Synthesis of enantiomerically pure acyclic α-sulfinyl ketimines

Article abstract of DOI:10.1016/S0957-4166(98)00211-0

Two different methods to obtain enantiomerically pure N-alkyl and N- aryl α-sulfinyl ketimines are reported. Reaction of enantiomerically pure α-sulfinyl ketones (1-6) with benzylamine or p-methoxyaniline, in the presence of molecular sieves (3 A), yields

Full text of DOI:10.1016/S0957-4166(98)00211-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2437–2450
Synthesis of enantiomerically pure acyclic α-sulfinyl ketimines
José L. García Ruano,∗ Antonio Lorente and Jesús H. Rodríguez Ramos ∗
Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Received 11 May 1998; accepted 25 May 1998
Abstract
Two different methods to obtain enantiomerically pure N-alkyl and N-aryl α-sulfinyl ketimines are reported.
Reaction of enantiomerically pure α-sulfinyl ketones (1–6) with benzylamine or p-methoxyaniline, in the presence
of molecular sieves (3 Å), yields the corresponding of N-benzyl and N-p-methoxyphenyl ketimines (7A–12A and
7B–12B). Better results were achieved by α-sulfinylation of ketimines (13A–18A and 13B–18B) with (−)-menthyl
p-toluenesulfinate in the presence of lithium (N-arylimines) or magnesium (N-benzylimines) bases. The different
tautomeric behaviour of the obtained N-aryl and N-alkyl derivatives is reported. © 1998 Published by Elsevier
Science Ltd. All rights reserved.
1. Introduction
The sulfinyl group has been used profusely as a chiral auxiliary in asymmetric synthesis.1 Its influence
on the stereochemical course of nucleophilic additions to α-sulfinyl ketones, such as hydride reductions,2
alkylations,3 and hydrocyanations,4 has been widely studied. By contrast, α-sulfinyl imines have been
much less studied despite their increasing importance in the synthesis of biologically active molecules,5
and their usefulness in asymmetric synthesis.6 This could be due to the fact that efficient synthetic
methods to prepare enantiomerically pure α-sulfinyl imines have only just recently been reported and
they usually lack general scope. Thus, if the reported methods of synthesising α-sulfinyl imines are
classified according to the bond of the fragment N–C–C–S which is created during the synthesis, those
involving the N–C bond formation, such as the Michael addition of amines to allenic sulfoxides7
(the low energetic barrier to racemize allenes precludes obtaining optically active substrates) and
8
condensation reactions of α-sulfinyl ketones with amines catalysed by TiCl4 (the yields are lower
than 30% presumably due to concomitant reduction of the sulfinyl group by the catalyst), are not very
efficient. Better results were obtained by addition of amines to sulfinyl acetylenes5a,9 and aza-Wittig
reactions of triphenyliminophosphoranes with α-sulfinyl ketones,6 but the first method is limited to
∗
Corresponding authors. E-mail: jesus.rodriguez@uam.es
0957-4166/98/$ - see front matter © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00211-0

2438
J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
the synthesis of sulfinyl enamines derived from aldehydes and the second one can be applied only
to α0-fluorinated ketones. Reactions of imidoyl chlorides with lithium enolates of chiral non-racemic
methyl p-tolyl sulfoxide, involving C(1)–C(2) bond formation, has been successfully used to prepare
N-substituted γ-fluorinated α-sulfinyl imines,10 but the authors only describe reactions of substrates
lacking an α-hydrogen. The same strategy was used in reactions of metallated sulfoxides with nitriles
to give unstable N-unsubstituted enamines, which are reduced in situ into equimolecular mixtures of
diastereoisomeric aminosulfoxides.11 This procedure has also been used to prepare racemic α-sulfenyl
α-sulfinyl enamines.12 Reactions involving C(2)–S bond formation were first reported by Annunziata
et al. in 1982,13 who studied the reaction of lithium enamines with menthyl p-toluenesulfinate to afford
optically active sulfinyl imines. Unfortunately, the yields described starting from ketimines were not
satisfactory. Good results in the synthesis of sulfinyl ketimines have only been reported for compounds
exhibiting endocyclic5b,14 and exocyclic15 C_N bonds.
Hence, we can conclude that efficient methods of preparing enantiomerically pure acyclic α-sulfinyl
ketimines have not yet been described. We report herein the complete results obtained in the synthesis
of the N-benzyl and N-p-methoxyphenyl imines by two different methods: condensation of α-sulfinyl
ketones with amines (C–N bond formation, route 1) and addition of α-metallated enamines to menthyl
p-toluenesulfinate (C–S bond formation, route 2) (Scheme 1).16
Scheme 1.
2. Results and discussion
α-Sulfinyl imines 7–12 were initially synthesised by reaction of the amines with enantiomerically pure
α-sulfinyl ketones 1–617 (route 1, Scheme 1) in the presence of molecular sieves (3 Å).18 The yields and
reaction conditions used with p-methoxyaniline (A) and benzylamine (B) are shown in Table 1. The use
of TiCl4 as a catalyst in the reactions of compounds 1–6 with benzylamine, under similar conditions
to those used by Kagan and Baldenius in similar processes,8 was not successful because it leads to the
reduction of the sulfinyl group to sulfenyl.
Benzene was the solvent used for the reactions of 1–4 (R1=alkyl) with benzylamine whereas diethyl
ether gave better results with 5 and 6 (R1=Ph). The reactions of 1 and 2 with p-methoxyaniline required
higher temperatures and evolved with lower yields than those corresponding to benzylamine, whereas
compounds 9A–12A could not be obtained by this procedure (Table 1).
The second route to obtain sulfinyl imines involved the α-sulfinylation of imines 13–18, prepared in
high yields (75–95%) from the corresponding ketones by condensation with p-methoxyaniline (A) or
benzylamine (B), in the presence of molecular sieves (3 Å).
Reaction of benzyl imines 15 and 17 with menthyl p-toluenesulfinate, using LDA as a base, yielded
the expected α-sulfinyl imines 9A and 11A, which were partially racemized (Scheme 2)20, as could be
demonstrated by their hydrolysis into sulfinyl ketones 3 (77% ee) and 5 (11% ee) respectively.19
This partial racemization can be explained as the result of the ambident nucleophilic character of
the azaenolates,21 determining the formation of the C-sulfinylated and N-sulfinylated products, the

