Visible-Light-Mediated Anti-Markovnikov Hydration of Olefins

Article abstract of DOI:10.1021/acscatal.6b03388

Considering that stoichiometric borane and oxidant are required in the classical alkene anti-Markovnikov hydration process, it remains appealing to achieve the transformation in a catalytic protocol. Herein, a visible-light-mediated anti-Markovnikov addition of water to alkenes by using an organic photoredox catalyst in conjunction with a redox-active hydrogen atom donor was developed, which avoided the need for a transition-metal catalyst, stoichiometric borane, as well as oxidant. Both terminal and internal olefins are readily accommodated in this transformation to obtain corresponding primary and secondary alcohols in good yields with single regioselectivity. This procedure can be scaled up to gram scale with a 230 turnover number based on photocatalyst.

Full text of DOI:10.1021/acscatal.6b03388

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Letter
Visible-Light Mediated Anti-Markovnikov Hydration of Olefins
Xia Hu, Guoting Zhang, Faxiang Bu, and Aiwen Lei
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03388 • Publication Date (Web): 18 Jan 2017
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ACS Catalysis
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Visible-light Mediated anti-Markovnikov Hydration of Olefins
Xia Hu,1‡ Guoting Zhang,1‡ Faxiang Bu1 and Aiwen Lei1,2*
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1. College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei
430072, P. R. China.
2. Lanzhou Institute of Chemical Physics Chinese Academy of Sciences Lanzhou 730000 P. R. China.
ABSTRACT: Considering that stoichiometric borane and oxidant are required in classical alkene anti-Markovnikov hydration pro-
cess, it remains appealing to achieve the transformation in a catalytic protocol. Herein, a visible-light mediated anti-Markovnikov
addition of water to alkenes by using an organic photo-redox catalyst in conjunction with a redox-active hydrogen atom donor was
developed, which avoided the need for transitional-metal catalyst, stoichiometric borane, as well as oxidant. Both terminal and inter-
nal olefins are readily accommodated in this transformation to obtain corresponding primary and secondary alcohols in good yields
with single regioselectivity. This procedure can be scaled up to gram scale with a 230 turnover number based on photocatalyst.
KEYWORDS: Photochemistry, Hydration, Anti-Markovnikov, Alkene, Alcohol, Radical
The direct addition of water to olefins, named hydration pro-
cess, is a fundamental transformation to yield alcohols that are
of importance to both synthetic and pharmaceutical industries
as raw materials and the industrial solvents.1 This conversion
features both of atom economy2 and redox neutrality3, pre-
vented neither waster nor thermal energy. The conventional hy-
dration process occurs on the treatment of alkenes with water
using strong acid catalyst through a carbocation intermediate.4
Therefore, except ethylene, the outcome of addition reactions
obeys in accordance with Markovnikov’s rule in most olefin hy-
dration processes. While the Markovnikov hydration process is
well established and utilized in the production of commodity
alcohols, the catalytic anti-Markovnikov hydration protocol is
less straightforward. Due to the wide demand for primary alco-
hols,1e the development of a complementary catalytic method
that generates anti-Markovnikov adducts is an attractive and
worthwhile pursuit. It is worth to mention that achieving anti-
Markovnikov hydration of alkenes under mild conditions is a
dream of synthetic chemist for a long time, which was referred
as one of top ten challenges of catalysis since 1993.5
reactions.8 Therefore, it is appealing to develop a less hazard-
ous, cost-effective and noble-metal-free catalytic system for the
direct anti-Markovnikov hydration of alkenes.
A. Indirect
of alcohols from olefins with anti-Markovnikov selectivity
synthesis
R'2BH
H
NaOH
2O2
,
BR'2
OH
R
R
R
B.
relay catalysis
for anti-Markovnikov olefin
Grubbs's
R
triple
system
PdCl
hydration
OH
CN)2
Shvo's catalyst, BQ
,
2(CH3
+
H2O
R
i-PrOH/t
85 o
C
-BuOH,
work:
This
R2
anti-Markovnikov
of alkenes through the radical cation
C.
hydration
-
cat. Acr+-Mes
ClO4
R1
via
R1
R1
R2
cat.
