An efficacious protocol for 4-substituted 3,4-dihydropyrimidinones: Synthesis and calcium channel binding studies

Article abstract of DOI:10.1002/ejoc.200900208

Ethyl 1,2-dihydro-l, 6-dimethyl/6-methyl-2-oxopyrimidine-5carboxylates react with C-nucleophiles as well as the anion of the enantiopure chiral auxiliary (l R, 2 S,5 R) - (-) - methyl (S)p-toluenesulfinate to afford 4-substituted and enantiopure congeners

Full text of DOI:10.1002/ejoc.200900208

FULL PAPER
DOI: 10.1002/ejoc.200900208
An Efficacious Protocol for 4-Substituted 3,4-Dihydropyrimidinones:
Synthesis and Calcium Channel Binding Studies
Kamaljit Singh,*[a] Divya Arora,[a] Danielle Falkowski,[b] Qingxin Liu,[b] and
Robert S. Moreland[b]
Keywords: Multicomponent reactions / Lithiation / Regioselectivity / Chiral auxiliaries / Medicinal chemistry / Vascular
smooth muscles
Ethyl 1,2-dihydro-1,6-dimethyl/6-methyl-2-oxopyrimidine-5-
carboxylates react with C-nucleophiles as well as the anion
of the enantiopure chiral auxiliary (1R,2S,5R)-(–)-methyl (S)-
p-toluenesulfinate to afford 4-substituted and enantiopure
congeners of medicinally potent Biginelli dihydropyrimid-
inones. The calcium channel blocking activity of some of the
compounds was evaluated and compared with nifedipine for
their ability to relax a membrane depolarization-induced
contraction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The scaffold decoration of bioactive molecules represents
one of the most vibrant research areas in organic chemistry
and has a rich history within the realm of fragment-based
drug design. The Biginelli 3,4-dihydropyrimidin-2(1H)-ones
(DHPMs) have been known for more than a century.[1]
These compounds and their appropriately functionalized
derivatives have interesting pharmacological profiles such
as antihypertensive agent 1 and 2,[2] mitotic kinesin inhibi-
tors 3,[3] α1a-adrenergic receptor antagonists 4[4] and hepati-
tis B virus replication inhibitors.[5]
The synthesis and scaffold decoration of the DHPM core
has played an important role in the total synthesis of poly-
cyclic guanidine-containing marine alkaloids such as batzel-
ladine A.[6] These are also common moieties in some of the
most bioactive natural products including dehydrocrambine
A (5) and Sch575948 (6),[7] which are inhibitors of HIV gp-
120-CD4 interaction. As a result of their diverse pharmaco-
logical profile, synthetic investigations on DHPMs have re-
ceived extensive attention by both synthetic organic chem-
ists and medicinal chemists. Synthetic approaches to
DHPMs can be divided into two major strategies.
Whereas multicomponent reactions (multi = three; see
Figure 1) for the construction of Biginelli libraries through
solution- and solid-phase strategies are amenable to a high
throughput or combinatorial format, the post-Biginelli con-
densation scaffold decoration tools are prized for ap-
pending tailor-made fragments at all possible (N-1, C-2, N-
3, C-4, C-5 and C-6) diversity-oriented centres[8] from sim-
ple starting materials. By using the latter tools, we pre-
viously described both racemic and diastereoselective meth-
ods for DHPM synthesis.[9]
[a] Organic Synthesis Laboratory, Department of Applied Chemi-
cal Sciences & Technology, Guru Nanak Dev University,
Amritsar 143005, India
Fax: +91-183-2258853
E-mail: kamaljit19in@yahoo.co.in
[b] Department of Pharmacology and Physiology, Drexel Univer-
sity College of Medicine,
Philadelphia, PA 19102, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900208.
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4-Substituted 3,4-Dihydropyrimidinones
dimethyl-2-oxopyrimidine-5-carboxylate (8a) and ethyl 1,2-
dihydro-6-methyl-2-oxopyrimidine-5-carboxylate (8b), res-
pectively (Scheme 1). Oxidation of 7 to 8 was also success-
fully achieved by us recently by using pyridinium chloro-
chromate (PCC).[15] The addition of stabilized carbanions,
aryllithium reagents and heterocyclic anions to 8a,b fur-
nished exclusively C-4-elaborated DHPM derivatives and
made available those DHPMs that are otherwise not access-
ible through traditional methods employing aldehydes as a
result of their unavailability and operational difficulties
with aliphatic counterparts. Therefore, the reactions in the
present case represent addition of only carbon nucleophiles.
