Download PDF
Synthesis 2016; 48(23): 4181-4188
DOI: 10.1055/s-0035-1562790
paper
© Georg Thieme Verlag Stuttgart · New York

Application of 5-Ethoxymethylfurfural (EMF) for the Production of Cyclopentenones

Aleksei Bredihhin*
Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia   Email: lauri.vares@ut.ee   Email: aleksei.bredihhin@ut.ee
,
Sirvo Luiga
Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia   Email: lauri.vares@ut.ee   Email: aleksei.bredihhin@ut.ee
,
Lauri Vares*
Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia   Email: lauri.vares@ut.ee   Email: aleksei.bredihhin@ut.ee
› Author Affiliations
Further Information

Publication History

Received: 19 April 2016

Accepted after revision: 06 July 2016

Publication Date:
17 August 2016 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

We describe a method for the conversion of 5-ethoxymethylfurfural (EMF) into substituted cyclopentenones in a stereoselective manner through application of the Piancatelli rearrangement. The strategy allows the utilization of biomass-derived C6-carbohydrates for the production of cyclopentenones, making them a possible platform chemical for the sustainable chemical industry.


#

Key words

cyclopentenone - 5-ethoxymethylfurfural - 5-hydroxymethylfurfural - Piancatelli rearrangement - biomass valorization

The development of new methods for the production of fine chemicals, materials, and pharmaceuticals from biomass has been a focus of research in recent years. Replacing fossil raw materials with sustainable biomass as a carbon source is highly desirable when environmental considerations and declining oil reserves are taken into account. The use of cellulose, which is the main component of biomass, is of particular interest because its utilization as a renewable resource avoids competition with food production.

Cyclopentenones are a common structural motif found in many bioactive compounds (Figure [1])[1] and serve as key intermediates in the synthesis of many relevant targets. Their importance has stimulated numerous studies on constructing this valuable unit using, for example, Nazarov cyclization[2] or the Pauson–Khand reaction.[3] However, furan derivatives can also be used as starting materials to obtain cyclopentenones. Thus, very recently, an efficient one-pot procedure for the synthesis of cyclopentenones through the oxidation of furans was reported by Vassilikogiannakis.[4] Another interesting method in which 2-furylcarbinols are rearranged under acidic conditions into cyclopentenone derivatives was developed by Piancatelli (Scheme [1]).[5]

Zoom Image
Figure 1 Examples of natural cyclopentenones
Zoom Image
Scheme 1 Proposed mechanism of the Piancatelli rearrangement (conr. = conrotatory)

Recently, de Alaniz made significant improvements to the Piancatelli rearrangement by demonstrating that a catalytic amount of Dy(OTf)3 can improve the efficiency considerably and produce cyclopentenones and spirocycles under mild conditions.[6] Studies on the Piancatelli rearrangement utilizing different catalytic systems have also been recently published by others.[7]

The Piancatelli rearrangement of furans has received considerable attention in recent years. However, this conversion has been mostly studied on 2-furylcarbinols that are potentially achievable from biomass-derived furfural (i.e., from C5-carbohydrates) and are lacking a substituent at C-5 of the furan core. C6-carbohydrates, on the other hand, are by far the most abundant in lignocellulosic biomass, but cannot be converted into furfural. Generally, C6-carbohydrates are converted into 5-hydroxymethylfurfural (HMF; 1), which is a platform chemical and a subject of intense research in recent decades.[8]

The Piancatelli rearrangement of furfuryl alcohol (obtained from furfural) to 4-hydroxy-2-cyclopentenone, which is an important building block for the synthesis of prostaglandins and other bioactive compounds,[9] is firmly established.[5] [10] However, unlike, for example, HMF, 2,5-furandicarboxylic acid (FDCA), levulinic acid, and γ-valerolactone, cyclopentenones are not widely acknowledged as renewable platform chemicals produced from biomass. Additionally, there are no studies concerning the Piancatelli rearrangement of HMF (1) or its close derivatives, and only two very recent publications by Ohyama describing hydrogenative conversion of HMF (1) into substituted cyclopentanone via the corresponding diol have appeared to date.[11]

5-Ethoxymethylfurfural (EMF; 3), a derivative of HMF, is considered to be a promising biofuel that can be obtained from C6-carbohydrates either directly[12] or through the etherification of biomass derived halomethylfurfurals[13] or HMF.[14]

In this publication, we present a methodology to convert biomass-derived EMF (3) into cyclopentenones with high diastereoselectivity by using the Piancatelli rearrangement as a key step.

We started our investigation by preparing a model compound 4a from EMF 3 in 92% yield by treating the latter with PhMgCl·LiCl (Scheme [2]). Compound 4a was then subjected to the Piancatelli rearrangement to give 5a by using 10% Dy(OTf)3 as catalyst, while the reaction medium, temperature, and time were varied (Table [1]).