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
2439
Table 1
Results obtained in the reaction of α-sulfinylketones 1–6 with benzylamine (A) and p-methoxyaniline
(B)
Scheme 2.
latter being able to act as a sulfinylating agent in a new attack of the azaenolate with inversion of the
configuration at sulfur (Scheme 3).22 Therefore mixtures of sulfinyl imine epimers at sulfur are obtained.
Scheme 3.
To avoid sulfur epimerization, magnesium azaenolates instead of the corresponding lithium ones

2440
J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
Table 2
Results obtained in the reaction of α-metallated imines 13–18 with menthyl p-toluenesulfinate
were used. The best results were obtained by reaction of the imine with LDA in THF followed by
transmetallation with MgBr2 prior to the addition of the sulfinate (the direct use of magnesium bases
is less satisfactory probably due to solubility problems). The yields and reaction conditions used with the
different substrates are collected in Table 2. The generation of the azaenolate by slow addition of imine
to the base (thus precluding the coexistence of imine/enolate and, therefore, their autocondensation)
improved the yield in the case of 11B. Steric hindrance probably precludes achieving high yields in the
synthesis of compounds 10B and 12B.
Lithium azaenolates derived from N-arylimines 13A–18A do not produce racemization at sulfur in
their reactions with menthyl p-toluenesulfinate. Their higher reactivity, as compared with the magnesium
ones, and the lower tendency of arylimines to give autocondensation, allowed better yields under
milder conditions to be achieved. As we can see in Table 2, the synthesis of compounds 7A–12A
was highly satisfactory in all cases. The lower nucleophilic character of the nitrogen in azaenolates
derived from arylimines would explain that ‘N-sulfinylation’ does not compete in these reactions with
‘C-sulfinylation’, thus avoiding the epimerization at sulfur.
Regioselectivity in the formation of azaenolates is a problem inherent to unsymmetrical imines 14 and
15 (with R1=n-Pr or i-Pr and R2=H), but it was only observed in the case of 14A (in the other cases the
azaenolate is formed exclusively on the less substituted methyl carbon). At −78°C sulfinylation of imine
14A afforded an 80:20 mixture of compounds 8A and 19A, whereas at 0°C the ratio of both products
in the mixture was inverted. These results are compatible with the known influence of temperature in
the kinetic (at low temperatures the less hindered positions are favoured) or thermodynamic (at higher
temperatures the most substituted positions are favoured) control of the formation of the enolates, but it
contrasts with the reported results indicating that syn-azaenolates on the less substituted carbon are the
most stable ones23 (in this sense, the expected behaviour is that of the N-benzylimine 14B, yielding the
same azaenolate regardless of the conditions used).
This different behaviour of 14A and 14B could be rationalised by considering the relative contribution

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
2441
of the two mesomeric forms describing the structure of their azaenolates (see Scheme 3). Carbanionic
form I must be the most important one for alkylimines such as 14B, whereas enamine anionic form II
would be the most important for arylimines such as 14A, due to the ability of the R3 to stabilise (aromatic
ring) or destabilise (alkyl group) the negative charge at the nitrogen. Thus, under thermodynamic control
conditions, factors governing the relative stability of the C_C double bonds (such as their degree of
substitution) will be the main ones responsible for the control of the regioselectivity for substrates
exhibiting higher contribution of the form II (arylimines), whereas factors accounting for the stability
of the carbanions (primary more stable than secondary) must be mainly invoked to predict or explain
the regioselectivity for substrates with form I as predominant (alkylamines). In any case, the strongly
negative influence of the substitution in the reactivity of the carbanions determines that the tertiary ones
do not react, the reactions conducted on 15A and 15B being completely regioselective.24
Sulfinylimine 19A was obtained as a mixture of epimers at C-α (19A and 19A0) (Scheme 4), their
ratio being dependent on the temperature of protonation in the work-up of the reaction mixture.25 Thus,
when the quenching is done at room temperature, mixtures of 19A and 19A0 (ranging between a 70:30
and an 80:20 ratio) were isolated, whereas if the reaction mixture obtained at 0°C is cooled to −78°C
before its hydrolysis, a 95:5 mixture of 19A and 19A0 was obtained, from which epimer 19A could be
isolated in high yield by easy column chromatography.
Scheme 4.
On the other hand, the equilibration of isomer 19A in an acidic medium (HCl(g):CH2Cl2) yielded a
1:1 mixture of epimers. Nevertheless, its treatment with LiHMDS (from −22°C to rt) in CH2Cl2 for 3
h followed by protonation at room temperature determines the formation of epimeric mixtures in which
compound 19A0 is clearly predominant. The composition of the mixture depends on the concentration,
being most favourable when dilution is increased (see Scheme 5).
Scheme 5.
Presumably the strong differences observed in the composition of the epimeric mixtures are mainly
related to the ability of the solvent to coordinate the metallic cation (Scheme 6). The THF used in the
reaction of formation of 19 from imine 14A is able to do this, and the azaenolate will exhibit conformation
C as the most stable one in order to minimise the electrostatic repulsion between the negative charge at
sulfinylic oxygen and nitrogen. In contrast, the poor coordinating ability of CH2Cl2 must determine that
the metal remains joined to the azaenolate forming a chelate D. By assuming that protonation takes place

