Diastereoselective Synthesis of Substituted Morpholines from N-Tethered Alkenols: Total Synthesis of (±)-Chelonin A

Article abstract of DOI:10.1021/acs.joc.6b02260

Intramolecular cyclization of nitrogen tethered alkenols catalyzed by palladium chloride leads to substituted morpholines in good yields. The methodology was used for the total synthesis of (±)-chelonin A.

Full text of DOI:10.1021/acs.joc.6b02260

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Article
Diastereselective Synthesis of Substituted Morpholines
from N-Tethered Alkenols: Total Synthesis of (+)-Chelonin A
Madhurjya Borah, Upasana Borthakur, and Anil K. Saikia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02260 • Publication Date (Web): 05 Jan 2017
Downloaded from http://pubs.acs.org on January 6, 2017
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Diastereoselective Synthesis of Substituted Morpholines from N-
Tethered Alkenols: Total Synthesis of (+)-Chelonin A
Madhurjya Borah, Upasana Borthakur, and Anil K. Saikia*
Department of Chemistry
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Indian Institute of Technology Guwahati, Guwahati - 781039, India.
Fax: +91-361-2690762.
e-mail: asaikia@iitg.ernet.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: Intramolecular cyclization of nitrogen tethered alkenols catalyzed by
palladium chloride leads to substituted morpholines in good yields. The methodology has
been used for the total synthesis of (+)-chelonin A.
INTRODUCTION
Substituted morpholine derivatives are widely distributed in many naturally occurring and
1
biologically active molecules. For example, viloxazine (1), reboxetine (2), and edivoxetine
2
(3) show antidepressant properties. Similarly, the compounds 4 and 5 containing morpholine
receptor-antagonist properties (Figure 1).3
unit have anti-inflammatory and GABA
B
4
Morpholines are not only used in organic synthesis as bases or N-alkylating agents but also
used as versatile synthetic units in organic synthesis particularly for the construction of
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agrochemicals, fungicides and bactericides. They are also used as chiral auxiliaries.
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Figure 1. Biologically important morpholines
Several synthetic approaches have been developed for the preparation of morpholines such as
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ring closure of amino diols, ring closure of amino alcohols and bromosulphonium salts,
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double allylic substitution by amino alcohols, cyclization of N-tethered haloalcohols,
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
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4
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subsequent cyclization, ring opening of aziridines and intramolecular cyclization of N-
tethered alkene-alkanols.16 These methods have their own merits and disadvantages.
Recently, we have developed a methodology for the synthesis of oxygen and nitrogen
heterocyclic compounds via intramolecular C-C bond formation from alkyne-epoxides
17
mediated by boron trifluoride etherate. We now present a methodology for the synthesis of
morpholines, using intramolecular C-O bond formation of N-tethered diols, consisting of
alkanol and alkenol, catalyzed by palladium (II) in good yields. Palladium (II) salts have
been used for the synthesis of oxygen heterocycles via intramolecular oxypalladation.18
Although gold (I) has been used for the synthesis of 2-vinyl morpholine from N-tethered
19
allylic alcohols, the use of palladium (II) in morpholine synthesis is not yet reported.
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RESULTS AND DISCUSSION
Considering the ability of palladium(II) compounds to participate in oxypalladation, alkenol
o
6
a was treated with 5 mol% of preformed PdCl
2
(Ph
3
P)
2
in toluene at 90 C for 20 h and 4-
tosyl-2-vinylmorpholine 7a was obtained in 85% yield (Table 1). The reaction was also
performed in the absence of PPh with 5mol% other palladium (II) sources such as Pd(OAc)
and PdCl to give the same product in 20% and 65% yields, respectively. Similarly, reaction
with a mixture of PdCl (5 mol%) and Ph P (10 mol%) gave 85% yields, which suggested
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that the complex catalyst was formed in situ. To investigate the oxidative addition,
cyclization and reductive elimination process, the reaction was also carried out with
Pd(Ph
3
P) but resulted in no yield (entry 5). This indicates that the reaction proceeds via
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oxypalladation and elimination processes.
Table 1. Optimization of the reaction condition
6
a
7a
entry
1
catalyst (mol %)
PdCl (Ph P) (5)
Pd(OAc) (5)
7a yield (%)a
2
3
2
85
2
3
4
5
2
20
65
PdCl
2
(5)
(5), Ph
P) (5)
PdCl
2
3
P (10)
85
Pd(Ph
3
4
No reaction
a
Yield refers to isolated yield.
With the optimized conditions in hand, we further examined the scope of the reaction with a
variety of substrates (Table 2). It was observed from the Table 2 that, primary (Table 2, 6a-e),
secondary including benzylic/or allylic (Table 2, 6f-o,q,r-s) and tertiary alcohols (Table 2,
6
p) undergo the reaction smoothly without giving elimination products indicating that which
is crucial for the reaction of secondary and tertiary alcohols, particularly benzylic alcohols,
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Table 2. Synthesis of morpholines
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under Lewis acidic or Brönsted acidic conditions. Success in the reaction of substrate 6q,
with its primary and secondary allylic alcohol groups (Table 2, entry 17), indicates that the
primary allylic alcohol react selectively in their coordination with palladium under these
reaction conditions and this accounts for the observed product 7q. Sterically hindered tertiary
alcohol 6p (Table 2, entry 16) gave comparatively lower yield (65%) indicating that
nucleophilic addition was rate limiting. The reaction works well for both electron-
withdrawing and electron-donating groups on the aromatic ring of benzylic alcohol substrates
suggesting little influence of the aryl group and produced the desired morpholines in good
yields.
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The reaction is highly diastereoselective, which is determined by proton NMR analysis of the
crude products. The relative stereochemistry of the preferred substituted morpholines was
determined by 2D nuclear Overhauser enhancement spectroscopy (NOESY) of compound 7o,
2 and X-ray crystallographic analysis of compounds 7e and 7o (see SI).20 The high
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stereoselectivity may be attributed to the energy differences in the highly coordinated
transition states A, A', C and C' formed by allylic alcohol with palladium (II) species
(Scheme 1). The formation of cis-2,6-disubstituted morpholine can be attributed to the more
stable transition state A, where both vinyl and R groups take the equatorial position to
minimise the 1,3-diaxial interaction (Scheme 1a). Similarly, selective formation of cis-2,5-
disubstituted morpholine is due to the favoured transition state C, where the R' group takes
the axial position to minimize the 1,2-lone pair and bond pair repulsion between the lone pair
over nitrogen and C-C bond pair of R' group attached to C-5 position. In contrast, the
substrate having E- configured alkene, alcohol 6s, (Table 2, entry 19) showed poor cis-trans
diastereoselectivity (63:37).19
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The proposed mechanism of the reaction is similar to that reported by Tragni and others.
The reaction proceeds via stepwise oxypalladation and elimination processes.18d Palladium
(
II) chloride forms a π-complex with allylic alcohol in an anti-fashion to form intermediates
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A and A' of which A' is unstable due to the presence of the allylic group and in the axial
position. The stability of the intermediate A may be increased by the formation of second six
membered ring due to the hydrogen bonding between the two hydroxyl groups.18d The
intermediate A after nucleophilic attack by hydroxyl group via a S 2′ pathway forms
N
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intermediate B. The intermediate B after either syn or anti elimination forms vinyl substituted
morpholines 7a, 7f-7r (Scheme 1a).18d The formation of compounds 7b-7e can be explained
as follows. The R′ groups take axial position in the transition state C to minimize the
repulsive force between the lone pair over nitrogen and C-C bond pair of R′ group attached to
C-5 position (Scheme 1b).
Scheme 1. Plausible mechanism of the reaction
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To investigate the further applicability of the strategy a total synthesis of (+)-chelonin A was
undertaken (Scheme 2). Chelonin A was isolated from marine sponge Chelonaplysilla sp.21
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2
and its first total synthesis was reported by Somei group. To start with diol 8 was treated
with palladium chloride to give diastereomeric mixture of morpholine 9 with a ratio of 95:5
in 65% yield along with 20% unreacted starting material. Conversion of the olefinic group of
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Scheme 2. Total synthesis of (+) - chelonin A
the major diastereomer of morpholine 9 into alcohol 10 followed by PCC oxidation gave
aldehyde 11 as a single diastereomer in 70% yield. The aldehyde 11 was treated with 2-
iodoaniline in the presence of palladium acetate to give tosylated (+)-chelonin A (12) in 80%
yield. The final compound 5 was obtained by detosylation with sodium naphthalide in 80%
yield and 26% overall yield. The spectral data were in good agreement with the literature.21
CONCLUSIONS
In conclusion, we have developed an efficient method for the synthesis of substituted
morpholines via palladium chloride intramolecular cyclization reaction of N-tethered diols in
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good yields. The reaction is compatible with a wide range of functional groups such as ether,
-
NO , chloro, bromo and furan. The major advantage of this reaction is that it regioselectively
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generates a vinyl group at position 2 of the morpholine ring, which can be used for the
synthesis of biologically active molecules (+)-chelonin A.
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EXPERIMENTAL SECTION
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 an open capillary tube and are uncorrected. Fourier transform-infra
red (FT-IR) spectra were recorded as neat liquid or KBr pellets. NMR spectra were recorded
1
13
in CDCl with tetramethylsilane as the internal standard for H (600 MHz, 400 MHz) or C
3
(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.
General procedure for the synthesis of N-tethered alkenols (6a-6s):
To a stirred solution of NaH (2.2 mmol, 60% in mineral oil) in dry DMF (5 mL) was added
o
dropwise a solution of the tosyl amides (2.0 mmol) in dry DMF (10 mL) at 0 C (N
2
atmosphere). After 20 minutes, a solution of (Z)-4-bromobut-2-en-1-ol (2 mmol) in DMF (5
mL) was added and the reaction mixture was stirred at room temperature for 16 h. After
o
completion of the reaction, a few drops of methanol was added at 0 C and the solution was
poured in ethylacetate (50 mL). The organic phase is washed with brine (3x30 mL), dried
over Na
2
SO and concentrated in vacuo and column chromatographed using ethyl acetate and
4
hexane as eluents to give the N-tethered alkenol 6a-6s.
