Preparation and structural analysis of (±)-cis-ethyl 2-sulfanylidenedeca­hydro-1,6-naphthyridine-6-carboxyl­ate and (±)-trans-ethyl 2-oxo­octa­hydro-1H-pyrrolo­[3,2-c]pyridine-5-carboxyl­ate

Bicycle ring closure on a mixture of (4aS,8aR)- and (4aR,8aS)-ethyl 2-oxo­deca­hydro-1,6-naphthyridine-6-carboxyl­ate, followed by conversion of the separated cis and trans isomers to the corresponding thio­amide derivatives, gave (4aSR,8aRS)-ethyl 2-sulfanylidenedeca­hydro-1,6-naphthyridine-6-carboxyl­ate, C₁₁H₁₈N₂O₂S. Structural analy­sis of this thio­amide revealed a structure with two crystallographically independent conformers per asymmetric unit (Z' = 2). The reciprocal bicycle ring closure on (3aRS,7aRS)-ethyl 2-oxo­octa­hydro-1H-pyr­rolo­[3,2-c]pyridine-5-carboxyl­ate, C₁₀H₁₆N₂O₃, was also accomplished in good overall yield. Here the five-membered ring is disordered over two positions, so that both enanti­omers are represented in the asymmetric unit. The compounds act as key inter­mediates towards the synthesis of potential new polycyclic medicinal chemical structures.

S1. Introduction

The bicyclic la­ctams (1-1), (1-2), (2-1) and (2-2) (see Scheme 1) represent both inter­esting chemical scaffolds and important synthetic precursors to novel polycyclic scaffolds for application in medicinal chemistry drug discovery programmes.

The resulting polycyclic compounds derived from these bicyclic scaffolds could be used in the design of molecules to modulate various biological targets and therefore represent a new class of privileged structures (Welsch et al., 2010; DeSimone et al., 2004) for targeting, for example, G protein-coupled receptors (GPCRs). GPCRs are 7-transmembrane receptors whose function is to regulate multiple disease states and represent one of the major target families for currently prescribed drugs in the clinic (Filmore, 2004). Continued efforts to discover new compounds that modulate these important biological targets therefore remain of great importance to the biopharmaceutical industry.

The chemical scaffolds (1-1), (1-2), (2-1) and (2-2) themselves appear underrepresented in the medicinal chemical literature and therefore warrant further investigation. It had been reported that compound (3) (Scheme 2) targets the bradykinin receptor (Hu et al., 2005), which is a member of the GPCR family and has a key role as a pro-inflammatory mediator (Hall, 1997; Yogi et al., 2009). Compounds (4a) and (4b) (Scheme 2) act as serotonin 5HT receptor ligands (Fevig et al., 2006). The serotonin receptors are found in the central and peripheral nervous system and mediate both excitatory and inhibitory neurotransmission (Wang et al. 2013; Wacker et al., 2013; Raote et al., 2007).

We were inter­ested in the synthesis of the core bicyclic molecular scaffolds [e.g. compounds of type (5) (see Scheme 2), where X = O) contained within these biologically active compounds, which therefore necessitated the synthesis, separation and full characterization of the resulting diastereoisomers obtained from our synthetic sequence. So far no robust synthetic procedure had been reported for the inter­esting bicyclic 6,6-la­ctam scaffolds (1-1) and (1-2) (see Scheme 1). However, the 6,5-system, e.g. compounds (2-1) and (2-2) (see Scheme 1), was recently reported in the literature (Martini et al., 2011). Unfortunately, in our hands, we were unable to repeat the published synthetic procedure and so we needed to further investigate both the synthesis and structural assignment of these key bicyclic inter­mediates. Upon completion of our robust and high-yielding synthetic sequence to both the 6,5 and 6,6-bicyclic ring systems, we were unable to assign the relative stereochemistry of the separated cis and trans isomers by NMR spectroscopic analysis due to the complexity of the overlapping proton signals and therefore we required final structural confirmation through X-ray crystallographic analysis.

S2. Experimental

We embarked on a racemic synthesis of compounds (1) [isomers (1-1) and (1-2)] and (2) [isomers (2-1) and (2-2)] (see Scheme 1). In our synthetic strategy, no enanti­oselective conditions were used to synthesize the bicyclic ring systems. As a consequence, each of the resulting separated diastereoisomers exists as a pair of enanti­omers, which are for simplicity drawn as one single stereoisomer. Our initial attempts to obtain crystals of sufficient quality for X-ray crystallographic analysis from the separated amide compounds (1-1) or (1-2)) were unprofitable. However, from isomer (1-1) it was subsequently discovered that corresponding thiol­actam (8-1) (see Scheme 3) was highly crystalline and delivered crystals of sufficient quality for X-ray crystallographic structure determination.

S2.1. Synthesis and crystallization of thiol­actam (8-1) (see Scheme 3)

The synthesis started from the known ethyl ester ethyl 3-(3-eth­oxy-3-oxo­propyl)-4-oxo­piperidine-1-carboxyl­ate, (6) (Borne et al., 1984), which was converted into the methoxime derivative ethyl 3-(3-eth­oxy-3-oxo­propyl)-4-(meth­oxy­imino)­piperidine-1-carboxyl­ate, (7), using O-methyl­hydroxyl­amine hydro­chloride in pyridine to yield a 1:1.5 mixture of diastereomers (see Scheme 3). Subsequent conversion to the bicyclic la­ctams ethyl (4aS,8aR)-2-oxodeca­hydro-1,6-naphthyridine-6-carboxyl­ate, (1-1), and ethyl (4aR,8aS)-2-oxo-deca­hydro-1,6-naphthyridine-6-carboxyl­ate, (1-2), was accomplished with Raney nickel in 7 N NH₃ in MeOH under an atmosphere of hydrogen. Final thio­amide formation on the separated la­ctam diastereoisomer (1-1) was achieved using Lawesson's reagent [i.e. 2,4-bis­(4-meth­oxy­phenyl)-1,3,2,4-di­thia­diphosphetane 2,4-di­sulfide; Occhiato et al., 2004], to give the racemic thiol­actams (4aS,8aR)-ethyl 2-sulfanylidenedeca­hydro-1,6-naphthyridine-6-carboxyl­ate, (8-1), and ent-(8-1) (see Scheme 3).

S2.1.1. Ethyl 3-(3-eth­oxy-3-oxo­propyl)-4-(meth­oxy­imino)­piperidine-1-carboxyl­ate, (7)

To a solution of ketone (6) (3.0 g, 11.0 mmol, 1.0 equivalent) in pyridine (21 ml) was added O-methyl­hydroxyl­amine hydro­chloride (1.11 g, 13.3 mmol, 1.2 equivalents) and the reaction was stirred at room temperature under a nitro­gen atmosphere overnight. The reaction mixture was evaporated and diluted with di­ethyl ether (150 ml) and water (150 ml). The organic phase was washed with hydro­chloric acid (1 M, 60 ml) and brine (150 ml). The combined organic phases were dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure to yield ethyl 3-(3-eth­oxy-3-oxo­propyl)-4-(meth­oxy­imino)­piperidine-1-carboxyl­ate, (7a)/(7b), as a yellow/orange oil (yield 2.80 g, 84%; 1:1.5 diastereomeric mixture).

R_F (petroleum ether/ethyl acetate, 2:1 v/v) = 0.56, ¹H NMR (400 MHz, CDCl₃): δ 4.16–4.08 (4H, m), 3.85 (1.7H, s), 3.81, 3.78 (3H, s), 3.61 (1H, m), 3.39 (1H, m), 3.23 (1H, m), 2.92–2.67 (2H, m), 2.43–2.21 (4H, m), 1.95 (1H, m), 1.82–1.72 (1H, m), 1.26, 1.25 (6H, 2t, J = 7.47 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 173.2, 173.0, 157.1, 155.7, 61.7, 61.5, 61.3, 60.5, 48.4, 44.3, 42.7, 40.6, 31.9, 24.9, 24.8, 14.7, 14.3, HRMS m/z: C₁₄H₂₄N₂O₅ calculated 301.1758 [M + H]⁺, found 301.1699.

S2.1.2. Ethyl 2-oxodeca­hydro-1,6-naphthyridine-6-carboxyl­ate, (1-1 and 1-2)

To a stirred solution of (7a)/(7b) (200 mg, 0.66 mmol, 1 equivalent) in methano­lic NH₃ (7 N, 5 ml) was added Raney nickel (50 mg, 50% slurry in water) and the resulting mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite and the filter cake was washed with methanol (3 × 10 ml). The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (ethyl acetate/petroleum ether/methanol 9:1:2 v/v/v) to yield two isomers of ethyl 2-oxodeca­hydro-1,6-naphthyridine-6-carboxyl­ate, viz. (1-1) (yield 40 mg, 26%; colourless oil) and (1-2) (yield 90 mg, 60%; colourless oil) (combined yield 130 mg, 86%).

