Efficient asymmetric selenocyclizations of alkenyl oximes into cyclic nitrones and 1,2-oxazines promoted by sulfur containing diselenides

Article abstract of DOI:10.1016/S0957-4166(02)00013-7

Treatment of the di-2-[(1S)-1-(methylthio)ethyl]phenyl diselenide or of the di-2-methoxy-6-[(1S)-1-methylthio)ethyl]phenyl diselenide with bromine and silver triflate afforded the corresponding electrophilic selenylating triflates which were used in situ

Full text of DOI:10.1016/S0957-4166(02)00013-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3297–3304
Efficient asymmetric selenocyclizations of alkenyl oximes into
cyclic nitrones and 1,2-oxazines promoted by sulfur containing
diselenides
Marcello Tiecco,* Lorenzo Testaferri, Luana Bagnoli, Valentina Purgatorio, Andrea Temperini,
Francesca Marini and Claudio Santi
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Universita` di Perugia, I-06123 Perugia, Italy
Received 5 December 2001; accepted 9 January 2002
Abstract—Treatment of the di-2-[(1S)-1-(methylthio)ethyl]phenyl diselenide or of the di-2-methoxy-6-[(1S)-1-methylthio)-
ethyl]phenyl diselenide with bromine and silver triflate afforded the corresponding electrophilic selenylating triflates which were
used in situ to promote the asymmetric selenocyclization of g-alkenyl oximes and d-phenyl-g-alkenyl oximes. The course of these
reactions and hence the structures of the cyclization products were dictated by the (E)- or (Z)-geometry of the starting oximes.
The two types of cyclization products were either the cyclic nitrones or the 1,2-oxazines; in both cases the reactions proceeded with
excellent yields, complete regioselectivity and good diastereoselectivity. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
obtained with high diastereoselectivity from the asym-
metric selenocyclization of alkenes containing oxygen
or nitrogen atoms as internal nucleophiles. The
diastereoselectivities observed in these reactions were
comparable or even better than those obtained with the
most efficient, but not so readily available, diselenides
which have been described in the literature.5–16 On the
basis of several experimental evidences17–19 it has been
proposed that the high stereoselectivity observed with
the previously described optically active diselenides is
due to a non-bonded interaction between the selenium
atom and an oxygen or nitrogen atom positioned in the
close proximity. The excellent results obtained with the
diselenides 1 and 2 seem to indicate that interaction of
the selenium with sulfur is probably more important
than those with oxygen or with nitrogen.
We have recently reported the synthesis of the two new
sulfur containing diselenides di-2-[(1S)-1-(methylthio)-
ethyl]phenyl diselenide 11 and di-2-methoxy-6-[(1S)-1-
methylthio)ethyl]phenyl diselenide 2.2 Upon treatment
with bromine and with silver triflate, 1 and 2 can be
easily converted into the electrophilic selenylating
reagents 3 and 4 (Scheme 1), which were employed to
effect
the
selenomethoxylation
and
seleno-
hydroxylation2 of alkenes. Excellent facial differentia-
tions were observed in both cases.
Similarly, cyclic ethers,2,3 lactones,2,3 lactams, N-pro-
tected pyrrolidines3 and isoxazolidines4 were also
From the results accumulated so far it can be antici-
pated that the diselenides 1 and 2 can be successfully
employed to effect the asymmetric synthesis of nitro-
gen-containing heterocyclic compounds starting from
properly substituted alkenes. Despite the numerous
examples of selenium-promoted cyclization reactions
reported in the literature, few of their applications to
the syntheses of nitrogen containing heterocycles have
been described.8,9,11–14 It therefore seemed of some
interest to test the efficiency of the electrophilic reagents
3 and 4 to promote such cyclization reactions.
Scheme 1.
* Corresponding author. Tel.: +39 075 5855100; fax: +39 075
5855116; e-mail: tiecco@unipg.it
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00013-7

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M. Tiecco et al. / Tetrahedron: Asymmetry 12 (2001) 3297–3304
2. Results and discussion
ally. The progress of the reaction was monitored by
TLC, GC–MS and/or H NMR spectroscopy. Reaction
1
We report herein that the cyclization of g-alkenyl
oximes 5a–b or of d-phenyl-g-alkenyl oximes 5c–d
(Scheme 2), promoted by 3 or 4, represents a conve-
nient method for the stereoselective preparation of 1,2-
oxazines 7a–b or 11a–b and/or five-membered 8a–b or
12a–b or six-membered cyclic nitrones 9c–d or 13c–d.
Compounds 6, 7, 8 and 9 were obtained using the
reagent 3 and compounds 10, 11, 12 and 13 using the
reagent 4. In every case the reaction products were
obtained as a mixture of two enantiomerically pure
diastereoisomers.
mixtures were worked-up in the usual way and com-
pounds were purified by column chromatography.
Reaction times, chemical yields and diastereomeric
ratios are collected in Table 1. The cyclizations pro-
moted by the ArSeOTf 4 were effected in the same way.
