Oxidative Dehydrosulfurative Carbon-Oxygen Cross-Coupling of 3,4-Dihydropyrimidine-2-thiones with Aryl Alcohols

Article abstract of DOI:10.1021/acs.joc.1c00273

A Pd-catalyzed/Cu-mediated oxidative dehydrosulfurative carbon-oxygen cross-coupling reaction of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) with aryl alcohols is described. Due to the ready availability of diverse DHPMs and aryl alcohols, the reaction method offers facile access to biologically and pharmacologically valuable 2-aryloxypyrimidine derivatives with rapid diversification.

Full text of DOI:10.1021/acs.joc.1c00273

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Note
Oxidative Dehydrosulfurative Carbon−Oxygen Cross-Coupling of
3,4-Dihydropyrimidine-2-thiones with Aryl Alcohols
Trong Nguyen Huu Phan, Jihong Lee, Hyunik Shin, and Jeong-Hun Sohn*
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ABSTRACT: A Pd-catalyzed/Cu-mediated oxidative dehydrosulfura-
tive carbon−oxygen cross-coupling reaction of 3,4-dihydropyrimidin-
1H-2-thiones (DHPMs) with aryl alcohols is described. Due to the
ready availability of diverse DHPMs and aryl alcohols, the reaction
method offers facile access to biologically and pharmacologically
valuable 2-aryloxypyrimidine derivatives with rapid diversification.
Scheme 1. Synthesis of 2-Aryloxypyrimidines
s well as being an integral part of DNA and RNA, the
pyrimidine motif has been of interest to organic and
A
medicinal chemists due to its diverse biological and
pharmacological properties.1 Comprehensive research on this
privileged scaffold has generated several commercial drugs,
such as the hypocholesterolemic agent rosuvastatin,2 the
potent anticancer drug imatinib,3 the tyrosine kinase inhibitors
ruxolitinib, tofacitinib,4 baricitinib,5 and ribociclib,6 and the
antifungal agent voriconazole.7 In addition to these 2-amino-
and 2-(H)pyrimidine drugs, 2-aryloxypyrimidine compounds,
such as bispyribac-sodium8 and pyriminobac-methyl9 as
herbicides and purmorphamine10 as an osteogenesis inducer,
have exhibited potent biological activity (Figure 1). Recently,
2-aryloxypyrimidine compounds were shown to selectively
inhibit PDGFRα, which induces apoptosis and autophagy in
carcinoma cells.11
Figure 1. Structures of purmorphamine, bispyribac-sodium, and
pyriminobac-methyl.
overcome this limitation, we have used 3,4-dihydropyrimidin-
1H-2-thione (DHPM), which is readily available via the
Traditionally, 2-aryloxypyrimidines have been prepared by
nucleophilic aromatic substitution12 or Ullmann-type C−O
cross-coupling of pyrimidine possessing (pseudo)halide at the
C2 position with aryl alcohol (Scheme 1A).13 Due to the
requirement for multistep synthesis of most of the pyrimidine
partners, especially for densely substituted ones, these reaction
protocols are limited with respect to rapid diversification. To
Received: February 3, 2021
Published: March 25, 2021
https://doi.org/10.1021/acs.joc.1c00273
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 5423−5430
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Note
Biginelli three-component reaction,14 as a surrogate for the C2-
(pseudo)halopyrimidine.
a
Table 1. Optimization of Reaction Conditions
DHPMs with diverse substituents at the C4−C6 positions
were demonstrated to be suitable substrates for Pd-catalyzed/
Cu-mediated dehydrosulfurative C−C or C−N cross-coupling
with concomitant oxidative dehydrogenation (aromatization)
to yield C2-arylated (azolated),15 -alkynylated,16 and -ami-
nated pyrimidines17 in a single step.18,19 Recently, we reported
a Cu-mediated oxidative dehydrosulfurative C−O cross-
coupling of DHPMs with primary, secondary, and tertiary
trialkylborates (boric esters) to yield the corresponding 2-
alkoxypyrimidines, in moderate-to-good yields (Scheme 1B).20
In the course of these studies, we found that triphenylborate
was also compatible with this method for producing the 2-
phenoxypyrimidine derivative (R1 = Ph, R2 = CO2Et, and R3 =
Me). However, this reaction protocol is not practical for
preparing various 2-aryloxypyrimidine derivatives due to
nontrivial triarylborate synthesis. This hurdle led us to use
readily available aryl alcohols instead of triarylborates. We
report herein a Pd-catalyzed/Cu-mediated oxidative dehydro-
sulfurative C−O cross-coupling of DHPMs with aryl alcohols
to yield 2-aryloxypyrmidines in a single step (Scheme 1C).
Due to the ready availability of both coupling partners, the
reaction method offers a shortcut to 2-aryloxypyrimidine
derivatives with rapid diversification. To our knowledge, no
other reports describing transition-metal-catalyzed direct C−O
cross-coupling of the substrate bearing the thiono (latent free-
thiol) leaving group with alcohol have been published.
