High substrate/catalyst organocatalysis by a chiral Bronsted acid for an enantioselective aza-ene-type reaction

Article abstract of DOI:10.1002/anie.200503477

(Chemical Equation Presented) Lowering the load: A very small amount of a binaphthol-derived monophosphoric acid organocatalyst accelerates an azaene-type reaction of N-benzoylimines with enecarbamates to provide β-aminoimines with high enantiomeric purit

Full text of DOI:10.1002/anie.200503477

Communications
Asymmetric Synthesis
DOI: 10.1002/anie.200503477
High Substrate/Catalyst Organocatalysis by a
Chiral Brønsted Acid for an Enantioselective
Aza-Ene-Type Reaction**
Masahiro Terada,* Kyoko Machioka, and
Keiichi Sorimachi
The enantioselective catalysis of organic reactions that
involve small organic molecules, known as organocatalysis,
has become a rapidly growing area of research, as it offers
operational simplicity together with mild reaction conditions
and is environmentally benign.[1] Although organocatalysis
has proven to be beneficial in many respects, one critical
drawback inherent in the methodologies reported to date is
the inadequate catalytic efficiency.[2] Most organocatalytic
reactions are performed at substrate-to-catalyst (S/C) molar
ratios of 10 or less to achieve sufficient yields and avoid loss of
[*] Prof. Dr. M. Terada, K. Machioka, K. Sorimachi
Department of Chemistry
Graduate School of Science
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6602
E-mail: mterada@mail.tains.tohoku.ac.jp
[**] This workwas partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, and The Tokuyama Science Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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enantioselectivity. One of the greatest challenges in practical
organocatalysis is to decrease the catalyst loading to ensure a
high efficiency. Akiyama and co-workers and our group have
independently developed binaphthol-derived monophos-
assumption, the dual function of 1 through these hydrogen-
bonding interactions allows the reaction to operate under
high S/C conditions.
We first set the S/C ratio to 50:1 (2 mol%) using the
binaphthol-derived monophosphoric acid 1 to ascertain the
viability of the high S/C ratio in the aza-ene-type reaction.
The catalytic efficiency was screened in the reaction of the
benzaldehyde-derived N-benzoylimine (2; Ar= Ph) with an
enamide 3a in various solvents at room temperature. The
yields and enantioselectivities were determined after the
hydrolysis of imine adducts 4 to b-aminoketones 5 under
acidic work-up conditions (concentrated HBr in MeOH).[8]
Representative results are given in Table 1. Among the
phoric acids
1 as organocatalysts for enantioselective
carbon–carbon bond-forming reactions.[3,4] Herein, we
report high S/C organocatalysis with 1 as the chiral Brønsted
acid[5,6] for enantioselective reactions of N-benzoylimines 2
with enamides or enecarbamates 3. The reaction conditions
allow imine/catalyst molar ratios of up to 2000 to afford the
corresponding b-aminoimine adducts 4 in high yields without
considerable loss of enantioselectivity [Eq. (1)].
Table 1: Chiral Brønsted acid-catalyzed reaction of imine 2 (Ar=Ph) with
an enamide 3a and enecarbamates 3b–d.[a]
Entry
3
S/C[b] (mol%) Solvent
t [h] Yield [%][c] ee [%][d]
1
2
3
4
5
3a
3a
3a
3a
3b
3c
3d
3d
50:1 (2)
50:1 (2)
50:1 (2)
50:1 (2)
50:1 (2)
50:1 (2)
50:1 (2)
50:1 (2)
CH2Cl2
(CH2Cl)2 0.5
Et2O
0.5
77
61
71
90
94
55
85
76
64
82
85
69
70
80
86
60
83
95
96
95
95
93
0.5
0.5
1
1
1
1
2
5
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
6
7
8[e]
9
3d 1000:1 (0.1)
3d 1000:1 (0.1)
3d 2000:1 (0.05)
10
11
[a] Unless otherwise noted, all reactions were carried out with 0.10 mmol
of 2 (Ar=Ph) and 0.12 mmol of 3 in a 0.1m solution at room
temperature. [b] Molar ratio of imine 2/catalyst 1. [c] Yield of the isolated
Recently Kobayashi and co-workers successfully demon-
strated the first use of enamides and enecarbamates as
nucleophiles in enantioselective reactions with either glyox-
ylates or glyoxylate-derived imines catalyzed by chiral copper
complexes.[7] Their mechanistic proposal, in which the reac-
tion proceeds by an aza-ene-type pathway, inspired us to
develop a highly efficient organocatalytic reaction using a
phosphoric acid catalyst 1 (Scheme 1). In our catalytic
reaction, it is thought that 1 is assembled into the transient
structure of the aza-ene-type reaction of 2 with 3 through a
hydrogen-bonding network (Scheme 1a). Thus, the key
aspect of catalysis is the dual function of the phosphoric
acid moiety,[3c,4b] which electrophilically activates 2 through
the proton (hollow circle) and accepts the NH proton (dashed
circle) of 3 through the Lewis basic phosphoryl oxygen atom.
