The 'non-oxidative' Pummerer reaction: Conclusive evidence for S(N)2- type stereoselectivity, mechanistic insight, and synthesis of enantiopure L- α-trifluoromethylthreoninate and D-α-trifluoromethyl-allo-threoninate

Article abstract of DOI:10.1021/jo991534p

Enantiopure methyl D-α-trifluoromethyl-allo-threoninate 18 and L-α- trifluoromethylthreoninate 19 were synthesized using (R)-ethyl p- tolylsulfoxide as chiral α-hydroxyethyl anion equivalent. The key step was the S(N)2-type replacement of the sulfinyl auxiliary with a hydroxy group, via trifluoroacetic anhydride promoted 'non-oxidative' Pummerer reaction (NOPR) of the diastereomeric intermediate β-sulfinyl amines 14 and 15, obtained by condensation of (R)-ethyl p-tolylsulfoxide 13 with the N-Cbz imine of methyl trifluoropyruvate 12. The conclusive evidence for S(N)2-type stereoselectivity of the NOPR was achieved by X-ray diffraction of both the starting diastereomer 14 and the p-bromobenzoate 25, obtained from the threoninate 19. NMR monitoring of the NOPR performed on 15 allowed the detection of a transient intermediate, which was identified as the four membered cyclic σ-sulfurane 27. This intermediate spontaneously rearranged (40 min, rt) into the corresponding sulfenamide 17, probably via an intramolecular displacement of the sulfinyl by a trifluoroacetoxy group, with inversion of configuration at the carbon stereocenter. The same process occurred for the diastereomeric β-sulfinyl amine 14, but the sulfenamide 16 was formed at very fast rate, thus precluding NMR detection of the corresponding σ-sulfurane intermediate 26. One-pot treatment of the diastereomeric sulfenamides 16 and 17 with NaBH₄ afforded very good yields of the corresponding threoninates 18 and 19.

Full text of DOI:10.1021/jo991534p

J . Org. Chem. 2000, 65, 2965-2971
2965
Th e “Non -Oxid a tive” P u m m er er Rea ction : Con clu sive Evid en ce
for SN2-Typ e Ster eoselectivity, Mech a n istic In sigh t, a n d Syn th esis
of En a n tiop u r e L-r-Tr iflu or om eth ylth r eon in a te a n d
D-r-Tr iflu or om eth yl-a llo-th r eon in a te1
Marcello Crucianelli,† Pierfrancesco Bravo,‡ Alberto Arnone,‡ Eleonora Corradi,†
Stefano V. Meille,† and Matteo Zanda*,†
Dipartimento di Chimica del Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy,
and CNR - CSSON, via Mancinelli 7, I-20131 Milano, Italy
Received September 30, 1999
Enantiopure methyl D-R-trifluoromethyl-allo-threoninate 18 and L-R-trifluoromethylthreoninate 19
were synthesized using (R)-ethyl p-tolylsulfoxide as chiral R-hydroxyethyl anion equivalent. The
key step was the SN2-type replacement of the sulfinyl auxiliary with a hydroxy group, via
trifluoroacetic anhydride promoted “non-oxidative” Pummerer reaction (NOPR) of the diastereomeric
intermediate â-sulfinyl amines 14 and 15, obtained by condensation of (R)-ethyl p-tolylsulfoxide
13 with the N-Cbz imine of methyl trifluoropyruvate 12. The conclusive evidence for SN2-type
stereoselectivity of the NOPR was achieved by X-ray diffraction of both the starting diastereomer
14 and the p-bromobenzoate 25, obtained from the threoninate 19. NMR monitoring of the NOPR
performed on 15 allowed the detection of a transient intermediate, which was identified as the
four membered cyclic σ-sulfurane 27. This intermediate spontaneously rearranged (40 min, rt) into
the corresponding sulfenamide 17, probably via an intramolecular displacement of the sulfinyl by
a trifluoroacetoxy group, with inversion of configuration at the carbon stereocenter. The same process
occurred for the diastereomeric â-sulfinyl amine 14, but the sulfenamide 16 was formed at a very
fast rate, thus precluding NMR detection of the corresponding σ-sulfurane intermediate 26. One-
pot treatment of the diastereomeric sulfenamides 16 and 17 with NaBH4 afforded very good yields
of the corresponding threoninates 18 and 19.
Sch em e 1
Stereochemically defined â-amino alcohol units are
frequently found in biologically active molecules.2 We
recently developed a new method for the synthesis of
these important units.3 R-Lithium alkyl arylsulfoxides 1
(Scheme 1), used as chiral R-hydroxyalkyl carbanion
equivalents 2, were reacted with N-protected imines 3,
synthetic equivalents of R-amino carbocations 4, to afford
the â-amino alcohols 6.
The key step in this strategy is the transformation of
the intermediate â-sulfinylamines 5, obtained by stereo-
controlled assembling of 1 with 3, into the targets 6. This
was achieved by means of a highly stereospecific variant
of the Pummerer reaction,4 which results in a one-pot
SN2-type displacement of the sulfinyl auxiliary by a
hydroxyl. Previous work from our laboratories5 showed
that trifluoroacetoxy sulfenamides 9 (Scheme 2) are the
true products of the rearrangement and that these
compounds can be in situ transformed into the final
â-amino alcohols 6.6
Since the original sulfinyl-bearing carbon of sulfena-
mides 9 has a lower oxidation state than that expected
from a classical Pummerer rearrangement product, the
process was termed a “non-oxidative Pummerer reaction”
(NOPR). The NOPR was shown to be applicable to a wide
† Dipartimento di Chimica del Politecnico di Milano.
