Tetrahedron Letters 54 (2013) 2462–2465

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Tetrahedron Letters

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Enantioselective additions of (trifluoromethyl)trimethylsilane to a-iminoketones derived from aryl glyoxals

Emilia Obijalska ⇑, Grzegorz Mloston, Alice Six �

University of Łódz, Department of Organic and Applied Chemistry, Tamka 12 Street, 91-403 Lódz, Poland

a r t i c l e i n f o

Article history:Received 21 December 2012Revised 12 February 2013Accepted 27 February 2013Available online 7 March 2013

Keywords:Asymmetric nucleophilictrifluoromethylation(Trifluoromethyl)trimethylsilaneb-Amino-a-(trifluoromethyl) alcoholsCinchonium bromidesa-Imino ketones

0040-4039/$ - see front matter � 2013 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetlet.2013.02.093

⇑ Corresponding author. Tel.: +48 42 635 5766; faxE-mail address: emilkaobijalska@gmail.com (E. Ob

� Visiting strudent from École Nationale Supérieurede Recherche, Caen, France.

a b s t r a c t

Chemoselective additions of (trifluoromethyl)trimethylsilane to a-imino ketones derived from arylglyoxals in the presence of a catalytic amount of enantiomerically pure ammonium bromides, derivedfrom Cinchona alkaloids and K2CO3 led to O-silylated b-imino alcohols. Subsequent reduction of theseproducts with NaBH4 gave b-(N-alkyl)amino-a-trifluoromethyl alcohols for which the ee values were30–71% under optimized conditions. Enantiomeric excesses were determined for the final products onthe basis of 1H or 19F NMR spectra registered in the presence of chiral solvating agents.

� 2013 Elsevier Ltd. All rights reserved.

The synthesis of organofluorine compounds is a challenge inmodern organic chemistry. Incorporation of fluorine atoms or per-fluoroalkyl groups into the structure of organic molecules results insignificant changes in their physical, chemical, and biological prop-erties.1 Among fluorinated compounds, particular interest is fo-cused on molecules bearing a trifluoromethyl group, which havefound wide applications in, for example, the synthesis of materialswith specific properties as well as biologically active compounds.1

They are also used as efficient catalysts for diverse reactions.2 (Tri-fluoromethyl)trimethylsilane (the so called Ruppert–Prakash re-agent, RPR) is recognized as a very convenient reagent for theintroduction of a CF3 group into electrophilic substrates.3 Extensiveresearch has been focused on the development of stereocontrolledRPR additions to carbonyl compounds. In a recent paper, we dem-onstrated that camphorquinone monoimines underwent nucleo-philic trifluoromethylation in a chemo- and diastereoselectivemanner.4 Effective protocols for the enantioselective trifluorome-thylation of prochiral aldehydes and ketones, using RPR, have beendescribed.5 In these procedures, reactions were performed usingmethods based on phase-transfer catalysis. Typically, reactionswere carried out in the presence of two catalysts: an enantiomeri-cally pure quaternary ammonium bromide and an achiral saltbeing a source of fluoride, for example KF or TMAF. It turned out

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: +48 42 665 5162.ijalska).

d’Ingénieurs de Caen & Centre

that the most efficient catalysts were ammonium salts derivedfrom Cinchona alkaloids.

From another point of view, b-amino alcohols are considered asversatile building blocks and are widely applied in organic synthe-sis.6 Many biologically active substances belong to this class ofcompounds, or contain in their structure the modified skeleton ofa b-amino alcohol.6 b-Amino alcohols are also employed as cata-lysts and chiral auxiliaries in asymmetric synthesis.7 Their deriva-tives, functionalized with a CF3 group, combine unique physical,chemical, and biological properties. Several methods for the prep-aration of such compounds in racemic form have already been re-ported.8 Presently, the development of new and general syntheticmethods for the preparation of such compounds in enantiomeri-cally pure form, based on the application of inexpensive and easilyavailable starting materials is a challenge in organic chemistry. Ste-reocontrolled methods for the preparation of the target com-pounds exploit the phenomenon of asymmetric induction or theuse of expensive, enantiomerically pure substrates bearing a CF3

group.8 To the best of our knowledge, there is only one report inwhich an enantioselective method for the preparation of such com-pounds is described,9 which involves a Henry reaction carried outin the presence of a chiral lanthanide(III) ‘(S)-binolam’ complex.

