Concise synthesis of 2,6-disubstituted morpholines by cyclization of epoxy alcohols

Article abstract of DOI:10.1002/ejoc.200700011

A novel, straightforward and high yielding synthesis of enantiomerically pure 2,6-disubstituted morpholines was developed by acid-catalyzed cyclization of epoxy alcohols. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700011

FULL PAPER
DOI: 10.1002/ejoc.200700011
Concise Synthesis of 2,6-Disubstituted Morpholines by Cyclization of Epoxy
Alcohols
Domenico Albanese,*[a] Matteo Salsa,[a] Dario Landini,[a] Vittoria Lupi,[a] and
Michele Penso[b]
Keywords: Phase-transfer catalysis / Cyclization / Sulfonamides / Epoxy alcohols / Morpholines
A novel, straightforward and high yielding synthesis of enan- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tiomerically pure 2,6-disubstituted morpholines was devel-
oped by acid-catalyzed cyclization of epoxy alcohols.
Germany, 2007)
new approach was designed to develop a more direct syn-
thesis. Therefore, epoxy alcohol 5, easily accessible by the
ring opening of an epoxide with a proper nitrogen nucleo-
phile, was envisioned as a potential precursor of 2,6-disub-
stituted morpholines by regioselective cyclization (Fig-
ure 1).
Introduction
Substituted morpholines have aroused great interest
owing to the presence of this skeleton in therapeutically and
biologically active compounds.[1] Moreover, C2-symmetric
morpholines have been used as chiral auxiliaries.[2] Palla-
dium-catalyzed tandem allylic substitution has been used to
build up enantiomerically enriched 2-vinyl morpholines in
moderate-to-good ee’s.[3] However, excellent ee’s are only
obtained by using a xylofuranose-based phosphanyloxazin-
ane ligand.[4] Optically pure 2,6-disubstituted morpholines
can also be prepared by diastereoselective alkylation of 6-
substituted 3-oxomorpholines, followed by the reduction of
the carbonyl moiety and removal of the chiral auxiliary.[5]
In a previous paper, we reported the synthesis of racemic
2,6-disubstituted morpholines 4 through the phase-transfer
catalyzed dialkylation of 4-methylbenzenesulfonamide (2)
by oxiranes 1, followed by cyclization of hydroxysulfon-
amides 3 thus obtained (Scheme 1).[6]
Figure 1. Retrosynthesis.
Herein we describe the concise, high-yielding synthesis of
enantiopure 2,6-disubstituted morpholines by the cycliza-
tion of epoxy alcohols, which affords regioselectively the
six-membered morpholine skeleton through a 6-exo-tet
pathway.[8]
Scheme 1.
A similar approach was successfully employed for the
synthesis of enantiomerically pure 2,6-disubstituted morph-
olines through the ring opening of enantiopure epoxides,
followed by protecting group manipulations.[7] However, a
Results and Discussion
[a] Dipartimento di Chimica Organica e Industriale
Via Venezian 21, 20133 Milano, Italia
Fax: +39-0250314159
(S)-N-(2,2-Dimethyl[1,3]dioxolan-4-ylmethyl)-4-methyl-
benzenesulfonamide (9), derived from (S)-solketal (7) by hy-
droxy group activation, followed by nucleophilic displace-
ment with sulfonamide 2 was chosen as the nitrogen nucleo-
phile bearing the right-hand side of the target morpholine
(Scheme 2).
E-Mail: domenico.albanese@unimi.it
[b] Istituto CNR-ISTM,
Via Golgi 19, 20133 Milano, Italia
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 2107–2113
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2107

D. Albanese, M. Salsa, D. Landini, V. Lupi, M. Penso
FULL PAPER
Scheme 2.
Mesylate 8 was obtained in quantitative yield by a known
procedure,[9] whereas its conversion to corresponding sul-
fonamide 9 required optimization. The reaction was carried
out under solid–liquid phase-transfer catalysis conditions
(SL-PTC) at 90 °C by using solid anhydrous K2CO3 as the
–
base in the presence of Bu4N+HSO4 as the catalyst. An
excess of sulfonamide 2 was used to minimize the formation
of bisalkylation product 10.[10] The best results were ob-
tained by using a fivefold excess of 2, which afforded sulfon-
amide 9 in 87% yield. The excess reagent was recovered by
crystallization of the reaction mixture.
The ring opening of epoxides 1a–c with sulfonamide 9
was carried out under SL-PTC conditions without sol-
vent[11] by using anhydrous K2CO3 as the base in the pres-
ence of BnEt3N+Cl– (TEBA) heated at 90 °C (Scheme 3).
High yields of enantiopure hydroxysulfonamides 11a–c
were obtained in short reaction times (Table 1).
Compound (R,S)-11a was chosen as a model for the in-
vestigation of the additional synthetic steps (Scheme 3).
Removal of the diol protection with 80% aqueous acetic
acid followed by selective sulfonylation of the primary hy-
droxy group with 2,4,6-triisopropylbenzenesulfonyl chloride
(Tris-Cl) afforded sulfonate ester (R,S)-12a in 63% overall
yield. When the latter was treated with 1 equiv. of K2CO3
in methanol at room temperature, epoxide (R,S)-5a could
be isolated in 78% yield along with trace amounts of cycli-
zation products (Table 2, Entry 1).
Scheme 3.
Table 1. Ring opening of epoxides 1a–c.[a]
Epoxide
R
t [h]
Product
Yield [%]
(R)-1a
(R)-1b
(S)-1c
Ph
Bn
H
2.5
4
2
(R,S)-11a
(R,S)-11b
(R,S)-11c
89
98
87
[a] Reaction conditions: 9 (1 equiv.), K2CO3 (0.1 equiv.), TEBA
(0.1 equiv.), 90 °C.
(Scheme 4). The structure of 13a was proved by comparison
with the compound prepared through an unambiguous syn-
thetic pathway.[12]
In contrast, mixtures of morpholine 4a and [1,4]ox-
azepan-6-ol 13a were isolated in good yields, but with poor
regioselectivity, through the base-promoted cyclization re-
action of (R,S)-5a with methanolic K2CO3 (Table 2, En-
tries 2, 3). These two heterocycles are formed depending
Scheme 4.
