Diversity-oriented microwave-assisted synthesis of the 3-benzazepine framework

Article abstract of DOI:10.1002/ejoc.201000583

An efficient diversity-oriented procedure for the two-step synthesis of 3-benzazepines is described. The Cd^I-catalyzed three-component coupling of an aldehyde, an alkyne and an amine (A³-couplingj provides the required propargylamine

Full text of DOI:10.1002/ejoc.201000583

FULL PAPER
DOI: 10.1002/ejoc.201000583
Diversity-Oriented Microwave-Assisted Synthesis of the 3-Benzazepine
Framework
Vsevolod A. Peshkov,[a] Olga P. Pereshivko,[a] Pavel A. Donets,[a] Vaibhav P. Mehta,[a] and
Erik V. Van der Eycken*[a]
Keywords: C-C coupling / Cyclization / Nitrogen heterocycles / Medium-ring compounds / Microwave chemistry
An efficient diversity-oriented procedure for the two-step
synthesis of 3-benzazepines is described. The CuI-catalyzed
three-component coupling of an aldehyde, an alkyne and an
amine (A3-coupling) provides the required propargylamines
and assures the generation of diversity. The Pd-catalyzed in-
tramolecular acetylene hydroarylation reaction selectively
creates the seven-membered 3-benzazepine framework with
full control over the ring size and the geometry around the
double bond. Microwave irradiation is demonstrated to be
highly efficient in promoting both steps.
azepines have been synthesized and studied for the use as
potent NMDA receptor antagonists (Figure 1).[5]
Introduction
The 3-benzazepine framework is widespread among bio-
logically active and natural compounds. Several efforts have
been made towards the synthesis of alkaloids such as
aphanorphine,[1] lennoxamine,[2] and cephalotaxine[3] (Fig-
ure 1) due to their challenging chemical structures and
interesting biological activities. Dizocilpine, also known as
MK-801, represents a noncompetitive N-methyl--aspart-
ate (NMDA) receptor antagonist and has been extensively
studied for treatment of neurodegenerative diseases such as
Huntington’s, Alzheimer’s, and amyotrophic lateral sclero-
sis.[4] Variously substituted at position 1, different 3-benz-
The seven-membered ring of the 3-benzazepine scaffold
has been constructed through various methods including
intramolecular Friedel–Crafts alkylation,[1b–1d,6] intramo-
lecular radical cyclization[1a,1e] and C–N bond formation
via intramolecular reductive amination.[5] Transition-metal-
catalyzed reactions were also used for generating the 3-
benzazepine framework.[3a,3b,7] Recently, we have reported
a novel approach towards the selective and facile formation
of 1-substituted 3-benzazepinones through the microwave-
assisted Pd-catalyzed intramolecular acetylene hydroaryl-
ation[8–9] reaction, which occurs with full regio- and stereo-
selectivity.[10]
Results and Discussion
Herein we wish to report a new and efficient two-step
protocol for the diversity-oriented synthesis of 3-benzazep-
ines 3, applying a microwave-assisted CuI-catalyzed three-
component coupling of an aldehyde, an alkyne and an
amine (well established multicomponent reaction com-
monly called A3-coupling)[11–12] providing the required pro-
pargylamines 2, followed by a regio- and stereoselective
Pd-catalyzed intramolecular acetylene hydroarylation
(Scheme 1).
The reaction conditions for the A3-coupling were opti-
mized applying the 2-phenylethylamine 1a,[13] isovaleral-
dehyde and phenylacetylene in a ratio (1:1.1:2).[14] The reac-
tion was performed with 10 mol-% CuI as the catalyst un-
der solventless conditions. Gratifyingly upon microwave ir-
radiation at a ceiling temperature of 90 °C and a maximum
power of 50 W for 30 min the desired propargylamine 2a
was formed in 79% yield (Table 1, entry 1). Increasing the
amount of catalyst to 15 mol-% resulted in an excellent
View this journal online at
Figure 1. Alkaloids and NMDA receptor antagonist containing the
3-benzazepine framework.
[a] Laboratory for Organic & Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, Katholieke Universiteit
Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax: +32-16-32-79-90
E-mail: erik.vandereycken@chem.kuleuven.be
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000583.
wileyonlinelibrary.com
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E. V. Van der Eycken et al.
FULL PAPER
coupling reaction with various amines 1a–c.[13] All reactions
proceeded smoothly delivering the corresponding propar-
gylamines 2a–j in 73–95% yield (Table 2, entries 1–10). To
circumvent problems associated with the handling of gas-
eous formaldehyde, 1,3,5-trioxane was successfully used
(Table 2, entry 6). In one case the use of toluene was re-
quired to prevent the formation of a side-product due to
double addition of alkyne to amine (vide infra) (Table 2,
entry 5).[15]
Table 2. Generation of propargylamines applying the optimized A3-
coupling protocol.[a]
Scheme 1. Retrosynthesis for the construction of the 3-benzazepine
framework.
yield of 92% (Table 1, entry 2). The application of CuBr
instead of CuI delivered compound 2a in a comparable
yield of 86% (Table 1, entry 3). However, when the reaction
was conducted at a lower temperature of 70 °C the propar- Entry (product) R1, n
R2
R3
Yield[b]
gylamine 2a was obtained in a moderate yield of 68%
(Table 1, entry 4). Also a shorter irradiation time of 20 min
resulted in a lower yield (Table 1, entry 5). Solventless con-
ditions seemed to be appropriate as the use of toluene re-
sulted in a comparable yield of 89% (Table 1, entry 6).
When the reaction was conducted under conventional heat-
ing at 90 °C for 3 h the desired propargylamine 2a was also
obtained in a high yield of 90% (Table 1, entry 7). However,
our attempt to perform the reaction at 25 °C met with fail-
ure (Table 1, entry 8).
1 (2a)
2 (2b)
3 (2c)
4 (2d)
5 (2e)
6 (2f)
7 (2g)
8 (2h)
9 (2i)
10 (2j)
PMB, 1
PMB, 1
PMB, 1
PMB, 1
PMB, 1
PMB, 1
iPr, 1
iPr, 1
PMB, 2
PMB, 2
iBu
iBu
Pr
Ph
92
87
95
4-fluorophenyl
Ph
Pr
4-methoxyphenyl
Ph
Ph
thiophene-3-yl
Ph
4-methoxyphenyl
Ph
Ph
73
81[c]
80
H[d]
iBu
iBu
iBu
Pr
86
81
82
91
[a] The reactions were carried out with the amine 1 (0.5 mmol), an
aldehyde (0.55 mmol) and an alkyne (1 mmol) in the presence of
CuI (15 mol-%), neat, under microwave irradiation at a ceiling tem-
perature of 90 °C and a maximum power of 50 W for 30 min. [b]
Isolated yields are reported. [c] The reaction was performed in tolu-
ene (2 mL). [d] The reaction was performed with 1,3,5-trioxane
(0.2 mmol).
