Asymmetric synthesis of trifluoromethylated propargylamines via 1,2-additions of trifluoromethylacetylide to N-tert-butanesulfinyl imines

Article abstract of DOI:10.1016/j.tet.2008.01.021

An efficient method for the asymmetric synthesis of the trifluoromethylated propargylamines was described. Addition of lithium trifluoromethylacetylide, in situ prepared from lithium diisopropylamide and the 2-bromo-3,3,3-trifluoropropene, to various N-te

Full text of DOI:10.1016/j.tet.2008.01.021

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2301e2306
www.elsevier.com/locate/tet
Asymmetric synthesis of trifluoromethylated propargylamines
via 1,2-additions of trifluoromethylacetylide
to N-tert-butanesulfinyl imines
Xian-Yin Chen a, Xiao-Long Qiu b, Feng-Ling Qing a,b,
*
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 21 November 2007; received in revised form 7 January 2008; accepted 8 January 2008
Available online 11 January 2008
Abstract
An efficient method for the asymmetric synthesis of the trifluoromethylated propargylamines was described. Addition of lithium trifluoro-
methylacetylide, in situ prepared from lithium diisopropylamide and the 2-bromo-3,3,3-trifluoropropene, to various N-tert-butanesulfinyl imines
provided a range of trifluoromethylated propargyl sulfinamides. Besides high yields and excellent diastereoselectivities, the additions featured
that the diastereoselectivities could be reversed when polar or nonpolar solvent was used. Acidic cleavage of the tert-butanesulfinyl groups
delivered highly optically pure trifluoromethylated propargylamines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Asymmetric synthesis; Trifluoromethyl group; Propargylamine; 1,2-Addition
1. Introduction
Cu(I)ebis(oxazoline)/stearic acid system was also reported
by Li et al.4 The other strategy was asymmetric addition of
alkynyl metal reagent to chiral sulfinylimine. As the chiral aux-
iliary, chiral sulfinylimine appeared to be very successful in the
asymmetric synthesis of propargylamines. Almost at the same
time, Hou group5 and Ellman group6 documented the highly
asymmetric synthesis of a-monobranched and a,a-dibranched
propargylamines through addition of lithium acetylide to
N-tert-butanesulfinimines and N-tert-butanesulfinyl ketimines,
respectively. Very recently, diastereoselective synthesis of
propargylamines via addition of alkynyl dimethyl aluminum
compounds onto N-p-tolylsulfinylimines was also investi-
gated.7 With chiral prolinol derivatives as chiral auxiliaries,
Che group also fulfilled the diastereoselective synthesis of
propargylamines by means of gold(III) salen complex-cata-
lyzed three-component coupling reaction of aldehydes, amines,
and alkynes.8
Propargylamines, especially chiral propargylamines, are im-
portant building blocks in the synthesis of many pharmaceuti-
cal intermediates and natural products.1 Recently, developing
the novel and efficient access to the chiral propargylamines
has received increasing attention of organic chemists. Gener-
ally, two major strategies were used to prepare chiral propargyl-
amines. One tactics utilized the chiral metaleligand complexes
to induce the addition of alkynes to enamines or imines. For
example, Knochel group described the addition of functional-
ized alkynes to enamines catalyzed by Cu(I)eQuinap com-
plexes.2 This group also found that Cu(I)eQuinap complexes
were also efficient in one-pot three-component addition of tri-
methylsilylacetylene, aldehydes, and Bn2NH.3 In addition,
asymmetric addition of alkynes to imines with a recyclable
Currently, it is well known that trifluoromethyl-containing
compounds play important roles in pharmaceutical, agrochem-
ical, and materials sciences.9 Trifluoromethyl group has an
* Corresponding author. Tel.: þ86 21 54925187; fax: þ86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.021

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X.-Y. Chen et al. / Tetrahedron 64 (2008) 2301e2306
electronegativity similar to that of oxygen10 and a high hydro-
phobic parameter.11 Furthermore, the high lipophilicity brought
about by the CF3 moiety confers a better bioavailability to the
molecules bearing this group.12 However, to the best of our
knowledge, there is no report about the preparation of chiral
trifluoromethylated propargylamines although many methodol-
ogies were developed to access propargylamines. Recently, our
group described the nucleophilic addition of 3,3,3-trifluoropro-
pynyllithium to D-glyceraldimine and the resultant products
were successfully used in the synthesis of the chiral 5,5,5-tri-
fluoronorvaline.13 As a part of our ongoing research about
developing the versatile fluorine-containing building blocks,
herein reported our results for the asymmetric synthesis of
4,4,4-trifluoromethylated propargylamines via addition of
lithium trifluoromethylacetylide to the various N-tert-butane-
sulfinyl imines.
Table 1
The 1,2-addition of lithium trifluoromethylacetylide to N-tert-butanesulfinyl
aldimines
+
+
..
CF3
H
R1
S
H
N
F3C
Li
Li
O
R1
NH
S
THF
CF3
O
O
S
H
(SS,R)-2
non-chelated TS A
N
R1
+
+
CF3
..
