Transition Metal-Free N-Arylation of Amino Acid Esters with Diaryliodonium Salts

Article abstract of DOI:10.1002/chem.202005351

A transition metal-free approach for the N-arylation of amino acid derivatives has been developed. Key to this method is the use of unsymmetric diaryliodonium salts with anisyl ligands, which proved important to obtain high chemoselectivity and yields. The scope includes the transfer of both electron deficient, electron rich and sterically hindered aryl groups with a variety of different functional groups. Furthermore, a cyclic diaryliodonium salt was successfully employed in the arylation. The N-arylated products were obtained with retained enantiomeric excess.

Full text of DOI:10.1002/chem.202005351

Full Paper
doi.org/10.1002/chem.202005351
Chemistry—A European Journal
&
Synthetic Methods |Hot Paper|
Transition Metal-Free N-Arylation of Amino Acid Esters with
Diaryliodonium Salts
Gabriella Kervefors, Leonard Kersting, and Berit Olofsson*[a]
Abstract: A transition metal-free approach for the N-aryla-
tion of amino acid derivatives has been developed. Key to
this method is the use of unsymmetric diaryliodonium salts
with anisyl ligands, which proved important to obtain high
chemoselectivity and yields. The scope includes the transfer
of both electron deficient, electron rich and sterically hin-
dered aryl groups with a variety of different functional
groups. Furthermore, a cyclic diaryliodonium salt was suc-
cessfully employed in the arylation. The N-arylated products
were obtained with retained enantiomeric excess.
Introduction
Amino acids are important building blocks in organic synthesis
as they are a substantial part of the chiral pool. Functionaliza-
tion of such species is attractive in drug discovery as a mean
of obtaining novel compounds that can act as an affinity
probe for enzyme studies[1] or exhibit bioactivity.[2] N-Arylated
amino acids are found as a core structure in biologically active
compounds such as the protein kinase C (PKC) activator indo-
lactam-V[3] and its analogue benzolactam-V8,[4] fibrinogen re-
ceptor antagonist SB 214857,[5] and NMDA receptor antagonist
L689560.[6]
Existing methods to reach N-aryl amino acids are mostly
based on transition metal catalysis.[7] Cu-catalyzed Ullman cross
couplings have a good scope, although high Cu loading and
extended reaction times at high temperatures or excess re-
agents are often needed.[1c,2a,8] Jain and co-workers recently re-
ported an N-arylation under milder conditions with the use of
a diketone ligand in DMF (Scheme 1a).[9] After adjustment of
the reaction conditions, also heterocycles could be trans-
ferred.[10] Alternatively, Cu-catalyzed couplings with excess aryl-
boronic acid can be performed at room temperature with a
limited scope.[11]
Scheme 1. Recent N-arylations of amino acid derivatives and amines.
The development transition metal-free coupling reactions
has received increasing attention to overcome drawbacks with
transition metals, such as toxicity, cost, need for substrate-de-
pendent designer ligands, reaction sensitivity and the risk of
product contamination in the pharmaceutical industry.[14] Tran-
sition metal-free syntheses of N-aryl amino acids and their de-
rivatives are, however, much less explored. Reported syntheses
of specific targets include reactions with anilines and suitable
electrophilic species through SN2 displacement or SNAr.[15] Reac-
tions with enantiomerically enriched trichloromethyl alcohols
provided N-aryl amino amides through a Jocic-type reaction.[16]
Alternatively, amino acid derivatives can be N-arylated with the
biobased reagent methyl-3-dehydroshikimate as aryl precur-
sor.[17] Triphenylsulfonium triflate can be employed in the N-ar-
ylation of racemic amino acid derivatives in a reaction pro-
ceeding through arynes.[18] A common feature with the meth-
ods above is that their scope is very limited.
Pd-catalyzed Buchwald-Hartwig arylations have been less ex-
plored, and early methods suffered from limited scope or par-
tial racemization.[12] Recent reports partly circumvent that
problem through the use of advanced catalytic systems.[13]
[a] G. Kervefors, L. Kersting, Prof. B. Olofsson
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, SE-106 91 Stockholm (Sweden)
E-mail: Berit.Olofsson@su.se
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202005351.