Table 1. Optimization of the A3-coupling conditions.[a]
We have also examined the CuI-catalyzed tandem anti-
Markovnikov hydroamination and alkyne addition reaction
recently reported by Li for the synthesis of propargyl-
amines[15] (Scheme 2). Gratifyingly propargylamines 2k,l re-
sulted from the reaction of alkyne and amine 1a in a ratio
(1.5:0.5), using similar microwave-assisted conditions as for
our A3-coupling protocol, at a slightly increased ceiling
temperature of 100 °C (Scheme 2).
Entry Temp. Catalyst
Time [min] Condition[b]
Yield[c]
[°C]
(mol-%)
1
2
3
4
5
6
7
90
90
90
70
90
90
90
CuI (10)
CuI (15)
CuBr (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
30
30
30
30
20
30
3 h
neat, MW
neat, MW
neat, MW
neat, MW
neat, MW
toluene, MW
toluene,
79
92
86
68
76
89
90
conventional
toluene,
[d]
8
25
CuI (5)
24 h
–
conventional
[a] The reactions were performed with the amine 1a (0.5 mmol),
isovaleraldehyde (0.55 mmol) and phenylacetylene (1 mmol). [b]
When the reaction was run under microwave irradiation a maxi-
mum power of 50 W was used. [c] Isolated yields are reported. [d]
2-Phenylethylamine 1a was recovered.
Scheme 2. Generation of propargylamines 2k,l via a CuI-catalyzed
tandem anti-Markovnikov hydroamination, alkyne addition reac-
tion.
We then investigated the cyclization of the generated pro-
Having the optimized microwave-assisted protocol at pargylamines 2a–h,k,l applying our previously reported Pd-
hand, we generated a small library of propargylamines 2a– catalyzed intramolecular acetylene hydroarylation protocol
j (Table 2). An array of aromatic and aliphatic alkynes and that was developed for propargylic amides.[10] Carrying out
aldehydes were successfully explored as partners in the A3- the reactions under microwave irradiation at a ceiling tem-
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Diversity-Oriented Synthesis of the 3-Benzazepine Framework
perature of 110 °C and a maximum power of 100 W for
15 min in the presence of 3 mol-% of Pd(PPh3)4 as the cata-
lyst and sodium formate as the reducing agent, the desired
3-benzazepines 3a–h,k,l were obtained in yields of 63–91%
(Table 3, entries 1–8, 11–12). To explore the general applica-
bility of our strategy for the synthesis of medium-sized
rings, we also evaluated the protocol for the generation of
benzo-azocines. Reacting the propargylamines 2i,j we were
able to achieve the expanded 8-membered rings 3i,j in 40%
and 32%, respectively (Table 3, entries 9 and 10). The lower
yields could probably be ascribed to the higher conforma-
tional freedom of the starting propargylamines 2i,j. As a
result the formation of considerable amount of debromi-
nated by-product 4 was observed (see Scheme 3).
Table 3. Scope and limitations of the process.[a]
Entry
(product)
R1, n
R2
R3
Yield[b]
1 (3a)
2 (3b)
3 (3c)
4 (3d)
5 (3e)
6 (3f)
7 (3g)
8 (3h)
9 (3i)
PMB, 1
PMB, 1
PMB, 1
PMB, 1
PMB, 1
PMB, 1
iPr, 1
iBu
iBu
Pr
Ph
Ph
H
iBu
iBu
iBu
Pr
Ph
80
84
91
77
70
70
72
73
40
32
71
4-fluorophenyl
Ph
Pr
4-methoxyphenyl
Ph
Ph
thiophene-3-yl
Ph
4-methoxyphenyl
Ph
iPr, 1
Scheme 3. Proposed pathway of the Pd-catalyzed intramolecular
acetylene hydroarylation reaction.
PMB, 2
PMB, 2
PMB, 1
10 (3j)
11 (3k)
Bn
formed (n = 1 or 2). An alternative pathway resulting in the
formation of the debrominated by-product 4 is also pre-
sented (Scheme 3).
12 (3l)
PMB, 1
3-fluorophenyl
63
[a] The reactions were carried out with propargylamines 2a–l
(0.4 mmol) in the presence of HCOONa (0.6 mmol) and Pd-
(PPh3)4 (3 mol-%) in DMF/H2O (3:1) (6 mL), under microwave ir-
radiation at a ceiling temperature of 110 °C and a maximum power
of 100 W for 15 min. [b] Isolated yields are reported.
Conclusions
In summary, we have developed a new and efficient two-
step protocol for the diversity-oriented synthesis of 3-
benzazepines. The first step is a CuI-catalyzed three-compo-
nent coupling of an aldehyde, an alkyne and an amine (A3-
coupling) leading to propargylamines, that are the key in-
termediates for the regio- and stereoselective Pd-catalyzed
intramolecular acetylene hydroarylation that generates the
3-benzazepine skeleton. Microwave irradiation is demon-
strated to be highly effecient in promoting both steps. The
applicability of this strategy for the synthesis of some
benzazepine alkaloids and analogues is under current inves-
tigation.
A possible pathway of the Pd-catalyzed intramolecular
acetylene hydroarylation is presented in Scheme 3. Due to
the syn-addition to the triple bond, our strategy exclusively
provides compounds 3 possessing the Z-configuration of
the exocyclic double bond. Moreover, the regioselectivity of
the hydroarylation reaction and, as a result, the ring size of
the generated medium-sized ring, is also governed by the
mode of reaction. As the initially generated arylpalladium
π-complex A is transformed into a σ-vinyl palladium com-
plex B via simultaneous syn-addition to the triple bond,
endocyclization via a hypothetical intermediate C is fairly
unlikely due to the high strain exerted by the trans-
geometry around the double bond in the medium-sized
Experimental Section
General: 1H and 13C NMR spectra were recorded on a Bruker Av-
ring. As a result only 7- or eight-membered rings are ance 300 instrument. The 1H and 13C chemical shifts were reported
Eur. J. Org. Chem. 2010, 4861–4867
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E. V. Van der Eycken et al.
