Tandem enlargement of the tetrahydropyridine ring in 1-aryl-tetrahydroisoquinolines using activated alkynes-a new and effective synthesis of benzoazocines

Article abstract of DOI:10.1016/j.tetlet.2006.04.151

Tetrahydroisoquinolines 3a-e underwent piperidine ring enlargement under the action of activated alkynes, giving benzoazocines 4, 5 and 7-11 in high yields.

Full text of DOI:10.1016/j.tetlet.2006.04.151

Tetrahedron Letters 47 (2006) 4585–4589
Tandem enlargement of the tetrahydropyridine ring in
1-aryl-tetrahydroisoquinolines using activated alkynes—a new
and effective synthesis of benzoazocines
Leonid G. Voskressensky,* Tatiana N. Borisova, Anna V. Listratova, Larisa N. Kulikova,
Alexander A. Titov and Alexey V. Varlamov
Organic Chemistry Department of the Russian People Friendship University, 6, Miklukho-Maklaia St., Moscow 117198, Russia
Received 27 February 2006; revised 18 April 2006; accepted 28 April 2006
Abstract—Tetrahydroisoquinolines 3a–e underwent piperidine ring enlargement under the action of activated alkynes, giving ben-
zoazocines 4, 5 and 7–11 in high yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
It is known that transformations of the tetrahydropyr-
idine (THP) ring in pyrrolo[3,2-c]pyridines, tetrahydro-
b- and c-carbolines under the action of activated alkynes
begin with the formation of the intermediate zwitterion
A, resulting from Michael addition of the piperidine
nitrogen to the triple bond of the activated alkyne.1 This
zwitterion undergoes further transformations via two
different pathways, both of which are controlled by the
reactivity of the anionic centre, the electronic effects
of the substituent and the nature of the solvent (Scheme
1).
The final products of these tandem transformations in
aprotic solvents are azocines 1: pyrrolo[2,3-d]azocines,1
azocino[4,5-b]-and [5,4-b]indoles,2 whereas in the case
of alcohols as the solvent—alkoxyalkyl-substituted py-
rroles and indoles 2, result.2,3 In some cases, the forma-
tion of mixtures of azocines and alkoxy-substituted
pyrroles or indoles in different proportions occurs. As
a rule, the most efficient solvent for synthesizing the
azocines 1 is acetonitrile, and for the alkoxy-substituted
2 is methanol or ethanol.
Analysis of the data obtained led us to presume that the
presence of an Ar-substituent, providing additional
delocalization of the partial positive charge +d1 appear-
ing on C-1 of the intermediate zwitterion, would facili-
tate cleavage of the C-1–N bond, thus favouring the
formation of azocines via the intramolecular SN1-pro-
cess (Scheme 2). To check this assumption, we studied
the tandem interaction of 1-aryl-6,7-dimethoxy-2-ethyl-
1,2,3,4-tetrahydroisoquinolines 3a–d with dimethyl acet-
ylene dicarboxylate (DMAD), methyl propiolate, acetyl-
acetylene and p-tosylacetylene4 in methanol and
acetonitrile.
N
1
N
N
OR
A
N
2
Ar
Scheme 1.
Ar
Ar
+δ
1
+δ
N
2
N
Keywords: Tetrahydroisoquinoline; Azocines; Glaucine; Alkyne; Tan-
N
dem reactions.
*
Corresponding author. Tel.: +7 495 955 07 44; fax: +7 495 955 07
79; e-mail: lvoskressensky@sci.pfu.edu.ru
Scheme 2.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.151

4586
L. G. Voskressensky et al. / Tetrahedron Letters 47 (2006) 4585–4589
According to Scheme 2, starting materials having a
benzhydryl fragment with differently substituted Ar rad-
icals attached to the C-1 position should have different
reactivities in SN1 reactions, subject to the electronic
properties of the substituents on the Ar rings. It is well
known that the SN1 reactivity dramatically increases
for the benzhydryl and trityl derivatives having addi-
tional substituents with electron-donating resonance
effects in the para-positions.5
POCl
3
NaBH
4
N
HN
O
MeOH
Ph
Ph
C H I
2
5
NH
N
Et
i-Pr NEt
2
Ph
argon
Ph
3e
Scheme 4.
