Deoxygenation of Phenolic Alkaloids by a Modified Pd/C-Catalyzed Hydrogenolysis Method

Article abstract of DOI:10.1055/s-0034-1380206

A modified palladium on carbon (Pd/C) catalyzed hydrogenolysis method for the removal of the phenolic-OH group in phenolic alkaloids as the 1-phenyl-1H-tetrazol-5-yl derivative by the addition of magnesium metal or ammonium acetate in acetic acid is descr

Full text of DOI:10.1055/s-0034-1380206

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, A–G
paper
A
C.-T. Lin, S.-S. Lee
Paper
Synthesis
Deoxygenation of Phenolic Alkaloids by a Modified Pd/C-Catalyzed
Hydrogenolysis Method
Chin-Ting Lin
TzO
H
H2 (13.8 bar)
10% Pd/C (30% w/w)
Mg (2.5 equiv)
Shoie-Sheng Lee*
N
N
MeO
Me
MeO
Me
School of Pharmacy, College of Medicine, National Taiwan University,
No. 33, Linsen S. Rd., Zhongzheng Dist., Taipei 100, Taiwan ROC
shoeilee@ntu.edu.tw
H
H
AcOH, 50 °C, 3 d
good yield
MeO
MeO
OTz
H
Received: 12.02.2015
Accepted after revision: 02.04.2015
Published online: 07.05.2015
are sometimes unsatisfactory in alkaloid chemistry, pre-
sumably due to steric hindrance or amine chemistry. For
example, the 1-phenyl-1H-tetrazol-5-yl ether method usu-
ally requires larger amounts of Pd/C than are generally used
for catalytic hydrogenation (≥40% vs. 10%, w/w) to complete
the reaction8 and thus it is not practical for larger-scale
preparations. The triflate ether method sometimes gives
lower yields when preparing the phenolic triflate ether of
alkaloids with the commonly used conditions (Tf2NPh, base,
r.t.) because of steric effects or solubility problems. For ex-
ample, when litebamine (1) was converted into the bis(tri-
flyl ether), the yield was lower than 30%,9 making subse-
quent de-phenolation impractical. The reason for the lower
yield could be due to the poor solubility of 1 that arises
from the planar phenanthrene core structure.
DOI: 10.1055/s-0034-1380206; Art ID: ss-2015-f0109-op
Abstract A modified palladium on carbon (Pd/C) catalyzed hydroge-
nolysis method for the removal of the phenolic-OH group in phenolic
alkaloids as the 1-phenyl-1H-tetrazol-5-yl derivative by the addition of
magnesium metal or ammonium acetate in acetic acid is described.
Five different types of isoquinoline alkaloids, i.e., phenanthrene alka-
loid, aporphine, pavine, protoberberine, and 1-benzyltetrahydroiso-
quinoline, were used as reactants. The results indicate that the addition
of either magnesium metal or ammonium acetate has the advantage of
decreasing the amount of Pd/C and the accelerating reaction rate over
the simple Pd/C-catalyzed hydrogenolysis, thus it is practical for larger-
scale preparation of de-phenolated alkaloids for pharmacological study.
Key words phenolic alkaloids, de-phenolation, 1-phenyl-1H-tetrazol-
5-yl ether, ammonium acetate, magnesium
Sajiki and co-workers have reported that the Pd/C-cata-
lyzed deoxygenation of phenol triflates or mesylates can be
undertaken efficiently with the aid of magnesium metal
and methanol in the presence of ammonium acetate with-
out the use of hydrogen gas.3 Attempts to use this method
to remove phenolic groups for phenolic alkaloids were
made, but unfortunately, this approach was unsuccessful
using boldine triflate, prepared from boldine (6), as the re-
actant. Thus this method might not be applicable to some
substrates that have secondary or tertiary amine moieties
within the molecules, such as alkaloids, due to the catalyst
poisoning effect of the amine moiety. Since both 1-phenyl-
1H-tetrazol-5-yloxy (TzO) and triflyl groups are electron-
withdrawing, Sajiki’s method was adopted using the O,O-
bis(1-phenyl-1H-tetrazol-5-yl) derivative of 6, i.e., 7. How-
ever, removal of the 1-phenyl-1H-tetrazol-5-yloxy group
this derivative did not occur under neutral (MeOH) or acid-
ic (AcOH) conditions. While in the presence of hydrogen gas
and either magnesium or ammonium acetate under acidic
conditions (AcOH), we found that not only the reaction was
successful, but also that the reaction rate increased dramat-
Phenolic alkaloids are widely present in several plant
families and they are reported to possess a variety of phar-
macological activity. For the study of structure-activity re-
lationships (SARs), chemical modification of these bioactive
compounds to obtain various derivatives is essential. Re-
moval of the phenolic-OH groups is an important approach
to clarify the role of this functional group in the pharmaco-
logical activity. Some direct methods, such as using reduc-
ing agents or Lewis acids, have been developed for this pur-
pose.1 However, they generally encounter the drawbacks of
requiring large amounts of reagent and give low yields. In-
direct methods, converting the phenolic-OH into electron-
withdrawing groups, including sulfonate,2,3 dimethyl thio-
carbonate,4 isourea,4 aryl ether,5 1-phenyl-1H-tetrazol-5-yl
ether,6 and phosphate ester,7 followed by reductive removal
of these groups, are another approach. Among these, palla-
dium on carbon (Pd/C) catalyzed hydrogenolysis of the 1-
phenyl-1H-tetrazol-5-yl ether or triflate to give non-pheno-
lic compounds is commonly used. However, these methods
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–G

B
C.-T. Lin, S.-S. Lee
Paper
Synthesis
Me
N
Me
N
Me
N
Me
N
Me
N
2a
12
11
TzO
TzO
TzO
HO
1
3
5
10
9
c
a
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
64%
8
MeO
MeO
7
OTz
OH
1
2
3
4
5
R1
TzO
HO
2
N
N
N
N
1
1
MeO
Me
MeO
MeO
Me
MeO
Me
MeO
Me
H
H
H
H
b
d
11
8
80%
10
MeO
MeO
MeO
9
R2
OTz
OH
9a R1 = OTz, R2 = H
9b R1 = H, R2 = OTz
6
7
8
Scheme 1 Reagents and conditions: (a) 5-chloro-1-phenyl-1H-tetrazole, K2CO3, DMF, 90 °C, 2 h; (b) 5-chloro-1-phenyl-1H-tetrazole, K2CO3, KI, MeCN,
90 °C, 1 d; (c) see Table 1; (d) see Table 2.
