Ga(OTf)3-promoted condensation reactions for 1,5-benzodiazepines and 1,5-benzothiazepines

Article abstract of DOI:10.1016/j.tetlet.2008.06.082

Condensation reactions of o-phenylenediamine and two equivalents of acetophenone under gallium(III) triflate catalysis produce biaryl-substituted 1,5-benzodiazepines. Similar reactions of o-phenylenediamine or o-aminothiophenol and o-hydroxy chalcones lead to formation of functionalized 1,5-benzodiazepines and 1,5-benzothiazepines in good to excellent yields. The ortho-hydoxy group of chalcones is crucial for this unprecedented condensation process.

Full text of DOI:10.1016/j.tetlet.2008.06.082

Tetrahedron Letters 49 (2008) 5302–5308
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Tetrahedron Letters
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Ga(OTf)3-promoted condensation reactions for 1,5-benzodiazepines
and 1,5-benzothiazepines
a
b,
Xiang-Qiang Pan a, Jian-Ping Zou a, , Zhi-Hao Huang , Wei Zhang
*
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, 1 Renai Street, Suzhou, Jiangsu 215123, China
b Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Condensation reactions of o-phenylenediamine and two equivalents of acetophenone under gallium(III)
triflate catalysis produce biaryl-substituted 1,5-benzodiazepines. Similar reactions of o-phenylenedi-
amine or o-aminothiophenol and o-hydroxy chalcones lead to formation of functionalized 1,5-benzodi-
azepines and 1,5-benzothiazepines in good to excellent yields. The ortho-hydoxy group of chalcones is
crucial for this unprecedented condensation process.
Received 16 May 2008
Revised 17 June 2008
Accepted 18 June 2008
Available online 22 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1,5-Benzodiazepines and 1,5-benzothiazepines are privileged
heterocyclic ring systems because of their broad and important
pharmacological properties.1 Many functionalized benzodiaze-
pines have been used as analgesic, sedative, anti-convulsant,
anti-anxiety, anti-depressive, and hypnotic agents.2 In addition to
their biological activities, they are valuable synthetic intermediates
for other heterocyclic compounds such as triazolo-, oxadiazolo-,
oxazino-, and furanobenzodiazepines.3
reported in the literature, gallium(III)-promoted reactions are
straightforward, give good yields, and also lead to the discovery
of a novel transformation for heterocycles.
o-Phenylenediamine and acetophenone were chosen as the sub-
strates for method development reactions (Eq. 1). Table 1 shows
the results using different reaction solvents under the conditions
A general way to construct the ring skeletons of 1,5-benzodiaz-
epine and 1,5-benzothiazepine is via reactions of o-phenylenedi-
Table 1
Ga(OTf)3-catalyzed reactions of o-phenylenediamine and acetophenonea
amines (o-PDA) or o-aminothiophenol (o-ATP) with ketones,4
a,b-
unsaturated carbonyl compounds, or b-haloketones.5 Catalysts
such as BF3ꢀEt2O, NaBH4, PPA/SiO2, MgO/POCl3, Amberlyst-15,
Yb(OTf)3, Al2O3/P2O5, AcOH/MW, sulfated zirconia, NBS, and ionic
liquids6 has been used to improve the reaction efficiency.
O
H
N
NH2
NH2
Ga(OTf)3
solvent
+
Ga(OTf)3 is a water-tolerant strong Lewis acid catalyst, which
has been used in organic reactions such as Beckmann rearrange-
ment,7 Friedel–Crafts reactions,8,9 dehydration of aldoximes,10
and highly regioselective rearrangement of 2-substituted vinylep-
oxides,11 aqueous asymmetric Mukaiyama aldol reactions,12 and
constructions of fused-bicyclolactones13 and fluorinated five-
membered heterocycles.14 As a part of our continuous effort on
the study of the catalytic properties of gallium(III) salts,15 we re-
port herein a new utility of gallium(III) triflate catalyst for conden-
sation reactions of o-phenylenediamine or o-aminothiophenol
with carbonyl compounds to form functionalized 1,5-benzodiaze-
pines and 1,5-benzothiazepines. Compared to other methods
N
1a
2a
ð1Þ
Entry
Solvent
Ga(OTf)3 (mol %)
Time (h)
2a Yieldb (%)
1
2
3
4
5
6
7
8
CH2Cl2
MeOH
10
10
10
10
5
1
20
0
12
12
12
4
12
24
4
56
Trace
Trace
92
50
23
1,4-Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
94
—
c
12
* Corresponding authors. Tel./fax: +86 512 65112371 (J.-P.Z.); tel.: +1 617 287
6147; fax: +1 617 287 6030 (W.Z.).
E-mail addresses: wuyanhong@pub.sz.jsinfo.net (J.-P. Zou), wei2.zhang@umb.
edu (W. Zhang).
a
b
c
Ambient temperature.
Isolated yield.
Imines were the major product.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.082