S
H
R1
H
(SS)-1
F3C
toluene
R1
N
NH
Li
O
S
F3C
O
Chelated Cyclic TS B
(SS,S)-2
Solvent Producta
THF
iPr (1b) THF
Pr (1c) THF
iBu (1d) THF
Et (1a)
iPr (1b) Toluene (SS,S)-2b 85
Pr (1c) Toluene (SS,S)-2c 76
iBu (1d) Toluene (SS,S)-2d 85
Yieldb (%) (SS,S)-2/(SS,R)-2 (dr)
2. Result and discussion
Entry R1
1
2
3
4
5
6
7
8
Et (1a)
(SS,R)-2a 69
(SS,R)-2b 73
(SS,R)-2c 67
(SS,R)-2d 76
7:93c
8:92d
6:94c
The N-tert-butanesulfinyl aldimines 1 were prepared by
a simple CuSO4-mediated condensation of tert-butanesulfina-
mide with aldehydes according to the reported procedure.14
The 1,2-addition of lithium trifluoromethylacetylide to 1 was
performed by the dropwise addition of a solution of 1 to a so-
lution of lithium trifuoromethylacetylide, in situ prepared
through the reaction of 2 equiv of LDA with 2-bromo-3,3,3-
trifluoropropene at ꢀ78 ꢁC. Uniformly, good diastereoselec-
tivities and medium yields were observed for a broad range
of aldimines (SS)-1 (Table 1). When the additions were
performed in THF, the desired trifluoromethylated propargyl
sulfinamides 2 were obtained in 89:11 to 94:6 dr and (SS,R)-
2aed observed to be the major diastereoisomers (entries
1e4, Table 1). Purification of the crude products 2aed by
silica gel chromatography readily delivered two pure isomers
(SS,R)-2aed and (SS,S)-2aed. The absolute configuration of
the major isomer (SS,R)-2a was determined by X-ray crystal-
lographic analysis (Fig. 1).15 Interestingly, reactions carried
out in toluene were found to favor the formation of the
(SS,S)-2aed, which were obtained in 86:14 to 99:1 dr (entries
5e8, Table 1). A rationale for the observed switchover in dia-
stereoselectivities through changing the solvent could be pro-
vided through two different transition states, the non-chelated
transition state A and chelated transition state B.16 That is,
chelated solvent THF could efficiently inhibit the formation
of transition state B and the trifluoropropynyl anion mainly
attacked the less shielded side of N-tert-butanesulfinyl aldi-
mines, which resulted in the formation of (SS,R)-2 as the major
isomers. However, nonchelating solvent toluene would be
essential to prevent competitive coordination of the solvent
to the metal cation and chelated cyclic transition state B pre-
dominantly occurred, which delivered the isomers (SS,S)-2
as the dominant adducts.
11:89c
86:14c
87:13d
91:9c
Toluene (SS,S)-2a 79
99:1c
a
Configurations were assigned by the transition state model.
Isolated yields of diastereomerically and analytically pure products after
b
chromatography.
c
Diastereomeric ratios were determined by 1H NMR from the crude
products.
d
Diastereomeric ratios were confirmed by 19F NMR from the crude
products.
isomers were observed. The ketimine 3b was isolated as a mix-
ture of E and Z isomers (6:1). We found that the 1,2-addition
of lithium trifluoromethylacetylide to N-tert-butanesulfinyl
The addition of lithium trifluoromethylacetylide to N-tert-
butanesulfinyl ketimines 3 was also investigated (Table 2).
The sulfinyl ketimines 3 used in this study were prepared by
Ti(OEt)4-mediated condensations of N-tert-butylsulfinamide
with ketones.14 For the ketimines 3a, 3c, and 3d, only the E
Figure 1. X-ray crystal structure of (SS,R)-2a.

X.-Y. Chen et al. / Tetrahedron 64 (2008) 2301e2306
2303
Table 2
The 1,2-addition of lithium trifluoromethylacetylide to N-tert-butanesulfinyl ketimines
+
+
CF3
R1
..
R2
R1
O
S
R1
S
F3C
Me3Al, toluene
Li
R2
N
NH
S
N
Li
R2
O
Al
F3C
O
(SS)-3
(SS,S)-4
Entry
R1
R2
Conditions
Product
Yieldc (%)
(SS,S)-4/(SS,R)-4 (dr)
1
2
3
4
5
6
7
8
a
Me
Me
Me
Me
Me
Me
Me
Me
iPr (3a)
iBu (3b)
iPr (3a)
iBu (3b)
iPr (3a)
iBu (3b)
Et (3c)
THF
THF
(SS,S)-4aa
55
45
79
74
88
83
69
31
74:26d
62:38d
93:7d
(SS,S)-4bb
(SS,S)-4aa
(SS,S)-4bb
(SS,S)-4aa
(SS,S)-4bb
(SS,S)-4cb
(SS,S)-4db
Toluene
Toluene
83:17d
94:6d
Toluene/Me3Al
Toluene/Me3Al
Toluene/Me3Al
Toluene/Me3Al
93:7e
>99:1e
>99:1e
Ph (3d)
Configuration was confirmed by X-ray crystal structure.
b
c
d
e
Configurations were deduced from 4a based on the comparison of TLC, 1H NMR, and 13C NMR.
Isoalted yields of diastereomerically and analytically pure products after chromatography.
Diastereomeric ratios were determined by 1H NMR of the crude products.
