Efficient assembly of 2,5,6-substituted pyrimidines via MgI 2-Mediated morita-baylis-hillman reaction

Article abstract of DOI:10.1021/cc100001e

A mild and efficient protocol for the synthesis of a 2,6-disubstituted pyrimidine-5-carboxylate library via a Morita-Baylis-Hillman (MBH) adduct is described. Herein, the three step methodology involves the use of substituted -iodomethylene β-keto ester intermediates obtained after oxidation of the MBH adducts, which are condensed with various types of amidine or guanidine derivatives, to generate the 2, 6-disubstituted pyrimidines-5-carboxylate libraries.

Full text of DOI:10.1021/cc100001e

J. Comb. Chem. 2010, 12, 327–331
327
Efficient Assembly of 2,5,6-Substituted Pyrimidines via MgI2-Mediated
Morita-Baylis-Hillman Reaction
Vasudha Sharma† and Mark L. McLaughlin*,†,‡
Drug DiscoVery Department, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., MRC 4E,
Tampa, FL 33612, and Department of Chemistry, UniVersity of South Florida, 4202 E. Fowler AVenue,
CHE205, Tampa, FL 33620
ReceiVed January 9, 2010
A mild and efficient protocol for the synthesis of a 2,6-disubstituted pyrimidine-5-carboxylate library via a
Morita-Baylis-Hillman (MBH) adduct is described. Herein, the three step methodology involves the use
of substituted R-iodomethylene ꢀ-keto ester intermediates obtained after oxidation of the MBH adducts,
which are condensed with various types of amidine or guanidine derivatives, to generate the 2, 6-disubstituted
pyrimidines-5-carboxylate libraries.
Introduction
Structurally diverse small molecules serve as selective
agents to dissect complex cellular signaling pathways dys-
regulated in disease.1,2 With the rapid development of high
throughput screening programs to identify potential drug
candidates, the current challenge is to feed and sustain the
screening efforts with diverse small molecule scaffolds. This
process largely depends on new leads discovered via a
rationally designed synthesis or screening of libraries gener-
ated via combinatorial synthesis. N-containing heterocycles
are commonly occurring structural motifs in natural products,
as well as pharmacophores in top-selling drugs.3,4 Not
surprisingly, they continue to be the inspiration for core
scaffolds for library synthesis in modern day drug discovery.
Pyrimidines and their derivatives are valued for their
pharmacological properties, such as anti-inflammatory prop-
erties,5 antiallergic properties,5 antidepressant properties,6 Ca-
Figure 1. Pyrimidine-5-carboxylates and carboxamides with known
biological activity.
sensing receptor antagonists,7 and also as fungicides and
pesticides.8,9 They have been utilized by several drug
discovery programs as core scaffolds for library development.
2,5,6-Trisubstituted pyrimidines, especially 5-amide, ester,
and carboxylate derivatives, have gained importance as
PGDS inhibitors, PPAR activators and cardiovascular agents
(Figure 1).5,10,11 A wide variety of synthetic routes are known
for efficient construction of the pyrimidine ring. The
condensation of a ꢀ-oxoester or related synthons with
amidine derivatives is the most commonly utilized method.12
Not many ꢀ-oxoesters are commercially available, thus,
efforts toward convenient library synthesis are hampered.
In addition, the desired substitution pattern can only be
accessed via multistep methods utilizing expensive or toxic
metal-mediated reactions.
alternative route to synthesize 2,6-disubstituted pyrimidines-
5-carboxylates from R-iodomethylene ꢀ-keto esters, 8 (Scheme
1) and amidine or guanidine derivatives suitable for library
development. The Morita-Baylis-Hillman (MBH) reaction
provides a rapid method for generation of R-iodomethylene
ꢀ-keto esters after a simple oxidation of the MBH adduct.
We were especially interested in utilizing the MBH reaction
because of the wide substrate tolerance, commercial avail-
ability, and ease of synthesis of the starting materials.13-15
The Lewis acid activated MBH-type coupling of aldehyde
with propiolic esters to produce substituted R-(hydroxym-
Scheme 1. General Scheme for the Synthesis of
2,6-Disubstituted Pyrimidine-5-carboxylates from Aldehydes
Our interest in the synthesis of heterocyclic libraries with
potential pharmaceutical activities led us to investigate an
* To whom correspondence should be addressed. E-mail: Mark.
McLaughlin@moffitt.org. Tel: 813-745-2623. Fax: 813-745-7264.
† H. Lee Moffitt Cancer Center.
‡ University of South Florida.
10.1021/cc100001e  2010 American Chemical Society
Published on Web 03/10/2010

