Synthesis and characterization of [1]benzopyrano[4,3-d][1,3]benzooxazocin- 13-one and its derivatives

Article abstract of DOI:10.1055/s-2006-950267

This work describes the efficient synthesis of functionalized cleft molecules 6, 6a, 16, 16a, 17, 19 and 20 derived from benzopyrano[4,3-d][1,3] benzooxazocin-13-one. X-ray crystal structure analysis of compounds 6a and 16a revealed that the cleft angles of the planes of the benzopyran moiety and the p-methoxybenzene ring are 109.4° and 108.6°, respectively. The conformation of the aromatic ring at the bridgehead of 16, 16a and 20 is restricted by the gem-dimethyl groups on the C-9 position and the methyl group on the nitrogen atom in the ring. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950267

LETTER
2791
Synthesis and Characterization of [1]Benzopyrano[4,3-d][1,3]benzooxazocin-
13-one and its Derivatives
Synthesis
eandCharac
n
terizationof
-
[1]Benz
F
opyrano[4,3-
d
e
][1,3]benzo
i
oxazocin-13
W-one ang, Yuan-Xiu Liao, Pei-Yu Kuo, Yung-Her Gau, Ding-Yah Yang*
Department of Chemistry, Tunghai University, 181, Taichung-Kang Rd. Sec. 3, Taichung 40704, Taiwan
Fax +886(4)23590426; E-mail: yang@thu.edu.tw
Received 21 June 2006
O
Abstract: This work describes the efficient synthesis of functional-
ized cleft molecules 6, 6a, 16, 16a, 17, 19 and 20 derived from ben-
N
zopyrano[4,3-d][1,3]benzooxazocin-13-one. X-ray crystal structure
analysis of compounds 6a and 16a revealed that the cleft angles of
the planes of the benzopyran moiety and the p-methoxybenzene
ring are 109.4° and 108.6°, respectively. The conformation of the
aromatic ring at the bridgehead of 16, 16a and 20 is restricted by the
gem-dimethyl groups on the C-9 position and the methyl group on
the nitrogen atom in the ring.
N
O
2
1
O
Key words: heterocycles, ring closure, ring opening, steric hin-
drance, bicyclic compounds
3
O
HN
NH
H
N
RN
Molecules with functional groups having cleft-like shapes
have recently emerged as useful tools in molecular recog-
nition studies. For instance, the rigid clefts derived from
Tröger’s base (1),1 a concave chiral diamine with a per-
pendicular arrangement of two aromatic rings, have been
used as hosts in molecular recognition,2 DNA
intercalation3 and enzyme inhibition,4 and as ligands for
asymmetric catalysis.5 A chiral cavity, similar to that
found in Tröger’s base, is also present in many related
systems whose skeletons differ from that of Tröger’s base
in the atoms that participate in the formation of the bridge-
head structure, conferring different bite angles on the
clefts. They include dione 2,6 Kagan’s ether (3),7 the tricy-
clic dibenzo[b,f][1,5]diazocine ring system 48 and the bi-
cyclo[3.3.1]nonane system 5,9 as shown in Figure 1.
These molecules have been incorporated into the design
of supramolecular systems such as crown-ether-based re-
ceptors,10 molecular tweezers11 and metallomacrocy-
cles.12 Therefore, the design and synthesis of a well-
defined cavity similar to Tröger’s base but with heteroat-
oms and aromatic rings incorporated at various positions
on the bicyclic ring systems may provide relatively rigid
chiral armatures to construct chelating and biomimetic
systems. This work describes the design, synthesis and
characterization of [1]benzopyrano[4,3-d][1,3]benzoox-
azocin-13-one (6) and its derivatives. A bridgehead and
heteroatoms that differ from those of Tröger’s base are in-
troduced into compound 6, which also contains a 4-hy-
droxycoumarin fused moiety on the ring system to extend
the cleft; also, two gem-dimethyl groups are incorporated
N
N
H
H
4
NH
O
5
H
H
N
O
H
O
O
6
Figure 1
into the C-9 position of the bicyclic structure to tune finely
the dimensions of the cleft.
