Regioselective Neighboring-Group-Participated 2,4-Dibromohydration of Conjugated Enynes: Synthesis of 2-(2,4-Dibromobut-2-enoyl)benzoate and Its Applications

Article abstract of DOI:10.1021/acs.orglett.7b03671

A regioselective 2,4-dibromohydration of conjugated enynes is reported for the synthesis of 2-(2,4-dibromobut-2-enoyl)benzoate. In the presence of tetra-n-butylammonium bromide and H₂O the transformation proceeds smoothly with good reaction efficiency and a broad reaction scope. Mechanism studies indicate that the neighboring ester group participates in the 2,4-dibromohydration, and the oxygen atom of ester is transferred into the C-C triple bond to form the keto carbonyl group in the product. 2-(2,4-Dibromobut-2-enoyl)benzoate is recognized as an important synthon toward phthalazin-1(2H)-one and the natural product Shihunine.

Full text of DOI:10.1021/acs.orglett.7b03671

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Neighboring-Group-Participated 2,4-
Dibromohydration of Conjugated Enynes: Synthesis of 2‑(2,4-
Dibromobut-2-enoyl)benzoate and Its Applications
Si-Tian Yuan,†,‡ Hongwei Zhou,† Liang Gao,§ Jin-Biao Liu,*,‡ and Guanyinsheng Qiu*,†
†College of Biological, Chemical Science and Engineerindg, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China
‡School of Metallurgical and Chemical Engineering, Jiangxi University of Science and Technology, 86 Hongqi Road, Ganzhou
341000, China
§Department of natural Science and Computer Science, Ganzhou Teacher’s College, Ganzhou, 341000, China
S
* Supporting Information
ABSTRACT: A regioselective 2,4-dibromohydration of conjugated enynes is reported for the synthesis of 2-(2,4-dibromobut-2-
enoyl)benzoate. In the presence of tetra-n-butylammonium bromide and H2O the transformation proceeds smoothly with good
reaction efficiency and a broad reaction scope. Mechanism studies indicate that the neighboring ester group participates in the
2,4-dibromohydration, and the oxygen atom of ester is transferred into the C−C triple bond to form the keto carbonyl group in
the product. 2-(2,4-Dibromobut-2-enoyl)benzoate is recognized as an important synthon toward phthalazin-1(2H)-one and the
natural product Shihunine.
lkyne-based chemistry has attracted continuous interest
from chemists due to its versatility in structural elaboration
electrophilic 6-endo-dig bromocyclization of o-alkynylbenzoate,
the 1,1-dibromohydration was finally accomplished by an NBS-
assisted nucleophilic ring opening, thus presenting an oxygen
atom transfer of ester into the C−C triple bond. Mechanism
studies suggested that an occurrence of water probably changed
the reaction pathway. To the best of our knowledge, it was
surprising to find that the annulation type of 6-endo-dig
dominated 2-alkynylbenzoate-based cyclization. On the other
hand, 5-exo-dig cyclization always required the use of 2-
alkynylbenzoic acid as the substrate or the assistance of
transitional metal catalysis and a base.9 Inspired by the above
information, we disclosed an electrophilic 5-exo-dig cyclization of
2-alkynylbenzoate (Scheme 1b). In the process, we envisioned
that the intermediate isobenzofuran-1(3H)-one cation formed
herein did not go through removal of the substituent R, but
underwent an oxygen transfer reaction toward useful building
blocks (Scheme 1b).
A
for the synthesis of diverse architectures.1 To date, it was
generally accepted that regioselectivity was still challenging for
some internal alkyne-based transformations. Consequently,
many research groups devoted themselves to developing new
strategies to control reaction regioselectivity.
