Multisite solid catalyst for cascade reactions: The direct synthesis of benzodiazepines from nitro compounds

Article abstract of DOI:10.1002/chem.200900492

Substituted 1,5-benzodiazepines are selectively synthesized in one pot from substituted nitroaromatics and ketones. The reaction is performed in the presence of hydrogen and in the absence of solvent by using a bifunctional solid catalyst with a chemoselective hydrogenation functional group capable of reducing the nitro group to a diamino group and an acid functional group, which catalyzes the cyclocondensation of the amino group with the ketone.

Full text of DOI:10.1002/chem.200900492

DOI: 10.1002/chem.200900492
Multisite Solid Catalyst for Cascade Reactions:
The Direct Synthesis of Benzodiazepines from Nitro Compounds
Maria J. Climent, Avelino Corma,* Sara Iborra, and Laura L. Santos[a]
Abstract: Substituted 1,5-benzodiazepines are selectively synthesized in one pot
from substituted nitroaromatics and ketones. The reaction is performed in the
presence of hydrogen and in the absence of solvent by using a bifunctional solid
catalyst with a chemoselective hydrogenation functional group capable of reducing
the nitro group to a diamino group and an acid functional group, which catalyzes
the cyclocondensation of the amino group with the ketone.
Keywords:
cascade
molecular
benzodiazepines
reactions
·
·
·
sieves
multisite catalysts · reduction
Introduction
above requires the neutralization of the acid while produc-
ing undesired waste. To avoid that, different heterogeneous
[15]
Benzodiazepines and their polycyclic derivatives are an im-
portant class of bioactive compounds that are prescribed as
tranquilizers, as well as anticonvulsant, antianxiety, analge-
sic, antidepressive, hypnotic, and anti-inflammatory drugs.[1]
More recently the use of 1,5-benzodiazepines has been ex-
tended to various diseases such as cancer, viral infection,
and cardiovascular disorders.[2]
acid catalysts such as sulfated zirconia,[14] AlPW12O40,
clay-supported heteropoly acids,[16] clinoptylolite-type zeolite
adsorbents,[17] and zeolites[18] (Heulandite, HY, ZSM-5) have
been used for preparing 1,5-benzodiazepines starting from
o-phenylenediamines, and, in most cases, the cyclocondensa-
tion between o-phenylenediamine and the ketone requires
catalyst-to-phenylenediamine mass ratios of between 2.5
and 5.
Commonly, 1,5-benzodiazepines are prepared by cyclo-
condensation of o-phenylenediamine with a,b,-unsaturated
carbonyl compounds,[3] b-haloketones,[4] or ketones in the
presence of Lewis acids and transition-metal salts as cata-
lysts. Among them, the condensation of o-phenylenediamine
with ketones in the presence of Brønsted or Lewis acids is
the most widely used method for preparing 1,5-benzodiaze-
pines. Many homogeneous catalysts, which sometimes need
to be used in lager amounts, have been reported for this
condensation. Accordingly, BF3–etherate,[5] NaBH4,[6] Yb-
Since nitroaromatics are first hydrogenated into the corre-
sponding amines, which can be condensed with ketones in a
second step,[19] it appeared to us that it would be of interest
to design a multisite solid catalyst and a process capable of
producing 1,5-benzodiazepines directly from substituted ni-
troaromatics and ketones through a cascade reaction. In the
first step the nitroaromatics would be chemoselectively hy-
drogenated with hydrogen in the presence of the ketone on
the hydrogenation sites, while in a one-pot consecutive step
the cyclocondensation between the aromatic amine and the
ketone would occur on the acid sites of the catalyst
(Scheme 1). Notice that in this synthesis process there are
two critical issues: 1) the selective reduction of the nitro
group in the presence of the carbonyl, and 2) the avoidance
of the hydrogenation of the imine group in the 1,5-benzodia-
zepine product. We will show here that the cascade reaction
gives a variety of 1,5-benzodiazepines with yields of the
order of 90% under very mild conditions (658C, 7 bar hy-
drogen, and a reaction time of 1.5 h). For doing this we have
optimized the two catalytic functions, that is, the acid and
the hydrogenation.
ACHTUNGTRENNUNG(OTf)3, GaACHTUNGTRENNUNG
(OTf)3,[7] polyphosphoric acid,[8] ceric ammonium
nitrate,[9] ZrCl4,[10] acetic acid under microwave irradia-
tion,[11] nitrobenzoic acid,[12] and ionic liquids,[13] among
others, have been used with variable success. Unfortunately,
many of the synthesis methods reported also catalyze the
formation of several side products, involve long reaction
times, give low yields, or use expensive reagents. Besides
these inconveniencies, the use of the catalysts described
[a] M. J. Climent, Prof. Dr. A. Corma, S. Iborra, L. L. Santos
Instituto de Tecnologꢀa Quꢀmica (UPV-CSIC)
Universidad Politꢁcnica de Valencia
Avenida de los Naranjos s/n, 46022 Valencia (Spain)
E-mail: acorma@itq.upv.es
8834
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Chem. Eur. J. 2009, 15, 8834 – 8841

FULL PAPER
(III), which cyclizes rapidly
yielding the seven-membered
benzodiazepines
(Scheme 2B).
ring
Kinetic results obtained with
the molecular sieve MCM-41
catalyst (Figure 1) clearly show
the formation of the imine I as
a primary unstable product, in-
dicating that with this type of
Scheme 1. One-pot process for the synthesis of benzodiazepines.