Scheme 1 presents the synthesis of the parent cleft 6. It be-
gan with a base-catalyzed aldol condensation of 2¢-ami-
noacetophenone (7) and benzaldehyde at room
temperature in ethanol for three hours, yielding 2-ami-
nochalcone 8. Ketone 8 was then cyclized by heating with
phosphoric acid and acetic acid (1:1) for one hour to yield
2-phenyl-2,3-dihydro-1H-quinolin-4-one (9). Further re-
duction of the ketone 9 with sodium borohydride in meth-
anol at room temperature for 30 minutes gave
tetrahydroquinolinol (10). Selective methylation of 10 at
the nitrogen atom with methyl iodide in the presence of
K2CO3 as a base in acetonitrile at room temperature yield-
ed the tertiary amine 11. The final coupling of 11 with 4-
hydroxycoumarin was realized by initially converting 11
to the corresponding chloride in situ using thionyl chlo-
ride in benzene, and then adding 4-hydroxycoumarin and
triethylamine as a base for 30 minutes to afford the target
compound 6. For the purpose of clear identification of
aromatic proton absorptions on NMR spectra, compound
6a13 with a strong electron-withdrawing nitro group on the
SYNLETT 2006, No. 17, pp 2791–2794
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950267; Art ID: W12006ST
© Georg Thieme Verlag Stuttgart · New York

2792
J.-F. Wang et al.
LETTER
NH2
O
O
bocation, which was then attacked by 4-hydroxycoumarin
to yield the coupling adduct. The second step was likely
to be an acid-mediated dissociation of a hydride anion
from the p-nitrobenzylic position to form an iminium ion,
along with the hydrogen gas evolution. The subsequent
intramolecular nucleophilic addition of the coumarin ox-
ygen atom to the iminium carbon furnished the heterobi-
cyclic skeleton. Final deprotonation of the resulting
oxonium ion by p-toluenesulfonate not only regenerated
the acid catalyst but also afforded the oxazobicycle 16a as
a stable end product. A similar Lewis acid mediated cy-
clization reaction has also been reported in the literature.17
The molecular structures of compounds 6a and 16a were
elucidated by X-ray crystallography, and are presented in
Figure 2.18 The cleft angles of the planes of the benzopyr-
an moiety and p-methoxy aromatic rings are 109.4° and
108.6°, respectively. These angles substantially exceed
those of Tröger’s base and its derivatives (80–104°).19
Apparently, the substitution of two relatively small meth-
yl groups at the C-9 position of the bicyclic ring on 6 only
slightly affects the dimensions of the cleft, perhaps bulki-
er groups should be added to influence the dimensions of
the cavity. Interestingly, the proton NMR spectra of 6a,
16a and 17 reveal that the splitting patterns of the four ar-
omatic hydrogens on the p-nitrophenyl ring of 16a were
much more finely resolved (four doublet doublets) than
that of 6a and 17 (two doublets). Similar observations
were also made of compounds 19 and 20, indicating that
p-nitrophenyl group at the bridgehead on the ring systems
of compounds 6a, 17 and 19 rather flexibly rotates, but it
is more rigid in 16a and 20, which have two methyl
groups at the C-9 position and a methyl group on the ni-
trogen atom. Accordingly, the conformation of the aro-
matic ring at the bridgehead of these bicycles is
constrained by the presence of the substituents at the C-9
position and on the ring nitrogen atom. This structural ri-
gidity may result in two conformational diastereomers, if
two or more substituents are introduced into the phenyl
ring at the bridgeheads in 16a and 20.
