Utility of pentachloropyridine in organic synthesis

Abstract

Pentachloropyridine is one of the most important perhalogenated compounds which find broad applications in many fields of chemistry. This review aims to describe the different strategies developed so far for the synthesis, reaction and use of pentachloropyridine as building blocks in the synthesis of chemical relevant organic compounds. In the first part of the review, the different synthetic approaches of pentachloropyridine have been described. In the other part, an overview of the utility of pentachloropyridine into heterocyclic compounds, as well as other organic derivatives derived from pentachloropyridine, is presented. It has been shown in the literature that many factors including the nature of nucleophile, reaction condition, and solvent can have significant influences in the regiochemistry of the reactions of this heteroaromatic compound.

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Vol.:(0123456789)
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Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01909-y
REVIEW
Utility ofpentachloropyridine inorganic synthesis
RezaRanjbar‑Karimi1· TayebehDavoodian1· HosseinMehrabi1
Received: 23 July 2019 / Accepted: 10 March 2020
© Iranian Chemical Society 2020
Abstract
Pentachloropyridine is one of the most important perhalogenated compounds which find broad applications in many fields
of chemistry. This review aims to describe the different strategies developed so far for the synthesis, reaction and use of pen‑
tachloropyridine as building blocks in the synthesis of chemical relevant organic compounds. In the first part of the review,
the different synthetic approaches of pentachloropyridine have been described. In the other part, an overview of the utility of
pentachloropyridine into heterocyclic compounds, as well as other organic derivatives derived from pentachloropyridine, is
presented. It has been shown in the literature that many factors including the nature of nucleophile, reaction condition, and
solvent can have significant influences in the regiochemistry of the reactions of this heteroaromatic compound.
Graphic abstract
Keywords Pentachloropyridine· Perchloropyridine· Aromatic nucleophilic substitution· Polysubstituted pyridine·
Macrocycle
Introduction
Heterocycles represent a larger group of organic compounds
and play an important role in all aspects of pure and applied
chemistry. The subgroup of this class called perhalogenated
heterocyclic compound since the intensive development of
the synthetic chemistry of heterocycles started in the last
few years [1–3].
* Reza Ranjbar‑Karimi
r.ranjbarkarimi@vru.ac.ir; Karimi_r110@yahoo.com
1 Department ofChemistry, Faculty ofScience, Vali‑E‑Asr
University, Rafsanjan77176, IslamicRepublicofIran

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Nowadays, chlorinated heterocyclic compounds can
be found among potent pharmaceuticals, crop protection
agents, and products of technical importance. This merg‑
ing area of organic, heterocyclic, and chlorine organic
chemistry is still rapidly growing, and in the last decades,
many chlorinated heterocyclic materials have been dis‑
covered. Substituted pyridines are an important material
in organic chemistry, biochemistry, and pharmaceutical
chemistry [4–7]. Preparation of highly substituted pyridine
derivatives from pyridine itself is very difficult, and only
limited progress has been made using such an approach
[8]. In contrast, perhalogenated pyridine is potentially
excellent scaffolds because they are highly reactive toward
nucleophilic attack as a result of their electron‑deficient
nature, and in principle, all halogen atoms may be dis‑
placed by nucleophiles. Mono‑, di‑, tri‑, tetra‑, and penta‑
substituted pyridine, fused heterocyclic compounds, mac‑
rocycles, and other useful organic compounds have been
synthesized from the reaction of the corresponding C‑, N‑,
S‑, P‑, and O‑centered nucleophiles as well as bidentate
nucleophiles with pentachloropyridine [9–12]. It should
be pointed out despite the use of pentachloropyridine in
organic synthesis, to the best of our knowledge, no com‑
prehensive review describing both synthesis and the reac‑
tivity of this interesting substrate has been reported in the
literature so far. Therefore, a systematic review that com‑
monly and exclusively describes the approaches as well as
the reactivity of pentachloropyridine, is highly desirable.
This review covers the works reported on the utility of
pentachloropyridine in organic synthesis from begin‑
ning to now, although we were trying to follow descrip‑
tion methods for the synthesis and reactivity of relevant
derivatives synthesized by pentachloropyridine and their
use as building blocks in the manufacturing of organic
compounds.
Synthesis ofpentachloropyridine
The first realistic and readily scaled synthesis of penta‑
chloropyridine 3 was reported by Kekule, and it is impor‑
tant to note that the report about this work has never
been written [13]. Alternatively, commercially available
pentachloropyridine 3 and its derivatives can be further
functionalized by Sell and Dootson [14]. By using this
methodology, the only by‑product, HCl, is spontaneously
eliminated from the reaction mixture, by allowing to cool
and opened from time to time of the tube to the escape of
hydrogen chloride. Another popular method for function‑
alization of pentachloropyridine 3 was represented in low
overall yield by heating a mixture of pyridine at 250°C
[15, 16], and with using an excess of phosphorus penta‑
chloride, the mixture of products can be formed [18–29].
Different approaches for the synthesis of pentachloropyri‑
dine are sumuraized in Scheme1.
Scheme1 Different approaches for the synthesis of pentachloropyridine

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Reactivity ofpentachloropyridine
Pentachloropyridine 3 has a broad and developing chem‑
istry that basically arises from the replacement of chlorine
atom by aromatic nucleophilic substitution reactions [29,
30]. Nucleophilic substitution of polychloropyridines by
various nucleophiles is of considerable interest and has
been extensively studied for all known polychloropyri‑
dines. It is surprising that pentachloropyridine 3 could be
a good starting as well as its reactivities is well docu‑
mented in a number of articles [31–34]. A great num‑
ber of reactions have been done via the AE‑mechanism,
SN(ANRORC), EA‑mechanism, and SRN1‑mechanism.
Differentiation reactivity of perchlorinated heteroaromatic
compounds toward nucleophiles was achieved by substi‑
tution at 2‑, 3‑, and 4‑positions of pyridine [35–37]. The
regioselectivity of nucleophilic substitution of pentachlo‑
ropyridine 3 was explained by the ortho and para sites
of pyridine ring nitrogen. The selectivity of nucleophilic
substitution in the 3‑position can successfully occur under
strong bases because of inducing EA‑mechanisms or metal
catalysis [38–41].
Reactions ofpentachloropyridine
The most important reaction of pentachloropyridine 3 covers
a broad range of nucleophilic substitution reactions. In gen‑
eral rule, reactions of nucleophiles with pentachloropyridine
3 occur almost exclusively to give products arising from
ortho and para to ring nitrogen in which bulky nucleophiles
are more likely to attack the less hindered 2‑position, while
small nucleophiles substitute the 4‑position (Fig.1). The
main approaches have been developed for the reaction of
pentachloropyridine 3 which is summarized in Scheme2
[16]. This reactivity profile has been utilized in organic syn‑
thesis and material sciences, to stabilize reactive anionic
species such as pyrimidinium‑olates [42], so nucleophilic
substitutions on pentachloropyridine 3 with aminopyridine
derivatives give a variety of mono‑, tri‑, and pentacationic
4‑aminopyridine derivatives 12 in quantitative yield.
Nucleophilic substitution reactions
ofpentachloropyridine
Reaction ofpentachloropyridine withN‑centered
nucleophiles
In general, several N‑centered nucleophiles, including
ammonia, piperidine, and diethylamine, reacted with pen‑
tachloropyridine 3, for giving substitution at the 4‑ (1–70%
yield) or 2‑position (30–99% yield) (Scheme3) [17, 18,
43–45].
As shown in Scheme3, there are comprehensive stud‑
ies on the substitution of pentachloropyridine 3; however,
the outcome of substitution is not as clear‑cut as it appears.
The reaction of pentachloropyridine 3 with amines in the
boiling point of ethanol or benzene is shown to be quite
efficient in the high stereoselectivity, and the tetrachloro‑
pyridine is formed as the product. Thus, the study of the
Fig. 1 Site selectivity of pentachloropyridine
Scheme2 Reaction of penta‑
chloropyridine in different posi‑
tions and with aminopyridine

