Scandium(III) triflate as an efficient and reusable catalyst for synthesis of 1,5-benzodiazepine derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.01.113

2,3-Dihydro-1H-1,5-benzodiazepines have been synthesized in solvent-free conditions in excellent yield from o-phenylenediamines and ketones in the presence of a catalytic amount of Sc(OTf)₃. This method is a very easy, rapid, and high yielding

Full text of DOI:10.1016/j.tetlet.2005.01.113

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1811–1813
Scandium(III) triflate as an efficient and reusable catalyst
for synthesis of 1,5-benzodiazepine derivatives
Surya K. De* and Richard A. Gibbs
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Cancer Center,
Purdue University, West Lafayette, IN 47906, USA
Received 14 December 2004; accepted 24 January 2005
Abstract—2,3-Dihydro-1H-1,5-benzodiazepines have been synthesized in solvent-free conditions in excellent yield from o-phenylene-
diamines and ketones in the presence of a catalytic amount of Sc(OTf)3. This method is a very easy,rapid,and high yielding reaction
for the synthesis of 1,5-benzodiazepine derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
Benzodiazepines are very important compounds because
of their pharmacological properties. Most of the mem-
bers of this family have wide applications in medicinal
chemistry such as tranquilizing,anticonvulsant,anti-
operational simplicity,reusability,economic viability,
and greater selectivity.
In recent years,scandium triflate has received consider-
able attention as a mild Lewis acid for an array of
organic transformations14 because the catalyst is quite
stable in water and is reusable. The catalyst scandium
triflate [Sc(OTf)3] is commercially available and can be
used for the preparation of 1,5-benzodiazepines from
o-phenylenediamines and ketones. In continuation of
our work to develop new synthetic methodologies,15
we report herein a facile method for the synthesis of
2,3-dihydro-1H-1,5-benzodiazepines by the condensa-
tion of o-phenylenediamine with ketones in the presence
of a catalytic amount of Sc(OTf)3 under solvent-free
conditions.
1
anxiety,and hypnotic agents. In addition,15, -benzodi-
azepines are valuable synthons used for the preparation
of other fused ring compounds such as triazolo,2 oxazino
or furano-benzodiazepines.3 Benzodiazepine derivatives
also find commercial use in photography4 (as dyes for
acrylic fibers) and also as anti-inflammatory agents.5
Despite their importance from a pharmacological,
industrial,and synthetic point of view,comparatively
few methods for the preparation of 1,5-benzodiazepines
have been reported. These include condensation reac-
tion of o-phenylenediamines with a,b-unsaturated car-
bonyl compounds,6 b-haloketones7 or ketones in the
presence of BF3–OEt2,8 NaBH4,9 polyphosphoric
acid,10 SiO2,10 MgO and POCl3,11 AcOH under micro-
wave irradiation,12 and ionic liquid.13 Unfortunately,
many of these processes suffer from one or other limita-
tions such as drastic reaction conditions,low yields,
tedious work-up procedures,relatively long reaction
times,and co-occurrence of several side reactions.
Moreover,the main disadvantage of almost all existing
methods is that the catalysts are destroyed in the
work-up procedure and cannot be recovered or reused.
Therefore,the search continues for a better catalyst
for the synthesis of 1,5-benzodiazepines in terms of
The reactions were carried out in neat at room temper-
ature for 3 h by taking a 1:2.2 mol ratio mixture of o-
phenylenediamine and the ketone in the presence of
5 mol % Sc(OTf)3 to give the desired products (Scheme
1) in excellent yield.16,17 As shown in Table 1,both acy-
clic and cyclic ketones react without any significant dif-
ference to give the corresponding 2,4-dihydro-1H-1,5-
benzodiazepines in good yield. It is noteworthy that
starting from unsymmetrical ketone such as 2-butanone
(entry 3),the ring closure occurs selectively only from
one side of carbon skeleton yielding a single product.
Among the various metal triflates such as Cu(OTf)2,
La(OTf)3,Lu(OTf) ,Nd(OTf) ,and Ce(OTf) studied
3
3
3
for this reaction,Sc(OTf) was found to be the most
3
*
effective catalyst in terms of conversion and reaction
rates. The scope and generality of this process is
Corresponding author. Tel.: +1 765 7439702; fax: +1 765 4941414;
e-mail: skd125@pharmacy.purdue.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.113

