Iodine(III)-Mediated tandem acetoxylation cyclization of o-acyl phenols for the facile construction of α-acetoxy benzofuranones

Article abstract of DOI:10.1021/ol902067x

An efficient tandem acetoxylation-cyclization of o-acylphenols mediated by the combination of iodobenzene diacetate with tetrabutylammonium iodide provides a new convenient and useful route to a-acetoxy benzofuranones.

Full text of DOI:10.1021/ol902067x

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5174-5177
Iodine(III)-Mediated Tandem
Acetoxylation-Cyclization of o-Acyl
Phenols for the Facile Construction of
r-Acetoxy Benzofuranones
Renhua Fan,* Yi Sun, and Yang Ye
Department of Chemistry, Fudan UniVersity, 220 Handan Road, Shanghai, 200433,
China, and Shanghai Key Laboratory of Molecular Catalysts and InnoVatiVe
Materials, Department of Chemistry, Fudan UniVersity, Shanghai, 200433, China
rhfan@fudan.edu.cn
Received September 6, 2009
ABSTRACT
An efficient tandem acetoxylation-cyclization of o-acylphenols mediated by the combination of iodobenzene diacetate with tetrabutylammonium
iodide provides a new convenient and useful route to r-acetoxy benzofuranones.
In the past decades, a variety of organic transformations have
been shown to be mediated by the hypervalent iodine
compounds.1 In addition to their superb oxidizing properties,
a remarkable feature of the organic iodine(III) compounds
is their capability, like transition metals, to undergo ligand
exchange and reductive elimination. This activity has been
utilized to induce carbon-carbon, carbon-heteroatom, or
hetero-heteroatom bond formations to construct various
carbon- and heterocycles.2 Benzofuranones (coumaranones)
are important structural components of many medicinally and
biologically active natural and unnatural substances.3,4 The
general synthetic pathways for the preparation of benzofura-
none derivatives have involved multistep procedures or
relatively harsh reaction conditions.5 Consequently, it is
desirable to search new efficient methods for the construction
of benzofuranone derivatives. As part of a program aimed
at developing synthetic application of hypervalent iodine
compounds,6 we have demonstrated the efficiency of the
iodine(III)-induced oxidative cyclizations for the preparation
of functionalized aziridines,6b cyclopropanes,6d and
oxetanes.6h With the aim of extending this approach, we
investigated the oxidative cyclization of o-acyl phenols.
(3) (a) Brooks, C. J. W.; Watson, D. G. Nat. Prod. Rep. 1985, 427–
459. (b) Aufmkolk, M.; Koerhle, J.; Hesch, R. D.; Cody, V. J. Biol. Chem.
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Gomes, S. L.; Giesbrecht, A. M.; Amaral, A. T. J. Med. Chem. 2001, 44,
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5299–5358.
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Jamalifar, H.; Shafiee, A. Bioorg. Med. Chem. Lett. 2005, 15, 1023–1025.
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A. J. Med. Chem. 2006, 49, 329–333. (d) Hadj-esfandiari, N.; Navidpour,
L.; Shadnia, H.; Amini, M.; Samadi, N.; Ali Faramarzid, M.; Shafiee, A.
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10.1021/ol902067x CCC: $40.75
Published on Web 10/14/2009
 2009 American Chemical Society

