Oxidative dearomatization of phenols and anilines via λ3 - and λ5-iodane-mediated phenylation and oxygenation

Article abstract of DOI:10.3390/10010201

Treatment of 2-methylphenols with chloro(diphenyl)-λ³- iodane led to their regioselective dearomatizing 2-phenylation into cyclohexa-2,4-dienone derivatives via a proposed ligand coupling reaction. In the same vein of investigation, treatment of 2-methylanilines with the λ⁵-iodane 2-iodoxybenzoic acid IBX reagent led to their regioselective dearomatization into previously undescribed ortho-quinol imines.

Full text of DOI:10.3390/10010201

Molecules 2005, 10, 201–216
molecules
ISSN 1420-3049
http://www.mdpi.org
Oxidative Dearomatization of Phenols and Anilines via λ3- and
λ5-Iodane-Mediated Phenylation and Oxygenation
Stéphane Quideau,* Laurent Pouységu, Aurélie Ozanne and Julien Gagnepain
Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, F-33607 Pessac Cedex, and
Laboratoire de Chimie des Substances Végétales, Centre de Recherche en Chimie Moléculaire,
Université Bordeaux 1, 351 cours de la Libération, F-33405 Talence Cedex. France. Tel. (+33) (0)
540003010, Fax (+33) (0) 540002215
* Author to whom correspondence should be addressed; e-mail s.quideau@iecb.u-bordeaux.fr
Received: 28 May 2004 / Accepted: 25 July 2004 / Published: 31 January 2005
Abstract. Treatment of 2-methylphenols with chloro(diphenyl)-λ3-iodane led to their
regioselective dearomatizing 2-phenylation into cyclohexa-2,4-dienone derivatives via a
proposed ligand coupling reaction. In the same vein of investigation, treatment of
2-methylanilines with the λ5-iodane 2-iodoxybenzoic acid IBX reagent led to their
regioselective dearomatization into previously undescribed ortho-quinol imines.
Keywords: Iodanes, phenols, anilines, dearomatization, cyclohexadienones, orthoquinol
imines.
Introduction
Arene dearomatization is a powerful tactic for the construction of complex organic molecules [1-3].
Our research efforts in this arena of synthetic organic chemistry rely in part on the use of λ3- and λ5-
iodanes, i.e., hypervalent iodine(III) and iodine(V) compounds (Scheme 1) [4-10]. For example, the
λ3-iodane of type ArIL2 (L = heteroatomic ligand) (diacetoxy)iodobenzene (DIB) enables high-
yielding conversion of 2-alkoxy and 2-alkylphenols into cyclohexa-2,4-dienone synthons that can then
be utilized into various heterocyclization processes [7-9,11]. The [bis(trifluoroacetoxy)]iodobenzene
(BTI) reagent can be used similarly to mediate regioselective carbon-carbon bond formation at
substituted centers on naphthols [8,10]. The λ5-iodane of the general type ArIL4 2-iodoxybenzoic acid
(IBX), or its stabilized version SIBX [4], can be used both as an oxidant and as a source of oxygen for
ortho-selective hydroxylation of 2-substituted arenols into orthoquinols [4,5,12]. We here wish to

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describe preliminary results from two other incursions into the realm of iodane chemistry. The first
one concerns the first example of the utilization of λ3-iodanes of type Ar2IL to mediate dearomatizing
phenylation of methylphenols, and the second incursion has to do with experimental observations
made during IBX-mediated oxidative dearomatization of anilines.
Scheme 1.
reductive elimination
with substitution
ligand exchange
L
Ar
L
Ar
I
ArIL2
I
HX
X
X
L
R
R
R
Y
Y
Z
Z
Z
- LH
- ArI, -L
1a
2a
3
L = heteroatomic ligand
R = alkyl or alkoxy group
X = O or NH
Y = O- and C-based nucleophiles, including L
Z = various substituents
Ar
Ar
I
L
L
L
X
I
L
L
L
L
ArIL4
HX
R
R
Z
Z
- LH
- ArIL2
1a
2b
Results and Discussion
Our previous investigation on carbon-carbon (C–C) bond-forming and dearomatizing reaction of 2-
substituted arenols was accomplished by a process that was apparently intermolecular and oxidatively
initiated by BTI in the presence of either an allylsilane or a silyl enol ether [8,10]. Intramolecular
variants of such a transformation are known and the most effective ones rely on the use of either a
lead(IV) [13,14] or a bismuth(V) [15,16] species bearing heteroatomic and aryl ligands. The starting 2-
substituted arenol first reacts with the aforementioned metallic species to exchange one of its labile
heteroatomic ligands. Once the aryloxy unit of the substrate is mounted onto the metallic center, a
reductive elimination step can take place with a concomitant C–C ligand coupling directed at the 2-
substituted position of the aryloxy unit to generate a cyclohexa-2,4-dienone product. Ligand coupling
is also possible on an hypervalent iodine(III) center [17,18], and it has been proposed that diaryl-λ3-
iodanes (i.e., Ar2IL)† do transfer, through this mechanistic path, an aryl group to enolates to furnish α-
C-arylated carbonyl compounds [17,19-21].
†Ar2IL-type compounds are usually referred to as diaryliodonium salts despite the fact that their geometry is not
tetrahedral, but pseudotrigonal bipyramidal, as expected for hypervalent iodine(III) species. The lamba iodane
terminology is thus used here to name hypervalent iodine compounds [17].

