A Copper-Catalyzed Aerobic [1,3]-Nitrogen Shift through Nitrogen-Radical 4-exo-trig Cyclization

Article abstract of DOI:10.1002/anie.201709894

A novel radical [1,3]-nitrogen shift catalyzed by copper diacetate under an oxygen atmosphere (1 atm) has been developed for the construction of a diverse range of indole derivatives from α,α-disubstituted benzylamine. In this reaction, oxygen was used as a clean terminal oxidant, and water was produced as the only by-product. Five inert bonds were cleaved, and two C?N bonds and one C?C double bond were constructed in one pot during this transformation. This unique method demonstrated broad application protential for the late-stage modification of biologically active natural products and drugs. Mechanistic investigations indicate that a unique 4-exo-trig cyclization of an aminyl radical onto a phenyl ring is involved in the catalytic cycle.

Full text of DOI:10.1002/anie.201709894

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Accepted Article
Title: Copper-Catalyzed Aerobic [1,3]-Nitrogen Shift via Nitrogen
Radical 4-Exo-Trig Cyclization
Authors: Xi-Sheng Wang, Yan Li, Rui Wang, Tao Wang, Xiu-Fen
Cheng, Xin Zhou, and Fan Fei
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709894
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10.1002/anie.201709894
Angewandte Chemie International Edition
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Copper-Catalyzed Aerobic [1,3]-Nitrogen Shift via Nitrogen
Radical 4-Exo-Trig Cyclization
Yan Li†, Rui Wang†, Tao Wang, Xiu-Fen Cheng, Xin Zhou, Fan Fei and Xi-Sheng Wang*
Abstract: A novel radical [1,3]-nitrogen shift catalyzed by copper
diacetate under 1 atm of oxygen atmosphere for the construction of a
diversity of indole structure motifs from α,α-disubstituted benzylamine
has been developed, in which oxygen was used as a clean terminal
oxidant and water was produced as the only byproduct. Of particular
note is five inert bonds were cleaved, and two C-N bonds and one C-
C double bond were constructed in one pot during this transformation.
This unique method demonstrated broad application prospect for late-
stage modification of biologically active natural products and drugs.
Mechanistic investigations indicate that a unique 4-exo-trig cyclization
of an aminyl radical to phenyl ring was involved in the catalytic cycle.
will stabilize the in situ-generated carbon radical and release the
strain of four-membered ring formed via retro-[4π]
electrocyclization, thus driving the sequential transformation to
afford some unique products (Scheme 1).
Because of the highly reactive nature of the radical species,
cascade radical reaction has long been realized as a powerful
Table 1. Copper-catalyzed [1,3]-nitrogen-shift: optimization of conditions[a]
Free radical reactions have been widely utilized in diverse areas
of organic chemistry for the past three decades or so.1 However,
most of their applications were focused on carbon-based radicals,
while heteroatom-centered radicals, such as nitrogen-centered
radicals,2 have attracted much less attention than they deserve
compared with their synthetic potential. The intramolecular free
radical attack on unsaturated acceptor groups has long been
realized as one of the most powerful strategies for facile synthesis
of organic ring compounds. The construction of four-membered
rings is still very difficult so far because of the big strain in such
small rings and the resulting faster reverse ring opening process.3
To the best of our knowledge, there was only one report that
nitrogen-centered radical could undergo 4-exo cyclization to
afford β-lactams, albeit in very low yield and with acyclic products
via 1,3-hydrogen shift as the major product4 (Scheme 1). We
envisioned that the replacement of the double bond with aryl ring
Entry
1
Cu(OAc)2 (mol%)
Additive (equiv.)
-
t (h)
12
12
12
12
12
12
24
24
24
24
24
24
24
30
30
30
30
30
30
Yield (%)[b]
32
10
10
10
10
10
10
10
10
10
10
10
10
20
20
20
20
20
0
2
AgOAc (2)
Trace
Trace
Trace
Trace
Trace
52
3
K2S2O8 (2)
4
Ce(SO4)2·4H2O (2)
TBHP (2)
5
6
Selectfluor (2)
-
7
8
Et3N (0.2)
64 (54)
45
9
TMEDA (0.1)
Li2CO3 (2)
10
11
12
13
14
15
16[c]
17[d]
18[d]
19[d,e]
64
MgSO4 (1.5)
64
Et3N (0.4)
66 (58)
70 (64)
74
Et3N (0.8)
Et3N (0.8)/MgSO4 (1.5)
Et3N (0.8)/Na2SO4 (1.5)
Et3N (0.8)/MgSO4 (1.5)
Et3N (0.8)/MgSO4 (1.5)
Et3N (0.8)/MgSO4 (1.5)
Et3N (0.8)/MgSO4 (1.5)
Scheme 1. N-centered radical 4-exo-trig cyclization.
