Radical-mediated synthesis of trifluoroethyl amines and trifluoromethyl ketones from alkyl iodides

Article abstract of DOI:10.1016/S0040-4039(02)01675-1

Radical reaction of alkyl iodides with trifluoromethyl phenylsulfonyl oxime ether 10 and hexamethylditin at 300 nm in benzene afforded the corresponding trifluoromethyl oxime ethers 11 in high yields, which were reduced into the 2,2,2-trifluoroethyl amines with lithium aluminium hydride. The trifluoroethyl amines could be converted into the corresponding trifluoromethyl ketones by treatment with NBS and DBU.

Full text of DOI:10.1016/S0040-4039(02)01675-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7189–7191
Radical-mediated synthesis of trifluoroethyl amines and
trifluoromethyl ketones from alkyl iodides
Sunggak Kim* and Rajesh Kavali
Center for Molecular Design and Synthesis and Department of Chemistry, School of Molecular Science,
Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea
Received 12 June 2002; revised 8 August 2002; accepted 9 August 2002
Abstract—Radical reaction of alkyl iodides with trifluoromethyl phenylsulfonyl oxime ether 10 and hexamethylditin at 300 nm in
benzene afforded the corresponding trifluoromethyl oxime ethers 11 in high yields, which were reduced into the 2,2,2-trifluoroethyl
amines with lithium aluminium hydride. The trifluoroethyl amines could be converted into the corresponding trifluoromethyl
ketones by treatment with NBS and DBU. © 2002 Elsevier Science Ltd. All rights reserved.
Trifluoromethylation of organic compounds has
attracted a great deal of attention among synthetic
chemists because the presence of a trifluoromethyl
group in organic molecules influences their chemical
and biological properties due to a strong electron-with-
drawing ability of the trifluoromethyl group.1 Thus, the
development of the methodologies for the introduction
of the trifluoromethylated building blocks would be
very important for the synthesis of many tri-
fluoromethylated target molecules. Among tri-
fluoromethylated compounds, trifluoromethyl ketones
have been widely utilized as simple fluorine building
blocks for further synthetic elaboration in addition to
their unique chemical and biological properties.2
Among several synthetic methods for the tri-
fluoromethyl ketones, the nucleophilic trifluoromethyla-
tion of esters has been widely utilized,3 while tri-
fluoromethyl aryl ketones can be prepared by Friedel–
Crafts acylations.4 A recently reported method for
direct preparation of trifluoromethyl ketones from car-
boxylic esters with (trifluoromethyl)trimethylsilane
seems to be very attractive.5 In addition, a new radical
approach involving trifluoroacetonyl radicals and alke-
nes was also reported.6
rect approaches have been reported. Free radical car-
bonylation approach to a ketone synthesis has been
reported by Ryu.8 We have also developed a novel free
radical acylation approach utilizing radical reactions of
alkyl iodides with phenylsulfonyl oxime ethers to
provide the corresponding oxime ethers.9
(1)
Since the synthesis of trifluoromethylated compounds
using radical acylation approach has not been reported,
we have studied the radical-mediated synthesis of tri-
fluoromethylated compounds. We initially investigated
the possibility of a direct trifluoroacetylation of an
alkyl iodide using trifluoromethyl thiol ester 2 (Eq.
(1)).10 We hoped that the presence of an electron-with-
drawing trifluoromethyl group would activate a car-
bonyl carbon toward a nucleophilic alkyl radical.11
However, irradiation of a solution of 4-phenoxybutyl
iodide (1), 2, and hexamethylditin in benzene at 300 nm
for 4 h did not give the trifluoromethyl ketone 3 and
the reaction was messy. Therefore, we next turned our
attention to an indirect acylation reaction using sulfo-
nyl imine 6 and/or sulfonyl oxime ether 10.
Although numerous reports on the synthesis of ketones
have appeared to date,7 a free radical-mediated ketone
synthesis is not presently available, and only two indi-
In order to use sulfonylimine 6 as a trifluoroacetyl
equivalent radical acceptor, we began our study with
previously known trifluoroacetimidoyl chloride 4.12
Treatment of 4 with sodium thiophenoxide in THF at
room temperature for 1 h afforded 5 in 88% yield.
Keywords: radicals and radical reactions; fluorine and compounds;
acylation; ketones; amines; sulfones; oximes.
* Corresponding author. Tel.: +82-42-869-2820; fax:+82-42-869-8370;
e-mail: skim@mail.kaist.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01675-1

