Efficient synthesis of bicyclo[3.3.1]nonane systems via tandem 1,3-dinucleophilic addition of 4-hydroxy-2-quinolinones to quinolinium salts

Article abstract of DOI:10.1080/00397911.2010.550703

The synthesis of bicyclo[3.3.1]nonane systems is reported. The synthesis is based on the tandem 1,3-dinucleophilic addition of 4-hydroxy-2-quinolinone to quinolinium salts.

Full text of DOI:10.1080/00397911.2010.550703

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Efficient Synthesis of
Bicyclo[3.3.1]nonane Systems via
Tandem 1,3-Dinucleophilic Addition of 4-
Hydroxy-2-quinolinones to Quinolinium
Salts
a
a
Firouz Matloubi Moghaddam , Zohreh Mirjafary , Hamdollah
a b
a
a
Saeidian
a
, Behzad Koushki Foroushani & Saghar Nourian
Laboratory of Organic Synthesis and Natural Products, Department
of Chemistry, Sharif University of Technology, Tehran, Iran
b
Department of Science, Payame Noor University, Zanjan, Iran
Accepted author version posted online: 27 Oct 2011.Published
online: 26 Mar 2012.
To cite this article: Firouz Matloubi Moghaddam , Zohreh Mirjafary , Hamdollah Saeidian , Behzad
Koushki Foroushani & Saghar Nourian (2012) Efficient Synthesis of Bicyclo[3.3.1]nonane Systems
via Tandem 1,3-Dinucleophilic Addition of 4-Hydroxy-2-quinolinones to Quinolinium Salts, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:13, 1941-1949, DOI: 10.1080/00397911.2010.550703
To link to this article: http://dx.doi.org/10.1080/00397911.2010.550703
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1
Synthetic Communications , 42: 1941–1949, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.550703
EFFICIENT SYNTHESIS OF BICYCLO[3.3.1]NONANE
SYSTEMS VIA TANDEM 1,3-DINUCLEOPHILIC
ADDITION OF 4-HYDROXY-2-QUINOLINONES TO
QUINOLINIUM SALTS
1
Firouz Matloubi Moghaddam, Zohreh Mirjafary,
1
1,2
1
Hamdollah Saeidian, Behzad Koushki Foroushani, and
1
Saghar Nourian
1
Laboratory of Organic Synthesis and Natural Products, Department of
Chemistry, Sharif University of Technology, Tehran, Iran
2
Department of Science, Payame Noor University, Zanjan, Iran
GRAPHICAL ABSTRACT
Abstract The synthesis of bicyclo[3.3.1]nonane systems is reported. The synthesis is based
on the tandem 1,3-dinucleophilic addition of 4-hydroxy-2-quinolinone to quinolinium salts.
Keywords Benzoxazocines; 1,3-dinucleophilic addition; quinolinium salts; quinolinones
INTRODUCTION
Quinolinones and annulated quinolinones are well known for their remarkable
biological activities. A large number of fascinating pharmaceutical activities are
associated with quinolinone derivatives. The synthesis of such compounds has been
the subject of several research studies that demonstrate the high importance of this
[
1,2]
class of compounds.
anticonvulsants, analgesics, orally active antagonists, herbicides, cardiovasculars,
Quinolinones act as antibacterials, antifungals, antivirals,
[
3–5]
and memory-enhancing and hypotensive agents.
have been reported to show activity against wild-type HIV-1. In addition, they
Some quinolinone derivatives
[
6]
Received July 6, 2010.
Address correspondence to Firouz Matloubi Moghaddam, Laboratory of Organic Synthesis and
Natural Products, Department of Chemistry, Sharif University of Technology, P.O. Box 11155-9516,
Tehran, Iran. E-mail: matloubi@sharif.edu
1
941

1942
F. M. MOGHADDAM ET AL.
Scheme 1. Synthesis of bicyclo[3.3.1]nonane systems.
are useful intermediates for the preparation of alkaloid, nonpeptide GnRH receptor
antagonists and wide varieties of biologically active organic compounds such as
condensed polycyclic heterocycles, pyrano quinolines, piperazinyl carbomides, oxa-
[
7,8]
zino quinolines, and isoxazolo quinolines.
systems, are a very important feature of biologically active organic compounds.
