A new substrate for the Biginelli cyclocondensation: Direct preparation of 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones from a β-keto carboxylic acid

Full text of DOI:10.1021/jo005512a

J . Org. Chem. 2000, 65, 6777-6779
6777
A New Su bstr a te for th e Bigin elli
Cyclocon d en sa tion : Dir ect P r ep a r a tion of
5-Un su bstitu ted
3,4-Dih yd r op yr im id in -2(1H)-on es fr om a
â-Keto Ca r boxylic Acid
J acqueline C. Bussolari* and Patricia A. McDonnell
The R.W. J ohnson Pharmaceutical Research Institute,
1000 Route 202, Raritan, New J ersey 08869
jbussola@prius.jnj.com
Received May 8, 2000
In tr od u ction
The first reported synthesis of 3,4-dihydropyrimidin-
2(1H)-ones using a multicomponent reaction milieu was
described by Biginelli in 1893.1 This multicomponent
reaction consisting of an aromatic aldehyde, urea, and
ethyl acetoacetate in an acidic ethanolic solution pro-
duced highly functionalized pyrimidones. This reaction
was reported over one century ago, and yet considerable
interest in this transformation has steadily increased
over the past decade.2 Much of this interest has arisen
from the multifaceted pharmacological profiles of such
heterocycles. These molecules have been shown to elicit
calcium channel modulatory activity,3 inhibit platelet
activating factor,4 and selectively antagonize the human
R1A receptors,5 to name a few.
Dihydropyrimidones have historically housed esters at
C(5) and an alkyl substituent at C(6). The ester derives
from the â-ketoester component. This malonate-like
portion of the substrate appears to be crucial in the
reaction mechanism6 as its enol tautomer captures the
N-acyliminium ion (Figure 1, la f 4a ). Therefore, the
types of coupling partners used in the Biginelli cyclocon-
densation have been limited.2 An interest in 5-unsubsti-
tuted dihydropyrimidones led to an exploration of unique
conditions and substrates for the cyclocondensation lead-
ing directly to 5-unsubstituted 3,4-dihydropyrimidin-
2(1H)-ones. Researchers at Merck recently described the
synthesis of certain 5-unsubstituted dihydropyrimidones.
This approach and other reported literature methods7
have typically accomplished the synthesis of 5-unsubsti-
tuted dihydropyrimidones in a multistep fashion via the
F igu r e 1.
saponification of the C(5) ester on the preassembled
pyrimidone followed by thermal decarboxylation. These
harsh and inefficient methods have resulted in low-
yielding transformations and multiple side-products.
Herein, the expedient synthesis of a novel series of
5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones using
oxalacetic acid as an unprecedented substrate for the
Biginelli reaction is reported. Also described herein is an
effectual set of conditions used to execute this cyclocon-
densation.
Resu lts a n d Discu ssion
Although this reaction was described over 100 years
ago, the Biginelli process lacks literature precedent for
the use of â-keto carboxylic acids as substrates. This is
understandable given that under the standard acidic
reaction conditions a typical â-keto carboxylic acid should
undergo spontaneous decarboxylation to give carbon
dioxide and a ketone. However, oxalacetic acid does not
undergo decomposition at low pH since the residing enol
forms are inactive to decarboxylation.8 The enol forms
of oxalacetic acid predominate in strongly acidic media.9
Steinberger and Westheimerm10 have shown that the
first-order rate constants for the decarboxylation of
oxalacetic acid depend on pH. Presumably the resonance
* Corresponding author.
(1) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(2) (a) Kappe, C. O. Tetrahedron 1993, 49, 32, 6937. (b) Hu, E. H.;
Sidler, D. R. Dolling, U.-H. J . Org. Chem. 1998, 63, 3454. (c) Kappe,
C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron 1997, 53, 8, 2803.
(d) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7816. (e)
Hamper, B. C.; Gan, K. Z.; Owen, T. J . Tetrahedron Lett. 1999, 40, 27,
4973. (d) Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman, L. E.;
Shaka, A. J . J . Org. Chem. 1999, 64 (5), 1512-1519.