The starting N-ethyl substituted isoquinolines 3a–d were
obtained by Pictet–Spengler condensation of 2-(3,4-
dimethoxyphenyl)ethanamine with the appropriate alde-
hydes,6 followed by N-ethylation of the intermediate
NH-isoquinolines with ethyl iodide7 (Scheme 3 and
Table 1). The methods for preparing the starting tetra-
hydroisoquinolines, described in the literature,8 were
unsuccessful in our case. After the addition of the
cyclizing agent (usually HCl), hydrolysis of the imines
occurred and none of the desired products were ob-
tained. Modifying the method to use H3PO4 instead of
HCl avoided this problem. Isoquinoline 3e was synthe-
sized by the well-known Bischler–Napieralski9 reaction
of N-benzoylphenethylamine, followed by N-ethylation
of the intermediate NH-isoquinolines with ethyl iodide
(Scheme 4).
X
N
MeO
MeO
MeO
Et
X
Y
N
MeO
Et
3a-d
Ar
Ar
4, 7-15
Y
DMAD/MeOH
Et
MeO
N
E
E
MeO
MeO
Et
N
OMe
E
MeO
F
F
E
Isoquinoline 3a reacted with methyl propiolate at 25 ꢁC
both in acetonitrile and in methanol to form azocine 4 in
high yields10 (Scheme 5 and Table 2).
6
5
E=CO Me
2
Me SiOTf
3
X=H, Y=CO Me, COMe, p-Ts
2
Benzoazocine 5 was the sole product from the reaction
of isoquinoline 3a with DMAD in acetonitrile; but in
methanol, a mixture of azocine 5 and the product of tan-
dem cleavage of the tetrahydropyridine ring—the substi-
tuted diarylmethane 6 was formed (ratio 1:1; derived
X=CO Me, Y=CO Me
2
2
Scheme 5.
1
Compound 6 was converted into azocine 5 by the action
of trimethylsilyltriflate. The only products isolated from
the reactions of 3a with methyl propiolate or p-tosyl-
acetylene in acetonitrile were azocines 7 and 8,
respectively.
from H NMR data). Similar results were obtained in
the case of tetrahydropyrrolopyridines and tetrahydro-
carbolines.1,2 This is presumably due to the lower reac-
tivity (higher stability) of the anionic centre in the
intermediate zwitterion caused by the additional nega-
tive charge delocalization between the two ester groups.
Analogously, the reactions of isoquinoline 3c with
methyl propiolate, DMAD and acetylacetylene gave
benzoazocines 9–11 in high yield. In the case of reac-
tions in acetonitrile, the yields were higher than in meth-
anol; this may arise from the higher nucleophilicity and
the lower steric factor of acetonitrile. The reaction of 3b
with methyl propiolate gave azocine 12, the yield of
which was again higher in acetonitrile than in methanol.
NH
2
MeO
MeO
MeO
MeO
H
+ ArCHO
N
H
Ar
MeO
MeO
C H I
2
5
N
The structure of compound 8 was investigated by X-ray
diffraction.15 Suitable crystals were obtained by recrys-
tallization from ethyl acetate by slow evaporation at
room temperature. The refined X-ray crystal structure
of 8 is shown in Figure 1. The conformation of the 8-
membered ring is a twisted boat with the planes of the
isoquinoline dimethoxy phenyl fragment and C-1-aryl
being mutually perpendicular.
i
-Pr NEt
2
argon
Et
3a-d
Ar
Scheme 3.
