An Alternative to the Classical α-Arylation: The Transfer of an Intact 2-Iodoaryl from ArI(O2CCF3)2

Article abstract of DOI:10.1002/anie.201405982

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 C-H functionalization reaction is thought to proceed through a [3,3] rearrangement of an iodonium enolate. The final α-(2-iodoaryl)ketones are versatile synthetic building blocks.

Full text of DOI:10.1002/anie.201405982

Angewandte
Chemie
DOI: 10.1002/anie.201405982
Synthetic Methods
An Alternative to the Classical a-Arylation: The Transfer of an Intact
2-Iodoaryl from ArI(O2CCF3)2**
Zhiyu Jia, Erik Gꢀlvez, Rosa Marꢁa Sebastiꢀn, Roser Pleixats, ꢂngel ꢂlvarez-Larena,
Eddy Martin, Adelina Vallribera,* and Alexandr Shafir*
Abstract: The a-arylation of carbonyl compounds is generally
accomplished under basic conditions, both under metal
catalysis and via aryl transfer from the diaryl l3-iodanes.
Here, we describe an alternative metal-free a-arylation using
ArI(O2CCF3)2 as the source of a 2-iodoaryl group. The
reaction is applicable to activated ketones, such as a-cyanoke-
À
tones, and works with substituted aryliodanes. This formal C
H functionalization reaction is thought to proceed through
a [3,3] rearrangement of an iodonium enolate. The final a-(2-
iodoaryl)ketones are versatile synthetic building blocks.
Scheme 1. The Beringer-type arylation of b-ketoesters using diaryliodo-
nium salts.
T
he transfer of an aryl group to a position a to a carbonyl is
an important class of C C bond-forming reactions, popular-
ized with the introduction of the metal-catalyzed (mainly Pd
and Cu) coupling of aryl halides (or equivalent) to eno-
lates.[1,2] Predating these advances, the metal-free a-arylation
has been in use since the 1960s, following reports by Beringer
et al. on the ability of the diaryl-l3-iodanes (e.g. [Ph2I]Cl) to
transfer an aryl ligand to an enolate (Scheme 1).[3,4] Recent
studies showed that both the C- and the O-iodonium enolate
intermediates can lead to the product through a [1,2] or [2,3]
shift, respectively.[5]
diaryliodanes.[7b] Although the use of the monoaryl iodonium
species (e.g. PhIX2) would thus be attractive, examples of such
usage are scarce.[9] As part of our own research on hyper-
valent iodine reactivity,[10] we wish to report an a-arylation
protocol that employs monoaryl iodonium species, exempli-
fied by phenyliodine bis(trifluoroacetate) (PIFA, 2a).
We found that exposing the b-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
À
This methodology, including its asymmetric versions,[6] has
since then gained importance as complementary to the cross-
coupling, in turn stimulating further research into diaryl l3-
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 a group (e.g. mesityl) is
often the key to a selective arylation using asymmetric
Scheme 2. The outcome of treating the b-ketoester 1 with
PhI(O2CCF3)2 (2a).
[*] Dr. Z. Jia, Dr. E. Gꢀlvez, Prof. Dr. R. M. Sebastiꢀn,
Prof. Dr. R. Pleixats, Prof. Dr. A. Vallribera
Table 1: Screening of conditions in the arylation of 1 with 2a (from
Department of Chemistry and Centro de Innovaciꢁn en Quꢂmica
Avanzada (ORFEO-CINQA), Universitat Autꢃnoma de Barcelona
Bellaterra (Spain)
Scheme 2).[a]
Entry
Solvent
PhIX2
Additive[b]
4 [%][c]
E-mail: adelina.vallribera@uab.cat
1
2
3
CH3CN
CH3CN
CH3CN
2a
PhI(OAc)2
PhI(OH)(OTs)
–
–
–
17
–
–
Dr. ꢄ. ꢄlvarez-Larena
Servei de Difracciꢁ de Raigs X, Universitat Autꢃnoma de Barcelona
4
5
6
7
8
9
10
11
12
CH2Cl2
CF3CO2H
2a
2a
2a
2a
2a
2a
–
–
–
14
34
48
57[d]
<5
<5
23
26
52
Dr. E. Martin, Dr. A. Shafir
Institute of Chemical Research of Catalonia (ICIQ)
Avda. Paꢅsos Catalans 16, 43007 Tarragona (Spain)
E-mail: ashafir@iciq.es
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
CH3CN-CF3CO2H
(CF3CO)2O
(CF3SO2)2O
H2O
(CF3CO)2O
(CF3CO)2O
(CF3CO)2O
[**] This work was supported by the ICIQ, MICINN (CTQ2011-22649),
the MEC (Cons. Ing. CSD2007-00006), the Generalitat de Catalunya
(2014SGR1192 and 2014SGR1105), and the 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).
