Iron-catalyzed ortho-selective functionalization of phenols: A straightforward strategy towards the 2′-hydroxyphenyl-1,2-dione skeleton

Article abstract of DOI:10.1002/ejoc.201001180

An iron-catalyzed ortho-functionalization of phenols was developed. The reactions of simple phenols with α-hydroxy ketones provide a novel and efficient method to construct 2′-hydroxyphenyl-1,2-dione derivatives. An iron-catalyzed ortho-functionalization of phenols was developed. The reactions of simple phenols with α-hydroxy ketonesprovide a novel and efficient method to construct 2′-hydroxyphenyl-1,2-dione derivatives.

Full text of DOI:10.1002/ejoc.201001180

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001180
Iron-Catalyzed ortho-Selective Functionalization of Phenols: A Straightforward
Strategy towards the 2Ј-Hydroxyphenyl-1,2-dione Skeleton
Xingwei Guo,[a] Wenjuan Li,[a] and Zhiping Li*[a]
Keywords: Iron / C-H activation / Ketones / Fused-ring systems / Phenols
An iron-catalyzed ortho-functionalization of phenols was de-
veloped. The reactions of simple phenols with α-hydroxy
ketones provide a novel and efficient method to construct 2Ј-
hydroxyphenyl-1,2-dione derivatives.
bonds reacted with indoles and pyrroles under the oxidative
conditions,[9] there is no example for simple phenols
(Scheme 1, pathway C).[10] Therefore, it is a great challenge
to achieve the ortho-specific functionalization of simple
phenols.
Introduction
Direct functionalization of phenolic C–H bond has at-
tracted much attention because phenols are one of the most
important aromatic compounds in nature and industry.[1]
The Friedel–Crafts reaction is one of the most well-known
and powerful strategies for such a transformation.[2] How-
ever, usually it is difficult to control the regio- and/or mono-
selectivity if no directing group is present in the benzene
ring (Scheme 1, pathway A). Although transition-metal-cat-
alyzed selective aromatic C–H bond activation reactions,
such as the Murai-type reaction,[3] have been studied exten-
sively, simple phenols are not suitable substrates due to the
formation of unfavorable four-membered metallacycles.[4]
To achieve ortho-selectivity,[5] attractive complementary ap-
proaches include he application of an extra stoichiometric
reagent,[6] a phosphinite co-catalyst,[7] or ligand.[8] In these
cases, only sp2-hybridized carbon atoms can be used
(Scheme 1, pathway B). Although enolizable sp3 C–H
Results and Discussion
The numerous advantages of iron make it highly attract-
ive as a catalyst or reagent for chemical synthesis.[11] The
challenge of selective functionalization of phenols
prompted us to investigate the reaction of phenol (1a) and
α-hydroxyphenylacetone (2a) in the presence of an iron cat-
alyst (Table 1). FeCl3·6H2O and FeCl3 failed to give any
oxidative coupling products (Table 1, Entries 1 and 2). A
trace amount of 1,2-dione derivative 3a[12] was found when
Fe(OAc)2 was used as the catalyst (Table 1, Entry 3). Inspi-
Table 1. Optimization of reaction conditions.[a]
Entry
[Fe]
1a [equiv.]
Oxidant
Yield [%][b]
1
2
3
4
5
6
7
8
9
FeCl3·6H2O
FeCl3
Fe(OAc)2
FeCl2
FeBr2
FeI2
1
1
1
1
1
1
3
3
3
3
3
3
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
tBuOOH trace
m-CPBA trace
(tBuO)2
–
N.D.[c]
N.D.
trace
57
55
N.D.
82
FeCl2
FeCl2
FeCl2
–
FeCl2
FeCl2
Scheme 1. Functionalization of phenol C–H bond.
10
N.D.
N.D.
trace
11
12[d]
(tBuO)2
[a] Department of Chemistry, Renmin University of China,
Beijing 100872, China
[a] Conditions: 2a (0.5 mmol), [Fe] (0.05 mmol), oxidant
(1.5 mmol), and CH2Cl2 (1.0 mL), 60 °C, 24 h. [b] Determined by
1H NMR spectroscopy. [c] Not detected by 1H NMR spectroscopy.
[d] TEMPO (0.5 mmol) was added.
