Synthesis of 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones by sequential 'condensation-iodolactonization' reactions of 1,1-bis(trimethylsilyloxy)ketene acetals with isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2005.10.108

Functionalized 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones were prepared by regio- and diastereoselective condensation of 1,1-bis(silyloxy) ketene acetals with isoquinolinium salts and subsequent regioselective and stereospecific iodolactonization.

Full text of DOI:10.1016/j.tetlet.2005.10.108

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8997–8999
Synthesis of 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones
by sequential Ôcondensation–iodolactonizationÕ reactions
of 1,1-bis(trimethylsilyloxy)ketene acetals with isoquinolines
Ehsan Ullah,a Sven Rotzoll,b Andreas Schmidt,b Dirk Michalikc and Peter Langerb,c,
*
aInstitut fu¨r Chemie und Biochemie, Universita¨t Greifswald, Soldmannstr. 16, D-17487 Greifswald, Germany
bInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, D-18059 Rostock, Germany
cLeibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e. V. (IfOK), Albert-Einstein-Str. 29a,
D-18059 Rostock, Germany
Received 16 September 2005; revised 19 October 2005; accepted 21 October 2005
Available online 9 November 2005
Abstract—Functionalized 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones were prepared by regio- and diastereoselective conden-
sation of 1,1-bis(silyloxy)ketene acetals with isoquinolinium salts and subsequent regioselective and stereospecific iodolactonization.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Quinolinium- and isoquinolinium salts represent impor-
tant synthetic building blocks.1 They are readily gener-
ated by alkylation or acylation of quinolines and
isoquinolines and have been used in a number of reac-
tions, for example, with Grignard reagents, cyanide
(Reissert reaction),2 trimethylsilylacetonitrile, allylsil-
anes, silyl enol ethers3,4 or diazoesters.5 We have studied
the synthesis of 7,8-benzo-3-hydroxy-9-azabicyclo-
[3.3.1]non-3-enes based on cyclocondensations of
1,3-bis-silyl enol ethers with isoquinolinium salts.6 Very
recently, Rudler et al. have reported the two-step cyclo-
condensation of silyl ketene acetals with pyridinium
salts.7 The publication of this work prompted us to dis-
close our own findings in this field: herein, we report
what are, to the best of our knowledge, the first cyclo-
condensations of 1,1-bis(trimethylsilyloxy)ketene acetals
with isoquinolinium salts. These reactions allow a con-
venient synthesis of densely functionalized 7,8-benzo-9-
aza-4-oxabicyclo[3.3.1]nonan-3-ones. Notably, bicyclic
N/O-acetals are present in a number of natural prod-
ucts, such as quinocarcin, tetrazomine and the bioxalo-
mycins, showing good antitumour or antimicrobial
activity.8
1,1-Bis(trimethylsilyloxy)ketene acetal 2a (R1 = Me)
was prepared by deprotonation of trimethylsilyl propi-
onic acid using lithio-1,1,1,3,3,3-hexamethyldisilazane
(LiHMDS) and subsequent addition of trimethylchloro-
silane.9 The reaction of 2a with isoquinoline (1a,
R2
R2
_
i
Cl
+
N
N
R3
1a-c
(R2 = H, NO2, Br)
A
OSiMe3
OSiMe3
R1
+
2a-j
(R1: see Table 1)
R2
R2
I
H
ii
N
H
O
R3
R1
N
R3
H
R1
O
OH
O
4a-n (R3 = CO2Me)
3a-n (R3 = CO2Me)
Keywords: Cyclizations; Heterocycles; Iminium salts; Isoquinoline;
Scheme 1. Cyclization of silyl enol ethers 2a–j with 1a–c: (i), 1
(1.0 equiv), 2 (2.0 equiv), ClCO2Me (1.2 equiv), CH2Cl2, 0 ꢁC, 2 h,
20 ꢁC, 12 h; (ii), I2 (2.0 equiv), CH2Cl2, 20 ꢁC, 12 h.
Silyl ketene acetals.
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381
4986412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.108

