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Journal logoSTRUCTURAL
CHEMISTRY
ISSN: 2053-2296

(2R*,4S*)-2-(Pyridin-3-yl)-2,3,4,5-tetra­hydro-1H-1-benzazepin-4-ol: a three-dimensional framework built from O—H⋯N, C—H⋯O and C—H⋯π(arene) hydrogen bonds

aLaboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, AA 678 Bucaramanga, Colombia, bDepartamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain, and cSchool of Chemistry, University of St Andrews, Fife KY16 9ST, Scotland
*Correspondence e-mail: cg@st-andrews.ac.uk

(Received 14 March 2011; accepted 17 March 2011; online 12 April 2011)

The title compound, C15H16N2O, crystallizes in the space group P212121 with Z′ = 1. The seven-membered ring adopts a chair-type conformation with the hy­droxy and pyridyl substituents in equatorial sites. Mol­ecules are linked into a three-dimensional framework structure by a combination of O—H⋯N, C—H⋯O and C—H⋯π(arene) hydrogen bonds, but N—H⋯O and N—H⋯π(arene) inter­actions are absent from the structure. Comparisons are made with some related compounds.

Comment

The chemistry of tetra­hydro-1-benzazepine systems has been extensively investigated, and many examples of this class have been the targets in synthetic investigations because of their known biological properties, such as nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors (Tsunoda et al., 2005[Tsunoda, T., Yamazaki, A., Mase, T. & Sakamoto, S. (2005). Org. Process Res. Dev. 9, 593-598.]), inhibitors of cyclin-dependent kinases (Kunick et al., 2006[Kunick, C., Bleeker, C., Prühs, C., Totzke, F., Schächtele, C., Kubbutat, M. H. G. & Link, A. (2006). Bioorg. Med. Chem. Lett. 16, 2148-2153.]), agents against HIV-1 infection (Seto et al., 2005[Seto, M., Miyamoto, N., Aikawa, K., Aramaki, Y., Kansaki, N., Iizawa, Y., Baba, M. & Shiraishi, M. (2005). Bioorg. Med. Chem. 13, 363-386.]) and antipsychotic agents (Zhao et al., 2003[Zhao, H., Zhang, X., Hodgetts, K., Thurkauf, A., Hammer, J., Chandrasekhar, J., Kieltyka, A., Brodbeck, R., Rachwal, A., Primus, R. & Manly, C. (2003). Bioorg. Med. Chem. Lett. 13, 701-704.]). The growing inter­est in tetra­hydro-1-benzazepines has recently been boosted by their high potential value as agents against promastigotes and amastigotes of Leishmania mexicana (Knockaert et al., 2002[Knockaert, M., Wieking, K., Schmitt, S., Leost, M., Grant, K. M., Mottram, J. C., Kunick, C. & Meijer, L. (2002). J. Biol. Chem. 277, 25493-25501.]), and as inhibitors of Trypanosoma cruzi dihydro­folate reductase (Zuccotto et al., 2001[Zuccotto, F., Zvelebil, M., Brun, R., Chowdhury, S. F., Di Lucrezia, R., Leal, I., Maes, L., Ruiz-Perez, L. M., Pacanowska, D. G. & Gilbert, I. H. (2001). Eur. J. Med. Chem. 36, 395-405.]). As an extension of our current work towards the synthesis of bioactive compounds containing the tetra­hydro-1-benzazepine ring system, we recently reported the synthesis and anti­parasitic activity of a new series of cis-2-aryl-4-hy­droxy­tetra­hydro­naphtho­[1,2-b]azepines against Trypanosoma cruzi and Leishmania chagasi parasites (Palma et al., 2009[Palma, A., Yépes, A. F., Leal, S. M., Coronado, C. A. & Escobar, P. (2009). Bioorg. Med. Chem. Lett. 19, 2360-2363.]). Here we report the structure of the title hy­droxy­benzazepine com­pound, (I)[link] (Fig. 1[link]), and we compare compound (I)[link] with its close analogues 2-vinyl-2,3,4,5-tetra­hydro-1-benzazepin-4-ol, (II), and 2-phenyl-2,3,4,5-tetra­hydro-1H-1,4-ep­oxy-1-benzaz­epine, (III), whose structures have been reported recently (Acosta et al., 2009[Acosta, L. M., Bahsas, A., Palma, A., Cobo, J., Hursthouse, M. B. & Glidewell, C. (2009). Acta Cryst. C65, o92-o96.]; Gómez et al., 2010[Gómez, S. L., Palma, A., Cobo, J. & Glidewell, C. (2010). Acta Cryst. C66, o233-o240.]). The constitution of compound (I)[link] differs from that of (II) in that the pendent substituent is a 3-pyridyl group in (I)[link] as opposed to a vinyl group in (II); the constitution of (I)[link] differs from that of (III) in that the pendent substituent is a 3-pyridyl group in (I)[link] as opposed to a phenyl group in (III) and the amino-alcohol functionality in (I)[link] is the reduction product of a 1,4-ep­oxy bridge as found in compound (III). The reductive cleavage of the N—O bond in such an ep­oxy bridge is readily accomplished by the use of zinc powder in 80% acetic acid, as employed in the preparation of compound (I)[link].

