A remarkable access to γ-fluoroalkylated propargylamine derivatives or fluoroalkylated dihydroisoxazoles via the reaction of fluoroalkylated acetylides with various nitrones

Article abstract of DOI:10.1055/s-0028-1087988

The reactions of fluoroalkylated acetylides with various nitrones were investigated. When nitrones with an alkyl substituent were employed, hydroxylamines were obtained in high yields, and smooth dehydroxylation followed, to give the corresponding proparg

Full text of DOI:10.1055/s-0028-1087988

PAPER
1087
A Remarkable Access to g-Fluoroalkylated Propargylamine Derivatives or
Fluoroalkylated Dihydroisoxazoles via the Reaction of Fluoroalkylated
Acetylides with Various Nitrones
Access to
F
luor
s
oalkylated
u
P
ropargyla
t
a
o
ndDihydroi
m
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Fax +81(75)7247580; E-mail: konno@chem.kit.ac.jp
Received 4 November 2008; revised 10 December 2008
4 with four equivalents of lithium diisopropylamide in tet-
Abstract: The reactions of fluoroalkylated acetylides with various
rahydrofuran at –78 °C for half an hour, followed by the
nitrones were investigated. When nitrones with an alkyl substituent
addition of one equivalent of nitrone 3a and stirring of the
reaction mixture for two hours, gave the corresponding
were employed, hydroxylamines were obtained in high yields, and
smooth dehydroxylation followed, to give the corresponding prop-
argylamines. Nitrones with an aryl substituent underwent nucleo- hydroxylamine 5a in 31% yield (Table 1, entry 1). As
philic addition and subsequent intramolecular cyclization, affording
shown in entry 2, a longer reaction time led to an increase
the corresponding fluoroalkylated dihydroisoxazoles in moderate
yields. These sequences were also extended to chiral versions.
in the yield from 31% to 58%. The reaction at –20 °C for
two hours proceeded very smoothly to afford 5a in 82%
yield (entry 3), whereas stirring of the reaction mixture for
15 hours did not provide a satisfactory result (entry 4).
Key words: fluorine-containing compounds, propargylamines, ni-
trones, amines, heterocycles
Additionally, higher temperatures caused a significant de-
crease of the yield as shown in entries 5 and 6. Interesting-
ly, a small amount of cyclization product 6a was obtained
in these cases. The use of only one equivalent of 4 provid-
ed 5a in only 38% yield (entry 7).
Propargylamines are considered to be one of the most im-
portant groups of synthetic intermediates in the synthesis
of various organic molecules of pharmaceutical and bio-
logical interest, such as amino acids and amino sugars.1
The introduction of fluorine atom(s) into lead molecules,
on the other hand, has been used quite often as one of the
most efficient tools for modification of the lead molecules
in view of biological activity.2 Therefore, it is not surpris-
ing that fluorine-containing propargylamines 1 have been
paid much attention by many scientists (Scheme 1). De-
spite the potential utility of fluorine-containing propargyl-
amines, their preparation has been studied to only a
limited extent.3 Herein is described a convenient and effi-
cient approach to g-fluoroalkylated propargylamine de-
rivatives 1 via the reaction of fluoroalkylated acetylides 2
with various nitrones 3 (Scheme 1).4 Additionally, we
also describe a one-pot synthesis of dihydroisoxazoles5
through the nucleophilic addition of acetylides to nitrones
and subsequent intramolecular cyclization.
Table 1 Investigation of Reaction Conditions
–
O
Bn
+
N
H
n-Pr
F3C
3a (1.0 equiv)
LDA (2n equiv)
THF, –78 °C
0.5 h
THF, temp, time
Br
4 (n equiv)
F3C
Bn
OH
N
O
+
n-Pr
n-Pr
N
F3C
Bn
6a
5a
Entry
n
Temp
(°C)
Time
(h)
Yielda (%) Yielda (%)
Our initial studies focused on the nucleophilic addition of
trifluoromethylated acetylide, prepared from commercial-
ly available 2-bromo-3,3,3-trifluoropropene (4),6 to ni-
trone 3a7 (Table 1). Thus, treatment of two equivalents of
(equiv)
of 5a
of 6a
1
2
3
4
5
6
7
2.0
2.0
2.0
2.0
2.0
2.0
1.0
–78
–78
–20
–20
0
2
15
2
31
0
0
58
NH2
R1
82 (73)
40
0
–
R2
H
O
+
N
15
2
3
–
RF
+
RF
R1
38
7
1
2
3
r.t.
2
27
18
0
RF = CF3, CHF2, etc.
–20
2
38
Scheme 1 Reaction under investigation
a Determined by 19F NMR spectroscopy. Isolated yields are given in
parentheses.
SYNTHESIS 2009, No. 7, pp 1087–1094
Advanced online publication: 06.03.2009
x
x
.
x
x
.2
0
0
9
DOI: 10.1055/s-0028-1087988; Art ID: F22808SS
© Georg Thieme Verlag Stuttgart · New York

1088
T. Konno et al.
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We next examined the nucleophilic addition to various ni- To expand the synthetic applications of the procedure, we
trones 3 (Table 2). Nitrones with an alkyl substituent, also examined the reactions of nitrones 3 with various
such as n-propyl, isopropyl, and cyclohexyl, gave the cor- fluoroalkylated acetylides, prepared from fluorinated io-
responding adducts 5 in high yields (entries 1–3). Howev- dides 7 and n-butyllithium8 (Table 4). The (trifluorometh-
er, the nitrone carrying a bulky tert-butyl group did not yl)-substituted acetylide (generated from 7, RF = CF3) was
participate in the reaction, giving only a trace of the de- found to be as reactive as the one generated from 2-bro-
sired adduct (entry 4). Additionally, the nitrone derived mo-3,3,3-trifluoropropene and lithium diisopropylamide,
from cinnamaldehyde also led to an unsatisfactory result giving the corresponding hydroxylamine 5a in 91% yield
(entry 5). The use of the nitrone of benzaldehyde resulted (entry 1). Changing the fluoroalkyl group from CF3 to
in the formation of 17% of dihydroisoxazole 6d, together CF2H or (CF2)2CF2H had no significant influence on the
with only 17% of hydroxylamine 5d (entry 6).
