Evaluation of 2-(piperidine-1-yl)-ethyl (PIP) as a protecting group for phenols: Stability to ortho-lithiation conditions and boiling concentrated hydrobromic acid, orthogonality with most common protecting group classes, and deprotection via Cope elimination or by mild Lewis acids

Article abstract of DOI:10.1016/j.tet.2021.132108

A new protecting group, 2-(piperidine-1-yl)-ethyl (PIP), was evaluated as a protecting group for phenols. The PIP group was stable to ortho-lithiation conditions and refluxing with concentrated hydrobromic acid. Deprotection was accomplished by two routes, oxidation to N-oxides followed by Cope elimination (CE) and subsequent hydrolysis or ozonolysis of the vinyl ether or one-step deprotection by BBr₃?Me₂S. The PIP group is orthogonal to the O-benzyl, O-acetyl, O-t-butyldiphenylsilyl, O-methyl, O-p-methoxybenzyl, O-allyl, O-tetrahydropyranyl and N-t-butoxy carbonyl groups. The CE step was systematically studied and was found to give higher yields when the reaction was performed in the presence of silylating agents.

Full text of DOI:10.1016/j.tet.2021.132108

Tetrahedron 88 (2021) 132108
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Evaluation of 2-(piperidine-1-yl)-ethyl (PIP) as a protecting group for
phenols: Stability to ortho-lithiation conditions and boiling
concentrated hydrobromic acid, orthogonality with most common
protecting group classes, and deprotection via Cope elimination or by
mild Lewis acids
ꢀ
Rolf Noren
€
Department of Chemistry, Kemicon, Hagvagen 3, 69370, Åtorp, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A new protecting group, 2-(piperidine-1-yl)-ethyl (PIP), was evaluated as a protecting group for phenols.
The PIP group was stable to ortho-lithiation conditions and refluxing with concentrated hydrobromic
acid. Deprotection was accomplished by two routes, oxidation to N-oxides followed by Cope elimination
(CE) and subsequent hydrolysis or ozonolysis of the vinyl ether or one-step deprotection by BBr3ꢀMe2S.
The PIP group is orthogonal to the O-benzyl, O-acetyl, O-t-butyldiphenylsilyl, O-methyl, O-p-methox-
ybenzyl, O-allyl, O-tetrahydropyranyl and N-t-butoxy carbonyl groups. The CE step was systematically
studied and was found to give higher yields when the reaction was performed in the presence of sily-
lating agents.
Received 12 February 2021
Received in revised form
12 March 2021
Accepted 19 March 2021
Available online 24 March 2021
Keywords:
Protecting group
Phenols
© 2021 Elsevier Ltd. All rights reserved.
Vinyl ether
Ortho-lithiation
Cope elimination
Lewis acid
1. Introduction
Moreover, orthogonality of protecting groups to many other pro-
tecting groups is a highly desirable property. [2].
The manipulation of complex organic molecules with many
functional groups creates a need for many different protecting
groups. [1]. A protecting group that is stable to strong acids and
bases, nucleophiles and electrophiles and that can be removed
under mild conditions is very desirable to organic chemists.
“Assisted removal” is an important concept in protecting group
chemistry. [1]. One example is the deprotection of allyl ethers such
as 1 via isomerization with a base or transition metal salts to vinyl
ethers 2. These vinyl ethers can then be cleaved with acid or
through oxidation to the parent hydroxy compounds 3 (eq 1). [1].
For 2-(phenylselenyl)ethyl protected compounds, deprotection
of 4 is accomplished via oxidation to selenoxides 5 followed by
E-mail address: rolnor@kemicon.se.
https://doi.org/10.1016/j.tet.2021.132108
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
elimination to vinyl ethers 6, are subsequently hydrolyzed to the
parent hydroxy compounds 7 (eq 2). [1].
3).
The greatest similarity to the 2-(piperidine-1-yl)-ethyl (PIP)
group described in the literature is in the work by Laatsch. [3]. In
that study, 2-iodoethoxy naphthalene 8 is reacted with trimethyl-
amine to give a quaternary ammonium iodide, which is treated
with silver oxide, and the resulting trimethylammonium hydroxide
9 is subjected to Hoffman elimination conditions to yield vinyl
ether 10. The yield in the elimination step is only 35%. The vinyl
ether is then hydrolyzed with acid to hydroxy naphthalene 11 (eq
Herein, I report that the PIP group has high stability under harsh
conditions and can be deprotected under mild oxidative conditions
via oxidation to N-oxide, Cope elimination (CE) and subsequent
cleavage of the formed vinyl ether. It can also be selectively
deprotected directly by BBr3ꢀMe2S.
2

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R. Noren
Tetrahedron 88 (2021) 132108
2. Results and discussion
(15) byproduct formed in the reaction. I theorized that silylating
agents such as N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA),
HMDS, and N,O-bis(trimethylsilyl)acetamide (BSA) would.
2.1. Protecting phenols with the PIP group
Phenols are efficiently protected with the PIP group via alkyl-
ation with 1-(2-chloroethyl)-piperidine hydrochloride and K2CO3
as the base, as demonstrated for p-nitrophenol in Scheme 1.
For sensitive phenols, Cs2CO3 and sonication gives similar yield
and the reaction can be performed at ambient temperature (see
compound 2a Table 2).
1. Remove any trace moisture in the N-oxide.
2. Silylate the 1-hydroxypiperidine formed and prevent it from
interfering with the CE process by hydrogen bonding to or
reduction of the N-oxide. [5].
A systematic study in which 13 was heated under varying con-
ditions to induce CE was conducted. The results of this study are
summarized in Table 1.
2.2. The Cope elimination PIP-deprotection route
When 13 was refluxed in dry toluene without an additive, vinyl
ether 14 was isolated in 66% yield (run 1). When 1 equiv. of water
was present, the yield decreased to 46% (run 2).
The first step in the deprotection of the PIP group via the CE
route is oxidation to the N-oxide (Scheme 2).
The low yield obtained in the presence of 1 equiv. of water can
explain why the synthesis of vinyl ethers via CE has not, to my
knowledge, been reported in the literature, as N-oxides are often
isolated in their non-anhydrous form. [6].
When 1 equiv. of 15 was present, the yield decreased to
approximately 41% (run 4). However, if the reaction was run in the
presence of 1 equiv. of BSA and 1 equiv. of 15, the yield was similar
to that without any additive (run 14), indicating that BSA neutral-
izes the negative effect of 15. The natural explanation for this effect
is that BSA silylates 15, thus neutralizing its negative effect on the
yield.
In the workup of 13, before evaporation, hexamethyldisilazane
(HMDS) was added to remove moisture, and 13 was isolated in its
non-hydrated form. HMDS was chosen as the drying agent because
the excess reagent and byproducts formed could be removed upon
evaporation. The 1H NMR peak at 3.14 ppm attributed to H2O
present in the N-oxide monohydrate 13b sample not treated with
HMDS before evaporation is absent from the spectrum of the
HMDS-treated sample 13 (see Supporting Info.).
2.3. Study of cope-elimination
When 1 equiv. of BSTFA was added, the yield was 85%, which
was similar to the yields obtained with 2 or 3 equiv. (runs 8, 9, and
10). The addition of 10 equiv. of CaH2 did not increase the yield (run
12) and did not protect against the negative effect of 15 (run 13).
It has been reported that anhydrous conditions greatly facilitate
CE [4a-c]. because water hydrogen bonds to the N-oxide and in-
terferes with the reaction.
This effect could also be applicable to the 1-hydroxypiperidine
Scheme 1. PIP Protection of p-Nitrophenol.
Scheme 2. First Step in the Deprotection of the PIP Group, Oxidation to the N-Oxide.
3

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R. Noren
Tetrahedron 88 (2021) 132108
Table 1
Study of cope Eliminationa.
run
additive
equiv.
yield of 14 (%)
1
e
66
46
43
41
2b
3b
4
H2O
H2O
15
1
2
1
5
15
2
31
6
7
8
9
10
11
12c
13d
14
15
16
HMDS
BSTFA
BSTFA
BSTFA
BSTFA
BSA
3
0.5
1
2
3
3
10
10 þ 1
1 þ 1
1 þ 1
69
64
85
88
84
81
69
35
CaH2
CaH2 þ 15
BSA þ 15
HMDS þ 15
4A MS
63
42
Complex mixture
a
Reactions run in a 0.1 M PhMe solution at reflux temperature.
13 was first dissolved in dichloromethane (DCM), H2O was then added, and the solution was finally sonicated for 30 min. PhMe was added, DCM was evaporated, and the
b
solution was refluxed.
c
13 was dissolved in DCM/PhMe, CaH2 was added, and the solution was stirred overnight; then, DCM was evaporated, and the solution was refluxed.
13 was dissolved in DCM/PhMe, CaH2þ15 was added, and the solution was sonicated for 60 min. DCM was evaporated and the solution was refluxed.
d
The addition of 3 equiv. of BSA is advantageous because it leads
to approximately the same yield as the addition of BSTFA but is
more economical. The addition of 3 equiv. of HMDS did not
significantly increase the yield (run 6) and did not protect from the
negative effect of 15 (run 15), probably because HMDS is a less
efficient silylating agent for this system.
reaction was performed in the presence of ground 4A MS, the so-
lution became brown and resulted in a complex mixture containing
only trace 14 (run 16).
2.4. Protection and de-protection of some phenols
In runs 4, material with a Rf value on thin-layer chromatography
(TLC) above that of 13 but much more polar than 14 was isolated in
22% yield through silica gel chromatography and was found to be
amine 12. This material was formed in all runs except for 8, 9, 10
and 11. 15 apparently reduced the N-oxide and thereby reduced the
yield of CE, which could be hindered by silylation of 15. Currently,
there is no experimental proof that 15 hydrogen bonds to the N-
oxide and thus reduces the yield. No silylated 15 was detected or
isolated and the reason for this is likely that TMS ethers are not
stable under the workup or purifying conditions used. When the
A set of phenols were protected and deprotected, and the results
of these experiments are summarized in Table 2.
The protection step gave yields above 90% in all cases and no
chromatography was necessary. Oxidation to N-oxide was also very
efficient. The Cope elimination step gave, as in Table 1, better yield
in all the examples when the reaction was run in presence of 3
equiv. BSA then with no BSA. The N-oxide 4b was not isolated
because it slowly degraded upon storage. The final step, hydrolysis
of the vinyl ether, also gave yields above 90% in all cases.
4

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R. Noren
Tetrahedron 88 (2021) 132108
Table 2
Protection and deprotection of some Phenols.
entry
Ar
yield (%)
(%)
(%)
(%)
1
2
3
4
3-NO2Ph
2-MeOPh
2-Naphtyl
4-CHOPh
1a
2a
3a
4a
96
1b
2b
3b
4b
95
88
95
NIe
1c
2c
3c
4c
64a
52a
63a
48a
78b
80b
77b
69b
1dd
2dc
3dc
4dc
95
91
95
96
95, 91f
96
95
Conditions: (a) No BSA. (b) 3 equiv. of BSA. (c) 90% HOAc (aq). (d) HOAc/H2O/TFA 90:10:1. (e) Not stable, not isolated. (f) Cs2CO3, sonication, ambient temperature.
2.5. Investigation of the orthogonality of the PIP group
First, deprotection of the PIP group was investigated, and the
results of these experiments are summarized in Table 3.
Conditions: (a) 1.2 equiv. of 39% peracetic acid in acetic acid/
DCM. (b) PhMe, 3 equiv. of BSA, reflux. (c) DMF, 3 equiv. of BSA,
120 ꢁC. (d) 90% HOAc reflux. (e) O3/MeOH (f) HOAc/H2O/TFA
90:10:1 reflux. (g) O3/DCM then 90% HOAc (aq) þ MeOH. (h) Not
stable, use immediately. (i) 3,6-(2-pyridyl)-1,2,4,5-tetrazine/DMF/
H2O, vide infra.
The oxidation to amine oxide was generally very fast (2e4 min),
and the product was formed in high yield. Allyl-protected com-
pound 11a did not epoxidize to any significant extent, and the
tetrahydropyran (THP) group in 12a was stable to peracetic acid
To test the orthogonality of the PIP group, compounds 5a-12a
were synthesized. 5d was alkylated in the usual way to give com-
pound 5a, and the methyl ether was hydrolyzed by boiling conc.
HBr (aq) to afford compound 17. Interestingly, only demethylation
was observed, and the PIP group was stable to these conditions
(vide infra). Then, 17 was protected with some common protecting
groups to give compounds 6a-9a and 11a-12a (Scheme 3).
Compound 10a was synthesized via reduction of p-nitro com-
pound 12 with iron in 90% HOAc (aq), followed by protection of the
amino group with Boc2O (Scheme 4).
Scheme 3. Protection of Resorcinol with the PIP group and some common protecting groups.
5

