Synthesis of N-acylated 1,5-benzodiazepines: Differentiation between two possible acylation sites via hydrogen bonding

Article abstract of DOI:10.5560/ZNB.2013-2338

Temperature-dependent regioselectivity between amino and hydroxyl groups mediated by hydrogen bonding was observed in the reaction of acetic anhydride with 2-(2,3-dimethoxyphenyl)- 4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5- benzodiazepine (1), obtaining 1-acetyl-2-(2,3-dimethoxyphenyl)-4-(2- hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine (1a), when these were reacted at room temperature, and 4-(2-acetoxyphenyl)-1-acetyl-2-(2,3-dimethoxyphenyl)-2, 3-dihydro-1H-1,5-benzodiazepine (1b), when they were refluxed (148 - 150 °C). Acylation of the less hindered analog 4-(2-hydroxyphenyl)-2-phenyl-2,3- dihydro-1H-1,5-benzodiazepine (2) via crotonyl chloride (a bulky acylating agent compared with acetic anhydride) afforded by refluxing only 1-crotonyl-4- (2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine (2a). All compounds were characterized spectroscopically, and the molecular structures of compounds 1a and 2a were determined by X-ray diffraction analysis.

Full text of DOI:10.5560/ZNB.2013-2338

Synthesis of N-Acylated 1,5-Benzodiazepines: Differentiation between
Two Possible Acylation Sites via Hydrogen Bonding
Carlos A. Escobara, Odette A. Alvaradoa, Judith A. K. Howardb, and
Mauricio Fuentealbab,c
a
Universidad Andres Bello, Facultad de Ciencias Exactas, Departamento de Ciencias Qu´ımicas,
Laboratorio de S´ıntesis Orga´nica, Av. Repu´blica 275, Santiago, Chile
Department of Chemistry, Durham University, Durham DH1 3LE, United Kingdom
Pontificia Universidad Cato´lica de Valpara´ıso, Facultad de Ciencias, Instituto de Qu´ımica, Av.
b
c
Universidad N. 330, Curauma, Valpara´ıso, Chile
Reprint requests to Dr. Carlos A. Escobar. Fax: (+56 2) 661 82 69. E-mail: cescobar@unab.cl
Z. Naturforsch. 2013, 68b, 397 – 402 / DOI: 10.5560/ZNB.2013-2338
Received December 26, 2012
Temperature-dependent regioselectivity between amino and hydroxyl groups mediated by hy-
drogen bonding was observed in the reaction of acetic anhydride with 2-(2,3-dimethoxyphenyl)-
4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine (1), obtaining 1-acetyl-2-(2,3-dimethoxy-
phenyl)-4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine (1a), when these were reacted at
room temperature, and 4-(2-acetoxyphenyl)-1-acetyl-2-(2,3-dimethoxyphenyl)-2,3-dihydro-1H-1,5-
benzodiazepine (1b), when they were refluxed (148 – 150 ◦C). Acylation of the less hindered
analog 4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine (2) via crotonyl chloride
(a bulky acylating agent compared with acetic anhydride) afforded by refluxing only 1-crotonyl-4-
(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine (2a). All compounds were charac-
terized spectroscopically, and the molecular structures of compounds 1a and 2a were determined by
X-ray diffraction analysis.
Key words: 1,5-Benzodiazepine, Intramolecular Hydrogen Bond, N-Acylation, Regioselectivity
Introduction
In contrast, differentiation in the acetylation re-
action between amino and hydroxyl groups has
Differentiation between functional groups in a poly- been achieved in 2,3-dihydro-1H-1,5-benzodiazepines
functionalized compound is the key step in a synthetic using acetic anhydride [8]. In this case, when
route if any orthogonal protection-deprotection strat- a 4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-
egy is available. Differentiation between groups of dif- benzodiazepine, a molecule presenting two possible
ferent reactivities, using other strategies than those pro- acetylation sites (e. g. the amino and the hydroxyl
vided by the protecting groups, in particular, those me- groups) was reacted with excess acetic anhydride, dif-
diated by hydrogen bonds, has been a subject of limited ferentiation between the two possible acylation sites
attention in the literature. Most of the examples cover- was observed. This differentiation was temperature de-
ing protection by hydrogen bonds are in the area of pendent, and mediated through an intramolecular hy-
sugar chemistry [1 – 4], but in other areas of chemistry drogen bond between the imine and the hydroxyl group
examples are scarce [5, 6].
of the 1H-1,5-benzodiazepine core.
