Molecular-iodine-catalyzed one-pot synthesis of 1,5-benzodiazepine derivatives under solvent-free conditions

Article abstract of DOI:10.1055/s-2005-868516

2,3-Dihydro-1H-1,5-benzodiazepines have been synthesized from o-phenylenediamine (OPDA) and ketones under solvent-free conditions in the presence of a catalytic amount of molecular iodine. All of the ketones, including cyclic ketones and acyclic ketones,

Full text of DOI:10.1055/s-2005-868516

LETTER
1337
Molecular-Iodine-Catalyzed One-Pot Synthesis of 1,5-Benzodiazepine
Derivatives under Solvent-Free Conditions
M
olecular-Iodine-Cataly
e
zedOne-P
i-hesis of
Y
1,5-Benzodiazepin
i
e
D
erivativesChen,* Jun Lu
College of Chemistry and Chemical Engineering, Suzhou University, Suzhou, 215006, P. R. China
Fax +86(512)65112371; E-mail: suzhoucwy@163.com
Received 7 March 2005
ketones in the presence of BF3·OEt2,8 NaBH4,9 polyphos-
phoric acid,10 SiO2,10 MgO and POCl3,11 Yb(OTf)3,12
Al2O3/P2O5 under MW,13 AcOH under MW,14 and ionic
liquid.15 Many of these processes suffer at least one limi-
Abstract: 2,3-Dihydro-1H-1,5-benzodiazepines have been syn-
thesized from o-phenylenediamine (OPDA) and ketones under
solvent-free conditions in the presence of a catalytic amount of
molecular iodine. All of the ketones, including cyclic ketones and
acyclic ketones, reacted smoothly with OPDA to furnish products. tation such as drastic reaction conditions, expensive
Compared to other reaction conditions, this new protocol has the
reagents, low to moderate yields, relatively long reaction
advantage of excellent yield and short reaction time at room temper-
ature.
times, or occurrence of several side reactions. Most of
them make use of an acid catalyst giving rise to tedious
work-up procedures for their separation and recycling or
disposal.
Key words: benzodiazepine, o-phenylenediamine, iodine, ketones,
solvent-free
In recent years, molecular iodine has received consider-
able attention as an inexpensive and easily available cata-
Benzodiazepines are interesting compounds because of
lyst for various organic transformations.16–18 Given the
their pharmacological properties.1 Many members of this
large number of similar condensation reactions that have
family are, in fact, nowadays widely used as anti-convul-
been reported to proceed readily under solvent-free condi-
sant, anti-anxiety, analgesic, sedative, anti-depressive,
tions,19,20 we proceeded to examine the synthesis of 1,5-
and hypnotic agents.2 Although the first benzodiazepine
benzodiazepine derivatives in the presence of a catalytic
was introduced as a drug nearly 30 years ago,3 research in
amount of molecular iodine under solvent-free conditions
this area is still very active and is directed towards the
(Scheme 1). The results are summarized in Table 1.
synthesis of compounds with enhanced pharmacological
activity. It was also found that 1,5-benzodiazepines are
R
N
O
valuable synthons used for the preparation of other fused
ring compounds such as triazolo-,4 oxadiazolo-5, oxa-
zino-6, or furano-benzodiazepines.7
NH2
NH2
I2, solvent-free
5–10 min, r.t.
+
R
CH3
CH3
N
H
R
Despite their wide range of pharmacological activity, in-
dustrial and synthetic applications, the synthesis of 1,5-
benzodiazepines has received little attention, and few
methods for their preparation are reported in the literature,
a great number of which have appeared only very recent-
ly. These include condensation reactions of OPDA with
a,b-unsaturated carbonyl compounds, b-haloketones or
1
2
3
Scheme 1
The reactions were carried out simply by mixing OPDA
with a ketone in the presence of a catalytic amount (10
mol%) of iodine under solvent-free condition. The mix-
R
R
N
NH2
NH2
N
N
O
I2
CH3
CH3
CH2
CH3
CH3
+
R
N
H
R
R
A
B
R
R
H
N
N
CH3
CH3
N
N
H
R
R
Scheme 2
SYNLETT 2005, No. 8, pp 1337–1339
1
7.
0
5.
2
0
0
5
Advanced online publication: 03.05.2005
DOI: 10.1055/s-2005-868516; Art ID: U06405ST
© Georg Thieme Verlag Stuttgart · New York

