The regioselective iodination of quinolines, quinolones, pyridones, pyridines and uracil

Article abstract of DOI:10.1039/c5cc07799k

A radical based direct C-H iodination protocol for quinolines, quinolones, pyridones, pyridines, and uracil has been developed. The iodination occurs in a C3 selective manner for quinolines and quinolones. Pyridones and pyridines undergo C3 and C5 iodination, while dimethyl uracil undergoes C5 iodination. Scope of the method was demonstrated through the rapid synthesis of both electron rich as well as electron poor heteroaromatic iodides. The protocol was found to be scalable and general, while a mechanism has been proposed.

Full text of DOI:10.1039/c5cc07799k

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The Regioselective Iodination of Quinolines, Quinolones,
Pyridones, Pyridines and Uracil
Uttam Dutta,a,b,c Arghya Deb,a David W. Lupton*b,c and Debabrata Maiti*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A radical based direct C–H iodination protocol for quinolines, and
therefore
limit
generality.
Direct
regioselective
quinolones, pyridones, pyridines, and uracil has been functionalization of heterocycles arguably has the greatest potential
developed. The iodination occurs in a C3 selective manner to deliver broadly applicable iodination methods. However,
for quinolines and quinolones. Pyridones and pyrdines selectivity with substrates bearing multiple C–H bonds makes this
undergo C3 and C5 iodination, while dimethyl uracil approach more challenging.
undergoes C5 iodination. Scope of the method was
demonstrated through the rapid synthesis of both electron
Previous Approaches to C3 iodination
Heterocycles
Br
I
rich as well as electron poor heteroaromatic iodides. The
protocol was found to be scalable and general, while a
mechanism has been proposed.
CuI/TMEDA
(1) Quinolines
NaI
N
N
N
1
2a
2a
H
I
Iodine containing compounds are integral to synthetic organic
chemistry. Beyond applications in traditional synthetic methods
such as metalation1 and aromatic nucleophilic substitution,2 they
are now ubiquitous in cross-coupling chemistry.3 Furthermore,
radiolabeled iodide analogues play a vital role in medicinal and
radiotherapeutic science.4 As a consequence, extensive efforts have
been made to develop useful protocols for preparing aryl iodides.5-7
However, their synthesis remains difficult, with limitations relating
to the use of expensive transition metals, need for highly polar
solvents, prefunctionalization, and modest regioselectivity, plaguing
many reported approaches.8 On contrary to simple aryl iodide, the
synthesis of heteroaromatic iodides is increasingly difficult.
I
2, TBHP
DCE
Quinolines
(2)
(3)
Isoquinoline
N
3
Quinolines
Isoquinolines
Quinolones
Pyridones
Uracil
This work
H
I
K2S2O8/ NaI
Ce(NO3)3.6H2O
N
N
O
O
Scheme 1 C3 selective iodination by C–H functionalization
With pyridyl and quinoline, halogenation can be addressed by
exploiting the N-oxide thereby allowing selective C2 halogenation.15
While in an orthogonal approach recently reported by Chang and
co-workers C8 iodination was achievable by rhodium catalyzed C–H
iodination of quinoline-N-oxide with NIS.16 While selective C2 and
C8 halogenation of quinolines can be achieved, mild regioselective
methods for other iodinations remain limited. As part of broader
studies on the functionalization of heterocycles17 in 2013 we
commenced studies focused on C3 selective halogenation of
quinolines, and related heterocycles. We envisaged a direct radical
iodination approach enabled by the mild generation of the iodo
radical. It was postulated that such an approach should allow
predictable C3 iodination due to the stability of the first formed
Quinoline, pyridone and other nitrogen containing heterocyclic
iodides are highly important structural motifs due to their presence
in innumerable natural products and pharmaceutical agents.9 In
recent years, much efforts have been devoted towards the
regioselective synthesis of iodinated heterocycles.10-12 Aromatic
Finkelstein reaction from bromides (i.e. 1) have developed as
popular method for accessing iodo-quinolines (2) (eq. 1, Scheme
1).13 Recently Li et al. have disclosed a photo induced metal free
Finkelstein reaction to access C3 and C4 iodinated quinoline.14
Unfortunately, such an approach demands prefunctionalization,
radical intermediate. Very recently
a related concept was
communicated by Sun and Jain which allowed the iodination of
different quinolone derivatives in a regioselective manner (3) (eq. 2,
Scheme 1).10f,g Stimulated by this report we wish to report our
approaches on this topic. While our conditions are related to those
of Sun and Jain, we have been able to achieve mild iodination of
both electron rich and poor quinolines, as well as pyridones, uracil
and pyridines. Mechanistically we believe that in-situ generation of
the iodo radical leads to selective C3 iodination, although with
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highly electron rich substrates alternate mechanistic pathways are (Table3). To our delight, we obtained the C3 iodinated N-benzyl
possible.
quinolone derivative 5a in 65% yield.
To achieve selective C3 iodination we commenced by reacting
quinoline with K2S2O8 and sodium iodide in the presence of MnSO4
in dichloroethane (DCE) heated at 130 °C. Unfortunately, these
conditions, and those in which the manganese was replaced by
either tin or cobalt failed to provide 3-iodo-quinoline (2a) (Table 1,
