Synthesis of nitrogen-containing benzoannulated eight- and nine-membered heterocycles from methyl 4-amino-3-iodobenzoate

Full text of DOI:10.1016/j.mencom.2014.04.011

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 159–160
Synthesis of nitrogen-containing benzoannulated eight- and
nine-membered heterocycles from methyl 4-amino-3-iodobenzoate
Mohammad Hassam, Shivaji V. More and Wen-Shan Li*
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan. Fax: +886 2 2783 1237;
e-mail: wenshan@chem.sinica.edu.tw
DOI: 10.1016/j.mencom.2014.04.011
Dibenzo[b,f]azocin-6(5H)-one and dibenzo[b,g]azonin-6(13H)-one were prepared in five steps from methyl 4-amino-3-iodobenzoate.
Nitrogen-containing heterocycles are widely distributed in nature
SnBu3
or
and play important role in medicinal chemistry.1 The eight- and nine
-
O
O
membered nitrogen-containing scaffolds are found in numerous
alkaloids such as apogalanthemine, manzamineA and tylophorine-
methine B.2 Some of the N-substituted dibenzoazocine derivatives
possess hypotensive and antiserotonin properties.3 Some dibenzo-
SnBu3
n
I
Pd(PPh3)4, K2CO3
MeO
MeO
toluene, ethanol,
90 °C, 8 h
NH2
NH2
2a n = 0
2b n = 1
1
a
zonine derivatives are used as NO synthase inhibitors.4 Numerous
methodologies have been reported for the synthesis of five- and
six-membered ring systems. However, few syntheses of eight- and
nine-membered heterocycles were published.5 The main obstacle
behind their formation are entropy factors and transannular inter-
action.6 Larock and coworkers reported the synthesis of tetra-
hydrobenzo[d]azocine derivatives bearing exocyclic double bond
by palladium-catalyzed heteroannulation of allenes.7 Majumdar
and coworkers have performed the palladium catalyzed intra-
molecular Heck coupling for the synthesis of dibenzoazocinone
with endocyclic double bond.8
Cl
O
Boc2O, Et3N,
DMAP, DCM
O
n
3
MeO
0 °C ® room
temperature,
12 h
dried DCM,
pyridine
N
H
O
0 °C ® room
temperature,
12 h
4a n = 0
4b n = 1
O
OH
HO
n
Grubbs II
MeO
toluene,
120 °C, 12 h
N
Boc
O
N
5a n = 0
5b n = 1
N
H
Me
N
H
Apogalanthemine
O
O
MeO
MeO
OMe
OH
N
H
MeO
MeO
n
n
TFA, DCM
0 °C, 1 h
NH
BocN
HN
N
Me
O
O
6 n = 0
7 n = 1
8 n = 0
9 n = 1
Manzamine A
OMe
Tylophorinemethine B
Scheme 1
Herein, we report a concise synthesis of dibenzoazocinone
and dibenzoazoninone using ring closing metathesis (Scheme 1).
The Stille coupling of methyl 4-amino-3-iodobenzoate 1 with
tributyl(vinyl)stannane and allyl(tributyl)stannane in the presence
of tetrakis(triphenylphosphine)palladium gave compounds 2a and
2b, respectively. The reaction between 2-vinylbenzoyl chloride 3
and compounds 2a,b in the presence of pyridine afforded corre-
sponding amides 4a,b. The amide NH group of compounds 4a,b
was Boc-protected to give compounds 5a,b. Ring closing meta-
thesis of compounds 5a,b using Grubbs II generation catalyst
resulted in eight- and nine-membered cyclic products 6 and 7.
Boc-deprotection in compounds 6, 7 was performed using trifluoro-
acetic acid and led to the target compounds 8, 9 in good yield.†
†
NMR spectra were recorded on Bruker AVA300, AVIII400 or AV500
instruments. High resolution mass spectra were recorded on a Bruker
Daltonics spectrometer.
