Studies on the biginelli reactions of salicylaldehyde and 2-hydroxy-l-naphthaldehyde

Article abstract of DOI:10.1002/jhet.1785

The Biginelli reactions of salicylaldehyde and 2-hydroxy-l-naphthaldehyde with ethyl or methyl acetoacetate, ethyl benzoylacetate, and urea have been reinvestigated both in the structures of the reaction products and in the reaction conditions. Salicylald

Full text of DOI:10.1002/jhet.1785

Month 2014
Studies on the Biginelli Reactions of Salicylaldehyde and 2-Hydroxy-
l-naphthaldehyde
*
Qingjian Liu, Jiehua Xu, Fei Teng, Anjun Chen, Ning Pan, and Wenwen Zhang
College of Chemistry, Chemical Engineering and Materials Science, Engineering Research Center of Pesticide and
Medicine Intermediate Clean Production, Ministry of Education, Shandong Normal University, Jinan 250014, People’s
Republic of China
*
E-mail: liuqj@sdnu.edu.cn
Additional Supporting information can be found in on line version of this article.
Received April 6, 2012
DOI 10.1002/jhet.1785
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
The Biginelli reactions of salicylaldehyde and 2-hydroxy-l-naphthaldehyde with ethyl or methyl acetoacetate,
ethyl benzoylacetate, and urea have been reinvestigated both in the structures of the reaction products and in the
reaction conditions. Salicylaldehyde with ethyl and methyl acetoacetate resulted in oxygen-bridged tricyclic
tetrahydro pyrimidines, whereas with ethyl benzoylacetate afforded the only normal 3,4-dihydropyrimidin-
2-one. 2-Hydroxy-l-naphthaldehyde with ethyl and methyl acetoacetate formed the tricyclic compounds. Steric
effect is likely to be the principal determinant in governing the formation of product dichotomy. Previous contro-
versial results as to the structure of the Biginelli products have been discussed and settled. The molecular structures
of the dihydropyrimidinones and bridged tricyclic products have been fully characterized and confirmed
unambiguously by single crystal X-ray diffraction.
J Heterocycl Chem., 00, 00 (2014).
INTRODUCTION
ethanol.[5] A number of more efficient and green synthetic
modifications and improved procedures have been devel-
oped.[6,7]
Recently, 3,4-dihydropyrimidin-2-ones (DHPMs) and the
derivatives have attracted considerable attention in natural
and synthetic organic chemistry because of their wide range
of biological activities and pharmacological properties, such
as antiviral, antibacterial, antitumour, calcium channel block-
ers, antihypertensive agents, a-1a-antagonists, and neuropep-
tide Y antagonists.[1] Among the biologically important
compounds, notably, monastrol 1, a recently highlighted
DHPM compound, is the only cell-permeable molecule
currently known to specifically inhibit mitotic kinesis Eg5
and is considered to be a lead for the development of new
anticancer drugs, [2] whereas the (R)-SQ 32926 2 has been
identified as a potent orally active antihypertensive agent.[3]
Moreover, several alkaloids containing the dihydropyrimi-
dione core unit have been isolated from marine source, which
also shows interesting biological properties. Most notably
among these are the batzelladine alkaloids, which have been
found to be potent HIV gp-120-CD4 inhibitors.[4]
As to the Biginelli reaction of ortho-hydroxy aromatic
aldehydes such as salicylaldehyde with ethyl or methyl acet-
oacetate and urea or thiourea, the product structure was
dihydropyrimidinones as Folkers [8] reported, but was later
disproved firstly in 1991 by Svĕtlík [9] as oxygen-bridged
tricycle, and then Kettmann,[10] Fu,[11] Bose,[12] and
Kumar [13] also obtained the tricyclic compound, respec-
tively. Svĕtlík et al.[14] recently reported the product dichot-
omy of dimethyl and diethyl 3-oxoglutarate with
salicylaldehyde. Dimethyl 3-oxoglutarate gave rise to a tricy-
clic structure, but diethyl 3-oxoglutarate afforded the normal
dihydropyrimidinones, to which the steric effect of ethoxy-
carbonyl was attributed. Two different monastrol products,
4-(2-hydroxyphenyl)pyrimidines and 9-methyl-11-oxo
(or thioxo)-8-oxa-10,12-diazatricyclotrideca derivatives
were synthesized by Cheng and the coauthors under
solvent-free conditions catalyzed by NaHSO4. [15]
Thus, formation of this heterocyclic nucleus has gained
prime importance in synthetic organic chemistry. The well-
known preparation is the Biginelli reaction, which involves
three components and one-pot condensation of an aldehyde,
b-ketoester, and urea catalyzed by hydrochloric acid in
In continuation of our interest in the green synthesis of
DHPMs and derivatives, we have made the studies on the
Biginelli reactions of ortho-hydroxy aromatic aldehydes
including salicylaldehyde and b-hydroxy-a-naphthaldehyde
with b-ketoesters, such as methyl and ethyl acetoacetate and
© 2013 HeteroCorporation

Q. Liu, J. Xu, F. Teng, A. Chen, N. Pan, and W. Zhang
Vol 000
ethyl benzoylacetate, and urea both in the molecular structures
of the products and the reaction conditions (Scheme 1).