Quinolinones, fused to heterocyclic
[
9,10]
Furthermore, benzoxazocines have received considerable attention because of their
pharmaceutical properties including antidepressant, antithrombotic, and antipsy-
[
11–13]
chotic activities as well as their activity against breast cancer.
Because of entropy and ring strain, the construction of medium-ring hetero-
cycles, especially eight-membered rings, remains a significant synthetic challenge in
modern organic synthesis. In recent papers, we have reported the novel and efficient
synthesis of a broad spectrum of polycyclic benzoxazocines via unique tandem
1
,3-dinucleophilic addition of different bifunctional nucleophiles to quinolinium and
[14]
isoquinolinium salts. The procedure is mild, and the substrates are easily accessible.
-Hydroxy-2-quinolinones were found to be effective in 1,3-nucleophiles, reacting with
a variety of electrophiles, and were used mainly for the synthesis of heterocyclic com-
4
[
15,16]
pounds.
Thus, we theorized that 4-hydroxy-2-quinolinones would also react with
quinolinium salts to produce the bicyclo[3.3.1]nonane systems. Herein, we describe an
unprecedented C-alkylation=intramolecular O-alkylation tandem process for the con-
struction of annulated quinolinones. The reaction generally involves the initial
addition of quinolinone to quinolinium salt to form an enamine intermediate, which
can be trapped by intramolecular O-alkylation of quinolinone (Scheme 1).
RESULTS AND DISCUSSION
4
anilides and phosphoryl chloride with malonic acid,
-Hydroxy-2-quinolinones were prepared in moderate yields by refluxing
[
17]
and quinolinium salts were
synthesized in good yields by alkylation of quinoline in acetone as solvent
[
18]
(
Scheme 2).
When a mixture of 4-hydroxy-2-quinolinone 1a (1 equiv.), N-methylquinoli-
nium salt 2a (1 equiv.), and Cs CO (1 equiv.) in 5 ml CH CN was stirred at room
2
3
3
temperature for 10 h, the desired product 3a was synthesized in 79% yield. The
results showed that the presence of a base is required to synthesize the desired
product under optimized conditions. CH CN and Cs CO were found to be the best
3
2
3

DINUCLEOPHILIC ADDITION OF QUINOLINONES
1943
Scheme 2. Preparation of starting materials.
solvent and base for greater yields and shorter reaction times. The assignment of
1
compound 3a was confirmed by elemental analyses, H NMR, C NMR, and 2D
13
1
NMR data of the expected chemical shifts. The H NMR spectra of 3a showed
two peaks (d 2.12 and 2.21) for the geminal aliphatic methylene protons, two singlet
peaks for the N-CH (d 3.22, 3.64), a multiplet for the deshielded benzylic proton (d
3
4
.43), and a multiplet for the N-CH-O (d 5.74). When 2-methyl quinolinium salt was
used as a starting material, the signal at d 5.74 disappeared, and instead a signal at d
1
.95 for the methyl group was observed (see H NMR of 3f). The H-decoupled
1
13
1
NMR spectrum of 3a showed 20 distinct resonances, in agreement with the proposed
C
1
3
structure. Distortionless enhancement by polarization transfer ( C DEPT) experi-
ment showed a resonance at d 26.2 readily recognized as the methylene carbon,
two peaks at d 28.2 and 85.8 for aliphatic methine carbons, two signals at d 29.7
and 37.4 (N-Me) and at d 162.6 (C=O), eight distinct resonances for aromatic meth-
ine carbons, and six other quaternary carbons. This outcome is in agreement with the
[
14]
relative topicity observed in previous nucleophilic substitutions of 2.
To investigate the scope of this reaction, we explored the reaction by varying
the structure of the 4-hydroxy-2-quinolinone 1 and the N-alkyl quinolinium salts 2
(Table 1). The reaction proceeds cleanly under mild conditions at room temperature,
and no undesirable side reactions were observed. In the case of quinolinium salt with
Table 1. Synthesis of quinolinone-annulated heterocycles
1
R
2
R
3
R
4
R
Entry
Product
Yield
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
79
76
65
68
61
42
78
73
71
70
60
0
C
6
H
5
CH
2
H
CH
CH
Me
Me
Me
Et
2
¼CHCH
2
H
2
CO
2
Et
H
H
Me
H
3g
3h
3i
C
C
C
C
6
6
6
6
H
5
CH
5
CH
5
CH
5
CH
2
2
2
2
H
H
H
H
1
1
1
0
1
2
Me
p-BrC
COCH
Me
H
3j
6
H
4
CH
2
3k
3l
Me
3
H

1944
F. M. MOGHADDAM ET AL.
Scheme 3. The reaction of N-methyl-4-hydroxy-2-quinolinone with N-methyl isoquinolinium salt.