328 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Table 1. MBH Reaction of Methyl Propiolate/Propiolamides
Sharma and McLaughlin
Table 2. Oxidation of MBH Adducts 9a-m Followed by
Condensation with Benzamidine
entry compound
R1
X
7 yield, %
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
Ph
OMe
OMe
OMe
OMe
OMe
60
69
49
94
4-methoxyphenyl
4-nitrophenyl
naphthyl
biphenyl
67
4-(N,N-dimethylamino) phenyl OMe
no reaction
7
8
9
10
11
12
13
14
7g
7h
7i
7j
7k
7l
2,4-dichlorophenyl
Me
Bn
propenyl
iBu
tBu
t-Bu
Me
OMe
OMe
OMe
OMe
OMe
OMe
NH2
85
82
69
87
96
95
98
7m
7n
NHBn 27
ethyl)-iodoacrylates, 7 (Scheme 1) has been well documented
in recent years.16-28 Various groups have reported isolation
of E or Z-selective synthetic methodologies toward substi-
tuted R-(hydroxymethyl)-iodoacrylates. Among the various
Lewis acids that have been used: TiCl4/Me2S,20 BF3 · Et2O/
TMSI,21 ZrCl4/(n-Bu)4-NI,22 TiCl4/(n-Bu)4NI,23 Et2AlI,17,24
and MgI2;25-28 MgI2 is readily available, nontoxic and less
sensitive to moisture. We herein report a new three step
method involving the MgI2 mediated MBH type reaction,
Dess-Martin periodinane oxidation of the MBH adduct and
subsequent condensation with amidine or guanidine deriva-
tives to produce a diverse 2, 6-disubstituted pyrimidines-5-
carboxylate library.
We synthesized a small library of substituted R-(hy-
droxymethyl)-iodoacrylates via MgI2-promoted MBH reac-
tion using a modified procedure of Pare´ et al.25-28 This
method predominantly generates Z-olefin as the major
product. Our initial studies also involved the use of various
Lewis acids including MgBr2 and Zn(II) halides. No reaction
was observed with Zn(II) halides even after 5 days; however,
MgBr2 formed the desired product albeit in low yield relative
to MgI2.
We investigated the scope of the MgI2-mediated MBH
reaction by examining a variety of electrophiles (Table 1).
The system proved efficient for both alkyl and aryl aldehydes
(49-98%, Table 1). For electron-deficient aldehydes, the
MBH adduct of p-nitrobenzaldehyde and methyl propiolate
was obtained after only 8 h in 49% yield (Table 1, entry 3).
Modest to good yields were obtained for electron rich
aldehydes such as p-methoxybenzaldehyde (Table 1, entry
2) despite incomplete conversion even after longer reaction
times. However, the highly electron rich N,N-dimethyl
benzaldehyde did not afford any product even after 7 days.
The MBH adducts from aromatic aldehydes were obtained
in 60-94% yield (Table 1, entries 1, 4, 5, 7), and the MBH
adducts from aliphatic aldehydes-acetaldehyde, trimethyl
acetaldehyde and isobutyraldehyde were obtained in 82%,
95% and 96% yields, respectively (Table 1, entries 8, 11,
12). The reaction conditions could be efficiently extended
to R,ꢀ-unsaturated aldehydes and resulted in 87% yield for
the MBH adduct from methacrolein (Table 1, entry 10). The
desired MBH adduct from reaction of aldehydes with
propiolamide could be isolated by simple precipitation in
high yield (Table 1, entries 13). Secondary amides of
propiolic acid also afforded the desired product albeit in low
yields (Table 1, entry 14).
The Dess-Martin periodinane is often used when a mild,
selective oxidant is required.29-34 We were able to cleanly
oxidize the MBH adducts with Dess-Martin periodinane to
generate the R-iodomethylene ꢀ-keto esters, 8 (Scheme 1).
Other oxidizing agents, such as PCC and Jones reagent,35
did not afford the products in similar purity and yields. The
R-iodomethylene ꢀ-keto esters, 8 were used immediately and
condensed with benzamidine under basic conditions to
generate the 2, 5, 6-trisubstituted pyrimidines in good to
excellent yields (9a-m, Table 2). In general, esters afforded
the products in better yield than the primary amide probably
due to the high polarity of the amides which led to problems
in product isolation (Table 2, entry 12). Among the aryl
substituted MBH adducts, substitutions on the phenyl ring
somewhat lowered the yield of the resulting pyrimidines
possibly because of steric effects (Table 2, entries 1, 4, 5,
6). All alkyl substituted starting materials, afforded good
yields of substituted pyrimidines. The oxidation product when
R1 was propenyl group was light sensitive and showed some
deterioration while handling, leading to lowering in yield of
the final product (Table 2, entry 9).
To further examine the scope and utility of this sequence
additional amidine and guanidine derivatives were treated
with the aliphatic R-iodomethylene ꢀ-keto ester, 8h and 8l,
under the same reaction system conditions (Table 3). In all
cases, the reaction proceeded smoothly in modest to high
yields. Notable examples from Table 3 include reactions with
benzamidine, guanidine, and a guanidylated amino acid

