Biginelli-like reaction with dialkyl acetone-1,3-dicarboxylates: a remarkable case of steric control

Article abstract of DOI:10.1016/j.tetlet.2008.03.136

A Biginelli-type condensation is described using dialkyl acetone-1,3-dicarboxylates as active methylene compounds for the preparation of monastrol analogues. Unexpectedly, the reaction with salicylaldehyde formed two different products depending on the es

Full text of DOI:10.1016/j.tetlet.2008.03.136

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3520–3523
Biginelli-like reaction with dialkyl acetone-1,3-dicarboxylates:
a remarkable case of steric control
*
ꢀ
´
´
Jan Svetlık , Lucia Veizerova, Viktor Kettmann
Department of Pharmaceutical Analysis and Nuclear Pharmacy, Comenius University, Odbojarov 10, SK-832 32 Bratislava, Slovak Republic
Received 29 January 2008; revised 5 March 2008; accepted 27 March 2008
Available online 29 March 2008
Abstract
A Biginelli-type condensation is described using dialkyl acetone-1,3-dicarboxylates as active methylene compounds for the prepara-
tion of monastrol analogues. Unexpectedly, the reaction with salicylaldehyde formed two different products depending on the ester alkyl
group. This product dichotomy was found to be caused by the steric effects exerted by the alcohol terminus of the ester group in the active
methylene component. Previous controversial results as to the structure of the Biginelli product 3 are also discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Monastrol ( )-1, ethyl 6-methyl-4-(3-hydroxyphenyl)-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, is
the cyclocondensation of alkyl acetoacetate with aldehydes
and urea or thiourea have been developed.5 We reported6
that the three-component heterocyclization with salicylal-
dehyde produced oxygen-bridged pyrimidine derivatives,
for example, 2,6-methano-4-oxo- and 4-thioxo-3,4,5,6-tet-
rahydro-2H-[1,3,5]-benzoxadiazocines (2) rather than the
previously reported7 4-(2-hydroxyphenyl)pyrimidines (3).
However, oxygen-bridged pyrimidine structures were not
discussed in several recent reports.8–11 but were supported
by others.12–14 Herein, we present an unexpected product
dichotomy in the Biginelli-like condensation of 2-hydroxy-
benzaldehyde with urea or thiourea and dimethyl or diethyl
acetone-1,3-dicarboxylate, respectively, as active methylene
components.
a
recently highlighted Biginelli compound,1 which showed
promise in a new strategic approach to cancer research.2
Compound 1 has been found1 to affect the function of
mitotic kinesin Eg5, a motor protein responsible for spindle
bipolarity.3 Thus, kinesin spindle protein represents an
attractive target for biochemical studies because human
Eg5 inhibitors induce cell death via apoptosis.4 With
regard to the pharmacological profile and other promising
medicinal applications of similarly functionalized 3,4-di-
hydropyrimidin-2(1H)-ones and -thiones, their synthesis
via the Biginelli reaction has been thoroughly studied.5
Numerous modifications and improved procedures for
HO
HO
RO2C
EtO2C
Me
RO2C
NH
NH
R: Me, Et
X: O, S
NH
O
N
H
S
N
H
X
Me
N
H
X
Me
1
2
3
*
Corresponding author.
E-mail address: svetlik@fpharm.uniba.sk (J. Svetlık).
ꢀ ´
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.136

