An Electrophilic Bromine Redox Catalysis for the Synthesis of Indole Alkaloid Building Blocks by Selective Aliphatic C?H Amination

Article abstract of DOI:10.1002/anie.201808939

A new homogeneous bromine(?I/I) redox catalysis is described, which is based on monomeric bromine(I) compounds containing transferable phthalimidato groups. These catalysts enable intermolecular C?H amination reactions at previously unaccessible aliphatic positions and thus enlarge the synthetic potential of direct C?N bond formation, including its application in the synthesis of alkaloid building blocks. This aspect is demonstrated by a new synthetic approach to aspidospermidine. In addition to the development of the catalyst system, the structures of the involved bromine(I) key catalysts were fully elucidated, including by X-ray analyses.

Full text of DOI:10.1002/anie.201808939

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Accepted Article
Title: An Electrophilic Bromine Redox Catalysis Manifold for Indole
Alkaloid Building Blocks from Selective Aliphatic C-H Amination
Authors: Kilian Muniz, Julien Berges, and Belen Garcia
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808939
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10.1002/anie.201808939
Angewandte Chemie International Edition
COMMUNICATION
An Electrophilic Bromine Redox Catalysis Manifold for Indole
Alkaloid Building Blocks from Selective Aliphatic C-H Amination
Julien Bergès,[a] Belén García[a] and Kilian Muñiz*[a,b]
Dedication ((optional))
Abstract: A new homogeneous bromine(-I/I) redox catalysis is
described, which is based on monomeric bromine(I) compounds
containing transferable phthalimidato groups. These catalysts enable
intermolecular C-H amination reactions at previously unaccessible
aliphatic positions and thus enlarge the synthetic potential of direct
C-N bond formation including its application in alkaloid building block
synthesis. This aspect is demonstrated for a new synthetic approach
to aspidospermidine. In addition to the catalysis development, the
structures of the involved bromine(I) key catalysts were fully
elucidated including X-ray analyses.
sometimes
troublesome.
For
complimentary
reaction
development, we focused on phthalimide as a more promising
candidate due to its established character as convenient,
oxidation compatible ammonia surrogate.[9]
N
N
N
E
D
D
D
E
E
A
C
A
C
A
C
B
N
B
N
H
B
H
F
N
H
H
G
H
O
O
Tubifolidine
Strychnine
Aspidospermidine
+ HNR'2
The strychnos alkaloid family and the aspidosperma alkaloid
family are prominent classes of complex alkaloid compounds
that have a fascinating history of biological, pharmacological and
medicinal application (Figure 1).[1,2] A common core structure
with respect to their A,B and C ring system is represented by the
4-amino tetrahydrocarbazole unit. Surprisingly, efficient synthetic
approaches to this class of nitrogenated compounds have so far
not been elaborated. We considered the C-H amination of
tetrahydrocarbazoles the logic strategy to this class of
compounds, for which only a single example of within rhodium-
nitrene catalysis had been reported previously.[3] In turn,
tetrahydrocarbazoles are readily accessible from Fischer indole
syntheses,[4] thus opening broad possibilities for structural
variations.
R'2N
H
C
A
[D, E ring
disconection]
[C-H amination]
B
N
R
N
R
(S)-2,3,4,9-tetrahydro-
1H-carbazol-4-amine
Figure 1. Representative members of the strychnos and aspidosperma
families and retrosynthetic analysis to the 4-amino tetrahydrocarbazole core.
Iodine(III) reagents incorporating phthalimide[10] are quite rare
with respect to structural characterization. The synthesis of
PhI(NPhth)2 (Phth = phthaloyl) by Varvoglis stands out,[11]
although the compound has been considered of limited stability.