Diastereomeric ratios were confirmed by 19F NMR of the crude products.
ketimines 3a and 3b in THF gave the desired a,a-dibranched
trifluoromethylated propargylamine 4 only in low diastereose-
lectivity and (SS,S)-4 were isolated as the main isomers (en-
tries 1 and 2, Table 2). Slightly surprisingly, also with
(SS,S)-4 as the main isomers, the corresponding propargyl-
amines were obtained in good diastereoselectivity when the
same reactions were carried out in toluene (entries 3e4). Ad-
ditionally, we were pleased to find that addition of AlMe3 to
the reaction systems could further increase the diastereoselec-
tivities and yields (entries 5 and 6). Especially noteworthy was
that, for the substrate (SS)-3b, the addition of AlMe3 could
significantly improve the diastereoselectivity from 83:17 to
93:7 despite that a mixture of E and Z isomers (6:1) (SS)-3b
was used (entry 4 vs 6). Most excitingly, performing the addi-
tion of lithium trifluoromethylacetylide to N-tert-butanesul-
finyl ketimine 3c in toluene/AlMe3 gave the corresponding
trifluoromethylated propargylamine (SS,S)-4c without any de-
tectable diastereoisomer (entry 7). Additions of trifluorome-
thylacetylide to the aryl-substituted N-tert-butanesulfinyl
ketimine 3d also delivered the diastereoisomer (SS,S)-4d in
very high diastereoselectivity (>99:1) although the yield
was low (entry 8). In our opinion, the stereochemistry of the
addition reaction was consistent with a cyclic six-membered
transition state with the bulky tert-butyl group preferring the
equatorial position and AlMe3 chelating with the nitrogen
atom of ketimine. The absolute configuration of the major iso-
mer (SS,S)-4a was confirmed by X-ray crystallographic analy-
sis (Fig. 2).17
Figure 2. X-ray crystal structure of (SS,S)-4a.
CF3
CF3
R2
R1
R2
R1
HCl
MeOH
NH
S
NH2 · HCl
O
i
i
As the several representative examples, the enantiomeri-
cally pure trifluoromethylated propargylamines 5b and 6a
could be readily accessed via acidic cleavage of the tert-buta-
nesulfinyl groups of the prepared sulfonamide derivatives 2b
and 4a (Scheme 1).18
(SS,S)-2b:R1 = H,R2 = Pr;
(S)-5b: R1 = H, R2 = Pr;
i
i
(SS,R) -2b:R1 = Pr,R2 = H;
(SS,S)-4a:R1 = Me,R2 = Pr;
(SS,R) -4a:R1 = Pr,R2 = Me.
(R) -5b:R1 = Pr,R2 = H;
(S)-6a:R1 = Me,R2 = Pr;
(R) -6a:R1 = Pr,R2 = Me.
i
i
i
i
Scheme 1.

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X.-Y. Chen et al. / Tetrahedron 64 (2008) 2301e2306
3. Conclusion
d 1.05 (t, J¼7.4 Hz, 3H), 1.23 (s, 9H), 1.77e1.86 (m, 2H),
3.42 (d, J¼7.0 Hz, 1H), 4.07e4.13 (m, 1H); 13C NMR
(100.6 MHz, CDCl3) d 12.11, 24.78, 31.59, 50.43, 58.85,
74.41 (q, J¼52.7 Hz), 89.35 (q, J¼6.4 Hz), 116.27 (q,
J¼255.9 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ50.27 (s,
3F). Anal. Calcd for C10H16F3NOS: C, 47.05; H, 6.32; N,
5.49. Found: C, 47.18; H, 5.93; N, 5.46.
In summary, we have developed a very practical method for
the asymmetric syntheses of a range of trifluoromethylated
propargylamines by 1,2-additions of lithium trifluoromethyla-
cetylide to N-tert-butanesulfinyl aldimines and ketimines in
good yields and in good diastereoselectivities. In many cases,
the major isomers can be isolated by chromatography. For
N-tert-butanesulfinyl aldimines’ substrates, the diastereoselec-
tivities could be tuned by changing the used solvent. With
AlMe3 as adductive in the addition to N-tert-butanesulfinyl
ketimines, the diastereoselectivities were significantly im-
proved. Acidic cleavage of the tert-butanesulfinyl groups
delivered optically pure trifluoromethylated propargylamines.
4.1.1.2. (SS,R)-(þ)-N-(1-Ethyl-4,4,4-trifluoro-but-2-ynyl)-2-meth-
ylpropanesulfinamide ((SS,R)-2a). White solid; mp 69e71 ꢁC;
[a]2D3 þ21.8 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax 1059, 1142,
1
1279, 1365, 1460, 2273, 3194; H NMR (400 MHz, CDCl3)
d 1.00 (t, J¼7.4 Hz, 3H), 1.16 (s, 9H), 1.75e1.84 (m, 2H),
3.40 (d, J¼7.0 Hz, 1H), 4.08e4.14 (m, 1H); 13C NMR
(100.6 MHz, CDCl3) d 9.81, 22.29, 29.48, 49.06, 56.32, 71.85
(q, J¼52.5 Hz), 86.72 (q, J¼6.4 Hz), 113.93 (q, J¼255.8 Hz);
19F NMR (376 MHz, CDCl3) d ꢀ50.32 (s, 3F). Anal. Calcd
for C10H16F3NOS: C, 47.05; H, 6.32; N, 5.49. Found: C,
47.19; H, 6.23; N, 5.43.
