Generation of Aryl Radicals through Reduction of Hypervalent Iodine(III) Compounds with TEMPONa: Radical Alkene Oxyarylation

Article abstract of DOI:10.1002/chem.201504852

A novel method for selective generation of aryl radicals from diaryliodonium salts and iodanylidene malonates with sodium 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPONa) as a single-electron transfer (SET) reducing reagent is described. In the presence of various alkenes, aryl radicals formed after SET-reduction of hypervalent iodine compounds undergo alkene addition and the adduct radicals that are thus generated are efficiently trapped by the concomitantly generated TEMPO radical to eventually afford oxyarylated products in moderate to very good yields. The efficiency of aryl radical generation of various iodine(III) reagents is studied and the generation of an iodanylidene malonate aryl radical is also investigated by computational methods.

Full text of DOI:10.1002/chem.201504852

DOI: 10.1002/chem.201504852
Full Paper
&
Synthetic Methods
Generation of Aryl Radicals through Reduction of Hypervalent
Iodine(III) Compounds with TEMPONa: Radical Alkene
Oxyarylation
Marcel Hartmann,[a] Yi Li,[a] Christian Mück-Lichtenfeld,[a, b] and Armido Studer*[a]
Abstract: A novel method for selective generation of aryl
radicals from diaryliodonium salts and iodanylidene
malonates with sodium 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPONa) as a single-electron transfer (SET) reducing re-
agent is described. In the presence of various alkenes, aryl
radicals formed after SET-reduction of hypervalent iodine
compounds undergo alkene addition and the adduct radi-
cals that are thus generated are efficiently trapped by the
concomitantly generated TEMPO radical to eventually afford
oxyarylated products in moderate to very good yields. The
efficiency of aryl radical generation of various iodine(III) re-
agents is studied and the generation of an iodanylidene
malonate aryl radical is also investigated by computational
methods.
Introduction
fully used these types of iodine compounds for the clean gen-
eration of trifluoromethyl-, perfluoroalkyl- or azidyl radicals.[8–10]
Importantly, given that azidyl radicals are reactive, high-energy
species,[10] we deduce from these results that iodine(III)
compounds should be valuable and perhaps even general
precursors for nonstabilised radicals through single-electron
transfer (SET) reduction.
For decades, carbon-centred radicals have played an important
role as reactive intermediates in the field of synthetic organic
chemistry. Along these lines, aryl radicals show great potential
for CÀC bond-forming reactions.[1] They can be used in aryl
couplings without the need for expensive transition-metal
catalyst. Aryl radicals have been generated by reduction of aryl
halides with reducing reagents such as tin hydride[1] or sam-
arium iodide,[2] by reduction of (in situ generated) diazonium
salts,[3,4,5a–e] or by oxidation of aryl hydrazines.[5f–h] However, de-
spite these achievements, the development of novel comple-
mentary methods that allow for selective and clean generation
of aryl radicals is still of importance, because novel processes
will offer new options for the design of radical cascades with
alternative radical precursors. A general problem in aryl radical
chemistry lies in the high reactivity of these intermediates,
which renders their clean and selective generation and, in par-
ticular, their application in intermolecular CÀC bond-forming
reactions challenging.
Iodanylidene malonates have mainly been used for cyclopro-
panation,[11] and, to our knowledge, their application for aryl
radical generation has not been reported. There are well-estab-
lished protocols that use diaryliodonium salts for metal-cata-
lysed cross-coupling reactions, a-arylations of carbonyl com-
pounds, heteroatom arylations or for benzyne generation.[12–14]
However, their application as aryl radical precursors is not well
explored. Diaryliodonium salts have been used in photoredox
catalysed radical arylations,[15a–d] and transition-metal-free
heteroarene arylation with such iodonium salts have been
reported.[15e]
Motivated by these results, we wondered whether hyper-
valent iodine compounds such as iodanylidene malonates and
diaryliodonium salts can be used for the selective generation
of aryl radicals in the absence of any transition metal upon
SET-reduction with an organic electron donor (Scheme 1). We
Hypervalent iodine(III) compounds derived from ortho-iodo-
benzoic acid have found widespread application in transition-
metal catalyzed cyanations or alkynylations proceeding
through nonradical mechanisms.[6,7] Recently, we have success-
[a] M. Hartmann, Dr. Y. Li, Dr. C. Mück-Lichtenfeld, Prof. Dr. A. Studer
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität
Corrensstraße 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
[b] Dr. C. Mück-Lichtenfeld
Center for Multiscale Theory and Computation
Westfälische Wilhelms-Universität
Corrensstraße 40, 48149 Münster (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504852.
