Hypervalent Iodine(III)-Mediated Counteranion Controlled Intramolecular Annulation of Exocyclic β-Enaminone to Carbazolone and Imidazo[1,2-a]pyridine Synthesis

Article abstract of DOI:10.1002/chem.201806299

A highly efficient and flexible protocol for intramolecular annulation of exocyclic β-enaminones has been disclosed for the synthesis of carbazolones and imidazo[1,2-a]pyridines through a counter-anion-controlled free-radical mechanism promoted by hypervalent iodine(III). The cooperative behavior of HTIB and AgSbF₆ plays a crucial role in the intramolecular annulation process through C?C and C?N bond formation to give the desired products. The mechanistic insights suggest that the two competitive reactions involved in the system are guided by the nature of the counteranion, which determines the formation of the final products. A wide variety of carbazolones and imidazo[1,2-a]pyridine molecules have been prepared and isolated in good to excellent yields.

Full text of DOI:10.1002/chem.201806299

A Journal of
Accepted Article
Title: Hypervalent Iodine(III) Mediated Counter Anion Controlled
Intramolecular Annulation of Exocyclic-β-Enaminone to
Carbazolone and Imidazo[1,2-a]pyridine Synthesis
Authors: Dhananjay Bhattacherjee, Shankar Ram, Arvind Singh
Chauhan, Yamini --, Sheetal --, and Pralay Das
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201806299
Link to VoR: http://dx.doi.org/10.1002/chem.201806299
Supported by

10.1002/chem.201806299
Chemistry - A European Journal
FULL PAPER
Hypervalent Iodine(III) Mediated Counter Anion Controlled
Intramolecular Annulation of Exocyclic-β-Enaminone to
Carbazolone and Imidazo[1,2-a]pyridine Synthesis
Dhananjay Bhattacherjee,[a],[b] Shankar Ram,[a],[b] Arvind Singh Chauhan,[a],[b] Yamini,[a] Sheetal,[a] and
Pralay Das*[a],[b]
Dedication ((optional))
Previous reports
Previous reports
Abstract: A highly efficient and flexible protocol for intramolecular
annulation of exocyclic-β-enaminones has been disclosed for the
synthesis of carbazolones and imidazo[1,2-a]pyridines via counter
anion controlled free radical mechanism promoted by hypervalent
iodine(III). The co-operative behavior of HTIB and AgSbF6 plays a
linchpin role in the intramolecular annulation process through C-C
and C-N bond formation to give the desired products. The mecha-
nistic insights suggest that the two competitive reactions involved in
the system guided by the nature of counter anion which decides the
formation of final products. A wide variety of carbazolones and
imidazo[1,2-a]pyridine molecules have been prepared and isolated
in good to excellent yields.
O
O
O
O
O
O
Pd/Ligand or
Pd/Ligand or
Cu- catalysis
Cu- catalysis
R
R
Br/I
Br/I
R
R
Pd/Ligand
Pd/Ligand
H
H
X
X
X
X
CuI (1.5-
CuI (1.5-
Ref. 8a, 12, 18
Ref. 8a, 12, 18
X = C-H, N
X = C-H, N
N
R
R
N
N
N
N
N
H
2.0 equiv.)
H
2.0 equiv.)
H
H
or Cu/ligand
or Cu/ligand
bond formation
Ref. 7, 8b
Ref. 7, 8b
Pd for C-C
Pd for C-C bond formation
bond formation
C-N
Cu for
Cu for C-N bond formation
Our work
Our work
O
O
O
O
1
R1
R
R
1
R
HTIB, AgSbF
HTIB, AgSbF66
R1
H
H
R
X
X
X
X
2
R2
DCE, 90 ooC
R
2
DCE, 90
C
R2
R
R
R
3
R3
N
N
3
R3
R
N
N
R
X = C-H, N
X = C-H, N
H
H
H
H
single reagent system for selective
bond formation
and
C-N
HTIB and AgSbF
C-C
HTIB and AgSbF66 single reagent system for selective C-C and C-N bond formation
Introduction
Scheme 1. Different strategies of carbazolones and imidazo[1,2-a]pyridines
synthesis
The transition metal free intramolecular arylation reactions have
received enormous attention for the synthesis of natural
products, medicinal agents and organic materials.[1] These
arylation reactions can be achieved either by C-C or C-N bond
formation strategy which remains a great challenge in organic
chemistry especially under iodine(III) conditions and currently
represents a powerful tool for the synthesis of complex building
blocks.[2] In recent years, the C-C and C-N bond formation
reactions has been achieved by the use of transition metal
catalyst using C-H functionalization strategy.[3] However,
iodine(III) oxidative C-C and C-N bond formation approach
remains a promising and up surging field in synthetic chemistry.