‡ CNR - CSSON.
(1) Presented in part at the 216th American Chemical Society
National Meeting, Boston, MA, 23-27 Aug 1998.
(2) For a detailed list of references see: (a) Volonterio, A.; Vergani,
B.; Crucianelli, M.; Zanda, M.; Bravo, P. J . Org. Chem. 1998, 63, 7236.
For a review on â-fluoroalkyl-â-amino alcohols, see: (b) Bravo, P.;
Crucianelli, M.; Ono, T.; Zanda, M. J . Fluorine Chem. 1999, 97, 27.
(3) Zanda, M.; Bravo, P.; Volonterio, A. In Asymmetric Fluoro-
Organic Chemistry: Synthesis, Applications, and Future Directions;
Ramachandran, P. V. Ed.; American Chemical Society Symposium
Series; American Chemical Society: Washington, DC, 1999.
(4) (a) Pummerer, R. Ber. 1909, 42, 2282. (b) De Lucchi, O.; Miotti,
U.; Modena, G. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New
York, 1991; Vol. 40. (c) Oae, S. Organic Sulfur Chemistry: Structure
and Mechanism; CRC Press: Boca Raton, 1991; pp 380-400. (d)
Padwa, A.; Gunn, D. E., J r.; Osterhout, M. H. Synthesis 1997, 1353.
(e) Kennedy, M.; McKervey, M. In Comprehensive Organic Chemistry;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp
193-216.
(5) (a) Arnone, A.; Bravo, P.; Bruche´, L.; Crucianelli, M.; Vichi, L.;
Zanda, M. Tetrahedron Lett. 1995, 36, 7301. (b) 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.
(6) In light of this unprecedented reactivity alkyl sulfoxides can be
regarded as chiral “chemical chameleons”. Indeed, in the first step
(C-C bond forming), the sulfinyl group imparts nucleophilic character
to the R-carbon, whereas in the second step (the NOPR) it acts as a
leaving group transforming the R-carbon in an electrophilic center. A
well-established class of “chemical chameleons” are sulfones, according
to the definition of Trost: (a) Trost, B. A.; Organ, M. G.; O’Doherty,
G. A. J . Am. Chem. Soc. 1995, 117, 9662.
10.1021/jo991534p CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/15/2000

2966 J . Org. Chem., Vol. 65, No. 10, 2000
Crucianelli et al.
Sch em e 2
Sch em e 3
Sch em e 4
range of â-sulfinylamines, fluorinated and not,7 provided
that the amino group is protected as a monoamide or
monocarbamate (NHCOR or NHCOOR, respectively).8
We would like to emphasize that the NOPR is the first
methodology which allows one to preserve and exploit the
stereochemical information of an R-sulfinyl stereocenter
for the synthesis of sulfur-free molecules, since this is
usually lost in the desulfinylation process.9
Despite the large number of successful applications of
the NOPR, little information about its mechanism is
known. This is mainly due to the fact that all the NOPR
transformations hitherto explored7 were found to be very
fast processes, therefore precluding the isolation or the
spectroscopic detection of any intermediate. The only
experimental evidence available was achieved by means
of deuterium labeling experiments,5 which indicated that
the “normal” R-sulfinyl proton removal does not take
place (Scheme 2). On the basis of these data, we hypoth-
esized that the NOPR might involve intramolecular
trapping of the tricoordinate sulfonium cation 7 by the
amidic/carbamic â-nitrogen, giving rise to the intermedi-
ate chiral σ-sulfurane 8. This intermediate then under-
goes a stereospecific SN2-type rearrangement providing
the final sulfenamide 9.
diffraction studies of substrate and product; (b) evidence
for formation of the sulfurane 8 (Scheme 2), based on
NMR spectroscopy; (c) and a novel application of the
NOPR for the synthesis of densely functionalized L-R-
trifluoromethyl (Tfm)-threoninate and D-R-Tfm-allo-thre-
oninate, using lithiated (R)-ethyl p-tolylsulfoxide 13
(Scheme 3) as a chiral R-hydroxyethyl carbanion equiva-
lent.10
In this paper, we present: (a) conclusive evidence for
SN2-type stereoselectivity of the NOPR, based on X-ray
Resu lts
The starting â-sulfinylamines 14 and 15 (Scheme 3)
were prepared according to known methodology.11 The
Staudinger (aza-Wittig) reaction of methyl trifluoropy-
ruvate 10 with the N-Cbz iminophosphorane 11 provided
the strongly electrophilic imine 12,12 which was reacted
in situ with R-lithium (R)-ethyl p-tolylsulfoxide 13.
A nearly equimolar ratio of 14 and 15 was produced
(55% overall yield), with no trace of the other two possible
diastereomers as evidenced by 1H and 19F NMR spec-
(7) (a) Bravo, P.; Capelli, S.; Meille, S. V.; Seresini, P.; Volonterio,
A.; Zanda, M. Tetrahedron: Asymmetry 1996, 7, 2321. (b) Bravo, P.;
Cavicchio, G.; Crucianelli, M.; Poggiali, A.; Zanda, M. Tetrahedron:
Asymmetry 1997, 8, 2811. (c) Bravo, P.; Farina, A.; Kukhar, V. P.;
Markovsky, A. L.; Meille, S. V.; Soloshonok, A. V.; Sorochinsky, A. E.;
Viani, F.; Zanda, M.; Zappala`, C. J . Org. Chem. 1997, 62, 3424. (d)
Bravo, P.; Guidetti, M.; Viani, F.; Zanda, M.; Markovsky, A. L.;
Sorochinsky, A. E.; Soloshonok, I. V.; Soloshonok, V. A. Tetrahedron
1998, 54, 12789. (e) Bravo, P.; Corradi, E.; Pesenti, C.; Vergani, B.;
Viani, F.; Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 1998, 9,
3731. (f) Bravo, P.; Capelli, S.; Crucianelli, M.; Guidetti, M.; Markovsky,
A. L.; Meille, S. V.; Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.;
Zanda, M. Tetrahedron 1999, 55, 3025.
