Lewis acid mediated intramolecular C-O bond formation of alkanol-epoxide leading to substituted morpholine and 1,4-oxazepane derivatives: Total synthesis of (±)-Viloxazine

Article abstract of DOI:10.1016/j.tet.2015.12.015

Substituted morpholines have been efficiently synthesised in good yields from nitrogen tethered alkanol-epoxide mediated by boron trifluoride etherate. The methodology has been used for the total synthesis of (±)-viloxazine.

Full text of DOI:10.1016/j.tet.2015.12.015

Accepted Manuscript
Lewis Acid Mediated Intramolecular C-O Bond Formation of Alkanol-Epoxide Leading
to Substituted Morpholine Derivatives: Total Synthesis of (+) - Viloxazine
Priya Ghosh, Manash J. Deka, Anil K. Saikia
PII:
S0040-4020(15)30265-9
10.1016/j.tet.2015.12.015
TET 27341
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 October 2015
Revised Date: 21 November 2015
Accepted Date: 7 December 2015
Please cite this article as: Ghosh P, Deka MJ, Saikia AK, Lewis Acid Mediated Intramolecular C-O Bond
Formation of Alkanol-Epoxide Leading to Substituted Morpholine Derivatives: Total Synthesis of (+) -
Viloxazine, Tetrahedron (2016), doi: 10.1016/j.tet.2015.12.015.
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Lewis acid mediated intramolecular C-O
bond formation of alkanol-epoxide leading to
substituted morpholine and 1,4-oxazepane
derivatives: Total synthesis of (+) -viloxazine
Leave this area blank for abstract info.
Priya Ghosh, Manash J. Deka and Anil K. Saikia*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India

1
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Tetrahedron
journal homepage: www.elsevier.com
Lewis acid mediated intramolecular C-O bond formation of alkanol-epoxide leading
to substituted morpholine and 1,4-oxazepane derivatives: Total synthesis of (+) -
viloxazine
Priya Ghosh, Manash J. Deka and Anil K. Saikia*
aDepartment of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Intramolecular cyclization of nitrogen tethered alkanols and epoxides mediated by boron
trifluoride etherate leads to substituted morpholines and 1,4-oxazepanes in good yields.
The methodology has been used for the total synthesis of (+)-viloxazine.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Lewis acid
Intramolecular
Alkanol-epoxide
Morpholine
Viloxazine
1. Introduction
Over the years, several synthetic approaches have been
developed for the preparation of morpholines such as ring closure
of amino diols,7 amino alcohols and sulfonium salts,8 double
allylic substitution by amino alcohols,9 cyclization of N-tethered
haloalcohols,10 reductive amination of diketones,11 reductive
etherification of N-tethered ketoalcohols,12 cyclization of O-
protected amino alcohols,13 oxirane ring opening by tosylamide
and subsequent cyclization,14 ring opening of aziridines,15
palladium catalyzed coupling of O-allylethanolamines and aryl
and alkenyl halide16 and intramolecular cyclization of N-tethered
alkene-alkanol.17 Moreover, there are also reports of
intramolecular cyclization of alkanol epoxide using strong bases
such as NaOMe,18 KOH/NaOH19 and Lewis acid like Cu(OTf)2.20
Although, many synthetic methodologies have been developed,
some of them suffer from serious problems of low yields10c,11,14
strong bases,18,19 long reaction time,18 metal triflates20 and harsh
reaction conditions.17a Therefore, there is a need for the protocol
which facilitates the preparation in good yields, mild reaction
condition and with a choice of wide variety of substrates.
Of the various nitrogen heterocyles known, morpholine
derivatives are of particular importance. Substituted morpholine
derivatives are widely distributed in many naturally occurring
and biologically active molecules.1 Many compounds of this
class have shown notable biological properties, for example,
viloxazine (1), reboxetine (2) and edivoxetine (3) show
antidepressant properties.2 Similarly, the compounds 4 and 5
containing morpholine unit have anti-inflammatory and GABAB
receptor-antagonist properties.3 Morpholines are not only used in
organic synthesis as bases or N-alkylating agents4 but also used
as versatile synthetic units in organic synthesis particularly for
the construction of agrochemical, fungicides and bactericides.5
They are also used as chiral auxiliary in some chemical
transformations.6
F
EtO
O
EtO
OMe
O
OH
H
H
O
Recently, we have developed a methodology for the synthesis
of oxygen and nitrogen heterocyclic compounds via
intramolecular C-C bond formation of alkyne-epoxide mediated
O
O
O
N
H
N
H
N
H
Reboxetine (2)
Edivoxetine (3)
1
)
Viloxazine (
by boron trifluoride etherate.21 This paper presents
a
Cl
Cl
methodology for the synthesis of morpholines, using
intramolecular C-O bond formation of alkanol-epoxide mediated
by boron trifluoride etherate at ambient temperature in moderate
to good yields. Furthermore, to demonstrate the scope of the
reaction we have also prepared (+)-viloxazine, an anti-depressant
agent in a very good yield.
H
O
N
N
O
NO2
N
O
H
P
H
H
O
OH
N
N
O
(4)
O
(5)
Fig. 1. Biologically important morpholines

2
Tetrahedron
2. Results and discussion
methyl substituent at C-2 14c showed a clear characteristic NOE
ACCEPTED MANUSCRIPT
correlation between the position. There is another NOE
correlation between the hydrogens of C-5Me and two hydrogens
of -CH2OH at C-2 position of 7c. Substrate 10d
To start with, alkanol epoxide 10a was treated with 1.2
equivalents of boron trifluoride etherate in dichloromethane at
room temperature for 1.5 and (4-Tosylmorpholin-2-yl)
h
methanol 14a was obtained in 78% yield. The reaction was also
performed using different Lewis acids and Brønsted acids and the
results are shown in Table 1. The reaction with metal triflates
such as Zn(OTf)2, Cu(OTf)2 and In(OTf)3 (entries 3-5) gave 30,
15 and19% yields, respectively. Bi(OTf)3 produced 40% of the
product, Sc(OTf)3 was found to be poor for the reaction resulting
only trace amount of the desired product (entry 10). On the other
hand, metal salts InCl3 (entry 2) gave 46%, whereas FeCl3
produced only trace amount (entry 11). Brønsted acids such as
camphor sulfonic acid (CSA) and triflic acid (TfOH) gave 33%
and 52% yields, respectively. Strong Lewis acid Trimethylsilyl
trifluoromethanesulfonate (TMSOTf) (entry 8) failed to produce
the desired product, instead starting material was found to be
decomposed.
Table 1
Optimization of the reaction condition
Ts
Ts
N
N
reagent
O
CH2Cl2
0 oC to rt
OH
HO
O
14a
10a
yield (%)a
reagent (mmol)
entry
.
1
78
BF3 OEt2 (1.2)
46
2
InCl3 (1.0)
3
4
Zn(OTf)2 (1.0)
Cu(OTf)2 (1.0)
30
15
Scheme 1. Synthesis of starting materials
R"
8
Br
Ts
R'
In(OTf)3 (1.0)
CSA (1.2)
5
6
7
8
19
33
TsCl / Et3N
R
N
R
NH2
OH
R
NHTs
OH
K2CO3 / acetone
reflux
CH2Cl2
rt
R"
9
HO
R'
TfOH (1.2)
52
--b
6
7
mCPBA
CH2Cl2
0 oC to rt
TMSOTf (1.0)
R = H, Me
R' = R" =H, Me, Ph
40
9
Bi(OTf)3 (1.0)
Sc(OTf)3 (1.0)
FeCl3 (1.0)
trace
10
11
Ts
R
N
trace
O
aYield refers to isolated yield. bDecomposed.
R"
10
HO
R'
gave two separable diastereomers 14d and 14d’ in 40 and 42%
yields, respectively. The stereochemistry of the two
diastereomers was determined by NOE experiment. There is a
NOE correlation between hydrogen C-6H and hydrogens of
methyl (-CH3) substituent at C-2 position of compound 14d´
(Figure 2). Again there is a NOE correlation between two
hydrogens of C-2CH2OH and hydrogens of C-6Me of 14d´.
R
MeNO2
12
R
TsCl / Et3N
Zn/ NH4HCO2
R
RCHO
HO
NO2
MeOH
KOH/ i-PrOH
HO
NH2
CH2Cl2
rt
HO
NHTs
7
11
13
6
NaH / DMF
0 oC to rt
Br
R = alkyl, aryl
8
Ts
N
Ts
N
mCPBA
NOE
NOE
O
R
OH
R
Ts
CH2Cl2
0 oC to rt
Ts
HO
Ts
N
Ts
N
N
N
10
9
Me
H
H3C
HO
H
HO
H
H
OH
NOE
OH
O
O
O
H
CH3
O
CH3
NOE
Once optimized conditions were obtained, we further
examined the scope of the reaction with variety of substrates 10a-
10m, which were prepared as per literature methods (Scheme 1).
