Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals by Highly Stereospecific Tandem Pummerer Rearrangement/1,2-p-Tolylthio Group Migration of (R)-α-(Fluoroalkyl)-β-sulfinylenamines

Article abstract of DOI:10.1021/jo970863j

Fluoropyruvaldehyde N,S-ketals (R)-2 have been prepared in good yields (up to 88%) and ee (up to 79%) from α-(fluoroalkyl)-β-sulfinylenamines (R)-(Z)-1, through a new self-immolative tandem sequential process, consisting of a Pummerer reaction, promoted by trifluoroacetic anhydride, followed by a 1,2-migration of the p-tolylthio group, triggered by addition of silica gel or aqueous base. Each transfer of stereogenic center, from sulfur to the α-carbon and then to the β-carbon, occurs with an average degree of enantioselectivity up to 94:6. Cis geometry between the sulfinyl and the amino groups of the starting enamine (R)-1 is necessary for achieving high level of stereocontrol, since neighboring group participation by the N-Cbz amino group prevents the sulfinyl center from racemization promoted by trifluoroacetic anhydride. NMR studies have shown that imines 3 are intermediate products of the Pummerer rearrangement, which are stable in the reaction environment.

Full text of DOI:10.1021/jo970863j

J . Org. Chem. 1997, 62, 8031-8040
8031
P r ep a r a tion of (R)-F lu or op yr u va ld eh yd e N,S-Keta ls by High ly
Ster eosp ecific Ta n d em P u m m er er Rea r r a n gem en t/1,2-p-Tolylth io
Gr ou p Migr a tion of (R)-r-(F lu or oa lk yl)-â-su lfin ylen a m in es†
Alessandro Volonterio and Matteo Zanda*
Dipartimento di Chimica del Politecnico, Via Mancinelli 7, I-20131 Milano, Italy
Pierfrancesco Bravo* and Giovanni Fronza
C.N.R.-Centro di Studio per le Sostanze Organiche Naturali, Via Mancinelli 7, I-20131 Milano, Italy
Giancarlo Cavicchio and Marcello Crucianelli
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita` di L’Aquila, Via Vetoio,
I-67010 Coppito, Italy
Received May 14, 1997X
Fluoropyruvaldehyde N,S-ketals (R)-2 have been prepared in good yields (up to 88%) and ee (up to
79%) from R-(fluoroalkyl)-â-sulfinylenamines (R)-(Z)-1, through a new self-immolative tandem
sequential process, consisting of a Pummerer reaction, promoted by trifluoroacetic anhydride,
followed by a 1,2-migration of the p-tolylthio group, triggered by addition of silica gel or aqueous
base. Each transfer of stereogenic center, from sulfur to the R-carbon and then to the â-carbon,
occurs with an average degree of enantioselectivity up to 94:6. Cis geometry between the sulfinyl
and the amino groups of the starting enamine (R)-1 is necessary for achieving high level of
stereocontrol, since neighboring group participation by the N-Cbz amino group prevents the sulfinyl
center from racemization promoted by trifluoroacetic anhydride. NMR studies have shown that
imines 3 are intermediate products of the Pummerer rearrangement, which are stable in the reaction
environment.
In tr od u ction
sensitive groups and provide hydrogen acceptor ability.3d,e
Furthermore, a large array of mechanism-based inhibi-
tors show increased activity thanks to fluoro-substitution;
among them, R-fluoromethyl- and â-fluoro-R-amino acids
have been widely used as selective inhibitors of pyridoxal-
dependent enzymes.4 The application of fluorine-con-
taining molecules as drugs, as medical diagnostics or as
probes for the investigation of methabolic pathways is
therefore of great interest for the scientific community.
Since fluoro-compounds are practically xenobiotic, con-
siderable efforts are directed toward the discovery of
highly efficient routes to single enantiomers of selectively
fluorinated molecules.5
Molecular recognition, which is the basis of biological
activity, arises from the interactions of the substrate
(drug) with the receptor site.1 Many factors contribute
to this phenomenon, like steric hindrance, dipole interac-
tions, lipophilicity, and others, which are always closely
related to the tridimensional structure of the two coun-
terparts. For this reason the relative and absolute
stereochemistry of a molecule plays a key-role in deter-
mining its biological properties, as witnessed by the
dramatic difference of activity featured by two diastereo-
isomers and even by two enantiomers of a chiral sub-
stance.2 On the other hand, the introduction of trifluo-
romethyl groups or the substitution of hydrogens or
hydroxyl groups with fluorine atoms in biologically active
molecules has become an important strategy for increas-
ing the biological activity of a molecule, since fluorine
substituents may assist drug absorption, modify its tissue
distribution, and significantly change preferred molecular
conformations.3 Fluoro-substitution may provide excel-
lent protection against oxidation or acid hydrolysis of
A few years ago we undertook a study for finding new
strategies for the stereoselective synthesis of biologically
relevant chiral nonracemic fluoro-amino compounds,
based on the use of the sulfinyl group as a stereocontrol-
ling agent.6 In a recent preliminary report we have
described a new class of three-carbon chiral nonracemic
fluorinated building blocks, namely fluoropyruvaldehyde-
N,S-ketals (F-PAKs) (R)-2,7 synthesized from R-(fluoro-
alkyl)-â-sulfinylenamines (F-SEs) (R)-1 (Scheme 1), flu-
* To whom correspondence should be addressed. Fax: (39-2) 2399
3080. E-mail: zanda@dept.chem.polimi.it.
(3) (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Filler, R.; Kobayashi, Y.;
Yagupolskii, L. M. Biomedical Aspects of Fluorine Chemistry; Elsevi-
er: Amsterdam, 1993. (c) Banks, R. E.; Tatlow, J . C.; Smart, B. E.
Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (d) Dunitz, J . D.; Taylor, R. Chem.
Eur. J . 1997, 3, 89. (e) Howard, J . A. K.; Hoy, V. J .; O’Hagan, D.; Smith,
G. T. Tetrahedron 1996, 52, 12613.
† Presented in part at the 17th International Symposium on the
Organic Chemistry of Sulfur (ISOCS), Tsukuba (J apan), J uly 7-12,
1996.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
(1) (a) Casy, A. F. The Steric Factor in Medicinal Chemistry.
Dissymmetric Probes of Pharmacological Receptors; Plenum Press:
New York, 1993. (b) Lemieux, R. U. Acc. Chem. Res. 1996, 29, 373. (c)
Kirby, A. J . Angew. Chem., Int. Ed. Engl. 1996, 35, 706. (d) Rebek, J .,
J r. Chem. Soc. Rev. 1996, 25, 255. (e) Trost, B. M. Acc. Chem. Res.
1996, 29, 355.
(2) (a) “Guideline for Submitting Supporting Documentation in Drug
Applications for the Manufacture of Drug Substances”, Office of Drug
Evaluation and Research, Food and Drug Administration, Washington,
DC, 1987; p 3. (b) Chem. Eng. News 1992, J une 15, 5. (c) Stinson, S.
C. Chem. Eng. News 1992, September 28, 46.
(4) Fluorine-Containing Amino Acids: Synthesis and Properties;
Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, 1994.
(5) (a) Resnati, G. Tetrahedron 1993, 49, 9385. See also: (b)
Fluoroorganic Chemistry: Synthetic Challenges and Biomedical Re-
wards; Resnati, G., Soloshonok, V. A., Eds.; Tetrahedron Symposium-
in-Print No. 58; Tetrahedron 1996, 52, 1-330.
(6) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.; Kukhar,
V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5, 2009.
S0022-3263(97)00863-3 CCC: $14.00 © 1997 American Chemical Society

8032 J . Org. Chem., Vol. 62, No. 23, 1997
Volonterio et al.
Sch em e 1a
Sch em e 2. “Tr a d ition a l” P u m m er er Rea ction
a
Key: (i) TFAA, THF; (ii) procedure A: NaHCO3 up to pH 7;
procedure B: (1) SiO2, (2) H2O.
Sch em e 3. “Non oxid a tive” P u m m er er Rea ction
orinated templates available in enantiomerically pure
form from fluoroacetic esters8 or acids9 as fluorine
sources. The absolute stereochemistry of (+)-(R)-triF-
PAK 2a has been determined by X-ray analysis and its
use for the stereoselective synthesis of trifluoro analogues
of Ephedra alkaloids has been also reported in a com-
munication.10 It is worth noting that, to the best of our
knowledge, F-PAKs (R)-2 are the first examples of
nonenolizable aldehydes simultaneously bearing a sulfur,
a nitrogen, and a carbon atom in the R-position.11
An investigation of the scope, limits, and mechanism
of the tandem process leading to the F-PAKs (R)-2 is
addressed in this study.
of the R1COO residue, or indirectly through the achiral
sulfonium cation D, which produces E by reassembling
with the R1COO- anion.