O
15% NaOH
(aq)
H
+
EtOH
NH2
R
R
7
8, R = H, 86%
R = H or NO2
8a, R = NO2, 78%
H3PO4–AcOH
90 °C
OH
O
NaBH4, MeOH
N
N
H
H
R
R
10, R = H, 76%
10a, R = NO2, 80%
9, R = H, 68%
9a, R = NO2, 68%
MeI, K2CO3
MeCN
R
H
H
OH
N
N
(1) SOCl2, benzene
O
H
(2) 4-hydroxycoumarin
Et3N, benzene
O
O
R
11, R = H, 92%
11a, R = NO2, 90%
6, R = H, 43%
6a, R = NO2, 45%
Scheme 1
bridgehead phenyl ring was prepared in a similar way, ex-
cept in that p-nitrobenzaldehyde was used as the starting
material, as shown in Scheme 1.
Compounds 16 and 16a14 are prepared, as indicated in
Scheme 2, to illustrate the potential for fine-tuning the di-
mensions of the cleft through substitutions at C-9 position
on the bicyclic ring. The synthetic strategy differed from
that of compound 6, which began with a MgSO4-mediated
condensation of p-anisidine 12 and benzaldehyde or p-ni-
trobenzaldehyde followed by a Yb(OTf)3-catalyzed cou-
pling with isobutyraldehyde to yield the cyclized alcohols
14 and 14a.15 Selective methylation of 14 and 14a at the
nitrogen site using methyl iodide followed by coupling
with 4-hydroxycoumarin in the presence of a catalytic
amount of p-toluenesulfonic acid at 80 °C gave the target
compounds 16 and 16a. The direct coupling of 14a with
4-hydroxycoumarin in the presence of p-TsOH in 1,2-
dichloroethane yielded the cyclized product 17, whose
methyl group on the nitrogen atom is absent, unlike that in
16a. A corresponding 1,3-cyclohexanedione derivative 20
was also similarly synthesized except in that 4-hydroxy-
coumarin was replaced by a cyclohexanedione derivative
18, as indicated in Scheme 2. Compound 18 was prepared
by a base-catalyzed cyclization of the commercially avail-
able diethyl 2-(2-oxopropyl)succinate via an intramolecu-
lar Dieckmann condensation.16
Figure 2 X-ray crystal structures of 6a and 16a.
In summary, this study reports the efficient synthesis of
several functionalized cleft molecules derived from ben-
zopyrano[4,3-d][1,3]benzooxazocin-13-one. These het-
erobicycles are easily prepared in no more than five steps
with relatively high atom efficiency, and have wide inter-
The proposed mechanism of the coupling of 15a with 4-
hydroxycoumarin and the subsequent cyclization reaction
involved the initial formation of an acid-catalyzed car-
Synlett 2006, No. 17, 2791–2794 © Thieme Stuttgart · New York

LETTER
Synthesis and Characterization of [1]Benzopyrano[4,3-d][1,3]benzooxazocin-13-one
2793
R
NH2
O
MgSO4
+
N
H
CH2Cl2
R
OMe
MeO
13, R = H, 95%
13a, R = NO2, 90%
12
R = H or NO2
NO2
isobutyraldehyde
Yb(OTf)3, H2O
THF
OH
NO2
NH
OH
MeO
O
MeO
18
NH
O
O
O
4-hydroxycoumarin
O
H
H
p-TsOH (cat.)
ClCH2CH2Cl
80 °C, 12 h
55%
p-TsOH (cat.)
ClCH2CH2Cl
80 oC, 90%
N
H
O
O
R
O
14, R = H, 30%
14a, R = NO2, 70%
19
O
O
O
17
MeI, K2CO3
MeCN 12 h,
90%
MeI, K2CO3
MeCN
NO2
R
OH
N
MeO
N
N
O
O
H
H
4-hydroxycoumarin
p-TsOH (cat.)
ClCH2CH2Cl
80 oC, 16 h
O
O
O
O
R
O
O
O
20
15, R = H, 85%
15a, R = NO2, 90%
16, R = H, 34%
16a, R = NO2, 85%
Scheme 2
(4) Johnson, R. A.; Gorman, R. R.; Wnuk, R. J.; Crittenden, N.
J.; Aiken, J. W. J. Med. Chem. 1993, 36, 3202.
planar angles between the planes of the aromatic rings on
the clefts. Additionally, the conformation of the p-nitro-
phenyl group at the bridgehead on the ring system of these
heterobicycles is restricted by the presence of two methyl
groups at the C-9 position and a methyl group on nitrogen
atom in the ring. Further modifications of these molecules
to serve as potential organic photochromic dyes are cur-
rently being conducted.
(5) (a) Harmata, M.; Kahraman, M. Tetrahedron: Asymmetry
2000, 11, 2875. (b) Blaser, H. U.; Jalett, H. P.; Lottenbach,
W.; Studer, M. J. Am. Chem. Soc. 2000, 122, 12675.
(6) Levkin, P. A.; Strelenko, Y. A.; Lyssenko, K. A.; Schurig,
V.; Kostyanovsky, R. G. Tetrahedron: Asymmetry 2003, 14,
2059.
(7) Chen, J. S.; Watson, W. H.; Kagan, J.; Agdeppa, D. A.;
Chen, S.-A. Acta Crystallogr., Sect. B: Struct. Crystallogr.
Cryst. Chem. 1978, 34, 3627.
Acknowledgment
(8) Molina, P.; Arques, A.; Tarraga, A.; del Rosario Obon, M.
Tetrahedron 1998, 54, 997.
The authors would like to thank the National Science Council of the
Republic of China, Taiwan, for financially supporting this research
under Contract No. NSC 93-2113-M-029-002. The anonymous re-
viewers and the associate coeditor are appreciated for their valuable
suggestions. We also thank Dr. Ching-Yuh Chern for helpful dis-
cussion.
(9) Stoncius, S.; Butkus, E.; Zyilinskas, A.; Larsson, K.;
Ohrstrom, L.; Berg, U.; Warnmark, K. J. Org. Chem. 2004,
69, 5196.
(10) Naemura, K.; Fukunaga, R.; Komatsu, M.; Yamanaka, M.;
Chikamatsu, H. Bull. Chem. Soc. Jpn. 1989, 62, 83.
(11) Harmata, M.; Murray, T. J. Org. Chem. 1989, 54, 3761.
(12) Harmata, M.; Kahraman, M. Tetrahedron Lett. 1999, 40,
4133.
(13) Representative Procedure for the Preparation of 6a.
To a solution of 11a (100 mg, 0.4 mmol) in benzene (10 mL)
was added six drops of SOCl2. The mixture was stirred for
10 min at r.t., and the solution was then evaporated. The
crude product was added to 4-hydroxycoumarin (162 mg,
1.0 mmol) and excess Et3N in benzene (10 mL). After the
mixture was stirred for another 10 min at r.t., the solution
was evaporated. Then, H2O (5 mL) was added to the mixture
and the product was extracted twice with CH2Cl2. The
combined organic extracts were dried over MgSO4, filtered
References and Notes
(1) Tröger, J. J. Prakt. Chem. 1887, 36, 225.
(2) Demeunynck, M.; Tatibouet, A. Recent Developments in
Tröger’s Base Chemistry, In Progress in Heterocyclic
Chemistry, Vol. 11; Gribble, G. W.; Gilchrist, T. L., Eds.;
Pergamon: Oxford, UK, 1999, 1.
(3) Bailly, C.; Laine, W.; Demeunynck, M.; Lhomme, J.
Biochem. Biophys. Res. Commun. 2000, 273, 681.
Synlett 2006, No. 17, 2791–2794 © Thieme Stuttgart · New York

2794
J.-F. Wang et al.
