Chiral oxazoline-1,3-dithianes: New effective nitrogen-sulfur donating ligands in asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2005.08.043

A series of new chiral oxazoline-1,3-dithianes has been easily synthesized and used as ligands for asymmetric catalysis. The conjugate addition of Et ₂Zn to enones resulted in ees of up to 69%, whereas the Pd-catalyzed allylic alkylation led to

Full text of DOI:10.1016/j.tetasy.2005.08.043

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3232–3240
Chiral oxazoline-1,3-dithianes: new effective
nitrogen–sulfur donating ligands in asymmetric catalysis
*
`
Elena Capito, Luca Bernardi, Mauro Comes-Franchini, Francesco Fini,
Mariafrancesca Fochi, Salvatore Pollicino and Alfredo Ricci*
`
Dipartimento di Chimica Organica ‘A. Mangini’, Universita di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Received 2 August 2005; accepted 30 August 2005
Abstract—A series of new chiral oxazoline-1,3-dithianes has been easily synthesized and used as ligands for asymmetric catalysis.
The conjugate addition of Et2Zn to enones resulted in ees of up to 69%, whereas the Pd-catalyzed allylic alkylation led to the
expected products in almost quantitative yields and up to 90% enantioselectivity. The ligandÕs conformation has been explored using
a combination of X-ray and NMR measurements, indicating the presence of a remarkable anomeric effect, which accounts for the
preference of the oxazoline ring for the axial location.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
which when associated with a positional scanning like
strategy allows the synthesis of a new type of ligands
and a quick optimization of their structure.
The development of new chiral ligands for metal-catal-
yzed asymmetric transformations is an important task
in the field of enantioselective asymmetric synthesis.1
The effect of sulfur chelation on the level of asymmetric
induction for bidentate ligands and catalysts has been
widely reported. An inherent characteristic of thioether
ligands is that upon coordination with the metal, the sul-
fur atom becomes stereogenic2 and the close proximity
of the chirality to the coordination sphere of the transi-
tion metal may be beneficial. Moreover, in combination
with N chelation sites, thioether ligands have been suc-
cessfully tested and a number of asymmetric catalytic
C–C bond forming reactions relying to Pd-catalyzed
allylic substitutions,3 to additions to aldehydes4 and to
conjugate additions,5 have been reported so far.
2. Result and discussion
2.1. Ligand synthesis
In all cases, homochiral oxazoline-1,3-dithianes were
prepared by cyclic dehydration of the intermediate
hydroxyamides. These were accessed by treating the
readily available 1,3-dithiane-2-carboxylic acid 1 and
2-methyl-1,3-dithiane-2-carboxylic acid 2 with enantio-
merically pure 2-amino alcohols from the chiral pool
in the presence of DCC in CH2Cl2 as the solvent. Con-
version of the hydroxyl group into a good nucleofuge8
followed by cyclization was performed through tosyla-
tion in the presence of DMAP and Et3N to give ligands
7–10. In the case of 1,2-disubstituted 2-amino alcohols,
oxazoline formation according to this procedure being
However, whereas the mono3c,e,6 and also to some
extent the S,S-dithioeter moiety7 have been used to date,
the 1,3-dithianyl motif appears unprecedented in the
design and synthesis of new hybrid ligands for asymmetric
catalysis.
unsuccessful, the modified protocol by Vorbruggen
¨
was applied.9 In this procedure, the acid and the
2-amino alcohols, (1R,2S)-norephedrine and (1S,2R)-2-
amino-1,2-diphenylethanol, were treated with hexa-
chloroethane/PPh3 and a base to generate oxazolines
(S,S)-11 and (R,R)-12, respectively, in a single step
without isolation of the intermediate hydroxyamide
(Scheme 1).
Herein, we report a simple, modular and efficient design
of enantiomerically pure chiral oxazoline-1,3-dithianes,
*
Corresponding authors. Tel.: +39 0512093635; fax: +39
0512093654; e-mail: ricci@ms.fci.unibo.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.043

`
E. Capito et al. / Tetrahedron: Asymmetry 16 (2005) 3232–3240
3233
R'''
O
R'
*
O
O
S
R''
R
S
N
R = H, R' = Bn 7
R = Me, R' = Bn 8
R = Me, R' = iPr 9
R = Me, R' = tBu 10
N
S
N
S
S
S
14
R'' = Me, R''' = Ph 11
R'' = Ph, R''' = Ph 12
b)
d)
c)
S
HO
O
S
R'
R
COOH
O
S
R
S
OH
a)
N
a)
S
N
H
H
R = H, R' = Bn 3
R = Me, R' = Bn 4
R = Me, R' = iPr 5
R = Me, R' = tBu 6
S
13
R = H 1
R = Me 2
Scheme 1. Reagents and conditions: (a) amino alcohol, DCC, CH2Cl2, 18 h, rt; (b) TsCl, DMAP, Et3N, CH2Cl2, 6 h, rt; (c) PPh3, Cl3CCCl3, Et3N,
CH3CN, CH2Cl2, 10 h, rt; (d) Zn(OAc)2, 170 ꢁC, 8 h.
O
O
Finally, starting from (1R,2S)-(+)-cis-1-amino-2-inda-
nol, a synthetic route to 14 was envisaged among those
reported in the literature,10 in which cyclization of the
intermediate carboxyamide 13 promoted by Zn acetate
occurred with full retention of configuration and com-
plete stereochemical integrity of the carbon–oxygen
bond at C-5, thus giving rise to the cis-oxazoline system
in good yields.
Cu(OTf) 2.1% / L* 4.2% / Et2Zn 1.2 equiv
R'
R'
Solvent / -20˚C - 0˚C / 6h
R
R
Ia R = Ph, R' = Ph
Ib R = Ph R' = Me
Ic R = H, R' = -(CH2)3-
Ia-c
IIa-c
Scheme 2.
2.2. Conjugate addition
able solvents, the former however leading to better
enantioselectivity.
The new ligands were used in the copper-catalyzed
conjugated addition of diethylzinc to enones. The asym-
metric formation of carbon–carbon bonds using the
asymmetric conjugate addition reaction has been widely
investigated. Conditions have been developed, using a
catalytic quantity of copper triflate and chiral ligands
associated to an organozinc reagent to perform this
reaction in high yield and good to excellent enantioselec-
tivity. In particular, chiral phosphonites,11 phospho-
ramidites12 and other chiral P, N ligands13 have been
used. However, an important limitation is that they
often exhibit high substrate specificity. Further efforts
are therefore required to design new chiral catalysts,
which can be applied more generally to different cyclic
and acyclic substrates. Despite the early results obtained
with thiolate ligands in the asymmetric copper catalyzed
conjugate addition to enones,5a,14 sulfur ligands have
been less studied than their phosphorus counterparts.