Zoom Image
Scheme 2 Synthesis of [5-(ethoxymethyl)furan-2-yl](phenyl)methanol (4a)

Table 1 Optimization of the Piancatelli Rearrangement Conditions

Entry

Solvent

Temp (°C)

Time (h)

Yield (%)a

 1

MeCN–H2O (10:1)

80

24

29

 2

MeCN–H2O (10:1)

80

48

12

 3

MeCN–H2O (5:1)

80

24

42

 4

MeCN–H2O (5:1)

80

24

40b

 5

t-BuOH–H2O (5:1)

80

24

54

 6

t-BuOH–H2O (5:1)

80

48

59

 7

t-BuOH–H2O (5:1)

90

24

60 (71)c

 8

t-BuOH–H2O (5:1), 5 mol% TFA

80

24

52d

 9

toluene

90

 0.5

decomp.

10

toluene–H2O (10:1`)

80

24

no reaction

a Isolated yield.

b Dy(OTf)3 (5 mol%) used.

c Determined by NMR.

d Conversion was more than 60% in 5 h.

The best yield of 5a was achieved by using a 5:1 mixture of t-BuOH–H2O as solvent at 90 °C (Table [1], entry 7). At 80 °C, the reaction proceeded more slowly, requiring 48 hours to obtain similar results (entry 6). The addition of 5% trifluoroacetic acid (TFA) accelerated the reaction considerably, affording 60% conversion after 5 hours (entry 8), but the resulting yield was somewhat lower compared with those without TFA (entry 7). In the MeCN–H2O solvent system, 50% conversion was achieved in 5 hours (entry 1); however, already at that moment the formation of numerous side products was observed. Increasing the amount of water (entry 3) in the reaction mixture partially suppressed side reactions and provided the desired product in 42% yield. Reduced catalyst loading gave somewhat lower yield (entry 4) and had no effect on the formation of side products. In toluene (entry 9), rapid decomposition of the starting material was observed. The addition of water to toluene (entry 10) hindered the decomposition of the starting material; however, the conversion was very slow, and only traces of product were observed after 24 hours at 80 °C.

To our delight, the formation of 5a occurred in a highly diastereoselective manner, and only small amounts of another diastereomer was detected by NMR (d.r. 23:1). The relative configuration of 5a was assigned based on NOE experiments (see the Supporting Information for details), which proved that the phenyl and CH2OEt groups are on the one side of the molecule and the hydrogen at the C5 position and OH groups are on the other side. These results are consistent with the reaction mechanism.

With the optimized conditions at hand, we explored the use of a series of furan derivatives 4a–d in the Piancatelli rearrangement; the starting materials were prepared from EMF (3) by the addition of different nucleophiles to the aldehyde functionality (Scheme [3]). Both aryl and alkyl substituents were tested. The aryl-substituted cyclopentenones 5a–c formed in moderate yields, but the formation of butyl-substituted cyclopentenone 5d did not proceed under the reaction conditions, leaving the starting compound 4d unreacted. The addition of TFA is reportedly of crucial importance for the Dy(OTf)3 catalyzed Piancatelli rearrangement of alkyl-substituted substrates.[6f] However, when 4d was stirred for 48 hours at 90 °C in the presence of TFA (5 mol%), the desired product 5d was obtained in 9% yield and contained some impurities. A small amount (9%) of the starting furan 4d was also separated from the reaction mixture, pointing to a decomposition of most of the material. Different substituents clearly influenced the dia­stereoselectivity, which varied from relatively poor (5b and 5d) to good (5a and 5c).

Zoom Image
Scheme 3 Synthesis of 4-hydroxycyclopenenones 5

We then turned our attention to the aza-version of the Piancatelli rearrangement (Table [2]), using aniline as a nucleophile and 4a as a model compound. Analogous to the original Piancatelli rearrangement, cyclopentenones 6 are produced through nucleophilic attack of the aniline nitrogen to the 5-position of cation B (Scheme [1]).

Table 2 Optimization of the Aza-Piancatelli Reaction with 4a

Entry

Solvent

Temp (°C)

Time (h)

Yield of 6a (%)a

1

MeCN

80

4

12

2

MeCN

80

0.5

12

3

toluene

80

4

12

4

t-BuOH

90

4

50

a Isolated yield

t-BuOH was the best solvent also for this rearrangement, furnishing the desired cyclopentenone 6a in 50% yield (Table [2], entry 4), whereas the use of acetonitrile and toluene gave a complex mixture of products (entries 1–3). Among the side product compounds, type 7 and 8 dominated. Compounds 7 are products of Dy(OTf)3 catalyzed amination of starting alcohol 4, which are probably obtained when carbocation A reacts with the amine, whereas compounds 8 are products of electrophilic attack of carbocation A on the aromatic core of aniline (Scheme [1]). Thus, in acetonitrile, the Friedel–Crafts alkylation product 8a was isolated in 39% yield together with 12% of the desired aza-Piancatelli­ rearrangement product 6a (entry 1). We also tried performing the reaction for a shorter time (entry 2), but this gave no improvement. Interestingly, in toluene, byproduct 7a was the main component of the reaction mixture after approximately 30 minutes, and was isolated in 38% yield. When the reaction was run for a longer period of time in toluene, the amount of 7a gradually decreased and could only be found in negligible amounts after 4 hours stirring (entry 3). However, at the same time, the amount of Friedel–Crafts side product 8a increased. The formation of compound 7a was observed in all solvents, but was most pronounced in toluene.