25
89
[*]
Dr. Y. Li, R. Wang, T. Wang, X.-F. Cheng, X. Zhou, F. Fei, Prof. Dr.
X.-S. Wang
95
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026, China
0
20
75
E-mail: xswang77@ustc.edu.cn
These authors contributed equally to this work.
[†]
[a] Reaction conditions: 1a (0.2 mmol), Cu(OAc)2, O2 (1 atm), toluene (2 mL),
130 °C. [b] GC yield. Isolated yield in parentheses. [c] 140 °C. [d] 150 °C. [e] Air
(1 atm).
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201709894
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COMMUNICATION
synthetic method to construct complex skeletons in organic
synthesis.5 While various carbon-centered radicals have been
widely used in intramolecular cascade cyclizations to construct
polycylics in total synthesis of natural products,6 only a few of
successful N-centered radical driven cascade reactions have
been reported,7 probably due to the lack of convenient generation
approach of such kind of nitrogen radicals. Moreover, the initiation
of these N-radical cascades were still limited to the addition of
radical to C-C double/triple bonds or [1,5]-hydrogen atom transfer,
the applications to other types of radial acceptor were scarce and
needed to be urgently exploited. Herein, we report copper-
catalyzed aerobic cascade reactions for the synthesis of
polysubstituted indoles from the benzylic amine, via a unique 4-
exo cyclization of aminyl radical to aryl ring with oxygen as the
clean terminal oxidant.8 The overall transformation produces
water as the only byproduct. Multiple inert bonds are cleaved9 and
several new bonds are constructed effectively in one pot.
Table 2. Copper-catalyzed [1,3]-nitrogen-shift: substrate scope[a,b]
Our study was initiated with N-methyl-2,2-diphenylethylamine
(1a) as the pilot substrate in the presence of a catalytic amount of
Cu(OAc)2 (10 mol%). While other oxidants gave only trace
amount of the desired product (Table 1, entries 2-6), to our delight,
1-methyl-3-phenylindole (2a) was obtained smoothly in 32% yield
in the presence of 10 mol% of Cu(OAc)2 in toluene under an
oxygen atmosphere (1 atm) at 130 ºC for 12 h (Table 1, entry 1).
Moreover, prolonging the reaction time to 24 hours could increase
the yield effectively to 52% (entry 7). To improve the yield further,
we next examined different ligands. While most of the other
ligands gave no enhancement (for details, see supporting
information), the use of Et3N led to a slight increase in yield (entry
8). Meanwhile, increasing the amount of Cu(OAc)2 to 20 mol%
resulted also in a little higher yield (entry 13). We envisioned that
two mole equivalents of water molecules might be produced
during the transformation, so MgSO4 was added to the reaction
system as a water scavenger. The yield was increased slightly
(entry 11). Intriguingly, byproducts were reduced dramatically and
excellent yield was obtained after raising the reaction temperature
to 150 ºC when Et3N and MgSO4 were added simultaneously
(entry 17). Moreover, the control experiments indicated that no
desired product was obtained in the absence of Cu(OAc)2 (entry
18), and the yield decreased to 75% using air in place of oxygen
as the terminal oxidant (entry 19).
With the optimized reaction conditions in hand, we next moved on
to examine the substrate scope for this radical cascade reaction.
A great variety of α,α-substituted benzylamines, as showed in
Table 2, were subjected to the aerobic copper-catalyzed nitrogen-
shift reaction system, giving the corresponding indoles smoothly
with satisfied yields (up to 98%). Initially, the investigation of N-
protecting groups revealed that N-ethyl-substituted substrate 1b
gave almost the same yield, while electron-withdrawing group-
protected benzylamines failed to afford the desired products.