Ph-S-S-Ph
OH
+
R2
H
2O
R3
visible
light
metal-free
R3
R3
1
2
Scheme 1. Anti-Markovnikov hydration of alkenes.
Inspired by our earlier study that the photo-induced electron
transfer of aryl alkenes allows the anti-Markovnikov oxygena-
tion of styrene derivatives with water by utilizing the combina-
tion of Fukuzumi’s catalyst and a cobaloxime catalyst,9 we en-
visaged that the anti-Markovnikov hydration of alkenes might
be achieved through adding a hydrogen atom transfer (HAT)
catalyst instead of cobaloxime catalyst. Recently, Nicewicz and
co-workers have developed a number of methods for the anti-
Markovnikov hydrofunctionalization of alkenes by using
photo-redox/hydrogen atom transfer dual catalytic system.10
Through the generation of an alkene radical cation intermediate,
the subsequent attack of several nucleophiles obeys high anti-
Markovnikov regioselectivity.11 Nevertheless, there still re-
mains elusive to take advantage of this reaction manifold to
anti-Markovnikov olefin hydration transformation. Herein, we
developed a direct anti-Markovnikov addition of water to al-
kenes for the rapid synthesis of a number of alcohols in good to
excellent yields (Scheme 1C). Furthermore, this alternative
pathway plays a good complementary role in current methods
Hydroboration/oxidation of olefins is currently the mostly
used approach for the preparation of alcohols with anti-Markov-
nikov regioselectivity (Scheme 1A).1a However, a stoichio-
metric amount of borane reagents and peroxides have to be re-
quired, which generate corresponding chemical waste and raise
safety problem restricting the application in large-scale produc-
tion. Hydroformylation/reduction provided another indirect
method to produce the primary alcohols from alkenes.6 For in-
stance, Beller and his co-workers developed a general ruthe-
nium catalyst system for linear alcohols synthesis from olefins
though a selective domino hydroformylation/hydrogenation se-
quence process.6e In 1986, Jensen and Trogler claimed to have
developed a catalytic system based on a platinum complex,
trans-PtHCl(PMe3)2, which can catalyze the anti-Markovnikov
hydration of 1-hexene.7 Currently, reported by Grubbs, a triple
relay catalytic system, involving anti-Markovnikov Wacker-ox-
idation step followed by reduction process enables the anti-
Markovnikov hydration of styrenes (Scheme 1B).1d However,
the expensive transition metal catalysts are employed in these
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for the construction of anti-Markovnikov alcohols,10d,12 which
prevent the need for metal catalyst and sacrificial oxidants.
withdrawing substituents to afford the corresponding primary
1
alcohols up to 85% yield with single anti-Markovnikov regiose-
lectivity (1aa−1ai). Functional group such as alkyl, trifluoro-
methyl, fluoro, chloro, bromine, can be well tolerant. The sty-
rene and styrene derivatives bearing electron-donating groups
were suitable in this transformation and furnished the corre-
sponding benzylethanol derivatives in moderate to good yields
(2aj−2an). Weak electron-poor styrene, 4-chlorostyrene (1am),
can be tolerant, while another electron-withdraw groups, such
as cyano, ester, would inhibit the hydration of styrene resulted
from the limitation of high redox potential. Notably, installation
of mono- or di-methyl on aromatic ring afforded corresponding
alcohol with complete anti-Markovnikov selectivity. It is worth
to mention that when one of the aryl groups was replaced by
alkyl group, such as methyl and isopropyl, the transformation
could also be carried out smoothly (1ao and 1ap). Other α-sub-
stituted styrene derivatives were also tested. Both of α-cyclo-
pentylvinyl (1aq) and α-cyclohexylvinyl styrene (1ar) are suit-
able substrates for this metal-free hydration process to give the
corresponding primary alcohols in good yields. Furthermore, 1-
methylene-1,2,3,4-tetrahydronaphthalene (1as) was also
proved to be compatible with the anti-Markovnikov hydration
system resulted in 41% yield.
