Facile preparation of polyfluoroalkylated aldimines from polyfluoroalkanoic acids

Article abstract of DOI:10.1055/s-2007-966055

Polyfluoroalkylated aldimines were prepared by reducing polyfluoroalkyl imidoyl chlorides, which are readily available from polyfluoroalkanoic acids, with LTBA (lithium tri-tert-butoxyaluminum hydride). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966055

1624
PAPER
Facile Preparation of Polyfluoroalkylated Aldimines from Polyfluoroalkanoic
Acids
P
reparatio
u
n of
P
olyfluo
n
roalkylated Aldim
T
ines akagi, Ryozo Takihana, Akiko Kuwano, Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, 3-1-1 Tsushimanaka, Okayama 700-8530, Japan
Fax +81(86)2518075; E-mail: uneyamak@cc.okayama-u.ac.jp
Received 15 March 2007; revised 2 April 2007
This work is dedicated to the late Professor Yoshihiko Ito.
however, the yields were unsatisfactory. Hydride reduc-
Abstract: Polyfluoroalkylated aldimines were prepared by reduc-
tion with LTBA6a and NaBH46b looks more promising. On
this basis, we have examined the feasibility for selective
ing polyfluoroalkyl imidoyl chlorides, which are readily available
from polyfluoroalkanoic acids, with LTBA (lithium tri-tert-butoxy-
preparation of polyfluoroalkylated aldimines from poly-
fluoroalkylated imidoyl chlorides using hydride-type re-
ducing agents.
aluminum hydride).
Key words: fluorine, aldimine, imidoyl chloride, reduction, hy-
dride
Ar
Cl
Ar
H
O
N
N
The fluorinated aldimines are useful building blocks for
fluorinated biologically active compounds such as fluori-
nated b-lactams, taxols, and aziridines.1 The polyfluoro-
alkylated aldimines can be prepared in principle by
condensation of the corresponding fluorinated aldehydes
or their hemiacetals with amines. However, the availabil-
ity of the fluorinated aldehydes or their hemiacetals and
hydrates is very poor. So far as fluoroalkyl group (Rf) is
CF3 or CF3CF2, the RfCHO or RfCH(OH)OEt (hemiace-
tals) are commercially available and they can be used for
obtaining corresponding polyfluoroalkylated aldimines in
high yields.2 However, the longer-polyfluoroalkylated al-
dehydes or their hemiacetals were only prepared in poor
yields by the reduction of the corresponding polyfluoroal-
kanoic acids and esters.3 No report on the preparation of
the longer-polyfluoroalkylated aldimines has appeared in
the literature. Therefore, facile preparation of the aldi-
mines 3 from the readily available starting materials is
highly desirable.
Rf
OH
Rf
Rf
1
2
3
Rf = polyfluoroalkyl
Scheme 1
At first, reducing agents, solvents, and reaction conditions
were surveyed to optimize the yields for the reduction of
trifluoroacetimidoyl chloride 2a as a model substrate
(Table 1). The use of NaBH4 (0.35 equiv) afforded amine
4 formed by further reduction of the initial product 3a and
no desired product 3a could be isolated (entry 1). The use
of the stronger reducing agent, such as LiAlH4 (0.35
equiv) led to higher conversion, but resulted in the forma-
tion of the larger amount of amine 4 (entry 2). The use of
aluminum hydride with a bulky alkoxyl group such as
LTBA (lithium tri-tert-butoxyaluminum hydride) sup-
pressed further reduction and afforded the desired trifluo-
roacetaldimine 3a selectively in high yield (entry 3). On
using 0.5 M diglyme solution, products could not be iso-
lated due to high boiling point of diglyme (entry 4). The
reaction was conducted under a dispersion of LTBA due
to the low solubility of LTBA in diethyl ether (entry 5).
The starting material 2a was not soluble in DIBAL-H so-
lution and no product was obtained (entry 6).
Here, we describe a facile two-step synthesis of polyfluo-
roalkylated aldimines from polyfluoroalkanoic acids via
imidoyl chlorides. The feasibility of the present prepara-
tion of 3 relies on: 1) high availability of polyfluoroal-
kanoic acids 1, 2) facile preparation and easy handing of
imidoyl chlorides 2, and 3) high productivity of aldimines
3.