(3) (a) Atwal, K. S.; Rovnyak, G. C.; Schwartz, J .; Moreland, S.;
Hedberg, A.; Gougoutus, J . Z.; Malley, M. F.; Floyd, D. M. J . Med.
Chem. 1990, 33, 1510. (b) Atwal, K. S.; Rovnyak, G. C.; Kimball, S.
D.; Floyd, D. M.; Moreland, S.; Swanson, B. N.; Gougoutus, J . Z.;
Schwartz, J .; Smillie, K. M.; Malley, M. F. J . Med. Chem. 1990, 33,
2629.
(4) Cooper, K. World Patent, WO 90/11281.
(5) Wong, W. C.; Lagu, B.; Nagararhnam, D.; Marzabadi, M. R.;
Gluchowski, C. World Patent WO 98/51311.
(6) (a) Folkers, K.; J ohnson, T. B. J . Am. Chem. Soc. 1933, 55, 3784.
(b) Sweet, F.; Fissekis, J . D. J . Am. Chem. Soc. 1973, 95, 26, 8741. (c)
Kappe, C. O. J . Org. Chem. 1997, 62, 7201.
(7) (a) Schramm, H. W.; Treiber, J .; Schubert-Zsilavecz, M. Sci.
Pharm. 1991, 59, 191. (b) Zigeuner, G.; Knopp, C.; Blaschke, H.
Montash. Chem. 1976, 107, 587. (c) Steele, T. G.; Coburn, C. A.; Patane,
M. A.; Bock, M. G. Tetrahedron Lett. 1998, 39, 9315.
(8) (a) Stefanovic, M.; Lipovac, S. N. Glas. Hem. Drus. Beograd 1965,
30, 4-6, 179. (b) Leussing, D. L. In Advanced Inorganic Biochemistry;
Etchhorn, G. L., Marzilli, L. G., Eds.; Elsevier Biomedical: New York,
1982; p 171. (c) Pederson, K. J . J . Am. Chem. Soc. 1929, 51, 2098.
(9) (a) Kozlowski, J .; Zuman, P. Bioelectrochem. Bioenerget. 1992,
28, 43. (b) Wiley: R. H.; Kim, K.-S. J . Org. Chem. 1973, 38, 20, 3582.
(10) (a) Steinberger, R.; Westheimer, F. H. J . Am. Chem. Soc. 1951,
73, 429. (b) Tsai, C. S. Can. J . Chem. 1967, 45, 873.
10.1021/jo005512a CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

6778 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
Ta ble 1. Cyclocon d en sa tion s of Oxa la cetic Acid
Sch em e 1
a
Method A: cat. H2SO4, absolute EtOH, ∆, 12 h, avg scale: 10
with a carbinol such as ethanol (Scheme 1). The acid 5
was also converted to the corresponding Weinreb amide15
and treated with a Grignard reagent. As shown in
Scheme 1, the transformation to the ketone 12 was
effected by reaction with 4-chloromagnesium bromide.
In summary, a novel substrate for the Biginelli reaction
has been identified and exploited to expeditiously syn-
thesize a diverse set of 5-unsubstituted 3,4-dihydropy-
rimidin-2(1H)-ones in high yield. Electron-rich as well
as electron-deficient aldehydes proved to be excellent
substrates for the cyclocondensation. The described py-
rimidones were prepared using standard cyclization
conditions and more effectively synthesized using a
unique set of conditions (i.e., TFA in refluxing dichloro-
ethane). The carboxylic acid appendage on C(6) offers
functionality capable of a wide variety of transformations.
b
mmoles. Method B: cat. TFA, DCE, ∆, 12 h, avg scale: 10
mmoles.
stabilization involving both acids also makes it somewhat
more stable than simple enols.