Methyl (Z)-5-tert-butoxycarbonyl-6-oxodibenzo[b,f]azocine-2-(6H)-
carboxylate 6. Grubb’s second generation catalyst (0.35 g, 0.41 mmol)
was added to a solution of compound 5a (1.0 g, 2.5 mmol) in dry toluene
(50 ml) under argon and reaction mixture was refluxed for 12 h. The reac-
tion mass was concentrated under reduced pressure and subjected to column
chromatography using hexane–ethyl acetate (80:20) to give 0.65 g of
product 6 (69%). 1H NMR (CDCl3, 400 MHz) d: 1.38 (s, 9H), 3.84
(s, 3H), 6.93–7.02 (m, 3H), 7.18–7.28 (m, 2H), 7.33 (d, 1H, J 8.4 Hz),
7.53 (dd, 1H, J 7.6 and 0.8 Hz), 7.80–7.86 (m, 2H). 13C NMR (CDCl3,
100 MHz) d: 27.8, 52.3, 83.6, 127.8, 128.1, 128.3, 129.0, 129.2, 129.4,
129.9, 130.5, 133.3, 133.6, 135.6, 136.0, 141.2, 150.6, 165.9, 170.2.
© 2014 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2014, 24, 159–160
In summary, we have used ruthenium-mediated ring closing
the way for the preparation of diverse eight- and nine-membered
nitrogen containing heterocycles.
metathesis for the construction of eight- and nine-membered
frameworks of dibenzoazocinone and dibenzoazoninone, respec-
tively, in good yield. The results demonstrated here should pave
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2014.04.011.
Methyl 5-tert-butoxycarbonyl-6-oxo-5H-dibenzo[b,g]azonine-2(6H,13H)-
carboxylate 7. Yield 0.77 g (55%). 1H NMR (400 MHz, CDCl3) d: 1.13
(s, 9H), 3.23 (dd, 1H, J 14.8 and 6.5 Hz), 3.33 (dd, 1H, J 14.8 and 11.6 Hz),
3.91 (s, 3H), 5.77 (td, 1H, J 11.6 and 6.5 Hz), 6.57 (d, 1H, J 11.6 Hz), 7.29
(d, 1H, J 7.6 Hz), 7.39 (td, 1H, J 7.6 and 1.2 Hz), 7.44 (d, 1H, J 8.8 Hz),
7.53 (td, 1H, J 7.6 and 1.2 Hz), 7.82 (dd, 1H, J 7.6 and 1.1 Hz), 8.01–8.03
(m, 2H). 13C NMR (100 MHz, CDCl3) d: 27.5, 33.6, 52.3, 83.0, 127.4,
127.7, 128.9, 128.9, 129.6, 130.0, 130.1, 130.8, 131.7, 132.8, 134.2, 134.6,
136.9, 144.8, 151.5, 166.5, 174.6.
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mp 135°C. H NMR (400 MHz, CDCl3) d: 3.87 (s, 3H), 6.85 (d, 1H,
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J 11.6 Hz), 7.02 (d, 1H, J 11.6 Hz), 7.05 (d, 1H, J 7.5 Hz), 7.22 (d, 1H,
J 8.2 Hz), 7.26 (dd, 1H, J 7.5 and 1.0 Hz), 7.32 (td, 1H, J 7.5 and 1.1 Hz),
7.45 (dd, 1H, J 7.5 and 1.1 Hz), 7.82 (d, 1H, J 1.6 Hz), 7.85 (dd, 1H, J 8.2
and 2.0 Hz), 8.23 (s, 1H), 13C NMR (125 MHz, CDCl3) d: 52.4, 126.3,
128.0, 128.2, 128.5, 128.9, 129.2, 129.5, 130.0, 131.1, 133.8, 134.0,
134.5, 135.1, 139.5, 166.2, 173.6. HRMS, m/z: 273.0894 [M]+ (calc. for
C17H13NO3, m/z: 273.0895).
Methyl 6-oxo-6,13-dihydro-5H-dibenzo[b,g]azonine-2-carboxylate 9.
1
Yield 0.185 g (71%), mp 182–184°C. H NMR (400 MHz, CDCl3) d:
3.51 (dd, 2H, J 14.8 and 11.8 Hz), 3.89 (s, 3H), 5.78 (td, 1H, J 11.8 and
7.3 Hz), 6.57 (d, 1H, J 11.8 Hz), 7.24–7.42 (m, 4H), 7.70 (s, 1H), 7.91
(d, 1H, J 6.5 Hz), 7.97 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 34.4, 52.3,
127.6, 128.5, 129.3, 129.4, 129.4, 130.3, 131.2, 131.5, 132.4, 134.4, 135.5,
135.6, 144.8, 144.8, 166.5, 173.8. HRMS, m/z: 292.0973 [M–H]– (calc. for
C18H14NO3, m/z: 292.0974).
For synthesis and characteristics of compounds 2a,b, 4a,b and 5a,b,
see Online Supplementary Materials.
Received: 17th October 2013; Com. 13/4228
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