Stereoselective nucleophilic trifluoromethylation of N-(tert-butylsulfinyl)imines by using trimethyl(trifluoromethyl)silane

Article abstract of DOI:10.1002/1521-3773(20010202)40:3<589::AID-ANIE589>3.0.CO;2-9

A very general reaction is presented to achieve the nucleophilic transfer of "CF₃" to chiral N-(tert-butylsulfinyl)imines in high yield and high stereoselectivity (see reaction scheme). Tetrabutylammonium difluorotriphenylsilicate (TBAT) functi

Full text of DOI:10.1002/1521-3773(20010202)40:3<589::AID-ANIE589>3.0.CO;2-9

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In a typical catalytic dihydroxylation, the 3b material (100 mg) was added
to a mixture of the olefin (1.6 mmol), NMO (1.6 mmol), and water (200 mL)
in tBuOH:CH2Cl2 (3 mL; 2:1) solvent. The mixture was stirred at room
temperature and regularly analyzed by GC.
importance in the drugs industry, direct asymmetric synthesis
of trifluoromethylated amines is a challenge. Pirkle et al.[4]
and Mosher and Wang[5] prepared 2,2,2-trifluoro-1-phenyl-
ethylamine, and Soloshonok and Ono[6] recently reported an
elegant method for the preparation of perfluorinated amines
by a novel [1,3]-proton shift reaction. However, all of these
methods require fluorinated ketones. Nucleophilic transfer of
ªCF3º to nitrones and imines for direct preparation of
trifluoromethylated amines was recently achieved by Nelson
et al.[7] and Blazejewski et al.,[8] respectively. These methods
suffer from low yield and lack generality. We now report the
first stereoselective synthesis of trifluoromethylated amines
by using TMSCF3 2 (TMS ˆ SiMe3).
Received: August 18, 2000 [Z15661]
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[2] C. Döbler, G. Mehltretter, M. Beller, Angew. Chem. 1999, 111, 3211;
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[4] W. A. Herrmann, R. M. Kratzer, J. Blümel, H. B. Friedrich, R. W.
Fischer, D. C. Apperley, J. Mink, O. Berkesi, J. Mol. Catal. A 1997, 120,
197.
Our systematic investigation began as an extension of our
earlier work,[9] based on the fact that imines are less electro-
philic than carbonyl compounds, and that O Si bonds are
stronger than N Si bonds. We predicted that strongly electro-
philic imines might be a solution to this problem under
noncatalytic conditions. When N-sulfonylaldimines[10] were
used as imine sources the reaction indeed proceeded smoothly
in the presence of CsF and gave only the trifluoromethylated
adducts in 45 ± 95% yield. Next we turned our attention to
sulfinylimines 1 to make this reaction stereoselective. When
chiral sulfinylimines[11] were subjected to similar reaction
conditions little or no products were obtained. Sulfinylimines
were recovered intact, but TMSCF3 decomposed. We sur-
mised that sulfinylimines are not reactive enough to add
TMSCF3. Use of different aprotic solvents and excess of
reagents was not helpful. When an excess of TMSCF3 was
used, a number of unidentified fluorinated products with little
or none of the expected adduct were obtained. TMS-
Imidazole,[8] was recently reported to facilitate addition of
TMSCF3 to imines. In our case, however, it was ineffective. In
all experiments the starting material was recovered.
Â
[5] E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schröder, K. B. Sharpless,
J. Am. Chem. Soc. 1988, 110, 1968.
[6] C. Bolm, A. Gerlach, Eur. J. Org. Chem. 1998, 21.
[7] S. Nagayama, M. Endo, S. Kobayashi, J. Org. Chem. 1998, 63, 6094.
[8] K. Akashi, R. E. Palermo, K. B. Sharpless, J. Org. Chem. 1978, 43,
2063.
[9] P. G. Andersson, K. B. Sharpless, J. Am. Chem. Soc. 1993, 115, 7047.