Previously, we found that the oxidative dehydrogenation
(aromatization) occurred under an argon atmosphere in both
the Pd-catalyzed/Cu-mediated and Cu-mediated reactions of
DHPMs, in which Cu species presumably served as
oxidants.15−17,20 Thus, our initial studies were accomplished
under an argon atmosphere with the reaction of DHPM 1a and
phenol. The reaction in the presence of palladium(II) acetate
(Pd(OAc)2) (20 mol %), Cu(I)-thiophene-2-carboxylate
(CuTC, 3.0 equiv), and K2CO3 (3.0 equiv) in toluene at
100 °C for 18 h provided the desired 2-phenoxypyrimidine
3aa21 in 47% yield. This result motivated us to perform
subsequent optimization studies under various reaction
conditions (Table 1). With respect to the base, we observed
that K3PO4, which provided the desired product in 63% yield,
was better than the other bases examined in the studies, such
as K2CO3, potassium t-butoxide (t-BuOK), lithium hexame-
thyldisilazide (LiHMDS), and Cs2CO3 (entries 1−5). Solvents
such as N,N-dimethylformamide (DMF), 1,4-dioxane, acetoni-
trile (MeCN), o-xylene, and N-methyl-2-pyrrolidone (NMP)
were less effective than toluene (entries 6−10). When
phosphine ligands, such as 2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl (BINAP), 1,1′-bis(diphenylphosphino)ferrocene
(dppf), tris(o-tolyl)phosphine (P(o-tolyl)3), 1,3-bis-
(diphenylphosphino)propane (dppp), 1,10-phenanthroline
(1,10-phen), 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl
(Tol-BINAP), and triphenylphosphine (PPh3), were inves-
tigated for further optimization (entries 11−17), we found that
P(o-tolyl)3 improved the reaction yield up to 80%. With
respect to Pd sources, tris(dibenzylideneacetone)-
dipalladium(0) (Pd2(dba)3), PdCl2, and PdCl2(PPh3)2 were
less effective than Pd(OAc)2 (entries 18−20). The CuTC was
best among the Cu sources examined in the studies, and three
equivalents of it were optimal for generating the desired
product,22,23 as shown in our previous studies on the synthesis
of 2-aryl- and 2-aminopyrimidines.15,17 In the absence of a Cu
entry
Pd/ligand
base
solvent
yield (%)
1
2
Pd(OAc)2
Pd(OAc)2
K2CO3
tBuOK
LiHMDS
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
dioxane
MeCN
o-xylene
NMP
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
47
37
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
28
20
63
trace
trace
trace
55
trace
51
30
80
65
58
48
35
45
78
10
11
12
13
14
15
16
17
18
19
20
Pd(OAc)2/BINAP
Pd(OAc)2/dppf
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/dppp
Pd(OAc)2/1,10-phen
Pd(OAc)2/Tol-BINAP
Pd(OAc)2/PPh3
Pd2(dba)3/P(o-tolyl)3
PdCl2/P(o-tolyl)3
PdCl2(PPh3)2/P(o-tolyl)3
PdCl2(PPh3)2/P(o-tolyl)3
P(o-tolyl)3
53
10
38
0
b
21
22
23
b
P(o-tolyl)3
a
Reaction conditions: DHPM 1a (0.18 mmol), PhOH 2a (0.18
mmol), Pd catalyst (20 mol %), phosphine ligand (30 mol %), CuTC
(0.54 mmol), base (0.54 mmol), and solvent (1.0 mL) at 100 °C for
18 h under Ar. The reaction in the absence of a Cu source.
b
or Pd source, the reaction afforded the desired product in 10%
or 38% yield, respectively (entries 21 and 22). When both Cu
and Pd sources were not present in the reaction, the desired
product was not produced (entry 23).24
Under the optimal reaction conditions, we examined the
scope of the reaction with diverse DHPM and aryl alcohol
coupling partners. With respect to aryl alcohols, we found no
clear preference for either electron-withdrawing or -donating
substituents at the para position of aryl alcohols. When DHPM
1a was reacted with p-cresol or 4-methoxyphenol, the desired
pyrimidine products 3ab21 and 3ac were produced in 63% and
78% yields, respectively (Scheme 2). Halides Cl, Br, and I at
the para position of the aryl alcohol provided the
corresponding products 3ad,21 3ae,25 and 3af in 70−73%
yields. Other electron-withdrawing groups, such as cyano and
nitro groups yielding 3ag (52%) and 3ah12e (70%),
respectively, were also compatible with the reaction, albeit
with a low yield in the case of the formyl group providing 3ai.
We next examined the reaction scope with respect to DHPM
substrates by varying the substituents at the C4−C6 positions.
For R1 at the C5 position, methyl, i-propyl, and t-butyl groups
afforded the desired products 3aj,12a 3ak, and 3al, respectively,
in good yields. With respect to the substituents at C6 (R2), we
found that both alkyl and aryl groups, which gave the
corresponding products 3am−ao in 65−79% yields, were
suitable for the reaction method. A functionalized aryl group,
such as 4-fluorophenyl at C6, also yielded the desired product
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Note
products 3ba, 3bb,21 and 3bc12d were produced in 42−78%
yields.
a
Scheme 2. Scope of the Reaction
Our previous oxidative dehydrosulfurative C−C, C−N, or
C−O cross-coupling of DHPM possessing the t-butyl group at
the C4 position provided the debutylated pyrimidine as the
major product.15−17,20 Similarly, the reaction of the DHPM 4
bearing the C4 t-butyl group with phenol also resulted in the
debutylated product 526 as the major product (eq 1, Scheme
3). The results support that the aromatization of the
Scheme 3. Related Reaction Studies
dihydropyrimidine proceeds via the generation of a radical
intermediate presumably due to the Cu species present in the
reaction, as described in the oxidative dehydrogenation of 2-
alkylthiodihydropyrimidines.27 When 2-mercaptopyrimidine 6
was reacted with phenol, the corresponding ether 7 was
obtained in 56% yield (eq 2), which is in line with the
proposition that tautomerization of the DHPM yielding the
corresponding thiol is involved in the reaction. We found that
pyrimidinyl thioether 828 was also compatible with the reaction
method (eq 3), and the reaction of dihydropyrimidinyl
thioether 929 proceeded via oxidative dehydrogenation to
yield 8 as an intermediate, prior to the C−O coupling (eq 4).
