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An Alternative to the Classical α-Arylation: the Transfer of an Intact
2-Iodoaryl from ArI(O2CCF3)2.
Zhiyu Jia, Erik Gálvez, Rosa María Sebastián, Roser Pleixats, Ángel Álvarez-Larena, Eddy Martin,
Adelina Vallribera,* Alexandr Shafir*
((Dedication----optional))
Abstract: The α-arylation of carbonyl compounds is generally
accomplished under basic conditions, both under metal catalysis
and via aryl transfer from the diaryl λ3-iodanes. Here, we describe
an alternative metal-free α-arylation using ArI(O2CCF3)2 as the
source of a 2-iodoaryl group. The reaction is applicable to activated
ketones, such as α-cyanoketones and works with substituted
aryliodanes. This formal CH functionalization reaction is thought to
proceed via [3,3] rearrangement of an iodonium enolate. The final
α-(2-iodoaryl)ketones are versatile synthetic building blocks.

The transfer of an aryl group to a position α to a carbonyl is an
important class of the C-C bond-forming reactions, popularized with
the introduction of the metal-catalysed (mainly Pd and Cu) coupling
of the aryl halides (or equivalent) to enolates.[1,2] Predating these
advances, the metal-free α-arylation has been in use since the 1960’s,
following reports by Beringer et al. on the ability of the diaryl-λ3iodanes (e.g. [Ph2I]Cl) to transfer an aryl ligand to an enolate
(Scheme 1).[3,4] Recent studies revealed that both the C- and the Oiodonium enolate intermediates can lead to the product via a [1,2] or
[2,3] shifts, respectively.[5]
This methodology, including its asymmetric versions,[6] has
since gained importance as complementary to the cross-coupling, in
turn stimulated further research into diaryl λ3-iodanes.[7,8] Despite
the attractiveness of the method, one of the two aryl groups must act
as a “spectator” ligand extruded in the form of ArI. The choice of
such group (e.g. mesityl) is often the key to a selective arylation
using asymmetric diaryliodoanes.[7b] Although the use of the monoaryl iodonium species (i.e. PhIX2) would thus be attractive,
examples of such usage are scarce.[9] As part of our own research on
hypervalent iodine reactivity,[10] we wish to report an α-arylation
protocol that employs mono-aryl iodonium species, exemplified by
phenyliodine bis(trifluoroacetate) (PIFA, 2a).

Scheme 1. Beringer-type arylation of β-ketoesters using diaryliodonium salts.

We found that exposing the β-ketoester 1 to 2a in CH3CN led to an
unexpected ortho-iodoaryl species 4 in 17% yield (Scheme 2); in
contrast, none of 4 was obtained using PhI(OAc)2 or PhI(OH)(OTs)
(entries 1-3, Table 1). The formation of 4 was found to be solventdependent (entries 1, 4-6), with a 48% yield achieved using a 1:1
CH3CN/CF3CO2H mixture. The addition of the trifluoroacetic
anhydride (1.5 equiv) led to a 57% yield of 4 after 2h at room temp.;
other additives proved detrimental (entries 7-9). Under the new
conditions, the use of other hypervalent iodine reagent was now
possible (entries 10-12), likely via the in situ formation of 2a.
Oxidative degradation of 1 accounts for the reaction mass balance.

Scheme 2. The outcome of treating the β-ketoester 1 with PhI(O2CCF3)2, 2a.

Table 1. Screening of conditions in the arylation of 1 with 2a (from Scheme 3).[a]

[]

Dr. Z. Jia, Dr. E. Gálvez, Prof. Dr. R. M. Sebastián, Prof. Dr.
R. Pleixats, Prof. Dr. A. Vallribera
Department of Chemistry and Centro de Innovación en
Química Avanzada (ORFEO-CINQA)
Universitat Autònoma de Barcelona, Bellaterra (Spain)
E-mail: adelina.vallribera@uab.cat
Dr. E. Martin, Dr. A. Shafir,
Institute of Chemical Research of Catalonia (ICIQ)
Avda. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: ashafir@iciq.es

[]

