Semipinacol Rearrangement Induced by Cleavage of Dibromocyclopropane

Article abstract of DOI:10.1002/ejoc.202000355

A novel semipinacol rearrangement using dibromocyclopropanes as sources of carbocations was developed. Heating dibromocyclopropanes bearing a 1-hydroxyalkyl group with silver perchlorate and 2,6-lutidine induced cleavage of the cyclopropane ring to form allyl cations, which underwent 1,2-shift of a substituent at the α-position of the hydroxy group to give β,γ-unsaturated carbonyl compounds having a quaternary carbon at the α-position. Because the products have convertible functional groups such as bromo, vinyl, and formyl groups, the method is expected to be applicable to the synthesis of various molecules.

Full text of DOI:10.1002/ejoc.202000355

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Semipinacol Rearrangement Induced by Cleavage of
Dibromocyclopropane
Authors: Michitaka Kurimoto, Daisuke Nakajima, Yoshitake Nishiyama,
and Satoshi Yokoshima
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000355
Link to VoR: https://doi.org/10.1002/ejoc.202000355
01/2020

10.1002/ejoc.202000355
European Journal of Organic Chemistry
COMMUNICATION
Semipinacol Rearrangement Induced by Cleavage of
Dibromocyclopropane
Michitaka Kurimoto,[a] Daisuke Nakajima,[a] Yoshitake Nishiyama,[a] and Satoshi Yokoshima*[a]
[a]
Mr. M. Kurimoto, Mr. D. Nakajima, Dr. Y. Nishiyama, and Prof. Dr. S. Yokoshima
Graduate School of Pharmaceutical Sciences
Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
E-mail: yokosima@ps.nagoya-u.ac.jp
http://www.ps.nagoya-u.ac.jp/lab_pages/natural_products/index-e.html
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
novel
semipinacol
rearrangement
using
electrocyclic reaction of D would generate carbocation E, which
would then undergo a pinacol-type 1,2-shift to form carbonyl
compound F having a quaternary carbon and a 1-bromoalkenyl
dibromocyclopropanes as sources of carbocations was developed.
Heating dibromocyclopropanes bearing a 1-hydroxyalkyl group with
silver perchlorate and 2,6-lutidine induced cleavage of the
cyclopropane ring to form allyl cations, which underwent 1,2-shift of
a substituent at the α-position of the hydroxy group to give β,γ-
unsaturated carbonyl compounds having a quaternary carbon at the
α-position. Because the products have convertible functional groups
such as bromo, vinyl, and formyl groups, the method is expected to
be applicable to synthesis of various molecules.
group.9 Herein, we disclose the first development of
a
semipinacol
rearrangement
induced
by
cleavage
of
dibromocyclopropane.
To investigate our idea, dibromocyclopropanes 3a and 3a’
bearing a 1-hydroxyalkyl group were prepared in two steps from
α,β-unsaturated aldehyde 1 (Scheme 2). Treatment of 1 with 4-
methoxyphenylmagnesium bromide in tetrahydrofuran (THF)
afforded allyl alcohol 2a in 92% yield. Subsequent
dibromocyclopropanation
was
conducted
using
Pinacol rearrangement is a reliable method used to construct
quaternary carbons. In this transformation, a hydroxy group in a
1,2-diol is activated with acids to generate a tertiary carbocation,
which undergoes 1,2-shift of a substituent at the α-position of
the remaining hydroxy group. Related methods involving the
electrophilic activation of a C–C double bond in allyl alcohol A
with electrophiles such as a halonium ion,1 proton,2 or metal
ion,3 have been used to generate a tertiary carbocation adjacent
to an alcohol moiety (B), which subsequently undergoes a 1,2-
shift to afford C (Scheme 1).
cetyltrimethylammonium bromide (CTAB)10 as a phase-transfer
catalyst to afford a mixture of two diastereomers 3a and 3a’.
After separation of the diastereomers, the major isomer 3a was
evaluated in the novel semipinacol rearrangement.
CHBr3
aq NaOH
CTAB
Br
Et
Br
Et
Et
Ar
ArMgBr
THF, 0 °C to rt
92%
CH2Cl2, rt
OH
O
H
Ar
OH
1
2a
3a: 60%
3a’: 40%
3a, 3a’
Ar = 4-(MeO)C6H4
Conventional Method
CTAB = n-C16H33NMe3Br
E
E+
E
(X+, H+, Mtl+)
R’
R’
R’
Scheme 2. Preparation of Substrates for the Attempted Semipinacol
Rearrangement.
R
Activation
with
Electrophiles
Semipinacol
Rearrangement
R
OH
R
OH
H
O
A
B
C
Dibromocyclopropane 3a was first heated to induce cleavage of
the cyclopropane ring (Table 1). Heating 3a at 160 °C in N,N-
dimethylformamide (DMF) resulted in formation of dihydrofuran
5 (entry 1).11 This result suggested that the electrocyclic ring