PhI(OAc)2
PhI(OH)(OTs)
PhIO
[a] Using 1 (1.0 mmol) and 2a (1.3 mmol) in 4 mL of solvent for 4 h at rt;
[b] 1.5 equiv; [c] GC yield corrected versus the internal standard
C6H11CN; [d] Yield of the isolated product.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405982.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
formation of 4 was found to be solvent-dependent (entries 1
and 4–6), with a 48% yield achieved using a 1:1 CH3CN/
CF3CO2H mixture. The addition of the trifluoroacetic anhy-
dride (1.5 equiv) led to a 57% yield of 4 after 2 h at room
temperature; other additives proved detrimental (entries 7–
9). Under the new conditions, the use of other hypervalent
iodine reagents was now possible (entries 10–12), likely
through the in situ formation of 2a. Oxidative degradation
of 1 accounts for the reaction mass balance.
20a, 21, and 22 after 6–8 h.[11] Next, 17 was exposed to eight
additional ArI(O2CCF3)2 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
cyanoketones 20b (63%), 20c (65%), 20d (71%), and 20e
À
(50%), with 20e featuring the iodine flanked by a C Br and
À
a C C bonds. A 76% yield of the carboxy-substituted 20 f was
achieved and the p-NO2 derivative 20g was isolated in 68%
yield. The transfer of a 2-iodo-3-methylphenyl group took
place with a 49% yield (product 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 À208C (see the Supporting Information).
Interestingly, although the secondary cyanoketones, including
benzoylacetonitrile, proved unsuitable, the 2-benzoylpropio-
nitrile, which only differs by a 2-methyl group, gave the
expected 23 in 60% yield. Finally, the protocol was used to
prepare a 19 g batch of 20a (74%, Scheme 4).[13]
To probe the reaction scope, the cyclic b-ketoesters 5–7
were transformed into products 11–13 in 2 h at room temper-
ature (Scheme 3, X-Ray structure of 13 shown). Similarly, a-
Scheme 4. Gram-scale preparation of 20a; a-arylation conditions as in
Table 2.
Scheme 3. The a-iodoarylation of b-dicarbonyl compounds using PIFA.
(2-iodoaryl)-diketones 14–16 were synthesized from the
corresponding b-diketones 8–10.
Particularly efficient was the arylation of a-cyanoketones
(Table 2). Thus, the cyclic substrates 17–19 underwent
a smooth reaction with PIFA to give a 76–80% yield of
Scheme 5. Two possible enolate rearrangement paths leading to 4.
Although a mechanistic study is currently underway, this
Table 2: Iodoarylation of the a-cyanoketones.[a]
À
formal C H alkylation may arise from a [3,3] shift of an O-
enolate A (Scheme 5) as seen in a related sulfoxide-mediated
a-arylation.[14] Alternatively, the selectivity could be
explained by a [1,3] shift of a C-enolate B.
A priori, the [1,3] shift appears less likely. Indeed, while
the C-enolates are intermediates in the formation of the
iodonium ylides[15] and can be isolated,[16] the existence (or
intermediacy) of the quaternary analogues (such as B in
Scheme 5) is less frequent.[5b] Furthermore, heating the
isolated C-enolates typically leads to the formation of the a-
[16]
À
À
C O (e.g. C OTs) bond.
In our hands, the isolated
=
phenyliodonium 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 favor a [3,3]
shift of an iodonium O-enolate (A, Scheme 5), akin the
iodonio-Claisen rearrangement introduced by Ochiai et al. in
the 1990s.[17,18] Despite our efforts, reaction intermediates
have so far proven elusive, possibly due to the rearrangement
[19]
À
proceeding faster than the I O-enolate formation.