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
Scheme 4. Synthesis of O-PIP, N-Boc Protected p-Aminophenol.
Table 3
Deprotection of the PIP group in presence of some common classes of protecting Groups.
entry
STM
X
Y
yield (%)
(%)
(%)
overall yield (%)
1
2
3
4
5
6
7
8
5a
6a
7a
8a
OMe
OAc
OBn
OPMB
OtBDPS
H
O-Allyl
OTHP
H
H
H
H
5ba
95
5cb
6cb
7cb
8cb
9cb
10cc
11c
12c
69
51
82
79
71
66
74
68
5dd
6de
7df
90
94
98
69
59
46
76
53
57
51, 32
58
——
6ba, h
7ba
95
96
84
88
95
95
8ba
8dg
9dg
10d
11dd
12di
9a
H
9ba
95
10a
11a
12a
NHBoc
H
H
10ba
11ba
12ba
88g, 55i
87
60
39
during the reaction. CE was performed in toluene for all samples
except for compound 10b, which was heated in dimethylforma-
mide (DMF) due to solubility issues. The vinyl ethers had different
stabilities; 90% HOAc (aq) was not sufficient for hydrolysis in some
cases, so HOAC/H2O/TFA (90:10:1) was used instead. Compounds
8c-10c were ozonolyzed in DCM, and the presumed ozonides were
treated with 90% HOAc (aq)þ MeOH. The ozonides decomposed to
phenols without reduction, which may have been a result of hy-
drolysis of the presumed acid-sensitive “ortho-ester like” ozonides.
Ozonolysis of compound 6c in MeOH gave the phenol in the
absence of acid. Compounds 10c and 12c were cleaved to phenols
via inverse electron-demand Diels-Alder (IEDDA) retro-Diels-Alder
elimination reaction (vide infra).
Deprotection of the other protecting groups was achieved under
standard conditions, and the results of these experiments are
summarized in Table 4.
Deprotection generally resulted in nice yields, which reflects the
high stability of the PIP group under various conditions. 17 Is very
6

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
Table 4
Deprotection of some common classes of protecting groups in the presence of the PIP Group.
entry
STM
product
yield (%)
1a
2b
3c
4f
5a
6a
7a
8a
X ¼ OMe, Y ¼ H
X ¼ OAc, Y ¼ H
X ¼ OBn, Y ¼ H
X ¼ OPMB, Y ¼ H
X ¼ OtBDPS, Y ¼ H
X ¼ H, Y ¼ NHBoc
X ¼ O-Allyl, Y ¼ H
X ¼ OTHP
17
17
17
17
17
18
17
17
X ¼ OH, Y ¼ H
X ¼ OH, Y ¼ H
X ¼ OH, Y ¼ H
X ¼ OH, Y ¼ H
X ¼ OH, Y ¼ H
X ¼ H, Y ¼ NH2
X ¼ OH, Y ¼ H
X ¼ OH, Y ¼ H
83
95
91
69
98
93
84
96
5d
6e
7g
8h
9a
10a
11a
12a
Conditions: a48% HBr (aq) reflux. bNH3/MeOH. cH2-PdC/MeOH, atmospheric pressure. dTBAF/THF r.t. e60% TFA/DCM r.t. fAcOH reflux. gConc. HCl (aq) 75 ꢁC. h90% HOAc (aq) refl.
€
polar and in some cases some yield was probably lost in the chro-
2.7. Stability to Bronsted Acids
matography purification step.
A methyl ether can be selectively hydrolyzed by refluxing in
hydrobromic acid in the presence of the PIP group, as demonstrated
in Scheme 3.
2.6. Stability of a PIP protected phenol to basic conditions
To determine whether this result is because the PIP group is
more sterically hindered than the methyl group, compound 23 was
synthesized and exposed to the same hydrolysis conditions
(Scheme 6).
The hydrolysis of compound 23 is very selective, and no sig-
nificant amount of resorcinol or 3-methoxyphenol was detected by
The PIP group is clearly very stable to basic conditions. Com-
pound 5a was ortho-lithiated with n-BuLi in THF, and the lithiated
derivative was quenched with DMF to afford aldehyde 19 in 80%
yield. This compound was deprotected via CE to phenol 22 (Scheme
5).
Scheme 5. Ortho-Lithiation of a PIP Protected Phenol.
7

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R. Noren
Tetrahedron 88 (2021) 132108
Scheme 6. Comparison of Acid-Stability of the PIP Group and 2-Cyclohexylethyl.
Table 5
The explanation for this selectivity is that the positive charge
first formed on the piperidine nitrogen repels formation of a charge
on the PIP-ether oxygen. This same effect was also observed in
diaminoalkanes and hydrazine and can be visualized as the differ-
ence between pKa1 and pKa2, as shown in Table 5 [7aed].The effect
was small when n > 2, but for ethylendiamine (n ¼ 2), in which the
distance between the nitrogen and oxygen is similar to that in the
PIP protected phenols, the effect is considerable. For hydrazine
(n ¼ 0), the effect is very large.
Comparison of pKa1 and pKa2 of Diaminoalkanes and Hydrazine.
n
pKa1
pKa2
Ka2/Ka1
0
2
3
4
5
6
8.0
ꢂ1.0
7.564
9.03
9.71
9.13
1,000,000,000
10.172
10.94
11.15
10.25
11.857
406
81
28
13
12
10.762
TLC. This experiment indicates that the selective hydrolysis of
methyl ether is not a consequence of steric hindrance.
€
Scheme 7. Hydrolysis of the PIP Group with Bronsted Acids.
8

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R. Noren
Tetrahedron 88 (2021) 132108
Scheme 8. Deprotection of the PIP Group by Lewis Acid.
Table 6
finding, one must assume that the displacement of dimethyl sulfide
by nitrogen and the formation of the cyclic transition state are
kinetically favored and faster than attack by the methyl ether ox-
ygen on the Lewis acid. This offers an important alternative PIP-
deprotection route, as the reaction is so selective that even the
highly acid-sensitive THP group in 12a is spared. As outlined in
Scheme 9, when compound 25 was treated with BBr3ꢀMe2S,
compound 26 was isolated in 70% yield (calculated from the 24%
recovery of 25), suggesting that Mechanism B is predominant, at
least in this case, since otherwise, bromo-compound 27 and alcohol
26 would form in a 1:1 M ratio (the experimentally observed molar
ratio was 1:170). This experiment also showed that the PIP group
can be used to protect alcohols. The BBr3ꢀMe2S reagent is relatively
mild, and hydrolyzing aryl methyl ethers by refluxing for 12e24 h
in dichloroethane (DCE) with a 4-fold molar excess of the reagent is
generally required, as demonstrated by Williard et al. [9] This re-
agent is surprisingly stable and must be thoroughly hydrolyzed in
the workup, or it will contaminate the product even after 2 rounds
of chromatography.
Deprotection of the PIP group by lewis acid.
entry
STM
product
yield (%)
1
2
3
4
5aa
X ¼ OMe, Y ¼ H
X ¼ OAc, Y ¼ H
X ¼ OBn, Y ¼ H
X ¼ OTHP, Y ¼ H
5d
6d
7d
12d
75
50c
70
51
6ab
7ab
12ab
Conditions: a1.16 equiv. Lewis acid/DCM, ambient temperature. b1.0 equiv. Lewis
acid/DCM, ambient temperature. cBased on 26% recovered 6a.
When compound 5a was refluxed for 2 min in conc. hydroiodic
acid, the methyl ether was hydrolyzed. PIP ether required 3 h of
reflux to be hydrolyzed, and resorcinol was isolated in 71% yield,
indicating that PIP is a very stable protecting group (Scheme 7).
2.8. Stability to Lewis Acids
When compounds 5a, 6a, 7a, and 12a were treated with
BBr3ꢀMe2S at ambient temperature in DCM, the ether groups on PIP
were selectively hydrolyzed. The proposed mechanism for this re-
action with 5a as an example is outlined in Scheme 8, and the yields
are presented in Table 6. Structures for compounds 6a, 7a and 12a
are presented in Table 3.
Piperidine nitrogen substitutes for dimethyl sulfide; thereafter,
the nitrogen is displaced by the ether oxygen of the PIP to form a
cyclic transition state. The ether bond in the PIP is then attacked by
the bromide ion (Mechanism A) or the nitrogen atom in the
piperidine ring (Mechanism B). The reaction is very selective, and
no significant amount of 17 was detected by TLC. To explain this
2.9. Deprotection of vinyl ethers by the inverse electron-demand
Diels-Alder/Retro Diels-Alder elimination reaction
Staderini et al. [10] showed that vinyl ethers can be de-caged via
an IEDDA/retro-Diels-Alder elimination reaction using 3,6-(2-
pyridyl)-1,2,4,5-tetrazine in DMF/H2O. When these conditions
were applied to compounds 10c and 12c, compounds 10d and 12d
were isolated in 55 and 60% yields, respectively (Scheme 10 and
Table 3). This reaction is an alternate way to hydrolyze vinyl ether
when the starting material is sensitive to acid or if ozone cannot be
used.
9

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
Scheme 9. Comparison of Mechanism A and B, Deprotection of a PIP Protected Alcohol with Lewis Acid.
Scheme 10. Deprotection of a Vinyl Ether by Inverse-Electron Demand Diels-Alder/Retro Diels Alder Elimination Reaction.
10

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
3. Conclusions
organic phase was diluted with hexane (20 ml), dried with Na2SO4
and filtered and evaporated under reduced pressure, and the res-
idue was dried in vacuo to give 1.72 g (96%) of the title compound as
an oil. The spectra were consistent with those of a commercial
sample.
In summary, the PIP group was evaluated as a protecting group
for phenols. The protection step was relatively mild and fast and
generally resulted in yields greater than 90% in the examples pre-
sented herein. Deprotection was accomplished with a very mild
three-step process via CE or with a one-step procedure with a mild
Lewis acid, and yields of approximately 50e70% were achieved
with both methods. The fact that the PIP group is both orthogonal
to sensitive protecting groups, such as N-Boc, O-THP and OeAc, and
stable to ortho-lithiation conditions as well as boiling concentrated
hydrobromic acid is a strength of this innovation. PIP is also
orthogonal to O-allyl groups, so alkenes do not epoxidize under the
conditions used in the CE-deprotection route, as the oxidation of
the PIP group to an N-oxide is much faster. If the substrate is very
sensitive to acid or ozone, hydrolysis of the vinyl ether can be
accomplished via an IEDDA/retro Diels-Alder elimination reaction.
Lewis acid deprotection involves treatment with BBr3ꢀMe2S, and an
OeMe, O-Bn, OeAc and O-THP group can be present on the aro-
matic nucleus; this is perhaps a more important deprotection route
than the CE route because it is a one-step procedure and gives
approximately the same yields. The finding that CE results in higher
yields of vinyl ether when run in the presence of silylating agents
because the reduction of the N-oxide can be suppressed by the
byproduct hydroxylamine can prove useful when CE is performed
on other types of substrates. The chemistry presented herein also
provides access to highly functionalized vinyl aryl ethers. The
mechanism analysis of the BBr3ꢀMe2S deprotection route also
involved one example in which an alcohol is protected with the PIP
group and subsequently deprotected.
3-Nitrophenol (1d). [12]. 1a (1.53 g, 6.11 mmol) was dissolved in
DCM (50 ml). The solution was stirred, and 39% peracetic acid (in
HOAc) (1.25 ml, 7.31 mmol) was added. The solution was stirred for
5 min. Then, 1 M K2CO3 (aq) (20 ml) was added, and the solution
was stirred for 2 min. The solution was filtered through phase-
separator (PS) paper, and the remaining aqueous phase was
extracted with DCM (5*10 ml) by siphoning the mixture back and
forth with a 5 ml single-use polyethylene Pasteur pipette in the
filter funnel as the organic phase passed through the PS-filter. The
organic phases were combined, and HMDS (6.00 ml) was added.
The solution was evaporated at reduced pressure to give 1b (1.54 g,
95%) as a semi-crystalline solid. The broad 1H NMR signal at
2.8 ppm was attributed to water, and the compound was highly
hygroscopic. 1H NMR (800 MHz, CDCl3)
d
7.84 (dd, J ¼ 8.3, 2.2 Hz,
1H), 7.76 (t, J ¼ 2.3 Hz, 1H), 7.45 (t, J ¼ 8.2 Hz, 1H), 7.26 (dd, J ¼ 8.3,
2.5 Hz, 1H), 4.82e4.65 (m, 2H), 3.68e3.54 (m, 2H), 3.40e3.30 (m,
2H), 3.26 (td, J ¼ 11.8, 11.2, 3.3 Hz, 2H), 2.41e2.24 (m, 2H), 1.81e1.73
(m, 1H), 1.69 (dt, J ¼ 14.5, 4.5 Hz, 2H), 1.46 (dd, J ¼ 10.0, 3.5 Hz, 1H);
13C NMR (201 MHz, CDCl3)
d 21.1, 22.0, 62.4, 66.9, 68.4109.7, 116.3,
130.2, 149.1, 158.3; HRMS ESI þ m/z [MþH]þ Calcd for C13H18N2O4,
267.1339; found, 267.1339. 1b (0.27 g, 1.01 mmol) was suspended in
toluene. BSA (0.73 ml, 3.00 mmol) was added, and the solution was
stirred and heated in an oil bath to reflux for 25 min. The solution
was evaporated under reduced pressure and purified by column
chromatography by elution with EtOAc/hexane (1:7) to give 0.13 g
(78%) of 1c [8] as an oil, and the spectra were consistent with
published data. 1c (0.13 g, 0.79 mmol) was dissolved in HOAc/H2O/
TFA (90:10:1, 3 ml). The solution was refluxed for 45 min. The so-
lution was evaporated at reduced pressure, and the crystalline
residue was dried in vacuo. Yield, 0.104 g (95%); mp, 95e97 ꢁC; Lit.,
97 ꢁC. The spectra were consistent with those of a commercial
sample.
4. Experimental section
4.1. General experimental section
Tetrahydrofuran (THF), dimethyl formamide (DMF) and toluene
were stored over 4 Å molecular sieves prior to use. Potassium
carbonate was oven dried at 300 ꢁC for 3 h and ground to a fine
powder in a porcelain mortar and pestle prior to use. All other
solvents and reagents were used as received. NMR spectra were
obtained at the indicated fields as solutions in CDCl3 or MEOD
unless otherwise indicated. TLC was performed on 0.2 mm Alugram
Sil G/UV254 60 Å silica gel plates using 254 nm UV light for moni-
toring and plates dipped in a 0.5% aqueous potassium permanga-
nate solution when the UV absorbance was low. This method
facilitated distinguishing alkenes from ozonides. Ozone was
generated with a Sander Certizon 50 ozone generator. Flash chro-
3-Nitrophenol (1d). The reaction was as above, but BSA was
omitted in the 1b-1c step, and the yield in this step decreased to
64%. The yields of the other steps were the same as above. The
spectra were consistent with those described above.
4.1.2. PIP protection of phenols, general reaction and isolation
procedure for electron-rich substrates, method B
1-(2-(2-Methoxyphenoxy)ethyl)piperidine
(2a).
[11].
2-
matography was performed on 40e63
reported eluents. Melting points were uncorrected.
m
m 60 Å silica gels with the
Methoxyphenol (2.00 g, 16.11 mmol) was dissolved in DMF
(100 ml) in a 250 ml Erlenmeyer flask. The solution was heated on a
magnetic stirrer to 80 ꢁC under heavy stirring, and K2CO3 (8.91 g,
64.47 mmol) was added. The mixture was stirred at 80 ꢁC for
10 min, and 16 (5.93 g, 32.21 mmol) was added. The mixture was
stirred at 100 ꢁC for 10 min K2CO3 (4.60 g, 33.28 mmol) was added,
and the solution was stirred at 100 ꢁC for 20 min. The solution was
cooled to ambient temperature, and conc. NH4OH (aq) (35 ml) was
added to quench any remaining excess of 16. The solution was
stirred for 60 min. The solution was diluted with water (150 ml) and
extracted with Et2O (4*50 ml). The organic phase was subjected to
acid-base partitioning with 5% HCl (aq) (100 ml) and 5% NH4OH
(aq) (150 ml), followed by extraction with Et2O (4* 50 ml) (for
sensitive compounds, 0.5 M citric acid (aq) and 0.5 M NaHCO3 (aq)
can be used). The solution was diluted with hexane (20 ml), dried
with Na2SO4, filtered and evaporated. The residual gum was dried
in vacuo to give 3.61 g (95%) of the title compound. The spectra are
consistent with those of a commercial sample.
4.1.1. PIP-protection of phenols, general reaction and isolation
procedure for electron-poor substrates, method A
1-(2-(3-Nitrophenoxy)ethyl)piperidine (1a). [11]. 3-Nitrophenol
(1.00 g, 7.19 mmol) was dissolved under stirring in DMF (50 ml)
in a 250 ml Erlenmeyer flask. K2CO3 (4.00 g, 28.94 mmol) was
added, and the mixture was heated on a magnetic stirrer to 80 ꢁC
under heavy stirring for 5 min. 16 (1.59 g, 8.64 mmol) was added,
and the solution was stirred at 80 ꢁC for 15 min. The solution was
cooled to ambient temperature, and conc. NH4OH (aq) (15 ml) was
added to quench any remaining 16, and the solution was stirred for
60 min. The solution was diluted with H2O (50 ml) and extracted
with Et2O (4*30 ml). The organic phase was subjected to acid-base
partitioning with 5% HCl (aq) (100 ml) and 5% NH4OH (aq) (150 ml),
followed by extraction with Et2O (4*50 ml) (for sensitive com-
pounds, 0.5 M citric acid and 0.5 M NaHCO3 can be used). The
11