The acid-catalyzed cyclization was addressed next. Un-
upon which of the two different epoxy ring carbon atoms der acidic conditions, the nucleophile is expected to attack
undergoes nucleophilic attack during cyclization the more highly substituted carbon atom of the epoxide
Table 2. Cyclization of sulfonate esters 12a,b.[a]
Entry
Substrate
Base [equiv.]
t1 [h][a]
Acid [equiv.]
t2 [h][b]
Yield [%][c]
4/13[d]
[e]
1
2
3
4
5
6
7
8
9
(R,S)-12a
(R,S)-12a
(R,S)-12a
(R,S)-5a
(R,S)-12a
(R,S)-12a
(R,S)-12a
(R,S)-12b
(R,S)-12b
(R,S)-12b
K2CO3 (1)
K2CO3 (5)
K2CO3 (2)
–
K2CO3 (1)
DBU (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
4
20
24
–
4
5
4
4
4
4
–
–
–
–
–
–
1
1
1
1
1
1
78
85
78
81
87
87
87
87
52
–
50:50
64:36
91:9
96:4
93:7
93:7
95:5
95:5
–
CSA (0.1)
CSA (0.1)
CSA (0.1)
Sn(OTf)2 (0.1)
CSA (0.1)
Sn(OTf)2 (0.1)
Yb(OTf)3 (0.1)
[f]
10
24
–
[a] Time for generation of epoxide 5. [b] Time for acid-promoted cyclization. [c] Isolated yield. [d] Determined by HPLC. [e] Epoxide 5a.
[f] Not isolated.
2108
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2,6-Disubstituted Morpholines by Cyclization of Epoxy Alcohols
ring as it bears more of the positive charge.[13] Moreover,
FULL PAPER
The ring opening of (S)-glycidol (1c) with sulfonamide
the acid-catalyzed cyclization of epoxy alcohols has been (S)-9 afforded dihydroxysulfonamide (R,S)-11c, which
exploited in the synthesis of various O-heterocycles.[14]
could directly generate morpholine (S,S)-14 through acid-
We were pleased to find that the cyclization smoothly promoted domino ketal-removal, cyclization of epoxide 18
proceeded in a highly regioselective fashion when epoxide (Scheme 6).
(R,S)-5a was treated with catalytic amounts of (1S)-(+)-
camphor-10-sulfonic acid monohydrate (CSA)[15] in CH2Cl2
at 25 °C. In fact, a 91:9 ratio of 4a/13a was obtained in an
81% yield after a reaction time of only 1 h (Table 2, En-
try 4). A more practical approach was developed by gener-
ating epoxide 5a in situ followed by the sequential acid-
promoted cyclization. In the first step of the reaction, epox-
ide 5a was generated from sulfonate ester 12a by using a
stoichiometric amount of solid K2CO3 in MeOH at room
temperature. After MeOH removal, CH2Cl2 was added and
undissolved material was filtered through a small SiO2 pad;
subsequently, a protic or Lewis acid was added to promote
Scheme 6.
epoxy alcohol cyclization. Under these reaction conditions,
Thus, diol (R,S)-11c was converted into epoxide 18 in
87% overall yield of 4a was obtained (Table 2, Entry 5). good yields with N-tosylimidazole or N-(2,4,6-triisopro-
Slightly lower regioselectivity was obtained by using DBU pylbenzenesulfonyl)imidazole in the presence of NaH.
instead of K2CO3 (Table 2, Entry 6), whereas Et3N proved However, a mixture of the two diastereoisomeric epoxides
to be ineffective. The cyclization of sulfonate ester (R,S)- was obtained as a result of the competition of the two hy-
12b afforded morpholine (R,R)-4b (Table 2, Entry 8) with droxy groups for sulfonylation. Nevertheless, epoxide 18 (de
high regioselectivity. Good results were also obtained by 20%) was subjected to a catalytic amount of CSA in
using Lewis acids such as Sn(OTf)2 (Table 2, Entries 7, 9), CH2Cl2 at room temperature to afford, after 24 h, a mixture
whereas the cyclization was slower in the presence of of diastereoisomeric morpholines 14 in 67% yield. The re-
Yb(OTf)3 (Table 2, Entry 10).
gioselective diol-to-epoxide conversion was performed and
C2-Symmetric 2,6-bis(hydroxymethyl)morpholine (R,R)- the product was obtained in 83% yield by the Mitsunobu
14 could be easily generated by hydrogenolysis of the benzyl reaction using di-tert-butylazodicarboxylate (DBAD) in the
moiety of morpholine (R,R)-4b and represents a key inter- presence of PPh3 in toluene (Scheme 6).
mediate in the preparation of a variety of C2-symmetric
The subsequent domino ketal-removal, cyclization reac-
morpholines through standard functional group chemistry tion promoted by CSA afforded (S,S)-14 in 69% yield as
(Scheme 5).
the cyclization proceeds with inversion of configuration at
the epoxide stereogenic centre. Both enantiomers of morph-
oline 14 can thus be prepared from a single epoxide precur-
sor by choosing the proper pathway. In fact, (R,R)-14 was
obtained from the ring opening of (R)-benzyl glycidol (1b),
which is commercially available, but it is also easily pre-
pared by benzylation of (S)-glycidol (1c).[16] The latter was
used to generate morpholine (S,S)-14 through the domino
ketal-removal, cyclization approach.
In summary, we developed a new straightforward
method for the synthesis of enantiomerically pure 2,6-di-
substituted morpholines through assembling, in a stereose-
lective fashion, a left hand epoxide-derived portion with a
right hand solketal-derived portion. Both starting material
are widely accessible in both enantiopure forms. The acid-
promoted cyclization of in situ generated epoxy alcohols
5a,b, or epoxide 18, proceeds in a highly regioselective fash-
ion and without racemization of the epoxide stereocentre.
The new approach is applicable to the synthesis of a variety
Scheme 5.
For example, (R,R)-16 could be obtained through O-al- of 2,6-disubstituted morpholines. As a matter of fact, the
kylation followed by detosylation, whereas fully deprotected 2-hydroxymethyl substituent is amenable to further func-
morpholine (R,R)-17 could be isolated upon treatment of tionalization, whereas the substituent in the 6-position can
(R,R)-4b with Na/NH3 (liquid).
be chosen by using the proper epoxide, which is readily
Morpholines 4a,b were isolated in an enantiomerically available in an enantiopure form. Studies are now in pro-
pure form, as proved by chiral HPLC, which indicates that gress to optimize the cyclization through the domino ketal-
the cyclization proceeds through a clean SN2 mechanism.
removal, cyclization of epoxide 18.
