Regioselective 5-endo-dig Electrophilic Iodocyclization of Enediynes: A Convenient Route to Iodo-substituted Indenes and Cyclopenta-Fused Arenes

Article abstract of DOI:10.1002/asia.201601085

An efficient iodine-mediated regioselective tandem approach for the synthesis of symmetric and asymmetric iodo-substituted indenes and stereoselective cyclopenta [b]pyridine/thiophenes from easily accessible enediynes that proceeds by in situ formation of an iodonium intermediate followed by a regioselective 5-endo-dig cyclization has been described. The intramolecular electrophilic iodocyclization was selectively triggered by a distribution of electronic density along the alkyne bond. Subsequently, the iodo-substituted indenes were diversified by employing palladium-catalyzed cross-coupling reactions and the coupled products were further confirmed by X-ray crystallographic studies.

Full text of DOI:10.1002/asia.201601085

CHEMISTRY
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Accepted Article
Title: Regioselective 5-endo-dig Electrophilic Iodocyclization of Enediynes: A Con-
venient Route to Iodo-substituted Indenes and Cyclopenta Fused Arenes
Authors: Akhilesh Kumar Verma; Rakesh K. Saunthwal; Abhinandan K. Danodia;
Monika Patel; Sushil K. Kumar
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COMMUNICATION
Regioselective 5-endo-dig Electrophilic Iodocyclization of
Enediynes: A Convenient Route to Iodo-substituted Indenes and
Cyclopenta Fused Arenes
Rakesh K. Saunthwal, Abhinandan K. Danodia, Monika Patel, Sushil Kumar and Akhilesh K. Verma*
Abstract: An efficient iodine-mediated regioselective tandem
approach for the synthesis of symmetric 4a−g and asymmetric 5a−f
electrophilic iodocylization provide a useful avenue for structure
elaboration to generate complex molecules.[14] The electrophilic
iodocyclization of alkynes and allene bound substrate are an
alternative powerful tool for the construction of diversely
functionalized carbocycles and heterocycles having a mono-iodo
substituent. However, a number of methods are available in the
literature for the synthesis of monoiodonated indenes by
electrophilic cyclization.[15] On introducing an electron-rich alkyne
moiety into the domino transformations via cross-coupling
chemistry leads to the rapid production of polycyclic frameworks.
iodo-substituted
indenes
and
stereoselective
cyclopenta
[b]pyridine/thiophene 6a−h from easily accessible enediynes 3a−u
via in situ formation of iodonium intermediate followed by
regioselective 5-endo-dig cyclization has been described. The
intramolecular electrophilic iodocyclization was selectively triggered
by the distribution of electronic density along the alkyne bond.
Subsequently, the iodo-substituted indenes have been diversified by
employing palladium-catalyzed cross-coupling reactions and the
coupled products were further confirmed by the X-ray
crystallographic studies.
The carbo- and heterocyclic compounds,[1] constitutes an
important class due to their presence in a large number of drug
molecules which acquire
a
remarkable pharmaceutical
activity.[2,3] For instance, indene skeleton with an exo-alkylidene
moiety is embedded in Sulindac (1) which is a non-steroidal anti-
inflammatory drug,[4] Dimethindene (2) an oral anti-histamine
agent and Donepezil (3) [5] an anti-Alzheimer drug (Figure 1).[6,7]
In addition to these commercial medicines, indenes are the
structural constituent of group IV metallocene bound catalyst
which are used for olefin polymerization.[8]
Figure 1 Biological significance of indenes
Due to immense biological activity, a number of synthetic
methodologies have been developed for the construction of
indene moiety such as the ring enlargement of substituted
cyclopropenes,[9] the Lewis acid mediated ring closure of
[10]
substituted 1,3-butadienes
and the reduction or dehydration
of indanones.[11] During the past decade, a rapid interest has
been developed in the area of electrophilic iodocyclization and it
emerge as an extremely active and original field for heterocyclic
synthesis.[12-13] The halide functionality introduced through
Scheme 1. Approach for the synthesis of indene derivatives.
