Enantioselective synthesis of 2-substituted-1,5-benzodiazepines through domino reaction of o-phenylenediamine and chalcone derivatives

Article abstract of DOI:10.1002/ejoc.201100938

Chiral 2-substituted-1,5-benzodiazepine derivatives were synthesized for the first time from an enantioselective domino reaction involving o-phenylenediamine and 2′-hydroxychalcones. The titanium complex formed from chiral ligand 1a derived from (S)-BINOL

Full text of DOI:10.1002/ejoc.201100938

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100938
Enantioselective Synthesis of 2-Substituted-1,5-Benzodiazepines through
Domino Reaction of o-Phenylenediamine and Chalcone Derivatives
Xuan Fu,[a] Juhua Feng,[a] Zhenhua Dong,[a] Lili Lin,[a] Xiaohua Liu,*[a] and
Xiaoming Feng*[a]
Keywords: Asymmetric synthesis / Nitrogen heterocycles / Titanium / Domino reactions / Michael addition
Chiral 2-substituted-1,5-benzodiazepine derivatives were
synthesized for the first time from an enantioselective dom-
1a derived from (S)-BINOL and
reaction and gave the products in good yields with up to
L-prolineamide promoted the
ino reaction involving o-phenylenediamine and 2Ј-hydroxy- 82%ee.
chalcones. The titanium complex formed from chiral ligand
benzodiazepine derivatives seems more difficult due to low
Introduction
activity and poor differentiation of the two amine groups of
o-PDA. Herein, we report the first enantioselective domino
reaction to prepare chiral 2-substituted-1,5-benzodiazep-
ines.
1,5-Benzodiazepines and their polycyclic derivatives are
important classes of heterocycles with pharmacological ac-
tivities, which are broadly used as analgesic, sedative, anti-
convulsant, antianxiety, antidepressive, and hypnotic
agents.[1] Recent medical research showed that 1,5-benzodi-
azepines could be extended to various diseases such as can-
cer, viral infection, and cardiovascular disorders.[2] There-
fore, over the last decade benzodiazepines have been very
appealing targets for synthetic purposes. One of the most
efficient methods for their preparation is the domino reac-
tion of o-phenylenediamine (o-PDA) with ketones,[3] α,β-
unsaturated carbonyl compounds, or β-haloketones.[4]
Catalysts such as BF3·OEt2,[5] NaBH4,[6] Yb(OTf)3,[7]
Ga(OTf)3,[8] polyphosphoric acid,[9] nitrobenzoic acid,[10]
multisite solid catalysts,[11] as well as ionic liquids,[12] and
microwave irradiation assisted methods[13] have been em-
ployed to improve the yield under mild reaction conditions.
Series of functionalized 1,5-benzodiazepine derivatives were
obtained as racemates, whereas the enantioselective synthe-
sis of these scaffolds has not been achieved.
Scheme 1. Possible processes of the reaction between o-PDA and
chalcone.
The asymmetric domino reaction involving o-PDA and
α,β-unsaturated carbonyl compounds and proceeding
through an enantioselective aza-Michael reaction as the key
Results and Discussion
An initial attempt to react chalcone with o-PDA was dis-
process is a facile variant to achieve optically active 2,3- appointing, and no desired product was obtained with sev-
dihydro-2-substituted-1H-1,5-benzodiazepines (Scheme 1). eral kinds of chiral catalysts. We envisioned that the main
Although attractive outcomes in enantioselective aza- issue would be the lack of synergy between the aza-Michael
Michael reaction[14] have been achieved in recent years, the step and the ring-closing step to form the imine. If a chiral
related domino reaction for the asymmetric synthesis of 1,5- Lewis acid or amine facilitates the aza-Michael step, it
would be unfavorable for the following cyclocondensation
[a] Key Laboratory of Green Chemistry & Technology, Ministry
of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
process (Scheme 1, path A). Likewise, if the ketimine is
preferentially generated, steric hindrance would not benefit
the activation of the α,β-unsaturated imine, therefore sup-
pressing the intermolecular aza-Michael process (Scheme 1,
path B). An alternative strategy to achieve asymmetric syn-
thesis of chiral 2-substituted-1,5-benzodiazepines is to in-
Fax: +86-28-8541-8249
E-mail: liuxh@scu.edu.cn
xmfeng@scu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100938.
