Diastereoselective addition of organomagnesium and organolithium reagents to chiral trifluoromethyl N-tert-butanesulfinyl hemiaminals

Article abstract of DOI:10.1002/ejoc.201300890

The asymmetric synthesis of trifluoromethylated tertiary and secondary carbinamines (α,α-dibranched and α-branched amines) was achieved by reaction of alkyl, aryl and allyl organomagnesium or organolithium reagents to trifluoromethyl N-tert-butanesulfinyl

Full text of DOI:10.1002/ejoc.201300890

FULL PAPER
DOI: 10.1002/ejoc.201300890
Diastereoselective Addition of Organomagnesium and Organolithium Reagents
to Chiral Trifluoromethyl N-tert-Butanesulfinyl Hemiaminals
Fabienne Grellepois,*[a] Abdelkhalek Ben Jamaa,[a] and Abdoulaye Gassama[a,b]
Keywords: Asymmetric synthesis / Allylation / Reduction / Alkylation / Fluorine
The asymmetric synthesis of trifluoromethylated tertiary and
secondary carbinamines (α,α-dibranched and α-branched
amines) was achieved by reaction of alkyl, aryl and allyl or-
ganomagnesium or organolithium reagents to trifluoromethyl
N-tert-butanesulfinyl hemiaminals, bench-stable analogs of
the corresponding ketoimines.
metallic reagents on trifluoromethylated oxazolidines or ke-
toimines derivatives.[11,12]
Introduction
In this paper, we report our efforts to develop the nucleo-
philic addition of alkyl and aryl organomagnesium and
organolithium reagents to trifluoromethyl N-tert-butane-
sulfinyl hemiaminals derived ketoimines. This constitutes
an approach complementary to the diastereoselective syn-
thesis of trifluoromethyl-substituted α,α-dibranched and α-
branched amines.
Organofluorine compounds have found a wide range of
applications as pharmaceuticals, agrochemicals or materials
due to the beneficial properties of fluorine.[1] In drug de-
sign, the selective incorporation of fluorinated substituents
into organic molecules is a well-established strategy by
which to modulate biological properties.[2] Among the fluo-
rinated motifs, α-trifluoromethylated amines are highly
popular[3] due to the strongly electron-withdrawing nature
of the fluorine atom which attenuates the basicity of the
adjacent amine functionality. Moreover, the trifluoromethyl
group may improve the metabolic stability, increase the bio-
availability and/or decrease the toxicity of biologically inter-
esting compounds.[2] As such, the development of asymmet-
ric syntheses of α-trifluoromethylated amines has gained
considerable attention over the past several years.[4] A vari-
ety of methods have been described for the preparation of
secondary carbinamines (α-branched amines) from tri-
fluoromethylated synthons (addition of organometallic rea-
gents to aldimine derivatives,[5] reduction[6] or transamina-
tion reactions[7] of ketoimines, and others[8]) or by direct
nucleophilic trifluoromethylation[9] of aldimines. However,
far fewer studies have been reported for the asymmetric
synthesis of trifluoromethylated tertiary carbinamines (α,α-
dibranched amines). To date, due to the lack of general
methods for nucleophilic trifluoromethylation of ketoim-
ines,[10] all strategies are based on the addition of organo-
Results and Discussion
Chiral aryl and alkyl trifluoromethyl N-tert-butanesulf-
inyl ketoimines are known to have a low hydrostability and
therefore must be generated quickly prior to use.[13] Conse-
quently, we recently reported the synthesis of the (SS)-hemi-
aminals 1a–d,[14] their bench-stable surrogates, to circum-
vent these problems. (Scheme 1).
[a] Université de Reims-Champagne-Ardenne, Institut de Chimie
Moléculaire de Reims, UMR CNRS 6229, UFR des Sciences
Exactes et Naturelles,
Scheme 1. Synthesis of chiral trifluoromethyl (S)-N-tert-butanesulf-
inyl hemiaminals.[14]
BP 1039, 51687 Reims cedex 2, France
E-mail: fabienne.grellepois@univ-reims.fr
Homepage: http://www.univ-reims.fr/rubrique-cachee/
laboratoires-labelises/icmr/les-groupes-de-recherche/
methodologie-en-synthese-organique,9949.html
[b] Département de Chimie, Université de Ziguinchor,
BP 523, Ziginchor, Sénégal
To determine the optimal conditions for asymmetric syn-
thesis of trifluoromethyl tertiary carbinamines, we exam-
ined the reaction of phenyl hemiaminal 1a with 2 equiv. of
methylmagnesium chloride (in THF) or methyllithium (in
Et2O) in various solvents and at different temperatures
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300890.
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Eur. J. Org. Chem. 2013, 6694–6701

Diastereoselective Carbanion Additions to Chiral Hemiaminals
(Table 1). With methylmagnesium chloride (Table 1, Entries reagents; homoallylic tertiary sulfinamides 2d, e, g, i, j were
1–5), the best diastereoselectivity (30:70), though moderate, obtained with the highest diastereomeric ratios (from 9:91
was obtained using either toluene or CH2Cl2 at room tem- to 5:95) (Table 2, Entries 5, 6, 9, 12, 13).
perature (Table 1, Entries 2 and 4). For practical reasons,
Table 2. Reaction of aryl hemiaminals 1a–c with methyl, benzyl, 2-
thienyl, allyl organomagnesium halides and methyllithium reagents.
this last solvent was selected for further scope and limita-
tion studies with organomagnesium reagents. With meth-
yllithium (Table 1, Entries 6–9) the best diastereoselectivity
and yield were observed when performing the reaction in
toluene from –78 °C to 0 °C (Table 1, Entry 8). Although
the diastereoselectivity of the addition was slightly greater
when using methyllithium instead of the Grignard reagent
(25:75 instead of 30:70), no reversal of induction was ob-
served,[15,16] (Table 1, Entries 4 and 8).
Table 1. Optimization of reaction conditions for additions of meth-
ylmagnesium chloride or methyllithium to phenyl hemiaminal 1a.
Entry Substrate RMgX or RLi[a] Product
dr[b]
(SS,R):(SS,S) [%][c]
Yield
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
MeMgCl
MeLi
2a
2a
2b
2c
2d
2e
30:70
25:75
29:71
27:73
8:92
75
77
69
71
83
70
BnMgCl
2-ThienylMgBr
AllylMgCl
2-Methyl-
allylMgCl
MeMgCl
MeLi
AllylMgCl
MeMgCl
MeLi
9:91
Entry Me-M[a]
Solvent
T [°C]
dr[b]
Yield [%][c]
7
8
9
10
11
12
13
1b
1b
1b
1c
1c
1c
1c
2f
2f
2g
2h
2h
2i
39:61
31:69
8:92
35:65
32:68
9:91
79
82
67
69
74
65
64
1
2
3
4
5
6
7
8
9
MeMgCl Me-THF r.t.
39:61
30:70
30:70
30:70[d]
33:67
62
72
75
75
71
–
63
77
–
MeMgCl toluene
MeMgCl toluene
MeMgCl CH2Cl2
MeMgCl CH2Cl2
r.t.
–10
r.t.
