Bromoetherification of Alkenyl Alcohols by Aerobic Oxidation of Bromide: Asymmetric Synthesis of 2-Bromomethyl 5-Substituted Tetrahydrofurans

Article abstract of DOI:10.1002/adsc.201801557

An asymmetric synthesis of 2-bromomethyl-5-substituted tetrahydrofurans via a chiral-ruthenium-catalyzed transfer hydrogenation of 3-butenyl ketones and bromoetherification of chiral pentenyl alcohols was developed. The inhibition of some side reactions furnished the desired products in high yields with high enantioselectivities. In addition, chiral pentenyl alcohols bearing electron-donating groups triggered substrate racemization in the aerobic bromoetherification.

Full text of DOI:10.1002/adsc.201801557

Title: Bromoetherification of Alkenyl Alcohols by Aerobic Oxidation of
Bromide: Asymmetric Synthesis of 2-Bromomethyl 5-Substituted
Tetrahydrofurans
Authors: Akihiko Tomizuka and Katsuhiko Moriyama
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801557
Link to VoR: http://dx.doi.org/10.1002/adsc.201801557

10.1002/adsc.201801557
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Bromoetherification of Alkenyl Alcohols by Aerobic Oxidation
of Bromide: Asymmetric Synthesis of 2-Bromomethyl 5-
Substituted Tetrahydrofurans
Akihiko Tomizukaa and Katsuhiko Moriyamaa*
a
Department of Chemistry, Graduate School of Science, and Molecular Chirality Research Center, Chiba University, 1-
33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
Phone: (+81)-43-290-3693; Fax: (+81)-43-290-3693; E-mail: moriyama@faculty.chiba-u.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
skeleton,[5]
chiral-ruthenium- bromoetherification that furnishes products with high
no
asymmetric
intramolecular
Abstract. An asymmetric synthesis of 2-bromomethyl-5-
substituted tetrahydrofurans via
a
catalyzed transfer hydrogenation of 3-butenyl ketones and
bromoetherification of chiral pentenyl alcohols was
developed. The inhibition of some side reactions furnished
the desired products in high yields with high
enantioselectivities. In addition, chiral pentenyl alcohols
bearing electron-donating groups triggered substrate
racemization in the aerobic bromoetherification.
optical purity has been established. We envisioned
that the enantioselective reduction of butenyl ketones,
followed by the intramolecular bromoetherification of
chiral pentenyl alcohols by the aerobic oxidation[6] of
bromide, would provide chiral substituted
tetrahydrofurans efficiently (Scheme 1b). To the best
of
our
knowledge,
transition-metal-free
bromoetherification via aerobic oxidation of bromide
has not been developed. The asymmetric reduction
using a transition-metal catalyst may lead to
isomerization, producing various internal alkene
products as byproducts.[7] Therefore, it is also
important to control the chemoselectivity of terminal
alkenes in the enantioselective reduction using a
transition-metal catalyst.[8,9] We report herein the
asymmetric synthesis of chiral substituted
Keywords: Aerobic Oxidation; Bromoetherification;
Enantioselective reduction; Catalytic reaction;
Tetrahydrofuran
The functional group selective transformation of
organic compounds is an important strategy to
provide desired products efficiently for fine organic
synthesis. Although the transformation by bromide
oxidation has attracted considerable attention as an
environmentally friendly and practical methodology,
the oxidized bromine causes some reactions in
organic molecules because it has both cationic and
radical characters that promote electrophilic addition
reaction, radical reaction, and so on.[1] For example,
the oxidation of alcohols using bromide and an
oxidant has been reported (Scheme 1a, top).[2] In
addition, dibromination and oxybromination by the
addition of oxygen nucleophiles as in the
electrophilic addition reaction of alkenes, easily
proceed with molecular bromine (Scheme 1a,
middle).[3] As shown above, the acceleration of the
intramolecular bromocyclization in these side
reactions is a challenging task for the transformation
via the oxidation of bromide (Scheme 1a, bottom).