Experiments show that ring transformation of 3b to 3a is
much easier than that of 4b to 4a, indicating that tricyclic
tetrahydropyrimidine 4b is more stable than 3b, to which less
steric effect of methoxycarbonyl CO2CH3 is attributed.
Obviously, the C-6 position is considerably hindered by the
adjacent ethoxycarbonyl CO2C2H5 of C-5, as compared with
the less bulkier methoxycarbonyl CO2CH3 group. Conse-
quently, the ring opening of 3b is easier to occur than that of
4b (Fig. 3).
RESULTS AND DISCUSSION
The results of the Biginelli reactions of salicylaldehyde and
2-hydroxy-1-naphthaldehyde with ethyl acetoacetate, methyl
acetoacetate, ethyl benzoylacetate, and urea under solvent-free
conditions are summarized in Table 1.
Ethyl acetoacetate with salicylaldehyde under solvent-free
conditions produced oxygen-bridged tricyclic compound 3b
and then converted to DHPM 3a after being refluxed in
ethanol catalyzed with HCl (Scheme 2).
The Biginelli reaction of 2-hydroxy-l-naphthaldehyde with
ethyl acetoacetate and urea under different reaction conditions,
including solvent-free with HCl catalyzed at 70ꢀC for 3h, in
refluxed ethanol catalyzed by HCl for 3 and 14 h, all gave rise
to tricyclic product 5b and failed to be converted to DHPM
(Scheme 3). Such a result is also found in the Biginelli reac-
tion of 2-hydroxy-l-naphthaldehyde with methyl acetoacetate
and urea under the same conditions. This can be rationalized
by the stabilization effect of cyclization of bulker naphthalyl.
In contrast to the reactions of 2-hydroxy-l-naphthaldehyde
with methyl or ethyl acetoacetate, ethyl benzoylacetate with
salicylaldehyde afforded only DHPM 7a, which is governed
by both electronic and steric effects of conjugate and bulkier
phenyl group bounded to C6. Phenyl substituent pushes the
ortho-hydroxy of C4—Ph away from its bonding contact,
and the conjugate effect of phenyl decreased the addition
reactivity with phenolic hydroxy. Moreover, the p-p conju-
gate system formed with phenyl and C═C makes the DHPM
structure 7a much more stable.
1
The H-NMR signal at dH 9.58 ppm in 3a indicates the
presence of the phenolic hydroxyl, which reveals that 3a is
1
the normal Biginelli DHPM product. In the H-NMR spec-
trum of 3b, dH 9.58 ppm is replaced with dH 3.24 ppm
assigned to C9—H. In addition, the 13C-NMR of 3b at dC
83.6 ppm attributed to sp3 C1 provides convincing evidence
of tricyclic structure resulted from the intramolecular conju-
gate addition of the phenolic hydroxyl to C5═C6—C═O of
the dihydropyrimidine. Under solvent-free or low-temperature
conditions, 3b is the main product (solvent-free at 70ꢀC for 3h
is the optimum conditions for 3b, and in ethanol at refluxed
temperature is the optimum conditions for 3a). Extending
the reaction time, the amount of 3b decreases and that of 3a
increases contrastively. This suggests that 3b is initially
formed and is isomerized to 3a via tricycle opening. In addi-
tion, 3b cannot be transformed into 3a in ethanol refluxed in
the absence of hydrochloric acid, which shows that acidic
catalysis is indispensable for the ring opening transformation.