ically. Accordingly, optimization and application of this
modified Pd/C-catalyzed method on compounds of five-
type isoquinoline alkaloids, the phenanthrene alkaloid lite-
bamine (1), the aporphine boldine (6), 8/9-hydroxy-2,3-di-
methoxypavine (10), 2,3-dihydroxy-9,10-dimethoxyproto-
berberine (13), and the benzylisoquinoline reticuline (16),
were undertaken.
Reaction of 3,7-O,O-bis(1-phenyl-1H-tetrazol-5-yl)lite-
bamine (2), prepared from litebamine (1) by reaction with
5-chloro-1-phenyl-1-H-tetrazole with potassium carbonate
as the base, with 50% w/w of 10% Pd/C and under 13.8 bar
hydrogen hydrogenolyzed only the 7-OTz group to give 3-
O-(1-phenyl-1H-tetrazol-5-yl)-7-dehydroxylitebamine (3),
followed by hydrogenation of the C9–C10 double bond to
yield 3-O-(1-phenyl-1H-tetrazol-5-yl)-7-dehydroxy-9,10-
dihydrolitebamine (4) (Scheme 1). This reaction gave low
yields of 3 and 4 together with the recovery of starting ma-
terial 2 (Table 1, entry 1). The 1H NMR spectrum of 3
showed an AMX system for H5, H7, and H8 at δ = 8.83, 7.26,
and 7.83, respectively, and an AB system for H9 and H10 at
δ = 7.80 and 7.78 (J = 9.1 Hz), while that of 4 showed a simi-
lar AMX system for H5, H7, and H8, but an A2B2 system for
H9 and H10 at δ = 2.82 and 2.72, supporting their struc-
tures.
A similar result was also found when removing the 1-
phenyl-1H-tetrazol-5-yloxy group from 2,9-O,O-bis(1-phe-
nyl-1H-tetrazol-5-yl)boldine (7). Low yield (25%) with in-
complete hydrogenolysis took place while reaction of 7
with 40% weight of 10% Pd/C (Table 2, entry 1). Increasing
the amount of 10% Pd/C up to 70% w/w and prolonging the
reaction time up to seven days did not improve the yield,
instead more byproducts were produced. The problem of
Table 1 Effect of Ammonium Acetate on the Pd/C Assisted Hydrogenolysis of 2 in Acetic Acid at 50 °C
Entry
Reactant 2
10% Pd/C (w/w)
NH4OAc (equiv)
H2 (bar)
Time (d)
Products [yield (%)]
1
2
3
4
5
105.1 mg
51.7 mg
10.6 mg
1.0 g
50%
50%
50%
30%
30%
–
3
13.8
13.8
13.8
13.8
1
3
3 (16) + 4 (16) + 2
3 (5) + 4 (50) + 5 (35)
4 + 5 (31:69)a
5 (64)
1.5
3
6
10
10
4
10.5 mg
2
3 major
a The ratio was determined by 1H NMR (200 MHz) spectroscopic analysis of the mixture without purification.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–G

C
C.-T. Lin, S.-S. Lee
Paper
Synthesis
Table 2 Effect of Magnesium and Hydrogen on the Pd/C Assisted Hydrogenolysis of 7 in Acetic Acid at 50 °C
Entry
Reactant (7)
10% Pd/C (w/w)
Mg (equiv)
H2 (bar)
Time (d)
Products [yield (%)]
1
2
3
4
5
6
7
500.0 mg
19.3 mg
101.4 mg
6.8 g
40%
50%
30%
30%
30%
30%
30%
–
13.8
13.8
13.8
13.8
6.9
3
3
3
3
3
3
3
8 (25) + 7
8 (~100)a
8 (~100)a
8 (87)
3
3
2.5
2.5
2.5
2.5
20.4 mg
20.3 mg
20.8 mg
8 + 9a + 9b + 7 (22:19:48:11)b
8 + 9a + 9b + 7 (13:19:32:36)b
no reaction
4.8
1
a The product without purification is 1H NMR essentially pure.
b The ratio was determined by 1H NMR (400 MHz) spectroscopic analysis.