The results of these reactions are reported in italics in
Table 1. The results reported in Table 1 indicate that
these cyclization reactions occur with excellent chemical
yield, complete regioselectivity and good diastereoselec-
tivity. The two diastereomeric 1,2-oxazines and the five-
or six-membered cyclic nitrones could not be separated
by column chromatography on silica gel. The
diastereomeric ratios were determined by 1H NMR
spectroscopy.
The formation of cyclic nitrones and/or 1,2-oxazines
indicates that the oxime group, depending on its
geometry, can act either as an oxy- or an aza-nucle-
ophile in the intramolecular capture of the initially
formed seleniranium intermediates 6a–d or 10a–d. This
data is in agreement with the results reported by our
research group in similar ring closure reactions of g-
alkenyl oximes promoted by phenylselenylating
sulfate.21
As indicated in Scheme 2, the electrophilic selenylating
reagent 3 attacks the double bond of the oximes 5a–d
giving rise to a mixture of two diastereomeric selenira-
nium intermediates 6a–d. The facial selectivity of this
attack determines the diastereoselectivity of the entire
process. When the reaction was carried out starting
from the g-alkenyl oximes 5a–b (R1=H) the
intramolecular trapping can be effected either by the
oxygen or by the nitrogen atoms affording 1,2-oxazines
7a–b (6-exo cyclization) or five-membered cyclic
nitrones 8a–b (5-exo cyclization), respectively. The pres-
ence of the phenyl group in the d-phenyl-g-alkenyl
oximes 5c–d (R1=Ph) controls the regioselectivity of
the process and the six-membered nitrones 9c–d are the
sole reaction products obtained (6-endo cyclization). In
all cases the cyclization process was a stereospecific anti
addition. A similar mechanism is proposed to operate
in the cases in which reagent 4 is employed. In these
cases the reaction products are 11a–b, 12a–b and 13c–d.
The oximes 5a–d (Table 1) were easily prepared accord-
ing to the procedures described in the literature.21,22
The single (E)-isomer was obtained in the case of 5c. In
all other cases mixtures of (E)- and (Z)-isomers were
obtained which could be separated by column chro-
matography, the only exception being oxime 5b, which
was obtained as a 1:2 mixture of the (Z)- and (E)-iso-
mers. In this case therefore the cyclization experiments
were carried out using a mixture of the two isomers.
The configurations of the geometrical isomers could be
assigned on the basis of their 13C NMR spectra.21,22
The cyclization reactions of these oximes were com-
pleted according to the following general procedure.
Treatment of a stirred solution of the diselenide 1, in
dichloromethane at −78°C, with bromine and then with
silver triflate afforded the selenylating reagent 3. After
20 min one of the oximes 5a–d was added at −78°C and
the reaction temperature was allowed to increase gradu-
Using either the diselenide 1 or the diselenide 2 the
6-endo cyclizations of the oximes 5c–d gave higher
diastereomeric ratios (up to 96:4) than the 5-exo and
6-exo cyclizations of the oximes 5a–b (up to 82:18).
This is in agreement with our previous observa-
tions that phenyl substituted alkenes give better
Scheme 2.

M. Tiecco et al. / Tetrahedron: Asymmetry 12 (2001) 3297–3304
3299
diastereomeric ratios than terminal olefins.3 As already
observed,2 the diastereomeric ratios obtained in the
reactions promoted by 4 in several cases are higher than
those observed with the use of the reagent 3.
(Table 1, entry 2). In contrast, starting from the oxime
5b, where R is a methyl group, the ratios of reaction
products do not reflect the ratio of the oxime 5b
(Z:E=1/2) (Table 1, entry 3). Monitoring the progress
of the reactions by TLC and GC–MS it was observed
that the initially formed 1,2-oxazines 7b or 11b were
gradually converted into the nitrones 8b or 12b. Start-
ing from the diselenide 1, after 7 h 7b and 8b were
present in a 1:4 ratio. In another experiment, starting
from the diselenide 2, after 17 h 11b was completely
converted and the nitrone 12b was the sole reaction
product. This can be explained on the basis of the
results of some independent experiments. As indicated
in Scheme 3, it was, in fact, observed that under these
The course of the ring closure reaction of the g-alkenyl
oximes is influenced by the nature of the R group. The
oxime 5a, in which R is a phenyl group, is configura-
tionally stable and the structures of the cyclization
products depend upon the geometry of the starting
oxime. In fact the reactions of the oxime (E)-5a gave
the 1,2-oxazines 7a or 11a as the sole reaction product
(Table 1, entry 1), and the isomeric (Z)-oxime 5a
afforded exclusively the cyclic nitrones 8a or 12a.
Table 1. Cyclization of g-alkenyl oximes 5a–b and d-phenyl-g-alkenyl oximes 5c–d promoted by the arylselenenyl triflates 3
or 4 in CH2Cl2 at −78°C

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M. Tiecco et al. / Tetrahedron: Asymmetry 12 (2001) 3297–3304
Scheme 3.
conditions the two isomers of the oxime 5b interconvert
and the formation of the 1,2-oxazines is reversible.
Thus, the entire process is shifted towards the forma-
tion of the thermodynamically more stable nitrones 8b
or 12b.
mixture of two diastereoisomers (D.r. 82:18) which
could not be separated.