4. Experimental section
4.1. General experimental methods
Unless otherwise noted, all reagents were obtained from
commercial suppliers and were used without further purifica-
tion. THF was distilled from sodium/benzophenone ketyl
and toluene was distilled from sodium immediately before
use. N-tert-Butanesulfinyl aldimines and ketimines were pre-
pared using known procedures. All reactions were carried
out in flame or dried glassware under a nitrogen atmosphere.
IR spectra of liquids were recorded as thin film on KBr plates
and IR spectra of solids were recorded as KBr pellets. Melting
points were determined on a Melt-Temp apparatus and were
4.1.1.3. (SS,S)-(þ)-N-(1-Isopropyl-4,4,4-trifluoro-but-2-ynyl)-
2-methylpropanesulfinamide ((SS,S)-2b). White solid; mp
72e74 ꢁC; [a]2D3 þ69.2 (c 1.0, CHCl3); IR (KBr, cmꢀ1
)
1
nmax 1062, 1141, 1279, 1367, 1468, 2255, 3190; H NMR
(400 MHz, CDCl3) d 0.96 (d, J¼6.8 Hz, 3H), 0.97 (d,
J¼6.8 Hz, 3H), 1.18 (s, 9H), 1.92e1.98 (m, 1H), 3.31 (d,
J¼7.4 Hz, 1H), 3.89e3.94 (m, 1H); 13C NMR (100.6 MHz,
CDCl3) d 19.89, 21.01, 24.83, 35.79, 55.29, 59.04, 75.14
(q, J¼52.7 Hz), 88.55 (q, J¼6.4 Hz), 116.25 (q,
J¼255.9 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ50.10 (s,
3F). Anal. Calcd for C11H18F3NOS: C, 49.05; H, 6.74; N,
5.20. Found: C, 49.53; H, 6.87; N, 4.94.
1
uncorrected. H NMR spectra were recorded on Bruker AM-
400 spectrometer with TMS as an internal standard. 19F
NMR spectra were recorded on Bruker AM-400 spectrometer
with CFCl3 as an external standard. 13C NMR spectra were
recorded on Bruker 400 (100.6 MHz) spectrometer. Mass
spectra were taken on a HP5989A spectrometer.
4.1.1.4. (SS,R)-(þ)-N-(1-Isopropyl-4,4,4-trifluoro-but-2-ynyl)-
2-methylpropanesulfinamide ((SS,R)-2b). White solid; mp
84e86 ꢁC; [a]D23 þ59.2 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax
1050, 1133, 1282, 1364, 1474, 2284, 3121; 1H NMR
(400 MHz, CDCl3) d 0.96e0.98 (m, 6H), 1.15 (s, 9H), 1.92e
4.1.1. General procedure for the 1,2-addition of lithium
trifluoromethylacetylide to N-tert-butanesulfinyl aldimines 1
A
1.0 M solution of 2-bromo-3,3,3-trifluoropropene
2.01 (m, 1H), 3.36 (d, J¼5.6 Hz, 1H), 3.89e3.94 (m, 1H); 13
C
(1.5 equiv) in toluene was added slowly to a solution of LDA
(3.0 equiv, 2.0 M in THF/n-heptane/ethylbenzene) at ꢀ78 ꢁC.
The resultant red/black solution was stirred at this temperature
for a further 15 min before a solution of N-tert-butanesulfinyl al-
dimine 1 (1.0 equiv) in toluenewas added dropwise. Stirring was
continued at ꢀ78 ꢁC for 2 h and then the mixture was allowed to
warm uptoꢀ40 ꢁC. Stirringwascontinuedfor5 h. Afterthat, the
reaction mixture was quenched by the addition of satd aq NH4Cl
and diluted with EtOAc. The organic layer was removed and the
aqueous layer was extracted with EtOAc. After the combined or-
ganic layers were dried with Na2SO4, filtered, and concentrated,
the residue was purified by chromatography to give the diaster-
eoisomerically pure trifluoromethylated propargylamines 2.
NMR (100.6 MHz, CDCl3) d 17.07, 19.04, 22.27, 33.53,
53.61, 56.35, 72.73 (q, J¼52.4 Hz), 85.54 (q, J¼6.3 Hz),
113.89 (q, J¼255.6 Hz); 19F NMR (376 MHz, CDCl3)
d ꢀ50.08 (s, 3F). Anal. Calcd for C11H18F3NOS: C, 49.05; H,
6.74; N, 5.20. Found: C, 49.19; H, 6.76; N, 5.07.
4.1.1.5. (SS,S)-(þ)-N-(1-Propyl-4,4,4-trifluoro-but-2-ynyl)-2-
methylpropanesulfinamide ((SS,S)-2c). White solid; mp 49e
51 ꢁC; [a]2D3 þ45.2 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax
1059, 1140, 1279, 1365, 1459, 2264, 3186; 1H NMR
(400 MHz, CDCl3) d 0.89 (t, J¼7.4 Hz, 3H), 1.16 (s, 9H),
1.37e1.47 (m, 2H), 1.67e1.74 (m, 2H), 3.41 (d, J¼7.3 Hz,
1H), 4.03e4.10 (m, 1H); 13C NMR (100.6 MHz, CDCl3)
d 15.60, 20.97, 24.69, 40.34, 48.93, 58.82, 73.90 (q,
J¼52.1 Hz), 89.84 (q, J¼6.4 Hz), 116.27 (q, J¼255.8 Hz);
19F NMR (376 MHz, CDCl3) d ꢀ50.30 (s, 3F). Anal. Calcd
for C11H18F3NOS: C, 49.05; H, 6.74; N, 5.20. Found: C,
49.05; H, 6.81; N, 5.15.
