An Organic Intermolecular Dehydrogenative Annulation Reaction

Article abstract of DOI:10.1021/acs.orglett.7b00562

The discovery of a direct method for the synthesis of three-ring heterocyclic carbazoles from unactivated arenes and anilides by a metal-free (organic) intermolecular dehydrogenative annulation reaction under ambient laboratory conditions is reported. Iodine(III) was used as the sole reagent either stoichiometrically from inexpensive phenyliodine diacetate or organocatalytically by in situ generation from PhI-mCPBA. In a single step, three C(sp²)-H bonds and one N(sp³)-H bond are functionalized from two different arenes for tandem C-C and C-N bond formation reactions.

Full text of DOI:10.1021/acs.orglett.7b00562

Letter
pubs.acs.org/OrgLett
An Organic Intermolecular Dehydrogenative Annulation Reaction
Saikat Maiti, Tapas Kumar Achar, and Prasenjit Mal*
School of Chemical Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, HBNI, P.O.
Bhimpur-Padanpur, Via Jatni, Khurda 752050, Odisha, India
S
* Supporting Information
ABSTRACT: The discovery of a direct method for the
synthesis of three-ring heterocyclic carbazoles from unactivated
arenes and anilides by a metal-free (organic) intermolecular
dehydrogenative annulation reaction under ambient laboratory
conditions is reported. Iodine(III) was used as the sole reagent
either stoichiometrically from inexpensive phenyliodine diac-
etate or organocatalytically by in situ generation from PhI−mCPBA. In a single step, three C(sp2)−H bonds and one N(sp3)−H
bond are functionalized from two different arenes for tandem C−C and C−N bond formation reactions.
Scheme 1. Approaches for Carbazole Synthesis
he use of readily available chemicals for atom- and step-
Teconomical syntheses of bioactive molecules, pharmaceut-
icals, and materials is a state-of-the-art practice in organic
synthesis.1 Nitrogen-based heterocycles are considered as highly
important among those molecules.2 Transition-metal catalysis of
annulation reactions has emerged as a powerful technique to
convert unreactive C−H and N−H bonds into C−C and C−N
bonds in heterocycle synthesis.3 Dehydrogenative coupling
reactions between C−H and N−H bonds are more popular
than traditional cross-coupling reactions because preactivation of
substrates can be avoided.4 Similarly, metal-free approaches are
preferable because any metal impurities may alter the biological
activities and physical properties of a compound.5 For the
functionalization of nonreactive C−H bonds, hypervalent
iodine(III) reagents are highly advantageous because of their
easy accessibility, low toxicity, high reactivity, and environ-
mentally benign nature.6 Notably, a very limited number of
intermolecular annulation reactions7 for heterocycle synthesis
using hypervalent iodine(III) have been documented.8
For the synthesis of carbazoles, a majority of the methods are
based on an intramolecular approach via formation of one bond
(either C−C or C−N) using either transition-metal catalysts or
metal-free conditions (Scheme 1a).9 Contrastingly, examples are
rare for the intermolecular approach, which can be more
advantageous in terms of step economy and the nonrequirement
of preorganization of substrates.10 To date, the known examples
of intermolecular approaches for carbazole synthesis are non-
dehydrogenative type, such as (a) the palladium-catalyzed
reaction of 2-iodoaniline with arenes reported by Liu and
Larock,11 (b) the coupling reaction between anilines and 1,2-
dihaloarene substrates based on palladium catalysis described by
Ackermann’s group (Scheme 1b),12 and (c) a reaction of aryne
precursors with nitrosoarenes developed by Studer and co-
workers (Scheme 1b).13 However, to the best of our knowledge,
there are no reports of a transition-metal-free intermolecular
dehydrogenative annulation approach for polycyclic heteroar-
omatic carbazoles.
Herein we report the discovery of a metal-free intermolecular
dehydrogenative annulation reaction for N-substituted carbazole
synthesis via tandem C−C/C−N bond formation through
simultaneous multiple C−H and N−H bond functionalizations
(Scheme 1c). Non-prefunctionalized arenes and anilides were
used for hypervalent iodine(III)-mediated intermolecular
coupling reactions under stoichiometric as well as organo-
catalytic conditions. The commercially available hypervalent
iodine(III) reagent phenyliodine(III) diacetate (PIDA)14 was
used as the sole reagent, and the reactions were completed at
room temperature within 1 h in fluorinated solvents under open
atmosphere. Similarly, in the organocatalytic method, iodoben-
zene and m-chloroperoxybenzoic acid (mCPBA)15 were used
under the same conditions. We anticipated that intermolecular
oxidative fusion of multiple rings might lead to a powerful
Received: February 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00562
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
approach for the synthesis of polycyclic heterocycles like
carbazoles. Carbazoles are extensively used as pharmaceuticals,
photoconducting materials, organic dyes, etc.16
organocatalytic approach established using various iodoarenes
(4-NO2C6H4I, 4-MeOC6H4I, PhI) and oxidants by in situ
generation of iodine(III) reagent (method B; Table S1 in the
Supporting Information (SI)). The best conditions were
achieved when 20 mol % PhI and 3.0 equiv of the oxidant
mCPBA were used at room temperature in HFIP/DCM (1:1).
