Synthesis of azoxabicyclo[3.3.1]nonanones based on diastereoselective reactions of 1,1-bis(trimethylsilyloxy)ketene acetals with isoquinolines and quinolines

Article abstract of DOI:10.1039/b804139c

Densely functionalized azoxabicyclo[3.3.1]nonanones were prepared by regio- and diastereoselective condensation of 1,1-bis(silyloxy)ketene acetals with isoquinolinium and quinolinium salts and subsequent regioselective and stereospecific iodolactonization

Full text of DOI:10.1039/b804139c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of azoxabicyclo[3.3.1]nonanones based on diastereoselective
reactions of 1,1-bis(trimethylsilyloxy)ketene acetals with isoquinolines
and quinolines†
Andreas Schmidt,a Dirk Michalik,*b Sven Rotzoll,a,b Ehsan Ullah,a,b Christine Fischer,b Helmut Reinke,a
Helmar Go¨rlsc and Peter Langer*a,b
Received 10th March 2008, Accepted 9th May 2008
First published as an Advance Article on the web 12th June 2008
DOI: 10.1039/b804139c
Densely functionalized azoxabicyclo[3.3.1]nonanones were prepared by regio- and diastereoselective
condensation of 1,1-bis(silyloxy)ketene acetals with isoquinolinium and quinolinium salts and
subsequent regioselective and stereospecific iodolactonization.
Introduction
1,1-Bis(trimethylsilyloxy)ketene acetals can be regarded as masked
carboxylic acid dianions and represent useful 1,3-dinucleophilic
building blocks in cyclization reactions.1–3 Rudler et al. have
reported the synthesis of lactones based on reactions of 1,1-
bis(trimethylsilyloxy)ketene acetals with chromium(0) complexes,4
allyl acetates,5 and tropylium ions.6 We have reported the cyclo-
condensation of 1,1-bis(trimethylsiloxy)ketene acetals with oxalyl
chloride7 and 3-(siloxy)alk-2-en-1-ones, respectively.8 Iminium
Scheme 1 Rotamers of compound 4k.
salts represent important synthetic building blocks.9,10 The cy-
clization of iminium salts with bis(silyl enol ethers) has been
known procedures.7,19 The reaction of alkyl-substituted 1,1-
recently reviewed.11 Rudler et al. have reported the reaction of
1,1-bis(trimethylsiloxy)ketene acetals with pyridine12a and related
N-heterocycles.12b Cyclizations of 1,1-bis(trimethylsiloxy)ketene
acetals with pyrazine and quinoxaline were reported by Rudler12b
and by us.13 The cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-
dienes (masked 1,3-dicarbonyl dianions)14 with isoquinoline,15
quinoxaline,16 and quinazoline17 provide a convenient approach
to various bridged N-heterocycles. Recently, we reported the syn-
thesis of 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones based
on the cyclocondensation of isoquinolinium salts with 1,1-
bis(trimethylsiloxy)ketene acetals.18 Herein, we report full details
of these studies and address questions related to the stereo-
chemistry of the reactions. In addition, the reaction of 1,1-
bis(trimethylsiloxy)ketene acetals with quinoline activated by
methyl chloroformate is reported.
bis(trimethylsilyloxy)ketene acetals 2a–d with isoquinoline (1a) in
the presence of methyl chloroformate afforded the condensation
products 3a–d (Scheme 1, Table 1). Treatment of 3a–d with
iodine in the presence of sodium bicarbonate (iodolactoniza-
tion) afforded the 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-
ones 4a–d. The reaction of 1a with aryl-substituted 1,1-
bis(trimethylsilyloxy)ketene acetals 2e–h gave the condensation
products 3e–h which were transformed into 4e–g. The transfor-
mation of 3h into 4h (R1 = 4-(MeO)C6H4) was unexpectedly
not successful. 7,8-Benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones
4i–k were prepared from 5-bromoisoquinoline (1b). Notably, the
formation of all condensation products 3a–k proceeded with
very good diastereoselectivity. In most cases, the syn-configured
diastereomer was formed. The anti-diastereomer was formed in
the case of 4c and 4e. Although the reason for the different
diastereoselectivity remains unclear at present, the results show
that stereochemical issues of the reactions reported herein have to
be treated with great care. In fact, different diastereoselectivities
were observed for similar types of substituents and substrates.
Minor changes of the reaction conditions may also play a role. It
is noteworthy that the iodolactonization of (diastereomerically
pure) acids 3a–k proceeded, as expected, with excellent trans-
stereospecificity and afforded products 4a–k as diastereomerically
pure racemic material.
Results and discussion
1,1-Bis(trimethylsilyloxy)ketene acetals 2 were prepared in two
steps from the corresponding carboxylic acids in analogy to
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str., 3a, 18059,
Rostock, Germany. E-mail: peter.langer@uni-rostock.de; Fax: +49 381
49864112; Tel: +49 381 4986410
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str., 29a, 18059, Rostock, Germany
The structure of all products was established by spectroscopic
cInstitut fu¨r Anorganische und Analytische Chemie, Universita¨t Jena, August-
Bebel-Str. 2, 07740, Jena, Germany
1
methods. The H and 13C NMR spectra of compounds 3 and 4
are largely dominated by the hindered rotation about the N–CO
bond of the carbamate moiety which gives rise to the existence
of two rotamers: I (major) and II (minor) (Scheme 1). Hence,
† Electronic supplementary information (ESI) available: For crys-
tallographic data in CIF or other electronic format. See DOI:
10.1039/b804139c
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Table 1 Synthesis of 4a–k
Scheme 2 The anti and syn structures of compounds 4e and 4k.
The 1H and 13C NMR spectra of 4c and 4e are very similar. For
example, a signal splitting is observed at ambient temperature,
while in the spectra of the other derivatives 4 only a broadening
of the respective signals is observed. The anti configuration of 4c
was also proved by NOE correlations between MeO and Me(13)
of rotamer II. For the MeO group of compound 4e, high-field
proton chemical shifts and a relatively large difference between
the respective signals of rotamers I and II (Dd = 0.50 ppm) is
observed compared to the MeO signals of compound 4k (Dd =
0.04 ppm). This finding can be explained by the anisotropic effect
of the phenyl group which is located in the spatial vicinity of
the N–CO2Me moiety of 4e. In addition, the coupling constants
of the vicinal coupling of protons H-8 and H-9, which could be
determined for compounds 4c, 4e (3J8,9 = 1.0 Hz) and 4k (3J8,9
=
5.7 Hz), indicate a different configuration at carbon atom C-9 of
these compounds.
1
2
3,4
R1
R2
3 (%)a
4 (%)a
a
a
a
a
a
a
a
a
b
b
b
a
b
c
d
e
f
g
h
c
d
e
a
b
c
d
e
f
g
h
i
Me
Et
H
H
H
H
H
H
H
H
Br
Br
Br
56
62
65
60
47
54
83
75
36
54
36
46
61
70
67
65
64
72
0
In contrast to 4c and 4e, the alkyl and aryl groups of all other
compounds 4 are spatially located close to the aromatic proton H-7
(syn configuration). In the case of the aryl-substituted compounds
4f, 4g and 4k, the vicinity of the aryl group and proton H-7 is also
supported by a characteristic high-field shift of proton H-7, which
can be explained by its location in the anisotropic cone of the
phenyl ring. Thus, no or only small shift differences are observed
for the MeO signals of the two rotamers, due to the absence of
the anisotropic effect of the phenyl ring. The configuration at C-
3 could be also confirmed by inspection of the NOESY spectra.
For 4c and 4e, correlations were observed for H-3 and H-4, which
proves that the iodine atom is located cis to the nitrogen. It should
be noted that in the phase-sensitive NOESY spectra, besides the
NOE correlations, EXSY signals are also displayed. For example,
in the case of 4c and 4e, EXSY signals for protons H-2(I) and H-
2(II), H-8(I) and H-8(II), and MeO(I) and MeO(II) (4e) independently
support the dynamic process operating in these compounds as
already mentioned above for 4k (Fig. 1).
nBu
nOct
Ph
4-MeC6H4
4-ClC6H4
4-(MeO)C6H4
nBu
nOct
Ph
73
67
53
j
k
a Yields of isolated products.
some signals appear at room temperature as broadened or doubled
signals. Fig. 1 shows the influence of the temperature on the H
NMR spectrum of compound 4k. At 243 K two sets of signals and
at 300 K only one set of signals are observed. The NMR signals
of 3 and 4 were assigned by DEPT and two-dimensional H,1H
1
1
COSY, H,1H NOESY and H,13C correlation spectra (HSQC,
HETCOR, HMBC). For example, in the HMBC spectrum of 4c
cross-peaks are observed between C-3 and H-4, between C-8 and
H-7, and between C–CO2Me and H-2, H-8, H-9 and H-10, which
confirm the assignment of the signals and the given structures.
The stereochemistry of compounds 4 was established based on
the analysis of anisotropic effects and coupling constants of the
1
1
Quinolines
The methyl chloroformate-mediated reaction of quinoline (5) with
1,1-bis(trimethylsilyloxy)ketene acetals 2i (R1 = nPr) afforded
the condensation product 7a as a 1 : 1 mixture of diastereomers
(Scheme 3, Table 2). Notably, 7a was formed with very good
regioselectivity (by attack of 2i onto carbon atom C-2 of the
quinolinium salt). A diastereomerically pure sample of syn-7a
could be separated by crystallization and characterized by
X-ray crystal structure analysis (Fig. 2). The reaction of 7a with
iodine and sodium bicarbonate afforded 8a by iodolactonization
(dr = 1 : 1). The reaction of 5 with 2d (R1 = nOct) afforded
diastereomerically pure anti-7b and syn-7b in 46 and 17% yields,
respectively (Scheme 3, Table 2). The iodolactonization of anti-7b
1H NMR spectra and based on the results of H,1H NOESY
1
measurements. From the NMR data of 4c and 4e it can be
concluded that the butyl and the phenyl group (located at carbon
C-9), respectively, are in the spatial vicinity of the N–CO2Me
moiety (anti position). In contrast, the alkyl or aryl substituent
of derivatives 4a,b,d,f–k is spatially close to the aromatic proton
H-7, which leads to the assumption that a syn configuration is
present (Scheme 2).
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Fig. 1 1H NMR spectra of 4k recorded at 300 K, 273 K and 243 K (CDCl3, 500 MHz).
Scheme 3 Cyclization of 1,1-bis(trimethylsilyloxy)ketene acetals 2d,e,I with 5. Reagents and conditions: i, 5 (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, NaHCO3, H2O, 20 ◦C, 12 h (the atom numbers refer to the NMR assignments; see
Experimental section).
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Table 2 Synthesis of 8a–c
Entry
R1
7 (%)a
syn/anti
8 (%)a
syn/anti
a
b
nPr
38
46
17
56
1 : 1b
2 : 98
98 : 2
1 : 1.2d
86
52
—
1 : 1
2 : 98
—
nOct
c
c
Ph
50
1 : 1e
a Yields of isolated products. b A sample of diastereomerically pure syn-
7a could be separated. c Experiment was not carried out. d Assignment
arbitrary. e A sample of diastereomerically pure anti-8c could be separated.
