Acceleration of the Eschenmoser coupling reaction by sonication: efficient synthesis of enaminones

Abstract

Enaminones are commonly prepared by the Eschenmoser coupling reaction. The duration of the reaction is often long. Here, we describe how sonication can accelerate this reaction. The reaction conditions provide an efficient method for the coupling of primary, secondary and tertiary thioamides with α-bromocarbonyl compounds.

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Introduction

Enaminones are enamines of a 1,3-diketone, β-ketoester or similar 1,3-difunctional reagents.¹ Enaminones are important building blocks in organic synthesis. They are used in the synthesis of natural products^2–4 and utilized in the development of pharmaceuticals,^5,6 peptidomimetics,^7,8 ligands for catalysis^9,10 and chiral auxiliaries.¹¹ Additionally, enaminones form part of biologically active compounds. These include compounds with anticonvulsive, anti-inflammatory, antitumor and antibiotic activity.^1,5 Enaminones can act either as electrophiles or nucleophiles and have been used widely in organic synthesis. A number of approaches are available for the synthesis of these compounds^1,2,12,13 and the development of new and efficient methods remains an active area of research.^3,14,15

The Eschenmoser coupling reaction has been extensively employed in the construction of enaminones.^1,2,4,13 The reaction couples a thioamide and an α-halocarbonyl compound (Scheme 1). The reaction generally requires a base, can be carried out with or without the need of a thiophile, and the reaction is known to work well with a range of different substrates.⁴

Scheme 1 The Eschenmoser coupling reaction.

The Eschenmoser coupling reaction often requires a long reaction time^16–18 and primary thioamides are not acceptable substrates as they tend to convert into nitriles under the reaction conditions.⁴ The Eschenmoser coupling reaction conducted under heterogeneous conditions^4,16,19 could benefit from sonication as sonication reduces the particle size and provides better mass and heat transfer compared to conventional heating.²⁰ In this paper, the effects of sonication on such heterogeneous Eschenmoser coupling reactions, and how it addresses the common issue of long reaction times and allows for the use of primary thioamides, are discussed.

Results and discussion

Usually, carbonate and bicarbonate bases have been used when the Eschenmoser coupling reaction is conducted under heterogeneous conditions. Both have been used in the coupling of 1,3-dicarbonyl compounds with thioamides.^4,16,19 Since the aim was to couple both mono- and di-carbonyl compounds with the thioamides, the stronger base Na₂CO₃ was selected for the present study. The pK_a of sodium carbonate (∼10) is close to the pK_a of amine bases (∼10) that have been used successfully for the coupling of monocarbonyl halides with thioamides under non-heterogeneous conditions.⁴

Synthesis of starting materials

The synthesis of thioamides 1 (Scheme 1) was carried out using literature conditions.^14,21 The synthesis of α-bromocarbonyl compounds 2 however, gave some unexpected challenges (Fig. 1). Attempts to prepare 2b by reacting ethyl acetoacetate with NaH and Br₂,²² TsOH and NBS,²³ or NH₄OAc and NBS²⁴ did not give a pure product. Efforts to purify the product by flash chromatography also failed as 2b decomposed on the column. Finally, the use of bromodimethylsulfonium bromide (BDMS)²⁵ provided 2b in pure form. We did not succeed in isolating 2c under solvent free conditions.²⁶ The bromide 2c was obtained in pure form by reacting ethyl benzoylacetate with the in situ generated bromo ion (Br⁺)²⁷ and isolating the product by column chromatography. Synthesis of 2d by the reaction of NBS on Meldrum's acid provided low yields (5%) of pure product.²⁸ A better yield of 2d (up to 95%) was obtained by reacting Meldrum's acid with Br₂ and NaOH.²⁹ However, the purity of the product varied from experiment to experiment. All of the other bromides were obtained from commercial sources.

Fig. 1 α-Bromocarbonyl compounds used in this study.

Synthesis of enaminones with the help of an ultrasonic bath

Ultrasonic baths are usually available in organic laboratories. They are the most economical and commercially available sources of ultrasonic irradiation for the chemical laboratory.²⁰ As such, they have the greatest potential to be used in organic synthesis. This type of equipment was initially used for the Eschenmoser coupling reaction. Both the primary and the secondary thioamides provided the enaminones after only 2.5 h of sonication (Table 1, entries 1–4). In comparison, a low product conversion was observed when the reaction was refluxed for 2.5 h through conventional heating (entry 4).