opening of the dibromocyclopropane ring occurred to generate
an allyl cation, which was intramolecularly trapped by the
hydroxy group. To lower the nucleophilicity of the hydroxy group,
the reaction was conducted at 100 °C in a 15:1 mixture of
acetonitrile and water12 instead of DMF. To our delight, the
desired aldehyde 4a was obtained under these conditions, albeit
in a low yield (entry 2).13 We next evaluated the addition of silver
salts, which are often used to cleave dibromocyclopropanes.14
Although addition of silver perchlorate alone had no significant
effect on the product yield (entry 3), further addition of 2,6-
lutidine as a base remarkably improved the yield to 84% (entry
4). When the reaction was conducted in acetonitrile without
water, product 4a was produced in only 22% yield (entry 5).
:CBr2
Br
O
Br
Br
R’
Br
–Br–
R’
R
R’
Electrocyclic
Ring
Opening
Semipinacol
Rearrangement
R
OH
H
R
OH
D
E
F
This Work
Scheme 1. Semipinacol Rearrangement.
Reactions involving the generation of carbocations adjacent to
an alcohol moiety followed by a pinacol-type 1,2-shift are usually
called semipinacol rearrangements.4,5 We designed a novel
semipinacol rearrangement using dibromocyclopropanes6,7 as
sources of carbocations. In this novel method, allyl alcohol A
would first be converted into dibromocyclopropane D.8 The
1
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10.1002/ejoc.202000355
European Journal of Organic Chemistry
COMMUNICATION
These results clearly demonstrate the importance of water in this
reaction. The use of silver triflate instead of silver perchlorate
resulted in a slight erosion of yield (entry 6).
Table 2. Substrate Scope.
Table 1. Optimization of the Conditions.
AgClO4 (1.5 eq)
lutidine (1.1 eq)
Br
Br
Br
R2
R2
R1
MeCN/H2O (15:1)
100 °C
Br
R1
additive (1.5 eq)
base (1.1 eq)
Br
Et
Br
Br
O
OH
H
O
Et
Et
Ar
3
4
Ar
solvent
Temp.
O
Yield
(%)
Ar
OH
H
entry
R1
R2
3
4
3a
4a
5
Ar = 4-(MeO)C6H4
3a
3a'
84[a]
70[b]
Temp.
(°C)
Yield
(%)
1
2
3
Et
Et
Et
4a
4b
4c
entry
additive
base
solvent
DMF
3b
3b'
58[a]
29[b]
1[a]
2
–
–
160
100
100
100
100
100
N.D.[b]
6
–
–
MeCN/H2O (15:1)
MeCN/H2O (15:1)
MeCN/H2O (15:1)
MeCN
3c
3c'
56[a]
53[b]
3
AgClO4
AgClO4
AgClO4
AgOTf
–
14
58[a]
83[b]
4[c]
5
lutidine
lutidine
lutidine
84
3d
3d'
4
Et
4d
22
3e
3e'
45[a]
32[b]
6
MeCN/H2O (15:1)
66
5
6
7
Et
Et
Et
4e
4f
25[a]
36[b]
[a] 40% of dihydrofuran 5 was isolated. [b] Not detected. [c] 76% of the
3f
3f'
product was obtained in a 1 mmol scale.
N.D.[a][c]
N.D.[b][c]
The optimal reaction conditions established in the optimization
study were applied to a variety of dibromocyclopropanes 3
(Table 2). Compound 3a’, a diastereomer of 3a, could be
converted into the desired aldehyde 4a in a comparable yield
(70%, entry 1). Reactions of substrates having electron-donating
groups at the para-position of the benzene ring gave the
corresponding products in moderate to good yields (entries 2–
5).15 The substrates with no substituent on the benzene ring
showed low reactivity under the conditions, affording aldehyde
4f in 25% and 36% yields from 3f and 3f’, respectively (entry 6).
When a substrate with an electron-withdrawing group such as a
trifluoromethyl group at the para-position of the benzene ring (3g
or 3g’) was used, the reaction gave a complex mixture, and we
could not determine the structure of any products (entry 7).
Changing the position of the substituent also affected the results.
The reactions of substrates with a meta- or ortho-methoxyphenyl
group furnished aldehydes 4h or 4i in lower yields (entries 8 and
9). Rearrangement of a methyl group did not proceed (entry 10).
Substituents other than ethyl on the dibromocyclopropane ring
were found to be compatible with the reaction conditions (entries
11 and 12).
3g
3g'
4g
3h
3h'
28[a]
21[b]
8
9
Et
Et
4h
4i
3i
3i'
36[a]
35[b]
3j
3j'
N.D.[a][c]
N.D.[b][c]
10
11
12
Me
Et
Ph(CH2)3
Ph
4j
4k
4l
3k
3k'
51[a]
48[b]
3l
3l'
44[a]
32[b]
[a] From the major diastereomer of 3. [b] From the minor diastereomer of 3. [c]
Not detected.
In addition to secondary alcohols, tertiary alcohols could be
employed as substrates for the semipinacol rearrangement, to
produce ketones instead of aldehydes. Rearrangement of 3m
having a 4-methoxyphenyl group and a methyl group at the α-
position of the hydroxy group afforded ketone 4m via selective
rearrangement of the aryl group (Scheme 3A). Treatment of
