Stereoselective addition of α-sulfinyl carbanions to N-p-tolylsulfinylketimines: Synthesis of optically pure 1,2,2′-trialkyl-2- aminoethanols

Article abstract of DOI:10.1021/jo049666s

The reactions of lithium carbanions derived from both enantiomers of methyl (1) and ethyl p-tolyl sulfoxide (2) with (S)-N-arylsulfinylketimines 3 and 4 took place in a highly stereoselective manner and good isolated yields. The configuration of the carbon bonded to nitrogen relies exclusively on the N-sulfinylimine configuration. When ethyl p-tolyl sulfoxide (2) is use as nucleophile, two chiral centers are created simultaneously, where the configuration of the carbon bonded to the sulfur is mainly controlled by 2. The asymmetric induction increases with the temperature, being total at room temperature in the case of the matched pair of reactants. A non-oxidative Pummerer reaction on the obtained aminosulfoxides allows a straightforward synthesis of optically pure 1,2-ethanolamines with one or two chiral centers, including amino alcohols with a bulky quaternary carbon bonded to the amine group.

Full text of DOI:10.1021/jo049666s

Ster eoselective Ad d ition of r-Su lfin yl Ca r ba n ion s to
N-p-tolylsu lfin ylk etim in es: Syn th esis of Op tica lly P u r e
1,2,2′-Tr ia lk yl-2-a m in oeth a n ols
J ose´ L. Garc´ıa Ruano,*,† J ose´ Alema´n,† Miriam del Prado,† and Inmaculada Ferna´ndez*,‡
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad Auto´noma de Madrid,
Cantoblanco 28049 Madrid, Spain, and Departamento de Quı´mica Orga´nica y Farmace´utica,
Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain
joseluis.garcia.ruano@uam.es; inmaff@us.es
Received February 27, 2004
The reactions of lithium carbanions derived from both enantiomers of methyl (1) and ethyl p-tolyl
sulfoxide (2) with (S)-N-arylsulfinylketimines 3 and 4 took place in a highly stereoselective manner
and good isolated yields. The configuration of the carbon bonded to nitrogen relies exclusively on
the N-sulfinylimine configuration. When ethyl p-tolyl sulfoxide (2) is use as nucleophile, two chiral
centers are created simultaneously, where the configuration of the carbon bonded to the sulfur is
mainly controlled by 2. The asymmetric induction increases with the temperature, being total at
room temperature in the case of the matched pair of reactants. A non-oxidative Pummerer reaction
on the obtained aminosulfoxides allows a straightforward synthesis of optically pure 1,2-
ethanolamines with one or two chiral centers, including amino alcohols with a bulky quaternary
carbon bonded to the amine group.
In tr od u ction
Moderate reactivity and stereoselectivity associated
with the use of enantiopure aldimines can be substan-
tially improved by using enantiopure N-sulfinylimines.5
The stereoselectivity of these reactions is usually high,
as it has been evidenced by several contributions from
the groups of Davis6 and Ellman.7 Despite the scarcity
of precedents concerning nucleophilic additions to N-
sulfinylketimines,8 the efficiency of the N-sulfinyl group
in stereoselectivity control has been clearly demonstrated
when the reactions are conducted in the presence of Me3-
Al.8 However, to the best of our knowledge, none of the
studied reactions involved the use of nucleophilic prochiral
carbons or R-oxygenated carbanions for the simultaneous
creation of two chiral centers and the formation of amino
alcohols with the nitrogen bonded to a quaternary chiral
carbon, respectively. In this sense, the use of the R-sulfi-
nyl carbanions has been shown to be one of the most
The importance of the amine function in drugs, to-
gether with the increasing awareness on the importance
of the chirality on their biological activity, make the
asymmetric synthesis of amines an active area of re-
search. Among the recent methods developed for this
task, the nucleophilic addition of organometallic reagents
to the CdN double bonds of aldimines1 constitutes one
of the most attractive approaches. The corresponding
reactions with ketimines, affording optically pure R,R-
disubstituted alkylamines, has been much less explored,
probably due to the lower reactivity of these electrophiles
and their propensity to enolization.2 Moreover, the dias-
tereoselectivity of the process may be compromised by
the facile E,Z isomerization of these compounds. In this
regard, it is worth mentioning that Grignard additions
to ketimines derived from (S)-phenylglycinol containing
2-heteroalkyl3 or R-methoxyalkyl4 residues have been
achieved with good stereoselectivities, owing to the ability
of heteroatoms to form chelated species with magnesium
and thus precluding the E,Z isomerization.
(5) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J . J . Org. Chem. 1997, 62, 2555.
(6) (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. Rev. 1998, 27,
13 and references therein. (b) Recent references: Davis, F. A.; Prasad,
K. R.; Carroll, P. J . J . Org. Chem. 2002, 67, 7802. (c) Davis, F. A.;
Deng, J .; Zhang, Y.; Haltiwanger, R. C. Tetrahedron 2002, 58, 7135.
(d) Davis, F. A.; Chao, B.; Andemichael, Y. W.; Mohanty, P. K.; Fang,
T.; Burns, D. M.; Rao, A.; Szewczyk, J . M. Heteroatom Chem. 2002,
13, 486.
(7) (a) Cogan, D. A.; Liu, G.; Kim, K.: Backes, B. J .; Ellman, J . A.
J . Am. Chem. Soc. 1998, 120, 8011. (b) Liu, G.; Cogan, D. A.: Owens,
T. D.; Tang, T. P.; Ellman, J . A. J . Org. Chem. 1999, 64, 1278. (c)
Ellman, J . A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984
and references therein.
† Universidad Auto´noma de Madrid.
‡ Universidad de Sevilla.
(1) (a) Volkmann, R. A. In Comprehensive Organic Synthesis;
Schreiber, S. L., Ed.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter
1.12, p 355. (b) Risch, N.; Arend, M. In Stereoselective Synthesis
(Houben-Weyl); Helmechen, G., Hoffmann, R. W., Mulzer, J ., Schau-
man, E., Eds.; Georg Thieme Verlag: Stuttgart, 1995; E21b, D.1.4, p
1833. (c) Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8,
1895.
(2) (a) Stork, G.; Dowd, S. R. J . Am. Chem. Soc. 1963, 85, 2178. (b)
Hua, D. H.; Miao, S. W.; Chen, J , S.; Iguchi, S. J . Org. Chem. 1991,
56, 4. (c) Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J , S. Tetrahedron:
Asymmetry, 1995, 6, 349.
(3) Spero, D. M.; Kapadia, S. R. J . Org. Chem. 1997, 62, 5537.
(4) Steining, A. G.; Spero, M. D. J . Org. Chem. 1999, 64, 2406.
(8) (a) Borg, G.; Chino, M.; Ellman, J . A. Tetrahedron Lett. 2001,
42, 1433. (b) Davis, F. A.; Lee, S.; Zhang, H., Fanelli, D. L. J . Org.
Chem. 2000, 65, 8704. (c) Cogan, D. A.; Liu, G.; Ellman, J . A.
Tetrahedron 1999, 55, 8883. (d) Cogan, D. A.; Ellman, J . A. J . Am.
Chem. Soc. 1999, 121, 268. (e) Tang, T. P.; Ellman, J . A. J . Org. Chem.
1999, 64, 12.
10.1021/jo049666s CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004
4454
J . Org. Chem. 2004, 69, 4454-4463

Synthesis of Optically Pure 1,2,2′-Trialkyl-2-aminoethanols
TABLE 1. Ad d ition of (S)-1 a n d (R)-1 to
N-Su lfin ylk etim in es 3 a n d 4
SCHEME 1. Syn th esis of Am in o Alcoh ols
efficient methods to control the stereoselectivity of the
nucleophilic additions to N-sulfinylaldimines resulting in
the simultaneous creation of two chiral centers.9 The
resulting â-aminosulfoxides were transformed in a com-
pletely stereoselective manner into â-amino alcohols
using a non-oxidative Pummerer reaction.10 The potential
interest of 2-aminoethanols as ligands11 with the amine
group bonded to a bulkier quaternary carbon prompted
us to investigate the reaction of R-sulfinyl carbanions
with N-sulfinylketimines and further transformation of
the resulting aminosulfoxides into the corresponding
â-amino alcohols (Scheme 1). Herein we report the results
obtained in the reactions of (R)- and (S)-methyl and -ethyl
p-tolyl sulfoxides, 1 and 2, with (S)-N-[(E)-1-phenyleth-
ylidene]-p-toluenesulfinamide (3) and (S)-N-[(E)-1-phe-
nylethylidene]-2-methoxy-1-naphthalenesulfinamide (4).
Studies concerning the non-oxidative Pummerer reaction
on the obtained â-aminosulfoxides, leading to the syn-
thesis of optically pure 1,2,2′-trialkyl-2-aminoethanols,
are also reported.
