Synthesis of oxathiane and morpholine from acyclic precursors: A modified Mitsunobu reaction

Article abstract of DOI:10.1016/j.tet.2012.06.029

Synthesis of a set of isomeric 2,4,6-triarylmorpholines and 2,6-diaryloxathianes from the corresponding 1,5-diols has been described. The method provides an efficient route to six-membered heterocycles from acyclic diols and is found to be better than Mitsunobu procedure in yield and waste management. In a related study, the ring contraction of pyranone to two isomeric cyclopentenone derivatives through Nazarov reaction has been noticed.

Full text of DOI:10.1016/j.tet.2012.06.029

Tetrahedron 68 (2012) 6892e6901
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Synthesis of oxathiane and morpholine from acyclic precursors: a modified
Mitsunobu reaction
,
Nidhin Paul a, Selvam Kaladevi a, Arockiam Jesin Beneto a, Shanmugam Muthusubramanian a
*
,
Nattamai Bhuvanesh b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
b Department of Chemistry, Texas A & M University, College Station, TX 77843, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2012
Received in revised form 1 June 2012
Accepted 5 June 2012
Available online 15 June 2012
Synthesis of a set of isomeric 2,4,6-triarylmorpholines and 2,6-diaryloxathianes from the corresponding
1,5-diols has been described. The method provides an efficient route to six-membered heterocycles from
acyclic diols and is found to be better than Mitsunobu procedure in yield and waste management. In
a related study, the ring contraction of pyranone to two isomeric cyclopentenone derivatives through
Nazarov reaction has been noticed.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Tagetitoxin11 is an oxathiane derivative produced by the plant
pathogenic bacterium Pseudomonas syrmgae pv. tagetis and it in-
Six-membered ring systems with more than one heteroatom
such as morpholine and oxathiane are present as important core
structures in many biologically active natural products1 and phar-
maceuticals.2 4-Phenylmorpholine derivatives possess antimicro-
bial, anti-inflammatory and central nervous system activities.3
Linezolide,3,4 the commercially available antimicrobial agent, has
a 4-phenylmorpholine nucleus. Aprepitant,5 an h-NK1 receptor
antagonist with a morpholine nucleus is the first FDA-approved
drug for the treatment of chemotherapy-induced nausea and
vomiting (CINV). Reboxetine,6 a selective noradrenaline uptake
inhibitor, is used in the treatment of depression. The (þ)-(S,S)-en-
antiomer of reboxetine7 is currently undergoing advanced clinical
evaluation for the treatment of fibromyalgia and neuropathic pain
and is currently marketed in Europe as an antidepressant. Polygo-
napholine, an alkaloid extracted from the rhizome of Polygonatum
alte-lobatum being used as a tonic drug in Taiwan, is a morpholine
derivative having its C-2 and C-6 substituents cis-oriented occu-
pying equatorial positions in the six-membered ring.8 Chenolin A
and chenolin C (Fig. 1), the first reported 2,6-disubstituted mor-
pholines from natural sources, are alkaloids isolated from the ma-
rine sponge Chelonaplysilla sp. collected from a lake in Palau.9
Substituted morpholines also display interesting biological prop-
erties such as antimicrobial, anti-inflammatory and anti-Alz-
heimer’s activities.10
duces chlorosis in the apex of the host plant by specifically inhib-
iting chloroplast RNA polymerase.
Raphanuside (Fig. 2) is an oxathiane-fused thioglucoside iso-
lated from the seeds of Raphanus sativus L. (Cruciferaceae), a tradi-
tional Chinese herbal medicine used for expectorant, anti-cough
and antiasthmatic purposes.12 Oxathianes possess fungicidal, pes-
ticidal and muscarinic agonists activities and also act as important
precursors for the synthesis of biologically significant 1,4-
oxathianes.13 Oxathianes have also been shown as glycosyl do-
nors for highly selective 1,2-cis-glycosylation.14
A variety of methods are known for building up morpholine and
thiomorpholine rings. Tsuji et al. reported ruthenium complex-cata-
lyzed N-heterocyclization between amines and 1,5-diols for the
preparation of morpholines.13 Nelson et al. reported that the con-
densation of amino alcohols with diethyl oxalate provided the corre-
sponding morpholine-2,3-diones.5 Reaction of ephedrine with oxalyl
chloride generates the morpholine dione.15 Asymmetric vinyl mor-
pholines have been prepared via palladium-catalyzed allylic sub-
stitution.16 Mitsunobu diol cyclization17 is also a method for the
preparation of morpholines. Fish et al. reported a procedure in which
thecondensationofN-benzylethanolamine with 2-chloroacrylonitrile
followed by t-BuOK-promotedcyclizationgavemorpholine.6a Harding
et al. procedure for morpholine synthesis involves the reaction of 1,5-
diols with NaH and tosylimidazole in THF.18 Dehydration of dihydroxy
compounds withacidsisalsoreported as a procedurefor thesynthesis
of morpholines.9b,10a,19 Fan et al. reported a reaction in which 2-
aminoethanol is reacted with DMAD to generate morpholines.20 Sil-
ica gel promoted synthesis of 1,4-oxathiane from dichlorosulfides had
* Corresponding author. Tel./fax: þ91 452 2459845; e-mail address: muthuma-
nian2001@yahoo.com (S. Muthusubramanian).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.029

N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
6893
Fig. 1. Morpholine drugs and alkaloids.
oxathiolane is reacted with methyl diazoacetate in the presence of
Rh2(OAc)4 yielding a mixture of cis and trans isomers of 1,4-
oxathiane.24 Oxathianes can also be obtained from hydroxythiols.25
Murray et al. identified diethoxytriphenylphosphorane and triphe-
nylphosphine/tetrachloro methane promoted cyclodehydration as an
efficient route to oxathianes.26 In Boons procedure, reductive cycli-
zation is adopted as an efficient method for oxathianes.14
H2N
OH
C
O
HO
O
S
HO
HO
S
H
AcO
O
H3N
H
H
H
O
OMe
COOH
O
O
P
MeO
OH
O
2. Results and discussion
HO
Tagetitoxin
Raphanuside
Like many other alicyclic structures with more than one het-
eroatom, the morpholine and oxathiane core provide numerous
avenues for further chemical modifications and there has been an
increasing interest in the development of methodologies for their
construction. This article describes a better protocol for the prep-
aration of six-membered nitrogen and oxygen heterocycles from
corresponding 1,5-diols (Scheme 1).
Fig. 2. Oxathiane drugs.
been reported by Minakata et al.21 Miyauchi reported an intra-
molecular Mitsunobu reaction of diols22 for the synthesis of 1,4-
oxathiane. Ioannou et al. reported a ring expansion in which 1,3-
oxathiane is treated with silylated diazoester for the preparation of
1,4-oxathiane.23 Stepakov et al. reported a reaction in which 1,3-
Scheme 1. Synthesis of six-membered heterocycles.

6894
N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
For the construction of oxathianes, the starting 1,5-diols 4 have
been prepared by the sodium borohydride reduction of substituted
diphenacyl sulfides 3. The diol obtained is a mixture of two di-
astereoisomers. In a representative example, 3a was reduced with
sodium borohydride in methanol and the mixture of di-
astereomeric diols 4a were treated with different acid catalysts in
a range of solvents. It was observed that among different conditions
analyzed, (ꢀ)-camphorsulphonic acid (CSA) in DMF at 75 ꢁC pro-
vides isomeric oxathianes in excellent yield (Table 1, entry 7). This
reaction condition is found to be better than Mitsunobu procedure
(Table 1, entries 16 and 17).