cyclobutanol 3n with 4.5 equivalents of silver perchlorate
afforded cyclopentanone 4n in moderate yield via ring expansion
(Scheme 3B).
2
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10.1002/ejoc.202000355
European Journal of Organic Chemistry
COMMUNICATION
A
Drug Discovery and Life Science Research (Basis for
Supporting Innovative Drug Discovery and Life Science
Research; BINDS) from the Japan Agency for Medical Research
AgClO4 (1.5 eq)
lutidine (1.1 eq)
Br
O
Br
Et
Br
Et
Ar
MeCN/H2O (15:1)
OH
100 °C
Ar
Me
and
Development
(AMED)
under
Grant
Number
Me
3m
4m
JP19am0101099 (S.Y.), "Graduate Program of Transformative
Chem-Bio Research" in Nagoya University, supported by MEXT
(WISE Program), the Uehara Memorial Foundation (Y.N.), and
the Tokyo Biochemical Research Foundation (Y.N.).
72%[a], 68%[b]
Ar = 4-(MeO)C6H4
B
Br
Me
Br
AgClO4 (4.5 eq)
lutidine (1.1 eq)
Br
O
Me
MeCN/H2O (15:1)
100 °C
OH
Keywords: Dibromocyclopropane • Semipinacol rearrangement
4n
3n
• Electrocyclic ring opening • Quaternary carbon
37%
Scheme 3. The Semipinacol Rearrangement of Tertiary Alcohols. [a] From the
major diastereomer 3m. [b] From the minor diastereomer 3m'.
[1]
[2]
[3]
[4]
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Chem. 2004, 69, 3087–3092.
We next investigated the stereochemical relationship between
the substrate and the product. An optically active allyl alcohol 2j*
was prepared by optical resolution,16 and it was converted into
dibromocyclopropanes 3k* and 3k’* (Scheme 4). After
separation, both the diastereomers were independently
subjected to the standard conditions for the semipinacol
rearrangement to afford 4k. The reactions gave the same (R)-
isomer as the major enantiomer with the same enantiomeric
excess of 40%. That is, the stereochemistry of the hydroxy
group is partially transferred to the product regardless of the
stereochemistry of the dibromocyclopropane. These results
indicate that the reactions of both diastereomers proceeded via
the common intermediate 5, and only the stereochemistry of the
hydroxy group contributed to the stereochemical outcome of this
reaction.
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Li, X.-C. Wang, H. Wang, Angew. Chem. Int. Ed. Accepted article (DOI:
10.1002/anie.202001100).
Br
R
Br
standard
conditions[a]
CHBr3
aq NaOH
CTAB
50%
Br
O
Br
Ar
OH
R
*
R
R
+
Ar
CH2Cl2, rt
Br
R
Br
Ar
OH
*
standard
conditions[a]
H
Ar
OH
*
2j*
(>99%ee)
26% + 21%
common
intermediate
5
(R)-4k
40%ee
50%
Ar
OH
*
R = (CH2)3Ph
Ar = 4-(MeO)C6H4
3k* or 3k’*
Scheme 4. Stereochemical Relationship. [a] Standard conditions: AgClO4 (1.5
eq), lutidine (1.1 eq), MeCN/H2O (15:1), 100 °C.
In summary, we have developed
a
novel semipinacol
rearrangement induced by cleavage of dibromocyclopropanes.
Heating the readily accessible dibromocyclopropanes with silver
perchlorate and 2,6-lutidine gave a variety of β,γ-unsaturated
carbonyl compounds having a quaternary carbon at the α-
position. Because the products have convertible functional
groups such as bromo, vinyl, and formyl groups, the method is
expected to be applicable to synthesis of various molecules.
[6]
[7]
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Acknowledgements
This work was financially supported by JSPS KAKENHI (Grant
Number JP17H01523, S.Y.), the Platform Project for Supporting
3
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10.1002/ejoc.202000355
European Journal of Organic Chemistry
COMMUNICATION
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product.
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[15] Attempted dibromocyclopropanation of an allyl alcohol having a 2-furyl
group resulted in a complex mixture probably due to the electron
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4
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10.1002/ejoc.202000355
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
A novel semipinacol rearrangement using dibromocyclopropanes as sources of carbocations was developed. Heating
dibromocyclopropanes bearing a 1-hydroxyalkyl group with silver perchlorate and 2,6-lutidine induced cleavage of the cyclopropane
ring to form allyl cations, which underwent 1,2-shift of a substituent at the α-position of the hydroxy group to give β,γ-unsaturated
carbonyl compounds having a quaternary carbon at the α-position.
Key Topic: Semipinacol Rearrangement
5
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