Conversion of phenols into aryl tert-butyl ethers under mitsunobu conditions utilizing neighboring group contribution

Article abstract of DOI:10.2174/1570178611310010003

Under Mitsunobu conditions N-Boc-2-(hydroxymethyl)piperidine acts as a source of tert-butyl residue for the conversion of phenols into aryl tert-butyl ethers under neutral conditions. This reactivity can be attributed to a neighboring group contribution which strongly depends on the structure of the employed N-Boc-aminoalcohol. Five other, closely related N-Boc-aminoalcohols investigated here did not show this special reactivity, and gave the regular Mitsunobu coupling products.

Full text of DOI:10.2174/1570178611310010003

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2
Letters in Organic Chemistry, 2013, 10, 2-7
Conversion of Phenols into Aryl Tert-Butyl Ethers Under Mitsunobu
Conditions Utilizing Neighboring Group Contribution
Annette Wolfgardt and Franz Bracher*
Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-University, Butenandtstr. 5–13, 81377
Munich, Germany
Received June 29, 2012: Revised October 19, 2012: Accepted October 29, 2012
Abstract: Under Mitsunobu conditions N-Boc-2-(hydroxymethyl)piperidine acts as a source of tert-butyl residue for the
conversion of phenols into aryl tert-butyl ethers under neutral conditions. This reactivity can be attributed to a neighbor-
ing group contribution which strongly depends on the structure of the employed N-Boc-aminoalcohol. Five other, closely
related N-Boc-aminoalcohols investigated here did not show this special reactivity, and gave the regular Mitsunobu cou-
pling products.
Keywords: N-Boc-aminoalcohols, tert-butyl ether, Mitsunobu reaction, neighboring group contribution, protecting group,
stereoselective reaction.
INTRODUCTION
tual source of the tert-butyl residue, we performed a control
experiment in which 1a was reacted with tert-butanol and
the Mitsunobu reagents under identical conditions, but not
even traces of 4a were detected. This is in line with the
known reluctance of tertiary alcohols to undergo Mitsunobu-
type couplings [3]. Consequently, the N-Boc-2-(hydroxy-
methyl)piperidine 2 acts as the tert-butyl group donor under
Mitsunobu conditions.
In a project aimed at the synthesis of new cholesterol
biosynthesis inhibitors we intended to connect selected phe-
nols with N-Boc-protected piperidine moieties through an
ether linkage. In order to accomplish the coupling under mild
reaction conditions, we selected the well established Mitsun-
obu reaction [1] for the synthesis of the ether moiety starting
from the phenols and N-Boc-2-(hydroxymethyl)piperidine
(2).
For this unexpected reaction we propose a mechanism
that includes a neighboring group contribution (Scheme 2).
In the first step, the hydroxymethyl group of 2 undergoes the
standard initial step of Mitsunobu activation, i.e. the forma-
tion of the oxyphosphonium intermediate 5 accompanied by
a phenolate. Nucleophilic attack of the carbonyl oxygen of
the Boc group at the activated side chain methylene carbon
should lead to a fragmentation of the molecule yielding
triphenylphosphane oxide, the cyclic carbamate 6, and a tert-
butyl cation, which itself combines with the phenolate to
give the aryl tert-butyl ether. In fact, we could detect the
carbamate 6 in the reaction mixture by GC-MS. An authentic
sample of 6 was easily obtained from 2-(hydroxymethyl)
piperidine, but by replacing phosgene [4] by less hazardous
triphosgene in analogy to a known protocol [5].
In this communication we report on an unexpected for-
mation of aryl tert-butyl ethers under Mitsunobu conditions,
and give evidence that a neighboring group contribution is
the driving force in this reaction.