Interestingly, free benzylamine 1c could also be cyclized to form
the desired indole, albeit with a low yield due to the decomposition
of the starting material. Next, the investigation of substituent
effects showed that both electron-donating groups (Me, OMe) and
electron-withdrawing groups (F, Cl, Br, CF3) on the phenyl ring
were well tolerated in this catalytic system. Of note is the
presence of halogen atoms (F, Cl and Br) in the products (2g, 2h,
[a] Reaction conditions: 1 (0.2 mmol), Cu(OAc)2 (0.04 mmol, 20 mol%), Et3N
(0.16 mmol, 80 mol%), MgSO4 (0.3 mmol, 1.5 equiv.) O2 (1 atm), toluene (2 mL),
150 °C, 30 h. [b] Isolated yield. [c] 36 h. [d] 140 °C. [e] 24 h. [f] Reaction
conditions: 1 (0.2 mmol), Cu(OAc)2 (0.06 mmol, 30 mol%), Et3N (0.24 mmol,
120 mol%), Na2SO4 (0.3 mmol, 1.5 equiv.) O2 (1 atm), PhCF3 (4 mL), 135 °C,
36 h. [g] Catalyzed by copper bis(2-ethylhexanoate) (Cu(EH)2, 30 mol%) without
Et3N. [h] 15 h. [i] 12 h. [j] 20 h. [k] 18 h.
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10.1002/anie.201709894
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Scheme 2. Synthetic application for modification of biologically active molecules.
2s) offers tremendous synthetic potential for a wide range of
indole derivatives by transition-metal-catalyzed cross-coupling
reactions. Remarkably, unsymmetric biaryl substrate 1k worked
Furthermore, loratadine, a medication used to treat allergies, had
also been installed with benzylamine and subjected into this
protocol, furnishing indole-derived loratadine 4d successfully as
also well in this catalytic system (2k and 2k’, 80% combined yield). the major product (Eq. D). Notably, starting from the natural
Although a mixture of two products resulting from cyclization
occurred on either of the aryl rings was obtained, these isomers
could easily be isolated by column chromatography. Moreover,
meta-substituted diarylethylamine (1e) gave a mixture of two
expected regioisomers and functionalization occurred at the less
hindered positions slightly preferentially (2e, C2/C6 = 1.8/1). The
substrates with a variety of α-substituents were also examined.
Therefore, ethyl and ethoxymethyl-substituted benzylic amines
could be transformed to 2-methyl (2i) and 2-ethoxy (2j) indoles in
91% and 76% yield. Importantly, diphenyl-aza-cycloalkanes
afforded the corresponding tricyclic dihydropyrrolo- (2l),
tetrahydropyrido- (2m), and tetrahydroazepino-[1,2-a]indole (2n)
in 52%, 85% and 60% yield, respectively. Of note is that dialkyl
benzylic amines gave relatively lower yields, which probably
caused by the oxidation of 3-methyl group in indole products.
Finally, spiro-cyclohexyl and spiro-cyclopentyl benzylamines
could also furnished tricyclic tetrahydrocarbazole (2v) and
tetrahydrocyclopenta[b]indole (2w) in 50% and 44% yield,
respectively.
product cholestan-3-one, seven-member cyclic amine was
obtained in 3 steps as a mixture (3e : 3f = 1.3/1), which was further
converted to totally new indole-containing polycyclic 3-aza-
cholestanones in 67% and 50% yield, respectively (Eq. E). Given
that α,α-disubstituted benzylamines could be made via various
methods, our newly developed protocol demonstrated a unique
approach to modify complex molecules to its indole-containing
derivatives via late-stage functionalization.
Scheme 3. Isolation and transformation of intermediate.
Since the vinyl product 5d was obtained along with indole-
containing product 4d as a byproduct (Eq. D, Scheme 2), it was
speculated that 5d might serve as the key intermediate during this
transformation. As expected, reinvestigation of the model reaction
showed N-methyl-(phenylvinyl)aniline 5a was isolated in 8% yield
along with the normal product 2a when the reaction time was
shortened to 5 hours. The subjection of 5a to the standard
conditions gave desired indole 2a in quantitative yield (Scheme
3), which demonstrated the existence of intermediated 5a that
To demonstrate the functional group tolerance and inherent
synthetic value of this method, several benzylamine derivatives
installed with different key motifs in biologically active molecules
has been tested in our catalytic system. As shown in Scheme 2,
glucose, amino acid, and 2’-deoxyuridine were all well compatible
with this reaction to afford the desired products (4a-4c) with
moderate yields (Eqs. A-C), albeit with higher catalyst loading,
presumably for the multi-heteroatom skeletons in these molecules
might ligate the copper center to reduce its catalytic activity.
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10.1002/anie.201709894
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formed via a [1,3]-nitrogen shift from benzylamine 1a in the
catalytic cycle.
reconstructs the phenyl ring and yields the isolated intermediate
5a. Similarly, N-radical species F, generated via copper-promoted
oxidation, attacks the carbon-carbon double bond via 5-endo
cyclization to give the aza-five-membered ring radical G. Indole
2a is finally obtained after single-electron oxidation and sequential
deprotonation.