It is well-known that phenols are ready to undergo the
oxidative dearomatization to yield quinones in the presence
of hypervalent iodine compounds.7 Meanwhile, Moriarty and
Prakash reported the oxidation of o-hydroxyacetophenones
to form coumaranones using PhI(OAc)2 and KOH in
MeOH.5a Interestingly, in our initial experiment with o-
propionylphenol 1a, which was carried out in CH3CN at 30
°C with 2 equiv of PhI(OAc)2 and 1 equiv of Bu4NI, we did
not observe the oxidative dearomatization of the phenol ring
and the formation of 2-methylbenzofuranone 3, but a product,
which was identified as 2-methyl-2-acetoxybenzofuranone
2a, was isolated in 56% yield.
Motivated by the synthetic potential of the possible
method, the reaction was further optimized by examining
various reaction conditions (Table 1). When 3 equiv of
PhI(OAc)2 and 2.5 equiv of Bu4NI were utilized, substrate1a
was consumed after 3 h and the yield of 2a was improved
to 71% (Table 1, entry 1). Some unidentifiable polar
compounds were obtained as the byproducts. In the control
experiment without Bu4NI, no 2a was formed. Substrate 1a
was recovered in 74% yield, and the same byproducts were
detected. CH3CN, CH2Cl2, THF, toluene, EtOAc, and DMF
are good solvents, while alcohols are not (Table 1, entries
1-9). When the reaction was carried out in MeOH or
t-BuOH, no 2-methyl-2-acetoxybenzofuranone 2a or 2-me-
thylbenzofuranone 3 was formed. Meanwhile, no corre-
sponding 2-alkoxy derivatives were isolated from the reac-
tions. NaOAc is a useful additive (Table 1, entry 16).
To understand the reaction pathway, several control
experiments were done (Scheme 1). As the countercation,
tetrabutylammonium cation is crucial to the reaction. Only
a trace amount of R-acetoxy benzofuranone 2a was formed
with the use of NaI or KI. When Bu4NI was replaced by
Bu4NBr, Bu4NCl, or Bu4NOAc, no reaction occurred. With
PhIO or PhI(OCOCF3)2 instead of PhI(OAc)2, reactions were
complicated and provided only a trace amount of 2a, while
some oxidative dearomatization products of substrate 1a were
isolated. It was proposed that the reaction might be mediated
by AcOI or I+, which was generated from the reaction of
Table 1. Evaluation of Reaction Conditions
entry
solvent
additive
time (h)
2a (%)a
1
2
3
CH3CN
CH2Cl2
THF
3
1
1
2
3
0.5
3
3
3
1
12
3
1
1
1
71
63
63
61
65
67
0
4
5
6
toluene
EtOAc
DMF
7
8
9
t-BuOH
MeOH
H2O
0
0
10b
11c
12
13
14
15
16
17
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
35
trace
15
61
58
83
88
55
HOAc (2 equiv)
K2CO3 (2 equiv)
t-BuOK (2 equiv)
NaOAc (2 equiv)
NaOAc (1 equiv)
NaOAc (3 equiv)
1
1
a Isolated yield based on 1a. b The reaction was carried out at 60 °C.
c The reaction was carried out at 0 °C.
PhI(OAc)2 with Bu4NI,8 and the generation of I2 was
observed during the reaction. However, when the combina-
tion of PhI(OAc)2/I2, I2/Bu4NOAc, or NIS/Bu4NOAc was
used instead of PhI(OAc)2/Bu4NI, no R-acetoxybenzofura-
none 2a was obtained. When the mixture of PhI(OAc)2,
Bu4NI, and NaOAc in CH3CN was stirred at 30 °C for 3 h
before the addtion of substrate 1a, the reaction only afforded
a trace amount of product 2a.
When 1 equiv of PhI(OAc)2 and 1 equiv of Bu4NI were
used, the reaction did not finish even after 12 h. While
product 2a was obtained in 11% yield, 48% of substrate 1a
was recovered, and an R-acetoxylation product 4 was isolated
in 38% yield.9 No 2-methylbenzofuranone 3 was isolated.
With the use of 3 equiv of PhI(OAc)2 and 2.5 equiv of Bu4NI
(Table 1, entry 1), only a trace amount of compound 4 was
detected from the reaction. R-Acetoxylation product 4 could
be converted into product 2a in 10 min with treatment with
the combination of PhI(OAc)2/Bu4NI or PhIO/Bu4NI under
the same conditions (Scheme 2). The combinations of
PhI(OAc)2/I2 and PhI(OAc)2/KOH/MeOH were not effective
in this conversion.
(5) (a) Moriarty, R. M.; Prakash, O.; Prakash, I. J. Chem. Soc., Chem.
Commun. 1984, 20, 1342–343. (b) Carvalho, C. F.; Sargebt, M. V. J. Chem.
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629–630. (f) Khanna, M. S.; Garg, C. P.; Kapoor, R. P. Synth. Commun.
1992, 22, 2555–2561. (g) Thakkar, K.; Cushman, M. J. Org. Chem. 1995,
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Org. Chem. 2005, 1731–1735.
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2492. (e) Fan, R.; Pu, D.; Gan, J.; Wang, B. Tetrahedron Lett. 2008, 49,
4925–4928. (f) Fan, R.; Li, W.; Wang, B. Org. Biomol. Chem. 2008, 6,
4615–4621. (g) Fan, R.; Li, W.; Pu, D.; Zhang, L. Org. Lett. 2009, 11,
1425–1428. (h) Ye, Y.; Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156–
3159.
A plausible reaction pathway for the PhI(OAc)2/Bu4NI-
mediated tandem acetoxylation-cyclization of o-propio-
nylphenol is outlined in Scheme 3. The reaction of PhI(OAc)2
with Bu4NI generates a higher reactive iodine(III) species
(7) (a) Moriarty, R. M.; Prakash, O. Org. React. 2001, 57, 327–415.
(b) Rodriguez, S.; Wipf, P. Synthesis 2004, 2767–2783. (c) Quideau, S.;
Pouysegu, L.; Deffieux, D. Curr. Org. Chem. 2004, 8, 113–148. (d)
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2007, 79, 701–713. (f) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008,
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React. 1999, 54, 273–418.
Org. Lett., Vol. 11, No. 22, 2009
5175