3. Conclusion
The oxime 5c was obtained as a single isomer having
(E)-configuration. In this oxime the substituent R is a
phenyl group and therefore it isomerizes only with
great difficulty. The intramolecular capture of the
seleniranium intermediate 6c or 10c by the oxygen atom
is difficult since it would lead to the formation of a
seven-membered cyclic compound. Moreover, the for-
mation of the 1,2-oxazine would require an anti-
Markovnikov addition reaction. Indeed the cyclization
of (E)-5c was a very slow process which afforded the
six-membered cyclic nitrones 9c and 13c clearly deriving
from a preliminary conversion of the starting oxime
into the (Z)-isomer (Table 1, entry 4).
In conclusion the results reported in this paper confirm
that the triflates of the chiral sulfur containing dise-
lenides 1 and 2 are efficient electrophilic reagents, which
promote the ring closure reactions of the g-alkenyl
oximes and d-phenyl-g-alkenyl oximes. These reactions
proceed with excellent chemical yield, complete regiose-
lectivity and good diastereoselectivity and represent
therefore a very convenient method to effect the asym-
metric synthesis of cyclic nitrones and 1,2-oxazines.
4. Experimental
New compounds were characterized by MS, 1H and 13
C
On the contrary, the cyclization reaction of the oximes
5d proceeded easily. In this case the (E)- and (Z)-iso-
mers could be isolated and obtained in a pure form.
However, since R is a methyl group, the two isomers
can easily interconvert. Their cyclization reactions, in
fact, afforded in both cases the thermodynamically
more stable six-membered cyclic nitrones (Table 1,
entries 5 and 6). Thus, using reagent 3 and starting
from either (E)-5d or (Z)-5d the same nitrone 9d was
obtained. Similarly, the cyclization of (E)-5d promoted
by reagent 4 afforded the nitrone 13d.
NMR spectroscopy. GLC analyses and MS spectra
were carried out with a HP 6890 gas chromatograph
(25 m dimethyl silicone capillary column) equipped
with an HP 5973 Mass Selective Detector; for the ions
containing selenium only the peaks arising from the
1
selenium 80 isotope are given. H and 13C NMR spec-
tra were recorded at 400 and 100.62 MHz, respectively,
on a Bruker DRX 400 instrument; unless otherwise
specified, CDCl3 was used as solvent and TMS as
standard. Elemental analyses were carried out on a
Carlo Erba 1106 Elemental Analyzer.
The arylseleno substituted cyclic nitrones and/or 1,2-
oxazines here prepared can find several useful synthetic
applications. Thus, the reductive deselenylation of
The oximes 5a and 5b were prepared by treating the
corresponding ketones with hydroxylamine hydrochlo-
ride.21 The oximes 5c and 5d were obtained by treating
the dianion of acetophenone or acetone oxime with
cinnamyl bromide.22 Physical and spectral data of 5a–c
are identical to those reported in the literature.21,22
Physical and spectral data of the oxime 5d are reported
below. The configurations were assigned on the basis of
their 13C NMR spectra.21
(arylseleno)-1,2-oxazines
affords
enantiomerically
enriched 1,2-oxazines. The cyclic nitrones can be dese-
lenylated or can be employed to effect 1,3-dipolar
cycloaddition reactions. Thus, for example, the reaction
of the nitrone 12b (D.r. 82:18) with methyl propiolate
at 10°C proceeded smoothly and gave the bicyclic
compound 14 in 89% yield (Scheme 4). This was a
Scheme 4.

M. Tiecco et al. / Tetrahedron: Asymmetry 12 (2001) 3297–3304
3301
4.1. (1E,4E)-1,5-Diphenylpent-4-en-1-one oxime 5d
Hz), 7.19 (dt, 1H, J=1.5, 7.7 Hz), 4.59 (quart, 1H,
J=7.0 Hz), 3.97 (dddd, 1H, J=2.3, 5.3, 7.7, 10.1 Hz),
3.33 (dd, 1H, J=5.3, 12.0 Hz), 3.03 (dd, 1H, J=7.7,
12.0 Hz), 1.98 (s, 3H), 1.60 (d, 3H, J=7.0 Hz); 13C
NMR: l 145.7, 133.1, 29.4.
(E)-Isomer: mp 89–92°C (petroleum ether); 1H NMR: l
9.30 (brs, 1H), 7.70–7.62 (m, 2H), 7.47–7.20 (m, 8H),
6.43 (d, 1H, J=15.8 Hz), 6.24 (dt, 1H, J=6.4, 15.8
Hz), 3.04–2.97 (m, 2H), 2.54–2.47 (m, 2H); 13C NMR:
l 159.0, 137.5, 135.6, 130.5, 129.3, 129.2, 128.6 (two
carbons), 128.4 (two carbons), 126.9, 126.4 (two car-
bons), 126.0 (two carbons), 29.6, 26.2; MS m/z (rel.
int.): 251 (5), 250 (10), 232 (18), 160 (15), 144 (21), 130
(70), 117 (100), 104 (46), 91 (47), 77 (25). Anal. calcd
for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C,
81.54; H, 6.71; N, 5.45%.
