One-pot synthesis and applications of N-heteroaryl iodonium salts

Article abstract of DOI:10.1002/open.201300042

An efficient one-pot synthesis of N-heteroaryl iodonium triflates from the corresponding N-heteroaryl iodide and arene has been developed. The reaction conditions resemble our previous one-pot syntheses, with suitable modifications to allow N-heteroaryl groups. The reaction time is only 30 min, and no anion exchange is required. The obtained iodonium salts were isolated in a protonated form, these salts can either be employed directly in applications or be deprotonated prior to use. The aryl groups were chosen to induce chemoselective transfer of the heteroaryl moiety to various nucleophiles. The reactivity and chemoselectivity of these iodonium salts were demonstrated by selectively introducing a pyridyl moiety onto both oxygen and carbon nucleophiles in good yields. N-Heteroarylation: An efficient one-pot synthesis of N-heteroaryl iodonium triflates from the corresponding N-heteroaryl iodide has been developed. The reactivity and chemoselectivity of these iodonium salts were demonstrated by selectively introducing a pyridyl moiety onto both oxygen and carbon nucleophiles in good yields.

Full text of DOI:10.1002/open.201300042

DOI: 10.1002/open.201300042
One-Pot Synthesis and Applications of N-Heteroaryl
Iodonium Salts
Marcin Bielawski, Joel Malmgren, Leticia M. Pardo, Ylva Wikmark, and Berit Olofsson*[a]
An efficient one-pot synthesis of N-heteroaryl iodonium tri-
flates from the corresponding N-heteroaryl iodide and arene
has been developed. The reaction conditions resemble our
previous one-pot syntheses, with suitable modifications to
allow N-heteroaryl groups. The reaction time is only 30 min,
and no anion exchange is required. The obtained iodonium
salts were isolated in a protonated form, these salts can either
be employed directly in applications or be deprotonated prior
to use. The aryl groups were chosen to induce chemoselective
transfer of the heteroaryl moiety to various nucleophiles. The
reactivity and chemoselectivity of these iodonium salts were
demonstrated by selectively introducing a pyridyl moiety onto
Scheme 1. Our one-pot syntheses of Ar2IX from A) the corresponding
both oxygen and carbon nucleophiles in good yields.
iodoarenes or B) iodine with arenes or C) employing arylboronic acids.
Diaryliodonium salts have recently been recognized as efficient
electrophilic arylation reagents with a wide range of nucleo-
philes under both metal-free and metal-catalyzed conditions.[1]
The accessibility of these reagents has been greatly simplified
by the recent development of efficient one-pot syntheses from
the corresponding iodoarenes or iodine with arenes (Sche-
me 1A,B).[2] A complimentary regiospecific route employing ar-
ylboronic acids gives access to diaryliodonium salts with all
kinds of substitution patterns (Scheme 1C).[3]
application of these salts to different nucleophiles are reported
herein.
The reaction of 3-iodopyridine (1a) with benzene (2a) to
give pyridyl iodonium salt 3a was chosen as a model system
(Scheme 2). Initial attempts to form 3a under our standard
Despite the wide scope of the one-pot methods described
above, they fail in the synthesis of N-heterocyclic iodonium
salts.[4] N-heterocycles are common organometallic ligands and
substructures in biologically active compounds,[5] and the in-
troduction of such a moiety from a diaryliodonium salt would
be of high utility in organic synthesis. Symmetric N-heterocy-
clic salts can be obtained in low yields by treatment of
a highly unstable vinyliodonium dichloride[6] with aryl lithium
reagents at À788C.[7] Unsymmetric salts can be obtained in
a similar way.[8] A four-step synthesis to 3-pyridyl(aryl)iodonium
salts via the corresponding 3-pyridyl-iododichloride has also
been reported.[9] The poor accessibility to N-heterocyclic diary-
liodonium salts inspired us to develop a general one-pot syn-
thesis of these compounds. The synthesis and chemoselective
Scheme 2. Model system.
conditions, 1.1 equiv meta-chloroperoxybenzoic acid (mCPBA)
and 3 equiv trifluoromethanesulfonic acid (TfOH),[2b] resulted in
mixtures due to competing N-oxidation of 1a.[10] This could be
prevented by treating 1a with TfOH before addition of
mCPBA, thus protecting the nitrogen from oxidation. The nitro-
gen remained protonated in the formed iodonium salt, and
the isolated product was found to be phenyl(3-pyridinium)io-
donium bistriflate (3a’) rather than 3a.
