Design and synthesis of novel benzopyrazolodiazepinones via intra-molecular alkylation of α-alkylcarbonyl radicals mediated by dilauroylperoxide

Article abstract of DOI:10.1016/j.tetlet.2011.05.105

Using a tin-free strategy, novel 4H-benzo[f]pyrazolo[1,5-a][1,3]diazepin- 5(6H)-ones were synthesized in acceptable yields via intra-molecular alkylation over a benzene ring, of α-alkylcarbonyl radicals generated from ethyl pyrazolylbenzylaminoxanthates,

Full text of DOI:10.1016/j.tetlet.2011.05.105

Tetrahedron Letters 52 (2011) 3998–4000
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Design and synthesis of novel benzopyrazolodiazepinones via
intra-molecular alkylation of
by dilauroylperoxide
a-alkylcarbonyl radicals mediated
⇑
Luz M. Jaramillo-Gómez, Gerson López, Braulio Insuasty, Jairo Quiroga, Rodrigo Abonia
Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a tin-free strategy, novel 4H-benzo[f]pyrazolo[1,5-a][1,3]diazepin-5(6H)-ones were synthesized in
acceptable yields via intra-molecular alkylation over a benzene ring, of -alkylcarbonyl radicals gener-
ated from ethyl pyrazolylbenzylaminoxanthates, using dilauroyl peroxide (DLP) as the radical initiator.
Received 8 April 2011
Revised 9 May 2011
Accepted 23 May 2011
Available online 30 May 2011
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
4H-Benzo[f]pyrazolo[1,5-a][1,3]diazepin-
5(6H)-ones
a-Alkylcarbonyl radicals
Ethyl pyrazolylbenzylaminoxanthates
Dilauroyl peroxide
Fused-tricyclic benzazepine and benzodiazepine moieties are
important frameworks owing to their presence in naturally occur-
ring as well as in synthetic products of pharmaceutical interest.1
Thus Cephalotaxine 1 is reported as the major alkaloid found in
the evergreen plum yews Cephalotaxus, which is indigenous in
South-East Asia. This alkaloid by itself shows no pronounced bio-
logical activity, but its succinate, known as Deoxyharringtonine
2, has displayed the highest IC50 value against leukemic cells,1d–g
compounds 3 were obtained to be screened as novel and selective
peripheral-type benzodiazepine receptor (PBR) ligands and to eval-
uate their ability to modulate steroid biosynthesis in rats,1h diaze-
pine 4 belongs to a family of potential antitumor agents obtained
from a naturally occurring Streptomyces species and recently by
synthetic approaches1i while diazepines 5 were designed and syn-
thesized as novel and potent arginine vasopressin antagonists1j
(Fig. 1).
Xanthates have recently emerged as versatile intermediates in
the formation of novel and diverse organic systems via free-radical
reactions.2 Particularly, several spiro-compounds have recently
been synthesized via intra-molecular alkylation of alkyl-radical
species generated from their corresponding xanthate derivatives
involving DLP (dilauroyl peroxide) as the radical initiator.2c
In continuation of our current studies on the use of diverse
strategies toward the formation of new C–C bonds via free-radical
intermediates3 and the synthesis and chemical transformation of
benzylaminopyrazoles,4 we describe herein a straightforward and
three-step protocol, involving a free-radical pathway, for the syn-
thesis of the novel 4H-benzo[f]pyrazolo[1,5-a][1,3]diazepin-
5(6H)-ones 9, Scheme 1. These compounds are closely related to
those biologically active structures shown in Figure 1, for sharing
a similar ABC core.
For this purpose a series of new chloroacetyl derivatives 7 was
initially obtained by treatment of the corresponding aminopyraz-
O
O
O
A
N
C
N
B
O
HO
H
O H
O
HO
OMe
OMe
1
CO2Me
2
R1
R
N
Y
O
HO
H
A
B
N
R2
R3
A
X
N
MeO
Z
O
C
O
4
O
Ar
3, X = CH, N; CH2, O
N
N
5
⇑
Corresponding author. Tel./fax: +57 2 3393248.
