Iodine-mediated regioselective C2-amination of indoles and a concise total synthesis of (±)-folicanthine

Article abstract of DOI:10.1039/c2cc16637b

Highly substituted 2-aminated indoles can be prepared in moderate to excellent yields by regioselective C2-amination of indoles promoted by iodine. As a key step in a concise synthesis of (±)-folicanthine, its core structure was easily obtained by one step cyclization-dimerization of substituted tryptophan in high yield on a gram scale. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2cc16637b

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COMMUNICATION
Iodine-mediated regioselective C2-amination of indoles and a concise
total synthesis of (ꢀ)-folicanthinew
Ying-Xiu Li, Hai-Xi Wang, Shaukat Ali, Xiao-Feng Xia and Yong-Min Liang*
Received 26th October 2011, Accepted 5th January 2012
DOI: 10.1039/c2cc16637b
Highly substituted 2-aminated indoles can be prepared in moderate
to excellent yields by regioselective C2-amination of indoles
promoted by iodine. As a key step in a concise synthesis of
(ꢀ)-folicanthine, its core structure was easily obtained by one
step cyclization–dimerization of substituted tryptophan in high
yield on a gram scale.
Indole is a privileged structural motif found in many clinically
used therapeutic drugs1 and natural products.2,3 Hence, there
Fig. 1 Some indole natural products with diverse pharmacological
properties.
is a continuing interest in reactions that allow for direct indole
functionalization. Among them, the direct formation of C–C
bonds of indole derivatives has been extensively studied.4
to give oligomeric structures. One widely explored strategy for the
synthesis of these natural products from tryptophan derivatives is
However, the direct formation of C–N bonds of indoles has
to utilize the intramolecular ring closure. Previously, Movassaghi’s
not been well studied up to now. Recently, our group developed
a Pd/Cu-catalyzed method5 for direct formation of C–N bonds
group reported a protocol for synthesis of (+)-folicanthine from
hexahydropyrroloindole. The procedure involves cyclization of
at the C2-position of indoles.
the N-methoxycarbonyl-tryptophan methyl ester to generate the
Over the past decades, many reactions have been reported
using iodine as a promoter or a catalyst.6 We have previously
tricyclic hexahydropyrroloindole and dimerization as the key
steps.11 However, the cyclization and dimerization were done in
reported the C–N bonds formation of N-protected indole
derivatives to prepare 2,30-biindoles and 4-(1H-indol-2-yl)-
morpholines.7 However, due to the structural restriction of
two distinct steps and require a stoichiometric amount of metal
complex to allow dimerization in good yield.
As part of our ongoing investigations on application of our
morpholines, 4-(1H-indol-2-yl)morpholines are difficult to
reaction, we envisioned that (ꢀ)-folicanthine could be constructed
convert into more useful derivatives of indoles. To further
starting from two molecules of 2-(1-methyl-1H-indol-3-yl)-N-
extend the scope and applicability of our reaction, we wished
tosylethaneamine 4 by applying the intramolecular version of
to develop a more useful amination reaction at the C2-position
our reaction (Scheme 2). Herein we describe a three step synthesis
of indoles. Herein, we report a successful example of iodine-
of (ꢀ)-folicanthine with an improved 50% overall yield.
induced regioselective C–N bonds formation of N-protected
We started our study by examining whether the indole 1a
indole derivatives with N-tosylbenzenamines affording 1-methyl-
could be converted into the corresponding indole derivative 3a.
N-phenyl-N-tosyl-1H-indol-2-amines.
To our delight, when K2CO3 was used as a base in acetonitrile,
Hexahydropyrroloindole alkaloids are a major class of
we found that 4-methyl-N-(1-methyl-1H-indol-2-yl)-N-(p-tolyl)-
natural products that are formally derived from tryptophan.
The alluring structure of these indole alkaloids (Fig. 1)8
benzenesulfonamide 3a could be isolated in 70% yield after 3 h
(Table 1, entry 1). In order to improve the reaction efficiency,
significant interest of synthetic chemists in their total syntheses.9
optimization studies were then performed by changing the nature
combined with their biological activities has stimulated a
of solvents (entries 8–14), bases (entries 1–7) and iodine loadings
and biologically fascinating class of natural products.10 The
(entries 15 and 16). With a series of detailed investigations, the
Polymeric tryptamine-based alkaloids belong to a structurally
reaction conditions were eventually optimized as: 0.5 mmol of 1a
vast majority of these molecules are linked through C–C bonds
and 1 mmol of 2a, 2.0 equiv. of I2, 2.0 equiv. of Cs2CO3 as base
in acetonitrile as solvent at room temperature (entry 3).
With the standard reaction conditions in hand, we then
explored the scope of the method. These conditions were
found to be compatible with a wide range of indoles and N-
tosylbenzenamines as illustrated in Table 2. The substituents
on the N-tosylbenzenamines had little effect on the reaction
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China. E-mail: liangym@lzu.edu.cn;
Fax: 0086-931-8912582; Tel: 0086-931-8912582
w Electronic supplementary information (ESI) available. CCDC
[CCDC NUMBER(S)]. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc16637b
c
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Chem. Commun., 2012, 48, 2343–2345 2343

