Switching the reaction pathways of electrochemically generated β-haloalkoxysulfonium ions - Synthesis of halohydrins and epoxides

Article abstract of DOI:10.3762/bjoc.11.27

β-Haloalkoxysulfonium ions generated by the reaction of electrogenerated Br⁺ and I⁺ ions stabilized by dimethyl sulfoxide (DMSO) reacted with sodium hydroxide and sodium methoxide to give the corresponding halohydrins and epoxides, respectively, whereas the treatment with triethylamine gave α-halocarbonyl compounds.

Full text of DOI:10.3762/bjoc.11.27

Switching the reaction pathways of electrochemically
generated β-haloalkoxysulfonium ions – synthesis of
halohydrins and epoxides
Akihiro Shimizu, Ryutaro Hayashi, Yosuke Ashikari, Toshiki Nokami§
and Jun-ichi Yoshida*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 242–248.
Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University,
Kyotodaigaku-Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
doi:10.3762/bjoc.11.27
Received: 30 November 2014
Accepted: 30 January 2015
Published: 13 February 2015
Email:
Jun-ichi Yoshida* - yoshida@sbchem.kyoto-u.ac.jp
This article is part of the Thematic Series "Electrosynthesis".
Guest Editor: S. R. Waldvogel
* Corresponding author
§ Present address: Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University, 4-101 Koyama-
chominami, Tottori 680-8552, Japan
© 2015 Shimizu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
DMSO; electrosynthesis; epoxides; halohydrins; halogen cations
Abstract
β-Haloalkoxysulfonium ions generated by the reaction of electrogenerated Br+ and I+ ions stabilized by dimethyl sulfoxide
(DMSO) reacted with sodium hydroxide and sodium methoxide to give the corresponding halohydrins and epoxides, respectively,
whereas the treatment with triethylamine gave α-halocarbonyl compounds.
Introduction
Alkene difunctionalization through three-membered ring halo- solution (the “cation pool” method) [12-17]. Although halogen
nium ion intermediates [1] is an important transformation in cations are too unstable to accumulate in solution as “cation
organic synthesis. Usually the halonium ions such as bromo- pools”, halogen cations stabilized by an appropriate stabilizing
nium or iodonium ions are generated by the reaction of alkenes agent that coordinates the cations can be accumulated in the
with Br2 and I2 [2]. However, the most straightforward method solution. For example, “I+” cations stabilized by acetonitrile
is the reaction of alkenes with halogen cations such as Br+ and (CH3CN) [18-20] or by trimethyl orthoformate (TMOF) [21]
I+. The I+ cation pool exists as reported by Filimonov et al. [3], were reported in the literature. Recently, we reported that
although the used solvent is concentrated sulfuric acid which is dimethyl sulfoxide (DMSO) can also be used to effectively
therefore not compatible with most organic compounds.
stabilize halogen cations (Scheme 1) [22].
Electrochemical oxidation [4-11] is a potent technique to The pools of stabilized halogen cations enable alkene difunc-
generate and accumulate highly reactive cationic species in tionalization. We previously reported that the reaction of
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Beilstein J. Org. Chem. 2015, 11, 242–248.
Scheme 1: Synthesis of halohydrins and epoxides through β-haloalkoxysulfonium ions generated by the reaction of alkenes with DMSO-stabilized
halogen cations.
alkenes with DMSO-stabilized halogen cations such as Br+ and sion, triethylamine cannot attack the sulfur atom in 3a-Br and
I+ gave β-haloalkoxysulfonium ions and their subsequent treat- acts as base to abstract a proton attached to the carbon adjacent
ment with triethylamine gave α-halocarbonyl compounds to the sulfur. The formed carbanion part of the resulting sulfur
through Swern–Moffatt-type oxidation [23-27]. Recently reac- ylide abstracts a proton attached to the carbon adjacent to the
tion integration [28-31] has received significant research oxygen to give α-bromoketone 4a-Br by the Swern–Moffatt-
interest because it enhances the power and speed of organic type oxidation mechanism [23-27]. On the other hand, the
syntheses and this is an example of integration of an electro- hydroxide ion attacks the sulfur atom in 3a-Br and cleaves the
chemical reaction and a chemical reaction using a reactive inter- S–O bond to give the alkoxide ion, which is protonated by
mediate. Herein, we report that the reaction pathways of water to give bromohydrin 5a-Br (Scheme 2). The stereochem-
β-haloalkoxysulfonium ions can be switched to give different istry determined by NMR (5a-Br was synthesized using NBS
products by changing the base, thus expanding the utility of the according to the literature; see Supporting Information File 1)
present method. The treatment of β-haloalkoxysulfonium ions indicated that the addition of Br+ and DMSO across the C–C
3-X with sodium hydroxide gave the corresponding halohy- double bond was anti-selective, which is consistent with the
drins 5-X, while the treatment with sodium methoxide gave results reported previously [22].
epoxides 6 (Scheme 1).