RESULTS AND DISCUSSION
The phenol 1a, easily prepared from 3-hydroxy-
benzaldehyde and the corresponding N-methylbenzylamine
by reductive amination with sodium cyanoborohydride as
reducing agent, was reacted with N-Boc-2-(hydroxymethyl)
piperidine (2) under Mitsunobu conditions (triphenylphos-
phane and diisopropyl azodicaboxylate, DIAD) [1]. To our
surprise, the attempted N-Boc-protected piperidinomethyl
ether 3 (R = Cl) could not be detected in the reaction mix-
ture, but we isolated the aryl tert-butyl ether 4a in 29 %
yield. In the same manner the bromo and nitro analogs 4b
and 4c were obtained (Scheme 1). This is in contrast to an
earlier report on a successful coupling of a phenol with 2
under comparable conditions [2]. In order to exclude that
tert-butanol, which might have been a contaminant or de-
composition product of the N-Boc-piperidine 2, was the ac-
The moderate to poor yields of the aryl tert-butyl ethers
can be explained by competing decomposition of the tert-
butyl cation under deprotonation to give isobutene. A related
route to aryl tert-butyl ethers via an intramolecular transfer
of a tert-butyl residue from a Boc-anhydride intermediate
has been described, but this method requires activation by a
Lewis acid (magnesium perchlorate) [6]. The loss (but not
further utilization) of a tert-butyl cation by an intramolecular
attack at the carbonyl oxygen of a Boc-protected sugar end-
ing up with a cyclic carbonate has been observed [7]; a simi-
lar mechanism has been claimed for iodocyclisations of ho-
moallylic tert-butyl carbonates [8].
*Address correspondence to this author at the Department of Pharmacy –
Center for Drug Research, Ludwig-Maximilians-University, Butenandtstr.
5–13, 81377 Munich, Germany; Tel: +49-89-218077301; Fax: +49-89-
218077802; E-mail: Franz.Bracher@cup.uni-muenchen.de
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

Synthesis of Aryl tert-butyl Ethers
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
3
N
R
O
3
N
N
Ph3P, DIAD
THF, r.t.
+
Boc
OH
R
N
N
O
O
OH
R
1a R = Cl
1b R = Br
1c R = NO2
2
4a R = Cl
4b R = Br
O
4c R = NO2
Scheme 1. Unexpected formation of aryl tert-butyl ethers.
Ph3P
DIAD
Ar-OH
O
OH
+ Ph3PO
N
PPh3
N
N
O
O
O
O
O
O
+ Ar-O
+
6
2
5
Ar
O
Scheme 2. Proposed mechanism of the neighboring group contribution.
In order to explore whether this unexpected reactivity
found for 2 is common to other N-Boc-aminoalcohols, we
reacted phenol 1a in the same manner with the five-
membered ring analogue N-Boc-2-(hydroxymethyl)pyrroli-
dine 7, the side-chain homologue N-Boc-2-(2-hydroxyethyl)
piperidine 8, the open-chain N-Boc-aminoethanols 9 and 10,
as well as N-Boc-3-hydroxypiperidine (11), in which an in-
tramolecular activation as proposed above cannot take place
for steric reasons. In all five experiments we obtained the
regular Mitsunobu products (12 - 16) resulting from coupling
of the phenol 1a with the hydroxyl groups of the N-Boc-
aminoalcohols. The ethers derived from the primary alcohols
were obtained in 50 to 83 % yield, the secondary alkyl ether
16 in 31 % yield. In neither of these reactions the tert-butyl
ether 4a was detected (Scheme 3).
hydroxybenzoate with 2, triphenylphosphane, and DIAD
gave the tert-butyl ethers 17 - 19 in 21 to 30 % yields
(Scheme 4). We undertook several attempts to improve the
yields of the tert-butyl ethers (higher amounts of reagents;
higher concentrations; isobutene as a solvent to reduce de-
composition of the tert-butyl cation), but did not obtain
considerably better yields.
In conclusion, we have detected a neighboring group
contribution in Mitsunobu reactions leading to the conver-
sion of phenols into aryl tert-butyl ethers. In principle, this
constitutes a new method for the protection of phenols under
very mild, neutral conditions, whereas established protocols
require either alkaline conditions (for the conversion to a
phenolate, followed by O-alkylation with a tert-butyl halide
[9]), or acidic conditions (mineral acids, Lewis acids) in
combination with tert-butanol or isobutene [6, 10, 11].
Working under strongly acidic conditions further bears the
risk of undesired C-alkylation of the substrate phenols [9b,
12]. But due to the poor yields an application of this method
will be restricted to the protection of phenols which are both
acid- and base-sensitive.
This leads to the conclusion that the unexpected reactiv-
ity of 2 with phenols under Mitsunobu conditions is not only
due to the proximity of both the primary alcohol and N-Boc
groups, but is significantly controlled by steric parameters.
This is particularly illustrated by the differences in reactivity
observed with 2 and its five-membered ring homologue 7, its
side chain homologue 8, and the failure of flexible open-
chain analogues to release the tert-butyl residue.
