Highly chemoselective multicomponent biginelli-type condensations of cycloalkanones, urea or thiourea and aldehydes

Article abstract of DOI:10.1002/ejoc.200400845

The classical Biginelli reaction is considerably extended by use of cycloalkanones instead of 1,3-dicarbonyl compounds. Use of TMSCl as a Lewis acid allowed one-pot chemoselective multicomponent Biginelli reactions between cycloalkanones, urea or thiourea, and aldehydes. Under similar reaction conditions, thiourea exhibited different behavior to urea, and aliphatic aldehydes showed lower reactivity than aromatic aldehydes. A possible mechanism to account for the reaction is proposed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400845

FULL PAPER
Highly Chemoselective Multicomponent Biginelli-Type Condensations of
Cycloalkanones, Urea or Thiourea and Aldehydes
Yu-lin Zhu,[a] Shen-lin Huang,[a] and Yuan-jiang Pan*[a]
Keywords: Chemoselective Biginelli-type reaction / Cycloalkanones / Spiro heterotricyclic scaffolds
The classical Biginelli reaction is considerably extended by
use of cycloalkanones instead of 1,3-dicarbonyl compounds.
Use of TMSCl as a Lewis acid allowed one-pot chemoselec-
tive multicomponent Biginelli reactions between cycloalk-
anones, urea or thiourea, and aldehydes. Under similar reac-
tion conditions, thiourea exhibited different behavior to urea,
and aliphatic aldehydes showed lower reactivity than aro-
matic aldehydes. A possible mechanism to account for the
reaction is proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Table 1. Ketone building blocks.
Introduction
Multicomponent reactions (MCRs) are of considerable
importance in organic and medicinal chemistry.[1–4] Bigi-
nelli reactions are ranked as one of the most powerful tools
for the facile synthesis of complex heterocyclic scaffolds for
therapeutic and pharmacological properties.[5–7]
Classical Biginelli reactions involve one-pot condensa-
tions of an aldehyde, a β-ketoester, and urea under strongly
acidic conditions (Scheme 1).[8]
Scheme 1.
The initial aim of our work was to discover and develop
novel reactions to extend the scope of the well known Bigi-
nelli reaction through the use of cycloalkanones instead of
1,3-dicarbonyl compounds.
In recent decades, the scope of the original Biginelli reac-
tion shown in Scheme 1 was extended by variation of the
1,3-dicarbonyl compound building blocks (Table 1). Many
groups have elegantly demonstrated the synthetic versatility
of numerous 1,3-dicarbonyl compounds, including β-keto
esters and cyclic β-diketones.[9–27]
Results and Discussion
[a] Department of Chemistry, Zhejiang University,
Hangzhou 310027, PR China
In order to confirm our hypothesis, we began to explore
the reaction between cyclopentanone (1a, 10 mmol), urea
(2a, 12 mmol), and benzaldehyde (3a, 10 mmol) to deter-
Fax: +86-571-87951264
E-mail: panyuanjiang@css.zju.edu.cn
2354
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400845
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Highly Chemoselective Multicomponent Biginelli-Type Condensations
FULL PAPER
mine the best promoter. Many catalysts or promoters such and aldehydes 3a–h to give three families of fused heterob-
as HCl,[8] BF3·OEt2,[9] polyphosphate ester,[10] LaCl3,[11] icyclic, benzylidene heterobicyclic, and spiro heterotricyclic
[23]
InCl3,[12] ZrCl4,[13] BiCl3,[14] NH2SO3H,[22] and Cu(OTf)2
pyrimidines 4, 5, 6 as key intermediates for preparations
were applied under Biginelli-type reaction conditions, but of many biologically active compounds in the presence of
no reactions were observed. However, a satisfactory result TMSCl.[31–39] The aldehyde building blocks 3a–h used in
was obtained when the reaction was carried out in the pres- the Biginelli-type reactions are shown in Table 2.
ence of TMSCl (10 mmol) in DMF/CH3CN (6 mL/
3 mL).[28–30] Curiously, the product, 7-benzylidene-4-
phenyl-1,3,4,5,6,7-hexahydro-cyclopentapyrimidin-2-one
(5a), shown in Figure 1 and confirmed by NMR measure-
ments (including two-dimensional NMR) and mass spec-
trometry, was obtained in 93% yield (yield based on benzal-
Biginelli-Type Reactions of Cycloalkanones 1a–e, Urea or
Thiourea, and Aromatic Aldehydes 3a–k in the Presence of
TMSCl
dehyde), while in contrast, the desired classical Biginelli
product (4, Scheme 2, below) was not obtained at all.
For aromatic aldehydes, the reactions were generally run
by an established procedure in which we used
a
1.0:1.2:1.0:1.0 molar ratio of cycloalkanones 1a–e, urea or
thiourea, aromatic aldehydes 3a–k, and TMSCl. The reac-
tions took place and were complete in 2–3 h at room tem-
perature. The products were precipitated from the medium
and were isolated simply by filtration and washing with ace-
tone. The total yields of isolated products were between
71% and 97%, with high purities by HLPC. The results are
shown in Scheme 2 and Table 3–7.
Cyclopentanone reacted with urea and aromatic alde-
hydes 3a–d, 3f–k to furnish mainly benzylidene heterob-
icyclic pyrimidines (Table 3, Entries 1–8, 5a–h) in yields
ranging from 78% to 95%.
Figure 1. Benzylidene heterobicyclic product 5a.
We similarly extended this procedure to various cycloalk-
anones by use of parallel organic synthesis arrays. Cycloalk-
anones such as cyclopentanone (1a), cyclohexanone (1b),
cycloheptanone (1c), cyclooctanone (1d), and cyclododeca-
none (1e) reacted cleanly with urea (2a) or thiourea (2b)
The products were affected by the substituent groups:
aromatic aldehydes bearing functional groups (such as
–H, –Cl, –Br, –CH3, –OCH3) in the ortho or para positions
reacted smoothly to give benzylidene heterobicyclic prod-
ucts (Table 3, compounds 5a–d, 5g–h) without the occur-
rence of side products (Scheme 3), whilst aromatic alde-
hydes bearing electron-withdrawing substituents (–F, –NO2)
in the para positions reacted to give mixtures of benzylidene
heterobicyclic products 5i, 5j and spiro-fused heterotricyclic
products 6a, 6b. The isolated ratio of 5i and 6a was 87:13
(Entry 9) and the ratio of 5j and 6b determined by 1H
NMR was 48:52 (Entry 10).
Table 2. Aldehyde building blocks 3a–h used in Biginelli-type reac-
tions.
Cyclopentanone reacted with thiourea and aromatic al-
dehydes such as benzaldehyde, 4-chlorobenzaldehyde (3d),
4-nitrobenzaldehyde (3f), and 2-methoxybenzaldehyde (3h)
to furnish mainly benzylidene heterobicyclic pyrimidines
(Entries 11–14, 5k–n; Scheme 3), but the reactions between
cyclopentanone, thiourea, and 4-fluorobenzaldehyde (3e),
3-nitrobenzaldehyde (3g), 2-fluorobenzaldehyde (3i), and 2-
chlorobenzaldehyde (3j) proceeded smoothly to give spiro-
fused heterotricyclic compounds (Entries 15–18, 6c–f;
Scheme 4) in high yields and with high HLPC purities.
The case of cyclohexanone (1b) was different. Interest-
ingly, two series of heterocyclic scaffolds, shown in
Scheme 5 and Scheme 6, were formed.
For urea, the reaction provided one-pot access to spiro-
fused heteropolycyclic compounds (Table 4, Entries 1–8;
Scheme 5, 6g–n) through formation of three new cycles and
six novel bonds. The molecular structure, based on 1H
NMR spectroscopic data, was asymmetric. The corre-
sponding coupling constants of ca. Ͻ4 Hz and ca. Ͼ11 Hz
in the two pyrimidine rings (for example, 6g) were charac-
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Y. Zhu, S. Huang, Y. Pan
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Scheme 2.
Table 3. Cyclopentanone products.
Entry
X
R
Product[a]
Yield
%
Ratio 5:6
[b]
1
2
3
4
5
6
7
8
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
3a: H
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
93
95
86
82
78
82
87
85
3b: 4-CH3
3c: 4-OCH3
3d: 4-Cl
3g: 3-NO2
3i: 2-F
3j: 2-Cl
3k: 2-Br
3e: 4-F
3f: 4-NO2
3a: H
3d: 4-Cl
3f: 4-NO2
3h: 2-OCH3
3e: 4-F
9
6a
6b
87:13[c]
48:52[d]
10
11
12
13
14
15
16
17
18
96
92
89
81
79
86
80
95
6c
6d
6e
6f
3g: 3-NO2
3i: 2-F
3j: 2-Cl
Scheme 3.
[a] All compounds were characterized by 1H NMR, 13C NMR, and
mass spectrometry. [b] Isolated yield (yield based on aromatic alde-
hyde). [c] Ratio based on isolated yield. [d] Ratio based on 1H
NMR.
teristic of equatorial hydrogen and axial hydrogen, respec-
tively.
Unlike those of urea, reactions of thiourea proceeded
smoothly to give fused heterobicyclic products (Entries 9–
18; Scheme 6, 4a–j) in yields ranging from 80% to 91% with
high purities, and no side products were detected. The
mechanism was in agreement with the classical Biginelli re-
action.
The products obtained from cycloheptanone with urea
and aromatic aldehydes were affected by the substituent
groups: aromatic aldehydes bearing functional groups Scheme 4.
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Highly Chemoselective Multicomponent Biginelli-Type Condensations
FULL PAPER
(–OCH3, –Br) reacted smoothly to form spiro-fused pyrimi-
dines (Table 5, below, Entries 5–6, 6p–q; Scheme 8) while
aromatic aldehydes bearing functional groups (–F, –NO2)
in the meta, ortho, or para positions proceeded to give ben-
zylidene heterobicyclic products (Entries 1–3, 5o–q;
Scheme 7). The products from the reaction between 4-chlo-
robenzaldehyde (3d), cycloheptanone (1c), and urea, how-
ever, were a mixture of 5r and 6o at a ratio of 31:69 based
1
on H NMR (Entry 4).
Table 5. Cycloheptanone products.
Entry
X
Ar
Product[a]
Yield Ratio[c]
[b]
%
5:6
1
2
3
4
5
6
7
8
O
O
O
O
O
O
S
S
S
S
S
3f: 4-NO2
3g: 3-NO2
3i: 2-F
3d: 4-Cl
3c: 4-OCH3
3k: 2-Br
3a: H
5o
5p
5q
85
81
81
Scheme 5.
5r
6o
31:69
6p
6q
6r
83
89
90
85
90
92
74
93
83
3c: 4-OCH3
3d: 4-Cl
3e: 4-F
6s
6t
6u
6v
6w
6x
9
10
11
12
13
3i: 2-F
S
S
3j: 2-Cl
3k: 2-Br
[a] All compounds were characterized by 1H NMR, 13C NMR, and
mass spectrometry. [b] Isolated yield (yield based on aromatic alde-
1
hyde). [c] Ratio based on H NMR.
