Asymmetric syntheses of 1-Aryl-2,2,2-trifluoroethylamines via diastereoselective 1,2-addition of arylmetals to 2-Methyl-N-(2,2,2- trifluoroethylidene)propane-2-sulfinamide

Article abstract of DOI:10.1021/ol063001q

Condensation of N-tert-butanesulfinamide (S)-1 with trifluoroacetaldehyde hydrate 2a afforded 2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfinamide 3. Without isolation and purification, imine 3 was added to various aryllithium reagents to give high

Full text of DOI:10.1021/ol063001q

ORGANIC
LETTERS
2007
Vol. 9, No. 4
683-685
Asymmetric Syntheses of
1-Aryl-2,2,2-trifluoroethylamines via
Diastereoselective 1,2-Addition of
Arylmetals to 2-Methyl-N-
(2,2,2-trifluoroethylidene)propane-2-sulfinamide
Vouy Linh Truong,*,† Madelaine S. Me´nard,‡ and Isabelle Dion§
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
16711 Trans Canada Highway, Kirkland, Que´bec H9H 3L1, Canada
Vouylinh_truong@merck.com
Received December 12, 2006
ABSTRACT
Condensation of N-tert-butanesulfinamide (S)-1 with trifluoroacetaldehyde hydrate 2a afforded 2-methyl-N-(2,2,2-trifluoroethylidene)propane-
2-sulfinamide 3. Without isolation and purification, imine 3 was added to various aryllithium reagents to give highly diastereomerically enriched
adducts 5a−g. Acidic methanolysis of 5a−g provided the desired 1-aryl-2,2,2-trifluoroethylamine hydrochloride compounds 6a−g.
1-Aryl-2,2,2-trifluoroethylamines are becoming increasingly
important in the pharmaceutical industry because fluorine
lowers the basicity of amines and improves the metabolic
stability of the bioactive agents.1 Consequently, they have
attracted considerable attention as synthetic targets, especially
in the area of asymmetric syntheses.2 Previously, Olah and
co-workers3 reported the stereoselective synthesis of 1-aryl-
2,2,2-trifluoroethylamines using TMSCF3 as CF3 source.
Enders and co-workers4 have also disclosed the asymmetric
synthesis of 1-aryl-2,2,2-trifluoroethylamines via nucleophilic
1,2-addition of alkyllithium reagents to trifluoroacetaldehyde
SAMP- or RAMP-hydrazone as a key step. More recently,
Gosselin et al.5 reported the asymmetric reduction of
ketimines to form the corresponding 1-aryl-2,2,2-trifluoro-
ethylamines. Our objective was to develop a more practical
method suitable for the rapid syntheses of analogues of 6.
The commercially available N-tert-butanesulfinamide 1 has
been widely used as a chiral reagent in the synthesis of a
variety of amines by virtue of its excellent diastereocontrol
† Merck Frosst Centre for Therapeutic Research.
‡ Undergraduate Co-op Student from the University of Ottawa, Ottawa.
§ Undergraduate Co-op Student from the Universite´ de Sherbrooke,
Sherbrooke.
(2) (a) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2436-
2439. (b) Wang, Y.; Mosher, H. S. Tetrahedron Lett. 1991, 32, 987-990.
(c) Soloshonok, V. A.; Ono, T. J. Org. Chem. 1997, 62, 3030-3031. (d)
Ishii, A.; Higashiyama, K.; Mikami, K. Synlett 1997, 1381-1382. (e) Ishii,
A.; Miyamoto, F.; Higashiyama, K.; Mikami, K. Chem. Lett. 1998, 119-
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M.; Olah, G. A. Org. Lett. 2001, 3, 2847-2850. (h) Jiang, J.; Shah, H.;
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O’Shea, P. D.; Chen, C.-y.; Volante, R. P. Org. Lett. 2004, 6, 641-644.
(3) Olah, G. A.; Prakash, G. K. S.; Mandal, M. Angew. Chem., Int. Ed.
2001, 3, 589-590.
(1) (a) Zanda, M.; Volonterio, A.; Bravo, P. Org. Lett. 2000, 2, 1827-
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Molteni, M.; Volonterio, A. Org. Lett. 2003, 5, 3887-3890. (d) Black, W.