Eur. J. Org. Chem. 2007, 2107–2113
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2109

D. Albanese, M. Salsa, D. Landini, V. Lupi, M. Penso
FULL PAPER
N-[(R)-2-Hydroxy-3-phenoxypropyl]-N-{(S)-2,2-dimethyl[1,3]di-
oxolan-4-ylmethyl}-4-methylbenzenesulfonamide (11a): (R)-1a,
2.5 h, AcOEt/PE (1:4). Yield: 89%, colourless oil. [α]2D5 = +17.5 (c
= 0.84, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H),
1.42 (s, 3 H), 2.42 (s, 3 H), 3.04 (dd, J = 8.2, 14.9 Hz, 1 H), 3.11
(dd, J = 8.2, 14.9 Hz, 1 H), 3.57–3.70 (m, 3 H), 3.98 (m, 2 H), 4.10
(m, 1 H), 4.31 (m, 1 H), 4.49 (m, 1 H), 6.87 (d, J = 8.1 Hz, 2 H),
6.96 (t, J = 7.4 Hz, 1 H), 7.30 (m, 4 H), 7.70 (d, J = 8.3 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4 (CH3), 25.2 (CH3),
26.6 (CH3), 53.9 (CH2), 54.5 (CH2), 67.1 (CH2), 69.4 (CH2), 69.7
(CH), 75.8 (CH), 110.0 (C), 114.4 (CH), 121.0 (CH), 127.3 (CH),
Experimental Section
General Remarks: Melting points were determined with a BÜCHI
535 and are corrected. Infrared (IR) spectra were recorded with
a Perkin–Elmer 1725 X FTIR spectrometer. NMR spectra were
recorded with a Bruker AC 300 or AC 200 spectrometer. Chemical
shifts are reported by using CHCl3 as an external standard (δ
=7.24 ppm for 1H NMR and 77.0 for 13C NMR). APT experiments
were used in the assignment of carbon spectra. Optical rotations
were measured with a Perkin–Elmer 241 polarimeter; the [α]D val-
ues are reported in 10–1 degcm–2 g–1, concentration (c) is reported
in grams per 100 mL of solvent. Mass spectra (ESI and APCI) were
measured with a LCQ Advantage Thermo-Finnigan spectrometer.
Column chromatography on silica gel (230–400 mesh) was per-
formed by the flash technique or by using MPLC. Chiral HPLC
separations were performed on an Agilent HP 1100 apparatus,
equipped with a diode array detector, by using mixtures of hexane/
2-propanol as the eluent with detection at 230 nm, unless otherwise
stated. The flux was set to 1 mLmin–1 and the volume of injection
was 20 µL. Petroleum ether (PE) refers to the fraction boiling in
the range of 40–60 °C.
129.4 (CH), 129.7 (CH), 135.4 (C), 143.8 (C) ppm. IR (nujol): ν =
˜
3380, 3064, 3037, 1598, 1334, 1270, 1159, 1095, 1062 cm–1
22H29NO6S (435.5): calcd. C 60.67, H 6.71, N 3.22; found C
60.54, H 6.70, N 3.23.
.
C
N-[(R)-3-Benzyloxy-2-hydroxypropyl]-N-{(S)-2,2-dimethyl[1,3]di-
oxolan-4-ylmethyl}-4-methylbenzenesulfonamide (11b): (R)-1b, 4 h,
AcOEt/PE (1:2). Yield: 98%, colourless oil. [α]2D5 = +5.8 (c = 0.35,
CHCl3). HPLC (Chiralcel OD, iPrOH/hexane, 10:90): tR (R,S) =
19.6 min, tR (racemic diastereoisomeric mixture) = 19.6, 21.2, 23.3,
1
25.4 min. H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.38 (s,
(R)-2-Phenoxymethyloxirane (1a) was prepared in 75% yield as de-
3 H), 2.42 (s, 3 H), 2.94–3.04 (m, 2 H), 3.51–3.63 (m, 6 H), 4.07–
4.12 (m, 2 H), 4.41–4.48 (m, 1 H), 4.54 (s, 2 H), 7.25–7.33 (m, 7
H), 7.68 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 21.4 (CH3), 25.3 (CH3), 26.6 (CH3), 53.8 (CH2), 54.5 (CH2), 67.2
(CH2), 70.1 (CH), 71.7 (CH2), 73.4 (CH2), 75.8 (CH), 109.9 (C),
127.3 (CH), 127.7 (CH), 128.3 (CH), 129.8 (CH), 135.6 (C), 138.0
scribed previously.[17]
(R)-2-Benzyloxymethyloxirane (1b) was prepared by O-alkylation
of (S)-glycidol (1c).[18]
Synthesis of (S)-N-(2,2-Dimethyl[1,3]dioxolan-4-ylmethyl)-4-methyl-
benzenesulfonamide (9): A mixture of solketal-mesylate 8 (4.15 g,
19.7 mmol), TsNH2 (16.9 g, 99 mmol), K2CO3 (5.40 g, 39.4 mmol),
(C), 143.7 (C) ppm. IR (neat): ν = 3406, 3061, 3032, 2989, 2924,
˜
2871, 1599, 1496, 1453, 1336, 1274, 1159, 1089, 1072 cm–1
.
–
Bu4N+HSO4 (0.67 g, 1.97 mmol) and dioxane (20 mL) was stirred
C23H31NO6S (449.6): calcd. C 61.45, H 6.95, N 3.12; found C
61.59, H 6.97, N 3.11.
