An Expeditious Benzannulation Reaction of Indol-3-yl-but-3-yn-2-ols to Substituted 2-Iodocarbazoles via Domino 5-endo Spirocyclization/Selective Vinyl Shift and Aromatization

Article abstract of DOI:10.1002/ejoc.201901393

Regioselective benzannulation reaction of indol-3-yl-but-3-yn-2-ols to functionaly embellished 2-iodocarbazoles is described for the first time using iodine at room temperature in an open flask. This reaction proceeds through a cascade of 5-endo spirocyclization, ring-rearrangement through a vinyl shift, and aromatization in a short time. This protocol offers direct access to uncovered 2-iodocarbazoles, with a broad substrate scope and good to moderate yields. Further, we have demonstrated the synthetic potential of these compounds using cross-coupling reactions.

Full text of DOI:10.1002/ejoc.201901393

A Journal of
Accepted Article
Title: An Expediuos Benzannulation reaction of Indol-3-yl-but-3-
yn 2-ols to substituted 2-Iodocarbazoles via Domino 5-endo
spirocyclization/selective vinyl shift and aromatization
Authors: SRINIVASARAO YARAGORLA, Ravikrishna Dada, and
Debojyoti Bag
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901393
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10.1002/ejoc.201901393
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/adsc.2019((will be filled in by the editorial staff))
An Expediuos Benzannulation reaction of Indol-3-yl-but-3-yn 2-
ols to substituted 2-Iodocarbazoles via Domino 5-endo
spirocyclization/selective vinyl shift and aromatization
Srinivasarao Yaragorla,*[a] Ravikrishna Dada[a] and Debojyoti Bag[a]
School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad, 500046, India.
Email:srinivas.yaragorla@uohyd.ac.in
Received:((will be filled in by the editorial staff))
Supporting information for this article is availableon the WWW under http://dx.doi.org/10.1002/adsc.201######.(Please
delete if not appropriate)
Abstract. Regioselective benzannulation reaction of indol-3-yl-but-3-yn-2-ols to functionally embellished 2-
iodocarbazoles is described for the first time using iodine at room temperature in open-flask. This reaction
proceeds through a cascade 5-endo spirocyclization, ring-rearrangement through a vinyl shift and aromatization
in short time. This protocol offers direct access to uncovered 2-iodocarbazoles, with a broad substrate scope and
good to moderate yields. Further, we have demonstrated the synthetic potential of these compounds using cross-
coupling reactions.
Keywords: 2-iodocarbazoles; 1,2-vinyl migration; iodocyclization; benzannulation; 5-endo-spirocycization
successfully employed as diene precursors for the
construction of carbazoles from indoles through
benzannulation protocol.[9] However, some of these
methods suffer from limitations such as usage of
precious metal catalysts (Pt, Au, Ag, Pd, etc.), harsh
reaction conditions and limited functional group
tolerance. Therefore it is highly desirable to develop a
one-pot, transition metal-free approach for the
construction of pre-functionalized carbazoles,
Introduction
Carbazoles belong to an important class of alkaloids
with high natural abundance, often found to exhibit a
wide range of biological activities such as anticancer,
antimicrobial, antibiotic, antipsychotic, and anti-
inflammatory to name a few (Figure 1).[1-2]. Further,
many molecules embedded with carbazole motifs
have found applications in material science,
particularly as organic light-emitting diodes (OLED),
due to its wide bandgap and high luminescent
properties.[3] Owing to the tremendous importance of
carbazole-based structures in these fields, various
synthetic strategies have been developed for the
construction of functionalized carbazoles.[1-4] Despite
the availability of various classical and transition
metal-mediated methods to construct carbazoles,
benzannulation strategy from indole has been
increasingly attracted in recent years because a vast
number of indoles are readily available and easily
particularly
iodocarbazoles[10] because
these
compounds can be easily transformed into desired
carbazole materials using suitable reaction conditions,
such as cross-coupling reactions.
Me
Me
RO
R
OMe
Me
OMe
Me
R
N
N
H
Ph
H
Me
N
H
OH
R=H, hyellazole
R=Me, carbazomycin A
R=H, carbazomycin B
R=Cl, 6-chlorohyellazole
OH
R=CHO, clausine D
R=CO2Me, clausine F
CO2Me
Cl
Me
prepared.
In general, alkenes,[5] alkynes,[6]
Me
nC5H15
carazostatin
N
N
H
CO2H
N
H
OMe
dicarbonyls,[7] and other compounds[4,8] have been
H
carprofen
mukonine
Figure 1. Representative examples of synthetic and natural carbazoles
[a] Dr. Srinivasarao Yaragorla (corresponding author)
Mr. Ravikrishna Dada and Mr. Debojyoti Bag
School of Chemistry, Gurbaksh Building, W-16, 17,
University of Hyderabad, P.O. Central University, Gachibowli,
Hyderabad, 5000046, Telangana State, India.