[Scheme 1]

Compound (I)[link] crystallizes in the space group P212121 with only one enanti­omorph present in any given crystal. It was not possible to establish the absolute configuration of the mol­ecules in the crystal selected for data collection, and the asymmetric unit was selected to be a mol­ecule having the R configuration at atom C2; on this basis the configuration at atom C4 is S. However, the method of synthesis employed for compound (I)[link], i.e. reduction of a racemic precursor under conditions which do not induce enanti­oselectivity, suggests that compound (I)[link] should be formed as a racemic mixture, so that conglomerate crystallization has subsequently occurred. The crystallization behaviour of (I)[link] may be contrasted with that of compounds (II) and (III), which crystallize as true racemates in the space groups P21/n and Cc, respectively (Acosta et al., 2009[Acosta, L. M., Bahsas, A., Palma, A., Cobo, J., Hursthouse, M. B. & Glidewell, C. (2009). Acta Cryst. C65, o92-o96.]; Gómez et al., 2010[Gómez, S. L., Palma, A., Cobo, J. & Glidewell, C. (2010). Acta Cryst. C66, o233-o240.]).

The seven-membered ring in compound (I)[link] adopts a chair-type conformation with both the pyridyl and the hy­droxy substituents in equatorial sites. The bond distances and the inter­bond angles present no unusual values.

The mol­ecules of compound (I)[link] are linked into a three-dimensional framework structure by a combination of O—H⋯N, C—H⋯O and C—H⋯π(arene) hydrogen bonds (Table 1[link]). The two independent C—H⋯O hydrogen bonds necessarily have a common acceptor atom, while the two C—H⋯π(arene) hydrogen bonds utilize as acceptors the two faces of the fused aryl ring. These two inter­actions subtend angles at the ring centroid, denoted Cg, whose values are close to 180°; thus the angles H25iCg⋯H9ii and C25iCg⋯C9ii [symmetry codes: (i) x, y + 1, z; (ii) x + [{1\over 2}], −y + [{3\over 2}], −z + 1] are 151 and 157.6 (2)°, respectively. It is striking that, although four C—H bonds are involved in hydrogen-bond formation, including three of the four C—H bonds of the pyridyl ring (Table 1[link]), the N—H bond does not participate at all in the inter­molecular hydrogen bonding. There are no potential acceptors within hydrogen-bonding range of the N1 atom and, in fact, all of the non-H atoms within 3.6 Å of the N1 atom are components of the same mol­ecule.

Although the hydrogen-bonded framework, based on five independent hydrogen bonds, is somewhat complex overall, its formation can readily be analysed using the substructure approach (Ferguson et al., 1998a[Ferguson, G., Glidewell, C., Gregson, R. M. & Meehan, P. R. (1998a). Acta Cryst. B54, 129-138.],b[Ferguson, G., Glidewell, C., Gregson, R. M. & Meehan, P. R. (1998b). Acta Cryst. B54, 139-150.]; Gregson et al., 2000[Gregson, R. M., Glidewell, C., Ferguson, G. & Lough, A. J. (2000). Acta Cryst. B56, 39-57.]), in terms of three substructures, two of them two-dimensional while the third substructure is one-dimensional.

The first substructure is built from the O—H⋯N and C—H⋯O hydrogen bonds. Acting individually, these three hydrogen bonds, having atoms O41, C22 and C24, respectively, as the donors, form chains of types C(8), C(7) and C(9) (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]), respectively, running parallel to the [010], [100] and [110] directions. Acting together, these three hydrogen bonds form a sheet parallel to (001) and lying in the domain 0.5 < z < 1.0 (Fig. 2[link]); two such sheets pass through each unit cell.

In the second substructure, the two C—H⋯π(arene) hydrogen bonds combine to form another type of sheet. Acting individually, the hydrogen bonds having atoms C9 and C25 as the donors form chains running parallel to the [100] and [010] directions, respectively. In combinations these two inter­actions generate a sheet lying parallel to (001) but now in the domain 0.3 < z < 0.7 (Fig. 3[link]); again, two sheets of this type pass through each unit cell.

The linking of the sheets is most simply understood in terms of the third substructure. Of the five independent hydrogen bonds (Table 1[link]), three link mol­ecules which are related to one another by translation; by contrast, the O—H⋯N hydrogen bond and the C—H⋯π(arene) hydrogen bond utilizing atom C9 as the donor, respectively, link mol­ecules related by the 21 screw axes along ([{1\over 2}], y, [{3\over 4}]) and (x, [{3\over 4}], [{1\over 2}]). The combination of these two hydrogen bonds, acting alternately, generates a chain running parallel to the [001] direction (Fig. 4[link]). This chain along [001] links together all of the sheets, of both types, parallel to (001), so that the combination of the three substructures generates a three-dimensional framework structure.