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use of the solvent was performed. When the aprotic solvent
was used, the amine probably formed the hydrogen bonds
to the ring nitrogen atom, thus promoting 2‑substitution and
affording comparable yields in all tested examples. In con‑
trast, in a protic solvent, it was observed that a competitive
hydrogen bonding with the ring nitrogen atom between the
solvent and the amine verified functionalized product 18 in
excellent yield [46]. Anyway, the success of conversion of
4‑alkylaminotetrachloropyridine to “3,4,5,6‑tetrachloro‑
2‑dimethylaminopyridine 16” in 88% yield is due to the
use of an aqueous ethanolic solution of dimethylamine and
subsequently by diazotization with HNO3/HCl (Scheme4).
As shown in Scheme4, it is important to point out that the
presence of substitution in 4‑position has a dramatic effect
on accelerating the reaction [47].
In this sense, pentachloropyridine 3 can be considered as a
suitable material on the reaction of with the various aliphatic
amines such as piperidine and morpholine which showed
a predominant form of 4‑alkylaminotetrachloropyridines
together with the corresponding 2,4‑derivatives 23 in 80%
yield (Scheme5).
The same group of researchers [48], in another study,
employed aromatic amines in dimethylformamide in
the presence of sodium carbonate for the preparation of
4‑arylaminotetrachloropyridine 24 in moderate‑to‑good
yields (36–65%) after successive reactions (Scheme6). The
reaction between pentachloropyridine 3 and nucleophilic
reagents takes place in position 4 of the pyridine ring, and
best results were obtained with amines which have nucleo‑
philic properties in all the examples except in aniline and
other aromatic amines containing electron‑accepting groups
in the benzene ring.
In another work, the reaction of several di‑functional
nucleophiles was described in boiling ethanol as solvent. By
reacting of pentachloropyridine 3 with ethane‑l,2‑diamine
25 or dodecane‑ 1,12‑diamine, the respective products were
obtained in low‑to‑moderate yields (5–41%) (Scheme7). In
the literature, these compounds are described as being useful
materials both because of their possible biological activity
and because of the initial products for further intramolecular
nucleophilic substitution to the synthesis of novel heterocy‑
clic systems [49, 50].
Synthesis andreaction ofheteroarenium‑substituted pyri‑
dines Chlorine atom in 4‑position of pentachloropyridine
Scheme 3 Substitution reaction of pentachloropyridine with some
amines
Scheme4 Synthesis of 2‑sub‑
stituted of polychloropyridines
Scheme5 Reaction between
pentachloropyridine, sodium
ethoxide and morpholine
Scheme6 Synthesis of 4‑aminosubstituted pyridine

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3 is the most susceptible leaving group toward substitution
reaction with nucleophiles. Of particular interest, the reac‑
tion of pentachloropyridine 3 with N,N‑dimethylpyridine‑
4‑amine 29 has been investigated and new bis‑heteroarenium
salt 30 was derived in high yield (99%). The development
of new methods for the synthesis of bis‑heteroarenium salt
30 has received significant attention due to the versatility
of this class of compounds as important synthetic targets,
which exhibit interesting in the forward step for the reac‑
tion toward O‑, N‑, and S‑nucleophiles. The conventional
method for the straightforward synthesis of products is the
nucleophilic substitution reaction at 4‑position. By using
the approach depicted in Scheme8, several other important
molecules were synthesized in moderate‑to‑good yields and
also with reducing agent in another work 5 obtained in 95%
yield [51–55].
It is obvious that heteroarenium‑substituted pyridines are
also powerful building blocks in organic chemistry, being
used, for instance, in the synthesis of highly substituted
pyridines and biologically active compounds [42, 55–59].
As mentioned above, betainic and oligocationic heteroaro‑
matics and their synthetic compound are susceptible toward
nucleophiles nitrogen and oxygen, and this methodology
allows introduced pyridines with two distinct types of het‑
eroarenium substituents (Scheme9, reaction a) [45, 60, 61].
Schmidt etal. [51–53, 62] have reported the synthesis
of (tetrachloropyridin‑4‑yl)pyridinium chloride 30 and the
(3,5‑dichloropyridine‑2,4,6‑triyl)‑tris‑pyridinium trichloride
34 that are available in quantitative yields (99%). Synthesis
of pyridine‑thioethers and 4‑ or 2,4‑alkoxy‑ or ‑phenoxy‑
substituted chloropyridines in low‑to‑good yields (20–99%)
(Scheme9, reaction b), where the DMAP‑activated pyri‑
dines 30 and 34. Both pathways showed the advantage of the
leaving group tendency and electron‑withdrawing properties
of the pyridinium substituents in heteroareniumsubstitution
reaction (Scheme9, reactions b and c). In the case of syn‑
thetic analogs of 36–39 was observed a drastic decrease in
the reaction yields which reflected instability and how reac‑
tion depends on the temperature, the reaction time and the
stoichiometric ratio of the starting materials. On the other
hands, the findings suggest that the method is suitable for
the synthesis of a broader range of highly substituted pyri‑
dines since other methods are tolerated [63–68]. In view of
the biological activity, tetrachloro‑4‑ethylsulfanylpyridines
31, 2,3,5‑trichloro‑4,6‑bis‑ethylsulfanylpyridines 33, and the
3,5‑dichloro‑2,4,6‑tris‑ethylsulfanylpyridines 35 can act as
intermediates for the synthesis of sulfones and sulfoxides,
which are reflected characteristic for controlling importance
as bactericides, pesticides, host compounds, fungi, bacteria,
and insect [69–76].
Synthesis andreaction of4‑azidotetrachloropyridine Aro‑
matic azides and sulfonylazides [77–79] are an important
class of azaheterocycle. These compounds are of prescribed
chemical interest because they can, for instance, be used in
synthetic organic chemistry. These are very reactive chemi‑
cal intermediates; they will, for example, react by site‑selec‑
tive for the reaction of 1,3‑dipolar systems in cycloaddition,
and they can also undergo photolysis to the corresponding
nitrenes or thermolysis [80–84, 87, 88]. Despite the high
number of works in the literature on the synthesis of other
aromatic azides and describe some of its chemistry [85, 86],
polychloroaromatic azides have received comparatively lit‑
tle attention. Structurally 4‑azidotetrachloropyridine 40 can
usually be synthesized in 62% yield by simple reaction of
pentachloropyridine and a metal azide in a favorable sol‑
vent, such as dimethylformamide and heating [87, 88]
(Scheme10, reaction a). It became apparent that the amount
Scheme7 Reaction of penta‑
chloropyridine with di‑func‑
tional nucleophiles

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of metal azide used and whether the pyridine compound
contains activating groups were crucial for the success of
the degree of substitution. Subsequent studies showed a
direct relationship exists concerning instability and the
number of azide groups per molecule, so no effort should be
made to force the reaction using severe conditions on reac‑
tion products. Cycloaddition reaction of the azides with ole‑
fins and thermal decomposition of aziridines was reported
by Bernard etal. The best yield was obtained for product
43 (70% yield) which is derived from an ethereal solution
of the strained olefin. To study the scope of this reaction,
azides reacted in the dark, at room temperature, affording
the aziridines (Scheme10, reaction b), and the preliminary
investigations of the thermal decomposition have been also
described [89]. In another example by this group, 4‑azido‑
tetrachloropyridine 40 undergoes the Staudinger reaction
with triphenylphosphine and gives the desired iminophos‑
phorane 44 in very good yields [90] (Scheme10, reaction c).
Additionally, reduced aromatic azides were observed [91,
92]. Likewise, this group successfully repeated the conver‑
sion of azidotetrachloropyridine 40 into 4‑aminotetrachlo‑
ropyridine 13 in 70% yield from the reaction of azide with
lithium aluminum hydride (Scheme10, reaction d).
In point of view of new energetic materials, the triazi‑
dopyridine 45 (84% yield) was synthesized based on the
reaction of pentachloropyridine 3 with excess sodium
azide in acetone at room temperature [93]. As shown in
Scheme11, cycloaddition of electron‑rich dipolarophiles
such as norbornene 41 and dimethyl ester of acetylenedi‑
carboxylic acid (DMAD) with 45 produces 46 and 47,
respectively.
Synthesis of 2,3,5,6‑tetrachloro‑4‑nitropyridine The
authors tested accessible polychloropyridine derivatives
with an oxidative agent such as trifluoroperacetic acid and
proxy acid at room temperature to give predominantly the
2,3,5,6‑tetrachloro‑4‑nitropyridine 49 (14–80% yield).
Alternatively, the 2,3,5,6‑tetrachloro‑4‑pyridinethiol (San‑
ti’s reagent) was successfully used to prepare 2,3,5,6 ‑tetra‑
chloro‑4‑nitropyridine 49 in 61.2% with an excess of nitric
acid which, in addition to the thiol group, are substituted
with more electron‑withdrawing groups (Scheme12) [44,
94].
Reactions of 2,3,5,6‑tetrachloro‑4‑nitropyridine Simi‑
larly, the development of chemistry of 4‑nitro‑isomer 54
with various nucleophiles carried out and, in all case, the
expulsion of the nitro‑group has been occurred to give
the corresponding 4‑substituted derivatives. The starting
point is based on experimental findings that 4‑substituted
tetrachloropyridine has reacted with bulky substituents in
the 2‑position; but in this case, authors discovered that
Scheme8 Synthesis and reac‑
tions of heteroarenium‑substi‑
tuted pyridine