In last few years, Takai,[16a] Larock,[16b,c] Kondo [1] and Tian
[16d]
groups have demonstrated the transition metal C-H
functionalization of alkynes followed by electrophilic annulation
[17a]
to generate indene. Alabugin and co-workers
have
[a]
Rakesh K. Saunthwal , Abhinandan K Danodia, Monika Patel, Sushil
kumar and Akhilesh K. Verma
Department of Chemistry
developed a two-step strategy for the synthesis of benzofulvene
via Bu3SnH mediated 5-exo-dig radical cyclization of diaryl
[17b]
enediyne. Subsequently, Lee et. al
have explored the
University of Delhi, Delhi-110007
E-mail: akverma@acbr.du.ac.in
synthesis of benzofulvenes via Bergman cyclization using
Pd/Cu-catalyst. Farinola group[17c] demonstrated the application
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of symmetric benzofulvene intermediate for the 5-exo-dig
cyclization of macro conjugated molecules with limited substrate
scope (Scheme 1a). In 2009, Khan[18a] and fellow workers
reported the iodine-mediated electrophilic cyclization of
substituted ethenylmalonates for the construction of 3-iodo-1H-
indene derivatives by 5-endo-dig carbocyclization (Scheme 1b).
The synthesis of iodinated indenes via electrophilic
desired product 4a/4a' was observed in 47% yield (entry 2).
Further increasing of the amount of molecular I2 from 1.5 equiv
to 2.0 and then to 2.4 equiv afforded the mixture of isomers
4a/4a' in 74 and 88% yields respectively (entries 3 and 4). When
the reaction was monitored at short interval of time with 2.4
equiv of molecular iodine, the yield of the corresponding
iodocyclized product 4a/4a' remain unchanged (entry 5). Inferior
results were obtained with K3PO4, NaOH, and CsCO3 (entries 6–
9), while no iodocyclized product was detected with Et3 N (entry
10). Although CH2Cl2 is an inadequate solvent for K2CO3
however; K2CO3 provides a mild basic condition which is
essential for a clean and high yielding reaction. K2CO3 is
presumed to avoid the by-product of the reaction which can
degrade the desired product.22 In the absence of base, no
progress in the reaction was observed (entry 11). The
electrophilic cyclization of 3a using ClCH2CH2Cl solvent at 25oC
and 60oC successfully provided the desired product 4a/4a' in 72
and 85% yields respectively with 60:40 stereoisomeric ratio
(entries 12 and 13). However, other solvents like THF, DMF,
MeCN failed to provide the iodocyclized product (entries 14–16).
carbocyclizations of propargylic alcohol in nitromethane have
[18b]
been described by Liang group
in 2011 (Scheme 1c). Later,
Wang and co-workers[18c] synthesized substituted 2,3-
diiodoindenes in dichloromethane (Scheme 1c). They extended
the chemistry for the synthesis of 13H-indeno[1,2-
I]phenanthrenes from synthesized 2,3-diiodoindene through
Suzuki and Scholl oxidative coupling reaction. In 2012, Hashmi
and co-workers,[19a] described gold-catalyzed synthesis of
benzofluvene, via dual activation of substrate (Scheme 1d).
During our manuscript preparation, an iodonium-induced
cyclization of arylallenes has been demonstrated by
Grandclaudon et al. for the synthesis of 2-iodoindenes (Scheme
1e). [19b]
Owing to the broad biological importance of indenes and
limitations in the previous reported strategies, such as use of
expensive metal catalysts, limited scope or availability of starting
materials and requirement of multistep procedures. Due to the
above drawbacks and presence of indenes in many natural
products, this motivated us for designing an efficient route to
synthesize iodo-substituted indenes and heterocycles.
Encouraged by our laboratory results for the synthesis of
Table 1. Optimization of iodocyclization of dialkynylbenzenea
Entry
Solvent
Base
I2
T(°C)
Time(h)
Yield(%)b
4a/4a'
reagent
(equiv)
1.2
pyrano[4,3-b]quinoline
via
iodine-mediated
electrophilic
(E:Z)c
cyclization,[20] herein we report the electrophilic iodocyclization
chemistry for the synthesis of diiodoindenes from dialkynyl
aromatic/heteroaromatic through sequential Sonogashira/
Sonogashira coupling reaction followed by 5-endo-dig
cyclization.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
K3PO4
NaOH
CsCO3
Et3N
25
25
25
25
25
25
25
25
25
25
25
25
60
60
60
60
0.5
1
1
37(75:25)
1.5
2.0
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
47(70:30)
74(70:30)
88(70:30)
88(70:30)
66(68:32)
78(68:32)
40(70:30)
61(70:30)
N. Rd
1
0.5
0.5
1
1
1
1
1
1
1
Our approach towards the synthesis of diiodoindene
involves
two
steps:
(i)
preparation
of
dialkynyl
aromatic/heteroaromatic (3) from 1-bromo-2-iodo-benzene (1)
by sequential Sonogashira/Sonogashira coupling reaction and
-
N. Rd
(ii)
electrophilic
iodocyclization
of
dialkynyl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
72(60:40)
85(60:40)
N. Rd
aromatic/heteroaromatic. The coupling products 3 were obtained
in 76-85% yield in the presence of 2.0 + 3.0 mol % of
Pd(PPh3)2Cl2 by coupling of 1 with terminal alkyne 2.[21] The
coupling reaction accommodates a wide variety of functional
groups (Scheme 2).