It is of inter­est briefly to compare the mol­ecular aggregation in compound (I)[link] with that in compounds (II) and (III). In the crystal structure of compound (II) (Acosta et al., 2009[Acosta, L. M., Bahsas, A., Palma, A., Cobo, J., Hursthouse, M. B. & Glidewell, C. (2009). Acta Cryst. C65, o92-o96.]), a combination of N—H⋯O and O—H⋯N hydrogen bonds links the mol­ecules into a chain of edge-fused R33(10) rings, while a single C—H⋯π(arene) hydrogen bond links chains of this type into a sheet. Thus, by contrast with compound (I)[link], the N—H bond in compound (II) participates in the inter­molecular hydrogen bonding, presumably because the steric shielding of the N—H unit afforded by the vinyl substituent in compound (II) is less than that provided by the pyridyl substituent in compound (I)[link]. There are neither N—H nor O—H bonds in compound (III), so that the inter­molecular aggregation in (III) is necessarily different from that in compounds (I)[link] and (II). Compound (III) crystallizes with Z′ = 2 in the space group Cc (Gómez et al., 2010[Gómez, S. L., Palma, A., Cobo, J. & Glidewell, C. (2010). Acta Cryst. C66, o233-o240.]), and mol­ecules related by translation are linked by C—H⋯π(arene) hydrogen bonds to form two independent chains running anti­parallel to one another and each containing only one type of mol­ecule.

[Figure 1]
Figure 1
The mol­ecular structure of the (2R,4S) enanti­omer of compound (I)[link], showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
[Figure 2]
Figure 2
A stereoview of part of the crystal structure of compound (I)[link], showing the formation of a sheet lying parallel to (001) and built from O—H⋯N and C—H⋯O hydrogen bonds. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
[Figure 3]
Figure 3
A stereoview of part of the crystal structure of compound (I)[link], showing the formation of a sheet lying parallel to (001) and built from C—H⋯π(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
[Figure 4]
Figure 4
A stereoview of part of the crystal structure of compound (I)[link], showing the formation of a chain running parallel to [001] and built from alternating O—H⋯N and C—H⋯π(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Experimental

Zinc powder (0.8 mmol) was added to a solution of racemic (2RS,4SR)-2-exo-(pyridin-3-yl)-1,4-ep­oxy-2,3,4,5-tetra­hydro-1-benzazepine (0.1 mmol) in 80% acetic acid (15 ml). The resulting mixture was stirred at 318 K for 3 h. The mixture was filtered, and the filtrate was neutralized with aqueous ammonia solution to pH = 8 and then extracted with ethyl acetate (3 × 50 ml). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the crude product which was purified by column chromatography on silica gel using hepta­ne–ethyl acetate (10:1 to 1:1 v/v) as eluent. Recrystallization from hepta­ne–ethyl acetate (1:4 v/v) gave colourless crystals suitable for single-crystal X-ray diffraction (yield 86%, m.p. 403–404 K). MS (70 eV) m/z (%): 240 (M+, 74), 221 (13), 195 (61), 130 (11), 118 (100), 106 (74), 91 (21), 77 (16).

Crystal data
  • C15H16N2O

  • Mr = 240.30

  • Orthorhombic, P 21 21 21

  • a = 6.0318 (9) Å

  • b = 8.3396 (10) Å

  • c = 25.361 (4) Å

  • V = 1275.7 (3) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.08 mm−1

  • T = 120 K

  • 0.40 × 0.22 × 0.20 mm

Data collection
  • Bruker–Nonius KappaCCD diffractometer

  • Absorption correction: multi-scan (SADABS; Sheldrick, 2003[Sheldrick, G. M. (2003). SADABS. Version 2.10. University of Göttingen, Germany.]) Tmin = 0.969, Tmax = 0.984

  • 10571 measured reflections

  • 1714 independent reflections

  • 1453 reflections with I > 2σ(I)

  • Rint = 0.034

Refinement
  • R[F2 > 2σ(F2)] = 0.035

  • wR(F2) = 0.086

  • S = 1.11

  • 1714 reflections

  • 163 parameters

  • H-atom parameters constrained

  • Δρmax = 0.16 e Å−3

  • Δρmin = −0.22 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

Cg is the centroid of the C5A/C6–C9/C9A ring.

D—H⋯A D—H H⋯A DA D—H⋯A
O41—H41⋯N23i 0.86 1.94 2.786 (2) 168
C22—H22⋯O41ii 0.95 2.47 3.288 (2) 145
C24—H24⋯O41iii 0.95 2.49 3.436 (2) 175
C9—H9⋯Cgiv 0.95 2.83 3.633 (2) 143
C25—H25⋯Cgv 0.95 2.77 3.633 (2) 151
Symmetry codes: (i) [-x+1, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]; (ii) x-1, y, z; (iii) x-1, y-1, z; (iv) [x-{\script{1\over 2}}, -y+{\script{3\over 2}}, -z+1]; (v) x, y-1, z.

