A catalyst free synthesis of 8, 9, 11-trihalo-5H-benzofuro[3,2-c]carbazol-10-ols

Article abstract of DOI:10.1016/j.tetlet.2017.09.009

8, 9, 11-Trichloro-5H-benzofuro[3,2-c]carbazol-10-ol analogues have been synthesized by treating 2,3-dihydro-1H-carbazol-4(9H)-one with chloranil/fluoranil without any catalyst and is found to be applicable across a range of carbazolone substrates. A possible mechanism has been proposed.

Full text of DOI:10.1016/j.tetlet.2017.09.009

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A catalyst free synthesis of 8, 9, 11-trihalo-5H-benzofuro[3,2-c]carbazol-
10-ols
B. Ravi Shankar a,b, V. Vijayakumar a, , H. Sivaramakrishnan , K. Nagarajan c
⇑
b
a
Centre for Organic and Medicinal Chemistry, School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
Sri Rugved Research Labs, PAP-A-280, MIDC, Mahape, Navi Mumbai 400710, Maharashtra, India
b
c
4A Atishi, Rose Garden Road, 15th Main, J.P. Nagar V Phase, Bangalore 560078, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
8, 9, 11-Trichloro-5H-benzofuro[3,2-c]carbazol-10-ol analogues have been synthesized by treating 2,3-
dihydro-1H-carbazol-4(9H)-one with chloranil/fluoranil without any catalyst and is found to be applica-
ble across a range of carbazolone substrates. A possible mechanism has been proposed.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 1 June 2017
Revised 31 August 2017
Accepted 6 September 2017
Available online xxxx
Keywords:
Benzofurocarbazole
Carbazolones
Chloranil
Nenitzescu reaction
The Nenitzescu reaction has been successfully employed for
assembling fused ring heterocycles. The reaction involves treating
intermediate for the well-known anti-hypertensive drug, carvedi-
lol). In the event, our efforts led to the formation of interesting ben-
zofurocarbazoles 7a–k as a serendipitous product. The reaction
was found to be general towards the reactants used and the results
are presented here.
1
,4-benzoquinone with b-aminocrotonic esters to afford 5-hydrox-
yindoles through the Michael addition followed by a nucleophilic
addition. The scope of the Nenitzescu reaction has been extended
in further by replacing the benzoquinone with tetrahalobezo-
In the reaction of quinones with enaminones, several competi-
tive pathways operate and the final outcome depends on the struc-
quinones, methoxybenzoquinone, anthradiquinones, naphtho-
quinones, dialkyl quinone-2,3-dicarboxylates.1
–7
Similarly, in
ture of the quinone, enaminone and the reaction conditions.
1,3,9
place of the b-aminocrotonic esters, compounds such as S, N-acet-
We envisaged that the reaction of 1a with chloranil 2 may have
three possibilities: path A, the Nenitzescu reaction path of Michael
addition via aza-ene addition followed by nucleophilic addition by
the carbazolone nitrogen to give compound 3 (or) path B, it may
also be possible that the Michael addition could be followed by a
nucleophilic addition of the carbazolone oxygen to form
benzofuro-carbozole 4. Both compounds 3 and 4 are novel scaf-
folds and hence were of interest (Scheme 1). The third possibility
(path C) is dehydrogenation of the hydroaromatic ring to form
4-hydroxycarbazole 12.
als and N,N-acetals, ketene aminals,6 heterocyclic ketene ami-
8
1
,2,5
2-aminomethylene-1-indanones,9 etc., have been
nals,
4
,10,11
studied. The reaction has also been studied in the presence
and absence of catalysts.
