Efficient synthesis of dihydropyrimidinones via a three-component Biginelli-type reaction of urea, alkylaldehyde and arylaldehyde

Article abstract of DOI:10.3762/bjoc.9.320

A one-pot three-component synthesis of dihydropyrimidinones via a molecular iodine-catalyzed tandem reaction of simple readily available mono-substituted urea, alkylaldehyde, and arylaldehyde has been developed. The reaction proceeds with high chemo- and

Full text of DOI:10.3762/bjoc.9.320

Efficient synthesis of dihydropyrimidinones via a
three-component Biginelli-type reaction of urea,
alkylaldehyde and arylaldehyde
Haijun Qu, Xuejian Li, Fan Mo and Xufeng Lin*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2846–2851.
Department of Chemistry, Zhejiang University, Hangzhou 310027,
China
doi:10.3762/bjoc.9.320
Received: 29 July 2013
Email:
Accepted: 14 November 2013
Published: 11 December 2013
Xufeng Lin* - lxfok@zju.edu.cn
* Corresponding author
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
Keywords:
Biginelli-type reaction; chiral phosphoric acid; dihydropyrimidinone;
iodine; multicomponent reaction
© 2013 Qu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A one-pot three-component synthesis of dihydropyrimidinones via a molecular iodine-catalyzed tandem reaction of simple readily
available mono-substituted urea, alkylaldehyde, and arylaldehyde has been developed. The reaction proceeds with high chemo- and
regioselectivity to give highly diverse dihydropyrimidinones in reasonable yields under mild reaction conditions. Moreover, the
first catalytic enantioselective version of this reaction was also realized by using chiral spirocyclic SPINOL-phosphoric acids.
Introduction
The dihydropyrimidinones (DHPMs) have exhibited interesting variants of Biginelli-type reactions for the preparation of novel
and multifaceted biological activities, such as antiviral, anti- DHPMs using various active methylene compounds [9-15],
tumor, antibacterial, and antiflammatory properties as well as such as enaminone, cyclic β-diketones, acetophenone, benzo-
calcium channel modulating activity [1,2]. As a consequence, cyclic ketones and β-oxodithioesters etc., have also been devel-
the synthesis of dihydropyrimidinone derivatives bearing oped to be carried out in the presence of a Lewis or protic acid.
diverse substitution patterns has attracted significant attention It is still highly valuable to develop new direct approaches for
since its discovery 120 years ago in 1893 by the Italian chemist the efficient synthesis of DHPMs due to the continued impor-
Pietro Biginelli [3,4]. Among them, the Biginelli multicompo- tance of the dihydropyrimidinone core in organic and medic-
nent reaction, involving a multicomponent condensation of inal chemistry.
aldehyde, β-ketoester, and urea, provides an easy access to the
preparation of DHPMs, because multicomponent reactions Recently, molecular iodine has emerged as an inexpensive, low-
(MCRs) are considered with high facileness, efficiency and toxic catalyst with moderate Lewis acidity and water-tolerance
economy in organic chemistry [5-8]. Recently, many one-pot in organic chemistry [16]. Previously, we have developed some
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Beilstein J. Org. Chem. 2013, 9, 2846–2851.
molecular iodine-catalyzed organic transformations [17-21],
herein we describe the first molecular iodine-catalyzed one-pot
three-component Biginelli-type synthesis of DHPMs from
simple readily available mono-substituted urea, alkylaldehyde,
and arylaldehyde under mild reaction conditions [22-24]. The
present method is suitable for a wide range of substrates, and
especially for functionalized arylaldehydes. The first catalytic
enantioselective version of this reaction is also presented by
using chiral spirocyclic SPINOL-phosphoric acids (SPAs) as
the catalyst.
