Ph 3 P/I - -Promoted Dichlorination or Dibromination of Epoxides with XCH 2 CH 2 X (X = Cl or Br)

Article abstract of DOI:10.1055/s-0037-1610308

Ph ₃ P/I ^- -promoted dichlorination and dibromination of epoxides by using XCH ₂ CH ₂ X (X = Cl or Br) as the halogen source and reaction solvent is described. All reagents are widely available and easy to handle, and mild conditions and operational simplicity make this protocol attractive.

Full text of DOI:10.1055/s-0037-1610308

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
Synlett
J. Long et al.
Letter
–
Ph P/I -Promoted Dichlorination or Dibromination of Epoxides
3
with XCH CH X (X = Cl or Br)
2
2
Jin Longa,b
Jia Chenb
O
Ph3P, I–
X
X
Rong Lia
R
XCH2CH2X (X = Cl or Br)
R
Zhuo Liua,b
Xuan Xiaoa,b
Jin-Hong Lin*b
Xing Zheng*a
Ji-Chang Xiao*b
a
Institute of Pharmacy and Pharmacology, Hunan Province
Cooperative Innovation Center for Molecular Target New
Drug Study, University of South China, 28 Western Chang-
sheng Road, Hengyang, Hunan, 421001, P. R. of China
zhengxing5018@yahoo.com
Key Laboratory of Organofluorine Chemistry, Shanghai Insti-
tute of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. of China
b
jlin@sioc.ac.cn
jchxiao@sioc.ac.cn
6
Received: 03.09.2018
Accepted after revision: 30.09.2018
Published online: 19.12.2018
lyzed halogenation and found that dichlorination of epox-
6b
ides could be achieved by this catalytic approach
DOI: 10.1055/s-0037-1610308; Art ID: st-2018-d0570-l
(Scheme 1, eq. 2). The usual stoichiometric triphenylphos-
phine oxide waste was avoided compared with traditional
Appel reaction, but this method suffers from the need for
simultaneous slow addition of the chlorine source, oxalyl
chloride, and the substrate. On the basis of Denton’s ap-
proach, Toy used heterogeneous polymer-supported triph-
enylphosphine oxides to realize dihalogenation (Scheme 1,
–
Abstract Ph P/I -promoted dichlorination and dibromination of epox-
3
ides by using XCH CH X (X = Cl or Br) as the halogen source and reac-
2
2
tion solvent is described. All reagents are widely available and easy to
handle, and mild conditions and operational simplicity make this proto-
col attractive.
Key words epoxide, dichlorination, dibromination, 1,2-dihalides,
triphenylphosphine
7
eq. 2). The polymer-supported triphenylphosphine oxides
could be recovered and reused with no appreciable de-
crease in reactivity, but the use of moisture-sensitive re-
agents, oxalyl chloride, or oxalyl bromide is required in the
dihalogenation reaction. Recently, Kartika reported a di-
chlorination promoted by a reagent system consisting of
Organohalogenated compounds have found widespread
application in various research areas, such as organic syn-
thesis, pharmaceuticals, agrochemicals, and functional
1
8
materials. 1,2-Dihalides, particularly organohalogen struc-
triphosgene and pyridine (Scheme 1, eq. 3). In contrast to
tural motifs found in various families of natural products
such as chlorosulfolipids isolated from fresh-water micro-
algae and polyhalogenated monoterpenoids isolated from
previous methods, no triphenylphosphine oxide was gener-
ated, and clean crude products could be obtained simply
upon aqueous workup. However, the use of the hazardous
reagent, triphosgene, may limit the synthetic utility of this
method. Apparently, the development of mild protocols for
dihalogenation of epoxides would be highly desirable.
The chemistry of phosphonium salts has evolved dra-
matically in that phosphonium salts could serve as versatile
1c
red algae, have received increasing attention from the
synthetic community. Many approaches have been devel-
oped for the synthesis of 1,2-dihalides, such as dihalogena-
2
tion of alkenes and dihalogenation of epoxides. Dihaloge-
nation of epoxides has become an efficient and straightfor-
ward strategy as epoxides are widely available starting
materials.
9
reagents, catalysts, or intermediates. We have found unex-
pectedly that the phosphonium salts could act as valuable
3
10
The dihalogenation of epoxides could occur well under
nucleophilic reagents under suitable conditions. Further
4
the Appel conditions (Scheme 1, eq. 1). This method is
studies into this interesting chemistry led us to discover
quite effective and has been applied to the total synthesis of
natural products, but a strong oxidant is required in the re-
that active iodophosphonium salts could be produced from
5
–
the Ph P/I /XCH CH X (X
=
Cl or Br) system or the
3
2
2
action, which would result in a poor functional group com-
Ph P/ICH CH I system. Since iodophosphonium salts are
3 2 2
patibility. The group of Denton developed a Ph P=O-cata-
quite reactive towards O-nucleophiles, these two reagent
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
Synlett
J. Long et al.
Letter
n
Previous work:
Our initial attempts at the Ph P/ Bu NI-promoted di-
3 4
Ph3P
X
(
1)
O
O
chlorination of epoxide 1a with the use of ClCH CH Cl as
X2, NCS, or NBS, etc.