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Scheme 2.
O
Ar
Ar
C-C
I
coupling
b
- L
3 (X = O, Y = Ar)
Z
R
- ArI
2d
reductive elimination
with ligand coupling
ligand exchange
a
L
I
Ar
Ar
Ar2IL
I
b
C-O
M
O
O
OAr
Ar
coupling
Ar
a
- L
R
R
R
R
- ArI
Z
Z
Z
M = R3NH, K, Na, Li
L = BF4, Cl
4
1b
2c
Ar = Ph
HO
O
C-C
Ar
Ar
Ar
I
coupling
c
R
H
- ArI
- L
Z
Z
5
2e
Phenolates being aromatic variants of generic enolates, we thus contemplated the idea of achieving
phenol dearomatization leading to 6-arylcyclohexa-2,4-dienone derivatives of type 3 using diaryl-λ3-
iodane species (Scheme 2). The desired ligand coupling reaction could imply either passage through an
aryloxy-λ3-iodane intermediate of type 2c (i.e., ligand exchange path a), which would then tautomerize
into a 6-λ3-iodanyl ketone of type 2d, or direct formation of 2d via participation of the 2-methylated
carbanionic form of the starting phenolate 1b (i.e., ligand exchange path b). In any event and to the
best of our knowledge, such an iodane-mediated reaction has never been described.
We commenced our investigation of this dearomatizing arylation process by identifying the most
appropriate reaction conditions to promote C–C ligand coupling (i.e., via 2d), while minimizing the C–
O ligand coupling alternative (i.e., via 2c) that leads to diaryl ethers of type 4 (Scheme 2). This
preliminary examination was carried out using 2,3,5-trimethylphenol (1a) with the aim of directing the
introduction of a phenyl group at its substituted 2-position to enable the desired dearomatization into
the cyclohexa-2,4-dienone 3a. The presence of a methyl group at the 3-position of 1a was chosen in
order to block [4+2] dimerization of 3a [5]. Indeed, the presence of such a small electron-releasing
group at the corresponding 5-position of cyclohexa-2,4-dienones is known to block their dimerization
[22,23]. Treatment of 1a with tetrafluoroboro(diphenyl)-λ3-iodane [24] in DMF at room temperature
using weak bases such as pyridine or triethylamine failed to initiate any reaction (Table 1, entries 1
and 2). The use of a strong alkoxide base [20,25,26] was necessary to engage the reaction, but the only
observed product was the diaryl ether 4a, which was isolated in a moderate yield of 41% (entry 3)
[27,28]. Change of the diphenyl-λ3-iodane reagent to chloro(diphenyl)-λ3-iodane led to some
improvement in the yield of 4a, but no formation of the desired dearomatized product 3a was observed
(entry 4).

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Table 1. Preliminary search of reaction conditions to promote
dearomatizing 2-phenylation of a 2-substituted phenol
Ph
OH
O
O
Ph
2
2
base
3
5
5
Ph2IL (1.1 equiv)
1a
3a
4a
entry
L
solvent
base
temp ( C) 3a (%)a 4a (%)a
BF4
BF4
BF4
1
2
3
4
5
6
7
8c
pyridine
Et3N
rt
rt
0
0
0
0
6
8
6
6
0
DMF
DMF
0
rt
41
53
33
63
56
51
DMF
KOt-Bu
KOt-Bu
KOt-Bu
rt
Cl
DMF
BF4
t-BuOH
t-BuOH
rt
KOt-Bub
Cl
Cl
Cl
rt
t-BuOH/THF KOt-Bu
- 20
Š
t-BuOH
rt
a Isolated yields. b Same result using LiOt-Bu. c Using the sodium
phenoxide prepared beforehand by treating 1a with NaOH (1.0 equiv)
in methanol.
The first glimpse of success was obtained by performing the reaction in a polar protic solvent (i.e.,
t-BuOH) at room temperature, in which case 3a was isolated in 6% or 8% using either a
tetrafluoroborate unit or a chloride atom as the ligand L on the iodine(III) of the reagent. In both cases,
the major product was again the diaryl ether 4a (entries 5 and 6). It is worth noting that no biaryl
product of type 5, which could have resulted from introduction of a phenyl residue at the unsubstituted
6-position of the starting phenol 1a via an α-λ3-iodanyl ketone of type 2e (Scheme 2), was observed. It
thus appears that a small alkyl group, such as a methyl group, at one phenoxy ortho-position plays a
role in directing delivery of a phenyl residue at that substituted position and not at the unsubstituted
position (vide infra). This observation is in agreement with a route via an α-λ3-iodanyl ketone
intermediate of type 2d (Scheme 2). Neither performing the reaction at –20 °C (entry 7) nor using a
smaller counter-cation such as Na+ or Li+ (entries 6b and 8c) to promote a change of chemoselectivity
in favor of C–C coupling resulted in any improvement of the yield of 3a. So, the use of
chloro(diphenyl)-λ3-iodane in the presence of potassium tert-butoxide in tert-butanol at room
temperature so far emerged as the best conditions to achieve the desired transformation, albeit in low
yields.
We then carried out a series of reactions under these conditions using three differently substituted
phenols 1b-d (Table 2). The unsubstituted phenol 1b led exclusively to the formation of the diaryl
ether 4b in a good yield of 75%. This observation corroborates that made with phenol 1a on the role of
a small alkyl substituent at one phenoxy ortho-position (vide supra) not only in directing the
introduction of the phenyl residue at that carbon position, but also in promoting C-phenylation. Hence,
starting from phenols bearing the same alkyl substituent at each of two equivalent ortho-positions
should significantly boost yields of C-phenylation over O-phenylation.

