Synthesis of fully substituted pyrimidines

Article abstract of DOI:10.1021/jo400090w

A novel approach to the synthesis of fully substituted pyrimidine derivatives armed with an oxy-functionalized acetate chain at the ring is described. The manifold uses amidines as the nitrogen source and activated skipped diynes as the electrophilic reactive partners in a coupled domino strategy. In the first domino reaction, two consecutive aza-Michael additions assemble the six-membered ring heterocycle, while in the second domino process, a [H]-shift and a [3,3]-sigmatropic rearrangement lead to the aromatization of the product.

Full text of DOI:10.1021/jo400090w

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Synthesis of Fully Substituted Pyrimidines.
David Tejedor, Sara López-Tosco, and Fernando Garcia-Tellado
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400090w • Publication Date (Web): 20 Feb 2013
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Synthesis of Fully Substituted Pyrimidines.
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David Tejedor,* Sara López-Tosco† and Fernando García-Tellado*
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Instituto de Productos Naturales y Agrobiología, Consejo Superior de Investigaciones Científicas, Astro-
físico Francisco Sánchez 3, 38206. La Laguna, Tenerife, Spain.
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fgarcia@ipna.csic.es; dtejedor@ipna.csic.es
KEYWORDS : pyrimidine; domino reactions; sigmatropic rearrangement; molecular diversity; micro-
wave chemistry, 1,4-diynes, amidines, 4,5-dihydropyrimidine, 1,4,5,6-tetrahydropyrimidine, hydrogen
shift, symmetry breaking.
ABSTRACT: A novel approach to the synthesis of fully substituted pyrimidine derivatives armed with
an oxy-functionalized acetate chain at the ring is described. The manifold uses amidines as the nitrogen
source and activated skipped diynes as the electrophilic reactive partners in a coupled domino strategy.
In the first domino reaction, two consecutive aza-Michael additions assemble the 6-membered ring het-
erocycle while in the second domino process, a [H]-shift and a [3,3]-sigmatropic-rearrangement lead to
the aromatization of the product.
Pyrimidine is the most common of the three possible diazines (6-membered aromatic rings with two
nitrogen atoms) and constitutes an important pharmacophore endowed with a wide range of pharmaco-
logical activities.1 As such, pyrimidine derivatives have received a great deal of attention from the syn-
thetic community.2 The most common synthetic approach involves the addition of an N-C-N fragment to
a compound possessing a reactive C-C-C connectivity. The most representative example of this type of
reactions is the well-known Pinner pyrimidine synthesis which involves the condensation of amidines 1
with 1,3-dicarbonyl compounds 2 or their synthetic equivalents (Scheme 1a). Although the nature and
reactivity profile of these C-C-C units have been widely explored,2 the number of available methods
incorporating an alkyne motive remains scarce3 and these are mainly related with the use of ethynyl
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ketone derivatives.3b-f Other important strategies involving alkynes rely on the [2+2+2]-intermolecular
cycloaddition of one alkyne molecule and two nitrile molecules3a,3i or the [4+2]-cycloaddition of 1,3-
diazadienes with electron deficient acetylenes to deliver the pyrimidine ring.3g-h Whereas the first one
utilizes two identical nitrile blocks affording a reduced functional diversity decorating the ring (symmet-
ric products, substituent redundancy), the second one requires the previous access to a reactive 1,3-
azadiene unit featuring a convenient leaving group installed at the 3-position (the leaving group steers
the final aromatization step).3g These limitations call for the development of new alkyne-based method-
ologies capable of providing these heterocyclic structures with multiple substitution patterns decorating
the ring. In addition, these methodologies should also be able to construct pyrimidine-focused chemical
libraries.4
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SCHEME 1. Manifolds for the synthesis of substituted pyrimidines.
As part of an ongoing project, we have developed efficient domino methodologies for the diversity-
oriented access to bioactive aromatic scaffolds from simple and readily available tertiary 1,4-diynes
blocks 4 (Scheme 1).5 These units are conveniently synthesized in multigram scale by a four component
A2BB´ reaction involving acid chlorides and alkyl propiolates.6 The multicomponent nature of this reac-
tion allows to obtain these 1,4-diynes blocks with a convenient grade of diversity at the tertiary position
(R1, R1COO) and the ester groups (R2) in a simple and fast manner. Herein, we report a simple, direct
and versatile methodology based on the use of these 1,4-diynes units for the fast access to fully substi-
tuted pyrimidines decorated with an convenient grade of functional diversity and bearing an oxy-
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functionalized side chain at the ring. The methodology is based on a novel domino manifold which uses
amidines 1 as the nitrogen source (N-C-N block) and a tertiary skipped diyne unit 4 as the source of the
C3 block (Scheme 1b).
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Recent reports from our laboratory have shown that 1,4-diynes 4 conveniently behave either as 1,3-
or 1,4-dicarbonyl compounds when they are made to react with aza-nucleophiles such as primary
amines,5a hydrazines,5b 1,n-diamines5c or secondary amines.5d We therefore envisioned that amidines 1
could react with these 1,4-diyne blocks to afford fully substituted pyrimidines 5 with complete atom
economy and good functional diversity decorating the aromatic ring (Scheme 1b). Based on our previ-
ous experience, we anticipated that amidines 1 would react with the alkyne functionalities of 4 through
two consecutive aza-Michael additions to afford the cyclic intermediates 6. This would be followed by a
[H]-shift to form a cyclic intermediates 7 with a new endocyclic unsaturation, and finally, a [3,3]-
sigmatropic rearrangement to form the desired pyrimidines 5 via an irreversible aromatization-driven
process (Scheme 2). This rearrangement would break the latent symmetry present in the two advanced
intermediates 6 and 7 by the installation of two chemically differentiated acetate chains at the ring of the
final pyrimidine product.
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SCHEME 2. Expected domino pathway affording pyrimidines 5.
As a proof of the concept, we studied the reaction of commercially available benzamidine 1a with
skipped diyne 4a. Although we were pleased to observe the consumption of the starting material 1a by
TLC analysis (in refluxing DCE, 1hr), we also noticed that the desired pyrimidine product was not ob-
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served among the mixture of reaction products which were isolated after flash column chromatography.
Instead, the E/Z mixture of the cyclic intermediate 6aa was identified as the main reaction product
(73%) with compound 8aa as a byproduct of the reaction (14%) coming from a different reaction path-
way (Scheme 3).7 Further attempts to obtain the aromatized product 5aa from 1a and 4a varying the
solvent (EtOH, t-BuOH, DMF, toluene) and the reaction temperature were unsuccessful. To begin test-
ing the generality of this process we carried out the reaction with other diynes obtaining similar results.
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SCHEME 3. Optimization of the domino manifold.
