4118 J . Org. Chem., Vol. 61, No. 12, 1996
Ta ble 3. Oth er Red u ction s of Am id es to Im in es
Schedler et al.
entry
reactant
reagent
product (% yielda
1
2
3
4
C6H5CONHC6H5 (15)
15
C6H5NHC10H21 (13)
CH3CONHPh (26)
DIBAL-TiCl3/DIBAL
DIBAL-Et3SiH
DIBAL-Et3SiH
DIBAL-Et3SiH
C6H5CHdNC6H5 (16)
16
C6H5CHdNC10H21 (14)
CH3CHdNPh (27)
(38)
(34)
(33)
(NR)
a
Products were identified by direct comparison with authentic samples.
reaction mixture was gradually warmed to rt over 2 h and then
pipetted into cold hexanes (10 mL) with vigorous stirring. The
heterogeneous mixture was filtered under vacuum through
Celite (hexane rinsing), and the combined filtrates were
concentrated on a rotary evaporator to afford pure 14 (0.124
g, 86%) as a pale yellow oil. 1H- and 13C-NMR and IR spectral
data of the product were identical with an authentic sample
prepared by the method of Stork and Dowd.16
Red u ction of N-Decylben za m id e (13) to Ben za ld eh yd e
N-Decylim in e (14) Usin g Cp 2Zr HCl: R ep r esen t a t ive
Exa m p le of Ta ble 1-Meth od B Red u ction . A solution of
13 (0.10 g, 0.38 mmol) in anhydrous THF (1 mL) was added
dropwise to a suspension of Cp2ZrHCl (0.24 g, 0.91 mmol) in
THF (1 mL) at -20 °C and after 10 min the reaction mixture
was gradually warmed to rt. After 4 h, the reaction mixture
was pipetted into cold hexanes (10 mL) with vigorous stirring.
The heterogeneous mixture was filtered under vacuum through
Celite (hexane rinsing), and the combined filtrates were
concentrated on a rotary evaporator to afford pure 14 (78 mg,
83%) as a pale yellow oil, which was spectroscopically identical
(1H-, 13C-NMR, IR) with an authentic sample.
The reduction of amide 15 was therefore attempted by
treating aluminated amide 12 (R, R′ ) Ph) with TiCl3/
DIBAL. The most promising results were obtained using
THF as solvent, where imine 16 was obtained in 38%
yield, along with recovered 15 after aqueous workup
(Table 3). No trace of N-benzylaniline was observed.
Parallel experiments using TiCl4-DIBAL produced sig-
nificant quantities (35-55%) of N-benzylaniline, together
with recovered carboxamide 15. In an attempt to bypass
the initial metalation step, carboxamide 15 was treated
directly with TiCl3-DIBAL, but no imine (and only
starting material) was recovered under those conditions.
Amides 15 and 13 could also be reduced via the
corresponding imidates using triethylsilane in THF at
rt to furnish imines 16 and 14 in 33-34% yield, with
about 30% of starting amide also recovered (Table 3).
Addition of catalysts such as ZnCl2, AlCl3, or BF3
diminished the yield of imine, whereas PdCl2 gave
N-benzylaniline instead of imine.
Red u ction of N-P h en ylben za m id e (15) to Ben za ld e-
h yd e N-Decylim in e (16) Usin g DIBAL-Cp 2Zr HCl. To a
toluene solution of DIBAL (Aldrich, 0.28 mmol) in anhydrous
THF (1 mL) at -10 °C was added a solution of 15 (50 mg,
0.25 mmol) in THF (1 mL) over 20 min. After 10 min, the
reaction mixture was warmed to 0 °C and stirred 20 min. The
resulting clear solution of aluminum amide was cooled to -20
°C, and Cp2ZrHCl (83 mg, 0.30 mmol) was added. After
warming gradually to rt and stirring for 7 h, the solution was
cooled to 0 °C, and dry hexanes (10 mL) were added, forming
a turbid mixture that was filtered through Celite (hexane
rinsing). The filtrate was concentrated in vacuo to afford
N-decylimine 16 (58 mg). The crude product was filtered
through column of silica gel (2 cm × 2 cm) eluting with 1:1
ether:hexanes (20 mL) to afford pure imine 16 (43 mg, 93%),
which was spectroscopically identical (1H-, 13C-NMR, IR) with
an authentic sample.