Poelarends and co-workers recently published an elegant
biocatalytic approach to N-arylated aspartic acids through en-
zymatic reactions of anilines with fumarate.[19] Moderate to
good yields with excellent ee were obtained, although sterical-
ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-
VCH GmbH. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and repro-
duction in any medium, provided the original work is properly cited.
Chem. Eur. J. 2021, 27, 5790 –5795
5790 ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH

Full Paper
doi.org/10.1002/chem.202005351
Chemistry—A European Journal
ly hindered or strongly electron deficient anilines were not tol-
erated.
Table 1. Optimization of the 4-nitrophenylation of 1a.[a]
Hypervalent iodine compounds have become efficient re-
agents for a wide variety of transition metal-free reactions.[20]
Diaryliodonium salts have several attractive features including
easy availability, high stability, and low toxicity. They are highly
reactive electrophilic arylation reagents, and have been applied
successfully in a variety of transition metal-free C-, O-, N- and
S-arylations.[21]
Entry
Salt 2a-X
T
[8C]
t
[h]
Yield [%][b] of
3a
Ar2
(equiv)
3-Ar2
1
2
3
4
2aa-OTf
2aa-OTf
2aa-OTf
2aa-OTf
2aa-BF4
2aa-OTs
2aa-Br
2ab-OTf
2ac-OTf
2ac-OTf
2ac-OTf
2ac-OTf
2ac-OTf
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Mesityl
Anisyl
Anisyl
Anisyl
Anisyl
Anisyl
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0[e]
2.0
2.0
110
130
150
150
150
150
150
150
150
150
150
130
110
22
22
4
4
4
4
4
4
4
4
4
4
24
16 (15)
(28)
0
0
47 (45)
59
34
12 (14)
0
(6)
12
14
(12)
0
Iodonium salts have been utilized to functionalize amino
acid derivatives through fluoroalkylation,[22] and a small set of
diaryliodonium bromides were employed in a Cu-catalyzed N-
arylation of amino acid esters, which required excess substrate
and a stochiometric amount of AgNO3 (Scheme 1b).[23] We
have recently reported a metal-free N-arylation of aliphatic
amines with diaryliodonium salts under mild conditions
(Scheme 1c).[24] The methodology has a broad amine scope,
but proved inefficient for arylation of amino acids. To facilitate
the access to enantiomerically enriched N-arylated amino acid
derivatives, we set out to develop a transition metal-free N-aryl-
ation of amino acids derivatives, and herein present our results.
5
6[c]
7[d]
8
49
85 (79)
66
10
0
0
9
10
11
12
13
73
0
78 (77)
60
0
0
[a] Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a-X (1–2 equiv) and
base (1 equiv) were mixed under argon. Degassed, anhydrous toluene
(1 mL) was added, and the reaction was heated in an oil bath with stir-
ring. [b] 1H NMR yield with trimethoxybenzene (TMB) as internal standard,
isolated yields given in parentheses. [c]>95% 4-OTs formed. [d]>95%
4-Br formed. [e] 2.0 equiv of 1a and base were used.
Results and Discussion
Phenylalanine methyl ester (1a) was chosen as the model sub-
strate, and was obtained by deprotonation of the correspond-
ing hydrochloride salt 1a-HCl. The free amine 1a proved to be
unstable upon storage,[23a,25] and was therefore prepared
within 5 days of use.
cient aryl groups.[27] Since the phenylated side-product was ob-
served in this reaction, we investigated iodonium salts with
other dummy groups to improve the chemoselectivity and
simplify the isolation of product 3a. Reactions with mesityl salt
2ab-OTf resulted in similar yield and chemoselectivity
(entry 8). The anisyl moiety is often a good dummy group[27]
and salt 2ac-OTf indeed reacted with complete chemoselectiv-
ity. More surprisingly, the conversion was also improved and
3a was isolated in 79% yield as the only product (entry 9).
