Activation of iodosobenzene by catalytic tetrabutylammonium iodide and its application in the oxidation of some isoquinoline alkaloids

Article abstract of DOI:10.1002/1522-2675(200204)85:4<1069::AID-HLCA1069>3.0.CO;2-I

Oxidation of N-methyltetrahydroisoquinolines with iodosylbenzene in the presence of a catalytic amount of tetrabutylammonium iodide in various solvents afforded N-methyl-2H-3,4-dihydroisoquinol-1-ones in almost quantitative yields. The application of this finding to the oxidation of other isoquinolines, including tetrahydroisoquinolines, lycorine diacetate, and benzyltetrahydroisoquinolines, also afforded the corresponding lactams in good yields, however, accompanied by a few minor byproducts. Under similar conditions, tetrahydroberberine gave a rearranged compound, berberal, as the major product, accompanied by 8-oxoberberine and berberine.

Full text of DOI:10.1002/1522-2675(200204)85:4<1069::AID-HLCA1069>3.0.CO;2-I

Helvetica Chimica Acta Vol. 85 (2002)
1069
Activation of Iodosobenzene by Catalytic Tetrabutylammonium Iodide
and Its Application in the Oxidation of Some Isoquinoline Alkaloids
by Wei-Jan Huang, Om V. Singh, Chung-Hsiung Chen, Sheng-You Chiou, and Shoei-Sheng Lee*
School of Pharmacy, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Sec. 1, Taipei,
Taiwan 100, Republic of China
Oxidation of N-methyltetrahydroisoquinolines with iodosylbenzene in the presence of a catalytic amount
of tetrabutylammonium iodide in various solvents afforded N-methyl-2H-3,4-dihydroisoquinol-1-ones in almost
quantitative yields. The application of this finding to the oxidation of other isoquinolines, including
tetrahydroisoquinolines, lycorine diacetate, and benzyltetrahydroisoquinolines, also afforded the corresponding
lactams in good yields, however, accompanied by a few minor byproducts. Under similar conditions,
tetrahydroberberine gave a rearranged compound, berberal, as the major product, accompanied by 8-
oxoberberine and berberine.
Introduction. During the last two decades, hypervalent iodine (III) reagents have
shown their versatility in organic syntheses because of their low toxicity, ready
availability, easy handling, and their application to many useful and unique trans-
formations [1]. Among these reagents, iodosylbenzene (ISB) is the least reactive one,
probably due to its poor solubility in most organic solvents except MeOH. It has been
reported that activation of ISB requires the addition of Lewis acids such as BF3ÀEt2O
[2], NO2BF4 [3], HBF4ÀEt2O [3], TMSOTf [4], etc., however, the number of
appropriate solvents from which to choose is limited. Recently, Kita and co-workers
have reported on the activation of ISB with catalytic amounts of cetyltrimethylammo-
nium bromide (CTAB) in a variety of solvents for the oxidation of sulfides to sulfoxides
via formation of micellar and reversed-micellar systems [5]. The oxidation of
heterocyclic amines by ISB in a two-phase system, CH2Cl2/H2O, yielded the
corresponding amides in moderate yield but required longer reaction times (36
96 h), depending on the reactant [6]. Our aim was to modify the above reaction
conditions to obtain higher yields and faster reaction rates.
Results and Discussion. The results of the oxidation of 6,7-dimethoxy-N-methyl-
1,2,3,4-tetrahydroisoquinoline (1a) to 6,7-dimethoxy-N-methyl-2H-3,4-dihydroisoqui-
nolin-1-one (N-methylcorydaldine, 2a), a naturally occurring cytotoxic alkaloid [7
10], with ISB in the presence or absence of quaternary ammonium salts under different
reaction conditions are summarized in Table 1. It was found that the reaction with ISB
alone and MeCN/H2O 9 :1 as solvent afforded 2a in only 45% yield, even after 24 h
(Entry 1). However, the yields were improved (to ca. quantitative, Entries 2 8) and
the reaction time was shortened dramatically after adding catalytic amounts of
tetrabutylammonium iodide (TBAI; Scheme 1). Addition of H2O had little effect on
the yield, but did increase the reaction rate (Entries 3 5). Similar results were

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Helvetica Chimica Acta Vol. 85 (2002)
Table 1. Oxidation of 6,7-Dimethoxy-2-methyltetrahydroisoquinoline (1a) with Iodosobenzene Under Various
Reaction Conditions
Entry
Quaternary Ammonium
Time
[h]
Yielda)
[%]
Salts
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
None
MeCN/H2O 90 : 10
MeCN
24
2
2
2
1
2
2
2
6
6
6
6
6
45
‡
Bu4N IÀ
quantitative
quantitative
quantitative
quantitative
quantitative
quantitative
quantitative
trace
‡
Bu4N IÀ
MeCN/H2O 98 : 02
MeCN/H2O 95 : 05
MeCN/H2O 90 : 10
THF/H2O 90 : 10
Toluene/H2O 90 : 10
CH2Cl2/H2O 90 : 10
MeCN/H2O 90 : 10
Toluene/H2O 90 : 10
CH2Cl2/H2O 90 : 10
MeCN/H2O 90 : 10
MeCN/H2O 90 : 10
‡
Bu4N IÀ
‡
Bu4N IÀ
‡
Bu4N IÀ
‡
Bu4N IÀ
‡
Bu4N IÀ
[C16H33N Me3]BrÀ
‡
[C16H33N Me3]BrÀ
8
‡
[C16H33N Me3]BrÀ
trace
trace
trace
‡
‡
Bu4N BrÀ
‡
Bu4N ClÀ
a
1
) Yields are based on H-NMRanalysis of the mixture obtained after workup of the reaction.