Finally, we used our optimized procedure to obtain a number of 4-phenylaminocylopentenones 6b–d (Scheme [4]). Unfortunately, the yields of the aza-Piancatelli rearrangement remained low. In the case of 4b, the Friedel–Crafts alkylation dominated and 8b was isolated in 40% yield; the desired product 6b was isolated in only 10% yield and contained some inseparable impurities. In the case of 4c, the aza-Piancatelli rearrangement product 6c was isolated in 28% yield. When alkyl-substituted 4d was used as starting material, the main product was 7d (52% yield) and the desired product was obtained in only minor amounts (6%). The diastereoselectivity, however, was high, with only the indicated diastereomer being observed by NMR spectroscopic analysis. We speculate that the significant influence of the different substituents of 5a–d on the diastereoselectivity and highly improved diastereomeric ratio for the aza-Piancatelli reaction (compounds 6a–d) may be related to epimerization of the tertiary alcohol at the 4-position of the cyclopentenone ring by an SN1 reaction mechanism. The stability of the corresponding carbocation derived from compounds 5a–d is influenced by electronic and steric properties of the neighboring substituents, whereas 4-phenylaminocylopentenones 6a–d do not undergo such transformation.

Zoom Image
Scheme 4 Synthesis of 4-amino-cyclopenenones 6a–d

In summary, we have demonstrated a diastereoselective method for obtaining novel cyclopentenones from HMF, which is the main platform chemical available from biomass. This provides access to highly functionalized derivatives and could become an important platform for the synthesis of various targets.

All reactions with organometallic reagents were carried out under an argon atmosphere in dried glassware. Syringes that were used to transfer anhydrous solvents or reagents were purged with argon prior to use. THF was continuously heated at reflux and freshly distilled from sodium benzophenone under nitrogen. Petroleum ether (PE) refers to the fraction boiling in the 40–65 °C range. NMR spectroscopy was performed with a 400 MHz spectrometer using the residual solvent peak (CDCl3, δ = 7.26 ppm for 1H and δ = 77.16 ppm for 13C spectra) as internal standard. Infrared spectra were measured with an ATR module fitted with a ZnSe crystal. The reactions were monitored by using thin-layer chromatography (TLC) and visualized with UV light and KMnO4 solution. The products were purified using flash chromatography on silica gel 60 (0.040–0.063 mm, 230–400 mesh ASTM).


#

[5-(Ethoxymethyl)furan-2-yl](phenyl)methanol (4a)

A flask was charged with iPrMgCl·LCl (1.2 M, 3.33 mL), then cooled to –20 °C and PhI (816 mg, 4 mmol) was added. The reaction mixture was stirred for 30 min, then EMF (617 mg, 4 mmol) was added and the mixture was stirred for 30 min at –20 °C and then at r.t. for 1.5 h. The reaction was then quenched with H2O (0.2 mL), and the mixture was transferred to a separation funnel and partitioned between Et2O (30 mL) and sat. aq NH4Cl (30 mL). The organic fraction was separated and the aqueous fraction was additionally extracted with Et2O (2 × 30 mL). Organic layers were dried with MgSO4 and evaporated to give the product.

Yield: 858 mg (92%); yellowish oil; Rf = 0.67 (EtOAc–PE, 1:1).

IR (ATR, neat): 3406, 3063, 3032, 2974, 2870, 1450, 1373, 1350, 1088, 1015, 949, 791, 729, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.43–7.28 (m, 5 H), 6.22 (dd, J = 3.2, 0.3 Hz, 1 H), 6.00 (dm, J = 3.2 Hz, 1 H), 5.77 (d, J = 2.2 Hz, 1 H), 4.39 (s, 2 H), 3.51 (q, J = 7.0 Hz, 2 H), 2.95 (d, J = 3.3 Hz, 1 H), 1.19 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.5, 152.1, 140.9, 128.4, 128.0, 126.7, 109.8, 108.1, 70.1, 65.7, 64.7, 15.1.

HRMS (ESI): m/z [M + Na]+ calcd for C14H16O3Na: 255.0992; found: 255.0987.


#

[5-(Ethoxymethyl)furan-2-yl](thiophen-2-yl)methanol (4b)

A flask was charged with iPrMgCl·LCl (1.2778 M, 3.13 mL), then cooled to –20 °C and 2-iodothiophene (840 mg, 4 mmol) was added. The reaction mixture was stirred for 1 h, then EMF (617 mg, 4 mmol) was added and the mixture was stirred for 30 min at –20 °C and then at r.t. for 2 h. The reaction was quenched with H2O (0.2 mL), and the mixture was transferred to a separation funnel and partitioned between Et2O (30 mL) and sat. aq NH4Cl (30 mL). The organic fraction was separated and the aqueous fraction was additionally extracted with Et2O (2 × 30 mL). The organic layers were dried with MgSO4 and purified by column chromatography (EtOAc–PE, 1:4) to give the product.