On the basis of these results, it is likely that the reaction
proceeds via tautomerization and oxidative dehydrogenation,
followed by C−O coupling.
In conclusion, we have developed a Pd-catalyzed/Cu-
mediated oxidative dehydrosulfurative C−O cross-coupling
of DHPMs with aryl alcohols to yield 2-aryloxypyrimidine
derivatives in a single step.30 The method is compatible with
diverse DHPM and aryl alcohol coupling partners. Together
with the ready availability of DHPM substrates prepared by the
Biginelli three-component reaction, the reaction method allows
facile access to biologically and pharmacologically valuable 2-
aryloxypyrimidine derivatives with rapid diversification.
a
Reaction conditions: DHPM 1 (0.18 mmol), aryl alcohol 2 (0.18
mmol), Pd(OAc)2 (0.036 mmol), P(o-tolyl)3 (0.054 mmol), CuTC
(0.54 mmol), K3PO4 (0.54 mmol), and PhMe (1.0 mL) at 100 °C
under Ar.
3ap (51%). Regarding the aryl group at the C4 position (Ar1),
the reaction of DHPM, bearing a 4-methyl, 4-methoxy group,
or 3,5-dimethyl group at the C4 aryl position, provided the
desired products 3aq,21 3ar, and 3as in 64−81% yields.
Halides F, Cl, and Br at the C4 aryl para position provided
3at−3av without formation of the potentially competitive
biaryl ether between the C4 aryl and phenol. The nitro group
at the C4 aryl position, giving 3aw in 70% yield, was also
suitable for the reaction method. The DHPMs possessing a
heterocyclic pyridinyl and thiophenyl group, or bicyclic
naphthyl group, at the C4 position were efficiently transformed
into the corresponding products 3ax−az. When some of the
above DHPMs were reacted with other aryl alcohols, such as p-
cresol, 4-bromophenol, and 4-nitrophenol, the corresponding
EXPERIMENTAL SECTION
■
General. Common solvents were purified before use. Toluene
(PhMe) was purified by distillation from sodium-benzophenone ketyl.
All reagents were reagent grade and purified where necessary. CuTC
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Note
was prepared following the synthetic procedure described in the
literature.31 Reactions were monitored by thin-layer chromatography
(TLC) using Whatman precoated silica gel plates. Flash column
chromatography was performed over ultrapure silica gel (230−400
mesh) from Merck. Melting points (mp) were determined in opened
PhOH (339 mg, 3.60 mmol), Pd(OAc)2 (161 mg, 0.717 mmol), P(o-
tolyl)3 (262 mg, 0.861 mmol), CuTC (2.06 g, 10.8 mmol), and
K3PO4 (2.29 g, 10.8 mmol). The reaction vessel was sealed by a
septum and degassed with argon three times. To the reaction mixture
was added PhMe (20 mL), and the resulting mixture was allowed to
stir at 100 °C in an oil bath for 18 h. The mixture was filtered through
a Celite pad and rinsed with EtOAc (100 mL). The filtrate was
washed with saturated aqueous K2CO3 solution (20 mL) and brine
(20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash column chromatography (n-
hexane/EtOAc, 10:1) to give 3aa (939 mg, 78%).
1
capillary tubes and are uncorrected. H NMR and 13C{1H} NMR
spectra were recorded on a Bruker AVANCE 300 (300 MHz) or 600
(600 MHz) spectrometer using residual solvent peaks as an internal
standard (CHCl3 δ 7.26 ppm for proton and δ 77.0 ppm for carbon
and CH2Cl2 δ 5.32 ppm for proton and δ 54.0 ppm for carbon).
Multiplicities for 1H NMR are designated as s = singlet, d = doublet, t
= triplet, q = quartet, sext = sextet, sept = septet, dd = doublet of
doublets, ddd = doublet of doublets of doublets, dt = doublet of
triplets, m = multiplet, and br = broad. Infrared spectra (IR) were
recorded on a JASCO FT/IR-4100 spectrometer and are reported in
reciprocal centimeters (cm−1). High-resolution mass spectra (HRMS)
were obtained on a BrukermicroTOF-Q.
Ethyl 4-Methyl-6-phenyl-2-(p-tolyloxy)pyrimidine-5-carboxylate
(3ab).21 Eluent in chromatography: n-hexane/EtOAc 10:1. Yield:
1
39.4 mg, 63%; pale yellow oil. H NMR (600 MHz, CDCl3): δ 7.59
(m, 2H), 7.45−7.38 (m, 3H), 7.20 (d, J = 8.3 Hz, 2H), 7.12 (d, J =
8.4 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.56 (s, 3H), 2.37 (s, 3H), 1.06
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.1,
168.1, 166.6, 164.0, 150.5, 137.4, 134.7, 130.2, 129.8, 128.39, 128.35,
121.2, 120.9, 61.8, 22.7, 20.9, 13.6.
