Regiospecific oxidation of polycyclic aromatic phenols to quinones by hypervalent iodine reagents

Article abstract of DOI:10.1016/j.tet.2009.12.022

The hypervalent iodine reagents o-iodoxybenzoic acid (IBX) and bis(trifluoro-acetoxy)iodobenzene (BTI) are shown to be general reagents for regio-controlled oxidation of polycyclic aromatic phenols (PAPs) to specific isomers (ortho, para, or remote) of polycyclic aromatic quinones (PAQs). The oxidations of a series of PAPs with IBX take place under mild conditions to furnish the corresponding ortho-PAQs. In contrast, oxidations of the same series of PAPs with BTI exhibit variable regiospecificity, affording para-PAQs where structurally feasible and ortho-PAQs or remote PAQ isomers in other cases. The structures of the specific PAQ isomers formed are predictable on the basis of the inherent regioselectivities of the hypervalent iodine reagents in combination with the structural requirements of the phenol precursors. IBX and BTI are recommended as the preferred reagents for regio-controlled oxidation of PAPs to PAQs.

Full text of DOI:10.1016/j.tet.2009.12.022

Tetrahedron 66 (2010) 2111–2118
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regiospecific oxidation of polycyclic aromatic phenols to quinones by hypervalent
iodine reagents
,
Anhui Wu a, Yazhen Duan a, Daiwang Xu a, Trevor M. Penning b, Ronald G. Harveya
*
a Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, University of Chicago, 929 East 57th Street, Room W308, Chicago, IL 60637, USA
b The Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2009
Received in revised form 3 December 2009
Accepted 4 December 2009
Available online 11 December 2009
The hypervalent iodine reagents o-iodoxybenzoic acid (IBX) and bis(trifluoro-acetoxy)iodobenzene (BTI)
are shown to be general reagents for regio-controlled oxidation of polycyclic aromatic phenols (PAPs) to
specific isomers (ortho, para, or remote) of polycyclic aromatic quinones (PAQs). The oxidations of a series
of PAPs with IBX take place under mild conditions to furnish the corresponding ortho-PAQs. In contrast,
oxidations of the same series of PAPs with BTI exhibit variable regiospecificity, affording para-PAQs
where structurally feasible and ortho-PAQs or remote PAQ isomers in other cases. The structures of the
specific PAQ isomers formed are predictable on the basis of the inherent regioselectivities of the
hypervalent iodine reagents in combination with the structural requirements of the phenol precursors.
IBX and BTI are recommended as the preferred reagents for regio-controlled oxidation of PAPs to PAQs.
Ó 2009 Published by Elsevier Ltd.
1. Introduction
A promising new reagent for regio-controlled oxidation of PAPs
is the hypervalent iodine compound o-iodoxybenzoic acid (IBX).
Although methods for regioselective oxidation of monocyclic
phenols to quinones have been extensively investigated, relatively
little is known concerning analogous oxidations of polycyclic aro-
matic phenols (PAPs) to polycyclic aromatic quinones (PAQs). In
connection with studies directed toward determination of the role
of the quinone metabolites of polycyclic aromatic hydrocarbons
(PAHs) in carcinogenesis,1–10 we required an efficient method for
regioselective synthesis of PAQs from PAPs.
IBX is a mild oxidant, that is, moderately soluble in organic solvents
and is widely employed for oxidation of alcohols.12 Its use for oxi-
dation of simple phenols to ortho-quinones has been described,13
and we reported several examples of IBX oxidation of PAPs to
the corresponding ortho-PAQs.14 Another potentially useful
hypervalent iodine reagent is bis(trifluoro-acetoxy)iodobenzene
[(CF3CO2)2IC6H5] (BTI). Oxidation of several 1-naphthol derivatives
by BTI was reported to furnish para-naphthoquinones.15
The reagent most frequently employed for oxidation of PAPs to
PAQs is Fremy’s salt [(KSO3)2NO].3,11 However, oxidations with
Fremy’s salt frequently afford mixtures of ortho- and para-quinone
isomers accompanied by secondary oxidation products, and the
results are often erratic and difficult to reproduce. Fremy’s salt also
has the limitation that aqueous media are required, and PAH
compounds are poorly soluble in water.