EXPERIMENTAL SECTION
Finally, we demonstrated that this new tert-butylation
protocol also works with other phenols bearing additional
functional groups. Reacting 2-naphthol, vanillin, and ethyl 4-
Melting points (uncorrected): Büchi B-540. IR spectra:
Perkin Elmer FT-IR Paragon 1000. Mass spectra: JMS

4
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
Wolfgardt and Bracher
stirred for 18 h at room temperature. The solvent was evapo-
rated, the residue was suspended in satd. Na2CO3 solution
(100 mL), and extracted with dichloromethane (3 x 50 mL).
The combined organic layers were dried over sodium sulfate
and evaporated. The residue was purified by flash column
chromatography (1:1 hexane/ethyl acetate with 2 % N-ethyl-
N,N-dimethylamine).
N
1a,
Ph3P, DIAD
Cl
OH
N
Boc
O
N
12
7
Boc
3-[N-(4-Chlorobenzyl)-N-methylaminomethyl]phenol
(1a)
N
1a,
Prepared following General Procedure 1 using N-methyl-
4-chlorobenzylamine. Yield: 79 %. mp 61-63 °C. IR (KBr) ꢀ
(cm-1) = 2792, 1589, 1489, 1456, 1273, 1089, 1015. 1H NMR
(500 MHz, CD2Cl2): ꢀ 7.30 (m, 4H), 7.16 (t, J = 7.8 Hz, 1H),
6.88 (m, 1H), 6.86 (m, 1H), 6.71 (m, 1H), 3.47 (s, 2H), 3.44
(s, 2H), 2.13 (s, 3H, N-CH3). 13C NMR (100 MHz, CD2Cl2):
ꢀ 156.5, 141.5, 138.5, 132.8, 130.7, 129.7, 128.6, 121.3,
116.1, 114.4, 61.9, 61.3, 42.3. HRMS calculated for
C15H16ClNO: 261.0920; found 261.0932.
Ph3P, DIAD
Cl
N
Boc
N
Boc
OH
O
13
8
N
1a,
Ph3P, DIAD
R
OH
Cl
N
R
N
3-[N-(4-Bromobenzyl)-N-methylaminomethyl]phenol
(1b)
Boc
Boc
9
R = H
N
14 R = H
15 R = CH3
10 R = CH3
O
Prepared following General Procedure 1 using N-methyl-
4-bromobenzylamine. Yield: 83 %. mp 58-60 °C. IR IR
(KBr) ꢀ (cm-1) = 2789, 1589, 1486, 1458, 1273, 1070, 1011.
1H NMR (400 MHz, CD2Cl2): ꢀ 7.45 (m, 2H), 7.27 (m, 2H),
7.17 (t, J = 7.8 Hz, 1H), 6.90 (m, 1H), 6.85 (m, 1H), 6.70 (m,
1H), 3.46 (s, 2H), 3.45 (s, 2H), 2.13 (s, 3H, N-CH3). 13C
NMR (125 MHz, CD2Cl2): ꢀ 156.9, 141.6, 139.1, 131.6,
131.1, 129.7, 121.0, 120.8, 116.1, 114.4, 61.9, 61.4, 42.3.
HRMS calculated for C15H16BrNO: 305.0415; found
305.0401.
1a,
Ph3P, DIAD
OH
Cl
Boc
N
Boc
N
11
O
16
Scheme 3. Control experiments with other N-Boc-aminoalcohols
leading to regular Mitsunobu products. All experiments were per-
formed in THF at room temperature.
3-[N-Methyl-N-(4-nitrobenzyl)aminomethyl]phenol (1c)
Prepared following General Procedure 1 using N-methyl-
GCmate II Jeol. NMR spectra: JNM-Eclipse+400 (1H NMR:
400 MHz, 13C NMR 100 MHz) and JNM-Eclipse+500 (1H
NMR: 500 MHz, 13C NMR: 125 MHz); chemical shifts are
reported in parts per million (ppm), tetramethylsilane (TMS,
0.00 ppm) as internal standard. Flash column chromatogra-
phy: silica gel 60 (0.040-0.063 mm; Merck). Solvents were
dried using standard procedures and freshly distilled prior to
use.