On the other hand, chiral 2,5-disubstituted
tetrahydrofuran derivatives are important structures in
natural products and biologically active products.[4]
Although the intramolecular bromoetherification of
substituted pentenyl alcohols is an extremely useful
way to construct the 2,5-disubstituted tetrahydrofuran
tetrahydrofurans involving
a
transition-metal-
catalyzed enantioselective reduction and an
intramolecular bromoetherification via the aerobic
a) Reactivity of alkenyl alcohols by oxidation of bromide
O
R
Br
Oxidation
O2
OH
Br
OH
Br
OH
or
Br
R
R
R
Br
OH
Dibromination or Oxybromination
Br
R
O
Bromocyclization
b) Asymmetric synthesis of 2-substituted 5-bromomethyl
tetrahydrofurans by aerobic oxidation of bromide
O
OH
*
Asymmetric reduction
R
R
Bromocyclization
by aerobic oxidation of bromide
Br
*
*
R
O
Scheme 1. Strategy for synthesis of chiral 2,5-disubstituted
tetrahydrofuran derivatives.
1
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10.1002/adsc.201801557
Advanced Synthesis & Catalysis
(S,S)-Ts-DENEB
OH
O
oxidation of bromide.
(1.0 mol%)
R1
R1
First, we focused on the chiral-ruthenium-catalyzed
enantioselective transfer hydrogenation[9] for the
enantioselective reduction of butenyl ketones and
performed a screening for ruthenium catalyst in the
reaction of 3-butenyl-phenyl-ketone (1a) (Table 1).
Treatment of 1a using RuCl[(S,S)-Tsdpen](p-
cymene) ((S,S)-A) as the chiral catalyst in
HCO2H/Et3N at room temperature gave the desired
alcohol ((S)-2a)[10] in 56% yield with 94% ee together
with 37% of recovered 1a (entry 1). Use of tethered
ruthenium catalysts ((S,S)-B and (S,S)-C) at room
temperature improved the yield and enantioselectivity
of (S)-2a without the formation of any byproduct
(entries 3 and 6). However, the use of (S,S)-A–C at
60 ºC resulted in the formation of byproducts 3 and 4
resulting from reactions at the terminal olefin moiety,
even though the reactivity of the reduction was
increased (entries 2, 4, and 6). An enantioselective
transfer hydrogenation of 1a on a 1 mmol scale also
gave (S)-2a in 94% yield with 97% ee (entry 7).
HCO2H/Et3N (5:2), rt
36 h
R2
R2
(S)-2
1
Product (2), Yield (%), and ee (%)
OH
OH
OH
F
Cl
2b: 93% (97% ee)
2c: 92% (97% ee)
2d: 93% (90% ee)
OH
OH
OH
F3C
Br
MeO
2g: 98% (96% ee)
2e: 96% (90% ee)
2f: 94% (92% ee)
OH
OH
OH
MeO
2j:[a] 90% (93% ee)
2h: 97% (95% ee)
2i: 97% (98% ee)
OH
OH
OH
2l:[a] 0% (91%)[b](- % ee)
2k:[a] 99% (97% ee)
2m:[a] 99% (91% ee)
OH
OH
OH
Ph
Table 1. Screening for chiral Ru catalyst in
enantioselective transfer hydrogenation.
S
2o: 89% (98% ee)
OH
Ru-catalyst
O
2n: 98% (97% ee)
2p:[a] 90% (96% ee)
HCO2H/Et3N (5:2)
Temp., Time
Ph
Ph
Ph
OH
(S)-2a
OH
1a
OH
+
+
Ph
2q:[a] 97% (11% ee)
3
4
< Ru-catalyst >
(S,S)-A
(S,S)-B
(S,S)-C
Scheme 2. Enantioselective transfer hydrogenation of 1.
[a] (S,S)-Ts-DENEB (5.0 mol%) was used. [b] Recovery of
1l.