4.4. 6-[({2-Methoxy-6-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)methyl]-3-phenyl-5,6-dihydro-4H-1,2-oxazine 11a
1
Major diastereoisomer: H NMR: l 7.73–7.68 (m, 2H),
7.42–7.36 (m, 3H), 7.34 (t, 1H, J=8.0 Hz), 7.18 (dd,
1H, J=1.2, 8.0 Hz), 6.80 (dd, 1H, J=1.2, 8.0 Hz), 4.95
(quart, 1H, J=7.0 Hz), 3.92 (s, 3H), 3.91–3.82 (m, 1H),
3.28 (dd, 1H, J=5.2, 12.2 Hz), 2.95 (dd, 1H, J=8.1,
12.2 Hz), 2.75–2.65 (m, 1H), 2.64–2.51 (m, 1H), 2.38–
2.28 (m, 1H), 1.99 (s, 3H), 1.88–1.78 (m, 1H), 1.58 (d,
3H, J=7.0 Hz); 13C NMR: l 159.6, 154.5, 148.4, 135.5,
129.6, 129.4, 128.3 (two carbons), 125.2 (two carbons),
119.3, 118.5, 109.2, 74.8, 56.0, 44.4, 29.9, 23.9, 21.8,
21.7, 14.1. Anal. calcd for C21H25NO2SSe: C, 58.07; H,
5.80; N, 3.22. Found: C, 57.95; H, 5.73; N, 3.11%.
4.2. Selenocyclization of g-alkenyl oximes and d-phenyl
g-alkenyl oximes. General procedure
The diselenide 1 (0.5 mmol), dissolved in dichloro-
methane (4 mL) was treated under nitrogen with
a solution of Br2 in carbon tetrachloride (1 M, 0.5
mmol) at −78°C. After 15 min silver trifluoromethane-
sulfonate (1.2 mmol) and methanol (1 mL) were added
and the mixture was stirred for 20 min. The oxime (1
mmol) was added at −78°C and the mixture was stirred
for the time reported in Table 1. The reaction mixture
was allowed to warm gradually to room temperature.
The progress of the reaction was monitored by TLC
and/or GC–MS. The reaction mixture was poured into
a 10% aqueous NaHCO3 solution and extracted with
dichloromethane. The organic layer was dried over
Na2SO4, filtered and evaporated under vacuo. The reac-
tion products were obtained in pure form after column
chromatography of the residue on silica gel. The same
procedure was applied to the diselenide 2. Reaction
times, yields and diastereomeric ratios of the obtained
products are reported in Table 1. Physical and spectral
data are reported below. D.r.s were measured by inte-
1
Minor diastereoisomer (distinct signals): H NMR: l
7.20 (dd, 1H, J=1.2, 8.0 Hz), 4.94 (quart, 1H, J=7.0
Hz), 3.27 (dd, 1H, J=5.2, 12.2 Hz), 1.98 (s, 3H), 1.57
(d, 3H, J=7.0 Hz); 13C NMR: l 73.7, 32.2, 22.7, 21.2.
4.5. 2-[({2-[(1S)-1-(Methylthio)ethyl]phenyl}seleno)-
methyl]-5-phenyl-3,4-dihydro-2H-pyrrole 1-oxide 8a
1
Oil; major diastereoisomer: H NMR: l 8.33–8.25 (m,
2H), 7.63 (dd, 1H, J=1.5, 7.6 Hz), 7.49–7.42 (m, 4H),
7.26 ( dt, 1H, J=1.5, 7.6 Hz), 7.16 (dt, 1H, J=1.5, 7.6
Hz), 4.74–4.60 (m, 1H), 4.50 (quart, 1H, J=7.0 Hz),
3.67 (dd, 1H, J=2.9, 12.6 Hz), 3.37 (dd, 1H, J=8.6,
12.6 Hz), 3.27–3.08 (m, 2H), 2.49–2.35 (m, 1H), 2.20–
2.02 (m, 1H), 1.93 (s, 3H), 1.53 (d, 3H, J=7.0 Hz); 13C
NMR: l 145.4, 141.9, 134.1, 131.1, 130.6, 129.3, 128.9
(two carbons), 128.4, 128.1, 128.0 (two carbons), 127.6,
75.0, 44.4, 31.3, 29.3, 23.3, 21.9, 14.5; MS m/z (rel. int.)
374 (M+−31, 4), 343 (11), 231 (9), 215 (15), 207 (22),
183 (42), 158 (100), 144 (18), 115 (14), 104 (28), 91 (16),
77 (14). Anal. calcd for C20H23NOSSe: C, 59.41; H,
5.73; N, 3.96. Found: C, 59.36; H, 5.49; N, 3.86%.
1
gration of H NMR signals. Assignments of 13C NMR
signals are tentative because of frequent coincidence
between signals from the two stereoisomers and the low
intensity of peaks from the minor products.
4.3. 6-[({2-[(1S)-1-(Methylthio)ethyl]phenyl}seleno)-
methyl]-3-phenyl-5,6-dihydro-4H-1,2-oxazine 7a
1
Minor diastereoisomer (distinct signals): H NMR: l
7.14 (dt, 1H, J=1.5, 7.6 Hz), 4.51 (quart, 1H, J=7.0
Hz), 3.71 (dd, 1H, J=3.3, 12.6 Hz), 3.31 (dd, 1H,
J=8.0, 12.6 Hz), 1.94 (s, 3H), 1.59 (d, 3H, J=7.0 Hz),
13C NMR: l 145.3, 133.8, 130.7, 129.4, 128.3, 128.2,
127.9 (two carbons), 127.5, 74.8, 44.3, 31.1, 29.2, 23.4,
14.4.