X.-Q. Pan et al. / Tetrahedron Letters 49 (2008) 5302–5308
5303
Table 2
1,5-Benzodiazepines from o-phenylenediamine and ketones
R2
R2
H
R3
R3
NH2
Ga(OTf)3
10 mol%
O
N
+
R2
CH2 R3
ð2Þ
NH2
1a,b
CH3CN
R1
N
2a-j
R1
Entry
o-PDA
Ketone
Product 2a
Yieldb (%)
H
N
NH2
NH2
O
1
92
N
1a
2a
H
N
O
2
1a
85
N
2b
OMe
H
N
O
3
1a
90
N
MeO
OMe
Cl
2c
H
N
O
4
1a
83
N
Cl
Cl
2d
NO2
H
N
O
5
1a
85
N
O2N
NO2
2e
(continued on next page)

5304
X.-Q. Pan et al. / Tetrahedron Letters 49 (2008) 5302–5308
Table 2 (continued)
Entry
o-PDA
Ketone
Product 2a
Yieldb (%)
NO2
NO2
H
N
O
6
1a
88
N
NO2
2f
H
N
O
7
8
9
1a
1a
1a
92
N
2g
H
N
75
O
N
2h
H
N
O
70
N
2i
H
N
NH2
NH2
O
10
86 (91:9)c
O2N
O2N
N
1b
2j
All products were characterized by 1H and 13C NMR and HRMS spectra.
All products were purified by flash column chromatography.
Product ratio was determined by 1H NMR.
a
b
c
of 10 mol % catalyst and 4–12 h at room temperature. Acetonitrile
was found to be a good solvent (Table 1, entry 4). Catalyst loading
test was also conducted. It was found that 10 mol % of Ga(OTf)3
was sufficient to catalyze the reaction, and gave 1,5-benzodiaze-
pine in 92% yield (Table 1, entry 4). Increasing the amount of
Ga(OTf)3 to 20 mol % did not significantly improve the yield (Table
1, entry 7). However, if the amount of the catalyst was reduced to 5
and 1 mol %, the product yield was reduced to 50% and 23%, respec-
tively (Table 1, entries 5 and 6). In a control reaction without using
the catalyst, no desired product was observed after 12 h.
2, entries 1–6). Reactions of alkylketones such as acetone, penta-
none-3, and cyclohexanone also gave benzodiazapines (Table 2,
entries 7–10), but low yields were obtained from the more hin-
dered alkylketones (Table 2, entries 8 and 9). 4-Nitrobenzene-
1,2-diamine was used as the substrate to evaluate the substituent
effect on o-phenylenediamine. Good product yield (86%) and
regioselectivity (91:9) were obtained from this reaction (Table 2,
entry 10).
The reaction of
a,b-unsaturated ketone (chalcone 4a) and o-
phenylenediamine 1a was carried out to study the reaction scope
(Eq. 3). No desired condensation product was detected from the
reaction conducted at 60 °C (Table 3, entry 1). We wonder if the
amino group is not nucleophilic enough for the addition. Thus,
o-aminothiophenol was used to replace the o-phenylenediamine
for the reaction. As we anticipated, 2,4-diphenyl-1,5-benzothiaze-
pine 5b was isolated at 30% yield (Table 3, entry 2). Even the yield
was low, but it encouraged us to further explore the reaction of
chalcone derivatives. To our surprise, when 2-hydroxychalcone
4b was used as the substrate, the reaction with o- aminothiophenol
The best condition for the synthesis of 1,5-benzodiazepine was
found to be as follows:
A mixture of o-phenylenediamine
(2 mmol), acetophenone (4.5 mmol), and Ga(OTf)3 (0.2 mmol) in
10 mL of MeCN was stirred at room temperature for 4–6 h.16 This
general procedure was used for reactions of o-phenylenediamine
with different aryl- and alkylketones (Table 2).
Reactions of o-phenylenediamine with acetophenones bearing
electron-donating and electron-withdrawn substitution groups
gave products in good to excellent yields (83–92%) (Eq. 2) (Table