T
yielda diastereomeric
(%)
de
(%)
entry imine sulfoxide (°C)
ratiob
1
2
3
4
5
6
7
8
3
3
4
4
3
3
4
4
(S)-1
(S)-1
(S)-1
(S)-1
(R)-1
(R)-1
(R)-1
(R)-1
-78
0
-78
82
67
82
65
85
65
83
67
5A (80)/5B (20)
5A
7A
7A
60
>98
>98
>98
80
>98
>98
>98
0
-78
0
-78
6A (90)/6B (10)
6A
8A
8A
0
Combined isolated yields. Determined by 1H NMR on the
a
b
crude product.
3 and 4. Reactions of 3 with both enantiomers of 1 at
-78 °C afford mixtures of amino sulfoxides 5A and 5B,
starting from (S)-1, or 6A and 6B, starting from (R)-1,
in combined yields higher than 80% (entries 1 and 5).
The diastereoselectivity from (R)-1 (80% de, entry 5) is
slightly higher than from (S)-1 (60% de, entry 1). Under
similar conditions, 4 evolves in a completely stereoselec-
tive manner with both enantiomers yielding 7A from
(S)-1 (entry 3) and 8A from (R)-1 (entry 7) with excellent
yields. At 0 °C, yields are in general moderate, around
65% (entries 2, 4, 6, and 8), but in some cases stereose-
lectivities are higher (compare entries 1 and 5 with 2 and
6 respectively). From the results in Table 1, it can thus
be concluded that the reactions of ketimine 3 with both
sulfoxides at 0 °C are completely stereoselective affording
compounds 5A (entry 2) and 6A (entry 6) as single
Resu lts a n d Discu ssion
Methyl and ethyl p-tolyl sulfoxides, 1 and 2, were
prepared in both configurations by reaction of methyl and
ethylmagnesium bromides with (R) and (S)-menthyl
p-toluenesulfinates using the conditions reported by
Solladie´.12 (S)-N-[(E)-1-phenylethylidene]-p-toluenesulfi-
namide (3)13 and (S)-N-[(E)-1-phenylethylidene]-2-meth-
oxy-1-naphthalenesulfinamide (4) were prepared accord-
ing to the procedure reported by Davis.14 The condensation
of R-sulfinyl cabanions of (R)-1 and (S)-1 on the N-
sulfinylketimines 3 and 4 afforded the desired products
with good yields and diastereoselectivities, Table 1.
The reactivity of both ketimines is clearly lower than
that of the previously studied aldimines9 as the reactions
usually require 24 h for completion. There is not a
significant difference in reactivity for N-sulfinylketimines
1
diastereomers (de > 98%, estimated by H NMR on the
reaction crudes).
Next, we focused our studies on the reactions of
N-sulfinylketimines 3 and 4 with both enantiomers of the
ethyl p-tolyl sulfoxide, (R)-2 and (S)-2. As before, the
condensation of the R-sulfinyl carbanions on N-sulfi-
nylketimines 3 and 4 afforded the corresponding com-
pounds 12-14, with good yields and variable diastereo-
selectivities, Table 2. As expected from a steric point of
view, the reactivity of the ethyl sulfoxide 2 is slightly
lower than that of the methyl sulfoxide 1, deduced from
the longer reaction times, around 30 h required with both
enantiomers. In all reactions, only two of the four possible
diastereomeric 2-sulfinyl-1-propylamines are formed,
which suggests that they evolve with a complete control
of the stereoselectivity in one of the two newly created
chiral centers.
(9) Garc´ıa Ruano, J . L.; Alcudia, A.; Prado, M.; Barros, D.; Maestro,
M. C.; Fernandez, I. J . Org. Chem. 2000, 65, 2856.
(10) (a) Bravo, P.; Capelli, S.; Crucianelli, M.; Guidetti, M.; Mark-
ovsky, A. L.; Meille, S. V.; Soloshonok, V. A.; Sorochinsky, A. E.; Viani,
F.; Zanda, M. Tetrahedron 1999, 55, 3025. (b) Crucianelli, M.; Pier-
francesco, B.; Arnone, A.; Corradi, E.; Meille, S. V.; Zanda, M. J . Org.
Chem. 2000, 65, 2965. (c) Armone, A.; Bravo, P.; Bruche´, L.; Crucianelli,
M.; Vichi, L.; Zanda, M. Tetrahedron Lett. 1995, 36, 7301. (d) Armone,
A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S. V.; Zanda, M. J . Org.
Chem. 1996, 61, 3375.
(11) Recent reviews: (a) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem.
Rev. 1996, 96, 835. (b) Bloch, R. Chem. Rev. 1998, 98, 1407. (c) Reetz,
M. T. Chem. Rev. 1999, 99, 1121. (d) Comprehensive Asymmetric
Catalyst; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 1999. (e) Ojima, I. Catalytic Asymmetric Synthesis, 2nd
ed.; VCH: New York, 2000. (f) Bergmeier, S. C. Tetrahedron 2000,
56, 2561. (g) Bonini, C.; Righi, G. Tetrahedron 2002, 58, 4981. (h) Tang,
Z.; J iang, F.; Yu, L.-T.; Xin, C.; Gong, L.-Z.; Mi, A.-Q.; J iang, Y.-Z.;
Wu, Y.-D. J . Am. Chem. Soc. 2003, 125, 5262.
Taking into account that the addition of methyl p-tolyl
sulfoxide 1 evolves with almost complete control of the
stereoselectivity at the iminic center, the same behavior
can be anticipated for the bulkier ethyl p-tolyl sulfoxide
2. Therefore, the isomers A and B should be epimers at
(12) Solladie´, G.; Hutt, J . Synthesis 1987, 173.
(13) Annunziata, R.; Cinquini, M.; Cozzi, F. J . Chem. Soc., Perkin
Trans. 1 1982, 339.
(14) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Portonovo, P. S.
Tetrahedron Lett. 1993, 34, 6229.
J . Org. Chem, Vol. 69, No. 13, 2004 4455

Garc´ıa Ruano et al.
TABLE 2. Ad d ition of (S)-2 a n d (R)-2 to
N-Su lfin ylk etim in es 3 a n d 4
SCHEME 2. Ch em ica l Cor r ela tion of Com p ou n d s
5-8
T
yielda diastereomeric
de (%)
at C(2)
entry imine sulfoxide (°C) ((%)
ratiob
SCHEME 3. Ch em ica l Cor r ela tion of Com p ou n d s
12-15
1
2
3
4
5
6
7
8
9
3
3
3
3
4
4
3
3
4
4
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(R)-2
(R)-2
(R)-2
(R)-2
-78
0
77
73
75
80
79
62
75
70
85
72
12A (15)/12B (85)
12A (10)/12B (90)
12A (3)/12B (97)
12B
14A (5)/14B (95)
14A (30)/14B (70)
13A (40)/13B (60)
13A (23)/13B (77)
15A (48)/15B (52)
15A (30)/15B (70)
70
80
94
>98
90
40
20
54
4
0-10
rt
-78
0
-78
0
-78
0
10
40
a
b
Combined isolated yields. Determined by 1H NMR on the
crude product.
C(2), which was later confirmed (see configurational
assignment). The magnitude and the sense of the changes
in diastereoselectivity are dependent on the configuration
of the sulfoxide and the structure of the N-sulfi-
nylketimine. The de for the reactions of ketimine 3 with
(S)-2 is higher by increasing the temperature (entries
1-4). At room temperature, 12B was obtained in 80%
isolated yield as a single diastereoisomer (entry 4).
Reactions of 3 with (R)-2 are less stereoselective (compare
entries 1 and 2 with 7 and 8 respectively). As in the
previous case, the increase of the temperature improves
the stereoselectivity (entries 7 and 8). Nevertheless, in
this case the total control of the diastereoselectivity has
not been possible because above 0 °C, the formation of
byproducts is quite important.15 The behavior of the
naphthyl derivative 4 seems to be anomalous. At 0 °C it
shows lower stereoselectivity than the p-tolyl derivative
3 in reactions with both ethyl sulfoxides, (R)-2 (compare
entries 8 and 10) and (S)-2 (compare entries 2 and 6).
The same behavior is observed in reactions of 3 and 4
with (R)-2 at -78 °C (entries 7 and 9) and with (S)-2
(compare entries 1 and 5). However, the de becomes
higher by increasing the temperature in reactions of 4
with (R)-2 (entries 9 and 10) but lower in those with (S)-2
(entries 5 and 6) (vide infra).
have a different configuration at sulfur (it only depends
on the starting sulfoxide), their configuration at carbon
bonded to the amine group must be identical. Absolute
stereochemistry was established as (S) by chemical
correlation of 9 with (S)-1116 via a nonoxidative Pum-
merer reaction.10 It also allowed us to assign as (S) the
configuration of 5A-8A, precursors of 9 and 10. Thus,
B isomers have an (R) configuration at the chiral carbon.
The configurational assignment of compounds 12-15
was accomplished as follows. The absolute configuration
of compound 15B (Scheme 3) was unambiguously estab-
lished by X-ray analysis.17 It has the (S) configuration
at its two chiral carbons and a configuration at its two
chiral sulfur identical to those of the starting products
(R)-2 and (S)-4.
