Regioselective hypervalent-iodine(III)-mediated dearomatizing phenylation of phenols through direct ligand coupling

Article abstract of DOI:10.1002/anie.200501638

(Chemical Equation Presented) Dearomatization: Treatment of phenols and naphthols substituted at the ortho position by a small electron-donating group D with chlorodiphenyl-λ³-iodane leads to their regioselective ortho phenylation to give cyclohexa-2,4-dienone derivatives (see scheme). The mechanism of this reaction involves a nonradical direct coupling of the ligands.

Full text of DOI:10.1002/anie.200501638

Angewandte
Chemie
Regioselective Reactions
DOI: 10.1002/anie.200501638
Regioselective Hypervalent-Iodine(iii)-Mediated
Dearomatizing Phenylation of Phenols through
Direct Ligand Coupling**
AurØlie Ozanne-Beaudenon and StØphane Quideau*
Dearomatization of phenols often constitutes an ultimate key
transformation in the biogenesis of many natural products
and a powerful strategy for the rapid construction of highly
[*] A. Ozanne-Beaudenon, Dr. S. Quideau
Institut EuropØen de Chimie et Biologie
2
rue Robert Escarpit, 33607 Pessac Cedex (France)
Fax: (+33)540-00-22-15
E-mail: s.quideau@iecb.u-bordeaux.fr
and
Laboratoire de Chimie Organique et OrganomØtallique (CNRS
UMR5802), Centre de Recherche en Chimie MolØculaire
UniversitØ Bordeaux 1
351 Coursde la LibØration, 33405 Talence Cedex (France).
[
**] We gratefully acknowledge Simafex and the Association Nationale
de la Recherche Technique (CIFRE Grant N8301/2002) for their
financial support and AurØlie Ozanne-Beaudenon’s graduate
research assistantship.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author. It includes
detailed descriptions of experimental procedures, characterization
1
13
data, and H and C NMR spectra of all compounds.
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functionalized intermediates in the elaboration of complex
(Ph ICl) in dimethylformamide (DMF) in the presence of
potassium tert-butoxide (tBuOK, 1.1 equiv) for 20 h at room
temperature. Only the diaryl ether 2a was isolated with a
2
[
1]
organic molecules. One class of chemical reagents that is
continuously finding new applications in this area of synthetic
3
5
organic chemistry is composed of hypervalent l -and l -
yield of 53%, but no formation of the desired cyclohexa-2,4-
[
2]
[10]
iodanes. Herein we report a new phenol dearomatization
dienone 3a was observed (Table 1, entry 1).
The first
3
process that involves the use diaryl l -iodanes (i.e., Ar IL, L =
glimpse of success was obtained by changing the reaction
solvent to a protic solvent with a low dielectric constant (i.e.,
2
[
3]
Cl, BF , OTs) to promote regioselective ortho phenylation
to give 6-phenylcyclohexa-2,4-dienones. Diaryl-l -iodane
4
3
[11]
tBuOH), whereupon 3a was isolated with a yield of 8%
reagents have previously been used with success to give a-
(Table 1, entry 1). It is worth noting that no diaryl product,
which could have resulted from introduction of the phenyl
group at the unsubstituted C6 position of the starting phenol
1a, was observed. A small and weakly electron-donating
substituent such as a methyl group at an ortho position thus
appears sufficient to direct delivery of the phenyl unit to that
substituted position. In accordance with this first observation,
only diaryl ether products were obtained in good yields when
starting from phenol (1b) or from the meta-substituted
phenol, 3,5-dimethylphenol (1c; Table 1, entries 2 and 3).