Scheme 1. Use of iodanylidene malonates and diaryliodonium salts as pre-
cursors for reactive intermediates.
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report herein two new protocols for aryl radical generation
from iodanylidene malonates and diaryliodonium salts with
the sodium 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPONa)
salt[4,8,10,16,17] as an organic SET reducing reagent. Moreover, we
will show that this approach for aryl radical generation can be
implemented in cascade reactions comprising alkene arylation
followed by TEMPO trapping to afford 1,2-oxyarylated prod-
ucts. In addition, we will discuss the mechanism of aryl radical
generation from iodanylidene malonates upon SET reduction
based on DFT calculations.
computational studies below). As a side product in this and
the following experiments, TEMPO-C6H5 derived from direct
trapping of the phenyl radical with TEMPO is formed.[18] A simi-
lar yield was achieved by using 2.0 equivalents of styrene
under otherwise identical conditions (entry 2). Further increas-
ing the amount of radical acceptor to 5.0 equivalents led to an
increase in the isolated yield (64%; entry 3) and the best result
(77%) was obtained with a tenfold excess of styrene (entry 4).
Extending the reaction time by adding TEMPONa over a longer
period provided worse results, likely due to decomposition of
starting 1a (entries 5 and 6). To suppress initial trapping of the
phenyl radical by TEMPO, we also tested a bulkier TEMPO ana-
logue. However, compared with TEMPONa, oxyarylation with
the 2,6-diethyl-2,3,6-trimethylpiperidin-N-oxy Na salt provided
the corresponding alkoxyamine in slightly lower yield (70%;
entry 7). Therefore, the following experiments were conducted
with the readily generated TEMPONa salt.
Results and Discussion
Iodanylidene malonates were investigated first. The IIII
reagents are readily prepared by first oxidising the iodoarene
with Selectfluor in acetic acid to give the corresponding bisa-
cetoxy IIII reagents. Treatment of these IIII reagents with the K-
enolate of the dialkylmalonate afforded the iodanylidene malo-
nates (for details, see the Supporting Information). As a test re-
action, oxyarylation of styrene with dimethyl 2-(phenyl-l3-ioda-
nylidene)malonate (1a) as a radical precursor and TEMPONa as
a stoichiometric SET reducing reagent to afford alkoxyamine
3a was chosen (Table 1). Reactions were conducted under an
argon atmosphere in tetrahydrofuran (THF) at room tempera-
ture and the TEMPONa solution was added over 2 min. We
noted slow decomposition of 1a in solution under the applied
conditions (see the Supporting Information), thus it was clear
that the reaction time had to be kept short.
We next tested whether the ester substituent in the iodany-
lidene has an effect on aryl radical generation. To this end,
phenyl radical precursors dibenzyl-, di-tert-butyl- diisopropyl-
and
2,2-dimethyl-5-(phenyl-l3-iodanylidene)-1,3-dioxane-4,6-
dione (1b–e) were reacted under the optimised conditions
(see Table 1, entry 4) with styrene and TEMPONa to yield 3a in
22–61% yield (Scheme 2). Compared with the methyl
Table 1. Oxyarylation of styrene with 1a and TEMPONa.
Scheme 2. Variation of the iodanylidene malonates.
Entry
2a [equiv]
Time [min][a]
Yield [%]
1
2
3
4
5
6
7
1.5
2.0
5.0
10.0
10.0
10.0
10.0
2
2
2
49
51
64
77
71
61
70[b]
congener 1a, use of bulkier malonates 1b–d led to slightly
lower yields, and the cyclic derivative 1e led to significantly
lower yield. These results reveal that methyl derivative 1a was
the most efficient phenyl radical precursor in this series.
