Acyl pyruvates as synthons in the Biginelli reaction

Article abstract of DOI:10.1016/j.tetlet.2010.06.032

Chlorotrimethylsilane-promoted Biginelli-type reaction of ethyl 2,4-dioxo-4-phenylbutanoate, benzaldehyde, and various (thio)ureas is explored. The outcome of the reaction depends on the structure of the (thio)urea used and is strongly affected by the acc

Full text of DOI:10.1016/j.tetlet.2010.06.032

Tetrahedron Letters 51 (2010) 4229–4232
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Tetrahedron Letters
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Acyl pyruvates as synthons in the Biginelli reaction
Sergey V. Ryabukhin a,b, , Andrey S. Plaskon a,b, Semen S. Bondarenko a, Eugeniy N. Ostapchuk a,
*
Oleksandr O. Grygorenko a,b, Oleg V. Shishkin c, Andrey A. Tolmachev a,b
a Enamine Ltd, 23 Alexandra Matrosova Street, Kyiv 01103, Ukraine
b Kyiv National Taras Shevchenko University, 62 Volodymyrska Street, Kyiv 01033, Ukraine
c STC ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, 60 Lenina ave., 61001 Kharkiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Chlorotrimethylsilane-promoted Biginelli-type reaction of ethyl 2,4-dioxo-4-phenylbutanoate, benzalde-
hyde, and various (thio)ureas is explored. The outcome of the reaction depends on the structure of the
(thio)urea used and is strongly affected by the acceptor electronic properties of the COOEt substituent
in the molecule of the starting b-dicarbonyl compound. The di- and tetrahydropyrimidine derivatives
obtained possess two functional groups with orthogonal reactivity, and thus represent promising build-
ing blocks for drug discovery.
Received 25 March 2010
Revised 12 May 2010
Accepted 7 June 2010
Available online 15 June 2010
Keywords:
Multicomponent reactions
Heterocycles
Ó 2010 Elsevier Ltd. All rights reserved.
Biginelli reaction
Dihydropyrimidines
Acyl pyruvates
Multicomponent reactions which employ three or more re-
agents that are combined into a single product have attracted sig-
nificant attention from chemists.1 The main reason is the huge
diversity of chemical space covered by the compounds thus pro-
duced. On the other hand, one-pot, high-yield procedures are em-
ployed in most cases which allow the multicomponent reactions
to be considered as reliable synthetic methods. These features are
particularly important in the early steps of drug discovery, by either
high-throughput screening or fragment-based design, as well as for
hit-to-lead optimization.2 The use of three or more building blocks
combined with the excellent efficacy of multicomponent reactions
is important for combinatorial chemistry as structurally and func-
tionally diverse libraries of compounds can be obtained.3
it was demonstrated that the chlorotrimethylsilane-promoted Bigi-
nelli reaction has wide applicability and allows various (hetero)aro-
matic aldehydes and (thio)ureas to be used as starting materials.9
Despite the initial publication of Biginelli5 reporting the use of
diethyl oxaloacetate 2 as a b-dicarbonyl component, b-acylpyru-
vates 3 are considered to be poor substrates for the Biginelli reac-
tion, mainly due to their high reactivity and sensitivity to acids. To
the best of our knowledge, apart from oxaloacetic acid10 and its
derivatives, no examples of substrates of general formula 3 being
used in the Biginelli reaction have been reported to date. 5-Acyltet-
rahydropyrimidine-4-carboxylates 4, which might be obtained in
the latter reaction, possess two functional groups with orthogonal
The Biginelli reaction is an acid-catalyzed three-component
condensation of an aldehyde, a b-ketoester, and an urea leading
to the formation of dihydropyrimidinones 1 (Scheme 1). The latter
have been shown to exhibit manifold biological effects such as cal-
cium channel modulator, mitotic kinesine inhibitor, adrenergic
receptor antagonist, and antibacterial and antiviral activities.4 Thus
dihydropyrimidines can be considered as privileged scaffolds for
drug discovery.