Scheme 6.
Table 4. Cyclohexanone products.
Entry
X
R
Product[a]
6g
Yield [%]
[b]
1
2
3
4
5
6
7
8
O
O
O
O
O
O
O
O
S
S
S
S
S
3a: H
3b: 4-CH3
3e: 4-F
3f: 4-NO2
3g: 3-NO2
3h: 2-OCH3
3i: 2-F
96
90
83
81
88
85
85
84
83
91
97
92
82
80
89
87
85
97
6h
6i
6j
6k
6l
Scheme 7.
The reactions of thiourea (2b) proceeded smoothly to
form spiro-fused heterotricyclic products (6r–x) in high
yields without the occurrence of benzylidene heterobicyclic
products (5) (Table 5, Entries 7–13; Scheme 8).
6m
6n
3j: 2-Cl
3a: H
9
4a
4b
4c
4d
4e
4f
10
11
12
13
14
15
16
17
18
3b: 4-CH3
3c: 4-OCH3
3d: 4-Cl
When cyclooctanone (1d) was treated with urea or thio-
urea and 2-chlorobenzaldehyde (3j) or 2-bromobenzalde-
hyde (3k), benzylidene heterobicyclic pyrimidines were
formed in excellent yields (Table 6, 5s–v; Scheme 9).
The reactions of cyclooctanone (1d) with thiourea and
aromatic aldehydes 3a–f, 3i, however, proceeded to yield
fused heterobicyclic products (Entries 5–11, 4k–q;
Scheme 10) in yields between 71 and 91% and with high
purities.
3e: 4-F
S
S
S
S
3f: 4-NO2
3g: 3-NO2
3h: 2-OCH3
3i: 2-F
4g
4h
4i
S
3k: 2-Br
4j
[a] All compounds were characterized by 1H NMR, 13C NMR, and
mass spectrometry. [b] Isolated yield (yield based on aromatic alde-
hyde).
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Y. Zhu, S. Huang, Y. Pan
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Scheme 10.
Scheme 8.
4-(4-Fluorophenyl)-3,4,5,6,7,8,9,10-octahydro-1H-cyclo-
octapyrimidine-2-thione (Table 6, Entry 9, 4o) was obtained
from DMF as colorless, block-shaped crystals. The struc-
tural features were established by X-ray crystal structure
analysis (Figure 2).[40]
Table 6. Cyclooctanone products.
Entry
X
Ar
Product[a]
5s
Yield [%][b]
1
2
3
4
5
6
7
8
O
O
S
S
S
S
S
S
S
S
S
3j: 2-Cl
3k: 2-Br
3j: 2-Cl
3k: 2-Br
3a: H
3b: 4-CH3
3c: 4-OCH3
3d: 4-Cl
3e: 4-F
93
96
92
86
90
87
91
89
78
71
82
5t
5u
5v
4k
4l
4m
4n
4o
4p
4q
9
10
11
3f: 4-NO2
3i: 2-F
[a] All compounds were characterized by 1H NMR, 13C NMR, and
mass spectrometry. [b] Isolated yield (yield based on aromatic alde-
hyde).
Figure 2. Crystal structure of 4-(4-fluorophenyl)-3,4,5,6,7,8,9,10-
octahydro-1H-cyclooctapyrimidine-2-thione (4o).
No reaction of cyclododecanone (1e) occurred even after
24 h, except when it was heated at reflux, when the products
were precipitated directly from the reaction mixture after
Table 7. Cyclododecanone products.
Entry
X
R
Product[a]
Yield (%)[b]
1
2
3
4
5
6
7
O
O
O
O
O
S
3a: 4-Cl
3h: 2-OCH3
3i: 2-F
4r
4s
87
96
93
90
85
89
83
4t
3j: 2-Cl
4u
4v
4w
4x
3k: 2-Br
3c: 4-CH3O
3i: 2-F
S
[a] All compounds were characterized by 1H NMR, 13C NMR, and
mass spectrometry. [b] Isolated yield (yield based on aromatic alde-
hyde).
Scheme 9.
2358
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Highly Chemoselective Multicomponent Biginelli-Type Condensations
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5–6 h. It gave only fused heterobicyclic compounds 4r–x Table 8. Cross condensation of cycloalkanones and aliphatic alde-
hydes.
with either urea or thiourea in yields between 83–96% and
R1
R2
Product
Yield[b]
in high purities, with no other side products being observed
(Table 7; Scheme 11). Cyclododecanone showed lower reac-
tion reactivity than cyclopentanone, cyclohexanone, cyclo-
heptanone, and cyclooctanone.
Entry
n
X
4[a]
1
2
3
4
5
6
7
8
9
3
4
4
4
4
8
8
8
8
S
S
S
S
S
S
S
O
O
CH3
H
CH3
H
H
CH3
H
CH3
C2H5
CH3
n-C3H7
n-C5H11
CH3
i-C3H7
CH3
4A
4B
4C
4D
4E
4F
4G
4H
4I
69
70
78
72
68
80
85
75
80
CH3
H
n-C5H11
[a] All compounds were characterized by 1H NMR, 13C NMR, and
mass spectrometry. [b] Isolated yield (yield based on aliphatic alde-
hyde).
As shown in Scheme 13, the reactions between cyclo-
pentanone, thiourea, and isobutyraldehyde (3m) or n-hep-
taldehyde (3p) proceeded to give only spiro-fused hetero-
tricyclic products 6y, 6z in moderate yields (68% and 45%,
respectively).
Scheme 11.
Biginelli-Type Reactions of Cycloalkanones 1a–e, Urea or
Thiourea, and Aliphatic Aldehydes 3l–p in the Presence of
TMSCl
Our interest in the preparation of novel scaffolds
prompted us to attempt the extension of this versatile reac-
tion to condensations of cycloalkanones and/or aliphatic
aldehydes in the Biginelli-type reaction. The same experi-
ment conditions were applied to reactions between cycloal-
kanones 1a–e, urea or thiourea, and aliphatic aldehydes 3l–
p such as n-butyraldehyde (3l), isobutyraldehyde (3m), n-
valeraldehyde (3n), isovaleraldehyde (3o), and n-heptal-
dehyde (3p).
Scheme 13.
Table 8 shows that aliphatic aldehydes displayed lower
The products of treatment of cyclohexanone (1b) with
reactivity than aromatic aldehydes, all reactions having to thiourea and isobutyraldehyde (3m) were a mixture of fused
be carried out at reflux. Two series of pyrimidine products pyrimidines 4y and spiro-fused pyrimidine 4z in a ratio of
were formed (Scheme 12).
59.3:40.7 as determined by HPLC (Scheme 14).
Scheme 12.
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Y. Zhu, S. Huang, Y. Pan
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Self-Condensation Reactions of Cycloalkanones 1 or
Aliphatic Aldehydes 3l–o and Urea or Thiourea in the
Presence of TMSCl
The self-condensation reactions of aliphatic aldehydes,
such as n-butyraldehyde (3l), isobutyraldehyde (3m), n-va-
leraldehyde (3n), and isovaleraldehyde (3o) on treatment
with urea or thiourea were also investigated. The reactions
were conducted by a procedure in which we used 1.0:1.2:1.0
molar ratios of aliphatic aldehydes 3l–p, urea or thiourea,
and TMSCl, and all reactions were complete after 4–6 h at
80 °C. We found that two molecules of aliphatic aldehydes
3l–p proceeded to react smoothly with one molecule of urea
or thiourea (Scheme 16, Scheme 18). As confirmed by
NMR measurements and mass spectrometry, the corre-
sponding heterocyclic pyrimidines were formed in moderate
yields.
Scheme 14.
The reaction between cycloheptanone (1c), isobutyral-
dehyde (3m), and thiourea proceeded cleanly to give the
fused heterobicyclic product (Table 8, Entry 1, 4A) in yield
69%, no side products being observed, but we completely
failed to obtain the fused heterobicyclic products 4 of cyclo-
hexanone (1b) or cycloheptanone (1c) on treatment with
thiourea (2b) and primary aldehydes such as n-butyral-
dehyde (3l), n-valeraldehyde (3n), isovaleraldehyde (3o), or
n-heptaldehyde (3p). Cyclooctanone (1d) and cyclododeca-
none (1e) reacted with aliphatic aldehydes 3l–p and thiourea
to yield the corresponding compounds (Entries 2–7, 4B–G)
in yields ranging from 70% to 85% and in high purities.
The reaction outcomes were consistent regardless of
whether α-unbranched or α-branched secondary aldehydes
were used as starting materials. There was no observed self-
condensation reaction of aliphatic aldehydes.
Scheme 16.
Urea showed lower reactivities than thiourea. No prod-
ucts were detected on treatment of aliphatic aldehydes 3l–
p with urea and cyclopentanone (1a), cyclohexanone (1b),
cycloheptanone (1c), or cyclooctanone (1d), but cyclodo-
decanone (1e) reacted with isobutyraldehyde (3m), n-heptal-
dehyde (3p), and urea to furnish the corresponding prod-
ucts (Entries 8 and 9, 4H and 4I; Scheme 15) in moderate
yields of 75% and 80%, respectively, with HPLC purities
higher than 84%.
In the course of our experiments, we found that the self-
condensation reactions of n-butyraldehyde (3i) and n-valer-
aldehyde (3n) in the presence of urea proceeded in yields of
1
53% and 62%, respectively (Scheme 16). The H and 13C
NMR analysis of products revealed the formation of 5-
ethyl-6-propyl-5,6-dihydro-1H-pyrimidin-2-one (4J) and 6-
n-butyl-5-propyl-5,6-dihydro-1H-pyrimidin-2-one (4K).
We envisaged that the rearrangement between 3,4-dihy-
dropyrimidinones and 5,6-dihydropyrimidinones might
take place (Scheme 17).
Scheme 17.
The products obtained from isovaleraldehyde (3o) and
urea or thiourea, however, were 3,4-dihydropyrimidinones
4L[41] and 4M, in 70% and 67% yields, respectively
(Scheme 18). We tried to promote the condensation reac-
tion by heating mixtures of α-branched aldehyde such as
Scheme 15.
2360
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Highly Chemoselective Multicomponent Biginelli-Type Condensations
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Scheme 19.
Scheme 18.
Scheme 20.
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Y. Zhu, S. Huang, Y. Pan
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not required for the reactions. Melting points were determined with
an XT-4 apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded in DMSO on a Bruker AVANCE DMX 500 spec-
trometer at 500 MHz and 125 MHz, respectively, chemical shifts
are given in ppm (δ), TMS was used as internal standard, and coup-
ling constants (J) are given in Hz.
isobutyraldehyde (3m) with urea or thiourea, but unfortu-
nately no reaction was observed even after 24 h at reflux.