obtained by replacing MeCN with CH2Cl2, toluene, or THF (Entries 6 8). Under the
conditions (CTAB as catalyst) for the oxidation of sulfides to sulfoxides [5], 1a
afforded 2a in very poor yield even after 6 h (Entries 9 11). In the presence of other
phase-transfer reagents, such as tetrabutylammonium bromide (TBAB, Entry 12) and
tetrabutylammonium chloride (TBAC, Entry 13), 2a was obtained in only trace
amounts, even after 6 h. This would suggest that the activation of ISB is not simply
attributable to the phase-transfer properties of these quaternary ammonium salts.
Based on these observations, we propose that ISB, which exists in polymeric form, upon
reaction with TBAI is cleaved in situ to form a reactive adduct 3, shown in Scheme 2, as
indicated by the immediate formation of a light brown solution upon treating ISB with
an equivalent amount of TBAI in MeCN/H2O 7:3 at room temperature. This
suggestion is further supported by the observation that the color of the suspension of
ISB persists even after 6 h when TBAI is replaced with TBAC or TBAB.
The generality of the above transformation was verified by treating various N-
methyl tetrahydroisoquinolines 1b d with ISB (2.2 equiv.) in the presence of TBAI
(10 mol-%, 0.2 equiv.) in MeCN/H2O 9 :1 at room temperature. The almost quanti-
tative yields (Table 2) of the respective dihydroisoquinolones 2b d (Scheme 1) proved
the practicability of this new procedure. The identities of all compounds prepared were
1
confirmed by comparison of their FT-IR, H-, 13C-NMRand MS data with those
reported in the literature. Yield and m.p. data of 2a d are given in Table 2. Of these
compounds, 2c was identified as the natural product oxohydrastinine [11][12].
Treatment of tetrahydroisoquinolines 1e f under conditions similar to those used
for 1a d in MeCN afforded 3,4-dihydro-2H-isoquinol-1-ones 4a b and isoquinolines
5a b, respectively. Similar results were obtained with CH2Cl2/H2O 9 :1 or MeCN/H2O
9 :1 as the solvent. Compounds 4a, 4b, and 5b are natural products corydaldine [14],
noroxyhydrastinine [15][16], and papraline [17], respectively. A plausible mechanism
for these transformations is depicted in Scheme 3. The first step is the dehydrogenation

Helvetica Chimica Acta Vol. 85 (2002)
1071
Scheme 1
R1O
R2O
R1O
i)
N
N
Me
R2O
Me
O
1a–f
2a–d
iii)
ii)
R1O
R2O
R1O
R2O
R1O
iv)
+
N
NH
N
R2O
O
6a–b
5a–b
4a–b
a R1= R2= Me
d R1= Me, R2= Ac
b R1+R2= –CH2–
e R1= R2= Me
c R1= Me, R2= Bn;
f R1+R2= –CH2–
i) PhIˆO (2.2 equiv.), TBAI (0.2 equiv.), MeCN/H2O (9 :1), r.t. 1 1.5 h. ii) PhIˆO (1 equiv.), TBAI (0.1
equiv.) MECN, 08, 15 min. iii) PhIˆO (2.2 equiv.), TBAI (0.2 equiv.), MeCN/H2O (9 :1), 08, 15 min and then
(r.t.,) 1 h. iv) PhIˆO (1.1 equiv.), TBAI (0.1 equiv.), MeCN, r.t. 1 h.
