Radical additions of aryl iodides to arenes are facilitated by oxidative rearomatization with dioxygen

Article abstract of DOI:10.1021/ja066077q

Inter- and intramolecular additions of aryl radicals derived from aryl iodides to arenes are promoted by tris(trimethylsilyl)silane and occur under exceptionally mild conditions (15-30 min at 25 °C) in nondegassed benzene. A chain mechanism involving reaction of the intermediate cyclohexadienyl radical with oxygen to directly generate the aromatized product and the hydroperoxy radical is proposed. Copyright

Full text of DOI:10.1021/ja066077q

Published on Web 10/04/2006
Radical Additions of Aryl Iodides to Arenes Are Facilitated by Oxidative
Rearomatization with Dioxygen
Dennis P. Curran* and Adam I. Keller
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received August 21, 2006; E-mail: curran@pitt.edu
Table 1. Yields of Addition of Methyl p-iodobenzoate to Benzene
A diverse assortment of useful synthetic transformations are
based on inter- and intramolecular additions of radicals to aromatic
rings.1 Such reactions are often conducted under reducing conditions
with reagents such as tributyltin hydride and tris(trimethylsilyl)-
silicon hydride,2 even though the reactions are not reductions and
often finish with oxidative rearomatization.3,4 Typically, nonchain
mechanisms are proposed for these formal homolytic aromatic
substitution reactions, and suggestions for rearomatization pathways
include reaction of an intermediate cyclohexadienyl or related
radical with solvent, with initiator, with other radicals, or with itself,
among other possibilities.5
Bu3SnH or
Ar-X + Ar2-H
8 Ar1-Ar2
(TMS)3SiH, AlBN
Homolytic aromatic substitutions often require high temperatures
and long reactions times and typically occur in moderate yields,
perhaps because of the relative stability of cyclohexadienyl radical
intermediates. We hypothesized that cyclohexadienyl radicals could
be intercepted by using even more stable radicals, taking advantage
of the “persistent radical effect”.6,7 We report herein the discovery
that radical additions of aryl iodides to arenes can be effected under
exceptionally mild conditions and in high yields in the presence of
air. We suggest that the selective interception of cyclohexadienyl
radicals by dioxygen, a stable triplet diradical, is a key step in this
process.
Table 2. Intermolecular Additions of Aryl Iodides to Arenesa,b
We initially selected stable nitroxide radicals such as TEMPO
to intercept the intermediate cyclohexadienyl radicals.7 The iden-
tification of the air-mediated reaction conditions stemmed from
control experiments for the TEMPO-mediated process. Results from
several key exploratory reactions are summarized in Table 1. Under
conditions typical of those used currently,1,2 the addition of methyl
p-iodobenzoate 1 to benzene at reflux was promoted ineffectively
by tributyltin hydride and a stoichiometric quantity of AIBN (entry
1). Biphenyl-4-carboxylic acid methyl ester 2 was formed in 27%
yield along with methyl benzoate 3 in 9% yield. Consistent with
the results of Alvarez-Builla,2a a better but still moderate yield of
2 (67%) was obtained with tris(trimethylsilyl)silane (1 equiv) and
AIBN (1 equiv) (entry 3). The addition of TEMPO improved both
reactions, providing 2 in 68% yield in the tin hydride reaction (entry
2) and in 90% yield in the tris(trimethylsilyl)silane reaction
(entry 4).
To our surprise, a routine control reaction under argon but in
nondegassed benzene in the absence of both AIBN and TEMPO
worked beautifully, providing 2 in 87% yield (entry 5). Further,
TLC analysis showed the reaction was complete in only 3 h at
room temperature. We initially had difficulty reproducing this
control experiment, but soon discovered that reliable results were
obtained on small scale only when nondegassed benzene was used.
On larger scale, it was helpful to actually expose the reaction
mixture to air. Attempted reactions under degassed conditions
resulted in little or no conversion of 1. Tributyltin hydride was not
an effective substitute for tris(trimethylsilyl) silane in this ambient
temperature, air-mediated process. These results showed that neither
AIBN, nor TEMPO, nor high temperatures were essential for a
high-yielding reaction.
For preparative reactions (Table 2), tris(trimethylsilyl)silane (1.2
equiv) and pyridine (5 equiv, to neutralize HI) were added to a
nondegassed benzene solution of the aryl iodide 1a-f (1 equiv,
0.004 M). The reaction mixture was stirred in an open flask and,
if rapid precipitation of pyridine hydroiodide was not observed,
then a small amount of iodine (0.02 equiv) was added.
As soon as the aryl iodide was consumed (TLC analysis), the
mixture was filtered, the solvent was removed, and the crude
product was directly subjected to flash chromatography to provide
the target biaryls 2a-f. Reactions were rapid (15-30 min) and
clean and isolated yields of biaryl adducts 2a-f were uniformly
high (75-90%).
Although these conditions are much milder and the yields are
higher than typical bimolecular additions of aryl radicals to arenes,
standard limitations presumably apply: the arene acceptor must
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10.1021/ja066077q CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Intramolecular Additions to Arenes
provides the aromatized product 2 and the hydroperoxy radical. In