Isomer 1, viz. (1-2): R_F (petroleum ether/ethyl acetate, 10:1 v/v + 15% MeOH) = 0.36; ¹H NMR (400 MHz, CDCl₃): δ 6.20 (1H, bs), 4.24, (2H, bm), 4.12 (2H, q, J = 7.6, 14.8 Hz), 3.06 (1H, dddd, J = 4.0, 9.8, 12.3 Hz), 2.81–2.74 (1H, m), 2.52–2.34 (3H, m), 1.83–1.76 (2H, m), 1.55–1.41 (3H, m), 1.24 (3H, t, J = 7.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 172.2, 155.4, 61.7, 56.4, 47.3, 42.3, 38.9, 32.2, 30.9, 24.5, 14.7. HMRS m/z: C₁₄H₁₉N₂O₃ calculated 227.1390 [M + H]⁺, found 227.1265.

Isomer 2, viz. (1-1): R_F (petroleum ether/ethyl acetate, 10:1 v/v + 15% MeOH) = 0.30; ¹H NMR (400 MHz, CDCl₃): δ 7.33 (1H, bs), 4.11–4.04 (2H, m), 3.57–3.51 (3H, m), 3.40–3.36 (1H, m), 3.26–3.20 (1H, m), 3.15 (2H, t, J = 6.9 Hz), 2.03–1.98 (1H, m), 1.86–1.62 (4H, m), 1.20 (3H, t, J = 7.2 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 155.6, 61.7, 50.6, 44.7, 40.5, 32.7, 30.5, 28.9, 22.0, 14.9; HRMS m/z: C₁₄H₁₉N₂O₃ calculated 227.1390 [M + H]⁺, found 227.1229.

S2.1.3. Ethyl 2-sulfanylidenedeca­hydro-1,6-naphthyridine-6-carboxyl­ate, (8-1) and ent-(8-1)

To a solution of (1-1) (80 mg, 0.35 mmol, 1 equivalent) in toluene (1 ml) was added Lawesson'sreagent (71 mg, 0.17 mmol, 0.5 equivalents) and the mixture was refluxed for 20 min. The reaction mixture was evaporated under reduced pressure and purified by flash chromatography (ethyl acetate/petrol ether/methanol, 10:1:0.5 v/v/v) to yield ethyl 2-sulfanylidenedeca­hydro-1,6-naphthyridine-6-carboxyl­ate [(8-1) and ent-(8-1)] as a colourless waxy oil (yield 80 mg, 94%). The resulting oil was dissolved in a mixture of ethyl acetate and di­ethyl ether and the solvent was allowed to slowly evaporate. After evaporation of half of the solvent, diiso­propyl ether was added and the solvent was allowed to evaporate slowly to afford clear colourless crystals, which were used for X-ray structural determination that allowed us an unambiguous assignment of the regiochemistry of the separated isomers (Fig. 1).

R_F (petroleum ether/ethyl acetate, 10:1 v/v) = 0.45; ¹H NMR (400 MHz, CDCl₃): δ 8.34 (1H, bs), 4.12 (2H, dq, J = 2.3, 7.2, 14.4 Hz), 3.64–3.52 (3H, m), 3.46–3.42 (1H, m), 3.33–3.27 (1H, m), 2.93 (2H, qt, J = 7.1, 19.6, 40.4 Hz), 2.10–2.06 (1H, m), 1.88–1.72 (4H, m), 1.25 (3H, t, J = 7.0 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 202.1, 155.7, 61.7, 53.1, 44.9, 40.6, 37.7, 31.7, 29.3, 21.4, 14.9; m.p. 401–403 K; HRMS m/z: C₁₁H₁₉H₂O₂S calculated 243.1162 [M + H]⁺, found 243.1003.

S2.2. Synthesis and crystallization of bicyclic la­ctam (2-1) (see Scheme 4)

Commercial ethyl 4-oxo­piperidine-1-carboxyl­ate, (9), was converted into the tert-butyl ester ethyl 3-(2-tert-but­oxy-2-oxyethyl)-4-oxo­piperidine-1-carboxyl­ate, (10), using LDA and tert-butyl bromo­acetate [OK?]. The tert-butyl ester (10) was converted to the substituted benzyl­amine ethyl 4-benzyl­amino-3-(2-tert-but­oxy-2-oxo­ethyl)­piperidine-1-carboxyl­ate, (11), via a reductive amination reaction using benzyl­amine and sodium tri­acet­oxy­borohydride in di­chloro­ethane. Compound (11) was transesterified with 0.6 M HCl in methanol to yield the ester ethyl 4-benzyl­amino-3-(2-meth­oxy-2-oxo­ethyl)­piperidine-1-carboxyl­ate, (12), which was catalytically deprotected (Pd/C in MeOH under an atmosphere of hydrogen). The final ring closure to the key bicyclic la­ctams ethyl 2-oxoo­cta­hydro-1H-pyrrolo­[3,2-c]pyridine-5-carboxyl­ate, viz. (2-1) and (2-2), was carried out with potassium carbonate in methanol (see Scheme 4). Unlike the [6,6]-membered ring compound (1), the [6,5]-membered compound (2) did not need further elaboration to the thio­amide to obtain high-quality crystals.

S2.2.1. Ethyl 3-(2-tert-but­oxy-2-oxyethyl)-4-oxo­piperidine-1-carboxyl­ate, (10)

To a solution of diiso­propyl­amine (5.6 g, 7.8 ml, 55.6 mmol, 1.9 equivalents) in tetra­hydro­furan (THF; 175 ml) at 273 K was added n-BuLi (18.5 ml, 2.5 M in hexane, 46.2 mmol, 1.6 equivalents) and the mixture was stirred for 30 min. The mixture was cooled to 195 K and ethyl 4-oxo­piperidine-1-carboxyl­ate, (16) (5.0 g, 4.4 ml, 29.2 mmol, 1 equivalent), was added and the mixture was stirred for an additional 30 min at 195 K. A solution of tert-butyl bromo­acetate [OK?] (9.2 g, 7.0 ml, 47.2 mmol, 1.62 equivalents) in THF (17.5 ml) and hexa­methyl­phospho­ramide (HMPT; 2.9 ml) was added and the yellow reaction mixture was warmed gradually to room temperature overnight. The mixture was quenched with saturated aqueous NH₄Cl (200 ml), the phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 200 ml). The combined organic layers were dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether/ethyl acetate, 3:1 v/v) to yield tert-butyl ester (10) in 50% yield.

R_F (petroleum ether/ethyl acetate, 3:1 v/v) = 0.28; ¹H NMR (400 MHz, CDCl₃): δ 4.34 (2H, bs), 4.13 (2H, q, J = 7.0, 14.5 Hz), 3.21 (1H, m), 2.94–2.80 (2H, m), 2.64–2.50 (2H, m), 2.39 (0.68 H, t, J = 3.9 Hz), 2.35 (0.32 H, t, J = 4.3 Hz), 2.25–2.18 (1H, m), 1.45 (9H, s), 1.28 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 207.2, 170.6, 155.2, 80.9, 61.9, 47.9, 46.5, 43.6, 40.7, 32.7, 28.0, 14.6.

S2.2.2. Ethyl 4-benzyl­amino-3-(2-tert-but­oxy-2-oxo­ethyl)­piperidine-1-carboxyl­ate, (11)

To a solution of tert-butyl ester (10) (1.43 g, 5.01 mmol, 1 equivalent) in di­chloro­ethane (22 ml) was added benzyl­amine (0.65 ml, 0.63 g, 5.90 mmol, 1.17 equivalents) and sodium tri­acet­oxy­borohydride (1.80 g, 8.53 mmol, 1.70 equivalents). The resulting mixture was stirred overnight under an atmosphere of dry nitro­gen. The reaction mixture was quenched with saturated aqueous NaHCO₃ (150 ml) and the aqueous phase was extracted with ethyl acetate (3 × 150 ml). The combined organic layers were dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether/ethyl acetate, 1:5 v/v) to yield ethyl (10) as a clear colourless oil (yield 1.77g, 94%).

R_F (ethyl acetate/petroleum ether 6:1 v/v) = 0.45; ¹H NMR (400 MHz, CDCl₃): δ 7.34–7.31, 7.29–7.23 (5H, m), 4.12 (2H, q, J = 7.1, 14.3 Hz), 4.04–3.69 (4H, m), 3.11–2.89 (1H, m), 2.86–2.81 (1H, m), 2.74–2.46 (1H, m), 2.37–2.30 (1H, m), 2.18–2.12 (1H, m), 1.91–1.76 (1H, m), 1.56–1.46 (1H, m), 1.45 (9H, s), 1.24 (3H, t, J = 6.8 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 155.8, 155.4, 140.6, 140.4, 128.4, 128.3 (2), 128.1 (2), 126.9 (2), 82.6, 80.4, 80.3, 62.2, 61.5, 61.2, 59.2, 50.9, 50.4, 45.9, 42.5, 42.4, 28.2, 14.7 (2); HRMS m/z: C₂₂H₃₃N₂O₄ calculated 377.2435 [M + H]⁺, found 377.2422.