C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Le´ger, S.;
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Robichaud, J.; Tsou, N.; Zamboni, R. Bioorg. Med. Chem. Lett. 2005, 15,
4741-4744. (e) Li, C. S.; Descheˆnes, D.; Desmarais, S.; Falgueyret, J.-P.;
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McKay, J. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; The´rien, M.;
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10.1021/ol063001q CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/26/2007

and the mild conditions for its cleavage.6 Consequently, we
decided to apply this chiral reagent to the asymmetric
syntheses of the 1-aryl-2,2,2-trifluoroethylamines 6 using
2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfin-
amide 3 as a key precursor. The advantage of this approach
is that a variety of chiral 1-aryl-2,2,2-trifluoroethylamine
analogues can be rapidly produced by simply changing the
organometallic reagents in the 1,2-addition step.
Table 1. Diastereoselective 1,2-Addition of Phenylmagnesium
Bromide to Imine 3
The representative preparation conditions for key inter-
mediate 3 are shown in Scheme 1. Variation of the source
entry
solvent
Lewis acids
yield of 5ad (%)
dre
1
2
3
4
5
7
8
9
10
11
PhMe
none
none
none
AlMe3
AlMe3
AlEt3
BF3‚Et2Oc
TiCl4
Zn(OTf)2
52
31
54
55
51
46
36
11
7
72:28
74:26
85:15
88:12
90:10
88:12
88:12
93:07
89:11
89:11
THFa
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Scheme 1. Preparation of Imine 3
b
c
c
c
b
b
Mg(OTf)2
34
a CH2Cl2 was removed by distillation and replaced by THF. b Precom-
plexation of imine 3 with Lewis acid at 0 °C, cooled to -78 °C, addition
of phenylmagnesium bromide solution. c Precomplexation of imine 3 with
Lewis acid at 0 °C; added to phenylmagnesium bromide solution at -78
°C. d Isolated yield. e Diastereomeric ratio (dr) was determined by chiral
HPLC of the unpurified amine salt 6a.
of trifluoroacetaldehyde, solvent, temperature, and condensa-
tion mediator identified 1.1 equiv of trifluoroacetaldehyde
hydrate 2a in dichloromethane or toluene at 40 °C in the
presence of 4 Å molecular sieves as the optimal conditions
for the preparation of 37 from 1. Imine 3 was converted to
an aminal upon aqueous quenching, and a poor yield (22%)
was obtained by distillation due to decompositon.
from the 1,2-addition, is also S (entry 1). This provided us
with a reliable method for determining the diastereomeric
ratio of different analogues of 5 in this report. After
establishment of the absolute stereochemistry of each dia-
stereomer in the mixture of sulfinamides, we then investi-
gated the solvent effect on the 1,2-addition reaction. When
the reaction was performed in THF, a similar diastereomeric
ratio of 5a was observed (entry 2). However, when dichloro-
methane was used as solvent, a modest improvement in
diastereoselectivity was observed (entry 3).
Since Lewis acids usually improve both the yield and
diastereoselectivity of the 1,2-additon reaction,6e,10 we screened
a variety of Lewis acids in the phenylmagnesium bromide
addition to imine 3 using dichloromethane as solvent. Table
1 highlights some Lewis acids which afforded a slight
improvement in the diastereoselectivity of 5a. The best
diastereoselectivity was achieved with TiCl4 as additive.
Unfortunately, these conditions afforded 5a in a very low
yield (entry 9). The order of addition had no effect on the
yield and diastereoselectivity of the reaction (entries 4 and
5).