It soon became evident that we needed to concentrate our efforts in determining the best reaction
conditions to allow intermediate 6aa to progress towards the desired pyrimidine through the [H]-shift
and the [3,3]-sigmatropic rearrangement. As a matter of fact, in the previous synthesis of pyrroles5a and
pyrazoles5b from tertiary skipped diynes 4, we had not encountered this difficulty in progressing past the
first cyclic intermediate, although we found that the pyrazole ring formation required more energic con-
ditions than the pyrrole ring (reaction differences mirror the aromatic differences!). After some experi-
mentation, we quickly turned our attention to the use of silica gel as a mild acidic catalyst with the com-
bination of heating to aid in the rearrangement. Hence, an E/Z mixture of 6aa was adsorbed on silica gel
and the opened vessel (round bottomed flask) was then heated in a domestic microwave oven (at 900W)
for different periods of time. While the reaction was incomplete at shorter reaction times, mixtures con-
taining the desired pyrimidine and decarboxylated products 9aa-11aa were obtained at longer reaction
times without selectivity in the product distribution (Scheme 4) (See Supporting Information). A similar
scenario took place when the same aromatization reaction was attempted using a scientific microwave
apparatus. Fortunately, with the use of conventional heating, with longer reaction times and the appro-
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priate reaction temperature a good selectivity towards the desired pyrimidine 5aa was obtained (3 days,
100-110 ºC, 90% NMR yield).
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SCHEME 4. Thermally-driven transformation of intermediate 6aa into pyrimidines 5aa and 9aa-
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11aa.
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Our next goal was to be able to implement both processes in the same reaction vessel by means of
the so called coupled domino reactions strategy,8 and thus, avoid the isolation of the E/Z mixture of the
cyclic products 6. Fortunately, the protocol was straightforward and consisted on absorbing on silica gel
the crude reaction mixture obtained in the first step (reaction of 1a and 4a) and subjecting it to the pre-
viously studied thermal conditions. In this manner, 5aa was isolated in 46% overall yield.
Once the reaction could be standardized, we next studied the scope of this coupled domino process
with regard to the diyne and the amidine (Table 1). In general, the reaction displayed a wide scope with
regard to both components. With regard to the 1,4-diyne component, the derivatives 4a-f6 were studied,
which feature electronically different aromatic rings at the diyne tertiary position and on the ester func-
tionality.
As it was expected, all of them expressed the same reactivity pattern with similar chemical efficien-
cies (entries 1- 6). Other commercially available amidines 1a-e were converted to the corresponding
fully substituted pyrimidines 5a-e with similar efficiencies.
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Table 1. Coupled domino reactions of activated skipped diynes 4 and amidines 1.
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Entry
1
5 (%)a
Ar
Ph
4
a
b
c
d
e
f
R
1
a
a
a
a
a
a
b
c
Ph
Ph
5aa (46)
5ba (42)
5ca (48)
5da (52)
5ea (42)
5fa (41)
5ab (48)
5ac (53)
5ad (48)
5ae (37)
2
4-ClC6H4
3,5-diOMeC6H3
4-MeC6H4
4-FC6H4
3-ClC6H4
Ph
3
Ph
4
Ph
5
Ph
6
Ph
9
3-NO2C6H4
4-ClC6H4
4-MeC6H4
Me
a
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a
a
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Ph
Ph
d
e
Ph
aYields of isolated products.
The extension of this protocol to the aliphatic substituted tertiary 1,4-diynes proved to be more dif-
ficult than previously expected and it resulted in a new reactivity profile for the 1,4,5,6-
tetrahydropyrimidine intermediate 6 (Scheme 5). The multicomponent methodology for the access to
these 1,4-diynes required that the aliphatic substituent at the C-sp3 position had to be necessarily
branched.9 With this structural constraint, we assayed the reaction of imidine 1a with 1,4-diynes 4g and
4h, armed with and isopropyl and a t-butyl group at the C-sp3 position, respectively. Both substrates
were smoothly transformed into the corresponding intermediates 6ga and 6ha (64% yield in each case),
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but reactions did no progress past these intermediates even after being submitted to the thermal condi-
tions of the second reaction (e.g., after the 3rd day of heating, the E/Z isomeric mixture of 6ga was
quantitatively transformed into a single isomer). Both intermediates showed a similarly high thermal
barrier to aromatize. The aromatization could be finally achieved by microwave-assisted heating of
these intermediates absorbed on silica gel [40 min, 900W, opened vessel, domestic oven], but it was at
the expense of the decarboxylative elimination of both methyl ester groups. Under these conditions, the
intermediate 6ga rearranged to the pyrimidine derivative 12 in 40 % yield. Significantly, this reaction
allowed us to install three differentiated aliphatic chains at the ring, one of them armed with a terminal
acyloxy group as a convenient chemical handle. Surprisingly, under the same reaction conditions, the
intermediate 6ha rearranged to the symmetric 5-pivaloyloxy-pyrimidine derivative 13 in 35% yield
(Scheme 5). Besides the expected decarboxylations, the reaction involved the loss of the original t-butyl
group without migration of the pivaloyloxy group. We believe that this different reaction pattern relies
on the steric congestion imposed by the t-butyl group at the C-sp3 position which increases the energy
for the [3,3]-sigmatropic rearrangement involving the ester group and it facilities the rearrangement in-
volving the aliphatic substituent (retro-ene reaction) which is probably also aided by the gem-dimethyl
effect exercised by the other two methyl groups of the substituent (See Scheme 5). The presence of an
O-substituent at the pyrimidine ring of 13 is quite interesting because the 5-pyrimidinol derivatives have
been shown to be suitable structural motives for the rational design of novel air-stable radical
scavengers and chain-breaking antioxidants that are more effective than phenols.11
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Scheme 5. Extension to the aliphatic series of tertiary skipped diynes. A new reactivity pattern.
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In summary, we have developed a novel alkyne-based approach for the synthesis of fully
substituted pyrimidine derivatives armed with a functionalized alkyl ester chain. The manifold uses
amidines as the nitrogen source and activated skipped diynes as the electrophilic reactive partners, and
utilizes a coupled domino reactions strategy to perform the whole transformation. Whereas a sequence
of two consecutive aza-Michael addition assembles the 6-membered ring heterocycle (the 1,4,5,6-
tetrahydropyrimidine core), a second domino process involving a [H]-shift and a [3,3]-sigmatropic
rearrangement leads to the aromatization of the product. The novelty of this reaction and its simple
experimental protocol make of this process an excellent candidate for the fast construction of structure-
focused libraries based on the pyrimidine unit decorated with an aryl, alkyl or hydroxyl group at the C-5
position of the ring and different alkyl/aryl functionalities adorning the rest of the ring. Importantly, the
protocol differentiates the otherwise identical alkyne chains of the starting 1,4-diyne and installs them as
two differentiated side chains at the ring of the final pyrimidine ring. Last but not least, the three esters
present in the 1,4-diyne precursor can be incorporated into the final pyrimidine structure to be used as
convenient chemical handles for further reactivity generation.
