Trifluoromethyl nitrones: From fluoral to optically active hydroxylamines

Article abstract of DOI:10.1039/c001791d

Trifluoromethyl nitrones were obtained in high yields by condensation of various hydroxylamines with trifluoroacetaldehyde hydrate. The nucleophilic diastereoselective additions of organometallic reagents to these nitrones afforded the corresponding optic

Full text of DOI:10.1039/c001791d

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Trifluoromethyl nitrones: from fluoral to optically active hydroxylamines†
Thierry Milcent, Nathan Hinks, Danie`le Bonnet-Delpon and Benoit Crousse*
Received 27th January 2010, Accepted 14th April 2010
First published as an Advance Article on the web 14th May 2010
DOI: 10.1039/c001791d
Trifluoromethyl nitrones were obtained in high yields by condensation of various hydroxylamines with
trifluoroacetaldehyde hydrate. The nucleophilic diastereoselective additions of organometallic reagents
to these nitrones afforded the corresponding optically active trifluoroethyl hydroxylamines in good
yields.
Table 1 Preparation of trifluoromethyl nitronesa
Introduction
Yield
(%)
N-Hydroxylamine derivatives are attractive synthetic targets due
Entry Hydroxylamine 1
Nitrone 2
to their potential applications as therapeutics in iron overload,1
and protease inhibition.2 On the other hand, optically active
trifluoromethyl-substituted nitrogen compounds, such as triflu-
oroethyl amines, are versatile and interesting building blocks
in organic and medicinal chemistry.3 The corresponding triflu-
oroethyl hydroxylamines should also find applications, offering
the specific properties of the trifluoromethyl group: electron
withdrawing character, resulting in decreased pKa of neighbouring
functions and increased hydrogen bonding.4 Surprisingly, only a
few syntheses of trifluoroethyl hydroxylamines have been reported:
(i) trifluoromethylation reactions of nitrones;5 (ii) reduction of
trifluoromethyl oximes;6 (iii) addition of hydroxylamines to tri-
fluorocrotonate derivatives.7 However, none of these reactions
are suitable for affording enantiopure hydroxylamines. Herein we
document our research on the first general method for the synthesis
of optically active trifluoroethyl N-hydroxylamines from fluoral
(Scheme 1).
1
CyclohexylNHOH 1a
2a
2b
80
2
3
BnNHOH 1b
86
89
(R)-PhCH(Me)NHOH 1c
2c
4
(R)-PhCH(CH2OMe)NHOH 1d
2d 93
a Reaction conditions: fluoral (1.1 mmol), hydroxylamine (1 mmol) in
refluxing toluene with Dean–Stark apparatus (entries 1, 2 and 4) or
chloroform in presence of MgSO4 (entry 3).
the synthesis of one N-methyl-trifluoromethyl nitrone. However,
due to its volatility, the N-methyl-trifluoromethyl nitrone was not
isolated, and was hence used in 1,3-dipolar cycloadditions in a
one-pot manner. Therefore, our attention was primarily focused
on the synthesis and isolation of trifluoromethyl nitrones using
commercially available trifluoroacetaldehyde hydrate.
Scheme 1 Synthetic scheme for trifluoroethyl hydroxylamines.
Nitrones 2a,b and 2d were easily prepared by treating the
corresponding hydroxylamines with fluoral hydrate in toluene for
2 h, using Dean–Stark apparatus (Scheme 2, Table 1). Evaporation
of toluene yielded nitrones 2a,b and 2d in high purity. In the case
of the nitrone 2c better results were obtained using MgSO4 in
refluxing chloroform. Finally, the nitrones were recovered in high
yields as stable solids and could be stored in a refrigerator for
several months.
Results and discussion
Our approach is based on the addition of organometallic reagents
to trifluoromethyl nitrones. Although nitrones find large applica-
tions in the field of age-related diseases,8 only two trifluoromethyl
nitrones are reported in the literature: Janzen et al.9 described the
synthesis of a C-trifluoromethyl endocyclic nitrone for the purpose
of spin trapping in free radical biology, and Tanaka et al.10 reported
Laboratoire BioCIS-CNRS, Faculte´ de Pharmacie, Univ. Paris-Sud,
rue J.B. Cle´ment, 92296 Chaˆtenay-Malabry, France. E-mail: benoit.
crousse@u-psud.fr; Fax: +33(0)146835740; Tel: +33(0)146835739
† Electronic supplementary information (ESI) available: Characterization
data (1H, 13C and 19F NMR spectra and elemental analysis) of the products
2–8 and X-ray structure of 2d. CCDC reference number 722468. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c001791d
Scheme 2 Preparation of trifluoromethyl nitrones 2a–d.
Org. Biomol. Chem., 2010, 8, 3025–3030 | 3025
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 2 Preparation of trifluoroethyl N-hydroxylamines
Entry
1
Nitrone 2
R2Met
Hydroxylamines
Product
Yield (%)
94
dr
—
2a
vinylMgBr
3a
2
3
2b
2c
vinylMgBr
vinylMgBr
3b
3c
87
94
—
75 : 25
4
2c
PhMgBr
4c
72
65 : 35
5
6
2c
2d
PhLi
vinylMgBr
4c
3d
63
88
67 : 33
76 : 24
7
8
2d
2d
PhLi
PhMgBr
4d
4d
99
81
85 : 15
78 : 22
9
2d
2d
AllylMgBr
EtMgBr
5d
6d
91
87
75 : 25
70 : 30
10
Homo- and hetero-nOe experiments indicated that nitrone 2b
adopted the Z configuration. X-ray analysis‡ of the nitrone 2d
confirmed this result and hence, all nitrones were assumed to adopt
the same Z configuration.
completion after 30 min. When treated with vinylMgBr, the achiral
nitrones 2a and 2b afforded the corresponding hydroxylamines 3a
and 3b in high yields and high purities (Table 2, entries 1 and 2).
