Phosphane-free Pd0-catalyzed cycloamination and carbonylation with Pd(OAc)2 and Cu(OAc)2 in the presence of K 2CO3: Preparation of benzocyclic amines and benzolactams

Article abstract of DOI:10.1002/ejoc.201101214

Phosphane-free Pd⁰-catalyzed intramolecular aromatic amination was studied. o-Halophenethylamines and 3-(o-halophenyl)propylamines were found to be transformed into indolines and quinolines in a catalytic system based on Pd(OAc)₂ and Cu(OAc)₂ in the presence of K ₂CO₃. Application of the method to substrates containing isoquinoline rings- the 1-(o-bromobenzyl)-3,4-dihydroisoquinolines 6, the 1-(o-bromobenzyl)-1,2,3,4-tetrahydroisoquinolines 7, and the 1-(o-bromophenethyl)isoquinolines 9- provided the indolo[2,1-a]isoquinoline and dibenzo[a,f]quinolizine ring systems 8 and 10. Extension of the method to β-carbolines (compounds 11, 12, and 17) produced the benz[f]indolo[2,3-a] indolizine-13-ones 15 and the benz[f]indolo[2,3-a]quinolizine 18. The benzo[f]pyrido[3,4-a]indolizine and indolo[f]pyrido[3,4-a]indolizin-12-one ring systems 27 and 31 were built in a similar manner. It was also found that under an atmosphere of CO the same catalytic system produced the corresponding benzolactams, the isoquino[2,1-a][2,7]naphthyridine 34 and the indolo[2,3-a]pyrido[g]quinolizin-8-one 36 [(±)-dihydronauclefine] in good yields. Copyright

Full text of DOI:10.1002/ejoc.201101214

FULL PAPER
DOI: 10.1002/ejoc.201101214
Phosphane-Free Pd0-Catalyzed Cycloamination and Carbonylation with
Pd(OAc)2 and Cu(OAc)2 in the Presence of K2CO3: Preparation of
Benzocyclic Amines and Benzolactams
Rika Harada,[a] Naoto Nishida,[a] Shiho Uchiito,[a] Yu Onozaki,[a] Nobuhito Kurono,[b]
Hisanori Senboku,[c] Tokuda Masao,[a] Takeshi Ohkuma,[b] and Kazuhiko Orito*[a]
Keywords: Nitrogen heterocycles / Cycloamination / Carbonylation / Palladium / Copper
Phosphane-free Pd0-catalyzed intramolecular aromatic amin-
ation was studied. o-Halophenethylamines and 3-(o-halo- (compounds 11, 12, and 17) produced the benz[f]indolo[2,3-
systems 8 and 10. Extension of the method to β-carbolines
phenyl)propylamines were found to be transformed into
indolines and quinolines in a catalytic system based on
Pd(OAc)2 and Cu(OAc)2 in the presence of K2CO3. Applica-
tion of the method to substrates containing isoquinoline
rings – the 1-(o-bromobenzyl)-3,4-dihydroisoquinolines 6,
the 1-(o-bromobenzyl)-1,2,3,4-tetrahydroisoquinolines 7, and
a]indolizine-13-ones 15 and the benz[f]indolo[2,3-a]quinoliz-
ine 18. The benzo[f]pyrido[3,4-a]indolizine and indolo[f]pyr-
ido[3,4-a]indolizin-12-one ring systems 27 and 31 were built
in a similar manner. It was also found that under an atmo-
sphere of CO the same catalytic system produced the corre-
sponding benzolactams, the isoquino[2,1-a][2,7]naphthyrid-
ine 34 and the indolo[2,3-a]pyrido[g]quinolizin-8-one 36
[(Ϯ)-dihydronaucléfine] in good yields.
the 1-(o-bromophenethyl)isoquinolines
9 – provided the
indolo[2,1-a]isoquinoline and dibenzo[a,f]quinolizine ring
clic ring systems. To the best of our knowledge, there is no
report on Pd0-catalyzed cycloamination without the use of
organic ligands, although many Pd-induced heterocyclic
syntheses have been reported.[11,12] It was also examined
whether or not cycloamination under CO would proceed
with carbonylation and provide the corresponding benzo-
lactams.
Introduction
Studies based on Buchwald–Hartwig aryl amination[1,2]
in the presence of homogeneous Pd0 catalysts containing
bulky monodentate or bidentate phosphane (P-P, P-N or P-
O) ligands made efficient preparation of benzocyclic amines
possible.[3,4] Cu, Ni, and Fe catalytic systems containing di-
ols, diamines, or N-heterocyclic carbene (NHC) ligands or
with use of polar solvents were also developed for aryl car-
bon-nitrogen bond formation of this type.[1g,1h,1i,1o,4–8]
Recently we reported a PdII-catalyzed direct aromatic
carbonylation that produced benzolactams from ω-arylalk-
ylamines without the need for phosphane ligands through
Results and Discussion
1. Cycloamination
The effects of bases and solvents on Pd0-catalyzed cyclo-
the use of Pd(OAc)2 (5 mol-%) and Cu(OAc)2 (50 mol-%).[9] amination were first examined in a stirred suspension of a
Here we report another phosphane-free catalytic reaction: substrate [either the 2-iodophenethylamine 1c-I (Table 1) or
an aromatic cycloamination catalyzed by a Pd0 species gen- the
N-(2-bromophenethyl)acetamide 1f-Br,
0.05 m],
erated in situ by addition of K2CO3 to the Pd(OAc)2 and Pd(OAc)2 (5 mol-%), and Cu(OAc)2 (50 mol-%) under Ar.
Cu(OAc)2 catalytic system.[10] The method was applied for As shown in Table 1, K2CO3 and NaOtBu were superior as
the construction of nitrogen-containing tetra- and pentacy- bases. Bu3N worked for the cyclization of the amine 1c-I,
but not for that of the amide 1f-Br. The reactions in sol-
vents other than toluene, such as boiling CH3CN, benzene,
[a] Laboratory of Organic Synthesis, Division of Molecular Chem-
istry, Graduate School of Engineering, Hokkaido University,
Sapporo 060-8628, Japan
and dioxane, resulted in lower levels of conversion of 1c-I.
Use of either Pd(OAc)2 or Cu(OAc)2 individually gave
none of the desired cyclization products. Although
Pd2(dba)3 or Pd(acac)2 in combination with Cu(OAc)2 was
found to be an effective precatalyst,[13] Pd(OAc)2 was pref-
erable, because, like Cu(OAc)2, it does not cause organic
contamination other than AcOH. Use of PPh3 (10 mol-%)
instead of Cu(OAc)2 resulted in only 6% formation of 2c
from 1c-I.
Fax: +81-11-761-5383
E-mail: orito@eng.hokudai.ac.jp
[b] Laboratory of Organic Synthesis, Division of Chemical Process
Engineering, Faculty of Engineering, Hokkaido University,
Sapporo 060-8628, Japan
[c] Laboratory of Organic Reaction, Division of Chemical Process
Engineering, Faculty of Engineering, Hokkaido University,
Sapporo 060-8628, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101214.
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Phosphane-Free Pd0-Catalyzed Reactions
Table 1. Cycloamination of the 2-iodo-N-methylphenethylamine
1c-I and the N-(2-bromophenethyl)acetamide 1f-Br.
Table 2. Preparation of the indolines 2a–h.[a]
Entry Reactant Solvent
Base
(mol-equiv.)
Ratio[a][b] of
1 and 2
1
2
3
4
5
6
7
8
1c-I
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
benzene
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K2CO3 (2.5)
K3PO4 (2.5)
Cs2CO3 (2.5)
NaOtBu (2.0)
KOtBu (2.0)
Bu3N (2.0)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K3PO4 (2.5)
Cs2CO3 (2.5)
KOtBu (2.0)
NaOtBu (2.0)
NaOtBu (3.0)
Bu3N (2.0)
0:10
2:8
7:3
7:3
7:3
1:9
7:3
9:1
4:6
0:10
4:6
9:1
9:1
3:7
0:10
9:1
1c-I
1c-I
1c-I
1c-I
1c-I
1c-I
1c-I
9
1c-I
10
11
12
13
14
15
16
1f-Br
1f-Br
1f-Br
1f-Br
1f-Br
1f-Br
1f-Br
1
[a] Determined by H NMR analysis. [b] The ratio “0:10” denotes
that the reactant 1 was not detected.
On the basis of these results, the preparation of a variety
of indolines – compounds 2a–h (Table 2) – under the
heterogeneous conditions with K2CO3 (5 mol-equiv.) or
[a] Reaction conditions:
Cu(OAc)2 (50 mol-%), K2CO3 (0.5 mmol) or NaOtBu (0.3 mmol),
1 (0.1 mmol), Pd(OAc)2 (5 mol-%),
NaOtBu (3 mol-equiv.) in toluene at reflux was examined. Ar, toluene (2 mL), reflux, 24 h. [b] Yields of 2a or 2b determined
by 1H NMR analysis. [c] Isolated yields of the corresponding
indoles 3a or 3b.
As shown in Entries 1 and 2 (Table 2), the primary amines
1a-Br and 1b-Br, each containing a bromophenyl group,
underwent smooth cyclization, but subsequent oxidation of
the initially formed indolines 2a and 2b took place in situ
Table 3. Preparation of the tetrahydroquinolines 5a and 5b.
and during isolation, ultimately to give the indoles 3a and
3b in 32% and 37% isolated yields. Secondary amines con-
taining a bromo- or iodophenyl group afforded the N-alkyl-
indolines 2c, 2d, and 2e (Entries 3–5). Amides (1f-Br, 1f-I,
1g-Br, 1g-I, 1h) also underwent cycloamination, and the N-
acetylindoline 2f and the N-benzyl-2-inolinones 2g and 2h
were obtained (Entries 6–8). In general, iodides were more
reactive than the corresponding bromides, and a bulky sub-
stituent on the nitrogen atom tended to decrease the effi-
ciency of the cycloamination.
Entry
Reactant
X, R
Product
Yield of 5
1
2
3
4
4a-Br
4a-I
4b-Br
4b-I
Br, H
I, H
Br, Ac
I, Ac
5a
5a
5b
5b
22%
76%
37%
82%
The tetrahydroquinolines 5 (Table 3) were obtained from
the 3-(2-iodophenyl)propylamine 4a-I and its N-acetyl de-
rivative 4b-I in satisfactory yields under the same condi-
tions, as shown in Table 3. Attempts to produce 1-benz-
azepines and benzazetidines have so far been unsuccessful. 3,4-dihydroisoquinolines 6[17] (Scheme 1). Indolo[2,1-a]-
The method was applied to the construction of isoquinolines with a substituent at their 8-position, such as
indolo[2,1-a]isoquinolines, the structural motif of which has 8b, cannot be produced by the benzyne method.[18,19] Cycli-
been found in dibenzopyrrocoline alkaloids[14,15] and re- zation with K2CO3/DMF[19l–19n] or aryl radical cycliza-
lated compounds with antileukemic and antitumor activi- tion[19j] are able to give both types of indolizines from the
ties.[16] Under the same conditions the 1-(2-bromobenzyl)- 3,4-dihydroisoquinoline derivatives but not from the tetra-
tetrahydroisoquinolines 7 (Scheme 1) smoothly cyclized to hydro derivatives. The benzyl ethers 7d and 7e have been
the indolizines 8 (5,6-dihydroindolo[2,1-a]isoquinolines) transformed into the dibenzopyrrocoline alkaloids cryp-
within 2 h in good yields. They were also obtained from the towoline and cryptaustoline.[18a] A homologue of 7c, the 1-
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K. Orito et al.
FULL PAPER
(β-phenethyl)tetrahydroisoquinoline 9, also underwent cy-
cloamination to the quinolizine 10 (7,11b,12,13-tetrahydro-
6H-dibenzo[a,f]quinolizine)[20] in 50% yield by this method.
Scheme 2. Preparation of the indolizines 15a–c and the quinolizine
18.
Scheme 1. Preparation of the indolizines 8a–e and the quinoliz-
ine10.
Napieralski reaction of the N-phenylacetyl derivative of 1-
methyltryptamine, and subjected to cyclization in air to give
the indolizine 20 (Scheme 3). In contrast, the 2-methyl-β-
carboline 21, prepared from N-methyltryptamine, did not
give any cyclization product at the Nb atom (such as 22)
under the conditions and was recovered unchanged. It was
thus found that no cyclization at the Nb atom occurred,
probably due to low nucleophilicity of the Nb atom and
steric repulsion by C8-H, and that a hydrogen atom on the
Nb atom was necessary for oxygenation on the C13-carbon,
as shown in the conversion of 13 into 15 (Scheme 2).