Polyfluoroalkylated imidoyl chlorides 2 are easily pre-
pared by one-pot reaction of the polyfluoroalkanoic acids
1 with aryl amines under refluxing conditions in the pres-
ence of triethylamine and triphenylphosphine in CCl4
(Scheme 1).4 Transformation of nonfluorinated imidoyl
chlorides to aldimines by Pd-catalyzed hydrogenation5a,
Table 2 shows a summary of the present reductive prepa-
ration of aldimines 3 from imidoyl chlorides 2. Pentafluo-
roethyl (2b), heptafluoropropyl (2c), undecafluoropentyl
(2d), pentadecafluoroheptyl (2e), and chlorodifluoro-
methyl (2f) imidoyl chlorides were converted to the corre-
sponding polyfluoroalkylated aldimines 3 in high yields
(entries 1, 4–8). The reduction of the polyfluoroalkylated
imidoyl chlorides 2 seems to be unaffected by the length
of fluorinated alkyl chain. The reduction of bromide 2a¢
provided product 3a in a low yield and rather large
amount of amine (6%). The bromide 2a¢ is less reactive
5b
reduction with Na-Hg/Fe(CO)5 and stannylation fol-
lowed by Li/Sn exchange in H2O–THF5c were reported,
SYNTHESIS 2007, No. 11, pp 1624–1628
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.05.2007
DOI: 10.1055/s-2007-966055; Art ID: F05407SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of Polyfluoroalkylated Aldimines
1625
Table 1 Reduction of Trifluoroacetimidoyl Chloride (2a) with Different Reducing Agents
PMP
PMP
PMP
HN
THF
N
N
reducing
agent
+
+
H
r.t., 30 min
F3C
F3C
Cl
F3C
H
H
(1 mmol)
2a
3a
4
PMP = p-methoxyphenyl
Entry
Reducing agent (equiv) Solvent (mL)
Conv. (%) of 2a
Yield (%)a
3a
4
1
2
3
4
5
6
NaBH4 (0.35)
LiAlH4 (0.35)
LTBA (1.4)
THF (9)
30
91
– (0)
(7)
THF (9)
– (50)
81 (80)
– (77)
63 (84)
– (0)
(15)
(1)
(2)
(2)
(0)
THF (9)
100
100
88
LTBA (1.4)b
LTBA (1.4)
diglyme (2.8)
Et2O (25)
toluene (9)
DIBAL-H (1.2)
0c
a Isolated yields. Yields determined by 19F NMR (using an internal standard) spectroscopy are given in parentheses.
b 0.5 M diglyme solution.
c Starting substrate 2a was recovered.
1H NMR spectra were recorded at 200 MHz and 300 MHz, and 19
F
than chloride 2a, but its reactivity is comparable with that
of the product 3a so that the product is always accompa-
nied with trifluoroethylamine. The fluoride 2a¢¢ was high-
ly reactive and provided product 3a in an excellent yield
without formation of trifluoroethylamine. Reduction of
difluoroacetimidoyl chloride 2g provided the desired ald-
imine 3g in a good yield (60%). However, chlorofluoro-
acetaldimine (13%) was formed as a by-product.
Compounds 3g and chlorofluoroacetaldimine could not
be separated due to their similar polarity and boiling point.
Therefore, analytically pure 3g was not obtained.
NMR at 282 MHz. The chemical shifts are reported in d (ppm) val-
ues relative to tetramethylsilane (d = 0 for 1H NMR) and C6F6 (d =
ppm for 19F NMR in CDCl3) as internal standards, respectively.
THF and Et2O were distilled from sodium/benzophenone ketyl.
AcOH was distilled from a mixture of anhyd AcOH and H2O. All
polyfluoroalkanoic acids were commercially available from DIKIN
Industries, Ltd. LTBA (lithium tri-tert-butoxyaluminum hydride)
97% was obtained from Aldrich Chemical Co., and other reagent
was employed without further purification. Kanto Chemical Co,
Inc. silica gel (silica gel 60 N spherical, neutral, 40–50 mm) was em-
ployed for chromatography. IR spectra were recorded on a Hitachi
270-30 spectrometer (cm–1). GC/MS analyses were performed on a
Shimadzu GCMS-QP5050A apparatus. Elemental analyses were
performed on a Perkin Elmer series Analyzer 2400 II.