With a new set of chiral ligands in hand, we first evalu-
ated their performance in the reaction of diethylzinc
with a representative acyclic enone, chalcone Ia. The
catalytic system was generated in situ by the addition
of a twofold excess of the corresponding ligand to a
solution of copper salts followed by the addition of
diethylzinc. Reactions were carried out in either toluene
or diethyl ether at ꢀ20 ꢁC giving in all cases as the sole
product, the 1,4 adduct in satisfactory yields (Scheme 2).
For all the additions, the product was obtained in good
yields. The presence of a methyl group on the dithianyl
ring had a fundamental influence, since the reaction per-
formed using 7 led (Table 1, entry 1) only to decompo-
sition of the ligand with no trace of the addition product
being recovered from the reaction mixture. Substituents
in close proximity to the oxazoline nitrogen were found
to exert a strong influence on the stereochemical out-
come. A significant improvement in the enantioselectiv-
ity (62% ee) with respect to the 15% ee obtained in the
case of compound 11 (entry 8) was achieved (entry 2)
by using ligand 8, in which instead of a methyl group,
a benzyl group lies adjacent to the nitrogen. This trend
also suggests that even bulkier substituents, such as phe-
nyl next to the oxygen, might exert only a negligible
influence. A further improvement in enantioselectivity
(69% ee) was obtained (entry 9) in the case of ligand
14 derived from the amino indanol in which a significant
steric hindrance at the a-position to nitrogen combines
with the formation of a tricyclic rigid motif. Strangely
enough, ligand 9 with a branched group such as the iso-
propyl group in proximity to the oxazoline nitrogen did
not prove beneficial regarding the enantioselectivity
(entry 5). We then examined the behaviour of other
Michael acceptors, benzalacetone Ib and 2-cyclohexene-1-
one Ic, under the optimized experimental conditions
previously used for chalcone using ligands 8, 9 and 14.
In the literature, catalytic conjugate additions of orga-
nometallic reagents with chiral ligand/metal complexes
are reported to show enantioselectivity for only one spe-
Different copper(I) or copper(II) salts could be used as
precursors of the active copper(I) catalyst, but only tri-
flates and in particular the CuOTf-based catalysts gave
higher conversions. Diethyl ether and toluene were suit-

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E. Capito et al. / Tetrahedron: Asymmetry 16 (2005) 3232–3240
3234
Table 1. Cu/L* catalyzed enantioselective 1,4-conjugate addition of Et2Zn to enonesa
Entry
L*
Enone
Adduct
Solvent
Yield (%)b
ee (%)c
Config.
1
2
3
4
5
6
7
8
(S)-7
(S)-8
(S)-8
(S)-8
(S)-9
(S)-9
(S)-9
(S,S)-11
(R,S)-14
(R,S)-14
(R,S)-14
Ia
Ia
Ib
Ic
Ia
Ib
Ic
Ia
Ia
Ib
Ic
IIa
IIa
IIb
IIc
IIa
IIb
IIc
IIa
IIa
IIb
IIc
Toluene
Et2O
Toluene
Toluene
Et2O
Toluene
Toluene
Et2O
—
80
55
>95
73
49
>95
60
77
54
>95
—
62
46
37
50
36
24
15
69
53
51
—
S
S
S
S
S
S
R
R
R
R
9
10
11
Et2O
Toluene
Toluene
a Reaction conditions as in Scheme 2.
b Yields of isolated products.
c For ee determination see Section 4.
cific type of enone. So far, NiII/chiral amino alcohol
complexes are enantioselective for the addition of Et2Zn
to acyclic enones, but for cyclic enones no enantioselec-
tivity was found.15 Conversely, the application to this
reaction of chiral phosphorus ligands derived from tad-
dol afforded poor enantioselectivities for acyclic enones,
the best results being obtained with chalcone.16 A sub-
stantial improvement was achieved by Feringa,17 who
obtained relatively high ee values for both cyclic and
acyclic enones by using phosphorus amidites. The trend,
which emerges from Table 1 indicates that both acyclic
enones Ib and c afford moderate to very good yields of
the expected adducts though with lower but still signifi-
cant enantioselectivities as compared to chalcone. It
should be pointed out that again ligand 14 gave the best
enantioselectivities for all the investigated enones afford-
ing 53% ee for the trans-4-phenyl-3-buten-2-one and
51% ee for the 2-cycloexen-1-one.
as an auxiliary donor atom providing enantioselectivi-
ties of 40–96%. The idea of using ligands containing
two different donor atoms has been exploited for palla-
dium catalyzed allylic substitution, wherein it is antici-
pated19 that the differing electronic behaviour of the
two donor atoms will be relayed to the intermediate pal-
ladium allyl complex and thereby import asymmetric
induction. The synthesized ligands 7–12 and 14 were
tested in this catalytic system to see if they were able
to bind to a suitable palladium precursor and interact
with the allylic substrate. Allylic substitutions of acetate
were carried out using [Pd(g3-C3H5)Cl]2 and a mixture
of dimethyl malonate, N,O-bis(trimethylsilyl)acetamide
(BSA) and potassium acetate in methylene chloride at
room temperature (Scheme 3). The ligand and palla-
dium pre-catalysts were premixed in CH2Cl2 at room
temperature for 1 h prior to the reaction. After 4 h,
the isolated product IV was assayed for enantiomeric
excess by employing HPLC analysis on a Daicel Chiralcel
AD-H column with absolute configuration determined
by comparison with literature values.20
Regarding the nature of the catalytic species in the con-
jugate addition, an ML2-type complex was formed using
both a 1:1 or a 1:2 ligand/metal ratio. This result is sup-
ported experimentally by the ESI mass spectrum of the
Cu2+/ligand complex. The observed ESI-MASS molecu-
lar peak of 649, indicates that four of the eight ligand
sites, and most likely one of the thienyl sulfur atom
and the nitrogen of each oxazoline ring, are bound to
the copper. The two OTf counterions are outside the
tetrahedral coordination sphere, and therefore the 1,3-
dithianyl oxazoline behaves as a bidentate ligand.
The results for the Pd-catalyzed allylic substitution are
reported in Table 2. The presence of a methyl substitu-
ent on the dithianyl ring had no influence on the reac-
tion outcome (compare entries 1 and 2) with both
ligands 7 and 8 providing the desired product in almost
quantitative yields and moderate enantioselectivity.
A significant improvement in the enantioselectivity
materialized with ligand 9, whereas the highest level of
enantioselectivity (90% ee) was achieved with ligand 10
(entry 4). This confirms that superior levels of asymmet-
ric induction can be rationalized in terms of steric
factors. The same trend emerges when considering
disubstituted ligands 11, 12 and 14. Significant improve-
ments of the enantioselectivity with respect to ligand 11
2.3. Pd-catalyzed allylic substitution
Pd-catalyzed allylic substitution reactions have been
intensively studied with sulfur containing ligands over
the past few years. Williams18 prepared various S,N
ligands containing oxazoline functionalities and sulfur
MeOOC
Ph
COOMe
Ph
AcO
Pd-cat. 2.5% / L* 10 mol%
Ph
Ph
CH2(CO2Me)2 / CH2Cl2 / r.t /4 h
IV
III
Pd-cat.= [Pd(η3-C3H5)Cl]2
Scheme 3.

