The first chemoselective tandem acylation of the Blaise reaction intermediate: A novel method for the synthesis of α-acyl-β-enamino esters, key intermediate for pyrazoles

Article abstract of DOI:10.1039/b813369g

The Blaise reaction intermediate, a zinc bromide complex of β-enamino ester, could be activated in situ by addition of a stoichiometric or catalytic amount of n-BuLi to allow chemoselective tandem C2-acylation providing α-acyl-β-enamino esters, which are

Full text of DOI:10.1039/b813369g

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The first chemoselective tandem acylation of the Blaise reaction
intermediate: a novel method for the synthesis of
a-acyl-b-enamino esters, key intermediate for pyrazolesw
Yu Sung Chun,a Ki Kon Lee,b Young Ok Ko,a Hyunik Shin*b and Sang-gi Lee*a
Received (in Cambridge, UK) 1st August 2008, Accepted 3rd September 2008
First published as an Advance Article on the web 23rd September 2008
DOI: 10.1039/b813369g
The Blaise reaction intermediate, a zinc bromide complex of
b-enamino ester, could be activated in situ by addition of a
stoichiometric or catalytic amount of n-BuLi to allow chemo-
selective tandem C2-acylation providing a-acyl-b-enamino
esters, which are valuable intermediates for the syntheses of
tri- and tetrasubstituted pyrazoles.
compounds.7 A similar trend was observed with free b-enamino
esters towards acylation: direct acylations of free b-enamino
esters with anhydrides or acyl chlorides led to the formation of
N-acylated product dominantly,8 whereas the reaction profile
was shifted towards C2-acylation exclusively as a substituent was
loaded at the nitrogen atom of b-enamino ester.9 Based on these
observations, we anticipated that chemoselective C2-acylation of
the Blaise reaction intermediate would serve as a convenient
method for a-acyl-b-enamino esters 2, which could be a useful
intermediate for the synthesis of bioactive heterocyclic molecules
such as pyrazoles. So far, the most popular route to 2 is
Knoevenagel condensation of b-ketoesters, commonly prepared
by Blaise reaction, with nitrile by using a stoichiometric amount
of tin(IV) chloride.10 Therefore, in view of atom economic and
environmental concern, the development of a direct synthetic
method for a-acyl-b-enamino esters 2 from the Blaise reaction
intermediate would be highly desirable. Herein we report the first
chemoselective tandem acylation of Blaise reaction intermediate
providing a-acyl-b-enamino esters 2 and their conversion to
tri- and tetrasubstituted pyrazoles.
Due to their excellent reactivity and high functional group
tolerance, organozinc compounds play critical roles in various
kinds of organic reactions.1 The reaction of Reformatsky
reagent with nitrile, the so-called Blaise reaction,2 is known
to proceed via a zinc bromide complex of a b-enamino ester.
Hydrolytic work-up of this reaction intermediate under acidic
or basic conditions provides the corresponding b-keto esters
and b-enamino esters, which have been engineered to build a
variety of molecules.3 During our ongoing studies on the
synthesis of b-amino acids4 and on a new process for the
synthesis of bioactive compounds by using the Blaise
reaction,5 we envisioned that the Blaise reaction intermediate
can be considered as a functionalized organozinc nucleophile
possessing potentially two reactive atoms, i.e. nitrogen and
C2-carbon. However, the latent potential of the Blaise reaction
intermediate as a functionalized organozinc nucleophile has
not been fully recognized to date.
Our initial efforts were directed at an examination of the
intrinsic reactivity of the Blaise reaction intermediate
generated in situ from the reaction of benzonitrile (1a) with
the Reformatsky reagent towards acylation.
Reaction of the Blaise reaction intermediate with various
acylating agents, such as acetyl chloride, isopropenyl acetate
and acetic anhydride, led to very sensitive outcomes depending
on acylating agents. For example, tandem reaction of the
Blaise intermediate AꢀZnBr with acetyl chloride resulted in
an intractable mixture and no reaction was observed with
isoprenyl acetate. In contrast, when the reaction was
conducted with acetic anhydride, both C2-acetylated product
2a and N-acetylated product were formed in 18 and 27% yield,
respectively, after prolonged reaction time of 3 d at room
temperature (entry 1, Table 1). This result clearly delineated
the ambivalent intrinsic reactivity profile of the Blaise
intermediate AꢀZnBr which is similar to that of the free
b-enamino ester. To improve the poor chemoselectivity
towards N vs. C-2, we tested various additives which would
modify its intrinsic reactivity. First, we added 1.0 equiv. of
n-BuLi on a simple assumption that it would displace the
bromide by an electron donating butyl group to change the
intrinsic reactivity as well as chemoselectivity of acylation of
the Blaise intermediate. To our delight, reaction of benzonitrile
(1a) with Reformatsky reagent followed by the sequential
To our best knowledge, there is only one report describing
in situ utilization of the Blaise reaction intermediate. Kouklovsky
and co-workers found that the zinc bromide complex generated
from the reaction of N-benzyl-N-Cbz protected chiral
a-aminonitrile with a Reformatsky reagent acts as a nitrogen
nucleophile: its nitrogen atom reacted with the protected Cbz
group intramolecularly to form imidazolidinones.6 In contrast, as
a work closely related to the Blaise reaction intermediate,
Nakamura et al. reported that ethylzinc complex of
N-monosubstituted b-aminocrotonamides, in situ generated with
diethylzinc, showed carbon nucleophile character, and under-
went sequential C2-alkynylation/isomerization to produce, upon
hydrolysis, the corresponding
a-alkylidine-b-dicarbonyl
a Department of Chemistry and Nano Science (BK21), Ewha Womans
University, Seoul, 120-750, Korea. E-mail: sanggi@ewha.ac.kr;
Fax: +82-2-3277-3419; Tel: +82-2-3277-4505
b Chemical Development Division, LG Life Sciences, LTd./R&D,
Daejeon, 305-380, Korea. E-mail: hisin@lgls.com
w Electronic supplementary information (ESI) available: Details of
synthetic procedure for 2, 3, 4 and 5, and 1H and 13C NMR spectral
data. See DOI: 10.1039/b813369g
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5098 | Chem. Commun., 2008, 5098–5100