S2.2.3. Ethyl 2-oxoo­cta­hydro-1H-pyrrolo­[3,2-c]pyridine-5-carboxyl­ate, (2-1) and (2-2)

To a solution of (11) (1.70 g, 4.52 mmol, 1.0 equivalents) in MeOH (50 ml) was added hydro­chloric acid (0.6 M, 4 ml) and the reaction mixture was stirred for 4 d. A further aliquot of hydro­chloric acid (concentrated, 1 ml) was added and the mixture was stirred for a further 2 d. The reaction mixture was evaporated under a reduced pressure and subsequently diluted in MeOH (30 ml) and dilute hydro­chloric acid (0.5 M, 2 ml). The reaction was stirred for 48 h at room temperature. After evaporation, the crude product was obtained as the hydro­chloride salt and was used without further purification. To a solution of the hydro­chloride salt (550 mg, 1.49 mmol, 1 equivalent) in MeOH (15 ml) was added Pd/C (10% w/w, 100 mg) and the reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen. The reaction mixture was filtered through Celite and the filter cake was washed with MeOH (3 × 10 ml) and the filtrate was evaporated to give (11) which was used without further purification. To a solution of the crude product 1-eth­oxy­carbonyl-3-(2-meth­oxy-2-oxo­ethyl)­piperidin-4-aminium chloride in MeOH (6 ml) was added anhydrous K₂CO₃ (200 mg) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (30 ml) and the aqueous phase was extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate/petrol ether/methanol, 10:1:1 v/v/v) to yield ethyl 2-oxoo­cta­hydro-1H-pyrrolo­[3,2-c]pyridine-5-carboxyl­ate which were separated by flash column chromatography to afford two isomers, viz. (2-1) (yield 168 mg, 16%) and (2-2) (yield 286 mg, 28%), (combined yield 454 mg, 45%), that slowly crystallized on standing. Crystals suitable for the X-ray crystallography were grown by the slow evaporation of an ethyl acetate solution and it was found that isomer (2-1) afforded crystals of sufficient quality to allow unambiguous assignment of regiochemistry (Fig. 2).

Isomer 1, (2-1): R_F (ethyl acetate/petroleum ether/methanol, 10:1:1 v/v/v) = 0.27; ¹H NMR (400 MHz, CDCl₃): δ 6.29 (1H, bs), 4.34 (2H, bm), 4.12 (2H, q, J = 7.4, 13.3 Hz), 3.19 (1H, dddd, J = 3.7, 10.2 Hz), 2.84–2.74 (2H, m), 2.32 (1H, dd, J = 6.7, 15.7 Hz), 2.08 (1H, dd, J = 12.9, 15.7 Hz), 2.01–1.87 (1H, m), 1.54 (1H, dddd, J = 4.4, 12.9, 24.5 Hz), 1.25 (3H, t, J = 7.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 178.2, 156.2, 61.5, 60.4, 59.5, 46.4, 43.8, 42.5, 34.9, 14.7, m.p. 377–378 K, HRMS m/z: C₁₀H₁₇N₂O₃ calculated 213.1234 [M + H]⁺, found 213.0807.

Isomer 2, (2-2): R_F (ethyl acetate/petroleum ether/methanol 10:1:1v/v/v) = 0.20; ¹H NMR (400 MHz, CDCl₃): δ 7.22 (1H, bs), 4.05 (2H, q, J = 7.4, 14.4 Hz), 3.80 (1H, q, J = 4.8, 11.5 Hz), 3.60 (1H, dd, J = 5.1, 13.9 Hz), 3.46–3.41 (1H, m), 3.24 (1H, dddd, J = 3.6, 9.7, 13.4 Hz), 3.15 (1H, dd, J = 7.1, 13.8 Hz), 2.52 (1H, bs), 2.38 (1H, dd, J = 10.6, 17.9 Hz), 1.97 (1H, dd, J = 4.7, 16.6 Hz), 1.87-1.78 (1H, m), 1.70–1.62 (1H, m), 1.18 (3H, t, J = 7.0 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 178.4, 155.5, 61.5, 51.1, 43.6, 39.3, 34.9, 27.6, 21.2, 14.7, HRMS m/z: C₁₀H₁₆KN₂O₃ calculated 251.0793 [M + H]⁺, found 251.0761.

S2.3. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. Upon initial refinement of the structure of (2-1) it became obvious that the five-membered ring was disordered over two possible positions and that both enanti­omers were present in the asymmetric unit. The reflection data and raw frames were examined and no signs of larger cells or twinning could be found. Structure solution was also attempted in the space groups P2₁ and Pn; in both cases, the disorder was still present. The structure was further examined for twinning with the PLATON (Spek, 2009) routine TWINROTMATR; again, no signs of twinning were found. During refinement, the occupancies of the two disorder components were refined competitively, converging at a ratio of 0.535 (3):0.465 (3). Although no geometric restraints were applied to the C, N and O atoms, it was necessary to restrain the N—H distances of (2-1) to 0.88 (3) Å, and also to restrain the C···H distances of this amine H atom to be approximately equal. The positions of the H atoms bound to atom C6 were refined, but all other H atoms of both (2-1) and (8-1) were placed in idealized positions and refined in riding modes, with C—H distances of 0.98, 0.99 and 1.00 Å for the CH₃, CH₂ and CH groups, respectively. U_iso(H) values were set at 1.5U_eq(C) for CH₃ groups and at 1.2U_eq(C,N) for all other H atoms.

S3. Results and discussion

The X-ray crystal structures of the separated isomers of la­ctam (2-1) and thiol­actam (8-1) were required to confirm the relative stereochemistry of the two separated cis and trans isomers as the ¹H NMR spectra could not categorically assign the relative stereochemistry of the synthesized and separated bicyclic ring systems.

In the case of compound (1-1), it was discovered that thiol­actam (8-1) proved highly crystalline and formed crystals of sufficient quality for X-ray crystallographic analysis. The synthesis of thio­amide (8-1) was achieved from ethyl 3-(3-eth­oxy-3-oxo­propyl)-4-oxo­piperidine-1-carboxyl­ate, (6), following a literature procedure (Shah et al., 2005), which was converted in a three-step synthesis (68% yield) to thiol­actam (8-1) (see Scheme 3).

The X-ray crystal structure analysis proved necessary for full structural characterization as the coupling constants in the NMR spectra for the separated diastereomers [(1-1) and (1-2)] could not be assigned completely due to the fact that the piperidine ring gave overlapping signals in the proton NMR spectra. The coupling constant ³J_HH for the syn-H atoms should be found in a range of 0-5 Hz and for the anti-H atoms in the range of 7–15 Hz (Reich, 2013).

The ¹H NMR spectra for the la­ctams displayed a clear difference for the ring-junction H atoms in both isomers (1-1) and (1-2) (Fig. 3). However, analysis of the ¹H NMR spectrum proved inconclusive as the spectrum clearly showed that only one coupling constant for the proton H_A of the isomer could be fully determined with ³J_HH = 9.8 Hz, for all other relevant H atoms was not possible to determine a clear coupling constant due to signal overlapping issues.

Fortunately, the conversion to the thiol­actam (8) delivered compound (8-1), which was crystalline and crystallized with two molecules in the asymmetric unit, which are related by a noncrystallographic axis of rotation, although they have different conformations of the carbamate chain (Figs. 4 and 5).

The crystal structure showed typical C—S bond lengths of 1.679 (2) and 1.686 (3) Å (Wiberg & Wang, 2011). The piperidine ring adopts a chair conformation with the carbamate group in an equatorial position, showing C5—N6—C11 angles of 119.3 (2)/121.5 (2)° and C7—N6—C11 angles of 123.5 (2)/123.8 (2)° for molecules A/B.

The torsion angles N1—C9—C10—C4 of 46.2 (3)/-46.8 (2)°, C8—C9—C10—C4 of -76.4 (2)/76.8 (3)° and C8—C9—C10—C5 of 49.2 (3)/-48.9 (3)° are all shown to be synclinal, and from the torsion angle N1—C9—C10—C5 of 171.73 (19)/-172.60 (19)° and the resulting anti­periplanar conformation it can be seen that the H atoms are arranged in a gauche conformation, giving rise to the chair-like conformation of the piperidine ring and the synclinal orientation of atoms H9 and H10 (Fig. 6).

For compounds (2-1) and (2-2), another synthetic route had to be established as the stable tert-butyl ester, (10), gave no direct conversion to the bicyclic la­ctam [(2-1) or (2-2)]. Ethyl 3-(2-tert-but­oxy-2-oxo­ethyl)-4-oxo­piperidine-1-carboxyl­ate, (9), was synthesised following the literature procedure for the BOC-protected compound (Hubschwerlen et al., 2008). The starting material was converted in a four-step synthesis into the desired isomers of the bicyclic la­ctam in an overall yield of 21%. It was found that the diastereomeric la­ctams [(2-1) and (2-2)] could be easily separated by flash chromatography.