Similarly, methyl acetoacetate with salicylaldehyde in
refluxed ethanol also afforded bridged tricyclic 4b and then
transformed into DHPM 4a after being refluxed but for pro-
longed time in ethanol with HCl catalyzed. Their structures
CONCLUSION
In summary, we have re-examined the Biginelli reactions of
ortho-hydroxy aromatic aldehydes, including salicylaldehyde
and 2-hydroxy-l-naphthaldehyde, with ethyl or methyl acetoa-
cetate, ethyl benzoylacetate, and urea both in the structures of
the reaction products and the reaction conditions. Salicylalde-
hyde with ethyl or methyl acetoacetate and urea under solvent-
free conditions resulted in oxygen-bridged tricyclic products
1
are characterized by H-NMR and 13C-NMR spectra and
confirmed unambiguously by single crystal X-ray diffraction
(Fig. 1 and Fig. 2).
Scheme 1. The Biginelli reactions of salicylaldehyde and 2-hydroxy-1-naphthaldehyde with b-ketoesters and urea under solvent-free conditions.
Journal of Heterocyclic Chemistry
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Studies on the Biginelli Reactions of Salicylaldehyde and 2-Hydroxy-l-naphthaldehyde
Table 1
The Biginelli reactions of salicylaldehyde and 2-hydroxy-1-naphthaldehyde with b-ketoesters and urea under solvent-free conditions.
Yield
(%)a
Time
(h)
T
(ꢀC)
mp c (lit)
(ꢀC)
No.
Ar
R1
R2
Et
Product structure
3b
2-HOC6H4
Me
98
2.5
70
198.2–200.3 (200–202)13
3a
2-HOC6H4
Me
Et
80
3
Reflux
216.4–217.2 (217)
4b
4a
2-HOC6H4
2-HOC6H4
Me
Me
Me
Me
92
78
3
3
70
209.1–210.3 (195–197)
Reflux
231.0–232.9
5b
6b
7a
2-HOC10H6
2-HOC10H6
2-HOC6H4
Me
Me
Ph
Et
Me
Et
61.6
88.5
45
3
3
5
70
70
70
231.4–232.7
215.3–215.8
240.1–241.8
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Q. Liu, J. Xu, F. Teng, A. Chen, N. Pan, and W. Zhang
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Scheme 2. The Biginelli reactions of salicylaldehyde with ethyl acetoacetate and urea under solvent-free conditions.
EXPERIMENTAL
General. 1H-NMR and 13C-NMR spectra were determined
on a Bruker Advance 300 spectrometer (Bruker AXS, Germany)
in DMSO-d6 with TMS as internal reference (300 MHz for 1H
and 75MHz for 13C). IR spectra were recorded on a Bruker
Tensor 27 spectrometer (Bruker AXS, Germany) in KBr plates.
Mass spectra were determined with an Agilent 5973N Mass
Selective Detector spectrometer in EI mode at 70eV. Elemental
analyses were carried out with a Perkin Elmer PE 2400 II HONS
analyzer (Perkin-Elmer Corporation, USA). Single crystal X-ray
diffraction was performed on a Bruker SMART APEX CCD
Diffractometer (Bruker AXS, Germany). Melting points are
uncorrected. Salicylaldehyde, ethyl and methyl acetoacetate, and
ethyl benzoylacetate were all reagent grade and were redistilled in
vacuo unless otherwise stated. 2-Hydroxy-l-naphthaldehyde was
prepared from 2-naphthol according to the literature procedure.
General procedures. General procedure for the synthesis
Figure 1. Dihydropyrimidine antagonists.
of 3a and 4a.
A mixture of salicylaldehyde (5 mmol), ethyl
or methyl acetoacetate (5.5 mmol), urea (5.5 mmol), and
hydrochloric acid (2 drops) was refluxed for 3 h. Upon cooling
to RT, the precipitates were filtered off and recrystallized from
isopropyl alcohol to afford 3a and 4a, respectively.
General procedure for the synthesis of all other compounds.
A mixture of aldehyde (5 mmol), b-ketoester (5.5 mmol), urea
(5.5 mmol), and hydrochloric acid (2 drops) was heated at 70ꢀC for
2.5–3 h (monitored by TLC). Upon cooling to RT, the reaction
mixture was poured into water. The solids were filtered off, washed
with water and 95% ethanol, and recrystallized from ethanol to
afford 3b, 4b, 5b, 6b, and 7a, respectively.