2
3
4
5
6
7
8
9
To investigate the suitable catalytic system for anti-Markov-
nikov hydration of alkenes, the direct addition of water to 1,1-
diphenylethene (1aa) for the production of corresponding pri-
mary alcohol was chosen as the model reaction. 9-Mesityl-10-
methylacridinium was chosen as the photocatalyst due to its
strong oxidizing triplet state, which is capable of gaining an
electron from electron-rich alkenes to produce corresponding
radical cation intermediate.13 Encouragingly, water can act as a
nucleophile to trap this radical ion species and the hydration re-
action proceeded smoothly in the aqueous acetonitrile solution
to construct desired product 2,2-diphenylethan-1-ol (2aa) in
good yield (Table 1, entry 1) by using 9-mesityl-10-methylac-
ridinium in conjunction with a hydrogen atom-transfer catalyst,
1,2-diphenyldisulfane. Different hydrogen-atom-transfer cata-
lysts were applied as the co-catalyst for achieving this transfor-
mation. Changing the diphenyldisulfane to benzenethiol or 1,2-
diphenyldiselane can provide the similar reactivity, while 1,2-
diphenylditellane dramatically decrease the yield of the desired
product. And control experiment show that the presence of
HAT co-catalyst is crucial for the radical hydration process.
Furthermore, no desired reaction would be observed when ei-
ther light or photocatalyst was omitted, which indicated that
every component and photoexcitation of photocatalyst are nec-
essary for the transformation.
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11
12
13
14
15
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60
Scheme 2. Scope of the alkenes in the visible-light mediated
anti-Markovnikov hydration reaction.a
-
3 mol% Acr+-Mes ClO4
H
OH
R3
20 mol%Ph-S-S-Ph
R1
R1
Table 1. Optimization of the reaction conditions.a
R3
=
CH3CN/H2O 10:1
R2
R2
blue LEDs, r.t., 24 h
1
2
Me
Alkenes
Alcohols,
Entry
Alkenes
Entry
Alcohols,
R
yield
yield
Acr+-Mes ClO4- 3 mol%)
OH
(3
Ph-S-S-Ph
mol%)
Ph
Me
Me
(20
Ph
R
OH
H
OH
=
=
Ph
20
21
22
23
24
25
26
27
28
29
R
1ba
Me, 1bb
1bc
F,
p Cl, 1bd
Br, 1be
2ba
87%
,
CH3CN/H2O 10:1
blue LEDs, r.t.,24 h
Ph
H,
R
R' R
R'
-
m
=
=
=
=
=
=
=
=
=
=
=
1
2
3
4
5
6
7
8
9
R
R'
1aa
2aa 86%
R
R
R
R
R
R
R
R
R
2bb
,
, 43%
H,
H,
-
p
-
N
=
2bc 83%
R =Me, R'
=
1ab
2ab
2ac
,
62%
50%
,
H,
1aa
2aa
-
2bd
2be
83%
60%
80%
93%
76%
=
=
,
ClO4
R
R
R
Cl, R'
Br, R'
1ac
1ad
,
H,
Me
-
o
,
=
=
2ad 74%
,
H,
=
-
-
Acr+-Mes ClO4- 3
H,
m
Br, 1bf
p Br, 1bg
2bf
,
2bg
2bh
1ae
CF3 R'
,
2ae 75%
,
,
,
=
=
=
=
=
2af
43%
,
R
R
R
R
Me, R' Me, 1af
-
-
-
p
p
1bh
I,
=
2ag 85%
,
R'
1ag
1ah
Entry
Variation form standard conditions
2aa (%)b
1bi
CF3,
p COOMe, 1bj
F,
F,
2bi
80%
84%
,
2ah
66%
Cl, =Cl,
R'
,
2bj
,
1ai
2ai
CF3 R' =Me,
,
,
62%
1
2
3
4
5
6
7
8
Standard conditions
PhSH instead of (Ph-S)2
(PhSe)2 instead of (Ph-S)2
(PhTe)2 instead of (Ph-S)2
No water
86
OH
n
R'
R'
n
82
n =
n =
n =
1bk
2bk 77%
,
30
31
32
1,
OH
1bl
2bl
96%
,
R
2,
R
86
1bm
2bm
52%
,
3,
=
=
H,
10
11
12
13
14
15
16
R
R'
1aj
2aj 58%
,
H,
o
=
=
=
=
OH
R
R
R
-Me, R'
1ak
1al
2ak 48%
H,
,
65
m
=
33
-Me, R'
2al 47%
,
H,
=
p-Cl, R'
1am
1an
H,
2am
54%
,
< 5
n.d.
n.d.
n.d.