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Table 2. Chloro(diphenyl)-λ3-iodane-mediated phenylation of phenols
entry
phenola
product(s): isolated yield (%)
Ph
O
OH
1
1b
4b: 75%
Ph
OH
O
O
Ph
2
3
1c
4c: 24%
3c: 37%
Ph
O
OH
O
O
Ph
Ph
6d: 7%
1d
4d: 7%
3d: 42%
a Reactions were carried out at room temperature using Ph2ICl (1.1 equiv)
and KOt-Bu (1.05 equiv) in t-BuOH.
This hypothesis was confirmed using the di- and trimethylphenols 1c and 1d, which gave rise to the
formation of the desired cyclohexa-2,4-dienones 3c and 3d in 37% and 42%, respectively (Table 2,
entries 2 and 3). Moreover, these cyclohexa-2,4-dienones are stable compounds that do not
spontaneously engage in [4+2] dimerization, despite the absence of an alkyl substituent at their 5-
position [22,23]. Interestingly, 2,4,6-trimethylphenol (1d) also led to phenylation at the methylated 4-
position (entry 3). Although the yield of the corresponding product 6d was only 7%, its formation is in
accordance with a ligand coupling event from a γ-λ3-iodanyl ketone of type 2f that would be formed
from a direct ligand exchange between the 4-methylated carbanionic form of the starting phenolate 1d
and the chloro(diphenyl)-λ3-iodane reagent (Scheme 3). Further mechanistic investigations need to be
performed to confirm that the observed products are generated through ligand coupling, but the
reactions described here are the first examples of iodane-mediated dearomatizing phenylation of
substituted phenols.
Scheme 3.
K
O
O
C-C
Cl
I
coupling
6d
Ph
- KCl
- PhI
Ph
Ph
1d
2f
I
Ph
We then turned our attention to another iodane-mediated dearomatization reaction involving the
oxygenation of anilines and anilides with the aim of preparing ortho-quinol imines. Quinonoid

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compounds are powerful intermediates for organic synthesis, and those bearing a nitrogen
functionality obviously expand their versatility as potential precursors and building blocks for the
synthesis of biologically relevant natural and non-natural substances [29]. Among those, quinonoid
imines such as quinone imines, quinone imine ketals and quinol imines occupy a valuable position as
potentially useful synthons, but their imine function is unfortunately very sensitive to hydrolysis,
unless the imine nitrogen is substituted by an acyl or a sulphonyl group [30,31] Most previous studies
on quinonoid imines and imides have focused on para-compounds, and their generation was based on
electrochemical or chemical oxidation of aniline and anilide parents [30,31]. Iodane reagents have
seldom been used for mediating such transformations [32-34], and the only examples in the ortho-
series [35] are those recently reported by Nicolaou and his co-workers, who exploited Dess–Martin
periodinane (DMP) generated ortho-quinone imides in Diels–Alder reactions [29,36,37]; DMP
belongs to the ArIL4 type of the λ5-iodane reagents. To the best of our knowledge, the formation of
ortho-quinol imines by any means has never been reported. In order to achieve the preparation of such
elusive species, we first went back to λ3-iodanes bearing two heteroatomic nucleofugal ligands (i.e.,
ArIL2 type) in order to promote the desired oxidative oxygenation process [17] starting from 2-
substituted anilines or anilides.
With this consideration in mind, we attempted to perform an oxidative ortho-acetoxylation of
aniline 7a with DIB either in pure CH2Cl2 or in a 3:1 CH2Cl2/AcOH mixture, but only intractable
mixtures were obtained. However, the use of the λ5-iodane of type ArIL4 IBX at room temperature
gave a 2:1 mixture of the para-quinone imine 10a and the ortho-quinol imine 11a, as evidenced by
NMR analysis (Scheme 4). Silica gel chromatography of this mixture furnished 10a in 42% and 11a in
11.5%, as well as traces (i.e. < 2%) of the Diels–Alder dimer 12a derived from 11a (vide infra) [5].
Compound 10a probably results from an initial IBX-mediated formation of the ortho-quinone imine 8a
(Schemes 4 and 7), which is rapidly trapped by some intact starting aniline 7a to furnish the Schiff
base 9a. This ortho-quinone bisimine can then be quenched in a conjugate manner by the water
released during the Schiff base formation and reoxidized to furnish the observed para-quinone imine
10a. Moreover, we were pleased to isolate 11a even in such a low yield, since, as mentioned above,
such an ortho-quinol imine has never been described before.
Scheme 4.
NH2
NH
NH
NH2
O
N
N
H2O
[O]
IBX (1.1 equiv)
THF, rt, 8 h
7a
- H2O
O
7a
8a
9a
+
10a
O
NH
2:1 ratio
OH
(NMR analysis)
OH
silica gel
11a (11.5%)
10a (42%)
+
+
OH
O
12a (traces)
11a