Scheme 2
I
Bu4N+I–
Ph
I
Ph
I
O
n
+
O–N+Bu4
3
Table 2. Oxidation of Tetrahydroisoquinolines with ISB in the Presence of TBAI
Reactant
Product
Time
[h]
Yielda)
[%]
M.p. [lit. m.p.]
[8]
1a
1b
1c
1d
1e
2a
2b
2c
2d
4a
5a
4b
5b
1
1
1
1.5
1.5
96
96
94
90
30
50
35
45
123 124 (124 125 [13])
98 99 (98 [13])
110 111
131 132
173 174 (174 175 [13])
93 94 (92 93 [19])
184 185 (185 186 [20])
120 121 (125 126 [21])
1f
2
a) Yields are based on isolated products.

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 3
MeO
H
I
MeO
MeO
3
3
Ph
1e
+
–I–
N
N
MeO
O–N+Bu4
H2O
–PhI
–NBu4I
–H2O
6a
7
MeO
MeO
MeO
H
I
Ph
O
N
I
N
MeO
O
Ph
HO
H
HO
8
8
b
a
Ph
I
OH
OH
H
4
MeO
–H2O
N
5
MeO
+
PhI
OH
9
Bu4N+ –OH
HI
Bu4N+ I– + H2O
+
of 1e to form dihydroisoquinoline 6a, which was confirmed by the following two
experiments. First, treating 1e f with 1 equiv. of ISB in the presence of TBAI at 08
afforded 6a (dehydroheliamine) [18] and 6b in almost quantitative yield. Second,
dihydroisoquinolines 6a b on treatment with ISB under the above reaction conditions
at room temperature afforded a mixture of 4a b and 5a b (Scheme 1). Nucleophilic
attack of H2O at the C(1) position of the adduct 7 gave 8 (Scheme 3, Path a), which,
upon elimination of iodobenzene and isomerization, would afford 4. In a competitive
pathway (Path b), the elimination of iodobenzene with concomitant loss of a HÀC(3)
of the adduct 8 would afford 9, which, upon elimination of H2O, leads to the
isoquinoline 5. Spontaneous reaction of the hydroiodic acid formed with tetrabutyl-
ammonium hydroxide regenerates TBAI to complete the catalytic cycle.
Oxidation of lycorine diacetate (10), prepared from O-acetylation of lycorine
(Ac2O-py) under similar conditions in MeCN/H2O 9 :1 afforded compound 11 in 80%
yield along with a minor compound 12 (5%). Compound 11 was identified as 7-
lycorinone diacetate, which has been obtained before by oxidation of 10 with KMnO4,

Helvetica Chimica Acta Vol. 85 (2002)
1073
however, in very low yield (10%) [22]. Compound 12 was identified as 2-acetoxyanhy-
drolycorine lactam [23], as demonstrated by its 1H-NMRspectrum, which displayed an
AX system (d 7.01, 7.42, ‡ J ˆ 1.7 Hz) for HÀC(3) and HÀC(1) in addition to two s
(d 7.42 and 7.89) for HÀC(8) and HÀC(11), respectively, in the aromatic region, and
only one Me(Ac) s and four mutually coupled protons in the aliphatic region.
Further study indicated that 12 was not produced from 11 by over oxidation, as
confirmed by the absence of a reaction upon treatment of 11 with ISB under similar
conditions. Hence, 12 would be formed from 10, and a probable mechanism is depicted
in Scheme 4. Elimination of iodobenzene with the loss of an allylic proton HÀC(16) of
the adduct 13 gives the iminium cation 14, which, after isomerization, affords 15.
Subsequent oxidation at C(7) and aromatization of ring A with the elimination of an
AcOH unit would yield 12.
Treatment of 1-benzyl-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (16a)
with 3 equiv. of ISB in presence of a catalytic amount of TBAI at room temperature
afforded 6,7-dimethoxy-2-methyl-2H-3,4-dihydroisoquinolin-1-one (2a) and benzalde-
hyde (17a) in 75% yields via the CÀC bond cleavage at the dibenzylic position
(Scheme 5). The CÀC bond cleavage is a very rare reaction in hypervalent iodine
chemistry except for cleavage of glycols to their respective ketones [24], and only
pentafluoroiodobenzene bis(trifluoroacetate), a highly reactive hypervalent iodine
reagent, is known to bring about CÀC bond cleavage of carbonyl compounds [25]. To
the best of our knowledge, this is the first example of CÀC bond cleavage by ISB. The
generality of this reaction was confirmed by treating benzylisoquinolines 16b d under
similar reaction conditions, which produced the common product 2a and the respective
substituted aromatic aldehydes 17b d in good yields.