Minakata reported a more readily available iodine(III) derivative
for the amination of activated C-H bonds.[12] We have
reinvestigated the synthesis of PhI(NPhth)2 1 and have arrived at
an optimized protocol for gram-scale synthesis that generates 1
under convenient conditions and allows to generate crystals for
its X-ray analysis (Table 1).[13,14] Attempted sole use of 1 in the
amination of tetrahydrocarbazoles did not proceed. To overcome
this lack in reactivity, we turned to halide catalysis (Table 1). For
the case of tetrahydrocarbazole 3a, clean aliphatic C-H
amination to the corresponding product 4a was accomplished
upon addition of a catalytic amount of tetrabutylammonium
iodide (40% isolated yield, entry 1). Directly from the outset, the
reaction proceeded with complete regioselectivity in favor of the
We here report a novel catalytic C(sp3)-H amination of fused
indoles under complete regioselectivity control and its
application to alkaloid synthesis. The underlying methodology is
based on an electrophilic homogeneous bromine catalysis. It
significantly expands the synthetic arsenal for catalytic
intermolecular C-H to C-N bond conversion, which is a field with
a development still significantly behind the more conventional C-
H
oxygenation.[5] Recent methodology development in
homogeneous oxidation has introduced environmentally benign
bromine redox catalysis, which has accounted for a series of
unique amination reactions.[6,7]
Our interest in developing intermolecular amination reactions
based on the iodine(III) methodology led us to explore the
reaction of preformed bissulfonimido iodine(III) reagents,[8a]
which have provided an unparalleled high scope in C-N bond
formation.[8b] Although the bissulfonimido group represents an
excellent nitrogen source, conversion to the free amine is
4-position of the annelated ring. This is
a noteworthy
accomplishment since related reactions usually proceed with
preferential C-H bond functionalization at the 1-position.[3,15,16]
However, substrate degradation was observed due to the
background oxidation of the free indole core by the iodine(III)
reagent 1. While the Boc-protected substrate did not provide the
desired amination product (entry 2), the N-methylated substrate
5a readily formed the amination product 6a in 71% isolated yield
(entry 3). Formation of second minor regioisomeric product was
observed under these conditions, which could be suppressed
when conducting the reaction at 40 ºC, although at the expense
of a loss in yield (entry 4). As an unusual result, the iodine
[a]
[b]
Prof. Dr. K. Muñiz, Dr. J. Bergès, Dr. B. García,
Institute of Chemical Research of Catalonia (ICIQ),
The Barcelona Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
Prof. Dr. K. Muñiz
ICREA, Pg. Lluís Companys 23, 08010 Barcelona (Spain)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201808939
Angewandte Chemie International Edition
COMMUNICATION
catalysis[17] was outperformed by the corresponding bromine
catalysis. The initial investigation with tetrabutylammonium
bromide provided a rapid reaction that was completed in one
hour, although minor amounts of regioisomeric by-product were
obtained (entry 5). Lowering the temperature to 40 ºC provided
pure 6a in 83% isolated yield (entry 6), and the unprotected N-H
group of the indole core was equally tolerated (entry 7). Further
exploration using different tetraalkylammonium sources
identified bis(n-octadecyl)dimethylammoniumbromide as the
optimum catalyst source providing 4a and 6a in 75 and 91%
isolated yield, respectively (entries 8-10).
substitution. Several additional observations are noteworthy: first,
the reaction proceeds readily with various substituents at
different positions of the arene of the indole group (products 4b-
g and 6b-g). It further tolerates different aliphatic ring sizes as
demonstrated for the cyclopenta[b]indole example 4k and the
important cyclohepta[b]indoles 4l,6l comprising seven-
membered ring annelation.[18] The stereochemistry at the newly
generated C-N bond can be influenced by neighboring
substituents next to the reactive methylene position. While a
diastereomeric ratio of 3:1 is obtained for a methyl substituent in
t
6m/6m’, larger substituents such as butyl and phenyl produce
products 6n and 6o with excellent selectivities of > 99:1 d.r.
Table 1. Halogen-catalyzed C-H amination: optimization.
PhthN
(n-C18H37)2(CH3)2N-Br
Al
Ar
(20 mol%)
Al
Ar
PhI(NPhth)2 1 (1.2 equiv)
N
R
N
R
CH3CN, 40 ºC, 12 h
3a-l (R = H),
5a-o (R = Me)
7a (R = Bn)
4a-l, 6a-o, 8a
PhthN
PhthN
PhthN
F
Cl
N
R
N
R
N
R
4a (R = H): 78%
6a (R = Me): 91%
8a (R = Bn): 65%
4b (R = H): 72%
6b (R = Me): 89%
4c (R = H): 68%
6c (R = Me): 65%
4a (X-ray)
PhthN
PhthN
PhthN
PhthN
Br
Me
MeO
Temp.