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in parts per million (ppm) relative to tetramethylsilane using the
residual solvent signal as the internal reference. Mass spectra were
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 2c as a yellow oil (255 mg, 95 %). 1H NMR
(CDCl3, 300 MHz): δ = 7.47–7.39 (m, 2 H), 7.34–7.20 (m, 5 H),
6.97 (s, 1 H), 6.83 (d, J = 8.6 Hz, 2 H), 6.65 (s, 1 H), 3.91 (d, J =
13.7 Hz, 1 H), 3.84 (s, 3 H), 3.82–3.78 (m, 6 H), 3.63 (t, J = 7.5 Hz,
1 H), 3.54 (d, J = 13.7 Hz, 1 H), 2.99–2.60 (m, 4 H), 1.71–1.58 (m,
2 H), 1.46–1.32 (m, 2 H), 0.85 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 158.55, 148.13, 147.85, 132.02, 131.91,
131.75, 129.94, 128.22, 127.77, 123.59, 115.41, 114.17, 113.68,
113.52, 88.75, 84.67, 56.14, 55.96, 55.31, 55.26, 53.09, 50.90, 36.23,
35.06, 19.73, 13.86 ppm. MS (ESI+) calcd. for C30H34BrNO3:
535.2; found: m/z 536.9 [M + H]+.
run using
a Micromass Quattro II apparatus (ESI) with
MASSLYNX data system or a Thermo Finnigan LCQ Advantage
apparatus (ESI). High-resolution mass spectra were recorded on a
Kratos MS50TC system. The ion source temperature was 150–
250 °C, as required. High-resolution EI-mass spectra were recorded
with a resolution of 10000.
Microwave Irradiation Experiments: All microwave irradiation ex-
periments were carried out in a dedicated CEM-Discover monom-
ode microwave apparatus, operating at a frequency of 2.45 GHz
with continuous irradiation power from 0–300 W. The reactions
were carried out in 10 mL glass tubes, sealed with Teflon septum
and placed in the microwave cavity. The reaction mixture was irra-
diated at the indicated ceiling temperature and maximum power
for the stipulated time. Then it was cooled to ambient temperature
with gas jet cooling.
N-(2-Bromo-4,5-dimethoxyphenethyl)-N-(4-methoxybenzyl)-1-
phenylhex-2-yn-1-amine (2d): Synthesized from benzaldehyde
(58 mg, 0.55 mmol), pent-1-yne (68 mg, 1 mmol) and amine 1a
(190 mg, 0.5 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20 %) yielding
propargylamine 2d as a yellow oil (196 mg, 73 %). 1H NMR
(CDCl3, 300 MHz): δ = 7.55–7.48 (m, 2 H), 7.30–7.18 (m, 5 H),
6.91 (s, 1 H), 6.82 (d, J = 8.6 Hz, 2 H), 6.48 (s, 1 H), 4.73 (s, 1 H),
3.85–3.70 (m, 10 H), 3.49 (d, J = 13.4 Hz, 1 H), 2.82–2.58 (m, 4
H), 2.39–2.30 (m, 2 H), 1.72–1.58 (m, 2 H), 1.08 (t, J = 7.3 Hz, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.56, 147.99, 147.70,
139.93, 131.89, 131.77, 129.98, 128.27, 127.77, 127.02, 115.23,
114.18, 113.55, 113.40, 88.08, 75.37, 56.32, 56.11, 55.86, 55.24,
54.93, 50.26, 34.59, 22.66, 20.89, 13.69 ppm. MS (ESI+) calcd. for
C30H34BrNO3: 535.2; found: m/z 536.8 [M + H]+.
N-(2-Bromo-4,5-dimethoxyphenethyl)-N-(4-methoxybenzyl)-5-
methyl-1-phenylhex-1-yn-3-amine (2a): General experimental pro-
cedure for A3-coupling: Amine 1a (190 mg, 0.5 mmol), isovaleral-
dehyde (47 mg, 0.55 mmol), phenylacetylene (102 mg, 1 mmol) and
CuI (14 mg, 15 mol-%) were loaded into the microwave instrument
vial. The vial was evacuated and flushed with argon. The vial was
sealed and irradiated with stirring at a ceiling temperature of 90 °C
at 50 W maximum power level for 30 min. Upon completion of the
reaction time the vial was cooled with a stream of air. The product
was isolated by column chromatography on silica gel (heptane/
EtOAc/10–20 %) yielding propargylamine 2a as a yellow oil
N-(2-Bromo-4,5-dimethoxyphenethyl)-N-(4-methoxybenzyl)-3-(4-
methoxyphenyl)-1-phenylprop-2-yn-1-amine (2e): Synthesized from
benzaldehyde (58 mg, 0.55 mmol), 1-ethynyl-4-methoxybenzene
(132 mg, 1 mmol) and amine 1a (190 mg, 0.5 mmol). Reaction was
1
(256 mg, 92%). H NMR (CDCl3, 300 MHz): δ = 7.50–7.42 (m, 2
H), 7.36–7.25 (m, 5 H), 7.00 (s, 1 H), 6.86 (d, J = 8.6 Hz, 2 H),
6.68 (s, 1 H), 3.93 (d, J = 13.5 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3
H), 3.83 (s, 3 H), 3.73 (t, J = 7.6 Hz, 1 H), 3.57 (d, J = 13.5 Hz, 1 carried out in 2 mL of toluene. The product was isolated by column
H), 2.99–2.78 (m, 3 H), 2.75–2.62 (m, 1 H), 1.88–1.74 (m, 1 H), chromatography on silica gel (heptane/EtOAc/10–20%) yielding
1.70–1.47 (m, 2 H), 0.86 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz, propargylamine 2e as a yellow oil (243 mg, 81 %). 1H NMR
3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.57, 148.11, 147.85,
(CDCl3, 300 MHz): δ = 7.61–7.54 (m, 2 H), 7.49 (d, J = 8.7 Hz, 2
131.95, 131.78, 131.73, 130.05, 128.21, 127.77, 123.56, 115.40, H), 7.33–7.21 (m, 5 H), 6.93–6.79 (m, 5 H), 6.50 (s, 1 H), 4.95 (s,
114.15, 113.67, 113.49, 88.79, 84.62, 56.12, 55.95, 55.23, 51.31,
50.87, 42.94, 35.12, 24.63, 22.78, 22.23 ppm. MS (ESI+) calcd. for
C31H36BrNO3: 549.2; found: m/z 550.8 [M + H]+.
1 H), 3.90 (d, J = 13.4 Hz, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.78
(s, 3 H), 3.72 (s, 3 H), 3.59 (d, J = 13.4 Hz, 1 H), 2.87–2.68 (m, 4
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.47, 158.63, 148.02,
147.74, 139.46, 133.26, 131.78, 131.57, 130.03, 128.30, 127.90,
127.21, 115.40, 115.24, 114.19, 113.92, 113.60, 113.39, 87.88, 83.73,
56.81, 56.11, 55.85, 55.33, 55.24, 55.07, 50.40, 34.58 ppm. MS
(ESI+) calcd. for C34H34BrNO4: 599.2; found: m/z 600.8 [M +
H]+.
