Dehydroxymethyl Bromination of Alkoxybenzyl Alcohols by Using a Hypervalent Iodine Reagent and Lithium Bromide

Article abstract of DOI:10.1055/s-0037-1610980

We describe the dehydroxymethylbromination of alkoxybenzyl alcohol by using a hypervalent iodine reagent and lithium bromide in F ₃ CCH ₂ OH at room temperature. Selective monobromination or dibromination was possible by adjusting the molar ratios of hypervalent iodine reagent and lithium bromide.

Full text of DOI:10.1055/s-0037-1610980

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
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A. Shibata et al.
Letter
Synlett
Dehydroxymethyl Bromination of Alkoxybenzyl Alcohols by Using
a Hypervalent Iodine Reagent and Lithium Bromide
Ayako Shibataa
Sara Kitamotoa
R'
Br
PhI(OAc)2, LiBr
Kazuma Fujimuraa
Yuuka Hirosea
Hiromi Hamamotob
OH
RO
RO
CF3CH2OH
r.t., 10 min
15 examples
up to 99% yield
Akira Nakamuraa,c
Yasuyoshi Mikia,c
0
0
0
0
0-
0
0
2
4-
4
6
9
6-
5
1
9
mild conversion of alkoxybenzyl alcohols to bromides
Tomohiro Maegawa*a
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1-
5
8
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1-
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a School of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae,
Higashi-osaka, Osaka 577-8502, Japan
maegawa@phar.kindai.ac.jp
b Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku,
Nagoya 468-8502, Japan
c Research Organization of Science and Technology, Research Center for
Drug Discovery and pharmaceutical Science Ritsumeikan University,
1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
Received: 31.07.2018
Accepted after revision: 26.08.2018
Published online: 26.09.2018
tion-metal catalysts5 or inorganic salt6 are required as oxi-
dants for the reaction. This report describes a novel trans-
formation
of
alkoxybenzyl
alcohols
into
their
DOI: 10.1055/s-0037-1610980; Art ID: st-2018-u0488-l
corresponding aromatic bromides by using a combination
of a hypervalent iodine reagent and lithium bromide under
mild reaction conditions (Scheme 1).
Abstract We describe the dehydroxymethylbromination of alkoxyben-
zyl alcohol by using a hypervalent iodine reagent and lithium bromide
in F3CCH2OH at room temperature. Selective monobromination or di-
bromination was possible by adjusting the molar ratios of hypervalent
iodine reagent and lithium bromide.
Previous work
Br
CO2H
PhI(OAc)2, LiBr
(CF3)2CHOH
MeO
MeO
Key words hypervalent iodine reagent, bromination, bromoarenes,
benzylic alcohol, regioselectivity
Br
benzoic acids
This work
Organic halides are an important class of compounds in
organic synthesis, and they are widely used as synthons for
nucleophilic substitution and transition-metal-catalyzed
coupling reactions. Therefore, synthetic methods for organ-
ic halides remain important. Decarboxylative halogenation
can be used to prepare organic halides by converting car-
boxylic acids into their corresponding halides by using oxi-
dants.1 The Hunsdiecker reaction is representative of decar-
boxylative halogenation but requires relatively harsh condi-
tions or a transition metal.1e We have recently developed a
mild process for decarboxylative halogenation of aromatic
carboxylic acids by using a combination of hypervalent io-
dine reagents and alkali metal halides,2 and we have also
applied this method to total syntheses of natural com-
pounds.3 Hypervalent iodine reagents are mild oxidants
with low toxicity that exhibit a unique reactivity similar to
that of highly toxic heavy-metal oxidants. Therefore, many
researchers have developed a number of useful reactions
that use hypervalent iodine reagents.4 Alkali-metal bro-
mides are also used in aromatic brominations, but transi-
Br
PhI(OAc)2, LiBr
CF3CH2OH
OH
MeO
MeO
benzyl alcohols
Scheme 1 Conversion of benzoic acids or benzylic alcohols into the
corresponding halide
There are a few reports describing the conversion of
benzylic alcohols into their corresponding halides.7 Unfor-
tunately, most of these studies focused on the oxidation of
benzylic alcohols to aldehydes, in which halide production
was treated as a side reaction. Therefore, a full substrate-
scope analysis has not yet been performed, and hypervalent
iodine reagents have never been used specifically to pre-
pare halides from benzylic alcohols. Here, we chose 4-me-
thoxybenzyl alcohol (1a) as a substrate and we conducted
the reaction using 3.0 equivalents of PhI(OAc)2 and 3.0
equivalents of LiBr in F3CCH2OH, on the basis our previous
report. The reaction proceeded successfully, and the corre-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
A. Shibata et al.
Letter
Synlett
sponding dibrominated compound 3a was obtained in 93%
yield at room temperature within ten minutes (Table 1, en-
try 1). When other solvents were examined, the monobro-
minated compound 2a was the main product (entries 2–5),
with the aldehyde also being obtained when THF was used
as the solvent (entry 4). Decreasing the proportions of both
PhI(OAc)2 and LiBr to one equivalent in F3CCH2OH afforded
the monobrominated product 2a in 91% yield at room tem-
perature in 10 min (Entry 7).
Table 2 Monobromination of Various Substituted Benzyl Alcohols
R'
PhI(OAc)2 (1.0 equiv)
LiBr (1.0 equiv)
Br
OH
RO
RO
CF3CH2OH
r.t., 10 min
1
2
Entry Substrate
Product
Yield (%)
91
Br
Br
OH
1
MeO
Table 1 Conversion of 4-Methoxybenzyl Alcohol (1a) into the
Corresponding Halide by Using PhI(OAc)2 and LiBr
MeO
1a
2a
Br
Br
OH
OH
OH
PhI(OAc)2, LiBr
+
2
80
MeO
BnO
solvent
r.t., 10 min
BnO
MeO
MeO
1a
2a
3a
1b
2b
Br
Br
Entry
PhI(OAc)2
(equiv)
LiBr (equiv) Solvent
Yield (%)
3a
48
2a
3a
MeO
Me
MeO
Me
1c
2c
1
2
3
4
5
6
7
3.0
3.0
3.0
3.0
3.0
2.0
1.0
3.0
3.0
3.0
3.0
3.0
2.0
1.0
F3CCH2OH
CH3OH
–
93
–
MeO
–
MeO
OH
OH
4
0 (quant)a
CH3CN
81
68a
73
17
91
–
MeO
Br
MeO
THF
–
1d
4d
CH2Cl2
–
Br
OH
OMe
OH
OMe
F3CCH2OH
F3CCH2OH
69
–
5
0 (98)a
quant
1e
4e
2a
a A small amount of the aldehyde was also obtained.
Me
We then investigated the substrate scope for the mono-
bromination of various alkoxybenzyl alcohols by using 1.0
equivalent of PhI(OAc)2 and 1.0 equivalents of LiBr in
F3CCH2OH at room temperature (Table 2): 4-(benzyl-
oxy)benzyl alcohol (1b) was converted into the correspond-
ing bromide 2b in 80% yield without any oxidized product
in the benzyl ether position (entry 2). A methyl substituent
ortho to the hydroxymethyl group decreased the yield to
48% (entry 3). Electron-donating substituents caused direct
bromination of the aromatic ring, and did not result in the
desired dehydroxymethyl bromination (entry 4). The reac-
tion of 2-methoxybenzyl alcohol (1e) also gave the aromat-
ic bromination product 4e (entry 5). The secondary benzyl-
ic alcohol 1f gave the corresponding bromide 2a in quanti-
tative yield (entry 6), whereas the tertiary benzyl alcohol
1g afforded the corresponding bromide 2a but with a yield
of only 25% (entry 7). No reaction occurred with 4-methyl-
benzyl alcohol under the aforementioned conditions (entry
8).
