Four related benzazepine derivatives in a reaction pathway leading to a benzazepine carboxylic acid: hydrogen-bonded assembly in zero, one, two and three dimensions

(2R*,4S*)-Methyl 2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-benz[b]azepine-2-carboxyl­ate, C₁₂H₁₃NO₃, (I), and its reduction product (2R*,4S*)-methyl 4-hy­droxy-2,3,4,5-tetra­hydro-1H-benz[b]azepine-2-carboxyl­ate, C₁₂H₁₅NO₃, (II), both crystallize as single enanti­omers in the space group P2₁2₁2₁, while the hydrolysis product (2RS,4SR)-4-hy­droxy-2,3,4,5-tetra­hydro-1H-benz[b]azepine-2-carb­oxy­lic acid, C₁₁H₁₃NO₃, (III), and the lactone (2RS,5SR)-8-(trifluoromethoxy)-5,6-dihydro-1H-2,5-methanobenz[e][1,4]oxazocin-3(2H)-one, C₁₂H₁₀F₃NO₃, (IV), both crystallize as racemic mixtures in the space group P2₁/c. The mol­ecules of compound (IV) are linked into centrosymmetric R₂²(10) dimers by N—H...O hydrogen bonds, and those of compound (I) are linked into chains by C—H...π(arene) hydrogen bonds. A combination of O—H...O and O—H...N hydrogen bonds links the mol­ecules of com­pound (III) into sheets containing equal numbers of R₄⁴(14) and R₄⁴(26) rings, and a combination of C—H...π(arene) hydrogen bonds and three-centre O—H...(N,O) hydrogen bonds links the mol­ecules of compound (II) into a three-dimensional frame­work structure. Comparisons are made with some related compounds.

S1. Introduction

We report here the molecular and supra­molecular structures of a series of four closely related benzazepine derivatives, corresponding to the inter­mediates (2R*,4S*)-methyl 2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-benz[b]azepine-2-carboxyl­ate, (I), and (2R*,4S*)-methyl 4-hy­droxy-2,3,4,5-tetra­hydro-1H-benz[b]azepine-2-carboxyl­ate, (II), in the synthetic sequence from a 2-allyl­aniline towards the formation of (2RS,4SR)-4-hy­droxy-2,3,4,5-tetra­hydro-1H-benz[b]azepine-2-carb­oxy­lic acid, (III), together with that of a related tricyclic by-product (2RS,5SR)-8-(tri­fluoro­meth­oxy)-5,6-di­hydro-1H-2,5-methano­benz[e][1,4]oxazocin-3(2H)-one, (IV) (see Scheme 1). Compounds of this type are of importance because of their potential value as anti­parasitic agents (Gómez-Ayala et al., 2010). In this synthetic methodology (Gómez Ayala et al., 2006; Acosta, Palma & Bahsas, 2010; Acosta Qu­intero et al., 2012), methyl 2-[(2-allyl­phenyl)­amino]­acetate was oxidized by aqueous hydrogen peroxide in the presence of a catalytic qu­antity of sodium tungstate to form the epoxide (I). Reduction of (I) with zinc and acetic acid gave the alcohol (II), hydrolysis of which gave the hy­droxy acid (III). On the other hand, similar reduction of the tri­fluoro­meth­oxy derivative (V), analogous to (I) (see Scheme 1), gave as a minor by-product the tricyclic lactone (IV), in addition to the expected alcohol (VI), with a product ratio of ca 1:6. Lactones such as (IV) could also be envisaged as arising by intra­molecular condensation reaction of the corresponding hy­droxy acid. Benzazepin-4-ols similar to compounds (II) and (III) have recently been described having either vinyl substituents (Acosta et al., 2009) or thienyl substituents (Blanco et al., 2009) at position 2.

S2. Experimental

S2.1. Synthesis and crystallization

For the synthesis of compound (I), sodium tungstate dihydrate (10 mol%), followed by 30% aqueous hydrogen peroxide solution (16 mmol), were added to a stirred and cooled (273 K) solution of methyl 2-[(2-allyl­phenyl)­amino]­acetate (4 mmol) in methanol (25 ml). The resulting mixture was then stirred at ambient temperature for 18 h and monitored by thin-layer chromatography (TLC). The mixture was filtered and the solvent was removed under reduced pressure. Toluene (15 ml) was added to the black solid residue and the resulting solution was heated under reflux for 6 h. After cooling the solution to ambient temperature, the solvent was removed under reduced pressure and the crude product was subject to column chromatographic purification over silica gel using heptane–ethyl acetate (10:1 v/v) as eluent. Crystallization from heptane, at ambient temperature and in the presence of air gave colourless crystals of compound (I) suitable for single-crystal X-ray diffraction (yield 48%, m.p. 388–389 K). HRMS, m/z found 219.0899, C₁₂H₁₃NO₃ requires 219.0895. For the synthesis of compounds (II) and (IV), zinc powder (40 mmol), glacial acetic acid (28 mmol) and concentrated hydro­chloric acid (28 mmol) were added to a stirred and cooled (273 K) solutions of the corresponding (2RS,4SR)-methyl 2,3,4,5-tetra­hydro-1,4-ep­oxy­benz[b]azepine-2-carboxyl­ates, prepared as for (I) (2 mmol) in methanol (10 ml). The resulting mixtures were stirred at 273 K for 1.5 h, and monitored by TLC. Each mixture was filtered and the filtrate was basified to pH 8 with aqueous ammonia solution (25%), and then extracted with ethyl acetate (3 × 40 ml). For each, the combined organic extracts were dried over anhydrous sodium sulfate and then the solvent was removed under reduced pressure. The resulting crude products were purified by silica-gel column chromatography using heptane–ethyl acetate as eluent (from 3:1 to 1:?? v/v). Crystallization from heptane–ethyl acetate (30:1 v/v) at ambient temperature and in the presence of air gave colourless crystals of (II) and (IV) suitable for single-crystal X-ray diffraction. For (II), yield 87%, m.p. 398–399 K; HRMS, m/z found 221.1054, C₁₂H₁₅NO₃ requires 221.1052; for (IV), MS (70 eV) m/z (%) 273 (M⁺, 40), 228 (100), 214 (28), 202 (34), 201 (31), 188 (6). For the synthesis of compound (III), aqueous sodium hydroxide solution (1 mol dm^-3, 0.55 mmol) was added to a stirred solution of compound (II) (0.50 mmol) in methanol (1 ml). The reaction mixture was stirred at 273 K for 30 min. Then hydro­chloric acid solution (1 mol dm^-3) was slowly added to the reaction mixture to pH 3.5, and the reaction product was extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were dried over anhydrous sodium sulfate and then the solvent was removed under reduced pressure. The resulting crude product was purified by crystallization, at ambient temperature and in air, from ethyl acetate–methanol (20:1 v/v) to give colourless crystals of (III) suitable for single-crystal X-ray diffraction (yield 84%, m.p. 437–438 K). HRMS, m/z found 207.0905, C₁₁H₁₃NO₃ requires 207.0895.

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. All H atoms were located in difference maps and subsequently treated as riding atoms. H atoms bonded to C atoms were permitted to ride a in geometrically idealized positions, with C—H = 0.95 (aromatic), 0.98 (CH₃), 0.99 (CH₂) or 1.00 Å (aliphatic C—H), and with U_iso(H) = kU_eq(C), where k = 1.5 for the methyl groups, which were permitted to rotate but not to tilt, and 1,2 for all other H atoms bonded to C atoms. H atoms bonded to N atoms were permitted to ride at the positions located in difference maps, with U_iso(H) = 1.2U_eq(N), giving the N—H distances shown in Table 3. Several low-angle reflections which had been partially or completely attenuated by the beam stop were omitted from the final refinements: for (I), 101, 012 and 002; for (II), 012; for (III), 011, 110 and -111; for (IV), 011 and 200. The values of the Flack x parameters (Flack, 1983) for compounds (I) and (II) were indeterminate (Flack & Bernardinelli, 2000); the values for (I) and (II), respectively, were -1.0 (14) for 975 Bijvoet pairs (99.3% coverage) and 1(3) for 983 Bijvoet pairs (96.8% coverage); accordingly, the Friedel-equivalent reflections were merged prior to the final refinements and the reference molecules for (I) and (II) were selected as those having the R configuration at atom C2.