ꢀ ´
J. Svetlık et al. / Tetrahedron Letters 49 (2008) 3520–3523
3521
Z
MeO2C
MeO2C
Z
H+
H2N
NH2
NH
+
MeO2C
CO2Me
+
CH=O
O
X
N
H
X
4a-f
a: X=O d: X=S Z=H; b: X=O e: X=S Z=3-OH; c: X=O f: X=S Z= 3,4-(OMe)2
Scheme 1.
In the course of our work on the synthesis of monastrol
analogues 4a–f, starting from dimethyl 3-oxopentanedioate
(Ref. 15, Scheme 1), a report appeared16 in which the
authors described a preparation of closely related diethyl
esters including a congener 5 possessing the 4-(2-hydroxy-
phenyl) moiety (Scheme 2). Considering the possible for-
mation of benzoxadiazocines 2, we decided to verify the
structure of the uncyclized molecule 5. A careful repeat
of the original experiment16 (solvent free, 80 °C, 3 h,
2 mol % TsOH as an acid catalyst) and the subsequent
comparison of the reported and our NMR spectra clearly
confirmed the published dihydropyrimidine structure 5
(Scheme 2). In contrast, when the condensation of salicyl-
aldehyde with dimethyl acetone-1,3-dicarboxylate was per-
formed under the above-described conditions a different
type of product resulted. Based on the spectroscopic
data,17 the product obtained from the methyl ester was
the conformationally restricted tricycle 6a (Scheme 2).
Intramolecular Michael addition of the phenolic hydroxyl
group has occurred as indicated by the 1H NMR spectrum
of the product displaying an AB quartet of the diastereo-
topic methylene protons of the 6-methoxycarbonylmethyl
substituent. In addition, the 13C NMR signal for the
N,O-acetal sp3 carbon at d 80 provides convincing evidence
of cyclization as well. The analogous reaction with thiourea
proceeded similarly to yield 4-thioxo derivative 6b (Ref. 17,
Scheme 2). Both cyclizations were found to be diastereose-
lective proceeding with exclusive formation of one isomer
as evidenced by NMR analysis of the reaction mixture.
In light of the above findings, we proceeded to explore
the rationale for the dichotomy in the reactivity of dimethyl
and diethyl acetone-1,3-dicarboxylates. Considering the
mechanism of the Biginelli condensation which leads to
the oxygen-bridged pyrimidines 2, there is no doubt that
electronic effects do not play a significant role in affecting
the reaction course. Consequently, steric control seems to
be the key factor in determining the products of the con-
densation. The formation of the oxygen bridge is likely to
depend on the effective distance between the phenol
ortho-hydroxyl and the pyrimidine C-6 atom. According
to molecular mechanics calculations,18 the optimum prox-
´
˚
imity of these centres was estimated to be 3.20–3.51 A.
Apparently, such an arrangement results from a suitable
molecular conformation. Inspection of Dreiding models
indicates that the C-6 position is considerably hindered
by the adjacent ethoxycarbonyl moiety, as compared to
the less bulkier COOMe group, while rotating about the
O@C(OR)–CH2 single bond. In contrast to the methyl ace-
tate unit, the 6-CH2COOEt substituent pushes the ortho-
hydroxyl away from its bonding contact. As a result, the
final ring closure via Michael addition is predicted to occur
only in the case of the dimethyl ester.
HO
R=Et
EtO2C
NH
EtO2C
N
H
O
OH
H2N
NH2
+
+
RO2C
CO2R
5
CH=O
O
X
R=Me
MeO2C
NH
O
MeO2C
N
H
X
6a: X=O
6b: X=S
Scheme 2.