N-(2-Bromo-4,5-dimethoxyphenethyl)-1-(4-fluorophenyl)-N-(4-meth-
oxybenzyl)-5-methylhex-1-yn-3-amine (2b): Synthesized from iso-
valeraldehyde (47 mg, 0.55 mmol), 1-ethynyl-4-fluorobenzene
(120 mg, 1 mmol) and amine 1a (190 mg, 0.5 mmol). The product
was isolated by column chromatography on silica gel (heptane/
EtOAc/10–20 %) yielding propargylamine 2b as a yellow oil
N-(2-Bromo-4,5-dimethoxyphenethyl)-N-(4-methoxybenzyl)-3-
phenylprop-2-yn-1-amine (2f): Synthesized from 1,3,5-trioxane
(18 mg, 0.2 mmol), phenylacetylene (102 mg, 1 mmol) and amine
1a (190 mg, 0.5 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 2f as a yellow oil (198 mg, 80 %). 1H NMR
1
(247 mg, 87%). H NMR (CDCl3, 300 MHz): δ = 7.47–7.40 (m, 2
H), 7.30 (d, J = 8.6 Hz, 2 H), 7.0.5–6.97 (m, 3 H), 6.87 (d, J =
8.6 Hz, 2 H), 6.68 (s, 1 H), 3.93 (d, J = 13.6 Hz, 1 H), 3.86 (s, 3
H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.72 (t, J = 7.6 Hz, 1 H), 3.55 (d,
J = 13.6 Hz, 1 H), 2.97–2.79 (m, 3 H), 2.72–2.62 (m, 1 H), 1.87–
1.74 (m, 1 H), 1.69–1.60 (m, 1 H), 1.57–1.47 (m, 1 H), 0.87 (d, J (CDCl3, 300 MHz): δ = 7.50–7.40 (m, 2 H), 7.32–7.22 (m, 5 H),
= 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3, 6.98 (s, 1 H), 6.85 (d, J = 8.5 Hz, 2 H), 6.74 (s, 1 H), 3.83–3.75 (m,
75 MHz): δ = 163.44, 160.97, 158.66, 148.23, 147.99, 133.59,
9 H), 3.71 (s, 2 H), 3.60 (s, 2 H), 2.96–2.80 (m, 4 H) ppm. 13C
133.51, 132.00, 131.80, 130.04, 119.71, 119.67, 115.55, 115.54, NMR (CDCl3, 75 MHz): δ = 158.80, 148.30, 147.94, 131.76,
115.32, 114.21, 113.83, 113.56, 88.53, 88.52, 83.57, 56.17, 56.01, 131.63, 130.58, 130.38, 128.32, 128.06, 123.35, 115.42, 114.23,
55.48, 55.26, 51.37, 50.95, 43.01, 35.20, 24.68, 22.79, 22.23 ppm.
MS (ESI+) calcd. for C31H35BrFNO3: 567.2; found: m/z 568.7 [M
+ H]+.
113.68, 113.36, 85.65, 84.58, 57.41, 56.15, 55.98, 55.28, 53.72,
42.28, 34.03 ppm. MS (ESI+) calcd. for C27H28BrNO3: 493.1;
found: m/z 494.6 [M + H]+.
N-(2-Bromo-4,5-dimethoxyphenethyl)-N-(4-methoxybenzyl)-1- N-(2-Bromo-4,5-dimethoxyphenethyl)-N-isopropyl-5-methyl-1-
phenylhex-1-yn-3-amine (2c): Synthesized from butyraldehyde
phenylhex-1-yn-3-amine (2g): Synthesized from isovaleraldehyde
(40 mg, 0.55 mmol), phenylacetylene (102 mg, 1 mmol) and amine
(47 mg, 0.55 mmol), phenylacetylene (102 mg, 1 mmol) and amine
1a (190 mg, 0.5 mmol). The product was isolated by column 1b (151 mg, 0.5 mmol). The product was isolated by column
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Eur. J. Org. Chem. 2010, 4861–4867

Diversity-Oriented Synthesis of the 3-Benzazepine Framework
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 2g as a brown oil (203 mg, 86 %). 1H NMR
CuI-catalyzed tandem anti-Markovnikov hydroamination and al-
kyne addition reaction: phenylacetylene (153 mg, 1.5 mmol), amine
(CDCl3, 300 MHz): δ = 7.41–7.33 (m, 2 H), 7.30–7.22 (m, 3 H), 1a (190 mg, 0.5 mmol) and CuI (14 mg, 15 mol-%) were loaded into
6.99 (s, 1 H), 6.72 (s, 1 H), 3.85–3.75 (m, 7 H), 3.25–3.07 (m, 1 H), the microwave instrument vial. The vial was evacuated and flushed
2.95–2.70 (m, 4 H); 1.90–1.72 (m, 1 H), 1.52 (t, J = 7.2 Hz, 2 H),
1.21–1.09 (m, 6 H), 0.95–0.85 (m, 6 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 148.13, 147.85, 132.26, 131.43, 128.18, 127.62,
with argon. The vial was sealed and irradiated with stirring at a
ceiling temperature of 100 °C at 80 W maximum power level for
25 min. Upon completion of the reaction time the vial was cooled
123.81, 115.40, 114.14, 113.77, 91.64, 83.99, 56.13, 55.97, 50.82, with a stream of air. The product was isolated by column
48.46, 47.28, 44.56, 36.94, 24.67, 22.62, 21.97, 18.28 ppm. MS
(ESI+) calcd. for C26H34BrNO2: 471.2; found: m/z 472.8
[M + H]+.
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 2k as yellow oil (216 mg, 74%). 1H NMR (CDCl3,
300 MHz): δ = 7.45–7.36 (m, 2 H), 7.33–7.19 (m, 6 H), 7.16–7.07
(m, 4 H), 6.98 (s, 1 H), 6.76 (d, J = 8.6 Hz, 2 H), 6.60 (s, 1 H),
3.99–3.71 (m, 11 H), 3.58 (d, J = 13.8 Hz, 1 H), 3.06–2.64 (m, 6
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.50, 148.15, 147.90,
138.70, 131.82, 131.69, 131.43, 129.78, 129.51, 128.22, 128.01,
127.89, 126.20, 123.38, 115.34, 114.14, 113.72, 113.48, 87.86, 85.69,
56.12, 55.94, 55.43, 55.30, 55.24, 50.97, 40.49, 34.95 ppm. MS
(ESI+) calcd. for C34H34BrNO3: 583.2; found: m/z 584.8
[M + H]+.