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Furthermore, this first reaction with aniline 7a showed us that IBX is capable of selectively
delivering an oxygen at the positions adjacent to the amine function, in a manner probably similar to
the one that we and others have suggested for analogous IBX- and SIBX-mediated ortho-
oxygenations of phenols (Scheme 7) [4,5,12]. Having thus successfully tested the feasibility of
dearomatizing an aniline into an ortho-quinol imine, the same reaction was performed using the anilide
7b in the hope of improving its yield, for quinonoid imides are known to be stable enough for isolation
as opposed to imines that are sensitive to hydrolysis and polymerization [29-31,37]. In addition, the
lower nucleophilicity of the anilide nitrogen should preclude nucleophilic trapping of the ortho-
quinone imine formed. For the same reason, the anilide 7b turned out to be a very robust starting
material, which necessitated a treatment with IBX for 48 h in refluxing THF to be entirely
transformed, as indicated by TLC monitoring [CH2Cl2/MeOH (40:1)] of the reaction progress (Scheme
5). Now IBX does react with hot THF [4,38-40], therefore additional quantities of IBX were added to
the reaction mixture every 12 h (see Experimental Section). These conditions led to the isolation of the
ortho-quinone imide 8b and the ortho-quinol imine 11b in 6% and 8% yield, respectively. The acetyl
group did not protect the imine double bond from hydrolysis, since dimer 12a was again obtained, this
time in 35% yield. No dimer with the two imide functions still intact was observed. However, the
formation of both 11b and its derived dimer 12a after treating 7b with IBX remains an interesting
observation, since treatment of analogous 2-substituted anilides using DMP in the presence of water
only led to ortho-quinone imides [29,37]. The mechanism proposed by Nicolaou and his co-workers
for this ortho-oxygenation implies the intermolecular participation of the DMP-derived acetate of IBX
(Ac-IBX) as the source of the oxygen atom [36,39], so the oxygen delivery by the bulky Ac-IBX may
be indeed blocked at the 2-substituted position because of steric impediment. However, when the same
authors used IBX in a mixed solvent system of THF/DMSO (10:1) at 90 °C to transform anilide
derivatives tethered with an olefin unit, they only observed nitrogen/olefin cyclization products
derived from one-electron oxidation at the nitrogen lone pair [39,40]. It is somewhat puzzling that they
did not observe any formation of ortho-oxygenation products, like in the examples reported herein for
which we propose that IBX acts as the oxygen source (Scheme 7).
Scheme 5.
O
O
NH
N
O
N
1. IBX (3.1 equiv),
THF, reflux, 48h
2. silica gel
OH
O
+
+
12a (35%)
7b
11b (8%)
8b (6%)
In any event, with this second dearomatization of a 2-substituted aniline derivative into an ortho-
quinol imine accomplished (Scheme 5), we then moved on to treat 2,4,6-trimethylaniline (7c), having
two equivalent 2-substituted ortho-positions, with IBX in order to boost the yield of the corresponding
ortho-quinol imine product. This reaction led to a very clean crude product showing NMR signals
assignable only to the expected ortho-quinol imine 11c (Scheme 6). This quinol imine did not survive
silica gel chromatography and was isolated in only 33.5% yield, together with the Diels–Alder
cycloadduct 12c in 13% yield. The use of the stabilized version of IBX (i.e., SIBX) [4] also led to the

Molecules 2005, 10
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isolation of 11c in 35% yield, again in concert with that of the dimer 12c (22%) (Scheme 6). This
dimer has been previously prepared from 2,4,6-trimethylphenol via sodium periodate-mediated Adler
oxidation [41], and via the benzeneseleninic anhydride-mediated Barton oxidation [42].
Scheme 6.
O
IBX (1.1 equiv)
THF, reflux, 3h
+
OH
11c (33.5%)
NH2
NH
OH
silica gel
OH
O
12c (13%)
SIBX (1.1equiv)
THF, reflux, 2h
+
11c (35%)
12c (22%)
7c
11c
IBX is the only obvious source of oxygen in these ortho-oxygenations of anilines 7a and 7c and
anilide 7b. In analogy with our previous mechanistic proposal for related oxygenations of phenols
[5,12], an ionic pathway is here depicted to rationalize these oxidative dearomatizing transformations
leading to the isolation of previously undescribed ortho-quinol imines such as 11a-c (Scheme 7). Thus,
once the amine or amide nitrogen of 7 has attacked the IBX iodine to give 13, reduction of this
iodine(V) center could proceed via an ionic and concerted path to yield 11 and o-iodosobenzoic acid
(IBA).
Scheme 7.
O
O
O
O
I
HO
RN
I
O
O
HO
NR
NHR
a
IBX
OH
OH
O
I
a
+
HO
Z
Z
Z
13
7
11
IBA
R = H, Ac
Z = alkyl substituent(s)
SET
O
O
O
I
O
I
HO
RN
HO
RN
OH
OH
Z
Z
15
14
Of course, a single electron transfer (SET) mechanism [43] leading to the nitrogen radical cation 14,
followed by delivery of an hydroxyl radical to the substrate aromatic ring to give the intermediate 15,
that would then fragment into 11 and IBA, cannot be excluded at this point. Further work is in
progress to delineate these mechanistic possibilities.
Acknowledgements

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We wish to thank SIMAFEX (www.simafex.com) and the Association Nationale de la Recherche
Technique (CIFRE n° 301/2002) for A.O.’s graduate research assistantship, and the Ministère de la
Recherche for J.G.’s graduate research assistantship. We are also grateful to SIMAFEX for their
financial support and their generous gifts of DIB and SIBX reagents. We also wish to thank the Centre
Régional de Mesures Physiques de l’Ouest, Université de Rennes 1, for electrospray high resolution
mass spectrometry data.
Experimental
General
Diacetoxyiodobenzene (DIB) and stabilized o-iodoxybenzoic acid (SIBX) [4] were obtained from
SIMAFEX. Chloro(diphenyl)-λ3-iodane (Ph2ICl, 97%) was purchased from Aldrich. Tetra-
fluoroboro(diphenyl)-λ3-iodane (Ph2IBF4) [20,24] and o-iodoxybenzoic acid (IBX) [44] were prepared
from DIB and 2-iodobenzoic acid, respectively. Dichloromethane (CH2Cl2) and tert-butyl alcohol (t-
BuOH) were used as received. Tetrahydrofuran (THF) was purified by filtration through alumina
under N2 immediately before use. Moisture and oxygen sensitive reactions were carried out in flame-
dried glassware under N2. Evaporations were conducted under reduced pressure at temperatures less
than 30 °C unless otherwise noted. Column chromatography was carried out under positive pressure
using 40-63 µm silica gel (Merck) and the indicated solvents. Further drying of the residues was
accomplished under high vacuum. Melting points are uncorrected. NMR spectra of samples in the
indicated solvent were run at 250, 300 or 400 MHz. Carbon multiplicities were determined by DEPT-
135 and J-MOD experiments. Electron impact (70 eV), chemical ionization and electrospray mass
spectrometry low and/or high resolution (EIMS, CIMS, ESIMS and HRMS) were obtained from the
mass spectrometry laboratory at the CESAMO, Université Bordeaux 1, from the mass spectrometry
laboratory at the Institut Européen de Chimie et Biologie, Pessac, and from the mass spectrometry
laboratory at the Centre Régional de Mesures Physiques de l’Ouest, Université de Rennes 1.
General Procedure for λ3-Iodane-Mediated Phenylation of Phenols
To a stirred solution of KOt-Bu (1.4 mmol, 1.05 equiv) in t-BuOH (4 mL, ca. 0.35 M) was added
the phenol 1a-d (1.3 mmol) at room temperature, and the mixture was stirred for 1 h. The diphenyl-λ3-
iodane reagent, i.e., Ph2IBF4 [24] or Ph2ICl (1.5 mmol, 1.1 equiv), was added in one portion to this
mixture. The resulting suspension was stirred for 20 h at room temperature, after which time water (20
mL) was added, and the mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic
extracts were washed once with water (5 mL), dried over Na2SO4, filtered, evaporated, and further
dried under high vacuum.

