An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)- ones

Article abstract of DOI:10.1039/c1ob06353g

An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)- ones has been developed using intramolecular 1,3-dipolar cycloaddition. The hydrazonoyl chloride, the precursor of the cycloadduct, is accessed easily through a two-step reaction carried out in one-pot. It is then used without purification for the base induced formation of the nitrilimine, which undergoes subsequent in situ intramolecular cycloaddition with an alkyne to afford the desired product. The reaction protocol has also been applied in bis-heteroannulation and in the synthesis of uracil derivatives of biological interest. The operational simplicity of the process, the use of cheap starting materials, and the relatively short reaction times required make the process convenient and practical. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06353g

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PAPER
An efficient strategy for the general synthesis of 3-aryl substituted
pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-
6(4H)-ones†‡
Kaushik Brahma,§ Anup Kumar Sasmal§ and Chinmay Chowdhury*
Received 9th August 2011, Accepted 6th September 2011
DOI: 10.1039/c1ob06353g
An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and
pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones has been developed using intramolecular 1,3-dipolar
cycloaddition. The hydrazonoyl chloride, the precursor of the cycloadduct, is accessed easily through a
two-step reaction carried out in one-pot. It is then used without purification for the base induced
formation of the nitrilimine, which undergoes subsequent in situ intramolecular cycloaddition with an
alkyne to afford the desired product. The reaction protocol has also been applied in
bis-heteroannulation and in the synthesis of uracil derivatives of biological interest. The operational
simplicity of the process, the use of cheap starting materials, and the relatively short reaction times
required make the process convenient and practical.
etc.). For example, flumazenil5 1 is used as an antihistaminic
Introduction
compound, while bretazenil6 2 is popular for its potential use
1,4-Benzoxazines have attracted considerable interest in recent
against neurodegenerative diseases (Fig. 1).
times because of their presence as a key structural component
in numerous biological and therapeutic compounds. Notable
examples are actinomycin D – an anticancer drug isolated from
Streptomyces,1a C-1027 – a potent antitumor chromprotein iso-
lated from Streptomyces globisporus C-1027,1b and benzoxazino-
rifamycin KRM-1648 known for antitubercular activities,1c besides
flumioxazin and thidiazimin used as herbicides.1d Additionally,
tricyclic pyrazolo-benzoxazines have been described as inhibitors
of mitotic kinesin2a and viral replications2b in recent patents,
while imidazolo-benzoxazines have been identified as modulators
of 5-HT1 receptors.2c Parallel to this, 1,4-benzodiazepin-5-ones
Fig. 1 Some important fused 1,4-benzodiazepin-5-ones and analogues.
are considered to constitute a privileged structure in medicinal
chemistry3 as they hit various pharmacologically significant
targets (e.g., enzymes, ion channels, GPCRs etc.). Thus this
class of compounds has been well recognised for the broad
range of activities such as anti-tumor,4a anti-depressant,4b anti-
insectan,4c analgesic,4d fibrinogenic receptor antagonist,4e etc.
The range of their therapeutic activities has been increased
further through development of scaffolds via fusion with different
nitrogen heterocycles (e.g., imidazole, triazole, oxazole, pyrimidine
Though there are many synthetic approaches towards 1,4-
benzoxazines,7 1,4-benzodiazepin-5-ones,8 and pyrazoles,9 only
few synthetic methods are available for pyrazoles fused
with 1,4-benzoxazine10 or 1,4-benzodiazepinone.11 Garanti
et al. reported the synthesis of 2-substituted 4H-pyrazolo[5,1-
c][1,4]benzoxazines10a from 1-nitro- and 1-phenylsulfonyl-N-[2-
(2-propynyloxy)phenyl]hydrazones through the intramolecular
cycloaddition of nitrilimines with terminal alkynes. The same
group reported the synthesis of 2-carbethoxy-4H-pyrazolo[5,1-
c][1,4]benzoxazines 3 (R1 = H/Ph) based on nitrilimine cy-
cloaddition utilising substituted ethylenes10b and acetylenes10c
as dipolarophiles. However, both of the approaches involved
harsh reaction conditions like prolonged heating (up to 108 h).
In addition, only one 3-substituted derivative (R1 = Ph)
of pyrazolo[5,1-c][1,4]benzoxazine 3 was reported,10b–c demon-
strating that the methodologies lacked generality. Recently,
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja
S. C. Mullick Road, Kolkata-700032, India. E-mail: chinmay@iicb.res.in
† Dedicated to Prof. Nitya. G. Kundu on the occasion of his 75th birth
anniversary.
‡ Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data and NMR spectra. CCDC reference
number 838046. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06353g
§ Contributed equally.
