Rapid synthesis of highly functionalised α-amino amides and medium ring lactones using multicomponent reactions of amino alcohols and isocyanides

Abstract

Four-component reactions between amino alcohols, aldehydes, isocyanides and thiols proceed rapidly under microwave or conventional heating at 60 °C in methanol. The reaction is successful with a wide range of components and gives access to potentially drug-like products containing amine, amide and thioether functionality in moderate to excellent yield. The reaction conditions are also applicable to the synthesis of a range of 8–10 membered medium ring lactonesvia three-component reactions of amino alcohols, isocyanides and acid-aldehydes. Incorporation of L-prolinol as the amino alcohol component in each case gives access to multicomponent products with moderate to high diastereoselectivity.

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Introduction

Multicomponent reactions (MCRs)—reactions in which three or more reagents are combined to give a single product—enable the efficient synthesis of complex molecular structures in a single step.¹ Reactions of this type which provide access to drug-like structures containing appropriate H-bond donors and acceptors are particularly valuable, as libraries of potentially bioactive compounds can be quickly synthesized. Isocyanides are widely used components in such reactions, as they typically lead to the formation of an amide or aromatic heterocycle in the resulting product.

The Ugi reaction,² the 4-component reaction (4-CR) between an amine, aldehyde, isocyanide and carboxylic acid, is of particular note, as it can provide access to large numbers of diverse amino acid amides from readily available starting materials. Acetals can potentially act as an alternative to the carbonyl component in an Ugi-type MCR, leading to more complex product skeletons and a greater scope for structural diversity (Scheme 1).^3–6 In the case of an Ugi (or related) reaction, addition of the isocyanide to the C=X bond leads to a molecule containing nucleophilic (XH) and electrophilic (nitrilium cation) sites in a 1,3 relationship (a), which then go on to react with the other components to generate the MCR product. By replacement of the C=X multiple bond with an acetal (b), a spacer is inserted between the nucleophilic (YH) and electrophilic (nitrilium cation) sites in the resulting adduct, providing an opportunity for greater diversity in the resulting MCR product.

Scheme 1 Replacement of a carbonyl derivative (a) with an acetal (b) to give a novel Ugi-like isocyanide MCR.

We have recently reported that 1,3-oxazolidines 1 (simple N,O-acetals derived from ethanolamines) readily undergo 3-CRs with isocyanides and carboxylic acids to give N-acyloxyethylamino acid amides 3, via the cyclic imino ester intermediate 2 (Scheme 2).^4,5

Scheme 2 3-CRs of 1,3-oxazolidines.

We also demonstrated that the carboxylic acid component could be replaced by thiophenol, thiobenzoic acid or 4-phenyltetrazole, providing access to different 3-CR products 4via nucleophilic ring-opening of intermediate 2.⁷ The yields for these latter 3-CRs with sulfur nucleophiles were low, and therefore only limited examples were explored. Given the fact that a large number of functionalised thiols are commercially available, we recognized that this reaction could be potentially valuable. We therefore sought to develop improved conditions for the reaction with a view to developing a more robust method applicable to 4-CRs, which could then be applied to a wide range of aldehydes, isocyanides, amino alcohols and thiols.

Results and discussion

4-CR of amino alcohols, aldehydes, isocyanides and thiols

As a representative reaction, we chose to optimise the 4-CR leading to amide 9a (Scheme 3). Our previous 3-CRs of pre-formed oxazolidines were carried out in MeCN in the presence of catalytic quantities of TsOH, but these conditions gave only a moderate yield of the product from a 4-CR. We subsequently found that MeOH was a superior solvent for this reaction, and that the acid catalyst was unnecessary. Although the reaction did proceed at room temperature, it was somewhat sluggish. However, heating the reaction at 60 °C for 20 min under microwave irradiation led to the formation of 4-CR product 9a in 81% isolated yield.

Scheme 3 ^a TsOH, MeCN, reflux, 24 h (NMR yield). ^b Yield of 4-CR under conventional heating (60 °C, MeOH, 20 min). ^c Yield obtained under 3-CR conditions from the corresponding 1,3-oxazolidine (TsOH, MeCN, reflux, 24 h).⁵

These optimized reaction conditions were then applied to a wide range of isocyanides, aldehydes, thiols and amino alcohols (Scheme 3). The yields of this new 4-CR were superior to those we employed previously in the corresponding 3-CR (9b)⁵ and could be applied to a range of aldehydes, including both aliphatic systems (e.g.9a, 9b, 9f) and functionalised aryl aldehydes (e.g.9g, 9h). Several different isocyanides could be employed, enabling the nitrogen substituent on the amide to be varied (e.g.9a, 9c, 9d). A variety of commercially available aromatic thiols, including those bearing bromide (9k), methoxy (9j) and acetamide substituents (9i) gave multicomponent products in good yield. 2-Pyridyl thiol could also be employed providing access to MCR products containing heteroaromatic rings, albeit in lower yield (9l and 9m). In terms of the amino alcohol component, a variety of N-substituted ethanolamines could be used (e.g.9a, 9o, 9p). The scaffold of the MCR products could also be extended by incorporating an N-substituted 1,3-propanolamine as one of the components (e.g.9q, 9r), with good yields of the homologous MCR products being obtained. Unsubstituted ethanolamine could also be used, although this gave the corresponding secondary amine product 9n in low yield. Although the reactions were typically carried out under microwave heating, an equally high yield was obtained for one example under thermal conditions (9a).

3-CR of acid-aldehydes, amino alcohols and isocyanides to give medium ring lactones

In our previous report,⁵ we also carried out a brief examination of the 3-CR of an acid-aldehyde,⁸amino alcohol and isocyanide to give medium ring lactone products (Scheme 4). Under our original conditions (TsOH, ⁱPrOH), prolonged reaction times were required and only moderate yields of the MCR products were obtained. Pleasingly under our new microwave conditions this reaction was also successful, giving rapid access to a wide range of medium ring lactone products in moderate to excellent yield. Structural variation of the amino alcohol and/or the acid-aldehyde components enabled a variety of eight- (10a–10c), nine- (10d–10f) and ten-membered (10g, 10h) lactones to be accessed. A bis-secondary amine component⁶ could also be used to synthesise an eight-membered lactam (10i). The synthesis of medium rings is often difficult due to the unfavourable thermodynamics of the ring closing process.⁹ These reactions are therefore potentially valuable as they offer an efficient one-step route to densely functionalised medium ring systems from readily available starting materials.

Scheme 4 3-CRs of acid-aldehydes, amino alcohols and isocyanides to give medium ring lactones.

We also examined the use of L-prolinol as a chiral amino alcohol component in both of these MCRs (Fig. 1).¹⁰ Interestingly, the 4-CR products 11a–11c were obtained as single diastereoisomers in good yield.¹¹ In contrast, the 3-CR of L-prolinol with an acid-aldehyde and an isocyanide led to the diastereomeric eight-membered lactones 12 in a 1.5 : 1 ratio. Pleasingly, these lactones could be easily separated by chromatography and the relative stereochemistry of each isomer was then assigned using nOe experiments.¹²

Fig. 1 4-CR and 3-CR products obtained using L-prolinol.

Conclusions

In conclusion, we have developed a generally high yielding and rapid procedure for the 4-CR of amino alcohols, aldehydes, thiols and isocyanides to give arylthioalkylamino acid amides. The reaction conditions can also be applied to the synthesis of medium ring 3-CR products by reaction of an amino alcohol and isocyanide with a bifunctional acid-aldehyde. In addition, we have shown that diastereoselective MCRs can be achieved in some cases using L-prolinol as a chiral amino alcohol component. Further work is underway on the development of other novel MCRs which will be reported in due course.

