Substrate-Controlled Regioselective Iodooxygenation of Olefins

Article abstract of DOI:10.1055/s-0037-1609968

An unexpected regioselective I ₂ /TBHP-mediated 1,2-iodooxygenation of alkenes with N -hydroxylamines is described. The reaction proceeds through a radical coupling mechanism or a iodonium mechanism, which is controlled by the structures of bot

Full text of DOI:10.1055/s-0037-1609968

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
X. Li et al.
Letter
Synlett
Substrate-Controlled Regioselective Iodooxygenation of Olefins
O
Xiaoqing Li*a
Kun Chena
Yucai Tangb
Huanhuan Zhua
Feng Chena
N
N
OH
N
(HOBt)
(NHPI)
N
O
OH
I2/TBHP
I
O
N
O
R'
N
I2/TBHP
radical coupling pathway
N
Ar
N
O
R''
Xinhuan Yana
Xiangsheng Xu*a
R
I
iodonium pathway
R
O
R'
I2/TBHP
R''
alkenes = styrenes
9 example, 46–80% yield
HOBt and NHPI
radical coupling pathway
a College of Chemical Engineering, Zhejiang University of
Technology, Hangzhou 310014, P. R. of China
xqli@zjut.edu.cn
alkenes = styrenes, α-methylstyrene,
1-octene and cyclohexene
I
O
N
future@zjut.edu.cn
10 examples, 52–78% yield
R
b College of Chemistry and Material Engineering, Hunan
University of Arts and Science, Changde, 415000, P. R. of
China
alkenes = 2-vinylpyridine, acrylates
6 examples, 32–72% yield
Received: 07.03.2018
Accepted after revision: 16.04.2018
Published online: 23.05.2018
depends on the reaction mechanism. Generally, electrophil-
ic iodine reagents tend to react with alkenes to form iodoni-
um space, then a nucleophilic reagent adds to the more
positive charged position (Scheme 1, Path B).7a–g For the
radical mechanism, as free radicals tend to add to the less
sterically impeded position, iodine was trapped at the
structurally hindered position (Scheme 1, Path A).8a–c Given
the fact that N-hydroxylamines can act both as radical pre-
cursors and nucleophilic reagent, we envisioned that the io-
dooxygenation of alkenes with N-hydroxylamines and mo-
lecular iodine would facilitate the convergent synthesis of
vicinal iodo-substituted N-alkoxyamines in two patterns.
Unfortunately, methods for controlling the regioselectivity
of the N-hydroxylamine-involved olefin difunctionalization
are less explored. Herein, we describe the first regioselec-
tive iodooxygenation of olefins with N-hydroxylamines and
molecular iodine controlled by the structures of N-hydrox-
ylamines and alkenes.
DOI: 10.1055/s-0037-1609968; Art ID: st-2018-u0150-l
Abstract An unexpected regioselective I2/TBHP-mediated 1,2-iodo-
oxygenation of alkenes with N-hydroxylamines is described. The reac-
tion proceeds through a radical coupling mechanism or a iodonium
mechanism, which is controlled by the structures of both N-hydroxyl-
amines and alkenes, to form vicinal iodo-substituted N-alkoxyamines
regioselectively. Both the iodo and alkoxyamine group of the resulting
products offer rich possibilities of synthetic manipulations.
Key words iodooxygenation, regioselectivity, alkenes, N-hydroxyph-
thalimide, 1-hydroxybenzotriazole
The regioselective olefin difunctionalization is a funda-
mental method for constructing synthetic useful 1,2-di-
functionalized products.1 Specifically, the direct oxidative
coupling of alkenes with oxo-containing compounds can
readily result in ubiquitous and versatile C–O functional-
ities.2 N-hydroxylamines, such as 1-hydroxybenzotriazole
(HOBt) and N-hydroxyphthalimide (NHPI), which are cheap
and commercially available, have been widely employed as
N-oxyl radical precursors in the radical-mediated dioxygen-
ation of alkenes (Scheme 1, Path A).3 Generally, N-oxyl radi-
cals tend to add to the less sterically impeded position of
alkenes to afford carbon-centered radicals, which would
further be trapped by oxidants, such as dioxygen,4 tert-bu-
tyl hydroperoxide (TBHP),5 and 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ)6 to form β-oxo N-alkoxyamines
regioselectively.
