Chemoselectivity of the 1,3-dipolar cycloaddition of some diazoalkanes with 1,5-benzodiazepine derivatives

Article abstract of DOI:10.3184/174751912X13300109535030

Benzodiazepines are pharmaceutically important synthetic materials. Reaction of the 4-(2-hydroxyphenyl)-1,5-benzodiazepin-2-one with 2-diazopropane (DAP) gave a mixture of the 2-isopropylether of 4-(2-hydroxyphenyl)-3H-1,5- benzodiazepine and 1-isopropyl-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepin-2-one. Whilst diphenyldiazomethane (DPDM) gave 1-benzhydryl-4-(2-hydroxyphenyl)-3H-1,5- benzodiazepin-2-one. Reaction of the corresponding thione with DAP led to the 2-isopropylthioether of 4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine and 1-isopropyl-4-(2-hydroxyphenyl)-1,5-benzodiazepine-2-thione while the reaction with DPDM gave the 2-benzhydrylthioether of 4-(2-hydroxyphenyl)-3H-1,5- benzodiazepine. The characterisation of these prepared-N,-O and-S alkylated benzodiazepines involved 1D and 2D-NMR techniques, mass spectrometry and elemental analysis.

Full text of DOI:10.3184/174751912X13300109535030

152 RESEARCH PAPER
MARCH, 152–156
JOURNAL OF CHEMICAL RESEARCH 2012
Chemoselectivity of the 1,3-dipolar cycloaddition of some diazoalkanes
with 1,5-benzodiazepine derivatives
Asma Nsiraa, Ahlem Karouib, Rafik Gharbib* and Moncef Msaddeka
aLaboratoire de Synthèse Hétérocyclique et Substances Naturelles Faculté des Sciences, Monastir, Tunisia
bEcole Préparatoire aux Académies Militaires, Sousse, Tunisia
Benzodiazepines are pharmaceutically important synthetic materials. Reaction of the 4-(2-hydroxyphenyl)-1,5-benzo-
diazepin-2-one with 2-diazopropane (DAP) gave a mixture of the 2-isopropylether of 4-(2-hydroxyphenyl)-3H-1,5-ben-
zodiazepine and 1-isopropyl-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepin-2-one. Whilst diphenyldiazomethane (DPDM)
gave 1-benzhydryl-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepin-2-one. Reaction of the corresponding thione with DAP
led to the 2-isopropylthioether of 4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine and 1-isopropyl-4-(2-hydroxyphenyl)-
1,5-benzodiazepine-2-thione while the reaction with DPDM gave the 2-benzhydrylthioether of 4-(2-hydroxyphenyl)-
3H-1,5-benzodiazepine. The characterisation of these prepared -N, -O and -S alkylated benzodiazepines involved 1D
and 2D-NMR techniques, mass spectrometry and elemental analysis.
Keywords: 1,5-benzodiazepin-2-ones, 1,5-benzodiazepine-2-thiones, triazolo-benzodiazepines, 1,3-dipolar cycloaddition,
2-diazopropane, diphenyldiazomethane, 2D-NMR
Benzodiazepines have a wide range of therapeutic properties
as analgesic, sedative, anxiolytic and anti-inflammatory
agents.1–7 The range of their therapeutic applications is wid-
ened on annulation of the benzodiazepine skeleton with another
heterocyclic ring.8–10 In particular, some triazole-fused benzo-
diazepine ring systems such as alprazolam, triazolam and mid-
azolam occupy a prominent place among drugs for treatment
of CNS disorders.11–13 Among the known routes to fused
triazolo-benzodiazepines, the most commonly used strategy
involves a preliminary transformation of a 1,5-benzodiazepine-
2-thione derivative into the corresponding 2-hydrazino-1,5-
benzodiazepine followed by a subsequent ring-closure into
[1,2,4]triazolo[4,3-a]benzodiazepine upon treatment with
orthoesters.14 A survey of the literature revealed a lack of infor-
mation related to the synthesis of triazolo-benzodiazepines via
the 1,3-dipolar cycloaddition reaction. The only work that we
have found was published by Essaber et al.15 who described
the condensation of 2-methyl-4-phenyl-3H-1,5-benzodiaze-
pine with an equivalent amount of a diarylnitrilimine as a
route to bis[1,2,4]triazolo[4,3-a:3′,4′-d]benzodiazepine. This
involved a regioselective double condensation of the dipole
on both C=N functionalities of the seven membered ring.