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E. Capito et al. / Tetrahedron: Asymmetry 16 (2005) 3232–3240
3235
Table 2. Allylic substitution of rac-III in the presence of oxazoline-
dithianyl ligandsa
Table 3. Effect of the substitution on the 1,3-dithianyl ring on the
catalytic efficiency
Entry
L*
Yield (%)b
ee (%)c
Config.
Entry L*a
Conjugate addition
Allylic substitution
1
2
3
4
5
6
7
(S)-7
(S)-8
(S)-9
(S)-10
(S,S)-11
(R,R)-12
(R,S)-14
94
96
96
96
98
98
94
50
54
62
90
48
74
72
S
S
S
S
S
R
R
1
2
3
(S)-8 Yield: 80% ee 62% (S) Yield: 94% ee 54% (S)
19a
19b
Yield: 45% ee 70% (S) Yield: 98% ee 48% (S)
Yield: 50% ee 44% (S) Yield: 98% ee 66% (S)
a For the description of 19a and 19b see Section 4.
respect to the reference compound (S)-8 (entry 1) and
for this reason they were not subjected to further inves-
tigations nor further efforts were made in order to estab-
lish their absolute stereochemistry.
a Reaction conditions as in Scheme 3.
b Yields of isolated products.
c For ee determination see Section 4.
2.4. Ligand conformational considerations
(ee 48%) were obtained using ligand 12 (ee 74%) con-
taining a phenyl group instead of a methyl group, while
ligand 14 provided good enantioselectivity (72% ee) con-
firming that hindered substituents on the oxazoline ring
were influential to ensure different enantiodiscrimina-
tion. The configuration of the final product was (S)
using ligand (S,S)-11 (entry 5) and (R) using (R,R)-12
(entry 6).
In order to understand these results better, it was essen-
tial to shed some light on the ligand structure. The
conformational analysis of several 2-substituted-1,3-
dithianes has been reviewed21 and the energy differences
between axially and equatorially substituted structures
have been evaluated in terms of anomeric effect (DE).
In general, for substituted heterocyclic systems, the axial
conformer is favoured when electronic delocalization is
dominant and the equatorial position is preferred when
steric effects predominate. According to the interpreta-
tion of the anomeric effect given by Edward,22 electro-
static dipole/dipole repulsions should disfavour the
equatorial conformer, while dipole–dipole attraction
should favour the axial one. Juaristi studied the confor-
mational equilibria of 2-substituted-1,3-dithianes, which
show23 the expected interplay of steric, electrostatic and
stereoelectronic interactions. The low temperature (ꢀ90
to ꢀ100 ꢁC) 13C NMR spectra of mobile dithianes give
rise to two sets of signals, which correspond to the axial
and equatorial conformers and integration of the peak
areas afforded the equilibrium constants and the confor-
mational free energy differences. On the other hand, in
the low temperature (ꢀ90 to ꢀ100 ꢁC) 13C NMR spectra
of 2-carboxylic-1,3-dithiane, no signals for the equato-
rial conformer were detected.24 In order to establish
the preferred conformation of the synthesized oxazoline
Having examined the effect of the oxazoline ring substit-
uents on the stereochemical outcome of the two proto-
typical reactions studied, and in an attempt to further
improve the enantioselectivity we turned our attention
to the effect of placing substituents on the thianyl ring.
For this, we synthesized the two 4,6-dimethyl-1,3-dithia-
nyl oxazolines 19a and 19b. The target ligands were ob-
tained following the sequence reported in Scheme 4.
Separation of the diastereomeric mixture of the
hydroxyamides followed by ring closure afforded the
stereochemically pure ligands, which were fully charac-
terized. However, serious difficulties encountered in
their crystallization hindered the establishment of their
absolute configuration.
Though not configurationally defined, these ligands
modified in the 1,3-dithianyl ring were engaged in the
conjugate addition and allylic alkylation under the opti-
mized reaction conditions previously found. The follow-
ing features emerged when their reaction outcome was
compared to that obtained using ligand (S)-8 bearing
the same substituent in the oxazoline ring (Table 3).
1
1,3-dithianes, a H NMR analysis was carried choosing
14 as a representative ligand. In C6D6, in the tempera-
ture range from ꢀ85 to +20 ꢁC, the spectra showed
the existence of a single isomer in solution. To establish
if the oxazoline ring occupied the equatorial (a) or axial
(b) position, a single crystal X-ray analysis25 was per-
formed on 14, which clearly showed that the oxazoline
ring occupies the axial position, thus confirming the
presence of a significant anomeric effect and the preva-
lence of the electronic over the steric effects (Fig. 1).
Whereas ligand 19a had an effect on the enantioselective
conjugate addition (ee increased) but was detrimental
for the allylic alkylation (ee decreased) (entry 2), the
opposite trend was observed on using ligand 19b (entry
3). However, both displayed marginal effects with
O
O
COOH
e), f)
N
N
Ph
Ph
+
S
S
OH OH
OTs OTs
b)
c), d)
S
S
a)
S
S
S
S
(d,l)-2,4-Pentanediol
( )-15
( )-16
( )-17
19a
19b
Scheme 4. Reagents and conditions: (a) TsCl, Pyridine, 0 ꢁC, 40 h. (b) Na2S, S8, DMF, 85 ꢁC, 72 h. (c) LiAlH4, THF, 3 h, 60 ꢁC. (d) pyruvic acid,
benzene, p-TsOH, 80 ꢁC, 3 h. (e) phenylalaninol, DCC, CH2Cl2, 18 h, rt. Separation of the two diastereoisomers by column chromatography.
(f) TsCl, DMAP, Et3N, CH2Cl2, 6 h, rt.

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E. Capito et al. / Tetrahedron: Asymmetry 16 (2005) 3232–3240
3236
chemicals were used as obtained or purified by conven-
tional methods if needed.
4.2. General procedures for the synthesis of the carboxylic
acid
To a solution of the appropriate thiane (33.3 mmol) in
167 mL of anhydrous THF, n-BuLi (solution 1.6 M in
hexane, 34.9 mmol) was added at ꢀ20 ꢁC. After 1.5 h
at ꢀ20 ꢁC, CO2 (dry ice) was added quickly (166.3 mmol)
and the mixture was stirred for 1 h and at room temper-
ature for 2 h. After quenching with NH4Cl, the mixture
was concentrated to reduce the volume of the solvent.