at 90 °C for 48 h. After cooling, the solvent was evaporated and
AcOEt (100 mL) added. The organic solution was washed with
water (2ϫ20 mL), dried (Na2SO4), filtered and concentrated in
vacuo to yield 21 g of a white solid. The latter was crystallized with
CHCl3 (95 mL). After filtration of TsNH2 (10.8 g, 76%), the crude
product was concentrated and purified by MPLC (AcOEt/PE, 1:2)
to provide 9 (4.85 g, 87%) along with 10 (0.23 g, 2.3%) and TsNH2
(3.63 g). 9: White solid, m.p. 91–92 °C. [α]2D5 = –10.6 (c = 1.1,
N-[(R)-2,3-Dihydroxypropyl]-N-{(S)-2,2-dimethyl[1,3]dioxolan-4-
ylmethyl}-4-methylbenzenesulfonamide (11c): (S)-1c, 2 h, AcOEt/PE
(3:1). Yield: 87%, white solid, m.p. 87–88 °C. [α]2D5 –10.4 (c = 1.0,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.34 (s, 3 H), 1.41 (s, 3
H), 2.37 (s, 3 H), 2.95 (dd, J = 14.7, 8.1 Hz, 2 H), 3.43–3.70 (m, 6
H), 3.83 (br. s, 1 H), 3.97–4.03 (m, 1 H), 4.09 (dd, J = 8.7, 6.6 Hz,
1 H), 4.45 (m, 1 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 8.2 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 25.2
(CH3), 26.6 (CH3), 54.2 (CH2), 54.4 (CH2), 63.7 (CH), 67.4 (CH),
71.1 (CH), 76.0 (CH), 110.1 (C), 127.3 (CH), 129.9 (CH), 135.1
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.28 (s, 3 H), 1.33 (s, 3
H), 2.41 (s, 3 H), 2.92 (m, 1 H), 3.12 (ddd, J = 14.3, 7.8, 4.6 Hz, 1
H), 3.66 (dd, J = 8.5, 5.9 Hz, 1 H), 3.98 (dd, J = 8.5, 6.4 Hz, 1 H),
4.15 (m, 1 H), 4.78 (t, J = 6.1 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 2 H),
7.71 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.5 (CH3), 25.1 (CH3), 26.8 (CH3), 45.3 (CH2), 65.5 (CH2), 74.0
(CH), 109.7 (C), 127.1 (CH), 129.8 (CH), 136.7 (C), 143.6 (C) ppm.
(C), 144.0 (C) ppm. ESI-MS: m/z = 383 [M + Na]+. IR (nujol): ν
˜
= 3349, 3054, 3042, 1599, 1335, 1253, 1214, 1161, 1108, 1058,
953 cm–1. C16H25NO6S (359.4): calcd. C 53.46, H 7.01, N 3.90;
found C 53.53, H 7.01, N 3.88.
IR (nujol): ν = 3282, 3042, 1599, 1430, 1319, 1308, 1218, 1168,
˜
1154, 1082, 1050 cm–1. MS (APCI): m/z = 286 [M + H]+.
C13H19NO4S (285.4): calcd. C 54.72, H 6.71, N 4.91; found C
54.90, H 6.73, N 4.89. 10: Colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 1.31 (s, 6 H), 1.39 (s, 6 H), 2.43 (s, 3 H), 3.31 (dd, J
= 14.7, 6.8 Hz, 2 H), 3.43 (dd, J = 14.7, 4.9 Hz, 2 H), 3.69 (dd, J
= 8.4, 6.5 Hz, 2 H), 4.06 (dd, J = 8.4, 6.2 Hz, 2 H), 4.31 (m, 2 H),
7.29 (d, J = 8.3 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H) ppm.
N-[(S)-2,3-Dihydroxypropyl]-N-[(R)-2-hydroxy-3-phenoxypropyl]-4-
methylbenzenesulfonamide (6a): Compound 11a (915 mg,
2.10 mmol) was dissolved in 80 % aq. CH3COOH (14 mL) and
stirred at room temp. for 24 h. After concentration in vacuo, the
residue was dissolved in AcOEt and washed with NaHCO3 (satd.)
The organic solution was dried (Na2SO4), filtered and concentrated
to give 6a (822 mg). Yield: 99%, white solid, m.p. 80.5–82.5 °C.
[α]2D5 = +17.9 (c = 1.0, CHCl3). HPLC (Chiralpak AD, iPrOH/
hexane, 20:80): tR (R,S) = 23.1 min, tR (R,R) = 16.1 min, de 98%.[3]
1H NMR (300 MHz, CDCl3): δ = 2.47 (s, 3 H), 3.09–3.21 (m, 2
H), 3.30–3.80 (m, 4 H), 3.96–3.99 (m, 2 H), 4.11 (m, 1 H), 4.39,
(m, 1 H), 6.88 (d, J = 7.8 Hz, 2 H), 6.96 (t, J = 7.3 Hz, 1 H), 7.30
(m, 4 H), 7.70 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.5 (CH3), 54.7 (CH2), 55.0 (CH2), 63.9 (CH2), 69.5
(CH2), 70.4 (CH), 71.9 (CH), 114.5 (CH), 121.3 (CH), 127.4 (CH),
129.5 (CH), 129.9 (CH), 134.8 (C), 144.0 (C), 158.3 (C) ppm. ESI-
General Procedure for the Ring Opening of Epoxides 1a–c: A mix-
ture of epoxide 1 (10 mmol), 9 (10 mmol), K2CO3 (1 mmol) and
TEBA (1 mmol) was stirred at 90 °C until the starting material was
no longer detectable (TLC analysis). After cooling, the crude mate-
rial was diluted with Et2O and washed with water (2ϫ5 mL). After
extraction of the aqueous phase with Et2O (2ϫ10 mL), the com-
bined organic extracts were dried (Na2SO4), filtered and concen-
trated in vacuo. The residue was purified by flash chromatography.
Starting epoxide, reaction time, eluent, yield and physical and spec-
troscopic data of 11a–c are as follows.
MS: m/z = 419 [M + Na]+. IR (nujol): ν = 3253, 1599, 1340, 1253,
˜
2110
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Eur. J. Org. Chem. 2007, 2107–2113

2,6-Disubstituted Morpholines by Cyclization of Epoxy Alcohols
1147, 1070, 1003 cm–1. C19H25NO6S (395.5): calcd. C 57.70, H (C), 150.9 (C), 153.9 (C) ppm. ESI-MS: m/z = 699 [M + Na]+. IR
FULL PAPER
6.37, N 3.54; found C 57.62, H 6.35, N 3.55.
(nujol): ν = 3278, 3061, 3033, 1601, 1342, 1176, 1155 cm–1
.
˜
C35H49NO8S2 (675.9): calcd. C 62.20, H 7.31, N 2.07; found C
61.99, H 7.33, N 2.06.