Moreover, the symmetrically ortho-substituted 2,6-di- and
2,4,6-trimethylphenols, 1d and 1e, gave rise to the formation
of the desired cyclohexa-2,4-dienones, 3d and 3e, in 37% and
42% yields, respectively (Table 1, entries 4 and 5). Interest-
ingly, the para-methylated phenol 1e also afforded 4-phenyl-
cyclohexa-2,5-dienone (4e) in 7% yield. Biasing the system
with sterically demanding alkyl groups at the two ortho
positions should lead to a quasi-exclusive phenylation at the
para-alkylated position. This was indeed the case with 4-
methyl-2,6-di-tert-butylphenol (1 f), the use of which only
furnished 4-methyl-4-phenylcyclohexa-2,5-dienone (4 f) in an
excellent yield of 94% (Table 1, entry 6). Further evidence of
the role played by the methyl group in mediating transfer of a
arylated ketones, esters, silyl enol ethers, and various 1,3-
[
3–5]
dicarbonyl compounds,
but the only products that were
obtained when phenolic substrates were used under basic
[
6]
conditions were derived from an O-arylation process. The
reaction conditions unveiled herein permit us to direct the
entry of an aryl group to a substituted position on the starting
phenol and offer an alternative to stoichiometric processes
that involve the use of toxic aryl–lead or aryl–bismuth
[
7,8]
reagents
and an alternative to transition-metal-catalyzed
[
9]
processes that only furnish diaryl products.
We selected 2,3,5-trimethylphenol (1a, see Table 1) as a
first model substrate to search for appropriate C-phenylation
3
conditions and treated it with chlorodiphenyl-l -iodane
3
[a]
Table 1: Phenylation of phenolsmediated by chorodiphenyl- l -iodane.
[
b]
Yield [%]
Entry
1
Substrate
O-phenylation
o-C-phenylation p-C-phenylation
[
c]
[c]
1
a
2a (53), (63)
3a (0), (8)
–
phenyl group from Ph ICl was then obtained by performing
2
the same reaction with 2,6-di-tert-butylphenol (1g; not
shown), in which case no phenylation product was isolated.
Having thus established the prominent role that is played
2
3
1b: R=H
1c: R=Me
2b (75)
2c (59)
–
–
–
–
3
by alkyl substituents in the regiocontrol of this l -iodane-
mediated phenylation of phenols, we turned our attention to a
series of 1-naphthols, each bearing an electronically different
4
ortho substituent. Experiments carried out with Ph ICl on 2-
2
methyl-( 1i), 2-methoxy- (1j), and 2-nitrosonaphthol (1k)
revealed a somewhat different reactivity from that of the
phenols as no diaryl ether was observed. Nevertheless, the
expected dearomatization products, 3i, 3j, or 3k, were
isolated as the sole products in increasing yields ranging
from 36 to 74% (Table 2, entries 1–3). Naphthols, as well as
phenols, that bear an electron-demanding ortho substituent
such as 2-carboxymethoxynaphthol (1l), 2-nitronaphthol
[
d]
[c]
1
1
1
d
e
f
2d (24), (35)
3d (37), (44)
–
5
[
e]
[e,f]
[e,f]
2e (7), (63)
3e (42)
4e (7)
(1m; see Scheme 2), 2-hydroxynaphthaldehyde, and 4-nitro-
phenol (1n, 1h; not shown) were all found to be refractory
substrates at room temperature (see below). Only the ester 1l
gave rise to the formation of the diaryl ether 2l and the
desired dearomatized phenylation product 3l, albeit in low
yields (Table 2, entry 4).
6
–
–
4 f (94)
3
[
a] Reactionswere carried out by adding chlorodiphenyl- l -iodane (1.3 mmol)
to a stirred solution of the starting phenol in tBuOH (4 mL) in the presence of
tBuOK (1.4 mmol) at room temperature. [b] Yield of isolated product. [c] This
reaction wascarried out with DMF. [d] Thisreaction wascarried out in
tetrafluoroboro)diphenyl-l -iodane. [e] Similar results were obtained in the
In contrast to the unsubstituted 1-naphthol (1o; not
shown) that led to a complex product mixture, the unsub-
3
stituted 2-naphthol (1p) was reactive towards Ph ICl and
2
(
underwent both O-and Cp-henylation to furnish three
products: the diaryl ether 2p (9%), 1-phenyl-2-naphthol
(3p, 18%), and the diaryl ether 4p (22%) through trans-
presence of 1,1’-diphenylethylene (2 equiv). [f] Products 3e and 4e could not
be cleanly separated by column chromatography on silica gel, so yields were
1
evaluated by H NMR spectroscopic analysis of the mixture.