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EXPERIMENTAL SECTION
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General information. H NMR and C NMR spectra of CDCl3 solutions were recorded either at 400
and 100 MHz or at 500 and 125 MHz, respectively. Microwave reactions were conducted in sealed glass
vessels (capacity 10 mL) using either a CEM Discover microwave reactor or a conventional microwave
oven (Whirlpool MD 131), using silica gel (particle size 0.063-0.200 mm). In all cases, the reagents
were first dissolved in dichloromethane, then mixed with silica gel and then followed by removal of the
solvent under reduced pressure. FT-IR spectra were measured in chloroform solutions using a FT-IR
spectrophotometer. Mass spectra (low resolution) (EI/CI) and HRMS (EI/TOF) were obtained with a
gas chromatograph/mass spectrometer. Analytical thin-layer chromatography plates used UV-active
silica on aluminum. Flash column chromatography was carried out with silica gel of particle size less
than 0.020 mm, using appropriate mixtures of ethyl acetate and hexanes as eluents. All reactions were
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performed in oven-dried glassware. All materials were obtained from commercial suppliers and used as
received unless otherwise noted. The free amidines 1b, 1c and 1d were obtained by treatment of solu-
tions of the commercially available HCl or HI salts with 2.0M aqueous KOH solutions. The aqueous
layers were extracted with CH2Cl2 and dried over Mg2SO4. Free acetamidine 1e was prepared as previ-
ously described.11
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General procedure for the synthesis of 6aa-6ca and 8aa-8ca: After skipped diyne 4a (376 mg; 1.0
mmol) was dissolved in 1,2-dichloroethane (10 mL), benzamidine (1a) (1.20 mmol) was added and the
reaction was heated to reflux for 1 hour. After the mixture was cooled, the solvent was removed under
reduced pressure. This was followed by isolation of the corresponding products by flash column chro-
matography (silica gel, n-hexane/EtOAc (80:20–60:40)).
(6aa) [(2E,/2Z) mixture]: (362 mg; 73% yield). Two isomers, separated by flash chromatography (30%
EtOc/Hexanes).1H NMR (400 MHz, CDCl3): (less polar isomer) δ 3.30 (s, 3H), 3.62 (s, 3H), 5.28 (s,
1H), 6.11 (s, 1H), 7.32 (tt, 1H, 3J(H,H) = 7.3 and 2.0 Hz), 7.39-7.43 (m, 2H), 7.48-7.65 (m, 8H), 8.16 (d,
2H, 3J(H,H) = 7.8 Hz), 8.20-8.22 (m, 2H), 12.03 (s, 1H) ppm; (more polar isomer) δ 3.65 (s, 3H), 3.68 (s,
3H), 5.28 (s, 1H), 5.56 (s, 1H), 7.31-7.35 (m, 1H), 7.37-7.41 (m, 2H), 7.51-7.60 (m, 7H), 7.64-7.67 (m,
1H), 8.16-8.18 (m, 2H), 8.23-8.25 (m, 2H), 12.1 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): (less polar
isomer) δ 50.9, 51.2, 74.2, 91.4, 114.9, 124.0 (2C), 127.1 (2C), 128.0, 128.56 (2C), 128.58 (2C), 129.0
(2C), 129.4, 130.2 (2C), 132.0, 132.3, 133.6, 142.5, 148.3, 154.3, 156.6, 164.9, 165.1, 170.2 ppm; (more
polar isomer) δ 51.2, 51.4, 75.0, 91.8, 109.5, 124.1 (2C), 127.6 (2C), 128.6, 128.8 (2C), 129.0 (2C),
129.1 (2C), 129.4, 130.0 (2C), 132.2, 132.4, 134.0, 142.7, 148.4, 155.37, 155.44, 164.2, 165.9, 170.0
ppm; FTIR (CHCl3): (less polar isomer)  1728.4, 1672.0, 1634.3, 1560.3, 1435.1, 1280.5, 1251.5 cm-
1; LRMS (70 eV): m/z (%): (less polar isomer) 496 (M+, 63), 376 (37), 360 (22), 359 (87), 318 (20), 317
(31), 105 (100), 77 (54); elemental analysis calcd (%) for C29H24N2O6: C 70.15; H 4.87; N 5.64; found:
(less polar isomer) C 69.83; H 5.10; N 5.48. Yellow amorphous solid.
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(6ba) [(2E,/2Z) mixture]: (379 mg; 67% yield). Two isomers, separated by flash chromatography (20%
1
2
3
EtOc/Hexanes).1H NMR (400 MHz, CDCl3): (less polar isomer, major isomer) δ 3.35 (s, 3H), 3.64 (s,
4
5
6
3
3
3H), 5.22 (s, 1H), 6.10 (s, 1H), 7.36 (d, 2H, J(H,H) = 8.6 Hz), 7.47 (d, 2H, J(H,H) = 8.6 Hz), 7.53-7.59
(m, 5H), 8.12 (d, 2H, 3J(H,H) = 8.6 Hz), 8.13-8.15 (m, 2H), 12.04 (s, 1H) ppm; (more polar isomer, repre-
7
8
9
13
sentative signals) δ 3.67 (s, 3H), 3.69 (s, 3H), 5.24 (s, 1H), 5.51 (s, 1H), 12.05 (s, 1H) ppm; C NMR
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(100 MHz, CDCl3): (less polar isomer) δ 51.0, 51.4, 73.9, 91.7, 115.1, 125.5 (2C), 127.1 (2C), 127.7,
128.9 (2C), 129.0 (2C), 129.1 (2C), 131.6 (2C), 132.0, 132.3, 134.1, 140.4, 140.8, 148.5, 154.1, 156.0,
164.0, 165.0, 170.12 ppm; LRMS (70 eV): m/z (%): (less polar isomer) 564 (M+, 0.4), 305 (37), 247
(49), 158 (24), 156 (84), 141 (37), 130 (100), 111 (38), 104 (24), 103 (53), 75 (28); HRMS calculated
for C29H22Cl2N2O6: 564.0855, found 564.0853. Yellowish amorphous solid.