Further investigations with salt 2ac-OTf showed that
changes in reaction stoichiometry had a negative impact (en-
tries 10, 11). Comparable results were obtained at 1308C
(entry 12), and the reaction could even be performed at 110 8C
with this salt, illustrating the reactivity difference to salt 2aa-
OTf (entry 13 vs. 1). Importantly, the enantiomeric excess of
product 3a was >98%,[26] demonstrating that the reaction
conditions were mild enough to not cause racemization de-
spite the high reaction temperature.
An extensive optimization was performed,[26] with initial
screening of the arylation conditions using 4-nitrophenyl(phe-
nyl)iodonium triflate (2aa-OTf). The conditions used in our
arylation of aliphatic amines[24a] gave poor conversion into
product 3a with substantial amounts of recovered 1a (Table 1,
entry 1). The conversion was improved by increasing the tem-
perature (entries 2,3), and the combination with excess iodoni-
um salt resulted in 59% yield of 3a (entry 4). Arylations with
iodonium salt 2aa-OTf generally give complete chemoselectiv-
ity,[27] with transfer of only the nitroaryl group, but we ob-
served small amounts of phenylated side-product 3-Ar2 and a
deterioration of the overall mass balance when the reaction
was performed at 1508C.
The reactivity of 4-nitrophenyl(phenyl)iodonium salts with
other anions (2aa-X) was next examined, and salts with tetra-
fluoroborate, tosylate or bromide anions proved to give inferi-
or results (entries 5–7). In fact, iodonium salts 2aa-OTs and
2aa-Br suffered from a competing pathway where the anion
acted as nucleophile to deliver the corresponding 4-nitrophen-
yl tosylate (4-OTs) and bromide (4-Br), respectively. Such side-
products have previously been reported with diaryliodonium
bromides,[28] whereas reactions with diaryliodonium tosylates
are often efficient also at elevated temperatures.[24a,28b,29]
Unsymmetric diaryliodonium salts are known to react with
high chemoselectivity when they have sufficiently different
electronic properties.[30] The non-transferable aryl group is
called a “dummy group”, and the phenyl group is generally a
sufficient dummy group in transfer of strongly electron-defi-
We next examined whether the deprotonation of 1a-HCl
could be combined with the arylation to circumvent the han-
dling of unstable amine 1a. 1a-HCl was thus reacted with salt
2ac-OTf (1–2 equiv) in the presence of 2 equiv sodium carbon-
ate (Scheme 2). However, only minor amounts of 3a were de-
tected and the major product was instead 4-Cl, which formed
when the released chloride anion acted as a competing nucle-
ophile. The mass balance in the first reaction shows that 1a is
rather stable at elevated temperatures once 2ac-OTf is con-
sumed, but partly decomposes in the presence of excess 2ac-
OTf, likely due to the high oxidation potential of the diaryl-
iodonium salt.[26]
The arylation scope of amino ester 1a with various aryl(ani-
syl)iodonium triflates 2-OTf was subsequently examined. Aryl
Chem. Eur. J. 2021, 27, 5790 –5795
www.chemeurj.org
5791 ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH

Full Paper
doi.org/10.1002/chem.202005351
Chemistry—A European Journal
highly functionalized aryl moiety could be transferred (3l). A
heteroaryliodonium salt was employed to give pyridyl product
3m in modest yield. Additionally, the 6-membred cyclic
diaryliodonium salt 2n could be used to generate the iodo-
substituted product 3n in 59% yield. Reactions with cyclic
diaryliodonium salts generally require transition metal catalysis
due to decreased reactivity,[32] and this result is conceptually
important as reactions with such salts have higher atom effi-
ciency and deliver products with a convenient iodine handle
for further transformations.[32d]
Scheme 2. Attempted arylation of amino acid ester salt 1a-HCl (1H NMR
yields with TMB as internal standard).