Fig. 3 Dimeric structure of syn-7a.
Conclusions
In conclusion, a number of densely functionalized azoxabi-
cyclo[3.3.1]nonanones were prepared by condensation of 1,1-
bis(silyloxy)ketene acetals with isoquinolinium and quinolinium
salts and subsequent iodolactonization. The structures of the
complex products, which show a dynamic behaviour, were thor-
oughly elucidated by NMR spectroscopy. The diastereoselectivity
of the reaction of isoquinoline with 1,1-bis(silyloxy)ketene acetals
depends on the substituents of the latter. However, a clear trend
was not observed. The regioselectivity of the attack of 1,1-
bis(silyloxy)ketene acetals onto quinoline again depends on the
substituents. C-4 regioselectivity was observed for aryl-substituted
and 2,2-disubstituted 1,1-bis(silyloxy)ketene acetals. In contrast,
the reaction of alkyl-substituted 1,1-bis(silyloxy)ketene acetals
with quinoline occurs at carbon atom C-2 of the latter.
Fig. 2 Ortep plot of syn-7a (CCDC 680062).†
afforded diastereomerically pure anti-8b. The reaction of 5
with 2e (R1 = Ph) gave 7c as a mixture of diastereomers. Product
7c was again formed with very good regioselectivity. However,
the attack of 2c onto the quinoline moiety occurred at carbon
C-4 rather than C-2. The iodolactonization of 7c afforded 8c as
a mixture of diastereomers. A diastereomerically pure sample of
anti-8c could be separated by repeated chromatography.
The syn/anti assignment of compounds 7 and 8 is based on
NMR results and on the X-ray crystal structure analysis of syn-
7a (Fig. 2 and 3).† Isomers syn-7b and anti-7b could not be
unambiguously assigned by simple comparison of the NMR data
with those of 7a. However, an assignment proved to be possible
by transformation of anti-7b into anti-8b as the stereochemistry
of the latter could be unambiguously established by NMR. In the
NOESY spectrum of 8b correlations are found between proton
H-3 and protons H-2, H-4 and H-10b, but not between H-3 and
H-9. Likewise, the anti configuration of 8c was established: in
the NOESY spectrum of 8c correlations were observed between
proton H-3 and protons H-2, H-4 and H-ortho, but not between H-
3 and H-9. In the case of compounds 7c and 8a, the diastereomers
could not be unambiguously assigned.
Experimental
General
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C
NMR, the deuterated solvents indicated were used. The 1H NMR
(250.13 and 300.13 MHz) and 13C NMR (62.9 and 75.5 MHz)
were recorded on Bruker spectrometers AC 250 and ARX 300,
respectively, at 300 K. In addition to the routine measurements,
selected NMR spectra were recorded on a Bruker spectrometer
AVANCE 500 (1H: 500.13 MHz and 13C: 125.8 MHz) at 300 K
(4k also at lower temperatures), which is indicated in the NMR
data. Calibration of spectra was carried out using the solvent
signals (CDCl3: d 1H = 7.25, d 13C = 77.0; DMSO-d6: d 1H = 2.50,
d 13C = 39.7). The NMR signals were assigned by DEPT and two-
dimensional 1H,1H COSY, 1H,1H NOESY and 1H,13C correlation
spectra (HSQC, HETCOR, HMBC). For assignment of NMR
signals the atoms are numbered according to Schemes 1 and 3.
The numbering of atoms of the aliphatic residues R1 follows the
carbon chain starting from 10. Atoms of R1 = aryl are given
corresponding to i-, o-, m-, p-nomenclature. Mass spectrometry
(MS) data were obtained by using the electron ionization (70 eV),
chemical ionization (CI, H2O), or electrospray (ESI) techniques.
For preparative scale chromatography, silica gel (60–200 mesh)
was used.
Rudler and coworkers have previously reported the reaction
of quinoline with 2,2-dimethyl-1,1-bis(trimethylsilyloxy)ethene.12b
The attack of the nucleophile occurred at carbon atom C-4 of
quinoline activated by methyl chloroformate. Due to the use of a
symmetrical bis(silyloxy)ketene acetal, no issue of diastereoselec-
tivity arose.
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Typical procedure for the synthesis of 1H-isoquinoline-
2-carboxylic acids 3
OH (I)); 7.24–7.04 (m, 4H(I), 4H(II), H-4,5,6,7(I),4,5,6,7(II)); 6.94 (dd,
3
4
3
1H, J2,3 = 7.5 Hz, J2,8 = 1.0 Hz, H-2(II)); 6.78 (dd, 1H, J2,3 =
7.5 Hz, 4J2,8 = 1.0 Hz, H-2(I)); 6.01 (d, 1H, 3J2,3 = 7.5 Hz, H-3(II));
To a CH2Cl2 solution (20 mL) of isoquinoline (0.250 g, 1.90 mmol)
was added 1,1-bis(trimethylsilyloxy)hex-1-ene (1.00 g, 3.80 mmol)
and methyl chloroformate (0.218 g, 2.30 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, hexane → hexane–EtOAc = 2 : 1) to give 3c as a slightly
brownish solid (0.384 g, 65%). Due to the restricted rotation of the
carbamate moiety, many compounds 3 exist as racemic mixtures
of two rotamers (doubled or broadened signals).
3
3
5.90 (d, 1H, J2,3 = 7.5 Hz, H-3(I)); 5.67 (dd, 1H, J8,9 = 8.5 Hz,
4J2,8 = 1.0 Hz, H-8(I)); 5.52 (dd, 1H, 3J8,9 = 9.0 Hz, 4J2,8 = 1.0 Hz,
H-8(II)); 3.81 (s, 3H, OMe(II)); 3.80 (s, 3H, OMe(I)); 2.79–2.73 (m,
1H(I), 1H(II), H-9(I),9(II)); 1.78–1.65 (m, 1H, H-10(II)); 1.49–1.39 (m,
1H, H-10(I)); 1.32–1.13 (m, 2H(I), 2H(II), H-11,12(I),11,12(II)); 0.84 (t,
3H(I), 3H(II), 3J = 7.2 Hz, OMe(I),(II)
.
13C NMR (126 MHz, CDCl3):
d = 178.8 (COOH(II)); 178.7 (COOH(I)); 154.2 (NCO(II)); 153.9
(NCO(I)); 130.6, 130.4 (C-3a(II),7a(II)); 130.4, 130.2 (C-3a(I),7a(I));
128.2, 126.9, 126.3, 125.0 (C-4,5,6,7(II)); 128.1, 127.1, 126.7, 124.8
(C-4,5,6,7(I)); 125.0 (C-2(II)); 124.4 (C-2(I)); 110.8 (C-3(II)); 110.4
(C-3(I)); 57.0 (C-8(II)); 56.4 (C-8(I)); 53.5 (OMe(I)); 53.2 (OMe(II));
50.5 (C-9(II)); 50.4 (C-9(I)); 29.5 (C-11(I)); 29.4 (C-11(II)); 28.1 (C-
10(I)); 28.0 (C-10(II)); 22.4, 22.4 (C-12(I),(II)); 13.8, 13.8 (Me(I),(II)); IR
(KBr, cm−1): m˜ = 3437 (m), 2956 (m), 1710 (s), 1693 (s), 1632 (m),
1456 (s), 1356 (s), 765 (m). MS (CI; pos.) m/z (%) = 304.0
([M + 1]+). HRMS (EI): calcd for C17H21NO4 ([M]+): 303.1465
found: 303.1472.
Methyl 1-(1-carboxyethyl)-1H-isoquinoline-2-carboxylate (3a).
Starting with isoquinoline (1a) (0.250 g, 1.93 mmol), 2a (0.632 g,
2.90 mmol) and methyl chloroformate (0.363 g, 3.87 mm◦ol), 3a
(0.283 g, 56%) was isolated as a colourless solid; mp. 126 C. 1H
NMR (250 MHz, CDCl3): d = 7.26–7.06 (m, 4H, ArH); 6.96, 6.80
(2 ‘d’, 1H, 3J2,3 = 7.6 Hz, H-2); 5.98, 5.89 (2 d, 1H, 3J2,3 = 7.6 Hz,
H-3); 5.71, 5.58 (2 ‘d’, 1H, 3J8,9 = 8.2 Hz, H-8); 3.79 (s, 3H, OMe);
2.83 (m, 1H, H-9); 1.19, 1.16 (2 d, 3H, 3J = 6.0 Hz, Me). 13C NMR
(63 MHz, CDCl3): d = 179.5, 179.3 (COOH); 154.1, 154.0 (NCO);
130.6, 130.5, 130.4, 130.3 (C-Ar); 128.2, 128.1, 127.1, 127.0, 126.8,
126.5, 125.2, 124.9, 124.8, 124.5 (CH-Ar, C-2); 110.4, 110.1 (C-3);
57.0, 56.6 (C-8); 53.6, 53.1 (OMe); 45.3, 44.9 (C-9); 13.7, 13.5
(Me). IR (KBr, cm−1): m˜ = 3414 (s), 2959 (s), 1712 (s), 1686 (m),
1603 (w), 1453 (s), 1340 (m), 775 (m). MS (EI; 70 eV) m/z (%) =
262.4 ([M + 1]+, 12), 203 (40), 188 (58), 129 (100), 102 (61), 75 (13).
HRMS (EI): calcd for C14H16NO4 ([M + 1]+): 262.1074; found:
262.1094.
Methyl 1-(1-carboxynonyl)-1H-isoquinoline-2-carboxylate (3d).
Starting with isoquinoline (1a) (0.250 g, 1.93 mmol), 2d (0.914 g,
2.90 mmol) and methyl chloroformate (0.363 g, 3.87 mm◦ol), 3d
(0.420 g, 60%) was isolated as a colourless solid; mp. 120 C. 1H
NMR (300 MHz, CDCl3): d = 7.23–7.06 (m, 4H, ArH); 6.93, 6.79
(2 d, 1H, 3J2,3 = 7.6 Hz, H-2); 6.03, 5.91 (2 d, 1H, 3J2,3 = 7.6 Hz,
H-3); 5.66, 5.52 (2 d, 1H, 3J8,9 = 8.8 Hz, H-8); 3.81, 3.81 (2 s, 3H,
OMe); 2.75 (m, 1H, H-9); 1.80–1.65 (m, 1H, H-10a); 1.50–1.35
(m, 1H, H-10b); 1.22 (br ‘s’, 12H, 6 CH2); 0.87 (t, 3H, 3J = 7.0 Hz,
Me). 13C NMR (76 MHz, CDCl3): d = 178.3, 178.0 (COOH);
153.9, 153.7 (NCO); 130.5, 130.3 (2), 130.1 (C-Ar); 128.6, 128.5,
127.5, 127.0, 126.7, 126.3, 125.4, 125.0, 124.8, 124.4 (CH-Ar, C-2);
110.8, 110.6 (C-3); 57.0, 56.8 (C-8); 53.5, 53.2 (OMe); 50.3 (C-9);
31.8 (2), 29.4, 29.3, 29.2 (2), 28.4, 27.3 (2), 22.6 (2) (CH2); 14.1
(Me). IR (KBr, cm−1): m˜ = 3444 (br), 3288 (m), 2919 (m), 1727 (s),
1683 (s), 1635 (m), 1460 (s), 1360 (s), 778 (s). MS (EI, 70 eV) m/z
(%) = 358.8 (M+, 2), 301 (4), 188 (100), 144 (90), 129 (84), 103
(44), 43 (49). HRMS (EI): calcd for C21H29NO4 ([M]+): 359.2091;
found: 359.2074.
