Efficient synthesis of 1,5-benzodiazepine derivatives by ytterbium trichloride-catalyzed condensation of o-phenylenediamine and ketones

Article abstract of DOI:10.1080/00397910500383527

1,5-Benzodiazepines are synthesized in good to excellent yields by ytterbium trichloride (YbCl₃)-catalyzed condensation of o-phenylenediamine and ketones under mild and solvent-free conditions. The Lewis acid-type catalyst, ytterbium trichlorid

Full text of DOI:10.1080/00397910500383527

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Efficient Synthesis of 1,5‐Benzodiazepine
Derivatives by Ytterbium
Trichloride–Catalyzed Condensation of
o‐Phenylenediamine and Ketones
Jianting Wu a , Fan Xu a , Zhuqing Zhou a & Qi Shen a
a Key Laboratory of Organic Synthesis, Department of Chemistry
andChemical Engineering , Suzhou University , Suzhou, China
Published online: 19 Aug 2006.
To cite this article: Jianting Wu , Fan Xu , Zhuqing Zhou & Qi Shen (2006) Efficient Synthesis of
1,5‐Benzodiazepine Derivatives by Ytterbium Trichloride–Catalyzed Condensation of o‐Phenylenediamine and
Ketones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 36:4, 457-464, DOI: 10.1080/00397910500383527
To link to this article: http://dx.doi.org/10.1080/00397910500383527
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Synthetic Communicationsw, 36: 457–464, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500383527
Efficient Synthesis of 1,5-Benzodiazepine
Derivatives by Ytterbium Trichloride–
Catalyzed Condensation of
o-Phenylenediamine and Ketones
Jianting Wu, Fan Xu, Zhuqing Zhou, and Qi Shen
Key Laboratory of Organic Synthesis, Department of Chemistry
and Chemical Engineering, Suzhou University, Suzhou, China
Abstract: 1,5-Benzodiazepines are synthesized in good to excellent yields by
ytterbium trichloride (YbCl3)–catalyzed condensation of o-phenylenediamine and
ketones under mild and solvent-free conditions. The Lewis acid–type catalyst,
ytterbium trichloride, is found to be water stable and reusable.
Keywords: 1,5-Benzodiazepine, catalysis, lanthanide, synthesis, ytterbium trichloride
INTRODUCTION
Benzodiazepines and their derivatives are well known as a class of biologi-
cally active materials, widely used as anticonvulsant, analgesic, hypnotic,
sedative, and antidepressive agents.[1] In addition, 1,5-benzodiazepines have
found applications as available intermediates in the synthesis of other fused
ring compounds such as triazolo-, oxazino-, oxadiazolo-, or furano-benzo-
diazepines.[2] Because of their wide range of pharmacological properties
and potential industrial and synthetic applications, the synthesis of 1,5-benzo-
diazepines has recently received considerable attention. As a result, several
methods for the preparation of 1,5-benzodiazepines have been
reported. These include condensation reactions of o-phenylenediamine with
Received in Japan July 23, 2005
Address correspondence to Qi Shen or Fan Xu, Key Laboratory of Organic
Synthesis, Department of Chemistry and Chemical Engineering, Suzhou University,
1 Shizi Street, Suzhou 215006, China. E-mail: xufan@suda.edu.cn
457

458
J. Wu et al.
a,b-unsaturated carbonyl compounds,[3] b-haloketones[4] and ketones
promoted by BF3-etherate,[5] NaBH4,[6] polyphosphoric acid,[7] SiO2,[7]
MgO/POCl3,[8] superacid sulfated zirconia,[9] Ln(OTf)3,[10] and SmI2.
Stoichiometric amount of ionic liquid–promoted[11] and microwave-
irradiated[12] preparation of 1,5-benzodiazepine have also been presented.
However, some of these processes suffered from limitations such as
expensive reagents, inconvenient catalyst preparation, high catalyst loading,
drastic reaction conditions, and presence of side reactions.
The applications of lanthanide reagents in organic synthesis have been
increasingly appreciated and widely studied[13] in recent years. A broad and
significant study identified lanthanide triflates [Ln(OTf)3][14] as an excellent
Lewis acid–type catalyst because it is water compatible and reusable, but
the more readily available and economical lanthanide chloride (LnCl3) did
not receive an adequate attention because of its relatively weaker Lewis
acidity. In continuation of our studies on lanthanide halides–catalyzed C–N
bond-forming reactions,[15] we investigated the application of lanthanide
chlorides as Lewis acid catalysts in the condensation of o-phenylenediamine
with ketones to form 1,5-benzodiazepines. We found that lanthanide
chlorides not only show high activity but also can be recovered and reused
without loss of efficiency. Herein we report the results.
As a starting point of our exploration, the condensation of o-phenylene-
diamine with acetone was carried out in the presence of 5 mol% LnCl3
(Scheme 1) at room temperature for 40 min. A series of lanthanide chlorides
(Ln: Y, La, Sm, Gd, Yb) are screened, and the results are summarized in
Table 1. The reactions all went smoothly, and 2,2,4-trimethyl-2,3-dihydro-
1H-1,5-benzodiazepine was obtained in high yields, and only a trace of the
product was obtained in the absence of the catalyst even when the reaction
time was prolonged to 24 h (entry 1). Of the lanthanide chlorides tested,
YbCl3 showed the best catalytic effect, and the yield of the product reached as
high as 98% when the reaction time was prolonged to 12h (entries 6 and 7).
The amount of YbCl3 greatly affected the rate of the reaction. Using
2.5 mol% YbCl3 as catalyst, an 88% yield was gained only when the reaction
time was prolonged to 20h (entry 8).
To investigate the feasibility of this synthetic methodology for benzo-
diazepine derivatives, the reactions of o-phenylenediamine with various
ketones were examined in the presence of 5 mol% YbCl3 at room temperature
(Scheme 2). The results are listed in Table 2. As shown in this table, both
Scheme 1.