Red u ction of N-P h en ylben za m id e (15) to Ben za ld e-
h yd e N-P h en ylim in e (16) Usin g DIBAL-TiCl3/DIBAL. To
a toluene solution of DIBAL (Aldrich, 0.17 mmol) was added
dropwise over 5 min a solution of N-phenylbenzamide (15) (32
mg, 0.16 mmol) in anhydrous THF (2 mL) at -20 °C. After
10 min at 0 °C the solution was cooled to -20 °C and treated
with a suspension of low-valent titanium reagent prepared12
by adding DIBAL (0.50 mmol) dropwise to TiCl3 (7.5 mg) in
THF (1 mL) over 5 min and then stirring an additional 10 min.
Following transfer of the DIBAL-TiCl3 reagent, the reaction
mixture was warmed to rt, stirred for 8 h and then treated
with cold hexanes (10 mL). The resulting slurry was filtered
through hexane-rinsed Celite, and the colorless filtrate was
concentrated to one-half the volume, whereupon a suspension
appeared that was refiltered through Celite. The final, clear
filtrate was concentrated in vacuo to afford pure 16 (11 mg,
38%) as a pale yellow oil that was spectroscopically identical
(1H-, 13C-NMR, IR) with an authentic sample.
Con clu sion
With its demonstrated scope and generality, the selec-
tive reduction of carboxamides to imines using either Cp2-
ZrHCl (Table 1) or DIBAL-Cp2ZrHCl (Table 2) illus-
trates new roles for early transition metal hydrides in
synthesis. By prior formation of an aluminated carboxa-
mide, it is possible to reduce by half the amount of
organozirconium reagent necessary to accomplish this
transformation (Table 2). Moreover, promising results
with other reagent combinations such as DIBAL-Et3SiH
(Table 3) suggest that it may eventually be possible to
eliminate the use of Cp2ZrHCl altogether in this process.
To our knowledge, the transformations reported herein
represent the first controlled reductions of carboxamides
and lactams to the corresponding imines, a transforma-
tion that is otherwise very difficult to achieve since
imines are reduced very rapidly to amines by most metal
hydride reagents. Moreover, no products of reductive
cleavage of the amides were observed. Since imines are
readily hydrolyzed to amines and aldehydes, the method
may prove to be a useful alternative to the partial
reduction of carboxamides, or to known reductive or
hydrolytic deprotection procedures for amides, especially
in situations where more drastic hydride reagents must
be avoided.
Exp er im en ta l Section 15
Red u ction of N-Decylben za m id e (13) to Ben za ld eh yd e
N-Decylim in e (14) Usin g KH-Cp 2Zr HCl: Rep r esen ta tive
Exa m p le of Ta ble 1-Meth od A Red u ction . A solution of
N-decylbenzamide (0.15 g, 0.59 mmol) in anhydrous THF (2
mL) was added dropwise to a suspension of KH (25 mg, 0.62
mmol) in THF (1 mL) at 0 °C. After stirring 10 min, the clear,
colorless solution of the enolate was transferred by syringe to
a -20 °C suspension of Cp2ZrHCl (Aldrich Chemical Co.,
freshly sublimed, 0.37 g, 1.46 mmol) in THF (0.5 mL). The
Red u ction of N-Decylben za m id e (13) to Ben za ld eh yd e
N-Decylim in e (14) Usin g DIBAL-Et3SiH. To a toluene
solution of DIBAL (Aldrich, 0.84 mmol) was added dropwise
over 10 min a solution of N-decylbenzamide (13) (200 mg, 0.77
mmol) in anhydrous THF (3 mL) at -20 °C. After stirring 20
min at 0 °C, the clear, colorless solution was cooled to -20 °C,
and Et3SiH (0.15 mL, 0.94 mmol) was added dropwise. The
solution was stirred for 20 min at -20 °C and then warmed
(15) For general experimental procedures, see King, S. B.; Ganem,
B. J . Am. Chem. Soc. 1994, 116, 562.
(16) Stork, G.; Dowd, S. R. J . Am. Chem. Soc. 1963, 85, 2178.