Preparation
of
(Z)-N-(4-Hydroxybut-2-en-1-yl)-N-(2-hydroxyethyl)-4-methylbenzene-
sulfonamide (6a):
To a stirred solution of NaH (88 mg, 2.2 mmol, 60% in mineral oil) in dry DMF (5 mL) was
o
added dropwise a solution of the tosyl amides (2 mmol) in dry DMF (5 mL) at 0 C (N
2
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atmosphere). After 20 minutes, a solution of (Z)-4-bromobut-2-en-1-ol (300 mg, 2 mmol) in
DMF (5 mL) was added and the reaction mixture was stirred at room temperature for 16 h.
o
After completion of the reaction, a few drops of methanol was added at 0 C and the solution
was poured in ethylacetate (50 mL). The organic phase is washed with brine (3x30 mL),
dried over Na
2
SO and concentrated in vacuo and column chromatographed (EtOAc: Hexane,
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3:2) to give the N-tethered alkenol 6a.
o
1
White solid; mp 48-50 C; R
f
(hexane/ EtOAc 3:2) 0.6; yield 342 mg, 60%; H NMR (600
), 3.24 (t, J = 5.4 Hz, 2 H, 1′-H), 3.73 (t, J = 5.4 Hz, 2 H,
′-H), 3.94 (d, J = 7.2 Hz, 2 H, 1-H), 4.13 (d, J = 6.6 Hz, 2 H, 4-H), 5.35-5.38 (m, 1 H, 2-H),
.74-5.79 (m, 1 H, 3-H), 7.30 (d, J = 8.4 Hz, 2 H, 3′′, 5′′-H), 7.68 (d, J = 8.4 Hz, 2 H, 2′′, 6′′-
MHz, CDCl
3
) δ 2.41 (s, 3 H, Ts-CH
3
2
5
1
3
H); C NMR (100 MHz, CDCl
3
) δ 21.7, 46.1, 49.9, 57.7, 61.7, 127.0, 127.3, 130.1, 133.0,
36.4, 143.9; IR (KBr, neat) 3579, 2959, 2853, 1923, 1652, 1593, 1449, 1163, 887, 764 cm-1;
1
+
HRMS (ESI) calcd. for C13
H
20NO S (M + H) 286.1108, found 286.1119.
4
(Z)-N-(4-Hydroxybut-2-en-1-yl)-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide
(6b):
1
Colourless oil; R
CDCl ) δ 0.95 (d, J = 7.2 Hz, 3 H, 2′-CH
.86 (dd, J = 16.2 and 7.8 Hz, 1 H, 1-H), 3.95-3.98 (m, 2 H, 1-H, 2′-H), 4.21 (d, J = 7.2 Hz, 2
H, 4-H), 5.55-5.60 (m, 1 H, 2-H), 5.71-5.76 (m, 1 H, 3-H), 7.29 (d, J = 8.0 Hz, 2 H, 3′′, 5′′-
f
(hexane/ EtOAc 3:2) 0.55; yield 400 mg, 67%; H NMR (400 MHz,
3
3
), 2.41 (s, 3 H, Ts-CH ), 3.49-3.57 (m, 2 H, 1′-H),
3
3
1
3
H), 7.71 (d, J = 8.0 Hz, 2 H, 2′′, 6′′-H); C NMR (100 MHz, CDCl
3
) δ 14.7, 21.7, 40.3, 55.5,
5
1
+
8.0, 64.8, 127.3, 129.5, 130.0, 131.3, 137.8, 143.7; IR (KBr, neat) 3477, 2980, 2856, 1920,
-1
647, 1599, 1457, 1324, 1153, 1014, 870, 760 cm ; HRMS (ESI) calcd. for C14
H
22NO S (M
4
+
20
H) 300.1264, found 300.1274. [α]
D
+24.9 (c 1.0 CHCl ).
3
(Z)-N-(1-Hydroxy-3-methylbutan-2-yl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6c):
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Pale yellow oil; R
CDCl ) δ 0.69 (d, J = 6.6 Hz, 3 H, 3-CH
H, 3-H, -OH), 2.20 (brs, 1 H, -OH), 2.42 (s, 3 H, Ts-CH
f
(hexane/ EtOAc 3:2) 0.51; yield 405 mg, 62%; H NMR (600 MHz,
), 0.91 (d, J = 6.6 Hz, 3 H, 3-CH ), 1.79-1.85 (m, 2
), 3.44-3.48 (m, 1 H, 2-H), 3.62 (dd,
3
3
3
3
J = 12.0 and 8.4 Hz, 1 H, 1-H), 3.75 (dd, J = 12.0 and 9.6 Hz, 1 H, 1-H), 3.91 (dd, J = 16.2
and 7.2 Hz, 1 H, 1′-H), 4.02 (dd, J = 16.2 and 7.2 Hz, 1 H, 1′-H), 4.21 (d, J = 7.2 Hz, 2 H, 4′-
H), 5.60-5.65 (m, 1 H, 2′-H), 5.72-5.77 (m, 1 H, 3′-H), 7.28 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-H),
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1
3
7
4
.72 (d, J = 7.8 Hz, 2 H, 2′′,6′′-H); C NMR (150 MHz, CDCl
3
) δ 20.3, 20.8, 21.7, 28.2,
1.3, 58.1, 62.4, 66.3, 127.6, 129.5, 129.8, 131.1, 138.2, 143.6; IR (KBr, neat) 3468, 2873,
-1
1920, 1654, 1470, 1290, 1170, 1008, 883, 773 cm ; HRMS (ESI) calcd. for C16
H
26NO S (M
4
+
20-5.7 (c 0.8 CHCl
).
+
H) 328.1577, found 328.1598. [α]
D
3
(
Z)-N-(2-Hydroxy-1-phenylethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzenesulfonamide
(6d):
1
Pale yellow oil oil; R
f
(hexane/ EtOAc 3:2) 0.53; yield 404 mg, 56%; H NMR (400 MHz,
), 2.57 (brs, 1 H, -OH), 3.75 (dd, J = 16.2
and 7.8 Hz, 1 H, 2-H), 3.91 (dd, J = 16.2 and 6.0 Hz, 1 H, 2-H), 4.00-4.10 (m, 4 H, 1′,4′-H),
CDCl
3
) δ 2.28 (brs, 1 H, -OH), 2.43 (s, 3 H, Ts-CH
3
5
7
.03 (t, J = 7.2 Hz, 1 H, 1-H), 5.28-5.32 (m, 1 H, 2′-H), 5.60-5.64 (m, 1 H, 3′-H), 6.99 (d, J =
.2 Hz, 2 H, 2′′′, 6′′′-H), 7.22-7.26 (m, 3 H, 3′′′, 4′′′, 5′′′-H), 7.28 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-
1
3
H), 7.72 (d, J = 7.8 Hz, 2 H, 2′′, 6′′-H); C NMR (100 MHz, CDCl
3
) δ 21.7, 41.7, 57.9, 62.1,
6
2.4, 127.6, 128.3, 128.5, 128.9, 129.0, 129.9, 131.3, 136.0, 137.9, 143.8; IR (KBr, neat)
-1
3
528, 2924, 1598, 1496, 1305, 1164, 1017, 891, 739 cm ; HRMS (ESI) calcd. for
+
20
C
19
H24NO
4
S (M + H) 362.1421, found 362.1431. [α]
D
-28.4 (c 0.8 CHCl ).
3
(
Z)-N-(1-Hydroxy-3-phenylpropan-2-yl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6e):
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2
2
2
2
2
2
3
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3
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3
3
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4
4
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5
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5
5
5
5
5
5
5
6
o
1
White solid, mp. 108-110 C; R
f
(hexane/ EtOAc 3:2) 0.50; yield 450 mg, 60%; H NMR
) δ 2.38 (s, 3 H, Ts-CH ), 2.64 (dd, J = 13.8 and 6.0 Hz, 1 H, 3-H), 2.78
dd, J = 13.8 and 8.4 Hz, 1 H, 3-H), 2.92 (brs, 1 H, -OH), 3.58-3.65 (m, 2 H, 1-H), 4.00 (d, J
6.6 Hz, 2 H, 1′-H), 4.04-4.09 (m, 1 H, 2-H), 4.21 (d, J = 6.6 Hz, 2 H, 4′-H), 5.54-5.59 (m, 1
H, 2′-H), 5.70-5.73 (m, 1 H, 3′-H), 7.03 (d, J = 7.2 Hz, 2 H, 2′′′, 6′′′-H), 7.18-7.20 (m, 5 H,
(600 MHz, CDCl
3
3
(
=
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
3
′′′, 4′′′, 5′′′-H, 3′′, 5′′-H), 7.58 (d, J = 7.8 Hz, 2 H, 2′′, 6′′-H); C NMR (150 MHz, CDCl
3
) δ
2
1.6, 36.2, 41.3, 58.0, 61.7, 62.6, 126.7, 127.3, 128.7, 129.1, 129.4, 129.8, 131.2, 137.6,
-1
1
37.8, 143.6; IR (KBr, neat) 3479, 2967, 1658, 1598, 1496, 1289, 1158, 872, 765 cm ;
+
20
HRMS (ESI) calcd. for C20
H
26NO
4
S (M + H) 376.1577, found 376.1576. [α]
D
-28.0 (c 0.9
CHCl ).
3
(
Z)-N-(2-Hydroxy-2-phenylethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzenesulfonamide
(6f):
1
Pale yellow oil; R
f
(hexane/ EtOAc 3:2) 0.52; yield 397 mg, 55%; H NMR (600 MHz,
), 3.29 (d, J = 6.0 Hz, 2 H, 1-H) 3.98 (dd, J = 15.6 and 7.2 Hz,
H, 1′-H), 4.02 (dd, J = 15.6 and 7.8 Hz, 1 H, 1′-H), 4.11 (dd, J = 12.6 and 6.6 Hz, 1 H, 4′-
CDCl
3
) δ 2.42 (s, 3 H, Ts-CH
3
1
H), 4.19 (dd, J = 12.6 and 6.6 Hz, 1 H, 4′-H), 4.98 (t, J = 6.0 Hz, 1 H, 2-H), 5.34-5.39 (m, 1
H, 2′-H), 5.78-5.83 (m, 1 H, 3′-H), 7.29 (d, J = 7.8 Hz, 3 H, 3′′, 5′′, 4′′′-H), 7.30-7.36 (m, 4 H,
1
3
2′′′, 3′′′, 5′′′, 6′′′-H), 7.69 (d, J = 7.8 Hz, 2 H, 2′′, 6′′-H); C NMR (100 MHz, CDCl
3
) δ 21.7,
4
6.5, 55.6, 58.0, 73.8, 126.1, 127.1, 127.5, 128.3, 128.8, 130.1, 133.1, 136.6, 141.5, 143.9; IR
-
1
(
KBr, neat) 3400, 2924, 1640, 1448, 1331, 1155, 1087, 816, 656 cm ; HRMS (ESI) calcd.
+
for C19
H24NO
4
S (M + H) 362.1421, found 362.1405.
