The palladium-catalyzed preparation of condensed tetracyclic heterocycles and their application to the synthesis of rac-mangochinine

Article abstract of DOI:10.1055/s-2006-926410

Dihydroisoquinoline derivatives and their analogues, prepared by the Bischler-Napieralsky reaction, were converted to their indole-fused derivatives. Scope and limitations of the palladium-catalyzed reaction, proceeding through the tautomeric enamine forms of these compounds, were studied and the process was extended to the preparation of racemic mangochinine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926410

FEATURE ARTICLE
1375
The Palladium-Catalyzed Preparation of Condensed Tetracyclic Heterocycles
and their Application to the Synthesis of rac-Mangochinine
P
alladium-Catal
o
yze
d
Synthe
l
sis of
C
t
ondens
á
ed Heteroc
n
ycles Vincze,1 A. Beatrix Bíró, Márton Csékei, Géza Timári,2 András Kotschy*
Institute of Chemistry, Eötvös Loránd University, Pázmány Péter s. 1/A, 1117 Budapest, Hungary
Fax +36(1)3722909; E-mail: kotschy@chem.elte.hu
Received 11 January 2006; revised 27 February 2006
Dedicated to Prof. György Hajós on the occasion of his 60th birthday.
cryptaustoline (1) and cryptowoline (2) by an intramolec-
Abstract: Dihydroisoquinoline derivatives and their analogues,
prepared by the Bischler–Napieralsky reaction, were converted to
their indole-fused derivatives. Scope and limitations of the palladi-
um-catalyzed reaction, proceeding through the tautomeric enamine
forms of these compounds, were studied and the process was ex-
tended to the preparation of racemic mangochinine.
ular aromatic nucleophilic substitution, while the absolute
stereochemistry of 1 has been established as R-(–) by
Meyers.12
Kametani’s process, carried out in the presence of a strong
base, probably proceeds through a benzyne intermediate.
This strategy was successfully extended by Kano also to
the synthesis of indolo[2,1-a]benzazepine and quinoli-
no[2,1-a]benzazepine derivatives.13,14 A recent develop-
ment in this direction, reported by Orito and co-workers,
is the formation of the tetracycle in the nucleophilic sub-
stitution of a tautomeric form, achieved by prolonged
heating (3–4 days) of the appropriate dihydroisoquinoline
derivatives in DMF at 140 °C in the presence of potassium
carbonate.15 The authors used this methodology to prepare
the racemic form of cryptaustoline (1) and cryptowoline
(2). Their attempts to extend the procedure to other ring
systems, however, remained in vain.
Key words: ring closure, palladium, catalysis, indoles, natural
products
Introduction
Following the isolation of the first dibenzopyrrocoline al-
kaloids, cryptaustoline (1) and cryptowoline (2), from
Cryptocaria bowiei by Ewing,3 reports on the isolation
and characterization of related natural products cryptowo-
lidine (3), cryptowolinol (4) were also published.4 A more
recent study of the bark of Manglietia chingii, used in tra-
ditional Chinese medicine revealed the presence of anoth-
er member of this family, mangochinine (5) in it5
(Figure 1). Besides their use in natural remedies, the anti-
leukemic and antitumor6,7 activity and curare-like paralyt-
ic action8 of benzopyrrocoline alkaloids were also
reported.
Following Kametani’s report several other methods were
published for the preparation of the dibenzopyrrocoline
core, including radical cyclizations16and silicon-mediated
ring-closure reactions.17 Recently Nolan and co-workers
replaced Kametani’s aryne reaction by the Buchwald–
Hartwig coupling to achieve the efficient synthesis of 1
and 2.18 The key to their success in the ring-closure reac-
tion was the use of N-heterocyclic carbenes as supporting
ligands with palladium.
MeO
HO
HO
I–
I–
N
+
N
+
MeO
OR1
OR2
O
As most other groups, we also planned to follow the well
established ‘dihydroisoquinoline route’ in our synthetic
efforts. Our aims were i) to test the scope of the palladi-
um-catalyzed preparation of dibenzopyrrocoline deriva-
tives; and ii) to utilize the gathered experience in the
synthesis of mangochinine (5).
R
1, 2, 5
3, 4
O
1 cryptastoline R1 = R2 = Me
3 cryptovolidine R = H
4 cryptovolinol R = OHm
2 cryptovoline R1 = R2 = -CH2-
5 mangochinine R1 = Me, R2 = H
Figure 1 Mangochinine and related dibenzopyrrocoline alkaloids
The key step in our strategy (Scheme 1) is the palladium-
The first reports on the preparation of the dibenzopyrro- catalyzed C–N bond formation reaction, which would re-
coline core by Robinson9 and Schöpf10 were the results of quire the use of appropriately substituted tetrahydro-, or
an unexpected transformation in both cases. These reports dihydroisoquinoline derivative 6. The preparation of com-
preceded the isolation of the natural products, although, pounds like 6 is very well established in the literature by
based on the ease of their formation, Schöpf had predicted the Bischler–Napieralsky ring-closure reaction, following
the presence of this framework in natural sources.10 The the acylation of the appropriate phenethylamine 8 ana-
first total synthesis of dibenzopyrrocolines was reported logue with a brominated phenylacetic acid derivative 7.
by Kametani and co-workers,11 who prepared racemic An important point in the early stage of synthesis is the
choice and introduction of protecting groups. A practical
feature of the envisaged approach is the fact that both 7
and 8 might be traced back to the same, easily available
SYNTHESIS 2006, No. 8, pp 1375–1385
Advanced online publication: 28.03.2006
DOI: 10.1055/s-2006-926410; Art ID: Z00806SS
x
x
.
x
x
.2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

1376
Z. Vincze et al.
FEATURE ARTICLE
Biographical Sketches
Zoltán Vincze was born in Péter Nemes on up-to-date es, Szent István University.
1974. He studied chemistry at preparative methods in the His research interests include
the Eötvös Loránd University synthesis of different con- transition-metal catalysis and
and worked for his M.Sc. de- densed isoquinoline deriva- microwave-mediated trans-
gree (1999) under the guid- tives. He is currently an formations in heterocyclic
ance of András Kotschy. He assistant professor in the In- chemistry.
is finishing his Ph.D. thesis stitute of Chemistry at the
with András Kotschy and Faculty of Veterinary Scienc-
Andrea Beatrix Bíró was in 2002 under the supervision transition-metal-catalyzed
born in Kolozsvár (Cluj, Ro- of Dr. Silaghi Luminita. Since transformations of heterocy-
mania) in 1978. After studies 2002 she is a Ph.D. student at clic systems under the super-
at the Babes Bolyai Universi- Eötvös Loránd University vision of András Kotschy.
ty in Kolozsvár, she received (Hungary), where she is about
her Master of Science degree to complete her thesis on the
Márton Csékei was born in the supervision of Dr. András preparation of tetrazine deriv-
Pécs (Hungary) in 1980. After Kotschy. His interests include atives. At present he is doing
receiving his M.Sc. degree at the synthesis of natural prod- an internship at BASF in Lud-
Eotvos Lorand University, he ucts containing the benzofu- wigshafen (Germany).
became a Ph.D. student under ran framework and the
Géza Timári received his di- where he is currently head of hydroxylation methodology.
ploma at Eötvös University in Medicinal Chemistry Labora- In 1995, as a Volkswagen
Budapest 1979, and his Ph.D. tory I. In 1988 he joined the Fellow, he joined Prof. E.
at the same university in laboratory of Prof. S. Winterfeldt’s group at the
1983. In 1984, he joined the Gronowitz for a year at the University of Hannover car-
group of Prof. A. Messmer at University of Lund, Sweden, rying out natural product syn-
the Central Research Institute where he worked on transi- thesis. His research interests
for Chemistry, Hungarian tion-metal-catalyzed cross- include the synthesis of bio-
Academy of Sciences (HAS) coupling reactions. He also logically active molecules us-
and obtained the Candidate of spent one year (1994) at the ing
organometallic
Sciences degree from the University of Geneva (Swit- approaches and asymmetric
HAS in 1993. He moved to zerland) in the group of Prof. synthesis.
the pharmaceutical company C. W. Jefford and worked on
Chinoin (Budapest) in 1998, the amplified asymmetric di-
András Kotschy was born in Eötvös Loránd University, stitution in early 2005. His re-
1969. He studied chemistry at where following two years of search interests span different
the Eötvös Loránd University postdoctoral stay (1996 – aspects of heterocyclic chem-
and worked for his M.Sc. Royal Society Postdoctoral istry from the preparation and
(1992) and Ph.D. (1995) de- Fellow with David Smith in functionalization of heterocy-
grees with András Messmer St Andrews, and 1999 – Alex- cles through the understand-
and György Hajós at the Cen- ander von Humboldt Re- ing of their chemical
tral Research Institute for search Fellow with Paul behavior, to their application
Chemistry of the Hungarian Knochel in München) he has in catalysis and molecular
Academy of Sciences. He been an Associate Professor recognition.
