Aryne Insertion into I-I σ-Bonds

Article abstract of DOI:10.1021/ol300439r

A new protocol for the efficient synthesis of o-diiodoarenes has been developed. This method allows the synthesis of substituted and polycyclic o-diiodoarenes, which are difficult to obtain by classical methods. This diiodination process involves the formal insertion of arynes into the I-I σ-bond.

Full text of DOI:10.1021/ol300439r

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1363–1365
Aryne Insertion into IÀI σ-Bonds
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Diego Rodrıguez-Lojo, Agustın Cobas, Diego Pena, Dolores Perez,* and
ꢀ
´
Enrique Guitian*
´
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ꢀ
´
ꢀ
Centro de Investigacion en Quımica Bioloxica e Materiais Moleculares (CIQUS), and
ꢀ
´
Departamento de Quımica Organica, Universidade de Santiago, 15782 Santiago de
Compostela, Spain
enrique.guitian@usc.es; dolores.perez@usc.es
Received December 9, 2011
ABSTRACT
A new protocol for the efficient synthesis of o-diiodoarenes has been developed. This method allows the synthesis of substituted and polycyclic
o-diiodoarenes, which are difficult to obtain by classical methods. This diiodination process involves the formal insertion of arynes into the
IÀI σ-bond.
The insertions of arynes into σ-bonds are interesting
processes from both theoretical and synthetic points of
view. Formally, the insertion of an aryne into an AÀB
σ-bond involves cleavage of the AÀB bond and the
formation of an arene derivative, which incorporates A
and B at the ortho positions. A wide spectrum of inser-
tions involving σ-bonds linking a great variety of atoms
(CÀC, CÀSi, SiÀSi, SnÀSn, BÀSi, CÀO, CÀN, CÀCl,
etc.) have been reported.1,2
o-Diiodoarenes are valuablesyntheticintermediates, but
the majority of these compounds are not commercially
available. Additionally, there is no general, efficient, and
straightforward route to o-diiodoarenes.3 Direct iodina-
tion of arenes with reagents such as HgO/I2, I2/HIO4,
I2/H2SO4, and ICl works reasonably well at activated
positions. In other cases, however, harsh conditions are
required and this leads to mixtures of regioisomers.4
Synthetic routes from more highly functionalized precur-
sors, such as o-dibromoarenes,5 o-bis(trimethylsilyl)arenes,6
o-iodoanilines,7 and aryneÀmetal complexes,8 have been
developed, but the synthesis of these compounds is not
always easy.
It has been known that benzyne (1a), generated from
benzenediazonium 2-carboxylate,9 diphenyliodonium
2-carboxylate,9 or 1-aminobenzo-triazole,10 inserts into
the IÀI σ-bond (Scheme 1). These reactions give moderate
yields for benzyne, but far lower yields are obtained for
substituted and polycyclic arynes.9,11
(1) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
(4) See for example: (a) Dallacker, F.; Adolphen, G. Ann. Chem.
1966, 691, 134. (b) Suzuki, H.; Nakamura, K.; Goto, R. Bull. Chem. Soc.
Jpn. 1966, 39, 128. (c) Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome,
H. Synthesis 1995, 1273.
(5) Suzuki, H.; Kondo, A.; Inouye, M.; Ogawa, T. Synthesis 1985,
121.
~
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ꢀ
Press: New York, 1967. (b) Pena, D.; Perez, D.; Guitian, E. Angew. Chem., Int.
Ed. 2006, 45, 3579. (c) Gallo, R. D. C.; Rezende, H. V.; Muzzi, R. M.;
Raminelli, C. Quim. Nova 2009, 32, 2437. (d) Yoshida, H.; Ohshita, J.;
Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199.
(2) For more recent examples, see: (a) C;C insertion: Liu, Y.-L.;
Liang, Y.; Pi, S.-F.; Li, J.-H. J. Org. Chem. 2009, 74, 5691. (b) C;N
insertion: Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168. (c) B;
B insertion: Yoshida, H.; Okada, K.; Kawashima, S.; Tanino, K.;
Ohshita, J. Chem. Commun. 2010, 46, 1763. (d) CdO insertion: Yoshioka,
E.; Kohtani, S.; Miyabe, H. Org. Lett. 2010, 12, 1956. (e) C;C insertion:
Yoshida, H.; Morishita, T.; Ohshita, J. Chem. Lett. 2010, 39, 508. (f) C;O
insertion: Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117. (g)
C;H insertion: Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49,
9761. (h) Sn;H insertion: Lakshmi, B. V.; Wefwelscheid, U. K.; Kazmaier,
U. Synlett 2011, 345. (i) C;O insertion: Łaczkowski, K. Z.; Garcıa, D.;
€
(6) Grutzmacher, H.-F.; Lohmann, J. Liebigs Ann. Chem. 1970,
733, 88.
^
(7) (a) Dunogues, J.; N’Gabe, D.; Laguerre, M.; Duffaut, N.; Calas,
R. Organometallics 1982, 1, 1525. (b) Berris, B. C.; Hovakeemian, G. H.;
Lai, Y. H.; Mestdagh, H.; Vollhardt, K. P. C J. Am. Chem. Soc. 1985,
107, 5670.
(8) Buchwald, S. L.; Lucas, E. A.; Davis, W. M. J. Am. Chem. Soc.
1989, 111, 397.
(9) Friedman, L.; Logullo, F. M. Angew. Chem., Int. Ed. 1965, 4, 239.
(10) Birkett, M. A.; Knight, D. W.; Little, P. B.; Mitchell, M. B.
Tetrahedron 2000, 56, 1013.
~
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ꢀ
Pena, D.;Cobas, A.;Perez, D.; Guitian, E. Org. Lett. 2011, 13, 960. (j)Bi;S
insertion: Chen, J.; Murafuji, T. Organometallics 2011, 30, 4532.
(3) Waldvogel, S. R.; Wehming, K. M. Sci. Synth. 2007, 31a, 235.
(11) Perry, R. J.; Turner, S. R. J. Org. Chem. 1991, 56, 6573.
r
10.1021/ol300439r
2012 American Chemical Society
Published on Web 03/08/2012