Consequently we have studied the behaviour of some 1,5-
benzodiazepines derivatives towards two diazoalkanes,
namely 2-diazopropane (DAP) and the diphenyldiazomethane
(DPDM).
reacting this compound with DAP our first aim was to build a
triazolo[3,4-d]benzodiazepine. The reaction at 0 °C , which
was monitored by TLC, showed the formation of a mixture
of two products which were identified on the basis of their
spectral data as the 2-isopropylether of 4-(2-hydroxyphenyl)-
3H-1,5-benzodiazepine(4a)andthe1-isopropyl-4-(2-hydroxy-
phenyl)-3H-1,5-benzodiazepin-2-one (5a) (Scheme 1).
The mass spectra recorded in ES+ mode, showed for both
products 4a and 5a, molecular ion peaks [MH+.] at m/z =
295 which represents the sum of the reactants molecular
weights diminished of 28. This value involving an evident loss
of a dinitrogen molecule obviously excluded the formtion of
the target triazole moiety. On the other hand, as well as the 1H
NMR spectrum of compound 4a as that of 5a both recorded at
300 MHz in DMSO-d6 exhibited characteristic signals which
from their chemical shifts and multiplicities, were readily
assigned as isopropyl groups. Thus, for compound 4a the spec-
trum showed a doublet at 1.26 ppm (J = 6.0 Hz) corresponding
to the methyl groups which are both coupled with the proton
H-1″ which appears as a septuplet at 5.19 ppm. It is worth
noting that in compound 5a the methyl groups were non equi-
valent. Thus one of the methyl groups was assigned as CH3(a)
at 1.50 ppm (d, 3H, J = 6.8 Hz) since a NOESY correlation
have proven a proximity with H-9 at 7,48 ppm whilst the
other CH3(b) appeared at 1.24 ppm (d, 3H, J = 7.0 Hz).
The heptuplet relative to H-1″ was located at 4.47 ppm. Here,
the non-equivalence of the methyl groups and also that of the
methylenic protons at C-3 (a pair of two doublets at 3.02 ppm
and 4.15 ppm) is undoubtedly consistent with a partial non-
planarity of the heptatomic ring. On another hand the iminic
carbon peaks which were depicted from the HMBC map
Results and discussion
Our first key intermediate was the 4-(2-hydroxyphenyl)-3H-
1,5-benzodiazepin-2-one (3a) which was easily prepared from
4-hydroxycoumarin and o-phenylenediamine.16,17 Thus, on
Scheme 1
* Correspondent. E-mail: raf_gharbi@yahoo.fr

JOURNAL OF CHEMICAL RESEARCH 2012 153
at 158.7 ppm and at 165.9 ppm for 4a and 5a, respectively
confirmed that the C4=N5 function in 3a remained unreacted.
The reluctance of the C=N functionality to react was ratio-
nalised in terms of a steric hindrance due to a strong intramo-
lecular H-bonding between the hydroxyl group (δ = 14.10 ppm)
and the nitrogen at the 5-position.18 In view of the spectro-
scopic observations we conclude that both structures 4a and
5a are benzodiazepines bearing an isopropyl group. Further
2D-NMR studies were carried out and were in total accordance
with the fact that compounds 4a and 5a are a 2-isopropylether
of 4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine and a 1-iso-
propyl-4(2-hydroxyphenyl)-3H-1,5-benzodiazepin-2-one,
respectively. Indeed, the HSQC spectrum of 4a showed a
correlation between H-1″ at 5.19 ppm and the quaternary
C-2 at 153.2 ppm while for compound 5a the proton H-1″ at
4.48 ppm correlates with both C-9a at 139.6 ppm and C-2 at
165.8 ppm. In the light of this finding, we have suggested a
mechanism to explain the observed competitive O-alkylation/
N-alkylation processes. As depicted in Scheme 2, the one-pot
mechanism proposed for the N-isopropylation may start by
a preliminary deprotonation of the amide nitrogen in 3a, the
so-formed anion i then attacks the diazonium species at the
electrophilic carbon with release of a nitrogen molecule thus
forming 5a.19,20
We have also studied the behaviour of derivative 3a towards
another diazoalkane namely the diphenyldiazomethane
(DPDM). Thus, when a mixture of 3a and the 1,3-dipole
were reacted in refluxing ethyl acetate, only the N-alkylation
process took place and gave the diazepine 6 as sole product
(Scheme 4).
The structure of 6 was characterised by mass spectrometry
1
(ES+ mode) and H, 13C NMR spectroscopy. Additional sup-
ports for our assignments were provided by a HMBC experi-
ment that revealed significant correlations between the proton
H-1″ (a singlet at 6.83 ppm) and both quaternary carbons
C-2 and C-9a at 133.9 ppm and at 166.1 ppm, respectively.