N-[(R)-3-Benzyloxy-2-hydroxypropyl]-N-[(S)-2,3-dihydroxypropyl]-
4-methylbenzenesulfonamide (6b): Compound 11b (4.75 g,
10.6 mmol) was dissolved in 80 % aq. CH3COOH (72 mL) and
stirred at room temp. for 22 h. The same procedure described above
for 6a was followed. Yield: 4.30 g (99%), white solid, m.p. 79.1–
80.7. [α]2D5 = +15.2 (c = 1.0, CHCl3). HPLC (Chiralpak AD, iPrOH/
N-[(R)-2-Hydroxy-3-phenoxypropyl]-N-[(S)-2-oxiranylmethyl]-4-
methylbenzenesulfonamide (5a): A stirred solution of 12a (46 mg,
0.072 mmol) was dissolved in MeOH (1 mL) and solid K2CO3
(10 mg, 0.072 mmol) was added. After stirring at room temp. for
hexane, 20:80): tR (R,S) = 21.3 min, tR (S,S) = 16.2 min, de 98%.[4] 4 h, the crude was purified by MPLC (MTBE/PE, 3:2). Yield:
1H NMR (300 MHz, CDCl3): δ = 2.01 (br. s, 3 H), 2.42 (s, 3 H),
21 mg (78%), colourless oil. [α]2D5 = +9.1 (c = 0.60, CHCl3). HPLC
2.99 (d, J = 9.4 Hz, 1 H), 3.04 (d, J = 10.3 Hz, 1 H), 3.46–3.58 (m, (Chiralcel AD, iPrOH/hexane, 20:80): tR (R,S) = 20.0 min, tR (R,R)
5 H), 3.67 (dd, J = 3.9, 11.7 Hz, 1 H), 4.06 (m, 1 H), 4.21 (m, 1 = 21.1 min.[6] 1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H), 2.65
H), 4.54 (s, 2 H), 7.25–7.33 (m, 7 H), 7.66 (d, J = 8.1 Hz, 2 H)
(dd, J = 3.9, 6.9 Hz, 1 H), 2.82 (t, J = 6.3 Hz, 1 H), 3.02–3.70 (m,
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 54.6 (CH2), 6 H), 4.03 (d, J = 7.8 Hz, 2 H), 4.25 (m, 1 H), 6.88–7.03 (m, 3 H),
55.0 (CH2), 63.9 (CH2), 70.7 (CH), 71.8 (CH2), 71.9 (CH), 73.4
(CH2), 127.3 (CH), 127.8 (CH), 128.4 (CH), 129.8 (CH), 134.9 (C),
7.25–7.32 (m, 4 H), 7.72 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.1 (CH3), 45.7 (CH2), 51.1 (CH), 52.1
137.7 (C), 143.8 (C) ppm. ESI-MS: m/z = 842 [2M + Na]+. IR (CH2), 53.0 (CH2), 69.0 (CH), 69.3 (CH2), 114.5 (CH), 121.2 (CH),
(nujol): ν = 3290, 3068, 3027, 1599, 1338, 1151, 1087, 999 cm–1.
127.3 (CH), 129.5 (CH), 130.1 (CH), 135.5 (C), 143.9 (C), 158.3
˜
C20H27NO6S (409.5): calcd. C 58.66, H 6.65, N 3.42; found C
58.62, H 6.64, N 3.43.
(C) ppm. ESI-MS: m/z = 378 [M + H]+. IR (nujol): ν = 3391,
˜
3068, 3033, 1735, 1599, 1497, 1341, 1243, 1160, 1093, 1044 cm–1.
C19H23NO5S (377.5): calcd. C 60.46, H 6.14, N 3.71; found C
60.41, H 6.13, N 3.72.
(R,S)-Sulfonate Ester (12a): In a round-bottomed flask, 6a
(746 mg, 1.89 mmol) was dissolved in CH2Cl2 (6 mL) and pyridine
(3.5 mL) was added. After cooling to 0 °C, 2,4,6-triisopropylben-
zenesulfonyl chloride (1.78 g, 5.87 mmol) was added, and the mix-
ture was then warmed to 25 °C. After 24 h, the reaction mixture
was made acidic with 10% aq. HCl. The organic solution was dried
(Na2SO4), filtered, concentrated in vacuo and purified by flash col-
umn chromatography [MTBE/PE, 1:1]. Yield: 788 mg (63%), white
solid, m.p. 98.4–99.7 °C. [α]2D5 = +6.1 (c = 0.29, CHCl3). HPLC
(Chiralcel OD, iPrOH/hexane, 10:90): tR (R,S) = 17.0 min, tR (R,R)
= 27.5 min, de 99%.[5] 1H NMR (300 MHz, CDCl3): δ = 1.24 (d,
(R,R)-2-Hydroxymethyl-6-phenoxymethyl-4-tosylmorpholine (4a):
In a screw cap vial, 12a (331 mg, 0.50 mmol) was dissolved in
MeOH (20 mL) and K2CO3 (69 mg, 0.50 mmol) was added. The
resulting solution was stirred at room temp. for 4 h. After evapora-
tion of MeOH, CH2Cl2 (20 mL) was added, and the mixture was
filtered through a small pad of SiO2. After concentration to 20 mL,
(1S)-(+)-camphor-10-sulfonic acid monohydrate (CSA) (12 mg,
0.05 mmol) was added, and the solution was stirred at room temp.
for 1 h. The crude product (4a/13a 96:4) was purified by MPLC
J = 6.9 Hz, 12 H), 1.25 (d, J = 6.9 Hz, 6 H), 2.42 (s, 3 H), 2.89 (m, (MTBE/PE, 2:1). Yield: 164 mg (87%) of 4a as a colourless syrup
1 H), 3.10–3.23 (m, 2 H), 3.51 (dd, J = 8.3, 14.9 Hz, 1 H), 3.56
(dd, J = 8.1, 15.1 Hz, 1 H), 3.94–4.18 (m, 6 H), 4.28–4.40 (m, 2
along with a trace amount of 13a (4a/13a 99:1). Data for 4a: HPLC
(Chiralcel AD, iPrOH/hexane, 20:80): tR (2R,6R) = 24.0 min, tR
H), 6.88 (d, J = 7.5 Hz, 2 H), 6.96 (t, J = 7.4 Hz, 1 H), 7.18 (s, 2 (13a) = 16.2 min. Other morpholine stereoisomers were absent: tR
H), 7.30 (m, 4 H), 7.70 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (2S,6S) = 16.6 min, tR (2R,6S) = 15.3 min, tR (2S,6R) = 13.1 min.