The reaction of chiral nitrones 2c and 2d with vinylMgBr furnished
pairs of diastereoisomeric trifluoroethyl hydroxylamine adducts,
3c and 3d in good yields and modest diastereoselectivities (Table 2,
entries 3 and 5).
The isomeric ratios of the hydroxylamine adducts were de-
termined by 19F NMR spectra analysis of the crude products.
Diastereoselectivities and yields were shown to not fluctuate in
different solvents (THF, toluene or dichloromethane). Surpris-
ingly the change of the chiral auxiliary carried by the nitrogen
atom of the nitrone (2c vs. 2d) did not significantly modify the
Nucleophilic addition to nitrones has been extensively studied;11
however, the addition of organometallics to their trifluoromethyl
analogues has never been described. This reaction was thus in-
vestigated with nitrones 2a–d, using Grignard and organolithium
reagents, as a synthetic route to trifluoroethyl hydroxylamines.
Typically, reactions of nitrones with organometallic reagents were
carried out in diethyl ether at -78 ◦C and had progressed to
‡ See the ORTEP view in supporting information.
3026 | Org. Biomol. Chem., 2010, 8, 3025–3030
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
diastereoselectivity. This can perhaps be explained by the reaction
rate. Indeed, there was no starting material after only 15 min,
indicating that the reaction is very fast. The scope of the reaction
was then extended to various other organometallic reagents. The
addition of phenylMgBr, allylMgBr and ethylMgBr reagents to
the nitrone 2d afforded the corresponding trifluoroethyl hydrox-
ylamines in good yields, with comparable diastereoselectivities
(Table 2, entries 7–9). Nevertheless, the reaction of phenyl lithium
with the same nitrone 2d provided hydroxylamine adducts 4d with
a slightly better diastereoselectivity (dr 85 : 15) (Table 2, entry 7).
In accordance with our previous work on vinylation reactions
of trifluoromethyl aldimines,12 the resulting chiral centre in the
major isomer of 4d was assumed to have (R) configuration. This
view is supported by the findings of Chang et al. on organometallic
additions to chiral nitrones (Fig. 1).11 Nevertheless, the modest
diastereoselectivity observed could be explained by a competition
between the previous model and another involving an metal-
fluorine type interaction, which has already been reported in the
literature.13
and subsequent acid hydrolysis (Scheme 4). The optically active
trifluoroethyl N-hydroxylamine 8 could then be isolated in good
yield (52% over two steps).16
Scheme 4 Removal of the (R)-phenylglycinol methyl ether.
Conclusions
In summary, we report a novel, general and practical method
for the preparation of trifluoromethyl nitrones and their di-
astereoselective conversion into optically active trifluoroethyl N-
hydroxylamines. The trifluoromethyl group may dramatically in-
fluence the physico-chemical properties of such compounds, which
are of increasing importance in medicinal chemistry. Furthermore,
due to their stable nature, the novel trifluoromethyl nitrones may
serve as a versatile platform for further synthetic transformations.
Experimental
Material and methods
Commercial reagents were purchased from ALDRICH or ACROS
and used as received. Trifluoroacetaldehyde-hydrate was gene-
rously offered by Central Glass Company. All organometallic
addition reactions were performed under argon atmosphere with
oven-dried glassware fitted with rubber septa. Ether and THF were
distilled under nitrogen from sodium/benzophenone prior to use.
Flash chromatography was performed on 254F Geduran SiO2 60
(40–63 mm or 63–200 mm.) silica gel. Thin layer chromatography
was performed on precoated aluminium sheets (Merck Silica gel
60G254). NMR spectra were recorded with a Bruker AC 200 or 300
spectrometer (1H: 200 or 300 MHz; 19F: 188 MHz; 13C: 75 MHz).
Chemical shifts (d) are reported in ppm relative to Me4Si and
CFCl3 [for 19F NMR (188 MHz, CDCl3, 25 ◦C)] as internal
standards. For the 13C NMR data, reported signal multiplicities
were measured relative to C–F coupling. Infrared (IR) spectra
were performed on a Bruker Vector 22. Specific rotations were
determined on an automatic polarimeter polAAr32 from Optical
Activity Limited. Melting points were measured on a Stuart
SMP10 apparatus.
Fig. 1 Chelated transition state model.
The major isomer of the 85 : 15 mixture of hydroxylamine 4d was
isolated by column chromatography, as a pure compound.14 Subse-
quently, we then investigated the removal of the (R)-phenylglycinol
chiral auxiliary, with the main challenge being to retain the
hydroxyl group on the nitrogen whilst avoiding racemisation.
The direct deprotection protocol involves an oxidation of 4d to
a nitrone followed by hydrolysis, to obtain the free hydroxylamine.
Unfortunately treatment of 4d with MnO2 in refluxing toluene15
afforded a mixture of inseparable structural isomers of nitrones in
the ratio 60 : 40 as indicated by 19F NMR spectrum (Scheme 3).
