A highly regio- and chemoselective addition of carbon nucleophiles to pyrimidinones. A new route to C4 elaborated Biginelli compounds

Article abstract of DOI:10.1016/j.tetlet.2006.12.111

Ethyl 6-methyl-pyrimidine-2-one-5-carboxylates react with C-nucleophiles in a diversity oriented synthetic sequence to afford C4 substituted congeners of medicinally potent Biginelli dihydropyrimidinones, in a highly regioselective manner.

Full text of DOI:10.1016/j.tetlet.2006.12.111

Tetrahedron Letters 48 (2007) 1349–1352
A highly regio- and chemoselective addition of carbon nucleophiles
to pyrimidinones. A new route to C4 elaborated Biginelli compounds
*
Kamaljit Singh, Divya Arora and Sukhdeep Singh
Organic Synthesis Laboratory, Department of Applied Chemical Sciences and Technology,
Guru Nanak Dev University, Amritsar 143 005, India
Received 21 November 2006; revised 9 December 2006; accepted 19 December 2006
Available online 23 December 2006
Abstract—Ethyl 6-methyl-pyrimidine-2-one-5-carboxylates react with C-nucleophiles in a diversity oriented synthetic sequence to
afford C4 substituted congeners of medicinally potent Biginelli dihydropyrimidinones, in a highly regioselective manner.
Ó 2006 Elsevier Ltd. All rights reserved.
The medicinal potential of ethyl 4-substituted-6-methyl-
,4-dihydropyrimidine-2-one-5-carboxylates (Biginelli
The synthetic route starts with readily available (80–85%
yield) ethyl 6-methyl-3,4-dihydropyrimidin-2-one-5-
7
3
DHPMs) continues to attract increasing interest from
the synthetic chemistry community. This is due, in no
carboxylates 1a and 1b, which were transformed to the
corresponding 6-methyl-pyrimidine-2-one-5-carboxyl-
1
small part, to the crucial roles played by DHPMs in bio-
logical processes and therapeutic applications. Exten-
ates 2 (2a: 80%, 2b: 75% yield) via a Kappe type dehy-
2
8
drogenation (40% HNO , 0 °C to rt, 30 min) of the
3
sive investigations of structure–activity relationships
have described opposite activities (agonistic or antago-
nistic) for enantiomers as a function of the substituent
and its absolute stereochemistry at the 4-position of
precursor 3,4-dihydropyrimidinone (Scheme 1).
The reaction of 2a and 2b with various nucleophiles such
as stabilized carbanions of carbon acids, Grignard
reagents, aryllithiums and heterocyclic anions proceeded
smoothly and exclusively at the C4 position. The ap-
proach is amenable to append a variety of substituents,
derived from appropriate nucleophiles, at the 4-position
of C4 unsubstituted pyrimidine-2-ones 2, in a syntheti-
cally useful manner. Further, in contrast to similar reac-
3
the DHPM. Molecular modifications at C4 of the
DHPM core thus hold potential for significant improve-
ment of the understanding of their structure–activity
relationship and their efficacy as drug candidates.
Recently, using chiral catalysts, enantiomerically pure
4
DHPMs have been obtained. In general, DHPMs are
9
readily available through the Biginelli three-component
synthesis, or related methods, the aldehyde component
tions with activated N-alkoxycarbonylpyridinium salts,
where introduction of carbon nucleophiles is strongly
dependent upon the choice of reagents and/or reaction
conditions, similar activation as the corresponding
N-acyl C4 unsubstituted pyrimidone derivatives was
not required, to yield the corresponding 3,4-dihydro-
pyrimidine-2-ones 3 and 4.
5
of which delivers the C4 substituent. However, these
methods suffer from the disadvantage of inaccessibility
of functionalized aldehydes and thus lack experimental
and conceptual simplicity to append tailored substitu-
ents at C4. Apart from the traditional Biginelli three-
6
component condensation and its variants, no other gen-
eral methodology has been reported for the elaboration
of C4 of DHPMs, a key feature responsible, in part, for
the biological activity of this system.