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
4.1.3. PIP protection with cesium carbonate/sonication. General
reaction and isolation procedure
129.5, 134.3, 155.6; HRMS ESI þ m/z [MþH]þ Calcd for C17H21NO2,
272.1645; Found, 272.1651. 3b (2.70 g, 9.95 mmol) was suspended
in toluene (50 ml) under stirring, BSA (7.33 ml, 28.00 mmol) was
added, and the solution was heated to reflux in an oil bath for
30 min. The solution was evaporated under reduced pressure, and
the residual oil was purified by column chromatography by elution
with EtOAc/hexane (1:25) to give 1.30 g (77%) of 3c [14] as an oil.
The spectra were consistent with published data.
3c (0.52 g, 3.06 mmol) was dissolved in 90% HOAc (aq) (15 ml).
The solution was heated to reflux under stirring in an oil bath for
30 min. The solution was evaporated under reduced pressure to
give 0.42 g (95%) of the title compound as a tan crystalline solid
(mp, 121e123 ꢁC; Lit., 123 ꢁC). The spectra were consistent with
those of a commercial sample.
1-(2-(2-Methoxyphenoxy)ethyl)piperidine
(2a).
2-
Methoxyphenol (0.093 g, 0.75 mmol) was dissolved in DMF
(2 ml) under N2 atmosphere and stirring. Cesium carbonate (0.78 g,
2.4 mmol) and 16 (0.18 g, 0.98 mmol) was added. The solution was
sonicated for 90 min at ambient temperature. The solution was
diluted with H2O (20 ml) and was extracted with Et2O (3*20 ml).
The combined organic phase was washed with H2O (2*20 ml) and
was dried with Na2SO4, filtered and evaporated to give 0.16 g (91%)
of the title compound. Spectra as above.
2-Methoxyphenol (2d). [12]. 2a (3.65 g, 15.51 mmol) was dis-
solved in DCM (40 ml) under stirring. Then, 39%, peracetic acid (in
HOAc) (3.10 ml, 18.12 mmol) was added, and the solution was
stirred for 10 min. Next, 1 M K2CO3 (48 ml) was added, and the
solution was stirred for 2 min. The solution was filtered through PS
paper, and the aqueous phase was extracted in the filter funnel with
DCM (6*20 ml) by siphoning the mixture back and forth with a 5 ml
single-use polyethylene Pasteur pipette as the organic phase
passed through the PS-filter. HMDS (17.00 ml) was added to the
organic phase, and the solution was evaporated at reduced pressure
to give 3.42 g (88%) of 2b as a semicrystalline solid; 1H NMR
2-Naphthol (3d). The reaction was performed as above, but BSA
was omitted in the 3b-3c step, and the yield in this step decreased
to 63%. Yield in the other steps were identical to those above. The
spectra were the same as described above.
4-(2-(Piperidin-1-yl)ethoxy)benzaldehyde (4a). [15]. The title
compound was prepared by Method A and was isolated as a gum
(3.57 g (93%) from 2.00 g (16.40 mmol) of 4-hydroxybenzaldehyde).
The spectra were consistent with those of a commercial sample.
4-Hydroxybenzaldehyde (4d). [12]. 4a (0.50 g 2.14 mmol) was
dissolved in DCM (20 ml). The solution was stirred, and 39% per-
acetic acid (in HOAc) (0.43 ml 2.51 mmol) was added. The solution
was stirred for 3 min. Conc. NH4OH (aq) (4 ml) (in this case, it
appeared to work better than 1 M K2CO3) was added, and the so-
lution was stirred for 1 min. The phases were separated, and the
aqueous phase was extracted with DCM (5*20 ml) in a separatory
funnel. The organic phase was dried with MgSO4 and filtered.
HMDS (2 ml) was added, and the solution was evaporated at
reduced pressure to give 4b as a gum. This material was not stable
over an extended time, did not give rise to good NMR spectra due to
degradation and was used immediately in the next step. HRMS
ESI þ m/z [MþH]þ Calcd for C14H19NO3, 250.1438; Found, 250.1434.
The gum was dissolved in DCM (3 ml). The solution was diluted
with toluene (30 ml), and BSA (2.1 ml, 8.60 mmol) was added. The
solution was heated until the DCM evaporated, and the solution
was refluxed for 20 min. The solution was evaporated at reduced
pressure, and the residual gum was purified by column chroma-
tography by elution with EtOAc/hexane (1:7) to give 0.22 g (69%, 2
steps) of 4c [13] as an oil. The spectra are consistent with published
data. 4c (0.19 g, 1.28 mmol) was dissolved in 90% HOAc (aq) (3 ml).
The solution was stirred and heated to reflux in an oil bath for 4 h
and was left at ambient temperature overnight. The solution was
evaporated at reduced pressure, the residue was dissolved in Et2O
(2 ml), and the solution was filtered through a plug of cotton and
evaporated to give 0.15 g (96%) of the title compound as a crystal-
line solid (mp, 112e115 ꢁC; Lit., 112e116 ꢁC). The spectra were
consistent with those of a commercial sample.
(800 MHz, CDCl3)
d 7.08e6.79 (m, 4H), 4.73e4.52 (m, 2H), 3.83 (s,
3H), 3.67e3.63 (m, 2H), 3.43e3.20 (m, 4H), 2.43e2.14 (m, 2H), 1.70
(td, J ¼ 9.4, 8.8, 4.2 Hz, 3H), 1.45 (s, 1H). 13C NMR (201 MHz, CDCl3)
d
21.2, 22.0, 55.7, 62.8, 66.5, 68.5, 111.8, 114.1, 120.9, 121.9147.3,
149.4. HRMS ESI þ m/z [MþH]þ Calcd for C14H21NO3, 252.1594;
Found, 252.1595. 2b (0.25 g, 1.00 mmol) was suspended in toluene
(9 ml). BSA (0.73 ml, 3.00 mmol) was added, and the solution was
heated to reflux in an oil bath under stirring. The solution was
heated to reflux for 30 min. The solution was evaporated under
reduced pressure, and the residual oil was purified by column
chromatography and eluted with EtOAc/hexane (1:20) to give 0.12 g
(80%) of 2c [13] as an oil. The spectra were consistent with pub-
lished data. 2c (0.12 g, 0.80 mmol) was dissolved in 90% HOAc (aq)
(4 ml). The solution was heated to reflux under stirring in an oil
bath for 10 min. The solution was evaporated under reduced
pressure to give 0.09 g (91%) of the title compound as an oil. The
spectra are consistent with those of a commercial sample.
2-Methoxyphenol (2d). The reaction was performed as above, but
BSA was omitted in the 2b-2c step. The yield was identical to those
above except for the 2b-2c step, where it decreased to 52%.
1-(2-(Naphthalen-2-yloxy)ethyl)piperidine (3a). [11]. The title
compound was prepared by Method B and was isolated as a crys-
talline solid (3.40 g (96%) from 2.00 g (13.90 mmol) of 2-naphthol).
Mp, 48e49 ꢁC. Lit., 48e49 ꢁC; the spectra were consistent with
those of a commercial sample.
2-Naphthol (3d). [12]. 3a (3.43 g, 13.4 mmol) was dissolved in
DCM (50 ml) under stirring. Then, 39% peracetic acid (in HOAc)
(2.50 ml, 14.62 mmol) was added, and the solution was stirred for
10 min. Next, 1 M K2CO3 (aq) (50 ml) was added, and the solution
was stirred for 2 min. The solution was filtered through PS paper,
and the aqueous phase was extracted in the filter funnel with DCM
(6*25 ml) by siphoning the mixture back and forth with a 5 ml
single-use polyethylene Pasteur pipette as the organic phase
passed through the PS-filter. HMDS (15 ml) was added to the
combined organic phases, and the solution was evaporated at
reduced pressure to give 3.45 g (95%) of 3b as a crystalline hygro-
4-Hydroxybenzaldehyde (4d). The reaction was performed as
above, but BSA was omitted in the 4b-4c step, and the yield for 4a-
4c decreased to 48%. The yield in the last step was the same as that
reported above. The spectra were the same as described above.
1-(2-(3-Methoxyphenoxy)ethyl)piperidine (5a). The title com-
pound was prepared according to Method B (7.21 g (30.64 mmol)
(95%) from 3-methoxyphenol (4.00 g, 32.23 mmol)). 1H NMR
(800 MHz, CDCl3)
d
7.16 (t, J ¼ 8.2 Hz,1H), 6.57e6.36 (m, 3H), 4.08 (t,
scopic solid (mp 58e59 ꢁC). 1H NMR (800 MHz, CDCl3)
d
7.79e7.69
J ¼ 6.1 Hz, 2H), 3.78 (s, 3H), 2.76 (t, J ¼ 6.1 Hz, 2H), 2.50 (s, 4H), 1.60
(m, 3H), 7.44 (t, J ¼ 7.5 Hz, 1H), 7.34 (t, J ¼ 7.4 Hz, 1H), 7.21 (d,
J ¼ 2.7 Hz, 1H), 7.09 (dd, J ¼ 8.9, 2.6 Hz, 1H), 4.84e4.64 (m, 2H),
3.79e3.55 (m, 2H), 3.34 (dt, J ¼ 10.1, 4.6 Hz, 2H), 3.26 (td, J ¼ 11.9,
11.1, 3.2 Hz, 2H), 2.30 (qd, J ¼ 10.2, 8.3, 4.6 Hz, 2H), 1.85e1.55 (m,
(p, J ¼ 5.6 Hz, 4H), 1.44 (t, J ¼ 6.0 Hz, 2H). 13C NMR (201 MHz, CDCl3)
d
24.2, 25.9, 55.0, 55.2, 57.9, 101.0, 106.3, 106.7, 129.8, 160.1, 160.8;
HRMS ESI þ m/z [MþH]þ Calcd for C14H21NO2, 236.1645; Found,
236.1651.
3H), 1.43 (dd, J ¼ 9.9, 3.5 Hz, 1H). 13C NMR (201 MHz, CDCl3)
d
21.2,
3-Methoxyphenol (5d). [12]. 5a (1.00 g, 4.25 mmol) was dis-
solved in DCM (20 ml). Next, 39% peracetic acid (in HOAc) (0.87 ml,
22.0, 61.5, 66.6, 66.7, 107.1, 118.3, 123.9, 126.5, 126.8, 127.5, 129.1,
12