All H atoms were located in difference maps and subsequently treated as riding atoms in geometrically idealized positions, with C—H distances = 0.95 (aromatic and heteroaromatic), 0.99 (CH2) or 1.00 Å (aliphatic CH), N—H = 0.88 Å and O—H = 0.86 Å, and with Uiso(H) = kUeq(carrier), where k = 1.5 for hy­droxy atom H41 and 1.2 otherwise. In the absence of significant resonant scattering, the values of the Flack x parameter (Flack, 1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]) and the Hooft y parameter (Hooft et al., 2008[Hooft, R. W. W., Straver, L. H. & Spek, A. L. (2008). J. Appl. Cryst. 41, 96-103.]), viz. 0.2 (15) and 0.6 (7), respectively, were indeterminate (Flack & Bernardinelli, 2000[Flack, H. D. & Bernardinelli, G. (2000). J. Appl. Cryst. 33, 1143-1148.]). Accordingly, the Friedel-equivalent reflections were merged prior to the final refinements, and the asymmetric unit was arbitrarily selected as having the R configuration at atom C2, and hence the S configuration at atom C4.

Data collection: COLLECT (Hooft, 1999[Hooft, R. W. W. (1999). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: DIRAX/LSQ (Duisenberg et al., 2000[Duisenberg, A. J. M., Hooft, R. W. W., Schreurs, A. M. M. & Kroon, J. (2000). J. Appl. Cryst. 33, 893-898.]); data reduction: EVALCCD (Duisenberg et al., 2003[Duisenberg, A. J. M., Kroon-Batenburg, L. M. J. & Schreurs, A. M. M. (2003). J. Appl. Cryst. 36, 220-229.]); program(s) used to solve structure: SIR2004 (Burla et al., 2005[Burla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L., De Caro, L., Giacovazzo, C., Polidori, G. & Spagna, R. (2005). J. Appl. Cryst. 38, 381-388.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]); software used to prepare material for publication: SHELXL97 and PLATON.

Supporting information


Comment top

The chemistry of tetrahydro-1-benzazepine systems has been extensively investigated, and many examples of this class have been the targets in synthetic investigations because of their known biological properties, such as non-peptide arginine vasopressin antagonists for both V1A and V2 receptors (Tsunoda et al., 2005), inhibitors of cyclin-dependent kinases (Kunick et al., 2006), agents against HIV-1 infection (Seto et al., 2005) and anti-psychotic agents (Zhao et al., 2003). The growing interest in tetrahydro-1-benzazepines has recently been boosted by their high potential value as agents against promastigotes and amastigotes of Leishmania mexicana (Knockaert et al., 2002), and as inhibitors of Trypanosoma cruzi dihydrofolate reductase (Zuccotto et al., 2001). As an extension of our current work towards the synthesis of bioactive compounds containing the tetrahydro-1-benzazepine ring system, we recently reported the synthesis and anti-parasitic activity of a new series of cis-2-aryl-4-hydroxytetrahydronaphtho[1,2-b]azepines against Trypanosoma cruzi and Leishmania chagasi parasites (Palma et al., 2009). Here we report the structure of the title hydroxybenzazepine compound, (I) (Fig. 1), and we compare compound (I) with its close analogues 2-vinyl-2,3,4,5-tetrahydro-1-benzazepin-4-ol, (II), and 2-phenyl-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (III), whose structures have recently been reported (Acosta et al., 2009; Gómez et al., 2010). The constitution of compound (I) differs from that of (II) in that the pendent substituent is a 3-pyridyl group in (I) as opposed to a vinyl group in (II); the constitution of (I) differs from that of (III) in that the pendent substituent is a 3-pyridyl group in (I) as opposed to a phenyl group in (III) and the amino-alcohol functionality in (I) is the reduction product of a 1,4-epoxy bridge as found in compound (III). The reductive cleavage of the N—O bond in such an epoxy bridge is readily accomplished by the use of zinc powder in 80% acetic acid, as employed in the preparation of compound (I).

Compound (I) crystallizes in the space group P212121 with only one enantiomorph present in any given crystal. It was not possible to establish the absolute configuration of the molecules in the crystal selected for data collection, and the asymmetric unit was selected to be a molecule having the R configuration at atom C2: on this basis the configuration at atom C4 is S in the selected asymmetric unit. However, the method of synthesis employed for compound (I), i.e. reduction of a racemic precursor under conditions which do not induce enantioselectivity, suggests that compound (I) should be formed as a racemic mixture, so that conglomerate crystallization has subsequently occurred. The crystallization behaviour of (I) may be contrasted with that of compounds (II) and (III), which crystallize as true racemates in the space groups P21/n and Cc, respectively (Acosta et al., 2009; Gómez et al., 2010).

The seven-membered ring in compound (I) adopts a chair-type conformation with both the pyridyl and the hydroxy substituents in equatorial sites. The bond distances and the interbond angles present no unusual values.

