Synthesis of 2,6-disubstituted morpholines through regioselective oxiranes ring opening by tosylamide under PTC conditions

Article abstract of DOI:10.1016/j.tet.2004.10.008

Symmetric and non-symmetric 2,6-disubstituted morpholines were synthesized through regioselective nucleophilic ring opening of oxiranes with tosylamide under solid-liquid phase transfer catalysis (SL-PTC) conditions followed by cyclization of the tosylami

Full text of DOI:10.1016/j.tet.2004.10.008

Tetrahedron 60 (2004) 11709–11718
Synthesis of 2,6-disubstituted morpholines through regioselective
oxiranes ring opening by tosylamide under PTC conditions
a
a
a
b
Vittoria Lupi,a, Domenico Albanese, Dario Landini, Davide Scaletti and Michele Penso
*
a
`
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, via Venezian 21, I-20133 Milano, Italy
bCNR-Istituto di Scienze e Tecnologie Molecolari (ISTM), via Golgi 19, I-20133 Milano, Italy
Received 6 July 2004; revised 7 September 2004; accepted 1 October 2004
Available online 19 October 2004
Abstract—Symmetric and non-symmetric 2,6-disubstituted morpholines were synthesized through regioselective nucleophilic ring opening
of oxiranes with tosylamide under solid–liquid phase transfer catalysis (SL-PTC) conditions followed by cyclization of the tosylamido diols
thus obtained and final deprotection of the corresponding N-tosyl morpholines. The morpholines prepared are interesting building blocks in
the synthesis of pharmaceuticals and agrochemicals.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
sulfuric acid.24 Alternatively, substituted morpholines have
been prepared by a catalyzed vapor phase reaction of a
dialkylene glycol with an aminating agent in the presence of
hydrogen.25
Substituted morpholines have attracted considerable interest
due to their presence in a number of therapeutically and
biologically active compounds1 or chiral reagents.2 In
particular, the 2,6-dimethylmorpholine skeleton is of
paramount importance for the construction of a large class
of agrochemical fungicides and bactericides.3–11 Further-
more, the C2-symmetric (2R,6R)-2,6-dimethylmorpholine
has been prepared and then incorporated in Fisher-type
aminocarbene complexes, behaving as an excellent chiral
auxiliary.12,13 Several 2,6-disubstituted morpholine deriva-
tives are used as antitumor agents,14 mild diuretics and
anorectics.15 This class of morpholines has been also
employed as CO2, H2S, and COS adsorbents in the
purification of liquids and gases,16 and as fuel additives to
provide fast-burning.17 Finally, some morpholine deriva-
tives have found applications as polymerization catalysts18
and additives for inks.19
This paper describes the synthesis of 2,6-disubstituted
morpholines through the phase transfer (PT) catalyzed
dialkylation of 4-toluenesulfonamide (1) by oxiranes 2
(Scheme 1), followed by cyclization of the tosylamido diols
4–7 thus obtained (Schemes 2 and 3), and final deprotection
of the N-tosyl morpholines 10–13 to produce the target
compounds 15 (Scheme 4). This procedure is regioselective
and of general application, both for symmetric and non-
symmetric morpholines.
2. Results and discussion
2.1. Oxirane ring opening by tosylamide
In spite of their industrial importance, few general
preparations of 2,6-disubstituted morpholines are reported
in the literature: (i) the dialkylation of a primary amine with
an oxirane;20 (ii) the reaction of a sulfonamide with excess
chlorohydrin.21,22 The amino or amido diols thus obtained
have been cyclized to the corresponding morpholines in the
presence of a base23 or cyclodehydrated using concentrated
2.1.1. Preparation of symmetric tosylamido diols. In a
previous paper,26 we reported the preparation of b-tosyl-
amido alcohols 3, realized through ring opening of epoxides
2 with excess tosylamide (1), under solid–liquid PT
catalysis (SL-PTC) conditions (Scheme 1, path a). As well
as the mono-N-alkylation products 3, small quantities of the
N-dialkylated by-products 4, 5 were isolated.
The direct dialkylation of 1 under analogous SL-PTC
conditions with excess 2 (Scheme 1, path c), gave excellent
yields (75–95%) (Table 1) of the (50:50) diastereoisomeric
mixture 4, 5 of the symmetric tosylamido diols, which could
Keywords: Morpholines; Phase transfer catalysis; Oxirane ring opening;
Cyclization.
* Corresponding author. Tel.: C39 02 50314165; fax: C39 02 50314159;
e-mail: vittoria.lupi@unimi.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.008

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V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
Scheme 1. (a) 1 (1 mol), 2 (0.5 mol), K2CO3 (0.05 mol), TEBA (0.05 mol), dioxane, 90 8C; (b) 2 (1.1 mol), 3 (1 mol), M2CO3 (0.1 mol), TEBA (0.1 mol),
dioxane, 90 8C (or DME, 80 8C); (c) 1 (1 mol), 2 (3 mol), M2CO3 (0.1 mol), TEBA (0.1 mol), dioxane, 90 8C (or DME, 80 8C).
be easily separated by column chromatography to give the
pure (G)-d,l 4 and meso 5 isomers.
later, the base–epoxide relationship is the determinant factor
for the in situ alkylation of the intermediate amido alcohol 3.
The efficiency of the different alkaline metal carbonates
M2CO3, used in catalytic amounts,24 is related to the nature
of the substituent on the oxirane ring: sodium carbonate is
the most active base in the case of 1,2-epoxyoctane (2a) and
1,2-epoxy-3-phenoxypropane (2b), while cesium carbonate
is more effective with styrene oxide (2c) (Table 1). Most
probably, as confirmed by the results concerning the
preparation of non-symmetric amido diols 6, 7 described
2.1.2. Preparation of non-symmetric tosylamido diols.
The synthesis of non-symmetric tosylamido diols 6 and 7
involves a two-step alkylation protocol. After the prep-
aration of the b-tosylamido alcohol 3 (Table 2, Step 1), this
intermediate was reacted under SL-PTC conditions with a
second epoxide 2 (R2sR1) (Scheme 1, path b; Table 2, step
2). From the (1:1) diastereoisomeric mixture 6, 7 formed
under these conditions, the pure tosylamido diols 6 and 7
Scheme 2. (a) 4–7 (1 mol), NaH (2.1 mol), RSO2X (Tf2O or TsCl, 1 mol), solvent, 0–25 8C. R1 and R2 substituents are described in Scheme 1.

V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
11711
2.2. Cyclization of tosylamido diols to 2,6-dialkyl-N-
tosyl-morpholines
Poor results were obtained in the cyclization of diols 4–7 to
N-tosyl-morpholines 10–13 by using literature methods of
direct dehydration,23,24 therefore, a detailed study for the
best cyclization conditions of the isolated stereoisomers 4–7
was undertaken (Scheme 2).
The best results were obtained by generating the oxy-
dianion 8 in the presence of excess NaH in dichloromethane
(DCM) or 1,2-dimethoxyethane (DME), and promoting the
cyclization through the in situ formation of the two possible
mono-triflates 9 with (trifluoromethane)sulfonic anhydride
(Tf2O). Cyclization of the intermediate 9 proceeds through
an intramolecular nucleophilic displacemement with stereo-
selective inversion of configuration at the reactive center.
Furthermore, the O-triflation of 8 was not a regioselective
process and, as a result, racemic morpholines were formed.
In the cyclization of symmetric tosylamido diols 4a,b and
5b (Table 3), the use of tosyl chloride (entries 1, 4, 6)
instead of Tf2O resulted in longer reaction times and lower
yields of N-tosyl morpholines 10a,b and 11b. In the case of
symmetric diols derived from 2-phenyl-oxirane (2c), it was
found that the formation of meso morpholine 10c, the less
hindered isomer, bearing equatorial phenyl groups, pro-
ceeded with a higher reaction rate than the formation of d,l
isomer 11c (Table 3, entries 8–11).
Scheme 3. (a) NaH (2.1 mol), TsCl (1 mol), DCM, 40 8C; (b) NaH
(2.1 mol), Tf2O (1 mol), DCM, 25 8C.
In particular, starting from 4c, in the presence of TsCl, 10c
was isolated as a sole product in 71% yield (entry 8), whilst
by using Tf2O a mixture of 10c:11c (entry 9), which
consisted mainly of meso 10c, was produced (Scheme 3). In
the same way, the activation of 5c with tosyl chloride
afforded the corresponding d,l 11c (entry 10), whereas with
Tf2O an analogous mixture of 10c:11c (entry 11) was
obtained. When the mono-O-tosylate 9 (Scheme 2, RZTol)
is the intermediate, the nucleophilic substitution proceeds
through a bimolecular mechanism, with complete inversion
of the carbon atom, while in the case of the mono-O-triflate
9 (Scheme 2, RZCF3), which bears a better leaving group, a
unimolecular mechanism, via a carbocation, is responsible
for the major formation of 10c.
Scheme 4. (a) 40% HBr–AcOH (PhOH), 25–80 8C.