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4‑nitro‑group is more readily replaced by nucleophiles
than any active chlorine atoms and tolerates sterically
hindered substituents which are reflected in products in
37–90% yields. By using this approach, chloronitropyri‑
dines are also useful for preparing authentic 2‑ and 4‑sub‑
stituted tetrachloropyridine (Scheme13) [44].
a
b
c
Scheme9 Reaction of heteroarenium‑substituted pyridines

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Reaction ofpentachloropyridine withO‑center
nucleophiles
Taking inspiration from works on amines with pentachloro‑
pyridine 3, the invention of 4‑methoxypolychloropyridines
as pesticides for the control of various pests was prepared
by Howard etal. by equimolecular proportions of sodium
methoxide and pentachloropyridine 3 [95, 96]. The only
by‑product sodium chloride is spontaneously eliminated
from the reaction mixture as a precipitate by filtration, giv‑
ing the 4‑methoxy‑2,3,5,6‑tetrachloropyridine 36 in 74.5%
yield (Scheme14). In addition, Xu and co‑workers reported
the synthesis of some new polychloroalkoxypyridines using
pentachloropyridine 3 and sodium methoxide as a nucleo‑
philic reagent at room temperature. The study was extended
to a series of sodium 2,2,2‑trifluoroethoxide and sodium
1.1,1,3.3,3‑hexafluoro‑2‑propoxide, and in all cases, no sub‑
stitution happened at the 3‑ and 5‑position of the pyridine
ring with higher electronic density. Surprisingly, the method
showed the synthesis of 2‑hydroxy‑4‑methoxy‑3,5,6‑trichlo‑
ropyridine 56 afforded 20% of the respective products result
of hydrolysis of 2.4‑dimethoxy‑3.5.6‑trichloropyridine 37
under workup in 10% hydrochloric acid (Scheme14).
In the following investigations on substitutions on halo‑
genated heteroaromatics, Moshchitskii etal. have synthe‑
sized 2,3,5,6‑tetrachloropyridin‑4‑ol 57 in quantitative yield
from pentachloropyridine 3 and sodium ethoxide in absolute
ethanol (Scheme15) [97].
Following this approach, we described in 2018 another
work on the O‑nucleophiles centered with pentachloropyri‑
dine 3. Pentachloropyridine 3 was reacted with a series of
quinazolinone 58 via a nucleophilic reaction to afford the
synthesis of new 4‑substituted tetrachloropyridine in good
yield (35–55%) (Scheme16). In general, the reaction yields
were affected by the reaction temperature, the mole ratio of
K2CO3 and solvent. This methodology also allowed access
to several biologically relevant in a straightforward manner
of quinazolinone drug with a 4‑quinazoline core [98, 99].
Reaction of2,3,5,6‑tetrachloro‑4‑methoxypyridine withoxi‑
dizing agent In a subsequent contribution of reaction of
2,3,5,6‑tetrachloro‑4‑methoxypyridine, 2,3,5,6‑tetrachloro‑
4‑hydroxypyridine 1‑oxide 60 in 50% yield and 2,3,5,6‑tet‑
rachloro‑4‑methoxypyridine 1‑oxide 61 in 80% yield were
synthesized using oxidizing agent. This methodology
applied for the substituent 4‑tetrachloropyridine 1‑oxide
which scaffold can be further diversified (Scheme17) [44].
Chemoselectivity ofO andN bidentate nucleophile
towardpentachloropyridine
An interestingly and different approach reaction of pen‑
tachloropyridine 3 with N‑aryl formamides 62 has been
developed by Ranjbar‑Karimi etal., who reported the
one‑pot reaction of bidentate nucleophile derived from
N‑aryl formamides anions. Their earlier work reveals that
one‑pot treatment of amide anions with pentachloropyri‑
dine 3 proceeded from both nitrogen and oxygen site. The
respective products 63a-d and 64e-j were obtained from
31–53 versus 30–90% yield, respectively. This article
introduces efforts depending on the X substituent bear‑
ing on aromatic ring, focusing on the synthetic methods
used to generate such molecules; when the substituent at
4‑position X is an electron‑releasing group, nucleophilic
Scheme10 Synthesis and reactions of 4‑azidotetrachloropyridine
Scheme11 Synthesis and reactions of triazidopyridine

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attack was accomplished by oxygen atom, and when the
substituent at 4‑position X is an electron‑withdrawing
group attached to benzene ring attack to pentachloropyri‑
dine was occurred by nitrogen site (Scheme18, reaction
a) [12]. In another study, Ranjbar‑Karimi and co‑workers
employed ambident nucleophile, oxygen, and nitrogen
nucleophile in the reaction with pentachloropyridine 3.
The success of this study leads using a range of pyridinols
65a–c and 70 which are presented in Scheme18, reaction
b [100]. Reaction proceeded selectively at the 4‑position in
Scheme12 Synthesis of
2,3,5,6‑tetrachloro‑4‑nitropyr‑
idine
Scheme13 Reaction of
2,3,5,6‑tetrachloro‑4‑nitropyr‑
idine

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pentachloropyridine, and good results (66: 80%; 67: 40%;
68: 25%, 69: 50%, 71: 50) were obtained in short reaction
time (6h) in the presence of potassium carbonate.
Reaction oforganolithium compounds
withpentachloropyridine
In the last years, Cook and co‑workers [101, 102]
described the reaction of organolithium compounds with
pentachloropyridine 3 to the respective solutions of tet‑
rachloropyridyl lithium compounds 72 and 75 by metal‑
halogen exchange [54]. As shown in this literature, the use
of different solvents to prepare organolithium compounds
is a major topic; when reaction proceeds in methylcy‑
clohexane, the combination of pentachloropyridine 3 with
the electron‑deficient organolithium compound has been
occurred due to coordinate of α‑chlorine atoms. On the
other hand, in diethyl ether, because the organolithium
compound was soluble, pentachloropyridine 3 is not able
to displace solvent molecules, and only nucleophilic attack
reaction takes place at 4‑position. For another reason, the
authors presumed that attack of n‑butyllithium in hydro‑
carbon solvents has faced with greater steric hindrance at
4‑position in pentachloropyridine than at 2‑position. These
organolithium compounds have general applicability, and
they were compatible with carboxylation to afford the mix‑
ture of acids in 36–40% yields (Scheme19a). Otherwise,
tetrachloropyridyl lithium 72 and 75 can be utilized at
room temperature, after hydrolysis, to give pyridine deriv‑
atives with various substitution patterns where products 73
and 74 were obtained in 43% and 40% yields, respectively.
The reaction of tetrachloro‑4‑pyridyl‑lithium 75
with an excess of benzonitrile 77 in diethyl ether under
reflux, followed by hydrolysis with water, gives 4‑ben‑
zimidoyltetrachloropyridine 82, 4‑(N‑benzoylbenzi‑
midoyl)tetrachloropyridine 80 and 5,6,8‑trichloro‑
2,4‑diphenylpyrido[3,4‑d]‑pyrimidine 81 (Scheme19b)
[101, 102].
Reaction ofpentachloropyridine withC‑centered
nucleophiles
Synthesis of 2,3,5,6‑tetrachloro‑4‑cyanopyridine The
number of alternative procedures for the functionaliza‑
Scheme14 Reaction of pen‑
tachloropyridine with sodium
methoxide
Scheme15 Synthesis of 2,3,5,6‑tetrachloropyridin‑4‑ol
Scheme16 Reaction of pentachloropyridine with quinazolinones
Scheme 17 Reaction of 2,3,5,6‑tetrachloro‑4‑methoxypyridine with
oxidizing agent