Difluoroacetaldimine 3g is used extensively as a useful
fluorinated compound,1c but is unstable to column chro-
matographic purification, and therefore other synthetic
method for 3g was surveyed. Difluorohemiacetal 6 could
be prepared by LTBA reduction of ethyl difluoroacetate
(5), and then converted to difluoroacetaldimine 3g in a
moderate yield by acid-catalyzed condensation with p-
anisidine (Scheme 2).
Polyfluoroalkylated Imidoyl Chlorides; N-(p-Methoxyphenyl)-
2,2,2-trifluoroacetimidoyl Chloride (2a); Typical Procedure
A two-necked flask (200 mL) equipped with a septum cap, a con-
denser, and a Teflon-coated magnetic stir bar was charged with
Ph3P (34.5 g, 132 mmol), Et3N (7.3 mL, 53 mmol), CCl4 (42.2 mL,
440 mmol) and p-anisidine (6.48 g, 53 mmol). Then, trifluoroacetic
acid (1a; 3.4 mL, 44 mmol) was added dropwise to the mixture. Af-
ter stirring at 0 °C for about 10 min, the mixture was refluxed for 3
h. Solvents were removed under reduced pressure and the residual
solid was washed several times with hexane (3 × 40 mL). The fil-
trate was concentrated under reduced pressure, and the residue was
distilled to afford 2a (9.4 g) in 90% yield as a yellow oil; bp 60 °C/
5 mmHg.
In summary, we have described the simple preparation of
polyfluoroalkylated aldimines by the reduction of imidoyl
chlorides. LTBA was found to be a useful reducing agent
for the selective reduction.
PMP
O
OH
OEt
N
PMPNH2
LTBA, THF
TsOH (0.1 equiv)
HF2C
OEt
HF2C
HF2C
H
0 °C, 20 min
MS 4 Å, r.t. to 40 °C
5
6
3g
2 steps, 52% purity
>95%
Scheme 2
Synthesis 2007, No. 11, 1624–1628 © Thieme Stuttgart · New York

1626
J. Takagi et al.
PAPER
Table 2 Preparation of Aldimines 3 from Imidoyl Chlorides 2 by Reduction with LTBA
PMP
X
PMP
H
N
N
LTBA, THF
r.t., 30 min
Rf
Rf
(1 mmol)
2
3
Entry
1
2
Product
Yield (%)a
81
PMP
N
PMP
2a
3a
N
F3C
Cl
F3C
H
2
3b
4
5
6
7
8
9
2a¢
3a
3a
3b
3c
3d
3e
3f
(38)
(98)c
86
PMP
N
PMP
N
F3C
F3C
Br
F3C
H
2a¢¢
2b
2c
PMP
N
PMP
N
F
F3C
H
PMP
N
PMP
N
F5C2
Cl
F5C2
H
92
PMP
PMP
N
N
N
N
N
N
F3C(CF2)2
F3C(CF2)4
F3C(CF2)6
Cl
PMP
F3C(CF2)2
F3C(CF2)4
F3C(CF2)6
H
2d
2e
PMP
88
Cl
PMP
H
94
PMP
Cl
PMP
H
2f
79d
(60)e
PMP
N
N
ClF2C
Cl
PMP
ClF2C
H
2g
3g
PMP
N
N
HF2C
Cl
HF2C
H
a Isolated yields. Yields determined by 19F NMR (using an internal standard) spectroscopy are given in parentheses.
b Compound 2a¢¢ was obtained by the reaction of imidoyl chloride (1.0 equiv) with CsF (3.0 equiv) in THF at 60 °C for 3 d.
c LTBA used: 1.3 equiv.
d LTBA used: 1.5 equiv.
e LTBA used: 1.6 equiv.
IR (neat): 1682 cm–1.
1H NMR (300 MHz): d = 3.85 (s, 3 H), 6.96 (d, J = 9.0 Hz, 2 H),
7.31 (d, J = 9.0, 2 H).
1H NMR (300 MHz): d = 3.85 (s, 3 H), 6.96 (d, J = 8.6 Hz, 2 H),
7.35 (d, J = 8.6 Hz, 2 H).
19F NMR (282 MHz): d = 48.2 (s, 2 F), 80.6 (s, 3 F).
19F NMR (282 MHz): d = 90.5 (s, 3 F).
EIMS: m/z (%) = 239 (29, [M+ + 2]), 237 (85, [M+]), 202 (100), 168
EIMS: m/z (%) = 289 (32, [M+ + 2]), 287 (99, [M+]), 252 (100), 168
(52), 133 (38), 119 (11), 77 (83), 50 (16).