Next, the cyclization of the 1-benzyl-1,2,3,4-tetrahydro-
β-carbolines 12 (Scheme 2) was examined. Treatment of 12a
under Ar afforded the ketone 15a as a main product after
2 h. We assume that the initially formed indolizine 13a was
so air-sensitive that it was soon converted to 15a, probably
through an oxygenation, as illustrated with the peroxide
14a. In fact, when this cyclization was executed in air over
24 h, 15a was formed together with 1-benzoyl-β-carboline
16 in 93:7 ratio and isolated in 69% yield. The byproduct
16 was stable and not transformable into 15a under the con-
ditions.[21] The dimethoxy derivatives 15b and 15c were ob-
tained in 76 and 75% yields, respectively. Identical aerobic
treatment of the 3,4-dihydro-β-carbolines 11a–c, however,
resulted in the formation of almost 1:1 mixtures of 15a–c
(36, 35, and 42% isolated yields) and 1-benzoyl-β-carbol-
ines such as 16 after 24 h. The 1-phenethyl-tetrahydro-β-
carboline 17 (Scheme 2) gave 18 (42%) under the same aer-
obic conditions. A “two-indole-fused pyridine ring system”
as in 13 and 15 has been found in the antimicrobial marine
sponge pigment fascaplysin,[22,23] whereas an “indole-and-
quinoline-fused” pyridine ring system as in 18 has been re-
ported by Takano[24a] and Prasad.[24b]
The nucleophilicities of the two nitrogen atoms in the
β-carboline ring system were compared. The 9-methyl-3,4-
dihydro-β-carboline 19 was prepared through a Bischler– 2-methyl-β-carbolines 21.
Scheme 3. Attempts to cyclize the 9-methyl-β-carboline 19 and the
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Phosphane-Free Pd0-Catalyzed Reactions
The method was extended to the construction of pyr- 2. Carbonylation
idine-fused tetra- and pentacyclic ring systems. The sub-
We were interested in whether this catalytic system would
strates – the 1-(4-pyridylmethyl)dihydroisoquinoline 25
(Scheme 4) and the tetrahydroisoquinoline 26 – were pre-
pared by condensation of phenethylamine with ethyl (3-
bromo-4-pyridyl)acetate (23),[25b,25c] prepared in turn from
4-methylpyridine[25] in boiling xylene and Bischler–Napier-
alski cyclization of the resultant acetamide 24 with
POCl3.[26] Cyclization in the phosphane-free Pd0-catalytic
system under Ar gave the pyridine-fused indolizine 27 both
from 25 and from 26, in 56 and 70% yields, respectively.
work for phosphane-ligated Pd0-catalyzed aromatic carbon-
ylation, first reported by Mori and Ban.[27] Their method
provides benzolactones or benzolactams from ω-(o-halo-
phenyl)alkanols or ω-(o-halophenyl)alkylamines such as the
substrates used in this study. We have previously achieved
the synthesis of 8-oxoberbines by a modification of their
method,[26] but found that some 8-oxoberbines and related
benzolactams happened to have chromatographic Rf = val-
ues fairly close to those of the formed phosphane oxides
such as O=PPh3, which caused difficulties in the isolation
and purification of the desired benzolactams.
In the current catalytic system [Pd(OAc)2-Cu(OAc)2-
K2CO3] under CO, one such substrate, the bromide 7a,
underwent the desired carbonylation in the absence of
phosphane ligands to afford the known benzolactam 2,3-
dimethoxy-8-oxoberbine (33, see Exp. Sect.) easily in 80%
isolated yield, as shown in Scheme 5.
Scheme 5. Preparation of the 8-oxoberbine 33.
The method was further evaluated in carbonylation of
substrates containing indole and/or pyridine rings, leading
to the preparation of two related diaza- and triazabenzolac-
tams, structural motifs of the benzo[a]pyrido[3,4-g]quinoliz-
idine alkaloid analogue (Ϯ)-epi-O-methylalamaridine and
of the indolo[2Ј,3Ј:3,4]pyrido[1,2-b][2,7]naphthyridine alka-
loid (Ϯ)-normalindine. Representatives of the former alka-
loid class, with a benzo[a]pyrido[3,4-g]quinolizine (iso-
quino[2,1-b][2,7]naphthyridine) skeleton, such as alamarid-
ine and alangimarine, were isolated from the Indian medici-
nal plant Alangium lamarckii Thw. by Pakrashi.[28] Several
methods for the synthesis of alamaridine have been re-
ported.[29] Since 1987 alkaloids of the latter class have been
isolated from Strychnos johnsonii and dicussat or
Ophiorrhiza.[30–32] In 1990, S. C. Pakrashi reported the first
synthesis of (Ϯ)-normalindine.[33a] Two syntheses of (–)-
normalindine, one by Fujii starting with l-alanine methyl
ester[33d,33e] and another by Davis using (S)-(+)-sulfinimine
as a chiral auxiliary,[33f] have been achieved.
The 1-pyridylmethyltetrahydroisoquinoline 26 similarly
underwent carbonylation to afford the benzolactam 34
Scheme 4. Preparation of the indolizine 27 and the indolizinone 31.
The acetamide 28 (Scheme 4) was only sparingly soluble (Scheme 6) in 83% yield. This had been transformed into
in conventional aprotic solvents such as benzene, toluene, (Ϯ)-epi-O-methylalamaridine (35) by MacLean [1) MeLi,
EtOAc, CH2Cl2, or CHCl3. It was therefore dissolved in 2) Pd/H2 or NaCNBH3] in 1987.[29c]
hot MeOH and treated with POCl3 (excess, 20-fold relative
Carbonylation of the tetrahydro-β-carboline 30, spar-
to MeOH, v/v). The obtained 3,4-dihydro-β-carboline 29 ingly soluble in toluene, was carried out in boiling dioxane
was subjected to the cycloamination conditions in air to for 24 h to afford the benzolactam (Ϯ)-dihydronaucléfine
give the yellow ketone 31 in 36% yield. Under the same (36, Scheme 7, 85%).[33b] Transformation of 36 into (Ϯ)-
conditions, the tetrahydro-β-carboline 30 was converted normalindine (37) has been achieved in 48% yield by Sza-
into 31 in a higher yield of 65%.
rek and MacLean.[33c,34]
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K. Orito et al.
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Experimental Section
General Remarks: Melting points were measured with a Yanagim-
oto micro melting point apparatus and are uncorrected. IR spectra
were recorded with a JASCO IR-810 spectrometer. LR- and HR-
EI-MS spectra were determined with JEOL JMS-HX110, JEOL
1
JMS-FABmate, or JEOL JMS-700TZ mass spectrometers. H and
13C NMR spectra were recorded with a JEOL JNM-JX270
spectrometer (270 MHz and 67.8 MHz). NMR samples were pre-
pared in CDCl3 [99.8 atom-% D, containing tetramethylsilane
(0.03% v/v), Aldrich Co.], unless otherwise noted. Chemical shifts
are reported in ppm relative to tetramethylsilane. TLC was carried
out on Merck silica gel (60 PF254). Elemental analyses were per-
formed with Yanako MT-6 CHN CORDER and Dionex DX-500
instruments at the Analytical Laboratory of the Faculty of Phar-
maceutical Science, Hokkaido University.
Scheme 6. Formal synthesis of (Ϯ)-epi-O-methylalamaridine (35).
The 2-bromophenethylamines 1a-Br,[36–39] 1b-Br,[36–40] 1c-Br,[39,41,42]
and 1d-Br and the N-(2-bromophenethyl)acetamide 1f-Br[43] were
prepared by addition of Br2 (4.8 g, 30 mmol) to stirred solutions
of the corresponding phenethylamines or acetamides (20 mmol) in
AcOH (75 mL). N-Benzyl-2-bromo-3,4-dimethoxyphenethylamine
(1e-Br)[44] was prepared by treatment of 1a-Br with benzaldehyde,
followed by NaBH4 reduction of the resultant imine. N-Benzyl-2-
bromophenylacetamide (1g-Br)[3d] was prepared by treatment of
benzylamine with 2-bromophenylacetyl chloride in benzene in the
presence of pyridine.
2-Bromo-4,5-dimethoxyphenethylamine (1a-Br):[36–39] A colorless oil
(85%, ref.[36] HCl salt, m.p. 195–197 °C; ref.[37] HBr salt, m.p. 202–
1
204 °C). H NMR: δ = 1.31 (br. s, 2 H, NH2), 2.78–2.90 (m, 4 H,
CH2CH2), 3.85, 3.86 (each s, each 3 H, OMe), 6.74, 7.01 (each s,
each 1 H, Ar-H) ppm.
Scheme 7. Formal synthesis of (Ϯ)-normalindine (37).
2-Bromo-4,5-methylenedioxyphenethylamine (1b-Br):[36–40] A color-
less oil (80%, ref.[36] oxalate, m.p. 214–216 °C). 1H NMR: δ = 1.48
(br. s, 2 H, NH2), 2.80, 2.93 (each t, J = 7.3 Hz, each 2 H,
CH2CH2), 5.95 (s, 2 H, OCH2O), 6.73, 7.00 (each s, each 1 H, Ar-
H) ppm.
Conclusions
2-Bromo-N-methyl-4,5-dimethoxyphenethylamine (1c-Br):[39,41,42]
A
We have developed
a method for phosphane-free
colorless oil (75%, HCl salt, ref.[41] m.p. 151–153 °C; ref.[39] m.p.
Pd0-catalyzed intramolecular aryl amination based on
Pd(OAc)2 and Cu(OAc)2 in the presence of K2CO3. This
led to efficient formation of the indolines 2 and the quin-
olines 5 from o-halogenated phenethylamines and 3-phenyl-
propylamines, respectively. Fused ring systems containing
an isoquinoline ring, such as the indolo[2,1-a]isoquinolines
8 or the dibenzo[a,f]quinolizine 10, were prepared by this
method from the 1-(2-bromobenzyl)- and 1-(2-bromophen-
ethyl)isoquinolines 6 and 7 and from the 1-(2-bromophen-
ethyl)isoquinoline 9, respectively. Application to the prepa-
ration of fused heterocyclic ring systems containing β-carb-
oline rings afforded the benz[f]indolo[2,3-a]indolizin-13-
ones 15 and the benz[f]indolo[2,3-a]quinolizine 18. The
benzo[a]pyrido[3,4-f]indolizine and indolo[2,3-a]pyrido[3,4-
f]indolizin-13-one skeletons 27 and 31 were obtained simi-
larly by the method.
1
152–153 °C). H NMR: δ = 2.48 (br. s, 3 H, NMe), 2.86 (br. s, 4
H, CH2CH2), 3.85, 3.86 (each s, each 3 H, OMe), 6.76, 7.01 (each
s, each 1 H, Ar-H) ppm.
2-Bromo-N-ethyl-4,5-dimethoxyphenethylamine (1d-Br): A colorless
1
oil (55%). H NMR: δ = 1.12 (t, J = 7.3 Hz, 3 H, Me), 1.54 (br. s,
1 H, NH), 2.71 (q, J = 7.3 Hz, 2 H, NCH2), 2.86 (s, 4 H, CH2CH2),
3.83 (s, 6 H, OMe), 6.76, 7.00 (each s, each 1 H, Ar-H) ppm. IR
(neat): ν = 3298, 1632, 1605, 1508 cm–1. MS (EI): m/z (%) = 208
˜
(13) [M – Br]+, 58 (100). HR-MS: calcd. for C12H18NO2 208.1337;
found 208.1334.
N-Benzyl-2-bromo-4,5-dimethoxyphenethylamine (1e-Br):[44] A col-
1
orless oil (72%): H NMR: δ = 2.89 (s, 4 H, CH2CH2), 3.83 (s, 2
H, benzylic 2 H), 3.83, 3.85 (each s, each 3 H, OMe), 6.74, 7.00
(each s, each 1 H, Ar-H), 7.22–7.35 (m, 5 H, phenyl H) ppm.
N-(2-Bromo-4,5-dimethoxyphenethyl)acetamide (1f-Br):[43] Color-
less crystals (84%), m.p. 102–103 °C (benzene, ref.[43] m.p. 102–
103 °C). 1H NMR: δ = 1.98 (s, 3 H, Ac), 2.90, 3.50 (each t, J =
6.9 Hz, each 2 H, CH2CH2), 3.86 (s, 6 H, OMe), 6.74, 7.01 (each
s, each 1 H, Ar-H) ppm.
