Rationally designed amide donors for organocatalytic asymmetric michael reactions

Article abstract of DOI:10.1002/anie.201200996

Amide nucleophiles on demand: Rationally designed pyrazoleamides function as Michael donors in urea-catalyzed asymmetric Michael reactions with excellent chemical and optical yields (see scheme). The pyrazoleamide group performs as an ester equivalent, a directing group, an activating group, and functions as a good leaving group in further transformations of the product. Copyright

Full text of DOI:10.1002/anie.201200996

Angewandte
Chemie
DOI: 10.1002/anie.201200996
Organocatalysis
Rationally Designed Amide Donors for Organocatalytic Asymmetric
Michael Reactions**
Bin Tan, Gloria Hernꢀndez-Torres, and Carlos F. Barbas III*
Michael reactions are among the most powerful and efficient
methods for carbon–carbon bond formation,[1] and a great
deal of effort has been devoted to the development of
organocatalytic asymmetric Michael reactions of carbonyl
compounds with nitroalkenes.[2,3] The carbonyl substrates for
these reactions are limited to aldehydes,[4] ketones,[5] 1,3-
dicarbonyl compounds,[6] and 3-substituted oxindoles[7] that
have a relatively low pKa value associated with the a hydrogen
atoms. To date, there have been no reports concerning the use
of amides as donors in these reactions. Recently, the use of
ester equivalents as pronucleophiles in direct transformations
has been demonstrated.[8] The use of ester equivalents is
challenging, however, because their pKa values (the values
being approximately 19) are much higher than those of
ketones, aldehydes, and 1,3-dicarbonyl substrates. In addition,
challenges still remain regarding substrate scope and reaction
selectivity, including diastereo- and enantioselectivity. We
have reported strategies based on the use of trifluoroethyl
thioesters as pronucleophiles in organocatalytic Michael
reactions.[8c] The drawbacks of this approach include the
cost of trifluoroethanethiol and the fact that the diastereose-
lectivity of these reactions is modest. Therefore, mild reaction
conditions for the direct organocatalytic asymmetric carbon–
carbon bond formation involving ester equivalents have yet to
be fully established. Furthermore, the use of amides as
pronucleophiles in such transformations has not been
reported.
enhancing stereocontrol, and as a good leaving group for
subsequent transformations. We hypothesized that the aro-
matic properties of the pyrazoleamide should engender an
amide of relatively low pKa value that would facilitate
enolization with weak amine bases, thus allowing the use of
amide pronucleophiles in organocatalysis to be explored.
From a synthetic point of view, it is noteworthy that these
pyrazoleamide derivatives are also stable and are readily
synthesized from carboxylic acids in a single step and in
quantitative yields. We assume that simple pyrazoleamides,
(Figure 1) should act as general amide substrates for a variety
of transformations.
Figure 1. Features of pyrazoleamide substrates.
We initiated our studies by evaluating the reaction
between pyrazoleamide 1a and nitrostyrene 2a in dichloro-
methane at room temperature, in the presence of the bifunc-
tional Takemoto catalyst I (Scheme 1). The reaction pro-
ceeded smoothly and afforded the desired product in high
yield, albeit with moderate diastereoselectivity (3:1 d.r.) and
enantioselectivity (52% ee). Given the pioneering studies of
the group of Deng[11] and other groups on cinchona alkaloid
catalysis[12] and our own findings that this class of catalyst
efficiently promotes pyrazole-based cycloaddition reactions,
we decided to test the use of catalyst II in the reaction under
investigation. With catalyst II, we obtained slightly better
yields and selectivities than those that were observed when
catalyst I was used (Scheme 1). However, the use of the
6’-hydroxy cinchona catalysts (III and IV), described by Deng
and co-workers, and the use of other thiourea-based catalysts
(V and VI) gave poor results (Scheme 1).