In the chemistry of benzodiazepines, for example,
In this work we report on (i) the synthesis
if both an amino and a hydroxyl group are present in of 1-acetyl-2-(2,3-dimethoxyphenyl)-4-(2-hydroxy-
the benzodiazepine core, but the hydroxyl group is not phenyl)-2,3-dihydro-1H-1,5-benzodiazepine (1a), its
taking part in an intramolecular hydrogen bond, acety- N,O-diacetylated analog 1b and 1-crotonyl-4-(2-hy-
lation at both centers (i. e. the amino and the hydroxyl) droxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodi-
has been observed when refluxing with acetic anhy- azepine (2a). The presence of the 2,3-dimethoxy-
dride [7].
phenyl substituent in the case of 1a and 1b was
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398
C. A. Escobar et al. · Synthesis of N-Acylated 1,5-Benzodiazepines
intended to augment the steric hindrance at the amino
side of the benzodiazepine, and thus, help to eval-
uate its effect on the regioselectivity differentiation
between the two possible acylation sites mediated
by both the temperature and the hydroxyl hydrogen
bond, using acetic anhydride as acylating agent. The
use of crotonyl chloride as acylating agent for the
preparation of 2a was intended to evaluate again the
same differentiation effect, but this time focused on
the size of the acylating agent. In this work, we report
also (ii) the complete spectroscopic characterization
of each compound and (iii) the crystal and molecular
structures of compounds 1a and 2a as determined by
X-ray diffraction analysis.
Results and Discussion
The benzodiazepine 1a was obtained as the only
product when an excess of acetic anhydride was re-
acted with 2,3-dihydro-1H-1,5-benzodiazepine 1 at
room temperature for 24 hours (Scheme 1). In con-
trast, compound 1b was obtained as the only product
when benzodiazepine 1 was refluxed (148 – 150 ◦C)
with excess acetic anhydride. Acylation of the less
hindered 2,3-dihydro-1H-1,5-benzodiazepine 2 with
crotonyl chloride (a bulky acylating agent com-
pared with acetic anhydride), afforded on reflux-
ing only 1-crotonyl-4-(2-hydroxyphenyl)-2-phenyl-
2,3-dihydro-1H-1,5-benzodiazepine (2a). All com-
pounds were characterized spectroscopically (see Ex-
perimental Section for details), and the molecular
structures of compounds 1a and 2a were determined
by X-ray diffraction analysis (vide infra).
Scheme 1. Acylation pathways of 2-(2,3-dimethoxyphenyl)-
4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine
(1) and 4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-
benzodiazepine (2).
The solid-state IR spectrum of 1a exhibits a medium be assigned to the acetyl, two methoxy and the pheno-
intensity band at 3434 cm−1, which can be attributed lic OH proton, respectively.
to a phenolic OH group connected with an sp2 nitro-
The solid-state IR spectrum of 2a exhibits a medium
gen atom through a hydrogen bond. A strong band intensity band at 3434 cm−1 which can be attributed
at 1660 cm−1 can be attributed to a N,N-disubstituted to an OH group associated with an sp2 nitrogen
amide, and a strong absorption band at 1590 cm−1 to atom through a hydrogen bond. A medium-intensity
the CN and/or CC vibrations; the characteristic band band at 3032 cm−1 can be assigned to C(sp2)–H
observed at 756 cm−1 is attributed to the aromatic vibrations, and a strong band at 1666 cm−1 to an
δ(C–H) mode in ortho position. The more remarkable N,N-disubstituted amide. The characteristic band at
1
feature of the H NMR spectrum of 1a recorded at 758 cm−1 is observed again, which is attributed to the
room temperature in deuterated chloroform is the pres- aromatic δ(C–H) mode in the ortho substitution. The
ence of three sets of signals corresponding to the two 1H NMR data (with double doublet signals at δ = 3.43
diastereotopic protons (i. e. double doublet signals at and 6.33 ppm corresponding to the two diastereotopic
δ = 3.48 and 6.51 ppm) and the adjacent isolated sp3 protons, and the neighboring isolated sp3 CH proton
CH proton (i. e. a triplet signal at 2.73 ppm). The sin- with a triplet signal at 3.10 ppm) are very similar to
glet signals at δ = 1.86, 3.89, 4.06, and 14.2 ppm can those of 1a (see above). One of the olefinic protons
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C. A. Escobar et al. · Synthesis of N-Acylated 1,5-Benzodiazepines
399
Fig. 1. ORTEP diagram of 1a (displacement ellipsoids at the
30% probability level).