N-Benzyl-2-bromophenylacetamide (1g-Br):[3d] A solution of 2-bro-
mophenylacetyl chloride (2.32 g, 10 mmol) was added dropwise to
a stirred solution of benzylamine (0.96 g, 9 mmol) and pyridine
(1.2 mL) in dry benzene (10 mL). After 15 h, the mixture was ex-
Furthermore, it was found that this catalytic system was
also useful for Pd0-catalyzed aromatic carbonylation and
successfully produced an 8-oxoberbine and related benzo-
lactams containing benzo[a]- or indolo[2,3-a]pyrido[3,4-g]-
quinolizine ring systems, which are synthetic precursors of
(Ϯ)-epi-O-methylalamaridine (35) and (Ϯ)-normalindine
(37).
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Phosphane-Free Pd0-Catalyzed Reactions
tracted with CH2Cl2 (3ϫ20 mL). The combined extracts were N-Ethyl-2-iodo-4,5-dimethoxyphenethylamine (1d-I): N-Alkylation
washed with NaOH (2 n, 20 mL), HCl (2 n, 20 mL), and water
(30 mL), dried with Na2SO4, and concentrated to give a solid
(2.4 g). Recrystallization from MeOH afforded 1h-Br, m.p. 131–
of N-(2-iodo-4,5-dimethoxyphenethyl)trifluoroacetamide with KH
and EtBr in a manner similar to the above methylation afforded
N-ethyl-N-(2-iodo-4,5-dimethoxyphenethyl)trifluoroacetamide
(93%) as colorless crystals; m.p. 52–54 °C (benzene/hexane). 1H
NMR: δ = 1.21, 1.25 (each t, J = 6.9 Hz, 2.5:1, 3 H, Me), 2.94–
3.02 (m, 2 H), 3.33, 3.52 (each q, J = 6.9 Hz, 2.5:1, 2 H, CH2),
3.54 (m, 2 H, CH2), 3.84, 3.85 (each s, each 3 H, OMe), 6.69, 6.75
(each s, each 1 H, 1:2.5, Ar-H), 7.21 (s, 1 H, Ar-H) ppm. IR (Nu-
1
132 °C (ref.[3d] m.p. 132–134 °C), as colorless crystals. H NMR: δ
= 3.78 (s, 2 H, benzylic 2 H), 4.43, 4.46 (each s, each 1 H, CH2),
5.75 (br. s, 1 H, NH), 7.12–7.40 (m, 8 H, benzyl 5 H and 2Ј,3Ј,4Ј-
H), 7.59 (dd, J = 7.9, 1.0 Hz, 1 H, 3Ј-H) ppm.
The 2-Iodophenethylamines 1c-I,[45] 1d-I, and 1e-I[46] were prepared
by iodination of the corresponding trifluoroacetamides with
HgO·I2 in CH2Cl2,[42] followed by removal of the trifluoroacetyl
group with K2CO3 in MeOH. The amides 1f-I[42,46] and 1g-I were
prepared by similar iodination of N-(3,4-dimethoxyphenethyl)acet-
amide and N-benzyl-(3,4-dimethoxyphenyl)acetamide, respectively.
N-Benzyl-(2-iodophenyl)acetamide (1h-I) was prepared by halogen
exchange of 1h-Br with KI and CuI.[47]
jol): ν = 1686, 1598 cm–1. MS (EI): m/z (%) = 431 (37) [M]+, 290
˜
(100), 277 (96), 150 (10), 140 (14). C14H17F3INO3 (431.19): calcd.
C 39.00, H 3.97, I 29.43, N 3.25; found C 38.95, H 3.63, I 29.22,
N 3.34.
This trifluoroacetamide was treated with K2CO3 in MeOH/H2O
solution (2:1) in a manner similar to that described for 1c-I to af-
ford 1d-I as pale yellow crystals. m.p. 44–46 °C (benzene, 80%). 1H
NMR: δ = 1.12 (t, J = 6.9 Hz, 3 H, Me), 1.27 (br. s, 1 H, NH),
2.70 (q, J = 6.9 Hz, 2 H, CH2), 2.85 (m, 4 H, CH2CH2), 3.85, 3.85
(each s, each 3 H, OMe), 6.77, 7.22 (each s, each 1 H, Ar-H) ppm.
2-Iodo-4,5-dimethoxy-N-methylphenethylamine (1c-I):[45]
HgO
(12.0 g, 56.3 mmol) and N-(3,4-dimethoxyphenethyl)trifluoroacet-
amide[48] (5.2 g, 56.3 mmol) were added to a stirred solution of I2
(14.2 g, 56.3 mmol) in CH2Cl2 (100 mL), and the mixture was
stirred at room temp. for 15 h. The resulting precipitates (HgCl2)
were removed by suction filtration through a Celite pad. The fil-
trate was washed with aqueous Na2S2O3 solution, water (20 mL),
and brine (20 mL), dried with Na2SO4, and concentrated to give a
solid (7.36 g). Recrystallization from MeOH/Et2O afforded N-(2-
iodo-4,5-dimethoxyphenethyl)trifluoroacetamide (6.7 g, 88%) as
colorless crystals; m.p. 129–130 °C. 1H NMR: δ = 2.97 (t, J =
7.3 Hz, 2 H, CH2), 3.61 (q, J = 6.6 Hz, 2 H, CH2), 3.84, 3.86 (each
s, each 3 H, OMe), 6.38 (br. s, 1 H, NH), 6.69, 7.23 (each s, each
IR (Nujol): ν = 3291, 1596, 1561, 1502 cm–1. MS (EI): m/z (%) =
˜
290 (10), 278 (65), 263 (6), 208 (75), 164 (11), 150 (13), 58 (100).
C12H18INO2 (335.18): calcd. C 43.00, H 5.41, I 37.86, N 4.18;
found C 43.23, H 5.36, I 37.63, N 4.17.
N-Benzyl-2-iodo-4,5-dimethoxyphenethylamine (1e-I):[46] Hydrolysis
of N-(2-iodo-4,5-dimethoxyphenethyl)trifluoroacetamide with
K2CO3 in MeOH afforded 2-iodo-3,4-dimethoxyphenethylamine as
a colorless oil (67%), which was treated with benzaldehyde and
then with NaBH4 in MeOH to give 1e-I as a colorless oil (87%,
1
ref.[46] HCl salt, m.p. 173–175 °C). H NMR: δ = 2.79–2.84 (m, 2
1 H, Ar-H) ppm. IR (Nujol): ν = 3304, 1702, 1597, 1562 cm–1. MS
H, CH2), 2.91–2.94 (m, 2 H, CH2), 3.82 (s, 2 H, benzylic H), 3.85,
3.86 (each s, each 3 H, OMe), 6.75, 7.22 (each s, each 1 H, Ar-H),
7.31–7.38 (m, 5 H, phenyl H) ppm.
˜
(EI): m/z (%) = 403 (50) [M]+ , 290 (51), 277 (100). C12H13F3INO3
(403.14): calcd. C 35.75, H 3.25, I 31.48, N 3.47; found C 35.84, H
3.29, I 31.77, N 3.37.
N-(2-Iodo-4,5-dimethoxyphenethyl)acetamide (1f-I):[42,46] Colorless
crystals (98%); m.p. 111–112 °C (benzene, ref.[42] m.p. 109–110 °C;
The above iodide (1.2 g, 3.0 mmol) was added under N2 at 0 to ca.
5 °C to a stirred suspension of KH (144 mg, 3.6 mmol, 35 wt.-%
dispersion in mineral oil, washed with hexane) in dry THF (6 mL).
After 5 min, 18-crown-6 (5 mg) and iodomethane (0.65 mL,
4.2 mmol) were added, and the mixture was stirred at room temp.
for 2 h and then heated at reflux for 15 h. The mixture was concen-
trated and dissolved in CH2Cl2 (50 mL), washed with water
(3ϫ20 mL) and brine (30 mL), dried with Na2SO4, and concen-
trated to give a solid (1.16 g). Recrystallization from benzene/
hexane gave N-methyl-N-(2-iodo-4,5-dimethoxyphenethyl)trifluo-
1
ref.[46] m.p. 110–111 °C). H NMR: δ = 1.97 (s, 3 H, Ac), 2.89 (t,
J = 7.3 Hz, 2 H, CH2), 3.48 (q, J = 7.3 Hz, 2 H, CH2), 3.85 (s, 6
H, OMe), 6.74 (s, 1 H, Ar-H), 7.21 (s, 1 H, Ar-H) ppm.
N-Benzyl-(2-iodo-4,5-dimethoxyphenyl)acetamide (1g-I): Colorless
crystals; m.p. 166–167 °C (MeOH/ether, 83%, prepared by treat-
ment of 2-iodo-4,5-dimethoxyphenylacetyl chloride with benzyl-
1
amine in the presence of pyridine in benzene). H NMR: δ = 3.70
(s, 2 H, benzylic 2 H), 3.84, 3.86 (each s, each 3 H, OMe), 4.41.
4.46 (each s, each 1 H, CH2), 5.72 (br. s, 1 H, NH), 6.86 (s, 1 H,
Ar-H), 7.23 (s, 1 H, Ar-H), 7.27–7.39 (m, 5 H, phenyl H) ppm. IR
1
roacetamide (1.07 g, 85%) as colorless crystals; m.p. 83–84 °C. H
(Nujol): ν = 3294, 1632, 1602, 1511 cm–1. MS (EI): m/z (%) = 411
NMR: δ = 2.99 (t, J = 7.9 Hz, 2 H, CH2), 3.04, 3.11 (each s, each
1 H, 2:1, NMe), 3.50–3.65 (m, 2 H, CH2), 3.84, 3.85 (each s, each
3 H, OMe), 6.60, 6.75 (each s, 1 H, 1:2, Ar-H), 7.21 (s, 1 H, Ar-
˜
(4) [M]+, 284 (100), 193 (7), 91 (70). C17H18INO3 (411.24): calcd.
C 49.65, H 4.41, I 30.86, N 3.41; found C 49.60, H 4.37, I 30.77,
N 3.28.
H) ppm. IR (Nujol): ν = 1689, 1599 cm–1. MS (EI): m/z (%) = 417
˜
(39) [M]+, 290 (100), 277 (99), 150 (16), 140 (14). C13H15F3INO3
(417.16): calcd. C 37.43, H 3.52, I 30.42, N 3.36; found C 37.65, H
3.43, I 30.22, N 3.34.
N-Benzyl-(2-iodophenyl)acetamide (1h-I):
A solution of 1h-Br
(152 mg, 0.5 mmol), KI (1.25 g, 7.5 mmol), and CuI (476 mg,
2.5 mmol) in DMF (2 mL) was heated at 160 °C for 9 h. After cool-
ing to 0 °C, the mixture was quenched with HCl solution (5%,
2 mL), extracted with diethyl ether (10 mL), and filtered. The fil-
trate was washed with a Na2S2O3 solution (10 mL) and brine
K2CO3 (2.5 g) was added to a stirred solution of this N-methyltri-
fluoroacetamide (1.05 mg, 2.5 mmol) in a MeOH/H2O solution
(2:1, 21 mL). After having been stirred at room temp. for 2 h, the
reaction mixture was acidified with HCl solution (2 n) and washed
with CH2Cl2 (10 mL). The water layer was basified with a NaOH
solution (2 n) and extracted with CH2Cl2 (3ϫ 20 mL), washed with
water (3ϫ 30 mL) and brine (30 mL), dried (Na2SO4), and concen-
(20 mL), dried (Na2SO4), and concentrated to give
a solid
(142 mg). Preparative TLC on silica gel (CH2Cl2) gave a band with
Rf = 0.1 corresponding to 1h-I (74 mg, 45%), as colorless crystals;
1
m.p. 166–168 °C. H NMR: δ = 3.79 (s, 2 H, benzylic 2 H), 4.42,
1
trated to give 1c-I[45] as a colorless oil (401 mg, 60%). H NMR: δ
4.47 (d, J = 5.9 Hz, 2 H, CH2), 5.67 (br. s, 1 H, NH), 6.98 (t, J =
= 1.27 (br. s, 1 H, NH), 2.48 (s, 3 H, NMe), 2.75–2.90 (m, 4 H,
CH2CH2), 3.85, 3.86 (each s, each 3 H, OMe), 6.76, 7.22 (each s,
6.9 Hz, 1 H, Ar-H), 7.20–7.40 (m, 7 H, phenyl 5 H and 2 Ar-H),
7.86 (d, J = 7.9 Hz, 1 H, Ar-H) ppm. IR (Nujol): ν = 3270, 1633,
˜
each 1 H, Ar-H) ppm. IR (neat): ν = 3328, 1592, 1566, 1505 cm–1.