Results and Discussion
In the case of the acid function, aluminosilicate molecular
sieves were selected since with these materials the number
and strength of the acid sites can be controlled by modifying
the framework Si/Al ratio and molecular sieve structure,
while the pore diameter and topology of the catalyst could
be adapted to the size of reactants and products. In the case
of 1,5-benzodiazepines, the relative large size of the product
led us to select three different aluminosilicate molecular
sieves as acid catalysts, that is, a large-pore zeolite with a
high Si/Al ratio (Beta), a delaminated zeolite (ITQ-2),[20]
with a large external surface area, and a structured mesopo-
rous aluminosilicate (MCM-41), as potential candidates to
catalyze the cyclocondensation reaction. The characteristics
of the solid acid catalysts are given in Table 1.
Figure 1. Kinetic curves of the different compounds during the cyclocon-
densation of o-phenylenediamine with acetone using MCM-41 (14) as a
^
catalyst: (*) o-phenylenediamine, (
imine I.
) benzodiazepine (3), and (&)
Table 1. Physicochemical characteristics of the catalysts.
Catalyst
Si/Al
1508C
BET Surface area
[m2 gÀ1
B[a]
L[a]
N
]
catalyst the second mechanism described above is the most
probable one. As observed in Table 2, the catalyst activity
follows the order MCM-41>ITQ-2>Beta. Interestingly
Beta
ITQ-2
MCM-41(14)
MCM-41(28)
MCM-41(50)
MCM-41(80)
13
14
12
28
50
80
60
28
13
16
5.7
6.9
78
67
47.9
30.3
13.9
11.9
666
850
890
940
1040
1050
Table 2. Cyclocondensation between 1,2-phenylenediamine and acetone
in the presence of different acid catalyst.[a]
[a] B and L stand for the intensity of the IR band in a.u. of pyridine re-
maining adsorbed on Brønsted (pyridinium ions) or on Lewis acid sites,
after desorption at 1508C and 10À4 Torr.
Catalyst
ro 103
Yield of
3 [%]
Yield of
imine (I) [%]
Selectivity
[%]
[molminÀ1 gÀ1
]
Beta
ITQ-2
MCM-41(14)
0.8
1.1
1.7
91
9
91
95
5
95
97[b]
3[b]
97[b]
Two mechanism have been proposed for the synthesis of
1,5-benzodiazepines starting from phenylenediamines and
ketones. The first one involves the aldol condensation of the
ketone giving the corresponding a,b-unsaturated carbonyl
compound, followed by reaction with the amine and cycliza-
tion to give the corresponding 1,5-benzodiazepines[5]
(Scheme 2A). As suggested by one of the referees the first
intermediate in Scheme 2A could also be formed by a mon-
oenamine from diaminobenzene with the ketone and a
second molecule of this ketone. In an alternative mechanism
it has been proposed[16] that the carbonyl group of the
ketone is protonated and reacts with the amine group to
give the corresponding imine (see intermediate imine I in
Scheme 2B). Then, the intermediate imine attacks the car-
bonyl group of a second activated ketone giving diimine II
and water. Finally a 1,3 shift of the hydrogen atom attached
to the methyl group occurs to form an isomeric enamine
[a] Reactions conditions: Diamine (2 mmol), acetone (40 mmol), catalyst
(50 mg), at 658C, 6 h. [b] Reaction time of 3 h.
MCM-41, with the lowest amount and strength of acid sites
(see Table 1), is not only the most active but also gives the
highest selectivity to 1,5-benzodiazepine.To explain this be-
havior one has to take into account the adsorption–desorp-
tion properties of the material. Indeed, if we consider that
the reactant (1,2-phenylenediamine), the intermediate
(imine), and the product (1,5-benzodiazepine) have basic
character, the presence of stronger acid sites on the crystal-
line than on the amorphous molecular sieve[21] will produce
a stronger adsorption of the intermediate and final product
on Beta and ITQ-2, which will strongly compete with the
adsorption of the ketone on the active sites. That stronger
adsorption of reactant and product will be responsible for a
Chem. Eur. J. 2009, 15, 8834 – 8841
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8835

A. Corma et al.
lower reaction rate and faster catalyst deactivation with
Beta and ITQ-2 than with MCM-41. Therefore, an optimum
for the cyclocondensation reaction is achieved with a solid
catalyst with structured mesoporous and mild acidity
(MCM-41(14)).
In a second step the acidity of the selected mesoporous
MCM-41 material was optimized by changing the frame-
work Si/Al ratio while keeping constant the pore diameter.