(6ca) [(2E,/2Z) mixture]: (291 mg; 76% yield). Two isomers, separated by flash chromatography (30%
1
EtOc/Hexanes). H NMR (400 MHz, CDCl3): (less polar isomer) δ 3.38 (s, 3H), 3.63 (s, 3H), 3.78 (s,
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6H), 3.83 (s, 6H), 5.29 (s, 1H), 6.10 (s, 1H), 6.40 (t, 1H, J(H,H) = 2.3 Hz), 6.69 (t, 1H, 3J(H,H)= 2.3 Hz),
6.77 (d, 2H, 3J(H,H)= 2.3 Hz), 7.34 (d, 2H, 3J(H,H) = 2.3 Hz), 7.52-7.54 (m, 3H), 8.12-8.14 (m, 2H), 12.01
(s, 1H) ppm; (more polar isomer, representative signals) δ 3.65 (s, 3H), 3.68 (s, 3H), 3.77 (s, 6H), 3.84
(s, 6H), 5.25 (s, 1H), 5.56 (s, 1H), 12.07 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): (less polar isomer)
δ 50.9, 51.2, 55.3 (2C), 55.5 (2C), 74.1, 91.3, 99.2, 102.8 (2C), 106.4, 107.7 (2C), 115.3, 127.0 (2C),
128.9 (2C), 131.2, 131.9, 132.3, 144.5, 148.1, 153.4, 156.2, 160.77 (2C), 160.79 (2C), 164.7, 165.1,
170.3 ppm; FTIR (CHCl3): (less polar isomer)  1727.5, 1672.3, 1633.5, 1598.2, 1562.3, 1460.9,
1431.6, 1283.0, 1249.8, 1158.4 cm-1; LRMS (70 eV): m/z (%): (less polar isomer) 616 (M+, 14), 451
(47), 436 (33), 403 (37), 377 (33), 376 (29), 375 (29), 182 (100), 165 (51), 122 (29); elemental analysis
calcd (%) for C33H32N2O10: (less polar isomer) C 64.28; H 5.23; N 4.54; found: C 64.01; H 5.26; N
4.90. Yellow amorphous solid.
(Z)-Methyl 2-(7-benzoyl-6-oxo-2,4a-diphenylfuro[3,2-d]pyrimidin-4(3H,4aH,6H)-ylidene)acetate
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(8aa): (65 mg; 14% yield). H NMR (400 MHz, CDCl3): δ 3.43 (s, 3H), 6.12 (s, 1H), 7.36-7.50 (m,
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9H), 7.55 (tt, 1H, J(H,H) = 7.3 and 1.2 Hz), 7.61 (tt, 1H, J(H,H) = 7.3 and 1.2 Hz), 7.79-7.81 (m, 2H),
7.96-7.98 (m, 2H), 11.47 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 52.0, 77.8, 96.8, 112.7, 125.8
(2C), 128.1 (2C), 128.3 (2C), 129.1 (2C), 129.2 (2C), 129.8 (2C), 130.2, 130.3, 133.5, 133.7, 135.6,
137.0, 149.8, 153.8, 168.1, 168.9, 169.5, 187.7 ppm; FTIR (CHCl3): 1768.8, 1650.9, 1599.9,
1587.9, 1541.2, 1469.3, 1434.5, 1358.9, 1252.5 cm-1; LRMS (70 eV): m/z (%): 464 (M+, 31), 432 (10),
405 (8.2), 387 (11), 365 (17), 359 (12), 105 (100), 77 (41); elemental analysis calcd (%) for
C28H20N2O5: C 72.41; H 4.34; N 6.03; found: C 72.38; H 4.48; N 5.95. Yellow amorphous solid.
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(Z)-Methyl
2-(7-(4-chlorobenzoyl)-4a-(4-chlorophenyl)-6-oxo-2-phenylfuro[3,2-d]pyrimidin-
4(3H,4aH,6H)-ylidene)acetate (8ba): (64 mg; 12% yield). 1H NMR (400 MHz, CDCl3): δ 3.83 (s,
3H), 6.11 (s, 1H), 7.33-7.39 (m, 4H), 7.44-7.48 (m, 4H), 7.59 (tt, 1H, 3J(H,H) = 7.3 and 1.2 Hz), 7.82 (dd,
2H, 3J(H,H) = 7.3 and 1.2 Hz), 7.88 (dd, 2H, 3J(H,H)) = 7.3 and 1.2 Hz), 11.51 (s, 1H) ppm; 13C NMR (100
MHz, CDCl3): δ 52.2, 77.1, 97.2, 112.1, 127.2 (2C), 128.1 (2C), 128.7 (2C), 129.3 (2C), 129.5 (2C),
130.0, 131.2 (2C), 134.0, 134.1, 135.5, 136.4, 140.0, 149.2, 154.2, 167.8, 168.7, 169.5, 186.2 ppm;
FTIR (CHCl3):  1771.8, 1652.0, 1588.2, 1539.0, 1492.36, 1467.8, 1434.6, 1358.6, 1253.4 cm-1;
LRMS (70 eV): m/z (%): 534 (31), 533 (15), 532 (M+, 41), 435 (18), 433 (25), 141 (33), 139 (100), 11
(22); HRMS calculated for C28H18Cl2N2O5: 532.0593, found 532.0604. Yellowish amorphous solid.
(Z)-Methyl
2-(7-(3,5-dimethoxybenzoyl)-4a-(3,5-dimethoxyphenyl)-6-oxo-2-phenylfuro[3,2-
1
d]pyrimidin-4(3H,4aH,6H)-ylidene) acetate (8ca): (40 mg; 11% yield). H NMR (400 MHz, CDCl3):
δ 3.73 (s, 6H), 3.78 (s, 6H), 3.82 (s, 3H), 6.08 (s, 1H), 6.42 (t, 1H, 3J(H,H) = 2.2 Hz), 6.60 (d, 2H, 3J(H,H
)
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= 2.4 Hz), 6.70 (t, 1H, J(H,H) = 2.4 Hz), 7.17 (d, 2H, J(H,H) = 2.3 Hz), 7.43 (t, 2H, J(H,H) = 7.8 Hz),
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7.54-7.58 (m, 1H), 7.84-7.86 (m, 2H), 11.41 (s, 1H) ppm; C NMR (100 MHz, CDCl3): δ 52.0, 55.4,
55.5, 77.6, 96.9, 101.4, 104.3, 106.5, 107.5, 112.9, 127.6, 128.1, 129.16, 129.21, 130.4, 133.7, 137.8,
138.8, 149.6, 153.9, 160.7, 161.3, 168.0, 168.8, 168.9, 187.3 ppm; LRMS (70 eV): m/z (%): 584 (M+,
13), 510 (14), 321 (35), 165 (100), 137 (28), 122 (27), 91 (42), 73 (53); HRMS calculated for
C32H28N2O9: 584.1795, found 584.1772. Yellowish amorphous solid.
