Synthesis of benzoazocines from substituted tetrahydroisoquinolines and activated alkynes in a tetrahydropyridine ring expansion

Article abstract of DOI:10.1002/ejoc.200700602

Tetrahydroisoquinolines underwent tandem piperidine ring enlargement in the presence of activated alkynes in acetonitrile or methanol, producing tetrahydrobenzo[d]azocines in high yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700602

FULL PAPER
DOI: 10.1002/ejoc.200700602
Synthesis of Benzoazocines from Substituted Tetrahydroisoquinolines and
Activated Alkynes in a Tetrahydropyridine Ring Expansion
Leonid G. Voskressensky,*[a] Anna V. Listratova,[a] Tatiana N. Borisova,[a]
Grigoriy G. Alexandrov,[a] and Alexey V. Varlamov[a]
Keywords: Azocine / Tetrahydroisoquinolines / Activated alkynes / Tandem transformation / Ring expansion
Tetrahydroisoquinolines underwent tandem piperidine ring
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
enlargement in the presence of activated alkynes in acetoni- Germany, 2007)
trile or methanol, producing tetrahydrobenzo[d]azocines in
high yields.
Introduction
Nitrogen heterocycles are structural elements of many
natural alkaloids and drug candidates.[1] Among them,
eight-membered (azocine) and larger N-containing fused-
ring systems occupy a prominent place and deserve more
investigation efforts from the point of view of organic chem-
istry. Alkaloids and drugs containing benzoazocine frag-
ments in their structures exhibit extensive evidence of dif-
ferent activities: inhibition of α-glucosidase,[2] acetylcho-
linesterase,[3] antinociception activity,[4] antitumor ac-
tivity,[5] antiinsectan activity,[6] and inhibition of HIV-1 rep-
lication.[7] Known synthetic routes towards the benzoazoc-
ine system include ring-closing metathesis,[8] intramolecular
catalytic Friedel–Crafts reactions,[9] and palladium-cata-
lyzed heteroannulation,[10] but only a few of these are really
effective.[11]
Recently, we have reported a novel method for the syn-
thesis of tetrahydropyrrolo[2,3-d]azocines,[12] tetrahydro-
azocino[4,5-b]- and -[5,4-b]indoles,[13] and hexahydroazo-
Scheme 1.
nino[5,6-b]indoles.[14] It is based on the enlargement of
either the tetrahydropyridine or hexahydroazepine frag-
ments in tetrahydropyrrolo[3,2-c]pyridines, tetrahydro-β-
or the fused aromatic system, and the nature of the solvent.
and -γ-carbolines, or tetrahydroazepino[3,4-b]- and -[4,3-b]-
indoles in the presence of activated alkynes. These reactions
proceed via the intermediate zwitterion A (Scheme 1), re-
sulting from the Michael addition of the tertiary nitrogen
atom to the activated alkynes.
The pathways of the further nucleophilic transformations
of the zwitterion A are presumably defined by the reactivity
of the anionic center, the electronic effects of the substituent
In aprotic solvents tetrahydropyrrolopyridines produce pyr-
rolo[2,3-c]azocines 1, but in the case of methyl-substituted
tetrahydropyridine fragments, mixtures of azocines and 3-
vinylpyrroles 3 (the products of Hofmann degradation) are
formed, while tetrahydrocarbolines under the same condi-
tions smoothly form azocino[4,5-b]- and -[5,4-b]indoles 1.
If the reaction is carried out in methanol, the tandem trans-
formation of the tetrahydropyridine ring takes place and
the formation of alkoxyalkyl-substituted pyrroles and in-
doles
2 occurs. Absolutely unexpectedly, tetrahydro-
[a] Organic Chemistry Department of the Russian Peoples Friend-
ship University,
azepino[4,3-b]indoles in the presence of activated alkynes
give azonino[5,6-b]indoles 4 in high yields both in acetoni-
trile and in methanol (Scheme 1).
6, Miklukho-Maklaya St., Moscow 117198, Russia
Fax: +7-4959550779
E-mail: lvoskressensky@sci.pfu.edu.ru
6106
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6106–6117

Benzoazocines from Tetrahydroisoquinolines and Activated Alkynes
Analysis of the data obtained earlier allowed us to con- the presence of Hünig’s base (Scheme 3).[16] The synthesis
sider the transformation of the tetrahydropyridine ring to of 1-aryltetrahydroisoquinolines described in the litera-
be an SN process. On the basis of this presumption we think ture[17] was unsuccessful in our case: after the addition of
that electron-donating effects both of the fused fragment the cyclizing agent (usually HCl), hydrolysis of the corre-
and of the substituents attached to the C-1 atom should sponding Schiff base occurred and none of the desired
diminish the partial positive charge (+δ1) appearing on the products was obtained. Modification of the method to use
C-1 atom in the intermediate zwitterion A and facilitate the H3PO4 instead of HCl avoided this problem. The modified,
cleavage of the C-1–N bond, thus favoring the formation of base-catalyzed alkylation protocol allowed the use of DMF
azocines. It is obvious that the steric effects of the substitu- to be avoided, thus simplifying the isolation procedure. In
ents at the C-1 and N atoms should also affect the forma- some cases, however, this method was unsuccessful, giving
tion of the intermediate zwitterion A (Scheme 2).
very low yields of the target products (Table 1).
Scheme 2.
Scheme 3.
The driving force behind the ring-expansion process is
still not determined, due to the lack of experimental mate-
Table 1. Yields and melting points of tetrahydroisoquinolines
rial. This paper reports on the behavior of tetrahydroiso- 5a–h.
quinolines as a new representative of the annulated tetra-
Compound
Ar
R
Yield [%]
M.p. [°C ]
hydropyridine (THPy) family in this reaction. We have re-
cently published preliminary results on the behavior of 1-
aryltetrahydroisoquinolines[15] in this reaction, and we now
report on expanded research on the reactivity of isoquinol-
ines with different substituents attached to the phenyl ring,
C-1 atom, and nitrogen atom.
To obtain more information on the reaction scope and
limitations, we studied the transformations of 2-substituted
1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines 5 in
the presence of methyl propiolate, acetylacetylene, p-tosyl-
acetylene, and dimethyl acetylenedicarboxylate (DMAD) in
methanol or acetonitrile.
The presence of a 1-phenyl substituent in isoquinolines 5
would most probably favor the loosening of the C-1–N
bond in the intermediate zwitterion A, thus facilitating the
subsequent nucleophilic attack of the anionic center on the
C-1 atom and the formation of benzoazocines. Therefore,
the process shown in Scheme 2 ought to depend on the re-
activity of the nucleophilic center rather than on the solvent
nucleophilic assistance.
5a
5b
5c
5d
5e
5f
p-MeO-C6H4
p-F-C6H4
p-F3C-C6H4
p-O2N-C6H4
o-F-C6H4
p-MeO-C6H4 p-MeO2C-C6H4
p-MeO-C6H4
p-MeO-C6H4
Me
Me
Me
Me
Me
75
69
77
52
81
65
56
53
64–66
54–55
85–86
71–73
69–70
141–142
145–146
139–140
5g
5h
p-F-C6H4
p-Me-C6H4
Isoquinolines 5i–m were synthesized by the well-known
Bischler–Napieralski reaction[18] starting from the appropri-
ate amines, anhydrides, or acid chlorides and the reduction
of the intermediate dihydroisoquinolines, followed by N-al-
kylation of the NH-isoquinolines with ethyl iodide or ben-
zyl bromides (Scheme 4, Table 2).[16]
Aryl-substituted isoquinolines 5a–e reacted with ter-
minal alkynes at 25 °C in either methanol or acetonitrile,
giving benzo[d]azocines 8–26 in high yields (Table 3). It was
demonstrated that the rates of reactions of isoquinolines 5a,
5b, 5d, and 5e with activated alkynes in acetonitrile and
methanol are almost equal. Generally, the yields in acetoni-
trile are higher than in methanol (Scheme 5).
The planes of the phenyl rings in the 1-aryl substituents
in isoquinolines 5 are perpendicular to the dimeth-
oxyphenyl fragment, so the intermediate zwitterion stabili-
Results and Discussion
The starting N-ethyl- and N-benzyl-substituted isoquino- zation is possible only through the inductive effect.
lines 5a–h were obtained by Pictet–Spengler condensation The reactions between isoquinolines 5a, 5b, 5d, or 5e and
of 2-(3,4-dimethoxyphenyl)ethylamine and the appropriate DMAD in acetonitrile (also 5a and 5d in methanol and 5e
aldehydes, followed by N-alkylation of the intermediate in DMSO) yielded benzoazocines 11, 15, 19, and 23. In the
NH-isoquinolines with ethyl iodide or benzyl bromides in cases of the reactions of isoquinolines 5b and 5e with
Eur. J. Org. Chem. 2007, 6106–6117
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L. G. Voskressensky et al.
FULL PAPER
Scheme 4.
Table 2. Yields and melting points of tetrahydroisoquinolines 5i–
m.
Compound
R
R1
R2
Yield [%] M.p. [°C ]
5i
5j
5k
5l
5m
OMe
OMe
H
OMe
OMe
Bn
Me
Ph
Me
Me
Me
65
69
74
64
53
–
–
34–35
78–79
88–89
Me p-Me-C6H4
Bn p-Me-C6H4
Scheme 5.
Table 3. Yields of tetrahydrobenzo[d]azocines 8–26 and diarylmeth-
anes 6 and 7.
the result of the cleavage process involving one molecule of
methanol. The formation of the diarylmethane 6 was only
demonstrated with the aid of NMR analysis (ratio 1:1),
whereas compounds 7 and 23 were isolated. We attribute
this result both to steric hindrance and to the lower nucleo-
philic activity of the anionic center in the intermediate zwit-
terion, since the negative charge is delocalized between two
ester groups. Compound 6 was converted into azocine 23
by treatment with trimethylsilyl triflate.
In the case of the N-benzyl-substituted isoquinolines 5f–
h, the reactions with activated alkynes in acetonitrile
(methyl propiolate or p-tosylacetylene) became possible
only with the use of an excess of the corresponding alkyne
and required more forcing reaction conditions (reflux). This
can most probably be explained by the steric hindrance of
the N-benzyl and 1-aryl substituents preventing the forma-
tion of the intermediate zwitterion and the subsequent nu-
cleophilic attack. Nevertheless, the target azocines 27–32
were isolated in good preparative yields (Scheme 6,
Table 4).
Compound
Ar
X
Y
Yield [%]
6
7
8
o-F-C6H4
p-F-C6H4
p-MeO-C6H4
CO2Me
CO2Me
H
CO2Me
CO2Me
CO2Me
–
42
75 (MeOH)
90 (MeCN)
85 (MeCN)
31 (MeCN)
55 (MeOH)
70 (MeCN)
77 (MeOH)
88 (MeCN)
73 (MeCN)
42 (MeCN)
29
66 (MeOH)
79 (MeCN)
43 (MeCN)
87 (MeCN)
27 (MeOH)
51 (MeCN)
88 (MeOH)
77 (MeCN)
87 (MeCN)
65 (MeCN)
19 (MeOH)
36 (MeCN)
88 (MeCN)
76 (MeCN)
67 (MeCN)
9
10
11
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4 CO2Me
H
H
COMe
p-Ts
CO2Me
12
p-F-C6H4
H
CO2Me
13
14
15
16
p-F-C6H4
p-F-C6H4
p-F-C6H4
H
H
CO2Me
H
COMe
p-Ts
CO2Me
CO2Me
p-O2N-C6H4
17
18
19
p-O2N-C6H4
p-O2N-C6H4
p-O2N-C6H4
H
H
CO2Me
COMe
p-Ts
CO2Me
20
o-F-C6H4
H
CO2Me
21
22
23
o-F-C6H4
o-F-C6H4
o-F-C6H4
H
H
CO2Me
COMe
p-Ts
CO2Me
To see whether the presence of the methoxy groups in
the isoquinolines was mandatory for the transformation of
the tetrahydropyridine ring, we examined the reaction be-
havior of isoquinoline 5k (Scheme 7) with methyl pro-
piolate, acetylacetylene, and p-tosylacetylene in acetonitrile.
The reactions proceeded smoothly, giving azocines 33–35 in
24
25
26
p-F3C-C6H4
p-F3C-C6H4
p-F3C-C6H4
H
H
H
CO2Me
COMe
p-Ts
DMAD in methanol the formation of two products was good yields (Table 5).
observed: along with the azocines 15 and 23, diarylmeth-
The ease of transformation of 1-aryl-substituted tetra-
anes 6 and 7 were also formed. The latter compounds were hydroisoquinolines 5a–h into benzoazocines 8–32 encour-
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Eur. J. Org. Chem. 2007, 6106–6117

Benzoazocines from Tetrahydroisoquinolines and Activated Alkynes
Scheme 8.
Table 6. Yields of tetrahydrobenzo[d]azocines 36–45.
Scheme 6.