The results obtained (Table 3) show that while the initial re-
hydroxyl groups of the aluminosilicate. This was indeed con-
firmed by performing the reaction with pure silica MCM-41
(see results with MCM-41-PS in Table 3).
The mesoporous catalyst can be recycled simply by wash-
ing the MCM-41 with acetone, and only a 3% decrease in
yield (96% yield for a reaction time of 6 h) has been ob-
served after four catalyst recycles. The generality of the
MCM-41 catalyst for producing benzodiazepines starting
from phenylenediamines has been explored by reacting dif-
ferent ketones and different 4-substituted 1,2-phenylenedia-
mines (Table 4). With an unsymmetrical aliphatic ketone (2-
butanone) only one regioisomer (2,3-dihydro-1H-1,5-benzo-
diazepine (4)) was obtained, indicating that ring closure
occurs selectively from one side of the carbonyl group. High
yields of the desired product are also observed with cyclic
(cyclopentanone) and aromatic substituted ketones (aceto-
phenone). When diamines with electron withdrawing (Cl) or
donating (CH3, OCH3) groups are reacted, a mixture of the
corresponding regioisomers 7- and 8-substituted 1,5-benzo-
diazepines are obtained in a 1:1 molar ratio. The presence
of electron-donating groups in the diamine ring increases
the yield and rate of formation of 1,5-benzodiazepine
(Table 4, entries 5 and 6), while electron withdrawing groups
decrease the reactivity (Table 4, entry 7). The decrease in re-
activity is larger when there is a fused aromatic ring to the
diamine (Table 4, entry 4).
Table 3. Results of cyclocondensation between 1,2-phenylenediamine
and acetone using MCM-41 catalyst with different Si/Al ratio.[a]
Catalyst
ro 103
TOF[b]
[minÀ1
Yield of
3 [%]
Yield of
imine (I) [%]
[molminÀ1 gÀ1
]
G
]
MCM-41(14)
MCM-41(28)
MCM-41(50)
MCM-41(80)
MCM-41-PS
1.7
1.6
1.3
1.3
0.4
25
46
64
97 (3 h)
97 (6 h)
96 (3 h)
98 (6 h)
92 (3 h)
96 (6 h)
91 (3 h)
99 (6 h)
76 (6 h)
3 (3 h)
3 (6 h)
4 (3 h)
2 (6 h)
8 (3 h)
4 (6 h)
9 (3 h)
1 (6 h)
20 (6 h)
111
–
[a] Reactions conditions: Diamine (2 mmol), acetone (40 mmol), catalyst
(50 mg), at 658C, 6 h. [b] Calculated as ro/([Al]/
[Al+Si]).
AHCTUNGTRENNUNG
action rate decreases when decreasing the Al content, it is
possible to achieve up to 99% yield of the desired product
with an MCM-41 material with a Si/Al ratio of 80. These re-
sults suggest that the cyclocondensation reaction does not
require strong acid sites and even silanol groups may carry
out the reaction, though at a slower rate than the bridging
Multisite catalyst: the cascade reaction: As mentioned
above the final objective of the work was to find a multisite
selective catalyst that allows one to produce 1,5-benzodiaze-
pines directly from nitroaromatics and ketones by means of
a cascade reaction in which the selective hydrogenation of
Scheme 2. Possible mechanisms for the formation of 1,5-benzodiazepines.
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Multisite Solid Catalyst for Cascade Reactions
FULL PAPER
Table 4. Synthesis of different 1,5-benzodiazepines using MCM-41(14) as acid catalyst.[a]
direct transformation of dini-
trobenzene plus a ketone into
the corresponding benzodiaze-
pine. The kinetic curves in
Figure 2 show the formation
of 2-nitroaniline, 1,2-phenyle-
nediamine, the imine inter-
mediate, and finally the corre-
sponding benzodiazepine.
The behavior of the kinetic
curves allows us to write a re-
action scheme (Scheme 3) in
which in a first hydrogenation
step the 2-nitroaniline (A) is
formed and this reacts more
slowly with hydrogen to pro-
duce the 1,2-phenylenedia-
mine (B). Product (B) is ob-
served in minor amounts be-
cause it quickly reacts with
the ketone to give the imine
(C), which is detected, while
we have not detected the
Entry
Diamine
Ketone
Product
T [8C]
t [h]
Yield[c]
[%]
1[b]
95
4
93 (95)
4
5
2[b]
100
100
2
1
94 (95)
3[b]
100 (100)
6
4
5
6
7
65
65
65
65
14
2
73 (73)
98(98)
96 (96)
96 (96)
7
imine
intermediate
(D)
8
coming from the condensation
of the amino group of 2-nitro-
aniline and the ketone.
Notably, under these reac-
tion conditions it is possible to
convert dinitrobenzene quan-
titatively and with 94% selec-
tivity to the benzodiazepine.
