Ytterbium triflate promoted synthesis of 1,5-benzodiazepine derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00413-0

2,3-Dihydro-1H-1,5 benzodiazepines have been synthetized in very good yield in solvent-free conditions from o-phenylendiamine and ketones in the presence of Yb(OTf)₃ as catalyst. The method is applicable to both cyclic or acyclic ketones withou

Full text of DOI:10.1016/S0040-4039(01)00413-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3193–3195
Ytterbium triflate promoted synthesis of 1,5-benzodiazepine
derivatives
Massimo Curini,* Francesco Epifano, Maria C. Marcotullio and Ornelio Rosati
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimiica Organica, Facolt a` di Farmacia, Universit a` degli Studi,
Via del Liceo, 06123 Perugia, Italy
Received 8 March 2001; accepted 12 March 2001
Abstract—2,3-Dihydro-1H-1,5 benzodiazepines have been synthetized in very good yield in solvent-free conditions from
o-phenylendiamine and ketones in the presence of Yb(OTf) as catalyst. The method is applicable to both cyclic or acyclic ketones
3
without significant differences. © 2001 Elsevier Science Ltd. All rights reserved.
Benzodiazepines are very important compounds, widely
used in the last decades as anticonvulsant, antianxiety
and hypnotic agents. In addition to the well known
pharmacological profile of 1,4-benzodiazepines, it has
been shown that also some 1,5-benzodiazepines exert a
tuted 2,4-dihydro-1H-1,5-benzodiazepines by condensa-
tion of ketones with o-phenylendiamine (Scheme 1).
The reaction was carried out neat at room temperature
for 4 h, using ketone (2.1 mmol) and o-phenylendi-
1
biological activity, similar to 1,4-derivatives. More-
amine (1 mmol) in the presence of Yb(OTf) . The
3
over, 1,5-benzodiazepines are valuable synthons used
for the preparation of other fused ring compounds such
as triazolo- or oxadiazolo-benzodiazepines.
results are summarized in Table 1.
2
3
As shown in Table 1, both acyclic and cyclic ketones
react without any significant difference to give the
corresponding 2,4-dihydro-1H-1,5-benzodiazepines in
nearly quantitative yield. It is noteworthy that, starting
from unsymmetrical ketones such as 2-butanone or
6-methyl-5-hepten-2-one, the ring closure occurs selec-
tively only from one side of the carbon skeleton giving
a single product. Best results were obtained using 0.05
Although 1,5-benzodiazepines are interesting com-
pounds from a pharmacological, industrial and syn-
thetic point of view, few methods for their preparation
are reported in the literature. These include condensa-
tion reactions of o-phenylendiamine, as free base or
hydrochloride, with a,b-unsaturated carbonyl com-
4
5
pounds, b-haloketones or ketones in the presence of
equivalents of Yb(OTf) , lower loading resulted in
3
6
7
8
8
BF –etherate, NaBH , polyphosphoric acid, SiO ,
MgO and POCl . Unfortunately, many of these pro-
lower yields, while upper loading did not increase reac-
tion times significantly. The catalyst, recovered by
filtration from the reaction media can be reused several
times without any loss of activity. In addition, it is
interesting to note that other lanthanide triflates, used
3
4
2
9
3
cesses suffer major or minor limitations, such as drastic
reaction conditions, low yields, tedious work-up proce-
dures and co-occurrence of several side reactions.
11
During the last decade rare earth metal triflates have
been found as unique Lewis acids in that they are water
tolerant reusable catalysts and they can effectively pro-
mote several carbon–carbon bond formation reactions
1
0
in good yield. As a part of our studies to explore the
utility of lanthanide triflates catalyzed reactions in sol-
vent-free conditions, we decided to investigate the use
of Yb(OTf) as a catalyst for the preparation of substi-
3
*
0
Corresponding author. E-mail: cecchere@unipg.it
Scheme 1.
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00413-0

3
194
M. Curini et al. / Tetrahedron Letters 42 (2001) 3193–3195
Table 1. Yb(OTf) catalyzed formation of 2,3-dihydro-1H-1,5 benzodiazepines
3
as catalysts in the same reaction conditions, namely
La(OTf)3 or Eu(OTf)3, yielded complex mix-
Experimental
a
ture of products. The mechanism of the reaction proba-
bly involves an intramolecular imine–enamine cyclisa-
Typical procedure: A mixture of o-phenylenediamine (1
mmol) and ketone (2.1 mmol) was well stirred with
tion promoted by Yb(OTf) , as already reported by
Yb(OTf) (0.05 mmol) at room temperature for 4 h.
3
3
Jung and coworkers by using polyphosphoric acid or
CH Cl (2 ml) was added to crystallize Yb(OTf) ; the
2
2
3
8
SiO2.
catalyst was removed under reduced pressure and the
residue was purified by SiO gel column chromatogra-
2
In summary, a simple work-up procedure, mild reaction
conditions, selectivity and very good yields make our
methodology a valid contribution to the existing pro-
cesses in the field of 1,5-benzodiazepine derivatives
synthesis.
phy using CH Cl /MeOH 95:5 as eluent.
2
2
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (1):
1
9 13
7
yellow solid; mp 137–139°C; IR; H NMR; C NMR;
GC/MS: M =188.
+