Previous work
OR'
N
OH
O
[O]
N
R
N
R'O
Ref. 4–6
I2
O
O
R
N
This work
I
Path A
Path B
O
R
R
N
N
HO
R
I+
Molecular iodine, which is readily available, has been
employed in olefin difunctionalization as electrophilic re-
agent7 and, to a lesser extent, as radical trapper8 for radical-
mediated reactions. It is important to recognize that the re-
gioselectivity of the olefin difunctionalization with iodine
N
R
O
I+
I2
I
[O]
Scheme 1 Regioselective 1,2-difunctionalization of alkenes
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
X. Li et al.
Letter
Synlett
We first investigated the iodooxygenation of styrene
with HOBt and molecular iodine. No reaction was detected
in the absence of the oxidant (Table 1, entry 1). Gratifyingly,
when TBHP was added as oxidant, the reaction at room
temperature afforded the iodooxygenation product 2a in
75% yield (Table 1, entry 2). This result indicated that the re-
action was performed through the iodonium mechanism.
Several solvents were then screened (Table 1, entries 3–7),
including DCE, MeOH, MeCN, THF, toluene, and DMF,
wherein DCE gave a better result. Other oxidants such as
K2S2O8, DTBP, and H2O2 were further evaluated (Table 1, en-
tries 8–10), and only H2O2 afford the desired product in 51%
yield. Increasing the temperature to 40 °C and 50 °C can
shorten the reaction time to 1.5 h (Table 1, entries 11 and
12), and a further increase of the temperature to 60 °C led
to a decrease of the yield (Table 1, entry 13). Screening of
different iodine sources showed that I– salts did not work,
while NIS was less effective (Table 1, entries 14–16).
With the optimal reaction conditions in hand, we sub-
sequently investigated the substrate scope of this regio-
selective iodooxygenation with HOBt (Table 2).9 Thus, sty-
rene bearing para-methyl and halo (F, Cl, Br) groups pro-
ceeded well to give the expected products 2a–e in moderate
to good yields. Styrene that incorporate an electrophilic
chloromethyl group can also be readily employed (2f, 64%
yield). It is noteworthy that styrene bearing a strong elec-
tron-withdrawing nitro group gave a mixture of two regi-
oselective products 2g and 2g′ in the ratio of 4:6, indicating
that radical coupling and iodonium pathways may both be
involved. Structurally hindered ortho-methyl-substituted
styrene also afforded product 2h in good yield. In addition,
α-methylstyrene underwent the iodooxygenation efficient-
ly to provide the desired product 2i in 57% yield. Notably,
this method is also compatible with aliphatic terminal and
internal alkenes, providing the expected products 2j–k in
good yields.
Table 1 Optimization of Reaction Conditionsa
Table 2 Scope of the Iodooxygenation with HOBta,b
N
N
N
N
I2 (0.5 equiv.)
TBHP (2 equiv)
[ I ] source
N
N
N
N
N
oxidant
O
R'
O
+
+
N
N
R''
I
I
DCE, 40 °C
solvent
N
R
R
1
1a
OH
OH
2
2a
2a R = H, 78%
2b R = Me, 62%
2c R = F, 66%
2d R = Cl,60%
2e R = Br, 52%
N
N
N
N
N
N
Entry [I]
Oxidant Solvent Temp (°C) Time (h) Yield (%)b
O
O
1
2
3
4
5
6
I2
–
DCE
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
5
5
5
5
5
5
0
I
I
I2
I2
I2
I2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
DCE
75
32
56
38
35
Cl
R
MeOH
MeCN
THF
2f 64%
N
N
N
I
N
N
N
O
N
N
N
O
O
tolu-
ene
+
I
O2N
7
I2
TBHP
K2S2O8
DTBP
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
r.t.
r.t.
r.t.
r.t.