[º C]
Yield
[%][a]
Entry
R
Catalyst
Time [h]
N
R
N
R
N
R
N
R
1
2
3
H (3a)
Boc
Bu4NI
Bu4NI
Bu4NI
70
70
70
12
12
12
40 (6a)
Me
4d (R = H): 67%
6d (R = Me): 65% 6e (R = Me): 72% 6f (R = Me): 64%
4e (R = H): 72%
4f (R = H): 70%
4g (R = H): 65%
6g (R = Me): 55%
0
O
O
71[b] (6a)
PhthN
Me
NPhth
PhthN
Me (5a)
O
N
[b]
4
Me (5a)
Me (5a)
Me (5a)
H (3a)
Bu4NI
40
70
40
40
40
40
40
12
1
53 (6a)
N
R
N
N
R
Me
R
70 (6a) [b]
83 (6a)
6i (R = Me): 82%
6h (R = Me): 71%
5
Bu4NBr
4j (R = H): 43%
NPhth
PhthN
6
Bu4NBr
12
12
12
12
12
7
Bu4NBr
57 (4a) [c]
87 (6a) [c]
75 (4a)[c]
91 (6a)[c]
N
N
R
R
8
Me (5a)
H (3a)
Oct4NBr
4k (R = H): 55%
4l (R = H): 71%
6l (R = Me): 77%
9
(C16H33)2Me2NBr
PhthN
PhthN
PhthN
PhthN
Ph
Me
+
Me
tBu
10
Me (5a)
(C18H37)2Me2NBr
[a] Estimated yield by 1H NMR of the crude reaction product. [b] Regioisomer
observed. [c] Isolated material after purification.
N
Me
N
Me
N
Me
N
Me
6o: 72%,
> 99:1 d.r
6n: 85%,
> 99:1 d.r
6m/6m’: 3:1 d.r., 68%
Under the determined optimum conditions, the reaction is
general as observed for a total of nine examples 3a-i with free
NH group and thirteen examples with protected indol core 5a-l
and 7a (Scheme 1). In particular, the successful examples of
Scheme 1. Selective 4-amination of tetrahydrocarbazoles: Scope.
substrates
3 are remarkable as unprotected indoles are
The present reaction adds to the still very limited number of
bromine-catalyzed oxidative amination reactions.[6,7] Although
the stability of homogeneous bromine oxidation catalysts had
been called into question[7a] the present method suggests that
bromine(-I/I) catalysis constitutes a versatile concept for future
notoriously difficult substrates in catalytic oxidation. The
naturally occurring N-methyl motif is also fully tolerated as
demonstrated for substrates 5. The successful reaction on
benzyl derivative 7a introduces readily removable alkyl
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10.1002/anie.201808939
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developments in oxidation catalysis. Regarding the underlying
structural background, ammonium bromides R’4NBr were
oxidized by 1 to the corresponding bromine(I) compounds
R’4N[Br(NPhth)2] 9 (Scheme 2).[13,14] This constitutes novel
bromide R’4NBr by the iodine(III) reagent 1. The resulting
bromine(I) catalyst 9 engages in alkene oxidation at the indole
core to provide the intermediary ion pair A. Phthalimide base-
controlled elimination provides the regioselectivity upon
generation of Michael acceptor B that adds phthalimide to form
the C-H amination products 4,6,8. The formally liberated
N
access to these compounds, which is corroborated through
alternative complex formation between tetraalkylammonium
amides and N-bromo amides.[13,19,20] Both compounds 9 were
structurally fully characterized including X-ray analyses,[13] and
hydrogen
bromide
undergoes
anion
exchange
with
tertraalkylammonium phthalimide to regenerate the pre-catalyst
state R’4NBr.