Treatment of 3a-Br with NaOMe resulted in a different product,
Results and Discussion
namely epoxide 6a in 95% yield. In this case, the methoxide ion
Reactions of β-bromoalkoxysulfonium ions
generated from (Z)-5-decene
attacks the sulfur atom and cleaves the S–O bond under forma-
tion of an alkoxide ion. The latter intramolecularly attacks the
carbon atom bearing the bromine substituent to give epoxide 6a
(Scheme 2). Presumably, the protonation of the alkoxide ion
with MeOH is slower than the intramolecular nucleophilic
attack. We could not exclude the possibility that a protonated
DMSO molecule presumably generated by the reaction of 3a-Br
with the hydroxide ion protonates the alkoxide ion to give
5a-Br, while a methylated DMSO molecule presumably gener-
ated by the reaction of 3a-Br with the methoxide ion cannot
protonate the alkoxide ion, which converts to 6a. The stereo-
chemistry determined by NMR [32] is consistent with a mecha-
nism involving the back-side attack of the alkoxide ion to form
epoxide 6a.
We first examined the reactions of β-bromoalkoxysulfonium
ion 3a-Br generated by the reaction of (Z)-5-decene (2a) with
Br+/DMSO (1-Br) [21] (Scheme 1, X = Br). Bu4NBr in DMSO/
CH2Cl2 (1:9 v/v) was electrochemically oxidized at −78 °C in a
divided cell using Bu4NBF4 as a supporting electrolyte until
2.1 F/mol of electricity was applied. After addition of 2a to the
solution, the mixture was stirred at 0 °C to give 3a-Br, which
was characterized by NMR spectroscopy [22]. The treatment of
3a-Br with triethylamine gave α-bromoketone 4a-Br in 83%
yield [22]. However, the treatment of 3a-Br with NaOH gave
bromohydrin 5a-Br in 89% yield as shown in Table 1. These
phenomena can be explained as follows: Due to the steric repul-
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Beilstein J. Org. Chem. 2015, 11, 242–248.
Table 1: Reaction of 3a-X (X = Br, I) with different bases.a
% Yield of productb
X = Br
5a-Br
X = I
Base
4a-Br
6a
4a-Ir
5a-I
6a
Et3N/CH2Cl2
NaOH/H2O
83
ND
89
ND
2
85
ND
84
1
ND
ND
ND
ND
1
NaOMe/MeOH
ND
95
ND
96
aThe electrolysis was carried out using 1.3 equiv of Bu4NBr or Bu4NI (based on the alkene which was added after electrolysis) with 2.1 F/mol of elec-
tricity based on Bu4NBr or Bu4NI. bYields were determined by GC.
Scheme 2: Proposed reaction mechanisms for the syntheses of bromohydrin 5a-Br and epoxide 6a.
Reactions of β-iodoalkoxysulfonium ions
generated from (Z)-5-decene
I2 and H2O2; see Supporting Information File 1) indicated that
the addition of I+ and DMSO across the C–C double bond was
We next examined the reactions of β-iodoalkoxysulfonium ion anti-selective as anticipated.
3a-I generated by the reaction of (Z)-5-decene (2a) with
Synthesis of halohydrins and epoxides from
I+/DMSO (1-I) cation pool [22] (Scheme 1, X = I). Bu4NI in
DMSO/CH2Cl2 (1:9 v/v) was electrochemically oxidized at −78 various alkenes
°C in a divided cell using Bu4NBF4 as a supporting electrolyte The present method was successfully applied to the synthesis of
until 2.1 F/mol of electricity was applied. After addition of 2a halohydrins and epoxides from various alkenes. The reactions
to the solution, the mixture was stirred at 0 °C to give 3a-I, of alkenes with 1-X followed by the treatment with NaOH gave
which was characterized by NMR spectroscopy [22]. The treat- the corresponding halohydrins as shown in Table 2. The reac-
ment of 3a-I with triethylamine gave α-iodoketone 4a-I in 85% tions of E and Z isomers of 1-phenyl-1-propene (2d) with 1-Br
yield as we reported previously [22]. However, the treatment of gave 5d-Br and 5d’-Br, respectively (Table 2, entries 7 and 9),
3a-I with NaOH and NaOMe gave iodohydrin 5a-I in 84% yield indicating the anti-addition of Br+ and DMSO across the C–C
and epoxide 6a in 96% yield, respectively (Table 1). The stereo- double bond. The reaction with 1-I also gave the anti-addition
chemistry as determined by NMR (5a-I was synthesized using products (Table 2, entries 8 and 10). Therefore, the reaction is
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Beilstein J. Org. Chem. 2015, 11, 242–248.
