For Peer Review
Transition Metal
-
Free
Direct C
–
H (Hetero)arylation of
Heteroarenes: A Sustainable Methodology to Access
(Hetero)aryl-Substituted Heteroarenes
Journal:
Advanced Synthesis & Catalysis
Manuscript ID:
Draft
Wiley - Manuscript type:
Review
Date Submitted by the Author:
n/a
Complete List of Authors:
Rossi, Renzo; Universita' di Pisa, Dipartimento di Chimica e Chimica
Industriale
Lessi, Marco; Universita' di Pisa, Dipartimento di Chimica e Chimica
Industriale
Manzini, Chiara; Universita' di Pisa, Dipartimento di Chimica e Chimica
Industriale
Marianetti, Giulia; Scuola Normale Superiore, Chemistry
Bellina, Fabio; Universita' di Pisa, Dipartimento di Chimica e Chimica
Industriale
Keywords:
direct C–H (hetero)arylation, heteroarenes, Regioselectivity, transition
metal-free reactions, sustainable chemistry
Wiley-VCH
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For Peer Review
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REVIEW
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transition Metal-Free Direct C–H (Hetero)arylation of
Heteroarenes: A Sustainable Methodology to Access
(Hetero)aryl-Substituted Heteroarenes
Renzo Rossi,
a,
* Marco Lessi,
a
Chiara Manzini,
a
Giulia Marianetti,
b
and Fabio Bellina
a,
*
a
Dipartimento di Chimica e Chimica Industriale, University of Pisa, via G. Moruzzi, 3 – 56124 Pisa, Italy
Phone: (+39) 050-2212111; fax: (+39) 05040834; e-mail: renzo371@alice.it; fabio.bellina@unipi.it
b
Scuola Normale Superiore, Piazza dei Cavalieri 7 – 56126 Pisa, Italy
Dedicated to the memory of Fausto Calderazzo
Received: ((will be filled in by the editorial staff))
Abstract.
In recent years, environmental and economic
reasons have motivated the development of transition metal
-
free carbon–
carbon bond forming reactions and some
excellent reviews have covered this research area of
particular interest for pharmaceutical industry.
However,
none of these reviews has been specifically dedicated to
summarize and discuss the results achieved in the rapidly
growing field of the transition metal-
free direct
(hetero)arylation reactions of heteroarenes.
This review,
which covers the litera
ture from 2008 to 2014, aims to
provide a thorough insight of the synthetic and mechanistic
aspects of these atom economical and environmental benign
reactions also highlighting their advantages and possible
disadvantages compared to conventional methods f
or the
synthesis of arylheteroarenes and biheteroaryls via transition
metal-catalyzed reactions.
1. Introduction
2.
Direct (Hetero)arylation of Heteroarenes with
(Hetero)aryl Halides or Pseudohalides
3.
Direct (Hetero)arylation of Heteroarenes with
(Hetero)aryl Iodonium Salts
4.
Direct Arylation of Heteroarenes with Anilines
Nitrosated in situ or Arylhydrazines
5.
Direct Arylation of Benzothiazoles with Aryl
Aldehydes
6.
Direct (Hetero)arylation of Heteroarenes with
(Hetero)arylmetals
7. Conclusions
Keywords: direct C–H (hetero)arylation; heteroarenes;
regioselectivity; transition metal-free reactions; sustainable
chemistry
1 Introduction
(Hetero)aryl-substituted heteroarenes are a
structural motif present in naturally-occurring
substances,
[1]
biologically-active compounds,
[2]
agrochemicals,
[3]
and conjugated polymers.
[4]
The
traditional approach for the synthesis of (hetero)aryl-
substituted heteroarenes involves Pd-catalyzed cross-
coupling reactions between previously activated
substrates, i.e. (hetero)aryl halides or pseudohalides
and (hetero)arylmetal derivatives including Grignard
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reagents, organozinc derivatives, organotin
compounds, organoboron derivatives, and
organosilicon reagents
[5]
(Scheme 1, eq. a). However,
in the last two decades more step-economical and
greener alternative methodologies for the synthesis of
arylheteroarenes and biheteroaryls including
unsymmetrical derivatives have emerged. One of
these methodologies, in which the preparation and use
of stoichiometric amounts of organometallic reagents
is avoided, involves transition metal-catalyzed direct
(hetero)arylation reactions of heteroarenes with
(hetero)aryl halides or pseudohalides (Scheme 1, eq.
b).