Table 1. Preparation of symmetric tosylamido diols 4, 5 under SL-PTC
conditionsa
R1
t (h)
Products
(%)b
(%)b
c
2a
2b
2c
C6H13
PhOCH2
Phd
10
6
6
4a
4b
4c
47
45
38
5a
5b
5c
48
45
37
A similar behavior was found in the cyclization reactions of
non-symmetric tosylamido diols 6, 7 (Table 4) and TsCl was
used as an activating agent when a phenyl group is present,
as in diols 6, 7b (entries 3, 4).
c
a Scheme 1, path c. Reaction conditions: TsNH2 (1) (1 mol), oxirane 2
(3 mol), TEBA (0.1 mol), Na2CO3 (0.1 mol).
b Isolated yields, after column chromatography.
c In DME at 80 8C.
2.3. N-Detosylation of N-tosyl-morpholines to 2,6-
dialkyl-morpholines
d In the presence of Cs2CO3 (0.1 mol), in dioxane at 90 8C.
The 2,6-disubstituted morpholines 15 (Scheme 4) can be
obtained by deprotection of the corresponding N-tosyl
morpholines 10–13 by reaction with 40% HBr–AcOH
(Table 5).27 In the case of the morpholines 10b,c, 11b and
12, 13c (entries 3–7), that contain phenyl and phenoxy-
methyl groups, the reactions were conducted in the presence
of phenol as bromine scavenger, to avoid aromatic
bromination of the products.
were separated by column chromatography. As found in the
synthesis of symmetric amido diols 4, 5, in the alkylation of
3 the choice of the base is crucial (Table 2). As expected, in
an attempt to prepare 6, 7 by using equimolar amounts of
oxiranes 2b and 2c, by operating in a one-pot reaction
conditions, a complex mixture of the possible symmetric
and non-symmetric amido diols was obtained.

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V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
Table 2. Preparation of non-symmetric tosylamido diols 6, 7 under SL-PTC conditions
Step 1a
t (h)
Product
Step 2b
Base
t (h)
Products
(%)c
Epoxide R1
3
(%)c
Epoxide R2
6, 7
(%)c
2b
2b
2c
2b
2d
2e
PhOCH2
PhOCH2
Ph
PhOCH2
AllylOCH2
MeOCH2
2
2
6
2
2
2
3a
3a
3b
3a
3c
3d
91
91
93
91
79
83
2a
2c
2b
2f
2f
2b
C6H13
Ph
PhOCH2
t-BuOCH2
t-BuOCH2
PhOCH2
K2CO3
11
22
6
48
20
20
6a
6b
6b
6, 7c
6, 7d
6, 7e
35
36
7a
7b
7b
—
—
—
35
36
32
—
—
—
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
33
70d
70d
82d
a Scheme 1, path a. Reaction conditions: TsNH2 (1) (1 mol), epoxide 2 (0.5 mol), TEBA (0.05 mol), K2CO3 (0.05 mol), dioxane, 90 8C.
b Scheme 1, path b. Reaction conditions: epoxide 2 (1.1 mol), tosylamido alcohol 3 (1 mol), TEBA (0.1 mol), M2CO3 (0.1 mol), dioxane, 90 8C.
c Isolated yields.
d Isolated as (50:50) inseparable mixture of the diastereoisomers 6 and 7.
Table 3. Cyclization of symmetric tosylamido diols 4 and 5 to N-tosyl
morpholines 10 and 11a
Table 5. Deprotection of N-tosyl morpholines 10–13
Entry
Substrate
Methoda
t (h)
Product
(%)b
Entry
Methodb
t (h)
Product
(%)c
1
2
3
4
5
6
7
10a
11a
10b
11b
10c
12a
13a
A
B
C
C
D
D
D
2
4
4
4
9
15a
15b
15c
15d
15e
15f
65
63
75
75
61
74
67
1
2
3
4
5
6
7
8
9
4a
4a
5a
4b
4b
5b
5b
4c
4c
A
B
C
A
B
13
6
6
48
13
23
6
22
1.5
10a
10a
11a
10b
10b
11b
11b
10c
10c
11c
11c
10c
11c
55
78
80
72
77
75
80
71
57
21
66
58
16
24
24
Ad
Bd
Dd
Bd
15g
a 10–13 (1 mol); A: 40% HBr–AcOH (30 mol), 60 8C; B: 40% HBr–AcOH
(30 mol), 80 8C; C: 40% HBr–AcOH (30 mol), PhOH (3 mol), 60 8C; D:
40% HBr–AcOH (30 mol), PhOH (3 mol), 25 8C.
b Isolated yields.
10
11
5c
5c
Dd
Bd
72
2.5
3. Conclusions
a Reaction conditions: tosylamido diol 4, 5 (1 mol), NaH (2.1 mol), RSO2X
(1 mol)—solvent, 0–25 8C.
In conclusion, in this work we have outlined a viable
synthesis of 2,6-disubstituted morpholines 15 through the
regioselective ring opening of a pair of easily accessible,
appropriately substituted epoxides 2 with TsNH2 1,
employing SL-PTC conditions. The strategy described
here, involving the cyclization of the tosyl amido diols
4–7 thus obtained, followed by deprotection of the
corresponding N-tosyl morpholines 10–13, enabled us to
prepare a variety of 2,6-disubstituted morpholines 15, which
are tools of great interest as building blocks in the synthesis
of pharmaceuticals and agrochemicals. Moreover, the
inexpensive, readily available and environmentally friendly
reagents add attractiveness to this method.
b A: TsCl–DME; B: Tf2O–DCM; C: Tf2O–DME; D: TsCl–DCM, 25 8C.
c Isolated yields.
d At 40 8C.
Table 4. Cyclization of non-symmetric tosylamido diols 6, 7 to N-tosyl
morpholines 12 and 13a
Entry
Methodb
t (h)
Product
(%)c
1
2
3
4
5
6
6a
7a
6b
7b
7b
6c, 7cg
B
B
D
D
B
B
2
7
54
28
5
12a
13a
12b
13b
13b
12c
13c
12d
13d
12e
13e
85
77
46d
65e
54f
74h
64i
70h
59i
57h
53i
5
4. Experimental
7
8
6d, 7dg
6e, 7eg
D
B
28
5
4.1. General informations
a Reaction conditions: tosylamido diol 6, 7 (1 mol), NaH (2.1 mol), RSO2X
(1 mol)—solvent, 25 8C.
Melting points were determined on a Bu¨chi 535 apparatus
and are corrected. H NMR spectra were recorded on a
1
b B: Tf2O–DCM; D: TsCl–DCM.
c Isolated yields.
Bruker AC 300 spectrometer operating at 300.133 MHz;
TMS was used as an external reference; d values are in ppm
and J values are in Hz. Reagent-grade commercially
available reagents and solvents were used and dried, when
required, before use. Petroleum ether (PE) having a boiling
range of 40–60 8C was used in the chromatographic
purifications. Epoxides 2a–f are commercially available.
Alkaline metal carbonates were dried by heating at 140 8C
d Together with 13b (7%).
e Together with 12b (3%) and 14b (14%).
f
Together with 12b (25%).
g Starting from the corresponding (50:50) diastereoisomeric mixture 6, 7.
h Isolated yield calculated from the molar amount of the corresponding
tosylamido diol 6.
i
Isolated yield calculated from the molar amount of the corresponding
tosylamido diol 7.

V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
11713
under vacuum (0.05 mmHg) for 6 h. Analytical TLC was
performed using Merck pre-coated silica gel F254 plates.
1055, 952, 901, 862, 816, 708, 662 cmK1; dH (300 MHz,
CDCl3) 7.73 (2H, d, JZ8.1 Hz, Ts), 7.29 (2H, d, JZ8.1 Hz,
Ts), 5.11 (1H, t, JZ5.9 Hz, NH), 3.87–3.80 (1H, m,
CHOH), 3.42–3.35 (2H, m, CH2OMe), 3.33 (3H, s, OMe),
3.14–3.06 (1H, m, CHaHbNH), 2.96–2.88 (1H, m, CHaHb-
NH), 2.70 (1H, bs, OH), 2.41 (3H, s, ArMe). Anal. calcd for
C11H17NO4S: C, 50.95; H, 6.61; N, 5.40. Found: C, 50.89;
H, 6.60; N, 5.46.
4.2. General method for the preparation of b-tosylamido
alcohols 3
A heterogeneous mixture of TsNH2 (1) (342 mg, 2 mmol),
TEBA (23 mg, 0.1 mmol) and epoxide 2 (1 mmol) solution
in anhydrous dioxane (0.5 mL) and anhydrous K2CO3
(14 mg, 0.1 mmol), was magnetically stirred at 90 8C until
no starting material 1 was detectable (TLC analysis). After
cooling, the crude product was diluted with DCM (10 mL),
filtered through celite, the solvent was evaporated under
reduced pressure and the residue was purified by flash
column chromatography on silica gel (230–400 mesh).
Starting epoxide 2, reaction time, chromatographic eluant,
yield and physical, spectroscopic and analytical data of
amido alcohols 3a–d are as follows.
