New versatile fluorinated chiral building blocks: Synthesis and reactivity of optically pure α-(fluoroalkyl)-β-sulfinylenamines

Article abstract of DOI:10.1021/jo952097r

Efficient synthesis of optically pure α-(fluoroalkyl)-β-sulfinyl enamines has been achieved by aza-Wittig reaction of triphenyliminophosphoranes with the corresponding α-fluorinated-α'-sulfinyl ketones. The title compounds 3,4 showed an overwhelming prefe

Full text of DOI:10.1021/jo952097r

J . Org. Chem. 1996, 61, 3375-3387
3375
New Ver sa tile F lu or in a ted Ch ir a l Bu ild in g Block s: Syn th esis a n d
Rea ctivity of Op tica lly P u r e r-(F lu or oa lk yl)-â-su lfin ylen a m in es
Alberto Arnone, Pierfrancesco Bravo,* Silvia Capelli, Giovanni Fronza, Stefano V. Meille, and
Matteo Zanda
C.N.R.-Centro di Studio per le Sostanze Organiche Naturali, Dipartimento di Chimica del Politecnico,
Via Mancinelli 7, I-20133 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 November 28, 1995X
Efficient synthesis of optically pure R-(fluoroalkyl)-â-sulfinyl enamines has been achieved by aza-
Wittig reaction of triphenyliminophosphoranes with the corresponding R-fluorinated-R′-sulfinyl
ketones. The title compounds 3,4 showed an overwhelming preference for the Z stereochemistry
of the enamine form. Their general reactivity has been studied. The reaction with some
electrophiles (i.e. benzyl chloroformate and benzyl and allyl bromide) occurs at the nitrogen atom
providing the corresponding N,N-disubstituted enamines. Nucleophiles add smoothly to C-2:
heteroatom-centered nucleophiles like methanol, ammonia, and thiophenol afford gem-disubstituted
derivatives under thermodynamic control, while a C-centered nucleophile like nitromethane adds
in irreversible fashion. The hydride- and deuteride-promoted reduction of 3,4 to the N-Cbz-protected
(14) and N-unprotected (15) R-fluorinated-R′-sulfinyl amines has been studied. Hydride addition
was stereoselective, while low stereoselection was obtained with the other tested nucleophiles.
Desulfurization of the optically pure 1,1,1-trifluoro-3-sulfinyl amine 15a afforded (R)-1-(trifluoro-
methyl)ethylamine 17. The Pummerer rearrangement of 14 occurs in an unusual nonoxidative
way affording the sulfenamide 24, that readily provided (R)-(2-H)- and -(2-D)-3,3,3-trifluoroalaninol
(19) and (R)-3,3,3-trifluoroalanine (22).
In tr od u ction
to γ-fluoro-â-nitrogen substituted sulfoxides would be an
important and interesting matter. This paper outlines
an experimental procedure for obtaining the title com-
pounds in high yield and in pure form from the corre-
sponding R-fluoro-substituted-R′-sulfinyl ketones and the
results of studies devoted to clarify their reactivity
pattern.
One of the continuing goals of our laboratories is to
develop new synthetic routes to optically pure and
selectively fluorinated organic molecules of biological
significance. Chiral sulfoxides are important building
blocks in organic synthesis:1 the preparation and reaction
of their R-lithium derivatives has been an active area of
research leading to numerous applications.2 They have
been key starting materials in our chemical develop-
ments, since upon acylation by fluorinated esters they
afford R-fluoro-substituted-R′-sulfinyl ketones,3 important
intermediates in many synthetic routes to complex
fluorinated molecules.
Among the different approaches that could be envis-
aged and have been used for the synthesis of R-fluoro-
imine derivatives, i.e. the addition of primary and
secondary amines to acetylenic sulfoxides,6a the addition
of amines to allenic sulfoxides,6b the reaction of metalated
sulfoxides with nitriles,6c the addition of lithio enamines
to sulfinic esters,6d and more recently the acid-catalyzed
condensation between aliphatic amines and R-sulfinyl
ketones,6e the last one seemed to us the most useful for
the synthesis of the title compounds, since starting R′-
sulfinyl ketones are available at any grade of fluorosub-
In previous contributions from our laboratories R-fluoro-
substituted-R′-sulfinyl ketones have been utilized mainly
in the construction of substances possessing oxygen
functionalities while much less attention has been paid,
by us and others, to the synthesis and use of the
corresponding nitrogen-substituted derivatives.4 Given
the synthetic versatility associated with sulfinyl moieties,
the ever increasing interest in fluoro-substituted com-
pounds in biochemistry and medicinal chemistry,5 and
the large variety of nitrogen-containing biologically active
compounds, it appeared that a new and general approach
(4) For the synthesis of chiral fluorinated cyclic alcohols: Arnone,
A.; Bravo, P.; Frigerio, M.; Viani, F.; Cavicchio, G.; Crucianelli, M. J .
Org. Chem. 1994, 59, 3459. For fluorinated nucleosides: Bravo, P.;
Mele, A.; Salani, G.; Viani, F.; La Colla, P. Gazz. Chim. Ital. 1995,
125, 295. For fluoro-oxiranes: Arnone, A.; Bravo, P.; Frigerio, M.;
Salani, G.; Viani, F.; Zappala`, C. Cavicchio, G.; Crucianelli, M.
Tetrahedron 1995, 51, 8289. For the synthesis of optically pure
R-trifluoromethyl amino acids: Bravo, P.; Capelli, S.; Meille, S. V.;
Viani, F.; Zanda, M.; Kukhar, V. P.; Soloshonok, V. A. Tetrahedron:
Asymmetry 1994, 5, 2009.
(5) (a) Resnati, G. Tetrahedron 1993, 49, 9385-9445. (b) Banks, R.
E.; Tatlow, J . C.; Smart, B. E. Organofluorine Chemistry: Principles
and Commercial Applications; Plenum Press: New York, 1994. (c)
Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
J ohn Wiley & Son Inc.: New York, 1991. (d) Filler, R.; Kobayashi, Y.;
Yagupolskii, L. M. Biomedical Aspects of Fluorine Chemistry; Elsevi-
er: Amsterdam, 1993. (e) Kukhar, V. P.; Soloshonok, V. A. In Fluorine
Containing Amino Acids; Kukhar, V. P., Soloshonok, V. A., Eds.; J ohn
Wiley & Son Inc.: New York, 1994.
X Abstract published in Advance ACS Abstracts, April 15, 1996.
(1) For some reviews see: Posner, G. H. In The Chemistry of
Sulphones and Sulphoxides; Patai, S., Rappoport, Z., Stirling, C. J .
M., Eds.; J ohn Wiley: New York, 1988; p 823. Solladie`, G. In
Asymmetric Synthesis; Morrison, J . D., Ed., 1983; Vol. 2, p 157.
Barbashyn, M. R., J ohnson, C. R. Ibid., Vol. 4, p 227. Posner, G. H.
Acc. Chem. Res. 1987, 20, 72.
(2) Walker, A. J . Tetrahedron: Asymmetry 1992, 3, 961 and refer-
ences therein quoted.
(3) Bravo, P.; Piovosi, E.; Resnati, G. Synthesis 1986, 579.
S0022-3263(95)02097-4 CCC: $12.00 © 1996 American Chemical Society

3376 J . Org. Chem., Vol. 61, No. 10, 1996
Arnone et al.
Sch em e 1
stitution (in R position and far away) and in optically pure
form, by the method we have already reported.3
However, the condensation of amines on R-fluoro or
R-perfluorinated ketones usually leads to gem-hydroxy-
amino compounds (hemiaminals) because of the high
stabilization of sp3 hybridized carbon induced by R-fluoro-
substitution; they can be dehydrated to the corresponding
imines with increasing difficulty as fluorosubstitution
increases: this can be incompatible with the presence of
the stereogenic sulfinyl moiety. Moreover, perfluorinated
imines are not easy to obtain in pure form because during
the isolation or purification procedures the excess of
amine, the solvent, or water can add to the reactive CdN
double bond forming undesired byproducts.7 Finally,
because of the presence of the electron-withdrawing
sulfinyl group, these molecules could exist both in imine
and enamine form, each one giving rise to two geo-
metrical isomers.
For these reasons, in order to obtain title compounds
in optically pure form, we turned our attention on the
aza-Wittig reaction, which can be performed in neutral
conditions, in non nucleophilic solvents, with equimolar
amounts of reagents. Though a number of iminophos-
phoranes have been reacted with fluorinated aldehydes,
ketones, and R-keto esters, this reaction does not belong
to the arsenal of reactions routinely used for the synthesis
of imines. In fact, a strong activation of the CdO moiety
by electron-withdrawing groups is generally required.
This is mainly due to the lower reactivity of iminophos-
phoranes with respect to the corresponding carbon-
phosphorus ylides,8 although the F values for the aza-
Wittig reactions of various carbonyl compounds are
reported to be similar, in many cases, to those of the
corresponding Wittig reactions.9
(benzyloxycarbonyl)iminophosphorane (N-Cbz iminophos-
phorane) 2a 11 with R-fluorinated-R′-sulfinyl ketones 1a -
d , mainly or totally existing in gem-diolic form (Scheme
1), was efficient in benzene at reflux temperature. The
reaction was quite slow (about 20 h), but purification by
flash chromatography (FC) afforded in good yields the
desired products 3a -d in optically pure form. Conver-
sions ranged from 70% to 86.5% (Table 1), and the
unreacted iminophosphorane 2a can be almost quanti-
tatively recovered in the same chromatographic condi-
tions.
In the case of the monofluorinated molecule 1e the
reaction was sluggish: after 60 h only a 10% yield was
reached, though the conversion was high (95%). When
the non-fluorinated R-sulfinyl ketone (R)-[(4-methyl-
phenyl)sulfinyl]propan-2-one was reacted in the same
conditions, after 16 h the unchanged starting materials
were recovered, while the R-substituted sulfinyl ketone
(R)-3-[(4-methylphenyl)sulfinyl]-3-phenyl-1,1,1-trifluoro-
propan-2-one rapidly decomposed upon heating.
Herein we wish to report a full account of the synthesis
of the title compounds by means of the aza-Wittig
reaction, and of their reactivity and their use in the
stereoselective synthesis of fluorinated analogues of
amines, amino alcohols, and amino acids.
Resu lts a n d Discu ssion
Syn th esis of Title Com p ou n d s.10 We were delighted
to see that the aza-Wittig reaction of stabilized N-
(6) (a) McMullen, C. H.; Stirling C. J . J . Chem. Soc. B 1966, 1217.
Chan, W.; Lee, A. W. M.; J iang, L. Tetrahedron Lett. 1995, 36, 715. (b)
Truce, W. E.; Markley, L. D. J . Org. Chem. 1970, 35, 3275. (c)
Tsuchihashi, G.; Iriuchijima, S.; Maniwa, K. Tetrahedron Lett. 1973,
14, 3389. Yokoyama, M.; Takeshima, T. Tetrahedron Lett. 1978, 19,
147. (d) Annunziata, R.; Cinquini, M.; Restelli, A.; Cozzi, F. J . Chem.
Soc., Perkin Trans. 1, 1982, 1183. Hua, D. H.; Park, J . G.; Katsuhira,
T.; Bharathi, S. N. J . Org. Chem. 1993, 58, 2144. Kawecki, R.; Kozerski,
L.; Urbanczyk-Lipkowska, Z.; Bocelli, G. J . Chem. Soc., Perkin Trans.
1, 1991, 2255. (e) Garcia Ruano, J . L.; Lorente, A.; Rodriguez, J . H.
Tetrahedron Lett. 1992, 33, 5637. Baldenius, K. U.; Kagan, H. B.
Tetrahedron: Asymmetry 1990, 1, 597. Kawecki, R.; Kozersky, L.
Tetrahedron 1986, 42, 1469.
(7) Osipov, S. N.; Kolomiets, A. F.; Fokin, A. V. Russ. Chem. Rev.
1992, 61 (8), 798. For a recent report on the preparation of R-(fluoro-
and -perfluoroalkyl) imines from the corresponding fluorinated ketones
and aldehydes and benzylamine see: Soloshonok, V. A.; Kirilenko, A.
G.; Kukhar, V. P.; Resnati, G. Tetrahedron Lett. 1994, 35, 3119. In
our hands, attempts to obtain the title compounds directly from acid
catalyzed condensation of benzylamine and R-(fluoroalkyl)-R′-sulfinyl
ketones did not gave satisfactory results.
Primary enamines 4a and 4c were obtained in high
yields (91% and 85%, respectively) after 16 h at rt from
the reaction of the trifluoro and the difluorochloro gem-
diols 1a and 1c with the N-SiMe3 iminophosphorane 2c,
that was prepared in situ and cleanly reacted with or
without in situ desilylation to the more reactive 2b (R )
H).12 In both cases only N-desilylated enamines were
recovered after FC. Finally, primary enamine 4b was
1
obtained in 85% yield (calculated from H NMR spectrum
of the crude reaction mixture), but hydrolysis occurred
during FC. Anyway, 4b may be employed for in situ
reactions.
As expected, the above described results show a clear-
cut increase of reactivity of the R-fluorinated-R′-sulfinyl
(8) Katritzky, A. R.; J iang, J . J . Org. Chem. 1994, 59, 4551.
(9) J ohnson, A. W.; Wong, S. C. K. Can J . Chem., 1966, 44, 2793.
For some reviews on the aza-Wittig reaction see: J ohnson, A. W.;
Kasha, W. C.; Starzewsky, K. A. O.; Dixon, D. A. Ylides and Imines of
Phosphorus; J ohn Wiley: New York, 1993; Chapt. 13. Molina, P.;
Vilaplana, M. J . Synthesis, 1994, 1197 and references cited therein.
(10) For a preliminary report see: Bravo, P.; Crucianelli, M.; Zanda,
M. Tetrahedron Lett. 1995, 36, 3043.
(11) Kricheldorf, H. R. Synthesis 1972, 695.
(12) Kloek, J . A.; Leschinsky, K. L. J . Org. Chem. 1978, 43, 1460
and references cited therein.