groups with electron-withdrawing groups (EWG) were efficient-
ly transferred using the optimized conditions (Scheme 3A), as
exemplified by the synthesis of p-CN substituted products 3b
and 3c. Aryl groups with CF3 substituents were also well toler-
ated (3d–3 f), where even the sterically encumbered product
3 f was formed in high yield. Also halogen-containing aryl moi-
eties could be transferred to provide 3 f–3h. Iodonium salts
with strong EWG reacted with similar efficiency at 130 and
1508C while the other salts showed reduced activity at
1308C.[26]
The transfer of aryls with electron-donating groups (EDG) is
generally more challenging in reactions with diaryliodonium
salts.[27a,31] We were hence pleased to see that such arylations
were feasible by prolonging the reaction time to 24 h. In this
fashion, the phenylated product 3i was isolated in 67% yield,
and a tert-butyl-substituted aryl moiety could also be trans-
ferred to provide 3j. The method demonstrated good compati-
bility with the sterically demanding mesityl group (3k) and a
The substrate scope of primary amino esters 1 was next ex-
amined. Arylation of benzyl ester 1b was first investigated and
provided the arylated products 3o and 3p in equally high
yields as the corresponding methyl ester 1a (cf. products 3a,
3b). Having demonstrated the compatibility of the benzyl pro-
tecting group, it was used to protect alanine (1c) and valine
(1d), as their corresponding methyl esters (1e, 1 f) proved to
be volatile and easily evaporated under vacuum or high tem-
peratures. Arylation of the alanine and valine benzyl esters was
successful providing 3q and 3r in moderate to good yields.
Substrates 1c and 1d could also be arylated with less activat-
ed diaryliodonium salts, providing the phenylated and tert-
butyl-substituted products 3s–3v. The reactions with valine
ester 1d gave consistently higher yields than the correspond-
ing reactions with 1c, a trend that has also been reported in
previous N-arylations.[2a,12a,13b]
Scheme 3. Arylation scope with amino acid esters 1, ee values 95–98% unless stated. [a] Reaction at 130 and 1508C gave similar results. [b] Symmetric salt 2
(Ar1 =Ar2) used.
Chem. Eur. J. 2021, 27, 5790 –5795
www.chemeurj.org
5792 ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH

Full Paper
doi.org/10.1002/chem.202005351
Chemistry—A European Journal
We next explored the compatibility with more challenging
substrates, such as unprotected, heteroatom-substituted
amino acid esters. Heteroatom substituents are usually well
tolerated in metal-free arylations with diaryliodonium salts,[21]
but such substrates proved difficult to arylate under the cur-
rent conditions. For example, reactions with tryptophan
methyl ester (1g) gave only 15% product with 2ac-OTf,[26]
which could be due to competing coordination of the indole
nitrogen to the iodine(III) reagent. To the contrary, arylation of
tyrosine methyl ester (1h) delivered the diarylated product
3w’ in high yield and retained ee, without detection of the cor-
responding monoarylated product 3w (Scheme 4).
Scheme 5. Arylation of amino acid esters 5. [a] Reaction at 1308C. [b] Sym-
metric salt 2 (Ar1 =Ar2) used, 24 h reaction time.
Scheme 4. Diarylation of tyrosine methyl ester.
without argon atmosphere gave a significantly lower yield. Ad-
dition of DPE as radical trap did not affect the outcome of the
reaction, indicating that a radical pathway is unlikely.[33] Fur-
thermore, reactions in the presence of furan (5 equiv) as aryne
trap did not result in formation of Diels–Alder adducts. Based
on that experiment and the formation of only one regioiso-
meric product in reactions with substituted diaryliodonium
salts, an aryne pathway can be excluded.[33] Additionally, an at-
tempted arylation of 1a with iodobenzene or 1-iodo-4-nitro-
benzene at 1508C resulted in quantitative recovery of the
starting materials, and an SNAr pathway with the iodoarene
formed from 2aa-OTf can therefore be ruled out.