2
30
120
120
We therefore kept 1a as radical precursor and then varied
the radical acceptor. Various styrenes 2b–i bearing either elec-
tron-donating or electron-withdrawing substituents were suc-
cessfully reacted under the optimised conditions to give the
oxyphenylated products 3b–i in high isolated yields (60–92%;
Scheme 3). Radical addition to internal alkenes was also possi-
ble, albeit with decreased yield. Hence, reaction with trans-b-
methyl styrene afforded 3j with complete regioselectivity and
high diastereoselectivity.[19] Cis-b-methyl styrene provided 3j
with slightly lower yield (30%) and, as expected, with the
same selectivity (dr=13:1). A low yield was also obtained for
oxyarylation of an unactivated alkene (see 3k; 23%).
[a] Time period used for TEMPONa addition (for the 0.5 h and 2.0 h ex-
periments, TEMPONa was added by using a syringe pump). [b] With 2,6-
diethyl-2,3,6-trimethylpiperidin-N-oxy-Na instead of TEMPONa.
The initial experiment was performed with 1.5 equivalent of
styrene, and we were delighted to see that the target oxyaryla-
tion product 3a was formed in 49% yield (Table 1, entry 1).
This initial result clearly revealed that the 2-(phenyl-l3-iodanyli-
dene)malonate serves as a phenyl radical precursor. Surprising-
ly, products derived from fragmentation towards the malonyl
radical anion were not identified, indicating that SET-reduction
leads to selective fragmentation of the phenyl radical (see also
We also tested aryl radical precursors bearing a range of
substituted aryl groups. Iodanylidene malonates 1 f–j were suc-
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by the transformations of 1g and 1h. We found that oxyaryla-
tion of 1g was more efficient when TEMPONa was added
slowly over 0.5 h by using a syringe pump, to provide 3q in
84% yield. In analogy, 1h was converted in good yield into 3r,
bearing a quaternary carbon-centre. Considering also the good
results obtained with 1i to give 3o and 1j to afford 3p, it
seems that the ortho-substituent in the starting iodanylidene
malonates stabilises the radical precursor (slower decomposi-
tion), which is reflected in the higher yields observed for these
substrates.
Given that the stability of some iodanylidene malonates was
not satisfactorily, we tested diaryliodonium salts as alternative
aryl radical precursors[15] in the reaction with TEMPONa. Diaryl-
iodonium salts were readily prepared according to a reported
procedure by oxidation of the corresponding aryl iodide and
subsequent coupling with an aryl boronic acid.[20] Reaction
conditions were optimised by using diphenyliodonium salts 4
and styrene as a radical acceptor to yield oxyarylation product
3a (Table 2). The first experiment was conducted with
Scheme 3. Variation of the aryl radical acceptor.
Table 2. Optimisation reactions for the oxyarylation with diaryliodonium
salts.
cessfully prepared and reacted with styrene under the opti-
mised conditions to give oxyarylated products 3l–p
(Scheme 4). Whereas ortho-substituted iodanylidene malonates
1o and 1p provided good results, use of the meta- and para-
congeners (in particular the Br-derivatives) led to significantly
lower yields. Given that the reactivity of the corresponding aryl
radicals did not differ significantly (steric effects in the para-
and meta-derivatives should be even smaller than in the two
ortho-systems), we assume that the lower yields are caused by
the lower stability of the meta- and para-substituted aryl radi-
cal precursors under the applied conditions. Good results were
also achieved for intramolecular oxyarylations, as documented
Entry
XÀ
2a [equiv]
Temp. [8C]
Time [h][a]
Yield [%]
1
2
3
4
5
6
BrÀ
5.0
1.5
5.0
5.0
10.0
5.0
5.0
5.0
5.0
5.0
5.0
20
20
20
20
20
0
50
20
20
20
20
3.0
3.0
3.0
3.0
3.0
3.0
3.0
5.0
3.0
1.0
3.0
41
36
54
56
57
52
51
51
50
43
49
À
PF6À
PF6À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4
7
8
9[b]
10
11[c]
[a] Time period used for TEMPONa syringe pump addition. [b] Run at 0.25
molar concentration. [c] In THF.