–10
AllylMgCl
2-Methyl-
allylMgCl
2j
5:95
[e]
MeLi
MeLi
MeLi
MeLi
toluene
toluene
toluene
CH2Cl2
–78
–
–25
–78–0
–78–0
34:66
25:75
[a] All reactions were performed with 2 equiv. of organometallic
reagent. [b] Diastereomeric ratio (dr) determined by 19F NMR of
the crude mixture. [c] Isolated yield of both diastereomers of sulfin-
amides 2 after silica gel purification.
[f]
–
[a] All reactions were performed with 2 equiv. of organometallic
reagent. [b] Diastereomeric ratio (dr) determined by 19F NMR of
the crude mixture. [c] Isolated yield of both diastereomers after sil-
ica gel purification. [d] Starting from a diastereomerically pure
sample of 1a led to the same diastereomeric ratio. [e] Very complex
crude mixture containing ca. 25% of tertiary amine 2a (dr = 23:77)
and ca. 60% of starting hemiaminals 1a according to the 19F NMR
spectroscopy. [f] Very messy crude mixture, only traces of tertiary
sulfinamide 2a were detected by 19F NMR spectroscopy.
The absolute configuration of the newly created stereo-
center of N-protected tertiary carbinamines (SS,R)-2a and
(SS,S)-2a was unequivocally assigned by cleaving the sulfin-
amide with HCl and examining the optical rotation of the
known salts (see Supporting Information for details).[12b,17]
The nucleophilic addition of organomagnesium and
The diastereoselective additions of methyl, benzyl, 2-thi- organolithium reagents was next explored with heminami-
enyl and allylic organomagnesium halides and methyllith- nal 1d bearing a methyl substituent (Table 3). Reaction of
ium to trifluoromethyl aryl N-tert-butanesulfinyl hemiamin- phenylmagnesium bromide under the previously optimized
als 1a–c were then screened using the optimized reaction reaction conditions afforded a complex mixture from which
conditions (organomagnesium halide in CH2Cl2 at room protected amine 2a was isolated with a poor yield (35%)
temp. or organolithium in toluene from –78 to 0 °C). The albeit with a very a high diastereoselectivity [93:7, in favour
results are depicted in Table 2. Although the addition of of the (SS,R) isomer] along with product 3[18] (Table 3, En-
methyl organometallic reagents and of benzyl and 2-thienyl try 1). Bis-trifluoromethylated compound 3 results from the
Grignard reagents occurred with poor to moderate dia- self-condensation[19] of the intermediate methyl ketoimine
stereoselectivity (dr ranging from 39:61 to 25:75), amines and further tautomerization towards the more stable en-
2a–c, f, h were isolated in good yields (69–89%) (Table 2, amine. Lowering the temperature of the organomagnesium
Entries 1, 3, 4, 7 and 10). It is worth noting that with all reaction to –20 °C or performing the reaction with phen-
aryl hemiaminals 1a–c, the diastereomeric ratio was slightly yllithium decreased the amount of 3 and increased slightly
enhanced when using methyllithium relative to the methyl the facial diastereoselectivity for the addition of the organo-
Grignard reagent (Table 2, Entries 1, 2, 7, 8 and 10, 11). metallic reagent. Using phenyllithium as the nucleophile,
As previously noticed,[15a,16] the allylation was much more protected amine 2a was obtained with a diastereomeric ra-
successful than was addition of other organomagnesium tio of 99:1 (Table 3, Entries 2 and 3). When AlMe3 was used
Eur. J. Org. Chem. 2013, 6694–6701
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F. Grellepois, A. Ben Jamaa, A. Gassama
FULL PAPER
as an additive with phenyllithium,[15] a much cleaner crude
1
mixture was obtained (according to the 19F and H NMR
spectra) but the yield of amines 2a was not improved and
the diastereoselectivity was lowered (Table 3, Entry 4). Fi-
nally, reaction of hemiaminal 1d with allylmagnesium chlor-
ide at –20 °C afforded the homoallylic amines 2k with a
good diastereoselectivity (89:11) and moderate yield (42%)
(Table 3, Entry 5).
Table 3. Reactions of methyl hemiaminal 1d with organomagnes-
ium and organolithium reagents.
Scheme 2. Rationalization of the observed diastereoselectivity for
the alkylation reactions with organometallic reagents.
Entry Nu[a]
T [°C]
dr[b] of
2(SS,R):(SS,S) 2[%][c]
Yield of Yield of 3
[%][d]
1
2
3
4
PhMgBr
PhMgBr
PhLi
r.t.
–20
–78–0
–78–0
93:7
95:5
99:1
2a, 35
2a, 36
2a, 44
2a, 44
18
9
9
PhLi +
83:17
–
[e]
AlMe3
5
AllylMgCl
–20
89:11
2k, 42
5
[a] All reactions were performed with 2 equiv. of organometallic
nucleophile (Nu). [b] Diastereomeric ratio (dr) determined by 19F
NMR of the crude mixture. [c] Isolated yield of both diastereomers
after silica gel purification. [d] After silica gel purification, only one
diastereomer of product 3 was detected by 19F NMR spectroscopy.
[e] A solution of AlMe3 (1.1 equiv.) and hemiaminal 1d in toluene
was stirred 20 min before the addition of PhLi.
Scheme 3. Rationalization of the observed diastereoselectivity for
the allylation reaction.
The observed diastereoselectivity for the addition of lated in good yields and, more importantly, with very high
methyl, benzyl, aryl and heteroaryl organomagnesium or diastereoselectivity (from 4:96 to 2:98) (Table 4, Entries 1,
organolithium reagent is consistent with a Zimmerman– 3, 4, 6, 7). The high facial stereoselectivity for reduction of
Traxler-type six-membered transition-state TS-1 with coor- 1a with Grignard reagent is comparable to that observed
dination of the sulfinyl oxygen of the intermediate imine[14] for the reduction of the trifluoromethyl phenyl ketoimine
to the metal[16] (Scheme 2). In this six-membered chair tran- with borohydride reagents.[6d] Performing the reaction of
sition state the trifluoromethyl group prefers to occupy the hemiaminal 1a with zincate complex at –78 °C or –20 °C to
equatorial position rather than the axial one due to steric favour the ethyl transfer and to avoid the reduction side
hindrance and to the electrostatic repulsion between the tri- reaction[22] proved futile (Table 4, Entry 2). Reaction of
fluoromethyl group and the lone pair electrons of the sulfur hemiaminal 1a with nBuLi gave secondary carbinamine 4a
group.[6c,11b,14,20] Consequently, approach of the organome- albeit in poor yield, due to the formation of a complex mix-
tallic reagent occurs by the re face.
ture, and with a diastereomeric ratio slightly lower than the
The same facial diastereoselectivity, though greater for one observed with Grignard reagent (Table 4, Entries 4 and
the allylation reaction relative to the alkylation with Grig- 5).
nard reagents, can be explained by a chelated transition-
The absolute configuration of the newly created stereo-
state model TS-2 (Scheme 3).[15a,16,21] In this cyclic transi- center of secondary N-protected sulfinamide (SS,S)-4a was
tion state where both the sulfinyl oxygen and the imine ni- unequivocally assigned by cleaving the sulfinamide with
trogen are coordinated to the magnesium, the approach of HCl and examining the optical rotation of the known salt
the allyl Grignard reagent occurs also from the re face.
