Hypervalent iodine(III)-LiX combination in fluoroalcohol solvent for aromatic halogenation of electron-rich arenecarboxylic acids

Article abstract of DOI:10.1055/s-0030-1260791

The novel reagent system, PhI(OAc)₂-LiX combination in fluoroalcohol solvents, was found to be effective for halodecarboxylation of electron-rich arenecarboxylic acids. The method provided an efficient route to halogenated phenol ether derivatives. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260791

LETTER
1563
Hypervalent Iodine(III)–LiX Combination in Fluoroalcohol Solvent for
Aromatic Halogenation of Electron-Rich Arenecarboxylic Acids
H
ypervalent Iodine
i
(III)–L
r
iXCom
o
binationinF
m
luoroalcohol Solve
i
nt Hamamoto, Sho Hattori, Kaori Takemaru, Yasuyoshi Miki*
School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Fax +81(6)67212505; E-mail: y_miki@phar.kindai.ac.jp
Received 12 March 2011
a,b-unsaturated carboxylic acids in many cases and they
are undesirable for the reaction of electron-rich arenecar-
boxylic acids. In this communication, we report the use of
novel reactivity of hypervalent iodine(III)–LiX combina-
tion in fluoroalcohol media for the effective iodination of
arenecarboxylic acids.
Abstract: The novel reagent system, PhI(OAc)2–LiX combination
in fluoroalcohol solvents, was found to be effective for halodecar-
boxylation of electron-rich arenecarboxylic acids. The method pro-
vided an efficient route to halogenated phenol ether derivatives.
Key words: carboxylic acids, hypervalent iodine, halogenation,
fluoroalchol, decarboxylation
In the course of our synthetic studies on the use of indole-
carboxylic acid as building blocks for bioactive com-
pounds via decarboxylative strategies, we have found the
novel ability of hypervalent iodine(III)–LiX combination
in halodecarboxylation.9 When we attempted to apply our
previous conditions,9b PhI(OAc)2–LiBr combination in
THF, for the purpose of bromodecarboxylation of elec-
tron-rich arenecarboxylic acids such as p-anisic acid, the
ring-halogenation product,10 3-bromo-p-anisic acid (2a),
was obtained but the halodecarboxylation product was not
detected (Table 1, entry 1). Additionally, no reaction oc-
curred in iododecarboxylation under our previous condi-
tions (Table 1, entry 2).
For many years, the use of arenecarboxylic acids as build-
ing blocks in chemical synthesis has received consider-
able attention due to their wide availability and low price.1
A great deal of effort has been invested to provide the syn-
thetic strategies starting from arenecarboxylic acids. De-
carboxylative transformations of arenecarboxylic acids
under the catalysis of late transition metals have generated
much interest in the past few years.1,2 On the other hand,
halodecarboxylation of carboxylic acids into halogenated
compounds, known as the Hunsdiecker-type reaction, is
another powerful alternative to offer the useful synthetic
applications of arenecarboxylic acids.3,4 Despite its im-
portance, the Hunsdiecker reaction is generally inefficient
for the conversion of arenecarboxylic acids relative to the
halodecarboxylation of aliphatic and alicyclic carboxylic
acids. Moreover, the conversion of arenecarboxylic acids
to the corresponding iodobenzene is quite difficult. There-
fore, these facts indicate the need for the creation of new
strategy for halodecarboxylation of arenecarboxylic ac-
ids.
The reluctant result prompted us to design new reaction
conditions utilizing hypervalent iodine reagent. We fo-
cused our attention on the use of the unique reactivity of
hypervalent iodine reagents in fluoroalcohol.11,12 Since
the pioneer work reported by Kita, this reactivity was
widely investigated in hypervalent iodine chemistry, and
many remarkable advantages appeared in the reaction
with phenol or phenol ether type substrates.11 In hope of
developing new reaction conditions to achieve the halode-
carboxylation of electron-rich arenecarboxylic acids, we
tried to use the fluoroalcohol solvents with the combina-
tion of PhI(OAc)2 and LiX. Gratifyingly, the bromodecar-
boxylation along with ring bromination proceeded cleanly
to provide a dibrominated product 4a when the reaction
was carried out in trifluoroethanol (TFE, CF3CH2OH) or
1,1,1,3,3,3-hexafluoroisopropanol [HFIP, CF3CH(OH)CF3]
(Table 1, entries 3 and 4). In addition, the iododecarboxy-
lation was successfully achieved by utilizing a combina-
tion of PhI(OAc)2 and LiI in fluoroalcohol solvents, and
diiodinated product 4b was smoothly obtained in HFIP,
while 4-iodoanisole (3b) was obtained in TFE as major
product (Table 1, entries 5 and 6). To our knowledge, this
is first example of high-yielding iododecarboxylation of
electron-rich arenecarboxylic acids. After tuning of
equivalence of the reagent system (Table 1, entries 7–9),
iododecarboxylation could be performed on 3 equivalents
of PhI(OAc)2 with 2 equivalents of LiI in HFIP (Table 1,
entry 9).
Over the past two decades, hypervalent iodine reagents
have gained much attention owing to their attractive fea-
tures such as low toxicity, high stability, and reactivity
similar to those of highly toxic heavy metal salts.5–7 It is
well known that upon irradiation trivalent iodine reagents,
PhI(OAc)2, undergo decarboxylative decomposition and
generate radical species.8 On the basis of this procedure,
Camps reported Hunsdiecker-type bromodecarboxylation
of aliphatic carboxylic acids and nitro-substituted benzoic
acids to the corresponding brominated compounds.8d Fur-
ther, several groups also reported the devising methodol-
ogy of hypervalent iodine mediated Hunsdiecker-type
decarboxylations. Although such heavy metal salt free ap-
proaches constitute an important method in this chemis-
try, their utility is limited for the reaction of aliphatic and
SYNLETT 2011, No. 11, pp 1563–1566
x
x
.x
x
.2
0
1
1
Advanced online publication: 15.06.2011
DOI: 10.1055/s-0030-1260791; Art ID: U02611ST
© Georg Thieme Verlag Stuttgart · New York