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a synthetic method for pyrido-/quinolino-fused pyrazolo[5,1-
c][1,3]benzoxazines has been reported.12 On the other hand,
pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones11a 4 (R1 = H, R2 =
Me) and the corresponding optically active 3,3a-dihydro
analogues13 were synthesised adopting the strategy of intramolec-
ular cycloaddition of nitrilimines with substituted ethylenes. To the
best of our knowledge, there is no report about the synthesis of 3-
substituted derivatives of 4. Therefore, there is an urgent need for
a general, convenient and practical method for the synthesis of 3-
substituted pyrazolo[5,1-c][1,4]benzoxazines 3 and pyrazolo[1,5-
a][1,4]benzodiazepin-6(4H)-ones 4.
The strategy adopted for the synthesis of targeted com-
pounds 3, 4 had its origin in our recent successful ef-
forts for the synthesis of 1,2,3-triazoles fused with vari-
ous heterocycles such as isoindoline,14a morpholine,14b 1,4-
benzoxazine,14c 1,4-benzodiazepin-5-one,14d 1,5-benzodiazocin-6-
one14d and piperazine14e using the intramolecular cycloaddition of
azide with suitably designed alkynes. We realised that the azide
can be replaced as the 1,3-dipole by a nitrilimine, which has been
applied popularly in the synthesis of different azole derivatives.15
With this in mind, we attempted to explore the potential of
the intramolecular cycloaddition of nitrilimines with alkynes,
culminating in the general synthesis of 3-substituted pyrazolo-
1,4-benzoxazine/[1,4]benzodiazepin-6(4H)-ones 3/4. We describe
herein the results obtained in this attempt.
The results prompted us to find an alternative “one-pot
strategy” as depicted under Scheme 2. Thus, 2-(3-phenylprop-2-
ynyloxy)aniline 8a (Ar = Ph), prepared in turn from amine 7a by
palladium catalysed Sonogashira reaction,16 was allowed to un-
dergo diazotisation and subsequent Japp–Klingemann reaction17
using ethyl 2-chloroacetoacetate followed by heating at 100 ◦C or
higher temperature (adding a high-boiling solvent) in the presence
of excess amounts of different types of bases. Once again no sign of
the formation of any product 3a was observed; only a tarry product
was encountered. In this context, it is noteworthy that smooth
conversion to a transient intermediate species 10a (Ar = Ph) was
evident from TLC monitoring and product isolation; however,
subsequent heating to effect cycloaddition possibly triggered the
formation of a tarry material instead of the product. Therefore, we
isolated the intermediate 10a (Ar = Ph) from the reaction mixture
as crude through standard work-up and then refluxed it in xylene
in the presence of Et3N (5.0 equiv.) as base. To our gratification,
it underwent cycloaddition smoothly within 6 h, affording the
product 3a with 49% yield starting from substrate 8a. We then
decided to pursue this strategy for the general synthesis of 3,4
with slight modification (discussed below) in the cycloaddition
step to reduce the reaction times and enhance the yields as well.
Results and discussion
At the outset, we chose to use propargylated hydrazonoyl chlorides
5a–b as substrates. We anticipated that substrate 5a (or 5b)
could undergo palladium catalysed C-arylation at the terminal
alkyne with initial base induced formation of nitrilimine followed
by in situ intramolecular cycloaddition, leading to the targeted
product 3 (or 4) in one pot (Scheme 1). To assess the idea, we
initiated a model study of the reaction between 5a and phenyl
iodide 6a under various reaction conditions employing copper(I)
iodide, palladium catalyst [e.g., Pd(PPh3)2Cl2, Pd(OAc)2/PPh3,
Pd(PPh3)4, PdCl2/PPh3, Pd-C/PPh3, etc.] and base [e.g., Et3N,
piperidine, pyridine, K2CO3/Bu4NBr, Cs2CO3/Bu4NBr etc.]. To
our surprise, these merely culminated in the polymerisation of
substrates leading to tarry products, furnishing (in few cases) the
C-phenylated product at the terminal alkyne (of 5a) in low yields
(10–15%). Replacing the substrate 5a by 5b also did not improve
the situation as neither the product 4a was formed nor did the
starting materials survive.
Scheme 2 Synthesis of the products 3–4. Reagents and conditions: i)
Pd(PPh3)2Cl2, CuI, Et3N, DMF (used only for product 9), rt, 2–6 h; ii)
a) NaNO2, HCl, 0–5 ◦C, 1 h; then b) ethyl 2-chloroacetoacetate, rt, 4–5 h;
iii) Condition A: NaOAc, Bu4NBr, chlorobenzene, 135 ◦C, 20–60 min;
Condition B: Et3N, xylene, 140 ◦C, 2.5–4.0 h.