2442
J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
from the less hindered face of C and D respectively, we can explain the stereochemistry assigned to
epimers 19A and 19A0.
Scheme 6.
2.1. Imine–enamine structure
All the prepared α-sulfinyl imines have α-hydrogens and therefore they can exhibit the imine–enamine
prototropic equilibrium. In general, the iminic form is the most stable one in the solid state,26 whereas
there have been described several examples of α-sulfinyl imines where the proportion of the enaminic
tautomer is significant or the major one in solution.13,15b,27,28 The interaction of the enaminic double bond
with aromatic and/or electron withdrawing groups and the formation of intra- or intermolecular hydrogen
bonding, are the main factors responsible for the stabilisation of the enaminic tautomer. However, the
relative contribution of both tautomers depends on the solvent, concentration, temperature, as well as the
substituents existing in the NCC framework of the studied compound.
Tautomers are easily identified from NMR parameters of the crude reaction mixtures or of the isolated
compounds. In Table 3 the significant NMR chemical shifts used for determination of the imine and/or
enamine structure of compounds 7–12 and 19 are collected.
The imine structure in compounds without substituents at C-2 (7–11) show an AB system at 4.4–3.5
1
ppm in the H-NMR spectrum, corresponding to methylenic protons at this carbon. In the enamine
tautomer this system is replaced by a singlet corresponding to a vinylic proton in the 5.4–4.9 ppm range
and other signals of the NH group. The identification of both tautomeric forms in the 13C-NMR spectrum
is also straightforward. The chemical shift of C-2 ranges from 101 to 98 ppm in the enamine form whereas
this signal appears at a higher field (69–56 ppm) in the imine form. The C–N signal can also be used
for differentiation since it appears up to 10 ppm deshielded in the imine tautomer with respect to that
corresponding to the enamine form, even though in some cases the difference can be smaller.
As we can see, N-benzyl derivatives adopt an exclusive [R1=n-Pr (8B), i-Pr (9B), Ph (11B)] or
predominantly [R1=Me (7B)] enaminic form, which can be explained by assuming the formation of an
intramolecular hydrogen bond in this form. Only t-butyl derivative 10B is present as an imine, probably
due to the steric hindrance between benzyl and t-butyl groups present in the intramolecularly associated
enaminic tautomer. It is important to emphasise that the imine–enamine equilibrium for compound 7B
(the only N-benzylderivative where both tautomers were present) showed a considerable dependence on
the concentration of the studied CDCl3 solutions. The imine–enamine ratio changed from 1:2.2 for a

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
2443
Table 3
Significant 1H- and 13C-NMR chemical shifts of compounds 7–12 and 19 (δ ppm, CDCl3)
30 mg/ml solution to 1:8 for a 140 mg/ml solution. On the other hand, we assume that all compounds,
including 7B, adopt a Z-configuration for the enaminic double bond, with an intramolecular associated
hydrogen bonding, because of the invariability of 1H-NMR parameters with concentration and according
to information given in the literature.26a,b27,13
The lower importance of the intramolecular hydrogen bond as the stabilising factor of the enaminic
form in N-aryl derivatives must be responsible for the presence of both tautomers 7A–9A and 12A
and only the iminic form in 10A, 11A, 19A and 19A0. The NMR spectra of the crude 9A and 12A
isolated by chromatography showed signals corresponding to several structures including tautomeric
and stereoisomeric forms, making their individual assignation and relative ratio determination difficult.
Fortunately, compounds 8A and 12A crystallise as exclusively enaminic tautomers in concentrated
solutions of diethyl ether or methylene chloride, allowing us to characterise them. Enamine 8A quickly
tautomerises to the original tautomer mixture whereas 12A remains unchanged after several days even in
solutions at low concentration.

2444
J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
3. Experimental
3.1. General methods
All moisture sensitive reactions were performed in flame-dried glassware equipped with rubber
septa under a positive pressure of argon and monitored by TLC. Solvents were dried according to
literature procedures.29 Flash chromatography was performed with silica gel 60 (230–400 mesh ASTM).
Melting points were determined in a Gallenkamp apparatus in open capillary tubes and are uncorrected.
The optical rotations were measured at room temperature (20–23°C) using a Perkin–Elmer 241 MC
polarimeter (concentration in g/100 ml). The NMR spectra were recorded in CDCl3 solutions at 200.1
1
and 50.3 MHz for H- and 13C-NMR respectively; δ chemical shifts refer to TMS (1H) or deuterated
chloroform (13C) signals. The IR spectra were obtained as CH2Cl2 solutions. Elemental analyses were
performed with a Perkin–Elmer 2400 CHN analyser.
3.2. Synthesis of sulfinyl imines
Method A: In a round bottomed flask containing 5–7 g of molecular sieves (3 Å) were introduced
2.23 mmol (1 equiv.) of the corresponding sulfinyl ketone and 1.1–2.0 equiv. of p-methoxyaniline or
benzylamine dissolved in 20 ml of benzene. The reaction mixture was gently stirred (in order to avoid the
break up of molecular sieves) at the indicated temperature for the corresponding reaction time (Table 1)
and filtered over Celite. The solid was washed with CH2Cl2, the combined filtrates were concentrated at
reduced pressure, and the residue purified by flash chromatography.
Method B: To a solution of 1.54 ml (11.22 mmol, 3.3 equiv.) of diisopropylamine in 10 ml of anhydrous
THF cooled at −48°C was added 4.65 ml (10.71 mmol, 3.15 equiv.) of a 2.3 M solution of n-butyllithium
in hexane. The mixture was stirred for 15 min and then a solution of 2.1–6.0 equiv. of the corresponding
imine in 20 ml of THF was slowly added (20–90 min). To N-benzylimines (after 15 min) at −48°C,
43 ml (11.9 mmol, 3.5 equiv.) of a freshly prepared 0.28 M solution of MgBr2 in THF was added (this
was not necessary for N-p-methoxyphenylimines). After 20 min, 1 g (3.4 mmol, 1 equiv.) of menthyl
(S)-p-toluenesulfinate dissolved in 10 ml of THF was added. The mixture was then allowed to reach
room temperature which decomposed after 1 h with 20 ml of a saturated aqueous NH4Cl solution. The
organic layer was washed with 20 ml of CH2Cl2, dried and concentrated, and the residue purified by
chromatography or crystallisation.
3.3. (R)-N-(p-Methoxyphenyl)-1-methyl-2-(p-tolylsulfinyl)ethylidenamine 7A
Compound 7A was prepared as an oil from sulfinyl ketone 1 and 1.5 equiv. of p-methoxyaniline
[method A; the crude product was purified by chromatography, hexane:acetone (35:10) containing 10%
triethylamine as the eluent; yield 65%] or from N-(p-methoxyphenyl)-1-methylethylidenamine (13A)
(2.1 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time of the imine was 45 min; the
crude product was purified by chromatography, AcOEt:hexane (20:25) containing 10% triethylamine as
the eluent; yield 80%]. The product was present as a mixture of two imines and one enamine (50:10:40,
NMR); [α]D +109 (c 0.6, CH2Cl2); δH imine (50): 7.60 and 7.36 (AA0BB0 system, 4H), 6.83 and 6.52
(AA0BB0 system, 4H), 3.91 and 3.80 (AB system, 2H, J 12.9 Hz), 3.78 (s, 3H), 2.43 (s, 3H), 1.89 (s, 3H);
imine (10): 7.60 and 7.36 (AA0BB0 system, 4H), 6.82 and 6.54 (AA0BB0 system, 4H), 3.78 (s, 3H), 3.73
and 3.53 (AB system, 2H, J 12.4 Hz), 2.41 (s, 3H), 2.33 (s, 3H); enamine (40): 7.45 and 7.22 (AA0BB0
system, 4H), 7.04 and 6.83 (AA0BB0 system, 4H), 5.63 (bs, 1H), 5.33 (s, 1H), 3.75 (s, 3H), 2.40 (s, 3H),