started his independent carrier since 2002. He received his
at the Institute of Chemistry at habilitation from the same in-
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

FEATURE ARTICLE
Palladium-Catalyzed Synthesis of Condensed Heterocycles
1377
MeO
PGO
PGO
COOH
MeO
HO
I–
MeO
MeO
N
7
CN
MeO
MeO
Br
Br
N
+
9
OMe
OH
6
5
OMe
NH2
8
PGO
OPG
Scheme 1 Retrosynthetic analysis for the preparation of mangochinine (5)
starting material, 3,4-dimethoxyphenylacetonitrile (9), [it gave 16 in 51% yield using a Pd(dba)2/SIMes catalyst
also known as homoveratronitrile.
system and Cs2CO3 in toluene], and decided to focus our
attention on the palladium-catalyzed construction of the
tetracyclic core starting from dihydroisoquinoline 13. Fol-
lowing the optimization of the reaction conditions in this
ring closure, we had two further aims in mind: i) to test the
Results and Discussion
The first experiments were directed at testing the feasibil- feasibility of the developed conditions in the preparation
ity of the planned synthetic route. To simplify our synthe- of natural product mangochinine (5); and ii) to study the
sis we selected such analogues of 6–8 as model systems scope and limitations of this new transformation.
that contained only methoxy groups. 3,4-Dimethoxyphen-
ylacetonitrile (9, homoveratronitrile) was converted to 2-
In the first attempt to convert 13 to 15 (Scheme 3) we
checked if the reaction worked in the absence of palladi-
um, but the starting material remained unchanged even on
prolonged heating under these conditions. The reactions,
bromo-4,5-dimethoxyphenylacetic acid (10) by hydroly-
sis and bromination in good yield.19 Reduction of 9 under
heterogeneous conditions yielded the other required re-
run at 80 °C, were followed by TLC and in later cases they
agent 11 in good yield. Acylation of 11 with the acid chlo-
were continued until the consumption of 13. Increase of
ride prepared from 10 and thionyl chloride gave the
the temperature was found, in general, to facilitate decom-
position and lead only to minor rate increase. The addition
of palladium (8 mol%) to the reaction in the absence of
ligands led to no conversion either. Monodentate ligands
desired amide 12 in good yield,20 which was converted to
the dihydroisoquinoline derivative 13 in Bischler–Napier-
alsky reaction in acetonitrile.6 Reduction of 13 to the ap-
propriate tetrahydroisoquinoline derivative 14 with
such as triphenylphosphine and tri(o-tolyl)phosphine
sodium borohydride also proceeded readily13 (Scheme 2).
(Table 1, entries 3–5), although initiated some transfor-
At this stage we had two alternate entry points to the for-
mation, gave only very poor conversion and no selective
mation of the tetracyclic core. We could either follow the
transformation. Switching to the bidentate dppf as ligand
(entries 6–10) improved the situation considerably. Of the
conditions tested, the use of Cs2CO3 as base and toluene
as solvent gave the highest yield (entry 7, 62%). In the
next series of experiments we tested some N-heterocyclic
carbenes that were also used by Nolan as ligand (entries
route pioneered by Nolan18 and convert 14 to 16, or we
could also try to extend Orito’s methodology15 and at-
tempt to convert 13 to 15 using transition metal catalysis.
This latter transformation would involve a Buchwald–
Hartwig coupling through a tautomeric form of 13, which
is not unprecedented in the literature for bicyclic systems.
11–17, IMes = N,N¢-dimesitylimidazolium tetrafluorobo-
The conversion of arylhydrazones to indole derivatives21
rate, IPr = N,N¢-bis(2¢,6¢-diisopropylphenyl)imidazolium
and the preparation of benzofuran derivatives22 utilizing
tetrafluoroborate, SIPr = N,N¢-bis(2¢,6¢-diisopropylphen-
such a sequence were both reported recently.
yl)dihydroimidazolium tetrafluoroborate). The first ex-
Since Nolan’s study has established the accessibility of periments revealed that the IMes ligand exerts a reactivity
the dibenzopyrrocoline core in conventional Buchwald– similar to dppf, but in this case the use of t-BuONa as base
Hartwig coupling, we only proved that it also works on 14 gives superior results (entries 11, 12). Switching to the
MeO
MeO
MeO
MeO
MeO
MeO
POCl3
MeCN
NaBH4
N
NH
Br
NH
O
MeO
MeO
Br
Br
MeOH
73%
12
13
NH2
11
14
1. SOCl2
OMe
OMe
OMe
Pd2(dba)3
Pd2(dba)3
ligand, base
2. 11, Et2O
aq Na2CO3
80%
OMe
OMe
H2/Pd
80%
OMe
ligand, base
MeO
MeO
MeO
1. NaOH, MeOH, 73%
2. Br2, CH2Cl2, 95%
COOH
9
N
N
MeO
MeO
MeO
Br
10
OMe
OMe
OMe
OMe
16
15
Scheme 2 Model chemistry
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

1378
Z. Vincze et al.
FEATURE ARTICLE
sterically more demanding IPr ligand framework we ob- Table 1 Efficiency of the Palladium-Catalyzed Conversion of 13 to
15 under Different Conditions
served an increased activity (entries 13, 14), a change op-
posite to what had been observed by Nolan in the 14 → 16
like transformation.18 Although the 78% isolated yield
achieved with this catalyst is already an acceptable result,
we could further improve the efficiency of the transforma-
tion by changing to the imidazoline-based ligand SIPr (en-
tries 15–17), which in toluene gave 15 in 85% yield. The
comparison of entries 11–17 also reveals that for this
transformation toluene is the best solvent amongst the
ones we tried, and sodium tert-butoxide is the base of
choice. We could also obtain the same yields when start-
ing from the hydrochloride salt of 13, preferable due to its
increased stability and the ease of its handling and purifi-
cation, only the amount of added base had to be increased
to 2.4 equivalents. The activity of the NHC ligands was
also manifested in the fact that the transformations in en-
tries 11–17 reached completion faster than with dppf or
other ligands.
Entry Ligand
Base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DME
Yield (%)a
1
2
–, no Pd
–, no Pd
–, Pd2(dba)3
PPh3
Cs2CO3
t-BuONa
–
0
0
3
0
4
t-BuONa
t-BuONa
t-BuONa
Cs2CO3
t-BuONa
Cs2CO3
Cs2CO3
Cs2CO3
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
0
5
P(o-tol)3
dppf
20
50
62
40
43
45
40
65
60
78
60
63
85
6
7
dppf
8
dppf
9
dppf
DME
10
11
12
13
14
15
16
17
dppf
dioxane
toluene
toluene
DME
IMes
IMes
IPr
MeO
MeO
MeO
MeO
N
Pd2(dba)3
Br
N
ligand, base
OMe
OMe
13
15
OMe
IPr
toluene
DME
OMe
SIPr
Scheme 3 Alternate ring-closing approach involving the tautomeric
enamine form
SIPr
dioxane
toluene
SIPr
To be able to test the utility of this transformation in the
preparation of mangochinine (5), first we had to prepare
the appropriate protected dihydroisoquinoline derivative
21. Our approach (Scheme 4.) started from homovera-
tronitrile (9), which was converted in a multistep se-
quence to the appropriately functionalized phenylacetic
acid 7 and phenethylamine 8 derivative, which through
formation of amide 20 and the Bischler–Napieralsky reac-
tion gave 21. The opening step of the synthesis was the se-
lective demethylation of 9, developed by Szántay,23 which
gave the two monomethylated isomers 17 and 18 in a
45:55 ratio. Since the separation of 17 and 18 by chroma-
tography or distillation is tedious, we used the selective
halogenation of the 17/18 mixture, of which 18 was pref-
erentially converted to 19 on treatment with bromine at
low temperature, while 17 remained intact. Both compo-
nents of the reaction mixture, 17 and 19, could be isolated
in good yield by simple manipulations.
a Isolated yields. Reactions were run in the presence of Pd [8 mol% as
Pd2(dba)3], ligand (16 mol%) and base (1.4 equiv) at 80 °C until com-
pletion.
amide, isolated in 61% yield, was benzylated to give 20 in
good yield. We had to protect the OH group since its pres-
ence was found to result in poor yields in the subsequent
Bischler–Napieralsky reaction. Following a series of test
reactions we found that the optimal conditions for the ring
closure included the use of phosphorous oxychloride in
acetonitrile, which gave 21 in 76% yield.