2. Results
With the aim of developing more efficient methods for regio-
controlled oxidation of PAPs to PAQs, we undertook to investigate
the use of the hypervalent iodine reagents IBX and BTI for this
purpose. Oxidation of PAPs may result in formation of three types of
PAQ isomersdortho, para, and/or remote. Remote quinone isomers
are defined as quinones with carbonyl functions in different rings,
e.g., pyren-1,6-dione.
O
OH
I
O
I(O-C-CF3)2
O
Oxidations of a series of PAPs by IBX were conducted at room
temperature in DMF. All reactions took place regiospecifically to
furnish the corresponding ortho-PAQ isomers (Table 1). Thus, IBX
oxidation of 1- and 2-naphthol both provided 1,2-naphthoquinone
(1) as the sole isomeric quinone product. Similarly, IBX oxidations
of 1- and 2-phenanthrol both furnished phenanthren-1,2-dione (3),
and IBX oxidations of 3- and 4-phenanthrol both provided phe-
nanthren-3,4-dione (5). It is worthy of note that oxidation of
O
BTI
IBX
* Corresponding author. Tel.: þ1 773 702 6998; fax: þ1 773 702 3184.
E-mail address: rharvey@uchicago.edu (R.G. Harvey).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.12.022

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A. Wu et al. / Tetrahedron 66 (2010) 2111–2118
Table 1
Oxidation of Polycyclic Aromatic Phenols to Quinones by IBX and BTIa
Phenol
IBX
Yield (%)
53
BTI
Yield (%)
68
O
O
O
OH
O
1
2
OH
1
51
70
1
61
75
O
O
O
O
OH
OH
3
4
3
51
59
3
5
68
38
O
OH
O
5
HO
5
62
61
4
6
50
95
O
OH
OH
O
6
O
O
O
O
63
65
67
69
8
7
OH
7
7
a
IBX oxidations were conducted in DMF at room temperature. BTI reactions were carried out in aqueous DMF at 0 ꢀC.
4-phenanthrol by IBX proceeded readily despite the severe steric
crowding of the hydroxyl group in the bay molecular region. Finally,
IBX oxidation of 9-phenanthrol provided phenanthren-9,10-dione
(6), and IBX oxidations of 1- and 2-anthracenol both took place
ortho-regiospecifically to furnish anthracen-1,2-dione (7). Oxida-
tion of 9-anthracenol by IBX could not investigated because this
phenol exists exclusively as the anthrone tautomer under the
conditions employed.
The analogous oxidations with BTI were carried out in aqueous
DMF at 0 ꢀC. They exhibited variable regioselectivities, affording
para-PAQs in some cases and ortho-PAQs in others (Table 1). Oxi-
dation of 1-naphthol by BTI gave 1,4-naphthoquinone (2), but ox-
idation of 2-naphthol by BTI furnished 1,2-naphthoquinone (1).
Oxidations of 1- and 4-phenanthrol by BTI both provided phe-
nanthren-1,4-dione (4).
corresponding ortho-quinone, phenanthren-9,10-dione (6). And
finally, BTI oxidation of1-anthracenolgave thepara-quinoneisomer,
anthracen-1,4-dione (8), whereas analogous oxidation of 2-anthra-
cenol gave the ortho-quinone isomer, anthracen-1,2-dione (7).
In order to further probe the scope of IBX/BTI oxidation of PAPs
for the synthesis of PAQs, several additional examples were
investigated (Table 2). The phenol and quinone isomers of ben-
zo[a]pyrene (BaP) were of particular interest because several
phenol and quinone isomers are among the principal metabolites
of this widespread environmental carcinogen,10b and recent re-
search has implicated BaP-7,8-dione (10) as an active metabolite of
BaP that contributes to induction of lung cancer.1,10 Oxidations of
the 7- and 8-phenols of BaP (9 and 12) with IBX both took place
ortho-regiospecifically to furnish 10.16 Analogous oxidations of the
BaP 9- and 10-phenols (13 and 15) with IBX also took place ortho-
regiospecifically to furnish BaP-9,10-dione (14).