40
50
60
40
40
5
0
I
O2N
Me
8
I2
5
0
2g + 2g′ 56% (4:6)
2h 75%
9
I2
5
0
N
N
N
N
N
N
N
N
10
11
12
13
14
15
16
I2
5
51
N
O
O
O
I2
1.5
1.5
1.5
1.5
1.5
2
78 (75c)
I
I
I
5
I2
78
69
0
Me
Me
I2
2j 75%
2i 57%
2k 71%
TBAId
KId
NISd
a Reaction conditions: 1 (0.3 mmol), HOBt (0.36 mmol, 1.2 equiv), I2 (0.15
mmol, 0.5 equiv), and TBHP (0.6 mmol, 2.0 equiv, 70% aqueous solution)
in DCE (2.0 mL) at 40 °C.
0
CH3CN 40
58
b Isolated yield based on olefins.
a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), HOBt (0.36 mmol, 1.2
equiv), TBHP (0.6 mmol, 2.0 equiv, 70% aqueous solution), I2 (0.15 mmol,
0.5 equiv), solvent (2.0 mL).
We next turned our attention to the scope of the iodo-
oxygenation with NHPI (Table 3).10 In contrast to the reac-
tion with HOBt, no reaction was detected at room tempera-
ture. Interestingly, when the temperature was increased to
80 °C, product 3a, delivered through the radical coupling
mechanism, was obtained in 72% yield under modified re-
b HPLC yield using phenacetone as internal standard.
c Isolated yield based on styrene.
d 0.3 mmol, 1.0 equiv.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
X. Li et al.
Letter
Synlett
action conditions. Styrene bearing a methyl, halo (F, Cl, Br),
and electrophilic chloromethyl group can be readily em-
ployed to provide the desired products 3b–i. Notably, dif-
ferent from the reaction with HOBt, styrene bearing a nitro
group afforded the product 3f as a single isomer. Unfortu-
nately, aliphatic alkenes failed in this reaction.
O
I
N
N
N
N
NHPI
HOBt
O
O
COOR
O
I2 (0.5 equiv)
TBHP (2 equiv)
DCE, 80 °C
I2 (0.5 equiv)
TBHP (2 equiv)
DCE, 50 °C
ROOC
I
ROOC
6, R = Et, 49%
7a, R = Me, 72%
7b, R= n-C4H9, 69%
7c, R = C(CH3)3, 70%
Table 3 Scope of the Iodooxygenation with NHPIa,b
O
I
O
I2 (0.5 equiv)
TBHP (2 equiv)
Scheme 3 Iodooxygenation of acrylates with HOBt and NHPI
O
Ar
N
Ar
+
N OH
DCE, 80 °C
1
O
3
O
It is worthwhile to note that our reactions could be
readily scaled up (Scheme 4). Thus, iodooxygenation of
styrene with HOBt gave 2.59 g of 2a (71%) based on styrene.
The iodooxygenation of styrene with NHPI was also amena-
ble to gram-scale synthesis in 63% yield of 3a (2.47 g) based
on NHPI.
Entry
Ar
C6H5
Product 3
Yield (%)b
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
72
46
76
80
58
50
63
67
77
p-MeC6H4
p-FC6H4
N
N
p-ClC6H4
p-BrC6H4
p-NO2C6H4
I2 (0.5 equiv)
TBHP (2 equiv)
N
N
N
O
N
+
I
DCE, 40 °C
OH
1a
12 mmol
p-ClCH2C6H4
m-ClC6H4
3g
3h
3i
(10 mmol)
2a
(71%, 2.59 g)
m-BrC6H4
O
N
O
I
O
I2 (0.5 equiv)
TBHP (2 equiv)
a Reaction conditions: alkene (1.5 mmol, 5.0 equiv), NHPI (0.3 mmol, 1.0
equiv), I2 (0.15 mmol, 0.5 equiv), and TBHP (0.6 mmol, 2.0 equiv, 70%
aqueous solution) in DCE (2.0 mL) at 80 °C for 6 h.