4.3. General method for the preparation of symmetric
tosylamido diols 4 and 5
A heterogeneous mixture of TsNH2 (1) (171 mg, 1 mmol),
TEBA (23 mg, 0.1 mmol), epoxide 2 (3 mmol) solution in
anhydrous dimethoxyethane or dioxane (0.75 mL) and
anhydrous alkaline carbonate (0.1 mmol), was magnetically
stirred at 80–90 8C until no starting material 1 was
detectable (TLC analysis). After the usual workup, as
described for the preparation of tosylamido alcohols 3, the
residue was purified by flash column chromatography on
silica gel (230–400 mesh). Starting epoxide 2, solvent,
temperature, base, reaction time, chromatographic eluant,
yield and physical, spectroscopic and analytical data of
amido diols 4 and 5 are as follows.
4.2.1. N-(2-Hydroxy-3-phenoxy-propyl)-4-methyl-ben-
zenesulfonamide (3a). 2-Phenoxymethyl-oxirane (2b);
2 h; AcOEt–PE 1:1. 3a, 292.5 mg, 91%; white solid, mp
63 8C (lit.,26 64–66 8C); nmax (Nujol) 3479, 3245, 1599,
1586, 1499, 1417, 1332, 1310, 1253, 1154, 1078, 1046,
1023, 952, 813, 750 cmK1; dH (300 MHz, CDCl3) 7.75 (2H,
d, JZ8.3 Hz, Ts), 7.32–7.25 (4H, m, Ar), 6.97 (1H, t, JZ
7.4 Hz, Ph), 6.85 (2H, d, JZ8.1 Hz, Ph), 5.12 (1H, t, JZ
6.3 Hz, NH), 4.11–4.07 (1H, m, CHOH), 3.96–3.91 (2H, m,
CH2OPh), 3.25 (1H, ddd, JZ3.9, 7.0, 13.2 Hz, CHaHbN),
3.13–3.05 (1H, m, CHaHbN), 2.64 (1H, d, JZ4.6 Hz, OH),
2.43 (3H, s, ArMe). Anal. calcd for C16H19NO4S: C, 59.79;
H, 5.96; N, 4.36. Found: C, 59.80; H, 5.93; N, 4.39.
4.3.1. Tosylamido diols 4a and 5a. 2-Hexyl-oxirane (2a);
dimethoxyethane; 80 8C; Na2CO3; 10 h; Et2O–PE 1:3. 4a,
201.0 mg, 47%; white solid, mp 61–62 8C; nmax (Nujol)
3392, 1909, 1737, 1600, 1494, 1343, 1158, 1099, 848, 764,
666 cmK1; dH (300 MHz, CDCl3) 7.68 (2H, d, JZ8.2 Hz,
Ts), 7.32 (2H, d, JZ8.2 Hz, Ts), 3.93–3.89 (2H, m,
2CHOH), 3.23 (2H, bs, 2OH), 3.02–2.99 (4H, m, 2CH2N),
2.42 (3H, s, ArMe), 1.43–1.27 (20H, m, 2C5H10), 0.86 (6H,
t, JZ6.9 Hz, 2Me). Anal. calcd for C23H41NO4S: C, 64.60;
H, 9.66; N, 3.28. Found: C, 64.71; H, 9.70, N, 3.26. 5a,
205.3 mg, 48%; white solid, mp 86–87 8C; nmax (Nujol)
3400–3200 (br), 1934, 1820, 1734, 1660, 1597, 1494, 1340,
1162, 1088, 848, 818, 726, 648 cmK1; dH (300 MHz,
CDCl3) 7.68 (2H, d, JZ8.2 Hz, Ts), 7.33 (2H, d, JZ
8.2 Hz, Ts), 4.02–3.98 (2H, m, 2CHOH), 3.68 (2H, bs,
2OH), 3.37 (2H, dd, JZ14.7, 2.4 Hz, 2CHaCHbN), 2.76
(2H, dd, JZ14.7, 9.8 Hz, 2CHaCHbN), 2.43 (3H, s, ArMe),
1.37–1.27 (20H, m, 2C5H10), 0.87 (6H, t, JZ6.9 Hz, 2Me).
Anal. calcd for C23H41NO4S: C, 64.60; H, 9.66; N, 3.28.
Found: C, 64.68; H, 9.72; N, 3.20.
4.2.2. N-(2-Hydroxy-2-phenyl-ethyl)-4-methyl-benzene-
sulfonamide (3b). 2-Phenyl-oxirane (2c); 6 h; Et2O–PE
1:1. 3b, 271.0 mg, 93%; white solid, mp 105–106 8C (lit.,26
107–108 8C); nmax (Nujol) 3401, 3149, 1918, 1662, 1598,
1318, 1148, 1098, 1088, 1065 cmK1; dH (300 MHz, CDCl3)
7.72 (2H, d, JZ8.3 Hz, Ts), 7.34–7.23 (8H, m, ArCNH),
5.01–4.99 (1H, m, CHOH), 3.05 (1H, dd, JZ3.6, 8.6 Hz,
CHaHbN), 3.01 (1H, dd, JZ4.6, 8.5 Hz, CHaHbN), 2.42
(3H, s, ArMe), 2.31 (1H, d, JZ3.5 Hz, OH). Anal. calcd for
C15H17NO3S: C, 61.83; H, 5.88; N 4.81. Found: C, 61.91; H,
5.92; N, 4.78.
4.2.3. N-(3-Allyloxy-2-hydroxy-propyl)-4-methyl-ben-
zenesulfonamide (3c). 2-Allyloxymethyl-oxirane (2f);
2 h; AcOEt–PE 1:2. 3c, 225.4 mg, 79%; wax; nmax (Nujol)
3470, 3280, 2974, 1728, 1599, 1340, 1160, 1090,
994 cmK1; dH (300 MHz, CDCl3) 7.71 (2H, d, JZ8.1 Hz,
Ts), 7.27 (2H, d, JZ8.1 Hz, Ts), 5.88–5.75 (1H, m,
]CHCH2O), 5.37 (1H, t, JZ6.0 Hz, NH), 5.24–5.13 (2H,
m, CH2]), 3.93 (2H, d, JZ5.2 Hz, ]CHCH2O), 3.88–3.81
(1H, m, CHOH), 3.44–3.34 (2H, m, CH2OAll), 3.12–3.04
(1H, m, CHaHbNH), 2.95–2.87 (1H, m, CHaHbNH), 2.90
(1H, bs, OH) 2.39 (3H, s, ArMe). Anal. calcd for
C13H19NO4S: C, 54.72; H, 6.71; N, 4.91. Found: C, 54.81;
H, 6.67; N, 4.81.
4.3.2. Tosylamido diols 4b and 5b. 2-Phenoxymethyl-
oxirane (2b); dimethoxyethane; 80 8C; Na2CO3; 6 h; Et2O–
PE 1:1. 4b, 212.2 mg, 45%; white solid, mp 75 8C; nmax
(Nujol) 3369 (br), 1598, 1587, 1335, 1248, 1146, 1087, 942,
917, 809, 751 cmK1; dH (300 MHz, CDCl3) 7.72 (2H, d, JZ
8.2 Hz, Ts), 7.35–7.24 (6H, m, Ar), 6.97 (2H, t, JZ7.4 Hz,
Ph), 6.89 (4H, d, JZ8.1 Hz, Ph), 4.38–4.31 (2H, m,
2CHOH), 4.02 (4H, d, JZ5.2 Hz, 2CH2OPh), 3.48 (2H, d,
JZ4.5 Hz, 2OH), 3.36 (4H, d, JZ5.7 Hz, 2CH2N), 2.42
(3H, s, ArMe). Anal. calcd for C25H29NO6S: C, 63.67; H,
6.20; N, 2.97. Found: C, 63.60; H, 6.26; N, 3.00. 5b,
212.2 mg, 45%; white solid, mp 112 8C; nmax (Nujol) 3233
(br), 1597, 1587, 1494, 1342, 1249, 1161, 1040, 993, 922,
813, 751 cmK1; dH (300 MHz, CDCl3) 7.72 (2H, d, JZ
8.2 Hz, Ts), 7.33–7.24 (6H, m, Ar), 6.96 (2H, t, JZ7.3 Hz,
Ph), 6.89 (4H, d, JZ8.2 Hz, Ph), 4.43–4.37 (2H, m,
2CHOH), 4.00 (4H, d, JZ5.2 Hz, 2CH2OPh), 3.66 (2H,
4.2.4. N-(2-Hydroxy-3-methoxy-propyl)-4-methyl-ben-
zenesulfonamide (3d). 2-Methoxymethyl-oxirane (2e);
2 h; AcOEt–PE 1:1. 3d, 215.2 mg, 83%; wax; nmax
(Nujol) 3392, 3284, 1926, 1662, 1598, 1332, 1162, 1222,

11714
V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
0
0
bs, 2OH), 3.60 (2H, dd, JZ15.0, 2.9 Hz, 2CHaHbN), 3.20
(2H, dd, JZ15.0, 8.6 Hz, 2CHaHbN), 2.42 (3H, s, ArMe).
Anal. calcd for C25H29NO6S: C, 63.67; H, 6.20; N, 2.97.
Found: C, 63.56; H, 6.25; N, 2.93.