Resu lts
We have recently reported that R-(fluoroalkyl)-â-sulfin-
ylamines F (Scheme 3) submitted to Pummerer condi-
tions (TFAA, sym-collidine) follow the so-called “nonox-
idative” 13 or “interrupted” 14 pathway. The trivalent
sulfonium cation formed from F undergoes intramolecu-
lar trapping by the nucleophilic â-nitrogen, leading to the
sulfurane intermediate G, which spontaneously gives rise
to a SN2-type displacement of the sulfinyl residue by the
trifluoroacetoxy group, with formation of the trifluoro-
acetoxy sulfenamide H (diastereoselectivity > 98:2),
easily transformed into the corresponding γ-fluoro-â-
amino alcohol J .
The unsaturated counterparts of F , namely F-SEs (R)-
1, upon treatment with 1 equiv of TFAA in dry THF at
0 °C immediately provide an intermediate compound
(Scheme 1, step 1), which, without isolation, further
reacts with diluted aqueous NaHCO3, or with SiO2 at the
same temperature (step 2, procedure A and B, respec-
tively), affording the F-PAKs (R)-2 as unique reaction
products. These new and structurally stable molecules
are produced with variable degree of enantiomeric purity
depending on the experimental conditions applied. The
same process occurs for F-SEs (R)-1 having diverse
R-fluoroalkyl residues, like CF3, CF2Cl, CF2H.
The Pummerer reaction (PR) is a well-known method
for the synthesis of R-substituted sulfides from the
corresponding sulfoxides.12 The “traditional” PR involves
an anhydride-promoted transformation of the sulfinyl
group of A into a trivalent sulfonium cation B (Scheme
2), followed by base removal of a labilized R-sulfur proton
and consecutive formation of the chiral ylide C. This
intermediate can afford directly the chiral R-substituted
sulfide E, which is a masked aldehyde, through migration
(7) Bravo, P.; Crucianelli, M.; Fronza, G.; Zanda, M. Synlett 1996,
249.
(8) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S. V.; Zanda,
M.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1996, 61, 3375.
Corrigenda: J . Org. Chem. 1996, 61, 9635.
(9) Bravo, P.; Cavicchio, G.; Crucianelli, M.; Markovsky, L. A.;
Volonterio, A.; Zanda, M. Synlett 1996, 887.
(10) Volonterio, A.; Bravo, P.; Capelli, S.; Meille, S. V.; Zanda, M.
Tetrahedron Lett. 1997, 38, 1847.
(11) For N-monoprotected R-amino aldehydes see: (a) J urczak, J .;
Golebiowski, A. Chem. Rev. (Washington, D.C.) 1989, 89, 149. (b)
Devant, R. M.; Radunz, H.-E. In Houben-Weyl: Methods in Organic
Synthesis; Mu¨ller, E., Ed.; Thieme Verlag: Stuttgart, 1995; Vol. E21b,
p 1151. For chiral R-trifluoromethylated aldehydes: (c) Konno, T.;
Yamazaki, T.; Kitazume, T. Tetrahedron 1996, 52, 199. For R-sulfenyl
aldehydes: (d) Eames, J .; de las Heras, M. A.; Warren, S. Tetrahedron
Lett. 1996, 37, 4077-4080. (e) Eames, J .; J ones, R. V. H.; Warren, S.
Ibid. 1996, 37, 4823-4826. (f) Sato, T.; Otera, J . Synlett 1995, 351. (g)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.; Consolandi, E. J .
Org. Chem. 1992, 57, 456 and references therein. (h) Enders, D.; Piva,
O.; Burkamp, F. Tetrahedron 1996, 52, 2893. For a very recent work
on the diastereoselectivity of the indium-promoted allylation of both
N-monoprotected R-amino and R-sulfenyl aldehydes: (i) Paquette, L.
A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.; Schomer, W. W. J . Org.
Chem. 1997, 62, 4293.
In view of the potential interest in the differently
fluoro-substituted F-PAKs (R)-2 as chiral nonracemic
building blocks for the synthesis of organofluorine com-
pounds, we explored a large set of starting F-SEs (R)-1,
(13) (a) Bravo, P.; Zanda, M.; Zappala`, C. Tetrahedron Lett. 1996,
37, 6005. (b) Bravo, P.; Farina, A.; Kukhar, V. P.; Markovsky, A. L.;
Meille, S. V.; Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.; Zanda,
M.; Zappala`, C. J . Org. Chem. 1997, 62, 3424.
(14) Bates, K. A.; Winters, R. T.; Picard, J . A. J . Org. Chem. 1992,
57, 3094 and references therein.
(12) (a) De Lucchi, O.; Miotti, U.; Modena, G. Organic Reactions;
Paquette, L. A., Ed.; J ohn Wiley and Sons: New York, 1991; Vol. 40.
(b) Oae, S. Organic Sulfur Chemistry: Structure and Mechanism, CRC
Press: Boca Raton, 1991; pp 380-400. (c) Pummerer, R. Ber. 1909,
42, 2282. Horner, L. Liebigs Ann. 1960, 631, 198.

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals
J . Org. Chem., Vol. 62, No. 23, 1997 8033
Ta ble 1. Syn th esis of â-F lu or op yr u va ld eh yd es N,S-Keta ls (R)-2 fr om r-(F lu or oa lk yl)-â-su lfin ylen a m in es (R)-1a
procedure Ab
procedure Bc
entry
enamine
Rf
product
[R]20 (CHCl3)
ee (%) yield (%) [1], M
[R]20 (CHCl3)
ee (%) yield (%) [1], M
D
D
1
(R)-(Z)-1a
(S)-(Z)-1a
(R)-(Z)-1b
(R)-(Z)-1c
(R)-(Z)-1d
(R)-E-1d
CF3
CF3
CF3
(+)-(R)-2a
(-)-(S)-2a
(+)-(R)-2b
+136.2 (c 0.65)
-134.9 (c 0.68)
+173.8 (c 0.52)
np
+193.0 (c 0.64)
+23.6 (c 0.66)
67
67
44
np
42
6
85
85
88
np
86
86
0.15
0.15
0.15
np
0.25
0.30
+138.6 (c 0.89)
np
+199.9 (c 1.23)
+185.0 (c 0.60)
+280.8 (c 0.64)
+36.7 (c 0.67)
69
np
52
79
62
8
57
np
71
70
58
56
0.10
np
0.10
0.10
0.10
0.10
2
3d
4
CF2Cl (+)-(R)-2c
CF2H
CF2H
5
6
(+)-(R)-2d
(+)-(R)-2d
a
b
Step 1 performed adding 1 equiv of TFAA to a solution of F-SE (R)-1 in THF cooled at 0 °C. Step 2 performed by treating the
reaction mixture with 5% aqueous NaHCO3 for 5 min at 0 °C. c Step 2 performed by treating the reaction mixture with ca. 50 mg of SiO2
for 5 min at 0 °C. 2 equiv of TFAA were used. np ) not performed.
d
Sch em e 4
Sch em e 5
treated with acetyl chloride in THF (Scheme 5). By this
procedure the achiral R-chlorovinyl sulfides 5a ,d were
produced as single geometric isomers after 4 h at rt. The
stereochemistries of 5 were not investigated.
reaction promoters, and conditions, the most significant
experiments being reported in Table 1. In all cases
tested, the best yields of (R)-2 were obtained when 5%
aqueous NaHCO3 was used in step 2, whereas better ees
were obtained with SiO2/water.
The N-Cbz triF-SE (R)-(Z)-1a provided the (+)-(R)
enantiomer of the corresponding triF-PAK 2a with ee up
to 67% and 69% (Table 1, entry 1, procedures A and B,
respectively). Obviously, the enantiomeric F-SE (S)-(Z)-
1a afforded the triF-PAK (-)-(S)-2a (entry 2).
Reaction of the N-unprotected triF-SE (R)-(Z)-1b re-
quired 2 equiv of TFAA to reach completion, affording
the N-trifluoroacetyl triF-PAK (R)-2b with ee up to 52%
(Table 1, entry 3, procedure B). It is clear that the first
equivalent of TFAA should trifluoroacetylate the unpro-
tected nitrogen of (R)-(Z)-1b, and the second one should
promote the rearrangement.