4-nitrobenzylamine. Yield: 89 %. mp 106-108 °C. IR (KBr)
1
ꢀ (cm-1) = 2925, 1607, 1585, 1513, 1341, 1099, 1005. H
NMR (500 MHz, CD2Cl2): ꢀ 8.16 (m, 2H), 7.57 (m, 2H),
7.18 (t, J = 7.9 Hz, 1H), 6.91 (m, 1H), 6.88 (m, 1H), 6.72 (m,
1H), 3.60 (s, 2H), 3.50 (s, 2H), 2.17 (s, 3H, N-CH3). 13C
NMR (100 MHz, CD2Cl2): ꢀ 156.3, 148.0, 147.5, 141.4,
129.8, 129.8, 123.8, 121.5, 115.9, 114.4, 62.1, 61.3, 42.5.
HRMS calculated for C15H16N2O3: 272.1161; found
272.1160.
General
Procedure
1: Synthesis
of the 3-
(aminomethyl)phenols 1a-c
General Procedure 2: Synthesis of aryl tert-butyl ethers
4a - 4c
3-Hydroxybenzaldehyde (20 mmol) and the correspond-
ing N-methylbenzylamine (8 mmol) were dissolved in
methanol (5 mL). Acetic acid (0.4 mL) and sodium cyano-
borohydride (16 mmol) were added and the mixture was
tert-Butyl 2-(hydroxymethyl)piperidine-1-carboxylate (2;
5 mmol), the corresponding phenol 1a-c (5 mmol), and
O
O
O
O
H
OC2H5
O
O
17
18
19
Scheme 4. Further aryl tert-butyl ethers obtained from phenols using the reagent combination 2/Ph3P/DIAD.

Synthesis of Aryl tert-butyl Ethers
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
5
triphenylphosphane (5 mmol) were dissolved in anhydrous
THF (7 mL), and diisopropyl azodicarboxylate (DIAD; 5
mmol) was added dropwise and the mixture was stirred for
18 h at room temperature. After evaporation of the volatile
components the product was purified by flash column chro-
matography (hexane with 2% N-ethyl-N,N-dimethylamine).
GC-MS analysis of 6: A Shimadzu GC 17-A with Shi-
madzu GCMS OP-5000 was equipped with a Varian Factor
Four EZ Guard VF 5 MS column (30 m x 0.25 mm x 0.25
ꢀm). The injector was held at 280 °C and operated in split
mode (split ratio: 1:68). The GC-MS conditions were as fol-
lowing: helium 5.0, constant flow of 1.3 mL min-1, linear
velocity 42.4 cm sec-1, injection volume 1 ꢀL, MS transfer
line temperature 280 °C. The initial GC oven temperature
was 100 °C held for 1 min, and ramped with 15 °C min-1 to
310 °C (hold time 5 min). The total run time was 20.0 min.
The MS was operated at a mass range from 100 to 500 m/z.
Retention time of 6: 5.66 min.
N-(3-tert-Butoxybenzyl)-1-(4-chlorophenyl)-N-
methylmethanamine (4a)
Prepared from 1a following General Procedure 2. Yield:
29 %. Viscous oil. IR (NaCl, film) ꢀ (cm-1) = 2977, 2786,
1600, 1489, 1365, 1260, 1145. 1H NMR (400 MHz, CD2Cl2):
ꢀ 7.30 (m, 4H), 7.20 (t, J = 7.8 Hz, 1H), 7.05 (m, 1H), 7.00
(m, 1H), 6.86 (m, 1H), 3.47 (s, 4H), 2.13 (s, 3H, N-CH3),
1.32 (s, 9H, (C(CH3)3). 13C NMR (125 MHz, CD2Cl2): ꢀ
155.9, 140.8, 138.8, 132.7, 130.6, 128.9, 128.6, 124.9, 124.1,
123.0, 78.5, 62.0, 61.2, 42.3, 29.0. HRMS calculated for
C19H24ClNO: 317.1546; found 317.1554.
Analysis of the reaction leading to 4a: 5.33 min: reduced
DIAD (diisopropyl hydrazodicarboxylate); 5.69 min: 6; 6.29
min: 2; 11.08 min: 1a; 11.15 min: 4a; 12.86 min: triphenyl-
phosphane oxide.
General Procedure 3: Regular Mitsunobu couplings giv-
ing ethers 12 - 16
Phenol 1a (1.5 mmol), the corresponding N-Boc-
aminoalcohol (7/8/9/10/11; 1.5 mmol), and triphenylphos-
phane (1.5 mmol) were dissolved in anhydrous THF (5 mL).
