A new and convenient approach to heterotetracyclic benzoxazocines through addition of 1,3-dicarbonyl compounds to quinolinium salts

Article abstract of DOI:10.1016/j.tetlet.2010.03.038

The synthesis of a series of benzoxazocines has been achieved in good yields by tandem C-alkylation and intramolecular O-alkylation of 1,3-dicarbonyl compounds with quinolinium salts. This is a novel example of the synthesis of eight-membered rings via a tandem process, which provides a method for the synthesis of medium-ring heterocycles.

Full text of DOI:10.1016/j.tetlet.2010.03.038

Tetrahedron Letters 51 (2010) 2704–2707
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Tetrahedron Letters
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A new and convenient approach to heterotetracyclic benzoxazocines
through addition of 1,3-dicarbonyl compounds to quinolinium salts
a
Firouz Matloubi Moghaddam a, , Zohreh Mirjafary , Hamdollah Saeidian a,b, Salman Taheri a,
*
Mohammad Reza Khodabakhshi a
a Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, PO Box 11155-9516, Tehran, Iran
b Department of Chemistry, Payame Noor University, Zanjan Branch, Zanjan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of benzoxazocines has been achieved in good yields by tandem C-alkylation and
intramolecular O-alkylation of 1,3-dicarbonyl compounds with quinolinium salts. This is a novel example
of the synthesis of eight-membered rings via a tandem process, which provides a method for the synthe-
sis of medium-ring heterocycles.
Received 3 January 2010
Revised 27 February 2010
Accepted 12 March 2010
Available online 15 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The complexity and diversity of nitrogen- and oxygen-contain-
ing heterocycles within alkaloids make them interesting com-
pounds.1 Tetrahydroquinolines constitute an important class of
organic compounds. Their fused analogues have found consider-
able utility as pharmaceutical agents demonstrating inhibition of
the cholesterol ester transfer protein and antiallergenic, antiin-
flammatory, antiviral, antimalarial and antihypertensive activi-
ties.2 On the other hand, polycyclic frameworks lead to relatively
rigid structures that might be expected to show substantial selec-
tivity in their interactions with enzymes or receptors.3
The synthesis of medium-ring heterocycles with a ring size in
the range of 7–11 has received much attention in organic chemis-
try due to their presence in natural products and wide applications
as drug candidates and in catalysis.4 Among them, benzoxazepines
show promising pharmacological activity including antidepres-
sant, antithrombotic and antipsychotic along with the activity
against breast cancer.5 However, limited attention has been given
to the synthesis of medium-ring heterocycles, examples include
cycloadditions, ring closing metathesis, ring expansion, Mitsunobu
reactions and metal-mediated ring cyclization.6 Therefore, the
development of methods to generate medium-ring systems that
contain nitrogen and oxygen for applications in natural product
or non-natural compound synthesis is a useful aim. Tandem reac-
tions (TRs) which result from the combination of multiple transfor-
mations in one pot are highly efficient tools for the synthesis of
complex compounds. Over the past few years, there has been a tre-
mendous development in TRs affording novel chemical compounds
for drug discovery efforts.7
taining heterocycles is one of our ongoing projects due to their
interesting bio-activities.9 We earlier demonstrated an efficient
synthesis of novel indole-annulated pentacyclic indolylhydroquin-
oline9a and indolyl-tetrahydroisoquinoline skeletons9b via addition
of indolin-2-thiones, as bifunctional nucleophiles, to quinolinium
and isoquinolinium salts. This protocol is a very mild and simple
method for the construction of eight-membered rings in fused het-
erocycles in a one-step process. We herein report an unprece-
dented C-alkylation/intramolecular O-alkylation tandem process
for the construction of heterotetracyclic benzoxazocines (Scheme
1) of which analogues are widely distributed in biologically inter-
esting natural products4i–k and synthetic molecules.
