molecules

Communication
Nickel-Catalyzed Removal of Alkene Protecting
Group of Phenols, Alcohols via Chain
Walking Process
Chenkai Meng, Haolin Niu, Juehan Ning, Wengang Wu and Jun Yi *
Jiangsu Laboratory of Advanced Functional Material, School of Materials Engineering, Changshu Institute of
Technology, Changshu 215500, China; mengchenkai@163.com (C.M.); niuhaolin1@126.com (H.N.);
juehanning@126.com (J.N.); 505609053@139.com (W.W.)
* Correspondence: yijun08@mail.ustc.edu.cn; Tel.: +86-512-5225-1842




Received: 11 December 2019; Accepted: 28 January 2020; Published: 30 January 2020


Abstract: An efficient nickel-catalyzed removal of alkene protection group under mild condition
with high functional group tolerance through chain walking process has been established. Not
only phenolic ethers, but also alcoholic ethers can be tolerated with the retention of stereocenter
adjacent to hydroxyl group. The new reaction brings the homoallyl group into a start of new type of
protecting group.

Keywords: deprotection; nickel; chain walking; phenol; alcohol

1. Introduction
Functional group protecting and deprotecting is a common strategy widely used in organic
chemistry especially in total synthesis [1]. The most conventional masking of phenols and alcohols are
allylethers derived from facile base-promoted substitution of allyl halides [2]. Meanwhile, allylethers
are easily removed under acidic, basic, reductive, or oxidative conditions with or without the aid
of transition metals (Scheme 1a) [3–11]. On the other hand, it means allylethers are not stable
in these conditions which diminished its usage in application. Long-chain alkene ethers such as
homoallylethers are significantly steadier than allylethers which have been serving as a protecting group
for decades [12–18], but lack of utility in practice due to the few deprotection methods. Ozonolysis
of homoallylic carboxylic esters was reported by Barrett [19]. Cossy [20] and Lipshutz [21] reported
removal of homoallyl group by Grubbs-Hoveyda catalyst through isomerization or metathesis. These
reports are encountered from harsh reaction conditions. Meanwhile, chain walking strategy in
bond construction has been emerging as a powerful tool utilizing alkene as feedstock in synthetic
chemistry [22–25]. Hu [26,27], Martin [28–30], Zhu [31–36], and Hartwig [37] recently demonstrated
that nickel was a prominent catalyst in chain walking chemistry. Streuff reported a zirconium catalyzed
deallylation through chain walking mechanism [38]. Inspired by these reports and our interest in
group transfer reactions [39] and nickel-catalyzed reactions [40], we envisaged that the nickel-hydride
complex I formed through en route nickel-boryl [41–43] water or methanol addiction intermediate
σ-bond metathesis would trigger the chain walking process (III, Scheme 1c). Low valent Nickel(I) was
reported to go through oxidative addition to allyl C-O bond [44–46], which made the formation of
intermediate V possible. The alkene (VI) was released after reductive elimination and regenerated
the catalyst. Free phenols or alcohols would be retrieved by simple acid workup of VIII. Herein, we
report the nickel-catalyzed removal of alkene protection group of phenols and alcohols under mild
condition with high functional group tolerance through chain walking process.

Molecules 2020, 25, 602; doi:10.3390/molecules25030602 www.mdpi.com/journal/molecules

Molecules 2020, 25, 602 2 of 12
Molecules 2020, 25, x FOR PEER REVIEW 2 of 13

Scheme1.1.Different
Scheme Differentremoval
removalof
of alkene
alkene protecting
protecting group
groupand
andnew
newmechanistic
mechanisticrationale.
rationale.

2. 2.
Results
Results
InIn order
ordertototestify ourproposal,
testify our proposal,wewe began
began ourour
study study by optimizing
by optimizing the reaction
the reaction conditions conditions
using
using 4-(but-3-enyloxy)biphenyl
4-(but-3-enyloxy)biphenyl (1a) as(1a)the
as the
modelmodel substrate
substrate (Table
(Table 1). 1). Investigation
Investigation of aofrange
a range of of
parameters,
parameters, wewe foundfound
thatthat the combination
the combination of nickel(II)
of nickel(II) chloride
chloride ethylene
ethylene glycolglycol dimethyl
dimethyl ether
ether complex
complex
(NiCl ·DME, (NiCl
5 2∙DME,
mol%), 6,65 0mol%),
-dimethyl-2,2 0 -bipyridine (L1) as ligand,
6,6′-dimethyl-2,2′-bipyridine (L1) as ligand, Bis(pinacolato)diboron
Bis(pinacolato)diboron (B pin
2 2 2 , 1.5
(B2pin
equiv) as2, the
1.5 reductant,
equiv) as the reductant,
Lithium Lithium tert-butoxide
tert-butoxide as the base, inasN,N-dimethylacetamide
the base, in N,N-dimethylacetamide
(DMA) (0.1M)
(DMA)
with methanol(0.1M)and with methanol
water and water
as additives gave as excellent
additives isolated
gave excellent isolated
yield (92%) yield1,(92%)
(entry Table(entry 1,
1). Other
Table 1). Other nickel sources such as zero valent Bis(1,5-cyclooctadiene)nickel
nickel sources such as zero valent Bis(1,5-cyclooctadiene)nickel (Ni(COD)2 , entry 2, Table 1) or less (Ni(COD) 2, entry 2,