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Chemie
3
Table 2: Phenylation of naphtholsmediated by chorodiphenyl- l -ioda-
[
a]
ne.
[
b]
Yield [%]
O-phenylation
Entry
Substrate
o-C-phenylation
1
2
3
1i, R=Me
1j, R=OMe
1k, R=NO
–
–
–
3i (36)
3j (52)
3k (74)
[
c]
[
c]
4
5
1l
2l (21)
2p (9)
3l (7)
1p
3p: R=H (18)
p: R=Ph (22)
Scheme 1. Mechanistic description of the phenol phenylation reactions through
direct ligand coupling. A, B, and C: 10-I-3 trigonal-bipyramidal intermediates; A’,
B’, and C’: tetragonal-pyramidal intermediates. R , R : various substituents.
4
3
[a] Reactionswere carried out by adding chlorodiphenyl- l -iodane
2
4
(
(
1.3 mmol) to a stirred solution of the starting phenol in tBuOH
4 mL) in the presence of tBuOK (1.4 mmol) at room temperature.
[
b] Yields of isolated products. [c] Similar results were obtained in the
iii
presence of 1,1’-diphenylethylene (2 equiv).
onal bipyramidal entities, as expected for hypervalent I
[
3]
species. To find evidence for one or the other mechanistic
alternative, we revisited some of the reactions we had
performed with the aim of characterizing any stable reaction
intermediates. This was accomplished by isolating an inter-
mediate from the reaction performed at room temperature
with the apparently refractory substrate, 2-nitronaphthol
(1m, see above). This intermediate was characterized as the
ferring a second phenyl unit to 3p (Table 2, entry 5). The C-
phenylation course is thus globally favored over the O-
phenylation alternative for this unsubstituted 2-naphthol
[
11]
treated under basic conditions in a protic solvent.
It is
interesting to note that 2-naphthol (1p) was also the only
phenol among those we used to furnish a diaryl product
through phenylation at its unsubstituted C1 center. This is
probably due to the more pronounced ambident character of
the delocalized 2-naphthoxide anion relative to that of
3
type-A (2-nitronaphthoxy)diphenyl-l -iodane, 5 (see Sup-
porting Information and Scheme 2). In contrast to reactions
[
11]
unsubstituted phenoxide anions
and to the aromaticity
retained when this anion engages itself in bond formation at
C1, but not at C3.
We next wondered about the mechanism that is operative
in these phenylation reactions of phenols and naphthols as
they constitute a novel aspect of hypervalent iodine chemis-
try. The first experimental observations of mechanistic
relevance were that iodobenzene was formed as a by-product
and that no reaction took place in the absence of a base strong
enough to deprotonate the starting phenol. The delocalized
phenolate nucleophile can then attack the iodine(iii) center of
Scheme 2. Evidence of ligand exchange: isolation of type-A intermedi-
ate 5 and itsheat-induced conver si on into the diaryl ether 2m.
Ph ICl in a ligand-exchange step, thus displacing the chloride
2
3
anion ligand to furnish (aryloxy)diphenyl-l -iodanes of type
A (Scheme 1, path a) and/or their C-iodanylated cyclohexa-
dienone variants of types B and C (Scheme 1 paths b and c)
depending upon the electronic and steric demands of the
substituents on the starting phenol.
carried out with phenols bearing electron-releasing ortho
substituents, this intermediate does not further evolve at
room temperature but gives the starting naphthol 1m upon
chromatography on silica gel. However, compound 5 fur-
nishes the O-phenylated product 2m in 70% yield when
heated to reflux in tBuOH for 8 h (Scheme 2).