Methyl
1-(1-carboxypropyl)-1H-isoquinoline-2-carboxylate
(3b). Starting with isoquinoline (1a) (0.250 g, 1.93 mmol),
2b (0.903 g, 3.87 mmol) and methyl chloroformate (0.363 g,
3.87 mmol), 3b (0.330 g, 62%) was isolated as a slightly brownish
solid; mp. 102–103 ◦C. 1H NMR (250 MHz, CDCl3): d =
3
7.23–7.05 (m, 4H, ArH); 6.94, 6.78 (2 dd, 1H, J2,3 = 7.6 Hz,
3
4J2,8 = 1.0 Hz, H-2); 6.01, 5.90 (2 d, 1H, J2,3 = 7.6 Hz, H-3);
Methyl
1-(1-carboxyphenylmethyl)-1H-isoquinoline-2-carbo-
5.67, 5.53 (2 dd, 1H, 3J8,9 = 8.5 Hz, 4J2,8 = 1.0 Hz, H-8); 3.80 (s,
xylate (3e). Starting with isoquinoline (1a) (0.250 g, 1.93 mmol),
2e (1.08 g, 3.87 mmol) and methyl chloroformate (0. 218 g,
2.32 mmol), 3e (0.290 g, 47%) was isolated as a colourless solid;
mp. 178 ◦C (major rotamer (I) 57%, minor rotamer (II) 43%).
1H NMR (500 MHz, CDCl3): d = 7.22–7.00 (m, 7H, H-4,5, Ph);
3H, OMe); 2.70 (m, 1H, H-9); 1.85–1.45 (m, 2H, CH2); 0.87 (t,
3
3H, J = 7.4 Hz, Me). 13C NMR (76 MHz, CDCl3): d = 179.1,
179.0 (COOH); 154.2, 153.9 (NCO); 130.5, 130.4, 130.3, 130.2
(C-Ar); 128.2, 128.1, 127.1, 127.0, 126.6, 126.3, 125.0 (2), 124.8,
124.4 (CH-Ar, C-2); 110.7, 110.4 (C-3); 56.9, 56.3 (C-8); 53.5,
53.2 (OMe); 52.4, 52.2 (C-9); 21.7, 21.6 (CH2); 11.8 (2) (Me).
IR (KBr, cm−1): m˜ = 3443 (m), 3282 (m), 2964 (m), 1728 (s),
1684 (s), 1636 (m), 1458 (s), 1363 (s), 779 (s). MS (EI; 70 eV) m/z
(%) = 275.0 (M+, 2), 188 (100), 129 (98), 115 (60), 102 (85), 59
(60). HRMS (EI): calcd for C15H17NO4 ([M]+): 275.1152; found:
275.1153.
3
6.97 (d, 1H, J2,3 = 7.5 Hz, H-2(II)); 6.81–6.77 (m, 2H(I), 1H(II),
3
H-2(I),6(I),6(II)); 6.39 (d, 1H, J6,7 = 8.0 Hz, H-7(I)); 6.34 (d, 1H,
3J6,7 = 8.0 Hz, H-7(II)); 6.03 (d, 1H, 3J2,3 = 7.5 Hz, H-3(II)); 6.01 (d,
1H, 3J8,9 = 9.5 Hz, H-8(I)); 5.93 (d, 1H, 3J2,3 = 7.5 Hz, H-3(I)); 5.83
(d, 1H, 3J8,9 = 9.5 Hz, H-8(II)); 3.99 (d, 1H, 3J8,9 = 9.5 Hz, H-9(II));
3
3.97 (d, 1H, J8,9 = 9.5 Hz, H-9(I)); 3.82 (s, 3H, OMe(II)); 3.75 (s,
3H, OMe(I)). 13C NMR (126 MHz, CDCl3): d = 176.6 (COOH(II));
176.3 (COOH(I)); 154.0 (NCO(II)); 153.6 (NCO(I)); 134.1, 134.1
(i-Ph(I),(II)); 130.4, 128.7 (C-3a(II),7a(II)); 130.1, 128.9 (C-3a(I),7a(I));
129.7 (o-Ph(I)); 129.5 (o-Ph(II)); 128.1 (2) (m-Ph(I),(II)); 128.0 (C-5(II));
127.9 (C-5(I)); 127.7 (2) (p-Ph(I),(II)); 127.4 (C-7(I)); 127.2 (C-7(II));
126.3 (C-6(I)); 126.0 (C-6(II)); 125.1 (C-2(II)); 124.6 (C-4(II)); 124.5
(C-4(I)); 124.4 (C-2(I)); 110.5 (C-3(II)); 110.3 (C-3(I)); 58.6 (C-8(II));
Methyl 1-(1-carboxypentyl)-1H-isoquinoline-2-carboxylate (3c).
Starting with isoquinoline (1a) (0.250 g, 1.93 mmol), 2c (1.00 g,
3.87 mmol) and methyl chloroformate (0.218 g, 2.32 mmol), 3c
(0.380 g, 65%) was isolated as a slightly brownish solid; mp. 82–
83 ◦C (major rotamer (I) 55%, minor rotamer (II) 45%). 1H NMR
(500 MHz, CDCl3): d = 9.40 (br s, 1H, OH(II)); 8.50 (br s, 1H,
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57.9 (C-8(I)); 54.0 (2) (C-9(I),(II)); 53.5 (OMe(I)); 53.3 (OMe(II)). IR
(KBr, cm−1): m˜ = 3429 (br), 2956 (m), 1716 (s), 1698 (s), 1630 (m),
1444 (s), 1353 (s), 766 (s). MS (CI; neg.) m/z (%) = 322.0 ([M −
H]−). Anal. Calcd for C19H17NO4 (323.00): C 70.58, H 5.26, N
4.33; found: C 70.85, H 5.01, N 3.41.
for C20H19NO5 (353.36): C 67.98, H 5.42, N 3.96; found: C 67.87,
H 5.43, N 3.73.
Methyl
5-bromo-1-(carboxybutyl)-1H-isoquinoline-2-carbo-
xylate (3i). Starting from 5-bromoisoquinoline (0.416 g,
2.0 mmol), 1,1-bis(trimethylsilyloxy)pent-1-ene (1.042 g,
4.0 mmol) and methyl chloroformate (0.230 g, 2.4 mmol),
3i (0.271 g, 36%) was isolated as a colourless oil. 1H NMR
Methyl 1-(1-carboxy-(4-tolyl)methyl)-1H-isoquinoline-2-carbo-
xylate (3f). Starting with isoquinoline (1a) (0.250 g, 1.93 mmol),
2f (0.850 g, 2.90 mmol) and methyl chloroformate (0.365 g,
3.87 mm◦ol), 3f (0.350 g, 54%) was isolated as a colourless solid;
(250 MHz, CDCl3): d = 7.45 (‘d’, 1H, 3J = 8.0 Hz, ArH);
3
7.08–6.94 [m (2H, ArH) (1H(II), H-2(II))]; 6.88 (‘d’, 1H(I), J2,3
=
1
mp. 208 C. H NMR (250 MHz, DMSO-d6): d = 12.60 (s, 1H,
8.0 Hz, H-2(I)); 6.37, 6.27 (2 d, 1H, 3J2,3 = 8.0 Hz, H-3); 5.63, 5.49
OH); 7.33–7.08 (m, 8H, ArH); 6.78, 6.67 (2 dd, 1H, 3J2,3 = 7.5 Hz,
(2 ‘d’, 1H, J8,9 = 9.0 Hz, H-8); 3.82 (s, 3H, OMe); 2.76 (m, 1H,
3
3
3
4J2,8 = 1.2 Hz, H-2); 6.24, 6.19 (2 d, 1H, J2,3 = 7.5 Hz, H-3);
H-9); 1.75–1.14 (m, 6H, CH2); 0.85 (t, 3H, J = 7.0 Hz, Me).
3
4
5.89, 5.73 (2 dd, 1H, J8,9 = 10.6 Hz, J2,8 = 1.2 Hz, H-8); 3.72,
13C NMR (63 MHz, CDCl3): d = 178.7 (COOH); 153.9, 153.7
(NCO); 132.4, 132.3, 127.9, 127.7, 126.7, 126.1, 125.9, 125.6
(CH-Ar, C-2); 132.1, 131.9, 130.2, 130.0, 120.7, 120.5 (C-Ar);
109.4, 109.0 (C-3); 57.0, 56.5 (C-8); 53.7, 53.4 (OMe); 50.0 (C-9);
29.4, 29.3, 28.1, 22.4 (CH2); 13.8 (Me). MS (CI; pos.): m/z (%) =
384 ([M + 1]+, 81Br), 382 ([M + 1]+, 79Br). HRMS (CI; neg.): calcd
for C17H20BrNO4 ([M]−, 79Br) 381.0576, found 381.0559; calcd for
C17H20BrNO4 ([M]−, 81Br) 383.0556, found 383.0536.
3
3.67 (2 d, 1H, J8,9 = 10.6 Hz, H-9); 3.37, 3.25 (2 s, 3H, OMe);
2.28, 2.27 (2 s, 3H, Me). 13C NMR (76 MHz, DMSO-d6): d =
172.5, 172.4 (COOH); 153.0, 152.7 (NCO); 137.1, 136.9 (p-C6H4);
132.2, 132.0, 131.1, 130.8, 130.4, 130.2 (C-Ar, i-C6H4); 128.7 (o-,
m-C6H4); 128.4, 128.3, 127.1, 127.0 (2), 126.9, 125.1 (2) (CH-Ar);
125.3, 124.9 (C-2); 110.6, 110.3 (C-3); 57.3, 56.0 (C-8); 54.5, 54.2
(C-9); 53.2, 52.6 (OMe); 20.8 (Me). IR (KBr, cm−1): m˜ = 3410 (br),
2940 (s), 1709 (m), 1692 (m), 1349 (m), 1245 (w), 778 (w). MS (CI;
pos.) m/z (%) = 338.2 ([M + 1]+). HRMS (CI, neg.): calcd for
C20H18NO4 ([M]−): 336.1230; found: 336.1224.