1561, 1497 cm–1. MS (EI): m/z (%) = 351 (5) [M]+, 224 (48), 91
˜
Eur. J. Org. Chem. 2012, 366–379
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
371

K. Orito et al.
(100). C15H14INO (351.19): calcd. C 51.30, H 4.02, I 36.14, N 3.99; ref.[60] m.p. 76–77 °C). H NMR: δ = 3.61 (s, 2 H, CH2), 4.91 (s, 2
FULL PAPER
1
found C 51.50, H 4.13, I 36.05, N 3.98.
H, benzylic H), 6.72 (d, J = 7.9 Hz, 1 H, Ar-H), 6.97–7.38 (m, 8
H, phenyl 5 H and Ar-H) ppm.
A General Procedure for Pd0-Catalyzed Aryl Amination: Pd(OAc)2
(1.1 mg, 0.005 mmol), Cu(OAc)2 (9.0 mg, 0.05 mmol), and K2CO3
(69.1 mg, 0.5 mmol) were added under Ar to a stirred solution of a
2-halophenylalkylamine (0.1 mmol) in toluene (2 mL). The mixture
was heated at reflux for 24 h, allowed to cool, and filtered through
a Celite pad. The filtrate was concentrated to give a crude product,
which was purified by crystallization from an appropriate solvent
or by preparative TLC on silica gel, unless otherwise noted. The
spectral data for the products 2a,[43,49–53] 2b,[50,54] 2c,[41,55] 2d,[56]
2f,[43,52] 2g,[57,58] and 2h[3d,48–52] were compared with those reported.
The 3-(2-halophenyl)propylamines substrates 4a-Br,[6b] 4a-I,[3d,6b]
4b-Br,[3d,3i] and 4b-I were prepared by the reported methods, and
their intramolecular aryl amination afforded the known quinoline
derivatives 5a (commercially available) and 5b.[37]
3-(2-Bromophenyl)propylamine (4a-Br):[3d,6b] A yellowish oil (52%).
1H NMR: δ = 1.26–1.47 (br, 2 H, NH2), 1.71–1.82 (m, 2 H, CH2),
2.74–2.81 (m, 4 H, CH2), 7.02–7.08 (m, 1 H, Ar-H), 7.20–7.25 (m,
2 H, Ar-H), 7.52 (d, J = 7.9 Hz, 1 H, Ar-H) ppm.
3-(2-Iodophenyl)propylamine (4a-I):[6b] A yellowish oil (58%). 1H
NMR: δ = 1.29–1.34 (br. s, 2 H, NH2), 1.69–1.80 (m, 2 H, CH2),
2.73–2.83 (m, 4 H, CH2), 6.85–6.91 (m, 1 H, Ar-H), 7.19–7.30 (m,
2 H, Ar-H), 7.82 (d, J = 7.9 Hz, 1 H, Ar-H) ppm.
5,6-Dimethoxyindole (3a):[43,49–53] Colorless crystals (32%); m.p.
153–154 °C (CH2Cl2/petroleum ether, ref.[49] m.p. 152–153 °C;
ref.[50] m.p. 152–154 °C; ref.[51] m.p. 153–155 °C; ref.[43] m.p. 154–
155 °C; ref.[52] m.p. 155–156 °C; ref.[53] m.p. 158–159 °C) (HCl salt,
N-[3-(2-Bromophenyl)propyl]acetamide (4b-Br):[3d,3i] This com-
pound was prepared by treatment of 4a-Br with Ac2O/pyridine; a
1
ref.[49] m.p. 108.5 °C); Rf = 0.8 (CH2Cl2/MeOH 2:1). H NMR: δ
= 3.92 (s, 6 H, OMe), 6.45 (br. s, 1 H, 3-H), 6.91 (s, 1 H, 7-H),
7.08 (s, 1 H, 4-H), 7.09 (s, 1 H, 2-H), 8.00 (br. s, 1 H, NH) ppm.
1
yellowish oil (96%). H NMR: δ = 1.78–1.89 (m, 2 H, CH2), 1.97
(s, 3 H, Ac), 2.78 (dd, J = 7.9, 7.3 Hz, 2 H, CH2), 3.31 (q, J =
7.3 Hz, 2 H, CH2), 5.47–5.55 (br, 1 H, NH), 7.03–7.10 (m, 1 H,
Ar-H), 7.20–7.25 (m, 2 H, Ar-H), 7.53 (d, J = 7.9 Hz, 1 H, Ar-
H) ppm.
5,6-Methylenedioxyindole (3b):[50,54] Colorless crystals (37%); m.p.
108–109 °C (CH2Cl2/petroleum ether, ref.[54] m.p. 108–110 °C;
1
ref.[50] m.p. 109–110 °C); Rf = 0.8 (CH2Cl2/MeOH 2:1). H NMR:
δ = 5.93 (s, 2 H, OCH2O), 6.43 (t, J = 2.3 Hz, 1 H, 3-H), 6.85 (s,
1 H, 7-H), 7.01 (s, 1 H, 4-H), 7.08 (dd, J = 2.3, 2.3 Hz, 1 H, 2-H),
8.03 (br. s, 1 H, NH) ppm.
N-3-(2-Iodophenyl)propylacetamine (4b-I): This compound was pre-
pared by treatment of 4a-I with Ac2O/pyridine; a colorless solid
(94%), m.p. 56–57 °C. 1H NMR: δ = 1.77–1.96 (m, 2 H, CH2), 1.98
(s, 3 H, Ac), 2.76 (dd, J = 8.3, 7.6 Hz, 2 H, CH2), 3.33 (q, J =
6.9 Hz, 2 H, CH2), 5.55 (br. s, 1 H, NH), 6.86–6.92 (m, 1 H, Ar-
H), 7.20–7.31 (m, 2 H, Ar-H), 7.81 (d, J = 7.9 Hz, 1 H, Ar-H) ppm.
N-Methyl-5,6-dimethoxyindoline (2c):[41,55] Yellowish crystals (90%)
from Ic-I; m.p. 40–41 °C (MeOH); Rf = 0.33 (developed twice with
1
CH2Cl2/hexane 1:1). H NMR: δ = 2.73 (s, 3 H, Me), 2.87 (t, J =
IR (Nujol): ν = 3303, 1624, 1555 cm–1. MS (EI): m/z (%) = 303
7.9 Hz, 2 H, 3-H), 3.24 (t, J = 7.9 Hz, 2 H, 2-H), 3.81, 3.87 (each
˜
s, each 3 H, OMe), 6.20, 6.76 (each s, each 1 H, 4- and 7-H) ppm.
(37), 176 (100), 134 (35), 117 (62), 73 (96). C11H14INO (303.14):
calcd. C 43.58, H 4.66, I 41.86, N 4.62; found C 43.62, H 4.69, I
41.78, N 4.49.
IR (Nujol): ν = 1614, 1602, 1505 cm–1. MS (EI): m/z (%) = 193
˜
(67), 178 (100).
N-Ethyl-5,6-dimethoxyindoline (2d):[56] A yellowish oil (90%) from
Id-I; Rf = 0.45 (MeOH/CH2Cl2, 2%). H NMR: δ = 1.20 (t, J =
N-Acetyl-1,2,3,4-tetrahydroquinoline (5b):[3i] A yellowish oil (82%)
1
from 4b-I. 1H NMR: δ = 1.91–2.01 (m, 2 H, CH2), 2.23 (s, 3 H,
7.3 Hz, 3 H, Me), 2.88 (t, J = 8.3 Hz, 2 H, 3-H), 3.07 (q, J = Ac), 2.72 (t, J = 6.6 Hz, 2 H, CH2), 3.80 (t, J = 6.6 Hz, 2 H, CH2),
7.3 Hz, 2 H, Ethyl 2 H), 3.27 (t, J = 8.3 Hz, 2 H, 2-H), 3.81, 3.86 7.08–7.21 (m, 4 H, Ar-H) ppm.
(each s, each 3 H, OMe), 6.20 (s, 1 H, 7-H), 6.75 (s, 1 H, 4-H) ppm.
The substrates 6 and 7 (benzylisoquinolines) were prepared by the
reported method based on the Bischler–Napieralski cyclization of
IR (neat): ν = 1616, 1505 cm–1. MS (EI): m/z (%) = 207 (62) [M]+,
˜
206 (8), 192 (100), 176 (7), 164 (25), 148 (11), 44 (12). HR-MS:
calcd. for C12H17NO2 207.1259; found 207.1258.
the corresponding N-(phenethyl)phenylacetamides, followed by
NaBH4 reduction of 6 to 7.[19m,19n] Physical and spectroscopic data
for the products 8 were compared with those reported for the
indolo[2,1-a]isoquinolines, 8a,[19j] 8b and 8c,[19m] and 8d and 8e.[19n]
Similarly, the substrates 9, 11, 12, 17, 19, and 21 (1-benzyl-β-carb-
olines) were prepared by Bischler–Napieralski cyclizations of the
corresponding N-(phenethyl)phenylacetamides followed by NaBH4
reduction.
N-Benzyl-5,6-dimethoxyindoline (2e): A yellowish oil (85%) from
Ie-I; Rf = 0.7 (CH2Cl2 on alumina TLC). H NMR: δ = 2.89 (t, J
1
= 8.3 Hz, 2 H, 3-H), 3.24 (t, J = 8.3 Hz, 2 H, 2-H), 3.79, 3.81 (each
s, each 3 H, OMe), 4.19 (s, 2 H, benzylic 2 H), 6.22, 6.77 (each s,
each 1 H, 7- and 4-H), 7.27–7.43 (m, 5 H, phenyl H) ppm. IR
(neat): ν = 1616, 1505 cm–1. MS (EI): m/z (%) = 270 (4), 269 (24),
˜
252 (22), 91 (100). HRMS (EI): calcd. for C17H19NO2 269.1416;
found 269.1414.
1-[2-(2-Bromo-3,4-dimethoxyphenyl)ethyl]-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (9): NaBH4 (70 mg, 1.84 mmol) was added
to a stirred solution of 1-(2-bromo-3,4-dimethoxyphenethyl)-6,7-
dimethoxy-3,4-dihydroisoquinoline[20a] (200 mg, 0.46 mmol) in
MeOH (20 mL). After the mixture had been stirred at room temp.
overnight, the solvent was evaporated. The residue was dissolved
in CH2Cl2 (10 mL), washed with water (5ϫ20 mL), dried
(Na2SO4), and concentrated to give 9 as a solid (175 mg, 87.5%).
1H NMR (270 MHz, CDCl3): δ = 2.00–2.11 (m, 2 H, phenethyl
CH2), 2.64–2.89 (m, 4 H, 4-H and phenethyl CH2), 2.98–3.07, 3.24–
3.32 (each m, each 1 H, 3-H), 3.84, 3.85 (each s, each 6 H, OMe),
3.90–4.02 (br. m, 1 H, 1-H), 6.57, 6.63, 6.77, 7.00 (each s, each 1
N-Acetyl-5,6-dimethoxyindoline (2f):[43,52] Colorless crystals (95%)
from If-I; m.p. 170–172 °C (MeOH, ref.[43] m.p. 173–174 °C; ref.[52]
1
m.p. 176 °C). H NMR: δ = 2.21 (s, 3 H, Ac), 3.14 (t, J = 8.6 Hz,
2 H, 3-H), 3.85, 3.90 (each s, each 3 H, OMe), 4.05 (t, J = 8.6 Hz,
2 H, 2-H), 6.73, 7.99 (each s, each 1 H, Ar-H) ppm.
N-Benzyl-5,6-dimethoxy-2-indolinone (2g):[57,58] Colorless crystals
(51%) from Ig-I; m.p. 119–120 °C (MeOH, ref.[57] m.p. 118–120 °C;
ref.[58] m.p. 119–120 °C). 1H NMR: δ = 3.58 (s, 2 H, CH2), 3.75,
3.83 (each s, each 3 H, OMe), 4.91 (s, 2 H, benzylic H), 6.32 (s, 1
H, Ar-H), 6.88 (s, 1 H, Ar-H), 7.29–7.33 (m, 5 H, phenyl H) ppm.
H, Ar-H and phenyl H) ppm. IR (neat): ν = 3304, 1605, 1573,
˜
N-Benzyl-2-indolinone (2h):[3d,58–61] A colorless oil (51%); Rf = 0.6 1507 cm–1. MS (EI) m/z (%) = 354 (25) [M – Br]+, 192 (100).
(MeOH/CH2Cl2, 2%, ref.[58] m.p. 66–68 °C; ref.[59] m.p. 66.5–67 °C;
HRMS: calcd. for C21H25BrNO4 434.0972; found 434.0963.
372
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 366–379

Phosphane-Free Pd0-Catalyzed Reactions
1-(2-Bromobenzyl)-3,4-dihydro-β-carboline (11a) and 1-(2-Bro- C20H21BrN2O3 (417.30): calcd. C 57.56, H 5.07, Br 19.15, N 6.71;
mobenzyl)-1,2,3,4-tetrahydro-β-carboline (12a).