reaction, with products 5h and 5i obtained in 86 and 88%
yield, respectively (entries 2 and 3). Reactions with ni-
trones with aryl substituents gave, in addition to hydroxyl-
amine 5, the corresponding dihydroisoxazoles 6 in
moderate yields (entries 4, 7, 8, and 10). Changing the
fluoroalkyl group from CF3 to CF2H or (CF2)2CF2H
caused a significant decrease in yield (entries 4–6). Addi-
tionally, the 4-nitrophenyl-substituted nitrone gave only a
trace of adduct (entry 9).
Table 2 Reaction of Trifluoromethylated Acetylide with Various
Nitrones
–
Bn
O
+
N
H
R
F3C
3 (1.0 equiv)
LDA (4.0 equiv)
THF, –78 °C
0.5 h
THF, –20 °C, 2 h
Br
Next, the reaction was extended to the chiral version, as
shown in Scheme 2. Thus, the reaction with the chiral ni-
trone (S)-3l, derived from (S)-methyl lactate, in tetrahy-
drofuran at –20 °C for two hours gave the corresponding
hydroxylamines 5lR and 5lS as a separable diastereomeric
mixture (74:26) in 82% yield, along with 8% of the cy-
clization product 6l.
4 (2.0 equiv)
F3C
Bn
OH
R
N
+
O
R
N
F3C
Bn
6
5
OBn
H
Entry
R
5
Yielda (%)
82 (73)
86 (85)
96 (95)
trace
6
Yielda (%)
F3C
Br
1
2
3
4
5
6
n-Pr
i-Pr
Cy
5a
5b
5c
–
6a
6b
6c
–
0
N
–
O
+
Bn
3
LDA (2 equiv)
(S)-3l
THF, –20 °C, 2 h
THF, –78 °C
0.5 h
4
t-Bu
trace
trace
17
F3C
OBn
CF3
+
OBn
CF3
(E)-CH=CHPh
–
trace
–
OBn
+
O
Ph
5d
17
6d
N
N
N
a Determined by 19F NMR spectroscopy. Isolated yields are given in
parentheses.
Bn
HO
Bn
HO
Bn
5lR
5lS
82% (74:26)
6l
8%
Scheme 2 Reaction of trifluoromethylated acetylide with the chiral
nitrone derived from (S)-methyl lactate
We next investigated the reaction with nitrones with aryl
substituents (Table 3). A higher reaction temperature
(0 °C instead of –20 °C) led to a significant increase in the
yield of 6d from 17% to 38% (entry 2). When three equiv-
alents of 4 and six equivalents of lithium diisopropyl-
amide were employed, the yield increased to 45%, and
only dihydroisoxazole 6d was obtained, with no hydroxyl-
amine 5d detected at all (entry 3). Conducting the reaction
at room temperature or using longer reaction times did not
influence the yield significantly (entries 4–6). The use of
aryl substituents other than phenyl, namely 4-chlorophe-
nyl, 4-methoxyphenyl, and 1-naphthyl, did not affect the
reaction significantly, with the corresponding products
6e, 6f, and 6g obtained in moderate to good yields (entries
7, 8, and 10). The 4-nitrophenyl-substituted nitrone did
not give significant amounts of adduct 6 (entry 9).
The thus-obtained hydroxylamines 5a, 5c, and 5lR were
easily converted into the corresponding propargylamines
8a, 8c, and 8lR in 59–85% yield in the presence of 1.5
equivalents of phosphorus trichloride in benzene at room
temperature for seven hours (Scheme 3).
The stereochemical assignment of 5lR and 5lS was made
as follows (Scheme 4). Treatment of (2S,RS)-sulfinimine
99 with the (trifluoromethyl)acetylide prepared from 2-
bromo-3,3,3-trifluoropropene and lithium diisopropyl-
amide, in tetrahydrofuran at –78 °C for two hours and
then at –40 °C for five hours, gave the corresponding pro-
pargylamines (1R,2S,RS)-10R and (1S,2S,RS)-10S in a ratio
of 81:19 in 94% combined yield, as described in the liter-
ature.3 The thus-obtained diastereomeric mixture was
Synthesis 2009, No. 7, 1087–1094 © Thieme Stuttgart · New York

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Access to Fluoroalkylated Propargylamines and Dihydroisoxazoles
1089
Table 3 Reaction of Trifluoromethylated Acetylide with Various Nitrones with Aryl Substituents
–
Bn
O
+
N
H
Ar
F3C
Bn
OH
Ar
F3C
N
3 (1.0 equiv)
LDA (2n equiv)
O
+
Ar
THF, –78 °C
0.5 h
THF, –20 °C, 2 h
N
Br
F3C
Bn
6
4 (n equiv)
5
Entry
Ar
n (equiv)
2.0
Temp (°C)
Time (h)
5
Yielda (%)
17
6
Yielda (%)
1
2
Ph
–20
0
2
2
5d
5d
5d
5d
5d
5d
5e
5f
–
6d
6d
6d
6d
6d
6d
6e
6f
17
Ph
2.0
3.0
2.0
2.0
3.0
3.0
3.0
3.0
3.0
trace
trace
trace
0
38
3
Ph
0
2
45 (42)
31
4
Ph
r.t.
r.t.
r.t.