Table NiCl
soluble 1) or less soluble NiCl2 (entry 3, Table 1) diminished the yield. Similar to the previous reports
2 (entry 3, Table 1) diminished the yield. Similar to the previous reports [31–36], more
[31–36], more bulky ligand was critical for the reaction and probably facilitate the chain walking
bulky ligand was critical for the reaction and probably facilitate the chain walking process (entry
process (entry 4–5, Table 1). Other common phosphine ligands such as triphenylphosphine (entry 6,
4–5, Table 1). Other common phosphine ligands such as triphenylphosphine (entry 6, Table 1) and
Table 1) and tricyclohexylphosphine (entry 7, Table 1) were all low efficient. Nickel(I) was proposed
tricyclohexylphosphine (entry 7, Table 1) were all low efficient. Nickel(I) was proposed as the active
as the active spices in the chain walking reactions [31–36], so we tested some reductant to generate of
spices in the chain walking reactions [31–36], so we tested some reductant to generate of nickel(I)
nickel(I) spices. B2pin2 in combination of base was reported as efficient reductant in nickel-catalyzed
spices. B2 pin2 in combination of base was reported as efficient reductant in nickel-catalyzed reductive
reductive reactions [47], to our pleased moderated yield was observed (entry 8, Table 1). Other widely
reactions
used metal [47],reductants
to our pleased moderated yield
in nickel-catalyzed cross was observed
reductive (entry
reaction such8,asTable
Zn and1). Mn
Other
gave widely
very few used
metal reductants in nickel-catalyzed cross reductive reaction such as Zn and
product (entry 9–10, Table 1) [48–52]. Next, we surveyed some additives to accelerate the reaction. Mn gave very few product
(entry 9–10, Table
We found that a1) [48–52].
certain Next,ofwe
amount surveyed
methanol someprompted
greatly additives theto accelerate
yield (entry the11,
reaction.
Table 1).We found
Water
that
was added to further boost the efficiency of the reaction. Both water and methanol might serve as a to
a certain amount of methanol greatly prompted the yield (entry 11, Table 1). Water was added
further
hydride boost the in
donor efficiency of the reaction.
σ-bond metathesis. Both water
Considering bothand methanol
Lithium might serve
tert-butoxide andas a hydride
water donor in
were added,
in situmetathesis.
σ-bond lithium hydroxide Considering
might be both Lithium
formed. tert-butoxide
Directly and water
using lithium hydroxidewereasadded,
base did innot
situhave
lithium
a
hydroxide
similar resultmight be formed.
(entry 13, TableDirectly using reaction
1). Switching lithium solvent
hydroxidefromasDMAbaseto did not
less have
polar a similar
solvent suchresult
as
tetrahydrofuran
(entry 13, Table 1). (THF) Switchingresulted in lower
reaction solvent yields
from(entries
DMA to15,less Table
polar1).solvent
Finally,such
control experiments
as tetrahydrofuran
showed
(THF) that both
resulted nickelyields
in lower and B(entries
2pin2 were 15,indispensable for the
Table 1). Finally, reaction.
control In order to showed
experiments demonstrate that its
both
possibility
nickel and B2in pin large
2 scale
were synthesis,
indispensable a 20
for mmol
the scale reaction
reaction. In was
order todone (entry
demonstrate 18, Table
its 1). The
possibility yield
in large
Molecules 2020, 25, 602 3 of 12
Molecules 2020, 25, x FOR PEER REVIEW 3 of 13

scale synthesis,
was lower a 20
but still mmol scaleThe
outstanding. reaction wastodone
attempt lower(entry 18, Table
the loading 1). The
of nickel yield was
catalyst and lower
ligandbut still
greatly
outstanding. The attempt to lower the loading of nickel catalyst and ligand
diminished the yield with substantial starting material left (entry 19, Table 1). greatly diminished the
yield with substantial starting material left (entry 19, Table 1).
Table 1. Optimization of removal homoallyl group.
Table 1. Optimization of removal homoallyl group.

entry Deviation from standard conditions Yield of 2 (%) a

1 None 96(92) b
entry Deviation from standard conditions Yield of 2 (%)a
2 Ni(COD)2 84
3 NiCl2 instead of NiCl2 (DME) 53
1 4 L2 instead of L1
None 37 b
96(92)
5 L3 9
6 L4 42
2 7 Ni(COD)2 L5 84
45
8 B2 pin2 w/o additives 61
9 Zn instead of B2 pin2 5<
3 10 NiCl2 instead
Mnofinstead
NiCl2(DME)
of B2 pin2 53
5<
11 No CH3 OH 73
12 No H2 O 78
4 13
L2 instead of L1
LiOH instead of LiOtBu
37
71
14 KOH instead of LiOtBu 68
15 THF instead of DMA 56
5 L3 9
16 No Ni 0
17 No B2 pin2 0
6 18 L420 mmol scale 86
42
19 1% loading of nickel, 2% L1 52(42) c
aConditions: 1a (0.2 mmol), Amine (1.5 equiv), 1
7
b c
L5 Determined by dibromomethane as an internal
45 standard by H
NMR. Isolated yield. 1a remained in reaction.

With 8the optimized condition

B2pinin2 w/o additives
hand, the scope of substrate of the reaction61 was examined
(Table 2). First, we tested the phenol scope. Ortho methyl group of phenol (1d) gave good yields,
9 position was moreZn
although ortho instead Electron
hindered. of B2pin2effect of the substitution groups
5< did not play great
roll on the yield. Strong electron-donating (benzyloxy, 1m) as well as strong electron-withdrawing
(trifluoromethyl,
10 1p) groups wereMn allinstead
tolerated.
of BMore
2pin2
strikingly, fragile groups in basic
5< conditions such
as aldehyde (1o), ester (1i), even free carboxylic acid (1l) were all tolerated in the reaction conditions,
although the yield of aldehyde (1o) was low Furthermore, different halides (1e–1h) even iodide were
untouched11during the reactions which Nocould
CH3OH 73
be used in the further elaborating reactions, for instance,
Suzuki reactions. It is worth highlighting that heteroaromatics (1q, 1r), which are prevalent structure
12
motifs in medicinal molecular, did notNo H2O the efficiency of the reaction.
corrupt 78

13 LiOH instead of LiOtBu 71

14 KOH instead of LiOtBu 68

 suchsuch such
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ester ester (1i),
(1i), (1i), even
even even free
free freecarboxylic
carboxylic
carboxylic acid
acidacid (1l)
(1l)
(1l) were
werewere all
all tolerated
all tolerated
tolerated inininthe thereaction
reaction
such
such
such
such such
such as
such
asas
as
such aldehyde
aldehyde
aldehyde
as aldehyde
aldehyde
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(1e–1h)
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of aldehyde
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aldehyde aldehyde (1o)
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waswaslow
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(1e–1h)
(1e–1h)(1e–1h)
(1e–1h) even
even
(1e–1h)
even even
even
even
iodide
iodide were
were untouched
untouched during
during the the reactions
reactions which
which could
could beFurthermore,
used
be usedin inthethe different
further
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halides
elaborating
elaborating
(1e–1h)
reactions, even
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2020, 25, structure
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Table
Table2. Scope
2. Scope of of
phenol. Conditions:
phenol. SeeSee
Conditions: Supplementary Materials
Supplementary forfor
Materials details.
details.
Table
Table
Table
Table 2.
Table 2.2.
Table
Table 2.
Scope
Table
Table
2. Scope
Scope
Scope
2.
Scope
2. Scope
2. 2. of
Scope
Scope ofof
of phenol.
phenol.
phenol.
ofScope
phenol.
of
phenol.
of ofof Conditions:
Conditions:
Conditions:
Conditions:
phenol.
phenol.
phenol. See
Conditions:
phenol.
Conditions: See
See
See
Conditions:
Conditions: Supplementary
See
Conditions:
See
See Supplementary
Supplementary
Supplementary
Supplementary
Supplementary
See
See Materials
Materials
Materials
Materials
SupplementaryMaterials
Supplementary
Materials
Supplementary for
for
Materialsfor
forfor
Materials
for
Materials details.
details.
details.
details.
details.
details.
forfor
for
details.
details.
details.
Table 2. Scope of phenol. Conditions: See Supplementary Materials for details.

