Synthesis of functionalized isobenzomorphans by two-step cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with isoquinolines

Article abstract of DOI:10.1002/ejoc.200800478

A great variety of functionalized 7,8-benzo-anellated 9-azabicyclo-[3.3.1] nonan-3-ones were prepared by methyl or benzyl chloroformate-mediated condensation of isoquinolines with 1,3-bis(silyloxy)-1,3-butadienes and subsequent TFA-mediated cyclization. The hydroxy group could be functionalized by Suzuki reactions of the corresponding enol triflates. The N-benzyloxycarbonyl-substituted products were successfully deprotected. The decarboxylation allowed the synthesis of the parent 7,8-benzo-anellated 9-azabicyclo[3.3.1]nonan-3-ones. The products can be regarded as functionalized isobenzomorphans - simple structural analogues of morphine. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800478

FULL PAPER
DOI: 10.1002/ejoc.200800478
Synthesis of Functionalized Isobenzomorphans by Two-Step Cyclocondensation
of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with Isoquinolines
Mirza A. Yawer,[a] Ibrar Hussain,[a] Jörg-Peter Gütlein,[a] Andreas Schmidt,[a] Haijun Jiao,[b]
Helmut Reinke,[a] Anke Spannenberg,[b] Christine Fischer,[b] and Peter Langer*[a,b]
Keywords: Nitrogen heterocycles / Cyclizations / Iminium salts / Silyl enol ethers / Regioselectivity
A great variety of functionalized 7,8-benzo-anellated 9-aza-
bicyclo-[3.3.1]nonan-3-ones were prepared by methyl or
benzyl chloroformate-mediated condensation of isoquinol-
ines with 1,3-bis(silyloxy)-1,3-butadienes and subsequent
TFA-mediated cyclization. The hydroxy group could be func-
tionalized by Suzuki reactions of the corresponding enol tri-
flates. The N-benzyloxycarbonyl-substituted products were
successfully deprotected. The decarboxylation allowed the
synthesis of the parent 7,8-benzo-anellated 9-azabicy-
clo[3.3.1]nonan-3-ones. The products can be regarded as
functionalized isobenzomorphans – simple structural ana-
logues of morphine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
callus cultures of Cryptocarya chinensis and are of consider-
able pharmacological relevance.[1,8] For example, they show
activity against Herpes simplex virus type 1[9a] and against
tumor necrosis factor production.[9b] Pavine-type alkaloids
are synthetically available.[10]
Morphine alkaloids represent the most important group
of naturally occurring isoquinolines.[1] They have been iso-
lated from opium, a crude product mixture which is pro-
duced from Papaver somniferum. Important natural prod-
ucts include, for example, morphine, codein, thebaine and
heroine[1] which possess a wide range of pharmacological
activities (e.g. analgetic, sedative, hypnotic, antitussivic,
miotic and antidiuretic activity).[1] Morphine, the structure
of which was elucidated by Sir Robert Robinson in
1925,[11] is a very important drug for the treatment of pain.
The synthesis of morphine-type alkaloids has been re-
ported.[12]
The development of simpler morphine analogues, which
show no dependence-producing and other undesirable side
effects, has been the subject of research for many years.
Simpler morphine-like compounds include, for example,
morphinan and benzomorphan (i.e., 1,2,3,4,5,6-hexahydro-
2,6-methano-3-benzazocine).[13] The first synthesis of a
benzomorphan has been reported by Barltrop in 1947.[14]
The trivial name “benzomorphan” is derived from the triv-
ial name “morphan” (azabicyclo[3.3.1]nonane) (Scheme 1).
Positional variation of the nitrogen atom leads to various
isomers some of which have been previously synthesized.[15]
Isobenzomorphans (i.e., 7,8-benzo-anellated 9-azabicy-
clo-[3.3.1]nonanes, 1,2,3,4,5,6-hexahydro-1,5-imino-benzo-
cyclooctenes) represent interesting structural isomers of
benzomorphans containing an imino bridge. These com-
pounds are, in a formal sense, simple structural analogues
of morphine and are present, for example, in pavine-type
Introduction
The isoquinoline moiety is present in a variety of phar-
macologically active alkaloids.[1] Benzylisoquinoline-type
alkaloids, such as papaverine or reticuline are isolated from
Papaver- und Rauwolfia plants and show spasmolytic ac-
tivity.[2] Bis(benzyl)isoquinoline alkaloids include, for exam-
ple, cycleanine, tetrandrine (antiinflammatory activity), iso-
chondodendrin (sedative activity) and oxyacanthin (sympa-
tholytic activity, adrenalin antagonist).[1] Tubocurarine is
the oldest muscle-relaxing agent and its dichloro derivative
is used as a narcotic. Phthalidisoquinoline alkaloids, iso-
lated from Papaveraceae, are characterized by a tetracyclic
system containing a γ-lactone moiety. Important examples
are hydrastin and narcotin (noscapin). Hydrastin is used as
a blood-stanching agent.[1] Noscapin is used as an antitus-
sivic.[3] Synthetic approaches to tetrahydroisoquinoline al-
kaloids rely on asymmetric Pictet–Spengler reactions and
on Bischler–Napieralski reactions and subsequent enantio-
selective reduction.[4] Aporphine-alkaloids contain a fused
tetracyclic system. For example, apomorphine is used as a
strong emetic.[5] Boldine represents a diuretic.[6] Aporphine
alkaloids have been prepared, for example, by application
of photochemical methods.[7] Pavine and isopavine alka-
loids, such as dinorargemonine, eschscholtzine, munitagine
and pavine, are isolated from Papaveraceae, Berberidaceae,
Ranunculaceae, Lauraceae and Menispermaceae or from
[a] Institut für Chemie, Universität Rostock,
Albert-Einstein-Straße 3a, 18059 Rostock
Fax: +49-381-498-6411
E-mail: peter.langer@uni-rostock.de
[b] Leibniz Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Straße 29a, 18059 Rostock
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 4193–4199
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Langer et al.