The aqueous layer was acidified to pH 3 with HCl 1 M,
extracted with EtOAc, dried over MgSO4, filtered and
concentrated. The crude was purified on column chro-
matography (petroleum ether/EtOAc 4:1) to afford the
corresponding products 1 and 2.
Figure 1. ORTEP drawing of 14.
3. Conclusions
The design and synthesis of a new class of chiral oxazo-
line 1,3-dithianes has been achieved and their efficiency
as ligands in both copper-catalyzed diethylzinc addition
to enones and palladium-catalyzed allylic substitution
investigated. Though there are not unifying views on
the ligand structure–enantioselectivity relationship as
yet, in both these reactions the asymmetric induction
appears closely related to the steric hindrance exerted by
the group adjacent to the oxazoline nitrogen. The poten-
tial of the reported ligands in other catalytic asymmetric
transformations is currently under investigation in our
laboratory.
4.2.1. 1,3-Dithiane-2-carboxylic acid 1. Yield: 45%. Mp
1
114–116 ꢁC. H NMR (300 MHz, CD3OD) d: 1.84–1.98
(2H, m), 2.48–2.55 (2H, m), 3.15–3.24 (2H, m), 4.14 (1H,
s), 4.80 (1H, br s) ppm. 13C NMR (75.3 MHz, CD3OD)
d: 25.18 (CH2), 26.07 (2CH2), 41.08 (CH), 172.17 (C@O)
ppm. EI-MS (m/z): 164 (M+).
4.2.2. 2-Methyl-1,3-dithiane-2-carboxylic acid 2. Yield:
1
70%. Mp 137.9–140.5 ꢁC. H NMR (300 MHz, CDCl3)
d: 1.55 (3H, s), 1.63–1.79 (1H, m), 2.01–2.12 (1H, m),
2.48–2.56 (2H, m), 3.25–3.36 (2H, m), 10.13 (1H, br s)
ppm. 13C NMR (75.3 MHz, CDCl3) d: 23.91 (CH3),
25.40 (CH2), 28.08 (2CH2), 45.63 (C), 178.06 (C@O)
ppm. EI-MS (m/z): 178 (M+).
4. Experimental
4.1. General remarks
Melting points (uncorrected) were determined with a
Buchi melting point apparatus. 1H NMR and 13C
4.3. General procedures for the synthesis of amides 3–6
¨
NMR spectra were recorded using CDCl3 solutions or
C6D6 as the solvent at 300 and 400 MHz and 75 and
100 MHz, respectively. Chemical shifts (d) are reported
To a solution of the carboxylic acid (3.04 mmol) in
18 mL of CH2Cl2, DCC (3.19 mmol) was added in small
portions at 0 ꢁC. After 30 min at 0 ꢁC, the amino alcohol
(2.9 mmol) was added and the mixture stirred at room
temperature for 18 h. After filtering on Celite, the solu-
tion was washed with 10% Na2CO3 and brine. The
organic phases were dried over MgSO4, filtered and
concentrated. The crude was purified by silica gel
column chromatography (petroleum ether/EtOAc 1:1)
to afford amides 3–6.
1
in parts per million relative to CHCl3 (d = 7.26 for H
and d = 77.0 for 13C). J values are given in hertz. 13C
NMR spectral assignments were made by DEPT experi-
ments. IR spectra were recorded on a Perkin–Elmer
model 257 grating spectrometer. Mass spectra were
obtained using a VG 7070-E spectrometer at an ionizing
voltage of 70 eV or with an electronspray ionization
source (ESIMS). All the ESIMS spectra were performed
20
using MeOH as the solvent. ½aꢁD values were determined
with Perkin–Elmer Polarimeter 341. Reactions were
conducted in oven-dried (120 ꢁC) glassware under a
positive Ar atmosphere. Transfer of anhydrous solvents
or mixtures was accomplished with oven-dried syringes/
septum techniques. THF was distilled from sodium/ben-
zophenone just prior to use and stored under Ar. Et2O
was distilled from phosphorus pentoxide twice. CH2Cl2
was passed through basic alumina and distilled from
CaH2 prior to use. Other solvents were purified by stan-
dard procedures. Light petroleum ether refers to the
fraction with bp 40–60 ꢁC. The reactions were moni-
tored by TLC performed on silica gel plates (Baker-flex
IB2-F). Column chromatography was performed with
Merck silica gel 60 (70–230 mesh). Preparative thick
layer chromatography was carried out on glass plates
using a 1 mm layer of Merck silica gel 60 Pf 254. All
4.3.1. N-[(1S)-1-Benzyl-2-hydroxyethyl]-1,3-dithiane-2-
carboxamide 3. Yield: 40%. [a]D = ꢀ29.2 (c 0.5,
1
CHCl3). H NMR (300 MHz, CDCl3) d: 1.81–1.92 (2H,
m), 2.43–2.55 (2H, m), 2.65–2.87 (4H, m), 3.48–3.64
(2H, m), 4.08–4.14 (1H, m), 4.19 (1H, s), 6.69 (1H, br
d, J = 7.59 Hz), 7.04–7.22 (5H, m) ppm. 13C NMR
(75.3 MHz, CDCl3) d: 25.22 (CH2), 27.82 (2CH2), 37.01
(CH2), 46.30 (CH), 53.67 (CH), 63.87 (CH2), 126.72
(ArCH), 128.75 (2ArCH), 129.54 (2ArCH), 137.82
(ArC), 168.85 (C@O) ppm. EI-MS (m/z): 297 (M+).
4.3.2.
N-[(1S)-1-Benzyl-2-hydroxyethyl]-2-methyl-1,3-
dithiane-2-carboxamide 4. Yield: 53%. [a]D = ꢀ17.8 (c
1
0.5, CHCl3). H NMR (300 MHz, CDCl3) d: 1.45 (3H,
s), 1.66–1.91 (2H, m), 2.36–2.41 (2H, m), 2.44–2.61
(2H, m), 2.64–2.95 (2H, m), 3.50–3.75 (2H, m), 4.16

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(1H, m), 7.10–7.24 (5H, m) 7.36 (1H, br d) ppm. 13C
NMR (75.3 MHz, CDCl3) d: 24.2 (CH2), 28.3 (CH3),
29.5 (2CH2), 37.1 (CH2), 53.4 (CH), 56.1 (C), 64.0
(CH2), 126.1 (ArCH), 128.3 (2ArCH), 129.5 (2ArCH),
138.2 (ArC), 172.6 (C@O) ppm. EI-MS (m/z): 311 (M+).
13C NMR (75.3 MHz, CDCl3) d: 24.78 (CH2), 26.75
(CH3), 28.38 (2CH2), 41.78 (CH2), 43.09 (C), 67.27
(CH), 71.84 (CH2), 126.40 (ArCH), 128.40 (2ArCH),
129.44 (2ArCH), 138.18 (ArC), 168.90 (C@N) ppm.