The reaction conditions were further optimized, as detailed
in Table 1. The amount of mCPBA was first investigated, and
a slight excess proved better than equimolar amounts (En-
tries 1–3). Increasing the amount of TfOH from three to four
equivalents further improved the yield, which can be explained
by one equivalent of acid being consumed for nitrogen proto-
nation (Entry 4). Subsequently, the reaction time and tempera-
ture were varied, and 30 min at 608C was as efficient as 3 h at
808C, while lower temperatures were insufficient (Entries 4–8).
The high temperature required could be explained by slow
I-oxidation of protonated 1a.
[a] Dr. M. Bielawski, J. Malmgren, Dr. L. M. Pardo, Y. Wikmark, Prof. B. Olofsson
Department of Organic Chemistry
Stockholm University
106 91 Stockholm (Sweden)
E-mail: berit@organ.su.se
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/open.201300042.
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Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited and is not used for commercial purposes.
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give the pure deprotonated product 3b in 97% yield. Unfortu-
nately, submitting the crude reaction mixture directly onto an
Al2O3 column gave back the protonated material, and isolation
of 3’ before deprotonation was necessary.
Table 1. Optimization of reaction conditions.[a]
The optimized synthesis of 3’ and deprotonation to 3 was
subsequently applied on a range of N-heterocyclic iodoarenes
1 and arenes 2. The arenes were selected to give good chemo-
selectivity in both metal-free and metal-mediated reactions
(Scheme 4). As mentioned above, the anisyl moiety is a good
dummy group in many reactions under metal-free condi-
Entry
mCPBA
[equiv]
TfOH
[equiv]
T
[8C]
t
Yield
[%]
[min]
1
2
3
4
5
6
7
8
1.1
1.5
2.0
1.5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
4.0
4.0
4.0
4.0
4.0
80
80
80
80
80
80
60
40
180
180
180
180
10
30
30
30
54
60
52
68
48
60
69
[b]
–
[a] 1.1 equiv 2a was used. The product was isolated by concentration of
the crude mixture in vacuo followed by precipitation by addition of Et2O.
[b] Product isolation was difficult.
Scheme 4. General chemoselectivity trends.
It is known that pyridyl(phenyl)iodonium salts provide insuf-
ficient chemoselectivity in reactions with nucleophiles under
metal-free conditions.[9,11] Therefore, further optimization was
performed with anisole (2b), which is known to be a useful
“dummy group” in reactions of diaryliodonium salts with vari-
ous nucleophiles.[12]
tions.[12] Sterically hindered groups, such as mesityl and 2,4,6-
triisopropylphenyl (TRIP) are useful in metal-mediated reactions
and in arylations with malonates.[12,14]
The selected heteroaryl salts were synthesized using the two
optimized methods described above, and selected salts were
deprotonated to illustrate the methodology (Scheme 5). 3-Io-
dopyridine (1a) was combined with a range of arenes to give
heteroaryl salts 3a–e. Salts 3b–d have the selected dummy
groups for chemoselective arylations under different condi-
tions.
Syntheses of diaryliodonium salts with electron-rich arenes
generally require special conditions, such as a milder acid or
oxidant, to avoid side reactions. We have previously reported
modified procedures in our one-pot syntheses, where the io-
doarene is oxidized to the iodine(III) intermediate before addi-
tion of the electron-rich arene at low temperature.[2b,3]
Because oxidation of protonated 1a is slow, it was deemed
unsuitable to change the oxidation conditions. Thus, 1a was
oxidized under the same conditions, followed by addition of
2 equiv water at 08C to quench the triflic acid and create
a milder acid. The electron-rich arene in dichloromethane was
added dropwise, and additional stirring for 10 min afforded
the desired product 3b’ in high yield (Scheme 3).