(8) NH-PMP â-sulfinylamines were found to behave in a totally
different manner when submitted to NOPR conditions: Arnone, A.;
Bravo, P.; Bruche´, L.; Crucianelli, M.; Zanda, M.; Zappala`, C. J . Chem.
Res. 1997, 416.
(9) A stereoselective one-pot displacement of a sulfinyl group via
desulfinylative formation of benzyl cations and their subsequent
trapping was reported, but that reaction is limited to the case of benzyl
sulfoxides: Casey, M.; Manage, A. C.; Murphy, P. J . Tetrahedron Lett.
1992, 33, 965.
(10) For a preliminary communication, see: (a) Bravo, P.; Zanda,
M.; Zappala`, C. Tetrahedron Lett. 1996, 37, 6005. For an overview on
the synthesis of fluorinated threonines, see: (b) Sting, A. R.; Seebach,
D. Tetrahedron 1996, 52, 279 and references therein.
(11) Bravo, P.; Viani, F.; Zanda, M.; Kukhar, V. P.; Soloshonok, V.
A.; Fokina, N.; Shishkin, O. V.; Struchkov, Yu. T. Gazz. Chim. Ital.
1996, 126, 645.
(12) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.;
Kukhar, V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5,
2009.

“Non-Oxidative” Pummerer Reaction
J . Org. Chem., Vol. 65, No. 10, 2000 2967
F igu r e 1. ORTEP view of compounds 14 and 25, showing the molecular labeling scheme. Displacement ellipsoids are plotted at
the 20% probability level.
troscopy of the crude. Diastereomerically pure 14 and 15
were obtained by flash chromatography (FC) and sepa-
rately treated with trifluoroacetic anhydride (TFAA) (5
equiv) in the presence of sym-collidine (3 equiv) at room
temperature in acetonitrile, providing the corresponding
trifluoroacetoxy sulfenamides 16 and 17 as single dia-
stereomers (Scheme 4).
reaction of 18 and 19 occurred.14 In that case, methyl
N-Cbz trifluoroalaninate 22, N-Cbz trifluoroalanine 23,
and their reduced derivative N-Cbz trifluoroalaninol 24
were produced in good yields,5b together with minor
amounts of other uncharacterized side-products.
Interestingly, while the rearrangement of 14 into 16
was instantaneous, in line with all the NOPR previously
explored,7 the transformation of 15 into 17 required ca.
40 min to reach completion (TLC monitoring). Sulfena-
mides 16 and 17 were separately treated with an excess
of NaBH4 (0 °C to room temperature, acetonitrile + 1
drop of water), smoothly affording the R-Tfm-allo-thre-
oninate 18 and the R-Tfm-threoninate 19, respectively.13
One-pot transformations of 14 into 18 and 15 into 19
were effectively achieved under the same conditions (87%
and 70%, respectively). In both cases, a diastereoselec-
tivity >98:2 was observed (the other diastereomer could
not be detected in the crude reaction mixture). The only
relevant byproducts observed in the crude reaction
mixture, under the optimized conditions, were methyl
N-Cbz R-Tfm-R-vinyl-glycinate 21 and its precursor
sulfenamide 20 (<5% overall), which should arise from
â-elimination of the sulfinyl residue. In contrast, when
the reactions of 16 and 17 into 18 and 19 were carried
out in the presence of an extra base (usually K2CO3) and/
or with larger amount of water, extended retro-aldol
Interestingly, 22, 23, and 24 were isolated by FC in
nonracemic form. For example, starting from 14, (S)-
trifluoroalaninol 24 having ca. 50% ee was obtained,
which means that the retro-aldol reaction takes place
with at least partial retention of configuration at the
amino acid center.15 To unambiguously assess the abso-
lute configuration of the NOPR products 18 and 19, and
the stereochemical outcome of the transformation, we
submitted to X-ray diffraction analysis both the substrate
14 and the p-Br-benzoate 25, prepared from the methyl
N-Cbz threoninate 19 (Figure 1).
The absolute stereochemistry of 15 was confidentially
assigned on the basis of its spectral and physicochemical
(14) For a closely related case, see: Van Hijfte, L.; Heydt, V.; Kolb,
M. Tetrahedron Lett. 1993, 34, 4793.
(15) For other examples of stereospecific fragmentations, see: Park,
Y. S.; Beak, P. J . Org. Chem. 1997, 62, 1574 and references therein.
We cannot rule out the hypothesis that the retro-aldol reaction might
(13) The main sulfur-containing product isolated by FC after treat-
ment of the NOPR mixture with NaBH4 was identified as (p-Tol-S)2.
be highly stereospecific and
afterward, under NOPR conditions.
a partial racemization might occur

2968 J . Org. Chem., Vol. 65, No. 10, 2000
Crucianelli et al.
served by NMR. In this case, a small amount of the
unsaturated side product 20 was also detected.