Subsequent bond recombination, which leads to the aza-ene-
type product and regeneration of the catalyst 1, would ideally
take place (Scheme 1b,c). On the basis of this mechanistic
product of
5 after hydrolysis of 4. [d] Enantiomeric excess was
determined by chiral HPLC analysis (see the Supporting Information).
[e] Reaction performed at 08C.
solvents tested, toluene was the best with respect to both
yield and enantiomeric excess (Table 1, entries 1–3 versus 4),
though the reaction also tolerated common organic solvents.
In addition to the enamide 3a, we examined enecarbamates
3b–d (Table 1, entries 5–7). The steric bulk of the alkoxy
moiety of the enecarbamates exhibited a dramatic effect on
the enantioselectivity. That is, the enantioselectivity increased
with the decrease in the steric demand of the alkoxy moiety,
thus following the order tBuO 3b < BnO 3c < MeO 3d and
reaching 95% ee in the reaction with the less hindered methyl
carbamate 3d (Table 1, entry 7). Lowering the reaction
temperature to 08C led to a slight increase in the enantio-
meric excess, although with some loss of catalytic efficiency
(Table 1, entry 8). With successful results for the catalytic
efficiency in the initial screening, we decreased the catalyst
loading and set the S/C ratio to more than 1000:1 (0.1 mol%;
Table 1, entries 9–11). The decrease in catalyst loading was
clearly still effective, although a prolonged reaction time was
required to achieve a comparable level of product formation
(Table 1, entries 9 and 10); the enantioselectivity and the
yield were maintained at an equally high level. It should be
emphasized that the reaction can be performed without
considerable loss of enantioselectivity, even when the S/C
Scheme 1. Mechanistic assumption of the aza-ene-type reaction cata-
lyzed by 1; see text for details.
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Communications
ratio was increased to as much as 2000:1 (0.05 mol%; Table 1,
entry 11).
product 4 (Ar= Ph) with high enantiomeric excess on
completion of the reaction.
The applicability of the present high S/C organocatalysis
Finally, the synthetic utility of this transformation was
demonstrated by derivatization of 4 to C2-symmetric 1,3-
diamine 7, which is potentially useful as a chiral ligand of
metal complexes and a building block in the synthesis of
to a series of N-benzoylimines 2 was investigated.[9] We set the
S/C ratio to 1000:1 (0.1 mol%) to ensure the catalytic
efficiency of 1. Table 2 shows para- and meta substitution or
natural
products
and
pharmaceutical
compounds
(Scheme 2).[10] The reduction of 4 (Ar= Ph, R = OMe)[11] by
Table 2: Enantioselective aza-ene-type reaction of an enecarbamate 3d
with various N-benzoylimines 2 catalyzed by (R)-1 with a S/C ratio of
1000:1 [0.1 mol%; Eq. (1)][a]
Entry
Ar
Yield [%][b]
ee [%][c]
ꢀ
1
2
3
p-Me-C6H4
m-Me-C6H4
90
83
61
84
82
89
85
53
82
89
84
97
88
91
81
95
93
93
93
92
96
95
95
96
95
95
98
95
95
93
ꢀ
ꢀ
o-Me-C6H4
4[d]
5
o-Me-C6H4
ꢀ
ꢀ
p-MeO-C6H4
Scheme 2. Synthetic utility of b-aminoimine products 4. Conditions:
a) Red-Al, THF, ꢀ78!ꢀ608C, 24 h, 79% (anti/syn=87:13);
b) PhCOCl/NaI, CH3CN, 608C, 12 h, 92%. Red-Al=sodium bis(2-
methoxyethoxy)aluminum hydride.
ꢀ
6
7
p-Br-C6H4
m-Br-C6H4
o-Br-C6H4
o-Br-C6H4
ꢀ
8[e]
9[d]
10
11
12
13
14
15
ꢀ
ꢀ
ꢀ
p-F-C6H4
p-Cl-C6H4
ꢀ
Red-Al afforded anti-1,3-diamine 6 in predominantly good
yield. A subsequent exchange reaction of the protecting
groups[12] from a methoxycarbonyl to a benzoyl moiety led to
C2-symmetric (R,R)-7 without any loss of enantiomeric excess
during the course of the experiments.