FULL PAPER
tadiene (2a), available from methyl acetoacetate,[23] afforded
the condensation product 3a (Scheme 3). The reaction pro-
ceeds by formation of the isoquinolinium salt A and subse-
quent regioselective attack of the terminal carbon of 2a.
Treatment of 3a with TFA afforded the 7,8-benzo-anellated
3-hydroxy-9-azabicyclo[3.3.1]non-3-ene 4a. The use of TFA
proved to be mandatory; employment of hydrochloric acid
gave unsatisfactory results. The best yields were obtained
when no aqueous work up was carried out. Dichlorometh-
ane and TFA were removed in vacuo and the residue was
directly purified by chromatography.
Scheme 1. Morphine and some of its simpler analogues.
alkaloids (Scheme 2). Isobenzomorphans have been pre-
pared by Dieckmann cyclization[16] and by reaction of an
acetoneberberine-type enamine with alkyl halides.[17]
Scheme 2.
Quinolinium- and isoquinolinium salts, generated by
alkylation or acylation of quinoline and isoquinoline,[18] are
important synthetic building blocks. They have been used,
for example, in condensations with Grignard reagents,
cyanides (Reissert reaction), (trimethylsilyl)acetonitrile, al-
lylsilanes or silyl enol ethers.[19] In recent years, a number
of cyclocondensation reactions of bis(silyl enol ethers) with
iminium salts have been reported.[20] Recently, we have re-
ported[21] a convenient approach to 7,8-benzo-anellated 3-
hydroxy-9-azabicyclo[3.3.1]non-3-enes (isobenzomorphan
derivatives) by condensation of 1,3-bis(silyloxy)-1,3-butadi-
enes[22] with isoquinolinium salts and subsequent acid-me-
diated cyclization. The products are not readily available by
other methods. Herein, we report a comprehensive study of
the preparative scope which has been considerably extended
with regard to our preliminary communication.[21] In ad-
dition, we report, for the first time, the deprotection of the
products, the synthesis of parent 7,8-benzo-anellated 9-aza-
bicyclo[3.3.1]nonan-3-ones by decarboxylation, and the
functionalization of the hydroxy group by Suzuki reactions
of the corresponding enol triflates.
Scheme 3. Possible mechanism of the cyclization of 1,3-bis(silyl
enol ether) 2a 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. TFA (2.0 equiv.),
CH2Cl2, 20 °C, 12 h.
The formation of 3a proceeds by regioselective attack of
the terminal carbon atom of 2a onto the iminium salt A
formed by reaction of 1a with methyl chloroformate. The
TFA-mediated cyclization proceeds by formation of the im-
inium salt B and attack of the enol carbon atom onto the
latter. The regioselective cyclization can be explained by the
higher thermodynamic stability of the iminium cation B
compared to the benzylic cation formed by protonation of
the other carbon atom of the enamine moiety (by 19.7 kcal/
mol at a B3LYP/6-31G* level). Product 4a is completely
present in its enol tautomeric form (which is more stable by
3.3 kcal/mol than the keto form at the same level of theory).
The methyl chloroformate-mediated reaction of 1a–d
with 1,3-bis(silyl enol ethers) 2a–s, prepared from the corre-
sponding 1,3-dicarbonyl compounds, afforded the conden-
sation products 3a–ad which were transformed into the
7,8-benzo-anellated 9-azabicyclo[3.3.1]non-3-enes 4a–ad
(Scheme 4, Table 1). All reactions proceeded in moderate to
Results and Discussion
The methyl chloroformate-mediated reaction of isoquin- excellent yields. Regarding the cyclization step, better yields
oline (1a) with 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-bu- were generally obtained for substrates derived from 1,3-di-
4194
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4193–4199

Synthesis of Functionalized Isobenzomorphans
ketones compared to those derived from β-keto esters. This
All structures were proved by spectroscopic methods.
can be explained by the higher extent of enolization of 1,3- Noteworthy, the 1H and 13C NMR spectra show a splitting
diketones compared to β-keto esters which is important for of several signals, due to dynamic processes of the carba-
the TFA-mediated cyclization step. Noteworthy, synthesis mate moiety possessing a significant double bond character.
and reactions of the pyridine- and thiophene-derived 1,3- The structures of 3e, 4e, 4p, and 4r were independently con-
bis(silyl enol ethers) 2w and 2x have not yet been reported. firmed by X-ray crystal structure analyses (Figure 1 and
Figure 2).[24]
Scheme 4. Synthesis of 4a–ad: i. 1 (1.0 equiv.), 2 (2.0 equiv.),
ClCO2Me (1.2 equiv.), CH2Cl2, 0 °C, 2 h, 20 °C, 12 h; ii. TFA
(2.0 equiv.), CH2Cl2, 20 °C, 12 h.