0
2
5
Ph
15
15
2
29
6
Ph
0
46
7
4-ClC6H4
4-MeOC6H4
4-O2NC6H4
1-naphthyl
trace
trace
trace
trace
36
8
0
2
58 (55)
trace
68 (65)
9
0
2
–
10
0
2
5g
6g
a Determined by 19F NMR spectroscopy. Isolated yields are given in parentheses.
then treated with 10% aqueous hydrogen chloride in
methanol at room temperature, followed by column chro-
matography over silica gel; this gave the corresponding
F3C
Br
1. LDA (4.0 equiv)
THF, –78 °C, 0.5 h
(2.0 equiv)
OBn
H
(1R,2S)-propargylamine 11R in 53% yield. Then, mono-
S
2. THF, –78 °C, 2 h, then –40 °C. 5 h
94%
benzylation10 of 11R afforded N-benzylpropargylamine
R
N
t-Bu
S
8lR in 88% yield. It was found from 1H NMR analysis that
O
the N-benzylpropargylamine 8lR obtained from 11R was
completely identical with that derived from the product of
(trifluoromethyl)acetylide and the chiral nitrone (S)-3l
(Schemes 2 and 3), thus indicating that the major isomer
5lR and the minor isomer 5lS have (1R,2S)- and (1S,2S)-
configurations, respectively.
9
OBn
CF3
t-Bu
OBn
CF3
R
R
1. 10% aq HCl, MeOH, r.t.
S
S
2. column chromatography
R
HN
NH2
S
53%
11R
O
Therefore, the proposed mechanism for the reaction with
the chiral nitrones is as follows (Scheme 5). On the basis
of a Felkin–Ahn model,11 intermediate A, in which a ben-
zyloxy group occupies a position perpendicular to the
C=N group, is more stable than intermediate B, because
10R
BnBr (1.1 equiv)
K2CO3 (1.1 equiv)
MeCN, r.t.
+
88%
OBn
CF3
t-Bu
S
OBn
CF3
S
R
R
HN
Bn
OH
Bn
H
S
S
N
N
PCl3 (1.5 equiv)
benzene, r.t., 7 h
O
NHBn
R
R
8lR
10S
10R/10S = 81:19
F3C
5a,5c,5lR
F3C
8
Scheme 4 Determination of stereochemistry
8a R = n-Pr
8c R = Cy
OBn
85%
59%
75%
the low-lying s*C–O orbital is aligned parallel with the p
and p* orbitals of the C=N group, allowing delocalization
of electron density by hyperconjugation from the reaction
center toward the benzyloxy. Then (trifluorometh-
yl)acetylide preferably attacks the re face of intermediate
8lR R =
Scheme 3 Conversion of hydroxylamines 5 into propargylamines 8
Synthesis 2009, No. 7, 1087–1094 © Thieme Stuttgart · New York

1090
T. Konno et al.
PAPER
Table 4 Reactions of Various Fluoroalkylated Acetylides with Various Nitrones
–
O
Bn
H
+
N
R
RF
RF
F
H
I
3 (1.0 equiv)
Bn
OH
R
n-BuLi (4.0 equiv)
N
+
THF, –78 °C
0.5 h
THF, –20 °C, 2 h
O
R
N
RF
Bn
6
7 (2.0 equiv)
5
Entry
RF
R
5
Yielda (%)
91 (90)
86 (83)
88 (76)
30 (29)
30 (28)
14
6
Yielda (%)
trace
14
1
2
CF3
CHF2
n-Pr
5a
5h
5i
6a
6h
6i
n-Pr
3
(CF2)2CF2H
CF3
n-Pr
n.d.b
33 (30)
5
4
Ph
5d
5j
5k
5e
5f
–
6d
6j
6k
6e
6f
–
5
CHF2
(CF2)2CF2H
CF3
Ph
6
Ph
17
7
4-ClC6H4
4-MeOC6H4
4-O2NC6H4
1-naphthyl
26
40
8
CF3
21 (16)
trace
21 (15)
trace
58
9
CF3
10
CF3
5g
8
6g
a Determined by 19F NMR spectroscopy. Isolated yields are given in parentheses.
b n.d. = not determined.
A, giving the corresponding (1R,2S)-adduct as the major converted into the desired propargylamines in high yields
isomer.
in the presence of phosphorus trichloride. Additionally,
this system could be extended to the chiral version, the
chiral propargylamines being obtained in high yields.
Bn
Bn
+
–
–
O
O
+
Me
BnO
N
N
BnO
Me
IR spectra were recorded on a JASCO FT/IR-4100 type A spec-
>
trometer; samples were prepared as films on NaCl plates. 1H and 13
C
H
H
H
H
NMR spectra were recorded on a Bruker DRX-500 NMR spectrom-
eter and a JEOL JNM-AL 400 NMR spectrometer; samples were
prepared as CDCl3 solns with TMS as internal reference. A JEOL
JNM-EX90A (84.21 MHz) FT-NMR spectrometer and a JEOL
JNM-AL 400-NMR spectrometer were used for determining the
yields of the products with the aid of C6F6. 19F NMR (376.05 MHz)
spectra were recorded on a JEOL JNM-AL 400 NMR spectrometer;
samples were prepared as CDCl3 solns with CFCl3 as internal stan-
dard. HRMS was carried out on a Hitachi M-80B mass spectrometer
by EI, CI, and FAB methods. All chemicals were of reagent grade
and, when necessary, were purified in the usual manner prior to use.
TLC was performed on aluminum sheets coated with Merck silica
gel 60 F254 plates, and column chromatography was carried out on
Wakogel C-200.