H
H
EtOOC
Me
EtOOC
Me
NH
N
Nitric acid (40%)
0 C- r.t.
o
Keywords: Lithiation; Biginelli compounds; Carbon nucleophiles;
Regioselective addition.
N
R
O
N
R
2
O
*
Corresponding author. Tel.: +91 183 2258853; PABX: +91 183
258802–09x3508; fax: +91 183 2258819 20; e-mail: kamaljit19in@
1
: a R = Me; b R = H
2
yahoo.co.in
Scheme 1. Synthesis of pyrimidine-2-ones 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.111

1350
K. Singh et al. / Tetrahedron Letters 48 (2007) 1349–1352
Table 1. Addition of C-nucleophiles (Nu) to pyrimidine-2-ones 2. Synthesis of C4 alkyl substituted Biginelli DHPMs 3
H
Nu
(i) C-nucleophile (Nu)/
EtOOC
Me
anhydrous THF/N2
EtOOC
Me
N
NH
atmosphere/low temp.
N
R
O
N
R
O
(
ii) Satd. NH Cl solution
4
3
2: a R = Me; b R = H
a
Entry
1
Nu
Product
3
R
Reaction conditions
Yield (%)
Mp (°C)
O
O
O
O
O
O
O
O
O
b
3a
3b
Me
H
À78 °C/NaH/n-BuLi (2.5 equiv)/THF
À78 °C/NaH/n-BuLi (2.0 equiv)/THF
73
57
131
135
EtO
CH Li
NH
2
Na
N
R
O
O
O
O
O
O
2
3
3c
H
À78 °C/NaH/n-BuLi (2.0 equiv)/THF
35
75
120
135
MeO
CH Li
NH
2
Na
N
R
O
O
O
O
O
H3C CH Li
3d
Me
À78 °C/LDA (2.5 equiv)/THF
NH
2
N
R
O
CN
O
O
NH
O
4
5
3e
3f
H
À78 °C/LDA (1.5 equiv)/THF
À78 °C/LDA (2.5 equiv)/THF
50
96
202
135
N CCH Li
2
N
R
O
O
O
O
Me
CH Li
NH
O
2
N
R
O O
S
O
O
O
O
S
6
7
3g
h
Me
H
À78 °C/n-BuLi (2.5 equiv)/THF
À78 °C/n-BuLi (2.0 equiv)/THF
77
52
168
145
CH Li
NH
2
3
N
R
O
O
O
NH
3i
3j
Me
H
À78 °C/(2.5 equiv)/THF
À78 °C/(1.0 equiv)/THF
92
51
138
180
IMgCH3
N
R
O
a
Isolated purified yield.
Mixture of keto–enol tautomers.
b
The results of the reactions of aliphatic C-nucleophiles
with 2 are listed in Table 1. As illustrated, the reactions
exhibited an impressive degree of generality to give the
73% yield. A similar reaction of 2b furnished the corre-
sponding product 3b. Likewise, reactions of the anions
1
1
12
12
of methyl acetoacetate, acetone, acetonitrile, aceto-
1
0
12
13
corresponding C4 elaborated DHPMs.
phenone and methyl phenyl sulfone furnished the
corresponding C-4 functionalized compounds 3, which
are difficult to synthesize using traditional Biginelli con-
densation requiring appropriate aliphatic aldehydes.
Use of the Grignard reagent (MeMgI) furnished the cor-
responding DHPMs 3i and 3j in 92% and 51% yields,
respectively.