Once more the ¹H NMR spectrum for the separated la­ctams [(2-1) and (2-2)] showed clear differences (Fig. 7). In this case, the coupling constant for H_A was ³J_HH = 10.1 Hz, which was the only measurable coupling constant due to extensive overlap of the other NMR signals (Fig. 7).

Compound (2-1) was recrystallized slowly from ethyl acetate to afford crystals of sufficient quality for structure determination. The compound was found to crystallize in the centrosymmetric space group P2₁/n, with one molecule in the asymmetric unit (Fig. 8).

Inter­estingly, the five-membered ring is disordered over two possible positions, so both enanti­omers are represented in the asymmetric unit. In this case, the overall packing of the crystal appears to be driven by the inter­actions of both the carbamate and the la­ctam functional groups. The molecules form hydrogen-bonded dimers, which pack in a classic herringbone fashion (Fig. 9). The piperidine ring crystallizes in a chair-like conformation and the C8—O15/C8A—O15A bond length is in the typical range at 1.234 (5)/1.237 (4) Å. The bond angle N9—C4—C3/N9—C4—C5 is 112.06 (15)/109.21 (16)° and C7—C3—C4/C7A—C5—C4 is 98.9 (2)/100.46 (18)°.

The torsion angles are determined as synclinal for C7—C3—C4—N9/C7A—C5—C4—N9 at -36.2 (2)/34.4 (2)° as well as for C2—C3—C4—C5/C6—C5—C4—C3 at 62.8 (2)/-63.0 (2)°. With the anti­periplanar torsion angles of -158.0 (2)/157.79 (19)° for C7—C3—C4—C5/C7A—C5—C4—C3 and -175.51 (15)/173.55 (16)° for C2—C3—C4—N9/C6—C5—C4—N9, the anti­periplanar positon of atoms H4 and H3, and hence the relative stereochemistry of the molecule was determined.

In conclusion, we have unambiguously determined the stereochemical outcome for the separated disatereomers of the molecular scaffolds (8-1)/(8-2) and (2-1)/(2-2) using X-ray crystallography. The X-ray analysis showed clearly the relative configuration of the bicyclic ring systems, resulting in a synclinal orientation for the [6,6] bicyclic ring system and an anti­periplanar configuration for the [6,5] ring system. The ¹H NMR comparison of compounds (1-1)/(1-2) and (2-1)/(2-2) showed a clear difference in the chemical shifts of the separated diastereoisomers, but could not be used to unambiguously assign the relative configurations of the separated cis and trans diastereoisomers.

Related literature

For related literature, see: Borne et al. (1984); DeSimone, Currie, Mitchell, Darrow & Pippin (2004); Fevig et al. (2006); Filmore (2004); Hall (1997); Hu et al. (2005); Hubschwerlen et al. (2008); Martini et al. (2011); Occhiato et al. (2004); Raote et al. (2007); Reich (2013); Shah et al. (2005); Spek (2009); Wacker et al. (2013); Wang et al. (2013); Welsch et al. (2010); Wiberg & Wang (2011); Yogi et al. (2009).

Computing details

For both compounds, data collection: CrysAlis PRO (Agilent, 2013); cell refinement: CrysAlis PRO (Agilent, 2013); data reduction: CrysAlis PRO (Agilent, 2013). Program(s) used to solve structure: OLEX2.SOLVE (Bourhis et al., 2014) for (I); OLEX2.SOLVE (Bourhis et al., 2014) for (II). Program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008) for (I); SHELXL2014 (Sheldrick, 2008) for (II). For both compounds, molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Figures

	Fig. 1. The molecular structures of the two rotamers of racemic (4aS,8aR)-(8-1). Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. An overlay of the two molecules of isomer (2-1) in the asymmetric unit, showing the different conformations of the carbamate chain.
	Fig. 3. ^1H NMR data for compound (1), showing isomer (1-2) in the upper spectrum and isomer (1-1) in the lower spectrum.
	Fig. 4. An overlay of the two molecules of isomer (8-1) in the asymmetric unit, showing the different conformations of the carbamate chain.
	Fig. 5. The packing of isomer (8-1).
	Fig. 6. ^1H NMR data for compound (2), showing isomer (2-2) in the upper spectrum and isomer (2-1) in the lower spectrum.
	Fig. 7. The herringbone packing of isomer (2-1) in the bc plane.

(I) (±)-cis-Ethyl 2-sulfanylidenedecahydro-1,6-naphthyridine-6-carboxylate

Crystal data

C11H18N2O2S	Dx = 1.316 Mg m^−3
Mr = 242.33	Cu Kα radiation, λ = 1.54184 Å
Orthorhombic, Pna21	Cell parameters from 13043 reflections
a = 15.06714 (17) Å	θ = 4.5–77.8°
b = 8.30759 (8) Å	µ = 2.26 mm^−1
c = 19.5481 (2) Å	T = 120 K
V = 2446.87 (5) Å^3	Plate, clear colourless
Z = 8	0.15 × 0.12 × 0.05 mm
F(000) = 1040

Data collection

GV1000 diffractometer	5117 independent reflections
Radiation source: microfocus sealed tube, Agilent Diffraction microfocus tube	5030 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.026
Detector resolution: 10.6296 pixels mm^-1	θmax = 77.9°, θmin = 4.5°
ω scans	h = −19→18
Absorption correction: gaussian (CrysAlis PRO; Agilent, 2013)	k = −10→9
Tmin = 0.769, Tmax = 0.976	l = −24→23
21836 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.034	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.091	w = 1/[σ^2(Fo^2) + (0.0615P)^2 + 0.418P] where P = (Fo^2 + 2Fc^2)/3
S = 1.07	(Δ/σ)max < 0.001
5117 reflections	Δρmax = 0.61 e Å^−3
297 parameters	Δρmin = −0.20 e Å^−3
1 restraint	Absolute structure: Flack x determined using 2311 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons & Flack, 2004)
Primary atom site location: iterative	Absolute structure parameter: 0.067 (6)

Special details

Experimental. Absorption correction: CrysAlisPro, Agilent Technologies, Version 1.171.36.28a (release 18-03-2013 CrysAlis171 .NET) (compiled Mar 18 2013,11:47:30) Numerical absorption correction based on gaussian integration over a multifaceted crystal model

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. 1. Fixed Uiso At 1.2 times of: All C(H) groups, All C(H,H) groups, All N(H) groups At 1.5 times of: All C(H,H,H) groups 2.a Ternary CH refined with riding coordinates: C9A(H9A), C10A(H10A), C9B(H9B), C10B(H10B) 2.b Secondary CH2 refined with riding coordinates: C3A(H3AA,H3AB), C4A(H4AA,H4AB), C5A(H5AA,H5AB), C7A(H7AA,H7AB), C8A(H8AA, H8AB), C14A(H14A,H14B), C3B(H3BA,H3BB), C4B(H4BA,H4BB), C5B(H5BA,H5BB), C7B(H7BA,H7BB), C8B(H8BA,H8BB), C14B(H14C,H14D) 2.c Idealised Me refined as rotating group: C15A(H15A,H15B,H15C), C15B(H15D,H15E,H15F)