can be seen as a doublet at δ = 5.54 ppm, the other
Fig. 2. ORTEP diagram of 2a (displacement ellipsoids at the
one being covered by the more complex aromatic mul-
tiplets. The singlet signal at δ = 14.3 ppm can be as-
signed to the phenolic OH proton. Finally, the double
30% probability level).
˚
doublet signal at δ = 1.70 ppm can be attributed to the (rms deviation: 0.049 A) corroborating the conjugated
methyl group.
sp2 character along the crotonyl group.
Compounds 1a and 2a crystallize in the monoclinic
The compounds 1a and 2a are stabilized by a strong
space groups P21/c and C2/c, respectively. The molec- intramolecular O–H···N hydrogen bond between the
ular plots of compounds 1a and 2a along with the atom hydroxyl group and the N1 atom forming a six-
labeling schemes are presented in Figs. 1 and 2, respec- membered ring conferring rigidity to the system char-
tively. Selected bond lengths and angles are presented acterized by the planarity of the N5/C4/C12/C13/O1
˚
˚
in Table 1. Tables 2 and 3 list the O–H···N and C–H···O skeleton (rms deviation 1a: 0.039 A; 2b: 0.014 A).
hydrogen bond parameters for 1a and 2a. This feature is also observed in other related 1,5 ben-
The molecular structures of the two benzodiazepine zodiazepines [8]. Also, the intramolecular weak C–
compounds exhibit seven-membered rings in a boat- H···O interactions C2–H2···O3, C2–H2···O2, C26–
like conformation. Two folding angles can be stated H26A···O4 in 1a and C2–H2···O2 in 2a stabilize the
along the imaginary N1–N5 and C2–C4 axes, 49.56(8) molecular structures.
and 48.83(13)◦ for 1a and 50.55(10) and 53.20(16)◦
On the other hand, considering weak intermolec-
for 2a. In both compounds the hybridization of C4 and ular C–H···O interactions, the molecular packing
2
˚
N5 atoms is sp , the bond length N5–C4 is 1.300(2) A of compound 1a in the crystal shows an intricate
for 1a and 1.302(2) for 2a indicating the presence of three-dimensional network generated by: (i) a C14–
a C=N double bond.
H14···O23 interaction along the b axis, (ii) a C25–
The molecular structure of compound 2a contains H25A···O32 interaction along the a axis, and (iii) the
one crotonyl substituent, the bond lengths C24–O2 and C6–H6···O11 and C27–H27C···O44 interactions along
C25–26 are 1.224(2) and 1.314(2), respectively, corre- the [–1 1 0] direction. In the same manner, the crystal
sponding to C=O and C=C double bonds, while the structure of 2a exhibits infinite chains along the c axis
bond lengths N1–C24, C24–C25 and C26–C27 corre- via the C22–H22···O22 interaction. Finally, a C26–
spond to C–N and C–C single bonds. Additionally, the H26···O21 intermolecular interaction forms a dimeric
framework N1/C24/O2/C25/C26/C27 is nearly planar unit in the crystal structure of 2a.
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400
C. A. Escobar et al. · Synthesis of N-Acylated 1,5-Benzodiazepines
Table 1. Selected bond lengths (A) and angles (deg) for 1a Table 3. Hydrogen bond parameters for 2aa.
and 2a with estimated standard deviations in parentheses.