The same hydrogen correlates with carbons C-2″ (138.8 ppm)
and C-8″ (138.6 ppm). This corresponds to the sequence
C9a–N1–C1″–C2″(8″) within the proposed molecular skeleton.
In the second part of our work we have studied the reactivity
of the thione 3b when reacted with DAP and DPDM. The
reactions of thiocarbonyl compounds with diazoalkanes
have been thoroughly studied over the last few years.21–23
Treatment of the thione 3b with an excess of DAP at 0 °C
in dry dichloromethane afforded the 2-isopropylthioether of
4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine (4b) and the 1-
isopropyl-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine-
2-thione (5b). It worth noting that we have never isolated
the spiranic thiadiazolo-benzodiazepine j resulting from the
1,3-dipolar cycloaddition to the C=S double bond. Although
condensation of the dipole with the thiocarbonyl functionality
On another hand the O-isopropylation pathway may involve
the formation of an intermediary tautomeric species i′. A fur-
ther nucleophilic substitution of the oxygen anion at the diazo-
nium carbon finally led to benzodiazepine 4a (Scheme 3).
Scheme 2
Scheme 3
Scheme 4

154 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 5
may have taken place, it was subsequently followed by a
thermal decomposition of the so-formed unstable spiro-
compound j′ (Scheme 5).24
analysis of the 13C NMR spectrum revealed a peak at 53.7 ppm
corresponding to the C-1″. The C=S peak for 3b observed
at 193.3 ppm was shifted up-field to 157.8 ppm in compound
7, this proved the regioselectivity of the attack on the
thiocarbonyl group (Scheme 6).
Additional confirmation arose from the HMBC spectrum
which revealed a correlation between the proton H-1″ at
6.10 ppm and the carbon C-2 at 157.8 ppm, showing that the
benzhydryl group was directly linked to the sulfur atom and
excluding the formation of a spiro-thiadiazolo-benzodiazepine
(Scheme 7).
The study of the HMBC map established of a whole set of
linkages and a complete assignment of the 1H and 13C spectra
supported the structures we have proposed (see experimental
section). Thus the condensation of 3b with DPDM performed
under the same experimental conditions gave the 2-benzhy-
drylthioether of 4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine
1
(7) as the exclusive product. The H spectrum revealed a
singlet at 6.10 ppm readily assigned to the H-1″. Moreover, the
Scheme 6
Scheme 7

JOURNAL OF CHEMICAL RESEARCH 2012 155
progressively enriched in ethylacetate allowed the separation of
compounds 4b and 5b.
Conclusion
Despite the failure to reach the initial target of a triazolo-
benzodiazpine scaffold by a 1,3-dipolar cycloaddition reaction
of some diazoalkanes with the 1,5-benzodiazepines 3a and 3b,
these results are of interest since we have demonstrated the
role of DAP and DPDM as N-, O- and S-alkylating agents
by different competitive pathways as a route to novel stable
alkylated benzodiazepines derivatives.
2-Isopropylthioether-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine
(4b): Yellow crystals (32%); m.p. 158 °C. 1H NMR (300 MHz,
CDCl3): δ (ppm) = 1.39 (d, 6H, CH3, J = 6.0 Hz), 3.43 (s, 1H, CH2),
3.89 (m, 1H, H-1″, J = 6.0 Hz), 6.91–8.24 (m, 8H, H-arom), 14.61 (s,
1H, OH). NMR 13C (75.47 MHz, CDCl3): δ (ppm) = 22.4 (C-a), 22.4
(C-b), 36.4 (C-1»), 38.3 (C-3), 117.7 (C-1′), 118.3 (C-3′), 118.6
(C-5′), 124.2 (C-7), 126.2 (C-8), 127.9 (C-9), 128.0 (C-6), 128.8
(C-6′), 133.5 (C-4′), 136.5 (C-5a), 141.5 (C-9a), 157.0 (C-2), 158.2
(C-4), 162.6 (C-2′) MS (ES+): m/z: 311.1[MH+]. Anal. Calcd for
C18H18N2OS: C, 69.65; H, 5.84; N, 9.02; S, 10.33. Found: C, 69.28; H,
5.94; N, 9.19; S, 10.18%.