2-Chloro-5-iodopyridine (1b) was reacted with mesitylene to
directly deliver salt 3 f without the need for deprotonation. Ap-
parently, the electron-withdrawing chloride diminishes the ba-
sicity of the nitrogen enough to avoid both N-oxidation and
protonation, which was previously noticed in iodonium salt
syntheses with 1b and benzene or anisole.[2b,4] 3-Iodoquinoline
(1c) was used to synthesize salts 3g–i, with all three dummy
groups. 4-Iodo-1H-pyrazole (1d) and 3,5-dimethyl-4-iodo-1H-
pyrazole (1e) could also be utilized in this reaction, forming
salts 3j–n with the selected dummy groups.
Aryl(uracyl)iodonium salts[15] have recently been
applied in the preparation of heteroaryl ketones
using an N-heterocyclic carbene (NHC) catalyst.[16]
While chemoselective, the cost of N,N-dimethylura-
cil makes this dummy group less attractive in stan-
dard reactions.[17] Still, uracyl salt 3o could be syn-
thesized in high yield with this methodology (see
Scheme 5).
Scheme 3. Modified synthesis with electron-rich arenes.
Pyridinium bistriflate 3’ might behave similarly to pyridyl
salts 3 in applications, but it was desirable to also have access
to deprotonated salts 3. A deprotonation procedure was there-
fore developed to remove the triflic acid from 3’ to obtain pyr-
idyl salts 3. Several basic workup procedures were attempted
to isolate salt 3b’, but unwanted anion exchanges complicated
such deprotonations.[13] Deprotonation was best achieved
using a basic Al2O3 column eluted with dichloromethane/meth-
anol (20:1). The eluted material was concentrated in vacuo to
The synthesis of salts 3’ was generally high yielding, and re-
actions with the anisyl dummy group consistently gave better
yields than the alkyl-substituted arenes. The modified proce-
dure used for anisyl salts was inefficient for synthesis of salts
with less electron-rich character. Also, the deprotonation of 3’
to 3 took place in good to excellent yields. The salts with an
anisyl moiety (3b, g, j) are expected to chemoselectively deliv-
er the pyridyl group in metal-free reactions with nucleophiles,
and salts with a mesityl (3c, f, h, k, m) or TRIP group (3d, i, l,
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lower yield. Reactions with salt
3b’ were performed with
2.1 equiv base instead of
1.1 equiv to compensate for the
TfOH present.[19] The yields with
this salt were lower than with
3b; but considering the facile
isolation of 3b’, it might still be
a useful alternative in some ap-
plications. The reactivity of
N-heteroaryl salts 3c and 3c’
was investigated by arylation of
diethyl methylmalonate (6),[20]
which has previously been che-
moselectively arylated using
a
mesityl dummy group.[12]
Again, the deprotonated salt
was more efficient than the pro-
tonated salt in formation of 7,
despite use of 2 equiv base
(Scheme 7). Complete chemose-
lectivity was obtained in all reac-
tions, illustrating the usefulness
of inexpensive anisole and mesi-
tylene as dummy groups in
these arylations.
An efficient synthesis of N-het-
eroaryl iodonium triflates has
been developed. The aryl groups
were chosen to induce chemose-
lective transfer of the heteroaryl
moiety to different nucleophiles.
Scheme 5. Synthesized N-heteroaryl iodonium salts. Method A was used unless specified (see Table 1, Entry 7).
Yield of 3 is from isolated 3’. [a] Method B was used (see Scheme 3).
n) should be chemoselective in metal-catalyzed reactions and
other reactions sensitive to steric hindrance, for example, mal-
onate arylations.
A reliable analytical tool was required to ensure that com-
plete deprotonation had taken place for all salts. While HRMS
delivered the same molecular weight for both 3’ and 3, the
Scheme 6. Chemoselective arylation of phenols.