1564
H. Hamamoto et al.
LETTER
Table 1 Iododecarboxylation of p-Anisic Acid
CO2H
X
CO2H
X
X
X
PhI(OAc)2, MX
+
+
MeO
MeO
MeO
3a X = Br
3b X = I
MeO
1a
2a X = Br
2b X = I
4a X = Br
4b X = I
Entry
1
Oxidant (equiv)
PhI(OAc)2 (6)
PhI(OAc)2 (6)
PhI(OAc)2 (6)
PhI(OAc)2 (6)
PhI(OAc)2 (6)
PhI(OAc)2 (6)
PhI(OAc)2 (4)
PhI(OAc)2 (1)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OCOCF3)2 (3)
PhIO (3)
MX (equiv)
LiBr (6)
LiI (6)
Solvent
Temp (°C) Time (h)
Yield of 2 (%)a Yield of 3 (%)a Yield of 4 (%)a
THF
50
50
50
r.t.
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
12
12
12
12
3
59
–
–
–
–
2
THF
–
3
LiBr (6)
LiBr (6)
LiI (6)
TFE
–
–
75
85
–
4
HFIP
TFE
–
–
5
11
–
83
–
6
LiI (6)
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
3
92
90
6
7
LiI (4)
3
4
–
8
LiI (1)
3
2
60
–
9
LiI (2)
3
7
88
83
85
75
–
10
11
12
13
14
15
16
17
18
KI (2)
3
7
–
NaI (2)
TBAI (2)b
LiI (2)
3
5
–
3
9
4
3
75
–
–
LiI (2)
24
24
24
3
–
–
DMP (3)c
LiI (2)
–
–
–
HgO [red] (3)
Tl(OCOCF3)2 (3)
VOCl3 (3)
LiI (2)
–
–
–
LiI (2)
84
36
–
4
LiI (2)
24
–
–
a Yield of isolated product.
b TBAI = tetrabutylammonium iodide.
c DMP = Dess–Martin periodinate [1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one].
Additionally, other iodine salts, such as KI, NaI, or TBAI that a reagent system of PhI(OAc)2 and LiI in HFIP is the
(Bu4NI), could also applicable for this reaction instead of best condition for the iododecarboxylation of electron-
LiI (Table 1, entries 10–12). In order to find the best io- rich arenecarboxylic acids.
dodecarboxylation method, the reaction was also carried
The exciting result obtained with the reaction of p-anisic
acid (1a) prompted us to extend our procedure to various
electron-rich arenecarboxylic acids (Table 2). The reac-
tion of arenecarboxylic acid possessing p-methoxy or o-
out with various oxidants in HFIP (Table 1, entries 13–
18).7 Although ring-iodination product 2b was obtained in
some cases, no other conditions gave the iododecarboxy-
lation products sufficiently. These results clearly indicate
methoxy substituents gave the corresponding iododecar-
PhI(OAc)2 (3 equiv)
LiBr (3 equiv)
PhI(OAc)2 (3 equiv)
LiBr (3 equiv)
Br
CO2H
Br
Br
TFE, r.t., 4 h
TFE, r.t., 5 min
MeO
MeO
2a (80%)
4a (81%)
1a
PhI(OAc)2 (3 equiv)
LiI (2 equiv)
PhI(OAc)2 (3 equiv)
LiI (2 equiv)
I
I
I
HFIP, r.t., 2 min
HFIP, 50 °C, 1 h
MeO
3b (70%)
MeO
4b (89%)
Scheme 1 Sequence for dibromination and diiodination
Synlett 2011, No. 11, 1563–1566 © Thieme Stuttgart · New York

