Improved enamine-type addition of dehydroaporphine using microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2010.04.008

Previous report demonstrated that 7-substituted aporphine, possessing interesting biological aspects, could be synthesized via an enamine-type addition of dehydroaporphine reacted with an electrophile, but it has the drawbacks of a long reaction time, low yield, and limitation to reactive electrophiles. Here we found that the reaction time and yield could greatly be improved under microwave irradiation in the presence of 4 equiv of sodium iodide for the synthesis of 7-benzyl dehydroglaucine. The application of this finding for treating dehydroglaucine with a variety of alkyl bromides also gave corresponding 7-substituted dehydroglaucines (2a-j) with yields of 14-89%. Other enamines such as 1,10-dimethoxydehydroaporphine (3a), 2,9-diacetyldehydroboldine (3b), and 7,8-dihydroberberine (5) were found to react with benzyl bromide under similar conditions as described above to give corresponding products (4a-b, 6) in satisfactory yields, indicating the versatility of this improved reaction condition.

Full text of DOI:10.1016/j.tetlet.2010.04.008

Tetrahedron Letters 51 (2010) 3062–3064
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved enamine-type addition of dehydroaporphine using
microwave irradiation
Wei-Jan Huang a, Chih-Chiang Huang a, Ling-Wei Hsin b, Yeun-Min Tsai c, Chin-Ting Lin b, Jung-Hsin Lin b,
Shoei-Sheng Lee b,
*
a Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan
b School of Pharmacy, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Sec. 1, Taipei 100, Taiwan
c Department of Chemistry, National Taiwan University, 1 Roosevelt Road, Sec. 4, Taipei 106, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Previous report demonstrated that 7-substituted aporphine, possessing interesting biological aspects,
could be synthesized via an enamine-type addition of dehydroaporphine reacted with an electrophile,
but it has the drawbacks of a long reaction time, low yield, and limitation to reactive electrophiles. Here
we found that the reaction time and yield could greatly be improved under microwave irradiation in the
presence of 4 equiv of sodium iodide for the synthesis of 7-benzyl dehydroglaucine. The application of
this finding for treating dehydroglaucine with a variety of alkyl bromides also gave corresponding 7-
substituted dehydroglaucines (2a–j) with yields of 14–89%. Other enamines such as 1,10-dimethoxyde-
hydroaporphine (3a), 2,9-diacetyldehydroboldine (3b), and 7,8-dihydroberberine (5) were found to react
with benzyl bromide under similar conditions as described above to give corresponding products (4a–b,
6) in satisfactory yields, indicating the versatility of this improved reaction condition.
Received 29 March 2010
Accepted 5 April 2010
Available online 13 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Aporphines are naturally occurring isoquinoline alkaloids that
are widely distributed in plants belonging to several families such
as the Annonaceae, Lauraceae, Monimiaceae, Menispermaceae,
Hernandiaceae, and Ranunculaceae.1 Various biosynthetic reac-
tions afforded versatile substitutions on rings A–D of the aporphine
skeleton, leading to the diverse structures and bioactivities includ-
ing serotonergic,2 dopaminergic,2 antiplatelet,3 antimicrobial,4 and
anticancer activities.5 Of these activities, structure–activity rela-
tionships (SARs) for binding affinity to either dopaminergic or
serotonergic receptors are well documented. Previous efforts fo-
cused on introducing heteroatoms such as nitrogen,6 oxygen,7 ha-
lide8 and sulfur,9 and alkyl groups into the A- or D-ring,10,11 and
different chain-length alkyl groups into N-612,13 to improve their
affinity and selectivity for receptors. We synthesized a series of
aporphine analogues from the commercially available boldine for
further pharmacological studies. Recently, the hypoglycemic effect
of boldine derivatives was demonstrated.14 To enrich the chemical
bank for the SAR study on this aspect, we tried to prepare 7-substi-
tuted dehydroaporphines. The semi-synthesis of 7-substituted
aporphines had been developed by Cava and co-workers15 by
reacting dehydroaporphines with an electrophile via an enamine-
type addition. Such an approach, however, was limited to highly
During last decade, microwave activation has increasingly been
used in pharmaceutical chemistry due to several advantages
including improved yields, enhanced reaction rates, and efficient
energy compared to conventional heating methods.18,19 We found
that microwave irradiation effectively improved yields and short-
ened the reaction time of this reaction. To our knowledge, no pre-
vious report mentioned the application of microwave-activation
for the enamine-type addition of dehydroaporphine. The following
describes the outcome of our efforts with this finding and the
application of this method to synthesize a variety of 7-substituted
dehydroglaucines (Fig. 1).
Dehydroglaucine (1) was prepared using boldine as the starting
material via selective O,O-dimethylation20 and C6a–C7 dehydroge-
nation.21 The results of the reaction of dehydroglaucine (1) with
benzyl bromide to afford 7-benzyl dehydroglaucine (2c) under dif-
MeO
MeO
MeO
MeO
6
A
B
N
R
N
1
C
7
11
MeO 10
D
reactive electrophiles such as acyl halides,
a,b-unsaturated carbox-
8
MeO
ylate esters, and benzoquinones.16,17
OMe
OMe
* Corresponding author. Tel./fax: +886 2 23916127.
Figure 1. Synthesis of 7-substituted dehydroglaucines via an enamine-type
E-mail addresses: shoeilee@ha.mc.ntu.edu, shoeilee@ntu.edu.tw (S.-S. Lee).
addition.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.008