In contrast, oxidations of 2- and 3-phenanthrol with BTI provided
the ortho-quinone isomers, 3 and 5, respectively. Oxidation of
9-phenanthrol by BTI also took place regiospecifically to furnish the
The oxidations of the same BaP phenol isomers with BTI took
a different course. Oxidations of the 7- and 10-phenols of BaP

A. Wu et al. / Tetrahedron 66 (2010) 2111–2118
2113
Table 2
Oxidation of phenol isomers of benzo[a]pyrene by IBX and BTI
Phenol
IBX
Yield (%)
68
BTI
Yield (%)
60
O
O
O
O
OH
9
10
11
10
80
10
46
HO
HO
12
O
O
82
95
14
11
82
47
13
14
OH
14
15
O
OH
OH
OH
78 reported
O
18
17
16
OH
OH
O
82 (reported)
OH
O
21
20
19
(9 and 15) with BTI both furnished the para-quinone isomer,
BaP-7,10-dione (11), as the sole product. In contrast, analogous
oxidations of the 8- and 9-phenols of BaP (12 and 13) with BTI
provided the ortho-quinone isomers, BaP-7,8-dione (10) and BaP-
9,10-dione (14), respectively. These findings parallel the findings
from the analogous oxidations of the phenol isomers of phenan-
threne and anthracene.
The 1- and 3-phenol isomers of BaP (16, 19) differ structurally
from the phenol isomers of BaP considered thus far (9, 12, 13, 15) by
the location of the phenolic OH group in a pyrenyl ring rather than
a benzo ring. Attempted oxidation of 16 and 19 by IBX failed to
furnish the expected ortho-quinone isomers, BaP-1,2-dione (22)
and BaP-2,3-dione (23) (neither of these isomers are known). TLC
structures are supported by evidence from similar oxidations of the
structurally related pyrene phenols (see below). In contrast, re-
actions of 16 and 19 with BTI took place readily to furnish the re-
mote quinone isomers, BaP-1,6-dione (18) and BaP-3,6-dione (21).
TLC showed that significant amounts of other quinone isomers
were not formed. Reaction at the 6-position is consistent with the
well-established propensity of BaP to undergo all types of reactions
at the 6-position.3
Oxidations of three additional PAH phenols (24–26) with IBX
and BTI were also investigated (Scheme 1). Oxidations of ben-
z[a]anthracen-7-ol (24) with IBX and BTI both gave the para-
quinone isomer, benz[a]anthracen-7,12-dione (27) as the sole
product. This is the only example of IBX oxidation furnishing a para-
quinone isomer.
O
Oxidation of 1-pyrenol (25) with IBX (Scheme 1) followed
a course similar to the oxidations of the 1- and 3-phenols of BaP (16,
19). Disappearance of 25 was shown by TLC to be accompanied by
formation of an unstable more polar product believed to be the
catechol, pyrene-1,2-diol (28a). The amount of 28a formed in-
creased with higher temperature, excess IBX, and longer reaction
time. When reaction appeared complete acetylation of 28a with
Ac2O/pyridine furnished the stable catechol diacetate (28b). Its
NMR spectrum was consistent with this structural assignment.
Oxidation of 1-pyrenol (25) with BTI provided a mixture of the
pyrene-1,6- and 1,8-dione isomers (29,30) in 3:2 ratio. Oxidation of
2-pyrenol (26) with IBX proceeded similarly to oxidation of 1-
pyrenol (25), furnishing an air-sensitive catechol that was
O
O
O
23
22
monitoring of these reactions showed disappearance of the phe-
nols with concurrent formation of more polar products that
decomposed on standing. These unstable products are believed to
be the catechol intermediates, BaP-1,2-diol (17) and BaP-2,3-diol
(20). Polycyclic aromatic catechols are known to be unstable and
susceptible to oxidative decomposition in air. The catechol

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A. Wu et al. / Tetrahedron 66 (2010) 2111–2118
O
O
O
O
O
O
IBX
I
O
I
O
O
HO
O
or TBI
O
O
I
O
H
DMF
-H2O
HO
HO
27
24
B
A
PAP
OR
OH
OR
OH
O
IBX
O
IBX
O
I
OH
O
CO2H
I
O
+
28a: R = H
b: R = OAc
c: R = Me
25
26
PAQ
BTI
BTI
C
Figure 1. Plausible mechanism for IBX oxidation of PAPs to PAQs.