Morita-Baylis-Hillman Reaction
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 329
Table 3. Pyrimidine Synthesis-Variation of the R2 Group
from commercial sources and used as received unless
otherwise noted. Moisture- and air-sensitive reactions were
carried out under an atmosphere of argon. Thin layer
chromatography (TLC) was performed on glass plates
precoated with 0.25 mm thickness of silica gel (60 F-254)
with fluorescent indicator (EMD or Whatman). Column
chromatographic purification was performed using silica gel
60 Å, #70-230 mesh (Selecto Scientific). 1H NMR and 13
C
NMR spectra were obtained using a 400 MHz Varian
Mercury plus instrument at 25 °C in chloroform-d (CDCl3),
unless otherwise indicated. Chemical shifts (δ) are reported
in parts per million (ppm) relative to internal tetramethyl-
1
silane (TMS) or chloroform (δ 7.26) for H NMR and
chloroform (δ 77.0) for 13C NMR. Multiplicity is expressed
as (s ) singlet, br ) broad, d ) doublet, t ) triplet, q )
quartet, or m ) multiplet) and the values of coupling
constants (J) are given in hertz (Hz). High Resolution Mass
Spectrometry (HRMS) spectra were carried out on an Agilent
1100 Series in the ESI-TOF mode. Microwave reactions were
performed in a closed vessel in a Biotage Initiator I
microwave reactor.
Scheme 2. Synthesis of 2,6-Disubstituted
Pyrimidine-5-carboxamides
General Procedure to Synthesize Substituted r-(Hy-
droxymethyl)ꢀ-iodoacrylates (7a-n). A dry flask was
flushed with N2 and loaded with MgI2 (1.2 equiv). Aldehyde
(1 mmol, 1 equiv) was added in a solution of dichlo-
romethane (5.0 mL) at 0 °C. The reaction mixture was
allowed to warm to room temperature and stirred for 30 min.
Methyl propiolate (1.3 equiv) was added dropwise, and the
reaction was stirred at room temperature for ∼30 h.
The reaction was quenched by addition of cold 1 N HCl.
The two phases were separated, and the aqueous layer was
extracted with EtOAc (3×, 15 mL). The organic extracts
were combined and washed with brine (1×, 15 mL). The
organic layer was collected, dried over Na2SO4, and filtered.
The solvent was removed in vacuo and the product was
purified by column chromatography (20% EtOAc/hexanes)
to afford the product in good to excellent yields. Note: The
reaction was found to be successful for Various aldehydes
at scales between 0.6-3.5 mmol.
(Table 3, entries 1, 4, 6), which gave 85%, 95% and 80%
yields, respectively, after condensation.
The direct assembly of 2,6-disubstituted pyrimidine-5-
carboxamides utilizing the MBH reaction between N-
substituted propiolamides and aldehydes resulted in low
yields (Table 1, entry 14). However, we were able to
synthesize the desired 2, 6-disubstituted pyrimidine-5-
carboxamides, 11 in excellent yields starting with the
corresponding ester (Scheme 2). The ester was first hydro-
lyzed to the pyrimidine carboxylic acid under basic condi-
tions. Treatment with SOCl2 followed by quenching with
the desired amine affords the desired 2, 6-disubstituted
pyrimidines-5-carboxamide, 11.
Methyl 3-Hydroxy-2-(iodomethylene)-4,4-dimethylpen-
1
tanoate, (7l): yield 95%; H NMR (400 MHz, CDCl3) δ
Conclusion
7.07(s, 1H), 4.24(d, J ) 4 Hz, 1H), 3.83(3.79)(s, 3H), 2.59(d,
J ) 4 Hz, 1H), 0.89(s, 9H);13C NMR (100 MHz CDCl3) δ
168.2, 165.2, 145.6, 129.7, 95.4, 85.9, 82.9, 52.2, 36.3, 25.8;
HRMS (ESI) calcd for C9H15INO3 [M + Na]+ 320.9958,
found 320.9951. Spectra confirmed with previously reported
results.9
In summary, we have developed a new three-step meth-
odology employing MgI2-mediated MBH reaction of an
aldehyde and propiolates or propiolamides, oxidation, fol-
lowed by condensation with the appropriate amidine or
guanidine derivatives. This sequence provides efficient access
to a library of 2, 6 disubsituted pyrimidine-5-carboxylates.
A variety of electrophiles, including electron-poor, electron-
rich, aliphatic, and aromatic aldehydes were successfully
employed to afford the MBH adducts. Amidine and guani-
dine derivatives including benzamidine and a guanidylated
amino acid were used for the condensation step. These
studies provide a valuable platform for the development of
methodology toward other heterocycles.
General Procedure to Synthesize the r-Iodomethyl-
ene ꢀ-Keto Ester (8a-m). A dry flask was flushed with N2
and loaded with substituted R-(hydroxymethyl)-ꢀ-iodoacry-
lates (1equiv) in a solution of dichloromethane (5 mL) at 0
°C. Dess-Martin periodinane (1.1 equiv) was added drop-
wise, and the reaction was allowed to stir at room temperature
for 1.5 h. The reaction was quenched by addition of cold
1:1 (v/v) solution of 10% Na2S2O3 and NaHCO3 (2×, 15
mL). The two phases were separated, and the aqueous layer
was extracted with dichloromethane (2×, 15 mL). The
organic extracts were combined and washed with cold brine
(1×, 15 mL). The organic layer was collected, dried over
Experimental Section
Materials and Methods. Starting materials, organic and
inorganic reagents (ACS grade), and solvents were obtained