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
2445
2.36 (s, 3H); δC 163.0, 161.3, 156.4, 155.8, 153.3, 152.0, 143.3, 142.5, 142.2, 141.7, 141.4, 139.8, 139.5,
139.1, 131.5, 129.7, 129.5, 129.0, 125.6, 124.0, 123.6, 123.4, 120.4, 120.3, 115.9, 114.2, 113.8, 113.7,
100.1, 68.1, 67.0, 59.9, 55.2, 54.9, 31.4, 27.3, 21.0, 20.8, 17.6; IR 3410, 2970, 1645, 1595, 1507, 1440,
1240, 1185, 1090, 1030, 840 cm−1
.
3.4. (R)-N-Benzyl-1-methyl-2-(p-tolylsulfinyl)ethylidenamine 7B30
Compound 7B was obtained as a white solid from sulfinyl ketone 1 and 1.5 equiv. of benzylamine
[method A; purification of the crude product was carried out by grinding it with a mixture of diethyl
ether:hexane (3:1); yield 88%] or from N-benzyl-1-methylethylidenamine (13B) (2.5 equiv.) and menthyl
(S)-p-toluenesulfinate [method B; addition time of the imine was 45 min; the crude product was purified
by chromatography, AcOEt:hexane (2:1) containing 10% triethylamine as the eluent; yield 83%]. The
product was present as a mixture of one imine and one enamine (31:69, NMR); mp 102–104°C; [α]D −8
(c 1.0, CH2Cl2); δH imine: 7.53–7.16 (m, 9H), 4.50 (s, 2H), 3.82 and 3.71 (AB system, 2H, J 10 Hz),
2.41 (s, 3H), 2.02 (s, 3H); enamine: 7.45–7.16 (m, 9H), 5.04 (s, 1H), 4.95 (m, 1H), 4.22–4.01 (m, 2H),
2.38 (s, 3H), 2.31 (s, 3H); δC imine: 162.5, 129.8, 128.3, 126.6, 68.5, 55.5, 21.3, 19.6; enamine: 154.2,
143.9, 139.5, 137.0, 129.3, 128.7, 127.7, 124.4, 124.2, 99.3, 47.4, 21.1, 18.0.
3.5. (R)-N-(p-Methoxyphenyl)-1-n-propyl-2-(p-tolylsulfinyl)ethylidenamine 8A
Compound 8A was obtained as an oil from sulfinyl ketone 2 and 1.1 equiv. of p-methoxyaniline
[method A; the crude product was purified by chromatography, AcOEt:hexane (4:3) containing 10%
triethylamine as the eluent; yield 60%] or from N-(p-methoxyphenyl)-1-methylbutylidenamine (14A)
(2.1 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time of the imine was 20 min; the
crude was stirred in hexane for 1 h at room temperature and at −20°C for 3 h. Work-up of the mixture
afforded an oil which was chromatographed using AcOEt:hexane (20:30) containing 5% triethylamine
as the eluent; yield 80%]. The product was obtained as an imine–enamine mixture (dependent on the
concentration) which solidified into a white solid on standing. NMR data refer to a 17% CDCl3 solution
where the enamine is the only tautomer present; mp 83–84°C; [α]D +153 (c 1.0, CH2Cl2); δH 7.55 and
7.31 (AA0BB0 system, 4H), 7.12 and 6.86 (AA0BB0 system, 4H), 5.38 (s, 1H), 5.37 (bs, 1H), 3.82 (s,
3H), 2.82 (m, 2H), 2.46 (s, 3H), 1.93 (m, 2H), 1.19 (t, 3H, J 7.4 Hz); δC 157.6, 156.7, 143.5, 139.3,
132.8, 129.2, 125.9, 124.2, 114.1, 99.8, 55.1, 33.7, 23.0, 21.0, 13.6. IR 3230, 3200, 2800, 1650, 1580,
1510, 1470, 1420, 1295, 1240, 1180, 1090, 1040, 840, 810 cm−1; anal. calcd for C19H23NO2S: C 69.27,
H 7.04, N 4.25. Found: C 69.34, H 7.21, N 4.34.
3.6. [2R,(S)R]-N-(p-Methoxyphenyl)-1-methyl-2-(p-tolylsulfinyl)butylidenamine 19A
Compound 19A was obtained as a white solid in the reaction of N-(p-methoxyphenyl)-1-
methylbutylidenamine (14A) (2.1 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition
time of the imine was 20 min. The reaction mixture was quenched at −78°C and the resulting mixture
was allowed to reach room temperature. The purification of the crude product was carried out as for
compound 8A using AcOEt:hexane (18:30) containing 5% triethylamine as the eluent; yield 80%]. The
product is present as the imine tautomer; mp 96–97°C; [α]D +115 (c 1.0, CH2Cl2); δH 7.51 and 7.34
(AA0BB0 system, 4H), 6.77 and 6.26 (AA0BB0 system, 4H), 3.75 (s, 3H), 3.46 (m, 1H), 2.43 (s, 3H),
2.04 (m, 2H), 1.83 (s, 3H), 1.11 (t, 3H, J 7.4 Hz); δC 166.8, 155.9, 143.0, 141.4, 138.1, 129.5, 124.7,
120.2, 113.9, 75.2, 55.3, 21.3, 20.2, 19.7, 11.6; IR 2940, 1610, 1509, 1470, 1370, 1295, 1250, 1100,