For the synthesis of N-tethered primary alkenol, commercially
available ethanol amine was treated with tosyl chloride in
dichloromethane to afford corresponding N-tosylated ethanol
amine, which was coupled with allyl bromide using potassium
carbonate as base.22 On the other hand, the secondary alcohol was
synthesized using Henry reaction and subsequent reduction of
nitro group to amine, which was then coupled with allyl bromide
using sodium hydride as base. The N-tethered alkenol was then
treated with m-chloroperbenzoic acid to give corresponding
epoxide.23 It was observed from the Table 2 that terminal
epoxides (entries 1-10) gave the desired morpholines whereas
1,2-disubstituted epoxides (entries 11-13) produced 1,4-
oxazepanes in good yields. It has been observed that yield is
determined by the nature of the substituent present in the
substrates. Alkanol epoxides 10a-c gave single isomer in 14a-c in
78, 80 and 72% yields, respectively. The relative stereochemistry
of compound 14c was determined from the NOE experiment
(Figure 2). The compound hydrogen C-5H and hydrogens of
NOE
NOE
14d'
14c
15m'
15l'
Fig. 2. NOE of compounds 14c, 14d´, 15l and 15m'
The formation of compounds 14c, 14d and 14d’ may be due to
the stability imparted by hydrogen bonding between the hydroxyl
group and the tertiary amine group (Figure 3). The starting
material for the synthesis of 14c is a chiral compound 10c and
therefore, it produces only single diastereomer 14c, whereas
diastereomeric mixture 10d produces both the diastereomers
hydrogen
bonding
hydrogen
bonding
hydrogen
bonding
O
O
O
H
N
H
N
H
N
H
Me
Ts
Ts
Ts
Me
Me
Me
Me
O
O
O
Me
H
14d'
H
14c
14d
Fig. 3. NOE of compounds 14c, 14d and 14d´

3
14d and 14d’ (Figure 3). On the other hand, substrates 10e-i
ACCEPTED MANUSCRIPT
Product 14/15
Yield (%)a
48
dr
Substrate 10
Sl.No.
furnished two inseparable diastereomers each with varied ratios.
Substrate 10j gave single isomer 14j with very good yield (95%).
Epoxide 10k-m having terminal groups produced seven
membered 1,4- oxazepanes. Epoxide 10k furnished only anti
diasteromer 15k with 48% yield
Ts
N
Ts
N
11
O
HO
OH
O
15k
10k
Ts
N
Ts
N
48
HO
O
O
OH
15l
12
10l
Ts
N
HO
35
O
15l'
Ts
N
Ts
N
15
51
13
HO
O
O
OH
15m
10m
Ts
N
Fig. 4. ORTEP diagram of compound 15k with 45% probability
ellipsoid
HO
O
15m'
Table 2
Ts
N
9:1
Synthesis of morpholines
25
OH
O
14m
a Yield refers to isolated yield. All the products were characterized by 1H, 13C NMR and
Mass spectrometry. bInseparable mixture of diastereomers. Ratio was determined by 1H NMR.
Product 14/15
Yield (%)a
78
dr
and 10l gave separable diastereomers 15l and 15l' with 48% and
35% yields, respectively. The relative stereochemistry of 15k
was determined from coupling constant (C-7H, 4.43ppm, J = 7.8
Hz) and X-ray crystallographic analysis (Figure 4).24 The relative
stereochemistry of compounds 15l and 15l' was determined from
NOE experiment of 15l'. There is a NOE correlation between
hydrogen C-7H and hydrogens of methyl (-CH3) substituent at C-
6 position of compound 15l' (Figure 2). The compound 10m
having terminal methyl group gave three isolable compounds,
two of which are diastereomeric oxazepanes 15m and 15m´ with
15% and 51% yields, respectively, and six membered
diastereomeric mixture 14m with a ratio of 9:1 and 25% overall
yield. The relative stereochemistry of these two compounds is
determined from NOE experiment of 15m´ (Figure 2). There was
no NOE between C-6H proton and protons of methyl group at C-
7Me, which indicates that OH group at C-6 and Me at C-7 are cis
to each other.
Substrate 10
Sl.No.
1
Ts
N
Ts
N
O
OH
O
OH
14a
10a
Ts
N
Ts
N
2
3
14b
O
O
OH
80
OH
10b
Ts
N
Ts
N
14c
OH
O
OH
O
72
40
10c
10d
Ts
Ts
N
N
4
O
OH
14d
H
O
OH
Ts
N
42
75
OH
14d'
O
H
Ts
N
Ts
N
5
6
O
OH
O
OH
The mechanism of formation of morpholine and oxazepanes can
be rationalized by considering the formation of different stable
carbocations. The boron trifluoride etherate opens the
monosubstituted terminal epoxide ring of 10 to give more stable
1:1
10e
14e
Ts
N
Ts
N
O
OH
O
OH
70
68
3:2
1:1
O2N
10f
14f
O2N
Scheme 2. Plausible mechanism of the reaction
Ts
N
Ts
N
Ts
Ts
R1
R
N
Ts
Ts
N
R1
R
N
BF3.OEt2
b
a
R1
R
N
R1
R
BF3.OEt2
R3
O
O
OH
BF3.OEt2
a
BF3.OEt2
7
8
R2
OH
R2
O
R2
O
R3
O
O
14g
10g
OH
MeO2C
Br
O
a
O
O
MeO2C
H
H
R2
Ts
N
R3
Ts
R3
H2
10
N
A
B
O
where R2 = Me, Ph; R3 = H
O
Br
Ts
N
O
OH
14h
R1
R
OH
BF3.OEt2
61
65
1:1
3:2
R2
10h
Ts
O
R1
N
OH
Ts
Ts
N
R3
O
N
H
R3
b
R
O
C
O
O
R2
OH
14i
OH
b
9
14
where R2 = H, Me; R3 = Me, Ph
10i
MeO
MeO
Ts
R1
Ts
Ts
Ts
N
R1
N
N
N
BF3.OEt2
H2O
O
R
R
OH
O
OH
O
O
10
O
OH
95
---
10j
R3
14j
15
D
R3

4
Tetrahedron
ACCEPTED MANUSCRIPT
1
either secondary or tertiary carbocation A, where R2 = Me, Ph;
standard for H (600 MHz, 400 MHz) or 13C (150 MHz, 100
MHz) NMR. Chemical shifts (δ) are reported in ppm and spin-
spin coupling constants (J) are given in Hz. HRMS spectra were
recorded using Q-TOF mass spectrometer.
R3 = H (entries 1-10, path a), which is attacked by alkanol to give
six membered intermediate B. The intermediate B is then
hydrolyzed to form morpholine 14. On the other hand,
disubstituted epoxide 10k,l opens under the same reaction
conditions to give more stable benzylic carbocation C, where R2
= H, Me; R3 = Me, Ph (entries 11,12, path b), or secondary
carbocation A or C, R2 = H; R3 = Me (entry 13, in this case both
carbocations A and C are secondary). The carbocation C is
subsequently attacked by alkanol to give seven membered
4.1. General Procedure for the Synthesis of N-Tethered
Alkanol-Epoxide:
The alkenols 10a-10m (1equiv) was treated with
metachloroperbenzoic acid (mCPBA) (1.5 equiv) in
dicholomethane (15 ml) at 0 0C. The reaction mixture was
brought to room temperature and stirred for a specific time. After
completion of the reaction, as determined by TLC, a saturated
aqueous solution of Na2SO3 was added to quench excess
mCPBA. Dichloromethane was added to the reaction mixture,
washed with saturated sodium bicarbonate and brine solutions,
and dried over anhydrous Na2SO4. Evaporation of the solvent
gave the crude product, which was purified by neutral alumina
using ethyl acetate and hexane as eluents.
intermaediate
D
(entries 11, 12). Similarly, secondary
carbocations A and C are attacked by alkanol to produce B and D
(entry 13), respectively. The intermediates B and D are then
hydrolysed to give morpholine 14 and oxazepane 15, respectively
(Scheme2).
The strategy is successfully applied for the synthesis of (+)-
viloxazine 1. The compound is considered as an anti depression
agent. Only a few protocols have been introduced for total
synthesis of viloxazine till date.1b,25 The synthesis started with the
bromination of alcohol 14a with carbon tetrabromide and
triphenyl phosphine in dichloromethane at room temperature to
give bromide 16, which was then treated with 2-ethoxyphenol 17
to provide N-tosyl protected (+)-viloxazine 18. Deprotection of
11 with sodium naphthalide gave the final product (+)-viloxazine
1 in 80% yield (Scheme 3).
4.2.1. Synthesis of N-(2-hydroxyethyl)-4-methyl-N-(oxiran-
2ylmethyl)benzene-sulfonamide (10a). To a stirred solution of N-
allyl-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide (254 mg,
1.0 mmol) in dichlorormethane (6.0 mL), was added m-
0
chloroperbenzoic acid (258.0 mg, 1.49 mmol) at 0 C. The
reaction mixture was brought to room temperature and stirred for
12 h. The progress of the reaction was monitored by TLC with
ethyl acetate and hexane as eluents. After completion of the
reaction, a saturated aqueous solution of Na2SO3 was added to
quench excess mCPBA. Dichloromethane was added to the
reaction mixture, washed with saturated sodium bicarbonate and
brine solution. The organic layer was dried over (Na2SO4) and
evaporated to leave the crude product which was purified by
column chromatography over neutral alumina using ethyl acetate
and hexane as eluents to give N-(2-hydroxyethyl)-4-methyl-N-
(oxiran-2-ylmethyl)benzenesulfonamide as a colourless oil. Rf
Scheme 3. Total synthesis of (+)-viloxazine 1
OEt
EtO
O
HO
OH
Br
O
17
CBr4 / Ph3P
O
O
K2CO3 /CH3CN
reflux
65%
N
CH2Cl2, reflux
95%
N
Ts
N
18
1
Ts
Ts
(hexane/ EtOAc 3:2) 0.50; yield 203 mg, 75%; H NMR (600
14a
16
MHz, CDCl3) δ 2.18 (t, J = 10.2 Hz, 1 H), 2.33 (t, J = 11.4 Hz, 1
H), 2.37 (s, 3 H), 3.44-3.48 (m, 2 H), 3.50-3.64 (m, 4 H), 3.86 (d,
J = 11.4 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.56 (d, J = 7.2 Hz, 2
H); 13C NMR (150 MHz, CDCl3) δ 21.5, 45.5, 47.1, 63.2, 65.8,
75.5, 127.8, 129.9, 131.9, 144.1; IR (KBr, neat) 3508, 2923,
2866, 1453, 1339, 1166, 1048, 754 cm-1; HRMS (ESI) calcd. for
C12H18NO4S (M + H)+ 272.0951, found 272.0950.
