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. 2020 Feb 12;5(7):3717–3724. doi: 10.1021/acsomega.9b04400

Rh-Catalyzed Hydroformylation-Initiated Bicyclization: Construction of Azabicyclic Systems

Wen-Hua Chiou 1,*, Kuo-Hsun Hsu 1, Wen-Wei Huang 1
PMCID: PMC7045571  PMID: 32118187

Abstract

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Here, we describe the recent progress toward construction of 1-azabicyclic structures using a domino hydroformylation double cyclization strategy of an amide bearing the trisubstituted alkene functionality. The method provides a rapid and atom-economic access to alkaloid structures under mild conditions, especially for quinolizidine and pyrrolidine-fused azepane skeletons with yields up to 82% and good diastereoselectivity. Subsequent oxidative cleavage conditions are developed for the synthesis of Dendrobatid alkaloid epi-epiquinamide.

Introduction

A domino reaction design has received attention in synthetic organic chemistry because it provides reliable, efficient, and environmentally friendly alternatives from readily available starting materials.1−5 The development of a new domino reaction sequence can be considered a significant intellectual challenge, which does not bring only practical efficiency but also an aesthetic appeal in the human mind.6−8 Therefore, it has been emerged as a mainstream in synthetic organic chemistry. Due to the mild conditions and compatibility for common functionalities, the Rh-catalyzed hydroformylation9−11 appears to be a useful tool in synthetic organic chemistry.12−18 As part of our interest in domino reaction, here we describe a novel one-pot Rh-catalyzed domino hydroformylation double cyclization for rapid construction azabicyclo heterocycles.

The design is outlined in Scheme 1: Rh-catalyzed hydroformylation of the monosubstituted alkene 1 produces desired linear aldehyde 2, which can trigger a series of intramolecular transformations spontaneously (Scheme 1). Aldehyde 2 undergoes the first condensation with the amide moiety to give aminal 3. Subsequent dehydration occurs to yield N-acyliminium 4. Different from our previous strategy,19,20 the present design takes advantage of a trisubstituted alkene as the π nucleophile21 to proceed the intramolecular Mannich cyclization to form a stable tertiary carbocationic bicyclized product 5. Releasing a proton in an E1 manner yields gem-disubstituted alkene 6 rather than a tetrasubstituted alkene, probably due to significant A1,3-strain in the latter situation. The resulting alkene 6 will not undergo further hydroformylation because it requires a higher pressure and forced conditions.

Scheme 1. Rh-Catalyzed Domino Hydroformylation Double Cyclization of Trisubstituted Alkenes, Illustrated by the Example of Allylamide Substrate 1a.

Scheme 1

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Compared to the nucleophilic arylacetylene group, the trisubstituted alkene group provides more diversity in the flowing chemical transformations. Moreover, the resulting isopropenyl group is able to provide more diversity in the following chemical transformations. Therefore, we design three kinds of amide substrates: allyl amides (1a, 1d, and 1g), butenamides (1b, 1e, and 1h), and homoallylamides (1c, 1f, and 1i), to investigate the scope and limitation of the idea (Figure 1).

Figure 1.

Figure 1

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Design substrates for the double reaction.

Results and Discussion

These amides are readily prepared from the corresponding acids and amines by means of a standard carbodiimide coupling or a chloroformate activation protocol. At first, allylamide 1a was chosen as the model system to find the conditions and subjected to the previously developed conditions, that is, the use of 10 mol % PTSA at 60 °C, 4 atm of CO/H2 (1:1), and 0.05 M substrate concentration. The results are summarized in Table 1. Pleasingly, we were able to isolate the desired product 6a albeit in 14% yield as a 1.4:1 inseparable cis/trans mixtures22 and monocyclized product aminal 3a in 20% (entry 1). The treatment of aminal 3a in with BF3·OEt2 in dichloromethane afforded the cyclized product 6a in 66% yield (eq 1).

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Table 1. Optimizations on Hydroformylation Double Cyclization Conditions for Alkene 1a.

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entrya PTSA 3a (%) 6a (%)b,c
1 10 mol % 42 14
2 50 mol % 20 28
3 1.0 equiv ND 66
4 1.5 equiv ND 44
5 2.0 equiv ND 45
6 3.0 equiv ND 40
7d 1.0 equiv ND 82
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a

All reactions were run with 1.0 mmol of 1a (0.05 M in 20 mL of solvent), for 16–20 h.

b

Isolated yield.

c

The cis/trans ratio was about 1.4 in all entries.

d

Without aqueous workup.

e

ND: not detected.

It suggested that the amount of acid might be a crucial role in the reaction. Thus, we attempted to increase the amount of the acid to improve the yield. Addition of 50 mol % PTSA in the reaction improved the cyclized product in 28% yield, as well as 3a in 20% yield (entry 2). The addition within 1 equiv of pTSA afford the desired product 6a in 66% isolated yield (entry 3). However, more amount of pTSA did not bring significant improvement in the yield of product 6a but resulted in disappearance of product 3a (entries 4–6). It was noteworthy to point out that the resulting germinal alkene moiety did not undergo further hydroformylation as we anticipated. In addition, we found that the monocyclized product 3a would suffer weight loss during purification, probably due to decomposition in silica gel or in acidic conditions for a long time. Thus, direct treatment of the crude residue with BF3·OEt2 in dichloromethane after evaporation to remove acetic acid brought satisfiying results. Such an operation rendered complete formation of bicyclized product 6a in 82% isolated yield (entry 7).

Once the optimized conditions were in hand, we were able to study the scope and limitation of the reaction using various amide substrates (Figure 2). The reaction of 3-butenamide 1b under the optimized conditions afforded only one diastereomer, trans 4-oxoquinolizidine 6b in 75% yield, while the reaction of the other isomer homoallylamide 1c afforded both cis- and trans-6-oxoquinolizidine 6c in 63% yield as inseparable mixtures (1.5:1). In addition, in the investigation on 6-methyl-5-heptenamide substrates (1d and 1f, m = 2), only the reaction of allylamide 1d could afford pyrrolidine-fused azepane 6d as a single trans product in a good yield of 78%, while the reactions of the butenamide 1e and the homoallylamide 1f could not provide the cyclized products. The reactions of allylamide 1g and homoallylamide 1i did not give the anticipated bicyclized product 6, but the reaction of butenamide 1h could produce the desired product only in 27% yield as a 2.5:1 inseparable mixture of cis/trans isomers.