To gain more insights into the mechanism of this transformation,
a series of control experiments were then carried out. First, the
reactions were performed in the presence of 1.0 equivalent of
radical inhibitors, including 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), butylated hydroxytoluene (BHT), 5,5-dimethylpyrroline
N-oxide (DMPO), and Galvinoxyl etc. All of these reactions
formed trace or even no desired products (Eq. 1, Scheme 4).
These results indicated that this cascade reaction may proceed
via a radical pathway. Inspired by Newcomb’s research on radical
clock,10 vinyl cyclopropane 6a has been designed to capture the
nitrogen-centered radical. However, the radical ring opening
product 7a was observed in GC-MS but not isolated-available,
probably because of its instability. Accordingly, we decided to
simplify the substrate by changing R group from phenyl to methyl.
Just as we expected, 7b was successfully obtained albeit with
only 10% yield, which showed the aminyl radical was involved in
the catalytic cycle (Eq. 2). It is worth noting that 7b decomposed
under the standard conditions, which distinctly indicated why the
radical ring opening products 7a and 7b were difficult to obtain.
Lastly, crossover experiments with 1b and 1d were performed
under the standard conditions. This reaction afforded indoles 2b
and 2d, and no crossover products were observed, which clearly
showed that only intramolecular [1,3]-nitrogen shift reaction
happened during the transformation (Eq. 3).
Scheme 5. Proposed mechanism.
In summary, we have developed a novel radical [1,3]-nitrogen
shift catalyzed by copper diacetate under 1 atm of oxygen
atmosphere for the construction of a diversity of indole structure
motifs from α,α-disubstituted benzylamines, in which a unique 4-
exo-trig cyclization of nitrogen-centered radical to phenyl ring was
involved in the catalytic cycle. Of particular note is that two C(sp3)-
H bonds, one C(sp2)-H bond, and one C-N bond were cleaved,
and two C-N bonds and one C-C double bond were constructed
in one pot during this transformation. This novel method
demonstrated broad application prospect for late-stage
modification of biologically active natural products and drugs.
Further efforts to elucidate the detailed mechanism and develop
more new transformations with this strategy is currently underway
in our laboratory.
Acknowledgements
We gratefully acknowledge the Strategic Priority Research
Program of the Chinese Academy of Sciences (Grant No.
XDB20000000), the National Basic Research Program of China
(973 Program 2015CB856600), the National Science Foundation
of China (21602213, 21522208, 21372209), the Fundamental
Research Funds for the Central Universities (WK2060190046) for
financial support.
Scheme 4. Mechanistic studies.
On the basis of all the results mentioned above and the work
reported before, a plausible mechanism via a radical [1,3]-
nitrogen shift is depicted, as shown in Scheme 5. The catalytic
cycle is initiated by copper-promoted oxidation of the secondary
amine to generate nitrogen-centered radical A. The unique 4-exo-
trig cyclization of aminyl radical A to the phenyl ring affords aza-
four-membered ring radical B. Single-electron oxidation of radial
B and subsequent proton removal would lead to cyclic amine D.
Subsequently, retro-[4π] ring-opening and [1,5]-H shift
Keywords: copper-catalyzed • nitrogen-centered radical • 4-
exo-trig • cascade reaction • nitrogen shift
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10.1002/anie.201709894
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Yan Li†, Rui Wang†, Tao Wang, Xiu-Fen
Cheng, Xin Zhou, Fan Fei and Xi-Sheng
Wang*
Page No. – Page No.
A novel radical [1,3]-nitrogen shift catalyzed by copper diacetate under 1 atm of
oxygen atmosphere for the construction of a diversity of indole structure motifs from
α,α-disubstituted benzylamine has been developed, in which oxygen was used as a
clean terminal oxidant and water was produced as the only byproduct. Of particular
note is five inert bonds were cleaved, and two C-N bonds and one C-C double bond
were constructed in one pot during this transformation. This unique method
demonstrated broad application prospect for late-stage modification of biologically
active natural products and drugs. Mechanistic investigations indicate that a unique
4-exo-trig cyclization of an aminyl radical to phenyl ring was involved in the catalytic
cycle.
Copper-Catalyzed
Nitrogen Shift via Nitrogen Radical 4-
Exo-Trig Cyclization
Aerobic
[1,3]-
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