Experimental section

All solvents and chemicals were used as obtained from commercial suppliers. Column chromatography was carried out using BDH (40–63 μm) silica gel and analytical thin layer chromatography was carried out using Merck Kieselgel aluminium-backed plates coated with silica gel. Components were visualised using combinations of ultra-violet light, phosphomolybdic acid and potassium permanganate. Melting points were determined using a Reichert hot-stage apparatus and are uncorrected. Optical rotations were measured using a Perkin-Elmer 343 polarimeter (sodium D-line, 529 nm) and α_D values are given in 10⁻¹ deg cm² g⁻¹, concentration (c) in g per 100 mL. Infrared (IR) spectra were recorded on a Perkin-Elmer spectrum 100 FT-IR spectrometer as thin films. ¹H and ¹³C NMR spectra were recorded respectively at 400 MHz and 100 MHz on a Bruker Avance 400 spectrometer or at 600 MHz and 150 MHz on a Bruker Avance 600 spectrometer in the stated solvent. Mass spectra were obtained using either a VG70-SE or MAT 900XP spectrometer at the Department of Chemistry, University College London.

General procedure for 4-CRs of amino alcohols, aldehydes, isocyanides and thiols

Aldehyde (1.0 mmol), isocyanide (1.0 mmol) and thiophenol (1.0 mmol) were added to a solution of amino alcohol (1.0 mmol) in methanol (1 ml). The mixture was stirred under microwave irradiation¹³ at 60 °C for 20 min. The solvent was evaporated and the crude product was purified by flash chromatography (petroleum ether/EtOAc 15 : 1 to 1 : 1) to afford the amide.

N-tert-Butyl-2-(methyl(2-(phenylthio)ethyl)amino)pentanamide (9a)

Colourless oil. 81% yield. ν_max/cm⁻¹ 3336 (NH), 2960, 2871 (CH), 1668 (CO), 1584, 1509, 1453 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.90 (3 H, t, J 7.3, CH₂CH₃), 1.29–1.35 (1 H, m, alkyl), 1.34 (9 H, s, tBu), 1.41–1.47 (1 H, m, alkyl), 1.49–1.54 (1 H, m, alkyl), 1.69–1.75 (1 H, m, alkyl), 2.25 (3 H, s, NCH₃), 2.76 (1 H, dt, J 13.4, 6.8, NCHH), 2.78 (1 H, dt, J 13.4, 6.5, NCHH), 2.87 (1 H, dd, J 7.0, 5.3, NCH), 3.04 (1 H, dt, J 12.8, 6.5, SCHH), 3.07 (1 H, dt, J 12.8, 6.8, SCHH), 7.18 (1 H, t, J 7.7, Ar), 7.20 (1 H, s, NH), 7.28 (2 H, app. t, J 7.7, Ar), 7.33 (2 H, dd, J 7.7, 1.2, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.4, 21.0, 28.9, 29.4, 32.9, 37.5, 50.6, 53.8, 68.6, 126.2, 129.1, 129.3, 136.5, 172.6; LRMS (CI) 323, 275, 222, 189; HRMS calcd for C₁₈H₃₁N₂OS [MH]⁺ 323.2157, found 323.2153.

N-(tert-Butyl)-2-(methyl(2-(phenylthio)ethyl)amino)octanamide (9b)⁵

Colourless oil. 78% yield. ν_max/cm⁻¹ 3335 (NH), 2957, 2927; 2856 (CH), 1661 (CO), 1585, 1509, 1453 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 0.87 (3 H, t, J 6.7, CH₂CH₃), 1.23–1.32 (7 H, m, alkyl), 1.35 (9 H, s, tBu), 1.37–1.47 (1 H, m, alkyl), 1.49–1.60 (1 H, m, alkyl), 1.69–1.81 (1 H, m, alkyl), 2.26 (3 H, s, NCH₃), 2.76 (1 H, dt, J 13.4, 7.0, NCHH), 2.80 (1 H, dt, J 13.4, 6.5, NCHH), 2.87 (1 H, dd, J 7.0, 5.8, NCH), 3.04 (1 H, dt, J 13.0, 6.5, SCHH), 3.08 (1 H, dt, J 13.0, 7.0, SCHH), 7.15–7.22 (2H, m, Ar, NH), 7.28 (2H, br t, J 8.0, Ar), 7.34 (2H, br d, J 8.0, Ar); δ_C (100 MHz; CDCl₃; Me₄Si) 14.1, 22.6, 27.2, 27.5, 28.8, 29.6, 31.7, 32.8, 37.4, 50.4, 53.8, 68.7, 126.1, 129.0, 129.2, 136.4, 172.4; LRMS (ES) 363, 279, 227; HRMS calcd for C₂₁H₃₅N₂OS [M−H]⁻ 363.2470, found 363.2470.

N-Cyclohexyl-2-(methyl(2-(phenylthio)ethyl)amino)pentanamide (9c)

Colourless oil. 81% yield. ν_max/cm⁻¹ 3314 (NH), 2929, 2853 (CH), 1641 (CO), 1584, 1509, 1450 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.89 (3 H, t, J 7.2, CH₂CH₃), 1.11–1.20 (3 H, m, cy), 1.28–1.38 (3 H, m, cy), 1.39–1.46 (1 H, m, alkyl), 1.50–1.60 (2 H, m, alkyl), 1.64–1.77 (3 H, m, alkyl), 1.81–1.87 (2 H, m, cy), 2.25 (3 H, s, NCH₃), 2.76 (1 H, dt, J 13.1, 6.8, NCHH), 2.78 (1 H, dt, J 13.1, 6.5, NCHH), 2.95 (1 H, t, J 6.4, NCHCO), 3.03 (1 H, dt, J 13.1, 6.5, SCHH), 3.06 (1 H, dt, J 13.1, 6.8, SCHH), 3.68–3.76 (1 H, m, NHCH), 7.18 (1 H, tt, J 7.7, 1.4, Ar), 7.21 (1 H, br d, J 7.8, NH), 7.27 (2 H, app. t, J 7.7, Ar), 7.32 (2 H, dd, J 7.7, 1.4, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.4, 20.8, 24.9, 25.7, 29.7, 32.9, 33.3, 37.6, 47.8, 53.9, 68.0, 126.3, 129.1, 129.4, 136.4, 172.3; LRMS (CI) 349, 239, 222, 137; HRMS calcd for C₂₀H₃₃N₂OS [MH]⁺ 349.2314, found 349.2326.

2-(Methyl(2-(phenylthio)ethyl)amino)-N-(2,4,4-trimethylpentan-2-yl)pentanamide (9d)

Colourless oil. 78% yield. ν_max/cm⁻¹ 3334 (NH), 2955, 2871 (CH), 1671 (CO), 1585, 1507, 1480 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.90 (3 H, t, J 7.2, CH₂CH₃), 1.00 (9 H, s, tBu), 1.28–1.37 (1 H, m, alkyl), 1.40 (6 H, s, 2 × CH₃), 1.42–1.52 (2 H, m, alkyl), 1.59 (1 H, d, J 14.9, CHHtBu), 1.72–1.80 (1 H, m, alkyl), 1.83 (1 H, d, J 14.9, CHHtBu), 2.24 (3 H, s, NCH₃), 2.78 (1 H, dt, J 13.2, 6.9, NCHH), 2.81 (1 H, dt, J 13.2, 6.4, NCHH), 2.87 (1 H, t, J 6.4, NCH), 3.03 (1 H, dt, J 12.8, 6.4, SCHH), 3.06 (1 H, dt, J 12.8, 6.9, SCHH), 7.17 (1 H, t, J 7.5, Ar), 7.27 (2 H, app. t, J 7.5, Ar), 7.31 (2 H, d, J 7.5, Ar), 7.33 (1 H, br s, NH); δ_C (150 MHz; CDCl₃; Me₄Si) 14.4, 21.4, 28.7, 28.9, 29.2, 31.7, 32.9, 37.6, 52.5, 54.0, 54.5, 68.5, 126.2, 129.1, 129.2, 136.5, 172.2; LRMS (CI) 379, 269, 222, 137; HRMS calcd for C₂₂H₃₉N₂OS [MH]⁺ 379.2783, found 379.2777.