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tion of the polychloropyridine compounds has increased
in the last years. In 1967, Banks etal. reported the synthe‑
sis of 2,3,5,6‑tetrachloro‑4‑cyanopyridine 85 in 71% yield
from 4‑cyanopyridine 84 under heating at 350°C for 20h
with phosphorus pentachloride and Ni (Scheme 20). A
few researches are being conducted on the introduction of
2,3,5,6‑tetrachloro‑4‑cyanopyridine in several heterocycles
in the literature [103, 104].
In another work, 2,3,5,6‑tetrachloro‑4‑cyanopyridine 85
has been synthesized in low yield (5%) by reaction of tetra‑
chloropyridine 1‑oxide 86. In the first step, tetrachloropyri‑
dine 1‑oxide 86 was heated in the steam bath with dimethyl
sulfate and aqueous cyanide was added which was generated
insitu by potassium cyanide in water (Scheme21) [105].
Reaction of 2,3,5,6‑tetrachloro‑4‑cyanopyridine The
reaction of 2,3,5,6‑tetrachloro‑4‑cyanopyridine 85 with
several monofunctional nucleophiles has been reported.
As shown in Scheme22, it was described earlier that the
nucleophilic attack mainly occurs at the 2(6)‑position by
replacement of chlorine of 2,3,5,6‑tetrachloro‑4‑cyano‑
pyridine 85, instead of nucleophilic reactions involving
substitute at the 4‑position (cyano group) to give products
87–92 (in 30–82% yield) and only with sodium nitrite fol‑
lowed by hydrolysis to give 2,3,5‑trichloro‑4‑cyano‑6‑hy‑
droxypyridine (in 16.5% yields) [103, 104, 106].
In line with the above finding, authors illustrated the
reaction of 2,3,5,6‑tetrachloro‑4‑cyanopyridine 85 with
ambident nucleophiles where it showed new heterocycles
94 in 92% and 96 in 18% and 98 in 15% yields are formed
by replacement of 2‑ and 3‑Cl (Scheme23). The results
did not show clarity in the mechanism that at first attack of
the nucleophile is driven predominantly at 2 or 3 position.
δ‑Carboline (100 and 101) and related natural deriva‑
tives have received importance due to their wide range of
biological activities. For several compounds of this class
have been reported antitumor, antimuscarinic, antiviral, and
antifungal characteristics [107–110]. In this context, a few
a
b
Scheme18 Reaction of pentachloropyridine with O‑ and N‑centered nucleophiles

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types of research are being conducted on the introduction of
δ‑carboline units in several heterocycles, but only limited
success was observed. To overcome this limitation, the reac‑
tion of different substituents into tetrachloro4‑cyanopyridine
is a common synthetic strategy. For instance, Dainter and co‑
workers reported the use of enamines as a nucleophilic sys‑
tem to the synthesis of the tetrahydrocarboline. A detailed
NMR study was performed to clarify the tetrahydrocarboline
100 and 101 were isomeric products. Similar results were
found by using a range of enamines (99a–d). However,
these results showed that there is differentiation in the yields
of products (0–48% yields). In some case, enamines 101
approaches to minor products of ketones 103 in low yield
Scheme19 a Reaction of
n‑BuLi with pentachloro‑
pyridine. b Reaction of 75 with
benzonitrile
a
b
Scheme20 Synthesis of 2,3,5,6‑tetrachloro‑4‑cyanopyridine
Scheme21 Another way for synthesis of 2,3,5,6‑tetrachloro‑4‑cyan‑
opyridine

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(5–8%) under hydrolysis condition. Additionally, on the fur‑
ther reaction of tetrahydrocarbolines, side chains are toler‑
ated and products rised from the reaction of the cyano group
of these compounds (Scheme24) [111].
Synthesis andsome reactions of diethyl 2‑(perchloropyri‑
din‑4‑yl)malonate Basically, the method to construct die‑
thyl 2‑(perchloropyridin‑4‑yl)malonate is the reaction of
diethyl malonate with pentachloropyridine 3 that has been
reported in 1970 by Moshchitskii and co‑workers [97]. It
is noteworthy that when ester hydrolysis in the presence of
sulfuric acid obtained 2,3,5,6‑tetrachloropyridin‑4‑yl ace‑
tic acid 104 in excellent yield (90%), then it was employed
in the functionalization of 2,3,5,6‑tetrachloroisonicotinic
acid 77 in 15% yield. On the other hand, when ester was
treated to alkaline hydrolysis, hydroxy group 106 in 92%
yield was substituted in position 2 in contrast chlorine atom
(Scheme25).
Reaction ofpentachloropyridine withS‑centered
nucleophiles
Diheteroaryl thioethers have demonstrated a wide spectrum
of pharmacological activities. This class of compounds is
also powerful building blocks in organic chemistry. Among
them, synthesis of heteroaryl sulfides has been developed
in the last years and will be discussed in the following sec‑
tion of this review. Recently, we have described the insitu
generations of nucleophilic species of S‑centered from
4,6‑diaminopyrimidine‑2(1H)‑thione 108 with pentachlo‑
ropyridine 3 in the presence of sodium carbonate and using
acetonitrile as solvent [112]. By this protocol, the reaction
Scheme22 Reaction of 2,3,5,6‑tetrachloro‑4‑cyanopyridine with monofunctional nucleophiles
Scheme23 Reaction of
2,3,5,6‑tetrachloro‑4‑cyanopyri‑
dine with ambident nucleophiles

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can be controlled to afford the single product 109 in 68%
yield. It was observed in the reaction with 4,6‑diaminopy‑
rimidine‑2(1H)‑thione 108 that the nucleophilic character
of the sulfur species is not influenced by other N‑centered
nucleophiles (Scheme26).
Thioalkylation of pentachloropyridine using the salts
ofalkyltrithio carbonic acids A close related work on the
introduction of the thioalkyl group into the backbone of
pentachloropyridine 3 was described by Sipyagin and co‑
workers [113, 114]. The authors credited a double function
in the reaction: solvent and initial polychloropyridines. By
using the approach depicted in Scheme27, isopropyltrithi‑
ocarbonate 111 in acetonitrile or ethanol solution reacted
with pentachloropyridine 3 regioselectively. In two cases,
the nucleophilic addition was very efficient, with short reac‑
tion times, room temperature, and substitution occurred at
position 4 of the pyridine ring by the isopropyltrithiocar‑
bonate 111 in acetonitrile (or with isopropanethiolate anion
112 in ethanol). It is important to note that in ethanol 111
in equilibrium with 112 and the latter is clearly a stronger
nucleophile. The formation of the isopropanethiolate anion
112 can be represented as the result of dissociation of the
isopropyltrithiocarbonate anion in ethanol, where the equi‑
Scheme24 Synthesis of δ‑carboline from 2,3,5,6‑tetrachloro‑4‑cyanopyridine
Scheme25 Synthesis and some reactions of diethyl 2‑(perchloropyridin‑4‑yl)malonate
Scheme26 Reaction of penta‑
chloropyridine with 4,6‑diami‑
nopyrimidine‑2(1H)‑thione

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librium of the process is displaced to the right to a significant
degree. Curiously, it was observed a significant degree in
favor of the isopropanethiolate anion formation. The yields
of the product in the successive reactions were 83 and 87%.
Synthesis and reaction of 4‑phenylsulfonyl‑2,3,5,6‑tetra‑
chloropyridine Ranjbar‑Karimi etal. [115] reported a new
methodology to prepare 4‑phenylsulfonyl‑2,3,5,6‑tetrachlo‑
ropyridine 115 in 85% yield. This reaction was performed
in a one‑pot optimized condition. This reaction is generally
depending on the solvent, the mole ratio of pentachloropyri‑
dine 3 and sodium benzenesulfinate 114 (1:2 respectively)
and temperature (Scheme28).
In this work, the authors observed that the nucleophilic
attack of some mono‑ and bidentate N- and O- nucleophiles
with 4‑phenylsulfonyl‑2,3,5,6‑tetrachloropyridine 115
gives products in moderate‑to‑high yields. Additionally, the
authors completed the study with two different conditions,
varying in the types of nucleophiles. The 4‑phenylsulfonyl‑
2,3,5,6‑tetrachloropyridine 115 was successfully used in the
nucleophilic substitution to give the corresponding products
in 45–90% yields. The presence of electron‑withdrawing
groups at the pyridine ring of 115 causes a good level of
efficiency with aliphatic and aromatic amines and oxygen
nucleophile whose products raised only from 4‑position
compared to the reaction with secondary N nucleophiles at
2‑ and 4‑position of the pyridine ring (Scheme29).
Synthesis of2,3,5,6‑tetrachloro‑4‑mercaptopyridine In the
extension of studies on the chemistry of pentachloropyri‑
dine 3, several derivatives have been described; 2,3,5,6‑tet‑
rachloro‑4‑mercaptopyridine 51 was prepared by treating
pentachloropyridine 3 with potassium or sodium hydrogen
sulfide (75% yield) or in another work with 3,5‑dichloro‑
2–6‑difluoro‑4‑pyridyl mercaptan (Scheme30) [116, 117].
The success of this study leads the authors to investigate
the synthesis of 4‑methylsulfanyl‑120 and 4‑methylsulfo‑
nylpyridine 121 in quantitative yield. These compounds are
used for several pursues, such as straightforward synthesis
of other heterocycles or relevant agriculture with the aim
for the kill and control of various pests. The mechanism of
the reaction starts by methylated from 2,3,5,6‑tetrachloro‑
4‑mercaptopyridine 51 in a short reaction time (5 min),
which subsequently is oxidized by hydrogen peroxide in
glacial acetic acid for overnight at 20°C.
Reaction of 2,3,5,6‑tetrachloro‑4‑mercaptopyridine As
commented through this review, 2,3,5,6‑tetrachloro‑4‑mer‑
captopyridine is known for its potential applications in
organic synthesis. In a closely related report, Moshchitskii
et al. developed an efficient procedure for the reaction of
2,3,5,6‑tetrachloro‑4‑mercaptopyridine 51, by a number
of nucleophiles. The substitutions reaction occurred from
S‑site which provides the corresponding pyridine deriva‑
tives such as 4‑methylthio‑2,3,5,6‑tetrachloropyridine 120
and other sulfides 122 and 124 in good‑to‑excellent yields
(85–98%) (Scheme31) [118].
In several methods to prepare 2,3,5,6‑tetrachloro‑4‑mer‑
captopyridine 51 from the reaction of pentachloropyridine
3 with potassium or sodium hydrogen sulfide and in most of
tested examples, the preference for the 4‑isomer was very
high. There are only a few approaches that provide, instead,
2‑isomer. Iddon and co‑workers [119] reported an alternative
procedure to prepare tetrachloropyridine‑2‑thiol 127. In this
sense, authors have demonstrated that pentachloropyridine
1‑oxide 125 also is a suitable substrate for the synthesis of
tetrachloropyridine‑2‑thiol 127. At first, high temperature
and reduction were mandatory, but an excellent yield (92%)
was obtained when pentachloropyridine 1‑oxide 125 was the
starting material and reduction occurs in granulated zinc in
the presence of acetic acid (Scheme32).
Ager and co‑workers [120] described the highly regiose‑
lective nucleophilic substitution of 4‑methylsulfonylpyridine
121, by using NaCN, NaOH, NaOMe, and MeNH2 under
reflux (Scheme33). In this work, the authors observed this
one‑pot procedure involves nucleophilic displacements of
the methylsulfonyl group within a few minutes (3–10min),
affording 36 and 85 in very good yields (96–97%), regardless
of the substituent by a hydroxy group in 8h. The reaction
was sensitive in the presence of sodium cyanide; for exam‑
ple, N,N‑dimethylformamide gave a single product compared
Scheme27 Thioalkylation of pentachloropyridine using the salts of
alkyltrithiocarbonic acids
Scheme28 Synthesis of 4‑phenylsulfonyl‑2,3,5,6‑tetrachloropyridine

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to the reaction in aqueous ethanol (97 vs. 19–61%). It was
possible to note that 4‑methylsulfonylpyridine 121 exhib‑
ited reactivity toward N,N‑dimethylamine and pyrrolidine
in 2‑position.
Synthesis and reaction of tetrachloropyridine‑4‑sulfonyl‑
chloride As mentioned before, heterocycles represent the
most general structural units in many natural and biologi‑
cally active compounds. Among them, those containing
nitrogen and sulfur atoms in the structure suffer from con‑
siderable disadvantages such as instability and reported to
rearrange under mild conditions at room temperature by an
SNI mechanism to give sulfur dioxide and chloropyridine.
Due to their use as substrates for accessing new compound,
there is a continued interest in the stability of formation
of tetrachloropyridine‑4‑sulfenyl chloride 132. To achieve
that, the reactions were conducted under focused on two
distinct types of materials tetrachloropyridine‑4‑thiol 51
Scheme29 Reaction of 4‑phe‑
nylsulfonyl‑2,3,5,6‑tetrachloro‑
pyridine with nucleophiles
Scheme30 Synthesis of 2,3,5,6‑tetrachloro‑4‑mercaptopyridine

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(Scheme 34) [121–124], or disulfide in the reaction with
chlorine in carbon tetrachloride. Besides the high yields
(88–100% yields) which is represented, in both protocols, a
plausible mechanism for the conversion of a thiol into sulfo‑
nyl chloride was not understood.
2,3,5,6‑Tetrachloropyridine‑4‑sulfenyl chloride is fre‑
quently used as convenient reagents for introducing various
functional groups into organic substrates, and this scaffold
is used as versatile building blocks in organic synthesis. In
this context, Sologub and co‑workers [125, 126] reported the
reactions of 2,3,5,6‑tetrachloropyridine‑4‑sulfenyl chloride
132 with nucleophilic reagents, such as phenylmagnesium
bromide, sodium methoxide, ammonia, and ethyl bromide
Scheme31 Reactions of
2,3,5,6‑tetrachloro‑4‑mercapto‑
pyridine
Scheme32 Synthesis of tetrachloropyridine‑2‑thiol
Scheme 33 Reaction of 2,3,5,6‑tetrachloro‑4‑(methylsulfonyl)pyri‑
dine with nucleophiles

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in alcohol. The authors described the insitu generation of
nucleophilic species, which followed in some case more eas‑
ily oxidized by using hydrogen peroxide, for the synthesis of
products in 66–90% yields (Scheme35‑reaction a).
The same group developed a new route to the synthe‑
sis of a mixture of isomeric β‑halogenoalkyl sulfides. The
conventional method for the straightforward synthesis of
β‑halogenoalkyl sulfides is the nucleophilic reaction of
the olefin double bond to the sulfenyl chloride. By using
the approach depicted in Scheme35 (reaction b), the reac‑
tion rate increases with the nucleophilicity of the double
bond. In addition, solvents are responsible for isomer ratio.
The authors did not provide any reason for this behavior,
but can be explained by the formation of the sulfonium
bridge and how it opens in polar and nonpolar solvents.
Scheme34 Synthesis of tetrachloropyridine‑4‑sulfenylchloride
a
b
Scheme35 Reaction of 2,3,5,6‑tetrachloropyridine‑4‑sulfenylchloride with olefins

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The formation and the relative amount of these type of
isomer were also followed by NMR spectroscopy. In this
sense, the scope of the reaction was expanded to olefins
containing a terminal double bond, bulky substituents
in olefins, and olefins with linear structures, which was
reacted with sulfenyl chloride to afford the respective
heterocyclic in low‑to‑excellent yields (25–95%). It was
possible to note that tow products obtained with termi‑
nal olefins and in both later case, addition generally leads
to the corresponding primary formation of Markovnikov
products. The authors also demonstrated that the protocol
takes advantages of epi‑sulfonium ion as an intermediate.
Synthesis andreaction oftetrachloro‑4‑triuoromethylthi‑
opyridine Various perfluoroalkylpolychloropyridines 144a–
c are an example of an organosulfide compound that has been
studied as a model capable bearing stability in reaction with
the mineral acid, halogenating, and oxidizing agents [127].
Generally, fluorosulfanyl derivatives of tetrachloropyridine
are generated insitu by reaction of mercaptopolychloropyri‑
dines, in the presence of fluorine‑containing reagent, based
on compounds of Xe(II) [128, 129]. In this context, a series
of new perfluoroalkylpolychloropyridines 144a-c are syn‑
thesized by Sipyagin and co‑workers (Scheme36, reaction
a). After extending their protocol with success to the syn‑
thesis of perfluoroalkylpolychloropyridines, containing site
selectivity for the reaction with nucleophiles, such as N‑,
O‑, and S‑nucleophiles, the authors performed the mono‑
substituted products 20, 51, 149, and 146 in 3–70% yields
(Scheme36, reaction b). The results obtained in these assays
indicated that the perfluoroalkylpolychloropyridines can act
as the same as pentachloropyridine in the reaction with the
S‑containing nucleophiles. Sipyagin et al. also suggested
clear evidence for the synthesis of the main procedure form
a
b
Scheme36 Synthesis and reaction of tetrachloro‑4‑trifluoromethylthiopyridine

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the reaction of tetrachloro‑4‑trifluoromethylthiopyridine
with N‑nucleophile reagents. The advantage of this method
is the use of reducing the mobility of CF3S group in order to
the synthesize new pyridine derivatives containing fluorine.
In addition, another easy route for the oxidation of thiols
to sulfofluorides 153 was published by using xenon com‑
pound as a selective oxidizing agent in the solution of HF
[130]. By using this method, 2,3,5,6‑tetrachloropyridine‑
4‑sulfonyl fluoride was synthesized from the respective thi‑
ols 151 in low yields (25%) (Scheme37). The authors used
IF5 in the presence of heating to promote the fluorination
of the SH group. The desired product 154 was obtained in
30–4‑% yields starting from thiol 51.
Reaction ofpentachloropyridine withhalogen nucleophiles
Synthesis of 3‑chloro‑2,4,5,6‑tetrauoropyridine
and 3,5‑dichloro‑2,4,6‑triuoropyridine In view of the
importance of polyhalogenated pyridine, several proce‑
dures for their preparation have been described and the
most common protocols involve the substitution of chlorine
atoms by fluorine. The first process involves the direct syn‑
thesis of 2,4,6‑trifluoro‑3,5‑dichloropyridine 155 from the
nucleophilic aromatic substitution of pentachloropyridine
3 at 83°C in the presence of catalytic conditions. Moder‑
ate yield (60%) of the 2,4,6‑trifluoro‑3,5‑dichloropyridine
155 was obtained only when an 18‑crown 6‑ester was used,
and the reverse process failed completely. The second
approach explored the addition of fluorine anion to penta‑
chloropyridine in the autoclave. The authors reported, how‑
ever, that these conditions are not suitable to the synthesis
of 3‑chloro‑2, 4, 5, 6‑tetrafluoropyridine 157, and only 7%
yield of the adduct was obtained after 48h without a solvent
at elevated temperatures (Scheme38) [131, 132].
Reaction of 3‑chloro‑2,4,5,6‑tetrauoropyridine
and 3,5‑dichloro‑2,4,6‑triuoropyridine Another interest‑
ing class of chloro‑containing compound is 3‑methyl‑2, 4,
5, 6‑tetrafluoropyridine 159. By starting from pentachloro‑
pyridine with KF in the first stage and then reaction with
nickel compounds, the respective fluorinated heteroaryl
complex could be obtained in 61% yield (Scheme39). In
the literature, 3‑fluoropyridyl nickel complex is described as
useful tools for the selective construction of other tetrafluo‑
ropyridines [133]. Sladek and co‑workers were delighted to
find that 3‑chlorotetrafluoropyridine in the presence of PEt3
or PCy3 and treatment with [Ni(COD)2] and consequently
in reaction with MeLi and air gave 3‑methyltetrafluoropyri‑
dine 159 in 16% yield. it is considered that O2 was used to
scavenger of the phosphine ligand formed in the reaction.
The authors also verified the C–C coupling synthetic meth‑
ods using alternative non‑classical nucleophilic reaction
where the product in different regiochemistry at 3‑position
was observed.
On the other hand, the design and study of polyfluo‑
ropyridine derivatives have become a very active area of
research within the field of macrocycles chemistry. The gen‑
eral approach to their synthesis and an example are given in
Scheme40 from pentachloropyridine 3. It is worth mention‑
ing the work of Chambers [134] who described the synthesis
of new macrocycles from pentachloropyridine 3. Starting
from the synthesis of 3,5‑dichloro‑2,4,6‑trifluoropyridine
Scheme37 Oxidation of 2,3,5,6‑tetrachloropyridine‑4‑thiol
Scheme38 Synthesis of polyhalogenated pyridine
Scheme39 Synthesis of 3‑methyl‑2,4,5,6‑tetrafluoropyridine

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[132, 135] and subsequent reaction with 2,2,7,7‑tetramethyl‑
3,6‑dioxa‑2,7‑disilaoctane 162 in three steps, an appropriate
macrocycle 164 (22% yield) can be synthesized.
Finally, model studies as shown in Scheme 41
describe that these systems are highly active toward
nucleophilic additions and displacement of fluorine
occurs easily rather than chlorine upon reaction of
3,5‑dichloro‑2,4,6‑trifluoropyridine 155 with O‑nucle‑
ophiles [136]. It is noteworthy that the 4‑position in
3,5‑dichloro‑2,4,6‑trifluoropyridine is more sterically hin‑
dered toward nucleophilic attackbecause of the presence
of the adjacent chlorine atoms. In principle, mixtures of
both products arising from sequential nucleophilic aro‑
matic substitution processes at both 4‑ and 2‑positions and
Scheme40 Synthesis of macro‑
cycle from pentachloropyridine
Scheme41 Reactions of 3,5‑dichloro‑2,4,6‑trifluoropyridine with oxygen nucleophile

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disubstituted products in which more than one fluorine atom
is substituted by the same nucleophile are indicated below as
further nucleophilic attack at either of the remaining 2‑ and
4‑carbon–fluorine sites (Scheme41).
Synthesis of2,4,6‑tribromodichloropyridine As mentioned
before, the halogen exchange in the reaction of pentachlo‑
ropyridine 3 to prepare a variety of the important perhalo
compounds is a very useful reaction and in the last year
new protocol to perform this reaction has been described.
Mutterer and Weis [137] developed a procedure for the syn‑
thesis of 2,4,6‑tribromodichloropyridine 170 starting from
pentachloropyridine 3 by HBr in acetic acid. Moderate yield
(72%) and a good selectivity in 21h of reaction at elevated
temperatures were observed (Scheme42).
Synthesis of 4‑bromotetrachloropyridine The increasing
interest in the use of 4‑bromotetrachloropydine 171 as a key
intermediate in organic synthesis is due to high versatility
for the photochemistry studies of reaction with copper. This
class of compound also has been used as a precursor to the
synthesis of other substituted tetrachloropyridine. There are
several methods for obtaining 4‑bromotetrachloropydine
171, which are well described in the literature. In 1979,
Suschitzky and co‑workers reported the use of hydrazine to
promote the synthesis of 4‑bromotetrachloropyridine in fair
yield (68%) (Scheme43) [138].
Coupling reaction ofpentachloropyridine
Synthesis of pentaarylpyridines from pentachloropyri‑
dine Fully arylated(hetero)arenes have received biologi‑
cal function in organic materials and active compounds as
a unique structural class [139–144]. Generally, synthesis
access to fully arylated(hetero)arenes with different aryl
substituents relies on functionalization of precursors and
has not been explored due to the difficulty of synthesizing
highly unsymmetrical aromatic cores and sterically hin‑
dered. Additional literature describing methods toward such
active molecules and general synthetic have recently been
developed for the discovery of unknown functional mol‑
ecules [145–150].
In 2014, Reimann and co‑workers [151] described the
use of Pd as a catalyst in the multiple Suzuki–Miyaura
cross‑coupling reaction of aryl boronic acids with penta‑
chloropyridine using toluene as the solvent and K3PO4 as
the base to prepare symmetrical 172 and unsymmetrical pen‑
taarylpyridine 174. In this context, aryl boronic acids with
electron‑withdrawing and electron‑donating groups reacted
with pentachloropyridine 3 and moderate‑to‑good yields of
the respective pentaarylpyridine were obtained (42–99%),
with an introduction of an influence of electronic effects in
the coupling reaction (Scheme44‑ reaction a). In the exam‑
ple, which boronic acid has fluorine substitution, the authors
observed a drastic decrease in the reaction yield using
because of side reaction (46% yield). The best results were
obtained with 10 equivalent of boronic acid. When an equi‑
molar mixture of arylboronic acid was decreased, a more
efficient procedure using the same system was employed in
the coupling reaction of 4‑aryl‑2,3,5,6‑tetrachloropyridine
166 to prepare different substitution of pyridines with bear‑
ing up to five different aryl groups (Scheme44‑ reaction
b‑d).
Synthesis ofarylated pyridines bySuzuki–Miyaura reactions
of 2,3,5,6‑tetrachloropyridine In recent decades, catalytic
systems are available which allow the activation of cross‑
coupling reactions and they have played imperative roles in
the design and study of the formation of carbon–carbon and
carbon–heteroatom bonds. This type of reaction is also a
crucial method with high chemoselectivity for the reactiv‑
ity of different inert carbon‑chlorine bonds and site selec‑
tivity by electronic factors or steric hindrance [152–162].
As shown in the previous section, the C–Cl band can be
activated by the Pd catalyst, which leads to the formation
of pentaarylpyridines. Recently, Reimann and co‑workers
[163] have developed a methodology for the synthesis of
tetraarylpyridines 182, using a catalytic system composed
by Pd2(dba)3 (1.25 mol%), in the presence of cataCXium
A (5mol%) as a ligand. In this very versatile protocol, the
authors employed different phenylboronic acids 181a–n,
toluene as solvent and K3PO4 as a base, to afford tetrasubsti‑
tuted pyridine 182 in moderate‑to‑good yields (Scheme45).
It was observed that the presence of two or three substitu‑
tion groups in the phenylboronic acid decreased the yield. In
Scheme42 Synthesis of 2,4,6‑tribromodichloropyridine
Scheme43 Synthesis of 4‑bromotetrachloropyridine