Na-naphthalene
80%
THF, -78 o
C
EtO
O
O
N
H
4.2.2
N-(2-Hydroxyethyl)-4-methyl-N-((2-methyloxiran-2-
(+)-viloxazine (1)
yl)methyl)benzenesulfonamide (10b). Colourless oil; Rf (hexane/
EtOAc 3:2) 0.47; yield 271 mg, 95%; 1H NMR (600 MHz,
CDCl3) δ 1.37 (s, 3 H), 2.41 (s, 3 H), 2.69 (d, J = 4.2 Hz, 1 H),
2.94 (d, J = 4.2 Hz, 1 H), 3.01-3.07 (m, 1 H), 3.24 (d, J = 15.0
Hz, 1 H), 3.32 (t, J = 6.0 Hz, 1 H), 3.34-3.38 (m, 1 H), 3.40 (d, J
= 15.0 Hz, 1 H), 3.69-3.72 (m, 1 H), 3.73-3.78 (m, 1 H), 7.31 (d,
J = 7.8 Hz, 2 H), 7.67 (d, J = 7.8 Hz, 2 H); 13C NMR (150 MHz,
CDCl3) δ 19.3, 21.7, 52.0, 53.5, 54.5, 57.2, 61.4, 127.5, 130.1,
135.7, 144.0; IR (KBr, neat) 3454, 2927, 1598, 1338, 1162, 1090,
1029, 816, 706 cm-1; HRMS (ESI) calcd. for C13H20NO4S (M +
H)+ 286.1108, found 286.1108.
3. Conclusions
In conclusion, we have developed a mild and efficient method
for the synthesis of substituted morpholines via intramolecular
cyclization reaction of N-tethered alkanols-epoxides in good
yields. The reaction is compatible with a wide range of functional
groups such as ester, ether, -NO2, and bromo. The major
advantage of this reaction is that it generates alcohols in side
chain of the morpholine ring, which is used for the synthesis of
biologically active molecule (+)-viloxazine 1.
4.2.3.
N-(1-Hydroxypropan-2-yl)-4-methyl-N-((2-
4. Experimental section
methyloxiran-2-yl)methyl)benzenesulfonamide (diastereomeric
mixture, 7:3: 10c). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.40;
yield 230 mg, 77%; H NMR (400 MHz, CDCl3) δ 0.69 (d, J =
General Information: All the reagents were of reagent grade
(AR grade) and were used as purchased without further
purification. Silica gel (60-120 mesh size) was used for column
chromatography. Reactions were monitored by TLC on silica gel
GF254 (0.25 mm). Melting points were recorded in open capillary
tubes and are uncorrected. Fourier transform-infra red (FT-IR)
spectra were recorded as neat liquid or KBr pellets. NMR spectra
were recorded in CDCl3 with tetramethylsilane as the internal
1
6.4 Hz, 3 H, major), 0.83 (d, J = 6.8 Hz, 3 H, minor), 1.41 (s, 3
H, major), 1.49 (s, 3 H, minor), 2.43 (s, 3 H), 2.71-2.84 (m, 2 H),
3.24-3.28 (m, 1 H), 3.36-3.41 (m, 1 H), 3.48-3.61 (m, 2 H), 3.72-
3.94 (m, 2 H), 7.30-7.33 (m, 2 H), 7.68-7.72 (m, 2 H); 13C NMR
(100 MHz, CDCl3) δ 13.0, 13.3, 18.9, 20.0, 21.7, 45.9, 49.9, 52.9,
53.2, 55.8, 56.8, 58.4, 64.9, 65.1, 127.2, 127.5, 129.9, 130.0,

5
137.2, 137.4, 143.8, 144.0; IR (KBr, neat) 3522, 2928, 2876,
1598, 1453, 1337, 1216, 1153, 1091, 1025, 756 cm-1; HRMS
(ESI) calcd. for C14H22NO4S (M + H)+ 300.1264, found
300.1263.
130.1, 130.2, 135.3, 135.7, 144.2, 144.3, 146.6, 146.9, 167.0,
ACCEPTED MANUSCRIPT
167.1; IR (KBr, neat) 3498, 2925, 2854, 1722, 1612, 1437, 1339,
1282, 1159, 1089, 1019, 987, 816, 758 cm-1; HRMS (ESI) calcd.
for C21H26NO6S (M + H)+ 420.1481, found 420.1478.
4.2.4.
N-(2-hydroxypropyl)-4-methyl-N-((2-methyloxiran-2-
4.2.8.
N-(2-(3-Bromophenyl)-2-hydroxyethyl)-4-methyl-N-((2-
yl)methyl)benzenesulfonamide (diastereomeric mixture, 3:2,
methyloxiran-2-yl)methyl)benzene-sulfonamide (diastereomeric
mixture, 1:1, 10h). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.39;
yield 312mg, 71%; 1H NMR (600 MHz, CDCl3) δ 1.34 (s, 1.5 H),
1.46 (s, 1.5 H), 2.40 (s, 3 H), 2.71 (d, J = 3.0 Hz, 0.5 H), 2.77 (d,
J = 3.6 Hz, 0.5 H), 2.96-3.02 (m, 1.5 H), 3.06-3.10 (m, 1 H), 3.26
(d, J = 15.0 Hz, 0.5 H), 3.35-3.44 (m, 1.5 H), 3.70 (d, J = 15.0
Hz, 0.5 H), 4.87 (d, J = 9.6 Hz, 0.5 H), 5.05 (d, J = 9.6 Hz, 0.5
H), 7.19 (t, J = 7.8 Hz, 1 H), 7.28-7.39 (m, 4 H), 7.52 (s, 0.5 H),
7.59 (s, 0.5 H), 7.65-7.68 (m, 2 H); 13C NMR (150 MHz, CDCl3)
δ 19.1, 19.3, 21.6, 51.9, 52.0, 53.5, 56.4, 56.7, 57.3, 58.3, 60.2,
70.8, 73.1, 122.7, 124.7, 124.8, 127.4, 127.5, 129.1, 129.2, 130.0,
130.1, 130.16, 130.2, 130.8, 130.9, 135.3, 135.5, 143.8, 144.1,
144.2, 144.3; IR (KBr, neat) 3492, 2925, 2855, 1597, 1428, 1338,
1159, 1090, 804, 762 cm-1; HRMS (ESI) calcd. for
C19H23BrNO4S (M + H)+ 440.0526, found 440.0526.
10d). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.45; yield 278 mg,
1
93%; H NMR (400 MHz, CDCl3) δ 1.12 (d, J = 6.4 Hz, 3 H,
major), 1.16 (d, J = 6.8 Hz, 3 H, minor), 1.37 (s, 3 H, minor),
1.42 (s, 3 H, major), 2.44 (s, 3 H), 2.71-2.74 (m, 1 H, major),
2.77-2.87 (m, 1 H, minor), 3.14-3.18 (m, 1 H), 3.20-3.23 (m, 1
H), 3.45 (d, J = 15.2 Hz, 1 H), 3.57 (d, J = 15.2 Hz, 1 H), 3.90-
3.98 (m, 1 H), 4.04-4.12 (m, 1 H), 7.34 (d, J = 7.6 Hz, 2 H), 7.69
(d, J = 8.0 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 19.2, 19.3,
19.5, 20.5, 20.7, 21.7, 52.0, 52.2, 53.6, 55.9, 57.0, 57.3, 58.4,
59.4, 65.2, 67.2, 127.4, 127.5, 129.9, 130.0, 135.4, 135.5, 144.0,
144.1; IR (KBr, neat) 3450, 2925, 1598, 1494, 1339, 1161, 1020,
908, 729 cm-1; HRMS (ESI) calcd. for C14H22NO4S (M + H)+
300.1264, found 300.1267.
4.2.5.