(see Supporting Information for details).[5e,6d,9a,17] A six-
The reaction of hemiaminals 1a–c with ethyl, isopropyl membered ring transition-state TS-3 where the sulfinyl oxy-
and n-butylmagnesium halides generated only secondary gen and the imine nitrogen are both coordinated to the
trifluoromethylated carbinamines 4a–c, resulting from the magnesium can be invoked to rationalize the high facial
reduction of the intermediate imines[14] via β-hydride trans- diastereoselectivity for the reduction by organometallics by
fer (Table 4). The secondary carbinamines 4a–c were iso- β-hydride elimination (Scheme 4).
6696
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Eur. J. Org. Chem. 2013, 6694–6701

Diastereoselective Carbanion Additions to Chiral Hemiaminals
Table 4. Reductions of aryl hemiaminals 1a–c with ethyl, isopropyl, propyl and n-butyl Grignard reagents all afforded second-
n-butyl organomagnesium halides and n-butyllithium reagents.
ary carbinamines with very high diastereoselectivities (dr
ranging from 96:4 to 98:2).
Experimental Section
Generals: CH2Cl2 (extra-dry, water Ͻ 0.003%), toluene (extra-dry,
on molecular sieves) and 2-Me-THF (extra-dry, water Ͻ 0.005%,
on molecular sieves) were purchased from Acros Organics. All
Grignard reagents were purchased from Aldrich or Acros Organics
and were titrated through the combined use of (+)-menthol and
(1,10)-phenanthroline as indicator.[23] Organolithium reagents were
purchased from Acros Organics and were titrated using N-pivaloyl-
o-toluidine as indicator.[24] Thin-layer chromatography using pre-
coated aluminium backed plates (Merck Kieselgel 60F254) were
visualized by UV light and/or by phosphomolybdic acid. Flash
chromatography was performed with silica gel 15–40 μm (Merck)
and an Armen flash pump. NMR spectra were recorded in CDCl3
with 250 MHz and 500 MHz spectrometers. Chemicals shifts (δ)
are reported in ppm relative to TMS for 1H and 13C NMR spectra
and to CFCl3 for 19F NMR spectra. In the 13C NMR spectroscopic
data, reported signal multiplicities are related to C-F coupling. The
following abbreviations are used to indicate the multiplicities: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Dia-
stereomeric ratios (dr) were determined by 19F NMR spectroscopy.
HRMS were recorded with an ESI-Q-TOF mass spectrometer
using an electrospray source in positive mode. Melting points (m.p.)
were determined using a Tottoli apparatus. Optical rotations were
measured at room temperature (ca. 20 °C).
Entry
Substrate Nu[a]
Product
dr[b]
(SS,R):(SS,S)
Yield
[%][c]
1
2
1a
1a
EtMgBr
4a
–
2:98
–
79
–
EtMgBr +
Me2Zn[d]
iPrMgCl
nBuMgCl
nBuLi
3
4
5
6
7
1a
1a
1a
1b
1c
4a
4a
4a
4b
4c
4:96
4:96
5:95
4:96
2:98
80
83
37
72
73
EtMgBr
EtMgBr
[a] All reactions were performed with 2 equiv. of organometallic
nucleophile (Nu) . [b] Diastereomeric ratio (dr) determined by 19F
NMR of the crude mixture. [c] Isolated yield of both diastereomers
of sulfinamides 4 after silica gel purification. [d] The reaction was
attempted at –78 °C and at –20 °C in the presence of Me2Zn
(2.5 equiv.). After 7 h of stirring at –78 °C, very complex crude mix-
ture containing ca. 50% of starting hemiaminal, ca. 40% of tertiary
amines (dr = 40:60) and traces of secondary amines, according to
the 19F NMR, which could not be separated by chromatography
on silica gel. After 7 h of stirring at –20 °C, very complex crude
mixture containing ca. 40% of tertiary amines (dr = 33:67) and
ca. 25% of secondary amines (dr Ͼ 99:1), according to the 19F
NMR, which could not be separated by chromatography on silica
gel.
General Procedure A: Reaction of Organomagnesium Reagents with
Hemiaminals 1a–d: The organomagnesium reagent (2 equiv.) was
added under Ar at 0 °C (for aromatic hemiaminals 1a–c) or –20 °C
(for methyl hemiaminal 1d) to a solution of hemiaminal 1a–d in
CH2Cl2. The reaction was stirred at room temp. (for aromatic hem-
iaminals 1a–c) or –20 °C (for methyl hemiaminal 1d) until comple-
tion and then hydrolyzed with a sat. aq. sol. of NH4Cl. The aque-
ous layer was extracted twice with CH2Cl2. The organic layers were
combined, washed with a sat. aq. sol. of NaHCO3 and brine, dried
(Na2SO4), filtered and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel.
General Procedure B: Reaction of Organolithium Reagents with
Hemiaminals 1a–d: The organolithium reagent (2 equiv.) was added
under Ar at –78 °C to a solution of hemiaminal 1a–d in toluene.
The reaction mixture was then slowly raised to 0 °C during 14 h
and then hydrolyzed with a sat. aq. sol. of NH4Cl. The aqueous
layer was extracted twice with Et2O. The organic layers were com-
bined, washed with brine, dried (Na2SO4), filtered and concen-
trated under reduced pressure. The residue was purified by
chromatography on silica gel.
Scheme 4. Transition state proposed for the reduction.
Conclusions
(+)-(SS,R)-2-Methyl-N-(1,1,1-trifluoro-2-phenylpropan-2-yl)-
propane-2-sulfinamide [(SS,R)-2a], (+)-(SS,S)-2-Methyl-N-(1,1,1-tri-
fluoro-2-phenylpropan-2-yl)propane-2-sulfinamide [(SS,S)-2a] and
(–)-(SS,SS)-N,NЈ-[(R,Z)-1,1,1,5,5,5-hexafluoro-4-methylpent-2-ene-
2,4-diyl]bis(2-methylpropane-2-sulfinamide) (3): Reaction of phenyl
hemiaminal 1a with methyl Grignard reagent: Following the general
procedure A, a solution of methylmagnesium chloride (2.45M in
THF, 747 μL, 1.83 mmol) was added to a solution of hemiaminal
1a (296 mg, 0.915 mmol) in CH2Cl2 (8 mL) and the reaction was
stirred 4 h. Purification of the residue [dr (SS,R):(SS,S) = 30:70] on
silica gel (petroleum ether/Et2O, 70:30) afforded sulfinamide
We have shown that the reaction of organomagnesium
halides and organolithium with chiral trifluoromethyl N-
sulfinyl hemiaminals, bench-stable surrogates of the corre-
sponding ketoimines, led to the N-protected amines with
moderate to excellent diastereomeric ratio (dr up to 99:1).