–
–
A
B
CF3
F3C
OBn
CF3
OBn
CF3
R
S
S
S
N
N
HO
Bn
HO
Bn
major
minor
Scheme 5 Felkin–Ahn model
In summary, we have investigated the reactions of fluoro-
alkylated acetylides with various nitrones in detail. The
reactions with nitrones with alkyl substituents took place
smoothly to give the corresponding hydroxylamines in
good to high yields. In the reactions with the nitrones with
aryl substituents, on the other hand, the nucleophilic addi-
tion was followed by intramolecular cyclization, afford-
ing the corresponding dihydroisoxazoles in moderate
yields. The thus-obtained hydroxylamines were easily
N-Benzyl-N-(4,4,4-trifluoro-1-propylbut-2-ynyl)hydroxyl-
amine (5a); Typical Procedure
A 1.6 M soln of n-BuLi (1.25 mL, 2.0 mmol) was added to a soln of
i-Pr2NH (0.28 mL, 2.0 mmol) in THF (3.0 mL) at –78 °C and the
mixture was stirred for 0.5 h. Then 2-bromo-3,3,3-trifluoropropene
(4; 0.11 mL, 1.0 mmol) was added dropwise, followed by (Z)-N-bu-
tylidenebenzylamine N-oxide (3a; 0.089 g, 0.50 mmol) in THF (1.0
mL). After the reaction mixture had stirred at –20 °C for 2 h, it was
quenched with aq NH4Cl (10 mL) and extracted with EtOAc (3 × 10
Synthesis 2009, No. 7, 1087–1094 © Thieme Stuttgart · New York

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Access to Fluoroalkylated Propargylamines and Dihydroisoxazoles
1091
mL). The organic layers were dried (Na2SO4) and concentrated in
vacuo. The residue was chromatographed (silica gel, hexane–
EtOAc, 3:1); this afforded 5a.
IR (KBr): 3089, 3065, 3033, 2926, 2855, 1685, 1602, 1496, 1455,
1357, 1247, 1183, 1144, 1087, 1029, 734, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.09 (d, J = 12.8 Hz, 1 H), 4.40 (d,
J = 13.2 Hz, 1 H), 5.06 (t, J = 2.4 Hz, 1 H), 7.19–7.39 (m, 10 H).
Yield: 99 mg (73%); yellow solid; mp 62–64 °C.
IR (KBr): 3255, 2972, 2263, 1727, 1458, 1276, 1162, 747, 700, 588,
504, 467 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 2.6 Hz, 3 H), 1.46–
1.53 (m, 2 H), 1.76–1.85 (m, 2 H), 3.65 (m, 1 H), 3.83 (d, J = 4.5
Hz, 1 H), 4.07 (d, J = 4.3 Hz, 1 H), 4.85 (s, 1 H), 7.28–7.36 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.6, 19.3, 34.2, 58.0, 61.1–61.5
(m), 73.8 (q, J = 52.0 Hz), 85.5 (q, J = 6.5 Hz), 114.0 (q, J = 257.1
Hz), 127.9, 128.5, 129.8, 136.2.
19F NMR (376 MHz, CDCl3): d = –50.0 (s, 3 F).
13C NMR (100 MHz, CDCl3): d = 63.3, 72.7, 103.9 (q, J = 2.4 Hz),
118.4 (q, J = 270.3 Hz), 126.9, 127.9, 128.2, 128.5, 128.7, 129.6,
139.6 (d, J = 1.7 Hz), 143.7.
19F NMR (376 MHz, CDCl3): d = –58.7 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C17H14F3NO: 305.1027;
found: 305.1010.
2-Benzyl-3-(4-methoxyphenyl)-5-(trifluoromethyl)-2,3-dihy-
droisoxazole (6f)
Dark brown solid; mp 39–42 °C.
HRMS–FAB: m/z [M + H]+ calcd for C14H18F3NO: 272.1262;
found: 272.1280.
IR (KBr): 2932, 1726, 1685, 1612, 1513, 1456, 1354, 1252, 1177,
1144, 1079, 1034, 834, 739, 698 cm–1.
N-Benzyl-N-(4,4,4-trifluoro-1-isopropylbut-2-ynyl)hydroxyl-
amine (5b)
Yellow solid; mp 71–73 °C.
1H NMR (400 MHz, CDCl3): d = 3.79 (s, 3 H), 4.07 (d, J = 13.2 Hz,
1 H), 4.37 (d, J = 13.2 Hz, 1 H), 5.01 (s, 1 H), 5.52–5.54 (m, 1 H),
6.85 (d, J = 8.8 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H), 7.30–7.37 (m, 5
H).
13C NMR (100 MHz, CDCl3): d = 55.2, 63.1, 72.3, 104.1 (q, J = 2.5
Hz), 114.1, 118.5 (q, J = 270.2 Hz), 127.9, 128.2, 128.4, 129.5,
131.6, 135.2, 143.4 (q, J = 39.7 Hz), 159.5.
IR (KBr): 3267, 2973, 2909, 2251, 1456, 1282, 1136, 1068, 1024,
916, 829, 746, 692, 550, 506 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.07 (t, J = 6.8 Hz, 6 H), 2.04–
2.17 (m, 1 H), 3.24–3.26 (m, 1 H), 3.82 (d, J = 13.2 Hz, 1 H), 4.11
(d, J = 13.2 Hz, 1 H), 4.65 (s, 1 H), 7.27–7.38 (m, 5 H).
19F NMR (376 MHz, CDCl3): d = –67.6 (s, 3 F).
13C NMR (100 MHz, CDCl3): d = 19.7 (d, J = 4.1 Hz), 30.4, 61.8,
65.0, 74.4 (q, J = 52.0 Hz), 85.1 (q, J = 256.2 Hz), 127.7, 128.47,
129.4, 136.8.
HRMS–FAB: m/z [M + H]+ calcd for C18H17F3NO2: 336.1211;
found: 336.1211.
2-Benzyl-3-(1-naphthyl)-5-(trifluoromethyl)-2,3-dihydroisox-
azole (6g)
Yellow oil.
19F NMR (376 MHz, CDCl3): d = –50.0 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C14H18F3NO: 272.1262;
found: 272.1271.
IR (neat): 3040, 2960, 2858, 2371, 1736, 1683, 1597, 1510, 1455,
1356, 1248, 1173, 1135, 1081, 1044, 934, 786, 740, 698, 518, 448
cm–1.