In the past few years, iodocyclization of
propargylic systems, particularly propargyl alcohols,
has been emerging as one of the potential strategies
for the construction of various pre-functionalized
carbo and heterocyclic compounds.[11] Recently, our
E-mail: srinivas.yaragorla@uohyd.ac.in
Home page: https://sites.google.com/view/srinivasarao-yaragorla
1
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10.1002/ejoc.201901393
European Journal of Organic Chemistry
group has demonstrated a one-pot synthesis of iodo-
yield of anticipated 2-iodocarbazole 2a was only 59%
(Table 1, Entry 1). However, this result encouraged
us to search for a better reaction condition to
maximize the yield of 2a.
quinolines,[11f,11h]
iodochromenes,[11g]
iodo-
fluorenopyrans[12b] though iodocyclization of
propargyl alcohols. Further, these strategic advances
have led to a general, one-pot synthesis of 3-iodo-
carbazoles from indole-tethered propargyl alcohols
(Figure 2).[11h] To the best of our knowledge, there is
no single report available to access 2-iodocarbazoles
through benzannulation or iodocyclization protocol
directly. Our continued investigations in the field of
benzannulation reactions[12] form indole to carbazole
lead us to disclose herein a highly regioselective, one-
pot, transition metal-free and first approach of 2-
iodocarbazole synthesis.
Table 2. Substrate scope.[a]
Figure 2. Our previous and current approaches of carbazoles.
Results and Discussion
Table 1. Optimization of reaction conditions.[a]
Entry Catalyst(equi
v.)
Solvent, Time
Yield(%)[b]
I2 (1.2)
I2 (1.2)
I2 (1.2)
I2 (1.2)
I2 (1.2)
I2 (1.2)
I2 (2.0)
I2 (1.5)
I2 (1.0)
1
THF, 30 min
1,2-DCE, 30 min
59
32
25
53
nr
2
3
Toluene, 1 h
4
CH3CN, 30 min
5
EtOH, 1 h
AcOEt, 15 min
6[c]
7
65
60
62
58
AcOEt, 10 min
8
AcOEt, 15 min
AcOEt, 1 h
9
I2 (1.2) /
NaHCO3 (1)
AcOEt, 1 h
10
48
[a] All reactions were performed with 0.24 mmol of 1a in 3 mL of solvent
with Catalyst at room temperature.
[b] Isolated Yields.
[c]
Optimum condition; DCE=1,2-dichloroethane, AcOEt=Ethyl acetate.
nr=no reaction.
We commenced our studies by investigating the
transformation of 1-(1H-indol-3-yl)-1,2,4-triphenyl
but-3-yn-2-ol 1a with molecular iodine (compound
1a was synthesized in two steps using a known
procedure).[13] The first reaction was performed by
stirring 1 equiv. of 1a and 1.2 equiv. of molecular
iodine in THF at room temperature and observed the
complete conversion of the starting material (1a) after
30 min. Despite of complete conversion, the isolated
[a] General Conditions: A mixture of 1 equiv. of 1 and1.2 equiv. of iodine
were stirred in 3 mL of ethyl acetate rt for a specified time.
2
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10.1002/ejoc.201901393
European Journal of Organic Chemistry
Therefore different solvents have been introduced,
and ethyl acetate was found to be the finest among
1,2-DCE, toluene and acetonitrile (Table 1, Entries 2-
4). The reaction in ethanol didn’t provide the desired
carbazole (Table 1, Entry 5). 1.2 equivalent of iodine
in EtOAc found to be furnishing the cleanest
conversion into the desired 2-iodocarbazole, but the
isolated yield was only 65% (Table 1, Entry 6).
Alteration in iodine stoichiometry resulted in a
moderate decrease in the yield of 2a (Table 1, Entry
7-9). Addition of 1.0 equivalent of NaHCO3 along
with iodine restricted the complete conversion (Table
1, Entry 10) even after 1 h and yielded 48% of 2a.[14]
Therefore the reaction conditions of entry 6 have
been taken as optimum for this benzannulation
reaction. With the optimized condition recognized,
we progressed to demonstrate the generality and
scope of this iodo-cycloisomerisation process
engaging diverse electronic and steric influences on
indolylynol moiety by the deployment of various
substitutions on indole (both N-1 & C-5) and alkyne
terminus of ynol fragment (Table 2). Along with
aromatic (2a-2d) and aliphatic substitutions (2e-2g),
unsubstituted alkynol terminus (2h) also provided the
anticipated iodo-carbazoles in good yields.