Not
even the o,o-disubstituted 2j allowed for the trapping of the I-
enolate, leading instead to non-arylative oxidation processes
(Scheme 6A). It should also be noted that the iodine-free
species 24 (5%), isolated during the synthesis of 20b, proved
[a] 1.3:1 ratio of 2/17. Using 17 (1 mmol) in CH3CN/CF3COOH (1:1,
4 mL). [b] From m-Br-C6H4I(O2CCF3)2 (2i). [c] At 608C for 48 h.
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
In summary, the ArI(O2CCF3)2 reagents have been used in
the a-arylation of b-dicarbonyls and a-cyanoketones. The aryl
transfer takes place with retention of the iodide ortho to the
À
newly formed C C bond. The method is complementary to
metal-catalyzed arylations, and could overcome the issues of
the aryl loss associated with the use of diaryliodonium salts. In
a more general sense, the concept of a reversible formation of
an iodonium-based Claisen precursor, shown here with O-
enolates, might open the door to the development of a range
of new synthetic methods.
Scheme 6. Additional observations in the arylation of 17.
Received: June 6, 2014
Revised: July 11, 2014
Published online: && &&, &&&&
to be the para-fluoro regioisomer, rather than the initially
assumed meta (Scheme 6B); the steps leading to 24 remain to
be investigated.
À
Keywords: a-arylation · C H functionalization ·
The cyanoketones 20a and 21 were readily converted to
the amides 25 and 26. Although PIFA was unsuitable for the
arylation of the parent cyclohexanone, the arylketone 27
could, nevertheless, be obtained through the decarboxylation
of 25 (Scheme 7, top). The substrates also underwent the
Suzuki (see the Supporting Information) and Sonogashira
coupling reaction (Scheme 7, bottom, products 28–30).
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 an equatorial o-iodophenyl group.[20]
Preliminary tests showed that 31 can be converted to the
.
À
iodonium-Claisen rearrangement · dehydrogenative C
C coupling · hypervalent iodine
[1] a) M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
11108 – 11109; b) J. M. Fox, X. Huang, A. Chieffi, S. L. Buch-
wald, J. Am. Chem. Soc. 2000, 122, 1360 – 1370; c) B. C. Hamann,
J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 12382 – 12383.
[2] For a review on metal-catalyzed a-arylation, see: a) C. C. C.
Johansson, T. J. Colacot, Angew. Chem. Int. Ed. 2010, 49, 676 –
707; Angew. Chem. 2010, 122, 686 – 718; b) F. Bellina, R. Rossi,
Chem. Rev. 2010, 110, 1082—1146.
[3] a) F. M. Beringer, P. S. Forgione, J. Org. Chem. 1963, 28, 714 –
717; b) F. M. Beringer, W. J. Daniel, S. A. Galton, G. Rubin, J.
Org. Chem. 1966, 31, 4315 – 4318; c) C. H. Oh, J. S. Kim, H. H.
Jung, J. Org. Chem. 1999, 64, 1338 – 1340.
hydroxy-spiroxindole 32 (X-ray structure shown for trans)
[21]
À
using a Cu-catalyzed C N coupling, with 32-cis represent-
ing the spiroxindole portion of Gelsemine, a synthetically
interesting natural product target (Scheme 8).[22,23]
À
À
[4] 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. Motherwell, M. T. Barros Papoula, J. Chem. Soc. Chem.
Commun. 1980, 827 – 829.
[5] a) M. Ochiai, Y. Kitagawa, M. Toyonari, Arkivoc 2003, 43 – 48;
b) P. O. Norrby, T. B. Petersen, M. Bielawski, B. Olofsson, Chem.
Eur. J. 2010, 16, 8251 – 8254.
[6] a) M. Ochiai, Y. Kitagawa, N. Takayama, Y. Takaoka, M. Shiro,
J. Am. Chem. Soc. 1999, 121, 9233 – 9234; b) V. K. Aggarwal, B.
Olofsson, Angew. Chem. Int. Ed. 2005, 44, 5516 – 5519; Angew.