Results and Discussion
Initially, the mixture of N-methylurea (1a, 2.5 mmol), phenyl-
acetaldehyde (2a, 2.5 mmol) and p-nitrobenzaldehyde (3a,
3.75 mmol) in toluene (3 mL) was treated with 10 mol % of
iodine under reflux for 12 hours. The functionalized dihydropy-
rimidinone 4a was obtained in 56% yield and the structure of
Figure 1: X-ray crystal structure of 4a.
the product was clearly assigned by both abundant spectral The substrate scope of the molecular iodine-catalyzed one-pot
analysis and X-ray single crystal diffraction (Figure 1).
three-component Biginelli-type reaction was then investigated,
and the results were presented in Table 2. First, we examined
For optimization of the reaction conditions, various trial reac- the scope of the aromatic aldehydes 3. Various aromatic alde-
tions were conducted with a combination of N-methylurea (1a), hydes 3a–3l and furfural (3m) were suitable substrates, and the
phenylacetaldehyde (2a) and p-nitrobenzaldehyde (3a) in order expected products were obtained in moderate isolated yields
to obtain the best yield of 4a, which is summarized in Table 1. (39–70%) (Table 2, entries 1–13). Electron-withdrawing as well
We examined some organic solvents, and have noted that aceto- as electron-donating groups on aromatic rings were tolerated,
nitrile was the most suitable solvent among others, such as although the latter gave slightly reduced yields. It is noted that a
toluene, 1,4-dioxane, THF, DCE, and DCM (Table 1, entries halogen group on the aromatic ring was well tolerated to give
1–6). The catalyst loading (10%) gave the good result for the the desired products, which can participate in subsequent trans-
formation of the desired product (Table 1, entries 6–8).
formations such as cross-coupling reactions (Table 2, entries
Table 1: Optimization of reaction conditions.a
Entry
Iodine (mol %)
Solvent
T
t (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
15
5
toluene
1,4-dioxane
THF
reflux
reflux
reflux
reflux
rt
12
12
12
12
24
12
10
24
12
56
53
58
52
10
70
70
58
0
DCE
DCM
MeCN
MeCN
MeCN
MeCN
reflux
reflux
reflux
reflux
0
aAll the reactions were carried out using 1a (2.5 mmol), 2a (2.5 mmol), and 3a (3.75 mmol) in 3 mL solvent. bIsolated yields.
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Beilstein J. Org. Chem. 2013, 9, 2846–2851.
Table 2: One-pot synthesis of dihydropyrimidinones.a
Entry
R1
R2
R3
Product
Yield (%)b
1
Me (1a)
1a
Ph (2a)
4-NO2C6H4 (3a)
3-NO2C6H4 (3b)
4-CNC6H4 (3c)
4-ClC6H4 (3d)
4-BrC6H4 (3e)
2-BrC6H4 (3f)
4-CF3C6H4 (3g)
Ph (3h)
4a
4b
4c
4d
4e
4f
70
67
68
63
70
67
56
57
53
46
39
49
42
81
48
55
54
72
66
67
58
63
2
2a
3
1a
2a
4
1a
2a
5
1a
2a
6c
7
1a
2a
1a
2a
4g
4h
4i
8
1a
2a
9
1a
2a
4-MeC6H4 (3i)
4-MeOC6H4 (3j)
piperonyl (3k)
1-naphthyl (3l)
2-furyl (3m)
Bn (2a)
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
2a
4j
1a
2a
4k
4l
1a
2a
1a
2a
4m
4n
4o
4p
4q
4r
1a
2a
1a
iPr (2b)
3a
1a
n-Bu (2c)
3a
1a
pentyl (2d)
3a
Et (1b)
Et (1b)
Et (1b)
Et (1b)
Et (1b)
2a
2a
2a
2a
2a
3a
3b
4s
4t
3c
3d
4u
4v
3e
aAll the reactions were carried out using 1 (2.5 mmol), 2 (2.5 mmol), 3 (3.75 mmol), and iodine (0.25 mmol) in 3 mL MeCN at reflux for 12 h. bIsolated
yields.