4.1.1.1. (SS,S)-(þ)-N-(1-Ethyl-4,4,4-trifluoro-but-2-ynyl)-2-meth-
ylpropanesulfinamide ((SS,S)-2a). White solid; mp 61e63 ꢁC;
[a]2D3 þ41.4 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax 1056, 1134,
1
1283, 1367, 1461, 2269, 3167; H NMR (400 MHz, CDCl3)

X.-Y. Chen et al. / Tetrahedron 64 (2008) 2301e2306
2305
4.1.1.6. (SS,R)-(þ)-N-(1-Propyl-4,4,4-trifluoro-but-2-ynyl)-2-
methylpropanesulfinamide ((SS,R)-2c). White solid; mp 55e
57 ꢁC; [a]2D3 þ42.8 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax 1059,
4.1.2.1. (SS,S)-(þ)-N-(1-Isopropyl-1-methyl-4,4,4-trifluoro-
but-2-ynyl)-2-methylpropanesulfinamide ((SS,S)-4a). White
solid; mp 69e71 ꢁC; [a]D23 þ66.4 (c 1.0, CHCl3); IR (KBr,
1
1
1143, 1280, 1365, 1459, 2267, 3192; H NMR (400 MHz,
cmꢀ1) nmax 1049, 1140, 1278, 1370, 1469, 2269, 3156; H
CDCl3) d 0.90 (t, J¼7.4 Hz, 3H), 1.16 (s, 9H), 1.42e1.48 (m,
2H), 1.71e1.77 (m, 2H), 3.30 (d, J¼7.3 Hz, 1H), 4.13e4.19
(m, 1H); 13C NMR (100.6 MHz, CDCl3) d 13.39, 18.80,
22.28, 38.17, 47.54, 56.29, 71.71 (q, J¼52.2 Hz), 86.96 (q,
J¼6.3 Hz), 113.95 (q, J¼255.8 Hz); 19F NMR (376 MHz,
CDCl3) d ꢀ50.28 (s, 3F). Anal. Calcd for C11H18F3NOS: C,
49.05; H, 6.74; N, 5.20. Found: C, 49.17; H, 6.44; N, 5.10.
NMR (400 MHz, CDCl3) d 0.97 (d, J¼6.8 Hz, 3H), 1.00 (d,
J¼6.8 Hz, 3H), 1.18 (s, 9H), 1.43 (s, 3H), 1.96 (septet,
J¼6.8 Hz, 1H), 3.23 (s, 1H); 13C NMR (100.6 MHz, CDCl3)
d 19.08, 19.78, 24.70, 26.06, 33.15, 40.39, 58.74, 74.40 (q,
J¼52.7 Hz), 92.17 (q, J¼6.5 Hz), 116.41 (q, J¼255.9 Hz); 19
F
NMR (376 MHz, CDCl3) d ꢀ50.10 (s, 3F). Anal. Calcd for
C12H20F3NOS: C, 50.87; H, 7.11; N, 4.94. Found: C, 50.79;
H, 7.13; N, 4.65.
4.1.1.7. (SS,S)-(þ)-N-(1-Isobutyl-4,4,4-trifluoro-but-2-ynyl)-2-
methylpropanesulfinamide ((SS,S)-2d). White solid; mp 91e
93 ꢁC; [a]2D3 þ56.2 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax 1040,
4.1.2.2. (SS,R)-(þ)-N-(1-Isopropyl-1-methyl-4,4,4-trifluoro-but-
2-ynyl)-2-methylpropanesulfinamide ((SS,R)-4a). White solid;
1
1140, 1287, 1365, 1468, 2275, 3157; H NMR (400 MHz,
mp 86e89 ꢁC; [a]D23 þ43.4 (c 1.0, CHCl3); IR (KBr, cmꢀ1
)
1
CDCl3) d 0.87e0.88 (m, 6H), 1.18 (s, 9H), 1.58e1.64 (m,
2H), 1.73e1.80 (m, 1H), 3.36 (d, J¼5.2 Hz, 1H), 4.05e4.11
(m, 1H); 13C NMR (100.6 MHz, CDCl3) d 21.02, 21.12,
21.44, 23.71, 44.12, 44.54, 55.61, 70.85 (q, J¼52.3 Hz), 86.58
(q, J¼6.3 Hz), 112.99 (q, J¼255.9 Hz); 19F NMR (376 MHz,
CDCl3) d ꢀ50.29 (s, 3F). Anal. Calcd for C11H20F3NOS: C,
50.87; H, 7.11; N, 4.94. Found: C, 50.86; H, 7.33; N, 4.64.
nmax 1058, 1142, 1275, 1385, 1464, 2272, 3203; H NMR
(400 MHz, CDCl3) d 0.97 (d, J¼6.8 Hz, 3H), 1.01 (d,
J¼6.8 Hz, 3H), 1.15 (s, 9H), 1.57 (s, 3H), 1.87 (septet,
J¼6.8 Hz, 1H), 3.14 (s, 1H); 13C NMR (100.6 MHz, CDCl3)
d 17.50, 22.37, 26.22, 38.70, 56.51, 58.29, 72.64 (q,
J¼52.2 Hz), 88.68 (q, J¼6.4 Hz), 114.03 (q, J¼255.8 Hz); 19
F
NMR (376 MHz, CDCl3) d ꢀ50.08 (s, 3F). Anal. Calcd for
C12H20F3NOS: C, 50.87; H, 7.11; N, 4.94. Found: C, 50.69;
H, 7.19; N, 4.60.