Con figu r a tion a l Assign m en t. The configurational
assignment of compounds 5-8 was made by chemical
correlation (Scheme 2). Compounds 5A and 7A were
transformed into the same aminosulfoxide 9 by hydroly-
sis of the N-S bond, which means that both compounds
only differed in the sulfinyl residue at nitrogen. The same
is true for 6A and 8A; both converted into 10 (Scheme
2). As compounds 9 and 10 are diastereomers (NMR) and
Compounds 15B and 13B were hydrolyzed into the
same compound 16B (Scheme 3). Compounds 13A and
15A were analogously correlated by conversion into 16A.
Compounds 16A and 16B are diastereomers (NMR)
(16) Garbarino, J . A. Ann. Chem. 1969, 59, 841.
(17) The authors have deposited atomic coordinates for 15B with
the Cambridge Crystallographic Data Centre (Deposit No. 218989).
The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.
(15) At 45 °C we could measure a 65% de from the NMR spectra on
the crude product, but the proportion of amino sulfoxides in the mixture
was lower than 60%.
4456 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of Optically Pure 1,2,2′-Trialkyl-2-aminoethanols
SCHEME 4. P ossible P a th w a ys for th e Non -Oxid a tive P u m m er er Rea ction s
indicating they only differ in the configuration of one or
two of the chiral carbons. A 60/40 mixture of 16A and
16B (obtained by hydrolysis of the 60/40 mixture of 13A
and 13B from conditions of the entry 7, Table 2) was
desulfinylated with Ra-Ni into the amine (R)-18 with a
very high optical purity (>95% ee, based on specific
rotation18). This indicates that 16A and 16B have the
same configuration at the benzylic position. As the
(2S,3S,SR) configuration had been unequivocally as-
signed to 16B (vide supra), the configuration (2S,3R,SR)
must be assigned to 16A (Scheme 4).
F IGURE 1. Transition states accounting for the stereoselec-
tivity at the carbon bonded to nitrogen.
aromatic residue are difficult to explain (entries 1 and
5, Table 1), but the E/Z isomerization of the imine2 and
the association of the 2-methoxynaphthyl residue to the
lithium may play some role.
The configurational assignment of compounds 12 and
14 indicated in Table 2 is based on the assumption that
the stereochemical evolution of the reactions of 3 and 4
with (S)-2 and (R)-2 must be similar. To confirm this
assignment, compound 12B was also correlated with the
amine (R)-18 (see Scheme 3), thus determining its
configuration at the benzylic carbon as (S). Compounds
16A and 17B were transformed into the same amino
alcohol 30, with (S) configuration at the hydroxylic
carbon, under the conditions of the non-oxidative Pum-
merer reaction conditions (see synthesis of the amino
alcohols), thus confirming they both have the R config-
uration in the carbon bonded to the sulfinyl group.
Mech an istic Con sider ation s. From the results shown
in Tables 1 and 2 it is evident that the configuration at
the carbon bonded to nitrogen is completely controlled
by the sulfur configuration at the sulfinyl ketimine,
regardless of the configuration of the sulfinyl group at
the nucleophile. The six-membered TS proposed by
Ellman8c involving the association of the lithium to the
sulfinyl oxygen and the nucleophilic carbon satisfactorily
accounts for the experimental results. The chair like TS
B, avoiding the 1,3-diaxial interaction between the
aromatic residue at the N-arylsulfinyl group and the
methyl group of the ketimine present in TS A (Figure
1), must be highly favored. This can explain the almost
complete stereoselective evolution of the (S)-N-arylsulfi-
nylimines 3 and 4 into amines with (S) configuration at
the carbon bonded to nitrogen. The de observed in these
reactions is higher than that found by Ellman in reac-
tions of RMgX and RLi reagents with N-tert-butanesulfi-
nylketimines in the absence of Me3Al,8c probably due to
the association of the lithium to the C-sulfinyl oxygen
(vide infra). The small variations observed in the stereo-
selectivity with variable temperature and nature of the
Results shown in Table 2 indicate that the configura-
tion at the carbon bonded to the sulfur atom is mainly
controlled by that of the nucleophile. Thus, (R)-2 mainly
induces the (S) configuration whereas (S)-2 gives the (R)
configuration. This control is much more efficient starting
from (S)-2 (the reaction becomes completely stereoselec-
tive) and increases for both enantiomers when the
temperature becomes higher. To explain these results we
propose the stereochemical course indicated in Figure 2.
On the basis that only TS B (Figure 1) can be involved,
we assume that the structure of the attacking carbon at
the TS of the nucleophilic addition could be described like
a trigonal bipyramid with the apical positions occupied
by the bulkier substituents (CdN and SOTol). Four
possible transition states can be postulated (Figure 2).
TS-IIS and TS-IIR have the C-sulfinyl oxygen associated
to the lithium atom whereas such association does not
exist for the corresponding TS-IS and TS-IR. In the two
latter cases, free rotation around the C-S bond is
possible and the S-O bond will arrange anti with respect
to the C-Li bond in order to minimize the electrostatic
interactions. Moreover, the methyl group joined to C-Li
will adopt the less hindered anti relationship with respect
to the bulkier phenyl. Thus, the methyl group adopts a
pseudoaxial arrangement in TS-IR (derived from (R)-2),
but a more stable pseudoequatorial position in TS-IS.
When the C-sulfinyl oxygen is associated with the
lithium, the relative stability of the TS’s is related to the
steric interactions of the substituents at the four-
membered ring, which necessarily adopt an eclipsed
arrangement. Thus, the preferred configuration of the
carbanion is the one that avoids the Tol/Me interaction.
From Figure 2 it is easily deduced that TS-IIS is now less
stable than TS-IIR, due to the relative orientation of the
methyl group in the chair like conformation. If we assume
(18) Kopecky, K. R.; Mojelsky, T. W.; Gillan, T.; Barry, J . A.; Lopez
Sastre, J . A. Can. J . Chem. 1977, 55, 1001.
J . Org. Chem, Vol. 69, No. 13, 2004 4457

Garc´ıa Ruano et al.
F IGURE 2. Stereochemical model accounting for the results in Tables 1 and 2.
the equilibration of the two possible transition states for
each enantiomer (TS-I and TS-II) the experimental
results can be satisfactorily explained. The equilibrium
must be shifted toward TS-I, thus explaining the higher
proportion of compounds B obtained in all the reactions
shown in Table 2. Nevertheless the shifting toward TS-
IS must be higher than for TS-IR. An increase of the
temperature would weak even more the association of
the sulfinyl group to the lithium atoms, thus provoking
the shift of the equilibrium toward TS-I, which would
increase the proportion of the B isomers.
sulfoxides, we decided to study some aspects of the
reaction on our substrates. We first explored the behavior
of the N-p-tolylsulfinylamine 12B in reaction with TFAA
and sym-collidine, followed by hydrolysis with K2CO3.
Unfortunately, only complex mixtures were formed under
these conditions.19 Thus, as a previous step to study the
nonoxidative Pummerer reaction, we first hydrolyzed the
N-S bond and then transformed the free amines into the
corresponding carbamates.
The hydrolysis of the N-S bonds was conducted with
TFA/MeOH at 0 °C in almost quantitative yields. The
free amines 9, 16A, 16B and 17B were selected to
continue this study.20 Compounds 9 and 16B were
initially treated in acetonitrile with (BOC)2O in the
presence of Et3N to obtain the corresponding protected
amines. The expected carbamates 19 and 20 were ob-
tained in moderate chemical yields (45% and 43%,
respectively). Compound 21, resulting from a new attack
of the amine to 19, was also obtained in 40% yield
(Scheme 5). On the other hand, compound 22 was
unexpectedly obtained in similar yield in the reaction
from 16B. To improve the yield in carbamate we modified
the reaction conditions21 by changing the solvent (THF,
CH2Cl2), the base (DMAP), the concentration, and the
order in the addition of the reagents. However, under all
these conditions, a high proportion of the ureas was
always obtained. We were also unsuccessful in converting
21 and 22 into 19 and 20, respectively, by hydrolysis
under different conditions.
Syn th esis of th e Am in o Alcoh ols. Once we obtained
the amino sulfoxides, our last synthetic step was their
conversion into the 1,2-ethanolamines containing two
chiral centers, with the nitrogen bonded to a quaternary
chiral carbon. This was made by using the conditions of
the non-oxidative Pummerer reaction reported by Zanda
et al.10 because it is the best of the few reactions allowing
the stereoselective substitution of sulfinyl by a hydroxyl
group. Within this study we have also investigated some
mechanistic aspects, mainly related to the nature of the
intermediate species involved in the reaction. According
to the stereochemical evolution suggested by Zanda, a
highly strained thia-azacyclobutane ring would be in-
volved as an intermediate10 (I in Scheme 4). The presence
of a quaternary carbon in our substrates suggested these
intermediates would be strongly destabilized (they will
always exhibit some Me/Me or Ph/Me eclipsed interac-
tion), hindering progression of the reaction. As a second
possibility the carbamoyl oxygen, instead of the nitrogen,
can act as nucleophile, forming a more stable six mem-
bered intermediate (II in Scheme 4). This duality of
intermediates was also considered by Zanda et al.10b in
the case of substrates also containing quaternary car-
bons, but II was discarded on the basis that products
having the Ar-S residue attached to the carbamic oxygen
have never been observed or detected. They support the
formation of the intermediates I on some NMR signals
presumably corresponding to the four-membered inter-
mediate.