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Conversion of 6aa into 2-Methoxy-1-(6-(2-methoxy-2-oxoethyl)-2,5-diphenyl-pyrimidin-4-yl)-2-
oxoethyl benzoate (5aa): 6aa (248 mg; 0.50 mmol) was absorbed on silica gel (2.0 g, with the aid of
CH2Cl2 which was then removed under reduced pressure) and the mixture was heated at 105 ºC for 3
days. The silica gel was thoroughly washed with ethyl acetate and the filtrate was concentrated and flash
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chromatographed (silica gel, 20% n-hexane/EtOAc) to afford the pure 5aa (218 mg; 88%). H NMR
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(400 MHz, CDCl3): δ 3.65 (s, 3H), 3.74 (s, 2H), 3.80 (s, 3H), 6.25 (s, 1H), 7.21-7.22 (m, 1H), 7.27-7.31
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(m, 1H), 7.36-7.48 (m, 8H), 7.54-7.58 (m, 1H), 8.01-8.03 (m, 2H), 8.49-8.52 (m, 2H) ppm; C NMR
(100 MHz, CDCl3): δ 41.9, 52.1, 52.6, 72.5, 128.4 (2C), 128.5 (4C), 128.8, 128.9, 129.0, 129.3, 129.4,
130.1 (2C), 131.0, 132.6, 133.39, 133.44, 136.7, 160.7, 162.8, 163.2, 165.0, 167.5, 169.8 ppm. 1 carbon
signal buried under aromatic region; FTIR (CHCl3) 1768.2, 1735.0, 1562.6, 1536.0, 1437.5, 1408.6,
1264.9 cm-1; LRMS (70 eV) m/z (%): 496 (M+, 25), 392 (16), 391 (66), 333 (20), 105 (100), 77 (18);
elemental analysis calcd (%) for C29H24N2O6: C 70.15; H 4.87; N 5.64; found: C 70.41; H 4.89; N 5.42.
Orange amorphous solid.
2-Methoxy-1-(6-methyl-2,5-diphenylpyrimidin-4-yl)-2-oxoethyl benzoate (9aa): (22 mg; 0.05
mmol). 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 3.80 (s, 3H), 6.25 (s, 1H), 7.20-7.22 (m, 1H), 7.29-
7.51 (m, 9H), 7.54-7.58 (m, 1H), 8.02-8.04 (m, 2H), 8.51-8.54 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): δ 23.5, 52.6, 72.6, 128.3 (4C), 128.45 (2C), 128.51, 128.8, 128.9, 129.0, 129.1, 129.2, 130.0
(2C), 130.7, 132.2, 133.4, 134.5, 137.2, 159.0, 162.9, 165.1, 167.0, 167.7 ppm; FTIR (CHCl3):
1767.1, 1730.7, 1562.6, 1536.3, 1406.6, 1270.5, 1108.3 cm-1; LRMS (70 eV): m/z (%): 438 (M+,
23), 333 (56), 245 (10), 115 (15), 105 (100), 77 (28); elemental analysis calcd (%) for C27H22N2O4: C
73.96; H 5.06; N 6.39; found: C 73.87; H 5.28; N 6.12. Yellowish amorphous solid.
(6(6-(2-Methoxy-2-oxoethyl)-2,5-diphenylpyrimidin-4-yl)methyl benzoate (10aa): (2.2 mg; 0.005
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mmol). H NMR (400 MHz, CDCl3): δ 3.65 (s, 3H), 3.72 (s, 2H), 5.26 (s, 2H), 7.30 (dd, 2H, J(H,H)
=
8.1 and 1.8 Hz), 7.36-7.46 (m, 8H), 7.55-7.60 (m, 1H), 8.06 (dd, 2H, 3J(H,H) = 8.6 and 1.5 Hz), 8.40 (dd,
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2H, J(H,H) = 7.8 and 1.3 Hz) ppm; C NMR (100 MHz, CDCl3): δ 41.6, 52.1, 64.6, 128.3 (2C), 128.4
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(4C), 128.7, 129.1 (4C), 129.8 (2C), 130.0, 130.7, 131.1, 133.0, 134.0, 137.2, 161.6, 161.7, 163.1,
166.1, 167.0 ppm; FTIR (CHCl3):  1729.9, 1561.4, 1538.3, 1408.1, 1266.9, 1114.5 cm-1; LRMS (70
eV): m/z (%): 438 (M+, 23), 334 (25), 333 (100), 115 (27), 105 (39), 77 (37); HRMS calculated for
C27H22N2O4: 438.1580, found 438.1569. Yellowish amorphous solid.
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(6-Methyl-2,5-diphenylpyrimidin-4-yl)methyl benzoate (11aa): (4 mg; 0.01 mmol). H NMR (400
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MHz, CDCl3): δ 2.38 (s, 3H), 5.23 (s, 2H), 7.27-7.29 (m, 2H), 7.37-7.47 (m, 8H), 7.57 (tt, 1H, J(H,H)
=
7.3 and 1.3 Hz), 8.04-8.06 (m, 2H), 8.39-8.41 (m, 2H), ppm; 13C NMR (100 MHz, CDCl3): δ 23.1, 64.7,
128.22 (2C), 128.28 (2C), 128.31 (2C), 128.38, 128.9 (2C), 129.0, 129.8, 130.1, 130.4, 130.8, 135.1,
137.6, 160.6, 162.8, 165.8, 166.2 ppm; FTIR (CHCl3):  1721.2, 1603.4, 1560.4, 1540.0, 1404.2,
1275.5, 1115.6 cm-1; LRMS (70 eV): m/z (%): 380 (M+, 12), 276 (19), 275 (100), 115 (16), 105 (27), 77
(22); elemental analysis calcd (%) for C25H20N2O2: C 78.93; H 5.30; N 7.36; found: C 78.83; H 5.44; N
7.36. White amorphous solid.
General procedure for the synthesis of pyrimidines 5: After skipped diyne 4a-f (1.0 mmol) was dis-
solved in 1,2-dichloroethane (10 mL), amidine 1a-e (1.20 mmol) was added and the reaction was heated
to reflux for 1 hour. After the mixture was cooled, the solvent was removed under reduced pressure. The
resulting mixture was absorbed on silica gel (2.0 g, with the aid of CH2Cl2 which was then removed
under reduced pressure) and it was heated for 3 days at 105 ºC. Extraction of the products with ethyl
acetate was followed by isolation of the desired products by flash column chromatography (silica gel,
appropriate mixtures of n-hexane/EtOAc).
1-(5-(4-Chlorophenyl)-6-(2-methoxy-2-oxoethyl)-2-phenylpyrimidin-4-yl)-2-methoxy-2-oxoethyl 4-
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chlorobenzoate (5ba): (179 mg; 42%). H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 3.72 (s, 2H), 3.80
(s, 3H), 6.21 (s, 1H), 7.16 (dd, 1H, 3J(H,H)= 8.3 and 2.3 Hz), 7.29-7.33 (m, 2H), 7.41 (d, 2H, 3J(H,H)= 8.8
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Hz), 6.45-7.50 (m, 4H), 7.95 (d, 2H, J(H,H)= 8.6 Hz), 8.46-8.49 (m, 2H) ppm; C NMR (100 MHz,
CDCl3): δ 41.8, 52.2, 52.8, 72.5, 127.2, 128.5, 128.8, 129.1, 129.3, 130.8, 130.9, 131.2, 131.4, 131.9,
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135.3, 136.5, 140.2, 160.0, 162.8, 163.5, 164.2, 167.2, 169.6 ppm. 1 carbon signal buried under aroma-
tic region; FTIR (CHCl3): 1766.3, 1734.6, 1595.8, 1562.8, 1535.1, 1488.9, 1437.7, 1408.1, 1265.5,
1173.4, 1093.3 cm-1; LRMS (70 eV): m/z (%): 566 (M+, 11), 564 (M+, 15), 427 (20), 425 (51), 141 (37),
139 (100); elemental analysis calcd (%) for C29H22Cl2N2O6: C 61.60; H 3.92; N 4.95; found: C 61.78; H
4.17; N 5.06. Yellowish amorphous solid.