S3. Results and discussion

We report here the molecular and supra­molecular structures of a series of four closely related benzazepine derivatives, corresponding to the inter­mediates (2R*,4S*)-methyl 2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-benz[b]azepine-2-carboxyl­ate, (I), and (2R*,4S*)-methyl 4-hy­droxy-2,3,4,5-tetra­hydro-1H-benz[b]azepine-2-carboxyl­ate, (II), in the synthetic sequence from a 2-allyl­aniline towards the formation of (2RS,4SR)-4-hy­droxy-2,3,4,5-tetra­hydro-1H-benz[b]azepine-2-carb­oxy­lic acid, (III), together with that of a related tricyclic by-product (2RS,5SR)-8-(tri­fluoro­meth­oxy)-5,6-di­hydro-1H-2,5-methano­benz[e][1,4]oxazocin-3(2H)-one, (IV) (see Scheme 1 and Figs. 1–4). Compounds of this type are of importance because of their potential value as anti­parasitic agents (Gómez-Ayala et al., 2010). In this synthetic methodology (Gómez Ayala et al., 2006; Acosta, Palma & Bahsas, 2010; Acosta Qu­intero et al., 2012), methyl 2-[(2-allyl­phenyl)­amino]­acetate was oxidized by aqueous hydrogen peroxide in the presence of a catalytic qu­antity of sodium tungstate to form the epoxide (I). Reduction of (I) with zinc and acetic acid gave the alcohol (II), hydrolysis of which gave the hy­droxy acid (III). On the other hand, similar reduction of the tri­fluoro­meth­oxy derivative (V), analogous to (I) (see Scheme 1), gave as a minor by-product the tricyclic lactone (IV), in addition to the expected alcohol (VI), with a product ratio of ca 1:6. Lactones such as (IV) could also be envisaged as arising by intra­molecular condensation reaction of the corresponding hy­droxy acid. Benzazepin-4-ols similar to compounds (II) and (III) have recently been described having either vinyl substituents (Acosta et al., 2009) or thienyl substituents (Blanco et al., 2009) at position 2.

In each of compounds (I)–(IV), the molecule contains two stereogenic centres and the relative stereochemistry at these two centres is the same in each of compounds (I)–(IV), and the purposes of the present study are threefold: firstly, to confirm the integrity of the relative stereochemistry of compound (I)–(IV) during the transformations described (Scheme 1), as noted above; secondly, to show how minor changes of substituent and/or functionality on a common fused-ring skeleton can lead to significant changes in the patterns of supra­molecular assembly; and thirdly to establish definitively the molecular constitution of compound (IV). For each compound, the reference molecule was selected to be one having the R configuration at atom C2; on this basis, the reference molecules in compounds (I)–(III) all have the S configuration at atom C4, while the reference molecule of compound (IV) has the S configuration at the corresponding atom, here labelled C5 (cf. Figs. 1–4). Compounds (III) and (IV) both crystallize in the space group P2₁/c as racemic mixtures, but compounds (I) and (II) both crystallize in the Sohnke space group P2₁2₁2₁. In the absence of significant resonant scattering, it was not possible to determine the absolute configurations of the molecules of (I) and (II) in the crystals selected for data collection, and hence the configuration of the reference molecules have been assigned to match those selected for the reference molecules in compounds (III) and (IV). In view of both of the synthetic procedures employed for the production of compounds (I) and (II), which utilize no enanti­oselective reagents, and of the racemic nature of compounds (II) and (IV), it seems probable that compounds (I) and (II) are both formed in solution as racemic mixtures, but that they crystallize as conglomerates rather than as racemates.

The H atom of the carb­oxy­lic acid group in compound (III) is fully ordered and the C21—O21 and C21—O22 bond lengths are similar to the corresponding distances in the esters, compounds (I) and (II) (Table 2), and fully consistent with the location of the carb­oxy­lic acid H atom as deduced from a difference map. Despite the markedly pyramidal geometry at atom N1, with a sum of the inter­bond angles of 330° [corresponding values for (II) and (IV) are 343 and 345°, respectively], there is no evidence for any zwitterions formation by transfer of a proton from atom O22 to atom N1. The remaining bond lengths in compounds (I)–(IV) present no unexpected features.

The hydrogen-bonded supra­molecular assembly in compounds (I)–(IV) is of considerable inter­est, as the resulting supra­molecular structures range from a simple dimer in compound (IV), via a chain in compound (I) and a sheet in compound (III) to a three-dimensional framework structure in compound (II). It may be noted here that while the structures of (I)–(IV) encompass a variety of hydrogen-bond types, aromatic π–π stacking inter­actions are absent from all of the structures reported here. It is convenient to consider the supra­molecular assembly in (I)–(IV) in order of increasing complexity.

The crystal structure of compound (IV) contains just one type of hydrogen bond (Table 3) and inversion-related pairs of N—H···O hydrogen bonds link the molecules into centrosymmetric dimers characterized by an R₂²(10) (Bernstein et al., 1995) motif (Fig. 5). There are no direction-specific inter­actions between adjacent dimers, so that the assembly in finite and thus it can be regarded as zero-dimensional. The supra­molecular assembly in compound (I) is again determined by just one type of hydrogen bond, this time of C—H···π(arene) type (Table 3), which links molecules related by the 2₁ screw axis along (x, 1/4, 1/2) to form a chain running parallel to the [100] direction (Fig. 6).

The supra­molecular assembly in compound (III) is determined by two hydrogen bonds, one each of the O—H···N and O—H···O types, both of which are nearly linear (Table 3). The N—H bond plays no part in the supra­molecular assembly, making only a short intra­molecular contact with the carbonyl O atom, in which the N—H···O angle (Table 3) is too small for this to be regarded as a structurally significant inter­action, but there are no other potential acceptors within range of atom N1 for plausible inter­molecular hydrogen-bond formation. The action of the O—H···N hydrogen bond, in which the hy­droxy group provides the donor, is to link molecules related by the c-glide plane at y = 0.5 into a C(6) (Bernstein et al., 1995) chain running parallel to the [001] direction. The O—H···O hydrogen bond, where the carb­oxy­lic acid group provides the donor, links molecules related by the 2₁ screw axis along (0, y, 1/4) into a C(7) chain running parallel to the [010] direction. The combination of the two hydrogen bonds generates a sheet lying parallel to (100) and built from centrosymmetric R₄⁴(14) and R₄⁴(26) rings arranged in a chessboard pattern (Fig. 7). The smaller rings are centred at (0, m, 0.5+n) and (0, 0. 5+m, n), and the larger rings are centred at (0, m, n) and (0, 0.5+m, 0.5+n), where m and n represent integers in all cases. Although both types of ring in the reference sheet are centred at x = 0, the sheet is markedly puckered, and it occupies the entire domain of x (Fig. 8); there are no direction-specific inter­actions between adjacent sheets. Four molecules, arranged in two inversion-related pairs, contribute to each type of ring. In the smaller R₄⁴(14) ring, each of the four component molecules acts as both a hydrogen-bond donor and as a hydrogen-bond acceptor, but in the larger R₄⁴(26) ring, one pair of inversion related molecules act as twofold donors of hydrogen bonds while the other pair act as twofold acceptors (Fig. 7).

There are only two independent hydrogen bonds in the structure of compound (II); one is a planar three-centre O—H···(N,O) hydrogen bond and the other is a C—H···π(arene) hydrogen bond (Table 3). However, these two inter­actions generate a three-dimensional framework structure, whose formation is readily analysed in terms of three one-dimensional substructures (Ferguson et al., 1998a,b; Gregson et al., 2000). The three-centre hydrogen bond, when acting alone, links molecules related by the 2₁ screw axis along (1/2, y, 1/4) into a C(6)C(7)[R₁²(5)] chain of rings (Bernstein et al., 1995) running parallel to the [010] direction (Fig. 9). The C—H···π(arene) hydrogen bond, again when acting alone, is to link molecules related by the 2₁screw axis along (x, 3/4, 0) into a chain running parallel to the [100] direction (Fig. 10). In combination, the two types of hydrogen bond generate a chain running parallel to the [001] direction in which the O—H···(N,O) and C—H···π(arene) hydrogen bonds alternate (Fig. 11). The combination of the chains along [100], [010] and [001] is sufficient to generate a continuous three-dimensional structure.