Table 1 Eschenmoser coupling reaction with the help of an ultrasonic bath

Entry	Thioamide	Product	Yield (%)	Time allowed
a Reaction was carried out in the absence of base. b Refluxed in a pressure vessel immersed in a 47 °C oil bath. c Product was obtained as an inseparable mixture of diastereomers. d Probe sonication was used. e Reaction was cooled by a (−8 °C) condenser.
1
			3a R = OEt (90)	2.5 h
			3b R = CH3 (60)	2.5 h
	1a
2
			3c R = OEt (98)	2.5 h
			(27)^a	2.5 h
			3d R = CH3 (84)	2.5 h
	1b
3
			3e R = OEt (80)	2.5 h
			3f R = CH3 (47)	2.5 h
	1c
4
			3g R = OEt (73)	2.5 h
			(24)^b	2.5 h
			3h R = Ph (74 E/Z 2 : 1)^c	2.5 h
	1d
5
			3i R = OEt (74)	20 h
			(97)^d	8.5 h
			3j R = Ph (99)^d	3.0 h
	1e
6
			3k (85)	46 h
			(89)^d	7.0 h
			(67 conversion by NMR)^d^,^e	7.0 h
	1f
7
			3l R = OEt (94)	5.0 days
			(87)^d	11.5 h
			3m R = Ph (100 dr 2.4 : 1)^c^,^d	6.0 h
	1g

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The mechanism of the Eschenmoser coupling reaction consists of two main steps (Scheme 2). The first step is the S-alkylation of thioamides with an electrophile. In the second step the resulting thioether gets deprotonated at the α-proton which is captured by the iminium 6 or the imine 7 to form the episulfide 8. The episulfide collapses, with or without the help of a thiophile, to give enaminones 3. When monoesters are used, tertiary thioamides tend to give higher yields of product with shorter reaction times. This rate and yield enhancement is explained as a result of a greater acidity of the side-chain α-proton. The greater acidity is due to the presence of the positive charge in the thioiminium salts 4. In the case of secondary thioamides, the iminium nitrogen does not retain its charge. Under reaction conditions, it loses its proton and is converted to an imine 5.^4,30

Scheme 2 Accepted mechanism of the Eschenmoser coupling reaction.

In contrast to the above reports, in this study the coupling reaction of tertiary thioamides proved to be more challenging than the coupling of secondary thioamides and required longer reaction times (compare entries 1–4 with entries 5–7). This could be attributed to the higher acidity of α-bromodicarbonyl compounds compared to α-monocarbonyl compounds. Greater acidity could make the conversion of 1→4 or 1→5 the rate determining step, resulting in the reactions of tertiary thioamides being slower as greater steric hindrance would pose greater energy requirements in the alkylation step (1→4, Scheme 2).³¹ Nonetheless, in all of the reactions of tertiary thioamides, good yields were obtained and the reaction was suitable for acyclic (entry 1), cyclic (entries 2–6) and acyclically positioned thiocarbonyl groups (entry 7). The α-bromoketoesters are generally considered unsuitable coupling partners for providing enaminones with primary thioamides. They instead give thiozoles.^32–34 Nevertheless, a primary thioamide did give the coupled product with α-bromodicarbonyls (entry 1), and both the α-bromodiester and α-bromoketoesters were also viable coupling partners for secondary and tertiary thioamides (entries 2–7).

The reaction of α-bromoketoesters with secondary thioamides (entries 2–4) provided predominantly E diastereomers. The E stereochemistry in such compounds provides better hydrogen bonding between the N–H and the ketone oxygen and lowers the energy of the product. The coupling of 1a and 2b (R₄ = OEt, R₅ = CH₃) (entry 1) gave a single diastereomer 3b. The stereochemistry of 3b was tentatively assigned as E on the basis of the H-bonding argument. The stereochemistry in the secondary enaminones was assigned by comparing the chemical shifts of the N–H protons, and by comparing the signals of the carbonyl ester groups in the IR of relevant compounds. The coupling of 1e with 2c (entry 5) provided just the E diastereomer 3j. Such selectivity has been observed before.^4,35,36 The reaction of 1g with 2c was less selective and produced an inseparable mixture of diastereomers 3m in a 2.4 : 1 ratio.

Synthesis of enaminones with the help of probe sonication

Ultrasonic probes are less common in organic laboratories than ultrasonic baths, even though they are not very expensive.³⁷ Furthermore, they are considered standard equipment for biochemistry and analytical chemistry laboratories. The ultrasonic probe provides much more acoustic energy than an ultrasonic bath. With an ultrasonic bath, the amount of energy that reaches the reaction is around 1–5 W cm⁻², while an ultrasonic probe can provide several hundred W cm⁻² to the reaction.²⁰ We hypothesized that the reaction time for the coupling of tertiary thioamides could be reduced by providing more energy to the reaction. Thus, the use of an ultrasonic probe for the coupling of tertiary thioamides was explored. Table 1 (entries 5–7) shows that probe sonication reduces reaction times from days to hours.