Discu ssion
The Pummerer reaction is a popular reaction to
transform alkyl sulfoxides 28 (Scheme 6) into the corre-
sponding R-substituted sulfides 31, which can be hydro-
lyzed to carbonyl compounds 32.4
similarity with a known molecule, differing only for the
protecting group of the amino function (ethoxycarbonyl
instead of Cbz).11
To achieve a better understanding of the mechanism
of the NOPR, both diastereomeric substrates 14 and 15
were submitted to reaction in a NMR tube, under the
usual conditions. In agreement with TLC monitoring of
the reaction, the addition of neat TFAA (5 equiv) to 14
in the presence of sym-collidine (3 equiv in CD3CN at
room temperature) instantaneously produced the ex-
pected sulfenamide 16, along with a small amount of
methyl N-Cbz R-Tfm-R-vinylglycinate sulfenamide 20.
When submitted to the same experimental conditions,
the diastereomer 15 immediately afforded a new com-
From the stereochemical point of view, the Pummerer
reaction is a self-immolative process, since the stereo-
genic center migrates from the sulfur atom to the
R-carbon. However, relatively few examples of stereospe-
cific Pummerer reactions have been described in the
literature.17 In contrast, many examples of “abnormal”
Pummerer reactions are known, some of them with good
synthetic usefulness.4,18 One “abnormal” pathway may
occur when the tricoordinate sulfur intermediate 29
(Scheme 6), formed by activation of the sulfinyl oxygen
with the electrophile, undergoes reaction with a nucleo-
phile at sulfur, forming a transient σ-sulfurane interme-
diate 33. Although nucleophilic attack on tricoordinate
sulfur has been reported in a large number of reactions,19
and the formation of σ-sulfuranes has been often hypoth-
esized in Pummerer-related processes,20 their isolation
or detection by NMR spectroscopy is relatively uncom-
mon.21 The σ-sulfurane 33 can undergo subsequent
fragmentation into the final products, which are usually
a sulfide 34 and a trifluoroacetoxy derivative 35. Such
an outcome has been defined earlier as an “interrupted”
Pummerer reaction.22
1
pound having a different H NMR spectrum from that of
the expected sulfenamide 17 (Figure 2). In particular, the
signals at 8.18 ppm that are attributable to the ortho
protons of the p-tolyl ring (with respect to the sulfur
atom) and the vicinal 4-methynic proton at 5.82 ppm both
exhibit a downfield shift of 0.47 and 1.47 ppm. This fact
clearly points to an increased deshielding about the sulfur
atom, which can be ascribed to a more electron-poor
character and increased valency.
On the basis of the spectral properties above, this
intermediate was assigned as the four-membered cyclic
σ-sulfurane 27 (Scheme 5).16
Within 30 min at room temperature, a complete
transformation of 27 into the sulfenamide 17 was ob-
The NOPR can be considered a stereospecific intramo-
lecular example of an “interrupted” Pummerer reaction.
The complete absence of any products derived from
proton removal from the R-sulfinyl position, as was
demonstrated by deuterium labeling experiments, is
typical of an “interrupted” Pummerer reaction. This
evidence, along with the NMR experiments outlined
above, strongly supports the picture of kinetic control
(16) The formation of a six-membered σ-sulfurane 38, via intramo-
lecular trapping of cation 7 by the carbamic oxygen, cannot be ruled
out. In that case, the observed sulfenamide products (such as 16, 17)
would arise from rearrangement of 38. However, we judge such
hypothesis quite unlikely, because products having the Ar-S residue
attached to the carbamic oxygen have never been either observed or
isolated after the NOPR.
(18) For some recent representative examples, see: (a) Kersey, I.
D.; Fishwick, C. W. G.; Findlay, J . B. C.; Ward, P. Tetrahedron 1995,
51, 6819. (b) Davis, F. A.; Reddy, V. A. Tetrahedron Lett. 1996, 37,
4349. (c) Pyne, S. G.; Hajipour, A. R. Tetrahedron 1994, 50, 13501.
(19) See, for example: (a) Bennasar, M. L.; J ime´nez, J .-M.; Sufi, B.
A.; Bosch, J . Tetrahedron Lett. 1996, 37, 9105. (b) Sharma, A. K.; Ku,
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1992, 33, 153. (d) Kita, Y.; Shibata, N.; Kawano, N.; Tohjo, T.; Fujimori,
C.; Matsumoto, K.; Fujita, S. J . Chem. Soc., Perkin Trans. 1 1995, 2045.
(e) Amat, M.; Bennasar, M.-L.; Hadida, S.; Sufi, B. A.; Zulaica, E.;
Bosch, J . Tetrahedron Lett. 1996, 37, 5217. (f) Amat, M.; Hadida, S.;
Pshenichnyi, G.; Bosch, J . J . Org. Chem. 1997, 62, 3158. (g) Kawasaki,
T.; Suzuki, H.; Sakata, I.; Nakanishi, H.; Sakamoto, M. Tetrahedron
Lett. 1997, 38, 3251. (h) Furukawa, N.; Kawada, A.; Kawai, T.;
Fujihara, H. J . Chem. Soc., Chem. Commun. 1985, 1266. (i) Schostarez,
H. J .; Schwartz, T. M. J . Org. Chem. 1996, 61, 8701. (j) Yamamoto,
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(17) (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,
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61, 9289.

“Non-Oxidative” Pummerer Reaction
J . Org. Chem., Vol. 65, No. 10, 2000 2969
F igu r e 2. 1H NMR spectrum of 27.