Further, whereas the addition reactions of pyridines with
aryllithium[16] reagents require activation of the pyridine
moiety as a 1-alkoxycarbonyl derivative, the regioselectivity
of the reactions of 1-acylpyridinium salts with Grignard
reagents[17] was additionally influenced by the structures of
the Grignard reagent and the 1-acyl group. However, the
addition reactions of pyrimidin-2(1H)-ones 7 with carbon
nucleophiles proceeded regioselectively without activation
of the pyrimidinone substrates.
Figure 1. Multistep (route a) construction of functionalized 3,4-
dihydropyrimidin-2(1H)-one derivatives and post-Biginelli conden-
sation scaffold decoration pathway (route b).
In a preliminary communication,[10] we recently reported
a nucleophilic addition sequence for the regioselective in-
corporation of substituents at the C-4 position of DHPMs,
and herein we provide a full account of our development
of this process and its further extension to asymmetric syn-
thesis. In addition, we describe highly regioselective ad-
dition reactions of a number of Grignard reagents to syn-
thesize DHPM derivatives, which in fact, are formed with
greater efficiency. Finally, we report on calcium channel
blocking studies of selected compounds to further extend
the existing understanding on structure–activity relation-
ships.
Scheme 1. Synthetic strategy for C-4-elaborated DHPMs 9.
Results and Discussion
Addition of Carbon Nucleophiles to Pyrimidine-2(1H)-ones
8: Formation of C-4-Elaborated DHPM Derivatives
The current understanding of calcium channel modula-
tion (antagonist vs. agonist activity) of DHPM derivatives,
Treatment of the appropriate DHPM derivative 8a or 8b
like 1,4-dihydropyridine drugs such as nifedipine, points to with the intensely yellow dianions of ethyl/methyl acetoace-
the nature (size, polarity, etc.) of the substituent at C-4 as tate,[18] generated by using NaH and nBuLi (2.5 equiv. each)
well as the absolute configuration of ring position 4.[11] Dif- in sequence in anhydrous THF at low temperature (Table 1)
ferent enantiomers of some DHPMs are found to possess under a blanket of nitrogen gas, furnished after extractive
opposing biological effects.[11] Whereas the approach to C- workup 4-substituted 9 and 10, depicting a clean addition
4-elaborated DHPMs by using the three-component Bigi- of the carbanion to ring position 4. No other product aris-
nelli condensation and its variants has thus far been mainly ing from addition at the C-5 ester or any other position was
through the use of aldehydes,[12] the C-4 addition method detected, pointing to the observed high regio- and chemose-
proved to be a highly useful and dependable method with lectivity of the transformation. Likewise, reactions of the
the added advantage that it proceeds with remarkably high anions of acetone,[19] acetonitrile,[19] acetophenone,[19]
regio- as well as chemoselectivity and does not require any methyl phenyl sulfone,[20] thiophene[21] and furan,[22] gener-
chemical activation.
ated by using standard methods, furnished the correspond-
The synthetic route of the current approach starts with ing C-4-elaborated DHPM derivatives in a synthetically
the synthesis of 4-unsubstituted ethyl 1,2,3,4-tetrahydro- useful manner. Only in the reactions of thiophene and furan
1,6-dimethyl-2-oxopyrimidine-5-carboxylate (7a) and ethyl were products of ester displacement detected (1H NMR
1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylate spectroscopy) and only in trace amounts. Similarly, the re-
(7b), for which we have relied on a formyl equivalent, a 1,3- action of phenyllithium[23] proceeded with complete re-
oxazinane derivative,[13] rather than direct use of formalde- gioselectivity to furnish 4-substituted DHPM derivative 9g.
1
hyde. Compounds 7a,b, upon further oxidation with nitric All the products were characterized by IR, H NMR and
acid[14] were readily transformed into ethyl 1,2-dihydro-1,6- 13C NMR spectroscopy, MS and elemental analysis.
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K. Singh, D. Arora, D. Falkowski, Q. Liu, R. S. Moreland
Table 1. Addition of carbon nucleophiles to pyrimidine-2(1H)-ones 8. Formation of 4-substituted DHPM derivatives 9.