E-mail address: rodrigo.abonia@correounivalle.edu.co (R. Abonia).
Figure 1. Some fused-polycyclic azepine derivatives of biological interest.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.105

L. M. Jaramillo-Gómez et al. / Tetrahedron Letters 52 (2011) 3998–4000
3999
tBu
O
tBu
tBu
4
4
7
S
Ar
Cl
Ar
N
2
N
Ar
N
H
2
N
1
N
N
N
N
KS OEt
ACN, rt
N
Cl
8
1
O
9
O
o
TEA, DCM,
Ar, rt
Cl
X
m
6
p
7
8a, Ar = p-MeOC6H5
X = SC(=S)OEt
tBu
DLP, Ar
3
12
DCE, reflux
OMe
1
tBu
N
O
N
4
N
10a
O
N
6
10
9
N
N
H
6a
NOE
Ph
H
7
H
8
9a
O
10
Scheme 1. Three step synthesis of novel benzopyrazolodiazepinones 9 promoted by DLP.
oles 6 with chloroacetyl chloride in DCM/TEA as shown in Scheme
1.
Compounds 7 were obtained in 56–91% yield after stirring the
reaction mixtures over argon atmosphere at room temperature
and purification of the crudes by column chromatography on silica
gel.5 Table 1 summarizes the obtained results.
this product showed the following main signals.
A
singlet
(d = 3.69 ppm, 2H) assigned to a methylene group and a singlet
(d = 3.77 ppm, 3H) corresponding to a methoxy group. It was also
observed as a singlet (d = 4.86 ppm, 2H) corresponding to a second
methylene group and a singlet (d = 5.92 ppm, 1H) assigned to the
4-H proton of the pyrazolic moiety. Two doublets at
(d = 6.79 ppm, J = 8.0 Hz, 2H and 7.05 ppm, J = 8.0 Hz, 2H, respec-
tively) showed that the p-methoxybenzyl fragment was un-
Compounds 7 were completely characterized by analytical and
spectroscopic methods (see Supplementary data). The most rele-
vant signal in the FTIR spectra corresponded to an intense absorp-
tion band at 1671–1692 cmÀ1, which was assigned to the carbonyl
group of the amide functionality. The most relevant feature in the
1H NMR spectra corresponded to the unequivalence of the four
geminal methylene protons. Therefore, four sets of doublets
(d = 3.75–3.91 ppm, d = 3.92–3.95 ppm, d = 3.96–4.13 ppm and
d = 5.14–5.30 ppm, respectively, 1H each one) were observed. In
the 13C NMR spectra a signal at (d = 40.5–41.9 ppm) assigned to
the new methylene group of the chloroacetyl fragment is the most
relevant feature. Finally, the growing of single-crystals of com-
pound 7a from a solution in ethanol and investigation by X-ray dif-
fraction unambiguously confirmed the assigned structures for
compounds 7.6
Treatment of chloroacetyl derivatives 7 with potassium O-
ethylcarbonodithioate in ACN at room temperature afforded the
expected xanthates 8 in 75–94% yield, Scheme 1, Table 1. In conse-
quence compounds 8 were formed from a nucleophilic substitution
of the chlorine atom in 7 by the potassium xanthate salt.7
The structure of compounds 8 was also assigned by analytical
and spectroscopic methods (see Supplementary data). The most
relevant features in the 1H NMR spectra corresponded to a triplet
(d = 1.31–1.37 ppm, 3H) and a quartet (d = 4.55–4.58 ppm, 2H) as-
signed to the methyl and methylene groups, respectively, of the
xanthate functionality. Like compounds 7 the unequivalence of
the same four geminal methylene protons was observed in 8 as
doublets at (d = 3.53–3.63 ppm, d = 3.89–4.05 ppm, d = 3.98–
4.13 ppm and d = 5.26–5.40 ppm, respectively). Growing of sin-
gle-crystals of compounds 8b and 8d from solutions in ethanol
and investigation by X-ray diffraction unambiguously confirmed
the assigned structures for compounds 8.6
changed during the course of reaction. Finally
a triplet at
(d = 7.31 ppm, J = 8.0 Hz, 1H), doublet at (d = 7.35 ppm,
a
J = 8.0 Hz, 1H), a triplet at (d = 7.43 ppm, J = 8.0 Hz, 1H) and a dou-
blet at (d = 7.75 ppm, J = 8.0 Hz, 1H) indicated that one of the five
Ph-protons proceeding from the starting xanthate 8a is absent in
the structure of this new isolated product. According to Scheme
1, the structure which matched with all 1H NMR signals corre-
sponded to compound 9a but not the spiro-compound 10. More-
over 13C NMR showed the expected 19 different carbon atoms
(eight of them were Cq) and the DEPT experiment showed two
methylenes and seven aromatic CH signals, in agreement with
structure 9a. A molecular ion in the mass spectrum (m/z = 375,
26%) and a base peak (m/z = 121, 100% corresponding to the meth-
oxytropylium ion) were also in agreement with the proposed
structure 9a.