O
N
Ph
+
Ph
OH
DCE, 80 °C
1a
(50 mmol)
b Isolated yield based on NHPI.
O
3a
10 mmol
(63%, 2.47 g)
To further understand the regioselectivity of the reac-
tion, we then examined the reactions of 2-vinylpyridine
with HOBt and NHPI (Scheme 2). Interestingly, the reac-
tions of 2-vinylpyridine with both HOBt and NHPI go
through the radical mechanism to provide compounds 4
and 5 in moderate yields. Moreover, the reaction of more
electron-deficient acrylates with both HOBt and NHPI also
go through the radical mechanism to provide compounds 6
and 7, respectively (Scheme 3).
Scheme 4 Larger-scale reactions
To gain further insight into the iodooxygenation, mech-
anistic studies were carried out (Scheme 5). The addition of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO,
have no significant influence on the reaction of styrene
with HOBt (Scheme 5, eq. 1), but completely inhibit the re-
action of styrene with NHPI (Scheme 5, eq. 2). The result
demonstrated that the regioselectivity of the iodooxygen-
ation resulted from the two different pathways. Moreover,
when the reaction of p-nitrostyrene with HOBt, which pro-
2 equiv)
N
N
O
I
N
N
I
NHPI
HOBt
O
O
O
N
I2 (0.5 equiv)
TBHP (2 equiv)
DCE, 80 °C
I2 (0.5 equiv)
TBHP (2 equiv)
DCE, 50 °C
N
N
4, 32%
5, 59%
Scheme 2 Iodooxygenation of 2-vinylpyridine with HOBt and NHPI
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Synlett
N
N
N
I2 (0.5 equiv)
TBHP (2.0 equiv)
TEMPO (2.0 equiv)
O
(1)
HOBt
+
I
DCE, 40 °C
2a, 68%
I
O
I2 (0.5 equiv)
TBHP (2.0 equiv)
TEMPO (2.0 equiv)
O
N
(2)
NHPI
+
DCE, 80 °C
O
3a, trace
N
N
N
O
I
N
I2 (0.5 equiv)
O
TBHP (2.0 equiv)
TEMPO (2.0 equiv)
O
O2N
N
(3)
+
N
N
DCE, 40 °C
I
O2N
O2N
O
N
N
N
8
O2N
2g:2g' = 5:4
Scheme 5 Mechanistic studies
1) HOBt (1.2 equiv), I2 (0.5 equiv)
DCM, 40 °C, 4 h
Cl
vided two products from two pathways, was performed in
the presence of TEMPO (2 equiv), the product ratio of
2g:2g′ changed from 4:6 to 5:4 based on the crude 1H NMR
analysis with the isolation of compound 84f (Scheme 5, eq.
3), indicating the partly inhibition of the radical pathway.
Several synthetic transformations were then carried out
to demonstrate the product utility (Scheme 6). The elimina-
tion reaction of 2a with tBuOK in MeCN gave compound 9 in
87% yield. It is noteworthy that compound 9 was before
synthesized by the addition of HOBt to the alkynes cata-
lyzed by an expensive gold catalyst.11 The nucleophilic dis-
placement reactions of 2a with acetyl chloride in DCM at
room temperature afforded 2-chloro-1-iodo-1-phenyl-
ethane (10) in 61% yield. Notably, compound 10 could also
be synthesized in 50% yield by a one-pot iodooxygenation
of styrene with HOBt and I2 in DCM followed by a displace-
ment reaction with acetyl chloride without the isolation of
intermediate 2a (Scheme 7). This process represents a prac-
tical and cost-effective method for the regioselective iodo-
chlorination of alkenes compared with the reactions using
dichloroiodanuide(I) salts.12
I
Ph
Ph
2) CH3COCl (5 equiv)
r.t., 16 h
1a
10
50%
Scheme 7 One-pot synthesis of compound 10 from styrene
In summary, we have identified that N-hydroxylamines,
such as HOBt and NHPI, can be used not only as radical pre-
cursors but also can function as nucleophilic reagent in the
presence of oxidant. This unique feature enables the regi-
oselective iodooxygenation of alkenes with N-hydroxyl-
amines and molecular iodine through two different path-
ways, depending on the structure of the N-hydroxylamines
and alkenes. The process is scalable and the resulting prod-
ucts have versatile synthetic utility.
