A three-component reaction based on a remote-group-directed dynamic kinetic aza-Michael addition: Stereoselective synthesis of imidazolidin-4-ones

Article abstract of DOI:10.1002/chem.200903508

(Figure Presented) In control: An α-amino amide reacted with an aldehyde and a Michael acceptor to form stable imidazolidin-4-ones with high stereoselectivity. A dynamic kinetic aza-Michael addition was discovered and applied to the three-component reacti

Full text of DOI:10.1002/chem.200903508

DOI: 10.1002/chem.200903508
A Three-Component Reaction Based on a Remote-Group-Directed Dynamic
Kinetic Aza-Michael Addition: Stereoselective Synthesis of
Imidazolidin-4-ones
Zhenghu Xu,[a] Tyler Buechler,[a] Kraig Wheeler,[b] and Hong Wang*[a]
Imidazolidin-4-ones, and compounds of similar structure,
constitute a widespread structural motif in natural products
and pharmaceuticals.[1] Imidazolidin-4-one derivatives have
shown a range of biological activities,[2] such as antimalarial
activity,[3] antiproliferative activity for melanoma,[4] and so
forth. Imidazolidin-4-ones have also been widely used in
peptidomimetics,[5] as chiral auxiliaries for the synthesis of
amino acids and other important compounds,[6] as an impor-
tant chiral building block in the total synthesis of natural
products,[7] and, most recently, as organocatalysts for imini-
um-based reactions.[8] Even though other methods are avail-
able,[9] the general synthetic approach to imidazolidin-4-ones
is through condensation of protected amino acids or pep-
tides with carbonyl compounds followed by intramolecular
cyclization.[3,8–10] This reaction can be catalyzed by an acid[11]
or a base.[5,12] Despite the presence of chiral center(s) in the
amino acids/peptides, the diastereoselectivity of the forma-
tion of imidazolidin-4-ones is low. Furthermore, N1-unsub-
stituted imidazolidin-4-ones are unstable and readily under-
go hydrolysis under acidic and neutral conditions.[10b] Given
the importance of this class of compounds, a stereoselective
synthesis of stabilized imidazolidin-4-ones is desirable.
chael additions,[17] in particular intermolecular addition of
simple amines, are very rare.[18] Herein, we report the highly
diastereoselective formation of stable imidazolidin-4-one de-
rivatives through a three-component reaction based on a
Brønsted acid catalyzed, remote-group-directed dynamic ki-
netic aza-Michael addition.
N1-unsubstituted imidazolidin-4-ones can be stabilized by
non-stereoselective formation of a salt[8] or by acylatio-
n.[3a,6b,19] We are interested in N1 alkylation through aza-Mi-
chael addition, which can provide a stable tertiary amine
and, at the same time, introduce a new functional group (a
carbonyl group) to the structural motif that could open up
the compound to wider reaction possibilities. For simple sec-
ondary amines there will be competition between iminium
activation and aza-Michael addition under acidic conditions
(Scheme 1), and iminium formation is generally favored. We
Scheme 1. Iminium activation and aza-Michael addition of a secondary
amine under acidic conditions.
Aza-Michael additions have grown into an important
strategy for constructing C N bonds.[13] These additions typi-
À
cally occur under basic conditions,[14] but Lewis acids[15] and
organocatalysts[16] have also been shown to catalyze aza-Mi-
chael additions. In contrast, Brønsted acid catalyzed aza-Mi-
intend to invert this by introducing a remote directing
group,[20] so that the carbonyl of the unsaturated ketone is
activated and the unstable secondary amine is oriented in a
favorable position for the aza-Michael addition.
To test this idea, we synthesized N1-unsubstituted imida-
zolidin-4-ones 3a and 4a (Scheme 2). Under acidic condi-
tions, pyridin-2-yl incorporated amino amide 1a reacted
with aldehyde 2a to give a mixture of two diastereomers
(3a/4a, 1:1.6). Compounds 3a and 4a were separated by
column chromatography (silica). Even though 3a and 4a
were stable enough to undergo column chromatography, iso-
merization was observed in solution under neutral condi-
tions within two days (see Supporting Information).[21] It is
expected that, under acidic conditions, the pyridyl moiety
[a] Dr. Z. Xu, T. Buechler, Prof. H. Wang
Department of Chemistry and Biochemistry
Miami University, 701 East High Street
Oxford, OH 45056 (USA)
Fax : (+1)513 529-5715
E-mail: wangh3@muohio.edu
[b] Prof. K. Wheeler
Department of Chemistry, Eastern Illinois University
600 Lincoln Ave., Charleston, IL 61920 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903508.
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Chem. Eur. J. 2010, 16, 2972 – 2976