The highest enantioselectivity was obtained for the
chlorodiF-PAK (+)-(R)-2c (79% ee), obtained in 70% yield
from the N-Cbz chlorodiF-SE (R)-(Z)-1c (Table 1, entry
4, procedure B).
The diF-SE (R)-1d was available also in pure E form,
namely with the sulfinyl and the amino groups in trans
configuration, thus allowing us to check the influence of
the double bond geometry on the reaction. In analogy
with the other cis F-SEs, the N-Cbz diF-SE (R)-(Z)-1d
produced the corresponding diF-PAK (+)-(R)-2d with
good yields and ees (Table 1, entry 5, 42% procedure A,
62% procedure B).
In contrast, the trans diF-SE (R)-E-1d produced the
diF-PAK (+)-(R)-2d with very low stereospecifity (ee
6-8%, Table 1, entry 6), although the reaction was
smooth as usual.
Scale-up of these reactions (up to ca. 3 g of (R)-(Z)-1a )
was possible, affecting neither the enantioselectivity nor
the yield.
N,N-Diprotected F-SEs8 (R)-4 proved to be unreactive
toward TFAA, under the same conditions, but were
recovered completely racemized after 5 min, as witnessed
by the lack of optical activity (Scheme 4).
The use of TFAA as promoter of the PR (step 1) was
found to be of paramount importance for achieving an
efficient formation of the F-PAKs (R)-2. Under standard
conditions, other Pummerer promoters such as acetic
anhydride or trimethylsilyl triflate led to recovery of
starting material, or to the formation of completely
different products, as observed when F-SEs (R)-1a ,d were
To (1) gain information on the reaction mechanism,15
(2) check the chemical and optical stability of F-PAKs
(R)-2, (3) find out the best conditions to accomplish the
title reaction, and (4) establish its scope and limits,
further investigations, described in the following sections,
were performed.
NMR Exp er im en ts for th e Elu cid a tion of th e
Rea ction P a th w a y. With the goal of elucidating the
reaction pathway, the F-SEs (R)-1a and (R)-1d were
treated with TFAA in a NMR tube, monitoring the
1
evolution of the system by H, 13C, and 19F NMR. As an
example we describe the results obtained for the reaction
of the diF-SE (R)-(Z)-1d . The compound (0.1 mmol) was
1
dissolved directly in the NMR tube in THF-d8 and its H
and 19F NMR spectra were recorded (Figure 1a and 2a).
Then 1 equiv of neat TFAA was added to the solution
1
via syringe at rt and new H and 19F NMR spectra were
immediately acquired (Figure 1b and 2b). The reaction
was found to be very fast, since the signals of the starting
(R)-(Z)-1d had already completely disappeared, but, to
our great delight, a product different from the final diF-
1
PAK 2d was detected. In the H spectrum the signal of
the amide proton at 9.9 ppm had disappeared, and the
resonances of the methyl and aromatic hydrogens of the
p-tolyl group shifted upfield (Figure 1b), characteristic
of the sulfoxide f sulfide transformation. On these
bases, the structure of the imine (R)-3d was assigned to
the reaction intermediate.16 Accordingly, the 19F spec-
trum (Figure 2b) showed the signal of a new trifluoro-
acetyl group at -73.4 ppm, besides that of TFA at -74.6
ppm and the resonances of the CF2H group at -120.7
and -123.2 ppm (broad signals due probably to the
occurrence of some exchange phenomena, as the syn/anti
equilibrium of the imine bond or the hindered rotation
(15) Tsuchihashi and Ogura reported a rearrangement of racemic
N-unprotected â-methylthio â-sulfinylenamines K (Scheme 6), pro-
moted by acetic anhydride in the presence of pyridine, producing the
thiolesters L. To our knowledge no details have appeared on the
mechanism of that process, which presents several analogies with the
title reaction. (a) Ogura, K.; Tsuchihashi, G. J . Am. Chem. Soc. 1974,
96, 1960. See also: (b) Ogura, K.; Ito, Y.; Tsuchihashi, G. Bull. Chem.
Soc. J pn. 1979, 52, 2013.
(16) The absolute stereochemistries of the intermediate imines (R)-3
are confidently assigned on the basis of the mechanistic rationale
discussed onward.

8034 J . Org. Chem., Vol. 62, No. 23, 1997
Volonterio et al.
F igu r e 2.
F igu r e 1.
unusual molecular array, F-PAKs (R)-2 are considerably
stable and can be stored neat for several months at 4 °C
without any decomposition or racemization, with the
exception of the N-trifluoroacetyl triF-PAK (R)-2b, which
requires lower temperature of storage. However, a strong
decrease of the ee of the isolated F-PAKs (R)-2, ac-
companied by formation of p-thiocresol, was evidenced
by simply increasing a few minutes the time of exposure
of the reaction mixture to the aqueous NaHCO3 solution
(step 2), when using procedure A. In light of this
observation, investigation of the chemical and optical
stability of the molecules (R)-2 was undertaken. Sub-
stantial optical stability was detected toward acids. For
around the carbamate bond, which was slow on the NMR
time scale). It was also possible to obtain the carbon
spectrum of (R)-3d , displaying a significant resonance at
δ 80.4, which can be assigned to the methine carbon
O-CH-S.
The intermediate (R)-3d was found to be stable over-
night in the NMR tube at rt. Subsequently, the reaction
mixture was poured in a flask, silica gel was added,
followed by water, and finally the mixture was routinely
worked up. 1H and 19F NMR spectra of the crude product
in THF-d8 were recorded (Figure 1c and 2c). The
resonance of the trifluoroacetyl group was found to be
absent, while the aldehyde signal at 9.45 ppm was
present, confirming the expected formation of the diF-
PAK (R)-2d .
example the [R]20 of (R)-2a in chloroform, treated with
D
TFA, did not change significantly after 3 d at rt. The
optical stability toward silica gel is only moderate, and
the extent of racemization strongly depends on the time
and the way of exposure. When SiO2 was added to a
chloroform solution of (R)-2a and kept under magnetic
stirring for several hours, a substantial optical stability
was detected. A fast elution on a short silica gel flash
chromatographic column did not remarkably affect the
ee of the F-PAKs (R)-2, but a 30-min stay in the column
produced ca. 50% of racemization. The optical stability
of (R)-2 toward bases was found to be higher in the
absence of water, whereas treatment with an aqueous
base, even weak, proved to have a dramatic effect.
Triethylamine produced complete racemization of (R)-2a
in chloroform after 3 d at rt, but the same compound in
THF was completely racemized by 5% aqueous NaHCO3
after ca. 30 min under stirring at rt. The proclivity of
F-PAKs (R)-2 to undergo racemization promoted by bases
An identical pathway, involving the formation of the
same intermediate difluoroimine (R)-3d , was observed
by monitoring by H and 19F NMR the reaction of the
1
trans diF-SE (R)-E-1d with TFAA. After one night (R)-
3d produced from (R)-E-1d was submitted to step 2, as
described above, and the diF-PAK (R)-2d was obtained
in ca. 60% yield. A very low ee value (ca. 8%) was
measured for the isolated sample.
Finally, NMR monitoring of the reaction involving the
triF-SE (R)-(Z)-1a showed the clean formation of the
corresponding intermediate trifluoroimine (R)-3a , in
THF-d8 solution (see Experimental Section), and of the
final triF-PAK (R)-2a , after quenching.
Ch em ica l a n d Op tica l Sta bility of th e F lu or op y-
r u va ld eh yd e N,S-Keta ls (R)-2. Despite their highly

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals
J . Org. Chem., Vol. 62, No. 23, 1997 8035
Ta ble 2. In flu en ce of th e Solven t on th e Con ver sion of
th e N-Cbz r-(Tr iflu or om eth yl)-â-su lfin ylen a m in e (R)-1a
to (R)-2a
Sch em e 6
entry
solvent
ee
yield, %
[R]20
D
1
2
3
4
THF
68%
32%
59%
67%
57
44
39
44
+138.6 (c 0.89)
+70.5 (c 0.22)
+123.0 (c 0.15)
+135.8 (c 0.22)
CH2Cl2
CH3CN
acetone
Sch em e 7
Sch em e 8. Rea ction of
r-(Diflu or om eth yl)-â-su lfin ylen a m in e (R)-(Z)-1d
in CDCl3
or silica gel can be interpreted in terms of an elimina-
tion-addition of p-thiocresol, probably through the cor-
responding achiral imine form 6 (Scheme 7).17 This
hypothesis should account for the formation of p-thio-
cresol observed under racemization conditions.