The requisite starting substrates 8a–l could be derived via
palladium catalysed reaction of 2-(prop-2-ynyloxy)aniline 7a with
a variety of aryl iodides 6a–l at room temperature for few hours
(Scheme 2). Next, diazotisation followed by Japp–Klingemann
reaction could be smoothly conducted in one pot, affording the
intermediate 10, the precursor compound of cycloadduct 3. To
find out the optimised reaction conditions for cycloaddition,
we tested the cycloaddition of crude intermediate 10a (Ar =
Ph) by varying the solvents and bases (for details see screening
studies in the ESI‡). Pleasingly, we observed that cycloaddition
affording the product 3a (53%) could be completed within 30
min only, through the employment of sodium acetate (4.0 equiv.)
and Bu4NBr (10 mol%) in chlorobenzene under reflux (condition
A, Scheme 2). Next we used these optimised reaction conditions
Scheme 1 Attempted synthesis of products 3a and 4a.
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for the synthesis of products 3b–l (Table 1). Various functional
groups including both electron donating (e.g., OMe, Me) and
electron withdrawing (e.g., CO2Me, NO2, F, CF3) types were
well tolerated. The electron withdrawing functional groups in
the aryl moiety (6 and 8) afforded higher yields compared to
electron donating groups in both Sonogashira and cycloaddition
reactions (Table 1, entries 6, 7, 10, 11 vs. 5, 8). Cycloadditions
were usually found to be complete within 20–30 min only (except
entry 8, Table 1). Interestingly, when the dialkynyl compound 8l
(derived from Sonogashira reaction using 1,2-diiodobenzene 6l)
was submitted to this reaction, a bis-benzoxazinyl derivative 3l
was formed (Table 1, entry 12), indicating the process to be viable
for polyheteroannulation reactions.
tion took place resulting in 5-substituted uracil derivatives 12 and
13, respectively (Scheme 3). Thus, we have enlarged the scope of
the reactions through the synthesis of novel uracil derivatives of
potential biological interest.21
The above reaction could be applied to the synthesis of
pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones 4 as well (Scheme
2 and Table 2). Accordingly, alkyne 9, produced from substrate
7b via palladium catalysed reaction, was subjected to one pot
diazotisation and subsequent Japp–Klingemann reaction to access
the intermediate 11 as per the earlier protocol. However, unlike
the previous systems, use of Et3N and xylene as base and solvent
prov◦ed to be the best conditions in this case. Thus refluxing (138–
140 C) the crude intermediate 11 in xylene for few hours in the
presence of Et3N (6.0 equiv.) furnished the targeted product 4 with
moderate yields. As can be seen from Table 2, various functional
groups (e.g., Me, OMe, F, NO2) were found to be compatible with
this reaction. Apparently, the electron donating substituents in
the aryl moiety of intermediate 11 ensured slightly better yields
of product 4 as compared to electron withdrawing groups (Table
2, entries 3, 4, 6 vs. 5, 8). In contrast to our earlier observations
(Table 1), the time period for cycloaddition to give product 4 was
somewhat higher, possibly because a seven membered product is
formed.
Scheme 3 Synthesis of uracil derivatives 12–13.
Conclusion
In conclusion, we have disclosed an elegant strategy for the general
synthesis of 3-substituted pyrazolo[5,1-c][1,4]benzoxazines and
pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones. A wide variety of
functionalised derivatives were synthesised. The intermediate hy-
drazonoyl chlorides, the precursor compounds of the cycloadduct,
could easily be accessed through a two-step reaction carried out
in one pot. The resulting crude product was used directly for
the subsequent cycloaddition step. This reaction protocol has
been applied for a bis-heteroannulation process also. The scope
of this reaction has also been demonstrated by the synthesis of
uracil derivatives of potential biological interest. The operational
simplicity of the process, coupled with the use of cheap starting
materials and relatively short reaction times makes the process
convenientandpractical. We believe that this reaction strategymay
find application in library generation based on diversity oriented
synthesis for lead development.
The structures of the products 3,4 were well characterised by
spectral (1H and 13C NMR, IR, and mass spectra) and analytical
data. Single crystal X-ray diffraction analysis18 of product 3j lent
further support to this (Fig. 2).‡
Experimental section
General procedure (condition A) for the synthesis of 3-aryl
substituted pyrazolo[5, 1-c][1,4]benzoxazines 3
To an ice-cooled (0–5 ◦C) solution of 8 (0.85 mmol) in MeOH
(1.5 mL), 6 M hydrochloric acid (0.5 mL) and NaNO2 (117 mg,
1.70 mmol) were added successively, and the reaction mixture
was allowed to stir at this temperature for one hour. The acidity
of the medium was then adjusted to pH 5 by careful addition
of sodium acetate. Next, a solution of ethyl 2-chloroacetoacetate
(0.12 mL, 0.85 mmol) in MeOH (1 mL) was added dropwise and
the mixture was allowed to stir vigorously at room temperature.