Structural characterization. Ethyl 4-(2-hydroxyphenyl)-6-
methyl-3,4-dihydropyrimidin-2(1H)-one-9-carboxylate 3a.
Colorless solid, mp 216.4–217.2ꢀC (lit.14 217ꢀC). 1H-NMR: dH 9.58 (s,
1H), 9.10 (s, 1H), 7.10–6.68 (m, 5H), 5.46 (s, 1H), 3.92 (q, J=7.0Hz,
2H), 2.27 (s, 3H), 1.03 (t, J= 7.0 Hz, 3H) ppm. IR: nmax 3414, 3349,
2938, 1699, 1651 cmꢁ1. Elemental Anal.: Calcd for C14H16N2O4:
C 60.86, H 5.84, N 10.14; found: C 61.05, H 5.84, N 10.10.
Ethyl 1-methyl-2-oxa-7-oxo-6,8-diazabenzo[c]bicyclo[3.3.1]
Figure 2. Crystal structure ORTEP of 4a. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com]
nonane-9-car-boxylate 3b.
Colorless solid, mp199.8–
200.3ꢀC (lit.13 200–202ꢀC); H-NMR: dH 7.58 (s, 1H), 7.18 (t,
J = 7.1 Hz, 3H), 6.89 (t, J = 7.1 Hz, 1H), 6.77 (d, J = 8.2 Hz,
1H), 4.46 (s, 1H), 4.16 (m, J = 7.0 Hz, 2H), 3.24 (s, 1H), 1.72
(s, 3H), 1.22 (t, J = 7.0 Hz, 3H) ppm. 13C-NMR: dC 168.8,
155.0, 151.1, 129.7, 129.0, 125.9, 120.9, 117.0, 83.6, 61.0,
48.2, 44.4, 24.4, 14.4 ppm. IR: nmax 3216, 3078, 1748,
1684 cmꢁ1. Elemental Anal.: Calcd for C14H16N2O4: C 60.86,
H 5.84, N 10.14; found: C 60.53, H 5.87, N 9.84.
1
3b and 4b, whereas salicylaldehyde with ethyl benzoylacetate
and urea afforded DHPM 7a. 2-Hydroxy-l-naphthaldehyde
with ethyl or methyl acetoacetate and urea under solvent-free
conditions formed tricyclic compounds 5b and 6b. Benzoyla-
cetic ethyl ester with salicylaldehyde resulted in only DHPM
7a. Steric effect is likely to be the principal determinant in
governing the formation of reaction product dichotomy. Previ-
ous controversial results as to the structure of the Biginelli
products have been discussed and settled.
Methyl 4-(2-hydroxyphenyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one-9-carboxylate 4a.
Colorless solid, mp 231.0–
1
232.9ꢀC. H-NMR: dH 9.62 (s, 1H), 9.12 (s, 1H), 7.06–6.68 (m,
5H), 5.44 (s, 1H), 3.47 (s, 3H), 2.27 (s, 3H) ppm. IR: nmax
3416, 3228, 2952, 2361, 1683, 1645 cmꢁ1. Elemental Anal.:
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Month 2014
Studies on the Biginelli Reactions of Salicylaldehyde and 2-Hydroxy-l-naphthaldehyde
Figure 3. Crystal structure ORTEP of 4b. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com]
Scheme 3. The Biginelli reaction of 2-hydroxy-1-naphthaldehyde with ethyl acetoacetate and urea under solvent-free conditions. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com]
Calcd for C13H14N2O4: C 59.54, H 5.38, N 10.68; found: C
60.04, H 5.30, N 10.60.