Table 1. Yields of tetrahydroquinolines 3a–e
3
a
b
c
d
e
Ar
Yield 81
(%)
o-F–C6H4 p-F–C6H4 p-MeO–C6H4 p-CF3–C6H4 Ph
To see whether the presence of methoxy groups on the
isoquinoline are mandatory for the transformation of
the tetrahydropyridine ring, we carried out the reaction
69
75
77
74

L. G. Voskressensky et al. / Tetrahedron Letters 47 (2006) 4585–4589
Table 2. Yields of azocines and reaction time
4587
Product
Ar
X, Y
Yields (%)
Time (h)
4
o-F–C6H4
X = H, Y = CO2CH3
72 (MeCN)
88 (MeOH)
36 (MeOH)
87 (MeCN)
65 (MeCN)
90 (MeCN)
75 (MeOH)
85 (MeCN)
70 (MeCN)
55 (MeOH)
88 (MeCN)
77 (MeOH)
88 (MeCN)
76 (MeCN)
67 (MeCN)
38 (MeCN)
41 (MeOH)
39
41
36
37 (MeCN)
39 (MeOH)
40
42 (MeCN)
40 (MeOH)
37 (MeCN)
38 (MeOH)
41
5
o-F–C6H4
o-F–C6H4
o-F–C6H4
p-MeO–C6H4
X = Y = CO2CH3
X = H, Y = COCH3
X = H, Y = p-Ts
7
811
9
X = H, Y = CO2CH3
10
1112
p-MeO–C6H4
p-MeO–C6H4
X = H, Y = COCH3
X = Y = CO2CH3
1213
p-F–C6H4
X = H, Y = CO2CH3
13
p-CF3–C6H4
p-CF3–C6H4
p-CF3–C6H4
X = H, Y = CO2CH3
X = H, Y = COCH3
X = H, Y = p-Ts
1414
15
42
39
2-propynal both in acetonitrile and in methanol17 led
neither to the desired azocine 18 nor to the formation
of alkoxy-alkyl-substituted derivatives of type 2.
In all cases, the formation of the intermediate zwitteri-
ons was followed by a Hoffman-like cleavage of the
tetrahydropyridine ring and the formation of phenanth-
renes 19a–c.18–20 According to 1H NMR data, com-
pound 19c exists as a mixture of isomers (presumably,
s-cis and s-trans conformers). A detailed study of the ste-
reochemistry is underway and will be reported else-
where. Our attempts to carry out the cyclization of
19b into azocine 18 by the action of AlCl3 and trimeth-
ylsilyltriflate were also unsuccessful. From the reaction
with AlCl3, the starting compound was isolated. Using
trimethylsilyltriflate in THF, amine 2021 was obtained
in 52% yield (Scheme 7).
OMe
MeO
Me
N
Figure 1. X-ray crystal structure of 8.
OMe
OMe
R
of isoquinoline 3e with methyl propiolate. The reaction
occurs at room temperature, giving azocine 1616 in a
yield of 50% (Scheme 6).
MeO
MeO
R'
17
OMe
N
Me
MeO
The ease of transformation of isoquinolines 3a–e into
benzoazocines 4 and 7–15 encouraged us to study the
transformation of the alkaloid glaucine 17 under the ac-
tion of activated alkynes. Glaucine 17 is used in medi-
cine as an anti-tussive agent (Scheme 7).
18
R1
OMe
R
MeO
OMe
MeO
However, the tandem transformations of glaucine 17
under the action of DMAD, methyl propiolate and
Me3SiOTf
THF
MeO
MeO
MeO
MeO
Me
b
HN
CO Me
2
a
Me
N
Et
R1
N
20
3e
R
48 h
19a-c
Ph
CO CH
2 3
19a R=H, R'=CO2Me, c R=H, R'=CHO
b R=R'=CO2Me
16
Scheme 7.
Scheme 6.

4588
L. G. Voskressensky et al. / Tetrahedron Letters 47 (2006) 4585–4589
36–42 h at 25 ꢁC (TLC monitoring). The solvent was
evaporated under reduced pressure and the residue was
recrystallized (ethyl acetate/hexane) to give benzoazocines
4, 7–16. In the case of the reaction of isoquinoline 3a with
DMAD, a mixture (1:1 according to 1H NMR data) of
azocine 5 and the product of the tandem cleavage of the
tetrahydropyridine ring 6 were formed. The mixture
(0.15 g) was dissolved in acetonitrile (10 ml) and a few
drops of trimethylsilyltriflate was added. The reaction was
kept for a week (TLC monitoring). The solvent was
evaporated under reduced pressure and the resulting
residue purified by column chromatography with ethyl
acetate as eluent to give benzoazocine 5.