8998
E. Ullah et al. / Tetrahedron Letters 46 (2005) 8997–8999
R2 = H) in the presence of methyl chloroformate affor-
ded the condensation product 3a (Scheme 1). Treat-
ment of 3a with iodine in the presence of sodium
bicarbonate afforded 7,8-benzo-9-aza-4-oxabicyclo-
[3.3.1]nonan-3-one 4a.à In contrast, the reaction of 3a
with TFA resulted in decomposition. During the optimi-
zation of the cyclocondensation, the activating agent,
temperature and concentration played an important
role.
Table 1. Products and yields
3, 4
R1
R2
% (3)a
% (4)a
a
b
c
d
e
f
Me
Et
nPr
nBu
nOct
Ph
H
H
H
H
H
H
H
H
56
62
60
65
60
47
54
83
75
30
70
36
54
36
46
61
48
70
67
65
64
72
0
71
50
73
67
53
g
h
i
4-MeC6H4
4-ClC6H4
4-(MeO)C6H4
nOct
H
The preparative scope of our methodology was studied
(Scheme 1 and Table 1). The reaction of 1a (R2 = H)
with 1,1-bis(silylyloxy)ketene acetals 2a–e (R1 = Me,
Et, nPr, nBu, nOct), prepared from the corresponding
alkanoic acids, afforded the condensation products 3a–
e, which were transformed into the alkyl-substituted
7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones 4a–e.
The reaction of 1a with 2f–h (R1 = Ph, 4-MeC6H4, 4-
ClC6H4), prepared from the corresponding arylacetic
acids, afforded the condensation products 3f–h, which
j
NO2
Br
Br
Br
Br
k
l
OPh
nBu
m
n
nOct
Ph
a Yields of isolated products.
were transformed into 4f–h. The transformation of 3i
into 4i (R1 = 4-(MeO)C6H4) was not successful. Starting
with 5-nitroisoquinoline (1b, R2 = NO2) and 5-bromo-
isoquinoline (1c, R2 = Br) the 7,8-benzo-9-aza-4-oxa-
bicyclo[3.3.1]nonan-3-ones 4j–n were prepared.
Typical procedure: To a CH2Cl2 solution (20 ml) of isoquinoline
(0.250 g, 1.9 mmol) were added the 1,1-bis(trimethylsilyloxy)hex-1-
ene (1.0 g 3.8 mmol) and methyl chloroformate (0.218 g, 2.3 mmol) at
0 ꢁC. The solution was stirred for 2 h at 0 ꢁC and for 12 h at 20 ꢁC. A
saturated aqueous solution of ammonium chloride (20 ml) was added
and the organic and the aqueous layers were separated. The latter was
extracted with CH2Cl2 (3 · 100 ml). The combined organic layers
were dried (Na2SO4), filtered and the filtrate was concentrated
in vacuo. The residue was purified by chromatography (silica gel,
n-heptane ! n-heptane/EtOAc = 2:1) to give 3d as a slightly brown-
ish solid (0.384 g, 65%), mp 82 ꢁC.
The condensation of 1,1-bis(trimethylsilyloxy)ketene
acetals 2 with isoquinolines 1 afforded the carboxylic
acids 3 with very good regio- and diastereoselectivity
(step 1). The formation of 7,8-benzo-9-aza-4-oxabicy-
clo[3.3.1]nonan-3-ones 4a–n can be explained by regio-
selective formation of an iminium salt from 3 and
subsequent trans-stereospecific iodolactonization (step
2). The formation of regioisomeric products, by genera-
tion of benzylic rather than iminium cations, was not
observed. The configuration of all products was estab-
lished by spectroscopic methods. For example, the
NMR signals of 4d were assigned by DEPT and two-
à Typical procedure: To a CH2Cl2 solution (6 ml) of 3d (0.1 g,
0.35 mmol) and I2 (0.17 g 0.70 mmol) was added a saturated solution
of NaHCO3 (3.5 ml) and the solution was stirred for 12 h at 20 ꢁC.
The excess of iodine was removed by addition of a saturated aqueous
solution of sodium sulfite (20 ml). The organic and the aqueous layers
were separated. The latter was extracted with CH2Cl2 (3 · 30 ml). The