Figure 1. ORTEP plot of 3e. The thermal ellipsoids of 50% prob-
ability are shown for the non-hydrogen atoms.
Table 1. Synthesis of 4a–ad.
1
2
3,4
R1
R2
% 3[a]
% 4[a]
a
a
a
a
a
a
b
b
b
c
a
b
c
d
e
f
b
g
e
b
g
e
h
i
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
OMe
Me
O(CH2)2OMe
CH2OMe
Ph
tBu
Me
OEt
Ph
H
H
H
H
H
H
NO2
NO2
NO2
Br
Br
Br
H
H
H
H
H
Et
H
Et
H
H
H
H
NO2
NO2
NO2
NO2
NO2
NO2
83
80
79
55
76
86
92
94
94
73
90
88
43
70
68
68
43
76
58
41
76
34
68
22
54
72
71
41
56
56
37
57
25
69
85
71
83
47
93
89
60
94
60
69
67
69
72
81
78
77
70
55
27
34
75
55
96
86
60
63
Me
OEt
Ph
c
c
a
a
a
a
a
d
a
d
a
a
a
a
b
b
b
b
b
b
4-(NO2)C6H4
4-ClC6H4
4-FC6H4
2-(MeO)C6H4
2-MeC6H4
2-FC6H4
2-ClC6H4
1-naph
j
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
z
aa
ab
ac
ad
2-naph
Figure 2. ORTEP plot of 4r. The thermal ellipsoids of 50% prob-
ability are shown for the non-hydrogen atoms.
3,4,5-(MeO)3C6H2
2-pyridyl
2-thienyl
4-ClC6H4
4-FC6H4
2-MeC6H4
2-FC6H4
2-ClC6H4
2-naph
s
i
The reaction of 1a–d with 1,3-bis(silyl enol ethers) 2a–c,
in the presence of benzyl chloroformate, afforded the con-
densation products 5a–e which were transformed into the
7,8-benzo-anellated 9-azabicyclo[3.3.1]non-3-enes 6a–e
(Scheme 5, Table 2). While all attempts to deprotect the
methoxycarbonyl-substituted products 4a–ad proved to be
j
l
m
n
p
[a] Yields of isolated products.
Eur. J. Org. Chem. 2008, 4193–4199
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4195

P. Langer et al.
FULL PAPER
unsuccessful, the deprotection (H2, Pd/C) of benzyloxycar- Table 3. Synthesis of 8a–c.
bonyl-substituted derivatives 6a–e was possible and gave the
desired products 7a–e. The hydrogenation of 6b resulted not
only in cleavage of the protective group, but also in trans-
formation of the nitro into an amino group. As expected,
no splitting of signals was observed for all products 7a–e,
due to the absence of the carbamate moiety.
4
8
R1
R2
R3
% 8[a]
a
h
k
a
b
c
H
NO2
Br
CO2Me
CO2Me
CO2Me
Me
Et
Et
46
44
62
[a] Isolated yields.
Scheme 5. Synthesis of 7a–e: i. 1 (1.0 equiv.), 2 (2.0 equiv.),
ClCO2Bn (1.2 equiv.), CH2Cl2, 0 °C, 2 h, 20 °C, 12 h; ii. TFA
(2.0 equiv.), CH2Cl2, 20 °C, 12 h; iii. MeOH, Pd/C (10 mol-%),
24 h, 20 °C.
Figure 3. Ortep plot of 8a. The thermal ellipsoids of 50% prob-
ability are shown for the non-hydrogen atoms.
Table 2. Synthesis of 7a–e.
1
2
5,6,7 R1
R2
H
NO2 97
NH2
Br
H
H
% 5[a] % 6[a] % 7[a]
a
b
b
c
a
a
a
a
a
b
c
a
b
b
c
d
e
OMe
OMe
OMe
Me
O(CH2)2OMe
Me
83
37
37
37
37
25
57
69
79
80
55
25
57
69
b
Scheme 7. Synthesis of 10a,b: i. 1) 4d (1.0 equiv.), Tf2O (1.2 equiv.),
pyridine (2.0 equiv.), CH2Cl2, –78 to 20 °C, 4 h; 2) 9 (1.0 equiv.),
ArB(OH)2 (1.3 equiv.), K3PO4 (1.6 equiv.), Pd(PPh3)4 (0.03 equiv.),
1,4-dioxane, reflux, 20 h.
[a] Isolated yields.