N-(2-Hydroxy-2-phenylethyl)-4-methyl-N-((2-
methyloxiran-2-yl)methyl)benzenesulfonamide (diastereomeric
4.2.9. N-(2-Hydroxy-2-(4-methoxyphenyl)ethyl)-4-methyl-N-((2-
methyloxiran-2-yl)methyl)benzene-sulfonamide (diastereomeric
mixture, 1:1, 10i). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.50;
mixture, 5:4, 10e). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.45;
1
yield 339 mg, 94%; H NMR (400 MHz, CDCl3) δ 1.35 (s, 3 H,
1
minor), 1.45 (s, 3 H, major), 2.40 (s, 3 H), 2.70 (d, J = 4.0 Hz, 1
H, minor), 2.76 (d, J = 4.0 Hz, 1 H, major), 2.97-3.04 (m, 3 H,
major), 3.06-3.15 (m, 3 H, minor), 3.28-3.35 (m, 1 H), 3.44-3.48
(m, 1 H, major), 3.68 (d, J = 15.6 Hz, 1 H, minor), 4.89 (d, J =
9.2 Hz, 1 H, major), 5.08 (d, J = 9.2 Hz, 1 H, minor), 7.26-7.43
yield 301 mg, 77%; H NMR (600 MHz, CDCl3) δ 1.33 (s, 1.5
H), 1.43 (s, 1.5 H), 2.39 (s, 3 H), 2.68 (d, J = 3.0 Hz, 0.5 H), 2.74
(d, J = 3.0 Hz, 0.5 H), 2.93-3.01 (m, 1.5 H), 3.06-3.13 (m, 1 H),
3.26 (d, J = 15.0 Hz, 0.5 H), 3.33 (d, J = 15.6 Hz, 0.5 H), 3.41-
3.47 (m, 1 H), 3.66 (d, J = 15.0 Hz, 0.5 H), 3.77 (s, 3 H), 4.84 (d,
J = 9.6 Hz, 0.5 H), 5.02 (d, J = 9.0 Hz, 0.5 H), 6.85 (d, J = 7.8
Hz, 2 H), 7.21-7.67 (m, 4 H), 7.65-7.70 (m, 2 H); 13C NMR (150
MHz, CDCl3) δ 19.0, 19.2, 21.6, 51.9, 52.0, 53.4, 53.6, 55.3,
56.1, 56.6, 57.2, 58.2, 60.0, 70.9, 72.1, 73.1, 113.8, 114.0, 127.1,
127.2, 127.3, 127.4, 129.9, 130.0, 133.5, 133.9, 135.5, 135.7,
143.9, 144.1, 159.2, 159.3; IR (KBr, neat) 3508, 2978, 1598,
1455, 1341, 1162, 1092, 815, 770 cm-1; HRMS (ESI) calcd. for
C20H26NO5S (M + H)+ 392.1526, found 392.1527.
(m, 6 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 2 H); 13
C
NMR (150 MHz, CDCl3) δ 19.1, 19.3, 21.6, 52.0, 52.1, 52.5,
56.2, 56.7, 57.3, 58.4, 60.3, 71.4, 73.6, 126.0, 126.1, 127.4,
127.5, 127.7, 128.0, 128.5, 128.6, 129.9, 130.0, 135.4, 135.6,
141.4, 141.7, 144.0, 144.2; IR (KBr, neat) 3485, 2924, 1495,
1334, 1161, 1091, 1024, 754 cm-1; HRMS (ESI) calcd. for
C19H24NO4S (M + H)+ 362.1421, found 362.1423.
4.2.6.
N-(2-hydroxy-2-(4-nitrophenyl)ethyl)-4-methyl-N-((2-
methyl-oxiran-2-yl)methyl)benzene-sulfonamide (diasteromeric
4.2.10.
N-(2-Hydroxyethyl)-4-methyl-N-((2-phenyloxiran-2-
mixture 4:3, 10f). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.50;
yield 292 mg, 72%; H NMR (600 MHz, CDCl3) δ 1.35 (s, 3 H,
yl)methyl)benzenesulfonamide (10j). Colourless oil; Rf (hexane/
EtOAc 3:2) 0.40; yield 336 mg, 97%; 1H NMR (400 MHz,
CDCl3) δ 2.43 (s, 3 H), 2.87 (d, J = 6.6 Hz, 1 H), 2.93 (dt, J = 9.6
and 4.4 Hz, 1 H), 3.41 (d, J = 6.6 Hz, 1 H), 3.46 (dt, J = 9.6 and
4.8 Hz, 1 H), 3.69-3.81 (m, 4 H), 7.29-7.39 (m, 5 H), 7.43 (d, J =
7.6 Hz, 2 H), 7.65 (d, J = 7.2 Hz, 2 H); 13C NMR (100 MHz,
CDCl3) δ 21.7, 53.1, 53.5, 53.6, 60.7, 61.3, 126.3, 127.6, 128.5,
128.8, 130.1, 135.1, 137.3, 144.2; IR (KBr, neat) 3508, 2977,
2876, 1598, 1452, 1336, 1153, 1091, 1024, 815, 679 cm-1;
HRMS (ESI) calcd. for C18H22NO4S (M + H)+ 348.1264, found
348.1262.
1
minor), 1.49 (s, 3 H, major), 2.42 (s, 3 H, major), 2.43 (s, 3 H,
minor), 2.75 (d, J = 4.2 Hz, 1 H, minor), 2.81 (d, J = 4.2 Hz, 1
H, major), 3.00-3.09 (m, 3 H), 3.29 (dd, J = 15.0 and 1.2 Hz, 1
H, minor), 3.41 (dd, J = 15.0 and 5.4 Hz, 1 H, major), 3.48 (d, J
= 15.0 Hz, 1 H, minor), 3.76 (d, J = 15.0 Hz, 1 H, major), 5.06
(d, J = 8.4 Hz, 1 H, minor), 5.23 (d, J = 8.4 Hz, 1 H, major),
7.30-7.34 (m, 2 H), 7.51-7.60 (m, 2 H), 7.64-7.71 (m, 2 H), 8.19
(d, J = 8.4 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 21.7, 36.0,
49.5, 62.2, 62.4, 116.3, 126.8, 126.9, 127.8, 128.5, 128.8, 128.83,
129.2, 130.0, 137.5, 138.0, 138.6, 143.9, 145.4; IR (KBr, neat)
3499, 2923, 2852, 1521, 1453, 1347, 1161, 1090, 853, 698 cm-1;
HRMS (ESI) calcd. for C19H23N2O6S (M + H)+ 407.1271, found
407.1275.
4.2.11.
N-(2-hydroxyethyl)-4-methyl-N-((3-phenyloxiran-2-
yl)methyl)benzenesulfonamide (10k). Colourles oil, Rf (hexane/
EtOAc 3:2) 0.50; yield 330 mg, 95%; 1H NMR (600 MHz,
CDCl3) δ 2.42 (s, 3 H), 3.25-3.30 (m, 2 H), 3.32-3.34 (m, 2 H),
(dd, J = 16.8 and 4.8 Hz, 1 H), 3.82 (t, J = 4.8 Hz, 2 H), 3.86 (d,
J = 1.8 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.29-7.35 (m, 5 H),
7.71 (d, J = 8.4 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 21.7,
51.2, 52.6, 57.6, 61.6, 61.7, 125.9, 127.4, 128.6, 128.7, 130.1,
135.7, 136.0, 144.1; IR (KBr, neat) 3499, 2923, 2873, 1598,
1451, 1337, 1160, 1089, 978, 815, 756 cm-1; HRMS (ESI) calcd.
for C18H22NO4S (M + H)+ 348.1264, found 414.1359.
4.2.7. Methyl 4-(1-hydroxy-2-(4-methyl-N-((2-methyloxiran-2-
yl)methyl)phenylsulfonamido)ethyl)-benzoate
(diastereomeric
mixture, 1:1, 10g). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.50;
yield 306 mg, 73%; 1H NMR (600 MHz, CDCl3) δ 1.24 (s, 3 H),
2.39 (s, 1.5 H), 2.41 (s, 1.5 H), 2.70 (s, 0.5 H), 2.77 (s, 0.5 H),
2.97 (s, 1 H), 3.01-3.10 (m, 2 H), 3.28 (d, J = 15.0 Hz, 0.5 H),
3.26-3.42 (m, 1 H), 3.69 (d, J = 15.0 Hz, 0.5 H), 3.89 (s, 3 H),
4.96 (d, J = 10.2 Hz, 0.5 H), 5.14 (d, J = 12.0 Hz, 0.5 H), 7.29
(d, J = 7.2 Hz, 2 H), 7.43-7.50 (m, 2 H), 7.65 (d, J = 7.8 Hz, 2
H), 7.98 (d, J = 8.4 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ
19.1, 19.3, 21.7, 22.8, 51.9, 52.0, 52.2, 53.6, 56.4, 56.8, 57.4,
58.3, 60.3, 71.2, 73.5, 126.0, 126.1, 127.4, 127.5, 129.9, 129.93,
4.2.12.