O
O
no reaction
3.1. Mechanisms of oxidation of PAPs to PAQs
O
The observed regioselectivities are consistent with current un-
derstanding of the mechanisms of these types of oxidations. The
strict ortho-selectivity of the IBX-mediated oxidations of PAPs is
most satisfactorily explained by the ionic mechanism proposed by
Quideau and associates for IBX-mediated oxidation of 1-naph-
thol.17,18 This pathway (Fig. 1) entails initial reaction of the phenol
with the iodine atom of IBX to form an intermediate complex (A)
with loss of H2O. Complex A may then undergo sigmatropic transfer
+
O
30
29
Scheme 1.
acetylated to yield the catechol diacetate (28b). However, BTI failed
to react with 26.
of oxygen from the
to the oxygen function of the PAP with concomitant reduction to
the
3-iodanyl state to form B. Then, only a tautomeric shift (C) is
l
5-iodanyl moiety to the carbon atom adjacent
3. Discussion
l
These studies demonstrate that the hypervalent iodine com-
pounds IBX and BTI are general reagents for regio-controlled
oxidation of PAPs to specific PAQ isomers (ortho, para, or remote)
under mild conditions. The IBX oxidations are regiospecific,
providing exclusively the ortho-PAQs. The only exception is ben-
z[a]anthracen-7-ol (24), which is incapable of forming an
ortho-isomer. In contrast, the BTI oxidations exhibit variable
regiospecificities, affording para-PAQ isomers where structurally
possible and ortho-PAQs or remote PAQs in other cases.
needed to generate the ortho-PAQ along with a two-electron dis-
placement to form reduced 2-iodobenzoic acid. It is not necessary
to postulate formation of a catechol intermediate, and the observed
stoichiometry is consistent with this mechanism.
The variable regiospecificities observed in the BTI-mediated
oxidations of PAPs are explicable in terms of a mechanism that
involves initial reaction of the phenols with BTI with displacement
of trifluoroacetate to form intermediate A (Fig. 2).15 The second
oxygen atom derives from reaction of A with water. For simple
O
O
C
O
C
O
F3C
O
I
O
O
F3C
CF3
F3C
O
I
I
O
O
OH
DMF
- TFAA
B
A
O
H
H
PAP
O
O
OH
BTI
- TFAA
- IB
repeat
H
OH
O
OH
PAQ
C
TFAA = F3CCO2H, IB = iodobenzene
Figure 2. Plausible mechanism for BTI oxidation of PAPs to PAQs.

A. Wu et al. / Tetrahedron 66 (2010) 2111–2118
2115
phenols that possess an unsubstituted para-position, such as
1-naphthol, reaction takes place preferentially at this position (B),
generating a para-ketol that rearranges to a para-catechol (C). In-
termediate C then undergoes a second oxidation via a similar
pathway to yield a para-PAQ plus iodobenzene and trifluoroacetic
acid. In contrast to the IBX-mediated oxidations that require only
one equivalent of IBX, two equivalents of BTI are required for
complete conversion to the PAQ via this pathway, and this agrees
with the observed stoichiometry.
The structural dependency of the regioselectivities of BTI-
mediated oxidation is also readily explicable on the basis of the
same mechanism. The principal determinant is the availability of an
unsubstituted para-position. Oxidation of PAPs that possess such
a position (1-naphthol, 1-phenanthrol, 4-phenanthrol, 1-anthra-
cenol, 9, 15, and 24) yield the para-PAQs. On the other hand, oxi-
dations of PAPs that lack an unsubstituted para-position (all
others), furnish the ortho-PAQ isomers. In the former instances, the
initially-formed intermediate A (Fig. 2) reacts with water at the less
sterically restricted para-position, yielding the para-PAQ isomer. In
cases where the PAP lacks an unsubstituted para-position, e.g., 2-
naphthol, reaction can only occur at a relatively crowded ortho-
position, resulting in formation of an ortho-PAQ.