The molecules of compound (I) are linked into a three-dimensional framework structure by a combination of O—H···N, C—H···O and C—H···π(arene) hydrogen bonds (Table 1). The two independent C—H···O hydrogen bonds necessarily have a common acceptor atom, while the two C—H···π(arene) hydrogen bonds utilize as acceptors the two faces of the fused aryl ring. These two interactions subtend angles at the ring centroid, denoted Cg, whose values are close to 180°; thus the angles H25i···Cg···H9ii and C25i···Cg···C9ii [symmetry codes: (i) x, y + 1, z; (ii) x + 1/2, -y + 3/2, -z + 1] are 151 and 157.6 (2)°, respectively. It is striking that, although four C—H bonds are involved in hydrogen-bond formation, including three of the four C—H bonds of the pyridyl ring (Table 1), the N—H bond does not participate at all in the intermolecular hydrogen bonding. There are no potential acceptors within hydrogen-bonding range of the N1 atom and, in fact, all of the non-H atoms within 3.6 Å of the N1 atom are components of the same molecule.

Although the hydrogen-bonded framework, based on five independent hydrogen bonds, is somewhat complex overall, its formation can readily be analysed using the substructure approach (Ferguson et al., 1998a,b; Gregson et al., 2000), in terms of three substructures, two of them two-dimensional while the third substructure is one-dimensional.

The first substructure is built from the O—H···N and C—H···O hydrogen bonds. Acting individually, these three hydrogen bonds, having atoms O41, C22 and C24, respectively, as the donors, form chains of types C(8), C(7) and C(9) (Bernstein et al., 1995), respectively, running parallel to the [010], [100] and [110] directions. Acting together, these three hydrogen bonds form a sheet parallel to (001) and lying in the domain 0.5 < z < 1.0 (Fig. 2); two such sheets pass through each unit cell.

In the second substructure, the two C—H···π(arene) hydrogen bonds combine to form another type of sheet. Acting individually, the hydrogen bonds having atoms C9 and C25 as the donors form chains running parallel to the [100] and [010] directions, respectively. In combinations these two interactions generate a sheet lying parallel to (001) but now in the domain 0.3 < z < 0.7 (Fig. 3); again, two sheets of this type pass through each unit cell.

The linking of the sheets is most simply understood in terms of the third substructure. Of the five independent hydrogen bonds (Table 1), three link molecules which are related to one another by translation; by contrast, the O—H···N hydrogen bond and the C—H···π(arene) hydrogen bond utilizing atom C9 as the donor, respectively, link molecules related by the 21 screw axes along (1/2, y, 3/4) and (x, 3/4, 1/2). The combination of these two hydrogen bonds, acting alternately, generates a chain running parallel to the [001] direction (Fig. 4). This chain along [001] links together all of the sheets, of both types, parallel to (001), so that the combination of the three substructures generates a three-dimensional framework structure.

It is of interest briefly to compare the molecular aggregation in compound (I) with that in compounds (II) and (III). In the crystal structure of compound (II) (Acosta et al., 2009), a combination of N—H···O and O—H···N hydrogen bonds links the molecules into a chain of edge-fused R33(10) rings, while a single C—H···π(arene) hydrogen bond links chains of this type into a sheet. Thus, by contrast with compound (I), the N—H bond in compound (II) participates in the intermolecular hydrogen bonding, presumably because the steric shielding of the N—H unit afforded by the vinyl substituent in compound (II) is less than that provided by the pyridyl substituent in compound (I). There are neither N—H nor O—H bonds in compound (III), so that the intermolecular aggregation in (III) is necessarily different from that in compounds (I) and (II). Compound (III) crystallizes with Z' = 2 in space group Cc (Gómez et al., 2010), and molecules related by translation are linked by C—H···π(arene) hydrogen bonds to form two independent chains running anti-parallel to one another and each containing only one type of molecule.

Related literature top

For related literature, see: Acosta et al. (2009); Bernstein et al. (1995); Ferguson et al. (1998a, 1998b); Flack (1983); Flack & Bernardinelli (2000); Gómez et al. (2010); Gregson et al. (2000); Hooft et al. (2008); Knockaert et al. (2002); Kunick et al. (2006); Palma et al. (2009); Seto et al. (2005); Tsunoda et al. (2005); Zhao et al. (2003); Zuccotto et al. (2001).

Experimental top

Zinc powder (0.8 mmol) was added to a solution of racemic (2RS,4SR)-2-exo-(pyridin-3-yl)-1,4-epoxy-2,3,4,5-tetrahydro-1-benzazepine (0.1 mmol) in 80% acetic acid (15 ml). The resulting mixture was stirred at 318 K for 3 h. The mixture was filtered, and the filtrate was neutralized with aqueous ammonia solution to pH = 8 and then extracted with ethyl acetate (3 × 50 ml). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the crude product which was purified by column chromatography on silica gel using heptane–ethyl acetate (10:1 to 1:1 v/v) as eluent. Recrystallization from heptane–ethyl acetate (1:4 v/v) gave colourless crystals suitable for single-crystal X-ray diffraction (yield 86%, m.p. 403–404 K). MS (70 eV) m/z (%): 240 (M+, 74), 221 (13), 195 (61), 130 (11), 118 (100), 106 (74), 91 (21), 77 (16).