FULL PAPER
Entry
Nu substrate
Reaction conditions[a]
Product 9/10, R2
Yield [%][b]
1
2
3
4
5
6
7
8
MeCOCH2COOEt
MeCOCH2COOEt
MeCOCH2COOMe
MeCOMe
MeCN
PhCOMe
–78 °C/NaH/nBuLi/THF
–78 °C/NaH/nBuLi/THF
–78 °C/NaH/nBuLi/THF
–78 °C/LDA/THF
–78 °C/LDA/THF
–78 °C/LDA/THF
–78 °C/nBuLi/THF
–78 °C/nBuLi/THF
–40 °C/nBuLi/THF
–40 °C/nBuLi/THF
–40 °C/nBuLi/THF
–40 °C/nBuLi/THF
–78 °C/THF
9a,[c] CH2COCH2COOEt
10a, CH2COCH2COOEt
10b, CH2COCH2COOMe
9b, CH2COMe
73
57
35
75
50
96
77
52
80
40
81
35
78
10c, CH2CN
9c, CH2COPh
9d, CH2SO2Ph
PhSO2Me
PhSO2Me
10d, CH2SO2Ph
9e, (C4H3S-2yl)
10e, (C4H3S-2yl)
9f, (C4H3O-2yl)
10f, (C4H3O-2yl)
9g, Ph
9
thiophene
10
11
12
13
thiophene[d]
furan
furan[d]
PhLi[e]
[a] Equivalents of base used are mentioned in the experimental section. [b] Isolated yields. [c] Mixture of keto–enol tautomers (1H NMR
spectroscopy). [d] Trace amounts of products of ester displacement[9a] were detected (see the Supporting Information). [e] Freshly prepared
from bromobenzene and lithium.
Addition of Grignard Reagents to Pyrimidine-2(1H)-ones 8:
Formation of DHPM Derivatives Bearing Aliphatic Chains
at C-4
Table 2. Addition of Grignard reagents to pyrimidine-2(1H)-ones
8. Formation of 4-substituted DHPM derivatives 11 and 12.
Whereas the DHPM derivatives listed in Table 1, particu-
larly Entries 6–13, were designed to evaluate calcium chan-
nel blocking properties, the derivatives outlined in En-
tries 1–5 were designed as probes to determine the effect of
aliphatic-functionalized chains at C-4 on the calcium chan- Entry
R2MgX (equiv.)[a]
Product 11/12, R2 Yield [%][b]
nel blocking activity. The importance of appending alkyl
chains at the C-4 position can also be gauged from the fact
that naturally occurring marine alkaloids such as 5 and 6
have long aliphatic chains (C5 and C11, respectively) ap-
pended at C-4. The reactions to append such chains
through the use of aliphatic aldehydes, under acid-catalyzed
conditions of the traditional Biginelli condensation reac-
tion, are prone to side reactions owing to the vulnerability
of the aldehydes.[8b] Herein we describe a useful protocol for
appending long aliphatic chains with the use of the above
methodology by using Grignard reagents[24] as nucleophiles,
and the examples mentioned in Table 2 (Entries 7 and 9)
demonstrate a useful protocol for appending long chains at
C-4, a synthetic sequence that is of considerable importance
in connection with the total synthesis of 5/6 and their ana-
logues.
1
2
3
4
5
6
7
8
MeMgI (2.5)
MeMgI (1.0)
EtMgBr (1.0)
11a, Me
92
51
88
85
79
77
90
85
80
65
45
12a, Me
12b, Et
12c, nPr
12d, nBu
12e, sBu
nPrMgBr (1.0)
nBuMgBr (1.0)
sBuMgBr (1.0)
n-C5H11MgBr (1.0)
n-C10H21MgBr (1.0)
n-C11H23MgBr (1.0)
AllMgBr (1.0)
PhMgBr (2.5)
12f, n-C5H11
12g, n-C10H21
12h, n-C11H23
12i, allyl
9
10
11
12j, Ph
[a] Freshly prepared reagent was used. [b] Isolated yields.
