Synthesis of novel benzo[b]pyrazolo[1,5]diazepines

Article abstract of DOI:10.1002/jhet.878

The synthesis and in vitro biological evaluation of two novel benzodiazepine derivatives are described. The compounds were synthesized divergently from the key amino alcohol 5, which was realized using the unusual Weinreb-enamino ketone 10..

Full text of DOI:10.1002/jhet.878

January 2012
Synthesis of Novel Benzo[b]pyrazolo[1,5]diazepines
221
Joseph Raker,* Yi Wang, Anthony D. Pechulis, James C. Haber, Michael A.
Lynch, and Stacey L. Spring
Department of Medicinal Chemistry, AMRI, Albany, New York 12212
*E-mail: joseph.raker@amriglobal.com
Received October 22, 2010
DOI 10.1002/jhet.878
Published online 22 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis and in vitro biological evaluation of two novel benzodiazepine derivatives are
described. The compounds were synthesized divergently from the key amino alcohol 5, which was real-
ized using the unusual Weinreb-enamino ketone 10.
J. Heterocyclic Chem., 49, 221 (2012).
INTRODUCTION
RESULTS AND DISCUSSION
The medicinal chemistry literature is replete with ben-
zodiazepine derivatives, GABAA agonists that have
been used for decades [1] as sedatives, hypnotics, anxio-
lytics, muscle relaxers, and anticonvulsants [2]. Their
widespread use is attributed to potent activity coupled
with a lack of respiratory side effects, a problem associ-
ated with barbiturate predecessors [2]. Fused heterocy-
clic benzodiazepines such as 1 [3] (Fig. 1) have been
extensively used as anxiolytics, but can have poor side
effect profiles such as impairing effects on cognitive and
psychomotor performance [4]. Less common are the
1,5-benzodiazepines such as compound 2, which are less
potent but have the advantage of vastly improved side
A retrosynthetic analysis reveals that compounds 3
and 4 can be accessed using amino alcohol 5 via an
intramolecular cyclization reaction [8,9] (Scheme 1).
Compound 5 can be obtained through a condensation
reaction between the appropriate phenylhydrazine and
acetylenic ketone 6 [10].
The attempted synthesis of intermediate 6 is shown in
Scheme 2. Jones oxidation [11] of commercially available
7 followed by standard HOBt/EDCI coupling conditions
afforded Weinreb amide 9. Treatment of 9 with ethynyl-
magnesium bromide gave a mixture of the unexpected
enamino ketone 10 [12] and the expected alkyne 6. It was
found that the ratio of 6/10 could be varied based on the
temperature and duration of the workup, with longer expo-
sures to saturated aqueous ammonium chloride at 50ꢀC
affording 10 exclusively. Although it was difficult to iso-
late 6 in acceptable yield, compound 10 was recognized
as a suitable alternative as enamino ketones are commonly
used as precursors in heterocycle formations [12(c),13].
The synthesis of cyclization precursor 5 is shown in
Scheme 3. A diazotization and reduction sequence [14]
afforded hydrazine hydrochloride 12, which was con-
densed with enamino ketone 10 to afford 5-substituted
pyrazole 13a as the major product. The alternate
regioisomer (compound 13b) was readily separated by
column chromatography and both structures were con-
firmed by one-dimensional (1D) NOE experiments. A
global deprotection of 13a via hydrogenation afforded
the key intermediate amino alcohol 5.
effect profiles [5].
A benzodiazepine core which
includes a fused heterocycle and the 1,5-nitrogen orien-
tation may show both potency and reduced off-target
issues displayed by the parent scaffolds, respectively.
To test the accessibility of the proposed scaffolds,
compounds 3 and 4 were targeted based on their homol-
ogy with compounds 1 and 2. There are no reports of
structures related to compound 3, although triazole
derivatives are known [2(c),3(b)]. Structures such as
compound 4 have been claimed as PAF-antagonists, but
their synthesis was not reported [6]. Pyrazolo-1,4-benzo-
diazepines appeared in a few reports from Hoffmann–La
Roche [7], but a search of the literature uncovered no
current uses of the structures. Herein, we report the syn-
thesis and GABAA binding results of a novel class of
benzo[b]pyrazolo[1,5]diazepines (compounds 3 and 4).