Scheme 4. Proposed mechanism for the formation of 3.
electron-withdrawing group on N (Table 1, entry 10) under optimized reaction con-
ditions, no reaction was observed. In the next step, we investigated the scope of the
reaction using the N-methyl isoquinolinium salt as a starting material, but the reac-
tion failed to produce the desired product under the optimized conditions (Scheme 3).
A possible reaction mechanism for the formation of annulated quinolinones is
shown in Scheme 4. 4-Hydroxy-2-quinolinone 1 undergoes a C-alkylation by attack
at C-4 of quinolinium salt 2. The resulting enamine 4 can in turn be reactivated via imi-
nium intermediate 5 to undergo a second nucleophilic addition. Finally, intramolecular
nucleophilic cyclization involving the hydroxyl group gives the desired product.
In summary, we have developed an efficient protocol for the preparation of
bicyclo[3.3.1]nonane systems. Good yield and selectivity and low cost of the reagents
are the salient features of this method. The reaction starts from easily accessible
starting materials, which makes it a useful and interesting process for the preparation
of quinolinone-annulated heterocycles in a one-step operation.
EXPERIMENTAL
The compounds all demonstrated satisfactory spectroscopic data. A Bruker
1 13
DRX-500 Avance) NMR was used to record the H NMR and C NMR spectra.
(

DINUCLEOPHILIC ADDITION OF QUINOLINONES
1945
All NMR spectra were determined in CDCl at ambient temperature. Melting points
3
were determined on a Buchi B540 apparatus. Elemental analysis was obtained using
a Perkin-Elmer 2004 (II) CHN analyzer. All the reactions were monitored by
thin-layer chromatography (TLC) carried out on silica gel with ultraviolet light
and iodine as detecting agents. Silica gel, petroleum ether, and ethyl acetate were
used for flash chromatography.
General Procedure for the Synthesis of Quinolinone-Annulated
Heterocycles 3a–k
A mixture of 4-hydroxy-2-quinolinone 1 (1 mmol), quinolinium salt 2
1 mmol), and Cs CO (1 mmol) in CH CN (5 mL) was stirred at room temperature
(
2 3 3
for 10 h. The progress of the reaction was monitored by TLC. After completion of
the reaction, the solvent was removed under reduced pressure, and the residue was
separated by flash column chromatography on silica gel with petroleum ether =
EtOAc (2:1) as eluent to afford the pure product.
Analytical Data for Selected Products
Compound 3a: 2,9-Dimethyl-2,8,9,14-tetrahydro-1H-8,14-methano-
ꢀ
1
quino[4,3-d][3,1]benzoxazocin-1-one. Mp 196–198 C. H NMR (500 MHz,
CDCl ): d 2.12 (ddd, J ¼ 12.8, 2.6, 2.2 Hz, 1H), 2.21 (ddd, J ¼ 12.8, 2.6, 3.1 Hz,
3
1
H), 3.22 (s, 3H), 3.64 (s, 3H), 4.42–4.43 (m, 1H), 5.74–5.75 (m, 1H), 6.67 (d,
J ¼ 8.1 Hz, 1H), 6.75 (t, J ¼ 7.4 Hz, 1H), 7.09 (t, J ¼ 7.4 Hz, 1H), 7.20 (t, J ¼ 7.2 Hz,
1
H), 7.26 (d, J ¼ 7.3 Hz, 1H), 7.50 (t, J ¼ 7.4 Hz, 1H), 7.58 (d, J ¼ 7.4 Hz, 1H), 7.96
3 2
1
3
(
(
(
d, J ¼ 8.0 Hz, 1H); C NMR (125 MHz, CDCl ): d 26.2 (CH ), 28.2 (CH), 29.7
CH ), 37.4 (CH ), 85.8 (CH), 110.7 (CH), 111.4 (C), 114.2 (CH), 116.6 (C), 118.6
3 3
CH), 121.9 (CH), 123.5 (CH), 127.0 (C), 127.7 (CH), 128.5 (CH), 130.7 (CH),
138.8 (C), 142.7 (C), 155.6 (C), 162.6 (C). Anal. calcd. for C H N O : C, 75.45;
20 18 2 2
H, 5.70; N, 8.80. Found: C, 75.24; H, 5.89; N, 8.67.