W.-J. Huang et al. / Tetrahedron Letters 51 (2010) 3062–3064
3063
Table 1
Table 2
Reaction conditions for the synthesis 7-benzyl dehydroglaucine (2c)
Synthesis of 7-substituted dehydroglaucines (2a–j) under microwave irradiation
MeO
MeO
MeO
MeO
MeO
MeO
N
N
R
N
N
RX, NaI
MeO
MeO
MeCN, MW, 20 mins
Br
MeO
MeO
MeO
MeO
OMe
OMe
2c
OMe
OMe
1
2a-j
1
Run
R
Product Mp (lit. mp) (°C)
Yielda (%)
Run
Solvent
Heating condition
Additive
Time
Yielda (%)
1
2
3
4
5
6
7
Me
Allyl
Bn
p-Br–Bn
p-CF3–Bn
p-MeO–Bn
p-NO2–Bn
2a
2b
2c
2d
2e
2f
151–154 (148–150)25 14
—
88–92
70–73
92–95
—
1
2
3
4
5
6
7
8
9
Dioxane
MeCN
DMF
MeCN
Toluene
DMF
MeCN
Toluene
DMF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
None
None
None
NaI
NaI
NaI
NaI
NaI
NaI
None
72 h
72 h
72 h
24 h
24 h
24 h
20 min
20 min
20 min
40 min
Trace
Trace
Trace
55
11
15
89
12
51
Trace
31
89
45
35
25
72
2g
50–54
Microwaveb
Microwaveb
Microwaveb
Microwaveb
O
8
9
2h
2i
148–151
160–162
53
51
10
MeCN
a
Isolated yields.
b
Reaction conditions: reaction temperature at 80 °C, irradiation time for 20 min
and the maximal output at 100 W.
CN
ferent conditions are summarized in Table 1. It was found that the
reaction using dioxane, acetonitrile, or DMF as a solvent (Table 1,
Runs 1–3) afforded only a trace amount of 2c, even after 72 h.22
An attempt to improve this reaction using 5 equiv of benzyl bro-
mide in acetonitrile, however, yielded N6,C-7-dibenzyldehydro-
glaucine. Evans et al.23 synthesized a morphine skeleton via an
intramolecular enamine alkylation by heating the chloroenamine
in acetonitrile in the presence of 4 equiv of sodium iodide. Hence,
we followed this reaction condition, and the yield increased to 55%
after 24 h (Table 1, Run 4). The replacement of acetonitrile by
either toluene or DMF, however, gave lower yields of 11% and
15%, respectively (Table 1, Runs 5 and 6). Owing to the reported
advantages of microwave irradiation, it was used as a heating
source, and we found that the reaction time was dramatically
shortened and the yield was also significantly improved (Table 1,
Run 7) compared to conventional heating. The solvent effect, which
gave 12% and 51% yield, respectively, upon replacing acetonitrile
with toluene or DMF (Table 1, Runs 8 and 9), was found to be sim-
ilar to what was indicated above. It was also noted that the addi-
tive, NaI, is critical for this reaction since devoid of NaI in Run 7,
the reaction did not work even with a prolonged reaction time
(120 min) (Table 1, Run 10). This finding suggests that the micro-
wave irradiation and the presence of sodium iodide play important
roles in providing a satisfactory yield and rapid reaction time for
the condensation of dehydroglaucine with benzyl bromide via an
enamine-type addition.
10
2j
195–200
62
a
Isolated yields.
bromides gave lower yields relative to the nonsubstituted one. Fur-
ther analysis indicated that those substituted with electron-with-
drawing groups (nitro-) afforded better yields than those
substituted with electron-donating groups (methoxy-). This sug-
gests that the electron-withdrawing effect has a positive contribu-
tion for the reaction. We finally treated dehydroglaucine (1) with
m-benzoyl-, p-phenyl, and o-(2-cyanophenyl)-benzyl bromides
(Table 2, Runs 8–10). It was shown that most of these had lower
yields than 2c, indicating that the steric effect of the N6-Me group
hampered the formation of the products to some extent.
The generality of the above-mentioned reaction conditions for
the preparation of 7-alkyl-dehydroaporphines was verified by treat-
ing dehydroglaucine (1) with various alkyl halides in acetonitrile un-
der microwave irradiation24 with the additive of sodium iodide
(4 equiv) (Table 2). It was found that more reactive halides such as
benzyl bromide and allyl bromide gave better yields than the less ac-
tive halides such as methyl iodide (Table 2, Runs 1–3). In spite of low
yields while dehydroglaucine (1) reacted with either methyl iodide
or allyl bromide, the yield was improved compared to that of a con-
ventional heating condition, whose reaction was undertaken in our
lab. In order to investigate the electronic effect on the enamine-type
addition, it was carried out by reacting with benzyl bromides substi-
tuted with electron-withdrawing or electron-donating groups
(Table 2, Runs 4–7). The result indicates that substituted benzyl
Scheme 1. Reagents and conditions: (a) BnBr, Nal, MeCN, MW; (b) K2CO3, MeOH,
N2, rt.