The best yields were obtained from aryl hemiaminals due
to competitive side reactions with methyl hemiaminals. Re-
action of aromatic hemiaminals with allylic Grignard rea-
gents gave the trifluoromethyl tertiary carbinamines with
the best diastereoselectivities (dr up to 95:5). Ethyl, iso- (SS,R)-2a (57 mg, 21%) as a colorless oil, an intermediate fraction
Eur. J. Org. Chem. 2013, 6694–6701
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F. Grellepois, A. Ben Jamaa, A. Gassama
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containing a mixture of both isomers of 2a (10 mg, 4%), and sulfin-
amide (SS,S)-2a (133 mg, 50%) as a white solid. Reaction of phenyl
hemiaminal 1a with methyllithium: Following the general procedure
H, major), 4.04 (s, 1 H, minor), 4.17 (s, 1 H, major), 6,88–7.71 (m,
10 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 22.7 (minor), 22.8
(major), 42.6 (major), 43.7 (minor), 57.5 (major), 57.6 (minor), 67.1
B, a solution of methyllithium (0.86M in Et2O, 2.30 mL, (q, J = 25.5 Hz, major), 68.0 (q, J = 26.0 Hz, minor), 125.7 (q, J =
1.97 mmol) was added to a solution of hemiaminal 1a (349 mg,
0.987 mmol) in toluene (8 mL). Purification of the residue [dr
(SS,R):(SS,S) = 25:75] on silica gel (petroleum ether/Et2O, 70:30)
afforded sulfinamide (SS,R)-2a (55 mg, 19%) as a colorless oil, an
intermediate fraction containing a mixture of both isomers of 2a
(12 mg, 4%), and sulfinamide (SS,S)-2a (156 mg, 54%) as a white
solid. Reaction of methyl hemiaminal 1d with phenyl Grignard rea-
gent: Following the general procedure A, a solution of phenylmag-
nesium bromide (1.95M in Et2O, 883 μL, 1.72 mmol) was added to
a solution of hemiaminal 1d (225 mg, 0.361 mmol) in CH2Cl2
(5 mL). Purification of the residue [2a dr (SS,R):(SS,S) = 95:5] on
silica gel (petroleum ether/Et2O 90 to, 70:30) afforded bis-sulfinam-
ide 3 (16 mg, 9%) as a colorless oil, sulfinamide (SS,R)-2a (86 mg,
34%) as a colorless oil, and sulfinamide (SS,S)-2a (5 mg, 2%) as a
white solid. Reaction of methyl hemiaminal 1d with phenyllithium:
Following the general procedure B, a solution of phenyllithium
(0.90M in nBu2O, 2.14 mL, 1.92 mmol) was added to a solution of
hemiaminal 1d (251 mg, 0.961 mmol) in toluene (8 mL). Purifica-
tion of the residue [2a dr (SS,R):(SS,S) = 99:1] on silica gel (petro-
leum ether/Et2O, 90:10 to 70:30) afforded bis-sulfinamide 3 (18 mg,
9%) as a colorless oil and sulfinamide (SS,R)-2a (123 mg, 44%) as
a colorless oil. (SS,R)-2a: [α]2D0 = +48.8 (c = 0.66, CHCl3). IR (film):
287.0 Hz, major), 126.0 (q, J = 287.0 Hz, minor), 127.3, 127.5,
127.9, 128.0, 128.2, 128.3, 128.4, 128.6, 129.1, 129.2, 131.1 (minor),
131.6 (major), 133.5 (minor), 133.6 (major), 134.8 (major), 136.6
(minor) ppm. HRMS: m/z calcd. for C19H22F3NaNOS [M + Na]+
392.1272, found 392.1266.
(SS)-2-Methyl-N-[2,2,2-trifluoro-1-phenyl-1-(thiophen-2-yl)ethyl]-
propane-2-sulfinamide (2c): Following the general procedure A, a
solution of 2-thienylmagnesium bromide (0.5M in THF, 3.58 mL,
1.79 mmol) was added to a solution of hemiaminal 1a (290 mg,
0.896 mmol) in CH2Cl2 (8 mL) and the reaction was stirred 4 h.
Purification of the residue [dr (SS,R):(SS,S) = 27:73] on silica gel
(petroleum ether/Et2O, 85:15) afforded a mixture of sulfinamides
(S ,R)-2c and (S ,S)-2c (230 mg, 71%) as a beige oil. IR (film): ν
˜
S
S
= 1636, 1260, 1164, 1075, 700 cm–1. 19F NMR (235 MHz, CDCl3):
δ = –71.5 (s, CF3 minor), –72.3 (s, CF3 major) ppm. 1H NMR
(500 MHz, CDCl3): δ = 1.26 (s, 9 H), 4.40 (s, 1 H), 6.98–7.65 (m,
9 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 22.7, 57.3 (major),
57.6 (minor), 68.9 (q, J = 28.4 Hz, minor), 69.3 (q, J = 33.0 Hz,
major), 125.2 (q, J = 286.5 Hz, minor), 125.4 (q, J = 286.5 Hz,
major), 126.7 (minor), 126.9 (major), 127.6 (minor), 127.7 (major),
128.3 (minor), 128.4 (major), 128.6 (d, J = 2.0 Hz, major), 128.9 (d,
J = 2.0 Hz, minor), 129.3 (major), 129.4 (minor), 129.9 (d, J =
1.5 Hz, minor), 130.7 (d, J = 1.5 Hz, major), 136.6 (minor), 137.5
(major), 139.5 (major), 141.2 (minor) ppm. HRMS: m/z calcd. for
C16H18F3NaNOS2 [M + Na]+ 384.0680, found 384.0690.
ν = 2690, 1500, 1274, 1156, 1072, 700 cm–1. 19F NMR (235 MHz,
˜
CDCl3): δ = –77.3 (s, CF3) ppm. 1H NMR (500 MHz, CDCl3): δ
= 1.24 (s, 9 H), 1.93 (s, 3 H), 3.97 (s, 1 H), 7.32 (d, J = 7.0 Hz, 1
H), 7.36 (dd, J = 7.0, 8.5 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H) ppm.
13C NMR (125.8 MHz, CDCl3): δ = 21.5, 22.5, 56.7, 63.8 (q, J =
27.5 Hz), 125.9 (q, J = 285.0 Hz), 126.7, 128.7, 138.8 ppm. HRMS:
m/z calcd. for C13H18F3NaNOS [M + Na]+ 316.0959, found
316.0959. (SS,S)-2a: M.p. 73–74 °C. [α]2D0 = +97.3 (c = 1.03,
(+)-(SS,S)-2-Methyl-N-(1,1,1-trifluoro-2-phenylpent-4-en-2-yl)-
propane-2-sulfinamide [(SS,S)-2d]: Following the general procedure
A, a solution of allylmagnesium chloride (1.71M in THF, 1.22 mL,
2.08 mmol) was added to a solution of hemiaminal 1a (337 mg,
1.04 mmol) in CH2Cl2 (8 mL) and the reaction was stirred 4 h. Pu-
rification of the residue [dr (SS,R):(SS,S) = 8:92] on silica gel (petro-
leum ether/Et2O, 80:20) afforded a mixture of sulfinamides (SS,R)-
2d and (SS,S)-2d (129 mg, 39 %), and sulfinamide (SS,S)-2d
(147 mg, 44%) as a colorless oil. (SS,S)-2d: [α]2D0 = +30.0 (c = 1.07,
CHCl ). IR (KBrν = 2974, 1449, 1274, 1156, 700 cm–1. 19F NMR
˜
3
1
(235 MHz, CDCl3): δ = –78.5 (s, CF3) ppm. H NMR (500 MHz,
CDCl3): δ = 1.12 (s, 9 H), 1.86 (s, 3 H), 3.76 (s, 1 H), 7.29 (m, 3
H), 7.47 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125.8 MHz, CDCl3):
δ = 22.3, 22.7, 56.7, 63.5 (q, J = 27.5 Hz), 125.6 (q, J = 285.0 Hz),
128.2, 128.8, 135.3 ppm. HRMS: m/z calcd. for C13H18F3NaNOS
CHCl ). IR (film): ν = 2961, 1500, 1158, 1069, 703 cm–1. 19F NMR
˜
3
[M + Na]+ 316.0959, found 316.0958. 3: M.p. 103–105 °C. [α]2D0
=
1
(235 MHz, CDCl3): δ = –73.6 (s, CF3) ppm. H NMR (500 MHz,
–36.0 (c = 0.52, CHCl ). IR (film): ν = 2360, 1367, 1272, 1174,
˜
3
CDCl3): δ = 1.25 (s, 9 H), 3.06 (dd, J = 7.5, 14.5 Hz, 1 H), 3.14
(dd, J = 7.0, 14.5 Hz, 1 H), 4.12 (s, 1 H), 5.20 (d, J = 10.5 Hz, 1 H),
5.27 (dd, J = 1.5, 17.5 Hz, 1 H), 5.63 (ddd, J = 7.0, 10.5, 17.5 Hz, 1
H), 7.39 (m, 3 H), 7.59 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 22.8, 40.0, 57.5, 65.9 (d, J = 26.0 Hz),
121.7, 125.7 (q, J = 287.0 Hz), 128.4, 129.0, 130.8, 134.9 ppm.