(
Z)-N-(2-(4-Chlorophenyl)-2-hydroxyethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6g):
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1
Pale yellow oil; R
CDCl ) δ 2.23 (brs, 1 H, -OH), 2.42 (s, 3 H, Ts-CH
brs, 1 H, -OH), 3.95-4.03 (m, 2 H, 1′-H), 4.13 (dd, J = 13.2 and 7.2 Hz, 1 H, 4′-H), 4.19 (dd,
J = 13.2 and 6.6 Hz, 1 H, 4′-H), 4.96 (t, J = 6.0 Hz, 1 H, 2-H), 5.33-5.38 (m, 1 H, 2′-H), 5.78-
f
(hexane/ EtOAc 3:2) 0.48; yield 482 mg, 61%; H NMR (600 MHz,
3
3
), 3.23 (d, J = 5.4 Hz, 2 H, 1-H), 3.38
(
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
2
1
1
.83 (m, 1 H, 3′-H), 7.26-7.30 (m, 6 H, 2′′′,3′′′,5′′′,6′′′-H, 3′′, 5′′-H), 7.67 (d, J = 8.4 Hz, 2 H,
1
3
′′, 6′′-H); C NMR (100 MHz, CDCl
3
) δ 21.7, 46.5, 55.5, 57.9, 73.1, 126.9, 127.4, 127.5,
28.9, 130.1, 133.2, 133.9, 136.4, 140.0, 144.1; IR (KBr, neat) 3500, 2924, 2870, 1597, 1492,
-1
+
334, 1159, 1090, 817, 658 cm ; HRMS (ESI) calcd. for C19
H
23ClNO S (M + H) 396.1031,
4
found 396.1038.
(Z)-N-(2-(3-Bromophenyl)-2-hydroxyethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6h):
o
1
White solid, mp. 108-110 C; R
600 MHz, CDCl ) δ 2.42 (s, 3 H, Ts-CH
H), 3.73 (brs, 1 H, -OH), 3.94-4.03 (m, 2 H, 1′-H), 4.11 (dd, J = 12.6 and 5.4 Hz, 1 H, 4′-H),
f
(hexane/ EtOAc 3:2) 0.50; yield 570 mg, 65%; H NMR
(
3
3
), 2.60 (brs, 1 H, -OH), 3.24 (d, J = 6.0 Hz, 2 H, 1-
4
2
5
.17 (dd, J = 12.6 and 7.2 Hz, 1 H, 4′-H), 4.93 (t, J = 6.0 Hz, 1 H, 2-H), 5.30-5.35 (m, 1 H,
′-H), 5.76-5.81 (m, 1 H, 3′-H), 7.19 (t, J = 7.8 Hz, 1 H, 5′′′-H), 7.27-7.30 (m, 3 H, 4′′′-H, 3′′,
′′-H), 7.39 (d, J = 8.4 Hz, 1 H, 6′′′-H), 7.49 (s, 1 H, 2′′′-H), 7.67 (t, J = 7.8 Hz, 2 H, 2′′, 6′′-
1
3
H); C NMR (100 MHz, CDCl
3
) δ 21.7, 46.4, 55.3, 57.8, 73.0, 122.8, 124.8, 126.8, 127.4,
1
1
29.2, 130.1, 130.3, 131.1, 133.2, 136.3, 143.9, 144.0; IR (KBr, neat) 3521, 2922, 2856,
-1
919, 1596, 1473, 1332, 1161, 889, 765 cm ; HRMS (ESI) calcd. for C19
H
23BrNO S (M +
4
+
H) 440.0526, found 440.0532.
(Z)-N-(2-(4-bromophenyl)-2-hydroxyethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6i):
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4
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5
5
5
5
5
6
o
1
White solid, mp. 111-113 C; R
f
(hexane/ EtOAc 3:2) 0.53; yield 570 mg, 65%; H NMR
(
600 MHz, CDCl ) δ 2.42 (s, 3 H, Ts-CH
3
3
), 3.22 (d, J = 6.0 Hz, 2 H, 1-H), 3.96 (dd, J = 15.6
and 7.2 Hz, 1 H, 1′-H), 4.00 (dd, J = 15.6 and 7.8 Hz, 1 H, 1′-H), 4.10 (dd, J = 13.2 and 6.6
Hz, 1 H, 4′-H), 4.16 (dd, J = 13.2 and 7.2 Hz, 1 H, 4′ -H), 4.92 (t, J = 6.0 Hz, 1 H, 2-H), 5.29-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
.33 (m, 1 H, 2′-H), 5.76-5.80 (m, 1 H, 3′-H), 7.21 (d, J = 7.8 Hz, 2 H, 2′′′, 6′′′-H), 7.28 (d, J
7.8 Hz, 2 H, 3′′, 5′′-H), 7.43 (d, J = 7.8 Hz, 2 H, 3′′′, 5′′′-H), 7.65 (d, J = 7.8 Hz, 2 H, 2′′, 6′′-
=
1
3
H); C NMR (100 MHz, CDCl
3
) δ 21.7, 46.3, 55.1, 57.7, 73.1, 121.9, 126.7, 127.3, 127.8,
1
30.1, 131.8, 133.2, 136.3, 140.5, 144.0; IR (KBr, neat) 3530, 2925, 2850, 1925, 1590, 1480,
-
1
+
1356, 1156, 878, 755 cm ; HRMS (ESI) calcd. for C19
H
23BrNO S (M + H) 440.0526,
4
found 440.0529.
(
Z)-N-(2-(4-Fluorophenyl)-2-hydroxyethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6j):
1
Pale yellow oil; R
f
(hexane/ EtOAc 3:2) 0.50; yield 500 mg, 66%; H NMR (600 MHz,
), 3.20-3.26 (m, 2 H, 1-H), 3.94 (dd, J = 15.6 and 6.6 Hz, 1 H,
′-H), 4.01 (dd, J = 15.6 and 7.8 Hz, 1 H, 1′-H), 4.09 (dd, J = 12.6 and 7.2 Hz, 1 H, 4′-H),
CDCl
3
) δ 2.41 (s, 3 H, Ts-CH
3
1
4
2
.15 (dd, J = 12.6 and 6.6 Hz, 1 H, 4′-H), 4.94 (t, J = 7.8 Hz, 1 H, 2-H), 5.27-5.32 (m, 1 H,
′-H), 5.74-5.78 (m, 1 H, 3′-H), 7.00 (t, J = 7.2 Hz, 2 H, 2′′′, 6′′′-H), 7.27-7.31 (m, 4 H, 3′′,
1
3
5′′-H, 3′′′, 5′′′-H), 7.66 (d, J = 7.2 Hz, 2 H, 2′′, 6′′-H); C NMR (100 MHz, CDCl
3
) δ 21.7,
4
1
6.3, 55.2, 57.7, 73.0, 115.5 (d, J = 22.5 Hz), 126.7, 127.3, 127.7 (d, J = 9.0 Hz), 130.1,
1
9
33.2, 136.4, 137.3, 144.0, 162.5 (d, J = 244.5 Hz, C-F); F NMR (376 MHz, CDCl
3
/C
6
6
F ) δ
-1
38.05; IR (KBr, neat) 3500, 2926, 2857, 1600, 1450, 1338, 1222, 737 cm ; HRMS (ESI)
+
calcd. for C19
H23FNO
4
S (M + H) 380.1326, found 380.1332.
(
Z)-N-(2-(3,4-Dichlorophenyl)-2-hydroxyethyl)-N-(4-hydroxybut-2-en-1-yl)-4-
methylbenzenesulfonamide (6k):
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Pale yellow oil; R
CDCl ) δ 2.42 (s, 3 H, Ts-CH
brs, 1 H, -OH), 3.96-4.03 (m, 2 H, 1′-H), 4.09-4.20 (m, 2 H, 4′-H), 4.90-4.94 (m, 1 H, 2-H),
f
(hexane/ EtOAc 3:2) 0.48; yield 549 mg, 64%; H NMR (600 MHz,
3
3
), 2.55 (brs, 1 H, -OH), 3.22 (d, J = 6.0 Hz, 2 H, 1-H), 3.79
(
5
.32-5.36 (m, 1 H, 2′-H), 5.78-5.82 (m, 1 H, 3′-H), 7.18 (d, J = 7.8 Hz, 1 H, 6′′′-H), 7.29 (d, J
7.8 Hz, 2 H, 3′′, 5′′-H), 7.37 (dd, J = 8.4 and 3.6 Hz, 1 H, 5′′′-H), 7.44 (s, 1 H, 2′′′-H), 7.65
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
=
1
3
(
dd, J = 7.8 and 1.8 Hz, 2 H, 2′′, 6′′-H); C NMR (150 MHz, CDCl
3
) δ 21.7, 46.5, 55.2, 57.8,
7
2.5, 125.6, 126.8, 127.3, 128.1, 130.1, 130.7, 131.9, 132.8, 133.2, 136.2, 141.8, 144.2; IR
-1
(
KBr, neat) 3419, 2925, 2854, 1641, 1470, 1337, 1159, 1089, 820, 739 cm ; HRMS (ESI)
+
calcd. for C19
H22Cl
2
NO
4
S (M + H) 430.0641, found 430.0643.
(
Z)-N-(2-Hydroxy-2-(p-tolyl)ethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzenesulfonamide
6l):
(
1
Pale yellow oil; R
CDCl ) δ 2.32 (s, 3 H, Tol-CH
Hz, 2 H, 1-H), 3.54 (brs, 1 H, -OH), 3.94 (dd, J = 15.6 and 6.6 Hz, 1 H, 1′-H), 4.03 (dd, J =
f
(hexane/ EtOAc 3:2) 0.51; yield 435 mg, 58%; H NMR (600 MHz,
3
3
), 2.40 (s, 3 H, Ts-CH ), 2.83 (brs, 1 H, -OH), 3.25 (d, J = 6.0
3
1
7
5
5.6 and 7.8 Hz, 1 H, 1′-H), 4.09 (dd, J = 12.6 and 6.6 Hz, 1 H, 4′-H), 4.15 (dd, J = 12.6 and
.2 Hz, 1 H, 4′-H), 4.90 (t, J = 5.4 Hz, 1 H, 2-H), 5.30 (dd, J = 17.4 and 7.8 Hz, 1 H, 2′-H),
.76 (dd, J = 17.4 and 6.6 Hz, 1 H, 3′-H), 7.12 (d, J = 7.8 Hz, 2 H, 2′′′, 6′′′-H), 7.21 (d, J = 7.8
Hz, 2 H, 3′′′, 5′′′-H), 7.26 (d, J = 8.4 Hz, 2 H, 3′′, 5′′-H), 7.66 (d, J = 8.4 Hz, 2 H, 2′′, 6′′-H);
13C NMR (150 MHz, CDCl
3
) δ 21.3, 21.7, 46.2, 55.2, 57.7, 73.6, 126.0, 126.8, 127.3, 129.4,
1
30.0, 133.1, 136.6, 137.8, 138.5, 143.8; IR (KBr, neat) 3498, 2923, 1640, 1330, 1153, 1086,
-1
+
939, 816, 754 cm ; HRMS (ESI) calcd. for C20
H
26NO S (M + H) 376.1577, found
4
3
76.1594.