Self-condensation of cyclohexanone with thiourea pro-
ceeded to furnish the spiro heterotricyclic product 4z
(Scheme 19) in a yield of 78%,[42] but no reaction was ob-
served for cyclopentanone, cycloheptanone, cyclooctanone,
or cyclododecanone.
General Procedures for the Synthesis of Heterobicyclic, Benzylidene
Heterobicyclic, and Spiro Heterotricyclic Products (Table 3–6): The
cycloalkanone (1a–d, 10 mmol), urea (12 mmol) or thiourea
(12 mmol), the aromatic aldehyde (10 mmol), and DMF/CH3CN
(3 mL/6 mL) were mixed in a flask, and TMSCl (10 mmol) was
added dropwise at room temperature. The reaction mixture was
stirred at room temperature for 2–3 h and precipitation was ob-
served. The products were isolated by filtered through a Büchner
funnel and washed with water followed by ethanol, and then dried
to give the crystalline powder products.
Proposed Possible Mechanism
Trimethylsilyl chloride showed remarkable reactivity as a
“hard-soft” reagent and considerably accelerated the reac-
tions. On the basis of all our experimental results, together
with literature reports,[42] we have proposed the mechanistic
pathway shown in Scheme 20 to account for the process.
The key step involves the formation of an N-acyliminium
ion intermediate 8 from urea or thiourea and aldehyde 3
precursors through two equilibrium steps[43] in the presence
of TMSCl as Lewis acid. For products 4, the nucleophilic
addition of intermediate 8 with only one α-carbon to form
intermediate 9 is facilitated, and this cyclizes to hexahy-
dropyrimidine 11 and undergoes acid-catalyzed elimination
to afford the fused heterobicyclic pyrimidines 4. For the
benzylidene heterobicyclic pyrimidine 5 and spiro hetero-
tricyclic pyrimidine 6 products, nucleophilic additions with
two α-carbons tend to form 10 and this then cyclizes to give
Compound 5a: M.p. 236–239 °C. 1H NMR: δ = 8.79 (s, 1 H), 7.38–
7.15 (m, 9 H), 6.63 (s, 1 H), 5.15 (s, 1 H), 2.85–2.75 (m, 2 H), 2.49
(m, 1 H), 2.02–1.97 (m, 1 H) ppm. 13C NMR: δ = 154.5, 144.4,
140.3, 138.8, 137.0, 129.7, 129.6, 129.0, 128.6, 127.6, 127.2, 119.7,
117.9, 58.6, 29.5 ppm. MS (ESI) [M + H]+ 303.
Compound 5b: M.p. 238–241 °C. 1H NMR: δ = 8.73 (s, 1 H), 7.23–
7.14 (m, 9 H), 6.58 (s, 1 H), 5.09 (s, 1 H), 2.82–2.71 (m, 2 H), 2.38–
2.33 (m, 1 H), 2.28 (s, 6 H), 2.00–1.96 (m, 1 H) ppm. 13C NMR: δ
= 154.2, 141.4, 139.1, 137.5, 136.7, 136.2, 135.9, 130.0, 128.8, 127.4,
119.1, 117.5, 58.1, 29.3, 29.2, 21.7, 21.6 ppm. MS (ESI) [M + H]+
331.
the key intermediate 12. Two trends were observed in the Compound 5c: M.p. 250–252 °C. 1H NMR: δ = 8.78 (s, 1 H), 7.33–
7.15 (m, 4 H), 7.01–7.88 (m, 5 H), 6.69 (s, 1 H), 5.49 (s, 1 H), 3.79
(s, 3 H), 3.78 (s, 3 H), 2.71–2.66 (m, 2 H), 2.35–2.30 (m, 1 H), 1.99–
1.95 (m, 1 H) ppm. 13C NMR: δ = 157.3, 156.7, 154.7, 139.9, 137.0,
132.2, 129.4, 128.9, 128.4, 128.0, 127.5, 121.7, 121.0, 118.8, 112.3,
111.9, 111.8, 56.4, 56.2, 51.7, 29.0 ppm. MS (ESI) [M + H]+ 363.
competitive nucleophilic substitution/elimination reaction:
one forming the elimination products, and another forming
nucleophilic substitution products. For elimination prod-
ucts it was difficult for the attacking –NH2 group to ap-
proach the substrate from a position 180° away from the
–OH leaving group. Acid-catalyzed elimination occurred
easily to form benzylidene heterobicyclic scaffold products
5. For the nucleophilic substitution products, backside at-
tack was more inclined to occur and inversion of configura-
tion gave access to spiro heterotricyclic scaffold products 6.
Compound 5d: M.p. 252–255 °C. 1H NMR: δ = 8.81 (s, 1 H), 7.44–
7.25 (m, 9 H), 6.62 (s, 1 H), 5.18 (s, 1 H), 2.85–2.73 (m, 2 H), 2.41–
2.36 (m, 1 H), 2.01–1.96 (m, 1 H) ppm. 13C NMR: δ = 154.0, 143.1,
140.8, 137.5, 137.0, 132.9, 131.2, 130.4, 129.5, 129.4, 129.3, 119.6,
116.6, 57.6, 29.2, 29.1 ppm. MS (ESI) [M + H] + 371.
Compound 5e: M.p. 235–239 °C. 1H NMR: δ = 8.89 (s, 1 H), 8.23–
8.02 (m, 4 H), 7.83–7.45 (m, 5 H), 6.81 (s, 1 H), 5.45 (s, 1 H), 2.97–
2.83 (m, 2 H), 2.53–2.48 (m, 1 H), 2.06–2.03 (m, 1 H) ppm. 13C
NMR: δ = 153.9, 149.0, 148.9, 146.2, 143.0, 140.1, 137.3, 134.9,
134.3, 131.3, 131.0, 123.5, 122.6, 122.0, 121.5, 120.3, 116.1, 57.5,
29.3, 29.1 ppm. MS (ESI) [M + H]+ 393.
Conclusions
We have demonstrated novel multicomponent reactions
of cycloalkanones, urea or thiourea, and aromatic alde-
hydes in the presence of TMSCl and have also studied the
self- and cross-condensations of cycloalkanones and/or ali-
phatic aldehydes under similar conditions. Thiourea exhib-
ited different behavior under such reaction conditions,
showing lower reactivity than urea, whilst aliphatic alde-
hydes exhibited different behavior to aromatic aldehydes. To
the best of our knowledge, cycloalkanones, unlike 1,3-keto
compounds, have not been used as suitable starting materi-
als for the Biginelli reaction. Undoubtedly, these reactions
should be useful to give the designer a simple route to syn-
thesize biologically active pyrimidinone scaffolds.
1
Compound 5f: M.p. 241–244 °C. H NMR: δ = 9.05 (s, 1 H), 7.50–
7.47 (t, J = 7.4 Hz, 1 H), 7.36–7.33 (m, 2 H), 7.25–7.14 (m, 6 H),
6.72 (s, 1 H), 5.45 (s, 1 H), 2.83–2.71 (m, 2 H), 2.41–2.37 (m, 1 H),
2.06–1.98 (m, 1 H) ppm. 13C NMR: δ = 161.4, 161.2, 159.4, 159.3,
154.3, 142.2, 137.3, 130.9, 130.8, 130.5, 130.4, 129.6, 129.0, 128.9,
126.3, 126.2, 125.9, 125.2, 119.0, 116.5, 116.3, 116.1, 109.4, 109.3,
52.3, 29.1, 28.8 ppm. MS (ESI) [M + H]+ 339.
Compound 5g: M.p. 232–234 °C. 1H NMR: δ = 9.15 (s, 1 H), 7.53–
7.20 (m, 9 H), 6.78 (s, 1 H), 5.62 (s, 1 H), 2.77–2.67 (m, 2 H), 2.44–
2.40 (m, 1 H), 1.99–1.94 (m, 1 H) ppm. 13C NMR: δ = 154.3, 142.3,
141.3, 137.2, 136.5, 133.4, 131.9, 130.3, 130.2, 130.1, 130.0, 129.0,
128.8, 127.9, 119.4, 114.4, 55.3, 28.8 ppm. MS (ESI) [M + H]+ 371.
Compound 5h: M.p. 242–246 °C. 1H NMR: δ = 9.17 (s, 1 H), 7.61–
7.21 (m, 9 H), 6.70 (s, 1 H), 5.58 (s, 1 H), 2.72–2.62 (m, 2 H), 2.44–
2.39 (m, 1 H), 1.96–1.91 (m, 1 H) ppm. 13C NMR: δ = 161.9, 156.4,
154.3, 142.9, 142.1, 139.8, 138.2, 137.0, 133.6, 130.3, 129.6, 129.4,
Experimental Section
General: Reagents and all solvents were analytically pure grade and
were used without further purification. Anhydrous conditions were
2362
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2354–2367

Highly Chemoselective Multicomponent Biginelli-Type Condensations
FULL PAPER
1
129.2, 128.5, 124.4, 122.1, 119.4, 117.1, 57.7, 28.9 ppm. MS (ESI)
Compound 5t: M.p. 251–257 °C. H NMR: δ = 8.54 (s, 1 H), 7.63–
7.62 (d, J = 7.6 Hz, 1 H), 7.55–7.53 (d, J = 7.9 Hz, 1 H), 7.47–7.41
(m, 2 H), 7.21–7.05 (m, 5 H), 6.55 (s, 1 H), 5.17 (s, 1 H), 2.48–2.37
(m, 2 H), 1.72–7.62 (m, 4 H), 1.40–1.30 (m, 4 H) ppm. 13C NMR:
δ = 153.5, 144.3, 139.6, 137.4, 133.1, 133.0, 130.9, 130.6, 130.3,
129.9, 129.8, 129.2, 128.4, 123.6, 122.6, 106.9, 57.7, 39.6, 30.0, 29.8,
27.9, 27.2 ppm. MS (ESI) [M + H]+ 501.
[M + H]+ 458.
1
Compound 5i: M.p. 203–205 °C. H NMR: δ = 10.07 (s, 1 H), 8.98
(s, 1 H), 7.41–7.17 (m, 10 H), 6.91 (s, 1 H), 5.19 (s, 1 H), 2.84–2.80
(m, 2 H), 2.46–2.41 (m, 1 H), 2.09–2.04 (m, 1 H) ppm. 13C NMR:
δ = 175.2, 143.1, 138.8, 138.5, 134.8, 129.6, 129.4, 128.9, 128.7,
127.5, 127.1, 122.0, 118.7, 58.8, 29.3, 28.8 ppm. MS (ESI)
[M + H]+ 319.
1
Compound 5u: M.p. 245–246 °C. H NMR: δ = 9.98 (s, 1 H), 8.74
(s, 1 H), 7.55–7.23 (m, 7 H), 7.05 (s, 1 H), 6.65 (s, 1 H), 5.23–5.22
(d, J = 1.8 Hz, 1 H), 2.44 (s, 2 H), 1.72–1.38 (m, 8 H) ppm. 13C
NMR: δ = 174.1, 141.4, 138.6, 135.3, 132.7, 131.7, 130.6, 130.4,
130.1, 129.6, 129.7, 129.5, 129.1, 128.5, 127.7, 127.7, 109.7, 29.0,
27.7, 27.3, 26.8 ppm. MS (ESI) [M + H]+ 429.