Reasons for the acceleration in reaction rates

The ultrasonic energy accelerates reactions primarily as a result of cavitation bubbles. These bubbles can act as micro-reactors which generate temperatures of several thousand degrees and pressures greater than one thousand atmospheres.²⁰ In heterogeneous liquid–solid ionic reactions, cavitation bubbles can form at or near a solid surface. When such a bubble collapses, a liquid jet is formed which is targeted at the solid surface. The liquid jet disrupts interfacial boundary layers, causing an increase in the amount of mass and heat transfer to the surface. The collapse of bubbles can also generate shock waves. These shock waves can cause pressure and temperature increases and other mechanical effects.³⁸ Additionally, cavitation has the ability to reduce the size of particles, which can also improve the mass transfer to the surface.²⁰ So, which of these factors are more important than others in the sonication promoted Eschenmoser coupling reaction? We designed a few experiments to answer this question.

Since α-halodicarbonyl species can exist in the enol form, they have the potential to react in the absence of a base to form enaminones.⁴ Hence, it was important to ascertain the impact of the use of a base in this transformation. When 1b was sonicated in a water bath with 2a in the absence of a base, only 27% of 3c was isolated after 2.5 h (Table 1 entry 2). The rest of the material remained in the thioether form indicating that without the base, sonication alone cannot complete this transformation in 2.5 h and the use of the base accelerates the conversion of 5 into enaminones (Scheme 2).

Thioamide 1f was reacted next with 2a using probe sonication (Table 1, entry 6). A short condenser (−8 °C) was attached to cool the vapor. After 7 h of sonication, 67% of 1f was converted to the enaminones 3k. Similar results were obtained when the reaction was cooled from outside by immersing the reaction vessel in a room temperature water bath. In contrast, without a condenser, 100% conversion of 1f and 89% isolated yield was obtained for 3k (Table 1, entry 6). This suggests that high temperatures and pressures are important factors and that mechanical effects are not solely responsible for the rate enhancement.²⁰

Particle distribution analysis (Fig. 2, see also the ESI†) was performed on commercial, water bath sonicated and probe sonicated Na₂CO₃. It showed that the probe sonicated base had the smallest mean volume diameter (MV) of particles (646 nm) and the narrowest range of particle size distribution (428–1060 nm). The cleaning bath sonicated base had finer particles and a smaller range of particle sizes (761–1450 nm) than the commercial base (1232–5640 nm).

Fig. 2 Particle distribution analysis of sodium carbonate.

The bath sonicated base was used in the reaction of 1b with 2a. After stirring for 2.5 h at room temperature all of 1b was converted to 3c, suggesting that reduction in particle size was the only factor responsible for the rate increase (compare with Table 1, entry 2). However, when probe sonicated Na₂CO₃ (sonicated for 8.5 h) was used to couple 1e and 2a, less than 50% conversion of 1e into product 3i was observed even after 8.5 h of stirring at room temperature (compare Table 1, entry 5). These results indicate that, for tertiary thioamides, a reduced particle size of the base is not the sole reason for the fast reaction. It seems that both a reduction in the size of particles and an increased temperature are important factors in the rate enhancement of this reaction.

Limitations and side reactions

When 2d was reacted with 1b, only a 24% yield of the enaminone 3n was obtained (Scheme 3). It was observed that bromide 2d reacts rapidly with 1b without the need for sonication. Immediate heating of the reaction vessel and effervescence were observed upon the addition of 2d to the CH₂Cl₂ solution of 1b and Na₂CO₃. TLC analysis suggested the complete disappearance of 1b within the amount of time it took to check the TLC (<5 min.). The fast reactivity of 2d is expected as it is sterically less hindered and more acidic than the open chain bromoesters and ketones (for comparison: the pK_a of Meldrum's acid is 7.3³⁹ while the pK_a of ethyl acetoacetate and diethyl malonate are 14.2⁴⁰ and 16.4³⁹ respectively). These attributes should enable 2d to alkylate easily 1→5 and deprotonate and cyclize efficiently 5→8 (Scheme 2). The low yield is possibly due to the thermolysis of the Meldrum's acid moiety of the enaminones 3n. It is known that such enaminones can decompose readily.⁴¹ A more controlled reaction and much better yield were possible with Et₃N.

Scheme 3 Coupling conditions for the cyclic diester 2d.

The coupling reaction of 1c and 2c provided the single diastereomer of the enaminone 3o as a minor product (Scheme 4).⁴² On the basis of 1D and 2D NMR spectroscopy and mass spectrometry, structure 9 was assigned to the major product. The formation of 9 can be explained as a result of the breaking of the episulfide bond and proton transfer. Production of 9 in this reaction provides strong evidence for the presence of an episulfide intermediate. Such intermediates 8 (Scheme 4) have never been isolated, but have been proposed in the mechanism of the Eschenmoser reaction.

Scheme 4 Formation of the unexpected thiol.