After completion (4 h) of the reaction, the solvent was removed
under reduced pressure and the residue was extracted with EtOAc
(2 ¥ 15 mL). The organic extracts were washed with saturated
aqueous NaHCO3 solution (15 mL) followed by water (30 mL),
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The resulting crude intermediate 10 was then
used directly. Thus, a solution of the product 10 in chlorobenzene
(4 mL) was refluxed in the presence of NaOAc (278 mg, 3.40 mmol)
and n-Bu4NBr (27 mg, 0.08 mmol) until complete consumption
of the starting material (TLC). After removal of the solvent, it
was extracted with ethyl acetate (3 ¥ 20 mL) and the combined
Fig. 2 ORTEP representation of product 3j.
In view of the immense biological activities of 5-substituted
uracils19 and because of our own interest20 in the development
of bioactive molecules, some of the synthesised compounds were
converted into novel uracil derivatives. When products 3i and 4g
were treated separately with chlorotrimethylsilane and sodium
iodide in dry acetonitrile at room temperature, a facile demethyla-
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Table 1 Synthesis of pyrazolo[5,1-c][1,4]benzoxazines 3 through intermediate 8
Entry
1
Aryl Iodide (6) Ar
Productsa 8 (Yield%)b
8a (89)
Productsc 3 (Yield%)d
3a (53)
Heating time
30 min
Overalle (Yield%)
47
2
3
8b (81)
8c (92)
3b (64)
3c (45)
30 min
30 min
52
41
4
5
8d (83)
8e (69)
3d (46)
3e (43)
20 min
20 min
38
30
6
8f (92)
3f (51)
20 min
47
7
8
8g (74)
8h (70)
3g (50)
3h (47)
25 min
37
33
1 h
9
8i (84)
8j (96)
3i (44)
3j (64)
25 min
30 min
37
61
10
11
8k (89)
3k (61)
30 min
54
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Table 1 (Contd.)
Entry
12
Aryl Iodide (6) Ar
Productsa 8 (Yield%)b
8l (51)
Productsc 3 (Yield%)d
Heating time
20 min
Overalle (Yield%)
18
a Reaction conditions: iodide 6 (1.0 mmol), acetylene 7a (1.2 mmol), Pd(PPh3)2Cl2 (0.03 mmol), CuI (0.05 mmol) in dry Et3N (4 mL) stirred at rt for
2–6 h. b Chromatographically isolated pure products. c Reaction conditions: 8 (0.85 mmol) in methanol (1.5 mL), 6 M hydrochloric acid (0.5 mL), NaNO2
(1.70 mmol) stirred at 0–5 ◦C for 1 h. After adjusting the pH of the reaction mixture to 5.0, ethyl 2-chloroacetoacetate (0.85 mmol) in MeOH (1 mL)
was added and then stirred at rt for 4h. After usual work-up a crude product 10 was obtained. The crude product in chlorobenzene (4 mL) was heated
under reflux in the presence of NaOAc (3.4 mmol) and Bu4NBr (0.085 mmol). d Yields of isolated pure products based on the alkyne 8. e Overall yield
was calculated based on starting iodide 6.
organic extracts were dried over anhydrous Na2SO4, filtered and
concentrated. Finally, the crude residue was purified by silica gel
(100–200 mesh) column chromatography using 4–30% EtOAc in
petroleum ether (v/v) as eluent.
2-Carbethoxy-3-(2-methyl-4-nitrophenyl)-4H-pyrazolo[5,1-c]-
[1,4]benzoxazine (3j). Yield: 64%; solid, m.p.: 192–194 ◦C; IR
1
(KBr): 2990, 1720, 1605, 1514, 1343, 1227, 1181, 860 cm-1; H
NMR (CDCl3, 600 MHz): d 1.23 (t, J = 7.2 Hz, 3H), 2.29 (s, 3H),
4.28–4.31 (m, 2H), 5.05 (d, J = 13.8 Hz, 1H), 5.13 (d, J = 14.4 Hz,
1H), 7.09 (d, J = 7.8 Hz, 1H), 7.16 (td, J = 1.2, 7.8 Hz, 1H), 7.25
(td, J = 1.2, 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1 H), 8.06 (dd, J =
1.2, 7.8 Hz, 1H), 8.09 (dd, J = 2.4, 8.4 Hz, 1H), 8.18 (d, J = 1.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz): 13.9, 20.2, 61.3, 61.8, 116.6,
117.6, 118.6, 120.6, 123.1, 124.6, 125.8, 128.1, 131.1, 132.4, 137.4,
139.5, 142.1, 146.3, 147.7, 161.5; ESI-MS: m/z 402.03 [M+Na]+;
Anal. Calcd. for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found:
C, 63.28; H, 4.48; N, 11.14.