Once confirmed the structure of compound 9a the calculated
yield corresponded to 52% yield. To evaluate the generality of this
approach, the reaction condition described in the last step of
Scheme 1 was extended to other xanthate derivatives 8b–i finding
a similar behavior and the same synthetic orientation in all cases.
In Table 1 and (Supplementary data) it is summarized the obtained
results.
Although attempts to grow single single-crystals for X-ray dif-
fraction of compounds 9 were unfruitful, all proton and carbon
atoms of the benzopyrazolodiazepine frameworks were fully as-
signed from 1H, 13C NMR. Particularly, 2D-NMR (HSQC, HMBC
and NOESY) experiments confirmed that the cyclization process in-
volved the phenyl C-ortho of the xanthates 8 and no other carbon
atom. In this sense, the 6-CH2 hydrogens appearing as a singlet
at 3.68–3.73 ppm showed HMBC correlations with C-6a, C-7, and
C-10a carbon atoms, appearing, respectively, at 126.4–129.1,
128.9–130.8, and 137.1–139.7 ppm. Additionally, NOESY correla-
tions of the same 6-CH2 protons with the 7-CH protons confirmed
the spatial proximity of such protons and hence the connectivity of
the 6-C and 6a-C carbon atoms supporting unambiguously the for-
mation of the structures 9 as depicted in Scheme 1.
It is worth mentioning that the subsequent cyclization process
of compounds 8 was initially planned with the expectation to ob-
tain new examples of spiro-derivatives 10 as shown in Scheme 1.
In this sense, following a similar procedure like described by
Miranda and co-workers,2c compound 8a (1 mmol) was treated
with DLP portion-wise (1.8 mmol) in DCE at reflux for 8 h. The
reaction was monitored by TLC and after total consumption of
the starting material 8a, several compounds were formed and the
main component was isolated and purified by column chromatog-
raphy on silica gel using DCM as eluent.8 The 1H NMR spectrum of
In summary, the straightforward synthesis of new 1,3-benzopy-
razolodiazepinones 9 was performed starting from ethyl pyra-
zolylbenzylaminoxanthates. This tin-free strategy involved an
unusual and selective
a-alkylcarbonyl radical cyclization process

4000
L. M. Jaramillo-Gómez et al. / Tetrahedron Letters 52 (2011) 3998–4000
Table 1
Analytical data for compounds (7, 8 and 9)a–i
Entry
Ar
Compound 7
Compound 8
Compound 9
Mp (°C)
Yield %
Mp (°C)
Yield %
Mp (°C)
Yield %
a
b
c
d
e
f
g
h
i