(
Z)-N-(2-hydroxy-2-(4-methoxyphenyl)ethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6m):
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
White solid, mp. 79-81 C; R
MHz, CDCl ) δ 2.41 (s, 3 H, Ts-CH
.43 (brs, 1 H, -OH), 3.78 (s, 3 H, -OCH
dd, J = 15.6 and 7.8 Hz, 1 H, 1′-H), 4.07 (dd, J = 12.6 and 6.0 Hz, 1 H, 4′-H), 4.16 (dd, J =
f
(hexane/ EtOAc 3:2) 0.4 5; yield 523 mg, 67%; H NMR (600
), 2.69 (brs, 1 H, -OH), 3.25 (d, J = 6.0 Hz, 2 H, 1-H),
), 3.94 (dd, J = 15.6 and 6.0 Hz, 1 H, 1′-H), 4.03
3
3
3
3
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
7
2.6 and 6.0 Hz, 1 H, 4′-H), 4.90 (t, J = 5.4 Hz, 1 H, 2-H), 5.31 (dd, J = 16.2 and 7.8 Hz, 1 H,
′-H), 5.76 (dd, J = 16.2 and 6.0 Hz, 1 H, 3′-H), 6.86 (d, J = 8.4 Hz, 2 H, 2′′′, 6′′′-H), 7.24-
1
3
.29 (m, 4 H, 3′′, 5′′-H, 3′′′, 5′′′-H), 7.67 (d, J = 8.4 Hz, 2 H, 2′′, 6′′-H); C NMR (150 MHz,
) δ 21.7, 46.2, 55.2, 55.5 57.7, 73.4, 114.1, 126.9, 127.3, 127.4, 130.0, 133.1, 133.6,
136.6, 143.8, 159.5; IR (KBr, neat) 3503, 2925, 2839, 1612, 1447, 1334, 1249, 1156, 1032,
CDCl
3
-1
+
8
35, 745 cm ; HRMS (ESI) calcd. for C20
H
26NO S (M + H) 392.1526, found 392.1530.
5
(
Z)-N-(2-Hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-N-(4-hydroxybut-2-en-1-yl)-4-
methylbenzenesulfonamide (6n):
o
1
White solid, mp. 78-79 C; R
f
(hexane/ EtOAc 3:2) 0.52; yield 506 mg, 59%; H NMR (400
MHz, CDCl
3
) δ 2.41 (s, 3 H, Ts-CH
3
), 3.25 (d, J = 6.0 Hz, 2 H, 1-H), 3.95-4.07 (m, 2 H, 1′-
H), 4.11-4.22 (m, 2 H, 4′-H), 5.03-5.06 (m, 1 H, 2-H), 5.34 (dd, J = 17.6 and 7.2 Hz, 1 H, 2′-
H), 5.77-583 (m, 1 H, 3′-H), 7.28 (d, J = 8.0 Hz, 2 H, 3′′, 5′′-H), 7.47 (d, J = 8.0 Hz, 2 H, 3′′′,
1
3
5
′′′-H), 7.57 (d, J = 8.0 Hz, 2 H, 2′′, 6′′-H), 7.66 (d, J = 8.0 Hz, 2 H, 2′′′, 6′′′-H); C NMR
(150 MHz, CDCl
3
) δ 21.7, 46.5, 55.4, 57.8, 73.2, 122.9, 125.7 (q, J = 3.8 Hz), 126.46, 126.5,
19
1
26.8, 127.4, 127.5, 130.1, 134.7 (q, J = 294.4 Hz), 144.2, 145.5; F NMR (376 MHz,
CDCl
3
/C
6
F ) δ 13.4; IR (KBr, neat) 3508, 2926, 2873, 1621, 1599, 1449, 1320, 1169, 1014,
6
-1
+
851, 739 cm ; HRMS (ESI) calcd. for C20
H
23
F
3
NO S (M + H) 430.1294, found 430.1308.
4
(
Z)-N-(2-Hydroxy-2-(4-nitrophenyl)ethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6o):
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o
1
White solid, mp. 75-77 C; R
MHz, CDCl ) δ 2.41 (s, 3 H, Ts-CH
.96 (brs, 1 H, -OH), 4.00 (d, J = 7.2 Hz, 2 H, 1′-H), 4.12-4.21 (m, 2 H, 4′-H), 5.08-5.10 (m,
f
(hexane/ EtOAc 3:2) 0.40; yield 416 mg, 51%; H NMR (600
3
3
), 2.50 (brs, 1 H, -OH), 3.25 (d, J = 7.8 Hz, 2 H, 1-H),
3
1
2
H, 2-H), 5.33 (dd, J = 18.0 and 7.8 Hz, 1 H, 2’-H), 5.80 (m, 1 H, 3′-H), 7.29 (d, J = 8.4 Hz,
H, 3′′, 5′′-H), 7.54 (d, J = 8.4 Hz, 2 H, 3′′′, 5′′′-H), 7.65 (d, J = 8.4 Hz, 2 H, 2′′, 6′′-H), 8.16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
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33
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
(
d, J = 8.4 Hz, 2 H, 2′′′, 6′′′-H); C NMR (150 MHz, CDCl
3
) δ 21.7, 46.4, 54.9, 57.7, 72.8,
1
2
23.8, 126.6, 127.0, 127.3, 130.1, 133.3, 136.0, 144.3, 147.5, 148.9; IR (KBr, neat) 3558,
-1
923, 2858, 1602, 1529, 1449, 1309, 1160, 1089, 747 cm ; HRMS (ESI) calcd. for
+
C
19
H
23
N
2
O
6
S (M + H) 407.1271, found 407.1279.
(
Z)-N-(2-Hydroxy-2-methylpropyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzenesulfonamide
(6p):
o
1
White solid, mp. 97-99 C; R
MHz, CDCl ) δ 1.23 (s, 6 H, 2-2CH
H, -OH), 3.66 (s, 2 H, 1-H), 4.13 (d, J = 6.0 Hz, 2 H, 1′-H), 4.21 (d, J = 6.0 Hz, 2 H, 4′-H),
.67-5.75 (m, 2 H, 2′’,3′-H) 7.29 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-H), 7.74 (d, J = 7.8 Hz, 2 H, 2′′,
f
(hexane/ EtOAc 3:2) 0.50; yield 375 mg, 60%; H NMR (600
3
3
), 2.15 (brs, 1 H, -OH), 2.42 (s, 3 H, Ts-CH ), 2.80 (brs,
3
1
5
6
1
1
3
′′-H); C NMR (150 MHz, CDCl
3
) δ 21.7, 25.0, 43.7, 58.3, 63.8, 69.8, 127.3, 129.9, 130.0,
31.3, 140.0, 143.6; IR (KBr, neat) 3505, 2926, 2880, 1646, 1472, 1310, 1147, 1090, 879,
-1
+
736, 660 cm ; HRMS (ESI) calcd. for C15
H
24NO S (M + H) 314.1421, found 314.1443.
4
(
Z)-N-(2-Hydroxy-4-methylpent-3-en-1-yl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6q):
1
Pale yellow oil; R
f
(hexane/ EtOAc 3:2) 0.55; yield 325 mg, 48%; H NMR (600 MHz,
), 1.69 (s, 3 H, 4′-CH ), 2.41 (s, 3 H, Ts-CH ), 2.80 (brs, 2 H, -
OH), 3.07 (d, J = 4.2 Hz, 2 H, 1-H), 3.97 (dd, J = 15.6 and 6.0 Hz, 1 H, 1′-H), 4.03 (dd, J =
CDCl
3
) δ 1.66 (s, 3 H, 5-CH
3
3
3
2
15.6 and 7.8 Hz, 1 H, 1′-H), 4.09 (dd, J = 12.6 and 6.0 Hz, 1 H, 4′-H), 4.15 (dd, J = 12.6 and
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7.2 Hz, 1 H, 4′-H), 4.56-4.61 (m, 1 H, 2-H), 5.07 (d, J = 7.2 Hz, 1 H, 3-H), 5.32-5.39 (m, 1 H,
2
2
1
1
′-H), 5.75-5.80 (m, 1 H, 3′-H), 7.29 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-H), 7.68 (d, J = 7.8 Hz, 2 H,
1
3
′′, 6′′-H); C NMR (150 MHz, CDCl
3
) δ 18.6, 21.7, 25.9, 46.4, 53.4, 57.7, 68.6, 124.5,
27.1, 127.4, 130.0, 133.0, 136.6, 137.3, 143.8; IR (KBr, neat) 3418, 2922, 1648, 1447, 1335,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
158, 1019, 817, 769 cm ; HRMS (ESI) calcd. for C17
H
26NO S (M + H) 340.1577, found
4
340.1598.
(Z)-N-(2-(Furan-2-yl)-2-hydroxyethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6r):
1
Pale yellow oil; R
CDCl ) δ 2.42 (s, 3 H, Ts-CH
Hz, 1 H, 1′-H), 4.00 (dd, J = 15.6 and 12.0 Hz, 1 H, 1′-H), 4.08 (dd, J = 13.2 and 6.8 Hz, 1 H,
f
(hexane/ EtOAc 3:2) 0.50; yield 414 mg, 59%; H NMR (400 MHz,
3
3
), 3.44 (d, J = 5.2 Hz, 2 H, 1-H), 3.90 (dd, J = 15.6 and 10.2
4
1
′-H), 4.15 (dd, J = 13.2 and 7.6 Hz, 1 H, 4′-H), 4.95 (t, J = 6.0 Hz, 1 H, 2-H), 5.29 (dd, J =
7.6 and 7.2 Hz, 1 H, 2′-H), 5.72-5.79 (m, 1 H, 3′-H), 6.29-6.32 (m, 2 H, 3′′′, 4′′′-H), 7.30 (d,
13
J = 8.4 Hz, 2 H, 3′′, 5′′-H), 7.35 (m, 1 H, 5′′′-H), 7.69 (d, J = 8.4 Hz, 2 H, 2′′, 6′′-H); C
NMR (150 MHz, CDCl
3
) δ 21.7, 46.3, 52.1, 57.7, 67.5, 107.4, 110.6, 126.6, 127.4, 130.1,
1
1
33.2, 136.5, 142.4, 143.9, 153.8; IR (KBr, neat) 3585, 2923, 2870, 1632, 1598, 1449, 1330,
-1
+
160, 1094, 917, 749 cm ; HRMS (ESI) calcd. for C17
H
22NO S (M + H) 352.1213, found
5
352.1211.