X.-Q. Pan et al. / Tetrahedron Letters 49 (2008) 5302–5308
5305
Table 3
Synthesis of 1,5-benzothiazepines/1,5-benzodiazepines from o-aminothiophenol/o-phenylenediamine and chalcones
O
R2
Ga(OTf)3
10 mol%
R1
R2
XH
R1
X
N
+
ð3Þ
NH2
1a
, X=NH
3a
, X=S
4a-f
5a-l
Entry
o-PDA/o-ATP
Ketone
Product 5a
Yieldb (%)
H
N
O
NH2
1
Trace
NH2
N
1a
4a
5a
O
SH
S
N
2
3
4
5
6
30
NH2
3a
4a
5b
OH
O
S
N
SH
95
NH2
3a
4b
HO
5c
OMe
OH
O
SH
S
93
NH2
OMe
N
3a
4c
HO
5d
S
OH
O
S
N
SH
S
95
NH2
3a
4d
HO
5e
HO
S
OH
O
OH
SH
91
NH2
N
3a
4e
HO
5f
(continued on next page)

5306
X.-Q. Pan et al. / Tetrahedron Letters 49 (2008) 5302–5308
Table 3 (continued)
Entry
o-PDA/o-ATP
Ketone
Product 5a
Yieldb (%)
OH
OH
O
SH
S
7
87
NH2
HO
OH
N
3a
4f
HO
OH
OH
5g
OH
O
SH
S
8
92
NH2
OH
N
3a
4g
HO
5h
O
S
N
SH
9
10
11
35
NH2
HO
3a
4h
OH
5i
O
SH
S
N
OH
—
NH2
HO
3a
4i
H
N
OH
O
NH2
85
NH2
N
1a
4b
HO
5j
OMe
OH
O
H
N
NH2
12
84
NH2
OMe
N
1a
4c
HO
5k
S
H
N
OH
O
NH2
S
13
88
NH2
N
1a
4d
HO
5l
a
Structures were characterized by 1H and 13C NMR and HRMS.
All products were purified by flash column chromatography.
b

X.-Q. Pan et al. / Tetrahedron Letters 49 (2008) 5302–5308
5307
only gave 35% yield of product (Table 3, entry 9). The reaction of
20-hydroxychalcone did not afford any product (Table 3, entry
10). Results from these two reactions indicated that the hydroxy
at 2-position of chalcone is critical for the condensation reactions.
To verify this observation, o-phenylenediamine was re-employed
for the reaction with 2-hydroxychalcone. Indeed, the reaction
proceeded and afforded 1,5-benzodiazepine product in 85% yield
(Table 3, entry 11). Reactions of 2-hydroxychalcones 4c and 4d
with o-phenylenediamine also generated products 5k and 5l in
84% and 88% yield, respectively (Table 3, entries 12 and 13).
A mechanism for the reaction of o-phenylenediamine 1a or o-
aminothiophenol 3a with 2-hydroxychalcone derivatives 4 to form
2,4-disubstituted 1,5-benzodiazepine or 2,4-disubstituted 1,5-ben-
zothiazepine was proposed (Scheme 1). At the first step, catalyst
Ga(OTf)3 and 2-hydroxychalcone I form complex II, which further
reacts with III to afford complex IV and then V after losing H2O.
The XH group attacks the C@C bond and leads to the formation
of condensation product 5. In this process the 2-hydroxy group
in chalcone has the following two important roles: (1) the 2-hydro-
xy group involves in the formation of stable complex III by chelat-
ing with Ga(OTf)3 and facilitates the dehydration process to from
Figure 1. X-ray structure of 5h.
complex V; (2) the 2-hydroxy makes the
a,b-unsaturated carbonyl
more reactive toward the addition of XH.
We have also explored the reactions of aniline or thiophenol
with chalcone using Ga(OTf)3 as a catalyst. No Michael addition
product was observed (Scheme 2).
In summary, Ga(OTf)3 was found to be an effective catalyst for
the synthesis of 2,2,4-trisubstituted-1,5-benzodiazepines under
mild reaction conditions. Ga(OTf)3 also promotes the reactions of
o-phenylenediamine and o-aminothiophenol with 2-hydroxychal-
cone derivatives to form 2,4-disubstituted-1,5-benzodiazepines
and 2,4-disubstituted-1,5-benzothiazepines through a previously
unreported condensation process.
3a gave the condensation product 5c in quantitative yield (Table 3,
entry 3).17 To find out the role of the 2-hydroxy group, other 2-
hydroxychalcone derivatives were tested (Table 3, entries 4–8).
The results showed that these reactions also gave high product
yields. Among them, the structure of 5h was confirmed by X-ray
analysis (Fig. 1). To evaluate the influence of the hydroxy group,
chalcones with the hydroxy group at different positions were
tested. The reaction of 4-hydroxychalcone with o-aminothiophenol
X
N
OH
O
R1
R2
HO
5
Ga(OTf)3
I
(OTf)3
Ga
(TfO)3Ga
HO
XH
HO
O
N
II
V
-H2O
H2N
XH
(OTf)3
Ga
III
N
XH
X = S, NH
H2
O
HO
IV
Scheme 1. Proposed mechanism for Ga(OTf)3-catalyzed reaction of 2-hydroxychalcones with o-phenylenediamine or o-aminothiophenol.