Where more than a one ortho-position is available, reaction with
water takes place preferentially at a position adjacent to a fused
aromatic ring. Thus, BTI oxidations of 2-naphthol, 2-phenanthrol,
3-phenanthrol, and 2-anthracenol occur at the ortho site adjacent
to the aromatic ring to furnish 1, 3, 5, and 7, respectively. The
alternative ortho-quinone isomers [naphthalen-2,3-one (31), phe-
nanthren-2,3-dione (32), and anthracen-2,3-one (33)] were not
detected, nor were any remote quinone isomers. Preferential oxi-
dation at an ortho site adjacent to a fused aromatic ring is likely due
to the stabilizing effect of the aromatic system on the reaction
intermediate.
exhibits variable regioselectivity, often providing mixtures of ortho-
and para-quinone isomers as well as secondary products. For
example, oxidation of 1-phenanthrol by Fremy’s salt affords the
1,2- and 1,4-quinones (3 and 4) in approximately equal ratio.19 In
contrast, oxidation of the same phenol by IBX gave only the ortho-
quinone (3), and its oxidation by BTI provided only the para-
quinone (4). Both reactions were regiospecific within experimental
limits. An alternative reagent that has also been employed for
oxidation of PAPs is phenylseleninic anhydride [(PhSeO)2O],20 also
known as Barton’s reagent. It tends to furnish predominantly the
ortho-PAQ isomers, but the results are variable.20 On the basis of the
demonstrated regioselectivity and predictability of IBX and BTI in
combination with the relative convenience and simplicity of the
procedures for their use, we recommend them as the reagents of
choice for oxidation of PAPs to PAQs.
3.2.1. Syntheses of the PAPs. Only three of the PAPs employed in this
investigation (1- and 2-naphthol and 9-phenanthrol) were avail-
able from commercial sources. Although procedures for the syn-
thesis of the remaining PAPs have been reported, they use classical
synthetic methods that entail large numbers of steps and/or have
other practical disadvantages. We, therefore, undertook to develop
more convenient new synthetic approaches.
Syntheses of the 1-, 3-, and 4-phenols of phenanthrene were
accomplished by modification of the Pd-catalyzed Suzuki cross-
coupling methodology that we previously reported.14 Synthesis of
1- and 3-phenanthrenol via this approach is shown in Scheme 2.
Br
Pd(PPh3)4
OMe
+
(HO)2B
OMe
Na2CO3
DME
CHO
CHO
36
OR
O
O
O
OMe
OR
O
+
OMe
O
O
37
38a: R = Me
b: R = H
39a: R = Me
b: R = H
35
33
34
Scheme 2.
Reaction of 2-bromoacetaldehyde with 3-methoxyphenylbor-
onic acid in the presence of a Pd(PPh3)4 catalyst gave 3’-methoxy-
biphenyl-2-carboxaldehyde (36), and Wittig reaction of 36 with
methyltriphenylphosphonium chloride and t-BuOK in THF gave 30-
methoxy-2-(2-methoxyvinyl)biphenyl (37) as a mixture of E- and
Z-isomers. Cyclization of 37 catalyzed by MeSO3H gave a mixture of
1- and 3-methoxyphenanthrene (38a and 39a). Separation of the
3.2. Comparison of IBX- and BTI-mediated oxidation of PAPs
with other methods
The observed regiospecificities of the oxidations of PAPs with
IBX and BTI contrast with the lower regioselectivities reported for
oxidations of PAPs with other reagents. Fremy’s salt, the reagent
most frequently employed proceeds via a radical mechanism and
O
OR
OAc
40
41
42a: R = Ac
b: R = H
O
OAc
OR
44
45
43
46a: R = Ac
b: R = H
Scheme 3.

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A. Wu et al. / Tetrahedron 66 (2010) 2111–2118
isomers by preparative TLC and demethylation by treatment with
BBr3 afforded 1- and 3-phenanthrol (38b and 39b).
eluted with EtOAc/hexanes (1:10) to yield 36 as a yellow oil
(381 mg, 90%). The NMR data were in agreement with the values
reported.26
4-Phenanthrol was prepared by modification of the same
approach, starting with 2-bromobenzaldehyde and 2-methoxy-
phenylboronic acid. The remaining isomer, 2-phenanthrol, was
synthesized by oxidation of 2-acetylphenanthrene to 2-acetoxy-
phenanthrene with m-chloroperbenzoic acid and basic hydrolysis
based on a procedure we reported for synthesis of 2-hydroxypyr-
ene derivatives.21
The 1-, 3-, 6-, 8-, 9-, and 12-phenol isomers of benzo[a]pyrene
were synthesized via the modifications of the Pd-catalyzed Suzuki
cross-coupling methodology recently reported.16 7-Hydroxy-BaP
(42b) was synthesized from 9,10-dihydrobenzo[a]pyrene-7(8H)-
one (40) via conversion to the enol acetate derivative (41), de-
hydrogenation with o-chloranil to the phenol acetate (42a), and
acid-catalyzed hydrolysis (Scheme 3).22
Benzo[a]pyren-10-ol (46b) was synthesized from 40 via indium-
catalyzed reduction with Me3SiHCl23 to 7,8,9,10-tetrahydrobenzo-
[a]pyrene (43). Oxidation of 43 with DDQ and H2O24 gave
7,8-dihydro-BaP-10(9H)-one (44), and this was transformed to
benzo[a]pyren-10-ol (46b) via acid-catalyzed reaction with Ac2O to
the enol acetate (45), followed by dehydrogenation with o-chlor-
anil, and acid-catalyzed hydrolysis.
