8
44
Papers
SYNTHESIS
We also attempted to carry out reactions with 2- and 3-py- warm to r.t. and then concentrated in vacuo. The residue was chro-
matographed (silica gel, 150 g; CHCl , ~500 mL). After evaporation
ridyllithium and quinolin-3-yllithium, prepared from the
corresponding bromopyridines and bromoquinoline by
the exchange reaction with butyllithium.17 These organo-
lithium compounds are much less stable and we found that
the reactions do not proceed in a temperature range from
3
of most of the solvent in vacuo, hexane (100 mL) was added and the
crystalline product was filtered. Yield 31.0 g (74%) of colorless solid;
23
mp 57–58°C (Lit. mp 58°C).
3
-(Dimethylaminomethylene)-1,1,1,5,5,5-hexafluoropentane-2,4-
–
100 to –70°C. Raising of the reaction temperature leads
dione (3):
only to decomposition of the organolithium compounds.
We believe that the reactivity of enamino ketones is insuf-
ficient for reactions with these organolithium compounds.
Trifluoroacetic anhydride (13.7 g, 65 mmol) was added to a stirred so-
lution of enamino ketone 2 (8.35 g, 50 mmol) and pyridine (5.14 g,
5 mmol) in CH Cl (50 mL) at –10°C. The mixture was allowed to
6
2 2
The reactions of enamino ketones 2 and 3 with butyllithi- warm to r.t. and then washed with ice-water (2 ´ 25 mL). The resulting
um and enamino ketone 3 with phenyllithium were also solution was dried (CaCl ) and passed through a short column of silica
gel (~10 g), eluent CH Cl (30 mL). The combined solutions were con-
2
studied. These reactions resulted only in complicated
product mixtures; trifluoromethyl enones (enediones)
could not be isolated. In our opinion, this is apparently due
to the high nucleophilicity and basicity of butyl- and
phenyllithium. Strong basicity can lead to the deprotona-
2
2
centrated in vacuo, and the product was crystallized by addition of hex-
ane (30 mL). Yield 12.5 g (95%) of colorless solid; mp 50–51°C.
H NMR (400 MHz, CDCl ): d = 2.76 (s, 3H, CH ), 3.41 (s, 3H, CH ),
.72 (s, 1H, H methylene).
1
3
3
3
7
13
C NMR (100 MHz, CDCl ): d = 43.09 (CH ), 48.83 (CH ), 101.16
3
3
3
22
1
tion of enamino ketones and further transformations.
Hence, we have used phenylmagnesium bromide instead
(3-C), 116.23 (q,
1
J
C–F = 289 Hz, 2CF ), 159.48 (C methylene),
3
2
79.41 (q, J
= 35.2 Hz, 2CO).
C–F
of phenyllithium in the reaction with enamino ketone 3;
however, the expected enedione was not formed. The
product of a double addition of organometallic compound
to the enamino ketone as a 1:1 mixture of (E)- and (Z)-iso- A solution of organolithium compound 4 (10 mmol) in THF
mers 9 was isolated in low yield (Scheme 6).