N-(2-Bromo-4,5-dimethoxyphenethyl)-N-isopropyl-5-methyl-1-
(thiophen-3-yl)hex-1-yn-3-amine (2h): Synthesized from iso-valeral-
dehyde (47 mg, 0.55 mmol), 3-ethynylthiophene (108 mg, 1 mmol)
and amine 1b (151 mg, 0.5 mmol). The product was isolated by
column chromatography on silica gel (heptane/EtOAc/10–20 %)
yielding propargylamine 2h as a brown oil (194 mg, 81 %). 1H
NMR (CDCl3, 300 MHz): δ = 7.36–7.28 (m, 1 H), 7.24–7.18 (m, 1
H), 7.07–7.01 (m, 1 H), 6.99 (s, 1 H), 6.72 (s, 1 H), 3.84 (s, 3 H),
3.83 (s, 3 H), 3.76 (t, J = 7.6 Hz, 1 H), 3.22–3.06 (m, 1 H), 2.94–
2.67 (m, 4 H); 1.90–1.70 (m, 1 H), 1.50 (t, J = 7.2 Hz, 2 H), 1.20–
1.07 (m, 6 H), 0.95–0.83 (m, 6 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 148.12, 147.85, 132.26, 129.92, 127.54, 125.01,
122.78, 115.40, 114.14, 113.78, 91.17, 78.91, 56.13, 55.97, 50.74,
48.43, 47.27, 44.55, 36.99, 24.62, 22.63, 22.57, 22.01, 18.28 ppm.
MS (ESI+) calcd. for C24H32BrNO2S: 477.1; found: m/z 478.7 [M
+ H]+.
N-(2-Bromo-4,5-dimethoxyphenethyl)-1,4-bis(3-fluorophenyl)-N-(4-
methoxybenzyl)but-3-yn-2-amine (2l): Synthesized from 1-ethynyl-
3-fluorobenzene (180 mg, 1.5 mmol) and amine 1a (190 mg,
0.5 mmol). The product was isolated by column chromatography
on silica gel (heptane/EtOAc/10–20%) yielding propargylamine 2l
1
as a yellow oil (251 mg, 81%). H NMR (CDCl3, 300 MHz): δ =
7.31–6.73 (m, 13 H), 6.60 (s, 1 H), 3.94 (d, J = 13.7 Hz, 1 H), 3.90–
3.74 (m, 10 H), 3.55 (d, J = 13.7 Hz, 1 H), 3.06–2.64 3.90–3.74 (m,
6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 164.25, 163.97, 161.00,
160.71, 158.66, 148.21, 148.02, 141.09, 141.00, 131.59, 131.05,
N-[3-(2-Bromo-4,5-dimethoxyphenyl)propyl]-N-(4-methoxybenzyl)-
5-methyl-1-phenylhex-1-yn-3-amine (2i): Synthesized from isovaler-
aldehyde (47 mg, 0.55 mmol), phenylacetylene (102 mg, 1 mmol) 129.90, 129.82, 129.78, 129.44, 129.33, 127.62, 127.58, 125.17,
and amine 1c (151 mg, 0.5 mmol). The product was isolated by
column chromatography on silica gel (heptane/EtOAc/10–20 %)
yielding propargylamine 2i as a yellow oil (231 mg, 82%). 1H NMR
125.13, 125.08, 124.95, 118.67, 118.37, 116.39, 116.11, 115.52,
115.41, 115.24, 114.15, 113.70, 113.57, 113.29, 113.01, 88.55, 84.78,
84.73, 56.13, 55.96, 55.41, 55.28, 54.94, 50.88, 39.97, 34.97 ppm.
(CDCl3, 300 MHz): δ = 7.50–7.44 (m, 2 H), 7.37–7.31 (m, 5 H), MS (ESI+) calcd. for C34H32BrF2NO3: 619.2; found: m/z 620.4 [M
7.02 (s, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.69 (s, 1 H), 3.91–3.81 (m, + H]+.
10 H), 3.75 (t, J = 7.6 Hz, 1 H), 3.46 (d, J = 13.6 Hz, 1 H), 2.86–
(Z)-1-Benzylidene-2-isobutyl-7,8-dimethoxy-3-(4-methoxybenzyl)-
2,3,4,5-tetrahydro-1H-benzo[d]azepine (3a): General experi-mental
procedure for Pd-catalyzed intramolecular acetylene hydroaryl-
ation: Pd(PPh3)4 (14 mg, 3 mol-%) and HCOONa (41 mg,
0.6 mmol) were loaded into the microwave instrument vial. The vial
was evacuated and flushed with argon. Propargylamine 2a (220 mg,
0.4 mmol) dissolved in DMF (4.5 mL) was added, followed by dis-
tilled water (1.5 mL). The vial was sealed and irradiated with stir-
ring at a ceiling temperature of 110 °C at 100 W maximum power
level for 15 min. Upon completion of the reaction time the vial was
cooled with a stream of air. The reaction mixture was concentrated
under reduced pressure. After dilution with DCM the organic
phase was washed several times with brine, dried (Na2SO4) and
concentrated under reduced pressure. The products were isolated
by column chromatography on silica gel yielding 3a as a yellow oil
2.67 (m, 2 H), 2.65–2.52 (m, 2 H), 2.00–1.88 (m, 1 H), 1.87–1.74
(m, 2 H), 1.71–1.54 (m, 2 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.87 (d, J
= 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.59,
148.39, 147.75, 133.99, 132.16, 131.76, 130.01, 128.25, 127.78,
123.69, 115.66, 114.04, 113.58, 112.93, 88.80, 84.77, 56.17, 56.05,
55.26, 51.34, 50.53, 43.16, 33.99, 28.88, 24.90, 22.76, 22.48 ppm.
MS (ESI+) calcd. for C32H38BrNO3: 563.2; found: m/z 564.8 [M +
H]+.
N-[3-(2-Bromo-4,5-dimethoxyphenyl)propyl]-N-(4-methoxybenzyl)-
1-(4-methoxyphenyl)hex-1-yn-3-amine (2j): Synthesized from butyr-
aldehyde (40 mg, 0.55 mmol), 1-ethynyl-4-methoxybenzene
(132 mg, 1 mmol) and amine 1c (151 mg, 0.5 mmol). The product
was isolated by column chromatography on silica gel (heptane/
EtOAc/10–20 %) yielding propargylamine 2j as a yellow oil
(264 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ = 7.38 (d, J =
8.6 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 6.98 (s, 1 H), 6.88–6.80 (m,
2 H), 6.65 (s, 1 H), 3.89–3.76 (m, 13 H), 3.63 (t, J = 7.4 Hz, 1 H),
3.42 (d, J = 13.6 Hz, 1 H), 2.86–2.46 (m, 4 H), 1.87–1.60 (m, 4 H),
1.56–1.41 (m, 2 H), 0.89 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 159.19, 158.47, 148.28, 147.63, 134.00,
133.09, 132.28, 129.92, 115.77, 115.49, 113.94, 113.83, 113.51,
112.80, 86.98, 84.48, 56.13, 56.00, 55.30, 55.23, 55.05, 52.96, 50.45,
36.37, 33.96, 28.81, 19.88, 13.92 ppm. MS (ESI+) calcd. for
C32H38BrNO4: 579.2; found: m/z 580.8 [M + H]+.