˚
D
H
A
d(D–H) d(H···A) d(D···A) D–H···A
˚
˚
˚
1a
2a
(A)
(A)
(A)
(deg)
Distances
N1–C2
C2–C3
C3–C4
C4–C5
N1–C10
N5–C11
C24–O2
N1–C24
C24–C25
C25–C26
C26–C27
Angles
C10–N1–C2
C24–N1–C2
C24–N1–C10
N5–C4–C3
N5–C4–C12
C12–C4–C3
C4–N5–C11
N1–C2–C3
N1–C2–C18
C18–C2–C3
O1
C2
C26
C22
H1
H2
N5
O2
0.82
0.98
0.93
0.93
1.82
2.30
2.53
2.58
2.547(2)
2.717(2)
3.411(2)
3.357(2)
146.7
104.6
157.5
141.1
1.483(2)
1.538(2)
1.511(2)
1.300(2)
1.435(2)
1.414(2)
1.225(2)
1.370(2)
1.509(2)
1.482(2)
1.538(2)
1.509(2)
1.302(2)
1.436(2)
1.419(2)
1.224(2)
1.378(2)
1.482(2)
1.314(2)
1.491(3)
H26 O21
H22 O22
a
Symmetry operations: 1 1/2−x, 3/2−y, −z; 2 +x, 1−y, 1/2+z.
temperature dependent, and mediated trough an in-
tramolecular hydrogen bond between the imine por-
tion and the aromatic hydroxyl group of the 1H-1,5-
benzodiazepine core. As a result, N-acetylated 1a or
its N,O-diacetylated analog 1b, were obtained depend-
ing on the reaction temperature. The presence of the
2,3-dimethoxyphenyl substituent in the case of 1 was
intended to augment the steric hindrance at the amino
side of the benzodiazepine, and thus help to evaluate its
effect on the regioselectivity or differentiation between
the two possible acylation sites mediated by both the
temperature and the hydroxyl hydrogen bond, using
acetic anhydride as acylating agent. Also the use of
crotonyl chloride as acylating agent for 2 was intended
to evaluate the same differentiation effect, but this time
focused on the size of the acylating agent. The results
have shown that the size of the acylating agent in 2 or
the steric hindrance imposed by the methoxyl groups
in 1 did not affect the acylation reaction at the amine
moiety of the benzodiazepine core. This is in accor-
dance with the fact that amino groups are more reactive
than hydroxyl groups toward electrophilic reagents [9].
In both cases excess acylating agent was not enough
at room temperature to produce acylation at the OH
group, suggesting a protective effect of the hydrogen
bond, as previously reported by us [8].
118.22(9)
119.39(10)
122.03(10)
120.96(11)
118.34(11)
120.41(10)
120.02(10)
109.07(9)
112.90(9)
110.12(10)
118.28(13)
117.77(13)
122.58(13)
121.00(15)
118.10(15)
120.67(14)
118.70(14)
108.16(13)
113.41(13)
114.15(13)
Table 2. Hydrogen bond parameters for 1aa.
D
H
A
d(D–H) d(H···A) d(D···A) D–H···A
˚
˚
˚
(A)
(A)
(A)
(deg)
O1
C2
C2
H1
H2
H2
N5
O3
O2
0.82
0.98
0.98
0.96
0.93
0.96
0.93
0.96
1.83
2.38
2.36
2.35
2.57
2.36
2.53
2.53
2.558(1)
2.865(1)
2.754(2)
2.940(2)
3.384(2)
3.265(2)
3.349(2)
3.282(2)
147.2
109.9
103.3
119.5
146.6
156.9
147.2
135.0
C26 H26A O4
C6 H6
O11
C25 H25A O32
C14
H14 O23
C27 H27C O44
a Symmetry operations: 1 −1−x, 2−y, −z; 2 −1+x, +y, +z; 3 −x,
1/2+y, 1/2−z; 4 1−x, 1−y, −z.