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
5.09 mmol) was added under stirring. The solution was stirred for
5 min. Then, 1 M K2CO3 (20 ml) was added, and the solution was
stirred for 4 min. The solution was filtered through PS paper, and
the aqueous phase was extracted in the filter funnel with DCM (5 *
10 ml) by siphoning the mixture back and forth with a 5 ml single-
use polyethylene Pasteur pipette as the organic phase passed
through the PS-filter. HMDS (5 ml) was added, and the solution was
evaporated under reduced pressure to give 1.01 g (95%) 5b as a
was evaporated under reduced pressure, and the residue was dried
in vacuo to give 6b, which was used immediately because it was not
stable for storage and did not give rise to good NMR spectra because
of degradation. HRMS ESI þ m/z [MþH]þ Calcd for C15H21NO4,
280.1543; Found, 280.1552. The gum was dissolved in DCM (3 ml),
and the solution was diluted with toluene (7 ml). BSA (0.84 ml,
3.43 mmol) was added, and the solution was heated until the DCM
evaporated. The solution was refluxed for 25 min under stirring.
The solution was evaporated under reduced pressure, and the re-
sidual oil was purified by column chromatography and eluted with
EtOAc/hexane (1:7) to give 0.076 g (51%, 2 steps) of 6c as an oil. 1H
gum; 1H NMR (800 MHz, MeO-d4)
d
7.18 (t, J ¼ 8.2 Hz, 1H), 6.55 (dd,
J ¼ 8.2, 2.4 Hz, 2H), 6.52 (t, J ¼ 2.4 Hz, 1H), 4.63e4.42 (m, 2H), 3.77
(s, 3H), 3.72e3.66 (m, 2H), 3.43 (td, J ¼ 11.7, 3.1 Hz, 2H), 3.37e3.32
(m, 2H), 2.16 (qd, J ¼ 11.0, 5.6 Hz, 2H), 1.72 (ddt, J ¼ 13.6, 9.5, 4.4 Hz,
NMR (800 MHz, CDCl3)
d
7.30 (t, J ¼ 8.2 Hz, 1H), 6.87 (ddd, J ¼ 8.2,
3H), 1.57e1.43 (m, 1H); 13C NMR (201 MHz, CDCl3)
d
22.0, 22.6, 55.7,
2.4, 0.9 Hz, 1H), 6.81 (ddd, J ¼ 8.1, 2.2, 0.9 Hz, 1H), 6.76 (t, J ¼ 2.3 Hz,
1H), 6.61 (dd, J ¼ 13.7, 6.0 Hz, 1H), 4.80 (dd, J ¼ 13.7, 1.8 Hz, 1H), 4.47
(dd, J ¼ 6.1, 1.8 Hz, 1H), 2.29 (s, 3H); 13C NMR (201 MHz, CDCl3)
62.6, 67.0, 69.5, 102.1, 107.8, 108.0, 131.1, 160.5, 162.5, 176.8; HRMS
ESI þ m/z [MþH]þ Calcd for C14H21NO3 252.1594; Found, 252.1592.
5b (0.19 g, 0.76 mmol) was suspended in toluene (7.5 ml) under
stirring. BSA (0.55 ml, 2.25 mmol) was added, and the solution was
heated to reflux in an oil bath under stirring for 30 min. The solu-
tion was evaporated under reduced pressure, and the residual oil
was purified by column chromatography by elution with EtOAc/
hexane (1:4) to give 0.079 g (69%) of 5c [16] as an oil. The spectra
were consistent with published data. 5c (0.079 g, 0.53 mmol) was
dissolved in HOAc (90%) (aq) (2 ml). The solution was stirred and
heated to reflux in an oil bath for 30 min. The solution was evap-
orated at reduced pressure to give 0.059 g (90%) of the title com-
pound as an oil. Trace HOAc was removed by aspirator vacuum. The
spectra were consistent with those of a commercial sample.
3-Methoxyphenol (5d). [12]. 5a (1.03 g, 4.40 mmol) was dissolved
in DCM (30 ml) under stirring in a N2 atmosphere. BBr3ꢀMe2S
(1.60 g, 5.12 mmol) was added, and the solution was stirred for
15 min. The solution was diluted with conc. NH4OH (aq) (6 ml) and
MeOH (20 ml), stirred vigorously for 10 min and left overnight. On
day 2, the solution was extracted with DCM (3*40 ml), and the
organic phase was dried with Na2SO4, filtered and evaporated at
reduced pressure. The residual solid was dissolved in MeOH/H2O
(2:1, 50 ml), and this solution was refluxed for 60 min to hydrolyze
the traces of boron reagent. The solution was evaporated at reduced
pressure, and the residue was purified with chromatography by
elution with EtOAc/hexane (1:2) to give 0.39 g (71%) of the title
compound as an oil. The spectra were consistent with those of a
commercial sample.
d
96.1, 110.7, 114.3, 116.2, 130.0, 147.6, 151.5, 157.5, 169.2. 6c (0.11 g,
0.62 mmol) was dissolved in MeOH (7.5 ml). Ozone mixed with air
was bubbled through the solution under stirring for 60 min at
ambient temperature at a rate of 50 mg ozone/h. The solution was
left for 240 min. The solution was evaporated at reduced pressure
to give 0.089 g (94%) of the title compound as a crystalline solid
(mp, 54e55 ꢁC; Lit., 55e56 ꢁC). The spectra were consistent with
those of a commercial sample.
3-Hydroxyphenyl acetate (6d). [12]. 6a (0.40 g, 1.52 mol) was
dissolved in DCM (5 ml) under stirring in a N2 atmosphere in a
flame-dried Schlenk tube. BBr3ꢀMe2S (0.49 g, 1.57 mmol) was
added. The solution was stirred for 10 min. The solution was poured
into a mixture of NaHCO3 (1.2 g), H2O (5 ml) and MeOH (30 ml). The
mixture was stirred for 4 h, diluted with H2O (30 ml) and extracted
with DCM (4*20 ml). The combined organic phase was dried with
Na2SO4, filtered and evaporated at reduced pressure. The residual
oil was purified with column chromatography by elution with a
stepwise gradient EtOAc/hexane (1:3)-EtOAc/TEA (9:1) to give
0.086 g (50%) of the title compound as an oil (based on 0.104 g
recovered 6a); spectra as above.
1-(2-(3-Benzyloxy)phenoxy)ethyl)piperidine (7a). 17 (0.50 g,
2.26 mmol) was dissolved in DMF (25 ml) under stirring in a N2
atmosphere. NaH (60% in oil, 0.12 g, 3.00 mmol) was added, and the
solution was heated to 55 ꢁC for 5 min. Benzyl bromide (0.30 ml,
2.52 mmol) was added, and the solution was stirred at RT for
20 min. The solution was diluted with H2O (40 ml) and Et2O (40 ml),
and the phases were separated. The aqueous phase was extracted
with Et2O (3*20 ml), and the combined organic phase was dried
with Na2SO4, filtered and evaporated. The residue was purified by
column chromatography and eluted with EtOAc/hexane/TEA
(5:15:1) (the column was packed with EtOAc/hexane 1:3) to give
0.52 g (74%) of the title compound as a gum. 1H NMR (800 MHz,
3-(2-(Piperidin-1-yl)ethoxy)phenyl acetate (6a). 17 (0.50 g,
2.26 mmol) was suspended in Ac2O (4 ml). The mixture was heated
to reflux under stirring for 5 min. The solution was cooled, and
MeOH (15 ml) was added, and the solution was left overnight. The
solution was diluted with DCM (50 ml) and water (50 ml), stirred
and neutralized with NaHCO3. The phases were separated, and the
aqueous phase was extracted with DCM (3*30 ml). The combined
organic phase was dried with Na2SO4, filtered and evaporated. The
residue was purified by column chromatography by elution with
EtOAc/hexane/triethylamine (TEA) (5:15:1) (the column was
packed with EtOAc/hexane 1:3) to give 0.41 g (69%) of the title
CDCl3)
d
7.42 (d, J ¼ 7.6 Hz, 2H), 7.39e7.34 (m, 2H), 7.31 (t, J ¼ 7.3 Hz,
1H), 7.16 (td, J ¼ 8.2, 1.7 Hz, 1H), 6.60e6.54 (m, 2H), 6.52 (dd, J ¼ 8.1,
2.4 Hz, 1H), 5.03 (s, 2H), 4.07 (td, J ¼ 6.0, 1.5 Hz, 2H), 2.75 (dd, J ¼ 7.1,
5.5 Hz, 2H), 2.49 (s, 4H), 1.60 (p, J ¼ 5.2 Hz, 4H), 1.44 (q, J ¼ 6.8,
6.2 Hz, 2H); 13C NMR (201 MHz, CDCl3)
d 24.2, 25.9, 55.0, 57.9, 65.9,
compound as an oil. 1H NMR (800 MHz, MeO-d4)
d
7.05 (t,
70.0, 101.9106.3, 107.1, 127.5, 127.9, 128.5, 129.8, 136.9, 159.96,
160.04; HRMS ESI þ m/z [MþH]þ Calcd for C20H25NO2, 312.1958;
Found, 312.1955.
J ¼ 8.0 Hz, 1H), 6.53e6.22 (m, 3H), 4.08 (t, J ¼ 5.6 Hz, 2H), 2.78 (t,
J ¼ 5.7 Hz, 2H), 2.57 (s, 4H), 2.02 (s, 3H), 1.64 (p, J ¼ 5.7 Hz, 4H), 1.49
(t, J ¼ 6.0 Hz, 2H). 13C NMR (201 MHz, CDCl3)
d
20.5, 24.9, 26.4, 55.9,
3-(Benzyloxy)phenol (7d). [12]. 7a (0.39 g, 1.25 mmol) was dis-
solved in DCM (15 ml). Next, 39% peracetic acid (in HOAc) (0.34 ml,
1.99 mmol) was added, and the solution was stirred for 4 min. Then,
1 M K2CO3 (8 ml) was added, and the solution was stirred for 2 min.
The solution was filtered through PS paper, and the aqueous phase
was extracted in the filter funnel with DCM (5 *10 ml) by siphoning
the mixture back and forth with a 5 ml single-use polyethylene
Pasteur pipette as the organic phase passed through the PS-filter.
HMDS (2 ml) was added to the organic phase, which was evapo-
rated at reduced pressure to give 0.39 g (95%) of 7b as a gum. 1H
58.9, 66.1, 103.0, 106.7, 109.1, 130.8, 130.9, 159.7, 161.3, 161.4, 173.4;
HRMS ESI þ m/z [MþH]þ Calcd for C15H21NO3, 264.1594; Found,
264.1593.
3-Hydroxyphenyl acetate (6d). [12]. 6a (0.22 g, 0.84 mmol) was
dissolved in DCM (4 ml) under stirring. Then, 39% peracetic acid (in
HOAc) (0.17 ml, 0.99 mmol) was added, and the solution was stirred
for 4 min. The solution was evaporated under reduced pressure and
co-evaporated with toluene/MeOH (1:1, 15 ml). The residue was
dissolved in DCM (3 ml), and HMDS (1 ml) was added. The solution
13