-
t
=
=
=
H,
R
R
p
Bu, R'
2an 40%
,
1bn
=
2bn 30%
,
R' Me, 1ao
2ao
76%
,
H,
H,
No photocatalyst
Without (Ph-S)2
No light
=
R' iPr, 1ap
HO
=
2ap 69%
,
R
OH
34
n
1ca
2ca
,
76%
n
n =
n =
1aq
1ar
2aq
,
96%
52%
17
18
1,
2,
aConditions: 1aa (0.3 mmol), photocatalyst (3 mol%), HAT catalyst
(20 mol%) and 0.2 mL water in solvent (2 mL) under a nitrogen atmos-
phere irradiation using 3 W blue LEDs at room temperature for 24 h.
bIsolated yields were shown.
O
2ar
,
O
OH
19
35
H
H
>
H
H
HO
2cb
HO
OH
d.r.
1as
2as 41%
,
1cb
99:1
, 67%,
We next examined the scope of olefins that could be em-
ployed in this visible-light mediated anti-Markovnikov hydra-
tion reaction. As revealed in Scheme 2, the combination of 9-
mesityl-10-methylacridinium and diphenyldisulfane permits
the addition of water with a wide range of olefins in good to
excellent yields. Importantly, all tested terminal or internal ole-
fins with different steric and electronic natures are readily ac-
commodated to the corresponding alcohols with satisfying anti-
Markovnikov regioselectivity. The hydration process pro-
ceeded good reactivity towards the 1,1-diphenylethene deriva-
tives bearing a range of electron-donating as well as electron
aConditions: alkenes 1 (0.3 mmol), photocatalyst 3 (3 mol%), diphe-
nyldisulfane (20 mol%) and 0.2 mL water in CH3CN (2 mL) under a
nitrogen atmosphere irradiation using 3 W blue LEDs at room temper-
ature for 24 h. Isolated yields were shown.
Encouraged by these promising results, we next further ap-
plied this method to prepare secondary alcohols by using inter-
nal alkenes as the substrates. Various β-methyl-substituted sty-
renes (cis- and trans- mixture) afforded the corresponding sec-
ondary alcohol in good yields with single anti-Markovnikov re-
gioselectivity (2ba−2bj, 43−96% yield). Moreover, the results
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demonstrated the yields were significantly different between was used (Scheme 4b). Therefore, we deduced that the disulfide
1
para-, meta- and ortho-bromine substituted β-methylstyrene
(1be−1bg), which might attribute to the influence of steric ef-
fects. Remarkably, the substituted 1,2-dihydronaphthalene
could undergo the anti-Markovnikov hydration to provide the
corresponding 1,2,3,4-Tetrahydro-1-naphthol (2bl) in 96%
yield. A similar pattern was also observed when indene was
subjected in the catalytic system, leading to the corresponding
2-indanol (2bk) with 77% yield, while 6,7-dihydro-5H-benzo-
annulene gave the corresponding alcohol 2bm in 52% yield un-
der the same conditions. To further probe the effect of alkene
structure on the title transformation, we examined several dif-
ferent aliphatic alkenes. Fortunately, hydration of cyclodode-
cene (1bn) could provide the desired product cyclododecanone
(2bn) in 30% yield. A trisubstituted alkenes, prop-1-ene-1,1-
diyldibenzene (1ca), can also afford the corresponding alcohol
product 2ca in good yield. Moreover, the anti-Markovnikov se-
lective addition of water to a steroid derivative, dehydroepi-
androsterone (1cb), was also successfully achieved (67% yield,
d.r. > 99:1), which highlights the good functional group toler-
ance and potential applications of this method.
might be initially converted to PhSH at the start stage of the
2
3
4
5
6
7
8
9
reaction.