Interestingly, when we switch to N-methylindole (2i),
it promoted the formation of the desired carbazole in
better yield (92%) than the corresponding
unsubstituted one (2a). Subsequently, N-1
substitution of indoles with ethyl (2j), benzyl (2k),
allyl (2l) and phenyl (2m) groups was found to be
well tolerated in this reaction conditions by providing
the desired carbazoles in excellent yields. Both
halogen (2n, 2p-2r) and methoxy (2o) substitution on
the C5 position of indole ring were compatible and
led to the formation of the desired carbazoles in good
yields. Later, we briefly studied the effect of different
electronic substitutions on the C1 and C2 phenyl
rings of the 1-(1H-indol-3-yl)-1,2,4-triphenyl but-3-
yn-2-ol moiety. Substitution of C2 phenyl ring with
4-methoxybenzene resulted in the formation of the
desired carbazole with a 4-methoxybenzene ring in
the 3rd position of the newly constructed 2-
iodocarbazole ring (2v). N-ethyl substitution on this
4-methoxybenzene substituted indolyl-ynol moiety
(1w) was also tolerated in this condition providing
the desired carbazole 2w in good yield. These
observations indicate that the N-substituted propargyl
alcohols of 1 are giving higher yields than that of NH
compounds. Astonishingly, replacement of both the
C1 and C2 phenyl rings with 4-methoxybenzene has
introduced a deviation from the straight forward
cyclomerization pathway by providing a mixture of
(4) in 1:1 ratio. The formation of 2-iodocarbazoles
2a-2y and 3,4 was protected through steady and
complementary spectral data and single-crystal X-ray
structure determination of 2b (CCDC No. 1842765),
2e (CCDC No. 1845701) and 3 (CCDC No.
1922296).[16]
OMe
OMe
MeO
OMe
OMe
OH
I2, AcOEt, rt
OMe
N
2 h, 61%, (1:0.5)
N
I
+
N
I
Et
Et
Ph
Ph
Et
Ph
1x
2x
3
OMe
OMe
MeO
I2, AcOEt, rt
OH
+
2 h, 71%,
(1:1)
N
I
N
H
I
H
N
H
Ph
Ph
Ph
2y
4
1y
X-ray structure of compound 3 (CCDC-1922296)
Scheme 1. Effect of substitutions of -phenyl rings of 1x
As depicted in Scheme 2, the formation of spirocyclic
intermediate in this tandem iodo-cycloisomerisation
process
was
tenable
through
isolation,
complementary spectral data, and X-ray structure
analysis of spiro-1f. The subjection of spiro-1f into
the iodocyclization conditions fruitfully resulted in
the corresponding 2-iodocarbazole 2f probing the
spirocyclization pathway. This helped us to propose a
more accurate reaction mechanism (Scheme 4).
Ph OH
Ph
Ph
HO
Ph
Ph
Ph
I
I2, AcOEt,
rt, 1.5 h
I2, AcOEt, rt
I
Me
N
NH
Me
H
2 min
N
Me
spiro-1f
2f
1f
X-ray structure of spiro-1f
[CCDC1842764]
2-iodocarbazole
2x
and
functionalized
dihydrocyclopenta[b]indole 3 in 2:1 ratio via
probable
competitive
cyclomerization
&
Scheme 2. Isolation of spirane intermediate
benzannulation pathway (Scheme 1).[15] The structure
of 3 was unambiguously established by single-crystal
X-ray
The overall study that we have conducted in this
report and our previous work on a similar
substrate[11h] indicate us that these reactions followed
diffraction
(CCDC
No.1922296).[16]
Furthermore, the presence of a 4-methoxyphenyl
group at C1 resulted in the mixture of 2-
iodocarbazole (2y) and dihydrocyclopenta[b]indole
a
different reaction mechanism to yield
regioselective-iodo-carbazoles. In all the cases, the
3
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10.1002/ejoc.201901393
European Journal of Organic Chemistry
basic structure of the reactant (1) is same, but
(importantly) the substitution on R2 in Scheme 3 is
dictating the reaction path. When R2 is 3-indolyl, or
trimethoxyphenyl, the reaction underwent a 1,2-alkyl
migration to yield 3-iodocarbazoles.[11h] In case of R2
is phenyl group, it proceeded through the 1,2-vinyl
migration to yield 2-iodocarbazoles (Table 2). When
R2 is 4-methoxy phenyl, a 5-exo trig cyclization was
operated to furnish cyclopenta-fused indoles 3 and 4
(Scheme 1). Though the exact reason is not yet
understood, we feel that the electronic effects of R2
are playing a significant role in deciding the reaction
path. To answer this question partly, we have
performed a preliminary computational study which
suggested that though the activation barrier for both
migrations is quite high in magnitude 25.55 kcal/mol
(1,2-alkyl migration) and 18.6 kcal/mol (1,2-vinyl
migration), the final product of 1,2-vinyl is preferred
minima in the potential energy surface (PES) by 9.97
kcal/mol (see the supporting information). However
this needs further investigations to conclude the exact
reason.