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
NMR (800 MHz, MeO-d4)
d
7.36e7.33 (m, 2H), 7.29 (t, J ¼ 7.6 Hz,
(m, 2H), 3.38 (td, J ¼ 11.7, 2.8 Hz, 2H), 3.30e3.27 (m, 2H), 2.14 (tt,
J ¼ 10.6, 5.3 Hz, 2H), 1.69 (dt, J ¼ 7.6, 4.7 Hz, 3H), 1.55e1.41 (m, 1H);
2H), 7.23 (t, J ¼ 7.5 Hz, 1H), 7.11 (td, J ¼ 8.2, 2.1 Hz, 1H), 6.56 (dd,
J ¼ 8.2, 2.4 Hz, 1H), 6.53 (t, J ¼ 2.4 Hz, 1H), 6.52e6.42 (m, 1H), 4.99
(s, 2H), 4.44 (q, J ¼ 4.1 Hz, 2H), 3.63e3.55 (m, 2H), 3.32 (td, J ¼ 11.5,
10.8, 2.8 Hz, 2H), 2.08 (tt, J ¼ 10.6, 5.1 Hz, 2H), 1.70e1.58 (m, 3H),
13C NMR (201 MHz, MeO-d4)
d 22.0, 22.6, 55.7, 62.6, 67.0, 69.5, 70.8,
103.1,108.0,109.1,114.9,130.3,130.5,131.1,160.5,160.9,161.6; HRMS
ESI þ m/z [MþH]þ Calcd for C21H27NO4, 358.2013; Found, 358.2009.
8b (0.16 g, 0.45 mmol) was suspended in toluene (5 ml). BSA
(0.33 ml, 1.40 mmol) was added, and the solution was refluxed for
45 min. The solution was evaporated at reduced pressure, and the
residue was purified by column chromatography by elution with
EtOAc/hexane (1:7) to give 0.091 g (79%) of 8c as a crystalline solid
1.51e1.37 (m, 1H); . 13C NMR (201 MHz, MeO-d4)
d 22.0, 22.6, 62.6,
67.0, 69.5, 71.0, 103.1, 108.1, 109.0, 128.5, 128.9, 129.5131.2, 138.6,
160.5, 161.5; HRMS ESI þ m/z [MþH]þ Calcd for C20H25NO3,
328.1907; Found, 328.1902. 7b (0.39 g, 1.19 mmol) was suspended
in toluene (7.5 ml). BSA (0.88 ml, 3.6 mmol) was added, and the
solution was heated to reflux under stirring for 35 min. The solution
was evaporated, and the resulting gum was purified by column
chromatography by elution with EtOAc/hexane (1:20) to give 0.22 g
(82%) of 7c [17] as an oil. The spectra were consistent with those of a
commercial sample. 7c (0.079 g, 0.35 mmol) was dissolved in
HOAc/H2O/TFA (90:10:1), and the solution was heated to reflux
under stirring for 4 min. The solution was evaporated under
reduced pressure to give 0.069 g (98%) of the title compound as an
oil. The spectra were consistent with those of a commercial sample.
3-(Benzyloxy)phenol (7d). [12]. 7a (1.02 g, 3.30 mmol) was dis-
solved in DCM under stirring in a N2 atmosphere in a flame-dried
round-bottom flask. BBr3ꢀMe2S (1.03 g, 3.30 mmol) was added.
The solution was stirred for 25 min. The solution was diluted with
conc. NH4OH (aq) (6 ml) and stirred for 3 min. The mixture was
poured into a mixture of MeOH (40 ml), H2O (30 ml) and NaHCO3
(4.2 g). The mixture was boiled for 20 min, and some of the MeOH
boiled off. The mixture was cooled to ambient temperature and
extracted with DCM (3*25 ml). The combined organic phase was
dried with Na2SO4, filtered and evaporated at reduced pressure. The
residual oil was purified by column chromatography by elution
with EtOAc/hexane (1:4) to give 0.46 g (70%) of the title compound
as an oil. The spectra were the same as described above.
(mp 56e58 ꢁC); 1H NMR (800 MHz, CDCl3)
d 7.37e7.30 (m, 2H), 7.20
(t, J ¼ 8.2 Hz, 1H), 6.94e6.87 (m, 2H), 6.69 (dd, J ¼ 8.4, 2.4 Hz, 1H),
6.64e6.56 (m, 3H), 4.96 (s, 2H), 4.77 (dd, J ¼ 13.7, 1.7 Hz, 1H), 4.42
(dd, J ¼ 6.1, 1.7 Hz, 1H), 3.80 (s, 3H); 13C NMR (201 MHz, CDCl3)
d
55.3, 69.9, 95.3, 104.1, 109.3, 109.6, 114.0, 128.7, 129.2, 130.0, 147.9,
157.9, 159.5, 160.0. 8c (0.043 g, 0.17 mmol) was dissolved in DCM
(7 ml), and ozone in air was bubbled through the solution at a rate
of 50 mg ozone/h for 20 min. The reaction was closely monitored by
TLC (8c has a Rf value of 0.45 (EtOAc/hexane 1:4), and ozonide has a
Rf value of 0.30). The ozone was discontinued immediately when
the starting material was completely consumed. Then, 90% HOAc
(aq) (0.5 ml) and MeOH (0.5 ml) were added, and the solution was
left overnight. On day 2, TLC showed 100% conversion of ozonide to
the title product (Rf 0.25). The solution was washed with H2O
(2*5 ml), dried with Na2SO4, filtered and evaporated at reduced
pressure to give 0.027 g (69%) of the title compound as a semi-
crystalline solid. The overall yield was 53%. The spectra were
consistent with those of a commercial sample.
1-(2-3-((tert-Butyldiphenylsilyl)oxy)phenoxy)ethyl)piperidine
(9a). 17 (1.00 g, 4.52 mmol) was dissolved in DMF (15 ml) under a
N2 atmosphere with stirring. tert-Butylchlorodiphenylsilane
(1.92 g, 6.99 mmol), TEA (2.00 ml) and 4-(dimethylamino)pyridine
(DMAP) (0.12 g) were added. The solution was stirred and heated to
70 ꢁC for 3 h in an oil bath. The solution was cooled and diluted with
Et2O (50 ml) and water (50 ml). The mixture was stirred for 4 min,
and the phases were separated. The aqueous phase was extracted
with Et2O (3*30 ml). The combined organic phase was dried with
Na2SO4 and filtered. The solution was evaporated at reduced
pressure. The residue was purified with column chromatography
and eluted with EtOAc/hexane/TEA (20:80:5) (the column was
packed with EtOAc/hexane 1:3) to give 1.31 g (63%) of the title
1-(2-(3-((4-Methoxybensyl)oxy)phenoxy)ethyl)piperidine (8a). 17
(1.00 g, 4.52 mmol) was dissolved in DMF (20 ml) under a N2 at-
mosphere with stirring. NaH (0.24 g, 6.00 mmol) was added, and
the solution was heated to 70 ꢁC in an oil bath. The solution was
cooled to ambient temperature. p-MeOBnCl (0.78 g, 5.00 mmol)
was added, and the solution was stirred for 2 h. The solution was
diluted with Et2O (40 ml) and H2O (40 ml). The aqueous phase was
extracted with Et2O (3*20 ml), and the combined organic phases
were dried with Na2SO4, filtered and evaporated. The residue was
purified by column chromatography by eluting with EtOAc/hexane/
TEA (5:15:1) (the column was packed with EtOAc/hexane 1:3) to
give 0.60 g (39%) of the title compound as a crystalline solid (mp
compound as a syrup. 1H NMR (800 MHz, CDCl3)
d 7.75e7.64 (m,
4H), 7.44e7.38 (m, 2H), 7.35 (t, J ¼ 7.5 Hz, 4H), 6.94 (d, J ¼ 8.8 Hz,
1H), 6.42 (dd, J ¼ 7.3, 2.0 Hz, 1H), 6.38e6.30 (m, 2H), 3.86 (t,
J ¼ 6.2 Hz, 2H), 2.63 (t, J ¼ 6.2 Hz, 2H), 2.41 (s, 4H),1.57 (p, J ¼ 5.7 Hz,
4H), 1.43 (d, J ¼ 6.2 Hz, 2H), 1.09 (s, 9H); 13C NMR (201 MHz, CDCl3)
48e52 ꢁC). 1H NMR (800 MHz, CDCl3)
d 7.42e7.30 (m, 2H), 7.15 (t,
J ¼ 8.2 Hz, 1H), 7.00e6.83 (m, 2H), 6.61e6.44 (m, 3H), 4.95 (s, 2H),
4.07 (t, J ¼ 6.1 Hz, 2H), 3.81 (s, 3H), 2.75 (t, J ¼ 6.1 Hz, 2H), 2.49 (s,
4H), 1.60 (p, J ¼ 5.6 Hz, 4H), 1.44 (d, J ¼ 6.0 Hz, 2H). 13C NMR
d
19.4, 24.2, 25.9, 26.5, 54.9, 57.7, 65.7, 106.3, 107.8, 112.2, 127.7,
127.7, 129.4, 129.8, 133.0, 135.5, 156.6, 159.7; HRMS ESI þ m/z
(201 MHz, CDCl3)
d 24.2, 25.9, 55.0, 55.3, 57.9, 65.9, 69.8, 101.9,
[MþH]þ Calcd for C29H37NO2Si, 460.2666; Found 460.2686.
107.05,107.13, 114.0,129.0,129.2,129.8,159.4,160.0; HRMS ESI þ m/
3-((tert-Butyldiphenylsilyl)oxy)phenol (9d). [11]. 9a (0.94 g,
2.04 mmol) was dissolved in DCM (20 ml). Next, 39% peracetic acid
(in HOAc) (0.48 ml, 2.81 mmol) was added under stirring for 4 min.
Then,1 M K2CO3 (10 ml) was added, and the solution was stirred for
3 min. The solution was filtered through phase-separator paper,
and the aqueous phase was extracted in the filter funnel with DCM
(7*3 ml) by siphoning the mixture back and forth with a 5 ml
single-use polyethylene Pasteur pipette as the organic phase
passed through the PS-filter. HMDS (2 ml) was added to the organic
phase, and this solution was evaporated at reduced pressure to give
0.92 g (84%) of 9b as a gum that contained 1 equiv. of HOAc. 1H NMR
z [MþH]þ Calcd For C21H27NO3 342.2064 Found 342.2068.
3-((4-Methoxybenzyl)oxy)phenol (8d). [18]. 8a (0.27 g,
0.79 mmol) was dissolved in DCM (15 ml) under stirring. Then, 39%
peracetic acid (in HOAc) (0.16 ml, 0.94 mmol) was added, and the
solution was stirred for 4 min. Next, 1 M K2CO3 (2 ml) was added,
and the mixture was stirred for 4 min. The solution was filtered
through PS paper, and the aqueous phase was extracted in the filter
funnel with DCM (7*2 ml) by siphoning the mixture back and forth
with a 5 ml single-use polyethylene Pasteur pipette as the organic
phase passed through the PS-filter. HMDS (2 ml) was added to the
combined organic phase and evaporated at reduced pressure to
give 0.27 g (96%) of 8b as a gum. 1H NMR (800 MHz, MeO-d4)
(800 MHz, CDCl3)
d 7.72e7.67 (m, 4H), 7.45e7.40 (m, 2H), 7.36 (t,
J ¼ 7.3 Hz, 4H), 6.96 (t, J ¼ 8.2 Hz, 1H), 6.39 (ddd, J ¼ 33.1, 8.2, 2.3 Hz,
2H), 6.30 (t, J ¼ 2.4 Hz, 1H), 4.41e4.35 (m, 2H), 3.77e3.72 (m, 2H),
3.60 (dt, J ¼ 11.9, 4.4 Hz, 2H), 3.20e3.09 (m, 2H), 2.28e2.14 (m, 2H),
1.72 (dd, J ¼ 9.2, 4.6 Hz, 1H), 1.65 (dt, J ¼ 14.6, 4.5 Hz, 2H), 1.41 (s,
d
7.35e7.30 (m, 2H), 7.17 (t, J ¼ 8.2 Hz, 1H), 6.93e6.87 (m, 2H), 6.61
(dd, J ¼ 8.2, 2.3 Hz, 1H), 6.58 (t, J ¼ 2.4 Hz, 1H), 6.55 (dd, J ¼ 8.2,
2.4 Hz, 1H), 4.96 (s, 2H), 4.54e4.46 (m, 2H), 3.78 (s, 3H), 3.67e3.60
14