1H NMR (400 MHz, CDCl3): d = 4.20 (d, J = 13.2 Hz, 1 H), 4.45
(d, J = 12.4 Hz, 1 H), 5.76 (s, 1 H), 7.28–7.89 (m, 12 H).
13C NMR (100 MHz, CDCl3): d = 63.2–63.3 (m), 69.5, 104.2–104.3
(m), 118.5 (q, J = 267.9 Hz), 122.2, 124.8, 125.7, 125.8, 126.4,
127.9, 128.5, 128.6, 129.0, 129.5, 130.1, 133.8, 134.7–134.8 (m),
135.4.
N-Benzyl-N-(1-cyclohexyl-4,4,4-trifluorobut-2-ynyl)hydroxyl-
amine (5c)
Yellow solid; mp 124–127 °C.
IR (KBr): 3449, 2940, 2855, 2251, 1638, 1450, 1282, 1135, 934,
826, 749, 692, 602, 505 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.93–1.04 (m, 2 H), 1.14–1.31 (m,
3 H), 1.67–1.82 (m, 4 H), 2.03 (dd, J = 12.8, 38.8 Hz, 2 H), 3.32–
3.35 (m, 1 H), 3.82 (d, J = 12.8 Hz, 1 H), 4.10 (d, J = 13.2 Hz, 1 H),
4.63 (s, 1 H), 7.34–7.37 (m, 5 H).
19F NMR (376 MHz, CDCl3): d = –67.6 (s, 3 F).
13C NMR (100 MHz, CDCl3) d = 25.6, 25.8, 26.3, 30.1, 30.3, 39.3,
61.5, 63.9, 114.1 (q, J = 256.2 Hz), 74.6 (q, J = 52.0 Hz), 85.0 (q,
J = 6.6 Hz), 127.7, 128.4, 129.4, 136.8.
HRMS–FAB: m/z [M]+ calcd for C21H16F3NO: 355.1184; found:
355.1176.
N-Benzyl-N-(4,4,4-trifluoro-1-phenylbut-2-ynyl)hydroxyl-
amine (5d) and 2-Benzyl-3-phenyl-5-(trifluoromethyl)-2,3-di-
hydroisoxazole (6d) (Table 4, entry 4); Typical Procedure
A 1.6 M soln of n-BuLi in hexane (1.25 mL, 2.0 mmol) was added
dropwise to a soln of 2,3,3,3-tetrafluoro-1-iodoprop-1-ene (0.24 g,
1.0 mmol) in THF (2 mL) at –78 °C. The reaction mixture was
stirred at that temperature for 0.5 h, before the addition of (Z)-N-
benzylidenebenzylamine N-oxide (0.114 g, 0.50 mmol) in THF (2.0
mL). After the reaction mixture had stirred for 2 h at –20 °C, it was
quenched with aq NH4Cl (10 mL) and extracted with EtOAc (3 × 10
mL). The organic layers were dried (Na2SO4) and concentrated in
vacuo. Chromatography (silica gel, hexane–EtOAc, 5:1) of the res-
idue afforded 5d and 6d.
19F NMR (376 MHz, CDCl3): d = –49.8 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C17H21F3NO: 312.1575;
found: 312.1583.
2-Benzyl-3-phenyl-5-(trifluoromethyl)-2,3-dihydroisoxazole
(6d); Typical Procedure
A 1.6 M soln of n-BuLi (1.88 mL, 3.0 mmol) was added to a soln of
i-Pr2NH (0.42 mL, 3.0 mmol) in THF (4.5 mL) at –78 °C, and the
mixture was stirred for 0.5 h. 2-Bromo-3,3,3-trifluoropropene (4;
0.17 mL, 1.5 mmol) was added dropwise, followed by (Z)-N-ben-
zylidenebenzylamine N-oxide (0.114 g, 0.50 mmol) in THF (1.0
mL). After the reaction mixture had stirred for 2 h at 0 °C, it was
quenched with aq NH4Cl (10 mL) and extracted with EtOAc (3 × 10
mL). The organic layers were dried (Na2SO4) and concentrated in
vacuo. Chromatography (silica gel, hexane–EtOAc, 5:1) of the res-
idue afforded 6d.
Yield (5d): 0.044 g (29%); yield (6d): 0.046 g (30%).
N-Benzyl-N-(4,4-difluoro-1-propylbut-2-ynyl)hydroxylamine
(5h)
Yellow oil.
Yield: 0.064 g (42%); yellow solid; mp 37–39 °C.
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N-Benzyl-N-(4,4,5,5,6,6-hexafluoro-1-phenylhex-2-ynyl)hy-
IR (neat): 3231, 2959, 2932, 2873, 2371, 2244, 1720, 1459, 1375,
1262, 1157, 1138, 1037, 861, 801, 737, 699, 499, 460 cm–1.
droxylamine (5k)
Dark brown solid; mp 100–103 °C.
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H), 1.43–
1.53 (m, 2 H), 1.71–1.87 (m, 2 H), 3.65 (br s, 1 H), 3.84 (d, J = 13.2
Hz, 1 H), 4.08 (d, J = 12.4 Hz, 1 H), 4.72–4.78 (m, 1 H), 6.30 (t,
J = 55.2 Hz, 1 H), 7.27–7.38 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.6, 19.4, 34.5 (t, J = 1.6 Hz),
58.1–58.3 (m), 61.2–61.4 (m), 77.9 (t, J = 33.9 Hz), 86.7 (t, J = 7.4
Hz), 127.7, 128.5, 129.7, 136.5.
IR (KBr): 3240, 2927, 2371, 2258, 1720, 1497, 1455, 1262, 1224,
1089, 1026, 818, 697, 539, 494 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.92 (d, J = 13.2 Hz, 1 H), 4.03 (d,
J = 13.2 Hz, 1 H), 4.89 (s, 1 H), 4.91 (s, 1 H), 6.16 (tt, J = 5.2, 52.0
Hz, 1 H), 7.27–7.52 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 60.5–60.9 (m), 62.1, 74.8 (t,
J = 36.3 Hz), 89.6 (t, J = 6.6 Hz), 104.7–110.7 (m, 3 C), 127.8,
128.5, 128.69, 128.74, 129.4, 130.9, 135.0, 136.4.