Ethyl 2-(4-Methoxyphenoxy)-4-methyl-6-phenylpyrimidine-5-
carboxylate (3ac). Eluent in chromatography: n-hexane/EtOAc
10:1. Yield: 51.1 mg, 78%; yellow oil. 1H NMR (300 MHz,
CDCl3): δ 7.59 (m, 2H), 7.41 (m, 3H), 7.16 (d, J = 8.9 Hz, 2H),
6.91 (d, J = 8.9 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.56
(s, 3H), 1.05 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
169.1, 168.1, 166.6, 164.2, 156.8, 146.3, 137.3, 130.2, 128.4, 128.3,
122.4, 120.8, 114.3, 61.8, 55.6, 22.7, 13.6. IR (film) cm−1: 3053, 2971,
1703, 1603, 1565, 1412, 1263, 729. HRMS (ESI) m/z: [M + H]+
calcd for C21H21N2O4, 365.1501; found, 365.1514.
Synthesis of DHPMs. Following the literature procedure,32 ethyl
6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxy-
late (1a),32 methyl 4-methyl-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyr-
imidine-5-carboxylate (1b),32 isopropyl 6-methyl-4-phenyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (1c),33 tert-butyl 6-meth-
yl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(1d),34 ethyl 6-ethyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (1e),35 ethyl 4-phenyl-6-propyl-2-thioxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (1f),16 ethyl 4,6-diphenyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (1g),36 6-(4-fluorophen-
yl)-4-phenyl-3,4-dihydropyrimidine-2(1H)-thione (1h),37 ethyl 6-
methyl-2-thioxo-4-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxy-
late (1i),32 ethyl 4-(4-methoxyphenyl)-6-phenyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1j),36 ethyl 4-(3,5-dimethyl-
phenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(1k),16 ethyl 4-(4-fluorophenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (1l),35 ethyl 4-(4-chlorophenyl)-6-phenyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1m),36 ethyl 4-(4-
bromophenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-car-
boxylate (1n),38 ethyl 4-(4-nitrophenyl)-6-phenyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1o),36 ethyl 6-phenyl-4-(pyridin-
3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1p),17
ethyl 6-phenyl-4-(thiophen-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (1q),15b ethyl 4-(naphthalen-2-yl)-6-phenyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1r),17 ethyl 6-
methyl-2-thioxo-4-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxy-
late (1s),32 ethyl 4-(4-fluorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (1t),32 and ethyl 4-(4-methoxyphen-
yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(1u)39 were prepared.
Ethyl 2-(4-Chlorophenoxy)-4-methyl-6-phenylpyrimidine-5-car-
boxylate (3ad).21 Eluent in chromatography: n-hexane/EtOAc
1
10:1. Yield: 48.4 mg, 73%; pale yellow solid. H NMR (300 MHz,
CDCl3): δ 7.60 (d, J = 1.4 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.46−
7.34 (m, 5H), 7.19 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H),
1.06 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 169.3,
167.9, 166.7, 163.6, 151.3, 137.1, 130.5, 130.4, 129.4, 128.5, 128.3,
123.0, 121.3, 61.9, 22.7, 13.6.
Ethyl 2-(4-Bromophenoxy)-4-methyl-6-phenylpyrimidine-5-car-
boxylate (3ae).25 Eluent in chromatography: n-hexane/EtOAc 10:1.
1
Yield: 52.0 mg, 70%; white solid. H NMR (600 MHz, CDCl3): δ
7.59 (m, 2H), 7.51 (m, 2H), 7.44 (m, 3H), 7.14 (m, 2H), 4.18 (q, J =
7.1 Hz, 2H), 2.57 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl3): δ 169.3, 167.9, 166.7, 163.5, 151.8, 137.1, 132.4,
130.4, 128.5, 128.3, 123.4, 121.4, 118.2, 61.9, 22.7, 13.6.
Ethyl 2-(4-Iodophenoxy)-4-methyl-6-phenylpyrimidine-5-car-
boxylate (3af). Eluent in chromatography: n-hexane/EtOAc 10:1.
1
Yield: 60.4 mg, 73%; yellow solid, mp 58−59 °C. H NMR (600
General Procedure for the Synthesis of 2-Aryloxypyrimi-
dine. To an oven-dried test tube with a magnetic stirring bar were
added DHPM or pyrimidine-2-thiol (0.18 mmol, 1.0 equiv), aryl
alcohol (0.18 mmol, 1.0 equiv), CuTC (103 mg, 0.54 mmol, 3.0
equiv), Pd(OAc)2 (8.0 mg, 0.036 mmol, 0.20 equiv), P(o-tolyl)3 (13
mg, 0.043 mmol, 0.24 equiv), and K3PO4 (114 mg, 0.54 mmol, 3.0
equiv) in PhMe (1 mL). The reaction mixture was degassed with Ar
and then stirred at 100 °C in an oil bath under Ar until the DHPM
completely disappeared. The mixture was filtered through a silica gel
pad and washed with EtOAc (25 mL). The filtrate was washed with
saturated aqueous K2CO3 solution (5 mL) and brine (5 mL), dried
with MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (silica
gel; eluent: n-hexane/EtOAc, 10:1 to 4:1) to give the corresponding
2-aryloxypyrimidine 3, 5, or 7.
MHz, CDCl3): δ 7.71 (m, 2H), 7.59 (m, 2H), 7.44 (m, 3H), 7.03 (m,
2H), 4.19 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 169.3, 167.9, 166.7, 163.5,
152.7, 138.4, 137.1, 130.4, 128.5, 128.3, 123.8, 121.4, 89.0, 61.9, 22.7,
13.6. IR (film) cm−1: 3012, 2932, 1722, 1544, 1476, 1365, 1236,
1081,999, 766, 695. HRMS (ESI) m/z: [M + H]+ calcd for
C20H18IN2O3, 461.0362; found, 461.0351.
Ethyl 2-(4-Cyanophenoxy)-4-methyl-6-phenylpyrimidine-5-car-
boxylate (3ag). Eluent in chromatography: n-hexane/EtOAc 10:1.