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Table 1 Additive effects on tandem Blaise-acylation reactionz
Entry
Additive
Equivalent
Yield 2a (%)
1a
2
3
4
5
6
None
n-BuLi
CH3Li
LiHMDS
NaHMDS
tert-BuOK
(CH3)2CHMgBr
n-BuLi
—
18
82
81
61
69
57
20
81
78
67
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.1
b
7
8b
9
n-BuLi
n-BuLi
10
a
Scheme 1 Proposed mechanism for the chemoselective acylation of
the Blaise intermediate AꢀZnBr with catalytic n-BuLi
Reaction carried out for three days. The acylation was conducted
with the THF solution of the Blaise reaction intermediate kept for one
week at room temperature.
Table 2 Chemoselective tandem Blaise-acylation for the formation of
a-acyl-b-enamino esters 2z
addition of 1.0 equiv. of n-BuLi and 1.2 equiv.
of acetic anhydride resulted in exclusive formation of
C2-acetylated product 2a in 82% yield (entry 2, Table 1). No
trace of N-acylated product was detected. A similar result can
be obtained by addition of CH3Li (entry 3, Table 1). Other
additives such as LiHMDS (entry 4, Table 1), NaHMDS (entry
5, Table 1), and tert-BuOK (entry 6, Table 1) also promoted
exclusive generation of the C2-acylated product 2a, but the
yields are lower than when n-BuLi is used. However, the
Grignard reagent did not activate the reaction efficiently
affording 2a in only 20% yield (entry 7, Table 1). We also
found that the Blaise intermediate AꢀZnBr has extraordinary
stability in THF. Thus, acylation reaction of a THF solution of
the intermediate, stored for a week at room temperature, leads
to the same result as is obtained from reaction of directly
formed intermediate (entry 8, Table 1). Very interestingly,
lowering the equivalency of n-BuLi to 0.5 showed similar
selectivity to lead to 2a with only slightly decreased yield of
78% (entry 9 in Table 1). Even in the presence of 10 mol% of
n-BuLi, the reaction profile did not change except slightly
diminishing the yield (67%) (entry 10 in Table 1).
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
82
72
53
57
60
95
83
86
57
80
89
45
94
81
1-CH3C6H4
4-FC6H4
3-Pyridyl
4-CH3OC6H4CH2
C6H4CH2
CH3
CH3CH2
(CH3)2CH
Ph
Ph
Ph
Ph
Ph
9
CH3
Ph
10a
11a
12b
13
14
a
4-CH3OC6H4CH2
(CH3)2CH
(CH3)2CHCH2
CF3
b
Yield of E : Z (ca. 2 : 1) mixture. Yield of E : Z (ca. 3 : 1) mixture.
These observation suggest that a second catalytic butylzinc
species is generated in situ, which causes bromide-to-butyl
exchange. The catalytic role of n-BuLi can be explained by
using the pathway outlined in Scheme 1. Ligand exchange of
AꢀZnBr intermediate with n-BuLi affords the corresponding
BꢀZnBu complex, which reacts with acetic anhydride to form
C2-acylated iminobutylzinc complex CꢀZnBu and acetate
anion. Owing to the increased acidity of C2-proton, acetate
promoted rapid isomerization of CꢀZnBu to the more stable
DꢀZnBu then leads to production of the C2-acylated 2a and
buthylzinc acetate E, which acts as a second catalytic species
for bromide exchange regenerating BꢀZnBu and unreactive
(or less reactive) acetoxyzinc bromide F.
as well as aliphatic nitriles such as acetonitrile, propionitrile
and isobutyronitrile (entries 5–9, Table 2) were converted to
their corresponding a-acetyl-b-aminoacrylates 2a–2i in
moderate to excellent yield. In addition to acetic anhydride,