1
1
1
DMF
MeCN
N. Rd
N. Rd
[a] Reaction were performed using 1,2-bis(phenylethynyl)benzene 3a
(0.5 mmol), I2, and base (2.0 equiv) and 1.5 mL of solvent unless otherwise
noted.[b]Total isolated yield of two isomers. [c] Stereoisomeric ratio. [d] no
reaction.
After establishing the optimal reaction conditions, we explored
the substrate scope of electrophilic iodocyclization chemistry by
employing various symmetrical 3a–g and unsymmetrical
dialkyne 3h–m in the presence of molecular iodine and afforded
the corresponding mixture of E and Z isomers in 67–88% yields.
Substrate 3a bearing phenyl substituent at R1 and R2 provided a
mixture of E and Z (70:30) isomer in 88% yield. Alkynes 3b–g
bearing electron-rich substituents at R1 and R2 on reaction with
iodine afforded the E:Z mixture of correponding products in 77–
88% yields. Substrates 3c, bearing methyl substitution at the
meta position of the phenyl ring afforded the desired product 4c
along with 4c' in comparatively lower yield. Reaction of 1,2-
bis((4-ethylphenyl) ethynyl)benzene 3d provided the mixture of
stereoisomers E:Z in equal ratio. Substrates 3e–f bearing a tert-
Scheme 2. Sonogashira Reaction of Hindered Aromatic/Heteroaromatic
Dihalide with Alkynes
To identify the optimal reaction conditions for the reaction, we
examined the reaction of 1,2-bis(phenylethynyl)benzene (3a)
with 1.2 equiv of I2, and 2.0 equiv of K2CO3, in 2.0 mL of CH2Cl2
at 25 °C for 0.5 h, the corresponding cyclized product was
obtained in 37% yield in a mixture of E and Z (E:Z::75:25)
isomers (Table 1, entry 1). Increasing the amount of I2 from 1.2
equiv to 1.5 equiv and reaction time from 0.5 h to 1 h, the
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performed using dialkynylbenzene 3 (0.50 mmol), 2.4 equiv of I2 and 2.0
equiv of K2CO3 in 2.0 mL of CH2Cl2 at 25 °C for 0.5 h. [b] Isolated yields.
CCDC number of 5c is 978613 .
butyl, and n-butyl were found suitable for the reaction and
provided the mixture of desired products (4+4') e–f in 87 and
84% yield respectively (entries 5 and 6). The structure of 4e (E-
isomer) was confirmed by the X-ray crystallographic studies.
The electron-rich thiophene alkyne 3g afforded the iodocyclized
product in 77% yield (Scheme 3).
Figure 2. Anisotropic effect
Encourage by the result from X-ray crystallography, NOESY and
NMR spectroscopy, we ascertained the mixture of E and Z
isomer. In Z-isomer, possibly the π orbital of phenyl ring A and B
are in same plane. When an external magnetic field is applied,
then Ha (δ 5.85-6.00 ppm) and Hb proton comes in same
region, therefore Ha proton comes perpendicular to applied
magnetic field and showed the shielding of Ha (δ 5.85-6.00 ppm)
proton (Figure 2). In E-isomer no anisotropic effect occurred
between phenyl ring A and B (as shown in Figure 2). We
presumed that the deshielding of Ha (δ 8.85-9.01 ppm) proton
might be due to induced dipole interaction. This anisotropic
effect also supports the formation of mixture of stereoisomers in
case of 1,2-bis((4-(alkyl)phenyl)ethynyl)benzenes (3).