(E)-N-(2-(4-Bromophenyl)-2-hydroxyethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzene-
sulfonamide (6s):
1
Pale yellow oil; Rf (hexane/ EtOAc 3:2) 0.50; yield 518 mg, 59%; H NMR (600 MHz,
CDCl ) δ 2.34 (s, 3 H, Ts-CH ), 3.06 (dt, J = 15.6 and 2.4 Hz, 1 H, 1-H), 3.16-3.26 (m, 1 H,
-H), 3.64-3.69 (m, 1 H, 1′-H), 3.74-3.76 (m, 1 H, 1′-H), 3.96 (brs, 2 H, 4′-H), 4.81-4.86 (m,
3
3
1
1 H, 2-H), 5.40-5.45 (m, 1 H, 2′-H), 5.62-5.65 (m, 1 H, 3′-H), 7.12-7.14 (m, 1 H), 7.19-7.22
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3
(m, 2 H), 7.25-7.37 (m, 2 H), 7.34-7.37 (m, 1 H), 7.57-7.60 (m, 2 H); C NMR (150 MHz,
CDCl ) δ 21.7, 51.7, 55.7, 62.6, 72.9, 121.8, 126.2, 127.5, 128.7, 130.0, 131.7, 134.5, 136.0,
3
-1
1
41.5, 143.9; IR (KBr, neat) 3604, 2922, 2865, 1597, 1457, 1377, 1164, 1096, 973, 747 cm ;
+
HRMS (ESI) calcd. for C19
H
23BrNO S (M + H) 440.0526, found 440.0529.
4
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59
60
General procedure for the synthesis of vinylmorpholine (7a-7s):
A solution of N-tethered alkenol (0.50 mmol) and PdCl
2
(PPh
3
2
) (0.025 mmol) in 10 mL of
o
toluene was heated at 90 C for 20 h. The reaction is monitored by checking TLC. After
completion of the reaction, ethyl acetate (15 mL) was poured in to the reaction mixture and
passed through celite. The filtrate was concentrated in vacuo and purified by column
chromatography using ethyl acetate and hexane as eluents to give the morpholine derivatives.
Synthesis of 4-Tosyl-2-vinylmorpholine (7a):
A solution of N-tethered alkenol (143 mg, 0.50 mmol) and PdCl
2
(PPh
3
2
) (18 mg, 0.025mmol)
o
in 10 mL of toluene was heated at 90 C for 20 h. The reaction is monitored by checking
TLC. After completion of the reaction, ethyl acetate (15 mL) was poured in to the reaction
mixture and passed through celite. The filtrate was concentrated in vacuo and purified by
column chromatography (EtOAc: Hexane, 1:4) to give the 7a.
4-Tosyl-2-vinylmorpholine (7a):19
o
o
White solid; mp 126-128 C (reported mp 126-128 C); R (hexane/ EtOAc 4:1) 0.55; yield
f
1
1
14 mg, 85%; H NMR (600 MHz, CDCl
3
) δ 2.12 (dd, J = 11.4 and 10.8 Hz, 1 H, 3-Ha), 2.40
), 3.52 (d, J = 11.4 Hz, 1 H, 5-Ha),
.60 (d, J = 11.4 Hz, 1 H, 5-He), 3.72 (dd, J = 11.4 and 10.8 Hz, 1 H, 6-Ha), 3.95 (d, J =
(dd, J = 11.4 and 3.0 Hz, 1 H, 3-He), 2.44 (s, 3 H, Ts-CH
3
3
1
1
7
1.4 Hz, 1 H, 6-He), 4.04-4.06 (m, 1 H, 2-H), 5.21 (d, J = 10.8 Hz, 1 H, 8-Hcis), 5.33 (d, J =
6.8 Hz, 1 H, 8-Htrans), 5.69-5.75 (m, 1 H, 7-H), 7.34 (d, J = 7.8Hz, 2 H, 3′,5′-H), 7.63 (d, J =
13
.8 Hz, 2 H, 2′,6′-H); C NMR (150 MHz, CDCl
3
) δ 21.7, 45.5, 50.2, 65.9, 75.9, 117.9,
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2
2
2
2
2
2
2
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5
6
128.0, 130.0, 132.3, 134.8, 144.2; IR (KBr, neat) 2923, 2856, 1651, 1451, 1267, 1163, 1095,
-1
+
9
38, 757 cm ; HRMS (ESI) calcd. for C13
H
18NO S (M + H) 268.1002 found 268.1023.
3
(
2S*,5S*)-5-Methyl-4-tosyl-2-vinylmorpholine (7b):19
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Colourless oil; R
f
(hexane/ EtOAc 4:1) 0.52; yield 124 mg, 88%; H NMR (400 MHz,
CDCl ) δ 1.08 (d, J = 7.2 Hz, 3 H, 5-CH
3
3
), 2.43 (s, 3 H, Ts-CH ), 2.87 (dd, J = 12.8 and 10.8
3
Hz, 1 H, 3-Ha), 3.60 (dd, J = 12.8 and 2.4 Hz, 1 H, 3-He), 3.67 (d, J = 1.2 Hz, 2 H, 6-H),
3.83-3.88 (m, 1 H, 2-H), 3.98 (q, J = 6.8 Hz, 1 H, 5-H), 5.24 (d, J = 10.8 Hz, 1 H, 9-Hcis),
5
.35 (d, J = 17.6 Hz, 1 H, 9-Htrans), 5.72-5.80 (m, 1 H, 8-H), 7.31 (d, J = 8.0 Hz, 2 H, 3′,5′-
1
3
H), 7.70 (d, J = 8.0 Hz, 2 H, 2′,6′-H); C NMR (100 MHz, CDCl
3
) δ 13.8, 21.7, 44.4, 48.4,
71.4, 76.4, 117.9, 127.3, 130.0, 134.9, 137.6, 143.6; IR (KBr, neat) 2982, 2857, 1648, 1598,
-1
+
1
457, 1258, 1183, 927, 764 cm ; HRMS (ESI) calcd. for C14
H
20NO S (M + H) 282.1158
3
20
found 282.1179. [α]
D
+22.9 (c 0.9 CHCl ).
3
(2S*,5S*)-5-Isopropyl-4-tosyl-2-vinylmorpholine (7c):19
o
White solid, mp. 100-102 C (reported liquid); R
f
(hexane/ EtOAc 4:1) 0.55; yield 111 mg,
), 0.96 (d, J = 7.2 Hz, 3
), 2.92 (dd, J = 15.0 and 11.4 Hz, 1
1
7
2%; H NMR (600 MHz, CDCl
3
) δ 0.91 (d, J = 7.2 Hz, 3 H, 7-CH
3
H, 7-CH
3
), 2.19-2.26 (m, 1 H, 7-H), 2.43 (s, 3 H, Ts-CH
3
H, 3-Ha), 3.28-3.30 (m, 2 H, 3-He, 6-Ha), 3.54-3.58 (m, 1 H, 2-H), 3.67 (dd, J = 15.0 and 4.2
Hz, 1 H, 6-He), 3.88 (d, J = 11.4 Hz, 1 H, 5-H), 5.17 (d, J = 10.8 Hz, 1 H, 11-Hcis), 5.24 (d, J
= 17.4 Hz, 1 H, 11-Htrans), 5.63-5.69 (m, 1 H, 10-H), 7.30 (d, J = 7.8 Hz, 2 H, 3′,5′-H), 7.71
13
(
d, J = 7.8 Hz, 2 H, 2′,6′-H); C NMR (150 MHz, CDCl
3
) δ 19.9, 20.1, 21.7, 25.5, 45.5, 59.1,
6
1
3
6.2, 75.0, 117.8, 127.1, 130.0, 135.0, 138.8, 143.5; IR (KBr, neat) 2980, 2857, 1649, 1598,
-1
24NO
S (M + H)+
466, 1277, 1179, 1088, 929, 818, 680 cm ; HRMS (ESI) calcd. for C16
H
3
2
0
10.1471 found 310.1460. [α]
D
+3.2 (c 0.9 CHCl ).
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(2R*,5R*)-5-Phenyl-4-tosyl-2-vinylmorpholine (7d, Diastereomeric mixture with a ratio of
7:3; Data Only for Major Isomer):19
9
1
Colourless oil; R
δ 2.39 (s, 3 H, Ts-CH
Hz, 1 H, 3-He), 3.82 (dd, J = 12.0 and 4.0 Hz, 1 H, 6-Ha), 3.85-3.90 (m, 1 H, 2-H), 4.32 (d, J
12.0 Hz, 1 H, 6-He), 4.93 (d, J = 3.2 Hz, 1 H, 5-H), 5.20 (d, J = 10.4 Hz, 1 H, 8-Hcis), 5.31
(d, J = 17.6 Hz, 1 H, 8-Htrans), 5.67-5.76 (m, 1 H, 7-H), 7.22 (d, J = 8.4 Hz, 2 H, 3′,5′-H),
f
(hexane/EtOAc 4:1) 0.54; yield 137 mg, 80%; H NMR (400 MHz, CDCl
3
)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
), 2.91 (dd, J = 14.0 and 11.2 Hz, 1 H, 3-Ha), 3.65 (dd, J = 14.0 and 2.4
=
7
.24-7.30 (m, 3 H, 3′′, 4′′, 5′′-H), 7.45-7.48 (m, 2 H, 2′′, 6′′-H), 7.59 (d, J = 8.4 Hz, 2 H, C-
1
3
2
′,6′-H); C NMR (100 MHz, CDCl
3
) δ 21.6, 45.5, 54.5, 68.7, 75.7, 117.9, 127.2, 127.8,
1
28.4, 128.5, 129.8, 134.8, 137.6, 137.9, 143.6; IR (KBr, neat) 2918, 2859, 1649, 1598, 1495,
-1
22NO
S (M + H)+
1
338, 1165, 1096, 937, 817, 737 cm ; HRMS (ESI) calcd. for C19
H
3
2
0
344.1315 found 344.1313. [α]
D
-17.4 (c 0.8 CHCl ).
3
(2S*,5S*)-5-Benzyl-4-tosyl-2-vinylmorpholine (7e, Diastereomeric mixture with a ratio of
7:3; Data Only for Major Isomer):19
9
o
o
White solid, mp. 118-120 C (reported 120-123 C); R
f
(hexane/ EtOAc 4:1) 0.50; yield 139
), 2.68 (dd, J = 13.2 and 4.8
1
mg, 78%; H NMR (400 MHz, CDCl
3
) δ 2.41 (s, 3 H, Ts-CH
3
Hz, 1 H, 3-Ha), 2.96-3.05 (m, 2 H, 7-H), 3.47 (dd, J = 12.0 and 2.0 Hz, 1 H, 6-Ha), 3.65 (dd,
J = 13.2 and 2.8 Hz, 1 H, 3-He), 3.69 (d, J = 12.0 Hz, 1 H, 6-He), 3.86-3.91 (m, 1 H, 2-H),
3
5
.97-4.02 (m, 1 H, 5-H), 5.27 (d, J = 10.8 Hz, 1 H, 9-Hcis), 5.31 (d, J = 16.0 Hz, 1 H, 9-Htrans),
.76-5.85 (m, 1 H, 8-H), 7.16-7.20 (m, 2 H, 3′,5′-H), 7.22-7.30 (m, 5 H, Ph-H ), 7.63 (d, J =
1
3
8.0 Hz, 2 H, 2′,6′-H); C NMR (100 MHz, CDCl
3
) δ 21.7, 34.1, 45.1, 54.3, 67.3, 76.2, 118.1,
1
1
26.8, 127.3, 128.9, 129.7, 130.1, 135.0, 137.7, 138.0, 143.7; IR (KBr, neat) 2921, 2857,
-1
599, 1495, 1344, 1164, 1090, 1057, 816, 703 cm ; HRMS (ESI) calcd. for C20
H
24NO S (M
3
+
20
+ H) 358.1471 found 358.1483. [α]
D
-7.6 (c 0.6 CHCl ).