Â
[10] J. S. M. Wai, I. Marko, J. S. Svendsen, M. G. Finn, E. N. Jacobsen, K. B.
Sharpless, J. Am. Chem. Soc. 1989, 111, 1123.
[11] J. H. Clark, D. J. Macquarrie, Chem. Commun. 1998, 853.
[12] J. Monnin, Helv. Chim. Acta 1958, 225, 2112.
[13] W. D. Lloyd, B. J. Navarette, M. F. Shaw, Synthesis 1972, 610.
[14] J. F. Moulder, W. F. Stickle, P. E. Sobol, K. D. Bomden, Handbook of
X-ray Photoelectron Spectroscopy, Perkin-Elmer Corp., 1992.
[15] V. Van Rheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976, 1973.
[16] K. B. Sharpless, D. R. Williams, Tetrahedron Lett. 1975, 35, 3045.
The above results indicate that TMSCF3 decomposes prior
to reacting with the starting material. Hence, we thought that
increasing the substrate concentration might be a solution to
this problem. Indeed, when neat TMSCF3 was added to a
concentrated solution of the imines, the desired adduct was
obtained. The mass balance corresponds to recovered starting
material. Attempts to complete the reaction by using excess of
reagent in different solvents was, however, unsuccessful.
Imines were treated with TMSCF3 in the presence of a
stoichiometric amount of CsF to give the corresponding
trifluoromethylated sulfinamides in 50 ± 65% yields of iso-
lated products (Table 1, entries 1 ± 7, values in parentheses).
Imines with acidic a-hydrogen atoms gave lower yields
because of competitive deprotonation. The diastereoselectiv-
ity was not very high.
Stereoselective Nucleophilic
Trifluoromethylation of N-(tert-Butylsulfinyl)-
imines by Using Trimethyl(trifluoromethyl)-
silane**
G. K. Surya Prakash,* Mihirbaran Mandal, and
George A. Olah*
Trifluoromethylated amines are important building blocks
for pharmaceutical research.[1] The CF3 group, because of its
strongly electron withdrawing nature, lowers the basicity of
the amide bond towards nonspecific proteolysis[2] when these
amines are incorporated into peptides, as well as modify the
solubility and desolvation properties.[3] In spite of its prime
During these investigations we thus encountered two
problems: a) Conversion of imines was incomplete even in
the presence of excess TMSCF3 and CsF; b) imines with an a-
hydrogen atom failed to react with TMSCF3 because of the
basic nature of CsF. However, we overcame these problems
by employing a nonmetallic fluoride source. DeShong et al.
reported that tetrabutylammonium difluorotriphenylsilicate
(TBAT),[12] a soluble fluoride source, is very effective for
nucleophilic displacement reactions. We found that TBAT is
also effective in our system. Reaction of N-sulfonylaldimines
[*] Prof. Dr. G. K. S. Prakash, Prof. Dr. G. A. Olah, M. Mandal
Loker Hydrocarbon Institute and Department of Chemistry
University of Southern California
University Park, Los Angeles, CA 90089-1661 (USA)
Fax : (‡1)213-740-6270
E-mail: gprakash@usc.edu
[**] Support of our work by Loker Hydrocarbon Research Institute is
gratefully acknowledged.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2001, 40, No. 3
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4003-0589 $ 17.50+.50/0
589

COMMUNICATIONS
Table 1. Nucleophilic trifluoromethylation of sulfinylimines 1 with CsF or TBATas
fluoride source (see Scheme 1). Unless otherwise mentioned, yields and diastereo-
meric ratios are for TBAT as the fluoride source.