HRMS: m/z calcd. for C15H20F3NaNOS [M + Na]+ 342.1115,
found 342.1126.
1140, 1062 cm–1. 19F NMR (235 MHz, CDCl3): δ = –71.2 (s, 3 F,
1
CF3), –80.2 (s, 3 F, CF3) ppm. H NMR (500 MHz, CDCl3): δ =
1.29 (s, 18 H), 1.67 (s, 3 H), 6.26 (s, 1 H), 6.65 (s, 1 H), 7.60 (s, 1
H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 21.3, 22.8, 23.1, 57.5,
57.8, 61.4 (q, J = 28.0 Hz), 121.2 (q, J = 275.0 Hz), 124.9 (q, J =
285.0 Hz), 128.4 (q, J = 3.5 Hz), 131.5 (q, J = 32.0 Hz) ppm.
HRMS: m/z calcd. for C14H24F6NaN2O2S2 [M + Na]+ 453.1081,
found 453.1062. A small amount has been recrystallized from
Et2O/petroleum ether for X-ray analysis.
(SS)-2-Methyl-N-(1,1,1-trifluoro-4-methyl-2-phenylpent-4-en-2-yl)-
propane-2-sulfinamide (2e): Following the general procedure A, a
(SS)-2-Methyl-N-(1,1,1-trifluoro-2,3-diphenylpropan-2-yl)propane- solution of 2-methylallylmagnesium chloride (0.44M in THF,
2-sulfinamide (2b): Following the general procedure A, a solution
of benzylmagnesium chloride (1.0 m in Et2O, 1.78 mL, 1.78 mmol)
was added to a solution of hemiaminal 1a (287 mg, 0.888 mmol)
in CH2Cl2 (8 mL) and the reaction was stirred 4 h. Purification of
the residue [dr (SS,R):(SS,S) = 29:71] on silica gel (petroleum ether/
4.49 mL, 1.97 mmol) was added to a solution of hemiaminal 1a
(319 mg, 0.987 mmol) in CH2Cl2 (8 mL) and the reaction was
stirred 4 h. Purification of the residue [dr (SS,R):(SS,S) = 9:91] on
silica gel (petroleum ether/Et2O, 80:20) afforded a mixture of sulfin-
amides (SS,R)-2e and (SS,S)-2e (231 mg, 70%) as a colorless oil. IR
Et2O, 85:15) afforded a mixture of sulfinamides (SS,R)-2b and (film): ν = 2961, 1390, 1156, 1075, 700 cm–1. 19F NMR (235 MHz,
˜
(S ,S)-2b (226 mg, 69%) as a colorless oil. IR (film): ν = 2960,
CDCl3): δ = –71.3 (s, CF3 minor), –72.6 (s, CF3 major) ppm. 1H
NMR (500 MHz, CDCl3): δ = 1.24 (s, 9 H, major), 1.25 (s, 9 H,
minor), 1.42 (s, 3 H), 2.95 (d, J = 14.0 Hz, 1 H, major), 2.96 (d, J
= 14.0 Hz, 1 H, minor), 3.05 (d, J = 14.5 Hz, 1 H, major), 3.11 (d,
J = 14.5 Hz, 1 H, minor), 4.03 (s, 1 H, minor), 4.31 (s, 1 H, major),
˜
S
1166, 1078, 702 cm–1. 19F NMR (235 MHz, CDCl3): δ = –69.5 (s,
CF3 minor), –71.5 (s, CF3 major) ppm. 1H NMR (500 MHz,
CDCl3): δ = 1.25 (s, 3 H, major), 1.30 (s, 3 H, minor), 3.55 (d, J =
14.0 Hz, 1 H, minor), 3.61 (d, J = 14.0 Hz, 1 H, minor), 3.64 (s, 2
6698
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6694–6701

Diastereoselective Carbanion Additions to Chiral Hemiaminals
4.60 (s, 1 H, minor), 4.84 (s, 1 H, major), 4.87 (s, 1 H, minor), 4.96
(s, 1 H, major), 7.35 (m, 3 H), 7.59 (d, J = 7.5 Hz, 2 H, minor), 7.67
(d, J = 8.0 Hz, 2 H, major) ppm. 13C NMR (125.8 MHz, CDCl3): δ
= 17.0 Hz, 1 H), 5.63 (ddd, J = 7.5, 10.0, 17.0 Hz, 1 H), 7.05 (t, J
= 8.5 Hz, 2 H), 7.57 (dd, J = 5.0, 8.5 Hz, 2 H) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 22.7, 40.4, 57.4, 65.6 (q, J = 26.0 Hz),
= 22.5 (major), 22.7 (minor), 43.7 (major), 43.9 (minor), 57.4 115.3 (d, J = 21.5 Hz), 122.1, 125.6 (q, J = 287.0 Hz), 130.5, 130.7
(minor), 57.6 (major), 66.1 (q, J = 26.0 Hz, major), 117.5 (minor),
118.5 (major), 125.7 (q, J = 287.0 Hz, major), 128.3 (major), 128.4
(d, J = 1.5 Hz, major), 128.8 (major), 135.5 (major), 137.0 (minor),
138.7 (minor), 139.0 (major) ppm. HRMS: m/z calcd. for
C16H22F3NaNOS [M + Na]+ 356.1272, found 356.1264.
(d, J = 8.5 Hz), 162.8 (d, J = 249.5 Hz) ppm. HRMS: m/z calcd.
for C15H19F4NaNOS [M + Na]+ 360.1021, found 360.1018.