The key step of the synthesis, the palladium-catalyzed
ring closure leading to the dibenzopyrrocoline frame was
achieved in excellent yield, using the established condi-
tions. Running the process in toluene at 80 °C in the pres-
ence of 8 mol% Pd in the form of Pd2(dba)3, 16 mol% SIPr
and 1.4 equivalents of t-BuONa afforded 22 in 89% yield.
The preparation of racemic mangochinine (5) from 22 was
achieved by following literature analogies. Compound 22
was reduced by NaBH3CN in acetic acid to give 23 in a
near quantitative yield. Since 23 is quite sensitive to oxi-
dation, it was stabilized by alkylation with excess methyl
iodide, which gave the desired salt in 89% yield. In the
concluding step deprotection of the two hydroxyl groups
led to the formation of rac-mangochinine (5) in good
yield.
Compound 17 was reduced to 8 in good yield by conven-
tional hydrogenation. The hydroxyl group of 19 was ben-
zylated and the protected nitrile was hydrolyzed to the
appropriate carboxylic acid 7. Attempts at converting 7
and 8 to the desired amide through an acid chloride gave
poor selectivity, since the unprotected hydroxyl group of
8 was also acylated. Its protection in the presence of the
free amine was also problematic, especially since we
wanted to use benzyl protection. The formation of the de-
sired amide was finally achieved by the direct reaction of
7 and 8 in their melt. The free hydroxyl group in the
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

FEATURE ARTICLE
Palladium-Catalyzed Synthesis of Condensed Heterocycles
1379
MeO
HO
MeO
HO
MeO
H2/Ra-Ni
CN
17
CN
MeO
NH2
8
EtOH, 80%
17
Br2, –78 o
C
AlCl3
CN
HO
HO
1. BnCl, K2CO3
EtOH, 86%
PhMe
75%
CH2Cl2, AcOH
75%
MeO
HO
BnO
MeO
9
CN
18
CN
COOH
2. NaOH, aq EtOH,
reflux, 5 h;
19
7
MeO
MeO
Br
Br
17:18 = 45:55
then 10% aq
HCl, 71%
MeO
MeO
BnO
MeO
N
NH
Br
O
NH2
BnO
POCl3
1. ∆, neat 61%
Br
8
HO
+
MeCN
76%
2. BnCl, K2CO3
EtOH, 80%
BnO
20
21
COOH
OMe
OMe
7
MeO
Br
OBn
OBn
I–
Me
MeO
BnO
MeO
MeO
BnO
8% Pd2(dba)3
16% SIPr
NaOtBu
N
1. MeI, MeOH, 89%
N
N
NaBH3CN
21
HO
+
OMe
2. concd HCl, KI
EtOH, 70%
OMe
OH
OMe
AcOH, 95%
22
5
PhMe, 89%
23
OBn
OBn
Scheme 4 Total synthesis of racemic mangochinine
Following the successful preparation of the indolo[2,1-a]- converted to the desired amide 26 through coupling with
isoquinoline frame and its use in the synthesis of rac- 3,4-dimethoxyphenethylamine (25) in their melt. The clo-
mangochinine we wanted to study the scope of this new sure of the dihydroisoquinoline ring proceeded smoothly
palladium catalyzed transformation. We hoped that exten- under standard conditions to give 27 in 86% yield.
sion of this strategy might open up a new synthetic route
to other systems, such as the dibenzo[a,f]quinolisine 34,
indolo[2,1-a]-2-benzazepine 35 and quinolo[2,1-a]-2-
The analogous benzazepine derivatives 32 and 33 were
prepared in a multistep sequence. Knoevenagel condensa-
tion of 3,4-dimethoxybenzaldehyde with cyanoacetic ac-
benzazepine 36. In the preparation of the ring-closed pre-
id, followed by reduction gave the cyanoacid 28 in good
cursors we followed a strategy similar to that developed
yield, which was decarboxylated to appropriate phenyl-
for dibenzopyrrocoline derivatives. The synthesis of inter-
propionitrile derivative. Reduction of the nitrile group
mediates and precursors is shown in Scheme 5.
with LiAlH4 gave the desired amine 29 in acceptable
The precursors to be prepared included the dihydroiso- yield. Compound 29 was acylated with the bromophenyl-
quinoline derivative 27, and the benzazepine derivatives alkanoic acids 11 and 24 at 180 °C, using solvent-free
32 and 33. The preparation of 27 started from 6-bromo- conditions. Although the desired amides 30 and 31 were
3,4-dimethoxyphenylpropionic acid (24)24 which was first isolated only in modest yield (55 and 49%, respectively),
MeO
MeO
MeO
MeO
COOH MeO
MeO
MeO
∆, neat
OMe
Br
POCl3
OMe
+
NH
OMe
NH2
N
OMe
MeCN
86%
O
85%
Br
MeO
24
25
26
27
Br
1. NCCH2CO2H
NH4Ac, toluene, 85%
MeO
MeO
CHO
MeO
MeO
COOH
CN
MeO
MeO
NH2
1. ∆, DMF, 91%
2. NaBH4, MeOH
80%
2. LiAlH4, THF, 60%
28
29
MeO
MeO
MeO
MeO
∆, neat
OMe
Br
POCl3, MeCN
29 + 11 or 24
OMe
N
HN
O
n
OMe
OMe
n
Br
30: n = 1, 55%
31: n = 2, 49%
32: n = 1, 62%
33: n = 2, 41%
Scheme 5 Preparation of starting materials for the study of the intramolecular Buchwald–Hartwig coupling through tautomeric enamines
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

1380
Z. Vincze et al.
FEATURE ARTICLE
the alternate routes utilizing the appropriate acid chlorides As the presented data show, the ring-closing reactions of
were less successful. The Bischler–Napieralsky-type ring 32, leading to the formation of the indolobenzazepine sys-
closure of the amides in acetonitrile gave the appropriate- tem, proceeded with varying efficiency. The results are in
ly substituted benzazepine derivatives 32 and 33.
good agreement with those obtained for the ring closure of
13. Dppf was in general less effective than the N-hetero-
cyclic carbene ligands, the latter giving good yields in cer-
tain cases. The bases tested gave similar results for dppf,
while for NHCs the use of sodium tert-butoxide gave su-
perior results. The increase of the catalyst loading had a
negligible effect on the yield, while its decrease led to di-
minished yields. Under the optimized conditions we were
able to convert 32 to the desired tetracycle 35 in 85%
yield.
The palladium-catalyzed ring-closing reactions of 27, 32
and 33 (Scheme 6) were carried out under inert conditions
using 8 mol% Pd in the form of Pd2(dba)3, 16 mol% ligand
and 1.4 equivalents of base (or 2.4 equivalents if the imine
hydrochloride salt was used as starting material). Results
of the ring-closure experiments are summarized in
Table 2.
MeO
MeO
MeO
MeO
Pd source
n
OMe
n
Following the successful preparation of the dibenzopyrro-
coline 15 and indolobenzazepine 35 systems through the
Buchwald–Hartwig coupling of their enamine tautomeric
forms, attempts were made at extending this methodology
to transformations that incorporate the formation of a six-
membered ring. Both 27 and 33 were subjected to a series
of such conditions that had previously initiated ring clo-
sure. To our disappointment, we were unable to achieve
any ring closure, even on prolonged heating at elevated
temperatures (Table 2). We were able to recover most of
the starting material from these reactions, which suggests
that, in spite of the likely formation of the arylpalladium
complexes, the ring closure does not take place. A proba-
ble explanation of this seemingly surprising fact might
arise on the closer observation of the proposed intermedi-
ates in these transformations (Figure 2). In the course of
the observed ring closure of 13 to 15 following the oxida-
tive addition of the palladium into the carbon–bromine
bond, tautomerization and intramolecular ligand ex-
change produces a six-membered palladacycle 37, from
which reductive elimination is expected to furnish the
dibenzopyrrocoline core. The analogous transformation
of 27 should proceed via the formation of a seven-mem-
bered palladacycle 38, which is less likely due to the size
of the formed ring. Another factor facilitating the forma-
tion of 37, and not being present in 38, is the fact that in
the former case the migration of the double bond from the
dihydroisoquinoline fragment to the exocyclic position
results in extended conjugation.