Before making additional efforts to solve this problem,
we investigated the behavior of 19 and 20 under the
Pummerer conditions. Fortunately, the results were
satisfactory and the acyloxycarbamates 23 and 24 were
exclusively obtained and then hydrolyzed into the cor-
(19) Their NMR spectra suggested that the sulfoxides had been
reduced into thioethers and the N-S bond partially hydrolyzed. These
results are similar to those previously obtained from the adducts
resulting from reactions of N-sulfinyl aldimines (ref 9).
(20) Diastereoisomers 16A and 16B differ in the configuration at
sulfinylated carbon, whereas 17B and 16A have different sulfur
configuration, which allows to have information about the influence
of all the chiral centers.
Taking into account that this non-oxidative Pummerer
reaction is very significant in the chemistry of chiral
(21) Basel, Y.; Hassner, A. J . Org. Chem. 2000, 65, 6368.
4458 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of Optically Pure 1,2,2′-Trialkyl-2-aminoethanols
SCHEME 5. Con ver sion of Am in o Su lfoxid es in to Am in o Alcoh ols via Boc Der iva tivesa
a
Key: (a) BOC2O, Et3N, CH3CN; (b) TFAA, sym-collidine, CH3CN; (c) HCl (1 N), THF.
SCHEME 6. Con ver sion of th e Am in o Su lfoxid es
in to Am in o Alcoh ols via Cbz Der iva tivesa
We checked the enantiopurity of the alcohols 29 and
1
30 from the H NMR spectra of their Mosher esters22 (ee
> 98%). These spectra confirmed the (R) configuration
for alcohol 29 and (S) for alcohol 30, in agreement with
the expected inversion of the configuration of these non-
oxidative Pummerer reactions.
We performed an NMR study of the Pummerer reac-
tions of 27, similar to that made by Zanda et al.10b but
changing the order in the addition of the reagents. First
we recorded the NMR spectrum of 27 in the presence of
5 equiv of TFAA (see the Supporting Information). The
instantaneous formation of the acyloxysulfonium salt 27′
was detected. The ∆δ values (δ27 - δ27′) for the CH-CH3
grouping are 2.03 ppm (CH) and 1.01 ppm (CH3),
respectively. The salt remained unaltered until the base
was added. The addition of sym-collidine effects the
immediate appearance of the signals which correspond
to the final trifluoroacetate 30′. No other signals could
be observed during the time of the experiment. We have
done two experiments by adding 2.0 and 4.0 equiv of sym-
collidine. The reaction rate, which can be followed by
NMR, is dependent on the base concentration.
From this study we can conclude that the only observed
signals are those corresponding to the acyloxy sulfonium
salt 27′ and the trifluoracetoxy derivative 30′. Taking into
account that the observed ∆δ values (vide supra) are
similar to those reported by Zanda,10b we believe that the
signals that he assigned as the four membered σ-sul-
furanes are those corresponding to sulfonium salts.
Concerning the structures of the intermediates in-
volved in these processes, the fact that reaction of 27
requires a shorter time than 26 (15 and 20 min, respec-
tively) to be transformed into its corresponding trifluo-
roacetate, cannot be explained by assuming as interme-
diates the four membered σ-sulfuranes, I27 and I26. From
Scheme 7 it can be deduced that I27 must be clearly less
stable than I26, which is not consistent with the observed
relative rates. By contrast, the relative stability of II27
and II26 (the first being slightly more stable,23 Scheme
7) accounts for the experimental results. Zanda et al. face
a similar problem10c because the substrate evolving more
slowly is a precursor of the most stable four-membered
a
Key: (a) ClCOOBn, NaH, THF; (b) TFAA, sym-collidine,
CH3CN; (c) NaBH4, K2CO3.
responding amino alcohol 11 (80% yield) and 25 (70%
yield), respectively. The comparison of the specific rota-
tion of compound 11 with that reported in the literature
for (S)-2-amino-2-phenylpropanol16 revealed its identity
as well as suggested a high optical purity for compound
11.
To avoid the formation of ureas 21 and 22 as byprod-
ucts (Scheme 5) and therefore improve the yield of the
carbamates, we decided increase the reactivity of the
electrophilic reagent by using benzyloxycarbonyl chloride/
NaH instead of (BOC)2O/Et3N. Under these conditions,
compounds 16A, 16B, and 17B were transformed into
their corresponding benzylcarbamates (26-28, Scheme
6) in isolated yields ranging between 77 and 86%, and
the formation of the ureas was not observed. Finally,
compounds 26-28 were treated with TFAA (4 equiv) and
sym-collidine (5 equiv) in acetonitrile. The reaction of 28
was almost instantaneous at 0 °C, but 26 and 27
remained unaltered after several hours under these
conditions. At room temperature, both compounds evolved
satisfactorily into the corresponding alcohols, and 27
required less time than 26 (15 and 20 min, respectively).
The resulting crudes were treated in situ with NaBH4
and K2CO3. The N-benzyloxycarbonyl ethanolamines 29
and 30 were obtained in 64% and 68-75% isolated yield,
respectively (Scheme 6).
(22) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092.
J . Org. Chem, Vol. 69, No. 13, 2004 4459

Garc´ıa Ruano et al.
SCHEME 7. P ossible In ter m ed ia tes in th e Non oxid a tive P u m m er er Rea ction
σ-sulfurane. They explain this by assuming the very
quick formation of the intermediates, followed by their
slow evolution (rate-determining step) into the rear-
ranged trifluoroacetates (the most stable sulfurane would
evolve more slowly). However, the increase of the reaction
rate when the concentration of sym-collidine becomes
higher (see above) and the fact that no signals attribut-
able to σ-sulfuranes can be observed suggest the reaction
of the acyloxysulfonium salt with the base as the rate-
determining step.24
that R-sulfinyl carbanions are able to add to the N-
sulfinylketimines in a highly stereoselective way. It
allows the efficient synthesis of the diastereomerically
pure â-aminosulfoxides. These compounds can be trans-
formed into optically pure 1,2,2′-trialkyl-2-aminoethanols
by a non-oxidative Pummerer reaction with TFAA and
sym-collidine. The six-membered σ-sulfuranes appear as
the most probable intermediates for these latter reac-
tions.
Exp er im en ta l Section
Con clu sion s
Ad d ition of En a n tiop u r e Alk yl p-Tolyl Su lfoxid e An -
ion s to N-Su lfin ylk etim in es. Gen er a l P r oced u r e (Ta bles
1 a n d 2). To a solution of iPr2NH (24.0 mmol) in THF (30 mL)
at 0 °C was added a 2.5 M solution of n-BuLi in hexane (24.0
mmol). After 30 min of stirring, the mixture was cooled at -78
°C and a solution of the alkyl sulfoxide (1 or 2, 24.0 mmol) in
THF (20 mL) was then added. After the mixture was stirred
for 30 min at -78 °C, a solution of the N-sulfinylketimine (3
or 4, 12.0 mmol) in THF (10 mL) was added at the temperature
indicated in Tables 1 and 2. After the reaction finished (24 h),
a saturated NH4Cl aqueous solution (10 mL) was added. The
organic phase was extracted with ethyl acetate (3 × 10 mL)
and dried with anhydrous Na2SO4 and the solvent evaporated
under vacuum. The crude product was purified by flash column
chromatography with the solvent indicated in each case.
(S)-N-[(1S,SS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)eth -
yl]-p-tolu en esu lfin a m id e (5A). The product was prepared
from (S)-1 and (S)-3 at 0 °C. It was obtained, after column
chromatography (AcOEt/hexane, 1:1), as a white crystalline
From the results obtained in reactions of sulfoxides 1
and 2 with the N-sulfinyl imines 3 and 4, we can conclude
(23) Their relative stability must not be too much different, because
the destabilization induced in II27 by the axial arrangement of the Me
group, must be compensated by the (Me/Me)gauche interaction in II26
If we take into account that II26 will be additionally destabilized by
the Me/OCOCF3 interaction, presumably small due to the long S-O
bond (see Scheme 7), the observed slightly lower reactivity of 27 is
not surprising.
(24) To check the possible evolution through the four membered
σ-sulfurane intermediates, we have prepared the N-sulfonyl amino-
sulfoxide 31, unable to form the six membered σ-sulfuranes, by reaction
of the N-sulfonylimine derived from benzophenone with racemic methyl
p-tolyl sulfoxide in the presence of LDA. The reaction of 31 with TFAA
(5 equiv) and sym-collidine (4 equiv) under the same experimental
conditions used for carbamates did not evolve into the amino alcohol
derivative 33 but yielded the aldehyde 34, resulting in a normal
Pummerer reaction. As the acidity of the NH group at 32 is higher
than that of any carbamate, the fact that this substrate does not
undergo the non-oxidative Pummerer reaction suggests that these
reactions evolve through a six membered σ-sulfuranes as intermediates
(instead of a four membered σ-sulfuranes), only possible for carbam-
ates. However, the observed evolution for 31 could be due to the lower
reactivity of the N-sulfonylamides.
