Synthesis of carbazolones and 3-acetylindoles via oxidative C-N bond formation through PIFA-mediated annulation of 2-aryl enaminones

Article abstract of DOI:10.1039/c2ob25348h

A series of carbazolone derivatives and 3-acetylindoles have been achieved via PIFA-mediated intramolecular cyclization of 2-aryl enaminones. This process allows the N-moiety on the side-chain to be annulated to the benzene ring via the metal-free oxidative aromatic C-N bond formation.

Full text of DOI:10.1039/c2ob25348h

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COMMUNICATION
Synthesis of carbazolones and 3-acetylindoles via oxidative C–N bond
formation through PIFA-mediated annulation of 2-aryl enaminones†
Xu Ban, Yan Pan, Yingfu Lin, Songqing Wang,* Yunfei Du* and Kang Zhao
Received 18th February 2012, Accepted 15th March 2012
DOI: 10.1039/c2ob25348h
give the stable 2H-azirine B,10 while the desired indole com-
A series of carbazolone derivatives and 3-acetylindoles have
pound C was not formed in this process. However, when the
cyclic enaminone D was treated with PhI(OAc)2 under identical
conditions, the formation of the aromatic C–N bond occurred to
give the carbazolone compound E. The corresponding 2H-
azirine F was not formed due to its highly strained bridged-ring
system.11 This unexpected finding revealed a complementary
route to the construction of the important carbazolone skeleton
(Scheme 1).
Although PIDA can provide the desired product in a good
yield (Table 1, entry 1), another hypervalent iodine(III) oxidant,
i.e., PIFA, was also tested since it is always taken as a more
potent hypervalent iodine(III) oxidant than PIDA. It was found
that the reaction could go to completion within a much shorter
time, affording the desired product in even better yield (Table 1,
entry 2). Both CH2Cl2 and DCE are desirable solvent for the
reaction since no obvious difference was observed (Table 1.
entries 2–3). Increasing the dosage of PIFA to 1.5 equivalents
decreased the yield due to the formation of some unidentified
by-products (Table 1, entry 4). Attempts to further improve the
yield by adding BF3·Et2O as Lewis acid or TFA as a protonic
catalyst was not successful since the reaction gave more compli-
cated mixtures, even at 0 °C (Table 1, entries 5–6). Our further
studies showed that other solvents including CH3CN, toluene,
been achieved via PIFA-mediated intramolecular cyclization
of 2-aryl enaminones. This process allows the N-moiety on
the side-chain to be annulated to the benzene ring via the
metal-free oxidative aromatic C–N bond formation.
The carbazolone unit, which can be categorized as an indole
skeleton bearing a specific cyclic ketone, is one of the most
important and abundant heterocycles in natural products.1 Fur-
thermore, substituted carbazolones are key intermediates in the
total synthesis of carbazolone alkaloids and drugs. For example,
murrayaquinone A (a HIV-integrase inhibitor), ondansetron and
alosetron (selective serotonin 5-HT3 receptor antagonists) can all
be accessed from carbazolone derivatives.2 Accordingly, many
varied methods have been reported for the construction of the
carbazolone skeleton (Fig. 1).3 The classic Fisher indole syn-
thesis is a common and important method in this area (Fig. 1,
type a).4 Heck-type coupling reactions can also be applied to the
synthesis of carbazolones starting from ortho-halo aryl enami-
nones via transition metal-catalyzed intramolecular cyclization
(Fig. 1, type b).5 Additionally, palladium-mediated cyclization
or photocyclization of aryl enaminones are also applicable routes
to carbazolones, which realize direct carbon–carbon bond for-
mation (Fig. 1, type c).6 The other approaches include the appli-
cation of reduction–cyclization of a reductive system of Fe–
AcOH to complete the cyclization of 3-hydroxy-2-(2-nitrophe-
nyl)enones (Fig. 1, type d),7 acid-catalyzed cyclization of 1H-
indole-2-butanoic acid (Fig. 1, type e)8 and oxidation of 2,3,4,9-
tetrahydro-1H-carbazole (Fig. 1, type f).9
In this communication, we report an alternative approach for
the construction of carbazolones: by joining the N-moiety on the
side-chain to the phenyl ring via oxidative C–N bond formation
mediated by hypervalent iodine reagents. This method can also
be extended to the synthesis of 3-acetylindoles.
In our previous work, we found that the acyclic enaminone A
could undergo PhI(OAc)2-mediated intramolecular azirination to
Tianjin Key Laboratory for Modern Drug Deliver & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin, 300072, P. R. China. E-mail: duyunfeier@tju.edu.cn,
wangsq57@sina.com; Fax: +86-22-27404031; Tel: +86-22-27404031
†Electronic supplementary information (ESI) available: NMR data. See
DOI: 10.1039/c2ob25348h
Fig. 1 General synthetic routes to the carbazolone motif.
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Table 2 Synthesis of carbazolone derivatives 2 by PIFAa
Entry
1
Substrate 1
Product 2
Yield (%)b
90
Scheme 1 The two different reaction routes when acyclic and cyclic
enaminones were treated with PIDA.
2
90
67
Table 1 Optimization of reaction conditions for the oxidative coupling
of enaminones 1aa
3c
4
87 (2d/2d′ = 3/1)
Entry
Oxidant
Solvent
Time (h)
Yields (%)b
1
2
3