Owing to the intriguing structural features and widespread
occurrence in natural products and drug intermediates such as
murrayaquinone,[4a] ondansetron[4b] and alosetron[4c] etc.,
carbazolones gained considerable interest in the synthetic
carbazolone synthesis via C-H bond activation strategies have
been well documented in the previous reports.[6],[8a] Among the
cyclization reactions, the CuI promoted intramolecular
cyclization of N-(2-haloaryl)-substituted enaminones are the
long-established methodology for the carbazolones synthesis.[7]
However, Pd-catalyzed C-H arylation of β-enaminones via
intramolecular Heck coupling strategy has also been reported by
various groups.[8] The researchers at Merck laboratories have
developed homogeneous palladium-catalyzed coupling of
vinylogous amides with aryl bromides and chlorides via tandem
Hartwig-Buchwald-Heck cyclisation strategy.[8a] Soderberg and
co-workers demonstrated palladium catalyzed intermolecular
Stille cross-coupling followed by a reductive N-heteroannulation
for the synthesis of carbazolones.[9] However, a vast majority of
reactions involve the palladium catalyzed intramolecular direct
C-H bond activation of enaminones.[10] Åkermark et al., in 1999
community.
Moreover,
these
tricyclic
neuroprotective
compounds have been known for the treatment of chronic and
acute diseases such as Parkinson, Alzheimer disease and
prostaglandin mediated diseases.[5] Over the last few decades,
the plethora of transition metal catalyzed methodologies for
disclosed
a
palladium-catalyzed
cyclizations
of
arylaminoquinones to biologically important carbazoloquinones
with limited substrate scope.[11] In 2011, Glorius and co-workers
manifested a Pd-catalyzed oxidative coupling of two C-H-bonds
within N-arylenamines that allows the efficient formation of
differently substituted indoles.[6a, 12] In a recent report, He et al.,
demonstrated a formal [3+2]-cycloaddition reaction for the
synthesis of carbazolequinones via the annulation of
aminoquinones with in situ generated aryne intermediates.[13]
Moreover, the hypervalent iodine(III) has also been employed to
achieve carbazolones via direct intramolecular N-arylation
reaction.[14] However, the same strategy has been failed for the
annulation of exocyclic- β-enaminones.
[a]
Natural Product Chemistry and Process Development Division,
CSIR- Institute of Himalayan Bioresource Technology, Palampur-
176061, H.P, India, Fax: +91-1894-230433,
E-mail: pdas@ihbt.res.in, pralaydas1976@gmail.com.
[b]
Academy of Scientific and Innovative Research, New Delhi, India
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/chem.201806299
Chemistry - A European Journal
FULL PAPER
Table 1. Optimization of reaction conditions for oxidative annulation of
exocyclic-β-enaminone[a]
O
O
O
O
AgSbF6
(1.2 equiv.)
DCE, 90 oC, 5h
H
OTs
HTIB (1.2 equiv.)
DCE, 90 oC, 1h
O
No Reaction
O
(a)
(b)
N
H
1a
N
H
H
Iodine (III), oxidant
76%
4a,
Temperature, Time
Solvent
N
H
N
H
O
OTs
IPh
AgSbF6
(1.2equiv.)
DCE, 90 oC, 5h
H
1a
2a
HTIB (1.2 equiv.)
DCE, rt, 30 min
counter-anion
species
N
H
1a
N
N
temperature (o
yield (%)b
H
entry Iodine (III)
solvent
time (h)
C)
H
5a
2a, 77%
O
O
O
OTs
IPh
(1.2 equiv.)
AgSbF6
TEMPO (1.2 equiv.)
nr
-
m-CPBA
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
ACN
DMF
Toluene
DCE
DCE
DCE
1
2
3
4
5
PIFA
PIFA
PIFA
PIFA
PIFA
60
60
60
60
60
60
60
60
60
60
60
90
100
100
10
10
10
10
10
10
10
10
10
10
10
10
12
12
H
HTIB (1.2 equiv.)
+
2a
not observed
4a
(c)
(d)
AgBF4
AgO
DCE, 90 oC, 5h
DCE, rt,
30 min
N
N
H
1a
53%
H
nr
5a
traces
O2
HTIB (1.2 equiv.)
(1.2 equiv.)
H
AgSbF6
51
No Reaction
AgSbF6
DCE, 90 oC, 6h
N
traces
6
PIFA
DIB
Cu(OAc)2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
CH3
6a
37
7
61
nd
8
HTIB
HTIB
HTIB
HTIB
HTIB
Scheme 2. Control experiments.
9
nd
nr
10
11
12
13
14c
imidazo[1,2-a]pyridines still unknown in literature.
80
80
79
In past few years, our research group dedicatedly involved in the
development of new and known class of cyclohexane-1,3-diones
and their applications in commercially valuable molecules
synthesis.[19] In continuation to our research on exploiting the
intrinsic reactivity of hypervalent iodine(III) reagents in organic
transformation, herein, we reported iodine(III) mediated
intramolecular annulation of exocyclic-β-enaminones triggered
by counter anion.
HTIB
HTIB
PIFA
DCE
DCE
63
49
15
16
AgSbF6
AgSbF6
90
90
10
5
HTIB
-
nd
nd
DCE
DCE
17
18
AgSbF6
-
90
90
10
10
HTIB
[a]Reaction conditions: 3-(phenylamino)cyclohex-2-enone (1a) (0.2655 mmol),
HTIB (0.3191 mmol), AgSbF6 (0.3191 mmol) in DCE (2 mL) at 90 oC (oil bath
temperature) for 12 hours; [b] yields referred to isolated yields; [c] 1.5 equivalent
of HTIB was used.
