K. Ramesh et al. / Tetrahedron Letters 52 (2011) 2362–2366
2365
MeO
EtOOC
H
MeO
MeO
EtOOC
H
MeO
EtOOC
MeO
EtOOC
H
O
O
H
O
MeO
O
H
O
O
H
H
O
H
O
H
O
O
H
N
N
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
N
EtOOC
NH
NH
O
N
H O
H O
H O
H O
HO
Figure 2. Possible mechanistic pathway for the formation of N-substituted azepines using b-cyclodextrin.
Table 3
Recyclability of b-CD
Acknowledgments
We thank CSIR, New Delhi, India, for fellowship to S.N.M. and
UGC for fellowship to K.R.
Cycles
Yield (%)
Catalyst recovered (%)
Native
92
88
85
81
91
89
85
83
1
2
3
Supplementary data
Supplementary data associated with this article can be found, in
and ortho-substituted anilines with 2,5-dimethoxytetrahydrofuran
in the presence of DMAD/DEAD, but no reaction was observed even
after prolonged reaction times (Table 2). Compared to p-substi-
tuted anilines meta-substituted anilines gave lower yields of the
products. All the products were characterized by 1H, 13C NMR, IR,
and mass spectrometry.14 The catalytic activity of the b-CD was
established by the fact that azepine formation was not observed
in satisfactory yield in the absence of b-cyclodextrin. The evidence
for the formation of N-aryl substituted azepine in the presence of
b-CD was supported by 1H NMR studies of inclusion complex be-
tween aniline and b-CD. The hydrophobic environment of the
cyclodextrin facilitates the formation of N-arylazepines via inclu-
sion complex of aniline/DMAD or DEAD carbanion stabilized by
the primary and secondary-OH groups of cyclodextrin, which fur-
ther reacts with 2,5-dimethoxytetrahydrofuran and subsequent
cyclization followed by elimination leads to the desired product
as indicated in Figure 2.
All the reactions were carried out with a catalytic amount
(10 mol %) of b-CD in water. But for NMR studies inclusion complex
was prepared by taking b-CD and aniline in a 1:1 ratio. A compar-
ative study of 1H NMR spectra of aniline, b-CD, and b-CD/aniline
complex has indicated the upfield shift of aromatic protons as well
as amine protons of aniline in the 1H NMR spectrum (in DMSO-d6)
of aniline/b-CD. In the 1H NMR spectrum (DMSO-d6) of aniline, the
aromatic protons from ortho position appear as a doublet at
6.61 ppm (J = 8.2 Hz), while meta and para protons appear as a trip-
let at 7.06 (J = 7.4 Hz) and 6.55 (J = 6.7 Hz), respectively. Singlet at
5.05 ppm represents amine protons of aniline. The upfield shift of
aniline protons in the NMR spectrum of b-CD/aniline complex con-
firms the incorporation of aniline inside the hydrophobic cavity of
b-CD on complexation. Apart from the upfield shift of aniline pro-
tons due to the incorporation of the aromatic ring inside the b-CD
cavity, the protons located in the b-CD cavity (C3–H and C5–H) are
also shifted upfield due to magnetic anisotropy caused by the ani-
line molecule.12b In all these reactions b-CD can be recovered and
reused. After the reaction, the reaction mass was cooled to room
temperature and b-CD was filtered and washed with ice-cold water
and dried. The recovered b-CD was further used in the reaction
with the same substrates and checked for the yields and catalytic
activity of the recovered catalyst (b-CD), as shown in Table 3. It
was observed that the yields of N-substituted azepines diminished
slightly after two to three recycles.
References and notes
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13. General experimental procedure for the synthesis of azepines using b-cyclodextrin:
b-Cyclodextrin (10 mol %) was dissolved in water (20 ml), and to this clear
solution, aniline (1.0 mmol) was added, stirred for 15 min, and followed by the
addition of dimethyl/diethyl acetylenedicarboxylate (DMAD/DEAD 1.0 mmol)
and 2,5-dimethoxytetrahydrofuran (1.0 mmol). The reaction mixture was
heated at 60 °C until completion of the reaction as indicated by TLC. The
reaction mixture was cooled to 5 °C and b-cyclodextrin was filtered. The
aqueous layer was extracted with ethyl acetate (4 Â 10 ml). The combined
organic layers were washed with water, saturated brine solution, and dried
over anhydrous Na2SO4. The combined organic layers were evaporated under
reduced pressure and the resulting crude product was purified by column
chromatography by using ethyl acetate and hexane (0.7:9.3) as eluent. The
product was confirmed by IR, 1H & 13C NMR, mass spectra.
In summary, we have developed an eco-friendly method to syn-
thesize N-substituted azepines in excellent yields under neutral
conditions in one-pot involving catalysis by b-cyclodextrin in
water.