(+)-(SS,R)-2-Methyl-N-[1,1,1-trifluoro-2-(3-methoxyphenyl)-
propan-2-yl]propane-2-sulfinamide [(SS,R)-2h] and (+)-(SS,S)-2-
Methyl-N-[1,1,1-trifluoro-2-(3-methoxyphenyl)propan-2-yl]-
(+)-(SS,R)-2-Methyl-N-[1,1,1-trifluoro-2-(4-fluorophenyl)propan- propane-2-sulfinamide [(SS,S)-2h]: Reaction of aryl hemiaminal 1c
2-yl]propane-2-sulfinamide [(SS,R)-2f] and (+)-(SS,S)-2-Methyl-N- with methyl Grignard reagent: Following the general procedure A,
[1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-yl]propane-2-sulfinamide a solution of methylmagnesium chloride (2.45M in THF, 726 μL,
[(SS,S)-2f]: Reaction of aryl hemiaminal 1b with methyl Grignard
reagent: Following the general procedure A, a solution of methyl-
magnesium chloride (2.45M in THF, 693 μL, 1.70 mmol) was
added to a solution of hemiaminal 1b (290 mg, 0.850 mmol) in
CH2Cl2 (8 mL) and the reaction was stirred 4 h. Purification of the
residue [dr (SS,R):(SS,S) = 39:61] on silica gel (petroleum ether/
Et2O, 70:30) afforded sulfinamide (SS,R)-2f (74 mg, 28%) as a col-
orless oil, an intermediate fraction containing a mixture of both
isomers of 2f (9 mg, 3%), and sulfinamide (SS,S)-2f (127 mg, 48%)
1.78 mmol) was added to a solution of hemiaminal 1c (314 mg,
0.890 mmol) in CH2Cl2 (8 mL) and the reaction was stirred 4 h.
Purification of the residue [dr (SS,R):(SS,S) = 35:65] on silica gel
(petroleum ether/Et2O, 70:30) afforded sulfinamide (SS,R)-2h
(71 mg, 25%) as a white solid, and sulfinamide (SS,S)-2h (128 mg,
44%) as a pale yellow solid. Reaction of aryl hemiaminal 1c with
methyllithium: Following the general procedure B, a solution of
methyllithium (0.86M in Et2O, 2.03 mL, 1.75 mmol) was added to a
solution of hemiaminal 1c (308 mg, 0.873 mmol) in toluene (8 mL).
as a white solid. Reaction of aryl hemiaminal 1b with methyllithium: Purification of the residue [dr (SS,R):(SS,S) = 32:68] on silica gel
Following the general procedure B, a solution of methyllithium
(0.86M in Et2O, 1.83 mL, 1.57 mmol) was added to a solution of
hemiaminal 1b (268 mg, 0.785 mmol) in toluene (8 mL). Purifica-
tion of the residue [dr (SS,R):(SS,S) = 31:69] on silica gel (petroleum
ether/Et2O, 70:30) afforded sulfinamide (SS,R)-2f (46 mg, 19%) as
a colorless oil, an intermediate fraction containing a mixture of
both isomers of 2f (26 mg, 11 %), and sulfinamide (SS,S)-2f
(126 mg, 52%) as a white solid. (SS,R)-2f: [α]2D0 = +43.0 (c = 0.51,
(petroleum ether/Et2O, 70:30) afforded sulfinamide (SS,R)-2h
(61 mg, 22%) as a white solid, an intermediate fraction containing
a mixture of both isomers of 2h (12 mg, 4 %), and sulfinamide
(SS,S)-2h (135 mg, 48%) as a pale yellow solid. (SS,R)-2h: M.p. 45–
46 °C. [α]2D0 = +45.0 (c = 0.49, CHCl ). IR (film): ν = 2959, 1263,
˜
3
1155, 1068 cm–1
.
19F NMR (235 MHz, CDCl3): δ = –73.0 (s,
CF3) ppm. 1H NMR (500 MHz, CDCl3): δ = 1.26 (s, 9 H), 1.94 (s,
3 H), 3.81 (s, 3 H), 3.92 (s, 1 H), 6.88 (ddd, J = 1.0, 2.0, 8.0 Hz, 1
H), 7.17 (d, J = 8.0 Hz, 1 H), 7.18 (s, 1 H), 7.30 (t, J = 8.0 Hz, 1
CHCl ). IR (film): ν = 2960, 1608, 1514, 1274, 1243, 1165, 1071,
˜
3
838 cm–1. 19F NMR (235 MHz, CDCl3): δ = –77.7 (s, 3 F, CF3), H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 21.6, 22.6, 55.4, 56.9,
–113.5 (m, 1 F, CF) ppm. 1H NMR (500 MHz, CDCl3): δ = 1.26
(s, 9 H), 1.93 (s, 3 H), 3.91 (s, 1 H), 7.06 (t, J = 8.5 Hz, 2 H), 7.57 129.9, 140.6, 159.8 ppm. HRMS: m/z calcd. for C14H21F3NO2S [M
64.0 (q, J = 27.5 Hz), 113.4, 113.9, 118.9, 126.0 (q, J = 285.0 Hz),
(dd, J = 5.0, 8.5 Hz, 2 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ
+ H]+ 324.1245, found 324.1239. (SS,S)-2h: M.p. 62–63 °C. IR
= 21.7, 22.6, 56.9, 63.7 (q, J = 27.5 Hz), 115.7 (d, J = 21.5 Hz), (film): ν = 2959, 1276, 1155 cm–1. [α]20 = +87.8 (c = 1.03, CHCl3).
˜
D
1
125.9 (q, J = 284.5 Hz), 129.0 (dd, J = 1.5, 18.5 Hz), 134.7 (d, J
= 3.5 Hz), 162.8 (d, J = 249.0 Hz) ppm. HRMS: m/z calcd. for
C13H17F4NaNOS [M + Na]+ 334.0865, found 334.0860. (SS,S)-2f:
19F NMR (235 MHz, CDCl3): δ = –78.4 (s, CF3) ppm. H NMR
(500 MHz, CDCl3): δ = 1.23 (s, 3 H), 1.94 (s, 3 H), 3.75 (s, 1 H),
3.79 (s, 3 H), 6.91 (dd, J = 2.5, 8.0 Hz, 1 H), 7.11 (s, 1 H), 7.13 (d,
J = 8.0 Hz, 1 H), 7.30 (t, J = 8.0 Hz, 1 H) ppm. 13C NMR
M.p. 93–94 °C. [α]2D0 = +97.0 (c = 0.50, CHCl ). IR (film): ν = 2961,
˜
3
1515, 1171, 1155, 1135, 1018, 836 cm–1
.
19F NMR (235 MHz, (125.8 MHz, CDCl3): δ = 22.6, 23.0, 55.2, 57.0, 63.7 (q, J =
CDCl3): δ = –78.9 (s, 3 F, CF3), –112.8 (m, 1 F, CF) ppm. 1H NMR
(500 MHz, CDCl3): δ = 1.23 (s, 9 H), 1.96 (s, 3 H), 3.73 (s, 1 H),
7.07 (t, J = 8.5 Hz, 2 H), 7.54 (dd, J = 5.5, 8.5 Hz, 2 H) ppm. 13C
NMR (125.8 MHz, CDCl3): δ = 22.6, 23.2, 57.1, 63.5 (q, J =
27.5 Hz), 115.4 (d, J = 21.5 Hz), 125.7 (q, J = 285.0 Hz), 130.7 (dd,
J = 1.0, 8.5 Hz), 131.1 (d, J = 3.5 Hz), 163.1 (d, J = 249.5 Hz) ppm.