Deter m in a tion of th e Ees a n d Assign m en t of th e
Absolu te Ster eoch em istr ies. Attempts to obtain sepa-
ration of the enantiomers of the F-PAKs (R)-2 by using
a chiral phase HPLC column (Chiralcel OB and OD) were
unsuccessful, because of extended decomposition. How-
1
ever, H and 19F NMR analysis of pure samples of (R)-2,
using the chiral shift reagent (+)-[Eu(hfc)3], allowed us
to assess their enantiomeric ratio.
The addition of (+)-[Eu(hfc)3] to the CDCl3 solution of
the samples 2a -d caused an extensive broadening of the
1
whole H spectrum, except for the signals of the p-tolyl
protons ortho to the methyl group. In the case of
compound (R)-2a , whose stereochemistry has been previ-
ously determined,10 we observed that the signals of the
(-)-(S)-enantiomer were shifted to low fields slightly
more than the signals of the (+)-(R)-enantiomer. This
behavior is common for all compounds 2a -d , strongly
suggesting that F-PAKs (+)-2b-d should have (R), while
the (-)-enantiomers should have (S)-configuration.
In flu en ce of Solven t, Tem p er a tu r e, a n d Con cen -
tr a tion . Further experiments were performed in order
to probe the influence of solvent, temperature, and
concentration of the starting F-PAKs (R)-2 on yield and
enantioselectivity of the process. Since F-PAKs (R)-2, as
described above, are rather stable both chemically and
optically toward silica gel in the reaction environment,
whereas extended racemization can be promoted by
aqueous NaHCO3, the following conditions were used: a
solution of triF-SE (R)-(Z)-1a in the appropriate solvent
was treated with 1 equiv of TFAA (step 1); after 1 min,
silica gel was added, and the resulting mixture was
stirred for 5 min (step 2); water was added, and 1 min
later the reaction was routinely worked up and the
product purified by flash chromatography. Each experi-
ment was repeated at least twice, to assess its reproduc-
ibility and to achieve reliable data.
Ta ble 3. In flu en ce of Tem p er a tu r e on th e Con ver sion of
th e N-Cbz r-(Tr iflu or om eth yl)-â-su lfin ylen a m in e
(R)-(Z)-1a to (R)-2a in THF
entry T (step 1 and 2), °C ee, % yield, %
[R]20
D
1
2
3
4
-30
0
10
20
60
62
63
69
61
64
59
64
+123.9 (c 0.53)
+128.6 (c 0.62)
+128.7 (c 0.73)
+141.8 (c 0.72)
(R)-(Z)-1d showed a quite similar behavior under stan-
dard conditions in the same solvents, but overnight
treatment with TFAA in chloroform at rt, followed by the
usual addition of silica gel, workup, and purification,
produced the unexpected achiral 4-(difluoromethyl)-∆-4-
oxazol-2-one 10 (Scheme 8). The experiment was re-
peated in a NMR tube by dissolving 0.1 mmol of (R)-(Z)-
1d in CDCl3 and adding 1.1 equiv of neat TFAA to the
solution at rt.
The intermediate imine 3d immediately formed, in a
mixture with a second compound, probably the chiral
tautomeric enamine form 7. However, the structure of
7 was not unequivocally determined, because of the
complexity of the spectra. After one night at rt, 3d was
found to be completely transformed into the correspond-
ing achiral enamine tautomer 8 (see Experimental Sec-
tion). After solvent evaporation, the crude was charged
in a flash chromatographic column. By action of silica
gel, the trifluoroacetyl group was cleaved and the result-
ing intermediate 9 produced the 4-(difluoromethyl)-∆-4-
oxazol-2-one 10 and benzyl alcohol through spontaneous
intramolecular cyclization.
It can be seen from the data reported in Table 2 that
the solvent is of paramount importance, THF being by
far the best choice (entry 1). CH2Cl2, acetonitrile, and
acetone (entries 2-4, respectively) provided much worse
yields and enantioselectivity. Only acetone produced a
degree of enantiocontrol comparable with that obtained
in THF. Chloroform gave disappointing results, because
the desired triF-PAK (R)-2a was produced only in traces,
along with several unidentified byproducts. The diF-SE
The effect of temperature was investigated by means
of some experiments performed on the conversion of triF-
SE (R)-(Z)-1a to (R)-2a between -30 °C and rt (Table 3),
using THF as solvent and keeping constant all the other
(17) An alternative racemization path involves the equilibrium
between the F-PAKs 2 and the R-hydroxy imine form 11 (Scheme 12).

8036 J . Org. Chem., Vol. 62, No. 23, 1997
Volonterio et al.
Sch em e 9. Gen er a l P a th s for th e Loss of
Ster eoch em ica l In for m a tion in th e P u m m er er
Rea ction
Ta ble 4. In flu en ce of Con cen tr a tion of N-Cbz
r-(Tr iflu or om eth yl)-â-su lfin ylen a m in e (R)-(Z)-1a on th e
Con ver sion to (R)-2a in THF
entry
concn, M
ee, %
yield, %
[R]20
D
1
2
3
0.02
0.1
0.2
65
62
55
64
64
52
+131.1 (c 0.73)
+128.6 (c 0.62)
+112.2 (c 0.62)
experimental factors (amount of reagents, concentration
of the starting F-SE, purification procedure). The best
result both in terms of ee and yield was obtained at rt
(entry 4), while the first three entries show that the
enantioselectivity decreased proportionally with decreas-
ing temperature.
An investigation of the influence of the concentration
of the starting F-SEs (R)-(Z)-1a was addressed next,
using THF as solvent under the same conditions de-
scribed above (Table 4). A remarkably favorable “dilution
effect” was experienced, and a clear-cut decrease of both
yield and ee occurred when the concentration of (R)-(Z)-1
was increased from 0.02 M (entry 1) to 0.2 M (entry 3).
Stereoselective deprotonation of the R-hydrogen atom
of the chiral trivalent sulfonium cation B, formed from
the starting sulfoxide A and TFAA (Scheme 2), plays a
key role in determining the stereoselection of the PR.22
Formation of the ylide C having a trans relationship
between the most sterically demanding R and Ar groups,
through removal of the pro-S proton, is favored over the
cis ylide C′. A nonstereoselective deprotonation (path 2)
or interconversion between the acyclic chiral ylides C and
C′ (path 3)23 should produce a nonstereoselective PR.
Finally, the formation of a free achiral sulfonium cation
D from the sulfonium ylide C through S-O bond break-
ing, followed by random recombination, should afford a
racemic final product E (path 4).12
Discu ssion
From the above-described experiments it clearly ap-
pears that the F-PAKs (R)-2 are produced from the
corresponding F-SEs (R)-1 through an unprecedented
self-immolative tandem sequential process (Scheme 1),18
consisting of a PR promoted by TFAA which produces
the imine (R)-3 (step 1), followed by a 1,2-migration of
the p-tolylthio group, triggered by addition of aqueous
NaHCO3 or silica gel (step 2). This reaction occurs with
an unusually high level of stereoselection, given the
acyclic nature of the substrates. In fact, though we have
not been able to determine the enantioselectivity of the
single steps, it can be calculated that each transfer of a
stereocenter features an average degree of stereoselec-
tivity up to 94:6, as observed for the chlorodiF-PAK (R)-
2c, obtained with 79% ee. With the current state of
knowledge, the influence of solvent and temperature
(Tables 2 and 3) is not easy to rationalize, but the
improvement of both yield and enantioselectivity (Table
4) obtained upon dilution of the starting F-SEs (R)-(Z)-1
strongly suggests that the whole process should have an
intramolecular character. To get a clear picture of the
reaction, it can be useful to focus the attention on the
stereochemical aspects of each step.
Step 1: th e P u m m er er r ea r r a n gem en t. In the PR
the stereogenic sulfinyl group is reduced to sulfenyl and
the stereocenter shifts to the vicinal R-carbon (Scheme
9). When an anhydride (R1CO)2O is used as a promoter,
the degree of stereoselectivity depends on the stereospeci-
fity of the migration of the R1COO group. Despite their
widespread use in synthesis, only a few examples of
stereoselective Pummerer-type reactions have been re-
ported so far.19 Four distinct “racemization paths” can
be held responsible for the loss of stereochemical infor-
mation.