Experimental Section
Conclusion
Solvents were used as purchased. Reagents were pur-
chased from commercial suppliers and used without fur-
ther purification. 2-(2,3-Dimethoxyphenyl)-4-(2-hydroxy-
phenyl)-2,3-dihydro-1H-1,5-benzodiazepine (1) and 4-(2-
hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiaze-
pine (2), were synthesized according to a published proce-
dure [10, 11]. Melting points were determined using a Stuart
Scientific SMP3 melting point apparatus. IR spectra were ob-
tained from KBr disks on a Perkin Elmer Spectrum BX FTIR
To sum up, as a result of our studies, we have
found differentiation in the acylation reaction between
amino and hydroxyl groups in a 2,3-dihydro-1H-1,5-
benzodiazepine core using both acetic anhydride and
crotonyl chloride. In the first case, when 2,3-dihydro-
1H-1,5-benzodiazepine 1, a molecule presenting two
possible acylation sites (i. e. the amino and the hy-
droxyl group), was reacted with excess acetic anhy-
dride, differentiation between the two possible acy-
spectrometer in the range of 4000 – 400 cm−1
.
1H and 13C
NMR spectra were acquired at 297 K on a Bruker Avance
lation sites was observed. This differentiation was 400 spectrometer. All chemical shifts are reported in ppm
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C. A. Escobar et al. · Synthesis of N-Acylated 1,5-Benzodiazepines
401
(δ) relative to tetramethylsilane. Coupling constants (J) are 3.81 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.36 (dd, 1H, CH,
reported in Hertz (Hz) and integrations are reported as num- J = 1.0 Hz, J = 7.7 Hz), 6.63 (t, 1H, Harom, J = 8.0 Hz), 6.70
bers of protons. The following abbreviations are used to de- (dd, 1H, Harom, J = 1.2 Hz, J = 8.1 Hz), 6.80 (m, 1H, Harom),
scribe peak patterns: br, broad; s, singlet; d, doublet; t, triplet; 6.85 (dd, 1H, Harom, J = 1.6 Hz, J = 7.7 Hz), 7.13 (m, 1H,
m, multiplet. Mass spectra were recorded in the EI mode on Harom), 7.27 (d, 1H, Harom, J = 8.1 Hz), 7.32 (d, 1H, Harom
,
a MAT 95XP Thermo Finnigan instrument, using perfluoro- J = 4.6 Hz), 7.36 (d, 1H, Harom, J = 7.2 Hz), 7.39 (dd, 1H,
kerosene as a reference.
Harom, J = 1.2 Hz, J = 7.9 Hz), 7.52 (m, 1H, Harom), 8.56
(dd, 1H, Harom, J = 1.5 Hz, J = 8.0 Hz). – 13C NMR (CDCl3,
100.6 MHz): δ = 18.2, 23.0, 31.3, 54.4, 56.2, 61.1, 112.9,
114.8, 117.4, 121.4, 123.7, 124.5, 125.2, 126.2, 128.2, 128.4,
130.0, 131.6, 132.0, 132.6, 144.4, 147.2, 151.1, 152.6, 153.8,
158.3, 169.5.
1-Acetyl-2-(2,3-dimethoxyphenyl)-4-(2-hydroxyphenyl)-
2,3-dihydro-1H-1,5-benzodiazepine (1a)
Compound 1 (200 mg, 0.534 mmol) was dissolved in ex-
cess acetic anhydride (40 mL, 0.39 mol). The reaction mix-
ture was stirred at room temperature for 24 h. Then, water
(20 mL) was added, and the mixture was extracted twice
with ethyl acetate. The organic fractions were concentrated
in a rotatory evaporator and then submitted to column chro-
matography (silica gel 60, ethyl acetate-hexane = 1 : 10, v/v).
The combined fractions containing the 1,5-benzodiazepine
1a were dried (MgSO4), filtered and concentrated to af-
ford a yellow solid. The solid was recrystallized from
methanol to give pale-yellow crystals (102.2 mg, 51%); m. p.