2-(Methyl(2-(phenylthio)ethyl)amino)-N-pentylpentanamide (9e)

Colourless oil. 88% yield. ν_max/cm⁻¹ 3334 (NH), 2960, 2932, 2873 (CH), 1655 (CO), 1518, 1481, 1439 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 0.86 (3 H, t, J 6.9, CH₃), 0.88 (3 H, t, J 7.3, CH₃), 1.22–1.37 (5 H, m, alkyl), 1.37–1.58 (4 H, m, alkyl), 1.69–1.80 (1 H, m, alkyl), 2.24 (3 H, s, NCH₃), 2.76 (2 H, app. t, J 6.5, CH₂NMe), 2.96 (1 H, t, J 6.4, NCH), 3.02 (1 H, dt, J 13.1, 6.5, SCHH), 3.05 (1 H, dt, J 13.1, 6.5, SCHH), 3.10–3.26 (2 H, m, CH₂NH), 7.14 (1 H, t, J 7.5, Ar), 7.25 (2 H, app. t, J 7.5, Ar), 7.30 (2 H, d, J 7.5, Ar), 7.32 (1 H, br s, NH); δ_C (100 MHz; CDCl₃; Me₄Si) 14.0, 14.2, 20.7, 22.3, 29.2, 29.3, 29.5, 32.7, 37.6, 39.0, 53.8, 67.9, 126.0, 128.9, 129.0, 136.3, 173.0; LRMS (CI) 337, 222, 137; HRMS calcd for C₁₉H₃₃N₂OS [MH]⁺ 337.2314, found 337.2314.

2-(Methyl(2-(phenylthio)ethyl)amino)-4-phenyl-N-(2,4,4-trimethylpentan-2-yl)butanamide (9f)

Colourless oil. 69% yield. ν_max/cm⁻¹ 3338 (NH), 2950 (CH), 1672 (CO), 1584, 1507, 1454 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 1.02 (9 H, s, tBu), 1.42 (3 H, s, NCCH₃), 1.44 (3 H, s, NCCH₃), 1.60 (1 H, d, J 14.9, CHHtBu), 1.72–1.80 (1 H, m, CHHCH), 1.90 (1 H, d, J 14.9, CHHtBu), 2.10–2.18 (1 H, m, CHHCH), 2.25 (3 H, s, NCH₃), 2.64 (1 H, ddd, J 13.5, 9.8, 6.9, CHHPh), 2.71 (1 H, dt, J 12.9, 6.5, NCHH), 2.77 (1 H, dt, J 12.9, 6.5, NCHH), 2.85–3.00 (4 H, m, CHHPh, NCH, SCH₂), 7.15–7.21 (4 H, m, Ar), 7.24–7.31 (6 H, m, Ar), 7.31 (1 H, br s, NH); δ_C (150 MHz; CDCl₃; Me₄Si) 27.6, 28.8, 29.3, 31.7, 31.8, 32.7, 34.2, 37.6, 52.4, 54.7, 66.9, 126.0, 126.2, 128.5, 128.7, 129.1, 129.2, 136.4, 142.1, 171.9; LRMS (CI) 441, 331, 284; HRMS calcd for C₂₃H₃₂N₂OS [MH]⁺ 441.2940, found 441.2936.

2-(4-Bromophenyl)-N-cyclohexyl-2-(methyl(2-(phenylthio)ethyl)amino)acetamide (9g)

White solid. 47% yield. M.p. 114–115 °C (hexanes); ν_max/cm⁻¹ 3296 (NH), 2928, 2851 (CH), 1645 (CO), 1584, 1521, 1480 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 1.14–1.29 (3 H, m, cy), 1.30–1.44 (2 H, m, cy), 1.58–1.67 (1 H, m, cy), 1.67–1.78 (2 H, m, cy), 1.80–1.95 (2 H, m, cy), 2.20 (3 H, s, NCH₃), 2.66 (2 H, app. t, J 6.7, NCH₂), 3.06 (1 H, dt, J 13.2, 6.7, SCHH), 3.09 (1 H, dt, J 13.2, 6.7, SCHH), 3.70–3.82 (1 H, m, NHCH), 3.96 (1 H, s, NCHAr), 7.15 (2 H, d, J 8.3, Ar), 7.19–7.27 (2 H, m, Ar), 7.28–7.32 (4 H, m, Ar, NH), 7.44 (2 H, d, J 8.3, Ar); δ_C (100 MHz; CDCl₃; Me₄Si) 24.8, 25.5, 31.9, 33.0, 39.4, 47.8, 53.9, 74.4, 122.1, 126.2, 129.0, 129.2, 130.7, 131.5, 134.9, 136.1, 169.7; LRMS (CI) 463, 461, 352, 336; HRMS calcd for C₂₃H₃₀N₂OSBr [MH]⁺ 461.1262, found 461.1271.

N-Cyclohexyl-2-(methyl(2-(phenylthio)ethyl)amino)-2-(4-(trifluoromethyl)phenyl)acetamide (9h)

White solid. 25% yield. M.p. 97–98 °C (hexanes); ν_max/cm⁻¹ 3302 (NH), 2933, 2853 (CH), 1649 (CO), 1583, 1543, 1481 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 1.13–1.28 (3 H, m, cy), 1.28–1.40 (2 H, m, cy), 1.56–1.64 (1 H, m, cy), 1.66–1.75 (2 H, m, cy), 1.78–1.92 (2 H, m, cy), 2.18 (3 H, s, NCH₃), 2.64 (2 H, app. t, J 6.7, NCH₂), 3.06 (1 H, dt, J 13.3, 6.7, SCHH), 3.09 (1 H, dt, J 13.3, 6.7, SCHH), 3.70–3.78 (1 H, m, NHCH), 4.05 (1 H, s, NCHAr), 7.18 (1 H, tt, J 7.7, 1.5, Ar), 7.24–7.30 (4 H, m, Ar), 7.31 (1 H, br s, NH), 7.37 (2 H, d, J 7.7, Ar), 7.44 (2 H, d, J 7.7, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 24.9, 25.6, 32.0, 33.1, 39.4, 48.0, 54.0, 74.6, 124.2 (q, J 272), 125.4 (q, J 3.6), 126.4, 129.2, 129.3, 129.6, 130.2 (q, J 32.4), 136.1, 139.9, 169.6; LRMS (ES) 449, 339, 324, 189; HRMS calcd for C₂₄H₂₈N₂OSF₃ [M−H]⁻ 449.1874, found 449.1874.

2-((2-((4-Acetamidophenyl)thio)ethyl)(methyl)amino)-N-(tert-butyl)octanamide (9i)

Colourless oil. 72% yield. ν_max/cm⁻¹ 3307 (NH), 2958, 2928, 2857 (CH), 1651 (CO), 1593, 1521, 1493, 1454 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.84 (3 H, t, J 6.6, CH₂CH₃), 1.17–1.28 (7 H, m, alkyl), 1.33 (9 H, s, tBu), 1.29–1.40 (1 H, m, alkyl), 1.48–1.56 (1 H, m, alkyl), 1.67–1.75 (1 H, m, alkyl), 2.15 (3 H, s, CH₃CO), 2.22 (3 H, s, NCH₃), 2.72 (2 H, app. t, J 6.6, NCH₂), 2.83 (1 H, t, J 6.2, NCH), 2.97 (1 H, dt, J 12.9, 6.6, SCHH), 3.00 (1 H, dt, J 12.9, 6.6, SCHH), 7.24 (1 H, br s, NHtBu), 7.29 (2 H, d, J 8.3, Ar), 7.46 (2 H, d, J 8.3, Ar), 7.93 (1 H, br s, NHAc); δ_C (150 MHz; CDCl₃; Me₄Si) 14.2, 22.7, 24.6, 27.4, 27.6, 28.9, 29.7, 31.8, 33.8, 37.4, 50.6, 54.0, 68.9, 120.6, 130.9, 131.1, 137.0, 168.8, 172.8; LRMS (CI) 422, 366, 321, 255; HRMS calcd for C₂₃H₄₀N₃O₂S [MH]⁺ 422.2841, found 422.2833.