Scheme 4. Gram scale reaction and Synthetic transformations of 2-
iodocarbazoles
After establishing a practicable new synthesis of 2-
iodocarbazoles, the synthetic utility of these 2-
iodocarbazoles
has
been
demonstrated
by
transforming into various functionalized carbazole
derivatives as described in Scheme 4. Pd-catalysed
Suzuki coupling[17] of 2a with PhB(OH)2 resulted in
the formation of 1,2,3,4-tetraphenyl carbazole (5) in
63% yield. Furthermore, Sonogashira coupling[18] of
2a with phenylacetylene furnished the carbazole 6 in
71%
yield.
A
copper-catalysed
methoxy-
substitution[19] of iodocarbazole 2h was achieved to
get compound 7 in 80% yield.
Conclusion
In summary, we have developed the first report of an
operationally
simple,
iodine
mediated
cycloisomerization of (indole-arylyl)methane tethered
propargyl alcohols to the multi-substituted 2-
iodocarbazoles. This benzannulation protocol
involved in a regioselective 5-endo-spirocyclization
followed by a selective 1,2-alkenyl migration and
aromatization cascade. The structure of the
compounds was unambiguously confirmed with the
help of single crystal X-ray data. Further, the
proposed spirane intermediate was isolated and
confirmed, thus affirmed the exact mechanism. This
protocol offers direct access to the 2-iodocarbazoles,
with a broad scope and good yields at rt in open-flask
conditions. The cross-coupling reactions of these
products were performed to show their synthetic
viability.
Scheme 3. Proposed reaction mechanism
Plausible reaction mechanism of formation of 2-
iodocarbazoles (2) and cyclopenta[b]indoles (3-4) is
depicted in Scheme 3. Initially, alkyne 1 is activated
by the electrophilic iodine to form the cyclic
iodonium intermediate [A], and a regioselective
spirocyclization of [A] via 5-endo trig-cyclization
yields the spirane [B]. Subsequent alkenyl migration
affords [C] which upon dehydration and
aromatization delivers the 2-iodocarbazoles (2). Even
though the mechanism of dihydrocyclopenta[b]indole
formation is not precise, it can be attributed to the
direct annulation of indole C2 into the electrophilic
cyclic iodonium intermediate [A] via a 5-exo trig
passion to give intermediate [E], followed by
dehydration to give 3 or 4.
4
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10.1002/ejoc.201901393
European Journal of Organic Chemistry
Experimental Section
General Procedure for 1,2,3,4-tetraphenyl-9H-
carbazole (5):[20]
General Considerations
Unless otherwise indicated chemicals & solvents
were purchased in high purity grade from commercial
suppliers and used without further purification. Thin
layer chromatography (TLC) carried out on Merck
silica plates (60F254). 1H and 13C{1H} NMR spectra
were recorded on a Bruker Ultra shield 500 MHz 400
MHz spectrometer and all chemical shift values refer
to CDCl3 (δH = 7.26 and δC = 77.16 ppm). Single
crystal X-ray diffraction data were collected in
Bruker D8-Quest, Rigaku Oxford and Bruker Apex-3
diffractometers. The HRMS analysis was obtained by
Bruker-Maxis (ESI-TOF) mass spectrometer. Melting
points were measured with a MEPA LABINDIA
melting point apparatus. Column chromatographic
purifications were performed on silica gel.
PhB(OH)2 (20 mg, 0.16 mmol) was added to a
solution of 2-iodo-1,3,4-triphenyl-9H-carbazole (2a)
(50 mg, 0.10 mmol) in DMF/H2O (2:1; 3.0 mL) that
contained Na2CO3 (11 mg,0.10 mmol), and the
resulting mixture was stirred at room temperature for
5 min. Pd(OAc)2 (5 mol%) was then added, and the
flask was flushed with N2 and sealed. The mixture
was stirred at 100 °C for 4 h and then filtered. The
filter cake was washed with diethyl ether, and the
combined filtrates were extracted with diethyl ether.
