An efficient synthesis of 3-substituted 3H-pyrimidin-4-ones

Article abstract of DOI:10.1021/ol049921v

(Equation presented) A novel and practical synthesis of 3-substituted 3H-pyrimidin-4-ones is described. The key step involves the cyclization of enamide esters, derived from readily available β-keto esters, with trimethylaluminum and various primary amines.

Full text of DOI:10.1021/ol049921v

ORGANIC
LETTERS
2004
Vol. 6, No. 6
1013-1016
An Efficient Synthesis of 3-Substituted
3H-Pyrimidin-4-ones
Jae Uk Jeong,* Xiaohong Chen, Attiq Rahman, Dennis S. Yamashita, and
Juan I. Luengo
Department of Medicinal Chemistry, MMPD CEDD, GlaxoSmithKline,
1250 South CollegeVille Road, CollegeVille, PennsylVania 19426
jae.u.jeong@gsk.com
Received January 13, 2004
ABSTRACT
A novel and practical synthesis of 3-substituted 3H-pyrimidin-4-ones is described. The key step involves the cyclization of enamide esters,
derived from readily available â-keto esters, with trimethylaluminum and various primary amines.
3-Substituted 3H-pyrimidin-4-ones and 3-substituted 3H-
quinazolin-4-ones are pharmacophores present in many
biologically active compounds (Figure 1). Examples include
PPAR agonist 1,1a angiotensin antagonist 2,1b sedative-
hypnotic 3,2a antitussive 4,2b and analgesic 5.2c
There are a wide variety of methods to synthesize
3-substituted quinazolinones.2 The known routes to 3-sub-
stituted pyrimidinones are much more limited and are
depicted below (Figure 2).
laboratories and confirmed that the alkylation procedure
works effectively with unhindered electrophiles such as
methyl iodide and allyl bromide, but it generally suffers from
competing O-alkylation (even with the addition of lithium
bromide)1d with more hindered alkylating agents. For ex-
ample, when isopropyl iodide was employed, no desired
N-alkylation product was observed. Route B is based on the
condensation of N-substituted amidines with malonyl dichlo-
rides. This route provides 1H-pyrimidine-4,6-diones that
could then be further functionalized at the 6 position, but it
generally produces low yields1e or requires lengthy reaction
times1f and is limited in scope to highly reactive malonyl
Route A utilizes the Pinner condensation of â-keto esters
with non-N-substituted amidines to pyrimidinones,1c followed
by N-alkylation.1d We have examined this approach in our
(1) (a) Madhavan, G. R.; Chakrabarti, R.; Vikramadithyan, R. K.;
Mamidi, R. N. V. S.; Balraju, V.; Rajesh, B. M.; Misra, P.; Kumar, S. K.
B.; Lohray, B. B.; Lohray, V. B.; Rajagopalan, R. Bioorg. Med. Chem.
2002, 2671. (b) Balmforth, A. J.; Bryson, S. E.; Aylett, A. J.; Warburton,
P.; Ball, S. G.; Pun, K. T.; Middlemiss, D.; Drew, G. M. Br. J. Pharmacol.
1994, 112, 277. (c) Pinner, A. Chem. Ber. 1889, 22, 1612. (d) Salimbeni,
A.; Canevotti, R.; Paleari, F.; Poma, D.; Caliari, S.; Fici, F.; Cirillo, R.;
Renzetti, A. R.; Subissi, A.; Belvisi, L.; Bravi, G.; Scolastico, C.; Giachetti,
A. J. Med. Chem. 1995, 38, 4806. (e) Jezewski, A.; Jurczak, J.; Lidert, Z.;
Tice, C. M. J. Heterocycl. Chem. 2001, 38, 645. (f) Sitte, A.; Paul, H. Chem.
Ber. 1969, 102, 615. (g) Taylor, E. C.; Zhou, P.; Tice, C. M. Tetrahedron
Lett. 1997, 38, 4343. (h) Takahashi, T.; Hirokami, S.; Nagata, M. J. Chem.
Soc., Perkin Trans. 1 1988, 2653. (i) Yamamoto, Y.; Morita, Y.; Minami,
K. Chem. Pharm. Bull. 1986, 34, 1980.
(2) (a) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campell, J. A.;
Greenwood, T. D. J. Med. Chem. 1990, 33, 161. (b)Buzas, A.; Hoffmann,
C. Bull. Soc. Chim. Fr. 1959, 1889. (c) Welch, W. M.; Ewing, F. E.; Huang,
J.; Menniti, F. S.; Pagnozzi, M. J.; Kelly, K.; Seymour, P. A.; Guanowsky,
V.; Guhan, S.; Guinn, M. R.; Critchett, D.; Lazzaro, J.; Ganong, A. H.;
DeVries, K. M.; Staigers, T. L.; Chenard, B. L. Bioorg. Med. Chem. Lett.
2001, 177.
Figure 1. Biologically potent pyrimidinones and quinazolinones.
10.1021/ol049921v CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/24/2004