COMMUNICATION
trans-isomers (4a) gave the cis-
product (6a) as the major
product with a d.r. of 14:1 and
12:1, respectively.
The preferred formation of
the cis-product is likely to
follow a dynamic kinetic path-
way
(Scheme 3).[22]
Our
Scheme 2. Formation of N1-unsubstituted imidazolidin-4-ones under acidic conditions.
1H NMR data have shown that
an equilibrium exists between
will be protonated, which will activate the Michael acceptor
(methyl vinyl ketone, MVK) and, more importantly, the pro-
tonated pyridyl group will act as a remote directing group to
position the Michael acceptor and the secondary amine in a
favorable orientation for aza-Michael addition (Figure 1).
3a and 4a (see Supporting Information). Therefore, we
speculate that the reaction of 3a with MVK is faster than
that of 4a due to its reduced steric hindrance (the isopropyl
group assumes a pseudo axial orientation in the trans-
isomer (4a), Figure 1),[23] and this rate difference enforces
the highly diastereoselective formation of the cis-product
6a.
Having observed the highly diastereoselective alkylation
of unstable secondary amines, we decided to attempt a
three-component reaction to take advantage of the dynamic
kinetic aza-Michael addition. Multicomponent reactions
(MCRs) have become an important synthetic strategy in or-
ganic synthesis to build up structural and functional com-
plexity owing to their reaction efficiency, low cost, and atom
economy.[24] However, due to the coexistence of multiple
substrates and functional groups, the chemo- and stereose-
lectivity of MCRs remains a challenge. The three-compo-
nent reaction was carried out by mixing 1a, 2a, and 5a di-
rectly in ethanol in the presence of trifluoroacetic acid
(TFA; Table 1, entry 2). Two equivalents of TFA were
Figure 1. Proposed transition states of the aza-Michael addition.
N1-unsubstituted imidazolidin-4-ones 3a and 4a were then
treated with MVK (5a) under acidic conditions (Scheme 3).
We were excited to observe that both 3a and 4a reacted
with MVK to afford the desired N1-substituted imidazoli-
din-4-ones 6a and 7a, respectively, in high yields (90 and
Table 1. Optimization of reaction conditions.[a]
91%, respectively). To our surprise, both the cis-ACTHNUGTRNEUNG(3a) and
Entry Acid
Solvent
T
t
d.r.[c]
Yield
[%][d]
[8C] [h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[b]
15[b]
–
EtOH
EtOH
EtOH
25
25
25
25
70
25
66
25
66
25
25
44
24
12
12
24
12
24
24
36
24
48
48
15
48
48
48
0
TFA (2 equiv)
TsOH (20%)
Cu
Yb
TFA (20%)
TFA (2 equiv)
TFA (1 equiv)
TFA (20%)
TFA (2 equiv)
TFA (2 equiv)
TFA (2 equiv)
TFA (2 equiv)
TFA (2 equiv)
TsOH (20%)
>50:1 37(51)[e]
23:1 40 (40)[e]
7:1 54
G
2A
N
3A
9:1 61
3:1 50
9:1 40
3:1 50
EtOH
THF
THF
THF
1.4:1 30
>50:1 63
14:1 50
>50:1 67
>50:1 85
5:1 35
DMF
CH3CN
CH2Cl2
isopropanol 25
isopropanol 25
isopropanol 25
9:1 67
[a] The reactions were carried out with 1a (0.2 mmol), aldehyde
(0.22 mmol), and MVK (0.1 mL) in 1.5 mL solvent. [b] Benzaldehyde
1
was used. [c] Determined by H NMR spectroscopy of the crude product,
cis-products are the major isomer. [d] Isolated yield of the major product.
Scheme 3. Dynamic kinetic aza-Michael addition.
[e] Yield of the byproduct is given in brackets.
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H. Wang et al.
Table 2. Substrate scope of the three-component reaction.
added to ensure the protonation of the pyridyl moiety. To
our delight, this three-component reaction occurred at room
temperature to give the desired product, 6a, in 37% yield,
but with excellent diastereoselectivity (6a/7a>50:1). The
excellent diastereoselectivity is attributed to the dynamic ki-
netic approach of the aza-Michael addition. The other major
byproduct was identified as acetal 8 (51% yield, Table 1).
Encouraged by these preliminary results, we decided to opti-
mize the reaction conditions (Table 1). It was found that the
strength and the amount of acid played pivotal roles in this
reaction (entries 1–9). The reaction did not occur at all in