General procedure for the synthesis of trifluoromethyl nitrones 2a,b
and 2d
Trifluoroacetaldehyde hydrate (1.1 eq) is added to a solution of the
hydroxylamine in toluene stirring in a hot oil bath. The reaction
mixture is then stirred at reflux with Dean–Stark apparatus. The
reaction is followed by 19F NMR till completion. The solvent is
then removed to afford the nitrone.
Scheme 3 Removal of the (R)-phenylglycinol chiral auxiliary.
N-Cyclohexyl-N-[(Z)-2,2,2-trifluoroethylidene]amine oxide (2a)
This obstacle was circumvented using milder conditions, in-
volving initial demethylation of the enantiopure 4d with BBr3 at
-78 ◦C, followed by oxidative cleavage with Pb(OAc)4 at 0 ◦C
Obtained from N-cyclohexyl hydroxylamine (0.3 g, 2.61 mmol)
following the general procedure for the synthesis of nitrones, as a
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 3025–3030 | 3027
©

View Article Online
pale orange solid (0.51 g, 99%); mp 109–111 ◦C; nmax/cm-1 1586,
1265, 1206, 1142, 943, 735; dH (300 MHz; CDCl3) 1.11–2.13 (10H,
m), 3.81–3.98 (1H, m), 7.10 (1H, q, J = 5.5 Hz); dC (75 MHz;
CDCl3) 24.7, 24.7, 30.9, 76.3, 119.6 (q, J = 270 Hz), 121.7 (q, J =
38 Hz); dF (188 MHz; CDCl3) -66.3 (d, J = 5.5 Hz). Found C,
49.33; H, 6.03; N, 7.27. calc. for C8H12F3NO: C, 49.23; H, 6.20; N,
7.18%.
saturated aqueous NaCl. The organic phase is dried (MgSO4) and
concentrated to yield the hydroxylamine.
N-Cyclohexyl-N-(1-trifluoromethyl-allyl)-hydroxylamine (3a)
According tothe generalprocedure for synthesis of trifluoromethyl
hydroxylamines, reaction of nitrone 2a (0.20 g, 1.03 mmol) with
vinyl magnesium bromide afforded the racemic mixture as a yellow
oil (0.21 g, 94%). nmax/cm-1 3540, 3065, 1586, 1704, 1223, 920; dH
(300 MHz; CDCl3) 0.95–2.17 (10H, m), 2.53–2.20 (1H, m), 3.77
(1H, p, J = 8.2 Hz), 5.10 (1H, s), 5.33 (1H, d, J = 17.5 Hz),
5.45 (1H, d, J = 10.4 Hz), 6.02 (1H, ddd, J = 10.4, J = 8.0 Hz,
J = 17.5 Hz). dC (75 MHz; CDCl3) 23.6, 23.7, 24.9, 27.6, 29.2,
61.2, 65.7 (q, J = 28 Hz), 122.7, 124.1 (q, J = 281 Hz), 126.0. dF
(188 MHz; CDCl3) -71.6 (d, J = 8.0 Hz). Found C, 55.10; H, 7.27;
N, 6.48. calc. for C10H16F3NO: C, 53.80; H, 7.22; N, 6.27%.
N-Benzyl-N-[(Z)-2,2,2-trifluoroethylidene]amine oxide (2b)
Obtained from the N-benzyl-hydroxylamine17 (4.21 g, 34.1 mmol)
following the general procedure for the synthesis of nitrones, as
a white solid after recrystallisation from hexane (5.95 g, 86%);
mp 66–67 ◦C. nmax/cm-1 3082, 1598, 1497, 1456, 951, 877; dH
(300 MHz; CDCl3) 5.05 (2H, s), 6.89 (1H, q, J = 5.5 Hz), 7.32–
7.57 (5H, m); dC (75 MHz; CDCl3) 71.5, 119.5 (q, J = 270 Hz),
123.6 (q, J = 39 Hz), 129.4, 129.8, 129.9, 130.8; dF (188 MHz;
CDCl3) -66.29 (d, J = 5.5 Hz); Found C, 53.10; H, 4.11; N, 6.88;
calc. for C9H8F3NO: C, 53.21; H, 3.97; N, 6.89%.
N-Benzyl-N-(1-trifluoromethyl-allyl)-hydroxylamine (3b)
According tothe generalprocedure for synthesis of trifluoromethyl
hydroxylamines, reaction of nitrone 2b (0.10 g, 0.49 mmol) with
vinyl magnesium bromide afforded the racemic mixture as a pale
yellow oil (0.10 g, 87%). nmax/cm-1 3402, 3083, 3032, 2978, 2924,
1813, 1695, 1235, 1083, 918, 732; dH (300 MHz; CDCl3) 3.52 (1H,
qd, J = 7.8, J = 8.1 Hz), 3.72 (1H, d, J = 12.8 Hz), 3.93 (1H,
d, J = 12.8 Hz), 5.32 (1H, dd, J = 1.3 Hz, J = 17.4 Hz), 5.56
(1H, dd, J = 1.3 Hz, J = 10.4 Hz), 5.65 (1H, sbr), 6.04 (1H, ddd,
J = 8.1 Hz, J = 10.4 Hz, J = 17.4 Hz), 7012–7.40 (5H, m); dC
(75 MHz; CDCl3) 61.5, 69.2 (q, J = 28 Hz), 124.7 (q, J = 281 Hz),
125.3, 126.0, 127.9, 128.6, 129.5, 136.3; dF (188 MHz; CDCl3)
-71.6 (d, J = 7.8 Hz); Found C, 57.54; H, 5.14; N, 5.95. calc. for
C11H12F3NO: C, 57.14; H, 5.23; N, 6.06%.