entries 1-3). In contrast the reaction in the presence of either
bismuth, nickel or cerium salts gave promising yields of the
expected product with Ce(NO3)3.6H2O optimal with 40% yield of 2a
(Table 1, entries 4-6). Addition of 1 equivalent of TFA increased the
yield, while an examination of alternate oxidants confirmed that
potasium peroxodisulphate was ideal (Table 1, entry 7), although
other common oxidants were also viable (Table 1, entries 8-11).
Finally, increasing the stoichiometry of sodium iodide to three
equivalents increased the yield further to 85% (Table 1, entry 12).
Finally, control experiments demonstrated that each reagent is
necessary for the formation of 3-iodoquinoline in synthetically
useful yields (See SI for detailed optimization).
Table 2 Scope of iodination for various quinolinesa
Table 1 Selected optimization of iodination
Entry
Metal salt
oxidant
solventa
yieldb
aIsolated yield. b Yield based on recovered starting material.
1
2
MnSO4.H2O
SnCl2.2H2O
K2S2O8
K2S2O8
DCE
DCE
-
-
Similar results were obtained in the preparation of the N-methyl
quinolone 5b, while C5 blocked (Cl, 4c or CF3, 4d) iodinated
pyridones (5c and 5d) were also prepared in excellent yield.
3
4
CoCl2.6H2O
Bi(NO3)3.5H2O
Ni(NO3)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
TBHP
DCE
DCE
1
30
Table 3 Scope of the iodination of pyridones, quinolones, uracil and
pyridinesa
5
DCE
37
6
7c
8c
9 c
10 c
11 c
12c,d
Ce(NO3)3.6H2O
Ce(NO3)3.6H2O
Ce(NO3)3.6H2O
Ce(NO3)3.6H2O
Ce(NO3)3.6H2O
Ce(NO3)3.6H2O
Ce(NO3)3. 6H2O
DCE
40
DCE
62
DCE
61
K2S2O8
K2S2O8
DTBP
1,2,3-TCP
tBuOH
DCE
45
20
59
85(78)e
K2S2O8
DCE
aAll reactions performed at 130 °C. bGC yield except as noted. c1
equiv TFA added. d3 equiv NaI. eIsolated yield.
With the optimized reaction condition, the generality of the
regioselective iodination was examined with the halogenation of
various quinoline derivatives (Table 2). In contrast to the studies of
Sun and Li who reported solely the iodination of electron poor
substrates our conditions allowed 6-methyl (2b, 62%) and 8-methyl
(2c, 45%), as well as electron deficient 8-NO2 (2d, 80%)
iodoquinolines to be prepared in acceptable isolated yields after
column chromatography. Similarly 6-bromoquinoline and electron
rich 6-amino quinoline gave C3 iodinated 2e and 2f in 65% and 55%
yields respectively. Isoquinoline gave C4-iodinated product 2g in
72% yield, as reported by Sun and Li. When the 6-methoxy
quinolines were examined the selectivity switches to C5-iodinated
products (2h, 60% and 2i, 70%).
Next, we thought to examine the related iodination of N-benzyl
quinolones (i.e. 4a) under the optimized reaction condition
aIsolated yield. bYield based on recovered starting material.
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When C3 blocked pyrdiones were subjected to the reaction Previous studies with pyridone demonstrated selective
condition (Cl, 4e; p-tolyl, 4f) the C5 iodinated products formed functionalization at C3 position via a radical based transformation.18
smoothly. The reaction was insensitive to steric congestion with the The observed C5-functionalized products, as in 6-methoxy quinoline
C5 iodinated C6-methyl-C3-p-tolyl pyridone prepared in 55% yield.
2h, likely forms by electrophilic iodination. Therefore, the present
protocol can promote iodination reaction both by a radical or
electrophilic path. By considering the C3 and C5 selectivity for
quinoline and pyridone, a mechanism is proposed in Scheme 3.
With N-phenylethyl, N-methyl or N-aryl pyridones bearing no
additional substituents the diiodinated pyridones 5h, 5i and 5j were
prepared in 66, 50 and 42% yields respectively. The electron
deficient pyridone 4j was diiodinated to give 5j smoothly, while
dimethyl uracil (4k) provided the product of monoiodination. Finally
a series of 2-hydroxy iodopyridines 5m-5p bearing either C3 or C5
substituents were smoothly formed in acceptable yields.
Conclusions
To assess the scalability of the protocol conversion of 8-NO2
quinoline to 3-iodo-8-nitro quinoline (2d) was performed with 1.3 g
of substrate. The expected iodide 2d was obtained in 77% yield,
only slightly lower than the yield achieved with the submilimolar
scale reaction (Scheme 2).
In conclusion, a variety of heterocyles can be iodinated in a
predictable and selective manner using simple reaction conditions.
This method is operationally simple and scalable. Due to high
demand of heterocyclic iodides, this protocol is expected to find
application in industry and academia.
Authors thanks IITB-Monash Research Academy. This activity is
supported by SERB-india (EMR/2015/001136). Financial support
received from CSIR (A.D.) is gratefully acknowledged.
Scheme 2 Scaled up iodination of 8-nitro quinoline
Notes and references
In order to gain insight into the reaction mechanism, a number
of control experiments were performed. When a radical quencher
(e.g. TEMPO) was introduced this suppressed the iodination
reaction with only a trace of the iodinated product of quinoline 2a.
Based on this observation, it may be assumed that one of the steps
for iodination is proceeding via a radical pathway.
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Path A: Quinoline iodination
via iodo radical and/or
iodonium ion
-
HSO4
_
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HSO4
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Scheme 3 Plausible mechanism
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