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
N1A	0.37864 (14)	0.8201 (3)	0.34763 (11)	0.0218 (4)
H1A	0.431 (2)	0.843 (4)	0.3636 (18)	0.026*
C2A	0.37282 (16)	0.7541 (3)	0.28650 (12)	0.0203 (5)
C3A	0.28143 (17)	0.7196 (3)	0.25801 (13)	0.0253 (5)
H3AA	0.2833	0.6157	0.2333	0.030*
H3AB	0.2663	0.8043	0.2244	0.030*
C4A	0.20793 (17)	0.7118 (3)	0.31162 (13)	0.0232 (5)
H4AA	0.2133	0.6111	0.3384	0.028*
H4AB	0.1492	0.7122	0.2889	0.028*
C5A	0.14022 (18)	0.8679 (3)	0.41139 (14)	0.0277 (5)
H5AA	0.1408	0.9757	0.4329	0.033*
H5AB	0.0827	0.8547	0.3876	0.033*
N6A	0.14841 (15)	0.7444 (3)	0.46469 (11)	0.0255 (4)
C7A	0.23147 (18)	0.7537 (3)	0.50294 (13)	0.0249 (5)
H7AA	0.2325	0.6691	0.5386	0.030*
H7AB	0.2360	0.8597	0.5258	0.030*
C8A	0.30997 (16)	0.7311 (3)	0.45444 (13)	0.0223 (5)
H8AA	0.3088	0.6207	0.4353	0.027*
H8AB	0.3662	0.7445	0.4800	0.027*
C9A	0.30603 (16)	0.8542 (3)	0.39585 (12)	0.0213 (5)
H9A	0.3165	0.9635	0.4158	0.026*
C10A	0.21577 (16)	0.8569 (3)	0.35911 (13)	0.0224 (5)
H10A	0.2136	0.9561	0.3302	0.027*
C11A	0.09854 (16)	0.6094 (3)	0.46049 (12)	0.0233 (5)
O12A	0.03464 (12)	0.5909 (3)	0.42264 (11)	0.0325 (4)
O13A	0.12539 (11)	0.4943 (2)	0.50474 (9)	0.0236 (4)
C14A	0.07651 (16)	0.3441 (3)	0.49856 (13)	0.0256 (5)
H14A	0.0819	0.3013	0.4515	0.031*
H14B	0.0129	0.3622	0.5085	0.031*
C15A	0.1152 (2)	0.2266 (3)	0.54899 (15)	0.0323 (6)
H15A	0.1781	0.2091	0.5385	0.049*
H15B	0.0833	0.1241	0.5459	0.049*
H15C	0.1095	0.2700	0.5954	0.049*
S16A	0.46349 (4)	0.71731 (7)	0.23903 (3)	0.02460 (15)
N1B	0.34317 (14)	0.1975 (2)	0.27186 (12)	0.0225 (4)
H1B	0.293 (2)	0.184 (4)	0.2560 (18)	0.027*
C2B	0.34770 (17)	0.2656 (3)	0.33252 (13)	0.0221 (5)
C3B	0.43783 (18)	0.3088 (4)	0.36040 (15)	0.0304 (6)
H3BA	0.4532	0.2312	0.3969	0.036*
H3BB	0.4341	0.4168	0.3817	0.036*
C4B	0.51294 (17)	0.3104 (3)	0.30797 (13)	0.0239 (5)
H4BA	0.5087	0.4083	0.2793	0.029*
H4BB	0.5710	0.3116	0.3317	0.029*
C5B	0.58308 (17)	0.1437 (3)	0.21291 (14)	0.0263 (5)
H5BA	0.6396	0.1628	0.2374	0.032*
H5BB	0.5842	0.0322	0.1950	0.032*
N6B	0.57620 (15)	0.2563 (3)	0.15571 (12)	0.0254 (4)
C7B	0.49354 (19)	0.2409 (4)	0.11689 (14)	0.0302 (6)
H7BA	0.4884	0.1307	0.0981	0.036*
H7BB	0.4936	0.3178	0.0782	0.036*
C8B	0.41511 (18)	0.2757 (3)	0.16390 (13)	0.0252 (5)
H8BA	0.3589	0.2619	0.1384	0.030*
H8BB	0.4182	0.3883	0.1803	0.030*
C9B	0.41713 (16)	0.1599 (3)	0.22531 (12)	0.0222 (5)
H9B	0.4075	0.0485	0.2074	0.027*
C10B	0.50574 (15)	0.1610 (3)	0.26325 (13)	0.0213 (4)
H10B	0.5067	0.0651	0.2942	0.026*
C11B	0.63325 (16)	0.3799 (3)	0.14858 (13)	0.0230 (5)
O12B	0.69827 (12)	0.4034 (2)	0.18489 (11)	0.0287 (4)
O13B	0.61209 (13)	0.4729 (2)	0.09457 (10)	0.0293 (4)
C14B	0.67052 (19)	0.6075 (3)	0.07952 (15)	0.0306 (5)
H14C	0.6742	0.6235	0.0294	0.037*
H14D	0.7309	0.5842	0.0968	0.037*
C15B	0.6353 (2)	0.7581 (4)	0.11298 (15)	0.0328 (6)
H15D	0.5739	0.7763	0.0984	0.049*
H15E	0.6720	0.8502	0.0995	0.049*
H15F	0.6372	0.7456	0.1628	0.049*
S16B	0.25652 (4)	0.29812 (7)	0.38058 (3)	0.02587 (15)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1A	0.0178 (10)	0.0224 (9)	0.0253 (10)	−0.0026 (8)	−0.0028 (8)	0.0020 (8)
C2A	0.0230 (12)	0.0140 (9)	0.0238 (11)	−0.0001 (9)	−0.0023 (9)	0.0041 (8)
C3A	0.0197 (12)	0.0312 (12)	0.0248 (12)	0.0004 (9)	−0.0042 (9)	−0.0001 (9)
C4A	0.0186 (11)	0.0242 (11)	0.0268 (12)	−0.0008 (8)	−0.0031 (9)	0.0039 (9)
C5A	0.0241 (12)	0.0275 (12)	0.0316 (13)	0.0064 (10)	0.0021 (10)	0.0057 (10)
N6A	0.0217 (10)	0.0292 (10)	0.0255 (11)	0.0023 (9)	0.0011 (8)	0.0054 (9)
C7A	0.0264 (12)	0.0257 (12)	0.0228 (11)	−0.0016 (10)	0.0001 (10)	0.0005 (10)
C8A	0.0200 (11)	0.0220 (11)	0.0247 (12)	−0.0005 (9)	−0.0025 (9)	0.0003 (9)
C9A	0.0211 (11)	0.0176 (10)	0.0251 (11)	−0.0006 (8)	−0.0006 (9)	−0.0012 (8)
C10A	0.0207 (11)	0.0194 (11)	0.0271 (11)	0.0022 (9)	0.0000 (9)	0.0048 (9)
C11A	0.0173 (10)	0.0297 (12)	0.0230 (11)	0.0045 (9)	0.0025 (9)	0.0022 (9)
O12A	0.0206 (9)	0.0413 (11)	0.0357 (10)	−0.0013 (8)	−0.0054 (7)	0.0076 (8)
O13A	0.0213 (7)	0.0252 (9)	0.0241 (8)	−0.0016 (7)	−0.0021 (6)	0.0019 (7)
C14A	0.0197 (11)	0.0287 (12)	0.0283 (12)	−0.0058 (9)	0.0003 (9)	−0.0009 (10)
C15A	0.0355 (14)	0.0304 (13)	0.0311 (14)	−0.0042 (11)	−0.0023 (12)	0.0033 (10)
S16A	0.0218 (3)	0.0232 (3)	0.0288 (3)	0.0009 (2)	0.0021 (2)	0.0004 (2)
N1B	0.0169 (10)	0.0226 (10)	0.0280 (11)	−0.0021 (7)	−0.0015 (8)	0.0010 (8)
C2B	0.0207 (11)	0.0179 (11)	0.0276 (11)	0.0022 (9)	−0.0020 (9)	0.0025 (9)
C3B	0.0216 (12)	0.0394 (15)	0.0302 (13)	0.0001 (10)	−0.0054 (10)	−0.0069 (11)
C4B	0.0195 (11)	0.0235 (11)	0.0285 (12)	−0.0009 (9)	−0.0056 (9)	0.0009 (10)
C5B	0.0233 (11)	0.0227 (12)	0.0328 (12)	0.0009 (10)	0.0018 (10)	0.0016 (10)
N6B	0.0230 (10)	0.0284 (10)	0.0248 (10)	−0.0058 (9)	−0.0010 (8)	0.0006 (9)
C7B	0.0280 (13)	0.0392 (14)	0.0235 (12)	−0.0104 (12)	−0.0023 (10)	−0.0015 (11)
C8B	0.0235 (11)	0.0285 (13)	0.0238 (11)	−0.0037 (9)	−0.0048 (10)	0.0018 (9)
C9B	0.0198 (11)	0.0206 (10)	0.0261 (12)	−0.0024 (9)	−0.0008 (9)	−0.0014 (9)
C10B	0.0180 (10)	0.0182 (10)	0.0278 (11)	0.0005 (9)	0.0004 (9)	0.0034 (9)
C11B	0.0183 (10)	0.0251 (11)	0.0255 (11)	0.0007 (9)	0.0038 (9)	−0.0015 (9)
O12B	0.0185 (8)	0.0292 (9)	0.0385 (10)	−0.0016 (7)	−0.0041 (7)	0.0015 (8)
O13B	0.0272 (8)	0.0307 (10)	0.0299 (9)	−0.0050 (7)	−0.0003 (7)	0.0056 (7)
C14B	0.0304 (13)	0.0290 (13)	0.0325 (13)	−0.0021 (11)	0.0073 (10)	0.0025 (11)
C15B	0.0297 (13)	0.0355 (14)	0.0332 (14)	0.0048 (11)	−0.0010 (11)	−0.0016 (12)
S16B	0.0217 (3)	0.0227 (3)	0.0332 (3)	0.0018 (2)	0.0025 (2)	−0.0009 (2)

Geometric parameters (Å, º)