4–6). Furthermore, when phenylacetaldehyde (2a) was used substituted urea 1 with the aromatic aldehyde 3 to give the
instead of an aromatic aldehyde, product 4n was isolated with intermediate 5. Then, the enamide 6 is generated through the
good yield (81%; Table 2, entry 14). Subsequently, we investi- condensation of imine 5 with substituted acetaldehyde 2. This
gated the scope of substituted acetaldehydes 2 (Table 2, entries
15–17). The variation of the alkyl substituent of acetaldehydes 2
is well tolerated to provide the desired products 4o–4q in
48–55% isolated yields. Finally, N-ethylurea 1b was also
investigated in the one-pot three-component reaction, and the
reactions proceeded smoothly to give the corresponding di-
hydropyrimidinones 4r–4v in 58–72% isolated yields (Table 2,
entries 18–22). Based on the experimental results above, the
iodine-catalyzed Biginelli-type reaction proved to be of broad
scope and provides higher yields of dihydropyrimidinones than
the earlier described method with BF3·Et2O as the catalyst.
Molecular iodine is a mild catalyst with moderate Lewis acidity.
Thus, a possible mechanism was proposed in Scheme 1. The
Scheme 1: Possible mechanism.
first step is the condensation via the primary nitrogen of mono-
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Beilstein J. Org. Chem. 2013, 9, 2846–2851.
could then undergo an iodine-catalytic intramolecular cyclisa- solvent, chiral SPINOL-phosphoric acid 5a was the best cata-
tion to afford the final dihydropyrimidinone 4.
lyst and the best temperature was room temperature, which
afforded product 4a with 77% ee in 62% yield (Table 3, entry
Based on the observations above, a preliminary investigation on 4). With these reaction conditions identified, the variation of the
the catalytic asymmetric version was performed. Recently, our reaction substrates was well tolerated to provide the desired
group has developed a novel class of spirocyclic SPINOL-phos- products with up to 77% ee (Figure 2). Although the enantio-
phoric acids derived from chiral 1,1'-spirobiindane-7,7'-diol, selectivity was low to moderate, it should be noted that this is
which could effectively catalyze some highly enantioselective the first catalytic enantioselective version of this multicompo-
reactions [25-31]. These previous successes led us to envision nent reaction.
that SPINOL-phosphoric acids would effectively catalyze the
enantioselective three-component reaction of mono-substituted Conclusion
ureas 1, alkylaldehydes 2 and arylaldehydes 3 to generate enan- In conclusion, we have demonstrated the first efficient, molec-
tioenriched dihydropyrimidinones 4 [32-35].
ular iodine-catalyzed three-component synthesis of dihydro-
pyrimidinones starting from simple readily available mono-
In our initial study, we examined the multicomponent model substituted ureas, alkylaldehydes, and arylaldehydes. A signifi-
reaction between N-methylurea 1a, phenylacetaldehyde 2a, and cant progress was obtained with an extremely broad substrate
p-nitrobenzaldehyde 3a. As shown in Table 3, optimization of scope, giving the corresponding DHPMs with reasonable yields
the reaction conditions revealed that toluene was the best under mild reaction conditions. Moreover, the catalytic asym-
Table 3: Optimization of the asymmetric reaction conditions.a
Entry
Catalyst
Solvent
T (°C)
Yield (%)b
eec
1
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
CH3CN
CH3CN
xylene
rt
75
51
60
62
0
17
34
72
77
–
2
0
3
rt
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
5
0
6
50
50
50
50
50
50
50
65
39
30
41
28
58
0
67
34
42
58
60
12
–
7
8
9
10
11
12
6
aReaction conditions: Catalyst (10 mol %, 0.02 mmol), 1a (0.2 mmol), 2a (0.2 mmol), 3a (0.3 mmol), MS 4 Å (0.1 g), solvent (1 mL), 2 days. bIsolated
yields. cDetermined by chiral HPLC analysis.
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Beilstein J. Org. Chem. 2013, 9, 2846–2851.
Figure 2: Scope of the enantioselective reaction. Reaction conditions: 5a (10 mol %, 0.02 mmol), 1 (0.2 mmol), 2 (0.2 mmol), 3 (0.3 mmol), MS 4 Å
(0.1 g), toluene (1 mL), rt, 2 days. Isolated Yields were given. The ee’s were determined by chiral HPLC.
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