2.3 Hz, CHaHbN), 3.08 (1H, dd, JZ14.9, 8.8 Hz, CHa Hb -
N), 2.87 (1H, dd, JZ14.7, 9.6 Hz, CHaHbN), 2.42 (3H, s,
ArMe), 1.41–1.26 (10H, m, C5H10), 0.87 (3H, t, JZ6.9 Hz,
Me). Anal. calcd for C24H35NO5S: C, 64.11; H, 7.85; N,
3.12. Found: C, 64.22; H, 7.90; N, 3.16.
4.3.3. Tosylamido diols 4c and 5c. 2-Phenyl-oxirane (2c);
dioxane; 90 8C; Cs2CO3; 6 h; Et2O–PE 2:3. 4c, 156.4 mg,
38%; white solid, mp 82–83 8C; nmax (Nujol) 3294 (br),
1730, 1599, 1343, 1158, 1065, 952, 844, 811 cmK1; dH
(300 MHz, CDCl3) 7.68 (2H, d, JZ8.3 Hz, Ts), 7.43–7.25
(12H, m, Ar), 5.13 (2H, dd, JZ10.0, 3.0 Hz, 2CHOH), 3.44
(2H, d, JZ3.0 Hz, 2OH), 3.33 (2H, dd, JZ14.7, 10.0 Hz,
2CHaHbN), 3.17 (2H, dd, JZ14.7, 3.0 Hz, 2CHaHbN), 2.38
(3H, s, ArMe). Anal. calcd for C23H25NO4S: C, 67.13; H,
6.12; N, 3.40. Found: C, 67.18; H, 6.18; N, 3.33. 5c,
152.2 mg, 37%; white solid, mp 166–168 8C; nmax (Nujol)
3310, 3196, 1733, 1599, 1344, 1154, 1088, 1056, 991, 869,
814 cmK1; dH (300 MHz, CDCl3) 7.67 (2H, d, JZ8.3 Hz,
Ts), 7.44–7.25 (12H, m, Ar), 5.24 (2H, dd, JZ9.8,
2.5 Hz, 2CHOH), 3.60 (2H, dd, JZ15.0, 2.5 Hz, 2CHaHb-
N), 4.16 (2H, bs, 2OH), 2.99 (2H, dd, JZ15.0, 9.8 Hz,
2CHaHbN), 2.38 (3H, s, ArMe). Anal. calcd for
C23H25NO4S: C, 67.13; H, 6.12; N, 3.40. Found: C, 67.20,
H, 6.08; N, 3.46.
4.4.2. Tosylamido diols 6b and 7b. Phenyl-oxirane (2c),
3a; Cs2CO3; 22 h; methyl-tert-butyl ether–PE 2:3. 6b,
159.0 mg, 36%; white solid, mp 104–106 8C; nmax (Nujol)
3552, 3320, 1733, 1599, 1590, 1344, 1246, 1154, 963, 812,
754, 660 cmK1; dH (300 MHz, CDCl3) 7.69 (2H, d, JZ
8.2 Hz, Ts), 7.40–7.25 (9H, m, Ar), 6.97 (1H, t, JZ7.3 Hz,
Ph), 6.91 (2H, d, JZ8.0 Hz, Ph), 5.15 (1H, dd, JZ2.9,
9.6 Hz, CHPh), 4.36–4.32 (1H, m, CHCH2OPh), 4.06 (2H,
d, JZ5.2 Hz, CH2OPh), 3.48 (1H, dd, JZ8.1, 14.0 Hz,
CHaHbN), 3.44 (2H, bs, 2OH), 3.34–3.25 (2H, m, CH2N),
3.21–3.17 (1H, m, CHaHbN), 2.40 (3H, s, ArMe). Anal.
calcd for C24H27NO5S: C, 65.28; H, 6.16; N, 3.17. Found:
C, 63.80; H, 6.70; N, 3.06. 7b, 159.0 mg, 36%; white solid,
mp 93.5–95.5 8C; nmax (Nujol) 3540, 3332, 1730, 1602,
1594, 1350, 1260, 1156, 964, 820, 758, 662 cmK1; dH
(300 MHz, CDCl3) 7.70 (2H, d, JZ8.2 Hz, Ts), 7.40–7.24
(9H, m, Ar), 7.00–6.89 (3H, m, Ph), 5.21 (1H, dd, JZ9.7,
2.5 Hz, CHPh), 4.52–4.42 (1H, m, CHCH2OPh), 4.00 (2H,
d, JZ5.3 Hz, CH2OPh), 3.66 (1H, dd, JZ15.0, 2.7 Hz,
0
0
CHa Hb N), 3.53 (1H, dd, JZ14.7, 2.5 Hz, CHaHbN), 3.12
4.4. General method for the preparation of non-
symmetric tosylamido diols 6 and 7
0
0
(1H, dd, JZ14.7, 8.7 Hz, CHa Hb N), 3.10 (1H, dd, JZ14.7,
9.7 Hz, CHaHbN), 2.62 (2H, bs, 2OH), 2.41 (3H, s, ArMe).
Anal. calcd for C24H27NO5S: C, 65.28; H, 6.16; N, 3.17.
Found: C, 64.90; H, 6.40; N, 3.12.
A heterogeneous mixture of tosylamido alcohol 3 (1 mmol),
TEBA (23 mg, 0.1 mmol), epoxide 2 (1.1 mmol) solution in
anhydrous dioxane (1.5 mL) and anhydrous alkaline
carbonate (0.1 mmol), was magnetically stirred at 90 8C
until no starting material 1 was detectable (TLC analysis).
After the usual workup, the residue was purified by flash
column chromatography on silica gel (230–400 mesh).
Starting oxirane 2, tosylamido alcohol 3, base, reaction
time, chromatographic eluant, yield and physical, spectro-
scopic and analytical data of non-symmetric tosylamido
diols 6 and 7 are as follows.
4.4.3. Tosylamido diols 6c, 7c. 2-tert-Butoxymethyl-
oxirane (2f), 3a; Na2CO3; 48 h; AcOEt–PE 1:3. 6c, 7c
(50:50), 316.1 mg, 70%; colourless oil; nmax (neat) 3391
(br), 3064, 3041, 2975, 2926, 2877, 1928, 1736, 1599, 1494,
1456, 1390, 1348, 1305, 1246, 1168, 1089, 974, 816, 755,
692, 665 cmK1; dH (300 MHz, CDCl3) 7.70 (2H-6cC2H-
7c, d, JZ8.8 Hz, Ts), 7.31–7.23 (4H-6cC4H-7c, m, Ar),
6.94 (1H-6cC1H-7c, t, JZ7.3 Hz, Ph), 6.88 (2H-6cC2H-
7c, d, JZ7.3 Hz, Ph), 4.39–4.32 (1H-7c, m, CHCH2OPh),
4.30–4.25 (1H-6c, m, CHCH2OPh), 4.16–3.92 (3H-6cC
3H-7c, m, 2CH2OPhC2CHCH2OBut), 3.76 (2H-6cC2H-
7c, bs, 4OH), 3.62 (2H-7c, dd, JZ14.7, 2.9 Hz, 2CHaHbN),
3.47 (2H-6c, dd, JZ14.7, 2.9 Hz, 2CHaHbN), 3.44–3.14
(2H-6cC2H-7c, m, 2CH2OBut), 3.10 (2H-6c, dd, JZ14.7,
8.8 Hz, 2CHaHbN), 3.03 (2H-7c, dd, JZ14.7, 8.8 Hz,
2CHaHbN), 2.41 (3H-6cC3H-7c, s, 2ArMe), 1.17 (9H, s,
CMe3), 1.16 (9H, s, CMe3). Anal. calcd for C23H33NO6S: C,
61.17; H, 7.37; N, 3.10. Found: C, 60.98; H, 7.21; N, 3.12.