EI-MS (m/z): 293 (M+). C15H19NOS2: C, 61.39; H,
6.53; N, 4.77. Found: C, 61.37; H, 6.50; N, 4.79.
4.3.3.
N-[(1S)-1-(Hydroxymethyl)-2-methylpropyl]-2-
methyl-1,3-dithiane-2-carboxamide 5. Yield: 43%.
[a]D = ꢀ18.6 (c 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3) d: 0.86–0.94 (6H, m), 1.62 (3H, s), 1.73–1.92
(2H, m), 1.99–2.07 (1H, m), 2.63–2.70 (2H, m), 2.83–
2.96 (2H, m), 3.20–3.26 (1H, m), 3.56–3.70 (3H, m),
7.45 (1H, br d, J = 8.9 Hz) ppm. 13C NMR
(75.3 MHz, CDCl3) d: 18.85 (CH3), 20.04 (CH3), 24.33
(CH2), 28.14 (CH3), 28.98 (2CH2), 29.13 (CH), 55.56
(C), 58.16 (CH), 63.70 (CH2), 171.73 (C@O) ppm.
EI-MS (m/z): 263 (M+).
4.4.3.
(4S)-4-Isopropyl-2-(2-methyl-1,3-dithiane-2-yl)-
4,5-dihydro-1,3-oxazole 9. Yield: 81%. [a]D = ꢀ64 (c
1
0.3, CHCl3). H NMR (300 MHz, CDCl3) d: 0.70 (3H,
m), 0.79 (3H, m), 1.53 (3H, m), 1.55–1.74 (2H, m),
1.91–1.98 (1H, m), 2.45 (2H, d, J = 12.89 Hz), 3.04–
3.16 (1H, m), 3.25–3.38 (1H, m), 3.71–3.93 (2H, m),
4.06–4.16 (1H, m) ppm. 13C NMR (75.3 MHz, CDCl3)
d: 18.22 (CH3), 18.57 (CH3), 24.70 (CH2), 26.79 (CH3),
28.18 (2CH2), 33.06 (CH), 42.81 (C), 70.33 (CH2),
72.08 (CH), 168.57 (C@N) ppm. EI-MS (m/z): 245
(M+). C11H19NOS2: C, 53.84; H, 7.80; N, 5.71. Found:
C, 53.81; H, 7.82; N, 5.70.
4.3.4. N-[(1S)-1-(Hydroxymethyl)-2,2-dimethylpropyl]-2-
methyl-1,3-dithiane-2-carboxamide 6. Yield: 41%. 1H
NMR (300 MHz, CDCl3) d: 0.98 (9H, s), 1.72 (3H, s),
1.79–1.95 (1H, m), 2.03–2.16 (1H, m), 2.38 (br s, 1H),
2.69–2.78 (2H, m), 2.91–3.06 (2H, m), 3.51–3.57 (1H,
m), 3.77–3.84 (1H, m), 3.95 (1H, dd, J = 3.6 Hz,
J = 11.1 Hz), 7.55 (1H, br d, J = 9.1 Hz) ppm. 13C
NMR (75.3 MHz, CDCl3) d: 25.32 (CH2), 27.32
(3CH3), 29.73 (CH3), 34.29 (2CH2), 56.44 (C), 61.54
(CH), 63.98 (CH2), 172.30 (C@O) ppm. EI-MS (m/z):
277 (M+).
4.4.4.
(4S)-4-tert-Butyl-2-(2-methyl-1,3-dithiane-2-yl)-
4,5-dihydro-1,3-oxazole 10. Yield: 60%. [a]D = ꢀ68 (c
1
0.3, CHCl3). H NMR (300 MHz, CDCl3) d: 0.97 (9H,
s), 1.75 (3H, s), 1.81–1.92 (1H, m), 2.12–2.20 (1H, m),
2.61–2.75 (2H, m), 3.25–3.39 (1H, m), 3.42–3.59 (1H,
m), 3.86–3.99 (1H, m), 4.18–4.35 (2H, m) ppm. 13C
NMR (75.3 MHz, CDCl3) d: 24.60 (CH2), 26.15
(3CH3), 27.06 (CH3), 28.42 (CH2), 28.51 (CH2), 34.08
(C), 69.51 (CH2), 75.74 (CH), 167.08 (C@N) ppm. EI-
MS (m/z): 259 (M+). C11H21NOS2: C, 55.56; H, 8.16;
N, 5.40. Found: C, 55.53; H, 8.15; N, 5.42.
4.4. General procedures for the synthesis of oxazoles 7–10
To a solution of the amide (1.2 mmol) in 8.5 mL of
CH2Cl2 were added TsCl (1.8 mmol), Et3N (3.6 mmol)
and DMAP (0.06 mmol). After 18 h at room tempera-
ture, a solution of Na2CO3 10% was added and the mix-
ture stirred for 20 min. The solution was extracted with
CH2Cl2 (3 · 30 mL). The organic phases were dried over
MgSO4, filtered and concentrated. The crude was puri-
fied on column chromatography on silica gel (petroleum
ether/EtOAc 3:1) to afford oxazoles 7–10.
4.5. General procedures for the synthesis of oxazoles 11–
12
To a stirred suspension of 0.18 g (1 mmol) of the carbox-
ylic acid 2 in 3.3 mL of dry CH3CN were added amino
alcohol (1 mmol), triphenylphosphine (0.66 g, 2.5 mmol)
and triethylamine (0.7 mL). The mixture was cooled to
0 ꢁC and then a solution of 0.52 g (2.2 mmol) of hexa-
chloroethane in 2 mL of CH2Cl2 was added slowly.
After 18 h at room temperature, water was added, the
mixture extracted with EtOAc (3 · 15 mL), dried over
MgSO4, filtered and concentrated. The crude was puri-
fied by silica gel column chromatography (petroleum
ether/EtOAc 5:1) to afford the oxazoles 11 and 12.
4.4.1. (4S)-4-Benzyl-2-(1,3-dithian-2-yl)-4,5-dihydro-1,3-
oxazole 7. Yield: 73%. Mp 81.3–83.2 ꢁC [a]D = ꢀ19 (c
1
0.3, CHCl3). H NMR (300 MHz, CDCl3) d: 1.26–1.38
(2H, m), 1.83–1.95 (2H, m), 2.15 (1H, dd, J = 7.7 Hz,
J = 13.7 Hz), 2.57 (1H, dd, J = 5.9 Hz, J = 13.7 Hz),
2.76–2.86 (2H, m), 3.29–3.44 (2H, m), 3.80–3.90 (1H,
m), 4.11 (1H, s), 6.61–6.81 (5H, m) ppm. 13C NMR
(75.3 MHz, CDCl3) d: 25.41 (CH2), 27.08 (2CH2),
37.85 (CH), 41.44 (CH2), 67.75 (CH), 71.81 (CH2),
126.36 (ArCH), 128.71 (2ArCH), 129.69 (2ArCH),
138.31 (ArC), 165.82 (C@N) ppm. EI-MS (m/z): 279
(M+). C14H17NOS2: C, 60.18; H, 6.13; N, 5.01. Found:
C, 60.13; H, 6.10; N, 5.03.