N-[(S)-1-Phenylethyl]-N-[(Z)-2,2,2-trifluoroethylidene]amine
oxide (2c)
(S)-N-(1-Phenylethyl)-hydroxylamine18 (1.32 g, 9.63 mmol) in
chloroform (60 mL) was treated with trifluoroacetaldehyde hy-
drate (1.1 eq, 10.6 mmol, 1.24 g) in the presence of MgSO4.
The reaction mixture was heated at reflux for 18 h before being
filtered and concentrated to yield a white solid. Purification by
flash chromatography (30% ethyl acetate in ◦cyclohexane) afforded
a white powder (1.85 g, 89%). mp 115–116 C; [a]20 -11 (c = 1,
589
CHCl3); nmax/cm-1 3097, 1589, 1456, 1317, 1247, 1149, 999, 921;
dH (300 MHz; CDCl3) 1.90 (3H, d, J = 6.9 Hz), 5.10 (1H, q, J =
6.9 Hz), 7.04 (1H, q, J = 5.5 Hz), 7.39–7.58 (5H, m); dC (75 MHz;
CDCl3) 18.9, 76.3, 119.3 (q, J = 270 Hz), 122.3 (q, J = 37 Hz),
127.4, 129.1, 129.6, 136.7. dF (188 MHz; CDCl3) -66.28 (d, J =
5.5 Hz). Found C, 55.87; H, 4.69; N, 6.20. calc. for C10H10F3NO:
C, 55.30; H, 4.64; N, 6.45%.
N-[(S)-1-Phenylethyl]-N-(1-trifluoromethyl-allyl)-hydroxylamine
(3c)
According tothe generalprocedure for synthesis of trifluoromethyl
hydroxylamines, reaction of nitrone 2c (0.10 g, 0.46 mmol) with
vinyl magnesium bromide afforded the mixture of diastereoiso-
mers (75 : 25, d.e. 50%) as a pale yellow oil (0.1 g, 94%). nmax/cm-1
3482, 3268, 3042, 1680, 1210, 924, 728; Found C, 59.07; H, 5.39;
N, 5.40. calc. for C12H14F3NO: C, 58.77; H, 5.75; N, 5.71%. Major
diastereoisomer: dH (300 MHz; CDCl3) 1.39 (3H, d, J = 6.4 Hz),
3.40 (1H, q, J = 8.1 Hz), 3.83 (1H, q, J = 6.4 Hz), 5.00 (1H, s,
Hd), 5.05 (1H, dd, J = 17.4 Hz, J = 1.2 Hz), 5.47 (1H, dd, J =
10.3 Hz, J = 1.2 Hz), 5.98–6.14 (1H, m), 7.14–7.40 (5H, m); dC
(75 MHz; CDCl3) 22.0, 64.4, 66.3 (q, J = 28 Hz), 124.9, 125.0
(q, J = 281 Hz), 125.9, 127.5, 129.0, 142.3; dF (188 MHz; CDCl3)
-72.1 (d, J = 8.1 Hz).
N-[(R)-2-Methoxy-1-phenylethyl]-N-[(Z)-2,2,2-
trifluoroethylidene]amine oxide (2d)
Obtained from N-(2-methoxy-1-phenylethyl)-hydroxylamine19
(2.20 g, 13.14 mmol) following the general procedure for the
synthesis of nitrones, as a pale yellow solid (3.24 g, 93%). mp
◦
94.5 C. [a]20
-27 (c = 1, CHCl3); nmax/cm-1 3402, 3103,
589
1596, 1455, 1326, 1256, 1197, 1126, 1030, 972, 885, 772, 747; dH
(300 MHz; CDCl3) 3.48 (3H, s), 3.74 (1H, dd, J = 3.2 Hz, J =
10.4 Hz), 4.37 (1H, t, J = 10.4 Hz), 5.19 (1H, dd, J = 3.2 Hz,
J = 10.4 Hz), 7.19 (1H, q, J = 5.5 Hz), 7.39–7.61 (5H, m); dC
(75 MHz; CDCl3) 59.4, 71.5, 80.1, 119.5 (q, J = 270 Hz), 123.9
(q, J = 38 Hz), 127.9, 129.0, 129.8, 132.9; dF (188 MHz; CDCl3)
-66.3 (d, J = 5.5 Hz). Found C, 54.65; H, 5.00; N, 5.89. calc. for
C11H12F3NO2: C, 53.44; H, 4.89; N, 5.67%.