Scheme 4
OAc
2
OAc
N
OAc
N
AcO
AcO
3
1
11
14
15
12
5
PhI=O/TBAI
MeCN/H2O
O
O
O
O
O
O
4
16
+
N
13
8
7
O
O
10
11
12
OAc
OAc
H
H
AcO
AcO
AcO
AcO
Ph
–Bu4NOH
–PhI
O
O
O
O
O
3
–H+
10
N
N+
N
O
I–
I
O
– +NBu4
15
14
13
[O]
–HOAc
12

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 5
5
4
MeO
MeO
MeO
MeO
3
CHO
N
N
MeO
MeO
Me
Me
1
8
i)
ii)
+
CH3
N
R2
O
R1
R1
R1
R2
R2
17a–d
2a
16a–d
20
a R1 = R2 = H b R1 = OMe, R2 = H c R1 = R2 = OMe d R1 = Br, R2 = H
i) PhIˆO (3.3 equiv.), TBAI (0.3 equiv.), r.t. 2 h. ii) PhIˆO (2.2 equiv.), TBAI (0.2 equiv.), r.t., 1.5 h.
The possible mechanism for the formation of 2a and 17a d from 16a d is depicted in
Scheme 6. Elimination of iodobenzene with concomitant loss of HÀC(1) of the adduct
18 afforded the iminium cation (19), which, upon isomerization, yielded 20. Hydration
of the adduct 21 together with the elimination of iodobenzene and H2O would give 22.
Subsequent hydration yields the 1,2-diol 23, and cleavage of the glycol, which was
shown to be effected by a similar reagent, iodobenzene diacetate [24], gives rise to the
lactam 2a and the respective aldehydes 17a d. That 20 is a key intermediate during this
transformation was evidenced indirectly by the reaction of 20 with 2.2 equiv. of ISB and
a catalytic amount of TBAI, affording 2a and 17a in 80% yields (Scheme 5).
To study the applicability of this CÀC-bond-cleavage reaction, tetrahydroberberine
(24), a benzylisoquinoline derivative prepared by NaBH4 reduction of berberine (25),
was treated under similar reaction conditions for 5 h at room temperature, yielding 25 as
the major product together with compounds 26 and 27 (Scheme 7). Compound 26 was
identified as berberal through comparison of its physical and spectral data with those
reported [26]. This structure was also confirmed by 2D NMRanalysis including
HMQC, NOESY, and HMBC. The key evidence included the shift correlation of HÀC(1)
(d 7.58) and HÀC(8) (d 7.96) to C(14) (d 164.4), and HÀC(8) and HÀC(12) (d 7.64) to
C(13) (d 168.3), confirming the location of the lactam and lactone moieties. Based on
these analyses, complete assignments of the 1H- and 13C-NMRdata of 26 were made for
the first time and the results are listed in the Exper. Part. Compound 27 was identified
as 8-oxoberberine based on comparison of its spectral data with those reported [27].
Raising the reaction temperature of 508 and prolonging the reaction time to 18 h 24
gave 25, 26, and 27 in 15%, 25%, and 6% yields, respectively. The increased yield of 26
and decreased yield of 25 due to the change of reaction conditions might indicate that
26 is derived from 25. Indeed, in support of this proposal, treatment of 25 under such
reaction conditions (3.3 equiv. ISB, MeCN/H2O 9 :1, 508, 18 h) yielded 26 as the major
product (37%) along with 27 (5%) and 28 (14%) as byproducts. Compound 28 was
1
recognized as 13-hydroxy-8-oxoberberine, as evidenced by its H-NMRspectrum,
which revealed only four aromatic proton signals, two s and one AX system in the
aromatic region, and by comparison of its physical data with those reported [28].
