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A.-E. Wang et al. / Chinese Chemical Letters 26 (2015) 1055–1058
1) Tf2O, 2-F-Py, DCM (0.044 mol/L)
2) RMgBr; 3) aq. HCl
acetate (3 mol/L, 5 mL) and concentrated under reduced pressure
to afford the desired amine hydrochloride salt.
The characterization data of amine hydrochlorides 2 and ketone
3 were provided in Supporting information.
O
Charette's method
O
R2
+
H2NR2
R1
R
R1
N
H
Our method
3. Results and discussion
(1) Tf2O, 2-F-Py, DCM (0.25 mol/L)
(2) RMgBr/ CeCl3; (3) aq. HCl
Our investigation is based on the direct alkylative deamination of
secondaryamides, a methoddevelopedrecentlyfromourlaboratory
for the synthesis of ketones [13b,c]. The N-deacylation of secondary
amide 1a was chosen as the model reaction. Following the general
procedure reported for the transformation of secondary amides into
ketones [13b,c], a dichloromethane solution of amide 1a and 2-
fluoropyridine(1.2 equiv) was treated successivelywith 1.1 equiv of
Tf2O (0 8C, 30 min) and 3.0 equiv of freshly prepared ethyl cerium
regent (ꢁ78 8C, 2 h), and the reaction was quenched with aqueous
HCl solution. After work-up through simple acid–base extraction,
only 62% of the corresponding primary amine was obtained. In our
further trials to improve the yield, we found that there might be
some magnesium complex of amines produced. So after the reaction
was quenched with aqueous HCl solution, aqueous ammonia was
added to facilitate the liberation of amines from amine–Mg
complexes. In view of high volatility of amines, the final products
were isolated as amine hydrochloride salts. In this way, the yield of
deacylation of 1a was improved to 88%.
Scheme 1. Reductive alkylation of secondary amides with Grignard and
organocerium reagents.
that acidic work-up of imines would produce amines as well. The
method could thus, on the other hand, serve as an alternative way
for the deprotection of secondary amides to produce primary
amines. Using Grignard reagents as alkylation reagents, Charette
et al. [14] have showed one example of isolation of amine moiety
by an acid/base workup after hydrolysis of the corresponding
imine. Such transformation, however, was performed in an
extremely diluted dichloromethane solution (0.044 mol/L), which
is environmentally harmful, thus preventing the scale-up of the
reaction. As a result of recent interest in the development of
methods for the deprotection of secondary amides, herein we
report our own results on the N-deacylation of secondary amides
by alkylation with organocerium reagents.
With the optimized reaction procedures in hand, we next
examined the scope of structurally different benzoylated aliphatic
amines (entries 1–6, Table 1). Various acylated primary amines
(1a–f) were deprotected to afford the corresponding amine
hydrochloride salts 2a–f in good yield upon isolation. It should
2. Experimental
Melting points were uncorrected. Infrared spectra were mea-
sured using film KBr pellet techniques. 1H NMR and 13C NMR
spectra were recorded on Bruker 400 MHz or 500 MHz spectrom-
be mentioned that chiral substrates 1f, which has an
a-chiral
eter. Chemical shifts are expressed in
d (ppm) units downfield
center, underwent facile N-deacylation smoothly to afford the
corresponding amine hydrochloride salt 2f without any epimer-
ization (ee value was determined by HPLC, for details see
Supporting information).
In addition to benzoyl group, other acyl groups such as acetyl,
pivaloyl and isovaleroyl groups in 1g–k could be removed to afford
amine hydrochloride salts in high yields (entries 7–11).
from TMS. High-resolution mass spectra (HRMS) were recorded
on a Bruker APEX II FT mass spectrometer. Silica gel (300–400
mesh) was used for flash column chromatography, eluting (unless
otherwise stated) with ethyl acetate/n-hexane mixture. Ether and
THF were distilled over sodium benzophenone ketyl under N2.
Dichloromethane was distilled over calcium hydride under N2.
Trifluoromethanesulfonic anhydride (Tf2O) was distilled over
phosphorous pentoxide and was stored for no more than a week
before redistilling. All other commercially available compounds
were used as received. Anhydrous cerium chloride was prepared
from CeCl3ꢀ7H2O according to the reported procedure [16].
General procedure for N-deacylation of secondary amides: Tf2O
Table 1
Deacylation of secondary amides.a
(185
m
L, 1.1 mmol) was added dropwise to a cooled (0 8C) solution
L, 1.2 mmol) in
of amide (1.0 mmol) and 2-fluoropyridine (103
m
dichloromethane (4 mL). After stirring at 0 8C for 30 min, the
mixture was cannulated to a freshly prepared organocerium
reagent/complex (3.0 mmol) in THF (15 mL) at ꢁ78 8C and stirred
for 2 h. Aqueous HCl solution (3 mol/L, 5 mL) was added to quench
the reaction and the mixture was allowed to warm to r.t. and
stirred for 2 h. Ammonium hydroxide solution (25%, 5 mL) was
then added to the mixture. The organic layer was separated and the
aqueous phase was extracted with diethyl ether (3ꢂ 10 mL). The
combined organic layers were washed with brine (3ꢂ 3 mL) and
concentrated under reduced pressure to about 1/3 volume. The
residual organic phase was then extracted with aqueous HCl
solution (3 mol/L, 3ꢂ 5 mL). The separated organic phase was
washed with brine (5 mL), dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure, and the residue was
purified by flash column chromatography on silica gel to afford
ketone. The aqueous phases were combined, washed with diethyl
ether (5 mL), basified with an ammonium hydroxide solution (25%,
5 mL) and back-extracted with diethyl ether (5ꢂ 20 mL). The ether
layers were combined, washed with brine (5 mL), dried over
anhydrous MgSO4, filtered, acidified with a solution of HCl in ethyl
Entry
Amide
R
R0
R2NH2ꢀHCl (yield %)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph(CH2)4
Ph(CH2)2
Bn
Ph
Ph
Ph
Ph
Ph
Ph
88
76
63
87
70
77
c-Hex
n-Bu
7
8
1g
1h
1i
c-Hex
Me
90
74
83
71
82
63
70
69
67
73
77
c-Hex
t-Bu
9
c-Hex
Me2CHCH2
n-C10H21
1-Adamantyl
Me2CHCH2
Me
10
11
12
13
14
15
16
17
1j
c-Hex
1k
1l
c-Hex
Ph
1m
1n
1o
1p
1q
Ph
3,5-diMeC6H3
p-EtOC6H4
p-FC6H4
p-NCC6H4
Me
Me
Me
Me
a
Reaction conditions: Tf2O (1.1 equiv.), 2-F-Py (1.2 equiv.), DCM (0.25 mol/L),
0 8C, 30 min; then organocerium reagent (3.0 equiv.), ꢁ78 8C, 2 h; then HCl (3 mol/L,
5 mL), r.t., 2 h.