To achieve the optimal reaction conditions for the tandem syn-
thesis of benzoxazocines, we initially investigated the effects of
solvent and base on the reaction of N-methylquinolinium salt 2
and 5,5-dimethylcyclohexane-1,3-dione as a simple model reac-
tion. In the absence of base, none of the desired product was ob-
tained, while good results were obtained in the presence of
K2CO3 after 4 h. The effect of solvent was studied using toluene,
CH3CN and H2O, with acetonitrile providing the highest yield and
shortest reaction time.
The IR spectrum of 3a exhibited peaks at 2953 cmꢀ1 and
1606 cmꢀ1 for the unsaturated carbonyl function. The 1H NMR
spectrum of 3a showed two singlets (d 0.99 and 1.08) for the
methyl protons, two resonances (d 1.98 and 2.02) for the geminal
aliphatic methylene protons of the hydroquinoline ring, two sig-
nals (d 2.16 and 2.20) for the allylic methylene protons and two
resonances (d 2.23 and 2.30) for the methylene protons
a to the
Addition of nucleophilic reagents to quinolinium salts has
proved to be a useful method for the synthesis of substituted quin-
oline derivatives.8 The preparation of bioactive heteroatom-con-
carbonyl, which are diastereotopic. A singlet for the N–CH3 group
(d 3.20), a multiplet for the deshielded benzylic proton (d 4.14–
4.15) and a multiplet for the N–CH–O hydrogen (d 5.54–5.55) were
also observed. When the 2-methylquinolinium salt was used as a
starting material, the signal at d 5.54 was absent, and instead a sig-
nal at d 1.82 for the methyl group was observed (see 1H NMR of 3h
* Corresponding author. Tel.: +98 2166165309; fax: +98 2166012983.
E-mail address: matloubi@sharif.edu (F.M. Moghaddam).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.038

F. M. Moghaddam et al. / Tetrahedron Letters 51 (2010) 2704–2707
2705
R'
R
N
14
H3C
O
O
Ha
15
16
K2CO3, r.t
CH3CN, 4 h
N
+
9
+
13
O
N
R'
X-
12
Hc
17
R
O
8
19
O
11
3a-l
Hd
1
2
18
3
R = Me, Et, Bn, allyl, propargyl,
p-BrC6H4CH2, CH2CO2Et
R' = H, Me
10
7
4
1
21
CH3
Hb
5
2
X = Br, I
O
Scheme 1. Synthesis of benzoxazocines.
6
CH3
20
Figure 1. The key HMBC correlations in compound 3a.
Table 1
Synthesis of 5,5-dimethylcyclohexane-1,3-dione-annulated benzoxazocines
R'
R
Table 2
Synthesis of pentane-2,4-dione-annulated benzoxazocines
O
N
O
R
O
+
+
N
O
O
N
R'
X-
O
+
R
+
O
N
X-
Entry
R
R0
Product
Yielda (%)
R
O
1
2
3
4
5
6
7
8
Me
Et
Bn
H
H
H
H
H
H
H
Me
3a
3b
3c
3d
3e
3f
83
81
78
76
71
68
70
61
Entry
R
Product
Yielda (%)
1
2
3
4
Me
Et
Bn
3i
3j
3k
3l
47
45
42
41
p-BrC6H4CH2
Allyl
Propargyl
CH2CO2Et
Me
Allyl
3g
3h
a
Isolated yield.
a
Isolated yield.
ring were at C-9 and C-10. Some of the key HMBC correlations are
shown in Figure 1.
and Table 1). The 1H-decoupled 13C NMR spectrum of 3a showed
18 distinct resonances in agreement with the proposed structure.
The 13C DEPT experiment showed resonances at d 25.8 for the ben-
zylic carbon (C-10), d 26.2 readily recognized as the methylene car-
bon (C-19), two resonances at d 27.7 and 29.9 (aliphatic methyl
carbons), d 37.5 (N–Me), two resonances at d 42.5 and 50.9 (C-1
and C-6, respectively), d 86.5 (C-9), four distinct resonances for
the aromatic methine carbons, d 168.8 (C–O), d 196.3 (C@O) and
three other quaternary carbons. Further evidence for the bridged
structure was provided by the HMBC spectrum. The key correla-
tions between Ha at d 5.54 and the carbons at d 168.8 (C-3) and
26.2 (C-19) implied that the connection points between the 5,5-
dimethylcyclohexane-1,3-dione ring and the tetrahydro-quinoline
To generalize this methodology, we reacted a series of other N-
alkylquinolinium salts 2 to give the corresponding benzoxazocines
under the optimized reaction conditions (Table 1). The reactions
proceeded cleanly under mild conditions at room temperature,
and no undesirable side reactions were observed to take place.