C
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tion of a variety of related diazepine derivatives to tar-
get GABAA agonism (or other biological targets), which
will be reported in due course.
In conclusion, we have synthesized two novel ben-
zo[b]pyrazolo[1,5]diazepine derivatives. The key inter-
mediate amino alcohol 5 was prepared in six overall
steps. Divergent cyclization of the key intermediate fol-
lowed by standard coupling conditions readily afforded
the two desired targets.
EXPERIMENTAL
Figure 1. Structures of known fused heterocyclic benzodiazepine
(compound 1), known [1,5]benzodiazepine (compound 2), and pro-
posed fused heterocyclic [1,5]benzodiazepines (compounds 3 and 4).
3-(Benzyloxy)propanoic acid (8). A mixture of 3-(benzy-
loxy)propan-1-ol (30.0 g, 180 mmol) in acetone (920 mL) at
0ꢀC was treated dropwise with Jones reagent over a period of
30 min. After the addition was complete, the mixture was
stirred at 0ꢀC for 2.25 h then allowed to warm to ambient tem-
perature over a period of 30 min. After this time, the reaction
was filtered through diatomaceous earth and the filtrate was
concentrated under reduced pressure. The residue obtained was
diluted with ethyl acetate (450 mL), washed with water (400
mL), dried over sodium sulfate, filtered, and the filtrate was
concentrated under reduced pressure. The residue obtained was
diluted with methylene chloride (500 mL) then extracted with
2M aqueous sodium hydroxide (2 ꢁ 300 mL). The aqueous
extracts were combined, washed with methylene chloride (2 ꢁ
400 mL), acidified with concentrated hydrochloric acid (pH
ꢂ1), and then extracted with chloroform (2 ꢁ 400 mL). The
organic layer was dried over sodium sulfate, filtered, and the
filtrate was concentrated under reduced pressure to afford 3-
(benzyloxy)propanoic acid (25.4 g, 78%) as yellow oil: 1H
NMR (300 MHz, CDCl3): d 7.36–7.29 (m, 5H), 4.56 (s, 2H),
3.76 (t, J ¼ 6.0 Hz, 1H), 2.68 (t, J ¼ 6.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d 176.9, 137.8, 128.4, 127.8, 127.7, 73.2,
65.2, 34.9; HRMS (TOF, ESþ) m/z [M þ H]þ calcd for
C10H13O3: 181.0865; found: 181.0871.
3-(Benzyloxy)-N-methoxy-N-methylpropanamide (9). A
mixture of 3-(benzyloxy)propanoic acid (25.4 g, 141 mmol),
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
(32.4 g, 169 mmol), 1-hydroxybenzotriazole (22.9 g, 169
mmol), N,N-diisopropylethylamine (54.7 g, 423 mmol), and
N,O-dimethylhydroxylamine hydrochloride (16.5 g, 169 mmol)
in DMF (125 mL) was stirred at ambient temperature for 3
days. After this time, the reaction was poured into water (1 L)
and extracted with ethyl acetate (2 ꢁ 750 mL). The combined
organic extracts were washed with water (1 L) then 5% aque-
ous lithium chloride (2 ꢁ 1 L), dried over sodium sulfate,
Initially, an iridium-catalyzed one-step cyclization pro-
cedure [8] was attempted to prepare 14, but the conditions
attempted (conditions a and b, Scheme 4) failed to pro-
vide acceptable yields. Alternatively, the two-step chlori-
nation/cyclization of 5 with thionyl chloride/NMP [15]
afforded 14 in excellent yield (condition c, Scheme 4).
Although the reaction of 14 with benzyne gave the
highest yield of 3 (condition a, Scheme 5) [16], a more
general palladium, catalyzed coupling reaction between
14 and halobenzene was desired. A survey of a variety
of coupling conditions was performed, yielding modest
results (conditions b–f, Scheme 5) [17].
The synthesis of lactam 15 using a rhodium-catalyzed
oxidative cyclization [9] is shown in Scheme 6. The liter-
ature conditions afforded a poor yield of 15 along with
unreacted starting material (condition a, Scheme 6).