1H NMR spectra in deuterated methanol differed. A concentra-
tion effect with slightly changing shifts is seen in samples of
3’, due to the interchangeable proton, while shifts of 3 are
constant.[13] Salt 3e’ was synthesized to confirm the accuracy
1
of this analytical method. Apart from the differences in H NMR
spectra described above, 19F NMR analysis of 3e’ gave a ratio
of 6:1 between the two detected peaks, indicating the pres-
ence of two triflate moieties. The same analysis after deproto-
nation to 3e indeed gave a ratio of 3:1.
Scheme 7. Chemoselective arylation of malonate 6.
Application studies were next undertaken to demonstrate
the utility of the prepared salts in chemoselective arylations.
Furthermore, the reactivities of the protonated salts 3’ and the
deprotonated salts 3 were compared. The electron-rich salts
3b’ and 3b were applied in the arylation of phenols, using our
previously reported protocol.[18] Arylation of 4a with 3b gave
pyridyl ether 5a in 88% yield (Scheme 6). The sterically hin-
dered phenol 4b was also arylated to give 5b, albeit in slightly
This was demonstrated by selectively introducing a pyridyl
moiety onto both oxygen and carbon nucleophiles. The pro-
tonated heteroaryl salts 3’ give lower yields than the deproton-
ated salts 3 in these reactions but might be as efficient in
transformations that are not base mediated.
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[3] M. Bielawski, D. Aili, B. Olofsson, J. Org. Chem. 2008, 73, 4602–4607.
[4] 5-(2-Chloro-pyridyl)iodonium salts were synthesized in ref. [2b]
(Scheme 1A), and other halide substituents in the same position are
also tolerated. Presumably the halide substituent makes the nitrogen
less oxidation prone, thereby preventing competing reaction pathways.
A cyclic pyridyl salt was also obtained using this methodology, see J.
Letessier, H. Detert, Synthesis 2012, 44, 290–296.
[5] a) J. Schranck, A. Tlili, M. Beller, Angew. Chem. 2013, 125, 7795–7797;
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[7] a) P. J. Stang, B. Olenyuk, K. Chen, Synthesis 1995, 937–938; For applica-
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[9] M. A. Carroll, J. Nairne, J. L. Woodcraft, J. Labelled Compd. Radiopharm.
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[10] Pyridine N-oxides are synthesized by mCPBA oxidation in dichlorome-
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Experimental Section
General experimental procedures
Method A: Iodoarene
1 (0.24 mmol) was stirred with TfOH
(4 equiv) in CH2Cl2 (1 mL) for 5 min at RT. Arene 2 (1.1 equiv) and
mCPBA (1.5 equiv) were added, and the solution was stirred at
608C for 30 min.
Method B: Iodoarene
1 (1.51 mmol) was stirred with TfOH
(4 equiv) in CH2Cl2 (10 mL) for 5 min at RT. mCPBA (1.75 equiv) was
added, and the solution was stirred at 608C for 30 min. After H2O
(2 equiv) was subsequently added at 08C and then arene 2
(1.1 equiv), the solution was stirred at 08C for 10 min.
Isolation of 3’: The crude mixture was concentrated in vacuo fol-
lowed by precipitation by addition of Et2O (1–3 mL). The solid was
collected by filtration and washed with Et2O.
Deprotonation to 3: Isolated 3’ was added on a basic Al2O3
column and eluted with CH2Cl2/MeOH (20:1). The eluted mixture
was concentrated in vacuo to give the pure deprotonated product
3.
[12] J. Malmgren, S. Santoro, N. Jalalian, F. Himo, B. Olofsson, Chem. Eur. J.
2013, 19, 10334–10342 and references cited therein.
Acknowledgements
[13] See Supporting Information for details.
This work was financially supported by the Swedish Research
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[17] The one-pot synthesis of heteroaryl(uracyl)salts using the methodology
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this reaction should have the same limitations as discussed in ref. [4].
The list price of N,N-dimethyluracil at Sigma–Aldrich is E 250 for 5 g.
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Council and University of the Basque Country UPV/EHU (MOV09/
23).
Keywords: arylation · heterocycles · hypervalent iodine ·
iodonium salts · oxidation
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Received: December 9, 2013
Published online on January 23, 2014
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