Under suitable reaction conditions, oxalacetic acid
proved to be an excellent substrate for the Biginelli
reaction. Cyclization and in-situ decarboxylation cleanly
yielded 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-
ones.11 As described in Table 1, using standard conditions
developed by Folkers and J ohnson12 to synthesize tradi-
tional dihydropyrimidones, the targeted 5-unsubstituted
adducts 5-10 were prepared in good to poor yields
(method A). A more effective method utilized conditions
more favorable for N-acyliminium ion formation and keto
to enol equilibrium manifestation. This method employed
trifluoroacetic acid as the acid catalyst and dichloroet-
hane as the solvent (method B). Conditions in method B
are advantageous for N-acyliminium ion formation, a
transient species believed to be a key intermediate in the
reaction pathway.6c Differences in the acidity and/or
dielectric constant of the media can play a role in the
relative keto-enol equilibrium.9a Indeed, the influence
of the solvent polarity may be quite different in method
A (sulfuric acid in refluxing ethanol) compared to that
of method B. The pH of the media has been reported to
have an inherent effect on the keto-enol population and
the rate of decarboxylation.13 In these studies, the
researchers have also shown that solvent effects on 3-keto
acid decarboxylations are small and somewhat variable.
In effort to determine if the decarboxylated form of
oxalacetic acid was playing a role in the cyclization, the
Biginelli reaction was performed on pyruvic acid. In this
experiment only 5% of the product was isolated using
method A. Therefore, it is believed that the decarboxy-
lation is occurring after the initial capture of the N-
acyliminium species by the enol of oxalacetic acid (Figure
1, 2b f 4b). The loss of CO2 may be occurring on the
acyclic and/or cyclic adduct in the reaction pathway.
Substituent effects in the â position can cause rate
enhancements for decarboxylation.14
Exp er im en ta l Section
Gen er a l Meth od s. All unspecified reagents were from com-
mercial sources. Reactions were routinely run in a nitrogen
atmosphere. 1H NMR spectra were recorded at 300 MHz.
Chemical shifts are reported in ppm relative to the residual
signal of the solvent. Medium-pressure liquid chromatography
(MPLC) was carried out on SiO2 (silica gel 60, particle size
0.040-0.063 mm). Drying of organic extracts during reaction
workup was performed over anhydrous Na2SO4. Evaporation of
organic solvents was achieved using a Brinkmann Rotavapor.
Microanalyses were performed by Quantitative Technologies
Inc., Whitehouse, NJ .
Syn th esis Usin g Gen er a l Meth od A. 6-(3,5-Dim eth ylp h e-
n yl)-2-oxo-1,2,3,6-tetr ah ydr o- pyr im idin e-4-car boxylic Acid
(5). Sulfuric acid (0.5 mL) was added to a mixture of urea (3.5798
g, 59.5 mmol) and 3,5-dimethylbenzaldehyde (6.38 mL, 47.6
mmol) stirred in absolute ethanol (25 mL). Oxalacetic acid (5.0
g, 39.67 mmol) was added to the reaction mixture, and the
reaction was heated to reflux for 12 h. The reaction mixture was
cooled to room temperature and diluted with water (100 mL).
The product was extracted with ethyl acetate (2 × 100 mL). The
organics were washed with saturated sodium chloride solution
(100 mL), dried, filtered, and concentrated. The residue was
purified by MPLC by eluting with ethyl acetate and hexane (1:
1, v/v). The product was isolated as a white solid (2.9058 g, 62.3%
yield).
1H NMR (300 MHz, DMSO-d6) δ: 2.26 (s, 6 H), 5.06-5.08
(m, 1 H), 5.73-5.75 (m, 1 H), 6.89-6.92 (m, 3 H), 7.25 (s, 1 H),
7.75 (s, 1 H). 13C NMR (75 MHz, DMSO-d6) δ: 163.31, 152.72,
144.6, 138.05, 129.25, 127.83, 124.15, 109.45, 55.10, 21.29. Anal.
Calcd for C13H14N2O3 × 0.5 mol H2O: C, 61.17%; H, 5.92%; N,
10.97%. Found: C, 61.51%; H, 5.59%; N, 11.37%.
Syn th esis Usin g Gen er a l Meth od B. 6-(3,5-Dim eth ylp h e-
n yl)-2-oxo-1,2,3,6-tetr ah ydr o- pyr im idin e-4-car boxylic Acid
(5). Trifluoroacetic acid (0.5 mL) was added to a mixture of urea
The resultant product can be further transformed by
activation of the free acid with EDC and esterification
(11) HMBC, COSY, and HMQC experiments were used to confirm
the location of the decarboxylation of C(5) carboxy acid by determina-
tion of the location of the C(5) hydrogen for example 5. The spectra
are available in the Supporting Information.