Compound
R
R1
Y
Yield [%]
36
37
38
39
40
41
42
43
44
45
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
p-Me-C6H4
p-Me-C6H4
Me
Me
Me
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
CO2Me
p-Ts
CO2Me
p-Ts
CO2Me
COMe
p-Ts
CO2Me
COMe
p-Ts
31 (MeCN)
40 (MeCN)
50 (MeCN)
54 (MeCN)
60 (MeCN)
55 (MeCN)
65 (MeCN)
83 (MeCN)
78 (MeCN)
64 (MeCN)
Table 4. Yields of tetrahydrobenzo[d]azocines 27–32.
Compound
R1
R2
Yield [%]
27
28
29
30
31
32
p-MeO2C-C6H4
p-MeO2C-C6H4
p-F-C6H4
p-F-C6H4
p-Me-C6H4
p-Me-C6H4
CO2Me
p-Ts
CO2Me
p-Ts
CO2Me
p-Ts
50 (MeCN)
83 (MeCN)
37 (MeCN)
81 (MeCN)
43 (MeCN)
54 (MeCN)
The structures of the compounds 8–45 were confirmed
by their NMR spectroscopic data. The H NMR spectra
1
have signals corresponding to all the protons of the mole-
cules, with reasonable chemical shifts and coupling constant
1
values. The H NMR spectra of benzoazocines 8–10, 12–
14, 16–18, 20–22, and 24–45 all have similar characteristic
signals: the enamine protons resonate as singlets at δ =
7.40–7.60 ppm.
Benzoazocines 8 and 11 were reduced to the correspond-
ing hexahydrobenzoazocines 46 and 47 by treatment with
NaCNBH3 in methanol (Scheme 9, Table 7).
Scheme 7.
Table 5. Yields of tetrahydrobenzo[d]azocine 33–35.
Compound
R
Yield [%]
33
34
35
CO2Me
COMe
p-Ts
50 (MeCN)
45 (MeCN)
82 (MeCN)
Scheme 9.
Table 7. Yields of hexahydrobenzo[d]azocines 46 and 47.
Compound
X
Y
Yield [%]
aged us to apply this approach to isoquinolines containing
1-benzyl or 1-methyl substituents. Isoquinolines 5i–m
(Scheme 8) reacted with activated alkynes at room tempera-
ture to yield benzoazocines 36–45 in 35–87% yields
46
47
H
CO2Me
CO2Me
CO2Me
80
62
Hexahydrobenzoazocine 46 was isolated as a mixture of
(Table 6). We had also expected the formation of vinyl-sub- two diastereoisomers (1:4 ratio), whereas benzoazocine 47,
stituted benzenes – possible products of the Hofmann de- according to its spectroscopic data, was formed as a single
gradation reaction. Indeed, the formation of vinylic by- diastereoisomer. The stereochemistry of compounds 46 and
products was registered (NMR analysis of the reaction mix- 47 was determined on the basis of the spin-spin coupling
ture), but none of them was isolated individually. In the constants of the 6-H and 5-H atoms. Thus, for the major
case of the N-benzyl-substituted isoquinoline 5m, the reac- isomer of 46 the 6-H atom resonates as a doublet with J =
tions required excesses of the alkynes to proceed.
12.0 Hz, such a high vicinal coupling constant value indi-
Eur. J. Org. Chem. 2007, 6106–6117
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L. G. Voskressensky et al.
FULL PAPER
100 MHz, respectively; peak positions are given in ppm (δ) with
cating a pseudoaxial orientation of 6-H and 5-H, whereas
for the minor isomer 6-H appears as a doublet with J =
3.8 Hz, indicating a pseudoequatorial orientation of 6-H
and 5-H. In compound 47 the 6-H atom resonates at δ =
4.99 ppm as a doublet with J = 11.4 Hz, also showing a
pseudoaxial orientation of the 6-H and 5-H atoms.
The three-dimensional structure of compound 47 was
also investigated by X-ray diffraction. A monocrystal was
obtained by recrystallisation from an ethyl acetate/hexane
mixture by slow concentration at room temperature, and
the refined X-ray crystal structure of 47 is shown in Fig-
ure 1. The conformation of the eight-membered ring is a
twisted chair-boat, in which atoms C(2), C(4), C(1), C(9),
N(1), C(10), and C(11) form the chair fragment, whereas
atoms C(3), C(2), C(4), C(1), C(9), N(1), and C(1) form the
boat fragment. The X-ray structure confirmed our pre-
sumption that 6-H and 5-H are pseudoaxially oriented.
tetramethylsilane as the internal standard. For the proton indexes
1
for compounds 6 and 7 see Scheme 5. A H-1H COSY experiment
was used for the assignment of the signals in the spectra of 46.
Mass spectra were obtained by the EI technique (Finnigan-MAT
95 XL Engine) or the ESI method (Agilent 1100 Series LC/MSD
Trap System VL). IR spectra were recorded with a Perkin–Elmer
Spectrum One instrument. Only noteworthy IR absorptions [cm–1]
are listed. Melting points were determined in a capillary tube and
are uncorrected.
General Procedure for the Synthesis of Tetrahydroisoquinolines: In
a flask fitted with a Dean–Stark apparatus, the amine (0.06 mmol),
the aldehyde (0.065 mmol), and toluene (70 mL) were mixed and
the reaction mixture was heated at reflux for 3–4 h. The reaction
mixture was allowed to cool to room temperature, and phosphoric
acid (85%, 50 mL) was added. The resulting mixture was heated at
reflux for 3 h and then allowed to cool to room temperature. The
organic layer was decanted. The residue was poured onto ice, and
the pH was adjusted to 9–10 (NaOH). The resulting solution was
extracted with CH2Cl2. The combined organic layers were dried
with MgSO4. The solvent was evaporated under reduced pressure
to give the target isoquinolines.
General Synthetic Procedure for the Synthesis of Benzo[d]azocines
8–26 and 33–45: DMAD, methyl propiolate, acetylacetylene, or p-
tosylacetylene (1.2 mmol) was added to a solution of one of the
isoquinoline derivatives 5a–e or 5i–m (1 mmol) in methanol or ace-
tonitrile (15 mL). The reaction mixture was stirred at 25 °C (TLC
monitoring). The solvent was evaporated under reduced pressure,
and the residue was recrystallized (ethyl acetate/hexane) to give
benzoazocines 8–26, 35, 37, or 39–45 or diarylmethane 7. In the
cases of benzoazocines 33, 34, 36, 38 they were purified by column
chromatography with mixtures of ethyl acetate/hexane as eluent
(1:40 for 33 and 34 or 1:15 for 36 and 38). In the case of the reac-
tion between isoquinoline 5e and DMAD in methanol, a mixture
1
(1:1 according to H NMR spectroscopic data) of the azocine 23
and the diarylmethane 6 was formed. This mixture (0.15 g) was
dissolved in acetonitrile (10 mL) and a few drops of trimethylsilyl
triflate were added. The reaction mixture was kept at room tem-
perature for a week (TLC monitoring). The solvent was evaporated
under reduced pressure, and the resulting residue was purified by
column chromatography with ethyl acetate as eluent to give benzo-
azocine 23.
Figure 1. X-ray crystal structure of 47.
Dimethyl (2E)-2-[(Ethyl)(2-{2-[(4-fluorophenyl)(methoxy)methyl]-
4,5-dimethoxyphenyl}ethyl)amino]but-2-enedioate (7): Yield 205 mg
(42%) in methanol, white crystals, m.p. 118–120 °C (ethyl acetate/
Conclusions
1
hexane). H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.1 Hz, 3
We presented a new one-step procedure for the synthesis
of tetrahydrobenzo[d]azocines, starting from readily avail-
able tetrahydroisoquinolines. This reaction could represent
a new and powerful tool for the construction of fused
azocine derivatives.
H, –CH2–CH3), 2.59 (dd, J = 4.5, J = 16.2 Hz, 1 H, CH2-α), 2.75–
2.85 (m, 2 H, –CH2–CH3 and CH2-α), 2.99 (qd, J = 7.1, J =
14.3 Hz, 1 H, –CH2–CH3), 3.23 (ddd, J = 1.9, J = 7.5, J = 15.3 Hz,
1 H, CH2-β), 3.30–3.36 (m, 1 H, CH2-β), 3.75 (s, 3 H, CH–OCH3),
3.82 (s, 3 H, CO2CH3), 3.87 (s, 3 H, CO2CH3), 3.90 (s, 3 H, OCH3),
3.92–3.93 (m, 4 H, OCH3 and =CH), 5.86 (s, 1 H, CH–OCH3),
6.63 (s, 1 H, CH-Ar), 6.83 (s, 1 H, CH-Ar), 6.94 (t, J = 8.6 Hz, 2
Experimental Section
H, CH-Ar), 7.05–7.08 (m, 2 H, CH-Ar) ppm. IR (KBr): ν = 1732,
˜
1681, 1605 cm–1. EI MS: m/z (%) = 489 (20) [M]+, 457 (20), 398
(30), 386 (100), 371 (12), 354 (17), 339 (12), 327 (11), 309 (5), 240
(95), 200 (20), 183 (13), 169 (10), 111 (30), 98 (5), 80 (7), 72 (70),
59 (15), 52 (13), 39 (20). C26H32FNO7 (489.22): calcd. C 63.79, H
6.59, N 2.86; found C 63.68, H 6.56, N 2.96.
General Remarks: All solvents were distilled and dried before use;
methyl propiolate, acetylacetylene and DMAD were purchased
from Acros Organics and were used without any additional purifi-
cation. p-Tosylacetylene was synthesized by a literature pro-
cedure.[19] Column chromatography was performed with aluminum
oxide 60 from Fluka. H and 13C NMR spectra were recorded in
CDCl3 solution at 25 °C or in [D6]DMSO solution at 40 °C with a
Bruker WM 400 NMR spectrometer operating at 400 and
Methyl 3-Ethyl-8,9-dimethoxy-6-(4-methoxyphenyl)-1,2,3,6-tetra-
hydrobenzo[d]azocine-5-carboxylate (8): Yield 308 mg (75%) in
methanol (90% in acetonitrile), white crystals, m.p. 100–102 °C
1
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Benzoazocines from Tetrahydroisoquinolines and Activated Alkynes
1
(ethyl acetate/hexane). H NMR (400 MHz, CDCl3): δ = 1.07 (t, J
Methyl 3-Ethyl-6-(4-fluorophenyl)-8,9-dimethoxy-1,2,3,6-tetra-
= 7.2 Hz, 3 H, –CH2–CH3), 2.76–2.87 (m, 3 H, CH2-1 and CH2- hydrobenzo[d]azocine-5-carboxylate (12): Yield 307 mg (77%) in
2), 3.16 (qd, J = 7.2, J = 14.1 Hz, 2 H, –CH2–CH3), 3.49–3.58 (m,
methanol (351 mg, 88% in acetonitrile), white crystals, m.p. 95–
1 H, CH2-2), 3.74 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 3.85 (s, 3 97 °C (ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 1.08
H, OCH3), 3.86 (s, 3 H, OCH3), 5.80 (s, 1 H, 6-H), 6.63 (s, 1 H, 7- (t, J = 7.2 Hz, 3 H, –CH2–CH3), 2.74–2.87 (m, 3 H, 2ϫCH2-1 and
H), 6.78–6.80 (m, 3 H, 2ϫCH-Ar and 10-H), 7.02 (d, J = 7.4 Hz,
2 H, 2ϫCH-Ar), 7.68 (s, 1 H, 4-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 15.3, 36.7, 48.6, 51.4, 54.9, 55.7, 55.7 56.0, 97.1, 114.2,
116.2, 116.2, 117.0, 117.1, 127.1, 129.6, 132.4, 139.4, 147.1, 147.5,
CH2-2), 3.13–3.23 (m, 2 H, –CH2–CH3), 3.42–3.50 (m, 1 H, CH2-
2), 3.75 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3),
5.81 (s, 1 H, 6-H), 6.64 (s, 1 H, 7-H), 6.77 (s, 1 H, 10-H), 6.93 (t,
J = 8.7 Hz, 2 H, 2ϫCH-Ar), 7.05–7.12 (m, 2 H, 2ϫCH-Ar), 7.67
152.9, 153.1, 157.5, 170.4 ppm. IR (KBr): ν = 1670, 1577 cm–1. EI
(s, 1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.9, 36.9,
˜
MS: m/z (%) = 411 (20) [M]+, 354 (20), 340 (35), 282 (10), 176 (20), 48.7, 49.0, 51.3, 51.9, 55.9, 56.0, 98.0, 115.0 (d, JC,F = 21 Hz, 2
2
3
164 (50), 151 (20), 135 (14), 121 (60), 91 (15), 72 (40), 58 (100), 56
(50), 42 (30). C24H29NO5 (411.20): calcd. C 70.05, H 7.10, N 3.40;
found C 70.04, H 7.12, N 3.39.
