Facile synthesis of dihydro-1,2,4-benzotriazepin-5-ones

Article abstract of DOI:10.1007/s00706-006-0532-y

Direct interaction between model anilines and an 1,3-dipolar nitrile imine, derived from 2-[N′-(1-chloro-2-oxopropylidine)hydrazine]benzoic acid, yielded the respective acyclic amidrazones. The latter adducts underwent CDI-induced cyclocondensation involv

Full text of DOI:10.1007/s00706-006-0532-y

Monatshefte f€ur Chemie 137, 1349–1355 (2006)
DOI 10.1007/s00706-006-0532-y
Facile Synthesis of Dihydro-1,2,4-
benzotriazepin-5-ones
Nisreen I. Hindawi1, Jalal A. Zahra1, Mustafa M. El-Abadelah1;ꢀ
Bassam A. Abu Thaher2, and Klaus-Peter Zeller3
,
1
Chemistry Department, Faculty of Science, University of Jordan, Amman, Jordan
2
Chemistry Department, Faculty of Science, Islamic University of Gaza, Gaza Strip
3
€
€
€
Institut fur Organische Chemie, Universitat Tubingen, Tubingen, Germany
€
Received February 13, 2006; accepted March 10, 2006
Published online September 15, 2006 # Springer-Verlag 2006
Summary. Direct interaction between model anilines and an 1,3-dipolar nitrile imine, derived
from 2-[N0-(1-chloro-2-oxopropylidine)hydrazine]benzoic acid, yielded the respective acyclic
amidrazones. The latter adducts underwent CDI-induced cyclocondensation involving the hydra-
zone–NH terminus and the activated carboxy group to produce the corresponding dihydro-1,2,4-
benzotriazepin-5-ones.
Keywords. N-(2-Carboxyphenyl)hydrazonoyl chloride; 1,3-Nucleophilic addition; N-Arylamidra-
zones; Cyclization; Dihydro-1,2,4-benzotriazepin-5-ones.
Introduction
Recently, we have reported on a facile synthesis of model 1,4-dihydro-1,3,4-
benzotriazepin-5-ones 2 via cyclocondensation of the respective N-arylamidrazone
precursors 1, induced by 1,10-carbonyldiimidazole (CDI) (Scheme 1) [1–3]. The
latter acyclic adducts 1 are readily accessible by direct interaction of anthranilic
acid with the appropriate hydrazonoyl chloride in the presence of triethylamine
[1–3].
Following this route, we envisaged that the isomeric dihydro-1,2,4-benzotria-
zepin-5-ones 5 would be similarly prepared via a CDI-induced lactamization of
N-arylamidrazones 4 (accessible from interaction of 3 and ArNH2), whereby an-
thranilic acid is already incorporated as part of their hydrazone moiety (Scheme 2).
As outlined in the latter scheme, this expectation is realized in the present study,
which deals with the synthesis and characterization of model dihydro-1,2,4-benzo-
triazepinones 5a–5c and their acyclic amidrazone precursors 4a–4c.
ꢀ
Corresponding author. E-mail: mustelab@ju.edu.jo

1350
N. I. Hindawi et al.
Scheme 1
Scheme 2
Results and Discussion
Synthesis
Benzeneamines (ArNH2), acting as nitrogen nucleophiles, add readily to nitrile
imine (the reactive 1,3-dipolar species generated in situ from its hydrazonoyl chlo-
ride precursor 3 in presence of triethylamine) to produce the respective N,N0-diaryl-
amidrazone adducts 4 (Scheme 2). This mode of nucleophilic addition reaction of
various nucleophiles to 1,3-dipoles is well-documented, and several amidrazone
adducts related to 4 have been obtained from the reaction of amines with hydra-
zonoyl chlorides (such as 3) [4, 5]. The required hydrazonyl chloride 3 is pre-
pared in this study via the Japp-Klingemann reaction [6–8] involving coupling of
2-carboxybenzenediazonium chloride (diazotized 2-aminobenzoic acid) with 3-
chloro-2,4-pentanedione in aqueous-ethanolic sodium acetate. In a separate step,
the acyclic adducts 4a–4c in tetrahydrofuran in the presence of the coupling reagent
CDI underwent cyclocondensation involving the activated carboxyl group and the
hydrazone–NH terminus to furnish the corresponding dihydrobenzotriazepinones
5a–5c (Scheme 2).