Fig. 3. NMR data of 50e with HMBC connections.
In the case of 500a, the 1H NMR spectrum indicates the com-
pound to be the trans isomer and it may not have a rigid arrange-
ment. Possibly a chair form with fast flipping is suggested for this
compound from the NMR data (Fig. 4). Though the signals due to
the heterocyclic ring hydrogens are well resolved doublet of dou-
blet with definite coupling constants in 500a, in all other compounds
except 500b, 500f and 500h these signals appear as narrow bands with
zero coupling in some cases.
Table 1
Reaction of 4a with acids under different conditions
No
Reaction condition
Time (h)
Temp (ꢁC)
Yield of 5aa (%)
1
2
3
4
5
6
7
8
HCl, DMF
H2SO4, DMF
HCl, toluene
p-PTSH, DMF
p-PTSH, toluene
p-PTSH, MeOH
(ꢀ)-CSA, DMF
(ꢀ)-CSA, toluene
(ꢀ)-CSA, THF
1.5
1.5
2
75
75
95
80
100
65
75
85
60
60
85
100
80
75
75
40
40
22
17
db
1.3
1.1
1.5
1.5
1.6
2.4
1.5
1.5
3.6
1.5
1.2
1.5
7
73
20
dc
87
14
9
db
db
db
dd
54
10
11
12
13
14
15
16
17
(ꢀ)-CSA, dioxane
(ꢀ)-CSA, DMSO
(ꢀ)-CSA, water
Acetic acid, DMF
Citric acid, DMF
PPA, DMF
50
db
17e
20e
TPP, DEAD, THF
TPP, DEAD, toluene
10
a
Yield as per NMR spectra of mixture of isomers.
Inseparable viscous mass.
Unidentified product.
Starting material recovered.
Mitsunobu reaction condition.
b
c
d
e
Fig. 4. Flipping forms of 500a.
It was also observed that in all the cases of reduction of diphe-
The separation of the diastereomeric diols from the crude re-
action mixture posed problems due to close Rf. In one attempt, it
was possible to get one diastereomer 400a in pure form, while the
other could not be obtained in pure, always contaminated with the
former. From the NMR spectra of the diol 400a (Fig. 5), the stereo-
chemistry for 400a has been assigned as racemic (vide infra).
nacyl sulfides and further cyclization, not only the diastereomeric
diol but also the isomeric oxathianes were obtained in nearly equal
amounts. The optimized reaction condition is applied to a number
of substituted systems and the results are given in Table 2.
Table 2
Synthesis and yield of oxathianes 50 and 500
Entry
Ar
Overall yielda (%)
Yielda (%)
50
500
Fig. 5. NMR chemical shifts for 400a.
a
b
c
d
e
f
C6H5
87
82
85
91
90
86
89
85
53
51
57
50
54
53
49
52
47
49
43
50
46
47
51
48
4-MeC6H4
4-OMeC6H4
4-ClC6H4
4-BrC6H4
4-PhC6H4
1-Naphthyl
2-Naphthyl
The diastereomeric diol 400a on cyclization resulted in exclu-
sively one isomer of oxathiane (Scheme 2). This indicates that from
the diastereoisomeric mixture of diols on cyclization each isomeric
oxathiane is exclusively formed from corresponding isomer of diol.
g
h
a
Yield as per NMR spectra of mixture.
The structure of oxathianes was confirmed by NMR and mass
analysis. In the case of 50e, the 1H NMR spectrum suggests that the
molecule seems to be in the rigid chair conformation with the
phenyl groups occupying equatorial positions (Fig. 3).
Scheme 2. Stereospecific formation of oxathiane 500a from diol 400a.

N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
6895
In an attempt to apply the cyclization procedure for the
construction of a relatively more complex systems, the sulfide
The presence of a mirror plane in 110 is very much realized from the
crystal structure and hence this is the meso form (Fig. 7). The other
form 1100 lacks any symmetry element and obviously is racemic
(Fig. 8).
from
a-tetralone has been prepared. This ketone 9 is diaster-
eomerically pure and the reduction with sodium borohydride
yielded a mixture of diols 10 (Scheme 3). This mixture has been
found to contain two diastereomeric diols from the crude NMR
spectrum in 1:1 ratio. The reaction seems to be partially dia-
stereoselective, because the diol has four stereocenters and more
diastereomers are expected. Attempts to separate the two diols
failed, though one of the diastereomer (1000) could be obtained in
pure form.
Fig. 7. ORTEP diagram for 110.
Scheme 3. Preparation of diol from a-tetralone.
In the 1H NMR spectrum of the diol 1000, the hydrogen geminal to
hydroxyl appears as a triplet with a coupling constant of 3.9 Hz.
There seems to be a coupling between this hydrogen and the hy-
droxyl hydrogen. The stereochemistry arrived from the X-ray
crystal structure27 of 1000 suggests the diol to be racemic (Fig. 6).
The diastereomeric mixture of diols was treated with (ꢀ)-CSA
in DMF and the cyclization has been effected. The NMR spectrum
of the crude product mixture indicates the formation of two iso-
meric fused oxathianes 110 and 1100 in almost equal amount
(Scheme 4). Obviously there is no equilibration during the re-
action. Compounds 110 and 1100 have been successfully separated
and individually characterized. From the X-ray crystal data27 the
structures of 110 and 1100 have been unambiguously assigned as
shown in Scheme 4.
Fig. 8. ORTEP diagram for 1100.
The pure diol 1000 upon cyclization under the same condition
yielded 1100 alone (Scheme 5), supporting the fact that there is no
equilibration during the reaction. There is a severe 1,3 diaxial in-
teraction in 110 and this is expected to be thermodynamically less
stable compared to 1100. As the product ratio is 1:1, it is very clear
that the diol 1000 does not have any other option during cyclization
except to yield 1100, as there is no epimerization possible during the
cyclization.
Fig. 6. ORTEP diagram for 1000.
The oxathiane ring is in the perfect chair form in both 110 and
1100. The hydrogens at ring junction in 110 are all cis to each other. In
the case of 1100 the ring fusion of the cyclohexene with the oxa-
thiane ring is cis, though between the ring junctions they are trans.
Scheme 5. Stereospecific formation of oxathiane.
Scheme 4. Synthesis of fused oxathianes.

6896
N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
The 1H spectra of 110 and 1100 are almost similar and the notable
from the preferential formation of one of the diol on reduction of
diphenacyl aniline 6.
point is the coupling between the ring junction hydrogens. In the
case of 110 it is 2.1 Hz and in 1100 it is 3.3 Hz though they are cis to
each other in both cases. The structure of fused oxathianes is also
confirmed from crystal analysis27 (Figs. 7 and 8).
In order to synthesize morpholines, the diols 7 were prepared
from 1,5-diketone, diphenacyl aniline 6. Sodium borohydride re-
duction of ketones 6 leads to a mixture of diols 70 and 700. It was not
possible to separate these diols in all cases. However in one case,
these two diastereomers have been successfully separated. It is
found that 70 is the major product in all the cases.
The structure of morpholine 80c was confirmed by NMR (Fig. 10)
and mass analysis. The molecule seems to be in the rigid chair con-
formationwiththephenylgroupsoccupyingtheequatorialpositions.