19F NMR (376 MHz, CDCl3): d = –105.3 (dd, J = 1.3, 12.1 Hz).
HRMS–FAB: m/z [M + H]+ calcd for C14H18F2NO: 254.1356;
found: 254.1351.
19F NMR (376 MHz, CDCl3): d = –137.1 (d quin, J = 7.5, 53.4 Hz,
2 F), –131.1 (m, 2 F), –99.9 (m, 2 F).
N-Benzyl-N-(4,4,5,5,6,6-hexafluoro-1-propylhex-2-ynyl)hy-
droxylamine (5i)
Brown solid; mp 43–45 °C.
HRMS–FAB: m/z [M + H]+ calcd for C19H16F6NO: 388.1136;
found: 388.1154.
IR (KBr): 3272, 3033, 2965, 2936, 2876, 2253, 1497, 1456, 1402,
1358, 1274, 1223, 1162, 1135, 998, 806, 745, 699 cm–1.
2-Benzyl-5-(1,1,2,2,3,3-hexafluoropropyl)-3-phenyl-2,3-dihy-
droisoxazole (6k)
Brown oil.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.6 Hz, 3 H), 1.45–
1.54 (m, 2 H), 1.73–1.89 (m, 2 H), 3.67 (m, 1 H), 3.83 (d, J = 13.2
Hz, 1 H), 4.07 (d, J = 13.2 Hz, 1 H), 4.78 (d, J = 6.0 Hz, 1 H), 6.14
(tt, J = 5.2, 52.0 Hz, 1 H), 7.28–7.35 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.5, 19.3, 34.2, 58.2, 61.2–61.7
(m), 73.2 (t, J = 36.3 Hz), 91.6 (t, J = 6.6 Hz), 105.1–110.8 (m, 3
H), 127.9, 128.5, 129.7, 136.3.
IR (neat): 3065, 3033, 2927, 2856, 1725, 1676, 1676, 1496, 1455,
1403, 1277, 1219, 1150, 1029, 980, 863, 802, 735, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.09 (d, J = 12.8 Hz, 1 H), 4.40 (d,
J = 13.2 Hz, 1 H), 5.07 (m, 1 H), 5.63–5.64 (m, 1 H), 6.02 (tt,
J = 5.2, 52.0 Hz, 1 H), 7.17–7.38 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 63.3, 72.8, 105.8 (t, J = 16.4 Hz),
107.4–110.8 (m, 3 C), 127.0, 128.0, 128.2, 128.5, 128.8, 129.5,
135.0, 139.6, 143.5.
19F NMR (376 MHz, CDCl3): d = –137.2 (d quin, J = 7.1, 51.5 Hz,
2 F), –131.5 (t, J = 4.9 Hz, 2 F), –99.7 (sext, J = 4.9 Hz, 2 F).
HRMS–FAB: m/z [M + H]+ calcd for C16H18F6NO: 354.1293;
found: 354.1301.
19F NMR (376 MHz, CDCl3): d = –137.5 to –137.2 (m, 2 F), –131.4
to –130.8 (m, 2 F), –116.2 to –112.4 (m, 2 F).
HRMS–FAB: m/z [M + H]+ calcd for C19H16F6NO: 388.1136;
found: 388.1143.
N-Benzyl-N-(4,4,4-trifluoro-1-phenylbut-2-ynyl)hydroxyl-
amine (5d)
Dark brown solid; mp 88–91 °C.
N-Benzyl-N-[1-(4-chlorophenyl)-4,4,4-trifluorobut-2-ynyl]hy-
droxylamine (5e)
Compounds 5e and 6e could not be purified by column chromatog-
raphy (silica gel). A small amount of a mixture of 5e and 6e was ob-
tained, and this was used to identify the two compounds.
1H NMR (400 MHz, CDCl3): d = 4.08 (d, J = 13.2 Hz, 1 H), 4.42 (d,
J = 12.4 Hz, 1 H), 4.87–4.91 (m, 1 H), 5.53 (q, J = 1.2 Hz, 1 H),
7.10–7.15 (m, 2 H), 7.26–7.36 (m, 7 H).
19F NMR (376 MHz, CDCl3): d = –64.87 (s, 3 F).
IR (KBr): 3423, 2926, 2370, 2251, 1638, 1498, 1457, 1268, 1135,
819, 755, 699, 555, 499 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.93 (d, J = 12.8 Hz, 1 H), 4.05 (d,
J = 12.8 Hz, 1 H), 4.76 (s, 1 H), 4.90–4.93 (m, 1 H), 7.27–7.53 (m,
10 H).
13C NMR (100 MHz, CDCl3): d = 60.3–60.7 (m), 61.8–61.9 (m),
75.3 (q, J = 52.1 Hz), 83.8 (q, J = 6.6 Hz), 114.1 (q, J = 257.0 Hz),
127.9, 128.55, 128.69, 128.70, 128.78, 129.5, 134.9, 136.3.
19F NMR (376 MHz, CDCl3): d = –50.2 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C17H14F3NO: 305.1027;
2-Benzyl-3-(4-chlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-
isoxazole (6e)
1H NMR (400 MHz, CDCl3): d = 4.07 (d, J = 13.2 Hz, 1 H), 4.41 (d,
J = 12.4 Hz, 1 H), 5.02 (m, 1 H), 5.53 (q, J = 1.2 Hz, 1 H), 7.10–
7.15 (m, 2 H), 7.26–7.36 (m, 7 H).
found: 305.1030.
N-Benzyl-N-(4,4-difluoro-1-phenylbut-2-ynyl)hydroxylamine
(5j)
Yellow solid; mp 101–104 °C.