PIDA (1.2 equiv)
PIFA (1.2 equiv)
PIFA (1.2 equiv)
PIFA (1.5 equiv)
PIFA (1.2 equiv)
PIFA (1.2 equiv)
PIFA (1.2 equiv)
PIFA (1.2 equiv)
PIFA (1.2 equiv)
PIFA (1.2 equiv)
PIFA (1.2 equiv)
DCE
DCE
4
80
88
90
83
45
32
75
67
52
5
90 (2e/2e′ = 1.2/1)
0.5
0.5
0.5
0.5
0.5
4
4
4
4
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Toluene
THF
4
5c
6d
7
6
7
79
87
8
9
10
11
DMSO
DMF
41
NDe
a All the reactions were carried out at rt unless otherwise stated.
b Isolated yields after silica gel chromatography. c BF3·Et2O (0.2 equiv.)
was added as additive, at 0 °C. d TFA (0.2 equiv.) was added as additive,
at 0 °C. e 2a was not detected.
8
84
82
74
64
THF and DMSO gave inferior yields, while no desired product
was obtained when DMF was used as the solvent (Table 1,
entries 7–11).
9
Under the optimal reaction conditions (Table 1, entry 3),
various substituted 2-arylenaminones were examined to explore
the scope of this oxidative system. The results showed that sub-
strates bearing both electron-donating and electron-withdrawing
groups can be well tolerated in the process. The presence of a
methyl group in the substrate does not influence the yield
(Table 2, entry 2). However, when strong electron-donating
groups were introduced, the yield was greatly decreased due to
the formation of some unidentified by-products. However, by
carrying out the reaction at 0 °C, the electron-rich enaminone 1c,
with two methoxy groups substituted on the phenyl ring, can
afford the single regio-isomer 2c in an acceptable yield (Table 2,
entry 3). In the case of meta-substituted substrates bearing either
an F or CF3 group (Table 2, entries 4–5), two regioisomeric
indole products were formed in each case.
10
11
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Table 2 (Contd.)
Entry
12
Substrate 1
Product 2
Yield (%)b
Scheme 3 Synthesis of 3-acetylindole 4 when N-substituted enami-
none 3 was treated with PIFA.
73
76
13
14
70
Scheme 4 Possible mechanism for PIFA-mediated cyclization.
a Reaction conditions: 1 (1.0 equiv) and PIFA (1.2 equiv) in CH2Cl2 at
rt. b Yield of isolated product. c The reaction was carried out at 0 °C.
Scheme 5 An alternative mechanism via a nitrene intermediate.
A plausible mechanistic sequence is proposed in Scheme 4.
Firstly, the N-iodo intermediate 5 is expected to be formed
directly from the intermolecular reaction of enaminone 1 and
PIFA by losing one molecule of trifluoroacetic acid. Next, when
R1 represents alkyl or aryl groups, a concerted process involving
the electrophilic attack of the N-center on the phenyl ring via
simultaneous release of PhI and CF3CO2H occurs in intermedi-
ate 5 to afford the Wheland intermediate 6. Considering that the
corresponding intermediate 6 from substrate 1f, in which the
phenyl ring is greatly deactivated by the NO2 group, is unstable,
we propose that the carbon cation 6 can be stabilized by the lone
pair on nitrogen through conjugation to give the iminium salt 7.
Finally, the rapid elimination of a proton from 7 regenerates
the aromatic system of the phenyl ring to afford the title carbazo-
lone 2.
Alternatively, when R in cyclic enaminones represents H, it
may also adopt the other pathway involving the formation of
nitrene intermediate 8 from intermediate 5, followed by insertion
into the Ar–H σ bond or π participation from the aromatic ring
to give the title 2 (Scheme 5).14
In summary, we have described an alternative approach to car-
bazolone and 3-acetylindoles derivatives mediated by PIFA from
enaminones. This method features mild reaction conditions, sim-
plicity of workup and the construction of carbazolone and indole
backbone by a metal-free oxidative annulation of the N-atom on
the side chain to the sp2-carbon on benzene ring at the last syn-
thetic step.
Scheme 2 Formation of azirine B when acyclic enaminone A was
treated with PIFA.
Notably, when a strong electron-withdrawing NO2 group was
introduced, the corresponding enaminone substrate 1f could also
lead conveniently to the desired product 2f in good yield
(Table 2, entry 6). Changing the phenyl ring into a naphthyl
ring, or installing the alkyl groups to the cyclic enaminone
moiety in the substrate did not influence the reaction and the
desired cyclized products can be reached, respectively (Table 2,
entries 7–8). Furthermore, this methodology also allows for both
N-alkyl and N-aryl substitution (Table 2, entries 9–14), thus pro-
viding an alternative route to N-substituted carbazolones, which
are always obtained via N-alkylation or metal-catalyzed N-aryla-
tion of N-unsubstituted carbazolones.12
Encouraged by the above results, we also studied the reaction
of acyclic enaminone under the same conditions. The treatment
of A with PIFA in CH2Cl2 was found to give 2H-azirine com-
pounds B (Scheme 2), the result of which indicated that PIDA
and PIFA showed no difference in this conversion. Delightedly,
when N-substituted acyclic enaminones were used, the oxidative
C–N bond formation occurred to give either the N-alkyl or
N-aryl 3-acyl indole compounds in good yields (Scheme 3).13
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Y.D. acknowledges the National Natural Science Foundation of
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