C), 116.0, 116.6, 127.6 (d, JC,F = 7 Hz, 2 C), 128.7, 132.2, 142.8
4
1
(d, JC,F = 3 Hz), 147.0, 147.6, 152.8, 161.0 (d, JC,F = 234 Hz),
170.8 ppm. IR (KBr): ν = 1670, 1605 cm–1. EI MS: m/z (%) = 399
˜
(72) [M]+, 384 (11), 370 (17), 354 (10), 342 (10), 341 (23), 340 (100),
329 (20), 328 (70), 312 (7), 295 (9), 270 (12), 240 (7), 183 (7), 164
(12), 133 (5), 109 (6), 59 (5). C23H26FNO4 (399.18): calcd. C 69.16,
H 6.56, F 4.76, N 3.51; found C 69.15, H 6.58, F 4.74, N 3.52.
1-[3-Ethyl-8,9-dimethoxy-6-(4-methoxyphenyl)-1,2,3,6-tetrahydro-
benzo[d]azocine-5-yl]ethan-1-one (9): Yield 336 mg (85%) in aceto-
nitrile, white crystals, m.p. 146–147 °C (ethyl acetate/hexane). 1H
NMR (400 Hz, CDCl3): δ = 1.13 (t, J = 7.2 Hz, 3 H, –CH2–CH3),
2.34 (s, 3 H, COCH3), 2.86 (m, 3 H, CH2-1 and CH2-2), 3.22 (dq,
J = 1.5, J = 7.2 Hz, 2 H, –CH2–CH3), 3.60 (m, 1 H, CH2-2), 3.76
(s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 6.11 (s,
1 H, 6-H), 6.63 (s, 1 H, 7-H), 6.74 (s, 1 H, 10-H), 6.77 (d, J =
8.4 Hz, 2 H, 2ϫCH-Ar), 6.92 (d, J = 8.4 Hz, 2 H, 2ϫCH-Ar),
1-[3-Ethyl-6-(4-fluorophenyl)-8,9-dimethoxy-1,2,3,6-tetrahydro-
benzo[d]azocin-5-yl]ethan-1-one (13): Yield 280 mg (73%) in aceto-
nitrile, white crystals, m.p. 131–132 °C (ethyl acetate/hexane). 1H
NMR (400 MHz, CDCl3): δ = 1.12 (t, J = 7.2 Hz, 3 H, –CH2–
CH3), 2.33 (s, 3 H, COCH3), 2.75–2.91 (m, 3 H, 2ϫCH2-1 and
CH2-2), 3.22 (dq, J = 1.2, J = 7.1 Hz, 2 H, –CH2–CH3), 3.45–3.55
(m, 1 H, CH2-2), 3.82 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 6.12
(s, 1 H, 6-H), 6.62 (s, 1 H, 7-H), 6.72 (s, 1 H, 10-H), 6.70 (t, J =
8.7 Hz, 2 H, 2ϫCH-Ar), 6.94–6.98 (m, 2 H, 2ϫCH-Ar), 7.50 (s,
1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.8, 25.1, 36.6,
7.51 (s, 1 H, 4-H) ppm. IR (KBr): ν = 1610, 1582 cm–1. EI MS:
˜
m/z (%) = 395 (15) [M]+, 295 (25), 281 (15), 58 (100), 43 (30).
C24H29NO4 (395.21): calcd. C 72.89, H 7.39, N 3.54; found C
72.91, H 7.40, N 3.52.
3-Ethyl-8,9-dimethoxy-6-(4-methoxyphenyl)-5-[(4-methylphenyl)-
sulfonyl]-1,2,3,6-tetrahydrobenzo[d]azocine (10): Yield 157 mg
(31%), white crystals, m.p. 185–186 °C (ethyl acetate/hexane). 1H
NMR (400 MHz, CDCl3): δ = 1.14 (t, J = 7.1 Hz, 3 H, –CH2–
CH3), 2.38 (s, 3 H, CH3–Ar), 2.71 (dd, J = 5.5, J = 15.1 Hz, 1 H,
CH2-1), 2.80–2.88 (m, 2 H, CH2-1 and –CH2–CH3), 3.21–3.27 (m,
2 H, CH2-2 and –CH2–CH3), 3.38 (s, 3 H, OCH3), 3.52–3.62 (m,
1 H, CH2-2), 3.78 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.89 (s, 1
H, 6-H), 5.57 (s, 1 H, 7-H), 6.58 (s, 1 H, 10-H), 6.78 (d, J = 8.5 Hz,
2 H, 2ϫCH-Ar), 7.18 (d, J = 8.5 Hz, 2 H, 2ϫCH-Ar), 7.23 (d, J
= 7.6 Hz, 2 H, 2ϫCH-Ar), 7.68–7.70 (m, 3 H, 2ϫCH-Ar and 4-
2
46.5, 49.0, 52.1, 55.8, 56.0, 113.2, 114.9, 115.0 (d, JC,F = 21 Hz, 2
3
3
C), 116.7, 127.5 (d, JC,F = 7 Hz, 2 C), 128.5, 132.1, 142 (d, JC,F
1
= 3 Hz), 147.0, 147.6, 154.9, 160.0 (d, JC,F = 240 Hz), 194.4 ppm.
IR (KBr): ν = 1574, 1503 cm–1. EI MS: m/z (%) = 383 (7) [M]+,
˜
340 (13), 312 (10), 283 (5), 269 (7), 218 (10), 183 (6), 133 (8), 109
(5), 72 (13), 58 (100), 43 (35). C23H26FNO3 (383.45): calcd. C 72.04,
H 6.83, N 3.65; found C 72.12, H 6.52, N 3.60.
3-Ethyl-6-(4-fluorophenyl)-8,9-dimethoxy-5-[(4-methylphenyl)sulfon-
yl]-1,2,3,6-tetrahydrobenzo[d]azocine (14): Yield 208 mg (42%) in
acetonitrile, white crystals, m.p. 201–202 °C (ethyl acetate/hexane).
1H (400 MHz, CDCl3): δ = 1.14 (t, J = 7.2 Hz, 3 H, –CH2–CH3),
2.38 (s, 3 H, CH3–Ar), 2.68 (dd, J = 5.2, J = 14.7 Hz, 1 H, CH2-
1), 2.78–2.88 (m, 2 H, –CH2–CH3 and CH2-1), 3.20–3.28 (m, 2 H,
–CH2–CH3 and CH2-2), 3.40 (s, 3 H, OCH3), 3.42–3.55 (m, 1 H,
CH2-2), 3.83 (s, 3 H, OCH3), 4.92 (s, 1 H, 6-H), 5.62 (s, 1 H, 7-H),
6.58 (s, 1 H, 10-H), 6.92 (t, J = 8.7 Hz, 2 H, 2ϫCH-Ar), 7.22–7.24
(m, 4 H, 4ϫCH-Ar), 7.66–7.69 (m, 3 H, 2ϫCH-Ar and 4-H) ppm.
H) ppm. IR (KBr): ν = 1614 cm–1. EI MS: m/z (%) = 507 (5)
˜
[M]+, 353 (23), 352 (100), 351 (57), 350 (15), 336 (33), 324 (12), 307
(10), 295 (10), 294 (12), 283 (97), 263 (10), 244 (20), 219 (25), 189
(12), 176 (14), 165 (27), 164 (30), 160 (12), 145 (46), 121 (50), 102
(14), 91 (93), 77 (14), 65 (30), 58 (35), 57 (27), 42 (10). C29H33NO5S
(507.21): calcd. C 68.61, H 6.55, N 2.76; found C 68.75, H 6.47, N
2.80.
Dimethyl 3-Ethyl-8,9-dimethoxy-6-(4-methoxyphenyl)-1,2,3,6-tetra-
hydrobenzo[d]azocine-4,5-dicarboxylate (11): Yield 258 mg (55%) in
methanol (70 % in acetonitrile), white crystals, m.p. 188–190 °C
IR (KBr): ν = 1624 cm–1. EI MS: m/z (%) = 495 (7) [M]+, 341 (23),
˜
340 (100), 339 (17), 324 (13), 312 (5), 283 (97), 207 (15), 183 (8),
133 (12), 109 (8), 91 (25), 58 (7). C28H30FNO4S (495.60): calcd. C
67.86, H 6.10, N 2.83; found C 67.91, H 6.06, N 2.85.
1
(ethyl acetate/hexane). H NMR (400 MHz, CDCl3): δ = 0.88 (t, J
= 7.1 Hz, 3 H, –CH2–CH3), 2.58 (ddd, J = 0.7, J = 5.3, J = 7.0 Hz,
1 H, CH2-1), 2.71–2.81 (m, 2 H, –CH2–CH3 and CH2-1), 2.96 (qd, Dimethyl 3-Ethyl-6-(4-fluorophenyl)-8,9-dimethoxy-1,2,3,6-tetra-
J = 7.2, J = 14.3 Hz, 1 H, –CH2–CH3), 3.19 (ddd, J = 1.8, J = 7.0,
J = 15.1 Hz, 1 H, CH2-2), 3.36–3.44 (m, 1 H, CH2-2), 3.72 (s, 3 H,
hydrobenzo[d]azocine-4,5-dicarboxylate (15): Yield 133 mg (29%),
white crystals, m.p. 132–134 °C (ethyl acetate/hexane). 1H NMR
OCH3), 3.76 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.87 (s, 3 H, (400 MHz, CDCl3): δ = 0.90 (t, J = 7.1 Hz, 3 H, –CH2–CH3), 2.59
OCH3), 3.90 (s, 3 H, OCH3), 5.82 (s, 1 H, 6-H), 6.60 (s, 1 H, 7-H), (ddd, J = 2.0, J = 5.9, J = 16.0 Hz, 1 H, CH2-1), 2.75–2.87 (m, 2
6.77 (d, J = 8.4 Hz, 2 H, 2ϫCH-Ar), 6.80 (s, 1 H, 10-H), 6.99 (d,
J = 8.4 Hz, 2 H, 2ϫCH-Ar) ppm. 13C NMR (100 MHz, CDCl3):
δ = 13.4, 34.2, 45.6, 50.3, 50.9, 51.6, 53.3, 55.1, 55.8, 55.8, 102.4,
H, –CH2–CH3 and CH2-1), 2.99 (qd, J = 7.1, J = 14.2 Hz, 1 H,
–CH2–CH3), 3.23 (ddd, J = 2.0, J = 7.3, J = 15.1 Hz, 1 H, CH2-
2), 3.30–3.39 (m, 1 H, CH2-2), 3.75 (s, 3 H, OCH3), 3.82 (s, 3 H,
113.4 (2 C), 114.1, 116.6, 127.3 (2 C), 129.6, 131.2, 137.0, 147.0, OCH3), 3.90 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 5.86 (s, 1 H, 6-
147.3, 155.6, 157.5, 167.3, 169.8 ppm. IR (KBr): ν = 1728, 1678, H), 6.63 (s, 1 H, 7-H), 6.83 (s, 1 H, 10-H), 6.94 (d, J = 8.7 Hz, 2
˜
1558 cm–1. EI MS: m/z (%) = 469 (5) [M]+, 410 (10), 398 (100), 382 H, 2ϫCH-Ar), 7.05–7.08 (m, 2 H, 2ϫCH-Ar) ppm. IR (KBr): ν
˜
(15), 350 (20), 339 (25), 283 (15), 59 (12). C26H31NO7 (469.21):
calcd. C 66.51, H 6.65, N 2.98; found C 66.53, H 6.63, N 3.00.
= 1731, 1683, 1563 cm–1. EI MS: m/z (%) = 457 (29) [M]+, 426 (5),
398 (27), 387 (23), 386 (100), 370 (20), 354 (17), 327 (10), 271 (5),
Eur. J. Org. Chem. 2007, 6106–6117
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6111

L. G. Voskressensky et al.
183 (7), 109 (95), 72 (46), 59 (11), 42 (7). C25H28FNO6 (457.49): 71 (30), 59 (17), 44 (23). C25H28N2O8 (484.50): calcd. C61.97, H
FULL PAPER
calcd. C 65.63, H 6.17, N 3.06; found C 65.67, H. 6.12, N 3.10.
5.83, N 5.78; found C 62.03, H 5.89, N 5.83.