Stirring of a DMSO solution of 3a,h,k in the presence of
LiCl[25] at 130 °C resulted in decarboxylation and formation
of the 7,8-benzo-anellated 9-azabicyclo-[3.3.1]nonan-3-ones
8a–c (Scheme 6, Table 3). The structures of 8a and 8b were
independently confirmed by X-ray crystal structure analysis
(Figure 3).[24]
Scheme 6. Synthesis of 8a–c: i. LiCl, DMSO/H2O, 130 °C, 8 h.
Product 4d was transformed into its triflate 9. The
Suzuki reaction of the latter with phenyl-, 4-meth-
oxyphenyl-, and 4-(trifluoromethyl)boronic acid afforded ability are shown for the non-hydrogen atoms.
Figure 4. Ortep plot of 10a. The thermal ellipsoids of 50% prob-
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Synthesis of Functionalized Isobenzomorphans
= 6.8, J = 14.4 Hz, 1 H, NCHCH2, keto), 2.97 (dd, 3J = 6.8, J =
14.4 Hz, 1 H, NCHCH2, keto), 3.29–3.56 (m, 2 H, COCH2CO,
keto), 3.66 (s, 3 H, OCH3, keto, rotamer), 3.68 (s, 3 H, OCH3, keto-
enol, rotamer), 3.69 (s, 3 H, OCH3, keto-enol, rotamer), 3.79 (s, 3
H, OCH3, keto, rotamer), 3.85 (s, 3 H, OCH3, keto-enol, rotamer),
4.79 (s, 1 H, COHCHCO, enol), 5.61–5.98 (m, 2 H, NCHCH2,
NCHCH), 6.77–6.96 (m, 1 H, NCHCH), 7.05–7.28 (m, 4 H, Ar),
11.91, 11.98 (s, 1 H, OH, rotamer) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 39.8, 40.3 (NCHCH2, enol, rotamer), 47.5 (NCHCH2,
keto), 49.2, 49.7 (COCH2CO, keto), 51.0, 51.6, 51.7 (NCHCH2,
keto-enol, rotamer), 52.2, 53.0, 53.3, 53.8 (OCH3, keto-enol, rot-
amer), 91.2 (COCHCOH, enol), 108.7, 109.0 (NCHCH, keto-enol,
rotamer), 124.1, 124.6, 124.7, 125.9, 126.1, 126.3, 126.9, 127.0,
127.2, 128.0 (NCHCH, CHAr, keto-enol, rotamer), 129.7, 131.1
(CAr), 153.1, 153.3 (NCOO, keto-enol, rotamer), 166.9, 167.3,
172.5, 173.5, 173.8 (CH2COO, COH, keto-enol, rotamer), 199.5
2
2
the isobenzomorphans 10a and 10b, respectively
(Scheme 7). The structures of 10a and 10b were indepen-
dently confirmed by X-ray crystal structure analyses (Fig-
ure 4).[24]
Conclusions
A great variety of functionalized 7,8-benzo-anellated 9-
azabicyclo-[3.3.1]nonan-3-ones were prepared by methyl or
benzyl chloroformate-mediated condensation of isoquinol-
ines with 1,3-bis(silyloxy)-1,3-butadienes and subsequent
TFA-mediated cyclization. The hydroxy group could be
functionalized by Suzuki reactions of the corresponding
enol triflates. The N-benzyloxycarbonyl-substituted prod-
ucts were successfully deprotected. The decarboxylation al-
(NCHCH CO) ppm. IR (neat): ν = 2956 (w), 1714 (s), 1634 (s),
˜
2
lowed the synthesis of the parent 7,8-benzo-anellated 9-aza- 1571 (w), 1447 (s), 1415 (m), 1353 (s), 1328 (s), 1290 (m), 1242 (s),
1200 (s), 1153 (m), 1124 (m), 1025 (w), 981 (w), 949 (w), 775 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 303 (2) [M+], 255 (5), 188 (100),
144 (37), 129 (11), 103 (8), 60 (8). HRMS (EI): = C16H17NO5 [M+]
303.1101; found 303.1103.
bicyclo[3.3.1]nonan-3-ones. The products can be regarded
as functionalized isobenzomorphans – simple structural an-
alogues of morphine.
Benzyl 1-(3-Methoxycarbonyl-2-oxopropyl)isoquinoline-2(1H)-car-
boxylate (5a): Starting with isoquinoline (0.516 g, 4.00 mmol), 2a
(2.112 g, 8.00 mmol) and benzyl chloroformate (0.819 g,
4.80 mmol), 5a was prepared as a pale yellow solid (1.099 g, 72%,
Experimental Section
General: 1H and 13C NMR spectra were taken in CDCl3 at 250,
300, and 500 MHz, respectively. Chemical shifts are reported in
parts per million using the solvent internal standard (chloroform,
7.26 and 77.0 ppm, respectively). Infrared spectra were recorded on
a FTIR spectrometer. Mass spectrometric data (MS) were obtained
by electron ionization (EI, 70 eV), chemical ionization (CI, isobut-
ane) or electrospray ionization (ESI). Melting points are uncor-
rected. CH2Cl2 (anhydrous, 99.8%) was purchased directly from
ACROS and used without further purification. Analytical thin
layer chromatography was performed on 0.20 mm 60 A silica gel
plates. Column chromatography was performed on 60 A silica gel
(60–200 mesh). All cyclization reactions were carried out in
Schlenk flasks in dried solvents under argon. Crystallographic data
were collected on a Bruker X8Apex with Mo-Kα radiation (λ =
0.71073 Å). Data of 4p were collected on a STOE IPDS II. The
structures were solved by direct methods using SHELXS-97 and
refined against F2 on all data by full-matrix least-squares with
SHELXL-97. All non-hydrogen atoms were refined anisotropically,
all hydrogen atoms (for 4p except for the H atom attached to oxy-
gen) were refined in the model at geometrically calculated positions
and refined by using a riding model.