Molecules
Molecules
Molecules
Molecules 2020,
2020, 25, 2020,
2020,
25,
x FOR 25,
x25,
FOR xFOR
FOR
xPEER
PEERPEER
PEER REVIEW
REVIEW
REVIEW
REVIEW 55 of
of513
of513
13 of 13

O
OO O
OH
O OHOH
OH
OO
2r: O
43%
2r:2r:
43%2r:
43% 43%
Next, different alkene protecting groups of phenol were tested (Table 3). Interestingly, vinyl (3a–
3c)Next,
Next,
Next, was different
different
removed
different alkeneatalkene
alkene the protecting
protecting
comparable
protecting groups
groups
yield
groups of of phenol
phenol
without
of phenol nickel
werewerewere
catalyst
tested tested
tested (Table
(Table
indicated
(Table 3). 3).
3).another Interestingly,
Interestingly,
mechanism
Interestingly, vinyl
vinyl
might
vinyl (3a– (3a–
(3a–
Next, different
be alkene
involved. Exceptprotecting
for groups of
the homoallyl phenol
group, the weregroup
allyl testedalso(Table
could 3).
be Interestingly,
easily removed vinyl
under
3c)3c)
was3c)
was was removed
removed
removed at at
the atcomparable
the the comparable
comparable yield
yield
yield without
without
without nickel
nickel
nickel catalyst
catalyst
catalyst indicated
indicated
indicated another
another
another mechanism
mechanism
mechanism might
might
might
(3a–3c) be
was be removed
existing
involved.
involved. atExcept
Exceptthefor
conditions comparable
(3d–3i).
for
the the yieldgroup,
homoallyl
homoallyl without
Interestingly, not
group,onlynickel
theallyl
the catalyst
acyclic
group indicated
alkene protecting
also could another
be groups,
easilymechanism
but also
removed theunder
be involved. Except for the homoallyl group, thethe allyl
allyl group
group also
also could
could bebe easily
easily removed
removed under
under
mightexisting
be involved.
cyclic
existing
existing Except
alkene
conditions
conditions was
conditions for
(3d–3i).
(3d–3i). the
smoothly
(3d–3i). homoallyl
detached
Interestingly,
Interestingly, group,
Interestingly,in
notnot not
only
only the
outstanding
only
thetheallyl
the group
yield
acyclic
acyclic
acyclic (3i). also
alkene
alkene
alkene could
Longer be
alkene
protecting
protecting
protecting easily removed
protecting
groups,
groups,
groups, but
but group
but
also
also also
thethethe
undercyclic
existing
cyclic (pentenyl)
cyclicconditions
alkene
alkene afforded
was was(3d–3i). products
smoothly
smoothly albeit ininrelatively
Interestingly,
detached
detached not
in onlylower
theyield
outstanding
outstanding yields
acyclic
yieldyield(3j–3m).
alkene
(3i).
(3i). Control
protecting
Longer
Longer experiments
groups,
alkene
alkene showed
but also
protecting
protecting group
group
alkene was smoothly detached in outstanding (3i). Longer alkene protecting group
that nickel
the cyclic alkene catalyst wasdetached
was smoothly indispensable for alkene protecting
in outstanding yield (3i). groups longer
Longer than vinyl.
alkene protecting group
(pentenyl)
(pentenyl)
(pentenyl) afforded
afforded
afforded products
products
products albeit albeit
albeitin in in relatively
relatively
relatively lower
lower
lower yields
yields
yields (3j–3m).
(3j–3m).
(3j–3m). Control
Control
Control experiments
experiments
experiments showed
showed
showed
(pentenyl)
that
that afforded
that nickel
nickel
nickel products
Tablecatalyst
catalyst
catalyst was
3.was
Scope albeit
was
of in relatively
indispensable
indispensable
alkene
indispensable forfor
protecting forlower
alkene
alkene
groups.
alkene yields (3j–3m).
protecting
protecting
Conditions:
protecting groups Control
groups longer
longer
a Without
groups Ni
longer experiments
than
than
catalyst
than ligand.showed
andvinyl.
vinyl.
vinyl. See
Supplementary
that nickel catalyst Materials for
was indispensable fordetails
alkene.
protecting groups longer than vinyl.
TableTable
Table
3. 3. 3. Scope
Scope
Scope of of of alkene
alkene
alkene protecting
protecting
protecting groups.
groups.
groups. Conditions:
Conditions:
a a
Conditions: a Without
Without
Without NiNi Ni catalyst
catalyst
catalyst andand and ligand.
ligand.
ligand. SeeSeeSee
Supplementary
Supplementary
Supplementary Materials
Materials
Materials forfor for details
details
details . . .

Substrate Product Substrate Product

2a: 92%, 88% 2s: 96%
Substrate
Substrate
Substrate Product
Product
Product Substrate
Substrate
Substrate Product
Product
Product
2a:
2a:2a: 92%,
92%,
92%, 88%
88%
88% 2s:2s:2s:
96%96%96%