In the case of 800c (Fig. 11), the 1H NMR spectrum suggests the
trans configuration with respect to C-2 and C-6 substituents and it
may not have a rigid arrangement. Possibly a chair form with fast
flipping is suggested for this compound (Fig. 11).
The structure of the compound was further confirmed by single
crystal analysis for compound27 800c (Fig. 12).
The diastereomeric selectivity can be explained from the pos-
sibility of intramolecular hydrogen bonding between the hydroxyl
groups in the stable conformation, which is depicted in the New-
man projection (Fig. 9). The vicinal coupling constant between
hydrogens Ha and Hb in 70b is very poor with no observable cou-
pling because of their geminal hetero atoms and a dihedral angle
closer to 90ꢁ.
Attempts to prepare the diol 1,5-dihydroxy-2,4-dimethyl-1,5-
diphenylpentan-3-one for a related study always ended up with
either 13 or 14. In a separate experiment, pyranone 13, prepared
from 3-pentanone 12 by a known procedure,28 was treated with
concd sulfuric acid in toluene (Scheme 7). The NMR spectral and
crystal analyses27 (Fig. 13) of the products indicate a reduction in
the ring size forming isomeric cyclopentenones. The reaction
Fig. 9. Newman projection and NMR chemical shifts for diols 70b and 700b.
The diols, as a mixture, were then subjected to cyclization under
different conditions. As a representative case, 7a is screened against
different acids in a range of solvents and the results are given in
Table 3. It was observed that polyphosphoric acid in toluene gave
the desired morpholines in high yield and is found to be better than
the Mitsunobu reaction conditions (Table 3, entries 11 and 12). The
generality of the reaction has been tested with a range of differently
substituted 7 and the results are given in Table 4.
would have gone following the Nazarov reaction route.29
As expected, it can be seen from Table 5 that the trans isomer of
cyclopentenone has beenpredominantly formed over the cis isomer.
The crystal structure27 of pyranone 13b exhibits a chair form
where all the methyl and aryl substituents are equatorially oriented
(Fig. 14).
3. Conclusions
Table 3
In conclusion, a highly efficient method for the preparation of
oxathiane and morpholine has been described. This protocol is
better than other methods, including the Mitsunobu procedure,
resulting in improved yields of the six-membered compounds with
minimum waste.
Screening of reaction condition for 7a
No
Reaction condition
Time (h)
Temp (ꢁC)
Yielda (%)
db
1
2
3
4
5
6
7
8
p-TsOH, DMF
3
80
110
65
95
75
75
100
75
p-TsOH, Toluene
p-TsOH, dioxane
H2SO4, toluene
(ꢀ)-CSA, DMF
(ꢀ)-CSA, toluene
(ꢀ)-CSA, DMSO
PPA, DMF
2.3
2.5
5
1.4
1.5
1.5
2
d
d
Trace
d
4. Experimental section
4.1. General
d
d
22
9
PPA, toluene
PPA, xylene
TPP, DEAD, THF
TPP, DEAD, toluene
1.5
1.5
6
80
140
40
85
All melting points reported in this work were measured in open
capillaries. The 1H and 13C NMR spectra have been measured at 300
and 75 MHz, respectively, using Bruker 300 MHz (Avance) in-
strument in CDCl3 using tetramethylsilane (TMS) as internal stan-
10
11
12
74
57c
51c
6.5
40
a
Yield as per NMR spectra of mixture.
Unseparable viscous mass.
Mitsunobu reaction condition.
b
c
dard. Chemical shifts are reported as
d values (ppm). All one- and
two-dimensional NMR spectra were obtained using standard
Bruker software throughout. Elemental analyses were performed
on a Perkin Elmer 2400 Series II Elemental CHNS analyzer.
The yield of 80 and 800 reflects the original yield of 70 and 700 in the
crude mixture of diols. This clearly shows that there is no equili-
bration or change in configuration in the original chiral centers. This
fact is again confirmed by carrying out the cyclization in the sepa-
rated diols 70b and 700b. In each case onlyone of isomeric morpholine
has been obtained with no trace of the other (Scheme 6).
4.2. General procedure for the preparation of 2,20-thiobis(1-
arylethanol) (4)
To a stirring solution of diphenacyl sulphide (1.0 mol) in
methanol, sodium borohydride (2.2 mol) was added in portions.
After the completion of the reaction, the reaction mixture was
The observed yield of morpholines indicates that one of the
diastereoisomer is formed in more amount, which can be attributed

N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
6897
Table 4
Synthesis and yield of morpholines 80 and 800
No
X
Y
Overall yielda (%)
85
79
83
80
89
82
87
83
88
Yielda (%)
80
800
a
b
c
d
e
f
g
h
i
H
H
H
H
Me
Me
Cl
Cl
Cl
H
99
86
89
99
90
92
99
99
89
Trace
14
11
Trace
10
8
Trace
Trace
11
Me
OMe
F
Me
OMe
Me
OMe
F
a
Yield as per NMR spectra of mixture.
Scheme 6. Stereospecific formation of morpholines from corresponding diols.
poured onto crushed ice and filtered off. The product was recrys-
tallized from methanol to get a diastereomeric mixture of 2-[(2-
hydroxy-2-arylethyl)sulfanyl]-1-aryl-1-ethanol 4 in good yield.
4.2.1. rac-2-[(2-Hydroxy-2-phenylethyl)sulfanyl]-1-phenyl-1-
ethanol (400a). Colorless crystals; mp 138.0 ꢁC, 1H NMR (300 MHz,
CDCl3)dH:2.36(brs,2H, OH),2.78(dd, 2H, J¼14.1, 9.0 Hz), 2.92(dd,2H,
J¼14.1, 3.3 Hz), 4.76 (dd, 2H, J¼9.0, 3.3 Hz), 7.07e7.53 (m,10H, AreH);
Fig. 10. NMR chemical shifts for 80c.
Fig. 11. Flipping forms of 800c.
Fig. 12. ORTEP diagram for compound 800c.

6898
N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
Scheme 7. Pyranone to cyclopentenones.
separated, which was filtered and purified and separated by column
chromatography using silica gel (60e120 mesh) to give 50 and 500.
4.3.1. cis-2,6-Diphenyl-1,4-oxathiane (50a). Colorless crystals;21 mp
75.1 ꢁC, 1H NMR (300 MHz, CDCl3): dH: 2.55 (dd, 2H, J¼12.9, 1.5 Hz),
2.84 (dd, 2H, J¼12.9, 10.8 Hz), 4.85 (dd, 2H, J¼10.8, 1.5 Hz),
7.22e7.41 (m, 10H); 13C NMR (75 MHz, CDCl3) dC: 32.7, 80.9, 125.5,
127.6, 128.3, 141.9. Anal. Calcd for C16H16OS: C, 74.96; H, 6.29. Found
C, 74.93; H, 6.27%.
4.3.2. trans-2,6-Diphenyl-1,4-oxathiane (500a). Colorless block like
crystals;21 mp 101.2 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.98 (dd, 2H,
J¼13.8, 3.3 Hz), 3.07 (dd, 2H, J¼13.8, 6.0 Hz), 5.07 (dd, 2H, J¼6.0,
3.3 Hz), 7.27e7.44 (m,10H); 13C NMR (75 MHz, CDCl3) dC: 29.9, 72.4,
126.7, 127.6, 128.5, 140.2. Anal. Calcd for C16H16OS: C, 74.96; H, 6.29.
Found C, 74.93; H, 6.25%.