N1A—H1A	0.87 (4)	N1B—H1B	0.83 (4)
N1A—C2A	1.318 (3)	N1B—C2B	1.315 (3)
N1A—C9A	1.472 (3)	N1B—C9B	1.472 (3)
C2A—C3A	1.513 (3)	C2B—C3B	1.507 (3)
C2A—S16A	1.679 (2)	C2B—S16B	1.686 (3)
C3A—H3AA	0.9900	C3B—H3BA	0.9900
C3A—H3AB	0.9900	C3B—H3BB	0.9900
C3A—C4A	1.526 (4)	C3B—C4B	1.527 (4)
C4A—H4AA	0.9900	C4B—H4BA	0.9900
C4A—H4AB	0.9900	C4B—H4BB	0.9900
C4A—C10A	1.526 (3)	C4B—C10B	1.522 (3)
C5A—H5AA	0.9900	C5B—H5BA	0.9900
C5A—H5AB	0.9900	C5B—H5BB	0.9900
C5A—N6A	1.467 (3)	C5B—N6B	1.461 (3)
C5A—C10A	1.533 (3)	C5B—C10B	1.532 (3)
N6A—C7A	1.460 (3)	N6B—C7B	1.464 (3)
N6A—C11A	1.352 (4)	N6B—C11B	1.347 (3)
C7A—H7AA	0.9900	C7B—H7BA	0.9900
C7A—H7AB	0.9900	C7B—H7BB	0.9900
C7A—C8A	1.527 (3)	C7B—C8B	1.525 (4)
C8A—H8AA	0.9900	C8B—H8BA	0.9900
C8A—H8AB	0.9900	C8B—H8BB	0.9900
C8A—C9A	1.537 (3)	C8B—C9B	1.539 (3)
C9A—H9A	1.0000	C9B—H9B	1.0000
C9A—C10A	1.538 (3)	C9B—C10B	1.527 (3)
C10A—H10A	1.0000	C10B—H10B	1.0000
C11A—O12A	1.224 (3)	C11B—O12B	1.225 (3)
C11A—O13A	1.351 (3)	C11B—O13B	1.347 (3)
O13A—C14A	1.454 (3)	O13B—C14B	1.453 (3)
C14A—H14A	0.9900	C14B—H14C	0.9900
C14A—H14B	0.9900	C14B—H14D	0.9900
C14A—C15A	1.505 (4)	C14B—C15B	1.508 (4)
C15A—H15A	0.9800	C15B—H15D	0.9800
C15A—H15B	0.9800	C15B—H15E	0.9800
C15A—H15C	0.9800	C15B—H15F	0.9800
C2A—N1A—H1A	118 (2)	C2B—N1B—H1B	116 (2)
C2A—N1A—C9A	127.7 (2)	C2B—N1B—C9B	127.5 (2)
C9A—N1A—H1A	114 (2)	C9B—N1B—H1B	116 (2)
N1A—C2A—C3A	118.3 (2)	N1B—C2B—C3B	118.4 (2)
N1A—C2A—S16A	121.51 (18)	N1B—C2B—S16B	121.93 (19)
C3A—C2A—S16A	120.16 (18)	C3B—C2B—S16B	119.6 (2)
C2A—C3A—H3AA	108.6	C2B—C3B—H3BA	108.5
C2A—C3A—H3AB	108.6	C2B—C3B—H3BB	108.5
C2A—C3A—C4A	114.6 (2)	C2B—C3B—C4B	115.3 (2)
H3AA—C3A—H3AB	107.6	H3BA—C3B—H3BB	107.5
C4A—C3A—H3AA	108.6	C4B—C3B—H3BA	108.5
C4A—C3A—H3AB	108.6	C4B—C3B—H3BB	108.5
C3A—C4A—H4AA	109.9	C3B—C4B—H4BA	109.9
C3A—C4A—H4AB	109.9	C3B—C4B—H4BB	109.9
C3A—C4A—C10A	109.1 (2)	H4BA—C4B—H4BB	108.3
H4AA—C4A—H4AB	108.3	C10B—C4B—C3B	109.0 (2)
C10A—C4A—H4AA	109.9	C10B—C4B—H4BA	109.9
C10A—C4A—H4AB	109.9	C10B—C4B—H4BB	109.9
H5AA—C5A—H5AB	107.9	H5BA—C5B—H5BB	107.9
N6A—C5A—H5AA	109.3	N6B—C5B—H5BA	109.2
N6A—C5A—H5AB	109.3	N6B—C5B—H5BB	109.2
N6A—C5A—C10A	111.7 (2)	N6B—C5B—C10B	112.2 (2)
C10A—C5A—H5AA	109.3	C10B—C5B—H5BA	109.2
C10A—C5A—H5AB	109.3	C10B—C5B—H5BB	109.2
C7A—N6A—C5A	113.5 (2)	C5B—N6B—C7B	113.7 (2)
C11A—N6A—C5A	119.3 (2)	C11B—N6B—C5B	121.5 (2)
C11A—N6A—C7A	123.5 (2)	C11B—N6B—C7B	123.8 (2)
N6A—C7A—H7AA	109.7	N6B—C7B—H7BA	109.8
N6A—C7A—H7AB	109.7	N6B—C7B—H7BB	109.8
N6A—C7A—C8A	109.8 (2)	N6B—C7B—C8B	109.3 (2)
H7AA—C7A—H7AB	108.2	H7BA—C7B—H7BB	108.3
C8A—C7A—H7AA	109.7	C8B—C7B—H7BA	109.8
C8A—C7A—H7AB	109.7	C8B—C7B—H7BB	109.8
C7A—C8A—H8AA	109.5	C7B—C8B—H8BA	109.7
C7A—C8A—H8AB	109.5	C7B—C8B—H8BB	109.7
C7A—C8A—C9A	110.5 (2)	C7B—C8B—C9B	109.7 (2)
H8AA—C8A—H8AB	108.1	H8BA—C8B—H8BB	108.2
C9A—C8A—H8AA	109.5	C9B—C8B—H8BA	109.7
C9A—C8A—H8AB	109.5	C9B—C8B—H8BB	109.7
N1A—C9A—C8A	108.69 (19)	N1B—C9B—C8B	109.5 (2)
N1A—C9A—H9A	107.9	N1B—C9B—H9B	107.6
N1A—C9A—C10A	111.15 (19)	N1B—C9B—C10B	111.11 (19)
C8A—C9A—H9A	107.9	C8B—C9B—H9B	107.6
C8A—C9A—C10A	113.1 (2)	C10B—C9B—C8B	113.1 (2)
C10A—C9A—H9A	107.9	C10B—C9B—H9B	107.6
C4A—C10A—C5A	113.3 (2)	C4B—C10B—C5B	113.0 (2)
C4A—C10A—C9A	109.94 (19)	C4B—C10B—C9B	110.3 (2)
C4A—C10A—H10A	107.7	C4B—C10B—H10B	107.6
C5A—C10A—C9A	110.3 (2)	C5B—C10B—H10B	107.6
C5A—C10A—H10A	107.7	C9B—C10B—C5B	110.6 (2)
C9A—C10A—H10A	107.7	C9B—C10B—H10B	107.6
O12A—C11A—N6A	125.3 (2)	N6B—C11B—O13B	111.6 (2)
O12A—C11A—O13A	122.2 (2)	O12B—C11B—N6B	124.9 (2)
O13A—C11A—N6A	112.4 (2)	O12B—C11B—O13B	123.5 (2)
C11A—O13A—C14A	113.73 (19)	C11B—O13B—C14B	117.2 (2)
O13A—C14A—H14A	110.1	O13B—C14B—H14C	109.7
O13A—C14A—H14B	110.1	O13B—C14B—H14D	109.7
O13A—C14A—C15A	107.8 (2)	O13B—C14B—C15B	109.7 (2)
H14A—C14A—H14B	108.5	H14C—C14B—H14D	108.2
C15A—C14A—H14A	110.1	C15B—C14B—H14C	109.7
C15A—C14A—H14B	110.1	C15B—C14B—H14D	109.7
C14A—C15A—H15A	109.5	C14B—C15B—H15D	109.5
C14A—C15A—H15B	109.5	C14B—C15B—H15E	109.5
C14A—C15A—H15C	109.5	C14B—C15B—H15F	109.5
H15A—C15A—H15B	109.5	H15D—C15B—H15E	109.5
H15A—C15A—H15C	109.5	H15D—C15B—H15F	109.5
H15B—C15A—H15C	109.5	H15E—C15B—H15F	109.5
N1A—C2A—C3A—C4A	−19.9 (3)	N1B—C2B—C3B—C4B	15.6 (3)
N1A—C9A—C10A—C4A	46.2 (3)	N1B—C9B—C10B—C4B	−46.8 (3)
N1A—C9A—C10A—C5A	171.73 (19)	N1B—C9B—C10B—C5B	−172.60 (19)
C2A—N1A—C9A—C8A	105.9 (3)	C2B—N1B—C9B—C8B	−108.1 (3)
C2A—N1A—C9A—C10A	−19.2 (3)	C2B—N1B—C9B—C10B	17.6 (3)
C2A—C3A—C4A—C10A	47.5 (3)	C2B—C3B—C4B—C10B	−44.9 (3)
C3A—C4A—C10A—C5A	175.3 (2)	C3B—C4B—C10B—C5B	−174.9 (2)
C3A—C4A—C10A—C9A	−60.9 (2)	C3B—C4B—C10B—C9B	60.7 (3)
C5A—N6A—C7A—C8A	−60.5 (3)	C5B—N6B—C7B—C8B	61.1 (3)
C5A—N6A—C11A—O12A	−13.9 (4)	C5B—N6B—C11B—O12B	5.4 (4)
C5A—N6A—C11A—O13A	167.7 (2)	C5B—N6B—C11B—O13B	−176.8 (2)
N6A—C5A—C10A—C4A	72.3 (3)	N6B—C5B—C10B—C4B	−74.7 (3)
N6A—C5A—C10A—C9A	−51.4 (3)	N6B—C5B—C10B—C9B	49.5 (3)
N6A—C7A—C8A—C9A	55.5 (3)	N6B—C7B—C8B—C9B	−57.5 (3)
N6A—C11A—O13A—C14A	−176.5 (2)	N6B—C11B—O13B—C14B	−177.7 (2)
C7A—N6A—C11A—O12A	−170.7 (2)	C7B—N6B—C11B—O12B	172.6 (3)
C7A—N6A—C11A—O13A	10.9 (3)	C7B—N6B—C11B—O13B	−9.6 (3)
C7A—C8A—C9A—N1A	−175.6 (2)	C7B—C8B—C9B—N1B	178.0 (2)
C7A—C8A—C9A—C10A	−51.7 (3)	C7B—C8B—C9B—C10B	53.5 (3)
C8A—C9A—C10A—C4A	−76.4 (2)	C8B—C9B—C10B—C4B	76.8 (3)
C8A—C9A—C10A—C5A	49.2 (3)	C8B—C9B—C10B—C5B	−48.9 (3)
C9A—N1A—C2A—C3A	5.5 (4)	C9B—N1B—C2B—C3B	−1.5 (4)
C9A—N1A—C2A—S16A	−177.68 (18)	C9B—N1B—C2B—S16B	−178.93 (18)
C10A—C5A—N6A—C7A	59.0 (3)	C10B—C5B—N6B—C7B	−57.4 (3)
C10A—C5A—N6A—C11A	−100.1 (3)	C10B—C5B—N6B—C11B	111.0 (3)
C11A—N6A—C7A—C8A	97.6 (3)	C11B—N6B—C7B—C8B	−107.0 (3)
C11A—O13A—C14A—C15A	178.2 (2)	C11B—O13B—C14B—C15B	−94.5 (3)
O12A—C11A—O13A—C14A	5.1 (3)	O12B—C11B—O13B—C14B	0.1 (4)
S16A—C2A—C3A—C4A	163.27 (17)	S16B—C2B—C3B—C4B	−166.86 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1A—H1A···O12A^i	0.87 (4)	2.02 (4)	2.867 (3)	165 (3)
N1B—H1B···O12B^ii	0.83 (4)	2.12 (4)	2.891 (3)	155 (3)

