Enantioselective syntheses of morpholines and their homologues via S N2-type ring opening of aziridines and azetidines with haloalcohols

Article abstract of DOI:10.1021/jo901297d

(Chemical Equation Presented) A highly regio- and stereoselective strategy for the syntheses in high yield and enantioselectivity of a variety of substituted nonracemic morpholines and their homologues is described. The reaction proceeds via an S_N2-type ring opening of activated aziridines and azetidines by suitable halogenated alcohols in the presence of Lewis acid followed by base-mediated intramolecular ring closure of the resulting haloalkoxy amine.

Full text of DOI:10.1021/jo901297d

pubs.acs.org/joc
Enantioselective Syntheses of Morpholines and Their Homologues via
SN2-Type Ring Opening of Aziridines and Azetidines with Haloalcohols
Manas K. Ghorai,* Dipti Shukla, and Kalpataru Das
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
mkghorai@iitk.ac.in
Received June 17, 2009
A highly regio- and stereoselective strategy for the syntheses in high yield and enantioselectivity of a
variety of substituted nonracemic morpholines and their homologues is described. The reaction
proceeds via an SN2-type ring opening of activated aziridines and azetidines by suitable halogenated
alcohols in the presence of Lewis acid followed by base-mediated intramolecular ring closure of the
resulting haloalkoxy amine.
Introduction
natural products, such as neurotoxin batrachotoxin (BTX)5
(Figure 1), and there are only a few reports for their syn-
thesis.6,16b The synthesis and biological activities of
1,5-oxazocanes are also not well explored.7 Apart from
pharmacological utility, morpholines are also used frequently
as simple bases, N-alkylating agents, catalysts, and chiral
auxiliaries in various organic transformations.8-10 Several
efforts have beendevoted towardthe synthesisof morpholines
from amino acids,11 amino alcohols,12 epoxides,13 olefins,14
carbohydrates,15 vinyl sulfonium salts,16 various other metal-
catalyzed cyclizations,17 and aziridines18 or aziridinium ion
intermediate.19 However, a general synthetic approach to
2-substituted morpholines, 2,3-disubstituted morpholines,
Morpholines are an important class of heterocyclic com-
pounds found in many naturally occurring or synthetically
important organic molecules that exhibit interesting biologi-
cal and pharmacological properties.1 Particularly, N- and/or
2-substituted morpholines are drug candidates with a wide
spectrum of biological activities (Figure 1). Morpholine such
as reboxetine is an antidepressant drug,2 and cis-2,3-disubsti-
tuted morpholine such as aprepitant (hNK1 antagonist) is
used for chemotherapy-induced nausea and vomiting (CINV)
and commercially available under the name of Emend.3
Furthermore, 2,6-disubstituted morpholines are used as
antitumor agents,4a mild diuretics, and anorectics.4b The
core structure of 1,4-oxazepanes is found in important
(6) Clark, S. M.; Osborn, H. M. I. Tetrahedron: Asymmetry 2004, 15,
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*To whom correspondence should be addressed. Tel: þ91-512-2597518;
Fax: þ91-512-2597436.
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4193–4195. (b) Quin, Y.-C.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 273–277.
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Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641-662 and references
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Tinholt, P. M.; Piercey, M. F. P.; Hoffmann, W. P.; Hyslop, D. K.; Franklin,
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DOI: 10.1021/jo901297d
r
Published on Web 08/12/2009
J. Org. Chem. 2009, 74, 7013–7022 7013
2009 American Chemical Society

Ghorai et al.
JOCArticle
SCHEME 1. Lewis Acid Mediated Ring Opening of (R)-2-Phenyl-
N-tosylaziridines with Haloalcohols Followed by Cyclization to
Morpholine
an SN2-type pathway instead of stable 1,3- or 1,4-dipolar
intermediates as invoked earlier.21
In continuation of our research activities in this area for
designing enantioselective ring opening reactions of chiral
aziridines and azetidines toward enantiopure targets, we
have developed a simple strategy for the synthesis of non-
racemic 2-substituted morpholines, 2,3-disubstituted mor-
pholines, enantiopure 2,6-disubstituted morpholines, homo-
morpholines, and higher homologues via the ring opening of
aziridines and azetidines with haloalcohols followed by
intramolecular ring closure in the presence of a base. Herein,
we report our results in detail.
FIGURE 1. Pharmaceutically active compounds possessing a
2-substituted morpholine unit.
homomorpholines, and higher homologues is scarce in the
literature.
Results and Discussion
We anticipated that 2-substituted nonracemic morpho-
lines and homologues could easily be made from the ring
opening of aziridines and azetidines by haloalcohols fol-
lowed by cyclization.
Recently we have reported the Lewis acid (LA) mediated
ring opening of enantiopure 2-aryl-N-tosylaziridines and
azetidines by a number of nucleophiles such as alcohols,
halides, nitriles, and carbonyls to provide nonracemic pro-
ducts in high enantiomeric excess.20 We have demonstrated
that the Lewis acid mediated nucleophilic ring opening of
2-aryl-N-tosylaziridines or azetidines does proceed through
Our investigation began with the ring opening of chiral
(R)-2-phenyl-N-tosylaziridine 1a (ee > 99%) with chloro-
ethanol in the presence of stoichiometric amount of Cu-
(OTf)2 at 0 °C, and we observed the formation of nonracemic
chloroethoxy amine (S)-3a22 and its regioisomer (R)-4a as an
inseparable mixture. The same reaction when performed
with bromoethanol produced the corresponding bro-
moethoxy amine 3a0 and its regioisomer 4a0 as an inseparable
mixture.23 When the mixture of 3a and 4a was treated with
KOH at room temperature in THF, nonracemic morpholine
5a was obtained in 70% yield (74% ee) along with aziridine
1a (10% yield, 33% ee) (Scheme 1). A similar result was
observed from the mixture of 3a0 and 4a0. Comparing the 1H
NMR and COSY spectra of the mixture of 3a and 4a with
that of pure 1a, we could conclude that there was no trace of
unreacted aziridine in the mixture of 3a and 4a. However,
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Org. Lett. 2009, 11, 257–260.
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€
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1
when this reaction mixture was treated with KOH, the H
NMR of the crude product indicates the presence of mor-
pholine 5a along with aziridine 1a. To confirm that the
reformed aziridine 1a originates from 4a, we treated 3a with
KOH, and the crude reaction mixture clearly indicated the
presence of only 5a in the sample.
Screening of Lewis Acid. To optimize the reaction condi-
tion to obtain better regioselectivity and yield, other Lewis
acids such as Zn(OTf)2, ZnBr2, BF3 OEt2, and Ti(OiPr)4
3
were screened in chloroethanol as the solvent. However,
there was not much improvement in regioselectivity of the ring
opening and yield of the final product 5a (Table 1). Interes-
tingly, with a catalytic amount of Cu(OTf)2 (20 mol %) and
chloroethanol as the nucleophile, the reaction was found to
be highly regioselective and 3a (yield 87%, ee 78%) was
produced as the only product; the other regioisomer 4a did
not form as indicated by the 1H NMR of the crude reaction
(20) (a) Ghorai, M. K.; Das, K.; Shukla, D. J. Org. Chem. 2007, 72, 5859–
5862. (b) Ghorai, M. K.; Kumar, A.; Das, K. Org. Lett. 2007, 9, 5441–5444.
(c) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48, 4373–
4377. (d) Ghorai, M. K.; Ghosh, K. Tetrahedron Lett. 2007, 48, 3191–3195.