Reaction of Enamino Ketones 2 and 3 with Organolithium Com-
pounds:
1
7–19
was
cooled to –70°C and a solution of the enamino ketone 2 (1.67 g, 10
mmol) or 3 (2.63 g, 10 mmol) in THF (10 mL) was added dropwise
while maintaining the temperature between –70 and –60°C. The mix-
ture was then allowed to warm slowly (over ~1 h) to 0°C. In the case
of (2,6-dimethoxyphenyl)lithium (4g) the temperature was kept be-
tween –40 and –30°C during the addition of the enamino ketone and
then allowed to warm to r.t. The resulting mixture was hydrolyzed
with 10% aq HCl (10 mL, 27 mmol) or sat. aq NH Cl (10 mL) (in the
4
case of furan derivatives 5b, 5d and 6b) with cooling below 0°C. The
organic layer was separated, and the aqueous layer was extracted with
CHCl (2 ´ 10 mL). The combined solutions were dried (CaCl ) and
Scheme 6
3
2
concentrated in vacuo. The residue was chromatographed (short silica
gel column, 15–20 g; hexane/benzene 1:1, ~50 mL); the target prod-
Thus, the reactions of enamino ketones 2 and 3 with lithi-
um derivatives of electron-rich aromatic and heteroaro-
matic compounds result in the corresponding aryl- and
hetaryl-substituted trifluoromethyl enones (enediones) in
ucts had R 0.2–0.5 (hexane/EtOAc 9:1). After evaporation of the sol-
ƒ
vents in vacuo, hexane (15 mL) was added and the products were
crystallized with cooling to –30 to –10°C, then the cold suspension
good yields. The aryl- and hetaryl-substituted enediones was filtered. The ketone 5e was crystallized from hexane/Et O 5:l
2
(
~30 mL) without purification by chromatography because of its low
with two trifluoroacetyl moieties were obtained for the
first time. The reactions investigated provide a convenient
route to the preparation of these compounds.
solubility. The product 7 was separated by chromatography (silica gel
column, 20–30 g; benzene) (R 0.55, CHCl /MeOH 9:1) and crystal-
lized from hexane. The indole derivatives 5f and 8 were chromato-
ƒ
3
graphed using CH Cl /acetone 9:1 or 1:1 (~50 mL) as eluent,
2
2
respectively; compound 8 was then crystallized from hexane/Et O 1: l
2
Mps were determined in sealed capillaries and are uncorrected. TLC
was performed on Silufol UV 254 plates visualizing by UV and by aq
(~20 mL). The mixture in the case of lithiated ferrocenes (4i and 4j)
was hydrolyzed with concd aq HCl (5.0 mL, ~50 mmol) and concen-
trated in vacuo without separation. The residue was shaken with ben-
zene (30 mL) and the mixture was passed through a silica gel column
KMnO . NMR spectra were recorded on Varian VXR-400 and Bruk-
4
er AMX 400 spectrometers with TMS as an internal standard. The IR
spectra were obtained with a UR-20 spectrometer. Column chroma-
tography was performed on silica gel (63–200 mesh, Merck). All sol-
vents used were dried and distilled according to standard procedures.
(~30 g); the insoluble residue and the silica gel column were then ad-
ditionally washed with benzene (~100 mL). The solvent was removed
in vacuo and the mixture of the products was chromatographed on a
Organolithium compounds were prepared according to the literature
techniques.1
7–19
Cymantrenyllithium was prepared according to the silica gel column (~50 g). Excess ferrocene was removed by elution
18
literature procedure. A mixture of mono- and dilithiated ferrocenes with hexane (150–200 mL); the ketones 5i and 6i were eluted with
4i and 4j) for the reaction with 10 mmol of enamino ketone 2 or 3 hexane/benzene 1:1 (~150 mL), the ketone 5j (in the case of the reac-
was prepared using excess BuLi (26 mmol) and ferrocene (3.72 g, tion with enamino ketone 2) was then eluted with benzene (~150 mL).
0 mmol) according to the literature protocol.19
(
2
(E)-4-(Dimethylamino)-1,1,1-trifluorobut-3-en-2-one (2):
Reaction of Enamino Ketone 3 with Phenylmagnesium Bromide:
Liquid Me NH (27.0 g, 0.60 mol) was added dropwise to a stirred and The reaction was carried out under a similar manner to that described
2
cooled (below 0 °C) solution of (E)-4-ethoxy-1,1,1-trifluorobut-3-en- above using a solution of PhMgBr (10 mmol) in THF.17 The residue
2
0
-one (1) in CH Cl , prepared from ethyl vinyl ether (18.0 g, after hydrolysis and evaporation of the solvents was chromato-
2 2
.25 mol) and trifluoroacetic anhydride (63.0 g, 0.30 mol) according graphed (silica gel column, 20–30 g; benzene). The product 9 (Rƒ
12
to the literature protocol. The resulting mixture was allowed to 0.84, CHCl /MeOH 9:1) was separated and distilled in vacuo.
3