turn, HOO• can abstract hydrogen from the silane to transfer the
chain.14 The so-formed hydrogen peroxide may be capable of
oxidizing another cyclohexadienyl radical 12.15
These results have important implications for both synthetic and
mechanistic radical chemistry. First, the mild reaction conditions
may be generally applicable to a diverse range of inter- and
intramolecular additions of aryl and alkenyl radicals to arenes and
heteroarenes. Though such transformations are commonly used, they
can often be stubbornly slow and low yielding. Second, the role of
oxygen and its unique reaction path with cyclohexadienyl radicals
have not been appreciated in these types of formal homolytic
aromatic substitution reactions. Such reactions are often conducted
with degassing to prevent premature interception of intermediate
radicals by O2. However, in cases where radical generation and
addition are fast enough, oxygen is actually likely to promote the
target reaction by providing a rapid and productive path for
aromatization of the intermediate cyclohexadienyl radical. Further
work will be needed to confirm the proposed path, and such work
could ultimately open the door to a general new approach to formal
homolytic aromatic substitution.
Scheme 2. Proposed Mechanism for Homolytic Aromatic
Substitution Mediated by TTMSS/O2
Acknowledgment. We thank the National Science Foundation
for funding this work.
Supporting Information Available: Full details of experiments
and characterization. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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(2) Representative recent examples: (a) Nunez, A.; Sanchez, A.; Burgos, C.;
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be used in large excess and regioselectivity is low for substituted
benzenoid acceptors (see Supporting Information).
These limitations should be overcome in the intramolecular
variant, and several early examples are shown in Scheme 1. The
cyclization reactions were conducted under the standard conditions
in benzene with iodine (0.02 equiv) as initiator. Reactions of 4 and
6a provided exclusively the corresponding cyclized products 5
(62%) and 7a (89%), while the reaction of 6b provided a major
cyclized product 7b (60%) alongside a minor benzene adduct 8b
(20%). Alkenyl iodide precursor 9 was selected to probe whether
alkenyl radical additions to benzene were possible, but we learned
instead that 1,6-cyclization to the phenyl ring of the tert-butyl-
diphenylsilyl group was preferred; 10 was isolated as a single
E-isomer in 64% yield. This transformation could form the basis
of a generally useful intramolecular aryl transfer reaction.8
A mechanistic pathway for the oxygen-promoted, bimolecular
radical addition to benzene is suggested in Scheme 2. Abstraction
of iodine from the aryl iodide 1 by tris(trimethylsilyl)silyl radical
provides aryl radical 11 (step 1),9 which in turn adds to benzene to
provide cyclohexadienyl radical 12 (step 2).10 Oxygen reacts rapidly
with both tris(trimethylsilyl)silyl11 and aryl radicals (k ≈ 109 M-1
s-1), but these side reactions will not compete with the proposed
reactions if the concentration of oxygen in the solution is sufficiently
low.12 The relatively stable cyclohexadienyl radical 12 will not react
with the silane to propagate a chain; however, it will react very
rapidly with triplet oxygen (step 3).13
(4) For reductive additions catalyzed by benzeneselenol, see: (a) Crich, D.;
Patel, M. Org. Lett. 2005, 7, 3625-3628 and references therein.
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by hydroperoxy radicals formed in situ by autoxidation has been
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70, 9077-9080.
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(9) (TMS)3Si• typically abstracts halogen atoms from halides with a rate
constant similar to Bu3Sn•. In turn, Bu3Sn• abstracts iodine from aryl
iodides with rate constants ∼109 M-1 s-1 at 80 °C. See (a) Chatgilialoglu,
C. Chem. ReV. 1995, 95, 1229-1251. (b) Curran, D. P.; Jasperse, C. P.;
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1992, 57, 2207-2208.
(12) Analogously, under suitable conditions, oxygen does not inhibit the tin
hydride reduction of alkyl iodides, but instead participates in a chain
oxygenation reaction. Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D.
J. Am. Chem. Soc. 1991, 113, 8980-8982.
(13) a) Hendry, D. G.; Schuetzle, D. J. Am. Chem. Soc. 1975, 97, 7123-
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Z. B., Ed.; Wiley: Chichester, U.K. 1997; p 283-334.
(14) The rate constant for the reaction of cumylperoxy radical with (TMS)3SiH
is only 66 M-1 s-1 at 25 °C: Chatgilialoglu, C.; Timokhin, V. I.;
Zaborovskiy, A. B.; Lutsyk, D. S.; Prystansky, R. E. Chem. Commun.
1999, 405-406. However, tertiary peroxy radicals can be considerably
less reactive than the hydroperoxy radical. See ref 13.
The reaction of the parent cyclohexadienyl radical with oxygen
is believed to occur not by the usual addition pathway to form a
cyclohexadienylperoxy radical but instead by hydrogen transfer to
produce benzene and the hydroperoxy radical (HOO•).13 Accord-
ingly, we propose that the reaction of 12 with oxygen directly
(15) We also checked for oxidation of benzene; no phenol was detected (GC).
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