2-Carbethoxy-3-phenyl-4H -pyrazolo[5◦,1-c][1,4]benzoxazine10c
(3a). Yield: 53%; solid, m.p.: 114–116 C (lit.10c 112 ◦C); IR
1
(KBr): 2989, 1714, 1605, 1495, 1386, 1227, 1164 cm-1; H NMR
(CDCl3, 300 MHz): d 1.29 (t, J = 7.1 Hz, 3H), 4.35 (q, J =
7.1 Hz, 2H), 5.24 (s, 2H), 7.08 (td, J = 1.2, 7.2 Hz, 1H), 7.14
(dd, J = 1.4, 7.7 Hz, 1H), 7.21 (td, J = 1.5, 7.7 Hz, 1H), 7.32–7.35
(m, 2H), 7.37–7.45 (m, 3H), 8.05 (dd, J = 1.5, 7.8 Hz, 1H); 13C
NMR (CDCl3, 75 MHz): d 14.1, 61.1, 62.1, 116.6, 117.5, 121.6,
122.8, 125.9, 127.66, 127.7, 128.1, 129.7, 130.3, 132.1, 141.7, 146.4,
162.1; ESI-MS: m/z 343.11 [M+Na]+; HRMS (EI, 70 eV) calcd
for C19H16N2O3 [M+] 320.1161, found 320.1158.
2-Carbethoxy-3-(4-carbomethoxyphenyl)-4H -pyrazolo[5,1-c]-
[1,4]benzoxazine (3k). Yield: 61%; solid, m.p.: 150–152 ◦C; IR
1
(KBr): 2990, 1720, 1612, 1494, 1365, 1284, 1170, 863 cm-1; H
2-Carbethoxy-3-(naphthalene-1-yl)-4H-pyrazolo[5,1-c][1,4]ben-
zoxazine (3b). Yield: 64%; solid, m.p.: 116–118 ◦C; IR (KBr):
NMR (CDCl3, 300 MHz): d 1.29 (t, J = 7.1 Hz, 3H), 3.95 (s,
3H), 4.35 (q, J = 7.2 Hz, 2H), 5.24 (s, 2H), 7.07–7.16 (m, 2H),
7.21 (dd, J = 1.4, 7.7 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 8.05
(dd, J = 1.4, 7.9 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d 14.0, 52.1, 61.2, 61.9, 116.7, 117.5, 120.6,
122.9, 125.8, 127.9, 129.3, 129.8, 132.4, 135.2, 141.7, 146.4, 161.9,
166.7; ESI-MS: m/z 401.36 [M+Na]+; HRMS (EI, 70 eV) calcd
for C21H18N2O5 [M+] 378.1216, found 378.1216.
1
2975, 1720, 1605, 1505, 1388, 1232, 1171, 1022 cm-1; H NMR
(CDCl3, 600 MHz): d 0.85 (t, J = 6.9 Hz, 3H), 4.05–4.13 (m, 2H),
5.06 (d, J = 13.8 Hz, 1H), 5.11 (d, J = 13.8 Hz, 1H) 7.07 (dd, J =
1.2, 8.4 Hz, 1H), 7.16 (td, J = 1.2, 7.8 Hz, 1H), 7.23 (td, J = 1.8,
7.8 Hz, 1H), 7.40 (dd, J = 1.2, 7.2 Hz, 1H), 7.42–7.45 (m, 1H),
7.48–7.54 (m, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz,
2H), 8.13 (dd, J = 1.8, 7.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz):
d 13.5, 60.8, 62.2, 116.7, 117.6, 119.1, 122.9, 125.1, 125.3, 125.9,
126.0, 126.3, 127.8, 127.9, 128.2, 128.3, 128.5, 132.4, 133.1, 133.5,
143.4, 146.4, 161.8; HRMS (EI, 70 eV) calcd for C23H18N2O3 [M+]
370.1317, found 370.1310.
General procedure (condition B) for the synthesis of 3-aryl
substituted pyrazolo[l,5-a][1,4]benzodiazepin-6(4H)-ones 4. To a
well stirred and cooled (0–3 ◦C) solution of 9 (0.50 mmol) in
2 M hydrochloric acid (8.0 mL) was added a solution of NaNO2
(48 mg, 0.70 mmol) in 2 mL H2O dropwise during 45 min and the
reaction mixture was allowed to stir for another 30 min at the same
temperature. Ethyl 2-chloroacetoacetate (90 mg, 0.55 mmol) was
added dropwise (during 2–3 min) at 0–3 ◦C. The temperature of the
reaction mixture was then allowed to attain room temperature (rt)
and stirred for another 5 h. It was then extracted with ethyl acetate
(2 ¥ 20 mL). The organic extracts were washed with water, dried
over Na2SO4, filtered and concentrated in vacuo. The resulting
crude product was refluxed (138–140 ◦C) in xylene (5.0 mL)
in the presence of triethylamine (0.42 mL, 3.0 mmol) for few
hours. Upon completion of the reaction (TLC), the solvent was
removed in vacuo and extracted with ethyl acetate (2 ¥ 20 mL).