A
General Pro-
found C 57.70, H 4.93, Br 18.90, N 6.65.
cedure: 2-Bromophenylacetic acid (2.150 g, 10 mmol) was dissolved
in SOCl2 (15 mL), and the solution was kept at room temp. over-
night. SOCl2 was removed by azeotropic distillation with benzene
in an oil bath at 60 °C. The obtained acid chloride was dissolved in
dry benzene (20 mL) and added to a stirred solution of tryptamine
(1.602 g, 10 mmol) and pyridine (1.22 mL, 15 mmol) in dry benz-
ene (10 mL). The mixture was stirred overnight and extracted with
CH2Cl2 (3ϫ20 mL). The extracts were washed with NaOH solu-
tion (2 n, 2ϫ20 mL), HCl solution (2 n, 2ϫ20 mL), and water
(2ϫ20 mL), dried with Na2SO4, and concentrated. The residue
(3.547 g) was crystallized from EtOH/hexane to give N-[2-(3-
indolyl)ethyl]-2-(2-bromophenyl)acetamide as colorless crystals
(3.195 g, 89%); m.p. 122–124 °C (EtOH/hexane). 1H NMR: δ =
2.93 (t, J = 6.6 Hz, 2 H, CH2), 3.55 (q, J = 6.3 Hz, 2 H, CH2), 3.66
(s, 2 H, CH2), 5.41 (br. s, 1 H, NH), 6.88 (d, J = 2.3 Hz, 1 H, 2-
H), 7.07–7.25 (m, 4 H, Ar-H), 7.35 (d, J = 8.3 Hz, 1 H, Ar-H),
7.54 (dt, J = 0.7, 6.9, 6.9 Hz, 2 H, Ar-H), 8.01 (br. s, 1 H, NH) ppm.
This amide (209 mg, 0.5 mmol) afforded the air-sensitive 3,4-dihy-
dro-β-carboline 11b as an oil (178 mg, 88%). H NMR: δ = 2.89
1
(t, J = 8.1 Hz, 2 H, 4-H), 3.87, 3.92 (each s, each 3 H), 3.93 (t, J
= 8.1 Hz, 2 H, 3-H), 4.12 (s, 2 H, benzylic CH2), 6.80, 7.07 (each
d, J = 8.6 Hz, each 1 H, phenyl H), 7.12, 7.30 (each t, J = 7.8 Hz,
each 1 H, Ar-H), 7.37, 7.57 (each d, J = 8.1 Hz, each 1 H, Ar-H),
8.17 (br. s, 1 H, NH) ppm.
NaBH4 reduction of 11b (103 mg, 0.25 mmol) afforded the 1,2,3,4-
tetrahydro-β-carboline 12b as an oil (92 mg, 81% from the amide).
1H NMR: δ = 2.78–2.84 (m, 2 H, CH2), 2.99–3.13 (m, 2 H, CH2),
3.30–3.39 (m, 2 H, CH2), 4.45 (br. m, 1 H, 1-H), 6.86, 7.05 (AB
type, J = 8.3 Hz, each 1 H, phenyl H), 7.08–7.19 (m, 2 H), 7.30
(dd, J = 1.0, 6.6 Hz, 1 H), 7.50 (dd, J = 1.3, 7.3 Hz, 1 H), 7.70 (br.
s, 1 H) ppm. IR (neat): ν = 3428, 1489 cm–1. MS (EI): m/z (%) =
˜
402 (0.3) [M]+, 400 (0.4) [M]+, 231 (1.3), 229 (1.3), 185 (22.7), 171
(100). HRMS: calcd. for C20H21BrN2O2 400.0786; found 400.0782.
IR (Nujol): ν = 3316, 3274, 1625 cm–1. MS (EI): m/z (%) = 358
˜
1-(2-Bromo-4,5-dimethoxybenzyl)-3,4-dihydro-β-carboline (11c) and
1-(2-Bromo-4,5-dimethoxybenzyl)-1,2,3,4-tetrahydro-β-carboline
(12c)
(7.0) [M]+, 356 (7.0) [M]+, 143 (100), 130 (32.0). C18H17BrN2O
(357.25): calcd. C 60.52, H 4.80, Br 22.37, N 7.84; found C 60.37,
H 4.69, Br 22.44, N 7.74.
2-(2-Bromo-4,5-dimethoxyphenyl)-N-[2-(3-indolyl)ethyl]acetamide:
209 mg (76 %), 0.5 mmol, colorless crystals; m.p. 177–179 °C
(EtOH/hexane). 1H NMR (270 MHz, CDCl3): δ = 2.93 (t, J =
6.6 Hz, 2 H, CH2), 3.55 (dt, J = 2.0, 3.6 Hz, 2 H, CH2), 3.58 (s, 2
H, CH2), 3.77, 3.87 (each s, each 3 H, OMe), 5.50 (br. s, 1 H, NH),
6.70, 6.96 (each s, each 1 H, phenyl H), 6.88 (d, J = 2.6 Hz, 1 H,
indole 2-H), 7.10 (dt, J = 1.0, 6.9 Hz, 1 H, Ar-H), 7.20 (dt, J =
1.0, 7.3 Hz, 1 H, Ar-H), 7.35 (d, J = 7.9 Hz, 1 H, Ar-H), 7.54 (d,
A mixture of the above amide (356 mg, 1 mmol) and POCl3
(0.94 mL, 10 mmol) in dry benzene (20 mL) was heated at reflux
for 3 h under Ar. Ice-water (50 mL) and benzene (20 mL) were
added, and the mixture was stirred. The organic layer was removed,
and the water layer was basified with NaOH solution (6 n) and
extracted with CH2Cl2 (3ϫ20 mL). The extracts were washed with
saturated brine (3ϫ20 mL), dried, and concentrated to afford the
air-sensitive 3,4-dihydro-β-carboline 11a as a solid (325 mg); m.p.
J = 7.9 Hz, 1 H, Ar-H), 7.95 (br. s, 1 H, NH) ppm. IR (Nujol): ν
˜
1
152–159 °C. H NMR: δ = 2.89, 3.93 (each t, J = 8.1 Hz, each 2
= 3312, 3280, 1626 cm–1. MS (EI): m/z (%) = 418 (4.7) [M]+, 416
(4.7) [M]+, 143 (100), 130 (26.0). C20H21BrN2O3 (417.30): calcd. C
57.56, H 5.07, Br 19.15, N 6.71; found C 57.37, H 5.04, Br 19.22,
N 6.71.]
H, 3- and 4-H), 4.12 (s, 2 H, benzylic H), 7.10–7.40 (m, 6 H, phenyl
4 H and Ar-H), 7.50–7.65 (m, 2 H, Ar-H), 8.17 (br. s, 1 H, Ar-
H) ppm.
This (226 mg, 0.66 mmol) was treated with NaBH4 (113 mg,
3.0 mmol) in MeOH (30 mL) for 2 h. MeOH was evaporated, and
the residue was treated with CH2Cl2 (20 mL) and water (20 mL).
The CH2Cl2 layer was washed with water (10 mL), dried, and con-
centrated. The residue (217 mg) was purified by preparative TLC
(MeOH/CH2Cl2, 5%). A band with Rf = 0.3 gave the 1,2,3,4-tetra-
hydro-β-carboline 12a (195 mg, ca. 83% from the amide) as an oil.
1H NMR: δ = 2.70–2.81, 2.88–3.10, 3.24–3.34 (each m, each 2 H,
CH2), 4.40 (br. s, 1 H, 1-H), 7.04–7.16 (m, 4 H, Ar-H), 7.19–7.30
(m, 2 H, Ar-H), 7.47 (dd, J = 1.7, 6.6 Hz, 1 H, Ar-H), 7.57 (d, J
This amide was converted into the air-sensitive 3,4-dihydro-β-carb-
oline 11c as an oil (185 mg, 92%). 1H NMR: δ = 2.88 (t, J = 8.1 Hz,
2 H, 4-H), 3.73, 3.82 (each s, each 3 H, OMe), 3.95 (t, J = 8.1 Hz,
2 H), 4.07 (s, 2 H, CH2), 6.88, 7.01 (each s, each 1 H, phenyl H),
7.14, 7.24 (each t, J = 8.1 Hz, each 1 H, Ar-H), 7.33, 7.56 (each d,
J = 8.1 Hz, each 1 H, Ar-H), 8.46 (br. s, 1 H, NH) ppm.
NaBH4 reduction of 11c (103 mg, 0.25 mmol) afforded the 1,2,3,4-
tetrahydro-β-carboline 12c as an oil (87 mg, ca. 79 % from the
amide). 1H NMR: δ = 2.78–2.82 (m, 2 H, CH2), 2.99–3.13 (m, 2
H, CH2), 3.20–3.39 (m, 2 H, CH2), 3.75, 3.88 (each s, each 3 H,
OMe), 4.41 (br. t, 1 H, 1-H), 6.77, 7.09 (each s, each 1 H, phenyl
H), 7.08–7.19 (m, 2 H, Ar-H), 7.29 (dd, J = 1.0, 6.6 Hz, 1 H, Ar-H),
7.50 (dd, J = 1.3, 7.3 Hz, 1 H, Ar-H), 7.75 (br. s, 1 H, NH) ppm. IR
= 7.6 Hz, 1 H, Ar-H), 8.16 (br. s, 1 H, NH) ppm. IR (neat): ν =
˜
3326, 1467 cm–1. MS (EI): m/z (%) = 342 [M]+ (2.2), 340 [M]+ (4.8),
185 (6.7), 171 (100). HRMS: calcd. for C18H17BrN2 340.0575;
found 340.0571.
(neat): ν = 3428, 1491 cm–1. MS (EI): m/z (%) = 402 (0.3) [M]+,
˜
1-(2-Bromo-3,4-dimethoxybenzyl)-3,4-dihydro-β-carboline (11b) and
1-(2-Bromo-3,4-dimethoxybenzyl)-1,2,3,4-tetrahydro-β-carboline
(12b)
401 (0.4) [M]+, 171 (100). HRMS: calcd. for C20H21BrN2O2
400.0786; found 400.0880.
1-[2-(2-Bromo-3,4-dimethoxyphenyl)ethyl]-1,2,3,4-tetrahydro-β-
carboline (17)
2-(2-Bromo-3,4-dimethoxyphenyl)-N-[2-(3-indolyl)ethyl]acetamide:
Colorless crystals (66 %); m.p. 128–132 °C (EtOH/hexane). 1H
NMR: δ = 2.91 (t, J = 6.6 Hz, 2 H, CH2), 3.55 (q, J = 6.3 Hz, 2 3-(2-Bromo-4,5-dimethoxyphenyl)-N-[2-(3-indolyl)ethyl]propion-
H, CH2), 3.61 (s, 2 H, CH2), 3.83, 3.85 (each s, each 3 H, OMe),
5.38 (br. s, 1 H, NH), 6.83, 6.93 (AB type, J = 8.3 Hz, each 1 H,
5Ј- and 6Ј-H), 6.89 (d, J = 1.7 Hz, 1 H, 2-H), 7.09 (dt, J = 1.0,
6.9 Hz, 1 H, Ar-H), 7.18 (dt, J = 1.0, 6.9 Hz, 1 H, Ar-H), 7.35 (dd,
J = 0.7, 7.9 Hz, 1 H, Ar-H), 7.54 (d, J = 7.3 Hz, 1 H, Ar-H), 8.02
amide: Colorless crystals (66%); m.p. 157–159 °C (EtOH/hexane).
1H NMR: δ = 2.38 (t, J = 7.3 Hz, 2 H, phenethyl H), 2.93 (t, J =
6.6 Hz, propionamide CH2), 2.99 (t, J = 7.3 Hz, phenethyl CH2),
3.59 (t, J = 6.6 Hz, propionamide CH2), 3.83, 3.85 (each s, each 3
H, OMe), 5.44 (br. s, 1 H), 6.79 (s, 1 H, phenyl H), 6.92 (br. s, 1
H, indole 2-H), 6.97 (s, 1 H, phenyl H), 7.12 (t, J = 7.9 Hz, 1 H,
(br. s, 1 H, NH) ppm. IR (Nujol): ν = 3376, 3290, 1643 cm–1. MS
˜
(EI): m/z (%) = 418 (2.2) [M]+, 416 (2.4) [M]+, 143 (100), 130 (28.6). Ar-H), 7.21 (t, J = 7.9 Hz, 1 H, Ar-H), 7.38 (dd, J = 8.3 Hz, 1 H,
Eur. J. Org. Chem. 2012, 366–379
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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373

K. Orito et al.
FULL PAPER
Ar-H), 7.57 (d, J = 7.9 Hz, 1 H, Ar-H), 8.02 (br. s, 1 H, NH) ppm.