Compound 3b: 9-Ethyl-2-methyl-2,8,9,14-tetrahydro-1H-8,14-methano-
ꢀ
1
quino[4,3-d][3,1]benzoxazocin-1-one. Mp 195–197 C. H NMR (500 MHz,
CDCl ): d 1.27 (t, J ¼ 7.1 Hz, 3H), 2.13 (ddd, J ¼ 12.8, 2.3, 2.4 Hz, 1H), 2.26 (ddd,
3
J ¼ 12.8, 3.1, 3.0 Hz, 1H), 3.52–3.60 (m, 1H), 3.68 (s, 3H), 3.86–3.93 (m, 1H),
4
1
.46–4.47 (m, 1H), 5.83–5.84 (m, 1H), 6.74 (d, J ¼ 8.1 Hz, 1H), 6.79 (t, J ¼ 7.4 Hz,
H), 7.13 (t, J ¼ 7.7 Hz, 1H), 7.24 (t, J ¼ 7.6 Hz, 1H), 7.28 (d, J ¼ 8.4 Hz, 1H), 7.52
1
3
(t, J ¼ 7.8 Hz, 1H), 7.65 (d, J ¼ 7.4 Hz, 1H), 8.01 (d, J ¼ 8.0 Hz, 1H). C NMR
(125 MHz, CDCl ): d 13.6 (CH ), 26.2 (CH ), 28.3 (CH), 29.7 (CH ), 44.6 (CH ),
3
3
2
3
2
8
1
1
4.8 (CH), 110.7 (CH), 111.4 (C), 114.2 (CH), 116.6 (C), 118.3 (CH), 121.9 (CH),
23.4 (CH), 127.3 (C), 127.7 (CH), 128.9 (CH), 130.7 (CH), 138.8 (C), 140.8 (C),
55.4 (C), 162.6 (C). Anal. calcd. for C H N O : C, 75.88; H, 6.06; N, 8.43. Found:
2
1
20
2
2
C, 75.93; H, 6.21; N, 8.50.
Compound 3c: 9-Benzyl-2-methyl-2,8,9,14-tetrahydro-1H-8,14-metha-
ꢀ
1
noquino[4,3-d][3,1]benzoxazocin-1-one. Mp 210–212 C. H NMR (500 MHz,
CDCl ): d 2.29 (ddd, J ¼ 12.8, 2.3, 2.2 Hz, 1H), 2.35 (ddd, J ¼ 12.8, 3.1, 3.0 Hz,
3
1
H), 3.72 (s, 3H), 4.55–4.56 (m, 1H), 4.76 (ABd, J ¼ 17.3 Hz, 1H), 5.01 (ABd,

1946
F. M. MOGHADDAM ET AL.
J ¼ 17.3 Hz, 1H), 5.89–5.88 (m, 1H), 6.61 (d, J ¼ 8.1 Hz, 1H), 6.80 (t, J ¼ 7.4 Hz, 1H),
.03 (t, J ¼ 7.7 Hz, 1H), 7.26 (t, J ¼ 7.6 Hz, 1H), 7.29–7.35 (m, 6H), 7.57 (t,
7
1
3
J ¼ 7.5 Hz, 1H), 7.69 (d, J ¼ 7.4 Hz, 1H), 7.99 (d, J ¼ 8.0 Hz, 1H). C NMR
(125 MHz, CDCl ): d 26.3 (CH ), 28.2 (CH), 29.8 (CH ), 53.4 (CH ), 84.5 (CH),
3 2 3 2
1
1
11.3 (C), 111.4 (CH), 114.3 (CH), 116.5 (C), 118.8 (CH), 122.0 (CH), 123.5 (CH),
26.7 (CH), 127.0 (C), 127.5 (CH), 127.8 (CH), 128.7 (CH), 129.2 (CH), 130.9
(CH), 138.5 (C), 138.8 (C), 141.6 (C), 155.4 (C), 162.6 (C). Anal. calcd. for
C H N O : C, 79.16; H, 5.62; N, 7.10. Found: C, 78.92; H, 5.71; N, 7.24.