Results and Discussion
We have started our initial assessment by choosing 3-
(phenylamino)cyclohex-2-enone (1a) as bench stable moiety for
the intramolecular annulation reaction under hypervalent
iodine(III) conditions. To establish the best reaction conditions
various parameters such as iodine(III) reagent, counter-anion
species, solvent, temperature and time were critically
investigated (Table 1, entry 1-11). The best yield of the
corresponding carbazolone were observed when 1 equiv. of 3-
(phenylamino)cyclohex-2-enone, 1.2 equiv. of HTIB and 1.2
equiv. of AgSbF6 subjected to react in dichloroethane solvent at
90 oC temperature for 10 hours (Table 1, entry 12). However,
increase in the time, temperature as well as hypervalent iodine
equivalency did not increase the yield of the final product (Table
1, entry 13-14). However, replacing HTIB with PIFA under same
reaction conditions gave 63% yield of the desired product (Table
1, entry 15). Furthermore, the synergistic effect of the reagents
was further observed where the absence of one reagent did not
lead to the product formation even in trace quantity (Table 1,
entry 17-18).
In 2014, Zhao and co-workers reported that hypervalent iodine
(III) conditions were not suitable for the carbazolone synthesis
starting from enaminones and α-iodo-N-arylated product was the
end result of the reaction.[1c] Moreover, in our previous report we
have observed the formation of α-tosylated product when β-
enaminones
subjected
to
react
under
hydroxy(tosyloxy)iodobenzene conditions.[15] Inspiring from
observation by Crivello et al., we postulated the introduction of
AgSbF6 in the reaction system for the desired annulation
reaction.[22] To our delight, the combine synergistic role of
hydroxyl(tosyloxy)iodobenzene
(HTIB)
and
silver
hexafluoroantimonate (AgSbF6) plays uniquely to bring about the
desired transformation to solve the lingering problem of
iodine(III) mediated annulation of exocyclic-β-enaminones.
On the other hand, imidazo[1,2-a]pyridine moiety with fused
imidazole and pyridine ring represents an important scaffold with
diverse range of biological activities.[16] The most highlighted
synthetic protocols involve oxidative coupling, multicomponent
reactions and hydroamination reactions.[17] In 2016, Liu et al.,
developed a practical method for the synthesis of imidazo[1,2-
a]pyridine derivatives using molecular iodine as a sole oxidant in
the presence of CuI.[18] However, iodine(III) mediated oxidative
annulation of enaminones for the synthesis of carbazolones and
In order to get insight into the reaction mechanism, several
control experiments were performed as shown in scheme 2. At
the commencement of reaction, we have observed the
formationof tosylation product 4a under HTIB condition.
This article is protected by copyright. All rights reserved.

10.1002/chem.201806299
Chemistry - A European Journal
FULL PAPER
However, the tosylation product 4a on separate treatment with
AgSbF6 did not
plausible mechanism has been sketched in Scheme 4. In the
first step, HTIB undergoes ligand exchange reaction with the
reactant 1a
1.5
1a-347 nm
1a+HTIB-362 nm (at the initial)
7a-385 nm (after the addition of AgSbF6)
H
O
H
O
H
H3C
H3C
H
H
H
1.2
5a-376 nm (10 mins after the addition of HTIB)
H
HTIB (1.2 equiv.)
(1.2 equiv.)
N
H
1r
AgSbF6
N
H
(a)
H
D
H
DCE, 90 o
C, 1.5h
2r
0.9
0.6
0.3
O
D
O
D
H3C
H3C
D
D
D
= 1.3
kH
kD
D
N
H
N
D
2r'
D
H
D
1r'
H
O
O
H
H3C
H3C
H
H
H
HTIB (1.2 equiv.)
(1.2 equiv.)
AgSbF6
(b)
H
N
H
1r
DCE, 90 o
C, 1.5h
N
H
H
0.0
H
2r,
49%
300 350 400 450 500 550 600 650 700
D
O
D
D
O
Wavelength (nm)
H3C
HTIB (1.2 equiv.)
D
(1.2 equiv.)