However, if the reaction is
continued in the presence of
2
9
4
10
[a] Reactions conditions: Diamine (2 mmol), acetone (40 mmol), catalyst (50 mg), at 658C, 6 h. [b] Diamine
(2 mmol), ketone (10 mmol). [c] Selectivity in brackets.
the nitro groups to form the aromatic amines is followed by
a cyclocondensation reaction between the diamines and ke-
tones. Since we have already seen that MCM-41 is an active
and selective catalyst for the cyclocondensation reaction
under very mild reaction conditions (658C), we need a hy-
drogenation catalyst capable of reducing, at low tempera-
ture (658C), the dinitroaromatic without reducing the car-
bonyl group of the ketone nor the C=N double bound in the
benzodiazepines. We have recently found[22] that nanocrys-
tals of Pt decorated with TiOx are able to selectively reduce
the nitro groups in a large variety of substituted nitroaro-
matics under mild reaction conditions owing to the effect of
Pt coverage by TiO2 on the preferential adsorption of the
nitro versus the double bond or carbonyl group.[22] The cata-
lyst can be prepared by supporting nanosized crystals of Pt
on TiO2 and decorating the exposed (111) and (110) Pt crys-
Figure 2. Kinetic curves of the different compounds during the one-pot
hydrogenation–cyclocondensation sequence of 1,2-nitrobenzene and ace-
tal faces with TiO2 from the support by means of a simple
activation at 4508C in the presence of hydrogen. Taking this
into account we have prepared a composite catalyst by com-
bining 0.2 wt% Pt/TiO2, and MCM-41 for carrying out the
^
tone in the presence of Pt/TiO2-MCM-41(14). ( ) 1,2-dinitrobenzene,
(*) 1,2-phenylenediamine B (&) imine C, (x) 2-nitroaniline A, (*)
^
product E, ( ) 1,5-benzodiazepine (3).
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8837

A. Corma et al.
dinitro compounds also react
selectively with acetone produc-
ing
a mixture of the corre-
sponding 7- and 8- substituted
1,5-benzodiazepines regioisom-
ers in a 1:1 molar ratio. In both
cases complete conversion and
similar selectivities were ob-
served (see Table 5). In the case
of entry 4 (Table 5), 3% of the
corresponding 2,3,4,5-tetrahy-
dro-1,5-benzodiazepine (com-
pound E in Scheme 3) and 7%
of the imine intermediate (C)
were also formed. When 1-
Scheme 3. Reaction scheme for the one-pot hydrogenation–cyclocondensation sequence.
chloro-3,4-nitrobenzene
and
acetone were allowed to react
hydrogen when the nitro groups have been fully converted,
it is possible to detect minor amounts of the product E due
to hydrogenation of the C=N double bound of the benzodia-
zepine.
The composite catalyst works with a series of dinitroaro-
matics and ketones, while solvent is not required. By adjust-
ing the reaction conditions, 1,2-dinitrobenzene reacts selec-
tively with various ketones (see Table 5). 4-Aryl-substituted
(entry 5, Table 5), 10% of imine intermediate was also
formed. Finally, reaction with an a, b-unsaturated ketone
(entry 6, Table 5<xtabr5), gives excellent conversion and
selectivity. In general conversions above 90% with selectivi-
ties of the order of 90% have been obtained in the cases
studied here by using the composite catalyst formed by the
decorated 0.2 wt% Pt/TiO2 and MCM-41. It should be re-
marked that if commercial 5 wt% Pt/C, Pt/Al2O3, Pt/C, or
Table 5. Synthesis of different 1,5-benzodiazepines using 0.2 wt% Pt/TiO2-MCM-41(14) as catalysts.[a]
Entry Dinitroaromatic Ketone
Product
P [bar][b] Thydrog. [8C] thydrog. [h] Treaction [8C] ttotal [h] Conversion [%][c] S [%][c,d]
1
7
7
55
65
1.25
1
65
2.5
100
94
3
4
2
3
95
4
92[e]
89
10
65
7
100
10
95[f]
84
5
4
7
55
55
65
1.25
1.75
3
65
65
65
3.25
3.75
100
100
95[f]
90
90
95
9
5
7
10
6[g]
10
10
3
[a] Reaction conditions: Dinitroaromatic (0.8 mmol), ketone (1.3 mL), 0.2 wt% Pt/TiO2 (60 mg), MCM-41(14) (30 mg). [b] Reactions were performed
under isobaric conditions. [c] Calculated by CG using o-xylene as internal standard. [d] Selectivity (%). [e] 2-Nitroaniline was detected in 7% yield. [f] 2-
Nitroaniline was detected in 5% yield. [g] Without MCM-41catalyst.
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Multisite Solid Catalyst for Cascade Reactions
FULL PAPER
undecorated Pt/TiO2 (reduced at 2008C) together with
MCM-41 (see Table 6) are used as catalysts, complete con-
versions are obtained but selectivities to the 1,5-benzodiaze-
pines are lower.
Since Au/TiO2 is also a chemoselective catalyst for the hy-
drogenation of nitroaromatic compounds,[22,23] thought at
higher temperatures than decorated Pt, we have carried out
the reaction with an Au/TiO2–MCM-41 composite catalyst
at 1208C. The results given in Table 6 (entry 8) show that
the composite Au/TiO2–MCM-41 also allows the reaction
with good selectivity but a higher reaction temperature is re-
quired.