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3,5,6-Trimethyl-6-phenylcyclohexa-2,4-dienone (3a) and 1,2,5-trimethyl-3-phenoxybenzene (4a)
Ph2ICl-mediated phenylation of 2,3,5-trimethyphenol (1a, 312 mg, 2.3 mmol) was carried out
according to the general procedure to afford a crude orange oil (600 mg), which was purified by
column chromatography, eluting with pentanes/EtOAc (5:1), to yield the cyclohexa-2,4-dienone 3a as
a yellow oil (40 mg, 8%), the diaryl ether 4a as a colorless oil (309 mg, 63%), and some recovered
starting phenol 1a (50 mg, 16%).
1
3a: IR (NaCl, neat) 3024, 2978, 1666, 1636, 1580, 846 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.55 (s,
13
3H), 1.63 (s, 3H), 2.02 (s, 3H), 5.75 (s, 1H), 6.00 (s, 1H), 7.08-7.22 (m, 5H); C-NMR (CDCl3, 75.5
MHz) δ 203.9, 155.5, 154.6, 140.6, 128.6, 126.9, 126.6, 122.5, 120.2, 56.7, 22.9, 22.1, 19.8; EIMS m/z
(rel intensity) 212 (M+, 100), 197 (42), 184 (68), 169 (88), 154 (21), 77 (25); HRMS (EI) calcd for
C15H16O 212.1201, found 212.1198.
1
4a: IR (NaCl, neat) 2929, 1489, 1224 cm-1; H-NMR (CDCl3, 250 MHz) δ 2.11 (s, 3H), 2.25 (s, 3H),
2.29 (s, 3H), 6.63 (s, 1H), 6.82 (s, 1H), 6.89 (d, J = 7.6 Hz, 2H), 6.99-7.06 (m, 1H), 7.26-7.33 (m, 2H);
13C-NMR (CDCl3, 62.9 MHz) δ 158.4, 153.9, 138.4, 136.1, 129.5, 126.5, 125.5, 121.9, 118.3, 116.9,
20.8, 20.0, 11.8; EIMS m/z (rel intensity) 212 (M+, 100), 197 (42), 135 (13), 119 (19), 77 (20); HRMS
(EI) calcd for C15H16O 212.1201, found 212.1199.
Phenoxybenzene (4b)
Ph2ICl-mediated phenylation of phenol (1b, 100 mg, 1.1 mmol) was carried out according to the
general procedure to afford the diaryl ether 4b [45] as a clean crude orange oil (140 mg, 75%), which
1
was not further purified: IR (NaCl, neat) 3066, 3044, 1582, 1485, 1285 cm-1; H-NMR (CDCl3, 300
13
MHz) δ 7.15-7.26 (m, 6H), 7.26-7.49 (m, 4H); C-NMR (CDCl3, 75.5 MHz) δ 157.4, 129.9, 123.4,
119.0; EIMS m/z (rel intensity) 170 (M+, 14), 51 (31), 39 (13), 18 (100).
2,6-Dimethyl-6-phenylcyclohexa-2,4-dienone (3c) and 1,3-dimethyl-2-phenoxybenzene (4c)
Ph2ICl-mediated phenylation of 2,6-dimethylphenol (1c, 155 mg, 1.3 mmol) was carried out
according to the general procedure to afford a crude orange oil (367 mg), which was purified by
column chromatography, eluting with cyclohexane/EtOAc (9:1), to yield the cyclohexa-2,4-dienone 3c
[16] as a yellow oil (93 mg, 37%) and the diaryl ether 4c [46] as a colorless oil (60 mg, 24%).
3c [16]: IR (NaCl, neat) 3034, 2978, 1660, 742, 692 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 1.62 (s, 3H),
1.88 (s, 3H), 6.26 (dd, J = 6.0, 9.4 Hz, 1H), 6.37 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 6.0 Hz, 1H), 7.21-
13
7.33 (m, 5H); C-NMR (CDCl3, 75.5 MHz) δ 203.9, 145.3, 140.9, 138.0, 132.5, 128.6, 127.2, 126.6,
119.8, 54.2, 23.8, 15.6; EIMS m/z (rel intensity) 198 (M+, 100), 183 (60), 170 (63), 155 (93).
1
4c [46]: IR (NaCl, neat) 3040, 2921, 1490, 1224, 750 cm-1; H-NMR (CDCl3, 300 MHz) δ 2.04 (s,
13
6H), 6.65-6.69 (m, 2H), 6.85-6.95 (m, 1H), 6.97-7.03 (m, 3H), 7.13-7.19 (m, 2H); C-NMR (CDCl3,