Compound 5v: M.p. 240–244 °C. 1H NMR: δ = 10.02 (s, 1 H), 9.54
(s, 1 H), 7.57–7.03 (m, 8 H), 6.58 (s, 1 H), 5.20 (s, 1 H), 2.43 (m, 2
H), 1.73–1.34 (m, 8 H) ppm. 13C NMR: δ = 174.1, 143.6, 143.5,
138.5, 137.2, 133.2, 133.1, 131.0, 130.8, 130.6, 130.5, 130.0, 129.3,
129.1, 128.5, 123.7, 122.4, 110.2, 57.4, 39.6, 29.4, 27.9, 27.3,
27.1 ppm. MS (ESI) [M + H]+ 517.
Compound 6a: 1H NMR: δ = 7.38–7.14 (m, 9 H), 6.81 (s, 1 H), 6.69
(s, 1 H), 6.56 (s, 1 H), 4.85 (d, J = 3.1 Hz, 1 H), 4.08 (d, J =
11.2 Hz, 1 H), 2.43 (m, 1 H), 2.17 (m, 1 H), 1.48 (m, 2 H), 1.10
(m, 2 H) ppm. 13C NMR: δ = 163.4 and 161.5 (split), 163.0 and
161.1 (split), 137.9, 137.7, 130.7, 130.5, 129.6, 129.4, 116.5, 116.1,
115.6, 74.8, 57.2, 51.3, 50.2, 49.7, 23.2, 21.3 ppm. MS (m/z) [M +
H]+ 399.
Compound 5j: 1H NMR: δ = 10.10 (s, 1 H), 9.05 (s, 1 H), 7.48–7.26
(m, 8 H), 6.92 (s, 1 H), 5.25 (s, 1 H), 2.87–2.74 (m, 2 H), 2.46–2.40
(m, 1 H), 2.09–2.05 (m, 1 H) ppm. 13C NMR: δ = 175.2, 141.9,
139.5, 137.3, 134.9, 133.2, 131.4, 130.9, 130.4, 129.6, 129.4, 129.0,
122.1, 117.5, 58.0, 29.2, 28.7 ppm. MS (ESI) [M + H]+ 387.
Compound 5k: M.p. 219–223 °C. 1H NMR: δ = 10.30 (s, 1 H), 9.18
(s, 1 H), 8.29–8.27 (d, J = 8.7 Hz, 2 H), 8.19–8.17 (d, J = 8.8 Hz,
2 H), 7.54 (m, 4 H), 7.09 (s, 1 H), 2.93–2.86 (m, 2 H), 2.52–2.49
(m, 1 H), 2.13–2.08 (m, 1 H) ppm. 13C NMR: δ = 175.4, 149.7,
147.8, 145.6, 145.1, 143.5, 135.2, 129.3, 128.6, 124.8, 124.6, 123.9,
117.3, 58.0, 29.2, 29.0 ppm. MS (ESI) [M + H]+ 409.
1
Compound 5l: M.p. 226–228 °C. H NMR: δ = 10.2 (s, 1 H), 8.69
(s, 1 H), 7.32–6.88 (m, 9 H), 5.49 (s, 1 H), 3.80 (s, 3 H), 3.77 (s, 3
H), 2.73–2.68 (m, 2 H), 2.40–2.36 (m, 1 H), 2.07–2.05 (m, 1
H) ppm. 13C NMR: δ = 175.9, 157.5, 156.5, 138.7, 134.9, 131.5,
129.8, 128.9, 128.6, 128.2, 127.4, 121.8, 121.7, 121.0, 113.5, 112.0,
111.8, 56.5, 56.3, 52.8, 29.3, 28.6 ppm. MS (ESI) [M + H]+ 379.
1
Compound 6c: M.p. 301–304 °C. H NMR: δ = 9.12 (s, 1 H), 8.62
Compound 5m: M.p. 203–207 °C. 1H NMR: δ = 8.80 (s, 1 H), 7.37–
7.30 (m, 4 H), 7.23–7.16 (m, 5 H), 6.64 (s, 1 H), 5.19 (s, 1 H), 2.86–
2.74 (m, 2 H), 2.41–2.36 (m, 1 H), 2.02–1.97 (m, 1 H) ppm. 13C
NMR: δ = 163.4 and 161.4 (split), 162.3 and 160.4 (split), 154.0,
140.5, 139.7, 136.8, 135.1, 130.6, 130.5, 129.4, 129.4, 119.1, 116.6,
116.4, 116.3, 116.2, 116.1, 57.5, 29.1 ppm. MS (ESI) [M + H]+ 339.
(s, 1 H), 8.52 (s, 1 H), 8.43 (s, 1 H), 7.34–7.16 (m, 8 H), 4.96 (s, 1
H), 4.14–4.12 (d, J = 11.3 Hz, 1 H), 1.45–1.41 (m, 1 H), 1.32–1.28
(m, 1 H), 1.10–1.08 (m, 2 H) ppm. 13C NMR: δ = 175.2, 141.9,
139.5, 137.3, 134.9, 133.2, 131.4, 130.9, 130.4, 129.6, 129.4, 129.0,
122.1, 117.5, 58.0, 29.2, 28.7 ppm. MS (ESI) [M + H]+ 431.
Compound 6d: M.p. 313–317 °C. 1H NMR: δ = 10.27 (s, 1 H), 9.20
(s, 1 H), 8.24–8.20 (m, 4 H), 7.82–7.63 (m, 5 H), 5.52 (s, 1 H), 2.97–
2.88 (m, 2 H), 2.57–2.51 (m, 1 H), 2.16–2.09 (m, 1 H) ppm. 13C
NMR: δ = 175.6, 148.9, 145.0, 143.6, 141.7, 140.0, 135.2, 134.9,
134.7, 134.3, 131.5, 131.1, 123.8, 123.7, 123.0, 122.9, 122.2, 117.1,
58.0, 29.4, 28.9 ppm. MS (ESI) [M + H]+ 485.
Compound 5o: M.p. 256–258 °C. 1H NMR: δ = 8.31 (s, 1 H), 8.27–
8.24 (m, 4 H), 7.65–7.62 (m, 4 H), 7.39 (s, 1 H), 6.93 (s, 1 H), 4.93
(s, 1 H), 2.34–2.12 (m, 2 H), 1.91–1.86 (m, 1 H), 1.75–1.59 (m, 3
H), 1.44 (m, 2 H),. 13C NMR: δ = 153.9, 152.7, 147.9, 146.9, 144.6,
139.7, 134.9, 130.8, 130.7, 129.2, 129.1, 127.9, 124.9, 124.7, 124.4,
124.1, 111.6, 61.0, 30.1, 29.8, 28.0, 26.3 ppm. MS (ESI) [M + H]+
421.
1
Compound 6e: M.p. 287–289 °C. H NMR: δ = 10.4 (s, 1 H), 8.94
(s, 1 H), 7.51–7.10 (m, 9 H), 6.99 (s, 1 H), 5.47 (s, 1 H), 2.83–2.74
(m, 2 H), 2.49–2.41 (m, 1 H), 2.08 (m, 1 H) ppm. 13C NMR: δ =
161.5 and 159.5 (split), 161.1 and 159.1 (split), 141.0, 135.2, 130.9,
130.8, 130.1, 130.0, 129.8, 129.6, 129.2, 129.1, 126.2, 126.0, 125.2,
121.9, 116.6, 116.4, 116.2, 110.6, 53.0, 29.0, 28.7 ppm. MS (ESI)
[M + H]+ 431.
Compound 5p: M.p. 239–242 °C. 1H NMR: δ = 8.28–8.13 (m, 5 H),
7.86–7.79 (m, 2 H), 7.72–7.68 (m, 2 H), 7.37 (s, 1 H), 6.95 (s, 1 H),
4.97 (s, 1 H), 2.32–2.20 (m, 2 H), 1.93–1.88 (m, 1 H), 1.76–1.62 (m,
3 H), 1.47–1.45 (m, 2 H) ppm. 13C NMR: δ = 153.8, 148.9, 148.7,
147.5, 139.2, 138.5, 135.9, 134.9, 134.6, 131.3, 130.8, 127.6, 124.4,
123.5, 123.0, 122.7, 122.5, 111.4, 60.8, 30.0, 29.8, 28.2, 26.4 ppm.
MS (ESI) [M + H]+ 421.
1
Compound 6f: M.p. 296–299 °C. H NMR: δ = 9.34 (s, 1 H), 8.63
(s, 1 H), 8.60 (s, 1 H), 8.51 (s, 1 H), 7.49–7.30 (m, 8 H), 5.39 (d, J
= 3.6 Hz, 1 H), 4.08 (d, J = 11.3 Hz, 1 H), 2.71–2.67 (m, 2 H),
1.56–1.52 (m, 1 H), 1.41–1.36 (m, 1 H), 1.15–1.09 (m, 1 H), 1.09–
1.02 (m, 1 H) ppm. 13C NMR: δ = 177.6, 136.9, 136.6, 134.1, 131.8,
130.4, 130.0, 129.7, 129.4, 128.5, 127.7, 74.4, 49.9, 45.1, 23.1,
21.5 ppm. MS (ESI) [M + H]+ 463.
Compound 6g: M.p. 330–332 °C (ref.[36] 335 °C). 1H NMR: δ =
7.37–7.25 (m, 10 H), 7.22 (s, 1 H), 6.84 (s, 1 H), 6.53 (s, 1 H), 6.47
(s, 1 H), 4.98 (d, J = 2.3 Hz, 1 H), 4.86–4.83 (d, J = 11.2 Hz, 1 H),
2.02–1.93 (m, 2 H), 1.44–1.40 (m, 2 H), 1.23–1.15 (m, 2 H), 0.89–
0.87 (t, J = 14.2 Hz, 2 H) ppm. 13C NMR: δ = 156.4, 155.0, 142.6,
140.9, 129.3, 128.9, 128.6, 128.3, 127.8, 127.7, 68.3, 54.0, 53.6, 43.9,
43.3, 22.8, 22.3, 19.1 ppm. MS (ESI) [M + H]+ 377.
Compound 5q: M.p. 248–250 °C. 1H NMR: δ = 8.03 (s, 1 H), 7.40–
7.17 (m, 9 H), 6.69 (s, 1 H), 5.04 (s, 1 H), 2.40–2.37 (m, 1 H), 2.20–
2.07 (m, 2 H), 1.79–1.66 (m, 1 H), 1.54 (m, 3 H), 1.28 (m, 1
H) ppm. 13C NMR: δ = 161.5 and 159.6 (split), 161.3 and 159.4
(split), 154.0, 139.6, 134.5, 132.0, 131.9, 131.6, 130.5, 130.2, 125.8,
125.3, 122.2, 116.5, 109.8, 55.4, 30.2, 29.6, 27.7, 26.4 ppm. MS
(ESI) [M + H]+ 367.