(e) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2009, 50, 1105-1109
and references cited therein.
(21) (a) Ungureanu, I.; Klotz, P.; Mann, A. Angew. Chem., Int. Ed. 2000,
39, 4615–4617. (b) Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A.
Chem. Commun. 2001, 958–959.
(22) Absolute configuration of a similar compound was determined in
our previous report; please see ref 20a.
(23) See Supporting Information for details.
7014 J. Org. Chem. Vol. 74, No. 18, 2009

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TABLE 1. Screening of Lewis Acids for Regioselective Nucleophilic Ring Opening of (R)-2-Phenyl-N-tosylaziridine with Chloroethanola
entry
Lewis Acid (LA)
time (min)
ratio 3:4b
yield (%)c of 3a þ 4a
85
yield (%)e of 5a
ee (%)f of 5a
1
2
3
4
5
6
7
1.0 equiv Cu(OTf)2
1.0 equiv Zn(OTf)2
1.0 equiv ZnBr2
2
15
10
1
10
5
89:11
72:28
76:24
81:19
77:23
100:0
100:0
70
66
60
72
73
80
80
74
74
74
74
74
78
35g
72
45
1.0 equiv BF3 OEt2
68
55
3
1.0 equiv Ti(OiPr)4
0.2 equiv Cu(OTf)2
0.2 equiv Cu(OTf)2
87d
3
76d
aReaction condition: 1.0 equivof LA was used, and unlessnoted otherwise all reactions were performedwith (R)-1a in choloroethanol as the solvent at
0 °C. bRatio was determined by 1H NMR analysis of the crude reaction mixture. cYield of isolated 3a þ 4a after passing through plug of silica gel. dYield
e
of isolated 3a after column chromatographic purification. Yield of isolated 5a after column chromatographic purification. Determined by chiral
f
HPLC. gReaction was performed in CH2Cl2 with 5.0 equiv of chloroethanol.
TABLE 2. Two-Step Synthesis of Nonracemic 2-Phenyl-N-sulfonylmorpholines from (R)-2-Phenyl-N-sulfonylaziridinesa
entry
substrates 1
Ar
yield (%)b of chloroethoxy amine 3
time (min)
yield (%)b of morpholines 5
time
ee (%)c of 5a
1
2
3
4
5
1a
1b
1c
1d
1e
4-MeC6H4
4-NO2C6H4
4-MeOC6H4
4-FC6H4
3a (87)
3b (81)
3c (85)
3d (82)
3e (88)
5
5
10
15
10
5a (80)
5b (85)
5c (90)
5d (86)
5e (72)
0.5 h
3 h
1 h
20 min
15 min
78
68
75
74
80
4-tBuC6H4
a0.2 equiv of Cu(OTf)2 was used, and all reactions were performed with (R)-1a-e in choloroethanol as the solvent. bYields of isolated 3 and 5 after
column chromatographic purification are given in parentheses. cDetermined by chiral HPLC using chiralcel OD-H or AS-H column.
mixture. Next 3a was treated with KOH at room tempera-
ture to produce morpholine 5a in 80% yield. On the other
hand, when the reaction was performed in CH2Cl2 as the
solvent with 5.0 equiv of chloroethanol, it was completed in
shorter time but the enantioselectivity of 5a was found to be
poor (ee 35%). Reaction was found to be highly efficient with
choloroethanol as the solvent, and with other solvents such
as DMF and THF the reaction was not successful.
TABLE 3. Cu(OTf)2-Catalyzed One-Pot Synthesis of 2-Phenyl-N-
sulfonylmorpholines from (R)-2-Phenyl-N-sulfonylaziridinesa
entry aziridine
Ar
product time (min) yield (%)b ee (%)c
1
2
3
4
5
1a
1b
1c
1d
1e
4-MeC6H4
4-NO2C6H4
4-MeOC6H4
4-FC6H4
5a
5b
5c
5d
5e
35
185
70
35
25
90
92
83
91
85
78
68
75
74
80
To study the electronic effect of an N-arylsulfonyl group, a
variety of N-arylsulfonyl aziridines 1a-e were prepared from
(R)-phenylglycinol.23 With the optimized reaction condition,
when (R)-2-phenyl-N-sulfonylaziridines 1a-e with different
arylsulfonyl groups on nitrogen were treated with chloro-
ethanol in the presence of catalytic amount of Cu(OTf)2, the
corresponding chloroethoxy amines 3a-e were produced in
excellent yields (up to 88%) and were cyclized to the corre-
sponding morpholines 5a-e in good yield and ee (up to 80%)
(Table 2). The reaction was found to be independent of
the electronic effect of N-arylsulfonyl groups as the reaction
time and yields of the products were almost same in all the
cases (ring opening step). However, the ee was found to be
lower with electron-withdrawing groups (Table 2, entries 2
and 4).
Encouraged by the aforementioned results, when we
attempted the one-pot synthesis of 5a via ring opening of
1a with chloroethanol in the presence of 20 mol % Cu(OTf)2
followed by KOH-assisted intramolecular cyclization, grat-
ifyingly the reaction proceeded smoothly to furnish 5a in
90% yield with 78% ee. Under identical reaction condition
morpholines 5b-e were obtained in excellent yields from the
corresponding aziridines 1b-e (Table 3).
4-tBuC6H4
a0.2 equiv of Cu(OTf)2 was used, and unless noted otherwise all
reactions were performed with (R)-1a-e in choloroethanol as the
solvent. bYield of isolated 5 after column chromatographic purification.
cDetermined by chiral HPLC.
corresponding amino acids24 were reacted under the same
reaction conditions.
Ring opening of alkyl aziridines 1f-h(ee>99%) withchloro-
ethanol was found to be slow, and the regioisomers 3f-h and
4f-h arising from internal attack and terminal attack, respec-
tively, were obtained as an inseparable mixture (Scheme 2).
However, after cyclization and chromatographic separation
2-alkyl morpholines 5f-h and 3-alkyl morpholines 6f-h were
obtained in pure forms with good yield (up to 72% overall yield)
(24) Aziridines 1f-h were prepared from the corresponding amino acids
L-Phe Ala, L-Val, L-Leu. These amino acids were reduced to corresponding 2-
aminoethanols with NaBH4/I2 in THF, which were then transformed into N-
tosyl derivatives with TsCl/Et3N in CH2Cl2. The N-tosyl derivatives were
then cyclized to corresponding aziridines with TsCl/ KOH in THF to afford
the corresponding aziridine in excellent yield.
To extend the scope of this methodology further, a
variety of 2-alkyl-substituted aziridines 1f-h prepared from
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SCHEME 2. Cu(OTf)2-Catalyzed One-Pot Synthesis of 2- and 3-Alkyl-N-tosylmorpholines via the Ring Opening of Aziridines with
Chloroethanol
TABLE 4. Cu(OTf)2-Catalyzed One-Pot Synthesis of 2- and 3-Alkyl-
N-tosylmorpholines via Ring Opening of Aziridines with Chloroethanola
TABLE 5. Cu(OTf)2-Catalyzed One-Pot Synthesis of 2,3-disubstituted
Morpholines via Ring Opening of 2,3-Disubstituted-N-tosylaziridinesa
a0.2 equiv of Cu(OTf)2 was used, and unless noted otherwise all
reactions were performed with 1f-h in choloroethanol as the solvent.
bYield of isolated products after column chromatographic purification
are given in parentheses. c1.0 equiv of Cu(OTf)2 was used. dDetermined
by HPLC using Chiralcel AD-H or OD-H or AS-H.
and excellent ee (up to 99%). Enhanced yield of the products
were obtained when the reaction was performed under one-pot
conditions, and the results are summarized in Table 4.