Ar
Ar
R'OOC
R
H+
R'OOC
R
O
NH
NH2
O
N
H
O
H2N
O
1
Scheme 1. Biginelli reaction.
Since the pioneering report of Biginelli,5 a range of modified con-
ditions have been developed to facilitate this reaction including the
use of various Lewis acids as reaction promoters,6 as well as micro-
wave assistance,7 and solid- and fluorophase techniques.8 Recently,
O
O
O
Ar
EtO
R
R
NH
EtOOC
O
R'OOC
O
R'OOC
N
H
O
2
3
4
* Corresponding author. Tel.: +38 044 228 96 52; fax: +38 044 502 48 32.
E-mail address: Ryabukhin@mail.enamine.net (S.V. Ryabukhin).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.032

4230
S. V. Ryabukhin et al. / Tetrahedron Letters 51 (2010) 4229–4232
O
Ph
O
Ph
R
X
Me3SiCl
DMF
Ph
O
Ph
N
NHR
X
EtOOC
O
EtOOC
N
R'
R'HN
5
6a-e
Urea Product
7a-e
R
R
H
X
Yield, %
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
H
H
O
O
O
S
84
75
73
78
76
CH3
CH3 CH3
H
H
CH3 CH3
S
Scheme 2. One-pot synthesis of dihydropyrimidines 7a–e.12
O
Ph
O
Ph
N
Me3SiCl
DMF
Figure 2. Molecular structure of compound 10a.
Ph
O
Ph
HOOC
NH
NH2
EtOOC
O
O
HN
O
5
In this Letter, we report our results on the chlorotrimethylsilane-
promoted Biginelli reaction involving ethyl 2,4-dioxo-4-phenylbut-
anoate (5) as a b-dicarbonyl component. As the applicability of the
method to various (hetero)aromatic aldehydes was demonstrated
previously,9b–d benzaldehyde was selected as the aldehyde
component. A set of (thio)ureas 6a–i varying in N,N-binucleophilic
reactivity was explored in this study.
Reaction of ester 5, benzaldehyde, and (thio)ureas 6a–e in the
presence of Me3SiCl in DMF at ambient temperature resulted in
the formation of the target dihydropyrimidines 7a–e in 73–84%
yields (Scheme 2).11 In the case of unsymmetric urea 6b, complete
regiospecificity was observed; the assignment of the structure of
7b was followed from routine 1H NMR spectroscopy (coupling
between the 1-NH and 6-CH protons was observed) and was in
accordance with our previous results.9b–d
R
R
6f, R = H
6g, R = CH3
8a, R = H, 54%
8b, R = CH3, 57%
Scheme 3. One-pot synthesis of carboxylic acids 8a,b.13
7a, 83%
7b, 77%
8a, 54%
1. Me3SiCl, DMF, 3 d
O
2. 6a, 6b or 6f
Ph
Ph
+
O
O
EtOOC
O
OH
Ph
When the above-mentioned conditions were applied to the
reaction of ester 5, benzaldehyde, and N-arylureas 6f,g, carboxylic
acids 8a,b were obtained in 54% and 57% yields instead of the
expected ester (Scheme 3). The structures of 8a,b were assigned
using NMR, LC–MS, and elemental analysis.
6a,b,f
Me3SiCl
5
X
Ph
O
O
9
O
Ph
Ph
O
Ph
1.Me3SiCl, DMF
NH
Ph
NH
To explain the formation of compounds 7f,g, several assump-
tions can be made. As the nucleophilicity of N-arylureas 6f,g
decreases, the reaction can start with condensation of the aldehyde
and b-ketoester at the first stage, resulting in the formation of com-
pound 9,14 or its silylated analogues, which then react with the
urea to give 7f,g. This is contrary to the standard Biginelli reaction
mechanism which involves the reaction between the urea and the
aldehyde in the first step, followed by condensation of the formed
iminium intermediate with the b-ketoester.15 To test this hypoth-
esis, ureas 6a,b,f were introduced to the reaction mixture after
compound 5 and benzaldehyde had been allowed to react over a
three-day period. However, this modification of the experiment
2.H2O (work-up)
58%
EtOOC
N
O
HOOC
N
O
Ph
Ph
7f
8a
Scheme 4.
reactivity (i.e., ketone and ester functions) which can be selectively
transformed into various pharmacophore units, or both used for
further heterocyclizations. It should be noted that compounds of
general formula 4 [Fig. 1, where R is alkyl, cycloalkyl, or (het)aryl]
have not been described in the literature.