Methyl 3-Ethyl-6-(o-fluorophenyl)-8,9-dimethoxy-1,2,3,6-tetra-
hydrobenzo[d]azocine-5-carboxylate (20): Yield 351 mg (88%) in
methanol (307 mg, 77% in acetonitrile), white crystals, m.p. 88–
90 °C (ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 1.05
(t, J = 7.2 Hz, 3 H, –CH2–CH3), 2.82–2.86 (m, 2 H, 2ϫCH2-1),
2.90–2.96 (m, 1 H, CH2-2), 3.16 (qd, J = 7.2, J = 14.1 Hz, 2 H,
–CH2–CH3), 3.60–3.68 (m, 1 H, CH2-2), 3.74 (s, 3 H, OCH3), 3.86
(s, 6 H, 2ϫOCH3), 5.96 (s, 1 H, 6-H), 6.60 (s, 1 H, 7-H), 6.78 (s,
1 H, 10-H), 6.94 (dd, J = 7.9, J = 11.6 Hz, 1 H, CH-Ar), 7.01 (t,
J = 7.1 Hz, 1 H, CH-Ar), 7.12–7.16 (m, 2 H, 2ϫCH-Ar), 7.61 (s,
1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.9, 36.6, 45.8,
Methyl 3-Ethyl-8,9-dimethoxy-6-(4-nitrophenyl)-1,2,3,6-tetrahydro-
benzo[d]azocine-5-carboxylate (16): Yield 281 mg (66%) in meth-
anol (336 mg, 79% in acetonitrile), yellow crystals, m.p. 79–80 °C
1
(ethyl acetate/hexane). H NMR (400 MHz, CDCl3): δ = 1.09 (t, J
= 7.2 Hz, 3 H, –CH2–CH3), 2.74 (dd, J = 5.1, J = 14.7 Hz, 1 H,
CH2-1), 2.83–2.95 (m, 2 H, –CH2–CH3 and CH2-1), 3.11–3.33 (m,
3 H, –CH2–CH3 and 2ϫCH2-2), 3.76 (s, 3 H, OCH3), 3.87 (s, 3
H, OCH3), 3.88 (s, 3 H, OCH3), 5.92 (s, 1 H, 6-H), 6.65 (s, 1 H, 7-
H), 6.77 (s, 1 H, 10-H), 7.29 (d, J = 8.8 Hz, 2 H, 2ϫCH-Ar), 7.70
(s, 1 H, 4-H), 8.12 (d, J = 8.8 Hz, 2 H, 2ϫCH-Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.9, 36.7, 48.8, 49.6, 51.4, 52.0, 55.9, 56.0,
97.0, 115.1, 116.5, 123.7 (2 C), 127.1 (2 C), 128.3, 130.9, 146.0,
2
49.5, 51.4, 55.9, 55.9, 98.0, 114.7, 115.6, 123.6 (d, JC,F = 23 Hz),
3
3
127.4 (d, JC,F = 8 Hz), 128.5 (d, JC,F = 8 Hz), 129.3, 133.4 (d,
147.3, 147.8, 152.9, 155.3, 170.6 ppm. IR (KBr): ν = 1735, 1670,
˜
2JC,F = 22 Hz), 135.7, 136.1, 146.7, 147.6, 152.2, 159.2, 159.0 (d,
1607, 1518 cm–1. EI MS: m/z (%) = 426 (65) [M]+, 397 (14), 367
(100), 355 (92), 339 (10), 322 (17), 297 (31), 267 (5), 244 (5), 218
(33), 205 (23), 176 (27), 164 (62), 151 (27), 121 (23), 91 (17), 71
(50), 58 (87), 56 (63), 42 (35). C23H26N2O6 (426.46): calcd. C 64.78,
H 6.15, N 6.57; found C 64.65, H 6.10, N 6.48.
1JC,F = 270 Hz), 170.1 ppm. IR (KBr): ν = 1672, 1605 cm–1. EI
˜
MS: m/z (%) = 399 (70) [M]+, 370 (12), 340 (100), 328 (95), 295
(20), 270 (35), 218 (40), 164 (60), 142 (65), 109 (35), 71 (20), 58
(60). C23H26FNO4 (399.18): calcd. C 69.16, H 6.56, N 3.51; found
C 69.13, H 6.58, N 3.53.
1-[3-Ethyl-8,9-dimethoxy-6-(4-nitrophenyl)-1,2,3,6-tetrahydrobenzo-
[d]azocin-5-yl]ethan-1-one (17): Yield 176 mg (43%) in acetonitrile,
yellow crystals, m.p. 90–91 °C (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3): δ = 1.17 (t, J = 7.3 Hz, 3 H, –CH2–CH3), 2.39
(s, 3 H, COCH3), 2.80 (dd, J = 5.6, J = 15.0 Hz, 1 H, CH2-1),
2.89–2.99 (m, 2 H, CH2-1 and CH2-2), 3.26 (q, J = 7.3 Hz, 2 H,
–CH2–CH3), 3.32–3.40 (m, 1 H, CH2-2), 3.86 (s, 3 H, OCH3), 3.90
(s, 3 H, OCH3), 6.31 (s, 1 H, 6-H), 6.68 (s, 1 H, 7-H), 6.75 (s, 1 H,
10-H), 7.21 (d, J = 8.7 Hz, 2 H, 2ϫCH-Ar), 7.29 (s, 1 H, 4-H),
1-[3-Ethyl-6-(o-fluorophenyl)-8,9-dimethoxy-1,2,3,6-tetrahydro-
benzo[d]azocin-5-yl]ethan-1-one (21): Yield 333 mg (87%) in aceto-
nitrile, white crystals, m.p. 149–151 °C (ethyl acetate/hexane). 1H
NMR (400 MHz, CDCl3): δ = 1.11 (t, J = 7.2 Hz, 3 H, –CH2–
CH3), 2.32 (s, 3 H, COCH3), 2.83–2.87 (m, 2 H, CH2-1), 2.95–3.00
(m, 1 H, CH2-2), 3.22 (q, J = 7.2 Hz, 2 H, –CH2–CH3), 3.67–3.75
(m, 1 H, CH2-2), 3.84 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 6.28
(s, 1 H, 6-H), 6.59 (s, 1 H, 7-H), 6.75 (s, 1 H, 10-H), 6.91 (dd, J =
8.2, J = 11.5 Hz, 1 H, CH-Ar), 6.98–7.07 (m, 2 H, 2ϫCH-Ar),
7.10–7.15 (m, 1 H, CH-Ar), 7.45 (s, 1 H, 4-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 15.2, 25.8, 35.9, 43.3, 49.0, 51.9, 55.7,
56.0, 111.1, 115.7 (d, 3JC,F = 10 Hz), 116.3 (d, 2JC,F = 22 Hz), 124.4
(d, 4JC,F = 3 Hz), 128.1 (d, 3JC,F = 9 Hz), 129.4, 129.9, 130.0, 132.8,
8.11 (d, J = 8.7 Hz, 2 H, 2ϫCH-Ar) ppm. IR (KBr): ν = 1737,
˜
1583 cm–1. EI MS: m/z (%) = 410 (16) [M]+, 367 (25), 339 (12), 218
(8), 189 (5), 164 (5), 58 (100), 43 (50). C23H26N2O5 (410.46): calcd.
C 67.30, H 6.38, N 6.82; found C 67.41, H 6.43, N 6.90.
2
1
3-Ethyl-8,9-dimethoxy-5-[(4-methylphenyl)sulfonyl]-6-(4-nitro-
phenyl)-1,2,3,6-tetrahydrobenzo[d]azocine (18): Yield 454 mg (87%)
in acetonitrile, yellow crystals, m.p. 229–231 °C (ethyl acetate/hex-
133.7 (d, JC,F = 11 Hz), 146.8, 147.5, 155.7, 160.3 (d, JC,F
=
246 Hz), 193.2 ppm. IR (KBr): ν = 1623, 1571 cm–1. EI MS: m/z
˜
(%) = 383 (38) [M]+, 384 (9), 354 (7), 341 (24), 340 (100), 327 (9),
326 (44), 325 (5), 324 (7), 313 (12), 312 (50), 311 (5), 297 (18), 296
(20), 218 (11), 196 (95), 164 (11), 133 (6), 109 (5), 72 (7), 58 (63),
43 (9). C23H26FNO3 (383.19): calcd. C 72.04, H 6.83, N 3.65; found
C 72.06, H 6.82, N 3.63.
1
ane). H NMR (400 MHz, CDCl3): δ = 1.15 (t, J = 7.2 Hz, 3 H,
–CH2–CH3), 2.40 (s, 3 H, CH3–Ar), 2.66 (dd, J = 4.9, J = 14.9 Hz,
1 H, CH2-1), 2.83–2.93 (m, 2 H, CH2-1 and CH2-2), 3.21–3.29 (m,
3 H, CH2-2 and –CH2–CH3), 3.39 (s, 3 H, OCH3), 3.84 (s, 3 H,
OCH3), 4.95 (s, 1 H, 6-H), 5.58 (s, 1 H, 7-H), 6.59 (s, 1 H, 10-H),
7.24–7.26 (m, 2 H, 2ϫCH-Ar), 7.47 (d, J = 7.7 Hz, 2 H, 2ϫCH-
Ar), 7.68 (d, J = 8.4 Hz, 2 H, 2ϫCH-Ar), 7.71 (s, 1 H, 4-H), 8.11
3-Ethyl-6-(o-fluorophenyl)-8,9-dimethoxy-5-[(4-methylphenyl)sulfon-
yl]-1,2,3,6-tetrahydrobenzo[d]azocine (22): Yield 322 mg (65%) in
acetonitrile, white crystals, m.p. 202–204 °C (ethyl acetate/hexane).
1H NMR (400 MHz, CDCl3): δ = 1.11 (t, J = 7.1 Hz, 3 H, –CH2–
CH3), 2.39 (s, 3 H, CH3–Ar), 2.62 (dd, J = 5.4, J = 15.8 Hz, 1 H,
CH2-1), 2.68–2.78 (m, 1 H, CH2-1), 2.98 (dd, J = 7.4, J = 15.8 Hz,
1 H, CH2-2), 3.18–3.28 (m, 2 H, –CH2–CH3), 3.42 (s, 3 H, OCH3),
3.73–3.79 (m, 4 H, OCH3 and CH2-2), 5.06 (s, 1 H, 6-H), 5.71 (s,
1 H, 7-H), 6.74 (s, 1 H, 10-H), 6.84 (dd, J = 8.1, J = 11.0 Hz, 1 H,
CH-Ar), 7.09 (t, J = 8.1 Hz, 1 H, CH-Ar), 7.15–7.20 (m, 1 H, CH-
Ar), 7.24 (d, J = 7.8 Hz, 2 H, 2ϫCH-Ts), 7.62 (t, J = 8.1 Hz, 1 H,
(d, J = 8.4 Hz, 2 H, 2 ϫ CH-Ar) ppm. IR (KBr): ν = 1613,
˜
1520 cm–1. EI MS: m/z (%) = 522 (3) [M]+, 367 (100), 351 (7), 218
(13), 207 (15), 189 (9), 176 (7), 164 (13), 151 (5), 115 (6), 105 (10),
91 (35), 77 (70), 65 (15), 58 (43), 44 (12). C28H30N2O6S (522.61):
calcd. C 64.35, H 5.79, N 5.36; found C 64.27, H 5.86, N 5.31.
Dimethyl 3-Ethyl-8,9-dimethoxy-6-(4-nitrophenyl)-1,2,3,6-tetra-
hydrobenzo[d]azocine-4,5-dicarboxylate (19): Yield 130 mg (27%) in
methanol (247 mg, 51% in acetonitrile), yellow crystals, m.p. 228–
229 °C (ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = CH-Ar), 7.68 (s, 1 H, 4-H), 7.70 (d, J = 7.8 Hz, 2 H, 2ϫCH-Ts)
0.91 (t, J = 7.1 Hz, 3 H, –CH2–CH3), 2.57 (dd, J = 5.5, J = 16.5 Hz, ppm. 13C NMR (100 MHz, DMSO): δ = 15.1, 21.4, 35.4, 46.8,
1 H, CH2-1), 2.77–2.91 (m, 2 H, –CH2–CH3 and CH2-1), 3.01 (qd, 49.7, 51.8, 55.0, 55.7, 102.8, 114.3, 115.3, 115.9, (d, 2JC,F = 22 Hz),
4
3
J = 7.1, J = 14.2 Hz, 1 H, –CH2–CH3), 3.15–3.30 (m, 2 H, 2ϫCH2-
2), 3.76 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3),
3.94 (s, 3 H, OCH3), 5.96 (s, 1 H, 6-H), 6.65 (s, 1 H, 7-H), 6.83 (s,
1 H, 10-H), 7.29 (d, J = 8.6 Hz, 2 H, 2ϫCH-Ar), 8.12 (d, J =
124.2 (d, JC,F = 4 Hz), 127.9 (2 C), 128.5, 129.1 (d, JC,F = 8 Hz),
130.1 (2 C), 131.5, 131.7 (d, 3JC,F = 3 Hz), 131.9 (d, 2JC,F = 10 Hz),
1
140.7, 142.8, 146.8, 146.9, 153.2, 160.5 (d, JC,F = 242 Hz) ppm.
IR (KBr): ν = 1728, 1608 cm–1. EI MS: m/z (%) = 495 (15) [M]+,
˜
8.6 Hz, 2 H, 2 ϫ CH-Ar) ppm. IR (KBr): ν = 1729, 1681,
340 (100), 324 (5), 207 (20), 164 (10), 133 (15), 109 (20), 91 (85),
˜
1560 cm–1. EI MS: m/z (%) = 484 (31) [M]+, 453 (5), 425 (933), 413 77 (15), 65 (57), 58 (45), 39 (20). C28H30FNO4S (495.19): calcd. C
(100), 381 (14), 355 (7), 298 (10), 252 (5), 189 (6), 164 (17), 72 (85), 67.86, H 6.10, N 2.83; found C 67.90, H 6.12, N 2.82.
