Bi(NO3)3·5H2O-TBAF as an efficient reagent for in situ oxidation: Dihydropyrimidinone formation from benzyl halides

Article abstract of DOI:10.1055/s-2005-861876

The oxidation of benzyl halides to aldehydes with bismuth nitrate pentahydrate in an ionic liquid was studied. Also, an efficient one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones from benzyl halides using bismuth nitrate pentahydrate in tetrabutylammonium fluoride (TBAF) as an in situ oxidant and catalyst is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-861876

PAPER
1301
Bi(NO3)3·5H2O–TBAF as an Efficient Reagent for in situ Oxidation:
Dihydropyrimidinone Formation from Benzyl Halides
Dihydropyrimidinone
o
h
om Benzyl
H
a
alides mmad Mehdi Khodaei,* Ahmad Reza Khosropour,* Mahbubeh Jowkar
Department of Chemistry, Razi University, Kermanshah 67149, Iran
Fax +98(831)4274559; E-mail: mmkhoda@razi.ac.ir
Received 17 November 2004; revised 14 January 2005
Abstract: The oxidation of benzyl halides to aldehydes with bis-
muth nitrate pentahydrate in an ionic liquid was studied. Also, an ef-
ficient one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones from
benzyl halides using bismuth nitrate pentahydrate in tetrabutylam-
monium fluoride (TBAF) as an in situ oxidant and catalyst is de-
scribed.
Scheme 1
Key words: dihydropyrimidinones, benzyl halides, oxidation–cy-
clocondensation, Bi(NO3)3·5H2O–TBAF, ionic liquid
This procedure develops the well known Biginelli reac-
tion while not limiting one of the substrates to being an al-
dehyde. It has the additional merits that there are more
commercially available alkyl halides than aldehydes and
that the intermediate aldehydes do not need isolation. This
should be particularly useful in cases where the aldehydes
are unstable (e.g. volatile, or prone to polymerization or
hydrolysis).
In recent years, 3,4-dihydropyrimidin-2(1H)-ones have
occupied an important place in synthetic organic chemis-
try due to their pharmacological and therapeutic proper-
ties.1 They have served as integral backbones of several
calcium channel blockers, antihypertensive agents, a-1a-
antagonists and neuropeptide Y(NPY) antagonists.2 Sev-
eral isolated marine alkaloids with biological activities
have been also found to contain the dihydropyrimidinone-
5-carboxylate core.3 Thus, synthetic methods for the prep-
aration of these heterocyclic compounds are of much im-
portance currently. The most simple and straightforward
procedure first reported by Biginelli, involves one-pot cy-
clo-condensation of an aldehyde, b-ketoester, and urea in
the presence of strong acid.4 This method often provides
Very recently, we have reported the ability of bismuth(III)
nitrate pentahydrate as an effective catalyst in the Biginel-
li reaction,8 while, the oxidative property of this salt has
been also investigated.9 By combining both of these char-
acteristics, we now examine a convenient alternative
method for the Biginelli reaction, which involves alkyl
halide as a precursor in the presence of Bi(NO3)3·5H2O in
TBAF.
low to moderate yields of the desired target molecules. We first examined the oxidation of alkyl halides with
Recently, several modified and improved procedures for Bi(NO3)3·5H2O in TBAF and the results are listed in
the one-pot synthesis of dihydropyrimidinones have been Table 1.
reported.5 Moreover, the reaction under microwave irradi-
Then, we studied alkyl halides as precursors in a one-pot
ation and solid-phase synthesis has also been performed.6
dihydropyrimidinone synthesis (Scheme 2).
Oxidation of alkyl halides to aldehydes is a well known
reaction. Many reagents have been used for this transfor-
mation.7 However, some of these methods have one or
more limitations including long reaction times, using high
temperature or toxic reagents, unsatisfactory yields, and
harsh reaction conditions. Therefore, the introduction of
new methods for the oxidation of alkyl halides is still in
demand
Scheme 2
In conventional organic synthesis, the combination of a
chemical oxidation and cyclo-condensation has not been
We chose ethyl acetoacetate and benzyl bromide as the
substrates and examined the reaction with several ionic
liquids in the presence of Bi(NO3)3·5H2O (Table 2). The
best result was obtained when TBAF was used (Table 2,
entry 6).
reported. We introduce a new process for the conversion
of alkyl halides into dihydropyrimidinones via an in situ
one-pot oxidation–dihydropyrimidinone formation se-
quence (Scheme 1).
We then examined the above reaction in different solvents
including acetonitrile, dichloromethane, chloroform, hep-
tane, methanol, water, water–acetonitrile, heptane–aceto-
SYNTHESIS 2005, No. 8, pp 1301–1304
Advanced online publication: 17.03.2005
DOI: 10.1055/s-2005-861876; Art ID: Z21704SS
x
x
.
x
x
.2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

