4-(2-Hydroxy-phen-yl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine and the 2-(2,3-dimethoxy-phen-yl)-, 2-(3,4-dimethoxy-phen-yl)- and 2-(2,5-dimeth-oxy- phen-yl)-substituted derivatives

Article abstract of DOI:10.1107/S0108270107024420

The 1,5-benzodiazepine ring system exhibits a puckered boat-like conformation for all four title compounds [4-(2-hydroxy-phen-yl)-2-phenyl-2,3- dihydro-1H-1,5-benzodiazepine, C21H18N2O, (I), 2-(2,3-dimethoxy-phen-yl)-4-(2- hydroxy-phen-yl)-2,3-dihydro-1H-

Full text of DOI:10.1107/S0108270107024420

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
compounds (Donoso-Tauda et al., 2006), our group has
focused considerable interest on the crystalline properties of
benzodiazepines, particularly in their packing by inter-
molecular hydrogen bonding. Benzodiazepines are well
studied because of their pharmacological properties, with their
antifungal, antibacterial, analgesic, tranquilizing and anti-
convulsant activities well established (Di Braccio et al., 2001;
Michaelidou & Hadjipavlou-Litina, 2005). Additionally, the
chemistry and structure of 1,5-benzodiazepines have become
increasingly interesting, owing to their potential as cocrystals
in supramolecular chemistry, showing ladder or brick super-
structures formed via hydrogen-bonding networks (Thakuria
et al., 2006).
ISSN 0108-2701
4-(2-Hydroxyphenyl)-2-phenyl-2,3-
dihydro-1H-1,5-benzodiazepine
and the 2-(2,3-dimethoxyphenyl)-,
2-(3,4-dimethoxyphenyl)- and
2-(2,5-dimethoxyphenyl)-substituted
derivatives
Carlos A. Escobar,a Oscar Donoso-Tauda,a Ramiro Araya-
b
a
Â
Maturana and Andres Vega *
a
Â
Laboratorio de Recursos Naturales, Departamento de Ciencias Quõmicas, Univer-
sidad Andres Bello, Av. Republica 275, Santiago, Chile, and bDepartamento de
Â
Â
Â
Â
Â
Â
Â
Quõmica Organica y Fisicoquõmica, Facultad de Ciencias Quõmicas y Farmaceuticas,
Universidad de Chile, Casilla 233 Santiago 1, Chile
Correspondence e-mail: andresvega@unab.cl
Received 26 April 2007
Accepted 17 May 2007
Online 23 June 2007
The structures of the title compounds, (I)±(IV) (Fig. 1), are
constructed around a central benzodiazepine C5N2 seven-
membered ring, which is fused with a benzene ring at atoms
C10 and C11. The heterocycle is substituted in all cases at
position 4 with an o-hydroxyphenyl group, and also with a
phenyl [for (I)] or a dimethoxyphenyl [for (II)±(IV)] ring at
position 2, as summarized in the scheme. The least-squares
plane de®ned by the C6±C11 aromatic ring plus atoms N1 and
N5 de®nes an acute angle with the plane de®ned by atoms C2,
C3 and C4 [85.0 (1)ꢀ for (I), 78.7 (2)ꢀ for (II), 89.3 (3)ꢀ for (III)
and 87.0 (1)ꢀ for (IV)]; the benzodiazepine ring system has a
puckered boat-like conformation for all four compounds. This
has also been noted in two related benzodiazepines, viz. 2,4-
bis(2,5-dipropoxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine
(Hormaza et al., 2004) and 2-methyl-4-p-tolyl-2,3-dihydro-1,5-
benzodiazepine (Qi et al., 1985). Bond distances are similar for
all four compounds and comparable to literature values (Qi et
al., 1985; Braun et al., 2000). Although some signi®cant
differences are observed in the torsion angles for the benzo-
diazepine ring systems [e.g. N1ÐC2ÐC3ÐC4 ranges from
44.7 (4)ꢀ in (III) to 76.0 (4)ꢀ in (II); Tables 1, 3, 5 and 7] the
boat-like conformation of the heterocycle is conserved across
the series. The substituted benzene rings occupying positions 2
and 4 in the 1,5-benzodiazepine ring system display, respec-
The 1,5-benzodiazepine ring system exhibits a puckered boat-
like conformation for all four title compounds [4-(2-hydroxy-
phenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine, C21H18-
N2O, (I), 2-(2,3-dimethoxyphenyl)-4-(2-hydroxyphenyl)-2,3-