5308
X.-Q. Pan et al. / Tetrahedron Letters 49 (2008) 5302–5308
O
SH
Ga(OTf)3
no reaction
no reaction
+
or
or
NH2
OH
O
SH
Ga(OTf)3
+
NH2
Scheme 2. Reaction condition: chalcone (1.0 equiv), aniline, or thiophenol (1.1 equiv), Ga(OTf)3 (10 mol %), CH3CN, room temperature, 6 h.
Green Chem. 2002, 4, 592; (f) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati,
Acknowledgement
O. Tetrahedron Lett. 2001, 42, 3193; (g) Kaboudin, B.; Navaee, K. Heterocycles
2001, 55, 1443; (h) Pozarentzi, M.; Stephanidou, S. J.; Tsoleridis, C. A.
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J.P.Z. thanks the financial support from National Natural Science
Foundation of China (No. 20772088).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.082.
References and notes
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O., Eds.; Raven Press: New York, 1973; p 27.
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V.; Rao, P. S.; Ashok, D. Synth. Commun. 2000, 30, 1825.
(Table 2):
A mixture of o-phenylenediamine (2 mmol), acetophenone
(4.5 mmol), and Ga(OTf)3 (0.2 mmol) in 10 mL of MeCN was stirred at room
temperature for 5–6 h. After completion of the reaction (TLC analysis), the
reaction mixture was diluted with water, and extracted with dichloromethane
(2 ꢁ 10 mL). The combined organic layer was dried over Na2SO4, concentrated
to dryness in vacuo, and the residue was purified by column chromatography
(eluted with 2:8 EtOAc–petroleum) to afford pure diazepine.
17. A general procedure for synthesis of 2,4-disubstituted-1,5-benzodiazepines and
4. Ried, W.; Torinus, E. Chem. Ber. 1959, 92, 2902.
5. Stahlhofen, P.; Ried, W. Chem. Ber. 1957, 90, 815.
2,4-disubstituted-1,5-benzothiaze-pines
5
(Table 3):
A
mixture of o-
aminothiophenol (1.1 mmol), chalcone (1 mmol), and Ga(OTf)3 (0.1 mmol) in
10 mL of MeCN was stirred at 60 °C for an appropriate time. After completion
of the reaction (TLC analysis), the residue was purified by column
chromatography (eluted with 2:8 EtOAc–petroleum ether) to afford pure
thiadiazepine.
6. (a) Herbert, J. A. L.; Suschitzky, H. J. Chem. Soc., Perkin Trans. 1 1974, 2657; (b)
Morales, H. R.; Bulbarela, A.; Contreras, R. Heterocycles 1986, 24, 135; (c) Jung,
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