After establishing the synthesis of 2-substiuted morpho-
lines, we envisioned that enantiopure 2,3-disubstituted mor-
pholines could be made easily from enantiopure 2,3-
disubstituted aziridines. The 2,3-disubstituted aziridines
1i-m were prepared from L-phenylglycine using the method
developed in our laboratory.25 Ring opening of enantiopure
trans-disubstituted aziridines 1i-m (de up to 99%) with
chloroethanol followed by cyclization in the presence of
KOH under one-pot conditions afforded the corresponding
cis-2,3-disubstituted morpholines as the major diastereo-
mers (Table 5, entries 1-5) with high yield and excellent de.
The strategy was extended further for the syntheses of homo-
morpholines via the Cu(OTf)2-catalyzed ring opening of (R)-
2-phenyl-N-tosylaziridine 1a with bromopropanol (10 equiv) to
afford bromopropoxy amine 7 (yield 85%), which was cyclized
in the presence of KOH to produce morpholine homologue
1,4-oxazepane 8 in good yield (76%) and ee (86%). The same
reaction when performed under one-pot condition furnished
nonracemic 8 in 87% yield and 86% ee (Scheme 3).
aIn all the cases the alcohol served as the solvent. bDiasteromeric
excess >99%, except for 1m (92%). cIsolated yield of pure product (5)
after column chromatographic purification. dDetermined by 1H NMR
of crude reaction mixture, in all the cases ee of the product was found
to be >99% as determined by chiral HPLC using Chiralcel AD-H
or OD-H.
was further demonstrated by the straightforward synthesis
of nonracemic seven- and eight-membered homologues of
morpholine. The ring opening of enantiopure (R)-2-phenyl-
N-tosylazetidine26 2a (ee > 99%) with bromoethanol and
bromopropanol in the presence of 50 mol % of Cu(OTf)2
afforded 9a and 10a, respectively, which were cyclized in the
presence of KOH to give morpholine homologues 11a and
12a with poor yields (up to 48%) and moderate ee (up to
56%). When the reaction was performed under one-pot
condition, 11a and 12a were obtained with better yields
After successful demonstration of the strategy for the
synthesis of morpholines and homomorpholines via the ring
opening of aziridines, the synthetic potential of the strategy
(26) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48,
(25) Kumar, A. Ph.D. thesis submitted to IIT-Kanpur, India, 2009.
7016 J. Org. Chem. Vol. 74, No. 18, 2009
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Ghorai et al.
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SCHEME 3. Cu(OTf)2-Catalyzed One-Pot Synthesis of Homo-
morpholine via the Ring Opening of (R)-2-Phenyl-N-tosylaziri-
dine
SCHEME 4. One-Pot Synthesis of Homomorpholine and Higher
Homologue via Ring Opening of 2-Phenyl-N-tosylazetidine
SCHEME 5. One-Pot Synthesis of Enantiopure Homomorpholines and Higher Homologue via Ring Opening of 2,4-Disubstituted-N-
tosylazetidine
TABLE 6. One-Pot Synthesis of Homomorpholines and Higher Homologues via Ring Opening of Azetidines with Haloalcoholsa
aIn all the cases the alcohol served as the solvent. bYield of isolated product after column chromatographic purification. cDetermined by HPLC using
Chiralcel AD-H or OD-H column. dDetermined by crude 1H NMR.
(up to 62%) and the same ee (up to 56%) (Scheme 4, Table 6,
entries 1 and 3).
amines undergo KOH-mediated intramolecular cyclization to
form the corresponding morpholines.
Similarly, (2R,4S)-2-ethyl-4-phenyl-N-tosylazetidine26 2b
(ee > 99%) was reacted with bromoethanol and bromopro-
panol in the presence of 50 mol % of Cu(OTf)2 followed by
cyclization in the presence of KOH to produce homomor-
pholine 11b and oxazocane 12b, respectively, as the major
products (Scheme 5, Table 6, entries 2 and 4).
Mechanistic Perspective. We do believe that the ring open-
ing of chiral aziridines 1 and azetidines 2 with haloalcohols
proceeds via an SN2 pathway, which is illustrated in Scheme 6.
The Lewis acid is coordinated to aziridine 1 or azetidine 2
nitrogen, generating a highly reactive species 13, which under-
goes nucleophilic attack by haloalcohols in SN2 fashion to
provide nonracemic 3/7 or 9/10, respectively. These haloalkoxy
We rationalized the reduced enantioselectivilty in all cases
on the basis of partial racemization of 1 or 2 before the
nucleophilic ring opening step, and this hypothesis is sup-
ported by the racemization of aziridine 1a. We studied the
racemization of enantiopure 1a by performing the reaction
with a catalytic amount of Cu(OTf)2 (20 mol %) in CH2Cl2
at 0 °C without adding any nucleophile. The aliquots were
taken out from the reaction mixture at different time inter-
vals and analyzed by chiral HPLC. The reduced ee with time
is shown in Figure 2. After 120 min, enantiopure (R)-1a was
found to be almost racemized (ee 10%).27
(27) See Supporting Information for details of racemization study.
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SCHEME 7. One-Pot Synthesis of Bicyclic Morpholines via
Ring Opening of Bicyclic Aziridines
Finally, another application of this methodology is de-
monstrated by the synthesis of cis- and trans-2,6-diphenyl-
morpholine derivatives 25 and 26 in enantiopure form. Ring
opening of racemic 2-phenyl N-tosylaziridine (1a) with
(R)-methyl 2-hydroxy-2-phenylacetate in the presence of
20 mol % of Cu(OTf)2 afforded corresponding products 21
and 22 in 1:1 ratio (Scheme 8).
Products 21 and 22 obtained in pure forms by column
chromatographic separation were reduced to the corre-
sponding alcohols 23 and 24 in excellent yield (up to 92%)
by the treatment of lithium borohydride in THF. Alcohols 23
and 24 were then cyclized to the corresponding morpholines
25 and 26 (yield up to 81%), respectively, using p-toluene
sulfonyl chloride and KOH in THF as the solvent
(Scheme 8). Structures of 25 and 26 were unambiguously
confirmed by X-ray crystallography (see Supporting
Information).
FIGURE 2. Racemization of (R)-1a in the presence of Cu(OTf)2 in
CH2Cl2 without any nucleophile.
SCHEME 6. Mechanism for the LA-Catalyzed Ring Opening
of 2-Phenyl-N-tosylaziridines and Azetidines with Haloalcohols
Detosylation of 25 and 26 was carried out in sodium
naphthalenide/tetrahydrofuran to get corresponding free
morpholines 27 and 28 in good yield (scheme 9). C2-sym-
metric morpholine 28 and its derivatives could find use as
ligands, chiral auxiliaries, and catalysts in asymmetric trans-
formations.