6112
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6106–6117

Benzoazocines from Tetrahydroisoquinolines and Activated Alkynes
Dimethyl 3-Ethyl-6-(o-fluorophenyl)-8,9-dimethoxy-1,2,3,6-tetra- 3.29 (m, 2 H, CH2-1 and CH2-2), 3.32–3.42 (m, 4 H, OCH3 and
hydrobenzo[d]azocine-4,5-dicarboxylate (23): Yield 87 mg (19%) in
methanol (164 mg, 36% in acetonitrile), white crystals, m.p. 148–
CH2-2), 3.83 (s, 3 H, OCH3), 4.96 (s, 1 H, 6-H), 5.61 (s, 1 H, 7-H),
6.59 (s, 1 H, 10-H), 7.24 (d, J = 7.9 Hz, 2 H, 2ϫCH-Ar), 7.40 (d,
150 °C (ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = J = 8.3 Hz, 2 H, 2ϫCH-Ar), 7.50 (d, J = 8.3 Hz, 2 H, 2ϫCH-
0.79 (t, J = 7.2 Hz, 3 H, –CH2–CH3), 2.63 (ddd, J = 2.8, J = 5.7,
Ar), 7.68 (d, J = 7.9 Hz, 2 H, 2ϫCH-Ar), 7.70 (s, 1 H, 4-H) ppm.
J = 9.0 Hz, 1 H, CH2-1), 2.71–2.80 (m, 1 H, CH2-1), 2.82–2.94 (m, 13C NMR (100 MHz, CDCl3): δ = 14.8, 21.3, 37.1, 48.8, 49.8, 51.9,
1
4
2 H, –CH2–CH3), 3.33 (ddd, J = 2.8, J = 7.1, J = 14.9 Hz, 1 H,
CH2-2), 3.50–3.60 (m, 1 H, CH2-2), 3.73 (s, 3 H, OCH3), 3.81 (s, 3 = 3 Hz, 2 C), 127.2 (2 C), 127.7 (2 C), 127.8 (q, J = 32 Hz, 2 C),
55.2, 55.8, 104.5, 115.1, 115.4, 124.2 (q, J = 275 Hz), 125.3 (q, J
2
H, OCH3), 3.89 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 5.97 (s, 1 H,
129.5 (2 C), 129.7, 139.8, 142.6, 147.1, 147.2, 150.0, 151.5 ppm. IR
6-H), 6.59 (s, 1 H, 7-H), 6.83 (s, 1 H, 10-H), 6.95 (dd, J = 8.5, J = (KBr): ν = 1611 cm–1. EI MS: m/z (%) = 545 (5) [M]+, 390 (100),
˜
11.4 Hz, 1 H, CH-Ar), 7.02 (t, J = 7.3 Hz, 1 H, CH-Ar), 7.09–7.12 374 (5), 319 (5), 229 (20), 207 (23), 178 (5), 164 (18), 151 (5), 91
(m, 1 H, CH-Ar), 7.15–7.17 (m, 1 H, CH-Ar) ppm. IR (KBr): ν = (30), 65 (7), 58 (35), 44 (18). C29H30F3NO4S (545.18): calcd. C
˜
1735, 1681, 1559 cm–1. EI MS: m/z (%) = 457 (5) [M]+, 456 (25),
455 (100), 424 (20), 394 (45), 336 (10), 28 (12). C25H28FNO6
(457.19): calcd. C 65.63, H 6.17, N 3.06; found C 65.65, H 6.15, N
3.07.
63.84, H 5.54, N 2.57; found C 63.85, H 5.58, N 2.56.
Methyl 3-Ethyl-6-phenyl-1,2,3,6-tetrahydrobenzo[d]azocine-5-car-
boxylate (33): Yield 161 mg (50%) in acetonitrile, white crystals,
m.p. 108–109 °C (ethyl acetate/hexane). 1H NMR (400 MHz,
CDCl3): δ = 1.05 (t, J = 7.2 Hz, 3 H, –CH2–CH3), 2.80–2.97 (m, 3
H, 2ϫCH2-1 and CH2-2), 3.08–3.22 (m, 2 H, –CH2–CH3), 3.51–
3.61 (m, 1 H, CH2-2), 3.74 (s, 3 H, OCH3), 6.00 (s, 1 H, 6-H), 7.12–
7.30 (m, 9 H, Ar), 7.67 (s, 1 H, 4-H) ppm. 13C NMR (100 Hz,
CDCl3): δ = 14.9, 37.4, 49.0, 49.7, 51.3, 52.0, 97.8, 125.3, 126.2 (2
C), 126.3, 127.2, 128.3 (2 C), 131.7, 133.6, 137.0, 140.0, 147.0,
Methyl 3-Ethyl-8,9-dimethoxy-6-(4-trifluoromethylphenyl)-1,2,3,6-
tetrahydrobenzo[d]azocine-5-carboxylate (24): Yield 395 mg (88%)
in acetonitrile, white crystals, m.p. 122–124 °C (ethyl acetate/hex-
1
ane). H NMR (400 MHz, CDCl3): δ = 1.09 (t, J = 7.2 Hz, 3 H,
–CH2–CH3), 2.75 (dd, J = 5.7, J = 14.5 Hz, 1 H, CH2-1), 2.83–
2.92 (m, 2 H, CH2-1 and CH2-2), 3.17 (qd, J = 7.2, J = 13.8 Hz, 2
H, –CH2–CH3), 3.30–3.40 (m, 1 H, CH2-2), 3.76 (s, 3 H, OCH3),
3.87 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 5.89 (s, 1 H, 6-H), 6.65
(s, 1 H, 7-H), 6.77 (s, 1 H, 10-H), 7.24 (d, J = 8.0 Hz, 2 H, 2ϫCH-
Ar), 7.50 (d, J = 8.0 Hz, 2 H, 2ϫCH-Ar), 7.71 (s, 1 H, 4-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.9, 36.8, 48.9, 49.3, 51.6, 51.9,
152.9, 170.9 ppm. IR (KBr): ν = 1675, 1605 cm–1. EI MS: m/z (%)
˜
= 321 (78) [M]+, 306 (12), 290 (15), 262 (100), 230 (13), 202 (27),
178 (24), 158 (15), 144 (11), 128 (15), 115 (27), 103 (7), 91 (28), 77
(13), 59 (17), 42 (6). C21H23NO2 (321.41): calcd. C 78.47, H 7.21,
N 4.36; found C 78.51, H 7.17, N 4.42.
1
55.9, 56.0, 97.3, 114.9, 116.5, 124.4 (q, JC,F = 275 Hz), 125.2 (q,
1-(3-Ethyl-6-phenyl-1,2,3,6-tetrahydrobenzo[d]azocin-5-yl)ethan-1-
one (34): Yield 137 mg (45%) in acetonitrile, white crystals, m.p.
135–137 °C (ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ
= 1.10 (t, J = 7.2 Hz, 3 H, –CH2–CH3), 2.34 (s, 3 H, COCH3),
2.84–3.01 (m, 3 H, 2ϫCH2-1 and CH2-2), 3.20 (q, J = 7.2 Hz, 2
H, –CH2–CH3), 3.56–3.68 (m, 1 H, CH2-2), 6.31 (s, 1 H, 6-H), 7.03
(d, J = 7.6 Hz, 2 H, 2ϫCH-Ar), 7.10–7.28 (m, 7 H, 7ϫCH-Ar),
2
3JC,F = 4 Hz, 2 C), 126.5 (2 C), 127.7 (q, JC,F = 32 Hz), 128.6,
131.4, 147.1, 147.6, 151.4, 153.2, 171.0 ppm. IR (KBr): ν = 1680,
˜
1588 cm–1. EI MS: m/z (%) = 449 (63) [M]+, 450 (17), 434 (12), 420
(13), 418 (8), 392 (5), 391 (24), 390 (100), 379 (17), 378 (73), 374
(5), 362 (7), 347 (5), 346 (6), 345 (10), 333 (7), 321 (15), 320 (20),
319 (10), 305 (5), 304 (8), 290 (10), 234 (6), 232 (5), 220 (5), 218
(10), 164 (16), 58 (5). C24H26F3NO4 (449.19): calcd. C 64.13, H
5.83, N 3.13; found C 64.14, H 5.87, N 3.12.
7.50 (s, 1 H, 4-H) ppm. IR (KBr): ν = 1622, 1571 cm–1. EI MS:
˜
m/z (%) = 305 (56) [M]+, 290 (5), 276 (21), 262 (67), 234 (32), 217
(14), 202 (28), 191 (22), 178 (23), 165 (15), 146 (17), 128 (12), 115
(28), 91 (26), 77 (17), 58 (65), 43 (100). C21H23NO (305.42): calcd.
C 82.58, H 7.59, N 4.59; found C 82.67, H 7.58, N 4.61.
1-[3-Ethyl-8,9-dimethoxy-6-(4-trifluoromethylphenyl)-1,2,3,6-tetra-
hydrobenzo[d]azocine-5-yl]-1-ethan-1-one (25): Yield 329 mg (76%)
in acetonitrile, white crystals, m.p. 126–128 °C (ethyl acetate/hex-
1
ane). H NMR (400 MHz, CDCl3): δ = 1.14 (t, J = 7.0 Hz, 3 H,
3-Ethyl-5-[(4-methylphenyl)sulfonyl]-6-phenyl-1,2,3,6-tetrahydro-
benzo[d]azocine (35): Yield 342 mg (82%) in acetonitrile, brownish
crystals, m.p. 192–193 °C (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3): δ = 1.12 (t, J = 7.2 Hz, 3 H, –CH2–CH3), 2.44
(s, 3 H, CH3–Ar), 2.74 (dd, J = 5.7, J = 15.4 Hz, 1 H, CH2-1), 2.79–
2.95 (m, 2 H, CH2-1 and CH2-2), 3.24 (qd, J = 7.2, J = 14.1 Hz, 2
H, –CH2–CH3), 3.55 (ddd, J = 5.7, J = 12.1, J = 15.4 Hz, 1 H,
CH2-2), 5.07 (s, 1 H, 6-H), 6.00 (d, J = 7.4 Hz, 1 H, 7-H), 6.79–
6.83 (m, 1 H, CH-Ar), 7.05–7.11 (m, 2 H, 2ϫCH-Ar), 7.20–7.25
(m, 5 H, 5ϫCHAr), 7.64 (d, J = 8.2 Hz, 2 H, 2ϫCH-Ar), 7.67 (s,
–CH2–CH3), 2.36 (s, 3 H, COCH3), 2.79 (dd, J = 5.4, J = 15.0 Hz,
1 H, CH2-1), 2.90 (qd, J = 7.0, J = 13.6 Hz, 2 H, –CH2–CH3), 3.24
(dd, J = 6.7, J = 13.8 Hz, 2 H, CH2-1 and CH2-2), 3.37–3.46 (m,
1 H, CH2-2), 3.83 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.24 (s, 1
H, 6-H), 6.65 (s, 1 H, 7-H), 6.73 (s, 1 H, 10-H), 7.14 (d, J = 7.8 Hz,
2 H, 2ϫCH-Ar), 7.48 (d, J = 7.8 Hz, 2 H, 2ϫCH-Ar), 7.53 (s, 1
H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.2, 20.3, 31.7,
3
42.4, 44.2, 47.5, 51.3, 51.4, 107.9, 109.9, 111.8, 120.6 (q, JC,F
=
=
2
1
4 Hz, 2 C), 121.7 (2 C), 122.8 (q, JC,F = 32 Hz), 123.5 (q, JC,F
1 H, 4-H) ppm. IR (KBr): ν = 1614 cm–1. EI MS: m/z (%) = 417
280 Hz), 123.6, 126.6, 142.3, 142.9, 146.7, 150.6, 189.7 ppm. IR
˜
(KBr): ν = 1613, 1571 cm–1. EI MS: m/z (%) = 433 (47) [M]+, 414
(11) [M]+, 263 (17), 262 (100), 261 (55), 246 (7), 232 (10), 217 (8),
205 (15), 204 (23), 203 (17), 191 (12), 178 (70), 165 (5), 158 (13),
147 (7), 141 (5), 128 (8), 115 (12), 105 (5), 91 (43), 77 (7), 65 (18),
56 (15), 51 (7). C26H27NO2S (417.56): calcd. C 74.79, H 6.52, N
3.35; found C 74.83, H 6.62, N 3.44.
˜
(9), 404 (7), 391 (24), 390 (100), 376 (12), 374 (6), 363 (13), 362
(50), 348 (6), 347 (21), 346 (23), 345 (5), 334 (6), 333 (18), 321 (7),
320 (8), 319 (20), 290 (6), 275 (5), 219 (6), 218 (13), 202 (6), 164
(9), 72 (7), 58 (72), 43 (11). C24H26F3NO3 (433.19): calcd. C 66.50,
H 6.05, N 3.23; found C 66.59, H 6.01, N 3.21.