O
Ph
O
Ph
O
H
H
NH2
Ph
Me3SiCl
DMF
Ph
NH
Ph
NH
Ph
+
+
+
O
RHN
S
EtOOC
HO
EtOOC
HO
N
R
S
N
R
S
EtOOC
O
6h, R = CH3
6i, R = C6H5
10a, R = CH3, 40%
10b, R = C6H5, 61% 11b, R = C6H5
11a, R = CH3
5
Scheme 5.

S. V. Ryabukhin et al. / Tetrahedron Letters 51 (2010) 4229–4232
4231
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.032.
References and notes
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Eur. J. Org. Chem. 2005, 2354–2367; (g) Zhu, Y.-L.; Pan, Y.-J.; Huang, S.-L.
Heterocycles 2005, 65, 133–142.
Figure 3. Molecular structure of compound 10b.
did not lead to any changes in the reaction outcome (i.e., the prod-
ucts 7a,b and 8a were obtained, respectively). We also prepared
compound 914 and subjected it to reaction with ureas 6a,b,f under
the conditions described above. In these cases, complex mixtures
were obtained. Therefore, we assumed that the formation of car-
boxylic acids 8a,b occurs via normal hydrolysis of the correspond-
ing esters. Indeed, ester 7f (which was obtained from 8a using a
standard method16) underwent hydrolysis to 8a upon reaction
with Me3SiCl in DMF and subsequent work-up (Scheme 4).
Reaction of ester 5, benzaldehyde, and thioureas 6h,i in the
presence of Me3SiCl in DMF led to the formation of tetrahydropyr-
imidines 10a,b and 11a,b in 70–80% combined yields (Scheme
5).17 As in the previous cases, complete regioselectivity was ob-
served. Nevertheless, the diastereoselectivity of the reaction was
moderate (10a:11a = 3:1, 10b:11b = 9:1). Both major isomers
10a,b were isolated in 40% and 61% yields, respectively. The stereo-
chemistry of products 10a,b was assigned by X-ray diffraction
(Figs. 2 and 3).18 Whereas minor isomer 11a (de 85%) was also iso-
lated, compound 11b could only be detected in the crude product
by NMR and GC–MS.
The formation of compounds 10a,b and 11a,b is connected to
our previous results on Biginelli-type reactions involving trifluoro-
methyl-substituted diketones.9c This can be rationalized from the
similarity of the electronic properties of the CF3 and COOEt substit-
10. (a) Bussolari, J. C.; McDonnell, P. A. J. Org. Chem. 2000, 65, 6777–6779; Several
examples of solid-phase synthesis of 3,4-dihydropyrimidine-2-ones
employing phenylpyruvic and 2-oxobutyric acids as the methylene
component have been reported recently, see: (b) Li, W.; Lam, Y. J. Comb.
Chem. 2005, 7, 721–725.
uents (r
p = 0.54 and 0.45, respectively).19 As the acceptor properties
of the carboxyethyl group are somewhat diminished compared to
the trifluoromethyl moiety, stable hydrates are formed only from
monosubstituted thioureas 6h,i. Therefore, in the light of its behav-
ior in the Biginelli reaction, the acylpyruvate 5 occupies an interme-
diate position between trifluoromethyl-substituted b-diketones
and common b-dicarbonyl compounds such as ethyl acetoacetate.
In conclusion, the chlorotrimethylsilane-promoted Biginelli
reaction involving ethyl 2,4-dioxo-4-phenylbutanoate (5) as the
b-dicarbonyl component is an efficient method for the synthesis
of di- and tetrahydropyrimidine derivatives possessing two func-
tional groups with orthogonal reactivity.