Symmetry codes: (i) x+1/2, −y+3/2, z; (ii) x−1/2, −y+1/2, z.

(II)

Crystal data

C10H16N2O3	F(000) = 456
Mr = 212.25	Dx = 1.326 Mg m^−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54184 Å
a = 8.5204 (6) Å	Cell parameters from 2539 reflections
b = 6.4089 (4) Å	θ = 4.5–73.6°
c = 19.5921 (16) Å	µ = 0.82 mm^−1
β = 96.381 (8)°	T = 120 K
V = 1063.22 (14) Å^3	Plate, clear colourless
Z = 4	0.33 × 0.14 × 0.08 mm

Data collection

GV1000 Atlas diffractometer	2130 independent reflections
Radiation source: microfocus sealed tube, Agilent Diffraction microfocus tube	1748 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.040
Detector resolution: 10.3271 pixels mm^-1	θmax = 74.9°, θmin = 4.5°
ω scans	h = −10→9
Absorption correction: gaussian (CrysAlis PRO; Agilent, 2013)	k = −7→7
Tmin = 0.906, Tmax = 1.120	l = −24→24
6951 measured reflections

Refinement

Refinement on F^2	Primary atom site location: iterative
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.048	Hydrogen site location: mixed
wR(F^2) = 0.136	H atoms treated by a mixture of independent and constrained refinement
S = 1.06	w = 1/[σ^2(Fo^2) + (0.0744P)^2 + 0.219P] where P = (Fo^2 + 2Fc^2)/3
2130 reflections	(Δ/σ)max < 0.001
177 parameters	Δρmax = 0.22 e Å^−3
5 restraints	Δρmin = −0.21 e Å^−3

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. The five-membered ring is disordered over two possible orientations; the occupancies were refined competitively, converging at a ratio of 0.54:0.46. The N-H bond distances were restrained to apprximately 0.88 Å, and the appropriate 1,3 C···H bond distances were restrained to be approximately equal.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
O12	0.34143 (12)	0.79593 (15)	0.33551 (5)	0.0303 (3)
O11	0.54957 (13)	0.94865 (16)	0.29389 (6)	0.0384 (3)
N1	0.57915 (14)	0.64122 (19)	0.35262 (6)	0.0321 (3)
C13	0.24599 (18)	0.9710 (2)	0.30787 (8)	0.0353 (4)
H13A	0.2625	0.9956	0.2593	0.042*
H13B	0.2754	1.0993	0.3344	0.042*
N9	0.87329 (18)	0.1893 (2)	0.45527 (7)	0.0433 (4)
H9A	0.970 (2)	0.148 (5)	0.457 (2)	0.052*	0.467 (3)
H9B	0.863 (4)	0.080 (4)	0.4805 (17)	0.052*	0.533 (3)
C14	0.07644 (18)	0.9158 (3)	0.31336 (8)	0.0370 (4)
H14A	0.0480	0.7912	0.2857	0.055*
H14B	0.0084	1.0323	0.2964	0.055*
H14C	0.0624	0.8879	0.3615	0.055*
C10	0.49508 (17)	0.8054 (2)	0.32461 (7)	0.0295 (3)
C3	0.6133 (2)	0.3487 (3)	0.43415 (9)	0.0501 (5)
H3A	0.6377	0.4562	0.4708	0.060*	0.467 (3)
H3BA	0.6306	0.4388	0.4753	0.060*	0.533 (3)
H3BB	0.5657	0.2160	0.4476	0.060*	0.533 (3)
C2	0.5023 (2)	0.4565 (2)	0.37905 (9)	0.0377 (4)
H2A	0.4722	0.3580	0.3409	0.045*
H2B	0.4050	0.4996	0.3985	0.045*
C4	0.7670 (2)	0.3061 (3)	0.40715 (9)	0.0473 (5)
H4	0.7461	0.2229	0.3639	0.057*
C5	0.8442 (2)	0.5074 (3)	0.39061 (12)	0.0569 (5)
H5AA	0.9493	0.4788	0.3756	0.068*	0.467 (3)
H5AB	0.8592	0.5965	0.4321	0.068*	0.467 (3)
H5B	0.8401	0.5963	0.4323	0.068*	0.533 (3)
C6	0.7414 (2)	0.6195 (3)	0.33408 (10)	0.0433 (4)
O15A	1.1508 (3)	0.1817 (5)	0.46728 (12)	0.0447 (6)	0.533 (3)
C7	0.5974 (5)	0.1598 (5)	0.46973 (17)	0.0402 (9)	0.467 (3)
H7A	0.5329	0.0595	0.4401	0.048*	0.467 (3)
H7B	0.5447	0.1851	0.5115	0.048*	0.467 (3)
C8	0.7622 (5)	0.0728 (6)	0.48912 (16)	0.0428 (9)	0.467 (3)
O15	0.7973 (4)	−0.0716 (6)	0.52967 (14)	0.0532 (8)	0.467 (3)
C7A	1.0055 (4)	0.4418 (5)	0.39332 (16)	0.0387 (7)	0.533 (3)
H7AA	1.0774	0.5568	0.4098	0.046*	0.533 (3)
H7AB	1.0303	0.3984	0.3472	0.046*	0.533 (3)
C8A	1.0236 (4)	0.2586 (5)	0.44299 (14)	0.0362 (7)	0.533 (3)
H6A	0.736 (2)	0.537 (3)	0.2890 (11)	0.043*
H6B	0.776 (2)	0.755 (3)	0.3260 (10)	0.043*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O12	0.0238 (5)	0.0269 (5)	0.0393 (5)	0.0012 (4)	−0.0011 (4)	0.0048 (4)
O11	0.0278 (6)	0.0313 (6)	0.0558 (7)	−0.0010 (4)	0.0029 (5)	0.0104 (5)
N1	0.0256 (7)	0.0299 (6)	0.0393 (7)	0.0023 (5)	−0.0027 (5)	0.0059 (5)
C13	0.0268 (8)	0.0293 (7)	0.0484 (8)	0.0042 (6)	−0.0018 (6)	0.0073 (6)
N9	0.0427 (9)	0.0477 (8)	0.0378 (7)	0.0196 (6)	−0.0024 (6)	0.0089 (6)
C14	0.0265 (8)	0.0397 (8)	0.0435 (8)	0.0021 (6)	−0.0017 (6)	−0.0012 (6)
C10	0.0256 (7)	0.0278 (7)	0.0334 (7)	−0.0013 (5)	−0.0040 (5)	−0.0009 (5)
C3	0.0605 (12)	0.0471 (10)	0.0407 (9)	0.0213 (8)	−0.0031 (8)	0.0080 (7)
C2	0.0340 (8)	0.0344 (8)	0.0437 (8)	0.0015 (6)	−0.0008 (6)	0.0099 (6)
C4	0.0507 (11)	0.0418 (9)	0.0454 (9)	0.0178 (8)	−0.0120 (8)	0.0035 (7)
C5	0.0413 (11)	0.0453 (10)	0.0775 (14)	0.0097 (8)	−0.0229 (9)	0.0030 (9)
C6	0.0269 (8)	0.0411 (9)	0.0613 (11)	0.0055 (7)	0.0016 (7)	0.0126 (8)
O15A	0.0391 (14)	0.0505 (16)	0.0423 (12)	0.0169 (11)	−0.0059 (10)	0.0069 (10)
C7	0.048 (2)	0.0383 (17)	0.0321 (15)	0.0117 (15)	−0.0030 (14)	0.0042 (13)
C8	0.052 (2)	0.0459 (19)	0.0278 (15)	0.0212 (17)	−0.0084 (14)	−0.0001 (13)
O15	0.062 (2)	0.0534 (19)	0.0417 (14)	0.0265 (16)	−0.0050 (13)	0.0092 (13)
C7A	0.0272 (15)	0.0395 (15)	0.0472 (16)	0.0072 (11)	−0.0050 (12)	0.0058 (12)
C8A	0.0356 (16)	0.0384 (15)	0.0331 (13)	0.0111 (12)	−0.0026 (11)	0.0006 (12)