Finally, the product stability was investigated by subjecting
3a to the reaction conditions (Scheme 6). No diarylated prod-
uct was formed and 3a could be recovered in 68% yield. The
ee of 3a remained intact, demonstrating that the arylated
product is stable to racemization under the reaction condi-
tions. However, partial decomposition of 3a had occurred,
which explains the mass balance problems observed in some
reactions. A stability test of 2ac-OTf in the absence of any
amino acid ester also showed partial decomposition at
1508C.[26]
To investigate the performance of the unsymmetric anisyl
salts, a few products in the scope were also synthesized using
the corresponding aryl(phenyl) salts or symmetric diaryliodoni-
um salts. Reagents with the anisyl dummy generally performed
best, as chemoselectivity problems were avoided and better
arylation yields were obtained.[26]
SFC and HPLC analyses were performed to determine the ee
of the products, since previously reported methods for N-aryla-
tion of amino esters showed partial racemization[7c,12a,13,25c] or
had insufficient data to judge the enantiomeric purity.[1c,9–10,12b]
As expected, the current methodology generally left the exist-
ing stereocenter intact and the majority of the products were
isolated with 95 to >98% ee. Even when prolonged reaction
time was applied in reactions with EDG salts, very little racemi-
zation occurred.
Secondary amino esters were evaluated next, and proline
methyl ester (5a) proved to be a suitable substrate (Scheme 5).
Arylation with electron-withdrawing aryl moieties provided
products 6a--6c in high yields. Upon prolonged reaction time,
also phenylation (6d) and mesitylation (6e) was feasible, these
transformations proved better with the symmetric iodonium
salts than with the anisyl salts. N-arylation of the N-methylated
a-phenylalanine ester 5b resulted in 58% yield of 6 f with
high enantiomeric excess, and b-phenylalanine ester (5c) gave
the nitrophenylated product 6g in good yield. The SFC analy-
sis of products 6 showed a small decrease of the enantiomeric
purity (90–94% ee).
N-Protected derivatives of 1a,b remained largely untouched
under the reaction conditions, which is useful in arylation of
more complex substates. To this end, acetyl- and tosyl-protect-
ed derivatives of 1a gave no arylation, whereas a Boc-protect-
ed derivative of 1b gave 9% of 3o with 82% recovered sub-
strate, meaning that the Boc-group had been partially frag-
mented under the reaction conditions.[26]
Scheme 6. Stability test of 3a.
Based on the experiments described above, we suggest that
the reaction follows a traditional ligand coupling pathway,
where the amine does a ligand exchange with the triflate to
give intermediate I, followed by deprotonation to II and ligand
coupling to yield product 3 (Scheme 7).
A series of control experiments were performed to indicate
a possible mechanism of the arylation.[26] Running the reaction
Chem. Eur. J. 2021, 27, 5790 –5795
www.chemeurj.org
5793 ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH

Full Paper
doi.org/10.1002/chem.202005351
Chemistry—A European Journal
Keywords: amino acids · arylation · diaryliodonium salts ·
hypervalent compounds · transition metal-free
[1] a) M. J. Wilson, D. L. Hatfield, Biochim. Biophys. Acta 1984, 781, 205–
215; b) D. Meredith, C. S. Temple, N. Guha, C. J. Sword, C. A. R. Boyd,
I. D. Collier, K. M. Morgan, P. D. Bailey, Eur. J. Biochem. 2000, 267, 3723–
3728; c) J. Haynes-Smith, I. Diaz, K. L. Billingsley, Org. Lett. 2016, 18,
2008–2011.
[2] a) D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J. Am. Chem. Soc. 1998, 120,
12459–12467; b) Y. Gong, S. Somersan Karakaya, X. Guo, P. Zheng, B.
Gold, Y. Ma, D. Little, J. Roberts, T. Warrier, X. Jiang, M. Pingle, C. F.
Nathan, G. Liu, Eur. J. Med. Chem. 2014, 75, 336–353; c) M.-C. Lu, X.
Zhang, F. Wu, S.-J. Tan, J. Zhao, Q.-D. You, Z.-Y. Jiang, J. Med. Chem.
2019, 62, 6796–6813.
Scheme 7. Suggested mechanism.