Methyl
5-bromo-1-(carboxyoctyl)-1H-isoquinoline-2-carbo-
xylate (3j). Starting from 5-bromoisoquinoline (0.416 g,
2.0 mmol), 1,1-bis(trimethylsilyloxy)dec-1-ene (1.264 g, 4.0 mmol)
and methyl chloroformate (0.230 g, 2.4 mmol), 3j (0.472 g, 54%)
was isolated as a colourless oil. 1H NMR (250 MHz, CDCl3): d =
8.60 (br, 1H, OH); 7.44 (m, 1H, ArH); 7.07–6.94 [m (2H, ArH),
Methyl 1-[carboxy-(4-chlorophenyl)methyl]-1H-isoquinoline-2-
carboxylate (3g). Starting with isoquinoline (1a) (0.250 g,
1.93 mmol), 2g (0.916 g, 2.90 mmol) and methyl chloroformate
(3.86 g, 3.87 mmol), 3g (0.583 g, 83%) was isolated as a colourless
3
4
(1H(II), H-2(II))]; 6.87 (dd, 1H(I), J2,3 = 8.0 Hz, J2,8 = 1.0 Hz,
solid; mp. 181 ◦C. 1H NMR (250 MHz, DMSO-d6): d = 12.60 (s,
H-2(I)); 6.37, 6.26 (2 d, 1H, J2,3 = 8.0 Hz, H-3); 5.63, 5.48 (2
3
3
3
4
1H, OH); 7.42–7.20 (m, 8H, ArH); 6.79, 6.68 (2 dd, 1H, J2,3
=
dd, 1H, J8,9 = 8.6 Hz, J2,8 = 1.0 Hz, H-8); 3.82, 3.81 (2 s, 3H,
OMe); 2.75 (m, 1H, H-9); 1.76–1.07 (m, 14H, CH2); 0.86 (t, 3H,
3J = 7.0 Hz, Me). 13C NMR (63 MHz, CDCl3): d = 179.1, 179.0
(COOH); 153.9, 153.7 (NCO); 132.4, 132.3, 127.9, 127.7, 126.7,
126.1, 125.9, 125.6 (CH-Ar, C-2); 132.1, 131.9, 130.2, 130.0,
120.7, 120.5 (C-Ar); 109.4, 109.0 (C-3); 57.0, 56.4 (C-8); 53.7, 53.4
(OMe); 50.1 (C-9); 31.8 (2), 29.4, 29.3, 29.2 (2), 28.4, 27.3, 27.2,
22.6 (2) (CH2); 14.1 (Me). IR (cap.): m˜ = 3072 (br, w), 2954 (s),
2925 (s), 2855 (s), 2671 (br, w), 1728 (s), 1707 (s), 1628 (m),
1555 (w), 1447 (s), 1410 (m), 1352 (s), 1276 (s), 1231 (m), 1195 (m),
1111 (m), 941 (m), 767 (m) cm−1. MS (CI; pos.): m/z (%) = 440
([M + 1]+, 81Br), 438 ([M + 1]+, 79Br). HRMS (CI; neg.): calcd for
C21H27BrNO4 ([M − H]−, 81Br) 436.1129, found 436.1120; calcd
for C21H27BrNO4 ([M − H]−, 79Br) 438.1109, found 438.1100.
4
3
7.5 Hz, J2,8 = 1.0 Hz, H-2); 6.25, 6.20 (2 d, 1H, J2,3 = 7.5 Hz,
3
4
H-3); 5.89, 5.75 (2 dd, 1H, J8,9 = 10.5 Hz, J2,8 = 1.0 Hz, H-
8); 3.79, 3.75 (2 d, 1H, 3J8,9 = 10.5 Hz, H-9); 3.40, 3.30 (2 s, 3H,
OMe). 13C NMR (63 MHz, DMSO-d6): d = 172.5, 172.1 (COOH);
152.9, 152.7 (NCO); 134.2, 134.0 (p-C6H4); 132.7, 132.5 (i-C6H4);
130.7 (o-C6H4); 130.6, 130.4 (2), 130.1 (C-Ar); 128.5, 128.4, 127.2,
127.0 (2), 126.9, 125.1 (2) (CH-Ar); 125.1, 124.6 (C-2); 110.7,
110.6 (C-3); 57.3, 56.1 (C-8); 54.2, 54.0 (C-9); 53.3, 52.6 (OMe).
IR (KBr, cm−1): m˜ = 3430 (br), 3028 (m), 1732 (s), 1706 (s), 1491 (s),
1334 (s), 1253 (s), 705 (s). MS (CI; pos.) m/z (%) = 358.0 ([M + 1]+).
Methyl 1-[carboxy-(4-methoxyphenyl)methyl]-1H-isoquinoline-
2-carboxylate (3h). Starting with isoquinoline (1a) (0.258 g,
2.00 mmol), 2h (0.846 g, 3.00 mmol) and methyl chloroformate
(0.376 g, 4.00 mmol), 3h (0.263 g, 75%) was isolated as a colourless
solid; mp. 213 ◦C. 1H NMR (250 MHz, DMSO-d6): d = 12.45 (s,
1H, OH); 7.31–7.15 (m, 6H, ArH, m-C6H4); 6.91–6.84 (m, 2H,
o-C6H4); 6.78, 6.68 (2 dd, 1H, 3J2,3 = 7.6 Hz, 4J2,8 = 1.0 Hz, H-2);
Methyl 5-bromo-1-(carboxyphenyl)-1H-isoquinoline-2-carbo-
xylate (3k). Starting from 5-bromoisoquinoline (0.416 g,
2.0 mmol), 2-phenyl-1,1-bis(trimethylsilyloxy)ethene (1.122 g,
4.0 mmol) and methyl chloroformate (0.230 g, 2.4 mmol), 3k
(0.292 g, 36%) was isolated as a colourless solid; mp. 202–203 ◦C.
1H NMR (300 MHz, CDCl3): d = 7.49–7.17 (m, 7H), 6.95–6.88
3
6.23, 6.18 (2 d, 1H, J2,3 = 7.6 Hz, H-3); 5.86, 5.72 (2 dd, 1H,
4
3J8,9 = 10.7 Hz, J2,8 = 1.0 Hz, H-8); 3.73, 3.73 (2 s, 3H, OMe);
3.70, 3.66 (2 d, 1H, 3J8,9 = 10.7 Hz, H-9); 3.39, 3.30 (2 s, 3H, OMe).
13C NMR (76 MHz, DMSO-d6): d = 173.2, 172.6 (COOH); 159.0,
158.9 (p-C6H4); 153.0, 152.7 (NCO); 131.2, 130.9, 130.5, 130.4 (C-
Ar); 130.0 (o-C6H4); 128.4, 128.3, 127.1, 126.9, 125.3, 125.1, 124.8
(CH-Ar, C-2); 113.6 (2) (m-C6H4); 110.5, 110.3 (C-3); 57.4, 56.1
(C-8); 55.3 (2) (MeOC6H4); 54.1, 53.9 (C-9); 53.2, 52.7 (OMe). IR
(KBr, cm−1): m˜ = 3443 (br), 3214 (s), 1725 (s), 1679 (s), 1458 (s),
1364 (s), 1248 (s), 779 (s). MS (EI; 70 eV) m/z (%) = 354.0 (M+, 2),
188 (100), 148 (26), 129 (23), 91 (5), 85 (30), 69 (72). Anal. Calcd
(m, 1H, ArH, Ph); 6.96, 6.74 (2 dd, 1H, J2,3 = 7.8 Hz, J2,8 =
3
4
1.2 Hz, H-2); 6.47, 6.38 (2 d, 1H, 3J2,3 = 7.8 Hz, H-3); 6.04, 5.79
3
4
(2 dd, 1H, J8,9 = 10.5 Hz, J = 1.2 Hz, H-8); 4.01, 3.96 (2 d,
2,8
1H, J8,9 = 10.5 Hz, H-9); 3.44, 3.30 (2 s, 3H, OMe). 13C NMR
3
(76 MHz, CDCl3): d = 176.5, 176.4 (COOH); 153.2, 152.9 (NCO);
133.8, 133.5 (i-Ph); 132.5, 132.4, 129.1, 128.9, 128.4, 128.3 (2),
128.2, 128.0, 127.8, 126.9, 126.3 (CH-Ar, o-, m-, p-Ph, C-2);
132.2, 131.7, 130.2, 129.8, 120.6, 120.5 (C-Ar); 109.1, 109.0 (C-3);
57.8, 56.4 (C-8); 54.2, 53.7 (C-9); 53.3, 52.7 (OMe). IR (KBr):
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m˜ = 3440 (w), 3089 (br, m), 1730 (s), 1671 (s), 1465 (s), 1449 (s),
1413 (m), 1366 (s), 1323 (m), 1257 (s), 1202 (w), 1166 (m), 1120
(w) cm−1. MS (CI; pos.): m/z (%) = 404 ([M + 1]+, 81Br), 402
([M + 1]+, 79Br). Anal. Calcd for C19H16BrNO4 (402.24): C 56.73,
H 4.01, N 3.48. Found: C 56.54, H 4.14, N 3.19.
Methyl 12-butyl-8-iodo-11-oxo-10-oxa-13-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-13-carboxylate (4c). Starting with 3c
(0.100 g, 0.35 mmol), iodine (0.177 g, 0.70 mmol) and a saturated
aqueous NaHCO3 solution (2.0 mL) in CH2Cl2 (6.0 mL), (4c)
(0.105 g, 70%) was isolated as a yellow oil (major rotamer (I)
1
55%, minor rotamer (II) 45%). H NMR (500 MHz, CDCl3):
d = 7.40–7.35 (m, 1H(I), 1H(II), H-4(I),4(II)); 7.30–7.24 (m, 2H(I),
Typical procedure for the preparation of 7,8-benzo-9-
aza-4-oxabicyclo[3.3.1]nonan-3-ones (4)
2H(II), H-5,6(I),5,6(II)); 7.02–6.97 (m, 1H(I), 1H(II), H-7(I),7(II)); 6.82
3
4
(‘t’, H, J2,3 = 1.8 Hz, J2,8 = 1.5 Hz, H-2(II)); 6.68 (‘t’, 1H,
3J2,3 = 1.8 Hz, 4J2,8 = 1.5 Hz, H-2(I)); 5.69 (d, 1H, 3J2,3 = 1.8 Hz,
To a CH2Cl2 solution (6 mL) of 3c (0.100 g, 0.35 mmol) and
iodine (0.17 g 0.70 mmol) was added a saturated aqueous 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 chromatography (silica gel, hexane →
hexane–EtOAc = 2 : 1) to give 4c as a yellow oil (0.10 g, 70%).
Due to the restricted rotation of the urethane moiety, compounds
4 exist as racemic mixtures of two rotamers (doubled or broadened
signals).