dihydro-1H-1,5-benzodiazepine, C23H22N2O3, (II), 2-(3,4-
dimethoxyphenyl)-4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-
benzodiazepine, C23H22N2O3, (III), and 2-(2,5-dimethoxy-
phenyl)-4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiaze-
pine, C23H22N2O3, (IV)]. The stereochemical correlation of
the two C6 aromatic groups with respect to the benzodiazepine
ring system is pseudo-equatorial±equatorial for compounds
(I) (the phenyl group), (II) (the 2,3-dimethoxyphenyl group)
and (III) (the 3,4-dimethoxyphenyl group), while for (IV) (the
2,5-dimethoxyphenyl group) the system is pseudo-axial±
equatorial. An intramolecular hydrogen bond between the
hydroxyl OH group and a benzodiazepine N atom is present
for all four compounds and de®nes a six-membered ring,
whose geometry is constant across the series. Although the
molecular structures are similar, the supramolecular packing is
different; compounds (I) and (IV) form chains, while (II)
forms dimeric units and (III) displays a layered structure. The
packing seems to depend on at least two factors: (i) the nature
of the atoms de®ning the hydrogen bond and (ii) the number
of intermolecular interactions of the types OÐHÁ Á ÁO, NÐ
HÁ Á ÁO, NÐHÁ Á Áꢀ(arene) or CÐHÁ Á Áꢀ(arene).
tively,
a
pseudo-equatorial±equatorial correlation for
compounds (I), (II) and (III) (e.g. Hormaza et al., 2004), and
pseudo-axial±equatorial correlation for (IV). The dihedral
angles between the C18±C23 least-squares plane and the
o-hydroxyphenyl plane (C12±C17) are 46.8 (1), 66.1 (1),
37.4 (2) and 4.0 (1)ꢀ for (I)±(IV), respectively.
Comment
Continuing our search for supramolecular synthons of
importance in the crystal engineering of substituted aromatic
o426 # 2007 International Union of Crystallography
DOI: 10.1107/S0108270107024420
Acta Cryst. (2007). C63, o426±o430

organic compounds
Figure 2
The molecular packing for (a) (I) [symmetry codes: (A) x, y + 1, z; (B) x,
y 1, z], (b) (II) [symmetry code: (A) x, y + 1, z + 2], (c) (III)
Figure 1
The molecular structures of (a) (I), (b) (II), (c) (III) and (d) (IV),
showing the atom-numbering schemes. Displacement ellipsoids are drawn
at the 50% probability level and H atoms are shown as small spheres of
arbitrary radii.
1
[symmetry codes: (A) x + 1, y + 2, z; (B) x
,
y + 32, z 12 ] and (d)
2
(IV) [symmetry codes: (A) x, y + 12, z 21; (D) x, y + 21, z + 12 ]. Some of
the H atoms have been omitted for clarity.
ꢁ
Acta Cryst. (2007). C63, o426±o430
Escobar et al.
C21H18N2O and three isomers of C23H22N2O3 o427

organic compounds
Data collection
The hydroxyl H atom on the o-hydroxyphenyl substituent
(H1) forms an intramolecular OÐHÁ Á ÁN hydrogen bond with
atom N5 for (I)±(IV) (Tables 2, 4, 6 and 8). The intramolecular
hydrogen bond is rather insensitive to the remainder of the
molecule or the different packing modes. This intramolecular
bond has been also been described in the synthetic precursor
2-hydroxy chalcone (Srivastava & Verma, 1990). An impor-
tant consequence of this hydrogen bond is that the N5/C4/C12/
C13/O1/H1 six-membered ring is signi®cantly planar in all
cases. This planarity is re¯ected in the low value measured for
the N5ÐC4ÐC12ÐC13 torsion angle (Tables 1, 3, 5 and 7).
Despite the close structural similarity between the
compounds, their packing modes, arising from NÐHÁ Á ÁO,
NÐHÁ Á Áꢀ(arene) or CÐHÁ Á Áꢀ(arene) interactions, differ
considerably. As in Fig. 2(a), the CÐHÁ Á Áꢀ(arene) inter-
actions give a supramolecular chain along the b axis. Mol-
ecules of (II) and (III) form supramolecular dimers by means
of NÐHÁ Á Áꢀ(arene) and CÐHÁ Á ÁOÐCH3 interactions,
respectively, as depicted in Figs. 2(b) and 2(c). In the case of
(III), the dimers are also connected by means of NÐHÁ Á ÁO
hydrogen bonds, leading to a two-dimensional suprastructure.