Extending the reaction time (condition b, Scheme 6)
afforded an improved yield when the temperature is
increased (conditions c and d). N-Arylation of 15 with
phenyl iodide under standard Buchwald coupling condi-
tions [18] afforded the desired target 4 in moderate yield.
Analogs 3 and 4 were evaluated in a specific binding
assay of GABAA [19] receptors, which are responsible
for the majority of neuronal inhibition in the mammalian
CNS [20]. We were surprised to find that in spite of the
homology with known GABAA agonists, no noticeable
binding was observed from either compound. However,
we envision our method to be applicable to the prepara-
Scheme 1
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Synthesis of Novel Benzo[b]pyrazolo[1,5]diazepines
223
Scheme 2
filtered, and the filtrate was concentrated under reduced pres-
sure. The residue obtained was purified by chromatography
(silica, heptane to 1:1 ethyl acetate/heptane) to afford 3-(ben-
zyloxy)-N-methoxy-N-methylpropanamide (23.9 g, 76%) as
clear colorless liquid: 1H NMR (500 MHz, CDCl3): d 7.34–
7.31 (m, 4H), 7.30–7.25 (m, 1H), 4.55 (s, 2H), 3.83–3.79 (m,
2H), 3.68 (s, 3H), 3.19 (s, 3H), 2.76 (t, J ¼ 6.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3): d 172.3, 138.3, 128.4, 127.7, 127.6,
73.3, 65.9, 61.3, 32.5, 32.1; HRMS (TOF, ESþ) m/z [M þ
H]þ calcd for C12H18NO3: 224.1287; found: 224.1280.
5-(Benzyloxy)-1-(methoxy(methyl)amino)pent-1-en-3-one
(10). A solution of 0.5M ethynylmagnesium bromide in THF
(268 mL, 134 mmol) was added to 3-(benzyloxy)-N-methoxy-
N-methylpropanamide (23.9 g, 107 mmol) then the mixture
was heated at 50ꢀC for 40 min. The reaction was cooled to
ambient temperature, treated with saturated aqueous ammo-
nium chloride (220 mL), and then heated at 50ꢀC for 40 min.
After this time, the reaction was cooled to ambient tempera-
ture, extracted with ethyl acetate (800 mL), washed with brine
(800 mL), dried over sodium sulfate, filtered, and the filtrate
was concentrated under reduced pressure. The residue obtained
was purified by chromatography (silica, heptane to 7:3 ethyl
acetate/heptane) to afford 5-(benzyloxy)-1-(methoxy(methyl)
amino)pent-1-en-3-one (23.5 g, 88%) as orange liquid: 1H
NMR (500 MHz, CDCl3): d 7.39 (d, J ¼ 13.0 Hz, 1H), 7.33–
7.25 (m, 5H), 5.45 (d, J ¼ 12.5 Hz, 1H), 4.53 (s, 2H), 3.79
(t, J ¼ 6.5 Hz, 2H), 3.65 (s, 3H), 3.11 (s, 3H), 2.71 (t, J ¼ 6.5
Hz, 2H); 13C NMR (125 MHz, CDCl3): d 196.3, 147.9, 138.4,
128.3, 127.7, 127.5, 98.3, 73.1, 66.6, 59.9, 41.8, 39.7; HRMS
(TOF, ESþ) m/z [M þ H]þ calcd for C14H20NO3: 250.1443;
found: 250.1433.
