α-(trifluoromethyl)amine derivatives via nucleophilic trifluoromethylation of nitrones

Article abstract of DOI:10.1021/jo000685l

(Trifluoromethyl)trimethylsilane (TMSCF₃) reacts with nitrones to afford α-(trifluoromethyl)hydroxylamines protected as O-trimethylsilyl ethers. Potassium t-butoxide initiates the nucleophilic trifluoromethylation. The reaction works best with α,N-diaryl nitrones, and the conditions are compatible with a range of substituents on the aryl groups. Acidic deprotection of the nitrone/TMSCF₃ adducts generates α-(trifluoromethyl)hydroxylamines. Catalytic hydrogenation of the adducts produces α-(trifluoromethyl)amines. Nitrone/TMSCF₃ adducts with strong electron-withdrawing groups on the α-aryl ring or heterocyclic α-aryl groups undergo an elimination/addition sequence to generate α, α-bis(trifluoromethyl)amines. Nitrones with alkyl groups bound directly to the 1,3-dipolar moiety fail to react with TMSCF₃, but trifluoromethylation of β,γ-unsaturated nitrones followed by reduction of the double bond can circumvent this limitation.

Full text of DOI:10.1021/jo000685l

2572
J . Org. Chem. 2001, 66, 2572-2582
r-(Tr iflu or om eth yl)a m in e Der iva tives via Nu cleop h ilic
Tr iflu or om eth yla tion of Nitr on es
Derek W. Nelson,* J ames Owens, and Diana Hiraldo
Department of Chemistry, Loyola University of Chicago, 6525 North Sheridan Road,
Chicago, Illinois 60626
dnelson@luc.edu
Received May 4, 2000
(Trifluoromethyl)trimethylsilane (TMSCF3) reacts with nitrones to afford R-(trifluoromethyl)-
hydroxylamines protected as O-trimethylsilyl ethers. Potassium t-butoxide initiates the nucleophilic
trifluoromethylation. The reaction works best with R,N-diaryl nitrones, and the conditions are
compatible with a range of substituents on the aryl groups. Acidic deprotection of the nitrone/
TMSCF3 adducts generates R-(trifluoromethyl)hydroxylamines. Catalytic hydrogenation of the
adducts produces R-(trifluoromethyl)amines. Nitrone/TMSCF3 adducts with strong electron-
withdrawing groups on the R-aryl ring or heterocyclic R-aryl groups undergo an elimination/addition
sequence to generate R,R-bis(trifluoromethyl)amines. Nitrones with alkyl groups bound directly to
the 1,3-dipolar moiety fail to react with TMSCF3, but trifluoromethylation of â,γ-unsaturated
nitrones followed by reduction of the double bond can circumvent this limitation.
Sch em e 1
In tr od u ction
Organic molecules containing small perfluoroalkyl
groups often exhibit behavior distinct from their hydro-
carbon counterparts. Moieties such as the trifluoromethyl
group can dramatically influence the polarity, solubility,
chemical reactivity, and intermolecular interactions of an
entire molecule. Applications for partially fluorinated
organic molecules include pharmaceuticals,1 agrochemi-
cals,2 and polymers.3 The utility of fluoroorganic mol-
ecules motivates the search for new synthetic methods
for their preparation.
A variety of strategies may be used to incorporate
perfluoroalkyl groups into organic molecules, including
nucleophilic, electrophilic, and radical processes.4 Recent
developments in nucleophilic perfluoroalkylation methods
have expanded the utility of this approach. The inherent
instability of small perfluoroalkanide nucleophiles has
been modified by the use of organometallic complexes.5
The use of these reagents can accomplish efficient nu-
cleophilic aromatic substitution, but is often not practical
for trifluoromethylation of carbonyl groups and related
π electrophiles.
Procedures for in situ generation of trifluoromethanide
equivalents exist, and these methods accomplish nucleo-
philic trifluoromethylation with varying degrees of suc-
cess.6 Perfluoroalkylsilane reagents such as (trifluoro-
methyl)trimethylsilane7 (TMSCF3, 2) efficiently generate
R-(trifluoromethyl)alcohols (4) from the corresponding
carbonyl compounds (1) (Scheme 1).8 The reactivity of 2
has been extended to include other perfluoroalkyl nu-
cleophiles and a range of electrophiles,9 but certain
limitations remain. Imines react poorly with 2, except
in the reactions of azirines (5)10 and azenes (7)11 (Scheme
* Corresponding author.
(5) (a) For brief reviews of the reactivity of specific reagents, see:
Tamborski, C. Chemistry of Organic Fluorine Compounds II: A Critical
Review; Hudlicky, M., Pavlath, A. E., Eds.; ACS Press: Washington,
1995; (a) copper, pp 699-708; (b) zinc, pp 674-691; (c) cadmium, pp
692-696. (b) Burton, D. J .; Yang, Y.-Z. Tetrahedron 1992, 48, 189.
(6) (a) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981,
1719. (b) Hartkopf, U.; de Meijere, A. Angew. Chem., Int. Ed. Engl.
1982, 21, 443. (c) Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker,
D. G. J . Chem. Soc., Perkin Trans. 1 1988, 921. (d) Pawelke, G. J .
Fluorine Chem. 1989, 42, 429. (e) Yokoyama, Y.; Mochida, K. Synlett
1996, 1191. (f) Yokoyama, Y.; Mochida, K. Tetrahedron Lett. 1997, 38,
3443. (g) Russell, J .; Roques, N. Tetrahedron 1998, 54, 13771. (h)
Mispelaere, C.; Roques, N. Tetrahedron Lett. 1999, 40, 6411.
(7) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25,
2195.
(8) (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J . Am. Chem.
Soc. 1989, 111, 393. (b) For a related procedure, see: Stahly, G. P.;
Bell, D. R. J . Org. Chem. 1989, 54, 2873.
(9) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b)
Singh, R. P.; Shreeve, J . M. Tetrahedron 2000, 56, 7613.
(10) Fe´lix, C. P.; Khatimi, N.; Laurent, A. J . Tetrahedron Lett. 1994,
35, 3303.
(1) (a) Organofluorine in Medicinal Chemistry and Biochemical
Applications; Filler, R., Kobayashi, Y., Yagupolski, L. M., Eds.;
Elsevier: Amsterdam, 1993. (b) Fluorine-Containing Amino Acids:
Synthesis and Properties; Kukhar, V. P., Soloshonok, V. A., Eds.;
Wiley: Chichester, 1994. (c) Biomedical Frontiers of Fluorine Chem-
istry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; American Chemical
Society: Washington, D.C., 1996. (d) Fluoroorganic Chemistry: Syn-
thetic Challenges and Biomedical Rewards; Resnati, G., Soloshonok,
V. A., Eds.; Tetrahedron Symposium-in-Print No. 58; Tetrahedron
1996, 52, 1-330.
(2) (a) Yoshika, H.; Nakayama, C.; Matsuo, N J . Synth. Org. Chem.
J pn. 1984, 42, 809. (b) The Agrochemicals Handbook, 2nd ed.; Ellis
Horwood: Chichester, U.K., 1979. (b) Bellus, D. Chimia 1991, 45, 154.
(3) (a) Schmiegel, W. W. In Chemistry of Organic Fluorine Com-
pounds II: A Critical Review; Hudlicky, M., Pavlath, A. E., Eds.; ACS
Press: Washington, 1995; p 1101-1118. (b) Organofluorine Chemistry
- Principals and Commercial Applications; Banks, R. E., Smart, B.
E., Tatlow, J . C., Eds.; Plenum Press: New York, 1994.
(4) (a) Topics in Current Chemistry - Organofluorine Chemistry:
Fluorinated Alkenes and Reactive Intermediates; Chambers, R. D., Ed.;
Springer: Berlin, 1997; Volume 192. (b) Topics in Current Chemistry
- Organofluorine Chemistry: Techniques and Synthons; Chambers,
R. D., Ed.; Springer: Berlin, 1997; Volume 193.
(11) Patel, N. R.; Kirchmeier, R. L.; Shreeve, J . M. Inorg. Chem.
1993, 32, 4802.
10.1021/jo000685l CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/17/2001

R-(Trifluoromethyl)amine Derivatives via Nitrones
J . Org. Chem., Vol. 66, No. 8, 2001 2573
Sch em e 2
of the t-butoxide in small quantities at regular intervals
was continued until the nitrone was consumed or until
byproduct formation was observed.
Lower temperatures (typically from -30 to -20 °C)
favored clean formation of the adducts. For highly soluble
nitrones, reactions were run under homogeneous condi-
tions at substrate concentrations of 0.2 M. Several
nitrone substrates were only partially soluble at lower
temperatures, however. For limitedly soluble substrates,
the nitrone concentration was decreased to 0.05-0.1 M.
The reactions could be performed under biphasic condi-
tions, and unreacted solid nitrones gradually dissolved
as the reaction progressed. The reactions were monitored
by thin-layer chromatography. The nonpolar adducts and
the polar nitrones decomposed quickly upon UV irradia-
tion (λ ) 254 nm). The products were easily purified by
flash chromatography (silica gel/0-5% ethyl acetate in
hexanes). The low-melting adducts were stable to the
atmosphere at room temperature for several weeks.
2). The combination of 2 and trimethylsilylimidazole (10)
accomplishes the trifluoromethylation of imines (9) of
nonenolizable carbonyl compounds (Scheme 2).12
We recently reported a method for the preparation of
R-(trifluoromethyl)hydroxylamine derivatives by nucleo-
philic trifluoromethylation of nitrone substrates (12)
using 2 (eq 1).13
The incorporation of the trifluoromethyl group was
confirmed by NMR analysis of the adducts (13). A
characteristic quartet appeared at 4-5 ppm in the 1H
NMR spectrum caused by heteronuclear H-F coupling
(3J H-F ∼ 8 Hz). The equivalent protons of the trimeth-
ylsilyl group resonated at ∼0.1 ppm, but the integration
for the TMS group ranged from 6 to 8H using delay (d1)
values of 1-2 s. Distinctive heteronuclear C-F coupling
was observed in the broadband decoupled 13C NMR
spectra of the adducts. The trifluoromethyl group pro-
duced a quartet at ∼125 ppm with a characteristically
The nitrone reaction offers certain advantages to direct
trifluoromethylation of imines.6e,f,12 Nitrones are acces-
sible by several different routes,14-16 the reaction does
not require additional silylating reagents, and inexpen-
sive potassium t-butoxide initiates the addition. Forma-
tion of the silylated hydroxylamine derivatives creates
opportunities for subsequent synthetic manipulation. The
scope of the nitrone trifluoromethylation, and transfor-
mations of the adducts, are reported here.
1
large J C-F coupling of ∼280 Hz. The C-F coupling
diminished by an order of magnitude with each interven-
ing carbon atom and was usually not observed beyond
2J C-F
.
Rea ction Scop e. Process optimization employed R,N-
diphenyl nitrone (12c). The compatibility of the reaction
with a variety of substrates was then investigated. Table
1 contains the isolated yields of a variety of R,N-diaryl
nitrone/TMSCF3 adducts (13). Few byproducts were
formed from nitrones bearing extended aromatic systems
or electron-donating substituents on the R-aryl ring.