2446
J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
1090, 1060, 1040 cm−1; anal. calcd for C19H23NO2S: C 69.27, H 7.04, N 4.25. Found: C 69.63, H 6.98,
N 4.24.
3.7. [2S,(S)R]-N-(p-Methoxyphenyl)-1-methyl-2-(p-tolylsulfinyl)butylidenamine 19A0
To a solution of 1 g (3 mmol, 1 equiv.) of 19A in 40 ml of anhydrous CH2Cl2 was added at −22°C,
3.3 ml of a 1 M solution of LiHMDS in hexane (3.3 mmol, 1.1 equiv.). The reaction mixture was allowed
to reach room temperature and then stirred for 3 h and hydrolysed with a saturated aqueous NH4Cl
solution. The organic layer was dried (Na2SO4) and concentrated. The resulting oil was purified by
chromatography using AcOEt:hexane (18:30) containing 5% triethylamine as the eluent; yield 80%
(white solid). The product was present as the imine tautomer; mp 115–116°C; [α]D −151 (c 1.0,
CH2Cl2); δH 7.60 and 7.32 (AA0BB0 system, 4H), 6.83 and 6.46 (AA0BB0 system, 4H), 3.74 (s, 3H),
3.50 (t, 1H, J 7.2 Hz), 2.40 (s, 3H), 2.25 (m, 2H), 1.56 (s, 3H), 1.09 (t, 3H, J 7.3 Hz); δC 166.6, 155.7,
142.6, 141.6, 139.0, 129.2, 125.0, 119.9, 113.7, 77.0, 54.8, 20.9, 20.7, 10.8; IR 2990, 1655, 1500, 1470,
1380, 1300, 1250, 1190, 1110, 1090, 1060, 1050, 840, 810 cm−1; anal. calcd for C19H23NO2S: C 69.27,
H 7.04, N 4.25. Found: C 69.05, H 6.94, N 4.16.
3.8. (R)-N-Benzyl-1-n-propyl-2-(p-tolylsulfinyl)ethylidenamine 8B
Compound 8B was obtained as a white solid from sulfinyl ketone 2 and 1.1 equiv. of benzylamine
[method A; the crude product was crystallised from acetone:hexane; yield 90%] or from N-benzyl-1-
methylbutylidenamine (14B) (2.3 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time of
the imine was 30 min; the crude product was purified by chromatography, hexane:acetone:triethylamine
(4:3:1) as the eluent; yield 80%]. The product was present as the enamine tautomer; mp 112–113°C; [α]D
−50 (c 1.0, CH2Cl2); δH 7.47–7.21 (m, 9H), 5.04 (s, 1H), 4.42 (m, 1H), 4.21–4.02 (m, 2H), 2.83–2.37
(m, 2H), 2.38 (s, 3H), 1.84–1.54 (m, 2H), 1.03 (t, 3H, J 7.3 Hz); δC 158.4, 144.0, 139.3, 137.2, 129.2,
128.5, 127.5, 127.4, 124.5, 98.6, 47.2, 33.9, 23.1, 21.1, 13.7; IR (CHCl3 solution): 3420, 3040, 1580,
1500, 1460, 1030, 810 cm−1; anal. calcd for C19H23NOS: C 72.80, H 7.40, N 4.47. Found: C 72.65, H
7.65, N 4.30.
3.9. (R)-N-(p-Methoxyphenyl)-1-isopropyl-2-(p-tolylsulfinyl)ethylidenamine 9A
Compound 9A was obtained as an oil from N-(p-methoxyphenyl)-1,2-dimethylpropylidenamine (15A)
(2.3 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time of the imine was 45 min; the
treatment of the crude product was carried out as compound 8A using AcOEt:hexane (13:30) containing
5% triethylamine as the eluent; yield 93%]. The product was present as a mixture of two imines and
one enamine [estimated ratio 52:42:6 (NMR)]; [α]D +71.34 (c 0.8, CH2Cl2); δH, assigned signals: imine
(52): 3.83 and 3.57 (AB system, 2H, J 12.4 Hz), 3.79 (s, 3H), 2.80 (septuplet, 1H, J 6.9 Hz), 2.43 (s, 3H),
1.24 (d, 3H, J 6.9 Hz), 1.22 (d, 3H, J 6.9 Hz); imine (42): 4.05 and 3.68 (AB system, 2H, J 14.6 Hz),
3.80 (s, 3H), 2.79 (septuplet, 1H, J 6.9 Hz), 2.38 (s, 3H), 1.02 (d, 3H, J 6.9 Hz), 0.72 (d, 3H, J 6.9 Hz);
enamine (6): 5.51 (bs, 1H), 5.20 (s, 1H), 3.74 (s, 3H), 2.40 (s, 3H), 1.35 (d, 3H, J 7.0 Hz), 1.39 (d, 3H,
J 7.0 Hz); δC 171.4, 168.8, 161.7, 156.9, 155.8, 143.6, 142.9, 141.8, 141.6, 141.0, 139.3, 129.8, 129.5,
129.2, 126.4, 124.7, 124.1, 123.6, 120.3, 119.7 116.1, 115.5, 114.5, 114.0, 99.7, 77.6, 61.4, 58.8, 55.4,
55.1, 37.2, 30.9, 29.1, 27.3, 21.4, 21.2, 21.0, 20.7, 19.7, 19.0, 18.8, 14.0; IR 3080, 3000, 2410, 1515,
1430, 1270, 1050, 910 cm−1
.