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(2R*,6S*)-2-Phenyl-4-tosyl-6-vinylmorpholine (7f, Diastereomeric mixture with a ratio of
9
7:3; Data Only for Major Isomer):
o
1
White solid, mp. 102-104 C; R
f
(hexane/ EtOAc 4:1) 0.51; yield 154 mg, 90%; H NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(600 MHz, CDCl
3
) δ 2.12-2.19 (m, 2 H, 3-Ha, 5-Ha), 2.43 (s, 3 H, Ts-CH
3
), 3.73 (d, J = 11.4
Hz, 1 H, 5-He), 3.78 (d, J = 10.8 Hz, 1 H, 3-He), 4.28-4.31 (m, 1 H, 6-H), 4.71 (dd, J = 10.8
and 2.4 Hz, 1 H, 2-H), 5.24 (d, J = 10.2 Hz, 1 H, 8-Hcis), 5.42 (d, J = 17.4 Hz, 1 H, 8-Htrans),
5.79-5.85 (m, 1 H, 7-H), 7.29-7.34 (m, 7 H, Ph-H, 3′,5′-H), 7.60 (d, J = 7.8 Hz, 2 H, 2′,6′-H);
13C NMR (100 MHz, CDCl
) δ 21.6, 49.6, 51.5, 71.2, 76.0, 117.7, 126.1, 127.8, 128.3, 128.5,
3
1
1
3
29.9, 132.2, 134.6, 138.7, 144.0; IR (KBr, neat) 2925, 2847, 1648, 1598, 1495, 1230, 1170,
-1
+
091, 930, 765 cm ; HRMS (ESI) calcd. for C19
H22NO
3
S (M + H) 344.1315 found
44.1293.
(2R*,6S*)-2-(4-Chlorophenyl)-4-tosyl-6-vinylmorpholine (7g):
o
1
White solid, mp. 141-143 C; R
f
(hexane/ EtOAc 4:1) 0.50; yield 151 mg, 80%; H NMR
(600 MHz, CDCl
3
) δ 2.08-2.15 (m, 2 H, 3-Ha, 5-Ha), 2.43 (s, 3 H, Ts-CH ), 3.72-3.77 (m, 2
3
H, 3-He, 5-He), 4.27-4.30 (m, 1 H, 6-H), 4.68 (dd, J = 11.4 and 1.8 Hz, 1 H, 2-H), 5.25 (d, J
= 10.8 Hz, 1 H, 8-Hcis), 5.41 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.77-5.83 (m, 1 H, 7-H), 7.27 (d, J
=
8.4 Hz, 2 H, 3′,5′-H), 7.30-7.33 (m, 4 H, 2′′, 3′′, 5′′, 6′′-H), 7.60 (d, J = 7.8 Hz, 2 H, 2′,6′-
1
3
H); C NMR (150 MHz, CDCl
3
) δ 21.8, 49.7, 51.6, 76.5, 76.7, 118.0, 127.6, 128.0, 128.9,
1
1
30.1, 132.3, 134.3, 134.6, 137.3, 144.3; IR (KBr, neat) 2987, 2852, 1648, 1598, 1491, 1349,
-1
S (M + H)+
166, 1087, 1017, 975, 776, 669 cm ; HRMS (ESI) calcd. for C19
H21ClNO
3
378.0925 found 378.0927.
(2R*,6S*)-2-(3-Bromophenyl)-4-tosyl-6-vinylmorpholine (7h):
o
1
White solid, mp. 115-117 C; R
f
(hexane/ EtOAc 4:1) 0.56; yield 179 mg, 85%; H NMR
(
600 MHz, CDCl
3
) δ 2.09-2.15 (m, 2 H, 3-Ha, 5-Ha), 2.43 (s, 3 H, Ts-CH ), 3.73 (d, J = 11.4
3
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Hz, 1 H, 5-He), 3.76 (d, J = 11.4 Hz, 1 H, 3-He), 4.26-4.29 (m, 1 H, 6-H), 4.68 (dd, J = 10.2
and 1.8 Hz, 1 H, 2-H), 5.26 (d, J = 10.2 Hz, 1 H, 8-Hcis), 5.41 (d, J = 16.8 Hz, 1 H, 8-Htrans),
5
.78-5.84 (m, 1 H, 7-H), 7.20 (t, J = 7.8 Hz, 1 H, 5′′-H), 7.25 (d, J = 7.8 Hz, 1 H, 6′′-H), 7.32
(d, J = 7.8 Hz, 2 H, 3′, 5′-H), 7.42 (d, J = 7.8 Hz, 1 H, 4′′-H), 7.50 (s, 1 H, 2′′-H), 7.60 (d, J =
10
11
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49
50
51
52
53
54
55
56
57
58
59
60
13
7
1
2
.8 Hz, 2 H, 2′,6′-H); C NMR (150 MHz, CDCl
3
) δ 21.7, 49.6, 51.5, 76.3, 76.6, 118.1,
22.8, 124.9, 127.9, 129.3, 130.1, 130.2, 131.5, 132.2, 134.5, 141.0, 144.3; IR (KBr, neat)
-1
923, 2849, 1597, 1570, 1451, 1345, 1169, 1092, 1025, 972, 737, 662 cm ; HRMS (ESI)
+
calcd. for C19
H21BrNO
3
S (M + H) 422.0420 found 422.0414.
(
2R*,6S*)-2-(4-Bromophenyl)-4-tosyl-6-vinylmorpholine (7i, Diastereomeric mixture with a
ratio of 97:3; Data Only for Major Isomer):
o
1
White solid, mp. 149-151 C; R
f
(hexane/ EtOAc 4:1) 0.60; yield 177 mg, 84%; H NMR
(600 MHz, CDCl
3
) δ 2.07-2.14 (m, 2 H, 3-Ha, 5-Ha), 2.43 (s, 3 H, Ts-CH
3
), 3.71-3.76 (m, 2
H, 3-He, 5-He), 4.26-4.32 (m, 1 H, 6-H), 4.67 (d, J = 10.8 Hz, 1 H, 2-H), 5.25 (d, J = 10.8
Hz, 1 H, 8-Hcis), 5.40 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.77-5.83 (m, 1 H, 7-H), 7.21 (d, J =
7
7
1
.8 Hz, 2 H, 2′′,6′′-H), 7.32 (d, J = 7.8 Hz, 2 H, 3′,5′-H), 7.46 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-H),
1
3
.60 (d, J = 7.8 Hz, 2 H, 2′,6′-H); C NMR (150 MHz, CDCl
3
) δ 21.8, 49.6, 51.5, 76.2, 76.7,
18.1, 122.4, 126.3, 128.0, 130.1, 131.8, 132.2, 134.5, 137.8, 144.3; IR (KBr, neat) 2923,
-1
2849, 1597, 1491, 1348, 1168, 1090, 1012, 975, 818, 670 cm ; HRMS (ESI) calcd. for
+
C
19
H
21BrNO
3
S (M + H) 422.0420 found 422.0433.
(
2R*,6S*)-2-(4-Fluorophenyl)-4-tosyl-6-vinylmorpholine (7j, Diastereomeric mixture with a
ratio of 97:3; Data Only for Major Isomer):
o
1
White solid, mp. 130-132 C; R
f
(hexane/ EtOAc 4:1) 0.52; yield 136 mg, 75%; H NMR
(600 MHz, CDCl
3
) δ 2.11-2.16 (m, 2 H, 3-Ha, 5-Ha), 2.43 (s, 3 H, Ts-CH
3
), 3.72-3.77 (m, 2
H, 3-He, 5-He), 4.27-4.27-4-30 (m, 1 H, 6-H), 4.68 (d, J = 13.2 Hz, 1 H, 2-H), 5.25 (d, J =
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5
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10.8 Hz, 1 H, 8-Hcis), 5.41 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.77-5.83 (m, 1 H, 7-H), 7.02 (t, J =
8
.4 Hz, 2 H, 2′′,6′′-H), 7.28-7.34 (m, 4 H, 3′,5′-H, 3′′,5′′-H), 7.60 (d, J = 8.4 Hz, 2 H, 2′,6′-H);
13C NMR (150 MHz, CDCl
) δ 21.7, 49.7, 51.7, 76.3, 76.8, 115.6 (d, J = 21.0 Hz), 118.0,
3
1
9
1
27.9, 128.0, 128.1, 130.1, 132.4, 134.6, 144.3, 162.8 (d, J = 246.0 Hz); F NMR (376 MHz,
CDCl /C ) δ 47.99 (t, J = 5.26 Hz); IR (KBr, neat) 2850, 1604, 1511, 1348, 1228, 1166,
088, 975, 762, 667 cm ; HRMS (ESI) calcd. for C19
62.1252.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
F
6 6
-1
+
1
3
H
21FNO S (M + H) 362.1221 found
3
(2R*,6S*)-2-(3,4-Dichlorophenyl)-4-tosyl-6-vinylmorpholine (7k):
o
1
White solid, mp. 117-119 C; R
f
(hexane/ EtOAc, 4:1) 0.48; yield 152 mg, 74%; H NMR
(600 MHz, CDCl
s, 3 H, Ts-CH ), 3.71-3.77 (m, 2 H, 3, 5-He), 4.25-4.28 (m, 1 H, 6-H), 4.67 (d, J = 10.8 Hz,
H, 2-H), 5.26 (d, J = 10.8 Hz, 1 H, 8-Hcis), 5.40 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.77-5.83 (m,
3
) δ 2.08 (t, J = 10.8 Hz, 1 H, 3-Ha), 2.12 (t, J = 10.8 Hz, 1 H, 5-Ha), 2.43
(
3
1
1
H, 7-H), 7.16 (d, J = 7.8 Hz, 1 H, 6′′-H), 7.32 (d, J = 7.8 Hz, 2 H, 3′,5′-H), 7.40 (d, J = 7.8
13
Hz, 1 H, 5′′-H), 7.44 (s, 1 H, 2′′-H), 7.60 (d, J = 7.8 Hz, 2 H, 2′, 6′-H); C NMR (150 MHz,
CDCl
3
) δ 21.8, 49.6, 51.4, 76.1, 76.3, 118.2, 125.6, 127.9, 128.2, 130.1, 130.7, 132.2, 132.4,
1
1
33.0, 134.4, 139.0, 144.4; IR (KBr, neat) 2923, 2850, 1646, 1598, 1471, 1350, 1168, 1090,
-1
+
030, 977, 820, 704, 670 cm ; HRMS (ESI) calcd. for C19
H20Cl
2
NO S (M + H) 412.0535
3
found 412.0547.