3
H-3(II)); 5.68 (d, 1H, J2,3 = 1.8 Hz, H-3(I)); 5.50 (br ‘s’, 1H,
3
4
4J2,8 = 1.5 Hz, J8,9 = 1.0 Hz, H-8(I)); 5.36 (br ‘s’, 1H, J2,8
=
3
1.5 Hz, J8,9 = 1.0 Hz, H-8(II)); 3.89 (s, 3H, OMe(I)); 3.88 (s,
3H, OMe(II)); 2.56–2.50 (m, 1H(I), 1H(II), H-9(I),9(II)); 1.75–1.35
(m, 6H(I), 6H(II), H-10,11,12(a,b)(I), 10,11,12(a,b)(II)); 0.944 (t,
3H, J = 7.2 Hz, Me(II)); 0.936 (t, 3H,3J = 7.2 Hz, Me(I)). 13C
3
NMR (126 MHz, CDCl3): d = 169.3 (COO(I)); 169.0 (COO(II));
154.3 (NCO(II)); 153.8 (NCO(I)); 132.2, 132.2 (C-3a(II),7a(II)); 132.2,
131.9 (C-3a(I),7a(I)); 131.6 (C-4(II)); 131.5 (C-4(I)); 129.5, 128.9
(C-5(I),6(I)); 129.4, 129.1 (C-5(II),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));
22.3 (C-12(II)); 22.2 (C-12(I)); 13.8, 13.8 (Me(I),(II)). IR (KBr, cm−1):
m˜= 3467 (br), 2956 (s), 1760 (s), 1716 (s), 1456 (m), 1333 (m),
1254 (m), 1002 (m), 763 (m). MS (EI, 70 eV): m/z (%) = 429 (M+,
2), 302 (7), 204 (19), 188 (100), 144 (25), 129 (36). HRMS (EI):
calcd for C17H20INO4 ([M]+): 429.0432; found: 429.0426.
Methyl 8-iodo-12-methyl-11-oxo-10-oxa-13-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-13-carboxylate(4a). Starting with 3a (0.080 g,
0.30 mmol), iodine (0.084 g, 0.34 mmol) and a saturated aqueous
NaHCO3 solution (3.5 mL) in CH2Cl2 (6.0 mL), 4a (0.054 g,
46%) was isolated as a brownish solid; mp. 53 ◦C. 1H NMR
3
4
(300 MHz, CDCl3): d = 7.44 (dd, 1H, J4,5 = 7.8 Hz, J4,6
=
3
Methyl 8-iodo-12-octyl-11-oxo-10-oxa-13-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-13-carboxylate (4d). Starting with 3d
(0.100 g, 0.27 mmol), iodine (0.077 g, 0.30 mmol) and a saturated
aqueous solution of NaHCO3 (2.0 mL) in CH2Cl2 (5.0 mL), 4d
(0.088 g, 67%) was isolated as a yellow oil. 1H NMR (250 MHz,
2.0 Hz, H-4); 7.35–7.27 (m, 2H, H-5,6); 7.00 (dd, 1H, J6,7
=
4
7.4 Hz, J5,7 = 1.3 Hz, H-7); 6.80–6.68 (br, 1H, H-2); 5.75 (d,
3
1H, J2,3 = 1.8 Hz, H-3); 5.35–5.21 (br, 1H, H-8); 3.91 (s, 3H,
3
OMe); 3.00 (br ‘s’, 1H, H-9); 1.15 (d, 3H, J = 7.2 Hz, Me). 13C
NMR (76 MHz, CDCl3): d = 169.8 (COO); 154.5, 154.1 (NCO);
132.6–132.2 (br, C-Ar); 131.9, 131.2, 129.3, 128.4, 128.1 (CH-
Ar); 86.6, 86.2 (br) (C-2); 54.0 (OMe); 52.8 (br), 52.7 (br) (C-8);
43.0 (br), 42.7 (C-9); 24.0, 23.6 (br) (C-3); 13.1, 12.9 (Me). IR
(KBr, cm−1): m˜= 3428 (br), 2956 (w), 1708 (s), 1635 (s), 1454 (m),
1333 (m), 1254 (m), 1250 (m), 766 (m). MS (EI, 70 eV): m/z
(%) = 389.0 ([M + 2]+, 10), 331 (39), 271 (19), 204 (39), 188 (100),
142 (9).
3
4
CDCl3): d = 7.43 (dd, 1H, J4,5 = 7.5 Hz, J4,6 = 2.0 Hz, H-4);
3
4
7.34–7.23 (m, 2H, H-5,6); 7.00 (dd, 1H, J6,7 = 7.0 Hz, J5,7
=
1.3 Hz, H-7); 6.80–6.65 (br, 1H, H-2); 5.75 (d, 1H,3J2,3 = 1.8 Hz,
H-3); 5.45–5.34 (br, 1H, H-8); 3.91 (s, 3H, OMe); 2.76 (br ‘s’,
1H, H-9); 1.83 (m, 1H, H-10(a)); 1.56 (m, 2H, H-10(b),11(a));
1.34–1.25 (m, 11H, H-11(b), 5 CH2); 0.88 (t, 3H, 3J = 7.2 Hz, Me).
13C NMR (76 MHz, CDCl3): d = 169.5 (COO); 154.0 (NCO);
132.7 (br), 132.5 (br) (C-Ar); 132.0, 129.3, 128.6, 128.3, 127.7
(CH-Ar); 86.2, 85.7 (br) (C-2); 54.0 (OMe); 51.6 (br), 50.9, 48.9
(br), 48.4 (C-8,9); 31.8 (C-10); 29.4, 29.3, 29.2, 27.3, 26.6, 22.6
(CH2); 24.2 (br), 23.7 (br) (C-3); 14.1 (Me). MS (CI; pos.): m/z
(%) = 486.1 ([M + 2]+). HRMS (CI; neg.): calcd for C21H27INO4
([M]−): 484.0979; found: 484.0984.
Methyl 12-ethyl-8-iodo-11-oxo-10-oxa-13-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-13-carboxylate (4b). Starting with 3b
(0.120 g, 0.43 mmol), iodine (0.120 g, 0.48 mmol) and a saturated
aqueous NaHCO3 solution (4.36 mL) in CH2Cl2 (7.0 mL),◦4b
(0.107 g, 61%) was isolated as a slightly yellow solid; mp. 63 C.
1H NMR (300 MHz, CDCl3): d = 7.43 (m, 1H, H-4); 7.33–7.23
(m, 2H, H-5,6); 7.02 (br d, 1H, H-7); 6.80–6.65 (br, 1H, H-2);
5.74 (d, 1H, 3J2,3 = 1.8 Hz, H-3); 5.47–5.34 (br, 1H, H-8); 3.91 (s,
3H, OMe); 2.69 (br ‘s’, 1H, H-9); 1.89 (m, 1H, CH2(a)); 1.30 (m,
1H, CH2(b)); 1.17 (t, 3H, 3J = 7.4 Hz, Me). 13C NMR (76 MHz,
CDCl3): d = 169.3 (br, COO); 154.0 (NCO); 132.7–132.3 (br,
C-Ar); 131.9, 131.4, 129.3, 128.6, 128.3, 127.6 (CH-Ar); 86.2,
85.7 (br) (C-2); 54.0 (OMe); 51.4 (br), 50.7, 50.0 (C-8,9); 24.1,
23.7 (br) (C-3); 20.0 (CH2); 12.2 (Me). IR (KBr, cm−1): m˜= 3439
(br), 2961 (s), 1743 (s), 1730 (s), 1442 (m), 1318 (m), 1250 (m),
1097 (m), 765 (m). MS (EI, 70 eV): m/z (%) = 401.0 (M+, 2), 314
(8), 204 (100), 188 (90), 144 (30), 129 (60). HRMS (EI): calcd for
C15H16INO4 ([M]+): 401.0119; found: 401.0112.
Methyl 8-iodo-11-oxo-12-phenyl-10-oxa-13-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-13-carboxylate (4e). Starting with 3e
(0.100 g, 0.30 mmol), iodine (0.152 g, 0.60 mmol) and a saturated
aqueous NaHCO3 solution (2.5 mL) in CH2Cl2 (5.0 mL), 4e
(0.088 g, 65%) was isolated as a yellow oil (major rotamer (I)
1
70%, minor rotamer (II) 30%). H NMR (500 MHz, CDCl3):
3
d = 7.45–7.21 (m, 9H, H-4,5,6,7, Ph); 7.01 (‘t’, 1H, J2,3
=
1.8 Hz, 4J2,8 = 1.5 Hz, H-2(I)); 6.85 (‘t’, 1H, 3J2,3 = 1.8 Hz, 4J2,8
=
3
1.5 Hz, H-2(II)); 5.78 (d, 1H, J2,3 = 1.8 Hz, H-3(I)); 5.76 (d, 1H,
4
3
3J2,3 = 1.8 Hz, H-3(II)); 5.61 (br ‘s’, 1H, J2,8 = 1.5 Hz, J8,9
=
4
3
1.0 Hz, H-8(II)); 5.45 (br ‘s’, 1H, J2,8 = 1.5 Hz, J8,9 = 1.0 Hz,
H-8(I)); 3.96 (br ‘s’, 1H(II), H-9(II)); 3.95 (br ‘s’, 1H(I), H-9(I)); 3.68
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3
3
(s, 3H, OMe(II)); 3.18 (s, 3H, OMe(I)). 13C NMR (126 MHz,
CDCl3): d = 166.8 (COO(I)); 167.0 (COO(II)); 154.5 (NCO(I)); 153.2
(NCO(II)); 136.2 (i-Ph(I)); 135.9 (i-Ph(II)); 132.4, 131.5 (C-3a(I),7a(I));
132.1, 131.8 (C-3a(II),7a(II)); 131.7 (C-4(I)); 131.6 (C-4(II)); 129.7,
129.3 (C-5(II),6(II)); 129.6, 129.5 (C-5(I),6(I)); 129.1 (m-Ph(I)); 129.0
(m-Ph(II)); 128.3 (p-Ph(II)); 128.0 (p-Ph(I)); 127.7 (o-Ph(I)); 127.5
(o-Ph(II)); 126.9 (C-7(II)); 126.7 (C-7(I)); 86.1 (C-2(II)); 85.7 (C-2(I));
57.5 (C-8(II)); 57.4 (C-9(I)); 56.4 (C-8(I)); 54.9 (C-9(II)); 53.7 (OMe(II));
53.0 (OMe(I)); 23.4 (C-3(II)); 22.8 (C-3(I)). IR (KBr, cm−1): m˜= 3429
(br), 2953 (w), 1745 (s), 1721 (s), 1444 (m), 1322 (m), 1238 (m),
1002 (m), 726 (w). MS (EI; 70 eV) m/z (%) = 449.0 (M+, 2),
355(3), 279 (30), 225 (15), 118 (100), 167 (63), 77 (50). HRMS
(EI): calcd for C19H16INO4 (449.0): 449.0119; found: 449.0138.