benzoic (entry 10, Table 2), p-methoxybenzoic (entry 11,
Table 2), isovaleric (entry 13, Table 2) and trifluoroacetic
anhydrides (entry 14, Table 2) also lead to the formation of
the corresponding C2-acylated products 2j, 2k, 2m and 2n in
high yields (up to 95%). In the case of sterically demanding
isobutyric anhydride, the yield was decreased to 45%
(entry 11, Table 2). Nevertheless, these results clearly demon-
strated that the Blaise reaction intermediate serves as a useful
functionalized organozinc nucleophile for chemoselective
C2-acylation reactions.
Based on the initial observation, we next investigated the
substrate scope of this transformation and the results are
summarized in Table 2. Aromatic nitriles (entries 1–4, Table 2)
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ethyl bromoacetate (0.83 mL, 7.5 mmol) over 1 h with syringe pump.
After 1 h at reflux, the reaction temperature was cooled to 0 1C. To the
reaction mixture was added n-BuLi (2.0 M in cyclohexane, 2.5 mL,
5.0 mmol) and acetic anhydride (0.62 mL, 6.5 mmol) in sequence.
After stirring for 3 h at room temperature, the reaction was quenched
with saturated aqueous NH4Cl, and the product was extracted with
ethyl acetate (10 mL ꢂ 3). The combined organic layer was dried with
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica chromatography to afford 2a
(0.96 g, 82%).
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are important pharmacophores in various biologically active
compounds.11 As shown in Scheme 2, reactions of 2 with hydra-
zine and phenylhydrazine in the presence of catalytic amounts
of p-TsOH afforded the corresponding 3,4,5-trisubstituted 3a–g
(70–96%) and 1,3,4,5-tetrasubstituted pyrazoles 4a–e (71–95%)
in good to excellent yields. The tetrasubstituted 4a could also
be transformed efficiently to 1,3,5-trisubstituted pyrazole 5
in 96% yield through the hydrolysis of the ester followed by
decarboxylation.
In summary, we have been investigated for the first time the
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bromide complex of b-enamino ester, for acylation, which
showed low levels of chemoselectivity (N vs. C2) with a low
efficiency. A modification of the reaction conditions, involving
the addition of a stoichiometric or catalytic amount of
n-BuLi, leads to highly regioselective C2-acylation to provide
a-acyl-b-enamino esters in moderate to excellent yields.
Transformation of a a-acyl-b-enamino ester to pyrazoles in
high yields showcases the overall methodology. This inves-
tigation has provided a platform for future studies probing
applications of the Blaise intermediate as a functionalized
organozinc complex. Further applications of the Blaise
reaction intermediate to other conceivable reactions are
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Notes and references
z A representative procedure for the synthesis of 2: To a stirred
suspension of commercial zinc dust (10 mm, 0.65 g, 10.0 mmol) was
added 5.0 mol% of methanesulfonic acid in THF (2.5 mL), and the
mixture was refluxed for 10 min. While maintaining reflux,
benzonitrile (0.52 mL, 5.0 mmol) was added all at once, followed by
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This journal is The Royal Society of Chemistry 2008
5100 | Chem. Commun., 2008, 5098–5100