the generation of the unreactive I2, which also consumes a
part of PhI(OAc)2 and Bu4NI, makes it necessary to use 3
equiv of PhI(OAc)2 and 2.5 equiv of Bu4NI.
Scheme 1
.
Control Experiments
Scheme 3
.
Plausible Reaction Pathway for the Tandem
Acetoxylation-Cyclization
Scheme 2
The scope of this reaction was then investigated under the
optimized conditions and these results are shown in Scheme
4. The reaction was found to tolerate a range of different
substituents with different electronic demands on the phenol
Scheme 4
. PhI(OAc)2/Bu4NI-Mediated Tandem
Acetoxylation-Cyclization of o-Acyl Phenols
II and Bu4NOAc, which acts as a base to deprotonate
o-propionylphenol. The resulting enolate anion of substrate
reacts with the reactive iodine(III) species II via a ligand
exchange reaction to form an intermediate D, which is ready
to undergo the reductive elimination to yield the R-acetoxy-
lation product 4. In the presence of another II and Bu4NOAc,
compound 4 is converted into an intermediate E. This is
finally followed by the intramolecular nucleophilic displace-
ment by the oxygen anion to afford R-acetoxybenzofuranone
2a accompanied by the reductive elimination of PhI. During
the reaction, acids (AcOH or HI) are generated as the
byproducts. However, the existence of acids is not good for
the reaction (Table 1, entry 12). When NaOAc is used as
the additive, it can work as a base to eliminate the influence
of acids. Moreover, the addition of NaOAc can increase the
concentration of acetate anion to prompt the acetoxylation.
When reaction is carried out in alcoholic solvents, PhI(OAc)2
will react with alcohol to yield some other iodine(III) species
to suppress the acetoxylation and cyclization reaction.1
According to the plausible reaction pathway, a catalytic
amount of Bu4NI and 2 equiv of PhI(OAc)2 are enough to
complete the tandem acetoxylation-cyclization. However,
5176
Org. Lett., Vol. 11, No. 22, 2009

reactive to undergo the Friedel-Crafts reaction with p-xylene
to afford 2-(2,5-dimethylphenyl)-2-methylbenzofuranone 6
in 87% or 98% yield, respectively.
Scheme 5
.
Conversion of the Resulting R-Acetoxy
Benzofuranone
Figure 1. X-ray diffraction structure of 2b.
rings involving electron-withdrawing and electron-donating
groups. A moderate electronic substrate effect was observed.
For example, reaction of p-methyl-o-propionylphenol gave
rise to the corresponding product 2j in 85% yield, while
reaction of chloro- or ester-o-propionylphenol afforded
R-acetoxybenzofuranone 2c and 2e in 68% or 60% yield,
respectively. The yield was diminished when R- or ꢀ-naph-
thyl substrate was employed under the conditions. With
respect to other o-acylphenols, o-acetyl- and butyrylphenols
were also found to be suitable substrates for the tandem
acetoxylation-cyclization and the desired products 2m10 and
2n were generated in moderate to good yields. No corre-
sponding R-acetoxybenzofuranone 2o was obtained when
o-phenylacetylphenol was utilized as the substrate. The
structure of the resulting R-acetoxybenzofuranone was
confirmed by the single-crystal diffraction analysis of 2b
(Figure 1).
The acetal structure of the resulting R-acetoxybenzofura-
none made it ready to be converted into some other
benzofuranone derivatives. We have briefly explored the
conversion (Scheme 5). The treatment of product 2a with a
catalytic amount of K2CO3 in MeOH generated 2-hydroxyl-
2-methylbenzofuranone 5 in 88% yield. In the presence of
trifluoromethanesulfonic acid, products 2a and 5 were
In summary, we report here an efficient tandem
acetoxylation-cyclization of o-acylphenols mediated by
the combination of iodobenzene diacetate with tetrabu-
tylammonium iodide. R-Acetoxybenzofuranones are syn-
thesized in moderate to good yields. The acetal structure
of the resulting R-acetoxybenzofuranone made it ready
to be converted into some other benzofuranone derivatives.
The scope, mechanism, and synthetic application are
ongoing and will be reported in due course.
Acknowledgment. Financial support from National Natu-
ral Science Foundation of China (20702006), the Shanghai
Rising-Star program (07QA14007), and Shanghai Key
Laboratory of Molecular Catalysts and Innovative Materials,
Department of Chemistry, Fudan University (2009KF02) is
gratefully acknowledged.
Supporting Information Available: Experimental details
and spectral data for the major products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Malaitong, N.; Thebtaranonth, C. Chem. Lett. 1980, 305–306.
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