2
6
22
2
2
Compound 3d: 9-Allyl-2-methyl-2,8,9,14-tetrahydro-1H-8,14-methano-
ꢀ
1
quino[4,3-d][3,1]benzoxazocin-1-one. Mp 153–155 C. H NMR (500 MHz,
CDCl ): d 2.17 (ddd, J ¼ 12.7, 2.3, 2.2 Hz, 1H), 2.29 (ddd, J ¼ 12.7, 3.1, 3.0 Hz,
3
1
5
6
H), 3.68 (s, 3H), 4.10–4.14 (m, 1H), 4.36–4.39 (m, 1H), 4.47–4.48 (m, 1H),
.19–5.26 (m, 2H), 5.80–5.81 (m, 1H), 5.90–5.95 (m, 1H), 6.68 (d, J ¼ 7.8 Hz, 1H),
.80 (t, J ¼ 7.1 Hz, 1H), 7.10 (t, J ¼ 7.1 Hz, 1H), 7.24 (t, J ¼ 7.2 Hz, 1H), 7.29 (d,
J ¼ 8.4 Hz, 1H), 7.53 (t, J ¼ 7.6 Hz, 1H), 7.65 (d, J ¼ 7.1 Hz, 1H), 7.99 (d, J ¼ 7.4 Hz,
1
3
1
8
1
H); C NMR (125 MHz, CDCl ): d 26.3 (CH ), 28.3 (CH), 29.7 (CH ), 52.1 (CH ),
3 2 3 2
4.1 (CH), 111.1 (C), 111.2 (CH), 114.2 (CH), 116.5 (C), 116.7 (CH ), 118.6 (CH),
2
21.9 (CH), 123.4 (CH), 127.1 (C), 127.7 (CH), 128.7 (CH), 130.8 (CH), 133.9
(CH), 138.8 (C), 141.3 (C), 155.2 (C), 162.6 (C). Anal. calcd. for C H N O : C,
22 20 2 2
7
6.72; H, 5.85; N, 8.13. Found: C, 76.81; H, 5.72; N, 8.26.
Compound 3e: Ethyl (2-Methyl-1-oxo-2,14-dihydro-1H-8,14-methano-
1
ꢀ
quino[4,3-d][3,1]benzoxazocin-9-yl)acetate. Mp
190–192 C.
H
NMR
(
500 MHz, CDCl ): d 1.32 (t, J ¼ 7.1 Hz, 3H), 2.16 (ddd, J ¼ 12.7, 2.4, 2.2 Hz, 1H),
3
2
4
1
.26 (ddd, J ¼ 12.7, 3.1, 3.0 Hz, 1H), 3.67 (s, 3H), 4.13 (ABd, J ¼ 18.1 Hz, 1H),
.19–4.25 (m, 2H), 4.41 (ABd, J ¼ 18.1 Hz, 1H), 4.43–4.44 (m, 1H), 5.85–5.86 (m,
H), 6.50 (d, J ¼ 8.1 Hz, 1H), 6.76 (t, J ¼ 7.4 Hz, 1H), 7.08 (t, J ¼ 7.4 Hz, 1H), 7.20
(
t, J ¼ 7.2 Hz, 1H), 7.50 (d, J ¼ 7.3 Hz, 1H), 7.61 (d, J ¼ 7.3 Hz, 1H), 7.72 (t,
1
3
J ¼ 7.4 Hz, 1H), 7.93 (d, J ¼ 8.0 Hz, 1H); C NMR (125 MHz, CDCl ): d 14.7
3
(
CH ), 26.3 (CH ), 28.1 (CH), 37.4 (CH ), 51.3 (CH ), 61.7 (CH ), 85.8 (CH),
3 2 3 2 2
1
1
1
10.8 (CH), 111.5 (C), 114.3 (CH), 116.6 (C), 118.8 (CH), 121.9 (CH), 123.6 (CH),
27.1 (C), 127.9 (CH), 128.7 (CH), 130.7 (CH), 138.9 (C), 142.7 (C), 154.9 (C),
63.1 (C), 170.8 (C). Anal. calcd. for C H N O : C, 70.75; H, 5.68; N, 7.17. Found:
2
3
22
2
4
C, 70.81; H, 5.72; N, 7.24.