2c: 87%, 90% a; 2c: 93%

2f: 92%,84% a

2c: 87%, a a a;
90% 2c: 93%
2c:2c: 87%,
87%, 90%
90% ; ; 2c:2c:
93%93%
a a a
2f:2f:2f: 92%,84%
92%,84%
92%,84%
2g: X = I, 63%; 2a: 81%
2h: X = Br,
 be involved.
be involved.
existing
existing
existing Except
conditions
conditions
conditions for
Except the
(3d–3i).
(3d–3i).
(3d–3i). homoallyl
forInterestingly,
the homoallyl
Interestingly, group,
Interestingly, not
not not the
group,
only
onlyonlyallyl
the
the
the thegroup
allyl
acyclic
acyclic
acyclic also
group
alkene
alkene
alkene could
also be easily
could
protecting
protecting
protecting be removed
easily
groups,
groups,
groups, removed
but
butbut under
also
also
also under
the
the the the
beexisting
cyclic existing
involved.
cyclic alkene
alkene
existing
conditionsconditions
Except was
was for the
smoothly
conditions
(3d–3i). (3d–3i).
smoothlyhomoallyl
(3d–3i). Interestingly,
detachedgroup,
detached
Interestingly, in
Interestingly,not the
onlynot
allyl
inoutstanding
outstanding
not only
only
the the
group
yield
the
acyclic acyclic
also
yield (3i).
acyclic
alkene alkene
could
(3i). Longer
alkene be
Longer
protectingprotecting
easily
alkene removed
alkene
protecting
groups, groups,
protecting
protecting
groups,
but alsobut
under
but also
group
group
also
the the
existing
cyclic
cyclic conditions
existing
alkene
alkene was
was (3d–3i).
conditionssmoothly
smoothly Interestingly,
(3d–3i). Interestingly,
detached
detached in not
in only
not
outstanding the acyclic
only
outstanding the
yield
yieldalkene
acyclic
(3i).
(3i). protecting
alkene
Longer
Longer groups,
protecting
alkene
alkene but also
groups,
protecting
protecting but the
also
group
group the
cyclic
existing alkene
cyclic
conditions
(pentenyl)
(pentenyl)
cyclic was
alkene
alkeneafforded
cyclic alkene smoothly
was
(3d–3i).
afforded was
was smoothly products
products
smoothlydetached
smoothly
Interestingly, detached
albeit
albeit
detached not
inin
detached
in in outstanding
only in
relatively
relatively outstanding
the lower
lower
in outstanding
outstanding yield
acyclicyields
yields
yield (3i).
yield
alkene Longer
(3i).
protecting
(3j–3m).
(3j–3m).
yield
(3i). Longer alkene
Longer
Control
(3i). Control
Longer protecting
alkene
groups, but
experiments
alkeneexperiments
alkene group
protecting
also the
showed
showed
protecting
protecting group group
group
cyclic alkene
cyclic
(pentenyl)
(pentenyl) was was
alkene
afforded
affordedsmoothly
smoothly
products
products detached
detached
albeit
albeitin in inrelatively
outstanding
relatively in outstanding
lower
lower yield
yields (3i).
yield
yields Longer
(3i).
(3j–3m).
(3j–3m). Longeralkene
Control
Control protecting
alkene protecting
experiments
experiments group
showed
showedgroup
(pentenyl)
cyclic
that alkene
that
(pentenyl) nickel
nickel afforded
(pentenyl)
was
catalyst
(pentenyl)
afforded products
afforded
smoothly
catalyst was
afforded
products albeit
products
detached
wasindispensable
indispensable
products
albeit in relatively
albeit
albeit
in forforin
inrelatively
outstanding
in alkene
alkene lower
relatively
relatively yields
lower
yield
protecting
protecting
lower lower
yields (3j–3m).
yields
(3i). Longer
groups
groups
yields
(3j–3m). Control
(3j–3m).alkene
longer
longer
(3j–3m).
Control experiments
Control
than
than
Controlvinyl.
vinyl. showed
experiments
protecting group
experiments
experiments showed showed
showed
(pentenyl)
that
thatnickel afforded
(pentenyl)
nickel catalyst
catalyst products
afforded
was
was productsalbeitalbeit
indispensable
indispensablein relatively
inalkene
forfor alkene lower
relatively yields
lower
protecting
protecting (3j–3m).
yields
groups
groups Control
(3j–3m).
longer
longer than experiments
Control
thanvinyl.experiments
vinyl. showed showed
that
(pentenyl)
that nickel
that
that
nickel catalyst
nickel
afforded
nickel
catalyst was
catalyst
products
catalyst
was indispensable
was
was for
indispensable
albeit in relatively
indispensable
indispensable for alkene
alkene for
for protecting
alkene
lower
alkene yields
protecting groups
protecting
(3j–3m).
protecting
groups longer
groups
Control
groups
longer than
longer
longer
than vinyl.
than
experiments
than
vinyl. vinyl.
vinyl. showed
that nickel
that
Table
Table catalyst
nickel
3.3.Scope
Scopewas
catalyst indispensable
was
ofofalkene
alkeneindispensableforgroups.
protecting
protecting alkene
for alkene
groups. protecting
Conditions:
Conditions: groups
protecting a Without
a Without
longer
groups NiNi than
longer vinyl.
than
catalyst
catalyst vinyl.
and
and ligand.See
ligand. See
that nickel
Molecules catalyst
25,
2020,Table
Table
wasofof
6023. 3.Scope
Table Scope
3. Scope
indispensable
of
alkene
alkene
alkene
for. alkene
protecting
protecting
protecting groups.
groups.
. groups.
protecting
Conditions: groups
Conditions:
Conditions:
longer
a Without
a Without
a Without Nithan
Ni Ni vinyl.
catalyst
catalyst
catalyst and
and and 5 of 12
ligand.
ligand.
ligand. See
See See
Table Table
Table
3. 3. of
Supplementary
Supplementary3.
Scope Scope
Scope of alkene
Materials
Materials
of
alkene alkene
for
protecting protecting
fordetails
details
protecting groups.
groups.groups. Conditions:
Conditions:
Conditions: Without
a Without
a Without Ni catalyst
Ni
Ni catalystcatalyst
a and ligand.
and
and ligand. ligand.
See See
See
Table 3. Scope
Table
Supplementary
Supplementary of
3. Scope alkene
Materials
Materials protecting
of alkene
forfor . .groups.
protecting
details
details Conditions:
. groups.
a Without
Conditions: Ni catalyst
a Without and ligand.
Ni catalyst See See
and ligand.
Supplementary
Table 3. Scope
Supplementary of Materials
Supplementary
alkene
Supplementary for
Materialsdetails
protecting
Materials
Materials for .
details
groups.
for details
for details . . Conditions: a Without Ni catalyst and ligand. See
Supplementary
SupplementaryMaterials for details
Materials for .
details .
Supplementary
Table 3. Scope of Materials for details
alkene protecting .
groups. Conditions: a Without Ni catalyst and ligand. See
Supplementary Materials for details.