ligand
base
N
OMe
OMe
N
OMe
m
m
Br
n = 1 m = 1 27
n = 2 m = 0 32
n = 2 m = 1 33
n = 1 m = 1 34
n = 2 m = 0 35
n = 2 m = 1 36
Scheme 6 Study of the intramolecular Buchwald–Hartwig coupling
through the tautomeric enamine forms
Table 2 Efficiency of the Palladium-Catalyzed Ring-Closure/Dou-
ble-Bond-Migration Process under Different Conditions
Starting material Ligand
Base
Solvent
dioxane
DME
Yield (%)a
32
dppf
dppf
dppf
dppf
IMes
IPr
Cs2CO3
Cs2CO3
Cs2CO3
32
33
55
50
67
65
68
61
85
40
32
32
toluene
32
t-BuONa toluene
t-BuONa toluene
t-BuONa DME
t-BuONa DME
t-BuONa dioxane
t-BuONa toluene
32
32
32
SIPr
SIPr
SIPr
SIPr
dppf
dppf
IPr
32
32
32
Cs2CO3
Cs2CO3
toluene
toluene
b
27 or 33
27 or 33
27 or 33
27 or 33
27 or 33
27 or 33
27 or 33
27 or 33
27 or 33
–
b
t-BuONa toluene
t-BuONa toluene
–
MeO
MeO
MeO
MeO
L
L
b
–
N
N
Pd S
Pd S
b
IPr
Cs2CO3
toluene
–
OMe
OMe
37
38
b
OMe
SIPr
SIPr
SIPr
SIPr
SIPr
t-BuONa toluene
–
OMe
b
Cs2CO3
Cs2CO3
Cs2CO3
DME
–
Figure 2 Proposed intermediates in the ring-closing reaction
b
DME
–
b
We also tried to initiate the formation of 37 like interme-
diates through the directed palladation of bromine-free
analogues of 27, but these attempts remained in vain.
toluene
–
b
t-BuONa dioxane
–
a Isolated yields. Reactions were run in the presence of Pd [8 mol% as
Pd2(dba)3], 16 mol% ligand (16 mol%) and base (1.4 equiv) at 80 °C
until completion.
b Starting material was recovered.
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

FEATURE ARTICLE
Summary
Palladium-Catalyzed Synthesis of Condensed Heterocycles
1381
to cool to r.t. and was diluted with H2O (200 mL). The solution was
washed with toluene (2 × 100 mL) and the orange colored aqueous
phase was acidified with 10% aq HCl (ca. 50 mL). The precipitated
crystals were collected, washed with H2O and recrystallized from
EtOH to afford 7 as white crystals (12.4 g, 71%).
We studied the use of the Buchwald–Hartwig coupling in
the formation of the dibenzopyrrocoline core and estab-
lished that the coupling of cyclic enamines, formed in a
tautomeric equilibrium, can be utilized to furnish the in-
dolo[2,1-a]dihydroisoquinoline skeleton. This approach
was successfully exploited in the preparation of rac-
mangochinine. Attempts at extending this new ring-clo-
sure protocol to other systems were only partially success-
ful. Transformations resulting in the formation of a five-
membered ring worked efficiently, while the analogous
closure of six-membered rings did not take place at all.
This striking difference in reactivity was attributed to the
different characteristics of the intermediate palladium
complexes.
7
Mp 142–143 °C (Lit.25b mp 145 °C).
1H NMR (250 MHz, CDCl3 + DMSO-d6): d = 3.08 (s, 2 H), 3.63 (s,
3 H), 4.60 (s, 2 H), 6.50 (s, 1 H), 6.58 (s, 1 H), 6.98–6.80 (m, 5 H),
7.25–7.30 (br s, 1 H).
13C NMR (62.5 MHz, CDCl3 + DMSO-d6): d = 42.4, 56.2, 71.0,
115.4, 116.0, 116.7, 127.4, 127.7, 128.0, 128.5, 136.6, 147.5, 149.2,
172.2.
2-(4¢-Hydroxy-3¢-methoxyphenyl)ethylamine (8)
A solution of 17 (3.88 g, 0.031 mol) in 10% NH3/EtOH (40 mL) was
reduced under 10 atm H2 pressure in the presence of Ra-Ni catalyst
(5%) at 70 °C. After the uptake of H2 had stopped, the hot suspen-
sion was filtered, and the catalyst was washed with EtOH (3 × 20
mL). The combined organic phases were concentrated to 40 mL,
left to stand overnight and the precipitated white crystals were col-
lected (3.88 g, 75%); mp 153–154 °C (Lit.23 mp 156–158 °C).
Unless otherwise indicated, all starting materials were obtained
from commercial suppliers (Aldrich, Fisher, Merck) and were used
without further purification. Analytical TLC was performed on
Polygram SIL G/UV 254 pre-coated plastic TLC plates with 0.25
mm silica gel from Macherey-Nagel. Silica gel column chromato-
graphy was carried out with Flash silica gel (0.040–0.063 mm) from
Merck. When using hexane–EtOAc mixtures for separation, the
column was prepared by using hexane and the chromatography was
carried out by increasing the EtOAc content of the eluent gradually.
Melting points were determined using a Büchi melting point appa-
1H NMR (250 MHz, CDCl3 + DMSO-d6): d = 1.19 (br s, 2 H), 2.56
(t, J = 6.3 Hz, 2 H), 2.81 (t, J = 6.3 Hz, 2 H), 3.70 (s, 3 H), 6.55 (dd,
J1 = 6.0 Hz, J2 = 1.8 Hz, 1 H), 6.58 (d, J = 1.8 Hz, 1 H), 6.60 (d,
J = 6.0 Hz, 1 H), 9.01 (br s, 1 H).
13C NMR (62.5 MHz, CDCl3 + DMSO-d6): d = 39.9, 44.0, 56.1,
111.5, 112.3, 121.0, 132.7, 143.6, 147.1.
1
ratus. The H and 13C NMR spectra were recorded on a Bruker
DRX-250 spectrometer in CDCl3 or DMSO-d6. Chemical shifts (d)
are expressed in parts per million using residual solvent protons as
internal standards: CHCl3 (d = 7.26 for 1H, d = 77 for 13C), DMSO
(d = 2.50 for 1H, d = 39.43 for 13C). Coupling constants (J) are re-
ported in Hertz (Hz). Melting points were determined on a hot plate
and are uncorrected. The IR spectra were obtained on a Bruker IFS-
55 FTIR spectrometer.
2-(2-Bromo-4,5-dimethoxyphenyl)-N-(3¢,4¢-dimethoxyphenyl-
ethyl)acetamide (12)
2-Bromo-4,5-dimethoxyphenylacetic acid (10; 5.00 g, 18.2 mmol)
was dissolved in SOCl2 (25 mL) and refluxed for 1 h. Following the
addition of toluene the excess SOCl2 was removed by azeotropic
distillation under reduced pressure. The resulting acid chloride was
dissolved in anhyd Et2O (50 mL) and added dropwise to a vigorous-
ly stirred mixture of 11 (3.42 g, 18.9 mmol) in Et2O (150 mL) and
5% aq Na2CO3 solution (150 mL) at 0–5 °C. The mixture was al-
lowed to warm to r.t. and stirred for an additional 6 h. The precipi-
tated white solid was filtered and dissolved in CH2Cl2 (50 mL). The
organic phase was washed with 10% aq NaOH solution (2 × 20 mL)
and 10% aq HCl (2 × 20 mL). The organic phase was dried
(MgSO4), filtered and the solvent was evaporated under reduce
pressure to yield white crystals (6.38 g, 80%); mp 158–159 °C (Lit.6
mp 158–159).
The following compounds were prepared according to literature
procedures: 2-bromo-4,5-dimethoxyphenylacetic acid (10),19 2-
(3¢,4¢-dimethoxyphenyl)ethylamine (11),25 4-hydroxy-3-methoxy-
phenylacetonitrile (17),23 2-bromo-5-hydroxy-4-methoxyphenyl-
acetonitrile (19)23 2-cyano-3-(3,4-dimethoxyphenyl)propionic acid
(28),26 and 3-(3¢,4¢-dimethoxyphenyl)propylamine (29).27
5-Benzyloxy-2-bromo-4-methoxyphenylacetic Acid (7)
Benzyl chloride (5.08 g, 0.040 mol) and K2CO3 (6.64 g, 0.048 mol)
were added to the suspension of 2-bromo-5-hydroxy-4-methoxy-
phenylacetonitrile (19; 10.00 g, 0.040 mol) in EtOH (200 mL). The
mixture was refluxed for 5 h, then the solvent was evaporated and
the solid residue was triturated with CH2Cl2 (100 mL). The organic
phase was washed with H2O (2 × 80 mL), dried (MgSO4) and re-
moval of the solvent under reduced pressure gave an off-white sol-
id, which was recrystallized from EtOH to yield 5-benzyloxy-2-
bromo-4-methoxyphenylacetonitrile as white crystals (11.42 g,
86%); mp 94–95 °C (Lit.28 mp 94–95 °C).
