A facile synthesis of pyrazolines from Baylis-Hillman adducts

Article abstract of DOI:10.1246/cl.2008.624

Buylis-Hillman adducts undergo smooth 1.3-dipolar cycloaddition reaction with ethyl diazoacetate in the presence of 2-iodoxybenzoic acid to produce pyrazolines in high yields under mild reaction conditions. Copyright

Full text of DOI:10.1246/cl.2008.624

624
Chemistry Letters Vol.37, No.6 (2008)
A Facile Synthesis of Pyrazolines from Baylis–Hillman Adducts
J. S. Yadav,Ã A. P. Singh, D. C. Bhunia, A. K. Basak, and P. Srihari
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received October 1, 2007; CL-071081; E-mail: yadavpub@iict.res.in)
Table 1. Synthesis of pyrazolines from Baylis–Hillman adducts
Baylis–Hillman adducts undergo smooth 1,3-dipolar cy-
cloaddition reaction with ethyl diazoacetate in the presence of
2-iodoxybenzoic acid to produce pyrazolines in high yields
under mild reaction conditions.
Entry
B.H.adducts
Pyrazolinesa
Reaction time/h
Yield/%b
O
OH
CO2Me
NH
CO2Me
1
2
85
N
EtO2C
O
OH
CO2Et
NH
CO2Et
2
2
90
82
2
3
Baylis–Hillman adducts are well-known carbon electro-
philes capable of reacting with various nucleophiles and their
ability to undergo nucleophilic substitution reactions contributes
largely to their synthetic value.1–4 The versatility of the function-
ality present in Baylis–Hillman adducts makes them the valuable
synthetic intermediates for the synthesis of a variety of heterocy-
cles such as quinolines, pyrimidones, isoxazolines, pyrazolones,
pyrrolidines, indolizines, azetidinone, diazacyclophanes, and
chromanones as well as biologically active natural products
including ꢀ-alkylidene-ꢁ-lactams, ꢀ-methylene-ꢂ-butyrolac-
tones, mikanecic acids, frontalin, trimethoprim, sarkomycin,
ilmofosine nuciferol, and many others.5 However, there have
been no reports for the synthesis of pyrazolines from Baylis–
Hillman adducts via a 1,3-dipolar cycloaddition reaction.
Pyrazolines are important class of heterocycles which exhib-
it potent biological activities, e.g. antibacterial,6 antifungal,7
antidiabetic,8 anti-inflammatory,9 antidepressant agents,10 and
active against many Mycobacterias.11 Herein, we report a rapid
synthesis of pyrazolines with high yields under mild reaction
conditions from Baylis–Hillman adducts via one-pot oxidative
1,3-dipolar cycloaddition reaction promoted by IBX. Initially,
we examined the oxidative cycloaddition reaction of methyl 2-
[hydroxy(phenyl)methyl]acrylate (1A) with ethyl diazoacetate
in the presence of 1.2 equiv of IBX in DMF. The reaction
proceeded smoothly at room temperature and the pyrazoline
3A was obtained in 85% yield (Scheme 1).
This result encouraged us to examine other substituted
Baylis–Hillman adducts (Table 1). Interestingly, this method
worked well with substrates derived from both aliphatic and
aromatic aldehydes. In all cases, the reactions were clean and
afforded the pyrazolines in good yields. The reaction conditions
were compatible with various functionalities such as halides,
aryl methyl ethers, esters, and alkenes (Table 1). All products
were characterized by 1H NMR, IR, and mass spectrometry.
Among the various hypervalent iodine reagents examined,
including iodosobenzene (PhIO), iodosobenzene diacetate
[PhI(OAc)2], and Dess–Martin periodinane (DMP), 2-iodoxy-
benzoic acid was found to be best in terms of conversion. Other
N
CO2Et
Br
Br
O
OH
OH
CO2Me
NH
N
CO2Me
CO2Me
Cl
Cl
EtO2C
O
CO2Me
NH
N
3
80
4
CO2Et
OPh
OPh
O
OH
OH
CO2Et
NH
N
CO2Et
2
4
85
80
5
6
F
F
EtO2C
O
CO2Me
NH
N
CO2Me
EtO2C
O
OH
OH
CO2Me
NH
N
CO2Me
3
83
7
MeO
MeO
MeO
MeO
EtO2C
O
CO2Me
NH
CO2Me
CO2Me
8
9
3
4
82
82
N
OMe
OMe
OH
CO2Et
O
CO2Me
NH
N
EtO2C
O
OH
OH
CO2Me
NH
N
10
CO2Me
CO2Et
6
3
5
85
87
85
EtO2C
O
CO2Et
NH
N
11
12
EtO2C
O
OH
CO2Me
NH
N
CO2Me
EtO2C
aAll products were characterized IR, H NMR and mass spec-
1
trometry analysis. bIsolated yields.
oxidizing agents such as OxoneÒ, CAN, MnO2, and KBrO3
failed to produce the desired product as no oxidation of
Baylis–Hillman adducts occured. To investigate whether iodoso-
benzoic acid, the by-product of oxidation with IBX plays any
crucial role in cycloaddition, a separate reaction was carried
out with isolated oxidized Baylis–Hillman adduct and ethyl
diazoacetate. The reaction was found to proceed smoothly
inferring no role of the by-product from oxidation reaction
in our protocol. However, the yields were better in a one-pot
reaction rather than two-step sequence done conventionally.12
In the absence of IBX, no cycloaddition took place even after
heating at 80 ꢀC for longer reaction times (2–6 h). As a solvent,
O
OH
CO2Me
CO2Me
CO2Et
IBX
NH
N
+
N2
DMF, r.t.
EtO2C
1A
2
3A
Scheme 1.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.6 (2008)
625
DMF yielded the best result compared to other solvents such
as CH3CN, THF, DMSO, and EtOAc. The scope of IBX promot-
ed one-pot oxidative cycloaddition reaction was investigated
with various Baylis–Hillman adducts and the results are present-
ed in the Table 1.
In conclusion, we have described a novel and efficient pro-
tocol for the one-pot oxidative cycloadditon of Baylis–Hillman
adducts with ethyl diazoacetate using IBX as the efficient oxi-
dant to produce various substituted pyrazolines in high yields.13
The method offers several advantages such as mild reaction
conditions, cleaner reaction profiles, operational simplicity,
and use of inexpensive and readily available reagents, which
makes it a useful and attractive strategy for the preparation of
various substituted pyrazolines.
6
7
8
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DCB and AKB thank CSIR, New Delhi for the award of
fellowships.
References and Notes
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12 In two-step sequence, isolated yields of the oxidized
Baylis–Hillman adducts were found to be low. This may
be attributed towards the high reactivity of the oxidized
product of Baylis–Hillman adducts.
2
3
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13 General experimental procedure: A mixture of Baylis–
Hillman adduct (1.0 mmol), IBX (1.2 mmol), and ethyl
diazoacetate (1.2 mmol) in DMF (7 mL) was stirred at room
temperature until complete reaction took place. The mixture
was then diluted with water (15 mL) and extracted with
ethyl acetate (3 Â 15 mL). The combined organic layer was
washed with water (2 Â 10 mL), brine (10 mL), dried
over anhydrous Na2SO4 and evaporated. The crude reaction
mixture was purified by column chromatography using
hexane:ethyl acetate (9:1) as eluent to afford pure pyrazo-
lines.
4
5
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Published on the web (Advance View) May 10, 2008; doi:10.1246/cl.2008.624