Table 1. Preparation of Enamide Esters 7 from â-keto Esters
Figure 2. Synthetic methods for pyrimidinones.
dichlorides.1g Route C involves the dehydration of an
enediamide. An example has been reported in which an
enediamide (Figure 2, Route C, R2 ) R3 ) R5 ) Me, R6
) t-Bu) is cyclized to a 3-substituted pyrimidinone by
refluxing in ethanol for 5 days, but the isolated yield in this
case is only 12%.1h In Route D, an oxazinone intermediate
is used to form an enediamide in situ, which then undergoes
cyclization as in Route C. An example starting with
oxazinone, 5-methyl-2-phenyl-6H-1,3-oxazin-6-one (Figure
2), and methylamine in ethanol has been published, but the
scope of the reaction has not been extensively examined.1i
In this paper, we describe a novel and efficient synthesis
of 3-substituted pyrimidinones from â-keto esters, acid
anhydrides, trimethylaluminum, and various primary amines
(Figure 2, Route C). We also delineate the syntheses of
oxazinones and quinazolinones using either dimethylalumi-
num amides or trimethylaluminum.
Enamide esters 7 were prepared for this study in high
isolated yields with a high Z/E ratio in a single reaction flask
by a two-step process (Table 1). â-Keto esters 63 were
combined with ammonium acetate in refluxing acetic acid
and toluene to form eneamines.4 Following Dean-Stark trap
removal of water, ammonium acetate, acetic acid, and most
of the toluene (without aqueous workup), the enamines were
acylated with acid anhydrides and acetic acid at 70 °C to
produce enamide esters 7.5 The acylation step could alter-
natively be achieved under basic conditions with pyridine
in refluxing THF, but generally gave lower yields.6
a Ratio was determined after isolation by flash column chromatography.
b Overall isolated yield of (Z)-isomers without purification of intermediates.
(formed in situ from trimethylaluminum and aniline in a 1:1
ratio at room temperature in methylene chloride with
evolution of methane) for 5 h at room temperature provided
the desired pyrimidinone 8a in 84% yield (Table 2, entry
1). Interestingly, when enamide ester 7a was stirred with 1
equiv of dimethylaluminum amide for 23 h at room tem-
perature, only 50% conversion to product 8a was observed
(with 50% recovery of enamide ester 7a). Even after reflux
for 6 h, the ratio of enamide ester 7a and pyrimidinone 8a
did not change significantly. However, the reaction with 2
equiv of dimethylaluminum amide for 20 h at room tem-
perature provided an 87% yield of product 8a along with
10% of enamide ester 7a. These results suggest that at least
2 equiv of dimethylaluminum amide reagent are required
for this reaction to run to completion.
Using our optimized reaction conditions with 3 equiv of
trimethylaluminum and 3 equiv of various primary amines,
including aromatic amines, bulky amines such as cyclohexyl-
amine, amines containing an alkoxy group, as well as
hydrazine, afforded good to excellent isolated yields of
3-substituted pyrimidinones 8 from a structurally diverse set
of enamide esters 7a-d (Table 2).8,9a In some cases, higher
reaction temperatures were used to shorten reaction times.
For example, 3-ethoxypropylamine (Table 2, entry 8) and
dimethyl hydrazine (Table 2, entry 9) reacted sluggishly at
room temperature, but proceeded smoothly in refluxing
methylene chloride with high yields (70-77%). Enamide
ester 7a was processed to pyrimidinone 8b within 1 h in
refluxing methylene chloride (Table 2, entry 3) compared
to 7 h at room temperature (Table 2, entry 2).
Enamide esters 7 were converted into pyrimidinones 8
using dimethylaluminum amides. For example, treatment of
enamide ester 7a with 3 equiv of dimethylaluminum amide7
(3) (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43,
2087. (b) Taber, D. F.; You, K.; Song, Y. J. Org. Chem. 1995, 60, 1093.
(4) Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.; Philips, N.
G.; Xiong, X.; Bower, J. J. Chem. Soc., Perkin Trans. 1 2002, 1663.
(5) Representative experimental procedure for 7a is described in Sup-
porting Information.
(6) (a) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry
1991, 2, 543. (b) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64,
6907.
We also explored the reactivity of an (E)-enamide ester.
Employing the standard reaction conditions led to the
(7) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4171.
1014
Org. Lett., Vol. 6, No. 6, 2004