0.20
0.28 mol/L 1a
0.18 mol/L 1a
0.09 mol/L 1a
(a)
(b)
3 mol% 3
5 mol% 3
8 mol% 3
0.3
0.2
0.1
0.0
0.15
0.10
0.05
10 mol% (PhS)2
20 mol% (PhS)2
30 mol% (PhS)2
(d)
20 mol% PhSH 0.09
40 mol% phSH
(c)
0.20
0.15
0.10
0.05
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
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44
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58
59
60
0.06
0.03
kobs = 4.7*10-4 mol*L-1*min-1
kobs = 2.4*10-4 mol*L-1*min-1
0.00
0
50
100
150
0
50
100
150
Reaction time (min)
Reaction Time (min)
Scheme 5. Kinetic experiments of each component.
To further assess the rate-determining step of this reaction,
kinetic experiments of each component were performed by us-
ing in-situ IR to monitor the consumption of 1a with respect to
time (Scheme 5). It is found that the rate of hydration reaction
remain quite constant with either increasing or decreasing the
concentration of alkene (Scheme 5a) and photosensitizer
(Scheme 5b). Only the concentration of (PhS)2 showed a posi-
tive correlation with the reaction rate (Scheme 5c). The de-
crease of the loading of (PhS)2 would markedly prolong the in-
duction period with the decrease of the photocatalytic reaction
rate. We speculate that the generation of PhSH might restrict
the reaction rate. In order to further confirm this result, we fur-
ther use thiophenol as HAT catalyst to perform the kinetic
study. The rate of hydration of 1a is almost exactly doubled
when the thiophenol concentration is doulbled. Based on the ki-
netic data of HAT between PhSH and carbon radical (k = 3.13
× 105 M-1s-1 for PhCH2·in hexane),14 HAT process is expected
to be a fast step. Therefore, we proposed that the protonation of
PhS− might be the rate-determining step of this transformation.
-
-
0.3 mol% Acr+-Mes ClO4
OH
2 mol% Ph-S-S-Ph
+
H2O
CH CN
mL)
(16
blue LEDs, 96 h
3
mmol,
mL
12
2.16 g
4
1.65
69%
g,
yield:
TON: 230
Scheme 3. Gram scale reaction of the anti-Markovnikov hy-
dration of 1,1-diphenylethene.
It is worth to note that the reaction can also be effectively
scaled up with the good efficiency when only 0.3 mol% loading
of photocatalyst and 2 mol% diphenyldisulfane co-catalyst
were used. As shown in Scheme 3, the hydration of 1aa opera-
tionally simple and amenable to gram-scale synthesis in 69%
yield with 230 TON based on acridinium photocatalyst, which
indicate that this visible-light mediated hydration reaction of
electron-rich alkenes provides a promising synthetic route for
the production of primary alcohols, due to the high regioselec-
tivity and efficiency.
3 mol% Acr+-Mes ClO4
OH
0.25
blue light irradiation
(a)
0.20
0.15
0.10
0.05
0.00
(b)
D
20 mol% (PhS)2
40 mol% PhSH
20 mol% Ph-S-S-Ph
1a
1b
0.20
0.15
0.10
0.05
0.00
=
CH3CN/D2O 10:1
blue LEDs, r.t., 24 h
2aa-D
80%, 82%-D
addition of 1a
-
3 mol% Acr+-Mes ClO4
20 mol% Ph-S-S-Ph
OH
H
0
50
100
150
200
250
300
0
50
100
150
200
250
=
CD3CN/H2O 10:1
blue LEDs, r.t., 24 h
Reaction Time (min)
Reaction Time (min)
2aa
76%
,
-
3 mol% Acr+-Mes ClO4
20 mol% Ph-S-S-Ph
18OH
Scheme 4. In-situ IR investigation for mechanistic insights.
H
To gain insights of this transformation, the hydration process
of 1aa was initially monitored by using in-situ IR (Scheme 4).
From the kinetic profile of the whole reaction course (Scheme
4a), an obvious decrease of the absorption in 781 cm-1 resulted
from the consumption of alkenes can be observed under the ir-
radiation of blue light. Meanwhile, the peak of the alcohols in-
creased at the wavenumber of 1061 cm-1. In contrast, no con-
version can be observed in the absence of visible light, which
indicated that the continuous irradiation of visible light is nec-
essary for the transformation. Interestingly, there is a short in-
duction period when (PhS)2 is employed as the HAT catalyst.