The spectral data of 2b were identical to those previously reported.4
(24), 133 (22), 77 (60).
The spectral data of 2a were identical to those previously reported.4
N-(p-Methoxyphenyl)-2,2,3,3,4,4,4-heptafluorobutanoimidoyl
Chloride (2c)
Yellow oil.
IR (neat): 1678, 1602 cm–1.
N-(p-Methoxyphenyl)-2,2,3,3,3-pentafluoropropanoimidoyl
Chloride (2b)
Yellow oil.
IR (neat): 1680, 1602 cm–1.
1H NMR (300 MHz): d = 3.85 (s, 3 H), 6.97 (d, J = 9.0 Hz, 2 H),
7.34 (d, J = 9.0 Hz, 2 H).
Synthesis 2007, No. 11, 1624–1628 © Thieme Stuttgart · New York

PAPER
Preparation of Polyfluoroalkylated Aldimines
1627
19F NMR (282 MHz): d = 36.7 (s, 2 F), 51.1 (s, 2 F), 81.7 (s, 3 F).
EIMS: m/z: (%) = 339 (38, [M+ + 2]), 337 (100, [M+]), 302 (96), 168
butoxyaluminum hydride (0.36 g, 1.4 mmol) in THF (6.0 mL) at
–78 °C under argon. Then, the mixture was warmed to r.t., and
stirred for 30 min. Afterwards, AcOH was added to the mixture un-
til pH 7–8. The resulting mixture was concentrated under reduced
pressure, and hexane added to the mixture. The solution was filtered
several times for the separation of aluminum salt, and the filtrate
was concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (hexane–Et2O, 20:1) to af-
ford 3a (0.17 g) in 81% yield as a yellow oil.
IR (neat): 3012, 2956, 1602, 1584, 1510, 1252, 1160, 418 cm–1.
1H NMR (200 MHz): d = 3.81 (s, 3 H), 6.94 (d, J = 9.0 Hz, 2 H),
7.29 (d, J = 9.0 Hz, 2 H), 7.83 (q, 2.8 Hz, 1 H).
(73), 133 (50), 119 (8), 77 (84), 50 (15).
Anal. Calcd for C11H7ClF7NO: C, 39.13; H, 2.09; N, 4.15. Found:
C, 38.98; H, 1.86; N, 4.16.
N-(p-Methoxyphenyl)-2,2,3,3,4,4,5,5,6,6,6-undecafluoro-
hexanoimidoyl Chloride (2d)
Yellow oil.
IR (neat): 1682, 1602 cm–1.
1H NMR (200 MHz): d = 3.85 (s, 3 H), 6.96 (d, J = 9.2 Hz, 2 H),
7.34 (d, J = 9.2 Hz, 2 H).
19F NMR (282 MHz): d = 35.7 (s, 2 F), 40.1 (s, 2 F), 41.3 (s, 2 F),
52.1 (s, 2 F), 81.1 (s, 3 F).
EIMS: m/z (%) = 439 (33, [M+ + 2]), 437 (100, [M+]), 402 (87), 168
(92), 133 (53), 77 (84), 50 (10).
19F NMR (282 MHz): d = 91.1 (s, 3 F).
EIMS: m/z (%) = 203 (70, [M+]), 134 (100), 107 (24), 77 (39), 64
(36).
The spectral data of 3a were identical to those previously reported.2
Anal. Calcd for C13H7ClF11NO: C, 35.68; H, 1.61; N, 3.20. Found:
C, 35.80; H, 1.64; N, 2.98.
N-(3,3,3,2,2-Pentafluoropropylidene)-p-methoxyaniline (3b)
Yellow oil
IR (neat): 2960, 1602, 1510, 1212, 832, 500 cm–1.
1H NMR (300 MHz): d = 3.84 (s, 3 H), 6.94 (d, J = 7.8 Hz, 2 H),
7.30 (d, J = 8.7 Hz, 2 H), 7.88 (t, J = 5.7 Hz, 1 H).
N-(p-Methoxyphenyl)-2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadeca-
fluorooctanoimidoyl Chloride (2e)
White solid; mp 33–34 °C.
IR (neat): 1596, 1506, 1220 cm–1.