O
Ms
O
Ts
Ru
N
Ru
N
Ru
Ts
Cl
Cl
Cl
N
N
N
H2N
H
H
Ph
Ph
Ph
Ph
(S,S)-Ms-DENEB
Ph
(S,S)-Ts-DENEB
Ph
RuCl[(S,S)-Tsdpen](p-cymene)
Table 2. Screening for additive and solvent in
bromoetherification of rac-2a via aerobic oxidation of
bromide.
Entry Cat. Temp. Time Yield (2a/3/4)
Ee of
2a
[ºC]
[h]
[%]
NaNO2 (10 mol%)
Mg(OTf)2 (x mol%)
aq. HBr (1.2 equiv.)
[%ee]
94
90
95
93
96
95
97
1
2
3
4
A
A
B
B
C
C
C
rt
60
rt
60
rt
60
rt
24
24
24
6
24
6
56/0/0 [37][a]
68/7/5 [8][a]
97/0/0
83/12/1
99/0/0
OH
Br
Ph
Solvent, rt, 1 h
Under O2
O
rac-5a
Ph
rac-2a
Entry
x
Solvent
Yield
[%]
Dr of 5a
[trans:cis]
71:29
5
6
78/16/4
94/0/0
1
2
3
4
5
6
0
0
0
0
0
0
MeCN
AcOEt
DMF
CH2Cl2
THF
80[19][a]
7[b]
36
19[20][a][58][b] 68:32
[a] Recovery of 1a. [b] Reaction on 1 mmol scale.
33[12][a][50][b] 73:27
46[1][a][47][b]
0[95][b]
65:35
-
71:29
To explore the substrate scope for the
enantioselective transfer hydrogenation, butenyl
ketones (1) were examined under the optimum
conditions (Table 1, entry 7) (Scheme 2). Treatment
of monosubstituted phenyl butenyl ketones bearing
electron-donating groups and electron-withdrawing
groups (1b–1j), as well as disubstituted phenyl
butenyl ketone (1k) furnished corresponding alcohols
(2b–2k) in excellent yields with 90–98% ee.
Unfortunately, trisubstituted phenyl substrate (2l) was
almost unreactive. Substrates with 1-naphthyl (1m),
benzothiophene (1n), disubstituted alkene (1o), and
MeCN:CH2Cl2 84[12][a]
(1:1)
7
0
MeCN:CH2Cl2 71[4][a][18][b]
(1:2)
68:32
69:31
69:31
70:30
8
10 MeCN:CH2Cl2 85[9][a]
(1:1)
9
20 MeCN:CH2Cl2 91[8][a]
(1:1)
10
20 MeCN:CH2Cl2 56[8][a][28][b]
(1:1)
-(3,4-dibromobutyl)-benzenemethanol.
[b]Recovery of 2a. [c] Under air.
[a]Yield
of
2
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10.1002/adsc.201801557
Advanced Synthesis & Catalysis
alkynyl (1p) groups also provided chiral alcohols
(2m–2p) in excellent yields with high enantiomeric
excess. The reaction of aliphatic ketone (1q)
generated product (2q) in excellent yield but with
unsatisfactory enantiomeric excess.
Next, we screened for the additive and the solvent in
the bromoetherification of rac-2a to unfurl the
When non-substituted alcohol (2a), p-substituted
alcohols bearing Cl (2d), Br (2e), and CF3 (2f) groups,
m-substituted alcohols (2h and 2i), and o-substituted
alcohol (2j) were used in the bromoetherification,
chiral bromomethyl tetrahydrofurans (5a, 5d, 5e, 5f,
and 5h–j) were obtained in high yields (81–92%)
with trans-selectivity (dr = 67:33–72:28) without loss
of optical purity. Treatment of alcohols bearing p-Me
(2b), p-F (2c), m-diMe (2k), and 1-naphthyl (2m)
phenyl groups with NaNO2/Mg(OTf)2/aq. HBr under
O2 gave corresponding products (5b, 5c, 5k, and 5m)
with 81–92% ee, indicating slight racemization. In
particular, the reaction of substrates with electron-
rich aryl groups, such as p-MeO phenyl (2g) and
asymmetric
synthesis
of
2,5-substituted
tetrahydrofurans (Table 2).