Dihydro-1,2,4-benzotriazepin-5-ones
1351
Spectroscopic Data
The IR, MS, and NMR spectral data and microanalyses of the new compounds 3,
4a–4c, 5a–5c conform to the suggested structures, and are given in the Experi-
mental part. Thus, their MS spectra display the correct molecular ions for which
the measured high-resolution (HRMS) data are in good agreement with the calcu-
lated values. Under electron impact, the main fragmentation pattern for Mþ of
compounds 5a–5c involves initial ring opening of the dihydrotriazepinone system
via heterolytic cleavage of the lactam bond to form the acyclic equivalent [A]
(Scheme 3). Subsequently, expulsion of ArNC from [A] produces the respective
radical cation at m=z ¼ 176, which then undergoes elimination of ketene to form
the dihydroindazolone radical cation as the base peak at m=z ¼ 134 (path (a)).
Alternatively, the acyclic radical cation [A] undergoes extrusion of 3-acetyldiazi-
1
rene with consequent production of the fragment ion at m=z ¼ 119 (path (b)). H
and 13C signal assignments follow from DEPT and 2D (COSY, HMQC and
HMBC) experiments. Thus, long range correlation is observed between H-6 and
each of C-9a and C-5 in HMBC experiments for compounds 5a–5c. Likewise, H-8
is correlated with C-9a, while H-30=H-50 show correlation with C-10.
Scheme 3

1352
N. I. Hindawi et al.
Scheme 4
Scheme 5
In this context, it is worth mentioning that the first examples of the 1,2,4-benzo-
triazepine system have been reported in 1974 by Conde et al. who synthesized
several 5-substituted 1,3-diphenyl-1H-1,2,4-benzotriazepines 7 via intramolecular
cyclization of the respective nitrilium salts 6A (obtained from the reaction of
benzhydrazidoyl chloride 6 with the appropriate nitrile in the presence of Lewis
acid) (Scheme 4) [9]. Several 1,2,4-benzotriazepin-5-ones 9 have been later prepared
from diethyl N-(2-nitrobenzoyl)aminomalonates 8 [10], via the Japp-Klingemann
reaction [6–8] as depicted in Scheme 5.
In conclusion, the two-step reaction described in the present work (Scheme 2)
provides an alternative and efficient route toward the synthesis of various sub-
stituted dihydro-1,2,4-benzotriazepin-5-ones 5 in good overall yield. This new
versatile route utilizes readily available and inexpensive reactants (appropriately
substituted anilines and N-(2-carboxyphenyl)hydrazonoyl chlorides), is conve-
niently conducted at or below room temp., and thus competes favorably with either
of the literature methods cited above.
Experimental
2-Aminobenzoic acid was purchased from Merck, 4-methylaniline from Fluka, aniline, 4-chloroani-
line, 3-chloro-2,4-pentanedine, and CDI from Acros. THF was dried over Na wire for 24 h before use.
€
Melting points were measured on a Buchi 510 melting point apparatus. IR spectra were determined on
KBr discs on a Nicolet Impact-400 FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded
on a Bruker-DPX 300 instrument with TMS as internal standard. Electron impact mass spectra (MS-EI)
were obtained using a Varian MAT 212 spectrometer at 70 eV at an ion source temperature of 200ꢁC.
The new products were purified by preparative thick layer plates using silica gel (DFG254, Merck) as
the adsorbent. Microanalyses were performed at the Microanalytical Laboratory of the Hashemite
University, Zarka-Jordan, and the results were found to be in good agreement (ꢂ0.4%) with the
calculated values.