the incomplete reaction described above was solved by ad-
dition of ammonium acetate or magnesium metal. Under
the optimized conditions, 10% Pd/C (30%, w/w), ammonium
acetate (10 equiv), hydrogen (13.8 bar), acetic acid (50 °C, 4
d; Table 1, entry 4), exhaustive hydrogenolysis of 2 was
achieved to give 5 exclusively in 64% isolated yield on 1.0
The effect of magnesium metal and hydrogen pressure
on the Pd/C-assisted hydrogenolysis was evaluated using
2,9-O,O-bis(1-phenyl-1H-tetrazol-5-yl)boldine (7) as the
reactant (Table 2). Complete hydrogenolysis could be
achieved to yield 1,10-dimethoxyaporphine (8) when mag-
nesium metal was added. Addition of three equivalents of
magnesium metal could reduce the amount of Pd/C from
70% to 30% w/w (H2, 13.8 bar) (Table 2, entry 3). The
amount of magnesium metal could be further reduced to
2.5 equivalents when the reaction was performed on a
gram scale (Table 2, entry 4). Decreasing the pressure of hy-
drogen gave a lower reaction rate resulting in incomplete
reaction and low yield (Table 2, entries 5–7). Although the
amount of Pd/C used is up to 30% w/w, it has been reduced
to some extent compared to the previous method (≥40%
w/w). Pd/C-catalyzed reduction of aporphine triflates also
used higher amounts of Pd/C (about 20% w/w).10 This phe-
nomenon could be attributed to alkaloids amine chemistry.
To explore the scope of this modified Pd/C assisted hy-
drogenolysis method, removal of the phenolic group on
three isoquinoline alkaloids of different type were investi-
gated (Scheme 2). 8/9-Hydroxy-2,3-dimethoxypavine
(10),11 prepared by sodium/liquid ammonia reductive
cleavage of O-methylcaryachine, was converted into 2,3-di-
methoxy-8/9-O-(1-phenyl-1H-tetrazol-5-yl)pavine 11 by a
method similar to that described above. Without adding
magnesium, complete hydrogenolysis on 11 to give 12
could not be reached (82% yield + 11) using 50% (w/w) 10%
Pd/C [H2 (3.4 bar), AcOH, 50 °C, 3 d]. This reaction yielded
2,3-dimethoxypavine (12) in 98% isolated yield when 1.3
equivalents of magnesium were added to the reaction mix-
ture, with the amount of 10% Pd/C reduced to 30% (w/w).
1
gram scale. The H NMR spectrum of 5 showed signals for
H5, H7, and H8 as an AMX system at δ = 7.86, 6.73, and 7.12,
respectively, and a singlet for H3 (δ = 6.55), supporting its
structure. Complete hydrogenolysis of 7 was achieved un-
der the optimized conditions of 10% Pd/C (30%, w/w), mag-
nesium (3 equiv), hydrogen (13.8 bar) (50 °C, 3 d; Table 2,
entry 3) to afford 8 almost quantitatively on a 0.1 gram
scale.
The 1H NMR spectrum of 8 showed an AB system for H2
and H3 (δ = 6.88 and 7.04; J = 8.4 Hz) and an AMX system
for H8, H9, and H11 at δ = 7.17, 6.78, and 7.90, respectively,
supporting its structure.
The effect of the amount of ammonium acetate added
on the Pd/C-assisted hydrogenolysis was evaluated. The re-
action rate was found to be proportional to the amount of
ammonium acetate added (Table 1). Complete hydrogeno-
lysis on 2 cannot be achieved in the presence of 3–6 equiva-
lents of ammonium acetate [H2 (13.8 bar), 50 °C, 1.5–3 d]
(Table 1, entries 2 and 3). Both O-(1-phenyl-1H-tetrazol-5-
yl) groups at the C3 and C7 positions in 2 could be removed
readily, accompanied by hydrogenation at the C9–C10 dou-
ble bond, increasing the amount of ammonium acetate to
10 equivalents required a reaction time of four days (Table
1, entry 4). Under 1 bar hydrogen, the addition of 10 equiv-
alents of ammonium acetate removed the 7-O-(1-phenyl-
1H-tetrazol-5-yl) group readily to give 3 as the major prod-
uct in two days without affecting the C9–C10 double bond
(Table 1, entry 5). This study indicated that the addition of
ammonium acetate could accelerate the reaction rate and
reduce the amount of Pd/C used. The relative reaction rate
of this modified method on the reactive sites in 2 was found
to be 7-O-Tz >Δ9 > 3-O-Tz.
1
The H NMR spectrum of 12 showed signals for four aryl
protons at δ = 7.11–7.04 (m, 3 H) and 6.95 (br d, J = 7.3 Hz, 1
H) and for H1 and H4 as two singlets at δ = 6.59 and 6.41,
respectively, supporting its structure. 2,3-Dihydroxy-9,10-
dimethoxyprotoberberine (13) and reticuline (16) were
also converted into the corresponding O,O-bis(1-phenyl-
1H-tetrazol-5-yl) derivatives 14 and 17, respectively. Subse-
quent hydrogenolysis using this modified method with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–G

D
C.-T. Lin, S.-S. Lee
Paper
Synthesis
1
10
7
R2
R1
OMe
OMe
OMe
OMe
R2
R1
OMe
9
8
a
c
N
N
Me
N
Me
Me
87%
98%
OMe
10 R1 = OH, R2 = H
and R1 = H, R2 = OH
11 R1 = OTz, R2 = H
and R1 = H, R2 = OTz
12
4
TzO
TzO
HO
HO
N
N
N
8
1
1
d
b
OMe
9
OMe
OMe
OMe
68%
80%
12
OMe
OMe
11
11
13
14
15
5
MeO
MeO
MeO
MeO
HO
2N
N
N
e
TzO
Me
Me
1
b
Me
8
14
H
H
H
13
76%
69%
9
10
MeO
OTz
MeO
OH
16
17
18
Scheme 2 Reagents and conditions: (a) 5-chloro-1-phenyl-1H-tetrazole, K2CO3, acetone, reflux, 1 d; (b) 5-chloro-1-phenyl-1H-tetrazole, K2CO3, KI,
MeCN, reflux, 1 d; (c) 10% Pd/C (30% w/w), Mg (1.3 equiv), H2 (3.4 bar), AcOH, 50 °C, 3 d; (d) 10% Pd/C (30% w/w), Mg (2.5 equiv), H2 (13.8 bar), AcOH,
50 °C, 2.5 d; (e) 10% Pd/C (35% w/w), Mg (4 equiv), H2 (13.8 bar), AcOH, 50 °C 3 d.