19F NMR (282 MHz): d = 42.5 (s, 2 F), 78.9 (s, 3 F).
1H NMR (300 MHz): d = 3.85 (s, 3 H), 6.96 (d, J = 9.0 Hz, 2 H),
7.33 (d, J = 9.0 Hz, 2 H).
EIMS: m/z (%) = 253 (56, [M+]), 134 (100), 107 (28), 77 (30), 64
(14).
19F NMR (282 MHz): d = 35.6 (s, 2 F), 39.1 (s, 2 F), 39.8 (s, 2 F),
40.9 (s, 2 F), 41.3 (s, 2 F), 52.0 (s, 2 F), 81.0 (s, 3 F).
Anal. Calcd for C10H8F5NO: C, 47.44; H, 3.19; N, 5.53. Found: C,
47.31; H, 3.02; N, 5.63.
EIMS: m/z (%) = 539 (26, [M+ + 2]), 537 (79, [M+]), 502 (70), 168
(100), 133 (55), 119 (27), 77 (88).
N-(4,4,4,3,3,2,2-Heptafluorobutylidene)-p-methoxyaniline (3c)
Yellow oil.
IR (neat): 3012, 2848, 1602, 1508, 1230, 1180, 1034, 978, 832 cm–1.
1H NMR (200 MHz): d = 3.85 (s, 3 H), 6.95 (d, J = 8.2 Hz, 2 H),
7.30 (d, J = 9.0 Hz, 2 H), 7.88 (t, J = 6.6 Hz, 1 H).
Anal. Calcd for C15H7ClF15NO: C, 33.51; H, 1.31; N, 2.61. Found:
C, 33.50; H, 1.38; N, 2.58.
2-Chloro-N-(p-methoxyphenyl)-2,2-difluoroacetimidoyl Chlo-
ride (2f)
Yellow oil.
19F NMR (282 MHz): d = 34.4 (s, 2 F), 43.9 (s, 2 F), 81.3 (s, 3 F).
EIMS: m/z (%) = 303 (22, [M+]), 134 (100), 107 (28), 92 (22), 77
IR (neat): 2964, 1680, 1602, 1506 cm–1.
1H NMR (200 MHz): d = 3.85 (s, 3 H), 6.96 (d, J = 9.0 Hz, 2 H),
7.30 (d, J = 9.0 Hz, 2 H).
19F NMR (282 MHz): d = 104.4 (s, 2 F).
EIMS: m/z (%) = 255 (35, [M+ + 2]), 253 (54, [M+]), 218 (61), 168
(34), 64 (17).
Anal. Calcd for C11H8F7NO: C, 43.58; H, 2.66; N, 4.62. Found: C,
43.90; H, 2.62; N, 4.38.
N-(6,6,6,5,5,4,4,3,3,2,2-Undecafluorohexylidene)-p-methoxy-
aniline (3d)
Yellow oil.
IR (neat): 2968, 2336, 1602, 1510, 1242, 832 cm–1.
1H NMR (300 MHz): d = 3.85 (s, 3 H), 6.95 (d, J = 9.0 Hz, 2 H),
7.30 (d, J = 9.0 Hz, 2 H), 7.89 (t, J = 6.6 Hz, 1 H).
(100), 77 (82), 64 (43).
Anal. Calcd for C9H7Cl2F2NO: C, 42.55; H, 2.78; N, 5.51. Found:
C, 42.56; H, 2.60; N, 5.52.
N-(p-Methoxyphenyl)-2,2-difluoroacetimidoyl Chloride (2g)
Yellow oil.
IR (neat): 1686, 1604 cm–1.
19F NMR (282 MHz): d = 35.5 (s, 2 F), 38.5 (s, 2 F), 39.4 (s, 2 F),
44.9 (s, 2 F), 81.0 (s, 3 F).
1H NMR (300 MHz): d = 3.85 (s, 3 H), 6.22 (t, J = 54.9 Hz, 1 H),
6.95 (d, J = 9.0 Hz, 2 H), 7.23 (d, J = 9.0 Hz, 2 H).
EIMS: m/z (%): 403 (18, [M+]), 134 (100), 107 (23), 92 (14), 77
(24), 64 (9).
19F NMR (282 MHz): d = 43.3 (d, J = 55.6 Hz, 2 F).