1
Compound 5s: M.p. 247–249 °C. H NMR: δ = 8.50 (s, 1 H), 7.64–
7.63 (t, J = 0.9 Hz, 1 H), 7.38–7.26 (m, 4 H), 7.22–7.17 (m, 2 H),
7.05–7.02 (m, 2 H), 6.62 (s, 1 H), 5.21 (d, J = 1.8 Hz, 1 H), 2.49–
2.40 (m, 2 H), 1.74–1.61 (m, 4 H), 1.39–1.37 (m, 4 H) ppm. 13C
NMR: δ = 153.6, 142.5, 139.9, 135.6, 132.9, 132.1, 130.8, 130.7,
130.6, 130.0, 129.9, 129.8, 129.7, 128.5, 127.9, 127.2, 106.5, 29.4,
27.9, 27.2 ppm. MS (ESI) [M + H]+ 413.
Compound 6h: M.p. 350–353 °C. 1H NMR: δ = 7.15 (m, 9 H), 6.84
(s, 1 H), 6.49 (s, 1 H), 6.40 (s, 1 H), 4.93 (s, 1 H), 4.49 (d, J =
Eur. J. Org. Chem. 2005, 2354–2367
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2363

Y. Zhu, S. Huang, Y. Pan
FULL PAPER
11.1 Hz, 1 H), 2.29 (s, 6 H), 2.07–1.90 (m, 2 H), 1.51–1.36 (m, 2 2 H), 1.87–1.82 (m, 1 H), 1.64–1.62 (m, 1 H), 1.40–1.13 (m, 6
H), 1.21–1.12 (m, 2 H), 0.89 (m, 2 H) ppm. MS (ESI) [M + H]+
405.
H) ppm. 13C NMR: δ = 156.5, 153.5, 140.1, 138.1, 133.0, 129.6,
129.0, 128.2, 122.1, 121.0, 120.7, 70.5, 54.0, 53.5, 44.9, 44.6, 30.5,
25.8, 22.6, 22.6, 20.1 ppm. MS (ESI) [M + H]+ 547.
1
Compound 6i: M.p. 302–303 °C. H NMR: δ = 7.96 (s, 1 H), 7.83–
1
6.88 (m, 11 H), 5.28 (d, J = 1.5 Hz, 1 H), 4.86 (d, J = 11.3 Hz, 1
H), 2.20–2.02 (m, 2 H), 1.71–1.16 (m, 4 H), 0.94–0.87 (m, 2 H),
1.43–1.36 (m, 2 H), 1.09 (m, 2 H), 0.85 (m, 1 H) ppm. 13C NMR:
δ = 162.3 and 160.3 (split), 161.1 and 159.1 (split), 156.5, 155.1,
130.6, 130.1, 129.9, 129.7, 129.1, 128.9, 127.4, 125.7, 124.8, 116.4,
68.3, 48.0, 47.6, 42.4, 22.9, 22.6, 19.8, 19.1 ppm. MS (ESI) [M +
H]+ 413.
Compound 6r: M.p. 307–310 °C. H NMR: δ = 8.95 (s, 1 H), 8.45
(s, 1 H), 7.95 (s, 1 H), 7.50–7.31 (m, 10 H), 7.05 (s, 1 H), 4.75 (d,
J = 11.8 Hz, 1 H), 4.55 (s, 1 H), 2.72–2.70 (m, 1 H), 2.16–2.12 (m,
1 H), 1.83–1.34 (m, 6 H), 1.03–1.01 (m, 1 H), 0.85–0.82 (m, 1
H) ppm. 13C NMR: δ = 179.0, 175.3, 140.9, 130.1, 129.9, 129.4,
129.3, 129.0, 128.9, 128.3, 127.6, 126.9, 70.8, 59.4, 56.8, 48.5, 44.4,
28.3, 26.4, 23.6, 23.3 ppm. MS (ESI) [M + H]+ 423.
Compound 6j: M.p. 341–344 °C (ref.[35] 330 °C, decomp.) 1H NMR:
δ = 7.72–7.44 (m, 9 H), 7.34 (s, 1 H), 7.00 (s, 1 H), 6.90 (s, 1 H),
5.74 (d, J = 2.7 Hz, 1 H), 4.86 (d, J = 11.3 Hz, 1 H), 2.19 (m, 1
H), 1.99 (m, 1 H), 1.90 (m, 1 H), 1.43–1.36 (m, 2 H), 1.09 (m, 2
H), 0.85 (m, 1 H) ppm. 13C NMR: δ = 157.7, 140.6, 137.7, 134.3,
132.2, 130.4, 130.2, 130.0, 129.8, 128.7, 127.7, 67.9, 51.6, 51.3, 48.3,
42.2, 41.2, 27.4, 24.4, 23.5 ppm. MS (ESI) [M + H]+ 445.
1
Compound 6s: M.p. 317–321 °C. H NMR: δ = 8.85 (s, 1 H), 8.31
(s, 1 H), 7.75 (s, 1 H), 7.40 (d, J = 8.5 Hz, 2 H), 7.28 (s, 1 H), 7.24
(d, J = 8.5 Hz, 2 H), 6.99 (d, J = 8.5 Hz, 2 H), 6.94–6.91 (d, J =
8.4 Hz, 2 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.48 (s, 1 H), 3.76 (s, 3
H), 3.74 (s, 3 H), 2.72–2.66 (m, 1 H), 2.11–2.07 (m, 1 H), 1.79–1.29
(m, 6 H), 1.02–1.00 (d, J = 14.6 Hz, 1 H), 0.87–0.84 (m, 1 H) ppm.
13C NMR: δ = 179.2, 175.3, 159.9, 159.8, 132.8, 132.5, 130.5, 128.9,
115.3, 114.7, 71.0, 58.7, 56.3, 56.1, 56.0, 48.5, 44.8, 27.8, 26.8,
23.5 ppm. MS (ESI) [M + H]+ 483.
Compound 6k: M.p. 335–336 °C. 1H NMR: δ = 7.31–7.17 (m, 9 H),
6.88 (s, 1 H), 6.62 (s, 1 H), 6.54 (s, 1 H), 4.97 (s, 1 H), 4.58 (d, J =
11.2 Hz, 1 H), 2.02–1.93 (m, 2 H), 1.44–1.40 (m, 2 H), 1.23–1.15
(m, 2 H), 0.89–0.87 (m, 2 H) ppm. 13C NMR: δ = 156.4, 155.0,
142.6, 140.9, 129.3, 128.9, 128.6, 128.3, 127.8, 127.7, 68.3, 54.0,
53.6, 43.9, 43.3, 22.8, 22.3, 19.1 ppm. MS (ESI) [M + H]+ 413.
1
Compound 6t: M.p. 314–317 °C. H NMR: δ = 8.97 (s, 1 H), 8.52
(s, 1 H), 7.84 (s, 1 H), 7.51–7.39 (m, 8 H), 7.27 (s, 1 H), 4.77 (d, J
= 11.9 Hz, 1 H), 4.58 (d, J = 4.0 Hz, 1 H), 2.73 (m, 1 H), 2.16–
2.12 (m, 1 H), 1.81–1.23 (m, 6 H), 0.98 (d, J = 13.6 Hz, 1 H), 0.85
(m, 1 H) ppm. MS (ESI) [M + H]+ 491.
1
Compound 6l: M.p. 348–350 °C. H NMR: δ = 8.25 (m, 4 H), 7.58
1
(m, 4 H), 7.49 (s, 1 H), 7.00 (s, 1 H), 6.90 (s, 1 H), 6.83 (s, 1 H),
5.09 (s, 1 H), 4.77 (d, J = 11.4 Hz, 1 H), 2.11–2.06 (m, 2 H), 1.46–
1.42 (m, 2 H), 1.25–1.17 (m, 2 H), 0.85–0.78 (m, 2 H) ppm. MS
(ESI) [M + H]+ 467.
Compound 6u: M.p. 290–293 °C. H NMR: δ = 8.95 (s, 1 H), 8.49
(s, 1 H), 7.83 (s, 1 H), 7.55–7.53 (m, 2 H), 7.38–7.35 (m, 2 H), 7.29–
7.17 (m, 5 H), 4.77 (d, J = 12.0 Hz, 1 H), 4.57 (d, J = 4.2 Hz, 1
H), 2.72 (t, J = 5.8 Hz, 1 H), 2.17–2.13 (m, 1 H), 1.81–1.78 (m, 1
H), 1.66–1.26 (m, 5 H), 0.99–0.96 (d, J = 14.6 Hz, 1 H), 0.86 (m,
1 H) ppm. 13C NMR: δ = 179.5, 145.4, 163.7, 161.7, 137.1, 136.9,
131.5, 1314, 130.0, 129.9, 116.8, 116.6, 116.2, 116.0, 71.0, 58.4,
56.1, 48.5, 44.7, 31.6, 27.6, 26.8, 23.5, 23.4 ppm. MS (ESI) [M +
H]+ 459.
Compound 6m: M.p. 331–335 °C. 1H NMR: δ = 8.19–8.15 (m, 5
H), 7.78–7.66 (m, 6 H), 7.14 (s, 1 H), 5.11 (d, J = 2.8 Hz, 1 H),
4.86 (d, J = 11.3 Hz, 1 H), 2.20–2.13 (m, 2 H), 1.49–1.47 (m, 2 H),
1.26–1.16 (m, 2 H), 0.88–0.80 (m, 2 H) ppm. 13C NMR: δ = 156.7,
155.6, 148.9, 148.6, 144.0, 142.9, 135.5, 134.7, 131.3, 130.8, 124.1,
123.2, 123.1, 122.6, 122.3, 68.6, 53.5, 53.4, 43.2, 42.2, 23.1, 22.4,
19.0 ppm. MS (ESI) [M + H]+ 467.
1
Compound 6v: M.p. 300–304 °C. H NMR: δ = 8.94 (s, 1 H), 8.64
(s, 1 H), 8.40 (s, 1 H), 7.54–7.16 (m, 8 H), 7.08 (s, 1 H), 5.11 (d, J
= 11.9 Hz, 1 H), 4.69 (s, 1 H), 2.72–2.69 (m, 1 H), 2.30–2.26 (m, 1
H), 1.82–1.77 (m, 1 H), 1.62–1.40 (m, 5 H), 1.00–0.85 (m, 2
H) ppm. 13C NMR: δ = 179.5, 175.5, 162.7, 160.7, 131.6, 159.7,
131.4, 131.3, 131.0, 130.8, 128.6, 127.8, 127.7, 126.3, 125.5, 117.0,
116.8, 116.5, 116.3, 70.7, 53.7, 47.3, 43.5, 28.6, 26.4, 23.6,
23.5 ppm. MS (ESI) [M + H]+ 459.