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
2447
3.10. (R)-N-Benzyl-1-isopropyl-2-(p-tolylsulfinyl)ethylidenamine 9B
Compound 9B was obtained as a white solid from sulfinyl ketone 3 and 1.1 equiv. of benzylamine
[method A; the crude product was purified by chromatography, AcOEt:hexane (2:1) containing 5%
triethylamine as the eluent; yield 54%] or from N-benzyl-1,2-dimethylpropylidenamine (15B) (2.3
equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time of the imine was 30 min; the crude
product was purified by chromatography, AcOEt:hexane (2:1) containing 5% triethylamine as the eluent;
yield 84%]. The product was present as the enamine tautomer; mp 136–138°C; [α]D −66.1 (c 1.0,
CH2Cl2); δH 7.60–7.19 (m, 9H), 4.94 (s, 1H), 4.39 (m, 1H), 4.22–3.97 (m, 2H), 3.75 (septuplet, 1H,
J 7.0 Hz), 2.40 (s, 3H), 1.26 (t, 6H, J 7.0 Hz); δC 166.4, 144.1, 139.3, 137.2, 129.2, 128.6, 127.5, 127.4,
124.3, 98.0, 47.0, 29.1, 21.7, 21.1, 20.8; IR 3485, 3000, 2415, 1590, 1510, 1215, 1020 cm−1; anal. calcd
for C19H23NOS: C 72.80, H 7.40, N 4.47. Found: C 72.90, H 7.39, N 4.33.
3.11. (R)-N-(p-Methoxyphenyl)-1-t-butyl-2-(p-tolylsulfinyl)ethylidenamine 10A
Compound 10A was obtained as a white solid from N-p-methoxyphenyl)-1,2,2-trimethylpropyliden-
amine (16A) (2.5 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time of the imine
was 90 min; the crude product was purified by chromatography, AcOEt:hexane (1:4) containing 5%
triethylamine as the eluent. The obtained oil was treated with AcOEt:hexane (1:4) until solidification
occurred; 82% yield]. The product was present as the imine tautomer; mp 96–98°C; [α]D −88.3 (c 0.8,
CH2Cl2); δH 7.22 and 7.12 (AA0BB0 system, 4H), 6.89 and 6.67 (AA0BB0 system, 4H), 3.82 (s, 3H),
3.83 and 3.71 (AB system, 2H, J 9.2 Hz), 2.38 (s, 3H), 1.31 (s, 9H); δC 171.3, 156.0, 143.6, 141.5, 129.8,
123.4, 120.2, 114.2, 57.8, 55.4, 40.3, 28.0, 21.3; IR 3060, 3000, 2310, 1430, 1270, 1160, 1050 cm−1
anal. calcd for C20H25NO2S: C 69.93, H 7.33, N 4.08. Found: C 69.99, H 7.06, N 4.35.
;
3.12. (R)-N-Benzyl-1-t-butyl-2-(p-tolylsulfinyl)ethylidenamine 10B
Compound 10B was obtained as a white solid from sulfinyl ketone 4 and 2.0 equiv. of benzylamine
[method A; the crude product was purified by chromatography, AcOEt:hexane (1:5) containing 10%
triethylamine as the eluent; yield 60%]. The product was present as the imine tautomer; mp 71–72°C;
[α]D +145.2 (c 1.0, CH2Cl2); δH 7.57 and 7.33 (AA0BB0 system, 4H), 7.31–7.26 (m, 5H), 4.71 and 4.52
(AB system, 2H, J 16.5 Hz), 4.04 and 3.66 (AB system, 2H, J 12.8 Hz), 2.42 (s, 3H), 1.21 (s, 9H); δC
167.7, 142.1, 141.2, 140.1, 130.1, 128.1, 127.1, 126.3, 123.7, 55.7, 55.3, 40.9, 28.4, 21.3; IR 3400, 2950,
1575, 1430, 1130, 1050 cm−1; anal. calcd for C20H25NOS: C 73.60, H 7.65, N 4.05. Found: C 73.35, H
7.70, N 4.27.
3.13. (R)-N-(p-Methoxyphenyl)-1-phenyl-2-(p-tolylsulfinyl)ethylidenamine 11A
Compound 11A was obtained as a yellow solid from N-(p-methoxyphenyl)-1-methylbenzylidenamine
(17A) (2.8 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time of the imine was 60 min;
the crude product was purified by chromatography, hexane:acetone (3:1) containing 7% triethylamine as
the eluent; 95% yield]. The product was present as the imine tautomer; mp 73–74°C; [α]D −144.6 (c 1.0,
CH2Cl2); δH 7.98–7.21 (m, 9H), 6.84 and 6.54 (AA0BB0 system, 4H), 4.37 and 4.10 (AB system, 2H,
J 12.7 Hz), 3.82 (s, 3H), 2.39 (s, 3H); δC 158.6, 156.1, 142.8, 141.8, 139.7, 137.4, 130.7, 129.6, 128.3,
127.7, 123.8, 120.4, 113.9, 57.4, 55.2, 21.1; IR 3200, 2625, 1725, 1690, 1610, 1405, 1330, 1150, 1040
cm−1; anal. calcd for C22H21NO2S: C 72.70, H 5.82, N 3.85. Found: C 72.19, H 5.74, N 3.86.