[3] a) J. Quick, B. Saha, Tetrahedron Lett. 1994, 35, 8553–8556; b) D. Ma, G.
Wang, S. Wang, A. P. Kozikowski, N. E. Lewin, P. M. Blumberg, Bioorg.
Med. Chem. Lett. 1999, 9, 1371–1374.
[4] a) L. D. Sasiambarrena, I. A. Barri, G. G. Fraga, R. D. Bravo, A. Ponzinibbio,
Tetrahedron Lett. 2019, 60, 264–267; b) U. Tran, G. C. Zhang, R. Eom,
K. L. Billingsley, A. E. Ondrus, ACS Chem. Biol. 2020, 15, 1321–1327.
[5] W. H. Miller, T. W. Ku, F. E. Ali, W. E. Bondinell, R. R. Calvo, L. D. Davis, K. F.
Erhard, L. B. Hall, W. F. Huffman, R. M. Keenan, C. Kwon, K. A. Newlander,
S. T. Ross, J. M. Samanen, D. T. Takata, C.-K. Yuan, Tetrahedron Lett. 1995,
36, 9433–9436.
[6] a) J. A. Kemp, P. D. Leeson, Trends Pharmacol. Sci. 1993, 14, 20–25; b) M.
Jansen, G. Dannhardt, Eur. J. Med. Chem. 2003, 38, 661–670.
[7] a) P. Zardi, A. Caselli, P. Macchi, F. Ferretti, E. Gallo, Organometallics
2014, 33, 2210–2218; b) F. Zhao, Q. Yang, J. Zhang, W. Shi, H. Hu, F.
Liang, W. Wei, S. Zhou, Org. Lett. 2018, 20, 7753–7757; c) Y. Kawamata,
J. C. Vantourout, D. P. Hickey, P. Bai, L. Chen, Q. Hou, W. Qiao, K. Barman,
M. A. Edwards, A. F. Garrido-Castro, J. N. deGruyter, H. Nakamura, K.
Knouse, C. Qin, K. J. Clay, D. Bao, C. Li, J. T. Starr, C. Garcia-Irizarry, N.
Sach, H. S. White, M. Neurock, S. D. Minteer, P. S. Baran, J. Am. Chem.
Soc. 2019, 141, 6392–6402.
Conclusions
A transition metal-free N-arylation of amino acid derivatives
with diaryliodonium salts has been presented. The moderate
reactivity of the substrates was overcome by increasing the re-
action temperature, which initially resulted in a chemoselectivi-
ty problem. The method has a broad arylation scope and is
compatible with transfer of both electron deficient and elec-
tron rich aryl groups in good to high yields. ortho-Substituents
and various functional groups are well tolerated, including a
cyclic diaryliodonium salt. The amino acid ester scope includes
primary and secondary a-amino esters, as well as b-amino
esters, and the products were generally obtained with excel-
lent enantiomeric excess. The use of aryl(anisyl)iodonium tri-
flates proved to be key to increase both the reactivity and che-
moselectivity of the process. This interesting observation will
be further studied in reactions with related nucleophiles.
[8] a) S. Rçttger, P. J. R. Sjçberg, M. Larhed, J. Comb. Chem. 2007, 9, 204–
209; b) C. Yuan, L. Zhang, Y. Zhao, Molecules 2019, 24, 4177.
[9] K. K. Sharma, S. Sharma, A. Kudwal, R. Jain, Org. Biomol. Chem. 2015, 13,
4637–4641.
[10] K. K. Sharma, M. Mandloi, N. Rai, R. Jain, RSC Adv. 2016, 6, 96762–
96767.
Experimental Section
Arylation of amino acid esters 1 and 5: Amino acid ester 1
(0.2 mmol), salt 2 (0.4 mmol, 2.0 equiv) and Na2CO3 (0.2 mmol,
1.0 equiv) were added to an oven-dried, pressure-stable microwave
vial and dried under vacuum for 15 min. The vial was flushed with
argon 3–4 times followed by the addition of anhydrous toluene
(1 mL, degassed by bubbling with argon for 20 min). The vial was
added to a preheated oil bath at 1508C, and stirred for 4–24 h.