combined organic layers were dried (Na2SO4), filtered and the filtrate
was concentrated in vacuo. The residue was purified by chromato-
graphy (silica gel, n-heptane ! n-heptane/EtOAc = 2:1) to give 4d as
a yellow oil (0.10 g, 70%). Due to the amide resonance and formation
of E/Z-isomers, doubling of some signals was observed. 1H NMR
(500.13 MHz, CDCl3) d = 7.40–7.35 (m, 1H(I), 1H(II), H-4(I), H-4(II));
1
1
1
dimensional H,1H COSY, H,1H NOESY and H,13C
correlation spectra (HSQC, HMBC). In the NOESY
spectrum of 4d cross peaks were found for protons H-
2 with H-3, H-3 with H-4, and H-7 with H-8,9. Besides
the relevant NOESY signals, EXSY signals have been
found between the signals of protons H-2(I) and H-2(II)
as well as H-8(I) and H-8(II), which confirm the presence
of two exchanging isomers (rotamers I and II). In the
HMBC spectrum cross peaks were found for C-3 with
H-4, C-8 with H-7, and for COO with H-2,8,9,10, which
confirm the given structures (Scheme 2). The two rota-
mers were observed owing to the rigidity of the urethane
7.30–7.24 (m, 2H(I), 2H(II), H-5,6(I), H-5,6(II)); 7.02–6.97 (m, 1H(I)
,
3
4
1H(II), H-7(I), H-7(II)); 6.82 (ÔtÕ, 1H, J2,3 = 1.8 Hz, J2,8 = 1.5 Hz, H-
3
4
2
(II)); 6.68 (ÔtÕ, 1H, J2,3 = 1.8 Hz, J2,8 = 1.5 Hz, H-2(I)); 5.69 (d, 1H,
3J2,3 = 1.8 Hz, H-3(II)); 5.68 (d, 1H, 3J2,3 = 1.8 Hz, H-3(I)); 5.50 (br s,
4
3
1H, J2,8 = 1.5 Hz, J8,9 = 1.0 Hz, H-8(I)); 5.36 (br s, 1H,
4J2,8 = 1.5 Hz, J8,9 = 1.0 Hz, H-8(II)); 3.89 (s, 3H, MeO(I)); 3.88 (s,
3
3H, MeO(II)); 2.56–2.50 (m, 1H(I), 1H(II), H-9(I), H-9(II)); 1.75–1.35
(m, 6H(I), 6H(II), H-10,11,12(a,b),(I), H-10,11,12(a,b),(II)); 0.944 (t, 3H,
J = 7.2 Hz, H-13(II)); 0.936 (t, 3H, J = 7.2 Hz, H-13(I)). 13C NMR
(125.8 MHz, CDCl3) d = 169.3 (COO(I)); 169.0 (COO(II)); 153.8
(NCO(I)); 154.3 (NCO(II)); 132.2, 132.2 (C-3a(II), C-7a(II)); 131.9,
132.2 (C-3a(I), C-7a(I)); 131.6 (C-4(II)); 131.5 (C-4(I)); 129.5, 128.9
(C-5,6(I)); 129.4, 129.1 (C-5,6(II)); 126.6 (C-7(I)); 126.4 (C-7(II)); 85.4
(C-2(I)); 84.8 (C-2(II)); 53.8 (OMe(I)); 53.6 (OMe(II)); 52.2 (C-9(I)); 51.9
(C-9(II)); 51.8 (C-8(II)); 50.6 (C-8(I)); 30.7 (C-10(I)); 30.5 (C-10(II));
29.4 (C-11(I)); 29.3 (C-11(II)); 23.5 (C-3(I)); 23.0 (C-3(II)); 22.2 (C-12(I));
22.3 (C-12(II)); 13.8 (C-13(I)); 13.8 (C-13(II)). IR (KBr): ~m ¼ 772ðmÞ,
1109 (w), 1231 (s), 1450 (s), 1780 (s), 3430 (br) cmꢀ1; MS (EI, 70 eV):
m/z (%) = 429 (M+, 2), 302 (7), 204 (19), 188 (100), 144 (25), 129 (36).
All products were prepared as racemic material. All new compounds
gave satisfactory spectroscopic and analytical and/or high resolution
mass data.
I
I
4
3
4
3
2
3a
H
5
6
2
3a
H
O
5
6
MeO
1
O
O
1
O
N
8
N
8
7a
7a
7
H
O
7
H
MeO
O
9
11
9
13
H
11
10
12
13
H
10
12
Rotamer I
major 55%
Rotamer II
minor 45%
4d (rac.)
Scheme 2. Relative configuration and rotamers of 4d.

E. Ullah et al. / Tetrahedron Letters 46 (2005) 8997–8999
8999
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methodology.
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Financial support from the state of Mecklenburg-
Vorpommern (Landesforschungsschwerpunkt ÔNeue
Wirkstoffe und ScreeningverfahrenÕ and Landesgradu-
iertenstipendium for A.S.), from Boehringer-Ingelheim
Pharma GmbH, BASF AG and from the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
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