N-(tert-Butyl)-2-((2-((4-methoxyphenyl)thio)ethyl)(methyl)amino)octanamide (9j)

Colourless oil. 82% yield. ν_max/cm⁻¹ 3331 (NH), 2957, 2926, 2855 (CH), 1671 (CO), 1593, 1493, 1453 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 0.87 (3 H, t, J 6.7, CH₂CH₃), 1.24–1.32 (7 H, m, alkyl), 1.35 (9 H, s, tBu), 1.33–1.45 (1 H, m, alkyl), 1.48–1.58 (1 H, m, alkyl), 1.68–1.80 (1 H, m, alkyl), 2.24 (3 H, s, NCH₃), 2.72 (2 H, app. t, J 6.7, CH₂N), 2.86 (1 H, dd, J 7.0, 5.8, NCH), 2.93 (1 H, dt, J 13.0, 6.7, SCHH), 2.96 (1 H, dt, J 13.0, 6.7, SCHH), 3.80 (3 H, s, OCH₃), 6.85 (2 H, d, J 8.8, Ar), 7.24 (1 H, br s, NH), 7.35 (2 H, d, J 8.8, Ar); δ_C (100 MHz; CDCl₃; Me₄Si) 14.1, 22.6, 27.2, 27.5, 28.8, 29.6, 31.7, 34.9, 37.4, 50.4, 54.0, 55.3, 68.6, 114.7, 126.2, 133.3, 159.1, 172.5; LRMS (CI) 395, 229, 173, 105; HRMS calcd for C₂₂H₃₉N₂O₂S [MH]⁺ 395.2732, found 395.2727.

2-((2-((2-Bromophenyl)thio)ethyl)(methyl)amino)-N-(tert-butyl)octanamide (9k)

Colourless oil. 55% yield. ν_max/cm⁻¹ 3342 (NH), 2956, 2926, 2856 (CH), 1665 (CO), 1576, 1509, 1449 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 0.89 (3 H, t, J 6.8, CH₂CH₃), 1.24–1.35 (7 H, m, alkyl), 1.37 (9 H, s, tBu), 1.40–1.50 (1 H, m, alkyl), 1.51–1.63 (1 H, m, alkyl), 1.71–1.84 (1 H, m, alkyl), 2.30 (3 H, s, NCH₃), 2.85 (1 H, dt, J 13.0, 6.7, NCHH), 2.89 (1 H, dt, J 13.0, 6.3, NCHH), 2.92 (1 H, dd, J 7.2, 5.4, NCH), 3.07 (1 H, dt, J 12.4, 6.3, SCHH), 3.12 (1 H, dt, J 12.4, 6.7, SCHH), 7.05 (1 H, ddd, J 8.0, 6.4, 2.5, Ar), 7.12 (1 H, br s, NH), 7.26–7.30 (2 H, m, Ar), 7.56 (1 H, dd, J 8.0, 1.1, Ar); δ_C (100 MHz; CDCl₃; Me₄Si) 14.1, 22.6, 27.1, 27.6, 28.8, 29.6, 31.7, 31.9, 37.4, 50.5, 53.1, 68.7, 123.6, 126.6, 127.8, 128.0, 133.1, 138.1, 172.3; LRMS (CI) 445, 443, 344, 255; HRMS calcd for C₂₁H₃₆N₂OSBr [MH]⁺ 443.1732, found 443.1715.

N-(tert-Butyl)-2-(methyl(2-(pyridin-2-ylthio)ethyl)amino)octanamide (9l)

Colourless oil. 25% yield. ν_max/cm⁻¹ 3330 (NH), 2956, 2926, 2856 (CH), 1671 (CO), 1578, 1509, 1453, 1414 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.85 (3 H, t, J 6.8, CH₂CH₃), 1.21–1.29 (7 H, m, alkyl), 1.31 (9 H, s, tBu), 1.36–1.46 (1 H, m, alkyl), 1.53–1.61 (1 H, m, alkyl), 1.69–1.77 (1 H, m, alkyl), 2.28 (3 H, s, NCH₃), 2.79 (1 H, dt, J 13.3, 6.5, NCHH), 2.83 (1 H, dt, J 13.3, 6.8, NCHH), 2.89 (1 H, br t, J 5.4, NCH), 3.32 (1 H, dt, J 13.4, 6.5, SCHH), 3.35 (1 H, dt, J 13.4, 6.8, SCHH), 6.97 (1 H, dd, J 6.8, 5.0, Ar), 7.15 (1 H, d, J 8.0, Ar), 7.18 (1 H, br s, NH), 7.46 (1 H, app. td, J 8.0, 1.6, Ar), 8.40 (1 H, br d, J 5.0, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.2, 22.8, 27.4, 27.6, 28.6, 28.8, 29.7, 31.8, 37.7, 50.5, 54.1, 68.9, 119.5, 122.4, 136.0, 149.6, 158.8, 172.7; LRMS (CI) 366, 229, 173; HRMS calcd for C₂₀H₃₆N₃OS [MH]⁺ 366.2579, found 366.2564.

N-(tert-Butyl)-2-(methyl(2-(pyridin-2-ylthio)ethyl)amino)pentanamide (9m)

Colourless oil. 26% yield. ν_max/cm⁻¹ 3331 (NH), 2954, 2854 (CH), 1670 (CO), 1578, 1508, 1453, 1415 (Ar); δ_H (600 MHz, CDCl₃) 0.91 (3 H, t, J 7.3, CH₂CH₃), 1.31–1.36 (10 H, m, CH₃CHH, tBu), 1.44–1.47 (1 H, m, CH₃CHH), 1.52–1.57 (1 H, m, NCHCHH), 1.69–1.73 (1 H, m, NCHCHH), 2.29 (3 H, s, NCH₃), 2.78–2.84 (2 H, m, SCH₂), 2.90 (1 H, dd, J 7.2, 5.5, NCH), 3.34 (2 H, m, NCH₂), 6.97 (1 H, ddd, J 7.6, 4.8, 0.9, Ar), 7.16 (1 H, br d, J 7.8, Ar), 7.18 (1 H, br s, NH), 7.46 (1 H, ddd, J 7.8, 7.6, 1.8, Ar), 8.40 (1 H, br d, J 4.8, Ar); δ_C (150 MHz, CDCl₃) 14.5, 20.9, 28.6, 28.9, 29.5, 37.8, 50.5, 54.0, 68.6, 119.5, 122.4, 136.0, 149.6, 158.8, 172.7; LRMS (CI) 324, 223, 221, 213, 84; HRMS calcd for C₁₇H₃₀N₃OS [MH]⁺ 324.2110, found 324.2111.

N-(tert-Butyl)-2-((2-(phenylthio)ethyl)amino)pentanamide (9n)

Colourless oil. 18% yield. ν_max/cm⁻¹ 3314 (NH), 2960, 2931, 2872 (CH), 1652 (CO), 1584, 1517, 1453 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.90 (3 H, t, J 7.4, CH₂CH₃), 1.27–1.42 (2 H, m, alkyl), 1.31 (9 H, s, tBu), 1.44–1.52 (1 H, m, alkyl), 1.61–1.68 (1 H, m, alkyl), 1.77 (1 H, br s, NHtBu), 2.73 (1 H, ddd, J 12.4, 7.0, 5.6, NCHH), 2.81 (1 H, ddd, J 12.4, 6.6, 5.4, NCHH), 2.88 (1 H, dd, J 7.8, 4.8, NCH), 2.99 (1 H, ddd, J 13.1, 6.6, 5.6, SCHH), 3.05 (1 H, ddd, J 13.1, 7.0, 5.4, SCHH), 7.14 (1 H, br s, CHNH), 7.19 (1 H, t, J 7.7, Ar), 7.27 (2 H, app. t, J 7.7, Ar), 7.33 (2 H, d, J 7.7, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.1, 19.2, 28.8, 34.6, 36.0, 47.2, 50.4, 63.3, 126.5, 129.1, 129.7, 135.7, 173.5; LRMS (CI) 309, 208, 130; HRMS calcd for C₁₇H₂₉N₂OS [MH]⁺ 309.2001, found 309.2007.