Saturated NH4Cl solution (2 mL) was added at lower temper-
ature, and the reaction mixture was warmed to room temper-
ature. The quenched reaction mixture was extracted three
times with ethyl acetate, and the combined organic layers
were dried over anhydrous Na2SO4. Evaporation of the
solvent under vacuum, Flash chromatography (silica gel,
hexanes:ethyl acetate 8:2) gave the sulfinamides as white
solids. The above conditions were applied to a wide array of
structurally diverse imines (Table 1, entries 2 ± 12). All ad-
ducts were hydrolyzed to amine salts by using a reported
procedure.[11]
Sulfinamide 4
Amine 5
Entry R1 in 1
Yield [%][a, g] (RS,S)/(RS,R)[b, c] Config.[e]
[a]2D5[f]
1
2
3
4
5
6
7
8
9
pClC6H4
pBrC6H4
pCF3C6H4 84 (57)
95 (53)
90 (50)
> 99 (85:15)
> 99 (80:20)
95:05 (85:15)
99:01 (90:10)
99:01 (85:15)
97:03 (80:20)
S
S
S
S
S
S
‡ 25.9 (c ˆ 0.72)
‡ 11.2 (c ˆ 1.5)
‡ 8.4 (c ˆ 1.5)
‡ 11.7 (c ˆ 2.0)
‡ 14.9 (c ˆ 1.0)
‡ 6.6 (c ˆ 2.0)
‡ 28.6 (c ˆ 0.65)
‡ 26.0 (c ˆ 0.75)
‡ 28.8 (c ˆ 3.0)
2.2 (c ˆ 3.0)
2-pyridyl
3-pyridyl
2-furyl
Ph
2-Naphthyl 83
9-Anthryl 90
Cyclohexyl 88
tBu 75
PhCH2CH2 84
95 (60)
92 (60)
85 (55)
80 (65)
97:03 (75:25) S[d]
96:04
99:01
99:01
99:01
90:10
S
S
S
S
S
The rationale for high stereoselectivity is depicted in
Scheme 1. In the presence of a stoichiometric amount of
fluoride source, pentavalent intermediate[13] 3 is formed. This
10
11
12
‡ 11.3 (c ˆ 0.65)
15.7 (c ˆ 1.5)
‡
pentavalent intermediate, with its large Bu4N counterion,
preferably adds to the imines from the less hindered Re face to
give the selective Cram products 4, which can be transformed
to the amines 5. The preferred conformation of imines[14] and
the addition of organometallic reagents to them under
nonchelating conditions[15] are well documented.
[a] In parentheses yields with CsF as fluoride source. [b] In parentheses d.r. values
with CsF as fluoride source. [c] Diastereomeric ratios were determined by 19F NMR
spectroscopy on the crude reaction mixture. [d] Configuration was determined by
comparison with the known compound. [e] Configurations were assigned from
transition state model. [f] Optical rotations were measured in methanol. [g] Yields
of isolated analytically pure material.
Received: July 20, 2000 [Z15492]
with TMSCF3 in the presence of TBAT afforded the tri-
fluoromethylated product in good to excellent yields.[10] When
chiral sulfinylimines were subjected to similar reaction con-
ditions, high diastereoselectivities and high yields were
obtained.
[1] ªUtility of Fluorine In Biologically Active Moleculesº: 219th Nat.
Meet. Am. Chem. Soc. Div. Fluorine Chem. Tutorial (San Francisco,
CA) 2000.
[2] I. Ojima, K. Kato, F. A. Jameison, J. Bioorg. Med. Chem. Lett. 1992, 2,
219 ± 222.
The above method provides a straightforward and powerful
tool for the preparation of trifluoromethylated amines in
enantiomerically pure form. A remarkable feature of this
reaction is that it can be applied to nonenolizable, enolizable,
aromatic, and heterocyclic imines alike. The optimized
reaction conditions for the p-chlorophenyl derivative (en-
try 1) in the presence of a stoichiometric amount of TBAT in
THF gave the corresponding trifluoromethylated sulfinamide
in good yield (95%) and diastereoselectivity (d.r. > 99%):
TMSCF3 (1.2 equiv, 0.6 mmol) in THF (2 mL) was added to a
mixture of the imine (0.5 mmol) and TBAT (1.1 equiv,
0.55 mmol) in THF (8 mL) at 558C. Reaction mixtures
were usually stirred over 0.5 to 1 h. Disappearance of the
white slurry of TBAT indicates completion of the reaction.