In a previous report, we showed that chemoselective nucleo-philic trifluoromethylation of a-imino ketones derived from arylglyoxals, with subsequent reduction of the C@N function led toracemic b-amino-a-(trifluoromethyl) alcohols.10 Substratesbearing an a-methylbenzyl substituent on the N-atom as a chiralauxiliary reacted with RPR with low diastereoselectivity. In the

O OHOH

Ar H2N-R

CH2Cl2, r.t.O NRAr CF3SiMe3 NR

OMe3SiF3C Ar

*NaBH4EtOH, r.t.

NHROH

F3C Ar*

1a-e 2a-h 3a-h 4a-hcat.*, co-cat.

N N

OH

OH

ArArBr Br

NN

Rcat.*:

CN-(8R,9S)-5a Ar2 = PhCD-(8S,9R)-5d Ar2 = anthracen-9-yl, R2 = H

QN-(8S,9R)-5g Ar2 = 3,5-(CF3)2C6H3, R2 = OMe

bis-CN-(8R,9S)-5b

NHO

2BrN N OH

N

1 1

1 1

2 2

2

1 1 11

CN-(8R,9S)-5c Ar2 = anthracen-9-ylCN-(8R,9S)-5e Ar2 = 3,5-(CF3)2C6H3 CD-(8S,9R)-5f Ar2 = 3,5-(CF3)2C6H3, R2 = H

Scheme 1. Enantioselective synthesis of b-amino-a-trifluoromethyl alcohols.

Table 1

Substrate Ar1 R1 Cat.⁄ Co-cat. MOL % Solvent T (�C) Yield (%) of 4a ee (%) [aD]b

2a Ph t-Bu CN-(8R,9S)-5a KF 15 CH2Cl2 �20 50 0 —2a Ph t-Bu CN-(8R,9S)-5a KF 15 Toluene �20 88 9 —c

2a Ph t-Bu Bis-CN-(8R,9S)-5b KF 15 Toluene �20 87 8 —c

2a Ph t-Bu CN-(8R,9S)-5c KF 15 Toluene �20 82 18 +0.72a Ph t-Bu CD-(8S,9R)-5d KF 15 Toluene �20 86 24 �0.92a Ph t-Bu CN-(8R,9S)-5e KF 15 Toluene �20 79 52 +1.92a Ph t-Bu CD-(8S,9R)-5f KF 15 Toluene �20 79 58 �2.02a Ph t-Bu QN-(8S,9R)-5g KF 15 Toluene �20 71 35 �1.12a Ph t-Bu CD-(8S,9R)-5f KF 10 Toluene �20 59 52 �1.72a Ph t-Bu CD-(8S,9R)-5f K2CO3 15 Toluene �20 85 65 �2.72a Ph t-Bu CD-(8S,9R)-5f K2CO3 10 Toluene �20 77 56 �1.92a Ph t-Bu CD-(8S,9R)-5f KOH 15 Toluene �20 87 46 �1.52a Ph t-Bu CD-(8S,9R)-5f KOH 10 Toluene �20 88 41 �1.52a Ph t-Bu CD-(8S,9R)-5f KF 15 Toluene �40 82 63 �2.22a Ph t-Bu CD-(8S,9R)-5f K2CO3 15 Toluene �40 85 67 �3.02a Ph t-Bu CD-(8S,9R)-5f K2CO3 10 Toluene �40 78 61 �2.32b p-MeOC6H4 t-Bu CD-(8S,9R)-5f K2CO3 15 Toluene �40 89 71 �3.92c p-NO2C6H4 t-Bu CD-(8S,9R)-5f K2CO3 15 Toluene �40 94 30 �1.52d Benzofuran-2-yl t-Bu CD-(8S,9R)-5f K2CO3 15 Toluene �40 92 68 �3.42e 7-Et-benzofuran-2-yl t-Bu CD-(8S,9R)-5f K2CO3 15 Toluene �40 87 50 �3.22f Ph i-Pr CD-(8S,9R)-5f K2CO3 15 Toluene �40 87 64 �2.82f Ph i-Pr CD-(8S,9R)-5f K2CO3 10 Toluene �40 75 61 �3.02g p-MeOC6H4 i-Pr CD-(8S,9R)-5f K2CO3 15 Toluene �40 78 64 �2.92h p-NO2C6H4 i-Pr CD-(8S,9R)-5f K2CO3 15 Toluene �40 81 32 �1.8

a Total yield for the two-step protocol (2a–h ? 4a–h).b c = 1 mg/ml (CHCl3).c [aD] value was not determined.