Fig. 13. ORTEP diagram for 140a.
4.3.3. cis-2,6-Di(4-methylphenyl)-1,4-oxathiane (50b). Colorless crys-
tals; mp 79.0 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.33 (s, 6H, 2CH3),
2.55 (d, 2H, J¼12.9 Hz), 2.85 (dd, 2H, J¼12.9, 10.8 Hz), 4.84 (d, 2H,
J¼10.8 Hz), 7.15 (d, 4H, J¼7.8 Hz), 7.30 (d, 4H, J¼7.8 Hz); 13C NMR
(75 MHz, CDCl3) dC: 21.1, 32.7, 80.9, 125.6, 129.0, 137.4, 139.2. Anal.
Calcd for C18H20OS: C, 76.01; H, 7.09. Found C, 75.99; H, 7.06%.
Table 5
Yields of cyclopentenones 14
No
Ar
Overall yield (%)
Yielda (%)
140 (trans)
1400 (cis)
a
b
C6H5
4-ClC6H4
69
76
83
86
17
14
4.3.4. trans-2,6-Di(4-methylphenyl)-1,4-oxathiane (500b). Colorless crys-
tals; mp 109.0 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.34 (s, 6H, 2CH3), 2.93
(dd, 2H, J¼13.8, 3.3 Hz), 3.02 (dd, 2H, J¼13.8, 6.3 Hz), 5.03 (dd, 2H, J¼6.3,
3.3 Hz), 7.17 (d, 4H, J¼7.8 Hz), 7.29 (d, 4H, J¼7.8 Hz); 13C NMR (75 MHz,
CDCl3) dC: 21.0, 30.0, 72.1, 126.6, 129.1, 137.2, 137.3. Anal. Calcd for
C18H20OS: C, 76.01; H, 7.09. Found C, 75.98; H, 7.04%.
a
Yield as per NMR spectra of mixture.
4.3.5. cis-2,6-Di(4-methoxyphenyl)-1,4-oxathiane (50c). Colorless crys-
tals;21 mp 79.0 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.53 (d, 2H,
J¼12.9 Hz), 2.85 (dd, 2H, J¼12.9, 10.8 Hz), 3.79 (s, 6H, 2CH3), 4.82 (d,
2H, J¼10.8 Hz), 6.87 (d, 4H, J¼8.7 Hz), 7.32 (d, 4H, J¼8.7 Hz); 13C
NMR (75 MHz, CDCl3) dC: 32.7, 55.2, 80.7, 113.7, 126.9, 134.4, 159.1.
Anal. Calcd for C18H20O3S: C, 68.33; H, 6.37. Found C, 68.31; H, 6.34%.
4.3.6. trans-2,6-Di(4-methoxyphenyl)-1,4-oxathiane (500c). Colorless
crystals;21 mp 109 ꢁC, 1H NMR (300 MHz, CDCl3) dC: 2.94e3.03 (m,
4H); 3.80 (s, 6H, 2OMe), 4.98e5.01 (m, 2H), 6.89 (d, 4H, J¼8.7 Hz),
7.33 (d, 4H, J¼8.7 Hz); 13C NMR (75 MHz, CDCl3) dH: 29.9, 55.2, 71.8,
113.8, 128.0, 132.4, 158.9. Anal. Calcd for C18H20O3S: C, 68.33; H,
6.37. Found C, 68.30; H, 6.33%.
Fig. 14. ORTEP diagram for compound 13b.
13C NMR (75 MHz, CDCl3) dC: 42.2, 73.2,125.7,127.9,128.5,142.5. Anal.
4.3.7. cis-2,6-Di(4-chlorophenyl)-1,4-oxathiane (50d). Colorless crys-
tals;21 mp 114.2 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.53 (d, 2H,
J¼13.5 Hz), 2.80 (dd, 2H, J¼13.5, 10.8 Hz), 4.83 (d, 2H, J¼10.8 Hz),
7.26e7.38 (m, 8H); 13C NMR (75 MHz, CDCl3) dC: 32.6, 80.3, 127.0,
128.6, 133.5, 140.2. Anal. Calcd for C16H14Cl2OS: C, 59.08; H, 4.34.
Found C, 59.05; H, 4.30%.
Calcd for C16H18O2S: C, 70.04; H, 6.61. Found C, 70.00; H, 6.58%.
4.3. General procedure for the preparation of 2,6-diaryl
substituted 1,4-oxathiane (5)
2-[(2-Hydroxy-2-arylethyl)sulfanyl]-1-aryl-1-ethanol
4
was
taken in 8 ml of DMF and to the mixture, a pinch of p-toluene sul-
phonic acid was added. The mixture was refluxed on a mantle for 2 h
and then cooled. Upon pouring the mixture into water, solid
4.3.8. trans-2,6-Di(4-chlorophenyl)-1,4-oxathiane (500d). Colorless crys-
tals;21 mp 115 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.96e2.98 (m, 4H),

N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
6899
4.99 (t, 2H, J¼4.5 Hz) 7.30e7.36 (m, 8H); 13C NMR (75 MHz, CDCl3) dC
:
128.3, 132.8, 133.2, 137.6. Anal. Calcd for C24H20OS: C, 80.86; H, 5.65.
Found C, 80.83; H, 5.62%.
29.9, 71.8, 128.2, 128.7, 133.4, 138.5. Anal. Calcd for C16H14Cl2OS: C,
59.08; H, 4.34. Found C, 59.04; H, 4.31%.
4.3.17. meso-2-[(2-Hydroxy-2-phenylethyl)-4-methylanilino]-1-
phenyl-1-ethanol (70b). Colorless crystals; mp 63.4 ꢁC, 1H NMR
(300 MHz, CDCl3) dH: 2.31 (s, 3H, CH3), 3.30 (dd, 2H, J¼15.3, 9.6 Hz),
3.76 (d, 2H, J¼15.3 Hz), 4.57 (br s, 2H, OH), 5.06 (d, 2H, J¼9.6 Hz), 6.76
(d, 2H, J¼7.8 Hz, AreH), 7.14 (d, 2H, J¼7.8 Hz, AreH), 7.30e7.42 (m,
10H, AreH); 13C NMR (75 MHz, CDCl3) dC: 20.2, 63.2, 72.6,113.1,125.8,
126.8, 127.9, 128.6, 130.0, 141.9, 145.7. Anal. Calcd for C23H25NO2: C,
79.51; H, 7.25, N, 4.03. Found C, 79.48; H, 7.20; N, 4.00%.
4.3.9. cis-2,6-Di(4-bromophenyl)-1,4-oxathiane (50e). Colorless crys-
tals; mp 142.0 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.54 (d, 2H,
J¼14.1 Hz), 2.80 (dd, 2H, J¼14.1, 10.8 Hz), 4.82 (d, 2H, J¼10.8 Hz), 7.27
(d, 4H, J¼8.4 Hz), 7.47 (d, 4H, J¼8.4 Hz); 13C NMR (75 MHz, CDCl3) dC
:
32.5, 80.4, 121.7, 127.3, 131.6, 140.7. Anal. Calcd for C16H14Br2OS: C,
46.40; H, 3.41. Found C, 46.36; H, 3.37%.
4.3.10. trans-2,6-Di(4-bromophenyl)-1,4-oxathiane (500e). Colorless
crystals; mp 123.5 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.93e2.95 (m,
4H), 4.95 (t, 2H, J¼4.5 Hz), 7.23 (d, 4H, J¼8.7 Hz, AreH), 7.47 (d, 4H,
J¼8.7 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 29.8, 71.7, 121.5,
128.4, 131.5, 138.9. Anal. Calcd for C16H14Br2OS: C, 46.40; H, 3.41.