Table 2: Synthesis of halohydrins by the reaction of 1-X with alkenes followed by the treatment with NaOH.a
Entry
Alkene
Product
Yield (%)b
1
2
5a-Br: 87
5a-I: 84c
2a
5a-Br, 5a-I
3
4
5b-Br: 74
(trans:cis = 79:21)
5b-I: 94
(trans:cis = 71:29)
2b
(Z:E = 72:28)
5b-Br, 5b-I
5c-Br, 5c-I
5
6
5c-Br: 57
5c-I: 53
2c
7
8
5d-Br: 73
5d-I: 35
(E)-2d
5d-Br, 5d-I
9
5d’-Br: 75
5d’-I: 51
10
(Z)-2d
5d’-Br, 5d’-I
aThe electrolysis of Bu4NBr and Bu4NI was carried out using 1.3 equiv of Bu4NX (based on the alkene which was added after the electrolysis) with
2.1 F/mol of electricity based on Bu4NX. bIsolated yield. cYield was determined by GC.
stereospecific, and the stereochemistry is consistent with the Alkenes having an alkoxycarbonyl group gave the corres-
proposed reaction mechanism (Scheme 2). The addition of Br+ ponding epoxides in moderate yields (Table 3, entries 11–14).
or I+ and DMSO to unsymmetrically substituted olefins 2c and Diene 2f reacted with 1-Br and 1-I to give monoepoxide 6f in
2d regioselectively gave bromohydrins as single regioisomers moderate yields (Table 3, entries 13 and 14). Interestingly, 2g
(Table 2, entries 5–10). The regioselectivity of the products can reacted with 1-Br to give 6g but not with 1-I (Table 3, entries 15
be explained by the stability of carbocations (benzyl > second- and 16), although the reason is not clear at present. The facial
ary > primary). In the case of terminal alkene 2c, Br and I were selectivity of the reaction is the opposite to that of the epoxida-
introduced to a primary carbon atom, whereas OH was intro- tion using conventional reagents such as m-chloroperoxy-
duced to a secondary carbon atom. In the case of styrene deriva- benzoic acid (mCPBA) which epoxidizes alkenes from the less
tive 2d, Br and I were introduced to a secondary carbon, hindered face [33,34]. In this reaction, Br+ adds to the C–C
whereas OH was introduced to the benzyl carbon. DMSO seems double bond of 2g from the less hindered face to form the
to attack the more positively charged carbon of the three- corresponding three-membered ring bromonium ion intermedi-
membered ring bromonium ion or iodonium ion.
ate. Subsequently, DMSO attacks the bromonium ion from the
more hindered face to form the corresponding β-haloalkoxysul-
The reaction of 1-X with alkenes followed by the treatment with fonium ion. The treatment of the β-haloalkoxysulfonium ion
NaOMe gave the corresponding epoxides as shown in Table 3. with NaOMe cleaves the O–S bond to generate the alkoxide
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Beilstein J. Org. Chem. 2015, 11, 242–248.
Table 3: Synthesis of epoxides by the reaction of 1-X with alkenes followed by the treatment with NaOMe.a
Entry
Alkene
Product
X
Yield (%)b
1
2
Br
I
95c
96c
2a
6a
68
3
4
Br
I
(cis:trans = 74:26)
89
(cis:trans = 74:26)
2b
6b
(Z:E = 72:28)
5
6
Br
I
73c
86c
2c
6c
6d
7
8
Br
I
53
38d
(E)-2d
9
Br
I
60
10
67d
(Z)-2d
6d’
6e
11
12
Br
I
52e
57e
2e
13
14
Br
I
49e
47e
2f
6f
15
16
Br
I
69
0
2g
6g
aThe electrolysis was carried out using 1.3 equiv of Bu4NBr or Bu4NI (based on the alkene which was added after electrolysis) with 2.1 F/mol of elec-
tricity based on Bu4NBr or Bu4NI. bIsolated yield. cYield was determined by GC. d2.0 Equiv of Bu4NI was used. eReacted with 2.5 equiv of NaOMe for
2 h.
ion, which attacks the carbon atom bearing bromine to give oxygen atom in the product originated from DMSO. Since 18O-
epoxide 6g. Therefore, the installation of the oxygen atom takes labeled DMSO can be easily obtained from H218O [35], the
place from the more hindered face.
present transformation serves as a convenient method for
synthesizing 18O-labeled epoxides, that can be used for various
mechanistic and biological studies.
Reaction mechanism
To confirm the mechanism shown in Scheme 2, the experiment
was repeated using 18O-labeled DMSO (96% 18O)/CH2Cl2 Conclusion
(1:50 v/v). As outlined in Scheme 3, epoxide 6c containing 18O In conclusion, we found that the reaction pathways of
(94% 18O) was obtained in 81% yield, indicating that the β-haloalkoxysulfonium ions generated by the reaction of elec-
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Beilstein J. Org. Chem. 2015, 11, 242–248.
Scheme 3: Mechanistic study using 18O-DMSO.
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trogenerated Br+ and I+ stabilized by dimethyl sulfoxide
(DMSO) can be switched by changing the nature of the base.
The present transformation serves as stereospecific route to
halohydrins and epoxides from alkenes. The method is also
useful for synthesizing 18O-labeled epoxides.
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Supporting Information File 1
Experimental and analytical data.
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[http://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
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We thank the Ministry of Education, Culture, Sports, Science &
Technology, Japan, for a Grant-in-Aid for Scientific Research
on Innovative Areas, 2105. We also thank Taiyo Nippon Sanso
Corporation for partial support of this work including providing
H218O.
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