In conclusion, we have elaborated an effective single-
step synthetic protocol towards benzoazocine deriva-
tives, based on a new tandem cleavage–cyclization reac-
tion of tetrahydroisoquinoline derivatives. The data
obtained shows that the reaction rate is not influenced
by the substituents on the phenyl rings. A more detailed
study on the reaction mechanism is underway and will
be reported elsewhere.
Acknowledgement
11. 3-Ethyl-6-(2-fluorophenyl)-8,9-dimethoxy-5-(4-methylphen-
ylsulfonyl)-1,2,3,6-tetrahydrobenzo[d]azocine 8: Yield 65%
The financial support of the Russian Foundation for
1
Basic Research (grant
#
05-03-08149-ofi-a and
white crystals, mp 202–204 ꢁC (ethyl acetate/hexane). H
05-03-32211-a) is gratefully acknowledged.
NMR (400 MHz, CDCl3): d = 1.11 (t, J = 7.1 Hz, 3H,
–CH2–CH3), 2.39 (s, 3H, –CH3(p-Ts)), 2.62 (dd, J = 5.4,
J = 15.8, 1H, CH2-1), 2.68–2.78 (m, 1H, CH2-1), 2.98 (dd,
J = 7.4, J = 15.8, 1H, CH2-2), 3.18–3.28 (m, 2H, –CH2–
CH3), 3.42 (s, 3H, OCH3), 3.73–3.79 (m, 4H, OCH3 and 2-
CH2), 5.06 (s, 1H, 6-H), 5.71 (s, 1H, 10-H), 6.74 (s, 1H, 7-
H), 6.84 (dd, J = 8.1, J = 11.0 Hz, 1H, CH–Ar), 7.09 (t,
J = 8.1 Hz, 1H, CH–Ar), 7.15–7.20 (m, 1H, CH–Ar), 7.24
(d, J = 7.8 Hz, 2H, 2CH-Ts), 7.62 (t, J = 8.1 Hz, 1H, CH–
Ar), 7.68 (s, 1H, 4-H), 7.70 (d, J = 7.8 Hz, 2H, 2CH-Ts)
ppm. 13C NMR (100 MHz, CDCl3): d = 15.1, 21.4, 35.4,
46.8, 49.7, 51.8, 55.0, 55.7, 102.8, 114.3, 115.3, 115.9 (d,
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.04.151.
References and notes
4
2J = 22 Hz), 124.2 (d, J = 2 Hz), 127.9 (2C), 128.5, 129.1
(d, 3J = 8 Hz), 130.1 (2C), 131.5, 131.7 (d, 3J = 3 Hz),
131.9 (2J = 10.Hz), 140.7, 142.8, 146.8, 146.9, 153.2, 160.5
1. Varlamov, A. V.; Borisova, T. N.; Voskressensky, L. G.;
Kulikova, L. N.; Soklakova, T. A.; Chernyshev, A. I.;
Alexandrov, G. G. Tetrahedron Lett. 2002, 43, 6767–6769.
2. Voskressensky, L. G.; Borisova, T. N.; Kulikova, L. N.;
Varlamov, A. V.; Catto, M.; Altomare, C.; Carotti, A.
Eur. J. Org. Chem. 2004, 3128–3135.
3. Borisova, T. N.; Voskressensky, L. G.; Kulikova, L. N.;
Soklakova, T. A.; Varlamov, A. V. Mol. Div. 2003, 6, 207–
212.
1
(d, J = 242 Hz) ppm. IR (KBr): m = 1728, 1608 cmꢀ1. EI
MS: m/z (%) = 495 (15) [M+], 340 (100), 324 (5), 207 (20),
164 (10), 133 (15), 109 (20), 91 (85), 77 (15), 65 (57), 58
(45), 39 (20). C28H30FNO4S (495.19): calcd C 67.86, H
6.10, F 3.83, N 2.83, O 12.91, S 6.47; found C 67.90, H
6.12, F 3.84, N 2. 82, O 12.92, S 6.43.
