Synthesis of CF3-substituted sulfoximines from sulfonimidoyl fluorides

Article abstract of DOI:10.1021/ol103030w

N-Protected trifluoromethyl-substituted sulfoximines have been prepared by treatment of sulfonimidoyl fluorides with a combination of the Ruppert-Prakash reagent (TMSCF₃) and tetrabutyl ammonium fluoride (TBAF). The starting materials were accessed following two synthetic routes, and for each reaction sequence the substrate scope was evaluated. Accordingly, a wide variety of aryl-substituted products were obtained in moderate to good yield.

Full text of DOI:10.1021/ol103030w

ORGANIC
LETTERS
2011
Vol. 13, No. 4
768–771
Synthesis of CF3-Substituted
Sulfoximines from Sulfonimidoyl
Fluorides
Rafal Kowalczyk,† Andrew J. F. Edmunds,‡ Roger G. Hall,‡ and Carsten Bolm*,†
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056
Aachen, Germany, and Syngenta Crop Protection AG, Stein, Schaffhauserstrasse,
CH-4332 Stein, Switzerland
Carsten.Bolm@oc.rwth-aachen.de
Received December 14, 2010
ABSTRACT
N-Protected trifluoromethyl-substituted sulfoximines have been prepared by treatment of sulfonimidoyl fluorides with a combination of the
Ruppert-Prakash reagent (TMSCF3) and tetrabutyl ammonium fluoride (TBAF). The starting materials were accessed following two synthetic
routes, and for each reaction sequence the substrate scope was evaluated. Accordingly, a wide variety of aryl-substituted products were obtained
in moderate to good yield.
The introduction of fluorine can substantially change
the chemical and physical properties of an organic
compound.1 For example, fluorinated molecules show
improved stability toward oxidation, increased solubility
in lipid membranes without loss of polarity, and enhanced
organization in enzyme receptor sites by interactions of
C-F bonds with NH-, CH-, and CO- moieties. As a
consequence, organic fluorine compounds have attracted a
great deal of attention in the fields of medicinal and crop
protection chemistry.2 For synthetic chemistry, the direc-
ted introduction of fluorine atoms and fluoroalkyl groups
has emerged as an interesting challenge.3,4
(3) For some reviews concerning introduction of fluorine or fluoro-
alkyl groups, see: (a) Harschneck, T.; Kirsch, S. F. Nachr. Chem. 2010,
58, 892. (b) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (c) Shibata, N.;
Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 1. (d) Hu, J.;
Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. (e) Prakash, G. K. S.;
Hu, J. Acc. Chem. Res. 2007, 40, 921. (f) Ma, J.-A.; Cahard, D. Chem.
Rev. 2004, 104, 6119. (g) Langlois, B. R.; Billard, T. Synthesis 2003, 185.
(h) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431.
(i) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (j)
McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555. (k)
Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189. For reviews
concerning stereoselective fluorinations or trifluoromethylations, see:(l)
Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry 2008, 19,
2633. (m) Iseki, K. Tetrahedron 1998, 54, 13887.
† RWTH Aachen University.
‡ Syngenta Crop Protection AG.
(1) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem Soc. Rev. 2008, 37, 320.
€
(c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d)
Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (e) O’Hagan, H; Rzepa, H. S.
Chem. Commun. 1997, 645. (f) Uneyama, K. Organofluorine Chemistry;
Blackwell: Oxford, 2006. (g) Kirsch, P. Modern Fluororganic Chemistry;
Wiley-VCH: Weinheim, 2004.
(2) (a) O‘Hagan, D. J. Fluorine Chem. 2010, 131, 1071. (b) Thayer,
A. M. Chem. Eng. News 2006, 84, 15. (c) Shofield, H. J. Fluorine Chem.
1999, 100, 7. (d) Fluorine in Medicinal Chemistry and Chemical Biology;
ꢀ
ꢁ
Ojima, I., Ed.; Blackwell: Oxford, 2009. (e) Begue, J. P.; Bonnet-Delpont, D.
Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons:
Hoboken, NJ, USA, 2008. (f) Maienfisch, P.; Hall, R. G. Chimia 2004, 58,
93.
(4) For a recent topical issue on organofluorine chemistry, see: Togni,
A. Adv. Synth. Catal. 2010, 352, 2689 and articles referred to therein. (b)
For a recent themed series in organo-fluorine chemistry, see: O’Hagan,
D. Beilstein J. Org. Chem. 2010, 6, 36.
r
10.1021/ol103030w
Published on Web 01/14/2011
2011 American Chemical Society

Sulfoximines have found applications as auxiliaries in
asymmetric synthesis, chiral ligands in enantioselective
metal catalysis, and structural units in pseudopeptides.5
Their recent wide emergence in the patent literature is
remarkable.6 Derivatives with perfluoroalkyl substituents
at sulfur have been used as neutral or electrophilic CF3
transfer agents by Hu and Shibata, respectively.3c,7 Further-
more, they were recognized as attractive compounds in
material science.8 However, perfluoroalkyl sulfoximine
derivatives remain relatively rare: early syntheses involved
iminations of the corresponding sulfoxides with NaN3 and
H2SO4 or oleum. These protocols proved difficult due to
low-yielding sulfide oxidations to afford the required sulf-
oxides and the need of a significant fine-tuning of the
nitrogen transfer step.8,9 Recently, Magnier reported an
alternative approach based on a Ritter-type sulfoxide-to-
sulfilimine conversion as the key step.10 Subsequent selec-
tive oxidation of the intermediately formed N-acylsulfili-
mines afforded trifluoromethyl- and nonafluorobutyl-
substituted aryl sulfoximines in moderate to good yields.11
Based on our expertise in catalyzed sulfur iminations,12 we
wondered if our previously developed protocols were also
applicable in the preparation of perfluoroalkyl sulfilimines
and sulfoximines. Unfortunately, the use of rhodium,
copper, or iron catalysts or the recently introduced metal-
free variant13 did not lead to success in attempted imina-
tions of both phenyl trifluoromethyl sulfide (1a) and
the corresponding sulfoxide 2a (Scheme 1, top), and the
desired products 3 and 4, respectively, remained inacces-
sible. Alternatively, oxidative halogenation of N-arylated
trifluoromethyl sulfinamide 5 was attempted analogous
tothe workof Yagupolskii,14 withthe goaltoapply carbon
Scheme 1. Attempted Preparations of Trifluoromethyl Phenyl
Sulfilimine 3 and Sulfoximines 4 and 7
Scheme 2. Synthesis of Trifluoromethyl Sulfoximines 11 via
Sulfonimidoyl Fluorides 10 Starting from Sulfonimidoyl
Chlorides 8 or Sulfinamides 9
nucleophiles subsequently in substitution reactions on
6 to provide 7 (Scheme 1, bottom). Oxidants NCS, NBS,
chloramine T, trichloroisocyanuric acid, and 1,3-dichloro-
5,5-dimethyl hydantoin were used, but none of them
proved applicable for the synthesis of target structures 6.
Treatment of 5 with the stronger oxidant chlorine led to
decomposition of the starting material.
Hypothesizing that the sulfur iminations of 1a and 2a
and the oxidative halogenations of 5 were hampered by the
low nucleophilicity of the sulfur reagents induced by the
fluoro substituents, we pursued an alternative strategy.
Accordingly, sulfonimidoyl halides became key targets
with the vision to convert those into trifluoromethyl
sulfoximines 11 by nucleophilic substitution with a formal
CF3- reagent. For the latter transformation, the Ruppert-
Prakash reagent (TMSCF3)3e,f appeared suitable (Scheme 2)
as suggested by a single example described by Yagupolskii,
who had described the reaction between TMSCF3 and a
highly activated N-Tf sulfonyl fluoride with tris(dimethyl-
amino)sulfonium difluorotrimethylsiliconate (TASF) as a
catalyst.15
Two routes were followed for the synthesis of sulfon-
imidoyl fluorides 10. The first involved the corresponding
sulfonimidoyl chlorides 8, which were available by a
known protocol via sulfinic chlorides 12 starting from
thiols,16 disulfides,17 and sulfinic acids.18 The conversions
of 12a-e into 8a-g are summarized in Table 1.