EIMS: m/z (%) = 221 (18, [M+ + 2]), 219 (56, [M+]), 184 (100), 134
Anal. Calcd for C13H8F11NO: C, 38.73; H, 2.00; N, 3.47. Found: C,
38.58; H, 1.91; N, 3.62.
(63), 77 (62), 51 (24)
N-(8,8,8,7,7,6,6,5,5,4,4,3,3,2,2-Pentadecafluorooctylidene)-p-
methoxyaniline (3e)
White solid; mp 32–33 °C.
Anal. Calcd for C9H8ClF2NO: C, 49.22; H, 3.67; N, 6.38. Found: C,
49.12; H, 3.46; N, 6.34
IR (neat): 2968, 2844, 1602, 1506, 1248, 1142, 1032, 838, 644 cm–1.
1H NMR (200 MHz): d = 3.85 (s, 3 H), 6.95 (d, J = 9.0 Hz, 2 H),
7.30 (d, J = 9.0 Hz, 2 H), 7.89 (t, J = 6.8 Hz, 1 H).
Polyfluoroalkylaldimines; N-(2,2,2-Trifluoroethylidene)-p-
methoxyaniline (3a); Typical Procedure
A solution of trifluoroacetimidoyl chloride (2a; 0.24 g, 1.0 mmol)
in THF (2.0 mL) was slowly added to a solution of lithium tri-tert-
Synthesis 2007, No. 11, 1624–1628 © Thieme Stuttgart · New York

1628
J. Takagi et al.
PAPER
19F NMR (282 MHz): d = 35.7 (s, 2 F), 38.8 (s, 2 F), 39.0 (s, 2 F),
39.7 (s, 2 F), 40.4 (s, 2 F), 44.9 (s, 2 F), 81.0 (s, 3 F).
EIMS: m/z (%) = 185 (42, [M+]), 184 (11), 134 (100), 119 (8), 107
(36), 92 (36), 77 (47), 64 (22) 51(12).
EIMS: m/z (%) = 503 (13, [M+]), 134 (100), 107 (18), 92 (12), 77
(19), 64 (7).
Anal. Calcd for C15H8F15NO: C, 58.38.; H, 4.90; N, 7.56. Found: C,
58.68; H, 4.90; N, 7.52.
Anal. Calcd for C15H8F15NO: C, 35.80.; H, 1.60; N, 2.78. Found: C,
35.96; H, 1.46; N, 2.85.
The spectral data of 3g were identical to those previously reported.2b
Acknowledgment
N-(2-Chloro-2¢,2¢-difluoroethylidene)-p-methoxyaniline (3f)
Yellow oil.
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology of Japan [Grant-in-Aid for Scienti-
fic Research (C), No. 17550104]. We thank the SC-NMR Labora-
tory of Okayama University for the 1H NMR and 19F NMR data, and
elemental analyses.
IR (neat): 3102, 2960, 2844, 1602, 1584, 1508, 1466, 1342, 1298,
1242, 1166, 1108, 1032, 978, 832 cm–1.
1H NMR (300 MHz): d = 3.83 (s, 3 H), 6.93 (d, J = 8.7 Hz, 2 H),
7.28 (d, J = 9.0 Hz, 2 H), 7.86 (t, J = 4.5 Hz, 1 H).
19F NMR (282 MHz): d = 102.9 (d, JF,H = 4.5 Hz, 2 F).
EIMS: m/z (%) = 221 (8, [M+ + 2]), 220 (3, [M+ + 1]), 219 (23,
References
[M+]), 184 (11), 134 (100), 107 (26), 92 (21), 77 (36), 64 (21).
(1) b-Lactam: (a) Enders, D.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895. (b) Bloch, R. Chem. Rev. 1998,
98, 1407. (c) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999,
99, 1069. Taxol: (d) Kuznetsova, L.; Ungureanu, I. M.;
Pepe, A.; Zanardi, I.; Wu, X.; Ojima, I. J. Fluorine Chem.
2004, 125, 487. (e) Battaglia, A.; Bernacki, R. J.; Bertucci,
C.; Bombardelli, E.; Cimitan, S.; Ferlini, C.; Fontana, G.;
Guerrini, A.; Riva, A. J. Med. Chem. 2003, 46, 4822.
Aziridine: (f) Crousse, B.; Narizuka, S.; Bonnet-Delpon, D.;
Begue, J.-P. Synlett 2001, 679.
(2) (a) Ingrassia, L.; Mulliez, M. Synthesis 1999, 1731.