12. Dimethyl
3-ethyl-6-(p-methoxyphenyl)-8,9-dimethoxy-
1,2,3,6-tetrahydrobenzo[d]azocine-4,5-dicarboxylate 11:
Yield 55% in methanol (70% in acetonitrile) white crystals
mp 188–190 ꢁC (ethyl acetate/hexane). 1H NMR
(400 MHz, CDCl3): d = 0.88 (t, J = 7.2 Hz, 3H, –CH2–
CH3), 2.58 (ddd, J = 0.7, J = 5.3, J = 7.0 Hz, 1H, CH2-1),
2.71–2.81 (m, 2H, –CH2–CH3 and 1-CH2), 2.96 (qd,
J = 7.2, J = 14.3 Hz, 1H, CH2–CH3), 3.19 (ddd, J = 1.8,
J = 7.3, J = 15.1, 1H, CH2-2), 3.36–3.44 (m, 1H, CH2-2),
3.72 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.79 (s, 3H,
OCH3), 3.87 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 5.82 (s,
1H, 6-H), 6.60 (s, 1H, 10-H), 6.77 (d, J = 8.4 Hz, 2H, H–
Ar), 6.80 (s, 1H, 7-H), 6.99 (d, J = 8.4 Hz, 2H, H–Ar)
ppm. 13C NMR (100 MHz, CDCl3): d = 13.4, 34.2, 45.6,
50.3, 50.9, 51.6, 52.3, 55.1, 55.8, 55.8, 102.4, 113.4 (2C),
114.1, 116.6, 127.3 (2C), 129.6, 131.2, 137.0, 147.0, 147.3,
155.6, 157.5, 167.3, 169.8. IR (KBr): m = 1728, 1678,
1558 cmꢀ1. EI MS: m/z (%) = 469 (5) [M+], 410 (20), 398
(100), 382 (15), 350 (20), 339 (25), 283 (15), 59 (12).
C26H31NO7 (469.21): calcd C 66.51, H 6.65, N 2.98, O
23.85; found C 66.53, H 6.63, N 3.00, O 23.87.
4. Waykole, L.; Paquette, L. A. Org. Synth. 1988, 67, 149–
155.
5. Bruckner, R. Advanced Organic Chemistry. Reaction
Mechanisms; Harcourt/Academic Press: San Diego,
2002; pp 68–69.
6. General procedure for the synthesis of tetrahydroisoquino-
lines: To a flask equipped with a Dean–Stark apparatus,
amine (0.06 mol), aldehyde (0.065 mol) and toluene
(70 ml) were added and refluxed until all the water had
been extracted. Then the mixture was allowed to cool to
room temperature and 85% phosphoric acid (50 ml) was
added. The resulting mixture was boiled for 3 h and then
cooled to room temperature. The organic layer was
decanted, the residue poured into a mixture of water and
ice and the pH adjusted to 9–10 (NaOH). The resulting
solution was extracted with CH2Cl2. The solvent was
evaporated under reduced pressure to give the target
isoquinolines.
7. Moore, J. L.; Taylor, S. M.; Soloshonok, V. A. Arkivoc
2005, vi, 287–292.
13. Methyl 3-ethyl-6-(p-fluorophenyl)-8,9-dimethoxy-1,2,3,6-
tetrahydrobenzo[d]azocine-5-carboxylate 12: Yield 77%
in methanol (88% in acetonitrile) white crystals, mp 74–
76 ꢁC (ethyl acetate/hexane). 1H NMR (400 MHz,
CDCl3): d = 1.08 (t, J = 7.2 Hz, 3H, –CH2–CH3), 2.74–
2.87 (m, 3H, CH2-1 and CH2-2), 3.13–3.23 (m, 2H, –CH2–
CH3), 3.42–3.50 (m, 1H, CH2-2), 3.75 (s, 3H, OCH3), 3.86
(s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.81 (s, 1H, 6-H), 6.64
(s, 1H, 10-H), 6.77 (s, 1H, 7-H), 6.93 (t, J = 8.7 Hz, 2H,
2CH–Ar), 7.05–7.12 (m, 2H, 2CH–Ar), 7.67 (s, 1H, 4-H)
ppm. IR (KBr): m = 1670, 1605 cmꢀ1. ESI MS 400
8. Cheung, G. K.; Earle, M. J.; Fairhurst, R. A.; Heaney, H.;
Shuhaibar, K. F.; Eyley, S. C.; Ince, F. Synlett 1991, 10,
721–722.