After completion, the reaction was cooled to rt and Celite was
added. The volatiles were removed under reduced pressure, and
the mixture was purified by column chromatography (SiO2 with
pentane/EtOAc as eluent system), to provide product 3 or 6. The
enantiomeric purity was analyzed by Chiral SFC, Diacel OJ-H, 258C,
0.3 cm 1, 15 cm column, 10% MeOH in CO2, flow rate:
[11] a) P. Y. S. Lam, D. Bonne, G. Vincent, C. G. Clark, A. P. Combs, Tetrahedron
Lett. 2003, 44, 1691–1694; b) M. J. West, J. W. B. Fyfe, J. C. Vantourout,
A. J. B. Watson, Chem. Rev. 2019, 119, 12491–12523; c) T. D. Quach, R. A.
Batey, Org. Lett. 2003, 5, 4397–4400.
[12] a) F. Ma, X. Xie, L. Ding, J. Gao, Z. Zhang, Tetrahedron 2011, 67, 9405–
9410; b) H. Hammoud, M. Schmitt, E. Blaise, F. Bihel, J.-J. Bourguignon,
J. Org. Chem. 2013, 78, 7930–7937.
[13] a) S. M. King, S. L. Buchwald, Org. Lett. 2016, 18, 4128–4131; b) S. Sharif,
D. Mitchell, M. J. Rodriguez, J. L. Farmer, M. G. Organ, Chem. Eur. J.
2016, 22, 14860–14863; c) H. A. Young, Q. A. E. Guthrie, C. Proulx, J.
Org. Chem. 2020, 85, 1748–1755.
[14] C.-L. Sun, Z.-J. Shi, Chem. Rev. 2014, 114, 9219–9280.
[15] a) T. P. Kogan, T. C. Somers, M. C. Venuti, Tetrahedron 1990, 46, 6623–
6632; b) F. Zaragoza, Tetrahedron 1995, 51, 8829–8834.
[16] a) C. Hobson, M. S. Perryman, G. Kirby, G. J. Clarkson, D. J. Fox, Tetrahe-
dron Lett. 2018, 59, 3965–3968; b) M. S. Perryman, M. E. Harris, J. L.
Foster, A. Joshi, G. J. Clarkson, D. J. Fox, Chem. Commun. 2013, 49,
10022–10024.
0.8 mLminÀ1
.
[17] Y. Zou, E. Zhang, T. Xu, W. Wu, Y. Chen, M. Yuan, W. Wei, X. Zhang, RSC
Adv. 2013, 3, 6545–6552.
Acknowledgements
[18] Z.-Y. Tian, X.-X. Ming, H.-B. Teng, Y.-T. Hu, C.-P. Zhang, Chem. Eur. J. 2018,
24, 13744–13748.
[19] H. Fu, A. Prats Lujµn, L. Bothof, J. Zhang, P. G. Tepper, G. J. Poelarends,
ACS Catal. 2019, 9, 7292–7299.
The Swedish Research Council (2015–04404, 2019–04232) is
kindly acknowledged for financial support.
[20] a) A. Yoshimura, V. V. Zhdankin, Chem. Rev. 2016, 116, 3328–3435; b) Hy-
pervalent Iodine Chemistry (Ed.: T. Wirth), Vol. 373, Springer, Cham, 2016;
c) Patai’s Chemistry of Functional Groups: The Chemistry of Hypervalent
Halogen Compounds (Eds.: B. Olofsson, I. Marek, Z. Rappoport), Wiley,
Chichester, 2019.
Conflict of interest
The authors declare no conflict of interest.
Chem. Eur. J. 2021, 27, 5790 –5795
www.chemeurj.org
5794 ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH

Full Paper
doi.org/10.1002/chem.202005351
Chemistry—A European Journal
[21] a) E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48, 9052–9070;
Angew. Chem. 2009, 121, 9214–9234; b) K. Aradi, B. L. Tóth, G. L. Tolnai,
Z. Novµk, Synlett 2016, 27, 1456–1485; c) P. Villo, B. Olofsson in Patai’s
Chemistry of Functional Groups: The Chemistry of Hypervalent Halogen
Compounds (Eds.: B. Olofsson, I. Marek, Z. Rappoport), Wiley, Chichester,
2019, pp. 461–522.