LETTER
Hypervalent Iodine(III)–LiX Combination in Fluoroalcohol Solvent
1565
boxylation products in good yields, where ring iodination
also occurred on para position of methoxy substituent
(Table 2, entries 1–10).13 In addition, the benzyl ether
moiety was not cleaved during the reaction (Table 2, en-
tries 3 and 6). When the reaction was performed with
m-anisic acid, the decarboxylation does not occur and the
ring-iodination product was obtained (Table 2, entry 11).
It is interesting to note that the reaction with the electron-
deficient arenecarboxylic acid such as p-nitrobenzoic acid
did not occur at all contrary to the previous hypervalent
iodine mediated procedures under irradiation (Table 2,
entries 12 and 13).8b,d This result suggests that our iodode-
carboxylation procedure would not involve the carboxy
radical pathway, but possibly involves the radical-cation
intermediate through an ionic path.8,12 When the reaction
was stopped in the early stages (after 2–15 min), com-
pound 2a was obtained as major product in the bromina-
tion of 1a, while 3b was obtained as major product in the
iodination of 1a.14 Therefore, ring bromination was faster
than bromodecarboxylation, while ring iodination was
slower than iododecarboxylation (Scheme 1).
Table 2 Iododecarboxylation of Arenecarboxylic Acids
PhI(OAc)2 (3 equiv), LiI (2 equiv), HFIP
Ar1CO2H
Ar2I
r.t., 1–6 h
1
4
Entry Ar1CO2H
Ar2I
Yield (%)a
88
I
I
CO2H
CO2H
CO2H
1
MeO
I
MeO
1a
1c
1d
4b
4c
4d
4b
4f
I
2
90
89
74
90
80
88
91
EtO
EtO
I
I
3
BnO
BnO
I
CO2H
I
4
OMe
MeO
MeO
1e
1f
In summary, we have developed an efficient decarboxyla-
tion method of electron-rich arenecarboxylic acids utiliz-
ing a PhI(OAc)2–LiX combination in fluoroalcohol
solvents. This new method provided an efficient route to
various iodinated phenol ether syntheses. Further applica-
tion of this method in organic synthesis and detailed in-
vestigation on the reaction mechanism are in progress.
MeO
CO2H
I
5
MeO
MeO
MeO
I
I
MeO
CO2H
CO2H
6
BnO
I
I
BnO
1g
1h
4g
4h
O
O
O
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
7
O
I
Acknowledgment
I
I
CO2H
OMe
8
This work was partially supported by Grant-in-Aid for Scientific
Research (C) from the Japan Society for the Promotion of Science
(JSPS), Young Scientists (B) from the Ministry of Education, Cul-
ture, Sports, Science and Technology (MEXT), Kinki University
Research Grant Project, and also in part ‘High-Tech Research Cen-
ter Project’ for Private Universities and matching fund subsidy.
MeO
OMe
MeO
1i
1j
4i
OMe
OMe
CO2H
I
I
9
83
OMe
OMe
I
4j
References and Notes
CO2H
I
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Synlett 2011, No. 11, 1563–1566 © Thieme Stuttgart · New York

1566
H. Hamamoto et al.
LETTER
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Synlett 2011, No. 11, 1563–1566 © Thieme Stuttgart · New York