H3C
D
AgSbF6
D
(c)
N
D
DCE, 90 o
D
C, 1.5h
Figure 1: UV-Vis studies of reaction intermediates
N
H
1r'
D
D
2r',
38%
lead to the formation of desired 2a. This experiment clearly ruled
out the intermediacy of 4a (Scheme 2-a). The compound 1a on
treatment with HTIB gives intermediate 5a which is quite stable
at room temperature and procures the desired product 2a in
77% yield on treatment with AgSbF6 (Scheme 2-b). To check the
involvement of free radicals, the intermediate 5a subjected to
react in presence of TEMPO under same reaction conditions; no
product (2a) formation was observed. However, in such case
formation of 4a was observed as an exclusive product. This
experiment clearly indicates the existence of two competitive
reactions i.e., free radical annulation and nucleophilic
substitution which are responsible for the formation of 2a and 4a
respectively. At standard conditions, the free radical annulation
pathway is faster than the nucleophilic substitution by tosylate
ion. However, in the presence of TEMPO which inhibits the
formation of free radicals makes the nucleophilic substitution
reaction to proceed much faster for 4a synthesis. The tertiary
enaminones 6a did not lead to any product formation indicates
the involvement of N-H bond in the annulation process. This fact
further proved by the deuterium labeling experiment (Scheme 3)
where deuterium incorporation was observed over N-center
(Scheme 3b). The isotopic scrambling was observed in the
product and in accordance with NMR spectra 60% H/D
exchanged product was noticed (Scheme 3a).[21] Moreover, the
deuterium labeling experiment revealed the observed kH/kD = 1.3,
indicating that the aromatic C-H bond cleavage may not be the
rate determining step of the reaction (Scheme 3). UV studies
were performed which is in support of the proposed metathesis
step involved in the mechanism (Figure 1). When HTIB added to
the reaction mixture a red shift at 362 nm was observed
indicates the interaction between 1a and HTIB. Moreover, the
red shift at 385 nm from 376 nm strongly supports the
metathesis step involved in the mechanism (Scheme 4). On the
basis of control experiments and precedent literature,[20],[15] most
Scheme 3. Isotopic scrambling experiment
and gave intermediate 5a. As stated previously intermediate 5a
could undergo nucleophilic substitution or metathesis to produce
4a or 7a respectively. Since metathesis step is faster under the
reaction conditions, intermediate 7a forms immediately over
intermediate 5a.
HTIB
HTIB
O
O
H
H
X
X
O
O
OTs
OTs
N
N
IPh
IPh
X
X
H
H
1a
1a
N
N
AgSbF
AgSbF66
H
H
O
O
X = CH/N
X = CH/N
metathesis
metathesis
5a
5a
nucleophilic
nucleophilic
substitution
substitution
X = CH
X = CH
= 376 nm
λ
λ
N
N
mmaaxx= 376 nm
H
H
O
O
SbF
SbF66
O
O
2a
2a
IPh
IPh
OTs
OTs
PhI
PhI
X
X
X
X
N
N
N
N
H
H
H
4a
4a
H
7a
7a
O
O
X = CH
X = CH
λ max
max = 385 nm
H
H
= 385 nm
λ
X = CH
X = CH
thermal
thermal
N
N
O
O
energy
energy
9a
9a
N
N
X = N
X = N
N
N
SbF
SbF66
O
O
3a
3a
IPh
IPh
O
O
X
X
X
X
N
N
H
H
N
N
O
O
7a'
7a'
Ref. 22
Ref. 22
8a'
8a'
X
X
PhI
PhI
N
N
H
H
8a
8a
+
+
SbF
SbF66
+
+
PhI
PhI
Scheme 4. Plausible mechanism of annulation of exocyclic-β-enaminones
This article is protected by copyright. All rights reserved.

10.1002/chem.201806299
Chemistry - A European Journal
FULL PAPER
The seminal work by Crivello and co-workers showed that
iodonium salts having hexafluoroantimonate as a counter ion
can act as a photo initiators and initiate free radical reaction via
radical-cation pathway.[22] Due to the low bond energy of the C-I
bond (26-27 kcal/mol), the intermediate can efficiently produce
reactions viz. annulation and α-tosylation depending on the
behavior and the availability of electron density at the nitrogen of
exocyclic-β-enaminones. In our study various EDG and EWG
substituted cyclopentane-1,3-dione derived enaminones were
also targeted to see the effect of ring size to the product yield.
However, no such significant difference was observed and the
corresponding products 2j-m were obtained in 52-71% yields.
Moreover, the N-benzyl substituted exocyclic-β-
Table 2. Effect of alkyl and aryl substitution and ring size of the oxidative
annulation reaction [a][b]
O
O
Rm
R1
R2
R3
R1
R2
R3
H
HTIB, AgSbF6
Table 3. Synthesis of imidazo[1,2-a]pyridine derivatives[a][b]
Rm
DCE, 90 o
C
n
N
H
N
n
O
H
n = 0, 1
m = 4-8
O
R1
R2
R1
H
2b-y
1b-y
N
HTIB, AgSbF6
DCE, 90 o
N
= 3-F, 4-CH
= 4-CH
C
O
R4
O
N
H
R2
R3
R3
,
[d], 58%,
(n = 1)
,
, 68%, (n = 1)
[c], 71%, (n = 1)
R4
R4
2h
2b
α = 1.25:1, 3