The same configuration was assumed for the other derivatives on
account of their spectroscopic similarities. This chemoselective
outcome is in agreement with the results observed in previous
nucleophilic substitutions of compounds 2.9a
We next examined the substrate scope by reaction between N-
alkylquinolinium salts 2 and pentane-2,4-dione. The reaction
worked well and the yields of products were satisfactory (Table 2).
O
O
O
K2CO3
+
N
OH
N
O
N
N
O
R
R
R
H
1
4
R
O
O
_
H
N
OH
R
O
Scheme 2. Proposed mechanism for the formation of compounds 3.

2706
F. M. Moghaddam et al. / Tetrahedron Letters 51 (2010) 2704–2707
11547; (b) Mishra, J. K.; Samanta, K.; Jain, M.; Dikshit, M.; Panda, M. Bioorg.
O
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Cs2CO3
CH3CN
reflux
+
+
N
N
I-
Me
O
O
Me
O
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Scheme 3. Reaction of 5,5-dimethylcyclohexane-1,3-dione with N-methylisoquin-
olinium salt.
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Tetrahedron Lett. 2010, 51, 540; (d) Moghaddam, F. M.; Kiamehr, M.; Taheri, S.;
Mirjafary, Z.; Helv. Chim. Acta. 2010, doi:10.1002/hlca.200900324.; (e)
Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.; Taheri, S.; Kheirjou, S. Synlett
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Synlett 2009, 2872; (h) Moghaddam, F. M.; Mirjafary, Z.; Saeidian, H.; Javan, M.
J. Synlett 2008, 892; (i) Saeidian, H.; Sadeghi, A.; Mirjafary, Z.; Moghaddam, F.
M. Synth. Commun. 2008, 38, 2043; (j) Moghaddam, F. M.; Saeidian, H.;
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Saeidian, H.; Mirjafary, Z.; Taheri, S. J. Sulfur Chem. 2006, 27, 545; (l)
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10. General procedure for the synthesis of benzoxazocines 3a–l: A mixture of a 1,3-
dione 1 (1 mmol), quinolinium salt 2 (1 mmol) and K2CO3 (0.14 g, 1 mmol) in
CH3CN (5 mL) was stirred at room temperature for 4 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.
A plausible mechanism for the formation of the products is
shown in Scheme 2. 5,5-Dimethylcyclohexane-1,3-dione (1)
undergoes C-alkylation by attack at C-4 of quinolinium salt 2. This
leads to the formation of an enamine on the pyridine ring of the
quinoline, which is protonated to form an iminium ion. Finally,
intramolecular nucleophilic cyclization involving the hydroxy
group gives the product.
We next investigated the addition of 5,5-dimethyl cyclohexane-
1,3-dione to an N-methylisoquinolinium salt as the starting mate-
rial, but the reaction failed to produce the desired product under
the optimized conditions. Only the nucleophilic addition of 5,5-
dimethylcyclohexane-1,3-dione was observed under heating and
using Cs2CO3 as a stronger base (Scheme 3).
In conclusion, we have described a novel and highly efficient
method for the synthesis of benzoxazocines. The present proce-
dure has advantages of high yields, good functional group toler-
ance, high selectivity and mild reaction conditions. The starting
materials are easily accessible making this procedure attractive
for the preparation of benzoxazocines in a single step.10
Acknowledgement
We gratefully acknowledge the financial support from the Re-
search Council of Sharif University of Technology.
References and notes
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H. A.; Jaroszewski, J. W. Org. Lett. 2003, 5, 2793.