1-Isopropyl-4-(2-hydroxyphenyl)-1,5-benzodiazepine-2-thione
(5b):Yellow powder (52%); m.p. 185 °C. 1H NMR (300 MHz, CDCl3):
δ (ppm) = 1.42 (d, 3H, CH3-b, J = 7.0 Hz), 2.18 (d, 3H, CH3-a, J =
7.0 Hz), 3.82 (d, 1H, H-3b, J = 12.0 Hz ), 5.28 (d, 1H, H-3a, J =
12.0 Hz), 5.86 (m, 1H, H-1″, J = 7.0 Hz), 7.47–8.68 (m, 8H, H-arom),
14.39 (s, 1H, OH). 13C NMR (75.47 MHz, CDCl3): δ (ppm) = 21.9
(C-a), 20.6 (C-b), 56.8 (C-1″), 47.3 (C-3), 117.5 (C-1′), 117.9 (C-3′),
119.0 (C-5′), 127.5 (C-7), 125.3 (C-8), 123.4 (C-9), 126.8 (C-6), 130.5
(C-6′), 134.1 (C-4′), 141.6 (C-5a), 135.4 (C-9a), 195.3 (C-2), 167.5
(C-4), 162.3 (C-2′), MS (ES+): m/z: 311.1[MH+]. Anal. Calcd for
C18H18N2OS: C, 69.65; H, 5.84; N, 9.02; S, 10.33. Found: C, 69.53; H,
5.78; N, 9.23; S, 10.21%.
Experimental
Melting points were taken on a Buchi-510 capillary apparatus. 1H and
13C NMR spectra were recorded with AC-300 Bruker spectrometer.
Two-dimensional NMR experiments were performed with an Avance-
500 Bruker spectrometer. Mass spectra were obtained with a Micro-
mass LCT spectrometer (ESI technique, positive mode). Elemental
analysis have been determined by a Perkin-Elmer 2400 analyser for
the C,H,N analysis and a Horiba Enya 220-V instrument for the C,S
analysis. All reactions were followed by TLC using aluminium sheets
of Merck silica gel 60 F254, 0.2 mm. Merck silica gel 60 (40–63 µm)
was used for column chromatography. The starting materials 3a16,17
and 3b18 were prepared according to the literature.
2-Diazopropane (DAP) is volatile and toxic. Its preparation should
be carried out in an efficient hood behind a protective screen. This
reagent was prepared via the oxidation reaction of acetone hydrazone
by yellow mercury (II) oxide according to the literature method.25
The diazoalkane was trapped as it was formed in a cooled receiver at
–60 °C. Titration was done by the measurement of the dinitrogen
volume released upon the addition of 1 mL of glacial acetic acid to the
DAP solution. The concentration values for our DAP preparations
usually range around 2 mol L−1.
Reaction of the benzodiazepinone 3a with 2-diazopropane: Small
quantities of an ethereal solution of 2-diazopropane cooled at –60 °C
were slowly added to a stirred and ice-cooled suspension of compound
3a (252 mg, 1 mmol) in anhydrous dichloromethane (50 mL) The
solution was allowed to react for 12 h at 0 °C and its progress was
monitored by a TLC control (cyclohexane:ethylacetate 95:5). After
completion of the reaction the solvents were removed in vacuo and the
resulted crude brownish oil was chromatographed on silica gel and
eluted with cyclohexane progressively enriched in ethylacetate. This
allowed the separation of compounds 4a and 5a.
2-Isopropylether of 4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine
(4a):Yellow powder (28%); m.p. 147 °C. 1H NMR (300 MHz, CDCl3):
δ (ppm) = 1.26 (d, H-a, CH3, J = 6.0 Hz), 3.33 (s, 1H, CH2), 5.19
(m, 1H, H-1″, J = 6.0 Hz ), 6.95–7.79 (m, 8H-arom), 14.1 (s, 1H, OH).
13C NMR (75.47 MHz, CDCl3): δ (ppm) = 21.6 (C-a), 21.6 (C-b),
70.7 (C-1»), 34.4 (C-3), 118.2 (C-1′), 118.2 (C-3′), 118.6 (C-5′), 123.9
(C-7), 126.5 (C-8), 127.6 (C-9), 127.8 (C-6) 128.7 (C-6′), 133.3
(C-4′), 136.9 (C-9a), 139.6 (C-5a), 153.9 (C-2), 158.7 (C-4), 162.4
(C-2′). MS (ES+): m/z: 295.1 [MH+]. Anal. Calcd for C18H18N2O2: C,
73.45; H, 6.16; N, 9.52. Found: C, 73.22; H, 6.19; N, 9.39%.