Figure 2.

Figure 2

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Results of hydroformylation double cyclization.

To extend the following functional group transformation, our attention next turns to examining a protocol for utilization of the isopropenyl group (Table 2). The exposure of indolizidine 6a in the ozonolysis conditions gave only a decomposed result (entry 1). The treatment with OsO4–oxone in DMF failed to produce methylketone product (entry 2).23 However, Upjohn dihydroxylation, that is, a catalytic amount of OsO4 and a stoichiometric amount of NMO followed by NaIO4 cleavage of the resulting diol afforded 31% of cis-ketone 7a and 27% of trans-ketone 7a (entry 3). A better result was achieved by employing the Nicolaou’s protocol.24 Treatment with NMO and 2,6-lutidine in the presence of a catalytic amount OsO4 in acetone/water followed by addition of DAIB (diacetoxyiodobenzene) produced 44% of cis-ketone 7a and 37% of trans-ketone 7a (entry 4).

Table 2. Optimizations on Oxidative Cleavage of Alkene 6a.

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entry reagent 1 solvent T (°C) reagent 2 cis-7a (%)a trans-7a (%)
1 O3 CH2Cl2 –78 Me2S (1.4 equiv) ND ND
2 OsO4 (1.0 mol %) DMF rt   ND ND
oxone (4.0 equiv)
3 OsO4 (3.3 mol %) acetone rt NaIO4 (2.0 equiv) 31 27
NMO (1.0 equiv)
4 OsO4 (3.3 mol %) acetone/H2O 40 DAIB (1.5 equiv) 44 37
NMO (1.0 equiv)
2,6-lutidine (2.0 equiv)
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a

Isolated yield.

After being treated with DBU in dichloromethane at room temperature overnight, cis-ketone 7a was transformed completely to the trans isomer 7a. The results indicated trans-ketone 7a was thermodynamically stable product. The condensation of trans ketone 7a with tosylhydrazine in refluxing methanol resulted in the formation of tosylhydrazone derivative trans-8a (Scheme 2). The precipitate could be recrystallized from the solution to give single crystals (see the Supporting Information, CCDC no. 1920287) for the X-ray diffraction analysis. It apparently possesses a trans configuration between two methines, that is, C-8 and C-8a.

Scheme 2. Epimerization of cis-Ketone 7a to trans Isomer and Tosylhydrazone Derivative 8a and ORTEP Structure of 8a.

Scheme 2

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To demonstrate the methodology, we develop a series of simple operations for synthesis of Dendrobatid alkaloid epi-epiquinamide (Scheme 3).25−32 Following the optimized oxidative cleavage conditions, trans quinolizidine 6b was transformed to trans-ketone 7b in 88% yield. Reduction with LiAlH4 to reduce two carbonyl groups afforded a diastereomeric mixture of quinolizidine alcohol 9b in 74% yield. Exposure of alcohol 9b with Dess–Martin periodinane afforded the methylketone 10b in 89% yield, in which the tertiary amine remained intact during oxidation. The methylketone 10b was subjected to condensation with hydroxylamine to afford oxime 11b, which would be converted to an amide group through Beckmann rearrangement. Thus, the resulting oxime 11b was treated with PCl5 in dichloromethane to produce amide 12 in 20% yield as a 1:1 mixture of cis/trans isomers, while with TFA to obtain methylketone 10b in 38% yield. The reaction of oxime 11b with sulfonyl chloride such as TsCl and MsCl gave the sulfonates as a leaving group,33 which should enhance the nucelofugality34,35 and improve the response. However, subsequent treatment with triethylamine led either to recovery of the starting materials or to complete destruction if in forcing conditions. Treatment of oxime 11b with cyanuric chloride in DMF at an elevated temperature36 afforded the arranged product as a 1:3 mixture37 of the cis (epiquinamide) to trans (epi-epiquinamide) amide 12 in a combined yield of 64%. The spectra data were identical to those reported.32

Scheme 3. Syntheses of Epiquinamide.

Scheme 3

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In summary, we have reported a novel reaction, trisubstituted alkene-mediated domino hydroformylation/double cyclization, to synthesize indolizidine, quinolizidine, and pyrrolidine-fused azepane skeleton from simple amide derivatives. Subsequent elaboration of the bicyclic product 6 into ketone 7 was effected by the optimized cleavage conditions and furnished a Dendrobatid alkaloid epi-epiquinamide in six steps. The methodology provides rapid construction of azabicyclo[4.4.0]decane and azabicyclo[5.3.0]decane systems based on the excellent diastereoselectivity. Further applications of other natural products are under investigation and will be reported in due course.

Experimental Section

The reactions were performed under an argon atmosphere and in an anhydrous solvent, unless otherwise stated. The solvents and reagents were dried or refined according to the literature procedures. The crude products were purified by flash column chromatography on silica gel to give isolated yields. All NMR spectra, for example, 1H, 13C, DEPT, gCOSY, gHSQC, and gHMBC, were recorded on a 400 MHz or a 600 MHz NMR spectrometer, which provided all necessary data for the full assignment of each compound. Chemical shifts (δ) are reported in ppm using residual undeuterated solvent as an internal standard. Coupling constants are described in Hertz. The X-ray crystal results have been checked to obtain the corresponding CCDC number. Mass spectra were recorded on a mass spectrometer with a magnetic sector using the electrospray ionization (ESI) or fast atom bombardment (FAB).

General Procedure for the Preparation of Amide Substrates 1a–1i38,39

Method A

To a solution of the corresponding acid (10.0 mmol, 1.0 equiv) in THF was added triethylamine (1.47 mL, 10.5 mmol, 1.05 equiv) at room temperature under an atmosphere of nitrogen followed by addition of methyl chloroformate (0.81 mL, 10.5 mmol, 1.05 equiv). After 20 min, the corresponding amine (1.05 equiv) was added. The reaction mixture was allowed to be stirred overnight (∼21 h) under nitrogen. On completion of the reaction, the solvent was removed in vacuo, and the reaction mixture was partitioned with diethyl ether (20 mL) and water (30 mL). The aqueous solution was extracted with diethyl ether (20 mL ×3) again. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a crude product. Purification of the crude product by flash chromatography on silica gel using EtOAc/n-hexane as the eluant afforded the corresponding amide in a high yield.