(5) Reviews: (a) Reggelin, M.; Zur, C. Synthesis 2000, 1. (b) Harmata,
M. Chemtracts 2003, 16, 660. (c) Okamura, H.; Bolm, C. Chem. Lett.
2004, 33, 482. (d) Bolm, C. In Asymmetric Synthesis with Chemical and
Biological Methods; Enders, D., Jaeger, K.-E., Eds.; Wiley-VCH: Weinheim,
Germany, 2007; p 149. (e) Worch, C.; Mayer, A. C.; Bolm, C. In
Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, Germany, 2008; p 209.
~
(6) See refs 3 and 4 in: Garcia Mancheno, O.; Dallimore, J.; Plant, A.;
Bolm, C. Adv. Synth. Catal. 2010, 352, 309.
(7) (a) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2009, 11, 2109. (b)
Zhang, W.; Huang, W.; Hu, J. Angew. Chem., Int. Ed. 2009, 48, 9858. (c)
Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M. Eur. J. Org.
Chem. 2008, 3465.
€
(8) (a) Kirsch, P.; Lenges, M.; Kuhne, D.; Wanczek, K.-P. Eur. J.
Org. Chem. 2005, 797. (b) For use as superacidifiers, see: Terrier, F.;
Magnier, E.; Kizilian, E.; Wakselman, C.; Buncel, E. J. Am. Chem. Soc.
2005, 127, 5563.
(9) (a) Kondratenko, N. V.; Radchenko, O. A.; Yagupolskii, L. M.
Zh. Org. Khim. 1984, 20, 2250. (b) Magnier, E.; Wakselman, C. Synthesis
2003, 565.
ꢀ
(10) Mace, Y.; Urban, C.; Pradet, C.; Marrot, J.; Blazejewski, J.-C.;
Magnier, E. Eur. J. Org. Chem. 2009, 3150.
(11) For a recent extension of this work, see: Urban, C.; Mace, Y.;
ꢀ
Cadoret, F.; Blazejewski, J.-C.; Magnier, E. Adv. Synth. Catal. 2010,
352, 2805.
(12) Rh: (a) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305. Ag:(b)
~
Cho, G. Y.; Bolm, C. Org. Lett. 2005, 7, 4983. Fe:(c) Garcı
´
a Mancheno,
The second route made use of N-benzoyl and N-Boc
sulfinamides 9 (R3 = Ph or Ot-Bu),19 which were first
oxidized with t-BuOCl to provide the corresponding
~
O.; Bolm, C. Org. Lett. 2006, 8, 2349. (d) Garcı
C. Chem.;Eur. J. 2007, 13, 6674. (e) Garcı
J.; Plant, A.; Bolm, C. Org. Lett. 2009, 11, 2429.
´
a Mancheno, O.; Bolm,
a Mancheno, O.; Dallimore,
~
´
~
(13) (a) Garcıa Mancheno, O.; Bolm, C. Org. Lett. 2007, 9, 2951. (b)
´
~
Garcıa Mancheno, O.; Bistri, O.; Bolm, C. Org. Lett. 2007, 9, 3809. (c)
´
(15) Garlyauskajte, R. Y.; Sereda, S. V.; Yagupolskii, L. M. Tetra-
hedron 1994, 50, 6891.
(16) Youn, J.-H.; Herrmann, R. Synthesis 1987, 72.
(17) Youn, J.-H.; Herrmann, R. Tetrahedron Lett. 1986, 27, 1493.
Pandey, A.; Bolm, C. Synthesis 2010, 2292.
(14) Garlyauskayte, R. Y.; Bezdudny, A. V.; Michot, C.; Armand,
M.; Yagupolskii, Y. L.; Yagupolskii, L. M. J. Chem. Soc. PerkinTrans. 1
2002, 1887.