Finally we have tested if the acidity of the TiO2 was suffi-
cient to perform the cyclocondensation when the reaction
was carried out at higher temperatures (1208C) since this
would avoid the use of MCM-41. Results in Table 6
(entry 7) show that in this case, longer reaction times are re-
quired for full conversion than with the composite catalyst,
while the selectivity to the benzodiazepine is much lower
owing to the remaining unreacted imine intermediate C. It
appears then that TiO2 is not acidic enough to efficiently fa-
cilitate the cyclocondensation reaction.
Experimental Section
General: MCM-41 with a Si/Al ratio of 14, 28, 50, and 80, and a pore di-
ameter of 3.5 nm were prepared in accordance with reference [24]. The
ITQ-2 delaminated material was synthesized from the corresponding
laminar precursor with the MWW structure following reference [20].
Beta zeolite was a commercial sample (Beta-CP811) provided by PQ-
Zeolyst. The 0.2 wt% Pt/TiO2 catalyst was prepared following a recently
described procedure.[22] This catalyst was obtained by the incipient wet-
ness technique using H2PtCl6 as the platinum precursor. Then, it was re-
duced under H2 flow over 3 h at 4508C before its use in the reaction.
The 0.2 wt% Pt/Al2O3 and 0.2 wt% Pt/C catalysts were prepared follow-
ing a known procedure.[22]
Acidity measurements were carried out by adsorption–desorption of pyri-
dine by IR spectroscopy. The IR spectra were recorded on a Nicolet 710
FTIR using self-supported wafers of 10 mgcmÀ2. The calcined samples
were outgassed overnight at 4008C and 10À3 Pa dynamic vacuum; then,
pyridine was admitted into the cell at room temperature. After satura-
tion, the samples were outgassed at 2508C for 1 h under vacuum, cooled
to room temperature and the spectra were recorded.
1-Chloro-3,4-dinitrotoluene was commercially available from ABCR
GmbH and Co. The rest of the reagents used in this paper including
5 wt% Pt/C were purchased from Sigma–Aldrich Co.
Cyclocondensation reaction procedure: A mixture of o-phenylenedia-
mine (2 mmol) with acetone (40 mmol) or derived ketone and nitroben-
zene (100 mg) as internal standard was prepared and added onto the cat-
alyst (50 mg) in a batch reactor. The resultant suspension was magnetical-
ly stirred and heated at the required temperature in a silicone oil bath
with an automatic temperature control system. Samples were taken at
regular time periods and analyzed by gas chromatography (GC). At the
end of the reaction the catalyst was filtered and washed with acetone,
and the organic solution was concentrated under reduced pressure,
Conclusions
We have shown that it is possible to synthesize 1,5-benzodia-
zepines directly from substituted nitroaromatics and ketones
in high yields in a one-pot system. The reaction is carried
out in the presence of hydrogen and without using solvents
by means of a bifunctional catalyst that chemoselectively
performs the hydrogenation of the nitro group to the amino
group, which subsequently cyclocondensates with the ketone
on the acid sites of the composite catalyst.
1
weighed, and analyzed by H NMR spectroscopy (300 MHz Varian VXR-
400S) and GC-MS (Hewlet-Packard 5988 A). All compounds are known
and spectroscopic data were in good agreement with those reported in
the literature.
After the reaction, the catalyst was submitted to continuous solid–liquid
extractions with acetone in micro-Soxhlet equipment. After removal of
the solvent the residue was also weighed and analyzed by GC-MS. In all
experiments the total recovered material accounted for more than 95%
of the starting o-phenylenediamine.
Cascade reaction procedure: Catalytic reactions were performed in a re-
inforced glass reactor (2 mL capacity) equipped with a manometer (for
Table 6. Product distribution for the synthesis of 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (3) using hydrogenation catalysts and MCM-
41(14).[a]
Entry Hydrogenation catalysts Reduction
P
Thydr. [8C] Timhydr [h] Treaction [8C] ttotal [h] Conv. [%][g] Sa [%][h] Sb [%][i] Sc
[%][j] [%][k]
Sd
T [8C]
[bar][b]
ACHTUNGTRENNUNG
1
2
3
4
0.2 wt% Pt/TiO2
0.2 wt% Pt/TiO2
0.2 wt% Pt/Al2O3
0.2 wt% Pt/C
450
200
450
450
–
7
7
7
7
7
7
55
55
55
55
55
55
1.25
1
1
10
0.5
1
65
65
65
65
65
85
2.5
3
3
10
1.5
14
100
100
99
97
100
100
94
77
77.5
85
33
5
1
6
10.7
8.2
–
–
3
0.7
4.1
26
5
14
11.2
2.7
41
6
5[c]
6[d]
5 wt% Pt/C
0.2 wt% Pt/TiO2
(without MCM-41)
1.5 wt% Au/TiO2
(without MCM-41)
1.5 wt% Au/TiO2
450
75
14
7[e]
–
–
10
10
120
120
1.7
1.7
120
120
14
4
100
99
73
93
1
1
19
10
8
–
8[f]
[a] Reaction conditions: Dinitrobenzene (0.8 mmol), acetone (1.3 mL), hydrogenation catalyst (60 mg), MCM-41(14) (30 mg). [b] Reactions were per-
formed under isobaric conditions. [c] Hydrogenation catalyst (30 mg). [d] Hydrogenation catalyst (120 mg). [e] Hydrogenation catalyst (100 mg). [f] Hy-
drogenation catalyst (100 mg) and MCM-41 (30 mg). [g] Calculated by CG using o-xylene as internal standard. [h] Sa =Selectivity of 1,5-benzodiazepine.