2-Carbethoxy-3-(4-fluorophenyl)-4H-pyrazolo[5,1-c][1,4]benzo-
xazine (3g). Yield: 50%; solid, m.p.: 146–147 ◦C; IR (KBr): 2984,
1
1716, 1599, 1500, 1390, 859 cm-1; H NMR (CDCl3, 300 MHz):
d 1.31 (t, J = 7.2 Hz, 3H), 4.35 (q, J = 7.1 Hz, 2H), 5.21 (s, 2H),
7.06–7.16 (m, 4H), 7.22 (td, J = 1.5, 7.7 Hz, 1H), 7.29–7.34 (m,
2H), 8.04 (dd, J = 1.5, 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d 14.1, 61.1, 61.9, 115.1 (d, J = 21.75 Hz), 116.6, 117.5, 120.7,
122.9, 125.9, 126.2 (d, J = 3.4 Hz), 127.8, 131.5 (d, J = 8.3 Hz),
132.2, 141.6, 146.4, 162.0, 162.4 (d, J = 246 Hz); ESI-MS: m/z
360.99 [M+Na]+; HRMS (EI, 70 eV) calcd for C19H15FN2O3 [M+]
338.1067, found 338.1053.
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Table 2 Synthesis of pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones 4 through intermediate 9
Entry
1
Aryl Iodide (6) Ar
Productsa 9 (Yield%)b
9a (85)
Productsc 4 (Yield%)d
4a (43)
Heating time
3.5 h
Overalle (Yield%)
37
2
3
4
9b (87)
9c (71)
9d (82)
4b (57)
4c (45)
4d (48)
3.5 h
3.5 h
4.0 h
50
32
39
5
9e (72)
4e (41)
2.5 h
30
6
7
9f (72)
9g (74)
4f (42)
4g (37)
2.5 h
4.0 h
30
27
8
9h (80)
4h (38)
2.5 h
30
a Reaction conditions: iodide 6 (1.0 mmol.), acetylene 7b (1.05 mmol), Pd(PPh3)2Cl2 (0.04 mmol), CuI (0.06 mmol), Et3N (7.0 mmol) in dry DMF (4 mL)
stirred at rt for 2 h. b Chromatographically isolated pure products. c Reaction conditions: 9 (0.50 mmol), 2 M hydrochloric acid (5 mL), aqueous solution of
NaNO2 (1.4 equiv.), stirred at 0–3 ◦C for 30 min. Ethyl 2-chloroacetoacetate (0.55 mmol) was added followed by stirring at rt for 5 h. After usual work-up
a crude product 11 was obtained and it was heated in xylene (5 mL) under reflux (140 ◦C) in the presence of Et3N (6.0 equiv.). d Chromatographically
isolated pure products and yields were calculated based on the alkyne 9. e Overall yield was calculated based on starting iodide 6.
The combined organic extracts were washed with water (15 mL),
dried over Na2SO4, filtered and concentrated. The resulting crude
product was purified through silica gel (100–200 mesh) column
chromatography (40–50% ethyl acetate in petroleum ether, v/v) to
furnish the desired product 4.
(m/z) 384.19 (M+Na+). Anal. Calcd for C21H19N3O3: C, 69.79; H,
5.30; N, 11.63; Found: C, 69.81; H, 5.33; N, 11.60.
2-Carbethoxy-5-methyl-3-(1-naphthyl)-pyrazolo[l,5-a][1,4]ben-
zodiazepin-6(4H)-one (4b). Yield 57%; Solid, mp 105–107 ◦C;
1H NMR (300 MHz, CDCl3) d 0.83 (t, J = 7.1 Hz, 3H), 2.99 (s,
3H), 4.04–4.13 (m, 4H), 7.38–7.46 (m, 2H), 7.49–7.60 (m, 4H),
7.70 (td, J = 7.4, 1.5 Hz, 1H), 7.94 (t, J = 7.2 Hz, 2H), 8.04 (d,
J = 7.8 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 13.3, 35.7, 42.2, 60.6, 120.4, 122.8, 124.9, 125.4, 125.9,
126.2, 127.5, 127.9, 128.0, 128.1, 128.5, 128.6, 131.7, 132.3, 132.9,
133.3, 135.3, 140.5, 143.6, 161.4, 166.6; IR (KBr, cm-1) 2981, 1725,
1643, 1480, 1168; MS (ESI) (m/z) 434.24 (M+Na+). Anal. Calcd
for C25H21N3O3: C, 72.98; H, 5.14; N, 10.21. Found: C, 72.94; H,
5.12; N, 10.25.