N-(tert-Butyl)-2-(ethyl(2-(phenylthio)ethyl)amino)octanamide (9o)

White solid. 68% yield. M.p. 52–53 °C (ether); ν_max/cm⁻¹ 3334 (NH), 2961, 2926, 2854 (CH), 1674 (CO), 1585, 1508, 1453 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.85 (3 H, t, J 6.9, CH₂CH₂CH₃), 0.99 (3 H, t, J 7.1, NCH₂CH₃), 1.21–1.30 (7 H, m, alkyl), 1.32 (9 H, s, tBu), 1.41–1.50 (2 H, m, alkyl), 1.74–1.83 (1 H, m, alkyl), 2.49 (1 H, dq, J 13.2, 7.1, NCHHCH₃), 2.54 (1 H, dq, J 13.2, 7.1, NCHHCH₃), 2.78 (1 H, dt, J 13.5, 7.0, NCHH), 2.81 (1 H, dt, J 13.5, 6.8, NCHH), 2.97–3.05 (3 H, m, NCH, SCH₂), 7.16 (1 H, tt, J 6.9, 1.4, Ar), 7.24–7.28 (2 H, m, Ar), 7.29–7.32 (2 H, m, Ar), 7.36 (1 H, br s, NH); δ_C (150 MHz; CDCl₃; Me₄Si) 13.6, 14.2, 22.8, 26.6, 28.5, 28.9, 29.7, 31.8, 33.2, 44.4, 49.6, 50.5, 65.3, 126.2, 129.1, 129.2, 136.4, 173.3; LRMS (CI) 379, 243, 159, 143; HRMS calcd for C₂₂H₃₉N₂OS [MH]⁺ 379.2783, found 379.2779.

2-(Benzyl(2-(phenylthio)ethyl)amino)-N-(tert-butyl)octanamide (9p)

Colourless oil. 55% yield. ν_max/cm⁻¹ 3338 (NH), 2957, 2926, 2856 (CH), 1671 (CO), 1584, 1508, 1453 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 0.92 (3 H, t, J 6.8, CH₂CH₃), 1.26–1.36 (7 H, m, alkyl), 1.37 (9 H, s, tBu), 1.47–1.64 (2 H, m, alkyl), 1.82–1.94 (1 H, m, alkyl), 2.83–3.11 (5 H, m, NCH₂, SCH₂, NCH), 3.63 (1 H, d, J 13.8, ArCHH), 3.80 (1 H, d, J 13.8, ArCHH), 6.85 (1 H, br s, NH), 7.14–7.19 (1 H, m, Ar), 7.22–7.37 (9 H, m, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.3, 22.8, 25.9, 28.6, 28.9, 29.8, 31.9, 32.7, 49.3, 50.7, 55.3, 64.4, 126.1, 127.5, 128.6, 128.9, 129.0, 129.1, 136.4, 139.1, 172.7; LRMS (CI) 441, 363, 171; HRMS calcd for C₂₇H₄₁N₂OS [MH]⁺ 441.2940, found 441.2940.

2-(Butyl(3-(phenylthio)propyl)amino)-N-cyclohexyloctanamide (9q)

Colourless oil. 84% yield. ν_max/cm⁻¹ 3376 (NH), 2926, 2854 (CH), 1623 (CO), 1583, 1449, 1439 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.78 (3 H, t, J 7.3, CH₃), 0.87 (3 H, t, J 7.1, CH₃), 0.87–1.66 (21 H, m, alkyl), 1.71–1.81 (4 H, m, alkyl), 1.81–1.89 (1 H, m, alkyl), 2.30 (1 H, ddd, J 12.9, 11.0, 5.2, NCHHPr), 2.47 (1 H, ddd, J 12.9, 11.0, 5.2, NCHHPr), 2.49–2.54 (1 H, m, NCHHCH₂CH₂S), 2.95 (1 H, ddd, J 12.9, 9.1, 3.5, NCHHCH₂CH₂S), 3.39 (1 H, dd, J 9.5, 4.3, NCHCO), 3.64–3.73 (2 H, m, SCH₂), 3.79–3.86 (1 H, m, NHCH), 5.00 (1 H, br s, NH), 7.28–7.36 (3 H, m, Ar), 7.41–7.47 (2 H, m, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.1, 14.2, 20.8, 22.7, 24.5, 25.9, 26.4, 26.5, 28.4, 29.5, 30.2, 31.8, 33.2, 49.9, 50.9, 61.7, 61.9, 64.5, 128.5, 129.3, 132.0, 134.9, 156.7; LRMS (ES) 447, 393, 282; HRMS calcd for C₂₇H₄₇N₂OS [MH]⁺ 447.3409, found 447.3405.

2-(Butyl(3-(phenylthio)propyl)amino)-N-pentyl-4-phenylbutanamide (9r)

Colourless oil. 63% yield. ν_max/cm⁻¹ 3365 (NH), 2955, 2928, 2858 (CH), 1622 (CO), 1583, 1496, 1455 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.78 (3 H, t, J 7.5, CH₃), 0.80–0.91 (2 H, m, alkyl), 0.95 (3 H, t, J 7.1, CH₃), 1.03–1.16 (2 H, m, alkyl), 1.37–1.49 (5 H, m, alkyl), 1.55–1.63 (1 H, m, alkyl), 1.72–1.81 (3 H, m, alkyl, NCHCHH), 2.17–2.25 (1 H, m, NCHCHH), 2.30 (1 H, ddd, J 12.8, 10.8, 5.3, NCHHPr), 2.41 (1 H, ddd, J 13.8, 10.1, 6.9, NHCHH), 2.46 (1 H, ddd, J 12.8, 10.8, 5.3, NCHHPr), 2.61 (1 H, ddd, J 13.8, 10.1, 4.9, NHCHH), 2.52 (1 H, ddd, J 12.8, 5.4, 4.2, NCHHCH₂CH₂S), 2.95 (1 H, ddd, J 12.8, 9.0, 4.9, NCHHCH₂CH₂S), 3.53 (1 H, dd, J 9.3, 4.4, NCHCO), 3.57 (1 H, app. quin, J 7.0, CHHAr), 3.65 (1 H, app. quin, J 7.0, CHHAr), 3.64–3.69 (1 H, m, SCHH), 3.70–3.75 (1 H, m, SCHH), 4.64 (1 H, br s, NH), 7.15 (2 H, d, J 7.0, Ar), 7.19 (1 H, t, J 7.5, Ar), 7.26–7.33 (5 H, m, Ar), 7.37–7.40 (2 H, m, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.1, 14.3, 20.7, 22.6, 28.0, 28.7, 30.0, 30.0, 30.4, 32.9, 49.6, 50.9, 53.6, 61.5, 64.1, 126.0, 128.5, 128.6, 128.7, 129.4, 131.5, 134.9, 142.2, 159.6; LRMS (CI) 455, 248, 195; HRMS calcd for C₂₈H₄₃N₂OS [MH]⁺ 455.3096, found 455.3103.

General procedure for 3-component reactions of amino alcohols, isocyanides and acid-aldehydes

A solution of acid-aldehyde (1.00 mmol), amino alcohol (1.00 mmol) and isocyanide (1.00 mmol) in methanol (1 ml) was stirred under microwave irradiation¹³ at 60 °C for 20 min. The solvent was removed in vacuo and the residue purified by column chromatography (petroleum ether/EtOAc 9 : 1) to afford the amide.

N-tert-Butyl-4-methyl-8-oxo-2,3,5-trihydrobenzo[f][1,4]oxazocine-5-carboxamide (10a)

White solid. 82% yield. M.p. 123–125 °C (hexanes); ν_max/cm⁻¹ 3332 (NH), 2968 (CH), 1704 (CO ester), 1665 (CO amide), 1602, 1515, 1454 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 1.29 (9 H, s, tBu), 2.43 (3 H, s, NCH₃), 2.95–3.00 (1 H, m, NCHH), 3.05–3.09 (1 H, m, NCHH), 3.83–3.87 (1 H, m, OCHH), 4.07–4.11 (1 H, m, OCHH), 4.21 (1 H, s, NCH), 6.79 (1 H, br s, NH), 7.14 (1 H, d, J 7.0, Ar), 7.33–7.36 (3 H, m, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 28.5, 42.2, 51.2, 55.7, 64.8, 71.5, 128.3, 128.5, 128.6, 130.2, 130.8, 134.8, 168.7, 173.3; LRMS (CI) 291, 206, 190; HRMS calcd for C₁₆H₂₃N₂O₃ [MH]⁺ 291.1709, found 291.1713.