2448
J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
3.14. (R)-N-Benzyl-1-phenyl-2-(p-tolylsulfinyl)ethylidenamine 11B
Compound 11B was obtained as a white solid from sulfinyl ketone 5 and 1.3 equiv. of ben-
zylamine using diethyl ether as the solvent [method A; the crude product was purified by chro-
matography, AcOEt:hexane (2:1) containing 10% triethylamine as the eluent; yield 50%] or from
N-benzyl-1-methylbenzylidenamine (17B) (4.0 equiv.) and menthyl (S)-p-toluenesulfinate [method B;
addition time of the imine was 90 min; the crude product was purified by chromatography, ace-
tone:hexane:triethylamine (3:4:1) as the eluent. The obtained oil was stirred in hexane until solidification
occurred (12 h); yield 92%]. The product was present as the enamine tautomer; mp 97–98°C; [α]D −121
(c 1.0, CH2Cl2); δH 7.63–7.20 (m, 14H), 5.34 (s, 1H), 4.43 (m, 1H), 4.35–4.15 (m, 2H), 2.38 (s, 3H);
δC 157.5, 144.0, 139.2, 136.8, 135.3, 129.6, 129.1, 128.8, 128.5, 128.2, 127.4, 127.0, 124.3, 101.0, 47.6,
21.0; IR (CHCl3 solution) 3440, 2980, 1580, 1500, 1430, 1020, 810 cm−1; anal. calcd for C22H21NOS:
C 76.05, H 6.09, N 4.03. Found: C 75.94, H 6.15, N 3.94.
3.15. (R)-N-(p-Methoxyphenyl)-1-phenyl-2-(p-tolylsulfinyl)propylidenamine 12A
Compound 12A was obtained from N-(p-methoxyphenyl)-1-ethylbenzylidenamine (18A) (3.3 equiv.)
and menthyl (S)-p-toluenesulfinate [method B; addition time of the imine was 60 min; the crude product
was purified by chromatography, hexane:acetone (3:1) containing 7% triethylamine as the eluent]. The
analysis of the obtained product showed the presence of a mixture of different isomers, from which the
major tautomer enamine could be isolated by precipitation from acetone (white solid; 87% yield); mp
163–165°C; [α]D −157 (c 1.0, CH2Cl2); δH 7.55–7.22 (m, 9H), 6.61 (s, 4H), 5.87 (bs, 1H), 3.68 (s, 3H),
2.39 (s, 3H), 1.69 (s, 3H); δC 155.0, 149.8, 141.0, 139.5, 134.0, 130.4, 129.3, 129.0, 128.0, 124.6, 122.8,
113.7, 113.3, 55.1, 21.1, 8.43; IR 3440, 3000, 1610, 1520, 1450, 1350, 1310, 1240, 1170, 1040, 1020,
940 cm−1; anal. calcd for C23H23NO2S: C 73.17, H 6.14, N 3.71. Found: C 72.72, H 6.25, N 3.80.
3.16. (R)-N-Benzyl-1-phenyl-2-(p-tolylsulfinyl)propylidenamine 12B
Compound 12B was obtained as a white solid from sulfinyl ketone 6 and 3.0 equiv. of benzyl-
amine using diethyl ether as the solvent [method A; the crude product was purified by chromatogra-
phy, AcOEt:hexane (1:1) containing 5% triethylamine as the eluent; yield 10%] or from N-benzyl-1-
ethylbenzylidenamine (18B) (6.0 equiv.) and menthyl (S)-p-toluenesulfinate [method B; addition time
of the imine was 90 min; the crude product was purified by chromatography, acetone:hexane (2:4)
containing 10% triethylamine as the eluent; yield 22%]. The product was present as the enamine
tautomer; mp 99–101°C; [α]D −179 (c 1.1, CH2Cl2); δH 7.42–7.05 (m, 14H), 4.73 (m, 1H), 4.02–3.98
(m, 2H), 2.34 (s, 3H), 1.64 (s, 3H); δC 154.3, 141.3, 139.5, 139.1, 133.3, 129.6, 129.1, 128.8, 128.3,
128.1, 127.0, 126.8, 124.6, 107.3, 48.0, 21.0, 7.4.
Acknowledgements
We thank Dirección General de Investigación Científica y Tecnica (DGICYT, Grant PB95-210) for
financial support.

