Silver-copper co-catalyzed cascade intramolecular cyclization/desulfinamide/dehydrogenation: One-pot synthesis of substituted carbazoles

Article abstract of DOI:10.1039/c8cc03600d

Herein, a silver and copper co-catalyzed cascade intramolecular cyclization/desulfinamide/dehydrogenation reaction for the synthesis of substituted carbazoles is reported. This reaction, which involved formation of new C-C and C-N bonds as well as C-N bond cleavage, afforded diverse carbazoles in high yields and showed good functional group tolerance.

Full text of DOI:10.1039/c8cc03600d

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Silver-Copper Co-catalyzed Cascade Intramolecular
Cyclization/Desulfinamide/Dehydrogenation: One-Pot Synthesis
of Substituted Carbazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Yuanqiong Huang, Zhonglin Guo, Hongjian Song,* Yuxiu Liu, and Qingmin Wang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein, a silver and copper co-catalyzed cascade intramolecular the Cadogan cyclization6 (Scheme 1b), transition-metal-
cyclization/desulfinamide/dehydrogenation reaction for the catalyzed cyclization,7 and variants of indole-templated
synthesis of substituted carbazoles is reported. This reaction, annulation reactions.8 In addition, the use of visible-light-
which involved formation of new C−C and C−N bonds as well as mediated cyclization for carbazole synthesis was recently
C−N bond cleavage, afforded diverse carbazoles in high yields and reported.9
showed good functional group tolerance.
a) Fischer-Borsche cyclization (one step or multi steps )
The aromatic heterocycle 9H-carbazole was first isolated from
NH2
O
NH
aq. HOAc
reflux
chloranil
R2
or Pd/C
the anthracene fraction of coal tar distillate more than 100
years ago.1 The 9H-carbazole skeleton is widespread in natural
products, as well as in synthetic compounds with applications
in materials chemistry and medicine.2,3Various carbazole
derivatives have been shown to have antitumor,2i,2k
antibiotic,2d antiviral,2e and antimalarial activities.2l Specific
examples include the antipsychotic drug Rimcazole,2g the
+
R2
R1
R1
R1
N
N
R2
H
H
b) Cadogan cyclization
N
H
NO2
c) Transition-metal-catalyzed cascade cyclization of two alkynes
R1
R2
antibiotics carbazomycins
A
and
B
(isolated from
Pd or Au
R1
R2
Streptouertcillium),2d and clausine K (isolated from Clausena
excavata stem bark), which exhibits anti-HIV activity2f (Figure
N
R4
R
R
4 = H, CH3
R = N3, N(Me)2
R1 = H, alkyl, aryl, R2 = aryl
1).
Y
This work
d)
X = Y = OMe,
X
N
S
carbazomycin A
N
X = OMe, Y = OH,
carbazomycin B
antibiotics
O
R1
R1
N
H
NH
N
N
O
S
O
O
S
R2
O
R2
HN
COOH
clausine K
anti-HIV
Rimcazole
antipsychotic
O
N
O
H
Scheme 1. Approaches to Carbazole Synthesis.
Figure 1. Bioactive molecules with a 9H-carbazole skeleton.
A catalytic cascade approach is a potential alternative
with many advantages. Catalytic cascade reactions are
efficient, atom-economical, and environmentally friendly and
are increasingly being used for the direct construction of target
molecules.10-12 In particular, gold- or palladium-catalyzed
intermolecular cascade reactions between two alkynes have
emerged as effective tools for the synthesis of aryl-
annulated[a]carbazoles (Scheme 1c). Herein, we report a
protocol for the synthesis of substituted carbazoles by means
of a silver and copper co-catalyzed tandem intramolecular
Therefore, the development of methods for constructing
carbazole derivatives has attracted increasing attention in
recent years. Reported methods include the classical Fischer–
Borsche cyclization4 (Scheme 1a) and Graebe–Ullmann5 routes,
cyclization/C
(Scheme 1d).
N
bond cleavage/dehydrogenation reaction
−
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Table 1. Optimization of reaction conditions.a
various substituted arylamines could be effectively converted
to the corresponding carbazoles (2a 2l) in good yields (48–
86%). Substrates with an electron-withdrawing group (1b 1d
–
–
,
1j, and 1l) on the aromatic ring gave better yields (78−86%
yields) than substrates with an electron-donating group (1e
and 1f). The steric bulk of the aryl substituent had no influence
on the reaction (1g
–1i). Note that the halogen atoms on
Entry
Cat.
Cu(OAc)2
(mol %)
Solvent
Yieldb (%)
products 1b–1d provide opportunities for subsequent
(mol %)
2a
2a′
functionalization. The position of the aryl substituent had little
influence on the reaction outcome; specifically, Cl-substituted
products 2c and 2k were produced in essentially the same
yields. The chirality of the N-sulfinyl imine moiety had no
effect on the reaction: both (R)- and (S)-N-sulfinyl imines gave
product 2a in the same yield.
1
AgSbF6 (100)
-
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
88
-
-
2
100
100
100
100
40
20
10
20
20
20
20
20
20
20
-
3
AgSbF6 (40)
AgSbF6 (20)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgOTf (10)
AgTFA (10)
AgOAc (10)
AgBF4 (10)
PhCOOAg (10)
AgSbF6 (10)
85
80
83
79
86
82
80
-
4
-
5
-
6
-
7
-
8
0
40
80
-
9
10
11
12
13
14
-
79
-
78
0
intractable mixture
starting material
recycled
15
AgSbF6 (10)
20
dioxane
Scheme 2. Effect of the aryl substituent on the cascade reaction. aIsolated yields are
starting material
recycled
given.
16
17
AgSbF6 (10)
AgSbF6 (10)
20
20
CH3CN
toluene
intractable mixture
a Reaction conditions, unless otherwise noted:: 1a (0.2 mmol), AgSbF6 (10 mol %),
Cu(OAc)2 (20 mol %), and chloranil (0.6 equiv) in DCE (2 mL) was heated in a