In order to avoid isolation and purification of 3, we decided
to investigate a one-pot, two-step process for the preparation
of sulfinamide 5. Our initial efforts were focused on the effect
of solvent on the addition of phenylmagnesium bromide 4
to substrate 3 and the establishment of the absolute stereo-
chemistry of the major isomer of 5a (Table 1). Reaction of
1 equiv of phenylmagnesium bromide 4 with the crude imine
3 in toluene at -78 °C for 1 h gave a 52% yield of 5a from
1. The chiral reagent of 5a was cleaved with HCl in
methanol6a,b,8 to afford the corresponding amine salt 6a,
which was subjected to chiral HPLC analysis. The enantio-
meric ratio of 6a was found to be 72:28. On the basis of the
comparison to an authentic standard,3,5 the absolute config-
uration of the major enantiomer 6a was assigned as S. As it
has previously been established that the sulfinamide auxiliary
cleavage usually occurs without any erosion of chirality,3,9
this indicated that the absolute configuration of the major
diastereomer 5a at the newly formed stereocenter, generated
(6) (a) Ellman, J. A.; Liu, G.; Cogan, D. A. J. Am. Chem. Soc. 1997,
119, 9913-9914. (b) Ellman, J. A.; Liu, G.; Cogan, D. A. Tetrahedron
1999, 55, 8883-8904. (c) Ellman, J. A.; Timothy, D. O.; Tang, T. P. Acc.
Chem. Res. 2002, 35, 984-995. (d) Senanayake, C. H.; Krishnamurthy,
D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichim. Acta 2005, 38, 93-104. (e)
Jiang, W.; Chen, C.; Marinkovic, D.; Tran, J. A.; Chen, C. W.; Arellano,
L. M.; White, N. S.; Tucci, F. C. J. Org. Chem. 2005, 70, 8924-8931.
(7) Only one isomer was observed by 1H, 13C, and 19F NMR spectrom-
etry. The stereochemistry of 3 was assigned as E based on NOE between
the proton of imine and the proton of tert-butyl and by analogy (see Davis,
F. A.; Reddy, R. E.; Szewczyk, G.; Reddy, V.; Portonovo, P. S.; Zhang,
H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997,
62, 2555-2563 and ref 5e).
As we were not successful in improving the diastereo-
selectivity of the phenylmagnesium bromide 4 addition to
imine 3 using Lewis acids as promoter, we explored the 1,2-
addition reaction using lithium reagents (Table 2).11 After
optimization of the solvent, temperature, order of addition,
and number of equivalents, it was found that the addition of
3 in toluene to 2.5 equiv of phenyllithium (freshly generated
from phenyl bromide and 2.5 M n-BuLi in THF) at -78 °C
(8) Ellman, J. A.; Cogan, D. A. J. Am. Chem. Soc. 1999, 121, 268-
269.
(10) (a) Ellman, J. A.; Cogan, D. A. J. Am. Chem. Soc. 1999, 121, 268-
269. (b) Senanayake, C.; Lu, B. Z.; Li, N.; Han, Z.; Bakale, R. P.; Wald,
S. A. Org. Lett. 2005, 7, 2599-2602. (c) Larhed, M.; Arefalk, A.;
Wannberg, J.; Hallberg, A. J. Org. Chem. 2006, 71, 1265-1268.
(9) Senanayake, C. H.; Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald,
S. A. Tetrahedron. Lett. 2002, 43, 923-926.
684
Org. Lett., Vol. 9, No. 4, 2007

configuration at the newly formed stereocenter. By analogy,
the stereocenter of the remaining products 5b-g is tentatively
assigned as S.
Consistent with the literature,6e,12 the addition of phenyl-
lithium to imine 3 appears to have proceeded via a non-
chelated transition-state model where phenyllithium prefer-
ably added to the imine from the less hindered face to
predominantly afford the major diastereomer adduct (Ss,S)-
5a (Figure 1). When Grignard reagents are used, previous
Table 2. Diastereoselective 1,2-Addition of Aryllithium
Reagents to Imine 3
yield of
5e (%)
yield of
6e (%)
enty
RLi
5
drf
6
1
2
3
4
5
6
7
8
9
PhLia
PhLib
PhLic
4-MeOPhLi
4-MeSPhLi
4-FPhLi
3,5-diFPhLid
2-MePhLi
5a
5a
5a
5b
5c
5d
5e
5f
66
42
58
55
53
50
36
40
15
98:2
98:2
96:4
97:3
98:2
100:1
83:17 6e 56
99:1
98:2
6a 86-95
6a 86-95
6a 86-95
6b 86
6c 85
6d 84
6f
52
pyridin-2-yllithium 5g
6g 69
a 2.5 equiv of PhLi was used. b 1.1 equiv of PhLi was used. c Precom-
plexation of imine with AlMe3 at 0 °C, added to PhLi solution at -78 °C.
d Unoptimized conditions. e Isolated yield. f Determined by chiral HPLC of
the unpurified amine salts 6.