Eur. J. Org. Chem. 2011, 5233–5236
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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X. Fu, J. Feng, Z. Dong, L. Lin, X. Liu, X. Feng
SHORT COMMUNICATION
troduce a side functional group into the α,β-unsaturated try 9). To further improve the enantioselectivity of the reac-
ketone to improve its coordination and activation. 2Ј-Hy- tion, we attempted to perform the reaction at a lower tem-
droxychalcone has been shown to be efficient in this seven- perature. If the temperature was dropped to –20 °C and the
membered ring-formation reaction by Zhang and co- concentration of the reaction system was increased, the ee
workers.[8] Then, we selected 2Ј-hydroxychalcone (4a) and value could be raised to 73% but the yield decreased dis-
o-PDA as the model substrates to realize the asymmetric tinctly (Table 1, Entry 10). Additive tests showed that 5 Å
transformation. After systematic investigation of the cata- molecular sieves increased the yield slightly, whereas the ee
lysts developed in our group [including N,NЈ-dioxide-Fe- value was maintained (71% yield, 73%ee; Table 1, En-
(acac)3 and cinchona alkaloid–BINOL–Ti(OiPr)4 catalysts, try 11).
see the Supporting Information for details], it showed that
Table 1. Optimization of the reaction conditions of the enantio-
chiral titanium complexes of BINOL derivatives (Figure 1)
selective domino reaction involving o-PDA and 2Ј-hydroxychalcone
could efficiently promote the asymmetric reaction.[15]
(4a).[a]
Entry TiIV/ligand
Solvent
T
[°C]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
Ti(OiPr)4/1a
Ti(OiPr)4/1b
Ti(OiPr)4/2
Ti(OiPr)4/3
TiCl4/1a
Ti(OiPr)4/1a
Ti(OiPr)4/1a
Ti(OiPr)4/1a tBuOMe
Ti(OiPr)4/1a
Ti(OiPr)4/1a
toluene
toluene
toluene
toluene
toluene
THF
0
0
0
0
0
0
0
0
0
88
23
90
55
61
85
59
65
90
60
71
47
11
35
0
37
61
47
45
23
73
73
Et2O
9
PhOMe
THF
THF
10[d]
–20
–20
11[d,e] Ti(OiPr)4/1a
Figure 1. Chiral ligands used in the domino reaction.
[a] Unless otherwise noted, reactions were carried out with o-PDA
(0.1 mmol) and 4a (0.1 mmol) in solvent (1.0 mL) at 0 °C for 72 h
with the catalyst (TiIV/ligand = 1:1, 10 mol-%). [b] Isolated yield.
[c] Determined by HPLC analysis. [d] Reactions were carried out in
THF (0.5 mL) at –20 °C for 72 h. [e] 5 Å MS (20 mg) were added.