.
solid: yield 67%; mp 66-67 °C; [R]20 ) -58.0 (c 0.5, CHCl3);
D
1H NMR (200 MHz) δ 7.72 (m, 2H), 7.58 (m, 2H), 7.42-7.25
(m, 9H), 5.94 (bs, 1H), 3.49 (d, J ) 13.4 Hz, 1H), 3.41 (d, J )
13.4 Hz, 1H), 2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H); 13C NMR
(50 MHz) δ 143.9, 143.0, 141.3, 141.1, 129.9, 129.6, 128.6,
127.8, 126.0, 125.5, 124.0, 71.2, 61.1, 43.8, 27.2, 21.2; MS
(electrospray) m/z 412 (M + 1). Anal. Calcd for C23H25NO2S2:
C, 67.12; H, 6.12; N, 3.40; S, 15.58. Found: C, 67.25; H, 6.28;
N, 3.37; S, 15.60.
(S)-N-[(1R,SS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)eth -
yl]-p-tolu en esu lfin a m id e (5B). The product was obtained
from (S)-1 and (S)-3 at -78 °C as the minor isomer of a 80:20
mixture of diastereomers 5A/5B. Both diastereomers were
separated by flash chromatography (AcOEt/hexane, 1:1), and
the spectroscopic data were taken from a mixture of 5B
uncontaminated with the starting sulfoxide (S)-1: 1H NMR
(200 MHz) δ 7.58-7.25 (m, 13H), 5.97 (s, 1H), 3.05 (AB-system,
∆υ ) 102.0 Hz, J ) 13.2 Hz, 2H), 2.64 (s, 3H), 2.37 (s, 3H),
4460 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of Optically Pure 1,2,2′-Trialkyl-2-aminoethanols
2.33 (s, 3H); 13C NMR (50 MHz) δ 143.9, 143.0, 131.3, 141.1,
129.9, 129.6, 128.6, 128.4, 127.7, 126.0, 125.5, 125.2, 124.9,
124.0, 123.8, 71.7, 65.7, 61.8, 29.8, 21.3.
(S)-N-[(1S,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)eth -
yl]-p-tolu en esu lfin a m id e (6A). The product was prepared
from (R)-1 and (S)-3 at 0 °C. It was obtained, after column
+ 1). Anal. Calcd for C24H27NO2S2: C, 67.73; H, 6.39; N, 3.29;
S, 15.07. Found: C, 67.56; H, 6.66; N, 3.24; S, 14.91.
(S)-N-[(1S,2S,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)-
p r op yl]-p-tolu en esu lfin a m id e (13B). The product was ob-
tained from (S)-3 and (R)-2 as the major isomer of a mixture
of both diastereomers 13A and 13B. After column chromatog-
raphy (hexane/AcOEt, 2:1), the product was obtained as a
chromatography (ether), as a white crystalline solid: yield
white solid: yield 54%; mp 79 °C; [R]20 ) +128.0 (c 1.0,
1
65%; mp 64-65 °C; [R]20 ) +290.0 (c 0.5, CHCl3); H NMR
D
D
CHCl3); IR (film) 3454, 2978, 1636, 1493, 1448, 1213, 1189
cm-1; 1H NMR (300 MHz) δ 7.71 (m, 4H), 7.57 (m, 4H), 7.48-
7.31 (m, 5H), 5.49 (s, 1H), 2.92 (q, J ) 7.0 Hz, 1H), 2.38 (s,
3H), 2,38 (s, 3H), 2.01 (s, 3H), 1.05 (d, J ) 7.0 Hz, 3H);13C
NMR (75 MHz) δ 143.3, 141.3, 141.0, 138.9, 129.8, 128.7, 127.9,
126.6, 125.2, 124.0, 70.4, 65.0, 25.5, 21.3, 4.9; MS (electrospray)
m/z 426 (M + 1). Anal. Calcd for C24H27NO2S2: C, 67.73; H,
6.39; N, 3.29; S, 15.07. Found: C, 67.83; H, 6.28; N, 3.13; S,
14.90.
(S)-N-[(1S,2R,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)-
p r op yl]-2-m eth oxy-1-n a p h th a len esu lfin a m id e (15A). The
product was obtained from (S)-4 and (R)-2 as the minor isomer
of a mixture of both diastereomers 15A and 15B. After column
(200 MHz) δ 7.77 (m, 2H), 7.57 (m, 2H), 7.53-7.25 (m, 9H),
6.35 (s, 1H), 3.48 (AB system, ∆υ) 138.0 Hz, J ) 13.4 Hz,
2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.01 (s, 3H); 13C NMR (50 MHz)
δ 141.1, 143.1, 142.0, 141.3, 140.8, 130.1, 129.8, 128.7, 125.8,
125.2, 124.6, 68.7, 62.0, 29.7, 29.2, 21.4. Anal. Calcd for C23H25
-
NO2S2: C, 67.12; H, 6.12; N, 3.40; S, 15.58. Found: C, 66.94;
H, 6.32; N, 3.55; S, 15.47.
(S)-N-[(1R,RS)-1-Met h yl-1-p h en yl-2-(p -t olylsu lfin yl)-
eth yl]-p-tolu en esu lfin a m id e (6B). The product was ob-
tained from (R)-1 and (S)-3 at -78 °C as the minor isomer of
a mixture of diastereomers 6A/6B. Both diastereomers were
separated, and the spectroscopic data were taken from a
mixture of 6B uncontaminated with the starting sulfoxide (R)-
1: 1H NMR (200 MHz) δ 7.70-7.25 (m, 13H), 6.95 (s, 1H) 3.52
(AB system, ∆υ ) 14.0 Hz, J ) 13.4 Hz, 2H), 2.42 (s, 3H),
2.39 (s, 3H), 2.21 (s, 3H).
chromatography (hexane/AcOEt, 2:1) the product was obtained
1
as a white solid: yield 22%; [R]20 ) +51.0 (c 0.4, CHCl3); H
D
NMR (200 MHz) δ 8.50 (d, J ) 8.6 Hz, 1H), 7.96 (m, 2H), 7.82
(d, J ) 8.1 Hz, 1H), 7.55-7.20 (m, 11H), 7.02 (s, 1H), 4.17 (s,
3H), 2.89 (q, J ) 7.0 Hz, 1H), 2.36 (s, 3H), 2.03 (s, 3H), 0.95
(d, J ) 7.0 Hz, 3H); 13C NMR (50 MHz) δ 155.1, 144.7, 140.8,
140.0, 133.2, 130.2, 129.7, 129.0, 128.7, 128.0, 127.7, 127.4,
126.7, 124.4, 123.8, 122.1, 113.7, 71.1, 63.8, 57.0, 26.8, 21.3,
4.4; MS (electrospray) m/z 492 (M + 1).
(S)-N-[(1S,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)eth -
yl]-2-m eth oxy-1-n a p h th a len esu lfin a m id e (8A). The prod-
uct was obtained as a unique diasteromer from (R)-1 and (S)-4
at -78 °C. After column chromatography (ether), it was
obtained as a white crystalline solid: yield 83%; mp 145-146
°C; [R]20 ) +210.0 (c 0.5, CHCl3); 1H NMR (200 MHz) δ 8.52
D
(S)-N-[(1S,2S,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)-
pr opyl]-2-m eth oxy-1-n a ph th a len elsu lfin a m id e (15B). The
product was obtained at 0 °C from (S)-4 and (R)-2 as the major
isomer of a 30:70 mixture of both diastereomers 15A and 15B.
After column chromatography (hexane/AcOEt, 2:1), the prod-
(d, J ) 8.6 Hz, 1H), 7.96 (m, 2H), 7.85 (d, J ) 8.1 Hz, 1H),
7.55-7.27 (m, 12H), 4.20 (s, 3H), 3.48 (AB system, ∆υ) 94.0
Hz, J ) 13.5 Hz, 2H), 2.40 (s, 3H), 2.12 (s, 3H); 13C NMR (50
MHz) δ 155.3, 144.3, 141.7, 141.0, 133.1, 130.2, 130.0, 128.8,
128.6, 128.4, 127.8, 127.4, 126.3, 125.9, 124.3, 124.2, 122.4,
113.6, 70.5, 61.9, 56.8, 29.4, 21.4; MS (electrospray) m/z 478
(M + 1).