Method B

To a mixture of the corresponding acid (10.0 mmol, 1.0 equiv), EDC (1.917 g, 10.0 mmol, 1.1 equiv), and HOBt (1.836 g, 12.0 mmol, 1.3 equiv) in CH2Cl2 (5.0 mL) in an ice bath was added the corresponding amine (10.0 mmol, 1.0 equiv) via a syringe. The reaction mixture was allowed to stir overnight (∼21 h) under nitrogen. The reaction mixture was partitioned with CH2Cl2 (20 mL) and saturated NaHCO3 solution (10 mL). The organic layer was washed with saturated NH4Cl solution (10 mL). The aqueous solution was extracted with CH2Cl2 (20 mL ×2) again. The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a crude product. Purification of the crude product by flash chromatography on silica gel using EtOAc/n-hexane as the eluant afforded the corresponding amide in a high yield.

N-Allyl-5-methyl-4-hexenamide (1a)

Method A; 85% yield; light yellow oil; Rf = 0.12 (EtOAc/n-Hex = 1:3); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.57 (s, 3H, H-6′), 1.63 (s, 3H, H-6), 2.16–2.20 (m, 2H, H-2), 2.27 (q, J = 7.2 Hz, 2H, H-3), 3.81 (q, J = 6.0 Hz, 2H, −NH–CH2), 5.08–5.14 (m, 3H, H-4 and —CH=CH2), 5.73–5.82 (m, 1H, —CH=CH2), 6.05 (brs, 1H, −NH–CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.6 (q, C-6′), 24.2 (t, C-2), 25.5 (q, C-6), 36.5 (t, C-3), 41.7 (t, −NH–CH2), 115.9 (t, —CH=CH2), 112.7 (d, C-4), 132.9 (s, C-5), 134.2 (d, —CH=CH2), 172.7 (s, C-1); EI-HRMS (m/z): [M]+ calcd for C10H17NO+, 167.1310; found, 167.1309 (Δ = 0.6 ppm).

N-(5-Methyl-4-hexen-1-yl)-3-butenamide (1b)

Method B; 77% yield; light yellow oil; Rf = 0.21 (EtOAc/n-Hex = 1:1); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.52 (quint, J = 7.2 Hz, 2H, H-2), 1.58 (s, 3H, H-6′), 1.67 (s, 3H, H-6), 2.00 (q, J = 7.2 Hz, 2H, H-3), 2.98 (d, J = 7.2 Hz, 2H, −COCH2), 3.23 (q, J = 7.2 Hz, 2H, H-1), 5.06–5.10 (m, 1H, H-4), 5.18–5.24 (m, 2H, —CH=CH2), 5.66 (brs, 1H, −NH–CH2), 5.86–5.96 (m, 1H, —CH=CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.5 (q, C-6′), 25.3 (t, C-2), 25.5 (q, C-6), 29.4 (t, C-3), 39.2 (t, −COCH2), 41.5 (t, C-1), 119.2 (t, —CH=CH2), 123.3 (d, C-4), 131.5 (s, C-5), 132.1 (d, —CH=CH2), 170.4 (s, −CONH−); EI-HRMS (m/z): [M]+ calcd for C11H19NO+, 181.1467; found, 181.1475 (Δ = 4.4 ppm).

N-(3-Buten-1-yl)-5-methyl-4-hexenamide (1c)

Method A; 81% yield; light yellow oil; Rf = 0.18 (EtOAc/n-Hex = 1:3); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.57 (s, 3H, H-6′), 1.63 (s, 3H, H-6), 2.12–2.28 (m, 6H, H-2 and H-3 and —CH2CH=CH2), 3.26 (q, J = 6.4 Hz, 2H, −NH–CH2), 5.01–5.06 (m, 3H, H-4 and —CH=CH2), 5.66–5.76 (m, 1H, —CH=CH2), 5.85 (brs, 1H, −NH–CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.6 (q, C-6′), 24.2 (t, C-3), 25.5 (q, C-6), 33.6 (t, C-2), 36.6 (t, —CH2CH=CH2), 38.3 (t, −NH–CH2), 116.9 (t, —CH=CH2), 122.7 (d, C-4), 132.9 (s, C-5), 135.2 (d, —CH=CH2), 172.7 (s, C-1); EI-HRMS (m/z): [M]+ calcd for C11H19NO+, 181.1467; found, 181.1470 (Δ = 1.7 ppm).

N-Allyl-6-methyl-5-heptenamide (1d)

Method A; 97% yield; light yellow oil; Rf = 0.23 (EtOAc/n-Hex = 1:2); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.57 (s, 3H, H-7′), 1.64–1.71 (m, 5H, H-7 and H-3), 2.00 (q, J = 6.8 Hz, 2H, H-4), 2.17 (t, J = 7.2 Hz, 2H, H-2), 3.84–3.87 (m, 2H, −NH–CH2), 5.06–5.18 (m, 3H, H-5 and —CH=CH2), 5.17 (brs, 1H, −NH–CH2), 5.76–5.85 (m, 1H, —CH=CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.7 (q, C-7′), 25.6 (q, C-7), 25.8 (t, C-3), 27.4 (t, C-4), 36.1 (t, C-2), 41.8 (t, −NH–CH2), 116.2 (t, —CH=CH2), 123.5 (d, C-5), 132.5 (s, C-6), 134.3 (d, —CH=CH2), 172.9 (s, C-1); EI-HRMS (m/z): [M]+ calcd for C11H19NO+, 181.1467; found, 181.1473 (Δ = 3.3 ppm).