1
Major diastereoisomer: H NMR: l 7.71–7.67 (m, 2H),
7.61 (dd, 1H, J=1.5, 7.7 Hz), 7.51 (dd, 1H, J=1.5, 7.7
Hz), 7.42–7.37 (m, 3H), 7.30 (dt, 1H, J=1.5, 7.7 Hz),
7.18 (dt, 1H, J=1.5, 7.7 Hz), 4.62 (quart, 1H, J=6.9
Hz), 3.95 (dddd, 1H, J=2.3, 5.4, 7.6, 10.1 Hz), 3.30
(dd, 1H, J=5.4, 12.4 Hz), 3.05 (dd, 1H, J=7.6, 12.4
Hz), 2.76–2.56 (m, 2H), 2.36–2.28 (m, 1H), 1.99 (s, 3H),
1.93–1.80 (m, 1H), 1.61 (d, 3H, J=6.9 Hz); 13C NMR:
l 154.4, 144.8, 137.3, 135.2, 133.2, 129.2, 128.2 (two
carbons), 127.6, 127.4, 126.8, 125.0 (two carbons), 74.0,
43.7, 30.8, 23.8, 21.5, 21.3, 13.9. Anal. calcd for
C20H23NOSSe: C, 59.41; H, 5.73; N, 3.46. Found: C,
59.14; H, 5.61; N, 3.11%.
4.6. 2-[({2-Methoxy-6-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)methyl]-5-phenyl-3,4-dihydro-2H-pyrrole
1-oxide 12a
1
Oil; major diastereoisomer: H NMR: l 8.48–8.38 (m,
2H), 7.50–7.40 (m, 3H), 7.31 (t, 1H, J=8.0 Hz), 7.12
(dd, 1H, J=1.2, 8.0 Hz), 6.80 (dd, 1H, J=1.2, 8.0 Hz),
4.79 (quart, 1H, J=7.0 Hz), 4.65–4.55 (m, 1H), 3.94 (s,
3H), 3.66 (dd, 1H, J=3.6, 12.4 Hz), 3.31–3.09 (m, 3H),
2.50–2.35 (m, 1H), 2.15–2.03 (m, 1H), 1.94 (s, 3H), 1.50
1
Minor diastereoisomer (distinct signals): H NMR: l
7.62 (dd, 1H, J=1.5, 7.7 Hz), 7.52 (dd, 1H, J=1.5, 7.7

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M. Tiecco et al. / Tetrahedron: Asymmetry 12 (2001) 3297–3304
(d, 3H, J=7.0 Hz); 13C NMR: l 159.6, 147.9, 140.4,
130.3, 129.5, 129.0, 128.3 (two carbons), 127.3 (two
carbons), 119.2, 118.4, 109.3, 75.1, 56.0, 44.3, 30.0,
28.6, 22.8, 21.5, 14.0; MS m/z (rel. int.): 404 (M+−31,
6), 373 (13), 261 (14), 245 (12), 213 (38), 198 (17), 181
(27), 158 (100), 144 (22), 115 (13), 104 (35), 91 (23), 77
(17), 55 (22). Anal. calcd for C21H25NO2SSe: C, 58.07;
H, 5.80; N, 3.22. Found: C, 57.98; H, 5.76; N, 3.09%.
7.8 Hz), 4.52 (quart, 1H, J=6.9 Hz), 3.67 (dd, 1H,
J=3.6, 12.5 Hz), 3.13 (dd, 1H, J=8.6, 12.4 Hz), 2.21
(dt, 3H, J=1.6, 1.7 Hz), 1.95 (s, 3H), 1.58 (d, 3H,
J=6.9 Hz); 13C NMR: l 144.7, 144.2, 133.4, 130.2,
127.7, 127.6, 126.9, 71.7, 21.4, 13.9.
4.9. 2-[({2-Methoxy-6-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)methyl]-5-methyl-3,4-dihydro-2H-pyrrole
1-oxide 12b
1
Minor diastereoisomer (distinct signals): H NMR: l
1
7.33 (t, 1H, J=8.0 Hz), 7.16 (dd, 1H, J=1.2, 8.0 Hz),
6.78 (dd, 1H, J=1.2, 8.0 Hz), 4.82 (quart, 1H, J=7.0
Hz), 4.53–4.45 (m, 1H), 3.92 (s, 3H), 3.74 (dd, 1H,
J=3.7, 12.1 Hz), 1.96 (s, 3H), 1.57 (d, 3H, J=7.0 Hz);
13C NMR: l 148.1, 140.2, 129.6, 75.0, 29.9, 28.5, 22.9.