similar reaction conditions gave 9,10-dimethoxyprotober-
berine (15) and 7,11-didehydroxyreticuline (18) in 68% and
76% yields, respectively (Scheme 2). The 1H NMR spectrum
of 15 showed signals for six aryl protons, including four be-
tween δ = 7.30 and δ = 7.10 (m) and two as an AB system at
δ = 6.86 and 6.79 (J = 8.4 Hz) for H11 and H12, supporting
phenyl-1H-tetrazol-5-yl ethers and reduction using Pd/C
and either magnesium metal or ammonium acetate under
moderate hydrogen pressure in acetic acid was developed.
The reactivity, reaction rate, and yield are improved to a
great extent by the addition of either magnesium or ammo-
nium acetate. Moreover, the amount of Pd/C used in these
conditions is significantly lower, making this modified
method more practical for larger-scale preparations of the
de-phenolated alkaloids.
1
its structure. The H NMR spectrum of 18 showed signals
for seven aryl protons, including an AA′BB′ system for
H10/H14 at δ = 6.98 and H11/H13 at δ = 6.77 (J = 8.6 Hz)
and an overlapped three-proton signal at δ = 6.58 for H5,
H7, and H8, supporting its structure.
Based on the mechanistic study of Pd/C-catalyzed re-
duction of aryl sulfonates proposed by Mori et al.,12 ammo-
nium acetate will dissociate to ammonia and acetic acid.
The generated ammonia will coordinate to the Pd(0) center
to enhance the electron density of palladium, speeding up
palladium-mediated electron transfer to the aromatic ring.
The magnesium metal, on the other hand, will reduce Pd(II)
to the active Pd(0), accelerating the single-electron-transfer
(SET) process.
IR spectra were obtained using a Jasco FT/IR-410. NMR spectra were
recorded on a Bruker Avance 400 spectrometer (Bremen, Germany)
using CDCl3 as calculated standard. Mass spectra were measured on
an Esquire 2000 ion trap mass spectrometer (ESIMS) and a mic-
roOTOF orthogonal ESI-TOF mass spectrometer (HRESIMS) (Bruker
Daltonics, Bremen, Germany). Column chromatography was carried
out on Silica gel 60 (40–63 μm) or alumina (neutral, 70–230 mesh),
purchased from Merck. Litebamine (1) and 2,3-dihydroxy-9,10-dime-
thoxyprotoberberine (13) were prepared according to the reported
procedure;13,14 reticuline (16) was isolated from Neolitsea konishii.15
All other reagents and solvents used are commercially available.
In summary, a modified method for complete removal
of the phenolic–OH group from phenolic alkaloids of vari-
ous types involving conversion into the corresponding 1-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–G

E
C.-T. Lin, S.-S. Lee
Paper
Synthesis
3,7-O,O-Bis(1-phenyl-1H-tetrazol-5-yl)litebamine (2); Typical Pro-
cedure
(m, 4 H, H5α, H11α), 2.73 (1 H), 2.71 (1 H), 2.62 (1 H), and 2.57 (1 H)
(each d, J = 16.6 Hz) (H5β, H11β), 2.531 (3 H) and 2.525 (3 H) (each s,
NMe).
MS (ESI): m/z = 456 ([M + H]+).
To a mixture of litebamine (1, 903 mg, 2.7 mmol), 5-chloro-1-phenyl-
1H-tetrazole (1.2 g, 6.7 mmol), and K2CO3 (2.2 g, 15.9 mmol) in DMF
(40 mL) was stirred at 90 °C. After completion of the reaction (TLC),
the solvent was removed in vacuo and the residue was suspended in
CHCl3 (80 mL), washed with water (3 × 80 mL), dried (anhyd Na2SO4),
and evaporated to dryness. The residue was chromatographed (silica
gel, 70 g, 0.5–10% MeOH–CHCl3, saturated with 25% aq NH3) to yield 2
(1.1 g, 64%) as a yellowish amorphous solid.
9,10-Dimethoxy-2,3-O,O-bis(1-phenyl-1H-tetrazol-5-yl)protober-
berine (14)
Prepared according to the typical procedure using 2,3-dihydroxy-
9,10-dimethoxyprotoberberine (13; 83.7 mg, 0.2 mmol), 5-chloro-1-
phenyl-1H-tetrazole (128.9 mg, 3.0 mmol), K2CO3 (417.8 mg, 72.4
mmol), with addition of KI (6.4 mg, 0.1 mmol) with MeCN (4 mL) as
the solvent at reflux for 1 d. Colorless amorphous solid; yield: 113.1
mg (80%).