(2R*,6S*)-2-(p-Tolyl)-4-tosyl-6-vinylmorpholine (7l, Diastereomeric mixture with a ratio of
9
7:3; Data Only for Major Isomer):
o
1
White solid, mp 104-106 C; R
f
(hexane/ EtOAc 4:1) 0.55; yield 147 mg, 82%; H NMR (600
), 2.43 (s, 3 H, Ts-
), 3.71-3.77 (m, 2 H, 3-He, 5-He), 4.26-4.29 (m, 1 H, 6-H), 4.66 (d, J = 11.4 Hz, 1 H, 2-
MHz, CDCl
3
) δ 2.10-2.17 (m, 2 H, 3-Ha, 5-Ha), 2.33 (s, 3 H, Tol-CH
3
CH
3
H), 5.23 (d, J = 10.8 Hz, 1 H, 8-Hcis), 5.41 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.78-5.84 (m, 1 H,
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7-H), 7.14 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-H), 7.21 (d, J = 7.8 Hz, 2 H, 2′′, 6′′-H), 7.30 (d, J = 7.8
13
Hz, 2 H, 3′, 5′’-H), 7.60 (d, J = 7.8 Hz, 2 H, 2′, 6′-H); C NMR (150 MHz, CDCl
3
) δ 21.3,
2
1
1.7, 49.7, 51.7, 76.2, 77.0, 117.8, 126.2, 128.0, 129.3, 130.0, 132.4, 134.8, 135.9, 138.2,
-1
44.1; IR (KBr, neat) 2924, 2846, 1598, 1353, 1231, 1168, 1087, 818, 758 cm ; HRMS
10
11
12
13
14
15
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19
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50
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52
53
54
55
56
57
58
59
60
+
(
ESI) calcd. for C20
H
24NO
3
S (M + H) 358.1471 found 358.1497.
(
2R*,6S*)-2-(4-Methoxyphenyl)-4-tosyl-6-vinylmorpholine (7m, Diastereomeric mixture with
a ratio of 97:3; Data Only for Major Isomer):
o
1
White solid, mp. 109-111 C; R
f
(hexane/ EtOAc 4:1) 0.45; yield 158 mg, 85%; H NMR
), 3.71-3.75 (m, 2
), 4.25-4.30 (m, 1 H, 6-H), 4.65 (d, J = 10.8 Hz, 1 H, 2-
H), 5.24 (d, J = 10.8 Hz, 1 H, 8-Hcis), 5.41 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.77-5.84 (m, 1 H,
-H), 6.86 (d, J = 8.4 Hz, 2 H, 3′′, 5′′-H), 7.25 (d, J = 8.4 Hz, 2 H, 2′′, 6′′-H), 7.32 (d, J = 8.4
(600 MHz, CDCl
3
) δ 2.11-2.17 (m, 2 H, 3-Ha, 5-Ha), 2.43 (s, 3 H, Ts-CH
3
H, 3-He, 5-He), 3.79 (s, 3 H, -OCH
3
7
1
3
Hz, 2 H, 3′, 5′-H), 7.61 (d, J = 8.4 Hz, 2 H, 2′, 6′-H); C NMR (150 MHz, CDCl
3
) δ 21.7,
4
1
9.7, 51.7, 55.5, 76.2, 77.0, 114.1, 117.9, 127.6, 128.0, 130.0, 131.0, 132.4, 134.8, 144.2,
-1
59.8; IR (KBr, neat) 2926, 1612, 1515, 1447, 1250, 1167, 1087, 1031, 831, 757 cm ;
+
HRMS (ESI) calcd. for C20
H24NO
4
S (M + H) 374.1421 found 374.1400.
(
2R*,6S*)-4-Tosyl-2-(4-(trifluoromethyl)phenyl)-6-vinylmorpholine (7n):
o
1
White solid, mp. 115-117 C; R
(400 MHz, CDCl ) δ 2.08-2.18 (m, 2 H, 3-Ha, 5-Ha), 2.43 (s, 3 H, Ts-CH
and 2.4 Hz, 1 H, 5-He), 3.80 (dt, J = 11.6 and 2.4 Hz, 1 H, 3-He), 4.29-4.34 (m, 1 H, 6-H),
.78 (dd, J = 11.6 and 2.4 Hz, 1 H, 2-H), 5.27 (dt, J = 11.2 and 1.6 Hz, 1 H, 8-Hcis), 5.43 (dt,
f
(hexane/ EtOAc 4:1) 0.55; yield 169 mg, 82%; H NMR
3
3
), 3.75 (dt, J = 11.4
4
J = 17.6 and 1.2 Hz, 1 H, 8-Htrans), 5.78-5.87 (m, 1 H, 7-H), 7.32 (d, J = 8.4 Hz, 2 H, 3′, 5′-
13
H), 7.47 (d, J = 8.4 Hz, 2 H, 2′′, 6′′-H), 7.60 (d, J = 8.4 Hz, 4 H, 2′, 6′-H, 3′′, 5′′-H); C NMR
(150 MHz, CDCl
3
) δ 21.8, 49.7, 51.5, 76.3, 76.7, 118.1, 124.2 (q, J = 271.5 Hz), 125.7,
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5
5
5
5
6
1
9
126.6, 128.0, 130.1, 130.6 (q, J = 33.0 Hz), 132.3, 134.4, 142.7, 144.4; F NMR (376 MHz,
CDCl /C ) δ 99.10 ; IR (KBr, neat) 2924, 2850, 1622, 1598, 1452, 1356, 1171, 1020, 972,
57, 738, 668 cm ; HRMS (ESI) calcd. for C20
12.1198.
3
6 6
F
-
1
+
8
4
H
21
F
3
NO S (M + H) 412.1189 found
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
(
2R*,6S*)-2-(4-Nitrophenyl)-4-tosyl-6-vinylmorpholine (7o, Diastereomeric mixture with a
ratio of 97:3; Data Only for Major Isomer):
o
1
White solid, mp. 128-130 C; R
f
(hexane/ EtOAc 4:1) 0.40; yield 163 mg, 84%; H NMR
(
600 MHz, CDCl
3
) δ 2.11 (dd, J = 11.4 and 10.2 Hz, 1 H, 3-Ha), 2.15 (dd, J = 11.4 and 10.8
), 3.76 (dd, J = 11.4 and 3.0 Hz, 1 H, 5-He), 3.83 (dd, J
Hz, 1 H, 5-Ha), 2.43 (s, 3 H, Ts-CH
3
= 11.4 and 2.4 Hz, 1 H, 3-He), 4.30-4.34 (m, 1 H, 6-H), 4.82 (dd, J = 10.2 and 2.4 Hz, 1 H, 2-
H), 5.29 (d, J = 10.8 Hz, 1 H, 8-Hcis), 5.45 (d, J = 16.2 Hz, 1 H, 8-Htrans), 5.80-5.85 (m, 1 H,
7
-H), 7.32 (d, J = 8.4 Hz, 2 H, 3′,5′-H), 7.53 (d, J = 8.4 Hz, 2 H, 2′′,6′′-H), 7.60 (d, J = 8.4
1
3
Hz, 2 H, 2′, 6′-H), 8.21 (d, J = 8.4 Hz, 2 H, 3′′,5′′-H); C NMR (150 MHz, CDCl
3
) δ 21.8,
4
9.6, 51.3, 76.3, 76.4, 118.3, 123.9, 127.1, 127.9, 130.1, 132.2, 134.3, 144.4, 145.8, 148.0; IR
-
1
(
KBr, neat) 3082, 2849, 1603, 1522, 1452, 1351, 1168, 1092, 862, 774, 664 cm ; HRMS
+
(
ESI) calcd. for C19
H
21
N
2
O
5
S (M + H) 389.1166 found 389.1178.
2
,2-Dimethyl-4-tosyl-6-vinylmorpholine (7p):
o
1
White solid, mp. 92-94 C; R
f
(hexane/ EtOAc 4:1) 0.50; yield 96 mg, 65%; H NMR (600
MHz, CDCl ) δ 1.14 (s, 3 H, 2-CH
3
3
), 1.33 (s, 3 H, 2-CH ), 2.43 (s, 3 H, Ts-CH ), 2.96 (t, J =
3
3
1
6
7
2.0 Hz, 1 H, 5-Ha), 3.38 (s, 2 H, 3-H), 3.77 (d, J = 12.0 Hz, 1 H, 5-He), 4.00-4.10 (m, 1 H,
-H), 5.39 (d, J = 10.8 Hz, 1 H, 8-Hcis), 5.41 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.79-5.85 (m, 1 H,
1
3
-H), 7.29 (d, J = 7.8 Hz, 2 H, 3′,5′-H), 7.69 (d, J = 7.8 Hz, 2 H, 2′,6′-H); C NMR (150
MHz, CDCl
3
) δ 20.1, 21.7, 24.8, 47.2, 56.9, 77.4, 77.9, 118.0, 127.4, 129.9, 134.9, 139.3,
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-
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143.5; IR (KBr, neat) 2978, 2854, 1646, 1599, 1454, 1330, 1160, 1093, 940, 818, 668 cm ;
+
HRMS (ESI) calcd. for C15
H22NO
3
S (M + H) 296.1315 found 296.1338.