Refinement top

All H atoms were located in difference maps and subsequently treated as riding atoms in geometrically idealized positions, with C—H distances = 0.95 (aromatic and heteroaromatic), 0.99 (CH2) or 1.00 Å (aliphatic CH), N—H = 0.88 Å and O—H = 0.86 Å, and with Uiso(H) = kUeq(carrier), where k = 1.5 for hydroxy atom H41 and 1.2 otherwise. In the absence of significant resonant scattering, the values of the Flack x parameter (Flack, 1983) and the Hooft y parameter (Hooft et al., 2008), viz.0.2 (15) and 0.6 (7), respectively, were indeterminate (Flack & Bernardinelli, 2000). Accordingly, the Friedel-equivalent reflections were merged prior to the final refinements, and the asymmetric unit was arbitrarily selected as having the R configuration at atom C2, and hence the S configuration at atom C4.

Computing details top

Data collection: COLLECT (Hooft, 1999); 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).

Figures top
[Figure 1] 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.
[Figure 2] Fig. 2. A stereoview of part of the crystal structure of compound (I), showing the formation of a sheet lying parallel to (001) and built from O—H···N and C—H···O hydrogen bonds. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
[Figure 3] Fig. 3. A stereoview of part of the crystal structure of compound (I), showing the formation of a sheet lying parallel to (001) and built from C—H···π(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
[Figure 4] Fig. 4. A stereoview of part of the crystal structure of compound (I), showing the formation of a chain running parallel to [001] and built from alternating O—H···N and C—H···π(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.
(2R*,4S*)-2-(Pyridin-3-yl)-2,3,4,5-tetrahydro-1H- 1-benzazepin-4-ol top
Crystal data top
C15H16N2OF(000) = 512
Mr = 240.30Dx = 1.251 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 1714 reflections
a = 6.0318 (9) Åθ = 2.9–27.5°
b = 8.3396 (10) ŵ = 0.08 mm1
c = 25.361 (4) ÅT = 120 K
V = 1275.7 (3) Å3Block, colourless
Z = 40.40 × 0.22 × 0.20 mm
Data collection top
Bruker–Nonius KappaCCD
diffractometer
1714 independent reflections
Radiation source: Bruker-Nonius FR591 rotating anode1453 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.034
Detector resolution: 9.091 pixels mm-1θmax = 27.5°, θmin = 2.9°
ϕ and ω scansh = 77
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
k = 1010
Tmin = 0.969, Tmax = 0.984l = 3232
10571 measured reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.035Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.086H-atom parameters constrained
S = 1.11 w = 1/[σ2(Fo2) + (0.038P)2 + 0.280P]
where P = (Fo2 + 2Fc2)/3
1714 reflections(Δ/σ)max = 0.001
163 parametersΔρmax = 0.16 e Å3
0 restraintsΔρmin = 0.22 e Å3
Crystal data top
C15H16N2OV = 1275.7 (3) Å3
Mr = 240.30Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 6.0318 (9) ŵ = 0.08 mm1
b = 8.3396 (10) ÅT = 120 K
c = 25.361 (4) Å0.40 × 0.22 × 0.20 mm
Data collection top
Bruker–Nonius KappaCCD
diffractometer
1714 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
1453 reflections with I > 2σ(I)
Tmin = 0.969, Tmax = 0.984Rint = 0.034
10571 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0350 restraints
wR(F2) = 0.086H-atom parameters constrained
S = 1.11Δρmax = 0.16 e Å3
1714 reflectionsΔρmin = 0.22 e Å3
163 parameters
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.5641 (3)0.66510 (18)0.58267 (6)0.0225 (4)
H10.44930.62190.56660.027*
C20.5329 (3)0.6467 (2)0.63979 (7)0.0213 (4)
H20.42850.73130.65260.026*
C30.7485 (3)0.6577 (2)0.67083 (7)0.0221 (4)
H3A0.71540.63720.70850.027*
H3B0.84870.57140.65860.027*
C40.8697 (3)0.8154 (2)0.66667 (7)0.0208 (4)
H40.76480.90480.67500.025*
C50.9656 (3)0.8408 (2)0.61214 (7)0.0225 (4)
H5A1.08920.91860.61460.027*
H5B1.02760.73800.59940.027*
C5A0.8016 (3)0.9007 (2)0.57285 (7)0.0214 (4)
C60.8450 (4)1.0411 (2)0.54530 (7)0.0249 (4)
H60.97421.10090.55380.030*
C70.7071 (4)1.0965 (3)0.50604 (8)0.0278 (5)
H70.74291.19140.48710.033*
C80.5160 (4)1.0123 (2)0.49452 (7)0.0264 (5)
H80.41931.04870.46750.032*
C90.4664 (4)0.8756 (2)0.52236 (7)0.0238 (4)
H90.33250.82000.51500.029*
C9A0.6077 (3)0.8171 (2)0.56089 (7)0.0208 (4)
O411.0497 (2)0.81953 (15)0.70290 (5)0.0223 (3)
H410.99270.82160.73400.033*
C210.4325 (3)0.4841 (2)0.64981 (7)0.0213 (4)