The remaining PAPs, benz[a]anthracen-7-ol (27) and pyren-1-
and -2-ol (25 and 26), were prepared by modifications of the
published methods.
4.2.3. 30-Methoxy-2-(2-methoxyvinyl)biphenyl (37). To a solution of
methyltriphenyl-phosphonium chloride (3.24 g, 9.5 mmol) in dry
ether (30 mL) under argon was added dropwise a 1.0 M solution of
t-BuOK (9.5 mL, 9.5 mmol) in dry THF at room temperature for 1 h,
then a solution of 36 (800 mg, 3.8 mmol) in THF (30 mL) was added
dropwise. The solution was stirred overnight and then evaporated
to dryness under vacuum, and the crude product was purified by
chromatography on a column of silica gel eluted with EtOAc/hex-
anes (1:40) to give a mixture of the E- and Z-isomers of 37 as
a yellow oil (848 mg, 93%) that was used directly in the next step.
4.2.4. 1-Methoxy- and 3-methoxyphenanthrene (38a and 39a). To
a solution of 37 (180 mg, 0.75 mmol) in CH2Cl2 (10 mL) was added
MeSO3H (0.05 mL) under argon at 0 ꢀC, and the solution was stirred
overnight. TLC showed the reaction to be complete. A saturated
solution of NaHCO3 (2 mL) was added, and stirring was continued
for 15 min. Then the organic layers were evaporated to dryness. The
residue was purified by preparative TLC with EtOAc/hexanes (1:50).
The first fraction was 39a (84 mg, 54%), and the second fraction was
38a (39 mg, 25%). The NMR data for 38a and 39a were in agreement
with the values reported.25
4.2.5. 1-Phenanthrol (38b). To a solution of 38a (60 mg, 0.31 mmol)
in dry CH2Cl2 (15 mL) at -78 ꢀC was added dropwise a solution of
BBr3 (1 M, 0.5 mL) in CH2Cl2, and the resulting solution was stirred
overnight, allowing the solution to warm to room temperature. The
solution was then cooled to 0 ꢀC, reaction was quenched with water
(1 mL), and solvent was removed under reduced pressure. The
aqueous suspension was extracted with EtOAc (15 mL ꢁ3), the
collected organic layers were washed with brine, dried over an-
hydrous Na2SO4 and evaporated to dryness. Chromatography of the
residue on a silica gel column eluted with EtOAc/hexanes (1:2) gave
38b as a yellow solid. NMR data were closely similar to those of an
authentic sample.
4. Experimental
4.1. General
Caution. Benzo[a]pyrene (BaP) has been designated a human
carcinogen by the World Health Organization.9 Carcinogens should
be handled with caution following the procedures recommended in
the publication NIH Guidelines for the Laboratory Use of Chemical
Carcinogens. The phenol and quinone isomers of BaP are not pres-
ently considered to pose carcinogenic hazards. However, recent
investigations have provided evidence that benzo[a]pyren-7,8-
dione (10) is an active metabolite of BaP that may contribute to
initiation of lung cancer.10a Prudence dictates that it should be
handled with appropriate caution.
4.2.6. 3-Phenanthrol (39b). Demethylation of 39a by the procedure
used for preparation of 38b gave 39b as a yellow solid. NMR data
matched that of an authentic sample.
o-Iodoxybenzoic acid (IBX) was prepared by the improved
procedure
reported
by
Frigero
et
al.25
Bis(tri-
fluoroacetoxy)iodobenzene (BTI) was used as supplied by the
Aldrich Chemical Co. The 1H and 13C NMR spectra were determined
in CDCl3 unless otherwise stated with TMS as an internal standard.