4-(3-Bromobenzyl)-N-(tert-butyl)-8-oxo-2,3,5-trihydrobenzo[f][1,4]oxazocine-5-carboxamide (10b)

Pale yellow solid. 49% yield. M.p. 135–136 °C (hexanes); ν_max/cm⁻¹ 3344 (NH), 2966 (CH), 1706, 1674 (CO), 1538 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 1.30 (9 H, s, tBu), 2.80 (1 H, ddd, J 14.2, 6.9 and 4.4, OCH₂CHH), 3.15 (1 H, ddd, J 14.2, 6.0 and 4.5, OCH₂CHH), 3.64 (1 H, br d, J 14.4, ArCHH), 3.72 (1 H, d, J 14.4, ArCHH), 3.84 (1 H, ddd, J 12.7, 6.0 and 4.5, OCHH), 4.07 (1 H, ddd, J 12.7, 6.9 and 4.4, OCHH), 4.40 (1 H, s, COCH), 6.57 (1 H, br s, NH), 7.20–7.21 (1 H, m, Ar), 7.22 (1 H, t, J 7.7, Ar), 7.27 (1 H, ddd, J 7.7, 1.6 and 1.3, Ar), 7.35–7.36 (3 H, m, Ar), 7.39 (1 H, ddd, J 7.8, 2.0 and 1.2, Ar), 7.44 (1 H, t, J 1.9, Ar); δ_C (150 MHz, CDCl₃) 28.7, 51.1, 51.7, 58.2, 65.0, 71.1 (br), 122.9, 127.0, 128.2, 128.67, 128.74, 130.4, 130.7, 130.8, 130.9, 131.5, 135.5, 140.1, 168.9, 173.8 (br); LRMS (CI) 447, 445, 348, 346, 259, 84; HRMS calcd for C₂₂H₂₆O₃N₂Br [MH]⁺ 445.1127, found 445.1116.

4-(4-Chlorobenzyl)-N-cyclohexyl-8-oxo-2,3,5-trihydrobenzo[f][1,4]oxazocine-5-carboxamide (10c)

Pale yellow solid. 57% yield. M.p. 117–119 °C (hexanes); ν_max/cm⁻¹ 3307 (NH), 2929 (CH), 1703, 1665 (CO), 1540 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 1.06–1.18 (3 H, m, Cy), 1.26–1.35 (2 H, m, Cy), 1.55–1.57 (1 H, br m, Cy), 1.63–1.66 (2 H, m, Cy), 1.73 (1 H, m, Cy), 1.83 (1 H, m, Cy), 2.75 (1 H, ddd, J 13.9, 10.3 and 5.6, OCH₂CHH), 3.13 (1 H, ddd, J 13.9, 7.2 and 5.6, OCH₂CHH), 3.68–3.81 (3 H, m, ArCH₂ and NHCH), 3.85 (1 H, ddd, J 12.4, 7.2 and 5.6 OCHH), 4.08 (1 H, ddd, J 12.4, 10.3 and 5.6, OCHH), 4.45 (1 H, s, COCH), 6.28 (1 H, br d, J 7.2, NH), 7.28–7.30 (3 H, m, Ar), 7.35 (2 H, d, J 8.5, Ar), 7.40–7.43 (3 H, m, Ar); δ_C (150 MHz, CDCl₃) 24.7, 25.5, 32.8, 48.5, 51.6, 58.6, 65.1, 71.5, 128.0, 128.8, 128.9, 129.2, 129.9, 130.4, 130.6, 133.6, 135.5, 135.9, 168.8, 174.1; LRMS (EI) 428, 426, 302, 300, 215; HRMS calcd for C₂₄H₂₇O₃N₂Cl [M]⁺ 426.1705, found 426.1703.

N-(tert-Butyl)-5-(4-chlorobenzyl)-9-oxo-2,3,4,6-tetrahydrobenzo[g][1,5]oxazonine-6-carboxamide (10d)

Pale yellow foam. 62% yield. ν_max/cm⁻¹ 3335 (NH), 2970 (CH), 1723, 1660 (CO), 1565 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 1.42 (9 H, s, tBu), 1.47–1.54 (1 H, m, OCH₂CHH) 1.74–1.84 (1 H, m, OCH₂CHH), 2.85 (1 H, ddd, J 14.2, 6.2 and 3.3, OCH₂CH₂CHH), 3.00 (1 H, ddd, J 14.2, 9.1 and 3.4, OCH₂CH₂CHH), 3.66 (1 H, d, J 13.8, ArCHH), 3.85 (1 H, d, J 13.8, ArCHH), 4.26 (1 H, ddd, J 14.8, 6.1 and 3.4, OCHH), 4.47 (1 H, ddd, J 14.8, 8.4 and 2.4, OCHH), 4.79 (1 H, s, COCH), 6.05 (1 H, br s, NH), 7.23 (2 H, d, J 8.4, Ar), 7.27 (2 H, d, J 8.4, Ar), 7.32–7.42 (3 H, m, Ar), 7.55 (1 H, dt, J 6.6 and 1.7, Ar); δ_C (150 MHz, CDCl₃) 25.6, 28.8, 50.9, 51.8, 55.8, 68.1, 69.4 (br), 127.8, 128.3, 128.4, 128.6, 130.2, 131.1, 133.0, 133.1, 136.8, 139.2, 169.0, 171.6; LRMS (CI) 417, 415, 316, 314, 273, 125; HRMS calcd for C₂₃H₂₈O₃N₂Cl [MH]⁺ 415.1789, found 415.1792.

5-(4-Chlorobenzyl)-9-oxo-N-pentyl-2,3,4,6-tetrahydrobenzo[g][1,5]oxazonine-6-carboxamide (10e)

Colorless oil. 70% yield. ν_max/cm⁻¹ 3325 (NH), 2858 (CH), 1710, 1651 (CO), 1491 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 0.92 (3 H, t, J 7.1, CH₃), 1.29–1.39 (4 H, pentyl), 1.48–1.55 (3 H, m, pentyl, OCH₂CHH), 1.72–1.78 (1 H, m, OCH₂CHH), 2.83 (1 H, ddd, J 14.1, 6.5, 3.3, NCHHCH₂), 2.99 (1 H, ddd, J 14.1, 8.6, 3.5, NCHHCH₂), 3.26–3.38 (2 H, m, NHCH₂), 3.64 (1 H, d, J 13.8, ArCHH), 3.85 (1 H, d, J 13.8, ArCHH), 4.26 (1 H, ddd, J 11.2, 6.4, 3.3, OCHH), 4.48 (1 H, ddd, J 11.2, 8.4, 2.9, OCHH), 4.91 (1 H, s, NCHCO), 6.26 (1 H, br s, NH), 7.21 (2 H, d, J 8.5, Ar), 7.26 (2 H, d, J 8.5, Ar), 7.35–7.40 (3 H, m, Ar), 7.54–7.56 (1 H, m, Ar); δ_C (150 MHz, CDCl₃) 13.8, 22.2, 25.6, 29.0, 29.1, 39.5, 51.1, 56.0, 68.0, 69.3 (br), 127.9, 128.3, 128.50 (br), 128.51 (br), 128.6, 130.3, 131.1, 133.1, 136.8, 139.1, 169.4, 171.7; LRMS (ES) 429, 427, 378, 302, 230; HRMS calcd for C₂₄H₂₈N₂O₃Cl [M−H]⁻ 427.1788, found 427.1778.