Yield: 33.6 mg, 52%; yellow oil. 1H NMR (600 MHz, CDCl3): δ 7.72
(d, J = 8.7 Hz, 2H), 7.57 (m, 2H), 7.47 (m, 1H), 7.42 (m, 2H), 7.37
(d, J = 8.6 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.07 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.5, 167.6,
166.8, 162.9, 156.1, 136.8, 133.7, 130.6, 128.5, 128.3, 122.5, 121.9,
118.4, 108.9, 62.0, 22.7, 13.6. IR (film) cm−1: 2917, 2849, 2123, 1719,
1540, 1243, 1082, 725. HRMS (ESI) m/z: [M + H]+ calcd for
C21H18N3O3, 360.1348; found, 360.1355.
Ethyl 4-Methyl-2-phenoxy-6-phenylpyrimidine-5-carboxylate
(3aa).21 Yield: 48.1 mg, 80%; pale yellow oil. H NMR (600 MHz,
1
CDCl3): δ 7.59 (m, 2H), 7.46−7.38 (m, 5H), 7.24 (m, 3H), 4.18 (q, J
= 7.1 Hz, 2H), 2.58 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl3): δ 169.1, 168.0, 166.5, 163.9, 152.7, 137.2, 130.2,
129.3, 128.33, 128.27, 125.1, 121.5, 121.0, 61.7, 22.7, 13.5. For the
scale-up synthesis, to an oven-dried round-bottom flask with a
magnetic stirring bar were added DHPM 1a (1.00 g, 3.60 mmol),
Ethyl 4-Methyl-2-(4-nitrophenoxy)-6-phenylpyrimidine-5-car-
boxylate (3ah).12e Eluent in chromatography: n-hexane/EtOAc 5:1.
1
Yield: 47.8 mg, 70%; white solid. H NMR (300 MHz, CDCl3): δ
8.31 (m, 2H), 7.58 (m, 2H), 7.50−7.39 (m, 5H), 4.18 (q, J = 7.1 Hz,
2H), 2.59 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (75 MHz,
5426
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Note
CDCl3): δ 169.5, 167.6, 166.8, 162.9, 157.6, 144.8, 136.8, 130.6,
128.6, 128.4, 128.3, 125.3, 122.1, 62.0, 22.7, 13.6.
4-(4-Fluorophenyl)-2-phenoxy-6-phenylpyrimidine (3ap). Eluent
in chromatography: n-hexane/EtOAc 10:1. Yield: 31.4 mg, 51%;
yellow oil. H NMR (600 MHz, CDCl3): δ 8.09 (m, 4H), 7.83 (s,
1
Ethyl 2-(4-Formylphenoxy)-4-methyl-6-phenylpyrimidine-5-car-
boxylate (3ai). Eluent in chromatography: n-hexane/EtOAc 10:1.
1H), 7.52−7.43 (m, 5H), 7.33 (d, J = 7.5 Hz, 2H), 7.28 (d, J = 7.4
Hz, 1H), 7.17 (t, J = 8.6 Hz, 2H). 13C{1H} NMR (151 MHz,
CDCl3): δ 167.6, 166.3, 165.8, 165.6 (C−F, 1JC−F = 252.2 Hz), 163.9
1
Yield: 17.6 mg, 27%; yellow oil. H NMR (600 MHz, CDCl3): δ
10.01 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.59 (m, 2H), 7.46 (m, 1H),
7.41 (m, 4H), 4.19 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 1.07 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 191.0, 169.4, 167.8,
166.8, 163.2, 157.6, 136.9, 133.5, 131.3, 130.5, 128.5, 128.3, 122.1,
121.8, 62.0, 22.7, 13.6. IR (film) cm−1: 2953, 2843, 1713, 1553, 1263,
1054, 863, 731. HRMS (ESI) m/z: [M + H]+ calcd for C21H19N2O4,
363.1345; found, 363.1358.
1
(C−F, JC−F = 252.2 Hz), 153.2, 136.4, 132.7, 131.2, 129.42 (C−F,
3
3JC−F = 8.8 Hz), 129.37 (C−F, JC−F = 8.8 Hz), 129.3, 128.9, 127.3,
125.0, 121.8, 116.0 (C−F, 2JC−F = 21.7 Hz), 115.9 (C−F, 2JC−F = 21.7
Hz), 107.0. IR (film) cm−1: 2920, 2833, 1727, 1524, 1339, 1216, 948,
833, 762, 686, 563. HRMS (ESI) m/z: [M + H]+ calcd for
C22H16FN2O, 343.1247; found, 343.1261.
Methyl 4-Methyl-2-phenoxy-6-phenylpyrimidine-5-carboxylate
Ethyl 4-Methyl-2-phenoxy-6-(p-tolyl)pyrimidine-5-carboxylate
(3aq).21 Eluent in chromatography: n-hexane/EtOAc 10:1. Yield:
(3aj).12a Eluent in chromatography: n-hexane/EtOAc 10:1. Yield:
1
1
40.4 mg, 65%; pale yellow oil. H NMR (600 MHz, CDCl3): δ 7.59
38.1 mg, 66%; pale yellow oil. H NMR (600 MHz, CDCl3): δ 7.59
(m, 2H), 7.45−7.38 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 7.13 (d, J =
8.4 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 2.37 (s, 3H), 1.06
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.0,
168.1, 166.6, 164.0, 150.5, 137.3, 134.7, 130.2, 129.8, 128.4, 128.3,
121.2, 120.9, 61.8, 22.7, 20.9, 13.6.