(4-Chloro-2-nitrophenyl)hydrazine hydrochloride (12). A
mixture of concentrated hydrochloric acid (381 mL) and 4-
chloro-2-nitroaniline (50.0 g, 290 mmol) was treated with a so-
lution of sodium nitrite (20.0 g, 290 mmol) in water (190 mL)
dropwise at a rate such that the internal temperature was main-
tained below 10ꢀC. The resultant mixture was poured into a
solution of tin(II) chloride dihydrate (131 g, 579 mmol) in
concentrated hydrochloric acid (141 mL) at 0ꢀC and the result-
ant mixture was stirred at 0ꢀC for 3 min then allowed to warm
to ambient temperature over a period of 45 min. After this
time, the solid that formed was collected by filtration and
recrystallized from 2-propanol to afford (4-chloro-2-nitrophe-
nyl)hydrazine hydrochloride (39.3 g, 61%) as yellow solid: mp
1
188–194ꢀC; H NMR (500 MHz, DMSO-d6): d 9.29 (m, 4H),
8.14 (d, J ¼ 2.5 Hz, 1H), 7.81 (dd, J ¼ 9.5, 2.5 Hz, 1H), 7.41
Scheme 3
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Vol 49
Scheme 4. Conditions: (a) [Cl2IrCp(CH3)5]2, K2CO3, toluene, 111ꢀC,
19 h, 23%; (b) [Cl2IrCp(CH3)5]2, K2PO4, toluene, 111ꢀC, 18 h; 120ꢀC,
1 h, 25%; (c) (1) SOCl2, 1,2-DME, room temperature, 19 h; (2) NMP,
120ꢀC, 17 h, 88%.
Scheme 5. Conditions: (a) o-TMSC6H4OTf, CsF, CH3CN, room tem-
˚
perature, 3 days, 60%; (b) PhB(OH)2, Cu(OAc)2, Et3N, 3 A sieves,
CH2Cl2, room temperature, 2.5 days, trace; (c) PhI, Pd2(dba)3, Dave-
Phos, t-BuONa, toluene, 100ꢀC, 4 h, 26%; (d) PhBr, Pd(OAc)2,
BINAP, t-BuOK, toluene, 100ꢀC, 16 h, 23%; (e) PhBr, Pd2(dba)3,
DavePhos, t-BuONa, toluene, 100ꢀC, 4 h, 52%; (f) PhBr, Pd2(dba)3,
JohnPhos, t-BuONa, toluene, 80ꢀC, 16 h, 54%.
(d, J ¼ 9.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6): d
140.1, 135.5, 133.7, 125.0, 123.2, 117.4; HRMS (TOF, ESþ)
m/z [M þ H]þ calcd for C6H7ClN3O2: 188.0227; found:
188.0219.
5-(2-(Benzyloxy)ethyl)-1-(4-chloro-2-nitrophenyl)-1H-pyr-
azole (13a). A solution of 5-(benzyloxy)-1-(methoxy(methyl)a-
mino)pent-1-en-3-one (23.5 g, 94.3 mmol) in methanol (380
mL) at 0ꢀC was treated with (4-chloro-2-nitrophenyl)hydrazine
hydrochloride (25.3 g, 113 mmol) and the reaction was
warmed to reflux, treated with sodium carbonate (19.0 g, 179
mmol) in water (50 mL) over a 10-min period, and then stirred
at reflux for 1.5 h. After this time, the reaction was cooled to
ambient temperature and the volatiles were removed under
reduced pressure. The resulting solution was diluted with ethyl
acetate (750 mL), washed with water (700 mL) then brine
(700 mL), dried over sodium sulfate, filtered, and the filtrate
was concentrated under reduced pressure. The solid obtained
was triturated with 1:9 ethyl acetate/heptane to afford 5-(2-
(benzyloxy)ethyl)-1-(4-chloro-2-nitrophenyl)-1H-pyrazole (24.3
g, 72%) as light brown solid. The filtrate was concentrated
under reduced pressure and the residue obtained was purified
by chromatography (silica, heptane to 1:5 ethyl acetate/hep-
tane) to afford additional 5-(2-(benzyloxy)ethyl)-1-(4-chloro-2-
nitrophenyl)-1H-pyrazole (1.94 g, 6%) as red solid: mp 83–
85ꢀC; 1H NMR (500 MHz, CDCl3): d 7.93 (d, J ¼ 2.5 Hz,
1H), 7.61 (d, J ¼ 1.5 Hz, 1H), 7.58 (dd, J ¼ 8.5, 2.5 Hz, 1H),
7.44 (d, J ¼ 8.5 Hz, 1H), 7.35–7.28 (m, 3H), 7.24–7.22 (m,
2H), 6.30 (d, J ¼ 1.5 Hz, 1H), 4.45 (s, 2H), 3.67 (t, J ¼ 6.5
Hz, 2H), 2.85 (t, J ¼ 6.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3): d 146.7, 142.3, 141.7, 137.8, 135.4, 133.1, 131.6,
130.9, 128.4, 127.8, 127.7, 125.4, 106.3, 73.2, 68.7, 26.5;
HRMS (TOF, ESþ) m/z [M þ H]þ calcd for C18H17ClN3O3:
358.0958; found: 358.0951.
