Intramolecular copper(I)-catalyzed 1,3-dipolar cycloaddition of azido-alkynes: Synthesis of triazolo-benzoxazepine derivatives and their biological evaluation

Article abstract of DOI:10.1016/j.tetlet.2010.12.040

Synthesis of a series of [1,2,3] triazolo [5,1-c] [1,4]benzoxazepine derivatives have been accomplished by the intramolecular Cu(I)-catalyzed cycloaddition of azido-alkynes derived from salicylaldehyde. The biological profile of these heterocyclic structu

Full text of DOI:10.1016/j.tetlet.2010.12.040

Tetrahedron Letters 52 (2011) 806–808
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Tetrahedron Letters
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Intramolecular copper(I)-catalyzed 1,3-dipolar cycloaddition of azido-alkynes:
synthesis of triazolo-benzoxazepine derivatives and their biological evaluation
Srivari Chandrasekhar a, , Mallikanti Seenaiah a, Abhishek Kumar a, Chada Raji Reddy a,
⇑
Suman Kumar Mamidyala b, Chityal Ganesh Kumar b, Sridhar Balasubramanian c
a Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Chemical Biology Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Center for X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a series of [1,2,3] triazolo [5,1-c] [1,4]benzoxazepine derivatives have been accomplished by
the intramolecular Cu(I)-catalyzed cycloaddition of azido-alkynes derived from salicylaldehyde. The bio-
logical profile of these heterocyclic structural scaffolds toward anti-bacterial as well as anti-fungal activ-
ity has also been illustrated.
Received 4 November 2010
Revised 3 December 2010
Accepted 9 December 2010
Available online 15 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dipolar cycloaddition
Copper-catalysis
Triazolo-benzoxazepine
Anti-microbial
Click chemistry
The synthesis of 1,2,3-triazoles by 1,3-dipolar cycloaddition of
azides with alkynes was discovered by Arthur Michael at the end
of the 19th century and significantly developed by Rolf Huisgen
in 1960s.1 In early 2002, Meldal and Sharpless research groups
independently reported the use of catalytic amount of Cu(I)-cata-
lyst in the regioselective cycloaddition of azide and alkynes.2 After
this discovery, in the past decade the Cu-catalyzed [3+2] cycload-
dition reaction between alkynes and azides has gained consider-
able attention as ‘click chemistry’, which has resulted in a variety
of applications in synthetic organic chemistry,3 material science,4
drug discovery,5 polymer chemistry6 and bio-conjugation,7 among
others.8 The 1,3-dipolar cycloaddition reaction has also been used
for the construction of various novel 1,2,3 triazolo heterocyclic
compounds.9 These cycloaddition reactions have been accom-
plished either in intermolecular or intramolecular version.10,11
The intramolecular click reaction provides fused triazoles, which
are endowed with a wide range of biological activities.4b,12 Hence,
in continuation to our ongoing research on ‘click chemistry’,13 we
were interested in exploring the cycloaddition reaction in an intra-
molecular fashion for the formation of triazolo-benzoxazepine
derivatives14 (Scheme 1).
O
O
R
Cu(0), CuSO4
N3
N
EtOH, reflux, 12 h
N
N
1
2
R
R= H, alkyl, aryl
Scheme 1. Intramolecular 1,3-dipolar cycloaddition.
salicylaldehyde (3) was alkylated with propargyl bromide in the
presence of K2CO3 in acetone under refluxing conditions to obtain
the O-propargylated aldehyde 4,15 in 92% yield. The reaction of 4
with phenyl magnesium bromide in dry diethyl ether at room
temperature provided the alcohol 5a in 89% yield. To install the
azide functionality, the alcohol 5a was treated with TMSN3 in the
presence of BF3Et2O (20 mol %) in CH2Cl2 at room temperature,
which provided the azido-alkyne 1a (98%). Having the azido-al-
kyne 1a in hand, the intramolecular Cu(I)-catalyzed cycloaddition
reaction was carried out for the synthesis of triazolo-[1,2,3]-ben-
zoxazepine derivative 2a.16 Thus, the azido-alkyne 1a was treated
with copper(I)-catalyst in ethanol under refluxing conditions to af-
ford the triazolo-[1,2,3]-benzoxazepine 2a in 84% yield via intra-
molecular 1,3-dipolar cycloaddition reaction. The structure of
compound 2a was determined by X-ray crystallographic studies17
(Fig. 1) and fully characterized by its spectral analysis.18
Starting from salicylaldehyde, the desired azido-alkyne 1 was
prepared in three-steps as shown in Scheme 2. In the first case,
With this success in the preparation of a novel heterocyclic scaf-
fold, we were encouraged to prepare various substituted fused
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.040