Substrate
Substrate Product
Product Substrate
Substrate Product
Product
Substrate
Substrate
Substrate
Substrate Product
Product
ProductProduct Substrate
Substrate
Substrate
Substrate Product
Product
ProductProduct
Substrate
Substrate
Substrate
Substrate Product
2a:
2a: Product
92%,88%
92%,
Product
Product Substrate
88% Substrate
Substrate
Substrate Product
2s: Product
2s:Product
Product96%
96%
Substrate Substrate 2a:
2a:
Product Product
92%,
2a:92%,
92%,92%,
2a:
88%
88%
92%,
92%, Substrate
88% 88%
2a: 88% 88%
Substrate Product
2s:
2s:
Product
2s: 96%
96%96%
2s: 96%
2s:96%
96%
2a:
2a: 92%, 88%88%
2a: 92%, 2s:
2s:96%
96%
2s:
2a: 92%, 88% 2s: 96%
2a: 92%, 88% a 2s: 96%

2c:2c:87%,
87%,90%90%aa;aa; 2c:93%
2c: 93%
2c:
2c: 2c:87%,
87%,
87%,
2c: 90%
90%
87%,90% ;;a ; aaa;;
aaa90% 2c:
2c:2c:
93%
93%93%
2c: 93%
2c:2f:
2c: 2c:
87%,
2f: 87%,
90%
92%,84%
92%,84%
87%,
2c: 90%
87%, a;90%
90% ; 2c: 93%2c:
2c: 93% 93%
2f:
2c:2f: 2f:
87%, 92%,84%
92%,84%
90% a
a;a a a aa;
a
2c: 93%
2c: 93%
2f: 92%,84%
2f:
2f:
2c:92%,84%
87%, 92%,84%
92%,84%
90% ;a a
2f:2f:92%,84%
2f: 92%,84%
aa 2c: 93%
2f: 92%,84%92%,84%

2g:XX==I,I,63%;
2g: 63%; 2a:81%
2a: 81%
2g:
2g:2g:XX2g:
X
==I,=I,X63%;
I,63%;
= 63%;
I,Br,
63%; 2a:
2a:2a:
81%
81% 81%
2a: 81%
XX =X I,XX 63%;=I,I,
= 63%; 2a: 2a:81%
81%
2a:81%
2g: 2h:
2h: 2g:
= XI, =63%;
= Br,
63%;
2g:
2h:
X2h:2g:
= X
I, X
63%; = = Br, Br, 81%
2a:
2g:2h:
2h:2g: XXX= I,==
2h:
2h: 63%;X Br,
XBr, == Br,
Br,
Br, 2a: 81%
2h:65%
65% X
2h:= = X Br,
= 2a: 81%
2h: 65%
65%
2h:
65%
X
X 65% Br,
= Br,
65%
65%
65%
65%65%
65%2i:2i:95%
95% 2d:74%
2d: 74%
2i:2i:
2i: 95%
95%95%
2i: 95% 2d:
2d:2d: 74%
74%74%
2d: 74%
2i: 95%
2i: 95% 2i:
2i: 95% 95% 2d: 74%
2d: 74%2d: 74%
2d: 74%
2i: 95%2i: 95% 2d: 2d:
74% 74%

2o:83%
2o: 83% 2e:72%
2e: 72%
2o:
2o:2o:83%
83% 83%
2o: 83% 2e:
2e:2e:72%
72%72%
2e: 72%
2o:
2o:83%2o:83%
83% 83% 2e:
2e:72% 2e:72%
72%
2o: 2e: 72%
2e:
Molecules 2020, 25, x FOR PEER REVIEW
2o: 83% 83%
2o:
2e: 72% 72%
6 of 13
Molecules 2020, 25, x FOR PEER REVIEW 6 of 13

2r: 53% 2p: 63%

2r: 53% 2p: 63%
2r: 53% 2p: 63%

We tried to expand the scope from phenols to aliphatic alcohols (Scheme 2). To our delight, allyl
We tried
protected to expand
alcohols the scope
were easily fromto
removed phenols to aliphatic
give both alcohols
aminoalcohol (Scheme
(5) and 2). To our
cholesterol delight,
(7) in allyl
moderate
protected
We tried
yield. alcohols
to expand
More were easily
the scope
importantly, removed to
from phenols
the stereocenter give both aminoalcohol
to aliphatic
adjacent alcoholsof
to hydroxyl (5)
(Scheme and cholesterol
2). To ourafter
7 was preserved (7)
delight,in moderate
the allyl
reaction.
yield.
protected More
alcoholsimportantly,
were easily the stereocenter
removed to give adjacent
both to hydroxyl
aminoalcohol (5)of 7
and was preserved
cholesterol (7) after
in the
moderate
For the homoallyl ether analogs the yield dropped to around 40% which was not practical in synthetic reaction.
For
yield.view.theimportantly,
More homoallyl ether analogs theadjacent
the stereocenter yield dropped to around
to hydroxyl 40%preserved
of 7 was which was notthe
after practical
reaction.in synthetic
For
view.
the homoallyl ether analogs the yield dropped to around 40% which was not practical in synthetic view.
 We tried to expand the scope from phenols to aliphatic alcohols (Scheme 2). To our delight, allyl
protected alcohols were easily removed to give both aminoalcohol (5) and cholesterol (7) in moderate
yield. More importantly, the stereocenter adjacent to hydroxyl of 7 was preserved after the reaction.
Molecules
For the 2020, 25, 602 ether analogs the yield dropped to around 40% which was not practical in synthetic
homoallyl 6 of 12
view.

Scheme
Scheme 2. Removal
2. Removal of alcohol
of alcohol protecting
protecting groups.
groups. Conditions:
Conditions: See Supplementary
See Supplementary Materials
Materials for
for details.
details.
Taking further advantage of our new reaction (Scheme 3, Method B), we compared it with the
Taking further
classic palladium advantageprotocol
deprotection of our new reaction
(Scheme 3, (Scheme
Method 3,A). Method
These B),twowe compared
methods wereit with thethe
about
classic
same palladium
efficiency when deprotection protocol (Scheme
the alkene protecting groups 3, Method
were A).toThese
closed two methods
the oxygen < 1).about
atom (nwere the
In contrast,
same efficiency when the alkene protecting groups were closed to the oxygen atom (n <
Method A drastically lost its activity when the interval between the alkene and oxygen is prolonged (n 1). In contrast,
Method
> 2), A drastically
meanwhile, Methodlost its activity
B still whenmedium
maintained the interval between
yield even atthe
n =alkene and oxygen
4. Through is prolongedit is
this comparison,
(n >
possible 2), meanwhile,
to remove Method
allyl and B still maintained medium yield even at n = 4. Through
homoallyl protecting groups sequentially by utilizing these this comparison,
methods.
Molecules 2020, 25, x FOR PEER REVIEW 7 of 13
it is possible to remove allyl and homoallyl protecting groups sequentially by utilizing these methods.