It is of inter­est briefly to compare the supra­molecular assembly in compounds (I)–(IV) reported here with that in some related compounds. In simple 1,4-ep­oxy-1-benzazepines analogous to compound (I), the direction-specific inter­molecular inter­actions are generally restricted to C—H···O and C—H···π(arene) hydrogen bonds, along with aromatic π–π stacking inter­actions but, nonetheless, these inter­actions can give rise to supra­molecular assembly in zero, one, two or three dimensions (e.g. Gómez et al., 2008, 2009; Acosta, Palma, Bahsas et al., 2010; Sanabria et al., 2010). Compounds (VII)–(IX) (see Scheme 2) (Acosta et al., 2009), which are analogues of compound (II), are isomorphous but not strictly isostructural, as small variations in the unit-cell imensions preclude in the structure of compound (IX) one of the inter­molecular inter­actions present in the structures of compounds (VII) and (VIII). In the structure of (IX), a combination of O—H···N and N—H···O hydrogen bonds gives rise to a chain of edge-fused R₃³(10) rings: similar chains are present also in compounds (VII) and (VIII) where, in addition, they are linked into sheets by C—H···π(arene) hydrogen bonds. Compounds (X) and (XI) both crystallize with Z' = 2 in the space group P1 (Blanco et al., 2012); in both compounds, the hy­droxy H atoms are all disordered over two sites with equal occupancy, and O—H···O hydrogen bonds give rise to C₄⁴(8) chains within which the locations of the hy­droxy H atoms are fully correlated, but with no necessary correlation of the directions of the hydrogen bonds in adjacent chains. An isolated example of a 1-benzazepine derivative carrying both a hy­droxy substituent and a non-esterified carb­oxy­lic acid group, and hence comparable with compound (III), is provided by 1-acetyl-4-benzoyl-2-hy­droxy-2,3,4,5-tetra­hydro-1H-benz[b]azepine-5-carb­oxy­lic acid, (XII) [Cambridge Structural Database (CSD; Allen, 2002) refcode DOJJER; Coda et al., 1986]. Unfortunately, the atomic coordinates deposited in the CSD do not include any H atoms, while the non-H atoms of the asymmetric unit are distributed amongst three separate molecules. However, the C—O distances of the carb­oxy­lic acid group (1.211 and 1.320 Å, no s.u. values available) indicate the presence of an un-ionized –COOH unit. Based on this conclusion and an examination of the inter­molecular N···O and O···O distances, the main features of the supra­molecular assembly can be deduced, despite the absence of any H-atom coordinates; the carb­oxy­lic acid OH group acts as hydrogen-bond donor to the amidic O atom, and the hydroxyl group acts as hydrogen-bond donor to the carbonyl O atom of the carb­oxy­lic acid group, but the N atom plays no part in the supra­molecular assembly. Overall, molecules related by a 2₁ screw axis along [001] are linked by these two hydrogen bonds to form a C(8)C(9)[R₂²(10)] chain of rings running parallel to the [001] direction (Fig. 12).

In summary, we have demonstrated the preservation of the relative stereochemistry throughout the reactiom sequence from compound (I), we have established the molecular constitution of compound (IV) and we have shown how minor changes in molecular constitution in the related compounds (I)–(XII) can lead to marked changes in supra­molecular assembly.

Related literature

For related literature, see: Acosta et al. (2009); Acosta Quintero, Palma, Nogueras & Cobo (2012); Acosta, Palma & Bahsas (2010); Acosta, Palma, Bahsas, Cobo & Glidewell (2010); Allen (2002); Bernstein et al. (1995); Blanco et al. (2009, 2012); Coda et al. (1986); Ferguson et al. (1998a, 1998b); Flack (1983); Flack & Bernardinelli (2000); Gómez et al. (2008, 2009); Gómez Ayala, Stashenko, Palma, Bahsas & Amaro-Luis (2006); Gómez-Ayala, Castrillón, Palma, Leal, Escobar & Bahsas (2010); Gregson et al. (2000); Sanabria et al. (2010).

Computing details

For all compounds, data collection: COLLECT (Hooft, 1998); cell refinement: DIRAX/LSQ (Duisenberg et al., 2000); data reduction: EVALCCD (Duisenberg et al., 2003); program(s) used to solve structure: SIR2004 (Burla et al., 2005); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009). Software used to prepare material for publication: SHELXL97(Sheldrick, 2008) and PLATON (Spek, 2009) for (I); SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009) for (II), (III), (IV).

Figures

	Fig. 1. The molecular structure of the (2R,4S) enantiomer of compound (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. The molecular structure of the (2R,4S) enantiomer of compound (II), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 3. The molecular structure of the (2R,4S) enantiomer of compound (III), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 4. The molecular structure of the (2R,5S) enantiomer of compound (IV), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 5. Part of the crystal structure of compound (IV), showing the formation of a centrosymmetric R2^2(10) dimer built from paired N—H···O hydrogen bonds. For the sake of clarity, H atoms not involved in the motif shown have been omitted. Atoms marked with an asterisk (*) are at the symmetry position (-x+1, -y+1, -z+1).
	Fig. 6. A stereoview of part of the crystal structure of compound (I), showing the formation of a chain along [100] built from C—H···π(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motif shown have been omitted.
	Fig. 7. A stereoview of part of the crystal structure of compound (III), showing the formation of a hydrogen-bonded sheet parallel to (100) and built from R4^4(14) and R4^4(26) rings. For the sake of clarity, H atoms bonded to C or N atoms have been omitted.
	Fig. 8. A projection of a sheet in compound (III), parallel to (100) and viewed along [001], showing the puckering of the sheet. For the sake of clarity, H atoms bonded to C or N atoms have been omitted.
	Fig. 9. Part of the crystal structure of compound (II), showing the formation of a chain of rings along [010] built from three-centre O—H···(N,O) hydrogen bonds. For the sake of clarity, H atoms not involved in the motif shown have been omitted. Atoms marked with an asterisk (*) or a hash(#) are at the symmetry positions (-x+1, y-1/2, -z+1/2) and (-x+1, y+1/2, -z+1/2), respectively.
	Fig. 10. A stereoview of part of the crystal structure of compound (II), showing the formation of a chain along [100] built from C—H···π(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motif shown have been omitted.
	Fig. 11. A stereoview of part of the crystal structure of compound (II), showing the formation of a chain along [001] in which the O—H···(N,O) and C—H···π(arene) hydrogen bonds alternate. For the sake of clarity, H atoms not involved in the motif shown have been omitted.
	Fig. 12. Part of the crystal structure of compound (XII), showing the formation of a C(8)C(9)[R2^2(10)] chain of rings running parallel to [001]. The original atomic coordinates (Coda et al., 1986) were used, modified by translations to assemble the asymmetric unit into a single molecule. H atoms bonded to O atoms are in positions calculated by assuming O—H distances of 0.85 Å and linear O—H···O hydrogen bonds. For the sake of clarity, the unit-cell outline has been omitted. Atoms marked with an asterisk (*) or a hash (#) are at the symmetry positions (-x+3/2, -y, z-1/2) and (-x+3/2, -y, z+1/2), respectively.

(I) (2R*,4S*)-Methyl 2,3,4,5-tetrahydro-1,4-epoxy-1H-benz[b]azepine-2-carboxylate

Crystal data

C12H13NO3	F(000) = 464
Mr = 219.23	Dx = 1.413 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 1378 reflections
a = 6.8549 (6) Å	θ = 3.1–27.5°
b = 11.4483 (12) Å	µ = 0.10 mm^−1
c = 13.1369 (14) Å	T = 120 K
V = 1030.94 (18) Å^3	Block, colourless
Z = 4	0.22 × 0.20 × 0.12 mm

Data collection

Bruker–Nonius KappaCCD diffractometer	1375 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1089 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.077
Detector resolution: 9.091 pixels mm^-1	θmax = 27.5°, θmin = 3.5°
ϕ & ω scans	h = −8→8
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −14→13
Tmin = 0.835, Tmax = 0.988	l = −17→16
12257 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.043	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.083	H-atom parameters constrained
S = 1.15	w = 1/[σ^2(Fo^2) + (0.0318P)^2 + 0.2372P] where P = (Fo^2 + 2Fc^2)/3
1375 reflections	(Δ/σ)max = 0.001
146 parameters	Δρmax = 0.20 e Å^−3
0 restraints	Δρmin = −0.21 e Å^−3