This study provides a quick and high yielding method involving much less-toxic
reagents for the conversion of tetrahydroisoquinolines to the corresponding dihydro-

Helvetica Chimica Acta Vol. 85 (2002)
1075
Scheme 6
MeO
MeO
MeO
– +NBu4
MeO
MeO
O
I
N
N
H
N
Ph
–H+
MeO
R1
Me
Me
Me
H
3
18
H
R1
R1
R2
R2
R2
18
19
20
3
MeO
MeO
MeO
MeO
O
I
– +NBu4
Ph
MeO
MeO
N
N
N
Me
Me
OH
–H+
CH3
OH
OH
O
H
H
R1
R1
R1
R2
R2
R2
21
23
22
3
17 + 2a
Scheme 7
4
5
4
1
O
O
O
O
O
O
6
N+
O
N
8
N
8
14
O
1
14
13
13
12
O
MeO
OMe
OMe
OMe
OMe
9
9
12
11
MeO
11
25
26
24
O
O
N
O
i)
24
26 + 27 + 25
6% 15%
OMe
OMe
R
25%
i)
25
26 + 27 + 28
5%
27 R= H
28 R= OH
37%
14%
i) PhIˆO (3.3 equiv.), TBAI (10 mol-%), MeCN/H2O 9 :1, 508, 18 h.
isoquinolones, one that could be used in place of reported methods involving toxic
reagents such as mercuric acetate [29]. Its application in the oxidation of lycorine
diacetate to lycorinone diacetate, which is useful for preparing bioactive lycorine
analogues, solved the low-yield problem. This study also provides an alternative

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Helvetica Chimica Acta Vol. 85 (2002)
method for the preparation of berberal, which had been synthesized from 26 in 32%
yield by photo-oxygenation [26].
We gratefully acknowledge the National Science Council, Taiwan, R. O. C., for the support of this work
under grant NSC89-2320-B-002-272 and the postdoctoral fellowship award to O . V. S.(NSC89-2811-B-002-0137).
Experimental Part
General. Iodosylbenzene (ISB) was prepared before use by hydrolysis of iodobenzene diacetate and stored
at r.t. in the dark for a maximum of 15 d. 1-Benzyl-2-methyl-1,2,3,4-tetrahydroquinolines (16a d) and 1-
benzylidene-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (20) were synthesized according to the
literature [30]. Lycorine and berberine were obtained from our collection. TLC (silica gel) plates were
developed with CHCl3/MeOH and visualized under UV at 254 nm and with Dragendorff×s spray reagent. M.p.:
in open capillaries, Fisher-Johns melting-point apparatus, uncorrected. [a]D: JASCODIP-181 digital polar-
imeter. UV/Spectra: Hitachi 150-20 spectrophotometer; MeOH soln. FT-IRSpectra: JASCOIR Report-100
spectrophotometer; KBr pellets n in cmÀ1. 1H- and 13C-NMR: Bruker DPX-200 and AMX-400 d in ppm, J in Hz.
EI-MS: JEOL JMS-SX-102 spectrometer; 70 eV; m/z (%).
Oxidation of N-Methyl-1,2,3,4-tetrahydroisoquinolines with ISB in the Presence of TBAI: General
Procedure. TBAI (74 mg, 0.2 mmol) was added to a suspension of ISB (484 mg, 2.2 mmol) in MeCN/H2O
9 :1 (20 ml) and stirred at r.t. for 5 min. To this suspension, N-methyltetrahydroisoquinoline (1a d, 1 mmol)
was added and the resultant mixture was stirred for additional 1 1.5 h until a clear soln. was obtained. The
reaction was monitored by TLC, and, after completion, the mixture was concentrated under reduced pressure to
give a residue that was then dissolved in CHCl3 (100 ml). The CHCl3 soln. was washed with 5% aq. Na2S2O3,
H2O, and dried (Na2SO4). After removal of the solvent, the residue was purified by column chromatography
(CC; silica gel) to afford the respective N-methyl-2H-3,4-dihydroisoquinolin-1-ones (2a d) (Table 2).
7-Benzyloxy-3,4-dihydro-6-methoxy-2-methyl-2H-isoquinolin-1-one (2c). FT-IR: 1654 (CˆO, amide).
1H-NMR(CDCl 3, 400 MHz): 2.86 (t-like, J ˆ 6.8, 2 H, HÀC(4)); 3.06 (s, MeN); 3.47 (t-like, J ˆ 6.8, 2 H,
HÀC(3)); 3.85 (s, MeOÀC(6)); 5.13 (s, OCH2); 6.59 (s, HÀC(5)); 7.23 7.27 (m, HÀC(4')); 7.30 7.34
(m, HÀC(2'), HÀC(6')); 7.42 7.44 (m, HÀC(3'), HÀC(5')); 7.63 (s, HÀC(8)). EI-MS: 297 (100).