IR (KBr): 2936, 1541, 1523, 1507, 1457, 1375, 1295, 1255 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.02 (s, 1 H, H5), 7.92 (s, 1 H, H8),
7.90–7.87 (m, 4 H, Tz-H), 7.76 (d, J = 9.3 Hz, 1 H, H10), 7.75 (d, J = 9.3
Hz, 1 H, H9), 7.65–7.48 (m, 6 H, Tz-H), 4.18 (br s, 2 H, H2a), 3.90 (s, 3
H, 6-OMe), 3.63 (s, 3 H, 4-OMe), 3.51 (br s, 2 H, H12), 3.26 (br s, 2 H,
H11), 2.78 (s, 3 H, NMe).
13C NMR (100 MHz, CDCl3): δ = 159.9 (Cq), 159.8 (Cq), 149.8 (Cq),
148.0 (Cq), 142.6 (Cq), 142.5 (Cq), 134.4 (Cq), 133.3 (Cq), 133.1 (Cq),
131.1 (Cq), 130.3 (Cq), 130.0 (CH), 129.8 (CH), 129.7 (CH), 129.4 (CH),
128.9 (Cq), 128.1 (CH), 127.4 (Cq), 123.1 (Cq), 122.2 (CH), 122.2 (CH),
120.2 (CH), 119.8 (CH), 110.0 (CH), 61.2 (CH3), 56.1 (CH3), 51.3 (CH2),
50.9 (CH2), 44.3 (CH3), 24.9 (CH2).
IR (KBr): 2939, 2831, 1596, 1548, 1531, 1501, 1454, 1329, 1279, 1082,
759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.72 (s, 1 H) and 7.55 (s, 1 H) (H1, H4),
7.42–7.37 (m, 10 H, Tz-H), 6.87 (d, J = 8.4 Hz, 1 H, H11), 6.80 (d, J = 8.4
Hz, 1 H, H12), 4.37 (br d, 1 H), 4.09 (m, 1 H), 3.86 (s, 3 H) and 3.84 (s, 3
H) (9-OMe, 10-OMe), 3.73 (m, 1 H), 3.44–3.23 (m, 3 H) and 3.10–2.92
(m, 3 H) (H5, H6, H13).
13C NMR (100 MHz, CD3CN): δ = 160.1 (Cq), 159.9 (Cq), 151.4 (Cq),
145.7 (Cq), 143.0 (Cq), 142.8 (Cq), 135.3 (Cq), 133.4 (Cq), 133.3 (Cq),
130.7 (CH), 130.5 (CH), 130.5 (CH), 127.0 (Cq), 124.8 (CH), 123.3 (CH),
123.2 (CH), 122.8 (CH), 120.6 (CH), 112.6 (CH), 60.4 (CH3), 59.5 (CH),
56.3 (CH3), 53.3 (CH2), 50.9 (CH2), 35.1 (CH2), 28.5 (CH2).
MS (ESI): m/z = 628 ([M + H]+).
2,9-O,O-Bis(1-phenyl-1H-tetrazol-5-yl)boldine (7)
MS (ESI): m/z = 616 ([M + H]+).
Prepared according to the typical procedure using boldine (6; 5.2 g,
14.3 mmol), 5-chloro-1-phenyl-1H-tetrazole (6.5 g, 35.7 mmol),
K2CO3 (10.0 g, 72.4 mmol), with addition of KI (129.2 mg, 0.8 mmol)
with MeCN (250 mL) as the solvent at 90 °C for 1 d. Colorless amor-
phous solid; yield: 7.0 g (80%).
7,11-O,O-Bis(1-phenyl-1H-tetrazol-5-yl)reticuline (17)
Prepared according to the typical procedure using reticuline (16;
100.9 mg, 0.3 mmol), 5-chloro-1-phenyl-1H-tetrazole (171.6 mg, 0.9
mmol), K2CO3 (442.3 mg, 3.2 mmol), with addition of KI (10.9 mg, 0.1
mmol) with MeCN (5 mL) as the solvent at reflux for 1 d. Colorless
amorphous solid; yield: 118.9 mg (63%).
IR (KBr): 2957, 2839, 2806, 1619, 1537, 1502, 1452, 1, 1393, 1317,
1294, 1236, 1072, 1000, 759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.04 (s, 1 H, H11), 7.87–7.84 (m, 4 H,
Tz-H), 7.58–7.54 (m, 4 H, Tz-H), 7.50–7.48 (m, 2 H, Tz-H), 7.31 (s, 1 H,
H8), 7.19 (s, 1 H, H3), 3.77 (s, 3 H, 10-OMe), 3.48 (s, 3 H, 1-OMe),
3.17–3.03, 2.76–2.57, 2.54 (m, 7 H), 2.54 (s, 3 H, NMe).
13C NMR (100 MHz, CDCl3): δ = 160.0 (Cq), 159.9 (Cq), 149.2 (Cq),
146.4 (Cq), 146.1 (Cq), 141.6 (Cq), 134.8 (Cq), 133.3 (Cq), 133.2 (Cq),
130.6 (Cq), 130.4 (Cq), 129.8 (CH), 129.6 (CH), 129.5 (Cq), 129.5 (CH),
129.3 (CH), 127.6 (Cq), 122.1 (CH), 122.1 (CH), 120.8 (CH), 120.7 (CH),
112.9 (CH), 62.3 (CH), 61.1(CH3), 56.3 (CH3), 52.7 (CH2), 43.8 (CH3),
33.4 (CH2), 28.8 (CH2).