4.5.1. (4S,5S)-4-Methyl-2-(2-methyl-1,3-dithian-2-yl)-5-
phenyl-4,5-dihydro-1,3-oxazole
11. Yield:
78%.
[a]D = +40 (c 0.3, CHCl3). 1H NMR (300 MHz, CDCl3)
d: 1.02 (3H, d, J = 6.76 Hz), 1.29–1.53 (2H, m), 1.86
(3H, s), 1.99–2.10 (2H, m), 3.23–3.41 (2H, m), 3.72–
3.84 (1H, m), 4.55 (1H, d, J = 7.6 Hz), 6.90–7.12 (5H,
m) ppm. 13C NMR (75.3 MHz, CDCl3) d: 21.29
(CH2), 24.42 (CH3), 26.92 (2CH2), 28.19 (CH3), 42.70
(C), 70.89 (CH), 88.24 (CH), 125.55 (2ArCH), 128.14
(2ArCH), 128.88 (ArCH), 141.57 (ArC), 167.96 (C@N)
ppm. EI-MS (m/z): 293 (M+). C15H19NOS2: C, 61.39;
H, 6.53; N, 4.77. Found: C, 61.37; H, 6.50; N, 4.75.
4.4.2.
(4S)-4-Benzyl-2-(2-methyl-1,3-dithian-2-yl)-4,5-
dihydro-1,3-oxazole 8. Yield: 90%. Mp 38.4–39.6 ꢁC
[a]D = ꢀ28 (c 0.3, CHCl3). 1H NMR (300 MHz, CDCl3)
d: 1.43–1.51 (2H, m), 1.71 (3H, s), 2.04–2.15 (2H, m),
2.30 (1H, dd, J = 7.7 Hz, J = 13.8 Hz), 2.69 (1H, dd,
J = 5.9 Hz, J = 13.8 Hz), 3.21–3.30 (2H, m), 3.44–3.60
(2H, m), 3.92–4.03 (1H, m), 6.84–7.00 (5H, m) ppm.
4.5.2.
(4R,5R)-4-Methyl-2-(2-methyl-1,3-dithian-2-yl)-
4,5-diphenyl-4,5-dihydro-1,3-oxazole 12. Yield: 72%.
Mp 102.5–103.1 ꢁC. [a]D = +77 (c 0.3, CHCl3). 1H

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E. Capito et al. / Tetrahedron: Asymmetry 16 (2005) 3232–3240
3238
NMR (300 MHz, CDCl3) d: 1.29–1.49 (2H, m), 1.90
(3H, s), 1.99–2.08 (2H, m), 3.26–3.43 (2H, m), 4.92
(1H, d, J = 7.15 Hz), 5.01 (1H, d, J = 7.15 Hz), 6.87–
7.10 (10H, m) ppm. 13C NMR (75.3 MHz, CDCl3) d:
24.41 (CH2), 26.97 (CH3), 28.17 (CH2), 28.31 (CH2),
42.50 (C), 78.76 (CH), 89.27 (CH), 125.78–129.19
(10ArCH), 141.47 (ArC), 142.82 (ArC), 169.98 (C@N)
ppm. EI-MS (m/z): 355 (M+). C20H21NOS2: C, 67.57;
H, 5.95; N, 3.94. Found: C, 67.59; H, 5.93; N, 3.92.
69 mmol) in 180 mL of dimethylformamide was refluxed
for 72 h and poured into 300 mL of water and 100 g of
ice. The mixture was extracted with petroleum ether
(3 · 50 mL), the organic solution washed with NaCl,
dried over MgSO4, filtered and concentrated. The sol-
vent was removed under reduced pressure and the
resulting oil was used in the next reaction without any
further purification. Spectroscopic data are in accor-
dance with the reported values.
4.5.3. N-[(1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl]-
2-methyl-1,3-dithiane-2-carboxamide 13. To a solution
of carboxylic acid 2 (0.30 g, 1.68 mmol) in 10 mL of
CH2Cl2, DCC (0.35 g, 1.68 mmol) was added in small
portions at 0 ꢁC. After 30 min at 0 ꢁC, (1R,2S)-(+)-cis-
1-amino-2-indanol (0.24 g, 1.60 mmol) was added and
the mixture stirred at room temperature for 18 h. After
filtering on Celite, the solution was washed with 10%
Na2CO3 and brine. The organic phases were dried over
MgSO4, filtered and concentrated. The crude was puri-
fied by silica gel chromatography (petroleum ether/
EtOAc 3:1) to afford 0.28 g (58%) of the amide.
[a]D = +17.6 (c 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3) d: 1.77 (3H, s), 1.83–1.94 (1H, m), 2.08–2.19
(2H, m), 2.70–2.77 (2H, m), 2.94–3.13 (2H, m), 3.22
(1H, dd, J = 5.64 Hz, J = 16.22 Hz), 4.68–4.73 (1H,
m), 5.35 (1H, dd, J = 6.48 Hz, J = 9.08 Hz), 7.25–7.30
(4H, m), 7.84 (1H, br d, J = 9.5 Hz) ppm. 13C NMR
(75.3 MHz, CDCl3) d: 24.38 (CH2), 28.16 (CH3), 29.08
(CH2), 29.11 (CH2), 40.10 (CH2), 55.07 (C), 58.73
(CH), 74.02 (CH), 124.78 (ArCH), 125.73 (ArCH),
127.63 (ArCH), 128.73 (ArCH), 140.19 (ArC), 140.55
(ArC), 171.85 (C@O) ppm. EI-MS (m/z): 309 (M+).
4.5.7. 2,4,6-Trimethyl-1,3-dithiane-2-carboxylic acid ( )-
17. To 60 mL of LiAlH4 (solution 1 M in THF,
60 mmol) was added dropwise a solution of ( )-16
(8.6 g, 64 mmol) in 96 mL of THF. The resulting mix-
ture was refluxed for 2 h and then carefully quenched
with 10 mL of H2SO4 (1.3 M). The mixture was
extracted twice with diethyl ether and the combined
organic phase washed with brine, dried over MgSO4,
filtered and concentrated to afford the corresponding
racemic 2,4-pentanedithiol. Condensation of the dithiol
with 8.1 g (92 mmol) of pyruvic acid in 140 mL of benzene
containing 0.11 g (0.6 mmol) of p-toluenesulfonic acid
was performed by refluxing with a Dean–Stark trap
until no more water was formed (3 h). The crude was
diluted with diethyl ether and NaHCO3 was added.