Nitrones bearing strong electron-withdrawing substitu-
ents on the R-aryl group (12e) and those with heterocyclic
R-aryl groups (12g-i) afforded poor yields of the adducts
but successfully produced a secondary product.
Resu lts
P r ocess a n d Ch a r a cter iza tion . Preliminary work
focused on optimization of reaction conditions that gener-
ated the nitrone/2 adducts (13).13 The anionic initiators
frequently used with 2 (tetrabutylammonium fluoride
(TBAF), cesium fluoride, and alkoxides) were evaluated.
The influences of temperature, stoichiometry, solvent,
and concentration were also studied. Of the anionic
initiators tested, potassium t-butoxide provided the high-
est yields of the adducts. The optimized procedure for the
formation of adducts (13) employed 2 equiv of 2. Complete
conversion of the nitrones required the addition of small
aliquots of a t-butoxide slurry (∼0.1 M) in THF at regular
intervals. The t-butoxide/2 ratio required to complete the
reactions depended on the specific nitrone and often
varied between identical reactions. Generally, addition
The reaction of the R-(p-nitrophenyl)-N-phenyl nitrone
(12e) with 2 illustrates the source of the secondary
product (Scheme 3). Addition of 2 to nitrone 12e afforded
the formal adduct 13e in modest yield, even though the
starting nitrone was entirely consumed. During the
reaction, the initial adduct 13e was converted to a second
product (15e) that accounted for the majority of the mass
balance. The structure of bis(trifluoromethyl)amine 15e
was difficult to deduce because the 1H NMR spectrum
1
lacked the distinctive H-19F splitting observed in the
nitrone/TMSCF3 adducts, and the trimethylsilyl group
was absent. The 13C NMR spectra of 15e exhibited
resonances characteristic of both the trifluoromethyl
group (δ ∼ 125 ppm, q, 1J C-F ∼ 280 Hz) and a quaternary
carbon bearing two equivalent trifluoromethyl groups (δ
∼ 70 ppm, sept, 2J C-F ∼ 28 Hz). The intensity of the latter
signal was very low, and it was easily overlooked if the
signal-to-noise ratio was poor. The IR spectrum of the
secondary product contained a typical secondary amine
N-H stretch at ∼3400 cm-1. The spectroscopic data from
(12) Blazejewski, J .-C.; Anselmi, E.; Wilmshurst, M. P. Tetrahedron
Lett. 1999, 40, 5475.
(13) Nelson, D. W.; Easley, R. A.; Pintea, B. N. V. Tetrahedron Lett.
1999, 40, 25.
(14) Bru¨ning, I.; Grashey, R.; Hauck, H.; Huisgen, R.; Seidl, H.
Organic Syntheses; Wiley and Sons: New York, 1973; Vol. V, p 1124.
(15) Lobo, A. M.; Prabhakar, S.; Rzepa, H. S.; Skapski, A. C.;
Tavares, M. R.; Widdowson, D. A. Tetrahedron 1983, 39, 3833.
(16) (a) Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth. 1991,
70, 265. (b) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.;
Watanabe, S. J . Org. Chem. 1990, 55, 1736.

2574 J . Org. Chem., Vol. 66, No. 8, 2001
Nelson et al.
Ta ble 1. Com p a tibility of Su bstitu ted Dia r yl Nitr on es
w ith Tr iflu or om eth yla tion Con d ition s
Ta ble 2. F or m a tion of Bis(tr iflu or om eth yl)a m in es fr om
Selected Nitr on es
Sch em e 3
F igu r e 1. Plot of product distribution vs time.
compounds 15e, g-i are consistent with those from
related compounds reported in the literature.12
To gain insight into the competition between the initial
and secondary trifluoromethylation processes, the reac-
tion of the R-(2-furyl)-N-phenyl nitrone (12g) with excess
2 at -40 °C was analyzed by gas chromatography. Figure
1 illustrates the composition of the reaction mixture
during the reaction. The data reveal that high yield
(>40-50%) of adduct 13g was not possible. The concen-
tration of 13g reached a plateau at ∼40% and then
decreased. The reaction depicted in Figure 1 was moni-
tored until approximately 75% of the starting nitrone was
consumed. At this level of nitrone conversion, the yield
of the bis(CF3) adduct 15g was relatively low. Continued
addition of the t-butoxide initiator eventually led to
complete conversion of the starting material and the
initial adduct to afford amine 15g as the major product
in 82% yield.
The proposed elimination-addition sequence requires
formation of an intermediate R-(trifluoromethyl)imine
(14e, Scheme 3). Such imines have been isolated from
nitrone/2 reactions,13 and precedence for addition of 2 to
electron-deficient C-N double bonds exists.11 In the
nitrone/2 reactions, longer reaction times and the use of
excess base and excess 2 favored formation of the R,R-
bis(CF3)amines. Modified reaction conditions, using 3.0
equiv of 2, provided the highest yields of 15, and isolated
yields from the optimized procedure are listed in Table
2. As with the procedure for formation of the initial
adducts, the precise quantity of potassium t-butoxide
necessary to produce only the bistrifluoromethylated
amines varied for different substrates, as well as for
different reactions using identical conditions. Aliquots of
the initiator solution were added at regular intervals
until the starting nitrone and the initial adduct were no
longer observed.
The addition of 2 to R,N-diaryl nitrones was successful
for a variety of aryl groups. Nitrones with alkyl substit-
uents worked poorly in the trifluoromethylation protocol.

R-(Trifluoromethyl)amine Derivatives via Nitrones
J . Org. Chem., Vol. 66, No. 8, 2001 2575
Ta ble 3. Hyd r oxyla m in e F or m a tion by Acid ic
Dep r otection
Ch a r t 1
Sch em e 4
a
The hydroxylamine decomposed before isolation and charac-
terization were completed.
amines were stable to air at room temperature for weeks.
In solution, particularly using halogenated solvents such
as dichloromethane and chloroform, decomposition oc-
curred. Hydroxylamines 24b, g, and h exhibited poor
stabilities that prevented their isolation and/or complete
1
characterization. For the stable hydroxylamines, the H
Several such nitrones (16-19, Chart 1) were treated with
2 and alkoxide and fluoride initiators, but at best trace
amounts (<5%) of impure adducts were obtained. The
reaction conditions (temperature, concentration, stoichi-
ometry, order of addition, etc.) were varied, but adduct
formation occurred in very low yields.
The failure of the trifluoromethylation protocol with
alkyl-substituted nitrones can be circumvented through
the use of â,γ-unsaturated nitrones. Addition of 2 to
nitrone 20 using the conditions outlined in Table 1
afforded adduct 21 in good yield (Scheme 4). Excess of
both t-butoxide and 2 in conjunction with long reaction
times provided good yields of the bis(trifluoromethyl)-
amine 22. Products obtained from conjugate addition to
nitrone 20 were not isolated in the reactions.
Saturation of the double bond in adduct 21 afforded
the R-(trifluoromethyl)hydroxylamine derivative. Cata-
lytic hydrogenation of 21, over 10% palladium on carbon
at room temperature, quickly reduced the double bond
to form 23. Reductive cleavage of the N-O bond also
occurred in the hydrogenation reaction, but formation of
the free amine was slow compared to alkene saturation.
The silylated hydroxylamine 23 was a stable oil at room
temperature.
and 13C NMR spectra indicated the presence of the
trifluoromethyl group. The resonances of the hydroxyl
protons appeared as sharp singlets at ∼5.3-5.5 ppm in
the 1H NMR spectra. The chemical shift and width of
these signals did not change appreciably with changes
in concentration.
Selective cleavage of the nitrogen-oxygen bond in the
nitrone/2 adducts proved more complex. Catalytic hy-
drogenation over palladium catalyst cleaved the N-O
bond, but complete conversion often required more than
72 h. Reductive cleavage using zinc meta117 afforded the
free amine, but the reaction was also sluggish. The most
efficient protocol for zinc reduction used 1:1 acetic acid:
THF as the solvent, excess zinc, and reflux conditions.
Complete reductive cleavage of the N-O bond under
these conditions required 48-72 h. Transfer hydrogena-
tion18 efficiently accomplished the reductive deprotection.
Treatment of a 0.2 M methanolic solution of the R-(tri-
fluoromethyl)hydroxylamine O-trimethylsilyl ethers with
10% Pd/C and 5 equiv of ammonium formate cleaved the
silyloxy group in 3-5 h at room temperature. The
isolated yields for the R-(trifluoromethyl)amines (25)
produced by this method are listed in Table 4.
Complications arose in the transfer hydrogenation
reactions using certain nitrone/2 adducts. Reductive
dechlorination occurred concomitantly with N-O cleav-
age in the reduction of adducts 13d and l. Rapid
dehalogenation of haloaromatics under transfer hydro-
genation conditions has been reported, particularly using
Syn th etic Ma n ip u la tion of Nitr on e/TMSCF 3 Ad -
d u cts. The silylated hydroxylamine derivatives acces-
sible by the nitrone/2 reactions were readily transformed
into the corresponding hydroxylamines or the free amine
compounds. Treatment of the adducts (13, 21, and 23)
with a 1:1 mixture of 1 N HCl:THF cleaved the oxygen-
silicon bond cleanly to produce the hydroxylamines (24).
Table 3 lists the isolated yields for this acid-catalyzed
deprotection. The products were purified by flash chro-
matography (silica gel/5% ethyl acetate in hexanes), and
analytical samples were obtained by recrystallization
from hexane. The solid R-(trifluoromethyl)hydroxyl-
(17) (a) Howell, A. R.; Pattenden, G. J . Chem. Soc., Chem. Comm.
1990, 103. (b) Moody, C. J .; Gallagher, P. T.; Lightfoot, A. P.; Slawin,
A. M. Z. J . Org. Chem. 1999, 64, 4419.
(18) For reviews on catalytic hydrogen transfer reductions, see: (a)
Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91. (b) J ohnstone, R. A.
W.; Wilby, A. H.; Entwhistle, T. D. Chem. Rev. 1985, 85, 129.

2576 J . Org. Chem., Vol. 66, No. 8, 2001
Nelson et al.
Ta ble 4. Am in e F or m a tion by Tr a n sfer Hyd r ogen a tion
Dep r otection
Sch em e 6
Sch em e 5
can explain the formation of the initial nitrone/2 adducts
(13). The proposed pathway for the adduct formation
closely parallels the pathway suggested for trifluoro-
methylation of carbonyl compounds using 2.9 In both
systems, a negatively charged pentavalent silane inter-
mediate transfers the trifluoromethanide group to the
electrophilic carbon. The trifluoromethyl and trimethyl-
silyl groups in the formal adducts originate from different
molecules of 2. Finally, both carbonyl and nitrone tri-
fluoromethylation require anionic initiation.
On first inspection of Scheme 6, addition of an external
anionic initiator may seem unnecessary. The negative
charge of the oxide group in the nitrone could function
as a nucleophile and attack 2, resulting in the spontane-
ous initiation of a catalytic mechanism. Nitrone nucleo-
philes react with a variety of electrophiles,20 and ex-
tremely hindered nucleophiles, including t-butoxide, react
with 2. In the present study, spontaneous reaction
between 2 and a nitrone in the absence of an anionic
initiator was never observed.