4.1.1.8. (SS,R)-(þ)-N-(1-Isobutyl-4,4,4-trifluoro-but-2-ynyl)-2-
methylpropanesulfinamide ((SS,R)-2d). White solid; mp 98e
101 ꢁC; [a]2D3 46.2 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax
1041, 1136, 1288, 1365, 1468, 2273, 3117; 1H NMR
(400 MHz, CDCl3) d 0.90 (d, J¼6.6 Hz, 3H), 0.92 (d,
J¼6.6 Hz, 3H), 1.18 (s, 9H), 1.62e1.67 (m, 2H), 1.76e1.81
(m, 1H), 3.19 (d, J¼5.2 Hz, 1H), 4.18e4.23 (m, 1H); 13C
NMR (100.6 MHz, CDCl3) d 24.09, 24.59, 24.81, 27.29,
47.30, 48.48, 58.60, 74.01 (q, J¼52.3 Hz), 89.49 (q,
J¼6.4 Hz), 116.30 (q, J¼255.9 Hz); 19F NMR (376 MHz,
CDCl3) d ꢀ50.28 (s, 3F). Anal. Calcd for C11H20F3NOS: C,
50.87; H, 7.11; N, 4.94. Found: C, 51.04; H, 7.18; N, 4.72.
4.1.2.3. (SS,S)-(þ)-N-(1-Isobutyl-1-methyl-4,4,4-trifluoro-but-
2-ynyl)-2-methylpropanesulfinamide ((SS,S)-4b). White solid;
mp 54e56 ꢁC; [a]D23 þ73.6 (c 1.0, CHCl3); IR (KBr, cmꢀ1
)
1
nmax 1040, 1140, 1284, 1387, 1469, 2273, 3148; H NMR
(400 MHz, CDCl3) d 0.95e0.99 (m, 6H), 1.15 (s, 9H), 1.51
(s, 3H), 1.60e1.64 (m, 2H), 1.75e1.83 (m, 1H), 3.27 (s,
1H); 13C NMR (100.6 MHz, CDCl3) d 24.65, 26.35, 26.51,
27.02, 30.60, 53.33, 55.16, 74.03 (q, J¼53.0 Hz), 92.75 (q,
J¼6.0 Hz), 116.41 (q, J¼255.8 Hz); 19F NMR (376 MHz,
CDCl3) d ꢀ50.42 (s, 3F). Anal. Calcd for C13H22F3NOS: C,
52.50; H, 7.46; N, 4.71. Found: C, 51.93; H, 7.57; N, 4.48.
4.1.2. General procedure for the 1,2-addition of lithium
trifluoromethylacetylide to N-tert-butanesulfinyl ketimines
with Me3Al
4.1.2.4. (SS,R)-(þ)-N-(1-Isobutyl-1-methyl-4,4,4-trifluoro-but-
2-ynyl)-2-methylpropanesulfinamide ((SS,R)-4b). White solid;
mp 61e63 ꢁC; [a]D23 þ46.8 (c 1.0, CHCl3); IR (KBr, cmꢀ1) nmax
1039, 1141, 1285, 1366, 1469, 2277, 3152; 1H NMR (400 MHz,
CDCl3) d 0.93e0.95 (m, 6H), 1.14 (s, 9H), 1.56e1.69 (m, 5H),
1.82e1.85 (m, 1H), 3.18 (s, 1H); 13C NMR (100.6 MHz,
CDCl3) d 21.36, 23.01, 23.10, 23.94, 28.71, 50.41, 52.95, 55.35,
70.89 (q, J¼52.3 Hz), 89.00 (q, J¼6.4 Hz), 113.11 (q,
J¼255.6 Hz); 19F NMR (376 MHz, CDCl3) d ꢀ50.43 (s, 3F).
Anal. Calcd for C13H22F3NOS: C, 52.50; H, 7.46; N, 4.71. Found:
C, 52.37; H, 7.80; N, 4.49.
A
1.0 M solution of 2-bromo-3,3,3-trifluopropene
(1.5 equiv) in toluene was added slowly to a solution of LDA
(3.0 equiv, 2.0 M solution in THF/n-heptane/ethylbenzene) at
ꢀ78 ꢁC. The resulting red/black solution was stirred at this
temperature for a further 15 min before a toluene solution of
N-tert-butanesulfinyl ketimine
3 (1.0 equiv, 0.5 M) and
Me3Al (1.2 equiv) was slowly added via cannula. Stirring
was continued at ꢀ78 ꢁC for 2 h and then the solution was
allowed to warm up to room temperature over 4 h. Stirring
was continued at room temperature for 12 h. After that, the
reaction mixture was cooled in an ice water bath and satd aq
Na2SO4 was added dropwise until no gas was released out.