Optically Pure R-(Fluoroalkyl)-â-sulfinyl Enamines
J . Org. Chem., Vol. 61, No. 10, 1996 3377
Ta ble 1. NOE a n d selected 1H NMR va lu es of en a m in es (see Sch em es 1 a n d 2)
compound
RF
CF3
CF2H
CF2H
CF2Cl
CF2CF3
CFH2
CF3
CF2H
CF2Cl
CF3
CF2H
CF3
R
R′
yield % (conv)
NOE %a {RF}/H-1
δH-1
δNH
δH-3 (RF)
(Z)-3a
(Z)-3b
(E)-3b
(Z)-3c
(Z)-3d
(Z)-3e
(Z)-4a
(Z)-4b
(Z)-4c
(Z)-6a
(Z)-6b
(Z)-7a
(Z)-7b
(E)-7b
(Z)-8a
(Z)-8b
(E)-8b
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
H
H
H
H
H
H
H
H
H
H
78 (85)
48
10.5
11.5
4.5
13.8
14.5
12.5
16.0
h
6.42
5.70
7.30
6.54
6.60
5.33
5.30
5.12
5.32
6.92
6.77
6.80
6.61
6.08
6.9
7.28
9.95
6.80
6.76
6.45
10.24
5.35
5.28
5.38
-
-
7.06
7.25
-
32 (86.5)b
72 (78)
58 (70)
10 (95)
91
-
5.42
-
H
H
85c
85
80
5.95
-
h
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
benzyl
benzyl
benzyl
allyl
9.4
9.5
h
-
54 (75)
-
6.08
-
70,d 65e
-
CF2H
CF2H
CF3
CF2H
CF2H
∼73f
8.6g
h
-
5.89
6.78
-
∼62.6 (85)f
76
-
h
h
h
-
allyl
allyl
56 (68.5),d 69 (73)e
∼35 (63)f
6.69
6.38
-
6.09
6.78
-
a
b
Heteronuclear NOE. Calculated from 1b recovered ((Z)- and (E)-3b were obtained in the same reaction). c Calculated from 1H NMR
spectrum of the crude. Method A (see Experimental Section). e Method B (see Experimental Section). f Obtained as mixture with Z (E)
d
g
h
isomer (method B see Experimental Section). Homonuclear NOE. Not measured.
ketones 1 toward iminophosphoranes 2 with increasing
R-halogenation.
The only relevant byproducts we have detected in the
aza-Wittig reaction have been the enol ethers 5c and 5d 13
(Figure 1), obtained in the reaction of the gem-diols 1c
and 1d with the phospha-azene 2a . The enol ether 5d
was independently synthesized by a reported method.14
F igu r e 1.
St r u ct u r e Det er m in a t ion . The N-Cbz-â-sulfinyl
enamines 3a -d are stable crystalline compounds that
can be stored for indefinite time at rt, while the primary
enamines 4a ,c are oily compounds which can be purified
by FC and stored at 0 °C for long time.
effect is much smaller (4.5%). The Z stereochemistry at
the double bond of the primary enamines 4b and 4c was
confidently assigned, given the similarity of their NMR
spectra with those of (Z)-4a (see Experimental Section).
The chemical shift of the carbamic proton shows strong
variations within the examined compounds. In the
spectra of (Z)-3a , (Z)-3c, (Z)-3d , and (E)-3b a broad
signal, that resonates in the range 6.4-7.3 ppm and is
shifted upfield with dilution, can be certainly assigned
to the NH proton. For compounds (Z)-3b and (Z)-3e,
bearing the difluoro- and monofluoromethyl substituent,
respectively, the NH resonance falls at ca. 10 ppm., and
no appreciable shift was observed upon dilution. These
data suggest the presence in solution of an intramolecular
hydrogen bond between the carbamic proton and the
sulfinyl oxygen for (Z)-3b and (Z)-3e, but not for (Z)-3a ,
(Z)-3c, (Z)-3d (and obviously for (E)-3b).
The absence of intramolecular hydrogen bond between
the NH and the sulfinyl oxygen in the latter compounds
means that the driving force for the overwhelming
preference of the N-Cbz enamines 3a ,c,d for the cis
stereochemistry at the double bond must be searched
elsewhere.15 Moreover, also the N,N-disubstituted en-
amines 6-8a show the same stereochemical behavior. A
possible explanation could be given by invoking a repul-
sive nonbonded interaction between the RF and the
oxygen atom of the sulfinyl group. On the other hand a
favorable nonbonded interaction between the sulfinyl
group and the nitrogen atom, possibly implying a hyper-
valent sulfur, may also be considered.16
The products of the aza-Wittig were entirely in en-
amine form: imine products A have never been detected
1
by H and 19F NMR analyses of the crude. Solid phase
IR spectra of 3a -c, purified by FC and crystallized,
confirmed the absence of a CdN band, while the strong
bands of N-H stretching were always clearly detectable
(see supporting information). The â-sulfinyl enamines
3 may exist as (E)- and (Z)-geometric isomers or as an
equilibrium mixture: however, for the 3a ,c-e, 4a -c
derivatives, obtained as pure compounds by FC, we have
been able to detect only the Z geometric isomer, both in
the solid state and in solution. Only the difluoro deriva-
tive 3b was obtained from the reaction as a Z:E ) 3:2
mixture of isomers, easily separable in pure form by FC.
Equilibration between the isomeric enamines (E)- and
(Z)-3b was experimentally observed: interconversion
occurred at very low rate in solution at rt and at neutral
pH, but starting from pure (Z)-3b a ratio of (Z)-3b:(E)-
3b ) 3:2 was reached after one night at 50 °C in benzene
solution.
The most significant NMR data of compounds 3a -e,
4a -c are reported in Table 1. The stereochemistry at
the double bond of the enamines 3a -e, 4a was estab-
lished from the heteronuclear NOE effect measured on
H-1 by irradiating the fluorine atoms. In the case of the
Z isomers the NOE for H-1 is very large, ranging from
10.5 to 16.0%. For the (E)-3b isomer, as expected, this
The N-monosubstituted (3b) and N,N-disubstituted
(6b, 7b, 8b) enamines bearing the CF2H group were
(13) In the preliminary report10 the enol ethers 5c,d were mistaken
for E isomers of 3c and 3d . Probably these byproducts do not arise
from the corresponding â-sulfinyl enamines, because under aza-Wittig
reaction conditions they did not afford the enol ethers 5. It is likely
that they are directly produced by reaction of the gem-diols 1c,d with
the iminophosphorane 2a .
(15) For a conformational study on â-sulfinyl enamines and R-sul-
finylimines see: Kozersky, L.; Kawecki, R.; Hanson, P. E. Magn. Reson.
Chem., 1994, 32, 517. For
a discussion about the intramolecular
hydrogen bonding in â-sulfinyl enamines see ref 6d.
(16) Oae, S. Organic Sulfur Chemistry: Structure and Mechanism,
CRC Press: Boca Raton, 1991; pp 21-26.
(14) Bravo, P.; Bruche´, L.; Crucianelli, M.; Merli, A. J . Fluorine
Chem. 1995, 74, 127.

3378 J . Org. Chem., Vol. 61, No. 10, 1996
Arnone et al.
Sch em e 2
obtained as mixtures of (E)- and (Z)-geometric isomers,
thus showing only slight preference for the cis geometry.
This feature, unique in the variety of enamines synthe-
sized in the present work, may be attributed to the
presence in solution of an intramolecular hydrogen bond
between the sulfinyl oxygen and the hydrogen of the
CF2H group.17 1H NMR Chemical shifts of H-1 and H-3
seem also to agree with this explanation.
Further investigations on these phenomena are pres-
ently underway by means of X-ray crystallographic
analysis of the N-Cbz-â-sulfinyl enamines 3, NMR stud-
ies of their properties in solution, and calculations. The
results of these efforts will be published in due time.
Rea ctivity of Title Com p ou n d s: Gen er a l Con sid -
er a tion s. We have studied the general reactivity of the
N-Cbz trifluoro derivative 3a and, for sake of comparison,
that of the difluoro enamine 3b, with the view of
assessing the employment of the R-(fluoroalkyl)-â-sulfinyl
enamines in the synthesis of sulfur-free fluorinated
analogues of naturally occurring molecules having bio-
logical interest. Title compounds show a complex reac-
tivity pattern. They possess at least four contiguous sites
which can enter into reaction: the sulfinyl group, the two
C-1 and C-2 sp2 atoms of the carbon-carbon double bond,
and the nitrogen atom. Because of the presence of the
fluoro-substituted alkyl group at the C-2 and of the Cbz
protecting group at the nitrogen atom, compounds 3
should be electron-poor systems when compared with
known R-sulfinyl imines and R-imino ketones and esters.
Therefore one should expect they will show a high
reactivity toward species having nucleophilic character.
R ea ct ion s w it h E lect r op h iles. The primary tri-
fluoro enamine 4a , upon treatment with n-BuLi in tetra-
hydrofuran (THF) at -78 °C, followed by ClCOOCH2Ph,
smoothly afforded the N-Cbz protected derivative 3a .
However, under these conditions the yield did not exceed
50%, and a reversed addition (the lithium derivative of
4a to a cooled solution of ClCOOCH2Ph) did not change
the situation. Presumably, since the N-Cbz product 3a
is more acidic than 4a , a half quantity of the former is
consumed, forming the lithium derivative of 3a , that is
not reactive in these conditions toward the excess of
chloroformate. Unreacted starting enamine 4a can be
quantitatively recovered by FC purification of the crude.
The nitrogen atom was found to be the reactive site of
the difluoro and trifluoro N-Cbz enamines 3a ,b, when
they were treated with the tested electrophiles in pres-
ence of bases, while in absence of the latter no reaction
was detected. The reactions of the N-Cbz-â-sulfinyl
enamines 3a and 3b with electrophiles are outlined in
Scheme 2. The N-Cbz trifluoro enamine 3a reacted with
benzyl chloroformate in dioxane/50% aqueous K2CO3 at
rt (method A), affording the (Z)-N,N-bis-Cbz derivative
6a (80%). The original cis double bond stereochemistry
was retained, as shown by NOE difference experiments.
The same enamine 3a reacted with benzyl and allyl
bromides both according to method A and in dimethyl-
formamide (DMF)/NaH from 0 °C to rt (method B) giving,
in moderate to good yields, the corresponding N-benzyl
and N-allyl derivatives 7a and 8a . Slightly better yields
were obtained by following method A.
Both the (E)- and (Z)-geometric isomers of the difluoro
enamine 3b were separately submitted to the above
described reactions with electrophiles. As clearly de-
tected by thin layer chromatography (TLC), (E)- and (Z)-
3b are prone to interconversion when treated with bases
(method A or B).
Method B was found to be considerably more efficient
but less diastereoselective than method A in the reaction
of (Z)- and (E)-3b with allyl and benzyl bromide. In fact
only (Z)-N,N-diprotected enamines were obtained with
method A starting separately from (Z)- or (E)-3b, while
when method B was adopted, mixtures of (E)- and (Z)-
N,N-diprotected enamines 7b and 8b were obtained, as
1
clearly detected by H and 19F NMR. The ratio of the
isomers 7b,8b produced with method B reflected the
geometry of the starting enamine. The stereochemistry
at the double bonds was unequivocally established by
means of homonuclear NOE experiments performed on
7b, while the stereochemistry of the two isomers of 8b
was assigned by comparison with the NMR spectra of
7b. Interestingly, upon treatment with benzyl chloro-
formate, the (Z)-3b isomer afforded only the correspond-
ing cis-N,N-bis-Cbz-enamine (Z)-6b, as shown by NOE
experiments. Moreover, (Z)-3b was found to react better
than (E)-3b with the tested electrophiles. The former
afforded the difluoro N,N-disubstituted enamines 6b-
8b in yields ranging from 54% to 94%, while for the latter
the yields were much lower (see Experimental Section).
The (Z)-N,N-disubstituted enamines are easily distin-
1
guishable from the (E)- isomers by means of their H and
19F NMR spectra. In fact, the signals of the (Z)- isomers
in CDCl3 at rt were very broad, while those of the (E)-
isomers in the same conditions were perfectly sharp. The
broad signals displayed by the (Z)-N,N-disubstituted
enamines 6-8 at rt should be due to the hindered
rotation around some C-N bond (most probably around
the enamine CdC-N bond); sufficiently sharp signals
can be obtained just by increasing the temperature of the
sample to 306-318 K.
It is noteworthy that the attack of all tested electro-
philic species described herein18 does not occur on carbon
C-1, the usual reactive site for “normal” metalated
enamines.19 The low reactivity of C-1 as nucleophilic site
is probably due to the presence of fluorine atoms, which
make the enamine π system electron-poor.
(18) The reactions of the â-sulfinyl enamines 3 with acyl halides
and anhydrides have a completely different and much more complex
outcome, presently not well understood and under active investigation.
The results will be reported in due course.
(19) Whitesell, J . K. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Academic Press: Oxford, 1991; Vol. 6, pp 703-
732. Martin, S. F. Ibid., Vol. 2, pp 475-502. Whitesell, J . K.; Whitesell,
M. A. Synthesis 1983, 517. Hickmott, P. W. Tetrahedron 1986, 40, 2989.
Only one geometric isomer was always detected, to
which a Z stereochemistry was confidently assigned in
analogy with 6a .
(17) Erickson, J . A.; Mc Loughlin, J . I. J . Org. Chem. 1995, 60,
1626-1631.