[6]
Unfortunately, this methodology, which is still a
very active area of research and development, suffers
from some limitations that include poor reactivity of
some substrates, lack of regioselectivity of some of
these coupling reactions, especially when the
heteroarene substrates possess multiple C–H acidic
bonds or multiple nucleophilic centers, and
impossibility to carry out direct (hetero)arylation
reactions at certain specific sites. Furthermore, the
efficiency and selectivity of the direct
(hetero)arylation reactions often depends strictly by
the use and nature of supporting ligands, which
sometimes are expensive and/or difficult to prepare,
as well as of special additives and cocatalysts.
Scheme 1. Methodologies for the synthesis of
(hetero)aryl-substituted heteroarenes
Another interesting methodology involves the
transition metal-catalyzed decarboxylative cross-
coupling reactions of heteroaryl carboxylic acids with
(hetero)aryl halides (Scheme 1, eq. c).
[7]
In these
reactions, in which the readily available heteroaryl
carboxylic acids are the source of carbon nucleophiles
and CO
2
is the by-product of the couplings, the
regioselectivity is insured by the carboxylic acid
functionality.
The transition metal-catalyzed dehydrogenative
coupling of two heteroarenes or a heteroarenes with
an arene (Scheme 1, eq d)
[8]
is another attractive
approach to construct (hetero)aryl-substituted
heteroarenes. In fact, it allows for superior atom- and
step-economic transformations as it does not require
preactivation of both coupling partners. However,
chemo- and regioselectivity issues limit the broad
application of these reactions, which in many cases
require the use of stoichiometric amounts of oxidants
such as silver or copper salts.
It must also be pointed out that, unfortunately, all
the four methodologies illustrated in eqs. a–d of
Scheme 1 have some significant drawbacks for their
industrial application, especially in the
pharmaceutical industry. In fact, they involve the use
of catalytic systems which are usually sensitive to
moisture and oxygen, are normally quite expensive
and sometimes toxic, and require expensive
procedures to be completely removed from the final
reaction products.
[9]
Notably, these drawbacks do not characterize the
synthesis of (hetero)aryl-substituted heteroarenes
through transition metal-free, UV- or visible light-
mediated reactions of heteroarenes with aryl halides
or pseudohalides as well as of arenes with heteroaryl
halides (Scheme 1, eq. e),
[10]
but this process often
suffers from low reaction rates and or low chemical
yields.
Finally, in the last decade, environmental and
economic concerns have motivated the development
of a conceptually different green methodology for the
synthesis of arylheteroarenes and unsymmetrical
biheteroaryls. In this methodology, which has
emerged as a useful alternative to traditional cross-
couplings, the synthesis of the target compounds is
achieved via transition metal-free direct
(hetero)arylation of heteroarenes with (hetero)aryl
halides or pseudohalides or (hetero)aryliodonium salts
in the presence of a strong base, a combination of a
strong base and an organic ligand, or a radical
initiator (Scheme 1, eq. f). The seminal study of the
transition metal-free direct heteroarylation reactions
of heteroarenes with aryl halides was performed ion
2008 by Itami and coworkers
[11]
and, since then, the
literature has been enriched by numerous reports that
illustrate various protocols to achieve the inexpensive,
high yielding and easy to conduct chemoselective
synthesis of a large variety of arylheteroarenes and
unsymmetrical biheteroaryls including highly
functionalized derivatives.
In this last decade, this methodology has also been
joined by some protocols in which (hetero)arylating
reagents different from (hetero)aryl halides or
pseudohalides have been used. In addition, two-step
procedures have been developed that involve the
transition metal-free reaction of heteroarenes with
(hetero)arylmetals and the subsequent reaction of the
resulting compounds with an oxidant (Scheme 1, eq.
g). Obviously, these procedures can not be included
among those with low economic and environmental
(Het)Ar
1
-X
+
(Het)Ar
2
-M (Het)Ar
1
-(Het)Ar
2
HetAr
1
-H
+
(Het)Ar
2
-X HetAr
1
-(Het)Ar
2
HetAr
1
-COOH
+
(Het)Ar
2
-X HetAr
1
-(Het)Ar
2
(Het)Ar
2
+
(Het)Ar
1
-(Het)Ar
2
(Het)Ar
1
-H (Het)Ar
2
-X
+
(Het)Ar
1
-(Het)Ar
2
(Het)Ar
1
-H (Het)Ar
2
-X
+
HetAr
1
-(Het)Ar
2
HetAr
1
-H HetAr
1
-(Het)Ar
2
(Het)Ar
1
-H
Pd
cat
Transition metal
catalyst
Transition metal
catalyst
Transition metal
catalyst
Oxidant
hν
strong base or
strong base + ligand
or radical initiator
1) (Het)Ar
2
-M
2) Oxidant
(a)
(b)
(c)
(d)
(e)
(f)
(g)
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impact as they involve the synthesis of the
organometallic reagents to be used as
(hetero)arylating reagents and some of these
compounds are water and air sensitive. Nevertheless,
it appeared appropriate to include these reactions in
this review taking into account of their efficiency and
the fact that they do not require a large molar excess
of one of the reagents, they operate in the absence of a
transition metal catalyst, and given that only one of
the reaction partners requires to be activated.