The amine NH group in (IV) interacts with a methoxy
substituent in a neighbouring molecule, leading to a chain
along the c axis (Fig. 2d).
Siemens SMART CCD area-
detector diffractometer
Absorption correction: part of
the re®nement model (ÁF)
(SADABS in SAINT-NT;
Bruker, 1999)
9815 measured re¯ections
2893 independent re¯ections
1696 re¯ections with I > 2ꢄ(I)
Rint = 0.055
Tmin = 0.977, Tmax = 0.983
Re®nement
R[F2 > 2ꢄ(F2)] = 0.055
wR(F2) = 0.139
S = 1.02
2893 re¯ections
222 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
3
Ê
Áꢅmax = 0.16 e A
3
Ê
0.12 e A
Áꢅmin
=
Table 1
Selected torsion angles (ꢀ) for (I).
C10ÐN1ÐC2ÐC3
N1ÐC2ÐC3ÐC4
C2ÐC3ÐC4ÐN5
32.0 (3)
51.1 (3)
76.3 (3)
C3ÐC4ÐN5ÐC11
N5ÐC4ÐC12ÐC13
N1ÐC2ÐC18ÐC23
4.0 (3)
2.2 (3)
149.0 (2)
Table 2
Hydrogen-bond geometry (A, ) for (I).
ꢀ
Ê
Cg1 is the centroid of the C6±C11 ring.
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
As previously stated (Desiraju, 2002), the relative magni-
tude of intramolecular interactions could be listed as CÐ
HÁ Á Áꢀ(arene) weaker than NÐHÁ Á Áꢀ(arene) and both still
weaker than the NÐHÁ Á ÁO interaction. In this context, the
relatively low melting point measured for (I) (379±382 K)
could be understood in terms of the weak CÐHÁ Á Áꢀ(arene)
interaction stabilizing the packing. Conversely, in (III) (with
the highest melting point, 440±441 K), stronger NÐHÁ Á ÁO
interactions are present in addition to the CÐHÁ Á Áꢀ(arene)
interactions. In the same way, (II) and (IV) exhibit inter-
mediate melting points (around 429 K).
O1ÐH1Á Á ÁN5
0.82
0.93
1.79
2.62
2.514 (3)
3.480 (2)
147
155
C23ÐH23Á Á ÁCg1i
Symmetry code: (i) x; y ‡ 1; z.
Compound (II)
Crystal data
C23H22N2O3
Mr = 374.43
Triclinic, P1
a = 8.250 (2) A
Ê
b = 9.889 (3) A
ꢆ = 90.594 (5)ꢀ
3
Ê
V = 948.1 (4) A
Z = 2
Ê
Mo Kꢂ radiation
1
ꢃ = 0.09 mm
T = 298 (2) K
Ê
c = 12.272 (3) A
ꢂ = 108.697 (4)ꢀ
ꢁ = 90.973 (5)ꢀ
0.30 Â 0.18 Â 0.11 mm
Experimental
Data collection
A methanol (40 ml) solution of the appropriate 3-(dimethoxyphen-
yl)-1-(2-hydroxyphenyl)prop-2-enone (0.704 mmol) and 1,2-
diaminobenzene (1.056 mmol) was heated under re¯ux for 24 h.
Concentration in vacuo followed by column chromatographic puri-
®cation (silica gel 60, ethyl acetate±hexane 1:10) of the reaction
mixture afforded a yellow solid that on recrystallization from
methanol gave yellow crystals of (I)±(IV) [(I): yield 60%, m.p. 379±
382 K; (II): yield 15%, m.p. 427±428 K; (III): yield 21%, m.p. 439.5±
440.7 K; (IV): yield 21%, m.p. 429±430 K].
Siemens SMART CCD area-
detector diffractometer
Absorption correction: part of
the re®nement model (ÁF)
(SADABS in SAINT-NT;
Bruker, 1999)
5882 measured re¯ections
3329 independent re¯ections
1625 re¯ections with I > 2ꢄ(I)
Rint = 0.040
Tmin = 0.974, Tmax = 0.990
Re®nement
R[F2 > 2ꢄ(F2)] = 0.062
wR(F2) = 0.179
S = 0.98
3329 re¯ections
259 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
Compound (I)
3
Ê
Áꢅmax = 0.16 e A
3
Ê
0.20 e A
Áꢅmin
=
Crystal data
3
Ê
C21H18N2O
Mr = 314.37
V = 3254.7 (9) A
Z = 8
Table 3
Selected torsion angles (ꢀ) for (II).