11. General procedure for the Biginelli reactions. A mixture of ester 5 (4 mmol),
benzaldehyde (4 mmol), thiourea
6 (6 mmol), and dry DMF (10 mL) was
sonicated for 1 h at rt to dissolve the starting materials, and then
chlorotrimethylsilane (16 mmol) was added dropwise. The resulting mixture
was allowed to stand for 3–4 d and then poured into water (20–30 mL). The
suspension was sonicated for 1 h and the precipitate was filtered and washed
with a small amount of iPrOH. The filtrate was evaporated under reduced
pressure, and the residue was triturated with a small amount of iPrOH and
filtered again. The combined solids were recrystallized to yield the products 7–
9 (see Schemes 2–4).
12. Ethyl 5-benzoyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-4-carboxylate (7a):
Yield: 84%; mp 180 °C (2-propanol). 1H NMR (500 MHz, DMSO-d6): d 0.85 (t,
3JHH = 7.1 Hz, 3H, CH2CH3), 3.50–3.72 (m, 2H, CH2CH3), 5.33 (s, 1H, 4-HDHPM),
Acknowledgments
7.23 (m, 3H, 2,4,6-HPh), 7.31 (t, 3JHH = 7.2 Hz, 2H, 3,5-HPh), 7.38 (t, 3JHH = 7.8 Hz,
3
0
0
2H, 3,5-HPh ), 7.46-7.54 (d+t, JHH = 7.8 Hz, 3H, 2,4,6-HPh ), 7.86 (s, 1H, NH), 9.16
(s, 1H, NH). 13C NMR (125 MHz, DMSO-d6): d 13.5, 56.8, 62.3, 115.0, 126.9,
128.4, 128.9, 129.2, 133.1, 133.9, 138.6, 142.9, 152.3, 161.9, 193.6. APSI MS:
M++1 = 351. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C,
68.42; H, 5.30; N, 8.08.
The authors thank Mr. Vitaliy V. Polovinko for NMR measure-
ments and Mrs. Olga V. Manoylenko for chromatographic
separations.

4232
S. V. Ryabukhin et al. / Tetrahedron Letters 51 (2010) 4229–4232
3
13. 5-Benzoyl-3,6-diphenyl-2-oxo-6-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid
(8a): Yield: 54%; mp >250 °C, dec. (MeOH). 1H NMR (400 MHz, DMSO-d6): d
5.97 (s, 1H, 4-HDHPM), 7.08 (t, 3JHH = 7.0 Hz, 1H, 4-HPh3), 7.19 (t, 3JHH = 7.4 Hz, 1H,
propanol). 1H NMR (500 MHz, DMSO-d6): d 0.96 (t, JHH = 7.1 Hz, 3H, CH2CH3),
3
3.11 (s, 3H, NCH3), 3.57 (m, 2H, CH2CH3), 4.63 (d, JHH = 11.2 Hz, 1H, 5-HTHPM),
3
3
4.95 (d, JHH = 11.2 Hz, 1H, 4-HTHPM), 7.18 (t, JHH = 7.4 Hz, 1H, 4-HPh), 7.25 (t,
3
3
3
0
4-HPh), 7.26 (t, JHH = 7.0 Hz, 2H, 3,5-HPh), 7.32 (t, JHH = 7.4 Hz, 2H, 3,5-HPh),
JHH = 7.4 Hz, 2H, 3,5-HPh), 7.34 (s, 1H, OH), 7.40 (t, JHH = 8.0 Hz, 2H, 3,5-HPh ),
3 3
3
0
7.39 (d, JHH = 7.0 Hz, 2H, 2,6-HPh), 7.47 (m, 4H, 2,3,5,6-HPh), 7.58 (t,
7.44 (d, JHH = 7.4 Hz, 2H, 2,6-HPh), 7.55 (t, JHH = 8.0 Hz, 1H, 4-HPh ), 7.66 (d,
3JHH = 7.0 Hz, 1H, 4-HPh), 7.71 (t, JHH = 7.8 Hz, 2H, 2,6-HPh), 10.25 (s, 1H, NH),
JHH = 8.0 Hz, 2H, 2,6-HPh ), 8.80 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6): d
3
3
0
12.00 (br s, 1H, COOH) 13C NMR (125 MHz, DMSO-d6): d 60.5, 120.1, 124.4,
127.7, 128.2, 128.7, 128.8, 129.3, 129.5, 133.5, 137.4, 137.8, 138.0, 148.2, 148.5,
168.1, 189.6. APSI MS: M++1 = 399, Mꢀꢀ1 = 397. Anal. Calcd for C24H18N2O4: C,
72.35; H, 4.55; N, 7.03. Found: C, 72.62; H, 4.28; N, 6.97.