Funding Information
Financial support from the National Key Research and Development
Program of China (2017YFC0210900), the National Natural Science
Foundation of China (21102130), the Natural Science Foundation of
Zhejiang Province (LY14B020005) and Training Plan for College Stu-
N
N
N
N
N
N
tBuOK
dents' Innovation and Entrepreneurship of ZJUT is greatly appreciated.
N
oaitnaN
l
autraSlci
e
n
ce
F
o
u
n
d
oaitno-f
CH3COCl
Cl
O
O
C
h
n
i
a
2(
1
1
0
2
1
3
0
N)
a
utarSlceince
F
o
u
n
d
oaitn
o
Zfhanie
j
g
Provn
i
ce
L(Y
1
4
B
0
2
0
0
0
5)
I
DCM, r.t.
61%
Ph
MeCN, r.t.
87%
I
Ph
Ph
10
2a
9
Supporting Information
Scheme 6 Synthetic applications of compound 2a
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609968.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
X. Li et al.
Letter
Synlett
References and Notes
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(9) General Procedure for the Synthesis of Compounds 2
Alkenes (0.3 mmol) and TBHP (0.6 mmol) was added to a solu-
tion of 1-hydroxybenzotriazole (0.36 mmol) and iodide (0.15
mmol) in 2 mL of DCE. After the reaction mixture was stirred at
40 °C for 2 h, the solvent was removed under reduced pressure,
and the residual was treated with silica gel chromatography to
give compounds 2.
1-(2-Iodo-2-phenylethoxy)-1H-benzo[d][1,2,3]triazole (2a)
Colorless oil. 1H NMR(500 MHz, CDCl3): δ = 7.93 (d, J = 8.3 Hz, 1
H), 7.39–7.32 (m, 6 H), 7.29 (m, 2 H), 5.69 (t, J = 7.0Hz, 1 H), 3.93
(dd, J = 10.8, 7.1 Hz, 1 H), 3.71 (dd, J = 10.8, 7.0 Hz, 1 H). 13C NMR
(125 MHz, CDCl3):
δ
=
143.12, 135.4, 130.1, 128.8,
127.90,127.87, 127.5, 124.4, 120.0, 108.8, 91.8, 2.9. HRMS (ESI):
m/z calcd for C14H13IN3O [M + H+]: 366.0098; found: 366.0096.
(10) General Procedure for the Synthesis of Compounds 3
Alkenes (1.5 mmol) and TBHP (0.6 mmol) was added to a solu-
tion of N-hydroxyphthalimide (0.3 mmol) and iodide (0.15
mmol) in 2 mL of DCE. After the reaction mixture was stirred at
80 °C for 6 h, the solvent was removed under reduced pressure,
and the residual was treated with silica gel chromatography to
give compounds 3.
2-(2-Iodo-2-phenylethoxy)isoindoline-1,3-dione (3a)
White solid; mp 134–135 °C. 1H NMR (500 MHz, CDCl3): δ =
7.77 (m, 2 H), 7.73 (m, 2 H), 7.52 (dd, J = 5.2, 3.4 Hz, 2 H), 7.31–
7.27 (m, 2 H), 7.22–7.18 (m, 1 H), 5.51 (dd, J = 9.8, 5.7 Hz, 1 H),
4.94–4.89 (m, 1 H), 4.69 (dd, J = 10.8, 5.7 Hz, 1 H). 13C NMR (125
MHz, CDCl3): δ = 163.1, 139.7, 134.6, 128.8, 128.6, 128.5, 127.8,
123.5, 81.3, 25.1. HRMS (ESI): m/z calcd for C16H13INO3 [M + H+]:
393.9935; found: 393.9928.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E