N-[(S)-1-Phenylethyl]-N-(1-trifluoromethyl-phenyl)-
hydroxylamine (4c)
According tothe generalprocedure for synthesis of trifluoromethyl
hydroxylamines, reaction of nitrone 2c (0.10 g, 0.46 mmol) with
phenyl lithium afforded the mixture of diastereoisomers (67 : 33,
d.e. 34%) as a pale yellow oil (0.85 g, 63%); nmax/cm-1 3502, 3018,
2987, 1483, 1218, 756; Found C, 64.95; H, 5.22; N, 5.03. calc. for
C16H16F3NO: C, 65.08; H, 5.46; N, 4.74%. Major diastereoisomer:
dH (300 MHz; CDCl3) 1.33 (3H, d, J = 6.4 Hz), 3.59 (1H, q,
Synthesis of trifluoromethyl hydroxylamines: general procedure
The organometallic reagent (1.5 eq) is added to a soluti◦on of the
nitrone stirring in anhydrous Et2O under argon at -78 C. After
30 min the reaction mixture is diluted in Et2O and washed with
3028 | Org. Biomol. Chem., 2010, 8, 3025–3030
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
J = 6.4 Hz), 4.04 (1H, q, J = 8.4 Hz), 4.87 (1H, s), 7.13–7.51
(10H, m); dC (75 MHz; CDCl3) 22.1, 64.1, 67.3 (q, J = 28 Hz,
C3), 124.2 (q, J = 281 Hz), 127.8, 127.9, 128.2, 128.5, 128.7, 128.9,
131.3, 142.1; dF (188 MHz; CDCl3) -69.4 (d, J = 8.4 Hz, CF3).
m), 4.00 (1H, dd, J = 8.1 Hz, J = 2.9 Hz), 4.83–4.95 (2H, m),
7.02–7.41 (10H, m); dC (75 MHz; CDCl3) 58.9, 67.1, 68.4 (q, J =
27 Hz), 74.6, 119.9–131.8 (m), 126.5, 127.2, 127.8, 127.9, 128.2,
128.6, 128.9, 131.2, 131.4, 139.5; dF (188 MHz; CDCl3) -68.6 (d,
J = 8.3 Hz).
N-[(R)-2-Methoxy-1-phenylethyl]-N-(1-trifluoromethyl-allyl)-
hydroxylamine (3d)
N-[(R)-2-Methoxy-1-phenylethyl]-N-(1-trifluoromethyl-but-3-
enyl)-hydroxylamine (5d)
According tothegeneralprocedure for synthesis oftrifluoromethyl
hydroxylamines, reaction of nitrone 2d (0.20 g, 0.81 mmol) with
vinyl magnesium bromide afforded the mixture of diastereoiso-
mers (76 : 24, d.e. 52%) as a pale yellow oil (0.19 g, 88%). Purifi-
cation by flash chromatography (5% ethyl acetate in cyclohexane)
yielded the major diastereoisomer and the minor diastereoisomer
According tothe generalprocedure for synthesis of trifluoromethyl
hydroxylamines, reaction of nitrone 2d (0.20 g, 0.81 mmol)
with allyl magnesium bromide afforded the crude mixture of
diastereoisomers as a pale yellow oil. Purification by flash
chromatography (5% ethyl acetate in cyclohexane) yielded the pure
mixture of inseparable diastereoisomers (75 : 25, d.e. 50%) as a pale
yellow oil (0.21 g, 91%). nmax/cm-1 3518, 3436, 1576, 1218, 946,
937, 703. Found C, 58.17; H, 6.21; N, 4.83. calc. for C14H18F3NO2:
C, 58.12; H, 6.27; N, 4.84%.
Major diastereoisomer: dH (300 MHz; CDCl3) 2.37 (1H, m),
2.71 (1H, m), 3.15 (1H, s, J = 8 Hz), 3.22 (3H, s), 3.64 (1H, dd,
J = 9.8 Hz, J = 5.3 Hz), 3.76 (1H, dd, J = 9.8 Hz, J = 5.3 Hz),
4.18 (1H, t, J = 5.3 Hz), 4.98 (2H, m), 5. 51 (1H, s) 5.68 (1H,
m), 7.18–7.35 (5H, m); dC (75 MHz; CDCl3) 27.0, 59.0, 62.5 (q,
J = 26 Hz), 68.7, 75.7, 117.4, 125.8 (q, J = 283 Hz), 128.0, 128.1,
128.2, 134.8, 138.4; dF (188 MHz; CDCl3) -72.04 (d, J = 8.1 Hz).
Minor diastereoisomer: dH (300 MHz; CDCl3) 2.37 (1H, m),
2.58 (1H, m), 3.25 (3H, s), 3.45 (1H, dd, J = 9.8 Hz, J = 5.4 Hz),
3.51 (1H, s, J = 8.5 Hz), 3.64 (1H, m), 4.27 (1H, dd, J = 5.4 Hz),
4.98 (2H, m), 5.05 (2H, m), 5.15 (1H, s), 5.68 (1H, m), 7.18–7.35
(5H, m); dC (75 MHz; CDCl3) 28.8, 58.6, 63.1 (q, J = 28 Hz),
68.8, 75.9, 117.0, 125.8 (q, J = 282 Hz), 127.8, 128.3, 128.7, 134.7,
139.1; dF (188 MHz; CDCl3) -70.0 (d, J = 8.3 Hz).