= 2-CH3
N
,
,
R4
R4
R4
R4
R4
R1
R2
R3
2c
2h:2h
= 4-Cl, 379%,
= 4-Br, 75%,
= 4-I, 58%,
(n = 1)
(n = 1)
(n = 1)
1z-aj
= 4-NO
3a-k
,
[e], 72%,(n = 1)
R4
R4
R4
2d
2i
2j
R4
= H, 712%,
(n = 0)
,
,
N
n
2e
O
O
O
Cl
Br
Br
H
= 4-Cl, 52%,
(n = 0)
,
,
2f
2k
n = 0 and 1, m = 4
= R2 = R3 = H
= 4-F
[c], 81%, (n = 1)
,
= 2-CH
[e], 57%, (n = 0)
,
N
R4
N
2g
N
N
2l
3
R1
= 4-CH
,
[e], 61%,(n = 0)
R4
2m
3
N
N
N
N
O
O
Cl
Br
: 68%[d]
: 55%
3b
: 83%
: 86%
3d
3a
3c
= H, 81%[f]
= 2-CH
,
,
,
R5
R5
R5
O
H3C
2o
2p
2q
R5
n = 1, m = 5
O
Br
O
Cl
O
N
, 71%[e]
H3C
Br
H3C
N
H
3
H
= 4-F, 97%
N
= R2 = H
N
R1
R3
N
N
,
not formed
2n
H3C
= CH
3
N
N
N
N
Cl
O
: 66%[c]
: 77%
: 69%[d]
: 67%
3h
3e
3f
3g
O
CH3
H3C
O
H3C
O
Br
H3C
O
CH3
R8
Cl
R6
O
H3C
N
R7
N
H
H
H3C
N
N
N
= H
= i-pr
H
R1
R2
N
= CH
R1
R2
H3C
H3C
R1
H
3C
H
3C
= R3 = CH
3
= R3 = H
= R3 = H
N
R2
3
N
Br
N
Cl
n = 1, m = 8
n = 1, m = 7
n = 1, m = 6
= H, 61%[g]
= 4-CH
= 2-CH3
3
:71%
3i
:96%
3j
: 65%
3k
,
= H, 69%
,
2w R8
R6
R6
R6
2r
= H, 63%
,
,
, 69%[e]
2x R8
2u
= 2-CH
R7
R7
,
, 78%[e]
2s
= 4-I, 58%[e]
,
3
,
, 75%[e]
2v
= 4-Cl, 71%[e]
,
2y R8
2t
[a]
Reaction conditions: 1z-aj (1 equiv.), HTIB (1.2 equiv.), AgSbF6 (1.2 equiv.)
in DCE (2 mL) at 90 oC (oil bath temperature) for 12 hours; [b] yields referred to
isolated yields; AgSbF6 was added after 30 mins, [d]reaction carried out for
[c]
[a]
8h.
Reaction conditions: 1b-y (1 equiv.), HTIB (1.2 equiv.), AgSbF6 (1.2 equiv.)
in DCE (2 mL) at 90 oC (oil bath temperature) for 12 hours; [b] yields referred to
isolated yields; [c]reaction time 8h; [d]yield referred to recovred starting material;
[e]2 equiv. HTIB was used; [f]1.5 equiv. HTIB was used; [g]reaction time 10h.
enaminones1n gave only tosylated product instead of desired
cyclisation product. This fact clearly indicates the direct
involvement of nitrogen lone pair of electron in conjugation with
aryl ring is necessary in the annulation process.
active radical species under the thermal condition. Hence the
hemolytic cleavage of intermediate 7a produces free radical
intermediate 8a via 7a՛. Once the intermediate 8a is formed it
starts free radical cyclisation led to 3a via intermediate 8a՛. The
re-aromatisation of 9a finally affords desired carbazolone2a.
This step further supported by the deuterium labeling experiment
(scheme 3).
The optimized reaction conditions were further applied to
explore the substrate versatility of exocyclic-β-enaminones for
the anticipated annulation reaction (Table 2). Various
electronically rich enaminones substituted with methyl group 1b-
c delivered the corresponding annulation product 2b-c in 68-
71% yields. The haloarylamino substituted β-enaminones 1d-g
gave the anticipated carbazolones 2d-g in 58-81% yields. Next
we have chosen unsymmetrical disubstituted β-enaminone 1h
which afforded two different regio-isomers (2h and 2hα) in 58%
yield in 1.25:1 ratio. In our reaction conditions the strongly
electron withdrawing group such as –NO2 substituted
enaminone 1i was also targeted for the synthesis of
carbazolones. Intriguingly the formation of α-tosylation product
2i was observed in 73% yield. This result forced us to thinkabout
the mechanism of the reaction. There may be two competitive
Next, we have focused on the effect of alkyl substitution on the
enaminone ring to the desired product formation process (Table
2). Electronically rich monoalkyl substituted exocyclic-β-
enaminones 1o-p gave the carbazolones 2o-p in 71-81% yields.
Previously, we have observed that the fluoro substituted
exocyclic-β-enaminones afforded the anticipated carbazolones
with excellent yield. Here, in case of 5-methyl substituted
exocyclic-β-enaminone 1q, no significant steric effect was
observed and 2q obtained in 97% yield. In the case of 4-methyl
substituted exocyclic-β-enaminones 1r-t, the profound electronic
effect was observed over steric effect which gave the good
yields of corresponding carbazolones 2r-t. On introducing
bulkier isopropyl group at the 4-position of exocyclic-β-
enaminones 1u-v, lower yield of the desired products 2u-v were
observed and the fact indicating the slower down of reaction rate
by the vicinal bulky group at rate determining C-H bond
activation process. Moreover, 5,5-dialkylsubstitued electron rich
exocyclic-β-enaminones 1w-y excellently gave the desired
corresponding products 2w-y in 61-75% yields. Inspired from
these results, we have attempted acyclic exocyclic-β-
enaminones under the standard reaction conditions for the
This article is protected by copyright. All rights reserved.