interesting to note that an excess of fluoride with re-
spect to iodine is required; otherwise 3a is recovered
unchanged (entry 4).
Scheme 1. Previous Benzyne Insertions into IÀI σ-Bond
The best selectivity for the diiodinated products was
obtained in acetonitrile with a 1/2.5/5 molar ratio of the
reactants 3a, I2, and an anhydrous fluoride source (CsF or
BnMe3NF) (entries 8 and 9), respectively.
Table 1. Optimization of Benzyne Iodination
In recent years, however, many classical aryne reactions
have been revisited using Kobayashi’s method for aryne
generation,12 i.e. the treatment of o-(trimethylsilyl)aryl
triflates with fluoride, and this approach has led to a
general improvement in yields.13 Bearing in mind our long
experience in the use of this method,14 we envisaged that
this approach could be applied to aryne insertions into IÀI
bonds (see Scheme 2).
I2
FÀ
FÀ
ratio
entry
equiv
source
equiv
solvent
2a:4a
1
2
3
4
5
6
7
8
9
1
Bu4NF
1.1
2.2
4.1
4.1
5.0
5.0
5.0
5.0
5.0
THF
75:25
55:45
68:32
NRb
2
Bu4NF
Bu4NF
Bu4NF
Bu4NF
Bu4NF
Bu4NF
CsFd
THF
4
THF
16
2.5
2.5
2.5
2.5
2.5
THF
CH3CN
CH2Cl2
DEEc
CH3CN
CH3CN
76:24
79:21
80:20
100:0
100:0
BnMe3NFd
Scheme 2. New Diiodination Method
a Ratio calculated (GC) at 100% of conversion. b NR: no reaction.
c DEE: 1,2-diethoxyethane. d Anhydrous.
In an optimized procedure for diiodination a solution
of o-(trimethylsilyl)aryl triflate (3a, 1 equiv) and iodine
(2.5 equiv) in acetonitrile is stirred under argon with dry
cesium fluoride (5 equiv) at rt for 16 h. It can be seen from
the results in Table 2 that this protocol was applied to
benzyne as well as substituted and polycyclic arynes. The
reaction of benzyne precursor 3a gave a good yield of
o-diiodobenzene (2a, entry 1, 81%), and this is an improve-
ment on previous results (54À67% yield).9 Significantly,
on using this procedure 4-methyl-1,2-diiodobenzene (2b,
entry 2) was isolated in 76% yield, which represents a
remarkable increase in the yield obtained by diazotiza-
tion of 5-methylanthranilic acid in the presence of iodine
(8%11 or 30%9).
Compounds 2cÀ2h and 2j (entries 3À8 and 10) had not
previously been prepared by aryne insertions into I2 using
the procedures outlined in Scheme 1. On using our proce-
dure these o-diiodoarenes were obtained in good yield.
Furthermore, 2,3-diiodonaphthalene (2i), which had pre-
viously been prepared from the corresponding 3-naphtha-
lenediazonium 2-carboxylate in only 0.5% yield,11 was
obtained in 69% yield from 3i.
We report here the results of an experimental study
of aryne insertion into IÀI σ-bonds and its use for the
synthesis of o-diiodoarenes, which are valuable synthetic
intermediates.
In order to assess the feasibility of the transforma-
tion we tested the reaction between iodine and benzyne,
generated from o-(trimethylsilyl)phenyl triflate (3a),12,15
and several fluoride sources in different solvents. The
results of selected experiments are shown in Table 1. A
key requirement for the success of the insertion is the use
of a dry solvent and an anhydrous fluoride source. The
use of Bu4NF containing variable amounts of water16
led to mixtures of 2a and 4 (entries 1À3 and 5À7). It is
(12) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
(13) (a) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 215. (b) Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701.
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(14) (a) Criado, A.; Pena, D.; Cobas, A.; Guitian, E. Chem.;Eur. J.
ꢀ
~
2010, 16, 9736. (b) Rodrıguez, D.; Pena, D.; Guitian, E. Org. Biomol.
Chem. 2010, 8, 3386. (c) Criado, A.; Gomez-Escalonilla, M. J.; Fierro,
~
J. L. G.; Urbina, A.; Pena, D.; Guitian, E.; Langa, F. Chem. Commun.
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Even tetraiodoarenes can be obtained in one pot by
double insertion processes involving bisaryne precursors
(entries 11À13). 1,2,4,5-Tetraiodobenzene (2k), 2,3,6,7-
tetraiodonaphthalene (2l), and 1,2,5,6-tetraiodonaphtha-
lene (2m) were obtained in 49%, 40%, and 30% yield,
2010, 7028.
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(15) Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis 2002, 1454.
(16) Commercially available Bu4NF solutions in THF (1.0 M) were
used. Although the initial water content of this solution is 5 wt %
(approx.), the level of water could be higher due to the hygroscopic
character of the salt.
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Org. Lett., Vol. 14, No. 6, 2012