Major diastereoisomer: H NMR: l 7.29 (t, 1H, J=7.8
Hz), 7.14 (dd, 1H, J=1.2, 7.8 Hz), 6.76 (dd, 1H,
J=1.2, 7.8 Hz), 4.84 (quart, 1H, J=7.0 Hz), 4.30–4.10
(m, 1H), 3.89 (s, 3H), 3.59 (dd, 1H, J=3.6, 12.1 Hz),
3.18 (dd, 1H, J=9.1, 12.1 Hz), 2.65–2.55 (m, 2H),
2.33–2.21 (m, 1H), 2.0 (dt, 3H, J=1.5, 1.6 Hz), 1.95 (s,
3H), 1.97–1.85 (m, 1H), 1.55 (d, 3H, J=7.0 Hz); 13C
NMR: l 159.5, 148.0, 144.2, 130.1, 129.5, 119.2 109.3,
72.5, 55.9, 44.3, 30.7, 29.8, 23.1, 21.7, 14.0, 12.7; MS
m/z (rel. int.): 357 (M+−16, 6), 310 (32), 261 (32), 245
(40), 230 (30), 213 (100), 198 (42), 181 (59), 96 (85), 82
(33), 55 (33). Anal. calcd for C16H23NO2SSe: C, 51.62;
H, 6.23; N, 3.76. Found: C, 51.56; H, 6.29; N, 3.59%.
4.7. 3-Methyl-6-[({2-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)methyl-5,6-dihydro-4H-1,2-oxazine 7b
1
Oil; major diastereoisomer: H NMR: l 7.55 (dd, 1H,
J=1.5, 7.8 Hz), 7.48 (dd, 1H, J=1.5, 7.8 Hz), 7.28 (dt,
1H, J=1.5, 7.8 Hz), 7.14 (dt, 1H, J=1.5, 7.8 Hz), 4.57
(quart, 1H, J=6.9 Hz), 3.75 (dddd, 1H, J=2.2, 5.2, 7.6,
10.2 Hz), 3.19 (dd, 1H, J=5.2, 12.5 Hz), 2.94 (dd, 1H,
J=7.6, 12.5 Hz), 2.25–2.09 (m, 3H), 1.96 (s, 3H), 1.89
(s, 3H), 1.75–1.60 (m, 1H), 1.57 (d, 3H, J=6.9 Hz); 13C
NMR: l 155.7, 145.0, 135.1, 133.3, 127.8, 127.5, 127.0,
73.4, 43.9, 31.2, 24.8, 24.1, 21.5 (two carbons), 14.1;
MS m/z (rel. int.): 343 (11), 231 (52), 183 (100), 102
(17), 91 (14), 77 (10), 51 (4). Anal. calcd for
C15H21NOSSe: C, 52.63; H, 6.18; N, 4.09. Found: C,
52.77; H, 5.99; N, 4.15%.
1
Minor diastereoisomer (distinct signals): H NMR: l
7.12 (dd, 1H, J=1.2, 7.8 Hz), 4.83 (quart, 1H, J=7.0
Hz), 3.90 (s, 3H), 3.63 (dd, 1H, J=3.6, 12.0 Hz), 2.97
(dd, 1H, J=9.4, 12.0 Hz), 2.01 (dt, 3H, J=1.5, 1.6 Hz),
1.94 (s, 3H); 13C NMR: l 72.3, 29.5, 21.6.
4.10. 3-({2-[(1S)-1-(Methylthio)ethyl]phenyl}seleno)-2,6-
diphenyl-2,3,4,5-tetrahydropyridine 1-oxide 9c
1
Oil; major diastereoisomer: H NMR: l 8.24–8.12 (m,
1
Minor diastereoisomer (distinct signals): H NMR: l
2H), 7.78 (dd, 1H, J=1.5, 7.8 Hz), 7.60–7.10 (m, 11H),
5.25 (d, 1H, J=2.9 Hz), 4.62 (quart, 1H, J=7.0 Hz),
3.98–3.88 (m, 1H), 3.35–3.15 (m, 1H), 3.10–2.89 (m,
1H), 2.27–2.19 (m, 1H), 2.18–1.90 (m, 1H), 1.95 (s, 3H),
1.61 (d, 3H, J=7.0 Hz), 13C NMR: l 146.5, 142.4,
138.5, 136.3, 136.1, 133.4, 129.7, 129.0, 128.7 (two
carbons), 128.0 (four carbons), 127.8, 127.6, 127.3,
126.1 (two carbons), 77.3, 45.1, 44.1, 27.3, 21.1, 20.7,
13.9. Anal. calcd for C26H27NOSSe: C, 65.00; H, 5.66;
N, 2.92. Found: C, 65.12; H, 6.17; N, 2.99%.
7.57 (dd, 1H, J=1.5, 7.8 Hz), 7.50 (dd, 1H, J=1.5, 7.8
Hz), 7.16 (dt, 1H, J=1.5, 7.8 Hz), 4.55 (quart, 1H,
J=6.9 Hz), 3.73 (dddd, 1H, J=2.2, 5.2, 7.6, 10.2 Hz),
3.22 (dd, 1H, J=5.2, 12.5 Hz), 2.92 (dd, 1H, J=7.6,
12.5 Hz), 1.95 (s, 3H), 1.56 (d, 3H, J=6.9 Hz); 13C
NMR: l 133.2, 130.7, 127.7, 31.1, 14.2.