Optically Pure R-(Fluoroalkyl)-â-sulfinyl Enamines
J . Org. Chem., Vol. 61, No. 10, 1996 3379
Sch em e 3
almost equimolar mixtures of addition products 9a , 10a ,
and 11a , arising, respectively, from the addition of O,
N, and C centered nucleophiles, were obtained from the
trifluoro enamine 3a . Both the (Z)- and (E)-isomers of
the difluoroenamine 3b were separately reacted with the
reported nucleophiles, but no significant differences in
the diastereomeric ratio of the resulting products 9b, 10b,
11b, and 12 was observed. The difluoro hemiaminal 9b,
the trifluoro aminal 10a , the trifluoro nitro derivative
11a , and the difluoro phenylthio derivative 12 were
obtained in diastereomerically pure form by FC.23
With the above described results in hand, we were not
surprised to find that the addition reactions of hetero-
atom centered nucleophiles on the enamines 3a ,b run
under thermodynamic control. In fact, after a few days
in chloroform solution at rt, the N,O-derivative 9 and the
N,N-derivative 10 partially or completely reconverted
into the corresponding starting enamine 3; moreover,
when the diastereomerically pure disubstituted deriva-
tives 9b, 10a , and 12 were submitted to the conditions
under which they were obtained from 3, the original
diastereomeric ratio was smoothly achieved. On the
other hand, in the case of nitromethane the reaction
probably occurs under kinetic control. In fact, no re-
equilibration was observed when diastereomerically pure
11b was left in nitromethane at rt in presence of a
catalytic amount of base for one week.
The high reactivity of the R-(fluoroalkyl)-â-sulfinyl
enamines 3 toward nucleophiles can be attributed to the
known stabilizing effect for quaternary species (hydrates,
hemiacetals, etc.) of perfluoroalkyl groups R to carbonyls
or imines, and to the fact that during the addition of
anions a negative charge evolving in reaction intermedi-
ates on carbon C-1 will be stabilized by the adjacent
sulfinyl group.
Rea ction s w ith Hyd r id e Red u cin g Agen ts. Chiral
â-sulfinyl amines are molecules of remarkable usefulness
for the stereoselective synthesis of natural and biologi-
cally active compounds.24 For this reason the efficient
and stereoselective reduction of the R-(fluoroalkyl)-â-
sulfinyl enamines 3,4 is a fundamental step with the view
of the synthesis of chiral fluorinated molecules of biologi-
cal interest. The hydride-promoted reduction of cyclic
and acyclic R-sulfinylimines has been extensively
studied,4d,e,25,26 but we have found that the fluorosubsti-
tution changes the usual reactivity of the title compounds
toward hydrides.
Sch em e 4
Rea ction s w ith Nu cleop h iles. Carbon C-2 is highly
reactive toward nucleophiles (Scheme 3) and a new
stereogenic center is formed in this reaction. R-(Tri-
fluoromethyl)- and R-(difluoromethyl)-N-Cbz-â-sulfinyl
enamines 3a and 3b reacted efficiently and under very
mild conditions with O, N, C, and S-centered nucleo-
philes.
Methanol (used as reagent and solvent in the presence
of a catalytic amount of conjugate base) added at rt in
12 h to the enamines 3a and 3b afforded good yields
of the diastereoisomeric N,O-disubstituted hemiaminals
9a ,b.
Ammonia (30% aqueous solution) reacted in 15 min
with THF solutions of 3a and 3b at rt giving, in almost
quantitative yield, diastereomeric mixtures of aminals
10a ,b. These compounds are quite stable and can be
easily purified by FC.
Also, carbon-centered nucleophiles like nitromethane
added to the â-sulfinyl enamines 3a ,b producing the
nitro-compounds 11a ,b. This modified Henry (nitroaldol)
reaction was carried out at rt for 24-48 h, using
nitromethane as solvent, with a catalytic amount of base.
The trifluoro derivative 11a was obtained in 80% yield;
the difluoro derivative 11b in 93% yield starting from
(Z)-3b.
The reaction of the enamines 3a ,b with a sulfur
nucleophile such as thiophenol was found to be highly
sensitive to the fluorination degree, which modulates the
reactivity of the substrate. When the trifluoro enamine
3a was reacted with 4 equiv of thiophenol and a catalytic
amount of base, only the vinyl sulfide 13 was surprisingly
obtained. On the other hand, the difluoro enamines (Z)-
and (E)-3b reacted in the expected fashion: the N,S-
disubstituted derivative 12 was obtained after 16 h in
70% and 63% yield, respectively (Scheme 4). Probably
13 arises from an anti-Michael addition of phenyl sulfide
ion to 3a and subsequent â-elimination of the p-toluene-
sulfenate ion.20
The reduction of the primary and N-Cbz R-(fluoro-
alkyl)-â-sulfinyl enamines to the corresponding â-sulfinyl
amines 14 and 15 (Scheme 5) was systematically studied
on 3a and 4a (a full account on the hydride-promoted
reduction of the â-sulfinyl enamines 3a , 4a , and 4c can
be found in supporting information).
(21) Bumgardner, C. L.; Bunch, J . E.; Whangbo, M.-H., J . Org.
Chem. 1986, 51, 4082.
(22) Martin, V.; Molines, H.; Wakselman, C. J . Org. Chem., 1992,
57, 5530.
(23) There is only one precedent of optically pure aminals like 10,
as stated by: Matsumura, Y.; Tomita, T. Tetrahedron Lett., 1994, 35,
3737.
(24) For the use of â-sulfinyl amines in the synthesis of alkaloids
see Hua and co-workers, ref 6d; see also Pyne, S. G.; Dikic, B. J . Org.
Chem., 1990, 55, 1932 and references cited therein. For their use as
ligands of transition metals see the works of Kagan, ref 6e. See also:
Lim, C. C.; Leung, P. H.; Sim, K. Y. Tetrahedron: Asymmetry 1994, 5,
1883.
Concerning the diastereoselectivity of the reactions of
the N-Cbz â-sulfinyl enamines 3a ,b with nucleophiles,
(20) Only few examples of anti-Michael additions are known, but
this unusual outcome has been already reported in the additions of
PhS- to 4,4,4-trifluoro-1-phenylbut-2-yn-1-one21 and â,â-bis(trifluo-
romethyl)acrylic esters.22 For a recent example of anti-Michael addi-
tions of heteroatom nucleophiles see: Back, T. G.; Wehrli, D. Tetra-
hedron Lett. 1995, 36, 4737 and references therein quoted.
(25) Carreno, M. C.; Dominguez, E.; Garcia Ruano J . L.; Pedregal,
C.; Rodriguez, J . H. Tetrahedron 1991, 47, 10035. Hua, D. H. Bharathi,
S. N.; Panangadan, J . A. K.; Tsujimoto, A. J . Org. Chem. 1991, 56,
6998.
(26) Ogura, K.; Tomori, H.; Fujita, M. Chem. Lett. 1991, 1407.

3380 J . Org. Chem., Vol. 61, No. 10, 1996
Arnone et al.
Sch em e 5
F igu r e 2.
The (2S,RS) absolute stereochemistry of 15a was as-
signed by X-ray crystallographic analysis (see supporting
information) of the major diastereoisomer obtained in the
L-Selectride promoted reduction of 4a . In the ORTEP
view of compound 15a it can be seen the all trans
conformation of the sulfoxide chain implying a gauche
value for the dihedral angle S(1)-C(1)-C(2)-N(1) and
consequently a possible interaction between the lone-pair
of N and the S atom.
The N-Cbz enamine 3a was reduced upon treatment
with NaBH4 in a 4:1 THF/H2O mixture at rt, affording
the diastereoisomeric amines 14 with low diastereo-
selection (68% yield). Surprisingly, using methanol as
solvent, upon treatment with NaBH4, 3a afforded the
N,O-disubstituted ketal 9a , while no appreciable reduc-
tion was detected. In our hands HB(OAc)3, BH3‚SMe2,
L-Selectride, NaBH3CN, and diisobutylaluminum hy-
dride (DIBALH) were not effective in the reduction of 3a
to the corresponding amine 14.
The stereochemistry of 14 was assigned by chemical
correlation. In fact, treatment of (2S,RS)-15a with benzyl
chloroformate and 50% K2CO3 in dioxane afforded the
major diastereoisomer of 14 obtained in the NaBH4/-20
°C reduction of the N-Cbz enamine 3a . The stereochem-
istry of the difluorochloro amine 15c was assigned by
1
comparison of the H NMR spectra, since the two pairs
of major and minor diastereoisomers of the L-Selectride-
promoted reduction of 4a and 4c showed great similarity
(see Experimental Section).
The primary R-(trifluoromethyl)-â-sulfinyl enamine 4a
was reduced to the diastereomeric amines 15a in the
same conditions and with the same low diastereoselection
already described for 3a . However, the reaction was
found to occur also in dry THF (the N-Cbz enamine 3a
was practically unreactive in dry THF toward NaBH4),
and even though the reaction rate was low (40 h at rt)
the diastereoselection was remarkably higher (60% de)
than that obtained in the presence of water, delivering
the diastereoisomeric â-sulfinyl amines 15a in 83% yield.
The K- or L-Selectride promoted reduction of the
primary trifluoro enamine 4a proved to be highly stereo-
selective affording 15a with a (2S,RS)/(2R,RS) ) 90:10
diastereomeric ratio in CH2Cl2 and 93:7 in THF. The
reduction was very fast, but required the use of a one-
pot stepwise procedure to reach a satisfying yield. When
a small excess of K- or L-Selectride was added to the
primary enamine at -20 °C, only about 40% of 15a
formed after the first addition. In fact, as already
reported,26 the reducing agent, acting as a strong base,
is able to remove an NH proton producing the corre-
sponding azaenolate, which proved to be unreactive
toward the hydride. The addition of a small excess of
ethanol can regenerate the unreacted enamine. Careful
removal of the excess of ethanol and further addition of
Selectride produces further reduction. Repeating this
procedure twice a yield of 75% was reached using CH2Cl2
as solvent (unreacted 4a was almost quantitatively
recovered).
As already hypothesized, a rationale for the high
diastereoselectivity showed by K- and L-Selectride in the
reduction of 4a ,c could be given considering that such
reducing agents are highly sterically demanding: so, the
attack of the hydride is expected to be much more easy
from the re face of the transient tautomeric imine form
of 4a ,c in the conformation in which the dipole-dipole
interactions between the CdN and the SdO groups are
minimized (Figure 2).27
Deuterium-substituted molecules are important and
useful tools for investigations on metabolism, on mech-
anism of action of enzymes, and on mechanism of
reactions. By means of the above described methods of
reduction of the enamines 3, we were able to synthesize
regio- and stereoselectively deuterium substituted â-sul-
finyl amines 15a . Selective deuterium substitution at
C-2 was achieved by reduction of 4a to (2-D)-15a with
NaBD4 in dry THF (Scheme 6). The diastereoselection
was similar to that obtained in the reduction of 4a with
NaBH4 in dry THF. Exhaustive deuterium substitution
was obtained upon preliminary exchange of 4a with D2O,
that afforded the corresponding (N,N,3-D3)-enamine,
which was treated, without isolation, with NaBD4 in dry
THF. After aqueous workup the â-sulfinyl amine (2,3,3-
D3)-15a was cleanly obtained, the substitution degree
being >95% both in the C-2 and C-3 positions.
Rea ction s a t th e Su lfin yl Moiety: (a ) Syn th esis
of Am in es a n d Am in o Acid s. For a suitable use of the
title compounds 3 in the synthesis of chiral fluorinated
analogues of naturally occurring or fluoro-substituted
biologically active compounds, it is necessary to have at
disposal efficient procedures for the removal of the
stereogenic auxiliary group. Herein we report the ap-
plication of two classical reactions for sulfur removal,
examined closely on the trifluoro-â-sulfinyl amines (2S,RS)-
15a and (2S,RS)-14 (Scheme 7).
Also the primary difluorochloro enamine 4c was stereo-
selectively reduced with L-Selectride in CH2Cl2 at -20
°C, affording the amines 15c in (2S,RS)/(2R,RS) ) 5:95
diastereomeric ratio. The reduction was performed as
already described for 4a .
In our hands no reaction occurred with DIBALH (even
in the presence of ZnBr2 or ZnI2) and BH3‚THF.
It is likely that the low reactivity of the tested R-(fluo-
roalkyl)-â-sulfinyl enamines 3 toward electrophilic reduc-
ing agents is due to the fluorosubstitution that makes
the enamine framework electron poor.
(27) Solladie`, G.; Demailly, G.; Greck, C. Tetrahedron Lett., 1985,
26, 435. Pyne, S. G.; Hajipour, A. R. Tetrahedron, 1994, 50, 13501 and
references cited therein.