Monoclinic, C2=c
Mo Kꢂ radiation
ꢃ = 0.08 mm
T = 298 (2) K
0.30 Â 0.27 Â 0.21 mm
1
Ê
a = 24.855 (4) A
C10ÐN1ÐC2ÐC3
N1ÐC2ÐC3ÐC4
C2ÐC3ÐC4ÐN5
22.7 (5)
76.0 (4)
65.1 (4)
C3ÐC4ÐN5ÐC11
N5ÐC4ÐC12ÐC13
N1ÐC2ÐC18ÐC23
0.6 (5)
7.7 (5)
13.2 (4)
Ê
b = 7.6825 (11) A
Ê
c = 19.455 (3) A
ꢁ = 118.824 (2)ꢀ
ꢁ
o428 Escobar et al. C21H18N2O and three isomers of C23H22N2O3
Acta Cryst. (2007). C63, o426±o430

organic compounds
Table 4
Hydrogen-bond geometry (A, ) for (II).
Data collection
ꢀ
Ê
Bruker APEXII diffractometer
Absorption correction: part of
the re®nement model (ÁF)
(SADABS in SAINT-NT;
Bruker, 1999)
12443 measured re¯ections
4181 independent re¯ections
3367 re¯ections with I > 2ꢄ(I)
Rint = 0.033
Cg2 is the centroid of the C12±C17 ring.
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
Tmin = 0.956, Tmax = 0.969
O1ÐH1Á Á ÁN5
0.82
0.90 (4)
1.78
2.60 (4)
2.514 (4)
3.445 (4)
147
159 (3)
N1ÐH1NÁ Á ÁCg2i
Re®nement
Symmetry code: (i) x; y ‡ 1; z ‡ 2.
R[F2 > 2ꢄ(F2)] = 0.039
wR(F2) = 0.126
S = 1.10
4181 re¯ections
338 parameters
20 restraints
H atoms treated by a mixture of
independent and constrained
re®nement
3
Ê
Áꢅmax = 0.30 e A
Compound (III)
3
Ê
0.31 e A
Áꢅmin
=
Crystal data
3
Ê
C23H22N2O3
Mr = 374.43
V = 1912.4 (4) A
Z = 4
Table 7
Selected torsion angles (ꢀ) for (IV).
Monoclinic, P21=n
Mo Kꢂ radiation
ꢃ = 0.09 mm
T = 300 (2) K
0.37 Â 0.07 Â 0.06 mm
1
Ê
a = 5.5372 (8) A
C10ÐN1ÐC2ÐC3
N1ÐC2ÐC3ÐC4
C2ÐC3ÐC4ÐN5
25.97 (16)
54.54 (13)
81.63 (15)
C3ÐC4ÐN5ÐC11
N5ÐC4ÐC12ÐC13
N1ÐC2ÐC18ÐC23
10.16 (18)
4.52 (18)
27.89 (17)
Ê
b = 23.144 (3) A
Ê
c = 15.131 (2) A
ꢁ = 99.520 (3)ꢀ
Data collection
Siemens SMART CCD area-
detector diffractometer
Absorption correction: part of
the re®nement model (ÁF)
(SADABS in SAINT-NT;
Bruker, 1999)
11881 measured re¯ections
3400 independent re¯ections
1703 re¯ections with I > 2ꢄ(I)
Rint = 0.105
Table 8
Hydrogen-bond geometry (A, ) for (IV).
ꢀ
Ê
Cg3 is the centroid of the C18±C23 ring.
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
Tmin = 0.969, Tmax = 0.995
O1ÐH1Á Á ÁN5
C24ÐH24BÁ Á ÁCg3ii
Symmetry codes: (i) x; y ‡ 12; z 21; (ii) x; y ‡ 21; z ‡ 21.