Scheme 3.
Scheme 3. Comparison
Comparison with
with previous
previous method.
method.

Althoughthe
Although theclear
clear panorama
panorama ofcatalytic
of the the catalytic cycle
cycle was stillwas
understill under the
pursuing, pursuing, the control
control experiments
experiments were designed to unveil the reaction mechanism (Scheme 4). First, butoxybenzene
were designed to unveil the reaction mechanism (Scheme 4). First, butoxybenzene (8) was put into (8)
wasoptimized
the put into the optimized
condition, condition,
no product wasno productItwas
detected. detected.
means It means the
the coordination coordination
of the of the
nickel catalyst of
nickel
the catalystwas
substrate of the substrate
necessary. was necessary.
Second, Second, ((2,2-dimethylbut-3-en-1-yl)oxy)benzene
((2,2-dimethylbut-3-en-1-yl)oxy)benzene (9) was subjected (9)
to
was subjected to optimal condition, similarly no desire product was observed (3), which means the
chain walking was intercepted with the quaternary carbon to stop the formation of key allyl ether.
When we analyzed the byproduct of the reaction 3j by GC-MS, the borylated alkene 10 was not
detected which means the reaction might not be initiated by Ni-Bpin. Due to the low boiling point of
pentene (30 °C), we did not see pentene signal on the GC-MS. Substrate (11) was synthesized to get
Molecules 2020, 25, 602 7 of 12

optimal condition, similarly no desire product was observed (3), which means the chain walking was
intercepted with the quaternary carbon to stop the formation of key allyl ether. When we analyzed the
byproduct of the reaction 3j by GC-MS, the borylated alkene 10 was not detected which means the
reaction might not be initiated by Ni-Bpin. Due to the low boiling point of pentene (30 ◦ C), we did
not see pentene signal on the GC-MS. Substrate (11) was synthesized to get more information of the
fate of deprotected group. Allylbenzene (12) was detected as equivalent to the product instead of the
corresponding borylation product (13) indicating the alkene was formed after the deprotection. The
combination of B2 pin2 and water/methanol might serve as a hydride donor to form the Ni-H species.
A preliminary survey with silane to generate Ni-H in situ [11] was done and a great amount of product
was also found which supported the possibility of Ni-H as the true catalyst in the reaction.
Molecules 2020, 25, x FOR PEER REVIEW 8 of 13

O Table 1, entry 1 OH
(3)

8
2b: 0%

Table 1, entry 1
O OH
(4)

9
2b: 0%

O Table 1, entry 1
1a + Bpin (5)
Ph
3j 81% 10, Undetectable

Table 1, entry 1
MeO (6)
O 2c + H

X 12, X = H : 93%;
11 95% 13, X = Bpin: 0%

NiCl2•DME (5 mol %)
O OH
L1 (10 mol %)

Ph PMHS (1.5 equiv) Ph

1a LiOtBu (2.0 equiv)
2a: 42%
0.2mmol DMA (2.0 mL), 30 C, 24h

Scheme4.4. Mechanistic
Scheme Mechanistic studies.
studies. Conditions:
Conditions: See Supplementary Materials for details.

3.
3. Discussion
Discussion
To
Tosummarize,
summarize,we wereported
reportedthethe nickel-catalyzed
nickel-catalyzed removal
removal of
of alkene
alkene protecting
protecting groups
groups of
of phenols
phenols
and
and alcohols through chain walking process. The facile and mild reaction condition as well as
alcohols through chain walking process. The facile and mild reaction condition as well as high
high
functional tolerance highlight its utilization in the future. More importantly, the nonconventional
functional tolerance highlight its utilization in the future. More importantly, the nonconventional
homoallyl
homoallyl may
may rival
rival as
as protecting
protecting group
group with
with this
this report
report that
that is complementary to
is complementary to existing
existing protocols.
protocols.
Future
Future efforts
efforts are
are directed
directed toward
toward expanding
expanding this
this type
type of
of new
new transformation
transformation inin practice
practice as
as well
well as
as
understanding the mechanism of the reaction.
understanding the mechanism of the reaction.

4. Experimental Section

4.1. Representative General Procedure for Nickel-Catalyzed Deprotecting Reaction

In glovebox, B2pin2 (76.17 mg, 0.3 mmol, 1.5 equiv), NiCl2(DME) (2.20 mg, 0.01 mmol, 0.05 equiv),
6,6-dimethyl-2,2-dipyridyl (3.68 mg, 0.02 mmol, 0.10 equiv), LiOtBu (32 mg, 0.4 mmol, 2.0 equiv), and
protected phenol (if solid) (0.2 mmol) were added to an oven-dried tube. The reaction tube was
equipped with a magnetic stir bar and sealed with Teflon-lined cap, refilled the system with argon
Molecules 2020, 25, 602 8 of 12

4. Experimental Section

4.1. Representative General Procedure for Nickel-Catalyzed Deprotecting Reaction

In glovebox, B2 pin2 (76.17 mg, 0.3 mmol, 1.5 equiv), NiCl2 (DME) (2.20 mg, 0.01 mmol, 0.05 equiv),
6,6-dimethyl-2,2-dipyridyl (3.68 mg, 0.02 mmol, 0.10 equiv), LiOtBu (32 mg, 0.4 mmol, 2.0 equiv),
and protected phenol (if solid) (0.2 mmol) were added to an oven-dried tube. The reaction tube was
equipped with a magnetic stir bar and sealed with Teflon-lined cap, refilled the system with argon and
performed two more evacuation-backfill cycles, protected phenol was added by syringe under argon
flow (if liquid). DMA (2.00 mL), H2 O (50 µL), MeOH (25 µL) were added to the tube sequentially. The
reaction mixture turned dark and was stirred at 30 ◦ C for 24 h. When the reaction was finished, 10 mL
aqueous HCl (0.1 M) was added to the mixture and extracted with CH2 Cl2 (2 × 10 mL), dried over
anhydrous MgSO4 , and concentrated in vacuo. The resulting residue was purified by silica gel flash
chromatography to give the product.