4.4.1. Tosylamido diols 6a and 7a. 2-Hexyl-oxirane (2a),
3a; K2CO3; 11 h; AcOEt–PE 1:6. 6a, 157.4 mg, 35%; white
solid, mp 67–69 8C; nmax (Nujol) 3316, 3258, 1918, 1733,
1602, 1589, 1500, 1343, 1247, 1158, 1042, 980, 911, 816,
752, 655 cmK1; dH (300 MHz, CDCl3) 7.70 (2H, d, JZ
8.2 Hz, Ts), 7.35–7.25 (4H, m, Ar), 6.95 (1H, t, JZ7.3 Hz,
Ph), 6.89 (2H, d, JZ8.1 Hz, Ph), 4.36–4.29 (1H, m,
0
CHc OH), 4.05–4.00 (2H, m, CH2OPh), 3.95 (1H, m,
CHcOH), 3.62 (1H, bs, OH), 3.35 (1H, dd, JZ14.7,
0
0
0
0
8.0 Hz, CHa Hb N), 3.26 (1H, dd, JZ14.7, 3.4 Hz, CHa Hb -
N), 3.19 (1H, bs, OH), 3.12 (1H, dd, JZ14.4, 3.7 Hz,
CHaHbN), 3.05 (1H, dd, JZ14.4, 8.2 Hz, CHaHbN), 2.43
(3H, s, ArMe), 1.43–1.25 (10H, m, C5H10), 0.88 (3H, t, JZ
6.9 Hz, Me). Anal. calcd for C24H35NO5S: C, 64.11; H,
7.85; N, 3.12. Found: C, 63.10; H, 7.90; N, 3.07. 7a,
157.4 mg, 35%; white solid, mp 88–89 8C; nmax (Nujol)
3320, 3272, 1912, 1730, 1600, 1590, 1504, 1350, 1252,
1156, 988, 912, 756 cmK1; dH (300 MHz, CDCl3) 7.69 (2H,
d, JZ8.3 Hz, Ts), 7.32–7.24 (4H, m, Ar), 6.95 (1H, t, JZ
7.3 Hz, Ph), 6.88 (2H, d, JZ8.0 Hz, Ph), 4.38–4.23 (1H, m,
4.4.4. Tosylamido diols 6d, 7d. 2-tert-Butoxymethyl-
oxirane (2f), 3c; Na2CO3; 20 h; AcOEt–PE 1:8. 6d, 7d
(45:55); 290.9 mg, 70%, wax; nmax (Nujol) 3402 (br), 2975,
1727, 1646, 1599, 1494, 1391, 1342, 1290, 1195, 1163,
1089, 996, 925, 816, 753, 659 cmK1; dH (300 MHz, CDCl3)
7.70 (2H-6dC2H-7d, d, JZ8.1 Hz, 2Ts), 7.31 (2H-6dC
2H-7d, d, JZ8.1 Hz, 2Ts), 5.95–5.82 (1H-6dC1H-7d, m,
2CH]CH2), 5.29–5.16 (2H-6dC2H-7d, m, 2CH2]),
4.17–4.14 (1H-7d, m, CHCH2OAll), 4.09–4.06 (1H-6d,
m, CHCH2OAll), 4.01 (2H-6dC2H-7d, dd, JZ2.9,
15.4 Hz, 2OCH2CH]CH2), 3.84 (2H, bs, 2OH), 3.70
(2H, bs, 2OH), 3.47 (2H-6dC2H-7d, d, JZ5.1 Hz, 2CH2-
OAll), 3.21 (2H-6dC2H-7d, d, JZ5.5 Hz, 2CH2OBut),
0
CHc OH), 4.20 (1H, bs, OH), 4.03–3.99 (1H, m, CHcOH),
3.99–3.92 (2H, m, CH2OPh), 3.65 (1H, bs, OH), 3.62 (1H,
0
0
dd, JZ14.9, 2.7 Hz, CHa Hb N), 3.38 (1H, dd, JZ14.7,

V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
11715
3.53–3.12 (5H-6dC3H-7d, m, (CHCH2OButC2CH2N)C
solid, mp 40–41 8C; nmax (Nujol) 1600, 1364, 1170, 1092,
949, 814, 677 cmK1; dH (300 MHz, CDCl3) 7.60 (2H, d, JZ
8.2 Hz, Ts), 7.32 (2H, d, JZ8.2 Hz, Ts), 3.79–3.73 (2H, m,
2CHO), 2.98 (2H, dd, JZ11.2, 3.3 Hz, 2CHaHbN), 2.67
(2H, dd, JZ11.2, 5.8 Hz, 2CHaHbN), 2.43 (3H, s, ArMe),
1.65–1.27 (20H, m, 2C5H10), 0.87 (6H, t, JZ6.9 Hz, 2Me).
Anal. calcd for C23H39NO3S: C, 67.44; H, 9.60; N, 3.42.
Found: C, 67.12; H, 9.52; N, 3.40.
t
(CHaHbNCCHa Hb NCCHCH2OBu ), 3.05–2.97 (1H-7d,
0
0
0
0
m, CHa Hb N), 3.04–2.96 (1H-7d, m, CHaHbN), 2.42 (3H-
6dC3H-7d, s, 2ArMe), 1.18 (9H, s, CMe3), 1.17 (9H, s,
CMe3). Anal. calcd for C20H33NO6S: C, 57.81; H, 8.00; N,
3.37. Found: C, 57.67; H, 8.09; N, 3.31.
4.4.5. Tosylamido diols 6e, 7e. 2-Phenoxymethyl-oxirane
(2b), 3d; Na2CO3; 20 h; AcOEt–PE 2:3. 6e, 7e (50:50),
335.8 mg, 82%; colourless oil; nmax (neat) 3392 (br), 3064,
2925, 1599, 1588, 1494, 1455, 1338, 1246, 1160, 1089, 995,
816, 757, 693, 658 cmK1; dH (300 MHz, CDCl3) 7.71 (2H-
6eC2H-7e, d, JZ8.3 Hz, Ts), 7.34–7.24 (4H-6eC4H-7e,
m, Ar), 6.96 (1H-6eC1H-7e, t, JZ7.3 Hz, Ph), 6.89 (2H-
6eC2H-7e, d, JZ7.9 Hz, Ph), 4.54 (2H-6eC2H-7e, bs,
4OH), 4.43–4.25 (1H-6eC1H-7e, m, 2CHOH), 4.22–4.03
(1H-6eC1H-7e, m, 2CHOH), 4.02–3.96 (2H-6eC2H-7e,
4.5.3. Morpholine 10b. Tosylamido diol 4b; Tf2O; DCM;
25 8C; 13 h; AcOEt–PE 1:10. 10b, 349.2 mg, 77%; white
solid, 125–127 8C; nmax (Nujol) 1599, 1586, 1494, 1341,
1254, 1211, 1160, 1119, 1052, 1036, 999, 814, 753, 692,
666 cmK1; dH (300 MHz, CDCl3) 7.66 (2H, d, JZ8.2 Hz,
Ts), 7.36–7.25 (6H, m, Ar), 6.96 (2H, t, JZ7.3 Hz, Ph), 6.87
(4H, d, JZ8.1 Hz, Ph), 4.08–4.04 (4H, m, 2CHOC
CH2OPh), 3.92–3.87 (4H, m, 2CHaHbNCCH2OPh), 2.44
(3H, s, ArMe), 2.26 (2H, dd, JZ10.8, 10.8 Hz, 2CHaHbN).
Anal. calcd for C25H27NO5S: C, 66.20; H, 6.00; N, 3.09.
Found: C, 66.11; H, 5.98; N, 3.06.
0
0
m, 2CH2OPh), 3.63–3.51 (2H-7e, m, CHaHbNCCHa Hb N),
3.48–3.42 (2H-6eC2H-7e, m, 2CH2OMe), 3.38 (3H, s,
OMe), 3.37 (3H, s, OMe), 3.34–3.22 (4H-6e, m, 2CH2N),
0
0
3.19–2.98 (2H-7e, m, CHaHbNCCHa Hb N), 2.43 (3H-6eC
3H-7e, s, 2ArMe). Anal. calcd for C20H27NO6S: C, 58.66;
H, 6.65; N, 3.42. Found: C, 58.72; H, 6.44; N, 3.32.
4.5.4. Morpholine 11b. Tosylamido diol 5b; Tf2O; DCM;
40 8C; 6 h; AcOEt–PE 1:8. 11b, 362.8 mg, 80%; white
solid, mp 143–145 8C; nmax (Nujol) 1601, 1582, 1492, 1341,
1252, 1160, 1120, 1050, 998, 814, 754, 690, 666 cmK1; dH
(300 MHz, CDCl3) 7.65 (2H, d, JZ8.2 Hz, Ts), 7.34–7.27
(6H, m, Ar), 6.97 (2H, t, JZ7.3 Hz, Ph), 6.89 (4H, d, JZ
8.0 Hz, Ph), 4.28–4.25 (2H, m, 2CHO), 4.13 (2H, dd, JZ
4.5. General method for the preparation of 2,6-dialkyl-4-
(toluene-4-sulfonyl)-morpholines 10–13
In a flame-dried round bottomed flask, 60% sodium hydride
(84 mg, 2.1 mmol) was rinsed with anhydrous n-pentane
(3!0.5 mL). A tosylamido diol 4–7 (1 mmol) solution in
anhydrous dichloromethane or dimethoxyethane (5 mL)
was cooled at 0 8C and then added to the NaH by syringe,
under nitrogen atmosphere. The reaction mixture was stirred
at 0 8C until hydrogen evolution ended. A solution of tosyl
chloride (TsCl, 1 mmol) or trifuoromethanesulfonic
anhydride (Tf2O, 1 mmol) in dichloromethane (DCM,
5 mL) or dimethoxyethane (DME, 5 mL) was added to the
reaction mixture and the stirring was continued at 25–40 8C
until disappearance of the starting diol 4–7 (TLC analysis).
After cooling, H2O (2 mL) was added, DCM was evapor-
ated under reduced pressure and the residue was extracted
with AcOEt (4!10 mL). The organic phase was dried over
sodium sulfate, the solvent was evaporated to dryness under
vacuum and the crude was purified by flash column
chromatography on silica gel (230–400 mesh). Starting
tosylamido diol 4–7, cyclization agent (TsCl or Tf2O),
solvent, temperature, reaction time, chromatographic
eluant, yield and physical, spectroscopic and analytical
data are as follows.