diphenyliodonium bromide, 5.0 equivalents of styrene and
TEMPONa (1.2 equiv) was added over 3 h by using a syringe
pump. The target 3a was isolated in 41% yield (entry 1). By
using diphenyliodonium hexafluorophosphate as a radical pre-
cursor, 3a was isolated in 54% yield (entry 3). Reducing the
amount of 2a to 1.5 equivalents provided a lower yield (36%;
entry 2). Compared with the hexafluorophosphate salt, use of
the corresponding diphenyliodonium tetrafluoroborate salt af-
forded a similar yield (56%; entry 4). Neither increasing the
amount of radical acceptor nor varying temperature affected
the outcome of the reaction significantly (entries 5–7). Extend-
ing the reaction time to 5 h or decreasing concentration did
also not lead to significant effect on the isolated yield (en-
tries 8 and 9). Furthermore, shorter reaction times or switching
Scheme 4. Variation of the aryl radical precursor and cyclisation.
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to THF as solvent did not affect the yield to a significant
extent (entries 10 and 11).
To study the electronic effects on the fragmentation reaction
of the iodonium salt, we prepared symmetric and asymmetric
diaryliodonium tetrafluoroborate salts bearing electron-with-
drawing and electron-donating substituents at the arene
moiety (Scheme 5). In the reaction with styrene, the symmetric
Scheme 6. Two possible mechanisms for reaction of 1a with styrene and
TEMPONa.
radical addition to styrene gives adduct radical C, which is
then trapped by TEMPO to eventually provide the oxyarylation
product 3a. Selective cross coupling of benzylic radical C with
TEMPO is controlled by the persistent radical effect.[23]
To challenge the possible “associative mechanism”, we
tested the very bulky Na-salt 5[24] in the reaction with 1a and
styrene under the optimised conditions (Scheme 7; see the
Scheme 5. Oxyarylation of styrene using diaryliodonium tetrafluoroborates.
para-CF3 salt 4b provided oxyarylation product 3s in 56%
yield. The iodonium salt 4c, bearing a phenyl and a p-
MeOC6H4 substituent, provided the oxyarylation products 3a
and 3t in 59% combined yield as a 1.3:1 mixture of separable
compounds (3a/3t, 1.3:1). Even for the electronically more dif-
·
ferentiated aryl radicals derived from 4d (p-MeOC6H4 versus p-
·
CF3C6H4 ), selectivity was moderate and products 3s and 3t
Scheme 7. Oxyphenylation of styrene with the Na-salt 5 and 1a.
were isolated in 38 and 14% yield, respectively (3s/3t, 2.8:1).
Low selectivities for aryl radical fragmentation of photoredox-
generated aryl radicals were observed before.[15] Notably, nu-
cleophilic aromatic substitutions on asymmetric diaryliodonium
salts occur with high selectivity.[21] Steric effects seem to be
negligible on aryl radical generation because reaction with salt
4e (phenyl versus mesityl radical generation) afforded oxy-
arylation products 3a and 3u in 52% combined yield with
a low 1.3:1 selectivity favouring the phenylated derivative 3a.
Two slightly different reaction mechanisms, which vary in
the aryl radical generation step, are considered for the oxyary-
lation of styrene with 2-(phenyl-l3-iodanylidene)malonate (1a)
and TEMPONa (Scheme 6). TEMPONa can react with 1a in an
associative process to generate the adduct A, which then frag-
ments to enolate B, phenyl radical and TEMPO (inner-sphere
SET, pathway a). Alternatively, 1a becomes reduced with
TEMPONa through single-electron transfer (outer-sphere SET)
to directly generate a phenyl radical, iodoenolate B and the
persistent TEMPO radical (dissociative, pathway b).[22] Phenyl
Supporting Information for the preparation of 5). The oxyphe-
nylated product 6 was formed, albeit in lower yield (50%)
compared with that with TEMPONa. It is clear that adduct for-
mation of 5 and 1a to give an intermediate of type A must be
more difficult than for the analogous reaction with the smaller
TEMPONa. However, the successful transformation of 5 into 6
cannot be taken as a proof for the occurrence of the SET-path-
way (against the associative route).