ide on carbon (614 mg, 50% water by weight) in THF (73
mL) was sparged with hydrogen for 5 min then stirred under
an atmosphere of hydrogen (balloon) at ambient temperature
for 16 h. After this time, the reaction was filtered through dia-
tomaceous earth and the filtrate was concentrated under
reduced pressure. The residue obtained was purified by chro-
matography (silica, methylene chloride to ethyl acetate) to
afford 2-(1-(2-amino-4-chlorophenyl)-1H-pyrazol-5-yl)ethanol
(1.44 g, 73%) as white solid: mp 113–115ꢀC; 1H NMR (500
MHz, DMSO-d6): d 7.60 (d, J ¼ 2.0 Hz, 1H), 7.05 (d, J ¼ 8.5
Hz, 1H), 6.89 (d, J ¼ 2.0 Hz, 1H), 6.64 (dd, J ¼ 8.5, 2.5 Hz,
1H), 6.31 (d, J ¼ 2.0 Hz, 1H), 5.12 (s, 2H), 4.69 (t, J ¼ 5.5
Hz, 1H), 3.54–3.51 (m, 2H), 2.59 (t, J ¼ 7.0 Hz, 2H); 13C
NMR (125 MHz, DMSO-d6): d 146.1, 141.5, 139.9, 133.6,
129.4, 122.8, 155.2, 114.7, 104.9, 59.5, 28.9; HRMS (TOF,
ESþ) m/z [M þ H]þ calcd for C11H13ClN3O: 238.0747; found:
238.0741.
Preparation of 8-chloro-5,6-dihydro-4H-benzo[b]pyrazolo
[1,5-d][1,4]diazepine (14). A mixture of thionyl chloride (751
mg, 6.31 mmol) in 1,2-dimethoxyethane (32 mL) was treated
with
2-(1-(2-amino-4-chlorophenyl)-1H-pyrazol-5-yl)ethanol
(500 mg, 2.10 mmol) in 1,2-dimethoxyethane (10 mL) drop-
wise over 1 h at ambient temperature then the reaction was
stirred at ambient temperature for 18 h. After this time, the
reaction was treated dropwise with 2M aqueous sodium hy-
droxide over 20 min (pH ꢂ 9) then the reaction was stirred at
ambient temperature for 40 min. The reaction was extracted
with ethyl acetate (150 mL then 75 mL) and the combined
extracts were dried over sodium sulfate, filtered and the filtrate
2-(1-(2-Amino-4-chlorophenyl)-1H-pyrazol-5-yl)ethanol (5). A
mixture of 5-(2-(benzyloxy)ethyl)-1-(4-chloro-2-nitrophenyl)-
1H-pyrazole (2.98 g, 8.33 mmol) and 20% palladium hydrox-
Scheme 6. Conditions: (a) acetone, sealed tube, 100ꢀC, 20 h, 14% yield, SM recovered; (b) acetone, sealed tube, 100ꢀC, 45 h, 32% yield, SM
recovered; (c) acetone, sealed tube, 120ꢀC, 15 h, 42% yield, SM recovered; (d) acetone, sealed tube, 140ꢀC, 7.5 h, 45% yield, SM recovered.