Org. Lett., Vol. 13, No. 4, 2011
769

Table 1. Preparation of Sulfonimidoyl Chlorides 8 from Sulfinic
Chlorides 12a
Table 3. Preparation of Trifluoromethyl Sulfoximines 11 Using
Sulfonimidoyl Fluorides 10 and TMSCF3 (Ruppert-Prakash
Reagent) in Combination with TBAFa
R1 (starting
material)
yield
(%)b
starting
material
yield
(%)b
entry
R2
product
entry
R1
R2
product
1
2
3
4
5
6
7
4-MeC6H4 (12a)
4-MeC6H4 (12a)
C6H5 (12b)
Ts
Ns
Ts
Ns
Ts
Ts
Ts
8a
8b
8c
8d
8e
8f
80
64
81
56
65
63
80
1
10a
10a
10b
10c
10d
10e
10f
4-MeC6H4
4-MeC6H4
4-MeC6H4
C6H5
Ts
11a
11a
11b
11c
11d
11e
11f
70
53
55
72
52
67
--
2c
3
Ts
Ns
Ts
C6H5 (12b)
4
4-t-BuC6H4 (12c)
Me (12d)
5
C6H5
Ns
Ts
6
4-t-BuC6H4
Me
Bu (12e)
8g
7
Ts
a Reaction conditions: sulfinyl chloride(1 equiv), chloramine(1 equiv),
8
10h
10i
4-MeC6H4
2-MeC6H4
C6H5
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Boc
11h
11i
76
69
79
74
59
54
51
75
toluene, 80 °C, 1-2 h under Ar. b After filtrationthrough a pad of silica gel.
9
10
11
12
13
14
16
10j
11j
10k
10l
4-ClC6H4
2-ClC6H4
4-FC6H4
4-t-BuC6H4
4-MeC6H4
11k
11l
10m
10n
10o
11m
11n
11o
Table 2. Preparation of Sulfonimidoyl Fluorides 10 According
to Scheme 2 (9a-g: R3 = Ph, 9h: R3 = Ot-Bu)a
a Reactionconditions:slowaddition ofa TBAF solution in THF (1M,
0.5 equiv) to a mixture of sulfonimidoyl fluoride (1 equiv) and TMSCF3
(2 equiv asTHF solution) at0 °Cfor 30 min, thenstirringat21 °C for 18h.
b After column chromatography. c Use of only 0.2 equiv of TBAF.
starting
material
yield
(%)b
entry
R1
R2
product
1
8a
8b
8c
8d
8e
8f
4-MeC6H4
4-MeC6H4
C6H5
Ts
10a
10b
10c
10d
10e
10f
81
87
76
72
79
35
74
67
89
71
75
86
78
78
81
79
2
Ns
Ts
3
8f and 8g use of AgF instead of KF proved beneficial.
Table 2 summarizes the results of this study.
4
C6H5
Ns
Ts
5
4-t-BuC6H4
Me
6
Ts
Attempts to use sulfonimidoyl chlorides 8 in reactions
with TMSCF3 remained unsuccessful under a variety of
conditions. To our delight, however, most reactions be-
tween sulfonimidoyl fluorides 10 and the TMSCF3 pro-
ceeded well, affording the corresponding trifluoromethyl
sulfoximines 11 in moderate to good yields (Table 3). In
contrast to the system studied by Yagupolskii, simple
tetrabutylammonium fluoride (TBAF) was applicable for
the activation of the CF3-transfer agent, thereby avoiding
the use of the expensive and water-sensitive TASF.22 No
additional solvent was required when commercially avail-
able THF solutions of TMSCF3 and TBAF were used.
Commonly, 0.5 equiv of TBAF was sufficient for the
activation. Smaller quantities of this reagent led to reduced
yields (Table 3, entries 1 and 2).
Various substituents on the aryl groups and the imino
nitrogens of the sulfonimidoyl fluorides were tolerated.
Electronic effects induced by electron-withdrawing or -donat-
ing groups on the arene appeared to have a minor impact.
Even substrates 10i and 10l with sterically demanding methyl
or chloro groups, respectively, in the ortho position (Table 3,
entries 9 and 12) reacted well, albeit the yields were slightly
lower than those observed in transformations of comparable
substrates with para substituents (Table 3, entries 8 and 11).