p-CH3OC6H4
p-CH3C6H4
3,4,5-(CH3O)3C6H2
p-ClC6H4
p-NO2C6H4
p-BrC6H4
4-OH-3-CH3OC6H3
p-(CH3)2NC6H4
3,4-(CH3O)2C6H3
80–81
86
73
80
82
56
82
80
63
91
110–111
86–87
98–99
94–95
118–119
95–96
106–108
131–132
134–135
93
94
90
92
85
80
84
75
94
153–154
181–182
130–131
193–194
197–198
157–158
151–153
140–141
179–180
52
58
52
54
60
54
48
50
56
115–116
129–130
159–160
172–173
149–150
134–136
104–105
76–77
from the cold bath. Then the mixture was stirred at room temperature for 10–
24 h and after complete disappearance of the starting material 6 (TLC control),
the solvent was evaporated under reduced pressure and the residues were
purified by column chromatography on silica gel (AcOEt/DCM gradient) to
obtain compounds 7. All reactions started with 200 mg of compound 6. N-(3-
tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-2-chloro-N-(4-methoxy-benzyl)acetamide
7a. Isolated as yellow solid, yield: 212 mg, IR (KBr disk, cmÀ1) 1685 (C@O),
1251 (C–O), 1032 (C–O); 1H NMR (400 MHz, CDCl3) dH 7.45–7.38 (m, 4H, Ar-
H), 7.34 (t, J = 8.0, 1H, Ar-H), 7.08 (d, J = 8.0, 2H, Ar-H), 6.79 (d, J = 8.0, 2H, Ar-
H), 5.85 (s, 1H, 4-H), 5.26 (d, J = 12.0, 1H, 7b-H), 3.99–3.92 (m, 2H, 9b-H and
7a-H), 3.79 (br s, 4H, 9a-H and OCH3), 1.30 (s, 9H, tBu). 13C NMR (100 MHz,
CDCl3) dC 166.5 (C@O), 162.4 (Cq), 159.5 (Cq), 138.4 (Cq), 137.7 (Cq), 130.6,
129.6, 127.7, 127.6 (Cq), 122.8, 113.8, 103.3 (C-4), 55.2 (OCH3), 52.0 (C-7), 41.8
(C-9), 32.5 (Cq, tBu), 30.1 (CH3, tBu). m/z (ESI, %) 413/411 (10/30, M+Å), 226
(43), 121 (100, C8H9O), 77 (7, Ph). Anal. Calcd for C23H26ClN3O2: C, 67.06; H,
6.36; N, 10.20. Found: C, 67.32; H, 6.36; N, 9.82.
over the 1-phenyl ring of the 5-aminopyrazole derivatives 6
promoted by dilauroyl peroxide (DLP) as the radical initiator. This
radical-mediated approach resulted in a useful synthetic alterna-
tive because this particular type of benzodiazepinones has not
been obtained previously under ionic reaction conditions. Studies
directed to improve the efficiency of the last step in Scheme 1,
the exploration of the broadest of this strategy and to evaluate
the practical usefulness of the obtained products 9 are currently
in progress.
Acknowledgments
Authors thank to COLCIENCIAS and Universidad del Valle for
financial support (Project CI No. 749).
6. López, G.; Jaramillo, L. M.; Abonia, R.; Cobo, J.; Glidewell, C. Acta Crystallogr., Sect.
C 2010, 66, o168–o173.