1-(2-Bromo-4,5-dimethoxybenzyl)-Na-methyl-1,2,3,4-tetrahydro-β-
carboline (21): Acylation of Na-methyltryptamine[63] with 3,4-di-
methoxyphenylacetyl chloride afforded Na-methyl-[2-(3-indolyl)-
ethyl]-2-(2-bromo-3,4-dimethoxyphenyl)acetamide as colorless
crystals (65%); m.p. 121–123 °C (AcOEt). 1H NMR: δ = 2.99, 3.03
(each s, 3 H, 1:1, NMe), 3.03 (each t, J = 7.6 Hz, 2 H, 1:1, CH2),
3.65, 3.74 (each t, J = 6.9 Hz, 1 H, 1:1, CH2), 3.54, 3.74 (each s, 2
H, 1:1, CH2), 3.81, 3.82, 3.83, 3.86 (each s, each 1.5 H, 1:1:1:1,
OMe), 6.64, 6.86, 7.00, 7.03 (each s, each 0.5 H, 1:1:1:1, phenyl H),
6.98–7.40 (m, 4 H, 3-H), 7.58, 7.67 (each d, J = 7.3 Hz, 1 H, 1:1,
5-H), 8.02, 8.11 (each br. s, each 0.5 H, 1:1, NH) ppm. IR (CDCl3):
IR (Nujol): ν = 3378, 3268, 1632 cm–1. MS (EI): m/z (%) = 432
˜
(6.4) [M + 2]+, 430 (6.3) [M]+, 143 (100), 130 (24.5). C21H23BrN2O3
(431.33): calcd. C 58.48, H 5.37, Br 18.53, N 6.49, O 11.13; found
C 58.33, H 5.32, Br 19.30, N 6.50.
1-(2-Bromo-4,5-dimethoxyphenethyl)-3,4-dihydro-β-carboline: An
1
oil (87%). H NMR: δ = 2.84 (t, J = 8.3 Hz, 2 H, 4-H), 2.90–3.15
(m, 4 H, phenethyl CH2), 3. 85 (t, J = 8.3 Hz, 2 H, 3-H), 3.65, 3.71
(each s, each 3 H, OMe), 6.64, 6.86 (each s, each 1 H, Ar-H), 7.13,
7.25 (each dt, J = 1.0, 7.3 Hz, each 1 H, Ar-H), 7.57, 7.74 (each d,
J = 8.0 Hz, Ar-H) ppm.
ν = 3264, 1637, 1508 cm–1. MS (EI): m/z (%) = 432 (1.2) [M]+, 430
˜
1
(1.5) [M]+, 143 (100.0), 130 (46.7). C21H23BrN2O3 (431.33): calcd.
C 58.48, H 5.37, Br 18.53, N 6.49; found C 58.28, H 5.39, Br 18.87,
N 6.30.
Compound 17: A yellow oil (91%). H NMR (270 MHz, CDCl3): δ
= 2.90, 3.10 (each m, each 1 H, phenethyl CH2), 2.60–2.95 (m, 4
H, 4-H and phenethyl CH2), 2.95–3.10, 3.27–3.40 (each m, each 1
H, 3-H), 3.74, 3.77 (each s, each 3 H, OMe), 4.06 (br. d, 1 H, 2-
H), 6.68, 6.96 (each s, each 1 H, phenyl H), 7.05–7.15 (m, 2 H, Ar-
H), 7.22, 7.47 (each d, J = 8.6 Hz, Ar-H), 8.21 (s, 1 H, NH) ppm.
This amide was subjected to Bischler–Napieralski cyclization fol-
1
lowed by NaBH4 reduction to afford 21 as a yellow oil (68%). H
NMR: δ = 2.59 (s, 3 H, NMe), 2.66–2.75, 2.84–3.04, 3.22–3.35
(each m, 1 H, 3 H and 2 H, benzylic, 4- and 3-H), 3.65, 3.88 (each
s, each 3 H, OMe), 3.80–3.99 (m, 1 H, 1-H), 6.60, 7.07 (each s,
each 1 H, phenyl H), 7.09 (t, J = 6.3, Hz, 1 H, 5-H), 7.16 (t, J =
6.9 Hz, 1 H, 8-H), 7.24 (d, J = 6.6, Hz, 1 H, 1-H), 7.49 (d, J =
IR (neat): ν = 3428, 1489 cm–1. MS (EI): m/z (%) = 416 (8.2)
˜
[M]+, 414 (8.4) [M]+, 229 (15.9), 185 (10.3), 171 (100). HRMS:
calcd. for C21H23BrN2O2 414.0943; found 414.0943.
1-(2-Bromo-4,5-dimethoxybenzyl)-Nb-methyl-1,2,3,4-tetrahydro-β-
carboline (19): 2-Bromo-4,5-dimethoxyphenylacetyl chloride[19m]
(1.960 g, 6.67 mmol) in dry benzene (30 mL) was added to a stirred
solution of 1-methyltryptamine[62] (968.9 mg, 5.56 mmol) and pyr-
idine (0.53 mL, 6.7 mmol) in benzene (20 mL) and THF (20 mL).
The reaction mixture was stirred at room temp. overnight, extracted
with CH2Cl2 (50 mL ϫ3), washed with NaOH (2 n, 30 mL), HCl
(2 n, 30 mL), water (100 mL ϫ 2), and brine (100 mL), dried
(Na2SO4), and concentrated to give a solid (2.1603 g). Recrystalli-
zation from AcOEt gave Na-[2-(Nb-methyl-3-indolyl)ethyl]-2-(2-
bromo-4,5-dimethoxyphenyl)acetamide as colorless crystals
6.6, Hz, 1 H, 4-H) ppm. IR (Nujol): ν = 3384, 1657 cm–1. MS (EI):
˜
m/z (%) = 416 (0.5) [M]+, 414 (0.5) [M]+, 333 (0.9), 231 (0.8),
229(0.8), 201 (2.6), 185 (100). HRMS: calcd. for C21H23BrN2O2
414.0942; found 414.0925.
2-(3-Bromo-4-pyridyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide
(24): A stirred mixture of 3,4-dimethoxyphenethylamine (544 mg,
3.0 mmol) and ethyl (3-bromo-4-pyridyl)acetate (23,[25b,25c] 732 mg,
3.0 mmol) was heated in dry boiling xylene (4 mL) for 2 d. Xylene
was removed in vacuo, and the residue was crystallized from tolu-
ene/hexane to give the acetamide 24 (1.06 g, 93%) as colorless crys-
tals; m.p. 137–138 °C. 1H NMR: δ = 2.74 (t, J = 7.0 Hz, 2 H,
ArCH2), 3.50, 3.52 (each t, J = 7.0 Hz, 1 H, CH2N), 3.62 (s, 2 H,
COCH2), 3.85, 3.87 (each s, each 3 H, OMe), 5.53 (br. s, 1 H, NH),
6.62 (dd, J = 8.1, 1.9 Hz, 1 H, 6Ј-H), 6.67 (d, J = 1.9 Hz, 1 H, 2Ј-
H), 6.75 (d, J = 8.1 Hz, 1 H, 5Ј-H), 7.26 (d, J = 4.9 Hz, 1 H, 5ЈЈ-
H), 8.45 (d, J = 4.9 Hz, 1 H, 6ЈЈ-H), 8.69 (s, 1 H, 2ЈЈ-H) ppm. 13C
NMR: δ = 34.9, 40.8, 43.0, 55.8, 55.9, 111.2, 111.6, 120.5, 123.2,
126.1, 130.8, 143.5, 147.7, 148.5, 149.0, 151.9. 167.6 ppm. IR (Nu-
1
(1.4978 g, 62%); m.p. 153–155 °C (AcOEt). H NMR: δ = 2.90 (t,
J = 6.6 Hz, 2 H, 2-H), 3.54 (q, J = 6.3 Hz, 2 H, 1-H), 3.58 (s, 2 H,
CH2), 3.70, 3.77, 3.86 (each s, each 3 H, OMe and NMe), 5.53 (br.
s, 1 H, NH), 6.71, 6.72 (each s, each 1 H, phenyl H), 6.97 (s, 1 H,
Indole 2-H), 7.08 (t, J = 7.3 Hz, 1 H, Ar-H), 7.19–7.29 (m, 2 H,
Ar-H), 7.53 (d, J = 7.9 Hz, 1 H, Ar-H) ppm. IR (Nujol): ν = 3284,
˜
2932, 1656, 1509, 743 cm–1. MS (EI): m/z (%) = 432 (4.0) [M]+, 430
(4.1) [M]+, 157 (100.0), 144 (46.7) ppm. HRMS: calcd. for
C21H23BrN2O3 430.0891; found 430.0904. C21H23BrN2O3: C 58.48,
H 5.37, Br 18.53, N 6.49; found C 58.56, H 5.44, Br 18.45, N 6.21.
jol): ν = 3294, 1641, 1518 cm–1. MS (EI) m/z (%) = 380 (4) [M]+,
˜
164 (100), 151 (28). C17H19BrN2O3 (379.25): calcd. C 53.84, H 5.05,
Br 21.07, N 7.39; found C 53.88, H 5.20, Br 20.92, N 7.56.
POCl3 (0.23 mL, 2.5 mmol) was added to a boiling solution of the
above amide (107.9 mg, 0.25 mmol) in dry benzene (10 mL). The
mixture was heated at reflux for 3 h and then quenched with ice-
water and benzene. The aqueous layer was made alkaline with
1-[(3-Bromo-4-pyridyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline (26): A mixture of the acetamide 24 (188 mg,
NaOH (2 n, 10 mL), extracted with CH2Cl2 (20 mL ϫ3), washed 0.5 mmol) and POCl3 (0.47 mL, 5.0 mmol) in dry toluene (4 mL)
with water (30 mL ϫ3) and brine (30 mL), dried (Na2SO4), and
concentrated. NaBH4 (38.0 mg, 1 mmol) was added dropwise to a
stirred solution of this residue in MeOH (10 mL). After having
been stirred for 3 h at room temp., the mixture was concentrated,
quenched with water (10 mL), extracted into CH2Cl2 (20 mL ϫ3),
washed with water (10 mL ϫ3), dried (Na2SO4), and concentrated.
Purification by preparative TLC on silica gel (AcOEt, band with
Rf = 0.2) gave 19 as a yellow oil (94.1 mg, 91%). 1H NMR: δ =
was heated at reflux for 4 h. The mixture was then poured into ice-
water (10 mL), and the toluene layer was discarded. The water layer
was made basic with NaOH solution (2 n), and extracted into
CH2Cl2 (3 ϫ 10 mL). The combined extracts were washed with
water (10 mL), dried (Na2SO4), and concentrated. The resultant
air-sensitive oily 3,4-dihydroisoquinoline 25 [1H NMR: δ = 2.68,
3.72 (each t, J = 7.3 Hz, each 2 H, CH2 CH2), 3.81, 3.87 (each s,
each 3 H, OMe), 4.15 (s, 2 H, CH2Py), 6.69, 6.85 (each s, each 1
2.81 (dd, J = 5.3, 8.6 Hz, 2 H, 4-H), 2.95–3.40 (m, 4 H, CH2), 3.65, H, 5- and 8-H), 7.21, 8.37 (each d, J = 4.9 Hz, each 1 H, 5Ј- and
3.78, 3.87 (each s, each 3 H, OMe and NMe), 4.42 (dd, J = 5.6,
9.6 Hz, 1 H, 1-H), 5.71, 7.06 (each s, each 1 H, phenyl H), 7.10,
7.21 (each t, J = 7.3 Hz, each 1 H, 6- and 7-H), 7.27, 7.50 (each d,
6Ј-H), 8.71 (s, 1 H, 2Ј-H) ppm] was dissolved in MeOH (10 mL),
and NaBH4 (37 mg, 1 mmol) was added. After 2 h at room temp.,
the mixture was concentrated. The residue was diluted with water
(10 mL), and extracted with CH2Cl2 (3ϫ20 mL). The combined
organic layers were washed with water (2 ϫ 10 mL) and dried
(Na2SO4). Evaporation of the solvent afforded the crude amine 26
(131 mg, 72%) as a pale yellow oil. An analytical sample was ob-
J = 7.9 Hz, each 1 H, 5-and 8-H) ppm. IR (CDCl ): ν = 3312,
˜
3
1708, 1603, 1499 cm–1. MS (EI) m/z (%) = 416 (0.3) [M]+, 414 (0.4)
[M]+, 333 (1.7), 331 (1.9), 255 (1.4), 231 (1.2), 229(1.3), 185 (100).