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1-(5-(3,5-Dimethoxyphenyl)-6-(2-methoxy-2-oxoethyl)-2-phenylpyrimidin-4-yl)-2-methoxy-2-
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oxoethyl 3,5-dimethoxybenzoate (5ca): (244 mg; 48%). H NMR (400 MHz, CDCl3): δ 3.53 (s, 3H),
3.68 (s, 3H), 3.77 (s, 2H), 3.79 (s, 3H), 3.79 (s, 6H), 3.81 (s, 3H), 6.30 (s, 1H), 6.32-6.33 (m, 1H), 6.44
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(t, 1H, J(H,H)= 2.3 Hz), 6.49-6.50 (m, 1H), 6.64 (t, 1H, J(H,H)= 2.5 Hz), 7.17 (d, 2H, J(H,H)= 2.5 Hz),
7.44-7.48 (m, 3H), 8.47-8.50 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 41.8, 52.2, 52.6, 55.2, 55.4,
55.6 (2C), 72.7, 101.0, 106.4, 107.1, 107.6 (2C), 107.7, 128.5 (4C), 130.8, 131.0, 132.5, 135.1, 136.8,
159.8, 160.7 (2C), 161.08, 161.12, 162.7, 163.2, 164.9, 167.5, 170.0 ppm; FTIR (CHCl3):  1766.3,
1736.9, 1601.4, 1461.2, 1407.4, 1352.1, 1330.4, 1158.2 cm-1; LRMS (70 eV): m/z (%): 616 (M+, 20),
452 (28), 451 (100), 165 (66), 137 (17), 122 (25); elemental analysis calcd (%) for C33H32N2O10: C
64.28; H 5.23; N 4.54; found: C 64.51; H 5.50; N 4.41. Yellowish solid.
2-Methoxy-1-(6-(2-methoxy-2-oxoethyl)-2-phenyl-5-p-tolylpyrimidin-4-yl)-2-oxoethyl
4-
methylbenzoate (5da): (241 mg; 52%).1H NMR (400 MHz, CDCl3): δ 2.35 (s, 3H), 2.40 (s, 3H), 3.66
(s, 3H), 3.74 (s, 2H), 3.79 (s, 3H), 6.23 (s, 1H), 7.09 (m, 2H), 7.21-7.28 (m, 4H), 7.45-7.48 (m, 3H),
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7.92 (d, 2H, J(H,H)= 8.3 Hz), 8.48-8.51 (m, 2H) ppm; C NMR (100 MHz, CDCl3): δ 21.2, 21.7, 41.9,
52.1, 52.6, 72.4, 126.2, 128.5 (4C), 129.06 (2C), 129.15, 129.23, 129.5, 129.6, 130.1 (2C), 130.3, 130.9,
132.7, 136.8, 138.7, 144.2, 160.3, 162.96, 163.01, 165.1, 167.7, 169.9 ppm; FTIR (CHCl3):  1767.3,
1733.4, 1564.9, 1535.6, 1408.8, 1267.8, 1179.0, 1102.1 cm-1; LRMS (70 eV): m/z (%): 524 (M+, 14),
406 (12), 405 (44), 347 (3.3), 317 (4.0), 287 (3.7), 119 (100), 91 (24); elemental analysis calcd (%) for
C31H28N2O6: C 70.98; H 5.38; N 5.34; found: C 70.97; H 5.45; N 5.39. Pale yellowish amorphous solid.
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1-(5-(4-Fluorophenyl)-6-(2-methoxy-2-oxoethyl)-2-phenylpyrimidin-4-yl)-2-methoxy-2-oxoethyl 4-
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fluorobenzoate (5ea): (215 mg; 42%). H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 3.72 (s, 2H), 3.80
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(s, 3H), 6.22 (s, 1H), 7.02 (td, 1H, J(H,H)= 8.6 and 2.8 Hz), 7.10 (t, 2H, J(H,H)= 8.6 Hz), 7.16-7.23 (m,
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2H), 7.34-7.38 (m, 1H), 7.44-7.50 (m, 3H), 8.03-8.06 (m, 2H), 8.48-8.50 (m, 2H) ppm; C NMR (100
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MHz, CDCl3): δ 41.9, 52.2, 52.7, 72.4, 115.6 (2C) (d, J(F,C) = 22.6 Hz), 116.0 (d, J(F,C) = 21.9 Hz),
116.2 (d, J(F,C) = 21.9 Hz), 125.1 (d, J(F,C) = 2.8 Hz), 128.5 (4C), 129.3 (d, J(F,C) = 3.5 Hz), 131.1, 131.4
(2C) (d, J(F,C) = 8.5 Hz), 131.6, 132.7 (2C) (d, J(F,C) = 9.9 Hz), 136.6, 160.3, 162.97 (d, J(F,C) = 249
Hz), 163.03, 163.4, 164.0, 166.2 (d, J(F,C) = 256 Hz), 167.3, 169.7 ppm; FTIR (CHCl3):  1767.1,
1736.3, 1604.3, 1565.0, 1535.2, 1508.9, 1409.6, 1264.8, 1239.2, 1156.3 cm-1; LRMS (70 eV): m/z (%):
532 (M+, 16), 410 (8.6), 409 (33), 351 (3.9), 321 (4.6), 133 (9.3), 123 (100), 95 (15); elemental analysis
calcd (%) for C29H22F2N2O6: C 65.41; H 4.16; N 5.26; found: C 65.51; H 4.30; N 4.97. Pale yellowish
amorphous solid.
