Nucleophilic addition of (difluoromethyl)trimethylsilane to selected α-imino ketones and aryl diketones

Article abstract of DOI:10.1016/j.tetlet.2015.06.025

Abstract Chemoselective addition of (difluoromethyl)trimethylsilane (CHF₂SiMe₃) to the carbonyl bond of aryl glyoxal derived α-imino ketones, and selected diaryl 1,2-diketones were studied in the presence of initiators, such as potas

Full text of DOI:10.1016/j.tetlet.2015.06.025

Accepted Manuscript
Nucleophilic addition of (difluoromethyl)trimethylsilane to selected α-imino
ketones and aryl diketones
Emilia Obijalska, Greta Utecht, Marcin K. Kowalski, Grzegorz Mlostoń,
Michał Rachwalski
PII:
S0040-4039(15)01018-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.025
TETL 46417
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 April 2015
27 May 2015
9 June 2015
Please cite this article as: Obijalska, E., Utecht, G., Kowalski, M.K., Mlostoń, G., Rachwalski, M., Nucleophilic
addition of (difluoromethyl)trimethylsilane to selected α-imino ketones and aryl diketones, Tetrahedron Letters
(2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.025
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Nucleophilic addition of
(difluoromethyl)trimethylsilane to selected α-
imino ketones and aryl diketones
Emilia Obijalska,* Greta Utecht,† Marcin K. Kowalski, Grzegorz Mlostoń, Michał Rachwalski

Nucleophilic addition of (difluoromethyl)trimethylsilane to selected α-imino
ketones and aryl diketones
Emilia Obijalska,* Greta Utecht,† Marcin K. Kowalski, Grzegorz Mlostoń, Michał
Rachwalski
Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Łódź,
Tamka 12, PL-91-403 Łódź, Poland
*Corresponding author: Tel.: +48 42 635 57 66
E-mail address:
emilkaobijalska@gmail.com
† Part of the Masters Thesis of G. U., University of Łódź, 2014.

Keywords: (difluoromethyl)trimethylsilane, α-imino ketones, diketones, difluoromethylation,
β-amino alcohols, 1,2-diols
ABSTRACT
Chemoselective addition of (difluoromethyl)trimethylsilane (CHF2SiMe3) to the carbonyl
bond of aryl glyoxal derived α-imino ketones, and selected diaryl 1,2-diketones were studied
in the presence of initiators, such as potassium tert-butoxide or cesium fluoride. Subsequent
reduction of the obtained α-imino alcohols and α-hydroxy ketones with sodium borohydride
gave the expected 2-amino 1-(difluoromethyl)alcohols and (difluoromethyl)-1,2-diols
respectively in moderate to good yields. High de values were observed for the reduction of
α-(difluoromethyl)-α-hydroxy ketones.
1. Introduction
The development of new methods for the synthesis of organofluorine compounds is
currently a challenging topic in current organic chemistry.1 Special interest is focused on the
synthesis of derivatives containing small fluoroalkyl groups (e.g. CF3, CHF2).1 Organic
compounds functionalized with these substituents are considered as attractive building blocks
and molecules with potential application in the preparation of drugs,1a,b agrochemicals1a or
materials with special properties.1a Methods for the incorporation of the CF3 group into the
structure of organic substrates are well known.1,2 Currently, (trifluoromethyl)trimethylsilane
(so-called Ruppert’s-Prakash reagent, CF3SiMe3) is well known as a universal
trifluoromethylating agent.2 On the other hand, protocols for the incorporation of a CHF2
group are less well known.1a,b,2e,3 Recently, (difluoromethyl)trimethylsilane (CHF2SiMe3) has
been reported as a promising difluoromethylating agent4 and this reagent has been utilised as
a nucleophilic reagent in the reaction with simple carbonyl compounds and activated N-
sulfinyl imines,4b,g as well as with aryl halides, vinyl halides, diazonium salts,4c,f and aromatic
N-oxides.4e
β-Amino alcohols are versatile building blocks that have been widely utilised as starting
materials for the preparation of more complex molecules and as powerful chiral auxiliaries
and/or catalysts in asymmetric synthesis.5 β-Amino alcohols containing fluoroalkyl groups
combine unique physico-chemical and biological properties resulting from the presence of the