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
1H), 1.09 (s, 9H); 13C NMR (201 MHz, CDCl3)
d
19.4, 20.9, 21.7, 26.5,
(66%) of 10c as a crystalline solid (mp 59e62 ꢁC); 1H NMR
61.3, 65.5, 67.3, 106.4, 107.3, 113.0, 127.8, 129.7, 129.9, 132.7, 135.5,
156.8, 158.3; HRMS ESI þ m/z [MþH]þ Calcd for C29H37NO3Si,
476.2615; Found, 476.2624. 9b (0.54 g, 1.01 mmol) was suspended
in toluene (7.5 ml) under stirring. BSA (0.83 ml, 3.40 mmol) was
added, and the solution was heated to reflux for 35 min. The so-
lution was evaporated at reduced pressure, and the resulting gum
was purified by column chromatography by elution with EtOAc/
hexane (1:20) to give 0.27 g (71%) of 9c as an oil. 1H NMR (800 MHz,
(800 MHz, MeO-d4)
d
7.34 (d, J ¼ 8.4 Hz, 2H), 6.95e6.87 (m, 2H),
6.67 (dd, J ¼ 13.7, 6.1 Hz, 1H), 4.61 (dd, J ¼ 13.6, 1.5 Hz, 1H), 4.34 (dd,
J ¼ 6.1, 1.5 Hz, 1H), 1.50 (s, 9H); 13C NMR (201 MHz, MeO-d4)
d 28.7,
80.8, 94.2, 118.5, 121.4, 136.0, 150.2, 153.6, 155.5; HRMS ESI þ m/z
[MþH]þ Calcd for C13H17NO3, 236.1281; Found, 236.1283.
10c (0.14 g, 0.60 mmol) was dissolved in DCM (5 ml) under
stirring, and then ozone in air was bubbled through the solution at
a rate of 50 mg/h for 30 min. HOAc (90%) (aq) (2 ml) and MeOH
(2 ml) were added, and the solution was left at ambient tempera-
ture. On day 3, the solution was diluted with DCM (10 ml) and H2O
(10 ml). The solution was stirred for 3 min, and the phases were
separated. The organic phase was washed with H2O (10 ml), dried
with Na2SO4, filtered and evaporated. The crystalline residue was
washed with DCM (1 ml) and dried in vacuo to give 0.11 g (88%) of
the title compound as a crystalline solid (mp, 141e143 ꢁC; lit.,
142e143 ꢁC). The spectra were consistent with those of a com-
mercial sample.
CDCl3)
d
7.74e7.67 (m, 4H), 7.45e7.38 (m, 2H), 7.36 (t, J ¼ 7.4 Hz,
4H), 6.99 (t, J ¼ 8.2 Hz, 1H), 6.51 (s, 1H), 6.47e6.35 (m, 3H), 4.64 (dd,
J ¼ 13.7, 1.6 Hz, 1H), 4.31 (dd, J ¼ 6.1,1.6 Hz,1H),1.10 (s, 9H). 13C NMR
(201 MHz, CDCl3)
d 19.4, 26.5, 94.9, 108.9, 109.8, 114.6, 127.8, 129.7,
129.9, 132.7, 135.5, 147.9, 156.7, 157.5; HRMS ESI þ m/z [MþH]þ
Calcd for C24H26O2Si, 375.1775; Found, 375.1775.
9c (0.096 g, 0.26 mmol) was dissolved in DCM/90% HOAc (aq)
(2:1, 10 ml), and ozone in air was bubbled through the solution at a
rate of 50 mg ozone/h for 45 min. The starting material had a Rf
value of 0.80 (EtOAc/hexane 1:4), and the ozone was discontinued
when this material was completely converted to the corresponding
presumed ozonide (Rf 0.70). MeOH (2.5 ml) was added, and the
solution was left overnight. The next day, the ozonide was
completely hydrolyzed to the title compound (Rf 0.60). The solution
was diluted with H2O (10 ml), and the mixture was extracted with
EtOAc/hexane (1:4, 3*15 ml). The organic phase was dried with
Na2SO4, filtered and evaporated at reduced pressure to give 0.086 g
(95%) of the title compound as an oil. The spectra were consistent
with those of a commercial sample.
4-tert-Butyl(4-hydroxyphenyl)carbamate (10d). 10c (0.066 g,
0.28 mmol) was dissolved in DMF (1.6 ml), and H2O (0.4 ml) was
added under stirring. 3,6-(Di(pyridine-2-yl)1,2,4,5-tetrazine
(0.080 g, 0.34 mmol) was added, and the solution was stirred and
heated to 60 ꢁC for 570 min. The solution was cooled and diluted
with Et2O (5 ml) and H2O (5 ml). The aqueous phase was extracted
with Et2O (3*5 ml). The combined organic phase was dried with
Na2SO4, filtered and evaporated at reduced pressure. The solid
residue was purified by column chromatography by elution with
EtOAc/hexane (1:2) to give 0.032 g (55%) of the title compound as a
crystalline solid. The spectra were the same as described above.
1-(2-(3-(Allyloxy)phenoxy)ethyl)piperidine (11a). 17 (0.300 g,
1.36 mmol) was dissolved in DMF (6.0 ml) under a N2 atmosphere,
and NaH (60% in mineral oil, 0.065 g, 1.63 mmol) was added under
stirring. The solution was heated in a polyethylene glycol (PEG)
bath to 120 ꢁC for 4 min. The mixture was cooled to ambient
temperature and stirred for 15 min. Allyl iodide (0.272 g,
1.62 mmol) was added, and the mixture was stirred for 25 min. The
solution was diluted with H2O (20 ml) and extracted with Et2O (3*
25 ml). The organic phase was subjected to acid-base partitioning
with HOAc (6.0 ml in 20 ml H2O) and conc. NH4OH (aq) (10 ml in
30 ml H2O). The organic phase was dried with Na2SO4, filtered and
evaporated at reduced pressure to give 0.24 g (68%) of the title
tert-Butyl(4-(2-piperidin-1-yl)ethoxy)phenyl)carbamate
(10a).
[19]. 18 (1.59 g, 7.22 mmol) was dissolved in DCM (40 ml). Boc2O
(2.20 g, 10.08 mmol) was added, and the solution was left over-
night. The solution was evaporated at reduced pressure, and the
residue was purified by column chromatography by eluting with
EtOAc/hexane/TEA (10:20:3) (the column was packed with EtOAc/
hexane 1:2) to give 1.72 g (74%) of the title compound as a crys-
talline solid (mp 78e80 ꢁC). 1H NMR (800 MHz, MeO-d4)
d 7.28 (d,
J ¼ 8.6 Hz, 2H), 6.92e6.72 (m, 2H), 4.07 (t, J ¼ 5.7 Hz, 2H), 2.74 (t,
J ¼ 5.7 Hz, 2H), 2.66e2.38 (m, 4H), 1.62 (p, J ¼ 5.7 Hz, 4H), 1.50 (s,
11H). 13C NMR (201 MHz, MeO-d4)
d 25.0, 26.4, 28.8, 55.9, 59.0,
66.6, 80.5, 115.7, 121.7, 133.7, 155.6, 156.0.
4-Tert-butyl(4-hydroxyphenyl)carbamate (10d). [12]. 10a (0.36 g,
1.12 mmol) was dissolved in DCM (25 ml) under stirring. Then, 39%
peracetic acid (in HOAc) (0.26 ml,1.52 mmol) was added, and the
solution was stirred for 4 min. Next, 1 M K2CO3 (4.2 ml) was added,
and the mixture was stirred for 4 min. The solution was filtered
through PS paper, and the aqueous phase was extracted in the filter
funnel with DCM (7*4 ml) by siphoning the mixture back and forth
with a 5 ml single-use polyethylene Pasteur pipette as the organic
phase passed through the PS-filter. HMDS (2 ml) was added to the
organic phase, and the solution was evaporated at reduced pressure
to give 0.33 g (88%) of 10b as a crystalline solid (mp 186e188 ꢁC). 1H
compound as an oil; 1H NMR (800 MHz, MeOD)
d
7.14 (t, J ¼ 8.1 Hz,
1H), 6.55e6.45 (m, 3H), 6.05 (ddt, J ¼ 17.3, 10.5, 5.2 Hz, 1H), 5.39
(dd, J ¼ 17.3, 1.7 Hz, 1H), 5.24 (dd, J ¼ 10.6, 1.5 Hz, 1H), 4.51 (d,
J ¼ 5.2 Hz, 2H), 4.09 (t, J ¼ 5.6 Hz, 2H), 2.76 (t, J ¼ 5.7 Hz, 2H), 2.55 (s,
4H), 1.63 (p, J ¼ 5.7 Hz, 4H), 1.48 (s, 2H). 13C NMR (201 MHz, MeO-
d4) d 25.0, 26.4, 55.9, 58.9, 66.3, 69.8,102.8,107.9,108.2,117.4,130.9,
135.0, 161.31, 161.34; HRMS ESI þ m/z [MþH]þ Calcd for C16H23NO2,
262.1807; Found, 262.1807.
3-(Allyloxy)phenol (11d). [11]. 11a (0.16 g, 0.61 mmol) was dis-
solved in DCM (4 ml) under stirring. Then, 39% peracetic acid (in
HOAc) (0.10 ml, 0.61 mmol) was added, and the solution was stirred
for 2 min. TEA (0.2 ml) was added to protect the alkene from
possible epoxidation if excess peracetic acid was present, and the
solution was stirred for 1 min. Next, 1 M K2CO2 (2.0 ml) was added,
and the mixture was stirred for 4 min. The mixture was filtered
through PS paper, and the aqueous phase was extracted with DCM
(7*5.0 ml) in the filter funnel by siphoning the mixture back and
forth with a single-use 5 ml polyethylene Pasteur pipette as the
organic phase passed through the PS-filter. The organic phase was
mixed with HMDS (1.0 ml), and the solution was evaporated at
reduced pressure to give 0.17 g (0.16 g, 95%) of 11b as a semi-
NMR (800 MHz, MeO-d4)
d
7.31 (d, J ¼ 8.5 Hz, 2H), 6.97e6.70 (m,
2H), 4.62e4.38 (m, 2H), 3.69e3.58 (m, 2H), 3.39 (td, J ¼ 11.6, 2.8 Hz,
2H), 3.30e3.24 (m, 2H), 2.16 (dd, J ¼ 10.9, 3.8 Hz, 2H), 1.79e1.65 (m,
3H), 1.50 (s, 10H); 13C NMR (201 MHz, MeO-d4)
d 22.0, 22.1, 22.7,
63.0, 67.1, 69.7, 80.6, 115.8, 121.7, 134.3, 155.1, 155.6; HRMS ESI þ m/z
[MþH]þ Calcd for C18H27N2O4, 336.2044; Found, 336.2038. 10b
(0.14 g, 0.42 mmol) was dissolved in DMF (7 ml) under stirring. BSA
(0.31 ml, 1.27 mmol) mmol) was added, and the solution was
heated to 120 ꢁC for 50 min. The solution was then cooled to
ambient temperature, and H2O (20 ml) was added. The mixture was
extracted with Et2O (3*10 ml). The organic phase was washed with
H2O (2* 10 ml), dried with Na2SO4, filtered and evaporated at
reduced pressure. The solid residue was purified by column chro-
matography by elution with EtOAc/hexane (1:7) to give 0.065 g
crystalline solid. 1H NMR (800 MHz, MeOD)
d
7.18 (t, J ¼ 8.1 Hz,
1H), 6.66e6.46 (m, 3H), 6.14e5.93 (m, 1H), 5.39 (dd, J ¼ 17.3, 1.7 Hz,
1H), 5.24 (dt, J ¼ 10.6, 1.5 Hz, 1H), 4.52 (dt, J ¼ 5.7, 1.9 Hz, 4H),
15