19F NMR (376 MHz, CDCl3): d = –67.63 (s, 3 F).
IR (KBr): 3231, 2918, 2370, 2251, 1726, 1453, 1373, 1265, 1147,
1044, 758, 739, 701, 523, 473 cm–1.
N-Benzyl-N-[4,4,4-trifluoro-1-(4-methoxyphenyl)but-2-
ynyl]hydroxylamine (5f)
1H NMR (400 MHz, CDCl3): d = 3.93 (d, J = 13.2 Hz, 1 H), 4.05 (d,
J = 13.2 Hz, 1 H), 4.78 (s, 1 H), 4.91 (br s, 1 H), 6.39 (t, J = 54.8
Hz, 1 H), 7.28–7.56 (m, 10 H).
Yellow oil.
IR (neat): 2500, 2962, 2370, 2245, 1736, 1610, 1516, 1459, 1264,
1139, 1035, 797, 701, 460 cm–1.
13C NMR (100 MHz, CDCl3): d = 60.1–60.5 (m), 61.9–62.0 (m),
79.5 (t, J = 33.8 Hz), 84.9 (t, J = 6.6 Hz), 103.6 (t, J = 232.2 Hz),
127.0, 127.8, 128.5, 128.6, 128.8, 129.6, 135.5–135.6 (m), 136.5.
19F NMR (376 MHz, CDCl3): d = –105.7 (dd, J = 4.9, 52.6 Hz).
HRMS–FAB: m/z [M + H]+ calcd for C17H16F2NO: 288.1200;
found: 288.1192.
1H NMR (400 MHz, CDCl3): d = 3.82 (s, 3 H), 3.88 (d, J = 12.4 Hz,
1 H), 3.98 (d, J = 12.4 Hz, 1 H), 4.83 (s, 1 H), 4.90 (s, 1 H), 6.91 (s,
1 H), 6.93 (s, 1 H), 7.28–7.43 (m, 7 H).
13C NMR (100 MHz, CDCl3): d = 55.3, 59.8–60.4 (m), 61.3–61.4
(m), 75.0 (q, J = 52.0 Hz), 84.2 (q, J = 6.6 Hz), 114.0, 114.1 (q,
J = 257.0 Hz), 126.8–126.9 (m), 127.8, 128.5, 129.6, 130.0, 136.4,
159.9.
Synthesis 2009, No. 7, 1087–1094 © Thieme Stuttgart · New York

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Access to Fluoroalkylated Propargylamines and Dihydroisoxazoles
1093
19F NMR (376 MHz, CDCl3): d = –50.2 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C18H17F3NO2: 336.1211;
HRMS–FAB: m/z [M + H]+ calcd for C14H17F3N: 256.1313; found:
256.1305.
found: 336.1211.
N-Benzyl-N-(1-cyclohexyl-4,4,4-trifluorobut-2-ynyl)amine (8c)
Yellow oil.
(1R,2S)-N-Benzyl-N-[2-(benzyloxy)-1-(3,3,3-trifluoroprop-1-
ynyl)propyl]hydroxylamine (5lR)
Low-polarity, major isomer; yellow solid; mp 49–50 °C; [a]D
+19.3 (c 0.98, CHCl3).
IR (neat): 3335, 3065, 3031, 2929, 2855, 2264, 1728, 1604, 1496,
1452, 1274, 1212, 1140, 1074, 1029, 894, 804, 735, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88–1.88 (m, 12 H), 3.26 (sext,
J = 2.8 Hz, 1 H), 3.78 (d, J = 13.2 Hz, 1 H), 4.02 (d, J = 13.2 Hz, 1
H), 7.25–7.35 (m, 5 H).
26
IR (KBr): 3389, 3033, 2981, 2934, 2251, 1604, 1496, 1455, 1378,
1278, 1214, 1143, 1028, 910, 818, 739, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 6.4 Hz, 3 H), 3.69
(sext, J = 3.2 Hz, 1 H), 3.84 (d, J = 12.8 Hz, 1 H), 3.90 (quin, J = 6.4
Hz, 1 H), 4.14 (d, J = 12.8 Hz, 1 H), 4.59 (d, J = 12.4 Hz, 1 H), 4.68
(d, J = 12.0 Hz, 1 H), 4.69 (s, 1 H), 7.28–7.38 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 25.83, 25.94, 26.21, 28.70, 29.77,
41.88, 51.48, 54.32–54.34 (m), 72.10 (q, J = 51.3 Hz), 88.95 (q,
J = 5.8 Hz), 114.21 (q, J = 257.0 Hz), 127.24, 128.28, 128.44,
139.24.
13C NMR (100 MHz, CDCl3): d = 17.4, 62.1 (d, J = 10.7 Hz), 63.1
(d, J = 1.7 Hz), 71.3, 74.1, 74.8 (q, J = 52.1 Hz), 83.5 (q, J = 6.6
Hz), 113.9 (q, J = 257.0 Hz), 127.7, 127.85, 127.89, 128.4, 128.5,
129.4, 136.5, 138.0.
19F NMR (376 MHz, CDCl3): d = –49.8 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C17H21F3N: 296.1616; found:
296.1625.
19F NMR (376 MHz, CDCl3): d = –50.2 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C20H21F3NO2: 364.1524;
(1R,2S)-N-Benzyl-N-[2-(benzyloxy)-1-(3,3,3-trifluoroprop-1-
ynyl)propyl]amine (8lR)
Yellow oil; [a]D28 +48.1 (c 0.62, CHCl3).
found: 364.1516.
IR (neat): 3335, 3065, 3032, 2977, 2932, 2872, 2269, 1952, 1726,
1604, 1496, 1454, 1376, 1276, 1212, 1139, 1028, 911, 804, 738,
698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.32 (d, J = 6.0 Hz, 3 H), 1.89 (br
s, 1 H), 3.49–3.51 (m, 1 H), 3.71–3.80 (m, 1 H), 4.03 (d, J = 13.2
Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.64 (d, J = 11.6 Hz, 1 H),
7.27–7.34 (m, 10 H).