separately. Major diastereoisomer: pale yellow oil (0.14 g); [a]20
589
+44◦(c = 1, CHCl3); nmax/cm-1 3484, 3118, 3034, 1583, 1207, 1183,
924, 736; Found C, 57.08; H, 5.80; N, 5.04. calc. for C13H16F3NO2:
C, 56.72; H, 5.86; N, 5.09%. dH (300 MHz; CDCl3) 3.23 (3H, s),
3.39 (1H, p, J = 8.4 Hz), 3.69 (1H, dd, J = 9.7 Hz, J = 5.5 Hz),
3.77 (1H, dd, J = 9.7 Hz, J = 4.8 Hz), 3.94 (1H, t, J = 5.1 Hz),
5.04 (1H, dd, J = 17.4 Hz, J = 1.0 Hz), 5.47 (1H, dd, J = 10.4 Hz,
J = 1.4 Hz), 5.68 (1H, s), 6.05 (1H, ddd, J = 17.4 Hz, J = 10.3 Hz,
J = 8.4 Hz), 7.20–7.32 (5H, m); dC (75 MHz; CDCl3) 59.2, 66.7 (q,
J = 29 Hz), 67.4, 75.6, 124.9 (q, J = 281 Hz), 125.1, 125.8, 128.3,
128.7, 128.8, 138.0; dF (188 MHz; CDCl3) -71.8 (d, J = 8.0 Hz,
CF3). Minor diastereoisomer pale yellow oil (0.04 g); Found C,
57.40; H, 5.66; N, 5.17. calc. for C13H16F3NO2: C, 56.72; H, 5.86;
N, 5.09%; [a]20589 -124◦(c = 1, CHCl3) dH (300 MHz; CDCl3) 3.24
(3H, s), 3.37 (1H, dd, J = 11.0 Hz, J = 2.7 Hz), 3.64 (1H, dd, J =
11.0 Hz, J = 8.1 Hz), 4.12 (1H, dd, J = 8.1 Hz, J = 2.6 Hz), 4.30
(1H, p, J = 8.3 Hz), 4.70 (1H, s), 5.42 (1H, dd, J = 17.4 Hz, J =
1.5 Hz), 5.51 (1H, dd, J = 10.4 Hz, J = 1.7 Hz), 6.03 (1H, ddd, J =
17.4 Hz, J = 10.5 Hz, J = 8.6 Hz), 7.17–7.34 (5H, m); dC (75 MHz;
CDCl3) 58.8, 67.1 (q, J = 28 Hz), 68.4, 75.7, 124.7, 125.2 (q, J =
281 Hz), 126.6, 127.8, 127.8, 128.7, 139.7; dF (188 MHz; CDCl3)
-71.8 (d, J = 8.2 Hz).
N-[(R)-2-Methoxy-1-phenylethyl]-N-(1-trifluoromethyl-propyl)-
hydroxylamine (6d)
According tothe generalprocedure for synthesis of trifluoromethyl
hydroxylamines, reaction of nitrone (0.10 g, 0.4 mmol) with ethyl
magnesium bromide afforded the crude mixture of diastereoiso-
mers. Purification by flash chromatography (5% ethyl acetate in
cyclohexane) yielded the pure mixture of diastereoisomers (70 : 30,
d.e. 40%) as a pale yellow oil (0.09 g, 87%). nmax/cm-1 3532, 3321,
3046, 3031, 2927, 1486, 1228, 1018, 976, 782. Found C, 56.03; H,
6.09; N, 4.91. calc. for C13H18F3NO2: C, 56.31; H, 6.54; N, 5.05%.
Major diastereoisomer: dH (300 MHz; CDCl3) 0.89 (3H, t, J =
7.4 Hz), 1.62 (2H, m), 2.90 (1H, m), 3.22 (3H, s), 3.60 (1H, dd,
J = 9.6 Hz, J = 5.1 Hz), 3.76 (1H, dd, J = 9.8 Hz, J = 5.1 Hz),
4.14 (1H, t, J = 5.1 Hz), 5.24 (1H, sbr), 7.20–7.41 (5H, m); dC
(75 MHz; CDCl3) 12.0,16.0, 58.9, 64.1 (q, J = 26 Hz), 68.9, 75.9,
125.9 (q, J = 284 Hz), 128.3, 128.5, 128.8, 138.8; dF (188 MHz;
CDCl3) -71.49 (d, J = 8.2 Hz, CF3).
N-[(R)-2-Methoxy-1-phenylethyl]-N-(2,2,2-trifluoro-1-phenyl-
ethyl)-hydroxylamine (4d)
According tothegeneralprocedure for synthesis oftrifluoromethyl
hydroxylamines, reaction of nitrone 2d (0.50 g, 2.02 mmol) with
phenyl lithium afforded a mixture of diastereoisomers (85 : 15,
d.e. 70%) as a pale yellow oil (0.65 g, 99%). Purification by flash
chromatography (5% ethyl acetate in cyclohexane) yielded the
major and minor isomer separately. Major diastereoisomer as a
pale yellow oil (0.54 g); nmax/cm-1 3487, 3031, 2925, 1530, 1031,
904. Found C, 62.21; H, 5.41; N, 4.32. calc. for C17H18F3NO2: C,
62.76; H, 5.58; N, 4.31%. [a]20589 -63 (c = 1, CHCl3); dH (300 MHz;
CDCl3) 3.18 (3H, s), 3.59 (1H, dd, J = 9.4 Hz, J = 5.2 Hz), 3.69
(1H, t, J = 5.3 Hz), 3.78 (1H, dd, J = 9.4 Hz, J = 5.5 Hz), 4.03
(1H, q, J = 8.2 Hz), 5.51 (1H, s), 7.17–7.40 (10H, m); dC (75 MHz;
CDCl3) 59.1, 67.4, 67.9 (q, J = 28 Hz), 75.1, 125.2 (q, J = 281 Hz),
128.3, 128.4, 128.7, 129.1, 129.2, 130.0, 131.1, 137.4; dF (188 MHz
CDCl3) -68.9 (d, J = 8.2 Hz).