10.1002/chem.201806299
Chemistry - A European Journal
FULL PAPER
(50% ethyl acetate in n-hexane) to afford the desired carbazolones 2a as
white solid in 80% (39.5 mg) yield. Melting point: 216-217 oC. The
molecule was characterised by 1H, 13C NMR spectra and HRMS and IR
analysis.1H NMR (300 MHz; DMSO-d6) δ (ppm) 2.09-2.13 (m, 2H), 2.42
(t, J = 12.26 Hz, 2H), 2.95 (t, J = 11.88 Hz, 2H), 7.11-7.19 (m, 2H), 7.39
(d, J = 6.63 Hz, 1H), 7.94 (d, J = 6.21 Hz 1H), 11.86 (brs, NH); 13C NMR
(75 MHz; DMSO-d6) δ (ppm) 22.70, 23.40, 37.78, 111.49, 111.73,
120.15, 121.46, 122.38, 124.50, 135.83, 152.25, 192.84; HRMS (ESI)
(M+Na)+ calcd. for C12H11NNaO+ is 208.0733 obsd. 208.0732; IR (cm-1)
3358, 3055, 3032, 2953, 2945, 1601, 1454, 1249, 1176.
synthesis of substituted indole derivatives. However, the
reactant remains unconsumed and the formation of the desired
product was not observed.[21]
In our ongoing work, we focused on the C-C bond formation
reactions for the synthesis of carbazolone analogues. However,
the striking outcome of this research was found when 2-
aminopyridine derived exocyclic-β-enaminones were efficiently
converted into imidazo[1,2-a]pyridine derivatives under the same
reaction protocol. When 2-aminopyridine derived exocyclic-β-
enaminones were subjected to react under the same reaction
conditions, the highly selective C-N bond formation reaction was
observed rather than C-C bond formation (Table 3). Imposing
the inherent biological importance of imidazo[1,2-a]pyridine
derivatives this method could be an useful protocol for synthetic
community.
The present reaction conditions were then applied for the
synthesis of various imidazo[1,2-a]pyridine from exocyclic-β-
enaminones. The various mono and di-substituted 2-
aminopyridine derived enaminones showed excellent selectivity
towards C-N bond formation to afford imidazo[1,2-a]pyridine
derivatives (Table 3, 3a-k). In such case, we have observed that
di-halosubstituted exocyclic-β-enaminones 1z-ac gave excellent
yield of 3a and 3d. Moreover, the variation in ring size did not
significantly affect the yield of the desired product 3e. Next,
mono-methyl, dimethyl and isopropyl substituted enaminones
1ae-aj were targeted for the anticipated imidazo[1,2-a]pyridine
synthesis. To our delight, the corresponding imidazo[1,2-
a]pyridines 3f-3k were obtained in good to excellent yields.
Typical
procedure
for
the
synthesis
of
7,8-
dihydrobenzo[4,5]imidazo[1,2-a]pyridin-9(6H)-one (3a): An oven dried
screw cap reaction vial was charged with 3-(pyridin-2-ylamino)cyclohex-
2-enone (50 mg, 0.265 mmol) in dichloroethane (2 mL) as a solvent and
then [hydroxy(tosyloxy)iodo]benzene (HTIB) (124.65 mg, 0.318 mmol)
and silverhexafluoroantimonate (109.26 mg, 0.318 mmol) was added to
the reacting solution. The mixture was allowed to stir for 8 hours at 90 oC
and the progress of reaction was monitored by TLC until completion. The
crude reaction mixture was concentrated under reduced pressure and
subsequently purified by silica gel (mesh 60-120) column
chromatography to afford 7,8-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-
9(6H)-one 3a in 68% yield (33.5 mg), as white semi-solid using 50%
EtOAc in n-hexane as eluent. 1H NMR (600 MHz; DMSO-d6) δ (ppm)
2.13-2.17 (m, 2H), 2.58 (t, J = 6.66 Hz, 2H), 2.96 (t, J = 6.24 Hz, 2H),
7.22-7.24 (m, 1H), 7.62-7.65 (m, 1H), 7.75 (d, J = 8.85 Hz, 1H), 9.20 (d, J
= 6.68 Hz, 1H); 13C NMR (150 MHz; DMSO-d6) δ (ppm) 23.36, 24.79,
37.82, 114.98, 116.55, 118.79, 127.65, 129.92, 147.04, 159.78, 187.53;
HRMS (ESI) (M+H)+ calcd. for C11H11N2O+ is 187.0866 obsd. 187.0865;
IR (cm-1) 2924, 2858, 1631, 1498, 1429, 1329, 1259, 1182.