4.2.7. 4-Phenanthrol. Synthesis of this isomer was carried out by
analogous sequence from reaction of 2-bromobenzaldehyde
(4.14 g, 22.4 mmol) with 2-methoxyphenylboronic acid (3.04 g,
20 mmol). The adduct was obtained as a yellow oil (381 mg, 90%)
whose NMR data were in good agreement with that reported.27
Wittig reaction of the adduct followed by the acid-catalyzed cy-
clization gave 4-methoxyphenanthrene, and demethylation by
treatment with BBr3 furnished 4-phenanthrol as a yellow solid. The
NMR data were in good agreement with those of an authentic
sample.
4.2. Synthesis of polycyclic aromatic phenols
4.2.1. Phenanthrol isomers. 1-, 3-, and 4-phenanthrol were syn-
thesized by the Pd-catalyzed Suzuki cross-coupling methodology
previously reported.14 Syntheses of 1- and 3-phenanthrol (38b and
39b) are depicted in Scheme 2.
4.2.2. 30-Methoxybiphenyl-2-carboxaldehyde (36). To a solution of
2-bromobenzaldehyde (3.68 g, 20 mmol) in dimethoxyethane
(50 mL) under argon was added Pd(PPh3)4 (462 mg, 0.4 mmol). The
resulting solution was stirred at room temperature for 20 min, then
a solution of 3-methoxyphenylboronic acid (3.65 g, 24 mmol) in
EtOH (38 mL) was added. After 20 min, a solution of Na2CO3
(6.36 g) in water (30 mL) was added, and the mixture was heated at
reflux overnight. The solution was cooled and concentrated under
reduced pressure. The residue was treated with CH2Cl2 (50 mL ꢁ3)
and water, and the organic phase was washed with brine and dried
over anhydrous Na2SO4. The solvent was removed by vacuum, and
the residue was purified by chromatography on a silica gel column
4.2.8. 2-Phenanthrol. To
a
solution of 2-acetylphenanthrene
(440 mg, 2.0 mmol) in CHCl3 (15 mL) was added m-CPBA (1.7 g,
9.8 mmol), and the resulting mixture was stirred at room temper-
ature overnight. A saturated solution of sodium metabisulfite
(30 mL) was added, and the mixture was stirred for 30 min and
extracted with CH2Cl2 (25 mL ꢁ3). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and evap-
orated to dryness under vacuum. Chromatography of the residue on
a silica gel column eluted with EtOAc/hexanes (1:10) gave 2-ace-
toxyphenanthrene as a white solid (220 mg, 47%). This was
deacetylated by treatment with KOH (400 mg, 3.0 mmol) in
refluxing EtOH (20 mL). 2-Phenanthrol was obtained as a pale

A. Wu et al. / Tetrahedron 66 (2010) 2111–2118
2117
yellow solid (120 mg, 81%). NMR data matched those of an au-
thentic sample.
vacuum. The residue was purified by chromatography on a silica gel
column to furnish the PAQ.
BTI Oxidation. To a solution of the PAP (1 equiv) in DMF and H2O
(2:1) was added dropwise a solution of BTI (2 equiv) in DMF/H2O at
0 ꢀC, and the resulting mixture was stirred at 0 ꢀC until TLC showed
disappearance of the PAP (~2 h). The mixture was extracted with
EtOAc, washed with water and brine, and the solvent was removed
under vacuum. Chromatography of the residue on a silica gel col-
umn provided the pure PAQ.
4.2.9. Other phenol isomers. 1- and 2-Anthrol,28 benz[a]anthracen-
7-ol (24),29–31 and pyrene-1- and -2-ol (25 and 26)32–34 were
synthesized by the modifications of the published methods.
4.2.10. Phenol isomers of benzo[a]pyrene. Benzo[a]pyren-1-, 3-, and
9-ol were prepared by the methods recently reported.16 Benzo[a]-
pyren-8-ol was synthesized by the published method.14a Ben-
zo[a]pyren-7-ol (42b) was synthesized from 9,10-dihydro-
benzo[a]pyrene -7(8H)-one (40) by conversion to the enol acetate
(41), dehydrogenation with o-chloranil, and hydrolysis (Scheme 3)
by the published procedure.22 Benzo[a]pyren-10-ol (46b) was
synthesized from 40 by the sequence depicted in Scheme 3.