Yield: 629 mg (66%); yellow oil; Rf = 0.31 (EtOAc–PE, 1:4).

IR (ATR, neat): 3387, 3105, 2974, 2870, 1439, 1373, 1350, 1088, 1011, 945, 799, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.27 (dd, J = 5.0, 1.3 Hz, 1 H), 7.00 (ddd, J = 3.5, 1.3, 0.8 Hz, 1 H), 6.96 (dd, J = 5.0, 3.5 Hz, 1 H), 6.25 (d, J = 3.2 Hz, 1 H), 6.20 (dm, J = 3.2 Hz, 1 H), 6.00 (d, J = 5.0 Hz, 1 H), 4.40 (s, 2 H), 3.52 (q, J = 7.0 Hz, 2 H), 3.20 (d, J = 5.3 Hz, 1 H), 1.19 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 155.4, 152.1, 144.6, 126.7, 125.5, 125.3, 109.9, 108.1, 66.2, 65.7, 64.6, 15.1.

HRMS (ESI): m/z [M + Na]+ calcd for C12H14O3SNa: 261.0556; found: 261.0546.


#

[5-(Ethoxymethyl)furan-2-yl](3-fluoro-4-methoxyphenyl)meth­anol (4c)

A flask was charged with 3-fluoro-4-methoxyphenylmagnesium bromide solution (0.4227 M in THF, 9.5 mL), cooled to –20 °C, and EMF (616 mg, 4 mmol) was added. The reaction mixture was stirred for 30 min at –20 °C, then cooling was removed and the mixture was stirred for at r.t. for 2 h. The reaction was quenched with H2O (0.2 mL), and the mixture was transferred to a separation funnel and partitioned between Et2O (30 mL) and sat. aq NH4Cl (30 mL). The organic fraction was separated and the aqueous fraction was additionally extracted with Et2O (2 × 30 mL). The organic fractions were combined, dried with MgSO4, and purified by column chromatography (Et2O–PE, 1:1) to give the product.

Yield: 709 mg (63%); colorless oil; Rf = 0.35 (Et2O–PE, 1:1).

IR (ATR, neat): 3395, 2974, 2936, 2870, 2847, 1624, 1589, 1516, 1443, 1273, 1219, 1119, 1088, 1022, 945, 880, 779, 756 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.14 (dd, J = 12.3, 2.1 Hz, 1 H), 7.09 (dm, J = 8.3 Hz, 1 H), 6.90 (t, J = 8.5 Hz, 1 H), 6.21 (d, J = 3.2 Hz, 1 H), 6.00 (dd, J = 3.2, 0.7 Hz, 1 H), 5.68 (d, J = 4.4 Hz, 1 H), 4.37 (s, 2 H), 3.86 (s, 3 H), 3.49 (q, J = 7.0 Hz, 2 H), 3.11 (d, J = 4.4 Hz, 1 H), 1.17 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.1, 152.3 (d, J = 246.1 Hz), 152.1, 147.3 (d, J = 11.0 Hz), 134.0 (d, J = 5.9 Hz), 122.5 (d, J = 3.3 Hz), 114.7 (d, J = 19.4 Hz), 113.2 (d, J = 2.2 Hz), 109.8, 108.1, 69.2 (d, J = 1.5 Hz), 65.8, 64.6, 56.3, 15.1.

HRMS (ESI): m/z [M + Na]+ calcd for C15H17FO4Na: 303.1003; found: 303.0991.


#

1-[5-(Ethoxymethyl)furan-2-yl]pentan-1-ol (4d)

A solution of EMF (617 mg, 4 mmol) in anhydrous THF (4 mL) was cooled to –78 °C and BuLi (2.2 M in hexane, 1.8 mL) was added dropwise. Cooling was removed and the mixture was stirred at r.t. for 2 h.

The reaction was quenched with H2O (0.2 mL), and the mixture was transferred to a separation funnel and partitioned between Et2O (30 mL) and sat. aq NH4Cl (15 mL). The organic fraction was separated and the aqueous fraction was additionally extracted with Et2O (2 × 30 mL). The organic fractions were combined, dried with MgSO4, and purified by column chromatography (Et2O–PE, 1:1) to give the product.

Yield: 514 mg (61%); light-yellow oil; Rf = 0.48 (Et2O–PE, 1:1).

IR (ATR, neat): 3410, 2955, 2932, 2862, 1458, 1377, 1350, 1092, 1007, 949, 791 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.23 (d, J = 3.1 Hz, 1 H), 6.16 (d, J = 3.1 Hz, 1 H), 4.60–4.65 (m, 1 H), 4.40 (s, 1 H), 3.52 (q, J = 7.0 Hz, 2 H), 2.14 (d, J = 5.1 Hz, 1 H), 1.77–1.87 (m, 2 H), 1.24–1.45 (m, 4 H), 1.20 (t, J = 7.0 Hz, 3 H), 0.89 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 157.4, 151.4, 109.8, 106.4, 67.9, 65.7, 64.7, 35.3, 27.8, 22.6, 15.2, 14.1.