N-(tert-Butyl)-5-butyl-9-oxo-2,3,4,6-tetrahydrobenzo[g][1,5]oxazonine-6-carboxamide (10f)

White solid. 61% yield. M.p. 152–154 °C (hexanes); ν_max/cm⁻¹ 3297 (NH), 2963, 2867 (CH), 1724 (CO ester), 1650 (CO amide), 1548, 1453 (Ar); δ_H (400 MHz; CDCl₃; Me₄Si) 0.86 (3 H, t, J 7.3, CH₂CH₃), 1.17–1.28 (2 H, m, alkyl), 1.38–1.49 (2 H, m, alkyl), 1.40 (9 H, s, tBu), 1.74–1.91 (2 H, m, OCH₂CH₂), 2.52–2.67 (2 H, m, NCH₂Pr), 2.80–2.92 (1 H, m, NCHH), 3.03–3.14 (1 H, m, NCHH), 4.21–4.30 (1 H, m, OCHH), 4.49–4.60 (1 H, m, OCHH), 4.70 (1 H, s, NCHCO), 6.31 (1 H, br s, NH), 7.31–7.43 (3 H, m, Ar), 7.47 (1 H, br d, J 7.1, Ar); δ_C (100 MHz; CDCl₃; Me₄Si) 13.7, 20.5, 25.3, 26.0, 28.7, 50.8, 51.2, 51.5, 67.7, 70.4, 127.6, 127.9, 128.5, 130.0, 133.3, 139.5, 169.3, 171.3; HRMS calcd for C₂₀H₃₀N₂O₃ [MNa]⁺ 369.2154, found 369.2146.

N-(tert-Butyl)-7-(2-chlorobenzyl)-3-oxo-2,3,5,6,7,8-hexahydrobenzo[i][1,4,7]dioxazecine-8-carboxamide (10g)

White solid. 14% yield. M.p. 138–140 °C (hexanes); ν_max/cm⁻¹ 3378 (NH), 2965 (CH), 1741, 1673 (CO), 1489 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 1.32 (9 H, s, tBu), 2.54–2.60 (1 H, m, OCH₂CHH), 2.75 (1 H, ddd, J 15.0, 11.6 and 3.1, OCH₂CHH), 3.85 (1 H, d, J 13.9, NCHHAr), 3.98 (1 H, d, J 13.9, NCHHAr), 4.16 (1 H, ddd, J 11.6, 3.6 and 2.0, CO₂CHH), 4.30–4.33 (1 H, m, CO₂CHH), 4.54 (1 H, d, J 13.4, ArOCHH), 4.73 (1 H, d, J 13.4, ArOCHH), 5.08 (1 H, s, ArCH), 6.56 (1 H, s, NH), 7.11 (1 H, ddd, J 7.9, 7.3 and 1.1, Ar), 7.17 (1 H, dd, J 8.3 and 1.1, Ar), 7.31 (1 H, ddd, J 8.3, 7.3 and 1.7, Ar), 7.34 (2 H, d, J 8.5, Ar), 7.37 (2 H, d, J 8.5, Ar), 7.42 (1 H, d, J 7.9, Ar); δ_C (150 MHz, CDCl₃) 28.8, 45.7, 51.1, 53.9, 60.8, 65.5, 72.9, 121.4, 124.8, 128.9, 129.0, 129.8, 129.9, 130.7, 133.3, 136.6, 157.0, 168.5, 171.3; LRMS (ES) 433, 431, 330, 224, 208; HRMS calcd for C₂₃H₂₈O₄N₂Cl [MH]⁺ 431.1738, found 431.1730.

7-(3-Bromobenzyl)-N-(tert-butyl)-3-oxo-2,3,5,6,7,8-hexahydrobenzo[i][1,4,7]dioxazecine-8-carboxamide (10h)

White solid. 22% yield. M.p. 135–136 °C (hexanes); ν_max/cm⁻¹ 3373 (NH), 2965 (CH), 1742, 1675 (CO), 1506, 1453 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 1.33 (9 H, s, tBu), 2.56–2.59 (1 H, m, OCH₂CHH), 2.78 (1 H, ddd, J 15.4, 11.8 and 3.2, OCH₂CHH), 3.84 (1 H, d, J 14.0, NCHHAr), 3.98 (1 H, d, J 14.0, NCHHAr), 4.17 (1 H, ddd, J 11.8, 4.0 and 1.9, CO₂CHH), 4.32–4.37 (1 H, m, CO₂CHH), 4.55 (1 H, d, J 13.4, ArOCHH), 4.73 (1 H, d, J 13.4, ArOCHH), 5.06 (1 H, s, ArCH), 6.58 (1 H, s, NH), 7.12 (1 H, ddd, J 8.3, 7.5 and 0.9, Ar), 7.17 (1 H, dd, J 8.2 and 0.9, Ar), 7.23–7.26 (1 H, m, Ar), 7.31 (1 H, ddd, J 8.2, 7.5 and 1.7, Ar), 7.37 (1 H, d, J 7.7, Ar), 7.41 (2 H, m, Ar), 7.59 (1 H, s, Ar); δ_C (150 MHz, CDCl₃) 28.8, 45.9, 51.3, 54.1 60.8, 65.5, 73.1, 121.4, 123.0, 124.8, 127.2, 128.9, 130.0, 130.4, 130.6, 130.8, 131.5, 140.5, 157.1, 168.5, 171.3; LRMS (EI) 476, 474, 377, 375, 218, 162; HRMS calcd for C₂₃H₂₇O₄N₂Br [M]⁺ 474.1149, found 474.1149.

N-Cyclohexyl-1,4-diethyl-8-oxo-2,3,5-trihydrobenzo[f][1,4]diazocine-5-carboxamide (10i)

Colourless oil. 69% yield. ν_max/cm⁻¹ 3326 (NH), 2859 (CH), 1645 (CO), 1490 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 0.91–0.95 (1 H, m, Cy), 0.96 (6 H, app. t, J 7.1, CH₃), 1.03–1.32 (4 H, m, Cy), 1.57–1.72 (4 H, m, Cy), 1.93–1.95 (1 H, m, Cy), 2.47–2.60 (4 H, m, NCH₂CH₃), 2.70 (1 H, app. dt, J 13.5, 6.3, CONCHHCH₂), 2.81 (1 H, app. dt, J 13.5, 6.2, CONCHHCH₂), 3.29 (1 H, app. dt, J 14.1, 6.3, CHNCHHCH₂), 3.70 (1 H, tdt, J 11.2, 7.9, 3.9, NHCH), 3.94 (1 H, app. dt, J 14.1, 6.4, CHNCHHCH₂), 5.26 (1 H, s, NCHCO), 6.56 (1 H, d, J 7.9, NH), 7.43 (1 H, dd, J 7.6, 7.4, Ar), 7.54 (1 H, ddd, J 7.6, 7.5, 1.1, Ar), 7.68–7.71 (2 H, m, Ar); δ_C (150 MHz, CDCl₃) 11.7, 25.0, 25.1, 25.5, 32.6, 33.1, 41.2, 47.6, 48.9, 50.6, 65.9, 123.0, 123.6, 128.9, 131.0, 132.3, 141.8, 167.3, 170.3; LRMS (CI) 358, 263, 247, 231; HRMS calcd for C₂₁H₃₂N₃O₂ [MH]⁺ 358.2495, found 358.2488.

N-(tert-Butyl)-2-((S)-2-((phenylthio)methyl)pyrrolidin-1-yl)octanamide (11a)

Colourless oil. 68% yield. [α]²⁵_D −44.0 (c 1.0, CHCl₃); ν_max/cm⁻¹ 3336 (NH), 2957, 2926, 2858 (CH), 1656 (CO), 1584, 1514, 1453 (Ar); δ_H (600 MHz; CDCl₃; Me₄Si) 0.86 (3 H, t, J 7.1, CH₂CH₃), 1.19–1.31 (8 H, m, alkyl), 1.29 (9 H, s, tBu), 1.50–1.57 (1 H, m, alkyl), 1.58–1.65 (1 H, m, alkyl), 1.67–1.81 (3 H, m, NCH₂CHHCH₂), 1.89–1.99 (1 H, m, NCH₂CHH), 2.74 (1 H, dt, J 9.0, 7.5, NCHH), 2.82 (1 H, dd, J 12.5, 8.2, SCHH), 2.95 (1 H, dd, J 8.4, 6.1, NCHCO), 2.96–3.00 (1 H, m, NCHCH₂), 3.04 (1 H, dd, J 12.5, 3.6, SCHH), 3.14 (1 H, ddd, J 11.8, 8.2, 3.6, SCH₂CH), 6.25 (1 H, br s, NH), 7.15 (1 H, t, J 7.6, Ar), 7.26 (2 H, app. t, J 7.6, Ar), 7.32 (2 H, d, J 7.6, Ar); δ_C (150 MHz; CDCl₃; Me₄Si) 14.2, 22.7, 23.4, 26.7, 28.9, 29.5, 31.1, 31.5, 31.8, 39.9, 50.7, 52.1, 58.4, 67.2, 126.0, 129.0, 129.2, 136.8, 172.8; LRMS (CI) 391, 290, 267, 137; HRMS calcd for C₂₃H₃₉N₂OS [MH]⁺ 391.2783, found 391.2790.