Addition of the Monoanion of (R)-(+)-Methyl p-Tolyl
Sulfoxide to 8b: Synthesis of (R)- and (S)-Enantiomers
Access to diastereomerically/enantiomerically pure
Treatment of 8a,b with freshly prepared Grignard rea- DHPM derivatives by utilizing the tools of asymmetric syn-
gents[24] of aliphatic groups with carbon chain lengths of thesis is of general current interest and has been a formida-
C
1–5, C10 and C11 at –78 °C under an atmosphere of nitro- ble task. The literature reports on the use of resolution
gen furnished the corresponding DHPMs (Table 2, En- methods employing fractional crystallization of the dia-
tries 1–9) in good yields. Similar reaction with allylmagne- stereomeric salts[25] and the use of chiral aldehydes.[26] Chi-
sium bromide furnished C-4 addition product 12i in 65% ral auxiliaries at the N-3 position can be used to resolve
yield after column chromatography. The reaction of phenyl- diastereomers to obtain ultimately enantiomerically en-
magnesium bromide with 8b leading to the exclusive forma- riched DHPM derivatives.[27] Analytical separation through
tion of 12j was very facile, as no side product was detected. the use of designer chiral stationary phases in chiral HPLC
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4-Substituted 3,4-Dihydropyrimidinones
has allowed useful and efficient separation of enantio-
mers.[28] Biocatalytic and chemical catalytic methods em-
ploying proteases,[29] Lewis acids in the presence of chiral
ligands,[30] enantioselective organocatalytic Biginelli reac-
tions[31a,31b,31c,31d] or cinchona alkaloid-catalyzed Mannich
reactions[31e,31f,31g] have also been advantageously em-
ployed.
Chiral sulfoxides have been used in numerous enantiose-
lective transformations of synthetic and biological inter-
est.[32] To further expand the scope of the C-4 elaboration
methodology, we sought to employ chiral sulfoxides for the
enantioselective synthesis of DHPMs.[33] Lithiation of en-
antiomerically pure (R)-(+)-methyl p-tolyl sulfoxide (13)
was achieved with LDA by using a standard method. Ad-
dition of this anion to 8b resulted in the smooth formation
of a diastereomeric mixture comprising 14 {[α]2D5 = +10
(methanol, c = 0.2)} and 15 {[α]2D5 = +185 (methanol, c =
Figure 2. X-ray crystal structure of 14.
heptafluoropropylhydroxymethylene)-(+)camphorate [Eu-
(hfc)3]. Similarly, desulfurization of minor diastereomer 15
with Raney Ni furnished (R)-enantiomer 17 {[α]2D5 = +160
(methanol, c = 0.2)}. (There is considerable variability in
the magnitude of the specific rotation of the minor enantio-
mer, which can presumably be attributed to purity.) The
(4S) configuration of the major enantiomer was also cor-
roborated by CD spectroscopic analysis (Figure 3) of 16
with that of a 4-methyl DHPM of known absolute configu-
ration.[34]
1
0.2)} in a 80:20 ratio determined from the H NMR spec-
trum of the crude reaction mixture (Scheme 2). Major dia-
stereomer 14 separated out from a hot methanol solution,
and it was recrystallized to obtain an analytically pure sam-
ple. The remaining mixture was resolved by column
chromatography to obtain an additional amount of 14 and
minor diastereomer 15.
Scheme 2. Addition of the monoanion of (R)-(+)-methyl p-tolyl
sulfoxide to 8b.
The assignment of the absolute configuration at the C-4
position of a series of DHPM derivatives was performed on
the basis of the combination of enantioselective HPLC and
circular dichroism (CD) spectroscopy,[28b] through corre-
lation with DHPM derivatives of known configuration. A
correlation of specific optical rotation was also used for pre-
dicting the configuration at C-4 bearing aryl substituents at
C-4.[30a] Because the chiral auxiliary used in this reaction
has (R)-configuration at the sulfur atom, diastereomers 14
Figure 3. Experimental CD spectra of 16 and 17.
Further, in view of the exceptional stabilization influence
of the sulfoxide sulfur to the α-carbanions, synthesis of a
number of derivatives of 14 could be envisaged.