7. General procedure for the synthesis of xanthates 8. A mixture of the corresponding
chloroacetyl derivative 7 (0.5 mmol) and potassium O-ethyl carbonodithioate
(0.75 mmol) was dissolved in acetonitrile (6–8 mL) and kept in the absence of
light. The mixture was stirred at room temperature for 2–3 h and after complete
disappearance of the starting material 7 (TLC control), the solvent was removed
under reduced pressure and the residue purified by column chromatography on
silica gel (AcOEt/DCM gradient) yielding compounds 8. All reactions started with
200 mg of compound 7. S-2-[(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)(4-
methoxybenzyl)amino]-2-oxoethyl-O-ethylcarbonodithioate 8a. Isolated as
yellow solid, yield: 225 mg. IR (KBr disk, cmÀ1) 1691 (C@O), 1237 (C–O), 1032
br (C–O); 1H NMR (400 MHz, CDCl3) dH 7.44–7.34 (m, 5H, Ar-H), 7.12 (d, J = 8.0,
2H, Ar-H), 6.81 (d, J = 8.0, 2H, Ar-H), 5.88 (s, 1H, 4-H), 5.32 (d, J = 12.0, 1H, 7b-H),
4.59 (q, J = 8.0, 2H, OCH2), 4.01 (d, J = 12.0, 1H, 7a-H), 3.92 (d, J = 16.0, 1H, 9b-H),
3.80 (s, 3H, OCH3), 3.55 (d, J = 16.0, 1H, 9a-H), 1.36 (t, J = 8.0, 3H, CH3), 1.31 (s,
9H, tBu). 13C NMR (100 MHz, CDCl3) dC 213.1 (C@S), 167.0 (C@O), 162.4 (Cq),
159.4 (Cq), 138.6 (Cq), 138.4 (Cq), 130.7, 129.5, 128.0 (Cq), 127.5, 122.9, 113.8,
103.3 (C-4), 70.5 (OCH2), 52.0 (C-7), 39.4 (C-9), 32.5 (Cq, tBu), 30.1 (CH3, tBu),
13.7 (CH3). m/z (ESI, %) 497 (2, M+Å), 376 (36), 344 (56), 121 (100, C8H9O), 77
(18), 29 (13). Anal. Calcd for C26H31N3O3S2: C, 62.75; H, 6.28; N, 8.44. Found: C,
62.88; H, 6.37; N, 8.60.
8. General procedure for the synthesis of the pyrazolodiazepinones 9. A mixture of the
corresponding xanthate 8 (1.0 mmol) and anhyd DCE (6–8 mL) was heated to
reflux under argon atmosphere. Then DLP (1.8 mmol) was added portion-wise
during 6–8 h and after complete disappearance of the starting material 8 (TLC
control), the solvent was removed under reduced pressure and the main
component of the residue was isolated and purified by column chromatography
on silica gel (AcOEt/DCM gradient) yielding compounds 9. All reactions started
with 200 mg of compound 8. 2-tert-Butyl-4-(4-methoxybenzyl)-4H-
benzo[f]pyrazolo[1,5-a][1,3]diazepin-5(6H)-one 9a. Isolated as yellow solid,
yield: 79 mg. IR (KBr disk, cmÀ1) 1670 (C@O), 1240 (C–O), 1038, (C–O); 1H NMR
(400 MHz, CDCl3) dH 7.75 (d, J = 8.0, 1H, 10-H), 7.43 (t, J = 8.0, 1H, 9-H), 7.35 (d,
J = 8.0, 1H, 7-H), 7.31 (t, J = 8.0, 1H, 8-H), 7.05 (d, J = 8.0, 2H, Ar-H), 6.79 (d, J = 8.0,
2H, Ar-H), 5.92 (s, 1H, 3-H), 4.86 (br s, 2H, 12-H), 3.77 (s, 3H, OCH3), 3.69 (s, 2H,
6-H), 1.31 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3) dC 169.1 (C@O), 162.8 (Cq),
158.9 (Cq), 141.3 (Cq), 137.4 (Cq), 128.9 (C-7), 128.8 (Cq and C-9), 128.5, 127.6
(C-8), 126.8 (Cq), 122.7 (C-10), 114.0, 94.7 (C-3), 55.2 (OCH3), 51.8 (C-12), 41.0
(C-6), 32.5 (Cq, tBu), 30.2 (CH3, tBu). m/z (ESI, %) 375 (26, M+Å), 151 (36), 121
(100, C8H9O), 120.0 (100), 91 (62), 77 (88), 57 (53). Anal. Calcd for C23H25N3O2:
C, 73.58; H, 6.71; N, 11.19. Found: C, 73.69; H, 6.48; N, 11.25.