IR (KBr): 2937, 2840, 1596, 1543, 1504, 1453, 1297, 1267, 1087, 1019,
758 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.80 (m, 4 H, Tz-H), 7.54–7.51 (m,
4 H, Tz-H), 7.46–7.43 (m, 2 H, Tz-H), 7.13 (d, J = 2.0 Hz, 1 H, H10), 6.96
(dd, J = 2.0, 8.4 Hz, 1 H, H14), 6.83 (d, J = 8.4 Hz, 1 H, H13), 6.75 (s, 1 H)
and 6.68 (s, 1 H) (H5, H8), 3.71 (s, 3 H) and 3.68 (s, 3 H) (6-OMe, 12-
OMe), 3.69 (m, 1 H, H1), 3.15–3.03 (m, 2 H), 2.89–2.72 (m, 4 H), 2.49
(s, 3 H, NMe).
13C NMR (100 MHz, CDCl3): δ = 160.1 (Cq), 160.0 (Cq), 148.6 (Cq),
148.4 (Cq), 141.9 (Cq), 140.1 (Cq), 134.3 (Cq), 133.3 (Cq), 133.2 (Cq),
132.2 (Cq), 129.7 (Cq), 129.5 (CH), 129.1 (CH), 129.1 (CH), 122.7 (CH),
122.3 (CH), 122.2 (CH), 120.7 (CH), 112.9 (CH), 112.6 (CH), 64.3 (CH),
55.8 (CH3), 55.8 (CH3), 47.0 (CH2), 42.7 (CH3), 39.9 (CH2), 26.2 (CH2).
MS (ESI): m/z = 616 ([M + H]+).
2,3-Dimethoxy-8-O-(1-phenyl-1H-tetrazol-5-yl)pavine (11a) and
2,3-Dimethoxy-9-O-(1-phenyl-1H-tetrazol-5-yl)pavine (11b)
MS (ESI): m/z = 618 ([M + H]+).
Prepared according to the typical procedure using 8/9-hydroxy-2,3-
dimethoxypavine (10; 780.0 mg, 2.5 mmol), 5-chloro-1-phenyl-1H-
tetrazole (500.0 mg, 2.8 mmol), K2CO3 (2.0 g, 14.5 mmol), with ace-
tone (50 mL) as the solvent at reflux for 1 d. Colorless amorphous sol-
id; yield: 992.0 mg (80%).
3,7-Didehydroxy-9,10-dihydrolitebamine (5); Typical Procedure
To a solution of compound 2 (1.0 g, 1.6 mmol) in AcOH (50 mL) was
added 10% Pd/C (326.6 mg, 30% w/w) and NH4OAc (1.2 g). The mix-
ture was stirred at 50 °C under 13.8 bar of H2 for 4 d. The catalyst was
filtered off and the filtrate was evaporated in vacuo. The residue was
suspended in H2O (70 mL) and the pH of the solution was adjusted to
7–8 by 25% aq NH3, extracted by CHCl3 (3 × 70 mL). The combined or-
ganic layers were dried (anhyd Na2SO4) and evaporated under re-
duced pressure to give a residue which was chromatographed (alumi-
na, 4.5 g, 3–20% EtOAc–hexanes) to give 3,7-didehydroxy-9,10-dihy-
drolitebamine (5, 317.9 mg, 64%) as a yellowish oil.
IR (KBr): 2905, 2832, 1596, 1541, 1497, 1450, 1239, 1214, 1126, 1109,
1095, 1019, 759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.78–7.71 (m, 4 H, Tz-H), 7.23–7.02 (m,
6 H), 6.58 (s, 1 H), 6.57 (s, 1 H), 6.42 (s, 1 H), and 6.41 (s, 1 H) (H1, H4),
4.12 (d, 1 H), 4.10 (d, 1 H), 4.04 (d, 1 H), and 4.03 (d, 1 H) (H6, H12),
3.83 (s, 3 H) and 3.82 (s, 3 H) (2-OMe), 3.76 (s, 6 H, 3-OMe), 3.50–3.39
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–G

F
C.-T. Lin, S.-S. Lee
Paper
Synthesis
IR (KBr): 2932, 2833, 2779, 1602, 1462, 1313, 1117, 1098 cm–1
.
2,3-Dimethoxypavine (12)
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 2.6 Hz, 1 H, H5), 7.12 (d,
J = 8.2 Hz, 1 H, H8), 6.73 (dd, J = 2.6, 8.2 Hz, 1 H, H7), 6.55 (s, 1 H, H3),
3.83 (s, 3 H, 6-OMe), 3.81 (s, 3 H, 4-OMe), 3.59 (br s, 2 H), 2.79–2.59
(m, 8 H).
Prepared according to the typical procedure using 11 (30.4 mg, 0.07
mmol), 10% Pd/C (10.0 mg, 30% w/w), and Mg (3.2 mg, 0.13 mmol)
with AcOH (3 mL) as the solvent at 50 °C under 3.4 bar of H2 for 3 d.
Yellowish oil; yield: 19.4 mg (98%).
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO2: 310.1807; found:
310.1812.