Minor diastereoisomer: dH (300 MHz; CDCl3) 0.91 (3H, t, J =
7.4 Hz), 1.85 (2H, m), 3.15 (1H, m), 3.24 (3H, s), 3.51 (1H, dd, J =
3.6 Hz, J = 10.4 Hz), 3.62 (1H, m), 4.32 (1H, dd, J = 7.4 Hz, J =
3.6 Hz), 5.12 (1H, sbr), 7.20–7.41 (5H, m); dC (75 MHz; CDCl3)
11.2, 18.0, 58.6, 64.1 (q, J = 26 Hz), 68.9, 76.2, 126.2 (q, J =
284 Hz), 128.1, 128.5, 128.7, 139.1; dF (188 MHz; CDCl3) -69.47
(d, J = 8.1 Hz).
Minor diastereoisomer as a pale yellow oil (0.08 g); Found C,
62.02; H, 5.10; N, 4.53. calc. for C17H18F3NO2: C, 62.76; H, 5.58;
N, 4.31%. [a]20 -16 (c = 1, CHCl3); dH (300 MHz; CDCl3) 3.26
589
(3H, s), 3.44 (1H, dd, J = 10.5 Hz, J = 3.0 Hz), 3.31–3.41 (1H,
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 3025–3030 | 3029
©

View Article Online
N-(2,2,2-Trifluoro-1-phenylethyl)-hydroxylamine, HCl (8)
Enantiopure N-[(R)-2-methoxy-1-phenylethyl]-N-(2,2,2-tri-
Res., 1988, 21, 333; M. Whittaker, C. D. Floyd, P. Brown and A. J. H.
Gearing, Chem. Rev., 1999, 99, 2735.
3 M. Zanda, New J. Chem., 2004, 28, 1401; H. J. Bohm, D. Banner,
S. Bendels, M. Kansy, B. Kuhn, K. Muller, U. Obst-Sander and M.
Stahl, ChemBioChem, 2004, 5, 637; J. P. Be´gue´, D. Bonnet-Delpon, B.
Crousse and J. Legros, Chem. Soc. Rev., 2005, 34, 562; N. Zhang, S.
Ayral-Kaloustian, T. Nguyen, R. Hernandez, J. Lucas, C. Discafani
and C. Beyer, Bioorg. Med. Chem., 2009, 17, 111.
4 J. P. Be´gue´ and D. Bonnet-Delpon, J. Fluorine Chem., 2006, 127,
992; J. -P. Be´gue´ and D. Bonnet-Delpon, in Bioorganic and Medicinal
Chemistry of Fluorine, Wiley-VCH Ltd., 2008, pp. 279; C. Isanbor
and D. O’Hagan, J. Fluorine Chem., 2006, 127, 303; F. M. D. Ismail,
J. Fluorine Chem., 2002, 118, 27.
5 D. W. Nelson, R. A. Easley and B. N. V. Pintea, Tetrahedron Lett., 1999,
40, 25; D. W. Nelson, J. Owens and D. Hiraldo, J. Org. Chem., 2001,
66, 2572.
6 S. Watanabe, T. Fujita, M. Sakamoto, H. Hamano, T. Kitazume and T.
Yamazaki, J. Fluorine Chem., 1997, 83, 15; F. A. J. Kerdesky and B. W.
Horrom, Synth. Commun., 1991, 21, 2203.
fluoro-1-phenylethyl)-hydroxylamine, 4d (0.53 g, 1.62 mmol)
in anhydrous CH2Cl2 (7 mL) was treated with BBr3 (2.5 eq,
1 M, 4.05 mL) at -78 ◦C then back to -10 ◦C under argon.
After 30 min the solution was basified with a saturated aqueous
solution of NaHCO3 and the product extracted into CH2Cl2.
The organic phase was washed with a saturated solution of
NaCl, dried (MgSO4) and concentrated to yield a yellow waxy
solid, which was treated with Pb(OAc)4 (1.2 eq, 1.94 mmol,
0.86 g) in a 2 : 1 mixture of MeOH–CH2Cl2 (10 mL) at 0 ◦C.
After 30 min the solution was filtered through Celite and the
filtrate concentrated to yield an orange waxy solid, which was
treated with HCl/H2O (6 N, 10 mL) at ambient temperature.
After 24 h the solution was washed with Et2O and the aqueous
phase basified with a saturated aqueous solution of NaHCO3.
The organic layer was dried (MgSO4) and concentrated to yield
a yellow oil. Purification by flash chromatography on silica gel
(10% ethyl acetate in cyclohexane) afforded the pure product as
7 V. Y. Sosnovskikh, M. A. Barabanov and B. I. Usachev, J. Org. Chem.,
2004, 69, 8297.
8 S. Goldstein and P. Lestage, Curr. Med. Chem., 2000, 7, 1255; R. A.
Floyd, K. Hensley, F. Jaffery, L. Maidt, K. Robinson, Q. Pye and C.
Stewart, Life Sci., 1999, 65, 1893; R. A. Floyd, K. Hensley, M. J. Forster,
J. A. Kelleher-Andersson and P. L. Wood, Mech. Ageing Dev., 2002,
123, 1021; Y. W. Sun, J. Jiang, Z. J. Zhang, P. Yu, L. D. Wang, C. L.