N-(2-Hydroxyethyl)-4-methyl-N-((2-methyl-3-
phenyloxiran-2-yl)methyl)benzenesulfonamide (diastereomeric
mixture, 4:1, 10l). Colourless oil, Rf (hexane/ EtOAc 3:2) 0.48
yield; 332 mg, 92%; 1H NMR (600 MHz, CDCl3) δ 1.13 (s, 3 H,

6
Tetrahedron
major), 1.58 (s, 3 H, minor), 2.38 (s, 3 H, minor), 2.44 (s, 3 H,
4.3.2. (2-Methyl-4-tosylmorpholin-2-yl)methanol (14b). Pale
ACCEPTED MANUSCRIPT
1
major), 3.03-3.08 (m, 1 H), 3.46 (d, J = 6.0 Hz, 2 H), 3.49-3.54
(m, 1 H), 3.66 (t, J = 4.8 Hz, 1 H), 3.77-3.81 (m, 1 H), 3.83-3.87
(m, 1 H), 3.99 (s, 1 H, minor), 4.32 (s, 1 H, major), 7.23-7.37 (m,
7 H), 7.53 (d, J = 7.8 Hz, 2 H, minor), 7.72 (d, J = 7.8 Hz, 2 H,
major); 13C NMR (150 MHz, CDCl3) δ 20.5, 21.6, 21.7, 51.4,
51.7, 53.4, 55.4, 61.1, 61.6, 61.7, 62.3, 63.7, 63.9, 126.5, 126.6,
127.4, 127.6, 127.9, 128.2, 128.3, 128.6, 130.0, 130.1, 135.0,
135.1, 135.5, 136.0, 143.8, 144.1; IR (KBr, neat) 3520, 2928,
1598, 1450, 1339, 1161, 1089, 751, 656 cm-1; HRMS (ESI)
calcd. for C19H24NO4S (M + H)+ 362.1421, found 380.1323.
yellow oil; Rf (hexane/ EtOAc 3:2) 0.47; yield 228 mg, 80%; H
NMR (600 MHz, CDCl3) δ 1.25 (s, 3 H), 2.42 (s, 3 H), 2.64-2.68
(m, 1 H), 2.77 (d, J = 12.0 Hz, 1 H), 2.95 (d, J = 12.0 Hz, 1 H),
3.19 (dt, J = 11.4 and 2.4 Hz, 1 H), 3.50 (dd, J = 11.4 and 5.4 Hz,
1 H), 3.55 (d, J = 10.8 Hz, 1 H), 3.75 (dt, J = 12.0 and 4.2 Hz, 1
H), 3.84-3.88 (m, 1 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.60 (d, J = 7.8
Hz, 2 H); 13C NMR (150 MHz, CDCl3) 19.2, 21.7, 45.8, 50.6,
60.5, 66.8, 73.5, 127.9, 130.0, 132.4, 144.1; IR (KBr, neat) 3509,
2925, 2879, 1598, 1455, 1350, 1166, 1090, 1057, 760 cm-1;
HRMS (ESI) calcd. for C13H20NO4S (M + H)+ 286.1108 found
286.1111.
4.2.13.
N-(2-Hydroxyethyl)-4-methyl-N-((3-methyloxiran-2-
yl)methyl)benzenesulfonamide (diastereomeric mixture, 1:2,
4.3.3. ((2R*,5S*)-2,5-dimethyl-4-tosylmorpholin-2-yl)methanol
10m). Colourless oil; Rf (hexane/ EtOAc 3:2) 0.46; yield 257 mg,
90%; H NMR (400 MHz, CDCl3) δ 1.25 (d, J = 5.2 Hz, 3 H,
(14c). Pale yellow oil; Rf (hexane/ EtOAc 3:2) 0.40; yield 215
1
25
1
mg, 72%; [α]D +13.6 (c 0.25, CHCl3); H NMR (400 MHz,
CDCl3) δ 1.09 (d, J = 5.2 Hz, 3 H), 1.22 (s, 3 H), 2.43 (s, 3 H),
2.96 (d, J = 13.6 Hz, 1 H), 3.37 (m, 2 H), 3.60 (d, J = 10. 8 Hz,
1 H), 3.73 (d, J = 11. 6 Hz, 1 H), 3.86-3.94 (m, 2 H), 7.26 (d, J =
6.8 Hz, 2 H), 7.67 (d, J = 7.2 Hz, 2 H); 13C NMR (100 MHz,
CDCl3) 13.8 21.7, 22.4 22.9 (minor), 45.2, 48.6, 62.3, 66.0, 73.2,
127.2, 130.0, 137.1, 143.8; IR (KBr, neat) 3434, 29 24, 2854,
1454, 1337, 1161, 1037, 953, 815, 680 cm-1; HRMS (ESI) calcd.
for C14H22NO4S (M + H)+ 300.1264 found 300.1278.
minor), 1.29 (d, J = 5.2 Hz, 3 H, major), 2.39 (s, 3 H), 2.93-3.00
(m, 2 H, major) 3.01-3.09 (m, 2 H, minor), 3.10-3.15 (m, 1 H,
major), 3.16-3.19 (m, 1 H, minor), 3.20-3.30 (m, 2 H), 3.45-3.51
(m, 1 H, minor), 3.57-3.63 (m, 1 H, major), 3.74 (t, J = 5.2 Hz, 2
H, major), 3.77-3.80 (m, 2 H, minor), 7.29 (d, J = 7.6 Hz, 2 H),
7.69 (d, J = 7.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 17.0,
18.7, 20.0, 21.5, 51.1, 51.6, 52.4, 52.7, 53.7, 55.7, 58.6, 61.4,
65.9, 68.0, 127.2, 129.8, 129.9, 135.5, 143.8; IR (KBr, neat)
3518, 2926, 2854, 1625, 1598, 1452, 1337, 1161, 1090, 1020,
802, 752 cm-1; HRMS (ESI) calcd. for C13H20NO4S (M + H)+
286.1108, found 328.1219.
4.3.4. ((2R*,6S*)-2,6-Dimethyl-4-tosylmorpholin-2-yl)methanol
(14d). White solid, mp 127-128 oC; Rf (hexane/ EtOAc 3:2) 0.45;
1
yield 120 mg, 40%; H NMR (400 MHz, CDCl3) δ 1.11 (d, J =
4.3. General Procedure for Lewis Acid Catalyzed
Intramolecular C−O Bond Formation of Alkanol-Epoxide.
6.0 Hz, 3 H), 1.16 (s, 3 H), 1.92 (t, J = 10.8 Hz, 1 H), 2.05 (d, J =
11.6 Hz, 1 H), 2.45 (s, 3 H), 3.52-3.60 (m, 2 H), 3.69 (d, J = 11.2
Hz, 1 H), 3.91 (d, J = 11.2 Hz, 1 H), 3.94-3.98 (m, 1 H), 7.36 (d,
J = 8.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H); 13C NMR (150 MHz,
CDCl3) 19.2, 21.7, 23.3, 50.4, 51.3, 62.5, 65.6, 73.7, 127.9,
130.0, 132.5, 144.2; IR (KBr, neat) 3463, 2925, 2852, 1598,
1493, 1342, 1166, 1094, 1030, 814, 662 cm-1; HRMS (ESI)
calcd. for C14H22NO4S (M + H)+ 300.1264 found 300.1271.
To a corresponding hydroxyl-epoxide substrates (1.0 equiv)
in CH2Cl2 (5.0 mL) at 0 °C was added BF3·Et2O (1equiv)
dropwise, and the reaction mixture was brought to room
temperature. The reaction was continued for a specified time and
monitored by TLC. After completion of the reaction, the reaction
mixture was treated with saturated sodium bicarbonate solution
(5.0 mL). The product was extracted with CH2Cl2 (2 × 10.0 mL)
and washed with brine. Organic layer was separated and dried
over anhydrous Na2SO4 and evaporated using rotary evaporator
to obtain the crude product. The crude product was purified by
silica gel column chromatography using ethyl acetate and hexane
as eluents to afford the cyclic compounds.
4.3.5. ((2S*,6S*)-2,6-Dimethyl-4-tosylmorpholin-2-yl)methanol
o
(14d’). White solid, mp 125-126 C; Rf (hexane/ EtOAc 3:2)
0.48; yield 126 mg, 42%; 1H NMR (400 MHz, CDCl3) δ 1.07 (d,
J = 6.4 Hz, 3 H), 1.29 (s, 3 H), 1.82 (t, J = 10.4 Hz, 1 H), 2.38 (d,
J = 11.2 Hz, 1 H), 2.42 (s, 3 H), 3.27-3.33 (m, 2 H), 3.50 (d, J =
7.2 Hz, 1 H), 3.55 (dt, J = 11.2 and 3.0 Hz, 1 H), 3.96-4.05 (m, 1
H), 7.31 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 2 H); 13C NMR
(150 MHz, CDCl3) 18.3, 19.0, 21.7, 49.8, 51.6, 65.4, 68.8, 74.0,
127.9, 130.0, 132.6, 144.0; IR (KBr, neat) 3463, 2925, 2852,
1598, 1493, 1342, 1166, 1094, 1030, 814, 662 cm-1; HRMS (ESI)
calcd. for C14H22NO4S (M + H)+ 300.1264 found 300.1271.
4.3.1. Synthesis of (4-Tosylmorpholin-2-yl)methanol (14a). To
a stirred solution of N-(2-hydroxyethyl)-4-methyl-N-(oxiran-2-
ylmethyl)benzenesulfonamide (270 mg, 1.0 mmol) in
dichloromethane(5.0 mL), was adeed boron triflouride etherate
0
(0.15 mL, 1.2 mmol) dropwise at 0 C. The reaction mixture was
brought to room temperature and stirred for 1.5 h. The progress
of the reaction was monitored by TLC with ethyl acetate and
hexane as eluents. After completion of the reaction, the reaction
mixture was washed with saturated sodium bicarbonate solution
and brine solution. The organic layer was dried over (Na2SO4)
and evaporated to leave the crude product which was purified by
column chromatography over silica gel using ethyl acetate and
hexane as eluents to give (4-tosylmorpholin-2-yl)methanol as a
4.3.6.