fluorinated substituents.6 Many protocols for the preparation of β-amino α-
(trifluoromethyl)alcohols have been described in the literature.6c However, methods for the
synthesis of β-amino α-(difluoromethyl)alcohols are only scarcely described7 and the Petasis
reaction of 2-hydroxy-3,3-difluoropropanal with arylboronic acids and secondary amines may
be considered as the only general method for the preparation of β-amino-α-(difluoromethyl)
alcohols.7d
The goal of the present study was the development of a straightforward method to
prepare β-amino α-(difluoromethyl)alcohols based on the reaction of α-imino ketones 1 with
(difluoromethyl)trimethylsilane. A similar protocol was previously applied by our group for
the synthesis of β-amino α-(trifluoromethyl)alcohols.8 Addition of CF3SiMe3 to α-imino
ketones 1 led chemoselectively to silyl ethers 2, which upon treatment with sodium
borhydride were converted into the desired trifluoromethylated amino alcohols 3 (Scheme 1).
Scheme 1. Synthesis of β-amino α-(trifluoromethyl) alcohols.
2. Results and discussion
α-Imino ketones 1a-h were prepared according to the known two-step procedure.8,9
Oxidation of the appropriate methyl ketones 4 using SeO2, gave 2,2-dihydroxyethanones 5,
which were converted into α-imino ketones 1a-h via their reaction with the appropriate
primary amines (Scheme 2).
Scheme 2
Due to their stability, substrates 1d (Ar = Ph) and 1e (Ar = 4-BrC6H4), bearing a bulky t-
Bu substituent on the nitrogen atom, were selected for preliminary experiments. The

difluoromethylation reactions were performed in the presence of a catalytic amount of cesium
fluoride in DMF at room temperature (method A) or alternatively, in the presence of a
stoichiometric amount of potassium tert-butoxide in THF at –78 oC (method B) (Scheme 3).10
Based on an earlier protocol,4b experiments were carried out using a two-fold excess of
(difluoromethyl)trimethylsilane. In analogy to the trifluoromethylation of 1 with CF3SiMe3,8a
addition of CHF2SiMe3 to the carbonyl occurred with complete chemoselectivity.
Next, the scope of the reaction was explored with various imino ketones 1. The initially
formed α-hydroxy imines 6 or their silyl ethers 6’ were used without purification for the
reduction using sodium borohydride (for compounds of type 6’ simultaneous reduction of the
C=N function and desilylation was observed).11 Yields for the obtained β-amino α-
(difluoromethyl)alcohols 7 performed according to method A or method B were comparable
(entries 4-7, Table 1). Characteristic splitting patterns resulting from the presence of the CHF2
1
13
group were observed in both H- and C-NMR spectra of the products. For example, in the
case of compound 7d, the signal for the CHF2 proton appeared as a dd at 5.70 ppm (2JH,F(1)
=
2JH,F(2) = 55.8 Hz) and a dd originating from the carbon atom was located at 117.6 ppm
(1JC,F(1) = 1JC,F(2) = 247.5 Hz).
We observed that the reaction was strongly dependent on the substituent located on the
nitrogen atom and only in the case of substrates bearing tert-butyl or cyclohexyl groups was
formation of the desired products 6 or 6’ observed. All attempts to utilise other iminoketones
1, possessing iso-propyl, 1-phenylethyl or methoxy substituents, were unsuccessful. We
postulate that, under the basic reaction conditions (F-/DMF, t-BuO-/THF), these less stable
substrates 1 underwent decomposition leading to the formation of complex reaction mixtures.
The substituent attached to the aromatic ring in substrates 1 also influenced the observed
yields and better results were observed for substrates bearing electron-donating groups on the
phenyl ring (Table 1). It is worth emphasising, that similar reactions of 1 with
(trifluoromethyl)trimethylsilane led to the expected products in higher yields irrespective of
the substituent at the nitrogen atom.8 This observation could be explained by the higher
reactivity of CF3SiMe3 towards electrophiles in comparison with CHF2SiMe3.4b Additionally,
more drastic conditions were required for the activation of CHF2SiMe3.