1
m.p. 98–100 °C). H NMR (250 MHz, CDCl3): δ = 2.67–2.81 (m,
1 H, NCHCH2), 2.93–3.04 (m, 1 H, NCHCH2), 3.37 (s, 2 H,
COCH2, isomer 1), 3.50 (s, 2 H, COCH2, isomer 2), 3.61 (s, 3 H,
CO2CH3, isomer 1), 3.66 (s, 3 H, CO2CH3, isomer 2), 5.21 (s, 2 H,
NCO2CH2, isomer 1), 5.25 (s, 2 H, NCO2CH2, isomer 2), 5.80–
5.97 (m, 2 H, NCH, =CH), 6.82 (d, 3J = 7.7 Hz, 1 H, =CH, isomer
3
1), 6.84 (d, J = 7.7 Hz, 1 H, =CH, isomer 2), 7.04–7.35 (m, 9 H,
Ar) ppm. 13C NMR (63 MHz, CDCl3): δ = 47.7, 49.4 (CH2), 51.8
(OCH3), 52.3 (NCHCH2), 68.2 (CO2CH2), 108.9 (NCHCH), 124.2
(NCHCH), 124.9, 125.0, 126.5, 127.4, 128.1, 128.4, 128.6 (Ar-CH),
129.8 131.2, 135.7, 152.6, 167.4, 199.6 (C) ppm. IR (ATR): ν =
˜
2949 (w), 1758 (m), 1702 (s), 1632 (m), 1452 (m), 1417 (s), 1388 (s),
1350 (s), 1323 (s), 1276 (s), 1241 (s), 1191 (m), 1119 (s), 1073 (s),
1028 (m), 1008 (m), 984 (s), 945 (m), 778 (s), 757 (s), 736 (s), 695
(s), 577 (m), 551 (m), 529 (s) cm–1. HRMS (TOF): m/z (%) calcd.
for C22H21NO5Na+ ([M + Na]+): 402.13119, found: 402.13055.
C22H21NO5 (379.41): calcd. C 69.64, H 5.58, N 3.69; found C
70.01, H 5.68, N 3.47.
General Procedure for the Synthesis of 4a–Ad and 6a–e: To a
CH2Cl2 solution (6 mL) of 3 or 5 (1.5 mmol) was added TFA
(3.0 mmol) and the solution was stirred for 12 h at 20 °C. The solu-
tion was concentrated in vacuo and the residue was purified by
chromatography (silica gel, hexane Ǟ hexane/EtOAc, 2:1). The
product was dried for 16 h at 50 °C and 0.01 mbar to remove hy-
drolyzed 2. Due to the amide resonance and formation of E/Z-
isomers, doubling of some signals was observed. In all products,
the 1,3-dicarbonyl moiety resides in the enolic form.
General Procedure for the Synthesis of 3a–ad and 5a–e: To a CH2Cl2
solution (40 mL) of isoquinoline (0.520 g, 4.0 mmol) was added the
1,3-bis-silyl enol ether (8.0 mmol) and methyl or benzyl chloro-
formate (0.460 g, 4.8 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 ϫ 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, heptanes Ǟ
heptanes/EtOAc, 2:1).
Methyl 11-Hydroxy-13-(1-methoxyvinyl)-13-azatricyclo[7.3.1.02,7]-
trideca-2,4,6,10-tetraene-10-carboxylate (4a): Starting with 3a
(0.735 g, 2.40 mmol), dichloromethane (12 mL) and TFA (0.550 g,
Methyl 1-[(Z)-2-Hydroxy-4-methoxy-4-oxo-2-butenyl]isoquinoline- 4.80 mmol), 4a was isolated as a colorless solid (0.270 g, 37%, m.p.