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Synthesis of Novel Benzo[b]pyrazolo[1,5]diazepines
225
was concentrated under reduced pressure to afford 5-chloro-2-
(5-(2-chloroethyl)-1H-pyrazol-1-yl)aniline (550 mg, quant.,
98% pure by mass) as yellow oil which was used without fur-
acetate/heptane) to afford 8-chloro-4H-benzo[b]pyrazolo[1,5-
d][1,4]diazepin-5(6H)-one (53 mg, 45%) as off-white solid:
1
mp >250ꢀC; H NMR (300 MHz, DMSO-d6): d 10.36 (s, 1H),
1
ther purification: H NMR (500 MHz, CDCl3): d 7.68 (d, J ¼
7.83–7.79 (m, 2H), 7.38 (dd, J ¼ 9.0, 2.4 Hz, 1H), 7.31 (d, J
¼ 2.4 Hz, 1H), 6.43 (d, J ¼ 1.5 Hz, 1H), 3.70 (s, 2H); 13C
NMR (75 MHz, DMSO-d6): d 169.1, 142.3, 137.2, 131.2,
130.7, 129.7, 125.1, 124.8, 121.8, 105.5, 32.9; HRMS (TOF,
ESþ) m/z [M þ H]þ calcd for C11H9ClN3O: 234.0434; found:
234.0439.
2.0 Hz, 1H), 7.02 (d, J ¼ 8.5 Hz, 1H), 6.84 (d, J ¼ 2.0 Hz,
1H), 6.78 (dd, J ¼ 8.0, 2.0 Hz, 1H), 6.35 (d, J ¼ 1.5 Hz, 1H),
3.90 (br s, 2H), 3.62 (t, J ¼ 7.0 Hz, 2H), 3.01 (t, J ¼ 7.5 Hz,
2H); HRMS (TOF, ESþ) m/z [M
þ
H]þ calcd for
C11H12Cl2N3: 256.0408; found: 256.0402.
A
solution of 5-chloro-2-(5-(2-chloroethyl)-1H-pyrazol-1-
8-Chloro-6-phenyl-4H-benzo[b]pyrazolo[1,5-d][1,4]diaze-
pin-5(6H)-one (4). A mixture of 8-chloro-4H-benzo[b]pyra-
zolo[1,5-d][1,4]diazepin-5(6H)-one (51 mg, 0.218 mmol),
cesium carbonate (213 mg, 0.654 mmol), and copper(I) iodide
(8 mg, 0.044 mmol) in 1,4-dioxane (1.5 mL) was treated with
iodobenzene (133 mg, 0.654 mmol) and trans-cyclohexane-
1,2-diamine (5 mg, 0.044 mmol) and the resulting mixture
was sparged with argon for 2 min then stirred at 102ꢀC for 48
h. After this time, the reaction was cooled to ambient temper-
ature, diluted with methylene chloride (10 mL), filtered
through diatomaceous earth, rinsed with 1:9 methanol/methyl-
ene chloride (50 mL), and the filtrate was concentrated under
reduced pressure. The residue obtained was purified by chro-
matography (silica, methylene chloride to 1:9 ethyl acetate/
methylene chloride), solvent exchanged with acetonitrile, and
freeze dried from acetonitrile/water to afford 8-chloro-6-
phenyl-4H-benzo[b]pyrazolo[1,5-d][1,4]diazepin-5(6H)-one (25
mg, 37%) as off-white solid: mp 83–84ꢀC; 1H NMR (500
MHz, DMSO-d6): d 7.88–7.83 (m, 2H), 7.49–7.34 (m, 4H),
7.17–7.15 (m, 2H), 6.94 (d, J ¼ 2.5 Hz, 1H), 6.51 (d, J ¼ 1.5
Hz, 1H), 3.92–3.81 (m, 2H); 13C NMR (75 MHz, DMSO-d6):
d 167.2, 142.7, 141.4, 138.2, 134.8, 131.5, 131.1, 129.4,
128.3, 127.6, 126.5, 125.8, 125.5, 105.5, 33.3; HRMS (TOF,
ESþ) m/z [M þ H]þ calcd for C17H13ClN3O: 310.0747; found:
310.0745.
yl)aniline (550 mg, 2.10 mmol, 98% pure by mass) in 1-
methyl-2-pyrrolidinone (70 mL) was stirred at 120ꢀC for 17 h.
