Biginelli reaction starting directly from alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.09.141

An efficient of one-pot oxidative access to 3,4-dihydropyrimidin-2-(1H)- ones directly from aromatic alcohols under mild conditions is reported. The protocol involves 1-methylimidazolium hydrogen sulphate [Hmim]HSO₄ catalyzed oxidation of aroma

Full text of DOI:10.1016/j.tetlet.2010.09.141

Tetrahedron Letters 51 (2010) 6436–6438
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Tetrahedron Letters
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Biginelli reaction starting directly from alcohols
⇑
Garima, Vishnu P. Srivastava, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient of one-pot oxidative access to 3,4-dihydropyrimidin-2-(1H)-ones directly from aromatic
alcohols under mild conditions is reported. The protocol involves 1-methylimidazolium hydrogen sul-
phate [Hmim]HSO4 catalyzed oxidation of aromatic alcohols to aromatic aldehydes with NaNO3 followed
by their cyclocondensation with 1,3-dicarbonyl compounds and urea in the same reaction vessel at 80 °C
within 2–4 h to afford 3,4-dihydropyrimidin-2-(1H)-ones in 55–97% overall yields. Thus, the present
work utilizing alcohols instead of aldehyde in Biginelli reaction is a valid and green alternative to the clas-
sical synthesis of 3,4-dihydropyrimidin-2-(1H)-ones.
Received 5 September 2010
Revised 26 September 2010
Accepted 29 September 2010
Available online 7 October 2010
Keywords:
Biginelli reaction
3,4-Dihydropyrimidin-2(1H)-ones
Ionic liquids
Ó 2010 Elsevier Ltd. All rights reserved.
Cyclocondensation reactions
Alcohols
Oxidation
One-pot sequential multi-step reactions are of increasing aca-
demic, economical, and ecological interest because they address
fundamental principles of synthetic efficiency and reaction de-
sign.1 Recently, tandem oxidative processes (TOP) in which oxida-
tion of alcohols combined with the subsequent elaboration of the
carbonyl intermediates (aldehyde) have gained considerable atten-
tion among synthetic chemists.2,3 Although a lot of work has been
done for developing bimolecular TOP processes, the literature re-
cords only a few examples of combining alcohol oxidation with a
multicomponent reaction (MCR) in a one-pot process.4
in the realm of natural and synthetic organic chemistry.6–9 The
reaction can be carried out in a one-pot fashion in alcoholic solu-
tion in the presence of a catalytic amount of hydrogen chloride.
A major drawback of the classical Biginelli reaction is the poor to
moderate yields, particularly when substituted aromatic aldehydes
are employed. In recent years, several synthetic procedures for the
preparation of DHPMs have been made to improve and modify this
reaction.10,11 However, to the best of our knowledge, there has
been only one report on the Biginelli reaction starting directly from
alcohols.4c
Aldehydes are ubiquitous substrates in many powerful MCRs.
However, they are in general, more volatile, toxic, or unstable,
especially because of aerial oxidation than their corresponding
alcohols. Thus, in many cases aldehydes must be purified just be-
fore their use because the presence of other products affects not
only the concentration of the active aldehyde but also that the
impurities often interfere with chemical reactions involving the
aldehyde. The difficulties associated with the development of
one-pot oxidation–MCR processes are self-evident due to the pres-
ence of mutli-functionalities/multiintermediates and the complex-
ity of the reaction mechanism intrinsic to MCRs. Thus, the use of a
single vessel oxidation–MCR protocol would widen significantly
the versatility and scope of the aldehyde-based MCRs.
Ionic liquids (ILs) are emerging as effective promoters and sol-
vents for green chemical reactions. Especially, one of the most
important advantages of ILs is the behavior of solvophobic interac-
tions that generate an internal pressure which promotes the asso-
ciation of the reagents in a solvent and shows an acceleration of
MCRs in comparison to conventional solvents.12 Recently, Brønsted
acidic ionic liquids have been deemed promising alternatives for
acid catalyzed reactions and play a dual solvent–catalyst role in a
variety of reactions including esterification of carboxylic acids, pro-
tection of alcohols and carbonyl groups, oxidation of alcohols, alco-
hol dehydrodimerization, pinacol/benzopinacol rearrangement,
Mannich reactions, and cleavage of ethers.13,14
Our continued quest for the development of environmentally
friendly alternatives15 along with the recent investigations involv-
ing oxidation of alcohols and the subsequent trapping of carbonyl
intermediates with appropriate nucleophiles in one-pot opera-
tion15d,e has led us to develop a green protocol for the Biginelli
reaction starting directly from alcohols. Herein, we report a
Brønsted acidic ionic liquid [Hmim]HSO4 catalyzed sequential
oxidation of aromatic alcohols with NaNO3 followed by their
Biginelli reaction5 is one of the fundamental strategies involving
a three-component condensation of ethyl acetoacetate, benzalde-
hyde, and urea for the synthesis of 4-aryldihydropyrimidinones
(DHPMs) and their derivatives which occupy an important place
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (Lal Dhar S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.141