Dihydro-1,2,4-benzotriazepin-5-ones
1353
2-[N0-(1-Chloro-2-oxopropylidene)hydrazino]benzoic acid (3, C10H9ClN2O3)
2-Aminobenzoic acid (15.1 g, 0.11mol) in 80cm3 cooled (0 to ꢃ5ꢁC) 5N aqueous HCl was treated
dropwise with a solution of 9.0 g aq NaNO2 (0.13 mol) in 15cm3 H2O under efficient stirring. The
resulting solution was further stirred for 30min at 0–4ꢁC and then poured portionwise onto a vigor-
ously stirred and cooled (ꢃ8 to ꢃ10ꢁC, ice-salt bath) solution of 13.5g 3-chloro-2,4-pentanedione
(0.1mol) and 16.4g sodium acetate (0.2mol) in 400 cm3 ethanol. The reaction mixture was stirred for
30min at 0–4ꢁC, and then diluted with 400cm3 cold H2O. The precipitated solid product 3 was col-
lected, washed several times with cold H2O, then with petroleum ether (bp 40–60ꢁC), dried, and re-
crystallized from methanol. Yield 20.2g (84%); mp 228–229ꢁC; IR: ꢀꢀ¼ 3240, 3015, 1696, 1666,
1
1548, 1449, 1220 cmꢃ1; H NMR (300 MHz, DMSO-d6): ꢁ ¼ 2.49 (s, COCH3), 7.07 (dd, J ¼ 7.1,
7.8 Hz, H-5), 7.57 (dd, J ¼ 8.2, 7.1 Hz, H-4), 7.69 (d, J ¼ 8.2 Hz, H-3), 7.91 (d, J ¼ 7.8 Hz, H-6),
11.97 (s, C2-NH), 13.80 (s, CO2H) ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 25.9 (COCH3), 113.9
(C-1), 114.8 (C-3), 122.3 (C-5), 129.8 (Cl–C¼N–), 131.9 (C-6), 135.4 (C-4), 144.3 (C-2), 170.0
(CO2H), 188.4 (Me–C¼O) ppm; MS-EI: m=z (%) ¼ 240 (Mþ, 76), 224 (17), 222 (49), 182 (19),
180 (56), 152 (11), 134 (62), 124 (28), 105 (13), 91 (50), 76 (14), 67 (37), 55 (100).
2-[N0-(1-(4-Methylphenylamino)-2-oxopropylidene)hydrazino]benzoic acid (4a, C17H17N3O3)
A homogeneous solution of 1.28g p-methylaniline (12 mmol) in aqueous methanol and 6 cm3 triethyl-
amine was added dropwise to a stirred and cooled (0ꢁC) solution of 2.41g 3 (10 mmol) in 40cm3 THF.
Additional triethylamine (4cm3) was then introduced dropwise into the reaction mixture which was
stirred at 0ꢁC for 1 h, then at room temp for 12–15 h. The organic solvents were removed in vacuo, and
then the aqueous solution was acidified with glacial acetic acid. The resulting crude solid product
was collected and recrystallized from CHCl3=methanol (4=1, v=v) to give the yellow solid product 4a.
1
Yield 2.21 g (71%); mp 217–218ꢁC; IR: ꢀꢀ¼ 3186, 2919, 1689, 1618, 1487, 1354 cmꢃ1; H NMR
0
0
0