Diisopropyl azodicarboxylate (1.5 mmol) was added drop-
wise and the mixture was stirred for 18 h at room tempera-
ture. After evaporation of the volatile components the prod-
uct was purified by flash column chromatography (hexane
with 2 % triethylamine).
1-(4-Bromophenyl)-N-(3-tert-butoxybenyl)-N-
methylmethanamine (4b)
Prepared from 1b following General Procedure 2. Yield:
29 %. Viscous oil. IR (NaCl, film) ꢀ (cm-1) = 2976, 1601,
1485, 1365, 1260, 1176, 1145 1H NMR (500 MHz, CD2Cl2):
ꢀ 7.44 (m, 2H), 7.26 (m, 2H), 7.20 (t, J = 7.8 Hz, 1H), 7.05
(m, 1H), 7.00 (m, 1H), 6.86 (m, 1H), 3.47 (s, 2H), 3.45 (s,
2H), 2.13 (s, 3H, N-CH3), 1.32 (s, 9H, (C(CH3)3). 13C NMR
(100 MHz, CD2Cl2): ꢀ 155.9, 140.8, 139.3, 131.6, 131.0,
128.9, 124.9, 124.1, 123.0, 120.8, 78.5, 62.0, 61.3, 42.3,
29.0. HRMS calculated for C19H24BrNO: 361.1041; found
361.1058.
(S)-tert-Butyl 2-{3-[N-(4-chlorobenzyl)-N-methylamino-
methyl]phenoxymethyl}pyrrolidine-1-carboxylate (12)
Prepared following General Procedure 3 using (S)-tert-
butyl
2-(hydroxymethyl)pyrrolidine-1-carboxylate
(7).
Yield: 50 % yield. Viscous oil. IR (NaCl, film) ꢀ (cm-1) =
N-(3-tert-Butoxybenzyl)-N-methyl-1-(4-
nitrophenyl)methanamine (4c)
1
2975, 1693, 1585, 1489, 1392, 1365, 1167. H NMR (400
MHz, CD2Cl2): ꢀ 7.31 (m, 4H), 7.21 (m, 1H), 6.93 (m, 2H),
6.82 (m, 1H), 4.11 (m, 2H), 3.87 (m, 1H), 3.46 (s, 4H), 3.36
(m, 2H), 2.13 (s, 3H, N-CH3), 2.00 (m, 3H), 1.85 (m, 1H),
1.45 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CD2Cl2): ꢀ
159.4, 153.0, 141.5, 138.7, 132.7, 130.6, 129.5, 128.6, 121.6,
115.4, 113.2, 79.5, 68.6, 62.1, 61.3, 56.5, 47.1, 42.3, 28.8,
28.6, 23.7. HRMS calculated for C25H33ClN2O3: 444.2180;
found 444.2160.
Prepared from 1c following General Procedure 2. Yield:
28 %. Viscous oil. IR (NaCl, film) ꢀ (cm-1) = 2976, 1601,
1
1520, 1484, 1245, 1260, 1176, 1145. H NMR (400 MHz,
CD2Cl2): ꢀ 8.16 (m, 2H), 7.56 (m, 2H), 7.21 (t, J = 7.7 Hz,
1H), 7.07 (m, 1H), 7.02 (m, 1H), 6.87 (m, 1H,), 3.59 (s, 2H),
3.52 (s, 2H), 2.18 (s, 3H, N-CH3), 1.32 (s, 9H, (C(CH3)3). 13
C
NMR (100 MHz, CD2Cl2): ꢀ 156.0, 148.3, 147.5, 140.5,
129.7, 129.0, 124.9, 124.1, 123.8, 123.2, 78.6, 62.2, 61.2,
42.5, 29.0. HRMS calculated for C19H24N2O3: 328.1787;
found 328.1800.
tert-Butyl N-{3-[N-(4-chlorobenzyl)-N-methylamino-
methyl]phenoxyethyl}-N-methylcarbamate (15)
Tetrahydro-1H-oxazolo-[3,4-a]pyridin-3(5H)-one (6)
Prepared following General Procedure 3 using tert-butyl
N-(2-hydroxyethyl)-N-methylcarbamate (10). Yield: 73 %.