The reaction of monocarbonyl halides was not successful under standard reaction conditions. When 1d was reacted with 2e the reaction did not proceed beyond the thioether stage 10 after 2.5 h of bath sonication (Scheme 5). However, on probe sonication, in the presence of the thiophile PPh₃ and xylene as a solvent, the reaction provided the enaminone 3p as a single diastereomer after 11 h.⁴³ In contrast, under these conditions, coupling of less acidic 1b with 2f remained unsuccessful. Even after 20 h of probe sonication, only thioether 11 could be recovered.

Scheme 5 Issues with the sulphide contraction of monocarbonyl thioethers.

Conclusions

It has been shown that sonication can accelerate the Eschenmoser coupling reaction. The method can be applied to the efficient coupling of primary, secondary and tertiary thioamides with α-bromodiesters and α-bromoketones. In the case of secondary thioamides, the rate enhancement is mainly due to the reduction in the size of Na₂CO₃ particles. For tertiary thioamides, other factors, such as heat and mechanical effects that are produced due to the rapid collapse of bubbles in sonication, are also important in the coupling process. In the future, the methodology will be expanded to include the coupling of α-halomonoesters and thioamides. The reaction will also be used in the synthesis of biologically important enaminones and natural products.

Experimental

General

¹H and ¹³C NMR spectra were obtained using a Varian 400/54 (400 MHZ) spectrometer. The residual solvent signals were used as references (CDCl₃: δ_H = 7.26 ppm, δ_C = 77.16 ppm). Infrared spectra were recorded on an Avatar 360 FT-IR. High resolution mass spectra and liquid chromatography were performed on a Thermo Scientific Exactive LC-MS instrument. The instrument was operated in a positive ion electrospray mode by Dr K. P. Roberts and J. Holland at the Department of Chemistry and Biochemistry, The University of Tulsa. Chromatographic separation was performed on this instrument with Thermo Scientific Hypersil Gold HPLC Column (50 × 2.1 mm I.D.; particle size 1.9 μm) coupled to a UV detector. Thin layer chromatography (TLC) was performed on 250 μm glass or aluminium-backed silica gel plates. Visualization was accomplished using short wavelength UV light (254 nm), an iodine chamber, or basic aqueous KMnO₄ solution. Flash column chromatography was performed using Sorbent silica gel 60 Å (40–63 μm). Petroleum ether refers to those fractions that distil at 30–60 °C. Anhydrous Na₂CO₃ was purchased from Fisher (LOT AD-9195-27). Unless specified, all chemical reagents and solvents were obtained from commercial sources. Aldrich's Zerostat® 3 gun was used to neutralize static electricity during the Na₂CO₃ weighing and transfer. Sonication was conducted either by an ultrasonic bath (VWR, model no. 97043-968) or probe sonicator (Sonics, Vibra cell, model no. VC X 130) equipped with a standard probe (tip dia. 6mm, length 113 mm). The pulse settings were 7 s on and then 1 s off with a 100% amplitude.

General procedure A: synthesis of enaminones using an ultrasonic bath

A solution of 1 (157 μmol) in 0.40 mL CH₂Cl₂ was added to a test tube containing Na₂CO₃ (3.2 eq). Bromide 2 (2 eq) was dissolved in 0.40 mL CH₂Cl₂ and added to the reaction vessel. Each vial, which originally contained 1 and 2, was washed twice with 0.10 mL CH₂Cl₂ and the contents were transferred to the reaction mixture. The test tube was capped and sonicated for the specified period of time (Table 1).

General procedure B: synthesis of enaminones using probe sonication

A solution of 1 (157 μmol) in 0.40 mL CH₂Cl₂ was added to a test tube containing Na₂CO₃ (3.2 eq). Bromide 2 (2 eq) was dissolved in 0.40 mL CH₂Cl₂ and added to the reaction vessel. Each vial, which originally contained 1 and 2, was washed twice with 0.10 mL CH₂Cl₂ and the contents were transferred to the reaction mixture. The sonication probe was inserted into the reaction tube and the tube was covered with paraffin. The reaction was sonicated for the specified period of time (Table 1). During sonication, the solvent level was monitored. If the level reduced to ∼0.40 mL, additional CH₂Cl₂ (0.80 mL) was added to make up the difference in lost solvent.