(75 MHz, CDCl3): δ = 21.5 (CH3), 23.5 (CH3) 24.7 (CH3), 29.7 [α]2D5 = +3.96 (c = 0.63, CHCl3), 1H NMR (300 MHz, CDCl3): δ =
(CH) 34.3 (CH), 54.7 (2 CH2), 69.4 (CH2), 69.5 (2 CH), 114.6 2.43 (s, 3 H), 2.83 (dd, J = 11.5, 7.2 Hz, 1 H), 3.05 (dd, J = 11.7,
(CH), 121.3 (CH), 123.9 (CH), 127.4 (CH), 128.8 (C), 129.5 (CH), 3.1 Hz, 1 H), 3.15–3.24 (m, 2 H), 3.74 (d, J = 5.2 Hz, 2 H), 3.94–
130.0 (CH), 134.9 (C), 144.1 (C), 151.0 (C), 154.0 (C), 158.3 (C) 3.97 (m, 1 H), 4.07 (dd, J = 9.1, 5.8 Hz, 1 H), 4.18–4.29 (m 2 H),
ppm. ESI-MS: m/z = 685 [M + Na]+. IR (nujol): ν = 3317, 3053,
6.90 (d, J = 8.1 Hz, 2 H), 6.97 (t, J = 7.3 Hz, 1 H) 7.25–7.34 (m,
˜
3036, 1598, 1494, 1343, 1246, 1179, 1167, 1038, 915 cm–1
.
4 H), 7.64 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
C34H47NO8S2 (661.9): calcd. C 61.70, H 7.16, N 2.12; found C δ = 21.5 (CH3), 46.3 (CH2), 46.6 (CH2), 62.0 (CH2), 66.4 (CH2),
61.81, H 7.17, N 2.11.
69.4 (CH), 70.6 (CH), 114.7 (CH), 121.4 (CH), 127.8 (CH), 129.5
(CH), 129.9 (CH), 132.0 (C), 144.1 (C), 158.3 (C) ppm. APCI-MS:
(R,S)-Sulfonate Ester (12b): In a round-bottomed flask, 6b (1.50 g,
3.66 mmol) was dissolved in CH2Cl2 (24 mL) and pyridine (1.6 mL)
was added. After cooling to 0 °C, 2,4,6-triisopropylbenzenesulfonyl
chloride (11.0 mmol, 3.33 g) was added, and the mixture was then
warmed to 25 °C. After 30 h, the reaction mixture was made acidic
with 10% aq. HCl. The organic solution was dried (Na2SO4), fil-
tered, concentrated in vacuo and purified by flash column
chromatography [MTBE/PE, 1:1]. Yield: 1.64 g (67%), white solid,
m.p. 90.5–91.5. [α]2D5 = +2.62 (c = 1.0, CHCl3). HPLC (Chiralcel
AD, iPrOH/hexane, 20:80): tR (R,S) = 8.4 min, tR (R,R) =
12.2 min, de 99%.[5] 1H NMR (300 MHz, CDCl3): δ = 1.24 (d, J =
6.6 Hz, 12 H), 1.26 (d, J = 7.0 Hz, 6 H), 2.43 (s, 3 H), 2.89–3.05
m/z = 378 [M + H]+. IR (nujol): ν = 3407, 3054, 3023, 1741, 1598,
˜
1494, 1346, 1168, 1041 cm–1. C19H23NO5S (377.5): calcd. C 60.46,
H 6.14, N 3.71; found C 60.51, H 6.13, N 3.72.
(R,R)-2-Hydroxymethyl-6-benzyloxymethyl-4-tosylmorpholine (4b):
In a screw cap vial, 12b (1.40 g, 2.07 mmol) was dissolved in MeOH
(30 mL) and K2CO3 (286 mg, 2.07 mmol) was added. The resulting
solution was stirred at room temp. for 4 h. After evaporation of
MeOH, CH2Cl2 (40 mL) was added, and the mixture was filtered
through a small pad of SiO2. After concentration, CSA (52 mg,
0.21 mmol) was added, and the solution was stirred at room temp.
for 1 h. The crude product was purified by MPLC (AcOEt/PE, 1:1).
(m, 3 H), 3.40–3.55 (m, 5 H), 4.00–4.38 (m, 7 H), 4.53 (s, 2 H), Yield: 710 mg (87%), colourless syrup. [α]2D5 = +3.59 (c = 1.1,
7.18 (s, 2 H) 7.27–7.35 (m, 7 H) 7.65 (d, J = 8.4 Hz, 2 H) ppm. 13
C
CHCl3). HPLC (Chiralcel AD, iPrOH/hexane, 20:80): tR (2R,6R)-
NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 23.5 (CH3), 24.7 (CH3), 4b = 19.9 min, tR (13b) = 14.7 min (4b/13b 95:5), tR (2S,6S) =
29.6 (CH), 34.2 (CH), 54.6 (CH2), 54.9 (CH2), 69.5 (CH), 70.3 15.9 min, tR (2R,6S + 2S,6R) = 11.8, 15.6 min, ee 99%, de 95%.
(CH2), 70.8 (CH), 71.5 (CH2), 73.4 (CH2), 123.8 (CH), 127.3 (CH), 1H NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.74 (dd, J = 11.5,
127.7 (CH), 128.4 (CH), 129.9 (CH), 134.9 (C), 137.2 (C), 143.9
7.2 Hz, 1 H), 2.89 (dd, J = 11.5, 3.6 Hz, 1 H), 3.09–3.20 (m, 2 H),
Eur. J. Org. Chem. 2007, 2107–2113
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2111

D. Albanese, M. Salsa, D. Landini, V. Lupi, M. Penso
FULL PAPER
3.60–3.68 (m, 4 H), 3.85 (m, 1 H), 4.04 (m, 1 H), 4.54 (ABq, J =
12.0 Hz, 2 H), 7.25–7.33 (m, 7 H), 7.60 (d, J = 8.2 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.2 (CH3), 46.0 (CH2), 46.3
8 mg, 0.33 mmol) was added at 0 °C to a stirred solution of (R,R)-
4b (102 mg, 0.26 mmol) in anhydrous THF (1 mL). After 30 min,
benzyl bromide (37 µL, 0.31 mmol) was added and the temperature
(CH2), 61.3 (CH2), 68.3 (CH2), 69.3 (CH), 70.5 (CH), 73.2 (CH2), was allowed to increase to 25 °C. After 5 h, excess NaH was
127.5 (CH), 128.2 (CH), 129.6 (CH), 132.1 (CH), 136.4 (C), 143.8 quenched by the careful addition of water, and dichloromethane
(C) ppm. APCI-MS: m/z = 392 [M + H]+. IR (neat): ν = 3435, was added. The organic phase was washed with satd. NH4Cl and
˜
3063, 3031, 1598, 1495, 1343, 1308, 1168, 1114, 1091 cm–1
20H25NO5S (391.5): calcd. C 61.36, H 6.44, N 3.58; found C
61.41, H 6.46, N 3.57.