2(1H)-carboxylate (3a): Starting with isoquinoline (0.520 g,
117–119 °C). 1H NMR (300 MHz, CDCl3): δ = 2.35 (2d, 2J =
4.00 mmol), 2a (2.080 g, 8.00 mmol) and methyl chloroformate 17.8 Hz, 1 H, CH2COH, rotamer), 2.83 (d, 2J = 16.6 Hz, 1 H,
(0.460 g, 4.80 mmol), 3a was prepared as an orange oil (1.000 g, CH2CAr), 2.94–3.07 (m, 1 H, CH2COH), 3.19–3.29 (m, 1 H,
83%). 1H NMR (300 MHz, CDCl3): δ = 2.25–2.41 (m, 1 H, CH2CAr), 3.73, 3.75 (s, 3 H, OCH3, rotamer), 3.81, 3.82 (s, 3 H,
3
3
NCHCH2, enol), 2.52–2.62 (m, 1 H, NCHCH2, enol), 2.76 (dd, J
OCH3, rotamer), 5.26 (d, J = 5.5 Hz, 1 H, NCHCCO, rotamer),
Eur. J. Org. Chem. 2008, 4193–4199
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4197

P. Langer et al.
FULL PAPER
5.36 (d, J = 6.2 Hz, 1 H, NCHCAr, rotamer), 5.39 (d, 3J = 5.5 Hz, LiCl (2.94 mmol) and the solution was stirred for 8 h at 130 °C.
3
3
1 H, NCHCCO, rotamer), 5.48 (d, J = 6.2 Hz, 1 H, NCHAr, rot-
After cooling to 20 °C, CH2Cl2 (30 mL) was added and the mixture
amer), 7.07–7.19 (m, 4 H, Ar), 12.05 (s, 1 H, OH) ppm. 13C NMR was washed with water (1ϫ20 mL) and brine (1ϫ20 mL). The
(75.5 MHz, CDCl3): δ = 33.4, 33.9 (CH2CAr, rotamer), 36.9, 37.3 combined aqueous layers were extracted with CH2Cl2 (3ϫ50 mL).
(CH2COH, rotamer), 44.5, 45.0 (NCHCCO, rotamer), 48.5, 49.2
(NCHCAr, rotamer), 51.7 (OCH3), 52.8 (OCH3), 99.6, 99.9 (CCOO,
rotamer), 126.3, 126.6, 127.3, 127.4, 129.5, 129.8 (CHAr, rotamer),
132.1, 132.5, 136.1, 136.3 (CAr, rotamer), 154.3, 154.4 (NCOO, rot-
amer), 170.0 (COH), 170.6, 170.8 (CCOO, rotamer) ppm. IR
The combined organic layers were dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes Ǟ heptanes/EtOAc, 2:1).
Methyl 11-Oxo-13-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-13-
carboxylate (8a): Starting with 6a (0.418 g, 1.40 mmol) and LiCl
(0.125 g, 2.94 mmol) in DMSO (13 mL, 2% water), 8a was isolated
as a colourless solid (0.159 g, 46%); m.p. 127–130 °C. 1H NMR
(250 MHz, CDCl3): δ = 2.37 (m, 1 H, COCH2), 2.49 (m, 1 H,
COCH2), 2.68–2.91 (m, 3 H, COCH2, NCHCH2CAr), 3.36 (br.dd,
(KBr): ν = 2954 (br., w), 1601 (s), 1617 (m), 1413 (m), 1385 (w),
˜
1334 (s), 1098 (m), 1265 (m), 1221 (s), 1115 (m), 1066 (m), 1021
(m), 819 (w), 766 (m), 673 (w) cm–1. MS (EI, 70 eV): m/z (%) = 303
(36) [M+], 212 (100), 188 (12), 180 (13), 116 (6), 114 (7). C16H17NO5
(303.31): calcd. C 63.36, H 5.65, N 4.62; found C 63.49, H 5.97, N
4.81.
3
2J = 17.7, J = 6.1 Hz, 1 H, NCHCH2CAr), 3.80 (s, 3 H, OCH3),
5.07 (br. m, 3J = 6.1 Hz, 1 H, NCHCH2CAr, rotamers), 5.20 (br.
10-Methyl 13-Benzyl 11-Hydroxy-13-azatricyclo[7.3.1.02,7]trideca-
2,4,6,10-tetraene-10,13-dicarboxylate (6a): Starting with 5a
(0.997 g, 2.63 mmol) and TFA (0.600 g, 5.26 mmol), 6a was iso-
lated as a colourless solid (0.340 g, 34%, m.p. 54–56 °C). 1H NMR
(250 MHz, CDCl3): δ = 2.35 (dd, 2J = 17.9, 3J = 7.1 Hz, 1 H,
NCHCH2), 2.78–3.32 (m, 3 H, NCHCH2), 3.81 (s, 3 H, CO2CH3),
5.07–5.26 (m, 2 H, CO2CH2), 5.29–5.51 (m, 2 H, NCH), 7.06–7.21
m, 1 H, NCHCH2CAr, rotamers), 5.58 (br. m, 1 H, COCH2CHCAr
,
rotamers), 5.70 (br. m, 1 H, COCH2CHCAr, rotamers), 7.03–7.07
(br. m, 2 H, Ar), 7.15–7.19 (m, 2 H, Ar) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 33.6, 33.9 (CH2, rotamers), 46.7, 46.9
(CH2, rotamers), 47.1, 47.6 (NCH, rotamers), 48.9, 49.2 (CH2, rot-
amers), 51.6, 51.9 (NCH, rotamers), 53.1 (OCH3), 126.2, 126.5,
127.0, 127.8, 129.3, 129.6 (CHAr, rotamers), 130.4, 130.8, 135.2,
135.4 (CAr, rotamers), 154.9 (NCOO), 206.9 (CO) ppm. IR (KBr):
(m, 4 H, Ar), 7.31–7.37 (m, 5 H, Ar), 12.05 (s, 1 H, OH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 33.6/34.0, 37.1/37.5 (NCHCH2), 44.6/
45.2, 48.7/49.3 (NCH), 51.7 (CO2CH3), 67.3/67.5 (CO2CH2), 99.6/
100.1 (C), 126.3/126.4, 126.6, 127.4/127.5, 127.9, 128.1/128.2, 128.5,
129.6/129.9 (Ar-CH), 132.2/132.6, 136.1/136.3, 136.5, 153.8/153.9,
ν = 3048 (w), 3005 (w), 2956 (w), 2933 (w), 2908 (w), 2852 (w),
˜
1712 (s), 1693 (s), 1493 (w), 1455 (s), 1412 (s), 1347 (m), 1326 (m),
1279 (m), 1220 (m), 1208 (m), 1119 (m), 1045 (m), 989 (w), 763
(m), 682 (w) cm–1. MS (EI, 70eV): m/z (%) = 245 (20) [M+], 202
(4), 188 (100), 144 (31), 128 (12), 115 (13), 91 (4), 77 (3), 59 (4).