Biological Results and Discussion
Some of the newly synthesized compounds were screened
and 15 were assigned the (R) and (S) configurations, respec- for their calcium channel blocking activity on the basis of
tively, at C-4. The assignment of absolute configuration of their ability to relax a membrane-depolarization-induced
major diastereomer 14 was unambiguously assigned from contraction of vascular smooth muscle. Swine carotid arter-
the single-crystal X-ray structure determination (Figure 2). ies were obtained from a local slaughterhouse and trans-
Desulfurization of major diastereomer 14 with Raney Ni ported to the laboratory in an ice-cold physiological salt
in methanol led to the corresponding optically active (S)- solution (PSS) buffered (pH 7.4) with 3-[N-morpholino]-
enantiomer 16 {[α]2D5 = –205.00 (methanol, c = 0.2)}. The propane sulfonic acid (MOPS). The PSS contained NaCl
1
purity of 16 was also confirmed by H NMR spectroscopy (140 m), KCl (4.7 m), MgSO4 (1.2 m), CaCl2 (1.6 m),
with the addition of the chiral shift reagent europium tris(3- Na2HPO4 (1.2 m), MOPS, -glucose (5 m) and diso-
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K. Singh, D. Arora, D. Falkowski, Q. Liu, R. S. Moreland
FULL PAPER
dium ethylenediaminetetraacetate (EDTA; 0.02 m). Arter- substituents with the possibility of further synthetic trans-
ies were cleaned of connective tissue, and then dissected free formations on the C-4 substituents. Also, this approach was
of both intima and adventitia leaving a thin medial layer extended to synthesize both enantiomers of DHPM
for experimentation. Intact medial strips of swine carotid through the use of optically pure sulfoxide carbanions. Fi-
artery (7ϫ0.7 mm) were suspended between a Grass FT.03 nally, DHPMs with variation in the substituents at C-4 were
force transducer and a stationary clip in water jacketed or- tested for their ability to relax a membrane-depolarization-
gan baths. The strips were equilibrated in PSS at 37 °C, induced contraction, which is almost exclusively dependent
pH 7.4 and bubbled with 100% O2 for 90–120 min. A pass- on the influx of extracellular calcium. Long aliphatic chains
ive force of ca. 2 g was applied to all tissues. This passive appended at C-4 do not seem to be particularly useful for
force sets the muscle at a length that approximates Lo, the calcium channel blocking activity in so far as their compari-
length at which maximal active force is generated. During son with 4-aryl derivatives of DHPMs is concerned.
the equilibration period, tissues were maximally contracted
with 110 m KCl (equimolar substitution for NaCl) several
times until similar levels of force were attained.
Experimental Section
The equilibrated vascular strips were contracted with
General: Freshly prepared n-butyllithium (2.0  in hexanes), phen-
110 m KCl containing PSS, allowed to achieve a stable
yllithium, LDA and Grignard reagents were employed. Tetra-
level of force and then subjected to the cumulative addition
hydrofuran and diethyl ether were dried (sodium benzophenone ke-
tyl) under an atmosphere of nitrogen and transferred with hypoder-
of calcium channel blocker (1 µ–30 m) or DMSO as a
vehicle control. Data are presented (Figure 4) as a percent
of the initial maximal response to 110 m KCl at each dose
of compound.
mic glass syringes. All liquid reagents were dried/purified following
recommended drying agents and/or distilled from 4 Å molecular
sieves. Reactions were run under an atmosphere of dry nitrogen in
a single-necked round-bottomed flask, sealed with a rubber septum
(Aldrich). The reagents were introduced through hypodermic syrin-
ges and/or cannula. The low temperature was achieved by using a
slush of liquid nitrogen with the appropriate solvent or alternatively
by using dry ice. Precoated aluminum TLC plates (60 F254, 0.2 mm)
were used for TLC monitoring of the reactions. The compounds
were purified by flash chromatography with the use of silica gel
(60–120 mesh) and mixtures of ethyl acetate/hexane as eluent.
Melting points were determined in open capillaries and are uncor-
rected. 1H and 13C NMR spectra were recorded with a JEOL
FTNMR AL-300 MHz spectrometer by using TMS as an internal
standard. The mass spectra were recorded with an Esquire 3000–
00037 mass spectrometer. Elemental analysis was performed with
a Thermo Flash EA 112. Analyses indicated by the symbols of
the elements were within Ϯ0.4% of the theoretical values. Optical
rotations were recorded with an Atago (AP-100) digital polarimeter
at 25 °C. The CD spectra were recorded with an Applied Pho-
tophysics Chirascan circular dichroism spectrometer with stop flow.
Figure 4. Medial strips from the swine carotid artery were contrac-
ted with 110 m KCl-PSS and then subjected to the cumulative
addition of calcium channel blocker to determine their potential
for relaxation. Nifedipine and 17 novel calcium channel blockers
were tested.