IR (KBr): 3300, 1645, 1593, 1492 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.55 (t, J = 7.0 Hz, 2 H), 3.34 (dt,
J1 = 7.0 Hz, J2 = 6.0 Hz, 2 H), 3.50 (s, 2 H), 3.74 (s, 3 H), 3.76 (s,
3 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 5.80–5.90 (br, 1 H), 6.58 (dd,
J1 = 8.0 Hz, J2 = 2.0 Hz, 1 H), 6.62 (d, J = 2.0 Hz, 1 H), 6.65 (d,
J = 8.0 Hz, 1 H), 6.78 (s, 1 H), 6.89 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 32.5, 35.1, 40.7, 56.2, 56.3, 56.5,
56.6, 111.5, 112.0, 114.1, 115.1, 115.9, 120.5, 127.1, 134.3, 147.6,
149.1, 149.2, 149.3, 170.2.
5-Benzyloxy-2-bromo-4-methoxyphenylacetonitrile
1H NMR (250 MHz, CDCl3 + DMSO-d6): d = 3.08 (s, 2 H), 3.63 (s,
3 H), 4.60 (s, 2 H), 6.50 (s, 1 H), 6.58 (s, 1 H), 6.98–6.80 (m, 5 H).
Bischler–Napieralski Ring-Closure Reaction; 1-(2¢-Bromo-
4¢,5¢-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline
(13); Typical Procedure
Freshly distilled POCl3 (3.64 mL, 6.00 g, 39.2 mmol) was added to
a solution of 13 (7.89 g, 18 mmol) in MeCN (150 mL) and the mix-
ture was refluxed for 4 h. The excess of POCl3 and the solvent were
removed under reduced pressure to yield a red oil. The residue was
crystallized from Et2O to give an orange solid. Conc. NH4OH (30
mL) was added to the filtered solid and the mixture was extracted
13C NMR (62.5 MHz, CDCl3 + DMSO-d6): d = 24.1, 56.3, 70.8,
112.0, 115.2, 117.8, 117.9, 127.3, 127.7, 128.0, 128.5, 136.5, 147.5,
148.9.
A mixture of 5-benzyloxy-2-bromo-4-methoxyphenylacetonitrile
(16.60 g, 0.050 mol) and NaOH (8.00 g, 0.200 mol) in H2O (40 mL)
and EtOH (40 mL) was refluxed for 5 h. The mixture was allowed
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

1382
Z. Vincze et al.
FEATURE ARTICLE
with CH2Cl2 (3 × 25 mL). The combined organic phases were
washed with H2O (20 mL), dried (MgSO4), and the solvent was
evaporated under reduce pressure to yield a pale-yellow oil, which
crystallized to a pale-yellow solid from isopropyl ether. If necessary
the product was further purified by column chromatography on sil-
ica gel using hexane–Et2O as eluent. Pale-yellow crystals; yield:
5.74 g (76%); mp (as HCl salt) 228–230 °C (Lit.6 mp 232 °C).
ed via syringe and the mixture was heated at 80 °C under argon until
consumption of the starting material. The solution was allowed to
cool to r.t. and the solvent was removed under reduced pressure.
The residue was dissolved in CH2Cl2 (4 mL) and the organic layer
was washed with H2O (2 × 5 mL), and dried (MgSO4). Following
the removal of the solvent under reduced pressure the mixture was
purified by column chromatography on silica gel using hexane–
EtOAc as eluent to give 16 as white crystals (40 mg, 51%); mp 104–
105 °C (Lit.11 mp 105–107 °C).
1H NMR (250 MHz, CDCl3): d = 2.36 (m, 1 H), 2.95 (m, 2 H), 3.24
(m, 1 H), 3.40 (m, 1 H), 3.78 (m, 13 H) 4.74 (d, J = 7.5 Hz, 1 H),
6.24 (s, 1 H), 6.40 (s, 1 H), 6.63 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = 40.7, 43.5, 55.9, 56.1, 56.5, 56.9,
98.4, 110.7, 112.3, 114.5, 114.8, 115.7, 118.8, 126.7, 129.2, 130.0,
146.2, 146.8, 147.3, 147.6.
IR (KBr): 2941, 2635, 1645, 1624, 1608, 1508 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.65 (t, J = 8.3 Hz, 2 H), 3.66 (t,
J = 8.3 Hz, 2 H), 3.84 (s, 3 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 3.90 (s,
3 H), 3.97 (s, 2 H), 6.84 (s, 1 H), 7.01 (s, 1 H), 7.03 (s, 1 H), 7.26
(s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 25.6, 38.3, 41,5, 56.5, 56.6, 56.8,
56.9, 111.3, 112.5, 113.5, 114.2, 116.1, 117.4, 125.5, 134.2, 148.9,
149.7, 149.9, 156.7, 174.8.
2-(5-Benzyloxy-2-bromo-4-methoxyphenyl)-N-(4¢-benzyloxy-
3¢-methoxyphenylethyl)acetamide (20)
1-(2¢-Bromo-4¢,5¢-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (14)13
A mixture of 7 (7.02 g, 0.02 mol) and 8 (3.34 g, 0.02 mol) was heat-
ed to 180 °C and the melt was stirred at the same temperature for
3 h. After cooling to r.t. and dilution with CH2Cl2 (50 mL), the or-
ganic layer was washed successively with 10% aq NaOH (2 × 15
mL), 10% aq HCl (2 × 15 mL) and H2O (15 mL). The organic phase
was dried (MgSO4), and the solvent was removed under reduced
pressure to give N-(4¢-benzyloxy-3¢-methoxyphenylethyl)-2-(2-
bromo-5-hydroxy-4-methoxyphenyl)acetamide as an off-white sol-
id, which was recrystallized from a mixture of MeOH–Et2O to give
white crystals (10.02 g, 61%).
To a solution of 13·HCl (0.20 g, 0.44 mmol) in MeOH (4 mL), was
added NaBH4 (0.017 g, 0.44 mmol) in small portions at r.t. under ar-
gon. The mixture was stirred for 7 h. After removal of the MeOH
under reduced pressure, the residue was treated with aq NH4Cl (4
mL) and extracted with CH2Cl2 (3 × 5 mL). The combined organic
phases were dried (MgSO4), and the solvent was removed under re-
duced pressure. The crude product was purified by column chroma-
tography on silica gel using hexane–EtOAc as eluent to give 14 as
a yellow oil (0.148 g, 73%).
1H NMR (250 MHz, CDCl3): d = 2.80 (m, 2 H), 2.91 (m, 2 H), 3.23
(m, 2 H), 3.72 (s, 3 H), 3.78 (t, J = 5.7 Hz, 9 H), 4.25 (m, 1 H), 6.55
(d, J = 6.1 Hz, 2 H), 6.74 (s, 1 H), 6.98 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 40.3, 42.4, 55.1, 55.8, 55.9, 56.1,
56.2, 109.7, 111.7, 114.5, 114.8, 115.7, 118.8, 126.7, 129.2, 130.0,
147.2, 147.8, 148.3, 148.4.
N-(4¢-Benzyloxy-3¢-methoxyphenylethyl)-2-(2-bromo-5-
hydroxy-4-methoxyphenyl)acetamide
Mp 143–144 °C.
IR (KBr): 3293, 1620, 1526, 1507, 1262, 1220 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.57 (t, J = 7.0 Hz, 2 H), 3.33 (dt,
J1 = 7.0 Hz, J2 = 6.0 Hz, 2 H), 3.46 (s, 2 H), 3.77 (s, 3 H), 3.80 (s,
3 H), 5.01 (s, 2 H), 5.27–5.35 (br, 1 H), 5.52–5.65 (br, 1 H), 6.42
(dd, J1 = 7.9 Hz, J2 = 1.7 Hz, 1 H), 6.53 (d, J = 1.7 Hz, 1 H), 6.69
(d, J = 7.9 Hz, 1 H), 6.73 (s, 1 H), 6.93 (s, 1 H), 7.22–7.36 (m, 5 H).