2-Carbethoxy-5-methyl-3-phenyl-pyrazolo[l,5-a][1,4]benzodia-
zepin-6(4H)-one (4a). Yield 43%; Solid, mp 134–136 ◦C; 1H
NMR (300 MHz, CDCl3) d 1.24 (t, J = 7.1 Hz, 3H), 3.15 (s, 3H),
4.26 (br, 2H), 4.32 (q, J = 7.1 Hz, 2H), 7.34–7.53 (m, 6H), 7.66 (td,
J = 7.7, 1.1 Hz, 1H), 8.03 (t, J = 6.45 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 13.9, 35.6, 42.3, 61.0, 122.9, 123.0, 127.5, 127.9, 128.0,
128.1, 130.0, 130.6, 131.7, 132.4, 135.3, 139.5, 142.3, 161.8, 166.7;
IR (KBr, cm-1) 2986, 2926, 1725, 1633, 1478, 1285, 1173; MS (ESI)
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2-Carbethoxy-5-methyl-3-(4-methylphenyl)-pyrazolo[l,5-a][1,4]-
benzodiazepin-6(4H)-one (4d). Yield 48%; Solid, mp 165–167 ◦C;
1H NMR (300 MHz, CDCl3) d 1.27 (t, J = 7.1 Hz, 3H), 2.42 (s,
3H), 3.15 (s, 3H), 4.25 (br, 2H), 4.33 (q, J = 7.1 Hz, 2H), 7.23–7.29
(m, 4H), 7.49 (t, J = 7.7 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 8.02 (t,
J = 7.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 13.9, 21.0, 35.4,
42.1, 60.8, 122.7, 122.8, 127.3, 127.7, 128.7, 129.7, 131.5, 132.2,
135.2, 137.5, 139.4, 142.1, 161.7, 166.5; IR (KBr, cm-1) 2923, 1720,
1636, 1480, 1385, 1172; MS (ESI) (m/z) 398.07 (M+Na+). HRMS
(EI, 70 eV) calcd for C22H21N3O3 [M+] 375.1583, found 375.1579.
2-Carbethoxy-5-methyl-3-(uracil-5-yl)-pyrazolo[l,5-a][1,4]ben-
zodiazepin-6(4H)-one (13). Yield 73%; Solid, mp >300 ◦C; IR
1
(KBr, cm-1) 3154, 1718, 1675, 1632, 1482, 1427, 1225, 1191; H
NMR (600 MHz, DMSO-d6) d 1.23 (t, J = 7.2 Hz, 3H), 3.08 (s,
3H), 4.22 (q, J = 7.2 Hz, 2H)), 4.38 (s, 2H), 7.55–7.58 (m, 2H),
7.75 (td, J = 7.65, 1.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.90
(dd, J = 7.8, 1.2 Hz, 1H), 11.12 (dd, J = 5.7, 1.5 Hz, 1H), 11.31
(s, 1H); 13C NMR (150 MHz, DMSO-d6) d 14.0, 35.3, 41.6, 60.4,
103.0, 113.5, 122.2, 127.6, 128.0, 131.6, 132.6, 134.8, 141.6, 141.7,
143.3, 151.3, 161.3, 163.4, 165.7; MS (ESI) (m/z) 418.15 (M+Na+).
Anal. Calcd. for C19H17N5O5: C, 57.72; H, 4.33; N, 17.71. Found:
C, 57.76; H, 4.35; N, 17.65.
2-Carbethoxy-5-methyl-3-(3-methoxyphenyl)-pyrazolo[l,5-a][1,
4]benzodiazepin-6(4H)-one (4f). Yield 42%; Oil; 1H NMR
(300 MHz, CDCl3) d 1.26 (t, J = 7.1 Hz, 3H), 3.16 (s, 3H), 3.85
(s, 3H), 4.27–4.36 (m, 4H), 6.90–6.98 (m, 3H), 7.38 (t, J = 7.8 Hz,
1H), 7.50 (td, J = 7.6, 1.1 Hz, 1H), 7.66 (td, J = 7.8, 1.5 Hz, 1H),
8.02 (m, 2H); 13C NMR (75 MHz, CDCl3) d 14.0, 35.7, 42.3, 55.2,
61.0, 113.2, 116.1, 122.5, 122.8, 122.9, 127.5, 128.0, 129.2, 131.7,
132.0, 132.4, 135.4, 139.5, 142.3, 159.2, 161.8, 166.7; IR (KBr,
cm-1) 2932, 1723, 1643, 1479, 1289, 1232, 1169; MS (ESI) (m/z)
414.13 (M+Na+). Anal. Calcd. for C22H21N3O4: C, 67.51; H, 5.41;
N, 10.74. Found: C, 67.45; H, 5.44; N, 10.72.