Conclusion
The observed high diasteroselectivities in the case of
disubstituted aziridines 1i-m are due to controlled and slow
epimerization of the benzylic carbon center during the reac-
tion. This is obvious as the epimerization would lead to the
formation of less stable cis-aziridines from the correspond-
ing more stable trans-aziridines. Moreover, the SN2 reaction
from the cis-isomer (if any) would be slower and less favor-
able for steric reasons. This rational has been evidenced from
the very slow epimerization of 1m compared to 1a during the
reaction; 1m (de 92%) was treated with Cu(OTf)2 (20 mol %)
in CH2Cl2 solvent and after 10 min it was recovered without
any loss of de (92%).27
Next the strategy was extended further to the synthesis of
bicyclic morpholines via the ring opening of bicyclic azir-
idines. Aziridines 15 and 16 were reacted with bromoethanol
in presence of catalytic amount (20 mol %) of Cu(OTf)2 to
afford the corresponding bromoethoxy amines 17 and 18 in
good yield (up to 76%), which were cleanly cyclized in the
presence of KOH to afford 19 and 20 (yield up to 80%).
Under one-pot condition 19 and 20 were obtained in
excellent overall yield (up to 84%) (Scheme 7). The bicyclic
morpholines have been reported to be used in 2-(cyclic
amino) pyrimidone derivatives as tau protein kinase 1
(TPK1) inhibitors.28
In conclusion, we have developed a simple and practical
protocol for the synthesis of nonracemic 2-substituted mor-
pholines, 2,3-disubstituted morpholines, enantiopure 2,6-
disubstituted morpholines, homomorpholines, and higher
homologues through a Cu(OTf)2-catalyzed SN2-type ring
opening of N-activated aziridines and azetidines with ha-
loalcohols. This method allows the use of a wide range of
aziridines/azetidines and haloalcohols to construct six- to
eight-membered N-O-heterocyles in excellent yield and en-
antioselectivity. The investigation on organocatalytic reac-
tion of substituted morpholines and further study in this area
is underway.
Experimental Section
General Procedure for Cu(OTf)2-Catalyzed Ring Opening of
2-Phenyl-N-sulfonylaziridines with Haloalcohols. A solution of
aziridines 1a-e (1.0 equiv) in haloalcohol (10 equiv) was added
at 0 °C to anhydrous copper triflate (20 mol %) under an argon
atmosphere. The mixture was stirred for appropriate time and
then the reaction was quenched with saturated aqueous sodium
bicarbonate solution. The aqueous layer was extracted with
dichloromethane (3 ꢀ 5.0 mL) and dried over anhydrous
sodium sulfate. The crude product was purified by flash column
chromatography on silica gel (230-400 mesh) using 15% ethyl
acetate in petroleum ether to provide the pure product.
(28) Fukunaza, K.; Kohara, T.; Watanabe, K.; Usui, Y.; Uehera, F.;
Yokoshima, S.; Sakai, D.; Kusaka, S.-I.; Nakayama, K. PCT Int. Appl. WO
2007119463, 2007.
(S)-N-(2-(2-Chloroethoxy)-2-phenylethyl)-4-methylbenzenes-
ulfonamide (3a). The general method described above was
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SCHEME 8. Synthesis of cis- and trans-2,6-Diphenylmorpholines
140.8, 137.1, 129.8, 128.8, 128.2, 127.3, 126.4, 81.8, 68.5, 41.1,
37.4, 31.5, 21.7; HRMS (ESI) C18H22BrNO3S, (M þ H)þ found
412.0579, calcd 412.0582.
SCHEME 9. Cleavage of N-Tosyl Bond of 25 and 26
General Procedure for KOH-Mediated Ring Closure of Halo-
alkoxy Amines 3a-e to Corresponding Morpholines 5a-e. To a
suspension of powdered KOH (2 equiv) in 1.0 mL dry THF was
added a solution of haloalkoxy amine (1.0 equiv) in 5.0 mL dry
THF. The mixture was stirred at room temperature for the
appropriate time. After completion of the reaction, water was
added, and the reaction mixture was extracted with ethyl acetate
(3 ꢀ 5.0 mL). The combined organic layer was washed with
brine and dried over anhydrous sodium sulfate, and the solvent
was removed under reduced pressure. The crude product was
purified by flash column chromatography on silica gel using
15% ethyl acetate and petroleum ether as the eluent.
followed when 1a (100 mg, 0.37 mmol) was reacted with
chloroethanol (0.25 mL, 3.7 mmol) at 0 °C for 5 min to afford
3a as a dense liquid (112 mg, 87% yield). [R]25D þ133.6 (c 0.060,
CHCl3) for a 78% ee sample. Enantiomeric purity was deter-
mined by chiral HPLC analysis (Chiralcel OD-H column),
hexane-isopropanol, 95:5; flow rate = 1.0 mL/min; tR 1:
21.92 min (major), tR 2: 29.89 min (minor). Rf 0.35 (ethyl
acetate-hexane, 1:4); IR νmax (film, cm-1) 3285, 2920, 1597,
1327, 1159, 1091, 810, 664, 552; 1H NMR (500 MHz, CDCl3) δ
7.74 (d, 2H, J = 8.1 Hz), 7.35-7.22 (m, 7H), 5.05 (dd, 1H, NH,
J = 9.7, 2.9 Hz), 4.34 (dd, 1H, J = 9.2, 3.5 Hz), 3.62-3.56 (m,
3H), 3.47-3.43 (m, 1H), 3.25 (ddd, 1H, J = 13.2, 9.8, 3.5 Hz),
3.02 (ddd, 1H, J = 13.2, 9.2, 2.9 Hz), 2.43 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 143.5, 138.0, 137.1, 129.7, 128.9, 127.1, 126.5,
80.9, 68.9, 49.4, 43.0, 21.5; HRMS (ESI) C17H20ClNO3S, (M þ
H)þ found 354.0932, calcd 354.0930.
(S)-N-(2-(3-Bromopropoxy)-2-phenylethyl)-4-methylbenzene-
sulfonamide (7). The general method described above was fol-
lowed when 1a (100 mg, 0.37 mmol) was reacted with
bromopropanol (0.33 mL, 3.7 mmol) at 0 °C for 15 min to afford
7 as a dense liquid (127 mg, 85% yield). Rf 0.39 (ethyl acet-
ate-petroleum ether, 1:4); IR νmax (film, cm-1) 3293, 2924, 2874,
1327, 1160, 1092, 702, 664, 555; 1H NMR (400 MHz, CDCl3) δ
7.66 (d, 2H, J = 8.0 Hz), 7.28-7.19 (m, 5H), 7.13 (d, 2H, J=1.9
Hz), 4.90 (br s, 1H, NH), 4.21 (dd, 1H, J = 9.3, 3.9Hz), 3.78-3.71
(m, 1H), 3.46-3.40 (m, 2H), 3.38-3.33 (m, 1H), 3.29-3.27 (m,
1H), 2.93-2.91 (m, 1H), 2.36 (s, 3H), 2.00-1.97 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 143.5, 138.4, 129.7, 128.7, 128.5,
127.1, 126.5, 80.6, 66.4, 49.3, 32.5, 30.3, 21.5; HRMS (ESI)
C18H22BrNO3S, (M þ H)þ found 412.0584, calcd 412.0582.