(S)-N-[(1S,2S,SS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)-
p r op yl]-p-tolu en esu lfin a m id e (12A). It is obtained from
(S)-3 and (S)-2 as the minor isomer of a mixture of diastere-
omers, 12A/12B. After column chromatography (hexane/
uct was obtained as a white solid: yield 50%; mp 133 °C; [R]20
D
) -11.6 (c 1.0, CHCl3); 1H NMR (300 MHz) δ 8.33 (d, J ) 8.2
Hz), 7.96 (m, 2H), 7.82 (d, J ) 8.0 Hz, 1H), 7.55-7.20 (m, 12H),
4.21 (s, 3H), 2.89 (q, J ) 7.0 Hz, 1H), 2.34 (s, 3H), 2.15 (s,
3H), 1.10 (d, J ) 7.0 Hz, 3H); 13C NMR (75 MHz) δ 155.1,
144.3, 140.7, 139.2, 132.8, 130.2, 129.6, 128.7, 128.4, 128.3,
127.7, 127.5, 127.0, 126.5, 124.3, 123.8, 123.7, 122.2, 113.7,
71.2, 64.8, 56.9, 25.6, 21.2; MS (electrospray) m/z 492 (M +
1). Anal. Calcd for C28H29NO3S2: C, 68.40; H, 5.95; N, 2.85; S,
13.04. Found: C, 68.44; H, 6.18; N, 2.70; S, 12.59.
AcOEt, 2:1), the product was obtained as a white solid: yield
1
12%; mp 78 °C; [R]20 ) -98.0 (c 1.0, CHCl3); H NMR (300
D
MHz) δ 7.60 (m, 4H), 7.47-7.22 (m, 9H), 5.11 (s, 1H), 2.85 (q,
J ) 7.0 Hz, 1H), 2.38 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 0.98
(d, J ) 7.0 Hz, 3H); 13C NMR (75 MHz) δ 143.3, 142.5, 141.2,
140.8, 139.0, 129.6, 128.5, 127.9, 127.4, 125.0, 123.8, 71.1, 64.0,
27.0, 21.2, 4.3; MS (electrospray) m/z 426 (M + 1).
Desu lfin ylation of N-(â-Su lfin ylalkyl)su lfin am ides. Gen -
er a l P r oced u r e. To a stirred solution of the corresponding
N-(â-sulfinylalkyl)sulfinamide (12.4 mmol) in methanol (120
mL) was added TFA (61.8 mmol, 4.7 mL). After the mixture
was stirred for 3 h at 0 °C, the solvent was evaporated under
vacuum and the residue obtained was chromatographed on a
SCX column, affording the corresponding â-aminosulfoxide.
(1S ,R S )-1-Me t h y l-1-p h e n y l-2-(p -t o ly ls u lfin y l)e t h y -
(S)-N-[(1S,2R,SS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)-
p r op yl]-p-tolu en esu lfin a m id e (12B). The product was ob-
tained as a unique diastereomer from (S)-3 and (S)-2 at room
temperature. After column chromatography (hexane/AcOEt,
2:1), it was obtained as a yellow solid: mp 81-83 °C; yield
80%; mp 62 °C; [R]20 ) -82.0 (c 0.3, CHCl3); IR (film) 3348,
la m in e (9). The product was obtained as a colorless oil from
D
1
5A: yield 90%; [R]20 ) +114.0 (c 0.6, CHCl3); H NMR (300
1597, 1493, 1445 cm-1
;
1H NMR (300 MHz) δ 7.78 (m, 4H),
D
MHz) δ 7.55 (m, 2H), 7.41-7.22 (m, 7H), 3.48 (AB system, ∆υ
) 24.0 Hz, J ) 13.4 Hz, 2H), 2.34 (s, 3H), 2.19 (bs, 2H), 1.61
(s, 3H); 13C NMR (75 MHz) δ 146.6, 141.6, 141.2, 129.8, 128.5,
127.0, 125.1, 123.7, 73.3, 55.6, 32.1, 21.3.
7.47 -7.22 (m, 13H), 2.82 (q, J ) 7.0 Hz, 1H), 2.39 (s, 3H),
2.17 (s, 3H), 1.88 (s, 3H), 0.81 (d, J ) 7.0 Hz, 3H); 13C NMR
(75 MHz) δ 146.9, 140.6, 140.0, 129.7, 128.4, 126.8, 125.2,
123.9, 70.5, 63.9, 29.6, 21.3, 4.2; MS (electrospray) m/z 426
(M + 1).
(1S ,S S )-1-Me t h y l-1-p h e n y l-2-(p -t o ly ls u lfin y l)e t h y -
la m in e (10). The product was obtained as a colorless oil from
(S)-N-[(1S,2R,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)-
p r op yl]-p-tolu en su lfin a m id e (13A). The product was ob-
tained from (S)-3 and (R)-2 as the minor isomer of a mixture
of diastereomers 13A/13B. After column chromatography
(hexane/AcOEt, 2:1) the product was obtained as a yellow
1
6A: yield 90%; [R]20 ) -99.0 (c 0.5, CHCl3); H NMR (300
D
MHz) δ 7.49-7.43 (m, 4H), 7.32-7.22 (m, 5H), 3.01 (AB
system, ∆υ ) 61 Hz, J ) 13.5 Hz, 2H), 2.34 (s, 3H), 2.09 (bs,
2H), 1.84 (s, 3H); 13C NMR (75 MHz): δ 147.3, 141.4, 141.2,
129.8, 128.3, 126.9, 124.8, 123.7, 72.9, 55.1, 29.7, 21.2.
(1S,2R,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)p r op y-
la m in e (16A). The product was obtained as a white solid from
solid: mp 73-76 °C; solid; [R]20 ) +134.0 (c 0.5, CHCl3); IR
D
(film) 3436, 3203, 1596, 1492, 1446, 1086, 1048 cm-1; 1H NMR
(300 MHz) δ 7.78 (m, 4H), 7.52-7.22 (m, 9H), 4.78 (s, 1H),
3.05 (q, J ) 7.0 Hz, 1H), 2.38 (s, 3H), 2.38 (s, 3H), 2.22 (s,
3H), 0.85 (d, J ) 7.0 Hz, 3H); 13C NMR (75 MHz) δ 143.9,
142.7, 141.4, 140.9, 140.4, 129.8, 129.7, 128.6, 127.6, 126.2,
126.0, 123.8, 71.1, 64.2, 26.9, 21.3, 4.4; MS (FAB) m/z 426 (M
15A: yield 90%; mp 33 °C; [R]20 ) +137.0 (c 0.5, CHCl3); IR
D
(film) 3369 (bs), 1598, 1493, 1445, 1084 cm-1; H NMR (300
1
MHz) δ 7.47 (m, 2H), 7.36-7.25 (m, 7H) 3.45 (bs, 2H), 2.85 (q,
J ) 6.95 Hz, 1H), 2.37 (s, 3H), 1,88 (s, 3H), 0.85 (d, J ) 6.95
J . Org. Chem, Vol. 69, No. 13, 2004 4461

Garc´ıa Ruano et al.
1
Hz, 3H); 13C NMR (75 MHz) δ 145.9, 140.7, 139.5, 129.7, 128.5,
cm-1; H NMR (300 MHz) δ 7.42 (m, 2H), 7.29 (m, 7H), 6.28
(s, 1H), 3.42 (q, 2H, J ) 6.9 Hz), 3.29 (q, 2H, J ) 6.9 Hz), 2.92
(m, 1H), 2.37 (s, 3H), 2.09 (s, 3H), 1.20 (m, 9H); 13C NMR (75
MHz) 156.6, 145.6, 140.8, 138.5, 129.7, 129.6, 128.4, 127.0,
125.7, 123.9, 70.0, 62.1, 41.2, 27.0, 21.3, 13.9.
127.1, 125.1, 123.8, 70.2, 58.4, 29.0, 21.2, 4.2; HRMS calcd for
C
C
17H21NOS [M+] 287.13438, found 287.13460. Anal. Calcd for
17H21NOS: C, 71.04; H, 7.36. Found: C, 70.96; H, 7.49.
(1S,2S,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfin yl)p r op y-
la m in e (16B). The product was obtained as a white solid from
Cbz-P r otection of â-Su lfin yla m in es. Gen er a l P r oce-
d u r e. To a solution of the corresponding â-amino sulfoxide (1.0
mmol) in THF (4 mL) at rt was added NaH (2 mmol). After
the solution was stirred for 2 min, benzyl chloroformate (1.05
mmol) was added. After an additional 5 h of stirring, a solution
of saturated NH4Cl aqueous solution was added slowly. The
mixture was extracted with diethyl ether (2 × 10 mL), washed
with brine, and dried over MgSO4 and the solvent evaporated
under vacuum. The desired protected amine was isolated in
pure form by column chromatography (hexane-AcOEt, 3:1).
Ben zyl N-[(1S,2S,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfi-
n yl)p r op yl]ca r ba m a te (26). The product was obtained as a
15B: yield 90%; mp 123 °C; [R]20 ) +110.0 (c 0.6, CHCl3);
D
1H NMR (200 MHz) δ 7.56 (m, 2H), 7.42-7.23 (m, 7H), 2.83
(q, J ) 6.95 Hz, 2H), 2.35 (s, 3H), 2.06 (s, 2H), 1.62 (s, 3H),
0.97 (d, J ) 6.95 Hz, 3H); 13C NMR (50 MHz) δ 147.1, 140.4,
140.3, 129.5, 128.4, 127.0, 125.6, 123.8, 71.7, 57.9, 28.1, 21.2,
4.5; HRMS calcd for
C
17H21NOS [M+] 287.13438, found
287.13495. Anal. Calcd for C17H21NOS: C, 71.04; H, 7.36.
Found: C, 69.91; H, 7.58.