1-Isopropyl-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepin-2-one
(5a):Yellow crystals; m.p (43%). 155 °C. 1H NMR (300 MHz, CDCl3):
δ (ppm) = 1.24 (d, 3H, CH3-b, J = 7.0 Hz), 1.50 (d, 3H, CH3-a, J = 6.8
Hz), 3.02 (d, 1H, H-3b, J = 12.2 Hz), 4.13 (d, 1H, H-3a, J = 12.2 Hz),
4.47 (m, 1H, H-1″, J = 7.0 Hz), 6.97–7.03 (m, 2H, H-arom), 7.29–7.41
(m, 4H, H-arom), 7.43 (d, 1H, H-9, J = 8.1 Hz), 7.88 (d, 1H, H-6′,
J = 8.1 Hz), 14.1 (s, 1H, OH). 13C NMR (75.47 MHz, CDCl3):
δ (ppm) = 22.1 (C-a), 20.3 (C-b), 52.3 (C-1»), 39.0 (C-3), 118.2
(C-1′), 118.1 (C-3′), 119.1 (C-5′), 126.1 (C-7), 126.2 (C-8), 123.9
(C-9), 126.8 (C-6), 129.6 (C-6′), 133.4 (C-4′), 134.4 (C-9a), 140.1
(C-5a), 165.8 (C-2), 165.9 (C-4), 162.1 (C-2′), MS (ES+): m/z: 295.1
[MH+]. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found:
C, 73.07; H, 6.39; N, 9.40%.
General procedure for the reaction of the benzodiazepinone 3a and
the thione 3b with diphenyldiazomethane
To a stirred suspension of compounds 3a (or 3b) (1 mmol) in ethyl-
acetate (75 mL) was added a slight excess of diphenyldiazomethane
(232.8, 1.2 equiv.). The mixture was heated at 60 °C for almost
eight hours. After the removal of the volatile components in vacuo,
the purification of the obtained brownish oily residue on silica gel
(cyclohexane/ethylacetate ) gave compounds 6 and 7, respectively. A
small amount of benzophenone azine was recovered as a side product
from both reactions.26
1-Benzhydryl-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepin-2-one
(6): White solid (52%); m.p. 187 °C. 1H NMR (300 MHz, DMSO-d6):
δ (ppm) = 3.17 (d, 1H, H-3a, J = 12.1 Hz), 4.24 (d, 1H, H-3b, J =
12.1 Hz), 6.83 (s, 1H, H-1″), 6.91–7.38 (m, 17H, H-arom), 7.80
(d, 1H, H-6′, J = 8.0 Hz), 13.92 (s, 1H, OH). 13C NMR (75.47 MHz,
DMSO-d6): δ (ppm) = 39.1 (C-3), 66.7 (C-1»), 118.4 (C-1′), 118.4
(C-3′), 119.5 (C-5′), 125.3 (C-7), 126.2 (C-8), 126.4 (C-9), 126.9
(C-6), 128.0 (C-6′), 128.8 (C-4′), 138.7 (C-5a), 140.3 (C-9a), 162.5
(C-2), 165.5 (C-4), 165.9(C-2′). MS (ES+): m/z: 419.1 [MH+]. Anal.
Calcd for C28H22N2O2: C, 80.36; H, 5.30; N, 6.69. Found: C, 80.59; H,
5.76; N, 6.32%.
2-Benzhydrylthioether-4-(2-hydroxyphenyl)-3H-1,5-benzodiazepine
(7): Pale green solid (43%); m.p. 194 °C. 1H NMR (300 MHz, DMSO-
d6): δ (ppm) = 3.32 (s, 2H, CH2), 6.10 (s, 1H, H-1″), 6.84–6.98 (m, 2H,
H-arom), 7.08–7.39 (m, 15H, H-arom), 7.68 (d, 1H, H-6′, J = 7.8 Hz),
14.29 (s, 1H, OH). 13C NMR (75.47 MHz, DMSO-d6): δ (ppm) = 37.9
(C-3), 53.7 (C-1»), 117.7 (C-1′), 118.3 (C-3′), 118.8 (C-5′), 125.1 (C-
7), 126.3 (C-8), 127.9 (C-9), 127.9 (C-6), 128.4(C-9»), 128.5
(C-10»), 128.7 (C-6′), 133.7 (C-4′), 136.8 (C-5a), 141.0 (C-9a), 155.1
(C-2), 158.9(C-4), 162.7 (C-2′), MS (ES+): m/z: 435.2 [MH+]. Anal.
Calcd for C28H22N2OS: C, 77.39; H, 5.10; N, 6.45; S, 7.38. Found: C,
77.15; H, 5.22; N, 6.52; S, 7.17%.
Received 30 November 2011; acceped 2 February 2012
Paper 1101014 doi: 10.3184/174751912X13300109535030
Published online: 22 March 2012
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