Sch em e 5
Sch em e 6
operating in the NOPR, where the driving force is
represented by the fast and irreversible formation of the
intermediate four membered σ-sulfuranes, such as 26 and
27.23 These intermediates have been shown to undergo
a spontaneous rearrangement, in which the O-S bond
breaks and the CF3COO group migrates to the R-sulfinyl
carbon producing inversion of configuration and C-S
bond breaking. The reasons for the uncommon stability
of the σ-sulfurane 27 are presently unclear.24 However,
its high degree of ring substitution, as well as the
apparent absence of strain, might slow the rearrange-
ment into 17 for steric reasons. In contrast, the unfavor-
able cis-interaction experienced by the CH3 and the
stereoelectronically demanding CF3 group25 of the dia-
stereomeric σ-sulfurane 26 should force the rearrange-
ment to occur rapidly in order to release the strain.
According to this mechanistic description, the R-ste-
reocenter is never lost during the course of the reaction.
This is in agreement with the observation that the
stereocontrol depends exclusively on the configuration of
the R-sulfinyl carbon. Indeed, if the NOPR would involve
a dissociated sulfenium ion, like 30 (Scheme 6), both
diastereomeric substrates 14 and 15 should produce the
same product.
Oae et al. demonstrated that σ-sulfuranes can undergo
a “ligand coupling reaction” which takes place with
retention of configuration at the R-sulfinyl carbon.26 In
contrast, the NOPR takes place with inversion of con-
figuration, which means that a different pathway must
be followed (Scheme 7).
The most likely one involves dissociation of the σ-sul-
furane (for example 27) into an intimate ion-pair 36,
which undergoes recombination via SN2-type attack of
the generated trifluoroacetate anion to the sulfur-
substituted stereogenic carbon of the resulting sulfonium
cation. To obtain some evidence regarding the “intramo-
lecular” nature of the NOPR, we performed a competition
experiment using a nucleophilic base instead of sym-
collidine (Scheme 8).
(23) For some examples of four membered cyclic compunds featuring
an S-N bond: (a) Tornus, I.; Schaumann, E.; Mayer, R.; Adiwidjaja,
G. Liebigs Ann. 1995, 1795. (b) Baxter, N. J .; Laws, A. P.; Rigoreau,
L.; Page, M. I. J . Chem. Soc., Chem. Commun. 1997, 2037. (c)
Warrener, R. N.; Amarasekara, A. S. Synlett 1997, 167.
(24) σ-Sulfuranes are known to be quite stable when the axial
ligands contain highly electronegative heteroatoms. However, under
NOPR conditions the transformations â-sulfinylamine f σ-sulfurane
f trifluoroacetoxy-sulfenamide were always found to be very fast, with
the only remarkable exception of 27 f 17 presented in this work.
(25) (a) Smart, B. E. In Organofluorine Chemistry: Principles and
Commercial Applications; Banks, R. E., Tatlow, J . C., Smart, B. E.,
Eds.; Plenum Press: New York, 1994; pp. 80-81. (b) Nagai, T.;
Nishioka, G.; Koyama, M.; Ando, A.; Miki, T.; Kumadaki, I. Chem.
Pharm. Bull. 1991, 39, 233.
We reasoned that since the trifluoroacetate anion is a
relatively weak nucleophile, if the displacement would
(26) Oae, S.; Kawai, T.; Furukawa, N.; Iwasaki, F. J . Chem. Soc.,
Perkin Trans. 2 1987, 405.

2970 J . Org. Chem., Vol. 65, No. 10, 2000
Crucianelli et al.
0.06 mm for 25) with graphite-monochromated Cu KR radia-
tion (1.541 78 Å). The structures were solved by direct methods
using SIR92,30 and refined by full-matrix least squares on F2,
using SHELXL97.31 Non-hydrogen atoms were refined aniso-
tropically. All hydrogen atoms were located at calculated
positions and refined with group temperature factors.
Syn t h esis of â-Su lfin yla m in es (RS,2S,3R)-14 a n d
(RS,2R,3R)-15. Substrates 14 and 15 were obtained, according
to a published method,11 with an overall yield of 55%, in a
nearly equimolar ratio.
Sch em e 7
(RS,2S,3R)-2-Ben zyloxyca r b on yla m in o-3-(t olu en e-4-
su lfin yl)-2-tr iflu or om eth ylbu tyr ic a cid m eth yl ester (14):
mp (i-Pr2O) 144-146 °C; [R]D +125.6 (c 0.83, CHCl3); 1H NMR
(CDCl3) δ 8.39 (br signal, 1H), 7.70-7.30 (m, 9H), 5.12 (br s,
2H), 3.82 (br s, 3H), 3.38 (qq, J ) 7.3, 1.3 Hz, 1H), 2.43 (br s,
3H), 0.89 (dq, J ) 7.3, 1.8 Hz, 3H); 13C NMR (CDCl3) δ 164.9,
154.5, 144.0, 138.9, 135.9, 130.3, 130.1, 128.5, 128.2, 126.2,
124.5 (q, J ) 289.0 Hz), 68.1 (q, J ) 28.0 Hz), 67.4, 61.8, 53.5,
21.6, 11.0; 19F NMR (CDCl3) δ - 69.47 (br s); MS (EI, 70 eV)
m/ z 458 (M+ + 1, 1), 139 (10), 91 (100). Crystal data: C21H22F3-
NO5S, fw 457.46; orthorhombic, space group P212121; a )
6.980(1) Å, b ) 10.783(1) Å, c ) 29.886(1) Å; V ) 2249(2) Å3;
Z ) 4; Dc ) 1.351 g/cm3; µ ) 1.789 mm-1; F(000) ) 952; final
R1 ) 11.29, wR2 (all data) ) 21.78, S ) 1.001; Flack’s
parameter32 ) 0.05(5); extinction coefficient ) 0.0023(5);
largest peak and hole ) 0.243 and -0.244 eÅ-3. Some disorder
involving the aromatic ring (C51 to C56) together with the poor
quality of the crystals results in the relatively high value of
the disagreement factor.