0
0
9.6, 5.4 Hz, CHa Hb OPh), 4.11 (2H, dd, JZ9.6, 6.4 Hz,
0
0
CHa Hb OPh), 3.25 (2H, dd, JZ11.6, 3.3 Hz, 2CHaHbN),
3.04 (2H, dd, JZ11.6, 5.7 Hz, 2CHaHbN), 2.43 (3H, s,
ArMe). Anal. calcd for C25H27NO5S: C, 66.20; H, 6.00; N,
3.09. Found: C, 66.31; H, 6.07; N, 3.05.
4.5.5. Morpholine 10c. Tosylamido diol 4c; TsCl; DCM;
40 8C; 22 h; Et2O–PE 1:3. 10c, 279.4 mg, 71%; white solid,
mp 128–130 8C; nmax (Nujol) 1960, 1821, 1732, 1597, 1494,
1341, 1228, 1166, 1068, 962, 814, 776, cmK1; dH
(300 MHz, CDCl3) 7.59 (2H, d, JZ8.2 Hz, Ts), 7.47–7.27
(12H, m, Ar), 4.85 (2H, dd, JZ10.6, 2.5 Hz, 2CHO), 3.89
(2H, dd, JZ10.6, 2.5 Hz, 2CHaHbN), 2.41 (3H, s, ArMe),
2.28 (2H, dd, JZ10.6, 10.6 Hz, 2CHaHbN). Anal. calcd for
C23H23NO3S: C, 70.20; H, 5.89; N, 3.56. Found: C, 70.09;
H, 5.60; N, 3.61.
4.5.6. Morpholine 11c. Tosylamido diol 5c; TsCl; DCM;
40 8C; 72 h; Et2O–PE 1:3. 11c, 259.7 mg, 66%; wax; nmax
(Nujol) 1962, 1823, 1732, 1596, 1495, 1342, 1306, 1230,
1167, 1089, 1065, 961, 926, 815, 774, 702, 692, 651 cmK1
;
dH (300 MHz, CDCl3) 7.65 (2H, d, JZ8.2 Hz, Ts), 7.46–
7.30 (12H, m, Ar), 4.90 (2H, dd, JZ5.7, 3.7 Hz, 2CHO),
3.35 (2H, dd, JZ11.6, 5.7 Hz, 2CHaHbN), 3.27 (2H, dd, JZ
11.6, 3.7 Hz, 2CHaHbN), 2.45 (3H, s, ArMe). Anal. calcd for
C23H23NO3S: C, 70.20; H, 5.89; N, 3.56. Found: C, 70.33;
H, 5.90; N, 3.60.
4.5.1. Morpholine 10a. Tosylamido diol 4a; Tf2O; DCM;
25 8C; 6 h; Et2O–PE 1:18. 10a, 319.5 mg, 78%; white solid,
mp 56 8C; nmax (Nujol) 1922, 1666, 1600, 1493, 1348, 1170,
1128, 1094, 1000, 956, 816, 784, 663, 619 cmK1; dH
(300 MHz, CDCl3) 7.61 (2H, d, JZ8.2 Hz, Ts), 7.32 (2H, d,
JZ8.2 Hz, Ts), 3.54 (2H, d, JZ10.8 Hz, 2CHaHbN), 3.50–
3.44 (2H, m, 2CHO), 2.43 (3H, s, ArMe), 1.92 (2H, dd, JZ
10.8, 10.8 Hz, 2CHaHbN), 1.54–1.25 (20H, m, 2C5H10),
0.87 (6H, t, JZ6.9 Hz, 2Me). Anal. calcd for C23H39NO3S: C,
67.44; H, 9.60; N, 3.42. Found: C, 67.20; H, 9.68; N, 3.41.
4.5.7. Morpholine 12a. Tosylamido diol 6a; Tf2O; DCM;
25 8C; 2 h; Et2O–PE 1:1. 12a, 366.8 mg, 85%; colourless
oil; nmax (neat) 1661, 1600, 1496, 1378, 1302, 1245, 1169,
1121, 1094, 815, 754, 692 cmK1; dH (300 MHz, CDCl3)
7.64 (2H, d, JZ8.2 Hz, Ts), 7.33 (2H, d, JZ8.2 Hz, Ts),
7.30–7.24 (2H, m, Ph), 6.95 (1H, t, JZ7.3 Hz, Ph), 6.87
(2H, d, JZ8.2 Hz, Ph), 4.05–4.00 (1H, m, CHO), 4.00–3.92
4.5.2. Morpholine 11a. Tosylamido diol 5a; Tf2O; DME;
25 8C; 6 h; AcOEt–PE 1:20. 11a, 327.7 mg, 80%; white

11716
V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
(1H, m, CHO), 3.86–3.81 (2H, m, CH2OPh), 3.63–3.57 (2H,
(50:50); Tf2O; DCM; 25 8C; 5 h; AcOEt–PE 1:10. 12c,
320.8 mg, 74%; wax; nmax (Nujol) 1599, 1580, 1346, 1247,
1167, 1120, 1087, 814, 756 cmK1; dH (300 MHz, CDCl3)
7.65 (2H, d, JZ8.4 Hz, Ts), 7.35–7.24 (4H, m, Ar), 6.95
(1H, t, JZ7.4 Hz, Ph), 6.86 (2H, d, JZ7.7 Hz, Ph), 4.10–
3.96 (1HC1H, m, 2CHO), 3.86–3.73 (4H, m, CH2OPhC
CH2OBut), 3.47 (1H, dd, JZ11.0, 4.8 Hz, CHaHbN), 3.23
0
m, CHaHbNCCHa Hb N), 2.43 (3H, s, ArMe), 2.16 (1H, dd,
0
0
0
JZ10.8, 10.4 Hz, CHa Hb N), 2.00 (1H, dd, JZ11.2,
11.2 Hz, CHaHbN), 1.49–1.25 (10H, m, C5H10), 0.87 (3H,
t, JZ7.0 Hz, Me). Anal. calcd for C24H33NO4S: C, 66.79;
H, 7.71; N, 3.25. Found: C, 66.64; H, 7.78; N, 3.20.
0
0
(1H, dd, JZ11.0, 7.0 Hz, CHa Hb N), 2.44 (3H, s, ArMe),
4.5.8. Morpholine 13a. Tosylamido diol 7a; Tf2O; DCM;
25 8C; 7 h; AcOEt–PE 1:9. 13a, 332.3 mg, 77%; colourless
oil; nmax (neat) 1662, 1598, 1588, 1496, 1376, 1300, 1244,
1168, 1120, 1093, 812, 754, 690 cmK1; dH (300 MHz,
CDCl3) 7.62 (2H, d, JZ8.2 Hz, Ts), 7.33–7.24 (4H, m, Ar),
6.96 (1H, t, JZ7.3 Hz, Ph), 6.87 (2H, d, JZ8.2 Hz, Ph),
4.20–4.17 (1H, m, CHCH2OPh), 4.12 (1H, dd, JZ9.4,
5.4 Hz, CHaHbOPh), 4.02 (1H, dd, JZ9.4, 6.4 Hz, CHaHb-
OPh), 3.84–3.81 (1H, m, CHC6H13), 3.15 (1H, dd, JZ11.4,
0
0
2.20 (1H, dd, JZ11.0, 11.0 Hz, CHa Hb N), 2.09 (1H, dd,
JZ11.0, 11.0 Hz, CHaHbN), 1.15 (9H, s, CMe3). Anal.
calcd for C23H31NO5S: C, 63.72; H, 7.21; N, 3.23. Found:
C, 63.42; H, 7.18; N, 3.20.
Compound 13c. 277.5 mg, 64%; wax; nmax (Nujol) 1600,
1576, 1346, 1246, 1168, 1120, 1086, 816, 758 cmK1; dH
(300 MHz, CDCl3) 7.63 (2H, d, JZ8.1 Hz, Ts), 7.34–7.25
(4H, m, Ar), 6.96 (1H, t, JZ7.4 Hz, Ph), 6.88 (2H, d, JZ
7.7 Hz, Ph), 4.22–4.17 (1H, m, CHCH2OPh), 4.14–4.08
(1H, m, CHCH2OBut), 4.00–3.89 (2H, m, CH2OPh), 3.54
(2H, d, JZ6.2 Hz, CH2OBut), 3.31 (1H, dd, JZ11.4,
0
0
3.3 Hz, CHa Hb N), 3.08 (1H, dd, JZ11.4, 3.3 Hz, CHaHb-
0
0
N), 2.98 (1H, dd, JZ11.4, 5.5 Hz, CHa Hb N), 2.73 (1H, dd,
JZ11.4, 6.0 Hz, CHaHbN), 2.42 (3H, s, ArMe), 1.70–1.66
(2H, m, CHCH2), 1.37–1.22 (8H, m, C4H8), 0.87 (3H, t, JZ
6.9 Hz, Me). Anal. calcd for C24H33NO4S: C, 66.79; H,
7.71; N, 3.25. Found: C, 66.90; H, 7.78; N, 3.20.
0
0
2.9 Hz, CHa Hb N), 3.07 (1H, dd, JZ11.4, 4.8 Hz, CHaHb-
N), 2.99 (1H, dd, JZ11.4, 3.6 Hz, CHaHbN), 2.83 (1H, dd,
0
0
JZ11.4, 6.2 Hz, CHa Hb N), 2.43 (3H, s, ArMe), 1.19 (9H,
s, CMe3). Anal. calcd for C23H31NO5S: C, 63.72; H, 7.21;
N, 3.23. Found: C, 63.82; H, 7.24; N, 3.18.