The aqueous layer was acidified to pH 3 with 6 M HCl,
extracted with EtOAc, dried over MgSO4, filtered and
concentrated. The crude was purified on silica gel
column chromatography (petroleum ether/EtOAc 4:1)
to afford 4.5 g (22 mmol) of the corresponding acid with
1
an overall yield of 35% in two steps. H NMR (300
MHz, CDCl3) d: 1.23 (3H, d, J = 6.9 Hz), 1.46 (3H, d,
J = 7.5 Hz), 1.76 (3H, s), 1.76–1.83 (1H, m), 1.91–1.96
(1H, m), 3.26–3.33 (1H, m), 3.51–3.63 (1H, m), 9.78
(1H, br s) ppm. 13C NMR (75.3 MHz, CDCl3) d:
21.03 (CH3), 21.19 (CH3), 27.47 (CH3), 32.57 (CH),
37.92 (CH), 39.91 (CH2), 50.69 (C), 179.74 (C@O)
ppm. EI-MS (m/z): 206 (M+).
4.5.4. (3aR,8aS)-2-(2-Methyl-1,3-dithian-2-yl)-8,8a-dihy-
14. Zn(OAc)2
dro-3aH-indeno-[1,2-d]-[1,3]-oxazole
(2.34 g, 12.9 mmol) previously dried at 160 ꢁC for 3 h
at 10ꢀ1 mmHg and amide 13 (0.4 g, 1.3 mmol) were stir-
red at 170 ꢁC for 8 h. Water was added and the mixture
extracted with EtOAc (3 · 20 mL), dried over MgSO4,
filtered and concentrated. The crude was purified by sil-
ica gel column chromatography (petroleum ether/
EtOAc, 3:1) to afford (14) (0.17 g, 45%). Mp 91.5–
92.1 ꢁC. [a]D = +175 (c 0.3, CHCl3). 1H NMR
(400 MHz, C6D6) d: 1.42–1.56 (2H, m), 1.80 (3H, s),
1.99–2.06 (1H, m), 2.17–2.20 (1H, m), 2.79 (1H, dd,
J = 5.18 Hz, J = 17.29 Hz), 2.99–3.11 (2H, m), 3.50–
3.59 (1H, m), 4.58 (1H, dd, J = 6.91 Hz, J = 15.56 Hz),
5.21 (1H, d, J = 8.64 Hz), 6.88–7.01 (3H, m), 7.43 (1H,
br d, J = 7.22 Hz) ppm. 13C NMR (75.3 MHz, C6D6)
d: 24.54 (CH2), 26.56 (CH2), 27.83 (CH2), 28.84 (CH3),
39.71 (CH2), 43.17 (C), 76.76 (CH), 82.94 (CH), 125.18
(2ArCH), 125.69 (2ArCH), 139.55 (ArC), 142.32
(ArC), 167.97 (C@N) ppm. EI-MS (m/z): 291 (M+).
C15H17NOS2: C, 61.82; H, 5.88; N, 4.81. Found: C,
61.80; H, 5.86; N, 4.83. CCDC: 279691.
4.5.8. (4R,6R)- and (4S,6S)-N-[(1S)-1-benzyl-2-hydroxy-
ethyl]-2,4,6-trimethyl-1,3-dithiane-2-carboxamide
18.
The title compound was obtained following the general
procedure for the synthesis of the amide starting from
the racemic carboxylic acid ( )-17. The two diastereo-
isomers were separated by column chromatography on
silica gel (CH2Cl2/EtOAc 5:1) in an overall yield of
50%. Amide with higher Rf 18a: [a]D = ꢀ28.8 (c 0.55,
1
CHCl3). H NMR (300 MHz, CDCl3) d: 1.16 (3H, d,
J = 6.9 Hz), 1.27 (3H, d, J = 7.01 Hz), 1.59 (3H, s),
1.64–1.83 (2H, m), 2.81–2.95 (2H, m), 3.01–3.20 (2H,
m), 3.62–3.78 (2H, m), 4.08–4.16 (1H, m), 7.21–7.34
(5H, m) 7.61 (1H, br d, J = 7.7 Hz) ppm. 13C NMR
(75.3 MHz, CDCl3) d: 20.93 (CH3), 21.37 (CH3), 29.31
(CH3), 33.45 (CH), 37.19 (CH2), 37.43 (CH), 40.32
(CH2), 54.40 (CH), 54.60 (C), 65.00 (CH2), 127.13
(ArCH), 129.02 (ArCH), 129.40 (ArCH), 129.58
(2ArCH), 137.67 (ArC), 173.90 (C@O) ppm. EI-MS
(m/z): 338 (M+). Amide with lower Rf 18b:
[a]D = ꢀ13.7 (c 0.52, CHCl3). 1H NMR (300 MHz,
CDCl3) d: 1.08 (3H, d, J = 6.9 Hz), 1.15 (3H, d,
J = 7.37 Hz), 1.59 (3H, s), 1.62–1.76 (2H, m), 2.64–
2.81 (2H, m), 3.00–3.12 (2H, m), 3.61–3.78 (2H, m),
4.09–4.25 (1H, m), 7.20–7.33 (5H, m), 7.53 (1H, br d,
4.5.5. 2,4-Pentanediol ditosylate ( )-15. Prepared
according to the procedure previously reported.26
4.5.6. 3,5-Dimethyl-[1,2]-dithiolane ( )-16. A solution
of (d,l)-2,4-pentanediol ditosylate (28.4 g, 69 mmol),
sodium sulfite (16.5 g, 69 mmol) and sulfur (2.23 g,

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E. Capito et al. / Tetrahedron: Asymmetry 16 (2005) 3232–3240
3239
J = 7.44 Hz) ppm. 13C NMR (75.3 MHz, CDCl3) d:
20.86 (CH3), 21.50 (CH3), 29.32 (CH3), 32.50 (CH),
37.05 (CH2), 37.28(CH), 39.91 (CH2), 54.53 (CH),
54.75 (C), 65.69 (CH2), 127.03 (ArCH), 128.89 (ArCH),
128.98 (ArCH), 129.29 (ArCH), 129.47 (ArCH), 137.67
(ArC), 173.89 (C@O) ppm. EI-MS (m/z): 338 (M+).