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general, n‑hexylboronic acid gave the successfully desired
product in 72% yield.
Langer and co‑workers [164] synthesized pentaaryl‑
containing heterocycles 184 by the coupling of pentachlo‑
ropyridine 3, and acetylene derivatives catalyzed by Pd in
dioxane (Scheme46). It is important to note that the authors
attributed the Sonogashira reactions for the first time with
polychlorinated arenes. This study was performed by 7
equivalent of acetylene derivatives and less than 1mol% of
the catalyst. However, CuI as a cocatalyst was necessary
and when electron‑donating groups were the starting alkene,
yielding of the respective products decrease compared to
electron‑withdrawing groups.
Scheme44 Synthesis of pentaarylpyridines from pentachloropyridine
Scheme45 Synthesis of arylated pyridines

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Reaction ofC‑metalated ofpentachloropyridine
Synthesis of 4‑methyl‑2,3,5,6‑tetrachloropyridine A gen‑
eral and suitable procedure for the synthesis of 4‑methyl‑2,
3, 5, 6‑tetrachloropyridine 105 was achieved using the reac‑
tion of pentachloropyridine 3 with halogenated magnesium
alkyl compounds (Scheme47) [165]. The authors made a
comparative study using THF and ether, and they observed
that the “on equal volumes of tetrahydrofuran and ether”
reaction (2h at 50–60°C) affords product 105 in best result
than in ether. By this procedure, methyliodide, ethylbro‑
mide, n‑propyl and n‑butyl, and benzylchloride were used
as starting materials and the corresponding 4‑alkyl‑2, 3,
5, 6‑tetrachloropyridines 186a–d were prepared in low‑to‑
good yields.
Reaction ofpentachloropyridine withreducing agent
Another class of polychloropyridines widely studied is
the tetrachloropyrine derivatives. These compounds are
prepared by reduction‑type reactions (3‑ or 4‑addition of
AlH4
− to form an intermediate and followed by cis‑elimina‑
tion), which provides an elegant strategy for the formation
of the carbon‑hydrogen bond. As illustrated by an example
shown in Scheme48, it has been reported that on the treat‑
ment with lithium aluminum hydride, pentachloropyridine
3 gives 2,3,6‑trichloropyridine 5 (95% yield) together with
the small amount of other well‑known compounds such as
2,3,5,6‑, 2,3,4,6‑ and 2,3,4,5‑tetrachloropyrine. Binns and
co‑workers reported that the smaller BH4
− group, in contrast
with AlH4
− is able to co‑ordinate with the pyridine nitrogen
despite the bulky ortho‑chlorine atoms, to give complex 187,
which on hydrolysis breaks down to yield 2,3,5,6‑tetrachlo‑
ropyridin 5[166].
Reaction ofpentachloropyridine withoxidizing agent
Synthesis of pentachloropyridine 1‑oxide Pyridines
1‑oxide is a class of organic compounds related to pyridine
derivatives with broad applications in organic and medici‑
nal chemistry [167–176]. Different methods to synthesize
these compounds from pyridines have been described in the
literature [177]. However, these compounds are most noted
low basicity and usual reagents were not suitable substrates
to this reaction. The first approach to the synthesis of pen‑
tachloropyridine 1‑oxide 125 has been reported by Roberts
etal. in 1967. The title compound can be formed from pen‑
tachloropyridine 3 and trifluoroperacetic acid by heating
trifluoroperacetic acid (20% yield) [45] or by another group
with hydrogen peroxide and aqueous sulfuric acid in the
quantitative yield (72%) (Scheme49) [123, 124].
The pentachloropyridine 1‑oxide 125 was identified as
more susceptible to nucleophilic attack analog in all the
examples than pentachloropyridine 3, and the outcome of
substitution in pentachloropyridine 1‑oxide 125 was not
affected by the nature of the solvent. By this method, a broad
variety of new highly substituted pyridines were prepared
with applied conditions and N‑, O‑, S‑nucleophiles. The
authors have found that in several cases the final products
were obtained in 2‑substitution and by sequential deoxy‑
genation to give the corresponding substitutedchloropyri‑
dines (51: 57%, 198: 36%, 200: 70%, 201: 85% yields)
(Scheme50) [44, 119, 178].
As mentioned above, authors have only been able to
prepare mono‑substituted products from the nucleophilic
substitution of pentachloropyridine 1‑oxide whatever the
solvent. Needless to say, the solvent independence of the
reaction is probably due to its more electrophilicity as com‑
pared to pentachloropyridine 3 which enables a successful
attack of enaminone derivatives in boiling benzene or tolu‑
ene for 16h on the most active position only (Scheme51)
[179]. As expected, the nucleophilic attack of enaminones
produced intermediate pyridylenamines 204. The plausible
mechanism for this reaction involves either hydrolysis and
deoxygenation of products (205–207) or started by cycload‑
dition and followed by dehydration (208).
Scheme46 Synthesis of pentaarylpyridines
Scheme47 Synthesis of 4‑methyl‑2,3,5,6‑tetrachloropyridine

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The method of photolysis of pentachloropyridine‑1‑oxide
125 [127, 180–182] in dry carbon tetrachloride like reaction
in sodium azide in aqueous acetone was investigated, and
in most cases, the corresponding products were isolated by
deoxygenation and give acid azide under identical reaction
conditions. Suschitzky and co‑workers supported photoly‑
sis of pentachloropyridine 1‑oxide using a medium pres‑
sure lamp in a photochemical reactor [183]. Basically, the
method of the photolysis of pentachloropyridine‑1‑oxide
125 involves the formation of three‑membered ring 209.
However, it can be expected that photolysis of pentachloro‑
pyridine‑1‑oxide 125 follows significantly different reaction
paths to generate an isocyanate 213 which was not previ‑
ously reported. Therefore, the authors assumed the following
reaction mechanism by analogy with the known photolytic
behavior of N‑oxides (Scheme52).
Recently, there are ongoing findings in the field of the
method for the replacement of all five chlorine atoms in
pentachloropyridine‑1‑oxide 125, with sodium azide [182].
This class of compounds is potentially useful as a start‑
ing material for producing of nitrenes, and it is also well
established that various pyridine‑1‑oxide derivatives with
azido groups in positions 2 and 4 of the pyridine ring have
importance for the synthesis of new heterocycles [181, 184,
185]. However, pyridine‑1‑oxides with two or more azido
groups are immense interest, but they are unknown and
only 2,6‑diazido‑3,4,5‑trichloropyridine‑1‑oxide 214 was
obtained starting from pentachloropyridine‑1‑oxide 125, and
using sodium azide in water, in short reaction time (6h) at
room temperature with good yield (96%) (Scheme53).
Grignard reactions on pentachloropyridine 1‑oxide In
view of the interest for direct introduction of alkyl or aryl
group into the 2‑ or 2‑ and 6‑positions of pentachloro‑
pyridine 3, many efforts have been spent. Among them,
Grignard reagents attack only in 4‑position as described
in Sect.4.1.9. In 1971, Binns and co‑workers [186] were
able to synthesize 2‑methyl and 2,6‑dimethyl derivatives
Scheme48 Reaction of penta‑
chloropyridine with reducing
agent
Scheme49 Synthesis of pentachloropyridine 1‑oxide

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217 in quantitative yield. In this protocol, the authors
observed that the formation of significant products 217a
and 217b is related to mol ratio of Grignard reagents and
when an excess of Grignard reagents was used, the com‑
plex mixtures of products were obtained. Additionally,
phenyl‑ and ethyl‑magnesium bromides in tetrahydro‑
furan, as well as methyl magnesium iodide in substitution
reactions, have been also reported. After simple reactions,
deoxygenation from products occurred by heating in all
cases (Scheme54).
Scheme50 Reaction of pentachloropyridine‑1‑oxide with nucleophiles
Scheme51 Reaction of pentachloropyridine‑1‑oxide with enaminones