4J5,7 = 1.1 Hz, H-5); 7.19 (‘t’, 1H, J5,6 = 8.0 Hz, J6,7 = 7.5 Hz,
H-6); 7.01 (br ‘d’, 1H, 3J6,7 = 7.5 Hz, H-7); 6.86–6.68 (br, 1H, H-2);
5.56 (d, 1H, 3J2,3 = 2.1 Hz, H-3); 5.47–5.34 (br, 1H, H-8); 3.92 (s,
3H, OMe); 2.77 (br ‘s’, 1H, H-9); 1.80 (m, 1H), 1.55 (m, 2H), 1.38
(m, 2H), 1.21 (m, 1H) (CH2); 0.95 (t, 3H, J = 7.3 Hz, Me). 13C
3
NMR (76 MHz, CDCl3): d = 169.1 (COO); 153.8 (NCO); 134.1,
129.4, 127.1 (CH-Ar); 131.8 (br), 130.9 (br), 127.0 (C-Ar); 85.8,
85.2 (C-2); 54.0 (OMe); 51.6, 50.9, 49.4, 48.7 (C-8,9); 29.4, 26.2,
22.4 (CH2); 26.1 (br, C-3); 13.8 (Me). IR (KBr): m˜ = 3433 (br, m),
2956 (m), 2928 (m), 2863 (w), 1756 (s), 1718 (s), 1561 (w), 1445 (s),
1416 (m), 1345 (s), 1300 (m), 1105 (m), 959 (s) cm−1. MS (ESI):
m/z = 509.96 ([M + 1]+, 81Br), 507.96 ([M + 1]+, 79Br). Anal. Calcd
for C17H19BrINO4 (508.15): C, 40.18; H, 3.77; N, 2.76. Found: C,
40.54; H, 3.73; N, 2.67.
Methyl 8-iodo-11-oxo-12-p-tolyl-10-oxa-13-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-13-carboxylate (4f). Starting with 3f
(0.090 g, 0.26 mmol), iodine (0.073 g, 0.30 mmol) and a saturated
NaHCO3 solution (2.5 mL) in CH2Cl2 (5 mL), 4f (0.077 g, 64%)
was isolated as a brownish solid; mp. 82 ◦C. 1H NMR (300 MHz,
CDCl3): d = 7.43 (‘d’, 1H, H-4); 7.25 (‘t’, 1H, H-5); 7.03 (‘d’,
2H, m-C6H4); 6.88–6.75 (br, 1H, H-2); 6.64 (br ‘d’, 2H, o-C6H4);
Methyl 6-bromo-8-iodo-11-oxo-12-octyl-10-oxa-13-azatricyclo-
[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate (4j). Starting with
3j (0.365 g, 0.83 mmol), iodine (0.316 g, 1.245 mmol) and a
saturated aqueous NaHCO3 solution (5.6 mL) in CH2Cl2 (9.0 mL),
4j (0.324 g, 67%) was isolated as a colourless solid; mp. 113–115 ◦C.
1H NMR (300 MHz, CDCl3): d = 7.57 (dd, 1H, J5,6 = 8.0 Hz,
3
3
3
4J5,7 = 1.1 Hz, H-5); 7.21 (‘t’, J5,6 = 8.0 Hz, J6,7 = 7.5 Hz, 1H,
H-6); 7.03 (br d, 1H, 3J6,7 = 7.5 Hz, H-7); 6.87–6.70 (br, 1H, H-2);
5.57 (d, 1H, 3J2,3 = 2.1 Hz, H-3); 5.49–5.36 (br, 1H, H-8); 3.94 (s,
3H, OMe); 2.80 (br ‘s’, 1H, H-9); 1.93 (m, 1H), 1.58 (m, 2H), 1.39–
1.23 (m, 11H) (7 CH2); 0.89 (t, 3H, 3J = 7.1 Hz, Me). 13C NMR
(76 MHz, CDCl3): d = 169.2 (br), 168.9 (COO); 153.8 (NCO);
134.1, 129.5, 127.1 (CH-Ar); 131.9 (br), 131.0 (br), 127.0 (C-Ar);
85.8, 85.2 (C-2); 54.0 (OMe); 51.6 (br), 50.9, 49.3 (br), 48.8 (C-
8,9); 31.8, 29.3 (2), 29.2, 27.3, 26.5, 22.6 (CH2); 26.2 (br), 25.9 (br)
(C-3); 14.1 (Me). IR (KBr): m˜ = 3432 (br, w), 2952 (m), 2922 (m),
2853 (m), 1754 (s), 1709 (s), 1449 (s), 1420 (w), 1355 (s), 1299 (m),
1115 (m), 959 (m), 765 (m) cm−1. MS (CI pos., isobutane): m/z
(%) = 566 ([M + 1]+, 81Br), 564 ([M + 1]+, 79Br). HRMS (EI): calcd
for C21H27BrINO4 (M+, 79Br) 563.0163, found 563.0149.
3
3
5.87 (‘d’, 1H, J6,7 = 7.8 Hz, H-7); 5.84 (d, 1H, J2,3 = 1.8 Hz,
H-3); 5.45–5.33 (br, 1H, H-8); 4.27 (br, 1H, H-9); 3.97 (s, 3H,
OMe); 2.31 (s, 3H, Me). 13C NMR (76 MHz, CDCl3): d = 167.7
(COO); 154.2 (NCO); 137.8 (p-C6H4); 132.2, 131.3, 130.2 (C-Ar,
i-C6H4); 130.1 (o-C6H4); 131.3, 129.5, 129.3, 127.3 (CH-Ar);
128.9 (m-C6H4); 86.7 (br, C-2); 54.5 (br), 54.2 (br), 54.1 (C-8,9,
OMe); 23.9 (br, C-3); 21.1 (Me). IR (KBr, cm−1): m˜= 3433 (br),
2955 (w), 1758 (s), 1718 (s), 1443 (s), 1316 (s), 1251 (m), 1044 (m),
767 (w). MS (EI; 70 eV) m/z (%) = 463.0 (M+, 10), 313 (18), 253
(53), 204 (25), 188 (100), 132 (87), 44 (48). HRMS (EI): calcd for
C20H18INO4 ([M]+): 463.0275; found: 463.0270.
Methyl 12-(4-chlorophenyl)-8-iodo-11-oxo-10-oxa-13-azatricy-
clo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate (4g). Starting
with 3g (0.200 g, 0.56 mmol), iodine (0.156 g, 0.61 mmol) and
a saturated aqueous NaHCO3 solution (5.6 mL) in CH2Cl2
Methyl 6-bromo-8-iodo-11-oxo-12-phenyl-10-oxa-13-azatricy-
clo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate (4k). Starting
with 3k (0.229 g, 0.57 mmol), iodine (0.217 g, 0.86 mmol) and
a saturated aqueous NaHCO3 solution (5.6 mL) in CH2Cl2
(9.0 mL), 4k (0.160 g, 53%) was isolated as a slightly yellow solid;
(9.0 mL), 4g (0.195 g, 72%) was isolated as a colourless solid; mp.
◦
1
3
93 C. H NMR (500 MHz, CDCl3): d = 7.44 (‘d’, 1H, J4,5
=
7.9 Hz, H-4); 7.27 (d‘t’, 1H, 3J4,5 = 7.9 Hz, 3J5,6 = 7.6 Hz, 4J5,7
=
1.3 Hz, H-5); 7.20 (m, 2H, m-C6H4); 6.94 (d’t’, 1H, 3J6,7 = 7.9 Hz,
3J5,6 = 7.6 Hz, 4J4,6 = 1.3 Hz, H-6); 6.85–6.76 (br, 1H, H-2); 6.71
◦
1
mp. 71–73 C. H NMR (500 MHz, CDCl3, 300K): d = 7.49
(dd, 1H, 3J5,6 = 8.0 Hz, 4J5,7 = 1.0 Hz, H-5); 7.27 (m, 1H, p-Ph);
3
(br ‘d’, 2H, o-C6H4); 5.88 (br ‘d’, 1H, J6,7 = 7.9 Hz, H-7); 5.83
7.22 (m, 2H, m-Ph); 6.99–6.81 (br, 1H, H-2); 6.78 (‘t’, 1H, 3J5,6
=
3
(d, 1H, J2,3 = 2.0 Hz, H-3); 5.41 (br, 1H, H-8); 4.27 (br, 1H,
3J6,7 = 8.0 Hz, H-6); 6.77 (br ‘d’, 2H, o-Ph); 5.79 (br ‘d’, 1H,
H-9); 3.97 (s, 3H, OMe). 13C NMR (126 MHz, CDCl3): d = 167.2
(COO); 154.1 (NCO); 134.1 (p-C6H4); 132.3 (br), 131.9, 127.2
(C-3a,7a, i-C6H4); 131.6 (o-C6H4); 131.5 (C-4); 129.6 (C-5); 129.2
(C-7); 128.5 (m-C6H4); 127.4 (C-6); 86.9 (br), 86.5 (br) (C-2); 54.3
(br), 54.2, 54.0 (br) (C-8,9, OMe); 23.4 (br), 23.1 (br) (C-3). IR
(KBr, cm−1): m˜ = 3433 (br), 2925 (w), 1727 (s), 1717 (s), 1445 (s),
1360 (m), 1249 (m), 1092 (m), 764 (w). MS (CI; 70eV) m/z (%) =
484.2 ([M + 2]+). HRMS (CI; neg.): calcd for C19H15INO4Cl
([M]−): 482.9729; found: 482.9716.
3
3J6,7 = 8.0 Hz, H-7); 5.67 (d, 1H, J2,3 = 2.2 Hz, H-3); 5.50–5.36
(br, 1H, H-8); 4.34 (br, 1H, H-9); 3.99 (s, 3H, OMe). 13C NMR
(126 MHz, CDCl3, 300K): d = 167.2 (br, COO); 153.9 (NCO);
134.1 (C-5); 133.2 (i-Ph); 131.6 (br, C-3a); 130.2 (o-Ph); 129.9 (br,
C-7a); 128.7 (br, C-7); 128.5 (C-6); 128.4 (m-Ph); 128.2 (p-Ph);
126.2 (br, C-4); 86.4 (br), 85.9 (br) (C-2); 55.3 (br), 55.0, 54.5, 54.3
1
(C-8,9, OMe); 25.8 (br), 25.4 (br) (C-3). H NMR (500 MHz,
CDCl3, 243K); (major rotamer (I) 70%, minor rotamer (II) 30%):
d = 7.51 (dd, 1H, 3J5,6 = 8.0 Hz, 4J5,7 = 1.0 Hz, H-5(II)); 7.50 (dd,
3
4
Methyl 6-bromo-8-iodo-11-oxo-12-butyl-10-oxa-13-azatricyclo-
[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate (4i). Starting with
3i (0.237 g, 0.62 mmol), iodine (0.236 g, 0.93 mmol) and a saturated
aqueous NaHCO3 solution (5.6 mL) in CH2Cl2 (9.0 mL), 4i
(0.229 g, 73%) was isolated as a colourless solid; mp. 123–124 ◦C.