Recently, Sibi and Itoh have described the use of the 3,5-
dimethyl pyrazole template as a hydrogen bond acceptor to
facilitate activation of the electrophilic substrate in an
organocatalytic Michael reaction.[9] We recently reported
a novel organocatalytic asymmetric [3+2] cycloaddition
reaction between pyrazoleamide[10] and methyleneindoli-
nones that allows extraordinary levels of stereocontrol in
the construction of spirocyclic oxindole derivatives. In these
studies the pyrazoleamide serves as a directing group for
[*] Dr. B. Tan, Dr. G. Hernꢀndez-Torres, Prof. Dr. C. F. Barbas III
The Skaggs Institute for Chemical Biology and the
Departments of Chemistry and Molecular Biology
The Scripps Research Institute
To improve stereocontrol, we modified the design of the
pyrazoleamide substrate to enhance its potential for hydrogen
bonding with catalysts. Specifically, we removed the pyrazole
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: carlos@scripps.edu
ꢀ
methyl groups to facilitate access of the catalyst to the N N
Dr. G. Hernꢀndez-Torres
moiety for hydrogen bonding. This derivative 1b was tested in
the reaction, using I as a catalyst, and almost complete
diastereocontrol and good enantioselectivity (80% ee) was
observed (Table 1, entry 1). Attempts to optimize the reac-
tion by conducting it in a different solvent or at different
temperatures failed to provide the desired improvements in
chemical and optical yield (see the Supporting Information).
Departamento de Quꢁmica Orgꢀnica
Universidad Autꢂnoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
[**] Research support from the Skaggs Institute for Chemical Biology is
gratefully acknowledged. We also thank Dr. A. L. Rheingold and Dr.
C. E. Moore for the X-ray crystallographic analysis. G.H.-T. also
thanks Universidad Autꢂnoma de Madrid for financial support.
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Table 1: Yields and selectivities of Michael reactions involving pyrazo-
leamide 1b in the presence of various catalysts.[a]
Entry
Catalyst
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
I
II
VII
VIII
IX
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
90
76
88
95
90
83
61
87
88
81
77
91
90
90
84
95
>20:1
14:1
>20:1
>20:1
>20:1
9:1
2:1
17:1
18:1
13:1
7:1
19:1
19:1
>20:1
>20:1
>20:1
80
72
51
75
70
72
29
74
84
78
75
89
87
91
93
95
X
XI
XIII
XIV
XV
XII
XIV
XIV
XIV[e]
XIV[f]
XIV[g]
9
10
11
12
13
14
15
16
o-xylene
CHCl3
CHCl3
CHCl3
[a] Unless otherwise specified, all reactions were carried out using
pyrazoleamide 1b (0.05 mmol, 1.0 equiv) and nitrostyrene 2a
(0.1 mmol, 2.0 equiv) in specified solvent (0.25 mL) with 20 mol% of
catalyst at 228C for 6 h. [b] Yields of isolated product. [c] Determined by
analysis of the 1H NMR spectrum of the crude product. [d] Determined
by HPLC using a chiral stationary phase. [e] Reaction was conducted at
08C. [f] Reaction was conducted at ꢀ208C with 10 mol% of catalyst for
12 h. [g] The reaction was carried out using 1b (0.11 mmol, 1.1 equiv)
and 2a (0.1 mmol, 1.0 equiv) with 10 mol% of the catalyst at ꢀ208C for
12 h.
Scheme 1. Initial test reactions involving dimethylpyrazoleamide 1a.
Bn=benzyl.
We therefore evaluated the effects that modifications to the
structure of catalyst I had on the reaction outcome. The use of
catalysts representing changes to the structure of the tertiary
amine moiety and the thiourea moiety of I resulted in poorer
enantioselectivity (Table 1, entries 3–8) compared to that
obtained when using catalyst I, thus suggesting that the
electronic properties of the aniline group and the steric
environment of the nitrogen center are important for
asymmetric induction. Recently, the groups of Wennemers[8a]
and Coltart[13] independently reported that the use of enolates
derived from thioesters in Michael and Mannich reactions
give products with higher enantioselectivity when urea
catalysts are used in place of thiourea catalysts. Although
thiourea-based catalysts are generally more effective in
Michael and Mannich reactions than urea-based analogues
because of the former’s increased hydrogen bonding capa-
bilities, the latter have been reported to possess superior
anion stabilizing properties in some cases.[14] Indeed, the
enantioselectivity of the Michael reaction between pyrazo-
leamide 1b and nitrostyrene 2a increased when urea-con-
taining cinchona-based catalysts XIV and XV (Table 1,
entries 9 and 10) were used in place of catalyst I. Similarly,
the use of the urea analogue of I (XII) provided enhanced
diastereo- and enantioselectivity (Table 1, entry 11). Of the
solvents tested for the reaction catalyzed by XIV, chloroform
proved optimal with respect to the catalytic activity, diaste-
reoselectivity, and enantioselectivity (Table 1, entry 12).