The optimized annulation protocol was subsequently applied
to a range of simple arenes and anilides to explore the substrate
scope of the multisubstituted carbazole synthesis (Scheme 2).
We considered N-(4-bromophenyl)methanesulfonamide (1a)
and anisole (2a) for optimization of the intermolecular
dehydrogenative annulation reaction. For stoichiometric opti-
mization (method A), substrates 1a and 2a (3.0 equiv) were
treated with 2.5 equiv of PIDA at room temperature in 2,2,2-
trifluoroethanol (TFE) (0.2 M), and the desired product, 6-
bromo-2-methoxy-9-(methylsulfonyl)carbazole (3a), was ob-
tained in 34% yield (Table 1, entry 1). Nevertheless, 1,1,1,3,3,3-
Scheme 2. Scope of the Intermolecular Annulation Reaction
a
Table 1. Optimization of Method A
iodine(III)
(2.5 equiv)
additive
(2.5 equiv)
yield of 3a
b
entry
solvent
(%)
1
2
3
4
5
6
7
8
9
PIDA
−
−
−
−
−
−
−
−
−
CF3CH2OH
DCM
34
10
0
PIDA
PIDA
ACN
PIDA
HFIP
57
21
<5
44
18
66
PIFA
HFIP
PhIO
HFIP
PhI(OCOPh)2
HFIP
c
HTIB
HFIP
PIDA
HFIP/DCM
(1:1)
10
11
PIDA
K2CO3
K2CO3
HFIP/DCM
(1:1)
78
41
PhI(OPiv)2
HFIP/DCM
(1:1)
12
13
14
PIDA
PIDA
PIDA
PIDA
K2CO3
AcOH
HFIP
HFIP
HFIP
67
35
<5
30
BF3·Et2O
K2CO3
d
15
HFIP/DCM
(1:1)
a
b
Unless otherwise mentioned, 3.0 equiv of 2a was used. Yields of the
c
isolated major product after column chromatography. HTIB =
hydroxy(tosyloxy)iodobenzene. 1.1 equiv of 2a was used.
d
hexafluoroisopropanol (HFIP) was found to be most efficient
among the solvents examined (Table 1). In addition, we
extended our investigation by using different iodine(III) reagents
as the oxidant. The stronger oxidant PhI(OCOCF3)2 (PIFA)
could not afford a better yield of 3a (entry 5), and PhIO was
found to be ineffective under the studied conditions (entry 6).
Oxidants like PhI(OCOPh)2, HTIB, and PhI(OPiv)2 were also
inefficient, providing less promising results than PIDA (entries 7,
8, and 11). A significant increase in yield was observed by diluting
the reaction mixture to 0.1 M using HFIP/DCM (1:1) (entry 9).
The most appropriate conditions were identified to be treatment
of 1 equiv of 1a and 3.0 equiv of 2a with 2.5 equiv of PhI(OAc)2
in the presence of 2.5 equiv of the additive K2CO3 at 0.1 M in
HFIP/DCM (1:1). The desired product 3a was isolated as the
major isomer in 78% yield within 1 h at room temperature under
aerobic conditions (entry 10). The formation of trace amounts of
the minor isomer, 3-bromo-5-methoxy-9-(methylsulfonyl)-9H-
carbazole (3a′) was also detected. The use of a Lewis acidic
additive like BF3·Et2O or an acidic additive like AcOH did not
offer better results (entries 13 and 14). Most of the arenes 2 are
volatile in nature, and therefore, the use of ∼3.0 equiv was
established as the optimum amount for the reaction. The
Carbazoles were isolated in good yields under the standard
conditions. A wide array of anilides with different functional
groups at the para position were compatible here. Electron-
withdrawing groups like halogen (3a−g, 3o−r, 3w) or phenyl
(3u) and electron-donating alkyl groups (3h−n, 3s, 3t, 3v) on
the anilide substrate were fair-yielding as well under both
stoichiometric and organocatalytic conditions. In general, aryl
rings with electron-donating groups like alkyl or alkoxy
underwent cyclization more readily on anilide substrates (see
the SI). Furthermore, various sulfonyl or carbonyl groups on the
N center of the aniline were also found to be efficient in carbazole
synthesis (Scheme 3, 3aa−ag). However, aniline substrates
containing an electron-donating benzyl group were unsuccessful
in providing carbazole (see the SI). Notably, using para-
unsubstituted acetanilides instead of sulfoanilides (1x), we
were unsuccessful in achieving product formation, which is in
good agreement with a previous report.17 In all cases, better
B
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Organic Letters
Letter
Scheme 3. Scope of N-Substituted Anilines
Scheme 5. Plausible Mechanism for the Annulation Reaction
in the (a) Stoichiometric and (b) Organocatalytic Approaches
yields were observed for the stoichiometric pathway than the
organocatalytic one.