(1R,2R)-N-Benzyl-N-[2-(benzyloxy)-1-(3,3,3-trifluoroprop-1-
ynyl)propyl]hydroxylamine (5lS)
High-polarity, minor isomer; yellow solid; mp 58–61 °C; [a]D
–22.0 (c 1.17, CHCl3).
27
IR (KBr): 3408, 3033, 2931, 2254, 1604, 1496, 1455, 1376, 1278,
1141, 910, 741, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.32 (d, J = 6.0 Hz, 3 H), 3.56 (m,
1 H), 3.86–3.94 (m, 2 H), 4.15 (d, J = 12.8 Hz, 1 H), 4.58 (d,
J = 11.2 Hz, 1 H), 4.67 (d, J = 11.2 Hz, 1 H), 4.97 (m, 1 H), 7.30–
7.39 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 16.3, 51.2, 53.9 (d, J = 1.7 Hz),
71.3, 72.0 (q, J = 52.1 Hz), 75.7 (d, J = 1.6 Hz), 87.7 (q, J = 6.5 Hz),
114.1 (q, J = 257.0 Hz), 127.2, 127.7, 127.8, 128.2, 128.39, 128.43,
137.9, 139.1.
13C NMR (100 MHz, CDCl3): d = 17.4, 62.4, 63.1, 71.7 (q, J = 45.9
Hz), 71.9, 73.4, 73.9, 74.1, 74.4, 75.4, 84.2 (q, J = 6.6 Hz), 114.0 (q,
J = 257.0 Hz), 127.9 (d, J = 5.8 Hz), 128.5 (d, J = 12.3 Hz), 129.3,
136.1, 137.7.
19F NMR (376 MHz, CDCl3): d = –50.2 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C20H21F3NO: 348.1575;
found: 348.1584
19F NMR (376 MHz, CDCl3): d = –50.0 (s, 3 F).
HRMS–FAB: m/z [M + H]+ calcd for C20H21F3NO2: 364.1524;
Stereochemical Determination
A 1.6 M soln of n-BuLi in hexane (1.88 mL, 3.00 mmol) was added
to a soln of i-Pr2NH (0.42 mL, 3.00 mmol) in THF (6 mL) at –78 °C.
After the mixture had stirred for 0.5 h, (2S,RS)-sulfinimine 9 (0.13
g, 0.50 mmol) was added and the mixture was stirred at –78 °C for
2 h and at –40 °C for 5 h. The reaction was quenched with sat. aq
NH4Cl (10 mL), and the mixture was extracted with EtOAc (3 × 10
mL). The combined organic fraction was dried (Na2SO4), filtered,
and concentrated in vacuo. Purification of the residue by column
chromatography (silica gel) gave the corresponding adducts as a
diastereomeric mixture (81:19); yield: 0.18 g (97%).
found: 364.1528.
N-Benzyl-N-(4,4,4-trifluoro-1-propylbut-2-ynyl)amine (8a);
Typical Procedure
Hydroxylamine 5a (0.041 g, 0.15 mmol) was dissolved in benzene
(0.75 mL). To this soln was added PCl3 (0.020 mL, 0.23 mmol) at
r.t., and the mixture was stirred for 6 h. The reaction was quenched
with sat. aq NaHCO3 (10 mL), and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic fraction was washed
with brine (10 mL), dried (Na2SO4), and concentrated in vacuo.
Chromatography (silica gel, hexane–EtOAc, 5:1) of the residue af-
forded 8a.
The thus-obtained diastereomeric mixture was dissolved in a mix-
ture of 10% HCl (3.5 mL) and MeOH (2.5 mL). The soln was stirred
at r.t. for several hours and was then poured into sat. aq NaHCO3 (10
mL). The resulting mixture was extracted with EtOAc (3 × 10 mL).
The combined organic fraction was dried (Na2SO4), filtered, and
concentrated. Column chromatography (silica gel) of the residue af-
forded pure 11R; yield: 0.066 g (53%).
Yield: 0.033 g (85%); yellow oil.
IR (neat): 3319, 3065, 3031, 2962, 2875, 2262, 1728, 1604, 1496,
1456, 1276, 1141, 1029, 869, 803, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.93 (t, J = 7.2 Hz, 3 H), 1.44–
1.54 (m, 3 H), 1.64–1.73 (m, 2 H), 3.45–3.49 (m, 1 H), 3.80 (d,
J = 12.8 Hz, 1 H), 4.01 (d, J = 12.8 Hz, 1 H), 7.28–7.35 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.65, 19.02, 36.94, 48.61–48.62
(m), 51.27, 89.46 (q, J = 6.6 Hz), 114.18 (q, J = 256.2 Hz), 127.31,
128.31, 128.50, 139.01.
Propargylamine 11R was dissolved in MeCN (2 mL). BnBr (0.050
g, 0.29 mmol) and K2CO3 (0.040 g, 0.29 mmol) were added, in this
order, to the soln. Then the mixture was stirred at r.t. for several
hours, after which it was poured into sat. aq NH4Cl (10 mL), and
subsequently extracted with EtOAc (3 × 10 mL). The combined or-
ganic fraction was dried (Na2SO4), filtered, and concentrated in vac-
uo. Purification of the residue by column chromatography (silica
gel) gave N-benzylpropargylamine 8lR; yield: 0.078 g (88%); phys-
ical data as described above.
19F NMR (376 MHz, CDCl3): d = –50.0 (s, 3 F).
Synthesis 2009, No. 7, 1087–1094 © Thieme Stuttgart · New York

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T. Konno et al.
PAPER
Carreira, E. M. Angew. Chem. Int. Ed. 2002, 41, 3054.
References
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Synthesis 2009, No. 7, 1087–1094 © Thieme Stuttgart · New York