N-(6-Methyl-5-hepten-1-yl)-3-butenamide (1e)

Method B; 78% yield; light yellow oil; Rf = 0.27 (EtOAc/n-Hex = 1:2); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.31 (quint, J = 7.6 Hz, 2H, H-3), 1.47 (quint, J = 7.2 Hz, 2H, H-2), 1.56 (s, 3H, H-7′), 1.65 (s, 3H, H-7), 1.96 (q, J = 7.2 Hz, 2H, H-4), 2.97 (d, J = 7.2 Hz, 2H, −COCH2), 3.21 (q, J = 7.2 Hz, 2H, H-1), 5.04–5.08 (m, 1H, H-5), 5.16–5.22 (m, 2H, —CH=CH2), 5.75 (brs, 1H, −NH–CH2), 5.85–5.96 (m, 1H, —CH=CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.6 (q, C-7′), 25.6 (q, C-7), 27.0 (t, C-3), 27.5 (t, C-2), 29.1 (t, C-4), 39.5 (t, −COCH2), 41.6 (t, C-1), 119.6 (t, —CH=CH2), 124.1 (d, C-5), 131.5 (d, —CH=CH2), 131.8 (s, C-6), 170.4 (s, −CONH−); EI-HRMS (m/z): [M]+ calcd for C12H21NO+, 195.1623; found, 195.1624 (Δ = 0.5 ppm).

N-(3-Buten-1-yl)-6-methyl-5-heptenamide (1f)

Method A; 95% yield; light yellow oil; Rf = 0.33 (EtOAc/n-Hex = 1:2); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.58 (s, 3H, H-7′), 1.61–1.67 (m, 5H, H-7 and H-3), 2.00 (q, J = 7.2 Hz, 2H, H-4), 2.14 (t, J = 7.6 Hz, 2H, H-2), 2.25 (q, J = 6.8 Hz, 2H, —CH2CH=CH2), 3.32 (q, J = 6.4 Hz, 2H, −NH–CH2), 5.06–5.11 (m, 3H, H-5 and —CH=CH2), 5.54 (brs, 1H, −NH–CH2), 5.70–5.78 (m, 1H, —CH=CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.7 (q, C-7′), 25.6 (q, C-7), 25.8 (t, C-3), 27.4 (t, C-4), 33.7 (t, C-2), 36.2 (t, —CH2CH=CH2), 38.3 (t, −NH–CH2), 117.2 (t, —CH=CH2), 123.6 (d, C-5), 132.4 (s, C-6), 135.3 (d, —CH=CH2), 173.1 (s, C-1); EI-HRMS (m/z): [M]+ calcd for C12H21NO+, 195.1623; found, 195.1632 (Δ = 4.6 ppm).

N-Allyl-4-methyl-3-pentenamide (1g)

Method B; 97% yield; light yellow oil; Rf = 0.14 (EtOAc/n-Hex = 1:3); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.55 (s, 3H, H-5′), 1.66 (s, 3H, H-5), 2.87 (d, J = 7.2 Hz, 2H, H-2), 3.74–3.76 (m, 2H, −NH–CH2), 4.98–5.02 (m, 2H, —CH=CH2), 5.19–5.23 (m, 1H, H-3), 5.66–5.77 (m, 1H, —CH=CH2), 6.28 (brs, 1H, −NH–CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.6 (q, C-5′), 25.4 (q, C-5), 35.6 (t, C-2), 41.6 (t, −NH–CH2), 115.6 (t, —CH=CH2), 116.6 (d, C-3), 134.1 (d, —CH=CH2), 134.2 (s, C-4), 171.3 (s, C-1); EI-HRMS (m/z): [M]+ calcd for C9H15NO+, 153.1154; found, 153.1146 (Δ = 5.2 ppm).

N-(4-Methyl-3-penten-1-yl)-3-butenamide (1h)

Method B; 83% yield; yellow oil; Rf = 0.37 (EtOAc/n-Hex = 1:1); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.52 (s, 3H, H-5′), 1.61 (s, 3H, H-5), 2.10 (q, J = 6.8 Hz, 2H, H-2), 2.90 (d, J = 6.8 Hz, 2H, —CH2CH=CH2), 3.11–3.17 (m, 2H, H-1), 4.97–5.00 (m, 1H, H-3), 5.08–5.13 (m, 2H, —CH=CH2), 5.78–5.89 (m, 1H, —CH=CH2), 6.16 (brs, 1H, −NH–CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.6 (q, C-5′), 25.5 (q, C-5), 27.8 (t, C-2), 39.1 (t, —CH2CH=CH2), 41.4 (t, C-1), 119.1 (t, —CH=CH2), 120.5 (d, C-3), 131.4 (d, —CH=CH2), 134.1 (s, C-4), 170.4 (s, −CONH−); EI-HRMS (m/z): [M]+ calcd for C10H17NO+, 167.1310; found, 167.1320 (Δ = 6.0 ppm).

N-(3-Buten-1-yl)-4-methyl-3-pentenamide (1i)

Method B; 80% yield; yellow oil; Rf = 0.12 (EtOAc/n-Hex = 1:2); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.50 (s, 3H, H-5′), 1.63 (s, 3H, H-5), 2.11–2.12 (m, 2H, —CH2CH=CH2), 2.81 (m, 2H, H-2), 3.15–3.18 (m, 2H, −NH–CH2), 4.91–4.95 (m, 2H, —CH=CH2), 5.15–5.16 (m, 1H, H-3), 5.59–5.70 (m, 1H, —CH=CH2), 6.16 (brs, 1H, -NH-CH2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.5 (q, C-5′), 25.3 (q, C-5), 33.4 (t, —CH2CH=CH2), 35.6 (t, C-2), 38.0 (t, −NH–CH2), 116.6 (t, —CH=CH2), 116.7 (d, C-3), 135.0 (d, —CH=CH2), 135.2 (s, C-4), 171.3 (s, C-1); EI-HRMS (m/z): [M]+ calcd for C10H17NO+, 167.1310; found, 167.1313 (Δ = 1.8 ppm).