[22] a) D. D. DesMarteau, V. Montanari, Chem. Commun. 1998, 2241–2242;
b) D. D. DesMarteau, V. Montanari, J. Fluorine Chem. 2001, 109, 19–23;
c) V. Montanari, K. Kumar, J. Am. Chem. Soc. 2004, 126, 9528–9529.
[23] a) J. D. McKerrow, J. M. A. Al-Rawi, P. Brooks, Synth. Commun. 2010, 40,
1161–1179; b) J. D. McKerrow, J. M. A. Al-Rawi, P. Brooks, Asian J. Chem.
2012, 24, 1227–1236.
[24] a) N. Purkait, G. Kervefors, E. Linde, B. Olofsson, Angew. Chem. Int. Ed.
2018, 57, 11427–11431; Angew. Chem. 2018, 130, 11597–11601; b) For
other recent N-functionalizations with iodonium salts see: A. H. Sand-
torv, D. R. Stuart, Angew. Chem. Int. Ed. 2016, 55, 15812–15815; Angew.
Chem. 2016, 128, 16044–16047; c) . MØszµros, A. SzØkely, A. Stirling, Z.
Novµk, Angew. Chem. Int. Ed. 2018, 57, 6643–6647; Angew. Chem. 2018,
130, 6753–6757.
[26] See the Supporting Information for details.
[27] a) J. Malmgren, S. Santoro, N. Jalalian, F. Himo, B. Olofsson, Chem. Eur. J.
2013, 19, 10334–10342; b) D. R. Stuart, Chem. Eur. J. 2017, 23, 15852–
15863.
[28] a) M. A. Carroll, R. A. Wood, Tetrahedron 2007, 63, 11349–11354; b) T. B.
Petersen, R. Khan, B. Olofsson, Org. Lett. 2011, 13, 3462–3465.
[29] P. Villo, G. Kervefors, B. Olofsson, Chem. Commun. 2018, 54, 8810–8813.
[30] M. Ochiai, Top. Curr. Chem. 2003, 224, 5–68.
[31] a) M. Ochiai, Y. Kitagawa, M. Toyonari, ARKIVOC 2003, vi, 43–48; b) H.
Pinto de Magalh¼es, H. P. Lüthi, A. Togni, Org. Lett. 2012, 14, 3830–
3833.
[32] a) X. Peng, Z. Sun, P. Kuang, L. Li, J. Chen, J. Chen, Org. Lett. 2020, 22,
5789–5795; b) N. Chatterjee, A. Goswami, Eur. J. Org. Chem. 2017,
3023–3032; c) L. D. Caspers, J. Spils, M. Damrath, E. Lork, B. J. Nacht-
sheim, J. Org. Chem. 2020, 85, 9161–9178; d) A. Boelke, P. Finkbeiner,
B. J. Nachtsheim, Beilstein J. Org. Chem. 2018, 14, 1263–1280.
[33] E. Stridfeldt, E. Lindstedt, M. Reitti, J. Blid, P.-O. Norrby, B. Olofsson,
Chem. Eur. J. 2017, 23, 13249–13258.
[25] a) A. Isidro-Llobet, M. lvarez, F. Albericio, Chem. Rev. 2009, 109, 2455–
2504; b) Nonappa, K. Ahonen, M. Lahtinen, E. Kolehmainen, Green
Chem. 2011, 13, 1203–1209; c) A. Dominguez-Huerta, I. Perepichka, C.-J.
Li, Commun. Chem. 2018, 1, 45.
Manuscript received: December 15, 2020
Accepted manuscript online: January 22, 2021
Version of record online: March 3, 2021
Chem. Eur. J. 2021, 27, 5790 –5795
www.chemeurj.org
5795 ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH