Magnesium Lewis Acid Assisted Oxidative Bromoetherification Involving Bromine Transfer from Alkyl Bromides with Aldehydes by Umpolung of Bromide

Article abstract of DOI:10.1002/chem.201602055

An oxidative bromoetherification involving a bromine transfer from alkyl bromides upon reacting them with aldehydes in a Grignard reaction with a concurrent oxidation of bromide was developed to provide substituted tetrahydrofurans in high yields. This reaction, which proceeds through two types of bromine transfer, was promoted by the addition of a Br?nsted acid. Mechanistic studies suggested that a magnesium Lewis acid activates hypobromate, which is generated in situ from the reaction of bromide and Oxone to improve the electrophilicity of the bromonium ion (Br⁺) for the oxidative bromoetherification of alkenyl alcohols. Furthermore, the magnesium Lewis acid catalyzed oxidative bromoetherification of an alkenyl alcohol proceeded to provide a cyclization product in 92 % yield.

Full text of DOI:10.1002/chem.201602055

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Title: Magnesium Lewis Acid Assisted Oxidative Bromo-etherification Involving Bro-
mine Transfer from Alkylbromides with Aldehydes via Umpolung of Bromide
Authors: Katsuhiko Moriyama; Chihiro Nishinohara; Hideo Togo
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To be cited as: Chem. Eur. J. 10.1002/chem.201602055
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COMMUNICATION
Magnesium Lewis Acid Assisted Oxidative Bromo-etherification
Involving Bromine Transfer from Alkylbromides with Aldehydes
via Umpolung of Bromide
Katsuhiko Moriyama,*[a,b] Chihiro Nishinohara[a] and Hideo Togo*[a]
Dedication ((optional))
Abstract: An oxidative bromo-etherification involving bromine
transfer from alkylbromides upon reacting with aldehydes via the
Grignard reaction and the oxidation of bromide was developed to
provide substituted tetrahydrofurans in high yields. This reaction,
which proceeds through the two types of bromine transfer, was
promoted by the addition of a Brønsted acid. Mechanistic studies
suggested that magnesium Lewis acid activates hypobromate
generated from the reaction of bromide and Oxone® in situ to
improve the electrophilicity of bromonium ion (Br+) for the oxidative
bromo-etherification of alkenyl alcohols. Furthermore, the
magnesium Lewis acid catalyzed oxidative bromo-etherification of
alkenyl alcohol proceeded to provide a cyclization product in 92%
yield.
Oxidative transformation via the umpolung of halides (I–, Br–,
and Cl–) into halonium ions (X+) using oxidants is an essential
process in many organisms[1] and has attracted much attention
as a green sustainable method in organic synthesis.[2] We have
developed various oxidative transformations via the umpolung of
bromide using alkali metal bromides[3], which are one of the
most abundant natural resources on earth. Alkali metal bromides
Figure 1. Novel synthetic strategy for oxidative bromo-cyclization via umpolung
are stable in air, easy to handle, natural, and non-toxic, and non-
elaborating products polluted the environment instead of utility of
organic bromo reagents, such as N-bromosuccinimide (NBS),[4]
of bromide.
1,3-dibromo-5,5-dimethylhydantoin
(DBH),[5]
2,4,4,6-
activation of bromonium intermediate. In 2013, Yamamoto and
Tomioka et al. reported an one-pot transformation that involved
the addition and PhI(OAc)2-mediated halo-cyclization of -
alkenyl Grignard reagents with aldehydes.[12] We report herein
the high performance of the magnesium Lewis acid assisted
oxidative bromo-etherification involving bromine transfer from
alkylbromides to -bromomethyl tetrahydrofurans in the
presence of aldehydes via the umpolung of bromide (Figure 1b).
First, we chose the transformation of 3-butenyl bromide (1a) with
benzaldehyde (2a) as an example of oxidative bromo-
etherification through bromine transfer and screened for the
optimum Brønsted acid, oxidant, and solvent in the second step
(Table 1). Treatment of 2a with 3-butenyl magnesium bromide
that was generated from 1a by reacting with magnesium in THF
at –10 ºC, followed by the oxidative bromo-etherification with
Oxone® in the absence of a Brønsted acid in a mixture of THF
tetrabromocyclohexa-2,5-dienone (TBCO),[6] and pyridinium
tribromide[7] (Figure 1a). Among these compounds, hypobromate
(HOBr), a bromonium intermediate generated by the oxidation of
bromide
from
alkali
metal
bromide
with
Oxone®
(2KHSO5•KHSO4•K2SO4) is activated by a Brønsted acid to
promote bromo-cyclization.[8] On the other hand, the
intramolecular halo-cyclization (5-exo-trig cyclization) of 5-
hydroxy pentene derivatives is a valuable process to provide
substituted tetrahydrofuran derivatives, which are important
structures in natural products and biologically active products.[9]
This reaction was previously developed by using ingenious
methodologies.[10] Based on the oxidative halo-etherification via
the umpolung of halide,[11] we focus our attention on the Lewis
acid assisted oxidative bromo-etherification as an acid assisted
and
dioxane
(2:1),
gave
2-(bromomethyl)-5-
[a]
[b]
Prof. Dr. K. Moriyama, Ms. C. Nishinohara, and Prof. Dr. H. Togo
Department of Chemistry, Graduate School of Science, Chiba
University
1-33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
E-mail: moriyama@faculty.chiba-u.jp, togo@faculty.chiba-u.jp
Prof. Dr. K. Moriyama
phenyltetrahydrofuran (3a) in 20% yield together with 1-phenyl-
4-penten-1-ol in 74% yield (Entry 1). The addition of TsOH•H2O
(3.0 equiv.) in the second step improved the oxidative bromo-
etherification to obtain 3a in 89% yield (trans:cis = 75:25) (Entry
2). Other combinations of Brønsted acids, oxidants, and
solvents were much less effective than that used in second step
of the reaction with TsOH•H2O and Oxone® in THF and dioxane
(Entries 3–15). The use of MeNO2 and MeCN as solvent
Molecular Chirality Research Center, Chiba University
1-33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))

Chemistry - A European Journal
10.1002/chem.201602055
COMMUNICATION
(Entries 5 and 6) and TfOH as Brønsted acid (Entry 12) gave
similar reactivities to the use of TsOH•H2O in THF and dioxane.
Interestingly, the oxidative bromo-etherification that employed
water as Brønsted acid provided desired product 3a in 61% yield
(trans:cis = 70:30) (Entry 16). Use of half the amount of
TsOH•H2O for the oxidative bromo-etherification drastically
decreased the yield of 3a (Entry 17).
and thiophene (2q) also gave corresponding products (3m–3q)
in high yields (70–93%) in the present reaction. It is noteworthy
that the reaction with aliphatic aldehydes (2r and 2s) and ,-
unsaturated aldehyde (2t) efficiently proceeded to provide
desired products (3r–3t) in 62%–76% yields. 3-Methyl-3-butenyl
bromide bearing disubstituted terminal alkene (2u) could also be
used, and tetrahydrofuran with a quaternary carbon center (3u)
was obtained in 74% yield with moderate diastereoselectivity
(trans:cis = 64:36).
TsOH•H2O
Table 1. Screening for oxidative bromo-etherification of 1a and 2a through
O
Mg
Oxone®
Br
R1
bromine transfer via umpolung of bromide.[a]
Br
Br
+
R2
R1
R2
H
O
THF
–10 ºC,Time1
THF: Dioxane
rt, Time2
Brønsted Acid
1
2
3
O
Mg
Oxidant
Br
Product, Yield (Dr = trans:cis), and (Time1, Time2)
Br
+
Ph
O
THF
–10 ºC, 2 h
THF: Solvent
rt, 20 h
Ph
H
Br
Br
1a
2a
3a
O
O
O
t-Bu
F
Entry
Brønsted Acid
Oxidant
Solvent
Yield
[%][b]
Dr
[trans:cis][c]
66:34
75:25
69:31
70:30
74:26
71:29
74:26
59:41
60:40
66:34
68:32
65:35
69:31
-
3b, 84% (73:27)
3c, 89% (75:25)
3d, 76% (73:27)
(6 h, 24 h)
(6 h, 24 h)
(2 h, 18 h)
1
-
Oxone®
Oxone®
Oxone®
Oxone®
Oxone®
Oxone®
Oxone®
mCPBA
PhI(OAc)2
K2S2O6
Oxone®
Oxone®
Oxone®
Oxone®
Oxone®
Oxone®
Oxone®
Dioxane
Dioxane
THF
20 [74]
89
Br
Br
Br
2
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
PhSO3H
TfOH
O
O
O
Cl
Br
MeO
3
84 [12]
57 [33]
86
3f, 85% (72:28)
3e, 81% (73:27)
(6 h[b], 48 h[c,d]
3g, 82% (67:33)
(0.5 h[d], 20 h[d,e]
(2 h, 20 h)
)
)
4
Et2O
Br
Br
Br
Br
Br
5
MeNO2
MeCN
O
O
O
F3C
6
83
3h, 84% (67:33)[f]
(0.5 h[d], 20 h[d]
3i, 79% (73:27)
(6 h, 24 h)
3j, 82% (73:27)
(12 h[c], 18 h[g]
)
)
7[d]
8
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
31 [25]
62 [10]
56 [31]
72 [10]
78 [8]
85
Br
Br
Br
O
O
O
9
3k, 81% (72:28)
3m, 93% (74:26)
3l, 62% (74:26)
10
11
12
13
14
15
16
17[e]
(6 h, 28 h)
(2 h, 18 h)
(12 h, 18 h)
Br
Br
Br
O
S
O
O
Tf2NH
56
3n, 70% (80:20)
3o, 87% (72:28)
3p, 83% (65:35)
(6 h[b], 18 h)
(2 h, 20 h)
(6 h, 30 h)
(PhO)2P(O)OH
PhCO2H
H2O
0 [96]
0 [92]
61 [11]
21 [67]
Br
Br
Ph
Br
-
O
O
O
S
70:30
66:34
3r, 76% (70:30)
3s, 73% (79:21)
3q, 73% (65:35)
(2 h[b], 18 h[e]
(2 h, 18 h)
(2 h, 18 h)
)
TsOH•H2O
Br
Br
Ph
O
[a] 1a (1.5 equiv.), Mg (1.5 equiv.), Brønsted acid (3.0 equiv.), and oxidant (2.0
equiv.) were used in THF (0.17 M) and solvent (0.5 M). [b] Number in brackets
indicates yield of 1-phenyl-4-penten-1-ol. [c] Diastereoselectivity of 3a was
determined by 1H-NMR analysis. [d] E2O was used instead of THF under first
step conditions. [e] TsOH•H2O (1.5 equiv.) was used.
O
3t, 62% (56:44)[f]
3u, 74% (64:36)
(6 h[b], 14 h)
(2 h, 18 h)
Scheme 1. Oxidative bromo-etherification of 1 and 2 through bromine transfer
via umpolung of bromide.[a] [a] 1a (1.5 equiv.), Mg (1.5 equiv.), TsOH•H2O (3.0
equiv.), and Oxone® (2.0 equiv.) were used in THF (0.17 M) and dioxane (0.5
M). [b] The reaction was carried out at –40 ºC. [c] Oxone® (1.8 equiv.) was
used in THF:dioxane (3:2, 0.1 M). [d] The reaction was carried out at 0 ºC. [e]
H2O (2.0 equiv.) was used instead of TsOH•H2O. [f] The reaction was carried
out in Et2O at first step, and in MeNO2 at the second step. [g] The reaction was
carried out in THF:dioxane (3:2, 0.1 M).
To explore the substrate scope for the oxidative bromo-
etherification through bromine transfer, alkylbromides (1) and
aldehydes (2) were examined under the optimum conditions
(Scheme 1). When monosubstituted benzaldehydes (2b–2l)
were used, corresponding tetrahydrofuran derivatives (3b–3l)
were obtained in high yields (62–89%), respectively. Di- and tri-
substituted benzaldehydes (2m and 2n), 1-naphthylaldehyde
(2o), and heterocyclic aldehydes bearing benzothiophene (2p)

Chemistry - A European Journal
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COMMUNICATION
The above-mentioned example of the oxidative bromo-
etherification through bromine transfer is formally composed of a
bromine-returned type transfer, which bromine atom released
from 4-butenyl group by the Grignard reaction returns to original
group via oxidative cyclization, with alkenylbromides and
aldehydes (Scheme 2, Type A). In contrast, this methodology
can be also developed into the bromine-released type oxidative
bromo-etherification, which bromine atom released from
hydrocarbon group on organic bromides by the Grignard
reaction adds to an alkenyl group on alkenyl aldehydes (Scheme
2, Type B).
O
Scheme 4. Various oxidative halo-etherifications through halogen transfer
umpolung of halide.
Br
Br
+
+
(Type A)
(Type B)
R
O
R
H
O
Br
R
Br
R
O
H
Scheme 2. Utility of oxidative bromo-etherification through bromine transfer via
umpolung of bromide.
Thus, we investigated the oxidative bromo-etherification with
various aryl bromides (4) and alkenyl aldehydes (5) as the next
examples (Scheme 3). Treatment of bromobenzene (4a) and 4-
pentenal (5a) with magnesium, TsOH•H2O, and Oxone® in a
mixture of THF and dioxane provided desired product (3a) in
79% yield, whose diastereoselectivity was similar to that of the
Type A reaction (refer to Table 1, entry 2). Use of bulky
bromomesitylene (4b) as an aryl bromide for the present
reaction also furnished corresponding product (3n) in high yield.
Other 4-pentenals bearing various substituents, such as 2,2-
dimethyl (5b), 2,2-diphenyl (5c), and 2-phenyl (5d), efficiently
reacted with 4a to produce tri- and tetra-substituted
tetrahydrofurans (3v–3x) in high yields (69–91%), respectively.
Product, Yield (Dr = trans:cis), and (Time1, Time2)
Br
Br
Br
O
Ph
O
Ph
O
3v, 85% (80:20)[b]
3a, 79% (73:27)
3n, 80% (84:16)
(2h, 18 h)
(2 h, 18 h)
(2 h, 18 h)
Ph
Ph
Ph
Ph
Ph
Br
Br
O
O
3w, 91% (91:9)
3x, 69% (71:13:10:6)
(2 h, 18 h)
(2 h, 18 h)
Scheme 3. Oxidative bromo-etherification of 4 and 5 through bromine transfer
via umpolung of bromide.[a] [a] 1a (1.5 equiv.), Mg (1.5 equiv.), TsOH•H2O (3.0
equiv.), and Oxone® (2.0 equiv.) were used in THF (0.17 M) and dioxane (0.5
M). [b] The reaction was carried out in Et2O at the first step, and in MeNO2 at
the second step.
Scheme 5. Mechanistic studies of magnesium Lewis acid assisted oxidative
bromo-etherification through bromine transfer via umpolung of bromide. [a]
Number in brackets indicates recovery of 10. [b] Diastereoselectivity of 3a was
determined by 1H-NMR analysis.

Chemistry - A European Journal
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COMMUNICATION
Furthermore, we investigated various halo-etherifications using
present manner (Scheme 4). For oxidative 6-exo bromo-
cyclization of 5-bromo pentene (6) with 2a, the corresponding
substituted tetrahydropyran 7 was obtained in 53% yield (dr =
20: 80) with cis-isomer as a major product (eq.1). Oxidative
iodo-etherification of iodobenzene (8) with 5a provided 2-
(iodomethyl)-5-phenyltetrahydrofuran (9) in 55% yield (trans:cis
= 65:35) (eq.2).
From the results of mechanistic studies of the present reaction,
we suggest that magnesium Lewis acid promotes the oxidative
bromo-etherification of alkenyl alcohols through the activation of
hypobromate. Based on the suggestion, we also found that the
Mg(OTf)2-catalyzed oxidative bromo-etherification of alkenyl
alcohol 6a proceeded well. We have high hopes that the
magnesium Lewis acid catalyzed transformation via oxidation of
bromide would be applicable to fine organic synthesis.
To elucidate the active species for the oxidative bromo-
etherification through bromine transfer, we investigated some
mechanistic studies for the reaction (Scheme 5). When phenyl
magnesium bromide was treated with an equal amount of H2O
or TsOH•H2O as Brønsted acid, which can generate respectively
Mg(OH)Br or Mg(OTs)Br in situ, for the oxidative bromo-
etherification of alkenyl alcohol 10, cyclization product 3a was
obtained in low yield. By contrast, use of twice the amount of
TsOH•H2O generated Mg(OTs)2 and HBr in situ, which proceed
the bromo-cyclization to give 10 in 80% yield with 73:27
diastereoselectivity (Scheme 5A). This result suggested that the
oxidative bromo-etherification was promoted by strong
magnesium Lewis acid and HBr to obtain the cyclization product.
Experimental Section
General procedure for oxidative bromo-etherification through
bromine transfer from alkylbromides (1) with aldehydes (2).
To a solution of Mg turnings (36.5 mg, 1.5 mmol) in dry THF (4.0 mL)
was added dropwise 4-bromo-1-butene (1a) (151.1 L, 1.5 mmol) at
room temperature. After the reaction mixture was stirred at room
temperature for 2 h, a solution of benzaldehyde (2a) (102.0 L, 1.0
mmol) in dry THF (2.0 mL) was added dropwise to the resulting solution
at –10 ºC. The reaction mixture was stirred at –10 ºC for 2 h. Then,
TsOH•H2O (570.6 mg, 3.0 mmol) was added and the reaction mixture
was warmed up to room temperature. This was followed by the addition
of Oxone® (1.23 g, 2.0 mmol) and 1,4-dioxane (2.0 mL). After the
reaction mixture was stirred at room temperature for 17 h, saturated
Na2SO3 aqueous solution (20 mL) was added and the product was
extracted with AcOEt (20 mL×3). The combined extracts were washed
with brine (20 mL) and dried over Na2SO4. The organic phase was
concentrated under reduced pressure and the crude product was purified
by silica gel column chromatography (eluent: hexane/AcOEt = 50/1) to
give desired product 3a (215.8 mg, 89% yield, trans:cis = 75:25).
Accordingly, the oxidative bromo-cyclization of 10 with aq. HBr
and Oxone® in the presence of a stoichiometric amount of
Mg(OTs)2 prepared from Mg(n-Bu)2 and TsOH•H2O provided
desired product 3a in 76% yield (Scheme 5B, eq.3). In contrast,
the reaction in the absence of Mg(OTs)2 showed moderate
reactivity, and 3a was produced in 50% yield (Scheme 5B, eq.4,
Entry 1). The addition of TsOH also gave 3a in moderate yield
(Scheme 5B, eq.4, Entry 2). It was found that magnesium but
not TsOH fulfilled the role of a Lewis acid activator for the
oxidative bromo-etherification. Moreover, use of commercially
available Mg(OTf)2, which has higher Lewis acidity than
Mg(OTs)2, for the oxidative bromo-etherification increased the
yield of 3a to 89% (Scheme 5C).
Magunesium Lewis acid catalyzed oxidative bromo-etherification of
alkenyl alcohol (10).
To a solution of 10 (40.6 mg, 0.25 mmol), Oxone® (184.4 mg, 0.30 mmol),
and Mg(OTf)2 (16.1 mg, 0.05 mmol) in MeCN (1.0 mL) was added 45%
HBr aq. (34.2 L, 0.30 mmol) at room temperature. After the reaction
mixture was stirred at room temperature for 18 h, saturated Na2SO3
aqueous solution (10 mL) was added and the product was extracted with
AcOEt (10 mL×3). The combined extracts were washed with brine (10
mL) and dried over Na2SO4. The organic phase was concentrated under
reduced pressure and the crude product was purified by silica gel column
chromatography (eluent: hexane/AcOEt = 50/1) to give desired product
3a (55.3 mg, 92% yield, trans:cis = 71:29).
Based on the results in Scheme 5, we carried out the
magnesium-catalyzed oxidative bromo-etherification of 10 and
obtained desired product 3a in high yield (92% yield) (Scheme
6). This reaction, which proceeded efficiently, involved the
treatment of 10 with aq.HBr and Oxone® in the presence of a
catalytic amount of Mg(OTf)2 (20 mol%) in MeCN at room
temperature.
Acknowledgements ((optional))
Financial support in the form of a Grant-in-Aid for Scientific
Reseach (No.2055033) from the Ministry of Education, Culture,
Sports, Science and Technology in Japan (K. M.) and the Naito
Foundation in Japan (K. M.) is gratefully ackowledged.
Scheme 6. Mg(OTf)2-catalyzed oxidative bromo-etherification of alkenyl
Keywords: Bromine-transfer • Bromo-etherification •
Magnesium • Umpolung • Tetrahydrofurans
alcohol 10.
In conclusion, we developed an oxidative bromo-etherification
that involved bromine transfer from alkylbromides or aryl
bromides upon reacting with aldehydes via the umpolung of
bromide to obtain substituted tetrahydrofurans in high yields.
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Chemistry - A European Journal
10.1002/chem.201602055
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Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
10.1002/chem.201602055
Katsuhiko Moriyama,* Chihiro
Nishinohara, Hideo Togo*
Page No. – Page No.
Magnesium Lewis Acid Assisted
Oxidative Bromo-etherification
involving Bromine Transfer from
Alkylbromides with Aldehydes via
Umpolung of Bromide
Activation of HOBr: An oxidative bromo-etherification involving bromine transfer
from alkylbromides or arylbromides upon reacting with aldehydes via Grignard
reaction and oxidation of bromide was developed to provide the various substituted
tetrahydrofurans in high yields. This reaction, which proceeds through the two types
bromine transfer, was promoted by the magnesium Lewis acid activation of
hypobromate.