Optically Pure R-(Fluoroalkyl)-â-sulfinyl Enamines
J . Org. Chem., Vol. 61, No. 10, 1996 3381
Sch em e 6
Sch em e 8
Sch em e 7a
The direct oxidation of (R)-18 to the N-Cbz-3,3,3-
trifluoroalanine 20 was achieved by the Sharpless method
with catalytic RuO2‚xH2O and NaIO4 at rt.28 The result-
ing product (R)-20 was isolated and characterized or in
situ transformed, upon treatment with ethereal diazo-
methane, into the corresponding methyl ester (R)-21
(65%), known in the literature, though only in racemic
form.29 Hydrogenolysis of the Cbz protection of (R)-21
with Pd(OH)2 in ethanol at rt cleanly afforded (R)-3,3,3-
trifluoroalanine 22 in 64% yield.30
(b) Non oxid a tive P u m m er er Rea r r a n gem en t of
1,1,1-Tr iflu or o-3-su lfin yl Am in e 14. Intensive efforts
to isolate the expected intermediate derivative 26 (Scheme
8), or the corresponding R-amino aldehyde, from the
Pummerer rearrangement of 14 were unsuccessful. More-
over, we observed that the NaBH4 reduction of the
intermediate product of the Pummerer rearrangement
to the alcohol 18 did not require, as usual and above
reported, a preliminary hydrolysis of the expected inter-
a
(a) ClCO2CH2Ph, 50% aqueous K2CO3, dioxane, rt (100%); (b)
TMSCl, NaI, 0 °C, CH3CN; (c) (i) H2, Ra-Ni, EtOH, rt; (ii) 1 N
HCl; (d) (i) trifluoroacetic anhydride, sym-collidine, CH3CN, 0 °C;
(ii) aqueous K2CO3; (iii) NaBH4; (e) RuO2‚xH2O (cat.), NaIO4, 3:2
acetone/water, rt, 1 h (65%); (f) CH2N2/Et2O (65%); (g) H2, Pd(OH)2,
EtOH, rt, 1 h (65%).
Specifically, the reduction of (2S,RS)-15a to the corre-
sponding sulfide 16 was smoothly achieved with TMSCl
and NaI in acetonitrile at 0 °C. Standard desulfurization
of (S)-16 with Raney Ni and H2 cleanly afforded (R)-1-
(trifluoromethyl)ethylamine that was isolated as hydro-
chloride (R)-17.
The Pummerer rearrangement performed on (2-H)-
and (2-D)-(2S,RS)-14, as expected, produced the removal
of the sulfinyl auxiliary group with the introduction of
an oxygen functionality in its place.
When (2-H)- and (2-D)-14 were treated first with
trifluoroacetic anhydride (TFAA) and sym-collidine at 0
°C and then with aqueous K2CO3 and finally with NaBH4
at rt, the (2-H)- and (2-D)-N-Cbz-amino alcohols (R)-18
were, respectively, obtained in one-pot in 86% yield. As
expected, no loss of deuterium was observed for (2-D)-
(R)-18. Deprotection of 18 by hydrogenolysis with Raney
Ni in H2 atmosphere afforded, after treatment with 1 N
aqueous HCl, the (2-H)- and (2-D)-3,3,3-trifluoroalaninol
hydrochlorides (R)-19.
(28) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936. See also: Garner, P.; Park, J . M. J .
Org. Chem. 1990, 55, 3772. Casiraghi, G.; Colombo, L.; Rassu, G.;
Spanu, P. J . Org. Chem. 1991, 56, 6523.
(29) Burger, K.; Hoss, E.; Gaa, K.; Sewald, N.; Schierlinger, C. Z.
Naturforsch. 1991, B46, 361.
(30) The yields of RuO2-catalyzed oxidation and of hydrogenolysis
have not been optimized.

3382 J . Org. Chem., Vol. 61, No. 10, 1996
Arnone et al.
Sch em e 9
mediate 26. Apparently, 26 was not formed at all and
the reaction followed a completely different course. So
we decided to further investigate this intriguing matter.
As outlined in Scheme 8, when (2S,RS)-14 was treated
with TFAA and sym-collidine in acetonitrile at 0 °C, the
R-sulfenamido trifluoroacetate 23 was surprisingly re-
covered as the only product. Upon treatment with
aqueous K2CO3, 23 smoothly provided the sulfenamido
alcohol 24, whose structure was confirmed by O-acetyl-
ation to 25. The sulfenamide 23 is clearly the product
of an abnormal Pummerer rearrangement. In the most
likely reaction path the sym-collidine, acting as a proton
scavenger on B (the normal acylated intermediate),
produces the zwitterionic intermediate C by preferential
removal of the carbamic proton. Probably, the fluoro-
substitution plays an important role making the abstrac-
tion of the NH proton more competitive with respect to
the protons in R to the sulfinyl moiety. Nitrogen atom
binding to the positively charged sulfur atom and S-O
bond breaking leads to the four-membered ring interme-
diate D.31 Attack of the trifluoroacetate ion on the CH2,
which occurs with cleavage of the S-C bond, gives the
R-sulfenamido trifluoroacetate 23.32,33
The formation of a σ-sulfurane intermediate (tetra-
coordinate sulfur), stabilized by the presence of two
electron-withdrawing ligands on sulfur (the trifluoro-
acetoxy group and the carbamic nitrogen), may also be
conceived as an alternative pathway.34
and, though the diastereoselection was found to be
modest, the process is efficient and occurs under mild
conditions.
The introduction of hydride species has been examined
in detail. â-Sulfinylamines have been obtained by this
route in good yields and with high diastereoselection, also
in deuterium-substituted form.
As a proof that the reaction does not involve the normal
H-1 removal, (2,3,3-D3)-(RS,2S)-14 was submitted to the
Pummerer rearrangement (Scheme 9).35 The sulfen-
amide intermediate, reduced in situ with NaBH4 to the
N-Cbz-amino alcohol (1,1,2-D3)-18, was found to have
retained the original deuterium in C-2.
The removal of the chiral auxiliary sulfinyl group was
achieved by reductive desulfurization or by introduction
of an oxygen function in its place. The latter transforma-
tion was obtained by Pummerer rearrangement of the
N-Cbz-1,1,1-trifluoro-3-[(4-methylphenyl)sulfinyl] amine
14, a reaction that proceeds through a sequence of
unusual intermediates.
The usefulness of the title compounds as fluorinated
nitrogen-substituted templates for the synthesis of flu-
orinated molecules of biological interest has been dem-
onstrated. (R)-1-(Trifluoromethyl)ethylamine (17), a small
chiral fluorinated amine, which has already been em-
ployed as a key constituent of molecules with herbicide,
insecticide, nematocide, and acaricide properties,36 has
been stereoselectively obtained starting from the primary
trifluoro sulfinyl amine 15a . Accordingly, the N-Cbz
derivative 14 delivered (R)-(2-H)- and (2-D)-(R)-3,3,3-
trifluoroalaninol (to our knowledge not reported in lit-
erature)37 and (R)-3,3,3-trifluoroalanine (until now not
described in optically pure form),38 that is reported to be
a potent mechanism-based inhibitor of a number of
pyridoxal phosphate-dependent enzymes.39
Con clu sion s. In the present paper we have reported
the aza-Wittig reaction of iminophosphoranes 2a -c with
R-fluoro-substituted-R′-sulfinyl ketones 1a -e for the
preparation of enantiomerically pure primary and N-Cbz
protected R-(fluoroalkyl)-â-sulfinyl enamines. Structural
studies showed an overwhelming preference for the
enamine form with a cis configuration between the amino
and the sulfinyl groups.
The title compounds 3a -e, 4a -c are new and versatile
fluorinated chiral building blocks as shown by their
manifold reactivity. The addition of O, N, C, and S-
centered nucleophiles gives rise to substituted R-(fluoro-
alkyl)-â-sulfinyl amines with a quaternary carbon atom,
(31) The formation of acylaminosulfonium ions as intermediates of
Pummerer rearrangement has been already proposed: Kita, Y.;
Shibata, N.; Kawano, N.; Tohjo, T.; Fujimori, C.; Matsumoto, K.;
Fujima, S. J . Chem. Soc., Perkin Trans. 1 1995, 2405, and references
cited therein. For
a four membered acylaminosulfonium ion see:
Exp er im en ta l Section
Yamamoto, K.; Yamazaki, S.; Murata, I.; Fukazawa, Y. J . Org. Chem.
1987, 52, 5239.
(32) This unusual nonoxidative pathway is probably general for
TFAA-promoted Pummerer rearrangement of N-Cbz 1,1,1-trifluoro-3-
sulfinyl amines as shown in the preliminary report: Arnone, A.; Bravo,
P.; Bruche´, L.; Crucianelli, M.; Vichi, L.; Zanda, M. Tetrahedron Lett.
1995, 36, 7301.
(33) A similar outcome was reported for various alkyl o-carbam-
oylphenyl sulfoxides, which afforded 1,2-benzisothiazole derivatives
upon treatment with Lewis acids: Uchida, Y.; Oae, S. Gazz. Chim.
Ital., 1987, 117, 649. See also: Wright, S. W.; Abelman, M. M.;
Bostrom, L. L.; Corbett, L. L. Tetrahedron Lett. 1992, 33, 153. For a
nonoxidative Pummerer rearrangement producing â-lactams see:
Kaneko, T. J . Am. Chem. Soc. 1985, 107, 5490.
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
or D2O. Chemical shifts (δ) are reported in parts per million
(36) For optically pure 1-(trifluoromethyl)ethylamine see: (a) Tar-
now, H.; Baasner, B.; Luerssen, K.; Santel, H. J .; Schmidt, R. R. Ger.
Offen. DE 3900300 A1 900712, 1990, Chem. Abstr. 113, 212024. (b)
Tarnow, H.; Baasner, B.; Homeyer, B.; Hartwig, J . Eur. Pat. Appl.,
EP 323637 A1 890712, 1990, Chem. Abstr. 112, 98219.
(37) The unfluorinated naturally occurring analogue is contained
in ergonovine (D-lysergic acid L-1-hydroxy-2-propylamide), an impor-
tant ergot alkaloid with therapeutic applications.
(34) See ref 16, pp 18-21.
(38) Very recently Uneyama and co-workers reported an interesting
approach to enantioenriched (R)-3,3,3-trifluoroalanine (ee 62%) by
enantioselective reduction of N-aryl imines of 3,3,3-trifluoropyruvic
esters: Sakai, T.; Yan, F.; Uneyama, K. Synlett 1995, 753.
(35) In this case, the deuteration degree in the 3 position was kept
at 75%, in order to better detect any change in the labeling degree
during the process.