1338
W.-Y. Chen, J. Lu
LETTER
Table 1 Synthesis of 1,5-Benzodiazepine Derivatives Catalyzed by
Iodine under Solvent-Free Conditions
ture was ground together in a mortar with a pestle at room
temperature for several minutes, then purified by column
chromatography, and the 1,5-benzodiazepine derivatives
were obtained in excellent yields.
Entry Ketone
Producta
Yield Time
(%)b (min)
As shown in Table 1, OPDA undergoes rapid condensa-
tion with ketones having hydrogens at the a-position in
the presence of 10 mol% iodine under extremely mild re-
action conditions to afford the corresponding 2,3-dihydro-
1H-1,5-benzodiazepines in excellent yields with high
selectivity. Interestingly, both cyclic and acyclic ketones
reacted with OPDA to give the corresponding products in
good yield, without any significant difference. This meth-
od offers several advantages such as high conversions,
short reaction times, cleaner reaction profiles, high regio-
selectivity in the case of unsymmetrical ketones, solvent-
free conditions, and simple experimental and work-up
procedures.
1
2
3
4
95
5
5
6
8
O
CH3
N
(97)c
H3C
CH3
CH3
CH3
N
H
3a
3b
3c
90
86
86
O
C2H5
N
H3C
CH3
CH3
N
H
C2H5
O
C2H5
N
H3C
CH3
A possible mechanism for the condensation of OPDA
with ketones is shown in Scheme 2; the amino group of
OPDA attacks the carbonyl group of the ketone, which is
activated by iodine, giving the intermediate diimine A. A
1,3-shift of the hydrogen attached to the methyl group
then occurs to form an isomeric enamine B, which
cyclizes to afford a seven-membered ring.
CH3
C2H5
C2H5
N
H
iPr
CH3
O
N
H3C
CH3
CH3
iPr
N
H
In conclusion, iodine was found to be a mild and effective
catalyst for the formation of 1,5-benzodiazepines in excel-
lent yields. The uses of this inexpensive and easily avail-
able catalyst under solvent-free conditions make this
protocol practical and economically attractive. The simple
work-up procedure, mild reaction conditions, selectivity,
and very good yields make our methodology a valid
contribution to the existing processes in the field of 1,5-
benzodiazepine derivatives synthesis.
3d
3e
3f
5
6
7
8
94
83
88
92
10
10
8
C6H5
O
N
CH3
CH3
N
H
C6H5
O
C6H4(p-CH3)
N
CH3
References
CH3
N
H
H3C
O
(1) (a) Schutz, H. Benzodiazepines; Springer: Heidelberg,
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C6H4(p-CH3)
N
N
H
3g
8
(3) Sternbach, L. H. Angew. Chem., Int. Ed. Engl. 1971, 10, 34.
(4) Aversa, M. C.; Ferlazzo, A.; Giannetto, P.; Kohnke, F. H.
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O
N
(5) Chimirri, A.; Grasso, S.; Ottana, R.; Romeo, G.; Zappala, M.
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N
H
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3h
a All products were characterized by NMR spectroscopy.
b Isolated yields.
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2000, 30, 1825.
(8) Herbert, J. A. L.; Suschitzky, H. J. Chem. Soc., Perkin
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c The reaction was carried out on 10 mmol scale.
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1986, 24, 135.
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Synlett 2005, No. 8, 1337–1339 © Thieme Stuttgart · New York