Compound 6n: M.p. 324–347 °C. 1H NMR: δ = 7.31 (s, 1 H), 7.28–
6.87 (m, 9 H), 6.80 (s, 1 H), 5.17 (s, 1 H), 3.80 (m, 3 H), 3.78 (m,
3 H), 2.46–2.28 (m, 2 H), 2.05–2.00 (m, 2 H), 1.83–1.79 (m, 1 H),
1.51–1.42 (m, 1 H), 1.28 (m, 1 H), 0.91–0.80 (m, 1 H) ppm. 13C
NMR: δ = 157.9, 157.1, 156.7, 154.7, 132.6, 131.1, 131.0, 129.9,
129.6, 129.1, 128.8, 128.3, 126.8, 121.7, 120.7, 119.1,
112.1,,111.8,,56.6, 56.1, 53.3, 27.6, 26.9, 23.4 ppm. MS (ESI) [M +
H]+ 437.
1
Compound 6w: M.p. 313–315 °C. H NMR: δ = 8.95 (s, 1 H), 8.72
(s, 1 H), 8.60 (s, 1 H), 7.58–7.33 (m, 8 H), 6.68 (s, 1 H), 5.27 (d, J
= 6.9 Hz, 1 H), 4.64 (s, 1 H), 2.72–2.70 (m, 1 H), 2.30 (m, 1 H),
1.83–1.36 (m, 6 H), 1.02–0.84 (m, 2 H) ppm. MS (ESI) [M + H]+
491.
1
Compound 6o: M.p. H NMR: δ = 7.55–7.29 (m, 11 H), 6.76 (s, 1
H), 5.01(s, 1 H), 4.45(d, J = 8.3 Hz, 1 H), 1.82–1.79 (m, 2 H), 1.57–
1.10 (m, 8 H) ppm. 13C NMR: δ = 156.5, 154.8, 142.4, 140.1, 133.1,
132.3, 130.1, 129.9, 129.7, 129.5, 129.3, 129.1, 129.0, 108.6, 71.8,
56.4, 53.9, 50.0, 47.8, 26.9, 24.4, 20.9 ppm. MS (ESI) [M + H]+
459.
1
Compound 6x: M.p. 328–333 °C. H NMR: δ = 8.98 (s, 1 H), 8.62
(s, 1 H), 7.74 (s, 1 H), 7.59–7.52 (m, 4 H), 7.44–7.34 (m, 4 H), 6.75
(s, 1 H), 5.11 (d, J = 11.5 Hz, 1 H), 4.59 (s, 1 H), 2.77–2.69 (m, 1
H), 2.32–2.28 (m, 1 H), 1.61–1.60 (m, 1 H), 1.54–1.24 (m, 5 H),
1.07–1.05 (m, 1 H), 0.85–0.81 (m, 1 H) ppm. 13C NMR: δ = 178.9,
175.1, 140.5, 139.5, 134.7, 133.4, 131.4, 130.9, 130.8, 129.8, 129.2,
129.0, 125.9, 123.7, 70.5, 60.0, 55.8, 46.3, 44.8, 29.4, 25.9, 23.8,
22.9 ppm. MS (ESI) [M + H]+ 578.
Compound 6p: M.p. 310–313 °C. 1H NMR: δ = 7.57 (s, 1 H), 7.34–
7.23 (m, 4 H), 7.07–6.92 (m, 5 H), 6.59 (s, 1 H), 6.06 (s, 1 H), 5.24
(s, 1 H), 4.73 (d, J = 8.0 Hz, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 2.06–
2.03 (m, 1 H), 1.75–1.73 (m, 1 H), 1.59–1.50 (m, 2 H), 1.28–1.03
(m, 6 H) ppm. 13C NMR: δ = 157.6, 156.9, 155.5, 130.1, 129.1,
128.8, 128.0, 121.7, 120.9, 112.5, 111.8, 72.0, 56.7, 56.6, 49.4, 45.6,
27.4, 21.8 ppm. MS (ESI) [M + H]+ 451.
1
Compound 4a: M.p. 221–224 °C. H NMR: δ = 9.41 (s, 1 H), 8.68
(s, 1 H), 7.16–7.11 (m, 5 H), 4.65 (s, 1 H), 2.07–2.03 (m, 2 H), 1.80
Compound 6q: M.p. 299–301 °C. 1H NMR: δ = 7.65–7.23 (m, 9 H), (d, J = 16.3 Hz, 1 H), 1.60–1.47 (m, 5 H) ppm. 13C NMR: δ =
6.67 (s, 2 H), 6.29 (s, 1 H), 5.28 (d, J = 2.3 Hz, 1 H), 4.75 (d, J = 173.7, 144.3, 130.0, 129.3, 127.9, 107.9, 60.0, 25.7, 23.5, 22.9 ppm.
9.5 Hz, 1 H), 5.04 (s, 1 H), 2.61–2.54 (m, 1 H), 2.20 (d, J = 8.4 Hz,
MS (ESI) [M + H]+ 245.
2364
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2354–2367

Highly Chemoselective Multicomponent Biginelli-Type Condensations
FULL PAPER
1
Compound 4b: M.p. 230–232 °C. H NMR: δ = 9.41 (s, 1 H), 8.66
Compound 4m: M.p. 208–211 °C (ref.[34] 204 °C). 1H NMR: δ =
9.38 (s, 1 H), 8.62 (s, 1 H), 7.17 (d, J = 8.3 Hz, 2 H), 6.91–6.89 (d,
J = 8.3 Hz, 2 H), 4.63 (s, 1 H), 3.73 (s, 3 H), 2.23 (m, 2 H), 1.93–
(s, 1 H), 7.16 (d, J = 7.5 Hz, 2 H), 7.11 (d, J = 7.7 Hz, 2 H), 4.60
(s, 1 H), 2.28 (s, 3 H), 2.04–2.02 (m, 2 H), 1.78 (d, J = 21.3 Hz, 1
H), 1.62–1.47 (m, 5 H) ppm. 13C NMR: δ = 173.7, 141.5, 137.9, 1.84 (m, 2 H), 1.56–1.35 (m, 7 H), 1.03 (m, 1 H) ppm. 13C NMR:
130.1, 128.6, 127.8, 107.9, 99.7, 25.7, 25.7, 22.9, 22.7, 21.8 ppm.
δ = 173.8, 159.7, 159.2, 137.2, 130.4, 130.2, 130.0, 129.2, 114.7,
114.5, 110.0, 58.9, 56.0, 29.6, 29.1, 28.2, 27.2, 27.0, 26.3 ppm. MS
(ESI) [M + H]+ 303.
MS (ESI) [M + H]+ 259.
1
Compound 4c: M.p. 226–229 °C. H NMR: δ = 9.40 (s, 1 H), 8.65
Compound 4n: M.p. 215–216 °C (ref.[34] 215 °C). 1H NMR: δ = 9.48
(s, 1 H), 8.72 (s, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 6.91–6.89 (d, J =
8.0 Hz, 2 H), 4.72 (s, 1 H), 2.23 (m, 2 H), 1.98–1.81 (m, 2 H), 1.56–
1.34 (m, 7 H), 1.01 (m, 1 H) ppm. 13C NMR: δ = 174.2, 144.0,
133.1, 131.0, 129.9, 129.4, 109.4, 58.7, 29.8, 29.1, 28.0, 27.2, 27.0,
26.3 ppm. MS (ESI) [M + H]+ 307.
(s, 1 H), 7.13 (d, J = 8.5 Hz, 2 H), 7.11 (d, J = 8.5 Hz, 2 H), 4.58
(s, 1 H), 3.74 (s, 3 H), 2.04–2.01 (m, 2 H), 1.79 (d, J = 16.3 Hz, 1
H), 1.60–1.46 (m, 5 H) ppm. 13C NMR: δ = 173.3, 159.7, 136.3,
129.0, 128.4, 114.8, 107.8, 59.1, 56.0, 25.5, 25.5, 22.8, 22.5 ppm.
MS (ESI) [M + H]+ 275.
1
Compound 4d: M.p. 218–220 °C. H NMR: δ = 9.50 (s, 1 H), 8.75
1
Compound 4o: M.p. 217–220 °C. H NMR: δ = 9.46 (s, 1 H), 8.71
(s, 1 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2 H), 4.68
(s, 1 H), 2.04–2.02 (m, 2 H), 1.81 (d, J = 16.0 Hz, 1 H), 1.55–1.43
(m, 5 H) ppm. 13C NMR: δ = 173.7, 143.1, 133.1, 129.6, 129.5,
128.8, 107.2, 59.0, 25.5, 25.4, 22.7, 22.4 ppm. MS (ESI) [M + H]+
279.
(s, 1 H), 7.30–7.16 (m, 4 H), 4.72 (s, 1 H), 2.23 (m, 2 H), 1.96–1.82
(m, 2 H), 1.57–1.34 (m, 7 H), 1.01 (m, 1 H) ppm. 13C NMR: δ =
174.0, 163.5 and 161.6 (split), 141.4, 141.3, 130.8, 130.0, 129.9,
116.2, 116.0, 109.6, 59.6, 29.8, 29.1, 28.0, 27.2, 27.0, 26.3 ppm. MS
(ESI) [M + H]+ 291.
1
Compound 4e: M.p. 211–214 °C. H NMR: δ = 9.47 (s, 1 H), 8.73
1
Compound 4p: M.p. 226–229 °C. H NMR: δ = 9.58 (s, 1 H), 8.83
(s, 1 H), 7.26 –7.16 (m, 2 H), 4.67 (s, 1 H), 2.04–2.01 (m, 2 H), 1.77
(d, 1 H), 1.55–1.46 (m, 5 H) ppm. 13C NMR: δ = 173.6, 163.5,
161.5, 140.4, 129.8, 129.7, 128.7, 116.3, 116.1, 107.5, 59.0, 25.6,
25.5, 22.7, 22.5 ppm. MS (ESI) [M + H]+ 263.
(s, 1 H), 8.23 (d, J = 8.6 Hz, 2 H), 7.54 (d, J = 8.6 Hz, 2 H), 4.90
(d, J = 2.3 Hz, 1 H), 2.24 (m, 2 H), 1.98–1.80 (m, 2 H), 1.48–1.25
(m, 7 H), 1.03 (m, 1 H) ppm. 13C NMR: δ = 174.5, 152.2, 147.9,
131.7, 129.7, 129.2, 127.9, 124.8, 124.3, 108.8, 58.7, 29.8, 29.1, 27.9,
27.3, 27.0, 26.1 ppm. MS (ESI) [M + H]+ 318.
1
Compound 4f: M.p. 217–220 °C. H NMR: δ = 9.60 (s, 1 H), 8.86
(s, 1 H), 8.27 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 8.0 Hz, 2 H), 4.85
(s, 1 H), 2.04–2.01 (m, 2 H), 1.87 (d, J = 15.7 Hz, 1 H), 1.67–1.46
(m, 5 H) ppm. 13C NMR: δ = 174.0, 151.4, 147.9, 129.3, 129.0,
124.9, 106.7, 59.1, 31.6, 25.6, 25.4, 22.7, 22.4 ppm. MS (ESI) [M +
H]+ 290.