Propagation of the catalytic cycle via a deprotonated
R-(trifluoromethyl)hydroxylamine (28) and subsequently
formed pentavalent silane intermediate (29) can ratio-
nalize adduct formation. The nucleophilicity of 28 was
demonstrated in an experiment where hydroxylamine
24c was deprotonated by potassium hydride, and the
resulting intermediate 28c was used to initiate the
addition of 2 to nitrone 12f (Scheme 7). Formation of
adduct 13c (32% isolated yield) and hydroxylamine 24f
(4% isolated yield) supports a catalytic mechanism with
a limited amount of turnover. The structure of putative
pentavalent silanes 26 and 29 has not been determined,
and the mechanism of trifluoromethanide transfer is not
known. For related species invoked as intermediates in
the trifluoromethylation of carbonyl compounds, different
geometries at silicon have been proposed.9,21
ammonium formate as the hydrogen source.19 Standard
catalytic hydrogenation afforded the secondary amine
from adduct 13d with the chlorophenyl moiety intact
(Scheme 5). Transfer hydrogenation also reduced the
trans double bond in adduct 21 at approximately the
same rate as N-O cleavage occurred. Zinc metal reduc-
tion of 21 cleanly produced the R-(trifluoromethyl)allylic
amine 25n , but the reaction required 24 h at reflux
(Scheme 5). The R-(trifluoromethyl)amines exhibited
absorbances of moderate intensity at ∼3400 cm-1 in their
1
IR spectra. The H and 13C NMR spectra were consistent
with the designated structures.
Discu ssion
Formation of the bis(trifluoromethyl)amines (15) is
more complex than initial adduct formation (Scheme 8).
Mech a n istic P r op osa l. The nucleophilic trifluoro-
methylation procedure described herein demonstrates the
suitability of nitrones as electrophiles for silane trifluo-
romethylation reagents. The choice of nitrone substrates
was based on the mechanistic hypothesis that 1,3-
addition of 2 should avoid formation of a weak and labile
N-Si bond.12 Scheme 6 proposes a catalytic cycle that
(20) Nitrones function as nucleophiles with the following common
electrophiles. (a) Acetic anhydride: Tamagaki, S.; Kozuka, S.; Oae, S.
Tetrahedron 1970, 26, 1795. (b) Acetyl chloride: Cummins, C. H.;
Coates, R. M. J . Org. Chem. 1983, 48, 2070. (c) Tosyl chloride: Barton,
D. H. R.; Day, M. J .; Hesse, R. H.; Pechet, M. M. J . Chem. Soc., Perkin
Trans. 1 1975, 1764.
(21) Walter, M. W.; Adlington, R. M.; Baldwin, J . E.; Schofield, C.
J . J . Org. Chem. 1998, 63, 5179.
(19) Rajagopal, S.; Spatola, A. F. J . Org. Chem. 1995, 60, 1347.

R-(Trifluoromethyl)amine Derivatives via Nitrones
J . Org. Chem., Vol. 66, No. 8, 2001 2577
Sch em e 7
initiate trifluoromethylation via 2 failed, and this pro-
vided evidence against propagation by pentavalent silane
(32). In addition, formation of anion 31e with chlorotri-
methylsilane at -20 °C did not produce detectable (GC)
levels of the silylated amine. Anion 31 may be protonated
directly by the aqueous workup or by another proton
source.
Con clu sion
The addition of 2 to nitrones in the presence of an
alkoxide initiator provides a direct route to the formation
of new trifluoromethylated amine derivatives. R-(Tri-
fluoromethyl)hydroxylamines, protected as O-trimethyl-
silyl, can be formed in good yields from a variety of R,N-
diaryl nitrones, but R-alkyl and N-alkyl nitrones fail to
react. The use of an â,γ-unsaturated nitrone in the
trifluoromethylation procedure works satisfactorily, and
catalytic hydrogenation of the double bond affords a
2/adduct with an alkyl group bound to the R-carbon of
the protected hydroxylamine. Certain diaryl nitrones,
specifically those with strong electron-withdrawing groups
on the R-aryl group or heterocyclic R-aryl groups, gener-
ate R,R-bis(trifluoromethyl)amines directly. A complex
series of catalytic cycles has been proposed to rationalize
the formation of both of the observed products.
Sch em e 8
Simple and efficient procedures for selective deprotec-
tion of the protected R-(trifluoromethyl)hydroxylamines
have been developed. Trifluoromethylated hydroxyl-
amines or free amines can be obtained in high yield. The
methods described here offer practical alternatives to
direct trifluoromethylation of imines6e,f,12 because the
yields for trifluoromethylation of nitrones are high and
expensive or esoteric reagents are not required. In
addition, the silylated hydroxylamine products are rela-
tively stable and can serve as intermediates in a variety
of subsequent synthetic transformations. The nitrone/2
reactions presented here should complement other meth-
ods4,23,24 for the preparation of R-CF3 amines.
Sch em e 9
Exp er im en ta l Section
Anhydrous tetrahydrofuran was distilled from sodium/
benzophenone under inert atmosphere (N2 or Ar). The (tri-
fluoromethyl)trimethylsilane (TMSCF3, 2) was prepared using
previously reported methods.25 Potassium t-butoxide was dried
under vacuum (<1 mmHg) for 1 h before use. Preparative
chromatography employed 230-400 mesh silica gel, and the
TLC plates were visualized using UV light (λ ) 254 nm). NMR
Elimination of the silyloxy group (30) from adduct 13
explains the formation of R-(trifluoromethyl)imine 14.
Related elimination of silyloxy groups has been observed
in the chemistry of the silyl nitronates used in 1,3-dipolar
cycloadditions.22 The R-(trifluoromethyl)imines (14) can
be isolated from nitrone/2 reactions, although yields vary
and higher temperatures are required.13 Resubmission
of adduct 13g to the trifluoromethylation conditions
(Scheme 9) cleanly produced bis(trifluoromethyl)amine
15g as the single major product, providing evidence for
the sequential formation of the mono- and bis(CF3)
products.
1
spectra were obtained in chloroform-d. H NMR spectra were
recorded at 400 MHz with chemical shifts referenced to
residual chloroform (δ 7.26 ppm) or tetramethylsilane (δ 0.00
ppm). 13C NMR spectra were recorded at 100 MHz with
chemical shifts referenced to the solvent triplet (δ 77.0 ppm).
Multiplicities for 13C resonances were determined by DEPT135
experiments. Melting points are uncorrected.
Rep r esen ta tive P r oced u r e for th e Ad d ition of TMSCF 3
(2) to Nitr on essP r ep a r a tion of 13c. An oven-dried, 100-
mL, round-bottomed flask containing a magnetic stir bar was
sealed with a septum, and dry nitrogen atmosphere was
introduced. The vacuum-dried nitrone 12c (1.79 g, 10.0 mmol)
was added as a solid followed by addition of anhydrous
As shown in Scheme 8, an R,R-bis(trifluoromethyl)-
amide anion 31 should be formed when 2 reacts with
imine 14. Comparable rates of initial adduct formation
and elimination result in a “steady-state” concentration
of 13 (Figure 1). An attempt to use amide anion 31e to
(23) Soloshonok, V. A.; Ono, T. J . Org. Chem. 1997, 62, 3030.
(24) Amouri, H.; Begue, J .-P.; Chennoufi, A.; Bonnet-Delphon, D.;
Gruselle, M.; Malezieux, B. Org. Lett. 2000, 2, 807.
(25) (a)Ramaiah, P.; Krishnamurti, R.; Prakash, G. K. S. Org. Synth.
1995, 72, 232. (b) Nelson, D. W.; O’Reilly, N. J .; Speier, J .; Gassman,
P. G. J . Org. Chem. 1994, 59, 8157. Due to difficulties in obtaining
bromotrifluoromethane, iodotrifluoromethane was used.
(22) (a) Torssell, K. B. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH: Weinheim, 1988. (b) Dehaen, W.; Hassner,
A. Tetrahedron Lett. 1990, 31, 743. (c) Kim, B. H.; Lee, J . Tetrahe-
dron: Asymmetry 1991, 2, 1359. (c) Stack, J . A.; Heffner, T. A.; Geib,
S. J .; Curran, D. P. Tetrahedron 1993, 49, 995.

2578 J . Org. Chem., Vol. 66, No. 8, 2001
Nelson et al.
tetrahydrofuran (50 mL) via cannula. Silane 2 (2.84 g, 2.95
mL, 20.0 mmol) was added via syringe. A balloon containing
anhydrous N2(g) was attached, and the flask was cooled to -20
°C for 15 min in a cryogenic bath. A slurry of anhydrous
potassium t-butoxide in THF (∼0.1 M) was prepared, and
aliquots (∼50-100 µL) of the slurry were added to the reaction
mixture at ∼15 min intervals. The reaction mixture turned
yellow upon addition of the initiator. The reaction was
monitored by TLC (silica gel/CH2Cl2: nitrone Rf ) 0.2; product
Rf ) 0.9), and alkoxide addition was continued until the
nitrone was consumed (∼48 h). The brown reaction mixture
was poured into a separatory funnel containing distilled water
and extracted with dichloromethane. The combined organic
extracts were dried (MgSO4), filtered, and concentrated by
rotary evaporation to give a yellow oil. The product was
purified by flash chromatography (silica gel/2% EtOAc in
hexanes: product Rf ) 0.3) to give a clear, colorless oil that
crystallized upon standing in the refrigerator.
temperature; 1H NMR δ 7.96 (d, J ) 7.2 Hz, 1H), 7.83 (d, J )
8.0 Hz, 1H), 7.78 (d, J ) 8.0 Hz, 1H), 7.51-7.47 (m, 2H), 7.38-
7.34 (m, 1H), 7.30-7.26 (m, 1H), 7.09-7.03 (m, 4H), 6.95-
3
6.90 (m, 1H), 5.61 (q, J H-F ) 8.4 Hz, 1H), 0.03 (s, 9H); 13C
NMR δ 151.9 (s), 133.4 (s), 132.6 (s), 129.5 (d), 128.8 (d), 128.3
1
(d), 127.9 (d), 127.1 (s), 126.2 (d), 125.2 (q, J C-F ) 282 Hz)
125.2 (d), 124.9 (d), 124.6 (d), 122.4 (d), 121.3 (d), 68.4 (dq,
2J C-F ) 28 Hz), -0.5 (q); IR (neat, NaCl plate, cm-1) 3059,
2958, 1597, 1489, 1253, 1161, 1126. Anal. Calcd for C21H22F3-
NOSi: C, 64.76; H, 5.69; N, 3.60. Found: C, 64.17; H, 5.66;
N, 3.67.