1H, J5,6 = 8.0 Hz, J5,7 = 1.0 Hz, H-5(I)); 7.29–7.20 (m, 3H(I),
3
4
3H(II), m-Ph(I),(II)), p-Ph(I),(II)); 6.97 (dd, 1H, J2,3 = 2.2 Hz, J2,8
=
1.3 Hz, H-2(II)); 6.83 (dd, 1H, 3J2,3 = 2.2 Hz, 4J2,8 = 1.3 Hz, H-2(I));
6.80 (‘t’, 1H(I), 1H(II), 3J5,6 = J6,7 = 8.0 Hz, H-6(I),6(II)); 6.73 (br,
3
2H(I), 2H(II), o-Ph(I),(II)); 5.79 (dd, 1H, 3J6,7 = 8.0 Hz, 4J5,7 = 1.0 Hz,
H-7(I)); 5.75 (dd, 1H, 3J6,7 = 8.0 Hz, 4J5,7 = 1.0 Hz, H-7(II)); 5.65 (d,
3
1H NMR (300 MHz, CDCl3): d = 7.55 (dd, 1H, J5,6 = 8.0 Hz,
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3
1H, 3J2,3 = 2.2 Hz, H-3(II)); 5.63 (d, 1H, 3J2,3 = 2.2 Hz, H-3(I)); 5.47
(br, 1H, H-2); 3.79 (s, 3H, OMe); 2.38 (d’t’, 1H, 3J9,10(a) = J2,9
=
3
(dd, 1H, 3J8,9 = 5.7 Hz, 4J2,8 = 1.3 Hz, H-8(I)); 5.40 (dd, 1H, 3J8,9
=
9.8 Hz, J9,10(b) = 4.0 Hz, H-9); 1.64–1.51 (m, 2H, H-10); 1.31–
5.7 Hz, 4J2,8 = 1.3 Hz, H-8(II)); 4.36 (d, 1H, 3J8,9 = 5.7 Hz, H-9(I));
1.11 (m, 12H, 6 CH2); 0.88 (t, 3H, J = 7.0 Hz, Me). 13C NMR
3
3
4.30 (d, 1H, J8,9 = 5.7 Hz, H-9(II)); 4.02 (s, 3H, OMe(II)); 3.98
(126 MHz, CDCl3): d = 178.6 (COOH); 155.1 (NCO); 134.1 (C-
8a); 127.7 (C-7); 127.4 (C-3); 127.3 (C-4a); 126.4, 126.4 (C-4,5);
125.0 (C-8); 124.8 (C-6); 53.2 (OMe); 53.0 (C-2); 48.4 (C-9); 31.8,
29.3, 29.2, 29.1, 28.5, 26.7, 22.6 (CH2); 14.0 (Me). IR (Nujol, cm−1):
m˜ = 3433 (br), 2925 (w), 1727 (m), 1445 (m), 1359 (m), 1249 (w),
764 (w). MS (EI; 70 eV) m/z (%) = 359.2 (M+, 1), 347(2), 204 (2),
188 (100), 144 (48), 129 (12). HRMS (EI): calcd for C21H29NO4
([M]+): 359.2091; found: 359.2084.
(s, 3H, OMe(I)). 13C NMR (126 MHz, CDCl3, 243K): d = 167.8
(COO(I)); 167.5 (COO(II)); 153.8, 153.8 (NCO(I),(II)); 134.1 (C-5(II));
134.0 (C-5(I)); 132.7 (i-Ph(II)); 132.6 (i-Ph(I)); 131.2 (C-3a(II)); 130.9
(C-3a(I)); 130.0, 130.0 (o-Ph(I),(II)); 129.4 (C-7a(I)); 129.2 (C-7a(II));
128.7 (C-7(I)); 128.6 (C-6(I)); 128.5, 128.5 (C-6(II),7(II)); 128.3, 128.3
(m-Ph(I),(II)); 128.3 (p-Ph(II)); 128.1 (p-Ph(I)); 126.1 (C-4(II)); 125.9
(C-4(I)); 86.0 (C-2(I)); 85.3 (C-2(II)); 55.3 (C-9(II)); 54.8 (C-8(II)); 54.6
(C-9(I)); 54.6 (OMe(II)); 54.4 (OMe(I)); 53.9 (C-8(I)); 25.8 (C-3(I));
25.4 (C-3(II)). IR (KBr): m˜ = 3449 (br, s), 1755 (m), 1725 (s),
1445 (m), 1354 (m), 1303 (m), 1264 (w), 753 (w) cm−1. MS (CI;
pos.): m/z (%) = 530 ([M + 1]+, 81Br), 528 ([M + 1]+, 79Br).
HRMS (CI; neg., isobutane): calcd for C19H15BrINO4 ([M − H]−)
527.9307, found 527.9291.
7b (syn): 1H NMR (500 MHz, CDCl3): d = 7.52 (br, 1H, H-8);
7.24 (m, 1H, H-7); 7.10 (m, 2H, H-5,6); 6.57 (d, 1H, 3J3,4 = 9.5 Hz,
H-4); 6.09 (dd, 1H, 3J3,4 = 9.5 Hz, 3J2,3 = 6.0 Hz, H-3); 5.26 (dd,
3
3
1H, J2,9 = 9.5 Hz, J2,3 = 6.0 Hz, H-2); 3.76 (s, 3H, OMe); 2.45
3
3
3
(ddd, 1H, J2,9 = 9.5 Hz, J9,10(a) = 11.0 Hz, J9,10(b) = 3.6 Hz, H-
9); 1.69 (m, 1H, H-10(a)); 1.46 (m, 1H, H-10(b)); 1.30–1.13 (m, 6
CH2); 0.85 (t, 3H, 3J = 7.0 Hz, Me). 13C NMR (126 MHz, CDCl3):
d = 178.3 (COOH); 154.8 (NCO); 134.4 (C-8a); 127.8 (C-7); 127.2
(C-4a); 126.5 (br, C-3); 126.5 (C-4); 126.1 (C-5); 125.6 (br, C-8);
124.7 (C-6); 53.5 (C-2); 53.1 (OMe); 49.2 (C-9); 31.8, 29.5, 29.2,
29.1, 27.8, 27.5, 22.6 (CH2); 14.1 (Me). IR (Nujol, cm−1): m˜ = 3224
(br), 2945 (m), 1742 (s), 1671 (m), 1342 (m), 1277 (m), 1180 (m),
763 (w). MS (EI; 70 eV) m/z (%) = 359.2 (M+, 1), 347 (2), 188
(100), 144 (48), 129 (12). Anal. Calcd for C21H29NO4 (359.45): C
70.17, H 8.13, N 3.90; found: C 70.36, H 8.36, N 4.20.
Typical procedure for the preparation of methyl
2H-quinoline-1-carboxylates 7
To
a CH2Cl2 solution (20 mL) of quinoline (0.250 g,
1.90 mmol) was added 1,1-bis(trimethylsilyloxy)pent-1-ene
(0.713 g, 2.90 mmol) and methyl chloroformate (0.362 g,
3.86 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, hexane → hexane–EtOAc = 2 : 1) to
give 7a as colourless crystals (0.214 g, 38%), mp. 105–106 ◦C.
Methyl 4-(carboxyphenylmethyl)-4H-quinoline-1-carboxylate
(7c). Starting with quinoline (5) (0.250 g, 1.93 mmol), 2c
(0.810 g, 2.90 mmol) and methyl chloroformate (0.362 g,
3.86 mmol), 7c (0.350 g, 56%) was isolated as a colourless solid;
mp. 42–43 ◦C. The product was obtained as a diastereomeric
mixture of enantiomers (major isomer (I) 55%, minor isomer (II)
Methyl 2-(1-carboxybutyl)-2H-quinoline-1-carboxylate (7a).
Starting with quinoline (5) (0.250 g, 1.93 mmol), 2a (0.713 g,
2.90 mmol) and methyl chloroformate (0.362 g, 3.86 mmol), syn-7a
(0.214 g, 38%) was isolated as a colourless solid; mp. 105–106 ◦C.
1H NMR (300 MHz, CDCl3): d = 7.52 (br ‘d’, 1H, H-8); 7.29–7.20
(m, 1H, H-7); 7.10 (m, 2H, H-5,6); 6.57 (d, 1H, 3J3,4 = 9.5 Hz, H-
4); 6.09 (dd, 1H, 3J3,4 = 9.5 Hz, 3J2,3 = 6.0 Hz, H-3); 5.26 (dd, 1H,
3J2,9 = 9.5 Hz, 3J2.3 = 6.0 Hz, H-2); 3.75 (s, 3H, OMe); 2.46 (m, 1H,
H-9); 1.68 (m, 1H, H-10(a)); 1.50–1.10 (m, 3H, H-10(b), H-11);
1
45%, dr = 1.2 : 1). H NMR (500 MHz, CDCl3): d = 9.55 (br,
3
1H, OH(I)); 8.94 (br, 1H, OH(II)); 7.90 (dd, 1H, J7,8 = 8.5 Hz,
4J6,8 = 1.2 Hz, H-8(I)); 7.84 (dd, 1H, 3J7,8 = 8.5 Hz, 4J6,8 = 1.2 Hz,
H-8(II)); 7.30–7.04 (m, 6H(I), 8H(II), H-7(I), Ph(I), H-5(II),6(II),7(II)
,
=
3
3
Ph(II)); 7.06 (d, 1H, J2,3 = 7.6 Hz, H-2(I)); 6.88 (d, 1H, J2,3
7.6 Hz, H-2(II)); 6.77 (d’t’, 1H, 3J5,6 = J6,7 = 7.6 Hz, 4J6,8 = 1.2 Hz,
3
3
4
H-6(I)); 6.33 (dd, 1H, J5,6 = 7.6 Hz, J5,7 = 1.6 Hz, H-5(I)); 5.60
(dd, 1H, 3J2,3 = 7.6 Hz, 3J3,4 = 6.0 Hz, H-3(I)); 5.19 (dd, 1H, 3J2,3
7.6 Hz, 3J3,4 = 6.0 Hz, H-3(II)); 4.17 (dd, 1H, 3J4,9 = 7.8 Hz, 3J3,4
=
=
3
0.84 (t, 3H, J = 7.2 Hz, Me). 13C NMR (76 MHz, CDCl3): d =
178.0 (COOH); 154.8 (NCO); 134.3, 127.1 (C-Ar); 127.9, 126.6,
126.5, 126.2, 125.7, 124.8 (CH-Ar); 53.5 (C-2); 53.2 (OMe); 49.0
(C-9); 30.0 (C-10); 20.7 (C-11); 14.0 (Me). IR (KBr, cm−1): m˜ =
3430 (br), 2953 (m), 1697 (s), 1443 (m), 1305 (s), 753 (w). MS (CI
pos.; 70 eV) m/z (%) = 290.1 ([M + 1]+, 10), 330 (5), 290 (80), 188
(100). HRMS (CI; neg.): calcd for C16H18NO4 ([M]−): 288.1230;
found: 288.1230.