o-Alkynylbenzoate was a powerful dual-function building
block.2−6 It was impressive that cyclization of o-alkynylbenzoate
was highly regioselective in a 6-endo-dig fashion, leading to an
isocoumarin core. A Brønsted acid,3 Lewis acid,4 and transitional
metal5 could enable this 6-endo-dig cyclization. The same
regioselectivity was observed to offer 4-substituted isocoumarins
through an electrophilic 6-endo-dig cyclization when o-
alkynylbenzoate was treated with an electrophile (such as Br2,
I2, ICl, disulfane, etc.).6 Considering our continuous interests in
developing application of dual-functional substrates in organic
synthesis,7 we were focused mainly on o-alkynylbenzoate
chemistry with a wish to exploit diverse o-alkynylbenzoate-
based transformations. Accordingly, a N-bromosuccinimide
(NBS)/water-mediated diketonization of o-alkynylbenzoate
was established by our group for the synthesis of benzil-o-
carboxylates.8 Interestingly, the diketonization of o-alkynylben-
zoate was ascribed to a neighboring-ester-participated 1,1-
dibromohydration of alkyne. Combined with the well-recognized
As we know, an electrophilic bromination of enyne is preferred
to occur on the double bond.10 Combined with 5-exo-dig
cyclization, an electrophilic bromocyclization of o-enynylben-
zoate 1 thus provided an intermediate A. Treated with water, the
Received: November 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03671
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Organic Letters
Letter
Scheme 1. Neighboring-Ester-Participated 2,4-
Dibromohydration of Enynes
Table 1. Three-Component Synthesis of 3a: Survey of
Reaction Conditions
a
b
entry Br source
oxidant
solvent
yield (%)
1
NBS
−
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
THF/H2O (1:1, v/v)
MeCN/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (1:1, v/v)
DCE/H2O (4:1, v/v)
DCE/H2O (1:4, v/v)
DCE/H2O (1:4, v/v)
13
2
TBAB
TBAB
TBAB
TBAB
TBAB
KBr
TBHP
Cu(OAc)2
K2S2O8
(NH4)2S2O8
oxone
trace
3
complex
20
4
5
35
6
70
7
oxone
53
8
ZnBr2
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
oxone
27
9
oxone
64
10
11
oxone
65
c
oxone
78
d
12
13
14
15
oxone
75
c
oxone
56
c
oxone
49
ce
,
oxone
48
a
Standard conditions: enyne 1a (0.2 mmol), bromo source (0.5
intermediate A underwent a nucleophilic addition, resulting in an
intermediate B. Finally, an electrophile-assisted ring opening
happened to the intermediate B to give 2,4-dibromohydrative
product 3. Based on the above proposed pathway, it was
reasonable that an oxygen atom of ester group was transferred
into the C−C triple bond to form a keto carbonyl group, and
dibromo atoms were regioselectively installed into the C2 and
C4 position of enyne function, respectively. Interestingly, a
formal 5-exo annulation of the alkynyl group in o-enynylbenzoate
1 was observed in the reaction. Distinctively, an elegant example
reported by Larock indicated that the electrophilic halocycliza-
tion of o-enynylbenzoate 1 took place on the C−C triple bond to
provide isocoumarin derivatives.11 This discrepancy implied that
the reaction developed herein represented a novel supplement of
2-enynylbenzoate-based transformations. To verify the practi-
cality of the projected transformation, we started to optimize the
reaction.
b
mmol), oxidant (0.4 mmol), solvent (2.0 mL), rt. Isolated yield based
c
d
e
on enyne 1a. TBAB (0.6 mmol). TBAB (0.8 mmol). The reaction
was run at 50 °C. NBS = N-bromosuccinimide; TBAB = tetra-n-
butylammonium bromide; TBHP = tert-butyl hydroperoxide; oxone =
potassium peroxylmonosulfate (2KHSO5·KHSO4·K2SO4).
excess of bromo sources (mol ratio Br−/1a = 3/1) was surveyed.
As expected, the yield of 3a was improved to 78% when 3.0 equiv
of TBAB were used (entry 11, Table 1). A further increase of
TBAB loading did not make a significant impact on the yield of
3a (entry 12, Table 1). After screening the percentage of water in
the mixed solvent, it was found that DCE/H2O (1:1, v/v) was the
best solvent system. An increase in the reaction temperature was
not favorable for the reaction (entry 15, Table 1). Thus, we
determined the optimized conditions as follows: 3.0 equiv of
TBAB, 2.0 equiv of oxone, DCE/H2O (2.0 mL, v/v = 1:1) at
room temperature.
Initially, methyl o-enynylbenzoate 1a was employed as a model
substrate. For convenience, we directly used a mixed solvent
containing water as a source of the substrate water. A preliminary
result from screening electrophilic bromo sources showed that
the use of NBS enabled 2,4-dibromohydration of 1a, leading to a
desired product 3a in 13% yield (entry 1, Table 1). This
promising result encouraged us to investigate more impactful
factors. Considering our findings on bromide-mediated oxidative
bromination,8,12 we geared the bromo source to tetra-n-
butylammonium bromide (TBAB). Accordingly, various oxi-
dants were evaluated (entries 2−6, Table 1). From the screening
results, it seemed that oxone was the best choice,13 providing the
desired product 3a in 70% yield (entry 6, Table 1), and the model
reaction completed within 0.5 h. Other oxidants including
Cu(OAc)2, TBHP, K2S2O8, and (NH4)2S2O8 did not give better
yields. Optimization on various bromide sources implied that the
use of KBr and ZnBr2 did not improve reaction efficiency (entries
7−8, Table 1). It was probably attributed to the fact that TBAB
behaved as a phase transfer catalyst, thus enhancing the reaction.
Subsequently, the solvent effect was also checked. Inferior yields
were observed when mixed solvents including THF/H2O and
MeCN/H2O were employed (entries 9−10, Table 1). Since 2
mol of bromo atom were incorporated into the product 3a, an
With the optimized conditions in hand, we then explored the
reaction scope and generality. The results are illustrated in
Scheme 2. From the results, we were pleased to find that a series
of 2,4-dibromohydrative products 3 were achieved in good
yields. Interestingly, 2,4-dichlorohydration was observed when
tetra-n-butylammonium chloride (TBAC) replaced TBAB under
standard conditions, leading to a desired product 3b in 76% yield.