4.2. Characterization Data for Products 2a–2s, 5 and 7 (Tables 2, 3 and Scheme 2)
4-Phenylphenol (2a): White solid. IR (cm−1 , KBr): 3434, 3367, 3130, 1662, 1611, 1522, 1477, 1459, 1401,
1257, 1139, 1069, 998, 954, 862, 833, 758, 686, 555, 517. 1 H NMR (400 MHz, CDCl3 ) δ 7.57 (d, J = 7.4 Hz,
2H), 7.51 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.3 Hz, 2H), 7.35 (d, J = 7.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 2H), 4.95
(s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 155.0, 140.7, 134.0, 128.7, 128.4, 126.7, 115.6. m.p.: 163–164 ◦ C.
Phenol (2b): White solid. IR (cm−1 , KBr): 3440, 3134, 1659, 1624, 1401, 1075, 989, 951, 858, 538. 1 H NMR
(400 MHz, CDCl3 ) δ 7.31 (t, J = 7.7 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 2H), 6.04 (s, 1H).
13 C NMR (101 MHz, CDCl ) δ 155.2, 129.9, 121.2, 115.6. m.p.: 103–104 ◦ C.
3

3-Methoxyphenol (2c): Brown liquid. IR (cm−1 , KBr): 3439, 3133, 1671, 1609, 1401, 1163, 1073, 991, 946,
856, 769, 689, 541. 1 H NMR (400 MHz, CDCl3 ) δ 7.16 (t, J = 8.0 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.47 (d,
J = 7.9 Hz, 2H), 5.65 (s, 1H), 3.80 (s, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 160.8, 156.7, 130.3, 108.1, 106.6,
101.7, 55.3.
o-Cresol (2d): Brown liquid. IR (cm−1 , KBr): 3439, 3134, 1661, 1401, 1075, 993, 952, 858, 536. 1 H NMR
(400 MHz, CDCl3 ) δ 7.28 (d, J = 7.2 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.90 (d, J =
8.0 Hz, 1H), 5.70 (s, 1H), 2.40 (s, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 153.7, 131.3, 127.3, 124.4, 121.1,
115.3, 15.9.
3-Fluorophenol (2e): Light yellow liquid. IR (cm−1 , KBr): 3441, 3134, 1666, 1627, 1131, 1074, 993, 952,
857, 774, 531. 1 H NMR (400 MHz, CDCl3 ) δ 7.22 (dd, J = 15.2, 7.9 Hz, 1H), 6.74–6.57 (m, 3H), 5.76 (s,
1H). 13 C NMR (101 MHz, Chloroform-d) δ 163.7 (d, J = 245.6 Hz), 156.3 (d, J = 11.3 Hz), 130.7 (d, J =
10.0 Hz), 111.3 (d, J = 2.9 Hz), 108.2 (d, J = 21.3 Hz), 103.3 (d, J = 24.7 Hz).
3-Chlorophenol (2f): Yellow liquid. IR (cm−1 , KBr): 3439, 3134, 1664, 1623, 1401, 1250, 1138, 1074, 996,
952, 857, 771, 682, 530. 1 H NMR (400 MHz, CDCl3 ) δ 7.19 (t, J = 8.1 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H),
6.89 (s, 1H), 6.75 (dd, J = 7.2, 0.9 Hz, 1H), 5.35 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 155.9, 135.0, 130.6,
121.3, 116.0, 113.8.
2-Iodophenol (2g): Brown solid. IR (cm−1 , KBr): 3440, 3133, 1658, 1624, 1401, 1050, 1075, 991, 951, 858,
535. 1 H NMR (400 MHz, CDCl3 ) δ 7.69 (d, J = 7.9 Hz, 1H), 7.27 (t, J = 6.4 Hz, 1H), 7.03 (d, J = 8.1 Hz,
1H), 6.75–6.63 (m, 1H), 5.36 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 154.8, 138.3, 130.2, 122.5, 115.2, 85.7.
m.p.: 41–42 ◦ C.
2-Bromophenol (2h): Brown liquid. IR (cm−1 , KBr): 3439, 3132, 1663. 1619, 1401, 1160, 1077, 993, 946,
858, 744, 539. 1 H NMR (400 MHz, CDCl3 ) δ 7.49 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.06 (d, J =
8.1 Hz, 1H), 6.84 (t, J = 7.7 Hz, 1H), 5.59 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 152.3, 132.1, 129.2, 121.8,
116.2, 110.3.
Molecules 2020, 25, 602 9 of 12