1812
S. K. De, R. A. Gibbs / Tetrahedron Letters 46 (2005) 1811–1813
R1
H
R2
R2
N
O
Sc(OTf)3
NH2
NH2
+
R1
CH2R2
rt
N
R1
Scheme 1.
Table 1. Sc(OTf)3 catalyzed formation of 2,3-dihydro-1H-1,5-benzodiazepines
Entry
Substrate
NH2
Ketone
Product
Yielda (%)
96
H
N
1
CH3COCH3
NH2
N
H
N
Ph
Ph
NH2
NH2
NH2
NH2
2
3
PhCOCH3
93
90
N
H
N
CH3COCH2CH3
N
H
NH2
NH2
N
N
4
5
CH3CH2COCH2CH3
89
87
H
N
O
NH2
NH2
N
H
N
NH2
O
6
7
91
81
NH2
N
H
N
NH2
CH3COCH3
NH2
N
H
N
NH2
NH2
CH2OCH3
8
84
N
a Yields refer to isolated pure products and were characterized by NMR and MS spectra.
illustrated with respect to various cyclic and acyclic ke-
tones and the results are summarized in Table 1.
intermediate diimine A. A 1,3-shift of the hydrogen at-
tached methyl group then occurs to form an isomeric en-
amine B,which cyclizes to afford seven-membered ring.
The mechanism of the reaction6–13 probably involves an
intramolecular imine–enamine cyclization promoted by
Sc(OTf)3 as shown in Scheme 2. Amine of o-phenylene-
diamine attacks carbonyl group of ketone giving the
In conclusion,we describe a mild and efficient method
for the synthesis of 2,3-dihydro-1H-1,5-benzodiaze-
pines. The easy work-up procedure,recyclable catalyst,

S. K. De, R. A. Gibbs / Tetrahedron Letters 46 (2005) 1811–1813
1813
R
O
R
NH2
NH2
N
N
N
CH3
CH3
R
CH3
CH3
N
H
C
Sc(OTf)3
R
R
B
A
R
R
CH3
H
N
N
CH3
N
H
N
R
R
Scheme 2.
14. (a) Kobayashi,S. Eur. J. Org. Chem. 1999, 73,4961; (b)
Kobayashi,S.; Siguira,M.; Kitagawa,H.; Lam,W. W.
Chem. Rev. 2002, 102,2227.
short reaction times,selectivity,and very good yields
make this method a valid contribution to the existing
methodologies.
15. (a) De,S. K. Tetrahedron Lett. 2003, 44,9055; (b) De,S.
K. Tetrahedron Lett. 2004, 45,1035; (c) De,S. K.
Tetrahedron Lett. 2004, 45,2339; (d) De,S. K. Tetrahe-
dron Lett. 2004, 45,2919; (e) De,S. K.; Gibbs,R. A.
Tetrahedron Lett. 2004, 45,7407; (f) De,S. K.; Gibbs,R.
A. Tetrahedron Lett. 2004, 45,8141.
16. General procedure: a mixture of o-phenylenediamine
(5 mmol) and ketone (11 mmol) was stirred at room
temperature in the presence of Sc(OTf)3 (5 mol %) for 3 h.
After completion of the reaction (TLC),the reaction
mixture was diluted with ethyl acetate (40 mL),washed
References and notes
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with water (15 mL),dried (MgSO ),and concentrated in
4
vacuo. The crude product was purified by silica gel column
chromatography (15% ethyl acetate in hexane) to afford
the pure product. All reactions were completed within 3 h.
All products were characterized by comparison of their
mp, 1H NMR spectra with those of authentic samples. The
aqueous layer containing the catalyst could be evaporated
under reduced pressure to give a white solid. The IR
spectrum of the recovered catalyst was identical to that of
the commercially available catalyst (Aldrich),which could
be reused for the next reaction with only a modest loss in
activity. The catalyst has been recovered and reused for
four times (reaction yields 96%,92%,83%,74%).
17. Selected data: 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodi-
1
azepine (entry 1): H NMR (300 MHz,CDCl ): d 1.34 (s,
3
6H),2.26 (s,2H),2.34 (s,3H),3.46 (br s,1H),6.61–7.28
(m,4H); EIMS m/z 188 (M+). 2,4-Diethyl-2-methyl-2,3-
dihydro-1H-1,5-benzodiazepine (entry 3): 1H NMR
(300 MHz,CDCl 3): d 0.97 (t, J = 7.2 Hz,3H),1.27 (t,
J = 7.2 Hz,3H),1.69 (q, J = 7.2 Hz,2H),2.14 (m,2H),
2.34 (s,3H),2.69 (q, J = 7.1 Hz,2H),3.28 (br s,1H),6.73–
7.32 (m,4H); 13C NMR (75 MHz,CDCl 3): d 8.6,10.5,
26.8,35.5,35.6,42.1,70.6,121.8,125.4,126.1,127.0,
11. Balakrishna,M. S.; Kaboudin,B. Tetrahedron Lett. 2001,
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dron Lett. 2002, 43,1755.
Tetrahe-
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2003, 44,1835.
137.8,140.8,175.5; MS m/z 216 (M+).