HRMS: m/z calcd. for C13H17F4NaNOS [M + Na]+ 334.0865,
found 334.0866.
27.5 Hz), 114.0, 115.0, 125.7 (q, J = 285.5 Hz), 129.3, 137.1,
159.4 ppm. HRMS: m/z calcd. for C14H20F3NaNO2S [M + Na]+
346.1065, found 346.1065.
(+)-(SS,S)-2-Methyl-N-[1,1,1-trifluoro-2-(3-methoxyphenyl)pent-4-
en-2-yl]propane-2-sulfinamide [(SS,S)-2i]: Following the general pro-
cedure A, a solution of allylmagnesium chloride (1.71M in THF,
1.16 mL, 1.99 mmol) was added to a solution of hemiaminal 1c
(351 mg, 0.993 mmol) in CH2Cl2 (8 mL) and the reaction was
stirred 4 h. Purification of the residue [dr (SS,R):(SS,S) = 9:91] on
silica gel (petroleum ether/Et2O, 80:20) afforded a mixture of sulfin-
amides (SS,R)-2i and (SS,S)-2i (62 mg, 18 %), and sulfinamide
(SS,S)-2i (163 mg, 47%) as a colorless oil. (SS,S)-2i: [α]2D0 = +13.4
(+)-(SS,S)-2-methyl-N-[1,1,1-trifluoro-2-(4-fluorophenyl)pent-4-en-
2-yl]propane-2-sulfinamide [(SS,S)-2 g]: Following the general pro-
cedure A, a solution of allylmagnesium chloride (1.71M in THF,
898 μL, 1.34 mmol) was added to a solution of hemiaminal 1b
(262 mg, 0.767 mmol) in CH2Cl2 (7 mL) and the reaction was
stirred 4 h. Purification of the residue [dr (SS,R):(SS,S) = 8:92] on
silica gel (petroleum ether/Et2O, 80:20) afforded a mixture of sulfin-
(c = 1.12, CHCl ). IR (film): ν = 2960, 1604, 1586, 1257, 1153,
˜
3
1073 cm–1. 19F NMR (235 MHz, CDCl3): δ = –73.4 (s, CF3) ppm.
1H NMR (500 MHz, CDCl3): δ = 1.24 (s, 9 H), 3.05 (qd, J = 7.0,
amides (SS,R)-2g and (SS,S)-2g (30 mg, 12 %), and sulfinamide 14.5 Hz, 2 H), 3.79 (s, 3 H), 4.08 (s, 1 H), 5.18 (d, J = 10.0 Hz, 1
(SS,S)-2g (142 mg, 55%) as a pale yellow oil. (SS,S)-2g: [α]2D0
=
H), 5.25 (dd, J = 1.5, 17.0 Hz, 1 H), 5.60 (m, 1 H), 6.89 (dd, J =
+35.9 (c = 1.01, CHCl ). IR (film): ν = 2962, 1515, 1241, 1163, 2.0, 8.0 Hz, 1 H), 7.15 (m, 2 H), 7.29 (t, J = 8.0 Hz, 1 H) ppm. 13
C
˜
3
1045, 839 cm–1. 19F NMR (235 MHz, CDCl3): δ = –73.7 (s, 3 F, NMR (125.8 MHz, CDCl3): δ = 22.8, 40.1, 55.3, 57.6, 66.0 (q, J =
1
CF3), –113.0 (m, 1 F, CF) ppm. H NMR (500 MHz, CDCl3): δ = 26.0 Hz), 114.0, 115.0, 120.4, 121.5, 125.7 (q, J = 287.0 Hz), 129.4,
1.22 (s, 9 H), 3.00 (dd, J = 7.5, 15.0 Hz, 1 H), 3.08 (dd, J = 7.0,
130.8, 136.5, 159.5 ppm. HRMS: m/z calcd. for C16H23F3NO2S [M
14.5 Hz, 1 H), 4.12 (s, 1 H), 5.21 (d, J = 10.0 Hz, 1 H), 5.26 (d, J + H]+ 350.1402, found 350.1410.
Eur. J. Org. Chem. 2013, 6694–6701
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6699

F. Grellepois, A. Ben Jamaa, A. Gassama
FULL PAPER
(+)-(SS,S)-2-Methyl-N-[1,1,1-trifluoro-2-(3-methoxyphenyl)-4-meth-
ylpent-4-en-2-yl]propane-2-sulfinamide [(SS,S)-2j]: Following the ge-
neral procedure A, a solution of 2-methylallylmagnesium chloride
(0.44M in THF, 2.49 mL, 1.10 mmol) was added to a solution of
hemiaminal 1c (194 mg, 0.549 mmol) in CH2Cl2 (6 mL) and the
reaction was stirred 4 h. Purification of the residue [dr (SS,R):(SS,S)
= 5:95] on silica gel (petroleum ether/Et2O, 80:20) afforded a mix-
ture of sulfinamides (SS,R)-2j and (SS,S)-2j (59 mg, 30%), and sulf-
inamide (SS,S)-2j (de = 96%, 68 mg, 34%) as a colorless oil. (SS,S)-
(SS,R)-4b and (SS,S)-4b (22 mg, 14%) as a colorless oil, and sulfina-
mide (SS,S)-4b (90 mg, 58%) as a white solid. (SS,S)-4b: M.p. 94–
96 °C. [α]2D0 = +113.0 (c = 0.51, CHCl ). IR (film): ν = 2961, 1515,
˜
3
1174, 1125, 1068 cm–1. 19F NMR (235 MHz, CDCl3): δ = –75.0 (d,
J = 7.0 Hz, 3 F, CF3), –111.6 (tt, J = 5.5, 8.5 Hz, 1 F, CF) ppm.
1H NMR (500 MHz, CDCl3): δ = 1.21 (s, 9 H), 3.95 (d, J = 1.5 Hz,
1 H), 4.88 (qd, J = 3.5, 7.5 Hz), 7.10 (t, J = 8.5 Hz, 2 H), 7.43 (dd,
J = 5.5, 8.5 Hz, 2 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
22.4, 56.4, 59.8 (q, J = 30.5 Hz), 116.0 (d, J = 22.0 Hz), 124.5 (q,
J = 281.5 Hz), 127.5, 131.3 (d, J = 8.5 Hz), 163.6 (d, J =
2j: [α]2D0 = +48.8 (c = 0.66, CHCl ). IR (film): ν = 2961, 1647, 1255,
˜
3
1174 cm–1. 19F NMR (235 MHz, CDCl3): δ = –72.4 (s, CF3) ppm. 249.5 Hz) ppm. HRMS: m/z calcd. for C12 H1 5F4NaNOS
1H NMR (500 MHz, CDCl3): δ = 1.27 (s, 9 H), 1.45 (s, 3 H), 2.90
(d, J = 14.0 Hz, 1 H), 3.02 (d, J = 14.0 Hz, 1 H); 3.82 (s, 3 H),
4.26 (s, 3 H), 4.87 (s, 1 H), 4.99 (s, 1 H), 6.90 (dd, J = 2.0, 8.0 Hz,
1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.30 (m, 2 H) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 22.9, 24.1, 44.1, 55.5, 57.8, 66.4 (q, J =
26.0 Hz), 114.2, 115.0, 118.6, 120.6, 125.8 (q, J = 287.0 Hz), 129.4,
137.4, 139.2, 159.6 ppm. HRMS: m/z calcd. for C17H24F3NaNO2S
[M + Na]+ 386.1378, found 386.1389.