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

	x	y	z	Uiso*/Ueq
N1	0.5882 (3)	0.53959 (17)	0.62664 (15)	0.0169 (5)
C2	0.7808 (4)	0.4788 (2)	0.63363 (18)	0.0172 (6)
H2	0.8029	0.4283	0.5726	0.021*
C3	0.7668 (4)	0.4041 (2)	0.73108 (18)	0.0207 (6)
H3A	0.7548	0.3201	0.7144	0.025*
H3B	0.8824	0.4158	0.7751	0.025*
C4	0.5806 (4)	0.4499 (2)	0.78270 (18)	0.0203 (6)
H4	0.6023	0.4608	0.8574	0.024*
C5	0.4015 (4)	0.3748 (2)	0.76360 (17)	0.0208 (6)
H5A	0.4294	0.2928	0.7828	0.025*
H5B	0.2915	0.4029	0.8059	0.025*
C5A	0.3467 (4)	0.3809 (2)	0.65235 (18)	0.0169 (5)
C6	0.2051 (4)	0.3078 (2)	0.61025 (19)	0.0188 (6)
H6	0.1366	0.2547	0.6528	0.023*
C7	0.1629 (4)	0.3117 (2)	0.50650 (19)	0.0196 (6)
H7	0.0650	0.2623	0.4789	0.024*
C8	0.2638 (4)	0.3878 (2)	0.44358 (19)	0.0190 (5)
H8	0.2374	0.3891	0.3726	0.023*
C9	0.4031 (4)	0.4619 (2)	0.48420 (18)	0.0174 (6)
H9	0.4719	0.5144	0.4413	0.021*
C9A	0.4419 (4)	0.4592 (2)	0.58782 (17)	0.0147 (5)
O14	0.5459 (3)	0.56224 (15)	0.73310 (12)	0.0193 (4)
C21	0.9367 (4)	0.5730 (2)	0.64079 (19)	0.0176 (5)
O21	1.0154 (3)	0.60550 (17)	0.71760 (13)	0.0269 (5)
O22	0.9732 (3)	0.61892 (15)	0.54844 (12)	0.0210 (4)
C22	1.1153 (4)	0.7122 (2)	0.5470 (2)	0.0247 (6)
H22A	1.0672	0.7780	0.5876	0.037*
H22B	1.1366	0.7378	0.4767	0.037*
H22C	1.2386	0.6841	0.5757	0.037*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0182 (11)	0.0168 (11)	0.0156 (10)	0.0001 (9)	0.0006 (9)	−0.0026 (9)
C2	0.0162 (13)	0.0163 (13)	0.0190 (12)	0.0030 (10)	−0.0024 (11)	−0.0005 (11)
C3	0.0244 (13)	0.0191 (14)	0.0186 (12)	−0.0001 (12)	−0.0036 (12)	0.0026 (11)
C4	0.0287 (15)	0.0187 (13)	0.0135 (11)	0.0007 (12)	0.0005 (11)	0.0009 (10)
C5	0.0266 (14)	0.0203 (13)	0.0155 (12)	−0.0030 (12)	0.0055 (11)	−0.0004 (11)
C5A	0.0184 (13)	0.0140 (12)	0.0184 (12)	0.0055 (11)	0.0041 (10)	−0.0011 (11)
C6	0.0175 (13)	0.0156 (13)	0.0233 (13)	−0.0006 (11)	0.0049 (11)	0.0001 (11)
C7	0.0158 (13)	0.0166 (13)	0.0264 (13)	0.0000 (11)	−0.0007 (11)	−0.0043 (11)
C8	0.0187 (12)	0.0182 (12)	0.0202 (12)	0.0038 (12)	−0.0013 (11)	−0.0022 (12)
C9	0.0156 (12)	0.0160 (13)	0.0207 (13)	0.0032 (11)	−0.0014 (10)	0.0052 (10)
C9A	0.0137 (12)	0.0113 (12)	0.0192 (12)	0.0025 (10)	0.0003 (10)	−0.0004 (10)
O14	0.0247 (10)	0.0185 (9)	0.0149 (9)	0.0019 (8)	0.0020 (8)	−0.0034 (7)
C21	0.0160 (12)	0.0174 (12)	0.0195 (12)	0.0043 (11)	0.0006 (11)	−0.0025 (10)
O21	0.0277 (10)	0.0335 (11)	0.0195 (9)	−0.0079 (9)	−0.0050 (9)	−0.0052 (9)
O22	0.0224 (9)	0.0216 (9)	0.0189 (8)	−0.0067 (9)	−0.0019 (8)	−0.0006 (8)
C22	0.0236 (14)	0.0214 (13)	0.0292 (14)	−0.0066 (12)	0.0018 (12)	−0.0018 (12)

Geometric parameters (Å, º)

N1—O14	1.452 (2)	C5A—C6	1.396 (4)
N1—C9A	1.454 (3)	C6—C7	1.394 (3)
N1—C2	1.496 (3)	C6—H6	0.9500
C2—C21	1.521 (3)	C7—C8	1.386 (4)
C2—C3	1.543 (3)	C7—H7	0.9500
C2—H2	1.0000	C8—C9	1.384 (4)
C3—C4	1.537 (4)	C8—H8	0.9500
C3—H3A	0.9900	C9—C9A	1.387 (3)
C3—H3B	0.9900	C9—H9	0.9500
C4—O14	1.461 (3)	C21—O21	1.203 (3)
C4—C5	1.520 (4)	C21—O22	1.346 (3)
C4—H4	1.0000	O22—C22	1.446 (3)
C5—C5A	1.511 (3)	C22—H22A	0.9800
C5—H5A	0.9900	C22—H22B	0.9800
C5—H5B	0.9900	C22—H22C	0.9800
C5A—C9A	1.395 (3)
O14—N1—C9A	108.26 (17)	C9A—C5A—C5	120.1 (2)
O14—N1—C2	101.56 (17)	C6—C5A—C5	121.9 (2)
C9A—N1—C2	109.64 (18)	C7—C6—C5A	120.8 (2)
N1—C2—C21	107.10 (19)	C7—C6—H6	119.6
N1—C2—C3	104.7 (2)	C5A—C6—H6	119.6
C21—C2—C3	112.7 (2)	C8—C7—C6	120.0 (3)
N1—C2—H2	110.7	C8—C7—H7	120.0
C21—C2—H2	110.7	C6—C7—H7	120.0
C3—C2—H2	110.7	C9—C8—C7	120.0 (2)
C4—C3—C2	103.2 (2)	C9—C8—H8	120.0
C4—C3—H3A	111.1	C7—C8—H8	120.0
C2—C3—H3A	111.1	C8—C9—C9A	119.8 (2)
C4—C3—H3B	111.1	C8—C9—H9	120.1
C2—C3—H3B	111.1	C9A—C9—H9	120.1
H3A—C3—H3B	109.1	C9—C9A—C5A	121.4 (2)
O14—C4—C5	107.0 (2)	C9—C9A—N1	117.5 (2)
O14—C4—C3	103.83 (19)	C5A—C9A—N1	121.1 (2)
C5—C4—C3	113.9 (2)	N1—O14—C4	103.88 (17)
O14—C4—H4	110.6	O21—C21—O22	123.5 (2)
C5—C4—H4	110.6	O21—C21—C2	125.9 (2)
C3—C4—H4	110.6	O22—C21—C2	110.6 (2)
C5A—C5—C4	109.5 (2)	C21—O22—C22	115.18 (19)
C5A—C5—H5A	109.8	O22—C22—H22A	109.5
C4—C5—H5A	109.8	O22—C22—H22B	109.5
C5A—C5—H5B	109.8	H22A—C22—H22B	109.5
C4—C5—H5B	109.8	O22—C22—H22C	109.5
H5A—C5—H5B	108.2	H22A—C22—H22C	109.5
C9A—C5A—C6	118.0 (2)	H22B—C22—H22C	109.5
O14—N1—C2—C21	−83.6 (2)	C6—C5A—C9A—C9	−2.3 (4)
C9A—N1—C2—C21	162.07 (19)	C5—C5A—C9A—C9	176.1 (2)
O14—N1—C2—C3	36.3 (2)	C6—C5A—C9A—N1	178.8 (2)
C9A—N1—C2—C3	−78.1 (2)	C5—C5A—C9A—N1	−2.8 (3)
N1—C2—C3—C4	−11.5 (2)	O14—N1—C9A—C9	154.2 (2)
C21—C2—C3—C4	104.5 (2)	C2—N1—C9A—C9	−95.8 (3)
C2—C3—C4—O14	−17.3 (2)	O14—N1—C9A—C5A	−26.9 (3)
C2—C3—C4—C5	98.7 (2)	C2—N1—C9A—C5A	83.1 (3)
O14—C4—C5—C5A	47.3 (2)	C9A—N1—O14—C4	66.8 (2)
C3—C4—C5—C5A	−66.8 (3)	C2—N1—O14—C4	−48.6 (2)
C4—C5—C5A—C9A	−7.6 (3)	C5—C4—O14—N1	−79.5 (2)
C4—C5—C5A—C6	170.8 (2)	C3—C4—O14—N1	41.2 (2)
C9A—C5A—C6—C7	1.1 (4)	N1—C2—C21—O21	99.8 (3)
C5—C5A—C6—C7	−177.3 (2)	C3—C2—C21—O21	−14.8 (3)
C5A—C6—C7—C8	0.8 (4)	N1—C2—C21—O22	−78.7 (2)
C6—C7—C8—C9	−1.6 (4)	C3—C2—C21—O22	166.7 (2)
C7—C8—C9—C9A	0.4 (4)	O21—C21—O22—C22	−0.3 (3)
C8—C9—C9A—C5A	1.6 (4)	C2—C21—O22—C22	178.2 (2)
C8—C9—C9A—N1	−179.4 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C7—H7···Cg1^i	0.95	2.48	3.409 (3)	165

Symmetry code: (i) x−1/2, −y+1/2, −z+1.

