Abstract
ABSTRACT
Electrophilic Iodination of Electron rich Aromatics and Alkynes their
Application in the Synthesis of Heterocycles and C-C bond formation
The present thesis primarily deals with the utilization of iodine or iodides in
substitution reactions or in catalytic organic transformations.
Iodine/Iodide
Substitution
reactions
Chapter-I
Chapter-II
Catalytic
reactions
Chapter-III
General introduction on
* Halogenation
* Iodination
* Synthetic application of
Iodo compunds
Chapter-IV
Chapter-V
*Oxyiodination of indoles and
application in C-C bond
formations
* Oxidative esterification of
aldehydes and alcohols
Oxy-iodination of
*Alkynes
*Phenols
*Application in the synthesis of
5-iodo-triazoles and 2-substituted
benzofurans
*Electrophilic iodination of anilines
*Synthesis of 2-alkynyl anilines
*Synthesis of 2-substituted indoles and
further transformation into
2-aryl-benzoxazinones
*Electrophilic iodination of anilines
*Oxidation of iodo-anilines to iodo-nitro compouns
*Application of iodo-nitro aromatic in C-C bond formations
Figure 1
i
Abstract
Major part of the work deals with the electrophilic or oxidative iodination of
electron rich organic moieties like phenols, anilines, indoles and alkynes their further
application in the synthesis of heterocyclic compounds as well as in C-C bond
formations. The other part of the work is on exploring the possibility of iodide mediated
catalytic organic transformations under oxidative conditions. Schematic representation of
the thesis is presented (Fig 1) above and which is further followed by a brief description
of each chapter.
Chapter I. Introduction
This chapter describes the general features of halogens and their reactivity
towards organic compounds viz., fluorination, chlorination and bromination using
different halogen based reagents. More emphasis is laid on iodination of various organic
compounds and their application in the synthesis of heterocycles and in the formation of
C-C bond via metal catalyzed reactions.
Chapter II. Mild and efficient Oxy-iodination of Alkynes and Phenols with
Potassium iodide and tert-butyl hydroperoxide
Iodoalkynes are useful precursors in synthetic organic chemistry. These
iodoalkynes have been utilized in the synthesis of asymmetric acetylenes, enynes and
enediynes and also for construction of C-C bonds. These motifs play a significant role in
pharmaceuticals and natural products. Similarly, iodophenols are used as building blocks
for the synthesis of various organic compounds that have importance in medicine, biochemistry and pharmaceutics and they were also useful for C-C, C-N and C-O bond
forming reactions.
Numerous methods have been appeared in the literature for the preparation of 1iodoalkynes employing various metal catalysts, anodic oxidation, hypervalent iodonium
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Abstract
salts, ionic liquids, bases, phase transfer catalysts (PTC), ultrasound, iodine oxide,
Grignard reagent and n-BuLi. Similarly, several reports have been developed for the
iodination of phenols using iodinating agents such as, N-iodosuccinimide (NIS),
bis(pyridinium)iodonium(I)tetrafluoroborate (IPy2BF4), iodochloride (ICl) and potassium
iodide (KI).
However, these procedures have disadvantages like, involving the complex
synthetic processes, use of expensive reagents such as hypervalent iodine reagents, metal
iodides and moreover generates considerable amount of waste materials. In order to
overcome some of the disadvantages associated with the above synthetic procedures in
preparation of iodoalkynes and iodophenols, we were interested in developing mild and
efficient methods.
The present chapter deals with the development of new methodology for the
synthesis of 1-iodoalkynes and iodophenols via oxy-iodination route. A simple treatment
of terminal alkynes and phenols at room temperature in the presence of potassium iodide
as iodinating source and tert-butyl hydroperoxide (TBHP) as an oxidant provided
selectively 1-iodoalkynes and iodophenols respectively. Further these iodo compounds
were used for synthesis of 5-iodo-triazoles and 2-substituted benzofurans (Scheme-1, 2).