To understand the reasons for the uncommonly high
stereocontrol of our reaction, three items should be kept
in mind: (1) N,N-diprotected F-SEs such as (R)-4 (Scheme
4) do not give rise to the rearrangement when treated
(19) (a) Shibata, N.; Matsugi, M.; Kawano, N.; Fukui, S.; Fujimori,
C.; Gotanda, K.; Murata, K.; Kita, Y. Tetrahedron: Asymmetry 1997,
8, 303 and references therein. (b) Harwood, L. M.; Lilley, I. A. Synlett
1996, 1010. (c) Abe, H.; Itani, J .; Masunari, C.; Kashino, S.; Harayama,
T. J . Chem. Soc., Chem. Commun. 1995, 1197. (d) Craig, D.; Daniels,
K.; MacKenzie, A. Tetrahedron 1993, 49, 11263. (e) Ikeda, M.; Kosaka,
K.; Sakakibara, M.; Okano, M. Heterocycles 1993, 35, 81. (f) Kita, Y.;
Shibata, N.; Kawano, N.; Tohjo, T.; Fujimori, C.; Ohishi, H. J . Am.
Chem. Soc. 1994, 116, 5116. (g) Kosugi, H.; Tagami, K.; Takahashi,
A.; Kanna, H.; Uda, H. J . Chem. Soc., Perkin Trans. 1 1989, 935. (h)
Ferreira, J . T. B.; Marques, J . A.; Marino, J . P. Tetrahedron: Asym-
metry 1994, 5, 641 and references therein. (i) Wolfe, S.; Kazmaier, P.
M.; Auksi, H. Can. J . Chem. 1979, 57, 2404. (j) Mikolajczyk, M.;
Zatorski, A.; Grzejszczak, S.; Costisella, B.; Midura, W. J . Org. Chem.
1978, 43, 2518. (k) Masuda, T.; Numata, T.; Furukawa, N.; Oae, S.
Chem. Lett. 1977, 903. (l) McCormick, J . E.; McElhinney, R. S. J . Chem.
Soc., Perkin Trans. 1 1985, 93 and references therein.
(20) See ref 19a and references therein. See also: (a) Numata, T.;
Oae, S. Tetrahedron Lett. 1977, 18, 1337.
(21) DCC has been used as a scavenger of acyloxy anions, sometimes
producing a remarkable improvement of stereoselection, but also a
dramatic lowering of yields: (a) Stridsberg, B.; Allenmark, S. Acta
Chem. Scand. 1976, B30, 219. (b) Numata, T.; Itoh, O.; Oae, S.
Tetrahedron Lett. 1979, 20, 1869. (c) Numata, T.; Itoh, O.; Yoshimura,
T.; Oae, S. Bull. Chem. Soc. J pn. 1983, 56, 257. (d) Itoh, O.; Numata,
T.; Yoshimura, T.; Oae, S. Bull. Chem. Soc. J pn. 1983, 56, 266. (e)
Oae, S., Itoh, O.; Numata, T.; Yoshimura, T. Bull. Chem. Soc. J pn.
1983, 56, 270.
(22) The deprotonation step of the PR has been elegantly studied
by Kita and Shibata, who used O-silylated ketene acetals for achieving
excellent stereocontrol: Kita, Y.; Shibata, N. Synlett 1996, 289 and
references therein.
The first cause, in the order of events but probably also
for importance, is the racemization of the sulfinyl ste-
reocenter (path 1). It is generally believed that epimer-
ization occurs via formation of an achiral σ-sulfurane
(M),20 this problem being particularly serious with highly
reactive anhydrides, like TFAA.21
(18) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. (Washington,
D.C.) 1996, 96, 137. (b) Tietze, L. F. Chem. Rev. (Washington, D.C.)
1996, 96, 115.
(23) For a discussion on this eventuality see: Kita, Y.; Shibata, N.;
Fukui, S.; Fujita, S. Tetrahedron Lett. 1994, 35, 9733 and references
therein.

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals
J . Org. Chem., Vol. 62, No. 23, 1997 8037
Sch em e 10. Step 1, th e P u m m er er Rea ction of cis
F -SEs (R)-(Z)-1
Sch em e 11. Step 1, th e P u m m er er Rea ction of
tr a n s d iF -SEs (R)-E-1d
with TFAA, but racemize completely within a few min-
utes; (2) the same intermediate difluoroimine 3d (Scheme
1) is cleanly produced from both the diF-SEs E- and
Z-(R)-1d , as clearly shown by the NMR experiments
described above, but (3) cis geometry of the enamine
double bond is strictly necessary for achieving high
stereoselectivity. All this evidence points to the fact that
the NHCbz group plays a key role in the step 1 of the
tandem process, namely the PR, preventing TFAA-
promoted racemization of the sulfinyl stereocenter,24 as
well as allowing an efficient transfer of the stereochem-
ical information from the sulfinyl group to the R-stereo-
genic center. In the mechanism proposed (Scheme 10)
the “usual” trivalent trifluoroacetoxysulfonium salt I
should forms by action of TFAA on the F-SEs (R)-(Z)-1.
Loss of TFA from I produces the chiral ylide II. An
attractive interaction between the positive sulfur and the
negatively charged nitrogen atom immediately locks the
conformation of II, which might be also conceived as a
highly reactive four-membered sulfurane III,25 thus
preventing the formation of an achiral sulfurane like M
(Scheme 9, path 1), that would occur through addition of
a second trifluoroacetoxy anion to the sulfonium cation
I.26 The electron-poor character of II and III, due to the
electron-withdrawing effect of the CF3 and NCbz groups,
and the stabilizing delocalization of the negative charge
of the ylide II, should strongly disfavor the formation of
the corresponding achiral sulfonium cation (see com-
pound D, Scheme 9, path 4),27 leading to a highly
stereospecific migration of the trifluoroacetoxy group
from the sulfur to the si face of the C-1 position.
On the contrary, the sulfur and the nitrogen atoms of
the diF-SE (R)-E-1d are far away and cannot interact
(Scheme 11). For this reason all racemization paths
described in Scheme 9 can be in principle operating,
though in the light of the discussion above, racemization
of the sulfinyl stereocenter through formation of the
achiral sulfurane V (path 1) should be the main event.
Step 2: th e 1,2-p-tolylth io gr ou p m igr a tion . The
intermediate imines (R)-3 formed in step 1 (Scheme 1)
are perfectly stable in the reaction environment (THF, 1
equiv of TFA), as clearly demonstrated by the NMR
experiments. Formation of the F-PAKs (R)-2 is triggered
by the addition of SiO2 or aqueous NaHCO3 which are
able to cleave the trifluoroacetyl group,28 leading to the
formation of the transient R-hydroxy R-p-tolylthio imine
(R)-11 (Scheme 12). The latter should immediately
undergo 1,2-migration of the p-tolylthio group, which
should occur in suprafacial fashion through the five-
membered cyclic conformation having a hydrogen bond
between the hydroxy and the imino functions, as already
proposed for cyclic analogues of (R)-11.29 Step 2 can be
formally considered an R-hydroxy-imine/R-amino-alde-
hyde rearrangement, which is known to be an equilibri-
um process, usually requiring high temperature and
prolonged heating to reach a satisfactory advancement
toward the aldehyde form. In this case the equilibrium
is strongly shifted toward the R-amino-aldehyde form
(R)-2 even at low temperature, probably because of the
strong stabilization of the sp3 N,S-ketal carbon induced
by the electron-withdrawing fluoroalkyl group.30
(24) For some examples of neighboring group participation by amino
functions under Pummerer conditions see: (a) Sharma, A. K.; Ku, T.;
Dawson, A. D.; Swern, D. J . Org. Chem. 1975, 40, 2758. (b) Yamamoto,
K.; Yamazaki, S.; Murata, I.; Fukuzawa, Y. J . Org. Chem. 1987, 52,
5239. (c) Uchida, Y.; Oae, S. Gazz. Chim. Ital. 1987, 117, 649. (d) Kita,
Y.; Shibata, N.; Kawano, N.; Tohjo, T.; Fujimori, C.; Matsumoto, K.;
Fujita, S. J . Chem. Soc., Perkin Trans. 1 1995, 2405. See also ref 19i.
(25) For stable four-membered cycles such as III see: Tornus, I.;
Schaumann, E.; Mayer, R.; Adiwidjaja, G. Liebigs Ann. 1995, 1795.
(26) We thank Prof. J o´zef Drabowicz (Polish Academy of Sciences,
Lodz, Poland) who suggested to us that the low enantioselectivity
featured by the diF-PAK (R)-E-1d could have been due to racemization
of the sulfinyl stereocenter by action of TFAA.
(28) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: London: 1991.
(29) (a) Stevens, C. L.; Hanson, H. T.; Taylor, K. G. J . Am. Chem.
Soc. 1966, 88, 2769. (b) Compain, P.; Gore´, J .; Vate`le, J .-M. Tetrahedron
1996, 52, 6647 and references therein.
(27) See ref 12b, p 388.