Methyl 3-Ethyl-8,9-dimethoxy-6-methyl-1,2,3,6-tetrahydrobenzo[d]-
azocine-5-carboxylate (36): Yield 99 mg (31%) in acetonitrile, yel-
low oil. 1H NMR (400 MHz, CDCl3): δ = 1.11 (t, J = 7.2 Hz, 3
H, –CH2–CH3), 1.52 (d, J = 7.5 Hz, 3 H, 6-CH3), 3.08 (ddd, J =
3-Ethyl-8,9-dimethoxy-5-[(4-methylphenyl)sulfonyl]-6-(4-trifluoro-
methylphenyl)-1,2,3,6-tetrahydrobenzo[d]azocine (26): Yield 365 mg
(67%), white crystals, m.p. 154–155 °C (ethyl acetate/hexane). 1H
NMR (400 MHz, CDCl3): δ = 1.15 (t, J = 7.2 Hz, 3 H, –CH2– 6.1, J = 10.0, J = 16.3 Hz, 1 H, CH2-1), 3.16–3.27 (m, 3 H, CH2-
CH3), 2.39 (s, 3 H, CH3–Ar), 2.67 (dd, J = 4.9, J = 15.2 Hz, 1 H, 1 and –CH2–CH3), 3.58 (ddd, J = 4.8, J = 6.1, J = 15.2 Hz, 1 H,
CH2-1), 2.86 (qd, J = 7.2, J = 13.8 Hz, 2 H, –CH2–CH3), 3.20–
CH2-2), 3.64–3.68 (m, 4 H, OCH3 and CH2-2), 3.82 (s, 3 H, OCH3),
Eur. J. Org. Chem. 2007, 6106–6117
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6113

L. G. Voskressensky et al.
3.85 (s, 3 H, OCH3), 4.57 (q, J = 7.5 Hz, 1 H, 6-H), 6.55 (s, 1 H, H, 7-H), 6.55 (s, 1 H, 10-H), 7.11–7.12 (m, 3 H, CH-Ar), 7.16–7.19
FULL PAPER
7-H), 6.74 (s, 1 H, 10-H), 7.50 (s, 1 H, 4-H) ppm. IR (KBr): ν =
(m, 2 H, CH-Ar), 7.52 (s, 1 H, 4-H) ppm. IR (KBr): ν = 1677,
˜
˜
1728, 1689 cm–1. EI MS: m/z (%) = 319 (50) [M]+, 304 (100), 288
(20), 272 (15), 260 (60), 248 (84), 323 (10), 218 (16), 215 (20), 203
(17), 191 (44), 190 (24), 175 (20), 164 (30), 160 (15), 145 (10), 128
(8), 115 (16), 91 (7), 77 (6), 58 (8), 42 (6), 29 (10). C18H25NO4
(319.39): calcd. C 67.69, H 7.89, N 4.39; found C 67.73, H 7.93, N
4.43.
1609 cm–1. ESI MS: m/z = 396 [M + 1]+. C24H29NO4 (395.49):
calcd. C 72.89, H 7.39, N 3.54; found C 72.93, H 7.31, N 3.62.
1-(6-Benzyl-3-ethyl-8,9-dimethoxy-1,2,3,6-tetrahydrobenzo[d]azocin-
5-yl)ethan-1-one (41): Yield 208 mg (55 %) in acetonitrile, white
crystals, m.p. 152–153 °C (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3): δ = 1.18 (t, J = 7.2 Hz, 3 H, –CH2–CH3), 2.17
(s, 3 H, COCH3), 3.03–3.18 (m, 3 H, 2ϫCH2-1 and CH2-2), 3.26–
3.36 (m, 3 H –CH2–CH3 and CH2-2), 3.64 (m, 4 H, OCH3 and
CH2–Ar), 3.66 (m, 4 H, OCH3 and CH2–Ar), 4.85 (dd, J = 5.2, J
= 8.4 Hz, 1 H, 6-H), 6.37 (br. s, 1 H, 7-H), 6.54 (s, 1 H, 10-H),
3-Ethyl-8,9-dimethoxy-6-methyl-5-[(4-methylphenyl)sulfonyl]-
1,2,3,6-tetrahydrobenzo[d]azocine (37): Yield 166 mg (40%) in ace-
tonitrile, brownish crystals, m.p. 139–140 °C (ethyl acetate/hexane).
1H NMR (400 MHz, CDCl3): δ = 1.16 (t, J = 7.2 Hz, 3 H, –CH2–
CH3), 1.59 (d, J = 7.2 Hz, 2 H, 6-CH3), 2.43 (s, 3 H, CH3–Ar),
2.99–3.09 (m, 1 H, CH2-1), 3.21–3.30 (m, 3 H, CH2-1 and –CH2–
CH3), 3.43–3.52 (m, 4 H, OCH3 and CH2-2), 3.76–3.85 (m, 5 H,
OCH3, 6-H and CH2-2), 5.60 (s, 1 H, 7-H), 6.50 (s, 1 H, 10-H),
7.27 (d, J = 8.1 Hz, 2 H, 2ϫCH-Ar), 7.57 (s, 1 H, 4-H), 7.71 (d,
7.07–7.17 (m, 5 H, Ar), 7.38 (s, 1 H, 4-H) ppm. IR (KBr): ν =
˜
1623, 1574 cm–1. EI MS: m/z (%) = 379 (3) [M]+, 288 (100), 244
(5), 218 (7), 189 (10), 175 (15), 144 (13), 91 (25), 65 (10), 43 (35).
C
24H29NO3 (379.49): calcd. C 75.96, H 7.70, N 3.69; found C
76.07, H 7.78, N 3.72.
J = 8.1 Hz, 2 H, 2ϫCH-Ar) ppm. IR (KBr): ν = 1613 cm–1. EI
˜
6-Benzyl-3-ethyl-8,9-dimethoxy-5-[(4-methylphenyl)sulfonyl]-1,2,3,6-
tetrahydrobenzo[d]azocine (42): Yield 319 mg (65%) in acetonitrile,
white crystals, m.p. 173–174 °C (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 3 H, –CH2–CH3), 2.34
(s, 3 H, CH3–Ar), 3.02–3.11 (m, 2 H, CH2-1), 3.17 (s, 3 H, OCH3),
3.26–3.43 (m, 4 H, –CH2–CH3 and CH2–Ar), 3.49–3.57 (m, 1 H,
CH2-2), 3.64–3.69 (m, 1 H, CH2-2), 3.79 (s, 3 H, OCH3), 3.83–3.96
(m, 1 H, 6-H), 5.06 (s, 1 H, 7-H), 6.51 (s, 1 H, 10-H), 6.94 (d, J =
7.5 Hz, 2 H, 2ϫCH-Ar), 7.07–7.14 (m, 3 H, 3ϫCH-Ar), 7.21 (d,
J = 8.0 Hz, 2 H, 2ϫCH-Ar), 7.62 (s, 1 H, 4-H), 7.71 (d, J = 8.0 Hz,
MS: m/z (%) = 415 (12) [M]+, 400 (5), 260 (100), 233 (100), 215
(14), 203 (11), 191 (15), 174 (5), 164 (10), 145 (7), 130 (5), 115 (10),
105 (7), 91 (35), 77 (7), 65 (18), 58 (16), 51 (6), 39 (13). C23H29NO4S
(415.54): calcd. C 66.48, H 7.03, N 3.37; found C 66.54, H 7.07, N
3.30.
Methyl 8,9-Dimethoxy-6-methyl-3-(4-methylbenzyl)-1,2,3,6-tetra-
hydrobenzo[d]azocine-5-carboxylate (38): Yield 198 mg (50 %) in
1
acetonitrile, yellow viscous oil. H NMR (400 MHz, CDCl3): δ =
1.53 (d, J = 7.5 Hz, 3 H, 6-CH3), 2.33 (s, 3 H, CH3–Ar), 2.75 (ddd,
J = 6.6, J = 10.1, J = 17.0 Hz, 1 H, CH2-1), 3.06–3.08 (m, 1 H,
CH2-1), 3.54 (ddd, J = 4.3, J = 6.6, J = 15.4 Hz, 1 H, CH2-2),
3.66–3.73 (m, 4 H, CH2-2 and OCH3), 3.76 (s, 3 H, OCH3), 3.86
(s, 3 H, OCH3), 4.23 (d, J = 14.8 Hz, 1 H, CH2–Ar), 4.35 (d, J =
14.8 Hz, 1 H, CH2–Ar), 4.60 (q, J = 7.5 Hz, 1 H, 6-H), 6.21 (s, 1
H, 7-H), 6.72 (s, 1 H, 10-H), 6.89 (d, J = 7.9 Hz, 2 H, 2ϫCH-Ar),
7.07 (d, J = 7.9 Hz, 2 H, 2ϫCH-Ar), 7.67 (s, 1 H, 4-H) ppm. IR
2 H, 2ϫCH-Ar) ppm. IR (KBr): ν = 1614, 1514 cm–1. EI MS: m/z
˜
(%) = 491 (3) [M]+, 400 (100), 244 (23), 230 (19), 219 (40), 189 (12),
175 (10), 145 (11), 130 (7), 91 (37). C29H33NO4S (491.21): calcd. C
70.85, H 6.77, N 2.85; found C 70.69, H 6.89, N 2.87.
General Synthetic Procedure for the Synthesis of Benzo[d]azocines
43–45: p-Tosylacetylene (2 mmol) or methyl propiolate (acetyl-
acetylene) (5 mmol) was added to a solution of the isoquinoline
derivative 5m (1 mmol) in acetonitrile. The mixture was stirred at
room temperature (TLC monitoring). The solvent was evaporated
under reduced pressure, and the residue was recrystallized (ethyl
acetate/hexane) to give benzoazocines 43–45.
(KBr): ν = 1670, 1584 cm–1. EI MS: m/z (%) = 395 (15) [M]+, 380
˜
(14), 364 (5), 336 (12), 290 (27), 276 (95), 258 (6), 248 (53), 234 (8),
215 (14), 203 (10), 191 (30), 175 (9), 164 (28), 147 (13), 134 (10),
128 (6), 115 (10), 105 (100), 91 (12), 77 (35), 65 (7), 59 (10), 42
(12). C24H29NO4 (395.49): calcd. C 72.89, H 7.39, N 3.54; found C
72.96, H 7.43, N 3.46.
Methyl 6-Benzyl-8,9-dimethoxy-3-(4-methylbenzyl)-1,2,3,6-tetra-
hydrobenzo[d]azocine-5-carboxylate (43): Yield 372 mg (79%) in
acetonitrile, white crystals, m.p. 136–138 °C (ethyl acetate/hexane).
1H NMR (400 MHz, CDCl3): δ = 2.53 (s, 3 H, CH3–Ar), 2.83–2.95
(m, 1 H, CH2-1), 3.11–3.18 (m, 2 H, CH2-1 and CH2-2), 3.24–3.30
(m, 1 H, CH2-2), 3.70–3.76 (m, 8 H, 2ϫOCH3 and 6-CH2–Ar),
3.78 (s, 3 H, OCH3), 4.27 (d, J = 14.8 Hz, 1 H, N–CH2–Ar), 4.38
(d, J = 14.8 Hz, 1 H, N–CH2–Ar), 4.70 (dd, J = 5.9, J = 8.6 Hz, 1
H, 6-H), 6.49 (s, 1 H, 10-H), 6.49 (br. s, 1 H, 7-H), 6.94 (d, J =
7.5 Hz, 2 H, 2ϫCH-Ar), 7.08–7.28 (m, 7 H, CH-Ar), 7.69 (s, 1 H,
4-H) ppm. 13C NMR (100 Hz, CDCl3): δ = 21.0, 36.3, 43.3, 46.5,
51.1, 52.3, 55.6, 55.8, 62.1, 101.4, 114.5, 114.9, 125.6, 127.6 (2 C),
127.9 (2 C), 128.8, 128.9 (2 C), 129.2 (2 C), 132.7, 134.4, 137.3,
8,9-Dimethoxy-6-methyl-3-(4-methylbenzyl)-5-[(4-methylphenyl)-
sulfonyl]-1,2,3,6-tetrahydrobenzo[d]azocine (39): Yield 265 mg
(54%) in acetonitrile, brownish crystals, m.p. 152–153 °C (ethyl ace-
tate/hexane). 1H NMR (400 MHz, CDCl3): δ = 1.60 (d, J = 7.7 Hz,
3 H, 6-CH3), 2.34 (s, 3 H, CH3–Ar), 2.41 (s, 3 H, CH3–Ar), 2.64–
2.74 (m, 1 H, CH2-1), 3.05 (dd, J = 5.4, J = 16.5 Hz, 1 H, CH2-1),
3.44 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 3.78–3.88 (m, 3 H,
2ϫCH2-2 and 6-H), 4.29 (d, J = 15.1 Hz, 1 H, CH2–Ar), 4.40 (d,
J = 15.1 Hz, 1 H, CH2–Ar), 5.57 (s, 1 H, 7-H), 6.16 (s, 1 H, 10-H),
6.89 (d, J = 7.6 Hz, 2 H, 2ϫCH-Ar), 7.07 (d, J = 7.6 Hz, 2 H,
2ϫCH-Ar), 7.26–7.29 (m, 2 H, 2ϫCH-Ar), 7.72–7.74 (m, 3 H,
2ϫCH-Ar and 4-H) ppm. IR (KBr): ν = 1614 cm–1. EI MS: m/z
˜
141.5, 146.3, 147.0, 152.6, 170.1 ppm. IR (KBr): ν = 1666,
˜
(%) = 491 (3) [M]+, 336 (50), 296 (5), 238 (10), 217 (80), 164 (7), 106
(37), 105 (100), 91 (16), 77 (17), 65 (7), 51 (95), 39 (7). C29H33NO4S
(491.64): calcd. C 70.85, H 6.77, N 2.85; found C 70.91, H 6.73, N
2.93.