330 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Sharma and McLaughlin
Na2SO4, and filtered. The solvent was removed in vacuo to
afford the product in good to excellent yields. The product
was used for further steps immediately. Note: The reaction
was found to be successful for Various substituted R-(hy-
droxymethyl)-iodoacrylates at scales between 0.2-1.1 mmol.
Methyl 3-Oxo-2-(iodomethylene)-4,4-dimethylpentanoate
mL). The organic layer was collected. The aqueous layer
was extracted with CH2Cl2 (2×, 15 mL). The organic layers
were combined and dried over Na2SO4 and filtered and
evaporated in vacuo. The crude product was then purified
by column chromatography (20% EtOAc/hexanes) to afford
the product in high yields. Note: The reaction was found to
be successful for Various pyrimidine esters at scales between
0.4-1.8 mmol.
1
(8l): yield 96%; H NMR (400 MHz, CDCl3) 7.52(s, 1H),
3.83(s, 3H), 1.19(s, 9H);13C NMR (100 MHz, CDCl3) δ
205.5, 164.3, 145.7, 93.3, 52.6, 44.8, 27.0.
N-Benzyl-4-methyl-2-phenylpyrimidine-5-carboxam-
ide (11h1): yield 86%; 1H NMR (400 MHz, CDCl3) δ 8.74(s,
1H), 8.45-8.43(m, 2H), 7.50-7.48(m, 3H), 7.39-7.33(m,
General Procedure to Synthesize the Pyrimidine Esters
(9a-r). A solution of R-iodomethylene ꢀ-keto ester (1 equiv)
in ethanol (3 mL) was mixed with TEA (2 equiv) and the
amidine or guanidine derivatives as the HCl salts (1 equiv)
and heated in a Biotage Initiator microwave reactor at 130
°C for 30 min. The reaction was allowed to cool, and the
solvent was evaporated. The residue was washed with brine
and extracted with ethyl acetate (2×, 10 mL). The organic
extracts were combined, dried over Na2SO4, and filtered. The
product was purified by column chromatography (20%
EtOAc/hexanes) to provide the product in modest to excellent
yields. Note: The reaction was found to be successful for
Various R-iodomethylene ꢀ-keto esters at scales between
0.2-1.1 mmol.
Methyl 4-tert-Butyl-2-methylpyrimidine-5-carboxylate
(9l): yield 85%;1H NMR (400 MHz, CDCl3) δ 8.56(s, 1H),
3.92(s, 3H), 2.76(s, 3H), 1.40(s, 9H); 13C NMR (100 MHz,
CDCl3) δ 174.2, 169.3, 168.2, 156.9, 123.2, 53.0, 39.6, 29.4,
26.4; HRMS (ESI) calcd for C11H16N2O2 [M + H]+
209.1285, found 209.1276.
5H), 6.23(br, 1H), 4.66(d, J ) 2.8 Hz, 2H), 2.74(s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 166.4, 166.3, 165.1, 155.1, 137.7,
137.1, 131.5, 129.2, 128.9, 128.8, 128.2, 128.1, 126.9, 44.5,
23.6; HRMS (ESI) calcd for C19H17N3O [M + H]+ 304.1444,
found 304.1442.
Acknowledgment. We thank the NIH for financial support
through grant NCI P01 CA118210. We also thank the HTS
Chemistry Core facility at Moffitt Cancer Center for the use
of microwave reactor.
Supporting Information Available. Experimental details
and spectroscopic characterization. This material is available
free of charge via the Internet at http://pubs.acs.org/.
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