X = Cl or Br
R2
2 2
strong oxidant
R1
the chlorine source and reaction solvent revealed that the
reaction temperature played an important role (Table 1,
entries 1–5). No desired product was detected at 40 °C
(Table 1, entry 1), a good yield was obtained at 80 °C (Table 1,
entry 3), and the yield was decreased at a higher tempera-
ture (Table 1, entries 4 and 5). The decreased yield at high
temperatures should be because benzyl chloride would be
converted into benzyl cation intermediate. The reaction
R1
R2
X
X
X
(
(
2)
3)
R3P=O, (COX)2
X = Cl or Br
R2 slow addition procedure
R1
R1
R2
and/or
moisture-sensitive reagent
O
Cl
triphosgene, pyridine
toxic reagent
Cl
R
R
R
This work:
4)
1
process was monitored by H NMR spectroscopy (Table 1,
entries 6 and 7), and it was found that a reaction time of 4 h
could give 74% yield (Table 1, entry 6). Increasing the load-
(
O
Ph3P, I–
X
mild conditions
operational simplicity
X
R
XCH2CH2X (X = Cl or Br)
ing of Ph P did not increase the yield (Table 1, entries 8–10).
Scheme 1 Dihalogenation of epoxides
3
The yield was not increased significantly either by increas-
n
ing the loading of iodide anion source, Bu NI (Table 1, en-
4
systems could be applied to deoxy functionalization of al-
tries 11–14). The desired product was obtained in 80% yield
11
n
cohols and aldehydes. Herein, we disclosed that the
by using slight excess of Ph P and Bu NI (Table 1, entry 11).
3
4
–
Ph P/I system can promote dichlorination and dibromina-
With the optimal conditions in hand (Table 1, entry 11),
3
–
tion of epoxides by using XCH CH X (X = Cl or Br) as the hal-
we then investigated the substrate scope of the Ph P/I -pro-
2
2
3
ogen source and reaction solvent (Scheme 1, eq. 4). All re-
agents are widely available and easy to handle, and mild
conditions and operational simplicity make this protocol
attractive.
moted dichlorination of epoxides. As shown in Scheme 2,
various epoxides were converted well into the desired
products in moderate to good yields. Since secondary ben-
zyl chlorides might readily undergo dechlorination to gen-
erate benzyl cation, the desired products were isolated in
Table 1 Optimization of the Reaction Conditions for Dichlorinationa
O
Cl
n
Ph3P/ Bu4NI
O
n
Cl
Cl
Ph3P/ Bu4NI
R
R
ClCH2CH2Cl
Cl
1
2
Ph
ClCH2CH2Cl
Ph
1a
2a
Cl
Cl
Cl
Cl
Cl
O
Cl
Cl
Entry
Ratiob
Temp (°C)
Time (h)
Yield (%)c
F
1
2
3
4
5
6
7
8
9
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.4:1.2
1:1.8:1.2
1:2.0:1.2
1:1.2:1.4
1:1.2:1.6
1:1.2:1.8
1:1.2:2.0
40
60
80
100
120
80
80
80
80
80
80
80
80
80
9.5
9.5
9.5
9.5
9.5
4
ND
43
80
70
54
74
76
75
71
75
80
75
71
72
2
a (64%)
2b (47%)
2c (88%)
Cl
O
tBu
Cl
O
Cl
O
Cl
Cl
2
d (86%)
2e (73%)
2f (70%)
8
O
Cl
Cl
Cl
4
Cl
O
Cl
O
Cl
4
N
H
O
10
11
12
13
14
4
2
g (67%)
2h (84%)
2i (88%)
4
4
CH3(CH2)11
Cl
Cl
Cl
4
Cl
Cl
2m (62%)
CH3(CH2)9
CH3(CH2)5
Cl
4
2k (74%)
Cl
Cl
2l (65%)
aReaction conditions: substrate 1a (0.2 mmol), Ph
n
4 2 2
P, Bu NI, and ClCH CH Cl
2j (57%)
3
(
2 mL) at the indicated temperature for the indicated time; ND = not
detected.
Scheme 2 Dichlorination of epoxides. Isolated yields are given.
b
n
3 4
Molar ratio of 1a/Ph P/ Bu NI.
1
Reagents and conditions: substrate 1 (0.5 mmol), Ph P (0.6 mmol), and
c
3
The yield was determined by H NMR spectroscopy with the use of PhCH
as an internal standard.
3
n
Bu NI (0.7 mmol) in ClCH CH Cl (5 mL) at 80 °C for 4 h.
4
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
Synlett
J. Long et al.
Letter
lower yields (2a,b). Interestingly, the epoxides, cyclic ethers,
smoothly underwent deoxychlorination, but the acyclic
ethers remained intact. This is apparently because of the
strong strain energy present in the cyclic substrates. A wide
range of functional groups could be tolerated, such as ether,
ester, alkene, and heterocycle.
termediate B. The coordination actives the terminal C–O
bond, and the attack of X at this bond generates halogena-
–
tion intermediate B. The C–O bond in this intermediate is
–
also quite active and a second attack of X affords the final
product.