7-Acetoxy-3,4-dihydro-6-methoxy-2-methyl-2H-isoquinolin-1-one (2d). FT-IR: 1760 (CˆO, ester), 1652
(CˆO, amide). 1H-NMR(CDCl 3, 400 MHz): 2.28 (s, Me(Ac)); 2.95 (t-like, J ˆ 6.8, 2 H, HÀC(4)); 3.09
(s, MeN); 3.52 (t-like J ˆ 6.6, 2 H, HÀC(3)); 3.83 (s, MeO); 6.68 (s, HÀC(5)); 7.72 (s, HÀC(8)). 13C-NMR
(CDCl3, 100 MHz): 20.5 (q, Me(Ac)); 27.9 (t, C(4)); 35.1 (q, MeN); 48.1 (t, C(3)); 56.0 (q, MeO); 110.3
(d, C(5)); 122.4 (s, C(8a)); 122.8 (d, C(8)); 137.5 (s, C(7)); 138.6 (s, C(4a)); 153.7 (s, C(6)); 164.0 (s, C(1)); 168.9
‡
(s, CO(Ac)). FAB-HR-MS: 250.1074 ([M ‡ 1] , C13H16O4N; calc. 250.1079).
Oxidation of 1,2,3,4-Tetrahydroisoquinolines (1e, f): General Procedure. TBAI (74 mg, 0.2 mmol) was added
to a suspension of ISB (484 mg, 2.2 mmol) in MeCN (20 ml) and stirred at r.t. for 5 min. The mixture was cooled
in an ice bath and 1e or 1f (1 mmol) was added in one portion. After stirring for 10 min, the mixture was brought to
r.t. and stirred for additional 2 h. The soln. was concentrated under reduced pressure. The residue was dissolved in
CHCl3, (100 ml) washed with 5% aq. Na2S2O3 and H2O, and dried (Na2SO4). After removal of solvent under reduced
pressure, the residue was purified by CC (neutral alumina, MeOH (0 5%) in CHCl3) to afford the corres-
ponding isoquinoline (5a or 5b) and 3,4-dihydroisoquinol-1-one (4a or 4b). See Table 2 for yield and m.p. data.
Oxidation of 1,2,3,4-Tetrahydroisoquinolines (12e, f) with ISB (1 equiv.), in the Presence of TBAI: General
Procedure. To a suspension of ISB (220 mg, 1 mmol) in MeCN (10 ml) was added TBAI (37 mg, 0.1 mmol) and
the mixture was stirred at r.t. for 5 min. The reagent mixture was cooled to 08 and the tetrahydroisoquinoline (1e
or 1f, 1 mmol) was added in one portion. The reaction mixture was stirred for further 15 min and a clear brown
soln. was obtained. Under work-up and separation similar to that described above, the product 3,4-
dihydroisoquinoline (6a or 6b, resp.) was obtained.
6,7-Dimethoxy-3,4-dihydro-2H-isoquinoline (6a). Yield 176 mg (92%). 1H-NMR(CDCl 3, 400 MHz): 2.68
(t-like, J ˆ 8.0, 2 H, HÀC(4)); 3.72 (m, 2 H, HÀC(3)); 3.89 (s, MeO); 3.90 (s, MeO); 6.66 (s, HÀC(5)); 6.81
(s, HÀC(8)); 8.14 (br. s, HÀC(1)).
6,7-Methylenedioxy-3,4-dihydro-2H-isoquinoline (6b). Yield 164 mg (94%). M.p. 96 978 (96 978 [31]).
1H-NMR(200 MHz, CDCl 3): 2.63 (t-like, J ˆ 7.3, 2 H, HÀC(4)); 3.66 (dt, J ˆ 2.1, 2 H, 7.5, HÀC(3)); 5.95
(s, OCH2O); 6.61 (s, HÀC(5)); 6.73 (s, HÀC(8)); 8.14 (br. s, HÀC(1)).
Oxidation of 3,4-Dihydroisoquinolines (6a,b) with ISB and TBAI: General Procedure. TBAI (18 mg,
0.05 mmol) was added to a suspension of ISB (121 mg, 0.55 mmol) in MeCN (10 ml) and stirred at r.t. for 5 min.

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To this mixture was added the respective 3,4-dihydroisoquinoline (6a or 6b, 0.5 mmol) in one portion, and, after
stirring for 1 h at r.t., the reaction was worked up as described above to afford the respective isoquinoline (5a or
5b) and 3,4-dihydro-isoquinol-1-one (4a or 4b). The yield and m.p. data of products 4a,b and 5a,b are given in
Table 2.