General Procedure for the Domino Double Cyclization

Rh(acac)(CO)2 (1.3 mg, 5.0 μmol, 0.5 mol %) and BIPHEPHOS (7.9 mg, 10 μmol, 1.0 mol %) were dissolved in AcOH (1 mL) under argon. The resulting catalyst solution was degassed by a frozen–thawed procedure at least three times. Amide (1a, 167 mg, 1.0 mmol, 1.0 equiv) and pTSA (17 mg, 0.1 mmol, 10 mol %) were placed in a 50 mL flask. The catalyst solution was transferred to the reaction flask containing the substrate by a pipette, and the total volume was adjusted to 20 mL with AcOH. The reaction flask was placed in a 300 mL stainless steel autoclave and then was pressurized with CO (2 atm) followed by H2 (2 atm). The reaction mixture was stirred at 60 °C for 16–20 h. Upon completion of the reaction, the gas was carefully released in a good ventilated hood, and the reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was partitioned with CH2Cl2 (20 mL) and NaHCO3(aq) (saturated, 10 mL). After separation of the organic layer, the aqueous layer was extracted with CH2Cl2 (15 mL ×5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica gel using MeOH/CH2Cl2 or EtOAc/n-hexane as the eluant to give the product.

8-(Propen-2-yl)-5-oxoindolizidine (6a)

82% yield (cis/trans = 3: 2); yellow oil; Rf = 0.24 (MeOH/CH2Cl2 = 1:20); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.34–1.39 (m, 1H, trans H-1), 1.71–1.81 (m, 12H, trans H-2 ×2, cis H-6 ×2, trans H-7 ×2, cis H-11 ×3, and trans H-11 ×3), 1.84–2.09 (m, 6H, trans H-1, cis H-2 ×2, cis H-7 ×2, and trans H-8), 2.31–2.43 (m, 3H, cis H-1 ×2 and trans H-6), 2.48–2.52 (m, 1H, trans H-6), 2.59 (q, J = 4.8 Hz, 1H, cis H-8), 3.33 (ddd, J = 4.8, 10.2, 10.2 Hz, 1H, trans H-8a), 3.44–3.60 (m, 4H, cis H-3 ×2 and trans H-3 ×2), 3.66 (ddd, J = 6.0, 6.0, 10.8, Hz, 1H, cis H-8a), 4.57–4.89 (m, 4H, cis H-10 ×2 and trans H-10 ×2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 20.0 (q, trans C-11), 21.6 (t, trans C-2), 21.9 (t, cis C-2), 23.6 (q, cis C-11), 24.8 (t, cis C-7), 27.2 (t, trans C-7), 28.3 (t, cis C-6), 29.1 (t, cis C-1), 31.3 (t, trans C-6), 32.3 (t, trans C-1), 41.0 (d, cis C-8), 44.7 (t, cis C-3), 45.2 (t, trans C-3), 48.4 (d, trans C-8), 60.5 (d, cis C-8a), 61.8 (d, trans C-8a), 112.1 (t, trans C-10), 113.0 (t, cis C-10), 143.1 (s, cis C-9), 145.0 (s, trans C-9), 168.7 (s, trans C-5), 169.3 (s, cis C-5); EI-HRMS (m/z): [M]+ calcd for C11H17NO+, 179.1310; found, 179.1315 (Δ = 2.9 ppm).

trans-9-(Propen-2-yl)-4-oxoquinolizidine (6b)

75% yield; light yellow oil; Rf = 0.31 (MeOH/CH2Cl2 = 1:30); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.39–1.54 (m, 4H, H-1, H-2, H-7 and H-8), 1.63–1.71 (m, 6H, H-2, H-7, H-8 and H-12 ×3), 1.82–1.83 (m, 1H, H-1), 1.94 (t, J = 10.2 Hz, 1H, H-9), 2.22–2.27 (m, 1H, H-3), 2.32–2.36 (m, 2H, H-3 and H-6), 3.12–3.16 (m, 1H, H-9a), 4.72–4.77 (m, 3H, H-11 ×2 and H-6). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 18.5 (t, C-2), 19.1 (q, C-12), 24.9 (t, C-7), 27.1 (t, C-1), 30.8 (t, C-8), 32.8 (t, C-3), 42.5 (t, C-6), 51.6 (d, C-9), 58.8 (d, C-9a), 112.5 (t, C-11), 145.9 (s, C-10), 169.4 (s, C-4); EI-HRMS (m/z): [M]+ calcd for C12H19NO+, 193.1467; found, 193.1469 (Δ = 1.0 ppm).

9-(Propen-2-yl)-6-oxoquinolizidine (6c)

63% yield (cis/trans = 3:2); yellow oil; Rf = 0.27 (MeOH/CH2Cl2 = 1:30); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.17–1.26 (m, 2H, trans H-1 and cis H-1), 1.32–1.51 (m, 6H, cis H-1, trans H-2, trans H-3 ×2, and cis H-8 ×2), 1.60–1.76 (m, 9H, cis H-2, cis H-3 ×2, cis H-12 ×3, and trans H-12 ×3), 1.80–1.95 (m, 5H, trans H-1, cis H-2, trans H-2 and trans H-8 ×2), 2.12–2.17 (m, 1H, trans H-9), 2.29–2.41 (m, 2H, cis H-4 and trans H-7), 2.43–2.52 (m, 5H, trans H-4, cis H-7 ×2, trans H-7 and cis H-9), 3.06 (ddd, J = 2.4, 11.4, 11.4 Hz, 1H, trans H-9a), 3.44 (dd, J = 5.4, 11.4 Hz, 1H, cis H-9a), 4.41–4.90 (m, 6H, cis H-4, trans H-4, cis H-11 ×2, and trans H-11 ×2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 19.6 (q, trans C-12), 21.2 (t, cis C-2), 22.3 (q, cis C-12), 24.2 (t, trans C-2), 24.9 (t, cis C-3), 25.05 (t, trans C-8), 25.13 (t, cis C-8), 25.5 (t, trans C-3), 26.8 (t, cis C-1), 32.0 (t, trans C-7), 32.3 (t, cis C-7), 32.5 (t, trans C-1), 42.4 (d, cis C-4), 43.4 (t, cis C-9), 44.6 (t, trans C-4), 49.1 (d, trans C-9), 59.0 (d, cis C-9a), 59.2 (d, trans C-9a), 111.8 (t, cis C-11), 112.9 (t, trans C-11), 144.0 (s, cis C-10), 145.0 (s, trans C-10), 168.1 (s, cis C-6), 168.8 (s, trans C-6); EI-HRMS (m/z): [M]+ calcd for C12H19NO+, 193.1467; found, 193.1468 (Δ = 0.5 ppm).