O-Tr im eth ylsilyl P h en yl[2-(2-[2-fu r yl]-1,1,1-tr iflu or o-
eth yl)]h yd r oxyla m in e (13g): chromatography, silica gel/3%
EtOAc in hexanes (product Rf ) 0.4); liquid at room temper-
ature; 1H NMR δ 7.29 (dd, J ) 1.6 and 0.8 Hz, 1H), 7.24-7.20
(m, 2H), 7.09-7.03 (m, 3H), 6.50 (d, J ) 3.6 Hz, 1H), 6.34 (dd,
3
J ) 3.6 and 2.0 Hz, 1H), 4.79 (q, J H-F ) 8.0 Hz, 1H), 0.05 (s,
9H); 13C NMR δ 151.7 (s), 143.9 (s), 142.7 (d), 128.4 (d), 124.8
1
O-Tr im et h ylsilyl P h en yl[2-(2-p h en yl-1,1,1-t r iflu or o-
eth yl)]h yd r oxyla m in e (13c): mp 32-33 °C; 1H NMR δ 7.33-
7.29 (m, 1H), 7.25-7.15 (m, 6H), 7.03-6.97 (m, 3H), 4.56 (q,
(d), 123.7 (q, J C-F ) 280 Hz), 120.4 (d), 112.6 (d), 110.4 (d),
2
69.2 (dq, J C-F ) 29 Hz), -0.6 (q); IR (neat, NaCl plate, cm-1
)
3066, 3032, 2962, 1597, 1493, 1257, 1169. Anal. Calcd for
C15H18F3NO2Si: C, 54.70; H, 5.51; N, 4.25. Found: C, 54.59;
3J H-F ) 8.4 Hz, 1H), 0.06 (s, 9H); 13C NMR δ 151.9 (s), 131.1
1
(d), 129.4 (s), 128.8 (d), 128.3 (d), 127.7 (d), 124.8 (q, J C-F
)
H, 5.50; N, 4.20.
2
280 Hz), 124.6 (d), 120.9 (d), 75.3 (dq, J C-F ) 29 Hz), -0.5
(q); IR (neat, NaCl plate, cm-1) 3066, 3035, 2962, 1597, 1489,
1257, 1164. Anal. Calcd for C17H20F3NOSi: C, 60.15; H, 5.94;
N, 4.13. Found: C, 60.03; H, 5.95; N, 4.12.
O-Tr im eth ylsilyl (4-Meth oxyp h en yl)[2-(2-p h en yl-1,1,1-
tr iflu or oeth yl)]h ydr oxylam in e (13j): chromatography, silica
gel/4% EtOAc in hexanes (product Rf ) 0.3); liquid at room
temperature; 1H NMR δ 7.33-7.29 (m, 1H), 7.26-7.18 (m, 4H),
6.90 (d, J ) 9.2 Hz, 2H), 6.67 (d, J ) 9.2 Hz, 2H), 4.44 (q,
3J H-F ) 8.0 Hz, 1H), 3.74 (s, 3H), 0.04 (s, 9H); 13C NMR δ 157.0
(s), 144.7 (s), 131.1 (d), 129.8 (s), 128.7 (d), 127.6 (d), 124.7 (q,
O-Tr im eth ylsilyl P h en yl[2-(2-[4-m eth oxyp h en yl]-1,1,1-
tr iflu or oeth yl)]h ydr oxylam in e (13a ): chromatography, silica
gel/8% EtOAc in hexanes (product Rf ) 0.4); mp 42-44 °C; 1H
NMR δ 7.19-7.15 (m, 2H), 7.10 (d, J ) 8.7 Hz, 2H), 7.04-
6.98 (m, 3H), 6.75 (d, J ) 8.7 Hz, 2H), 4.50 (q, 3J H-F ) 8.3 Hz,
1H), 3.77 (s, 3H), 0.06 (s, 9H); 13C NMR δ 159.9 (s), 152.0 (s),
2
1J C-F ) 280 Hz), 123.2 (d), 113.3 (d), 75.4 (dq, J C-F ) 28 Hz),
55.2 (q), -0.5 (q); IR (neat, NaCl plate, cm-1) 3035, 2959, 1504,
1250, 1165. Anal. Calcd for C18H22F3NO2Si: C, 58.52; H, 6.00;
N, 3.79. Found: C, 57.89; H, 5.89; N, 3.61.
1
132.3(d), 128.3 (d), 124.9 (q, J C-F ) 280 Hz), 124.6 (d), 121.5
(s), 120.9 (d), 113.0 (d), 74.8 (dq, 2J C-F ) 29 Hz), 55.0 (q), -0.5
(q); IR (melt, NaCl plate, cm-1) 3006, 2960, 1612, 1514, 1252,
1182, 1036. Anal. Calcd for C18H22F3NO2Si: C, 58.52; H, 6.00;
N, 3.79. Found: C, 58.22; H, 6.07; N, 4.02.
O-Tr im et h ylsilyl (4-Met h ylp h en yl)[2-(2-p h en yl-1,1,1-
tr iflu or oeth yl)]h ydr oxylam in e (13k): chromatography, silica
gel/2% EtOAc in hexanes (product Rf ) 0.3); liquid at room
temperature; 1H NMR δ 7.34-7.30 (m, 1H), 7.26-7.18 (m, 4H),
6.96 (d, J ) 8.0 Hz, 2H), 6.87 (d, J ) 8.0 Hz, 2H), 4.52 (q,
3J H-F ) 8.4 Hz, 1H), 2.26 (s, 3H), 0.06 (s, 9H); 13C NMR δ 149.4
(s), 134.2 (s), 131.1 (d), 129.6 (s), 128.9 (d), 128.8 (d), 127.6
O-Tr im eth ylsilyl P h en yl[2-(2-[2-m eth oxyp h en yl]-1,1,1-
tr iflu or oeth yl)]h ydr oxylam in e (13b): chromatography, silica
gel/4% EtOAc in hexanes (product Rf ) 0.3); liquid at room
temperature; 1H NMR δ 7.85 (d, J ) 7.6 Hz, 1H), 7.32 (ddd, J
) 8.1, 7.5, and 2.0 Hz, 1H), 7.22-7.18 (m, 2H), 7.10-7.08 (m,
2H), 7.04-7.00 (m, 2H), 6.73 (dd, J ) 8.0 and 0.8 Hz, 1H),
5.56 (q, 3J H-F ) 8.8 Hz, 1H), 3.34 (s, 3H), 0.12 (s, 9H); 13C NMR
δ 157.7 (s), 152.4 (s), 132.0 (d), 129.9 (d), 127.8 (d), 125.2 (q,
1J C-F ) 281 Hz), 124.1(d), 120.6 (d), 119.8 (d), 118.4 (s), 110.5
(d), 65.0 (dq, 2J C-F ) 29 Hz), 55.4 (q), -0.5 (q); IR (neat, NaCl
plate, cm-1) 3062, 2962, 1601, 1489, 1250, 1161. Anal. Calcd
for C18H22F3NO2Si: C, 58.52; H, 6.00; N, 3.79. Found: C, 58.16;
H, 6.02; N, 3.91.
1
2
(d), 124.8 (q, J C-F ) 280 Hz), 121.1 (d), 75.4 (dq, J C-F ) 28
Hz), 20.8 (q), -0.5 (q); IR (neat, NaCl plate, cm-1) 3032, 2962,
1506, 1257, 1161, 1122. Anal. Calcd for C18H22F3NOSi: C,
61.17; H, 6.27; N, 3.96. Found: C, 61.21; H, 6.34; N, 3.95.
O-Tr im eth ylsilyl (4-Ch lor op h en yl)[2-(2-p h en yl-1,1,1-
tr iflu or oeth yl)]h ydr oxylam in e (13l): chromatography, silica
gel/4%EtOAc in hexanes (product Rf ) 0.4); mp 51-52 °C; 1H
NMR δ 7.35-7.31 (m, 1H), 7.27-7.23 (m, 2H), 7.18 (d, J )
7.6 Hz, 2H), 7.13 (d, J ) 9.0 Hz, 2H), 6.92 (d, J ) 9.0 Hz, 2H),
4.50 (q, 3J H-F ) 8.4 Hz, 1H), 0.06 (s, 9H); 13C NMR δ 150.5 (s),
131.0 (d), 129.9 (s), 129.0 (d), 128.4 (d), 127.8 (d), 124.6 (q, 1J C-F
O-Tr im et h ylsilyl P h en yl[2-(2-[4-ch lor op h en yl]-1,1,1-
tr iflu or oeth yl)]h ydr oxylam in e (13d): chromatography, silica
gel/4% EtOAc in hexanes (product Rf ) 0.4); liquid at room
2
) 281 Hz), 122.4 (d), 75.2 (dq, J C-F ) 28.6 Hz), -0.5 (q);26 IR
(neat, NaCl plate, cm-1) 3035, 2962, 1485, 1369, 1254, 1169,
1126. Anal. Calcd for C17H19ClF3NOSi: C, 54.61; H, 5.12; N,
3.75. Found: C, 54.48; H, 5.11; N, 3.52.
1
temperature; H NMR δ 7.23-7.16 (m, 2H), 7.21 (d, J ) 8.8
Hz, 2H), 7.11 (d, J ) 8.8 Hz, 2H), 7.05-7.01 (m, 1H), 6.98-
3
6.94 (m, 2H), 4.53 (q, J H-F ) 8.4 Hz, 1H), 0.07 (s, 9H); 13C
O-Tr im eth ylsilyl [3-(Tr iflu or om eth yl)ph en yl][2-(2-ph en -
yl-1,1,1-tr iflu or oeth yl)]h yd r oxyla m in e (13m ): chromatog-
raphy, silica gel/2% EtOAc in hexanes (product Rf ) 0.3); mp
NMR δ 151.6 (s), 135.0 (s), 132.3 (d), 128.4 (d), 127.9 (d), 127.6
1
(s), 124.8 (d), 124.5 (q, J C-F ) 280 Hz), 120.8 (d), 74.7 (dq,
2J C-F ) 29 Hz), -0.5 (q); IR (neat, NaCl plate, cm-1) 3066,
2962, 1597, 1489, 1257, 1169. Anal. Calcd for C17H19ClF3-
NOSi: C, 54.61; H, 5.12; N, 3.75. Found: C, 54.41; H, 5.10;
N, 3.66.
1
3
28-30 °C; H NMR δ 7.36-7.16 (m, 9H), 4.58 (q, J H-F ) 8.4
Hz, 1H), 0.07 (s, 9H); 13C NMR δ 152.5 (s), 130.9 (d), 130.9 (q,
2J C-F ) 32 Hz), 129.2 (d), 128.9 (d), 127.9 (d), 124.6 (q, J C-F
1
) 280 Hz), 124.1 (d), 123.8 (q, 1J C-F ) 271 Hz), 121.3 (dq, 3J C-F
3
2
O-Tr im eth ylsilyl P h en yl[2-(2-[4-n itr op h en yl]-1,1,1-tr i-
flu or oeth yl)]h yd r oxyla m in e (13e): liquid at room temper-
ature; chromatography, silica gel/5% EtOAc in hexanes (prod-
uct Rf ) 0.2); 1H NMR δ 8.09 (d, J ) 8.8 Hz, 2H), 7.37 (d, J )
8.8 Hz, 2H), 7.22-7.17 (m, 2H), 7.07-7.03 (m, 1H), 6.97-6.95
) 4 Hz), 117.5 (dq, J C-F ) 4 Hz), 75.2 (dq, J C-F ) 29 Hz),
-0.5 (q); IR (neat, NaCl plate, cm-1) 3035, 2962, 1331, 1169,
1126. Anal. Calcd for C18H19F6NOSi: C, 53.06; H, 4.70; N, 3.44.
Found: C, 53.38; H, 4.81; N, 3.43.