The combined organic layers were washed with water
and brine and then dried with anhydrous Na2SO4.
After filtration, the solvent was evaporated under
reduced pressure, and the crude residue was purified
by column chromatography on silica gel to isolate
pure product in 63% (56 mg) yield.
General Procedure for the synthesis of indole
tethered propargyl alcohols (1):[13]
General
Procedure
for
1,3,4-triphenyl-2-
To a solution of phenylacetylene (0.09 g, 0.9 mmol)
at 0 ºC in THF (3 mL), was added n-BuLi (0.479 mL
of a 2 M solution in cyclohexane, 0.9 mmol). The
solution was stirred at 0 ºC for 20 min, then 2-(1H-
indol-3-yl)-1,2-diphenylethan-1-one (0.1 g, 0.32
mmol) in THF (1 mL) was added (2 mmol, 1.0
equiv.) at -45ºC. The resulting mixture was stirred at
room temperature until the starting ketone was
consumed as determined by TLC. The reaction was
quenched with a saturated aqueous NH4Cl solution
and extracted with AcOEt (3 × 15 mL). The
combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated at reduced
pressure. The residue was purified by flash
chromatography on silica gel using mixtures of
hexane and AcOEt as eluents to obtain the 1-(1H-
indol-3-yl)-1,2,4-triphenylbut-3-yn-2-ol (1a) in 98%
(128 mg) yield.
(phenylethynyl)-9H-carbazole (6):
First Pd(OAc)2 (2 mol%) was dissolved in MeCN
(1mL). Then, the indicated amount of Pd(OAc)2
acetonitrile solution was added to a mixture of alkyne
(21 mg, 0.20 mmol) and 2-iodo-1,3,4-triphenyl-9H-
carbazole (2a) (50 mg, 0.10 mmol), DABCO (35 mg,
0.30 mmol), and MeCN (4 mL). Then mixture was
stirred under N2 at room temperature for 12 h.The
resulting mixture was filtered off, washed and
extracted with diethyl ether. The combined organics
were washed with water and then with brine and
dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the residue
was purified by column chromatography with silica
gel to give of product in 71% (33 mg) yield.
General Procedure for 2-methoxy-3,4-diphenyl-
9H-carbazole (7):
-iodo-3,4-diphenyl-9H-carbazole (1g) (50 mg, 0.11
mmol), was added to solution of CuI (10 mol%) in
DMF (2 mL) after 10 min MeONa solution (0.5 mL)
of 25% MeONa in MeOH and HCO2Me (0.2 mL)
General Procedure for Synthesis of 2-
iodocarbazole (2):
Molecular iodine (95 mg, 0.37 mmol) was added to a
°
stirred
solution
of
1-(1H-indol-3-yl)-1,2,4-
was added. The mixture was stirred at 120 C for 12
triphenylbut-3-yn-2-ol (1a) (130 mg, 0.31 mmol) in
AcOEt (3 mL). The resulting mixture was stirred at
room temperature until 1a was consumed as
determined by TLC. The reaction was quenched with
a saturated aqueous solution of Na2S2O3 and extracted
with AcOEt (3×10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated
at reduced pressure. The residue was purified by flash
chromatography on deactivated silica gel (60-120
mesh) using mixtures of hexane and EtOAc as
eluents to obtain the corresponding products 2-iodo-
1,3,4-triphenyl-9H-carbazole (2a) in 65% (110 mg)
yield.
h. The reaction was quenched with a saturated NH4Cl
aqueous solution and extracted with AcOEt (3 × 20
mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated at
reduced pressure. The residue was purified by flash
chromatography on deactivated silica gel using
mixtures of hexane and AcOEt as eluents to obtain
the pure product in 80% (31 mg) yield.
Acknowledgement
SY is thankful for the financial support from CSIR
(02/333/18/EMR-II) India and SERB-2016/4812. RD
thankful to SERB for the fellowship. We also
5
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10.1002/ejoc.201901393
European Journal of Organic Chemistry
acknowledge Dr Jovan Jose for his support for
mechanism.
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7
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FULL PAPER
Benzannulation via iodocyclization
and 1,2-vinyl migration*
Srinivasarao Yaragorla* Ravikrishna
Dada and Debojyoti Bag
Page No. – Page No.
An Expediuos Benzannulation
reaction of Indol-3-yl-but-3-yn 2-ols
to substituted 2-Iodocarbazoles via
Domino 5-endo
spirocyclization/selective vinyl
shift and aromatization
First approach of 2-iodocarbazoles from benzannulation of indole-tethered propargyl alcohols is developed at room temperature in
open-flask reaction using iodine.
8
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