Bromoetherification of rac-2a in MeCN provided
rac-5a in 80% yield (entry 1). The use of CH2Cl2 as
solvent gave rac-5a in 46 % yield together with a
small amount of byproduct, indicating the high
chemoselectivity of the reaction (entry 4). Other
solvents did not improve the yield of rac-5a (entries 2, benzothiophene (2n), was found to cause significant
3, and 5). Further screening for the reaction
conditions (entries 6–10) revealed that the optimum
conditions would be attained in the presence of 20
mol% Mg(OTf)2 as the additive in the solvent
mixture of MeCN and CH2Cl2 (1:1) under O2, which
gave rac-5a in 91% yield (entry 9).
We further examined the substrate scope in the
asymmetric bromoetherification of chiral substituted
pentenyl alcohols ((S)-2) via the aerobic oxidation of
bromide (Scheme 3).
racemization of products 5g and 5n (2–64% ee).
Alkynyl alcohol with 96% ee (2p) also underwent the
bromoetherification to give corresponding product
(5p) in 87% yield with the desired enantiomeric
excess. The bromoetherification of racemic tri-
substituted phenyl alcohol (2l) and aliphatic alcohol
(2q) occurred to give desired products (5l and 5q) in
high yields (75% and 84%, respectively) with trans-
selectivity (dr = 79:21 and 70:30, respectively).
To elucidate the racemization mechanism in the
bromoetherification, we carried out supporting
experiments of the reaction (Scheme 4).
Bromoetherification of 2g with NBS provided desired
product (5g) in 97% yield but with low optical purity
(39% ee/40% ee) (eq. 1). Treatment of 2g with aq.
HBr led to the low recovery of 2g (24%) with 1% ee
and the generation of many byproducts (eq. 2).[11]
NaNO2 (10 mol%)
Mg(OTf)2 (20 mol%)
aq. HBr (1.2 equiv.)
OH
Br
R2
R1
R1
MeCN/CH2Cl2 (1:1), rt
Under O2
O
R2
(R)-5
(S)-2
Product (5), Time (h), Yield (%) (Dr (trans:cis)), and ee (%)
Br
Br
Br
O
O
Ph
O
F
OH
Br
NBS (1.2 equiv.)
5a: 1 h, 91% (69:31)
(95% ee/ 96% ee)
5b:[a,b] 1 h, 89% (70:30)
(90% ee/ 88% ee)
5c: 1 h, 91% (69:31)
(91% ee/ 89% ee)
(1)
O
MeCN/CH2Cl2 (1:1)
rt, 4 h
MeO
MeO
MeO
Br
Br
Br
Br
2g (95% ee)
5g: 97% (51:49)
(39% ee/40% ee)
OH
O
O
O
F3C
Br
Cl
Br
OH
5d: 2 h, 88% (68:32)
(89% ee/ 89% ee)
5e:[b] 1 h, 87% (69:31)
(90% ee/ 90% ee)
5f: 2 h, 89% (67:33)
(90% ee/ 90% ee)
aq.HBr (1.2 equiv.)
(2)
MeCN/CH2Cl2 (1:1), rt
1 h
MeO
MeO
Br
2g (95% ee)
2g, 24%, 1% ee
O
O
O
MeO
5g:[a,b] 1 h, 92% (63:37)
5h:[a,b] 1 h, 81% (68:32) 5i:[a] 1 h, 90% (69:31)
Scheme 4. Mechanistic studies of the racemization in the
bromoetherification.
(2% ee/ 3% ee)
(94% ee/ 93% ee)
(94% ee/ 95% ee)
Br
Br
Br
O
O
O
Based on the results in Scheme 4, we suggest that the
racemization of substrates in this reaction is caused
by the bromo radical or proton under the acidic
conditions.