microwave at 100 W for 2.5 h at 80 °C. bIsolated yields are provided.
To initiate our study, we used (E)-N-(2-(6-((tert-
butylsulfinyl)imino)hex-1-yn-1-yl)phenyl)-4-
methylbenzenesulfonamide (1a) as a model substrate (Table 1).
Reaction of 1a in the presence of 100 mol % of AgSbF6 in DCE
afforded target product 2a in 88% yield (entry 1). When 100
mol % of Cu(OAc)2 was used alone, 2a′ was the sole product
(20%, entry 2). When the reaction was carried out with both
AgSbF6 and Cu(OAc)2 (100 mol %), reducing the amount of
AgSbF6 to 10 mol % had little effect on the outcome (entries
3−5). When the amount of Cu(OAc)2 was also reduced (to 20%
mol), 2a was obtained in 86% yield (entries 6−8). No beꢀer
results were obtained when AgSbF6 was replaced with a
different silver catalyst (entries 9–13). To investigate the effect
of the solvent, we screened various solvents (entries 14–17);
compared with THF, dioxane, CH3CN, and toluene, DCE proved
to be optimal.
Scheme 3. Effect of the sulfonyl protecting group on the cascade reaction. aIsolated
yields are given. CCDC 1827723 contains the supplementary crystallographic data for 2s.
We next examined the effects of various substituted
sulfonyl protecting groups (Scheme 3). All of the tested
substrates gave the expected products (2m–2v) in moderate to
good yields (60−83%), and the structure of 2s was confirmed
With the optimal conditions in hand, we then evaluated
the substrate scope of the reaction (Scheme 2) and found that
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Scheme 5. Control experiments and proposed reaction mechanism.
by X-ray crystallography. The electronic properties of the
substituent on the sulfonyl protecting group had only a slight
effect on the reaction outcome: substrates with an electron-
donating group (1q and 1s) and with an electron-withdrawing
To obtain insight into the reaction mechanism, we
performed several control experiments (Scheme 5). When
reacted 1a with AgSbF6 and Cu(OAc)2 at room temperature
(instead of 80 °C) in the absence of chloranil gave a tandem
group (1n
group furnished good yields of the corresponding products.
Remarkably, halogenated substrates 1n 1p were also well
–1p and 1r) on the phenyl ring of the protecting
intramolecular cyclization product
be obtained in 90% yield by subjecting
conditions as mentioned above in Table 1 (Scheme 5a). This
result suggests that may be a reaction intermediate.
A
(80% yield), and 2a could
–
A
to the standard
tolerated; again, the halogen atoms allow the possibility of
further elaboration. When we changed the benzenesulfonyl
group to a thiophen-2-ylsulfonyl group, 2t was obtained in
good yield; and compounds with a methyl or cyclopropyl
sulfonyl protecting group gave expected products 2u and 2v in
60% and 65% yields, respectively.
A
Reaction with Cu(OAc)2 and chloranil under the standard
conditions in the absence of AgSbF6 afforded hydroamination
intermediate 2a′ (20% yield), and the desired product could be
obtained in 90% yield by adding AgSbF6 under the standard
conditions (Scheme 5b). This result suggests that 2a′ is also a
possible intermediate. In the absence of Cu(OAc)2, 2a was
obtained in 34% yield (Scheme 5c), which means that copper
salt can promote this reaction. When the same reaction
performed under standard conditions in the absence of
chloranil, a mixture of 2a and 2a′′ was detected by 1H NMR
(Scheme 5d). Compound 2a′′ could be converted to 2a by
adding chloranil to the reaction mixture.
Scheme 4. Scaled-up reactions and further transformations.
The reaction could easily be scaled up to 4 mmol under
the standard conditions; specifically, reaction of 1d furnished
desired products 2d in 78% yield (Scheme 4). Brominated
On the basis of the above-described experimental results,
we propose the reaction mechanism outlined in Scheme 5e.
Initially, coordination of the metal catalyst (silver or copper) to
carbazole 2d was subjected to
a palladium-catalyzed
the carbon−carbon triple bond to generate 1A, upon activation
Sonogashira cross-coupling reaction with phenylacetylene to
synthesize more-conjugated carbazole derivative 2d′ (82%
yield).
of the triple bond of substrate 1A by the metal catalyst (silver
or copper) acting as a Lewis acid, 2A is generated via a
intramolecular cyclization reaction. 2a′ is formed via a proton-
shift from the N-atom to the 3-position of the indole core with
subsequent protodemetallation of the intermediate 2A
.
AgSbF6 catalyses the intermediate 2a′ undergoes
intramolecular cyclization to the tethered imine, resulting in 4-
amino-tetrahydrocarbazole intermediate
bond cleavage and an oxidation reaction provide aromatized
product 2a
In summary, we have developed
A. Subsequent C−N
.
a
straightforward
method for accessing substituted carbazoles via a silver and
copper co-catalyzed cascade cyclization reaction. This
transformation involves the formation of new C−N and C−C
bonds and simultaneous cleavage of a C−N bond. Diverse
carbazoles were obtained in high yields, and the method
exhibited good functional group tolerance and scalability.
We are grateful to the National Natural Science
Foundation of China (21602117, 21732002, 21672117) and the
Tianjin Natural Science Foundation (16JCZDJC32400) for
generous financial support for our programs.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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