[i] Sb =Selectivity of product E. [j] Sc =Selectivity of imine C. [k] Sd =Selectivity of other products (entries 2 and 3: 3% and 0.7% of a mixture of two
compounds with MW 190–192, respectively; entry 4: 4.1% of compound with MW 228; entry 5: 22% of a mixture of two compounds with MW 190–192
and 4% of another compound with MW 150; entry 6: 3% hydrogenated intermediate (MW = 150) and 2% of 1,2-phenylenediamine; entry 7: 8% of 1,2-
phenylenediamine).
Chem. Eur. J. 2009, 15, 8834 – 8841
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www.chemeurj.org
8839

A. Corma et al.
pressure control) and a capillary tube coupled to a Luer-lock valve
through which H2 can be introduced into the reactor and through which
samples can be withdrawn for analysis at after desired period of reaction.
CDCl3,): d=171.4 (N=C-), 141.1, 137.8, 135.3 (Cqar), 127.1, 127.0, 126.1
(CHar), 67.7 (NH-Cq), 45.3 (CH2), 30.6, 20.9 ppm (2:1, Me); MS (80 eV):
m/z (%): 202 [M+], 147 (100), 146 (100), 187 (100), 145 (100), 188 (92),
77 (77), 39 (62), 41 (54), 130 (50).
A mixture of the appropriate dinitroaromatic (0.8 mmol) and ketone
7-Chloro-2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine (10):[11] Mix-
ture of regioisomers. 1H NMR (300 MHz, CDCl3): d=6.99, 6.88, 6.68 (s,
m, m, 1 H each, 3 CHar), 3.23 (sa, 1H, NH), 2.30 (s, 3H, -Me), 2.21 (s,
2H, -CH2), 1.29 ppm (s, 6H, -C(Me)2); 13C NMR (75 MHz, CDCl3): d=
172.8 (N=C-), 139.2, 138.5, 130.3 (Cqar), 128.3, 121.6, 120.9 (CHar), 67.7
(NH-Cq), 45.3 (CH2), 30.6, 30.4 ppm (2:1, Me); MS (80 eV): m/z (%): 222
[M+], 207 (100), 166 (50), 167 (48), 209 (32), 168 (20), 169 (14), 165 (13),
208 (13).
(1.3 mL) was introduced into the reactor together with
a catalytic
amount of 0.2 wt% Pt/TiO2 (60 mg) and MCM-41 (14) (30 mg). o-Xylene
was used as internal standard in all cases. Afterwards, the reactor was
sealed and air was purged by flushing three times with 7 bar of hydrogen.
Then, the reaction mixture was magnetically stirred, heated at the select-
ed temperature in a silicone oil bath, and the reactor was pressurized
with H2 at the required pressure. During the hydrogenation reaction, the
pressure was maintained constant and the reaction was monitored by gas
chromatography. When the hydrogenation reaction was finished, the re-
actor was depressurized and the reaction temperature was increased. The
reaction mixture was then stirred at the required temperature until the
reaction was complete. Finally, the catalysts were filtered and the organic
solution was concentrated under vacuum and analyzed by GC-MS (Agi-
lent 5973N).
Acknowledgements
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine
(3):[25]
1H NMR
Financial support by CiCYT MAT 2006-14274-CC02-01 and the PROM-
ETEO project from the Generalitat Valenciana, is gratefully acknowl-
edged. The authors also thank A. Velty for the cyclocondensation of phe-
nylenediamine using MCM-41 and P. Ramos for the support in carrying
out the experimental work.
(300 MHz, CDCl3): d=7.11, 6.96, 6.71 (m, m, m, 1:2:1, 4 CHar), 2.94 (sa,
1H, NH), 2.34 (s, 3H, N=C-Me), 2.21 (s, 2H, -CH2), 1.32 ppm (s, 6H,
-C(Me)2); 13C NMR (75 MHz, CDCl3): d=172.4 (N=C-), 140.7, 137.9
(Cqar), 126.9, 125.5, 122.1, 121.7 (CHar), 68.4 (NH-Cq), 45.1 (CH2), 30.5 (-
C(Me)2), 29.9 ppm (N=C-Me); MS (80 eV): m/z (%): 188 [M+], 173
(100), 132 (87), 133 (72), 131 (33), 174 (18), 39 (14), 92 (13), 65 (13), 41
(12).
[1] a) H. Schutz, Benzodiazepines, Springer, Heidelberg, 1982; b) K.