(2-Methyl-6-phenyl-4-tosylmorpholin-2-yl)methanol
(diastereomeric mixture, 1:1, 14e). White solid, M. P. 133-136 0
o C; Rf (hexane/ EtOAc 3:2) 0.40; yield 271 mg, 75%; H NMR
1
(600 MHz, CDCl3) δ 1.26 (s, 1.5 H), 1.43 (s, 1.5 H), 2.07-2.17
(m, 1.5 H), 2.40 (s, 1.5 H), 2.42 (s, 1.5 H), 2.53 (d, 11.2 Hz, 0.5
H), 3.44 (dd, J = 10.8 and 3.2 Hz, 1 H), 3.60 (d, J = 11.6 Hz, 0.5
H), 3.67 (d, J = 11.6 Hz, 0.5 H), 3.76 (dd, J = 11.6 and 1.6 Hz, 1
H), 3.81 (d, J = 11.6 Hz, 0.5 H), 3.94 (d, J = 11.2 Hz, 0.5 H),
4.88 (dd, J = 10.8 and 2.8 Hz, 0.5 H,), 4.94 (d, J = 10.4 Hz, 0.5
H), 7.28-7.32 (m, 7 H), 7.58 (d, J = 6.8 Hz, 2 H); 13C NMR (150
MHz, CDCl3) 18.0, 21.6, 23.2, 50.0, 50.4, 51.8, 51.9, 62.2, 68.8,
71.5, 71.6, 74.1, 74.5, 126.3, 126.4, 127.7, 127.8, 128.4, 128.5,
128.57, 128.6, 129.9, 130.0, 132.2, 132.4, 138.7, 138.8, 144.0,
144.1; IR (KBr, neat) 3531, 2925, 1598, 1454, 1342, 1160, 1092,
1021, 816, 755 cm-1; HRMS (ESI) calcd. for C19H24NO4S (M +
H)+ 362.1421 found 362.1418.
o
white solid; mp 120-121 C; Rf (hexane/ EtOAc 3:2) 0.47; yield
1
211 mg, 78%; H NMR (600 MHz, CDCl3) δ 2.27 (dd, J = 11.6
and 10.4 Hz, 1 H), 2.39 (dt, J = 11.6 and 3.6 Hz, 1 H), 2.45 (s, 3
H), 3.52-3.59 (m, 3 H), 3.64-3.70 (m, 2 H), 3.74 (dd, J = 11.2
and 2.8 Hz, 1 H), 3.92-3.97 (m, 1 H), 7.34 (d, J = 8.4 Hz, 2 H),
7.63 (t, J = 8.4 Hz, 2 H); 13C NMR (150 MHz, CDCl3) 21.6, 45.6,
47.1, 63.3, 65.9, 75.5, 128.0, 129.9, 132.1, 144.2; IR (KBr, neat)
3498, 2921, 2863, 1597, 1344, 1168, 1097, 974, 756 cm-1;
HRMS (ESI) calcd. for C12H18NO4S (M + H)+ 272.0951 found
272.0951.
4.3.7.
(2-Methyl-6-(4-nitrophenyl)-4-tosylmorpholin-2-
yl)methanol (diastereomeric mixture, 3:2, 14f). White solid, mp

7
142-144 oC; Rf (hexane/ EtOAc 3:2) 0.45; yield 284 mg, 70%; 1H
NMR (600 MHz, CDCl3) δ 1.30 (s, 3 H, major), 1.46 (s, 3 H,
minor), 2.05-2.10 (m 1 H), 2.19 (d, J = 12.0 Hz, 1 H, major),
2.42 (s, 3 H, minor), 2.43 (s, 3 H, major), 2.55 (d, J = 11.5 Hz, 1
H, minor), 3.50 (t, J = 12.0 Hz, 1 H), 3.67 (d, J = 11.4 Hz, 1 H,
minor), 3.71 (dd, J = 11.4 and 1.2 Hz, 1 H, major), 3.82 (d, J =
12.0 Hz, 1 H), 3.86 (d, J = 11.4 Hz, 1 H, major), 3.99 (d, J = 11.4
Hz, 1 H, minor), 5.05 (dd, J = 10.8 and 2.4 Hz, 1 H, major), 5.08
(dd, J = 10.8 and 2.4 Hz, 1 H, minor), 7.32 (t, J = 8.4 Hz, 2 H),
7.49-7.53 (m, 2 H), 7.59 (d, J = 8.4 Hz, 2 H), 8.18 (d, J = 8.4 Hz,
2 H); 13C NMR (100 MHz, CDCl3) δ 18.0, 21.7, 22.9, 23.2, 50.1,
50.5, 51.5, 51.7, 62.4, 68.9, 70.8, 71.0, 74.7, 75.2, 123.8, 123.9,
126.5, 127.2, 127.8, 127.9, 128.1, 128.5, 130.1, 130.2, 132.3,
144.4, 144.5, 146.0, 148.0; IR (KBr, neat) 3528, 2925, 1600,
1522, 1454, 1349, 1166, 1092, 1022, 759, 698 cm-1; HRMS (ESI)
calcd. for C19H23N2O6S (M + H)+ 407.1271 found 407.1277.
2 H); 13C NMR (150 MHz, CDCl3) δ 18.2, 21.7, 23.4, 49.9,
ACCEPTED MANUSCRIPT
50.5, 52.0, 55.5, 62.5, 68.9, 71.3, 71.5, 74.2, 74.4, 114.1, 114.2,
127.7, 127.8, 127.86, 127.9, 128.4, 128.7, 130.0, 131.0, 132.5,
144.1, 144.2, 159.8, 159.9; IR (KBr, neat) 3527, 2925, 2853,
1613, 1456, 1341, 1249, 1165, 1092, 1033, 815, 755 cm-1;
HRMS (ESI) calcd. for C20H26NO5S (M + H)+ 392.1526, found
392.1525.
4.3.11. (2-Phenyl-4-tosylmorpholin-2-yl)methanol (14j). Pale
yellow oil; Rf (hexane/ EtOAc 3:2) 0.45; yield 330 mg, 95%; H
1
NMR (400 MHz, CDCl3) δ 2.45 (s, 3 H), 2.50-2.57 (m, 1 H),
2.88 (d, J = 12.4 Hz, 1 H), 3.33 (d, J = 11.6 Hz, 1 H), 3.50 (d, J =
11.6 Hz, 1 H), 3.67 (d, J = 12.4 Hz, 1 H), 3.72 (d, J = 7.6 Hz, 2
H), 4.17 (d, J = 12.4 Hz, 1 H), 7.32-7.37 (m, 3 H), 7.42 (t, J = 7.6
Hz, 2 H), 7.51 (d, J = 7.6 Hz, 2 H), 7.66 ((d, J = 7.6 Hz, 2 H);
13C NMR (150 MHz, CDCl3) δ 21.6, 45.7, 47.9, 60.8, 69.3, 78.2,
127.3, 127.9, 128.1, 128.8, 129.9, 131.9, 138.3, 144.1; IR (KBr,
neat) 3509, 2925, 2854, 1598, 1450, 1350, 1166, 1092, 1017,
816, 759 cm-1; HRMS (ESI) calcd. for C18H22NO4S (M + H)+
348.1264, found 348.1267.
4.3.8. Methyl 4-(6-(hydroxymethyl)-6-methyl-4-tosylmorpholin-2-
yl)benzoate (diastereomeric mixture, 1:1, 14g). White solid, mp
150-152 oC; Rf (hexane/ EtOAc 3:2) 0.40; yield 285 mg, 68%; 1H
NMR (600 MHz, CDCl3) δ 1.27 (s, 1.5 H), 1.44 (s, 1.5 H), 2.05-
2.10 (m, 1 H), 2.18 (d, J = 12.0 Hz, 0.5 H), 2.40 (s, 1.5 H), 2.41
(s, 1.5 H), 2.54 (d, J = 11.4 Hz, 0.5 H), 3.46 (t, J = 12.0 Hz, 1 H),
3.64 (d, J = 11.4 Hz, 0.5 H), 3.67 (d, J = 11.4 Hz, 0.5 H), 3.78
(dd, J = 12.0 and 1.2 Hz, 1 H), 3.81 (d, J = 11.4 Hz, 0.5 H), 3.89
(s, 1.5 H), 3.90 (s, 1.5 H), 4.00 (d, J = 11.4 Hz, 0.5 H), 4.95 (d, J
= 10.2 Hz, 0.5 H), 4.98 (d, J = 10.8 Hz, 0.5 H), 7.30 (t, J = 8.4
Hz, 2 H), 7.36-7.40 (m, 2 H), 7.57 (d, J = 7.8 Hz, 2 H), 8.98 (dd,
J = 8.4 and 3.6 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 18.1,
21.7, 22.9, 23.3, 50.0, 50.5, 51.7, 51.8, 52.4, 62.4, 68.9, 71.3,
71.4, 74.4, 74.8, 126.3, 126.32, 127.8, 127.9, 129.9, 130.0, 130.1,
130.2, 130.3, 132.4, 143.7, 143.8, 144.2, 144.3, 166.8, 166.9; IR
(KBr, neat) 3492, 2925, 2854, 1721, 1455, 1342, 1282, 1166,
1091, 1020, 779, 705 cm-1; HRMS (ESI) calcd. for C21H26NO6S
(M + H)+ 420.1475, found 420.1480.
4.3.12. (6S*,7R*)-7-Phenyl-4-tosyl-1,4-oxazepan-6-ol (14k).