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75.5 MHz) δ 157.8, 151.0, 131.5, 129.6, 128.9, 124.9, 121.2, 114.6, 16.3; EIMS m/z (rel intensity) 198
(M+, 31), 183 (18), 77 (97), 76 (75).
2,4,6-Trimethyl-6-phenylcyclohexa-2,4-dienone (3d), 1,3,5-trimethyl-2-phenoxybenzene (4d) and
2,4,6-trimethyl-4-phenylcyclohexa-2,5-dienone (6d)
Ph2ICl-mediated phenylation of 2,4,6-trimethylphenol (1d) (172 mg, 1.3 mmol) was carried out
according to the general procedure to afford a crude orange oil (503 mg), which was purified by
column chromatography, eluting with cyclohexane/EtOAc (99:1), to yield the diaryl ether 4d [47] as a
colorless oil (18 mg, 7%), the cyclohexa-2,4-dienone 3d [15] as a yellow oil (84 mg, 31%), and a 3:2
mixture of 3d/6d as a yellow oil (47 mg, 18%).
1
3d [15]: IR (NaCl, neat) 3030, 2978, 1656, 1458, 710 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.63 (s,
13
3H), 1.91 (s, 3H), 2.03 (s, 3H), 6.08 (s, 1H), 6.80 (s, 1H), 7.25-7.34 (m, 5H); C-NMR (CDCl3, 75.5
MHz) δ 203.8, 142.7, 141.9, 139.9, 132.1, 128.8, 127.4, 127.3, 126.9, 53.7, 24.4, 21.5, 15.9; EIMS m/z
(rel intensity) 212 (M+, 100), 184 (42), 169 (35), 154 (9).
1
4d [47]: IR (NaCl, neat) 3022, 2926, 1592, 1490, 1223 cm-1; H-NMR (CDCl3, 300 MHz) δ 2.00 (s,
13
3H), 2.22 (s, 6H), 6.66-6.69 (m, 2H), 6.82 (s, 2H), 6.84-6.89 (m, 1H), 7.13-7.18 (m, 2H); C-NMR
(CDCl3, 75.5 MHz) δ 158.0, 148.7, 134.4, 131.0, 129.5, 121.1, 114.6, 20.8, 16.2; EIMS m/z (rel
intensity) 212 (M+, 59), 197 (60), 120 (100).
1
13
6d: H-NMR (CDCl3, 300 MHz) δ 1.66 (s, 6H), 1.96 (s, 3H), 6.73 (s, 2H), 7.23-7.35 (m, 5H); C-
NMR (CDCl3, 75.5 MHz) δ 187.5, 151.2, 132.9, 129.0, 127.5, 126.6, 44.6, 24.6, 16.5. These NMR
data were read on the spectrum of the 3:2 mixture of the ortho- and the para-phenylated products 3d
and 6d.
4-tert-Butyl-2-methylaniline (7a)
To a stirred solution of 4-tert-butyltoluene (500 mg, 3.4 mmol) in Ac2O (15 mL) was added
dropwise HNO3 (598 µL, 8.4 mmol) in AcOH (800 µL, 13.5 mmol) [48]. The solution turned slowly
bright yellow, and was stirred at room temperature for 1 h. The reaction mixture was diluted with ice-
cold water, and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were washed with
20% aqueous NaOH (3 × 10 mL), brine (3 × 10 mL), dried over Na2SO4, filtered and evaporated.
Purification by column chromatography, eluting with hexane, afforded 4-tert-butyl-2-nitrotoluene
[49,50] as a bright yellow oil (479 mg, 73%): IR (NaCl) 2972, 1532, 1354 cm-1; 1H-NMR (CDCl3, 400
MHz) δ 1.36 (s, 9H), 2.57 (s, 3H), 7.29 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H);
13C-NMR (CDCl3, 100 MHz) δ 150.5, 148.9, 132.3, 130.4, 130.1, 121.3, 34.5, 30.9, 19.8; EIMS m/z
(rel intensity) 193 (M+, 117), 178 (100). Hydrogenation of this material, collected from two runs (500
mg, 2.6 mmol) in dry THF (10 mL) was carried out under H2 for 8 h at room temperature in the
presence of 10% Pd/C as a catalyst (50 mg) using an autoclave (5 bars) with mechanical stirring. The
reaction mixture was filtered through Celite, and the solid was washed with Et2O. Evaporation of the
combined filtrates and washings furnished a crude product, which was submitted to column