I
R
H + KI
1.5 mmol TBHP
Methanol, r.t, 6h
R= Aromatic or Aliphatic
R
I
Upto 97%
Scheme 1
iii
Ph
N3, CuI
DMSO, 80oC
R
N
N N
Upto 99%
Abstract
R1
OH + KI
1.5 mmol TBHP
Methanol, r.t, 6h
R1= EWD or ED group
R1
OH
H
R2, Cu2O
Pyridine,120oC
R1
R2
O
I
Upto 92%
R2= n-Pentyl, Ph
Upto 92%
Scheme 2
Key feature of this chapter:
 This is one of the mild and efficient routes for the synthesis 1-iodo-alkynes, avoiding
the use of external base, additives and air sensitive reagents.
 The present methods also do not require any expensive metal catalysts or hypervalent
iodine reagents, which are generally used for iodination.
 In this method 100% iodine atom-economy was achieved
 Application of iodo-alkynes and iodo-phenols were shown by synthesizing 5-iodo-1,
4-disubstituted-1, 2, 3-triazoles and 2-arylbenzofuran derivatives in high yields.
Chapter III. Synthesis of Iodo-Substituted Aromatic Nitro Compounds and Their
Application in C-C Coupling Chemistry
Aromatic nitro compounds have greater importance in many industrial
applications, such as in the preparation of explosives, dyes, perfumes, pharmaceutics and
in plastic industries. Seebach quoted them as “ideal intermediates in organic synthesis”
and introduction of halogen particularly iodine on the ring, which can facilitate the
coupling chemistry will further expand the synthetic importance of these compounds.
One can visualize three approaches for the synthesis of iodo-substituted aromatic nitro
compounds (Scheme 3). One of the approaches is the direct iodination on the aromatic nitro
compounds (A). However, it is known that the unlike chlorine and bromine, iodine is the
least reactive halogen towards the electrophilic aromatic substitution and needs a more
powerful iodinating species than iodine for direct aromatic iodination. Moreover,
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Abstract
electrophilic iodination is even more difficult by the presence of electron withdrawing
nitro group and needs harsh reaction conditions. Alternatively, direct nitration of
aromatic iodo compounds (B) with classical methods which involves harsh reaction
conditions results in a mixture of ortho- and para- compounds. Hence, an ideal and more
practical approach could be an indirect two step method involving electrophilic
iodination of anilines followed by selective oxidation of aromatic amines to nitro
derivatives (C and D).
NO2
I
NO2
B
A
I
D
NH2
NH2
C
I
.
Scheme 3
This chapter deals with the two step strategy for the synthesis of iodo-substituted
aromatic nitro compounds. We have developed a mild procedure for the iodination of
anilines with molecular iodine in 1N acetic acid to provide the iodo-substituted anilines
in high yields. A novel method using catalytic amount of potassium iodide in
combination of TBHP developed in our laboratory is efficiently utilized in selective
oxidation of aromatic amines to corresponding nitro derivatives. These compounds are
further successfully applied for C-C coupling chemistry. We have generalized the
reactivities for Suzuki, Sonogashira and Heck reactions using different palladium
catalysts (Scheme 4).
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Abstract
R1
NH2
R
NO2
NH2
I2, 1N AcOH
r.t 8h.
/C
Pd o C
) 2,
H
, 70
(O
tOH
R-B
E
,
CO 3
K2
KI, TBHP
R
I CH CN, 80oC
3
16 Examples
Yields 51-91%
R
R
I
9 Examples
Yields 51-98%
H
Pd/C, K2CO3
DMF, 100oC
A lk
e
TB ne, P
d(
AC
DM l, N OAc)
a
F,
80 o 2 CO 2
C 3
O2N
R
R1=-OCH3, Br, NO2, CF3
10 Examples,Yields 56-95%
R1
O2N
R
R1=n-C6H11, Ph, PhCH3,
PhOCH3
9 Examples,Yields 40-98%
O2N
R
R1
R1=tolyl, CO2Me, C6H5
15 Examples,Yields 70-95%
Scheme 4
Key feature of this chapter:
 It avoids the use of expensive metal catalysts and hypervalent iodine reagents in
iodination of anilines.
