.
Angewandte
Communications
a one-pot synthesis, the targeted chiral 3-substituted morpho-
lines can be prepared. Herein, we show that Ti-amidate
precatalyst 1 can be used for regioselective intramolecular
hydroamination with functionalized ether-containing amino-
alkynes, and we also demonstrate that this N,O-chelated
catalyst is suitable for applications in sequential, one-pot
catalytic approaches using the Noyori–Ikariya transfer hydro-
genation catalyst, [{(S,S)-Ts-dpen}(h6-p-cymene)RuCl] (Ts-
dpen = (1S,2S)-N-p-toluenesulfonyl-1,2-diphenylethanedia-
mine).[17] Using this approach, 3-substituted morpholines (5)
can be obtained in good yield with excellent enantiomeric
excesses (Table 1).
is used and yields a morpholine product that could be further
derivatized using Pd-catalyzed cross-coupling methods.
Medicinally relevant fluorinated substituents can be incorpo-
rated (entry 7) and even strong electron-donor/hydrogen-
bonding substituents, such as the pyridine moiety of entry 8,
do not inhibit these catalyst systems.
The described method, which avoids column chromatog-
raphy, yields 3-substituted morpholines as yellow-brown oils.
Further derivatization of these crude products to the oxalate
salt allows for recrystallization, which removes any trace
impurities and also increases the ee from 97% to 99.8%
(entry 6).[15] Thus, this method results in the one-pot synthesis,
isolation, and purification of 3-substituted morpholines with
excellent ee values while avoiding chromatographic separa-
tions. Remarkably, the outstanding stereoselectivity observed
is in contrast to previous literature reports for similar simple
cyclic imines.[18] Indeed, our one-pot synthetic method can be
used to prepare piperidines and piperazines to give hetero-
cycles in high yield, but only low to modest ee values are
observed (Scheme 3). The mechanistic rationale for the
outstanding ee values obtained specifically for morpholines
is an area of ongoing investigation.
Table 1: One-pot enantioselective synthesis of 3-substituted morpho-
lines.
Entry
R1
Product
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
H
Et
5a
5b
5c
5d
5e
5 f
65%
78%
79%
74%
78%
80%
77%
66%[d]
>99%[c]
97%[c]
97%
BnO(CH2)2
tBu
Ph
p-BrC6H4
C6F5
2-Py
74%[c]
98%
97%[e]
98%
99%
5g
5h
[a] Yield of crude isolated product (>95% pure by NMR spectroscopy).
[b] Determined by supercritical fluid chromatography. [c] Determined
after derivatization with p-toluenesulfonyl chloride. [d] Yield of isolated
product after flash chromatography. [e] ee values can be increased to
>99% ee by recrystallization of the oxalate salt. Bn=benzyl, Noyori’s
cat.=[{(S,S)-Ts-dpen}(p-cymene)RuCl], Py=pyridyl.
Scheme 3. Enantioenriched heterocycle synthesis. Noyori’s
cat.=[{(S,S)-Ts-dpen}(p-cymene)RuCl].
The synthesis of the requisite aminoalkyne starting
materials requires multistep syntheses, as has been previously
reported for diastereoselective late transition metal
approaches.[19] However, with proof of concept established
for the use of Ti–amidate precatalyst 1 in one-pot reactions, as
well as the successful ring closure of oxygen-tethered amino-
alkenes with Zr–ureate precatalyst 2, a novel strategy that
takes advantage of these attractive reactivity features in the
synthesis of disubstituted piperazines was envisaged
(Scheme 4). This efficient approach uses commercially avail-
able benzylamines, allyl bromides, and alkyne starting mate-
rials to assemble 2,5-substituted piperazines, while avoiding
the use of amino acid derivatives and protection/deprotection
sequences during synthesis.
2,5-Asymmetrically substituted piperazines are tradition-
ally prepared from amino acids to give diketopiperazines,
which, upon reduction, yield the desired heterocyclic com-
pounds.[20] Although attractive for the preparation of hetero-
cycles derived from naturally occurring amino acids, this
approach requires sequential protection/deprotection steps
and stoichiometric amino acid coupling reagents.[21] Further-
more, these approaches do not facilitate the assembly of
heterocycles with a broad range of substituents that may be
desired for exploring structure/biological activity relation-
ships. Herein, we take advantage of our previously reported
strategy for a one-pot, modified Strecker reaction with
For example, using the simplest aminoalkyne 4a in
combination with precatalyst 1 (10 mol%), regioselective
cyclohydroamination proceeds smoothly at 1108C overnight
to give the desired imine intermediate and its enamine
isomer. Using a one-pot method, the crude reaction mixture is
then treated with a dimethylformamide (DMF) solution of
[{(S,S)-Ts-dpen}(h6-p-cymene)RuCl] (1 mol%)[17] and subse-
quently a solution of formic acid in NEt3 is added. The
reaction mixture is left to stir overnight before isolating the
crude product using a simple aqueous wash of the acidified
morpholine product, followed by treatment with base before
extraction of the desired product with ethyl acetate. Upon
removal of volatiles, product 5a was obtained in good yield
(65%, reduced yield owing to volatility of the product) as
a crude product with 98% ee (Table 1, entry 1). Using this
same general procedure, substrate scope was explored and
good yields and high enantioselectivities were obtained in
almost all cases. Notably, alkyl substituents with varying steric
bulk are tolerated (entries 2–4) and most importantly, further
functional groups can be incorporated (entry 3). Aryl sub-
stituted substrates are particularly well suited for this method
(entries 5–8). Entry 6 highlights an advantage of early tran-
sition metal catalysts: a substrate containing an aryl bromide
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 12219 –12223