Chem. 2005, 117, 5652 – 5655; c) A. E. Allen, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2011, 133, 4260 – 4263.
[7] a) E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48,
9052 – 9070; Angew. Chem. 2009, 121, 9214 – 9234; b) J. Malmg-
ren, S. Santoro, N. Jalalian, F. Himo, B. Olofsson, Chem. Eur. J.
2013, 19, 10334 – 10342.
Scheme 7. Functional group manipulation in the a-(2-iodoaryl) deriva-
tives.
[8] For further reading on hypervalent iodine chemistry, see: V. V.
Zhdankin, Hypervalent Iodine Chemistry: Preparation, Structure
and Synthetic Applications of Polyvalent Iodine Compounds,
Wiley, Chichester, 2014.
[9] PhIX2 are also net 2eÀ oxidants in the a-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.
[10] E. Faggi, R. M. Sebastiꢀn, R. Pleixats, A. Vallribera, A. Shafir,
A. Rodrꢁguez-Gimeno, C. Ramꢁrez de Arellano, J. Am. Chem.
Soc. 2010, 132, 17980 – 17982.
[11] The mass balance is made up by the ketone a-oxidation products
À
À
C OH and C O2CF3 and those stemming from oxidative ring-
opening.
Scheme 8. Some simple transformations of the ketoamide 25.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[12] A. A. Zagulyaeva, M. S. Yusubov, V. V. Zhdankin, J. Org. Chem.
2010, 75, 2119 – 2122.
[19] Only the PhI(O2CCF3)2 and the coupling product were detected
by NMR during the reaction.
[13] For the synthesis of a-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.
[14] a) X. L. Huang, N. Maulide, J. Am. Chem. Soc. 2011, 133, 8510 –
8513; b) X. L. Huang, S. Klimczyk, N. Maulide, Synthesis 2012,
175 – 183; for a related Au-catalyzed process, see c) A. B.
Cuenca, S. Montserrat, K. M. Hossain, G. Mancha, A. Lledꢂs,
M. Medio-Simꢂn, G. Ujaque, G. Asensio, Org. Lett. 2009, 11,
4906 – 4909.
[15] 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.
[16] G. F. Koser, A. G. Relenyi, A. N. Kalos, L. Rebrovic, R. H.
Wettach, J. Org. Chem. 1982, 47, 2487 – 2489.
[20] CCDC 1005725 (13), 1005726 (25), 1005727 (31-trans), 1005728
(32-trans) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
[21] For a review on Cu-catalyzed coupling, see: I. P. Beletskaya,
A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337 – 2364; for
the Cu-catalyzed N-arylation of amides, see A. Klapars, J. C.
Antilla, X. H. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001,
123, 7727 – 7729.
[22] For strategies in Gelsemine synthesis: H. Lin, S. J. Danishefsky,
Angew. Chem. Int. Ed. 2003, 42, 36 – 51; Angew. Chem. 2003, 115,
38 – 53.
À
[23] In both cases, a competing C O coupling yielded small amounts
(5–15%) of the dihydrobenzofuran 33 (Figure 2, Supporting
[17] 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, 2274 – 2275; c) H. R. Khatri, J. L. Zhu, Chem. Eur. J. 2012, 18,
12232 – 12236.
Information).
[18] The mechanism was 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; Angew.
Chem. 2004, 116, 1259 – 1263.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
Z. Jia, E. Gꢁlvez, R. M. Sebastiꢁn,
R. Pleixats, ꢂ. ꢂlvarez-Larena, E. Martin,
A. Vallribera,* A. Shafir*
&&&& — &&&&
[3,3] Iodonium enolate rearrangement:
Activated ketone derivatives, including b-
dicarbonyl and a-cyanoketones, react
with ArI(O2CCF3)2 reagents to give an a-
arylated product with the iodine atom
reaction takes place under acidic condi-
À
An Alternative to the Classical a-
Arylation: The Transfer of an Intact 2-
Iodoaryl from ArI(O2CCF3)2
tions. This formal C H functionalization
reaction presumably proceeds through
a [3,3] rearrangement of an iodonium
enolate. The final a-(2-iodoaryl)ketones
are versatile synthetic building blocks.
À
retained ortho to the new C C bond. The
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!