Work supported by ICIQ, MICINN (CTQ2011-22649), MEC
(Cons. Ing. CSD2007-00006), Generalitat de Catalunya
(2014SGR1192 and 2014SGR1105) and China Scholarship
Council (fellowship to Z. J.). We thank MINECO for support
through grant CTQ2013-46705-R and Severo Ochoa
Excellence Accreditation 2014-2018 (SEV-2013-0319).
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.((Please delete if not appropriate))

Entry Solvent
1
2
3
4
5
6
7
8
9
10
11
12

CH3CN
CH3CN
CH3CN
CH2Cl2
CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H

PhIX2

Additive[b]

%4[c]

2a
PhI(OAc)2
PhI(OH)(OTs)
2a
2a
2a
2a
2a
2a
PhI(OAc)2
PhI(OH)(OTs)
PhIO

(CF3CO)2O
(CF3SO2)2O
H2O
(CF3CO)2O
(CF3CO)2O
(CF3CO)2O

17
--14
34
48
57[d]
<5
<5
23
26
52

[a] Using 1.0 mmol 1, 1.3 mmol 2a in 4 mL of solvent for 4h at rt; [b]
1.5 equiv; [c] GC yield corrected vs int. C6H11CN; [d] % Isolated yield.

1

To probe the reaction scope, the cyclic β-ketoesters 5-7 were
transformed into products 11-13 in 2h at room temp (Scheme 3, XRay structure of 13 shown). Similarly, the α-(2-iodoaryl)-diketones
14-16 were synthesized from the corresponding β-diketones 8-10.

Scheme 4. Gram-scale preparation of 20a; α-arylation conditions as in Table 2.

Although a mechanistic study is currently underway, this formal CH
alkylation may arise via a [3,3] shift of an O-enolate A (Scheme 5),
as seen in a related sulfoxide-mediated α-arylation.[14] Alternatively,
the selectivity could be explained by a [1,3] shift of a C-enolate B.

Scheme 3. The α-iodoarylation of β-dicarbonyl compounds using PIFA.

Particularly efficient was the arylation of α-cyanoketones (Table 2).
Thus, the cyclic substrates 17-19 underwent a smooth reaction with
PIFA to give a 76-80% yield of 20a, 21 and 22 after 6-8h.[11] Next,
17 was exposed to eight additional ArI(O2CCF3) reagents (2b-2i)
prepared by a method developed by Zhdankin et al.[12]. The use of
the halo derivatives 2b-2e led to the formation of the dihaloaryl
derivatives 20b (63%), 20c (65%), 20d (71%) and 20e (50%), with
20e featuring the iodine flanked by a C-Br and a C-C bonds. A 76%
yield of the carboxy-substituted 20f was achieved, while the p-NO2
derivative 20g was isolated in a 68% yield. The transfer of a 2-iodo3-Me-phenyl group took place with a 49% yield (prod. 20h). The
coupling at the two ortho CH sites of the meta-Br iodane 2i took
place in a 3:1 ratio, with the minor isomer 20i’ (17%) observed as
two rotamers (70:30) at -20 oC (Supp. Info). Interestingly, while
secondary cyanoketones, including benzoylacetonitrile, proved
unsuitable, the 2-benzoylpropionitrile, which only differs by a 2-Me
group, gave the expected 23 in 60% yields. Finally, the protocol was
used to prepare a 19 g batch of 20a (74%, Scheme 4).[13]
Table 2. Iodoarylation of the α-cyanoketones.[a]

Scheme 5. Two of the possible enolate rearrangement paths leading to 4.

A priori, the [1,3] shift appears less likely. Indeed, while the Cenolates are intermediates in the formation of the iodonium
ylides[15,16], the quaternary analogs (such as B in Scheme 3) are less
frequent.[5b] Furthermore, heating the isolated C-enolates typically
leads to the formation of the α-C-O (e.g. C-OTs) bond.[16] In our
hands, the isolated phenyliododium ylide PhCOC(=IPh)CN,
expected to give a C-enolate upon protonation,[15c] failed to undergo
the aryl transfer under the reaction conditions. Thus, we favour a
[3,3] shift of an iodonium O-enolate (Scheme 3), akin the iodonioClaisen rearrangement introduced by Ochiai et al. in 1990’s.[17,18]
Despite our efforts, such intermediates have so far proven elusive,
possibly due to the rearrangement proceeding faster than the I-Oenolate formation.[19] Not even the o,o-disubstituted 2j allowed for
the trapping of the I-enolate, leading, instead, to non-arylative
oxidation processes (Scheme 6A). We note that the iodine-free
species 24 (5%), isolated during the synthesis of 20b, proved to be
the para-fluoro regioisomer, rather than the initially assumed meta
(Scheme 6B); the steps leading to 24 remain to be investigated.