Compound 3f: 2,8,9-Trimethyl-2,8,9,14-tetrahydro-1H-8,14-methano-
ꢀ
1
quino[4,3-d][3,1]benzoxazocin-1-one. Mp 186–188 C. H NMR (500 MHz,
CDCl ): d 1.98 (s, 3H), 2.21 (dd, J ¼ 12.8, 2.8 Hz, 1H), 2.25 (dd, J ¼ 12.8, 3.1 Hz,
3
1
H), 3.13 (s, 3H), 3.66 (s, 3H), 4.37–4.38 (m, 1H), 6.69 (d, J ¼ 8.1 Hz, 1H), 6.77 (t,
J ¼ 7.3 Hz, 1H), 7.11 (t, J ¼ 7.4 Hz, 1H), 7.24 (t, J ¼ 7.2 Hz, 1H), 7.29 (d, J ¼ 8.5 Hz,
1
3
1
H), 7.53 (t, J ¼ 7.2 Hz, 1H), 7.59 (d, J ¼ 7.4 Hz, 1H), 8.03 (d, J ¼ 8.0 Hz, 1H);
C
NMR (125 MHz, CDCl ): d 26.2 (CH ), 29.6 (CH ), 30.1 (CH), 32.2 (CH ), 34.9
3
3
3
3
(
CH ), 87.9 (C), 110.5 (C), 111.6 (CH), 114.2 (CH), 116.6 (C), 118.3 (CH), 121.8
2
(CH), 123.3 (CH), 127.6 (CH), 127.9 (C), 128.1 (CH), 130.7 (CH), 138.8 (C), 143.9
(C), 155.6 (C), 162.7 (C). Anal. calcd. for C H N O : C, 75.88; H, 6.06; N, 8.43.
Found: C, 76.05; H, 6.18; N, 8.35.
2
1
20
2
2

DINUCLEOPHILIC ADDITION OF QUINOLINONES
1947
Compound 3g: 2,9,12-Trimethyl-2,8,9,14-tetrahydro-1H-8,14-methano-
ꢀ
1
quino[4,3-d][3,1]benzoxazocin-1-one. Mp 191–193 C. H NMR (500 MHz,
CDCl ): d 2.17 (ddd, J ¼ 12.7, 2.3, 2.2 Hz, 1H), 2.23 (ddd, J ¼ 12.7, 3.1, 3.0 Hz,
3
1
6
H), 2.32 (s, 3H), 3.24 (s, 3H), 3.68 (s, 3H), 4.44–4.45 (m, 1H), 5.77–5.78 (m, 1H),
.63 (d, J ¼ 8.2 Hz, 1H), 6.95 (d, J ¼ 7.4 Hz, 1H), 7.24 (t, J ¼ 7.5 Hz, 1H), 7.29 (t,
1
3
J ¼ 7.3 Hz, 1H), 7.47 (s, 1H), 7.52 (t, J ¼ 7.5 Hz, 1H), 8.01 (d, J ¼ 7.9 Hz, 1H).
C
NMR (125 MHz, CDCl ): d 20.8 (CH ), 26.4 (CH ), 28.1 (CH), 29.8 (CH ), 37.4
3
3
2
3
(CH ), 86.0 (CH), 110.9 (CH), 111.4 (C), 114.2 (CH), 116.6 (C), 121.9 (CH), 123.5
3
(CH), 127.1 (C), 127.8 (C), 128.2 (CH), 129.2 (CH), 130.7 (CH), 138.8 (C), 139.8
(C), 155.7 (C), 162.5 (C). Anal. calcd. for C H N O : C, 75.88; H, 6.06; N, 8.43.
Found: C, 75.70; H, 5.92; N, 8.35.
2
1
20
2
2
Compound
methanoquino[4,3-d][3,1]benzoxazocin-1-one. Mp 203–205 C.