Oxidation of Lycorine Diacetate (10) with ISB and TBAI. To the suspension of TBAI (37 mg, 0.1 mmol) and
ISB (308 mg, 1.4 mmol) in MeCN/H2O 9 :1 (10 ml) was added lycorine diacetate (185 mg, 0.5 mmol). The
resultant mixture was stirred at r.t. for 2 h. At the end of reaction, a clear brown soln. formed and was
concentrated under reduced pressure. After work-up similar to that described above, except with Me2CO/
toluene (5 10%) as eluent, two products, 2-acetoxyanhydrolycorine lactam (12) and (‡)-lycorinone diacetate
(11), were obtained.
Data of 11. Yield 153 mg (80%). M.p. 114 1158 (1148 [22]). [a]2D5 ‡ 60 (c 1, MeOH).1H-NMR(CDCl
400 MHz): 1.98 (s, Me(Ac)); 2.04 (s, Me(Ac)); 2.73 2.80 (m, 2 H, HÀC(4)); 2.94 3.03 (m, HÀC(15)); 3.71
,
3
3.80 (m, HÀC(5)); 4.19 (d, J ˆ 12.5, HÀC(16)); 5.24 (br. d, J ˆ 1.5, HÀC(1)); 5.57 (br. s, HÀC(2)); 5.69 (br. s,
HÀC(3)); 5.95 (s, OCH2O); 6.62 (s, HÀC(11)); 7.48 (s, HÀC(8)).
Data of 12. Yield 8 mg (5%). M.p. 248 2508 (248 508 [23]). 1H-NMR(CDCl 3, 200 MHz): 2.33
(s, Me(Ac)); 3.41 (t, J ˆ 7.8, 2 H, HÀC(4)); 4.48 (t, J ˆ 7.9, 2 H, HÀC(5)); 6.12 (s,OCH2O); 7.01 (d, J ˆ 1.7,
HÀC(3)); 7.42 (m, HÀC(1), HÀC(8)); 7.89 (s, HÀC(11)). 13C-NMR(CDCl 3, 50 MHz): 21.1 (q, Me(Ac)); 29.7
(t, C(4)); 47.0 (t, C(5)); 101.0 (s); 102.2 (t, OCH2O); 106.8 (d); 112.3 (d); 116.8 (s); 118.2 (d); 130.0 (s); 132.9 (s);
137.1 (s); 146.9 (s, C(9)); 148.8 (s, C(10)); 151.9 (s, C(2)); 160.5 (s, C(7)); 170.2 (s, AcCO). EI-HR-MS: 323.0801
‡
(M , C18H13NO5; calc. 323.0794).
Oxidation of 1-Benzyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (16a d): General Procedure. TABI (37 mg,
0.1 mmol) was added to a suspension of ISB (242 mg, 1.1 mmol) in MeCN/H2O 9 :1 (20 ml) and the mixture was
stirred at r.t. for 5 min. To this suspension was added the respective reactant (16a d, each 0.33 mmol,
corresponding to 99, 109, 125 and 119 mg, respectively), and the resultant mixture was stirred for additional
1.5 h until a clear soln. was obtained. After work-up similar to that described above, the residue was separated by
column chromatography over silica gel (10 g, 70 230 mesh), eluted by hexane-CHCl3 (1:3) and CHCl3 to
afford the aldehydes (17a, 21 mg, 60%; 17b, 27 mg, 60%; 17c, 37 mg, 70%; 17d, 41 mg, 75%) and 2-methyl-2H-
3,4-dihydroisoquinol-1-one (2a: 58 mg, 80%; 62 mg, 85%; 60 mg, 82%; 62 mg, 85%) from the respective reactant
(16a 16d).
Oxidation of 1-benzylidene-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (20). TABI (26 mg,
0.07 mmol) was added to a suspension of ISB (160 mg, 0.73 mmol) in MeCN/H2O 9 :1 (20 ml) and the mixture
was stirred at r.t. for 5 min. To this suspension was added 20 (0.33 mmol, 98 mg), and the resultant mixture was
stirred for an additional 1.5 h until a clear soln. was obtained. The reaction was worked up as described above to
afford benzaldehyde (17a, 24 mg, 70%) and 2-methyl-2H-3,4-dihydroisoquinol-1-one (2a: 59 mg, 80%).
Oxidation of Tetrahydroberberine (24) with ISB. To the suspension of ISB (145 mg, 0.66 mmol) and 24
(68 mg, 0.20 mmol) in MeCN/H2O 9 :1 (20 ml) was added TBAI (22 mg, 0.06 mmol). The mixture was stirred at
508 for 18 h, and, after a work-up procedure similar to that described above, the residue was separated by CC
(silica gel, 5 g, 70 230 mesh, 5 15% acetone in toluene, sat. with aq. NH4OH (28%), as eluent to afford
berberal (26, 19 mg, 25%), 8-oxoberberine (27, 4 mg, 6%), and berberine (25, 11 mg, 15%).