1
Compound 4q: M.p. 215–217 °C. H NMR: δ = 9.53 (s, 1 H), 8.65
(s, 1 H), 7.35–7.15 (m, 4 H), 5.02 (s, 1 H), 2.26–2.17 (m, 2 H), 1.96–
1.86 (m, 2 H), 1.56–1.32 (m, 7 H), 0.94 (m, 1 H) ppm. 13C NMR:
δ = 174.5, 161.2 and 159.2 (split), 132.0, 131.9, 131.2, 130.7, 130.6,
130.5, 130.5, 125.8, 116.5, 116.3, 108.4, 53.4, 29.9, 29.1, 28.0, 27.2,
27.0, 26.3 ppm. MS (ESI) [M + H]+ 291.
1
Compound 4g: M.p. 223–224 °C. H NMR: δ = 9.61 (s, 1 H), 8.87
(s, 1 H), 8.18–8.06 (m, 2 H), 7.71 (m, 2 H), 4.90 (s, 1 H), 2.10–2.04
(m, 2 H), 1.85 (d, J = 16.2 Hz, 1 H), 1.51–1.46 (m, 5 H) ppm. MS
(ESI) [M + H]+ 290.
General Procedures for Synthesis of Pyrimidinone Scaffolds from
Table 7: Cyclododecanone (1e, 10 mmol), urea (12 mmol) or thio-
urea (12 mmol), the aromatic aldehyde (10 mmol), and DMF/
CH3CN (3 mL/6 mL) were mixed in a flask and TMSCl (10 mmol)
was added dropwise at room temperature. After 30 minutes, the
reaction mixture was stirred at reflux for 5–6 h and precipitation
was observed. The product was isolated by filtered through a
Buechner funnel and washed with water followed by ethanol, and
then dried to give the crystalline powder products.
1
Compound 4h: M.p. 224–226 °C. H NMR: δ = 9.39 (s, 1 H), 8.34
(s, 1 H), 7.26–6.94 (m, 4 H), 5.07 (s, 1 H), 3.80 (s, 3 H), 2.02–2.00
(m, 2 H), 1.81 (d, J = 17.0 Hz, 1 H), 1.60–1.42 (m, 5 H) ppm. 13C
NMR: δ = 173.9, 156.7, 132.1, 129.4, 128.3, 121.5, 111.8, 107.5,
56.2, 52.8, 25.4, 25.2, 22.6, 22.3 ppm. MS (ESI) [M + H]+ 275.
1
Compound 4i: M.p. 207–209 °C. H NMR: δ = 9.53 (s, 1 H), 8.69
1
(s, 1 H), 7.34–7.15 (m, 4 H), 4.99 (s, 1 H), 2.08–2.02 (m, 2 H), 1.83
(d, J = 16.0 Hz, 1 H), 1.61–1.43 (m, 5 H) ppm. 13C NMR: δ =
174.1, 161.1 and 159.1 (split), 131.3, 131.1, 130.5, 129.9, 128.8,
125.9, 116.4, 116.2, 106.6, 53.5, 25.5, 25.2, 22.7, 22.4 ppm. MS
(ESI) [M + H]+ 263.
Compound 4r: M.p. 210–213 °C. H NMR: δ = 7.97 (s, 1 H), 7.40
(d, J = 7.6 Hz, 2 H), 7.27 (d, J = 7.6 Hz, 2 H), 7.02 (s, 1 H), 4.68
(s, 1 H), 2.33–2.30 (m, 1 H), 2.16–2.14 (m, 1 H), 1.90–1.87 (m, 1
H), 1.57–1.25 (m, 17 H) ppm. 13C NMR: δ = 154.1, 144.6, 132.9,
132.7, 129.6, 129.3, 107.4, 57.2, 35.2, 26.0, 25.9, 25.8, 25.4, 25.3,
25.2, 24.8, 22.9, 22.6 ppm. MS (ESI) [M + H]+ 347.
1
Compound 4j: M.p. 210–211 °C. H NMR: δ = 9.56 (s, 1 H), 8.72
1
(s, 1 H), 7.57–7.20 (m, 4 H), 5.17 (s, 1 H), 2.08–2.04 (m, 2 H), 1.83
(m, 1 H), 1.59–1.43 (m, 5 H) ppm. 13C NMR: δ = 173.9, 143.5,
133.4, 130.7, 130.6, 129.7, 128.7, 122.5, 107.5, 59.0, 25.6, 25.2, 22.7,
22.4 ppm. MS (ESI) [M + H]+ 323.
Compound 4k: M.p. 230–232 °C (ref.[34] 230 °C). 1H NMR: δ = 9.41
(s, 1 H), 8.67 (s, 1 H), 7.36–7.24 (m, 5 H), 4.68 (s, 1 H), 2.23 (s, 2
H), 1.97–1.83 (m, 2 H), 1.57–1.34 (m, 7 H), 1.02 (m, 1 H) ppm.
13C NMR: δ = 174.1, 145.1, 130.7, 129.4, 128.7, 128.1, 109.9, 59.6,
29.8, 29.2, 28.2, 27.3, 27.1, 26.4 ppm. MS (ESI) [M + H]+ 273.
Compound 4l: M.p. 234–237 °C (ref.[34] 230 °C). 1H NMR: δ = 9.39
(s, 1 H), 8.63 (s, 1 H), 7.17–7.12 (m, 4 H), 4.64 (d, J = 2.3 Hz, 1
H), 3.73 (s, 3 H), 2.22 (m, 2 H), 1.95–1.82 (m, 2 H), 1.58–1.34 (m,
7 H), 1.00 (m, 1 H) ppm. 13C NMR: δ = 174.0, 142.2, 137.7, 130.5,
129.9, 127.9, 109.9, 59.2, 29.8, 29.1, 28.1, 27.2, 27.0, 26.3,
21.6 ppm. MS (ESI) [M + H]+ 287.
Compound 4s: M.p. 237–241 °C. H NMR: δ = 7.90 (s, 1 H), 7.23–
7.18 (m, 2 H), 6.98–6.90 (m, 2 H), 6.61 (s, 1 H), 5.13 (d, J = 1.8 Hz,
1 H), 3.77 (s, 3 H), 2.35–2.32 (m, 1 H), 2.15–2.13 (m, 1 H), 1.87–
1.85 (m, 1 H), 1.57–1.19 (m, 17 H) ppm. 13C NMR: δ = 157.0,
154.8, 133.3, 132.8, 129.4, 128.4, 121.6, 111.9, 10.7, 55.6, 45.0, 42.6,
125.9, 25.9, 25.5, 25.4, 25.3, 25.1, 24.9, 22.9, 22.7 ppm. MS (ESI)
[M + H]+ 343.
1
Compound 4t: M.p. 220–222 °C. H NMR: δ = 8.03 (s, 1 H), 7.45–
7.02 (m, 4 H), 6.77 (s, 1 H), 5.05 (s, 1 H), 2.33–2.30 (m, 1 H), 2.16–
2.15 (m, 1 H), 1.89–1.87 (m, 1 H), 1.45–1.05 (m, 17 H) ppm. 13C
NMR: δ = 161.1 and 159.2 (split), 133.1, 132.6, 132.5, 130.3, 130.2,
129.8, 125.9, 116.3, 116.2, 106.6, 51.0, 31.7, 26.1, 25.9, 25.5, 25.4,
25.2, 24.8, 24.6, 23.0, 22.6 ppm. MS (ESI) [M + H]+ 331.
Compound 4u: M.p. 183–185 °C. 1H NMR: δ = 8.04 (s, 1 H), 7.42–
7.26 (m, 1 H), 7.04 (s, 1 H), 5.20 (d, J = 1.9 Hz, 1 H), 2.33–2.30
Eur. J. Org. Chem. 2005, 2354–2367
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2365

Y. Zhu, S. Huang, Y. Pan
FULL PAPER
1
(m, 1 H), 2.16–2.13 (m, 1 H), 1.91–1.88 (m, 1 H), 1.59–1.18 (m, 17 Compound 4C: M.p. 178–183 °C. H NMR: δ = 9.18 (s, 1 H), 8.21
H) ppm. MS (ESI) [M + H]+ 347.
(s, 1 H), 3.45 (s, 1 H), 2.22–1.93 (m, 4 H), 1.67–1.65 (m, 1 H), 1.53–
1.42 (m, 8 H), 0.86–0.76 (m, 6 H) ppm. 13C NMR: δ = 175.9, 132.1,
109.2, 60.2, 34.2, 30.3, 29.0, 28.4, 27.4, 27.0, 26.6, 19.5, 17.1 ppm.
MS (ESI) [M + H]+ 239.
1
Compound 4v: M.p. 257–260 °C. H NMR: δ = 8.03 (s, 1 H), 7.55
(d, J = 7.9 Hz, 1 H), 7.43–7.38 (m, 2 H), 7.20–7.17 (t, J = 7.5 Hz,
1 H), 7.04 (s, 1 H), 5.17 (s, 1 H), 2.33–2.30 (m, 1 H), 2.15–2.12 (m,
1 H), 1.91–1.88 (m, 1 H), 1.61–1.18 (m, 17 H) ppm. 13C NMR: δ
= 174.3, 163.2, 144.0, 133.4, 131.9, 130.7, 130.5, 129.7, 122.6, 110.8,
56.6, 31.7, 26.2, 26.1, 25.7, 25.5, 25.4, 25.2, 24.9, 22.9, 22.5 ppm.
MS (ESI) [M + H]+ 391.
1
Compound 4D: M.p. 143–146 °C. H NMR: δ = 9.15 (s, 1 H), 8.24
(s, 1 H), 3.69 (d, J = 2.6 Hz, 1 H), 2.16–1.96 (m, 4 H), 1.52–1.23
(m, 14 H), 0.85 (t, J = 4.6 Hz, 3 H) ppm. 13C NMR: δ = 175.1,
131.4, 109.6, 54.8, 35.8, 30.2, 28.9, 27.9, 27.3, 27.0, 26.5, 26.4, 23.1,
15.0 ppm. MS (ESI) [M + H]+ 253.
1
Compound 4w: M.p. 168–170 °C. H NMR: δ = 9.36 (s, 1 H), 8.75
1
(s, 1 H), 7.15 (d, J = 8.5 Hz, 2 H), 6.91 (d, J = 8.5 Hz, 2 H), 4.66
(s, 1 H), 2.33–2.30 (m, 1 H), 2.16–2.14 (m, 1 H), 1.90–1.87 (m, 1
H), 1.57–1.25 (m, 17 H) ppm. 13C NMR: δ = 163.3, 159.8, 136.3,
131.3, 129.1, 114.7, 111.3, 56.8, 55.7, 36.8, 26.3, 25.7, 25.6, 25.5,
25.2, 24.5, 24.1, 23.1, 22.4 ppm. MS (ESI) [M + H]+ 359.