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Table 1 Optimization of reaction conditionsa
Scheme 1 Proposed mechanism for C2-amination of indoles.7
Entry
Base
Solvent
t/h
I2 [equiv.]
Yieldb [%]
is replaced by a methyl group, HI is more easily eliminated (see
the mechanism in Scheme 1). The yields of 3o and 3p were similar
to the yields of 1,3-dimethyl-1H-indole and 1-methyl-1H-indole
substrates. After this we examined the effect of substituents on the
indolic N-atom. We found that methyl and allyl groups were well
tolerated (Table 2, products 3a–3q and 3r) but with tosyl, benzyl
groups and free N–H no reaction was observed. Furthermore,
simple tosylamide or other free amides as substrates were also
investigated. However, for the C2-amination reaction of indoles
with simple tosylamide or other free amides, no desired product 3
was observed under the standard reaction conditions. To our
disappointment, when benzofuran was subjected to the reaction
conditions, no reaction was observed.
The proposed reaction mechanism5d is shown in Scheme 1
which involves the cyclic iodonium ion A formed by coordination
of the indole double bond to an iodine cation. Anti attack by the
tosylated amino group on B and subsequent elimination of a HI
molecule in the presence of base give 2-aminated indole 3.
Encouraged by the successful intermolecular 2-amination of
N-protected indoles, the intramolecular 2-amination of N-protected
indoles was next examined. A surprising and interesting
transformation of compound 4 to skeleton 5 was observed in
one step and in excellent 90% yield. When the similar reaction
conditions were applied to N-methyl tosylated tryptophan
methyl ester, the expected dimerization product was not
obtained but only the cyclization product was recovered in
good yield. Detosylation12 and subsequent methylation13 of
compound 5 afforded (ꢀ)-folicanthine in 50% overall yield
over three steps. To our excitement, step a of our reaction
(Scheme 2) can be enlarged to a gram scale without affecting the
reaction yield. In addition, in the structure of both compound 5
and natural product (ꢀ)-folicanthine was unambiguously
confirmed through X-ray crystallography analysis.
1
2
3
4
5
6
7
8
K2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
Dioxane
DMF
Toluene
DCE
3
3
3
3
3
3
3
3
3
3
3
3
3
3
8
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0.1
1
70
Trace
84
72
68
20
80
55
50
46
41
50
51
NR
8
NaHCO3
Cs2CO3
NaOH
(CH3)3COK
NaOAc
LiOHꢁH2O
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
CH3NO2
CH3CN
CH3CN
76
a
Conditions: 0.5 mmol 1a, 1.0 mmol 2a, 1.0 mmol I2 and 1.0 mmol of
b
base in acetonitrile (2.0 mL) at room temperature. Isolated yield.
Table 2 Scope of metal-free C2-amination of indolesa,b
In order to have more insight into the mechanism of step a
in Scheme 2, TEMPO was added to the reaction mixture as a
radical scavenger. It was found that the yield of 5 was
decreased dramatically. When the amount of TEMPO was
increased to 10 equiv., the desired product was not afforded.
a
Conditions: 0.5 mmol 1a, 1.0 mmol 2a with 1.0 mmol I2, 1.0 mmol
b
Cs2CO3 in acetonitrile 2.5 mL at room temperature. Isolated yield.
(products 3b–3e), although a slightly lower yield was obtained
with disubstituted N-tosylbenzenamines (product 3c). When
the substituents on the benzene ring of N-methyl indole were
changed, moderate yields of the corresponding products were
afforded (products 3f–3i). Interestingly, the yields of 1,3-dimethyl-
1H-indole substrates (products 3j–3n) were higher than those of
1-methyl-1H-indoles and 1-allyl-1H-indoles (products 3a–3i and
3r). It may be due to the fact that when hydrogen at C3 of indoles
Scheme 2 Total synthesis of (ꢀ)-folicanthine: (a) 10 mmol 4, 20 mmol I2,
20 mmol Cs2CO3 in 25 mL acetonitrile at room temperature, 1 h, 90%
yield. (b) Sodium-naphthalenide (0.5 M), (freshly prepared sodium-
naphthalenide solution was used), 5 (122 mg, 0.19 mmol) in THF (5 mL)
at ꢂ78 1C, 56% yield. (c) Formalin (37%, 5.5 mL, 0.0734 mmol,
5.2 equiv.) sodium triacetoxyborohydride (15.6 mg, 0.0734 mmol,
5.2 equiv.), 6 (5.0 mg, 0.0145 mmol, 1 equiv.) in acetonitrile (700 mL)
at 23 1C and placed under an argon atmosphere, 99% yield.
c
2344 Chem. Commun., 2012, 48, 2343–2345
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This shows that step a most probably involves a free radical
mechanism. The experimental and theoretical study of the
exact mechanism for the transformation is in progress.
In conclusion, we have developed a highly efficient, atom-
economical, environmentally friendly and metal-free methodology
for direct C2 amination of indoles with N-tosylbenzenamines at
ambient temperature. The mild conditions permit a broad set of
functionalities both in the indoles and in the N-tosylbenzenamines
and a variety of compounds can be prepared in moderate to
excellent yields. As a key step in a concise synthesis of
(ꢀ)-folicanthine, its core structure was easily obtained by
one step cyclization–dimerization of substituted tryptophan
in high yield on a gram scale.
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We thank the National Science Foundation (NSF 21072080)
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c
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Chem. Commun., 2012, 48, 2343–2345 2345