.
water. The resulting organic solution was dried (Na2SO4), filtered
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (AcOEt/PE, 1:3). Yield: 93 mg (74%), white
solid, m.p. 76–79 °C. [α]2D5 = +19.6 (c = 0.8, CHCl3). HPLC (Chi-
ralpak AD, iPrOH/hexane, 20:80): tR (meso) = 14.0 min, tR (S,S)
= 16.1 min, tR (R,R) = 23.2 min, ee 96%, de 96%. 1H NMR
(300 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.92 (dd, J = 12.0, 6.0 Hz, 2
H), 3.04 (dd, J = 12.0, 11.4 Hz, 2 H), 3, 60 (m, 4 H), 3.99 (m, 2
H), 4.53 (dd, J = 14.2, 12.1 Hz, 2 H), 7.28–7.35 (m, 7 H), 7.61 (d,
J = 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5
(CH3), 46.7 (2 CH2), 68.8 (CH2), 69.7 (CH2), 73.5 (CH), 127.7
(CH), 127.9 (CH), 128.4 (CH), 129.7 (CH), 132.1 (C), 137.8 (C),
C
(R,R)-2,6-Bis(hydroxymethyl)-4-tosylmorpholine (14): Morpholine
(R,R)-4b (100 mg, 0.255 mmol) was dissolved in EtOH (5 mL),
10% Pd/C (27 mg) was added and the mixture was subjected to
hydrogenation under atmospheric pressure after three vacuum/H2
cycles to remove air from the reaction vessel. After 1 h, the mixture
was filtered through a pad of Celite and the filtrate evaporated.
The residue was purified by flash chromatography by using AcOEt/
PE (3:1). Yield: 67 mg (87%), white solid, m.p. 103.5–106.5. [α]2D5
–10.9 (c = 1.06, CHCl3). HPLC (Chiralcel AD, iPrOH/hexane,
20:80): tR (R,R) = 19.3 min, tR (S,S) = 16.0 min, tR (meso) =
143.9 (C) ppm. APCI-MS: m/z = 482 [M + H]+. IR (neat): ν =
˜
3435, 3063, 3031, 1598, 1495, 1343, 1308, 1168, 1114, 1091 cm–1.
C27H31NO5S (481.6): calcd. C 67.34, H 6.49, N 2.91; found C
67.57, H 6.50, N 2.92.
1
12.0 min, ee 99%, de 96%. H NMR (300 MHz, CDCl3): δ = 2.43
(s, 3 H), 2.90 (dd, J = 5.8, 11.5 Hz, 2 H), 3.01 (dd, J = 3.4, 11.5 Hz,
2 H), 3.71 (dd, J = 5.0, 11.6 Hz, 1 H), 3.79 (dd, J = 6.5, 11.6 Hz,
1 H), 3.90–4.00 (m, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.60 (d, J =
8.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3),
46.1 (CH2), 61.4 (CH2), 70.8 (CH), 127.8 (CH), 129.9 (CH), 131.9
(R,R)-2,6-Bis(benzyloxymethyl)morpholine (16): In a two-necked
flask under a nitrogen atmosphere, Na (138 mg, 6.0 mmol) was
added at room temperature to a stirred solution of naphthalene
(769 mg, 6 mmol) in DME (8 mL). The freshly prepared sodium
naphthalenide solution (0.81 mL, 0.61 mmol) was added to a
stirred solution of (R,R)-15 (101 mg, 0.21 mmol) in DME (5 mL)
under a nitrogen atmosphere at –78 °C. After stirring for 1 h at
–78 °C, the reaction mixture was quenched with water, the tempera-
ture was allowed to rise to 25 °C and the solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography (CH2Cl2/PE, 95:5). Yield: 62 mg (90%), colourless
oil. [α]2D5 = +5.6 (c = 1.2, CHCl3). HPLC (Chiralcel OJ-H, iPrOH/
hexane, 20:80, 220 nm): tR (R,R) = 20.3 min, tR (S,S) = 23.0 min,
tR (meso) = 23.6 min, ee 99%, de 96%. 1H NMR (300 MHz,
CDCl3): δ = 2.18 (br. s, 1 H), 2.18 (br. s, 1 H), 2.87 (dd, J = 5.9,
12.5 Hz, 2 H), 3.03 (dd, J = 3.7, 12.5 Hz, 2 H), 3.62 (m, 4 H), 3.94–
4.01 (m, 2 H), 4.55 (s, 4 H), 7.28–7.33 (m, 10 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 46.2 (2 CH2), 69.7 (CH), 70.6 (CH2), 73.5
(CH2), 127.7 (CH), 127.8 (CH), 128.4 (CH), 137.8 (C) ppm. APCI-
(C), 144.2 (C) ppm. APCI-MS: m/z = 302 [M + H]+. IR (nujol): ν =
˜
3388, 3068, 3037, 1743, 1599, 1342, 1162, 1054 cm–1. C13H19NO5S
(301.4): calcd. C 51.81, H 6.35, N 4.65; found C 51.91, H 6.37, N
4.66.
N-[(S)-2,2-Dimethyl[1,3]dioxolan-4-ylmethyl]-N-[(R)-2-oxiranyl-
methyl]-4-methylbenzenesulfonamide (18): PPh3 (176 mg,
0.67 mmol) and di-tert-butylazodicarboxylate (154 mg, 0.67 mmol)
were added to a stirred solution of 11c (162 mg, 0.45 mmol) in
toluene (4 mL). After stirring at 90 °C for 24 h, the solvent was
removed, and the residue was purified by flash chromatography
(AcOEt/PE, 1:2). Yield: 128 mg (83%), colourless oil. [α]2D5 –1.3 (c
= 1, CHCl3). HPLC (Chiralpak IB, EtOH/hexane, 5:95, flow
0.6 mLmin–1): tR (S,R) 21.6, tR (S,S) 20.3 min, de 95%.[7] 1H NMR
(300 MHz, CDCl3): δ = 1.30 (s, 3 H), 1.38 (s, 3 H), 2.41 (s, 3 H),
2.55 (dd, J = 2.6, 4.8 Hz, 1 H), 2.78 (t, J = 4.4 Hz, 1 H), 2.99 (dd,
J = 14.9, 6.3 Hz, 1 H), 3.07–3.15 (m, 2 H), 3.52 (dd, J = 14.4,
5.5 Hz, 1 H), 3.67 (dd, J = 14.9, 3.7 Hz, 1 H), 3.78 (dd, J = 8.5,
6.3 Hz, 1 H), 4.09 (dd, J = 8.5, 6.2 Hz, 1 H), 4.34 (m, 1 H), 7.30
(d, J = 8.2 Hz, 2 H), 7.70 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.5 (CH3), 25.3 (CH3), 26.8 (CH3), 45.7
(CH2), 50.4 (CH), 51.7 (CH2), 52.0 (CH2), 67.5 (CH2), 74.7 (CH),
109.6 (C), 127.2 (CH), 129.8 (CH), 136.2 (C), 143.7 (C) ppm. ESI-
MS: m/z = 328 [M + H]+. IR (neat): ν = 3346, 3085, 3061, 3028,
˜
1495, 1366, 1207, 1099 cm–1. C20H25NO3 (327.4): calcd. C 73.37,
H 7.70, N 4.28; found C 73.56, H 7.72, N 4.26.