O-Tr im et h ylsilyl P h en yl[3-(tr a n s-1-p h en yl-4,4,4-t r i-
flu or obu t-1-en yl)]h yd r oxyla m in e (21): chromatography,
silica gel/4% EtOAc in hexanes (product Rf ) 0.4); mp 36-37
3
(m, 2H), 4.67 (q, J H-F ) 8.0 Hz, 1H), 0.08 (s, 9H); 13C NMR δ
151.2 (s), 148.2 (s), 136.0 (s), 132.0 (d), 128.6 (d), 125.2 (d),
1
2
1
124.1 (q, J C-F ) 280 Hz), 122.7 (d), 120.5 (d), 74.6 (dq, J C-F
°C; H NMR δ 7.33-7.23 (m, 7H), 7.18-7.16 (m, 2H), 7.07-
) 29 Hz), -0.6 (q).
O-Tr im eth ylsilyl P h en yl[2-(2-[1-n a p h th yl]-1,1,1-tr iflu -
or oeth yl)]h yd r oxyla m in e (13f): chromatography, silica gel/
2% EtOAc in hexanes (product Rf ) 0.3); liquid at room
(26) Accidental equivalence was observed for at least one resonance
in the 13C NMR spectrum. The spectra are included in the Supporting
Information.

R-(Trifluoromethyl)amine Derivatives via Nitrones
J . Org. Chem., Vol. 66, No. 8, 2001 2579
7.03 (m, 1H), 6.45 (dd, J ) 16.2 and 9.0 Hz, 1H), 6.25 (d, J )
Resu bm ission Exp er im en t. To a 25-mL round-bottomed
flask, containing a magnetic stir bar, was added adduct 13g
(329 mg, 1.00 mmol). The flask was sealed, and dry N2(g)
atmosphere was introduced. Anhydrous THF (10 mL) was
added via cannula followed by addition of 2 (284 mg, 295 µL,
2.00 mmol) via syringe. A balloon containing N2(g) was
attached, and the flask was cooled to -40 °C for 15 min. A
slurry of potassium t-butoxide (∼1 M in THF) was added to
the reaction mixture at 15 min intervals, and the reaction was
monitored by TLC. When the adduct was entirely consumed,
the reaction mixture was quenched with water and extracted
with dichloromethane. The combined extracts were dried
(MgSO4), filtered, and concentrated by rotary evaporation.
Amine 15g was purified by flash chromatography (87% yield).
P h en yl[2-(2-[2-fu r yl]-1,1,1,3,3,3-h exa flu or op r op yl)]-
a m in e (15g): liquid at room temperature; 1H NMR δ 7.54
(dd, J ) 1.8 and 0.6 Hz, 1H), 7.11-7.07 (m, 2H), 6.88 (m, 1H),
6.73 (dd, J ) 3.4 and 0.6 Hz, 1H), 6.50 (dd, J ) 3.2 and 1.6
Hz, 1H), 6.44-6.42 (m, 2H), 4.32 (br s, 1H); 13C NMR δ 144.3
3
16.0 Hz, 1H), 4.08 (dq, J H-F ) 8.2 and 8.0 Hz, 1H), 0.08 (s,
9H); 13C NMR δ 152.1 (s), 138.3 (d), 136.0 (s), 128.5 (d), 128.4
1
(d), 128.3 (d), 126.8 (d), 124.5 (q, J C-F ) 280 Hz), 124.4 (d),
120.5 (d), 116.9 (d), 74.0 (dq, 2J C-F ) 29 Hz), -0.5 (q); IR (neat,
NaCl plate, cm-1) 3062, 3032, 2962, 1597, 1489, 1254. Anal.
Calcd for C19H22F3NOSi: C, 62.44; H, 6.07; N, 3.83. Found:
C, 62.21; H, 6.14; N, 3.81.
Ca ta lytic Hyd r ogen a tion of Ad d u ct 21sP r ep a r a tion
of 23. To a 25-mL, round-bottomed flask, containing magnetic
stir bar, were added nitrone 21 (365 mg, 1.00 mmol) and ethyl
acetate (8 mL). The solution was sparged with nitrogen gas
for 10 min. The palladium catalyst (35 mg, 10% Pd/C) was
added, followed by the addition of ethyl acetate (2 mL). A
balloon filled with hydrogen gas was attached, and the reaction
mixture was stirred at room temperature. The reaction was
monitored by 1H NMR. After 4 h, the starting material was
consumed. The catalyst was removed by filtration through a
small plug of silica gel. The solvent was removed by rotary
evaporation, and the product was purified by flash chroma-
tography (silica gel/4% EtOAc in hexanes; product Rf ) 0.4)
to give 330 mg (91%) of a clear, colorless oil.
1
(d), 142.0 (s), 140.9 (s), 128.8 (d), 122.9 (q, J C-F ) 290 Hz),
2
121.8 (d), 118.6 (d), 114.4 (d), 111.1 (d), 67.0 (sept, J C-F ) 28
Hz); IR (neat, NaCl plate, cm-1) 3421, 3062, 3032, 1604, 1500,
1250, 1203, 1157. Anal. Calcd for C13H9F6NO: C, 50.50; H,
2.93; N, 4.53. Found: C, 50.34; H, 3.17; N, 5.04.
O-Tr im eth ylsilyl P h en yl[2-(4-p h en yl-1,1,1-tr iflu or obu -
tyl)]h yd r oxyla m in e (23): 1H NMR δ 7.28-7.15 (m, 5H),
7.10-7.07 (m, 2H), 7.04-6.99 (m, 1H), 6.94 (d, J ) 6.8 Hz,
2H), 3.67-3.57 (m, 1H), 2.71-2.63 (m, 1H), 2.60-2.51 (m, 1H),
2.54-2.36 (m, 1H), 2.05-1.96 (m, 1H), 0.12 (s, 9H); 13C NMR
δ 152.9 (s), 140.6 (s), 128.6 (d), 128.4 (d), 128.3 (d), 126.0 (d),
P h en yl[2-(2-[4-n itr op h en yl]-1,1,1,3,3,3-h exa flu or op r o-
p yl)]a m in e (15f): chromatography, silica gel/5% ethyl acetate
in hexanes (product Rf ) 0.3); yellow, crystalline solid; mp
180-182 °C; 1H NMR δ 8.31 (d, J ) 9.6 Hz, 2H), 7.96 (d, J )
8.8 Hz, 2H), 7.10-7.06 (m, 2H), 6.88-6.84 (m, 1H), 6.40 (d, J
) 8.0 Hz, 2H), 4.54 (br s, 1H); 13C NMR δ 148.9 (s), 141.1 (s),
1
2
125.7 (q, J C-F ) 281 Hz), 123.1 (d), 118.1 (d), 69.7 (dq, J C-F
) 27 Hz), 32.4 (t), 25.2 (t), -0.3 (q); IR (neat, NaCl plate, cm-1
3028, 2962, 1597, 1489, 1257, 1122. Anal. Calcd for C19H24F3-
NOSi: C, 62.10; H, 6.58; N, 3.81. Found: C, 62.16; H, 6.82;
N, 3.76.
)
1
134.9 (s), 130.5 (d), 128.9 (d), 123.7 (d), 123.1 (q, J C-F ) 291
2
Hz), 121.2 (d), 117.3 (d), 70.0 (sept, J C-F ) 27 Hz); IR (thin
film, NaCl plate, cm-1) 3406, 3055, 1523, 1350, 1242, 1180.
Anal. Calcd for C15H10F6N2O2: C, 49.46; H, 2.77; N, 7.69.
Found: C, 49.38; H, 2.82; N, 7.66.
Rep r esen ta tive P r oced u r e for th e Ad d ition of TMSCF 3
(2) to Nitr on es to for m Bis(tr iflu or om eth yl)a m in ess
P r ep a r a tion 15g. To a 100-mL, round-bottomed flask, con-
taining a magnetic stir bar, was added nitrone 12g (0.936 g,
5.00 mmol). The flask was sealed with a septum, and the
atmosphere was displaced with dry N2(g). Anhydrous THF (50
mL) was added via cannula. Silane 2 (2.21 mL, 2.13 g, 15.0
mmol) was added via syringe. A balloon containing dry N2(g)
was attached, and the reaction mixture was cooled to -25 to
-30 °C in a low-temperature bath for 15 min. A slurry of
potassium t-butoxide in anhydrous THF (∼0.1 M) was pre-
pared, and small aliquots (50-100 µL) of the slurry were added
to the reaction mixture at ∼15 min intervals. A brown color
formed upon addition of the base. The reaction was monitored
by TLC (silica gel/3% ethyl acetate in hexanes: nitrone Rf )
0, initial nitrone adduct Rf ) 0.4, bis(trifluoromethyl)amine
Rf ) 0.3), and alkoxide addition was continued until both the
nitrone and the initial adduct were completely converted. The
reaction mixture was poured into a separatory funnel contain-
ing distilled water. The cloudy mixture was extracted with
dichloromethane. The combined organic extracts were dried
(MgSO4), filtered, and concentrated by rotary evaporation to
give a yellow oil. The product was purified by flash chroma-
tography (silica gel/3% ethyl acetate in hexanes) to give 1.22
g (82%) of a pale, yellow oil.
P r od u ct Distr ibu tion Stu d y. The analysis of the competi-
tion between formation of the mono- and bistrifluoromethy-
lated products (Figure 1) was performed as described above,
but all quantities were scaled for use with 2.00 mmol of the
nitrone. An internal standard (tetrahydronaphthalene, 2.00
mmol) was added, and the progress of the reaction was
monitored by gas chromatography (HP-1 capillary column, 30
m, isothermal analysis at 100 °C). Aliquots (50 µL) of the
t-butoxide slurry (5.00 mmol in 10 mL of anhydrous THF) were
added at 5 min intervals over 5 h. Aliquots of the reaction
mixture were removed via syringe at 15 min intervals. Each
aliquot was quenched by addition to a mixture of 1:1 dichlo-
romethane:water. The aqueous layer was separated before
injection. Calibration curves for each of nitrone, the initial
adduct, and the bis(trifluoromethyl)amine were prepared using
samples obtained from preparative reactions.
P h en yl[2-(2-[4-p yr id yl]-1,1,1,3,3,3-h exa flu or op r op yl)]-
a m in e (15h ): chromatography, silica gel/5% ethyl acetate in
hexanes (product Rf ) 0.2); mp 144-146 °C; 1H NMR δ 8.76-
8.74 (m, 2H), 7.65 (d, J ) 5.2 Hz, 2H), 7.09-7.05 (m, 2H),
6.87-6.85 (m, 1H), 6.42 (d, J ) 8.0 Hz, 2H), 4.49 (br s, 1H);
13C NMR δ 150.5 (d), 141.3 (s), 137.4 (s), 128.9 (d), 123.6 (d),
123.0 (q, 1J C-F ) 288 Hz), 121.1 (d), 117.3 (d), 69.7 (sept, 2J C-F
) 27 Hz); IR (thin film, NaCl plate, cm-1) 3305, 3062, 2924,
1601, 1234, 1180. Anal. Calcd for C14H10F6N2: C, 52.51; H,
3.15; N, 8.75. Found: C, 52.73; H, 3.20; N, 8.75.