4.4. Polycyclic aromatic quinones
4.4.1. Phenanthren-1,2-dione (3). Red solid, mp 201–203 ꢀC (lit.19
202–204 ꢀC, red needles). 1H NMR data are in agreement with
values reported.19,37
4.4.2. Phenanthrene-1,4-dione (4). Yellow solid, mp 151–152 ꢀC
(lit.19 152–154 ꢀC, yellow needles). 1H NMR data agree with values
reported.19,37
4.2.11. 7,8,9,10-Tetrahydrobenzo[a]pyrene (43). Compound 40 was
deoxygenated to 43 by indium-catalyzed reduction with
Me2SiClH.23 To a solution of 40 (270 mg, 1 mmol) in CH2Cl2 (1 mL)
under argon was added a solution of InCl3 (22 mg, 0.1 mmol) and
Me2SiClH, 0.27 mL, 3 mmol) in CH2Cl2 (1 mL). The solution was
stirred overnight, then EtOAc (10 mL) and silica gel (10 g) were
added, and the solvent was evaporated. Chromatography of the
product on a silica gel column eluted with EtOAc/hexanes (1: 25)
afforded 43 as a white solid (84.5 mg, 33%), mp 91–93 ꢀC (lit.35 92–
93 ꢀC).
4.4.3. Phenanthren-3,4-dione (5). Mp 131–132 ꢀC (lit.37 133 ꢀC).
NMR data agree with values reported.37
4.4.4. Anthracen-1,2-dione (7). Mp 170–175 ꢀC (decomp.) (lit.20
169–176 ꢀC decomp.). 1H NMR data agree with values reported.20
4.4.5. Anthracen-1,4-dione (8). Mp 219–221 ꢀC (lit.38 218–221 ꢀC).
NMR data agree with values reported.38
4.2.12. 7,8-Dihydrobenzo[a]pyrene-10(9H)-one (44). Oxidation of
43 with DDQ and H2O by the method of Lee and Harvey24 furnished
44 as a red solid (87 mg, 75%), mp 174–175 ꢀC (lit.24 173–175 ꢀC).
The structural assignments of the benzo[a]pyrenedione isomers
were confirmed by comparison of their 1H and 13C NMR spectra
with those of authentic samples and/or with NMR spectral data
reported: benzo[a]pyren-7,8-dione (10),14 benzo[a]pyren-7,10-
4.2.13. 10-Acetoxy-7, 8-dihydrobenzo[a]pyrene (45). To a solution of
43 (108 mg, 0.4 mmol) in isopropenyl acetate (10 mL) was added p-
toluenesulfonic acid monohydrate (10 mg) and Ac2O (1 mL), and
the solution was heated at reflux for 24 h. The solvents were
evaporated by vacuum, and chromatography of the residue on
a silica gel column eluted with EtOAc/hexanes (1: 20) afforded 45 as
a pale-red solid (184.6 mg, 97%).
39
dione (11). benzo[a]pyren-9,10-dione (14),16 benzo[a]pyren-1,6-
dione (18),16 benzo[a]pyren-3,6-dione (21),16
Acknowledgements
This investigation was supported by NIH Grants (P01 CA 92537,
R01 CA 039504, R01 ES 015857, and P30 ES 013508).
4.2.14. 10-Acetoxybenzo[a]pyrene (46a). To a solution of 45 (75 mg,
0.24 mmol) in toluene (15 mL) was added o-chloranil (62 mg,
0.25 mg), and the solution was stirred for 24 h at 80 ꢀC. Following
evaporation of the solvent, the residue was chromatographed on
a silica gel column eluted with EtOAc/hexanes (1: 10 to 1: 5).
Compound 46a was obtained as a yellow solid (66 mg, 58%).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.12.022.
References and notes
4.2.15. 7,8-Benzo[a]pyren-10-ol (4bb). To a solution of 46a (76 mg,
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monohydrate (75 mg), and the solution was heated at reflux over-
night. Following removal of the solvent under vacuum, the residue
was purified by chromatography on a silica gel column. Elution
with EtOAc: hexanes (1:5) gave 46b as a yellow solid (40 mg, 57%),
mp 156–157 ꢀC (lit.36 155–157 ꢀC). NMR data are in agreement with
that reported.36
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