(300 MHz, DMSO-d6): ꢁ ¼ 2.13 (s, C4 –CH3), 2.46 (s, COCH3), 6.47 (d, J ¼ 8.1Hz, H-2 þ H-6 ), 6.88
(dd, J ¼ 7.5, 7.9 Hz, H-5), 6.92 (d, J ¼ 8.1 Hz, H-30 þ H-50), 7.55 (dd, J ¼ 8.1, 7.5 Hz, H-4), 7.75–7.78
(m, H-3 þ H-6), 8.09 (s, C1 –NH), 10.80 (s, C2-NH), 12.90 (br s, CO2H) ppm; 13C NMR (75 MHz,
0
0
0
0
DMSO-d6): ꢁ ¼ 20.7 (C4 –CH3), 25.0 (COCH3), 112.3 (C-1), 114.1 (C-3), 117.4 (C-2 þ C-6 ), 119.9
(C-5), 129.3 (C-40), 129.6 (C-30 þ C-50), 131.6 (C-6), 135.1 (C-4), 137.8 (NH–C¼N–), 138.1 (C-10),
145.9 (C-2), 169.6 (CO2H), 194.3(Me–C¼O) ppm; MS-EI: m=z (%) ¼ 311 (Mþ, 20), 265 (45), 222
(30), 194 (14), 133 (30), 104 (100), 90 (68), 76 (15), 65 (17); HRMS: calcd for Mþ 311.1270, found
311.1282.
2-[N0-(1-(4-Chlorophenylamino)-2-oxopropylidene)hydrazino]benzoic acid (4b, C16H14ClN3O3)
This compound was prepared from 1.53g p-chloroaniline (2mmol) and 2.41g 3 (10 mmol) by follow-
ing the same procedure and experimental conditions described above for 4a. The product was preci-
pitated as an orange solid. Further purification was achieved by recrystallization from CHCl3=methanol
1
(4=1, v=v). Yield 2.06 g (62%); mp 235–236ꢁC; IR: ꢀꢀ¼ 3460, 1651, 1487, 1356 cmꢃ1; H NMR
(300 MHz, DMSO-d6): ꢁ ¼ 2.51 (s, COCH3), 6.55 (d, J ¼ 8.7 Hz, H-20 þ H-60), 6.91 (dd, J ¼ 7.4,
7.5 Hz, H-5), 7.16 (d, J ¼ 8.7 Hz, H-30 þ H-50), 7.56 (dd, J ¼ 7.6, 7.4 Hz, H-4), 7.76–7.80 (m,
H-3 þ H-6), 8.42 (s, C1 –NH), 10.87 (s, C2-NH), 13.08 (br, s, CO2H) ppm; 13C NMR (75 MHz,
0
DMSO-d6): ꢁ ¼ 25.1 (COCH3), 112.6 (C-1), 114.1 (C-3), 118.6 (C-20 þ C-60), 120.3 (C-5), 124.1
(C-40), 129.0 (C-30 þ C-50), 131.7 (C-6), 135.1 (C-4), 137.4 (NH–C¼N–), 139.6 (C-10), 145.8
(C-2), 169.8 (CO2H), 194.1 (Me–C¼O) ppm; MS-EI: m=z (%) ¼ 331 (Mþ, 67), 152 (21), 134
(100), 119 (14), 91 (18), 65 (12); HRMS: calcd for Mþ 331.0723, found 331.0715.
2-[N0-(1-Phenylamino-2-oxopropylidene)hydrazino]benzoic acid (4c, C16H15N3O3)
This compound was prepared from 1.12 g aniline (12mmol) and 2.41g of 3 (10 mmol) by following
the same procedure and experimental conditions described above for obtaining 4a. The brown solid
product that formed was recrystallized from CHCl3=methanol (4=1, v=v). Yield 2.05g (69%); mp
187–189ꢁC; IR: ꢀꢀ¼ 3460, 1639, 1432, 1356 cmꢃ1
;
1H NMR (300MHz, DMSO-d6): ꢁ ¼ 2.46 (s,