trans-9-(Propen-2-yl)-hexahydropyrrolo[1,2-a]azepin-5-one (6d)

78% yield; yellow oil; Rf = 0.33 (MeOH/CH2Cl2 = 1:25); 1H NMR (600 MHz, 25 °C, C6D6, δ): 1.14–1.23 (m, 2H, H-1 and H-2), 1.24–1.31 (m, 2H, H-2 and H-7), 1.34 (s, 3H, H-12 ×3), 1.37–1.54 (m, 4H, H-1, H-7 and H-8 ×2), 1.68 (ddd, J = 3.0, 9.6, 12.0 Hz, 1H, H-9), 2.04 (t, J = 12.6 Hz, 1H, H-6), 2.57 (dd, J = 7.2, 13.8 Hz, 1H, H-6), 3.12 (q, J = 7.2 Hz, 1H, H-9a), 3.28 (ddd, J = 6.6, 6.6, 11.4 Hz, 1H, H-3), 3.73 (ddd, J = 6.0, 6.0, 12.0 Hz, 1H, H-3), 4.50–4.59 (m, 2H, H-11 ×2). 13C NMR (100 MHz, 25 °C, C6D6, δ): 19.2 (q, C-12), 22.9 (t, C-2), 23.3 (t, C-7), 32.1 (t, C-8), 36.4 (t, C-1), 37.9 (t, C-6), 47.1 (t, C-3), 52.7 (d, C-9), 60.1 (d, C-9a), 112.2 (t, C-11), 147.7 (s, C-10), 172.9 (s, C-5); EI-HRMS (m/z): [M]+ calcd for C12H19NO+, 193.1467; found, 193.1460 (Δ = 3.6 ppm).

8-(Propen-2-yl)-4-oxoindolizidine (6h)

27% yield (cis/trans = 5:2); light yellow oil; Rf = 0.22 (MeOH/CH2Cl2 = 1:30); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.09–1.16 (m, 1H, trans H-1), 1.22–1.29 (m, 1H, cis H-1), 1.60–1.73 (m, 7H, trans H-1, cis H-11 ×3, and trans H-11 ×3), 1.80–1.90 (m, 7H, cis H-1, cis H-2 ×2, trans H-2 ×2, and cis H-7 ×2), 1.96–2.03 (m, 2H, trans H-7 ×2), 2.14–2.25 (m, 2H, cis H-3 and trans H-8), 2.34–2.41 (m, 3H, cis H-3 and trans H-3 ×2), 2.79 (t, J = 6.6 Hz, 1H, cis H-8), 3.23 (ddd, J = 3.0, 10.2, 10.2 Hz, 1H, trans H-8a), 3.35–3.39 (m, 1H, cis H-6), 3.48 (q, J = 11.4, Hz, 1H, trans H-6), 3.52–3.57 (m, 2H, trans H-6 and H-8a) 3.72 (q, J = 9.0, Hz, 1H, cis H-6), 4.59–4.77 (m, 2H, cis H-10 ×2), 4.81 (s, 2H, trans H-10 ×2). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 20.0 (q, trans t-11), 20.8 (2C, t, cis C-2 and trans C-2), 22.0 (q, cis C-11), 25.2 (t, cis C-1), 27.2 (t, cis C-7), 27.7 (t, trans C-7), 28.0 (t, trans C-1), 30.9 (2C, t, cis C-3 and trans C-3), 44.0 (t, trans C-6), 44.3 (d, cis C-6), 48.7 (t, cis C-8), 53.3 (d, trans C-8), 61.2 (d, cis C-8a), 61.4 (d, trans C-8a), 112.3 (t, trans C-10), 112.9 (t, cis C-10), 142.6 (s, trans C-9), 144.6 (s, cis C-9), 168.9 (s, cis C-4), 169.2 (s, trans C-4); EI-HRMS (m/z): [M]+ calcd for C11H17NO+, 179.1310; found, 179.1311 (Δ = 0.6 ppm).

General Procedure of the Oxidative Cleavage

To the mixed solution of acetone (16.5 mL) and water (1.5 mL) of the alkene substrate (6a, 323 mg, 1.80 mmol, 1.0 equiv) under argon was added 2,6-dimethylpyridine (0.42 mL, 3.60 mmol, 2.0 equiv), N-methylmorpholine oxide (50%, 0.6 mL, 2.70 mmol, 1.5 equiv), and OsO4 (2.3 mg, 0.009 mmol, 0.5 mol %). The solution was allowed to be stirred overnight (∼20 h) at 40 °C. The reaction was monitored by TLC in which the Rf value of the starting material alkene is about 0.24 (MeOH/CH2Cl2 = 1:20), while the Rf value of the product diol is about 0.10 in the same eluent. Upon completion of the reaction, PhI(OAc)2 (DAIB, 870 mg, 2.7 mmol, 1.5 equiv) was added and stirred overnight (∼20 h) at 60 °C. TLC analysis was used to follow the reaction. After evaporating the volatiles, the resulting reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated Na2S2O4 solution (30 mL). The aqueous layer was extracted with dichloromethane (20 mL ×3). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a crude product. Purification of the crude product by flash chromatography on silica gel using ethyl acetate and n-hexane as the eluant gave the two titled products.

trans-8-Acetyl-5-oxoindolizidine (trans-7a)

44% yield; yellow oil; Rf = 0.37 (MeOH/CH2Cl2 = 1:20); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.29–1.38 (m, 1H, H-1), 1.71–1.79 (m, 2H, H-2, and H-7), 1.90–1.98 (m, 1H, H-2), 2.08–2.12 (m, 1H, H-7), 2.15–2.18 (m, 1H, H-1), 2.22 (s, 3H, H-10 ×3), 2.35–2.46 (m, 2H, H-6 and H-8), 2.53 (dd, J = 6.6, 18.6 Hz, 1H, H-6), 3.44 (t, J = 10.2 Hz, 1H, H-3), 3.50–3.58 (m, 2H, H-3 and H-8a). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 22.0 (t, C-2), 24.9 (t, C-7), 29.4 (q, C-10), 30.7 (t, C-6), 32.0 (t, C-1), 44.7 (t, C-3), 53.1 (d, C-8), 59.5 (d, C-8a), 167.8 (s, C-5), 208.3 (s, C-9); EI-HRMS (m/z): [M]+ calcd for C10H15NO2+, 181.1103; found, 181.1100 (Δ = 1.7 ppm).