HRMS: calcd. for C21H23BrN2O2 414.0942; found 414.0959.
374
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 366–379

Phosphane-Free Pd0-Catalyzed Reactions
tained by preparative TLC (Rf = 0.3, MeOH/CH2Cl2, 5 %). 1H
NMR: δ = 2.74, 3.00, 3.24 (each m, each 2 H, CH2), 3.83, 3.87
(each s, each 3 H, OMe), 4.27 (dd, J = 10.0, 3.5 Hz, 1 H, 1-H),
heated at reflux for 24 h, allowed to cool, and filtered through a
Celite pad. The filtrate was concentrated to give a crude product,
which was purified by crystallization from an appropriate solvent
6.61, 6.68 (each s, each 1 H, 5- and 8-H), 7.25 (d, J = 4.9 Hz, 1 H, or by preparative TLC on silica gel. Physical and spectroscopic
5Ј-H), 7.70 (br. s, 1 H, NH), 8.44 (d, J = 4.9 Hz, 1 H, 6Ј-H), 8.72
(s, 1 H, 2Ј-H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 29.2, 39.8,
42.4, 54.4, 55.8. 55.9, 109.4, 111.8, 123.5, 126.7, 127.2, 129.8, 147.2,
data for the products were compared with those reported for the
5,6-dihydroindolo[2,1-a]isoquinolines, 8a,[19j] 8b and 8c,[19m] and 8d
and 8e.[19n]
147.7, 147.8, 148.0, 152.0 ppm. IR (Nujol): ν = 3330, 1605, 1582,
˜
2,3,9,10-Tetramethoxy-7,11b,12,13-tetrahydro-6H-dibenzo[a,f]-
quinolizine (10): A colorless oil (50%) from 9: H NMR: δ = 2.02–
1514 cm–1. FAB–MS m/z (%) = 363 [M]+ (17). HRMS (FAB–):
1
calcd. for C17H20BrN2O2 363.0709; found 363.0705.
2.20, 2.21–2.32 (each m, each 1 H, 13-H), 2.68–2.98 (m, 4 H, 5-
and 12-H), 3.22–3.35, 3.67–3.79 (each m, each 1 H, 6-H), 3.81,
3.86, 3.87, 3.88 (each s, each 3 H, OMe), 4.24 (br. dd, J = 9.2,
2.0 Hz, 13a-H), 6.55, 6.57, 6.61, 6.72 (each s, each 1 H, Ar-H) ppm.
2-(3-Bromo-4-pyridyl)-N-[2-(3-indolyl)ethyl]acetamide (28): A solu-
tion of 23[25b,25c] (4.00 g, 16.4 mmol) and tryptamine (2.63 g,
16.4 mmol) in xylene (40 mL) was heated at reflux for 2 d. Xylene
was removed in vacuo, and the residue was crystallized from EtOAc
to give the acetamide 28 (5.15 g, 88%) as colorless crystals; m.p.
IR (Nujol): ν = 1608, 1572, 1518 cm–1. MS (EI): m/z (%) = 355
˜
(100) [M]+, 354 (57), 340 (65). HR-MS: calcd. for C21H25NO4
355.1783; found 355.1763.
1
133 °C. H NMR: δ = 2.96 (t, J = 6.6 Hz, 2 H, ArCH2), 3.59 (s, 2
Pd0-Catalyzed Intramolecular Cycloamination of 11, 12, and 17.
Preparation of 15a–c and 18: Pd(OAc)2 (1.1 mg, 0.005 mmol),
Cu(OAc)2 (9.0 mg, 0.05 mmol), and K2CO3 (69.1 mg, 0.5 mmol)
were added to a stirred solution of 12a (34.1 mg, 0.1 mmol) in tolu-
ene (2 mL). The mixture was heated at reflux for 24 h, allowed to
cool, and filtered through a Celite pad, and the filtrate was concen-
trated to give a crude product (20 mg) consisting 15a and ketone
16[23e,64] (9:1), which was purified by preparative TLC on silica gel
(MeOH/CH2Cl2, 5%). A band with Rf = 0.4 gave benz[f]indolo[2,3-
a]indolizin-13-one (15a, 8.5 mg, 69%) as pale yellow crystals, m.p.
254–259 °C (EtOH/hexane). 1H NMR: δ = 7.45 (t, J = 7.9 Hz, 2
H, 10- and 9-H), 7.71 (t, J = 7.3 Hz, 1 H, 3-H), 7.84 (dt, J = 1.3,
7.3, 7.3 Hz, each 1 H, 2-H), 8.11 (d, J = 5.0 Hz, 1 H, 7-H), 8.15,
8.18 (dt, J = 7.9 Hz, each 1 H, 8- and 11-H), 8.27 (d, J = 8.6 Hz,
1 H, 4-H), 8.68 (dd, J = 8.6, 1.3 Hz, 1 H, 1-H), 8.97 (d, J = 5.0 Hz,
1 H, 6-H) ppm. 13C NMR: δ = 114.1, 115.3, 118.0, 123.1, 123.5,
123.8, 124.3, 126.2, 129.5, 130.8, 132.1, 134.3, 135.2, 135.5, 138.7,
H, CH2CO), 3.61 (t, J = 6.6 Hz, 2 H, CH2N), 5.54 (br. s, 1 H,
NH), 6.91 (d, J = 2.3 Hz, 1 H, 2Ј-H), 7.12, 7.21 (each t, J = 7.3 Hz,
1 H, 5Ј- and 6Ј-H), 7.19 (d, J = 5.0 Hz, 1 H, 5ЈЈ-H), 7.37 (d, J =
7.3 Hz, 1 H, 4Ј-H), 7.56 (d, J = 7.3 Hz, 1 H, 7Ј-H), 8.07 (br. s, 1
H), 8.39 (d, J = 5.0 Hz, 1 H, 6ЈЈ-H), 8.64 (s, 1 H, 2ЈЈ-H) ppm. 13C
NMR: δ = 24.9, 39.9, 43.0, 111.3, 112.4, 118.5, 119.5, 122.1, 122.2,
123.3, 126.1, 127.1, 136.4, 143.6, 148.4, 151.9, 167.7 ppm. IR (Nu-
jol): ν = 3266, 1644, 1568 cm–1. EI–MS m/z (%) = 359 [M]+ (3),
˜
357 [M]+ (3), 143 (100), 130 (67). C17H15BrN3O: calcd. C 57.00, H
4.50, Br 22.31, N 11.73; found C 57.07, H 4.57, Br 22.41, N 11.60.
1-[(3-Bromo-4-pyridyl)methyl]-1,2,3,4-tetrahydro-β-carboline (30):
POCl3 (20 mL) was added to a solution of the acetamide 28
(358 mg, 1.0 mmol) in MeOH (1 mL). The mixture was heated at
80 °C for 5 h and poured onto ice (50 g). After having been stirred
for 1 h, the mixture was basified with NaOH solution (6 n),
extracted with CH2Cl2 (3 ϫ 100 mL), washed with water
(3ϫ100 mL), and dried with Na2SO4. The solvent was evaporated
to afford the air-sensitive 3,4-dihydro-β-carboline 29 as a solid;
m.p. 152–159 °C. 1H NMR: δ = 2.91, 3.95 (each t, J = 5.6 Hz, each
1 H, CH2CH2), 4.09 (s, 2 H, CH2Py), 7.14, 7.16 (each t, J = 4.6 Hz,
each 1 H, 6- and 7-H), 7.39 (d, J = 5.7 Hz, 1 H, 5-H), 7.49 (d, J =
3.8 Hz, 1 H, 5Ј-H), 7.56 (d, J = 5.7 Hz, 1 H, 8-H), 8.37 (d, J =
3.8 Hz, 1 H, 6Ј-H), 8.66 (s, 1 H, 2Ј-H) ppm.
139.6, 144.9, 177.7 ppm. IR (Nujol): ν = 1650 cm–1. MS (EI): m/z
˜
(%) = 271 (20.6) [M + H]+ , 270 (100) [M]+, 241 (12.1), 149 (20.4),
142 (17.1), 121 (9.8), 57 (19.7). C18H10N2O (270.29): calcd. C 79.99,
H 3.73, N 10.36; found C 79.84, H 3.96, N 10.29. Similarly, 15a
was obtained from 11a in 36% yield.
3,4-Dimethoxy-13H-benz[f]indolo[2,3-a]indolizin-13-one (15b): This
compound was obtained in 76% yield from 12b, 35% from 11b;
This compound was dissolved in MeOH (20 mL), and NaBH4
(113 mg, 3 mmol) was added. The mixture was stirred at room
temp. for 2 h and concentrated, diluted with water (20 mL) and
CH2Cl2 (3 ϫ 20 mL), washed with water (20 mL), and dried
(Na2SO4). The solvent was evaporated, and the residue (348 mg)
was treated with CHCl3 to give the amine 30 as colorless crystals
(216 mg, 0.63 mmol, 63%); m.p. 176 °C (CHCl3). 1H NMR: δ =
2.75, 3.03, 3.29 (each m, each 2 H, each CH2), 4.42 (dd, J = 9.6,
4.6 Hz, 1 H, 1-H), 7.12, 7.17 (each t, J = 7.3 Hz, each 1 H, 6- and
7-H), 7.31 (d, J = 4.9 Hz, 1 H, 5Ј-H), 7.33 (d, J = 7.3 Hz, 1 H, 5-
H), 7.51 (d, J = 7.3 Hz, 1 H, 8-H), 7.71 (br. s, 1 H, NH), 8.48 (d,
J = 4.9 Hz, 1 H, 6Ј-H), 8.77 (s, 1 H, 2Ј-H) ppm. 13C NMR (CDCl3/
[D6]DMSO): δ = 39.5, 39.9, 41.4, 51.6, 110.8, 110.8, 117.8, 118.8,
121.2, 123.3, 126.2, 127.0, 134.8, 135.7, 147.1, 147.9, 151.7 ppm.
1
pale yellow crystals; m.p. 185–187 °C (EtOH/hexane). H NMR: δ
= 3.59, 4.12 (each s, each 3 H, OMe), 7.16 (d, J = 8.9 Hz, 1 H, 2-
H), 7.47 (t, J = 7.3 Hz, 1 H, 10-H), 7.68 (dt, J = 1.3, 7.3 Hz, 1 H,
9-H), 8.18 (d, J = 5.0 Hz, 1 H, 7-H), 8.19 (d, J = 8.6 Hz, 1 H, 11-
H), 8.54 (d, J = 8.6 Hz, 9-H), 8.55 (d, J = 8.9 Hz, each 1 H, 1-H),
9.00 (d, J = 5.0 Hz, 1 H, 6-H) ppm. IR (neat): ν = 1656 cm–1. MS
˜
(EI): m/z (%) = 331 (22.7) [M + 1]+, 330 (100) [M]+, 315 (87.2),
300 (33.7), 272 (18.9). C20H14N2O3 (330.34): calcd. C 72.72, H 4.27,
N 8.48; found C 72.52, H 4.15, N 8.52.
2,3-Dimethoxy-13H-benz[f]indolo[2,3-a]indolizin-13-one (15c): This
compound was obtained in 75% yield from 12c, 42% from 11c;
1
pale yellow crystals; m.p. 281–283 °C (EtOH/hexane). H NMR: δ
= 4.07, 4.18 (each s, each 3 H, OMe), 7.53 (t, J = 7.9 Hz, 1 H, 10-
H), 7.75 (s, 1 H, 4-H), 7.78 (t, J = 7.9 Hz, 1 H, 9-H), 8.12 (s, 1 H,
1-H), 8.15 (d, J = 6.9 Hz, 1 H, 8-H), 8.17 (d, J = 5.0 Hz, 1 H, 7-
H), 8.27 (dd, J = 6.9, 0.7 Hz, 1 H, 11-H), 9.05 (d, J = 5.0 Hz, 1 H,
IR (Nujol): ν = 3280, 1587 cm–1. EI–MS: m/z (%) = 343 (11)
˜
[M]+, 341 (12) [M]+, 169 (100), 93 (45). C17H16BrN3: calcd. C 59.66,
H 4.71, Br 23.35, N 12.28; found C 59.49, H 4.68, Br 23.37, N
12.26.
6-H) ppm. IR (neat): ν = 1614 cm–1. MS (EI): m/z (%) = 331 (24.2)
˜
[M + H]+, 330 (100) [M]+, 315 (36.2), 287 (21.4), 272 (11.4).
C20H14N2O3 (330.34): calcd. C 72.72, H 4.27, N 8.48; found C
72.81, H 4.24, N 8.39.