6.0 Hz, H-4(II)); 3.95 (dd, 1H, 3J4,9 = 9.5 Hz, 3J3,4 = 6.0 Hz, H-4(I));
3
3.87 (s, 3H, OMe(I)); 3.76 (s, 3H, OMe(II)); 3.72 (d, 1H, J4,9
=
7.8 Hz, H-9(II)); 3.52 (d, 1H, J4,9 = 9.5 Hz, H-9(I)). 13C NMR
(126 MHz, CDCl3): d = 177.9 (COOH(I)); 177.8 (COOH(II)); 152.8
(NCO(I)); 152.5 (NCO(II)); 137.0 (C-8a(I)); 136.7 (C-8a(II)); 135.5
(i-Ph(I)); 134.7 (i-Ph(II)); 129.2 (C-5(I)); 129.1, 128.9 (o-Ph(I),(II));
128.7 (C-4a(II)); 128.4 (C-5(II)); 128.3, 128.0 (m-Ph(I),(II)); 128.1,
128.1 (C-2(I),(II)); 127.7 (C-4a(I)); 127.6 (p-Ph(I)); 127.4 (p-Ph(II));
126.9 (C-7(II)); 126.4 (C-7(I)); 125.0 (C-6(II)); 124.2 (C-6(I)); 121.5
(C-8(II)); 121.1 (C-8(I)); 111.6 (C-3(I)); 110.0 (C-3(II)); 58.2 (C-9(II));
57.9 (C-9(I)); 53.3 (OMe(II)); 53.1 (OMe(I)); 42.2 (C-4(I)); 41.1
(C-4(II)). IR (Nujol, cm−1): m˜ = 3155 (br), 2945 (m), 1729 (m),
1708 (m), 1339 (m), 1239 (w), 1353 (s), 764 (w). MS (CI pos.;
70 eV) m/z (%) = 323.0 ([M + 1]+, 80), 244 (12), 220 (66), 188
(100), 130 (15), 85 (33). HRMS (CI neg.): calcd for C19H16NO4
([M]−): 322.1074; found: 322.1075.
3
Methyl 2-(1-carboxynonyl)-2H-quinoline-1-carboxylate (7b).
Starting with quinoline (5) (0.250 g, 1.93 mmol), 2b (0.919 g,
2.89 mmol) and methyl chloroformate (0.364 g, 3.88 mmol),
anti-7b (0.320 g, 46%) was isolated as a colourless solid; mp.
77–78 ◦C. The second diastereomer, syn-7b (0.120 g, 17%), was
isolated as a colourless oil.
7b (anti): 1H NMR (500 MHz, CDCl3): d = 7.49 (br, 1H, H-8);
3
7.23 (m, 1H, H-7); 7.11–7.08 m, 2H, H-5,6); 6.55 (d, 1H, J3,4
=
9.5 Hz, H-4); 6.09 (dd, 1H, 3J3,4 = 9.5 Hz, 3J2,3 = 6.0 Hz, H-3); 5.23
2812 | Org. Biomol. Chem., 2008, 6, 2804–2814
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Typical procedure for the preparation of
azoxabicyclo[3.3.1]nonanones 8
204 (20), 188 (100), 144 (30), 129 (15). HRMS (EI): calcd for
C21H28NIO4 ([M]+): 485.10575; found: 4485.10581.
To a CH2Cl2 solution (6 mL) of 7a (0.100 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 chromatography (silica gel, hexane → hexane–EtOAc = 2 : 1)
to give 8a (0.110 g, 86%) as a yellow oil.
Methyl 13-iodo-11-oxo-12-phenyl-10-oxa-8-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-8-carboxylate (8c). Starting with 7c (0.300 g,
0.93 mmol, dr = 1.2 : 1), iodine (0.260 g, 1.02 mmol) and
a saturated aqueous NaHCO3 solution (10.0 mL) in CH2Cl2
(15.0 mL), 8c (0.210 g, 50%) was isolated as light yellow solid; mp.
73 ◦C (2 diastereomers, dr = 1 : 1). A sample of diastereomerically
pure anti-8c could be separated. Data of anti-8c: 1H NMR
3
4
(500 MHz, CDCl3): d = 8.27 (dd, 1H, J7,8 = 8.5 Hz, J6,8
=
1.0 Hz, H-8); 7.44 (m, 2H, m-Ph); 7.39–7.35 (m, 2H, H-7, p-Ph);
3
3
7.28 (m, 3H, H-5, o-Ph); 7.21 (d’t’, 1H, J5,6 = J6,7 = 7.3 Hz,
4J6,8 = 1.0 Hz, H-6); 6.84 (dd, 1H, 3J2,3 = 3.8 Hz, 4J2,4 = 2.0 Hz,
Methyl 13-iodo-11-oxo-10-propyl-12-oxa-8-azatricyclo[7.3.1.02,7]-
trideca-2,4,6-triene-8-carboxylate (8a). Starting with a 1 : 1
diastereomeric mixture of 7a (0.090 g, 0.31 mmol), iodine (0.086 g,
0.34 mmol) and a saturated aqueous NaHCO3 solution (3.6 mL)
in CH2Cl2 (7.0 mL), 8a (syn/anti = 1 : 1) (0.110 g, 86%) was
isolated as a yellow oil. The product contained a small amount of
hydrolyzed silyl enol ether which could not be separated. 1H NMR
(500 MHz, CDCl3) (2 diastereomers, dr = 1 : 1): d = 7.78 (br, 1H,
H-8); 7.38 (m, 1H, H-7); 7.35–7.31 (m, 2H, H-5,7); 7.17 (m, 2H,
H-6,6); 5.62 (br, 1H, H-2); 5.35–5.27 (m, 4H, H-2,3,4,4); 4.92 (‘t’,
3
3
H-2); 4.94 (dd, 1H, J2,3 = 3.8 Hz, J3,4 = 2.2 Hz, H-3); 4.18 (d,
1H, 3J4,9 = 2.2 Hz, H-9); 3.93 (s, 3H, OMe); 3.55 (‘q’, 1H, 3J4,9
=
3J3,4 = 2.2 Hz, 4J2,4 = 2.0 Hz, H-4). 13C NMR (126 MHz, CDCl3):
d = 167.2 (COO); 153.5 (NCO); 136.6 (i-Ph); 132.2 (C-8a); 129.5
(C-5); 129.4 (m-Ph); 129.3 (C-7); 128.2 (p-Ph); 127.6 (o-Ph); 125.1
(C-6); 124.6 (C-4a); 122.0 (C-8); 84.4 (C-2); 57.8 (C-9); 53.9 (OMe);
48.0 (C-4); 12.8 (C-3). MS (CI; 70 eV) m/z (%) = 449.0 (M+, 9),
321(53), 219 (34), 203 (100), 159 (32), 129 (54), 90 (25). HRMS
(CI): calcd for C19H16NIO4 ([M]+): 449.0119; found: 449.0113.
3
3
1H, J2,3 = J3,4 = 3.0 Hz, H-3); 3.88 (s, 3H, OMe); 3.78 (s, 3H,
OMe); 2.90–2.86 (m, 1H, H-9); 2.74 (m, 1H, H-9); 1.91–1.84 (m,
1H, H-10); 1.66–1.36 (m, 7H, H-10,11); 0.95 (t, 3H, 3J = 7.3 Hz,
Me); 0.90 (t, 3H, 3J = 7.3 Hz, Me). 13C NMR (126 MHz, CDCl3):
d = 171.3 (COO); 155.3 (NCO); 136.3, 133.3 (C-8a); 131.2, 130.4
(C-7); 129.6 (C-5); 127.8, 127.7 (br) (C-5,8); 126.9 (br), 125.4 (C-
6); 124.4 (C-8); 123.0 (C-4a); 81.4, 77.5 (C-4); 55.4, 55.2 (C-2); 53.8
(OMe); 45.3, 43.3 (br) (C-9); 31.0, 27.3 (C-10); 20.8, 20.3 (C-11);
14.0, 13.8 (Me). IR (KBr, cm−1): m˜ = 3432 (br), 2923 (w), 1698 (s),
1494 (m), 1213 (m), 921 (w), 703 (s). MS (EI, 70 eV): m/z (%) =
415.0 (M+, 17), 314 (28), 288 (62), 204 (100), 188 (27), 144 (27), 128
(21). HRMS (EI): calcd for C16H18INO4 ([M]+): 415.0275; found:
415.0268.
Acknowledgements
Financial support from the state of Mecklenburg-Vorpommern
(Landesgraduiertenstipendium for A. S.), from Boehringer-
Ingelheim Pharma AG, and from the Deutsche Forschungsge-
meinschaft is gratefully acknowledged.
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trideca-2,4,6-triene-8-carboxylate (anti-8b). Starting with anti-
7b (0.147 g, 0.41 mmol), iodine (0.133 g, 0.45 mmol) and a
saturated aqueous NaHCO3 solution (4.0 mL) in CH2Cl2 (7.0 mL),
anti- 8b (0.103 g, 52%) was isolated as a brownish solid; mp. 101–
102 ◦C. 1H NMR (500 MHz, CDCl3): d = 7.97 (br ‘d’, 1H, 3J7,8
=
8.5 Hz, H-8); 7.39 (ddd, 1H, 3J7,8 = 8.5 Hz, 3J6,7 = 7.5 Hz, 4J5,7
=
3
4
1.5 Hz, H-7); 7.35 (dd, 1H, J5,6 = 7.7 Hz, J5,7 = 1.5 Hz, H-5);
7.15 (d’t’, 1H, 3J5,6 = 7.7 Hz, 3J6,7 = 7.5 Hz, 4J6,8 = 1.0 Hz, H-6);
3
4
5.34 (‘t’, 1H, J3,4 = 3.0 Hz, J2,4 = 2.5 Hz, H-4); 4.98 (br, 1H,
3
H-2); 4.77 (‘t’, 1H, 3J3,4 = J2,3 = 3.0 Hz, H-3); 3.89 (s, 3H, OMe);
3
3
3
2.73 (ddd, 1H, J9,10(a) = 8.5 Hz, J9,10(b) = 4.5 Hz, J2,9 = 1.0 Hz,
H-9); 1.91 (m, 1H, H-10(a); 1.77 (m, 1H, H-10(b)); 1.53, 142 (2 m,
3
2H, H-11(a),(b)); 1.36–1.23 (m, 10H, 5 CH2); 0.88 (t, 3H, J =
7.0 Hz, Me). 13C NMR (126 MHz, CDCl3): d = 170.5 (COO);
154.2 (NCO); 134.0 (C-8a); 131.5 (C-5); 130.7 (C-7); 124.6 (C-
6); 123.0 (C-8); 121.7 (C-4a); 77.6 (C-4); 56.8 (C-2); 53.6 (OMe);
47.4 (C-9); 33.2 (C-10); 31.8, 29.3, 29.3, 29.2 (CH2); 26.7 (C-11);
22.6 (C-16); 17.8 (C-3); 14.0 (Me). IR (KBr, cm−1): m˜ = 3416 (br),
2916 (s), 1771 (s), 1716 (s), 1442 (m), 1331 (s), 1166 (m), 950 (m),
759 (m). MS (EI, 70 eV): m/z (%) = 485.0 (M+, 74), 314 (82),
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2814 | Org. Biomol. Chem., 2008, 6, 2804–2814
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©