(b) Abouabdellah, A.; Bégué, J.-P.; Bonnet-Delpon, D.;
Nga, T. T. T. J. Org. Chem. 1997, 62, 8826. (c) Arnone, A.;
Bruche, L.; Panzeri, W.; Pesenti, C.; Viani, F.; Zucca, C. J.
Chem. Res., Synop. 2002, 131. (d) Guanti, G.; Banfi, L.;
Narisano, E.; Scolastico, C.; Bosone, E. Synthesis 1985, 609.
(3) (a) Henne, A. L.; Pelley, R. L.; Alm, R. M. J. Am. Chem. Soc.
1950, 72, 3370. (b) Braid, M.; Iserson, H.; Lawlor, F. E. J.
Am. Chem. Soc. 1954, 76, 4027. (c) Ogden, R. P.; Thomas,
G. K. J. Am. Chem. Soc. 1954, 76, 300. (d) Husted, D. R.;
Ahlbrecht, A. H. J. Am. Chem. Soc. 1952, 74, 5422.
(e) Ono, N.; Kawamura, H.; Maruyama, K. Bull. Chem. Soc.
Jpn. 1989, 62, 3386.
Anal. Calcd for C15H8F15NO: C, 49.22.; H, 3.67; N, 6.38. Found: C,
49.0; H, 3.63; N, 6.45.
The spectral data of 3f were identical to those previously reported.2b
N-(2,2-Difluoroethylidene)-p-methoxyaniline (3g)
Ethyl difluoroacetate (5; 0.15 mL, 1.0 mmol) was slowly added to
a solution of lithium tri-tert-butoxyaluminum hydride (0.56 g, 2.2
mmol) in THF (5.0 ml) at 0 °C under argon. The mixture was stirred
for 20 min. Aq sat. NH4Cl solution was added to the mixture until
pH 7 and the resulting mixture was extracted with Et2O. The Et2O
and THF layers were combined, washed with brine (2 × 5 mL), and
dried (MgSO4). The mixture of difluoroacetaldehyde ethyl hemi-
acetal 6 was used for further reaction without purification. 19F NMR
analysis of the mixture showed the yield of difluoroacetaldehyde
ethyl hemiacetal 6 to be 73% (1,3-bistrifluoromethylbenzene was
used as an internal standard.). After removal of most of the solvents
at 50 °C, the concentrated mixture was added to p-anisidine (0.073
g, 0.6 mmol), p-toluenesulfonic acid (0.019 g, 0.1 mmol) and mo-
lecular sieves 4Å (6 g) at 0 °C.The mixture was stirred for 2 h at 0
°C, 12 h at r.t., and 29 h at 40 °C. The resulting mixture was con-
centrated under reduced pressure and Et2O (20 mL) was added to
the residue. The solution was filtered to separate molecular sieves,
and the filtrate was concentrated under reduced pressure to afford
3g (0.095 g, 52% from ethyl difluoroacetate 5); white solid; mp 46–
48 °C.
(4) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32.
(5) (a) Tanaka, M.; Kobayashi, T. Synthesis 1985, 967.
(b) Alper, H.; Tanaka, M. Synthesis 1978, 781.
(c) Jousseaume, B.; Vilcot, N.; Ricci, A.; Tiekink, E. R. T. J.
Chem. Soc., Perkin Trans. 1 1994, 2283.
(6) (a) Karady, S.; Amato, J. S.; Weinstock, L. M.; Sletzinger,
M. Tetrahedron Lett. 1978, 403. (b) Luo, J. K.; Zektzer, A.
S.; Castle, R. N. J. Heterocycl. Chem. 1991, 28, 737.
IR (neat): 2972, 1604, 1510, 1296, 1250, 1146, 1110, 1024 cm–1.
1H NMR (300 MHz): d = 3.84 (s, 3 H), 6.16 (dt, JF,H = 54.0,
JH,H = 5.4 Hz, 1 H), 6.93 (d, J = 8.7 Hz, 2 H), 7.23 (d, J = 9.3 Hz, 2
H), 7.86 (td, JF,H = 5.4 Hz, JH,H = 2.4 Hz, 1 H).
19F NMR (282 MHz): d = 42.7 (d, J = 56 Hz, 2 F).
Synthesis 2007, No. 11, 1624–1628 © Thieme Stuttgart · New York