Fax: +86-10-6251-6444
E-mail: zhipingli@ruc.edu.cn
Supporting information for this article is available on the
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X. Guo, W. Li, Z. Li
SHORT COMMUNICATION
rationally, moderate yields of 3a were obtained by the appli- Table 2. Reactions of phenols 1 and α-hydroxy ketones 2.[a]
cation of FeCl2 and FeBr2 (Table 1, Entries 4 and 5). How-
ever, FeI2 did not promote this reaction (Table 1, Entry 6).
We were pleased to find that an 82% yield of 3a was
achieved when 3 equiv. of phenol was used (Table 1, En-
try 7). Other oxidants were not effective (Table 1, Entries 8
and 9). The control experiments suggested that both the
iron catalyst and the oxidant are essential for the formation
of 3a (Table 1, Entries 10 and 11). TEMPO, a radical trap-
ping reagent, prohibited the reaction (Table 1, Entry 12).
The generality of the reaction was investigated under the
optimized conditions (Table 2). Phenols with ortho- and
para-substituents were transformed smoothly into the cor-
responding products in good yields (Table 2, Entries 1–5).
A halogen substituent such as iodine was tolerated under
the reaction conditions, which facilitates further transfor-
mation (Table 2, Entry 3). meta-Substituted phenols pro-
vided the completely regioselective products 3g and 3h
(Table 2, Entries 6 and 7). These results indicate that the
regioselectivity of the reactions is dependent on the steric
hindrance of phenols 1. An allyl substituent was also toler-
ated (Table 2, Entry 8). Importantly, polyhydroxy phenols
afforded the desired products smoothly (Table 2, Entries 9
and 10). These results suggest that the phenoxy radical is
unlikely involved due to the radical quenching effect of
polyhydroxy phenols. Vinyl and alkyl α-hydroxy ketones re-
acted with phenols to give the desired products in moderate
to good yields (Table 2, Entries 11–14). It should be noted
that benzofuranones were obtained for alkyl α-hydroxy
ketone substrates (Table 2, Entries 13 and 14).[13] 2Ј-Hy-
droxyphenyl-1,2-dione derivatives are present in a variety
of natural products and exhibit biological activity.[14] How-
ever, multistep procedures are generally required to con-
struct the 2Ј-hydroxyphenyl-1,2-dione skeleton.[15] On the
other hand, although regioselective acylation of phenols
can be accomplished by other means, it would be very diffi-
cult to prepare acylation reagents for the synthesis of 2Ј-
hydroxyphenyl-1,2-dione derivatives. Thus, we envisioned
that the present method would provide an alternative strat-
egy to build this unique skeleton.
A tentative reaction pathway for the present transforma-
tion is proposed in Scheme 2. The ortho-selectivity of the
reaction invokes iron-chelated intermediate A,[9e] which has
one molecule of phenol attached. An intramolecular Frie-
del–Crafts reaction leads to ortho-specific intermediate B.
This step is reversible because of the isotopic effect (KIE =
2.5) attributed to the ability of B to return to A[16] was ob-
served in our study. The tautomerization of B would pro-
vide C. Subsequently, hydrogen abstraction affords radical
intermediate D. Finally, ferric oxidation gives desired prod-
uct 3 and regenerates the ferrous catalyst.
[a] Conditions: 1 (1.5 mmol), 2 (0.5 mmol), FeCl2 (0.05 mmol),
(tBuO)2 (1.5 mmol), and CH2Cl2 (1.0 mL), 60 °C, 24 h. [b] Isolated
yield.
We did some preliminary studies of the reaction mecha-
nism. The reaction of 1a with 2-oxo-2-phenylacetaldehyde (3)]. The oxidation of 2a was performed in the absence of
(4) was carried out under the standard reaction conditions phenols 1 [Equation (2)]. Although this reaction gave a
[Equation (1)]. To our delight, desired product 3a was complex mixture of products, aldehyde 4 was indeed ob-
1
formed in 77% yield, which is consistent with the result of served by H NMR spectroscopic analysis, combined with
Entry 7 in Table 1. In order to further verify this hypothesis, a trace amount of formal oxidative product 5.[17] This result
two control experiments were performed [Equations (2) and indicated that oxidation of 2a to aldehyde 4 occurred in this
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Iron-Catalyzed ortho-Selective Functionalization of Phenols
(4)
Conclusions
In summary, we have developed a novel ortho-selective
functionalization of simple phenols, which allows the
unique 2Ј-hydroxyphenyl-1,2-dione scaffold to be con-
structed. The mild reaction conditions, the generality of the
substrates, and the application of an iron catalyst are also
attractive merits for the present transformation. Further
studies on the mechanism, scope, and synthetic applications
of the reactions are in progress.