7c
8c
9
8f
Me
Ts
10f
8g
9a
9b
9c
9d
9e
9f
Bu
Ts
10g
10h
10i
4-MeC6H4
2-MeC6H4
C6H5
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Boc
10
11
12
13
14
15
16
10j
4-ClC6H4
2-ClC6H4
4-FC6H4
4-t-BuC6H4
4-MeC6H4
10k
10l
10m
10n
10o
9g
9h
a Reaction conditions: sulfonimidoyl chloride (1 equiv), KF (2 equiv),
18-crown-6 (cat.), MeCN, 21 °C, 16 h. b After column chromatography.
c Use of AgF (1.05 equiv) instead of KF.
sulfonimidoyl chlorides in situ.20 Sulfonimidoyl fluorides
10 were then obtained from 8 or 9 (after t-BuOCl oxi-
dation) by treatment with a combination of potassium
fluoride and catalytic amounts of 18-crown-6 (Scheme 2).21
In reactions with alkyl-substituted sulfonimidoyl fluorides
(18) Krasnova, L. B.; Yudin, A. K. J. Org. Chem. 2004, 69, 2584.
(19) Their syntheses protocols are outlined in: (a) Brownbridge, P.;
Jowett, I. C. Synthesis 1988, 252. (b) Davis, F. A.; Zhang, Y.; Andemichael,
Y.; Fang, T.; Fanelli, D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
(c) Backes, B. J.; Dragoli, D. R.; Ellman, J. A. J. Org. Chem. 1999, 64,
5472. (d) Worch, C.; Atodiresei, I.; Raabe, G.; Bolm, C. Chem.;Eur. J.
2009, 16, 677.
(20) Johnson, C. R.; Wambsgans, A. J. Org. Chem. 1979, 44, 2278.
(21) For such a conversion, see also: Johnson, C. R.; Bis, K. G.;
Cantillo, J. H.; Meanwell, N. A.; Reinhard, M. F. D.; Zeller, J. R.; Vonk,
G. P. J. Org. Chem. 1983, 48, 1.
(22) Attempts to use CsF, KOtBu, or trimethylamine N-oxide for the
activation failed.
(23) Johnson, C. R.; Jonsson, E. U.; Bacon, C. C. J. Org. Chem. 1979,
44, 2055.
770
Org. Lett., Vol. 13, No. 4, 2011

Attempts to convert alkyl-substituted sulfonimidoyl fluoride
10f failed (Table 3, entry 7). Presumably, the methyl hydro-
gens were too acidic, and the fluoride ions acted as a base,
resulting in deprotonation followed by unselective decom-
position as observed by Johnson in analogous reactions of
sulfonimidoyl chlorides.23
readily available commercial reagents. As a wide variety of
useful intermediates are accessible starting from various
precursors,24 the introduced reaction sequences appear
attractive for library syntheses. Related studies are currently
ongoing in our laboratories.
In summary, we have developed a flexible synthetic
approach toward aryl trifluoromethyl sulfoximines using
Acknowledgment. This study was supported by the
Fonds der Chemischen Industrie and a postdoctoral fellow-
ship from Syngenta Crop Protection for R.K.
(24) For examples for synthetic approaches toward sulfonimidoyl
chlorides or sulfinamides with various N-protecting groups, see: (a)
Toth, J. E.; Grindey, G. B.; Ehlhardt, W. J.; Ray, J. E.; Boder, G. B.;
Bewley, J. R.; Klingerman, K. K.; Gates, S. B.; Rinzel, S. M.; Schultz,
R. M.; Weir, L. C.; Worzalla, J. F. J. Med. Chem. 1997, 40, 1018. (b)
Kluge, R.; Hocke, H.; Schulz, M.; Schilke, F. Phosphorus, Sulfur and
Silicon 1999, 149, 179. (c) Savile, C. K.; Maglorie, V. P.; Kazlauskas,
R. J. J. Am. Chem. Soc. 2005, 127, 2104.
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
of NMR spectra. This material is available free of charge
via the Internet http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
771