Typical Procedure for the Synthesis of 8a,b
Method A: To a stirred aqueous solution of nitric acid (40% v/v,
6.5 mL) maintained at 0 °C was added powdered DHPM 7a or 7b
(4.0 mmol) portionwise over 5–10 min. The reaction was stirred for
an additional 5 min at the same temperature, after which the mix-
ture was warmed to room temperature over 30 min. The mixture
was poured onto crushed ice (10 g) and neutralized to pH 7.0 by
using solid potassium carbonate. The resulting aqueous solution
was subsequently extracted with dichloromethane (3ϫ30 mL), the
organic layer was dried with anhydrous sodium sulfate, and the
solvents were evaporated under reduced pressure. The residual
product was purified by recrystallization from ethanol to obtain 8.
The calcium channel blockers were compared against ni-
fedipine for their ability to relax a membrane-depolariza-
tion-induced contraction, which is almost exclusively de-
pendent on the influx of extracellular calcium.[35] The novel
compounds and nifedipine were tested across a concentra-
tion range of 1 µ to 30 m. Nifedipine completely relaxed
the KCl-induced contraction with an IC50 value in the
10 µ range. In contrast, these compounds maximally re-
laxed the KCl-induced contractions by only 40% with IC50
values ranging from 100–300 µ (Figure 4).
Method B: A solution of DHPM 7 (1.97 mmol) in dichloromethane
was stirred with PCC (5.90 mmol) (Aldrich) until the reaction was
complete (16–25 h, TLC). The reaction mixture was filtered
through Celite to remove any suspension, and the residue obtained
after removal of the solvent was purified by flash chromatography
to obtain corresponding pyrimidinone 8.
Conclusions
In summary, inspired by the biological potential of a
number of dihydropyrimidinone-based natural products, we
developed a method for the highly regio- and chemoselec-
tive synthesis of C-4-elaborated DHPMs. This approach al-
Ethyl 1,2-Dihydro-1,6-dimethyl-2-oxopyrimidine-5-carboxylate (8a):
Cream-coloured solid. Rf = 0.5 (70% ethyl acetate/hexane). Yield:
lows incorporation of aliphatic, aromatic and heterocyclic 80%. M.p. 212 °C (dichloromethane). IR (KBr): ν = 1680,
˜
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4-Substituted 3,4-Dihydropyrimidinones
1690 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.37 (t, J =
7.2 Hz, 3 H), 2.71 (s, 3 H), 3.61 (s, 3 H), 4.33 (q, J = 7.2 Hz, 2 H),
8.39 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.2,
26.1, 39.1, 61.2, 108.1, 152.6, 155.0, 163.1, 176.6 ppm. MS: m/z =
temperature and stirring was continued to complete the reaction
(TLC), after which a saturated aqueous solution of NH4Cl was
introduced. The reaction was extracted with ethyl acetate
(3ϫ25 mL) and treated in sequence with brine. The extracts were
219 [M + 23]. C9H12N2O3 (196.21): calcd. C 55.10, H 6.12, N 14.28; dried with anhydrous Na2SO4, and the mixture was concentrated
found C 54.75, H 6.01, N 14.14.
under reduced pressure. Diastereomers 14 and 15 were resolved by
crystallization (methanol) of the column chromatographed mixture.
Ethyl 1,2-Dihydro-6-methyl-2-oxopyrimidine-5-carboxylate (8b):
Cream-coloured solid. Rf = 0.5 (80% ethyl acetate/hexane). Yield:
(4R,SR)-Ethyl 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-(p-tolylsulfinyl-
methyl)pyrimidine-5-carboxylate (14): Major diastereomer, white
solid. Rf = 0.5 (45% ethyl acetate/hexane). Yield: 70%. M.p. 216–
1
75%. M.p. 210 °C (methanol). IR (KBr): ν = 1675, 1680 cm–1. H
˜
NMR (300 MHz, [D6]DMSO, 25 °C): δ = 1.23 (t, J = 7.2 Hz, 3 H),
2.49 (s, 3 H), 4.18 (q, J = 7.2 Hz, 2 H), 8.69 (s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3/[D6]DMSO, 25 °C): δ = 14.0, 20.8, 60.4,
106.2, 152.6, 155.5, 163.5, 165.0 ppm. MS: m/z = 205 [M + 23].
C8H10N2O3 (182.18): calcd. C 52.74, H 5.53, N 15.38; found C
52.45, H 5.42, N 15.14.