On the basis of control experiments (Scheme 4) and literature
precedents,18 a plausible mechanism of the intermolecular
Scheme 4. Control Experiments
N bond through an ionic pathway. The availability of a free NH
group in the C-arylated intermediate opened up an additional
opportunity for the intermediate to react further with additional
hypervalent iodine(III) reagent. From intermediate 7, the
oxidative C−N bond formation was controlled by attack of the
phenyl ring on the nitrenium ion.9c The ligand exchange of PIDA
with HFIP could not be anticipated.22 Interestingly, according to
Kita’s report, the moderate steric size of the Ms group prevented
overoxidation of the biaryl product, whereas we could fruitfully
overcome that restriction also during the annulation reaction by
creating the C−N bond in addition to the C−C bond. The role of
the additive K2CO3 might be to neutralize the acetic acid released
during the reaction.21 A trace amount of the 4-substituted isomer
was also formed through electrophilic substitution of the arene at
the sterically less preferable ortho position by an electron-
donating group.23 Thus, apart from the major 2-substituted
carbazole derivative, a trace amount of the 4-substituted product
also formed. Although the minor isomer could not be isolated in
pure form, it was detected by NMR spectroscopy as mixture with
the major isomer (see the SI for details). Hence, representative
yields correspond to the isolated pure major isomers.
In the organocatalytic approach, we believe that iodobenzene
is oxidized by mCPBA to generate the trivalent organoiodine
species, which enables the intermolecular annulation of arenes
and anilides to form the final product 3 (Scheme 5b).9c
For further synthetic utility, compound 3a was converted into
6-bromo-2-methoxycarbazole (4a) in 93% yield (Scheme 6a)
using 3.0 equiv of Cs2CO3 in THF/MeOH (1:1).24 In addition,
the synthesis of the carbazole alkaloid ( )-mahanimbicine
(Scheme 6b) can possibly be achieved in two steps from 2-
methoxy-6-methyl-9-tosylcarbazole (3aa).25 We have synthe-
sized the alkaloid clauszoline-K (5ah) from N-(p-tolyl)-
benzenesulfonamide (1ah) and anisole (2a) (Scheme 6c).26
Moreover, this method might lead to the easy synthesis of the
potent anti-HIV-active drug siamenol in two steps from 2-
dehydrogenative annulation reaction is proposed in Scheme 5.
Upon reaction with PIDA, anilide 1 generates nitrenium ion19
intermediate 5 (Scheme 5). Reaction of sulfoanilide 1i and 1.0
equiv of PIDA in TFE led to the formation of N-(4-ethylphenyl)-
N-(2,2,2-trifluoroethoxy)methanesulfonamide (4i) in 55% yield
(Scheme 4a). Formation of the solvent-incorporated product 4i
established the presence of nitrenium ion 5. Similarly, the
existence of nitrenium ion in an iodine(III)-mediated alkox-
ylation reaction was also reported by Kikugawa et al.19b The
nitrenium ion intermediate would be expected to get stabilized
by charge delocalization to form carbenium ion intermediate 6
(Scheme 5). Nucleophilic attack by the arene could possibly take
place on either carbenium ion 6 (C−C bond formation) or
nitrenium ion 5 (C−N bond formation). In the reaction of N-(4-
chlorophenyl)methanesulfonamide (1h) with m-xylene in the
presence of 1.0 equiv of PIDA, the C-arylated product N-(5-
chloro-2′,4′-dimethyl-[1,1′-biphenyl]-2-yl)methanesulfonamide
(2hg) was isolated in 92% yield (Scheme 4b). Addition of 1.5
equiv of PIDA to C-arylated product 2hg afforded 6-chloro-2,4-
dimethyl-9-(methylsulfonyl)carbazole (3hg) in 71% yield
(Scheme 4c).
This observation led to the conclusion that the C−C bond is
preferentially formed over the C−N bond during the carbazole
ring construction. Hypervalent iodine(III)-mediated selective C-
arylation of para-substituted N-sulfonyl anilides in polar
fluorinated solvents was formerly described by Kita20 and
Canesi,21 where it was anticipated that the σ-donation effect of
the sulfonyl group is operative to stabilize the positively charged
aromatic ring to form the C−C bond preferentially over the C−
C
DOI: 10.1021/acs.orglett.7b00562
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Organic Letters
Letter
Scheme 6. Postsynthetic Modifications
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Corresponding Author
*pmal@niser.ac.in
ORCID
Prasenjit Mal: 0000-0002-7830-9812
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank DST (New Delhi, India) for support and Dr. Milan Kr.
Barman (NISER) for crystallography. S.M. and T.K.A. thank
CSIR (India) and UGC (India), respectively, for fellowships.
D
DOI: 10.1021/acs.orglett.7b00562
Org. Lett. XXXX, XXX, XXX−XXX