The slurry was filtered and the filtered cake was rinsed with
EtOAc. The combined filtrates were dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified
by silica gel chromatography to afford the diastereomerically
pure trifluoromethylated propargylamines 4.
4.1.2.5. (SS,S)-(þ)-N-(1-Ethyl-1-methyl-4,4,4-trifluoro-but-2-
ynyl)-2-methylpropanesulfinamide ((SS,S)-4c). Viscous oil;
[a]2D3 þ81.4 (c 1.0, CHCl3); IR (film, cmꢀ1) nmax 1059, 1140,
1
1273, 1365, 1460, 2270, 3186; H NMR (400 MHz, CDCl3)
d 0.99 (t, J¼7.4 Hz, 3H), 1.15 (s, 9H), 1.48 (s, 3H), 1.74e1.87
(m, 2H), 3.24 (s, 1H); 13C NMR (100.6 MHz, CDCl3) d 10.83,
24.63, 29.40, 37.86, 56.09, 58.59, 73.85 (q, J¼52.1 Hz), 92.12

2306
X.-Y. Chen et al. / Tetrahedron 64 (2008) 2301e2306
(q, J¼6.4 Hz), 116.40 (q, J¼255.9 Hz); 19F NMR (376 MHz,
CDCl3) d ꢀ50.18 (s, 3F). Anal. Calcd for C11H18F3NOS: C,
49.05; H, 6.74; N, 5.20. Found: C, 49.64; H, 7.02; N, 4.95.
J¼53.1 Hz), 86.99 (q, J¼6.3 Hz), 116.03 (q, J¼256.0 Hz);
19F NMR (376 MHz, CD3OD) d ꢀ52.46 (s, 3F). Anal. Calcd
for C8H13ClF3N: C, 44.56; H, 6.08; N, 6.50. Found: C,
44.20; H, 6.00; N, 6.28.
4.1.2.6. (SS,S)-(þ)-N-(1-Methyl-1-phenyl-4,4,4-trifluoro-but-2-
ynyl)-2-methylpropanesulfinamide ((SS,S)-4d). White solid;
mp 107e109 ꢁC; [a]D23 þ41.6 (c 1.0, CHCl3); IR (KBr,
cmꢀ1) nmax 697, 763, 1046, 1140, 2279, 3151; 1H NMR
(400 MHz, CDCl3) d 1.25 (s, 9H), 1.91 (s, 3H), 3.69 (s, 1H),
7.35e7.60 (m, 5H); 13C NMR (100.6 MHz, CDCl3) d 24.74,
33.30, 58.39, 58.99, 75.86 (q, J¼52.8 Hz), 91.65 (q,
J¼6.6 Hz), 116.50 (q, J¼256.4 Hz), 127.98, 131.12, 131.23,
143.77; 19F NMR (376 MHz, CDCl3) d ꢀ50.34 (s, 3F).
Anal. Calcd for C13H22F3NOS: C, 52.50; H, 7.46; N, 4.71.
Found: C, 51.93; H, 7.57; N, 4.48.
4.1.3.4. (R)-(þ)-1-Isopropyl-1-methyl-4,4,4-trifluoro-but-2-ynyl-
amine hydrochloride ((R)-6a). White solid; [a]2D3 þ14.2 (c
1.0, CH3OH); IR (KBr, cmꢀ1) nmax 1145, 1248, 1285, 1508,
2019, 2283, 2906, 3448; 1H NMR (400 MHz, CD3OD)
d 1.05 (d, J¼6.8 Hz, 3H), 1.08 (d, J¼6.8 Hz, 3H), 1.61 (s,
3H), 2.12 (septet, J¼6.8 Hz, 1H); 13C NMR (100.6 MHz,
CD3OD) d 16.03, 16.28, 21.73, 35.91, 54.87, 73.38 (q,
J¼53.3 Hz), 84.64 (q, J¼6.2 Hz), 113.68 (q, J¼256.1 Hz);
19F NMR (376 MHz, CD3OD) d ꢀ52.40 (s, 3F). Anal. Calcd
for C8H13ClF3N: C, 44.56; H, 6.08; N, 6.50. Found: C,
44.50; H, 6.16; N, 6.12.
4.1.3. General procedure for cleavage of the tert-
butanesulfinyl groups
Acknowledgements
To a solution of propargyl sulfinamide (2.0 mmol) in MeOH
(10 mL) was added 4 M HCl in 1,4-dioxane solution (2.0 mL,
8.0 mmol). The mixture was stirred at room temperature for
1 h. Then, hexanewas added to precipitate the amine hydrochlo-
rides (in some cases, the mixture was concentrated to near
dryness before the addition of hexane to ensure a high yield of
amine hydrochlorides). The precipitate was then filtered off
and washed with hexane to provide the pure amine
hydrochloride.
National Natural Science Foundation of China, the Program
for Changjiang Scholars and Innovative Research Team in
University (No. IRT0526) and Shanghai Municipal Scientific
Committee are greatly acknowledged for funding this work.
References and notes
1. For selected examples, see: (a) Brik, A.; Alexandratos, J.; Lin, Y.-C.;
Elder, J. H.; Olson, A. J.; Wlodawer, A.; Goodsell, D. S.; Wong, C.-H.