Methyl 4-hydroxybenzoate (2i): White solid. IR (cm−1 , KBr): 3305, 2963, 2846, 2806, 1919, 1684, 1372,
1114, 954, 851, 691. 1 H NMR (400 MHz, CDCl3 ) δ 7.98 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.33 (s,
1H), 3.92 (s, 2H). 13 C NMR (101 MHz, CDCl3 ) δ 167.3, 160.2, 131.9, 122.3, 115.2, 52.0. m.p.: 130–131 ◦ C.
Ethyl 3-hydroxybenzoate (2j): Colorless liquid. IR (cm−1 , KBr): 3350, 2385, 2581, 1692, 1597, 1512, 1459,
1415, 1311, 1232, 1163, 1108, 1074, 926, 881, 760, 670, 565, 522. 1 H NMR (400 MHz, DMSO) δ 9.83 (s,
1H), 7.43–7.35 (m, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.03 (d, J = 7.9 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 1.30 (t, J
= 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 167.6, 156.3, 131.3, 129.7, 121.6, 120.5, 116.4, 61.6, 14.1.
4-tert-Butylphenol (2k): White solid. IR (cm−1 , KBr): 3144, 2962, 2868, 1608, 1513, 1447, 1399, 1269, 1175,
822, 543. 1 H NMR (400 MHz, CDCl3 ) δ 7.32 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.53 (s, 1H), 1.36
(s, 9H). 13 C NMR (101 MHz, CDCl3 ) δ 152.9, 143.7, 126.5, 115.0, 34.1, 31.6. m.p.: 97–99 ◦ C.
4-Hydroxybenzoic acid (2l): White solid. IR (cm−1 , KBr): 3382, 3130, 3013, 1676, 1600, 1402, 1321, 1286,
1238, 1160, 1096, 1000, 929, 848, 611, 541. 1 H NMR (400 MHz, DMSO) δ 12.41 (s, 1H), 10.21 (s, 1H), 7.79
(d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 167.6, 162.0, 132.0, 121.8,
115.5. m.p.: 213–215 ◦ C.
4-Benzyloxyphenol (2m): White solid. IR (cm−1 , KBr): 3429, 3132, 1659, 1614, 1510, 1401, 1236, 1164, 1086,
1012, 818, 734, 520. 1 H NMR (400 MHz, CDCl3 ) δ 7.48–7.39 (m, 4H), 7.38–7.33 (m, 1H), 6.89 (d, J = 8.8
Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 5.04 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 153.0, 149.7, 137.2, 128.5,
127.9, 127.5, 116.1, 116.1, 70.8. m.p.: 122–124 ◦ C.
2-Naphthol (2n): White solid. IR (cm−1 , KBr): 3501, 3190, 1628, 1590, 1510, 1459, 1401, 1277, 1215, 1168,
955, 845, 813, 741, 476. 1 H NMR (400 MHz, CDCl3 ) δ 7.84–7.77 (m, 2H), 7.71 (d, J = 8.2 Hz, 1H), 7.48 (t,
J = 7.5 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.21–7.11 (m, 2H), 5.52 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ
153.3, 134.6, 129.9, 129.0, 127.8, 126.6, 126.4, 123.7, 117.8, 109.6. m.p.: 120–122 ◦ C.
p-Hydroxybenzaldehyde (2o): White solid. IR (cm−1 , KBr): 3144, 2962, 1608, 1513, 1399, 1239, 1176, 821,
543. 1 H NMR (400 MHz, DMSO) δ 10.59 (s, 1H), 9.79 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz,
2H). 13 C NMR (101 MHz, DMSO) δ 191.3, 163.7, 132.5, 128.9, 116.3. m.p.: 116–118 ◦ C.
3-Trifluoromethylphenol (2p): Yellow liquid. IR (cm−1 , KBr): 3440, 3132, 1662, 1622, 1401, 1160, 1076, 946,
858, 538. 1 H NMR (400 MHz, CDCl3 ) δ 7.38 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.12 (s, 1H), 7.04
(d, J = 8.1 Hz, 1H), 5.36 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 155.3, 132.4 (q, J = 32.7 Hz), 130.3, 123.8
(q, J = 271.3 Hz), 117.9 (q, J = 4.1 Hz), 112.3 (q, J = 4.1 Hz).
tert-Butyl 4-hydroxy-1H-indole-1-carboxylate (2q): Corlorless liquid. IR (cm−1 , KBr): 3449, 3135, 1664,
1626, 1400, 1136, 1074, 962, 855. 1 H NMR (400 MHz, CDCl3 ) δ 7.76 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 3.5
Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 6.68 (dd, J = 10.2, 5.8 Hz, 2H), 5.40 (s, 1H), 1.70 (s, 9H). 13 C NMR (101
MHz, CDCl3 ) δ 149.8, 148.7, 136.9, 125.1, 124.7, 119.6, 108.3, 107.7, 103.5, 83.8, 28.2.
6-Hydroxyflavone (2r): White solid. IR (cm−1 , KBr): 3437, 3128, 3013, 1621, 1569, 1402, 1255, 1077, 835.
1H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 8.08 (d, J = 6.9 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.59 (d, J =
6.5 Hz, 3H), 7.34 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 9.1, 2.3 Hz, 1H), 6.95 (s, 1H). 13 C NMR (101 MHz,
DMSO) δ 177.4, 162.6, 155.3, 149.8, 132.0, 131.8, 129.5, 126.7, 124.7, 123.5, 120.3, 107.9, 106.4. m.p.:
238–240 ◦ C.
4-Cyanophenol (2s): White solid. IR (cm−1 , KBr): 3283, 2229, 1603, 1505, 1441, 1391, 1283, 1221, 1159, 834,
696, 534. 1 H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 7.61 (s, 2H), 7.13–6.68 (m, 2H). 13 C NMR (101
MHz, CDCl3 ) δ 160.6, 134.3, 119.3, 116.5, 102.5. m.p.: 112–114 ◦ C.
2-(N,N-Dibenzylamino)-2-phenylethan-1-ol (2t): White solid. IR (cm−1 , KBr): 3440, 3134, 1661, 1624, 1401,
1070. 1 H NMR (400 MHz, CDCl3 ) δ 7.53–7.19 (m, 15H), 4.17 (t, J = 10.6 Hz, 1H), 4.00–3.91 (m, 3H), 3.64
(dd, J = 10.6, 5.1 Hz, 1H), 3.18 (d, J = 13.4 Hz, 2H), 3.04 (s, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 139.1,
135.1, 129.3, 129.0, 128.5, 128.4, 128.0, 127.2, 63.0, 60.4, 53.5. m.p.: decomposed.
Molecules 2020, 25, 602 10 of 12

Cholesterol (7): White solid. IR (cm−1 , KBr): 3435, 3132, 2943, 1666, 1624, 1459, 1399, 1057. 1 H NMR (400
MHz, CDCl3 ) δ 5.37 (d, J = 4.3 Hz, 1H), 3.69–3.35 (m, 1H), 2.35–2.19 (m, 2H), 2.01 (t, J = 14.8 Hz, 2H),
1.86 (d, J = 9.9 Hz, 3H), 1.60–0.85 (m, 34H), 0.70 (s, 3H). 13 C NMR (101 MHz, CDCl3 ) δ 140.7, 121.7, 71.7,
56.7, 56.1, 50.1, 42.3, 42.3, 39.8, 39.5, 37.2, 36.5, 36.2, 35.8, 31.9, 31.6, 28.2, 28.0, 24.3, 23.8, 22.8, 22.5, 21.1,
19.4, 18.7, 11.8. m.p.: 146–148 ◦ C.

Supplementary Materials: The followings are available online.

Author Contributions: J.Y. conceived and designed the experiments; C.M., H.N., J.N., W.W. performed the
experiments; W.W., J.Y. checked and analyzed the data; J.Y. wrote and revised the paper. All authors have read
and agreed to the published version of the manuscript.
Funding: Financial Support from National Natural Science Foundation of China (Grant 21602017), Natural Science
Foundation of Jiangsu Province (Grant No. BK20160405) and Research Start-up Fund of Changshu Institute of
Technology (No. XZ1508).
Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 2a–2p are available from the authors.

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