HRMS (ESI): m/z [M + Na]+ calcd for C12H20O3Na: 235.1305; found: 235.1295.


#

Piancatelli Rearrangement: (4R,5S)-4-(Ethoxymethyl)-4-hydroxy-5-phenylcyclopent-2-en-1-one (5a); Typical Procedure

Compound 4a (116 mg, 0.5 mmol) was dissolved in a mixture of t-BuOH (7 mL) and H2O (1.4 mL), then Dy(OTf)3 (30 mg, 10 mol%) was added. The reaction flask was fitted with a reflux condenser and placed in a preheated (90 °C) oil bath. After 24 h stirring, the reaction was quenched with sat. aq NaHCO3 (7 mL), and the mixture was diluted with H2O (15 mL) and extracted with Et2O (3 × 30 mL). The organic fractions were combined, dried with MgSO4, evaporated and purified by flash column chromatography (EtOAc–PE, 1:1) to give the desired product.

Yield: 70 mg (60%); light-yellow oil; Rf = 0.49 (EtOAc–PE, 1:1).

IR (ATR, neat): 3422, 3063, 3032, 2974, 2928, 2870, 1709, 1450, 1381, 1346, 1107, 1076, 880, 745, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 5.9 Hz, 1 H), 7.19–7.27 (m, 3 H), 7.06–7.08 (m, 2 H), 6.27 (d, J = 5.9 Hz, 1 H), 3.76 (s, 1 H), 3.12–3.26 (m, 3 H), 2.96 (dd, J = 48.1, 9.4 Hz, 2 H), 0.98 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 205.7, 163.6, 134.2, 133.6, 129.9, 128.5, 127.6, 81.4, 74.6, 67.1, 62.5, 15.0.

HRMS (ESI): m/z [M + H]+ calcd for C14H17O3: 233.1172; found: 233.1165.


#

(4R,5S)-4-(Ethoxymethyl)-4-hydroxy-5-(thiophen-2-yl)cyclopent-2-en-1-one (5b)

Reaction time was 3 h. The product was purified by flash column chromatography (EtOAc–PE, 1:1 and Et2O–PE, 1:1).

Yield: 46 mg (37%); orange oil; Rf = 0.56 (EtOAc–PE, 1:1), 0.25 (Et2O–PE, 1:1).

IR (ATR, neat): 3426, 3102, 3075, 2974, 2928, 2870, 1709, 1435, 1381, 1346, 1111, 1072, 1049, 891, 817, 760, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 5.9 Hz, 1 H), 7.19–7.21 (m, 1 H), 6.94 (dd, J = 5.1, 3.5 Hz, 1 H), 6.86 (dm, J = 3.5 Hz, 1 H), 6.26 (d, J = 5.9 Hz, 1 H), 4.05 (s, 1 H), 3.20–3.32 (m, 2 H), 3.17 (br. s, 1 H), 3.10 (s, 2 H), 1.02 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 203.0, 163.0, 134.8, 133.0, 127.7, 126.9, 125.4, 81.2, 74.4, 67.2, 57.9, 15.0.

HRMS (ESI): m/z [M + H]+ calcd for C12H15O3S: 239.0736; found: 239.0729.


#

(4R,5S)-4-(Ethoxymethyl)-5-(3-fluoro-4-methoxyphenyl)-4-hydroxycyclopent-2-en-1-one (5c)

The product was purified by flash column chromatography (EtOAc–PE, 1:1).

Yield: 93 mg (66%); yellow crystals; mp 91–92 °C; Rf = 0.43 (EtOAc–PE, 1:1).

IR (ATR, neat): 3426, 3075, 2974, 2936, 2874, 1709, 1516, 1443, 1277, 1219, 1126, 1026, 910, 822, 810, 756, 729 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 5.9 Hz, 1 H), 6.85–6.92 (m, 3 H), 6.31 (d, J = 5.9 Hz, 1 H), 3.86 (s, 3 H), 3.75 (s, 1 H), 3.33 (s, 1 H), 3.21–3.31 (m, 2 H), 3.01 (dd, J = 23.7, 9.2 Hz, 2 H), 1.06 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 204.9, 163.4, 152.2 (d, J = 246.9 Hz), 147.1 (d, J = 10.6 Hz), 133.4, 126.9 (d, J = 6.6 Hz), 125.9 (d, J = 3.7 Hz), 117.6 (d, J = 18.7 Hz), 113.5 (d, J = 2.2 Hz), 81.3, 74.4, 67.1, 61.7 (d, J = 1.5 Hz), 56.4, 14.9.

HRMS (ESI): m/z [M + H]+ calcd for C15H18FO4: 281.1184; found: 281.1174.


#

(4R,5S)-5-Butyl-4-(ethoxymethyl)-4-hydroxycyclopent-2-en-1-one (5d)

The product was purified by flash column chromatography (EtOAc–PE, 1:4).

Yield: 10 mg (9%); yellowish oil; Rf = 0.25 (EtOAc–PE, 1:4).