(2R*,6S*)-2-(2-Methylprop-1-en-1-yl)-4-tosyl-6-vinylmorpholine
(7q,
Diastereomeric
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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50
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53
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58
59
60
mixture with a ratio of 97:3; Data Only for Major Isomer):
1
Colourless oil; R
CDCl ) δ 1.71 (s, 6 H, 2′-2CH
(dt, J = 12.0 and 1.6 Hz, 1 H, 5-He), 3.62 (dt, J = 12.0 and 2.0 Hz, 1 H, 3-He), 4.12-4.16 (m,
H, 6-H), 4.31-4.37 (m, 1 H, 2-H), 5.02 (d, J = 10.0 Hz, 1 H, 1′-H), 5.20 (d, J = 10.4 Hz, 1
H, 8-Hcis), 5.33 (d, J = 17.6 Hz, 1 H, 8-Htrans), 5.68-5.77 (m, 1 H, 7-H), 7.34 (d, J = 8.0 Hz, 2
f
(hexane/ EtOAc 4:1) 0.60; yield 112 mg, 70%; H NMR (400 MHz,
3
3
), 2.00-2.06 (m, 2 H, 3-Ha, 5-Ha), 2.44 (s, 3 H, Ts-CH ), 2.96
3
1
13
H, 3′′,5′′-H), 7.62 (d, J = 8.0 Hz, 2 H, 2′′,6′′-H); C NMR (150 MHz, CDCl
3
) δ 18.9, 21.8,
2
6.0, 49.4, 49.5, 72.9, 75.9, 118.1, 121.6, 128.0, 130.0, 132.3, 135.0, 139.1, 144.1; IR (KBr,
-1
neat) 2924, 2854, 1598, 1453, 1378, 1167, 1078, 971, 818, 778 cm ; HRMS (ESI) calcd. for
+
C
17
H24NO
3
S (M + H) 322.1471 found 322.1457.
(2S*,6S*)-2-(Furan-2-yl)-4-tosyl-6-vinylmorpholine (7r, Diastereomeric mixture with a ratio
of 97:3; Data Only for Major Isomer):
1
Colourless oil; R
CDCl ) δ 2.18 (dd, J = 11.2 and 10.8 Hz, 1 H, 5-Ha), 2.45 (s, 3 H, Ts-CH
1.2 and 11.2 Hz, 1 H, 5-He), 3.70 (dt, J = 11.2 and 2.0 Hz, 1 H, 3-Ha), 3.81 (dt, J = 11.2 and
2.4 Hz, 1 H, 3-He), 4.23-4.28 (m, 1 H, 6-H), 4.74 (dd, J = 10.8 and 2.8 Hz, 1 H, 2-H), 5.24
f
(hexane/ EtOAc 4:1) 0.60; yield 120 mg, 72%; H NMR (400 MHz,
3
3
), 2.53 (dd, J =
1
(
d, J = 10.8 Hz, 1 H, 8-Hcis), 5.37 (d, J = 17.6 Hz, 1 H, 8-Htrans), 5.71-5.80 (m, 1 H, 7-H), 6.31
d, J = 3.6 Hz, 1 H, 3′′-H), 6.34 (dd, J = 3.2 and 1.6 Hz, 1 H, 4′′-H), 7.33-7.37 (m, 3 H, 3′, 5′
(
1
3
and 5′′-H), 7.64 (d, J = 8.4 Hz, 2 H, 2′,6′-H); C NMR (150 MHz, CDCl
3
) δ 21.7, 48.2, 49.5,
7
1.2, 76.5, 108.3, 110.5, 118.6, 128.0, 130.1, 132.2, 134.4, 142.9, 144.3, 151.1; IR (KBr,
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
neat) 2922, 2853, 1648, 1598, 1454, 1344, 1168, 1095, 934, 819, 664 cm ; HRMS (ESI)
+
calcd. for C17
H20NO
4
S (M + H) 334.1108 found 334.1111.
(
2R*,6S*)-2-(4-Bromophenyl)-4-tosyl-6-vinylmorpholine and (2S*,6S*)-2-(4-bromophenyl)-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4-tosyl-6-vinylmorpholine (7s, 7s′:: 63:37):
o
1
Colourless solid, mp (mixed) 150-152 C; Rf (hexane/ EtOAc 4:1) 0.60; yield mg, 70%; H
NMR (600 MHz, CDCl
major, 3,5-He), 3.70 (m, 2 H, minor, 5-He), 4.19-4.23 (m, 1 H, 6-H), 4.59 (dd, J = 10.8 and
.4 Hz, 1 H, major, 2-H), 4.63 (dd, J = 10.8 and 3.0 Hz, 1 H, minor, 2-H), 5.17 (dd, J = 10.8
3
) δ 1.96-2.11 (m, 2 H, 3,5-Ha), 2.35 (s, 3 H, Ts-CH
3
), 3.66 (m, 2 H,
2
and 3.0 Hz, 1 H, 8-Hcis), 5.33 (d, J = 17.4 Hz, 1 H, major, 8-Htrans), 5.35 (d, J = 16.8 Hz, 1
H, minor, 8-Htrans), 5.70-5.77 (m, 1 H, 7-H), 7.13 (d, J = 8.4 Hz, 2 H, major, 2′′,6′′-H), 7.22-
7
.26 (m, 2 H, major and minor, 3′, 5′ and 2′′, 6′′-H), 7.39 (d, J = 7.8 Hz, 2 H, major, 3′′, 5′′-
1
3
H), 7.52 (d, J = 7.8 Hz, 2 H, major, 2′,6′-H), 7.53 (d, J = 7.8 Hz, 2 H, minor, 2′,6′-H); C
NMR (150 MHz, CDCl ) δ 21.7, 49.6, 49.7, 51.5, 51.7, 76.2, 76.3, 76.7, 77.4, 117.9, 118.0,
22.4, 126.3, 127.9, 128.0, 128.4, 128.7, 130.0, 130.1, 131.8, 132.3, 134.6, 134.8, 137.8,
38.8, 144.2, 144.3; IR (KBr, neat) 3090, 3063, 2847, 1650, 1598, 1492, 1268, 1176, 1097,
3
1
1
9
4
-1
+
29, 852, 775 cm ; HRMS (ESI) calcd. for C19
H
21BrNO S (M + H) 422.0420 found
3
22.0430.
Preparation of (Z)-N-(2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl)-N-(4-hydroxybut-2-
en-1-yl)-4-methylbenzenesulfonamide (8): To a stirred solution of NaH (176 mg, 4.4 mmol,
6
0% in a mineral oil) in dry DMF (10 mL) was added drop wise solution of the N-(2-
hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl)-4-methylbenzenesulfonamide (1.524 g, 4 mmol)
o
in dry DMF (15 mL) at 0 C (N
2
atmosphere). After 20 minutes, DMF (5ml) solution of (Z)-
4
-bromobut-2-en-1-ol (600 mg, 4 mmol) was added and reaction was stirred at room
temperature for 16 h. After completion of the reaction, a few drops of methanol was added at
0 oC and the solution was poured in ethylacetate (60 mL). the organic phase is washed with
brine ( 3 x 40 mL), dried over Na
2
SO and concentrated in vacuo and purified by column
4
chromatography (EtOAc: Hexane, 3:2) to give 1.074 g (60%) of (Z)-N-(2-hydroxy-2-(3,4,5-
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
trimethoxyphenyl)ethyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylbenzenesulfonamide 8 as light
o
1
yellow solid, mp 92-93 C. H NMR (600 MHz, CDCl
Ts-CH ), 3.24-3.31 (m, 2 H, 1-H), 3.81 (s, 3 H, 4′′′-OCH
.93 (dd, J = 16.2 and 6.6 Hz, 1 H, 1′-H), 3.98 (dd, J = 16.2 and 7.8 Hz, 1 H, 1′-H), 4.10 (dd,
3
) δ 1.92 (brs, 2H, -2OH), 2.41 (s, 3 H,
3
3
), 3.84 (s, 6 H, 3′′′, 5′′′-2CH ),
3
3
J = 12.6 and 6.6 Hz, 1 H, 4′-H), 4.16 (dd, J = 12.6 and 7.2 Hz, 1 H, 4′-H), 4.90 (dd, J = 7.2
and 3.6 Hz, 1 H, 2-H), 5.31 (dd, J = 10.8 and 7.8 Hz, 1 H, 2′-H), 5.78 (dd, J = 10.8 and 4.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hz, 1 H, 3′-H), 6.58 (s, 2 H, 2′′′, 6′′′-H), 7.29 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-H), 7.68 (d, J = 7.8
13
Hz, 2 H, 2′′, 6′′-H); C NMR (150 MHz, CDCl
3
) δ 21.7, 46.3, 55.5, 56.3, 57.8, 61.0, 73.8,
1
02.9, 126.8, 127.4, 130.1, 133.2, 136.5, 137.3, 144.0, 153.5; IR (KBr, neat) 3475, 2939,
-1
2835, 1596, 1462, 1332, 1232, 1160, 1002, 916, 839, 772 cm ; HRMS (ESI) calcd. for
+
C
22
H30NO
7
S (M + H) 452.1737 found 452.1733. Anal. calcd for C22
H
29NO S: C, 58.52; H,
7
6
.47; N, 3.10. Found: C, 58.45; H, 6.43; N, 3.07.
Preparation of 4-tosyl-2-(3,4,5-trimethoxyphenyl)-6-vinylmorpholine (9):
To a solution of (Z)-N-(2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl)-N-(4-hydroxybut-2-en-
-yl)-4-methylbenzenesulfonamide 8 (902 mg, 2 mmol) in toluene was added PdCl (PPh
70 mg, 5 mol %) and refluxed it for 20 h. After completion of the reaction (monitored by
1
2
)
3 2
(
TLC), the reaction mixture was filtered through celite and filtrate was purified by column
chromatography (EtOAc: Hexane, 1:3) to give 4-tosyl-2-(3,4,5-trimethoxyphenyl)-6-
vinylmorpholine (0.56 g, 65% yield). (R = 0.50 (hexane/EtOAc: 4/1 (v/v)). White solid, mp
f
o
1
42-144 C.
1H NMR (600 MHz, CDCl
d, J = 11.4 Hz, 1 H, 5-He), 3.77 (d, J = 11.4 Hz, 1 H, 3-He), 3.81 (s, 3 H, 4′-OCH
H, 3′,5′-2OCH ), 4.27-4.30 (m, 1 H, 6-H), 4.63 (d, J = 11.4 Hz, 1 H, 2-H), 5.24 (d, J = 10.8
) δ 2.13-2.17 (m, 2 H, 3-Ha, 5-Ha), 2.42 (s, 3 H, Ts-CH
), 3.72
3
3
(
3
), 3.84 (s,
6
3
Hz, 1 H, 8-Hcis), 5.40 (d, J = 17.4 Hz, 1 H, 8-Htrans), 5.79-5.85 (m, 1 H, 7-H), 6.54 (s, 2 H, 2′,
13
6
′-H), 7.32 (d, J = 7.8 Hz, 2 H, 3′′, 5′′-H), 7.61 (d, J = 7.8 Hz, 2 H, 2′′, 6′′-H); C NMR (100
MHz, CDCl
3
) δ 21.7, 49.6, 51.8, 56.4, 61.0, 76.4, 77.6, 103.3, 118.0, 128.0, 130.1, 132.5,
134.4, 134.7, 138.0, 144.2, 153.5; IR (KBr, neat) 3446, 2938, 2844, 1592, 1461, 1341, 1237,
-1
+
1
169, 1089, 973, 839, 776 cm ; HRMS (ESI) calcd. for C22
H
28NO S (M + H) 434.1632
6
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