9. See e.g. (a) Whaley, W. M.; Govindachari, T. R. Org.
React. 1951, 6, 74–150; (b) Wender, P. A.; Smith, T. E.
J. Org. Chem. 1996, 61, 824–825.
10. General synthetic procedure for the synthesis of benzoazo-
cines 5, 7–16: DMAD, methyl propiolate, acetylacetylene
or p-tosylacetylene (1.2 mmol) was added to a solution of
the isoquinoline derivative 3a–e (1 mmol) in methanol or
acetonitrile (10 ml). The reaction mixture was stirred for

L. G. Voskressensky et al. / Tetrahedron Letters 47 (2006) 4585–4589
4589
(M++1) C23H26FNO4 (399.18): calcd C 69.16, H 6.56, F
4.76, N 3.51, O 16.02; found C 69.15, H 6.58, F 4.74, N
3.52, O 16.00.
@CH), 7.10 (s, 1H, CH-2), 7.22 (s, 1H, CH-8), 7.45 (d, 1H,
J = 12.9 Hz, N–CH@), 7.58 (d, 1H, J = 9.2 Hz, CH-9),
7.67 (d, 1H, J = 9.2 Hz, CH-10), 9.27 (s, 1H, CH-5). IR
(KBr): m = 1685, 1611 cmꢀ1. EI MS: m/z (%) = 439 (40)
[M+], 408 (10), 324 (15), 311 (100), 265 (10), 128 (75), 45
(10). C25H29NO6 (439.2): calcd C 68.32, H 6.65, N 3.19, O
21.84; found C 68.33, H 6.68, N 3.20, O 21.87.
14. 1-[3-Ethyl-8,9-dimethoxy-6-(4-trifluoromethyl-phenyl)-1,2,
3,6-tetrahydrobenzo[d]azocine-5-yl]-1-ethanone 14: Yield
76% white crystals (ethyl acetate/hexane) mp 126–128 ꢁC.
1H NMR (400 MHz, CDCl3): d = 1.14 (t, J = 7.0 Hz, 3H,
–CH2–CH3), 2.36 (s, 3H, COCH3), 2.79 (dd, J = 5.4,
J = 15.0 Hz, 1H, 1-CH2), 2.90 (qd, J = 7.0, J = 13.6 Hz,
2H, –CH2–CH3), 3.24 (dd, J = 6.7, J = 13.8 Hz, 2H, 1-
CH2 and 2-CH2), 3.37–3.46 (m, 1H, 2-CH2), 3.83 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 6.24 (s, 1H, 6-H), 6.65 (s, 1H,
7-H), 6.73 (s, 1H, 10-H), 7. 14 (d, J = 7.8 Hz, 2H, CH–
Ar), 7.48 (d, J = 7.8 Hz, 2H, CH–Ar), 7.53 (s, 1H, 4-H)
ppm. 13C NMR (100 MHz, CDCl3): d = 10.2, 20.3, 31.7,
42.4, 44.2, 47.5, 51.3, 51.4, 107.9, 109.9, 111.8, 120.6 (q,
19. Dimethyl (E)-2-methyl-[2-(3,4,6,7-tetramethoxy-1-phen-
anthryl)ethyl]amino-2-butendioate 19b: Yield 58% in
methanol (72% in acetonitrile) yellow crystals mp 109–
110 ꢁC (ethyl acetate/hexane). 1H NMR (400 MHz,
CDCl3): d = 2.71 (s, 3H, N–CH3), 3.34 (t, 2H,
J = 6.8 Hz, CH2-b), 3.48 (t, 2H, J = 6.8 Hz, CH2-a),
3.66 (s, 3H, O–CH3), 3.90 (s, 3H, OCH3), 3.91 (s, 3H,
OCH3), 4.03 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 4.07 (s,
3H, OCH3), 4.65 (s, 1H, @CH) 7.12 (s, 1H, CH-2), 7.21 (s,
1H, CH-8), 7.56 (d, 1H, J = 9.1 Hz, CH-9), 7.71 (d, 1H,
J = 9.0 Hz, CH-10), 9.27 (s, 1H, CH-5). IR (KBr):
m = 1739, 1689, 1574 cmꢀ1. EI MS: m/z (%) = 497 (5)
[M+], 186 (100), 82 (30), 45 (25). C27H31NO8 (497.20):
calcd C 65.18, H 6.28, N 2.82, O 27.73; found C 65.20, H
6.31, N 2.25, O 27.77.