Optically Pure R-(Fluoroalkyl)-â-sulfinyl Enamines
J . Org. Chem., Vol. 61, No. 10, 1996 3383
(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.
Peak multiplicities are abbreviated: singlet, s; doublet, d;
triplet, t; quartet, q; multiplet, m. Coupling constants (J ) are
119.7 (q, J ) 276 Hz), 68.6, 21.5; 19F NMR (CDCl3) 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.
(Z)-3b: Rf (3:1 hexane/ethyl acetate) 0.40; mp 119-121 °C
1
(ethyl acetate); [R]20 536.9 (c 1.0, CHCl3); H NMR (CDCl3)
D
reported in hertz (Hz). The H homonuclear and the H-19F
heteronuclear NOE difference experiments were performed
with the decoupler on resonance and then subtracted from a
control spectrum with the decoupler off resonance. The
irradiation time was 4 s and the relaxation delay 8 s. The
signals of the aromatic protons and of the methyl protons on
the tolyl group have not been tabulated, but were always
consistent with the proposed structures. [R]D and [R]365 values
were taken on a J asco-Dip polarimeter. Anhydrous solvents
were obtained by distillation from sodium (ethyl ether, ben-
zene) or from CaH2 (diisopropylamine). 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 under nitrogen. A routine workup of the reaction
means that the quenched reaction mixture was extracted with
ethyl acetate, the collected organic phases were dried over
anhydrous Na2SO4 and filtered, and the solvent was removed
under reduced pressure. Melting points are uncorrected and
were obtained on a capillary apparatus. Analytical TLC was
routinely used to monitor reactions. 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 for
column chromatography. HPLC analyses were performed on
a LiChrosorb Si60 (5 µm, Merck) prepacked column, and
hexane and ethyl acetate HPLC-grade solvents (Merck) were
used. Combustion microanalyses were performed by Redox
SNC, Cologno M. (Milano). Synthesis of compounds 1a -e has
been already described.3
1
1
9.95 (1H, s), 7.06 (1H, t, J ) 55 Hz), 5.7 (1H, s), 5.15 (2H, s);
13C NMR (CDCl3) 152.3, 142.8, 139.8 (t, J ) 23.8Hz), 139.4,
135.2, 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) 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.
(E)-3b: Rf (3:1 hexane/ethyl acetate) 0.20; mp 117-119 °C
1
(ethyl acetate); [R]20 70.1 (c 1.10, CHCl3); H NMR (CDCl3)
D
7.25 (1H, t, J ) 56 Hz), 6.8 (1H, br s), 5.13 (2H, s); 13C NMR
(CDCl3) 152.3, 141.8, 140.5, 135.8 (t, J ) 23 Hz), 134.8, 130.2,
128.8, 128.7, 128.5, 124.3, 121.8 (t, J ) 6.92 Hz), 108.4 (t, J )
242.2 Hz), 68.0, 21.4; 19F NMR (CDCl3) 120.2 (2F, m, J ) 308,
56 and 8 Hz).
(Z)-3c: Rf (3:1 hexane/ethyl acetate) 0.30; mp 162-163 °C
1
(ethyl acetate); [R]20 156.4 (c 1.03, CHCl3); H NMR (CDCl3)
D
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) 153.7, 142.3, 139, 135, 132.9
(t, J ) 29.2 Hz), 130.2, 129.9 (t, J ) 3.1 Hz), 128.8, 128.7, 128.4,
125.3, 122.3 (t, J ) 292.5 Hz), 68.7, 21.5; 19F NMR (CDCl3)
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.
The enol ether (Z)-5c was obtained as byproduct in 4%
yield: Rf (3:1 hexane/ethyl acetate) 0.35; 1H NMR (CDCl3) 6.25
(1H, s), 5.46 (1H, d, J ) 12 Hz), 5.40 (1H, d, J ) 12 Hz); 19F
NMR (CDCl3) 57.9 (1F, d, J ) 170 Hz), 58.8 (1F, d, J ) 170
Hz).
(Z)-3d : Rf (3:1 hexane/ethyl acetate) 0.45; mp 122-125 °C
1
(ethyl acetate); [R]20 149.6 (c 1.01, CHCl3); H NMR (CDCl3)
D
Syn t h esis of [(Ben zyloxyca r b on yl)im in o]t r ip h en yl-
p h osp h or a n e (2a ). To a solution of trimethylsilyl azide (1.0
g, 8.7 mmol) and benzyl chloroformate (0.48 mL, 6.2 mmol) in
dry benzene (10 mL) under nitrogen were added three drops
of pyridine, and the solution was heated for 30 min at reflux
temperature and then diluted with benzene (10 mL) and cooled
to 0 °C. To the solution was slowly added a solution of
triphenylphosphine (1.6 g, 6.2 mmol) in benzene (15 mL).
When nitrogen evolution ceased, the mixture was stirred for
30 min at rt, and then the solvent was removed under reduced
pressure. Crystallization of the residue (ethyl acetate) afforded
2a as white crystals (2.5 g, 98% yield): Rf (1:1 hexane/ethyl
acetate) 0.43; mp 101-103 °C (ethyl acetate); 1H NMR (CDCl3)
5.05 (2H, s).
Syn th esis of Su lfin ylen a m in es 3a -e. Gen er a l P r oce-
d u r e. The synthesis of 3b is described as example. To a
stirred solution of sulfinyl ketone 1b (0.80 g, 3.4 mmol) in dry
benzene (14 mL) was added iminophosphorane 2a (1.39 g, 3.4
mmol) under nitrogen. The mixture was refluxed for 18 h,
and then the solvent was removed under reduced pressure.
The residue was purified by FC (hexane/ethyl acetate from 7:3
to 3:2), giving 0.99 g of a 3:2 mixture of sulfinyl enamines (Z)-
3b and (E)-3b (80% overall yield, 86.5% conversion) and 72
mg of unreacted starting material 1b (9%).
6.60 (1H, s), 6.45 (1H, br s), 5.22 (1H, d, J ) 12 Hz), 5.28 (1H,
d, J ) 12 Hz); 13C NMR (CDCl3) 153.5, 142.3, 138.9, 134.9,
134.8 (t, J ) 3.65 Hz), 130.2, 128.8, 128.7, 128.3, 125.3, 118.2
(qt, J ) 287.1 and 37.2 Hz), 68.8, 21.5; 19F NMR (CDCl3) 119.7
(1F, d, J ) 270 Hz), 122.6 (1F, d, J ) 270 Hz), 84.6 (3F, s);
MS (CI, 70 eV) m/ z (%) 433 (M+, 100); Anal. Calcd for
C19H16F5NO3S: C, 52.66; H, 3.72; N, 3.23. Found: C, 52.52;
H, 3.71; N, 3.17.
The enol ether (Z)-5d was obtained as byproduct in 14%
yield: Rf (3:1 hexane/ethyl acetate) 0.50; oily compound; [R]20
D
204.2 (c 1.39, CHCl3); 1H NMR (CDCl3) 6.30 (1H, s), 5.48 (1H,
d, J ) 12 Hz), 5.42 (1H, d, J ) 12 Hz); 13C NMR (CDCl3) 148.4
(t, J ) 25 Hz), 142.1, 140.5, 134.2, 130.4, 129.1, 128.8, 128.0,
124.1, 121.4, 77.5, 21.4; 19F NMR (CDCl3) 83.7 (3F, s), 119.2
(2F, s); MS (CI, 70 eV) m/ z (%) 390 (M+, 100).
(Z)-3e: Rf (3:1 hexane/ethyl acetate) 0.45; [R]20 284.9 (c
D
1
1.02, CHCl3); H NMR (CDCl3) 10.24 (1H, br s), 5.42 (2H, m,
J ) 46 and 2 Hz), 5.33 (1H, s), 5.10 (2H, s); 19F NMR (CDCl3)
221.65 (1F, t, J ) 46 Hz). Anal. Calcd for C18H18FNO3S: C,
62.23; H, 5.22; N, 4.03. Found: C, 62.41; H, 5.33; N, 3.92.
Syn th esis of Su lfin ylen a m in es 4a -c. Gen er a l P r oce-
d u r e. The synthesis of 4a is described as example. For the
synthesis of iminophosphorane 2c, a modified Kloek-Leschin-
sky procedure12 was used: a solution of trimethylsilyl azide
(133 µL, 1.0 mmol) and triphenylphosphine (262 mg, 1.0 mmol)
in toluene (0.5 mL) was refluxed for 4 h under nitrogen. The
mixture was cooled to rt. The crude [(trimethylsilyl)imino]-
triphenylphosphorane 2c solution was added via cannula to
a dry benzene (1.5 mL) solution of sulfinyl ketone 1a (250 mg,
1.0 mmol). The solution was kept for 14 h at rt under nitrogen,
and then the solvent was removed under reduced pressure.
FC of the residue (1:1 hexane/ethyl acetate) afforded 227 mg
of (Z)-4a (91% yield). Following the Kloek-Leschinsky pro-
cedure, where the iminophosphorane 2b is generated in situ
from 2c, comparable results were obtained.
Following the same procedure the sulfinyl enamines 3a ,c-e
were obtained as (Z)-isomers (Table 1). Yields, % (conversions
%) were the following: 3a , 78 (85); 3c, 72 (78); 3d , 58 (70); 3e,
10 (95).
(Z)-3a : Rf (3:1 hexane/ethyl acetate) 0.35; mp 145-147 °C
1
(ethyl acetate); [R]20 12.9 (c 0.54, CHCl3); H NMR (CDCl3)
D
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) 153.2, 142.5, 138.8, 135.0,
130.3, 129.7, 128.7, 128.6, 128.4, 125.3, 128.1 (q, J ) 3.6 Hz),
(39) Wang, E. A.; Walsh, C. Biochemistry 1981, 20, 7539. Laske,
R.; Schoenenberger, H.; Holler, E. Arch. Pharm. 1989, 322, 857. Faraci,
W. S.; Walsh, C. T. Biochemistry, 1989, 28, 431. Liger, D.; Blanot, D.;
Van Heijenoort, J . FEMS Microbiol. Lett., 1991, 80, 111. Laber, H.;
Gerbling, K.-P.; Harde, C.; Neff, K.-H.; Verdhoff, E.; Pohlenz, H.-D.
Biochemistry, 1994, 33, 3413. Silverman, R. B.; Abeles, R. H. Biochem-
istry, 1976, 15, 4718. Silverman, R. B.; Abeles, R. H. Biochemistry,
1977, 16, 5515. Wang, E. A.; Kallen, R.; Walsh, C. J . Biol. Chem., 1981,
256, 6917.
(Z)-4a : Rf (3:1 hexane/ethyl acetate) 0.25; [R]20 458.9 (c
D
1
1.22, CHCl3); H NMR (CDCl3) 5.35 (2H, br s), 5.31 (1H, s);
13C NMR (CDCl3) 141.7, 141.6 (q, J ) 33.2 Hz), 140.8, 130,
124.7, 119.9 (q, J ) 276.2 Hz), 98 (q, J ) 3.97 Hz), 21.23; 19F
NMR (CDCl3) 73.0 (3F, s).
(Z)-4b (85% yield, calculated by 1H and 19F NMR of the
1
crude): Rf (1:1 hexane/ethyl acetate) 0.31; H NMR (CDCl3)

3384 J . Org. Chem., Vol. 61, No. 10, 1996
Arnone et al.
5.95 (1H, t, J ) 55 Hz), 5.28 (2H, br s), 5.12 (1H, s); 13C NMR
(CDCl3) 146.2 (t, J ) 22.5 Hz), 111.0 (t, J ) 243.8 Hz), 96.9 (t,
J ) 6.9 Hz), 20.8; 19F NMR (CDCl3) 123.1 (2F, dd, J ) 55 and
15 Hz).
35.2 Hz), 130.2, 129.6, 128.8, 128.5, 128.5, 128.4, 128.1, 124.5,
120.5 (q, J ) 278.7 Hz), 68.9, 52.7, 21.4; 19F NMR (CDCl3) 67.6
(3F, s). Anal. Calcd for C25H22F3NO3S: C, 63.41; H, 4.68; N,
2.96. Found: C, 63.65; H, 4.84; N, 2.89.
Meth od B. To a solution of enamino sulfoxide (Z)-3a (150
mg, 0.39 mmol) in DMF (1.0 mL) were added oil-free NaH (12
mg, 0.5 mmol) and, after 5 min, benzyl bromide (116 mL, 0.98
mmol) at 0 °C. The mixture was vigorously stirred for 2 h at
rt, and then the solvent was evaporated under reduced
pressure. The residue was treated with water and routinely
worked-up. The residue was purified by FC, giving pure
benzyl derivative 7a (65% yield).
(Z)-4c (85% yield): Rf (3:1 hexane/ethyl acetate) 0.20; [R]20
D
+200.3 (c 0.65, CHCl3); 1H NMR (CDCl3) 5.38 (2H, br s), 5.32
(1H, s); 13C NMR (CDCl3) 145.9 (t, J ) 27.7 Hz), 142, 140.9,
130.2, 124.9, 122.2 (t, J ) 292.3 Hz), 96.7 (t, J ) 4.9 Hz), 21.4;
19F NMR (CDCl3) 59.7 (1F, d, J ) 167 Hz), 60.9 (1F, d, J )
167 Hz).
Syn th esis of th e En ol Eth er 5d . To a solution of sulfinyl
ketone 1d (100 mg, 0.33 mmol) in DMF (1.5 mL) were added
benzyl bromide (158 L, 1.33 mmol) and K2CO3 (46 mg, 0.33
mmol). After stirring the mixture at rt for 24 h, water (2 mL)
was added and the reaction was routinely worked-up. The
residue was purified by FC (3:1 hexane/ethyl acetate), afford-
ing 39 mg of the enol ether (Z)-5d (30%).
Rea ction of P r im a r y Su lfin ylen a m in e 4a w ith Ben zyl
Ch lor ofor m a te. Syn th esis of 3a . To a solution of primary
â-sulfinyl enamine 4a (100 mg, 0.4 mmol) in dry THF (3.0 mL),
cooled at 78 °C was added 160 L of a 2.5 M solution of
n-butyllithium in hexane dropwise. After 15 min at 78 °C neat
benzyl chloroformate (68 mg, 0.4 mmol) was added. The
resulting solution was stirred at 78 °C for 5 min, quenched at
the same temperature with a saturated aqueous solution of
NH4Cl, and routinely worked-up. Purification by FC of the
crude (hexane/ethyl acetate from 3:1 to 7:3) afforded 77 mg
(50% yield) of N-Cbz â-sulfinyl enamine 3a and 49 mg (49%)
of the starting primary enamine 4a .
Rea ction of Su lfin ylen a m in es 3a ,b w ith Ben zyl Ch lo-
r ofor m a te. Syn th esis of 6a ,b. Meth od A. To a solution
of 3a (160 mg, 0.42 mmol) in dioxane (1.0 mL) were added
160 L of 50% aqueous K2CO3 and benzyl chloroformate (150
L, 1.05 mmol). The solution was stirred at rt for 2 d
(separation of KCl was observed). After evaporation of the
organic solvent the residue was diluted with water (5 mL) and
routinely worked-up. The crude was submitted to FC, and 167
mg of (Z)-6a (80% yield) was obtained. Under the same
conditions, (Z)- and (E)-3b gave very poor yields of 6b after 4
days.
Meth od B. To a solution of (Z)-3b (150 mg, 0.41 mmol) in
DMF (1.0 mL) at 0 °C are added oil-free NaH (11 mg, 0.45
mmol) and, dropwise, after 5 min (a suspension formed), a
solution of benzyl chloroformate (117 L, 0.82 mmol) in DMF
(0.5 mL). The mixture was warmed to rt in 30 min and, after
40 min, the workup and purification already described for
method A gave 107 mg of (Z)-6b (54% yield, 75% conversion).
Under the same conditions, (E)-3b gave a partial equilibration
into the (Z)-3b isomer and only traces of the expected product
after several hours.
The same A and B methods were separately performed on
both (Z)- and (E)-3b. The method A gave (Z)-7b as single
product with 64% yield (71% conversion) starting from (Z)-
3b, and 41% (62%) starting from (E)-3b. The method B gave
a mixture of (Z)- and (E)-7b (not separable by FC) with an
about 3.5:1 Z/E ratio and 94% yield starting from (Z)-3b, and
about 6:1 E/Z ratio, 73% yield (85% conversion) starting from
(E)-3b.
(Z)-7b: Rf (7:3 hexane/ethyl acetate) 0.35; [R]20 107.8 (c
D
1
0.76, CHCl3); H NMR (CDCl3) 6.61 (1H, s), 5.89 (1H, t, J )
55 Hz), 5.20 (2H, s), 4.95 (1H, d, J ) 15 Hz), 4.73 (1H, d, J )
15 Hz); 13C NMR (CDCl3) 154.7, 142.1, 139.6, 139.5, 138.7 (t,
J ) 24 Hz), 135.8, 135.5, 130.1, 129.1, 128.8, 128.6, 128.4,
128.3, 128.1, 124.6, 110.9 (t, J ) 246 Hz), 68.6, 53.3, 21.3; 19
F
NMR (CDCl3) 119.5 (2F, br signal).
1
(E)-7b: Rf 0.35; H NMR (CDCl3) 6.78 (1H, t, J ) 54 Hz),
6.08 (1H, s), 5.18 (1H, d, J ) 12 Hz), 5.10 (1H, d, J ) 12 Hz),
4.74 (1H, d, J ) 15 Hz), 4.58 (1H, d, J ) 15 Hz); 13C NMR
(CDCl3) 154.5, 142.0, 141.0, 139.1, 138.4 (t, J ) 24.3 Hz), 136,
135.4, 130.2, 128.6, 128.5, 128.38, 128.1, 127.9, 124.5, 110.3
(t, J ) 243 Hz), 68.5, 53.1, 21.4; 19F NMR (CDCl3) 112.9 (1F,
dd, J ) 56 and 307 Hz), 120.5 (1F, dd, J ) 56 and 307 Hz). 1H
NMR spectra of compounds (Z)- and (E)-7b were recorded at
318 K.
Rea ction of Su lfin ylen a m in es 3a ,b w ith Allyl Br om id e.
Syn th esis of 8a ,b. Meth od A. To a solution of enamino
sulfoxide (Z)-3b (160 mg, 0.44 mmol) in dioxane (1.2 mL) were
added 50% aqueous K2CO3 (160 L) and allyl bromide (160 L,
1.32 mmol). Then the above described method A was followed.
Purification of the crude gave (Z)-8b in 56% yield (68.5%
conversion). The same method A was performed on (Z)-3a ,
giving (Z)-8a in 76% yield.
Meth od B. To a solution of (Z)-3b (0.44 mmol) in DMF (1.0
mL) at 0 °C was added oil-free NaH (0.53 mmol). After 5 min
the suspension was treated with allyl bromide (1.32 mmol).
After 40 min at rt the reaction mixture was worked-up as
described above (method B), giving (Z)-8b: 69% (73% conver-
sion). The same method B performed on (E)-3b gave a mixture
of (E)- and (Z)-8b (about 2:1 E/Z ratio) not separable by FC in
52% yield (63% conversion).
(Z)-6a : Rf (3:1 hexane/ethyl acetate) 0.4; mp 80-82 °C (ethyl
acetate); [R]20 3.6 (c 1.03, CHCl3); 1H NMR (CDCl3) 6.92 (1H,
D
s), 5.36-5.16 (4H, br m); 13C NMR (CDCl3) 143.3, 142.8 (q, J
) 2.53 Hz), 137.9, 134.2, 130.4, 128.7, 128.6, 128.3, 125, 119.7
(q, J ) 276.7 Hz), 69.9, 21.5; 19F NMR (CDCl3) 69.4 (3F, s).
Anal. Calcd for C26H22F3NO5S: C, 60.34; H, 4.28; N, 2.71.
Found: C, 60.18; H, 4.31; N, 2.69.
(Z)-8a : Rf (3:1 hexane/ethyl acetate) 0.45; [R]20D 130.5 (c 0.5,
CHCl3); 1H NMR (CDCl3) 6.9 (1H, s), 6.1-5.9 (1H, m), 5.35
(2H, s), 5.3-5.1 (2H, m), 4.5-4 (2H, m); 13C NMR (CDCl3)
142.7, 133.6 (q, J ) 35.7 Hz), 131.3, 130.3, 128.6, 128.4, 128.1,
124.8, 120.8, 120.3 (q, J ) 278 Hz), 68.7, 52.4, 21.5; 19F NMR
(CDCl3) 68.6 (3F, br signal).
(Z)-6b: Rf (7:3 hexane/ethyl acetate) 0.35; [R]20 34.56 (c
D
1
0.65, CHCl3); H NMR (CDCl3) 6.77 (1H, s), 6.08 (1H, t, J )
(Z)-8b: Rf (65:35 hexane/ethyl acetate) 0.35; [R]20 120.35
D
55 Hz), 5.26 (4H, s); 13C NMR (CDCl3) 150.6, 142.6, 139.9 (t,
J ) 4.5 Hz), 138.6, 135.2 (t, J ) 25.3 Hz), 134.3, 130.3, 128.7,
128.6, 128.3, 124.7, 109.9 (t, J ) 246 Hz), 69.7, 21.5; 19F NMR
(CDCl3) 123.0 (d, 2F, J ) 55 Hz).
(c 0.8, CHCl3); H NMR (CDCl3) 6.69 (1H, dd, J ) 0.95 and
1
0.91 Hz), 6.09 (1H, t, J ) 55 Hz), 6.05-5.87 (1H, m), 5.4-5.1
(4H, m), 4.35-4.09 (2H, m); 13C NMR (CDCl3) 142.3, 139.1,
135.4, 132, 130.2, 128.6, 128.4, 128.1, 124.6, 120, 110.6 (t, J )
245.7 Hz), 68.5, 52.9, 21.4; 19F NMR (CDCl3) 120.5-121.5 (2F,
br signal). 1H NMR spectra were recorded at 306 K for (Z)-
8a and 308 K for (Z)-8b.
Rea ction of Su lfin ylen a m in es 3a ,b w ith Ben zyl Br o-
m id e. Syn th esis of 7a ,b. Meth od A. To a solution of
sulfinyl enamine 3a (150 mg, 0.39 mmol) in dioxane (1.0 mL)
were added 150 L of a 50% aqueous solution of K2CO3 and
then benzyl bromide (116 L, 0.98 mmol). The resulting
biphasic system was vigorously stirred at rt for 2 d (slow
separation of KBr was observed). After evaporation of the
organic solvent the residue was diluted with water and
routinely worked-up. The crude was submitted to FC, giving
pure (Z)-7a (70% yield).
1
(E)-8b: Rf 0.35; H NMR (CDCl3) 6.78 (1H, t, J ) 56 Hz),
6.38 (1H, br signal), 5.83-5.6 (1H, m), 5.34-4.98 (4H, m), 4.2-
4.0 (2H, m); 13C NMR (CDCl3) 154.0, 142.1, 139.7, 135.3, 132.1,
130.3, 128.6, 128.4, 128.2, 124.5, 119.1, 110.3 (t, J ) 243.3 Hz),
68.4, 52.8, 21.4.19F NMR (CDCl3) 112.8 (1F, dd, J ) 56 and
307 Hz), 121.2 (1F, dd, J ) 56 and 307 Hz).
Rea ction of Su lfin ylen a m in es 3a ,b w ith Meth a n ol.
Syn th esis of 9a ,b. To a solution of (Z)-3b (0.36 mmol) in
methanol (1.2 mL) was added a catalytic amount of oil-free
NaH, and the mixture was left at rt for 12 h. After evaporation
(Z)-7a : Rf (3:1 hexane/ethyl acetate) 0.45; [R]20 128.8 (c
D
1.11, CHCl3); 1H NMR (CDCl3) 6.80 (1H, s), 5.40-4.60 (4H, br
m); 13C NMR (CDCl3) 154.0, 142.4, 138.6, 135.2, 133.2 (q, J )