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J. Svetlık et al. / Tetrahedron Letters 49 (2008) 3520–3523
3522
Fig. 1. ORTEP views of tetrahydropyrimidines 4a (left) and 5 (right).
Since we were able to grow single crystals of two model
support of the Slovak National Research and the Develop-
ment Program No. 2003SP200280203.
compounds, 4a and 5, we determined X-ray structures to
compare their molecular conformations.19 ORTEP draw-
ings (Fig. 1) reveal evidently different spatial arrangement
of the ester groups between these tetrahydropyrimidines
in both the positions 5 and 6.
In order to clarify the previously reported structures
3,8–11 we re-examined some of the reported catalysts,9
namely NiCl2ꢀ6H2O and FeCl3ꢀ6H2O, that were used in
the Biginelli reaction with salicylaldehyde. As seen from
NMR spectra, the product prepared according to the pub-
lished protocol9 was not pyrimidine 3 but benzoxadiazo-
cine 2. Apparently, the discrepancy between our and
some of the literature results originates from the use of
Folkers’s7 structure 3 dating back to 1932, which has been
disproved by our detailed spectroscopic analysis.
In summary, we have elucidated the structures of two
heterocyclic products formed in the Biginelli-like reaction
of salicylaldehyde with urea/thiourea and dimethyl or
diethyl acetone-1,3-dicarboxylate. The results have shown
that the steric effect of the alcohol ester group is the main
determinant for the final cyclization step. The Biginelli
dihydropyrimidines prepared here represent attractive
monastrol analogues which are under in vitro and in vivo
chemical genetic studies. Moreover, the molecular confor-
mation of the target dihydropyrimidine dimethyl esters
conform to the Triggle dihydropyridine receptor binding
model,20 and thus the compounds could become the suit-
able candidates for calcium channel modulatory activity
trials.
References and notes
1. (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. J.; Mitchison, T. J. Science 1999, 286, 971; (b) Kapoor,
T. M.; Mayer, T. U.; Coughlin, M. L.; Mitchison, T. J. J. Cell Biol.
2000, 150, 975.
2. (a) Wood, K. W.; Cornwell, W. D.; Jackson, J. R. Curr. Opin.
Pharmacol. 2001, 1, 370; (b) Wood, K. W.; Bergnes, G. Annu. Rep.
Med. Chem. 2004, 39, 173.
3. (a) Sharp, D. J.; Rogers, G. C.; Scholey, J. M. Nature 2000, 407, 41;
(b) Endow, S. A.; Baker, D. S. Annu. Rev. Physiol. 2003, 65, 161; (c)
Sawin, K. E.; Mitchison, T. J. Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
4289.
4. (a) Walczak, C. E.; Vernos, I.; Mitchison, T. J.; Karsenti, E.; Heald,
R. Curr. Biol. 1998, 8, 903; (b) Marcus, A. I.; Peters, U.; Thomas, S.
L.; Garrett, S.; Zelnak, A.; Kapoor, T. M.; Giannakakou, P. J. Biol.
Chem. 2005, 280, 11569.
5. For reviews see: (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b)
Kappe, C. O. Molecules 1998, 3, 1; (c) Kappe, C. O. Acc. Chem. Res.
2000, 33, 879; (d) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043; (e)
Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1.
6. (a) Svetlik, J.; Hanus, V.; Bella, J. J. Chem. Res. (S) 1991, 4; (b)
Kettmann, V.; Svetlik, J. Acta Crystallogr., Sect. C 1996, 52, 1496.
7. Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem. Soc. 1932,
54, 3751.
8. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett. 2000,
41, 9075.
9. Lu, J.; Bai, Y. Synthesis 2002, 466.
10. Tu, S.; Fang, F.; Zhu, S.; Li, T.; Zhang, X.; Zhuang, Q. Synlett 2004,
537.
11. Rafiee, E.; Jafari, H. Bioorg. Med. Chem. Lett. 2006, 16, 2463.
12. Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.; Peppe, C.
Tetrahedron 2002, 58, 4801.
13. Kumar, A.; Maurya, R. A. Tetrahedron Lett. 2007, 48, 4569.
14. Bose, D. S.; Sudharshan, M.; Chavhan, S. W. Arkivoc 2005, iii, 228.
15. Although the condensation proceeds in refluxing ethanol under HCl,
p-TsOH or H2NSO3H catalysis, the reaction time was too long
(>30 h), thus solvent free conditions and the corresponding protocol
as described in Ref. 16 were employed. All the compounds reported
here gave satisfactory CHN microanalyses. Characteristic data for 4a:
Mp 180–182 °C (EtOH), isolated yield 39%; IR (KBr) mmax 3409
Acknowledgements
This work was supported by a Grant Agency of the
Slovak Republic (# 1/4299/07, # 1/4298/07) and a Grant
of the Comenius University (# UK/45/2007). The NMR
experimental part of this work was facilitated by the