Acknowledgements
Partial financial support from CSIR network projects (IAP 0001
and NWP-0009) is gratefully acknowledged. K.B. and A.K.S are
thankful to CSIR, New Delhi for their fellowships.
Notes and references
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2-Carbethoxy-5-methyl-3-[(2,4-dimethoxy)pyrimidine-5-yl]-py-
razolo[l,5-a][1,4]benzodiazepin-6(4H)-one (4g). Yield 37%; Solid,
mp 114–116 ◦C; 1H NMR (300 MHz, CDCl3) d 1.28 (t, J = 7.2 Hz,
3H), 3.16 (s, 3H), 3.97 (s, 3H), 4.07 (s, 3H), 4.22 (br, 2H), 4.33 (q,
J = 7.1 Hz, 2H)), 7.51 (t, J = 7.5 Hz, 1H), 7.66 (t, J = 7.4 Hz,
1H), 8.02 (t, J = 9.0 Hz, 2H), 8.16 (d, J = 8.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 14.0, 35.9, 42.5, 54.1, 54.9, 61.1, 105.8, 113.4,
122.9, 127.4, 128.1, 131.7, 132.4, 135.2, 140.3, 143.2, 158.6, 161.5,
165.3, 166.6, 168.9; IR (KBr, cm-1)2986, 1721, 1646, 1561, 1475,
1387, 1181; MS (ESI) (m/z) 446.16 (M+Na+). Anal. Calcd. for
C21H21N5O5: C, 59.57; H, 5.00; N, 16.54. Found: C, 59.54; H, 5.04;
N, 16.59.
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Synthesis of 2-carbethoxy-5-methyl-3-(uracil-5-yl)-pyrazolo[l,5-
a][1,4]benzodiazepin-6(4H)-one (13)
To a well-stirred solution of 4g (85 mg, 0.20 mmol) in acetonitrile
(4.0 mL) was added anhydrous sodium iodide (90 mg, 0.60 mmol)
followed by chlorotrimethylsilane (0.60 mmol, 65 mg) under an
argon atmosphere. The reaction mixture was then allowed to stir
at room temperature for 24 h. The solvent was evaporated under
reduced pressure and the residue was washed with aqueous sodium
metabisulfite solution (3 mL) and water (3 mL), successively. It was
then filtered and dried to furnish the pure product 13.
The same procedure was adopted for the conversion of com-
pound 3i to product 12.
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2-Carbethoxy-3-(uracil-5-yl)-4H-pyrazolo[5,1-c][1,4]benzoxa-
zine (12). Yield: 84%; solid, m.p.: >300 ◦C; IR (KBr): 3260,
3199, 3076, 1736, 1696, 1505, 1312, 1209 cm-1; 1H NMR (DMSO-
d6, 300 MHz): d 1.25 (t, J = 7.1 Hz, 3H), 4.23 (q, J = 7.1 Hz,
2H), 5.31 (s, 2H), 7.15–7.30 (m, 3H), 7.61 (d, J = 6.0 Hz, 1H), 7.83
(d, J = 7.5 Hz, 1H), 11.16 (d, J = 5.1 Hz, 1H), 11.32 (s, 1H); 13
C
NMR (DMSO-d6, 75 MHz): d 14.0, 60.5, 62.2, 102.6, 111.9,115.8,
117.7, 123.0, 125.5, 127.9, 133.5, 141.5, 142.7, 146.2, 151.2, 161.5,
162.9; ESI-MS: m/z 377.08 [M+Na]+; HRMS (EI, 70 eV) calcd
for C17H14N4O5 [M+] 354.0964, found 354.0965.
8428 | Org. Biomol. Chem., 2011, 9, 8422–8429
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18 Product 3j was crystallised by slow evaporation of a solution of
dichloromethane–petroleum ether (1 : 1, v/v) at room temperature;
¯
crystal data: C20H17N3O5, M = 379.37, triclinic, space group P1, a =
˚
˚
˚
9.3525(4) A, b = 10.0265(5) A, c = 10.8420(5) A, V = 907.85(7)
3
A , Z = 2, Dcalcd = 1.388 Mg m-3,T = 296(2)K, m = 0.102 mm-1,
˚
˚
F(000) = 396, l = 0.71073 A, processed reflections 13611 and unique
reflections 3186, Final R factor = 0.0477. The crystal data has
been deposited at Cambridge Crystallographic Data Centre [CCDC
No. 838046]. Copies of the data can be obtained free of charge
via www.ccdc.ac.uk/conts/retrieving.html or CCDC, 12 union Road,
Cambridge CB2 1EZ, UK.
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21 Cytotoxicity assays of compounds 12 and 13 against various cancer cell
lines are currently under study.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8422–8429 | 8429
©