Typical
procedure
for
the
synthesis
of
6-oxo-2-
(phenylamino)cyclohex-1-en-1-yl 4-methylbenzenesulfonate (4a): An
oven dried screw cap reaction vial were charged with 1a (50 mg, 0.267
Conclusions
mmol) in dichloroethane (2 mL) as
a
solvent and then
[hydroxy(tosyloxy)iodo]benzene (HTIB) (1.2 equiv) was added to the
reacting solution. The mixture was allowed to stir for 1h at 90 oC and the
progress of reaction was monitored by TLC until completion. The crude
reaction mixture was concentrated under reduced pressure and
subsequently purified by silica gel (mesh 60-120) chromatography (40%
EtOAc in n-hexane) to afford the 4a as light brown semi-solid (72.5 mg,
76%). 1H NMR (600 MHz; CD3OD) δ (ppm) 1.85-1.87 (m, 2H), 2.33 (t, J =
6.24 Hz, 2H), 2.43 (s, 3H), 2.57 (d, J = 6.12 Hz, 2H), 7.02 (d, J = 7.56 Hz,
2H), 7.26 (t, J = 7.28 Hz, 1H), 7.36-7.40 (m, 4H), 7.90 (d, J = 8.22 Hz,
2H);13C NMR (150 MHz; CD3OD) δ (ppm) 20.27, 20.36, 26.86, 35.85,
123.65, 125.15, 126.27, 128.63, 128.83, 129.25, 132.92, 137.26, 145.55,
157.74, 188.87; HRMS (ESI-TOF) (M+H)+ calcd. for C19H20NO4S+ is
358.1108 obsd. 358.1122.
In conclusion, operationally simple and efficient reagent system
has been developed for the synthesis of diverse array of
carbazolones and imidazo[1,2-a]pyridine molecules under
iodine(III) conditions. Moreover, the expanded scope of this
single reagent system is highly useful for the C-C as well as C-N
bond formation reaction with wide functional group accessibility
and could be a complementary to Pd and Cu catalysis. An
interesting mechanistic pathway was found to be responsible for
the transformation has been investigated with spectral
evidences. Furthermore, this transformation would inspire
synthetic chemists for drug development research under milder
condition.
Acknowledgements ((optional))
Experimental Section
We are grateful to the Director of CSIR-IHBT for providing the
necessary facilities during the course of this work. The authors
thank CSIR, New Delhi for financial support as part of the project
no MLP-0203. We also thank AMRC, IIT Mandi, for HRMS. DB,
SR, ASC, Y and S thank UGC and CSIR, New Delhi for
awarding fellowships.
Typical procedure for the synthesis of 2,3-dihydro-1H-carbazol-
4(9H)-one (2a): An oven dried screw cap reaction vial was charged with
3-(phenylamino)cyclohex-2-enone
dichloroethane (2 mL)
(50
mg,
0.267
mmol)
and
in
then
as
a
solvent
[hydroxy(tosyloxy)iodo]benzene (HTIB) (125.71 mg, 0.3207 mmol) and
silver hexafluoroantimonate (110.19 mg, 0.3207 mmol) was added to the
reacting solution. The mixture was allowed to stir for 12 hours at 90 oC
and the progress of the reaction was monitored by TLC until completion.
The crude reaction mixture was concentrated under reduced pressure
and subsequently purified by silica gel (mesh 60-120) chromatography
Keywords: carbazolones• imidazo[1,2-a]pyridine• hypervalent
iodine• annulation• metathesis
This article is protected by copyright. All rights reserved.

10.1002/chem.201806299
Chemistry - A European Journal
FULL PAPER
[1]
a) Q. Yan, E. Gin, M. Wasinska-Kalwa, M. G. Banwell and P. D. Carr; J.
Org. Chem. 2017, 82, 4148-4159; b) S. Kotha, M. Saifuddin and V. R.
Aswar; Org. Biomol. Chem., 2016, 14, 9868-9873; c) H. Shi, T. Guo, D.
Zhang-Negrerie, Y. Du, K. Zhao; Tetrahedron, 2014, 70, 2753-2760.
a) J. Peng, C. Chen, C. Xi, Chem. Sci., 2016, 7, 1383-1387; b) E. A.
Merritt and B. Olofsson, Angew. Chem. Int. Ed. 2009, 48, 9052-9070; c)
N. Purkait, G. Kervefors, E. Linde and B. Olofsson, Angew. Chem. Int.
Ed. 2018, 57, 1-6; d) T. Wirth, Angew. Chem. Int. Ed. 2005, 44, 3656-
3665.
[20] l. Papoutsis, S. Spyroudis and A. Varvoglis, Tetrahedron Letters, 1996,
37, 913-916.
[21] See supporting information.
[22] J. V. Crivello and J. L. Lee, Journal of Polymer Science: Part A:
Polymer Chemistry, 1989, 27, 3951-3968.
[2]
[3]
[4]
a) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem. Int. Ed.
2009, 48, 9792-9826; b) S. I. Gorelsky, D. Lapointe and K. Fagnou, J.
Org. Chem. 2012, 77, 658−668; c) W. Li, Z. Xu, P. Sun, X. Jiang and M.
Fang, Org. Lett., 2011, 13, 1286-1289; d) R. Shang, L. Ilies and E.
Nakamura, Chem. Rev. 2017, 117, 9086-9139. e) D. Alberico, M. E.
Scott, M. Lautens, Chem. Rev., 2007, 107, 174-238; f) J. Yuan, C. Liu
and A. Lei, Chem. Commun., 2015 ,51, 1394-1409.
a) S. M. Bhosale, A. A. Momin, R. S. Kusurkar, Tetrahedron, 2012, 68,
6420-6426; b) US Patent: DusanHesoun, Jiri Hykl, US 7,041.834 B2,
2006; c) US Patent: B.R Reguri, S. Upparapalli, NilamSahu,
Karunakara Rao Javvaji, Brahma Reddy Gade, US 2012/0178937 A1,
2012.