(12) Folkers, K.; J ohnson, T. B. J . Am. Chem. Soc. 1933, 55, 2886.
(13) Pollack, R. M. In Transition States of Biochemical Processes;
Plenum: New York, 1978; p 467.
(14) Sakkab, N. Y.; Martell, A. E. J . Am. Chem. Soc. 1976, 98, 5285.
(15) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 39, 3851.

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6779
(0.6832 g, 11.35 mmol) and 3,5-dimethylbenzaldehyde (1.12 mL,
8.33 mmol) stirred in dichloroethane (15 mL, anhydrous).
Oxalacetic acid (1.00 g, 7.57 mmol) was added to the reaction
mixture, and the reaction was heated to reflux for 12 h. The
reaction mixture was cooled to room temperature, and a white
precipitate formed upon cooling. The product was simply col-
lected by filtration to give a white powder 5 (1.3928 g, 75.1%
yield).
Eth yl 6-(3,5-Dim eth ylp h en yl)-2-oxo-1,2,3,6-tetr a h yd r o-
p yr im id in e-4-ca r boxyla te (11). To a solution of acid 5 (0.5217
g, 2.12 mmol) in dimethylformamide (DMF, 7 mL, anhydrous)
were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (EDC, 0.4465 g, 2.33 mmol), 1-hydroxy-7-azabenzo-
triazole (HOAT, 0.3172 g, 2.33 mmol), and N-methylmorpholine
(NMM, 0.47 mL, 4.24 mmol). Ethanol (1 mL, absolute) was
added to the reaction, and the mixture was stirred overnight at
room temperature. The reaction mixture was diluted with water
(50 mL), extracted with ethyl acetate (2 × 50 mL), dried, filtered,
and concentrated. The residue was purified by MPLC eluting
with ethyl acetate and hexane (3:7, v/v). The product was isolated
6-P h en yl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e-4-ca r boxy-
1
lic Acid (6). H NMR (300 MHz, DMSO-d6) δ: 5.13-5.16 (m, 1
H), 5.77-5.79 (m, 1 H), 7.29-7.41 (m, 5 H), 7.79 (s, 1 H). 13C
NMR (75 MHz, DMSO-d6) δ: 163.30, 152.79, 144.11, 129.04,
128.06, 127.89, 126.45, 109.26, 55.08. Anal. Calcd for C11H10N2O3
× 0.1 mol H2O: C, 66.02%; H, 7.03%; N, 5.92%. Found: C,
66.11%; H, 7.47%; N, 6.26%.
1
as a colorless solid (0.5322 g, 91.0% yield). H NMR (300 MHz,
DMSO-d6) δ: 1.37 (t, J ) 2.79 Hz, 3 H), 2.37 (s, 6 H), 4.38 (q, J
) 7 Hz, 2 H), 7.23 (bs, 1 H), 7.68 (bd, J ) 7 Hz, 1 H), 7.69-7.73
(m, 3 H). Anal. Calcd for C26H31N2O3: C, 66.02%; H, 7.03%; N,
5.92%. Found: C, 66.11%; H, 7.47%; N, 6.26%.
6-(2,3-Dich lor op h en yl)-2-oxo-l1,2,3,6-tetr a h yd r op yr im i-
1
d in e-4-ca r boxylic Acid (7). H NMR (300 MHz, DMSO-d6) δ:
5.52-5.54 (m, 1 H), 5.78-5.79 (m, 1 H), 7.35-7:50 (m, 3 H), 7.62
(dd, J ) 7.89 and 1.44 Hz, 1 H). 13C NMR (75 MHz, DMSO-d6)
δ: 163.03, 152.81, 143.31, 132.49, 130.01, 129.37, 129.28,
128.622, 126.99, 105.57, 53.45. Anal. Calcd for C11H8Cl2N2O3:
C, 46.02%; H, 2.81%; N, 9.76%. Found: C, 45.89%; H, 2.60%; N,
9.64%.