After this time, the reaction was cooled to ambient tempera-
ture, diluted with water (400 mL) and extracted with ethyl ace-
tate (400 mL). The organic layer was washed with water (2 ꢁ
400 mL), 5% aqueous lithium chloride (3 ꢁ 400 mL) then
brine (400 mL), dried over sodium sulfate, filtered, and the fil-
trate was concentrated under reduced pressure. The residue
obtained was purified by chromatography (silica, methylene
chloride to 1:9 ethyl acetate/methylene chloride) to afford 8-
chloro-5,6-dihydro-4H-benzo[b]pyrazolo[1,5-d][1,4]diazepine
1
(407 mg, 88%) as off-white solid: mp 94–96ꢀC; H NMR (500
MHz, CDCl3): d 7.78 (d, J ¼ 8.5 Hz, 1H), 7.58 (d, J ¼ 1.5
Hz, 1H), 6.89 (dd, J ¼ 8.5, 2.0 Hz, 1H), 6.77 (d, J ¼ 2.0 Hz,
1H), 6.18 (d, J ¼ 1.5 Hz, 1H), 3.91 (br s, 1H), 3.68–3.65 (m,
2H), 3.01 (t, J ¼ 5.5 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d 142.1, 140.3, 138.8, 132.3, 125.6, 120.1, 119.4, 105.1, 48.7,
25.3; HRMS (TOF, ESþ) m/z [M
C11H11ClN3: 220.0642; found: 220.0648.
þ
H]þ calcd for
8-Chloro-6-phenyl-5,6-dihydro-4H-benzo[b]pyrazolo[1,5-d]
[1,4]diazepine (3). A mixture of 8-chloro-5,6-dihydro-4H-ben-
zo[b]pyrazolo[1,5-d][1,4]diazepine (120 mg, 0.546 mmol),
tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.009 mmol),
2-(di-tert-butylphosphino)biphenyl (7 mg, 0.022 mmol), so-
dium tert-butoxide (61 mg, 0.637 mmol), and bromobenzene
(71 mg, 0.455 mmol) in toluene (1.5 mL) was stirred at 80ꢀC
for 16 h. After this time, the reaction was cooled to ambient
temperature, diluted with ethyl acetate (50 mL), and filtered
through diatomaceous earth. The filtrate was concentrated
under reduced pressure and the residue obtained was purified
by chromatography (silica, heptane to 2:3 ethyl acetate/hep-
tane) to afford 8-chloro-6-phenyl-5,6-dihydro-4H-benzo[b]pyr-
azolo[1,5-d][1,4]diazepine (73 mg, 54%) as clear colorless
film: 1H NMR (500 MHz, CDCl3): d 7.71 (d, J ¼ 8.5 Hz,
1H), 7.60 (d, J ¼ 2.0 Hz, 1H), 7.29–7.26 (m, 2H), 7.20–7.16
(m, 2H), 6.87–6.84 (m, 1H), 6.77 (dd, J ¼ 8.5, 1.0 Hz, 2H),
6.23 (d, J ¼ 1.5 Hz, 1H), 3.97 (t, J ¼ 6.5 Hz, 2H), 3.00 (t, J
¼ 6.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): d 148.7, 140.9,
140.6, 139.6, 135.8, 133.0, 128.9, 128.9, 126.2, 125.4, 120.4,
117.4, 104.9, 53.9, 23.8; HRMS (TOF, ESþ) m/z [M þ H]þ
calcd for C17H15ClN3: 296.0955; found: 296.0947.
8-Chloro-4H-benzo[b]pyrazolo[1,5-d][1,4]diazepin-5(6H)-
one (15). A mixture of 5-(2-(benzyloxy)ethyl)-1-(4-chloro-2-
nitrophenyl)-1H-pyrazole (119 mg, 0.500 mmol), potassium
carbonate (7 mg, 0.050 mmol), and dichloro(pentamethylcyclo-
pentadienyl)rhodium(III) dimer (8 mg, 0.013 mmol) in acetone
(12.5 mL) was sparged with nitrogen for 10 min then it was
stirred at 140ꢀC in a heavy walled pressure vessel for 7.5 h.
After this time, the reaction was cooled to ambient temperature
and concentrated under reduced pressure. The residue obtained
was purified by chromatography (silica, heptane to 1:1 ethyl
Acknowledgment. The authors thank the Department of Medici-
nal Chemistry at AMRI for funding.
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