Diethyl 2-(1-amino-3-phenylpropylidene)malonate (3a)¹⁴

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1a¹⁴ (20.0 mg, 121 μmol) into crude 3a. Column chromatography (CH₂Cl₂ then 10% ethyl acetate in CH₂Cl₂) provided pure 3a (31.6 mg, 108 μmol, 90%) as yellow oil. R_f 0.23 (CH₂Cl₂). IR (neat) ν_max/cm⁻¹: 3416, 3314, 3028, 2981, 2936, 2904, 1664, 1614, 1526, 1497, 1454, 1366, 1253, 1072, 798; ¹H NMR (400 MHz, CDCl₃) δ: 8.78 (s, broad, 1H), 7.31–7.26 (m, 2H), 7.23–7.19 (m, 3H), 4.90 (s, broad, 1H), 4.23 (q, J = 7.2 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 168.9, 168.5, 165.8, 140.5, 128.8, 128.5, 126.6, 93.4, 60.6, 59.8, 37.1, 34.8, 14.4; HRMS (ESI⁺): Calcd. for C₁₆H₂₁NO₄ (M + H⁺): 292.1543, found 292.1544; m/z (ESI⁺): 292 (M + H⁺, 100%), 246 (38%); HPLC, R_t = 8.44 min.

(E)-Ethyl 2-acetyl-3-amino-5-phenylpent-2-enoate (3b)

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1a (20.0 mg, 121 μmol) into crude 3b. Column chromatography (30% ethyl acetate in CH₂Cl₂) provided pure 3b (19.0 mg, 72.5 μmol, 60%) as a single diastereomer. R_f 0.36 (dichloromethane : EtOAc 7 : 3). IR (neat) ν_max/cm⁻¹: 3370, 2921, 2844, 1710, 1645, 1551, 1320, 1260, 1093, 913; ¹H NMR (400 MHz, CDCl₃) δ: 7.32–7.27 (m, 2H), 7.25–7.20 (m, 3H), 4.31 (q, J = 7.2 Hz, 2H), 3.28 (t, J = 7.8 Hz, 2H), 3.10 (t, J = 7.8 Hz, 2H), 2.71 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.25 (s, broad, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 128.8, 35.7, 35.0, 29.8, 14.4; HRMS (ESI⁺): Calculated for C₁₅H₁₉NO₃, (M + H⁺): 262.1437 found 262.1438; m/z (ESI⁺) 262 (M + H⁺); HPLC, R_t = 9.29 min.

Diethyl 2-(pyrrolidin-2-ylidene)malonate (3c)^14,42

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1b¹⁴ (12.0 mg, 114 μmol) into crude 3c. Column chromatography (CH₂Cl₂ then ethyl acetate) provided pure 3c (25.4 mg, 112μmol, 98%). R_f 0.37 (hexanes : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 3317, 2980, 1685, 1643, 1577, 1437, 1366, 1334, 1247, 1084, 1038, 797; ¹H NMR (400 MHz, CDCl₃) δ: 9.52 (s, broad 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.58 (t, J = 7.2 Hz, 2H), 3.09 (t, J = 8.0 Hz, 2H), 2.02 (tt, J = 7.2, 8.0 Hz, 2H), 1.27 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 173.4, 170.1, 167.9, 87.4, 59.8, 59.7, 47.5, 34.3, 21.8, 14.5; HRMS (ESI⁺): Calcd. for C₁₁H₁₇NO₄ (M + H⁺): 228.1230, found 228.1220; m/z (ESI⁺): 228 (M + H⁺, 100%), 182 (79%); HPLC, R_t = 6.59 min.

(E)-Ethyl 3-oxo-2-(pyrrolidin-2-ylidene)butanoate (3d)^14,35

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1b¹⁴ (20.0 mg, 198 μmol) into crude 3d. Column chromatography (40% ethyl acetate in petroleum ether) provided pure 3d (32.9 mg, 167μmol, 84%). R_f 0.31 (petroleum ether : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 3316, 2981, 1743, 1691, 1652, 1570, 1367, 1247, 1017, 1035, 798; ¹H NMR (400 MHz, CDCl₃) δ: 11.59 (s, br, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.63 (t, J = 7.6 Hz, 2H), 3.15 (t, J = 8.0 Hz, 2H), 2.41 (s, 3H), 2.02 (t, J = 7.6, 8.0 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 197.8, 174.7, 169.0, 99.0, 59.6, 48.0, 35.2, 30.9, 21.2, 14.6; HRMS (ESI⁺): Calcd. for C₁₀H₁₅NO₃ (M + H⁺): 198.1125, found 198.1115; m/z (ESI⁺): 198 (M + H⁺, 100%), 152 (17%); HPLC, R_t = 6.02 min.

Diethyl 2-(piperidine-2-ylidene)malonate (3e)^14,19

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1c¹⁴ (30.0 mg, 173 μmol) into crude 3e. Column chromatography (17%, then 20% ethyl acetate in hexanes) provided pure 3e (33.7 mg, 140 μmol, 80%). R_f 0.26 (hexanes : EtOAc 4 : 1). IR (neat) ν_max/cm⁻¹: 3248, 2979, 1697, 1643, 1600, 1480, 1281, 1225, 1071; ¹H NMR (400 MHz, CDCl₃) δ: 10.08 (s, broad 1H), 4.18–4.11 (m, 4H), 3.35–3.32 (m, 2H), 2.64 (t, J = 6.4 Hz, 2H), 1.78–1.68 (m, 4H), 1.30–1.22 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 169.5, 168.9, 165.7, 89.8, 60.2, 59.3, 41.6, 27.2, 21.8, 19.4, 14.5, 14.4; HRMS (ESI⁺): Calcd. for C₁₂H₁₉NO₄ (M + H⁺): 242.1386, found 242.1377; m/z (ESI⁺): 242 (M + H⁺) ; HPLC, R_t = 9.29 min.