White solid, mp 132-134 o C; Rf (hexane/ EtOAc 3:2) 0.37; yield
167 mg, 48%; 1H NMR (600 MHz, CDCl3) δ 2.45 (s, 3 H), 3.05-
3.10 (m, 1 H), 3.40 (dd, J = 15.0 and 3.6 Hz, 1 H), 3.73 (dd, J =
15.0 and 1.2 Hz, 1 H), 3.88 (d, 3.0 Hz, 1 H), 3.89 (d, 3.0 Hz, 1
H), 3.91-3.95 (m, 1 H), 4.19 (dd, J = 12.6 and 3.0 Hz, 1 H), 4.43
(d, J = 7.8 Hz, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.33-7.36 (m, 4
H), 7.40 (d, J = 7.8 Hz, 2 H), 7.72 (d, J = 7.8 Hz, 2 H); 13C NMR
(150 MHz, CDCl3) δ 21.7, 52.6, 54.5, 73.5, 76.2, 88.3, 126.6,
127.2, 128.0, 128.6, 130.1, 136.0, 141.2, 144.0; IR (KBr, neat)
3508, 2923, 1597, 1494, 1336, 1161, 1089, 1029, 816, 757 cm-1;
HRMS (ESI) calcd. for C18H22NO4S (M + H)+ 348.1264 found
348.1268.
4.3.13. (6R*,7S*)-6-Methyl-7-phenyl-4-tosyl-1,4-oxazepan-6-ol
(15l). Pale yellow oil; Rf (hexane/ EtOAc 3:2) 0.40; yield 173
mg, 48%; 1H NMR (600 MHz, CDCl3) δ 0.75 (s, 3 H), 2.44 (s, 3
H), 3.00 (dt, J = 12.6 and 4.2 Hz, 1 H), 3.10 (d, J = 15.6 Hz, 1
H), 3.64 (d, J = 15.0 Hz, 1 H), 3.88 (dt, J = 12.0 and 3.6 Hz, 1
H), 3.98 (dd, J = 13.8 and 3.6 Hz, 1 H), 4.17 (dd, J = 12.6 and 4.2
Hz, 1 H), 4.68 (s, 1 H), 7.23-7.26 (m, 1 H), 7.31 (t, J = 7.8 Hz, 2
H), 7.34 (d, J = 7.8 Hz, 2 H), 7.41 (d, J = 7.2 Hz, 2 H), 7.72 (d, J
= 7.8 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 21.2, 21.7, 53.3,
61.6, 74.0, 76.4, 89.2, 126.9, 127.0, 127.2, 127.7, 130.1, 136.0,
139.3, 144.0; IR (KBr, neat) 3507, 2929, 2872, 1595, 1451, 1335,
1157, 1024, 815, 750 cm-1; HRMS (ESI) calcd. for C19H24NO4S
(M + H)+ 362.1421 found 362.1431.
4.3.9.
(6-(3-Bromophenyl)-2-methyl-4-tosylmorpholin-2-
yl)methanol (diastereomeric mixture, 1:1, 14h). Pale yellow oil;
1
Rf (hexane/ EtOAc 3:2) 0.48; yield 268 mg, 61%; H NMR (600
MHz, CDCl3) δ 1.26 (s, 1.5 H), 1.42 (s, 1.5 H), 2.02-2.07 (m, 1
H), 2.14 (d, J = 12.0 Hz, 0.5 H), 2.40 (s, 1.5 H), 2.42 (s, 1.5 H),
2.50 (d, J = 11.4 Hz, 0.5 H), 3.45 (dd, J = 11.4 and 6.0 Hz, 1 H),
3.61 (d, J = 11.4 Hz, 0.5 H), 3.66 (d, J = 12.0 Hz, 0.5 H), 3.74 (d,
J = 11.4Hz, 1 H), 3.81 (d, J = 11.4 Hz, 0.5 H), 3.92 (d, J = 11.4
Hz, 0.5 H), 4.87 (dd, J = 10.2 and 3.0 Hz, 0.5 H), 4.90 (d, J =
10.8 Hz, 0.5 H), 7.16-7.23 (m, 2 H), 7.30 (t, J = 9.0 Hz, 2 H),
7.40 (t, J = 6.0 Hz, 1 H), 7.45 (s, 0.5 H), 7.47 (s, 0.5 H), 7.57 (d,
J = 7.8 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 18.0, 21.2, 23.2,
50.4, 51.7, 51.8, 62.3, 68.8, 70.9, 71.0, 72.1, 74.4, 74.8, 122.8,
125.0, 125.1, 127.8, 129.3, 129.9, 130.1, 130.2, 130.3, 131.5,
131.6, 132.1, 132.3, 141.1, 141.2, 144.2, 144.3; IR (KBr, neat)
3509, 2925, 2853, 1597, 1341, 1165, 1071, 808, 774, 682 cm-1;
HRMS (ESI) calcd. for C19H23BrNO4S (M + H)+ 440.0526, found
440.0527.
4.3.14. (6R*,7R*)-6-Methyl-7-phenyl-4-tosyl-1,4-oxazepan-6-ol
(15l'). Pale yellow oil; Rf (hexane/ EtOAc 3:2) 0.45; yield 126
mg, 35%; 1H NMR (600 MHz, CDCl3) δ 1.13 (s, 3 H), 2.44 (s, 3
H), 3.24 (d, J = 13.8 Hz, 1 H), 3.27-3.31 (m, 1 H), 3.45 (d, J =
14.4 Hz, 1 H), 3.53 (dt, J = 13.8 and 3.6 Hz, 1 H), 3.77-3.82 (m,
1 H), 4.10-4.15 (m, 1 H), 4.41 (s, 1 H), 7.29-7.35 (m, 7 H), 7.70
(d, J = 7.8 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 21.7, 24.4,
51.9, 60.8, 71.4, 74.8, 88.0, 127.4, 128.1, 128.2, 128.3, 130.1,
135.5, 138.1, 143.9; IR (KBr, neat) 3507, 2929, 2872, 1595,
1451, 1335, 1157, 1024, 815, 750 cm-1; HRMS (ESI) calcd. for
C19H24NO4S (M + H)+ 362.1421 found 362.1431.
4.3.10.
(6-(4-Methoxyphenyl)-2-methyl-4-tosylmorpholin-2-
yl)methanol (diastereomeric mixture, 3:2, 14i). Colourless oil; Rf
1
(hexane/ EtOAc 3:2) 0.38; yield 254 mg, 65%; H NMR (600
MHz, CDCl3) δ 1.25 (s, 3 H, major), 1.43 (s, 3 H, minor), 2.04-
2.14 (m, 1 H), 2.18 (d, J = 12.0 Hz, 1 H, minor), 2.42 (s, 3 H,
major), 2.43 (s, 3 H, minor), 2.55 (d, J = 11.4 Hz, 1 H, major),
3.41-3.44 (m, 1 H), 3.61 (d, J = 11.4 Hz, 1 H, major), 3.65 (dd, J
= 11.4 and 1.2 Hz, 1 H, minor), 3.72 (d, J = 11.4 Hz, 1 H), 3.76
(d, J = 11.4 Hz, 1 H, major), 3.78 (s, 3 H), 4.02 (dd, J = 11.4 and
2.4 Hz, 1 H, minor), 4.83 (dd, J = 10.2 and 2.4 Hz, 1 H, minor),
4.90 (d, J = 10.2 and 2.4 Hz, 1 H, major), 6.83-6.87 (m, 2 H),
7.20-7.26 (m, 2 H), 7.32 (t, J = 8.4 Hz, 2 H), 7.58 (d, J = 7.8 Hz,
4.3.15. (6R*,7S*)-7-Methyl-4-tosyl-1,4-oxazepan-6-ol (15m).
Pale yellow oil; Rf (hexane/ EtOAc 3:2) 0.45; yield 43 mg, 15%;
1H NMR (600 MHz, CDCl3) δ 0.87 (d, J = 6.6 Hz, 3 H), 2.43 (s,
3 H), 3.28 (d, J = 13.8 and 4.2 Hz, 1 H), 3.31-3.34 (m, 1 H), 3.44
(dt, J = 13.8 and 4.2 Hz, 1 H), 3.49 (dd, J = 14.4 and 4.2 Hz, 1
H), 3.64 (dt, J = 12.6 and 3.0 Hz, 1 H), 3.78-3.83 (m, 2 H), 3.97
(dt, J = 12.0 and 4.2 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.67 (d,

8
Tetrahedron
CCEPTED MANUSCRIPT
J = 7.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) 18.5, 21.7, 51.2,
oC; Rf (hexane/ EtOAc 4:2) 0.40; yield 381 mg, 65%; H NMR
(600 MHz, CDCl3) δ 1.41 (t, J = 7.2 Hz, 3 H), 2.36 (t, J = 5.4
Hz, 1 H), 2.43 (s, 3 H), 2.45 (dt, J = 11.4 and 3.6 Hz, 1 H), 3.55
(d, J = 11.4 Hz, 1 H), 3.72 (dt, J = 11.4 and 2.4 Hz, 1 H), 3.80 (d,
J = 11.4 Hz, 1 H), 3.93-3.97 (m, 3 H), 4.02-4.05 (m, 3 H), 6.84-
6.89 (m, 3 H), 6.92-6.96 (m, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.64
(d, J = 7.8 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 15.0. 21.7,
45.7, 48.0, 64.6, 66.1, 70.5, 73.8, 114.0, 116.1, 121.1, 122.7,
128.0, 129.9, 132.3, 144.1, 148.4, 149.6; IR (KBr, neat) 2924,
2854, 1596, 1504, 1453, 1346, 1256, 1167, 1122, 1041, 961, 754
cm-1; HRMS (ESI) calcd. for C20H26NO5S (M + H)+ 392.1526,
found 392.1536.