500 MHz, CDCl ): d 2.21 (ddd, J ¼ 12.8, 2.2, 2.1 Hz, 1H), 2.30 (ddd, J ¼ 12.8, 3.1,
3h:
2-Benzyl-9-methyl-2,8,9,14-tetrahydro-1H-8,14-
ꢀ
1
H
NMR
(
3
3
.0 Hz, 1H), 3.29 (s, 3H), 4.54–4.55 (m, 1H), 5.29 (ABd, J ¼ 17.3 Hz, 1H), 5.76
ABd, J ¼ 17.3 Hz, 1H), 5.83–5.84 (m, 1H), 6.75 (d, J ¼ 8.1 Hz, 1H), 6.82 (t,
J ¼ 7.4 Hz, 1H), 7.17 (t, J ¼ 6.8 Hz, 1H), 7.20–7.33 (m, 7H), 7.40 (t, J ¼ 7.8 Hz,
(
1
3
1
H), 7.67 (d, J ¼ 6.2 Hz, 1H), 8.03 (d, J ¼ 7.7 Hz, 1H); C NMR (125 MHz, CDCl ):
3
d 26.2 (CH ), 28.2 (CH), 37.5 (CH ), 46.4 (CH ), 85.9 (CH), 110.8 (CH), 111.3 (C),
2
3
2
1
1
1
7
15.1 (CH), 118.7 (CH), 122.0 (CH), 123.6 (CH), 127.0 (CH), 127.1 (C), 127.5 (CH),
27.8 (CH), 128.6 (CH), 129.1 (CH), 129.2 (CH), 129.3 (C), 130.7 (CH), 132.3 (CH),
37.4 (C), 138.3 (C), 142.1 (C), 156.0 (C), 162.7 (C). Anal. calcd. for C H N O : C,
2
6
22
2
2
9.16; H, 5.62; N, 7.10. Found: C, 79.03; H, 5.54; N, 7.19.
Compound 3i: 2-Benzyl-9-ethyl-2,8,9,14-tetrahydro-1H-8,14-methano-
ꢀ
1
quino[4,3-d][3,1]benzoxazocin-1-one. Mp 198–200 C. H NMR (500 MHz,
CDCl ): d 1.31 (t, J ¼ 7.1 Hz, 3H), 2.17 (ddd, J ¼ 12.7, 2.1, 2.0 Hz, 1H), 2.31 (ddd,
3
J ¼ 12.7, 3.1, 3.0 Hz, 1H), 3.56–3.63 (m, 1H), 3.88–3.96 (m, 1H), 4.53–4.54 (m,
1
6
H), 5.23 (ABd, J ¼ 17.3 Hz, 1H), 5.81 (ABd, J ¼ 17.3 Hz, 1H), 5.88–5.89 (m, 1H),
.77 (d, J ¼ 8.1 Hz, 1H), 6.80 (t, J ¼ 7.4 Hz, 1H), 7.15 (t, J ¼ 7.4 Hz, 1H), 7.20–7.32
(
m, 7H), 7.38 (t, J ¼ 7.4 Hz, 1H), 7.67 (d, J ¼ 6.8 Hz, 1H), 8.02 (d, J ¼ 7.8 Hz, 1H);
1
3
C NMR (125 MHz, CDCl ): d 13.7 (CH ), 26.2 (CH ), 28.3 (CH), 44.7 (CH ),
3 3 2 2
4
1
6.4 (CH ), 84.9 (CH), 110.8 (CH), 111.3 (C), 115.1 (CH), 116.9 (C), 118.3 (CH),
22.0 (CH), 123.5 (CH), 127.0 (CH), 127.5 (CH), 127.7 (CH), 129.0 (CH), 129.1
2
(CH), 129.3 (C), 130.7 (CH), 137.4 (C), 138.4 (C), 140.8 (C), 155.8 (C), 162.8 (C).
Anal. calcd. for C H N O : C, 79.39; H, 5.92; N, 6.86. Found: C, 79.30; H,
2
7
24
2
2
6
.01; N, 6.91.
Compound 3j: 2-Benzyl-9,12-dimethyl-2,8,9,14-tetrahydro-1H-8,14-
1
ꢀ
methanoquino[4,3-d][3,1]benzoxazocin-1-one. Mp 196–198 C.