1354
N. I. Hindawi et al.
COCH3), 6.56 (d, J ¼ 7.8Hz, H-20 þ H-60), 6.75 (t, J ¼ 7.3Hz, H-40), 6.89 (dd, J ¼ 7.5, 7.5 Hz, H-5),
7.12 (dd, J ¼ 7.8, 7.3Hz, H-30 þ H-50), 7.55 (dd, J ¼ 8.1, 7.5Hz, H-4), 7.77–7.80 (m, H-3 þ H-6), 8.21
(s, C1 –NH), 10.93 (s, C2-NH), 13.20 (br, s, CO2H) ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 25.1
0
(COCH3), 112.7 (C-1), 114.1 (C-3), 117.0 (C-20 þ C-60), 120.1 (C-5), 120.6 (C-40), 129.1 (C-30 þ C-
50), 131.7 (C-6), 135.0 (C-4), 137.8 (NH–C¼N–), 140.6 (C-10), 145.8 (C-2), 169.7 (CO2H), 194.3
(Me–C¼O) ppm; MS-EI: m=z (%) ¼ 297 (Mþ, 75), 152 (16), 134 (100), 119 (18), 104 (46), 91 (21),
76 (17), 65 (13); HRMS: calcd for Mþ 297.1113, found 297.1108.
3-Acetyl-4-(4-methylphenyl)-1,4-dihydro-1H-1,2,4-benzotriazepin-5-one (5a, C17H15N3O2)
CDI (0.41 g, 2.5mmol) was added to a cooled (0ꢁC) and stirred solution of 0.62 g 4a (2mmol) in
20cm3 dry THF, and the resulting mixture was further stirred at room temp for 2–3 h. The reaction
mixture was then immediately treated with 20 cm3 cold H2O, most of the THF was then removed
in vacuo and the aqueous layer was extracted with 2ꢄ20 cm3 CH2Cl2. The combined organic extracts
were dried (MgSO4) and the solvent was evaporated in vacuo. The residual yellow solid product was
recrystallized from CHCl3=petroleum ether (1=2, v=v). Yield 0.43 g (73%); mp 160–161ꢁC; IR:
ꢀꢀ¼ 3316, 1677, 1649, 1578, 1486, 1217 cmꢃ1; 1H NMR (300 MHz, DMSO-d6): ꢁ ¼ 2.15 (s, COCH3),
0
0
0
0
0
2.24 (s, C4 –CH3), 6.76 (d, J ¼ 7.7 Hz, H-2 þ H-6 ), 7.10–7.15 (m, H-7 þ H-3 þ H-5 ), 7.26 (d,
J ¼ 7.7 Hz, H-9), 7.63 (dd, J ¼ 7.7, 7.4 Hz, H-8), 7.68 (d, J ¼ 7.7Hz, H-6), 11.21 (s, N1-H) ppm;
13
0
C NMR (75 MHz, DMSO-d6): ꢁ ¼ 20.9 (C4 –CH3), 30.9 (COCH3), 113.1 (C-9), 115.3 (C-5a),
121.1 (C-20 þ C-60), 122.1 (C-7), 124.5 (C-6), 130.0 (C-30 þ C-50), 133.9 (C-40), 135.1 (C-8), 143.7
(C-10), 148.6 (C-9a), 148.8 (C-3), 161.1 (C-5), 195.0 (Me–C¼O) ppm; MS-EI: m=z (%) ¼ 293 (Mþ,
22), 176 (19), 134 (100), 119 (42), 90 (13); HRMS: calcd for Mþ 293.1164, found 293.1151.
3-Acetyl-4-(4-chlorophenyl)-1,4-dihydro-1H-1,2,4-benzotriazepin-5-one (5b, C16H12Cl N3O2)
This compound was prepared from 0.66 g 4b (2 mmol) and 0.41 g CDI (2.5mmol) by following the
same procedure and experimental conditions described above for 5a. The light-green product was
recrystallized from CHCl3=petroleum ether (1=2, v=v). Yield 0.52 g (83%); mp 140–141ꢁC; IR:
ꢀꢀ¼ 3200, 1684, 1641, 1485, 1407, 1357cmꢃ1; 1H NMR (300MHz, DMSO-d6): ꢁ ¼ 2.00 (s, COCH3),
6.89 (d, J ¼ 8.8 Hz, H-20 þ H-60), 7.13 (dd, J ¼ 7.7, 7.7Hz, H-7), 7.27 (d, J ¼ 8.2 Hz, H-9), 7.36 (d,
J ¼ 8.8 Hz, H-30 þ H-50), 7.63 (dd, J ¼ 8.2, 7.7 Hz, H-8), 7.71 (d, J ¼ 7.7 Hz, H-6), 11.20 (s, N1-H)
ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 31.0 (COCH3), 113.1 (C-9), 115.2 (C-5a), 122.3 (C-7),
123.1 (C-20 þ C-60), 124.5 (C-6), 129.0 (C-40), 129.5 (C-30 þ C-50), 135.3 (C-8), 145.3 (C-10), 148.8
(C-9a), 149.2 (C-3), 161.2 (C-5), 194.7 (Me–C¼O) ppm; MS-EI: m=z (%) ¼ 313 (Mþ, 25), 235 (4),
176 (33), 134 (100), 119 (14), 91 (16); HRMS: calcd for Mþ 313.0618, found 313.0685.
3-Acetyl-4-phenyl-1,4-dihydro-1H-1,2,4-benzotriazepin-5-one (5c, C16H13N3O2)
This compound was prepared from 0.59 g 4c (2mmol) and 0.41 g CDI (2.5mmol) by following the
same procedure and experimental conditions described above for 5a. The light-green product was
recrystallized from CHCl3=petroleum ether (1=2, v=v). Yield 0.22 g (40%); mp 170–172ꢁC; IR:
ꢀꢀ¼ 3311, 1693, 1620, 1487, 1355 cmꢃ1
;
1H NMR (300MHz, DMSO-d6): ꢁ ¼ 2.15 (s, COCH3),
6.76 (d, J ¼ 7.7Hz, H-20 þ H-60), 7.07–7.16 (m, H-7 þ H-40), 7.26–7.34 (m, H-9 þ H-30 þ H-50),
7.63 (dd, J ¼ 8.0, 7.4 Hz, H-8), 7.70 (d, J ¼ 7.8 Hz, H-6), 11.20 (s, N1-H) ppm; 13C NMR (75 MHz,
DMSO-d6): ꢁ ¼ 31.0 (COCH3), 113.1 (C-9), 115.3 (C-5a), 121.2 (C-20 þ C-60), 122.2 (C-7), 124.5
(C-6), 124.8 (C-40), 129.5 (C-30 þ C-50), 135.2 (C-8), 146.3 (C-10), 148.7 (C-9a), 148.8 (C-3), 161.2
(C-5), 194.8 (Me–C¼O) ppm; MS-EI: m=z (%) ¼ 279 (Mþ, 25), 176 (24), 134 (100), 119 (14), 104
(19), 91 (12); HRMS: calcd for Mþ 279.1008, found 279.1021.
Acknowledgements
We wish to thank the Deanship of Scientific Research, University of Jordan (Amman-Jordan) for
financial support.

Dihydro-1,2,4-benzotriazepin-5-ones
1355
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