Landquist in Comprehensive Heterocyclic Chemistry, Vol. 1 (Eds.:
A. R. Katrizky, C. W. Rees), Pergamon, Oxford, 1984, pp. 166–177;
c) L. O. Randall, B. Kappel in Benzodiazepines (Eds.: S. Garattini,
E. Mussini, L. O. Randall), Ravpan Press, New York, 1973, pp. 27–
38; d) G. Grossi, M. Di Braccio, G. Roma, V. Ballabeni, M. Tognoli-
ni, F. Calcina, E. Barocelli, Eur. J. Med. Chem. 2002, 37, 933–944.
[2] a) M. Di Braccio, G. Grossi, G. Roma, L. Vargiu, M. Mura, M. E.
Marongiu, Eur. J. Med. Chem. 2001, 36, 935–949; b) G. D. Glick,
A. W. Opipari, University of Michigan, US 2003119029, 2001.
[3] W. Ried, P. Stahlhofen, Chem. Ber. 1957, 90, 815–824.
[4] W. Ried, E. Torinus, Chem. Ber. 1957, 90, 2902–2916.
[5] J. A. Herbert, H. Suschitzky, J. Chem. Soc. Perkin Trans. 1 1974,
2657–2661.
2,4-Diethyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (4):[25] 1H NMR
(300 MHz, CDCl3): d=7.11, 6.93, 6.67 (m, m, m, 1:2:1, 4 CHar), 3.32 (sa,
1H, NH), 2.56 (q, 2H, -CH2CH3), 2.15 (m, 2H, -CH2), 1.58 (m, 2H,
-CH2CH3), 1.21 (t, 3H, -CH2CH3), 1.20 (s, 3H, -CH3), 0.90 ppm (t, 3H,
-CH2CH3); 13C NMR (75 MHz, CDCl3): d=174.8 (N=C-), 139.8, 136.9
(Cqar), 126.0, 124.3, 120.7 (1:1:2, CHar), 69.7 (NH-Cq), 41.0, 34.6 (CH2),
25.9, 9.6, 7.5 ppm (CH3); MS (80 eV): m/z (%): 216 [M+], 187 (100), 145
(22), 188 (14), 133 (13), 147 (12), 146 (10), 201 (10), 132 (6), 131 (6).
2-Methyl-2,4-diphenylyl-2,3-dihydro-1H-1,5-benzodiazepine
(5):[25]
1H NMR (300 MHz, CDCl3): d=7.62, 7.29, 7.09, 6.87 (m, m, m, m,
4:7:2:1, 14 CHar), 3.55 (sa, 1H, NH), 3.09 (dd, 2H, -CH2), 1.79 ppm (s,
3H, -CH3); 13C NMR (75 MHz, CDCl3): d=167.7 (N=C-), 147.6, 140.1,
139.6, 138.1 (Cqar), 129.7, 128.7, 128.3, 128.0, 127.6, 127.1, 126.4, 125.4
(1:1:2:2:3:1:2:1:1, CHar), 73.7 (NH-Cq), 43.1 (CH2), 29.9 ppm (Me); MS
(80 eV): m/z (%): 340 [M+], 195 (100), 194 (98), 235 (84), 297 (54), 77
(31), 312 (30), 193 (29), 103 (21), 311 (19), 65 (19).
[6] H. R. Morales, A. Bulbarela, R. Contreras, Heterocycles 1986, 24,
135–139. .
[7] a) M. Curini, F. Epifano, M. C. Marcotullio, O. Rosati, Tetrahedron
Lett. 2001, 42, 3193–3195; b) X. Q. Pan, J. P. Zou, Z. H. Huang, W.
Zhang, Tetrahedron Lett. 2008, 49, 5302–5308.
10-Spirocyclopentane-1,2,3,9,10,10a-hexahydrobenzo[b]cyclopentane[e]-
ACHTUNGTRENNUNG
[1,4]diazepine (6):[25] 1H NMR (300 MHz, CDCl3): d=7.39–6.74 (m, 4H).
[8] D. I. Jung T. W. Choi, Y. Y. Kim, I. S. Kim Y. M. Park, Y. G. Lee,
D. H. Jung, Synth. Commun. 1999, 29, 1941–1951.
[9] R. Varala, R. Enugala, S. Nuvula, Synlett 2006, 1009–1014.
[10] K. S. Reddy, C. V. Reddy, M. Mahesh, K. R. Reddy, P. V. K. Raju,
V. V. N. Reddy, Can. J. Chem. 2007, 85, 184–188.
[11] M. Pozarentzi, J. Stephanidou-Stephanatou, C. A. Tsoleridis, A.
Constantinos, Tetrahedron Lett. 2002, 43, 1755–1758.
[12] R. Varala, R. Enugala, S. R. Adapa, R. Srinivas, J. Braz. Chem. Soc.
2007, 18, 291–296.
[13] D. V. Jarikote, S. A. Siddiqui, R. Rajagopal, T. Daniel, R. J. Lahoti,
K. V. Srinivasan, Tetrahedron Lett. 2003, 44, 1835–1838.
[14] B. M. Reddy, P. M. Sreekanth, P. Lakshmanan, J. Mol. Catal. A 2005,
237, 93–100.