Sch em e 8
(RS,2R,3R)-15: oil; [R]D +55.0 (c 0.85, CHCl3); 1H NMR
(CDCl3) δ 7.81 (br signal, 1H), 7.70-7.20 (m, 9H), 5.14 and
5.08 (br d, J ) 12.2 Hz, 2H), 3.87 (s, 3H), 3.39 (q, J ) 7.2 Hz,
1H), 2.42 (br s, 3H), 0.93 (d, J ) 7.2 Hz, 3H); 13C NMR (CDCl3)
δ 165.1, 154.6, 143.6, 138.1, 135.5, 130.1, 128.5, 128.3, 128.0,
126.2, 123.7 (q, J ) 288.0 Hz), 72.0 (q, J ) 30.8 Hz), 67.5,
60.0, 54.2, 21.5, 11.7; 19F NMR (CDCl3) δ - 73.86 (br s); FT
IR (cm-1) 3246, 1755, 1739.
(2S,3S)-2-Ben zyloxycar bon yl[N-(tolu en e-4-th io)am in o]-
3-tr iflu or oa cetoxy-2-tr iflu or om eth ylbu tyr ic Acid Meth yl
Ester (16). This compound was not isolated, but just detected
by NMR of crude NOPR of 14: 1H NMR (CD3CN) δ 7.40-7.10
(m, 9H), 6.05 (br signal, 1H), 5.20 (br s, 2H), 3.68 (s, 3H), 2.32
(br s, 3H), 1.55 (br signal, 3H); 19F NMR (CD3CN) δ -63.9 and
-72.10 (br s, 6F).
not occur within the intimate ion pair 36, addition of the
remarkably more nucleophilic cyanide anion27 to the
reaction mixture should give competitive displacement
of the sulfinyl residue, thus producing the corresponding
nitrile 37. In agreement with our “intramolecular” hy-
pothesis, a NOPR experiment using KCN instead of sym-
collidine as base, afforded the hydroxylated product 18
in very good yields, with no trace of the nitrile 37 detected
in the crude mixture. The last question to be answered
was how the side products 20,21 are formed during the
NOPR. More than likely, 20 and 21 arise from competi-
tive deprotonation of the methyl â-hydrogen of the cyclic
sulfonium cation in 36 by trifluoroacetate (or alterna-
tively by sym-collidine), resulting in â-elimination. For-
mation of related unsaturated side-products was observed
by Oae in closely related “interrupted” Pummerer reac-
tions.28
(2R,3S)-17. To a cooled (0 °C) and stirred solution of 15 (35
mg, 0.076 mmol) in 0.8 mL of acetonitrile were added 31 µL
of sym-collidine (0.23 mmol), followed by 54 µL of TFAA (0.38
mmol) under nitrogen. After 5 min, the reaction was allowed
to stay at rt, under stirring, until TLC analysis (7/3 n-hexane/
ethyl acetate) showed the disappearance of the starting
material (about 40 min). After removal of the solvent, the crude
was purified by FC (n-hexane/ethyl acetate from 90/10 to 80/
20) giving 35 mg of (2R,3S)-17 (83% yield): oil; [R]D -11.5 (c
1
0.57, CHCl3); H NMR (CDCl3) δ 7.40-7.00 (m, 9H), 5.95 (br
In summary, this study provides a deeper insight into
the mechanism of the NOPR, additional evidence for
inversion of configuration at the R-sulfinyl carbon ste-
reocenter, and a further application of the NOPR for the
synthesis of densely functionalized and substituted R-Tfm-
threoninates. We believe that the NOPR process could
open up new synthetic perspectives and lead to new
applications of the sulfinyl auxiliary in organic synthesis.
q, J ) 6.7 Hz, 1H), 5.19 (br s, 2H), 3.73 (s, 3H), 2.32 (br s,
3H), 1.55 (d, J ) 6.7 Hz, 3H); 19F NMR (CDCl3) δ -68.20 and
-76.40 (br s, 6F).
Non oxid a tive P u m m er er Rea ction of 14 a n d 15: Syn -
th esis of Meth yl N-CBz-r-tr iflu or om eth yl-a llo-th r eon i-
n a te (18) a n d Meth yl N-Cbz-r-tr iflu or om eth ylth r eon i-
n a te (19). To a cooled (0 °C) and stirred solution of 14 (250
mg, 0.55 mmol) in 4 mL of acetonitrile, under nitrogen, was
added sym-collidine (218 µL, 1.64 mmol), followed by TFAA
(387 µL, 2.73 mmol). After 2 min at room temperature, TLC
analysis (7/3 n-hexane/ethyl acetate) showed the disappear-
ance of the starting material. To the reaction mixture, cooled
longer at 0 °C, was added one drop of H2O, and portionwise
one drop of water was added at 0 °C, followed by an excess of
NaBH4 (about 3 equiv). After 2 min, the reaction was warmed
Exp er im en ta l Section
Gen er a l P r oced u r e. For general experimental information
see ref 29. X-ray diffraction data were collected from colorless
crystal platelets (size 0.05 × 0.2 × 1.0 for 14 and 0.08 × 0.3 ×
(27) March. J . Advanced Organic Chemistry; Wiley: New York,
1992; pp 348-352.