Optically Pure R-(Fluoroalkyl)-â-sulfinyl Enamines
J . Org. Chem., Vol. 61, No. 10, 1996 3385
of the solvent under reduced pressure, FC of the crude (7:3
hexane/ethyl acetate) gave a 87.5% overall yield of a 1.5:1.0
mixture of the methoxy derivatives 9b.
Under the same conditions (Z)-3a gave a 81% overall yield
of about 1:1 mixture of the methoxy derivatives 9a not
separable by FC.
on (Z)-3a , giving a 1:1 mixture of derivatives 11a (80% overall
yield) after shorter reaction time (24 h).
11a (first diastereoisomer): Rf (3:1 hexane/ethyl acetate)
1
0.45; [R]20 107.2 (c 0.56, CHCl3); H NMR (CDCl3) 7.23 (1H,
D
br s), 5.48 (1H, d, J ) 14 Hz), 5.24 (1H, d, J ) 12 Hz), 5.16
(1H, d, J ) 12 Hz), 5.00 (1H, d, J ) 14 Hz), 4.04 (1H, d, J )
14 Hz), 2.82 (1H, d, J ) 14 Hz); 13C NMR (CDCl3) 154.4, 142.7,
138.9, 135.5, 130.4, 128.7, 128.5, 128.2, 124 (q, J ) 288.4 Hz),
123.9, 75, 67.8, 60.5 (q, J ) 30.14 Hz), 58.1, 21.5; 19F NMR
(CDCl3) 76.9 (3F, s).
9a : Rf (3:1 hexane/ethyl acetate) 0.30: 1H NMR (CDCl3) of
the mixture 6.16 and 6.13 (1H, br s), 5.14 and 5.16 (2H, s),
[3.67 (1H, d, J ) 14 Hz), 3.35 (1H, d, J ) 14 Hz)] and 3.59
(2H, s), 3.52 and 3.50 (3H, s); 19F NMR (CDCl3) of the mixture
79.45 and 79.6 (3F, s). Anal. Calcd for C19H20F3NO4S: C,
54.93; H, 4.85; N, 3.37. Found: C, 54.26; H, 4.88; N, 2.93.
9b (major diastereoisomer): Rf (7:3 hexane/ethyl acetate)
11a (second diastereoisomer): Rf (3:1 hexane/ethyl acetate)
1
0.40; [R]20 122.3 (c 0.51, CHCl3); H NMR (CDCl3) 6.54 (1H,
D
br s), 5.58 (1H, d, J ) 13 Hz), 5.49 (1H, d, J ) 13 Hz), 5.17
(1H, d, J ) 12 Hz), 5.10 (1H, d, J ) 12 Hz), 3.37 (1H, d, J )
14 Hz), 3.26 (1H, d, J ) 14 Hz); 19F NMR (CDCl3) 76.4 (3F, s).
11b (major diastereoisomer): Rf (7:3 hexane/ethyl acetate)
0.41; oily compound; [R]20 235.9 (c 0.59, CHCl3); 1H NMR
D
(CDCl3) 6.96 (1H, dd, J ) 57.5 and 54 Hz), 5.13 (2H, s), 3.58
(3H, s), 3.14 (1H, d, J ) 14 Hz), 3.06 (1H, d, J ) 14 Hz); 13C
NMR (CDCl3) 155, 142.5, 139.7, 135.7, 130.3, 128.6, 128.3,
128.1, 123.9, 110.5 (dd, J ) 247.4 Hz), 85.8 (t, J ) 25.2 Hz),
67.2, 58.2, 52.3, 21.5; 19F NMR (CDCl3) 135.0 (1F, dd, J ) 281
and 54 Hz), 135.4 (1F, dd, J ) 281 and 57.5 Hz).
1
0.36; H NMR (CDCl3) 7.17 (1H, br s), 6.36 (1H, t, J ) 55.4
Hz), 5.3-5.0 (4H, m), 3.52 (1H, J ) 14 Hz), 2.87 (1H, J ) 14
Hz); 13C NMR (CDCl3) 155, 142.6, 139.2, 135.5, 130.3, 128.6,
128.4, 128.0, 123.8, 113.4 (t, J ) 252 Hz), 74, 67.6, 59.3 (t, J
) 23 Hz), 57.4, 21.4; 19F NMR (CDCl3) 128.8 (2F, d, J ) 55.4
Hz); MS (EI, 70 eV) m/ z (%) 426 (M+, 18), 319 (20), 139 (16),
91 (100).
9b (minor diastereoisomer): Rf 0.35; oily compound; [R]20
D
1
122.5 (c 0.22, CHCl3); H NMR (CDCl3) 6.72 (1H, br s), 6.59
(1H, t, J ) 55.6 Hz), 5.16 (1H, J ) 12.2 Hz), 5.08 (1H, J )
12.2 Hz), 3.43 (1H, J ) 14 Hz), 3.32 (3H, s), 3.02 (1H, J ) 14
Hz); 13C NMR (CDCl3) 154.2, 142.3, 140.2, 135.7, 130.3, 128.6,
128.4, 128.1, 123.8, 113.5 (t, J ) 250.5 Hz), 85.5 (t, J ) 24.4
Hz) 67.2, 56.9, 50.0, 21.5; 19F NMR (CDCl3) 132.9 (1F, dd, J )
281 and 55.6 Hz), 131.1 (1F, dd, J ) 281 and 55.6 Hz).
Rea ction of Su lfin ylen a m in es 3a ,b w ith Am m on ia .
Syn th esis of 10a ,b. To a solution of (Z)-3b (140 mg, 0.38
mmol) in THF (1 mL) was added an excess of 30% aqueous
solution of ammonia (two drops). The solution was left at rt.
After 15 min the solvent was removed under reduced pressure,
and the residue was purified by FC (3:2 hexane/ethyl acetate),
giving 134 mg of an about 1:1 mixture of the diastereoisomeric
aminal derivatives 10b (92% overall yield) not separable by
FC.
11b (minor diastereoisomer): Rf 0.36; 1H NMR (CDCl3) 6.72
(1H, br s), 6.71 (1H, t, J ) 55.4 Hz), 5.3-5.0 (4H, m), 3.42
(1H, d, J ) 14 Hz), 3.14 (1H, d, J ) 14 Hz); 19F NMR (CDCl3)
131.6 (1F, dd, J ) 288 and 55.4 Hz), 133.1 (1F, dd, J ) 288
and 55.4 Hz).
Rea ction of Su lfin ylen a m in es 3a ,b w ith Th iop h en ol.
Syn th esis of 12 a n d 13. To a solution of (Z)-3b (145 mg,
0.397 mmol) in THF (1.2 mL) were added thiophenol (163 mL,
1.59 mmol) and a catalytic amount of oil-free NaH. The
mixture was kept at rt for 16 h, then solvent was evaporated
under reduced pressure. The crude was purified by FC (from
8:2 to 65:35 hexane/ethyl acetate) giving 132 mg of an about
2:1 mixture (70% overall yield) of thiophenyl derivatives 12.
Under the same conditions (E)-3b gave a 63% overall yield
of about 2.5:1 ratio of the same mixture of derivatives 12, while
(Z)-3a , after 1 h, gave a 70% yield of vinyl sulfide 13 as the
main product.
Under the same conditions (Z)-3a gave a 90% overall yield
of a 1:1 mixture of the aminals 10a .
10a (first diastereoisomer): Rf (7:3 hexane/ethyl acetate)
1
0.35; [R]20 117.6 (c 0.63, CHCl3); H NMR (CDCl3) 6.17 (1H,
12 (major diastereoisomer): Rf (7:3 hexane/ethyl acetate)
D
1
0.62; [R]20 166.1 (c 0.74, CHCl3); H NMR (CDCl3) 7.15 (1H,
br s), 5.12 (1H, d, J ) 12 Hz), 5.18 (1H, d, J ) 12 Hz), 3.73
(1H, J ) 13 Hz), 3.03 (1H, J ) 13 Hz), 2.87 (2H, br s); 13C
NMR (CDCl3) 154.2, 142.3, 139.4, 135.7, 130.2, 128.6, 128.4,
128.2, 123.9 (q, J ) 287.3 Hz), 123.9, 70.7 (q, J ) 31.2 Hz),
67.2, 59.6, 21.5; 19F NMR (CDCl3) 84.1 (3F, s).
D
br s), 6.96 (1H, t, J ) 56 Hz), 4.96 (1H, d, J ) 10 Hz), 4.86
(1H, d, J ) 10 Hz), 3.28 (1H, d, J ) 14 Hz), 3.19 (1H, d, J )
14 Hz); 13C NMR (CDCl3) 154.1, 142.3, 139.5, 138.5, 135.5,
130.2, 130.1, 128.9, 128.5, 128.3, 128.2, 123.9, 113.1 (dd, J )
256 Hz), 69.6 (dd, J ) 25.6 Hz), 67.2, 58.6 (d, J ) 4.9 Hz),
21.4; 19F NMR (CDCl3) 125.5 (1F, dd, J ) 290 and 65 Hz),
132.9 (1F, dd, J ) 290 and 65 Hz), MS (EI, 70 eV) m/ z (%)
335 (M+, 8), 200 (5), 149 (16), 91 (100).
10a (second diastereoisomer): Rf 0.30: [R]20 159.6 (c 0.68,
D
1
CHCl3); H NMR (CDCl3) 6.48 (1H, br s), 5.16 (1H, d, J ) 12
Hz), 5.10 (1H, d, J ) 12 Hz), 3.17 (1H, J ) 14 Hz), 3.06 (2H,
br s), 2.97 (1H, J ) 14 Hz); 19F NMR (CDCl3) 82.75 (3F, s).
10b: Rf 0.35: 1H NMR (CDCl3) of the mixture 6.98 and 6.32
(1H, br s), 6.38 and 6.14 (1H, t, J ) 56 Hz), 5.11 (2H, s) and
5.13 (1H, d, J ) 12 Hz), 5.05 (1H, d, J ) 12 Hz), 3.48 (1H, d,
J ) 13.8 Hz), 3.0 (1H, d, J ) 13.8 Hz), and 3.14 (1H, d, J ) 14
Hz), 2.92 (1H, d, J ) 14 Hz), 2.64 (only one signal, 2H, br s);
13C NMR (CDCl3) of the mixture 155.4 and 154.9, 142.3 and
142.0, 139.9 and 139.7, 135.8 and 135.7, 130.2 and 130.1, 128.5
and 128.5, 128.3 and 128.2, 128.0 and 128.0, 123.9 and 123.9,
113.3 (t, J ) 249.4 Hz) and 112.9 (dd, J ) 246 Hz), 69.8 (t, J
) 22.4 Hz) and 69.7 (dd, J ) 22.6 Hz), 67.0, 60.4 and 59.9,
21.4; 19F NMR (CDCl3) of the mixture [136.6 (1F, dd, J ) 279
and 56 Hz), 134.3 (1F, dd, J ) 279 and 56 Hz)] and [136.6
(1F, dd, J ) 275 and 56 Hz), 131.1 (1F, dd, J ) 275 and 56
Hz)].
12 (minor diastereoisomer): Rf (7:3 hexane/ethyl acetate)
1
0.53; [R]20 123 (c 0.41, CHCl3); H NMR (CDCl3) 6.91 (1H, t,
D
J ) 56 Hz), 6.54 (1H, br s), 5.20 (1H, d, J ) 12 Hz), 5.00 (1H,
d, J ) 12 Hz), 3.47 (1H, d, J ) 14 Hz), 3.03 (1H, d, J ) 14 Hz);
13C NMR (CDCl3) 153.9, 142.4, 138.0, 135.8, 131.4, 130.4,
130.3, 129.6, 129.2, 128.6, 128.4, 123.8, 114.3 (dd, J ) 255.4
Hz), 69.3 (dd, J ) 24.69 Hz), 67.2, 61.0, 21.5; 19F NMR (CDCl3)
123.3 (1F, dd, J ) 290 and 65 Hz), 128.4 (1F, dd, J ) 290 and
65 Hz). Anal. Calcd for C24H23F2NO3S2: C, 60.61; H, 4.87;
N, 2.95. Found: C, 60.62; H, 4.87; N, 2.89.
13: Rf (9:1 hexane/ethyl acetate) 0.35; 1H NMR (CDCl3) 7.08
(1H, s), 5.98 (1H, br s), 5.23 (2H, s); 13C NMR (CDCl3) 153.1,
135.6, 133.8, 132.9, 131.3, 129.5, 128.6, 128.5, 128.4, 128.3,
121.0 (q, J ) 272.6 Hz), 118.7 (q, J ) 35.21 Hz), 68; 19F NMR
(CDCl3) 70.3 (s, 3F). Anal. Calcd for C17H14F3NO2S: C, 57.78;
H, 3.99; N, 3.96. Found: C, 57.35; H, 4.28; N, 3.57.
Red u ction s w ith Na BH4 a n d Na BD4. Gen er a l P r oce-
d u r e. To a solution of trifluoro N-Cbz-â-sulfinyl enamine 3a
(77 mg, 0.2 mmol) in a THF/H2O ) 4:1 mixture, cooled at 0
°C, was added NaBH4 (2 equiv) portionwise and the mixture
was kept under stirring for 30 min, then heated to rt and
stirred for 3 h. The reaction was quenched with 1 N HCl and
routinely worked up. FC of the crude (7:3 hexane/ethyl
acetate) afforded 20 mg (27%) of (2S,RS)-14 and 32 mg (41%)
of (2R,RS)-14. When methanol was used as solvent an about
Reaction of Su lfin ylen am in es 3a,b with Nitr om eth an e.
Syn th esis of 11a ,b. To a solution of (Z)-3b (125 mg, 0.34
mmol) in nitromethane (1 mL) was added a catalytic amount
of oil-free NaH, and the mixture was kept at rt for 36 h. After
evaporation of the solvent under reduced pressure, the residue
was purified by FC (from 7:3 to 3:2 hexane/ethyl acetate),
giving 135 mg of an about 2:1 mixture of the derivatives 11b
not separable by FC (93% overall yield).
The same reaction was performed on (E)-3b giving, after
longer reaction time (48 h), about 2.7:1 ratio of the same
mixture of derivatives 11b (44% yield, 68% conversion), and