Found C, 46.37; H, 3.37%.
4.3.18. rac-2-[(2-Hydroxy-2-phenylethyl)-4-methylanilino]-1-
phenyl-1-ethanol (700b). Colorless crystals; mp 57.7 ꢁC, 1H NMR
(300 MHz, CDCl3) dH: 1.8 (br s, 2H, OH), 2.28 (s, 3H, CH3), 3.42 (dd,
2H, J¼14.7, 9.6 Hz), 3.56 (dd, 2H, J¼14.7, 3.3 Hz), 5.01 (dd, 2H, J¼9.6,
3.3 Hz), 6.87 (d, 2H, J¼8.7 Hz, AreH), 7.09 (d, 2H, J¼8.7 Hz, AreH),
7.29e7.44 (m, 10H, AreH); 13C NMR (75 MHz, CDCl3) dC: 20.3, 60.9,
71.3, 115.3, 125.9, 127.8, 128.6, 129.8, 130.0, 142.0, 146.4. Anal. Calcd
for C23H25NO2: C, 79.51; H, 7.25, N, 4.03. Found C, 79.47; H, 7.21; N,
3.99%.
4.3.11. cis-2,6-Di(biphenyl-4-yl)-1,4-oxathiane (50f). Colorless crys-
tals; mp 201.0 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.65 (d, 2H,
J¼13.2 Hz), 2.95 (dd, 2H, J¼13.2, 10.8 Hz), 4.96 (d, 2H, J¼10.5 Hz),
7.34 (t, 2H, J¼7.5 Hz, AreH), 7.44 (t, 4H, J¼7.5 Hz, AreH), 7.51 (d, 4H,
J¼8.1 Hz, AreH), 7.57e7.61 (m, 8H, AreH); 13C NMR (75 MHz,
CDCl3) dC: 32.7, 80.9, 126.2 (2C), 127.1, 127.2, 127.3, 128.8, 140.8,
140.9. Calcd for MS (m/z): 426.1 [Mþ18]; Found 426.0 [Mþ18]. Anal.
Calcd for C28H24OS: C, 82.31; H, 5.92. Found C, 82.28; H, 5.89%.
4.3.19. rac-2-[(1-Hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)sul-
fanyl]-1,2,3,4-tetrahydro-1-naphthalenol (1000). Monoclinic crystals;
mp 189.0 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.00e2.09 (m, 2H),
2.14e2.27 (m, 2H), 2.82e2.93 (m, 4H), 3.04 (dt, 2H, J¼16.5, 5.4 Hz),
3.41 (dt, 2H, J¼10.5, 3.0 Hz), 4.79 (t, 2H, J¼3.9 Hz), 7.12e7.14 (m, 2H,
AreH), 7.19e7.26 (m, 4H, AreH), 7.40e7.43 (m, 2H, AreH); 13C NMR
(75 MHz, CDCl3) dC: 25.1, 28.2, 47.9, 68.5, 126.3, 128.2, 128.8, 129.6,
135.6, 136.5. Anal. Calcd for C20H22O2S: C, 73.58; H, 6.79. Found C,
73.54; H, 6.76%.
4.3.12. trans-2,6-Di(biphenyl-4-yl)-1,4-oxathiane (500f). Colorless crys-
tals; mp 113.1 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 3.04 (dd, 2H, J¼13.8,
3.3 Hz), 3.12 (dd, 2H, J¼13.8, 6.0 Hz), 5.16 (dd, 2H, J¼6.0, 3.3 Hz), 7.34
(t, 2H, J¼7.2 Hz, AreH), 7.44 (t, 4H, J¼7.2 Hz, AreH), 7.51 (d, 4H,
J¼8.1 Hz, AreH), 7.59e7.63 (m, 8H, AreH); 13C NMR (75 MHz, CDCl3)
dC: 30.0, 72.3, 127.1, 127.2, 127.3 (2C), 128.8, 139.2, 140.6, 140.7. Anal.
Calcd for C28H24OS: C, 82.31; H, 5.92. Found C, 82.30; H, 5.89%.
4.3.20. meso-5,6,6a,7a,8,9,13b,14a-Octahydrodibenzo[c,h]phenoxa
thiine (110). Monoclinic crystals; mp 158.0 ꢁC, 1H NMR (300 MHz,
CDCl3) dH: 2.10e2.16 (m, 2H), 2.35e2.49 (m, 2H), 2.69 (dt, 2H,
J¼13.5, 2.1 Hz), 2.76e2.85 (m, 4H), 4.95 (d, 2H, J¼2.1 Hz), 7.43 (d,
2H, J¼8.4 Hz, AreH), 7.13e7.23 (m, 4H, AreH), 7.36e7.39 (m, 2H,
AreH); 13C NMR (75 MHz, CDCl3) dC: 29.9, 30.5, 36.3, 77.9, 126.2,
128.2, 128.6, 130.9, 136.1, 136.3. Anal. Calcd for C20H20OS: C, 77.88;
H, 6.54. Found C, 77.84; H, 6.49%.
4.3.13. cis-2,6-Di(1-naphthyl)-1,4-oxathiane (50g). Colorless crys-
tals; mp 167 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.88 (d, 2H,
J¼14.1 Hz), 3.09 (dd, 2H, J¼14.1, 11.1 Hz), 5.76 (d, 2H, J¼11.1 Hz),
7.44e7.55 (m, 6H, AreH), 7.76e7.86 (m, 6H, AreH), 7.10 (d, 2H,
J¼8.4 Hz); 13C NMR (75 MHz, CDCl3) dC: 32.8, 79.2, 122.8, 123.2,
125.5, 125.6, 126.2, 128.2, 128.9, 129.7, 133.6, 137.6. Anal. Calcd for
C24H20OS: C, 80.86; H, 5.65. Found C, 80.82; H, 5.61%.
4.3.21. rac-5,6,6a,7a,8,9,13b,14a-Octahydrodibenzo[c,h]phenoxa
thiine (1100). Orthorhombic crystals; mp 176.0 ꢁC, 1H NMR
(300 MHz, CDCl3) dH: 2.03e2.12 (m, 2H), 2.35e2.46 (m, 2H), 2.74 (dt,
2H, J¼16.5, 6.3 Hz), 3.05 (dt, 2H, J¼16.5, 6.3 Hz), 3.21e3.24 (m, 2H),
4.93 (d, 2H, J¼3.3 Hz), 7.14 (d, 2H, J¼7.2 Hz, AreH), 7.19e7.34 (m, 4H,
4.3.14. trans-2,6-Di(1-naphthyl)-1,4-oxathiane (500g). Colorless crys-
tals; mp 191 ꢁC, 1H NMR (300 MHz, CDCl3) dC: 3.22e3.35 (m, 4H),
5.74 (t, 2H, J¼4.5 Hz), 7.20 (t, 2H, J¼7.2 Hz, AreH), 7.35 (t, 2H,
J¼7.2 Hz, AreH), 7.50 (t, 2H, J¼7.8 Hz, AreH), 7.77e7.86 (m, 6H),
7.99 (d, 2H, J¼7.2 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 30.1,
69.9, 123.9, 124.9, 125.0, 125.4, 125.9, 128.5, 128.6, 131.3, 133.7,
135.7. Anal. Calcd for C24H20OS: C, 80.86; H, 5.65. Found C, 80.83;
H, 5.62%.