(28) Uchida, Y.; Oae, S. Gazz. Chim. Ital. 1987, 117, 649.
(29) Fustero, S.; Navarro, A.; Pina, B.; Asensio, A.; Bravo, P.;
Crucianelli, M.; Volonterio, A.; Zanda, M. J . Org. Chem. 1998, 63, 6210.
(30) Altomare, A.; Cascarano, G.; Guagliardi, A. J . Appl. Crystallogr.
1993, 26, 343.
(31) Sheldrick, G. M., SHELXL97, Program for crystal structure
refinement; University of Go¨ttingen; Go¨ttingen, Germany, 1997.
(32) Flack, H. D. Acta Crystallogr. 1983, A 39, 876.

“Non-Oxidative” Pummerer Reaction
J . Org. Chem., Vol. 65, No. 10, 2000 2971
at rt and stirred for 1.5 h. The mixture was quenched, at 0
°C, with a saturated aqueous solution of NH4Cl and extracted
with ethyl acetate (3 × 5 mL). The collected organic layers
were washed twice with a 1 N HCl solution to remove sym-
collidine and then with aqueous NaHCO3. After routine
workup, the crude was purified by FC (80/20 n-hexane/ethyl
acetate) affording 160 mg of (2S,3S)-18 (87% yield).
2-Ben zyloxyca r b on yla m in o-3,3,3-t r iflu or op r op ion ic
a cid (23): 1H NMR (CDCl3) δ 16.65 (br signal, 1H), 7.50-
7.20 (m, 5H), 5.70 (d, J ) 9.8 Hz, 1H), 5.62 (dq, J ) 9.8, 5.5
Hz, 1H), 5.15 (br s, 2H); 19F NMR (CDCl3) δ - 83.05 (br d, J
) 5.5 Hz).
(2-Hyd r oxy-1-tr iflu or om eth yleth yl)ca r ba m ic a cid ben -
zyl ester (24): [R]D +5.92 (0.41, CHCl3) (ca. 49% ee); 1H NMR
(CDCl3) δ 7.50-7.20 (m, 5H), 5.49 (d, J ) 9.5 Hz, 1H), 5.15
(br s, 2H), 4.38 (m, 1H), 3.98 and 3.86 (m, 2H); 19F NMR
(CDCl3) δ - 75.16 (br d, J ) 7.9 Hz). The same reaction
performed on the substrate 15 gave 23 as main product (ca.
45% yield).
(2S,3S)-2-Ben zyloxyca r b on yla m in o-3-h yd r oxy-2-t r i-
flu or om eth ylbu tyr ic a cid m eth yl ester (18): mp (i-Pr2O)
68-70 °C; [R]D -7.65 (c 0.34, CHCl3); 1H NMR (CDCl3) δ 7.50-
7.20 (m, 5H), 6.26 (br signal, 1H), 5.58 (br d, J ) 11.5 Hz,
1H), 5.18 and 5.14 (br d, J ) 12 Hz, 2H), 4.65 (dq, J ) 11.5,
6.5 Hz, 1H), 3.90 (s, 3H), 1.15 (d, J ) 6.5 Hz, 3H); 13C NMR
(CDCl3) δ 166.3, 156.1, 153.3, 128.6, 128.5, 128.3, 123.5 (q, J
) 287.9 Hz), 70.1 (q, J ) 27.7 Hz), 68.2, 68.2, 54.7, 18.2; 19F
NMR (CDCl3) δ -72.55 (br s); FT IR (cm-1) 3393 (br), 1753,
1710; MS (EI, 70 eV) m/ z 335 (M+, 2), 108 (29), 91 (100).
The same experimental conditions described above (with the
exception of longer reaction time in the first step: 40 min at
room temperature instead of 2 min) were applied for the
synthesis of product (2R,3S)-19 obtained, as an oil, in 70%
yield.
Syn th esis of p-Br -Ben zoa te (2R,3S)-25. To a solution of
19 (40 mg, 0.119 mmol) and 2 equiv of triethylamine in 2 mL
of dichloromethane were added 29 mg of p-Br-benzoyl chloride
(1.1 equiv) dissolved in 1 mL of CH2Cl2 and a catalytic amount
of DMAP at room temperature, under stirring. After 45 min,
TLC control (7/3 n-hexane/ethyl acetate) showed the disap-
pearance of starting material. After removal of solvent, the
crude was purified by FC, affording 58 mg (94% yield) of
(2R,3S)-25.