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chlorobenzoate (5fa): (181 mg; 41%). 1:1 mixture of atropisomers. H NMR (400 MHz, CDCl3): δ
3.67 (s, 3H), 3.73 and 3.73 (s and s, 2H), 3.80 and 3.82 (s and s, 3H), 6.23 and 6.24 (s and s, 1H), 7.11-
7.13 (m, ½H), 7.20-7.21 (m, ½H), 7.25-7.30 (m, 1H), 7.36-7.42 (m, 3H), 7.44-7.49 (m, 3H), 7.53-7.56
(m, 1H), 7.88-7.92 (m, 1H), 7.98-7.99 (m, 1H), 8.48-8.50 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ
41.90 and 41.95, 52.3, 52.78 and 52.82, 72.8 and 72.9, 127.5, 127.6, 128.2, 128.5, 129.2, 129.3, 129.7,
129.8, 130.0, 130.1, 130.35, 130.38, 131.1 and 131.21, 131.25, 133.6, 134.7, 135.0, 135.1, 135.2, 135.3,
136.5, 159.8, 159.9, 162.75, 162.82, 163.6, 163.7, 163.9, 167.0, 167.1, 169.6 ppm; FTIR (CHCl3): 
1768.2, 1736.9, 1564.3, 1536.1, 1417.3, 1400.8, 1252.6, 1224.8 cm-1; LRMS (70 eV): m/z (%): 566
(11), 564 (M+, 16), 427 (14), 425 (36), 141 (32), 139 (100), 111 (26); elemental analysis calcd (%) for
C29H22Cl2N2O6: C 61.60; H 3.92; N 4.95; found: C 61.60; H 3.92; N 4.73. Pale yellowish amorphous
solid.
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2-Methoxy-1-(6-(2-methoxy-2-oxoethyl)-2-(3-nitrophenyl)-5-phenylpyrimidin-4-yl)-2-oxoethyl
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benzoate (5ab): (262 mg; 48%). H NMR (400 MHz, CDCl3): δ 3.67 (s, 3H), 3.77 (s, 2H), 3.82 (s,
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3H), 6.29 (s, 1H), 7.24 (d, 1H, 3J(H,H) = 7.6 Hz), 7.30-7.35 (m, 3H), 7.43 (t, 2H, 3J(H,H) = 8.1 Hz), 7.49 (t,
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8
3
3
3
1H, J(H,H) = 7.6 Hz), 7.57 (t, 1H, J(H,H) = 7.6 Hz), 7.65 (t, 1H, J(H,H) = 7.8 Hz), 8.01-8.03 (m, 2H),
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8.31-8.34 (m, 1H), 8.80-8.83 (m, 1H), 9.31-9.32 (m, 1H) ppm; C NMR (100 MHz, CDCl3): δ 41.8,
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52.3, 52.8, 72.4, 123.4, 125.4, 128.4 (2C), 128.8, 128.9, 129.1, 129.17, 129.20, 129.23, 129.5, 130.0
(2C), 132.9, 133.6, 133.8, 134.0, 138.6, 148.8, 160.7, 161.0, 163.5, 165.0, 167.3, 169.6 ppm; FTIR
(CHCl3):  3690.1, 3462.0, 3024.5, 1768.2, 1735.7, 1602.6, 1560.6, 1438.7, 1406.0, 1349.7, 1268.9,
1107.2 cm-1; LRMS (70 eV): m/z (%): 541 (M+, 3.0), 437 (4.6), 436 (18), 243 (3.4), 140 (5.7), 115 (5.8),
105 (100), 77 (19); elemental analysis calcd (%) for C29H23N3O8: C 64.32; H 4.28; N 7.76; found: C
64.50; H 4.66; N 7.71. Pale yellowish amorphous solid.
1-(2-(4-Chlorophenyl)-6-(2-methoxy-2-oxoethyl)-5-phenylpyrimidin-4-yl)-2-methoxy-2-oxoethyl
1
benzoate (5ac): (280 mg; 53%). H NMR (400 MHz, CDCl3): δ 3.65 (s, 3H), 3.73 (s, 2H), 3.79 (s, 3H),
6.25 (s, 1H), 7.21 (d, 1H, 3J(H,H) = 7.6 Hz), 7.30 (t, 1H, 3J(H,H) = 7.8 Hz), 7.35-7.50 (m, 7H), 7.57 (t, 1H,
3J(H,H) = 7.5 Hz), 8.01 (d, 2H, 3J(H,H) = 8.3 Hz), 8.44 (d, 2H, 3J(H,H) = 7.6 Hz) ppm; 13C NMR (100 MHz,
CDCl3): δ 41.9, 52.2, 52.6, 72.4, 128.4 (2C), 128.7 (2C), 128.9, 129.0 (2C), 129.3, 129.4, 129.8 (2C),
130.0 (2C), 132.8, 133.2, 133.5, 135.3, 137.3, 160.2, 162.3, 163.0, 165.0, 167.4, 169.7 ppm. 1 carbon
signal buried under aromatic region at 128.9; FTIR (CHCl3):  1766.3, 1735.3, 1562.2, 1534.7,
1408.4, 1266.5, 1176.0, 1092.6 cm-1; LRMS (70 eV): m/z (%): 530 (M+, 6.2), 427 (6.7), 425 (17), 141
(3.7), 140 (8.1), 115 (7.8), 105 (100), 77 (33); elemental analysis calcd (%) for C29H23ClN2O6: C 65.60;
H 4.37; N 5.28; found: C 65.39; H 4.52; N 5.40. Pale yellowish amorphous solid.
2-Methoxy-1-(6-(2-methoxy-2-oxoethyl)-5-phenyl-2-p-tolylpyrimidin-4-yl)-2-oxoethyl
benzoate
1
(5ad): (299 mg; 48%). H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 3.65 (s, 3H), 3.73 (s, 2H), 3.79 (s,
3
3H), 6.24 (s, 1H), 7.20-7.22 (m, 1H), 7.25-7.30 (m, 3H), 7.35-7.49 (m, 5H), 7.56 (t, 1H, J(H,H) = 7.5
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Hz), 8.02 (d, 2H, 3J(H,H) = 7.3 Hz), 8.39 (d, 2H, 3J(H,H) = 8.1 Hz), ppm; 13C NMR (100 MHz, CDCl3): δ
21.5, 41.9, 52.1, 52.6, 72.6, 128.3 (2C), 128.5 (2C), 128.77, 128.84, 128.9, 129.2 (2C), 129.3, 129.5,
130.1 (2C), 132.2, 133.4, 133.5, 134.1, 141.3, 160.0, 162.7, 163.3, 165.0, 167.6, 169.8 ppm. 1 carbon
signal buried under aromatic region; FTIR (CHCl3): 1766.3, 1734.4, 1561.3, 1533.7, 1438.0,
1408.9, 1347.7, 1266.7, 1176.9, 1107.6 cm-1; LRMS (70 eV): m/z (%): 510 (M+, 30), 405 (42), 347
(6.9), 317 (10), 140 (11), 116 (20), 105 (100), 77 (30); elemental analysis calcd (%) for C30H26N2O6: C
70.58; H 5.13; N 5.49; found: C 70.42; H 5.26; N 5.86. Pale yellowish amorphous solid.