P h en yl[2-(2-[2-p yr id yl]-1,1,1,3,3,3-h exa flu or op r op yl)]-
a m in e (15i): chromatography, silica gel/5% ethyl acetate in
hexanes (product Rf ) 0.4); liquid at room temperature; 1H
NMR δ 8.78 (m, 1H), 7.78-7.77 (m, 2H), 7.46-7.40 (m, 1H),
7.14-7.09 (m, 2H), 6.90-6.86 (1H), 6.64 (d, J ) 8.0 Hz, 2H),
5.33 (br s, 1H); 13C NMR δ 148.8 (d), 148.6 (s), 142.1 (s), 136.9
1
(d), 128.7 (d), 125.0 (d), 124.7 (d), 123.3 (q, J C-F ) 290 Hz),
2
121.4 (d), 119.1 (d), 70.3 (sept, J C-F ) 28 Hz); IR (neat, NaCl
plate, cm-1) 3410, 3267, 3062, 1604, 1500, 1254. Anal. Calcd
for C14H10F6N2: C, 52.51; H, 3.15%, N, 8.75. Found: C, 52.43;
H, 3.19; N, 8.69.
P h en yl[2-(tr a n s-3-[tr iflu or om eth yl]-1-p h en yl-4,4,4-tr i-
flu or obu t-1-en yl)]a m in e (22): chromatography, silica gel/
5% ethyl acetate in hexanes (product Rf ) 0.4); liquid at room
temperature; 1H NMR δ 7.42-7.34 (m, 5H), 7.20-7.16 (m, 2H),
7.06 (d, J ) 16.8 Hz, 1H), 6.95-6.91 (m, 3H), 6.19 (d, J ) 16.4
Hz, 1H), 4.22 (br s, 1H); 13C NMR δ 141.9 (s), 139.2 (d), 135.1
1
(s), 129.3 (d), 128.9 (d), 128.8 (d), 127.1 (d), 123.6 (q, J C-F
)
2
288 Hz), 121.8 (d), 119.8 (d), 115.6 (d), 67.5 (sept, J C-F ) 27
Hz); IR (neat, NaCl plate, cm-1) 3417, 3062, 3032, 2927, 1601,
1500, 1254, 1165. Anal. Calcd for C17H13F6N: C, 59.13; H, 3.79;
N, 4.06. Found: C, 59.44; H, 3.98; N, 3.94.
Rep r esen ta tive P r oced u r e for Acid ic Dep r otection of
r-CF 3 O-Tr im eth ylsilyl Hyd r oxyla m in e Der iva tivess
P r ep a r a tion of 24c. To a 50-mL, round-bottomed flask
containing a magnetic stir bar were added adduct 13c (339
mg, 1.00 mmol), reagent grade tetrahydrofuran (10 mL), and
1 N HCl (10 mL). The flask was stoppered, and the biphasic
reaction was stirred vigorously at room temperature for 24 h.
A light yellow color formed in the reaction mixture. The

2580 J . Org. Chem., Vol. 66, No. 8, 2001
Nelson et al.
reaction was monitored by TLC (silica gel/5% ethyl acetate in
hexanes; product Rf ) 0.3). The reaction mixture was poured
into a separatory funnel containing a saturated sodium
bicarbonate solution. When gas evolution ceased, 2 N KOH-
(aq) was added to adjust the pH to ∼10. The aqueous mixture
was extracted with dichloromethane. The combined organic
extracts were dried (MgSO4), filtered, and concentrated by
rotary evaporation to give a yellow oil. The product was
purified by flash chromatography (TLC conditions) to give 249
mg (93%) of a white powdery solid. Recrystallization from
hexanes afforded an analytically pure sample.
NaCl plate, cm-1) 3313, 3032, 2923, 1508, 1273, 1160, 1122.
Anal. Calcd for C15H14F3NO: C, 64.05; H, 5.02; N, 4.98.
Found: C, 64.02; H, 5.03; N, 4.90.
(4-Ch lor op h en yl)[2-(2-p h en yl-1,1,1-tr iflu or oeth yl)]h y-
d r oxyla m in e (24l): chromatography, silica gel/5% EtOAc in
hexanes (product Rf ) 0.2); recrystallized from hexanes; mp
1
80-81 °C; H NMR δ 7.37-7.27 (m, 5H), 7.20 (d, J ) 9.2 Hz,
2H), 6.99 (d, J ) 8.8 Hz, 2H), 5.34 (s, 1H), 4.81 (q, 3J H-F ) 8.3
Hz, 1H); 13C NMR δ 149.0 (s), 130.2 (d), 129.2 (d), 129.0 (s),
128.8 (d), 128.2 (d), 124.8 (1J C-F ) 280 Hz), 119.4 (d), 72.9 (dq,
2J C-F ) 29 Hz);26 IR (thin film, NaCl plate, cm-1) 3305, 3066,
2924, 1485, 1277, 1172, 1122. Anal. Calcd for C14H11ClF3NO:
C, 55.74; H, 3.68; N, 4.64. Found: C, 55.67; H, 3.67; N, 4.61.
[3-(Tr iflu or om eth yl)p h en yl)[2-(2-p h en yl-1,1,1-tr iflu o-
r oeth yl)]h yd r oxyla m in e (24m ): chromatography, silica gel/
5% EtOAc in hexanes (product Rf ) 0.3); recrystallized from
hexanes; mp 38 °C; 1H NMR δ 7.39-7.21 (m, 9H), 5.43 (s, 1H),
P h e n yl[2-(2-p h e n yl-1,1,1-t r iflu or oe t h yl)]h yd r oxyl-
1
a m in e (24c): mp 80-81 °C; H NMR δ 7.36-7.23 (m, 7H),
3
7.08-6.99 (m, 3H), 5.25 (s, 1H), 4.89 (q, J H-F ) 9.2 Hz, 1H);
13C NMR δ 150.4 (s), 130.2 (d), 129.3(s), 129.0 (d), 128.8 (d),
1
128.1 (d), 125.0 (q, J C-F ) 281 Hz), 123.5 (d), 117.9 (d), 72.7
2
(dq, J C-F ) 29 Hz); IR (KBr pellet, cm-1) 3356, 3062, 3032,
3
1597, 1489, 1369, 1281, 1180. Anal. Calcd for C14H12F3NO: C,
62.92; H, 4.53; N, 5.24. Found: C, 62.83; H, 4.55%, N, 5.12.
P h en yl[2-(2-[4-m eth oxyp h en yl]-1,1,1-tr iflu or oeth yl)]-
h yd r oxyla m in e (24a ): chromatography, silica gel/5%EtOAc
in hexanes (product Rf ) 0.2); liquid at room temperature; 1H
NMR δ 7.28-7.23 (m, 2H), 7.22 (d, J ) 9.2 Hz, 2H), 7.06-
6.99 (m, 3H), 6.81 (d, J ) 8.8 Hz, 2H), 5.26 (s, 1H), 4.83 (q,
3J H-F ) 8.4 Hz, 1H), 3.78 (s, 3H); 13C NMR δ 159.9 (s), 150.5
4.92 (q, J H-F ) 8.0 Hz, 1H); 13C NMR δ 150.8 (s), 131.4 (q,
2J C-F ) 32 Hz), 130.2 (d), 129.4 (d), 128.9 (s), 128.3 (d), 124.8
(q, 1J C-F ) 281 Hz), 123.9 (q, 1J C-F ) 271 Hz), 120.8 (d), 120.7
3
3
(d), 120.1 (dq, J C-F ) 4 Hz), 114.6 (dq, J C-F ) 4 Hz), 72.5
(dq, J C-F ) 29 Hz); IR (melt, NaCl plate, cm-1) 3506, 3070,
2
3035, 2979, 1454, 1331, 1277, 1126. Anal. Calcd for C15H11F6-
NO: C, 53.74; H, 3.31%, N, 4.18. Found: C, 53.49; H, 3.21%,
N, 4.00.
1
(s), 131.5 (d), 128.7 (d), 125.1 (q, J C-F ) 281 Hz), 123.4 (d),
P h en yl[3-(tr a n s-1-p h en yl-4,4,4-tr iflu or obu t-1-en yl)]h y-
d r oxyla m in e (24n ): chromatography, silica gel/5% EtOAc in
hexanes (product Rf ) 0.2); recrystallized from hexanes; mp
2
121.3 (s), 117.9 (d), 113.5 (d), 72.2 (dq, J C-F ) 29 Hz), 55.1
(q); IR (KBr pellet, cm-1) 3421, 3035, 2939, 2843, 1612, 1516,
1250, 1165, 1126. Anal. Calcd for C15H14F3NO2: C, 60.60; H,
4.75; N, 4.71. Found: C, 60.38; H, 4.87; N, 4.60.
1
80-82 °C; H NMR δ 7.35-7.26 (m, 7H), 7.17-7.14 (m, 2H),
7.05-7.01 (m, 1H), 6.50-6.40 (m, 2H), 5.25 (s, 1H), 4.37 (dq,
3
P h en yl[2-(2-[2-m eth oxyp h en yl]-1,1,1-tr iflu or oeth yl)]-
h yd r oxyla m in e (24b): chromatography, silica gel/5%EtOAc
in hexanes (product Rf ) 0.2); recrystallized from hexanes; mp
J ) 8.0, J H-F ) 8.0 Hz, 1H); 13C NMR δ 150.5 (s), 138.5 (d),
135.6 (s), 128.8 (d), 128.5 (d), 128.4 (d), 126.8 (d), 124.9 (q, 1J C-F
2
) 284 Hz), 123.5 (d), 117.8 (d), 116.1 (d), 71.7 (dq, J C-F ) 29
91-93 °C; H NMR δ 7.78 (d, J ) 7.6 Hz, 1H), 7.32-7.20 (m,
Hz); IR (thin film, NaCl plate, cm-1) 3471, 3082, 3055, 3028,
2962, 1593, 1485, 1269. Anal. Calcd for C16H14F3NO: C, 65.52;
H, 4.81; N, 4.78. Found: C, 65.84; H, 4.98; N, 4.68.
1
3H), 7.09-7.07 (m, 2H), 7.00-6.93 (m, 2H), 6.77 (d, J ) 8.4
3
Hz, 1H), 5.71 (q, J H-F ) 8.8 Hz, 1H), 5.25 (s, 1H), 3.45 (s,
3H); 13C NMR δ 157.6 (s), 150.8 (s), 131.3 (d), 130.2 (d), 128.3
Rep r esen ta tive P r oced u r e for F or m a tion of th e r-CF 3
Am in es by Tr a n sfer Hyd r ogen a tion sP r ep a r a tion of 25c.