AreH), 7.59 (d, 2H, J¼7.2 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC
:
25.5, 27.2, 34.1, 70.3,126.3,127.7,128.7,128.9,135.2,136.6. Anal. Calcd
for C20H20OS: C, 77.88; H, 6.54. Found C, 77.85; H, 6.50%.
4.4. General procedure for the preparation of 2,4,6-
triarylmorpholine (8)
4.3.15. cis-2,6-Di(2-naphthyl)-1,4-oxathiane (50h). Colorless crys-
tals; mp 94.1 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 2.70 (d, 2H,
J¼13.8 Hz), 3.01 (dd, 2H, J¼13.8, 10.8 Hz), 5.11 (d, 2H, J¼10.8 Hz),
7.43e7.50 (m, 4H, AreH), 7.55e7.59 (m, 2H, AreH), 7.81e7.91 (m,
8H, AreH); 13C NMR (75 MHz, CDCl3) dC: 32.7, 81.2, 123.8, 124.5,
125.9, 126.1, 127.6, 128.0, 128.2, 132.9, 133.2, 139.3. Calcd for MS (m/
z): 374.1 [Mþ18]; Found 374.1 [Mþ18]. Anal. Calcd for C24H20OS: C,
80.86; H, 5.65. Found C, 80.82; H, 5.60%.
To a stirring solution of diphenacyl aniline (6) (1.0 mol) in
methanol, sodium borohydride (2.2 mol) was added in portions.
After the completion of the reaction, the reaction mixture was
poured onto crushed ice and filtered off. The product was recrys-
tallized from methanol to get a diastereomeric mixture of 2-[(2-
hydroxy-2-arylethyl)anilino]-1-aryl-1-ethanol 7 in good yield. To
2-[(2-hydroxy-2-arylethyl)anilino]-1-aryl-1-ethanol
7 taken in
4.3.16. trans-2,6-Di(2-naphthyl)-1,4-oxathiane (500h). Colorless crys-
tals; mp 114.8 ꢁC, 1H NMR (300 MHz, CDCl3) dH: 3.06 (dd, 2H, J¼13.8,
3.0 Hz), 3.17 (dd, 2H, J¼13.8, 6.6 Hz), 5.23 (dd, 2H, J¼6.6, 3.0 Hz),
7.44e7.53 (m, 6H, AreH), 7.79e7.88 (m, 8H, AreH); 13C NMR
(75 MHz, CDCl3) dC: 30.0, 72.6, 124.8, 125.7, 126.0, 126.1, 127.6, 128.1,
10 ml of toluene, a drop of polyphosphoric acid was added. The
mixture was refluxed on mantle for 2 h and then cooled. Upon
pouring the mixture into water, solid separated, which was filtered
and purified and separated through column chromatography using
(60e120 mesh) silica gel.

6900
N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
4.4.1. cis-2,4,6-Triphenylmorpholine (80a). Isolated as colorless
crystal; mp 142 ꢁC; 1H NMR (300 MHz, CDCl3) dH: 2.76 (t, 2H,
J¼10.2 Hz), 3.69 (d, 2H, J¼10.2 Hz), 4.86 (d, 2H, J¼10.2 Hz),
6.82e6.93 (m, 3H, AreH), 7.20e7.37 (m, 8H, AreH), 7.46e7.49 (m,
4H, AreH); 13C NMR (75 MHz, CDCl3) dC: 55.6, 78.0, 116.0, 120.1,
126.2, 127.9, 128.3, 129.1, 139.9, 150.6. Anal. Calcd for C22H21NO: C,
83.78; H, 6.71; N, 4.44%. Found C, 83.74; H, 6.68; N, 4.41%.
CDCl3) dH: 2.69 (t, 2H, J¼11.7 Hz), 3.54 (d, 2H, J¼11.7 Hz), 3.76 (s, 3H,
OCH3), 4.89 (d, 2H, J¼11.7 Hz), 6.84 (d, 2H, J¼9.0 Hz, AreH), 6.92 (d,
2H, J¼9.0 Hz, AreH), 7.32e7.46 (m, 8H, AreH); 13C NMR (75 MHz,
CDCl3) dC: 55.5, 57.2, 77.7, 114.6, 118.5, 127.6, 128.6, 133.7, 138.3,
144.7, 156.0. Anal. Calcd for C23H21Cl2NO2: C, 66.67; H, 5.11; N,
3.38%. Found C, 66.63; H, 5.08; N, 3.35%.
4.4.9. cis-2,6-Di(4-chlorophenyl)-4-(4-fluorophenyl)morpholine
(80i). Isolated as colorless crystal; mp 178 ꢁC. 1H NMR (300 MHz,
CDCl3) dH: 2.71 (t, 2H, J¼10.8 Hz), 3.57 (d, 2H, J¼10.8 Hz), 4.88 (d,
2H, J¼10.8 Hz), 6.87e6.99 (m, 4H, AreH), 7.28e7.52 (m, 8H, AreH);
13C NMR (75 MHz, CDCl3) dC: 56.6, 77.5, 115.5, 118.2, 128.3, 128.6,
133.2, 138.2, 147.2, 157.3. Anal. Calcd for C22H18Cl2FNO: C, 65.68; H,
4.51; N, 3.48%. Found C, 65.65; H, 4.47; N, 3.44%.
4.4.2. cis-4-(4-Methylphenyl)-2,6-diphenylmorpholine
(80b). Isolated as colorless crystal; mp 117 ꢁC; 1H NMR (300 MHz,
CDCl3) dH: 2.24 (s, 3H, CH3), 2.75 (t, 2H, J¼10.8 Hz), 3.65 (d, 2H,
J¼10.8 Hz), 4.90 (d, 2H, J¼10.8 Hz), 6.84 (d, 2H, J¼8.7 Hz, AreH), 7.05
(d, 2H, J¼8.4 Hz, AreH), 7.27e7.39 (m, 6H, AreH), 7.49 (d, 4H,
J¼8.4 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 20.4, 56.3, 78.2,116.4,
126.3,127.9,128.3,129.6,129.7,140.0,148.6. Anal. CalcdforC23H23NO:
C, 83.85; H, 7.04; N, 4.25%. Found C, 83.82; H, 7.01; N, 4.22%.
4.4.10. trans-4-(4-Methylphenyl)-2,6-diphenylmorpholine
(800b). Isolated as colorless crystal; mp 122 ꢁC; 1H NMR (300 MHz,
CDCl3) dH: 2.13 (s, 3H, CH3), 3.26 (dd, 2H, J¼12.3, 3.6 Hz), 3.34 (dd,
2H, J¼12.3, 6.0 Hz), 4.84 (dd, 2H, J¼6.0, 3.6 Hz), 6.90 (d, 2H,
J¼8.1 Hz, AreH), 7.11 (d, 2H, J¼8.1 Hz, AreH), 7.26e7.38 (m, 6H,
4.4.3. cis-4-(4-Methoxyphenyl)-2,6-diphenylmorpholine
(80c). Isolated as colorless crystal; mp 161 ꢁC; 1H NMR (300 MHz,
CDCl3) dH: 3.38 (dd, 2H, J¼11.7, 3.9 Hz), 3.46 (dd, 2H, J¼11.7, 5.7 Hz),
3.77 (s, 3H, OCH3), 4.99 (dd, 2H, J¼5.7, 3.9 Hz), 6.87 (d, 2H, J¼9.0 Hz,
AreH), 6.97 (d, 2H, J¼9.0 Hz, AreH), 7.27e7.40 (m, 6H, AreH), 7.52 (d,
4H, J¼7.2 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 54.2, 55.5, 72.4,
114.5, 118.0, 127.2, 127.7, 128.4, 139.9, 145.3, 154.0. Anal. Calcd for
C23H23NO2: C, 79.97; H, 6.71; N, 4.05%. Found C, 79.94; H, 6.67; N, 4.01%.