8038 J . Org. Chem., Vol. 62, No. 23, 1997
Volonterio et al.
Compounds (R)-1a -d were prepared according to the
procedure described in the literature.8
Sch em e 12. Step 2, th e 1,2-p-Tolylth io Gr ou p
Migr a tion
(R)-(Z)-1a : Rf (3:1 hexane/ethyl acetate) 0.35; mp 145-147
°C (ethyl acetate); [R]20 -12.9 (c 0.54, CHCl3); 1H NMR
D
(CDCl3) δ 7.28 (1H, br s), 6.42 (1H, s), 5.25 (1H, d, J ) 12 Hz),
5.19 (1H, d, J ) 12 Hz); 13C NMR (CDCl3) δ 153.18, 142.5,
138.77, 135.04, 130.3, 129.7, 128.7, 128.6, 128.38, 125.3, 128.15
(q, J ) 3.6 Hz), 119.74 (q, J ) 276 Hz), 68.6, 21.5; 19F NMR
(CDCl3) δ -70.5 (3F, s). Anal. Calcd for C18H16F3NO3S: C,
56.33; H, 4.21; N, 3.65. Found: C, 56.07; H, 4.19; N,3.69.
(R)-(Z)-1b: Rf (3:1 hexane/ ethyl acetate) 0.25; [R]20D +458.9
1
(c 1.22, CHCl3); H NMR (CDCl3) δ 5.35 (2H, br s), 5.31 (1H,
s); 13C NMR (CDCl3) δ 141.75, 141.56 (q, J ) 33.2 Hz), 140.8,
130, 124.7, 119.94 (q, J ) 276.2 Hz), 98 (q, J ) 3.97 Hz), 21.23;
19F NMR (CDCl3) δ -73.0 (3F, s).
(R)-(Z)-1c: Rf (3:1 hexane/ethyl acetate) 0.30; mp 162-163
°C (ethyl acetate); [R]20 -156.4 (c 1.03, CHCl3); 1H NMR
D
(CDCl3) δ 6.76 (1H, br s), 6.54 (1H, s), 5.28 (1H, d, J ) 12 Hz),
5.22 (1H, d, J ) 12 Hz); 13C NMR (CDCl3) δ 153.7, 142.3, 139,
135, 132.9 (t, J ) 29.2 Hz), 130.2, 129.86 (t, J ) 3.1 Hz), 128.76,
128.74, 128.36, 125.3, 122.35 (t, J ) 292.5 Hz), 68.74, 21.5;
19F NMR (CDCl3) δ -59.3 (1F, d, J ) 170 Hz), -60.4 (1F, d, J
) 170 Hz). Anal. Calcd for C18H16ClF2NO3S: C, 54.07; H,
4.03; N, 3.50. Found: C, 53.21; H, 4.09; N, 3.38.
Con clu sion s
In summary, we have presented the synthesis of
fluoropyruvaldehyde N,S-ketals (R)-2, new fluorinated
chiral nonracemic building blocks, through an unprec-
edented highly stereoselective tandem sequential PR/1,2-
p-tolylthio group migration. The reaction pathway has
been now elucidated and further improvements could be
achieved through a careful screening and choice of
reagents and conditions. The work currently in progress
by means of chemometric methods should hopefully lead
to a fully optimized protocol in the next future. Further-
more, the highly efficient transfer of stereochemical
information here described, and similar results regarding
the stereospecific “nonoxidative” PR of R-(fluoroalkyl)-â-
sulfinylamines F (Scheme 3),13 suggest a new strategy
for useful applications of the PR in asymmetric synthe-
sis: a properly located NHCbz function can prevent a
sulfinyl group, submitted to Pummerer conditions, from
racemization and produce a highly stereoselective process
via stereospecific formation of a chiral sulfurane inter-
mediate. Further studies on the exploitation of this
methodology are currently in progress.
(R)-(Z)-1d : Rf (3:1 hexane/ethyl acetate) 0.40; mp 119-121
°C (ethyl acetate); [R]20 +536.9 (c 1.0, CHCl3); 1H NMR
D
(CDCl3) δ 9.95 (1H, s), 7.06 (1H, t, J ) 55 Hz), 5.7 (1H, s),
5.15 (2H, s); 13C NMR (CDCl3) δ 152.34, 142.77, 139.8 (t, J )
23.8 Hz), 139.41, 135.25, 130.4, 128.6, 128.5, 128.3, 125.1,
109.5 (t, J ) 9.1 Hz), 108.3 (t, J ) 242.7 Hz), 67.8, 21.4; 19F
NMR (CDCl3) δ -122.3 (2F, d, J ) 55 Hz). Anal. Calcd for
C18H17F2NO3S: C, 59.17; H, 4.69; N, 3.83. Found: C, 59.29;
H, 4.73; N, 3.80.
(R)-E-1d : Rf (3:1 hexane/ethyl acetate) 0.20; mp 117-119
°C (ethyl acetate); [R]20 +70.1 (c 1.10, CHCl3); 1H NMR
D
(CDCl3) δ 7.25 (1H, t, J ) 56 Hz), 6.8 (1H, br s), 5.13 (2H, s);
13C NMR δ (CDCl3) 152.29, 141.8, 140.5, 135.76 (t, J ) 23 Hz),
134.8, 130.25, 128.77, 128.72, 128.5, 124.32, 121.78 (t, J ) 6.92
Hz), 108.4 (t, J ) 242.2 Hz), 68.05, 21.4; 19F NMR (CDCl3) δ
-120.2 (2F, m, J ) 308, 56 and 8 Hz).
Syn th esis of th e F lu or op yr u va ld eh yd e N,S-Keta ls (R)-
2. P r oced u r e A. Step 1. To a stirred 0.15 M solution of
N-Cbz triF-SE (R)-(Z)-1a (0.38 g, 1 mmol) in dry THF, cooled
at 0 °C, was added neat TFAA (1 mmol, 0.14 mL) via syringe
and left 1 min under stirring. TLC monitoring showed the
immediate disappearance of (R)-1, with the formation of a
unique spot at much higher Rf (0.45 in n-hexane/AcOEt 85:
15).
Exp er im en ta l Section
Step 2. A 5% NaHCO3 aqueous solution was added at 0
°C, until neutral pH was reached, and the resulting solution
was left 5 min under stirring. The aqueous layer was
extracted with AcOEt. The collected organic phases dried over
anhydrous sodium sulfate were filtered, and the solvent was
removed under reduced pressure. FC of the crude reaction
mixture on a short silica gel column afforded 0.32 g (85%) of
Gen er a l P r oced u r e. 1H, 19F, and 13C nuclear magnetic
resonance samples were prepared as dilute solutions in CDCl3.
Chemical shifts (δ) are reported in parts per million (ppm) of
the applied field. Me4Si was used as internal standard (δH
and δC ) 0.00) for 1H and 13C nuclei, while C6F6 was used as
external standard (δF ) -162.90) for 19F nuclei. Ees have been
determined by 1H and 19F NMR analysis of pure samples of
F-PAKs (R)-2, by using the chiral shift reagent (+)-[Eu(hfc)3]
in CDCl3 solution. Anhydrous THF was distilled from sodium
and benzophenone. In all other cases commercially available
reagent-grade solvents were employed without purification.
Reactions performed in dry solvents were carried out in
nitrogen atmosphere. Melting points are uncorrected and were
triF-PAK (R)-2a , having [R]20 +136.2 (c 0.65, CHCl3) and ee
D
67%.
P r oced u r e B. Step 1. A 0.1 M solution of (R)-(Z)-1a (0.38
g, 1 mmol) was used, following the same protocol described
for procedure A.
Step 2. Silica gel (ca. 0.4 g) was added in one portion at 0
°C, and the resulting mixture was vigorously stirred for 5 min
at the same temperature. Then water (ca. 10 mL) was added
at 0 °C, and the phases were immediately separated. The
aqueous layer was extracted with AcOEt. The collected
organic phases dried over anhydrous sodium sulfate were
filtered, and the solvent was removed under reduced pressure.
FC of the crude reaction mixture on a short silica gel column
afforded 0.22 g (57%) of triF-PAK (R)-2a , having [R]20D +138.6
(c 0.89, CHCl3) and ee 69%.
obtained on
a capillary apparatus. Analytical thin-layer
chromatography (TLC) was routinely used to monitor reac-
tions. Plates precoated with E. Merck silica gel 60 F254 of 0.25
mm thickness were used. Merck silica gel 60 (230-400 ASTM
mesh) was employed as a reagent (step 2, procedure B) and
for flash column chromatography (FC). Combustion mi-
croanalyses were performed by Redox SNC, Cologno M.