[15] R. Fazaeli, H. Aliyan, S. Tangestaninejad, Heterocycles 2007, 71,
805–814.
[16] R. Fazaeli, H. Aliyan, Appl. Catal. A 2007, 331, 78–83.
[17] A. Hegedꢃs, Z. Hell, A. Potor, Catal. Lett. 2005, 105, 229–232.
[18] M. Tajbakhsh, M. H. Heravi, B. Mohajerani, A. N. Ahmadi, J. Mol.
Catal. A 2006, 247, 213–215.
[19] W. Werner, W. Jungstand, W. Gutsche, K. Wohlrabe, W. Romer, D.
Tresselt, Pharmazie 1979, 34, 394–397.
4.52 (s, br, NH, 1H), 2.60–2.35 (m, 3H), 1.90–1.32 ppm (m, 12H);
13C NMR (75 MHz, CDCl3): d =178.0, 143.3, 139.8, 132.2, 126.9, 119.5,
118.4, 67.3, 54.5, 39.0, 38.5, 33.4, 28.8, 24.2, 24.1, 23.5 ppm; MS (80 eV):
m/z (%): 240 [M+].
2,3-Dihydro-2,2,4-trimethyl-1H-naphtho
G
G
(7):[11]
1H NMR (300 MHz, CDCl3): d=7.72, 7.62, 7.55, 7.32, 7.13 (m, m, s, m, s,
1:1:1:2:1, 6 CHar), 3.70 (sa, 1H, NH), 2.40 (s, 3H, N=C-Me), 2.22 (s, 2H,
-CH2), 1.36 ppm (s, 6H, -C(Me)2); 13C NMR (75 MHz, CDCl3): d=171.4
(N=C-), 136.7, 131.0, 129.6, 129.5 (Cqar), 126.7, 124.8, 123.1, 122.8, 116.7
(CHar), 65.0 (NH-Cq), 43.8 (CH2), 29.1 (-C(Me)2), 28.8 ppm (N=C-Me);
MS (80 eV): m/z (%): 238 [M+], 223 (100), 183 (40), 182 (31), 224 (18),
115 (17), 181 (10), 140 (9), 180 (7), 114 (7).
2,3-Dihydro-7-methoxy-2,2,4-trimethyl-1H-1,5-benzodiazepine
(8):[11,26]
1
Mixture of regioisomers. H NMR (300 MHz, CDCl3,): d=6.99, 6.78, 6.59
(m, m, s, 1 H each, 3 CHar), 3.70 (s, 3H, -OMe), 3.01 (sa, 1H, NH), 2.26
(s, 3H, N=C-Me), 2.15 (s, 2H, -CH2), 1.29 ppm (s, 6H, -C(Me)2);
13C NMR (75 MHz, CDCl3,): d=172.5 (N=C-), 138.0, 135.2, 131.8 (Cqar),
122.7, 122.0, 121.8 (CHar), 68.4 (NH-Cq), 55.0 (-OMe), 45.1 (CH2), 30.2,
20.6 ppm (2:1, Me); MS (80 eV): m/z (%): 218 [M+].
2,3-Dihydro-2,2,4,7-tetramethyl-1H-1,5-benzodiazepine (9):[11,26] Mixture
of regioisomers. 1H NMR (300 MHz, CDCl3,): d=6.91, 6.76, 6.62 (m, m,
s, 1 H each, 3 CHar), 2.87 (sa, 1H, NH), 2.31 (s, 3H, -Me), 2.24 (s, 3H,
-Me), 2.19 (s, 2H, -CH2), 1.30 ppm (s, 6H, -C(Me)2); 13C NMR (75 MHz,
[20] A. Corma, V. Fornes, J. M. Guil, S. Pergher, T. L. M. Maesen, J. G.
Buglass, Microporous Mesoporous Mater. 2000, 38, 301–309.
[21] A Corma, Chem. Rev. 1997, 97, 2373–2419.
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Chem. Eur. J. 2009, 15, 8834 – 8841

Multisite Solid Catalyst for Cascade Reactions
FULL PAPER
[22] A. Corma, P. Serna, P. Concepciꢄn, J. Calvino, J. Am. Chem. Soc.
2008, 130, 8748–8753.
[25] M. A. Pasha, V. P. Jayashankara, J. Pharm. Toxicol. 2006, 1, 573–
578.
[23] A. Corma, P. Concepciꢄn, P. Serna, Angew. Chem. 2007, 119, 7404–
7407; Angew. Chem. Int. Ed. 2007, 46, 7266–7269.
[24] C. T. Kresge, M. E. Leonowicz, W. J. Roth, J. C. Vartulli, J. S. Beck,
Nature 1992, 359, 710–712.
[26] G. Kaupp, U. Pogodda, J. Schmeyers, Chem. Ber. 1994, 127, 2249–
2261.
Received: February 23, 2009
Published online: July 20, 2009
Chem. Eur. J. 2009, 15, 8834 – 8841
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8841