219 °C (methanol). [α]2D5 = +10 (methanol, c = 0.2). IR (KBr): ν =
˜
1
1676, 1706 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.29 (t,
J = 7.2 Hz, 3 H), 2.25 (s, 3 H), 2.41 (s, 3 H), 2.87–3.18 (AB part
of ABX, JAX = 13.2 Hz, JBX = 3.6 Hz, 2 H), 4.14–4.24 (m, 2 H),
5.03 (dd, JAX+BX = 9.0 Hz, 1 H), 6.18 (s, NH, exchanged with
D2O), 7.29–7.54 (m, 4 H), 7.67 (br., 1 H, NH, exchanged with D2O)
ppm. 13C NMR (75 MHz, CDCl3/[D6]DMSO, 25 °C): δ = 14.1,
18.5, 21.2, 49.2, 59.9, 62.7, 97.8, 123.7, 129.9, 140.6, 141.6, 149.1,
152.7, 165.1 ppm. MS: m/z = 359 [M + 23]. C16H20N2O4S (336.41):
calcd. C 57.14, H 5.95, N 8.33, S 9.52; found C 57.15, H 6.00, N
8.50, S 9.38.
Synthesis of 9a: A solution of ethyl acetoacetate (6.37 mmol) in
anhydrous THF (10 mL) under an atmosphere of dry nitrogen was
cooled to 0 °C and treated with NaH (6.37 mmol). After the cess-
ation of hydrogen gas, freshly prepared nBuLi (2.0  in hexanes,
6.37 mmol) was introduced through a hypodermic syringe at the
same temperature, and the reaction was then stirred at ambient
temperature for 30 min, whereupon an intense yellow-coloured
anion formed. The dianion suspension was cooled to –78 °C and
quenched by the addition of 8a (2.5 mmol) dissolved in THF
(20 mL). The progress of the reaction was monitored by TLC. After
completion of the reaction, it was quenched with cold saturated
aqueous solution of NH4Cl at low temperature. The organic phase
was washed with brine and extracted with ethyl acetate. The extract
was dried with anhydrous sodium sulfate, and the mixture was con-
centrated under reduced pressure. Corresponding product 9a was
isolated in 73% yield after column chromatography (silica gel; ethyl
acetate/hexane).
(4S,SR)-Ethyl 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-(p-tolylsulfinyl-
methyl)pyrimidine-5-carboxylate (15): Minor diastereomer, white
solid. Rf = 0.5 (45% ethyl acetate/hexane). Yield: 20%. M.p. 180–
181 °C (methanol). [α]2D5 = +185 (methanol, c = 0.2). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.07 (t, J = 7.2 Hz, 3 H), 2.27 (s, 3
H), 2.43 (s, 3 H), 2.71–3.34 (AB part of ABX, JAX = 13.2 Hz, JBX
= 3.6 Hz, 2 H), 3.88–4.03 (m, 2 H), 4.84 (dd, JAX+BX = 9.6 Hz, 1
H), 6.27 (s, NH, exchanged with D2O), 7.35–7.53 (m, 4 H), 7.67
(br., 1 H, NH, exchanged with D2O) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 14.2, 18.6, 21.3, 47.5, 59.8, 97.9, 124.1, 130.0,
139.2, 141.5, 149.5, 153.4, 164.7 ppm. MS: m/z = 359 [M + 23].
C16H20N2O4S (336.41): calcd. C 57.14, H 5.95, N 8.33, S 9.52;
found C 57.20, H 6.92, N 8.28, S 9.56.
Formation of DHPM Derivatives 9 and 10: For the synthesis of 9
and 10 (Table 1), appropriate 8a and 8b (Table 1) was similarly
treated with anions of various carbon acids [read: carbon acid
(equivalents of base used) product]: ethyl acetoacetate (2.0), 10a;
methyl acetoacetate (2.0), 10b; acetone (2.5), 9b; acetonitrile (1.5),
10c; acetophenone (2.5), 9c; methyl phenyl sulfone (2.5), 9d; methyl
phenyl sulfone (2.0), 10d; thiophene (2.5), 9e; thiophene (2.5), 10e;
furan (2.5), 9f; furan (2.5), 10f; PhLi (2.5 mmol), 9g.