(II) (2R*,4S*)-Methyl 4-hydroxy-2,3,4,5-tetrahydro-1H-benz[b]azepine-2-carboxylate

Crystal data

C12H15NO3	F(000) = 472
Mr = 221.25	Dx = 1.372 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 1425 reflections
a = 6.2528 (13) Å	θ = 3.1–27.5°
b = 10.758 (3) Å	µ = 0.10 mm^−1
c = 15.927 (5) Å	T = 120 K
V = 1071.4 (5) Å^3	Block, colourless
Z = 4	0.25 × 0.16 × 0.12 mm

Data collection

Bruker–Nonius KappaCCD diffractometer	1424 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1117 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.090
Detector resolution: 9.091 pixels mm^-1	θmax = 27.5°, θmin = 3.5°
ϕ & ω scans	h = −7→7
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −13→12
Tmin = 0.616, Tmax = 0.988	l = −20→20
12235 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.069	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.187	H-atom parameters constrained
S = 1.19	w = 1/[σ^2(Fo^2) + (0.0725P)^2 + 1.5397P] where P = (Fo^2 + 2Fc^2)/3
1424 reflections	(Δ/σ)max = 0.001
146 parameters	Δρmax = 0.58 e Å^−3
0 restraints	Δρmin = −0.34 e Å^−3

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

	x	y	z	Uiso*/Ueq
N1	0.7715 (6)	0.7491 (4)	0.1659 (2)	0.0189 (8)
H1	0.8771	0.8002	0.1540	0.023*
C2	0.7976 (7)	0.6958 (4)	0.2502 (3)	0.0181 (10)
H2	0.8697	0.6133	0.2443	0.022*
C3	0.5864 (7)	0.6757 (5)	0.2961 (3)	0.0222 (10)
H3A	0.6164	0.6534	0.3553	0.027*
H3B	0.5046	0.7545	0.2962	0.027*
C4	0.4505 (8)	0.5742 (5)	0.2565 (3)	0.0247 (11)
H4	0.5356	0.4958	0.2519	0.030*
O4	0.2758 (6)	0.5563 (4)	0.3138 (2)	0.0399 (11)
H41	0.2102	0.4751	0.3032	0.060*
C5	0.3632 (8)	0.6105 (5)	0.1700 (3)	0.0260 (11)
H5A	0.2400	0.5561	0.1569	0.031*
H5B	0.3093	0.6969	0.1731	0.031*
C5A	0.5220 (7)	0.6021 (5)	0.0987 (3)	0.0198 (9)
C6	0.4727 (8)	0.5318 (5)	0.0278 (3)	0.0236 (10)
H6	0.3446	0.4842	0.0276	0.028*
C7	0.6033 (8)	0.5284 (5)	−0.0425 (3)	0.0236 (11)
H7	0.5622	0.4820	−0.0907	0.028*
C8	0.7956 (8)	0.5938 (4)	−0.0416 (3)	0.0205 (10)
H8	0.8881	0.5914	−0.0889	0.025*
C9	0.8512 (8)	0.6625 (4)	0.0288 (3)	0.0192 (10)
H9	0.9825	0.7069	0.0294	0.023*
C9A	0.7168 (8)	0.6674 (4)	0.0988 (3)	0.0177 (9)
C21	0.9463 (8)	0.7813 (4)	0.2990 (3)	0.0232 (10)
O21	1.0501 (9)	0.8637 (4)	0.2670 (2)	0.0466 (12)
O22	0.9470 (6)	0.7562 (3)	0.38004 (19)	0.0253 (8)
C22	1.1035 (8)	0.8224 (5)	0.4304 (3)	0.0275 (12)
H22A	1.2479	0.8008	0.4114	0.041*
H22B	1.0870	0.7990	0.4895	0.041*
H22C	1.0814	0.9122	0.4243	0.041*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.022 (2)	0.0165 (18)	0.0184 (19)	−0.0040 (18)	0.0017 (15)	0.0002 (16)
C2	0.016 (2)	0.025 (2)	0.0129 (19)	−0.004 (2)	−0.0003 (18)	−0.0010 (18)
C3	0.013 (2)	0.029 (3)	0.024 (2)	−0.003 (2)	0.0037 (19)	−0.001 (2)
C4	0.016 (2)	0.040 (3)	0.018 (2)	−0.009 (2)	0.0044 (19)	0.002 (2)
O4	0.023 (2)	0.064 (3)	0.033 (2)	−0.014 (2)	0.0091 (17)	0.000 (2)
C5	0.013 (2)	0.043 (3)	0.022 (2)	−0.002 (2)	0.0022 (19)	−0.002 (2)
C5A	0.012 (2)	0.027 (2)	0.020 (2)	0.0001 (19)	−0.0006 (18)	0.0016 (18)
C6	0.017 (2)	0.026 (2)	0.028 (2)	0.000 (2)	−0.005 (2)	0.003 (2)
C7	0.029 (3)	0.022 (2)	0.019 (2)	0.003 (2)	−0.007 (2)	−0.0046 (19)
C8	0.021 (2)	0.024 (2)	0.017 (2)	0.003 (2)	0.0002 (19)	0.0014 (18)
C9	0.015 (2)	0.017 (2)	0.025 (2)	0.0032 (18)	−0.0001 (19)	0.0035 (19)
C9A	0.020 (2)	0.018 (2)	0.015 (2)	0.000 (2)	−0.0032 (18)	0.0018 (17)
C21	0.023 (2)	0.024 (2)	0.023 (2)	−0.005 (2)	0.005 (2)	−0.0032 (19)
O21	0.073 (3)	0.042 (2)	0.0241 (19)	−0.037 (2)	−0.001 (2)	−0.0010 (17)
O22	0.0260 (17)	0.0295 (18)	0.0204 (16)	−0.0080 (17)	−0.0034 (14)	−0.0028 (14)
C22	0.025 (3)	0.033 (3)	0.024 (2)	−0.007 (2)	−0.005 (2)	−0.008 (2)

Geometric parameters (Å, º)