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
2449
References
1. Carreño, C. Chem. Rev. 1995, 95, 1717.
2. (a) Solladié, G.; Damailly, G.; Greck, C. Tetrahedron Lett. 1985, 26, 435. (b) Carreño, C.; García Ruano J. L.; Martín
Castro, A. M.; Pedregal, C.; Rodríguez J. H.; Rubio, A.; Sánchez, J.; Solladié, G. J. Org. Chem. 1990, 55, 2120. (c)
Barros, D.; Carreño, C.; García Ruano J. L.; Maestro, M. C. Tetrahedron Lett. 1992, 33, 2733.
3. Carreño, C.; García Ruano J. L.; Maestro, M. C.; Perez González, M.; Bueno, A. B.; Fisher, J. Tetrahedron 1993, 49,
11009.
4. (a) García Ruano J. L.; Martín Castro, A. M.; Rodríguez J. H. J. Org. Chem. 1992, 57, 7235. (b) Escribano A. M.; García
Ruano J. L.; Martín Castro, A. M.; Rodríguez J. H. Tetrahedron 1994, 50, 7567. (c) García Ruano J. L.; Martín Castro,
A. M.; Rodríguez J. H. J. Org. Chem. 1994, 59, 533. (d) García Ruano J. L.; Martín Castro, A. M.; Rodríguez Ramos,
J. H. Tetrahedron Lett. 1996, 37, 4569. (e) García Ruano J. L.; Martín Castro, A. M.; Rodríguez Ramos, J. H.; Rubio
Flamarique, A. C. Tetrahedron: Asymmetry 1997, 8, 3503. (f) Cifuentes García, M. M.; García Ruano J. L.; Martín Castro,
A. M.; Rodríguez Ramos, J. H.; Fernandez, I. Tetrahedron: Asymmetry 1998, 9, 859.
5. (a) Chan, W. H.; Lee, A. W. M.; Jiang, L. Tetrahedron Lett. 1995, 36, 715. (b) Hua, D. H.; Park, G.-J.; Katsuhira, T.;
Bharathi, S. N. J. Org. Chem. 1993, 58, 2144 and references cited therein.
6. Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S. V.; Zanda, M.; Cavicchio, G.; Crucianelli, M. J. Org. Chem. 1996,
61, 3375.
7. Truce, W. E.; Markey, L. D. J. Org. Chem. 1970, 35, 3275.
8. Baldenius, K.; Kagan, H. B. Tetrahedron: Asymmetry 1990, 1, 597.
9. (a) Mullen, C. H.; Stirling, C. J. M. J. Chem. Soc. (B) 1966, 1217. (b) Lee, A. W. M.; Chan, W. H.; Lee, Y. K. Tetrahedron
Lett. 1991, 32, 6861.
10. Fustero, S.; Navarro, A.; Asensio, A. Tetrahedron Lett. 1997, 38, 4891.
11. (a) Tsuchihashi, G.; Iriuchijima, S.; Maniwa, N. Tetrahedron Lett. 1973, 14, 3389. (b) Yokoyama, M.; Takeshima, T.
Tetrahedron Lett. 1978, 19, 147.
12. Ogua, K.; Tsuchihashi, G.; Katah, N.; Yoshimura, O. Tetrahedron Lett. 1978, 19, 375.
13. Annunziata, R.; Cinquini, M.; Restelli, A.; Cozzi, F. J. Chem. Soc., Perkin Trans. 1 1982, 1183.
14. Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto, A.; Panangadan, J. A. K.; Hung, M. H.; Bravo, A. A.; Erpelding,
A. M. J. Org. Chem. 1989, 54, 5659.
15. (a) Carreño, M. C.; García Ruano, J. L.; Pedregal, C.; Rubio, A. J. Chem. Soc., Perkin Trans. 1 1989, 1335. (b) Carreño,
M. C.; Domínguez, E.; García Ruano, J. L.; Pedregal, C.; Rodríguez J. H. Tetrahedron 1991, 47, 10035.
16. A preliminary communication has been previously reported (García Ruano, J. L.; Lorente, A.; Rodríguez Ramos J. H.
Tetrahedron Lett. 1992, 33, 5637).
17. Compounds 1–6 were prepared by reaction of (R)-(+)-methyl p-tolyl sulfoxide with the corresponding esters in the
presence of LDA (see Ref. 4a and references therein). Compound 6, obtained as a mixture of epimers at C-α, was used
without separation in further reactions.
18. Taguchi, K.; Westheimer, F. H. J. Org. Chem. 1971, 36, 1570. Reaction rates decreased on using 4 Å and 5 Å molecular
sieves.
19. A similar problem has been found in reactions of cyclohexylidenbenzylamine with menthyl p-toluenesulfinate (see Ref.
15c).
20. Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin Trans. 1 1979, 1678.
21. Herszwolf, G. S.; Kloosterziel, H. Rec. Trav. Chem. 1970, 89, 1217.
22. Hose, D. R. J.; Raguham, T.; Wills, M. Tetrahedron: Asymmetry 1993, 4, 2159.
23. Caine, D. Alkylation of Carbon. In Comprehensive Organic Synthesis; Trost B. M., Ed.; Pergamon Press: Oxford, 1991;
Vol. 3, p. 32.
24. To check this assumption, we prepared imine 20A and studied its reaction with menthyl p-toluenesulfinate at room
temperature. The reaction is completely regioselective, yielding only imino sulfoxide 21A.

2450
J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 2437–2450
25. Configurational assignment of compounds 19A and 19A0 could be unequivocally established from the results obtained in
the stereoselective reductions of these substrates and mainly from the stereochemistry of rigid cyclic substrates (aziridines
and sulfonium salts derived from 1,4 oxathian) obtained from them through stereoselective processes. All these results
will be published in due course.
26. See Tennan, G. Imines, Nitrones, Nitriles, and Isocyanides. In Comprehensive Organic Chemistry; Barton, D.; Ollis, W.
D., Eds; Pergamon Press: Oxford, 1979, Vol. 2 (Sutherland, I. O., Ed.), p. 397 and references cited therein.
27. (a) Stirling, C. J. M. J. Chem. Soc. 1964, 5863. (b) McMullin, C. H.; Stirling, C. J. M. J. Chem. Soc. 1966, B, 1217. (c)
Rajappa, S. Tetrahedron 1981, 37, 1453. (d) Neplyuer, V. M.; Sinenko, T. A.; Khoina, E. V. Ukr. Khim. Zh. (Russ. Ed.)
1978, 44, 183. (e) Bates, G. S.; Ramaswamy, S. J. Chem. Soc., Chem. Commun. 1980, 904. (f) Shainyan, B. A.; Mirskova,
A. N. Russ. Chem. Rev. (Eng. Trans.) 1979, 48, 107.
28. Kozerski, L.; Kawecki, R.; Beduarek, E. Mag. Reson. Chem. 1987, 25, 712.
29. Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of Laboratory Chemicals, 2nd edn; Pergamon Press: New
York, 1980.
30. Ogura, K.; Tomori, H.; Fusita, M. Chem. Lett. 1991, 1407.