2
S.-B. Lin et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Examination of one-pot reaction from 10 and 6 to prepare 11.a
Scheme 1. Retrosynthetic analysis of 6-methylellipticine 3.
Entry
Base
Time (h)
Temp. (°C)
Yield (%)
1
2
3
4
Cs2CO3
KOH
KOH
12
2
5
130
130
110
80
Traceb
16b
56b
KOH
8
75b (68)c
a
Reaction conditions: 1) 10 (0.2 mmol), aminating reagent 6 (0.24 mmol), KOH
(0.24 mmol), DMSO (1 mL), 50 °C, 3 h; 2) base (0.24 mmol).
b
Yields determined by analysis of the crude mixture by 1H NMR spectroscopy.
Isolated yield.
c
Scheme 2. Synthesis of 12.
amination of 10, a key step in the total synthesis of 3, was investi-
gated under transition metal-free conditions (Table 1). When we
treated 10 with Cs2CO3 as the base (1.2 equiv) in DMSO solvent
at 130 °C, only the trace product 11 was obtained (Table 1, entry
1). Happily, the desired C–N bond-forming reaction was observed
with KOH as the base, albeit in low yield (Table 1, entry 2). Our
breakthrough came when the reaction temperature was reduced
from 130 °C to 110 °C, affording product 11 in 56% yield (Table 1,
entry 3). The further optimization on the reaction temperature
gave compound 11 in 68% isolated yield (Table 1, entry 4). After
the screening, the optimum conditions for the amination of 10
were as follows: KOH as the base and DMSO as the solvent; the
reaction was carried out at 80 °C. The N-methylation of 11 was
easy and gave 12 in 95% yield.
Recently, a novel approach to carbazoles via a direct transition
metal-free intramolecular arylation has been developed by our
group [16]. Therefore, we re-examined the reaction conditions
for the selective preparation of carbazole 13 by this reaction. At
first, A1 was used as an additive. No reaction occurred at 30 °C in
DMSO (Table 2, entry 1). To improve the reaction efficiency, other
additives were examined. We found that 1,10-phenanthroline A2
and bathophenanthroline A3 improved the conversion, but a
majority of byproduct 130 was produced at 30 °C in the same sol-
vent system (Table 2, entries 2 and 3). Then, we tested other sol-
vents in this transformation. The use of mesitylene as a solvent
still did not improve yields of 13 whether the reaction occurred
at 160 °C or 100 °C (Table 2, entries 4 and 5). Lowering the temper-
ature dramatically decreased the conversion of 12 (Table 2, entry
5). Notably, we tested bathophenanthroline, a highly active addi-
tive in benzene, giving the product 13 in 50% yield (Table 2, entry
6). Then, the use of pyridine as a solvent and 1,10-phenanthroline
as an additive afforded the desired product 13 in 63% yield (Table 2,
entry 7). Without any additive, this transformation resulted in
lower yield (Table 2, entry 8). Thus, 1,10-phenanthroline (A2,
40 mol%) and KOtBu (3.0 equiv.) in pyridine at 140 °C for 3 h were
accepted as the optimized reaction conditions.
6-methylellipticine was also from carbazole via the Vilsmeier-
Haack reaction as a key step [11,13]. Moreover, the direct methy-
lation of ellipticine has also been reported [13]. However, few
syntheses have been high-yielding and regioselective, and some
required triazene, a potential carcinogen. Most syntheses need
some transition metal catalyst. However, trace residues of the tran-
sition metal are harmful to humans and influence the results of the
bioactivity test.
Although synthetic routes to 6-methylellipticine have been
devised, a green and efficient synthetic approach is still desirable.
In recent years, numerous metal-free cross-coupling methods have
been established [14]. Our group developed a direct amination of
phenol via an alkylation-Smiles rearrangement [15] and an
intramolecular C–H bond arylation promoted by potassium tert-
butoxide [16]. Herein, a protocol for the synthesis of 6-methylellip-
ticine using commercially available 2,5-dimethyphenol as the
starting material was achieved based on our previous study. This
procedure has no need of any transition metal catalyst.
A general design of our approach to 6-methylellipticine 3 is
shown in Scheme 1. Compound 3 could be synthesized through
the direct amination of phenol 7 with aminating reagent 6, fol-
lowed by transition metal-free intramolecular direct C–H bond
arylation and cyclization of the formylated carbazole derivative 4.
Our synthesis began with commercially available 2,5-
dimethylphenol 8 through the classical procedure to afford 4-
hydroxy-2,5-dimethylbenzaldehyde 9 in 73% yield (Scheme 2)
[4r]. The benzaldehyde
9 was then subjected to iodination
reaction using iodinating reagent I2/NaOAc [1:1 in a mixture of
MeOH/H2O (1:1)], giving the desired product 7 in 86% yield [4r].
Next, the direct amination of o-iodophenol 7 was examined
according to our reported procedure [16]. Surprisingly, the conver-
sion of 7 was very low. We assumed that the formyl group of 7
hampered the direct amination of 4, because the formyl group is
sensitive to the base. We decided to protect the formyl group using
1,3-propandiol in the presence of tetrabutylammonium bromide
(TBATB) and CH(OEt)3 to afford 10 in 94% yield. Then, the direct
Then, we tried a one-pot, two-step process for the large-scale
synthesis of key intermediate 4 in total synthesis of 6-methylellip-
ticine, affording desired product 4 in 59% yield for two steps. This
Please cite this article as: S.-B. Lin, W. W. Wang, J. P. Meng et al., A transition metal-free approach to a regioselective total synthesis of the natural product
Lin, Song-Bo