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
3.72e3.61 (m, 2H), 3.39 (ddd, J ¼ 12.8, 11.3, 2.8 Hz, 2H), 3.30e3.22
(m, 2H), 2.16 (qd, J ¼ 10.8, 3.9 Hz, 2H), 1.71 (dt, J ¼ 14.3, 5.0 Hz, 3H),
(qd, J ¼ 10.8, 3.8 Hz, 2H), 2.07e1.94 (m, 1H), 1.91e1.75 (m, 2H),
1.75e1.61 (m, 5H), 1.61e1.53 (m, 1H), 1.51 (tdd, J ¼ 11.1, 7.7, 4.4 Hz,
1.50 (tdd, J ¼ 11.4, 7.8, 4.9 Hz,1H); 13C NMR (201 MHz, MeOD)
d
22.1,
1H); 13C NMR (201 MHz, MeOD)
d 19.9, 22.1, 22.7, 26.3, 31.5, 62.7,
22.7, 62.7, 67.1, 69.7, 69.8, 102.9, 108.0, 108.8, 117.4, 131.1, 134.9,
160.5, 161.4; HRMS ESI þ m/z [MþH]þ Calcd for C16H23NO3,
278.1757; Found, 278.1756. 11b (0.15 g, 0.54 mmol) was suspended
in toluene (6.0 ml). BSA (0.39 ml, 1.60 mmol) was added, and the
solution was refluxed for 36 min. The solution was evaporated at
reduced pressure, and the oily residue was purified by column
chromatography by elution with EtOAc/hexane (1:20) to give
63.1, 67.1, 69.7, 97.7, 104.5, 108.7, 110.6, 131.0, 159.8, 160.4; HRMS
ESI þ m/z [MþH]þ Calcd for C18H27NO4, 322.2018; Found, 322.2018.
12b (0.111 g, 0.345 mmol) was suspended in toluene (9.0 ml). BSA
(0.30 ml, 1.23 mmol) was added, and the mixture was heated under
stirring in a PEG bath to reflux for 35 min. The solution was evap-
orated at reduced pressure, and the resulting oil was purified by
chromatography by elution with EtOAc/hexane (1:20) to give
0.066 g (70.1%) of 11c as an oil; 1H NMR (800 MHz, MeOD)
d
7.21 (t,
0.052 g (68%) of 12c as an oil; 1H NMR (700 MHz, MeOD)
d 7.21 (t,
J ¼ 8.1 Hz, 1H), 6.71 (dd, J ¼ 13.6, 6.1 Hz, 1H), 6.66 (ddd, J ¼ 8.3, 2.4,
0.9 Hz, 1H), 6.61e6.55 (m, 2H), 6.05 (ddt, J ¼ 17.3, 10.5, 5.2 Hz, 1H),
5.39 (dd, J ¼ 17.3, 1.7 Hz, 1H), 5.25 (dd, J ¼ 10.6, 1.5 Hz, 1H), 4.70 (dd,
J ¼ 13.7, 1.5 Hz, 1H), 4.53 (dt, J ¼ 5.1, 1.6 Hz, 2H), 4.41 (dd, J ¼ 6.1,
J ¼ 8.2 Hz,1H), 6.76 (ddd, J ¼ 8.3, 2.3, 0.8 Hz, 1H), 6.73e6.70 (m, 1H),
6.70e6.68 (m, 1H), 6.62 (ddd, J ¼ 8.1, 2.4, 0.9 Hz, 1H), 5.41 (t,
J ¼ 3.4 Hz, 1H), 4.70 (dd, J ¼ 13.7, 1.5 Hz, 1H), 4.41 (dd, J ¼ 6.1, 1.5 Hz,
1H), 3.88 (ddd, J ¼ 11.4, 9.4, 3.0 Hz,1H), 3.60 (dtd, J ¼ 11.4, 4.1,1.2 Hz,
1H), 2.04e1.94 (m, 1H), 1.86 (dddd, J ¼ 13.5, 10.5, 4.4, 3.0 Hz, 1H),
1.83e1.76 (m, 1H), 1.72e1.63 (m, 2H), 1.63e1.54 (m, 1H)); 13C NMR
1.5 Hz, 1H). 13C NMR (201 MHz, MeOD)
d 69.9, 95.2, 104.9, 110.1,
110.5, 117.5, 131.2, 134.8, 149.3, 159.4, 161.4.
11c (0.054 g, 0.31 mmol) was dissolved in 90% HOAc (aq)
(3.0 ml), and the solution was refluxed for 30 min. The solution was
evaporated at reduced pressure to give 0.040 g (87%) of the title
product. The spectra were consistent with those of a commercial
sample.
(201 MHz, MeOD) d 19.9, 26.3, 31.4, 63.1, 95.2, 97.8, 106.5, 110.9,
112.3, 131.1, 149.5, 159.2, 159.7. 12c (0.030 g, 0.0137 mmol) was
suspended in DMF (1.0 ml), and H2O (0.2 ml) was added. 3,6-Di-2-
pyridyl-1,2,4,5-tetrazine (50 mg, 0.212 mmol) was added, and the
mixture was heated in a PEG bath to 60 ꢁC for 4.5 h. The mixture
was diluted with EtOAc/hexane (1:2, 10 ml) and washed with H2O
(1*20 ml). The organic phase was dried with Na2SO4, filtered and
evaporated. The resulting solid was purified by column chroma-
tography by elution with EtOAc/hexane (1:2) to give 0.016 g (60%)
of the title compound as an oil. The spectra were consistent with
those of a commercial sample.
3-((Tetrahydro-2H-pyran-2-yl)oxy)phenol (12d). 12a (0.50 g,
1.64 mmol) was dissolved in DCM under stirring in a N2 atmo-
sphere in a flame-dried round-bottom flask. BBr3ꢀMe2S (0.51 g,
1.64 mmol) was added, and the solution was stirred for 10 min. The
solution was diluted with conc. NH4OH (aq) (2 ml) and stirred for
3 min. The mixture was poured into a mixture of MeOH (40 ml),
H2O (30 ml) and NaHCO3 (4.2 g) and boiled for 20 min. DCM and
some of the MeOH were boiled off. The mixture was cooled to
ambient temperature and extracted with DCM (3*25 ml). The
combined organic phase was dried with Na2SO4, filtered and
evaporated at reduced pressure. The residual oil was purified by
column chromatography by elution with EtOAc/hexane (1:3) to
give 0.162 g (51%) of the title compound as an oil. The spectra were
the same as described above.
1-(2-(4-Nitrophenoxy)ethyl)piperidine (12). [20]. 4-Nitrophenol
(2.00 g, 14.40 mmol) was dissolved in DMF (50 ml) under stirring
in an Erlenmeyer flask. K2CO3 (5.96 g, 43.12 mmol) was added, and
the mixture was heated to 90 ꢁC on a magnetic stirrer. 16 (2.65 g,
14.4 mmol) was added, and the solution was stirred for 30 min. The
solution was cooled, water (100 ml) was added, and the solution
was extracted with Et2O (4*40 ml). The organic phase was sub-
jected to acid-base partitioning with 5% HCl (aq) (100 ml) and 5%
NH4OH (aq) (150 ml), followed by extraction with Et2O (4* 60 ml).
The solution was diluted with hexane (40 ml), dried with Na2SO4,
filtered and evaporated. The crystalline residue was dried in vacuo
to give 3.40 g (94%) of the title compound. The spectra were
consistent with published data. mp, 62e64 ꢁC; Lit., 63e64 ꢁC.
1-(2-(3-((Tetrahydro-2H-pyran-2-yl)oxy)phenoxy)ethyl)piperi-
dine (12a). 17 (1.00 g, 4.52 mmol) was mixed with p-TSA*H2O
(0.936 g, 4.92 mmol) in a Schlenk flask in vacuo, and the mixture
was stirred and heated until a melt formed (approx. 60 ꢁC) and the
bubbling stopped. The mixture was cooled to ambient temperature,
and toluene (3 ml), DCM (9 ml) and DMSO (2 ml) were added. The
mixture was sonicated for 2 min. 3,4-Dihydro-2H-pyrane (2.24 ml,
24.6 mmol) was added, and the mixture was stirred for 1 h. Then,
3,4-dihydro-2H-pyrane (1.00 ml, 11.00 mmol) was added, and the
solution was stirred for 1.5 h. At this point, a clear solution was
formed. The solution was poured into a mixture of conc. NH4OH
(aq) (9 ml) and Et2O (150 ml) under stirring. The aqueous phase was
extracted with Et2O (3*25 ml). The combined organic phase was
washed with H2O (1*40 ml), dried with Na2SO4, filtered and
evaporated at reduced pressure. The resulting oil was purified by
column chromatography by elution with EtOAc/hexane/TEA
(10:10:1) to give 0.91 g (66%) of the title compound as an oil; 1H
NMR (700 MHz, MeOD)
d
7.14 (t, J ¼ 8.5 Hz, 1H), 6.66e6.59 (m, 2H),
6.56 (ddd, J ¼ 8.3, 2.3, 1.0 Hz, 1H), 5.39 (t, J ¼ 3.4 Hz, 1H), 4.10 (t,
J ¼ 5.7 Hz, 2H), 3.91e3.84 (m, 1H), 3.61e3.55 (m, 1H), 2.76 (t,
J ¼ 5.6 Hz, 2H), 2.55 (s, 4H), 2.03e1.94 (m, 1H), 1.86 (dddd, J ¼ 13.5,
10.5, 4.4, 3.0 Hz, 1H), 1.79 (dddd, J ¼ 13.0, 6.1, 4.6, 3.4 Hz, 1H),
1.72e1.61 (m, 6H), 1.59 (ddt, J ¼ 11.8, 7.4, 4.3 Hz, 1H), 1.49 (q,
J ¼ 5.9 Hz, 2H); 13C NMR (201 MHz, MeOD)
d 20.0, 25.0, 26.35,
26.44, 31.5, 55.9, 59.0, 63.2, 66.4, 97.8, 104.4, 108.7, 110.1, 130.8,
159.7, 161.2; HRMS ESI þ m/z [MþH]þ Calcd for C18H27NO3, 306.
2069; Found, 306.2069.
3-((Tetrahydro-2H-pyran-2-yl)oxy)phenol (12d). [15]. 12a
(0.135 g, 0.44 mmol) was dissolved in DCM (6 ml) under stirring.
Next, 39% peracetic acid (in HOAc) (0.091 ml, 0.53 mmol) was
added, and the solution was stirred for 4 min. Then, 1 M K2CO3 (aq)
(3.5 ml) was added, and the solution was stirred for 4 min. The
mixture was filtered through PS paper, and the aqueous phase was
extracted with DCM (7*10 ml) by siphoning the mixture back and
forth with a 5 ml single-use polyethylene Pasteur pipette in the
filter funnel as the organic phase passed through the PS- filter.
HMDS (2.0 ml) was added to the combined organic phase, and the
solution was evaporated at reduced pressure to give 0.135 g (95%) of
12b as a semi-crystalline solid; 1H NMR (800 MHz, MeOD)
4.1.4. Isolation of reduced N-oxide, Table 1, run 4
1-(2-(4-Nitrophenoxy)ethyl)piperidine (12). 13
0.68 mmol) was suspended in toluene (6.8 ml) in a flame-dried
Schlenk flask under N2 atmosphere. 1-Hydroxypiperidine
(0.18 g,
a
(0.070 g, 0.69 mmol) and HMDS (0.43 ml, 2.05 mmol) were
added, and the mixture was heated to reflux in an oil bath under
stirring for 15 min. The solution was evaporated at reduced pres-
sure, and the residual oil was purified by column chromatography
by elution with EtOAc/MeOH/H2O/TEA (56:4:2:1) to give 0.037 g
d
7.22e7.12 (m,1H), 6.71e6.65 (m, 2H), 6.60 (ddd, J ¼ 8.2, 2.3,1.0 Hz,
1H), 5.41 (t, J ¼ 3.4 Hz, 1H), 4.55e4.49 (m, 2H), 3.87 (ddd, J ¼ 11.4,
9.4, 3.0 Hz, 1H), 3.69e3.62 (m, 2H), 3.59 (dtd, J ¼ 11.5, 4.2, 1.2 Hz,
1H), 3.40 (ddd, J ¼ 13.8, 11.0, 2.8 Hz, 2H), 3.35e3.23 (m, 4H), 2.16
16

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
(22%) of the title compound (mp, 61e63 ꢁC; Lit., 63e64 ꢁC). The
spectra were the same as described above.
a solid. The spectra were the same as described above.
3-(2-(Piperidin-1-yl)ethoxy)phenol (17). 7a (0.48 g, 1.54 mmol)
was dissolved in MeOH (5 ml). Pd/C (5%, 0.15 g) was added, and the
mixture was hydrogenated at ambient pressure under stirring for
60 min. The solution was filtered and evaporated at reduced pres-
sure to give 0.31 g (91%) of the title compound as a solid. The
spectra were the same as described above.
3-(2-(Piperidin-1-yl)ethoxy)phenol (17). 8a (0.050 g, 0.15 mmol)
was dissolved in HOAc. The solution was refluxed for 150 min,
evaporated at reduced pressure and purified by column chroma-
tography by elution with EtOAc/TEA/MeOH (90:10:5) (the column
was packed with ETOAc) to give 0.023 g (69%) of the title compound
as a solid. The spectra were the same as described above.
1-(2-(4-Nitrophenoxy)ethyl)piperidine 1-oxide (13). 12 (1.53 g,
6.11 mmol) was dissolved in DCM (50 ml). The solution was stirred,
and 39% peracetic acid (in HOAc) (1.25 ml, 7.31 mmol) was added.
The solution was stirred for 5 min. Then,1 M K2CO3 (aq) (25 ml) was
added, and the solution was stirred for 4 min. The solution was
filtered through PS paper, and the remaining aqueous phase was
extracted with DCM (7*10 ml) by siphoning the mixture back and
forth with a 5 ml single-use polyethylene Pasteur pipette in the
filter funnel as the organic phase passed through the PS-filter.
HMDS (6.00 ml) was added to the organic phase, and the solution
was evaporated at reduced pressure to give 1.55 g (95%) of the title
compound as
a
deliquescent semi-crystalline solid. 1H NMR
3-(2-(Piperidin-1-yl)ethoxy)phenol (17). 9a (0.24 g, 0.52 mmol)
was dissolved in THF (20 ml). Tetrabutylammonium fluoride (TBAF)
(1 M in THF, 0.58 ml) was added, and the solution was stirred for
(800 MHz, CDCl3)
d
8.20 (d, J ¼ 9.2 Hz, 2H), 7.04 (d, J ¼ 9.2 Hz, 2H),
4.88e4.68 (m, 2H), 4.09e3.98 (m, 2H), 3.66 (dd, J ¼ 11.9, 4.9 Hz, 2H),
3.49e3.43 (m, 2H), 2.25 (qd, J ¼ 11.1, 5.7 Hz, 2H), 1.79 (dt, J ¼ 9.5,
4.1 Hz, 3H), 1.54 (dddd, J ¼ 11.3, 7.9, 5.7, 2.9 Hz, 1H); 13C NMR
5 min. HOAc (56 ml) was added, and the solution was evaporated at
reduced pressure. The residual gum was purified by column chro-
matography by elution with EtOAc/TEA/MeOH (90:10:5) (the col-
umn was packed with EtOAc) to give 0.113 g (98%) of the title
compound as a solid. The spectra were the same as described
above.
(201 MHz, CDCl3)
d 20.9, 21.4, 62.4, 65.9, 67.6, 114.7, 126.0, 142.1,
162.3; HRMS ESI þ m/z [MþH]þ Calcd for C13H18N2O4, 267.1339;
Found, 267.1335.
1-(2-(4-Nitrophenoxy)ethyl)piperidine 1-oxide hydrate (13b). 13
(0.50 g, 1.87 mmol) was left in a stoppered flask for 1 month. The
content in the flask was dissolved in DCM (20 ml), and sufficient
toluene to remove the hydrate was added (approximately 30 ml).
The crystalline precipitate was collected on a filter, washed with
Et2O (2*5 ml) and dried with an aspirator vacuum to give 0.35 g
(66%) of the title compound as white crystals. This material was not
deliquescent and was stable in air (mp 73e77 ꢁC); 1H NMR
3-(2-(Piperidin-1-yl)ethoxy)phenol
(17). 11a
(0.098
g,
0.375 mmol) was dissolved in conc. HCl (aq) (1.0 ml) and the so-
lution was heated under stirring to 75 ꢁC for 60 min. The solution
was evaporated and the residue was dissolved in H2O (1.5 ml). The
solution was neutralized with NaHCO3 and was filtered through PS
paper. The remaining aqueous phase was extracted with EtOAc
(6*3 ml) by siphoning the mixture back and forth with a 5 ml
single-use polyethylene Pasteur pipette in the filter funnel as the
organic phase passed through the PS-filter. The combined organic
phase was dried with Na2SO4, filtered and evaporated to give
0.070 g (84%) of the title compound as a semi-crystalline solid. The
spectra were the same as described above.
(800 MHz, CDCl3)
d
8.20 (d, J ¼ 8.7 Hz, 2H), 7.00 (d, J ¼ 9.2 Hz, 2H),
4.87e4.50 (m, 2H), 3.76e3.55 (m, 2H), 3.32 (dd, J ¼ 11.0, 5.5 Hz, 2H),
3.26 (dd, J ¼ 10.9, 3.2 Hz, 2H), 3.14 (s, 2H), 2.46e2.19 (m, 2H), 1.72
(ddt, J ¼ 51.3, 14.4, 4.6 Hz, 3H), 1.46 (dtd, J ¼ 14.2, 10.6, 8.6, 5.2 Hz,
1H); 13C NMR (201 MHz, CDCl3)
d 21.1, 22.0, 62.4, 66.9, 68.2, 114.5,
125.9, 141.9, 162.7. HRMS ESI þ m/z [MþH]þ Calcd for C13H18N3O4,
3-(2-(Piperidin-1-yl)ethoxy)phenol
(17).
12a
(0.158
g,
267.1339; Found, 267.1331.
0.517 mmol) was dissolved in 90% HOAc (aq). The solution was
heated to reflux for 1 min. The solution was evaporated and the
residue was dissolved in H2O. The solution was neutralized with
NaHCO3 and was extracted with EtOAc (6*3 ml). The combined
organic phase was dried with Na2SO4, filtered and evaporated to
give 0.110 g (96%) of the title compound as a semi-crystalline solid.
The spectra were the same as described above.
3-(2-(Piperidin-1-yl)ethoxy)phenol (17). 23 (0.15 g, 0.45 mmol)
was dissolved in conc. HBr (aq) (1.0 ml), and the solution was
heated under stirring to reflux in an oil bath for 70 min. The solu-
tion was cooled to ambient temperature, diluted with H2O (7 ml)
and neutralized with NaHCO3 (2.00 g). The mixture was extracted
with EtOAc (6*10 ml). The organic phase was dried with Na2SO4,
filtered and evaporated at reduced pressure. The solid residue was
purified with column chromatography by elution with EtOAc/TEA/
MeOH (90:10:5) (the column was packed with EtOAc) to give
0.065 g (65%) of the title compound as a solid. The spectra were the
same as described above.
4-(2-Piperidin-1-yl)ethoxy)aniline (18). [15,22]. 10a (1.62 g,
5.06 mmol) was dissolved in DCM (4 ml) under stirring, and TFA
(6 ml) was added. The solution was stirred for 15 min. The solution
was diluted with H2O (20 ml) and conc. NH4OH (aq) (12 ml) was
added under stirring. The organic phase was separated, and the
aqueous phase was extracted with DCM (3*20 ml). The combined
organic phase was diluted with hexane (20 ml), dried with Na2SO4,
filtered and evaporated to give 1.04 g (93%) of the title compound as
a crystalline solid (mp, 64e65 ꢁC; Lit., 65e66.5 ꢁC). The spectra
were consistent with those of a commercial sample.
4.1.5. Typical run, Table 1, run 9
1-Nitro-4-(vinyloxy)benzene (14). [21a,b]. 13 (0.20 g, 0.75 mmol)
was suspended in toluene (7.5 ml) in a flame-dried Schlenk flask
under stirring in a N2 atmosphere. BSTFA (0.40 ml, 1.52 mmol) was
added, and the solution was refluxed for 20 min. The solution was
evaporated at reduced pressure, and the residual gum was purified
by column chromatography by elution with EtOAc/hexane (1:3) to
give 0.11 g (88%) of the title compound as a crystalline solid (mp,
55e56 ꢁC; Lit., 55e56 ꢁC). The spectra were consistent with pre-
viously reported data.
3-(2-(Piperidin-1-yl)ethoxy)phenol (17). [11]. 5a (4.00 g,
17.00 mmol) was dissolved in HBr (48%) (aq) (10 ml), and the so-
lution was heated to reflux for 70 min. The solution was cooled,
poured into H2O (35 ml) and neutralized with NaHCO3 (7.40 g)
under stirring. The separated solid was filtered and washed with
ice-cold H2O (3 ml) and Et2O (10 ml). This solid was the first batch
of 17. The reaction solution was extracted with EtOAc (5*40 ml). The
organic phase was dried with Na2SO4, filtered and evaporated to
give the second batch of 17. The first and second batches of 17 were
combined and sonicated with DCM (30 ml) for 10 min. The solid
was collected on a filter and dried in vacuo to give 3.14 g (83%) of
the title compound as a semi-crystalline solid. The spectra were
consistent with those of a commercial sample.
3-(2-(Piperidin-1-yl)ethoxy)phenol (17). 6a (0.15 g, 0.57 mmol)
was dissolved in NH3/MeOH (5%, 6 ml) under stirring at ambient
temperature. The solution was evaporated after 20 min, and the
solid residue was dried at 50 ꢁC at reduced pressure to remove the
acetamide byproduct, yielding 0.12 g (95%) of the title compound as
4-(2-Piperidin-1-yl)ethoxy)aniline (18). 12 (0.50 g, 2.00 mmol)
was dissolved in 90% HOAc (aq) (8 ml) under stirring and heating to
17