N1—C9A	1.426 (6)	C5A—C6	1.394 (6)
N1—C2	1.469 (5)	C5A—C9A	1.406 (7)
N1—H1	0.8798	C6—C7	1.386 (7)
C2—C21	1.522 (7)	C6—H6	0.9500
C2—C3	1.525 (6)	C7—C8	1.393 (7)
C2—H2	1.0000	C7—H7	0.9500
C3—C4	1.521 (7)	C8—C9	1.387 (6)
C3—H3A	0.9900	C8—H8	0.9500
C3—H3B	0.9900	C9—C9A	1.397 (6)
C4—O4	1.436 (6)	C9—H9	0.9500
C4—C5	1.533 (7)	C21—O21	1.211 (6)
C4—H4	1.0000	C21—O22	1.318 (6)
O4—H41	0.9800	O22—C22	1.452 (6)
C5—C5A	1.512 (6)	C22—H22A	0.9800
C5—H5A	0.9900	C22—H22B	0.9800
C5—H5B	0.9900	C22—H22C	0.9800
C9A—N1—C2	118.1 (4)	C6—C5A—C9A	117.6 (4)
C9A—N1—H1	113.8	C6—C5A—C5	119.7 (4)
C2—N1—H1	111.0	C9A—C5A—C5	122.6 (4)
N1—C2—C21	107.4 (4)	C7—C6—C5A	122.6 (4)
N1—C2—C3	113.4 (4)	C7—C6—H6	118.7
C21—C2—C3	111.7 (4)	C5A—C6—H6	118.7
N1—C2—H2	108.1	C6—C7—C8	119.1 (4)
C21—C2—H2	108.1	C6—C7—H7	120.5
C3—C2—H2	108.1	C8—C7—H7	120.5
C4—C3—C2	112.7 (4)	C9—C8—C7	119.6 (4)
C4—C3—H3A	109.0	C9—C8—H8	120.2
C2—C3—H3A	109.0	C7—C8—H8	120.2
C4—C3—H3B	109.0	C8—C9—C9A	120.9 (4)
C2—C3—H3B	109.0	C8—C9—H9	119.5
H3A—C3—H3B	107.8	C9A—C9—H9	119.5
O4—C4—C3	104.9 (4)	C9—C9A—C5A	120.1 (4)
O4—C4—C5	109.5 (4)	C9—C9A—N1	118.5 (4)
C3—C4—C5	112.9 (4)	C5A—C9A—N1	121.1 (4)
O4—C4—H4	109.8	O21—C21—O22	124.1 (5)
C3—C4—H4	109.8	O21—C21—C2	123.7 (4)
C5—C4—H4	109.8	O22—C21—C2	112.2 (4)
C4—O4—H41	109.2	C21—O22—C22	116.2 (4)
C5A—C5—C4	115.3 (4)	O22—C22—H22A	109.5
C5A—C5—H5A	108.5	O22—C22—H22B	109.5
C4—C5—H5A	108.5	H22A—C22—H22B	109.5
C5A—C5—H5B	108.5	O22—C22—H22C	109.5
C4—C5—H5B	108.5	H22A—C22—H22C	109.5
H5A—C5—H5B	107.5	H22B—C22—H22C	109.5
C9A—N1—C2—C21	154.8 (4)	C8—C9—C9A—C5A	0.0 (7)
C9A—N1—C2—C3	−81.3 (5)	C8—C9—C9A—N1	−173.8 (4)
N1—C2—C3—C4	68.2 (5)	C6—C5A—C9A—C9	1.4 (6)
C21—C2—C3—C4	−170.3 (4)	C5—C5A—C9A—C9	−175.9 (4)
C2—C3—C4—O4	172.1 (4)	C6—C5A—C9A—N1	175.0 (4)
C2—C3—C4—C5	−68.7 (5)	C5—C5A—C9A—N1	−2.2 (7)
O4—C4—C5—C5A	−165.8 (4)	C2—N1—C9A—C9	−123.1 (5)
C3—C4—C5—C5A	77.6 (6)	C2—N1—C9A—C5A	63.2 (6)
C4—C5—C5A—C6	125.6 (5)	N1—C2—C21—O21	−12.0 (7)
C4—C5—C5A—C9A	−57.3 (6)	C3—C2—C21—O21	−136.9 (5)
C9A—C5A—C6—C7	−2.7 (7)	N1—C2—C21—O22	167.3 (4)
C5—C5A—C6—C7	174.6 (5)	C3—C2—C21—O22	42.4 (6)
C5A—C6—C7—C8	2.5 (7)	O21—C21—O22—C22	−8.0 (8)
C6—C7—C8—C9	−1.0 (7)	C2—C21—O22—C22	172.6 (4)
C7—C8—C9—C9A	−0.2 (7)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H41···O21^i	0.98	2.31	3.178 (6)	147
O4—H41···N1^i	0.98	2.48	3.334 (6)	145
C9—H9···Cg1^ii	0.95	2.55	3.350 (5)	142

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

(III) (2RS,4SR)-4-Hydroxy-2,3,4,5-tetrahydro-1H-benz[b]azepine-2-carboxylic acid

Crystal data

C11H13NO3	F(000) = 440
Mr = 207.22	Dx = 1.391 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 2263 reflections
a = 9.4389 (5) Å	θ = 2.8–27.5°
b = 11.9081 (5) Å	µ = 0.10 mm^−1
c = 9.2702 (4) Å	T = 120 K
β = 108.275 (3)°	Block, colourless
V = 989.41 (8) Å^3	0.25 × 0.22 × 0.18 mm
Z = 4

Data collection

Bruker–Nonius KappaCCD diffractometer	2260 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1411 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.075
Detector resolution: 9.091 pixels mm^-1	θmax = 27.5°, θmin = 4.1°
ϕ & ω scans	h = −12→12
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −15→15
Tmin = 0.724, Tmax = 0.982	l = −12→12
16576 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.048	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.119	H-atom parameters constrained
S = 1.08	w = 1/[σ^2(Fo^2) + (0.0438P)^2 + 0.515P] where P = (Fo^2 + 2Fc^2)/3
2260 reflections	(Δ/σ)max = 0.001
136 parameters	Δρmax = 0.25 e Å^−3
0 restraints	Δρmin = −0.29 e Å^−3

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

	x	y	z	Uiso*/Ueq
N1	0.31915 (16)	0.43639 (13)	0.16425 (18)	0.0189 (4)
H1	0.3134	0.4850	0.0940	0.023*
C2	0.2315 (2)	0.48806 (16)	0.2543 (2)	0.0186 (4)
H2	0.3009	0.5322	0.3390	0.022*
C3	0.1533 (2)	0.39999 (17)	0.3228 (2)	0.0198 (4)
H3A	0.0871	0.4389	0.3710	0.024*
H3B	0.0897	0.3527	0.2398	0.024*
C4	0.2594 (2)	0.32434 (16)	0.4402 (2)	0.0189 (4)
H4	0.3155	0.3707	0.5299	0.023*
O4	0.16312 (14)	0.24735 (12)	0.48549 (16)	0.0218 (3)
H41	0.2150	0.2023	0.5464	0.033*
C5	0.3703 (2)	0.25765 (16)	0.3849 (2)	0.0198 (4)
H5A	0.4141	0.1985	0.4608	0.024*
H5B	0.3141	0.2194	0.2892	0.024*
C5A	0.4971 (2)	0.32279 (16)	0.3567 (2)	0.0188 (4)
C6	0.6453 (2)	0.29549 (18)	0.4340 (2)	0.0227 (5)
H6	0.6661	0.2395	0.5108	0.027*
C7	0.7634 (2)	0.34807 (18)	0.4015 (2)	0.0245 (5)
H7	0.8634	0.3273	0.4547	0.029*
C8	0.7343 (2)	0.43083 (18)	0.2911 (2)	0.0242 (5)
H8	0.8142	0.4665	0.2672	0.029*
C9	0.5879 (2)	0.46130 (17)	0.2155 (2)	0.0225 (5)
H9	0.5680	0.5189	0.1409	0.027*
C9A	0.4699 (2)	0.40855 (16)	0.2477 (2)	0.0189 (4)
C21	0.1217 (2)	0.56892 (16)	0.1495 (2)	0.0191 (4)
O21	0.12155 (15)	0.58915 (11)	0.02143 (16)	0.0235 (4)
O22	0.03051 (15)	0.61649 (12)	0.21547 (16)	0.0243 (3)
H22	−0.0291	0.6663	0.1471	0.029*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0193 (9)	0.0187 (9)	0.0184 (9)	0.0008 (7)	0.0056 (7)	0.0019 (7)
C2	0.0176 (10)	0.0184 (10)	0.0193 (10)	0.0008 (8)	0.0050 (8)	−0.0019 (8)
C3	0.0173 (9)	0.0208 (10)	0.0209 (10)	0.0000 (8)	0.0056 (8)	0.0011 (8)
C4	0.0199 (10)	0.0176 (10)	0.0198 (10)	−0.0033 (8)	0.0071 (8)	−0.0010 (8)
O4	0.0200 (7)	0.0221 (7)	0.0222 (8)	−0.0018 (6)	0.0054 (6)	0.0039 (6)
C5	0.0216 (10)	0.0184 (10)	0.0200 (11)	0.0012 (8)	0.0074 (8)	0.0011 (8)
C5A	0.0198 (10)	0.0191 (10)	0.0191 (10)	0.0014 (8)	0.0082 (8)	−0.0020 (8)
C6	0.0239 (11)	0.0224 (11)	0.0215 (11)	0.0034 (9)	0.0066 (9)	0.0011 (9)
C7	0.0178 (10)	0.0279 (11)	0.0254 (12)	0.0037 (9)	0.0036 (8)	−0.0033 (9)
C8	0.0210 (10)	0.0257 (11)	0.0268 (11)	−0.0038 (9)	0.0088 (9)	−0.0043 (9)
C9	0.0248 (11)	0.0218 (11)	0.0221 (11)	0.0003 (9)	0.0091 (9)	0.0010 (9)
C9A	0.0194 (10)	0.0188 (10)	0.0181 (10)	0.0020 (8)	0.0053 (8)	−0.0026 (8)
C21	0.0185 (10)	0.0154 (10)	0.0219 (11)	−0.0023 (8)	0.0040 (8)	−0.0026 (8)
O21	0.0236 (8)	0.0232 (8)	0.0235 (8)	0.0007 (6)	0.0070 (6)	0.0029 (6)
O22	0.0257 (8)	0.0245 (8)	0.0231 (8)	0.0077 (6)	0.0082 (6)	0.0019 (6)