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Analytical data for selected products: 3,3,7-trimethyl-2,3,4,6,7,12-hexahydro-1H-
6,12-methanodibenzo[d,g][1,3] oxazocin-1-one (3a); mp: 128–130 °C. 1H NMR
(500 MHz, CDCl3): d 0.99 (s, 3H), 1.08 (s, 3H), 1.95–2.04 (m, 2H), 2.16 (ABd,
J = 17.5 Hz, 1H), 2.20 (ABd, J = 17.5 Hz, 1H), 2.23 (ABd, J = 17.1 Hz, 1H), 2.30 (ABd,
J = 17.1 Hz, 1H), 3.20 (s, 3H), 4.14–4.15 (m, 1H), 5.54–5.55 (m, 1H), 6.70 (d,
J = 8.1 Hz, 1H), 6.74 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.39 (d, J = 7.3 Hz,
1H). 13C NMR (125 MHz, CDCl3): d 25.8 (CH), 26.2 (CH2), 27.7 (CH3), 29.9 (CH3),
32.6 (C), 37.5 (CH3), 42.5 (CH2), 50.9 (CH2), 86.5 (CH), 110.7 (CH), 115.5 (C), 118.5
(CH), 127.4 (CH), 127.6 (C), 128.4 (CH), 141.7 (C), 168.8 (C), 196.3 (C) ppm. IR
(KBr): 2953, 1606, 1495, 1381, 1331, 1204, 820, 776, 613 cmꢀ1; Anal Calcd for
C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.06; H, 7.32; N, 5.09. 7-Benzyl-
3,3-dimethyl-2,3,4,6,7,12-hexahydro-1H-6,12-
methanodibenzo[d,g][1,3]oxazocin-1-one (3c); mp: 155–157 °C. 1H NMR
(500 MHz, CDCl3): d 1.04 (s, 3H), 1.12 (s, 3H), 2.08–2.13 (m, 2H), 2.22 (ABd,
J = 16.3 Hz, 1H), 2.26 (ABd, J = 16.3 Hz, 1H), 2.28 (ABd, J = 16.1 Hz, 1H), 2.32 (ABd,
J = 16.1 Hz, 1H), 4.22–4.23 (m, 1H), 4.74 (ABd, J = 17.4 Hz, 1H), 4.94 (ABd,
J = 17.4 Hz, 1H), 5.64–5.65 (m, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.76 (t, J = 6.9 Hz, 1H),
7.02 (t, J = 7.4 Hz, 1H), 7.26–7.33 (m, 3H), 7.38 (t, J = 7.3 Hz, 2H), 7.47 (d,
J = 7.3 Hz, 1H). 13C NMR (125 MHz, CDCl3): d 26.0 (CH), 26.4 (CH2), 27.9 (CH3),
29.9 (CH3), 32.6 (C), 42.5 (CH2), 51.0 (CH2), 53.5 (CH2), 85.3 (CH), 111.3 (CH),
115.4 (C), 118.7 (CH), 126.7 (CH), 127.51 (CH), 127.54 (CH), 127.55 (C), 128.6
(CH), 129.2 (CH), 138.6 (C), 141.1 (C), 168.4 (C), 196.4 (C) ppm. IR (KBr): 2947,
1652, 1618, 1495, 1447, 1382, 983, 786, 751 cmꢀ1; Anal Calcd for C24H25NO2: C,
80.19; H, 7.01; N, 3.90. Found: C, 80.34; H, 6.88; N, 4.01. 7-Allyl-3,3-dimethyl-
2,3,4,6,7,12-hexahydro-1H-6,12-methanodibenzo[d,g][1,3]oxazocin-1-one
(3e); mp: 102–104 °C. 1H NMR (500 MHz, CDCl3): d 0.99 (s, 3H), 1.09 (s, 3H), 1.97
(ddd, J = 12.7, 2.4, 2.3 Hz, 1H), 2.04 (ddd, J = 12.7, 3.1, 3.0 Hz, 1H), 2.18 (ABd,
J = 16.3 Hz, 1H), 2.21 (ABd, J = 16.3 Hz, 1H), 2.24 (ABd, J = 17.3 Hz, 1H), 2.29 (ABd,
J = 17.3 Hz, 1H), 4.06–4.10 (m, 1H), 4.14–4.15 (m, 1H), 4.26–4.31 (m, 1H), 5.17–
