Bronsted acid catalyzed enantioselective three-component reaction involving the α addition of isocyanides to imines

Full text of DOI:10.1002/anie.200902385

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DOI: 10.1002/anie.200902385
Multicomponent Reactions
Brønsted Acid Catalyzed Enantioselective Three-Component Reaction
Involving the a Addition of Isocyanides to Imines**
Tao Yue, Mei-Xiang Wang,* De-Xian Wang, Gꢀraldine Masson, and Jieping Zhu*
The Passerini three-component reaction (P-3CR)[1] and the
Ugi four-component reaction (U-4CR)[2] are two of the most
important multicomponent reactions (MCRs) known to date.
Because of the mildness of reaction conditions, the wide
application scope, and the high variability (four diversity
points for U-4CR) they are ideally suited for generating
molecular diversity and complexity; they are widely used in
the syntheses of natural products and medicinally relevant
compounds.[3] In these reactions, one chiral center is created,
which results from the a addition of divalent isonitrile carbon
atom to polarized double bonds (carbonyl or imine groups),
therefore the ability to control the stereochemical outcome
would significantly expand their synthetic utility. Although
diastereoselective P-3CR[4] and U-4CR[5] using chiral sub-
strates or chiral auxiliaries have been reported,[6] the develop-
ment of an enantioselective version of these reactions remains
a significant challenge. In spite of the great efforts dedicated
to this field, only limited success has been made, thereby
highlighting the difficulties associated with the development
of such a catalyst.[7] In this context, Denmark and Fan
developed an elegant Lewis base catalyzed enantioselective
two-component Passerini reaction.[8] Dꢀmling and co-workers
discovered that a stoichiometric amount of a titanium–taddol
(taddol = 1,1,4,4-tetraphenyl-2,3-O-isopropylidene-d-threi-
tol) complex was capable of promoting the P-3CR reaction to
afford the a-acyloxyamides in moderate enantioselectivi-
ties.[9] Schreiber and co-workers demonstrated that an indan
copper(II)–pybox (pybox = pyridine-2,6-bisoxazoline) com-
plex was able to catalyze the P-3CR; however, the enan-
tioenriched Passerini adducts were obtained only when
chelating aldehydes were used as reaction partners.[10] We
have recently reported that the chiral aluminum–salen
(salen = N,Nꢁ-bis(salicylidene)ethylenediamine) complex[11]
was an efficient catalyst for the enantioselective Passerini
three-component reaction.[12] All these enantioselective cata-
lytic processes involve an a addition of isocyanides to
aldehydes as a key step. To the best of our knowledge, there
is no single report on Ugi-type reactions which involve the
a addition of isocyanides to imines for generating the chiral
centers. As a continuation of our interests in developing
enantioselective isocyanide-based transformations, we report
herein that the chiral phosphoric acid 5g is able to catalyze
the three-component reaction of the aldehydes 2, anilines 3,
and a-isocyanoacetamides 4, leading to 2-(1-aminoalkyl)-5-
aminoxazoles (1) in excellent yields and moderate to good
enantioselectivities (Scheme 1).[13]
Scheme 1. Chiral phosphoric acid catalyzed enantioselective a addition
of a-isocyanoacetamides to imines: Three-component synthesis of
2-(1-aminoalkyl)-5-aminooxazoles.
[*] T. Yue, Dr. M.-X. Wang, Dr. D.-X. Wang
National Natural Laboratory for Molecular Sciences
Laboratory of Chemical Biology, Institute of Chemistry
Chinese Academy of Sciences, Beijing 100190 (China)
and
Chiral phosphoric acids are now well-established as
bifunctional organocatalysts, particularly in catalyzing the
addition of nucleophiles to imines/acylimines.[14,15] As a
prelude of our work, we examined the reaction of the
preformed imine 6a (R1 = tBu) and the a-isocyanoacetamide
4a (R2 = Bn)[16] in the presence of chiral phosphoric acids.[17]
As it can be seen from Table 1, all the phosphoric acids
investigated were able to catalyze the oxazole formation,
however the enantioselectivity varied significantly with 5g
and 5l being the most efficient. The N-triflyl phosphoramide
5o,[18] a stronger Brønsted acid than 5l, efficiently catalyzed
the reaction but with reduced asymmetric induction (Table 1,
entry 18). Among the solvents screened, toluene was found to
be the most appropriate (Table 1, entries 19–21). Overall, the
optimum conditions consisted of performing the reaction in
toluene (c = 0.05m) at À208C in the presence of 5g or 5l
(0.2 equiv) as a catalyst. Oxazoles synthesized under these
The Key Laboratory of Bioorganic Phosphrous Chemistry and
Chemical Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
http://www.mxwang.iccas.ac.cn
E-mail: mxwang@iccas.ac.cn
Dr. G. Masson, Dr. J. Zhu
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
http://www.icsn.cnrs-gif.fr/article.php3?id article=122
E-mail: zhu@icsn.cnrs-gif.fr
[**] We gratefully acknowledge the National Science Foundation of
China (NSFC), the Chinese Academy of Science, and CNRS, ANR
(France) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902385.