A General Procedure for Pd0-Catalyzed Cycloamination of 6, 7, and
9. Preparation of 8 and 10: Pd(OAc)2 (1.1 mg, 0.005 mmol),
Cu(OAc)2 (9.0 mg, 0.05 mmol), and K2CO3 (69.1 mg, 0.5 mmol)
were added under Ar to a stirred solution of a 2Ј-halophenyl-alk-
ylamine 6, 7, or 9 (0.1 mmol) in toluene (2 mL). The mixture was
2,3-Dimethoxy-13,14-dihydrobenz[f]indolo[2,3-a]quinolizine (18):
This compound was obtained in 42% yield from 17; yellow crystals;
Eur. J. Org. Chem. 2012, 366–379
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
375

K. Orito et al.
FULL PAPER
m.p. 199–201 °C (EtOH). 1H NMR: δ = 3.15–3.35, 3.44–3.48 (each
br. m, each 2 H, 13- and 14-H), 3.84, 3.97 (each s, each 3 H, OMe),
6.89, 7.36 (each s, each 1 H, 1- and 4-H), 7.35 (dt, J = 1.0, 7.6,
7.6 Hz, Ar-H), 7.59 (dt, J = 1.3, 7.3, 7.3 Hz, 1 H, Ar-H), 7.83 (d,
J = 5.3 Hz, 1 H, 7-H), 7.91 (d, J = 8.6 Hz, 1 H, Ar-H), 8.17 (dd,
J = 1.0, 7.6 Hz, 1 H, Ar-H), 8.38 (d, J = 5.3 Hz, 1 H, 6-H) ppm.
5,6,8,13,13a,14-Hexahydro-indolo[2,3-a]pyrido[3,4-g]quinolizin-8-
one (36) [(؎)-Dihydronaucléfine]: The amine 30 (34 mg, 0.1 mmol)
was carbonylated in boiling dioxane (1.5 mL) for 24 h in a manner
similar to that described above to give a crude oily product (32 mg),
which was purified by preparative TLC (MeOH/CH2Cl2, 3%). A
main band with Rf = 0.1 gave 36 (24 mg, 83%) as pale-yellow crys-
IR (Nujol): ν = 3020, 1619, 1573, 1518, 1452 cm–1. MS (EI): m/z tals, m.p. 245 °C (AcOEt/hexane, ref.[33b] m.p. 266–268 °C).
˜
(%) = 331 (23.9), 330(100), 315(31.9), 287(21.7), 149(9.3), 128(6.8).
Supporting Information (see footnote on the first page of this arti-
C
21H18N2O2 (330.39): calcd. C 76.34, H 5.49, N 8.48; found C
1
cle): Copies of the H and 13C NMR spectra of the produced new
76.27, H 5.41, N 8.43.
tetra- and pentacyclic compounds 10, 15a, 15b, 15c, 18, 20, 27, and
31.
12-Methyl-2,3-dimethoxy-7,12-dihydro-6H-benz[f]indolo[2,3-a]indol-
izine (20): This was obtained from 19 by the method for the cyclo-
amination of 12. Dark green crystals (75%). 1H NMR: δ = 3.24 (t,
J = 6.6 Hz, 2 H, 7-H), 3.95 (s, 3 H, NMe), 3.99, 4.01 (each s, each
3 H, OMe), 4.24 (t, J = 6.6 Hz, 2 H, 6-H), 6.69, 6.84 (each s, each
1 H, 1- and 4-H), 7.10 (s, 1 H, 13-H), 7.14 (dt, J = 1.0, 6.9, 6.9 Hz,
1 H, 9-H), 7.23 (dt, J = 1.3, 6.9, 6.9 Hz, 1 H, 10-H), 7.35 (d, J =
7.9 Hz, 1 H, 11- or 8-H), 7.56 (dd, J = 1.0, 7.6 Hz, 1 H, 8- or 11-
Acknowledgments
We thank the Akiyama Foundation for generous financial support
and N. E. ChemCat. Co. Ltd. for the generous donation of palla-
dium catalysts.
H) ppm. IR (CHCl ): ν = 1713, 1610 cm–1. MS (EI): m/z (%) =
˜
3
332 (100) [M]+, 317(53.0), 166(27.4), 144(11.7). HRMS: calcd. for
[1] For selected recent reviews on Pd-, Ni-, Cu-, or Fe-catalyzed
aryl amination, see: a) J. F. Hartwig, Synlett 1997, 329–340; b)
J. P. Wolfe, S. Wagaw, J. F. Marcoux, S. L. Buchwald, Acc.
Chem. Res. 1998, 31, 805–818; c) J. F. Hartwig, Acc. Chem. Res.
1998, 31, 852–860; d) J. F. Hartwig, Angew. Chem. 1998, 110,
2154; Angew. Chem. Int. Ed. 1998, 37, 2046–2067; e) B. H.
Yang, S. L. Buchwald, J. Organomet. Chem. 1999, 576, 125–
146; f) A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002,
219, 131–209; g) S. V. Ley, A. W. Thomas, Angew. Chem. 2003,
115, 5558; Angew. Chem. Int. Ed. 2003, 42, 5400–5449; h) A.
Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350; Angew. Chem.
Int. Ed. 2002, 41, 4176–4211; i) K. Kunz, U. Ascholz, D.
Ganzer, Synlett 2003, 2428–2439; j) B. Schlummer, U. Schholz,
Adv. Synth. Catal. 2004, 346, 1599–1626; k) R. B. Bedford,
C. S. J. Cazin, D. Holder, Coord. Chem. Rev. 2004, 248, 2283–
2321; l) J. P. Wolfe, J. S. Thomas, Curr. Org. Chem. 2005, 9,
625–655; m) J. F. Hartwig, Synlett 2006, 1283–1294; n) J.-P.
Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651–2710; o) D.
Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450–1460; p) M. Catel-
lani, E. Motti, N. D. Cá, Acc. Chem. Res. 2008, 41, 1534–1544;
q) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534–1544; r) F.
Monnier, M. Taillefer, Angew. Chem. 2008, 120, 3140; Angew.
Chem. Int. Ed. 2008, 47, 3096–3099.
C21H20N2O2 332.1525; found 332.1528.
2,3-Dimethoxy-5,6-dihydrobenzo[a]pyrido[3,4-f]indolizine (27): This
compound was obtained in 56% yield from 25, 70% yield from 26;
m.p. 188–190 °C (MeOH/Et2O). 1H NMR: δ = 3.18 (each t, J =
6.6 Hz, 2 H, 5-H), 3.94, 3.97 (each s, each 3 H, OMe), 4.33 (t, J =
6.6 Hz, 2 H, 6-H), 6.70. 6.80 (s, 1 H, 1- and 4-H), 7.26 (s, 1 H, 12-
H), 7.47, 8.22 (each d, J = 7.3 Hz, 1 H, 11- and 10-H), 8.73 (s, 1
H, 8-H) ppm. 13C NMR (67.8 MHs, [D6]DMSO): δ = 27.6, 39.5
(overlapped, 40.5 in CDCl3), 55.6, 55.8, 94.4, 108.5, 111.8, 114.1,
119.6, 126.2, 132.6, 132.6, 133.4, 138.4, 138.9, 148.1, 149.5 ppm.
IR (Nujol): ν = 1600, 1597 cm–1. MS (EI): m/z (%) = 280 (91)
˜
[M]+, 265 (22) [M – 15]+, 237 (37.9) [M – 43]+. C17H16N2O2
(280.33): calcd. C 72.84, H 5.75, N 9.99; found C 72.78, H 5.49, N
9.92.
13-Oxo-13H-indolo[2,3-a]pyrido[3,4-f]indolizine (31): This com-
pound was obtained in 36% yield from 29, 65% from 30, as a dark
1
green oil. H NMR: δ = 7.60 (t, J = 7.6 Hz, 1 H, 10-H), 7.87 (dt,
J = 1.0, 7.6, 7.6 Hz, 1 H, 9-H), 8.29 (d, J = 5.3 Hz, 1 H, 7-H), 8.30,
8.37 (each d, J = 7.6 Hz, each 1 H, 8- or 11-H), 8.52 (d, J = 5.3 Hz,
1 H, 6-H), 8.79 (dd, J = 4.6, 0.7 Hz, 1 H, 2-H), 9.11 (d, J = 4.6 Hz,
1 H, 1-H), 9.98 (br. s, 1 H, 4-H) ppm. IR (CDCl ): ν = 1671 cm–1.
[2] R. Laxmidhar, P. Saha, J. Suribabu, T. Punniyamurthy, Adv.
Synth. Catal. 2008, 350, 395–398.
˜
3
MS (EI): m/z (%) = 272 (21.1) [M + 1]+, 271 (100) [M]+, 242 (9.9),
216 (35.8), 188 (9.0), 149 (6.4). HRMS: calcd. for C17H9N3O
271.0745; found 271.0747.
[3] For selected papers (1995–2004) on benzocyclic amine synthe-
sis through Pd0-catalyzed intramolecular aryl amination, see:
a) A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem.
1995, 107, 1456; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348–
1350; b) M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1995,
117, 4708–4709; c) A. J. Peat, S. L. Buchwald, J. Am. Chem.
Soc. 1996, 118, 1028–1030; d) J. P. Wolfe, R. A. Rennels, S. L.
Buchwald, Tetrahedron 1996, 52, 7525–7546; e) S. Wagaw,
R. A. Rennels, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
8451–8458; f) J. L. Wood, B. M. Stolz, H.-J. Dietrich, D. A.
Pflum, D. T. Petsch, J. Am. Chem. Soc. 1997, 119, 9641–9651;
g) A. Abouabdellah, R. H. Dodd, Tetrahedron Lett. 1998, 39,
2119–2122; h) K. Aoki, A. J. Peat, S. L. Buchwald, J. Am.
Chem. Soc. 1998, 120, 3068–3073; i) B. H. Yang, S. L. Buch-
wald, Org. Lett. 1999, 1, 35–37; j) T. Iwaki, A. Yasuhara, T.
Sakamoto, J. Chem. Soc. Perkin Trans. 1 1999, 1505–1510; k) T.
Emoto, N. Kubosaki, Y. Yamagiwa, T. Kamikawa, Tetrahedron
Lett. 2000, 41, 355–358; l) J. Brown, Tetrahedron Lett. 2000,
41, 1623–1626; m) J. J. Song, N. K. Yee, Org. Lett. 2000, 2,
519–521; n) Y.-M. Zhu, Y. Kiryu, H. Katayama, Tetrahedron
Lett. 2002, 43, 3577–3580; o) K. Yamazaki, Y. Nakamura, Y.
Kondo, J. Chem. Soc. Perkin Trans. 1 2002, 2137–2138; p) G.
Evindar, R. A. Batey, Org. Lett. 2003, 5, 133–136; q) B. J. Mag-
2,3-Dimethoxyberbin-8-one (33). A General Procedure for Carbon-
ylation: A mixture of 1-(2-bromobenzyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline[65] (7a, 36 mg, 0.10 mmol), Cu(OAc)2
(9.1 mg, 0.05 mmol), Pd(OAc)2 (1.1 mg, 0.005 mmol), and K2CO3
(28 mg, 0.20 mmol) in toluene (1.5 mL) was heated at reflux under
CO gas for 12 h. The resulting mixture was filtered through a pow-
dered anhydrous MgSO4 pad and concentrated to give an oily resi-
due (34 mg), which was crystallized from MeOH to give 33 as col-
orless crystals (25 mg, 80%), m.p. 142–144 °C (ref.[65,66c] m.p. 141–
132 °C; ref.[66a] m.p. 142 °C; ref.[66b] m.p. 143–145 °C).
2,3-Dimethoxy-5,6,13,13a-tetrahydro-8H-isoquino[2,1-b][2,7]-
naphthyridin-8-one (34): The amine 26 (36 mg, 0.1 mmol) was car-
bonylated in boiling toluene (1.5 mL) in a manner similar to that
described in the above general procedure. The oily crude product
(35 mg) was purified by preparative TLC (MeOH/CH2Cl2, 5%). A
main band with Rf = 0.4 was crystallized from CH2Cl2/hexane to
give the lactam 34 (26 mg, 83%) as pale yellow crystals, m.p. 174–
175 °C (ref.[29a,29d] m.p. 173–175 °C).
376
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 366–379

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For selected papers (2005–2010) on benzocyclic amine synthe-
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Pd -catalytic systems generated with the other reagents
Pd2(dba)3/Cu(OAc)2 and Pd(acac)2/Cu(OAc)2 in the presence
of K2CO3 also afforded 9:1 mixtures of the cyclization product
2c and the reactant 1c-I.
Eur. J. Org. Chem. 2012, 366–379
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
377

K. Orito et al.
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378
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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