Methyl 1-methyl-2-oxa-7-oxo-6,8-diazanaphtho[2,1-c]bicyclo
[3.3.1]nonane-9-carboxylate 6b. Colorless solid, mp 215.3–
215.8ꢀC. 1H-NMR: dH 8.04 (d, J=8.3Hz, 1H), 7.84 (q, J=8.8Hz,
2H), 7.63 (s, 2H), 7.55 (t, J=7.4Hz, 1H), 7.40 (t, J= 7.4 Hz, 1H),
7.06 (d, J= 8.8 Hz, 1H), 5.09 (s, 1H), 3.75 (s, 3H), 1.81 (s, 3H)
ppm. 13C-NMR: dC 169.5, 154.9, 148.7, 131.2, 130.2, 129.1,
128.8, 127.3, 124.1, 122.2, 118.9, 117.2, 83.6, 52.4, 44.6, 44.1,
24.3 ppm. IR: nmax 3247, 1745, 1690, 1627 cmꢁ1. MS: m/z (%)
312 (M+, 54), 169 (56), 144 (100), 115 (92). Elemental Anal.:
Calcd for C17H16N2O4: C 65.38, H 5.16, N 8.97; found: C 65.65,
Methyl 1-methyl-2-oxa-7-oxo-6,8-diazabenzo[c]bicyclo[3.3.1]
nonane-9-car-boxylate 4b. Colorless solid, mp 209.1–210.3ꢀC
(lit.13 195–197ꢀC). 1H-NMR: dH 7.62 (s, 1H), 7.19 (q, J = 7.2 Hz,
3H), 6.89 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.47 (s, 1H),
3.69 (s, 3H), 3.30 (s, 1H), 1.72 (s, 3H) ppm. 13C-NMR: dC 169.3,
154.9, 151.1, 129.8, 129.1, 125.8, 120.9, 116.0, 83.5, 52.3, 48.1,
44.3, 24.5ppm. IR: nmax 3225, 3085, 1749, 1698cmꢁ1. Elemental
Anal.: Calcd for C13H14N2O4: C 59.54, H 5.38, N 10.68; found:
C 59.11, H 5.43, N 10.50.
Ethyl 1-methyl-2-oxa-7-oxo-6,8-diazanaphtho[2,1-c]bicyclo
H 5.37, N 8.91.
Ethyl 4-(2-hydroxyphenyl)-6-phenyl-3,4-dihydropyrimidin-
[3.3.1]nonane-9-carboxylate 5b.
Colorless solid, mp 231.4–
2(1H)-one-9-carboxylate 7a.
Colorless solid, mp 240.1–
232.7ꢀC. 1H-NMR: dH 8.04 (d, J = 8.4 Hz, 1H), 7.83 (q,
J = 8.9Hz, 2H), 7.55 (t, J = 7.5 Hz, 3H), 7.39 (t, J = 7.5Hz, 1H),
7.04 (d, J = 8.9 Hz, 1H), 5.07 (s, 1H), 4.20 (t, J = 7.0 Hz, 2H), 3.32
(s, 1H), 1.80 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H) ppm. 13C-NMR: dC
169.0, 154.8, 148.8, 131.2, 130.2, 129.0, 128.8, 127.3, 124.1,
122.2, 118.9, 117.2, 83.6, 61.1, 44.6, 44.2, 24.3, 14.5 ppm. IR:
nmax 3261, 1747, 1698, 1624, 1600 cmꢁ1; MS: m/z (%) 326 (M+,
100), 297 (40), 280 (61), 253 (50), 235 (57), 183 (71), 144 (71),
115 (59). Elemental Anal.: Calcd for C18H18N2O4: C 66.25, H
5.56, N 8.58; found: C 65.95, H 5.67, N 8.11.
241.8ꢀC. 1H-NMR: dH 9.68 (s, 1H), 9.17 (s, 1H), 7.43–6.77
(m, 10H), 5.54 (d, J = 3.0 Hz, 1H), 3.68 (q, J = 7.1 Hz, 2H),
0.71 (t, J = 7.1 Hz, 3H) ppm. 13C-NMR: dC 165.6, 155.3,
152.7, 149.6, 135.8, 130.0, 129.2, 128.9, 128.8, 128.2, 127.6,
119.4, 116.0, 99.6, 59.4, 50.0, 13.8 ppm. IR: nmax 3407, 3241,
2985, 2361, 1661, 1598 cmꢁ1. MS: m/z (%) 338 (M+, 38), 309
(57), 291 (55), 265 (100), 245 (59), 104 (49). Elemental Anal.:
Calcd for C19H18N2O4: C 67.44, H 5.36, N 8.28; found: C
66.97, H 5.64, N 7.89.
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Acknowledgments. College of Chemistry, Chemical Engineering
and Materials Science, Shandong Normal University is
acknowledged.
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