C14H15NO3 (245.27): calcd. C 68.56, H 6.16, N 5.71; found C
68.23, H 6.35, N 5.39.
170.0, 170.7/170.9 (C) ppm. IR (ATR): ν = 2951 (w), 1697 (s), 1655
˜
(s), 1614 (m), 1496 (w), 1424 (s), 1321 (s), 1295 (s), 1257 (s), 1217
(s), 1201 (s), 1113 (s), 1096 (s), 1063 (s), 1014 (s), 976 (m), 811 (m),
758 (s), 734 (s), 693 (s), 670 (s), 624 (m), 611 (m), 591 (m), 572 (m)
cm–1. MS (EI): m/z (%) = 379 (26) [M+], 288 (33), 244 (49), 212 Synthesis of 9 and of 10a–c: To a CH2Cl2 solution of 4d
(39), 91 (100). HRMS (EI): calcd. for C22H21NO5 (M+): 379.14142; (2.80 mmol) was added pyridine (5.60 mmol) at –78 °C. To the
found: 379.14077.
solution was added dropwise trifluoromethanesulfonic acid anhy-
dride (3.36 mmol) at –78 °C. The solution was warmed to 20 °C
during 4 h with stirring. The solvent was removed in vacuo and
the residue was purified by chromatography (silica gel, heptanes Ǟ
heptanes/EtOAc, 2:1) to give 9. The product was dried in vacuo
and directly used for the synthesis of 10a–c. To a 1,4-dioxane solu-
tion (2.5 mL) of 9 (1.00 mmol) were added the boronic acid
(1.30 mmol), potassium phosphate (1.60 mmol) and tetrakis(tri-
phenylphosphane)palladium(0) (0.03 mmol) at 20 °C. The solution
was stirred under reflux for 20 h. After cooling to 20 °C, an aque-
ous solution of ammonium chloride was added (3 mL) and to the
mixture was added CH2Cl2 (15 mL). The organic and the aqueous
layer were separated and the latter was extracted with CH2Cl2
(20 mL). The combined organic layers were dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo. The residue was purified
by chromatography (silica gel, heptane Ǟ heptane/EtOAc, 2:1).
General Procedure for the Synthesis of 7a–e: To a stirred methanol
suspension (25 mL) of Pd/C (0.1 equiv.) was added 6a–e
(1.0 equiv.). The reaction mixture was set under hydrogen atmo-
sphere and stirred for 24 h at 20 °C. The reaction mixture was fil-
tered (celite) and the filtrate was concentrated in vacuo. The residue
was purified by chromatography (silica gel, heptanes Ǟ heptanes/
EtOAc, 0:1).
Methyl
11-Hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2(7),3,5,10-
tetraene-10-carboxylate (7a): Starting with 6a (0.275 g, 0.72 mmol),
7a was isolated as a pale yellow solid (0.150 g, 85%), m.p. 134–
1
2
3
135 °C. H NMR (250 MHz, CDCl3): δ = 2.31 (dd, J = 17.9, J
2
= 1.1 Hz, 1 H, NCHCH2), 2.80 (d, J = 16.8 Hz, 1 H, NCHCH2),
2.92 (dd, 2J = 17.9, 3J = 6.1 Hz, 1 H, NCHCH2), 3.16 (dd, 2J =
16.8, 3J = 5.6 Hz, 1 H, NCHCH2), 3.79 (s, 3 H, CO2CH3), 4.27 (d,
3J = 5.5 Hz, 1 H, NCH), 4.37 (d, J = 6.0 Hz, 1 H, NCH), 7.02–
3
7.18 (m, 4 H, Ar), 11.89 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 34.7, 38.2 (NCHCH2), 45.2, 49.8 (NCH), 51.5
(CO2CH3), 101.2 (C), 126.1, 126.7, 127.0, 129.8 (Ar-CH), 132.8,
Methyl
10-Acetyl-11-phenyl-13-azatricyclo[7.3.1.02,7]trideca-
2(7),3,5,10-tetraene-13-carboxylate (10a): Starting with 4d (0.804 g,
2.80 mmol), pyridine (0.443 g, 5.6 mmol) and trifluoromethanesul-
fonic anhydride (0.948 g, 3.36 mmol) in CH2Cl2 (28 mL), 9 was iso-
lated as a slightly yellow oil (0.906 g, 77%). Starting with 9
(0.419 g, 1.00 mmol), phenylboronic acid (0.159 g, 1.30 mmol), po-
tassium phosphate (0.340 g, 1.60 mmol) and tetrakis(triphenyl-
phosphane)palladium(0) (0.035 g, 0.03 mmol) in 1,4-dioxane
(2.5 mL), 10a was isolated as a colourless solid (0.197 g, 57%); m.p.