Geometric parameters (Å, º)

N1—C9A	1.429 (2)	C5—H5B	0.9900
N1—C2	1.481 (2)	C5A—C6	1.395 (3)
N1—H1	0.8600	C5A—C9A	1.403 (3)
C2—C21	1.521 (3)	C6—C7	1.392 (3)
C2—C3	1.530 (3)	C6—H6	0.9500
C2—H2	1.0000	C7—C8	1.385 (3)
C3—C4	1.522 (3)	C7—H7	0.9500
C3—H3A	0.9900	C8—C9	1.388 (3)
C3—H3B	0.9900	C8—H8	0.9500
C4—O4	1.443 (2)	C9—C9A	1.390 (3)
C4—C5	1.525 (3)	C9—H9	0.9500
C4—H4	1.0000	C21—O21	1.211 (2)
O4—H41	0.8201	C21—O22	1.329 (2)
C5—C5A	1.516 (3)	O22—H22	0.9200
C5—H5A	0.9900
C9A—N1—C2	115.39 (15)	C5A—C5—H5B	108.1
C9A—N1—H1	112.4	C4—C5—H5B	108.1
C2—N1—H1	103.5	H5A—C5—H5B	107.3
N1—C2—C21	107.00 (15)	C6—C5A—C9A	117.82 (18)
N1—C2—C3	112.13 (16)	C6—C5A—C5	120.72 (18)
C21—C2—C3	112.21 (15)	C9A—C5A—C5	121.40 (17)
N1—C2—H2	108.5	C7—C6—C5A	121.77 (19)
C21—C2—H2	108.5	C7—C6—H6	119.1
C3—C2—H2	108.5	C5A—C6—H6	119.1
C4—C3—C2	114.04 (16)	C8—C7—C6	119.57 (19)
C4—C3—H3A	108.7	C8—C7—H7	120.2
C2—C3—H3A	108.7	C6—C7—H7	120.2
C4—C3—H3B	108.7	C7—C8—C9	119.62 (19)
C2—C3—H3B	108.7	C7—C8—H8	120.2
H3A—C3—H3B	107.6	C9—C8—H8	120.2
O4—C4—C3	104.53 (15)	C8—C9—C9A	120.77 (19)
O4—C4—C5	109.15 (15)	C8—C9—H9	119.6
C3—C4—C5	115.79 (16)	C9A—C9—H9	119.6
O4—C4—H4	109.1	C9—C9A—C5A	120.41 (17)
C3—C4—H4	109.1	C9—C9A—N1	120.50 (18)
C5—C4—H4	109.1	C5A—C9A—N1	118.99 (17)
C4—O4—H41	108.7	O21—C21—O22	124.37 (18)
C5A—C5—C4	116.98 (16)	O21—C21—C2	122.89 (18)
C5A—C5—H5A	108.1	O22—C21—C2	112.71 (17)
C4—C5—H5A	108.1	C21—O22—H22	107.6
C9A—N1—C2—C21	147.73 (16)	C7—C8—C9—C9A	−1.0 (3)
C9A—N1—C2—C3	−88.84 (19)	C8—C9—C9A—C5A	−0.5 (3)
N1—C2—C3—C4	65.2 (2)	C8—C9—C9A—N1	−176.90 (18)
C21—C2—C3—C4	−174.35 (16)	C6—C5A—C9A—C9	2.0 (3)
C2—C3—C4—O4	−178.50 (16)	C5—C5A—C9A—C9	−175.05 (18)
C2—C3—C4—C5	−58.4 (2)	C6—C5A—C9A—N1	178.51 (17)
O4—C4—C5—C5A	−170.24 (16)	C5—C5A—C9A—N1	1.4 (3)
C3—C4—C5—C5A	72.2 (2)	C2—N1—C9A—C9	−116.1 (2)
C4—C5—C5A—C6	121.5 (2)	C2—N1—C9A—C5A	67.4 (2)
C4—C5—C5A—C9A	−61.5 (3)	N1—C2—C21—O21	−5.3 (2)
C9A—C5A—C6—C7	−2.2 (3)	C3—C2—C21—O21	−128.6 (2)
C5—C5A—C6—C7	174.87 (19)	N1—C2—C21—O22	176.63 (15)
C5A—C6—C7—C8	0.8 (3)	C3—C2—C21—O22	53.3 (2)
C6—C7—C8—C9	0.8 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O21	0.86	2.12	2.644 (2)	119
O22—H22···O4^i	0.92	1.75	2.665 (2)	172
O4—H41···N1^ii	0.82	2.05	2.859 (2)	167

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

(IV) (2RS,5SR)-8-(trifluoromethoxy)-5,6-dihydro-1H-2,5-methanobenz[e][1,4]oxazocin-3(2H)-one

Crystal data

C12H10F3NO3	F(000) = 560
Mr = 273.21	Dx = 1.620 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 2569 reflections
a = 15.0601 (8) Å	θ = 2.7–27.5°
b = 9.2204 (5) Å	µ = 0.15 mm^−1
c = 8.072 (4) Å	T = 120 K
β = 91.668 (10)°	Block, colourless
V = 1120.4 (6) Å^3	0.28 × 0.21 × 0.19 mm
Z = 4

Data collection

Bruker–Nonius KappaCCD diffractometer	2567 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1854 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.055
Detector resolution: 9.091 pixels mm^-1	θmax = 27.5°, θmin = 3.5°
ϕ & ω scans	h = −19→19
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −11→11
Tmin = 0.788, Tmax = 0.972	l = −10→10
18683 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.043	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.105	H-atom parameters constrained
S = 1.07	w = 1/[σ^2(Fo^2) + (0.0431P)^2 + 0.5504P] where P = (Fo^2 + 2Fc^2)/3
2567 reflections	(Δ/σ)max = 0.001
172 parameters	Δρmax = 0.21 e Å^−3
0 restraints	Δρmin = −0.31 e Å^−3