1
A
54.1, 70.0, 72.2, 79.2, 127.0, 130.0, 135.9, 143.8; IR (KBr, neat)
3508, 2973, 2925, 1598, 1495, 1337, 1163, 1089, 1039, 763, 701
cm-1; HRMS (ESI) calcd. for C13H20NO4S (M + H)+ 286.1108
found 332.1318.
4.3.16. (6S*,7S*)-7-Methyl-4-tosyl-1,4-oxazepan-6-ol (15m').
Pale yellow oil; Rf (hexane/ EtOAc 4:1) 0.38; yield 145 mg,
51%; H NMR (600 MHz, CDCl3) δ 1.30 (d, J = 6.0 Hz, 3 H),
1
2.42 (s, 3 H), 2.87-2.92 (m, 1 H), 3.02 (d, J = 8.4 Hz, 1 H), 3.22
(d, J = 15.0 Hz, 1 H), 3.53-3.56 (m, 2 H), 3.64 (d, J = 15.0 Hz, 1
H), 3.74 (ddd, J = 12.0, 9.0 and 3.0 Hz, 1 H), 4.04 (dd, J = 12.0
and 3.6 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 2
H); 13C NMR (100 MHz, CDCl3) 20.1, 21.7, 52.8, 54.5, 73.1
76.6, 83.1, 127.0, 130.0, 136.0, 143.9; IR (KBr, neat) 3508, 2973,
2925, 1598, 1495, 1337, 1163, 1089, 1039, 763, 701 cm-1;
HRMS (ESI) calcd. for C13H20NO4S (M + H)+ 286.1108 found
332.1318.
4.4.3. 2-((2-Ethoxyphenoxy)methyl)morpholine, (±)-viloxazine
(1). To a cooled (-78 °C) green suspension of sodium metal (33
mg, 1.44 mmol) and naphthalene (208 mg, 1.62 mmol) in dry
THF (4.0 mL) was added the corresponding N-tosyl protected
(+)-viloxazine 11 (140 mg, 0.36 mmol) under argon, and the
mixture wasstirred for 45 min at the same temperature. Then, the
reactionwas hydrolyzed with brine (10.0 mL) and extracted with
CH2Cl2 (3x10 mL). The combined organic layers were dried
overanhydrous MgSO4 and evaporated. The resulting residue was
purified by flash chromatography (deactivated silica gel,
ether/acetone) to yield the corresponding pure product as
4.3.17.
1-(4-Tosylmorpholin-2-yl)ethanol
(diastereomeric
mixture, 9:1, 14m). Pale yellow oil; Rf (hexane/ EtOAc 3:2) 0.40;
yield 75 mg, 25%; 1H NMR (600 MHz, CDCl3) δ 1.19 (d, J = 6.0
Hz, 3 H), 2.21 (t, J = 10.8 Hz, 1 H), 2.30 (brs, 1 H), 2.38 (dd, J =
10.8 and 1.8 Hz, 1 H), 2.45 (s, 3 H), 3.35 (dd, J = 7.8 and 7.2 Hz,
1 H), 3.53-3.62 (m, 3 H), 3.69 (t, J = 12.0 Hz, 1 H), 3.96 (d, J =
11.4 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 2 H, minor), 7.35 (d, J = 8.4
Hz, 2 H, major), 7.63 (d, J = 7.8 Hz, 2 H, major), 7.67 (d, J = 8.4
Hz, 2 H, minor); 13C NMR (100 MHz, CDCl3) 18.9, 20.2, 21.7,
22.8, 45.6, 47.2, 52.8, 54.6, 66.0, 68.2, 73.2, 76.7, 79.2, 83.2,
127.0, 128.0, 130.0, 130.1, 132.3, 143.9, 144.2; IR (KBr, neat)
3508, 2973, 2925, 1598, 1495, 1337, 1163, 1089, 1039, 763, 701
cm-1; HRMS (ESI) calcd. for C13H20NO4S (M + H)+ 286.1108
found 332.1318.
o
colourless solid, M.P. 177-179 C; Rf (MeOH/ CHCl3, 9:1) 0.40;
yield 145 mg, 80%; H NMR (600 MHz, CDCl3) δ 1.41 (t, J =
1
7.2 Hz, 3 H), 2.81 (t, J = 11.4 Hz, 1 H), 2.89 (d, J = 9.0 Hz, 1 H),
2.95 (dd, J = 12.6 and 6.6 Hz, 1 H), 3.15 (d, J = 12.0 Hz, 1 H),
3.70 (t, J = 11.4 Hz, 1 H), 3.75 (t, J = 6.0 Hz, 1 H), 3.91-3.97 (m,
3 H), 4.04-4.08 (m, 3 H), 6.87-6.89 (m, 2 H), 6.91-6.93 (m, 2 H);
13C NMR (150 MHz, CDCl3) δ 15.1, 45.7, 48.3, 64.7, 67.8, 71.0,
74.9, 114.1, 115.4, 121.2, 122.2, 148.8, 149.5; IR (KBr, neat)
3440, 2924, 1503, 1453, 1255, 1125, 1039, 1002, 745 cm-1;
HRMS (ESI) calcd. for C13H20NO3 (M + H)+ 238.1438, found
238.1437.
4.4. Synthesis of (±)-viloxazine 1
Acknowledgements
4.4.1. 2-(Bromomethyl)-
4-tosylmorpholine (9). Carbon
PG is thankful to Council of Scientific and Industrial Research
(CSIR), New Delhi, for her fellowship. Authors are also grateful
to CSIR, New Delhi, for financial support (Grant No.
02/0159/13/EMR-II). Authors are also grateful to Central
Instruments Facility (CIF) of Indian Institute of Technology
Guwahati for NMR facilities.
tetrabromide (671 mg, 2.0 mmol) was added in one portion to a
solution of 7a (500 mg, 1.84 mmol) in dry CH2Cl2 (3.5 mL) at 0
°C, and the reaction was stirred at 0 °C. After 10 minutes, a
solution of Ph3P (530 mg, 2.0 mmol) in CH2Cl2 (1.5 mL) was
added via cannula and stirred at 0 °C for 10 min. Then the
reaction mixture was allowed to warm to room temperature and
further stirred for 2 h. After reaction completed, the mixture was
evaporated in vacuo. The residue was purified by silica gel
column chromatography to give the bromide 9 as white solid
Supplementary data
o
1
M.P. 81-82 C; Rf (hexane) 0.80; yield 583 mg, 95%; H NMR
(600 MHz, CDCl3) δ 2.24 (t, J = 10.2 Hz, 1 H), 2.42-2.47 (m, 1
H), 2.45 (s, 3 H), 3.31 (dd, J = 10.8 and 5.4 Hz, 1 H), 3.35 (dd, J
= 10.2 and 5.4 Hz, 1 H), 3.51 (d, J = 11.4 Hz, 1 H), 3.69-3.77 (m,
3 H), 3.95 (d, J = 10.2 Hz, 1 H), 7.36 (d, J = 7.8 Hz, 2 H), 7.64
(d, J = 7.8 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 21.7, 31.5,
45.4, 49.0, 66.2, 74.3, 128.0, 130.0, 132.2, 144.3; IR (KBr, neat)
2920, 2862, 1597, 1452, 1344, 1167, 1097, 974, 756 cm-1;
HRMS (ESI) calcd. for C12H17BrNO3S (M + H)+ 334.0107, found
334.0115.
Supplementary data related to this article can be found online
at doi:10.
References and notes
1. (a) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van
Delft, F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004,
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M. S. Bioorg. Med. Chem. Lett. 2008, 18, 3188-3191; (d)
Grinsteiner, T. J.; Kishi, Y. Tetrahedron Lett. 1994, 35, 8333-
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2. (a) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown,
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Versiani, M.; Cassano, G.; Perugi, G.; Benedetti, A.; Mastalli,
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(c) Wong, E. H. F.; Sonders, M. S.; Amara, S. G.; Tinholt, P.
4.4.2. 2-((2-Ethoxyphenoxy)methyl)-4-tosylmorpholine (11). To a
solution 2-ethoxyphenol 10 (414 mg, 3 mmol) in CH3CN (10
mL) was added K2CO3 (620 mg, 4.5 mmol) at room temperature,
followed by a solution of 9 (1200 mg, 4.5 mmol) in CH3CN (1
mL). The reaction mixture was heated to reflux overnight. After
cooling to rt, silica gel was added to the reaction mixture and the
solvent was removed on the vacuum. The residue was purified by
column chromatography to give 11 as a white solid, M.P. 90-92

9
M.; Piercey, M. F. P.; Hoffmann, W. P.; Hyslop, D. K.;
21. Ghosh, P.; Saha, P.; Bondalapati, S.; Indukuri, K.; Saikia,
A. K. J. Org. Chem. 2014, 79, 4119-4124.
ACCEPTED MANUSCRIPT
Franklin, S.; Porsolt, R. D.; Bonsignori, A.; Carfagna, N.;
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Audouze, K.; Nielsen, O.; Peters, D. J. Med. Chem. 2004, 47,
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23. Gudla, V.; Balamurugan, R. J. Org. Chem. 2011, 76, 9919-
9933.
24. The crystallographic data for compounds 8k has been
deposited with the Cambridge Crystallographic Data Centre as
Supplementary publication numbers CCDC 1419078.
25. (a) Balsamo, A.; Giorgi, I.; Lapucci, A.; Lucacchini, A.;
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