20. (E)-3-Methyl-[2-(3,4,6,7-tetramethoxy-1-phenanthryl)eth-
yl]amino-2-propenal 19c: Propargyl aldehyde (10 mmol)
was added to a solution of glaucine 17 (1 mmol) in
methanol (10 ml). The reaction mixture was kept for
10 days at 30 ꢁC (TLC monitoring). The solvent was
evaporated under reduced pressure and hexane was added
to the residue, causing precipitation of 19c (241 mg, 59%);
pink crystals mp 168–170 ꢁC. 1H NMR (400 MHz,
CDCl3): d = 2.84 (s, 2H, N–CH3 maj), 2.85 (br s, 1H,
N–CH3 min), 3.35 (m, 2H, CH2-b), 3.55 (m, 0.66 H, CH2-
a min), 3.65 (m, 1.34H, CH2-a maj), 3.92 (s, 3H, O–CH3),
4.02 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 4.07 (s, 3H,
OCH3), 5.10 (m, 0.66H, @CH–CHO maj), 5.10 (m, 0.34H,
@CH–CHO min), 6.80 (m, 0.66H, N–CH@-maj), 7.10 (s,
1H, CH-2), 7.12 (m, 0.34H, N–CH@-min), 7.23 (s, 1H,
CH-8), 7.61 (d, 1H, J = 8.9 Hz, CH-9), 7.71 (br d, 1H,
J = 8.9 Hz, CH-10), 8.90 (br d, 0.66 H, –CHO maj), 9.12
(br d, 0.34H, –CHO min), 9.30 (s, 1H, CH-5). IR (KBr):
m = 1604, 1515 cmꢀ1. EI MS: m/z (%) = 409 (20) [M+], 324
(45), 311 (95), 265 (20), 98 (100). C24H27NO5 (409.48):
calcd C 70.40, H 6.65, N 3.42, O 19.54; found C 70.43, H
6.67, N 3.41, O 19.55.
2
3JC,F = 4 Hz, 2C), 121.7 (2C), 122.8 (q, JC,F = 32 Hz),
123.5 (q, 1JC,F = 280 Hz), 123.6, 126.6, 142.3, 142.9, 146.7,
150.6, 189.7 ppm. IR (KBr): m = 1613, 1571 cmꢀ1. EI MS:
m/z (%) = 433 (47) [M+], 414 (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 (320), 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, F 13.15, N 3.23, O 11.07; found C 66.59, H
6.01, F 13.13, N 3.21, O 11.09.
15. Crystal structure analysis for 8: C28H30FNO4S,
Mr = 495.59 g molꢀ1, orthorhombic, space group Pbca,
˚
a = 14.2575(10), b = 16.6195(10), c = 21.2819(10) A, a =
3
˚
90ꢁ, b = 90ꢁ, c = 90ꢁ, V = 5042.8(5) A , Z = 8, q =
1.306 g cm3, l = 1.490 mmꢀ1, F(000) = 2096, crystal size:
0.80 · 0.40 · 0.20 mm. Crystal data were collected on a
Cad-4 diffractometer (kCu Ka radiation, graphite mono-
chromator; x scanning). A total of 5151 reflections
(4.58 < h < 69.49ꢁ) were collected of which 4687 were
unique (R(int) = 0.0771). The structure was solved with
the program SHELXS-9722 and refined using SHELXL-9723 to
R1 = 0.0695 and wR(F2) = 0.2057 for 3367 reflections with
I > 2r(I); maxnmin residual electron density 0.535 and
ꢀ0.523 e Aꢀ3. Crystallographic data (excluding structure
˚
factors) for compound 8 have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 298845.