Ethyl 4-(4-Methoxyphenyl)-2-phenoxy-6-phenylpyrimidine-5-
carboxylate (3ar). Eluent in chromatography: n-hexane/EtOAc
10:1. Yield: 62.1 mg, 81%; brown oil. 1H NMR (600 MHz,
CDCl3): δ 7.65 (m, 4H), 7.47−7.40 (m, 5H), 7.29 (m, 2H), 7.23
(m, 1H), 6.93 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.00 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 168.5, 167.5,
166.6, 164.0, 161.5, 152.9, 137.3, 130.2, 130.1, 129.3, 128.36, 128.35,
125.1, 121.6, 120.3, 113.9, 61.9, 55.3, 13.5. IR (film) cm−1: 2922,
2835, 1725, 1532, 1364, 1246, 1125, 1059, 1015, 843, 767, 694, 534.
HRMS (ESI) m/z: [M + H]+ calcd for C26H23N2O4, 427.1658; found,
427.1655.
Ethyl 4-(3,5-Dimethylphenyl)-2-phenoxy-6-phenylpyrimidine-5-
carboxylate (3as). Eluent in chromatography: n-hexane/EtOAc 10:1.
Yield: 48.9 mg, 64%; yellow oil. 1H NMR (600 MHz, CD2Cl2): δ 7.60
(d, J = 7.0 Hz, 2H), 7.50−7.43 (m, 5H), 7.28−7.23 (m, 5H), 7.14 (s,
1H), 4.06 (q, J = 7.1 Hz, 2H), 2.35 (s, 6H), 1.00 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (151 MHz, CD2Cl2): δ 168.6, 168.4, 167.7, 164.7,
153.6, 138.8, 137.9, 137.7, 132.4, 130.8, 130.0, 129.0, 128.8, 126.5,
125.9, 122.2, 121.7, 62.4, 21.6, 13.9. IR (film) cm−1: 3017, 2934,
1720, 1538, 1472, 1344, 1236, 1152, 1021, 965, 721. HRMS (ESI) m/
z: [M + H]+ calcd for C27H25N2O3, 425.1865; found, 425.1890.
Ethyl 4-(4-Fluorophenyl)-2-phenoxy-6-phenylpyrimidine-5-car-
boxylate (3at). Eluent in chromatography: n-hexane/EtOAc 10:1.
Yield: 53.7 mg, 72%; yellow oil. 1H NMR (600 MHz, CDCl3): δ 7.66
(m, 4H), 7.44 (m, 5H), 7.29 (d, J = 7.6 Hz, 2H), 7.24 (t, J = 7.4 Hz,
1H), 7.12 (t, J = 8.6 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 0.99 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 168.1, 167.7, 166.2,
(d, J = 6.9 Hz, 2H), 7.45−7.39 (m, 5H), 7.25 (m, 3H), 3.70 (s, 3H),
2.56 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 169.2, 168.6,
166.4, 164.0, 152.7, 137.1, 130.4, 129.3, 128.5, 128.3, 125.2, 121.6,
120.7, 52.6, 22.8.
Isopropyl 4-Methyl-2-phenoxy-6-phenylpyrimidine-5-carboxy-
late (3ak). Eluent in chromatography: n-hexane/EtOAc 10:1. Yield:
1
45.8 mg, 73%; yellow oil. H NMR (600 MHz, CDCl3): δ 7.59 (m,
2H), 7.45−7.37 (m, 5H), 7.24 (m, 3H), 5.08 (sept, J = 6.3 Hz, 1H),
2.56 (s, 3H), 1.09 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (151 MHz,
CDCl3): δ 168.8, 167.5, 166.4, 163.8, 152.8, 137.3, 130.2, 129.3,
128.41, 128.37, 125.1, 121.53, 121.52, 69.7, 22.6, 21.3. IR (film)
cm−1: 2954, 2836, 1722, 1535, 1479, 1245, 1223, 1009, 765, 670.
HRMS (ESI) m/z: [M + H]+ calcd for C21H21N2O3, 349.1552; found,
349.1560.
tert-Butyl 4-Methyl-2-phenoxy-6-phenylpyrimidine-5-carboxy-
late (3al). Eluent in chromatography: n-hexane/EtOAc 10:1. Yield:
1
48.9 mg, 75%; yellow oil. H NMR (300 MHz, CDCl3): δ 7.65 (m,
2H), 7.45−7.38 (m, 5H), 7.24 (m, 3H), 2.59 (s, 3H), 1.39 (s, 9H).
13C{1H} NMR (75 MHz, CDCl3): δ 168.5, 166.8, 166.1, 163.4, 152.8,
137.3, 130.0, 129.2, 128.5, 128.2, 125.0, 122.5, 121.4, 82.8, 27.5, 22.5.
IR (film) cm−1: 2925, 2842, 1710, 1542, 1486, 1387, 1266, 1197,
1142, 1088, 836, 771, 691. HRMS (ESI) m/z: [M + H]+ calcd for
C22H23N2O3, 363.1709; found, 363.1700.
Ethyl 4-Ethyl-2-phenoxy-6-phenylpyrimidine-5-carboxylate
(3am). Eluent in chromatography: n-hexane/EtOAc 10:1. Yield:
1
40.7 mg, 65%; yellow oil. H NMR (300 MHz, CDCl3): δ 7.59 (m,
2H), 7.43−7.36 (m, 5H), 7.26−7.20 (m, 3H), 4.17 (q, J = 7.1 Hz,
2H), 2.84 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H), 1.06 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 173.5, 168.1, 166.6,
164.2, 152.8, 137.4, 130.2, 129.3, 128.4, 128.3, 125.1, 121.6, 120.7,
61.8, 28.9, 13.6, 12.6. IR (film) cm−1: 2926, 2836, 1716, 1540, 1485,
1379, 1250, 1239, 1079, 1025, 763, 689. HRMS (ESI) m/z: [M + H]+
calcd for C21H21N2O3, 349.1552; found, 349.1539.