Ti(OiPr)4 combined with chiral ligand 1a, which was pre-
pared from (S)-BINOL and l-prolineamide, could acceler-
ate the domino reaction, and benzodiazepine 5a was ob-
tained in 88% yield with 47%ee at 0 °C in toluene (Table 1,
Under the optimal conditions (Table 1, Entry 11), the
Entry 1). When ligand 1b derived from (S)-H8-BINOL was scope of 2Ј-hydroxychalcone derivatives was examined, and
employed, both the yield and the enantioselectivity dropped the results are shown in Table 2. The electronic nature of
sharply (23% yield, 11%ee; Table 1, Entry 2). The results the substituent on the β-phenyl moiety had an obvious in-
indicated that the dihedral angle of the axial biaryl group in fluence on the activity of the reaction. 2Ј-Hydroxychalcones
the BINOL moiety was crucial for the outcome. Although with electron-withdrawing substituents, except for the para-
diastereomeric ligand 2, which is derived from (R)-BINOL nitro group, on the β-phenyl group showed higher yields
and l-prolineamide, promoted the reaction with a suitable than those with electron-donating substituents (Table 2, En-
yield, the enantioselectivity decreased somewhat (90% tries 5–11 vs. 2–4). 3-Trifluoromethyl-substituted α,β-unsat-
yield, 35%ee; Table 1, Entry 3). Disappointingly, ligand 3, urated ketone 4j gave the best yield with moderate enantio-
the N-oxidation product of ligand 1a, only gave racemic 5a selectivity (Table 2, Entry 10). Optically pure product 5j was
in moderate yield (Table 1, Entry 4). This poor results obtained through recrystallization, and its absolute configu-
might be due to a change in the coordination model if an ration was confirmed to be S by X-ray analysis (Fig-
additional coordinated oxygen atom was introduced. The ure 2).[16] 2-Chloro-substituted 4g afforded the correspond-
employment of chiral 1a with TiCl4 did not afford better ing 2-aryl-1,5-benzodiazepine in 93% yield with 82%ee
results (Table 1, Entry 5 vs. 1). The screening of the solvents (Table 2, Entry 7). However, 2-methoxy-substituted sub-
showed that the reaction proceeded well in THF, and the strate 4d yielded the product in only 23% yield with 69%ee
ee value was improved to 61% with the yield remaining (Table 2, Entry 4). Generally, moderate to excellent yields
nearly the same (Table 1, Entry 6). Other solvents such as (up to 94%) with good enantioselectivities (up to 82%ee)
Et2O and tBuOMe decreased the yield of the reaction with- were observed.
out improving the enantioselectivity (Table 1, Entries 7 & 8
To evaluate the possible pathway of the domino reaction,
vs. 6). The reactivity of the substrate was maintained in comparative reactions of 2Ј-hydroxychalcone (4a) were car-
PhOMe, but the ee value decreased to 23% (Table 1, En- ried out. No aza-Michael addition product was detected
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Eur. J. Org. Chem. 2011, 5233–5236

Enantioselective Synthesis of 2-Substituted-1,5-Benzodiazepines
Table 2. Substrate scope for the catalytic asymmetric domino reac- an intramolecular hydrogen bond of the hydroxy group. In
tion involving 2Ј-hydroxychalcones 4 and o-PDA.[a]
the presence of the chiral titanium complex, intermediate
A1 can coordinate to the metal with the oxygen atom of the
hydroxy group and the nitrogen atom of the imine moiety
to generate intermediate A2. In intermediate A2, the amino
group prefers to attack the β-Si face of the C=C bond due
to the fact that there is less steric hindrance between the
aniline moiety and the neighboring pyrrolo[1,2-c]imidazol-
1-one moiety of the ligand. Thus, (S)-5j is afforded and the
Entry
R
Product
Yield
[%][b]
ee
[%][c]
chiral titanium complex is released.
1
2
3
4
5
6
7
8
Ph (4a)
5a
5b
5c
5d
5e
5f
5g
5h
5i
71
62
73
23
83
93
93
74
87
94
75
66
73
71
73
69
79
78
82
65
65
2-MeC6H4 (4b)
3-MeC6H4 (4c)
2-MeOC6H4 (4d)
4-ClC6H4 (4e)
4-BrC6H4 (4f)
2-ClC6H4 (4g)
3-BrC6H4 (4h)
3-ClC6H4 (4i)
3-CF3C6H4 (4j)
3-FC6H4 (4k)
3-NO2C6H4 (4l)
Conclusions
In conclusion, we report the asymmetric synthesis of 2-
aryl-1,5-benzodiazepine derivatives for the first time by
using a chiral titanium complex with a ligand derived from
(S)-BINOL and l-prolineamide. The 2Ј-hydroxy group of
the α,β-unsaturated ketones was critical for both the reac-
tivity and stereoinduction. Moderate to excellent yields and
enantioselectivities were achieved. Further efforts will be
dedicated to improve the enantioselectivity as well as the
synthesis of chiral 2,3-disubstituted-1,5-benzodiazepines
from the three-component reaction of ketones.