[M + Na]+ 320.0708, found 320.0706.
(+)-(SS,S)-2-Methyl-N-[2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl]-
propane-2-sulfinamide [(SS,S)-4c]: Following the general procedure
A, a solution of ethylmagnesium bromide (2.99M in Et2O, 871 μL,
1.74 mmol) was added to a solution of hemiaminal 1c (308 mg,
0.871 mmol) in CH2Cl2 (8 mL) and the reaction was stirred 4 h.
Purification of the residue [dr (SS,R):(SS,S) = 2:98] on silica gel
(petroleum ether/Et2O, 75:25) afforded sulfinamide (SS,S)-4c
(196 mg, 73%, de = 96%) as a colorless oil. [α]2D0 = +91.4 (c = 0.99,
(+)-(SS,R)-2-Methyl-N-(1,1,1-trifluoro-2-methylpent-4-en-2-yl)-
propane-2-sulfinamide [(SS,R)-2k]: Following the general procedure
A, a solution of allylmagnesium chloride (1.71M in THF, 1.19 mL,
2.03 mmol) was added to a solution of hemiaminal 1d (265 mg,
1.02 mmol) in CH2Cl2 (8 mL) and the reaction was stirred 15 h.
Purification of the residue [2k dr (SS,R):(SS,S) = 89:11] on silica
gel (petroleum ether/Et2O, 80:20) afforded bis-sulfinamide 3
(10 mg, 5%) as a colorless oil, an intermediate fraction containing
sulfinamide (SS,R)-2k (78 mg, 30%, de = 97%) as a white solid,
and a fraction containing a mixture of both isomers of 2k (30 mg,
CHCl ). IR (film): ν = 2960, 1605, 1458, 1261, 1172, 1124,
˜
3
1070 cm–1. 19F NMR (235 MHz, CDCl3): δ = –74.3 (d, J = 7.5 Hz,
CF3 minor), –74.6 (d, J = 7.0 Hz, CF3 major) ppm. 1H NMR
(500 MHz, CDCl3): δ = 1.20 (s, 9 H), 3.77 (s, 3 H), 4.01 (d, J =
3.5 Hz, 1 H), 4.81 (qd, J = 4.0, 7.0 Hz, 1 H), 6.92 (m, 1 H), 6.96
(s, 1 H), 6.98 (d, J = 7.5 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H) ppm.
13C NMR (125.8 MHz, CDCl3): δ = 22.4, 55.2, 56.5, 60.5 (q, J =
30.5 Hz), 115.0, 115.1, 121.6, 124.5 (q, J = 281.5 Hz), 129.8, 133.2,
159.8 ppm. HRMS: m/z calcd. for C13H18F3NaNO2S [M + Na]+
332.0908, found 332.0915.
12%). (S ,R)-2k (de = 97%): M.p. 92–93 °C. IR (film): ν = 2981,
˜
S
1275, 1185, 1095, 915, 703 cm–1. [α]2D0 = +96.0 (c = 0.51, CHCl3).
Supporting Information (see footnote on the first page of this arti-
cle): Description of general procedure for the cleavage of the N-
tert-butanesulfinyl group and configuration assignment of (SS,R)-
2a, (SS,S)-2a and (SS,S)-4a, copies of 19F, 1H and 13C NMR spectra
(sulfinamides 2a–k, 3 and 4a–c) and X-ray structural data of
product 3.
19F NMR (235 MHz, CDCl3): δ = –79.2 (s, CF3 minor), –80.2 (s,
CF3 major) ppm. H NMR (500 MHz, CDCl3): δ = 1.19 (s, 9 H),
1
1.54 (s, 3 H), 2.43 (dd, J = 8.5, 14.0 Hz, 1 H), 2.55 (dd, J = 6.5,
14.0 Hz, 1 H), 3.64 (s, 1 H), 5.23 (d, J = 17.0 Hz, 1 H) 5.28 (d, J
= 9.0 Hz, 1 H), 5.81 (td, J = 9.0, 17.0 Hz, 1 H) ppm. 13C NMR
(125.8 MHz, CDCl3): δ = 18.9, 22.6, 41.4, 56.6, 59.7 (q, J =
26.5 Hz), 122.0, 126.4 (q, J = 284.5 Hz), 130.7 ppm. HRMS: m/z
calcd. for C10H18F3NaNOS [M + Na]+ 280.0959, found 280.0968.
Acknowledgments
(+)-(SS,S)-2-Methyl-N-(2,2,2-trifluoro-1-phenylethyl)propane-2-
sulfinamide [(SS,S)-4a]: Following the general procedure A, a
solution of ethylmagnesium bromide (2.99M in Et2O, 572 μL,
1.71 mmol) was added to a solution of hemiaminal 1a (276 mg,
0.854 mmol) in CH2Cl2 (8 mL) and the reaction was stirred 4 h.
Purification of the residue [dr (SS,R):(SS,S) = 2:98] on silica gel
(petroleum ether/Et2O, 75:25) afforded sulfinamide (SS,S)-4a
(142 mg, 60%, de = 96%) as a colorless oil. [α]2D0 = +103.8 (c =
The authors thank Dominique Harakat for the HRMS analyses
and Emmanuel Wenger (Institut Jean Barriol, Université de Lor-
raine, Nancy) for the X-ray structure determination. Financial sup-
port from the Centre National de la Recherche Scientifique
(CNRS), the Conseil Regional Champagne-Ardenne, the Conseil
General de la Marne, and the EU-program Fundo Europeu de De-
senvolvimento Regional (FEDER) for the PlAneT CPER project
(Analytical platform) is gratefully acknowledged. A. G. thanks the
Senegalese Ministère de l’Enseignement Supérieur for the funding
of his stay in France.
0.69, CHCl ). IR (film): ν = 2960, 1262, 1171, 1124, 1071, 702 cm–1.
˜
3
19F NMR (235 MHz, CDCl3): δ = –74.4 (d, J = 7.5 Hz, CF3 minor),
–74.7 (d, J = 7.0 Hz, CF3 major) ppm. 1H NMR (500 MHz,
CDCl3): δ = 1.20 (s, 9 H), 3.97 (d, J = 3.0 Hz, 1 H), 4.85 (qd, J =
4.0, 7.0 Hz, 1 H), 7.39 (m, 5 H) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 22.4. 56.4, 60.6 (q, J = 30.5 Hz), 124.6 (q, J =
281.5 Hz), 128.8, 129.3, 129.8, 131.8 ppm. HRMS: m/z calcd. for
C12H16F3NaNOS [M + Na]+ 302.0802, found 302.0798.
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6700
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Eur. J. Org. Chem. 2013, 6694–6701

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Received: June 18, 2013
Published Online: August 23, 2013
Eur. J. Org. Chem. 2013, 6694–6701
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6701