LETTER
and concentrated. The resulting crude product was purified
by column chromatography (EtOAc–hexane, 1:9) to give a
light orange solid with a 45% yield; mp 210–211 °C. 1H
NMR (300 MHz, CDCl3): d = 8.36 (d, J = 9.0 Hz, 2 H), 7.96
(dd, J = 8.1, 1.8 Hz, 1 H), 7.85 (d, J = 8.7 Hz, 2 H), 7.55 (td,
J = 9.0, 1.8 Hz, 2 H), 7.32 (td, J = 6.9, 1.5 Hz, 2 H), 7.20 (td,
J = 7.5, 1.5 Hz, 1 H), 6.87 (td, J = 9.3, 1.8 Hz, 2 H), 2.86 (s,
3 H), 2.41, 2.30 (ABdq, J = 13.5, 2.7 Hz, 2 H), 1.26 (t,
J = 3.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 161.6,
158.2, 152.2, 148.2, 148.0, 142.7, 131.9, 127.9, 127.8,
127.4, 126.6, 124.2, 124.0, 122.2, 119.5, 116.8, 115.5,
112.3, 105.6, 92.2, 36.6, 34.6, 29.6. IR (KBr): n = 2361,
1703, 1342, 1030 cm–1. HRMS (EI): m/z calcd for
H), 7.54 (ddd, J = 8.1, 7.2, 1.8 Hz, 1 H), 7.34–7.28 (m, 2 H),
7.08 (d, J = 2.7 Hz, 1 H), 6.76 (d, J = 8.7 Hz, 1 H), 6.71 (dd,
J = 8.7, 2.7 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 1 H), 2.81 (s, 3
H), 0.94 (s, 3 H), 0.91 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 161.9, 158.0, 153.1, 152.3, 148.0, 144.4, 136.7, 131.8,
130.2, 130.0, 127.4, 124.0, 123.5, 122.8, 122.2, 116.8,
115.2, 113.7, 113.5, 113.2, 105.8, 99.9, 55.7, 42.2, 36.3,
34.8, 23.2, 22.8. IR (KBr): n = 2939, 1626, 1572, 1343,
1184, 811 cm–1. HRMS (EI): m/z calcd for C28H24N2O6:
484.1634; found: 484.1636 [M+].
(15) Annunziata, R.; Cinquini, M.; Cozzi, F.; Molteni, V.;
Schupp, O. Tetrahedron 1997, 53, 9715.
(16) Huang, J. L.; Liu, H. G.; Yang, D. Y. Bioorg. Med. Chem.
C25H18N2O5: 426.1216; found: 426.1219 [M+].
Lett. 2003, 13, 927.
(14) Representative Procedure for the Preparation of 16a.
To a solution of 15a (100 mg, 0.29 mmol) in CH2Cl2 (10 mL)
was added 4-hydroxycoumarin (47 mg, 0.29 mmol) and a
catalytic amount of p-TsOH. After the mixture was stirred at
80 °C for 16 h and cooled to r.t., H2O (10 mL) was added and
the product was extracted twice with CH2Cl2. The combined
organic extracts were dried over MgSO4, filtered and
concentrated. The resulting crude product was purified by
column chromatography (1:9 EtOAc–hexane) to give a
yellow solid with a 85% yield; mp 317–318 °C. 1H NMR
(300 MHz, CDCl3): d = 8.38 (dd, J = 8.7, 2.4 Hz, 1 H), 8.30
(dd, J = 8.7, 2.4 Hz, 1 H), 8.02 (dd, J = 8.7, 1.8 Hz, 1 H),
7.88 (dd, J = 8.4, 1.8 Hz, 1 H), 7.61 (dd, J = 8.7, 1.8 Hz, 1
(17) Chen, D. U.; Kuo, P. Y.; Yang, D. Y. Bioorg. Med. Chem.
Lett. 2005, 15, 2665.
(18) Crystallographic data (excluding structure factors) for 6a
and 16a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC-263524 and CCDC-263525, respectively.
These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223)336033.
(19) Kimber, M. C.; Try, A. C.; Painter, L.; Harding, M. M.;
Turner, P. J. Org. Chem. 2000, 65, 3024.
Synlett 2006, No. 17, 2791–2794 © Thieme Stuttgart · New York