Palladium-Catalyzed Ring Closure Reaction; 2,3,9,10-Tetra-
methoxy-5,6-dihydroindolo[2,1-a]isoquinoline (15); Typical
Procedure
A Schlenk tube was charged with the cyclic imine 13 (336 mg, 0.80
mmol), t-BuONa (108 mg, 1.12 mmol), ligand (0.128 mmol, 16
mol%), Pd2(dba)3 (29 mg, 8 mol% Pd), and flushed with argon. Fol-
lowing the addition of anhyd toluene (4 mL) via syringe the mixture
was heated under argon at 80 °C until consumption of the starting
material. The solution was allowed to cool to r.t. and the solvent was
removed under reduced pressure. The residue was dissolved in
CH2Cl2 (8 mL) and the organic layer was washed with H2O (2 × 5
mL), dried (MgSO4), and the solvent was removed under reduced
pressure to give an off-white solid, which was purified by column
chromatography on silica gel using hexane–EtOAc as eluent. Pale-
green crystals; yield: 230 mg (85%); mp 205–206 °C (Lit.15 mp
207–208 °C).
13C NMR (62.5 MHz, CDCl3): d = 34.0, 39.8, 42.5, 54.9, 55.2, 68.8,
70.1, 110.0, 113.3, 114.4, 115.0, 115.4, 120.3, 125.3, 126.4, 127.1,
127.6, 129.3, 135.3, 143.2, 145.6, 146.7, 148.7, 168.8.
Anal. Calcd for C25H26BrNO5: C, 60.01; H, 5.24; N, 2.80. Found: C,
59.85; H, 5.20; N, 2.70.
Benzyl chloride (1.27 g, 0.010 mol) and K2CO3 (1.66 g, 0.012 mol)
were added to a suspension of N-(4¢-benzyloxy-3¢-methoxyphenyl-
ethyl)-2-(2-bromo-5-hydroxy-4-methoxyphenyl)acetamide (5.00 g,
0.010 mol) in EtOH (50 mL). The mixture was refluxed for 6 h, then
the solvent was evaporated under reduced pressure and the solid
residue was triturated with CH2Cl2 (30 mL). The organic phase was
washed with H2O (2 × 30 mL), dried (MgSO4) and the solvent was
removed under reduced pressure to give a yellow solid, which was
triturated with Et2O to yield an off-white solid. The product was re-
crystallized from EtOH to yield 20 as white crystals (4.72 g, 80%).
IR (KBr): 1623, 1609, 1547, 1503 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.14 (t, J = 6.9 Hz, 2 H), 3.94 (s,
3 H), 3.96 (s, 3 H), 3.98 (s, 3 H), 3.99 (s, 3 H), 4.19 (t, J = 6.9 Hz,
2 H), 6.67 (s, 1 H), 6.78 (s, 1 H), 6.83 (s, 1 H), 7.10 (s, 1 H), 7.20 (s,
1 H).
20
Mp 130–131 °C.
IR (KBr): 3336, 2934, 1643, 1506, 1259, 1029, 697 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.57 (t, J = 7.1 Hz, 2 H), 3.35 (dt,
J1 = 7.1 Hz, J2 = 5.8 Hz, 2 H), 3.46 (s, 2 H), 3.77 (s, 3 H), 3.78 (s,
3 H), 5.01 (s, 2 H), 5.03 (s, 2 H), 5.27–5.34 (br, 1 H), 6.42 (dd,
J1 = 8.0 Hz, J2 = 1.9 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 6.57 (d,
J = 1.9 Hz, 1 H), 7.22–7.37 (m, 10 H), 6.92 (s, 1 H), 6.74 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 29.1, 40.7, 55.9, 56.1, 56.5, 56.6,
92.4, 98.4, 102.3, 111.8, 112.3, 120.6, 125.9, 130.4, 134.0, 140.2,
145.2, 146.8, 147.7, 148.8.
2,3,9,10-Tetramethoxy-5,6,12,12a-tetrahydroindolo[2,1-a]iso-
quinoline (16)
A Schlenk tube was charged with 14 (0.100 g, 0.23 mmol), Cs2CO3
(0.149 g, 0.46 mmol), SIPr (2.1 mg, 2 mol%), Pd2(dba)3, (4.2 mg,
2 mol% Pd) and flushed with argon. Anhyd DMA (2 mL) was add-
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

FEATURE ARTICLE
Palladium-Catalyzed Synthesis of Condensed Heterocycles
IR (KBr): 1606, 1570, 1508, 1348 cm–1.
1383
13C NMR (62.5 MHz, CDCl3): d = 35.4, 41.0, 43.9, 56.3, 56.6, 71.5,
112.7, 114.5, 115.8, 116.4, 116.7, 120.9, 126.8, 127.6, 127.8, 128.2,
128.5, 128.9, 129.0, 132.0, 136.7, 137.6, 147.2, 148.1, 150.0, 170.1.
1H NMR (250 MHz, CDCl3): d = 3.04–2.84 (m, 2 H), 3.30–3.15 (m,
2 H), 3.61–3.52 (m, 1 H), 3.72–3.66 (m, 1 H), 3.74 (s, 3 H), 3.78 (s,
3 H), 4.67–4.64 (m, 1 H), 4.90 (s, 2 H), 5.04 (s, 2 H), 6.21 (s, 1 H),
6.43 (s, 1 H), 6.57 (s, l H), 6.60 (s, 1 H), 7.44–7.23 (m, 10 H).
Anal. Calcd for C32H32BrNO5: C, 65.09; H, 5.46; N, 2.37; Found: C,
64.89; H, 5.35; N, 2.40.
13C NMR (62.5 MHz, CDCl3): d = 32.0, 37.2, 43.1, 56.4, 57.0, 63.3,
95.1, 71.9, 71.8, 112.6, 112.8, 114.9, 120.9, 127.8, 127.8, 128.1,
128.2, 128.7, 128.9, 131.4, 137.6, 138.5, 127.9, 141.6, 145.9, 147.2,
148.7, 150.6.
7-Benzyloxy-1-(5¢-benzyloxy-2¢-bromo-4¢-methoxybenzyl)-6-
methoxy-3,4-dihydroisoquinoline (21)
The typical procedure described for the synthesis of 13 was applied
to 20 (4.0 g, 6.78 mmol). The crude product was recrystallized from
hexane–EtOAc to give 21 as white crystals (2.95 g, 76%); mp 105–
106 °C.
Anal. Calcd for C32H31NO4: C, 77.87; H, 6.33; N, 2.84. Found: C,
78.01; H, 6.52; N, 2.50.
IR (KBr): 1622, 1602, 1569, 1509, 1507, 1504, 1464 cm–1.
2,10-Dihydroxy-3,9-dimethoxy-7-methyl-5,6,12,12a-tetrahydro-
indolo[2,1-a]isoquinolinium Iodide (5, Mangochinine Iodide)
MeI (2 mL, 4.56 g, 32 mmol) was added to a solution of 23 (394 mg,
0.80 mmol) in MeOH (4 mL). Upon standing for 1 day 2,10-di(ben-
zyloxy)-3,9-dimethoxy-7-methyl-5,6,12,12a-tetrahydroindolo[2,1-
a]isoquinolinium iodide crystallized as white needles. The product
was recrystallized from H2O–EtOH to yield gray-white crystals
(477 mg, 94%).
1H NMR (250 MHz, CDCl3): d = 2.52 (t, J = 7.6 Hz, 2 H), 3.64 (t,
J = 7.6 Hz, 2 H), 3.84 (s, 3 H), 3.89 (s, 3 H), 3,97 (s, 2 H), 5.00 (s,
2 H), 5.04 (s, 2 H), 6.64 (s, 1 H), 6.75 (s, 1 H), 6.94 (s, 1 H), 7.03 (s,
1 H), 7.26–7.35 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = 26.1, 42.5, 47.7, 56.4, 56.6, 71.0,
71.5, 110.9, 112.2, 115.0, 115.2, 116.1, 121.4, 121.6, 127.8, 128.1,
128.3, 128.8, 128.9, 129.8, 132.3, 137.0, 137.2, 146.8, 147.9, 149.2,
151.8, 165.6.
2,10-Di(benzyloxy)-3,9-dimethoxy-7-methyl-5,6,12,12a-
tetrahydroindolo[2,1-a]isoquinolinium Iodide
Mp 240–242 °C.
Anal. Calcd for C32H30BrNO4: C, 67.14; H, 5.28; N, 2.45. Found: C,
66.99; H, 5.39; N, 2.38.