Scheme 3. Scope of symmetrical dialkyne [a] The reactions were performed
using dialkynylbenzene 3 (0.50 mmol), 2.4 equiv of I2 and 2.0 equiv of K2CO3
in 2.0 mL of CH2Cl2 at 25 °C for 0.5 h. [b] Isolated yields. Data CCDC number
of 4e is 845040 .
The reaction of unsymmetrical alkyne, 1,2-bis((4-(alkyl)phenyl)
ethynyl)benzene containing different substituent at the end of
triple bond have also been investigated. Under similar condition
the various substrates 3h–m bearing different alkyl coupling
partner were found successful for the reaction and provided the
mixture of E and Z isomers 5a–f in 67−80% yields. The structure
of 5c (Z-isomer) was confirmed by the X-ray crystallographic
studies. Interestingly, when substrates 3j were used for
iodocyclization, the formation of Z-isomer was predominated; the
possible reason could be due to the spatial arrangement of
intermediate during the course of reaction. It is noteworthy that
alkynes 3m bearing a electron-withdrawing trifluoromethyl group
at 4-position of the phenyl ring was found successful for the
reaction and provided the desired product (5+5')f in E:Z ::74:26
stereoisomeric ratio in 73% yield (Scheme 4).
Scheme 5. Synthesis of cyclopenta fused arenes via electrophilic
iodocyclization
We further extended the scope of the developed chemistry for
Scheme 4. Scope of unsymmetrical dialkyne. [a] The reactions were
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the synthesis of an important class of heterocyclic scaffold. In
contrast to the phenyl dialkyne, introduction of heteroatom in the
phenyl ring helped in controlling the stereoselectivity of product
(Scheme 5). When we performed the reaction using electron-
deficient pyridyl substrates containing symmetrical alkynes
bearing –Ph (3n),–p-tolyl (3o) and 4-methoxyphenyl (3p) groups
with iodine, we observed exclusive Z isomer of 6a, 6b and 6c in
70%, 72% and 75% yields, respectively. Unsymmetrical
alkyne(3q) were also successful in providing the iodocyclized
product 6d in 73% yield. Interestingly, 2,3-bis (phenylethynyl)
pyrazine (3r) and 2,3-bis(phenylethynyl)quinoxaline (3s) were
also capable in providing the intriguing iodocyclized products
6e–f in 68–72% yields with excellent stereoselectivity. The
synthesis of (E)-6-iodo-4-(iodo(4-methoxyphenyl)methylene)-5-
(4-methoxy phenyl) -4H-cyclopenta[b]thiophene (6g) and (E)-4-
(6-iodo-4-(iodo(4-methoxyphenyl) methylene)-4H-cyclopenta[b]
thiophen-5-yl)-N,N-dimethylaniline (6h) were carried out in good
yields with high stereoselectivity using dialkynylthiophene 3t and
3u using optimized reaction conditions. It is noteworthy, that the
reaction of heterocyclic dialkyne provided a single stereoisomer
probably due to the electronic effect of the heterocyclic moiety.
Scheme 7. Synthetic elaboration using Pd-catalyzed cross-coupling reactions
We further investigated the structural elaboration of iodo-
substituted indene via palladium-catalyzed cross-coupling
reactions. To this end, mixture of (4+4')e was functionalized by
applying palladium-catalyzed Suzuki and Sonogashira coupling
reactions and the corresponding coupling products 8 and 9 were
obtained in 78% and 80% yields, respectively (Scheme 7). The
structure of Sonogashira coupled product was further confirmed
by X-ray crystallographic data (Figure 3).
C25
O1
C1
C24
C23
C48
C46
C26
C27
C2
O2
C7
C3
C4
C47
C40 C41
C42
C22
C8
C6
C9
C5
C45
C28
C29
C30
C21
C10
C11
C43 C44
C31
C35
C34
C12
C16
C32
C33
C13
C14
C15
C36
C37
C18
C17
C20
C39
C38
C19
9
Figure 3. X-ray crystallographic ORTEP drawing of compound 9 drawn at the
50% probability level . CCDC number of 9 is 978612
In summary, we have described the iodine-mediated 5-
endo-dig cyclization for the regio- and stereoselective synthesis
of diiodo-substituted indenes, cyclopenta[b]pyridine/thiophene
from easily accessible enediynes via in situ formation of
iodonium intermediate. It is noteworthy, that the reaction of
heterocyclic arenes provided the single stereoisomers in good
yields. Iodo-cyclization method leads to the synthesis of
halogen containing indene derivatives which thereafter
elaborated using palladium catalyzed coupling reactions, such
as Suzuki-Miyaura and Sonogashira coupling reactions. The X-
ray crystallographic studies confirmed the stereochemistry of the
reaction products. Due to the immense diversity in the
substitution pattern, this developed chemistry can be used for
the synthesis of various heterocyclic systems.