IR (KBr): 2996, 2918, 2892, 2851, 2832, 2804, 2779, 1607, 1515, 1455,
1373, 1352, 1337, 1261, 1241, 1212, 1109, 1076, 1009, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.11–7.04 (m, 3 H, H7–9), 6.95 (d,
J = 7.3 Hz, 1 H, H10), 6.59 (s, 1 H, H1), 6.41 (s, 1 H, H4), 4.10 (d, J = 5.6
Hz, 1 H, H6), 4.04 (d, J = 5.6 Hz, 1 H, H12), 3.82 (s, 3 H, 2-OMe), 3.74 (s,
3 H, 3-OMe), 3.48 (dd, J = 5.6, 16.4 Hz, 1 H, H11α), 3.44 (dd, J = 5.6,
16.4 Hz, 1 H, H5α), 2.71 (d, J = 16.4 Hz, 1 H, H11β), 2.60 (d, J = 16.4 Hz,
1 H, H5β), 2.54 (s, 3 H, NMe).
13C NMR (100 MHz, CDCl3): δ = 147.8 (Cq), 147.5 (Cq), 138.1 (Cq),
132.0 (Cq), 129.5 (Cq), 129.1 (CH), 127.2 (CH), 126.6 (CH), 125.9 (CH),
123.6 (CH), 111.4 (CH), 109.9 (CH), 56.6 (CH3), 56.4 (CH3), 55.9 (CH),
55.6 (CH), 40.8 (CH3), 34.2 (CH2), 33.3 (CH2).
3-O-(1-Phenyl-1H-tetrazol-5-yl)-7-dehydroxylitebamine (3) and
3-O-(1-phenyl-1H-tetrazol-5-yl)-7-dehydroxy-9,10-dihydrolite-
bamine (4)
Prepared according to the typical procedure using 2 (51.7 mg, 0.08
mmol), 10% Pd/C (25.9 mg, 50% w/w), and NH4OAc (20.9 mg, 0.27
mmol) with AcOH (4 mL) as the solvent at 50 °C under 13.8 bar of H2
for 1.5 d. Both 3 (2.3 mg, 6%) and 4 (20.4 mg, 50%) were obtained as
yellowish oils.
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO2: 296.1645; found:
3-O-(1-Phenyl-1H-tetrazol-5-yl)-7-dehydroxylitebamine (3)
1H NMR (400 MHz, CDCl3): δ = 8.83 (d, J = 2.4 Hz, 1 H, H-5), 7.98−7.96
(m, 2 H, Tz-H), 7.83 (d, J = 8.7 Hz, 1 H, H-8), 7.80 (d, J = 9.1 Hz, 1 H) and
7.78 (d, J = 9.1 Hz, 1 H) (H9, H10), 7.74−7.59 (m, 3 H, Tz-H), 7.26 (dd,
J = 2.4, 8.7 Hz, 1 H, H-7), 4.15 (s, 2 H), 3.89 (s, 3 H) and 3.63 (s, 3 H) (4-
OMe, 6-OMe), 3.41 (br s, 2 H), 3.21 (br s, 2 H), 2.74 (s, 3 H, NMe).
HRMS (ESI): m/z [M + H]+ calcd for C27H26N5O3: 468.2036; found:
468.2049.
296.1660
9,10-Dimethoxyprotoberberine (15)
Prepared according to the typical procedure using 14 (20.0 mg, 0.03
mmol), 10% Pd/C (6.5 mg, 30% w/w), and Mg (2.1 mg, 0.08 mmol)
with AcOH (1.5 mL) as the solvent at 50 °C under 13.8 bar of H2 for 2.5
d. Yellowish oil; yield: 6.5 mg (68%).
IR (KBr): 2833, 1727, 1658, 1642, 1613, 1495, 1454, 1357, 1277, 1084,
1057, 738 cm–1
.
3-O-(1-Phenyl-1H-tetrazol-5-yl)-7-dehydroxy-9,10-dihydrolite-
bamine (4)
1H NMR (400 MHz, CDCl3): δ = 7.30–7.10 (m, 4 H, H1–4), 6.87 (d,
J = 8.4 Hz, 1 H, H12), 6.79 (d, J = 8.4 Hz, 1 H, H11), 4.29 (d, J = 15.6 Hz,
1 H, H8), 3.84 (s, 3 H) and 3.83 (s, 3 H) (9-OMe, 10-OMe), 3.77–3.62
(m, 2 H), 3.36–3.28 (m, 3 H), 2.95–2.75 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.4 (Cq), 145.1 (Cq), 133.9 (Cq),
129.7 (Cq), 128.9 (CH), 127.1 (Cq), 126.5 (CH), 126.2 (CH), 125.5 (CH),
123.9 (CH), 122.1 (Cq), 111.2 (CH), 60.2 (CH3), 59.6 (CH), 55.9 (CH3),
53.7 (CH2), 51.1 (CH2), 35.6 (CH2), 28.8 (CH2).
1H NMR (400 MHz, CDCl3): δ = 7.90−7.88 (m, 2 H, Tz-H), 7.79 (d, J = 2.5
Hz, 1 H, H-5), 7.74−7.59 (m, 3 H, Tz-H), 7.13 (d, J = 8.2 Hz, 1 H, H-8),
6.77 (dd, J = 2.5, 8.2 Hz, 1 H, H-7), 3.76 (s, 3 H) and 3.37 (s, 3 H) (4-
OMe, 6-OMe), 3.59 (s, 2 H), 2.82 (t-like, 2 H), 2.72 (t-like, 2 H), 2.67
(m, 4 H), 2.43 (s, 3 H, NMe).