cis-8-Acetyl-5-oxoindolizidine (cis-7a)

37% yield; yellow oil; Rf = 0.33 (MeOH/CH2Cl2 = 1:20); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.64–1.78 (m, 2H, H-1 and H-2), 1.85–2.01 (m, 3H, H-1, H-2, and H-7), 2.04–2.11 (m, 1H, H-7), 2.15 (s, 3H, H-10 ×3), 2.22–2.37 (m, 2H, H-6 ×2), 3.10 (q, J = 4.8, Hz, 1H, H-8), 3.41–3.44 (m, 1H, H-3), 3.49–3.54 (m, 1H, H-3), 3.59 (ddd, J = 5.4, 5.4, 10.2 Hz, 1H, H-8a). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 22.1 (t, C-2), 23.3 (t, C-7), 28.1 (t, C-6), 28.8 (t, C-1), 30.7 (q, C-10), 44.8 (t, C-3), 46.0 (d, C-8), 58.9 (d, C-8a), 168.2 (s, C-5), 207.9 (s, C-9); EI-HRMS (m/z): [M]+ calcd for C10H15NO2+, 181.1103; found, 181.1104 (Δ = 0.6 ppm).

trans-9-Acetyl-4-oxoquinolizidine (trans-7b)40

86% yield; yellow oil; Rf = 0.33 (MeOH/CH2Cl2 = 1:25); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.35–1.51 (m, 3H, H-1, H-7 and H-8), 1.59–1.67 (m, 1H, H-2), 1.73–1.79 (m, 2H, H-2 and H-7), 1.98–2.03 (m, 2H, H-1 and H-8), 2.18 (s, 3H, H-11 ×3), 2.26–2.32 (m, 1H, H-3), 2.37–2.42 (m, 2H, H-3 and H-6), 2.48 (ddd, J = 4.2, 11.4, 11.4 Hz, 1H, H-9), 3.50 (ddd, J = 6.0, 9.0, 9.0 Hz, 1H, H-9a), 4.80–4.83 (m, 1H, H-6). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 18.6 (t, C-2), 24.1 (t, C-7), 27.7 (t, C-1), 28.4 (t, C-8), 30.2 (q, C-11), 32.6 (t, C-3), 41.8 (t, C-6), 56.2 (d, C-9), 57.0 (d, C-9a), 169.4 (s, C-4), 210.0 (s, C-10); EI-HRMS (m/z): [M]+ calcd for C11H17NO2+, 195.1259; found, 195.1263 (Δ = 2.0 ppm).

trans-8-Acetyl-5-oxoindolizidine Tosylhydrazone (trans-8a, CCDC No. 1920287)

To the methanol solution (4 mL) of methylketone trans-7a (197 mg, 1.09 mmol, 1.0 equiv) under argon was added tosylhydrazide (223 mg, 1.19 mmol, 1.1 equiv). The solution was allowed to be stirred under reflux for 1 h. The reaction was monitored by TLC in which the Rf value of the product is about 0.13 (pure EtOAc). Upon completion of the reaction, the reaction mixture was allowed to stand to cool slowly down to room temperature. A large quantity of white crystals separate during that time. The resulting white crystal was isolated by carefully washing with cold methanol and dried under vacuum for X-ray analysis (127 mg, 0.36 mmol, 33%): mp 236–238 °C; Rf = 0.13 (pure EtOAc); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 1.07–1.26 (m, 1H), 1.49–1.71 (m, 2H), 1.71–1.80 (m, 1H), 1.82 (s, 3H), 1.92 (m, 1H), 2.02–2.20 (m, 1H), 2.20–2.41 (m, 2H), 2.43 (s, 3H), 2.46–2.61 (m, 1H), 3.46–3.38 (m, 2H), 3.48–3.68 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 8.02 (brs, 1H, NH); 13C NMR (100 MHz, 25 °C, CDCl3, δ): 15.3 (q), 21.6 (q), 22.0 (t), 26.1 (t), 31.0 (t), 31.9 (t), 45.2 (t), 48.7 (d), 60.6 (d), 128.0 (d), 129.4 (d), 135.3 (s), 144.1 (s), 156.2 (s), 168.4 (s).

1-(trans-Quinolizidin-1-yl)-1-ethanol (trans-9b)

To a reaction flask containing a mixture of LiAlH4 (858 mg, 22.6 mmol, 5.0 equiv) and triethylamine hydrochloride (3.11 g, 22.6 mmol, 5.0 equiv) in an ice bath was added THF (30 mL). The solution was allowed to be stirred for about 15 min in an ice bath until vigorous bubbling has ceased. To the reagent was added a THF solution (15 mL) of lactam trans-7b (883 mg 4.52 mmol, 1.0 equiv) via a cannula. The reaction mixture was allowed to be stirred at room temperature for 16 h. Upon the reaction completed, the reaction mixture was cooled in an ice bath, and then was quenched by slow addition of water (4.5 mL), aqueous sodium hydroxide solution (15%, 4.5 mL), and water (4.5 mL). White precipitates were filtered off by a short Celite pad. The resulting filtrate was concentrated under reduced pressure to give a crude product. Purification of the crude product by flash chromatography on Chromatorex N-H typed silica gel using ethyl acetate/n-hexane as the eluant afforded the titled product as a light yellow oil (614 mg, 3.35 mmol, 74%): Rf = 0.37 (EtOAc/n-Hex = 1:1); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.06–1.27 (m, 7H), 1.51–1.65 (m, 4H), 1.69–1.77 (m, 3H), 1.81–1.87 (m, 1H), 1.97–2.06 (m, 3H), 2.74–2.82 (m, 2H), 4.06–4.13 (m, 1H). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 17.0 (q), 21.2 (q), 22.3 (t), 22.6 (t), 24.5 (t), 24.6 (t), 24.8 (t), 24.9 (t), 25.2 (t), 25.4 (t), 29.0 (t), 29.1 (t), 47.1 (d), 47.7 (d), 56.4 (t), 56.6 (t), 56.8 (t), 57.0 (t), 63.9 (d), 64.7 (d), 66.2 (d), 66.5 (d); EI-HRMS (m/z): [M]+ calcd for C11H21NO+, 183.1623; found, 183.1621 (Δ = 1.1 ppm).