(R)-N-(3-(2-Bromoethoxy)-3-phenylpropyl)-4-methylbenzene-
sulfonamide (9a). The general method described above was
followed when 2a (100 mg, 0.35 mmol) was reacted with
bromoethanol (0.24 mL, 3.5 mmol) at 0 °C for 1 h to afford
9a as a dense liquid (117 mg, 82% yield). Rf 0.25 (ethyl
acetate-petroleum ether, 1:4); 1H NMR (400 MHz, CDCl3) δ
7.71 (d, 2H, J = 8.3 Hz), 7.29-7.09 (m, 7H), 5.21 (br s, 1H, NH),
4.31 (dd, 1H, J = 8.8, 3.9 Hz), 3.61-3.56 (m, 1H), 3.43-3.34 (m,
3H), 3.17-3.13 (m, 1H), 3.03-2.98 (m, 1H), 2.37 (s, 3H),
1.84-1.74 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 143.4,
(S)-2-Phenyl-4-tosylmorpholine (5a). The general method de-
scribed above was followed when 3a (100 mg, 0.28 mmol) was
reacted with KOH (31 mg, 0.56 mmol) at rt for 30 min in dry
THF to afford 5a as a white solid (93 mg, 80% yield), mp
102-104 °C. [R]25 þ153.0 (c 0.049, CHCl3) for a 78% ee
D
sample. Enantiomeric purity was determined by chiral HPLC
analysis (Chiralcel OD-H column), hexane-isopropanol, 95:5;
flow rate = 1.0 mL/min; tR 1: 18.15 min (major), tR 2: 36.14 min
(minor). Rf 0.37 (ethyl acetate-hexane, 1:4); IR νmax (film,
cm-1) 2963, 2924, 2855, 1448, 1342, 1306, 1167, 1109, 964,
814, 745, 588; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, 2H, J =
8.3 Hz), 7.29-7.21 (m, 7H), 4.53 (dd, 1H, J = 10.5, 2.7 Hz), 4.00
(dd, 1H, J = 11.7, 2.2 Hz), 3.78 (ddd, 1H, J = 14.2, 11.4, 2.4
Hz), 3.71-3.67 (m, 1H), 3.58-3.55 (m, 1H), 2.43 (ddd, 1H, J =
14.9, 11.5, 3.4), 2.36 (s, 3H), 2.20-2.14 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 143.9, 138.7, 132.3, 129.8, 128.5, 128.3, 127.9,
127.8, 126.0, 77.4, 66.2, 51.9, 45.4, 21.5; HRMS (ESI)
C17H19NO3S (M þ H)þ found 318.1165, calcd 318.1165.
General Procedure for One-Pot Synthesis of Morpholines and
Homologues. A solution of the aziridine (1.0 equiv) in chloro-
ethanol (10 equiv) was added to anhydrous copper triflate
(20 mol %) at 0 °C under an argon atmosphere and stirred for
the appropriate time. After completion of the reaction (as
monitored by TLC) the reaction mixture was diluted with
THF (2.0 mL), and excess KOH (12 equiv) was added to it.
The reaction mixture was stirred further at rt for the appropriate
time and then quenched with saturated aqueous sodium bicar-
bonate solution. The aqueous layer was extracted with ethyl
acetate (3 ꢀ 5.0 mL), washed with brine, and dried over
anhydrous sodium sulfate. After removal of the solvent under
reduced pressure, the crude product was purified by flash
column chromatography on silica gel (230-400 mesh) using
ethyl acetate in hexane as eluent to afford pure product.
(S)-4-(4-tert-Butylphenylsulfonyl)-2-phenylmorpholine (5e).
The general procedure for one-pot synthesis of morpholine
was followed when 1e (100 mg, 0.32 mmol) was reacted with
chloroethanol (0.21 mL, 3.2 mmol) at 0 °C for 10 min followed
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Ghorai et al.
JOCArticle
by cyclization with excess KOH (215 mg, 3.83 mmol) in dry THF
at rt for 15 min to afford pure 5e as a white solid (102.5 mg, 90%
yield); mp 112-115 °C; [R]25D þ47.2 (c 0.072, CHCl3) for a 80%
ee sample. Enantiomeric purity was determined by chiral HPLC
analysis (Chiralcel OD-H column), hexane-isopropanol, 95:5,
flow rate = 1.0 mL/min; tR 1: 13.72 min (major), tR 2: 22.37 min
(minor). Rf 0.38 (ethyl acetate-hexane, 3:7); IR νmax (KBr,
cm-1) 2923, 1343, 1170, 1101, 966, 772, 562; 1H NMR (400
MHz, CDCl3) δ 7.58 (d, 2H, J = 8.5 Hz), 7.45 (d, 2H, J = 8.5
Hz), 7.28-7.23(m, 5H), 4.54 (dd, 1H, J = 10.2, 2.2 Hz), 4.01(dd,
1H, J = 10.7, 2.2 Hz), 3.80 (ddd, 1H, J = 11.7, 11.5, 2.7 Hz),
3.73-3.70 (m, 1H), 3.59-3.56 (m, 1H), 2.47 (ddd, 1H, J = 11.7,
11.5, 3.4 Hz), 2.23-2.18 (m, 1H), 1.27 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 156.8, 138.7, 128.5, 128.3, 127.7, 126.1, 125.9,
77.3, 66.2, 51.9, 45.4, 31.0; HRMS (ESI) C20H25NO3S, (M þ
H)þ found 360.1631, calcd 360.1633.
(2R,3S)-2-Phenyl-4-tosyl-3-vinylmorpholine (5j). The general
procedure for one-pot synthesis of morpholine was followed
when 1j (100 mg, 0.33 mmol) was reacted with chloroethanol
(0.22 mL, 3.3 mmol) at 0 °C for 15 min followed by cyclization
with excess KOH (222 mg, 3.96 mmol) in dry THF at rt for
45 min to afford 5j as a dense liquid (80 mg, 70% yield); de 98%;
Enantiomeric purity was determined by chiral HPLC analysis
(Chiralcel AS-H column), hexane-isopropanol, 95:5, flow rate =
1.0 mL/min; tR 1: 17.58 min (minor), tR 2: 21.43 min (major).
Rf 0.43 (ethyl acetate-hexane, 1:5); IR νmax (neat, cm-1) 2924,
1
2854, 1728, 1345, 1274, 1163, 1111, 1019, 666, 567; H NMR
(500 MHz, CDCl3) δ 7.67 (d, 2H, J = 8.3 Hz), 7.32-7.21 (m, 7H),
5.59-5.52 (m, 1H), 4.90 (d, 1H, J = 10.6 Hz), 4.83 (d, 1H,
J=13.8 Hz), 4.72 (d, 1H, J=2.9 Hz), 4.57-4.52 (m, 1H), 4.08
(dd, 1H, J = 11.5, 3.7 Hz), 3.79 (ddd, 1H, J = 11.5, 11.5, 3.2 Hz),
3.60 (dd, 1H, J = 12.9, 5.7 Hz), 3.22 (ddd, 1H, J=12.3, 12.3, 3.7
Hz), 2.40 (s, 3H); HRMS (ESI) C19H21NO3S, (M þ H)þ found
344.1245, calcd 344.1242.