AreH), 7.51 (d, 4H, J¼7.5 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC
:
20.5, 53.1, 72.4, 115.9, 125.2, 127.9, 128.0, 128.1, 128.3, 128.5, 129.5.
Anal. Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25%. Found C,
83.81; H, 7.00; N, 4.21%.
4.4.11. trans-4-(4-Methoxyphenyl)-2,6-diphenylmorpholine
(800c). Orthorhombic crystal; mp 134 ꢁC; 1H NMR (300 MHz, CDCl3)
dH: 2.74 (t, 2H, J¼11.4 Hz), 3.58 (d, 2H, J¼11.4 Hz), 3.73 (s, 3H, OCH3),
4.93 (d, 2H, J¼11.4 Hz), 6.82 (d, 2H, J¼9.0 Hz, AreH), 6.91 (d, 2H,
J¼9.0 Hz, AreH), 7.28e7.40 (m, 6H, AreH), 7.51 (d, 4H, J¼7.2 Hz,
AreH); 13C NMR (75 MHz, CDCl3) dC: 55.4, 57.2, 78.2, 114.5, 118.3,
126.3, 127.9, 128.3, 140.0, 145.0, 154.1. Anal. Calcd for C23H23NO2: C,
79.97; H, 6.71; N, 4.05%. Found C, 79.95; H, 6.68; N, 4.02%.
4.4.4. cis-4-(4-Fluorophenyl)-2,6-diphenylmorpholine
(80d). Isolated as colorless crystal; mp 188 ꢁC; 1H NMR (300 MHz,
CDCl3) dH: 2.75 (t, 2H, J¼11.4 Hz), 3.60 (d, 2H, J¼11.4 Hz), 4.91 (d, 2H,
J¼11.4 Hz), 6.85e6.89 (m, 2H, AreH), 6.93 (d, 2H, J¼8.4 Hz, AreH),
7.28e7.40 (m, 6H, AreH), 7.50 (d, 4H, J¼7.5 Hz, AreH); 13C NMR
(75 MHz, CDCl3) dC: 53.2, 78.2, 115.7, 127.3, 127.4, 127.8, 128.1, 140.2,
145.5, 158.2. Anal. Calcd for C22H20FNO: C, 79.26; H, 6.05; N, 4.20%.
Found C, 79.23; H, 6.02; N, 4.17%.
4.4.12. trans-4-(4-Fluorophenyl)-2,6-diphenylmorpholine
(800d). Isolated as colorless crystal; mp 165 ꢁC. 1H NMR (300 MHz,
CDCl3) dH: 3.37 (dd, 2H, J¼12.0, 3.6 Hz), 3.45 (dd, 2H, J¼12.0,
6.0 Hz), 4.99 (dd, 2H, J¼6.0, 3.6 Hz), 6.81e7.00 (m, 4H, AreH),
7.23e7.38 (m, 6H, AreH), 7.49 (d, 4H, J¼6.9 Hz, AreH); 13C NMR
(75 MHz, CDCl3) dC: 53.7, 72.3, 115.5, 127.1, 127.2, 127.7, 128.3, 139.7,
147.6, 157.4. Anal. Calcd for C22H20FNO: C, 79.26; H, 6.05; N, 4.20%.
Found C, 79.22; H, 6.01; N, 4.17%.
4.4.5. cis-2,4,6-Tri(4-methylphenyl)morpholine (80e). Isolated as
colorlesscrystal;mp175 ꢁC;1HNMR (300 MHz, CDCl3)dH:2.17(s, 3H,
CH3), 2.26 (s, 6H, CH3), 2.66 (t, 2H, J¼11.7 Hz), 3.56 (d, 2H, J¼11.7 Hz),
4.78 (d, 2H, J¼11.7 Hz), 6.77 (d, 2H, J¼8.1 Hz, AreH), 6.98 (d, 2H,
J¼8.1 Hz, AreH), 7.09 (d, 4H, J¼8.1 Hz, AreH), 7.31 (d, 4H, J¼8.1 Hz,
AreH); 13C NMR (75 MHz, CDCl3) dC: 20.4, 21.2, 56.4, 78.0, 116.3,
126.3,129.0,129.6,129.7,137.1,137.5,148.6. Anal. Calcd for C25H27NO:
C, 83.99; H, 7.61; N, 3.92%. Found C, 83.98; H, 7.59; N, 3.89%.
4.4.13. trans-2,4,6-Tri(4-methylphenyl)morpholine (800e). Isolated as
colorless crystal; mp 110 ꢁC; 1H NMR (300 MHz, CDCl3) dH: 2.23 (s,
3H, CH3), 2.34 (s, 6H, CH3), 3.41 (dd, 2H, J¼12.0, 3.6 Hz), 3.49 (dd,
2H, J¼12.0, 6.0 Hz), 4.96 (dd, 2H, J¼6.0, 3.6 Hz), 6.51 (d, 2H,
J¼8.4 Hz, AreH), 6.90 (d, 2H, J¼8.4 Hz, AreH), 7.16 (d, 4H, J¼7.8 Hz,
4.4.6. cis-4-(4-Methoxyphenyl)-2,6-di(4-methylphenyl) morpholine
(80f). Isolated as colorless crystal; mp 185 ꢁC. 1H NMR (300 MHz,
CDCl3) dH: 2.34 (s, 6H, CH3), 2.72 (t, 2H, J¼10.8 Hz), 3.55 (d, 2H,
J¼10.8 Hz), 3.72 (s, 3H, OCH3), 4.87 (d, 2H, J¼10.8 Hz), 6.81 (d, 2H,
J¼9.0 Hz, AreH), 6.90 (d, 2H, J¼9.0 Hz, AreH), 7.17 (d, 4H, J¼7.5 Hz,
AreH), 7.40 (d, 4H, J¼7.8 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC
:
AreH), 7.38 (d, 4H, J¼7.5 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC
:
21.0, 21.1, 53.2, 72.2, 113.3, 127.1, 127.9, 129.0, 129.3, 137.0, 137.3,
145.6. Anal. Calcd for C25H27NO: C, 83.99; H, 7.61; N, 3.92%. Found C,
83.96; H, 7.58; N, 3.88%.
21.1, 55.5, 57.2, 78.1,114.5,118.2,126.2,129.0,137.2,137.5,145.1,154.0.
Calcd for MS (m/z): 374.2 [Mþ1]; Found 374.1 [Mþ1]. Anal. Calcd for
C25H27NO2:C, 80.40; H, 7.29;N, 3.75. FoundC, 80.37;H, 7.25; N, 3.71%.