3386 J . Org. Chem., Vol. 61, No. 10, 1996
Arnone et al.
equimolar mixture of the diastereoisomeric N,O-disubstituted
hemiaminals 9a was recovered in almost quantitative yield
after FC.
(2S,RS)-15c: Rf (2:3 hexane/ethyl acetate, 1% NEt3) 0.40;
[R]20D 236.9 (c 0.68, CHCl3); mp 133-136 °C (AcOEt); 1H NMR
(CDCl3) 3.88 (1H, m), 3.07 (1H, dd, J ) 13.2 and 2.5 Hz), 2.67
(1H, dd, J ) 13.2 and 11.5 Hz), 2.43 (3H, s), 1.80 (2H, br s);
13C NMR (CDCl3) 142.1, 140.2, 130.7 (t, J ) 296.7 Hz), 130.2,
124.0, 59.0 (d, J ) 1.16 Hz), 55.2 (t, J ) 26.4 Hz), 21.4; 19F
NMR (CDCl3) 63.75 (1F, br d, J ) 165 Hz), 64.35 (1F, br d, J
) 165 Hz); Anal. Calcd for C10H12F2ClNOS: C, 44.86; H, 4.52;
N, 5.23. Found: C, 45.71; H, 4.50; N, 5.24.
(2R,RS)-15c: Rf (2:3 hexane/ethyl acetate, 1% NEt3) 0.35;
we were not able to obtain this product sufficiently pure for a
polarimetric analysis; 1H NMR (CDCl3) 3.63 (1H, m), 3.04 (2H,
m), 2.43 (3H, s), 1.77 (2H, br signal); 19F NMR (CDCl3) 63.8
(1F, br d, J ) 128 Hz), 65.1 (1F, br d, J ) 128 Hz).
The same procedure was applied for the reduction of the
primary trifluoro enamine 4a (100 mg, 0.4 mmol); in this case
the reaction was quenched with a saturated aqueous NH4Cl
solution, giving after FC (2:3 hexane/ethyl acetate 1% NEt3),
the unprotected diastereoisomeric â-sulfinyl amines 15a .
When a THF/H2O ) 4:1 mixture was used as solvent 40 mg
(40%) of (2S,RS)-15a and 40 mg (40%) of (2R,RS)-15a were
obtained. When dry THF was used as solvent, 66 mg (66%)
of (2S,RS)-15a and 17 mg (17%) of (2R,RS)-15a were obtained.
When NaBD4 was used as reducing agent with the primary
trifluoro enamine 4a , the reaction was performed in dry THF,
strictly following the above described procedure: the dia-
steroisomeric (2-D)-1,1,1-trifluoro-3-sulfinyl amines 15a were
recovered in a (2S,RS):(2R,RS) ) 4:1 ratio, with a substitution
degree >95%.
Deoxygen a t ion of (2S,RS)-15a : Syn t h esis of (S)-16.
Neat trimethylsilyl chloride (0.30 mL, 2.38 mmol) was added
to a stirred, cooled (0 °C) solution of sulfoxide (2S,RS)-15a (200
mg, 0.80 mmol) in acetonitrile (6 mL). After 5 min at 0 °C,
NaI (0.59 g, 3.95 mmol) was added portionwise. In 5 min at
the same temperature the reaction mixture became dark red.
The reaction was quenched at 0 °C with an excess of saturated
aqueous Na2SO3. A routine workup afforded a residue, which,
upon FC (9:1 hexane/ethyl acetate) gave 138 mg (74%) of the
â-thio amine (S)-16.
The preparation of the perdeuterated derivative (2,3,3-D3)-
15a was accomplished by repeated addition and evaporation
at reduced pressure (60 °C) of D2O to the primary â-sulfinyl
enamines 4a and subsequent treatment with NaBD4 in dry
THF according to the previously reported procedure. Gener-
ally, after five additions and evaporations of D2O the substitu-
tion degree in position 3 of the products 15a was found to be
>95%, while a lower 3-deuteration degree was obtained with
a less intensive exchange with D2O.
(S)-16: Rf (9:1 hexane/ethyl acetate) 0.45; [R]20 97.36 (c
D
0.65, CHCl3); 1H NMR (CDCl3) 3.31 (1H, dd, J ) 14 and 3 Hz),
3.28 (1H, ddd, J ) 10.5, 7 and 3 Hz), 2.77 (1H, dd, J ) 14 and
10.5 Hz), 2.33 (3H, s), 1.61 (2H, br signal); 19F NMR (CDCl3)
78.84 (3F, d, J ) 7 Hz). Anal. Calcd for C10H12F3NS: C, 51.05;
H, 5.14; N, 5.96. Found: C, 50.97; H, 5.12; N, 5.91.
(2S,RS)-14: Rf (7:3 hexane/ethyl acetate) 0.30; [R]20 159.8
D
(c 0.92, CHCl3); mp 155-157 °C (AcOEt); 1H NMR (CDCl3)
6.13 (1H, br d, J ) 10 Hz), 5.15 (2H, s), 4.78 (1H, m), 3.04
(2H, m), 2.40 (3H, s); 13C NMR (CDCl3) 155.4, 142.4, 139.5,
135.7, 130.3, 128.6, 128.3, 128.2, 124.4 (q, J ) 282.9 Hz), 123.9,
67.7, 55.3, 49.8 (q, J )32.2 Hz), 21.4; 19F NMR (CDCl3) 76.15
(3F, d, J ) 7 Hz). Anal. Calcd for C18H18F3NO3S: C, 56.10;
H, 4.71; N, 3.63. Found: C, 56.14; H, 4.74; N, 3.59.
Syn th esis of (R)-17. To a stirred solution of the thio amine
(S)-16 (134 mg, 0.57 mmol) in absolute ethanol (5.0 mL) was
added Raney Ni (ca. 0.5 g), and the slurry was vigorously
stirred overnight under hydrogen. Raney Ni was removed by
filtration on a Celite pad, and a 1 N HCl solution (1.2 mL)
was added to the resulting solution. The solvent was removed
under reduced pressure, affording 71 mg (86%) of the hydro-
chloride (R)-17 as a white powder.
(2R,RS)-14: Rf (7:3 hexane/ethyl acetate) 0.25; we were not
able to obtain this product sufficiently pure for a polarimetric
analysis; 1H NMR (CDCl3) 5.52 (1H, br d, J ) 10 Hz), 5.12
(2H, s), 4.66 (1H, m), 3.15 (2H, m), 2.38 (3H, s); 19F NMR
(CDCl3) 77.55 (3F, d, J ) 7 Hz).
(R)-17: [R]20 2.29 (c 1.06, CH3OH), (in lit.37a the (S)
D
enantiomer is reported to have a negative value of [R]20D); mp
> 195 °C dec; 1H NMR (MeOD) 4.22 (1H, m), 1.49 (3H, d, J )
7 Hz); 13C NMR (D2O) 126.6 (q, J ) 279.3 Hz), 51.3 (q, J )
32.9 Hz), 14.1; 19F NMR (MeOD) 75.3 (3F, d, J ) 7 Hz).
P u m m er er Rea ction on 14: Syn th esis of (2-H)- a n d (2-
D)-N-Cbz-3,3,3-Tr iflu or oa la n in ol (R)-18. All the reactions
used for the synthesis of N-Cbz-3,3,3-trifluoroalaninol 18,
described below, were performed, without any modification,
also on the corresponding deuterium substituted compound
(2,3,3-D3)-14. The synthesis of the latter was performed as
described above for perdeuterated 15a . Loss of deuterium was
never detected during the above mentioned procedures.
To a stirred solution of (2S,RS)-14 (0.52 g, 1.4 mmol) and
sym-collidine (0.54 mL, 4.1 mmol) in acetonitrile (10 mL) under
nitrogen at 0 °C was added TFAA (0.96 mL, 6.8 mmol) was
added dropwise. The reaction mixture was stirred at 0 °C and
after 10 min 0.5 mL of water was added, followed by solid
K2CO3 until pH 7 was reached. The reaction was warmed up
to rt and after 15 min an excess of NaBH4 (about 3 equiv) was
added portionwise. After 5 min the reaction was quenched
with a saturated aqueous NH4Cl solution and extracted with
AcOEt. The collected organic layers were treated twice with
a 1 N HCl solution (5 mL) to remove the excess of sym-collidine
and then washed with aqueous NaHCO3. After a routine
workup the residue was submitted to FC (65:35 hexane/ethyl
acetate), affording 0.31 g (86%) of (R)-18 as a white solid.
(R)-18: Rf (7:3 hexane/ethyl acetate) 0.25; [R]20D 10.9 (c 0.91,
CHCl3); 1H NMR (CDCl3) 5.54 (1H, br d, J ) 9.5 Hz), 5.14
(2H, s), 4.37 (1H, m), 3.94 (1H, br dd, J ) 12.0 and 4.1 Hz),
(2S,RS)-15a :40 Rf (2:3 hexane/ethyl acetate, 1% NEt3) 0.35;
[R]20 263.8 (c 0.23, CHCl3); mp 126-127 °C (iPr2O); 1H NMR
D
(CDCl3) 3.81 (1H, ddd, J ) 11.5, 7.1 and 2.6 Hz), 2.98 (1H, dd,
J ) 13.1 and 2.6 Hz), 2.71 (1H, dd, J ) 13.1 and 11.5 Hz),
2.43 (3H, s), 1.73 (2H, br s); 13C NMR (CDCl3) 142.1, 140.0,
130.2, 125.7 (q, J ) 281.4 Hz), 123.9, 58.0, 49.7 (q, J ) 30.8
Hz), 21.4; 19F NMR (CDCl3) 79.38 (3F, d, J ) 7.1 Hz). Anal.
Calcd for C10H12F3NOS: C, 47.80; H, 4.81; N, 5.57. Found:
C, 47.67; H, 4.80; N, 5.53.
(2R,RS)-15a : Rf (2:3 hexane/ethyl acetate 1% NEt3) 0.30; 1H
NMR (CDCl3) 3.67 (1H, m), 3.07-2.95 (2H, m), 2.43 (3H, s),
1.72 (2H, br signal); 19F NMR (CDCl3) 79.9 (3F, d, J ) 7.2 Hz).
Red u ction s w ith Selectr id e. Gen er a l P r oced u r e. To
a solution of the primary R-(trifluoromethyl)-â-sulfinyl en-
amine 4a (250 mg, 1.0 mmol) in dry CH2Cl2 cooled at -20 °C
was added 1 mL of a 1 M THF solution of L- or K-Selectride
(1 equiv). After 5 min at -20 °C the reaction was quenched
with a small excess of ethanol. The mixture was heated to rt,
and the solvent was carefully removed. The procedure was
repeated twice. The reaction was finally quenched with
saturated aqueous NH4Cl and routinely worked up. FC gave
150 mg (60%) of the â-sulfinyl amine (2S,RS)-15a and 37 mg
(15%) of about an equimolar mixture of the same product
(2S,RS)-15a with (2R,RS)-15a . The same procedure was ap-
plied on the primary R-(difluorochloromethyl)-â-sulfinyl en-
amine 4c (268 mg, 1.0 mmol), and after FC were obtained 170
mg (63%) of â-sulfinyl amine (2S,RS)-15c and 30 mg (11%) of
an about equimolar mixture of the same product (2S,RS)-15c
and of (2R,RS)-15c.
3.84 (1H, br dd, J ) 12.0 and 4.3 Hz), 2.12 (1H, br signal); 19
F
NMR (CDCl3) 75.18 (3F, d, J ) 9 Hz); MS (EI, 70 ev) m/z (%)
263 (M+, 15), 108 (90), 91 (100).
(40) The authors have deposited atomic coordinates for compound
(2S,RS)-15a with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
3,3,3-Tr iflu or oa la n in ol h yd r och lor id e (R)-19. To a
stirred solution of (R)-18 (132 mg, 0.5 mmol) in absolute
ethanol (4.0 mL), was added Raney Ni (ca. 0.4 g) and the slurry
was vigorously stirred overnight at rt under hydrogen. Raney