1
(151 mg, 80%). H NMR (CDCl3, 300 MHz): δ = 7.33–7.19 (m, 5
H), 6.97 (d, J = 8.5 Hz, 2 H), 6.76–6.65 (m, 4 H), 6.60 (s, 1 H),
4.05 (t, J = 7.5 Hz, 1 H), 3.89 (s, 6 H), 3.77 (s, 3 H), 3.71 (d, J =
13.6 Hz, 1 H), 3.41 (d, J = 13.6 Hz, 1 H), 3.36–3.24 (m, 1 H), 3.14–
3.01 (m, 1 H), 2.82–2.70 (m, 1 H), 2.31–2.18 (m, 1 H), 1.74–1.58
(m, 1 H), 1.56–1.43 (m, 1 H), 1.18–1.05 (m, 1 H), 0.75 (d, J =
6.6 Hz, 3 H), 0.67 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 158.23, 147.45, 146.87, 146.27, 137.92, 135.35,
132.07, 131.98, 131.05, 129.66, 129.01, 128.16, 126.59, 113.77,
113.26, 112.27, 57.09, 56.16, 56.01, 55.91, 55.22, 45.86, 38.60,
N-(2-Bromo-4,5-dimethoxyphenethyl)-N-(4-methoxybenzyl)-1,4- 33.66, 24.51, 23.13, 22.46 ppm. HRMS (EI) for C31H37NO3, calcd.
diphenylbut-3-yn-2-amine (2k): General experimental procedure for 471.2773, found 471.2778.
Eur. J. Org. Chem. 2010, 4861–4867
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4865

E. V. Van der Eycken et al.
(Z)-1-(4-Fluorobenzylidene)-2-isobutyl-7,8-dimethoxy-3-(4-meth- (Z)-1-Benzylidene-7,8-dimethoxy-3-(4-methoxybenzyl)-2,3,4,5-tetra-
FULL PAPER
oxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3b): Synthesized
from 2b (227 mg, 0.4 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
hydro-1H-benzo[d]azepine (3f): Synthesized from 2f (198 mg,
0.4 mmol). The product was isolated by column chromatography
on silica gel (heptane/EtOAc/10–20%) yielding propargylamine 3f
1
propargylamine 3b as a yellow oil (165 mg, 84 %). 1H NMR as a yellow oil (116 mg, 70%). H NMR (CDCl3, 300 MHz): δ =
(CDCl3, 300 MHz): δ = 7.28–7.19 (m, 2 H), 7.01–6.91 (m, 4 H), 7.53–7.42 (m, 2 H), 7.35–7.18 (m, 5 H), 6.89 (s, 1 H), 6.85 (d, J =
6.76–6.68 (m, 3 H), 6.61 (s, 1 H), 6.60 (s, 1 H), 3.98 (t, J = 7.5 Hz,
1 H), 3.89 (s, 6 H), 3.78 (s, 3 H), 3.70 (d, J = 13.6 Hz, 1 H), 3.45
8.6 Hz, 2 H), 6.70 (s, 1 H), 6.64 (s, 1 H), 3.93 (s, 3 H), 3.88 (s, 3
H), 3.80 (s, 3 H), 3.59 (s, 2 H), 3.39 (br. s, 2 H), 2.96–2.72 (m, 4
(d, J = 13.6 Hz, 1 H), 3.35–3.22 (m, 1 H), 3.16–3.02 (m, 1 H), 2.84– H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.71, 147.78, 147.13,
2.72 (m, 1 H), 2.32–2.19 (m, 1 H), 1.72–1.56 (m, 1 H), 1.55–1.42
(m, 1 H), 1.16–1.03 (m, 1 H), 0.75 (d, J = 6.6 Hz, 3 H), 0.68 (d, J
= 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 163.27,
141.54, 137.46, 136.93, 131.87, 130.71, 130.62, 130.38, 129.23,
128.20, 126.76, 113.64, 112.53, 111.10, 61.76, 56.26, 56.19, 56.02,
55.29, 54.33, 34.32 ppm. HRMS (EI) for C27H29NO3, calcd.
160.02, 158.30, 147.52, 146.90, 146.52, 135.15, 133.88, 133.83, 415.2147, found 415.2137.
131.95, 131.81, 130.61, 130.51, 129.91, 129.53, 115.15, 114.87,
(Z)-1-Benzylidene-2-isobutyl-3-isopropyl-7,8-dimethoxy-2,3,4,5-
113.69, 113.28, 112.30, 57.16, 56.18, 55.92, 55.60, 55.23, 46.18,
38.28, 33.82, 24.49, 23.07, 22.59 ppm. HRMS (EI) for
C31H36FNO3, calcd. 489.2679, found 489.2672.
tetrahydro-1H-benzo[d]azepine (3g): Synthesized from 2g (189 mg,
0.4 mmol). The product was isolated by column chromatography
on silica gel (heptane/EtOAc/10–20%) yielding propargylamine 3g
1
(Z)-1-Benzylidene-7,8-dimethoxy-3-(4-methoxybenzyl)-2-propyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepine (3c): Synthesized from 2c
(215 mg, 0.4 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 3c as a yellow oil (167 mg, 91 %). 1H NMR
(CDCl3, 300 MHz): δ = 7.33–7.18 (m, 5 H), 6.98 (d, J = 8.2 Hz, 2
H), 6.77–6.67 (m, 4 H), 6.60 (s, 1 H), 4.00–3.93 (m, 1 H), 3.89 (s,
6 H), 3.77 (s, 3 H), 3.71 (d, J = 13.7 Hz, 1 H), 3.42 (d, J = 13.7 Hz,
1 H), 3.36–3.23 (m, 1 H), 3.17–3.02 (m, 1 H), 2.83–2.70 (m, 1 H),
2.34–2.20 (m, 1 H), 1.61–1.47 (m, 1 H), 1.40–1.20 (m, 3 H), 0.80–
0.72 (m, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.24,
147.51, 146.92, 145.89, 137.92, 135.20, 132.07, 132.04, 131.46,
129.60, 129.08, 128.21, 126.59, 113.70, 113.32, 112.29, 57.93, 57.18,
56.21, 55.95, 55.25, 46.07, 33.74, 31.98, 19.59, 14.18 ppm. HRMS
(EI) for C30H35NO3, calcd. 457.2617, found 457.2591.