(S)-2-Isopropyl-4-tosylmorpholine (5g). The general proce-
dure for one-pot synthesis of morpholine was followed when
1g (100 mg, 0.42 mmol) was reacted with chloroethanol (0.28
mL, 4.2 mmol) at rt for 9 h followed by cyclization with excess
KOH (282 mg, 5.04 mmol) in dry THF at rt for 2 h to afford pure
isomers 5g and 6g (1:2 ratio) as a white solid. Regioisomer 5g:
(2R,3S)-3-Methyl-2-phenyl-4-tosylmorpholine (5k). The gen-
eral procedure for one-pot synthesis of morpholine was fol-
lowed when 1k (100 mg, 0.35 mmol) was reacted with
chloroethanol (0.24 mL, 3.5 mmol) at 0 °C for 10 min followed
by cyclization with excess KOH (222 mg, 3.96 mmol) in THF
at rt for 1 h to afford 5k as a dense liquid (97.8 mg, 85% yield);
de > 99%; Enantiopuric purity was determined by chiral HPLC
analysis (Chiralcel OD-H column), hexane-isopropanol,
95:5, flow rate = 1.0 mL/min; tR: 12.06 min. Rf 0.43 (ethyl
acetate-hexane, 1:5); IR νmax (neat, cm-1) 2922, 2851, 1598,
1382, 1348, 1275, 1157, 1125, 1091, 1000, 920, 858, 701, 557;
1H NMR (400 MHz, CDCl3) δ 7.67 (d, 2H, J = 8.3 Hz),
7.28-7.17 (m, 7H), 4.56 (d, 1H, J = 2.7 Hz), 4.14-4.12 (m,
1H), 3.98 (dd, 1H, J = 11.5, 3.2 Hz), 3.64 (ddd, 1H, J=14.6,
12.2, 3.2 Hz), 3.55-3.52 (dd, 1H, J = 12.9, 3.2 Hz), 3.18 (ddd,
1H, J=16.3, 12.4, 3.7 Hz), 2.36 (s, 1H), 0.65 (d, 3H, J = 6.8 Hz);
HRMS (ESI) C18H21NO3S, (M þ H)þ found 332.1326, calcd
332.1320.
(2R,3S)-3-Isopropyl-2-phenyl-4-tosylmorpholine (5l). The
general procedure for one-pot synthesis of morpholine was
followed when 1 L (100 mg, 0.32 mmol) was reacted with
chloroethanol (0.22 mL, 3.2 mmol) at 0 °C for 20 min followed
by cyclization with excess KOH (222 mg, 3.96 mmol) in THF at
rt for 70 min to afford 5 L as a dense liquid (81 mg, 72% yield);
de 94%; Enantiomeric purity was determined by chiral HPLC
analysis (Chiralcel AS-H column), hexane-isopropanol, 95:5,
flow rate = 1.0 mL/min; tR 1: 15.98 min (major), tR 2: 18.23 min
(minor). Rf 0.41 (ethyl acetate-hexane, 1:5); IR νmax (neat,
cm-1) 2958, 2924, 2853, 1741, 1599, 1495, 1339, 1275, 1158,
1090, 936, 702, 554; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, 2H,
J=8.3 Hz), 7.34-7.21 (m, 7H), 4.35 (d, 1H, J = 3.2 Hz), 3.87-
3.85 (m, 1H), 3.80-8.78 (m, 1H), 3.75-3.72 (m, 1H),
3.42-3.37(m, 2H), 2.38(s, 3H), 2.02-1.97 (m, 1H), 0.84 (d, 3H,
J=6.6 Hz), 0.36 (d, 3H, J = 6.6 Hz); HRMS (ESI) C20H25-
NO3S, (M þ H)þ found 360.1636, calcd 360.1633.
yield 29%, mp 93-95 °C; [R]25 þ44.9 (c 0.069, CHCl3) for a
D
96% ee sample. Enantiomeric purity was determined by chiral
HPLC analysis (Chiralcel AS-H column), hexane-isopropanol,
98:2, flow rate = 0.80 mL/min; tR 1: 30.79 min (major), tR 2:
34.44 min (minor). Rf 0.46 (ethyl acetate-hexane, 1:5); 1H
NMR (400 MHz, CDCl3) δ 7.57 (d, 2H, J = 8.0 Hz), 7.28 (d,
2H, J = 8.3 Hz), 3.83 (dd, 1H, J = 11.5, 3.2 Hz), 3.60-3.52 (m,
2H), 3.45-3.42 (m, 1H), 3.16-3.11 (m, 1H), 2.38 (s, 3H), 2.29
(ddd, 1H, J = 11.5, 11.2, 3.2 Hz), 2.03-1.98 (m, 1H), 1.58-1.53
(m, 1H), 0.85 (d, 3H, J = 6.8 Hz), 0.82 (d, 3H, J = 6.8 Hz); 13
C
NMR (100 MHz, CDCl3) δ 143.8, 132.5, 129.7, 127.8, 80.3, 66.0,
48.3, 45.6, 45.5, 31.1, 21.5, 18.3; HRMS (ESI) C14H21NO3S,
(M þ H)þ found 284.1327, calcd 284.1320.
(S)-3-Isopropyl-4-tosylmorpholine (6g). White solid, yield
57%; mp 99-101 °C; [R]25D þ39.4 (c 0.011, CHCl3) for a 98%
ee sample. Enantiomeric purity was determined by chiral HPLC
analysis (Chiralcel AS-H column), hexane-isopropanol, 98:2,
flow rate = 0.80 mL/min; tR 1: 21.62 min (minor), tR 2: 26.08
min (major). Rf 0.38 (ethyl acetate-hexane, 1:5); IR νmax (KBr,
cm-1) 2962, 2859, 1459, 1342, 1157, 926, 745, 677, 555; 1H NMR
(400 MHz, CDCl3) δ 7.65 (d, 2H, J = 8.3 Hz), 7.23 (d, 2H, J =
8.1 Hz), 3.75 (d, 1H, J=11.9 Hz), 3.56-3.51 (m, 2H), 3.27-3.05
(m, 4H), 2.36 (s, 3H), 2.26-2.18 (m, 1H), 0.90 (d, 3H, J =
6.6 Hz), 0.85 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3)
δ 143.2, 138.9, 129.8, 127.0, 66.2, 65.5, 59.7, 41.3, 25.4, 21.5,
19.9, 19.8; HRMS (ESI) C14H21NO3S, (M þ H)þ found
284.1328, calcd 284.1320.
(2R,3S)-3-Ethyl-2-phenyl-4-tosylmorpholine (5i). The general
procedure for one-pot synthesis of morpholine was followed
when 1i (100 mg, 0.33 mmol) was reacted with chloroethanol
(0.22 mL, 3.3 mmol) at 0 °C for 10 min followed by cyclization
with excess KOH (222 mg, 3.96 mmol) in dry THF at rt for 1 h to
afford 5i as a dense liquid (89 mg, 78% yield); de 99%;
Enantiomeric purity was determined by chiral HPLC analysis
(Chiralcel AS-H column), hexane-isopropanol, 98:2, flow rate
= 0.80 mL/min; tR 1: 37.66 min (major), tR 2: 45.79 min (minor).
Rf 0.40 (ethyl acetate-hexane, 1:5); IR νmax (neat, cm-1) 2965,
2924, 2856, 1343, 1158, 1089, 995, 702, 552; 1H NMR (400 MHz,
CDCl3) δ 7.74 (d, 2H, J = 8.3 Hz), 7.28-7.14 (m, 7H), 4.35 (d,
1H, J = 2.7 Hz), 3.89-3.86 (m, 1H), 3.84-3.80 (m, 1H),
3.68-3.60 (m, 1H), 3.43 (ddd, 1H, J = 12.2, 12.2, 2.9 Hz),
3.27-3.19 (m, 1H), 2.36 (s, 3H), 1.57-1.49 (m, 1H), 1.04-0.99
(m, 1H), 0.59 (t, 3H, J = 7.6 Hz); 13C NMR (125 MHz, CDCl3)
δ 143.6, 138.8, 130.0, 128.4, 127.5, 127.1, 125.3, 79.3, 66.6, 59.5,
39.9, 21.6, 16.7, 10.6; HRMS (ESI) C19H23NO3S, (M þ H)þ
found 346.1475, calcd 346.1476.