S. Chandrasekhar et al. / Tetrahedron Letters 52 (2011) 806–808
807
CH2Br
O
O
R
NaBH4, MeOH
rt, 1.5 h, 89%
TMSN3, BF3Et2O
OH
O
K2CO3, acetone
RMgBr, Et2O
rt, 1 h
4
OH
CH2Cl2, rt, 3 h, 98%
OH
ref lux, 6 h, 92%
CHO
CHO
5k
5
3
4
O
O
O
O
R
Cu(0), CuSO4
EtOH, reflux, 12 h, 72%
TMSN3, BF3Et2O
CH2Cl2, rt, 30 min.
Cu(0), CuSO4
N3
N3
N
N
EtOH, reflux, 12 h
N
N
N
N
R
2k
1k
1
2
Scheme 3. Synthesis of 2k from salicylaldehyde.
nyl (1j) substituted azido-alkynes successfully participated in the
intramolecular cycloaddition reaction.19
Finally, unsubstituted triazolo-benzoxazepine derivative 2k
was also prepared in a three-step sequence, where the aldehyde
4 was reduced (NaBH4/MeOH) to the primary alcohol 5k followed
by azide formation (TMSN3/BF3ÁEt2O) and 1,3-dipolar cycloaddition
under the optimized reaction conditions (Scheme 3).
Further, the biological profile of the above prepared fused
[1,2,3] triazolo [5,1-c] [1,4] benzoxazepines has been evaluated
for anti-bacterial and anti-fungal activities. All the derivatives
2a–k were tested using the microtiter broth dilution method for
in vitro antimicrobial studies20 and found that four compounds
2g–j were moderately active. However, one of the derivatives 2h
was found to be promising and showed the lowest MIC value of
93.75 lg/ml against both Gram-positive and Gram-negative bacte-
ria like Staphylococcus aureus, Escherichia coli, Klebsiella planticola
and also against Candida albicans, suggesting the broad spectrum
nature of the antimicrobial activity.
Scheme 2. Synthesis of [1,2,3] triazolo [5,1-c] [1,4] benzoxazepines.
In conclusion, we have successfully employed an intramolecular
click chemistry of azido-alkynes to generate fused [1,2,3] triazolo
[5,1-c] [1,4] benzoxazepine derivatives. Additionally, the prelimin-
ary screening of the compounds obtained was carried out for anti-
microbial activity.
Acknowledgments
M.S. and S.K.M. are grateful to CSIR, New Delhi and A.K. thank
NIPER, Hyderabad for fellowships.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.040.
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808
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group P212121, a = 8.1550(5)Å, b = 9.8788(6)Å, c = 16.8120(11)Å, V =
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l ,
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r
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7.24 (m, 4H), 7.23–7.07 (m, 2H), 6.95–6.90 (m, 3H), 5.28 (d, 1H, J = 15.1 Hz),
5.03 (d, 1H, J = 15.1 Hz); 13C NMR (75 MHz, CDCl3): d 156.7, 139.5, 130.9 (2C),
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19. General experimental procedure for Cu(I)-catalyzed cycloaddition of azido-
alkynes: To
a stirred solution of azido-alkyne 1a–k (0.38 mmol) in EtOH
(10 mL) was added saturated copper sulfate solution (0.2 mL, 1 M), Cu-turnings
(20 mg) and the reaction mixture was refluxed for 12 h. After completion of the
reaction (monitored by TLC), the mixture was filtered through celite. The celite
pad was washed with ethyl acetate and the combined organic volatiles were
removed on
a rotary evaporator. The residue was purified by column
chromatography over silica gel with ethyl acetate/hexanes (3:7) as eluent to
furnish the corresponding [1,2,3] triazolo [5,1-c] [1,4] benzoxazepines, 2a–k.
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