Compound 4E: M.p. 154–157 °C. H NMR: δ = 9.15 (s, 1 H), 8.24
(s, 1 H), 3.68 (d, J = 2.7 Hz, 1 H), 2.16–1.97 (m, 4 H), 1.52–1.23
(m, 18 H), 0.85 (t, J = 6.3 Hz, 3 H) ppm. 13C NMR: δ = 175.1,
131.4, 109.6, 54.9, 36.0, 32.3, 30.2, 29.6, 28.9, 27.9, 27.3, 27.0, 26.5,
24.1, 23.0, 14.9 ppm. MS (ESI) [M + H]+ 281.
1
1
Compound 4x: M.p. 159–163 °C. H NMR: δ = 9.46 (s, 1 H), 8.76
Compound 4F: M.p. 180–182 °C. H NMR: δ = 9.07 (s, 1 H), 8.23
(s, 1 H), 7.35–7.09 (m, 4 H), 5.07 (d, J = 2.1 Hz, 1 H), 2.33–2.29
(m, 1 H), 2.20–2.17 (m, 1 H), 2.01–1.98 (m, 1 H), 1.63–0.99 (m, 17
H) ppm. 13C NMR: δ = 174.6, 160.9, 158.9, 131.7, 131.4, 130.7,
129.9, 116.4, 109.9, 50.7, 31.6, 26.2, 25.6, 25.5, 25.3, 25.2, 25.1,
24.5, 23.7, 23.1, 22.4, 22.1 ppm. MS (ESI) [M + H]+ 347.
(s, 1 H), 3.54 (s, 1 H), 2.49–2.41 (m, 2 H), 2.38–2.20 (m, 2 H), 1.76–
1.72 (m, 1 H), 1.81–1.13 (m, 16 H), 0.86–0.74 (m, 6 H) ppm. 13C
NMR: δ = 175.6, 131.9, 110.5, 58.3, 33.4, 26.2, 25.8, 25.8, 25.6,
25.3, 25.2, 25.1, 24.7, 24.2, 23.3, 22.9, 22.4, 19.6, 16.8 ppm. MS
(ESI) [M + H]+ 295.
1
General Procedures for Synthesis of Pyrimidinone Scaffolds
Compound 4G: M.p. 150–153 °C. H NMR: δ = 9.14 (s, 1 H), 8.43
(Scheme 13,
Schemes 15–16,
and
Schemes 18–19):
Urea
(s, 1 H), 3.63 (q, J = 3.5 Hz, 1 H), 2.30–2.24 (m, 2 H), 1.92–1.73
(m, 3 H), 1.52–1.49 (m, 1 H), 1.38–1.19 (m, 14 H), 1.10–1.08 (m,
1 H), 0.85 (t, J = 5.2 Hz, 6 H) ppm. 13C NMR: δ = 175.1, 131.5,
112.5, 51.1, 44.0, 26.2, 25.8, 25.6, 25.3, 25.1, 24.7, 24.4, 23.7, 23.1,
22.7, 22.5 ppm. MS (ESI) [M + H]+ 309.
(12.0 mmol) or thiourea (12.0 mmol), the cycloalkanones and/or
the aliphatic aldehyde (10.0 mmol), DMF (3.0 mL), and CH3CN
(6.0 mL) were mixed in a flask and TMSCl (10.0 mmol) was added
dropwise at room temperature. The resulting reaction mixture was
stirred at reflux for 4–6 h and then poured into crashed ice with
stirring. The precipitation was isolated by filtered through a
Buechner funnel and washed with water followed by ethanol, and
then dried to give the crystalline powder.
1
Compound 4H: M.p. 167–169 °C. H NMR: δ = 7.60 (s, 1 H), 6.47
(s, 1 H), 3.53 (s, 1 H), 2.43–2.41 (m, 1 H), 2.36–2.22 (m, 2 H), 1.78–
1.50 (m, 8 H), 1.32–1.13 (m, 10 H), 0.89–0.73 (m, 6 H) ppm. 13C
NMR: δ = 157.4, 134.5, 108.9, 60.2, 34.6, 27.9, 27.7, 27.5, 27.0,
26.9, 26.5, 26.3, 25.0, 24.8, 24.4, 21.8, 18.1 ppm. MS (ESI) [M +
H]+ 279.
Compound 6y (Scheme 13): M.p. 285–288 °C. 1H NMR: δ = 8.61
(s, 1 H), 8.29 (s, 1 H), 7.61 (s, 1 H), 7.56 (s, 1 H), 3.00 (d, J =
11.2 Hz, 1 H), 2.15 (s, 2 H), 1.89 (t, J = 6.8 Hz, 1 H), 1.74 (m, 1
H), 1.63–1.56 (m, 2 H), 1.49–1.47 (m, 1 H), 1.23–1.21 (m, 1 H),
1.18–0.92 (m, 6 H), 0.83–0.82 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR:
δ = 177.7, 176.8, 75.8, 59.4, 55.3, 44.5, 41.3, 30.1, 28.6, 25.1, 20.9,
20.8, 20.1, 19.6, 15.8 ppm. MS (ESI) [M + H]+ 327.
1
Compound 4I: M.p. 155–156 °C. H NMR: δ = 7.58 (s, 1 H), 6.47
(s, 1 H), 3.68 (s, 1 H), 2.36–2.20 (m, 2 H), 1.82–1.722 (m, 2 H),
1.54 (m, 4 H), 1.43–1.25 (m, 22 H), 0.88–0.73 (t, J = 6.1 Hz, 3
H) ppm. 13C NMR: δ = 153.3, 129.5, 106.0, 50.7, 33.2, 30.0, 29.8,
27.8, 23.7, 23.5, 23.4, 23.2, 23.1, 23.0, 22.8, 22.7, 22.2, 20.7, 20.4,
20.3, 12.5 ppm. MS (ESI) [M + H]+ 321.
Compound 6z (Scheme 13): M.p. 284–286 °C. 1H NMR: δ = 8.48
(s, 1 H), 8.18 (s, 1 H), 7.99 (s, 1 H), 7.93 (s, 1 H), 3.58–3.57 (m, 1
H), 3.04–3.02 (m, 1 H), 2.26–2.15 (m, 3 H), 1.63–1.49 (m, 6 H),
1.44–1.41 (m, 1 H), 1.44–1.16 (m, 16 H), 0.88–0.84 (m, 6 H) ppm.
13C NMR: δ = 175.7, 175.6, 74.5, 53.7, 48.4, 44.3, 42.6, 31.7, 31.6,
31.3, 30.6, 29.2, 29.1, 28.5, 25.1, 23.9, 23.6, 22.4, 19.8, 14.4 ppm.
MS (ESI) [M + H]+ 411.
1
Compound 4J: M.p. 178–180 °C. H NMR: δ = 9.92 (s, 1 H), 7.65
(s, 1 H), 3.14 (s, 1 H), 2.16 (m, 1 H), 1.60–1.55 (m, 2 H), 1.37–1.26
(m, 4 H), 0.98–0.86 (m, 6 H) ppm. 13C NMR: δ = 174.1, 153.5,
51.0, 47.1, 37.6, 23.8, 19.1, 14.7, 12.3 ppm. MS (ESI) (m/z) [M +
H]+ 169.
1
Compound 4z (Scheme 19): M.p. 228–233 °C. 1H NMR: δ = 9.47
(s, 1 H), 7.60 (s, 1 H), 3.46 (s, 1 H), 1.97 (d, J = 18.0 Hz, 4 H),
1.67–1.62 (m, 2 H), 1.55–1.39 (m, 10 H), 1.11–1.09 (m, 1 H) ppm.
13C NMR: δ = 174.6, 128.6, 113.1, 56.8, 34.4, 25.9, 25.6, 23.3, 23.0,
22.3, 20.6 ppm. MS (ESI) [M + H]+ 237.
Compound 4K: M.p. 182–185 °C. H NMR: δ = 9.89 (s, 1 H), 7.63
(s, 1 H), 3.08 (d, J = 2.7 Hz, 1 H), 2.23 (m, 1 H), 1.53–1.48 (m, 2
H), 1.37–1.24 (m, 8 H), 0.89–0.86 (m, 6 H) ppm. 13C NMR: δ =
174.2, 153.4, 51.6, 45.4, 35.2, 32.9, 28.1, 22.9, 20.5, 14.9, 14.7 ppm.
MS (ESI) [M + H]+ 197.
Compound 4L:[41] M.p. 186–189 °C. 1H NMR: δ = 7.77 (s, 1 H),
6.75 (s, 1 H), 5.72 (d, J = 4.8 Hz, 1 H), 3.67 (d, J = 9.3 Hz, 1 H),
2.15–2.13 (m, 1 H), 1.79–1.76 (m, 1 H), 1.40–1.35 (m, 1 H), 1.10–
1.08 (m, 1 H), 1.12–0.85 (m, 12 H) ppm. 13C NMR: δ = 155.1,
120.3, 119.4, 51.2, 45.6, 28.8, 24.9, 23.7, 23.6, 22.5, 21.7 ppm. MS
(ESI) [M + H]+ 197.
1
Compound 4A: M.p. 190–193 °C. H NMR: δ = 9.09 (s, 1 H), 8.23
(s, 1 H), 3.44 (s, 1 H), 2.22 (s, 2 H), 2.04–1.90 (m, 2 H), 1.68–1.35
(m, 7 H), 0.84–0.76 (m, 6 H) ppm. 13C NMR: δ = 175.1, 135.1,
111.0, 62.6, 34.2, 32.4, 31.2, 31.0, 27.7, 26.4, 19.1, 16.9 ppm. MS
(ESI) [M + H]+ 225.
1
Compound 4B: M.p. 128–132 °C. H NMR: δ = 9.15 (s, 1 H), 8.24
(s, 1 H), 3.67 (s, 1 H), 2.16–1.96 (m, 4 H), 1.45–1.25 (m, 12 H), Compound 4M: M.p. 232–235 °C. 1H NMR: δ = 9.38 (s, 1 H), 8.54
0.95–0.84 (m, 3 H) ppm. 13C NMR: δ = 175.1, 131.4, 109.7, 54.8,
38.4, 30.2, 28.9, 27.9, 27.3, 27.0, 26.5, 17.6, 14.9 ppm. MS (ESI)
[M + H]+ 239.
(s, 1 H), 5.76 (d, J = 3.8 Hz, 1 H), 3.75 (q, J = 3.0 Hz, 1 H), 2.21–
2.18 (m, 1 H), 1.77 (m, 1 H), 1.42–1.38 (m, 1 H), 1.14–1.08 (m, 1
H), 1.02–0.87 (m, 12 H) ppm. 13C NMR: δ = 174.7, 123.2, 118.5,
2366
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2354–2367

Highly Chemoselective Multicomponent Biginelli-Type Condensations
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Received: November 27, 2004
Eur. J. Org. Chem. 2005, 2354–2367
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2367