(E)-Ethyl 3-oxo-2-(piperidine-2-ylidene)butanoate (3f)⁴²

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1c¹⁴ (20.0 mg, 174 μmol) into crude 3f. Column chromatography (40% ethyl acetate in petroleum ether) provided pure 3f (17.4 mg, 82.2 μmol, 47%) as a single diastereomer. R_f 0.31 (petroleum ether : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 3398, 2928, 2855, 1692, 1599, 1463, 1448, 1358, 1332, 1307, 1278, 1192, 1108, 1070, 1054, 1025; ¹H NMR (400 MHz, CDCl₃) δ: 12.77 (s, br, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.40–3.38 (m, 2H), 2.70 (t, J = 6.2 Hz, 2H), 2.25 (s, 3H), 1.81–1.67 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 195.4, 170.1, 168.7, 101.8, 60.1, 41.7, 27.8, 21.3, 19.2, 14.4; HRMS (ESI⁺): Calcd. for C₁₁H₁₇NO₃ (M + H⁺): 212.1281, found 212.1270; m/z (ESI⁺): 212 (M + H⁺, 100%), 166 (16%); HPLC, R_t = 6.41min.

(S)-5-(Di(ethoxycarbonyl)methylidene)-pyrrolidine-2-carboxylic acid ethyl ester (3g)⁴⁴

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1d⁴⁴ (30.0 mg, 173 μmol) into crude 3g. Column chromatography (40% ethyl acetate in petroleum ether) provided pure 3g (37.5 mg, 125 μmol, 73%). R_f 0.59 (hexanes : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 3316, 2981, 1743, 1691, 1652, 1570, 1441, 1417, 1367, 1247, 1077, 1036; ¹H NMR (400 MHz, CDCl₃) δ: 9.62 (s, br 1H), 4.45 (dd, J = 6.0, 8.8 Hz, 1H), 4.23–4.14 (m, 6H), 3.21–3.06 (m, 2H), 2.34 (dddd, J = 7.2, 8.8, 8.8, 13.2 Hz, 1H), 2.16 (dddd, J = 6.0, 6.0, 9.2, 13.2 Hz, 1H), 1.31–1.22 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 172.1, 171.2, 169.5, 167.5, 89.0, 60.9, 60.8, 59.9, 59.8, 33.2, 26.0, 14.4, 14.2; HRMS (ESI⁺): Calcd. for C₁₄H₂₁NO₆ (M + H⁺): 300.1442, found 300.1417; m/z (ESI⁺): 300 (M + H⁺, 100%), 254 (42%), 225 (60%); HPLC, R_t = 6.99 min.

(S)-Ethyl 5-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-ylidene)pyrrolidine-2-carboxylate (3h)

The reaction was performed according to the general procedure A. It was sonicated for 2.5 h to convert 1d⁴⁴ (30.0 mg, 173 μmol) into crude 3h. Column chromatography (columned packed in petroleum ether and run in 20%, then 30% ethyl acetate in petroleum ether) provided pure 3h (42.5 mg, 128μmol, 74%) as an inseparable mixture of diasteromers in a ratio of 1 : 2 (Z: E). R_f 0.56 (petroleum ether : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 3314, 2981, 1742, 1685, 1593, 1573, 1537, 1230; ¹H NMR (400 MHz, CDCl₃) δ: 10.98 (s, br, 1H, major), 9.48 (s, br, 1H, minor), 7.61 (d, J = 6.8 Hz, 1H), 7.46–7.31 (m, 4H), 4.55–4.43 (m, 1H), 4.23 (d, J = 7.2 Hz, 2H), 3.89–3.79 (m, 2H), 3.34–3.14 (m, 2H), 2.46–2.36 (m, 1H), 2.28–2.15 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 0.73–0.70 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: (major) 195.3, 173.4, 170.8, 169.1, 143.3, 129.8, 127.8, 126.9, 98.9, 62.0, 61.6, 59.6, 33.2, 25.5, 14.2, 13.5; (minor) 195.3, 172.2, 171.1, 169.7, 142.6, 130.9, 128.1, 127.8, 96.8, 62.0, 61.0, 59.4, 32.5, 26.2, 14.2, 13.5; HRMS (ESI⁺): Calcd. for C₁₈H₂₁NO₅ (M + H⁺): 332.1465, found 332.1492; m/z (ESI⁺) 332 (M + H⁺, 100%), 207 (56%), 172 (24%); HPLC, R_t = 7.87 min.