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3523
(NH), 1729 (COO), 1702 (COO+NCON), 1650 (C@C) cmꢁ1
;
1H
150.1 (C-10a), 154.2 (CO), 168.9 (COO ester-11), 169.2 (COO ester); a
four-bond interaction of W type between NH-5 and H-11 found in the
HMBC spectrum together with a weaker cross-peak between NH-3
and H-11 in the COSY spectrum proved clearly an axial orientation
of the 11-COOMe group. 6b: Mp 198–200 °C (MeOH), yield 21%; IR
NMR (DMSO-d6, 300 MHz) d 3.48 (s, 3H, OMe 5-ester), 3.65 (s, 3H,
OMe ester), 3.68 (d, 1H, J = 16.8 Hz, CH2), 3.82 (d, 1H, J = 16.8 Hz,
CH2), 5.17 (d, 1H, J = 3.3 Hz, H-4), 7.22–7.29 (m, 1H, HAr), 7.30–
7.37 (m, 4H, HAr), 7.84 (br s, 1H, NH-3), 9.32 (s, 1H, NH-1); 13C
NMR (DMSO-d6, 75 MHz) d 36.8 (CH2), 51.0 (OMe 5-ester), 51.9
(OMe ester), 53.8 (CH-4), 100.6 (C-5), 126.5 (CH-20 and 60), 127.5
(CH-40), 128.5 (CH-30 and 50), 144.2 (C-10), 145.1 (C-6), 152.0
(NCON), 165.4 (COO 5-ester), 169.2 (COO ester). Anal. Calcd for
(KBr) mmax 3398, 3356 (NH), 1751 (COO), 1737 (COO) cmꢁ1 1H
;
NMR (DMSO-d6, 300 MHz) d 3.36 (t, 2H, J = 17.0 Hz, CH2), 3.62 (s,
3H, OMe ester), 3.72 (s, 3H, OMe ester-11), 3.76 (br s, 1H, H-11),
4.69 (dd, 1H, J = 4.8 and 2.7 Hz, H-6), 6.84 (d, 1H, J = 7.8 Hz, H-
10), 6.98 (t, 1H, J = 7.4 Hz, H-8), 7.22 (d, 1H, J = 7.2 Hz, H-7), 7.26
(t, 1H, J = 8.0 Hz, H-9), 9.18 (br s, 1H, NH- 3), 9.34 (d, 1H,
J = 4.2 Hz, NH-5); 13C NMR (DMSO-d6, 75 MHz) d 39.7 (CH2),
40.0 (CH-11), 47.9 (CH-6), 51.8 (OMe ester), 52.4 (OMe ester-11),
81.3 (C-2), 116.6 (CH-10), 121.4 (CH-8), 123.4 (C-6a), 129.0 (CH-7),
129.9 (C-9), 150.0 (C-10a), 168.3 (COO ester-11), 169.1 (COO ester),
176.6 (C@S); EI MS (m/z) 336 (M+).
C15H16N2O5 (304.31): C, 59.21; H, 5.30; N, 9.21. Found: C, 59.32; H,
5.33; N, 9.09. Product 4b: Mp 154–156 °C (EtOH), yield 36%; Product
4c: Mp 189–190 °C (EtOH), yield 48%; Product 4d: Mp 175–177 °C
(MeOH), yield 35%; Product 4e: Mp 185–187 °C (MeOH); Product
4f: Mp 186–188 °C (MeOH), yield 44%.
16. Azizian, J.; Mohammadi, A. A.; Kohshari, M.; Karimi, A. R.;
Mohammadizadeh, M. R. J. Heterocycl. Chem. 2007, 44, 455.
17. Methyl (2R*,6R*,11S*)-2-methoxycarbonylmethyl-4-oxo-3,4,5,6-tetra-
hydro-2H-2,6-methano-1,3,5-benzoxadiazocine-11-carboxylate (6a):
Mp 214–216 °C (MeOH), yield 63%; IR (KBr) mmax 3201 (NH),
1746 (COO), 1731 (COO), 1678 (NCON) cmꢁ1; 1H NMR (DMSO-d6,
600 MHz) d 3.13 (d, 1H, J = 15.9 Hz, 6-CHACO2), 3.43 (d, 1H,
J = 15.9 Hz, 6-CHBCO2), 3.62 (s, 3H, OMe ester), 3.70 (m, 1H,
H-11), 3.72 (s, 3H, OMe ester-11), 4.57 (dd, 1H, J = 4.8 and 3.0 Hz,
H-6), 6.80 (d, 1H, J = 7.8 Hz, H-10), 6.95 (dt, 1H, J = 7.5 and 1.4 Hz,
H-8), 7.20 (dt, 1H, J = 7.3 and 1.5 Hz, H-9), 7.21 (d, 1H, J = 7.7 Hz,
H-7), 7.43 (d, 1H, J = 4.2 Hz, NH-5), 7.66 (br s, 1H, NH-3); 13C
NMR (DMSO-d6, 150 MHz) d 40.4 (CH2), 41.6 (CH-11), 47.4
(CH-6), 51.7 (OMe ester), 52.1 (OMe ester-11), 83.0 (C-2), 116.8
(CH-10), 121.1 (CH-8), 125.1 (C-6a), 128.8 (CH-7), 129.5 (CH-9),
18. Bartashevich, E. V.; Plekanov, P. V.; Rusinov, G. L.; Potemkin, V.
A.; Belik, A. V.; Chupakhin, O. N. Izv. Akad. Nauk SSSR, Ser. Khim.
1999, 1573.
19. Crystallographic data (excluding structures factors) for the structures
in this Letter have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication nos. CCDC
679852 for 4a and 679853 for 5. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk.
20. Triggle, D. J. In Calcium Channel Pharmacology; McDonough, S. I.,
Ed.; Kluwer Academic/Plenum Publishers: Norwell, 2004, Chapter 3,
pp 33–38.