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2-Methoxy-1-(6-(2-methoxy-2-oxoethyl)-2-methyl-5-phenylpyrimidin-4-yl)-2-oxoethyl
benzoate
1
(5ae): (161 mg; 37%). H NMR (400 MHz, CDCl3): δ 2.77 (s, 3H), 3.60 (s, 3H), 3.62 (s, 2H), 3.75 (s,
3H), 6.16 (s, 1H), 7.15-7.17 (m, 1H), 7.27-7.32 (m, 1H), 7.35-7.47 (m, 5H), 7.53-7.57 (m, 1H), 7.98-
13
8.01 (m, 2H) ppm; C NMR (100 MHz, CDCl3, 25ºC): δ 25.8, 41.6, 52.1, 52.6, 72.3, 128.3 (2C),
128.76, 128.80, 128.85, 128.88, 129.3, 129.5, 130.0 (2C), 131.9, 133.35, 133.43, 159.9, 162.3, 165.0,
167.3, 167.5, 169.7 ppm; FTIR (CHCl3):  1766.0, 1736.0, 1603.2, 1566.0, 1543.1, 1421.8, 1267.2,
1108.3 cm-1; LRMS (70 eV): m/z (%): 434 (M+, 10), 329 (22), 271 (22), 231 (39), 172 (19), 105 (100),
103 (41) 77 (40); HRMS calculated for C24H22N2O6: 434.1478, found 434.1490. Yellowish oil.
(2'Z)-Dimethyl
2,2'-(5-(isobutyryloxy)-5-isopropyl-2-phenylpyrimidine-4,6(1H,5H)-
diylidene)diacetate (6ga): Two isomers. Separated by flash chromatography (20% EtOc/Hexanes);
1
major isomer (more polar) (263 mg; 60%), minor isomer (15 mg; 4%). (Major isomer): H NMR (400
3
3
3
MHz, CDCl3): δ 0.96 (d, 3H, J(H,H) = 6.8 Hz), 0.99 (d, 3H, J(H,H) = 6.8 Hz), 1.19 (d, 6H, J(H,H) = 7.1
Hz), 2.22-2.29 (m, 1H), 2.55-2.62 (m, 1H), 3.72 (s, 3H), 3.74 (s, 3H), 5.09 (s, 1H), 5.35 (s, 1H), 7.44-
13
7.53 (m, 3H), 8.07-8.09 (m, 2H), 11.87 (s, 1H) ppm; C NMR (100 MHz, CDCl3, 25ºC): δ 16.1, 16.2,
18.4, 18.5, 34.2, 41.8, 51.1, 51.3, 90.4, 108.3, 127.4 (2C), 128.9 (2C), 132.1, 132.4, 148.2, 153.4, 154.8,
165.7, 169.9, 173.9 ppm, 1C signal buried under the CDCl3 signals; FTIR (CHCl3): 1744.2, 1720.8,
1675.1, 1632.1, 1591.7, 1567.6, 1435.3, 1283.8, 1251.3, 1159.4 cm-1; LRMS (70 eV): m/z (%): 428
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(M+, 12), 358 (33), 357 (100), 284 (25), 283 (25), 270 (33), 251 (21), 210 (34); elemental analysis calcd
(%) for C23H28N2O6: C 64.47; H 6.59; N 6.54; found: C 64.37; H 6.58; N 6.30. Orange amorphous solid.
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2
3
4
5
6
7
1
(5-Isopropyl-6-methyl-2-phenylpyrimidin-4-yl)methyl isobutyrate (12): (76 mg; 40%). H NMR
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9
3
3
(400 MHz, CDCl3): δ 1.24 (d, 6H, J(H,H)= 7.1 Hz), 1.38 (d, 6H, J(H,H) = 7.3 Hz), 2.62-2.73 (m, 1H),
2.67 (s, 3H), 3.27-3.34 (m, 1H), 5.29 (s, 2H), 7.42-7.45 (m, 3H), 8.38-8.41 (m, 2H) ppm; 13C NMR (100
MHz, CDCl3, 25ºC): δ 19.0 (2C), 20.9 (2C), 24.1, 27.5, 34.0, 65.1, 128.0 (2C), 128.3 (2C), 130.1, 134.2,
137.7, 160.9, 161.1, 165.8, 176.7 ppm; FTIR (CHCl3):  2977.5, 1732.6, 1545.5, 1469.0, 1436.2,
1401.8, 1189.5, 1155.9 cm-1; LRMS (70 eV): m/z (%): 312 (M+, 19), 242 (25), 241 (100), 224 (67), 200
(13), 104 (33), 57 (20); elemental analysis calcd (%) for C19H24N2O2: C 73.05; H 7.74; N 8.97; found: C
73.12; H 7.81; N 9.33. Yellowish oil.
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4,6-Dimethyl-2-phenylpyrimidin-5-yl pivalate (13): (63 mg; 35%). H NMR (400 MHz, CDCl3): δ
13
1.42 (s, 9H), 2.42 (s, 6H), 7.43-7.47 (m, 3H), 8.39-8.41 (m, 2H) ppm; C NMR (100 MHz, CDCl3,
25ºC): δ 19.1 (2C), 27.1 (3C), 39.3, 128.2 (2C), 128.4 (2C), 130.1, 137.5, 141.9, 159.1 (2C), 160.9,
175.4 ppm; FTIR (CHCl3):  2978.9, 1748.9, 1601.7, 1573.4, 1535.4, 1435.7, 1403.6, 1348.5, 1273.0,
1226.4, 1107.1 cm-1; LRMS (70 eV): m/z (%): 284 (M+, 11), 251 (9.3), 200 (62), 130 (17), 104 (29), 85
(18), 57 (100); elemental analysis calcd (%) for C17H20N2O2: C 71.81; H 7.09; N 9.85; found: C 71.77;
H 7.30; N 10.09. White amorphous solid.
ASSOCIATED CONTENT
13
Optimization of the reaction conditions for the conversion of 6aa into 5aa. Copies of 1H NMR and
C
NMR spectra for compounds 5, 6, 8, 9, 11 and 12. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: fgarcia@ipna.csic.es; dtejedor@ipna.csic.es
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Present Addresses
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†Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse
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11, 44227 Dortmund, Germany.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Spanish Ministerio de Economía y Competitividad (MICINN) and
the European Regional Development Fund (CTQ2011- 28417-C02-02). S.L.T. thanks the Spanish MEC
for a FPU grant.
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tínez, A. G.; Fernandez, A. H.; Álvarez, R. M.; Silva Losada, M. C.; Vílchez, D. M.; Subrama-
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nian, L. R.; Hanack, M. Synthesis 1990, 881.
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5. (a)Tejedor, D.; López-Tosco, S.; González-Platas, J.; García-Tellado, F. Chem. Eur. J. 2009,
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9. The reaction requires an acid chloride, alkyl propiolate and stoichiometric amounts of triethyl-
amine. Under these conditions, primary aliphatic acid chlorides are transformed into the corre-
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