0.82
0.892 (16)
0.996 (9)
1.81
2.311 (16)
2.744 (13)
2.5443 (14)
3.201 (2)
3.5462 (16)
148
177
140 (1)
N1ÐH1NÁ Á ÁO3i
Re®nement
R[F2 > 2ꢄ(F2)] = 0.086
wR(F2) = 0.167
S = 1.04
3400 re¯ections
259 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
3
Ê
Áꢅmax = 0.15 e A
3
Ê
0.16 e A
Áꢅmin
=
H atoms attached to C atoms were included at calculated positions
and treated as riding atoms for (I)±(III) using SHELXL97 (Shel-
drick, 1997) default values; for (IV), these were re®ned with the CÐ
Table 5
Selected torsion angles (ꢀ) for (III).
Ê
Ê
H distances restrained to be 0.93 A for aromatic and 0.99 A for
aliphatic H atoms. In all four compounds, hydroxy atom H1 was
treated as a riding atom, and amino atom H1N was re®ned with
isotropic displacement parameters. Analysis of the diffraction pattern
suggests that the rather high R factor obtained for (III) could be
attributed to poor crystal quality.
C10ÐN1ÐC2ÐC3
N1ÐC2ÐC3ÐC4
C2ÐC3ÐC4ÐN5
38.8 (5)
44.7 (4)
76.8 (5)
C3ÐC4ÐN5ÐC11
N5ÐC4ÐC12ÐC13
N1ÐC2ÐC18ÐC23
8.4 (6)
1.5 (6)
136.1 (4)
For compounds (I)±(III), data collection: SMART-NT (Bruker,
2001); cell re®nement: SAINT-NT (Bruker, 1999); data reduction:
SAINT-NT; program(s) used to solve structure: SHELXTL-NT
(Bruker, 2000); program(s) used to re®ne structure: SHELXTL-NT;
molecular graphics: SHELXTL-NT; software used to prepare
material for publication: SHELXTL-NT. For compound (IV), data
collection: SMART-NT; cell re®nement: SAINT-NT; data reduction:
SAINT-NT; program(s) used to solve structure: SHELXS97 (Shel-
drick, 1997); program(s) used to re®ne structure: SHELXL97
(Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997);
software used to prepare material for publication: WinGX (Farrugia,
1999).
Table 6
Hydrogen-bond geometry (A, ) for (III).
ꢀ
Ê
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
O1ÐH1Á Á ÁN5
0.82
1.76
2.494 (5)
3.017 (4)
3.385 (6)
3.501 (5)
148
N1ÐH1NÁ Á ÁO1i
C8ÐH8Á Á ÁO3ii
C15ÐH15Á Á ÁO2iii
0.91 (3)
0.93
0.93
2.20 (3)
2.48
2.64
150 (3)
163
154
Symmetry codes: (i) x ‡ 12; y ‡ 23; z ‡ 21; (ii)
x ‡ 12; y
;
z ‡ 12; (iii)
x ‡ 1,
1
2
y ‡ 2; z.
Compound (IV)
Â
The authors gratefully acknowledge Universidad Andres
Crystal data
Bello (UNAB) for ®nancial support through grant DI 41-04
awarded to CAE, and thank Dr M. T. Garland, Universidad de
Chile, and Therry Roisnel, University of Rennes, for data
collection. ODT is grateful to UNAB for a graduate fellow-
ship. AV acknowledges FONDECYT (grant No. 11060176)
3
Ê
C23H22N2O3
Mr = 374.43
Monoclinic, P21=c
a = 10.5071 (3) A
Ê
b = 20.3901 (6) A
V = 1826.34 (10) A
Z = 4
Mo Kꢂ radiation
1
Ê
ꢃ = 0.09 mm
T = 296 (2) K
Ê
c = 8.7280 (3) A
ꢁ = 102.390 (2)ꢀ
0.50 Â 0.50 Â 0.35 mm
Â
and Universidad Andres Bello (grant No. DI-20-06/R).
ꢁ
Acta Cryst. (2007). C63, o426±o430
Escobar et al.
C21H18N2O and three isomers of C23H22N2O3 o429

organic compounds
Di Braccio, M., Grossi, G., Roma, G., Vargiu, L., Mura, M. & Marongiu, M. E.
(2001). Eur. J. Med. Chem. 36, 935±949.
Donoso-Tauda, O., Escobar, C. A., Araya-Maturana, R. & Vega, A. (2006).
Acta Cryst. C62, o631±o632.
Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: GG3095). Services for accessing these data are
described at the back of the journal.
Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837±838.
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73±76.
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o430 Escobar et al. C21H18N2O and three isomers of C23H22N2O3
Acta Cryst. (2007). C63, o426±o430