Treatment of 2a with the intense yellow coloured dian-
1
1
ion of ethyl acetoacetate, generated using NaH/n-BuLi
2.5 equiv each), in sequence, in anhydrous THF at
(
À78 °C, under a blanket of nitrogen gas, after extractive
workup and chromatography furnished product 3a in

K. Singh et al. / Tetrahedron Letters 48 (2007) 1349–1352
1351
Table 2. Addition of C-nucleophiles (Nu) to pyrimidine-2-ones 2. Synthesis of C4 aryl/heterocyclic substituted Biginelli DHPMs 4
H
Ar/Het
NH
(i) C-nucleophile (Ar/Het)/
EtOOC
Me
EtOOC
Me
anhydrous THF/N2
N
atmosphere/low temp.
N
O
N
R
O
(ii) Satd. NH Cl solution
4
R
2: a R = Me; b R = H
4
a
Entry
1
Nu
Product
4
R
H
Reaction conditions
Yield (%)
Mp (°C)
O
O
MgBr
4a
À78 °C/(2.5 equiv)/THF
45
207
NH
N
R
O
O
O
Li
2
4b
Me
À78 °C/(2.5 equiv)/THF
78
180
NH
N
R
O
S
O
O
b
S
3
NH
4c
4
Me
H
À40 °C/n-BuLi (2.5 equiv)/THF
80
40
158
215
Li
d
N
R
O
O
O
O
b
O
4
NH
4e
4
Me
H
À40 °C/n-BuLi (2.5 equiv)/THF
81
35
162
199
Li
f
N
R
O
a
Isolated purified yield.
Products of ester displacements were also detected ( H NMR) albeit in trace amounts.
b
1
The reactions of C-nucleophiles derived from aromatic
and heterocyclic substrates are reported in Table 2.
The Grignard reagents, phenyl magnesium bromide
and phenyllithium, both demonstrated similar patterns
of reactivity at C4 and furnished exclusively 4-phenyl
DHPM derivatives 4a and 4b in fair to good yields.
The reaction of phenyllithium was cleaner, in so far as
isolation of the product was concerned. Similarly, carba-
and 2) and 4-heterocyclic (Table 2, entries 3 and 4),
substituted DHPMs. Further investigations in procuring
enantiomerically pure DHPMs using this methodology
are underway.
Acknowledgements
1
4
15
nions derived from thiophene and furan were also
reacted with 2a and 2b at À40 °C, to give the corre-
sponding DHPMs 4c–f. All the products were character-
Financial support from CSIR (01(1960)/04/EMR-II)
and UGC (31-53/2005/SR), New Delhi, is gratefully
acknowledged. D.A. and S.S. thank CSIR and UGC,
New Delhi, for Research Fellowships.
1
13
ized by IR, H NMR, C NMR, MS and elemental
analysis.
1
6
In summary, we have demonstrated that C4 unsubsti-
tuted pyrimidone derivatives undergo regio- and chemo-
selective additions at C4, exclusively, with a variety of
nucleophiles to furnish C4 elaborated DHPMs in good
yields. This methodology permits a variety of nucleo-
philic functionalities to be introduced at C4 of unsubsti-
tuted pyrimidones (Table 1, entries 1–7), to give the
corresponding DHPMs, which can serve as valuable
templates for further synthetic transformations at C4.
Also, the method allows for the preparation of the
important class of 4-aryl substituted (Table 2, entries 1
References and notes
1
2
. Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1–116.
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(
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263.
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K. Singh et al. / Tetrahedron Letters 48 (2007) 1349–1352
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem.
995, 38, 119–129.
. (a) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005,
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was then introduced via a glass syringe. The solution was
stirred for an additional 10 min at the same temperature
before use.
1
4
1
13. Generated using n-BuLi (À78 °C).
14. Jones, E.; Moodie, I. M. Org. Synth. Coll. Vol. 1988, 6,
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. (a) Kappe, C. O. Tetrahedron 1993, 49, 6937–6963; (b)
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15. Perri, S. T.; Rice, P.; Moore, H. W. Org. Synth. Coll. Vol.
1993, 8, 179–181.
16. Selected data. Ethyl 1,6-dimethyl-2-oxo-4-(ethyl-3-oxobuty-
rate-4-yl)-3,4-dihydropyrimidine-5-carboxylate (3a): Creamy
70, 6114–6117; (b) Singh, K.; Singh, S. Tetrahedron Lett.