[5]
[6]
a) US Patent: E. Wulfert, C.J Suckling, A.I Khalaf, S.P Mackay, B.F
Johnston, US 2009/0259043 A1, 2009; b) US Patent: A. Fecher, H.
Fretz and M. Riederer, US 8,039,474 B2, 2011.
a) S. Wurtz, S. Rakshit, J. J. Neumann, T. Droge, and F. Glorius,
Angew. Chem. Int. Ed. 2008, 47, 7230-7233; b) B. Akermark, J. D.
Oslob and U. Heuschert, Tetrahedron Letters, 1995, 36, 1325-1326; c)
D. Janreddy, V. Kavala, J. W. J. Bosco, C-W Kuo and C-F Yao; Eur. J.
Org. Chem. 2011, 2011, 2360–2365.
[7]
[8]
a) A. Osuka, Y. Mori and H. Suzuki, Chemistry Letters, 1982, 2031-
2034; b) S. Yan, H. Wu, N. Wu, Y. Jiang, Synlett, 2007, 17, 2699-2702.
a) S. D. Edmondson, A. Mastracchio and E. R. Parmee, Org. Lett.,
2000, 2, 1109-1112; b) A. Mandal, S. K. Mondal, A. Jana, S.K Manna,
S.A Ali and S. Samanta, J. Heterocyclic Chem., 2017, 54, 2529-2535.
T. L. Scott and B. C. G. Soderberg, Tetrahedron, 2003, 59, 6323-6332.
[9]
[10] a) M. P. Krahl, A. Jager, T. Krause and H-J Knolker, Org. Biomol.
Chem., 2006, 4, 3215-3219; b) V. Sridharan, M. A. Martin, and J. C.
Menendez,European Journal of Organic Chemistry, 2009, 2009, 4614-
4621.
[11] H. Hagelin, J. D. Oslob and B. Akermark, Chem. Eur. J. 1999, 5, 2413-
2416.
[12] J. J. Neumann, S. Rakshit,T. Droge, S. Wurtz and F. Glorius, Chem.
Eur. J. 2011, 17, 7298-7303.
[13] J. Guo, I. N. C. Kiran, R. S. Reddy, J. Gao, M. Tang, Y. Liu and Y. He,
Org. Lett. 2016, 18, 2499-2502.
[14] X. Ban, Y. Pan, Y. Lin, S. Wang, Y. Du and K. Zhao, Org. Biomol.
Chem., 2012, 10, 3606-3609.
[15] D. Bhattacherjee, V. Thakur, S. Sharma, S. Kumar, R. Bharti, C. B.
Reddy and P. Das, Adv. Synth. Catal. 2017, 359, 2209-2214.
[16] For review on imidazo[1,2-a]pyridine see a) A.K Bagdi, S. Santra, K.
Monir and A. Hajra, Chem. Commun., 2015, 51, 1555-1575. b) T. L.S.
Kishbaugh, Current Topics in Medicinal Chemistry, 2016, 16, 3274-
3302.
[17] a) Y. Li, F. Wang, S. Yu and X. Lia, Adv. Synth. Catal. 2016, 358, 880-
886; b) U. Balijapalli, M.K.D Thiyagarajan, S.K Manickam, and K.I
Sathiyanarayanan, Chemistry Select, 2016, 1, 2900-2908; c) T. B.
Nguyen, M. Corbin, P. Retailleau, L. Ermolenko and A. Al-Mourabit,
Org. Lett. 2015, 17, 4956-4959.
[18] J. Liu, W. Wei, T. Zhao, X. Liu, J. Wu, W. Yu and J. Chang, J. Org.
Chem. 2016, 81, 9326-9336.
[19] a) P. Das, D. Sharma, B. Singh, WO Patent WO/2011/117881, 2011; b)
D. Sharma, Bandna, A. K. Shil, B. Singh, P. Das, Synlett, 2012, 23,
1199-1204; c) D. Bhattacherjee, V. Thakur, A. K. Shil, and P. Das, Adv.
Synth. Catal. 2017, 359, 2202-2208; d) V. Thakur, D. Sharma, P. Das,
Mol Divers, 2016, 20, 29-40.
This article is protected by copyright. All rights reserved.

10.1002/chem.201806299
Chemistry - A European Journal
FULL PAPER
FULL PAPER
Dhananjay Bhattacherjee,Shankar Ram,
Arvind Singh Chauhan, Yamini,
Sheetaland Pralay Das*
Page No. – Page No.
Hypervalent Iodine(III) Mediated
Counter Anion Controlled
Intramolecular Annulation of
Exocyclic-β-Enaminone to
Carbazolone and Imidazo[1,2-
a]pyridine Synthesis
An unique reagent system: A co-operative behaviour of two reagent systems has
been described in the intramolecular annulation process of exocyclic-β-
enaminones. These single reagent system is highly efficient for the C-C as well as
C-N bond formation process. Moreover, the specific behaviour of different counter
anions for the final product formation has been evaluated with spectral evidences.
This article is protected by copyright. All rights reserved.