E. Obijalska et al. / Tetrahedron Letters 54 (2013) 2462–2465 2463

present letter, an enantioselective version of this protocol based onthe use of modified Cinchona alkaloids is described

The preparation of 1-aryl-2,2-dihydroxyethanones 1a–e wasbased on the known oxidation of aryl-methyl ketones using SeO2

in an aqueous 1,4-dioxane solution.11 Further condensation of1a–e with primary amines led to a-imino ketones 2a–h(Scheme 1).10,12 As chiral catalysts, quaternary ammonium bro-mides 5a–g, derived from Cinchona alkaloids were tested. Theywere prepared according to the literature procedures.5e,13

The enantioselective synthesis of the target compounds wasbased on the modified protocol for obtaining racemic products(rac)-4.10 In the key step, addition of RPR to 2 was performed inthe presence of a catalytic system consisting of enantiomericallypure ammonium bromide and an achiral co-catalyst. The mixtureof both salts replaced cesium fluoride as an efficient initiator ofthe nucleophilic trifluoromethylation reaction. The obtained sily-lated ethers 3a–h were used in further transformations withoutpurification or determination of the enantiomeric excess. Reduc-tion of the C@N bond and desilylation of the adducts of type 3a–h with sodium borohydride gave b-amino-a-(trifluoromethyl)alcohols 4a–h. The initial experiments were carried out with the

model substrate N-tert-butylphenyl-a-imino ketone 2a in orderto optimize the reaction conditions for the enantioselective addi-tion of RPR (Scheme 1, Table 1).

On the basis of literature data and preliminary experiments, tol-uene was used as a non-polar solvent. Reactions were performed inthe presence of 15 mol % of the catalysts: potassium fluoride andan appropriate chiral salt 5. In all cases, the final products were ob-tained in good yields. The use of bis-cinchonium bromide bis-CN-(8R,9S)-5b, which gave the best results in additions to aldehydesand ketones,5f led to the desired product 4a with very low enantio-meric excess. Tetramethylammonium fluoride was not tested as aco-catalyst in the present studies due to difficulties with the prep-aration of the catalyst in anhydrous form. Application of catalystswith an anthracenylmethyl substituent CN-(8R,9S)-5c and CD-(8S,9R)-5d did not improve the results significantly. A derivativeof cinchonidine containing a 3,5-bis(trifluoromethyl)benzyl groupCD-(8S,9R)-5f appeared to be the most effective catalyst and anee of 60% was obtained. Application of quinidinium bromide QN-(8S,9R)-5g gave a worse result. In the case of pseudoenantiomericcatalysts CN-(8R,9S)-5c,e and CD-(8S,9R)-5d,f, product 4a was ob-tained with an opposite configuration and comparable ee values. In

NHOH

F3CPh

*

(rac )-4 a (S )-6

t-Bu .

.

OP SH

PhBut - NH

OHF3C

Ph*

(enantiomerically enriched) -4a (S )-6

OP SH

PhBut-t -Bu .

.

Figure 1. 1H NMR spectra of racemic and enantiomerically enriched 4a recorded in the presence of (S)-6.

2464 E. Obijalska et al. / Tetrahedron Letters 54 (2013) 2462–2465

order to find the best co-catalyst, potassium fluoride, potassiumcarbonate, and potassium hydroxide were tested. Comparable re-sults were achieved for KF and K2CO3, and the latter was chosenfor further experiments. It was noticed that lowering the tempera-ture of the reactions caused a slight increase in the ee value ofproduct 4a. Also, decreasing the loading of the catalyst CD-(8S,9R)-5f to 10 mol % resulted in a slight decrease in the ee value.However, product 4a was not observed when the reactions werecarried out in the presence of 5 mol % of catalyst CD-(8S,9R)-5f.