4.4.14. trans-4-(4-Methoxyphenyl)-2,6-di(4-methylphenyl) morpho-
line (800f). Isolated as colorless crystal; mp 132 ꢁC. 1H NMR
(300 MHz, CDCl3) dH: 2.35 (s, 6H, 2CH3), 3.36 (dd, 2H, J¼12.0,
3.6 Hz), 3.44 (dd, 2H, J¼12.0, 6.0 Hz), 3.77 (s, 3H, OCH3), 4.96 (dd,
2H, J¼6.0, 3.6 Hz), 6.86 (d, 2H, J¼9.0 Hz, AreH), 6.95 (d, 2H,
J¼9.0 Hz, AreH), 7.17 (d, 4H, J¼7.8 Hz, AreH), 7.40 (d, 4H, J¼8.1 Hz,
AreH); 13C NMR (75 MHz, CDCl3) dC: 21.1, 54.3, 55.6, 72.3, 114.6,
117.9, 127.1, 129.1, 137.1, 137.3, 145.5, 154.0. Calcd for MS (m/z): 374.2
[Mþ1]; Found 374.1 [Mþ1]. Anal. Calcd for C25H27NO2: C, 80.40; H,
7.29; N, 3.75. Found C, 80.37; H, 7.25; N, 3.71%.
4.4.7. cis-2,6-Di(4-chlorophenyl)-4-(4-methylphenyl)morpholine
(80g). Isolated as colorless crystal; mp 161 ꢁC; 1H NMR (300 MHz,
CDCl3) dH: 2.26 (s, 3H, CH3), 2.69 (t, 2H, J¼10.8 Hz), 3.62 (d, 2H,
J¼10.8 Hz), 4.85 (d, 2H, J¼10.8 Hz), 6.84 (d, 2H, J¼8.7 Hz, AreH),
7.07 (d, 2H, J¼8.7 Hz, AreH), 7.34 (d, 4H, J¼8.7 Hz, AreH), 7.41 (d,
4H, J¼8.7 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 20.4, 56.2, 77.5,
116.5, 127.6, 128.6, 129.8, 130.1, 133.7, 138.2, 148.3. Calcd for MS (m/
z): 398.1 [Mþ1]; Found 398.0 [Mþ1]. Anal. Calcd for C23H21Cl2NO:
C, 69.35; H, 5.31; N, 3.52%. Found C, 69.31; H, 5.28; N, 3.49%.
4.4.8. cis-2,6-Di(4-chlorophenyl)-4-(4-methoxyphenyl) morpholine
4.4.15. trans-2,6-Di(4-Chlorophenyl)-4-(4-fluorophenyl) morpholine
(800i). Isolated as colorless crystal; mp 152 ꢁC; 1H NMR (300 MHz,
(80h). Isolated as colorless crystal; mp 143 ꢁC; 1H NMR (300 MHz,

N. Paul et al. / Tetrahedron 68 (2012) 6892e6901
6901
CDCl3) dH: 3.62e3.42 (m, 4H), 4.90e4.93 (m, 2H), 6.85e6.89 (m, 4H,
References and notes
AreH), 7.25e7.50 (m, 8H, AreH); 13C NMR (75 MHz, CDCl3) dC: 53.7,
71.8, 117.9, 128.3, 128.5, 128.6, 130.9, 138.0, 148.2, 157.5. Anal. Calcd for
C22H18Cl2FNO: C, 65.68; H, 4.51; N, 3.48%. Found C, 65.64; H, 4.48; N,
3.47%.
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given below:
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4.5.1. trans-2,5-Dimethyl-3,4-diphenyl-2-cyclopenten-1-one
(140a). Monoclinic crystal; 1H NMR (300 MHz, CDCl3) dH: 1.35 (d,
3H, J¼7.2 Hz, CH3), 2.02 (s, 3H, CH3), 2.39 (qd, 1H, J¼7.2, 1.8 Hz, CH),
3.97 (d, 1H, J¼1.8 Hz, CH), 7.05e7.31 (m, 10H, AreH); 13C NMR
(75 MHz, CDCl3) dC: 10.1, 15.3, 51.3, 56.5, 126.6, 127.6, 128.3 (2C),
128.7, 128.9, 135.3, 136.7, 142.1, 166.9, 210.8. Calcd for MS (m/z):
263.13 [Mþ1]; Found 263.33 [Mþ1]. Anal. Calcd for C19H18O: C,
86.99; H, 6.92%. Found C, 86.94; H, 6.88%.
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4.5.2. trans-3,4-Di(4-chlorophenyl)-2,5-dimethyl-2-cyclopenten-1-
one (140b). Isolated as colorless crystal; 1H NMR (300 MHz,
CDCl3) dH: 1.33 (d, 3H, J¼7.5 Hz, CH3), 2.00 (s, 3H, CH3), 2.34 (qd,
1H, J¼7.5, 2.1 Hz, CH), 3.94 (d, 1H, J¼2.1 Hz, CH), 6.99 (d, 2H,
J¼8.4 Hz, AreH), 7.17 (d, 2H, J¼8.4 Hz, AreH), 7.23e7.30 (m, 4H,
AreH); 13C NMR (75 MHz, CDCl3) dC: 10.0, 14.9, 51.1, 55.4, 128.6,
128.7, 128.9, 129.5, 132.5, 133.2, 134.9, 137.3, 140.1, 164.7, 209.8.
Anal. Calcd for C19H16Cl2O: C, 68.89; H, 4.87%. Found C, 68.86; H,
4.85%.
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4.5.3. cis-2,5-Dimethyl-3,4-diphenyl-2-cyclopenten-1-one
(1400a). Isolated as colorless crystals;28 1H NMR (300 MHz, CDCl3)
dH: 0.74 (d, 3H, J¼7.5 Hz, CH3), 2.08 (s, 3H, CH3), 2.91 (qd, 1H,
J¼7.5, 6.9 Hz, CH), 4.60 (d, 1H, J¼6.9 Hz, CH), 7.00e7.39 (m, 10H,
AreH); 13C NMR (75 MHz, CDCl3) dC: 10.1, 12.2, 45.5, 52.7, 126.8,
128.2, 128.3, 128.4 (2C), 128.9, 135.8, 137.0, 139.2, 166.2, 211.2.
Anal. Calcd for C19H18O: C, 86.99; H, 6.92%. Found C, 86.96; H,
6.90%.
4.5.4. cis-3,4-Di(4-chlorophenyl)-2,5-dimethyl-2-cyclopenten-1-one
(1400b). Isolated as colorless crystals;28 1H NMR (300 MHz, CDCl3)
dH: 1.10 (d, 3H, J¼6.9 Hz, CH3), 2.27 (s, 3H, CH3), 3.26 (dq, 1H,
J¼11.4, 6.9 Hz, CH), 4.02 (d, 1H, J¼11.4 Hz, CH), 7.03e7.26 (m, 8H,
AreH); 13C NMR (75 MHz, CDCl3) dC: 17.0, 20.9, 43.9, 53.7, 127.3,
128.7, 128.8, 129.3, 129.5, 130.1, 132.4, 136.3, 139.5, 140.9, 179.5.
Anal. Calcd for C19H16Cl2O: C, 68.89; H, 4.87%. Found C, 68.85; H,
4.83%.
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27. Crystallographic data (excluding structure factors) for compounds 8c00, 1000, 110,
1100, 13b and 14a discussed in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication number
CCDC 830291, 875991, 875992, 875993, 875994 and 875995. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44 (0) 1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk].
Acknowledgements
The authors thank DST, New Delhi for funds under IRHPA program
toward high resolution NMR spectrometer to Madurai Kamaraj Uni-
versity. Financial support from UGC, New Delhi to N.P. is gratefully
acknowledged.
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Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.06.029.