Alternatively, the phenolate anion could engage itself in
an aromatic nucleophilic-substitution reaction (i.e., S Ar)
N
and directly attack Ph ICl at one of its two phenyl carbon
These observations are in agreement with an initial
2
atoms bonded to the iodine(iii) center. This S Ar mechanistic
ligand-exchange step, but not with a direct S Ar-type
N
N
path is generally proposed to rationalize the reactivity of
mechanism. Furthermore, the isolation of the 10-I-3 species
5 is particularly revealing of the mechanistic path followed in
this process as the presence of a strongly electron-withdraw-
ing ortho substituent on the starting phenol is usually
[
12]
species such as Ph ICl towards nucleophiles.
It must be
2
recalled that these species are not tetrahedral diaryliodonium
salts, as commonly thought, but 10-I-3 T-shaped pseudotrig-
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associated with the stabilization of S Ar Meisenheimer-type
intermediates.
these centers larger in comparison to those at the unsubsti-
tuted ortho position in 1a and at the unsubstituted para
position in 1d and 1g, respectively. The dearomatizing C-
phenylation path of the reaction would thus seem to be
essentially under this orbital control. The results obtained
with naphthols 1i–l are in agreement with this substituent-
controlled modulation of reactivity, since the more electron-
releasing the substitutent at C2, the better is the yield of the
dearomatizing ortho-phenylation reaction (Table 2, entries 1–
3).
N
[
12,13]
Hence, the phenylation products observed with concom-
itant reductive elimination of iodobenzene can, in principle,
3
result either from collapse of the l -iodanyl intermediate into
a phenyl and a phenoxy radical, which would then pair off, or
from a concerted ligand coupling on the iodine(iii) center
[
4,13]
itself.
trapping agent, 1,1-diphenylethylene (DPE)
to the reaction medium during the phenylation of 1e, 1j, and
k (Table 1, entry 5 and Table 2, entries 2 and 3). The
To address this question, the efficient phenyl radical
[
5g,8d,8e]
was added
1
In conclusion, the work described herein presents a novel
aspect of the versatility of hypervalent iodine(iii) reagents in
presence of DPE did not affect the outcome of the reaction,
thus showing that no radical-based intermediate plays any
determinant role in the process. These observations are in
agreement with the proposal of an exclusive nonradical
ligand-coupling mechanism. Thus, the 10-I-3 intermediates of
types A, B, and C may evolve through coupling of their
phenolate-derived ligand with one of the phenyl groups.
Ligand coupling is symmetry-forbidden on these trigonal-
bipyramidal structures, but bond-forming events can occur
from tetragonal-pyramidal transient species of types A’, B’,
and C’ during ligand pseudorotation around the iodine(iii)
organic synthesis, which is illustrated by the use of the diaryl-
3
l -iodane Ph ICl to promote regioselective C-phenylation of
2
ortho-and/or para-substituted phenols to give cyclohexadie-
none derivatives under basic conditions. The presence of a
small electron-donating substituent at the ortho and/or para
positions of the starting phenol determines the efficacy and
regioselectivity of the process, which involves a nonradical
coupling of the phenolate-derived and phenyl ligands directly
around the iodine(iii) center. Evidence of such a direct ligand-
coupling mechanism is also given for the competitive O-
phenylation process, which is commonly thought to follow an
intermolecular aromatic nucleophilic-substitution reaction
path.
[
3,12,13]
center (Scheme 1).
Formation of diaryl ethers of type 2 would then result
from intermediates of type A’ through a nonsynchronous
ipso–ipso coupling (path d) with a polar transition state as a
consequence of the difference of polarity between the two
Received: May 12, 2005
Revised: July 13, 2005
Published online: October 6, 2005
[
13]
ligands (i.e., LC -type coupling). The formation of cyclo-
N
hexa-2,4-dienone products of type 3 could either also arise
from intermediates of type A’ through an ipso–allyl LC -type
N’
Keywords: aromaticity · hypervalent compounds· iodine ·
reaction mechanisms · regioselectivity
coupling (path e) or from B’ through a quasi-synchronous
.
[
13]
ipso–ipso LC-type coupling (path f). The fact that Ph ICl
2
was also capable of transferring one of its phenyl ligands to
the para position of 2,4,6-trimethylphenol (1e) and 4-methyl-
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