Figure 1. Speculative models for diastereoselectivity.
rapidly generated 5a in 66% overall yield with an excellent
98:2 diastereomeric ratio (entry 1). However, the yield was
significantly decreased when 1.1 equiv of phenyllithium was
employed (entry 2). The use of Lewis acids such as AlMe3
did not improve the diastereoselectivity of the reaction and
resulted in a lower yield of 5a (entry 3).
reports proposed a six-membered chelating transition state
where magnesium coordinates to the oxygen of the sulfinyl
group and dictates the addition from the same face. However,
contrary to this model, addition of the phenylmagnesium
bromide to imine 3 also appeared to proceed via a non-
chelated transition-state model to give the sulfinamide (Ss,S)-
5a as the major diastereomer. To our knowledge, this is the
first example of Grignard reagent addition to imine 3 in
dichloromethane in the absence of Lewis acid that proceeded
via a nonchelated transition state.
In conclusion, we have developed a very practical method
for the syntheses of a variety of 1-aryl-2,2,2-trifluoroethyl-
amine analogues in moderate to good yields with high optical
purities using 2-methyl-N-(2,2,2-trifluoroethylidene)propane-
2-sulfinamide 3 as a key precursor. Further application of 3
in the preparation of a variety of chiral amine analogues are
under investigation and will be reported in due course.
Encouraged by the above results, we then examined the
scope of the diastereoselective 1,2-addition of a various
aryllithium reagents to imine 3 using the optimized reaction
conditions. The results are shown in Table 2. In general,
various aryllithium reagents participated successfully in the
1,2-addition reaction to provide the corresponding sulfin-
amides 5a-g in moderate to good yields and good to
excellent diastereoselectivities. All sulfinamides 5a-g were
then hydrolyzed to provide the corresponding amine hydro-
chloride salts 6a-g, which were subjected to chiral HPLC
analysis. It was determined that the addition of phenyllithium
to imine 3 also generated sulfinamide 5a with the S absolute
Acknowledgment. We thank Dr. Sheldon Crane and Dr.
Francis Gosselin (Merck Frosst) for helpful chemistry
discussions and Dr. Dan Sorensen (Merck Frosst) for NMR
analyses. We are also thankful to NSERC for an Under-
graduate Student Research Award to Isabelle Dion.
(11) Experimental Procedure for 5a. To a solution of N-tert-butane-
sulfinamide (S)-1 (200 mg, 1.65 mmol) in toluene (3.3 mL) were added
trifluoroacetaldehyde hydrate 2a (75% in aqueous solution, 200 µL, 1.82
mmol) and molecular sieves pellets 4 Å (1 g) from Acros. The reaction
mixture was stirred at 40 °C for 6 h under nitrogen to provide the crude
imine 3. A solution of bromobenzene (530 µL, 4.95 mmol) in THF (3.3
mL) in a flame-dried round-bottom flask under nitrogen was cooled to -78
°C, and a solution of n-BuLi (2.5 M in hexanes, 1.65 mL, 4.13 mmol) was
added dropwise. The reaction mixture was aged at -78 °C for 1 h. The
crude imine 3 was cooled to -78 °C and transferred via cannula to the
reaction mixture. The resulting mixture was aged at -78 °C for 5 min and
transferred to a cooled (0 °C) saturated aqueous NH4Cl. The aqueous layer
was extracted three times with ethyl acetate. The organic extracts were
combined, washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash chromatography
on silica gel using ethyl acetate-hexanes (25:75) to afford 5a in 66% yield
(302 mg).
Supporting Information Available: Experimental pro-
cedures and characterization data for 5a-g and 6a-g. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL063001Q
(12) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303-
310.
Org. Lett., Vol. 9, No. 4, 2007
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