4.5.9. Morpholine 12b. Tosylamido diol 6b; TsCl; DCM;
25 8C; 54 h; AcOEt–PE 1:7. 12b, 194.8 mg, 46%; white
solid, mp 124–126 8C; nmax (Nujol) 1598, 1586, 1492, 1344,
1238, 1166, 1122, 1066, 1052, 966, 774, 756 cmK1; dH
(300 MHz, CDCl3) 7.62 (2H, d, JZ8.2 Hz, Ts), 7.37–7.25
(9H, m, Ar), 6.97 (1H, t, JZ7.3 Hz, Ph), 6.89 (2H, d, JZ
8.2 Hz, Ph), 4.73 (1H, dd, JZ10.5, 2.4 Hz, CHPh), 4.20–
4.12 (1HC1H, m, CHCH2OPhCCHaHbN), 3.99–3.93 (2H,
4.5.12. Morpholines 12d and 13d. Tosylamido diols 6d, 7d
(45:55); TsCl; DCM; 25 8C; 28 h; AcOEt–PE 1:8. 12d,
278.3 mg, 70%; colourless oil; nmax (neat), 3066, 2975,
2922, 2872, 1730, 1646, 1598, 1494, 1455, 1348, 1195,
1168, 1088, 996, 816, 787, 664 cmK1; dH (300 MHz,
CDCl3) 7.64 (2H, d, JZ8.1 Hz, Ts), 7.33 (2H, d, JZ
8.1 Hz, Ts), 5.91–5.78 (1H, m, CH]CH2), 5.26–5.16 (2H,
m, CH2]), 3.96 (2H, d, JZ5.5 Hz, OCH2CH]CH2), 3.78–
3.64 (4H, m, 2CH2O), 3.53–3.43 (2H, m, CHO), 3.39 (1H,
dd, JZ11.0, 5.2 Hz, CHaHbN), 3.18 (1H, dd, JZ11.0,
0
0
m, CH2OPh), 3.82 (1H, d, JZ11.0 Hz, CHa Hb N), 2.43
(3H, s, ArMe), 2.32 (1H, dd, JZ10.5, 10.5 Hz, CHaHbN),
0
0
2.22 (1H, dd, JZ11.0, 11.0 Hz, CHa Hb N). Anal. calcd for
C24H25NO4S: C, 68.06; H, 5.95; N, 3.31. Found: C, 67.92;
H, 5.91; N, 3.23. Together with 13b (29.6 mg, 7%).
0
0
7.4 Hz, CHa Hb N), 2.43 (3H, s, ArMe), 2.14 (1H, dd, JZ
0
0
11.0, 11.0 Hz, CHa Hb N), 2.03 (1H, dd, JZ10.7, 10.7 Hz,
CHaHbN), 1.14 (9H, s, CMe3). Anal. calcd for C20H31NO5S:
C, 60.43; H, 7.86; N, 3.52. Found: C, 60.56; H, 7.78; N,
3.53.
4.5.10. Morpholine 13b. Tosylamido diol 7b; TsCl; DCM;
25 8C; 28 h; AcOEt–PE 1:7. 13b, 275.3 mg, 65%; white
solid, mp 146–148 8C; nmax (Nujol) 1598, 1587, 1493, 1345,
1236, 1167, 1131, 1122, 1065, 1051, 968, 813, 776, 757,
682 cmK1; dH (300 MHz, CDCl3) 7.64 (2H, d, JZ8.2 Hz,
Ts), 7.44–7.24 (9H, m, Ar), 6.96 (1H, t, JZ7.3 Hz, Ph), 6.90
(2H, d, JZ8.2 Hz, Ph), 4.95 (1H, dd, JZ6.9, 3.2 Hz,
CHPh), 4.24–4.18 (1H, m, CHCH2OPh), 4.21–4.18 (2H, m,
CH2OPh), 3.41 (1H, dd, JZ11.8, 3.2 Hz, CHaHbN), 3.29
Compound 13d. 234.5 mg, 59%; colourless oil; nmax (neat)
3526 (br), 3068, 2972, 2923, 2870, 1726, 1646, 1594, 1494,
1456, 1344, 1170, 1094, 994, 814, 785, 664 cmK1; dH
(300 MHz, CDCl3) 7.62 (2H, d, JZ8.1 Hz, Ts), 7.33 (2H, d,
JZ8.1 Hz, Ts), 5.93–5.78 (1H, m, CH]CH2), 5.28–5.17
(2H, m, CH2]), 3.98 (2H, d, JZ5.9 Hz, OCH2CH]CH2),
3.89–3.87 (1H, m, CHO), 3.58–3.43 (5H, m, CHOC
2CH2O), 3.15 (1H, dd, JZ11.4, 2.9 Hz, CHaHbN), 3.03
0
0
(1H, dd, JZ11.5, 3.9 Hz, CHa Hb N), 3.10 (1H, dd, JZ11.5,
0
0
2.6 Hz, CHa Hb N), 3.06 (1H, dd, JZ11.8, 6.9 Hz, CHaHb-
N), 2.43 (3H, s, ArMe). Anal. calcd for C24H25NO4S: C,
68.06; H, 5.95; N, 3.31. Found: C, 68.20; H, 5.92; N, 3.42.
Together with 12b (12.7 mg, 3%) and 14b (59.3 mg, 14%).
Vinyl tosylamide 14b; wax; nmax (Nujol) 3320, 3040, 1734,
1600, 1588, 1345, 1246, 1156, 964, 814, 756, 660 cmK1; dH
(300 MHz, CDCl3) 7.64 (2H, d, JZ8.2 Hz, Ts), 7.44–7.24
(9H, m, Ar), 6.96 (1H, t, JZ7.3 Hz, Ph), 6.90 (2H, d, JZ
8.2 Hz, Ph), 5.97 (1H, dt, JZ6.2, 6.2 Hz, CH]CHN), 5.48
(1H, d, JZ7.7 Hz, CH]CHN), 4.88–4.73 (3H, m, CH2-
OPhCCHPh), 3.42–3.34 (1HC1H, m, OHCCHaHbN),
3.15–3.07 (1H, m, CHaHbN), 2.40 (3H, s, ArMe). Anal.
calcd for C24H25NO4S: C, 68.06; H, 5.95; N, 3.31. Found:
C, 68.21; H, 5.89; N, 3.08.
0
0
(1H, dd, JZ11.4, 4.8 Hz, CHa Hb N), 2.94 (1H, dd, JZ11.4,
0
0
3.7 Hz, CHa Hb N), 2.74 (1H, dd, JZ11.4, 7.0 Hz, CHaHb-
N), 2.43 (3H, s, ArMe), 1.15 (9H, s, CMe3). Anal. calcd for
C20H31NO5S: C, 60.43; H, 7.86; N, 3.52. Found: C, 60.60;
H, 7.81; N, 3.44.
4.5.13. Morpholines 12e and 13e. Tosylamido diols 6e, 7e
(50:50); Tf2O; DCM; 25 8C; 5 h; AcOEt–PE 1:15. 12e,
223.1 mg, 57%; colourless oil; nmax (neat) 3063, 3040,
2917, 2850, 2057, 1929, 1746, 1599, 1494, 1456, 1347,
1245, 1168, 1000, 816, 757, 687 cmK1; dH (300 MHz,
CDCl3) 7.64 (2H, d, JZ8.1 Hz, Ts), 7.35–7.24 (4H, m, Ar),
6.95 (1H, t, JZ7.4 Hz, Ph), 6.86 (2H, d, JZ8.1 Hz, Ph),
4.5.11. Morpholines 12c and 13c. Tosylamido diols 6c, 7c

V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
11717
4.08–4.01 (1H, m, CHCH2OPh), 4.00–3.98 (1H, m,
CHCH2OMe), 3.87–3.85 (2H, m, CH2OPh), 3.84–3.82
1036, 813, 755, 694 cmK1; dH (300 MHz, CDCl3) 7.37–
6.76 (10H, m, Ph), 4.09–3.85 (6H, m, 2CH2OPhC2CHO),
3.14–3.06 (2H, m, 2CHaHbN), 2.75–2.66 (2H, m, 2CHaHb-
N), 1.80 (1H, bs, NH). Anal. calcd for C18H21NO3: C, 72.22;
H, 7.07; N, 4.68. Found: C, 72.33; H, 7.04; N, 4.72.
0
0
(1H, m, CHaHbN), 3.68 (1H, dd, JZ11.0, 1.0 Hz, CHa Hb -
N), 3.43 (2H, dd, JZ4.4, 1.5 Hz, CH2OMe), 3.34 (3H, s,
OMe), 2.44 (3H, s, ArMe), 2.23 (1H, dd, JZ11.0, 11.0 Hz,
0
0
CHa Hb N), 2.21 (1H, dd, JZ11.0, 11.0 Hz, CHaHbN). Anal.
calcd for C20H25NO5S: C, 61.36; H, 6.44; N, 3.58. Found:
C, 61.42; H, 6.32; N, 3.53.