5.22 (m, 2H), 5.54–5.55 (m, 1H), 5.88–5.95 (m, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.73 (t,
J = 7.3 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H). 13C NMR (125 MHz,
CDCl3): d 25.9 (CH), 26.3 (CH2), 27.7 (CH3), 29.9 (CH3), 32.6 (C), 42.5 (CH2), 50.9
(CH2), 52.1 (CH2), 84.9 (CH), 111.2 (CH), 115.3 (C), 116.6 (CH2), 118.5 (CH), 127.4
(CH), 127.6 (C), 128.5 (CH), 133.9 (CH), 140.7 (C), 168.6 (C), 196.6 (C) ppm. IR
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F. M. Moghaddam et al. / Tetrahedron Letters 51 (2010) 2704–2707
2707
(KBr): 2961, 1618, 1496, 1384, 1044, 750 cmꢀ1; Anal Calcd for C20H23NO2: C,
77.64; H, 7.49; N, 4.53. Found: C, 77.44; H, 7.55; N, 4.60. 3,3,6,7-Tetramethyl-
76.73; H, 7.80; N, 4.71. Found: C, 76.51; H, 7.94; N, 4.62. 1-(1-Methyl-4-methyl-
1,6-dihydro-2H-2,6-methano-3,1-benzoxazocin-5-yl)ethanone (3i); mp: 111–
113 °C. 1H NMR (500 MHz, CDCl3): d 1.93 (ddd, J = 12.6, 2.6, 2.4 Hz, 1H), 1.99
(ddd, J = 12.6, 3.1, 3.0 Hz, 1H), 2.25 (s, 3H), 2.37 (s, 3H), 3.19 (s, 3H), 4.19–4.20 (m,
1H), 5.42–5.43 (m, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 7.15 (t,
J = 7.4 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H). 13C NMR (125 MHz, CDCl3): d 21.8 (CH3),
25.9 (CH2), 29.3 (CH), 31.5 (CH3), 37.4 (CH3), 85.0 (CH), 110.8 (CH), 118.0 (C),
118.1 (CH), 127.6 (CH), 127.7 (C), 127.8 (CH), 142.0 (C), 163.8 (C), 197.5 (C) ppm.
IR (KBr): 2947, 1652, 1618, 1495, 1447, 1382, 983, 786, 751 cmꢀ1; Anal Calcd for
C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C, 73.88; H, 7.15; N, 5.66.
2,3,4,6,7,12-hexahydro-1H-6,12-methanodibenzo[d,g][1,3]
oxazocin-1-one
(3h); mp: 126–128 °C. 1H NMR (500 MHz, CDCl3): d 0.98 (s, 3H), 1.08 (s, 3H),
1.82 (s, 3H), 1.98 (dd, J = 12.9, 3.4 Hz, 1H), 2.05 (dd, J = 12.9, 2.5 Hz, 1H), 2.18 (s,
2H), 2.25 (s, 2H), 3.08 (s, 3H), 4.05–4.06 (m, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.71 (t,
J = 8.0 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H). 13C NMR (125 MHz,
CDCl3): d 26.1 (CH3), 27.68 (CH3), 27.74 (CH), 29.9 (CH3), 32.2 (CH3), 32.6 (C), 34.9
(CH2), 42.6 (CH2), 51.0 (CH2), 88.6 (C), 111.5 (CH), 114.4 (C), 118.2 (CH), 127.3
(CH), 127.9 (CH), 128.5 (C), 143.5 (C), 168.9 (C), 196.7 (C) ppm. IR (KBr): 2953,
1606, 1495, 1381, 1331, 1204, 820, 776, 613 cmꢀ1; Anal Calcd for C19H23NO2: C,