Higher diastereoselectivities, enantioselectivities, and yields
were observed when the reaction catalyzed by XIV was
conducted at lower temperatures and in the presence of
a higher ratio of pyrazoleamide to nitrostyrene (Table 1,
compare entry 12 to entries 14–16).
We then evaluated the use of various nitro olefins as
reactants (Table 2). Most reactions were complete within
24 hours and gave products in good to excellent yields (85–
99%) and with excellent enantioselectivities (88-97% ee) and
diastereoselectivities (10:1! > 20:1 d.r.). For the use of b-aryl
nitro olefins, the position and the electronic properties of the
substituents on the aromatic ring appeared to have a very
limited effect on stereoselectivity. Regardless of the type of
substituents on the aromatic rings, be them electron-with-
drawing (Table 2, entries 2–6), electron-donating (Table 2,
2
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Table 2: Generality of reaction demonstrated with a variety of nitro
olefins electrophiles.[a]
Entry
R
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
12
12
3b, 95
3c, 90
>20:1
95
94
18:1
Scheme 2. Generality of the reaction with respect to the pyrazoleamide
derivative. For procedures, please see the Supporting Information.
3
4
5
12
12
12
3d, 89
3e, 89
3 f, 98
>20:1
>20:1
>20:1
94
94
97
aromatic functionality is required to bring the pKa value
into a functional range for these organocatalytic conditions.
The pyrazoleamide group was introduced because it
engenders an acidic a center and provides a handle for
stereochemical control through hydrogen bonding with
a chiral catalyst. The introduction of the pyrazole group
also provides other advantages. Its intrinsic reactivity can be
exploited in subsequent reactions to produce a diverse range
of products; for example, the pyrazole moiety can be easily
displaced by nucleophiles such as alcohols and amines in one-
pot or multistep methods (Scheme 3).
6
7
8
9
12
18
12
18
3g, 96
3h, 91
3i, 93
3j, 92
>20:1
>20:1
>20:1
>20:1
94
92
90
90
10
11
12
24
3k, 99
3l, 85
10:1
93
88
>20:1
[a] Unless otherwise specified, all reactions were carried out using
pyrazoleamide 1b (0.11 mmol, 1.1 equiv) and nitrostyrene 2a–2k or 2l
(0.1 mmol, 1.0 equiv) in chloroform (0.5 mL) with 10 mol% of catalyst at
ꢀ208C. [b] Yield of isolated product. [c] Determined by 1H NMR
spectroscopy. [d] Determined by HPLC using a chiral stationary phase.
Scheme 3. Synthetic transformation involving the pyrazole functional
group.
entries 7–8), or neutral (Table 2, entry 1) groups, or the
substitution pattern (para, meta, or ortho; Table 2, entries 2–
5), the reactions of these nitro olefins gave excellent yields
and selectivities. The use of nitro olefins with heteroaromatic
groups, such as furyl and thienyl, also afforded the desired
product with excellent stereocontrol (Table 2, entries 9 and
10). Although alkyl nitro olefins derived from octanal were
not optimal electrophiles, the desired product was obtained
under the optimized reaction conditions (Table 2, entry 11).