The reactivity of iodine is compatible with this mechanism
since it can act as either a nucleophile or an electrophile.
However, most theoretical and experimental studies high-
light the highly electrophilic character for benzyne.18,19
In fact, inter- and intramolecular additions to arynes of a
broad variety of polar species such as water, alcohols,
amines, etc. have been interpreted as nucleophilic addi-
tions to an electrophilic aryne.1 In this context the mecha-
nistic proposal by Hoffmann, in which benzyne acts as a
nucleophile, is controversial.
Table 2. Synthesis of Di- and Tetraiodoarenes 2a
To account for our experimental results we propose a
new mechanism outlinedinScheme 3. First, fluoridewould
react with iodine to generate iodide. Excess fluoride, if
available, would react with 3a to form benzyne (1a).
Nucleophilic attack of iodide to benzyne would afford
carbanion 5, which could be iodinated to 2a. By contrast,
in the presence of a proton source such as H2O, carbanion
5 would lead to iodobenzene (4) through protonation.
Scheme 3. Mechanistic Proposal for the Insertion
In summary, a new procedure for the efficient insertion
of arynes into the IÀI σ-bond has been developed. This
method is applicable to arynes bearing electron-donating
or -withdrawing substituents, to polycyclic arynes, and
even to bisarynes. From the synthetic point of view, this
procedure opens up a short and efficient route for the
synthesis of o-diiodoarenes and related tetraiodoarenes
under mild reaction conditions.
Acknowledgment. Financial support from the Spanish
Ministry of Science and Innovation (MICINN,
CTQ2010-18208, CTQ2010-11423-E), Xunta de Galicia
(10PXIB2200222PR), and FEDER is gratefully acknowl-
edged. D. Rodrıguez-Lojo thanks the MEC for the award
of an FPU fellowship. We thank Dr. Łaczkowski (Faculty
of Pharmacy, Nicolaus Copernicus University, Bydgoszcz,
Poland) for the synthesis of aryne precursor 3m. Dedicated
to Professor Rafael Suau in memoriam.
a Reaction conditions: o-(Trimethylsilyl)aryl triflate (3, 1 equiv), I2
(2.5 equiv), CsF (5 equiv), CH3CN, rt, 16 h. b See Supporting Information
respectively. Isolation problems due to the low solubility of
these compounds led to lower yields.
Supporting Information Available. Experimental de-
tails and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
We also became interested in the mechanism of the
insertion reaction, particularly after the remarkable mech-
anistic proposal by Hoffmann,1 who pointed out that the
insertion reaction begins with the nucleophilic attack of
benzyne (1a) to iodine, to afford a 2-iodophenylcation.17
(18) Rondan, G.; Domelsmith, L. N.; Houk, K. N.; Bowne, A. T.;
Levin, R. H. Tetrahedron 1979, 35, 3237.
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(19) Domingo, L. R.; Perez, P.; Contreras, R. Eur. J. Org. Chem.
2006, 2, 498.
(17) Hoffmann’s mechanistic proposal is based on experimental
results obtained by Friedman, although there is a discrepancy between
the product named by this group and the chemical formula drawn by
Hoffmann. See refs 1 and 9 for details.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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