Scheme 6. Additional observations in the arylation of 17.

The cyanoketones 20a and 21 were readily converted to the
amides 25 and 26. While PIFA was unsuitable for the arylation of
parent cyclohexanone, the arylketone 27 could, nevertheless, be
obtained via the decarboxylation of 25 (Scheme 7, top). The
substrates also underwent the Suzuki (Supp. Info) and Sonogashira
coupling reaction (Scheme 7, bottom, prod. 28-30).

2

[4]

[5]

[6]

Scheme 7. Functional group manipulation in the α-(2-iodoaryl) derivatives.

[7]

The reduction of 25 led to the alcohol 31 as a 4:1 trans:cis mixture
(Scheme 8), with the solid state structures of both 25 and 31-trans
showing equatorial o-iodophenyl group.[20] Preliminary tests showed
that 31 can be converted to the hydroxy-spiroxindole 32 (X-Ray
structure shown for trans) using Cu-catalyzed C-N coupling,[21] with
32-cis representing the spiroxindole portion of Gelsemine, a
synthetically interesting natural product target (Scheme 8).[22,23]
In summary, the ArI(O2CCF3)2 reagents have been used in the
α-arylation of β-dicarbonyls and α-cyanoketones. The aryl transfer
takes place with retention of the iodide ortho to the newly formed CC bond. The new method is complementary to the metal-catalyzed
arylation, and could overcome the issues of the aryl loss associated
with the use of the diaryliodonium salts. In a more general sense, the
concept of a reversible formation of iodonium-based Claisen
precursor, shown here with O-enolates, might open the door to the
development of a range of new synthetic methods.

[8]

[9]

[10]

[11]
[12]
[13]

[14]

[15]

[16]
[17]

[18]
Scheme 8. Some simple transformations of the ketoamide 25.