IR (ATR, neat): 3399, 2956, 2932, 2862, 1690, 1458, 1377, 1123, 1084, 926, 787 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.80 (d, J = 10.2 Hz, 1 H), 6.01 (d, J = 10.2 Hz, 1 H), 4.41–4.59 (m, 2 H), 3.52–3.79 (m, 2 H), 2.57 (s, 1 H), 1.79–1.98 (m, 2 H), 1.30–1.44 (m, 5 H), 1.22–1.27 (m, 3 H), 0.91 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 197.0, 147.8, 145.2, 128.4, 126.8, 92.9, 74.5, 29.5, 29.2, 27.3, 22.7, 14.1.

HRMS (ESI): m/z [M + Na]+ calcd for C12H20O3Na: 235.1305; found: 235.1297.


#

Aza-Piancatelli Rearrangement: (4R,5S)-4-(Ethoxymethyl)-5-phenyl-4-(phenylamino)cyclopent-2-en-1-one (6a); Typical Procedure

Compound 4a (116 mg, 0.5 mmol) was dissolved in t-BuOH (6 mL), then Dy(OTf)3 (30 mg, 10 mol%) followed by PhNH2 (47 mg, 0.5 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated (90 °C) oil bath. After 4 h stirring, the reaction was quenched with sat. aq NaHCO3 (0.2 mL), the mixture was concentrated on a rotary evaporator and absorbed on Celite. All remaining volatiles were then removed and the residue was purified by flash column chromatography (EtOAc–PE, 1:4) to give the desired product.

Yield: 77 mg (49%); light-yellow oil; Rf = 0.56 (EtOAc–PE, 1:4).

IR (ATR, neat): 3368, 3055, 3028, 2974, 2870, 1705, 1601, 1497, 1450, 1315, 1257, 1231, 1153, 1115, 1080, 903, 883, 741, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 5.9, 0.5 Hz, 1 H), 7.18–7.24 (m, 3 H), 7.11–7.15 (m, 2 H), 7.01–7.03 (m, 2 H), 6.76 (tt, J = 7.5, 1.3 Hz, 1 H), 6.70 (dm, J = 8.5 Hz, 2 H), 6.43 (d, J = 5.9 Hz, 1 H), 4.37 (br. s, 1 H), 4.25 (s, 1 H), 2.96–3.13 (m, 4 H), 0.89 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 204.7, 165.7, 145.3, 134.7, 134.1, 130.1, 129.7, 128.3, 127.3, 119.9, 115.9, 74.9, 68.8, 66.8, 57.2, 14.8.

HRMS (ESI): m/z [M + H]+ calcd for C20H22NO2: 308.1645; found: 308.1635.


#

(4R,5S)-4-(Ethoxymethyl)-4-(phenylamino)-5-(thiophen-2-yl)cyclopent-2-en-1-one (6b)

Reaction time was 3 h. Purified by flash column chromatography (EtOAc–PE, 1:4 and Et2O–PE, 1:1).

Yield: 16 mg (10%); yellowish oil; Rf = 0.44 (EtOAc–PE, 1:4), 0.56 (Et2O–PE, 1:1).

IR (ATR, neat): 3364, 3102, 3055, 2974, 2928, 2870, 1782, 1709, 1601, 1497, 1435, 1315, 1296, 1258, 1223, 1115, 907, 845, 752, 694 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 6.0, 0.8 Hz, 1 H), 7.25 (dd, J = 5.1, 1.0 Hz, 1 H). 7.18–7.22 (m, 2 H), 7.00 (dd, J = 5.1, 3.5 Hz, 1 H), 6.90 (dt, J = 3.5, 1.0 Hz, 1 H), 6.86 (tt, J = 7.3, 1.0 Hz, 1 H), 6.79 (dm, J = 8.8 Hz, 2 H), 6.49 (d, J = 6.0 Hz, 1 H), 4.53 (s, 1 H), 4.30 (br. s, 1 H), 3.13–3.26 (m, 4 H), 1.04 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 202.3, 164.5, 145.1, 134.0, 129.7, 127.5, 126.7, 125.2, 120.4, 116.4, 74.4, 66.9, 53.2, 14.9.

HRMS (ESI): m/z [M + H]+ calcd for C18H20NO2S: 314.1209; found: 314.1198.


#

(4R,5S)-4-(Ethoxymethyl)-5-(3-fluoro-4-methoxyphenyl)-4-(phenylamino)cyclopent-2-en-1-one (6c)

Reaction time was 3 h. Purified by flash column chromatography (EtOAc–PE 1:4).

Yield: 50 mg (28%); colorless crystals; mp 117–118 °C; Rf = 0.30 (EtOAc­–PE 1:4).

IR (ATR, neat): 3368, 3055, 2974, 2931, 2870, 1705, 1601, 1516, 1439, 1315, 1277, 1258, 1219, 1126, 1016, 910, 752, 733, 694 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.73 (dd, J = 6.0, 0.8 Hz, 1 H), 7.22–7.18 (m, 2 H), 6.91–6.79 (m, 4 H), 6.76 (dm, J = 8.5 Hz, 2 H), 6.49 (d, J = 6.0 Hz, 1 H), 4.30 (br. s, 1 H), 4.25 (s, 1 H), 3.87 (s, 3 H), 3.06–3.25 (m, 4 H), 1.01 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 204.0, 165.3, 152.2 (d, J = 245.8 Hz), 146.9 (d, J = 10.6 Hz), 145.2, 134.5, 129.7, 127.0 (d, J = 6.6 Hz), 125.9 (d, J = 3.7 Hz), 120.0, 117.7 (d, J = 18.3 Hz), 115.8, 113.3 (d, J = 2.2 Hz), 74.4, 68.8, 66.8, 56.4, 56.3 (d, J = 1.1 Hz), 14.8.

HRMS (ESI): m/z [M + H]+ calcd for C21H23FNO3: 356.1656; found: 356.1647.


#

(4R,5S)-5-Butyl-4-(ethoxymethyl)-4-(phenylamino)cyclopent-2-en-1-one (6d)

Reaction time was 4 h. Purified by flash column chromatography (Et2O–PE, 1:1).

Yield: 8 mg (6%); yellowish oil; Rf = 0.59 (Et2O–PE, 1:1).

IR (ATR, neat): 3372, 3055, 3020, 2955, 2932, 2866, 1705, 1601, 1501, 1458, 1315, 1285, 1258, 1111, 748, 694 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 5.8 Hz, 1 H), 7.11–7.15 (m, 2 H), 6.78 (tt, J = 7.4, 1.0 Hz, 1 H), 6.66 (dm, J = 8.5 Hz, 2 H), 6.32 (d, J = 5.8 Hz, 1 H), 4.47 (br. s, 1 H), 3.51 (q, J = 7.0 Hz, 2 H), 3.40 (dd, J = 9.0, 1.0 Hz, 1 H), 3.37 (d, J = 9.0 Hz, 1 H), 2.89–2.93 (m, 1 H), 1.77–1.84 (m, 1 H), 1.39–1.50 (m, 3 H), 1.21 (t, J = 7.0 Hz, 3 H), 1.17–1.27 (m, 3 H), 0.85 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 206.9, 166.1, 145.5, 134.0, 129.5, 119.7, 115.9, 74.7, 67.6, 67.3, 52.2, 30.7, 24.3, 23.1, 15.1, 14.0.

HRMS (ESI): m/z [M + H]+ calcd for C18H26NO2: 288.1958; found: 288.1946.


#

N-{[5-(Ethoxymethyl)furan-2-yl](phenyl)methyl}aniline (7a)

Compound 4a (116 mg, 0.5 mmol) was dissolved in toluene (6 mL), then Dy(OTf)3 (30 mg, 10 mol%) followed by PhNH2 (47 mg, 0.5 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated (80 °C) oil bath. After 30 min stirring, the reaction was quenched with sat. aq NaHCO3 (0.2 mL), and the mixture was concentrated on a rotary evaporator and absorbed on Celite. All remaining volatiles were removed and the residue was purified using flash column chromatography (EtOAc–PE, 1:4) to give 7a.

Yield: 58 mg (38%); yellowish oil; Rf = 0.75 (EtOAc–PE, 1:4).

IR (ATR, neat): 3406, 3364, 3051, 3028, 2974, 2928, 2866, 1601, 1501, 1450, 1431, 1315, 1250, 1184, 1087, 1018, 795, 748, 694 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.43–7.46 (m, 2 H), 7.35–7.39 (m, 2 H), 7.29–7.33 (m, 1 H), 7.13–7.17 (m, 2 H), 6.73 (tm, J = 7.3 Hz, 1 H), 6.62 (dm, J = 8.8 Hz, 2 H), 6.25 (d, J = 3.0, 1 H), 6.04 (dd, J = 3.0, 1.0 Hz, 1 H), 5.60 (br. s, 1 H), 4.42 (br. s, 3 H), 3.54 (q, J = 7.0 Hz, 2 H), 1.24 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 155.5, 152.0, 147.0, 140.6, 129.2, 128.8, 127.8, 127.4, 118.1, 113.6, 110.0, 108.5, 65.8, 64.7, 57.0, 15.2.

HRMS (ESI): m/z [M + Na]+ calcd for C20H21NO2Na: 330.1465; found: 330.1452.


#

N-{1-[5-(Ethoxymethyl)furan-2-yl]pentyl}aniline (7d)

According to procedure described for 6d, compound 7d was obtained and purified by flash column chromatography (EtOAc–PE, 1:4 and Et2O–PE, 1:3).

Yield: 75 mg (52%); yellowish oil; Rf = 0.77 (EtOAc–PE, 1:4), 0.66 (Et2O–PE, 1:3).