ꢀ
R. Noren
Tetrahedron 88 (2021) 132108
50 ꢁC. Fe (Dust, 0.50 g) was added, and the mixture was stirred at
50 ꢁC for 30 min. The solution was cooled and diluted with Et2O
(40 ml), and conc. NH4OH (aq) (20 ml) was added. The solution was
stirred for 5 min. The phases were separated, and the aqueous
phase was extracted with Et2O (3*20 ml). The combined organic
phase was diluted with hexane (30 ml), dried with Na2SO4, filtered
and evaporated under reduced pressure to give 0.31 g (70%) of the
title compound as a crystalline solid. The spectra were the same as
described above.
2-Methoxy-6-(2-piperidin-1-yl)ethoxy)benzaldehyde (19). 5a
(2.00 g, 8.50 mmol) was dissolved in THF (40 ml) under stirring in a
N2 atmosphere at 10 ꢁC. n-BuLi (1.6 M in hexane, 8.00 ml,
12.80 mmol) was added. The solution was stirred for 10 min. DMF
(4.00 ml) was added, and the solution was stirred for 5 min. The
solution was diluted with H2O (40 ml) and Et2O (100 ml). The
phases were separated, and the aqueous phase was extracted with
Et2O (3* 25 ml). The combined organic phase was dried with
Na2SO4, filtered and evaporated at reduced pressure to give 1.79 g
(80%) of the title compound as a syrup. 1H NMR (800 MHz, CDCl3)
TEA (9:9:1) to give 0.47 g (39%) of the title compound as an oil; 1H
NMR (800 MHz, CDCl3)
d
7.14 (t, J ¼ 8.1 Hz, 1H), 6.54e6.42 (m, 3H),
4.08 (t, J ¼ 6.1 Hz, 2H), 3.96 (t, J ¼ 6.7 Hz, 2H), 2.76 (t, J ¼ 6.1 Hz, 2H),
2.50 (s, 4H), 1.78e1.73 (m, 2H), 1.70 (dt, J ¼ 13.3, 3.6 Hz, 2H), 1.66 (q,
J ¼ 6.8 Hz, 3H), 1.60 (p, J ¼ 5.7 Hz, 4H), 1.53e1.46 (m, 1H), 1.44 (q,
J ¼ 5.6 Hz, 2H),1.29e1.20 (m, 2H),1.16 (d, J ¼ 12.5 Hz,1H),1.00e0.93
(m, 2H). 13C NMR (201 MHz, CDCl3)
d 24.2, 25.9, 26.2, 26.5, 55.0,
57.9, 65.88, 65.92, 101.5, 106.6, 106.9, 129.7, 160.0, 160.3; HRMS
ESI þ m/z [MþH]þ Calcd for C21H33NO2, 332.2584; Found, 332.2582.
Resorcinol (24). [12]. 5a (0.15 g, 0.64 mmol) was dissolved in HI
(aq) (58%, 4 ml) under stirring in a N2 atmosphere. The solution was
heated to reflux in an oil bath for 2 min. TLC (EtOAc/TEA 9:1)
showed that 5a (Rf 0.8) was 100% hydrolyzed to 17 (Rf 0.3, tailing).
The solution was refluxed for 80 min. TLC showed that 17 was 100%
hydrolyzed to the title compound (Rf 0.6). The solution was cooled
and neutralized with NaHCO3 (4 g) and then extracted with EtOAc
(3*15 ml). The organic phase was dried with Na2SO4, filtered and
evaporated at reduced pressure. The solid residue was purified by
column chromatography by elution with an EtOAc/hexane gradient
(1:2 to 1:1) to give 0.050 g (71%) of the title compound as a crys-
talline solid (mp 109e110 ꢁC). The spectra and mp were consistent
with those of a commercial sample.
d
10.51 (s, 1H), 7.42 (t, J ¼ 8.4 Hz, 1H), 6.57 (dd, J ¼ 8.5, 2.3 Hz, 2H),
4.18 (t, J ¼ 6.0 Hz, 2H), 3.89 (s, 3H), 2.82 (t, J ¼ 6.0 Hz, 2H), 2.51 (s,
4H), 1.67e1.52 (m, 4H), 1.43 (s, 2H); 13C NMR (201 MHz, CDCl3)
d
24.0, 25.9, 55.1, 56.0, 57.6, 67.3, 103.9, 104.8, 114.5, 135.8, 161.5,
1-(2-(4-Methoxyphenethoxy)ethyl)piperidine
(25).
2-(4-
162.0, 189.4; HRMS ESI þ m/z [MþH]þ Calcd for C15H21NO3,
Methoxyphenyl)ethan-1-ol (2.46 g, 16.16 mmol) was dissolved in
DMF (35 ml) under stirring in a N2 atmosphere. 16 (3.60 g,
19.60 mmol) and NaH (48% in mineral oil, 2.42 g, 48.4 mmol) were
added, and the mixture was heated in a PEG bath to 80 ꢁC for
20 min and cooled to ambient temperature. Conc. NH4OH (aq)
(9 ml) was added, and the solution was stirred for 80 min. The
solution was diluted with H2O (50 ml) and extracted with Et2O
(3*40 ml). The combined organic phase was washed with H2O
(2*30 ml), dried with Na2SO4, filtered and evaporated. The oily
residue was purified by column chromatography by elution with
EtOAc/TEA (20:1) to give 2.72 g (64%) of the title compound as an
264.1594; Found, 264.1590.
2-Hydroxy-6-methoxybenzaldehyde (22). [12]. 19 (0.50 g,
1.90 mmol) was dissolved in DCM (15 ml) Then, 39% peracetic acid
(in HOAc) (0.39 ml, 2.30 mmol) was added, and the solution was
stirred for 5 min. Next, 1 M K2CO3 (aq) (6 ml) was added, and the
solution was stirred for 2 min. The phases where separated by
filtration through PS paper. The aqueous phase was extracted with
DCM (6* 2 ml) in the PS filter by siphoning the mixture back and
forth with a 5 ml single-use polyethylene Pasteur pipette as the
organic phase passed through the filter. The combined organic
phase was dried with MgSO4, filtered and evaporated under
reduced pressure to give 0.38 g (72%) of 20 as a syrup; HRMS
ESI þ m/z [MþH]þ Calcd for C15H21NO4, 280.1543; Found, 280.1545.
HMDS was not added before evaporation because adding it at that
time seemed to increase the degradation of the sensitive N-oxide,
and the material did not give rise to good NMR spectra. 20 (0.30 g,
1.07 mmol) was suspended in toluene (9 ml), BSA (1.60 ml,
6.5 mmol) was added, and the solution was refluxed for 30 min. The
solution was evaporated at reduced pressure, and the residue was
purified by column chromatography by elution with EtOAc/hexane
(1:4) to give 0.13 g (68%) of 21 (mp, 36e38 ꢁC). 1H NMR (800 MHz,
oil. 1H NMR (800 MHz, CDCl3)
d 7.16e7.11 (m, 2H), 6.84e6.80 (m,
2H), 3.78 (s, 3H), 3.60 (t, J ¼ 7.2 Hz, 2H), 3.57 (t, J ¼ 6.1 Hz, 2H), 2.82
(t, J ¼ 7.3 Hz, 2H), 2.53 (t, J ¼ 6.1 Hz, 2H), 2.40 (s, 4H), 1.57 (p,
J ¼ 5.7 Hz, 4H), 1.41 (s, 2H); 13C NMR (201 MHz, CDCl3)
d 24.2, 25.9,
35.3, 55.0, 55.2, 58.5, 68.8, 72.3, 113.7, 129.8, 129.9, 131.0, 158.0;
HRMS ESI þ m/z [MþH]þ Calcd for C16H25NO2, 264.1958; Found,
264.1962.
2-(4-Methoxyphenyl)ethan-1-ol 26 [12] and 1-(2-bromoethyl)-4-
methoxybenzene 27. [12]. BBr3ꢀMe2S (0.96 g, 3.10 mmol) was dis-
solved in DCM (20 ml) under stirring in a N2 atmosphere in a flame-
dried flask. 25 (0.41 g, 1.56 mmol) dissolved in DCM (2 ml) was
added. The solution was stirred for 15 min, poured into a stirred
mixture of NaHCO3 (8 g)/H2O (30 ml)/MeOH (40 ml) and heated to
boiling for 30 min (The DCM was evaporated after 5 min) (It’s very
important to quench TLC-samples with aqueous NaHCO3/MeOH
solution before running TLC, otherwise more 27 will show). NH4OH
(aq) was avoided due to the risk of any formed 27 alkylating NH3
and forming amine. The mixture was cooled and extracted with
DCM (4*15 ml). The combined organic phase was dried with
Na2SO4, filtered and evaporated. The oily residue was purified by
column chromatography by elution with a stepwise gradient of
EtOAc/hexane (1:7), EtOAc, EtOAc/TEA (9:1) to give 0.12 g (70%
based on 0.10 g recovered starting material) of the title compound
as an oil. As determined by careful examination of the TLC plates,
1.0 mg of 27 was isolated. The spectra for both compounds were
consistent with those of commercial samples.
CDCl3)
d
10.47 (s, 1H), 7.46 (t, J ¼ 8.4 Hz, 1H), 6.71 (d, J ¼ 8.5 Hz, 1H),
6.66e6.64 (m, 1H), 6.63 (dd, J ¼ 13.7, 6.0 Hz, 1H), 4.84 (dd, J ¼ 13.7,
2.0 Hz, 1H), 4.55 (dd, J ¼ 6.1, 2.0 Hz, 1H), 3.92 (s, 3H); 13C NMR
(201 MHz, CDCl3)
d 56.1, 97.1, 106.3, 109.0, 115.5, 135.6, 147.5, 159.1,
161.7, 188.7; HRMS ESI þ m/z [MþH]þ Calcd for C10H10O3, 179.0703;
Found, 179.0705. 21 (0.16 g, 0.90 mmol) was dissolved in 90% HOAc
(aq) (7.5 ml). The solution was refluxed for 50 min and then
evaporated under reduced pressure, and the residue was purified
by column chromatography by elution with EtOAc/hexane (1:3) to
give 0.11 g (80%) of the title compound as a semi-crystalline solid.
The spectra were consistent with those of a commercial sample.
1-(2-(3-(2-Cyclohexylethoxy)phenoxy)ethyl)piperidine (23). 17
(0.81 g, 3.66 mmol) was dissolved in DMF (7 ml) under stirring in a
N2 atmosphere. NaH (60% in mineral oil) (0.18 g, 4.50 mmol) was
added, and the mixture was heated to 50 ꢁC. (2-Bromoethyl)
cyclohexane (0.69 ml, 4.41 mmol) was added, and the mixture was
stirred at 40 ꢁC for 60 min. The solution was diluted with H2O
(10 ml) and extracted with Et2O (3*30 ml). The organic phase was
dried with Na2SO4, filtered and evaporated. The residual syrup was
purified by column chromatography by elution with EtOAc/hexane/
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
18

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R. Noren
Tetrahedron 88 (2021) 132108
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Acknowledgments
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The Swedish NMR Centre at the University of Gothenburg is
acknowledged for support.
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19