HRMS (ESI): m/z [M + H]+ calcd for C27H28N5O3: 470.2192; found:
470.2194.
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO2: 296.1645; found:
296.1634
1,10-Dimethoxyaporphine (8)
Prepared according to the typical procedure using 7 (6.8 g, 11.1
mmol), 10% Pd/C (2.0 g, 30% w/w), and Mg (675.5 mg, 27.8 mmol)
with AcOH (80 mL) as the solvent at 50 °C under 13.8 bar of H2 for 3 d.
Yellowish oil; yield: 2.8 g (87%).
7,11-Didehydroxyreticuline (18)
Prepared according to the typical procedure using 17 (30.6 mg, 0.05
mmol), 10% Pd/C (11.0 mg, 35% w/w), and Mg (4.8 mg, 0.20 mmol)
with AcOH (3 mL) as the solvent at 50 °C under 13.8 bar of H2 for 3 d.
Yellowish oil; yield: 11.3 mg (76%).
IR (KBr): 2958, 1655, 1459, 1268, 1071, 1031 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 2.6 Hz, 1 H, H11), 7.17 (d,
J = 8.2 Hz, 1 H, H8), 7.04 (d, J = 8.4 Hz, 1 H, H3), 6.88 (d, J = 8.4 Hz, 1 H,
H2), 6.78 (dd, J = 2.6, 8.2 Hz, 1 H, H9), 3.85 (s, 3 H, 10-OMe), 3.83 (s, 3
H, 1-OMe), 3.13–3.00, 2.70–2.55, and 2.50–2.48 (7 H, m), 2.54 (s, 3 H,
N-Me).
13C NMR (100 MHz, CDCl3): δ = 158.0 (Cq), 154.9 (Cq), 136.6 (Cq),
133.0 (Cq), 128.6 (CH), 128.5 (Cq), 128.5 (CH), 125.5 (Cq), 121.9 (Cq),
114.7 (CH), 112.1 (CH), 110.8 (CH), 63.2 (CH), 55.7 (CH3), 55.3 (CH3),
53.2 (CH2), 43.9 (CH3), 33.8 (CH2), 28.5 (CH2).
IR (KBr): 2938, 2834, 1611, 1512, 1463, 1373, 1246, 1177, 1037, 821
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.98 (d, J = 8.6 Hz, 2 H, H10, H14) and
6.77 (d, J = 8.6 Hz, 2 H, H11, H13), 6.60–6.56 (m, 3 H, H5, H7, H8), 3.77
(s, 3 H) and 3.75 (s, 3 H) (6-OMe 12-OMe), 3.73 (m, 1 H, H1), 3.22–
3.10 (m, 2 H), 2.89–2.73 (m, 3 H), 2.66 (dt, J = 16.2, 5.0 Hz, 1 H), 2.49
(s, 3 H, NMe).
13C NMR (100 MHz, CDCl3): δ = 157.9 (Cq), 157.7 (Cq), 135.1 (Cq),
131.5 (Cq), 130.6 (CH), 129.0 (CH), 113.5 (CH), 113.1 (CH), 111.7 (CH),
64.8 (CH), 55.2 (CH3), 55.1 (CH3), 46.8 (CH2), 42.5 (CH3), 40.5 (CH2),
26.0 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO2: 296.1645; found:
296.1655.
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO2: 298.1802; found:
298.1798.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–G

G
C.-T. Lin, S.-S. Lee
Paper
Synthesis
Acknowledgment
(8) (a) Lu, S. T.; Wu, Y. C.; Leou, S. P. Phytochemistry 1985, 24, 1829.
(b) Cannon, J. G.; Mohan, P.; Bojarski, J.; Long, J. P.; Bhatnagar, R.
K.; Leonard, P. A.; Flynn, J. R.; Chatterjee, T. K. J. Med. Chem.
1988, 31, 313. (c) Amaravathi, M.; Pardhasaradhi, M. Synth.
Commun. 1990, 20, 789. (d) Olugbade, T. A.; Waigh, R. D.;
We gratefully acknowledge Ministry of Science and Technology, Tai-
wan, ROC, for financial support for this work under grant NSC 100-
2325-B-002-021.
Mackay, S. P. J. Chem. Soc., Perkin Trans.
1 1990, 2657.
(e) Newman, A. H.; Bevan, K.; Bowery, N.; Tortella, F. C. J. Med.
Chem. 1992, 35, 4135. (f) Cannon, J. G.; Raghupathi, R.; Moe, S.
T.; Johnson, A. K.; Long, J. P. J. Med. Chem. 1993, 36, 1316.
(g) Grauert, M.; Bechtel, W. D.; Ensinger, H. A.; Merz, H.; Carter,
A. J. J. Med. Chem. 1997, 40, 2922. (h) Tadic, D.; Linders, J. T. M.;
Flippen-Anderson, J. L.; Jacobson, A. E.; Rice, K. C. Tetrahedron
2003, 59, 4603. (i) Spetea, M.; Schullner, F.; Moisa, R. C.;
Berzetei-Gurske, I. P.; Schraml, B.; Dorfler, C.; Aceto, M. D.;
Harris, L. S.; Coop, A.; Schmidhammer, H. J. Med. Chem. 2004, 47,
3242.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380206.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–G