In conclusion, we have successfully developed a highly
efficient enantioselective aza-ene-type reaction of N-benzoyl-
imines 2 with enecarbamates. The reaction can be performed
at extremely low loading of the chiral Brønsted acid catalyst 1
without notable loss in enantioselectivity. The present method
provides a practical route to synthetically useful b-amino-
imine derivatives which can be readily transformed to 1,3-
diamine derivatives of synthetic and biological importance.
Further investigation of the reaction mechanisms and poten-
tial of the high S/C organocatalysis is in progress with the aim
of developing practical organic transformations.
ꢀ
p-NC-C6H4
ꢀ
1-naphthyl
ꢀ
2-naphthyl
=
ꢀ
(E)-C6H5-CH CH
[a] Unless otherwise noted, all reactions were carried out using 0.1 mmol
of imine 2 in 0.1m toluene solution at room temperature for 5 h. The
molar ratio of imine 2/enecarbamate 3d/catalyst 1 was 1000:1200:1 (S/
C=1000:1). [b] Yield of the isolated product of 5 after hydrolysis of 4.
[c] Enantiomeric excess was determined by chiral HPLC analysis (see the
Supporting Information). [d] The molar ratio of imine 2/enecarbamate
3d/catalyst 1 was 200:240:1 (S/C=200:1). [e] Reaction performed for
12 h.
connection with a fused-ring system resulted in excellent
yields and enantioselectivities, irrespective of the electronic
nature of the substituents. Although ortho substitution led to
a decrease in the catalytic efficiency, thus giving the product
in moderate yields (Table 2, entries 3 and 8), the yields were
improved in these cases by lowering the S/C ratio to 200:1
(0.5 mol%; Table 2, entries 4 and 9). An imine derived from
an a,b-unsaturated aldehyde was also applicable to the
present high S/C organocatalysis, thus giving the product in
good yield with high enantioselectivity (Table 2, entry 15).
The utility of the high S/C process was further evaluated
by performing a large-scale experiment [Eq. (2)]. The reac-
Experimental Section
A typical procedure for the enantioselective aza-ene-type reaction
catalyzed by chiral Brønsted acid (R)-1 (S/C = 1000:1): A dried test
tube was charged with N-benzoylaldimine (2; Ar= Ph; 20.9 mg,
0.10 mmol) and the atmosphere replaced with nitrogen. After 2 (Ar=
Ph) was dissolved in toluene (0.9 mL), a solution of chiral phosphoric
acid (R)-1 (0.1 mL, 0.0001 mmol) in toluene (0.001m) and then
enecarbamate 3d (21.3 mg, 0.12 mmol) was added at room
temperature.The reaction mixture was stirred for over 5 h
at ambient temperature. The reaction was quenched by
addition of saturated aqueous NaHCO3, and the resulting
solution was extracted with dichloromethane and dried
over anhydrous Na2SO4. After the solvent was evaporated,
the residue was dissolved in methanol (2.0 mL) and an
aqueous solution of HBr (48%, 0.6 mL) was added. The
reaction mixture was stirred at room temperature for
5 min, and then the reaction was quenched by addition of
saturated aqueous NaHCO3 at 08C. The resulting mixture
was warmed up to room temperature and extracted with
dichloromethane. The combined organic layers were dried over
anhydrous Na2SO4. After the solvents were evaporated, the crude
material was purified by chromatography (hexane/EtOAc, 8:1!1:1)
tion proceeded smoothly without any detrimental effect even
on a gram scale. It is noteworthy that only an amount of
3.5 mg of 1 was sufficient to yield 1.7 g of the b-aminoimine
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Chemie
to give b-aminoketone 5 (Ar= Ph) in 82% yield (95% ee) as a white
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Received: October 1, 2005
Published online: March 3, 2006
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scope. The reaction of 8 with imine 2 (Ar= Ph) worked well
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hydrolysis gave the corresponding product 9 in good yield
(80%). Unfortunately, however, the enantiomeric excess was
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[11] A single geometric isomer of 4 was obtained, but the config-
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[12] M. Ihara, A. Hirabayashi, N. Taniguchi, K. Fukumoto, Hetero-
cycles 1992, 33, 851 – 858.
Keywords: asymmetric synthesis · Brønsted acids · ene reaction ·
organocatalysis · phosphoric acid
.
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