Scheme 2. A tentative mechanism for the formation of 3.
transformation. To our surprise, the reaction of 1a with a
1:1 mixture of 2a and 4 led to 3a in only 23% yield [Equa-
tion (3)]. This result could not support free 4 as one inter-
mediate, because the reactions of 2a with 4 and/or them-
selves are much faster and lead to other byproducts rather
than desired product 3a. Thus, aldehyde 4 is most likely
generated in situ through the coordination of 2a to the iron
catalyst (e.g. intermediate A).
Experimental Section
Representative Procedure: To a mixture of phenol (1a; 1.5 mmol), α-
hydroxyphenylacetone (2a; 0.5 mmol), and FeCl2 (0.05 mmol) was
added dichloromethane (1.0 mL) under a nitrogen atmosphere at
room temperature. Then, di-tert-butyl peroxide (1.5 mmol) was
slowly dropped into the mixture under a nitrogen atmosphere. The
reaction temperature was raised to 60 °C for 24 h. The reaction
solution was cooled to room temperature. The resulting reaction
solution was quenched with saturated NaHCO3 (2 mL) and ex-
tracted with dichloromethane (3ϫ3 mL). The extract was washed
with saturated NaHCO3 (2ϫ10 mL) and deionized water (10 mL).
The extract was dried with MgSO4. The solvent was evaporated in
vacuo to afford the crude product. NMR yields were determined by
1H NMR spectroscopy by using mesitylene as an internal standard.
Solvent was evaporated, and the residue was purified by flash col-
umn chromatography (silica gel; ethyl acetate/petroleum ether,
1:100). The fraction with Rf = 0.6 (ethyl acetate/petroleum ether,
(1)
1
1:6) was collected to give desired product 3a. H NMR: δ = 11.39
(s, 1 H), 7.97 (d, J = 7.2 Hz, 2 H), 7.68 (t, J = 7.2 Hz, 1 H), 7.57–
7.47 (m, 3 H), 7.46 (dd, J = 8.0, 1.6 Hz, 1 H), 7.07 (dd, J = 8.4,
0.8 Hz, 1 H), 6.87 (td, J = 8.0, 0.8 Hz, 1 H) ppm. 13C NMR: δ =
199.2, 191.9, 163.3, 138.0, 135.1, 132.6, 132.3, 129.9, 129.1, 119.7,
(2)
(3)
118.6, 116.8 ppm. FTIR (ATR): ν = 3064, 2987, 2315, 1726, 1680,
˜
1620, 1579, 1481, 1452, 1385, 1311, 1228, 1157, 1028, 887, 758,
721 cm–1. MS (EI): m/z (%) = 226 [M]+, 121 (100), 105, 93, 77,
65, 63, 51, 39, 27. HRMS calcd. for C14H10NaO3 249.0522; found
249.0523.
Supporting Information (see footnote on the first page of this arti-
cle): Representative experimental procedure and characterization
of all new compounds.
Another possible reaction pathway is that a sequence of
oxidative esterification[18] and Fries rearrangement could
also provide the regioselective product. Accordingly, phenyl
2-oxo-2-phenylacetate (6) was synthesized and subjected to
the reaction under the standard conditions [Equation (4)].
As 3a was not observed, a Fries rearrangement of 6 is ex-
cluded. However, other reaction pathways still cannot be
ruled out at the present stage. The details of the mecha-
nisms need further investigation and will be reported in due
time.
Acknowledgments
We thank the National Natural Science Foundation of China
(20832002) for financial support. We also thank Profs. Zhenfeng
Xi and Zhi-Xiang Yu at Peking University for helpful discussions.
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X. Guo, W. Li, Z. Li
SHORT COMMUNICATION
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Received: August 23, 2010
Published Online: September 17, 2010
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