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Table 1: Brønsted acid catalyzed reaction of 4a and 6a.
Entry
Catalyst
Solvent
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5l
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
iPr2O
RT
À7
99
97
96
87
77
99
92
93
47
99
21
99
76
89
99
99
74
99
94
97
99
38
39
52
32
26
12
7
À20
À40
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
6
9
25
54
53
18
23
19
58
40
33
25
52
35
3
10
11
12
13
14
15
16
17
18
19
20
21
Figure 1. General reaction conditions: preformed imine 6/4=1:1 (6
not shown), in toluene c=0.05m, 5 (0.2 equiv). Yield refers to
chromatographically pure material; ee value was determined by chiral
HPLC analysis. Catalyst 5l was used for the preparation of 1a–1c and
catalyst 5g was used for the preparation of 1d–1i.
5l
5l
CH2Cl2
MeCN
Table 2: Three-component reaction catalyzed by the phosphoric acid 5g.
[a] Reaction conditions: 6a/4a=1:1, in toluene c=0.05m, 5 (0.2 equiv).
[b] Yield of chromatographically pure material. [c] Determined by chiral
HPLC analysis. Bn=benzyl, PMP=para-methoxyphenyl, Tf=trifluoro-
methanesulfonyl.
Entry
3
Additive
1
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
X=OMe
X=OMe
X=OMe
X=OMe
X=F
X=Cl
X=Br
X=CF3
none
1e
1e
1e
1e
1j
1k
1 l
1m
95
92
90
80
91
89
92
82
84
77
67
66
84
88
88
90
3 ꢀ M.S.
4 ꢀ M.S.
5 ꢀ M.S.
none
none
none
none
M.S.=molecular sieves.
summarized in Table 2. Gratefully, the three-component
reaction proceeded smoothly to afford the enantioenriched
adduct in excellent yield and enantioselectivity. The best
result was obtained when 4-trifluoroaniline was used as an
amine, which led to 1m in 82% yield and 90% ee (Table 2,
entry 8). The addition of molecular sieves reduced the
ee value of the products (Table 2, entries 2–4). In contrast,
by using 2-hydroxyaniline, the corresponding oxazole was
obtained in 54% yield with only 13% ee.
The generality of this chiral phosphoric acid catalyzed
three-component reaction was next examined and the results
are summarized in Figure 2. The reaction was applicable to
representative aliphatic aldehydes including linear heptalde-
hyde, a-branched cyclohexanecarbaldehyde, isobutyralde-
hyde, and highly hindered pivalaldehyde, with the latter
being the best substrate in terms of the ee value of the
product. The aromatic aldehydes also participated in the
reaction to provide the corresponding adducts, albeit with
conditions are listed in Figure 1. A simple recrystallization of
1d from diethyl ether increased the ee value of the product to
90%.
Whereas these results represented the first examples of
enantioselective a addition of isocyanides to imines, the use
of a preformed imine as a reactant limited its application
scope. Indeed imines derived from aliphatic aldehydes are
generally unstable and difficult to access, therefore we set out
to examine the more challenging three-component version.
Reasoning that the basicity of aniline might influence the
catalytic efficiency of the process, the reaction of the
4-substituted aniline 3, having different electronic properties,
with pivalaldehyde (2a) and a-isocyano-a-phenylacetamide
(4b) in the presence of 5g was investigated and the results are
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oxidative conditions furnished dipeptide 7. Alternatively, the
authentic amide (S)-7 was synthesized from (S)-N-Boc-tert-
leucine (8) and the glycine amide 9 by using a standard three-
step sequence. Comparison of the sign of the optical rotation
allowed the assignment of the R configuration to the oxazole
1d.