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M. M. Khodaei et al.
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Table 1 Conversion of Benzyl Halides to Carbonyl Compounds with Bi(NO3)3·5H2O in TBAF
Entry
Benzyl halide
Yielda (%)
Time (min)
Carbonyl compoundb
Mpc (°C)
Found
Reported10
1
2
C6H5CH2Br
91
90
95
95
89
85
87
83
90
87
90
1.0
1.5
1.5
2.7
4.5
3.8
4.8
4.0
2.0
4.0
3.5
C6H5CHO
234–236
234–236
318–320
318–320
246–247
255–257
211–213
250–253
231–233
249–251
268–269
237
237
320
320
248
257
213.6
254
232.5
–
C6H5CH2Cl
C6H5CHO
3
4-NO2- C6H4CH2Br
4-NO2C6H4CH2Cl
3-ClC6H4CH2Br
4-BrC6H5CH2Br
2-ClC6H4CH2Cl
4-ClC6H4CH2Cl
4-CH3 C6H4CH2Cl
4-FC6H4CH2Cl
4-NO2C6H4CHO
4-NO2C6H4CHO
3-ClC6H4CHO
4-BrC6H5CHO
2-ClC6H4CHO
4-ClC6H4CHO
4-CH3C6H4CHO
4-FC6H4CHO
4
5
6
7
8
9
10
11
270
12
55
7.0
235–237
238
a Isolated yields.
b All products were characterized as their 2,4-dinitrophenylhydrazone derivatives.
c Melting point of their 2,4-dinitrophenylhydrazone derivatives.
nitrile, TBAF, and under solvent-free conditions. We materials recovered. Aliphatic alkyl halides with excep-
found the optimum conditions for the reaction were using tion of benzylic halides gave less than 30% of the respec-
TBAF as a solvent at 120 °C. Therefore, the reactions of tive dihydropyrimidinones under the present reaction
several alkyl halides with ethyl acetoacetate and urea in conditions. This may be considered as a limitation for
TBAF using Bi(NO3)3·5H2O afforded a range of 3,4-dihy- practical achievement in the Biginelli reaction.
dropyrimidin-2(1H)-ones in good to excellent yields. In
all cases, 3,4-dihydropyrimidin-2(1H)-ones were the sole
products and no by-product was observed. The outcome is
summarized in Table 3.
The effectiveness of the catalyst was evaluated by exami-
nation of the oxidation reaction of benzyl bromide in the
absence of Bi(NO3)3·5H2O and we found that no benzal-
dehyde was obtained as the product. It was also observed
The reactions of acetylacetone with different alkyl halides that the reaction of aldehyde with urea and ethyl aceto-
and urea under similar reaction conditions (at 80 °C) also acetate under the same reaction conditions without the salt
provided the corresponding 3,4-dihydropyrimidin-2(1H)- gave no dihydropyrimidinone.
ones in excellent yields (Table 3). This is a novel, one-pot
Use of 1.1 mmol of Bi(NO3)3.5H2O was sufficient to push
combination that not only preserves the simplicity of Bigi-
the oxidation and cyclo-condensation reactions forward.
nelli’s reaction but, also consistently produces excellent
Higher amounts of the reagent did not improve the result
to a grater extent. However, an increased quantity of
Bi(NO3)3·5H2O, 1.3 mmol, was required for completion
yields of dihydropyrimidin-2(1H)-ones from an alterna-
tive precursor to aldehydes.
In both cases, benzylic halides with substituents carrying of the reaction when 2-chloromethylnaphthalene used.
either electron-donating or electron-releasing groups re-
acted almost quantitatively and gave the products in high
purity. Thiourea was also used, but no corresponding di-
hydropyrimidinethiones were obtained and the starting
halides in place of aldehydes in the presence of bismuth
In conclusion, we have developed a new methodology for
the direct synthesis of 3,4-dihydropyrimidin-2(1H)-ones
by three component condensation in one-pot using benzyl
Synthesis 2005, No. 8, 1301–1304 © Thieme Stuttgart · New York