As a part of our effort to synthesize the novel fused heterocyclic
ring scaffolds, we would like to explore the Nenitzescu reaction
with 2,3-dihydro-1H-carbazol-4(9H)-one (1a) since it is having
enaminone function as a part of a rigid ring system. Moreover
the reaction of carbazolones with chloranil and fluoranil as elec-
trophiles is also hither to unreported. On the other hand we aware
that chloranil had been extensively used for the dehydrogenation
Initially the compound 1a was treated with chloranil 2 (Table 1)
1
in acetone without any catalyst at room temperature. Though we
1
2
of 1,2,3,4-tetrahydrocarbazoles into aromatic carbazoles and so
we were curious to find out whether this reagent would aromatize
were gratified to find the progress of the reaction (by TLC), we
failed to observe the completion of the reaction. The same reaction
with various solvents at room temperature even failed to proceed
except in acetone and hence acetone was found to be the better
solvent at the room temperature (Entries 1, 2 and 3). Further the
raise in reaction temperature improved the yield in all the solvents
studied (Entries 4, 5 and 6) and the isolated yield was found to be
1
,2,3,4-tetrahydro-4-oxocarbazole to 4-hydroxycarbazole (a key
⇑
Corresponding author.
E-mail address: kvpsvijayakumar@gmail.com (V. Vijayakumar).
http://dx.doi.org/10.1016/j.tetlet.2017.09.009
040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
B. Ravi Shankar et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Path A
O
O
Cl
O
Cl
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
H
O
HO
Cl
Cl
O
O
OH
Cl
H
Cl
Cl
OH
Cl
O
O
OH
OH
Cl
Cl
N
N
N
Cl
Cl
3
Cl
Path B
Cl
Cl
Cl
Cl
OH
Cl
Cl
OH
O
O
O
O
O
O
O
Cl
Cl
Cl
O
O
Cl
Cl
Cl
N
H
Cl
O
N
N
N
Cl
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OH
O
O
O
O
O
O
HO
Cl
HO
Cl
Cl
Cl
N
N
N
OH
H
4
Path C
O
O
Cl
Cl
Cl
Cl
OH
Path C
HN
HN
O
1
a
Chloranil 2
12
Scheme 1. Possible products from the reaction of 1a and chloranil 2.
Table 1
Reaction of carbazolone 1a with chloranil 2 under various solvents.
Entry
Solvent
T (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
Acetone
Dioxane
DMF
Acetone
Dioxane
DMF
RT
RT
RT
55–60
85–90
115–120
12
12
12
12
12
5
5
No reaction
No reaction
39
38
44
a
Isolated yield, RT: room temperature.
higher in DMF (Entry 6). The reaction was found be to clean on TLC
even at the increased temperature.
the quaternary carbon) hence the possible formation of compound
3 through Nenitzescu mechanism was not considered. All signals in
1
3
1
The obtained product was characterized using spectral data.
the C NMR were found to be the downfield of 105 ppm. H NMR
exhibited only eight signals between d11.88 and d7.33 ppm
revealed that the structure of product has to be completely
1
3
The examination of C NMR spectrum of isolated solid product
showed no signal up-field of 100 ppm (indicating the absence of
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B. Ravi Shankar et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
surprisingly none of the expected compounds 3, 4 or 12 were
formed.
An attempt to improve the yield of the reaction under the acid
catalysis at room temperature was failed (entry 1, entry 2 & entry
4
, Table 2). The isolated yields under heating with or without acid
catalyst also afforded the similar yield (Table 1 entry 4 vs. Table 2
entry 6, Table 1 entry 5 vs. Table 2 entry 3 and Table 1 entry 6 vs.
Table 2 entry 5). The decomposition of the product under base
catalysis in all solvents at room temperature (showed decomposi-
tion with multiple spots on the TLC) was observed and hence not
pursued further (Entries 7, 8 and 9, Table 2). Thus, the reaction
in DMF at 115–120 °C was regarded as an optimized condition
and this was chosen as a standard reaction condition for further
studies.
Fig. 1. Structure and ORTEP plot the compound 7a.
The literature survey revealed that the closely related benzo-
furo-carbazole compounds have drawn immense interest in the
aromatized one. Of the eight, only six signals showed cross peaks
with carbon in the HSQC indicating a total of six aromatic protons.
As four of the six aromatic protons were found to be contributed by
the phenyl hydrazine moiety of the product, it was felt that the
cyclohexanone portion of the molecule had aromatized and had
only two aromatic protons indicating that one of the carbons of
the cyclohexanone moiety was probably connected to chloranil.