C220.2805 (3)0.4645 (2)0.69002 (7)0.0221 (4)
H220.23630.55690.70920.026*
N230.1921 (3)0.3246 (2)0.70353 (6)0.0248 (4)
C240.2547 (4)0.1954 (2)0.67638 (8)0.0270 (5)
H240.19370.09420.68570.032*
C250.4033 (4)0.2023 (2)0.63554 (8)0.0306 (5)
H250.44320.10810.61680.037*
C260.4938 (4)0.3487 (2)0.62222 (8)0.0280 (5)
H260.59770.35610.59420.034*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0250 (9)0.0204 (7)0.0220 (8)0.0057 (8)0.0025 (7)0.0009 (6)
C20.0221 (10)0.0196 (9)0.0223 (9)0.0016 (9)0.0003 (8)0.0006 (7)
C30.0235 (10)0.0209 (9)0.0220 (9)0.0015 (9)0.0005 (8)0.0016 (8)
C40.0195 (9)0.0219 (9)0.0210 (8)0.0020 (9)0.0021 (8)0.0011 (8)
C50.0208 (9)0.0228 (9)0.0238 (9)0.0031 (9)0.0011 (8)0.0001 (8)
C5A0.0234 (10)0.0206 (8)0.0201 (9)0.0011 (8)0.0015 (8)0.0014 (8)
C60.0282 (11)0.0219 (9)0.0247 (9)0.0044 (9)0.0015 (9)0.0016 (8)
C70.0355 (12)0.0222 (9)0.0256 (10)0.0017 (10)0.0019 (10)0.0034 (8)
C80.0319 (11)0.0253 (10)0.0219 (9)0.0046 (9)0.0043 (9)0.0012 (8)
C90.0237 (10)0.0245 (9)0.0231 (9)0.0017 (9)0.0013 (8)0.0045 (8)
C9A0.0239 (10)0.0194 (9)0.0191 (8)0.0004 (8)0.0026 (8)0.0026 (7)
O410.0216 (6)0.0251 (7)0.0201 (6)0.0021 (7)0.0021 (6)0.0013 (6)
C210.0208 (10)0.0198 (9)0.0231 (9)0.0016 (9)0.0034 (9)0.0007 (7)
C220.0225 (10)0.0196 (9)0.0241 (9)0.0001 (9)0.0002 (8)0.0013 (8)
N230.0271 (9)0.0240 (8)0.0234 (8)0.0033 (8)0.0003 (7)0.0003 (7)
C240.0336 (12)0.0198 (9)0.0276 (10)0.0065 (10)0.0018 (9)0.0014 (8)
C250.0405 (13)0.0204 (9)0.0310 (10)0.0021 (10)0.0070 (10)0.0059 (8)
C260.0297 (11)0.0252 (10)0.0291 (10)0.0042 (9)0.0076 (9)0.0039 (8)
Geometric parameters (Å, º) top
N1—C9A1.408 (2)C6—H60.9500
N1—C21.469 (2)C7—C81.381 (3)
N1—H10.8800C7—H70.9500
C2—C211.506 (3)C8—C91.374 (3)
C2—C31.523 (3)C8—H80.9500
C2—H21.0000C9—C9A1.385 (3)
C3—C41.509 (3)C9—H90.9500
C3—H3A0.9900O41—H410.8604
C3—H3B0.9900C21—C261.379 (3)
C4—O411.423 (2)C21—C221.381 (3)
C4—C51.514 (2)C22—N231.327 (3)
C4—H41.0000C22—H220.9500
C5—C5A1.490 (3)N23—C241.333 (3)
C5—H5A0.9900C24—C251.371 (3)
C5—H5B0.9900C24—H240.9500
C5A—C61.388 (3)C25—C261.379 (3)
C5A—C9A1.395 (3)C25—H250.9500
C6—C71.378 (3)C26—H260.9500
C9A—N1—C2120.34 (15)C7—C6—H6118.9
C9A—N1—H1109.5C5A—C6—H6118.9
C2—N1—H1108.2C6—C7—C8119.09 (19)
N1—C2—C21108.19 (15)C6—C7—H7120.5
N1—C2—C3113.19 (16)C8—C7—H7120.5
C21—C2—C3108.07 (15)C9—C8—C7119.7 (2)
N1—C2—H2109.1C9—C8—H8120.2
C21—C2—H2109.1C7—C8—H8120.2
C3—C2—H2109.1C8—C9—C9A121.4 (2)
C4—C3—C2115.49 (15)C8—C9—H9119.3
C4—C3—H3A108.4C9A—C9—H9119.3
C2—C3—H3A108.4C9—C9A—C5A119.56 (18)
C4—C3—H3B108.4C9—C9A—N1118.61 (17)
C2—C3—H3B108.4C5A—C9A—N1121.43 (17)
H3A—C3—H3B107.5C4—O41—H41106.7
O41—C4—C3110.24 (15)C26—C21—C22117.06 (17)
O41—C4—C5107.15 (15)C26—C21—C2122.96 (18)
C3—C4—C5111.79 (16)C22—C21—C2119.89 (17)
O41—C4—H4109.2N23—C22—C21124.16 (18)
C3—C4—H4109.2N23—C22—H22117.9
C5—C4—H4109.2C21—C22—H22117.9
C5A—C5—C4113.84 (16)C22—N23—C24117.60 (17)
C5A—C5—H5A108.8N23—C24—C25122.75 (18)
C4—C5—H5A108.8N23—C24—H24118.6
C5A—C5—H5B108.8C25—C24—H24118.6
C4—C5—H5B108.8C24—C25—C26118.77 (19)
H5A—C5—H5B107.7C24—C25—H25120.6
C6—C5A—C9A118.05 (18)C26—C25—H25120.6
C6—C5A—C5119.61 (18)C25—C26—C21119.66 (18)
C9A—C5A—C5122.29 (17)C25—C26—H26120.2
C7—C6—C5A122.2 (2)C21—C26—H26120.2
C9A—N1—C2—C21165.60 (17)C5—C5A—C9A—C9177.25 (18)
C9A—N1—C2—C374.7 (2)C6—C5A—C9A—N1172.71 (17)
N1—C2—C3—C461.8 (2)C5—C5A—C9A—N14.7 (3)
C21—C2—C3—C4178.38 (16)C2—N1—C9A—C9122.91 (19)
C2—C3—C4—O41171.70 (15)C2—N1—C9A—C5A64.4 (2)
C2—C3—C4—C569.2 (2)N1—C2—C21—C2639.1 (3)
O41—C4—C5—C5A158.11 (16)C3—C2—C21—C2683.8 (2)
C3—C4—C5—C5A81.0 (2)N1—C2—C21—C22144.45 (18)
C4—C5—C5A—C6124.50 (19)C3—C2—C21—C2292.6 (2)
C4—C5—C5A—C9A58.2 (2)C26—C21—C22—N230.3 (3)
C9A—C5A—C6—C71.9 (3)C2—C21—C22—N23176.35 (19)
C5—C5A—C6—C7175.55 (18)C21—C22—N23—C240.1 (3)
C5A—C6—C7—C81.7 (3)C22—N23—C24—C250.4 (3)
C6—C7—C8—C90.2 (3)N23—C24—C25—C260.6 (3)
C7—C8—C9—C9A2.0 (3)C24—C25—C26—C210.4 (3)
C8—C9—C9A—C5A1.8 (3)C22—C21—C26—C250.1 (3)
C8—C9—C9A—N1171.01 (17)C2—C21—C26—C25176.5 (2)
C6—C5A—C9A—C90.1 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O41—H41···N23i0.861.942.786 (2)168
C22—H22···O41ii0.952.473.288 (2)145
C24—H24···O41iii0.952.493.436 (2)175
C9—H9···Cgiv0.952.833.633 (2)143
C25—H25···Cgv0.952.773.633 (2)151
Symmetry codes: (i) x+1, y+1/2, z+3/2; (ii) x1, y, z; (iii) x1, y1, z; (iv) x1/2, y+3/2, z+1; (v) x, y1, z.