Various o-enynylbenzoates were compatible, and the corre-
sponding products 3c−3g were provided in 65−89% yields. For
example, allylic benzoate 1e was a good reaction partner,
resulting in 3e in a moderate yield. The reaction of tollyl
benzoate 1g gave rise to 3g in 85% yield. The structure of the
product 3g was verified by X-ray diffraction (CCDC number:
1572355). According to the structure of 3g, we determined the
exact structures of other products.
The substituent effect of R2 was explored as well. Based on the
results, it was found that the substrates with methyl, methoxyl,
fluoro, chloro, and bromo at the R2 position of the phenyl ring
were compatible for the reaction under standard conditions.
Interestingly, the reaction of cyclohexene-connected enyne ester
1n delivered a corresponding product 3n in an excellent yield
(90%). To our surprise, the reaction efficiency was greatly
B
DOI: 10.1021/acs.orglett.7b03671
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Organic Letters
Letter
To exploit applications of the products 3 in organic synthesis, a
reduction of a keto group of the product 3a was carried out in the
presence of NaBH4/MeOH at room temperature (Scheme 4).
Scheme 2. Synthesis of 2-(2,4-Dibromobut-2-enoyl)benzoate
Scheme 4. Application Exploration of the Product 3a
Surprisingly, the keto carbonyl group in product 3a survived in
the reaction, and a distinctive compound 4 was synthesized in
97% yield through a debrominative cyclopropanation. To the
best of our knowledge, 4 was an important synthon toward a
privileged structural core phthalazin-1(2H)-one 5. Moreover, 4
was also a key intermediate for a total synthesis of natural product
Shihunine.14
On the basis of the aforementioned results, several control
experiments were conducted. As shown in Scheme 5, the reaction
Scheme 5. Control Experiments
hindered when a cyclopentene-linked substrate 1o was used. A
corresponding product 3o was obtained in 57% yield. The
reaction of methyl 2-(cyclohex-1-en-1-ylethynyl)benzoate 1p
was also tested. Desired product 3p was observed in 70% yield
accordingly. Based on NMR data analysis, we found that 3p was a
mixture of two E/Z isomers, and the ratio was 4.3:1. To our
surprise, other substituted enyenes such as 2-(pent-3-en-1-yn-1-
yl)benzoate and 2-(3-phenylbut-3-en-1-yn-1-yl)benzoate were
not tolerated accordingly.
Subsequently, we investigated other neighboring groups. As
presented in Scheme 3, the neighboring groups could be the
aceto group, aldehyde group, and benzamide group. The
dibromohydration worked well under standard conditions, and
the corresponding products 3q−3s were prepared in 75−88%
yields.
of 1a in the absence of water was first run. A dibrominative
product 6 was uniquely observed in 92% yield. The formation of
compound 6 was attributed to an electrophilic 1,2-dibromination
of enyne function. Interestingly, under standard conditions the
compound 6 converted into the 2,4-dibromohydrative product
3a in 95% yield within 10 min.15 However, we did not detect the
formation of 6 when 1a was treated with TBAB under standard
conditions.
Scheme 3. Effect of Various Neighboring Groups
To identify the oxygen atom transfer reaction illustrated in
Scheme 1, we started the reaction of 1a at DCE/H2O18 (Scheme
5). Electrospray ionization mass spectroscopic analysis of the
product 3a-O18 showed a strong signal at [M + H] = 363,
suggesting 1 equiv of H2O18 was incorporated into 3a. To clarify
the exact site of oxygen-18, the reduction and condensation of
C
DOI: 10.1021/acs.orglett.7b03671
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Organic Letters
Letter
3a-O18 with hydrazine were conducted. The reaction offered the
desired phthalazin-1(2H)-one 5-O18. Electrospray ionization
mass spectroscopic analysis showed the product 5-O18 contained
one oxygen-18, whose [M + H] was equal to 189. The above
information implied that 1 equiv of water was installed into the
ester group, and the oxygen atom of ester was transferred into the
C−C triple bond to form a keto carbonyl group.
In conclusion, we have developed a regioselective neighboring
group-participated 2,4-dibromohydration of o-enynylbenzoate
for the synthesis of 2-(2,4-dibromobut-2-enoyl)benzoates in
good to excellent yields. The transformation worked well in the
presence of TBAB and oxone at room temperature. Mechanism
studies showed that an oxygen atom transfer of ester was
involved. The detailed mechanism and application of the product
in organic synthesis are ongoing in our group, and the results will
be reported in due course.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03671.
Experimental procedures, product characterization data,
1H and 13C NMR spectra for new compounds (PDF)
Accession Codes
CCDC 1572355 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: qiuguanyinsheng@mail.zjxu.edu.cn (G.Q.).
*E-mail: liujbgood@hotmail.com (J.L.).
ORCID
Hongwei Zhou: 0000-0001-8308-960X
Guanyinsheng Qiu: 0000-0002-6587-8522
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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Financial support from the Natural Science Foundation of China
(Nos. 21502069, 21502075, 21762018, and 21772067), the
Natural Science Foundation of Jiangxi Province
(20171BAB213008), the Postdoctoral Science Foundation of
Jiangxi Province (2017KY22), and Science and Technology
Project of Jiangxi Provincial Education Department (No.
151357) is gratefully acknowledged.
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