Scheme 1
Table 2. Cyclization to 3-Substituted Pyrimidinones 8
of deacetylated enamine 9 (Scheme 1). Furthermore, the
reaction with the E/Z mixture of the enamide esters 7a/7a(E)
without purification starting from â-keto ester 6a under the
standard reaction conditions provided the desired product 8a
in good yield (52% for three steps).9b
We further investigated the scope of our pyrimidinone
synthesis methodology by assessing sterically hindered
amines. For instance, when enamide ester 2c was subjected
to the standard conditions with tert-butylamine, there was
no reaction (only starting material without any desired
product formation) at room temperature. In refluxing meth-
ylene chloride for 6 h, there was still no desired product
observed. Instead, oxazinone 10, enediamide 11, and car-
boxylic acid 12 were isolated following aqueous workup and
silica gel chromatography (Scheme 2). Oxazinone 10 was
Scheme 2
also made from enamide ester 2c with 3 equiv of trimethyl-
aluminum (no amine) in refluxing methylene chloride. But,
the resultant oxazinone 10 was unstable and slowly hydro-
lyzed to carboxylic acid 12 at room temperature.
When enamide ester 7d was exposed to the standard
reaction conditions with cyclohexylamine at room temper-
ature, only 19% of the desired compound 8j was isolated
along with oxazinone 13 in 59% yield and enediamide 14
in 5% yield (Scheme 3). Unlike oxazinone 10, oxazinone
13 was found to be chemically stable.
Oxazinone 13 could alternatively be fashioned from
enamide ester 7d and trimethylaluminum (no amine) at room
temperature. Following purification by silica gel column
chromatography, oxazinone 13 was successfully converted
into pyrimidinone 8i from aniline and trimethylaluminum
at room temperature in 82% yield (Scheme 3). Pyrimidinone
8j was obtained from enamide ester 7d with trimethylalu-
minum and cyclohexylamine in refluxing 1,2-dichloroethane
a All reactions were carried out in CH2Cl2 except entry 11, which was
carried out in ClCH2CH2Cl. b Enamine 9 was obtained in <5% yields
(8) All pyrimidinones were characterized by 1H NMR, 13C NMR, IR,
and LCMS.
(9) (a) Representative experimental procedure for pyrimidinones 8a is
described in Supporting Information. (b) Experimental procedure is
described in Supporting Information.
transformation of the (E)-isomer of the enamide ester 7a(E)
into pyrimidinone 8b in 81% yield along with a small amount
Org. Lett., Vol. 6, No. 6, 2004
1015

Scheme 3
Scheme 4
(Table 2, entry 11). Cyclization using a branched amine like
cyclohexylamine could be achieved by raising the reaction
temperature, but in the case of the more hindered tert-
butylamine, cyclization could not be realized.
These results help to rationalize the requirement of 2 equiv
of dimethylaluminum amide for the reaction to run to
completion. Use of 1 equiv forms oxazinone intermediates
from the esters and at least another equivalent forms the
diamides, which undergo subsequent cyclization to pyrimi-
dinones.
Finally, we extended our investigation to the synthesis of
quinazolinones. Applying our standard conditions in reflux-
ing methylene chloride, benzoate 15 was converted to
quinazolinone 16 in 68% yield, accompanied by 11% yield
of benzodiamide 17. The isolated yield of 16 was increased
to 76% by changing the reaction conditions to refluxing 1,2-
dichloroethane. Also, exposure of benzodiamide 17 to 3
equiv of trimethylaluminum (no amine) in refluxing meth-
ylene chloride or 1,2-dichloroethane provided quinazolinone
16 in 80 and 93% yields, respectively.10 Methaqualone 3 was
efficiently prepared from commercially available benzoate
18 with 2-methyl aniline and trimethylaluminum in one step
in 72% yield (Scheme 4).11
Dimethylaluminum amides have been developed for the
preparation of amides from esters.7 This transformation plays
a key role in our synthesis of 3-substituted pyrimidinones
from enamide esters. We have further discovered that
dimethylaluminum amides or trimethylaluminum can also
promote the cyclization of enamide esters to oxazinones,
enediamides to pyrimidinones, and benzodiamides to quinazoli-
nones. These reactions can be conducted in tandem and can
provide access to a broad scope of these heterocyclic systems
in high yields.
Acknowledgment. We thank Priscilla Offen and Bing
Wang for their assistance with characterization of compounds
by NMR.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Reactions were monitored and yields were reported by LCMS.
(11) Trace amount (less than 5%) of 2-acetylamino-N-o-tolyl-benzamide
(not shown) was also isolated.
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Org. Lett., Vol. 6, No. 6, 2004