Viscous oil. IR (NaCl, film) ꢀ (cm-1) = 2928, 1695, 1488,
2-(Hydroxymethyl)piperidine (2.0 mmol) and triethyl-
amine (6.0 mmol) were dissolved in anhydrous dichloro-
methane (3 mL). A solution of triphosgene (1.0 mmol) in
anhydrous dichloromethane (1 mL) was added dropwise, and
the mixture was stirred for 3 h at room temperature. The sol-
vent was evaporated at room temperature and the residue
purified by flash column chromatography (1:1 hexane/ethyl
acetate with 2 % triethylamine). The fractions were not
evaporated to complete dryness, since the product tends to-
wards polymerisation [4]. The mass spectrum corresponded
to the one published in lit [4].
1
1451, 1391, 1365, 1154. H NMR (500 MHz, CD2Cl2): ꢀ
7.30 (m, 4H), 7.22 (m, 1H), 6.93 (m, 2H), 6.78 (m, 1H), 4.07
(m, 2H), 3.58 (m, 2H), 3.47 (s, 2H), 3.46 (s, 2H), 2.95 (s,
3H, N-CH3), 2.13 (s, 3H, N-CH3), 1.43 (m, 9H, C(CH3)3).
13C NMR (125 MHz, CD2Cl2): ꢀ 159.3, 155.9, 141.6, 138.8,
132.7, 130.6, 129.5, 128.6, 121.7, 115.2, 113.2, 79.6, 66.7,
62.1, 61.3, 48.7, 42.4, 35.9, 28.5. HRMS calculated for
C23H31ClN2O3: 418.2023; found 418.2023.

6
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
Wolfgardt and Bracher
tert-Butyl N-{3-[N-(4-chlorobenzyl)-N-methylamino-
methyl]phenoxyethyl}carbamate (14)
4-(tert-Butoxy)-3-methoxybenzaldehyde (18)
Prepared following General Procedure 4 from vanillin.
Yield: 21 %. The spectroscopic data correspond to those
published in lit. [13].
Prepared following General Procedure 3 using tert-butyl
N-(2-hydroxyethyl)carbamate (9). Yield: 73 %. Viscous oil.
IR (NaCl, film) ꢀ (cm-1) = 2977, 1710, 1585, 1490, 1365,
1
1252, 1167. H NMR (500 MHz, CD2Cl2): ꢀ 7.30 (m, 4H),
Ethyl 4-(tert-butoxy)benzoate (19)
7.22 (m, 1H), 6.93 (m, 2H), 6.78 (m, 1H), 5.03 (s, 1H, NH),
4.01 (m, 2H), 3.51 (m, 2H), 3.47 (s, 4H), 2.13 (s, 3H, N-
CH3), 1.43 (s, 9H, C(CH3)3). 13C NMR (125 MHz, CD2Cl2):
ꢀ 159.2, 156.2, 141.7, 138.7, 132.7, 130.6, 129.6, 128.6,
121.8, 115.2, 113.2, 79.5, 67.5, 62.1, 61.4, 42.3, 40.6, 28.5.
HRMS calculated for C22H29ClN2O3: 404.1867; found
404.1876.
Prepared following General Procedure 4 from ethyl 4-
hydroxybenzoate. Yield: 21 %. Viscous oil. IR (NaCl, film)
ꢀ (cm-1) = 2979, 1715, 1605, 1367, 1275, 1159, 1098. H
1
NMR (400 MHz, CD2Cl2): ꢀ 7.93 (m, 2H), 7.01 (m, 2H),
4.31 (q, J = 7.1 Hz, 2H), 1.39 (s, 9H, C(CH3)3), 1.36 (t, J =
7.1 Hz, 3H).13C NMR (100 MHz, CD2Cl2): ꢀ 166.6, 160.5,
131.0, 125.2, 122.9, 79.8, 61.1, 29.0, 14.6. HRMS calculated
for C13H18O3: 222.1256; found 222.1265.