ChemBioChem 2005, 6, 1167; (b) Trost, B. M.; Chung, C. K.; Pinkerton,
A. B. Angew. Chem., Int. Ed. 2004, 43, 4327; (c) Porco, J. A., Jr.;
Schoenen, F. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem.
Soc. 1990, 112, 7410.
2. (a) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41,
2535; (b) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763.
4.1.3.1. (S)-(ꢀ)-1-Isopropyl-4,4,4-trifluoro-but-2-ynylamine hy-
drochloride ((S)-5b). White solid; [a]2D3 ꢀ8.2 (c 1.0, CH3OH);
1
IR (KBr, cmꢀ1) nmax 1152, 1279, 1512, 2000, 2283, 3446; H
NMR (400 MHz, CD3OD) d 1.05 (d, J¼6.8 Hz, 3H), 1.06 (d,
J¼6.8 Hz, 3H), 2.16 (septet, J¼6.8 Hz, 1H), 4.27e4.30 (m,
1H); 13C NMR (100.6 MHz, CD3OD) d 15.78, 17.76, 30.70,
73.93 (q, J¼53.3 Hz), 81.75 (q, J¼6.2 Hz), 113.61 (q,
J¼255.9 Hz); 19F NMR (376 MHz, CD3OD) d ꢀ52.42 (s, 3F).
Anal. Calcd for C7H11ClF3N: C, 41.70; H, 5.50; N, 6.95. Found:
C, 41.45; H, 5.58; N, 6.80.
3. Gommermann, N.; Knochel, P. Chem. Commun. 2004, 2324.
4. Liu, J.; Liu, B.; Jia, X.; Li, X.; Chan, A. S. C. Tetrahedron: Asymmetry
2007, 18, 396.
5. Ding, C.-H.; Chen, D.-D.; Luo, Z.-B.; Dai, L.-X.; Hou, X.-L. Synlett 2006,
1272.
6. Patterson, A. W.; Ellman, J. A. J. Org. Chem. 2006, 71, 7110.
7. Turcaud, S.; Berhal, F.; Royer, J. J. Org. Chem. 2007, 72, 7893.
8. Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529.
9. (a) Ramachandran, P. V. Asymmetric Fluoroorganic Chemistry:Synthesis,
Application, and Future Directions. ACS Symposium Series; American
Chemical Society: Washington, DC, 2000; Vol. 746; (b) Ren, J.; Milton,
J.; Weaver, K. L.; Short, S. A.; Stuart, D. I.; Stammers, D. K. Structure
2000, 8, 1089; (c) Pedersen, O. S.; Pedersen, E. B. Synthesis 2000, 479;
4.1.3.2. (R)-(þ)-1-Isopropyl-4,4,4-trifluoro-but-2-ynylamine hy-
drochloride ((R)-5b). White solid; [a]2D3 þ8.3 (c 1.0, CH3OH);
1
IR (KBr, cmꢀ1) nmax 1152, 1277, 1511, 1995, 2285, 3442; H
NMR (400 MHz, CD3OD) d 1.04 (d, J¼6.8 Hz, 3H), 1.06 (d,
J¼6.8 Hz, 3H), 2.16 (septet, J¼6.8 Hz, 1H), 4.24e4.28 (m,
1H); 13C NMR (100.6 MHz, CD3OD) d 15.79, 17.78, 30.77,
73.80 (q, J¼53.0 Hz), 82.03 (q, J¼6.2 Hz), 113.64 (q,
J¼255.8 Hz); 19F NMR (376 MHz, CD3OD) d ꢀ52.37 (s,
3F). Anal. Calcd for C7H11ClF3N: C, 41.70; H, 5.50; N,
6.95. Found: C, 41.36; H, 5.49; N, 6.67.
(d) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
¨
10. Huheey, J. E. J. Phys. Chem. 1965, 69, 3284.
11. McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
12. (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3; (b) O’Hagan, D.; Rzepa,
H. S. Chem. Commun. 1997, 645.
13. Chen, Q.; Qiu, X.-L.; Qing, F.-L. J. Fluorine Chem. 2007, 128, 1182.
14. Liu, G.; Cogan, D. A.; Owens, T.; Tang, T. P.; Ellman, J. A. J. Org. Chem.
1999, 64, 1278.
4.1.3.3. (S)-(ꢀ)-1-Isopropyl-1-methyl-4,4,4-trifluoro-but-2-ynyl-
amine hydrochloride ((S)-6a). White solid; [a]2D3 ꢀ14.4 (c
1.0, CH3OH); IR (KBr, cmꢀ1) nmax 1145, 248, 1286, 1509,
2058, 2284, 2906, 3431; 1H NMR (400 MHz, CD3OD)
d 1.11 (d, J¼6.8 Hz, 3H), 1.14 (d, J¼6.8 Hz, 3H), 1.66 (s,
3H), 2.16 (septet, J¼6.8 Hz, 1H); 13C NMR (100.6 MHz,
CD3OD) d 18.39, 18.65, 24.08, 38.25, 57.25, 75.76 (q,
15. Crystal data have been deposited at the Cambridge Crystallographic Data
Center with reference number: CCDC 669005.
16. Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869.
17. Crystal data have been deposited at the Cambridge Crystallographic Data
Center with reference number: CCDC 667051.
18. Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913.