as a yellow oil (113 mg, 72%). H NMR (CDCl3, 300 MHz): δ =
7.40–7.29 (m, 4 H), 7.28–7.21 (m, 1 H), 6.72 (s, 1 H), 6.67 (s, 1 H),
6.59 (s, 1 H), 4.17 (t, J = 7.2 Hz, 1 H), 3.88 (s, 6 H), 3.22–2.81 (m,
4 H), 2.51–2.33 (m, 1 H), 1.68–1.51 (m, 1 H), 1.41–1.29 (m, 1 H),
1.28–1.17 (m, 1 H), 1.01 (d, J = 6.5 Hz, 3 H), 0.81–0.72 (m, 6 H),
0.67 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
147.60, 146.81, 146.62, 138.24, 134.64, 131.67, 131.17, 129.01,
128.11, 126.61, 113.71, 112.14, 56.20, 55.90, 55.16, 50.26, 42.33,
40.96, 35.52, 24.64, 23.05, 22.81, 21.79, 20.78 ppm. HRMS (EI) for
C26H35NO2, calcd. 393.2668, found 393.2657.
(Z)-2-Isobutyl-3-isopropyl-7,8-dimethoxy-1-(thiophen-3-ylmeth-
ylene)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3h): Synthesized from
2h (191 mg, 0.4 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 3h as a brown oil (117 mg, 73 %). 1H NMR
(CDCl3, 300 MHz): δ = 7.35–7.29 (m, 1 H), 7.20–7.14 (m, 1 H),
7.13–7.06 (m, 1 H), 6.69 (s, 1 H), 6.58 (s, 1 H), 6.53 (s, 1 H), 4.33–
4.22 (m, 1 H), 3.88 (s, 3 H), 3.88 (s, 3 H), 3.19–2.91 (m, 4 H), 2.52–
2.37 (m, 1 H), 1.68–1.53 (m, 1 H), 1.42–1.30 (m, 1 H), 1.29–1.18
(m, 1 H), 1.03 (d, J = 6.5 Hz, 3 H), 0.83–0.76 (m, 9 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 147.63, 146.80, 138.80, 134.44,
131.50, 128.83, 125.60, 125.23, 122.57, 113.67, 112.11, 56.17, 55.89,
55.80, 50.63, 42.50, 41.21, 35.50, 24.74, 23.17, 22.89, 21.72, 20.71
ppm. HRMS (EI) for C24H33O2NS, calcd. 399.2232, found
399.2193.
(Z)-1-Butylidene-7,8-dimethoxy-3-(4-methoxybenzyl)-2-phenyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepine (3d): Synthesized from 2d
(215 mg, 0.4 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 3d as a yellow oil (141 mg, 77 %). 1H NMR
(CDCl3, 300 MHz): δ = 7.36–7.26 (m, 4 H), 7.23–7.10 (m, 3 H),
6.84 (d, J = 8.6 Hz, 2 H), 6.51 (s, 1 H), 6.48 (s, 1 H), 5.64 (t, J =
7.2 Hz, 1 H), 4.88 (s, 1 H), 3.87–3.77 (m, 10 H), 3.59 (d, J =
13.7 Hz, 1 H), 3.14–2.83 (m, 3 H), 2.57–2.43 (m, 1 H), 2.37–2.22
(m, 1 H), 2.19–2.03 (m, 1 H), 1.56–1.41 (m, 2 H), 0.95 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.51, 147.52,
146.52, 142.46, 141.10, 134.12, 132.26, 131.25, 129.49, 127.97,
127.85, 126.31, 114.88, 113.57, 111.88, 65.56, 57.51, 56.21, 55.80,
55.26, 47.52, 34.17, 30.64, 23.17, 14.09 ppm. HRMS (EI) for
C30H35NO3, calcd. 457.2617, found 457.2623.
(Z)-1-Benzylidene-2-isobutyl-8,9-dimethoxy-3-(4-methoxybenzyl)-
1,2,3,4,5,6-hexahydrobenzo[d]azocine (3i): Synthesized from 2i
(226 mg, 0.4 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20%) yielding
propargylamine 3i as a yellow oil (78 mg, 40%). 1H NMR (CDCl3,
300 MHz): δ = 7.32–7.18 (m, 5 H), 6.99 (d, J = 8.5 Hz, 2 H), 6.73
(d, J = 8.5 Hz, 2 H), 6.66 (s, 1 H), 6.59 (s, 1 H), 6.43 (s, 1 H), 4.11
(t, J = 7.2 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.82–3.74 (m, 4
H), 3.71 (d, J = 13.7 Hz, 1 H), 2.98–2.81 (m, 1 H), 2.57–2.34 (m,
3 H), 1.94–1.76 (m, 1 H), 1.70–1.57 (m, 1 H), 1.39–1.17 (m, 3 H),
0.78–0.62 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.27,
148.03, 146.22, 145.66, 138.00, 134.67, 132.90, 132.06, 129.91,
129.67, 128.92, 128.11, 126.45, 113.60, 113.29, 111.40, 58.69, 56.35,
56.09, 55.88, 55.25, 41.60, 39.18, 32.53, 30.52, 24.66, 23.13, 22.69
ppm. HRMS (EI) for C32H39NO3, calcd. 485.2930, found 485.2939.
(Z)-7,8-Dimethoxy-3-(4-methoxybenzyl)-1-(4-methoxybenzylidene)-
2-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3e): Synthesized
from 2e (240 mg, 0.4 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20 %) yielding
propargylamine 3e as a brownish solid (146 mg, 70%); m.p. 75–
77 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.50–7.40 (m, 2 H), 7.26–
7.18 (m, 2 H), 7.17–7.07 (m, 3 H), 6.95–6.88 (m, 3 H), 6.83 (s, 1
H), 6.76 (d, J = 8.6 Hz, 2 H), 6.61 (d, J = 8.6 Hz, 2 H), 6.48 (s, 1
H), 5.25 (s, 1 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 3.73 (s,
3 H), 3.69 (d, J = 13.6 Hz, 1 H), 3.61 (d, J = 13.6 Hz, 1 H), 3.36–
3.18 (m, 2 H), 3.07–2.95 (m, 1 H), 2.41–2.28 (m, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 158.68, 158.17, 147.60, 146.80,
(Z)-8,9-Dimethoxy-3-(4-methoxybenzyl)-1-(4-methoxybenzyl-
142.22, 141.78, 134.49, 134.06, 132.17, 131.57, 130.26, 129.86, idene)-2-propyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine (3j): Synthe-
129.53, 128.19, 127.92, 126.28, 115.42, 113.77, 113.21, 112.22, sized from 2j (232 mg, 0.4 mmol). The product was isolated by col-
61.21, 56.67, 56.26, 55.81, 55.22, 55.13, 48.20, 33.34 ppm. HRMS
(EI) for C34H35NO4, calcd. 521.2566, found 521.2573.