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chromatography, eluting with hexane/Et2O (4:1), to give the aniline 7a [51] as a colorless oil (360 mg,
85%), which was immediately protected from light: IR (NaCl) 3260, 2574, 1633, 1056 cm-1; 1H-NMR
(CDCl3, 250 MHz) δ 1.41 (s, 9H), 2.24 (s, 3H), 3.62 (s, 2H), 6.83 (d, J = 1.8 Hz, 1H), 6.87 (dd, J =
1.8, 7.9 Hz, 1H), 7.1 (d, J = 7.9 Hz, 1H); 13C-NMR (CDCl3, 62.9 MHz) δ 150.0, 144.0, 130.0, 119.4,
115.6, 112.1, 34.2, 32.0, 16.8; EIMS m/z (rel intensity) 163 (M+, 47), 148 (100).
N-acetyl-5-tert-butyl-2-methylaniline (7b)
Hydrogenation of 4-tert-butyl-2-nitrotoluene (300 mg, 1.55 mmol) in 2:1 Ac2O/AcOH (30 mL)
was carried out under H2 for 3 h at room temperature in the presence of 10% Pd/C as a catalyst (30
mg) using an autoclave (5 bars) equipped with mechanical stirring [52]. The reaction mixture was
filtered through Celite, and the solid was washed with Et2O (50 mL). The combined filtrates and
washings were washed successively with saturated aqueous NaHCO3 (3 × 10 mL) and brine (2 × 10
mL), dried over Na2SO4, filtered and evaporated to furnish an amorphous solid, which was purified by
crystallization from Et2O, to yield the anilide 7b [51] as white fine needles (284 mg, 89%): mp 102 °C
(lit. [51] mp 97-98 °C); IR (neat) 3268, 2925, 1661 cm-1; 1H-NMR (CDCl3, 400 MHz) δ 1.29 (s, 9H),
2.08 (s, 3H), 2.15 (s, 3H), 7.07 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.82 (s, 1H);
13C-NMR (CDCl3, 100 MHz) δ 168.6, 149.6, 135.2, 130.0, 127.4, 122.6, 121.2, 34.4, 31.2, 24.0, 17.3;
EIMS m/z (rel intensity) 205 (M+, 75), 190 (100), 163 (42), 148 (90).
2,4,6-trimethylaniline (7c)
To a stirred ice-cold solution of mesitylene (5.0 g, 41.7 mmol) in Ac2O (10 mL) was added fuming
HNO3 (6.5 mL, 145.6 mmol). The mixture was stirred for 1 h at 0 °C, and then poured into ice-cold
water (30 mL). The aqueous phase was extracted with Et2O (3 × 30 mL), and the combined organic
extracts were washed successively with 20% aqueous NaOH (6 × 20 mL), water (20 mL), and brine
(20 mL), dried over MgSO4, filtered, and evaporated to furnish a crude yellow solid (6.6 g).
Purification by column chromatography, eluting with a cyclohexane/Et2O gradient (100:0 → 95:5),
afforded 2-nitromesitylene as pale yellow crystals (5.5 g, 80%): mp 43 °C (lit. [53] mp 44 °C); IR
(NaCl) 2928, 2871, 1604, 1521, 1367, 1041 cm-1; 1H-NMR (CDCl3, 250 MHz) δ 2.26 (s, 6H), 2.30 (s,
3H), 6.90 (s, 2H); 13C-NMR (CDCl3, 62.9 MHz) δ 149.7, 140.2, 129.3, 20.9, 17.4; EIMS m/z (rel
intensity) 165 (M+, 16), 148 (31), 91 (100). To a stirred ice-cold solution of 2-nitromesitylene (4.2 g,
25.5 mmol) in MeOH/H2O (9:1) (30 mL) were added successively NH4Cl (4.1 g, 76.4 mmol) and Zn
dust (16.0 g, 250 mmol) [54,55]. The resulting suspension was stirred overnight at room temperature,
filtered through a pad of Celite, and concentrated. The aqueous residue was taken up with Et2O (30
mL), washed with saturated aqueous Na2CO3 (20 mL) and brine (20 mL), dried over MgSO4, filtered
and evaporated to give the aniline 7c [56] as a colorless oil (3.1 g, 90%), which was not further
1
purified, but immediately stored in the dark. IR (NaCl) 3462, 3379, 2923, 1626, 1491 cm-1; H-NMR
13
(CDCl3, 250 MHz) δ 2.22 (s, 6H), 2.28 (s, 3H), 3.45 (bs, 2H), 6.84 (s, 2H); C-NMR (CDCl3, 62.9
MHz) δ 140.0, 128.7, 127.0, 121.7, 20.3, 17.5; EIMS m/z (rel intensity) 135 (M+, 79), 120 (100).

Molecules 2005, 10
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3-Amino-5-tert-butyl-4-[5-tert-butyl-2-methylphenylimino]-2-methylcyclohexa-2,5-dienone (10a) and
4-tert-butyl-6-imino-1-methylcyclohexa-2,4-dienol (11a).
To a stirred solution of the aniline 7a (56 mg, 0.34 mmol) in anhydrous THF (2.5 mL) was added
IBX (105 mg, 0.38 mmol) as a solid in one portion. The resulting suspension was vigorously stirred at
room temperature for 8 h, after which time it was diluted with EtOAc (10 mL), washed with 5%
aqueous NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and evaporated. The resulting
brown oil (71 mg) was submitted to column chromatography, eluting with hexane/Et2O (95:5 → 1:1),
and then CH2Cl2/MeOH (6:1), to furnish the p-quinone imine 10a as a dark red solid (24 mg, 42%),
the o-quinol imine 11a as a pale red oil (7 mg, 11.5%), and traces of dimer 12a [5].
1
10a: mp 88 °C; IR (NaCl) 3483, 3382, 2957, 1633, 1601, 1566 cm-1; H-NMR (CDCl3, 250 MHz) δ
1.18 (s, 9H), 1.29 (s, 9H), 2.14 (s, 3H), 4.42 (s, 2H), 6.52 (d, J = 1.8 Hz, 1H), 6.73 (s, 1H), 7.07 (dd, J
13
= 1.8, 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H); C-NMR (CDCl3, 62.9 MHz) δ 182.6, 156.4, 148.8,
148.0, 141.0, 129.8, 126.7, 123.7, 121.3, 117.5, 113.7, 35.0, 34.4, 31.4, 29.1, 17.6, 10.1; EIMS m/z (rel
intensity) 338 (M+, 60), 323 (100), 281 (76), 163 (29), 148 (75); HRMS (EI) calcd for C22H30N2O
338.2358, found 338.2352.
11a: IR (NaCl) 3388, 2920, 2857, 1597 cm-1; 1H-NMR (CDCl3, 250 MHz) δ 1.16 (s, 9H), 2.29 (s, 3H),
5.21 (d, J = 1.1 Hz, 1H), 6.35 (dd, J = 1.1, 12.2 Hz, 1H), 6.45 (d, J = 12.2 Hz, 1H); 13C-NMR (CDCl3,
62.9 MHz) δ 197.5, 170.9, 136.0, 132.4, 117.4, 93.8, 37.7, 30.1, 28.7; CIMS m/z (rel intensity) 197
+
(MNH4 , 30), 195 (100); HRMS (ESI) calcd for C11H15NONa 200.1051, found 200.1060.
6-tert-Butyl-3-methyl-1,2-benzoquinone-2-(N-acetyl)imine (8b) and 6-(N-acetylimino)-4-tert-butyl-1-
methyl-cyclohexa-2,4-dienol (11b)
To a stirred solution of the anilide 7b (50 mg, 0.24 mmol) in anhydrous THF (2.5 mL) was added
IBX (74 mg, 0.26 mmol) as a solid in one portion. The resulting suspension was brought to reflux for
48 h, and further additions of IBX (0.5 equiv) were carried out every 12 h. The reaction mixture was
then allowed to cool down to room temperature, diluted with EtOAc (10 mL), washed with 5%
aqueous NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and evaporated. The residue
was submitted to column chromatography, eluting with CH2Cl2/MeOH (100:0 → 100:1), to furnish the
o-quinone imine 8b as a bright orange oil (3 mg, 6%), the o-quinol imine 11b as a brown oil (4 mg,
8%), and the dimer 12a [5] as a beige solid (15 mg, 35%).
1
8b: IR (NaCl) 3388, 2920, 2857, 1597 cm-1; H-NMR (CDCl3, 250 MHz) δ 1.19 (s, 9H), 2.04 (d, J =
1.5 Hz, 3H), 2.29 (s, 3H), 6.53 (dq, J = 1.5, 7.0 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H); 13C-NMR (CDCl3,
62.9 MHz) δ 186.4, 178.0, 150.0, 146.1, 138.9, 135.8, 131.4, 34.9, 29.1, 23.1, 17.2; CIMS m/z (rel
intensity) 222 ([MH + 2]+, 100); HRMS (ESI) calcd for C13H17NO2Na 242.1157, found 242.1155.
11b: IR (NaCl) 2959, 1698, 1602, 1196 cm-1; 1H-NMR (CDCl3, 250 MHz) δ 1.18 (s, 9H), 1.38 (s, 3H),
2.07 (s, 3H), 6.05 (dd, J = 0.6, 1.8 Hz, 1H), 6.22 (dd, J = 0.6, 10.0 Hz, 1H), 6.38 (dd, J = 1.8, 10.0 Hz,