Geometric parameters (Å, º)

O12—C13	1.4547 (17)	C3—C4	1.492 (3)
O12—C10	1.3510 (18)	C3—C7	1.411 (4)
O11—C10	1.2176 (18)	C2—H2A	0.9900
N1—C10	1.3545 (18)	C2—H2B	0.9900
N1—C2	1.4744 (19)	C4—H4	1.0000
N1—C6	1.474 (2)	C4—C5	1.500 (3)
C13—H13A	0.9900	C5—H5AA	0.9900
C13—H13B	0.9900	C5—H5AB	0.9900
C13—C14	1.503 (2)	C5—H5B	1.0000
N9—H9A	0.867 (15)	C5—C6	1.515 (2)
N9—H9B	0.869 (15)	C5—C7A	1.432 (4)
N9—C4	1.442 (2)	C6—H6A	1.03 (2)
N9—C8	1.426 (5)	C6—H6B	0.93 (2)
N9—C8A	1.401 (4)	O15A—C8A	1.237 (4)
C14—H14A	0.9800	C7—H7A	0.9900
C14—H14B	0.9800	C7—H7B	0.9900
C14—H14C	0.9800	C7—C8	1.519 (5)
C3—H3A	1.0000	C8—O15	1.234 (5)
C3—H3BA	0.9900	C7A—H7AA	0.9900
C3—H3BB	0.9900	C7A—H7AB	0.9900
C3—C2	1.519 (2)	C7A—C8A	1.522 (4)
C10—O12—C13	114.69 (11)	N9—C4—C3	112.06 (15)
C10—N1—C2	122.06 (12)	N9—C4—H4	108.5
C10—N1—C6	116.22 (12)	N9—C4—C5	109.21 (16)
C2—N1—C6	118.40 (12)	C3—C4—H4	108.5
O12—C13—H13A	110.3	C3—C4—C5	110.04 (16)
O12—C13—H13B	110.3	C5—C4—H4	108.5
O12—C13—C14	107.08 (12)	C4—C5—H5AA	109.8
H13A—C13—H13B	108.6	C4—C5—H5AB	109.8
C14—C13—H13A	110.3	C4—C5—H5B	104.9
C14—C13—H13B	110.3	C4—C5—C6	109.51 (16)
C4—N9—H9A	136 (2)	H5AA—C5—H5AB	108.2
C4—N9—H9B	134 (2)	C6—C5—H5AA	109.8
C8—N9—H9A	120 (2)	C6—C5—H5AB	109.8
C8—N9—C4	100.08 (19)	C6—C5—H5B	104.9
C8A—N9—H9B	120 (2)	C7A—C5—C4	100.46 (18)
C8A—N9—C4	104.05 (17)	C7A—C5—H5B	104.9
C13—C14—H14A	109.5	C7A—C5—C6	129.8 (2)
C13—C14—H14B	109.5	N1—C6—C5	110.28 (16)
C13—C14—H14C	109.5	N1—C6—H6A	108.1 (11)
H14A—C14—H14B	109.5	N1—C6—H6B	106.2 (12)
H14A—C14—H14C	109.5	C5—C6—H6A	110.5 (11)
H14B—C14—H14C	109.5	C5—C6—H6B	113.3 (13)
O12—C10—N1	112.27 (12)	H6A—C6—H6B	108.2 (16)
O11—C10—O12	122.80 (13)	C3—C7—H7A	110.2
O11—C10—N1	124.92 (14)	C3—C7—H7B	110.2
H3BA—C3—H3BB	108.2	C3—C7—C8	107.6 (3)
C2—C3—H3A	105.1	H7A—C7—H7B	108.5
C2—C3—H3BA	109.8	C8—C7—H7A	110.2
C2—C3—H3BB	109.8	C8—C7—H7B	110.2
C4—C3—H3A	105.1	N9—C8—C7	109.5 (3)
C4—C3—H3BA	109.8	O15—C8—N9	124.5 (4)
C4—C3—H3BB	109.8	O15—C8—C7	126.0 (4)
C4—C3—C2	109.44 (14)	C5—C7A—H7AA	110.5
C7—C3—H3A	105.1	C5—C7A—H7AB	110.5
C7—C3—C2	130.9 (2)	C5—C7A—C8A	106.2 (2)
C7—C3—C4	98.9 (2)	H7AA—C7A—H7AB	108.7
N1—C2—C3	110.44 (14)	C8A—C7A—H7AA	110.5
N1—C2—H2A	109.6	C8A—C7A—H7AB	110.5
N1—C2—H2B	109.6	N9—C8A—C7A	108.9 (2)
C3—C2—H2A	109.6	O15A—C8A—N9	125.9 (3)
C3—C2—H2B	109.6	O15A—C8A—C7A	125.2 (3)
H2A—C2—H2B	108.1
C13—O12—C10—O11	−0.2 (2)	C4—N9—C8A—C7A	7.8 (3)
C13—O12—C10—N1	178.67 (12)	C4—C3—C2—N1	−52.7 (2)
N9—C4—C5—C6	173.55 (16)	C4—C3—C7—C8	25.7 (3)
N9—C4—C5—C7A	34.4 (2)	C4—C5—C6—N1	52.9 (2)
C10—O12—C13—C14	170.01 (12)	C4—C5—C7A—C8A	−27.7 (3)
C10—N1—C2—C3	−154.18 (14)	C5—C7A—C8A—N9	13.7 (3)
C10—N1—C6—C5	152.80 (15)	C5—C7A—C8A—O15A	−167.6 (3)
C3—C4—C5—C6	−63.0 (2)	C6—N1—C10—O12	170.47 (13)
C3—C4—C5—C7A	157.79 (19)	C6—N1—C10—O11	−10.6 (2)
C3—C7—C8—N9	−9.9 (3)	C6—N1—C2—C3	47.2 (2)
C3—C7—C8—O15	167.7 (3)	C6—C5—C7A—C8A	−154.3 (2)
C2—N1—C10—O12	11.40 (19)	C7—C3—C2—N1	−174.2 (2)
C2—N1—C10—O11	−169.72 (15)	C7—C3—C4—N9	−36.2 (2)
C2—N1—C6—C5	−47.3 (2)	C7—C3—C4—C5	−158.0 (2)
C2—C3—C4—N9	−175.51 (15)	C8—N9—C4—C3	30.1 (2)
C2—C3—C4—C5	62.8 (2)	C8—N9—C4—C5	152.3 (2)
C2—C3—C7—C8	151.2 (2)	C7A—C5—C6—N1	176.0 (2)
C4—N9—C8—C7	−11.8 (3)	C8A—N9—C4—C3	−148.57 (19)
C4—N9—C8—O15	170.5 (3)	C8A—N9—C4—C5	−26.4 (2)
C4—N9—C8A—O15A	−170.9 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N9—H9A···O15^i	0.87 (2)	2.03 (2)	2.889 (4)	174 (4)
N9—H9B···O15A^i	0.87 (2)	1.97 (2)	2.841 (3)	176 (3)

Symmetry code: (i) −x+2, −y, −z+1.