180.5 – 181.5 ◦C. – IR (KBr): ν = 3434 (OH), 3004 (=C–
H), 1660 (CO), 1002 (=C–H) cm−1. – 1H NMR (CDCl3,
400 MHz): δ = 1.86 (s, 3H, COCH3), 2.73 (t, 1H, CH,
J = 13.7 Hz), 3.48 (dd, 1H, CH2a, J = 3.3 Hz, J = 13.6 Hz),
3.89 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 6.51 (dd, 1H, CH2b,
J = 3.3 Hz, J = 13.8 Hz), 6.86 (t, 1H, Harom, J = 4.7 Hz),
6.95 (t, 1H, Harom, J = 7.5 Hz), 7.04 (m, 3H, Harom), 7.42
(m, 5H, Harom), 7.95 (d, 1H, Harom, J = 7.9 Hz), 14.2 (s, 1H,
OH). – 13C NMR (CDCl3, 100.6 MHz): δ = 23.4, 34.7, 55.8,
60.8, 63.3, 111.5, 116.8, 118.2, 118.4, 118.9, 124.5, 126.4,
126.6, 129.0, 129.2, 130.6, 132.6, 134.0, 136.4, 143.9, 144.9,
152.8, 162.6, 170.7, 175.0. – EI-MS: m/z (%) = 416.1 (64)
[M]+, 401.1 (38), 385.1 (100), 373.1 (78), 282.1 (33), 210.1
(57). – C25H24N2O4 (416.5): calcd. C 72.10, H 5.81, N 6.73;
found C 72.10, H 6.03, N 7.15.
1-Crotonyl-4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-
1H-1,5-benzodiazepine (2a)
To a solution of 2,3-dihydro-1H-1,5-benzodiazepine
2
(1.0 g; 3.2 mmol), 4-dimethylaminopyridine (0.6 g,
4.91 mmol) and triethylamine (1 mL, 1.36 g, 13 mmol) were
dissolved in dry methylene chloride (80 mL). Then, under
nitrogen, crotonyl chloride (0.66 g, 6.4 mmol) was added.
The reaction mixture was kept under nitrogen and stirred
under reflux for 24 h. Then, water (20 mL) was added, and
the mixture was extracted with ethyl acetate. The organic
fractions were concentrated in a rotatory evaporator and
then submitted to column chromatography (silica gel 60,
ethyl acetate-hexane = 1 : 10, v/v). The combined fractions
containing the crotonylated 1,5-benzodiazepine 2a were
dried (MgSO4), filtered and concentrated, to afford a yellow
Table 4. Crystal structure data for 1a and 2a.
1a
2a
Formula
Mr
Crystal size, mm3
Crystal system
Space group
C25H24N2O4
416.46
C25H22N2O2
382.45
0.20×0.18×0.12 0.38×0.21×0.19
monoclinic
P21/c
monoclinic
C2/c
4-(2-Acetoxyphenyl)-1-acetyl-2-(2,3-dimethoxyphenyl)-
2,3-dihydro-1H-1,5-benzodiazepine (1b)
˚
a, A
7.80978(12)
19.4246(3)
14.1513(2)
103.7673(15)
2085.10(5)
4
1.33
0.1
880
30.0009(11)
7.5964(2)
17.0719(6)
93.392(3)
3883.8(2)
8
1.31
0.1
1616
˚
b, A
˚
c, A
Compound 1 (200 mg, 0.534 mmol) was dissolved in ex-
cess acetic anhydride (40 mL, 0.39 mol). The reaction mix-
ture was stirred under reflux (148 – 140 ◦C) for 8 h. Then,
water (20 mL) was added, and the mixture was extracted
twice with ethyl acetate. The organic fractions were concen-
trated in a rotatory evaporator and then submitted to column
chromatography (silica gel 60, ethyl acetate-hexane = 1 : 2,
v/v). The combined fractions containing the diacetylated 1,5-
benzodiazepine 1b were dried (MgSO4), filtered and con-
centrated to afford a yellow solid. The solid was recrystal-
lized from ethanol to give yellow crystals (70 mg, 35%); m.