(1S,2R,SS)-1-Met h yl-1-p h en yl-2-p -t olylsu lfin ylp r op y-
la m in e (17B). The product was obtained as a colorless oil from
1
12B: yield 93%; [R]20 ) +15.6 (c 1.7 CHCl3); H NMR (300
D
colorless oil from 16B: yield 86%; [R]20 ) -172.2 (c 0.4,
MHz) δ 7.54 (d, J ) 8.2 Hz, 2H), 7.26 (t, J ) 7.3 Hz, 2H), 7.35-
7.20 (m, 5H), 2.83 (q, J ) 6.9 Hz, 1H), 2.41 (bs, 2H), 2.35 (s,
3H),0.97 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz): δ 146.9,
140.4, 140.1, 129.5, 129.5, 127.1, 125.6, 123.8, 71.6, 58.0, 28.0,
21.2, 4.5. Anal. Calcd for C17H21NOS: C, 71.04; H, 7.36.
Found: C, 71.11; H, 7.65.
D
CHCl3); IR (film) 3314, 2983, 1712, 1599, 1522, 1336, 1253
cm-1; 1H NMR. (300 MHz) δ 7.42-7.23 (m, 14H), 6.25 (bs, 1H),
5.09 (AB system, ∆υ ) 30.0 Hz, J ) 132.3 Hz, 2H), 2.81 (m,
1H), 2.38 (s,3H), 2.24 (s, 3H), 0.76 (d, J ) 7.0 Hz, 3H); 13C
NMR (75 MHz) δ 155.1, 142.5, 141.0, 138.7, 136.6, 129.7, 128.4,
128.3, 128.0, 127.9, 127.2, 125.8, 124.0, 69.0, 66.4, 61.3, 25.7,
21.3, 4.2. Anal. Calcd for C25H27NO3S: C, 71.23; H, 6.46.
Found: C, 71.31; H, 6.62.
Ben zyl N-[(1S,2R,RS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfi-
n yl)p r op yl]ca r ba m a te (27). The product was obtained as a
colorless oil from 16A: yield 84%; [R]20D ) -92.4 (c 0.7, CHCl3);
1H NMR (300 MHz) δ 7.42-7.23 (m, 14H), 6.24 (bs, 1H), 5.09
(AB system, ∆υ) 30.0 Hz, J ) 12.3 Hz, 4H), 2.82 (m, 1H),
2.39 (s, 3H), 2.24 (s, 3H), 0.76 (d, J ) 7.0 Hz, 3H); 13C NMR
(75 MHz) δ 155.1, 142.6, 141.0, 138.8, 136.5, 129.8, 128.4,
128.3, 128.0, 127.9, 127.3, 125.8, 124.0, 69.0, 66.4, 61.3, 25.7,
21.3, 4.2. Anal. Calcd for C25H27NO3S: C, 71.23; H, 6.46.
Found: C, 71.01; H, 6.72.
(R)-2-P h en yl-2-bu tyla m in e (18).18 To a stirred solution
of the corresponding â-amino sulfoxide 17B or 16A/16B (0.2
mmol) in THF (2 mL) was added a suspension of activated
Raney-nickel (1.2 g) in THF. The reaction was stirred for 2 h,
and then the crude was purified by SCX column to afford the
amine: yield 69% from 17B and 58% from 16A/16B; [R]20
)
D
+15.6 (c 0.5,EtOH) [lit.18 [R]20 ) +16.0 (c 0.6, EtOH)]; 1H
D
NMR (300 MHz) δ 7.49 (d, J ) 7.1 Hz, 2H), 7.40-7.24 (m,
3H), 2.05 (m, 2H), 1.72 (s, 3H), 0.80 (t, J ) 7.5, 3H).
Boc-P r otection of â-Su lfin yla m in es. Gen er a l P r oce-
d u r e. To a solution of the corresponding â-aminosulfoxide (0.5
mmol) in CH3CN (2 mL) and triethylamine (180 µL, 1.25
mmol) was added (t-BuOCO)2O (0.65 mmol). After the mixture
was stirred for 15 h at room temperature, 10% HCl aqueous
solution was added and the mixture extracted with AcOEt (4
× 25 mL). The organic phase was dried over Na2SO4, evapo-
rated under vacuum, and purified by column chromatography
on silica gel (AcOEt/hexane, 1:1) to give the corresponding
carbamate.
ter t-Bu tyl N-[(1S,RS)-1-Meth yl-1-p h en yl-2-p-tolylsu lfi-
n yleth yl]ca r ba m a te (19). The product was obtained as a
white solid from 9: yield 45%; mp 70 °C; [R]20D ) +82.0 (c 0.5,
CHCl3); 1H NMR (300 MHz) δ 7.52 (m, 2H), 7.32-7.21 (m, 7H),
5.99 (s, 1H), 3.51(AB system, ∆υ ) 114.0 Hz, J ) 13.3 Hz,
2H), 2.39 (s, 3H), 1.81 (s, 3H), 1.45 (s, 9H); 13C NMR (75 MHz)
δ 154.5, 141.2, 129.9, 128.6, 127.0, 123.7, 68.7, 57.7, 30.3, 28.3,
27.3, 21.3.
Ben zyl N-[(1S,2R,SS)-1-Meth yl-1-p h en yl-2-(p-tolylsu lfi-
n yl)p r op yl]ca r ba m a te (28). The product was obtained as a
colorless oil from 17B: yield 77%; IR (film) 3301, 1729, 1521,
1448 cm-1; [R]20 ) -68.2 (c 0.4, CHCl3); 1H NMR (300 MHz)
D
δ 7.42-7.23 (m, 14H), 6.24 (bs, 1H), 5.08 (m, 2H), 2.82 (m,
1H), 2.39 (s,3H), 2.24 (s, 3H), 0.76 (d, J ) 7.0 Hz, 3H); 13C
NMR (75 MHz) δ 155.1, 142.7, 141.0, 138.8, 136.6, 129.8, 128.4,
128.3, 128.0, 127.9, 127.3, 125.8, 124.0, 69.0, 66.5, 61.3, 25.8,
21.3, 4.3; Anal. Calcd for C25H27NO3S: C, 71.23; H, 6.46.
Found: C, 71.21; H, 6.52.
P u m m er er Rea ction a n d Dep r otection of Boc-P r o-
tected â-Am in o Su lfoxid es. To a stirred solution of the â-(N-
Boc-amino)sulfoxide 19 or 20 (1.0 mmol) and sym-collidine
(0.42 mL, 3.0 mmol) in acetonitrile (10 mL) at 0 °C was added
trifluoroacetic anhydride (0.8 mL, 5.0 mmol) dropwise. After
the solution was stirred for 5 min, a 20% K2CO3 aqueous
solution was added until basic pH was reached. The mixture
was warmed to room temperature and, after 5 min, quenched
with saturated NH4Cl aqueous solution (5 mL), and the organic
phase was extracted with ethyl acetate (5 × 10 mL). The
organic layers were treated with 10% HCl aqueous solution
(5 mL) to remove the excess sym-collidine, dried over Na2SO4,
and evaporated under vacuum. The crude mixture was treated
with a mixture of 1 N HCl aqueous solution (3 mL) and THF
(2 mL). After 48 h of vigorous stirring, the crude product was
extracted with CH2Cl2 (10 mL), and the aqueous layer was
evaporated under vacuum, affording the corresponding â-ami-
no alcohol hydrochloride.
ter t-Bu tyl N-[(1S,2S,RS)-1-Meth yl-1-p h en yl-2-(p-tolyl-
su lfin yl)p r op yl]ca r ba m a te (20). The product was obtained
as a colorless oil from 16B: yield 42%; [R]20 ) +54.0 (c 0.5,
D
CHCl3); 1H NMR (300 MHz) δ 7.49 (m, 2H), 7.46-7.24 (m, 7H),
6.00 (bs, 1H), 3.19 (m, 1H), 2.37 (s, 3H), 1.89 (s, 3H), 1.43 (s,
9H), 1.05 (d, J ) 6.96 Hz, 3H).13C NMR (75 MHz) δ 154.9,
144.7, 140.7, 139.0, 129.6, 128.4, 127.2, 125.7, 123.9, 79.4, 68.0,
61.2, 28.3, 25.3, 21.3, 4,6.
1,3-Bis[(1S,SS)-1-m eth yl-1-ph en yl-2-(p-tolylsu fin yl)eth yl]-
u r ea (21). The product was obtained as a byproduct from 9,
together with the corresponding Boc-amine 19: white solid;
mp 148-150 °C; yield 40%; [R]20 ) +41.1 (c 1.3, CHCl3); IR
D
(film) 3353, 1682, 1547, 1493, 1445 cm-1; 1H NMR (300 MHz)
δ 7.41-7.05 (m, 18H), 3.75 (AB system, ∆υ ) 30.0 Hz, J )
13.5 Hz, 4H), 2.34 (s, 3H), 1.64 (s, 3H); 13C NMR (75 MHz) δ
155.9, 147.7, 141.0, 140.1, 129.7, 128.3, 126.2, 124.1, 123.9,
67.7, 56.7, 32.0, 21.2.
(2S)-2-Am in o-2-p h en ylp r op a n -1-ol Hyd r och lor id e (11).