umn chromatography on silica gel (heptane/EtOAc/10–20%) yield-
ing propargylamine 3j as a slightly yellow oil (64 mg, 32%). 1H
4866
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4861–4867

Diversity-Oriented Synthesis of the 3-Benzazepine Framework
NMR (CDCl3, 300 MHz): δ = 7.19 (d, J = 8.5 Hz, 2 H), 7.04 (d,
J = 8.5 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2 H), 6.76 (d, J = 8.5 Hz, 2 [1] a) J. F. Bower, P. Szeto, T. Gallagher, Chem. Commun. 2005,
5793–5795; b) H. Zhai, S. Luo, C. Ye, Y. Ma, J. Org. Chem.
2003, 68, 8268–8271; c) J. R. Fuchs, R. L. Funk, Org. Lett.
2001, 3, 3923–3925; d) M. Katoh, H. Inoue, A. Suzuki, T.
Honda, Synlett 2005, 18, 2820–2822; e) J. F. Bower, P. Szeto,
T. Gallagher, J. Org. Biomol. Chem. 2007, 5, 143–150; f) P. A.
Donets, J. L. Goeman, J. Van der Eycken, K. Robeyns, L.
Van Meervelt, E. V. Van der Eycken, Eur. J. Org. Chem. 2009,
793–796 and references cited therein.
H), 6.69 (s, 1 H), 6.63 (s, 1 H), 6.40 (s, 1 H), 4.12–4.05 (m, 1 H),
3.92 (s, 3 H), 3.90 (s, 3 H), 3.85–3.79 (m, 7 H), 3.49 (d, J = 13.8 Hz,
1 H), 2.99–2.85 (m, 1 H), 2.57–2.42 (m, 3 H), 1.95–1.81 (m, 1 H),
1.54–1.43 (m, 1 H), 1.42–1.28 (m, 4 H), 0.87–0.81 (m, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 158.21, 158.20, 147.97, 146.22,
144.59, 134.88, 132.91, 132.09, 130.42, 130.04, 129.58, 129.51,
113.50, 113.22, 111.41, 60.17, 56.38, 56.09, 55.87, 55.21, 55.19,
41.82, 32.53, 32.33, 30.57, 19.94, 14.24 ppm. HRMS (EI) for
C32H39NO4, calcd. 501.2879, found 501.2878.
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98; b) S. Couty, B. Liegault, C. Meyer, J. Cossy, Tetrahedron
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(Z)-2-Benzyl-1-benzylidene-7,8-dimethoxy-3-(4-methoxybenzyl)-
2,3,4,5-tetrahydro-1H-benzo[d]azepine (3k): Synthesized from 2k
(234 mg, 0.4 mmol). The product was isolated by column
chromatography on silica gel (heptane/EtOAc/10–20 %) yielding
propargylamine 3k as a yellow oil (144 mg, 71 %). 1H NMR
(CDCl3, 300 MHz): δ = 7.23–7.12 (m, 6 H), 6.98–6.82 (m, 6 H),
6.71–6.58 (m, 5 H), 4.28–4.18 (m, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H),
3.78 (s, 3 H), 3.72 (d, J = 13.6 Hz, 1 H), 3.42 (d, J = 13.6 Hz, 1
H), 3.37–3.14 (m, 2 H), 2.94–2.80 (m, 2 H), 2.78–2.66 (m, 1 H),
2.49–2.36 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.24,
147.64, 146.80, 144.05, 139.68, 137.63, 134.57, 132.24, 132.01,
131.54, 129.58, 129.53, 128.81, 128.01, 127.83, 126.55, 125.86,
114.28, 113.30, 112.27, 60.25, 57.62, 56.05, 55.97, 55.26, 46.84,
36.94, 34.07 ppm. HRMS (EI) for C34H35NO3, calcd. 505.2617,
found 505.2608.
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(Z)-2-(3-Fluorobenzyl)-1-(3-fluorobenzylidene)-7,8-dimethoxy-3-
(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3l): Syn-
thesized from 2l (248 mg, 0.4 mmol). The product was isolated by
column chromatography on silica gel (heptane/EtOAc/10–20%)
yielding propargylamine 3l as a yellow oil (137 mg, 63%). 1H NMR
(CDCl3, 300 MHz): δ = 7.22–7.08 (m, 2 H), 6.94- 6.83 (m, 4 H),
6.74–6.64 (m, 5 H), 6.63–6.54 (m, 4 H), 4.20–1.07 (m, 1 H), 3.92
(s, 3 H), 3.89 (s, 3 H), 3.79 (s, 3 H), 3.72 (d, J = 13.6 Hz, 1 H),
3.45 (d, J = 13.6 Hz, 1 H), 3.36–3.10 (m, 2 H), 2.95–2.80 (m, 2 H),
2.77–2.62 (m, 1 H), 2.53–2.37 (m, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 164.20, 164.16, 160.96, 160.91, 158.41, 147.88,
146.94, 144.83, 142.17, 142.07, 139.70, 139.60, 133.84, 131.97,
131.18, 131.07, 129.53, 129.42, 129.38, 129.27, 125.11, 125.08,
124.49, 124.46, 116.49, 116.21, 115.75, 115.47, 114.05, 113.69,
113.38, 112.94, 112.66, 112.39, 60.15, 57.80, 56.01, 55.97, 55.28,
47.16, 36.47, 34.24 ppm. HRMS (EI) for C34H33F2NO3, calcd.
541.2429, found 541.2417.
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Supporting Information (see also the footnote on the first page of
this article): Complete experimental procedures, as well as 1H
NMR and 13C NMR spectroscopic data for all new compounds.
Acknowledgments
[13] The 2-phenylethylamine 1a–c were synthesized following
known procedures (see Supporting Information).
Support was provided by the Research Fund of the Katholieke
Universiteit Leuven and by the Belgian Fund for Scientific Re-
search (F.W.O.) – Flanders. P. A. D. is grateful to the University of
Leuven for obtaining a doctoral scholarship. V. P. M. is grateful to
the Interfacultaire Raad voor Ontwikkelingssamenwerking (IRO)
for obtaining a doctoral scholarship.
[14] The large access of phenylacetylene (2 equiv.) was taken ac-
cording to described procedures (see ref.[12]).
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940.
Received: April 27, 2010
Published Online: July 16, 2010
Eur. J. Org. Chem. 2010, 4861–4867
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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