3064
W.-J. Huang et al. / Tetrahedron Letters 51 (2010) 3062–3064
5. Chen, I. S.; Chen, J. J.; Duh, C. Y.; Tsai, I. L.; Chang, C. T. Planta Med. 1997, 63,
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154–157.
with an enamine moiety, two dehydroaporphines (3a and 3b) to-
gether with 7,8-dihydroberberine (5) were treated in the similar
manner as described in Scheme 1. Compound 3a was synthesized
from boldine via three reaction steps: reaction with 5-chloro-1-
phenyltetrazole,26 hydrogenolysis,26 and dehydrogenation.21 Com-
pound 3b was prepared from boldine via acetylation followed by
dehydrogenation.21 The reaction of 3a and 3b with benzyl bromide
under general microwave irradiation gave 4a and 4b in 77% and
71% yields, respectively. Similarly, the reaction of 7,8-dihydroberb-
erine (5), prepared from sodium borohydride reduction of berber-
ine,27 gave 13-benzyl-7,8-dihydroberberine (6) in an 82% yield. In
conclusion, this study provides a highly efficient method to pre-
pare substituted enamine, in particular dehydroaporphine and
7,8-dihydroberberine, relative to the conventional method. This
method not only accelerates the enamine-type addition, using
microwave irradiation as a heating source, but also improves yields
by the addition of sodium iodide.
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Acknowledgment
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We gratefully acknowledge the National Science Council, Tai-
wan, R. O. C., for the support of this work under Grants NSC97-
2323-B-002-015 and NSC97-2320-B-038-010-MY3.
24. The microwave reactor Discovery Benchmate (CEM) was used for microwave
irradiation as a sealed vessel technique. The temperature of reaction mixture
was measured and controlled to a constant level using an infrared temperature
detector. The general condition for the synthesis of 7-substituted
dehydroglaucines (2a–j, 3a–b, 5) is described as follows. The mixture of
dehydroglaucine (100 mg, 0.28 mmol) of MeCN (2 mL) was added to NaI
(166 mg, 1.12 mmol) and substituted alkyl halide (1.40 mmol), and the
resulting suspension was heated to 80 °C under microwave irradiation for
20 min. The reaction mixture was condensed under reduced pressure. The
residue was suspended in CH2Cl2 (50 mL), and partitioned against distillated
H2O (25 mL Â 2) and brine (25 mL). The organic layer was dried over
anhydrous Na2SO4 and condensed under reduced pressure. The residue was
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.008.
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