(Milano).
(R)-2a : yellowish oil; Rf 0.45 (85:15 n-hexane/AcOEt); 1H
NMR (CDCl3) δ 9.37 (1H, q, J FH ) 1.7 Hz), 7.43-7.32 (5H, m),
7.20 (2H, d, J ) 8 Hz), 7.01 (2H, d, J ) 8 Hz), 5.53 (1H, br s),
5.20 (1H, d, J ) 12 Hz), 5.07 (1H, d, J ) 12 Hz), 2.32 (3H, s);
19F NMR (CDCl3) δ - 70.45 (q, J HF ) 1.7 Hz); 13C NMR (CDCl3)
δ 183.0 (q, J CF ) 1.8 Hz), 153.3, 141.7, 138.1, 135.3, 130.3,
P r ep a r a tion of th e r-(F lu or oa lk yl)-â-su lfin ylen a m in es
(F -SEs) (R)-1.
(30) Lindner, P. E.; Lemal, D. M. Tetrahedron Lett. 1996, 37, 9165
and references therein.

Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals
128.8, 128.7, 122.7 (q, J CF ) 287 Hz), 120.7, 72.8 (q, J CF
J . Org. Chem., Vol. 62, No. 23, 1997 8039
)
Ch em ica l a n d Op tica l Sta bility of th e F lu or op yr u va l-
d eh yd e N,S-Keta ls (R)-2. Tow a r d TF A. A chloroform
solution (1 mL) of triF-PAK (R)-2a (6 mg) having [R]20D +136.2
(c 0.65, CHCl3) was treated with 1 drop of TFA. After 3 d at
28.9 Hz), 67.9, 21.4; MS (EI, 70 eV) m/ z (%) 383 (M+, 8), 124
(35), 91 (100). Anal. Calcd for C18H16NO3F3S: C, 56.39; H,
4.21; N, 3.65. Found: C, 56.49; H, 4.30; N, 3.50.
rt, neither significant change of the [R]20 value nor decom-
(R)-2b: for yields, [R]20D, and ees see Table 1; yellowish oil;
Rf 0.63 (80:20 n-hexane/AcOEt); 1H NMR (CDCl3) δ 9.39 (1H,
q, J HF ) 1.2 Hz), 7.25 (2H, d, J ) 8 Hz), 7.17 (2H, d, J ) 8
Hz), 6.99 (1H, br signal), 2.37 (3H, s); 19F NMR (CDCl3) δ -68.9
(3F, d, J HF ) 1.2 Hz), -76.8 (3F, d, J HF ) 1.1 Hz); 13C NMR
(CDCl3) δ 181.9 (q, J CF ) 2.5 Hz), 155.3 (q, J CF ) 38.5 Hz),
142.7, 137.9, 130.8, 128.7, 122.3 (q, J CF ) 287.1 Hz), 115.1 (q,
J CF ) 289.2 Hz), 72.1 (q, J CF ) 30.2 Hz), 21.4; MS (EI, 70 eV)
m/ z (%) 345 (M+, 13), 317 (18), 316 (10), 123 (100), 91 (35);
FT IR (cm-1) 3344, 1755, 1728, 1523, 1275, 1170. Anal. Calcd
for C12H9NO2F6S: C, 41.75; H, 2.63; N, 4.06. Found: C, 41.60;
H, 2.77; N, 3.98.
D
position were detected. The same chemical and optical stabil-
ity toward TFA was detected for a sample of diF-PAK (R)-2d
having [R]20 +193.0 (c 0.64, CHCl3).
D
Tow a r d Silica Gel. A chloroform solution (1 mL) of triF-
PAK (R)-2a (8 mg) having [R]20 +136.2 (c 0.65, CHCl3) was
D
treated with 20 mg of silica gel. The slurry was vigorously
stirred at rt for 8 h and then filtered. Neither significant
change of the [R]20 value nor decomposition were detected.
D
Under the same conditions, chemical and optical stability
toward silica gel were detected for a sample of diF-PAK (R)-
2d having [R]20 +193.0 (c 0.64, CHCl3).
D
(R)-2c: for yields, [R]20D, and ees see Table 1; solid; Rf 0.46
(80:20 n-hexane/AcOEt); 1H NMR (CDCl3) δ 9.40 (1H, s), 7.44-
7.32 (5H, m), 7.22 (2H, d, J ) 8 Hz), 7.01 (2H, d, J ) 8 Hz),
5.65 (1H, br s), 5.22 (1H, d, J ) 12 Hz), 5.08 (1H, d, J ) 12
Hz), 2.32 (3H, s); 19F NMR (CDCl3) δ -54.6 (1F, d, J FF ) 168
Hz), -58.2 (1F, d, J FF ) 168 Hz); 13C NMR (CDCl3) δ 183.1,
153.3, 141.6, 138.2, 135.5, 130.3, 128.8, 128.7, 128.6, 127.9,
(dd, J CF ) 299 and 306 Hz), 121.7, 68.1, 21.3; MS (EI, 70 eV)
m/ z (%) 399 (M+, 4), 371 (4), 262 (12), 244 (18), 124 (100), 91
(100); FT IR (cm-1) 3372 (br), 1721, 1494, 1245. Anal. Calcd
for C18H16NO3F2ClS: C, 54.07; H, 4.03; N, 3.50. Found: C,
54.15; H, 4.05; N, 3.47.
A sample of triF-PAK (R)-2a (40 mg) having [R]20 +136.2
D
(c 0.65, CHCl3) and ee 67% was charged in a silica gel
chromatographic column. After 30 min at rt the sample was
eluted with a 85:15 n-hexane/AcOEt mixture. Evaporation of
the solvent at reduced pressure afforded 35 mg of (R)-2a
having [R]20 +64.8 (c 0.68, CHCl3) and 37% ee.
D
Tow a r d Tr ieth yla m in e. A chloroform solution of diF-PAK
(R)-2d (8 mg) having [R]20D +191.4 (c 0.81, CHCl3) was treated
with one drop of triethylamine. After 60 h a polarimetric
analysis of the sample was carried out: [R]20 +40.1 (c 0.81,
D
CHCl3). After 12 h more at rt no optical activity was detected.
1
The solvent was evaporated, and H and 19F NMR analysis of
(R)-2d : for yields, [R]20D, and ees see Table 1; white solid,
the racemate could be crystallized from diisopropyl ether: mp
the sample confirmed its substantial chemical stability.
A
sample of triF-PAK (R)-2a with [R]20 +136.4 (c 0.72, CHCl3),
D
1
81-82 °C; Rf 0.67 (80:20 n-hexane/AcOEt); H NMR (CDCl3)
under the same conditions, was racemized after 3 d.
δ 9.49 (1H, s), 7.48-7.32 (5H, m), 7.07 (2H, d, J ) 8 Hz), 6.95
(2H, d, J ) 8 Hz), 6.90 (1H, t, J HF ) 55 Hz), 5.64 (1H, br s),
5.22 (1H, d, J ) 12 Hz), 4.98 (1H, d, J ) 12 Hz), 2.30 (3H, s);
Tow a r d Aqu eou s Na HCO3. A THF solution (1 mL) of
triF-PAK (R)-2a (30 mg) having [R]20 +136.4 (c 0.72, CHCl3)
D
was treated with 0.5 mL of an aqueous NaHCO3 solution, and
vigorously stirred for 30 min at rt. After standard workup,
the residue was flash chromatographed on a short silica gel
column, affording 22 mg of pure (R)-2a having no optical
activity.
19F NMR (CDCl3) δ -132.6 (1F, dd, J HF ) 55 Hz and J FF
)
290 Hz), -122.1 (1F, dd, J HF ) 56 Hz and J FF ) 290 Hz); 13C
NMR (CDCl3) δ 183.2 (t, J CF ) 4 Hz), 153.7, 141.3, 137.9, 135.5,
130.2, 128.9, 121.2, 113.4 (dd, J CF ) 247.6 and 252.4 Hz), 73.2
(t, J CF ) 23 Hz), 67.6, 21.4; MS (EI, 70 eV) m/ z (%) 365 (M+,
4), 124 (35), 91 (100); FT IR (cm-1) 3372 (br), 1721 (br), 1494,
1245. Anal. Calcd for C18H17NO3F2S: C, 59.17; H, 4.69; N,
3.83. Found: C, 59.48; H, 4.85; N, 3.58.
P u m m er er Rea ction P r om oted by Acetyl Ch lor id e.