Garima et al. / Tetrahedron Letters 51 (2010) 6436–6438
6437
R1
O
OH
R1
O
R1
H2N NH2
2
H
R1
HO
H
NH2
O
R1CHO
HN
NH2
O
HN
-H2O
R2
Me
NH
1
[Hmim]HSO4 - NaNO3
O
R2
Me
NH2
O
O
H2O
-HNO2
R1
NO + NO2
º
N
H
O
80 C, 2-4 h
H2N
55-97% yield
Me
O
4
-H
R2
2
3
O
3
O
O
Scheme 1. Preparation of 3,4-dihydropyrimidin-2-(1H)-ones directly from aro-
matic alcohols.
N
R1
H
R2OC
Me
O
NH
O
NH2
O
O
condensation with urea and dicarbonyl compounds in the same
vessel at 80 °C for an overall time period of 2–4 h to afford 3,4-
dihydropyrimidin-2(1H)-ones in 55–97% yields (Scheme 1).
Initially, we studied the tandem oxidative cyclocondensation of
benzyl alcohol (3 mmol), urea (3 mmol) and ethyl acetoacetate
(3 mmol) in the presence of [Hmim]HSO4 (1.2 mmol) with NaNO3
(3 mmol) at 80 °C, disappointingly no reaction took place even
after stirring the reaction mixture for 10 h. However, to our delight,
we observed the formation of 3,4-dihydropyrimidin-2(1H)-ones
when urea and ethyl acetoacetate were added to the reaction after
the oxidation of the alcohol to the aldehyde was complete.
O N O
-H2O
-H2O
R1CH2OH2
R1
R2OC
Me
H
[Hmim]HSO4
N
R1CH2OH
N
H
O
1
4
Scheme 2. Plausible mechanism for one-pot oxidative Biginelli reaction.
To explore the scope and limitations of this reaction, we ex-
tended the procedure to various aryl substituted alcohols carrying
either electron-releasing or electron-withdrawing substituents in
the ortho, meta, and para positions. Aryl alcohols with a strong
electron-withdrawing group (such as nitro group) required a rela-
tively longer time for completion of the reaction (Table 1, entries 4,
8, 11, and 14) whereas alcohols carrying electron-donating substit-
uents gave excellent yields of DHPMs (Table 1, entries 3, 6, 7, 10,
and 12) in a shorter reaction time. Another important feature of
this procedure is the compatibility with a variety of functional
groups such as ethers, nitro, hydroxyl, and halides under the pres-
ent reaction conditions. Both b-ketoesters and acetylacetone re-
acted smoothly under the reaction conditions (Table 1) affording
the corresponding 3,4-dihydropyrimidinones in excellent yields.
Aliphatic alcohols were unreactive under the present reaction con-
ditions (Table 1, entries 15 and 16).
We also attempted the oxidative Biginelli reaction using
[Hmim]NO3 as well as NaNO3–[Hmim]H2PO4 separately under
the same reaction conditions. The reaction was unsuccessful in
the former case indicating the need for an acidic hydrogen which
is absent in [Hmim]NO3 to catalyze the oxidation of alcohols to
aldehyde (Scheme 2). However, the reaction proceeded with
the NaNO3–[Hmim]H2PO4 system but relatively low yields of
Table 1
Synthesis of 3,4-dihydropyrimidin-2(1H)-onesa
R1
O
R1
HO
H
O
R2
Me
NH
1
[Hmim]HSO4 - NaNO3
80 º
R2
Me
NH2
O
N
H
O
C
H2N
O
4
2
3
Entry
Product
R1
R2
Time (h)
Yieldb (%)
Mp (°C)
Found
Reported
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
C6H5
2-ClC6H4
2-HOC6H4
4-O2NC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
3-O2NC6H4
4-O2NC6H4
4-MeOC6H4
4-O2NC6H4
4-MeOC6H4
4-ClC6H4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
3
3.5
2
94
92
97
62
91
95
96
59
62
96
65
95
92
55
—
201–202
215–219
202–204
206–208
214–215
214–217
207–208
230–232
227–229
169–171
236–238
191–193
204–207
277–279
202–20310d
215–21810d
201–20310d
207–208.510d
213–21510d
216–21810e
208–20910e
232–23410e
23010d
4
3.5
2.5
2
4
4
2
4
2
3.5
4
Me
168–17010d
235–23710d
192–19410d
204–20710d
278–28010f
157–15810b
155–15711f
OMe
OMe
OMe
OMe
OEt
OEt
3-O2NC6H4
n-Butyl
n-Propyl
6
6
—
Reaction condition: alcohol (3 mmol), urea (3.0 mmol), b-dicarbonyl compound (3 mmol), NaNO3 (3 mmol) and [Hmim]HSO4 (1.20 mmol) at 80 °C for 2–4 h.16
Isolated yields.
a
b