This compound was obtained from 19 as a colorless oil: yield
80%; [R]20 ) +17.0 (c 0.5, H2O); IR (film): 3286, 1601, 1485,
D
1027 cm-1
;
1H NMR (200 MHz) δ 7.26 (m, 5H), 3.65 (AB
N,N-Dieth yl-N′-[(1S,2S,RS)-1-Meth yl-1-ph en yl-2-(p-tolyl-
su lfin yl)p r op yl]u r ea (22). The product was obtained as a
byproduct from 16B, together with the corresponding Boc-
system, ∆υ ) 17.0 Hz, J ) 12.3 Hz, 2H),1.98 (s, 3H, CH3); 13
C
NMR (50 MHz) δ 145.4, 127.4, 125.8, 124.2, 70.7, 55.3, 26.1;
(2R,3S)-3-Am in o-3-ph en ylbu tan -2-ol Hydr och lor ide (25).
This compound was obtained from 20 as a colorless oil: yield
amine 20: white solid;, mp 147-149 °C; yield 41%; [R]20
)
D
+43.1 (c 1.5, CHCl3); IR (film) 3371, 1681, 1547, 1493, 1446
4462 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of Optically Pure 1,2,2′-Trialkyl-2-aminoethanols
70%; [R]20D ) -4.0 (c 0.5, H2O); 1H NMR δ 7.45-7.22 (m, 5H),
4.12 (q, J ) 6.5 Hz, 1H), 1.6 (s, 3H), 0.94 (d, J ) 6.5 Hz, 3H).
P u m m er er Rea ction of Cbz-P r otected â-Am in osu lfox-
id es. Gen er a l P r oced u r e. To a stirred solution of the
corresponding â-(N-Cbz-amino)sulfoxide (1.0 mmol) 26-28 and
sym-collidine (0.42 mL, 3.0 mmol) in acetonitrile (10 mL),
under a nitrogen atmosphere at 0 °C, was added trifluoroacetic
anhydride (0.8 mL, 5.0 mmol) dropwise. After the solution was
stirred for 5 min, a 20% K2CO3 aqueous solution was added
until basic pH was reached. NaBH4 (excess) was then added
portionwise at 0 °C, and the mixture was warmed to room
temperature. When the reaction was completed as evidenced
by TLC, it was quenched with a saturated NH4Cl aqueous
solution and extracted with AcOEt. The organic layer was
dried over MgSO4, evaporated under vacuum, and purified by
column chromatography on silica gel (hexane/AcOEt, 2:1) to
give the corresponding Cbz-protected amino alcohol.
Ben zyl N-[(1S,2R)-1-Meth yl-1-ph en yl-2-h ydr oxypr opyl]-
ca r ba m a te (29). This compound was obtained from 26 as a
colorless oil: yield 64%; [R]20D ) + 5.2 (c 0.3, CHCl3); 1H NMR
(300 MHz) δ 7.40-7.23 (m, 10H), 5.6 (bs, 1H), 5.06 (s, 2H),
3.99 (m, 1H), 1.75 (s, 3H), 1.11 (d, J ) 6.4 Hz, 3H); 13C NMR
(75 MHz) δ 156.0, 143.8, 136.5, 128.6, 128.5, 128.3, 128.1,
127.2, 125.7, 74.7, 66.6, 62.3, 21.6, 17.3.
was extracted with ethyl acetate (3 × 10 mL) and dried with
anhydrous Na2SO4 and the solvent evaporated under vacuum.
The crude product was purified by flash column chromatog-
raphy with 3/1 hexane-AcOEt. It was obtained as a white
solid: yield 68%; IR (film) 3165 (bs), 1595, 1493, 1446, 1326
1
cm-1; H NMR (300 MHz) δ 7.55-7.29 (m, 12H), 7.11 (d, J )
8.4 Hz, 2H), 7.00-6.91 (m, 4H), 3.70 (AB-system, ∆υ ) 222.0
Hz, J ) 12.9 Hz, 1H), 3.33 (d, J ) 12.9 Hz, 1H), 2.42 (s, 3H),
2.31 (s, 3H); 13C NMR (75 MHz) δ 142.0, 141.9, 141.8, 140.2,
139.4, 139.0, 129.9, 129.2, 128.6, 128.3, 127.7 (2C), 127.6,
127.2, 126.7, 124.0, 68.2, 66.6, 21.3, 21.2. Anal. Calcd for
C
28H27NO3S2: C, 68.68; H, 5.56. Found: C, 68.75; H, 5.52.
N -(1,1-D ip h e n y l-1-fo r m y le t h y l)-p -t o lu e n e s u lfo n a -
m id e (34). To a stirred solution of 31 (0.02 mmol) and sym-
collidine (0.1 mL, 0.07 mmol) in dry acetonitrile (5 mL), under
a nitrogen atmosphere at 0 °C, was added trifluoroacetic
anhydride (0.2 mL, 0.10 mmol) dropwise. After the solution
was stirred for 5 min, a 20% K2CO3 aqueous solution was
added until basic pH was reached. NaBH4 (excess) was then
added portionwise at 0 °C, and the mixture was warmed to
room temperature. When the reaction was completed as
evidenced by TLC, it was quenched with a saturated NH4Cl
aqueous solution and extracted with AcOEt. The organic layer
was dried over MgSO4, evaporated under vacuum, and purified
by column chromatography on silica gel (hexane/AcOEt, 6:1)
to give the corresponding aldehyde. It was obtained as a
colorless oil: yield 55%; IR (film) 1715, 1659, 1597, 1591, 1556,
Ben zylN-[(1S,2S)-1-Meth yl-1-p h en yl-2-h yd r oxyp r op yl]-
ca r ba m a te (30). This compound was obtained as a white solid
from 27 (68% yield) or 28 (75% yield): [R]20 ) + 10.8 (c 1.4,
D
1
1277 cm-1; H NMR (400 MHz) 9.63 (s, 1H), 7.80 (d, J ) 8.0
MeOH); IR (film) 3403, 2984, 1705, 1497, 1454 cm-1; 1H NMR
(400 MHz) δ 7.40-7.20 (m, 10H), 5.50 (m, 1H), 5.13 (m, 1H),
5.00 (m, 2H), 3.85 (q, J ) 6.4 Hz, 1H), 1.75 (s, 3H), 0.95 (t, J
) 6.4 Hz, 3H); 13C NMR (100 MHz) δ 156.0, 141.7, 136.5, 135.3,
128.6, 128.5, 128.3, 128.2, 128.1, 127.2, 126.3, 74.1, 67.8, 66.6,
22.4, 17.8; MS (FAB) m/z 300 (M + 1, 85), 254 (70), 238 (54),
210 (100); HRMS calcd for C18H21NO3 [M + 1] 300.1600, found
300.1606.
Hz, 2H), 7.58 (t, J ) 7.2 Hz, 2H), 7.47 (t, J ) 7.6 Hz, 2H),
7.35-7.24 (m, 5H), 7.00 (d, J ) 8.0 Hz, 2H), 6.95 (d, J ) 8.0
Hz, 2H), 2.26 (s, 3H); 13C NMR (100 MHz) 190.6, 139.8, 137.7,
137.6, 136.7, 132.4, 130.0, 129.6, 129.5, 128.3, 128.2, 127.9,
126.1, 70.8, 21.2. Anal. Calcd for C21H19NO3S: C, 69.02; H,
5.24. Found: C, 69.29; H, 5.66.
Ack n ow led gm en t. We thank CAICYT (Grant Nos.
BQU2003-04012 and CTQ2004-01057) for financial sup-
port. J .A. also thanks the Spanish Ministerio de Ciencia
y Tecnolog´ıa for a predoctoral fellowship.
N -[1,1-Dip h e n y l-2-p -t o ly lsu lfin y le t h y l]-p -t o lu e n e -
su lfon a m id e (31). To a solution of iPr2NH (1.20 mmol) in THF
(5 mL) at 0 °C was added a 2.5 M solution of n-BuLi in hexane
(1.20 mmol). After 20 min of stirring, the mixture was cooled
at -78 °C and a solution of racemic methyl p-tolyl sulfoxide
(1.20 mmol) in THF (2 mL) was then added. After the mixture
was stirred for 30 min at -78 °C, a solution of the N-
sulfonylketimine 3525 (1.20 mmol) in THF (4 mL) was added
at -78 °C. After the reaction finished (2 h), a saturated NH4-
Cl aqueous solution (10 mL) was added. The organic phase
Su p p or tin g In for m a tion Ava ila ble: NMR study of non-
1
oxidative Pummerer reaction. Synthesis and H NMR spectra
of Mosher esters of Cbz-protected amino alcohols 29a ,b and
30a ,b.Copies of 1H and the 13C NMR spectra of compounds
5B, 8A, 12A,B, 15A, 9, 10, 18-20, 22, 11, 29, and 21. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) N-Sulfonylimine was prepared following the procedure de-
scribed in the following reference: Ram, R. N.; Khan, A. A. Synth.
Commun. 2001, 31, 841.
J O049666S
J . Org. Chem, Vol. 69, No. 13, 2004 4463