Next, imino ketones 2b–h, which contain different Ar1 and R1

substituents were tested under the optimized conditions usingCD-(8S,9R)-5f as the catalyst and K2CO3 as the co-catalyst, in tolu-ene at �40 �C.14 It was found that replacement of the t-Bu substi-tuent with i-Pr on the N-atom only caused a slight change in the eevalues of the products 4b–h. On the other hand, the stereochemicaloutcomes of the reactions were highly influenced by the type ofaryl substituent. The presence of an electron-withdrawing groupon the phenyl ring caused a noticeable decrease in the ee values.Therefore it is possible that the enantioselectivity of the processdepends on electronic effects more than on steric factors.

It is worth mentioning that the enantiomeric excesses of the fi-nal products 4a–h were determined on the basis of 1H and/or 19FNMR spectra recorded in the presence of chiral solvating agents,for example, (S)-(tert-butyl)phenylthiophosphinic [(S)-6] or (R)-mandelic acid. An example of a characteristic fragment of the 1HNMR spectra for racemic and enantiomerically enriched product4a recorded with (S)-6 is presented in Figure 1. In these studiesthe absolute configurations of the main enantiomers of the prod-ucts 4a–h were not determined.

In conclusion, a new, simple, and promising method for theenantioselective synthesis of b-amino-a-(trifluoromethyl) alcoholsof type 4, based on readily available starting materials, has beendeveloped. Chemoselective addition of CF3SiMe3 to the carbonylgroup of a-imino ketones 2a–h was performed in the presence ofenantiomerically pure bromides of type 5, derived from Cinchonaalkaloids and potassium fluoride or carbonate, followed by reduc-tion and desilylation to yield the desired products, 4a–h in verygood yields and with moderate ee values. Although the obtainedee values were moderate, the results are comparable with these re-ported for additions of CF3SiMe3 to simple carbonyl substrates.5

Further studies will be focused on modification of the catalyststructure in order to achieve improved stereochemical outcomesand to decrease the amount of the catalysts applied.

Acknowledgments

We gratefully acknowledge the National Science Center of Po-land for the financial support (Grant ‘SONATA’ # DEC-2011/03/D/ST5/05231) (E.O.).

Supplementary data

Supplementary data (experimental details and the characteriza-tion data for compounds 4a–h) associated with this article can befound, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.093.

References and notes

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14. General procedure for the enantioselective synthesis of b-amino-a-(trifluoromethyl) alcohols 4: A solution of the a-imino ketone 2a–h(0.5 mmol) in anhydrous toluene (1.0 ml), was placed in a dry, two-neckedflask, equipped with a septum and a balloon with argon. Next,enantiomerically pure catalyst CD-(8S,9R)-5f (45 mg, 0.075 mmol) andfreshly dried K2CO3 (10 mg, 0.075 mmol) or KF (4.3 mg, 0.075 mmol) wereadded. Subsequently, (trifluoromethyl)trimethylsilane (100 mg, 0.7 mmol) wasadded while cooling the reaction flask (�40 �C). The mixture was stirred at�40 �C for ca. 5 h, and left overnight in the cooling bath. Next, the mixture wasquenched with H2O (5 ml). The solution was extracted with CH2Cl2 (3 � 10 ml).

The organic layers were combined and dried over anhydrous Na2SO4. Afterfiltration, the solvents were evaporated and the crude, oily products 3a–h wereused for reactions without further purification.To a magnetically stirred solution of the corresponding adduct 3a–h in EtOH(�3 ml), NaBH4 (228 mg, 6 mmol) was added in small portions while coolingthe reaction flask in an ice-bath. When the evolution of H2 was complete, themixture was stirred at room temperature for 12 h. After this time, the solventwas evaporated and the solid residue was treated with H2O (�10 ml), andsubsequently extracted with CH2Cl2 (3 � 10 ml). The organic layers werecombined, and dried over anhydrous Na2SO4. After filtration, the solvent wasevaporated and the crude products 4a–h were purified by columnchromatography on silica gel using hexane/Et2O (85:15) as eluent. Theoverall yields of the products for this two-step protocol are given in Table 1.The enantiomeric excesses were determined after chromatographicpurification. All spectroscopic data were in agreement with the literature.10

Products were not crystallized in order to determine the correct ee value.