Molecules 2005, 10
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13
1H); C-NMR (CDCl3, 62.9 MHz) δ 199.2, 186.6, 163.4, 140.9, 122.3, 119.4, 78.0, 35.4, 28.2, 23.8,
23.2; CIMS m/z (rel intensity) 222 (MH+, 100); HRMS (ESI) calcd for C13H18DNO2Na 245.1376,
found 245.1377.
6-Imino-1,3,5-trimethyl-cyclohexa-2,4-dienol (11c) and 3,10-dihydroxy-3,5,7,8,10,12-hexamethyl-
tricyclo[6.2.2.02,7]dodeca-5,11-diene-4,9-dione (12c).
To a stirred solution of the aniline 7c (56 mg, 0.415 mmol) in anhydrous THF (2.5 mL) was added
IBX (130 mg, 0.46 mmol) as a solid in one portion. The resulting suspension was brought to reflux for
3 h, after which time it was allowed to cool down to room temperature, diluted with EtOAc (10 mL),
washed with 5% aqueous NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and
evaporated. The resulting brown oil was submitted to column chromatography, eluting with
hexane/acetone (6:1), and then with CH2Cl2/MeOH (6:1), to furnish the o-quinol imine 11c as a red
gum (21 mg, 33.5%) and the dimer 12c [42] as a brown solid (8 mg, 13%). The SIBX-mediated
oxygenation of aniline 7c (135 mg, 1.0 mmol) in refluxing THF (6 mL) was carried out for 2 h,
according to our previously described procedure [4]. Purification by column chromatography, eluting
with hexane/acetone (6:1), and then with CH2Cl2/MeOH (6:1), yielded the o-quinol imine 11c as a red
gum (53 mg, 35%) and the dimer 12c [42] as a brown amorphous solid (33 mg, 22%).
11c: IR (NaCl) 2959, 2213, 1682, 1577, 1177 cm-1; 1H-NMR (CDCl3, 250 MHz) δ 2.08 (d, J = 1.5 Hz,
3H), 2.19 (s, 3H), 2.25 (d, J = 1.5 Hz, 3H), 6.16 (s, 1H), 7.65 (s, 1H); 13C-NMR (CDCl3, 62.9 MHz) δ
+
198.0, 145.4, 142.0, 129.3, 118.7, 111.5, 31.7, 22.7, 22.2; CIMS m/z (rel intensity) 169 (MNH4 , 16),
168 (31), 167 (100), 150 (38), 108 (22); HRMS (ESI) calcd for C9H12NO 150.0919, found 150.0907.
Dimer 12c: mp 158 °C (lit. [41,42] mp 181-183 °C); IR (NaCl) 3481, 2972, 2927, 1719, 1681, 1448,
1361 cm-1; 1H-NMR (CDCl3, 250 MHz) δ 1.16 (s, 3H), 1.23 (s, 6H), 1.36 (s, 3H), 1.70 (d, J = 1.5 Hz,
3H), 1.83 (d, J = 1.5 Hz, 3H), 2.8 (d, J = 2.1 Hz, 1H), 3.13 (m, 1H), 3.93 (bs, 1H), 5.03 (m, 1H), 6.02
(s, 1H); 13C-NMR (CDCl3, 62.9 MHz) δ 214.1, 202.4, 145.2, 145.1, 133.1, 127.6, 76.5, 73.7, 72.2,
57.7, 48.7, 48.6, 45.3, 32.4, 25.2, 23.2, 21.4, 16.2, 12.4; EIMS m/z (rel intensity) 304 (M+, 10), 153
(26), 152 (42), 135 (100), 110 (40), 109 (52).
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