Data of 26. M.p. 151 1528 (150 1518 [26]). FT-IR: 1768 (CˆO, lactone), 1656 (CˆO, amide). 1H-NMR
(CDCl3, 200 MHz): 2.73 (t-like, J ˆ 6.5 Hz, 2 H, HÀC(5)); 2.99 (m, HÀC(6)); 3.15 (m, HÀC(6)); 3.85
(s, MeO); 3.95 (s, MeO); 6.00 (s,OCH2O); 6.58 (s, HÀC(4)); 7.12 (d, J ˆ 8.3, HÀC(11)); 7.58 (s, HÀC(1)); 7.64
(d, J ˆ 8.3, HÀC(12)); 7.96 (br. s, HÀC(8)). 13C-NMR(CDCl 3, 50 MHz): 27.8 (t, C(5)); 40.1 (t, C(6)); 56.5
(q, MeOÀC(10)); 60.7 (q, MeOÀC(9)); 82.1 (d, C(8)); 101.6 (t, OCH2O); 107.0 (d, C(4)); 108.5 (d, C(1)); 115.0
(d, C(11)); 120.6 (s, C(12a)); 121.8 (d, C(12)); 122.3 (s, C(14a)); 134.5 (s, C(4a)); 135.7 (s, C(8a)); 143.9
(s, C(9)); 147.0 (s, C(2)); 151.3 (s, C(3)); 157.2 (s, C(10)); 164.4 (s, C(14)); 168.33 (s, C(13)). HMBC (CDCl3):
HÀC(1) to C(2), C(3), C(4a), C(14), and C(14a); HÀC(4') to C(2), C(3), C(5), and C(14a); HÀC(5') to C(4),
C(4a), C(6), and C(14a); HÀC(6') to C(5), HÀC(11') to C(9) and C(12a); HÀC(12') to C(8a), C(10), and
C(13); MeOÀC(9) to C(9); MeOÀC(10) to C(10); OCH2O to C(2) and C(3). NOESY (CDCl3): HÀC(1) $
HÀC(6) $ HÀC(5); HÀC(5) $ HÀC(8) MeOÀC(9); HÀC(12) $ HÀC(11) $ MeOÀC(10); EI-HR-MS:
‡
383.0991 (M , C20H17NO7; calc. 383.1005).
1
Data of 27. M.p. 200 2018 (2008 [27]). H-NMR(CDCl 3, 400 MHz): 2.86 (t-like, J ˆ 6.0, HÀC(5)); 3.92
(s, MeO); 3.98 (s, MeO); 4.26 (t, J ˆ 6.0, HÀC(6)); 5.98 (s, OCH2O); 6.67 (s, HÀC(3)); 6.69 (s, HÀC(14)); 7.19
(s, HÀC(1)); 7.24 (d, J ˆ 8.6, HÀC(11)); 7.29 (d, J ˆ 8.6, HÀC(12)).
Oxidation of Berberine (25) with ISB. To a suspension of ISB (145 mg, 0.66 mmol) and 25 (80 mg,
0.20 mmol) in MeCN/H2O 9 :1 (20 ml) was added TBAI (22 mg, 0.06 mmol). The mixture was stirred at 508 for

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Helvetica Chimica Acta Vol. 85 (2002)
18 h. After work up similar to that described above, the residue was separated by CC (silica gel, 5 g, 70 230
mesh, eluted stepwise with 5 15% acetone in toluene, saturated with aq. NH4OH (28%)) to afford 26 (30 mg,
37%). 27 (4 mg, 5%), and 13-hydroxy-8-oxoberberine (28, 11 mg, 14%).
Data of 28. M.p. 216 2178 (216 2178 [28]). 1H-NMR(CDCl 3, 200 MHz): 2.80 (t, J ˆ 5.9, 2 H, HÀC(5));
3.96 (s, MeO); 3.98 (s, MeO); 4.18 (t, J ˆ 5.7, 2 H, HÀC(6)); 6.01 (s, OCH2O); 6.72 (s, HÀC(3)); 7.39 (d, J ˆ 9.1,
HÀC(11)); 7.72 (s, HÀC(1)); 7.86 (d, J ˆ 9.1, HÀC(12)).
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Received October 1, 2001