Efficient Synthesis of 1,5-Benzodiazepine Derivatives
459
Table 1. LnCl3-catalyzed condensation of o-phenylene-
diamine with acetonea
Isolated yield
(%)
Entry
Catalyst
—
Time
1
2
3
4
5
6
7
8b
9
24 h
trace
90
YCl3
40 min
40 min
40 min
40 min
40 min
12 h
LaCl3
SmCl3
GdCl3
YbCl3
YbCl3
YbCl3
88
87
80
92
98
88
20 h
40 min
.
YbCl3 H2O
89
aTypical reaction conditions: o-phenylenediamine/
ketone 1 : 2.1, 5 mol% LnCl3 relative to o-phenylenedia-
mine, room temperature.
b2.5 mol% YbCl3 was used.
aromatic and aliphatic ketones reacted with o-phenylenediamine, affording
the corresponding 1,5-benzodiazepines in fair to excellent yields. However,
the ketones tested afterward were all less active than acetone. To get the
desired yield of corresponding 1,5-benzodiazepines, the reaction time
should be prolonged over 24 h. The steric effect can be observed in the con-
densation of o-phenylenediamine with linear aliphatic ketones. The reaction
involving butanone gave the corresponding 1,5-benzodiazepine in 91%
yield at room temperature for 30 h (entry 2), whereas only 81% yield with
3-pentanone (entry 3). The reactions with cyclic ketones instead of linear
ketones also proceeded smoothly and gave good yields (entries 4 and 5).
However, the yield dropped significantly when the aromatic ketone bearing
methoxy group on the benzene ring was used instead of acetophenone
(entries 6 and 8). The reason for it may be not only the deactivation of
carbonyl group in the presence of electron-donating substituent but also the
competitive coordination of –OCH3 with lanthanide cation.
Scheme 2.

460
J. Wu et al.
Table 2. YbCl3-catalyzed condensation of o-phenylenediamine with ketonesa
Time
(h)
Isolated
yield (%)
Entry
1
Ketone
Product
98 (94, 95, 95)b
3a
CH3COCH3
12
30
2
CH3CH2COCH3
91c
3b
3b0
3c
3d
3e
3f
3
4
5
6
CH3CH2COCH2CH3
30
24
36
36
81
82
87
83
PhCOCH3
3g
7
8
p-ClPhCOCH3
36
36
75
p-CH3OPhCOCH3
3h 49
aTypical reaction conditions: o-phenylenediamine/ketone 1 : 2.1, 5 mol% YbCl3
relative to the o-phenylenediamine, room temperature.
bThe yields in the second, third, and fourth cycle reactions using the recovered catalyst.
cThe overall yield of a pair of diastereoisomers.