References and notes
1. (a) García, J.; Andrés, J.; Fraile, A.; Martín, A.; Martín, M. Tetrahedron Lett. 2004,
45, 4653–4656; (b) Novikov, M.; Khlebnikov, A.; Shevchenko, M. J. Fluorine
Chem. 2003, 123, 177–181; (c) Abonia, R.; Cuervo, P.; Insuasty, B.; Quiroga, J.;
Nogueras, M.; Cobo, J. Eur. J. Org. Chem. 2008, 4684–4689; (d) Jalil Miah, M.;
Hudlicky, T.; Reed, J. In The Alkaloids; Brossi, A., Ed.; Academic: New York, NY,
´
1998; Vol. 51, pp 199–269; (e) Sacchi, S.; Kantarjian, H.; OBrien, S.; Cortes, J.;
Rios, M.; Giles, F.; Beran, M.; Koller, C.; Keating, M.; Talpaz, M. Cancer 1999, 86,
2632–2641; (f) Tietze, L.; Braun, H.; Steck, P.; El Bialy, S.; Tölle, N.; Düfert, A.
Tetrahedron 2007, 63, 6437–6445; (g) Koseki, J.; Sato, H.; Watanabe, Y.;
Nagasaka, T. Org. Lett. 2002, 4, 885–888; (h) Campiani, G.; Ramunno, A.; Fiorini,
I.; Nacci, V.; Morelli, E.; Novellino, E.; Goegan, M.; Mennini, T.; Sullivan, S.;
Zisterer, D.; Williams, C. J. Med. Chem. 2002, 45, 4276–4281; (i) Kamal, A.;
Laxman, E.; Laxman, N.; Rao, N. Bioorg. Med. Chem. Lett. 2000, 10, 2311–2313;
(j) Sum, F.-W.; Dusza, J.; Delos Santos, E.; Grosu, G.; Reich, M.; Du, X.; Albright,
J.; Chan, P.; Coupet, J.; Ru, X.; Mazandarani, H.; Saunders, T. Bioorg. Med. Chem.
Lett. 2003, 13, 2195–2198.
2. (a) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Angew. Chem., Int. Ed. 2000, 39,
731–733; (b) Boivin, J.; Boutillier, P.; Zard, S. Tetrahedron Lett. 1999, 40, 2529–
2532; (c) Ibarra-Rivera, T.; Gámez-Montaño, R.; Miranda, L. Chem. Commun.
2007, 3485–3487; (d) Boint, G.; Quiclet-Sire, B.; Salet, T.; Zard, S. Synlett 2003,
382–384; (e) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Angew. Chem. 2000,
112, 747–749; (f) Bacqué, E.; Qacemi, M.; Zard, S. Org. Lett. 2004, 6, 3671–3675.
3. (a) Jaramillo, L. M.; Restrepo, N.; Gómez, F.; Hudlicky, T. Synth. Commun. 1999,
29, 2795–2806; (b) Jaramillo, L. M.; Martin, J. Bol. Soc. Chil. Quim. 1998, 43, 259–
266; (c) Jaramillo-Gómez, L. M.; Loaiza, A.; Martín, J.; Ríos, L. A.; Wang, P. G.
Tetrahedron Lett. 2006, 47, 3909–3912.
4. (a) Castillo, J.; Abonía, R.; Hursthouse, M.; Cobo, J.; Glidewell, C. Acta Crystallogr.,
Sect. C 2009, C65, o495–o497; (b) Castillo, J.; Abonia, R.; Cobo, J.; Glidewell, C.
Acta Crystallogr., Sect. C 2009, 65, o303–o310; (c) Abonia, R.; Rengifo, E.; Cobo, J.;
Low, J. N.; Glidewell, C. Acta Crystallogr., Sect. C 2007, 63, o29–o32; (d) Abonia, R.;
Castillo, J.; Insuasty, B.; Quiroga, J.; Nogueras, M.; Cobo, J. Eur. J. Org. Chem. 2010,
6454–6463.
5. General procedure for the synthesis of chloroacetyl derivatives 7. A mixture of
chloroacetyl chloride (0.1 mL, 1.25 mmol), dichloromethane (8 mL) and
triethylamine (0.3 mL, 2.15 mmol) was cooled on an ice-water bath under
argon atmosphere. Then the corresponding arylpyrazolylamine 6 (0.6 mmol),
dissolved in dichloromethane (2 mL) was added and the solution was removed