 It avoids the use of strong acids as well as strong bases in iodinations as well as in
oxidation of iodoaniline derivatives.
 An alternative route under milder conditions for the synthesis of iodo-nitro
compounds is achieved by selective oxidation of anilines using KI-TBHP system.
 Iodo nitro compound which were prepared in high yields were further successfully
utilized in various C-C coupling reactions.
Chapter IV. Mild and efficient synthesis of 2-Aryl-4H-3,1-Benzoxazin-4-ones via 2substituted Indoles by using KI/TBHP system
The indole ring system is probably the most ubiquitous heterocycle in nature.
Owing to the great structural diversity of biologically active indoles, it is not surprising
that the indole ring system has become an important structural component in many
pharmaceutical agents. Substituted indoles have been referred to as “privileged
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Abstract
structures” since they are capable of binding to many receptors with high affinity and
several 2-substituted indole derivatives were useful in medicine and pharmaceutics.
Similarly, 4H-3,1-benzoxazin-4-one derivatives which were first synthesized in
1883. These compounds were used as precursors for the synthesis of biologically active
compounds like antimicrobial and analgesics. Several synthetic routes are available in the
literature for the synthesis of indoles and benzoxazinone.
In most of the cases, 2-substituted indoles were prepared by using oalkynylaniline derivatives with transition metal catalysts like palladium and/or copper.
This reaction follows two main steps (i) alkynylation of 2-bromo or iodoaniline
derivative via Sonogashira coupling (ii) followed by cyclization with a base or catalyst.
Regarding the synthesis of 4H-3, 1-benzoxazin-4-one derivatives several methods
have been reported. Among one of N-anthranilic acid derivatives is the most preferred
one. Other methods reported are, from isatoic anhydrides, from oxidation of 2-substituted
indoles and indole derivatives and from other compounds.
In this chapter we have developed a new methodology for the synthesis of 4H-3,
1-benzoxazin-4-one derivatives via oxidation of 2-substituted indoles using KI-TBHP
combination. Moreover, 2-substituted indoles were synthesized using 2-iodo-anilines
which in turn synthesized from a mild iodination route developed as a part of the thesis
work (Scheme 5, 6).
R1
NH2
R
I2, IN AcOH
r.t
I
R
R
Alkyne, PdCl2(PPh3)2
CuI, Et2NH, DMF,70oC
NH2
R
Scheme 5
vii
ZnBr2, toluene
o
NH2
110 C
R1
N
H
Abstract
O
R
KI, TBHP
CH3CN, r.t
R1
N
H
R
O
N
R1
Scheme 6
Key feature of this chapter:
 A new synthetic methodology is developed for the preparation of 2-arylbenzoxazinone derivatives via oxidation of 2-aryl-indoles in the presence of KITBHP. The present procedure provides high yields of the desired products compare to
previous reports.
Chapter V. Oxy-iodination of Indoles by using KI/TBHP and its Application on C-C
bond formation and Catalytic Oxidative Esterification of Aldehydes and Alcohols
Using KI-TBHP
This chapter is divided into two sections.
Chapter V. Section A. Oxy-iodination of Indoles by using KI/TBHP and its
Application on C-C bond formation
Iodo indoles are the best synthetic precursors for the synthesis of a wide range of
3-indole derivatives having biological and pharmaceutical importance. The general
synthetic strategy involves the compounds of 3-iodoindoles using Heck, Suzuki,
Sonogashira and other C-C coupling reactions.
Few synthetic procedures for the preparation of 3-iodoindoles have been reported,
by using molecular iodine or iodinating agents with base or acid. However, these
procedures have disadvantages like, involving the moisture sensitive reagents, use of
strong bases in stoichiometric or more than stoichiometric amounts, use of expensive
reagents such as hypervalent iodine reagents and use of strong acidic media such as HCl,
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Abstract
H2SO4 in 2-10 equivalents and moreover generates considerable amount of waste
materials.