Synthesis of Enantiomeric DHPMs 16 and 17 by the Reductive De-
sulfurization of 14 and 15: A solution of compound 14 or 15
(0.14 mmol) in dry methanol (50 mL) was treated with an excess
amount of Raney Ni (2 g) at 0 °C. Whereas complete desulfuriza-
tion of 14 required stirring at room temperature followed by over-
night reflux, the desulfurization of 15 was complete at 0 °C. After
completion (TLC), reaction mixtures were filtered through Celite,
and the solvent was removed under reduced pressure. The crude
product was purified by crystallization in methanol.
Formation of DHPM Derivatives 11 and 12 – Typical Procedure for
the Synthesis of 11a: Grignard reagent[24] (6.37 mmol) prepared by
using activated magnesium metal (6.37 mmol) and iodomethane
(6.37 mmol) in anhydrous ether was transferred to a solution of
8a (2.55 mmol) in anhydrous THF maintained at –78 °C under a
nitrogen atmosphere. Extractive workup from ethyl acetate and col-
umn chromatography furnished product 11a in 92% yield. Similar
reaction of 8 with other Grignard reagents (Table 2) furnished cor-
responding products 12a–j.
(4S)-Ethyl 1,2,3,4-Tetrahydro-4,6-dimethyl-2-oxopyrimidine-5-car-
boxylate (16): White solid. Rf = 0.5 (60% ethyl acetate/hexane).
Yield: 51%. M.p. 206–210 °C (methanol). [α]2D5 = –205.00 (meth-
anol, c = 0.2).1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.25–1.31
(m, 6 H), 2.28 (s, 3 H), 4.15–4.23 (m, 2 H), 4.41–4.44 (m, 1 H),
5.25 (br., 1 H, NH, exchanged with D2O), 7.14 (br., 1 H, NH,
exchanged with D2O) ppm. 13C NMR (75 MHz, CDCl3/[D6]-
DMSO, 25 °C): δ = 13.7, 17.6, 22.9, 46.4, 59.0, 101.2, 146.5, 153.7,
165.4 ppm. MS: m/z = 221 [M + 23]. C9H14N2O3 (198.22): calcd.
C 54.53, H 7.12, N 14.13; found C 54.65, H 7.14, N 14.20.
Synthesis of DHPM Diastereomers 14 and 15: (R)-(+)-Methyl p-
tolyl sulfoxide was prepared from (1R,2S,5R)-(–)-menthyl (S)-p-tol-
uenesulfinate following the procedure of Solladie.[33] To a solution
of diisopropylamine (8.35 mmol) in THF (2 mL) was added nBuLi
(8.25 mmol) dropwise at –78 °C under a nitrogen atmosphere. The
solution was warmed to 0 °C and stirred for an additional 10 min.
The solution was cooled to –78 °C and precooled THF (25 mL at
–78 °C) was added with stirring. (R)-(+)-Methyl p-tolyl sulfoxide
(5.50 mmol) dissolved in THF (10 mL) was then introduced by hy-
podermic syringe, and the solution was stirred for an additional
10 min to ensure complete deprotonation to the monoanion. A
solution of 8b (2.75 mmol) dissolved in THF (20 mL) was intro-
duced with the help of cannula. The reaction was warmed to room
(4R)-Ethyl 1,2,3,4-Tetrahydro-4,6-dimethyl-2-oxopyrimidine-5-car-
boxylate (17): White solid. Rf = 0.5 (60% ethyl acetate/hexane).
Yield: 45%. M.p. 195–198 °C (methanol). [α]2D5 = +160 (methanol,
c = 0.2).1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.25–1.31 (m, 6
H), 2.28 (s, 3 H), 4.15–4.23 (m, 2 H), 4.40–4.44 (m, 1 H), 5.08 (br.,
1 H, NH, exchanged with D2O), 6.57 (br., 1 H, NH, exchanged
with D2O) ppm. 13C NMR (75 MHz, CDCl3 25 °C): δ = 14.3, 18.5,
23.6, 47.5, 59.8, 102.6, 146.1, 154.2, 165.7 ppm. MS: m/z = 221 [M
Eur. J. Org. Chem. 2009, 3258–3264
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3263

K. Singh, D. Arora, D. Falkowski, Q. Liu, R. S. Moreland
FULL PAPER
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Received: March 1, 2009
Published Online: May 15, 2009
3264
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Eur. J. Org. Chem. 2009, 3258–3264