16. Methyl 3-ethyl-6-phenyl-1,2,3,6-tetrahydro benzo[d]azo-
cine-5-carboxylate 16: Yield 50% white crystals mp 108–
109 ꢁC (ethyl acetate/hexane). 1H NMR (400 MHz,
CDCl3): d = 1.05 (t, J = 7.2 Hz, 3H, –CH2–CH3), 2.80–
2.97 (m, 3H, 1-CH2 and 2-CH2), 3.08–3.22 (m, 2H, –CH2–
CH3), 3.51–3.61 (m, 1H, 2-CH2), 3.74 (s, 3H, OCH3),
6.00 (s, 1H, 6-H), 7.12–7.30 (m, 9H, Ar), 7.67 (s, 1H, 4-H)
ppm. IR (KBr): m = 1675, 1605 cmꢀ1. ESI MS 322
(M++1). C21H23NO2 (321.17): calcd C 78.47, H 7.21, N
4.36, O 9.96; found C 78.50, H 7.19, N 4.37, O 9.98.
17. General synthetic procedure for the synthesis of phenanth-
renes 19a–c: DMAD or methyl propiolate (1.2 mmol) was
added to a solution of glaucine 17 (1 mmol) in methanol
or acetonitrile (10 ml) (TLC monitoring). The reaction
mixture was kept for 2–3 days at room temperature. The
solvent was evaporated under reduced pressure and the
residue was recrystallized (ethyl acetate/hexane) to give
phenanthrenes 19a–c.
18. Methyl (E)-3-methyl-[2-(3,4,6,7-tetramethoxy-1-phenan-
thryl)ethyl]amino-2-propenoate 19a: Yield 73% in metha-
nol (85% in acetonitrile) white crystals mp 131–133 ꢁC
(ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3):
d = 2.73 (s, 3H, N–CH3), 3.31 (t, 2H, J = 6.9 Hz, CH2-
b), 3.52 (t, 2H, J = 6.9 Hz, CH2-a), 3.66 (s, 3H, O–CH3),
3.92 (s, 3H, O–CH3), 4.01 (s, 3H, O–CH3), 4.04 (s, 3H, O–
CH3), 4.07 (s, 3H, O–CH3), 4.59 (d, 1H, J = 12.9 Hz,
21. Methyl
[2-(3,4,6,7-tetramethoxy-1-phenanthryl)ethyl]-
amine 20: To a solution of phenanthrene 19a (100 mg,
0.23 mmol) in acetonitrile (5 ml), three drops of trimeth-
ylsilyltriflate was added. The reaction mixture was kept for
3 days at 30 ꢁC (TLC monitoring). The solvent was
evaporated under reduced pressure, the residue was
treated with a 30% aqueous solution of Na2CO3 (10 ml)
and extracted with ether (3 · 25 ml). The organic layer was
dried over MgSO4. The solvent was evaporated under
reduced pressure and hexane was added to the residue,
causing precipitation of 20 (43 mg, 52%); yellow crystals,
mp 94–96 ꢁC. 1H NMR (400 MHz, CDCl3): d = 2.48 (s,
3H, N–Me), 3.00 (t,2H, J = 7.1 Hz, CH2-b), 3.32 (t, 2H,
J = 7.1 Hz, CH2-a), 3.91 (s, 3H, O–CH3), 4.03 (s, 3H,
OCH3), 4.05 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 7.21 (s,
1H, CH-2), 7.23 (s, 1H, CH-8), 7.54 (d, 1H, J = 9.0 Hz,
CH-9), 7.80 (d, 1H, J = 9.0 Hz, CH-10), 9.27 (s, 1H, CH-
5). EI MS: m/z (%) = 355 (10) [M+], 312 (40), 297 (10), 58
(10), 44 (100). C21H25NO4 (355.18): calcd C 70.96,
H 7.09, N 3.94, O 18.01; found C 70.99, H 7.06, N 3.95,
O 17.99.
22. Sheldrick, G. M. SHELXS, Program for Crystal Structure
Solution, University of Go¨ttingen, Germany, 1997.
23. Sheldrick, G. M. shelxl, Program for Crystal Structure
Refinement, University of Go¨ttingen, Germany, 1997.