1
(2R,3S)-19: [R]D -5.64 (c 0.4, CHCl3); H NMR (CDCl3) δ
(2R,3S)-4-Br om oben zoic acid 2-ben zyloxycar bon ylam i-
n o-3,3,3-tr iflu or o-2-m eth oxyca r bon yl-1-m eth ylp r op yl es-
ter (25): mp (i-Pr2O) 118-120 °C; [R]D +31.93 (c 0.56, CHCl3);
1H NMR (CDCl3) δ 7.85 (d, J ) 8.5 Hz, 2H), 7.59 (d, J ) 8.5
Hz, 2H), 7.35 (m, 5H), 5.82 (q, J ) 6.6 Hz, 2H), 5.73 (br signal,
1H), 5.12 (br s, 2H), 3.85 (br signal, 3H), 1.51 (dd, J ) 6.6, 1.2
Hz, 3H); 19F NMR (CDCl3) δ -69.89 (s, 3F). Crystal data:
7.50-7.20 (m, 5H), 5.64 (br signal, 1H), 5.16 (br s, 2H), 4.49
(br q, J ) 6.6 Hz, 1H), 3.90 (s, 1H), 3.86 (br s, 3H), 1.36 (dd,
J ) 6.6, 1.5 Hz, 3H); 13C NMR (CDCl3) δ 166.0, 155.8, 135.4,
128.6, 128.5, 128.3, 123.4 (q, J ) 287.0 Hz), 70.0 (q, J ) 27
Hz), 69.0, 68.0, 53.7, 18.5; 19F NMR (CDCl3) δ -70.94 (br s).
2-Ben zyloxyca r b on yl[N-(t olu en e-4-t h io)a m in o]-2-t r i-
flu or om eth ylbu t-3-en oic Acid Meth yl Ester (20). Ob-
served by NMR as a byproduct from the crude of the NOPR
C
21H19BrF3NO6, fw 518.28; monoclinic, space group C2; a )
24.665(3) Å, b ) 7.336(1) Å, c ) 14.690(2) Å, â ) 117.78(1)°; V
) 2351.7(5) Å3; Z ) 4; Dc ) 1.464 g/cm3; µ ) 2.924 mm-1
1
described above: H NMR (CDCl3) δ 7.50-7.00 (m, 9H), 6.16
;
(m, 1H), 5.43 and 5.42 (m, 2H), 5.19 (br d, 2H), 3.72 (s, 3H),
2.31 (br s, 3H).
F(000) ) 1048; final R1 ) 9.27, wR2 (all data) ) 18.80, S )
1.076; Flack’s parameter32 ) 0.02(4); extinction coefficient )
2-Ben zyloxyca r b on yla m in o-2-t r iflu or om et h ylb u t -3-
en oic Acid Meth yl Ester (21). Observed by NMR as a
byproduct from the crude of the NOPR described above: 1H
NMR (CDCl3) δ 7.50-7.30 (m, 5H), 6.19 (m, 1H), 5.57 (br s,
1H), 5.57 and 5.55 (m, 2H), 5.13 (br s, 2H), 3.86 (s, 3H); 19F
NMR (CDCl3) δ -75.71 (br s).
0.0004(1); largest peak and hole ) 0.309 and -0.367 e Å-3
.
Non oxid a tive P u m m er er Rea ction P er for m ed on 15
in a n NMR Tu be To Detect th e σ-Su lfu r a n e 27. To a NMR
tube containing 65 mg of 15 (0.142 mmol) and 56 µL (0.43
mmol) of sym-collidine dissolved in 0.5 mL of CD3CN were
added 98 µL of TFAA (0.71 mmol) at room temperature. After
4 min, 1H and 19F NMR spectra were recorded giving the
following signals attributable, as described in the text, to the
σ-sulfurane 27: 1H NMR (CD3CN) δ 8.18 and 7.46 (m, 4H),
7.40-7.20 (m, 5H), 5.82 (q, J ) 7.3 Hz, 1H), 5.19 (br s, 2H),
4.02 (s, 3H), 2.45 (br s, 3H), 1.58 (d, J ) 7.3 Hz, 3H); 19F NMR
(CD3CN) δ -63.50 and -72.20 (br s, 6F).
Non oxid a tive P u m m er er Rea ction of Su bstr a tes 14
a n d 15 in th e P r esen ce of K2CO3: Isola tion of Byp r od -
u cts 22-24. To a stirred solution of 14 (47 mg, 0.103 mmol)
and sym-collidine (41 µL, 0.308 mmol) in acetonitrile (1 mL)
under a nitrogen atmosphere at 0 °C was added dropwise neat
TFAA (73 µL, 0.514 mmol). After 2 min at rt, TLC analysis
(7/3 n-hexane/ethyl acetate) showed the disappearance of
starting material. The reaction mixture was slowly added with
a 50% aqueous solution of potassium carbonate at 0 °C, until
pH 8 was reached. After 10 min, an excess of NaBH4 (about 3
equiv) was added portionwise. After 2 min, the reaction was
warmed at room temperature and stirred for 1.5 h. The
reaction was quenched and worked up as described above.
After purification by FC (n-hexane/ethyl acetate from 80/20
to 70/30) the main product isolated was 24 (71% yield) along
with minor amounts of 22 and 23.5b
Ack n ow led gm en t . We thank MURST COFIN
(Rome) and CNR-CSSON for financial support. We
gratefully acknowledge Dr. Charles Mioskowski and Dr.
Alain Wagner (Universite´ Louis Pasteur de Strasbourg,
France) for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 14, 15, 18, and 19 and crystal data
of compounds 14 and 25. This material is available free of
charge via the Internet at http://pubs.acs.org.
2-Ben zyloxyca r b on yla m in o-3,3,3-t r iflu or op r op ion ic
a cid m eth yl ester (22): 1H NMR (CDCl3) δ 7.50-7.30 (m,
5H), 5.67 (br d, J ) 9.4 Hz, 1H), 5.16 (br s, 2H), 5.07 (dq, J )
9.4, 7.7 Hz, 1H) 3.86 (s, 3H); 19F NMR (CDCl3) δ - 74.24 (br
d, J ) 7.7 Hz).
J O991534P