Scheme 3. Chemoselective additions of (difluoromethyl)trimethylsilane to α-iminoketones 1
Table 1 Nucleophilic difluoromethylation of α-imino ketones 1a-h
Yield of 7
Entry
Substrate Methoda
Ar
R
(%)b
65
55
48
65
63
45
43
63
30
43
X
1
2
B
B
B
A
B
A
B
B
B
B
H
H
3,4-(OCH2O)C6H3
3,4-(MeO)2C6H3
4-MeOC6H4
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
cHex
1a
1b
1c
1d
1d
1e
1e
1f
3
H
4
SiMe3
H
5
Ph
6
SiMe3
H
4-BrC6H4
4-BrC6H4
4-F3CC6H4
4-NO2C6H4
Ph
7
8
H
9
H
1g
1h
10
H
aMethod A: CsF (cat.), DMF, r.t, 12 h; Method B: t-BuOK (2.0 equiv.), THF, –78 C, 12 h
bTotal yield for the two-step protocol (1 → 7)
In an extension of this study, addition of (difluoromethyl)trimethylsilane to symmetrical,
diaryl 1,2-diketones 8 was performed under the optimized reaction conditions.10 Benzil (8a)
and phenanthrenequinone (8b) were reacted with CHF2SiMe3 to give the α-hydroxy ketones 9
as the sole products in moderate yields (Scheme 4, Table 2). Remarkably, experiments
performed with two equivalents of the difluoromethylating agent resulted in exclusive
formation of the 1:1 adducts. Upon treatment with NaBH4, the obtained α-hydroxy ketones 9
were reduced to the corresponding 1,2-diols 10 in high yields.11 In the case of 9a a mixture of
both isomers was obtained (dr 88:12), whereas the reduction of 9b led to the formation of a
single diastereoisomer. Unfortunately crystals of 10a,b and their 1,3-dioxolanone derivatives
were not suitable for X-ray analysis and the syn/anti configuration of the major products was
thus not established. The structure of the obtained products 10a,b was tentatively assigned as

the anti-isomer based on the results of analogous reductions reported for the α-hydroxy-α-
(trifluoromethyl) ketones.12
Scheme 4. Chemoselective addition of (difluoromethyl)trimethylsilane to aryl diketones 8a-b
Table 2
Nucleophilic addition of (difluoromethyl)trimethylsilane to symmetrical aryl diketones 8a-b
9
Yield (%)
53
10
Ar, Ar
Substrate
dea
Yield (%)
55 (89)b
Ph, Ph
76
8a
8b
51
>99
91
aOn the basis of the 19F NMR spectra of crude reactions mixtures.
b Yield of pure anti diastereoisomer of 10a-b; in parentheses total yield of both isomers.
4. Conclusions
A new, straightforward method for the synthesis of a series of new 2-amino-1-
(difluoromethyl)alcohols 7 and 1-(difluoromethyl)-1,2-diols 10, based on relatively
inexpensive and readily accessible starting materials was described. In the case of amino
alcohols 7, the presented method complements an already reported protocol based on the
Petasis reaction. In most of the described cases, products 7 and 10 were obtained in
satisfactory yields. They can be considered as new, attractive building blocks for the synthesis
of more complex fluorinated compounds. To the best of our knowledge, this is the first
protocol, which provides access to difluoromethylated diols via the selective nucleophilic
difluoromethylation of 1,2-diketones. This compares well to a recently published patent
leading to azido-functionalized diols containing the CHF2 moiety.13