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

	x	y	z	Uiso*/Ueq
N1	0.61135 (10)	0.59820 (16)	0.61634 (18)	0.0218 (3)
H1	0.5681	0.6279	0.5337	0.026*
C2	0.57188 (12)	0.50477 (19)	0.7412 (2)	0.0219 (4)
H2	0.5080	0.5308	0.7543	0.026*
C3	0.58000 (12)	0.3450 (2)	0.6930 (2)	0.0222 (4)
O31	0.53420 (8)	0.27667 (14)	0.59480 (16)	0.0271 (3)
O4	0.65026 (8)	0.28484 (14)	0.77298 (15)	0.0242 (3)
C5	0.69319 (12)	0.3941 (2)	0.8832 (2)	0.0233 (4)
H5	0.7107	0.3484	0.9917	0.028*
C6	0.77490 (12)	0.4539 (2)	0.8014 (2)	0.0245 (4)
H6A	0.8216	0.3784	0.8087	0.029*
H6B	0.7965	0.5374	0.8683	0.029*
C6A	0.76701 (12)	0.5033 (2)	0.6213 (2)	0.0208 (4)
C7	0.84494 (12)	0.4894 (2)	0.5318 (2)	0.0216 (4)
H7	0.8955	0.4445	0.5829	0.026*
C8	0.85009 (12)	0.53906 (19)	0.3717 (2)	0.0219 (4)
C9	0.77828 (12)	0.6040 (2)	0.2918 (2)	0.0235 (4)
H9	0.7826	0.6400	0.1820	0.028*
C10	0.70001 (12)	0.61538 (19)	0.3759 (2)	0.0219 (4)
H10	0.6495	0.6564	0.3205	0.026*
C10A	0.69255 (12)	0.56800 (18)	0.5413 (2)	0.0201 (4)
C25	0.62034 (12)	0.5060 (2)	0.9089 (2)	0.0234 (4)
H25A	0.5807	0.4766	0.9986	0.028*
H25B	0.6456	0.6029	0.9346	0.028*
O81	0.93234 (8)	0.53034 (14)	0.28898 (15)	0.0254 (3)
C81	0.95115 (12)	0.4006 (2)	0.2242 (2)	0.0258 (4)
F81	0.96324 (8)	0.29714 (13)	0.33838 (14)	0.0348 (3)
F82	1.02571 (7)	0.41217 (13)	0.14159 (14)	0.0351 (3)
F83	0.88729 (8)	0.35243 (14)	0.11937 (14)	0.0361 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0216 (8)	0.0206 (8)	0.0233 (7)	0.0026 (6)	0.0026 (6)	0.0023 (6)
C2	0.0210 (9)	0.0196 (9)	0.0255 (9)	0.0005 (7)	0.0056 (7)	−0.0005 (7)
C3	0.0205 (9)	0.0220 (9)	0.0246 (9)	0.0004 (7)	0.0070 (7)	0.0019 (8)
O31	0.0256 (7)	0.0224 (7)	0.0333 (7)	−0.0016 (5)	0.0018 (6)	−0.0026 (6)
O4	0.0258 (7)	0.0200 (6)	0.0270 (7)	0.0039 (5)	0.0026 (5)	−0.0001 (5)
C5	0.0270 (10)	0.0232 (9)	0.0199 (8)	0.0007 (8)	0.0015 (7)	−0.0003 (7)
C6	0.0223 (9)	0.0327 (10)	0.0187 (8)	0.0025 (8)	0.0014 (7)	0.0033 (8)
C6A	0.0230 (9)	0.0200 (9)	0.0195 (9)	−0.0014 (7)	0.0017 (7)	−0.0003 (7)
C7	0.0220 (9)	0.0212 (9)	0.0214 (9)	−0.0011 (7)	−0.0008 (7)	−0.0005 (7)
C8	0.0223 (9)	0.0215 (9)	0.0222 (9)	−0.0040 (7)	0.0065 (7)	−0.0026 (7)
C9	0.0319 (10)	0.0200 (9)	0.0187 (8)	−0.0018 (8)	0.0022 (8)	0.0009 (7)
C10	0.0250 (9)	0.0188 (9)	0.0217 (9)	0.0007 (7)	−0.0018 (7)	0.0010 (7)
C10A	0.0223 (9)	0.0155 (8)	0.0224 (9)	−0.0013 (7)	0.0019 (7)	−0.0031 (7)
C25	0.0259 (9)	0.0213 (9)	0.0234 (9)	0.0007 (7)	0.0064 (7)	−0.0002 (7)
O81	0.0241 (7)	0.0261 (7)	0.0266 (7)	−0.0042 (5)	0.0091 (5)	−0.0010 (6)
C81	0.0243 (10)	0.0318 (11)	0.0215 (9)	−0.0023 (8)	0.0041 (8)	−0.0005 (8)
F81	0.0403 (7)	0.0338 (7)	0.0308 (6)	0.0084 (5)	0.0097 (5)	0.0075 (5)
F82	0.0282 (6)	0.0467 (8)	0.0312 (6)	−0.0012 (5)	0.0138 (5)	−0.0013 (5)
F83	0.0319 (6)	0.0459 (7)	0.0304 (6)	−0.0013 (5)	−0.0010 (5)	−0.0135 (6)

Geometric parameters (Å, º)

N1—C10A	1.408 (2)	C6A—C10A	1.410 (2)
N1—C2	1.465 (2)	C7—C8	1.375 (3)
N1—H1	0.9581	C7—H7	0.9500
C2—C25	1.520 (3)	C8—C9	1.380 (3)
C2—C3	1.530 (2)	C8—O81	1.427 (2)
C2—H2	1.0000	C9—C10	1.381 (3)
C3—O31	1.212 (2)	C9—H9	0.9500
C3—O4	1.343 (2)	C10—C10A	1.413 (3)
O4—C5	1.481 (2)	C10—H10	0.9500
C5—C6	1.517 (3)	C25—H25A	0.9900
C5—C25	1.525 (3)	C25—H25B	0.9900
C5—H5	1.0000	O81—C81	1.340 (2)
C6—C6A	1.525 (2)	C81—F82	1.327 (2)
C6—H6A	0.9900	C81—F81	1.335 (2)
C6—H6B	0.9900	C81—F83	1.338 (2)
C6A—C7	1.402 (2)
C10A—N1—C2	123.67 (14)	C8—C7—C6A	121.66 (17)
C10A—N1—H1	109.8	C8—C7—H7	119.2
C2—N1—H1	111.5	C6A—C7—H7	119.2
N1—C2—C25	114.48 (15)	C7—C8—C9	121.26 (17)
N1—C2—C3	110.77 (14)	C7—C8—O81	119.63 (16)
C25—C2—C3	101.19 (14)	C9—C8—O81	119.03 (15)
N1—C2—H2	110.0	C8—C9—C10	118.16 (16)
C25—C2—H2	110.0	C8—C9—H9	120.9
C3—C2—H2	110.0	C10—C9—H9	120.9
O31—C3—O4	121.68 (17)	C9—C10—C10A	122.23 (16)
O31—C3—C2	128.21 (17)	C9—C10—H10	118.9
O4—C3—C2	110.08 (15)	C10A—C10—H10	118.9
C3—O4—C5	109.39 (14)	N1—C10A—C6A	125.15 (16)
O4—C5—C6	109.33 (14)	N1—C10A—C10	116.06 (16)
O4—C5—C25	103.83 (14)	C6A—C10A—C10	118.68 (16)
C6—C5—C25	114.17 (16)	C2—C25—C5	101.68 (14)
O4—C5—H5	109.8	C2—C25—H25A	111.4
C6—C5—H5	109.8	C5—C25—H25A	111.4
C25—C5—H5	109.8	C2—C25—H25B	111.4
C5—C6—C6A	118.80 (15)	C5—C25—H25B	111.4
C5—C6—H6A	107.6	H25A—C25—H25B	109.3
C6A—C6—H6A	107.6	C81—O81—C8	115.44 (14)
C5—C6—H6B	107.6	F82—C81—F81	107.71 (15)
C6A—C6—H6B	107.6	F82—C81—F83	108.21 (15)
H6A—C6—H6B	107.0	F81—C81—F83	106.30 (16)
C7—C6A—C10A	117.96 (15)	F82—C81—O81	108.41 (15)
C7—C6A—C6	114.90 (15)	F81—C81—O81	113.23 (15)
C10A—C6A—C6	127.02 (16)	F83—C81—O81	112.76 (16)
C10A—N1—C2—C25	71.1 (2)	O81—C8—C9—C10	−178.06 (15)
C10A—N1—C2—C3	−42.5 (2)	C8—C9—C10—C10A	2.5 (3)
N1—C2—C3—O31	−79.9 (2)	C2—N1—C10A—C6A	−36.1 (3)
C25—C2—C3—O31	158.32 (18)	C2—N1—C10A—C10	147.94 (16)
N1—C2—C3—O4	97.98 (17)	C7—C6A—C10A—N1	−175.86 (16)
C25—C2—C3—O4	−23.81 (18)	C6—C6A—C10A—N1	−0.1 (3)
O31—C3—O4—C5	179.70 (16)	C7—C6A—C10A—C10	0.0 (3)
C2—C3—O4—C5	1.67 (18)	C6—C6A—C10A—C10	175.80 (17)
C3—O4—C5—C6	−100.92 (16)	C9—C10—C10A—N1	174.42 (16)
C3—O4—C5—C25	21.31 (18)	C9—C10—C10A—C6A	−1.8 (3)
O4—C5—C6—C6A	48.3 (2)	N1—C2—C25—C5	−84.37 (17)
C25—C5—C6—C6A	−67.5 (2)	C3—C2—C25—C5	34.79 (17)
C5—C6—C6A—C7	−150.27 (17)	O4—C5—C25—C2	−34.96 (17)
C5—C6—C6A—C10A	33.8 (3)	C6—C5—C25—C2	84.00 (17)
C10A—C6A—C7—C8	1.1 (3)	C7—C8—O81—C81	80.9 (2)
C6—C6A—C7—C8	−175.20 (17)	C9—C8—O81—C81	−102.34 (19)
C6A—C7—C8—C9	−0.4 (3)	C8—O81—C81—F82	175.46 (13)
C6A—C7—C8—O81	176.27 (16)	C8—O81—C81—F81	−65.1 (2)
C7—C8—C9—C10	−1.3 (3)	C8—O81—C81—F83	55.7 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O31^i	0.96	2.03	2.970 (2)	166

Symmetry code: (i) −x+1, −y+1, −z+1.