Diethyl 2-(methylpyrrolidin-2-ylidene)malonate (3i)^14,36

By the general procedure A. The reaction was performed according to the general procedure A with a few changes. After 4 and 8 h of sonication, 0.74 eq. of additional 2a was added. The reaction was sonicated for 20 h in total to convert 1e¹⁴ (500 mg, 434 μmol) into crude 3i. Column chromatography (20% ethyl acetate in CH₂Cl₂) provided pure 3i (77.9 mg, 323 μmol, 74%).

By the general procedure B. The reaction was performed according to the general procedure B. It was sonicated for 8.5 h to convert 1e¹⁴ (20.0 mg, 174 μmol) into crude 3i. Column chromatography (40% ethyl acetate in petroleum ether) provided pure 3i (40.5 mg, 168 μmol, 97%). R_f 0.22 (petroleum ether : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 2965, 2926, 2852, 1680, 1574, 1450, 1366, 1286, 1223, 1189, 1069, 915; ¹H NMR (400 MHz, CDCl₃) δ: 4.14 (q, J = 7.2 Hz, 4H), 3.48 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.6 Hz, 2H), 2.82 (s, 3H), 1.94 (tt, J = 7.2, 7.6 Hz, 2H), 1.24 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 168.3, 166.7, 89.2, 59.9, 57.2, 36.8, 35.1, 20.6, 14.4; HRMS (ESI⁺): Calcd. for C₁₂H₁₉NO₄ (M + H⁺): 242.1386, found 242.1375; m/z (ESI⁺) 242 (M + H⁺, 43%), 196 (100%); HPLC, R_t = 6.33 min.

(E)-Ethyl 2-(methylpyrrolidin-2-ylidene)-3-oxo-3-phenylpropanoate (3j)³⁶

The reaction was performed according to the general procedure B. It was sonicated for 3 h to convert 1e¹⁴ (20.0 mg, 174 μmol) into crude 3j. Column chromatography (40% ethyl acetate in petroleum ether) provided pure 3j (47.1 mg, 172 μmol, 99%) as a single diastereomer. R_f 0.16 (petroleum ether : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 2925, 2854, 1682, 1615, 1598, 1558, 1447, 1408, 1364, 1316, 1285, 1233, 1173, 1123, 1094, 1060, 910, 880, 827; ¹H NMR (400 MHz, CDCl₃) δ: 7.73–7.69 (m, 2H), 7.43–7.39 (m, 1H), 7.37–7.33 (m, 2H), 3.82 (q, J = 7.2 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.6 Hz, 2H), 2.74 (s, 3H), 2.05 (tt, J = 7.2, 7.6 Hz, 2H), 0.70 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl3) δ: 194.0, 170.7, 169.3, 142.6, 130.8, 128.2, 127.9, 96.9, 59.3, 57.7, 38.9, 35.6, 20.7, 13.6; HRMS (ESI⁺): Calcd. for C₁₆H₁₉NO₃ (M+H)⁺: 274.1437, found 274.1425; m/z (ESI⁺) 274 (M + H⁺, 100%), 228 (83%), 105 (17%); HPLC, R_t = 6.85 min.

Diethyl 2-(benzylpyrrolidin-2-ylidene)malonate 3k

By the general procedure A. The reaction was performed according to the general procedure A with a few changes. During sonication, the solvent level was monitored. After 9 h additional CH₂Cl₂ (1.00 mL) was added to make up the difference in lost solvent. After 37 h of sonication, 1.10 eq. of additional 2a was added. The reaction was sonicated for 46 h in total to convert 1f (30.0 mg, 157 μmol) into crude 3k. Column chromatography (20%, then 30% ethyl acetate in petroleum ether) provided pure 3k (42.4 mg, 134 μmol, 85%).

By the general procedure B. The reaction was performed according to the general procedure B. It was sonicated for 7 h to convert 1f (30.0 mg, 157 μmol) into crude 3k. Column chromatography (20%, then 30% ethyl acetate in petroleum ether) provided pure 3k (44.5 mg, 140 μmol, 89%). R_f 0.56 (petroleum ether : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 2979, 1684, 1570, 1454, 1364, 1234, 1190, 1147, 1091, 1048, 955; ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.25 (m, 3H), 7.19–7.17 (m, 2H), 4.40 (s, 2H), 4.06 (q, J = 7.2 Hz, 4H), 3.31 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 7.6 Hz, 2H), 1.92 (tt, J = 7.2, 7.6 Hz, 2H), 1.17 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 168.5, 165.0, 135.8, 128.8, 127.8, 127.7, 90.6, 60.1, 54.3, 52.6, 35.4, 20.8, 14.3; HRMS (ESI⁺): Calcd. for C₁₈H₂₃NO₄ (M + H⁺): 318.1700, found 318.1674; m/z (ESI⁺) 318 (M + H⁺, 100%), 272 (90%); HPLC, R_t = 7.85 min.