Efficient Synthesis of 1,5-Benzodiazepine Derivatives
461
We noticed that the present reaction catalyzed by YbCl3 proceeded without
any water absorber, such as molecular sieves, as additives, although two
equivalents of water were generated during the condensation of o-phenylene-
diamine with ketone. This observation indicated that YbCl3 seems stable
toward water. To confirm the inference, the reaction of o-phenylenediamine
.
and acetone catalyzed by hydrated lanthanide chloride, YbCl3 H2O, was
tried, and 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine was obtained
in good yield (Table 1, entry 9). Thus, unlike most traditional Lewis acids,
lanthanide chloride was shown to be water stable and functioned well with
high catalytic activity as a Lewis acid.
The recyclable character of YbCl3 was also investigated. The catalyst was
recovered from the reaction system by centrifugation and subsequent drying in
vacuo at 1008C for 1 h. Then the recovered catalyst was used again in the next
reaction. As shown in Table 2, the yield of 2,2,4-trimethyl-2,3-dihydro-1H-
1,5-benzodiazepine in the fourth use of the catalyst was almost same as that
in the first use (Table 2, entry 1).
It is noteworthy that all the reactions were carried out under solvent-free
conditions. Taking the reusability of the catalyst into consideration, the
present YbCl3-catalyzed condensation of o-phenylenediamine and ketone is,
without doubt, a clean and environmentally friendly reaction.
In conclusion, we have demonstrated here a new and efficient procedure
for the synthesis of 1,5-benzodiazepine derivatives by YbCl3-catalyzed con-
densation of o-phenylenediamine with ketones under mild and convenient
conditions. This methodology gives us the chance to make better use of
YbCl3, which is found to be water stable and reusable as a new type of
Lewis acid catalyst, in organic synthesis.
EXPERIMENTAL
Materials and Methods
All the manipulations were conducted under dry Ar atmosphere with flame-
dried glassware. Lanthanide chlorides were synthesized according to the
method described by Taylor et al.[16] Ketones were distilled prior to use.
o-Phenylenediamine was recrystallized from hot water containing sodium
1
hydrosulfite and treated with decolorizing charcoal. H NMR spectra were
obtained on Varian Inova-400 spectrometer using TMS as internal reference.
Elemental analyses were determined on a Carlo Erba EA1110-CHNS-O
analyzer. Mass spectra were recorded on a Micromass GCT instrument.
General Procedures for the Synthesis of 1,5-Benzodiazepines
A mixture of o-phenylenediamine (1 mmol) and ketone (2.1 mmol) was stirred
in the presence of YbCl3 (0.05 mmol) at room temperature for the given time.

462
J. Wu et al.
After completion of the reaction (TLC), water was added, and the mixture was
extracted with ethyl acetate (5 ml ꢀ 4). The organic layer was dried over
anhydrous sodium sulfate and evaporated under reduced pressure. The
crude product was purified by chromatography on silica gel using ethyl
acetate–petroleum ether (1 : 7) as eluent to afford 1,5-benzodiazepine.
Spectra Data of the Selected Products
3a: 1H NMR (400 MHz, CDCl3): d 7.17–6.73 (m, 4H), 3.01 (br, 1H), 2.40
(s, 3H), 2.25 (s, 2H), 1.35 (s, 6H).
3e: 1H NMR (400 MHz, CDCl3): d 7.29–6.71 (m, 4H), 3.79 (br, 1H), 2.60
(t, J ¼ 6.4 Hz, 2H), 2.39 (t, J ¼ 6.0 Hz, 1H), 1.89–1.22 (m, 16H); MS (EI):
m/z ¼ 268 (Mþ); calcd. for C18H24N2: C, 80.55; H, 9.01; N, 10.44. Found:
C, 80.35; H, 9.12; N, 10.40.
1
3f: H NMR (400 MHz, CDCl3): d 7.61–6.84 (m, 14H), 3.53 (br, 1H),
3.15 (d, J ¼ 13.6 Hz, 1H), 2.98 (d, J ¼ 13.6 Hz, 1H), 1.77 (s, 3H).
1
3g: H NMR (400 MHz, CDCl3): d 7.54–6.84 (m, 12H), 3.46 (br, 1H),
3.10 (d, J ¼ 13.2 Hz, 1H), 2.91 (d, J ¼ 13.2 Hz, 1H), 1.75 (s, 3H); MS (EI):
m/z ¼ 380 (Mþ–H); calcd. for C22H18N2Cl2: C, 69.30; H, 4.76; N, 7.35.
Found: C, 69.19; H, 4.97; N, 7.35.
3 h: 1H NMR (400 MHz, CDCl3) d 7.51–6.77 (m, 12H), 3.88 (s, 3H), 3.78
(s, 3H), 3.01–2.95 (m, 2H), 1.76 (s, 3H); MS (EI): m/z ¼ 372 (Mþ); calcd. for
C24H24N2O2: C, 77.39; H, 6.50; N, 7.52. Found: C, 77.23; H, 6.68; N, 7.13.
ACKNOWLEDGMENT
We thank the National Science Foundation of China (Grant No. 20272040),
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, and Key Laboratory of
Organic Synthesis of Jiangsu Province for financial support.
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