(2R,3S)-3-Allyl-2-phenyl-4-tosylmorpholine (5m). The general
procedure for one-pot synthesis of morpholine was followed
when 1m (100 mg, 0.32 mmol) was reacted with chloroethanol
(0.22 mL, 3.2 mmol) at 0 °C for 10 min followed by cyclization
with excess KOH (222 mg, 3.96 mmol) in THF at rt for 45 min to
afford 5m as a dense liquid (86 mg, 75% yield); de 92%; Rf 0.44
(ethyl acetate-hexane, 1:5); IR νmax (neat, cm-1) 2922, 2854,
1639, 1493, 1336, 1159, 1091, 1023, 918, 814, 724, 702, 682, 557;
1H NMR (500 MHz, CDCl3) δ 7.77 (d, 2H, J = 8.4 Hz),
7.34-7.23 (m, 7H), 5.42-5.36 (m, 1H), 4.83-4.81(m, 1H),
4.79 (s, 1H), 4.49 (d, 1H, J = 3.1 Hz), 4.16-4.13 (m, 1H),
3.93 (dd, 1H, J = 11.45, 3.5 Hz), 3.66 (dd, 1H, J = 14.2, 3.1 Hz),
3.56 (ddd, 1H, J = 15.3, 12.2, 3.1 Hz), 3.29 (ddd, 1H, J = 14.1,
12.2, 3.5 Hz), 2.42 (s, 3H), 2.36-2.29 (m, 1H), 1.86-1.81 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 143.6, 138.5, 134.7, 129.9,
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Ghorai et al.
JOCArticle
128.5, 127.6, 127.3, 125.3, 116.9, 79.3, 66.8, 57.5, 40.0, 29.8, 28.8,
21.6; HRMS (ESI) C20H23NO3S, (M þ H)þ found 358.1478,
calcd 358.1477.
(minor). Rf 0.30 (ethyl acetate-hexane, 1:4); IR νmax (neat,
cm-1) 2922, 2854, 1335, 1156, 1104, 713, 697, 549; 1H NMR (400
MHz, CDCl3) δ 7.66 (d, 2H, J = 8.0 Hz), 7.27-7.18 (m, 7H),
4.66 (dd, 1H, J = 10.0, 4.2 Hz), 3.82-3.78 (m, 1H), 3.72-3.62
(m, 2H), 3.52-3.48 (m, 1H), 3.17-3.11 (m, 1H), 2.99-2.93 (m,
1H), 2.36 (s, 3H), 2.23-2.14 (m, 2H), 1.84-1.76 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 143.1, 129.7, 128.3, 126.9, 125.7,
66.5, 49.0. 47.6, 37.4, 30.4, 21.5; HRMS (ESI) C19H23NO3S,
(M þ Na)þ found 368.1292, calcd 368.1296.
(S)-2-Phenyl-4-tosyl-1,4-oxazepane (8). The general proce-
dure for one-pot synthesis of homomorpholine was followed
when 1a (100 mg, 0.37 mmol) was reacted with bromopropanol
(0.33 mL, 3.7 mmol) at 0 °C for 15 min followed by cyclization
with excess KOH (249 mg, 4.44 mmol) in dry THF at rt for 16 h
to afford 8 as a dense liquid (105 mg, 87% yield); [R]25D þ158.3
(c 0.084, CHCl3) for a 86% ee sample. Enantiomeric purity was
determined by chiral HPLC analysis (Chiralcel OD-H column),
hexane-isopropanol, 95:5, flow rate = 1.0 mL/min; tR 1: 12.26
min (major), tR 2: 14.44 min (minor). Rf 0.41 (ethyl aceta-
te-hexane, 3: 7); IR νmax (neat, cm-1) 2923, 2853, 1729, 1338,
1160, 1018, 700, 659, 549; 1H NMR (500 MHz, CDCl3) δ 7.59 (d,
2H, J = 8.3 Hz), 7.27-7.19 (m, 7H), 4.56 (dd, 1H, J = 10.0, 2.4
Hz), 4.14- 4.08 (m, 1H), 3.92-3.89 (m, 1H), 3.84-3.77 (m, 2H),
2.99-2.92 (m, 1H), 2.74 (dd, 1H, J = 14.2, 10.0 Hz), 2.36 (s,
3H), 2.04-1.99 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.3,
139.7, 136.4, 129.7, 128.5, 127.9, 126.9, 126.0, 83.9, 68.6, 57.7,
46.9, 30.6, 21.4; HRMS (ESI) C18H21NO3S, (M þ H)þ found
332.1323, calcd 332.1320.
(R)-7-Phenyl-4-tosyl-1,4-oxazepane (11a). The general proce-
dure for one-pot synthesis of morpholine homologues was
followed when 2a (100 mg, 0.35 mmol) was reacted with
bromoethanol (0.24 mL, 3.5 mmol) at 0 °C for 1 h followed by
cyclization with excess KOH (235.6 mg, 4.2 mmol) in dry THF
at rt for 32 h to afford 11a as a white solid (72 mg, 62% yield); mp
113-114 °C; [R]25D þ22.5 (c 0.08, CHCl3) for a 56% ee sample.
Enantiomeric purity was determined by chiral HPLC analysis
(Chiralcel OD-H column), hexane-isopropanol, 95:5, flow rate
= 1.0 mL/min; tR 1: 21.72 min (major), tR 2: 25.31 min (minor).
Rf 0.32 (ethyl acetate-hexane, 1:4); 1H NMR (400 MHz,
CDCl3) δ 7.63 (d, 2H, J = 8.0 Hz), 7.27-7.16 (m, 7H), 4.60
(dd, 1H, J = 9.5, 2.7 Hz), 4.04-4.00 (m, 1H), 3.73-3.51 (m,
3H), 3.28-3.20 (m, 1H), 3.19-3.14 (m, 1H), 2.37 (s, 3H),
2.25-2.21 (m, 1H), 1.98-1.95 (m, 1H); 13C NMR (100 MHz
CDCl3) δ 143.1, 142.6, 129.5, 128.1, 127.1, 126.8, 125.3, 81.2,
69.7, 51.4, 46.0, 37.5, 21.2; HRMS (ESI) C18H21NO3S, (M þ
Na)þ found 354.1147, calcd 354.1140.
(2R,4R)-4-Ethyl-2-phenyl-5-tosyl-1,5-oxazocane (12b). The
general procedure for one-pot synthesis of morpholine homo-
logues was followed when 2b (100 mg, 0.32 mmol) reacts with
bromopropanol (0.29 mL, 3.2 mmol) followed by cyclization
with excess KOH (215.5 mg, 3.8 mmol) in dry THF at rt for 30 h
to afford 12b as the major diastereomer as a dense liquid (85 mg,
74% yield); [R]25D þ63.5 (c 0.23, CHCl3) for a >99% ee sample.
Rf 0.37 (ethyl acetate-hexane, 1:4); IR νmax (neat, cm-1) 2922,
2854, 1335, 1156, 1104, 713, 697, 549; 1H NMR (500 MHz,
CDCl3) δ 7.74 (d, 1H, J = 8.0 Hz), 7.30-7.21 (m, 7H), 4.52 (dd,
1H, J = 9.6, 1.6 Hz), 3.98-3.90 (m, 2H), 3.80-3.77 (m, 1H),
3.54-3.50 (m, 1H), 3.19-3.09 (m, 1H), 2.39 (s, 3H), 2.22-2.15
(m, 2H), 1.85-1.73 (m, 2H), 1.34-1.30 (m, 2H), 0.57 (t, 3H, J =
7.7 Hz); HRMS (ESI) C21H27NO3S, (M þ H)þ found 374.1794,
calcd 374.1789.