(R,R)-2,6-Bis(hydroxymethyl)morpholine (17): In
a two-necked
flask, ammonia (10 mL) was condensed at –78 °C and Na (120 mg,
5.2 mmol) was added. A solution of (R,R)-4b (340 mg, 0.87 mmol)
in THF (3 mL) was added, and the reaction was heated at reflux
for 45 min. Ammonia was evaporated under a nitrogen atmosphere,
and the solvent was evaporated under reduced pressure. The resi-
due was purified by flash column chromatography (MeOH/
CH2Cl2, 80:20). Yield: 106 mg (83%), colourless oil. [α]2D5 –24.3 (c
= 1, H2O). HPLC (Chiralcel OJ-H, iPrOH/hexane, 7:93, 210 nm):
tR (R,R) = 42.7 min, tR (S,S + meso) = 36.1, 38.4, ee 99%, de 99%.
1H NMR (300 MHz, CD3OD): δ = 2.71 (dd, J = 12.8, 5.6 Hz, 2
H), 2.90 (dd, J = 3.5, 12.8 Hz, 2 H), 3.58 (dd, J = 4.3, 10.7 Hz, 2
H), 3.71–3.82 (m, 4 H) ppm. 13C NMR (75 MHz, CD3OD): δ =
47.6 (CH2), 63.8 (CH2), 73.5 (CH) ppm. APCI-MS: m/z = 148 [M
MS: m/z = 365 [M + Na]+. IR (neat): ν = 3062, 2985, 2933, 2879,
˜
1597, 1452, 1371, 1342, 1253, 1213, 1160, 1090, 1068, 1020 cm–1.
C16H23NO5S (341.4): calcd. C 56.29, H 6.79, N 4.10; found C
56.15, H 6.77, N 4.11.
(S,S)-2,6-Bis(hydroxymethyl)-4-tosylmorpholine (14): CSA (11 mg,
0.043 mmol) was added to a stirred solution of 18 (109 mg,
0.432 mmol) in CH2Cl2 (6 mL). After 22 h at room temp., the sol-
vent was removed, and the residue was purified by flash chromatog-
raphy (AcOEt/PE, 1:3). Yield: 90 mg (69%), white solid, m.p. 102–
104 °C. [α]2D5 = +11.7 (c = 1, CHCl3). HPLC (Chiralcel AD, iPrOH/
hexane, 20:80): tR (S,S) = 16.0 min, tR (meso) = 12.0 min, tR (R,R)
= 19.4 min, ee 99%, de 96%. 1H- and 13C NMR spectroscopic data
were identical to that of (R,R)-14.
+ H]+. IR (neat): ν = 3250, 2921, 1111, 1037, 936 cm–1. C H NO
˜
6
13
3
(147.2): calcd. C 48.97, H 8.90, N 9.52; found C 48.81, H 8.93, N
9.48.
(R,R)-2,6-Bis(benzyloxymethyl)-4-tosylmorpholine (15): In a two-
Supporting Information (see footnote on the first page of this arti-
necked flask under a nitrogen atmosphere, NaH (60% mineral oil,
cle): Experimental procedures and full characterization of new
2112
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2107–2113

2,6-Disubstituted Morpholines by Cyclization of Epoxy Alcohols
FULL PAPER
dron: Asymmetry 2000, 11, 3561–3568; e) M. C. Wilkinson,
Tetrahedron Lett. 2005, 46, 4773–4775.
[4] H. Nakano, J.-i. Yokoyama, R. Fujita, H. Hongo, Tetrahedron
Lett. 2002, 43, 7761–7764.
compounds towards an unambiguous synthesis of 13a along with
1
copies of H and 13C NMR spectra.
[5] E. Bouron, G. Goussard, C. Marchand, M. Bonin, X. Panne-
coucke, J.-C. Quirion, H.-P. Husson, Tetrahedron Lett. 1999,
40, 7227–7230.
Acknowledgments
[6] V. Lupi, D. Albanese, D. Landini, D. Scaletti, M. Penso, Tetra-
hedron 2004, 60, 11709–11718.
Financial support from MIUR (Nuovi metodi catalitici stereoselet-
tivi e sintesi stereoselettiva di molecole funzionali) and CNR is
gratefully acknowledged.
[7] This work will be published elsewhere.
[8] J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734–736.
[9] F. S. Gibson, M. Sook Park, H. Rapoport, J. Org. Chem. 1994,
59, 7503–7507.
[1] For recent examples, see: a) B. A. Lanman, A. G. Myers, Org.
Lett. 2004, 6, 1045–1047; b) K. Audouze, Ø. E. Nielsen, D.
Peters, J. Med. Chem. 2004, 47, 3089–3104; c) R. Wijtmans,
M. K. S. Vink, H. E. Schoemaker, F. L. van Delft, R. H.
Blaauw, F. P. J. T. Rutjes, Synthesis 2004, 641–662.
[10] When stoichiometric amounts of 2 were used, 39% of 10 was
isolated along with 48% of 9.
[11] D. Albanese, D. Landini, M. Penso, Chem. Commun. 1999,
2095–2096.
[12] The synthesis of 13a is fully described in the Supporting Infor-
[2] a) D. Enders, O. Meyer, G. Raabe, J. Runsink, Synthesis 1993,
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[15] The same results were obtained by using anhydrous (Ϯ)-CSA.
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[18] See ref.[16] Compound (R)-1b is also commercially available.
Received: January 5, 2007
Published Online: March 13, 2007
Eur. J. Org. Chem. 2007, 2107–2113
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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