PAPER
Dihydropyrimidinone Formation from Benzyl Halides
1303
Table 2 Bi(NO3)3·5H2O-Promoted Biginelli Reaction in Different
Ionic Liquids
nitrate pentahydrate in TBAF. Primary and secondary
benzyl halides were also converted to the corresponding
carbonyl compounds with this reagent in ionic liquids in
good to excellent yields.
Oxidation of Benzyl Bromide; Typical Procedure
To a 25 mL round bottom flask containing molten TBAF (0.158 g
0.5 mmol) and Bi(NO3)3·5H2O (0.534 g 1.1 mmol), BnBr (0.171 g
1 mmol) was added. The mixture was stirred magnetically at 100 °C
for the period of time required to complete the reaction (1 h). The
progress of the reaction was monitored by TLC. After completion
of the reaction, the mixture was then allowed to cool to r.t. and ex-
tracted with Et2O (2 × 10 mL). The combined organic layers were
washed with water and dried over anhyd Na2SO4. Evaporation of
the solvent followed by column chromatography over silica gel
(EtOAc–hexane, 1:9) afforded the pure product in 91% yield.
Entry
Ionic liquid
(n-Bu)4NBr
(n-Bu)4NBF4
Yield (%)
1
2
3
80
35
40
4
40
5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one; Typical Procedure
To a 25 mL round bottom flask charged with Bi(NO3)3·5H2O (0.534
g 1.1 mmol) in molten TBAF (0.158 g 0.5 mmol) BnBr (0.171 g 1
mmol) was added. The reaction mixture was stirred magnetically at
120 °C until the substrate had been completely consumed (55 min).
The progress of the reaction was monitored by TLC. Then ethyl
acetoacetate (0.143 g 1.1 mmol) and urea (0.090 g 1.5 mmol) were
added to the reaction mixture and stirring was continued at 120 °C
5
6
7
(n-Bu)4NIO4
(n-Bu)4NF
(n-Bu)4PBr
0
90
70
Table 3 Bi(NO3)3·5H2O-Promoted Synthesis of Dihydropyrimidinonesa in TBAF
Entry
Benzyl halide
Ethyl acetoacetateb
Melting point (°C)
Found
Acetyl acetonec
Yieldd (%)/Time (min)
Reported
Yieldd (%)/Time (min)
1
2
C6H5CH2Br
90/1.5
84/3.0
93/2.0
95/3.3
87/5.3
79/4.5
77/5.7
79/4.5
84/2.5
84/4.5
89/3.5e
202–203
202–203
209–211
209–211
192–193
197–198
215–216
213–215
169–171
174–177
248–250
203–20411a
203–20411a
209–21011a
209–21011a
192–19311a
19711b
91/1.5
97/3.0
95/2.0
95/3.5
88/6.0
82/5.3
79/6.0
81/5.3
81/3.5
80/5.5
98/5.0
C6H5CH2Cl
3
4-NO2- C6H4CH2Br
4-NO2C6H4CH2Cl
3-ClC6H4CH2Br
4-BrC6H5CH2Br
2-ClC6H4CH2Cl
4-ClC6H4CH2Cl
4-CH3C6H4CH2Cl
4-F-C6H4CH2Cl
4
5
6
7
215–21711c
215–21611a
170–17111d
175–17711e
248–25011f
8
9
10
11
a All products are known compounds and were characterized by comparison of their spectral data (IR, 1H NMR, 13C NMR) and mp values with
those reported in the literature.
b At 120 °C.
c At 80 °C.
d Isolated yields.
e For completion of the reaction, 1.3 mmol of the reagent is needed.
Synthesis 2005, No. 8, 1301–1304 © Thieme Stuttgart · New York

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M. M. Khodaei et al.
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added to the mixture. The solution was filtered and the filtrate was
cooled until the product precipitated. The product was washed with
a cooled mixture of H2O–EtOH (1:1) and then dried. The pure prod-
uct was obtained by recrystallization (H2O–EtOH, 1:1) in 90%
yield.
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