Optically Pure R-(Fluoroalkyl)-â-sulfinyl Enamines
J . Org. Chem., Vol. 61, No. 10, 1996 3387
Ni was removed by filtration through a Celite pad, and a 1 N
HCl solution (1.2 mL) was added to the resulting solution. The
solvent was removed under reduced pressure affording 76 mg
(93%) of the hydrochloride (R)-19 as a white powder.
(R)-19: [R]20D 7.86 (c 0.70, EtOH); mp >145 °C dec; 1H NMR
(CD3OD) 4.22-4.08 (1H, m), 4.00-3.86 (2H, m). 13C NMR
(CD3COCD3) 125.9 (q, J ) 279.5 Hz), 58.8 (d, J ) 2.18 Hz),
55.7 (q, J ) 30.3 Hz). 19F NMR (CD3OD) 71.3 (3F, d, J )
8 Hz).
(R)-23: Rf (8:2 hexane/ethyl acetate) 0.85; 1H NMR (CDCl3)
5.41 (1H, m), 5.35 and 5.31 (2H, br d, J ) 12.2 Hz), 4.79 (1H,
br dd, J ) 11.6 and 9.3 Hz), 4.60 (1H, br dd, J ) 11.6 and 3.9
Hz), 2.31 (3H, br s); 19F NMR (CDCl3) 72.11 (3F, br signal)
and 75.94 (3H, br s). A partial hydrolysis to (R)-24 (ca. 10%)
was observed during the FC.
Syn th esis of Su lfen a m id o Alcoh ol 24. The above de-
scribed procedure of the Pummerer reaction performed on
(2S,RS)-14 is followed to the point where solid K2CO3 was
added. To the reaction mixture was added H2O (5 mL) and
then routinely worked-up. The residue was submitted to FC
(3:1 hexane/ethyl acetate), giving (R)-24 in 90% yield.
(R)-24: Rf (4:1 hexane/ethyl acetate) 0.40; [R]20D 34.4 (c 0.56,
Syn th esis of N-Cbz-3,3,3-Tr iflu or oa la n in e (R)-20. To
a solution of N-Cbz-amino alcohol (R)-18 (263 mg, 1.0 mmol)
in 5.0 mL of a 3:2 acetone/H2O mixture was added solid NaIO4
(0.34 g, 1.6 mmol), followed by RuO2‚xH2O (30 mg, 0.22 mmol).
The mixture was stirred at rt for 1 h and then quenched by
addition of 5 mL of i-PrOH. The suspension was filtered
through a Celite pad, and the filtrate was concentrated under
reduced pressure. The crude was dissolved in ethyl acetate
(5 mL) and extracted three times with 5 mL of a 5% aqueous
NaHCO3 solution. The collected aqueous phases were treated
with 1 N HCl until an acidic pH was reached. The milky
mixture was then extracted with ethyl acetate until it became
clear. The residue was purified by FC (2:3 hexane/ethyl
acetate), affording 180 mg (65%) of (R)-20, as a white solid.
1
CHCl3); H NMR (CD3COCD3) 5.28 (2H, br s), 5.16 (1H, ddq,
J ) 8.7, 8.5 and 4.6 Hz), 4.33 (1H, br dd, J ) 5.8 and 5.2 Hz),
4.13 (1H, br ddd, J ) 11.6, 8.7 and 5.8 Hz), 4.00 (1H, ddd, J )
11.6, 5.2 and 4.6 Hz), 2.3 (3H, br s); 13C NMR (CDCl3) 158.2,
132.8, 135.2, 133.6, 130.1, 128.6, 128.5, 128.2, 128.2, 124.0 (q,
J ) 283.5 Hz), 69.7 (t, J ) 149 Hz), 62.0 (dq, J ) 142 and 29
Hz), 57.9 (t, J ) 145.5 Hz), 21.2 (q, J ) 126.5 Hz); 19F NMR
(CD3COCD3) 67.47 (3F, br d, J ) 8.5 Hz); MS (EI, 70 eV) m/ z
(%) 385 (M+, 100), 341 (20), 250 (40), 123 (90), 91 (100).
Syn th esis of Acetyl Der iva tive (25) of Su lfen a m id o
Alcoh ol 24. To a THF (0.5 mL) solution of the sulfenamido
alcohol (R)-24 (38 mg, 0.1 mmol) were added neat acetic
anhydride (22 µL, 0.2 mmol) and triethylamine (28 µL, 0.2
mmol) at rt. After 10 h at the same temperature the solvent
was removed at reduced pressure. FC (4:1 hexane/ethyl
acetate) of the crude afforded 38 mg (90%) of the acetyl
sulfenamide (R)-25.
(R)-25: Rf (4:1 hexane/ethyl acetate) 0.50; 1H NMR (CDCl3)
5.32 (2H, br s), 5.28 (1H, m), 4.54 (1H, br dd, J ) 11.9 and 9.6
Hz), 4.39 (1H, br dd, J ) 11.9 and 4.2 Hz), 2.32 (3H, br s), 1.8
(3H, br signal); 13C NMR (CDCl3) 170.0, 157.8, 138.5, 135.3,
133.4, 129.7, 128.6, 128.5, 128.3, 128.2 (q, J ) 281.2 Hz), 128.2,
69.7, 58.9 (q, J ) 30 Hz), 58.8, 21.1, 20.3; 19F NMR (CDCl3)
72.46 (3F, br signal); MS (EI, 70 eV) m/ z (%) 427 (M+, 65),
383 (25), 232 (70), 91 (100).
(R)-20: [R]20 -6.98 (c 0.83, MeOH); mp 103-105 °C
D
(AcOEt); 1H NMR (CD3OD) 5.16 (2H, s), 4.99 (1H, q, J ) 8
Hz); 19F NMR(CD3OD) 72.7 (d, J ) 8 Hz).
Syn th esis of N-Cbz-Meth yl Ester 21 of 3,3,3-Tr iflu or o-
a la n in e 20. The crude reaction mixture of the above described
RuO2‚xH2O-catalyzed oxidation was dissolved in ether and
treated at 0 °C with a freshly prepared ethereal diazomethane
solution. The resulting solution was kept 5 min at 0 °C and
then concentrated under reduced pressure. The residue was
purified by FC (85:15 hexane/ethyl acetate) giving the pure
methyl ester (R)-21 in 65% yield, starting from the amino
alcohol (R)-18 (quantitative yield was obtained in the esteri-
fication step).29
(R)-21: [R]20D 8.00 (c 0.52, CHCl3); mp 101-103 °C (AcOEt);
1H NMR (CDCl3) 5.63 (1H, br d, J ) 7 Hz), 5.16 (2H, s), 5.06
(1H, m), 3.87 (3H, s); 19F NMR (CDCl3) 74.2 (d, J ) 7 Hz); MS
(EI, 70 ev) m/ z (%) 291 (M+, 8), 108 (90), 91 (100).
Ack n ow led gm en t. Dr. Matteo Zanda and Dr. Mar-
cello Crucianelli are grateful to the Politecnico di Milano
and Universita` di L’Aquila for a scholarship. The
authors gratefully acknowledge Consiglio Nazionale
delle Ricerche of Italy for financial support.
Syn th esis of 3,3,3-Tr iflu or oa la n in e (R)-22. To a stirred
solution of N-Cbz-3,3,3-trifluoroalanine (R)-20 (75 mg, 0.27
mmol) in absolute ethanol (4.0 mL) was added about 30 mg of
Pd(OH)2 (Pd 20%), and the slurry was vigorously stirred for 1
h at rt under hydrogen. Pd(OH)2 was removed by filtration
on a Celite pad, and the solvent was evaporated under reduced
pressure affording 25 mg (64%) of 3,3,3-trifluoroalanine (R)-
22 as a white powder.
Su p p or t in g In for m a t ion Ava ila b le: Crystal data and
ORTEP drawing of (2S,RS)-15a ; copies of the following spec-
(R)-22: [R]20D 15.42 (c 0.78, MeOH), (lit.38 value for [R]20D (c
0.76, MeOH) of enantioenriched (R)-22 (ee 62%) has been
reported ) +6.8); mp 205-207 °C (sublimate: lit.29 sublima-
1
tra: 1H NMR of compound (R)-18, H and 19F NMR of (R)-20,
13C NMR of (R)-22, 1H and 13C NMR of (R)-24, (R)-25;
reductions of sulfinyl enamines 3a , 4a ,c by some hydride
reducing agents are discussed and the results are reported in
Table 2; selected IR characteristic bands of several compounds
are collected in Table 3 (15 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
1
tion T > 205 °C) (EtOH); H NMR (D2O) 4.32 (1H, q, J ) 9.0
Hz); 13C NMR (D2O) 164.7, 122.1 (q, J ) 280 Hz), 54.9 (q, J )
30 Hz); 19F NMR (D2O) 69.1 (3F, d, J ) 9.0 Hz).
Syn th esis of Tr iflu or oa ceta te Su lfen a m id e 23. The
above described procedure of the Pummerer reaction per-
formed on (2S,RS)-14 is followed to the point where TFAA was
added. After 5 min the solvent was removed at reduced
pressure and the crude submitted to FC (hexane/ethyl acetate
9:1), affording (R)-23 as a yellowish oil.
J O952097R