5. Acknowledgements
E. O. acknowledges the National Science Center (PL-Cracow) for financial support (Grant
‘SONATA’ # DEC-2011/03/D/ST5/05231).
References
1.
a) Kirsch, P. Modern Fluoroorganic Chemistry, Wiley-VCH: Weinheim, Germany,
2013; b) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of
Fluorine, Wiley: Hoboken, New Jersey, 2008; c) Müller, K.; Faeh, C.; Diedrich, F.
Science 2007, 317, 1881–1886; d) Nenajdenko, V. Fluorine in Heterocyclic Chemistry,
Springer Verlag: erlin, 2013 e ang, . Sanchez-Rosello, M. Ace a, J.L.; del Pozo,
C.; Sorochinsky, A.E.; Fustero, S.V.; Soloshonok, A.; Liu, H. Chem. Rev. 2014, 114,
2432–2506.
2.
a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757–786; b) Ma, J.-A.; Cahard,
D. Chem. Rev. 2008, 108, PR1–PR43; c) Rubiales, G.; C. Alonso, C.; DeMarigorta,
E.M.; Palacios, F. Arkivoc 2014, 362–405; d) Liu, X.; Xu, M., Liu, Q. Chem. Rev. 2015,
115, 683–730; e) Yang, X.; Wu, T.; Phipps, J.; Toste, F. D. Chem. Rev. 2015, 115, 826–
870.
3.
4.
a) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M.
R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494–1497; b) Ni, C.;
Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765-825.
a) Tyutyunov, A.; Boyko, S.; Igoumnov, S. Fluorine Notes 2011, 74, 1–2; b) Zhao, Y.;
Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13, 5342–5345; c) Fier, P. S.; Hartwig, J.
F. J. Am. Chem. Soc. 2012, 134, 5524–5527; d) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew.
Chem. Int. Ed. 2013, 52, 12390–12394; e) Stephens, D. E; Chavez, G.; Valdes, M.;
Dovalina, M.; Arman, H. D.; Larionov, O. V. Org. Biomol. Chem. 2014, 12, 6190–
6199; f) Matheis, C.; Jouvin, K.; Goossen, L. J. Org. Lett. 2014, 16, 5984–5987; g)
Román, R.; Navarro, A.; Wodka, D.; Alvim-Gaston, M.; Husain, S.; Franklin, N.;
Simón-Fuentes, A.; Fustero, S. Org. Process Res. Dev. 2014, 18,1027–1036.
a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856; b) Ager, D. J.; Prakash, I.; Schaad,
D. R. Chem. Rev. 1996, 96, 835–875; c) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed.
1998, 37, 1986–2012; d) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296–18304.
a) Bravo, P.; Crucianelli, M.; Ono, T.; Zanda, M. J. Fluorine Chem. 1999, 97, 27–49; b)
Fujwara, Y.; Katagiri, T.; Uneyama, K. Tetrahedron Lett. 2003, 44, 6161–6165; c)
5.
6.