tert-Butyl 3-{3-[N-(4-chlorobenzyl)-N-methylamino-
methyl]phenoxyethyl}piperidine-1-carboxylate (13)
CONFLICT OF INTEREST
Prepared following General Procedure 3 using tert-butyl
2-(hydroxyethyl)piperidine-1-carboxylate (8). Yield: 83 %
yield. Viscous oil. IR (NaCl, film) ꢀ (cm-1) = 2977, 2932,
1697, 1418, 1366, 1240, 1167. 1H NMR (400 MHz, CD2Cl2):
ꢀ 7.30 (m, 4H), 7.20 (m, 1H), 6.91 (m, 2H), 6.74 (m, 1H),
4.47 (m, 1H), 3.92 (m, 3H), 3.46 (s, 4H), 2.80 (m, 1H), 2.23
(m, 1H), 2.12 (s, 3H, N-CH3), 1.84 (m, 1H), 1.60 (m, 6H),
1.36 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CD2Cl2): ꢀ
159.5, 155.2, 141.5, 138.7, 132.7, 130.6, 129.5, 128.6, 121.3,
115.1, 113.2, 79.2, 65.6, 62.2, 61.3, 48.2, 42.3, 39.0, 30.0,
29.4, 28.5, 26.1, 19.5. HRMS calculated for C27H37ClN2O3:
472.2493; found 472.2491.
The author(s) confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
Declared none.
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Kyle, J. A.; Klimkowski, V. J.; Smith, G. F.; Towner, R. D.;
Froelich, L. L.; Buben, J.; Craft, T. J. Anthranilamide inhibitors of
factor Xa. Bioorg. Med. Chem. Lett., 2007, 17, 4832-4836; no ex-
perimental details and analytical data are presented in this publica-
tion.
tert-Butyl 3-{3-[N-(4-chlorobenzyl)-N-methylamino-
methyl]phenoxy}piperidine-1-carboxylate (16)
Prepared following General Procedure 3 using tert-butyl
3-hydroxypiperidine-1-carboxylate (11). Yield: 31 %. Vis-
cous oil. IR (NaCl, film) ꢀ (cm-1) = 2929, 1694, 1488, 1422,
1
1365, 1258, 1146. H NMR (500 MHz, CD2Cl2): ꢀ 7.30 (m,
[3]
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(a) Shi, Y.-J.; Hughes, D. L.; McNamara, J. M. Stereospecific
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4H), 7.22 (m, 1H), 6.94 (m, 2H), 6.80 (m, 1H), 4.26 (m, 1H),
4.03–3.00 (m, 4H), 3.47 (s, 4H), 2.14 (s, 3H, N-CH3), 2.00
(m, 1H), 1.81 (m, 1H), 1.46 (m, 2H), 1.34 (m, 9H, C(CH3)3).
13C NMR (100 MHz, CD2Cl2): ꢀ 157.9, 155.0, 141.7, 138.7,
132.7, 130.6, 129.6, 128.6, 121.7, 116.5, 114.4, 79.6, 71.3,
62.1, 61.3, 47.8, 43.9, 42.4, 30.4, 28.4, 22.6. HRMS calcu-
lated for C25H33ClN2O3: 444.2180; found 444.2179.
[5]
[6]
General Procedure 4: Synthesis of aryl tert-butyl ethers
17 - 19
Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre,
P.; Sambri, L. Unusual and unexpected reactivity of t-butyl dicar-
bonate (Boc2O) with alcohols in the presence of magnesium per-
chlorate. A new and general route to t-butyl ethers. Org. Lett.,
2005, 7, 427-430.
tert-Butyl 2-(hydroxymethyl)piperidine-1-carboxylate (2;
1.5 mmol), the corresponding phenol (1.5 mmol), and
triphenylphosphane (1.5 mmol) were dissolved in anhydrous
THF (5 mL). Diisopropyl azodicarboxylate (1.5 mmol) was
added dropwise and the mixture was stirred for 18 h at room
temperature. After evaporation of the volatile components
the product was purified by flash column chromatography
(9:1 hexane/ethyl acetate).
[7]
[8]
[9]
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2-(tert-Butoxy)naphthalene (17)
Prepared following General Procedure
4 from 2-
naphthol. Yield: 30 % yield. The spectroscopic data corre-
spond to those published in lit [9d].

Synthesis of Aryl tert-butyl Ethers
cient synthesis of tert-butyl ethers under solvent-free conditions.
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
7
[11]
Bartoli, G.; Bosco, M.; Carlone, A.; Dalpozzo, R.; Locatelli, M.;
Melchiorre, P.; Sambri, L. Alcohols and di-tert-butyl dicarbonate:
How the nature of the Lewis acid catalyst may address the reaction
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9588.
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[12]
[13]
Ploypradith, P.; Cheryklin, P.; Niyomtham, N.; Bertoni, D. R.;
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