Scheme 6. Plausible mechanism
On the basis of the above observations, a plausible reaction
mechanism for 5-endo-dig iodocylization has been described in
Scheme 6. Presumably the electrophile (I2) and the enediynes 3
would generate the cyclic iodonium intermediate P and Q upon
electrophilic attack of the I2 on the electron deficient carbon of
alkyne. Subsequent attack of nucleophile provides the mixture of
E and Z isomers via 5-endo-dig cyclization. The formation of E
and Z isomer depends upon the attack of the iodine nucleophile
on to alkyne carbon via route a or b. The present strategy
depicts the dual role of I2 as an electrophile as well as
nucleophile.
Experimental Section
General Information Method
Nuclear magnetic resonance spectra were recorded in CDCl3, 1H NMR
(400 MHz) and 13C NMR (100 MHz), at ambient temperature. Chemical
shifts (δ) for all protons are reported in parts per million (ppm) and were
measured relative to the residual CHCl3 resonance as an internal
reference in the deuterated solvent. Chemical shifts were reported as
parts per million (δ in ppm) using tetramethylsilane (TMS) as internal
standard or by reference to proton resonances resulting from incomplete
deuteration of the NMR solvent. The following abbreviations were used to
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COMMUNICATION
describe the multiplicities: when appropriate (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, dd = doublet of doublet, td = triplet of
doublet). Reactions were monitored using thin-layer chromatography on
commercially prepared silica gel plates and visualized by either UV
irradiation or by staining with I2. Chemical yields are referred to the pure
isolated substances. Chromatographic purification of the compounds was
accomplished by column chromatography using 100− 200 mesh size
silica gels.
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General Procedure for the Synthesis of Diiodoindene 4+4'
To a vial dialkynyl aromatic/heteroaromatic 3 (0.50 mmol) and 2.4 equiv
of I2 and 2.0 equiv of K2CO3 was added in CH2Cl2. The reaction vial was
then sealed and stirred at room temperature until TLC revealed complete
conversion of the starting material. The solution was washed with
saturated solution of Na2S2O3 and then extracted with EtOAc(3X10
mL).The combined organic layers were dried over Na2SO4, concentrated
under vacuum, and purified by column chromatography using 100− 200
mesh size silica gels (hexane) to afford the corresponding product 3
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Acknowledgements
The work was supported by SERB (DST) and University of Delhi.
R.K.S , A.K.D and M.P. are thankful to DST, RGNF and and
UGC for fellowship.
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Keywords Regioselective • 5-endo-dig • Electrophilic
Iodocyclization • Indenes • Enediynes
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Chemistry - An Asian Journal
10.1002/asia.201601085
COMMUNICATION
COMMUNICATION
Rakesh K. Saunthwal, Abhinandan K.
Dahanodia, Monika Patel, Sushil Kumar
and Akhilesh K. Verma*
Page No. – Page No.
Regioselective 5-endo-dig
Electrophilic Iodocyclization of
Enediynes: A Convenient Route to
Iodo-substituted Indenes and
Cyclopenta Fused Arenes
An efficient iodine-mediated regioselective tandem approach for the synthesis of
symmetric 4a−g and asymmetric 5a−f iodo-substituted indenes and stereoselective
cyclopenta [b]pyridine/thiophene 6a−h from easily accessible enediynes 3a−u via in
situ formation of iodonium intermediate followed by regioselective 5-endo-dig
cyclization has been described. The intramolecular electrophilic iodocyclization was
selectively triggered by the distribution of electronic density along the alkyne bond.
Subsequently, the iodo-substituted indenes have been diversified by employing
palladium-catalyzed cross-coupling reactions and the coupled products were further
confirmed by the X-ray crystallographic studies.
For internal use, please do not delete. Submitted_Manuscript
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