p. 229 – 231 ◦C. – 1H NMR (CDCl3, 400 MHz): δ = 2.07
(s,3H, COCH3), 2.18 (s, 2H, CH2), 2.84 (s, 3H, COCH3),
β, deg
3
˚
V, A
Z
Dcalcd., g cm−3
µ(MoKα ), cm−1
F(000), e
hkl range
((sinθ)/λ)max, A
Refl. measured / unique / 58749 / 5396 /
Rint
±10,±26,±19
±40,±10,±22
−1
˚
0.687
0.683
30149 / 4806 /
0.0686
264
0.0876 / 0.1151
1.088
0.265 / −0.261
0.0513
284
Param. refined
R(F) / wR(F2) (all refls.) 0.0575 / 0.1052
GoF (F2)
∆ρfin (max / min), e A
1.034
0.300 / −0.211
−3
˚
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C. A. Escobar et al. · Synthesis of N-Acylated 1,5-Benzodiazepines
solid. The solid was recrystallized from ethyl acetate to give a well-shaped crystal was mounted with epoxy cement on
yellow crystals (254 mg, 21%); m. p. 216.7 – 217.2 ◦C. – the tip of a glass fiber. A summary of the experimen-
IR (KBr): ν = 3434 (OH), 3032 (=C–H), 1666 (CO), 1630 tal and crystallographic data for each compound are given
1
(CO), 1002 (=C–H) cm−1. – H NMR (CDCl3, 400 MHz): in Table 4. Intensity data were collected at 120 K on an
δ = 1.70 (3H, dd, CH3, J = 1.6 Hz, J = 6.9 Hz), 3.10 Oxford Diffraction Gemini CCD diffractometer and pro-
(1H, t, CH, J = 13.9 Hz), 3.43 (1H, dd, CH, J = 4.4 Hz, cessed using the Oxford Diffraction CRYSALISPRO software
J = 13.6 Hz), 5.54 (1H, dd, CH, J = 1.6 Hz, J = 15.0 Hz), using graphite-monochromatized MoKα radiation (λ =
˚
6.33 (1H, dd, J = 4.3 Hz, J = 14.0 Hz), 6.86 ( 1H, m), 0.71073 A). Using OLEX2 [12], the structures were solved
6.95 (1H, dd, CH, J = 1.1 Hz, J = 8.2 Hz), 7.07 (1H, with the SHELXS [13] structure solution program using Di-
dd, Harom, J = 1.0 Hz, J = 8.3 Hz), 7.12 (1H, dd, Harom
,
rect Methods. They were refined with the SHELXL [14] re-
J = 1.1 Hz, J = 7.8 Hz), 7.37 (8H, m, Harom), 7.53 (1H, ddd, finement package using full-matrix least-squares techniques
Harom, J1 = J2 = 7.7 Hz, J3 = 1.3 Hz), 7.69 (1H, dd, Harom
,
based on F2. All non-hydrogen atoms were refined with
J = 1.3 Hz, J = 8.1 Hz), 14.3 (1H, s, OH). – 13C NMR anisotropic displacement parameters. H atoms were finally
(CDCl3, 100.6 MHz): δ = 18.1, 34.4, 67.43, 118.5, 118.6, included in their calculated positions.
118.8, 119.0, 119.3, 119.7, 122.8, 123.2, 126.2, 127.1,
CCDC 816714 (1a) and 816715 (2a) contain the supple-
128.6, 129.1, 129.6, 131.3, 131.5, 132.1, 134.5, 140.7, 144.5 mentary crystallographic data for this paper. These data can
(C=), 163.0 (C–OH), 166.3 (C=O), 174.8 (C=N). – EI-MS: be obtained free of charge from The Cambridge Crystallo-
m/z (%) = 382.1 (52) [M]+, 341.1 (17), 313.1 (100), 237.1 graphic Data Centre via www.ccdc.cam.ac.uk/data request/
(17), 222.1 (30). – C25H22N2O2 (382.4): calcd. C 78.51, H cif.
5.80, N 7.32; found C 77.96, H 6.11, N 7.62.
Acknowledgement
X-Ray crystal structure determination of compounds 1a
and 2a
1080147 and by Universidad Andres Bello though grant
Suitable single crystals of compounds 1a, and 2a were no. DI-57-12/R; M. F. thanks the BECASCHILE Program
obtained as described in the previous section. In each case, (Chile) for support of a postdoctoral fellowship.
This work was supported by Fondecyt though grant no.
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