1966, 31, 4315-4318; c) C. H. Oh, J. S. Kim, H. H. Jung, J. Org.
Chem. 1999, 64, 1338-1340.
For the related usage of the Ar-Pb and Ar-Bi species, see a) J. T.
Pinhey, B. A. Rowe, Aust. J. Chem. 1979, 32, 1561-1566; b) D. H. R.
Barton, J.-C. Blazejewski, B. Charpiot, D. J. Lester, W. B.
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2005, 117, 5652–5655; c) A. E. Allen, D. W. C. MacMillan, J. Am.
Chem. Soc. 2011, 133, 4260–4263.
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Santoro, N. Jalalian, F. Himo, B. Olofsson, Chem. Eur. J. 2013, 19,
10334-10342.
For further reading on hypervalent iodine chemistry, see: b) V. V.
Zhdankin, Hypervalent Iodine Chemistry: Preparation, Structure and
Synthetic Applications of Polyvalent Iodine Compounds, Wiley,
Chichester, 2014.
PhIX2 is also a net 2e- oxidants in the α-arylation using ArH: a) Y.
Kita, H. Tohma, K. Hatanaka, T. Takada, S. Fujita, S. Mitoh, H.
Sakurai, S. Oka, J. Am. Chem. Soc. 1994, 116, 3684-3691; b) T. C.
Turner, K. Shibayama, D. L. Boger, Org. Lett. 2013, 15, 1100-1103.
E. Faggi, R. M. Sebastián, R. Pleixats, A. Vallribera, A. Shafir, A.
Rodríguez-Gimeno, C. Ramírez de Arellano, J. Am. Chem. Soc. 2010,
132, 17980-17982.
The mass balance is made up by the ketone α-oxidation products COH and C-O2CF3 and those stemming from oxidative ring-opening.
A. A. Zagulyaeva, M. S. Yusubov, V. V. Zhdankin, J. Org. Chem.
2010, 75, 2119-2122.
For the synthesis of α-cyanoketones: H.-J. Liu, T. W. Ly, C.-L. Tai,
J.-D. Wu, J.-K. Liang, J.-C. Guo, N.-W. Tseng, K.-S. Shia,
Tetrahedron 2003, 59, 1209-1226.
a) X. L. Huang, N. Maulide, J. Am. Chem. Soc. 2011, 133, 8510-8513;
b) X. L. Huang, S. Klimczyk, N. Maulide, Synthesis-Stuttgart 2012,
44, 175-183; for a related Au-catalyzed process, see c) A. B. Cuenca,
S. Montserrat, K. M. Hossain, G. Mancha, A. Lledós, M. MedioSimón, G. Ujaque, G. Asensio, Org. Lett. 2009, 11, 4906-4909.
a) E. Malamidou-Xenikaki, S. Spyroudis, Synlett, 2008, 2725-2740; b)
S. R. Goudreau, D. Marcoux, A. B. Charette, J. Org. Chem. 2009, 74,
470–473; c) K. Gondo, T. Kitamura, Molecules 2012, 17, 6625-6632.
G. F. Koser, A. G. Relenyi, A. N. Kalos, L. Rebrovic, R. H. Wettach,
J. Org. Chem. 1982, 47, 2487-2489.
a) M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, J. Am. Chem. Soc. 1991,
113, 1319-1323; b) M. Ochiai, T. Ito, J. Org. Chem. 1995, 60, 22742275; c) H. R. Khatri, J. L. Zhu, Chem. Eur. J. 2012, 18, 12232-12236.
The mechanism also invoked by Porco et al. to explain the formation
of the species C: J. L. Zhu, A. R. Germain, J. A. Porco, Angew. Chem.
Int. Ed. 2004, 43, 1239-1243.

Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: α-arylation · dehydrogenative C-C coupling · hypervalent
iodine · iodonio-Claisen · C-H functionalisation

[19]
[20]
[21]

[1]

[2]

[3]

a) M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 1110811109; b) J. M. Fox, X. Huang, A. Chieffi, S. L. Buchwald, J. Am.
Chem. Soc. 2000, 122, 1360-1370; c) B. C. Hamann, J. F. Hartwig, J.
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Bellina, R. Rossi, Chem. Rev. 2010, 110, 1082–1146.
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F. M. Beringer, W. J. Daniel, S. A. Galton, G. Rubin, J. Org. Chem.

[22]

[23]

Only the PhI(O2CCF3)2 and the coupling product detected by NMR.
CCDC 1005725 -1005728 contains the supplementary
crystallographic data for this paper.
For a review on Cu-catalyzed coupling, see: I. P. Beletskaya, A. V.
Cheprakov, Coord. Chem. Rev. 2004, 248, 2337–2364; for Cucatalyzed N-arylation of amides, see A. Klapars, J. C. Antilla, X. H.
Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727–7729.
For strategies in Gelsemine synthesis: H. Lin, S. J. Danishefsky,
Angew. Chem. 2003, 115, 38 – 53; Angew. Chem. Int. Ed. 2003, 42,
36 – 51.
In both cases, a competing C-O coupling yielded small amounts (515%) of the dihydrobenzofuran 33 (Figure 2, Supp. Info).

3

((Catch Phrase))
Z. Jia, E. Gálvez, R. M. Sebastián, R.
Pleixats, Á. Álvarez-Larena, E. Martin,
A. Vallribera,* A. Shafir* __________
Page – Page
An Alternative to the Classical αArylation: the Transfer of an Intact 2Iodoaryl from ArI(O2CCF3)2

Activated ketone derivatives, including β-dicarbonyl and α-cyanoketones, react with
ArI(O2CCF3)2 reagents to give an α-arylated product with the iodine atom retained
ortho to the new C-C bond. The reaction takes place under acidic conditions. This
formal CH functionalization reaction is thought to proceed via [3,3] rearrangement
of an iodonium enolate. The final α-(2-iodoaryl)ketones are versatile synthetic
building blocks.

4