Recently, the transition metal-free carbon–carbon
bond forming reactions have been covered by some
excellent reviews,
[12]
but none of them has been
specifically devoted to summarize completely and
discuss the results achieved in the context of the
transition metal-free direct C–H (hetero)arylation
reactions of heteroarenes. This review with 258
references aims to provide a thorough insight of this
subject highlighting the synthetic and mechanistic
aspects of these transition metal-free (hetero)arylation
reactions as well as the practicality and limitations of
the various developed protocols. A comparison
between the results achieved using the transition
metal-free direct (hetero)arylation reactions of
heteroarenes and those obtained by other methods fro
the formation of C
(hetero)aryl
–C
heteroaryl
bonds will be also
reported.
The review, which covers the literature from 2008
to December 2014, has been organized in the
following sections: (i) direct (hetero)arylation of
heteroarenes with (hetero)aryl halides or
pseudohalides; (ii) direct (hetero)arylation of
heteroarenes with (hetero)aryliodonium salts; (iii)
direct (hetero)arylation of heteroarenes with anilines
nitrosated in situ or arylhydrazines; (iv) arylation of
benzothiazoles with aryl aldehydes; and (v) direct
(hetero)arylation of (hetero)arenes with
(hetero)arylmetals.
However, it should be pointed out that, for reasons
of space, this review does not deal with a summary
and discussion of the synthesis of (hetero)aryl-
substituted heteroarenes via transition metal-free
oxidative (dehydrogenative) cross-coupling
reactions
[13]
and via aryl radical additions to
heteroarenes involving the use of catalytic amounts of
AIBN and over-stoichiometric amounts of Bu
3
SnH,
[14]
a compound that is very harmful to the environment.
Also, the patent literature has not been taken into
account.
2 Direct (Hetero)arylation of
Heteroarenes with (Hetero)aryl halides
or Pseudohalides
In 2008, Itami and coworkers reported
the first
examples of synthesis of arylheteroarenes via
intermolecular transition metal-free direct C–H
arylation of heteroarenes with aryl halides.
[11]
They
discovered that the reaction of 1 equiv of aryl iodides
with 40 equiv of electron deficient nitrogen
heteroarenes, including pyrazine (1), pyridine (2),
pyrimidine (3), piperazine (4) and quinoxaline (5),
and 1.5 equiv of sublimed KO-t-Bu at 50 °C under
microwave irradiation for 5 min produced
arylheteroarenes in good to excellent yields (Scheme
2). Interestingly, the arylation reactions were carried
out in the absence of any amine or bipyridine catalyst
such as N,N’-dimethylethylenediamine or 1,10-
phenanthroline.
Scheme 2. Synthesis of compounds 6–10 by KO-t-
Bu-mediated direct arylation of heteroarenes 1–5 with
aryl iodides under microwave irradiation
Unfortunately, poor regioselectivity with respect to
the heteroarene was observed in the arylation of
compounds 2–5 with iodobenzene, but regioisomers
with respect to the aryl iodides were not detected in
the arylation reactions of pyrazine (1) with 4-iodo-
and 3-iodoanisole and 3-iodothiophene, which
provided compounds 6b, 6c and 6d in 83, 64 and 71%
yield, respectively (Scheme 2). This meant that the
arylation reactions did not proceed through aryne
intermediates. The reaction mechanism was not
elucidated, but the radical nature of the reaction was
supported by experiments showing that the reaction of
pyrazine (1) with iodobenzene in the presence of 1.5
equiv of KO-t-Bu and 1 equiv of a radical scavenger
such as TEMPO, galvinoxyl or acrylonitrile did not
gave 2-phenylpyrazine (6a). Itami and coworkers then
formulated a plausible mechanism for the KO-t-Bu-
HetAr- H +
I
R
1
HetAr
R
1
HetAr-H:
N
N
N N
N
N
N
N
N
N
N Ph
N
N
N
N
N
N
OMe
OMe
S
N
Ph
N
N
Ph
N
N
1-5 (40 equiv.) (1 equiv.)
KOtBu (1.5 equiv.)
