entry	R	Productb	drc
1	n-heptyl	4a	33:67
2	t-butyl	4b	26:74
3	C6H5	4c	30:70
4	2-NO2C6H4	4d	36:64
5	4-NO2C6H4	4e	35:65
6	4-ClC6H4	4f	34:66
7	3,5-(CH3)2C6H3	4g	32:68
8	1,4,6-(CH3)3C6H2	4h	15:85
9	2-napthyl	4i	29:71

^aReaction performed in actone at 0°C with dimethyldioxirane as oxidant.

^bQuantative yield of products 4 were obtained.

^cDetermined by ¹H NMR of the crude product 4.

The hemiketal form of furanone 4 then underwent acid catalyzed dehydration to form 3-hydroxyfuran-2-carboxylates 5 (Scheme 3) by the same procedure as that employed by Wasserman and Lee.⁸ However, reactions in refluxing benzene together with catalytic PTSA resulted in product decomposition, and isolation of 5 by silica gel chromatography occurred in relatively low yield. However, changing the reaction solvent to methanol resulted in the expected conversion of hemiketal 4 to 3-methoxyfuran-2-carboxylates 6 (Table 3). This modification also allowed for ease in purification since the 3-hydroxyfuran-2-carboxylates 5 were otherwise difficult to purify.

Scheme 3.

Table 3.

Acid catalyzed dehydration for the synthesis of 3-methoxy-2-carboxylate furans.^a

entry	R	Product		Yield (%)b
1	n-heptyl		6a	90
2	t-butyl		6b	91
3	C6H5		6c	80
4	2-NO2-C6H4		6d	86
5	4-NO2-C6H4		6e	92
6	4-Cl-C6H4		6f	75
7	3,5-(CH3)2-C6H3		6g	75
8	1,4,6-(CH3)3-C6H2		6h	60c
9	2-napthyl		6i	85

^aReaction was refluxed in methanol with p-toluenesulfonic acid monohydrate (PTSA) overnight.

^bIsolated yield.

^cCombined yield of product and impurity from reaction mixture, which is unable separated by general silica gel chromatography.

A proposed mechanism for the formation of 3-methoxyfuran-2-carboxylates 6 is given in Scheme 4. Hemiketal formation at position 3 is proposed to precede formation of vinyl ether A, which subsequently undergoes acid catalyzed dehydration to generate furan 6. By replacing methanol with a different alcohol, the potential for further modifications in product formation at position 3 is suggested in this mechanism.

Scheme 4.

Proposed mechanism

3. Conclusion

In summary, we have developed an efficient method for the synthesis of 3-methoxyfuran-2-carboxylates and developed an improved methodology for the preparation of 3-hydroxyfuran-2-carboxylates. We also have open up the possibility of derivatization at C3 position by the use of different nucleophile. Application of this methodology is currently on the way for preparing the side chain of roseophilin.