2006, 47, 8143–8146.
solid; R
f
: 0.5 (50% ethyl acetate/hexane); yield: 73%; mp
7
8
9
. Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron
999, 55, 12873–12880.
. Puchala, A.; Belaj, F.; Bergman, J.; Kappe, C. O. J.
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131 °C (dichloromethane); IR (KBr): mmax 1750, 1709,
À1
1
1
1649 cm ; H (300 MHz, CDCl , 25 °C): d 1.26 (m, 6H),
3
2.29 (s, 3H), 2.42–2.71 (m, 2H), 2.90 (s, 3H), 3.45 (s, 1.75H),
4.18 (m, 4H), 4.65 (m, 0.22H), 4.78 (m, 0.78H), 7.96 (br,
. Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47,
0.22H, NH, exchanged with D
2
O), 8.02 (br, 0.78H, NH,
13
4315–4319.
exchanged with D O), 12.04 (s, 0.25 H); C NMR
2
1
0. Contrary to our findings, C4 unsubstituted dihydropyri-
midinones lacking a C5 ester substituent have shown
variation in reactivity depending upon the reagent used.
Whereas only MeLi could be added at C-4, RMgX
invariably reacted at C-6, see: Kashima, C.; Katoh, A.;
Yokota, Y.; Omote, Y. J. Chem. Soc., Perkin Trans. 1
(75 MHz, CDCl , 25 °C): d 14.0, 14.3, 18.4, 34.0, 39.3,
3
47.5, 49.8, 54.1, 56.5, 60.1, 61.5, 91.7, 100.0, 148.1, 153.1,
165.2, 166.8, 172.2, 174.1 and 200.2. Anal required for
C H N O : C, 55.21; H, 6.74; N, 8.58; found: C, 55.60; H,
1
5
22
2
6
6.96; N, 8.16; MS: m/z 349 (M+23).
Ethyl 1,6-dimethyl-2-oxo-4-(2-oxopropyl)-3,4-dihydropy-
1
981, 489–492.
1. Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96,
082–1087.
2. To a solution of diisopropylamine (0.58 mL, 0.42 g,
.42 mmol) in THF (2 mL), n-BuLi (1.85 mL, 2.2 M)
rimidine-5-carboxylate (3d): White solid; R
f
: 0.5 (60% ethyl
1
1
acetate/hexane); yield: 75%; mp 135 °C (dichloromethane);
À1
1
1
IR (KBr): mmax (KBr): 1650, 1710, 1720 cm ; H NMR
(300 MHz, CDCl
3
, 25 °C): d 1.27 (t, 3H, J 7.2 Hz), 2.17 (s,
4
3H), 2.28 (s, 3H), 2.72 (ABX system, 2H, J 16.2 Hz, J
6.9 Hz, J 3.9 Hz), 2.97 (s, 3H), 4.17 (q, 2H, J 7.2 Hz), 4.75
(dd, 1H, J 6.6 Hz, J 4.2 Hz), 7.50 (br, 1H, NH, exchanged
was added dropwise at À78 °C, under a nitrogen atmo-
sphere. The solution was allowed to warm to 0 °C and
stirred for an additional 10 min. The solution was cooled
to À78 °C and pre-cooled THF (25 mL at À78 °C) was
added with stirring. The appropriate carbon acid, for
example, acetone, acetonitrile, acetophenone (4.42 mmol),
1
3
2 3
with D O); C NMR (75 MHz, CDCl , 25 °C): d 14.2, 18.3,
30.7, 34.0, 48.2, 54.3, 60.1, 100.3, 147.9, 153.3, 165.3 and
206.0. Anal required for C H N O : C, 56.68; H, 7.13; N,
1
2
18
2
4
11.02; found: C, 56.40; H, 6.96; N, 10.86; MS: 277 (M+23).