IR (KBr): 1620, 1545, 1507, 1484, 1447, 1351, 1253 cm–1
2,10-Di(benzyloxy)-3,9-dimethoxy-5,6-dihydroindolo[2,1-a]iso-
quinoline (22)
1H NMR (250 MHz, DMSO-d6): d = 2.82–2.89 (m, 1 H), 3.04–3.09
(m, 1 H), 3.10–3.15 (m, 1 H), 3.45 (s, 3 H), 3.52–3.55 (m, 1 H),
3.56–3.60 (m, 1 H), 3.70 (s, 3 H), 3.80 (s, 3 H), 3.80–3.85 (m, 1 H),
5.02 (s, 2 H), 5.04 (s, 2 H), 5.25 (m, 1 H), 6.85 (s,1 H), 7.05 (s, 1 H),
7.15 (s, 1 H), 7.28–7.37 (m, 10 H), 7.53 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 28.3, 35.2, 49.8, 56.0, 56.3, 57.1,
70.4, 71.1, 74.2, 105.2, 109.4, 111.9, 112.6, 121.4, 124.9, 128.1,
128.2, 128.3, 128.7, 128.8, 128.9, 131.7, 134.5, 137.0, 143.8, 147.2,
147.6, 148.7, 150.6.
A Schlenk tube was charged with 21 (2.00 mmol), t-BuONa (270
mg 2.80 mmol), ligand SIPr (136 mg, 0.32 mmol, 16 mol%),
Pd2(dba)3 (72 mg, 8 mol% Pd) and flushed with argon. Anhyd tolu-
ene (10 mL) was added via syringe and the mixture was heated at
80 °C under argon for 6 h. The solution was allowed to cool to r.t.
and the solvent was removed under reduced pressure. The residue
was dissolved in CH2Cl2 (20 mL), the organic layer was washed
with H2O (2 × 10 mL) and dried (MgSO4). The solvent was re-
moved under reduced pressure to give a yellow solid, which was pu-
rified by column chromatography on silica gel using hexane–
EtOAc as eluent to give 22 as off-white crystals (884 mg, 89%); mp
117–118 °C.
Anal. Calcd for C33H34INO4: C, 62.37; H, 5.39; N, 2.20. Found: C,
62.21; H, 5.35; N, 2.20.
5
IR (KBr): 1608, 1547, 1498, 1481, 1348, 1250, 1215, 1121 cm–1.
Concd HCl (5 mL) was added to a suspension of 2,10-di(benzyl-
oxy)-3,9-dimethoxy-7-methyl-5,6,12,12a-tetrahydroindolo[2,1-a]-
isoquinolinium iodide (317.5 mg, 0.5 mmol) in benzene (3 mL) and
the mixture was refluxed for 3 h. The mixture was allowed to cool
to r.t. and the precipitated crystals were filtered. The crystals were
taken up in 95% EtOH (5 mL), and KI (150 mg, 0.90 mmol) was
added. After the mixture was warmed to 75 °C, the solution was fil-
tered and the filtrate was evaporated to dryness. Recrystallization
from EtOH afforded 5 as white solid (168 mg, 75%); mp 262–
263 °C.
1H NMR (250 MHz, CDCl3): d = 3.10 (t, J = 6.5 Hz, 2 H), 3.92 (s,
3 H), 3.97 (s, 3 H), 4.14 (t, J = 6.5 Hz, 2 H), 5.20 (s, 2 H), 5.21 (s,
2 H), 6.49 (s, 1 H), 6.76 (s, 1 H), 6.82 (s, 1 H), 7.09 (s, 1 H), 7.20 (s,
1 H), 7.52–7.31 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = 29.2, 40.8, 56.9, 56.5, 71.7, 72.4,
93.3, 95.2, 106.2, 110.6, 112.1, 122.0, 122.3, 125.1, 127.8, 127.8,
128.0, 128.4, 128.9, 129.0, 132.0, 135.0, 137.5, 138.2, 144.5, 147.8,
147.9, 149.3.
Anal. Calcd for C32H29NO4: C, 78.19; H, 5.95; N, 2.85. Found: C,
78.33; H, 6.07; N, 2.71.
IR (KBr): 3200, 1607, 1510, 1464, 1225, 1020 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.75–2.83 (m, 1 H), 2.93–3.03
(m, 1 H), 3.07–3.13 (m, 1 H), 3.45 (s, 3 H), 3.52–3.56 (m, 1 H),
3.56–3.59 (m, 1 H), 3.64 (s, 3 H), 3.72 (s, 3 H), 3.75–3.82 (m, 1 H),
5.17 (dd, J1 = 7.8 Hz, J2 = 9.6 Hz, 1 H), 6.60 (s,1 H), 6.74 (s, 1 H),
6.72 (s, 1 H), 7.43 (s, 1 H), 9.17 (s, 1 H), 9.72 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 23.5, 35.9, 49.3, 55.7, 56.5, 57.7,
74.1, 102.1, 111.7, 111.8, 113.1, 119.6, 122.3, 124.5, 137.7, 146.0,
147.6, 148.2, 148.8.
2,10-Dibenzyloxy-3,9-dimethoxy-5,6,12,12a-tetrahydroindolo-
[2,1-a]isoquinoline (23)
NaBH3CN (315 mg, 5 mmol) was added in small portions at 0 °C to
a solution of 22 (490 mg, 1 mmol) in AcOH (4 mL). The mixture
was stirred for 1 h at r.t., then it was cooled to 0 °C, and H2O (4 mL)
was added dropwise to the mixture. After the gas evolution had
stopped, the mixture was extracted with CH2Cl2 (2 × 10 mL) and
the combined organic phases were washed with aq 2 M NaOH so-
lution (2 × 15 mL), H2O (10 mL), and dried (MgSO4). Removal of
the solvent under reduced pressure gave a yellow solid, which was
triturated with Et2O. The product was filtered and recrystallized
from hexane–EtOAc to give 23 as white crystals (568 mg, 95%); mp
163–165 °C.
Anal. Calcd for C19H22INO4: C, 50.12; H, 4.87; N, 3.08. Found: C,
49.89; H, 4.68; N, 3.05.
3-(2¢-Bromo-4¢,5¢-dimethoxyphenyl)propionic Acid (24)
Br2 (3.48 g, 21.8 mmol) was added slowly to a solution of 3-(4¢,5¢-
dimethoxyphenyl)propionic acid (4.58 g, 21.8 mmol) in glacial
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

1384
Z. Vincze et al.
FEATURE ARTICLE
AcOH (45 mL) at 0 °C. After the addition was complete, the mix-
ture was stirred at r.t. for 3 h. The mixture was poured onto crushed
ice to give white crystals. The precipitated product was filtered,
washed with H2O and dried (6.90 g, 80%); mp 119–121 °C (Lit.29
mp 120–123 °C).
1H NMR (250 MHz, CDCl3): d = 2.67 (t, J = 7.8 Hz, 2 H), 2.99 (t,
J = 7.4 Hz, 2 H), 3.82 (s, 3 H), 3.84 (s, 3 H), 6.77 (s, 1 H), 6.99 (s,
1 H).
3-(2¢-Bromo-4¢,5¢-dimethoxyphenyl)-N-[3-(3¢,4¢-dimethoxy-
phenyl)propyl]propionamide (31)
The same procedure was followed as the opening step in the prepa-
ration of 20. Starting from 3-(3¢,4¢-dimethoxyphenyl)propylamine
(29; 3.91 g, 0.02 mol) and 2-bromo-4,5-dimethoxyphenylacetic
acid (11; 5.50 g, 0.02 mol), white crystals were obtained (4.57 g,
49%); mp 107–109 °C (Lit.14 mp 108–110 °C).
IR (KBr): 3279, 3080, 2939, 2836, 1646, 1510 cm–1.
13C NMR (62.5 MHz, CDCl3): d = 30.8, 34.1, 56.0, 56.1, 113.1,
1H NMR (250 MHz, CDCl3): d = 1.68 (m, 2 H), 2.34 (t, J = 7.3 Hz,
2 H), 2.45 (t, J = 7.9 Hz, 2 H), 2.92 (t, J = 7.9 Hz, 2 H), 3.17 (dt,
J1 = 7.4 Hz, J2 = 6.3 Hz, 2 H) 3.74 (s, 3 H), 3.75 (s, 3 H), 3.77 (s, 3
H), 3.79 (s, 3 H), 5.37–5.48 (br, 1 H), 6.59 (dd, J1 = 7.9 Hz, J2 = 2.0
Hz, 1 H), 6.62 (d, J = 2.0 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H), 6.90
(s, 1 H), 7.20 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 31.7, 32.3, 33.1, 37.3, 39.6, 56.2,
56.3, 56.4, 56.5, 111.6, 111.9, 113.7, 114.1, 115.8, 120.4, 132.4,
134.3, 147.6, 148.4, 148.7, 149.2, 172.2.