13.9, 37.0, 53.0, 54.2, 62.6, 85.6, 128.5, 128.6, 128.7, 128.9, 129.0, 133.9, 137.6,
138.7, 168.8, 178.8, 195.2. APSI MS: M++1 = 399. Anal. Calcd for C21H22N2O4S: C,
63.30; H, 5.56; N, 7.03; S, 8.05. Found: C, 63.48; H, 5.44; N, 6.92; S, 8.20. Minor
isomer 11a: 1H NMR (500 MHz, DMSO-d6): d 1.33 (t, 3JHH = 7.1 Hz, 3H, CH2CH3),
3
14. (a) Coudert, P.; Leal, F.; Duroux, E.; Rubat, C.; Couquelet, J. Biol. Pharm. Bull.
1996, 19, 220–223; (b) Bonadies, F.; Scarpati, M. L. Gazz. Chim. Ital. 1983, 113,
421–426.
15. See Ref. 9d and citations therein.
16. (a) Dean, F. H.; Amin, J. H.; Pattison, F. L. M. Org. Synth. 1973, Coll. Vol. 5, 580; (b)
Hartman, W. W.; Rahrs, E. J. Org. Synth. 1955, Coll. Vol. 3, 650.
17. Ethyl [rel-(4S,5S,6R)-5-benzoyl-4-hydroxy-3-methyl-6-phenyl-2-thioxohexahydro-
pyrimidine-4-carboxylate (10a) and ethyl [rel-(4S,5S,6S)-5-benzoyl-4-hydroxy-3-
methyl-6-phenyl-2-thioxohexahydropyrimidine-4-carboxylate (11a): A sample of
the mixture of isomers 10a and 11a obtained in 74% total yield via the general
procedure was subjected to flash chromatography (460 mm ꢁ 36 mm silica gel
column, 5–6 bar, detection at 254 nm, CHCl3–EtOAc (95:5) as eluent) to give 10a
(0.54 g, 40%) and 11a (0.16 g, 12%, 85% de). Major isomer 10a: mp 170 °C (2-
3.15 (s, 3H, NCH3), 4.33 (m, 2H, CH2CH3), 4.58 (d, JHH = 11.0 Hz, 1H, 5-HTHPM),
3
3
4.88 (d, JHH = 11.0 Hz, 1H, 4-HTHPM), 7.11 (t, JHH = 7.4 Hz, 1H, 4-HPh), 7.18 (t,
3JHH = 7.4 Hz, 2H, 3,5-HPh), 7.24 (d, JHH = 7.4 Hz, 2H, 2,6-HPh), 7.28 (s, 1H, OH),
3
3
3
0
0
7.34 (t, JHH = 8.0 Hz, 2H, 3,5-HPh ), 7.51 (t, JHH = 8.0 Hz, 1H, 4-HPh ), 7.70 (d,
3JHH = 8.0 Hz, 2H, 2,6-HPh), 8.74 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): d 13.7,
37.3, 52.9, 55.6, 63.6, 85.3, 127.5, 128.2, 128.5, 129.0, 129.2, 134.1, 136.4, 136.7,
169.0, 180.1, 197.7. APSI MS: M++1 = 399.
18. Final atomic coordinates, geometrical parameters, and crystallographic data
have been deposited with the Cambridge Crystallographic Data Centre, 11
Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk) and are available on request quoting the deposition
number CCDC 759878 (10a) and CCDC 759879 (10b).
19. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.