(0.042 mmol, 4.2 mol %) in dry solvent (1 mL) was stir-
red at room temperature under argon. After 1 h, the a,b-
unsaturated ketone (0.5 mmol) was added. The solution
was then cooled to ꢀ20 ꢁC and Et2Zn (0.6 mmol,
0.6 mL of a 1 M solution of diethylzinc in hexane) was
added dropwise. The mixture was stirred from 20 to
0 ꢁC for 6 h. The reaction was quenched with HCl 1 M
(5 mL) and the aqueous layer was extracted twice with
EtOAc (2 · 5 mL). The combined organic extracts were
dried (Na2SO4), filtered and evaporated. Purification on
column chromatography on silica gel afforded the prod-
ucts. 1,3-Diphenyl-1-pentanone: The enantiomeric excess
was determined by HPLC analysis on a Daicel Chiralcel
OD column at k = 254 nm; flow rate 0. 2 mL/min;
eluent: hexane/i-PrOH 99.75/0.25, tS = 70.30 min, tR =
74.92 min. 3-Ethylcyclohexanone: The enantiomeric
excess was determined by chiral GC analysis on a Lipo-
dex E column at T = 60 ꢁC; tR = 23.21 min, tS =
24.48 min.
4.5.9.
(4S)-4-Benzyl-2-[(4R,6R)-2,4,6-trimethyl-1,3-
dithian-2-yl]-4,5-dihydro-1,3-oxazole and (4S)-4-benzyl-
2-[(4S,6S)-2,4,6-trimethyl-1,3-dithian-2-yl]-4,5-dihydro-
1,3-oxazole 19. The title compound was obtained fol-
lowing the general procedure for the synthesis of the
oxazoles starting from the corresponding enantiopure
amides 18a and 18b. Starting from the amide with higher
Rf 19a: Yield: 42%. [a]D = ꢀ37 (c 0.3, CHCl3). 1H NMR
(300 MHz, CDCl3) d: 1.25 (3H, d, J = 7.12 Hz), 1.40
(3H, d, J = 7.12 Hz), 1.74 (3H, s), 1.76–1.82 (1H, m),
1.88–1.94 (1H, m), 2.67 (1H, dd, J = 9.29 Hz,
J = 13.88 Hz), 3.19 (1H, dd, J = 4.86, J = 13.34 Hz),
3.23–3.30 (1H, m), 3.58–3.67 (1H, m), 4.08 (1H, t,
J = 8.23 Hz), 4.29 (1H, t, J = 8.56 Hz), 4.40–4.48 (1H,
m), 7.17–7.31 (5H, m) ppm. 13C NMR (75.3 MHz,
CDCl3) d: 21.10 (CH3), 21.24 (CH3), 28.74 (CH3),
33.09 (CH), 37.55 (CH), 40.43 (CH2), 40.92 (CH2),
47.45 (C), 67.88 (CH), 73.29 (CH2), 126.79 (ArCH),
128.76 (ArCH), 128.79 (ArCH), 129.51 (2ArCH),
137.95 (ArC), 170.40 (C@N) ppm. EI-MS (m/z): 321.
C17H23NOS2: C, 63.51; H, 7.21; N, 4.36. Found: C,
63.53; H, 7.19; N, 4.33. Starting from the amide with
4.8. General procedure for palladium catalyzed allylic
alkylation
In a 10 mL flame-dried Schlenk, [Pd(g3-C3H5)Cl]2
(4.6 mg, 0.0125 mmol, 2.5 mol %) and the chiral ligand
(0.05 mmol, 10 mol %) were dissolved under argon in
dry and degassed CH2Cl2 (1 mL) and the resulting solu-
tion was stirred at room temperature. After 1 h, the 1,3-
diphenylprop-3-en-1-yl acetate (126 mg, 0.5 mmol) and
dimethyl malonate (198 mg, 1.5 mmol), respectively, in
1 and 0.5 mL of dry and degassed CH2Cl2 were added
successively, followed by N,O-(trimethylsilyl)acetamide
(BSA, 304 mg, 1.5 mmol, 0.366 mL) and a catalytic
amount of potassium acetate (1 mol %). The resulting
mixture was stirred at room temperature for 4 h, then
the solvent concentrated in vacuo to afford a dark crude.
The excess of dimethyl malonate was removed by bulb
to bulb distillation (65–75 ꢁC/2 mmHg) and the dark
crude mixture was purified by flash chromatography
(AcOEt/light petroleum 1/9), to afford 90–98% of prod-
uct as a colourless oil that solidified on standing. The
enantiomeric excess was determined by HPLC analysis
on a Daicel Chiralcel AD-H column at k = 254 nm; flow
rate 0.75 mL/min; eluent: hexane/i-PrOH 90/10,
tR = 17.69 min, tS = 25.00 min.
1
lower Rf 19b: Yield: 48%. [a]D = +7 (c 0.3, CHCl3). H
NMR (300 MHz, CDCl3) d: 1.25 (3H, d, J = 6.78 Hz),
1.39 (3H, d, J = 7.52 Hz), 1.75 (3H, s), 1.76–1.81 (1H,
m), 1.88–1.94 (1H, m), 2.64 (1H, dd, J = 9.45 Hz,
J = 13.99 Hz), 3.20 (1H, dd, J = 4.63 Hz, J = 13.89 Hz),
3.23–3.31 (1H, m), 3.57–3.66 (1H, m), 4.07 (1H, t,
J = 7.74 Hz), 4.24 (1H, t, J = 8.57 Hz), 4.38–4.45 (1H,
m), 7.19–7.31 (5H, m) ppm. 13C NMR (75.3 MHz,
CDCl3) d: 20.91 (CH3), 21.11 (CH3), 28.69 (CH3),
33.39 (CH), 37.41 (CH), 40.54 (CH2), 41.30 (CH2),
47.53 (C), 67.78 (CH), 72.86 (CH2), 126.76 (ArCH),
128.76 (2ArCH), 129.56 (2ArCH), 137.84 (ArC),
170.29 (C@N) ppm. EI-MS (m/z): 321. C17H23NOS2:
C, 63.51; H, 7.21; N, 4.36. Found: C, 63.52; H, 7.22;
N, 4.37.
4.6. General procedure for the preparation of the complex
Cu(OTf)2/ligand
Acknowledgements
In a 10 mL flame dried flask, a solution of Cu(OTf)2
(4 mg, 0.0105 mmol, 2.1 mol %) and the chiral ligand
(0.042 mmol, 4.2 mol %) in dry toluene (1 mL) was stir-
red at room temperature under argon for 1 h. The sol-
vent was removed in vacuo and the residue was
analyzed by ESI-MS. Complex Cu(OTf)2/8: ESI-MS
(m/z) = 649 [Cu+2L], 356 [M+ꢀL], 294 [M+ꢀLꢀCu].
We acknowledge financial support by the National Pro-
ject ÔStereoselezione in Sintesi Organica. Metodologie ed
Applicazioni 2003Õ and by RTN project ÔDesign, Analy-
sis and Computation for Catalytic Organic ReactionsÕ,
contract HPRN-CT-2001-00172.
Complex
Cu(OTf)2/19a:
ESI-MS
(m/z) = 705
[Cu+2L], 384 [M+ꢀL], 321 [M+ꢀLꢀCu].
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