4.8. 5-Methyl-2-[({2-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)methyl]-3,4-dihydro-2H-pyrrole 1-oxide 8b
1
1
Oil; major diastereoisomer: H NMR: l 7.61 (dd, 1H,
Minor diastereoisomer (distinct signals): H NMR: l
J=1.5, 7.8 Hz), 7.48 (dd, 1H, J=1.5, 7.8 Hz), 7.27 (dt,
1H, J=1.5, 7.8 Hz), 7.14 (dt, 1H, J=1.5, 7.8 Hz), 4.55
(quart, 1H, J=6.9 Hz), 4.30–4.20 (m, 1H), 3.64 (dd,
1H, J=3.6, 12.4 Hz), 3.15 (dd, 1H, J=8.6, 12.4 Hz),
2.70–2.55 (m, 2H), 2.35–2.20 (m, 1H), 2.10 (dt, 3H,
J=1.6, 1.7 Hz), 1.96 (s, 3H), 1.95–1.85 (m, 1H), 1.59
(d, 3H, J=6.9 Hz); 13C NMR: l 144.9, 144.1, 133.5,
130.1, 127.8, 127.5, 127.0, 71.9, 43.8, 30.8, 30.5, 23.1,
21.5, 14.0, 12.7; MS m/z (rel. int.): 327 (M+−16, 4), 312
(8), 281 (30), 231 (19), 215 (44), 200 (11), 183 (100), 102
(16), 96 (89), 82 (27), 55 (16). Anal. calcd for
C15H21NOSSe: C, 52.63; H, 6.18; N, 4.09. Found: C,
52.57; H, 6.11; N, 3.99%.
5.36 (d, 1H, J=2.9 Hz), 4.68 (quart, 1H, J=7.0 Hz),
1.96 (s, 3H), 1.58 (d, 3H, J=7.0 Hz). 13C NMR: l
128.4, 128.3, 127.4, 43.8.
4.11. 3-({2-Methoxy-6-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)-2,6-diphenyl-2,3,4,5-tetrahydropyridine 1-oxide
13c
1
Oil; major diastereoisomer: H NMR: l 8.23–8.19 (m,
2H), 7.52–7.14 (m, 10H), 6.86 (dd, 1H, J=1.2, 8.1 Hz),
5.21 (d, 1H, J=2.9 Hz), 4.80 (quart, 1H, J=6.9 Hz),
4.22–4.19 (m, 1H), 3.96 (s, 3H), 3.28–3.22 (m, 1H),
3.05–2.90 (m, 1H), 2.20–2.10 (m, 1H), 2.05–1.96 (m,
1H), 1.95 (s, 3H), 1.59 (d, 3H, J=6.9 Hz), 13C NMR: l
160.1, 149.3 (two carbons), 139.3, 133.9, 130.6, 130.3,
129.1 (two carbons), 128.7 (two carbons), 128.6 (two
carbons), 128.2, 126.7 (two carbons), 120.3, 117.9,
1
Minor diastereoisomer (distinct signals): H NMR: l
7.63 (dd, 1H, J=1.5, 7.8 Hz), 7.46 (dd, 1H, J=1.5, 7.8
Hz), 7.29 (dt, 1H, J=1.5, 7.8 Hz), 7.16 (dt, 1H, J=1.5,

M. Tiecco et al. / Tetrahedron: Asymmetry 12 (2001) 3297–3304
3303
109.9, 77.9, 56.6, 44.9, 42.9, 27.9, 21.8, 20.7, 14.5. Anal.
calcd for C27H29NO2SSe: C, 63.53; H, 5.73; N, 2.74.
Found: C, 63.45; H, 5.79; N, 2.65%.
of the reaction was monitored by TLC and GC–MS.
The reaction mixture was worked-up in the usual way
and the reaction product was purified by column chro-
matography on silica gel. Compound 14 was obtained
in 89% yield as a mixture of two diastereoisomers (D.r.
82:18) which could not be separated. Physical and
spectral data are reported below.
1
Minor diastereoisomer (distinct signals): H NMR: l
6.74 (dd, 1H, J=1.2, 8.2 Hz), 5.14 (d, 1H, J=2.9 Hz),
4.60 (quart, 1H, J=6.9 Hz), 3.95 (s, 3H), 1.94 (s, 3H),
1.57 (d, 3H, J=6.9 Hz). 13C NMR: l 128.5, 30.1.