5j:[b] 2 h, 92% (72:28)
(90% ee/ 88% ee)
5l:[a,b] 3 h, 75% (79:21)
5k: 1 h, 85% (71:29)
(90% ee/ 92% ee)
(- % ee/ - % ee)
Br
Br
Br
O
S
Ph
O
We propose
a
reaction mechanism for the
O
Me
bromoetherification of chiral alkenyl alcohols (2) via
the aerobic oxidation of bromide, including the
racemization of alcohols, on the basis of mechanistic
studies (Scheme 5). The aerobic oxidation of bromide
with NaNO2 and O2 occurs to generate Br2, which
functions as a bromo cation or a bromo radical in
situ.[2d,6] In addition, Mg(OTf)2 as a Lewis acid
catalyst assists in the formation of the bromo cation
species by trapping the counteranion to control
chemoselectivity of the aerobic bromoetherification.
The bromo cation species reacts with the -electron
5m:[a,b] 3 h, 91% (67:33)
(87% ee/ 81% ee)
5n:[b] 24 h, 86% (62:38) 5o:[a,c] 1 h, 74% (70:30)
(64% ee/ 64% ee)
(98% ee/ 97% ee)
Br
Br
O
O
5p: 2 h, 87% (57:43)
(95% ee/ 96% ee)
5q: 24 h, 84% (70:30)
(- % ee/ - % ee)
Scheme 3. Asymmetric bromoetherification of (S)-2 via
aerobic oxidation of bromide. [a] MeCN/CH2Cl2 (1:1, 0.25
M). [b] NaNO2 (20 mol%). [c] NaNO2 (50 mol%).
3
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10.1002/adsc.201801557
Advanced Synthesis & Catalysis
< Reaction mechanism including racemization of chiral alcohols >
HCO2H and Et3N, to give the desired product (5a) in
74% yield with high enantioselectivity (97% ee/97%
ee).
O2
path B
NO2
H2O
Br
HO
H
NO
H2O
HNO3
To demonstrate the synthetic utility of the chiral
bromoetherification product, we investigated the
path A
HBr
Br2
MeO
Br
derivatization
of
2-bromomethyl-5-
path A
phenyltetrahydrofuran (5a) via simple C–heteroatom
bond formation to obtain heteroatom combined
products (Scheme 7). Treatment of 5a with sodium
benzoate as the oxygen nucleophile and potassium
phthalimide as the nitrogen nucleophile in DMSO at
80 ºC provided corresponding products (6a and 7a) in
high yields in unchanged diastereomeric and
enantiomeric ratios.
HO
H
Br
Br
path B
O
MeO
MeO
racemization path
Br
H
High optical purity
OH
HO
H
Br
MeO
path B
MeO
O
MeO
MeO
Low optical purity
or
Ph
PhCO2Na (1.2 equiv.)
O
OH2
HO
H
Ph
O
DMSO, 80 ºC, 48 h
O
H
6a: 85% (dr = 71: 29)
(96% ee/ 96% ee)
O
Br
MeO
H2O
(path via dehydration under acidic conditions (path C))
Ph
(1.2 equiv.)
NK
O
5a
(dr = 69:31)
(95 %ee/ 96 %ee)
O
N
O
DMSO, 80 ºC, 48 h
Scheme 5. Plausible reaction mechanism in the
bromoetherification via aerobic oxidation.
Ph
O
O
7a: 84% (dr = 70: 30)
(96% ee/ 95% ee)
on alkene to promote intramolecular cyclization. This
electrophilic addition reaction of alkene is favored
and the cyclization products have high optical purity
(path A). On the other hand, the bromo radical
abstracts a hydrogen atom from the substrate benzyl
position to generate a benzyl radical intermediate that
immediately promotes the racemization of substrate
(path B). The concerted abstraction of benzylic
hydrogen atom on substrate bearing a p-methoxy
phenyl group (2g) with a strong resonance effect is
more favored than the bromocyclization to obtain the
low optical purity product. In addition, it is also
possible that the racemization of these substrates
occurs via formation of benzyl cation intermediate by
dehydration under the acidic conditions (path C).