4.6.4. Morpholine 15d. N-tosyl morpholine 11b; 60 8C;
4 h; MeOH–CH2Cl2 1:20. 15d, 224.5 mg, 75%; white solid,
mp 75–77 8C; nmax (Nujol) 3348, 1600, 1584, 1491, 1252,
1160, 1120, 1050, 816, 756, 692 cmK1; dH (300 MHz,
CDCl3) 7.31–7.25 (4H, m, Ph), 6.98–6.91 (6H, m, Ph),
4.18–4.16 (2H, m, 2CHO), 4.20–4.10 (4H, m, 2CH2OPh),
3.12 (2H, dd, JZ12.2, 3.0 Hz, 2CHaHbN), 2.93 (2H, dd, JZ
12.2, 4.5 Hz, 2CHaHbN), 2.21 (1H, bs, NH). Anal. calcd for
C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C, 72.10; H,
7.04; N, 4.63.
Compound 13e. 207.5 mg, 53%; colourless oil; nmax (neat)
3064, 3042, 2918, 2848, 2058, 1927, 1746, 1600, 1496,
1456, 1350, 1244, 1169, 1000, 814, 758, 686 cmK1; dH
(300 MHz, CDCl3) 7.63 (2H, d, JZ8.1 Hz, Ts), 7.34–7.25
(4H, m, Ar), 6.96 (1H, t, JZ7.4 Hz, Ph), 6.89 (2H, d, JZ
8.1 Hz, Ph), 4.25–4.20 (1H, m, CHCH2OMe), 4.18–4.15
(1H, m, CHCH2OPh), 4.07–4.02 (2H, m, CH2OPh), 3.60
0
0
(1H, dd, JZ10.3, 5.1 Hz, CHa Hb N), 3.51 (1H, dd, JZ10.3,
0
0
5.1 Hz, CHa Hb N), 3.37 (3H, s, OMe), 3.15 (2H, d, JZ
11.7 Hz, CH2OMe), 3.06 (1H, dd, JZ11.7, 5.1 Hz, CHaHb-
N), 2.88 (1H, dd, JZ11.7, 6.6 Hz, CHaHbN), 2.43 (3H, s,
ArMe). Anal. calcd for C20H25NO5S: C, 61.36; H, 6.44; N,
3.58. Found: C, 61.28; H, 6.52; N, 3.52.
4.6.5. Morpholine 15e. N-tosyl morpholine 10c; 25 8C; 9 h;
MeOH–CH2Cl2 1:30. 15e, 146.0 mg, 61%; wax; nmax
(Nujol) 3344, 1962, 1820, 1734, 1597, 1496, 1226, 1164,
1068, 964, 812, 774, cmK1; dH (300 MHz, CDCl3) 7.46–
7.25 (10H, m, Ph), 4.71 (2H, dd, JZ10.5, 2.4 Hz, 2CHO),
3.13 (2H, dd, JZ12.7, 2.4 Hz, 2CHaHbN), 2.80 (2H, dd, JZ
12.7, 10.5 Hz, 2CHaHbN), 2.00 (1H, bs, NH). Anal. calcd
for C16H17NO: C, 80.30; H, 7.06; N, 5.85. Found: C, 80.42;
H, 7.02; N, 5.78.
4.6. General method for the preparation of 2,6-dialkyl-
morpholines 15
A mixture of N-tosyl morpholine 10–13 (1 mmol), 30%
HBr–AcOH (6 mL, 30 mmol) and, if it is the case, phenol
(0.28 g, 3 mmol) was magnetically stirred at 25–80 8C until
no starting material was detectable (TLC analysis). After
cooling, the reaction mixture was poured into ice (20 g),
NaOH pellets were added until pH 8 was reached and the
aqueous phase was extracted with AcOEt (4!10 mL); the
organic phase was dried over sodium sulfate, evaporated
under vacuum and purified by flash column chromatography
on silica gel (230–400 mesh). Starting N-tosyl morpholine
10–13, reaction time, chromatographic eluant, yield and
physical, spectroscopic and analytical data of morpholines
15 are as follows.
4.6.6. Morpholine 15f. N-tosyl morpholine 12a; 25 8C;
24 h; MeOH–CH2Cl2 1:14. 15f, 205.3 mg, 74%; colourless
oil; nmax (neat) 3342, 1662, 1599, 1586, 1498, 1300, 1244,
1166, 1122, 814, 754 cmK1; dH (300 MHz, CDCl3) 7.29–
7.24 (2H, m, Ph), 6.94–6.87 (3H, m, Ph), 4.04 (1H, dd, JZ
8.6, 4.2 Hz, CHaHbOPh), 4.00–3.91 (1H, m, CHCH2OPh),
3.89 (1H, dd, JZ8.6, 5.3 Hz, CHaHbOPh), 3.62–3.50 (1H,
m, CHC6H13), 3.19 (1H, dd, JZ11.4, 11.4 Hz, CHaHbN),
0
0
2.99 (1H, dd, JZ11.2, 11.2 Hz, CHa Hb N), 2.95 (1H, bs,
0
0
NH), 2.72 (1H, dd, JZ11.2, 11.2 Hz, CHa Hb N), 2.55 (1H,
dd, JZ11.4, 11.4 Hz, CHaHbN), 1.49–1.25 (10H, m,
C5H10), 0.87 (3H, t, JZ6.9 Hz, Me). Anal. calcd for
C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.72;
H, 9.76; N 5.12.
4.6.1. Morpholine 15a. N-tosyl morpholine 10a; 60 8C; 2 h;
MeOH–CH2Cl2 1:20. 15a, 166.0 mg, 65%; wax; nmax
(Nujol) 3350, 1920, 1668, 1600, 1497, 1168, 1096, 1000,
816, 784, 663, 619 cmK1; dH (300 MHz, CDCl3) 5.82 (1H,
bs, NH), 3.71–3.66 (2H, m, 2CHO), 3.14 (2H, dd, JZ11.4,
1.2 Hz, 2CHaHbN), 2.56 (2H, dd, JZ11.4, 11.4 Hz, 2CHa-
HbN), 1.45–1.26 (20H, m, 2C5H10), 0.87 (6H, t, JZ6.9 Hz,
2Me). Anal. calcd for C16H33NO: C, 75.23; H, 13.02; N,
5.48. Found: C, 75.11; H, 13.00; N, 5.51.
4.6.7. Morpholine 15g. N-tosyl morpholine 13a; 25 8C;
24 h; MeOH–CH2Cl2 1:36. 15g, 185.9 mg, 67%; colourless
oil; nmax (neat) 3338, 1660, 1599, 1588, 1494, 1302, 1245,
1166, 1118, 1095, 813, 756, 692 cmK1; dH (300 MHz,
CDCl3) 7.28–7.23 (2H, m, Ph), 6.95–6.90 (3H, m, Ph), 4.13
(2H, d, JZ5.7 Hz, CH2OPh), 4.09–4.02 (1H, m, CHCH2-
OPh), 3.76–3.69 (1H, m, CHC6H13), 3.04 (1H, dd, JZ12.4,
0
0
3.5 Hz, CHa Hb N), 2.96 (1H, dd, JZ12.2, 3.3 Hz, CHaHb-
0
0
4.6.2. Morpholine 15b. N-tosyl morpholine 11a; 80 8C; 4 h;
MeOH–CH2Cl 1:30. 15b, 160.9 mg, 63%; wax; nmax (Nujol)
3320, 1602, 1168, 1090, 949, 810, 678 cmK1; dH (300 MHz,
CDCl3) 6.82 (1H, bs, NH), 3.94–3.87 (2H, m, 2CHO), 3.17
(2H, dd, JZ12.6, 3.6 Hz, 2CHaHbN), 2.86 (2H, dd, JZ12.6,
6.1 Hz, 2CHaHbN), 1.86–1.77 (2H, m, CH2CH), 1.51–1.39
(2H, m, CHCH2CH2), 1.36–1.27 (16H, m, 2C2H4), 0.86
(6H, t, JZ6.9 Hz, 2Me). Anal. calcd for C16H33NO: C,
75.23; H, 13.02; N, 5.48. Found: C, 75.34; H, 13.10; N, 5.40.
N), 2.87 (1H, dd, JZ12.4, 4.9 Hz, CHa Hb N), 2.61 (1H, dd,
JZ12.2, 6.4 Hz, CHaHbN), 2.01 (1H, bs, NH), 1.70–1.25
(10H, m, C5H10), 0.87 (3H, t, JZ6.9 Hz, Me). Anal. calcd
for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.72;
H, 9.75; N, 5.02.
Acknowledgements
`
Financial supports from the Ministero Istruzione Universita
4.6.3. Morpholine 15c. N-tosyl morpholine 10b; 60 8C; 4 h;
MeOH–CH2Cl2 1:30. 15c, 224.5 mg, 75%; wax; nmax
(Nujol) 3340, 1600, 1586, 1494, 1250, 1162, 1119, 1054,
e Ricerca (MIUR), the Consiglio Nazionale delle Ricerche
(CNR) and the Fondo per gli Investimenti della Ricerca di
Base (FIRB) are gratefully acknowledged.

11718
V. Lupi et al. / Tetrahedron 60 (2004) 11709–11718
13. Baldoli, C.; Del Buttero, P.; Licandro, E.; Maiorana, S.;
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