97–98 °C. 1H NMR (250 MHz, CDCl3): δ = 1.55, 1.56 (s, 3 H,
COCH3, rotamers), 2.21, 2.24 (s, 3 H, COCH3, rotamers), 2.66 (m,
2 H, CH2), 3.13 (m, 2 H, CH2), 3.68, 3.74, 3.76 (s, 3 H, OCH3),
5.27–5.59 (m, 2 H, NCH), 6.97–7.00 (m, 2 H, Ar), 7.07–7.20 (m, 5
H, Ar), 7.27–7.29 (m, 2 H, Ar), 7.45 (m, 1 H, Ar) ppm. 13C NMR
138.3, 170.4, 171.2 (C) ppm. IR (ATR): ν = 3314 (w), 3214 (w),
˜
2925 (w), 1651 (s), 1609 (s), 1442 (s), 1417 (m), 1377 (m), 1347 (m),
1327 (m), 1291 (s), 1264 (s), 1244 (m), 1215 (s), 1197 (s), 1074 (s),
986 (m), 849 (m), 834 (s), 815 (s), 792 (m), 775 (s), 758 (s), 738 (s),
675 (m), 635 (m), 588 (m) cm–1. MS (EI): m/z (%) = 245 (19) [M+],
154 (97), 129 (91), 57 (100), 43 (91). HRMS (EI): calcd. for
C14H15NO3 (M+): 245.10464, found 245.10539. C14H15NO3
(245.27): calcd. C 68.56, H 6.61, N 5.71; found C 68.48, H 6.12, N
5.38.
General Procedure for the Decarboxylation of 4a,h,k: To a solution
of 9 (1.40 mmol) in wet DMSO (13 mL, 2% of water) was added
4198
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4193–4199

Synthesis of Functionalized Isobenzomorphans
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(75.5 MHz, CDCl3): δ = 31.0 (COCH3), 33.0, 33.3, 34.7, 34.9 (CH2,
rotamers), 40.8, 41.1 (CH2, rotamers), 47.4, 47.8, 49.0, 49.7, 50.0,
50.7, 51.3, 51.5, 52.7 (NCH, OCH3, rotamers), 126.2, 126.4, 126.5,
127.2, 127.6, 127.7, 128.6, 129.3, 129.6 (CHAr, rotamers), 132.4,
132.9, 136.8, 136.9, 137.8, 138.0, 140.6, 142.5, 143.1, 144.4 (CAr
,
CCO, CCAr, rotamers), 154.3, 154.5 (NCOO, rotamers), 202.3,
[11] J. M. Gulland, R. Robinson, Mem. Proc. Manchester Lit. Phil.
Soc. 1925, 69, 79; Chem. Abstr. 1926, 20, 765.
202.6 (COCH ) ppm. IR (KBr): ν = 3021 (w), 2953 (w), 2886 (w),
˜
3
2847 (w), 1693 (s), 1672 (s), 1628 (w), 1491 (w), 1453 (s), 1415 (m),
1352 (m), 1334 (m), 1323 (m), 1286 (w), 1251 (m), 1236 (m), 1190
(w), 1119 (m), 1029 (m), 764 (m), 745 (m), 705 (m) cm–1. MS (EI,
70eV): m/z (%) = 347 (100) [M+], 304 (10), 288 (23), 272 (36), 256
(83), 229 (50), 215 (8), 204 (22), 188 (74), 115 (11), 59 (4).
C22H21NO3 (347.41): calcd. C 76.06, H 6.09, N 4.03; found C
75.78, H 6.16, N 3.87.
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characterization of all new compounds.
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Acknowledgments
Financial support from the State of Pakistan (HEC scholarship to
I. H. and M. A. Y.), and from the State of Mecklenburg-Vorpom-
mern (scholarship to A. S.) is gratefully acknowledged.
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[24] CCDC-688473 (for 3e), -685727 (for 4p), -688449 (for 4r),
-688475 (for 8a), -688474 (for 8b), -688476 (for 10a), and
-688477 (for 10b), contain the supplementary crystallographic
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Received: May 15, 2008
Published Online: July 4, 2008
Eur. J. Org. Chem. 2008, 4193–4199
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4199