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Synthesis andreaction of2,3,5,6‑tetrachloropyridine
In this section, we will present the synthesis and reaction
of different classes of polyhalogenated compounds, which
have biologically important properties or are key interme‑
diates in organic synthesis. As mentioned in part 4.1.4, tet‑
rachloropyridine 5 can be synthesized by reaction of pen‑
tachloropyridine 3 and the organometallic compound. To
study the scope of this reaction, a metal‑halogen exchange
and different solvent had various effects. Of course, with an
understanding of such an effect, the control of the position
of metal‑halogen exchange can be achieved and provide an
appropriate approach for the synthesis of tetrachloropyri‑
dine. Furthermore, several approaches to the synthesis of
pyridine derivatives have been reported from a reaction of
tetrachloropyridine with different nucleophiles (Scheme55).
In this sense, tetrachloropyridine 5 was successfully used
by Berry and co‑workers [187], and dimethylamino‑(218 in
74% yield), pyrrolidino‑(219 in 73% yield) methoxy‑(220
in 41% yield) were obtained. In another study, Finger etal.
[188] described the synthesis of fluoropyridine 221 (33%
yield) in a halogen‑exchanged reaction by using potassium
fluoride.
It is noteworthy that the case of tetrachloropyridine is
special. Since the pioneering work on the reaction of tetra‑
chloropyridine from 1985, the synthesis of new compounds
based on tetrachloropyridine, has received a great attention.
In the same line, a new band of carbon‑halogen in products
can be formed [189, 190]. In a more recent work, Joshi and
Scheme52 A plausible mechanism for the photolysis of pentachloro‑
pyridine 1‑oxide
Scheme53 Synthesis of 2,6‑diazidotrichloropyridine‑1‑oxide
Scheme54 Grignard reactions
on pentachloropyridine 1‑oxide

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co‑workers proved that mild electrophilic halogenation of
chloropyridines using CCl4 or C2Cl6 with basic phase trans‑
fer conditions is necessary for the synthesized of pentachlo‑
ropyridine 3 as a major product (Scheme56) [191].
According to experimental evidence (GC–MS analy‑
sis), yields of products can also be controlled by the time
and ratio of the dichloromethyl anion. With reaction times
varying from 4 to 20h, the yields of side products can be
increased.
Finally, 2,3,5,6‑tetrachloropyridine 5 is also an active
compound with four chlorines, which can be acquired
a diversity of useful intermediates for the synthesis of
fluoroxypyridine and chlorpyrifos which was selected
as a successful pyridine‑based agrochemical compound
such as insecticide, acaricide, nematicide. 2,3,5,6‑Tetra‑
chloropyridine reacts with paraformaldehyde and sodium
cyanide to form the pyridinyloxyacetic acid 225 in good
yield (83%) where it is an important material for the syn‑
thesis of fluoroxypyridine which is non‑phytotoxic for the
crops (Scheme57) [192, 193].
As shown in this review, the tetrachloropyridine has
proven to be available for an extremely efficient and thus
exploited resource for the synthetic chemist. No doubt
there is still much to advance in the search for reaction
conditions for these group of compounds and meet as
many of the principles for the synthesis of newly sub‑
stituted pyridine. The substitution of conventional reac‑
tion with different groups of N‑, O‑nucleophiles, such
as sodium methoxide, sodium hydroxide, methylamine
and piperidine, is a critical decision toward this way, and
the respective products could be obtained (2–75% yield)
(Scheme58) [194].
Scheme55 Reaction of tetra‑
chloropyridine with different
nucleophiles
Scheme56 Reaction of tetra‑
chloropyridine with CCl4 and
C2Cl6

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Synthesis oftetrachloro‑4‑hydroxypyridine
The success in the use of pentachloropyridine 3 as start‑
ing material for the synthesis of new compounds and the
recognized biological activities, there is a continued inter‑
est in the functionalization of heterocycles. To achieve that,
Bratt and co‑workers demonstrated a simple route for the
synthesis tetrachloro‑4‑hydroxypyridine 57 in 73% yield
from the treatment of this compound with sodium nitrite in
dimethylformamide in short reaction time 15min) at room
temperature (Scheme59) [195].
Synthesis ofpolychlorobipyridines
Polychlorobipyridine 237 is the organic heterocyclic com‑
pound used prominently in many areas of chemistry and
common precursors to many derivatives. Also, they have
a special characteristic of forming stable complexes with
transition metals. Many bipyridine derivatives have been
used as bidentate ligands of transition metal complexes for
the dye‑sensitized solar cell [196–198]. Bipyridines have
also been utilized for the catalytic process and in asym‑
metric catalysis. In this context, a number of researches
are being conducted on the introduction of bipyridine units
in several heterocycles; for instance, 4,4′‑octachlorobipy‑
ridine 237 has been synthesized by phenyllithium in 50%
yield in the reaction of pentachloropyridine 3 with the
organometallic compound (Scheme60) [199].
Scheme57 Synthesis of hydroxylated material from 2, 3, 5, 6‑tetra‑
chloropyridine
Scheme58 Reaction of
2,4,5,6‑tetrachloropyridine with
nucleophiles
Scheme59 Synthesis of tetrachloro‑4‑hydroxypyridine

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Reactions ofpolychlorobipyridines
Following the line of synthesis of bipyridines, we will
describe a new strategy for employing of bipyridine 238
for further reaction with the organometallic compound
in anhydrous conditions (Scheme61) [200]. By reacting
organolithium reagent, with octachloro‑4,4′‑bipyridyl 238,
by metal‑halogen exchange in 3‑position this π‑system, sys‑
tem showed an electron‑withdrawing activity to prepare the
cyclized product of 239 obtained for 4h under refluxed (21%
yield).
Electrochemical reduction
ofpolychloroopyridine
Analogously to the methodology presented above, another
group reported the electrochemical reduction of polyhal‑
ogenopyridines for the synthesis of bipyridines, but no
sign of these compounds was observed. Perhalogenated
aromatic compound may be reduced at a mercury cathode
and suggested a way to explore the electron distributions.
By this protocol, pentachloropyridine 3 has been reduced
and tetrachloropyridine 5 and bis(tetrachloropyridyl)mer‑
cury 243 were only obtained (Scheme62) [201]. It was
observed that in all the tested examples, the structure of
products was confirmed by calculation.
Scheme60 Synthesis of 4,4′‑octachlorobipyridine
Scheme61 Reaction of polychlorobipyridine
Scheme62 Electrochemical
reduction of polychloroopyri‑
dine

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Photochemical reaction
ofpolychloropyridines
Due to the considerable interest in the development
of highly efficient methods to the use of polyhalogen‑
ated pyridine, with diverse patterns of substitution,
important issues for the synthesis of 3,4,5‑trichloro‑
2,6‑bis‑[bis(pentachlorophenyl)methyl]pyridine
248 have been investigated. 3,4,5‑Trichloro‑2,6‑bis‑
[bis(pentachlorophenyl)methyl]pyridine 248 is the pre‑
cursor for the synthesis of biradical and the monoradical.
In this sense, from starting 3,4,5‑trichloro‑2,6‑dimethyl‑
pyridine 217a (which was prepared in the literature from
pentachloropyridine), Chaler and co‑workers have pre‑
sented perchloro‑2,6‑bis(diphenylmethyl)pyridine‑α,αʹ‑
ylene 248, which was isolated in 46% yield. The reaction
involved a very stable biradical (Scheme63) which could
be reacted by photochlorination with Cl2 or photobromi‑
nation with Br2 in the subsequent reaction [202].
Summary andoutlook
Perchloropyridines represent an extremely interesting
class of organic compounds that can be utilized as precur‑
sor and building block for the synthesis of a wide range
of substituted heterocyclic compounds. Despite this fact,
needed for the comprehensive review of these compounds
were neglected but they have gained much interest from the
organic chemistry community and there remains much to
be discovered. Moreover, some interesting reactions have
been reported, also there has been a lack of study of many
reactions of perchloropyridines. It is likely that in the near
future additional and novel synthesis strategies will be devel‑
oped to access this important class of compounds, and it is
certain that pentachloropyridine will continue to attract the
attention of many chemistsin the filled of organic chemistry,
especially heterocycles, due to its unique property which
makes it ideal reagent in nucleophilic reactions.
Acknowledgements The authors wish to thank Vali‑e‑Asr University
of Rafsanjan for partially funding this work.
Scheme63 Photochemical
reaction of polychloropyridine

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