By contrast, the induction period was disappeared when the
HAT catalyst is PhSH. The whole kinetic profile of the hydra-
tion transformation exhibited approximately linear when PhSH
CH3CN/H2O18 10:1
=
blue LEDs, r.t., 24 h
18O-2aa 86%
,
Scheme 6. Isotope labelling experiments.
Then, a number of labelling-experiments were conducted to
examine the mechanistic hypothesis (Scheme 6). When D2O
was used instead of water in the hydration of 1aa, the deuterized
at the β-position of hydroxyl 2aa-D can be observed. Because
the H/D exchange of hydroxyl group might occur during the
column chromatography process, deuterated hydroxy group
cannot be observed. To investigate the O-source of the alcohols,
the reaction was performed in an acetonitrile/H218O mixture,
which gave almost completely 18O labelled 2,2-diphenylethan-
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Page 4 of 5
This work was supported by the National Natural Science Foundation
1-ol. Therefore, it suggest that the O-atom of alcohols originates
from water.
of China (21390400, 21520102003, 21272180, 21302148), the Hubei
Province Natural Science Foundation of China (2013CFA081), the Re-
search Fund for the Doctoral Program of Higher Education of China
(20120141130002), and the Ministry of Science and Technology of
China (2012YQ120060). The Program of Introducing Talents of Dis-
cipline to Universities of China (111 Program) is also appreciated.
1
2
3
4
5
6
7
8
Based on the experimental mechanistic studies and current
literature,10e a detailed description of the proposed mechanistic
cycle for this reaction was outlined in Scheme 7. Initially, under
the irradiation of visible light, the photocatalyst Acr+-Mes is ex-
cited to provide its excited species Acr•-Mes•+, which then un-
dergoes single electron transfer (SET) process with alkene com-
pounds to generate alkene radical cation intermediate 10 and
acridine radical (Mes-Acr•) 5. On the other hand, the photolytic
cleaveage of the disulfide bond of (Ph-S)2 9 would generate a
thiophenol radical 6, which is a suitable one-electron-oxidant
for the acridine radical (Mes-Acr•) 5 to complete the photocata-
lytic cycle. The protonation of generated thiophenol anion yield
thiophenol 8. Then, the alkene radical cation 10 can be trapped
by subsequent anti-Markovnikov addition of water to give a dis-
tonic radical cation 11. Deprotonation of distonic cation radical
11 furnishes a carbon radical 12, which is further to produce the
alcohol products through a HAT process.
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OH2
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R3
-H+
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R1
R1
R1
R3
R3
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R2
11
R2
R2
R2
1
10
12
8
Acr•-Mes
6
OH
R3
PhS
5
R1
6
Acr•-Mes•+
R2
Ph-S-S-Ph
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4
9
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Rate-determining step
or
11
H2O
hv
PhSH
PhS
Acr+-Mes
7
8
3
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In summary, we have reported a visible-light mediated direct
anti-Markovnikov hydration method of ionizable alkenes using an
organic photocatalyst and a cocatalyst diphenyl disulfide. The re-
action conditions are mild and tolerate wide range of alkenes to
give important primary and secondary alcohols. We have also
demonstrated that this protocol can be scaled up to the gram scale
with good efficiency and regioselectivity. In-situ IR and isotope-
labelling experiments gave a preliminary mechanistic insight.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via the In-
ternet at http://pubs.acs.org, which included NMR data; extended
data about mechanism study, control experiments, scale-up reac-
tion, and characterization (PDF)
AUTHOR INFORMATION
(13) Fukuzumi, S.; Kotani, H.; Ohkubo, K.; Ogo, S.; Tkachenko, N. V.;
Lemmetyinen, H. J. Am. Chem. Soc. 2004, 126, 1600–1601.
(14) Franz, J. A.; Bushaw, B. A.; Alnajjar, M. S. J. Am. Chem. Soc.
1989, 111, 268–275.
Corresponding Author
* Corresponding author, E-mail: aiwenlei@whu.edu.cn.
Author Contributions
‡ These authors contributed equally to this work
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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ACS Catalysis
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cat. Acr+-Mes
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Visible-light
Metal-free
photoexcitation
30-96%
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cat.
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+
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H2O
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