Experimental details

Crystal data
Chemical formulaC15H16N2O
Mr240.30
Crystal system, space groupOrthorhombic, P212121
Temperature (K)120
a, b, c (Å)6.0318 (9), 8.3396 (10), 25.361 (4)
V3)1275.7 (3)
Z4
Radiation typeMo Kα
µ (mm1)0.08
Crystal size (mm)0.40 × 0.22 × 0.20
Data collection
DiffractometerBruker–Nonius KappaCCD
diffractometer
Absorption correctionMulti-scan
(SADABS; Sheldrick, 2003)
Tmin, Tmax0.969, 0.984
No. of measured, independent and
observed [I > 2σ(I)] reflections
10571, 1714, 1453
Rint0.034
(sin θ/λ)max1)0.650
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.035, 0.086, 1.11
No. of reflections1714
No. of parameters163
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.16, 0.22

Computer programs: COLLECT (Hooft, 1999), DIRAX/LSQ (Duisenberg et al., 2000), EVALCCD (Duisenberg et al., 2003), SIR2004 (Burla et al., 2005), SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O41—H41···N23i0.861.942.786 (2)168
C22—H22···O41ii0.952.473.288 (2)145
C24—H24···O41iii0.952.493.436 (2)175
C9—H9···Cgiv0.952.833.633 (2)143
C25—H25···Cgv0.952.773.633 (2)151
Symmetry codes: (i) x+1, y+1/2, z+3/2; (ii) x1, y, z; (iii) x1, y1, z; (iv) x1/2, y+3/2, z+1; (v) x, y1, z.
 

Acknowledgements

The authors thank `Centro de Instrumentación Científico-Técnica of Universidad de Jaén' and the staff for data collection. SLG and AP thank COLCIENCIAS for financial support (grant No. 1102-408-20563). JC thanks the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain), the Universidad de Jaén (project reference UJA_07_16_33) and Ministerio de Ciencia e Innovación (project reference SAF2008-04685-C02-02) for financial support.

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