7190
S. Kim, R. Ka6ali / Tetrahedron Letters 43 (2002) 7189–7191
Table 1. Preparation of trifluoromethyl amines and
ketones
However, MCPBA oxidation of 5 did not yield 6 but
only p-methoxytrifluoroacetanilide (7) was isolated in
90% yield. Similarly, the direct substitution of 4 with
sodium phenyl sulfinate in DMF afforded 7 without
giving the desired product 6. Apparently, 6 was
unstable and was hydrolyzed to give 7 (Scheme 1).
Since oxime ether groups are very stable and syntheti-
cally useful functional groups to transform either to
carbonyl groups or to amino groups,13 we prepared
trifluoromethyl phenylsulfonyl oxime ether 10.
Chlorooxime ether 8 was prepared in 90% yield by
treatment of N-benzyloxyamine with triphenylphos-
phine and triethylamine in carbon tetrachloride at
reflux for 2 h.12 Treatment of 8 with sodium thiophen-
oxide in THF at room temperature for 1 h afforded 9 in
90% yield, which was oxidized with MCPBA/NaHCO3
to yield 10 in 82% yield.14 Oxime ether 10 was obtained
as a stable crystalline solid (Scheme 2).
According to our previous results,9 the energy of
LUMO in phenylsulfonyl oxime ether is lowered by
introducing an electron-withdrawing group, which
would increase the rate of the addition of an alkyl
radical onto the sulfonyl oxime ether. Therefore, we
anticipated that 10 would be highly reactive due to the
presence of
a
strong electron-withdrawing tri-
fluoromethyl substituent. Irradiation of a solution of
4-phenoxybutyl iodide, 10 (1.5 equiv.) and hexa-
methylditin (1.5 equiv.) in benzene at 300 nm for 4 h
afforded oxime ether 11 in 93% yield (Eq. (2)). As
shown in Table 1, the present method worked well not
only with primary and secondary alkyl iodides but also
with sterically hindered tertiary alkyl iodides (entries 4
and 8), yielding the corresponding trifluoromethyl
oxime ethers in high yields. However, benzylic iodides
(entries 9 and 10) gave relatively low yields of the
a
Reaction time: 5 h for 11, 4 h for 13, 2 h for 3.
b,c The yield of the dimerized product.
products together with the formation of a significant
amount of dimeric products, apparently due to rela-
tively low reactivity of benzylic radicals. Also, radical
reaction of iodobenzene (entry 11) with 10 did not
proceed smoothly, yielding the corresponding oxime
ether in 52% yield after 10 h.
(2)
As we observed previously that oxime ethers substi-
tuted by strong electron-withdrawing groups were
extremely inert to various acidic and oxidative cleavage
conditions,15 our attempts for the direct conversion of
oxime 11 into trifluoromethyl ketone 3 with reported
methods were unsuccessful.16 Since trifluoroethyl
amines are known to have important biological activi-
ties,17 we next tried to reduce the oxime ether group
into the amino group by the known method (Scheme
3).18 When 11 was treated with an excess amount of
lithium aluminium hydride in THF at 0°C, we initially
observed the formation of benzyloxy amine 12. Further
reduction of 12 with lithium aluminium hydride in
THF at 80°C for 4 h provided the 2,2,2-trifluoroethyl
amine 13 in good yield. Previously, an amino group
was converted into a keto group by treatment with
NBS followed by dehydrobromination with DBU.19 As
shown in Table 1, when 13 was treated with NBS (1.2
Scheme 1.
Scheme 2.

S. Kim, R. Ka6ali / Tetrahedron Letters 43 (2002) 7189–7191
7191
6. Denieul, M.-P.; Quiclet-Sire, B.; Zard, S. Z. Chem. Com-
mun. 1996, 2511.
7. (a) O’Neill, B. T. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 1, Chapter 1.13; (b) Davis B. R.; Garratt P. J.
In Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 2, Chapter
3.6; (c) Larock, R. C. Comprehensive Organic Transforma-
tions; John Wiley & Sons: New York, 1999; pp. 583–818.
8. For reviews, see: (a) Ryu, I.; Sonoda, N. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1050; (b) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. Rev. 1996, 96, 177.
9. (a) Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem.
Soc. 1996, 118, 5138; (b) Kim, S.; Yoon, J.-Y. J. Am. Chem.
Soc. 1997, 119, 5982; (c) Kim, S.; Yoon, J.-Y.; Lee, I. Y.
Synlett 1997, 475; (d) Kim, S.; Song, H.-J.; Choi, T.-J.;
Yoon, J.-Y. Angew. Chem., Int. Ed. 2001, 2524.
10. Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260.
Scheme 3.
equiv.) and DBU (2 equiv.) in dichloromethane at
room temperature for 2 h, trifluoromethyl ketone 3 was
isolated in modest yield.
In conclusion, we have found that trifluoromethyl sul-
fonyl oxime ether 10 is highly efficient for the radical-
mediated synthesis of trifluoromethylated oxime ethers
which can be converted into the synthetically useful
2,2,2-trifluoroethyl amines and trifluoromethyl ketones.
11. (a) Giese, B. Radicals in Organic Synthesis: Formation of
CarbonꢀCarbon Bonds; Pergamon Press: New York, 1986;
Chapter 2; (b) Fleming, I. Frontier Orbitals and Organic
Chemical Reactions; John Wiley & Sons: London, 1976;
Chapters 4 and 5.
Acknowledgements
12. Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32.
This work was financially supported by the Center for
Molecular Design and Synthesis (CMDS) and BK 21.
13. (a) Corsaro, A.; Chiacchio, U.; Pistara, V. Synthesis 2001,
1903; (b) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetra-
hedron Lett 2001, 42, 5029; (c) Miyata, O.; Muroya, K.;
Kobayashi, T.; Yamanaka, R.; Kajisa, S.; Koide, J.; Naito,
T. Tetrahedron 2002, 58, 4459; (d) Larock, R. C. Compre-
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