1603 cm–1. EI MS: m/z (%) = 471 (5) [M]+, 440 (50), 380 (35), 175
(5), 105 (100), 79 (12), 65 (6). C30H33NO4 (471.58): calcd. C 76.41,
H 7.05, N 2.97; found C 76.54, H 6.99, N 3.02.
1-[6-Benzyl-8,9-dimethoxy-3-(4-methylbenzyl)-1,2,3,6-tetrahydro-
benzo[d]azocin-5-yl]ethan-1-one (44): Yield 378 mg (83%) in aceto-
nitrile, white crystals, m.p. 159–161 °C (ethyl acetate/hexane). 1H
Methyl 6-Benzyl-3-ethyl-8,9-dimethoxy-1,2,3,6-tetrahydrobenzo[d]-
azocine-5-carboxylate (40): Yield 237 mg (60%) in acetonitrile, vis-
1
cous yellowish oil. H NMR (400 MHz, CDCl3): δ = 1.14 (t, J = NMR (400 MHz, CDCl3): δ = 2.22 (s, 3 H, COCH3), 2.35 (s, 3 H,
6.5 Hz, 3 H, –CH2–CH3), 3.09–3.31 (m, 7 H, –CH2–CH3, CH2-1, CH3–Ar), 2.78–2.90 (m, 1 H, CH2-1), 3.03–3.24 (m, 3 H, CH2-1
CH2-2, and CH2–Ar), 3.65–3.68 (m, 7 H, CH2–Ar and 2ϫOCH3), and CH2-2), 3.60–3.66 (m, 4 H, OCH3 and 6-CH2–Ar), 3.76 (s, 3
3.82 (s, 3 H, OCH3), 4.66 (t, J = 7.1 Hz, 1 H, 6-H), 6.44 (br. s, 1
H, OCH3), 3.82–3.93 (m, 1 H, 6-CH2–Ar), 4.31 (d, J = 14.9 Hz, 1
6114
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6106–6117

Benzoazocines from Tetrahydroisoquinolines and Activated Alkynes
H, N–CH2–Ar), 4.39 (d, J = 14.9 Hz, 1 H, N–CH2–Ar), 4.85 (dd,
(s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.32 (d, J = 15.4 Hz, 1 H,
J = 5.0, J = 8.7 Hz, 1 H, 6-H), 6.24 (s, 1 H, 10-H), 6.38 (br. s, 1 CH2–Ar), 4.52 (d, J = 15.4 Hz, 1 H, CH2–Ar), 4.96 (s, 1 H, 6-H),
H, 7-H), 6.92 (d, J = 7.9 Hz, 2 H, 2ϫCH-Ar), 7.09–7.19 (m, 7 H,
5.64 (s, 1 H, 7-H), 6.21 (s, 1 H, 10-H), 6.77 (d, J = 8.2 Hz, 2 H,
CH-Ar), 7.54 (s, 1 H, 4-H) ppm. 13C NMR (100 Hz, CDCl3): δ = 2ϫCH-Ar), 7.04 (d, J = 7.9 Hz, 2 H, 2ϫCH-Ar), 7.15 (d, J =
21.0, 36.3, 43.2, 46.4, 51.0, 52.3, 55.3, 55.8, 62.1, 114.5, 115.3, 7.7 Hz, 2 H, 2ϫCH-Ar), 7.25–7.29 (m, 2 H, 2ϫCH-Ar), 7.68 (d,
115.5, 125.6, 127.6 (2 C), 127.9 (2 C), 128.6, 128.9 (2 C), 129.3 (2
J = 7.7 Hz, 2 H, 2ϫCH-Ar), 7.82 (s, 1 H, 4-H), 7.93 (d, J = 8.2 Hz,
C), 132.5, 133.9, 137.6, 141.6, 146.3, 147.0, 154.7, 195.1 ppm. IR 2 H, 2ϫCH-Ar) ppm. 13C NMR (100 MHz, DMSO): δ = 21.4,
(KBr): ν = 1574, 1515 cm–1. EI MS: m/z (%) = 455 (3) [M]+, 364 36.5, 49.2, 50.1, 52.6, 55.1, 55.3, 55.4, 59.7, 106.1, 114.0 (2 C),
˜
(100), 258 (5), 174 (7), 105 (73), 91 (15), 79 (10), 43 (14).
30H33NO3 (455.59): calcd. C 79.09, H 7.30, N 3.07; found C
780.3, H 7.35, N 3.02.
115.7, 115.8, 127.9 (2 C), 128.0 (2 C), 128.4 (2 C), 128.8, 129.2,
129.7 (2 C), 130.0 (2 C), 130.5, 137.5, 140.6, 142.9, 144.0, 146.8,
C
146.9, 152.9, 157.9, 166.4 ppm. IR (KBr): ν = 1716, 1613 cm–1. EI
˜
MS: m/z (%) = 627 (2) [M]+, 472 (35), 444 (10), 340 (5), 322 (53),
308 (7), 295 (25), 280 (12), 264 (17), 249 (10), 221 (7), 190 (11), 165
(15), 149 (91), 121 (83), 91 (65), 77 (20), 55 (15), 44 (30).
C36H37NO7S (627.75): calcd. C 68.88, H 5.94, N 2.23; found C
68.97, H 5.86, N 2.31.
6-Benzyl-8,9-dimethoxy-3-(4-methylbenzyl)-5-[(4-methylphenyl)-
sulfonyl]-1,2,3,6-tetrahydrobenzo[d]azocine (45): Yield 363 mg
(64%) in acetonitrile, white crystals, m.p. 182–183 °C (ethyl acetate/
1
hexane). H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3–Ar),
2.36 (s, 3 H, CH3–Ar), 2.73–2.82 (m, 1 H, CH2-1), 3.05–3.09 (m, 1
H, CH2-1), 3.19–3.26 (m, 4 H, OCH3 and CH2-2), 3.37 (dd, J =
2.1, J = 12.8 Hz, 1 H, CH2-2), 3.46–3.53 (m, 1 H, 6-CH2–Ar), 3.71–
3.73 (m, 4 H, OCH3 and 6-CH2–Ar), 3.87–3.96 (m, 1 H, 6-H), 4.34
(d, J = 14.8 Hz, 1 H, N–CH2–Ar), 4.44 (d, J = 14.8 Hz, 1 H, N–
CH2–Ar), 5.05 (s, 1 H, 7-H), 6.19 (s, 1 H, 10-H), 6.92–6.96 (m, 4
H, CH-Ar), 7.09–7.13 (m, 5 H, CH-Ar), 7.23–7.25 (m, 2 H,
2ϫCH-Ar), 7.73 (d, J = 8.2 Hz, 2 H, 2ϫCH-Ar), 7.79 (s, 1 H, 4-
Methyl 3-(4-Fluorobenzyl)-8,9-dimethoxy-6-(4-methoxyphenyl)-
1,2,3,6-tetrahydrobenzo[d]azocine-5-carboxylate (29): Yield 181 mg
(37%) in acetonitrile, white crystals, m.p. 117–119 °C (ethyl acetate/
1
hexane). H NMR (400 MHz, CDCl3): δ = 2.36 (ddd, J = 6.8, J =
13.2, J = 16.1 Hz, 1 H, CH2-1), 2.58 (dd, J = 5.4, J = 16.1 Hz, 1
H, CH2-1), 2.79 (dd, J = 6.8, J = 15.4 Hz, 1 H, CH2-2), 3.58 (ddd,
J = 5.4, J = 13.2, J = 15.4 Hz, 1 H, CH2-2), 3.76 (s, 3 H, OCH3),
3.77 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
4.16 (d, J = 14.7 Hz, 1 H, CH2–Ar), 4.36 (d, J = 14.7 Hz, 1 H,
CH2–Ar), 5.84 (s, 1 H, 6-H), 6.19 (s, 1 H, 7-H), 6.77–6.79 (m, 3 H,
10-H and 2ϫCH-Ar), 6.90–6.93 (m, 4 H, 4ϫCH-Ar), 7.02 (d, J
= 8.0 Hz, 2 H, 2ϫCH-Ar), 7.83 (s, 1 H, 4-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 36.4, 48.6, 50.2, 51.4, 55.2, 55.7, 55.9, 61.2,
99.6, 113.7 (2 C), 115.0, 115.2 (d, 2JC,F = 22 Hz, 2 C), 116.6, 127.1
H) ppm. IR (KBr): ν = 1616 cm–1. EI MS: m/z (%) = 567 (3)
˜
[M]+, 476 (30), 188 (5), 105 (100), 91 (12), 65 (5), 43 (11).
C35H37NO4S (567.74): calcd. C 74.04, H 6.57, N 2.47; found C
74.10, H 6.65, N 2.39.
General Synthetic Procedure for the Synthesis of Benzo[d]azocines
27–32: p-Tosylacetylene (3 mmol) or methyl propiolate (11 mmol)
was added to a solution of the isoquinoline derivative 5f–h
(1 mmol) in acetonitrile. The mixture was heated at reflux (TLC
monitoring). The solvent was evaporated under reduced pressure,
and the residue was recrystallized (ethyl acetate/hexane) to give
benzoazocines 27–32.
3
4
(2 C), 128.7, 129.2 (d, JC,F = 8 Hz, 2 C), 132.4, 133.2 (d, JC,F
=
1
3 Hz), 139.1, 146.7, 147.5, 153.3, 157.5, 162.1 (d, JC,F = 246 Hz),
170.9 ppm. IR (KBr): ν = 1677, 1605 cm–1. EI MS: m/z (%) = 491
˜
(13) [M]+, 432 (17), 382 (15), 350 (10), 340 (20), 121 (13), 109 (100),
83 (12), 59 (7). C29H30FNO5 (491.55): calcd. C 70.86, H 6.15, N
2.85; found C 70.90, H 6.12, N 2.93.
Methyl 8,9-Dimethoxy-3-[4-(methoxycarbonyl)benzyl]-6-(4-meth-
oxyphenyl)-1,2,3,6-tetrahydrobenzo[d]azocine-5-carboxylate (27):
Yield 265 mg (50%) in acetonitrile, white crystals, m.p. 160–161 °C
(ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 2.36 (ddd,
J = 7.2, J = 12.9, J = 16.3 Hz, 1 H, CH2-1), 2.59 (dd, J = 4.7, J =
16.3 Hz, 1 H, CH2-1), 2.78 (dd, J = 7.2, J = 15.5 Hz, 1 H, CH2-2),
3.58–3.66 (m, 1 H, CH2-2), 3.76 (s, 3 H, OCH3), 3.77 (s, 3 H,
OCH3), 3.78 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 3.91 (s, 3 H,
OCH3), 4.24 (d, J = 15.3 Hz, 1 H, CH2–Ar), 4.44 (d, J = 15.3 Hz,
1 H, CH2–Ar), 5.83 (s, 1 H, 6-H), 6.19 (s, 1 H, 7-H), 6.77–6.79 (m,
3 H, 10-H and 2ϫCH-Ar), 6.99–7.02 (m, 4 H, 4ϫCH-Ar), 7.82
(s, 1 H, 4-H), 7.90 (d, J = 8.4 Hz, 2 H, 2ϫCH-Ar) ppm. 13C NMR
(100 Hz, CDCl3): δ = 36.6, 48.7, 50.6, 51.6, 52.3, 55.2, 55.7, 56.0,
61.7, 99.9, 113.7 (2 C), 115.0, 116.4, 127.1 (2 C), 127.8 (2 C), 128.6,
129.6, 130.1 (2 C), 132.2, 139.0, 142.7, 146.7, 147.5, 153.3, 157.5,
3-(4-Fluorobenzyl)-8,9-dimethoxy-6-(4-methoxyphenyl)-5-[(4-meth-
ylphenyl)sulfonyl]-1,2,3,6-tetrahydrobenzo[d]azocine (30): Yield
475 mg (81%) in acetonitrile, white crystals, m.p. 112–113 °C (ethyl
acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 2.39–2.44 (m, 4
H, CH2-1 and CH3-Ts), 2.53 (dd, J = 5.2, J = 15.8 Hz, 1 H, CH2-
1), 2.78 (dd, J = 6.4, J = 15.4 Hz, 1 H, CH2-2), 3.40 (s, 3 H, OCH3),
3.60 (ddd, J = 5.2, J = 13.6, J = 15.8 Hz, 1 H, CH2-2), 3.76 (s, 3
H, OCH3), 3.77 (s, 3 H, OCH3), 4.22 (d, J = 15.0 Hz, 1 H, CH2–
Ar), 4.25 (d, J = 15.0 Hz, 1 H, CH2–Ar), 4.94 (s, 1 H, 6-H), 5.60
(s, 1 H, 7-H), 6.21 (s, 1 H, 10-H), 6.78 (d, J = 8.9 Hz, 2 H, 2ϫCH-
Ar), 6.95–6.96 (m, 4 H, 4 ϫ CH-Ar), 7.15 (d, J = 8.1 Hz, 2 H,
2ϫCH-Ar), 7.70 (d, J = 8.1 Hz, 2 H, 2ϫCH-Ar), 7.83 (s, 1 H, 4-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5, 36.8, 49.2, 49.9,
55.1, 55.2, 55.6, 60.9, 106.9, 113.7 (2 C), 115.1, 115.2, 115.3 (d,
166.7, 170.9 ppm. IR (KBr): ν = 1719, 1659, 1600 cm–1. EI MS:
˜
3
2JC,F = 21 Hz, 2 C), 127.8 (2 C), 127.8 (2 C), 128.4, 129.3 (d, JC,F
m/z (%) = 531 (30) [M]+, 500 (10), 472 (50), 382 (53), 364 (50), 350
(20), 340 (72), 307 (10), 282 (27), 237 (12), 178 (20), 164 (30), 149
(87), 136 (40), 121 (100), 105 (20), 90 (30), 77 (17), 59 (17), 44 (28).