To a 25-mL, round-bottomed flask, containing a magnetic stir
bar, was added adduct 13c (679 mg, 2.00 mmol). Reagent grade
methanol was added to the reaction mixture, followed by
addition of 10% Pd/C (50 mg). Ammonium formate (630 mg,
10.0 mmol) was added to the reaction mixture. The flask was
stoppered, and the reaction mixture was stirred vigorously at
room temperature. The reaction was monitored by TLC (silica
gel/5% ethyl acetate in hexanes: adduct Rf ) 0.4, amine Rf )
0.3). After 4 h, the starting material was consumed. The
catalyst was removed by filtration through a plug of cotton
wool, and the solvent was removed by rotary evaporation. The
crude product, which contained unreacted ammonium formate,
was purified by flash chromatography (TLC conditions) to give
234 mg (93%) of a clear colorless oil.
1
(d), 125.4 (q, J C-F ) 281 Hz), 122.9 (d), 120.3 (d), 118.5 (s),
117.4 (d), 110.7 (d), 63.2 (dq, 2J C-F ) 29 Hz), 55.4 (q); IR (thin
film, NaCl plate, cm-1) 3309, 3028, 2976, 1601, 1493, 1250,
1126. Anal. Calcd for C15H14F3NO2: C, 60.60; H, 4.75; N, 4.71.
Found: C, 60.59; H, 4.67; N, 4.59.
P h en yl[2-(2-[4-ch lor op h en yl]-1,1,1-tr iflu or oeth yl)]h y-
d r oxyla m in e (24d ): chromatography, silica gel/5% EtOAc in
hexanes (product Rf ) 0.2); recrystallized from hexanes; mp
90 °C; 1H NMR δ 7.28-7.20 (m, 6H), 7.05-7.00 (m, 3H), 5.28
(s, 1H), 4.83 (q, 3J H-F ) 8.0 Hz, 1H); 13C NMR δ 150.2 (s), 135.3
1
(s), 131.6 (d), 128.9 (d), 128.4 (d), 127.7 (s), 124.8 (q, J C-F
)
281 Hz), 123.8 (d), 118.0 (d), 72.3 (dq, 2J C-F ) 29 Hz); IR (NaCl,
thin film, cm-1) 3344, 3035, 1593, 1493, 1284, 1122. Anal.
Calcd for C14H11ClF3NO: C, 55.74; H, 3.68; N, 4.64. Found:
C, 55.70; H, 3.76; N, 4.58.
P h en yl[2-(2-[1-n a p h th yl]-1,1,1-tr iflu or oeth yl)]h yd r ox-
yla m in e (24f): chromatography, silica gel/5% EtOAc in hex-
anes (product Rf ) 0.2); recrystallized from hexanes; mp 124-
P h en yl[2-(2-p h en yl-1,1,1-tr iflu or oeth yl)] Am in e (25c):
liquid at room temperature; 1H NMR δ 7.46-7.44 (m, 2H),
7.41-7.35 (m, 3H), 7.18-7.13 (m, 2H), 6.79-6.74 (m, 1H),
6.65-6.62 (m, 2H), 4.91 (dq, 3J H-F ) 7.2 and 7.2 Hz, 1H), 4.32
(d, J ) 6.0 Hz, 1H); 13C NMR δ 145.5 (s), 134.1 (s), 129.3 (d),
129.1 (d), 128.9 (d), 127.9 (d), 125.1 (q, 1J C-F ) 281 Hz), 119.2
1
126 °C; H NMR δ 8.01 (d, J ) 7.2 Hz, 1H), 7.84 (d, J ) 8.4
Hz, 1H), 7.80 (d, J ) 8.0 Hz, 1H), 7.53 (d, J ) 8.4 Hz, 1H),
7.49 (dd, J ) 7.8 and 7.8 Hz, 1H), 7.39 (ddd, J ) 7.9, 7.4, and
1.2 Hz, 1H), 7.31 (ddd, J ) 8.0, 7.8, and 1.6 Hz, 1H), 7.18-
7.14 (m, 2H), 7.09 (dd, J ) 8.8 and 1.2 Hz, 2H), 6.96-6.92 (m,
1H), 5.82 (q, 3J H-F ) 8.1 Hz, 1H), 5.41 (s, 1H); 13C NMR δ 150.4
(s), 133.6 (s), 132.2 (s) 129.8 (d), 129.0 (d), 128.9 (d), 128.8 (d),
2
(d), 113.9 (d), 60.6 (dq, J C-F ) 30 Hz); IR (neat, NaCl plate,
cm-1) 3417, 3059, 1604, 1504, 1250, 1172, 1122. Anal. Calcd
for C14H12F3N: C, 66.93; H, 4.81; N, 5.57. Found: C, 66.84;
H, 4.77; N, 5.39.
1
126.6 (d), 125.9 (s), 125.5 (d), 125.4 (q, J C-F ) 282 Hz), 124.9
P h en yl[2-(2-[4-m et h oxyp h en yl]-1,1,1-t r iflu or oet h yl)]
Am in e (25a ): chromatography, silica gel/5% ethyl acetate in
hexanes (product Rf ) 0.2); liquid at room temperature; 1H
NMR δ 7.36 (d, J ) 8.4 Hz, 2H), 7.17-7.13 (m, 2H), 6.90 (d, J
) 8.8 Hz, 2H), 6.78-6.74 (m, 1H), 6.64-6.62 (m, 2H), 4.86 (q,
3J H-F ) 7.3 Hz, 1H), 4.27 (br s, 1H), 3.79 (s, 3H); 13C NMR δ
160.1 (s), 145.6 (s), 129.3 (d), 129.1 (d), 126.0 (s), 125.1 (q, 1J C-F
2
(d), 123.7 (d), 122.4 (d), 118.1 (d), 66.7 (dq, J C-F ) 28 Hz); IR
(thin film, NaCl plate, cm-1) 3317, 3062, 1597, 1485, 1277,
1153, 1126. Anal. Calcd for C18H14F3NO: C, 68.13; H, 4.45;
N, 4.41. Found: C, 67.74; H, 4.38; N, 4.27.
(4-Meth ylp h en yl)[2-(2-p h en yl-1,1,1-tr iflu or oeth yl)]h y-
d r oxyla m in e (24k): chromatography, silica gel/5% EtOAc in
hexanes (product Rf ) 0.3); recrystallized from hexanes; mp
2
) 280 Hz), 119.1 (d), 114.3 (d), 113.9 (d), 60.0 (dq, J C-F ) 30
59-60 °C; H NMR δ 7.36-7.25 (m, 5H), 7.03 (d, J ) 8.4 Hz,
Hz), 55.3 (q); IR (neat, NaCl plate, cm-1) 3410, 3008, 2939,
1608, 1511, 1307, 1254, 1172. Anal. Calcd for C15H14F3NO: C,
64.05; H, 5.02; N, 4.98. Found: C, 63.66; H, 5.00; N, 4.85.
P h en yl[2-(2-[2-m et h oxyp h en yl]-1,1,1-t r iflu or oet h yl)]
Am in e (25b): chromatography, silica gel/5% ethyl acetate in
1
2H), 6.93 (d, J ) 8.8 Hz, 2H), 5.28 (s, 1H), 4.80 (q, 3J H-F ) 8.4
Hz, 1H), 2.27 (s, 3H); 13C NMR δ 148.0 (s), 133.2 (s), 130.3 (d),
1
129.4 (s), 129.2 (d), 128.9 (d), 128.0 (d), 125.0 (q, J C-F ) 281
Hz), 118.4 (d), 73.0 (dq, 2J C-F ) 29 Hz), 20.6 (q); IR (thin film,

R-(Trifluoromethyl)amine Derivatives via Nitrones
J . Org. Chem., Vol. 66, No. 8, 2001 2581
1
hexanes (product Rf ) 0.3); liquid at room temperature; 1H
NMR δ 7.38 (d, J ) 7.2 Hz, 1H), 7.31 (ddd, J ) 8.3, 7.4, and
1.8 Hz, 1H), 7.17-7.13 (m, 2H), 6.98-6.94 (m, 1H), 6.93 (d, J
) 8.4 Hz, 1H), 6.76-6.72 (m, 1H), 6.67-6.65 (m, 2H), 5.55 (br
s, 1H), 4.48 (br s, 1H), 3.89 (s, 3H); 13C NMR δ 157.5 (s), 145.8
132.5 (s), 129.4 (d), 129.2 (d), 129.1 (d), 124.8 (q, J C-F ) 280
2
Hz), 119.5 (d), 114.0 (d), 60.0 (dq, J C-F ) 30 Hz); IR (neat,
NaCl plates, cm-1) 3417, 3059, 2931, 1604, 1493, 1254, 1176.
Anal. Calcd for C14H11ClF3N: C, 58.86; H, 3.88; N, 4.90.
Found: C, 58.88; H, 3.75; N, 4.80.
1
(s), 130.1 (d), 129.3 (d), 128.1 (d), 125.4 (q, J C-F ) 281 Hz),
Zin c Meta l Red u ction of Ad d u ct 21sP r ep a r a tion of
25n . To a 25-mL, round-bottomed flask, containing a magnetic
stir bar, were added adduct 21 (365 mg, 1.00 mmol), glacial
acetic acid (5 mL), and anhydrous THF (5 mL). Fine mesh zinc
powder (981 mg, 15.0 mmol) was then added to the reaction
mixture. A reflux condenser with an N2(g) inlet was attached
to the flask. The reaction mixture was stirred vigorously to
prevent the zinc from settling and heated to ∼60 °C for 24 h.
The gray slurry gradually turned lighter in color. The reaction
was monitored by TLC (silica gel/4% EtOAc in hexanes; adduct
Rf ) 0.4, amine Rf ) 0.3). The zinc/zinc oxide solids were
removed by filtration through a glass frit. The acid was
neutralized by dropwise addition of a saturated sodium
bicarbonate solution, and a few drops of 2 N KOH solution
was added to adjust the pH to ∼10. The reaction mixture was
extracted with dichloromethane. The combined extracts were
dried (MgSO4), filtered, and concentrated by rotary evaporation
to give a yellow oil. Purification by flash chromatography (TLC
conditions) afforded a clear, colorless oil (225 mg, 81%).
P h en yl[3-(tr a n s-1-p h en yl-4,4,4-t r iflu or ob u t -1-en yl)]
122.6 (s), 121.0 (d), 118.9 (d), 113.7 (d), 111.1 (d), 55.8 (q), 53.6
2
(dq, J C-F ) 30 Hz); IR (neat, NaCl plate, cm-1) 3410, 3008,
2939, 1608, 1509, 1307. Anal. Calcd for C15H14F3NO: C, 64.05;
H, 5.02; N, 4.98. Found: C, 63.72; H, 5.07; N, 4.80.
