Aluminium nitrate nonahydrate (Al(NO3)3·9 H2O): An efficient oxidant catalyst for the one-pot synthesis of biginelli compounds from benzyl alcohols

Article abstract of DOI:10.1002/hlca.201100242

A clean and efficient tandem oxidative cyclocondensation process is reported for the synthesis of 3,4-dihydropyrimidin-2(1H)-one or -thione derivatives from primary aryl alcohols, β-keto esters, and urea or thiourea in the presence of Al(NO₃)

Full text of DOI:10.1002/hlca.201100242

Helvetica Chimica Acta – Vol. 95 (2012)
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Aluminium Nitrate Nonahydrate (Al(NO3)3 · 9 H2O): An Efficient Oxidant
Catalyst for the One-Pot Synthesis of Biginelli Compounds from Benzyl
Alcohols
by Eskandar Kolvari*a), Mohammad Ali Zolfigolb), and Maryam Mirzaeeana)
a) Faculty of Science, Department of Chemistry, Semnan University, 35351-19111 Semnan, Iran
(e-mail: kolvari@semnan.ac.ir)
b) Faculty of Chemistry, Bu-Ali Sina University, P.O. Box 651783868, Hamedan, Iran
A clean and efficient tandem oxidative cyclocondensation process is reported for the synthesis of
3,4-dihydropyrimidin-2(1H)-one or -thione derivatives from primary aryl alcohols, b-keto esters, and
urea or thiourea in the presence of Al(NO3)3 · 9 H2O as oxidant catalyst (Scheme, Table 5).
Introduction. – The Biginelli reaction attracts still organic chemists interested in
finding milder and more efficient procedures for the synthesis of dihydropyrimidinones
[1][2]. At present, several general methods are known for the preparation of
dihydropyrimidinones, in the presence of various Lewis or protic acids such as
[Cu(OTf)2] [3], metal acetate [4], GaI3 [5], FeCl3 immobilized in Al-MCM 41 [6],
melamine trisulfonic acid [7], 4-aminobenzenesulfonic acid [8], nano-BF3 · SiO2 [9],
silica-gel-supported polyphosphoric acid (PPAꢀSiO2) [10], alumina/H2SO4 [11],
dodecylphosphonic acid [12], and 1,3-dichloro-5,5-dimethylhydantoin [13].
Results and Discussion. – Following our work [14 – 16] on the development of
useful and more sustainable synthetic methodologies, and leading with the recent
investigations involving oxidation of alcohols and the subsequent trapping of C¼O
intermediates with appropriate nucleophiles in a one-pot manner [17], we report here
our preliminary investigation dealing with the use of Al(NO3)3 · 9 H2O as an oxidant
catalyst to accomplish the Biginelli one-pot reaction starting from benzyl alcohols by
means of a tandem oxidative process (Scheme).
Scheme
At the beginning of this work, we studied the efficiency of Al(NO3)3 · 9 H2O as an
oxidant catalyst in the Biginelli reaction by mixing BnOH (1 mmol), ethyl acetoacetate
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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(¼ethyl 3-oxobutanoate; 1 mmol), urea (1.5 mmol), and Al(NO3)3 · 9 H2O (1.0 mmol)
at 808, in a one-step-one-pot tandem oxidative cyclocondensation manner, but,
unfortunately, no product was observed even after long reaction times. However, when
we added ethyl acetoacetate (1 mmol) and urea (1.5 mmol) to a reaction mixture
containing BnOH (1 mmol) oxidized by Al(NO3)3 · 9 H2O (1.0 mmol), the 3,4-
dihydropyrimidin-2(1H)-one derivative was formed at 808 within 10 min.
Therefore, we decided to accomplish the Biginelli reaction in a two-step-one-pot
oxidative cyclocondensation. To answer our question ꢂcan other nitrates act the same as
or perhaps better than Al(NO3)3 · 9 H2O in the Biginelli oxidative cyclocondensation
reactions?ꢃ, we decided to study first the efficiency of other metal nitrates (1 mmol) in
the oxidation of BnOH (1 mmol) as a model substrate under solvent-free condition at
808. As it can be seen from Table 1, the best result was was obtained with Al(NO3)3 · 9
H2O.
Table 1. Reactivity Trend of Some Metal Nitrates in the Oxidation of BnOH to PhCHOa)
Metal nitrate
Time [min]
Yield [%]b)
Metal nitrate
Time [min]
Yield [%]b)
Al(NO3)3
NaNO3
Ni(NO3)2
15
240
90
93
49
36
Bi(NO3)3
Zn(NO3)2
Cu(NO3)2
15
60
100
90
76
67
a) Reaction conditions: BnOH (1 mmol), metal nitrate (1 mmol), no solvent, 808. b) Yield determined
by GC.
Concomitant tests were carried out to optimize the reaction conditions with respect
to the reaction media, oxidant amount, and temperature. Comparing the oxidation of
BnOH in different solvents including MeCN, EtOH, dioxane, THF, hexane, and H2O
under reflux with the reaction at 708 without solvent showed that the best result was
achieved under solvent-free conditions (Table 2); the oxidation in solvents gave
significantly lower yields and needed longer reaction times.
Table 2. Oxidation of BnOH to PhCHO in the Presence of Al(NO3)3 · 9 H2O: Comparing Solvent-Free
Conditions with Various Solventsa)
Solvent
Time [min]
Yield [%]b)
Solvent
Time [min]
Yield [%]b)
–
15
480
150
92
0
90
EtOH
THF
hexane
350
210
480
59
40
0
H2O
MeCN
a) Reaction conditions: BnOH (1 mmol), metal nitrate (1 mmol), 708. b) Yield determined by GC.
In ꢂlinearꢃ synthesis, the overall yield quickly drops with each reaction step.
Therefore, optimizing the yield of the oxidation step is very important in the
cyclocondensation procedure. To increase the yield of PhCHO, we decided to evaluate
the influence of the amount of Al(NO3)3 · 9 H2O and temperature on the yield of
oxidation of BnOH. Increasing the amount of Al(NO3)3 · 9 H2O from 0.3 to 1.5 mmol
led to an increase of yield of PhCHO from 81 to 99% (Table 3). Decreasing the