IR (ATR, neat): 3372, 3098, 3051, 3021, 2955, 2932, 2859, 1601, 1504, 1315, 1257, 1088, 1018, 791, 748, 691 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.12–7.17 (m, 2 H), 6.70 (tt, J = 7.3, 1.1 Hz, 1 H), 6.62 (dm, J = 8.5 Hz, 2 H), 6.25 (d, J = 3.1 Hz, 1 H), 6.04 (dd, J = 3.1, 0.6 Hz, 1 H), 4.43–4.46 (m, 1 H), 4.40 (s, 2 H), 3.90 (br. s, 1 H), 3.50 (q, J = 7.0 Hz, 2 H), 1.80–1.99 (m, 2 H), 1.29–1.45 (m, 4 H), 1.21 (t, J = 7.0 Hz, 3 H), 0.91 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.8, 151.1, 147.4, 129.3, 117.7, 113.6, 109.9, 106.6, 65.5, 64.7, 52.2, 35.0, 28.3, 22.6, 15.2, 14.1.

HRMS (ESI): m/z [M + H]+ calcd for C18H26NO2: 288.1958; found: 288.1948.


#

4-{[5-(Ethoxymethyl)furan-2-yl](phenyl)methyl}aniline (8a)

Compound 4a (116 mg, 0.5 mmol) was dissolved in acetonitrile (6 mL), then Dy(OTf)3 (30 mg, 10 mol%) followed by PhNH2 (47 mg, 0.5 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated (80 °C) oil bath. After 4 h stirring, the reaction was quenched with sat. aq NaHCO3 (0.2 mL), and the mixture was concentrated on a rotary evaporator and absorbed on Celite. All remaining volatiles were removed and the residue was purified using flash column chromatography (EtOAc–PE, 1:4 and Et2O–PE, 3:1) to give 8a.

Yield: 60 mg (39%); yellowish oil; Rf = 0.20 (EtOAc–PE, 1:4), 0.56 (Et2O–PE, 3:1).

IR (ATR, neat): 3456, 3364, 3229, 3059, 3028, 2974, 2928, 2866, 1624, 1516, 1493, 1450, 1281, 1180, 1088, 1018, 952, 787, 737, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.18–7.22 (m, 2 H), 7.10–7.15 (m, 1 H), 7.06–7.08 (m, 2 H), 6.85–6.87 (m, 2 H), 6.52–6.54 (m, 2 H), 6.14 (d, J = 3.3 Hz, 1 H), 5.73 (dd, J = 3.3, 1.1 Hz, 1 H), 5.26 (s, 1 H), 4.30 (s, 2 H), 3.53 (br. s, 2 H), 3.42 (q, J = 7.0 Hz, 2 H), 1.11 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 157.7, 151.5, 145.1, 142.5, 132.0, 129.8, 128.8, 128.4, 126.6, 115.3, 109.7, 109.0, 65.6, 64.8, 50.3, 15.3.

HRMS (ESI): m/z [M + Na]+ calcd for C20H21NO2Na: 330.1465; found: 330.1454.


#

4-{[5-(Ethoxymethyl)furan-2-yl](thiophen-2-yl)methyl}aniline (8b)

According to procedure described for 8a, compound 8b was obtained and purified by flash column chromatography (EtOAc–PE, 1:4 and Et2O–PE, 3:1).

Yield: 62 mg (40%); colorless oil; Rf = 0.18 (EtOAc–PE, 1:4), 0.53 (Et2O–PE, 3:1).

IR (ATR, neat): 3453, 3364, 3225, 3102, 3032, 2974, 2866, 1620, 1512, 1439, 1373, 1350, 1281, 1177, 1084, 1018, 950, 837, 783, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.18 (dd, J = 5.1, 1.2 Hz, 1 H), 7.03–7.07 (m, 2 H), 6.92 (dd, J = 5.1, 3.5 Hz, 1 H), 6.78 (dt, J = 3.5, 1.2 Hz, 1 H), 6.61–6.64 (m, 2 H), 6.23 (dd, J = 3.2, 0.4 Hz, 1 H), 5.97 (dd, J = 3.2, 0.9 Hz, 1 H), 5.53 (s, 1 H), 4.40 (s, 2 H), 3.60 (br. s, 2 H), 3.51 (q, J = 7.0 Hz, 2 H), 1.21 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 157.0, 151.5, 146.3, 145.5, 131.8, 129.4, 126.6, 125.7, 124.4, 115.3, 109.8, 108.4, 65.6, 64.7, 45.6, 15.2.

HRMS (ESI): m/z [M + Na]+ calcd for C18H19NO2SNa: 336.1029; found: 336.1017.


#
#

Acknowledgment

This work has received support from the European Regional Development Fund (Project No.3.2.0501.10-0004), the Estonian State Forest Management Centre, and the Estonian Environmental Investment Centre (Project No 11064).

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1562790.
  • Supporting Information


   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Examples of natural cyclopentenones
Zoom Image
Scheme 1 Proposed mechanism of the Piancatelli rearrangement (conr. = conrotatory)
Zoom Image
Scheme 2 Synthesis of [5-(ethoxymethyl)furan-2-yl](phenyl)methanol (4a)
Zoom Image
Scheme 3 Synthesis of 4-hydroxycyclopenenones 5
Zoom Image
Scheme 4 Synthesis of 4-amino-cyclopenenones 6a–d