We have previously demonstrated that Ugi-type reactions
can be performed in toluene in the presence of weak Brønsted
acid such as ammonium chloride.[19] Hence, a possible
reaction scenario is proposed in Scheme 3. Protonation of
Scheme 3. Reaction pathway of phosphoric acid catalyzed three-com-
ponent synthesis of 5-aminooxazoles.
imine 6 by the phosphoric acid would lead to the formation of
the iminium salt 10. The nucleophilic addition of the divalent
carbon atom of isonitrile 4 onto the Si face of the iminium
group would afford the nitrilium intermediate 11, which could
undergo cyclization to afford 12. Deprotonation of the proton
on C4 of 12 by the phosphate anion would afford the
5-aminooxazole 1 with concurrent regeneration of the
phosphoric acid. The 5-aminooxazole is apparently stable
under the reaction conditions as no hydrolysis product was
observed.[20]
By using the silver salt of the phosphoric acid 5a as a
catalyst, the reaction of 6a and 4a afforded the racemic
oxazole 1a in only 20% yield. This result indicated that the
reaction is indeed catalyzed by the Brønsted acid. A control
experiment showed that asymmetric induction depended only
on the chirality of the phosphoric acids. Therefore, the
reaction of (S)-4a or (Æ )-4a with imine 6a in the presence of
catalyst (R)-5 l afforded the oxazole 1a with identical
enantiofacial selectivity and enantiomeric excess.
Figure 2. 5g-catalyzed three-component reaction of aldehyde, aniline,
and a-isocyanoacetamide.
reduced ee values (results not shown). The parent a-isocya-
noacetamide, having a phenyl, benzyl, and methyl substituent
at the a-position, as well as a dipeptide isocyanide partici-
pated in this reaction to provide the corresponding oxazoles
in excellent yields and moderate to good ee values (56–90%).
The absolute configuration of oxazole 1d was determined
as shown in Scheme 2. Hydrolysis of 1d under acidic
conditions and subsequent removal of the PMP group under
The aminooxazole 1 bearing three basic nitrogen atoms
can potentially compete with the imine 6 to form a salt or a
hydrogen bond with the phosphoric acid, which is detrimental
to the desired catalytic cycle. To gain mechanistic insight, we
did the following NMR titration experiments. When one
equivalent each of the imine 6a and the phosphoric acid 5g
was mixed in C6D6 at room temperature, the imine was
completely protonated as indicated by the downfield shift of
imine proton (Dd = 1.57 ppm). In contrast, the 1H NMR
spectrum of 1e was almost unchanged upon addition of one
equivalent of the phosphoric acid 5g. Finally, when an NMR
Scheme 2. Determination of the absolute configuration of 1d. TFA=
trifluoroacetic acid, THF=tetrahydrofuran, CAN=ceric ammonium
nitrate, Boc=tert-butoxycarbonyl, EDC=1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide, HOBt=1-hydroxybenzotriazole.
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[6] “Asymmetric Isocyanide-based MCRs”: L. Banfi, A. Basso, G.
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spectrum of a mixture of 1e, 6a, and 5g in C6D6 was recorded,
only the spectrum of imine 6a was shifted (see the Supporting
Information). These experiments demonstrated that the
phosphoric acid was capable of activating selectively the
imine and that the product inhibition was minimum.
In summary, we have reported a chiral phosphoric acid
catalyzed three-component synthesis of enantioenriched 2-(1-
aminoalkyl)-5-aminooxazoles. This represented the first
example of enantioselective a-addition of a-isocyanides to
imines for the creation of chiral molecules and may lay the
foundation for the development of long-awaited enantiose-
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Experimental Section
General procedure: Aldehyde (0.25 mmol), aniline (0.25 mmol), and
dry toluene (2.0 mL), were added to a flame-dried round-bottom
flask equipped with a stir bar. The solution was stirred at room
temperature for about 0.5–1 h. The phosphoric acid 5g (0.05 mmol)
was then introduced and the resulting mixture was cooled to À208C.
A solution of a-isocyano acetamide (0.25 mmol) in toluene (3.0 mL)
was added slowly via a syringe pump (addition time 1.5 h). After
being stirred at À208C for 20–24 h, the reaction mixture was purified
by flash column chromatography (SiO2, petroleum ether/EtOAc =
4:1) to give the corresponding oxazole.
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Received: May 5, 2009
Published online: August 5, 2009
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Keywords: asymmetric synthesis · heterocycles ·
.
multicomponent reactions · organocatalysis · Ugi reaction
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