Next we explored the generality of the reaction with
regards to variation of the pyrazoleamide reactant
(Scheme 2). The electronic properties of the aromatic ring
substituents affected the reactivity of the pyrazoleamide. The
presence of electron-withdrawing groups, such as a nitro
group, halogens, or a trifluoromethyl group, facilitated the
reaction. The presence of chlorine, bromine, or fluorine
substituents on an aromatic moiety can also alter the
pharmacological activity of a compound class.[15] The use of
hetereoaromatic pyrazoleamides gave the desired product in
good yield and diastereoselectivity, but in lower enantiose-
lectivity. Derivatives with alkyl, bromine, or trifluoromethyl
groups in place of an aromatic ring were virtually unreactive
under the reaction conditions, thus suggesting that an
Our findings, together with the dual activation model
proposed by the group of Takemoto and co-workers[6a,16] and
the theoretical calculations performed by Papai and co-
workers,[17] and Zhong and co-workers,[12m] suggest that the
nitro olefin and the pyrazoleamide substrates, might be
activated simultaneously by the catalyst (see the Supporting
Information, Figure S2). Enolization of pyrazoleamide com-
pounds under mild reaction conditions might occur by
a productive combination of favourable pyrazoleamide acid-
ity and assistance from the bifunctional catalyst. The urea
moiety of the catalyst likely forms hydrogen bonds to both the
carbonyl group and a nitrogen atom of the pyrazole moiety,
while the tertiary amine moiety most likely functions as
a base, thus enabling intracomplex deprotonation. Electro-
philic activation of the Michael acceptor through its binding
to the protonated amine group of the catalyst is believed to
create a steric environment that determines the relative
ꢀ
orientation of the approaching substrates for the C C bond
formation, thus inducing stereoselectivity. The absolute con-
figuration of 3o was determined by X-ray crystallographic
analysis (see the Supporting Information, Figure S3) and it is
in accordance with the configuration predicted by this model.
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The lack of reactivity of methoxy derivative 1v and
pyrrolidinyl 1w (Scheme 4) indicate that an activating
substituent on the carbonyl group is required to bring the
Scheme 4. Control experiments in support of the proposed mecha-
nism.
pKa value into a functional range. The aromatic function-
alities in 1a and 1b may stabilize the enolate and thus
promote its formation. This hypothesis is supported by the
observance of high selectivity in the reaction using the
pyrrolyl derivative 1x. Thus, the reaction of 2-(4-nitro-
phenyl)-1-(1H-pyrrol-1-yl)ethanone (1x) and 2a, under the
optimized reaction conditions, afforded the Michael product
in 90% yield and 88% ee. Furthermore, the presence of
another coordinating group in the amide moiety, as in the
benzotriazolyl 1y, compromises the enantioselectivity of the
reaction; the reaction of 1y gave the Michael adduct with only
20% ee (Scheme 4).
In summary, we have developed an organocatalytic
asymmetric Michael reaction through the rational design of
pyrazoleamides as Michael donors, thus providing a rare
example of the use of amides as pronucleophiles in organo-
catalysis. Reactions with pyrazoleamide derivatives gave
products in excellent yields and selectivities. Pyrazoleamide
functions as an ester equivalent, an activating group, a direct-
ing group, as well as a good leaving group for further
transformation. The straightforward process described here
makes use of simple starting materials and proceeds under
mild reaction conditions and will be useful in medicinal
chemistry and diversity-oriented syntheses. This class of novel
amide substrate as a pronucleophile should facilitate the
development of a wide range of asymmetric reactions that can
be catalyzed by organic and metal catalysts; a number of these
reactions have already been realized in our group and will be
reported in the near future.
Received: February 6, 2012
Published online: && &&, &&&&
Keywords: amides · asymmetric synthesis · cinchona alkaloids ·
.
Michael addition · organocatalysis
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Organocatalysis
B. Tan, G. Hernꢁndez-Torres,
C. F. Barbas*
&&&& — &&&&
Rationally Designed Amide Donors for
Organocatalytic Asymmetric Michael
Reactions
Amide nucleophiles on demand: Ration-
ally designed pyrazoleamides function as
Michael donors in urea-catalyzed asym-
metric Michael reactions with excellent
chemical and optical yields (see scheme).
The pyrazoleamide group performs as an
ester equivalent, a directing group, an
activating group, and functions as a good
leaving group in further transformations
of the product.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!