OH
6
MeO
1f
Me Me
OH
7
2a
25
MeO
1g
Br
OH
8
0b
Me
Me
1h
2h
a The aromatic ring-brominated compound 4 was obtained.
b The corresponding aldehyde was obtained.
entry 2). 4-Methoxy-2-methylbenzyl alcohol (1c) was con-
verted into an inseparable mixture of dibrominated regio-
isomers 3c and 3c′ in 66% and 16% yield, respectively (entry
3). Dibromination of 3,4-dimethoxybenzyl alcohol (1d) suc-
cessfully gave the corresponding dibrominated product 3d
in 91% yield, whereas monobromination of 1d was unsuc-
cessful (entry 4 and Table 2, entry 4). These results demon-
strate that dehydroxymethyl bromination of 1d is possible.
However, when using one equivalent of reagent, direct bro-
mination of the aromatic ring is preferred due to the high
Next, we dibrominated the various alkoxybenzyl alco-
hols by using 3.0 equivalents of PhI(OAc)2 and LiBr in
F3CCH2OH at room temperature (Table 3). The reaction of 4-
(benzyloxy)benzyl alcohol (1b) proceeded in 90% yield to
give the dibrominated compound 3b for one hour (Table 3,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
A. Shibata et al.
Letter
Synlett
electron density of the aromatic ring as a result of the two
methoxy substituents. Dibromination of 1e proceeded to
afford 3e, but in low yield (13%), possibly due to steric hin-
drance (entry 5). In the monobromination reaction, the or-
tho-substituted substrate 1c resulted in a significantly low-
er yield of product (48%) than with substrate 1a (compare
entry 3 and Table 1, entry 1). Therefore, whereas the pres-
ence of an o-methoxy group caused a low yield of 3e, it was
effective in allowing the reaction to proceed. The reactions
of secondary and tertiary alkoxybenzyl alcohols 1f and 1g,
respectively, gave the corresponding dibrominated product
3a (entries 6 and 7, respectively).
Table 3 Dibromination of Various Alkoxybenzyl Alcohols
R'
PhI(OAc)2 (3.0 equiv)
Br
LiBr (3.0 equiv)
OH
RO
Entry
1a
RO
CF3CH2OH
r.t., 10 min
1
Br
3
Substrate
Product
Yield (%)
93
Br
OH
MeO
MeO
Br
1a
3a
We initially hypothesized that the reaction proceeds
through the oxidation of the alkoxybenzyl alcohol to the
corresponding carboxylic acid in the presence of PhI(OAc)2
and LiBr,8 with subsequent conversion of the carboxylic
acid into the corresponding bromide. However, because the
reaction even proceeded when only 1.0 equivalent of each
reagent was used, another reaction pathway was consid-
ered. Previous reports describe two reaction mechanisms.
One is the ipso-substitution of benzyl alcohol by a bromoni-
um species,7a and the other is the ipso- substitution of the
aldehyde generated by oxidation of benzyl alcohol (Scheme
2).7c In our reaction, a bromonium species such as
PhI(OAc)Br or BrOAc might be generated from the combina-
tion of PhI(OAc)2 and LiBr.8 In this case, ipso-substitution
should occur at the benzylic alcohol and not the aldehyde.
This is likely, because 1.0 equivalents of PhI(OAc)2 and LiBr
promoted the reaction, and the tertiary benzylic alcohol
underwent dehydroxymethyl bromination under our reac-
tion conditions (Table 2, entry 7 and Table 3, entry 7, re-
spectively).
Br
OH
2a
90
BnO
BnO
Br
1b
3b
Br
Br
MeO
Me
3c
OH
66b
16b
3a
Br
MeO
Me
1c
MeO
Me
Br
3c’
MeO
Br
Br
MeO
OH
4
5
91
13
MeO
MeO
1d
3d
OH
OMe
3a
3a
1) Ipso-substitution of benzyl alcohol
Br
1e
OAc–
Br
OH
OH
Me
– HCHO
MeO
MeO
MeO
OH
6
7
quant
PhIH(OAc)2
Br+
MeO
+
LiBr
1f
2) Ipso-substitution of aldehyde
Me Me
OH
Br+
Br
3a
55
PhI(OAc)2
LiBr
OH
O
O
MeO
MeO
MeO
MeO
1g
OAc–
– HCOOAc
a The reaction time was 1 h.
b These products were obtained as inseparable mixtures and the yields
were determined by 1H NMR.