Diethyl 2-(phenyl(piperidine-1-yl)methylene)malonate (3l)^14,45

By the general procedure A. The reaction was performed according to the general procedure A. The reaction was sonicated for 5 days in total to convert 1g¹⁴ (24.0 mg, 117 μmol) into crude 3l. Column chromatography (20%, then 33% ethyl acetate in hexanes) provided pure 3l (36.6 mg, 110 μmol, 94%).

By the general procedure B. The reaction was performed according to the general procedure B. It was sonicated for 11.5 h to convert 1g¹⁴ (20.0 mg, 97.4 μmol) into crude 3l. Column chromatography (20%, then 30% ethyl acetate in petroleum ether) provided pure 3l (28.3 mg, 85.4 μmol, 87%). R_f 0.26 (petroleum ether : EtOAc 3 : 2). IR (neat) ν_max/cm⁻¹: 2925, 2854, 1690, 1524, 1446, 1365, 1291, 1253, 1222, 1155, 1113, 1078, 1027, 858, 765; ¹H NMR (400 MHz, CDCl₃) δ: 7.45–7.42 (m, 3H), 7.39–7.35 (m, 2H), 3.98 (q, J = 7.2 Hz, 4H), 3.14–3.11 (m, br, 4H), 1.72–1.63 (m, br, 6H), 1.10 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 169.0, 167.9, 138.1, 130.5, 129.8, 128.5, 98.4, 60.0, 52.7, 27.0, 23.9, 14.2; HRMS (ESI⁺): Calcd. for C₁₉H₂₅NO₄ (M + H⁺): 332.1856, found 332.1836; m/z (ESI⁺) 332 (M + H⁺, 53%), 286 (100%); HPLC, R_t = 8.68 min.

Ethyl 2-benzoyl-3-phenyl(piperidine-1-yl)acrylate (3m)

The reaction was performed according to the general procedure B. It was sonicated for 6 h to convert 1g¹⁴ (20.0 mg, 97.4 μmol) into crude 3m. Column chromatography (40% petroleum ether in CH₂Cl₂) provided pure 3m (35.4 mg, 97.4 μmol, 100%) as an inseparable mixture of diastereomers (2.4 : 1). R_f 0.14 (petroleum ether : EtOAc 9 : 1). IR (neat) ν_max/cm⁻¹: 2935, 2855, 1670, 1668, 1507, 1446, 1364, 1273, 1243, 1220, 1208, 1168, 1156, 1110, 1059, 1026, 1000, 904, 772, 761; ¹H NMR (400 MHz, CDCl₃) δ: (Major) 7.77 (d, J = 7.6 Hz, 2H), 7.37–7.28 (m, 8H), 4.20 (q, J = 7.2 Hz, 2H), 3.27–3.26 (m, 4H), 1.70–1.68 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H); (Minor) 8.07 (d, J = 7.2 Hz, 2H), 7.61–7.40 (m, 8H), 3.73 (q, J = 7.2 Hz, 2H), 3.20 (m, br, 4H), 1.59 (m, br, 6H), 0.69 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: (Major) 193.5, 170.2, 166.6, 137.8, 137.3, 132.8, 130.3, 129.5, 128.5, 128.3, 127.3, 81.0, 60.3, 53.2, 27.1, 27.0, 14.8; (Minor) 191.8, 171.6, 169.2, 139.5, 136.9, 133.3, 130.3, 129.9, 128.7, 128.3, 127.6, 85.1, 60.1, 52.5, 29.8, 26.9, 13.7; HRMS (ESI⁺): Calcd. for C₂₃H₂₅NO₃ (M + H⁺): 364.1907, found 364.1892; m/z (ESI⁺) 364 (M + H⁺); HPLC, R_t = 10.38 min.

Acknowledgements

Financial support was provided by The University of Tulsa new faculty Lab-startup funds. B.H. and H.S. gratefully acknowledge both the TURC and the CSURP scholarship funds from The University of Tulsa. The authors thank J. Holland for her help with the spectroscopic measurements. This material is based upon work supported by the National Science Foundation under Grant No. (CHE-1048784).

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures for benzylpyrrolidin-2-one, 1f, 2c, 3n, 3o, 9, 10, 3p and 11, preparation of bath sonicated and probe sonicated Na₂CO₃ and related experiments, particle distribution graphs and ¹H and ¹³C NMR spectra of all the relevant compounds. See DOI: 10.1039/c2ra22033d

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