trans-9-Acetylquinolizidine (trans-10b)

To a CH2Cl2 solution (4 mL) of alcohol trans-8b (34 mg, 0.185 mmol, 1.0 equiv) in an ice bath under argon was added Dess–Martin reagent (86.5 mg, 0.204 mmol, 1.1 equiv) in three portions. The ice bath was removed, and the reaction mixture was allowed to be stirred at room temperature for 4 h. Upon completion of the reaction monitored by TLC analysis, the reaction was quenched with saturated NaHCO3 solution (15 mL). After filtration with a short Celite pad and separation of the organic layer, the aqueous layer was extracted with CH2Cl2 (10 mL ×4) again. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography on Chromatorex N-H typed silica gel using ethyl acetate/n-hexane as the eluant afforded the titled product as a light yellow oil (29 mg, 0.16 mmol, 86%): Rf = 0.37 (EtOAc/n-Hex = 1:5); 1H NMR (600 MHz, 25 °C, CDCl3, δ): 1.12–1.18 (m, 1H, H-1), 1.22–1.36 (m, 2H, H-2 and H-8), 1.53–1.61 (m, 3H, H-1 and H-3 ×2), 1.64–1.72 (m, 3H, H-2 and H-7 ×2), 1.83–1.87 (m, 1H, H-8), 2.00–2.08 (m, 3H, H-4, H-6 and H-9a), 2.14 (s, 3H, H-11), 2.44 (ddd, J = 3.6, 10.2, 13.2 Hz, 1H, H-9), 2.76–2.83 (m, 2H, H-4 and H-6). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 24.2 (t, C-2), 24.7 (t, C-7), 25.6 (t, C-3), 28.4 (t, C-8), 30.4 (q, C-11), 30.7 (t, C-1), 55.9 (t, C-6), 56.3 (d, C-9), 56.5 (t, C-4), 63.2 (d, C-9a), 211.6 (s, C-10); EI-HRMS (m/z): [M]+ calcd for C11H19NO+, 181.1467; found, 181.1477 (Δ = 5.5 ppm).

Epi-Epiquinamide (12b)

To a mixture of ketone trans-10b (179 mg, 0.987 mmol, 1.0 equiv) and hydroxylamine (0.36 mL, 5.92 mmol, 6.0 equiv) in in a 50 mL single-necked round-bottom flask was added benzene (14 mL) and EtOH (6 mL). The flask was equipped with a Dean-Stark trapper and a condenser, and the reaction mixture was allowed to be refluxed overnight (∼18 h) under argon to remove water. Upon completion of the reaction monitored by TLC analysis, in which the Rf value of the starting material ketone was 0.24 (EtOAc/n-Hex = 1:5), the reaction mixture was concentrated under vacuum to afford light yellow oil crude product oxime. The product was used directly without further purification. To a DMF solution (1 mL) was added cyanuric chloride (182 mg, 0.987 mmol, 1.0 equiv). After being stirred at room temperature for 30 min, the solution was slowly added with the crude oxime solution in DMF (10 mL) by a cannula. The reaction mixture was allowed to be stirred under reflux overnight. Upon completion of the reaction monitored by TLC analysis, water (2.0 mL) and saturated Na2CO3 solution (1.5 mL) were slowly added into the reaction mixture. After separation of the organic layer, the aqueous layer was extracted with CH2Cl2 (10 mL ×3). The combined organic dried over Na2SO4. After removal of the solid dehydrating agent, the organic layer was concentrated under reduced pressure to give a crude product. Purification of the crude product by flash chromatography on silica gel EtOAc/n-Hex as the eluant gave the titled product as a light yellow solid (124 mg, 0.632 mmol, 64%, cis/trans = 1:3): mp 158–162 °C; Rf = 0.14 (EtOAc/ n-Hex = 1:1); 1H NMR (400 MHz, 25 °C, CDCl3, δ): 0.83–1.01 (m, 1H), 1.05–1.25 (m, 3H), 1.49–1.83 (m, 7H), 1.92–2.03 (m, 5H), 2.16–2.17 (m, 0.5H), 2.73–2.87 (m, 2H), 3.65–3.74 (m, 0.5H), 5.35 (brs, 0.5H), 5.86 (brs, 0.5H). 13C NMR (100 MHz, 25 °C, CDCl3, δ): 11.4 (q), 23.4 (q), 23.8 (t), 24.27 (t), 24.33 (t), 24.7 (t), 25.37 (t), 25.44 (t), 28.8 (t), 29.1 (t), 30.3 (t), 31.9 (t), 48.7 (d), 51.0 (d), 55.6 (t), 56.2 (t), 56.3 (t), 56.6 (t), 64.1 (d), 67.3 (d), 169.5*2 (s); EI-HRMS (m/z): [M]+ calcd for C11H20N2O+, 196.1576; found, 196.1574 (Δ = 1.0 ppm).

Acknowledgments

The authors would like to thank the Ministry of Science and Technology, Taiwan, R.O.C. (MOST 104-2113-M-005-004 and MOST 105-2113-M-005-002) and National Chung Hsing University for their long-term support on the research.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b04400.

  • Details of the experimental procedures for preparation of amide substrate 1a–1i and tosylhydrazone derivative trans-8a and 1H and 13C NMR spectra of all compounds (PDF)

    X-ray crystallographic data of 8a (CCDC no. 1920287) (CIF)

The authors declare no competing financial interest.

Supplementary Material

ao9b04400_si_001.pdf (7.5MB, pdf)
ao9b04400_si_002.cif (139KB, cif)

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