Br
MeO
Scheme 2 Plausible reaction mechanism
(Scheme 3, equation 1). Moreover, the reaction of p-me-
thoxybenzyl methyl ether afforded bromoarene 2a, indicat-
ing that no oxidation of the benzyl alcohol occurred
(Scheme 3, equation 2). These results strongly imply that
the brominated product is formed by direct ipso-substitu-
We also conducted the reaction with p-anisaldehyde
under the same conditions but none of the desired product
was obtained, and only aromatic bromination proceeded
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

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A. Shibata et al.
Letter
Synlett
(e) Crich, D. In Comprehensive Organic Synthesis;
7
V
o.
l
Trost, B. M.;
PhI(OAc)2 (1.0 equiv)
LiBr (1.0 equiv)
O
O
(eq. 1)
(eq. 2)
Fleming, I., Eds.; Pergamon: Oxford, 1991, 717. (f) Wang, Z.;
Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,
4258.
(55%)
MeO
MeO
CF3CH2OH
r.t., 10 min
Br
(2) (a) Hamamoto, H.; Umemoto, H.; Umemoto, M.; Ohta, C.;
Doshita, M.; Miki, Y. Synlett 2010, 21, 2593. (b) Hamamoto, H.;
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Lett. 2012, 53, 1924.
PhI(OAc)2 (3.0 equiv)
LiBr (1.0 equiv)
Br
OMe
CF3CH2OH
r.t., 10 min
MeO
MeO
(72%)
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Scheme 3 The reactions of p-anisaldehyde and 4-methoxybenzyl
methyl ether under the optimized conditions
tion of the benzylic alcohol followed by aromatization
through dehydroxymethylation.
In conclusion, we describe a novel method for the dehy-
droxymethyl bromination of alkoxybenzyl alcohols by us-
ing a hypervalent iodine reagent and lithium bromide in
F3CCH2OH at room temperature.9,10 This is the first study
detailing the direct conversion of alkoxybenzyl alcohols to
aryl bromides. This method affords the corresponding bro-
mide regiospecifically, which might be more useful than
the Friedel–Crafts-type bromination. Selective monobromi-
nation and dibromination were achieved by changing the
proportions of reagents. This reaction is currently being ap-
plied to other halogenation processes and the elucidation of
a detailed reaction mechanism is underway.
Funding Information
This work was supported by JSPS KAKENHI Grant Numbers 18K05132
and 15K18840, and also by the MEXT-Supported Program for the
Strategic Research Foundation at Private Universities, 2014–2018
(S1411037).
)(
Acknowledgment
We thank Kindai University Joint Research Center for use of facilities.
We also thank the reviewers for their fruitful suggestions.
(8) Tohma, H.; Maegawa, T.; Takizawa, S.; Kita, Y. Adv. Synth. Catal.
2002, 344, 328.
(9) 1-Bromo-2-methoxybenzene (2a) (see Ref. 10); Typical Pro-
cedure
Supporting Information
LiBr·H2O (0.2 mmol) and PhI(OAc)2 (0.2 mmol) were added to a
solution of 4-methoxybenzyl alcohol (1a; 0.2 mmol) in
F3CCH2OH (1 mL) at r.t. When the reaction was complete (TLC),
sat. aq Na2SO3 was added and the mixture was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was
purified by column chromatography (silica gel) to give a yellow
oil; yield: 34.1 mg (91%); 1H NMR (CDCl3): δ = 3.79 (s, 3 H), 6.79
(dd, J = 2.0, 8.6 Hz, 2 H), 7.38 (dd, J = 2.0, 8.6 Hz, 2 H).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610980.
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References and Notes
(1) (a) Hunsdiecker, H.; Hunsdiecker, C. Ber. Dtsch. Chem. Ges. B
1942, 75, 291. (b) Johnson, R. G.; Ingham, R. K. Chem. Rev. 1956,
56, 219. (c) Wilson, C. V. Org. React. (N.Y.) 1957, 9, 332.
(d) Sheldon, R. A.; Kochi, J. K. Org. React. (N.Y.) 1972, 19, 279.
(10) Braddock, D. C.; Cansell, G.; Hermitage, S. A. Synlett 2004, 461.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D