This chapter deals with the development of mild and efficient method for the
synthesis of 3-iodoindole derivatives (Scheme 7). We have shown that treatment of a
variety of indoles with simple potassium iodide as iodinating source and tert-butyl
hydroperoxide (TBHP) as an external oxidant at room temperature selectively provides 3iodoindole derivatives respectively. These 3-iodo indoles are protected with Boc
anhydride and further used in C-C coupling reactions.
R1
R
N
Boc
R1=Aromatic, Aliphatic
I
Cu
)3 2,
h
.t
PP
l 2( N, r
C
d
t
3
P
E
R1
I
R
a,b
R
N
H
(a) KI, TBHP, methanol, r.t
(b)Boc-anhydride, DMAP, Et3N
DCM, r.t.
R
Pd(OAc)2, P(O-Tol)3
N
Boc
K2CO3, Acetone-H2O
70oC
TB
Pd ACl
(O , D
M
Ac
)2 , F, 8
Na
0o
2 CO C
N
Boc
R1= -OCH3, -CF3
O
3
R1
O
R
N
Boc
R1= methyl, t-Butyl, n-butyl, iso-butyl
Scheme 7
Key feature of this chapter:
 No need of any expensive metal catalyst or hypervalent iodine reagent, by using a
simple KI is required as iodinating source.
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Abstract
 No need of strong basic media, in situ generated potassium hydroxide is enough.
 Further iodinated compounds were utilized in the synthesis of C-C bond formation
reactions like Sonogashira, Suzuki and Heck with palladium catalysts.
Chapter V. Section B. Catalytic Oxidative Esterification of Aldehydes and Alcohols
Using KI/TBHP
Direct conversion of aldehydes to ester is one such reaction, which is often
required in the synthesis of natural products. Traditional synthesis of esters generally
involves the nucleophilic addition of an alcohol to activated carboxylic acid derivatives
such as acid anhydrides or chlorides. Recently, several catalytic methods have been
reported for the direct conversion of aldehydes to esters using different catalysts and
reagents for example, MnO2-HCN, (Ipy2BF4), NIS, MTO-H2O2, Oxone, V2O5-SPB or
SPC, Cu(ClO4)2–InBr3–TBHP, Pd-siloxane, and NaIO4-LiBr. Unfortunately, several of
these methods have limitations in terms of cost, ready availability, safety and easy
handling of the reagents and catalysts.
In this chapter a catalytic oxidative esterification of aldehydes and alcohols using
KI-TBHP as an external oxidant is described (Scheme 8). The KI-TBHP catalyzed
oxidative esterification occurred smoothly to provide the desired ester in good yields. The
oxidative esterification reaction was amenable to both electron-rich and electron-poor
aromatic aldehydes. Electron-withdrawing groups on the aromatic ring enhance the
activity. More gratifying was the compatibility of the reaction to proceed successfully
with hetero-aromatic and aliphatic aldehydes as substrates.
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Abstract
O
H
R
O
KI-TBHP
Methanol, 65o C
(or)
OMe
R
OH
Upto 98%
R
Scheme 8
Key feature of this chapter:
 It is a metal-free system.
 A catalytic amount of potassium iodide was required to promote the reaction,
whereas an equivalent amount of iodine was used in earlier methods.
 It is a green process, where the by-products are water and t-BuOH.
 This method does not require the use of any external base.
Significant Achievements:
 The iodination of alkynes, phenols, anilines and indoles doesn’t require any
external base, metal catalyst or hypervalent iodine reagent. By using KI-TBHP,
we achieved the iodinated products in good to excellent yields.
 In oxidation reaction, catalytic amount of KI is required.
 Selectively para-iodo nitro compounds were prepared in good yields in two steps.
 2-Aryl-benzoxazinones were prepared in good yields from 2-aryl-indoles.
 Iodinated products were further used in either synthesis of heterocycles or in C-C
bond forming reactions.
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