the absence of an acid (entry 1). A stronger Brønsted acid
(TsOH) gave the desired product in very good diastereose-
lectivity (d.r.=23:1), but in low yield (40%) and quantita-
tive formation of byproduct 8 (40% yield; entry 3). Metal
Lewis acids also catalyzed the reaction, but with lower dia-
stereoselectivity (entries 4 and 5). When less TFA was used,
the diastereoselectivity decreased significantly both in etha-
nol (entries 2 and 6) and in THF (entries 7–9). Other sol-
vents were also screened in order to suppress the formation
of byproduct 8. When isopropanol was used (entry 13), 6a
was obtained in 85% yield and excellent diastereoselectivity
(d.r.>50:1).
Entry
Product
Entry
Product
1[a]
2[a]
6a
6c
6e
6b
6d
6 f
3[a]
4[a]
5[b]
6[b]
7[b]
8[b]
Having established optimum conditions for the three-
component reaction, we investigated the substrate scope of
aldehyde 2. All of the electron-poor aromatic aldehydes
gave the desired product in good yields and excellent diaste-
reoselectivities when reacted in the presence of two equiva-
lents of TFA in isopropanol (Table 2, entries 1–4, 12–14).
However, when an electron-rich aromatic aldehyde, for ex-
ample benzaldehyde, was used under similar conditions the
reaction resulted in a low yield (35%) and low diastereose-
lectivity (d.r. 5:1; Table 1, entry 14). The reaction conditions
were then optimized for electron-rich aromatic aldehydes
(20 mol% of TsOH, isopropanol, Table 1, entry 15). Under
these optimized conditions, all the electron-rich aromatic al-
dehydes produced the desired products in good yields and
diastereoselectivities (entries 5–9). Electron-rich aliphatic al-
dehydes required higher temperatures, but also generated
the desired product in reasonable yields and excellent dia-
stereoselectivities (entries 10 and 11). Amino amides de-
rived from l-alanine and l-phenylalanine were examined
for this three-component reaction and lead to the desired
product with excellent diastereoselectivities (entries 12 and
13). The reaction of ethyl vinyl ketone (EVK), another Mi-
chael acceptor, gave the expected product in 90% yield and
d.r.>50:1. However, chalcone and methyl acrylate are not
reactive enough to furnish any product.
6g
6h
6j
6l
9[b]
10[c]
6i
11[c]
12[a]
6k
13[a]
14[a]
6m
6n
[a] TFA (2 equiv), RT. [b] TsOH (20 mol%), RT. [c] TsOH (20 mol%),
808C.
To illustrate the importance of the directing group,
amides 1b, 1c, and 1d were prepared (see Supporting Infor-
mation for synthetic details). In sharp contrast to the reac-
tion of 1a, the reaction of 1b–1d with 2a and 5a did not
generate any desired three-component product (Scheme 4).
These results strongly suggest that the presence of the di-
recting group (the protonated pyridyl group) is crucial for
the three-component reaction (compare 1a and 1d); these
results also demonstrate that the directing group must be ar-
ranged in a favorable position in order to facilitate the reac-
tion (compare 1a with 1b and 1c).
The structures of the products from the three-component
reactions were determined using 1H NMR, 13C NMR, 1H-
COSY, NOESY, ESI-MS and HR-MS (see Supporting Infor-
mation). A crystal structure was also determined for com-
pound 6c (Figure 2), further confirming its absolute configu-
ration.
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Aza-Michael Addition
COMMUNICATION
Acknowledgements
Z.X. and H.W. thank Prof. Mike
Novak at the Department of Chemis-
try and Biochemistry of Miami Uni-
versity for helpful discussions. K.W.
acknowledges
an
NSF
grant
(0722547). Financial support was pro-
vided by Miami University.
Keywords: Brønsted
acid
catalysis · diastereoselectivity ·
dynamic kinetic alkylation
Michael addition
multicomponent reactions
·
·
Scheme 4. Three-component reaction and the effect of remote group control.
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Received: December 21, 2009
Published online: February 11, 2010
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