H
NMR
(
3
1
500 MHz, CDCl ): d 2.21 (ddd, J ¼ 12.8, 2.2, 2.1 Hz, 1H), 2.29 (ddd, J ¼ 12.8, 3.1,
3
.0 Hz, 1H), 2.32 (s, 3H), 3.28 (s, 3H), 4.52–4.53 (m, 1H), 5.28 (d, J ¼ 17.3 Hz,
H), 5.78 (d, J ¼ 17.3 Hz, 1H), 5.82–5.83 (m, 1H), 6.67 (d, J ¼ 8.1 Hz, 1H), 6.98 (d,
J ¼ 8.1 Hz, 1H), 7.20 (t, J ¼ 8.2 Hz, 1H), 7.23–7.38 (m, 5H), 7.36 (d, J ¼ 7.7 Hz,
1
3
1
(
H), 7.41 (t, J ¼ 7.5 Hz, 1H), 7.49 (s, 1H), 8.03 (d, J ¼ 7.9 Hz, 1H); C NMR
125 MHz, CDCl ): d 20.8 (CH ), 26.4 (CH ), 28.2 (CH), 37.6 (CH ), 46.4 (CH ),
3
3
2
3
2
8
6.3 (CH), 111.0 (CH), 111.3 (C), 115.1 (CH), 122.0 (CH), 123.2 (CH), 123.6

1948
F. M. MOGHADDAM ET AL.
(
(
(
CH), 126.9 (C), 127.0 (CH), 127.2 (C), 127.4 (CH), 128.2 (CH), 129.1 (CH), 129.2
CH), 129.3 (C), 130.7 (CH), 132.3 (CH), 137.4 (C), 138.3 (C), 139.8 (C), 156.1
C), 162.7 (C) ppm. Anal. calcd. for C H N O : C, 79.39; H, 5.92; N, 6.86; Found:
2
7
24
2
2
C, 79.39; H, 5.92; N, 6.86.
Compound 3k: 2-Benzyl-9-(4-bromobenzyl)-2,8,9,14-tetrahydro-1H-
1
ꢀ
8
,14-methanoquino[4,3-d][3,1]benzoxazocin-1-one. Mp
222–224 C.
H
NMR (500 MHz, CDCl ): d 1.99 (ddd, J ¼ 12.8, 2.5, 2.4 Hz, 1H), 2.08 (ddd,
3
J ¼ 12.8, 3.1, 3.0 Hz, 1H), 4.23–4.24 (m, 1H), 4.41 (ABd, J ¼ 17.5 Hz, 1H), 4.68
(
5
ABd, J ¼ 17.5 Hz, 1H), 4.96 (ABd, J ¼ 13.7 Hz, 1H), 5.47 (ABd, J ¼ 13.7 Hz, 1H),
.61–5.62 (m, 1H), 6.25 (d, J ¼ 8.1 Hz, 1H), 6.45 (t, J ¼ 7.4 Hz, 1H), 6.70 (t,
J ¼ 7.0 Hz, 1H), 6.87 (d, J ¼ 8.2 Hz, 2H), 6.90–6.99 (m, 7H), 7.12 (t, J ¼ 7.2 Hz,
1
H), 7.13 (d, J ¼ 8.2 Hz, 2H), 7.31 (d, J ¼ 7.4 Hz, 1H), 7.64 (d, J ¼ 7.9 Hz, 1H);
C NMR (125 MHz, CDCl ): d 26.0 (CH ), 28.0 (CH), 46.0 (CH ), 53.0 (CH ),
1
3
3
2
2
2
8
1
1
1
4.5 (CH), 110.7 (C), 111.1 (CH), 114.9 (CH), 116.2 (C), 118.6 (CH), 122.0 (CH),
20.9 (C), 123.3 (CH), 126.7 (CH), 126.9 (C), 127.3 (CH), 127.6 (CH), 128.4 (CH),
28.5 (CH), 128.9 (CH), 130.8 (CH), 131.9 (CH), 137.1 (C), 137.5 (C), 138.1 (C),
41.0 (C), 155.3 (C), 162.3 (C). Anal. calcd. for C H BrN O : C, 69.95; H, 4.59;
3
2
25
2
2
N, 5.10. Found: C, 70.13; H, 4.68; N, 4.49.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council of
Sharif University of Technology.
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