Helvetica Chimica Acta – Vol. 95 (2012)
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temperature from 808 to room temperature reduced the yield of PhCHO from 99 to
37% (Table 4).
Table 3. Influence of the Amount of Al(NO3)3 · 9 H2O on the Oxidation of BnOH to PhCHOa)
Al (NO3)3 · 9 H2O [mmol]
Yield [%]b)
Al (NO3)3 · 9 H2O [mmol]
Yield [%]b)
1.5
1.3
1.2
99
98
98
1
0.6
0.3
93
86
81
a) Reaction condition: BnOH (1 mmol), 808, 15 min. b) Yield determined by GC.
Table 4. Influence of Temperature on the Oxidation of Neat BnOH by Al(NO3)3 · 9 H2Oa)
Temperature [8]
Time [h]
Yield [%]b)
Temperature [8]
Time [h]
Yield [%]b)
80
60
0.25
4
99
79
40
r.t.
7
24
62
37
a) 1.5 mmol of Al(NO3)3 · 9 H2O per mmol of BnOH was used. b)Yield determined by GC.
Thus, the optimized conditions for the oxidation of 1 mmol of BnOH is as follows:
1.5 mmol of Al(NO3)3 · 9 H2O at 808 in the absence of solvent.
Next, we added urea and ethyl acetoacetate to the PhCHO obtained from the
oxidation of BnOH under optimized conditions. The reaction was completed at 808
within 10 min. After adding cold EtOH to the reaction mixture, almost pure 3,4-
dihydropyrimidin-2(1H)-one derivative was precipitated in 90% yield, which did not
require further purifcation (Table 5, Entry 1). We also explored the use of
functionalized benzyl alcohols carrying either electron-releasing or electron-with-
drawing substituents in meta- and para-position to establish the scope and limitation of
the current procedure. The 3-nitro derivative of benzyl alcohol required relatively long
reaction times to complete the Biginelli reaction (Table 5, Entries 4 and 6), while
BnOH and 4-bromobenzyl alcohol required shorter reaction times (Entries 1, 3, 7 and
11). The highest yields were found for 4-fluorobenzyl alcohol (Entries 8 and 9).
Conclusions. – We developed an efficient catalytic protocol wherein Al(NO3)3 · 9
H2O was explored as an oxidant catalyst for the sequential oxidation and condensation
reaction of alcohols with b-keto esters and urea or thiourea to result in the formation of
corresponding 3,4-dihydropyrimidin-2(1H)-one or -thione derivatives. The present
procedure provides an efficient and improved modification of the Biginelli reaction.
Mild reaction conditions, ease of workup, simple procedure, good to excellent yields,
and a cheap and nontoxic oxidant catalyst are features of this new procedure.
Moreover, the method tolerates a wide variety of substituents in all three components.
The authors acknowledge the Semnan University Research Council, Bu-Ali Sina University
Research Council (Grant Number 32-1716), and Center of Excellence in Development of Chemical
Methods (CEDCM).

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Table 5. Synthesis of 3,4-Dihydropyrimidin-2(1H)-one or -thione Derivatives in the Presence of
Al(NO3)3 · 9 H2O as Oxidant Catalyst (cf. Scheme)a)
Entry
R1
R2
X
Time [min]
Yield [%]b)
1
2
3
4
5
6
7
8
9
Ph
Et
Et
Et
Et
Me
Me
Me
Me
Me
Et
O
O
O
O
O
O
O
O
O
S
10
30
20
90
30
90
20
45
30
15
10
120
90
80
89
80
80
83
92
98
98
82
86
80
4-MeOꢀC6H4
4-BrꢀC6H4
3-NO2ꢀC6H4
4-MeOꢀC6H4
3-NO2ꢀC6H4
4-BrꢀC6H4
4-FꢀC6H4
4-FꢀC6H4
Ph
10
11
12
4-BrꢀC6H4
Et
Et
S
O
PhCH¼CH
a) Reaction conditions: alcohol (1 mmol) and Al(NO3)3 · 9 H2O (1.5 mmol) at 808; then urea (1.5 mmol)
and b-keto ester (1 mmol) at 808. b) Yield refers to the isolated product. The products were characterized
by comparison of their spectroscopic and physical data with those of samples synthesized by reported
procedures.
Experimental Part
Typical Procedure: Synthesis of Ethyl 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-phenylpyrimidine-5-
carboxylate (Table 5, Entry 1). A mixture of BnOH (1 mmol, 108 mg) and Al(NO3)3 · 9 H2O (1.5 mmol,
562 mg) was heated at 808 for 15 min in a test tube (TLC monitoring). After completion of the oxidation
process, ethyl acetoacetate (1 mmol, 105 mg) and urea (1.5 mmol, 90 mg) were added to the mixture,
which was heated with stirring at 808. The reaction was completed within 10 min. After cooling to r.t.,
96% EtOH (ca. 10 ml) was added under vigorous stirring. The almost pure product was gradually
precipitated. The precipitate was filtered, washed with cold EtOH (5 ml), and dried under vacuum; ethyl
1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenylpyrimidine-5-carboxylate (468 mg, 90%). M.p. 202 – 2048
[18]: 200 – 2028).
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Received June 8, 2011