N
the superior catalyst 9b is depicted in Scheme 2. In a
H
H
stoichiometric control reaction, is
olated bromine(I) 9b generates 6a in 95% isolated yield
confirming that this Br compound represents the active catalyst
from Table 1, entry 10. This is the first successful example of a
complex bromenium derivative with amidato substituents as an
active catalyst in C-H oxidation.
H2N
PhthN
N2H4 H2O
(1)
THF/CH3OH (3/2)
25 ºC, 12 h
N
R
N
R
10a 95%
10b 97%
6a (R = CH3)
8a (R = Bn)
R2N
HN
X
n
(2)
(3)
N
H
N
H
HO
(n-C18H37)2(CH3)2N-Br
(20 mol%)
recovered 3z
PhI(NPhth)2 1 (1.2 equiv)
CH3CN, 40 ºC, 12 h
N
H
3z
Scheme 3. Conditions for phthalimide deprotection (1), retrosynthesis
approach (2) and unreactive neopentylic position (3).
The deprotection of the phthalimide moiety to primary amino
derivatives 10a,b is straightforward (Scheme 3, eq. 1). This
aspect led us to consider the retrosynthesis of aspidospermidine
through a D ring construction by a C-H amination followed by an
appropriately engineered intramolecular substitution reaction
(eq. 2). However, upon exploration of the model substrate 3z, it
was discovered that the desired C-H amination reaction did not
proceed at the neopentylic position, and only starting material
was recovered (eq. 3).
Scheme 2. Synthesis of monomeric phthalimidato bromenium catalysts 9a,b
with defined Br-N bonds.
PhI(NPhth)2
PhI
1
R'4N[Br(NPhth)2]
R'4NBr
The
synthesis
of
aspidosperimidine
from
9
tetrahydrocarbazole C-H amination was therefore realized within
an intramolecular transformation (Scheme 4). Gratifyingly,
elaboration of 4-(ethoxycarbonyl)cyclophexanone 11 including a
final Fischer indole synthesis generated tetrahydrocarbazole
12.[13] Subsequent cyclization under bromine catalysis
proceeded with the anticipated regioselectivity to provide the
desired tetracycle 13 in 65% as a single diastereomer, which
was structurally confirmed by X-ray analysis.[14] Removal of the
nosyl group under standard Fukuyama conditions to 14[21] was
followed by derivatization to the α-chloro acetamide 15, which
yielded aspidospermidine 16 as previously reported.[22] This
successful approach to aspidospermidine demonstrates that
halide-based oxidation methodology can provide innovative
solutions to the selective C-H amination of elaborated
hydrocarbon frameworks.
3, 5 or 7
HNPhth
R'4N-
NPhth
R'4N-NPhth
Br
HBr
N
R
NPhth
A
NPhth
N
R
4,6 or 8
B
Figure 2. Bromide-catalyzed C-H amination: mechanistic context.
We propose the following catalytic cycle for the new
halogen-catalyzed C-H amination reactions (Figure 2): The
reaction starts with the oxidation of the tetraalkylammonium
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10.1002/anie.201808939
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characterization and catalytic application of phthalimide-
containing bromine(I) centers and have developed their
performance as catalysts in a new series of C(sp3)-H amination
reactions with unusual position-selectivity, which has proven
useful for alkaloid building block synthesis. The new Br(-I/I)
redox manifiold was applied successfully to the synthesis of
aspidospermidine.
[13] See Supporting Information for details.
[14] X-ray crystallographic data for compounds 1, 4a, 7, 9a, 9b, 13 and 17
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Keywords: C–H bond amination • bromine catalysis •
homogeneous catalysis • iodine(III) reagents • natural products
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Entry for the Table of Contents
COMMUNICATION
J. Bergès, B. García, K. Muñiz*
Page No. – Page No.
An Electrophilic Bromine Redox
Catalysis Manifold for Indole Alkaloid
Building Blocks from Selective
Aliphatic C-H Amination
New Aces in the Game: Green halogen catalysis provides the winning cards in C-
H amination of tetrahydroindoles.
New Bromine Redox Catalysis: A novel C-H amination can be conveniently accomplished within a
unique Br(-I/I) catalyst manifold, which opens versatile access to alkaloid building block synthesis.
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