MW, 50 °C, 5 min
6-10
(1); (2); (3)
(4); (5)
6a: 98% 6b: 83% 6c: 64% 6d: 71%
7a: 63%
(2-/3-/4- = 36/21/43)
8a: 59%
(2-/4-/5- = 23/52/25)
N
N Ph
9a: 56%
(3-/4- = 24/76)
10a: 75%
(2-/5- = 64/36)
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mediated arylation of 1 with iodobenzene in which
the initial step was the generation of the radical anion
species A by single electron transfer (SET) from KO-
t-Bu to iodobenzene (Scheme 3).
[11]
Scheme 3. Plausible mechanism for the of KO-t-Bu-
mediated arylation of pyrazine (1) with iodobenzene
In this mechanism, elimination of KI from A would
provide phenyl radical B, which by addition to
pyrazine would generate phenylpyrazyl radical C.
Finally, abstraction of hydrogen radical from C by t-
butoxide radical would give compound 6a (Scheme
3).
[11]
One year after the publication of these results, Li and
Hua reported that pyrazine (1) and pyridine (2)
underwent Cy
3
PAuCl-catalyzed direct arylation with
aryl bromides at 100 °C in the presence of KO-t-Bu to
give monoarylated products, which in the case of
electron-rich aryl bromides were obtained in moderate
to good yields.
[15]
Scheme 4. Gold-catalyzed direct arylation of
pyrazine (1) and pyridine (2) with aryl bromides
This method (Scheme 4) also allowed the preparation
of compound 6a in 90% yield, but in the case of the
arylation of pyridine provided mixtures of
regioisomers.
[15]
In the same year, Liu and Yang synthesized
compound 6a and 2-(p-tolyl)pyrazine (6e) in 80 and
82% yield respectively, by oxygen-promoted, ligand-
free Pd(OAc)
2
-catalyzed Suzuki reaction of 2-
chloropyrazine (11) with the required arylboronic
acids in 50% aqueous isopropanol at 80 °C for 40 min
(Scheme 5).
[16]
Interestingly, a similar protocol
allowed the preparation of 2-aryl-substituted
pyridines from 2-bromopyridines in excellent
yields.
[16]
Scheme 5. Ligand-free Pd(OAc)
2
-catalyzed Suzuki
coupling of 2-chloropyrazine (11) with arylboronic
acids
More recently, Zhu, Xu and coworkers showed that p-
toluenesulfonylhydrazide (PTSH) promotes the
efficient direct arylation of pyrazine (1) with 4-
iodoanisole at 110 °C in the presence of 3 equiv of
KO-t-Bu, but in the absence of any amine or
bipyridine catalyst, providing compound 6b in 90%
yield (Scheme 6).
[17]
However, a regioisomeric
mixture of arylated compounds favouring the ortho
product was obtained by the PTSH-initiated direct
arylation of pyridine with 4-iodoanisole.
[17]
Scheme 6. p-Toluenesulfonylhydrazide-initiated
direct arylation of pyrazine with 4-iodoanisole
The PTSH-initiated arylheteroarene syntheses were
proposed to occur through a chain base-promoted
homolytic aromatic substitution involving the aryl
radical II, which would be formed by the reaction
between deprotonated PTSH and 4-iodoanisole
followed by elimination of iodide anion from the
resulting radical anion I (Scheme 7).
[17]
KOt-Bu
+
I
K
+
I
N
N
, K
+
N
N
K
+
N
N
N
N Ph
SET
tBuO
-
A
KI
B
Ph
H
tBuO
-
tBuOH
C
Y
N
+
Br
R
1
Y
N
R
1
1: Y = N
2: Y = CH
(10 equiv.)
(1 equiv.)
Cy
3
PAuCl (2 mol%)
KOtBu (2 equiv.)
100 °C, 12-24 h
(24-90%)
6: Y = N (12 examples)
7: Y = CH (6 examples)
N
N
Cl
+
B(OH)
2
R
1
N
N
R
1
11 (1 equiv.) (1.5 equiv.)
Pd(OAc)
2
(1.5 mol%)
K
3
PO
4
⋅7H
2
O (2 equiv.)
50% iPrOH
80 °C, 40 min
under air 6a: R
1
= H (80%)
6b: R
1
= Me (82%)
N
N
+
I
Me
SO
2
NHNH
2
N
N
OMe
1 (5 mL) (1.0 mmol)
(10 mol%)
KOtBu (3 equiv.)
110 °C, 24 h
(90%)
6b
MeO
+
MeO
I
p
_ _
NH
2
I
MeO
+
K
+
TsN
MeO
+ KI
p
_ _
NH
2
TsN
K
I
II
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