Mlostoń, G.; Obijalska, E.; Heimgartner, H. J. Fluorine Chem. 2010, 131, 829–843 d)
Obijalska, E. Kowalski, M. Mlostoń, G. Linden, A. Heimgartner, H. J. Fluorine
Chem. 2014, 168, 151–157 .
7.
a) Imperiali, B.; Abeles, R. H. Tetrahedron Lett. 1986, 27, 135–138; b) Shimizu, M.;
Yokota, T.; Fujimori, K.; Fujisawa, T. Tetrahedron: Asymmetry 1993, 4, 835–838; c)
Arnone, A.; Bravo, P.; Frigerio M.; Viani, F.; Soloshonok, V. A. Tetrahedron 1998, 54,
11841–11860; d) Prakash, G. K. S.; Mandal, M.; Schewizer, S.; Petasis, N. A.; Olah, G.
A. J. Org. Chem. 2002, 67, 3718–3723; e) Shaitanova, E. N.; Gerus, I. I.; Yu, M.;
Kukhar, B.; Kukhar V. P. Tetrahedron: Asymmetry 2007, 18, 192–198; f) V. P.; Liu, J.;
Ni, C.; Wang, F.; Hu, J. Tetrahedron Lett. 2008, 49, 1605-1608; g) Wan, W.; Gao. Y.;
Jiang, H.; Hao, J. J. Fluorine Chem. 2008, 129, 510–514.
8.
9.
a Mlostoń, G. Obijalska, E. Tafelska-Kaczmarek, A.; Zaidlewicz, M. J. Fluorine
Chem. 2010, 131, 1289–1296 b Mlostoń, G.; Obijalska, E.; Heimgartner, H. J.
Fluorine Chem. 2011, 132, 951–955.
a) Fodor, G.; Kovács, Ö. J. Am. Chem. Soc. 1949, 71, 1045–1048; b) Rioux-Lacoste, C.;
Viel, C. Bull. Soc. Chim. Fr. 1974, 2463–2470; c) Alcaide, B.; Escobar, G.; Pérez-
Ossorio, R.; Plumet, J.; Sanz, D. J. Chem. Res. Mini Print 1984, 1464–1472.
10. a) General procedure for the reactions of α-imino ketones 1 and 1,2-diketones 8 with
(difluoromethyl)trimethylsilane. Method A: The appropriate α-imino ketone 1 (1.0
mmol) dissolved in anhydrous DMF (~1 mL) was placed in a dry two-neck flask,
equipped with a septum and an argon balloon. A catalytic amount of freshly dried CsF
and CHF2SiMe3 (250 mg, 2.0 mmol) were added at room temperature. The reaction
mixture was left for 24 h and quenched with H2O (~2 mL). The solution was extracted
with CH2Cl2 (4 x 5 mL), and the organic layers combined and dried over anhydrous
Na2SO4. After filtration, the solvents were removed under reduced pressure. Method B:
The appropriate substrate 1 or 8 (1.0 mmol) was dissolved in anhydrous THF (~5 mL)
and placed in a dry two-neck flask, equipped with a septum, an argon balloon and a tube
filled with anhydrous CaCl2. Then reaction flask was cooled to –78 ºC. Next, t-BuOK
(220 mg, 2.0 mmol) and CHF2SiMe3 (250 mg, 2.0 mmol) were added. The reaction
mixture was stirred for 4 h and quenched with H2O (~4 mL). The solution was extracted
with Et2O (4 x 5 mL). The organic layers were combined and dried over anhydrous
Na2SO4. After filtration, the solvents were evaporated. The obtained (difluoromethyl)
imino alcohols 6 or their silyl ethers 6ʹ were used in the next step without purification.
(Difluoromethyl)hydroxy ketones 7 were purified by flash column chromatography.

11. General procedure for the reduction of (difluoromethyl)imino alcohols 6, their silyl
ethers 6ʹ and (difluoromethyl)hydroxyl ketones 9. Compound 6, 6ʹ or 9 (1.0 mmol) was
dissolved in EtOH (~5 mL), and NaBH4 (110 mg, 3.0 mmol) was added. The reaction
mixture was stirred at room temperature for 12 h. The solvent was then removed under
reduced pressure. Next, H2O (~5 mL) was added and the reaction mixture was extracted
with CH2Cl2 (4 x 5 mL). The organic layers were combined, dried over anhydrous
Na2SO4 and the solvent was evaporated. The obtained β-(difluoromethyl)-α-amino
alcohols 7 or (difluoromethyl)-1,2-diols 10 were purified by flash column
chromatography eluting with hexane/Et2O 8:2 and/or crystallization from an appropriate
solvent.
12 a) Iskra, J.; Bonnet-Delpon, D.; Bégué, J.-P. Eur. J. Org. Chem. 2002, 3402–3410; b)
Prakash, G. K. S.; Do, C.; Wang, F.; Mathew, T.; Olah, G. A. Synthesis 2010, 1891–
1898.
13. Kusakabe, K.-I.; Yoshida S.; Nakahara, K.; Hasegawa; T., Tadano, G.; Fuchino, K
Shinogi and Co., Ltd.; Patent: WO2014/65434 A1, 2014.