[3] D. Shirlin, C. Tarnus, S. Baltzer, J. Bioorg. Med. Chem. Lett. 1992, 2,
651 ± 654.
[4] a) W. H. Pirkle, J. R. Hanske, J. Org. Chem. 1977, 42, 2436 ± 2439;
b) W. H. Pirkle, K. A. Simmons, J. Org. Chem. 1981, 46, 3239 ± 3249.
[5] Y. Wang, H. S. Mosher, Tetrahedron Lett. 1991, 32, 987 ± 990.
[6] V. A. Soloshonok, T. Ono, J. Org. Chem. 1997, 62, 3030 ± 3031.
[7] D. W. Nelson, R. A. Easley, B. N. V. Pintea, Tetrahedron Lett. 1999, 40,
25 ± 28.
[8] J. C. Blazejewski, E. Anselmi, M. P. Wilmshurst, Tetrahedron Lett.
1999, 40, 5475 ± 5478.
[9] a) G. K. S. Prakash, R. Krishnamurti, G. A. Olah, J. Am. Chem. Soc.
1989, 111, 393 ± 395; b) R. Krishnamurti, D. Bellew, G. K. S. Prakash,
J.Org. Chem. 1991, 56, 984 ± 989; c) G. K. S. Prakash, A. K. Yudin,
Chem. Rev. 1997, 97, 757 ± 786; d) J. Wiedemann, T. Heiner, G.
Mloston, G. K. S. Prakash, G. A. Olah, Angew. Chem. 1998, 110, 880 ±
881; Angew. Chem. Int. Ed. 1998, 37, 820 ± 821.
[10] Nucleophilic trifluoromethylation of N-p-toluenesulfonylaldimines
was achieved: G. K. S. Prakash, M. Mandal, G. A. Olah, Synlett, in
press.
[11] We have prepared both N-(tert-butylsulfinyl)imine and N-(p-tolylsul-
finyl)imine. N-(tert-butylsulfinyl)imine gave higher de in the ªCF3º
addition reaction. a) G. Liu, D. A. Cogan, J. A. Ellman, J. Am. Chem.
Soc. 1997, 119, 9913 ± 9914; b) G. Liu, D. A. Cogan, T. D. Owens, T. P.
Tang, J. A. Ellman, J. Org. Chem. 1999, 64, 1278 ± 1284; c) F. A. Davis,
P. Zhou, B.-C. Chen, Chem. Soc. Rev. 1998, 27, 13.
_
_
Ph3SiF
F
CF3
+
+
Ph
Me
TMSCF3
Si Ph NBu4
Si Me NBu4
+
Ph
Me
F
F
2
TBAT
_
3
' CF3 '
R1
H
O
S
[12] A. S. Pilcher, H. L. Ammon, P. DeShong, J. Am. Chem. Soc. 1995, 117,
5166 ± 5167.
O
tBu
N
R1
N
[13] N. Maggiarosa, W. Tyrra, D. Naumann, N. V. Kirij, Y. L. Yagupolskii,
Angew. Chem. 1999, 111, 2392 ± 2393; Angew. Chem. Int. Ed. 1999, 38,
2252 ± 2253.
1
TMSF
[14] F. A. Davis, W. McCoull, J. Org. Chem. 1999, 64, 3396 ± 3397.
[15] Y. Yamamoto, S. Nishii, K. Maruyama, T. Komatsu, W. Ito, J. Am.
Chem. Soc. 1986, 108, 7778 ± 7786.
O
S
CF3
R1
CF3
O
S
CF3
NH4Cl
4N HCl
MeOH
_
+
_
N
tBu
N
H
R1
H3N
Cl
R1
tBu
nBuN+
5
4
Scheme 1. Mechanism of trifluoromethylation of imines by 2 in the
presence of TBAT.
590
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Angew. Chem. Int. Ed. 2001, 40, No. 3