M. Curini et al. / Tetrahedron Letters 42 (2001) 3193–3195
3195
1
6 13
2
-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiaze-
139°C; IR; H NMR; C NMR (50 MHz, CDCl ) l
3
pine (2): yellow solid; mp 151–152°C; IR 3330 (s br),
178.6, 142.7, 138.0, 129.4, 126.3, 121.4, 121.2, 63.0,
52.5, 40.5, 39.2, 34.3, 33.1, 25.3, 24.3, 23.2, 21.7, 21.7;
−
1
1
8 13
1
635 (s) cm ; H NMR; C NMR (50 MHz, CDCl3)
+
l 167.5, 146.6, 140.1, 139.5, 138.2, 129.8, 128.6, 128.4,
GC/MS: M =268.
1
4
28.1, 127.1, 127.1, 126.4, 125.5, 121.7, 121.5, 73.9,
3.0, 29.9; GC/MS: M =312.
+
10-Spirocycloheptan-6,7,8,9,10,10a,11,12-octahydroben-
zo[b]cyclohepta[e][1,4]diazepine (8): yellow solid; mp
1
6 13
7
+
2
,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiaze-
136–137°C; IR; H NMR; C NMR; GC/MS: M =
pine (3): yellow solid; mp 144–145°C; IR 3330 (s br),
296.
−
1 1
1
638 (s) cm ; H NMR (200 MHz, CDCl ) l 0.76–1.48
3
(
m, 13H), 1.61 (s, 3H), 2.87 (q, 1H, J=7.0 Hz), 3.75 (s
13
br, 1H), 6.65–7.40 (m, 4H); C NMR (50 MHz,
Acknowledgements
CDCl ) l 173.8, 142.4, 139.0, 132.7, 126.7, 118.0, 117.5,
3
6
8+.7, 46.2, 35.6, 28.4, 28.0, 12.2, 11.5, 7.8, 7.3; GC/MS:
M =244.
Financial support from CNR, Rome and MURST,
Italy is gratefully acknowledged.
2
,4-Diethyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine
(
4): yellow solid; mp 137–138°C; IR 3330 (s br), 1637
−
1
1
(
s) cm ; H NMR (200 MHz, CDCl ) l 0.98 (t, 3H,
3
J=7.0 Hz), 1.26 (t, 3H, J=7.1 Hz), 1.69 (q, 2H, J=7.0
Hz), 2.12 (m, 2H), 2.35 (s, 3H), 2.69 (q, 2H, J=7.1 Hz),
References
13
3.25 (s br, 1H), 6.75–7.30 (m, 4H); C NMR (50 MHz,
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3
+
7
0.6, 42.1, 35.6, 35.6, 26.9, 10.6, 8.5; GC/MS: M =216.
2
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3
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−
1 1
330 (s br), 1638 (s) cm ; H NMR (200 MHz, CDCl )
3
l 1.34 (s, 3H), 1.66 (s, 3H), 1.68 (s, 3H), 1.73 (s, 3H),
1
5
.74 (s, 3H), 2.01–2.70 (m, 10H), 3.15 (s br, 1H),
13
.03–5.24 (m, 2H), 6.67–7.19 (m, 4H); C NMR (50
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3
1
2
3
25.48, 123.8, 123.4, 121.8, 121.7, 70.6, 43.0, 42.9, 42.7,
7. Morales, H. R.; Bulbarela, A.; Contreras, R. Heterocy-
+
7.5, 25.7, 25.7, 25.1, 23.0, 17.7, 17.7; GC/MS: M =
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24.
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11. The reaction to yield compound 1 has been repeated five
times, through the catalyst washed with dichloromethane
and dried for 2 h at 70°C with the following yields: 96,
95, 96, 93, 93%.
1
0-Spirocyclopentan-1,2,3,9,10,10a-hexahydrobenzo[b]-
cyclopenta[e][1,4]diazepine (6): yellow solid; mp 138–
1
6 13
1
1
5
39°C; IR; H NMR; C NMR (50 MHz, CDCl ) l
3
78.1, 143.4, 139.1, 132.0, 126.9, 119.3, 118.6, 67.2,
4+.3, 39.2, 38.3, 33.3, 28.9, 24.2, 24.0, 23.4; GC/MS:
M =240.
1
0 - Spirocyclohexan - 2,3,4,10,11,11a - hexahydro - 1H-
dibenzo[b,e][1,4]diazepine (7): yellow solid; mp 137–
.
.