Two broad singlets observed at down field 10.86 and 11.89 were
1
3
areas of organic field-effect transistors (OFETs) and organic light
1
4
emitting diodes (OLEDs). Those compounds were reported to
1
4
synthesise through the palladium catalyzed pathway. The pre-
sent work emphasizes an alternate and greener strategy to synthe-
size new benzofuro-carbazole derivatives without the use of any
costlier catalyst. In this attempt we have synthesized a series of
carbazolones 1a–j and which in turn are treated with chloranil to
afford benzofuro-carbazole 7a–j.
2
found to be D O exchangeable protons and hence considered as
either NH/OH. The HR-MS spectrum exhibited m/z at 373.9
The substituted carbazolone derivatives 1a–j required for the
study were prepared via Fischer Indole synthesis by condensing
1,3-cyclohexanedione (5) with different substituted phenyl hydra-
zine or their hydrochlorides 6a–j in acetonitrile using one pot pro-
À
(
MÀH) with multiple satellites differing by 2 mass units indicat-
ing the presence of chlorine atoms and a molecular formula of C18
-
H
7
Cl NO leading to the tentative structure 7a. The point of ring
3
2
1
5,16
fusion was best established with single crystal X-ray diffraction
studies of 7a. The crystallographic data was deposited with the
Cambridge Crystallographic Data Centre (CCDC Number
cedure.
After the formation of the hydrazones (Schiff’s base),
the reaction mass was concentrated and the product obtained
was treated with acid under reflux to yield substituted carbazolone
derivatives 1a–j in low to moderate yields of 11–48% (Scheme 2
and Table 3). Although the reaction was done as a one pot reaction,
the pure Schiff’s base can be isolated just by filtering the reaction
mixture, since the unreacted reactants and other impurities were
1
537477). The ORTEP of 7a confirmed that the obtained compound
is 8,9,11-trichloro-5H-benzofuro[3,2-c]carbazol-10-ol (Fig. 1).
Thus, the reaction of 1a with chloranil 2 in DMF led to the forma-
tion of 8, 9, 11-trichloro-5H-benzofuro[3,2-c]carbazol-10-ol (7a);
Table 2
Optimization of the reaction of carbazolone 1a with chloranil 2 under various condition.
Entry
Solvent
Catalyst
Temp
°C)
Time (h)
Yield (%)a
(
1
2
3
4
5
6
7
8
9
Acetone
Dioxane
Dioxane
DMF
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
RT
RT
85–90
RT
RT
55–60
RT
RT
12
12
12
12
5
12
12
12
12
5% by TLC
No reaction
38
No reaction
40
DMF
Acetone
Acetone
Dioxane
DMF
39
5
K
K
K
2
CO
2
CO
2
CO
3
3
3
No reaction
No reaction
RT
a
Isolated yield, RT: room temperature.
Table 3
Synthesis of 2,3-dihydro-1H-carbazol-4(H)-ones 1a–j.
Reactant
Products
R
1
R
2
R
3
R
4
Acid
Yield (%)a
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
g
h
i
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
H
H
H
H
F
Cl
OCH
H
H
H
H
Cl
F
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
Cl
F
conc. HCl
conc. HCl
conc. HCl
no acid
conc. HCl
conc. HCl
18
48
15
29
19
12
11
29
16
19
3
50% H
2
SO
4
C
2 5
H
conc. HCl
Cl
F
50% H
50% H
2
SO
SO
4
4
j
1j
2
a
:
Isolated yields.
Please cite this article in press as: Ravi Shankar B., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.09.009

4
B. Ravi Shankar et al. / Tetrahedron Letters xxx (2017) xxx–xxx
getting retained in the mother liquor. The synthesis of car-
bazolones 1a–j required variation in acidic conditions depending
on the phenylhydrazines used (Table 3), hence the general proce-
dure could not be employed for synthesis of 1a–j.