N-(tert-Butyl)-2-((S)-2-((phenylthio)methyl)pyrrolidin-1-yl)pentanamide (11b)

Colourless oil. 70% yield. [α]²⁵_D −51.3 (c 1.0, CHCl₃); ν_max/cm⁻¹ 3334 (NH), 2934 (CH), 1663 (CO), 1514 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 0.87 (3H, t, J 7.4, CH₂CH₃), 1.28–1.36 (11H, m, tBu, CH₃CH₂), 1.50–1.55 (1H, m, NCHCHH), 1.58–1.63 (1H, m, NHCHCHH), 1.70–1.80 (3H, m, NCH₂CH₂, NCH₂CH₂CHH), 1.93–1.97 (1H, m, NCH₂CH₂CHH), 2.74 (1H, app. q, J 8.2, NCHH), 2.82 (1H, dd, J 12.6, 8.3, SCHH), 2.96–3.00 (2H, m, NCHCO, NCHH), 3.04 (1H, dd, J 12.6, 3.7, SCHH), 3.13–3.17 (1H, m, NCHCH₂), 6.26 (1H, br s, NH), 7.16 (1H, t, J 7.6, Ar), 7.26 (2H, dd, J 7.8, 7.6, Ar), 7.33 (2H, d, J 7.8, Ar); δ_C (150 MHz, CDCl₃) 14.3, 20.0, 23.5, 28.9, 31.1, 33.7, 39.9, 50.8, 52.1, 58.4, 67.0, 126.1, 129.0, 129.2, 136.8, 172.8; LRMS (ES) 349, 248, 239, 180; HRMS calcd for C₂₀H₃₃N₂OS [MH]⁺ 349.2314, found 349.2319.

N-(Cyclohexyl)-2-((S)-2-((phenylthio)methyl)pyrrolidin-1-yl)pentanamide (11c)

Colourless oil. 60% yield. [α]²⁵_D −30.7 (c 1.0, CHCl₃); ν_max/cm⁻¹ 3306 (NH), 2931 (CH), 1643 (CO), 1520, 1439 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 0.85 (3H, t, J 7.4, CH₂CH₃), 1.01–1.14 (3H, m, Cy), 1.29–1.34 (4H, m, CH₃CH₂, Cy), 1.51–1.79 (10H, m, NCHCH₂, NCH₂CH₂, SCH₂CHCHH, Cy), 1.89–1.96 (1H, m, SCH₂CHCHH), 2.74 (1H, app. q, J 8.1, NCHH), 2.81 (1H, dd, J 12.7, 8.3, SCHH), 2.95–2.99 (1H, m, NCHH), 3.02–3.07 (2H, m, SCHH, NCHCO), 3.10–3.14 (1H, m, SCH₂CH), 3.67–3.74 (1H, m, NHCH), 6.24 (1H, br d, J 7.2, NH), 7.15 (1H, tt, J 7.7, 1.3, Ar), 7.25 (2H, dd, J 8.3, 7.7, Ar), 7.32 (2H, dd, J 8.3, 1.3, Ar); δ_C (150 MHz, CDCl₃) 14.3, 19.9, 22.4, 25.0, 25.6, 31.0, 33.1, 33.4, 39.8, 47.6, 51.9, 58.5, 66.2, 126.1, 129.1, 129.3, 136.8, 172.3; LRMS (ES) 375, 248, 208, 180; HRMS calcd for C₂₂H₃₅N₂OS [MH]⁺ 375.2470, found 375.2465.

(3S,8S)-N-(tert-Butyl)-8-oxo-2,5-dihydrobenzo[f]pyrrolo[3,4-c][1,4]oxazocine-5-carboxamide and (3S,8R)-N-(tert-butyl)-8-oxo-2,5-dihydrobenzo[f]pyrrolo[3,4-c][1,4]oxazocine-5-carboxamide (12)

White solid. 78% yield (S,S : S,R 1.5 : 1). S,S-Isomer: M.p. 133–135 °C (hexanes); [α]²⁵_D −96.1 (c 1.0, CHCl₃); ν_max/cm⁻¹ 3305 (NH), 2968 (CH), 1737, 1662 (CO), 1539, 1455 (Ar); δ_H (600 MHz, CDCl₃, Me₄Si) 1.17 (9H, s, tBu), 1.72–1.76 (1H, m, NCH₂CHH), 1.81–1.93 (2H, m, NCH₂CHH, NCHCHH pyrrolo), 2.04 (1H, dddd, J 16.5, 12.5, 8.0, 4.3, NCHCHH pyrrolo), 2.68 (1H, ddd, J 15.9, 8.7, 7.2, NCHH), 2.78 (1H, ddd, J 15.9, 7.8, 4.3, NCHCH₂), 3.20 (1H, app. ddd, J 9.5, 7.5, 5.3, NCHH), 3.72 (1H, dd, J 12.3, 4.4, OCHH), 3.95 (1H, app. d, J 12.3, OCHH), 4.13 (1H, s, NCHCO), 6.13 (1H, br s, NH), 7.26–7.27 (1H, m, Ar), 7.34–7.40 (3H, m, Ar); δ_C (150 MHz, CDCl₃) 22.4, 28.3, 31.4, 51.2, 52.9, 62.6, 68.8, 75.4, 127.1, 127.8, 128.8, 130.0, 130.2, 136.4, 169.6, 174.8; S,R-Isomer: M.p. 144–145 °C (hexanes); [α]²⁵_D +73.4 (c 1.0, CHCl₃); ν_max (film/cm⁻¹) 3305, 2968, 1737, 1662, 1539, 1455; δ_H (600 MHz, CDCl₃, Me₄Si) 1.42 (9H, s, tBu), 1.67–1.71 (1H, m, NCH₂CHH), 1.78–1.82 (2H, m, NCH₂CHH, NCHCHH pyrrolo), 1.96–1.99 (1H, m, NCHCHH pyrrolo), 3.04–3.06 (2H, m, NCH₂), 3.60 (1H, app. ddd, J 9.0, 5.9, 3.6, NCHCH₂), 3.75 (1H, dd, J 12.1, 3.6, OCHH), 3.85 (1H, app. d, J 12.1, OCHH), 4.23 (1H, s, NCHCO), 6.48 (1H, d, J 7.3, Ar), 7.12 (1H, ddd, J 7.8, 7.6, 1.1, Ar), 7.19 (1H, dd, J 7.6, 1.0, Ar), 7.23 (1H, br s, NH), 7.26 (1H, dd, J 7.8, 7.3, Ar); δ_C (150 MHz, CDCl₃) 23.7, 29.0, 30.7, 52.0, 54.4, 55.8, 65.3, 69.3, 126.8, 127.0, 127.8, 130.2, 131.4, 137.3, 168.3, 174.7; LRMS (ES) 316, 217, 84; HRMS calcd for C₁₈H₂₄N₂O₃ [MH]⁺ 317.1865, found 317.1874.

Acknowledgements

We would like to thank the EPSRC (Advanced Research Fellowship EP/E052789/1 to TDS), AstraZeneca (summer research bursary to MB) and University College London (Studentship to SEM) for supporting this work.

Notes and references

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11. The stereochemistry at the newly created chiral centre (*) was not determined.
12. An enhancement of the methine signal on the pyrrolidine ring was observed upon irradition of the benzylic methine proton for the (S,S) isomer. No such enhancement was observed for the (S,R) isomer. The nOe difference spectra are provided in the supporting information.
13. Microwave reactions were performed using a CEM Explorer microwave with an external IR temperature sensor (150 W power).

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra for all MCR products 9–12 and 2D/nOe spectra for compound 12. See DOI: 10.1039/c1ob06534c

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