6438
Garima et al. / Tetrahedron Letters 51 (2010) 6436–6438
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probably due to the lower Brønsted acidity associated with
[H2PO4]. Thus, [Hmim]HSO4 plays a dual role, that is, as an acid cat-
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subsequent condensation with urea and 1,3-dicarbonyl com-
pounds. A plausible mechanism for the present one-pot oxidative
cyclocondensation of aromatic alcohols, urea, and 1,3-dicrbonyl
compounds is depicted in Scheme 2.
In summary, we have developed a new method for an efficient
Biginelli reaction starting directly from alcohols using NaNO3–
[Hmim]HSO4 system. The protocol involves [Hmim]HSO4 catalyzed
oxidation of alcohols to aldehydes with NaNO3 at 80 °C followed by
their cyclocondensation with the urea and dicarbonyl compounds
to afford 3,4-dihydropyrimidin-2(1H)-ones in a one-pot operation.
Thus, the present work could find useful applications in view of the
power of the Biginelli reaction and that the concept could be ex-
tended as a valid and green alternative to other MCRs involving
aldehyde substrates.
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Acknowledgments
The authors sincerely thank SAIF, Punjab University, Chandigarh,
for providing microanalyses and spectra. One of us (Garima) is grate-
ful to the CSIR, New Delhi, for the award of a Junior Research
Fellowship.
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16. A typical procedure for the formation of 3,4-dihydropyrimidin-2-(1H)-ones 4: A
mixture of an aryl alcohol (3 mmol), sodium nitrate (3 mmol), and
[Hmim]HSO4 (1.20 mmol) was heated with stirring at 80 °C for 5–30 min in
a round-bottomed flask. After oxidation of the aromatic alcohol (monitored by
TLC, n-hexane/ethyl acetate, 80:20), b-dicarbonyl compound (3 mmol) and
urea (3.0 mmol) were added. The mixture was heated with stirring at 80 °C for
1.5–4 h. On completion of the reaction, as indicated by TLC (n-hexane/ethyl
acetate: 60:40), the reaction mixture was cooled to rt, then cold water was
added. The precipitated product was separated by simple filtration. The crude
product was recrystallized from ethanol to obtain an analytical sample of 4.
The structure of the products was confirmed by comparison of their mp, TLC,
IR, and 1H NMR data with authentic samples obtained commercially or
prepared by the literature method.10b,d–f,11f
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