Finally, one-pot synthesis of chiral 2-bromomethyl-5-
phenyl tetrahydrofuran (5a) was investigated from 3-
butenyl-phenyl-ketone (1a) via the enantioselective
transfer hydrogenation and the bromoetherification
(Scheme 6). After the enantioselective transfer
hydrogenation of 1a with (S,S)-Ts-DENEB catalyst,
the bromoetherification via aerobic oxidation of
bromide proceed under the present conditions by
evaporation of the crude product, which removes
Scheme 7. Derivatization of substituted bromomethyl
tetrahydrofuran (5a).
In conclusion, we have developed an asymmetric
synthesis
of
2-substituted-5-bromomethyl
tetrahydrofurans via the chiral-ruthenium-catalysed
transfer hydrogenation of alkenyl 3-butenyl ketones,
followed by the bromoetherification by the aerobic
oxidation of bromide. This method controls the
chemoselectivity of the substrates to give desired
products
with
high
stereoselectivity.
The
development of an asymmetric synthesis of chiral
organic molecules by the aerobic oxidation of
halogens and the application of chiral 2-substituted-5-
bromomethyl tetrahydrofurans as chiral building
blocks are underway in our laboratory.
Experimental Section
General
Procedure
for
Ruthenium-catalyzed
Enantioselective Transfer Hydrogenation of Alkenyl
Ketones (1) (Table 1; entry 7 and Scheme 2).
A solution of 3-butenyl phenyl ketone (1a) (160.2 mg, 1.0
mmol) and (S,S)-Ts-DENEB (6.5 mg, 0.01 mmol) in a
solution mixture of HCO2H and Et3N (5:2, 500 L) was
sttierd at room temperature for 36 h under argon
atomosphere. To the reaction mixture was added water (10
mL), 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 = 8/1) to give desired product 2a (152.6 mg,
94% yield, 97% ee).
General Procedure for Bromo-etherification of Chiral
Alkenyl Alcohols (2) by Aerobic Oxidation of Bromide
(Table 2; entry 9 and Scheme 3).
Scheme 6. One-pot synthesis of chiral 2-substituted-5-
bromomethyl tetrahydrofuran (5a).
4
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10.1002/adsc.201801557
Advanced Synthesis & Catalysis
To a solution of 1-phenyl-4-penten-1-ol (2a) (40.6 mg,
0.25 mmol), NaNO2 (1.7 mg, 0.025 mmol), and Mg(OTf)2
(16.1 mg, 0.050 mmol) in a solution mixture of MeCN and
CH2Cl2 (1:1, 2.0 mL) was added 47% HBr aq. (34.7 L,
0.30 mmol) under oxygen atmosphere. After the reaction
mixture was stirred at room temperature for 1 h under
oxygen atmosphere, saturated Na2SO3 aqueous solution
(10 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/ether = 15/1) to give
desired product 5a (54.9 mg, 91% yield, trans:cis = 69:31,
95% ee/96% ee).
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Acknowledgements
Financial support by Grant for Basic Science Research Projects
from The Sumitomo Foundation in Japan is gratefully
acknowledged.
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5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801557
Advanced Synthesis & Catalysis
UPDATE
Bromoetherification of Alkenyl Alcohols by
Aerobic Oxidation of Bromide: Asymmetric
Synthesis of 2-Bromomethyl 5-Substituted
Tetrahydrofurans
O
O
Ts
Br
R2
up to dr = 79:21
(trans selectivity)
aq. HBr
Under O2
Ru
N
NaNO2
Cl
N
R1
R1
Mg(OTf)2
O
Adv. Synth. Catal. Year, Volume, Page – Page
R2
H
Ph
Ph
up to 98% ee
Akihiko Tomizuka and Katsuhiko Moriyama*
6
This article is protected by copyright. All rights reserved.