A 0.1 M solution of F-SE (R)-1 in dry THF (1 mL) was
treated at rt with 2 equiv of acetyl chloride (16 µL). The
mixture was stirred for 4 h at rt. The solvent was removed at
reduced pressure, and the crude mixture was submitted to FC,
affording the corresponding R-chloro sulfides 5 as white solids.
5a : yield 95%; Rf 0.46 (85:15 n-hexane/AcOEt); mp 119-
121 °C (n-hexane/AcOEt); 1H NMR (CDCl3) δ 7.36 (2H, d, J )
8 Hz), 7.34 (5H, m), 7.17 (2H, d, J ) 8 Hz), 6.07 (1H, br s),
5.18 (2H, s), 2.36 (3H, s); 19F NMR (CDCl3) δ -61.1 (s); 13C
NMR (CDCl3) δ 153.4, 140.0, 135.6, 135.5, 133.7, 130.3, 128.7,
128.5, 128.2, 126.4, 121.1 (q, J HF ) 267 Hz), 68.2, 21.3; MS
(EI, 70 eV) m/ z (%) 403 (M+ + 2, 22), 401 (M+, 66), 367 (10),
322 (6), 91 (100); FT IR (cm-1) 3433, 3260, 1707, 1503, 1333,
1258, 1119. Anal. Calcd for C18H15NO2F3SCl: C, 53.80; H,
3.76; N, 3.49. Found: C, 53.90; H, 3.80; N, 3.45.
When step 1 was performed in a NMR tube, the intermedi-
ate imines (R)-3 formed immediately after addition of TFAA
to a THF-d8 solution of (R)-(Z)-1a ,d and (R)-E-1d (ca. 0.1 M),
at rt. These compounds are substantially stable after 48 h at
rt in the reaction environment.
(R)-3a : 1H NMR (THF-d8) δ 7.39 (2H, d, J ) 8 Hz), 7.38-
7.28 (5H, m), 7.15 (2H, d, J ) 8 Hz), 6.91 (1H, s), 5.20 (1H, d,
J ) 12 Hz), 5.10 (1H, d, J ) 12 Hz), 2.27 (3H, s); 19F NMR
(THF-d8) δ -67.0 (3F, br s), -73.4 (3F, s); 13C NMR (THF-d8)
δ 157.8, 155.5 (q, J CF ) 45.8 Hz), 152.2 (br signal), 141.9, 136.5,
135.7, 130.9, 129.3, 129.1, 124.5 (br signal), 118.4 (q, J CF
281 Hz), 115.0 (q, J CF ) 285 Hz), 80.3, 69.5, 21.0.
)
(R)-3d : 1H NMR (THF-d8) δ 7.40 (2H, d, J ) 8 Hz), 7.38-
7.30 (5H, m), 7.12 (2H, d, J ) 8 Hz), 6.87 (1H, s), 6.53 (1H, t,
J HF ) 53.5 Hz), 5.17 (1H, d, J ) 12.3 Hz), 5.11 (1H, d, J )
12.3 Hz), 2.28 (3H, s); 19F NMR (THF-d8) δ -73.4 (3F, s),
-120.7 (1F, br signal), -123.2 (1F, dd, J HF ) 53.5 Hz and J FF
) 305.8 Hz); 13C NMR (THF-d8) δ 159.3, 158.2 (t, J CF ) 23.6
Hz), 156.3 (q, J CF ) 42.4 Hz), 141.7, 136.6, 136.2, 131.0, 129.3,
129.2, 124.6, 116.0 (q, J CF ) 284 Hz), 80.4, 69.3, 21.4.
In flu en ce of Solven t, Con cen tr a tion , a n d Tem p er a -
tu r e. Gen er a l P r oced u r e for th e Exp er im en ts of Ta bles
2-4. The procedure B described for the synthesis of the
F-PAKs (R)-2 was carried out on a 0.1 mmol scale (38 mg) of
triF-SE (R)-1a , using the appropriate solvent (Table 2), tem-
perature (Table 3), and concentration (Table 4). Experiments
reported in Tables 2 and 3 were carried out with [(R)-1a ] )
0.1 M. Experiments described in Tables 2 and 4 were carried
out at 0 °C. Dry THF was used as solvent for the experiments
reported in Tables 3 and 4. Purifications were performed on
a flash chromatographic column having 1 cm of inside diam-
eter, charged with 13 cm of silica gel, using a mixture 85:15
n-hexane/AcOEt as eluant, with 5 min of elution time for all
the experiments reported in Tables 2-4.
5d : yield 90%; Rf 0.46 (85:15 n-hexane/AcOEt); mp 94-96
1
°C (n-hexane/AcOEt); H NMR (CDCl3) δ 7.35 (5H, m), 7.30
(2H, d, J ) 8 Hz), 7.15 (2H, d, J ) 8 Hz), 7.02 (1H, t, J HF
)
54.3 Hz), 6.17 (1H, s), 5.18 (2H, s), 2.35 (3H, s); 19F NMR
(CDCl3) δ -117.05 (d, J HF ) 54.5 Hz); 13C NMR (CDCl3) δ
152.7, 139.2, 135.6, 134.4, 131.7, 130.3, 130.0, 128.6, 128.4,
128.2, 127.0, 110.3 (t, J HF ) 238.9 Hz), 68.0, 21.2; MS (EI, 70
eV) m/ z (%) 385 (M+ + 2, 5), 383 (M+, 15), 339 (4), 304 (34),
212 (29), 124 (26), 91 (100); FT IR (cm-1) 3400, 3273, 1719,
1524, 1234, 1110, 1032. Anal. Calcd for C18H16NO2F2SCl: C,
56.32; H, 4.20; N, 3.65. Found: C, 56.50; H, 4.34; N, 3.45.
Syn th esis of th e 4-(Diflu or om eth yl)-∆-4-oxa zol-2-on e
(10). The general procedure described for the step 1 of the
preparation of F-PAKs (R)-2 was followed, running the reac-
tion in a NMR tube, with a 0.1 M solution of (R)-1d in CDCl3.
The imine 3d formed immediately after addition of TFAA at
rt, in equilibrium with a second compound, probably the chiral
enamine tautomer 7. Due to the complexity of the related
NMR spectra, we have been not able to unambigously deter-
mine the structure of 7. After one night at rt the achiral
enamine 8 was present as a unique product.

8040 J . Org. Chem., Vol. 62, No. 23, 1997
Volonterio et al.
8: 1H NMR (CDCl3) δ 9.47 (1H, br s) 7.46-7.36 (5H, m),
7.35 (2H, d, J ) 8 Hz), 7.18 (2H, d, J ) 8 Hz), 6.75 (1H, t, J HF
) 53.4 Hz), 5.36 (2H, s), 2.36 (3H, s); 19F NMR (CDCl3) δ -76.2
(3F, s), -116.7 (2F, d, J HF ) 53.4 Hz); 13C NMR (CDCl3) δ 160.4
(q, J CF ) 42.7 Hz), 156.8, 139.8, 133.2, 131.5, 130.7, 129.7,
(3H, s). 19F NMR (CDCl3) δ -116.55 (d, J HF ) 52 Hz). 13C
NMR (CDCl3) δ 155.2, 139.2, 133.9 (t, J CF ) 10.0 Hz), 130.9,
130.4, 128.7, 125.0, (t, J CF ) 25.7 Hz), 106.9 (t, J CF ) 235.9
Hz), 21.1; MS (EI, 70 eV) m/ z (%) 257 (M+, 72), 237 (45), 91
(28), 45 (100). Anal. Calcd for C11H9NO2F2S: C, 51.36; H,
3.53; N, 5.44. Found: C, 51.66; H, 3.59; N, 5.33.
129.3, 128.7, 126.3, 124.8 (t, J CF ) 26.4 Hz), 114.5 (q, J CF
284.9 Hz), 106.7 (t, J CF ) 235.8 Hz), 69.8, 21.1.
)
The solvent was then removed at reduced pressure, and the
crude mixture was submitted to FC. The oxazolone 10 was
obtained in 62% yield as a white solid, together with benzyl
alcohol.
10: Rf 0.28 (85:15 n-hexane/AcOEt); mp 147-150 °C
(CHCl3); 1H NMR (CDCl3) δ 8.68 (1H, br s), 7.31 (2H, d, J ) 8
Hz), 7.16 (2H, d, J ) 8 Hz), 6.72 (1H, t, J HF ) 52 Hz), 2.34
Ack n ow led gm en t. Consiglio Nazionale delle Ricer-
che is gratefully acknowledged for financial support. Dr.
Alessandro Volonterio thanks Politecnico di Milano for
a scholarship.
J O970863J