In the case of methoxyphenyl hydrazine hydrochloride (6d), the
carbazolone (1d) was obtained without any acid catalyst. All the
synthesized carbazolones 1a–j were characterized by their spectral
data and included in the supplementary data. The compounds 1e,
at 115–120 °C (Table 4) which led to the formation of respective
benzofuro-carbazoles 7b–j in a reasonable yield (Scheme 3 and
Table 4). Further, the carbazolone 1a was made to react with fluo-
ranil (11) in place of chloranil under the same reaction condition to
afford the product 7k. The product formation was confirmed using
1
13
H NMR, C NMR and mass spectral data. All the benzofuro-car-
bazoles synthesized in this work are hither to unreported.
A probable mechanism for the formation of benzofuro-car-
bazole 7a is shown in Scheme 4. As in Nenitzesu reaction, the lone
pair of electron on the enamine nitrogen provides the driving force
but the initial attack on the quinone moiety is via the extended
conjugated system as shown in Scheme 4. The first step possibly
involves nucleophilic attack by the extended conjugated form of
the carbazolone 8a on the quinone led to the intermediate 9a. A
subsequent dehydration followed by ring closure and aromatiza-
1
h–j are hither to unreported, whereas remaining compounds
(
their spectral data found to be in accord with the literature) in
16–20
the series were available in the literature.
Reagents and conditions: Carbazolone, chloranil/fluoranil in
DMF, 115–120 °C, 4–5 h.
The synthesized carbazolones 1b–j in turn were made to react
with chloranil (2) under the optimized reaction condition in DMF
Table 4
Synthesis of 8, 9, 11-Trichloro-5H-benzofuro[3,2-c]carbazol-10-ols 7a–k.
Entry
Product
R
1
R
2
R
3
R
4
X
Yield (%)a
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
H
H
H
H
H
H
H
H
H
H
H
F
Cl
OCH
H
H
H
H
Cl
F
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
Cl
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
44
28
21
42
18
21
25
26
52
26
30
3
C H
2 5
Cl
F
H
1
1
0
1
7j
7k
H
a
Isolated yields.
R2
R1
R4
O
R1
R3
R2
i & ii
O
NH2 . HCl
R4
R3
N
H
O
NH
5
6a-j
1a-j
Scheme 2. Synthesis of 2,3-dihydro-1H-carbazol-4(H)-ones 1a–j.
O
R2
Cl
Cl
Cl
Cl
R2
R1
R3
R4
Cl
R1
R3
R4
HO
Cl
O
O
O
Chloranil 2
NH
NH
Cl
F
1
a-j
7a-j
O
F
F
F
O
HO
F
O
O
NH
Fluoranil 11
F
NH
F
1
a
7k
Scheme 3. Synthesis of 8, 9, 11-trichloro-5H-benzofuro[3,2-c]carbazol-10-ol 7a–k.
Please cite this article in press as: Ravi Shankar B., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.09.009

B. Ravi Shankar et al. / Tetrahedron Letters xxx (2017) xxx–xxx
5
Cl
O
HO
O
Cl
Cl
Cl
HO
Cl
Cl
Cl
Cl
OH
N
H
N
H
O
N
9a
8a
O
Cl
O
O
Cl
Cl
Cl
Cl
HO
Cl
Cl
Cl
O
O
Cl
Cl
N
N
N
10a
OH
OH
Cl
Cl
Cl
Cl
Cl
Cl
O
O
N
H
N
7a
Scheme 4. Probable mechanism of 8, 9, 11-trihalo-5H-benzofuro[3,2-c]carbazol-10-ol 7a.
tion yield the product 7a. (The reaction is visualized as being ionic
but an equivalent radical pathway can also be formulated). The fact
that heating helped the reaction possibly indicates that formation
of the five membered furan ring, which may be probable driving
force. The expected initial attack by the b carbon of the enamine
1537477. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.09.
009.
(
by path A or B) on the electrophilic C-2 carbon of chloranil may
not be favored due to steric constraints.
In summary, a novel, catalyst free method for the synthesis of
halo substituted benzofuro-carbazoles has been developed by
treating carbazolones with chloranil and fluoranil. The reaction is
general and has a good scope. We believe that this transformation
will serve as a useful method for the metal free synthesis of newer
scaffolds for OLEDs materials. Work on further tuning the reaction
conditions for improvement of yields and use of different kinds of
quinones and carbazolones is in progress and the results will be
reported elsewhere.
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