C31H33NO7 (531.60): calcd. C 70.04, H 6.26, N 2.63; found C
69.97, H 6.29, N 2.71.
4
= 8 Hz, 2 C), 129.4 (2 C), 130.7, 132.9 (d, JC,F = 3 Hz), 137.4,
1
139.9, 142.5, 146.7, 146.9, 151.8, 157.9, 162.1 (d, JC,F = 247 Hz)
ppm. IR (KBr): ν = 1614 cm–1. EI MS: m/z (%) = 587 (3)
˜
[M]+, 432 (7), 295 (8), 145 (11), 121 (18), 109 (100), 91 (23), 65 (6).
C34H34FNO5S (587.70): calcd. C 69.48, H 5.83, N 2.38; found C
69.55, H 5.90, N 2.29.
Methyl 4-({8,9-Dimethoxy-6-(4-methoxyphenyl)-5-[(4-methyl-
phenyl)sulfonyl]-1,6-dihydrobenzo[d]azocin-3(2H)-yl}methyl)-
benzoate (28): Yield 520 mg (83%) in acetonitrile, white crystals,
m.p. 184–185 °C (ethyl acetate/hexane). 1H NMR (400 MHz,
Methyl 8,9-Dimethoxy-6-(4-methoxyphenyl)-3-(4-methylbenzyl)-
1,2,3,6-tetrahydrobenzo[d]azocine-5-carboxylate (31): Yield 210 mg
CDCl3): δ = 2.37–2.45 (m, 4 H, CH3-Ts, CH2-1), 2.50–2.59 (m, 1 (43%) in acetonitrile, white crystals, m.p. 122–124 °C (ethyl acetate/
1
H, CH2-1), 2.78 (dd, J = 7.8, J = 15.4 Hz, 1 H, CH2-2), 3.42 (s, 3
H, OCH3), 3.60–3.65 (m, 1 H, CH2-2), 3.74 (s, 3 H, OCH3), 3.76
hexane). H NMR (400 MHz, CDCl3): δ = 2.33 (s, 3 H, CH3–Ar),
2.40–2.50 (m, 1 H, CH2-1), 2.60 (dd, J = 5.1, J = 15.5 Hz, 1 H,
Eur. J. Org. Chem. 2007, 6106–6117
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6115

L. G. Voskressensky et al.
FULL PAPER
CH2-1), 2.81 (dd, J = 7.0, J = 15.5 Hz, 1 H, CH2-2), 3.58 (m, 1 H, Dimethyl 3-Ethyl-8,7-dimethoxy-6-(4-methoxyphenyl)-1,2,3,4,5,6-
CH2-2), 3.77 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.80 (s, 3 H, hexahydrobenzo[d]azocine-4,5-dicarboxylate (47): NaCNBH3
OCH3), 3.89 (s, 3 H, OCH3), 4.17 (d, J = 14.8 Hz, 1 H, CH2–Ar),
4.35 (d, J = 14.8 Hz, 1 H, CH2–Ar), 5.84 (s, 1 H, 6-H), 6.26 (s, 1
H, 7-H), 6.78–6.80 (m, 3 H, 10-H and 2ϫCH-Ar), 6.87 (d, J =
7.7 Hz, 2 H, 2ϫCH-Ar), 7.02–7.07 (m, 4 H, 4ϫCH-Ar), 7.86 (s,
1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.0, 36.4, 48.6,
(165 mg, 2.63 mmol) and a few drops of acetic acid, as catalyst,
were added to a solution of benzo[d]azocine 11 (350 mg,
0.75 mmol) in methanol (20 mL). The reaction mixture was heated
at reflux (TCL monitoring). The solvent was evaporated under re-
duced pressure. The residue was extracted with ethyl acetate
49.8, 51.3, 55.2, 55.6, 55.9, 61.4, 98.9, 113.7 (2 C), 115.2, 116.5, (3ϫ25 mL). The solvent was evaporated under reduced pressure to
127.1 (2 C), 127.6 (2 C), 128.8, 129.1 (2 C), 132.5, 134.2, 137.3,
139.2, 146.6, 147.4, 153.5, 157.4, 171.0 ppm. IR (KBr): 1670,
give hexahydrobenzo[d]azocine 47 (221 mg, 62%); white crystals,
m.p. 130–131 °C (ethyl acetate/hexane). 1H NMR (400 MHz,
1605 cm–1. EI MS: m/z (%) = 487 (10) [M]+, 428 (21), 382 (30), 340 CDCl3): δ = 1.15 (t, J = 6.9 Hz, 3 H, –CH2–CH3), 2.54 (qd, J =
(17), 281 (70), 192 (7), 151 (5), 121 (15), 105 (100), 79 (13), 59 (50). 6.9, J = 13.9 Hz, 1 H, –CH2–CH3), 2.62 (dd, J = 3.7, J = 13.3 Hz,
C
30H33NO5 (487.58): calcd. C 73.90, H 6.82, N 2.87; found C
1 H, CH2-1), 2.67–2.78 (m, 1 H, CH2-1), 2.83 (qd, J = 6.9, J =
13.9 Hz, 1 H, –CH2–CH3), 3.23–3.37 (m, 4 H, 2ϫCH2-2, 4-H, and
5-H), 3.51 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3), 3.66 (s, 3 H,
OCH3), 3.79 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 4.99 (d, J =
11.4 Hz, 1 H, 6-H), 6.46 (s, 1 H, 7-H), 6.59 (s, 1 H, 10-H), 6.84 (d,
J = 8.7 Hz, 2 H, 2ϫCH-Ar), 7.26 (d, J = 8.7 Hz, 2 H, 2ϫCH-Ar)
73.99, H 6.77, N 2.95.
8,9-Dimethoxy-6-(4-methoxyphenyl)-3-(4-methylbenzyl)-5-[(4-meth-
ylphenyl)sulfonyl]-1,2,3,6-tetrahydrobenzo[d]azocine (32): Yield
315 mg (54%) in acetonitrile, white crystals, m.p. 165–166 °C (ethyl
acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 3 H,
CH3–Ar), 2.41 (s, 3 H, CH3–Ar), 2.43–2.56 (m, 2 H, CH2-1), 2.79
(dd, J = 6.1, J = 15.4 Hz, 1 H, CH2-2), 3.39 (s, 3 H, OCH3), 3.57
(ddd, J = 6.1, J = 12.8, J = 15.4 Hz, 1 H, CH2-2), 3.76 (s, 3 H,
OCH3), 3.77 (s, 3 H, OCH3), 4.25 (d, J = 14.8 Hz, 1 H, CH2–Ar),
4.40 (d, J = 14.8 Hz, 1 H, CH2–Ar), 4.93 (s, 1 H, 6-H), 5.58 (s, 1
H, 7-H), 6.24 (s, 1 H, 10-H), 6.77 (d, J = 8.9 Hz, 2 H, 2ϫCH-Ar),
6.89 (d, J = 7.9 Hz, 2 H, 2ϫCH-Ar), 7.07 (d, J = 7.5 Hz, 2 H,
2ϫCH-Ar), 7.24–7.26 (m, 2 H, 2ϫCH-Ar), 7.69 (d, J = 7.9 Hz, 2
H, 2ϫCH-Ar), 7.84 (s, 1 H, 4-H) ppm. IR (KBr): 1620 cm–1. EI
MS: m/z (%) = 583 (3) [M]+, 428 (53), 322 (15), 295 (10), 206 (13),
165 (70), 155 (5), 145 (6), 121 (20), 105 (100), 91 (21), 77 (13), 65
(7). C35H37NO5S (583.74): calcd. C 72.01, H 6.39, N 2.40; found
C 72.11, H 6.44, N 2.37.
ppm. IR (KBr): ν = 1735 cm–1. EI MS: m/z (%) = 471 (12) [M]+,
˜
412 (10), 295 (7), 233 (15), 220 (25), 207 (100), 192 (11), 165 (8), 142
(20), 130 (70), 121 (30), 82 (5), 72 (20), 56 (14), 45 (31). C26H33NO7
(471.54): calcd. C 66.22, H 7.05, N 2.97; found C 66.01, H 7.12, N
3.04.
Crystal Structure Analysis for 47: C26H33NO7, Mr = 471.54 gmol–1,
monoclinic, space group P21/c, a = 11.7535(11), b = 9.2742(13), c
= 23.647(3) Å, β = 98.251(8)°, V = 2551.0(6) Å3, Z = 4, ρ =
1.228 gcm3, µ = 0.089 mm–1, F(000) = 1008. A total of 8286 reflec-
tions (1.74° Ͻ θ Ͻ 30.00°), of which 7320 were unique [R(int.) =
0.0277], were collected with a Bruker-P4 diffractometer with use of
monochromatized Mo-Kα radiation. The structure was solved with
the program SHELXS-97 and refined by use of SHELXL-97 to R1
= 0.065 and wR(F2) = 0.2024 for 7320 reflections with I Ͼ 2σ(I);
max./min. residual electron density 0.182/–0.385 eÅ–3. CCDC-
646020 (for 47) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Methyl 3-Ethyl-8,9-dimethoxy-6-(4-methoxyphenyl)-1,2,3,4,5,6-
hexahydrobenzo[d]azocine-5-carboxylate (46): NaCNBH3 (104 mg,
1.66 mmol) and a few drops of acetic acid, as catalyst, were added
to a solution of benzo[d]azocine 8 (340 mg, 0.83 mmol) in methanol
(20 mL). The reaction mixture was heated at reflux (TCL monitor-
ing). The solvent was evaporated under reduced pressure. The resi-
due was extracted with ethyl acetate (3ϫ25 mL). The solvent was
evaporated under reduced pressure to give hexahydrobenzo[d]azoc-
ine 46 (275 mg, 80 %) as a viscous yellowish oil. 1H NMR
(400 MHz, CDCl3): δ = 0.94 (t, J = 6.3 Hz, 2.4 H, –CH2–CH3 maj),
1.06 (t, J = 6.3 Hz, 0.6 H, –CH2–CH3 min), 2.10 (dd, J = 2.5, J =
15.0 Hz, 0.8 H, CH2-1 maj), 2.25 (br. d, J = 13.4 Hz, 0.2 H, CH2-
1 min), 2.42–2.61 (m, 2 H, –CH2–CH3), 2.63–2.74 (m, 1 H, 2-CH2),
Acknowledgments
The financial support of the Russian Foundation for Basic Re-
search (grant #03-05-32211) is gratefully acknowledged.
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J = 8.0 Hz, 1.6 H, CH-Ar maj), 7.25 (d, J = 8.0 Hz, 0.4 H, CH-Ar
min) ppm. 13C NMR (100 Hz, CDCl3): δ maj (min) = 11.7 (12.7),
36.7 (37.3), 43.3 (43.7), 51.4 (49.9), 52.3 (51.1), 54.2 (53.3), 55.1,
55.2, 55.7, 55.8, 55.8, 111.4 (112.1), 112.5 (113.2), 113.7 (2 C), 129.0
(129.2, 2 C), 132.7 (131.6), 134.3 (133.6), 135.3 (135.1), 147.2
(146.6), 147.5 [157.8 (157.5), 174.2 (173.6) ppm. IR (KBr): ν =
˜
1743 cm–1. EI MS: m/z (%) = 413 (30) [M]+, 411 (6), 356 (5), 354
(8), 283 (13), 282 (6), 271 (5), 296 (5), 234 (8), 220 (10), 208 (14),
207 (100), 206 (13), 192 (23), 165 (5), 164 (6), 147 (9), 121 (10), 72
(9), 58 (5). C24H31NO5 (413.51): calcd. C 69.71, H 7.56, N 3.39;
found C 69.78, H 7.47, N 3.30.
6116
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6106–6117

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Published Online: October 16, 2007
Eur. J. Org. Chem. 2007, 6106–6117
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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