To gain a clearer picture of whether an associative process is
viable, we performed DFT calculations on the reaction of
TEMPO anion and TEMPONa with 2-(phenyl-l3-iodanylidene)-
malonate (1a).[25] Irrespective of the presence or absence of
the Na cation, the trivalent iodine(III) intermediate A is formed
in an exergonic reaction (Scheme 8, for the results of the reac-
tion with TEMPONa and more details, see the Supporting Infor-
mation). We were not able to identify a transition structure for
homolytic cleavage of the IÀO bond in A. The radical anion of
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Scheme 8. Associated pathway for reductive cleavage of 1a based on DFT
calculations.
1a is not a stable intermediate, but immediately fragments
into a loose complex of phenyl radical and iodoenolate B. The
dissociation of the complex BÀ·Ph· is entropically favoured and
contributes to the total reaction free energy of almost 30 kcal
molÀ1. The reaction of 2,2,6,6-tetraethylpiperidin-1-yloxyl (as
a model for 5) instead of TEMPOÀ gives comparable free
reaction energies, which indicates that an associative mecha-
nism would also be possible with 5 (see the Supporting
Information).
The higher intrinsic propensity of (1a)·À to cleave the
IÀphenyl bond can be demonstrated by partial optimisations
along the dissociating bonds (Figure 1). Assuming that this
path is not qualitatively changed by the sodium cation, we
have ignored the presence of Na+ in that step. The release of
the phenyl radical proceeds without any barrier and leads di-
rectly to the van der Waals (vdW) complex BÀ·Ph· (Figure 1 (a)).
In contrast, for the elongation of the malonylÀiodine bond
(Figure 1 (b)), almost 30 kcalmolÀ1 must be overcome before
the malonyl radical anion and phenyl iodide are formed.
The results of the DFT calculations provide further evidence
that an associative electron-transfer mechanism is likely and
explains the selective formation of phenyl radicals from 1a.
Figure 1. Partial optimisation (TPSS-D3/def2-TZVP) of 1a (radical anion) as
a function of the I–C(phenyl) and I–C(malonyl) distance. Energies (PW6B95-
D3/def2-TZVP) include solvation implicitly (THF) and are given relative to
TEMPOÀ adduct AÀ (excluding enthalpic and entropic contributions).
sponding aryl radicals along with TEMPO. For nonsymmetrical
diaryliodonium salts, selectivity in aryl radical generation is low.
Aryl radical generation from diaryliodonium salts with TEMPO-
Na has also been implemented in a novel method for alkene
oxyarylation. Notably, such oxyarylation products are useful
compounds with which to conduct follow-up chemistry, as
previously shown.[4f]
Summary and Conclusion
We have shown that iodanylidene malonates are efficiently
reduced with TEMPONa to give aryl radicals. Computational
studies reveal that aryl radical generation occurs through an
associative electron transfer for which reaction of the iodanyli-
dene malonate with TEMPONa provides an intermediate,
which then further fragments in a second step to the aryl radi-
cal, TEMPO and Na-iodomalonate. In the presence of alkenes,
these aryl radicals undergo addition and the adduct radicals
thus generated are selectively trapped by the concomitantly
formed TEMPO radical. Selective cross coupling with TEMPO is
steered by the persistent radical effect. The overall process rep-
resents an alkene oxyarylation that is high yielding if the initial
iodanylidene malonate shows sufficiently high stability in
solution. The concept can also be applied to intramolecular
oxyarylation. In addition, we have shown that readily prepared
diaryliodonium salts react with TEMPONa to give the corre-
Acknowledgements
We thank the Westfälische Wilhelms-University Münster and
the Deutsche Forschungsgemeinschaft (DFG) for supporting
our work.
Keywords: density functional calculations
·
hypervalent
compounds · radical reactions · radicals · synthetic methods
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Received: December 3, 2015
Published online on February 2, 2016
Chem. Eur. J. 2016, 22, 3485 – 3490
www.chemeurj.org
3490
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