4.15. Methyl 6-[({2-methoxy-6-[(1S)-1-(methylthio)-
ethyl]phenyl}seleno)methyl]-3a-methyl-3a,4,5,6-tetra-
hydropyrrolo[1,2-b]isoxazolo-3-carboxylate 14
4.12. 6-Methyl-3-({2-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)-2-phenyl-2,3,4,5-tetrahydropyridine 1-oxide 9d
1
Oil; major diastereoisomer: H NMR: l 7.66 (dd, 1H,
1
Oil; major diastereoisomer: H NMR: l 7.33 (t, 1H,
J=1.5, 7.7 Hz), 7.51 (dd, 1H, J=1.5, 7.7 Hz), 7.40–
7.25 (m, 4H), 7.21 (dt, 1H, J=1.5, 7.7 Hz), 7.07–7.05
(m, 2H), 5.09–5.01 (m, 1H), 4.60 (quart, 1H, J=6.9
Hz), 3.85 (quart, 1H, J=3.5 Hz), 2.98–2.80 (m, 1H),
2.70–2.60 (m, 1H), 2.33–2.31 (m, 3H), 2.15–2.05 (m,
1H), 1.97 (s, 3H), 1.94–1.82 (m, 1H), 1.62 (d, 3H,
J=6.9 Hz); 13C NMR: l 146.4, 145.9, 144.1, 138.1,
135.9, 128.9, 128.7 (two carbons), 127.8, 127.6, 127.3,
126.1 (two carbons), 75.1, 45.3, 44.0, 28.7, 21.1, 19.9,
18.6, 13.8; MS m/z (rel. int.): 403 (M+−16, 1), 357 (3),
231 (14), 183 (32), 172 (100), 104 (19), 91 (20), 77 (6).
Anal. calcd for C21H25NOSSe: C, 60.29; H, 6.02; N,
3.35. Found: C, 60.12; H, 5.99; N, 3.23%.
J=7.8 Hz), 7.21 (s, 1H), 7.19 (dd, 1H, J=1.2, 7.8 Hz),
6.79 (dd, 1H, J=1.2, 7.8 Hz), 4.92 (quart, 1H, J=7.0
Hz), 3.90 (s, 3H), 3.73 (s, 3H), 3.45–3.30 (m, 1H), 3.19
(dd, 1H, J=4.7, 12.0 Hz), 2.98 (dd, 1H, J=8.8, 12.0
Hz), 2.25–2.15 (m, 1H), 2.0–1.90 (m, 2H), 1.97 (s, 3H),
1.70–1.58 (m, 1H), 1.56 (d, 3H, J=7.0 Hz), 1.49 (s,
3H); 13C NMR: l 164.1, 159.6, 152.2, 148.3, 142.2,
129.4, 119.3, 113.3, 109.1, 74.3, 71.5, 55.9, 51.0, 44.5,
36.0, 30.6, 27.6, 27.5, 21.8, 14.1; MS m/z (rel. int.): 457
(1), 439 (28), 261 (100), 213 (86), 198 (23), 178 (34), 146
(31), 118 (27), 91 (14). Anal. calcd for C20H27NO4SSe:
C, 52.63; H, 5.96; N, 3.07. Found: C, 52.51; H, 5.89; N,
3.19%.
1
Minor diastereoisomer (distinct signals): H NMR: l
1
Minor diastereoisomer (distinct signals): H NMR: l
5.25–5.24 (m, 1H), 4.65 (quart, 1H, J=6.9 Hz), 1.99 (s,
3H), 1.58 (d, 3H, J=6.9 Hz); 13C NMR: l 44.1, 22.5.
7.22 (s, 1H), 6.78 (dd, 1H, J=1.2, 7.8 Hz), 3.91 (s, 3H),
3.74 (s, 3H), 3.23 (dd, 1H, J=4.7, 12.0 Hz), 2.94 (dd,
1H, J=8.9, 12.0 Hz), 1.54 (d, 3H, J=7.0 Hz), 1.48 (s,
3H); 13C NMR: l 129.3, 119.1, 35.9; MS m/z (rel. int.):
457 (1), 439 (27), 263 (23), 261 (100), 213 (87), 198 (24),
178 (35), 146 (32), 118 (28), 91 (15).
4.13. 3-({2-Methoxy-6-[(1S)-1-(methylthio)ethyl]phenyl}-
seleno)-6-methyl-2-phenyl-2,3,4,5-tetrahydropyridine
1-oxide 13d
1
Oil; major diastereoisomer: H NMR: l 7.40–7.25 (m,
4H), 7.19 (dd, 1H, J=1.2, 7.9 Hz), 7.08–7.02 (m, 2H),
6.84 (dd, 1H, J=1.2, 7.9 Hz), 5.08–5.01 (m, 1H), 4.78
(quart, 1H, J=7.0 Hz), 4.08 (quart, 1H, J=3.5 Hz),
3.93 (s, 3H), 3.01–2.92 (m, 1H), 2.63–2.57 (m, 1H),
2.32–2.29 (m, 3H), 2.02–1.93 (m, 1H), 1.97 (s, 3H),
1.83–1.76 (m, 1H), 1.59 (d, 3H, J=7.0 Hz); 13C NMR:
l 160.0, 149.3, 147.0, 139.0, 130.6, 129.1 (two carbons),
128.1, 126.6 (two carbons), 120.3, 118.0, 109.9, 75.8,
56.6, 45.0, 43.5, 29.2, 21.8, 20.2, 19.2, 14.4; MS m/z
(rel. int.) 433 (M+−16, 1), 261 (20), 213 (29), 172 (100),
104 (15), 91 (22), 77 (6). Anal. calcd for C22H27NO2SSe:
C, 58.93; H, 6.07; N, 3.12. Found: C, 58.85; H, 6.18; N,
2.99%.
Acknowledgements
Financial support from MURST, National Project
‘Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni’, the University of Perugia, Progetti di
Ateneo, and CNR, Rome, is gratefully acknowledged.
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