Xu, W. Liu and Y. Q. Wang, Bioorg. Med. Chem., 2008, 16, 8868; R. A.
Floyd, Aging Cell, 2006, 5, 51; K. Hensley, J. M. Carney, C. A. Stewart,
T. Tabatabaie, Q. Pye and R. A. Floyd, in Neuroprotective Agents and
Cerebral Ischaemia, ed. A. R. G. a. A. J. Cross, Academic Press, Volume
40 edn, 1996, pp. 299.
a pale yellow oil (136 mg, 52% over 2 steps). [a]20 -10 (c = 1,
589
CHCl3); dH (300 MHz; CDCl3) 4.42 (1H, q, J = 7.2 Hz), 5.53 (1H,
s), 7.20–7.53 (5H, m); dC (75 MHz; CDCl3) 68.2 (q, J = 28 Hz),
124.4 (q, J = 281 Hz), 128.7, 128.9, 129.6, 131.7; dF (188 MHz
CDCl3) -72.5 (d, J = 7.2 Hz); nmax/cm-1 3486, 3031, 2986, 1213,
1180, 942, 770, 736.
9 E. G. Janzen, Y. K. Zhang and M. Arimura, J. Org. Chem., 1995, 60,
5434.
10 K. Tanaka, O. Honda, K. Minoguchi and K. Mitsuhashi, J. Heterocycl.
Chem., 1987, 24, 1391; K. Tanaka, M. Ohsuga, Y. Sugimoto, Y. Okafuji
and K. Mitsuhashi, J. Fluorine Chem., 1988, 39, 39; K. Tanaka, Y.
Sugimoto, Y. Okafuji, M. Tachikawa and K. Mitsuhashi, J. Heterocycl.
Chem., 1989, 26, 381.
11 R. Bloch, Chem. Rev., 1998, 98, 1407; J. Hamer and A. Macaluso,
Chem. Rev., 1964, 64, 473; M. Lombardo and C. Trombini, Synthesis,
2000, 759; P. Merino, S. Franco, F. L. Merchan and T. Tejero, Synlett,
2000, 442; Z. Y. Chang and R. M. Coates, J. Org. Chem., 1990, 55,
3464; P. Merino, C. R. Chimie, 2005, 8, 775.
Acknowledgements
Nathan Hinks thanks the University of St. Andrews (monitor
Pr. D. O’Hagan) and BioCIS (University Paris South) for financial
support. We thank Central Glass Co. Ltd. for the generous
gift of trifluoroacetaldehyde hydrate, DSM for the kind gift of
phenylglycine and P. Herson (University Paris-6) for X-ray analysis
of 2d.
12 N. T. N. Tam, G. Magueur, M. Ourevitch, B. Crousse, J. P. Begue and
D. Bonnet-Delpon, J. Org. Chem., 2005, 70, 699.
13 G. Sini, A. Tessier, J. Pytkowicz and T. Brigaud, Chem.–Eur. J., 2008,
14, 3363, and references therein.
14 The chromatographic separation of the 2 diastereoisomers was achieved
only with hydroxylamine 3d and 4d. In the case of 5d and 6d, we did
not optimize the separation.
Notes and references
1 Q. X. H. Wang, J. King and O. Phanstiel, J. Org. Chem., 1997, 62, 8104;
Y. Hara and M. Akiyama, J. Am. Chem. Soc., 2001, 123, 7247; M. D.
Surman and M. J. Miller, Org. Lett., 2001, 3, 519; J. A. Ferreras, J. S.
Ryu, F. Di Lello, D. S. Tan and L. E. N. Quadri, Nat. Chem. Biol.,
2005, 1, 29; S. C. Polomoscanik, C. P. Cannon, T. X. Neenan, S. R.
Holmes-Farley, W. H. Mandeville and P. K. Dhal, Biomacromolecules,
2005, 6, 2946; X. Zhang, W. J. Xie, S. Qu, T. H. Pan, X. T. Wang and
W. D. L e , Biochem. Biophys. Res. Commun., 2005, 333, 544.
15 S. Cicchi, M. Marradi, A. Goti and A. Brandi, Tetrahedron Lett., 2001,
42, 6503.
16 The ee (≥98%) of the resulting hydroxylamine 8 could be determined
by 19F NMR in the presence of the chiral shift reagent Eu(hfc)3. See
supporting information. This phenylglycinol removal procedure should
be applicable to the other hydroxylamines.
17 H. Maskill and W. P. Jencks, J. Am. Chem. Soc., 1987, 109, 2062.
18 O. Phanstiel, Q. X. Wang, D. H. Powell, M. P. Ospina and B. A. Leeson,
J. Org. Chem., 1999, 64, 803.
2 M. Marastoni, M. Bazzaro, S. Salvadori, F. Bortolotti and R. Tomatis,
Bioorg. Med. Chem., 2001, 9, 939; D. Leung, G. Abbenante and D. P.
Fairlie, J. Med. Chem., 2000, 43, 305; B. W. Matthews, Acc. Chem.
19 P. M. Wovkulich and M. R. Uskokovic, Tetrahedron, 1985, 41, 3455.
3030 | Org. Biomol. Chem., 2010, 8, 3025–3030
This journal is
The Royal Society of Chemistry 2010
©