9
10
11
12
5j
5k
5l
67 (S)[d]
78
59
[a] Unless otherwise noted, reactions were carried out with
Ti(OiPr)4/1a (1:1, 10 mol-%), 4 (0.1 mmol), o-phenylenediamine
(0.1 mmol), and 5 Å MS (20 mg) in THF (0.5 mL) at –20 °C for
72 h. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
[d] Determined by X-ray analysis.
Experimental Section
Typical Procedure for the Asymmetric Domino Reaction of 2Ј-Hy-
droxychalcones and o-PDA: A mixture of ligand 2a (3.4 mg,
0.01 mmol, 10 mol-%), Ti(OiPr)4 (1 m in THF, 10.0 μL, 0.01 mmol,
10 mol-%), o-PDA (10.8 mg, 0.10 mmol), and 5 Å MS (20 mg) was
stirred in THF (0.5 mL) in a tube under a N2 atmosphere at 25 °C
for 0.5 h. Then, 2Ј-hydroxychalcone (4a; 22.4 mg, 0.10 mmol) was
added at –20 °C, and the reaction system was stirred at this tem-
perature for 72 h. The reaction was monitored by TLC and purified
by flash chromatography on silica gel (petroleum ether/ethyl acet-
ate, 20:1) to give pure product 5a in 71% yield with 73%ee. The
ee value was determined by chiral HPLC. HPLC (DAICEL CHI-
RALCEL AD-H column, 2-propanol/n-hexane = 20:80, flow rate
= 1.0 mL/min, λ = 254 nm): tR = 11.68 (minor), 14.81 min (major).
Figure 2. X-ray structure of product 5j.
when 4a was treated with anilines under the optimized reac-
tion conditions. Considering the crucial role of the hydroxy
group at the 2Ј-position of chalcone, we rationalized a pos-
sible catalytic cycle. As shown in Scheme 2, the α,β-unsatu-
rated ketimine intermediate formed might be stabilized by
1
[α]2D8 = +61.4 (c = 0.214, CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 15.28 (s, 1 H, O-H), 7.42–6.72 (m, 13 H, Ar-H), 5.22–5.17 (dd,
J = 3.2, 8.8 Hz, 1 H, C-H), 3.85 (s, 1 H, C–NH–C), 3.35–3.31 (dd,
J = 3.6, 14.0 Hz, 1 H, -CH2), 3.09–3.03 (dd, J = 8.8, 13.6 Hz, 1
H, -CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.14, 162.63,
144.29, 139.09, 135.26, 132.86, 129.01, 128.38, 128.32, 128.07,
127.44, 125.91, 121.50, 120.74, 119.12, 118.34, 118.02, 69.99,
36.56 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra and HPLC
chromatograms.
Acknowledgments
We gratefully acknowledge the National Natural Science Founda-
tion of China (Nos. 20732003, 21021001, and 20872097) and the
National Basic Research Program of China (973 Program: No.
2011CB808600) for financial support. We also appreciate Sichuan
University Analytical & Testing Center for NMR spectroscopic
analysis.
Scheme 2. Proposed catalytic cycle.
Eur. J. Org. Chem. 2011, 5233–5236
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X. Fu, J. Feng, Z. Dong, L. Lin, X. Liu, X. Feng
SHORT COMMUNICATION
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Received: June 29, 2011
Published Online: August 17, 2011
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Eur. J. Org. Chem. 2011, 5233–5236