O
The successful dichlorination prompted us to investigate
the dibromination of epoxides by using BrCH CH Br as the
X
I–
X
X
I–
X–
3
Ph P
+
R
2
2
–
I2
Ph3P–I I
–
I
– CH2=CH2
reaction solvent (Scheme 3). A brief survey of the reaction
conditions revealed that 82% yield (3a) could be obtained at
a lower reaction temperature (40 °C) compared with di-
chlorination (see Supporting Information). In contrast to di-
chlorides, dibromides were isolated in lower yields. This is
because secondary bromides showed lower stability due to
the debromination process to generate secondary cation.
(X = Cl, Br)
–
X–
A
I
I
PPh3
X
O
PPh3
X–
O
X–
R
R
– Ph3P=O
– I–
R
X
X
B
C
Scheme 4 The proposed reaction mechanism
O
Br
n
Ph3P/ Bu4NI
Br
R
BrCH CH Br
R
2
2
1
2
As shown in the proposed mechanism, iodophosphoni-
um salt A could be directly formed from the Ph P/I system.
tBu
O
Br
3
2
Br
It has been reported that the Ph P/I system could be ap-
Br
Br
3 2
plied to esterification1
4b,15
and iodination. However, the
16
O
Br
N
Br
H
high toxicity of I2 would lead to operationally inconve-
nience. In sharp contrast, the operational simplicity and the
wide availability of XCH CH X (X = Cl or Br) make our pro-
3a (57%)
3b (62%)
3c (43%)
2
2
CH3(CH2)9
CH3(CH2)11
tocol attractive.
Cl
Cl
–
In summary, we have described the Ph P/I -promoted
Cl
d (53%)
Cl
3e (62%)
3
3
dichlorination and dibromination of epoxides by using
XCH CH X (X = Cl or Br) as the halogen source and reaction
solvent. XCH CH X (X = Cl or Br) are widely available chem-
icals, and the dichlorination and dibromination occurred
smoothly under mild conditions. The operational simplicity
makes this protocol attractive, and therefore it may find
application in the synthesis of 1,2-dihalogenated pharma-
ceuticals or organic intermediates.
2
2
Scheme 3 Dibromination of epoxides. Isolated yields are given.
2
2
Reagents and conditions: substrate 1 (0.5 mmol), Ph P (0.6 mmol), and
3
n
Bu NI (0.7 mmol) in BrCH CH Br (5 mL) at 40 °C for 2 h.
4
2
2
Although iodide anion was present in the reaction sys-
tems, no iodination product was detected, probably be-
cause the attack of chloride or bromide anion was more
rapidly due to the stronger C–X bond (X = Cl or Br) than C–I
bond.
Funding Information
On the basis of their mechanistic investigations, Hine
and co-workers proposed that BrCH CH Br would readily
We thank the National Basic Research Program of China
(2015CB931903), the National Natural Science Foundation
(21421002, 21472222, 21502214, 21672242, 81273537), the Chinese
Academy of Sciences (XDA02020105, XDA02020106), the Key
Research Program of Frontier Sciences (CAS) (QYZDJSSW-SLH049),
the Key Project of Hunan Province Science and Technology Depart-
ment (2016DK2001), the Key Project of Hunan Provincial Education
Department (No. 17A190), the Zhengxiang Scholar Program of the
University of South China, Hunan Provincial Hengyang City Joint Fund
(2017JJ4050), and the Key Project of Hengyang Science and Technolo-
2
2
–
react with I via an S 2 process to generate ICH CH Br,
N
2
2
–
– 12
which further reacts with I to give I , CH =CH and Br .
2
2
2
Deuterated experimental evidence collected by Rabinovitch
and co-workers revealed that the overall elimination of 1,2-
–
dibromoethane promoted by I is a cis-elimination pro-
13
cess, further supporting the mechanism proposed by
Hine. Taking into account of the above results and our pre-
11a
vious observation, the plausible mechanism is proposed
gy Department(2017KJ166) for financial support.
N
ati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
4
2
1
0
0
2)Nati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
4
7
2
2
2
2)Nati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
5
0
2
2
1
4)Nati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
6
7
2
2
4
2)Nati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(8
1
2
7
3
5
3
7)C
h
i
n
ese
A
c
a
d
e
m
y
of
S
c
i
e
n
c
es(X
D
A
0
2
0
2
0
1
0
5)C
h
i
n
ese
A
c
a
d
e
m
y
of
S
c
i
e
n
c
es(X
D
A
0
2
0
2
0
1
0
6)
–
as shown in Scheme 4. The solvent XCH CH X reacts with I
2
2
via a substitution process followed by elimination to pro-
vide molecular iodine I , which would readily oxidize Ph P
to form iodophosphonium salt A. The active salt A can act
Supporting Information
2
3
14
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610308.
as a Lewis acid and its coordination with epoxide gives in-
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
Synlett
J. Long et al.
Letter
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Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D