P h en yl[2-(2-[1-n a p h th yl]-1,1,1-tr iflu or oeth yl)] Am in e
(25f): chromatography, silica gel/5% ethyl acetate in hexanes
(product Rf ) 0.3); liquid at room temperature; 1H NMR δ 8.11
(d, J ) 8.4 Hz, 1H), 7.93 (d, J ) 8.8 Hz, 1H), 7.89 (d, J ) 8.4
Hz, 1H), 7.78 (d, J ) 7.2 Hz, 1H), 7.63-7.48 (m, 3H), 7.16-
7.12 (m, 2H), 6.78-6.74 (m, 1H), 6.65-6.62 (m, 2H), 5.84 (q,
3J H-F ) 6.8 Hz, 1H), 4.49 (br s, 1H); 13C NMR δ 145.5 (s), 133.9
(s), 131.6 (s), 129.9 (s), 129.7 (d), 129.4 (d), 129.2 (d), 127.0
1
(d), 125.9 (d), 125.6 (q, J C-F ) 281 Hz), 125.3 (d), 125.2 (d),
122.2 (d), 119.2 (d), 113.6 (d), 55.6 (dq, 2J C-F ) 30 Hz); IR (neat,
NaCl plate, cm-1) 3413, 3055, 1604, 1508, 1250, 1169, 1122.
Anal. Calcd for C18H14F3N: C, 71.75; H, 4.68; N, 4.65. Found:
C, 71.47; H, 4.78; N, 4.55.
(4-Met h oxyp h en yl)[2-(2-p h en yl-1,1,1-t r iflu or oet h yl)]
Am in e (25j): chromatography, silica gel/5% ethyl acetate in
hexanes (product Rf ) 0.2); liquid at room temperature; 1H
NMR δ 7.45-7.36 (m, 5H), 6.74 (d, J ) 8.8 Hz, 2H), 6.60 (d, J
1
Am in e (25n ): H NMR δ 7.41-7.21 (m, 7H), 6.84-6.80 (m,
1H), 6.81 (d, J ) 16.4 Hz, 1H), 6.76-6.72 (m, 2H), 6.21 (dd, J
) 15.8 and 6.0 Hz, 1H), 4.63 (dq, J ) 7.2 and 6.0 Hz, 1H),
3.70 (br s, 1H); 13C NMR δ 145.6 (s), 135.5 (d), 129.4 (d), 128.7
3
) 8.8 Hz, 2H), 4.80 (q, J H-F ) 7.2 Hz, 1H), 4.07 (br s, 1H),
3.71 (s, 3H); 13C NMR δ 153.3 (s), 139.4 (s), 134.3 (s), 129.0
1
1
(d), 128.8 (d), 127.9 (d), 125.1 (q, J C-F ) 281 Hz), 115.7 (d),
(d), 128.5 (d), 126.7 (d), 125.2 (q, J C-F ) 281 Hz), 120.8 (d),
2
2
114.8 (d), 61.7 (dq, J C-F ) 29 Hz), 55.6 (q); IR (neat, NaCl
119.3 (d), 113.8 (d), 58.2 (dq, J C-F ) 30 Hz); IR (neat, NaCl
plate, cm-1) 3390, 3035, 2939, 1515, 1246, 1176, 1126. Anal.
Calcd for C15H14F3NO: C, 64.05; H, 5.02; N, 4.98. Found: C,
63.59; H, 5.15; N, 4.90.
plate, cm-1) 3413, 3059, 3028, 1604, 1500, 1250, 1180. Anal.
Calcd for C16H14F3N: C, 69.30; H, 5.09; N, 5.05. Found: C,
68.92; H, 5.00; N, 5.03.
(4-Methylphenyl)[2-(2-phenyl-1,1,1-trifluoroethyl)]Amine
(25k): chromatography, silica gel/5% ethyl acetate in hexanes
(product Rf ) 0.3); liquid room temperature; 1H NMR δ 7.47-
7.45 (m, 2H), 7.42-7.36 (m, 3H), 6.99-6.95 (m, 2H), 6.56 (d,
Ca ta lytic Hyd r ogen a tion of Ad d u ct 21sP r ep a r a tion
25o. To a 25-mL, round-bottomed flask, containing a magnetic
stir bar, were added silylated hydroxylamine 21 (365 mg, 1.00
mmol) and ethyl acetate (8 mL). The solution was sparged with
N2(g) gas for 10 min. The palladium catalyst (100 mg of 10%
Pd/C) was washed into the flask with additional ethyl acetate
(2 mL). A balloon of H2(g) was attached, and the reaction was
stirred vigorously. The reaction was monitored by TLC (silica
gel/6% ethyl acetate in hexanes; adduct Rf ) 0.6, amine Rf )
0.4). After 24 h, no starting material remained. The reaction
mixture was filtered through a small plug of silica gel. The
product was purified by flash chromatography (TLC condi-
tions) to give 260 mg (93%) of a clear, colorless oil.
3
J ) 8.4 Hz, 2H), 4.88 (q, J H-F ) 7.3 Hz, 1H), 4.20 (br s, 1H),
2.22 (s, 3H); 13C NMR δ 143.2 (s), 134.2 (s), 129.8 (d), 129.0
1
(d), 128.9 (d), 128.5 (s), 127.8 (d), 125.2 (q, J C-F ) 281 Hz),
2
114.2 (d), 60.9 (dq, J C-F ) 30 Hz), 20.3 (q); IR (neat, NaCl
plates, cm-1) 3417, 3032, 2924, 1620, 1520, 1249, 1172, 1122.
Anal. Calcd for C15H14F3N: C, 67.91; H, 5.32; N, 5.28. Found:
C, 68.11; H, 5.44; N, 5.22.
[3-(Tr iflu or om eth yl)p h en yl][2-(2-p h en yl-1,1,1-tr iflu o-
r oeth yl)] Am in e (25m ): chromatography, silica gel/5% ethyl
acetate in hexanes (product Rf ) 0.4); liquid at room temper-
ature; 1H NMR δ 7.47-7.39 (m, 5H), 7.27-7.23 (m, 1H), 7.02-
7.00 (m, 1H), 6.88 (br s, 1H), 6.79-6.75 (m, 1H), 4.93 (dq, 3J H-F
) 7.2 and 7.2 Hz, 1H), 4.52 (d, J ) 6.0 Hz, 1H); 13C NMR δ
Reductive deprotection of 21 by transfer hydrogenation
afforded 25o in 86% yield in 4 h.
P h en yl[2-(4-p h en yl-1,1,1-tr iflu or obu tyl)] Am in e (25o):
1H NMR δ 7.31-7.26 (m, 2H), 7.24-7.18 (m, 3H), 7.13-7.11
(m, 2H), 6.81-6.77 (m, 1H), 6.63-6.60 (m, 2H), 3.85-3.83 (m,
1H), 3.58-3.56 (m, 1H), 2.92-2.86 (m, 1H), 2.73 (ddd, J ) 14.0,
8.4, and 8.2 Hz, 1H), 2.22 (dddd, J ) 14.2, 8.4, 8.2, and 0.8
Hz, 1H), 1.94-1.85 (m, 1H); 13C NMR δ 146.4 (s), 140.1 (s),
2
145.8 (s), 133.4 (s), 131.8 (q, J C-F ) 31 Hz), 129.9 (d), 129.4
1
(d), 129.1 (d), 127.8 (d), 124.9 (q, J C-F ) 280 Hz), 124.1 (q,
1J C-F ) 271 Hz), 116.2 (d), 115.7 (dq, 3J C-F ) 4 Hz), 110.5 (dq,
2
3J C-F ) 4 Hz), 60.4 (dq, J C-F ) 30 Hz); IR (neat, NaCl plate,
cm-1) 3437, 3039, 2923, 1616, 1496, 1342, 1169. Anal. Calcd
for C15H11F6N: C, 56.43; H, 3.47; N, 4.39. Found: C, 56.62;
H, 3.61; N, 4.37.
129.3 (d), 128.6 (d), 128.5 (d), 126.3 (d), 126.2 (q, J C-F ) 282
1
Hz), 118.7 (d), 113.4 (d), 54.6 (dq, 2J C-F ) 29 Hz), 31.3 (t), 31.1
(t); IR (neat, NaCl plate, cm-1) 3410, 3028, 2931, 1604, 1512,
1254, 1165, 1122. Anal. Calcd for C16H16F3N: C, 68.80; H, 5.77;
N, 5.01. Found: C, 68.60; H, 5.99; N, 5.09.
Ca ta lytic Hyd r ogen a tion of Ad d u ct 13d sP r ep a r a tion
of 25d . To a 10-mL, round-bottomed flask, containing a
magnetic stir bar, were added reagent grade ethyl acetate (5
mL) and 10% Pd/C (100 mg). Adduct 13d (374 mg, 1.00 mmol)
was added. The solution was sparged with N2(g) for 5 min,
and a balloon of H2(g) was attached. The reaction mixture was
stirred at room temperature for 72 h. The reaction was
monitored by TLC (silica gel/4% ethyl acetate in hexanes;
adduct Rf ) 0.4, product Rf ) 0.3). The catalyst was removed
by filtration through a small plug of silica gel. The solvent was
removed by rotary evaporation to give a clear, colorless oil.
The product was purified by flash chromatography (TLC
conditions) to give 249 mg (87%) of 25d .
Tu r n over Exp er im en t. To a 25-mL, round-bottomed flask
was added a mineral oil slurry of potassium hydride. The flask
was sealed and a nitrogen atmosphere was introduced. The
mineral oil was removed by successive washings with pentane
to give a white powdery solid (32 mg, 0.80 mmol). Anhydrous
THF (3 mL) was added to the solid via syringe. A solution of
hydroxylamine 24c (214 mg, 0.800 mmol) in dry THF (2 mL)
was added to the KH slurry at 0 °C. When gas evolution
ceased, the mixture containing the deprotonated hydroxyl-
amine was added dropwise to a 25-mL round-bottomed flask
containing a solution of nitrone 12f (198 mg, 0.800 mmol) and
2 (228 mg, 237 µL, 1.60 mmol) in THF (5 mL) at -20 °C. The
reaction was stirred at -20 °C for 12 h, and then the reaction
was quenched with water. The biphasic mixture was extracted
with dichloromethane. The combined extracts were dried
P henyl[2-(2-[4-chlorophenyl)-1,1,1-trifluoroethyl)]Amine
1
(25d ): liquid at room temperature; H NMR δ 7.42-7.36 (m,
4H), 7.18-7.14 (m, 2H), 6.81-6.77 (m, 1H), 6.62-6.59 (m, 2H),
4.90 (br s, 1H), 4.31 (br s, 1H); 13C NMR δ 145.1 (s), 135.1 (s),

2582 J . Org. Chem., Vol. 66, No. 8, 2001
Nelson et al.
(MgSO4), filtered, and concentrated by rotary evaporation. The
product mixture was separated by flash chromatography (silica
gel, 5% ethyl acetate in hexanes) to give adduct 13c (32%),
hydroxylamine 24c (26%), and hydroxylamine 24f (4%).
pated in this work: Ankur Patel, Michelle Chaumont,
Maya Campara, Regina Easley (Norfolk State Univer-
sity, sponsored by the NSF REU program), Alexander
Latzigrass, Faye Ahn, and Eric Gage.
Ack n ow led gm en t. Financial support was provided
by Loyola University of Chicago in part in the form of a
Summer Research Stipend (J une-August 1998). Ac-
knowledgment is made to the donors of the Petroleum
Research Fund for support of this research. The Illinois
Minority Graduate Incentive Program provided a fel-
lowship to D.H. The following undergraduates partici-
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of nitrone starting materials, including charac-
terization data; 1H NMR and 13C NMR spectra for selected
compounds; selected chromatograms used for Figure 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000685L