113.9, 115.5, 131.2, 148.2, 148.3, 179.0.
3-(2¢-Bromo-4¢,5¢-dimethoxyphenyl)-N-[2-(3¢,4¢-dimethoxy-
phenyl)ethyl]propionamide (26)24
The same procedure was followed as in the opening step in the prep-
aration of 20 starting from 3,4-dimethoxyphenethylamine (25;
3.42 g, 18.2 mmol) and 3-(2¢-bromo-4¢,5¢-dimethoxyphenyl)propi-
onic acid (24; 5.46 g, 18.2 mmol). The crude product was recrystal-
lized from EtOH to yield 26 as white crystals (7.00 g, 85%); mp
123–125 °C (Lit.24 mp 123–125 °C).
1-(2¢-Bromo-4¢,5¢-dimethoxybenzyl)-7,8-dimethoxy-4,5-
dihydro-3H-benzo[c]azepine (32)
IR (KBr): 3303, 2936, 2833, 1634, 1512 cm–1.
Prepared according to the typical procedure described for the prep-
aration of 13. Starting from 30 (8.14 g, 18 mmol), the product 32
was obtained as pale-yellow crystals (4.84 g, 62%); mp (as HCl salt)
182–184 °C (Lit.13 mp 180–182 °C).
1H NMR (250 MHz, CDCl3): d = 2.45 (t, J = 7.5 Hz, 2 H), 2.60 (t,
J = 7.0 Hz, 2 H), 2.99 (t, J = 7.5 Hz, 2 H), 3.36 (dt, J1 = 7.0 Hz,
J2 = 6.0 Hz, 2 H), 3.74 (s, 3 H), 3.76 (s, 3 H), 3.78 (s, 3 H), 3.81 (s,
3 H), 5.84–5.94 (br, 1 H), 6.57 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1 H),
6.63 (d, J = 2.0 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 6.90 (s, 1 H),
7.20 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 27.6, 35.0, 37,8, 40.7, 56.2, 56.3,
56.4, 56.5, 111.6, 111.9, 113.7, 114.0, 115.8, 120.4, 131.8, 134.3,
147.6, 148.5, 148.8, 149.2, 172.2.
IR (KBr): 2952, 2941, 2858, 2834, 2635, 1638, 1602 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.26 –2.30 (m, 2 H), 2.44–2.58
(m, 4 H), 3.76 (dt, J1 = 6.6 Hz, J2 = 3.0 Hz, 2 H), 3.74 (s, 2 H), 3.79
(s, 3 H), 3.80 (s, 3 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 6.69 (s, 1 H), 6.77
(s, 1 H), 7.21 (s, 1 H), 7.27 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 29.3, 29.4, 42.1, 45.8, 55.5, 55.6,
55.6, 55.7, 113.5, 114.7, 115.7, 121.1, 124.9, 125.5, 128.4, 129.1,
137.0, 147.5, 148.5, 149.3, 153.5.
1-[2-(2¢-Bromo-4¢,5¢-dimethoxyphenyl)ethyl]-6,7-dimethoxy-
3,4-dihydroisoquinoline (27)
Prepared according to the typical procedure described for the prep-
aration of 13. Starting from 26 (8.14 g, 18 mmol) 27 was obtained
as pale-yellow crystals (6.72 g, 86%); mp 94–95 °C (Lit.24 mp 95–
96 °C).
1-[2-(2¢-Bromo-4¢,5¢-dimethoxyphenyl)ethyl]-7,8-dimethoxy-
4,5-dihydro-3H-benzo[c]azepine (33)
Prepared according to the typical procedure described for the prep-
aration of 13. Starting from 31 (8.39 g, 18 mmol), the product 33
was obtained as pale-yellow crystals (3.31 g, 41%); mp (as HCl salt)
175–176 °C (Lit.14 mp 181 °C).
IR (KBr): 3010, 2970, 2910, 2772, 1642, 1605 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.98 (t, J = 8.0 Hz, 2 H), 3.07 (t,
J = 8.0 Hz, 2 H), 3.36–3.44 (m, 2 H), 3.48 (t, J = 8.0 Hz, 2 H), 3.72
(s, 3 H), 3.73 (s, 3 H), 3.80 (s, 3 H), 3.90 (s, 3 H), 6.78 (s, 1 H), 6.82
(s, 1 H), 7.01 (s, 1 H), 7.14 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 29.3, 35.9, 41.9, 45.7, 55.7, 55.8,
56.1, 56.2, 113.4, 113.6, 114.6, 115.7, 115.8, 121.3, 125.2, 136.9,
147.4, 148.5, 149.2, 153.4, 164.8.
IR (KBr): 2930, 2923, 2833, 2625, 1640, 1600 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.34 (m, 4 H), 2.82 (t, J = 7.9 Hz,
2 H), 3.40 (m, 2 H), 3.59 (t, J = 8.1 Hz, 2 H), 3.78 (s, 3 H), 3.80 (s,
3 H), 3.84 (s, 3 H), 3.93 (s, 3 H), 6.31 (s, 1 H), 6.69 (s, 1 H), 6.79 (s,
1 H), 6.89 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 27.9, 29.1, 34.8, 35.0, 44.6, 55.4,
55.7, 55.8, 55.9, 95.8, 110.9, 112.2, 119.1, 121.1, 121.2, 133.2,
136.2, 147.7, 153.4, 156.5, 157.3, 186.5.
2-(2¢-Bromo-4¢,5¢-dimethoxyphenyl)-N-[3-(3¢,4¢-dimethoxy-
phenyl)propyl]acetamide (30)
The same procedure was followed as the opening step in the prepa-
ration of 20. Starting from 3-(3¢,4¢-dimethoxyphenyl)propylamine
(29; 3.91 g, 0.02 mol) and 3-(2¢-bromo-4¢,5¢-dimethoxyphenyl)pro-
pionic acid (24; 6.00 g, 0.02 mol) white crystals were obtained (4.97
g, 55%); mp 127–129 °C (Lit.13 mp 128–130 °C).
2,3,10,11-Tetramethoxy-6,7-dihydro-5H-benz[3,4]azepino-
[1,2-a]indole (35)
Prepared by the typical procedure described for the preparation of
15. Starting from 32 (363 mg, 0.8 mmol), the product 35 was ob-
tained as white crystals (240 mg, 85%); mp 158–160 °C.
IR (KBr): 3281, 3086, 2940, 2836, 1646, 1559 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.66 (m, 2 H), 2.47 (t, J = 7.9 Hz,
2 H), 3.36 (dt, J1 = 7.0 Hz, J2 = 6.0 Hz, 2 H), 3.54 (s, 2 H), 3.74 (s,
3 H), 3.76, (s, 3 H), 3.78, (s, 3 H), 3.81 (s, 3 H), 5.84–5.94 (br, 1 H),
6.57 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1 H), 6.60 (d, J = 2.0 Hz, 1 H),
6.74 (d, J = 8.0 Hz, 1 H), 6.90 (s, 1 H), 7.20 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 31.7, 33.0, 39.5, 44.1, 56.2, 56.3,
56.5, 56.6, 111.5, 111.9, 114.1, 115.1, 115.9, 120.5, 127.07, 134.3,
147.6, 149.1, 149.2, 149.3, 170.2.
IR (KBr): 3093, 2997, 2932, 2834, 1717 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.35–2.23 (m, 2 H), 2.67 (t,
J = 6.6 Hz, 2 H), 3.93 (s, 3 H), 3.94 (s, 3 H), 3.96 (s, 3 H), 3.97 (s,
3 H), 4.03 (t, J = 6.5 Hz, 2 H), 6.48 (s, 1 H), 6.80 (s, 1 H), 6.84 (s,
1 H), 7.06 (s, 1 H), 7.11 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 30.7, 31.1, 41.2, 56.0, 56.1, 56.3,
56.4, 92.5, 98.3, 102.3, 111.8, 112.7, 120.7, 125.9, 130.4, 134.2,
140.5, 144.9, 146.7, 147.7, 148.6.
Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York

FEATURE ARTICLE
Palladium-Catalyzed Synthesis of Condensed Heterocycles
1385
Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C,
71.39; H, 6.48; N, 3.80.
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Acknowledgment
Financial support of the Hungarian Scientific Research Fund (OT-
KA F047125) is gratefully acknowledged.
(18) Cammerer, S. S.; Viciu, M. S.; Stevens, E. D.; Nolan, S. P.
Synlett 2003, 1871.
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Synthesis 2006, No. 8, 1375–1385 © Thieme Stuttgart · New York