LETTER
Molecular-Iodine-Catalyzed One-Pot Synthesis of 1,5-Benzodiazepine Derivatives
1339
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3c: Mp 142–144 °C. IR (KBr): 3320, 1638, 1596 cm–1.1H
NMR (CDCl3): d = 0.81–1.15 (m, 10 H), 1.22–1.42 (m, 4 H),
1.52–1.66 (m, 2 H), 2.38–2.56 (m, 2 H), 2.91 (q, 1 H, J = 7.0
Hz), 3.78 (br s, 1 H), 6.56–7.38 (m, 4 H). 13C NMR (CDCl3):
d = 7.6, 7.9, 11.9, 12.4, 28.1, 28.5, 35.5, 46.4, 68.4, 117.6,
118.2, 126.4, 132.7, 139.1, 142.2, 173.9.
3d: Mp 118–120 °C. IR (KBr): 3265, 1651, 1600 cm–1. 1H
NMR (CDCl3): d = 0.96–1.085 (m, 12 H), 1.34 (s, 3 H),
1.50–1.52 (m, 2 H), 1.66–1.75 (m, 1 H), 2.07–2.26 (m, 3 H),
2.25 (d, 2 H, J = 12.7 Hz), 6.60–7.15 (m, 4 H). 13C NMR
(CDCl3): d = 22.6, 22.9, 24.1, 24.8, 25.1, 26.2, 28.3, 43.4,
51.7, 51.9, 70.9, 121.4, 121.5, 125.3, 127.4, 137.9, 140.5,
173.9.
3e: Mp 150–152 °C. IR (KBr): 3268, 1640, 1601 cm–1. 1H
NMR (CDCl3): d = 1.81 (s, 3 H), 3.01 (d, 1 H, J = 12.8 Hz),
3.16 (d, 1 H, J = 12.8 Hz) 3.45 (br s, 1 H), 6.56–7.02 (m, 3
H), 7.14–7.40 (m, 7 H), 7.56–7.65 (m, 4 H). 13C NMR
(CDCl3): d = 29.8, 42.9, 73.5, 121.2, 121.5, 125.3, 126.1,
126.7, 126.9, 127.8, 128.2, 128.5, 129.6, 137.9, 139.4,
139.9, 147.5, 167.6.
(21) General Experimental Procedure: A mixture of OPDA (1
mmol), ketone (2 mmol), and iodine (0.1 mmol) were
ground together in a mortar with a pestle at room
temperature for several minutes. After completion of the
reaction (TLC), the reaction was treated with aqueous
Na2S2O3 to furnish the crude products, which were further
purified by column chromatography.
3f: Mp 141–143 °C. IR (KBr): 3270, 1644, 1602 cm–1. 1H
NMR (CDCl3): d = 2.11 (s, 9 H,), 3.05 (d, 1 H, J = 13.6 Hz),
3.17 (d, 1 H, J = 13.6 Hz,), 3.60 (br s, 1 H), 7.12–7.61 (m, 11
H). 13C NMR (CDCl3): d = 21.3, 24.4, 28.4, 29.0, 46.4, 52.5,
114.7, 122.2, 126.2, 127.1, 128.6, 132.7, 133.1, 133.6,
135.5, 136.1, 164.9.
3a: Mp 145–146 °C. IR (KBr): 3341, 1637, 1600 cm–1. 1H
NMR (CDCl3): d = 1.37 (s, 6 H), 2.25 (s, 2 H), 2.39 (s, 3 H),
3.44 (br s, 1 H), 6.64–7.41 (m, 4 H). 13C NMR (CDCl3): d =
29.4, 30.8, 44.9, 68.1, 121.6, 122.3, 126.1, 126.8, 138.2,
140.9, 171.6.
3g: Mp 136–138 °C. IR (KBr): 3342, 1656, 1604 cm–1. 1H
NMR (CDCl3): d = 1.29–1.88 (m, 12 H), 2.31–2.58 (m, 3 H),
4.36 (br s, 1 H), 6.71–7.39 (m, 4 H). 13C NMR (CDCl3): d =
23.5, 24.1, 24.4, 28.9, 33.4, 38.5, 39.4, 54.4, 67.3, 118.6,
119.5, 126.9, 132.3, 139.3, 143.3, 178.4.
3b: Mp 137–138 °C. IR (KBr): 3328, 1640, 1608 cm–1.1H
NMR (CDCl3): d = 0.98 (t, 3 H, J = 6.8 Hz), 1.24 (t, 3 H,
J = 7.1 Hz), 1.72 (q, 2 H, J = 6.8 Hz), 2.18 (m, 2 H), 2.34 (s,
3 H), 2.71 (q, 2 H, J = 7.1 Hz), 3.28 (br s, 1 H), 6.78–7.33
(m, 4 H). 13C NMR (CDCl3): d = 8.8, 11.2, 26.8, 35.9, 36.0,
42.3, 70.8, 121.9, 125.2, 126.4, 126.8, 137.6, 140.9, 175.8.
3h: Mp 137–139 °C. IR (KBr): 3321, 1654, 1600 cm–1. 1H
NMR (CDCl3): d = 1.88–2.58 (m, 16 H), 2.46–2.79 (m, 3 H),
4.55 (br s, 1 H), 6.65–7.36 (m, 4 H). 13C NMR (CDCl3): d =
21.5, 21.7, 23.3, 24.5, 25.4, 33.4, 34.4, 39.3, 40.5, 52.4, 63.2,
121.1, 121.4, 126.3, 129.7, 138.2, 142.4, 178.8.
Synlett 2005, No. 8, 1337–1339 © Thieme Stuttgart · New York