4-Tosyloctahydrocyclopenta[b][1,4]oxazine (19). The general
procedure for one-pot synthesis of morpholines was followed
when 15 (100 mg, 0.42 mmol) reacts with bromoethanol (0.38
mL, 4.2 mmol) at 0 °C for 7 h followed by cyclization with excess
KOH (282 mg, 5.04 mmol) in dry THF at rt for 1 h to afford 19
as a white solid (99 mg, 84% yield); mp 115-116 °C; Rf 0.35
(ethyl acetate-hexane, 1:3); 1H NMR (400 MHz, CDCl3) δ 7.57
(d, 2H, J = 8.3 Hz), 7.29 (d, 2H, J = 8.1 Hz), 3.88 (dd, 1H, J =
10.5, 2.2 Hz), 3.71 (ddd, 1H, J = 11.7, 11.7, 2.4 Hz), 3.57-3.54
(m, 1H), 3.37-3.31 (m, 1H), 2.39 (s, 3H), 2.32 (ddd, 1H, J =
11.9, 11.7, 3.6 Hz), 2.16-2.13 (m, 1H), 1.99-1.81 (m, 3H),
1.67-1.60 (m, 1H), 1.37-1.29 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 143.9, 131.9, 129.7, 128.0, 82.6, 67.1, 62.0, 47.7, 26.7,
25.3, 21.5, 17.1; HRMS (ESI) C14H19NO3S, (M þ H)þ found
282.1162, calcd 282.1163.
(S)-Methyl-2-((R)-2-(4-methylphenylsulfonamido)-1-phenyl-
ethoxy)-2-phenylacetate (21). A solution of the aziridine (()
1a (200 mg, 0.732 mmol) and (S)-mandelic acid ester (304 mg,
1.83 mmol) in 5.0 mL dichloromethane was added to anhydrous
copper triflate (52.9 mg, 0.146 mmol) at 0 °C under an argon
atmosphere. The mixture was stirred for 2 h and then the reac-
tion was quenched with aqueous saturated sodium bicarbo-
nate solution. The aqueous layer was extracted with dichloro-
methane (3 ꢀ 5.0 mL) and dried over anhydrous sodium
sulfate. After removal of the solvent under reduced pressure,
the crude product was purified by flash column chromatography
using 15% ethyl acetate in hexane as eluent to afford pure
products 21 and 22 as dense liquids in 1:1 ratio (272 mg, 85%
combined yield); diastereomer 21; Rf 0.28 (ethyl acetate-hexane,
3: 7); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 2H, J = 8.3 Hz),
7.27-7.19 (m, 10H), 7.09-7.07 (m, 2H), 5.96 (d, 1H, NH, J=
7.7 Hz), 4.67 (s, 1H), 4.37 (dd, 1H, J = 9.8, 2.7 Hz), 3.71 (s,
3H), 3.19-3.17 (m, 1H), 3.08-3.03 (m, 1H), 2.37 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 172.1, 143.2, 137.6, 137.3,
135.9, 129.6, 128.7, 128.6, 128.5, 127.3, 127.0, 126.5, 80.8, 78.5,
52.6, 49.7, 21.5.
(5R,7R)-5-Ethyl-7-phenyl-4-tosyl-1,4-oxazepane (11b). The
general procedure for one-pot synthesis of morpholine homo-
logues was followed when 2b (100 mg, 0.32 mmol) was reacted
with bromoethanol (0.20 mL, 3.2 mmol) at 0 °C for 20 min
followed by cyclization with excess KOH (215.5 mg, 3.8 mmol)
in dry THF at rt for 40 h to afford 11b as the major diastereomer
as a dense liquid (68 mg, 60% yield); [R]25 þ56.9 (c 0.20,
D
CHCl3) for a >99% ee sample. Rf 0.38 (ethyl acetate-hexane,
1:4); IR νmax (neat, cm-1) 2922, 2852, 1621, 1453, 1334, 1156,
1117, 1019, 813, 699, 547; 1H NMR (400 MHz, CDCl3) δ 7.70 (d,
2H, J = 8.3 Hz), 7.26-7.15 (m, 7H), 4.33 (d, 1H, J = 8.8 Hz),
4.02- 3.98 (m, 1H), 3.85-3.79 (m, 2H), 3.65 (dd, 1H, J = 12.9,
1.7 Hz), 3.28-3.23 (m, 1H), 2.37 (s, 3H),2.34-2.25 (m, 2H),
1.87-1.82 (m, 1H), 1.46-1.39 (m, 1H), 0.66 (t, 3H, J = 7.6 Hz);
13C NMR (125 MHz, CDCl3) δ 143.3, 141.8, 138.5, 134.4, 129.6,
128.6, 128.0, 127.2, 126.3, 79.3, 69.4, 54.3, 41.9, 30.6, 21.6, 10.1;
HRMS (ESI) C20H25NO3S, (M þ H)þ found 360.1641, calcd
360.1633.
(R)-2-Phenyl-5-tosyl-1,5-oxazocane (12a). The general proce-
dure for one-pot synthesis of morpholine homologues was
followed when 2a (100 mg, 0.35 mmol) was reacted with
bromopropanol (0.32 mL, 3.5 mmol) at 0 °C for 30 min followed
by cyclization with excess KOH (235.6 mg, 4.2 mmol) in dry
THF at rt for 28 h to afford 12a as a dense liquid (72 mg, 60%
(S)-Methyl-2-(S)-2-(4-methylphenylsulfonamido)-1-phenylet-
hoxy)-2-phenylacetate (22). Diastereomer 22; Rf 0.24 (ethyl
acetate-hexane, 3: 7); IR νmax (neat, cm-1) 2923, 1742, 1454,
1332, 1161, 1091, 701, 663, 554; 1H NMR: (400 MHz, CDCl3)
δ 7.59 (d, 2H, J = 8.3 Hz), 7.39-7.38 (m, 2H), 7.33-7.12
(m, 12H), 5.09 (br s, 1H, NH), 4.64 (s, 1H), 4.23 (t, 1H,
J = 6.8 Hz), 3.57 (s, 3H), 3.14 (d, 2H, J = 7.1 Hz), 2.39
(s, 3H), 13C NMR (100 MHz, CDCl3) δ 170.5, 143.2, 137.2,
yield); [R]25 þ53.1 (c 0.16, CHCl3) for a 50% ee sample.
D
Enantiomeric purity was determined by chiral HPLC analysis
(Chiralcel OD-H column), hexane-isopropanol, 95:5, flow
rate = 1.0 mL/min; tR 1: 13.17 min (major), tR 2: 15.06 min
J. Org. Chem. Vol. 74, No. 18, 2009 7021

Ghorai et al.
JOCArticle
135.5, 129.7, 129.2, 128.9, 128.8, 127.8, 127.1, 127.0, 78.2, 78.0,
52.2, 48.9, 21.5.
Supporting Information Available: Spectroscopic data of
1
other compounds, copies of H and 13C spectra for all new
compounds, X-ray crystallographic structure of 25 and 26,
and HPLC chromatograms for ee determination. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. M.K.G. is grateful to IIT-Kanpur and
DST, India. D.S. thanks IIT-Kanpur India for senior re-
search fellowship.
7022 J. Org. Chem. Vol. 74, No. 18, 2009