6-(3,5-Dim eth ylp h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im i-
d in -4-yl-(4-ch lor op h en yl)m eth a n on e (12). To solution of acid
5 (0.5217 g, 2.12 mmol) in DMF (7 mL, anhydrous) were added
EDC (0.4465 g, 2.33 mmol), NMM (0.47 mL, 4.24 mmol), HOAT
(0.3172 g, 2.33 mmol), and N,O-dimethylhydroxylamine hydro-
chloride (0.2275 g, 2.33 mmol). The reaction was stirred over-
night at room temperature. The reaction mixture was diluted
with water (50 mL), extracted with ethyl acetate (2 × 50 mL),
dried, filtered, and concentrated. The crude residue was solu-
bilized in THF (10 mL, anhydrous) and cooled to 0 °C with an
external ice-bath. 4-Chlorophenylmagnesium bromide was slowly
added, and the reaction was warmed to room temperature. After
stirring for 5 h, the reaction was quenched with brine (50 mL),
extracted with ethyl acetate (2 × 50 mL), dried, filtered, and
concentrated. The residue was purified by MPLC by eluting with
ethyl acetate and hexane (4:1, v/v). The ketone 12 was isolated
as a pale yellow solid (0.2713 g, 37% yield). 1H NMR (300 MHz,
CDCl3) δ: 2.41 (s, 6 H), 6.89-6.86 (m, 1 H), 7.26-7.40 (m, 1 H),
7.51 (d, J ) 8.54 Hz, 2 H), 7.56 (s, 1 H), 8.06 (d, J ) 8.52 Hz, 2
H). Anal. Calcd for C19H17N2O2: C, 66.96%; H, 5.03%; N, 8.22%.
Found: C, 66.83%; H, 5.34%; N, 8.12%.
6-(3-Nitr op h en yl)-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e-4-
1
ca r boxylic Acid (8). H NMR (300 MHz, DMSO-d6) δ: 5.36-
5.38 (m, 1 H), 5.86-5.87 (m, 1 H), 7.50 (bs, 1 H), 7.70 (dd, J )
7.63 and 7.70 Hz, 1 H). 7.80 (d, J ) 7.70 Hz, 1 H), 8.01 (s, 1 H),
8.17-8.19 (m, 2 H). 13C NMR (DMSO-d6) δ: 163.11, 152.70,
148.33, 146.22, 133.27, 130.76, 128.81, 122.88, 121.05, 108.09,
54.32. Anal. Calcd for C11H9N3O5: C, 50.20%; H, 3.45%; N,
15.96%. Found: C, 49.89%; H, 3.27%; N, 15.73%.
6-Cycloh exyl-2-oxo-1,2,3,6-tetr a h yd r op yr im id in e-4-ea r -
1
boxylic Acid (9). H NMR (300 MHz, DMSO-d6) δ: 0.95-2.51
(m, 11 H), 3.87 (s, 1 H), 5.65-5.67 (m, 1 H), 6.81 (s, 1 H), 7.46
(s, 1 H). 13C NMR (75 MHz, DMSO-d6) δ: 163.15, 153.55, 129.55,
107.79, 56.37, 44.85, 27.68, 27.41, 26.03, 25.98. Anal. Calcd for
C
26H31N2O3 × 1.0 H2O: C, 66.02%; H, 7.03%; N, 5.92%. Found:
C, 66.1 1%; H, 7.47%; N, 6.26%.
6-(2-Th ien yl)-2-oxo-l,2,3,6-tetr a h yd r op yr im id in e-4-ca r -
boxylic Acid (10). 1H NMR (300 MHz, DMSO-d6) δ: 5.44-5.46
(m, 2 H), 5.80-5.82 (s, 1 H), 6.99 (d, J ) 3.09 Hz, 1 H), 7.46-
7:50 (m, 2 H), 7.94 (s, 1 H). 13C NMR (75 MHz, DMSO-d6) δ:
163.25, 160.03, 152.29, 148.37, 128.52, 127.34, 125.84, 124.38,
108.51, 50.50. Anal. Calcd for C9H8N2O3S: C, 48.21%; H, 3.60%;
N, 12.49%. Found: C, 48.01%; H, 3.68%; N, 12.41%.
Su p p or tin g In for m a tion Ava ila ble: Proton and/or car-
bon NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O005512A