1
1
164.9 (C−F, JC−F = 251.3 Hz), 164.0, 163.2 (C−F, JC−F = 251.3
3
Hz), 152.8, 137.0, 133.1, 130.7 (C−F, JC−F = 8.8 Hz), 130.6 (C−F,
Ethyl 2-Phenoxy-4-phenyl-6-propylpyrimidine-5-carboxylate
3JC−F = 8.8 Hz), 130.3, 129.4, 128.42, 128.36, 125.3, 121.5, 120.7,
(3an). Eluent in chromatography: n-hexane/EtOAc 10:1. Yield:
2
2
115.6 (C−F, JC−F = 21.9 Hz), 115.5 (C−F, JC−F = 21.9 Hz), 62.0,
13.5. IR (film) cm−1: 2925, 2832, 1706, 1533, 1378, 847, 693, 569,
523. HRMS (ESI) m/z: [M + H]+ calcd for C25H20FN2O3, 415.1458;
found, 415.1471.
1
51.5 mg, 79%; yellow oil. H NMR (300 MHz, CDCl3): δ 7.61 (m,
2H), 7.47−7.36 (m, 5H), 7.24 (m, 3H), 4.18 (q, J = 7.1 Hz, 2H), 2.80
(t, J = 7.6 Hz, 2H), 1.77 (sext, J = 7.5 Hz, 2H), 1.07 (t, J = 7.1 Hz,
3H), 0.99 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
172.4, 168.1, 166.6, 164.1, 152.8, 137.4, 130.2, 129.3, 128.4, 128.3,
125.1, 121.5, 121.0, 61.7, 37.4, 21.9, 13.9, 13.6. IR (film) cm−1: 2927,
2840, 1719, 1540, 1486, 1376, 1238, 1078, 1004, 765, 691. HRMS
(ESI) m/z: [M + H]+ calcd for C22H23N2O3, 363.1709; found,
363.1701.
Ethyl 2-Phenoxy-4,6-diphenylpyrimidine-5-carboxylate (3ao).
Eluent in chromatography: n-hexane/EtOAc 10:1. Yield: 49.2 mg,
69%; white solid, mp 58−59 °C. 1H NMR (600 MHz, CDCl3): δ 7.65
(d, J = 7.0 Hz, 4H), 7.48−7.40 (m, 8H), 7.29 (d, J = 7.7 Hz, 2H),
7.23 (t, J = 7.4 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 0.96 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3): δ 168.1, 167.5, 164.1, 152.8,
137.1, 130.3, 129.4, 128.4, 128.3, 125.2, 121.5, 120.9, 61.9, 13.4. IR
(film) cm−1: 2929, 2844, 1714, 1533, 1486, 1385, 1252, 1059, 767,
693, 523. HRMS (ESI) m/z: [M + H]+ calcd for C25H21N2O3,
397.1552; found, 397.1538.
Ethyl 4-(4-Chlorophenyl)-2-phenoxy-6-phenylpyrimidine-5-car-
boxylate (3au). Eluent in chromatography: n-hexane/EtOAc 10:1.
Yield: 68.2 mg, 88%; yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.65
(m, 4H), 7.50−7.40 (m, 6H), 7.37 (m, 2H), 7.24 (m, 2H), 4.07 (q, J
= 7.1 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (75 MHz,
CDCl3): δ 168.0, 167.7, 166.1, 164.1, 152.7, 136.9, 136.7, 135.4,
130.4, 129.8, 129.4, 128.7, 128.4, 128.3, 125.3, 121.5, 120.7, 62.1,
13.5. IR (film) cm−1: 2918, 2844, 1721, 1530, 1483, 1385, 1250,
1131, 1060, 1005, 951, 768, 693, 524. HRMS (ESI) m/z: [M + H]+
calcd for C25H20ClN2O3, 431.1162; found, 431.1160.
Ethyl 4-(4-Bromophenyl)-2-phenoxy-6-phenylpyrimidine-5-car-
boxylate (3av). Eluent in chromatography: n-hexane/EtOAc 10:1.
Yield: 57.3 mg, 67%; yellow oil. 1H NMR (600 MHz, CDCl3): δ 7.67
(d, J = 8.1 Hz, 2H), 7.58 (m, 4H), 7.49 (m, 1H), 7.45 (m, 4H), 7.28
(m, 3H), 4.10 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 168.0, 167.8, 166.2, 164.1, 152.8, 136.9,
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Note
135.9, 131.7, 130.4, 130.1, 129.4, 128.5, 128.4, 125.3, 125.1, 121.5,
120.7, 62.1, 13.5. IR (film) cm−1: 2923, 2835, 1722, 1530, 1484, 1385,
1249, 1130, 1059, 1004, 951, 768, 693, 523. HRMS (ESI) m/z: [M +
H]+ calcd for C25H20BrN2O3, 475.0657; found, 475.0673.
Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-(4-nitrophenoxy)-
pyrimidine-5-carboxylate (3bc).12d Eluent in chromatography: n-
hexane/EtOAc 10:1. Yield: 57.4 mg, 78%; white solid. 1H NMR (600
MHz, CDCl3): δ 8.31 (d, J = 9.1 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H),
7.41 (d, J = 9.1 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.26 (q, J = 7.1 Hz,
2H), 3.84 (s, 3H), 2.56 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 169.2, 168.1, 165.8, 162.8, 161.9, 157.8,
144.8, 130.1, 129.0, 125.3, 122.1, 121.4, 114.1, 62.0, 55.4, 22.7, 13.8.
Ethyl 4-Methyl-2-phenoxypyrimidine-5-carboxylate (5).26 Eluent
in chromatography: n-hexane/EtOAc 10:1. Yield: 27.8 mg, 60%; pale
Ethyl 4-(4-Nitrophenyl)-2-phenoxy-6-phenylpyrimidine-5-car-
boxylate (3aw). Eluent in chromatography: n-hexane/EtOAc 5:1.
1
Yield: 55.6 mg, 70%; yellow solid, mp 58−59 °C. H NMR (300
MHz, CDCl3): δ 8.31 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H),
7.68 (m, 2H), 7.47 (m, 5H), 7.28 (m, 3H), 4.10 (q, J = 7.1 Hz, 2H),
1.00 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 168.2,
167.5, 165.1, 164.2, 152.6, 148.8, 143.0, 136.6, 130.7, 129.6, 129.5,
128.5, 128.4, 125.5, 123.6, 121.5, 121.0, 62.3, 13.4. IR (film) cm−1:
2922, 2832, 1725, 1532, 1347, 1249, 1134, 1056, 1009, 852, 768, 690,
525. HRMS (ESI) m/z: [M + H]+ calcd for C25H20N3O5, 442.1403;
found, 442.1390.
1
yellow oil. H NMR (600 MHz, CDCl3): δ 9.00 (s, 1H), 7.43 (t, J =
7.9 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 4.38
(q, J = 7.1 Hz, 2H), 2.79 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 173.1, 165.6, 164.4, 162.2, 152.5, 129.6,
125.7, 121.6, 118.9, 61.3, 24.7, 14.2.
2-Phenoxypyrimidine (7).13d Eluent in chromatography: n-
hexane/EtOAc 4:1. Yield: 17.3 mg, 56%; white solid. 1H NMR
(300 MHz, CD2Cl2): δ 8.55 (d, J = 2.7 Hz, 2H), 7.44 (m, 2H), 7.27
(t, J = 7.4 Hz, 2H), 7.20 (m, 2H), 7.04 (t, J = 4.7 Hz, 1H). 13C{1H}
NMR (75 MHz, CD2Cl2): δ 165.9, 160.1, 153.6, 130.1, 125.8, 122.3,
116.8.
Ethyl 2-Phenoxy-4-phenyl-6-(pyridin-3-yl)pyrimidine-5-carboxy-
late (3ax). Eluent in chromatography: n-hexane/EtOAc 4:1. Yield:
39.4 mg, 55%; yellow oil. 1H NMR (600 MHz, CDCl3): δ 8.54 (t, J =
1.9 Hz, 1H), 8.33 (ddd, J = 8.3, 2.3, 1.1 Hz, 1H), 8.02 (ddd, J = 7.7,
1.7, 1.1 Hz, 1H), 7.64 (m, 3H), 7.50 (m, 1H), 7.44 (m, 4H), 7.30−
7.25 (m, 3H), 4.11 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 168.2, 167.7, 164.7, 164.2,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00273.
152.6, 148.1, 138.5, 136.7, 134.5, 130.6, 129.5, 128.5, 128.4, 125.5,
124.9, 123.6, 121.5, 120.9, 62.4. 13.5. IR (film) cm−1: 2949, 2846,
1711, 1548, 1335, 1262, 1167, 1032, 865, 731. HRMS (ESI) m/z: [M
+ H]+ calcd for C24H20N3O3, 398.1505; found, 398.1486.
■
sı
Ethyl 2-Phenoxy-4-phenyl-6-(thiophen-2-yl)pyrimidine-5-car-
boxylate (3ay). Eluent in chromatography: n-hexane/EtOAc 10:1.
Yield: 52.1 mg, 72%; yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.66
(m, 2H), 7.61 (d, J = 3.9 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H) 7.42 (m,
5H), 7.25 (m, 3H), 7.06 (t, J = 4.8 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),
1.04 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 168.3,
167.9, 163.7, 158.5, 152.7, 140.6, 137.2, 131.5, 130.2, 129.8, 129.3,
129.1, 128.4, 128.3, 125.2, 121.7, 117.8, 62.3, 13.5. IR (film) cm−1:
2922, 2833, 1713, 1526, 1381, 1253, 1029, 856, 764, 688, 629. HRMS
(ESI) m/z: [M + H]+ calcd for C23H19N2O3S, 403.1116; found,
403.1129.
1H and 13C{1H} NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3aa−3az, 3ba−3bc, 5, and 7 (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Jeong-Hun Sohn − Department of Chemistry, Chungnam
National University, Daejeon 34134, Republic of Korea;
orcid.org/0000-0001-8800-7941; Email: sohnjh@
cnu.ac.kr
Ethyl 4-(Naphthalen-2-yl)-2-phenoxy-6-phenylpyrimidine-5-car-
boxylate (3az). Eluent in chromatography: n-hexane/EtOAc 10:1.
1
Yield: 41.1 mg, 51%; colorless oil. H NMR (600 MHz, CDCl3): δ
Authors
8.21 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 7.7, 2.9 Hz, 2H),
7.76 (d, J = 8.5 Hz, 1H) 7.69 (d, J = 7.3 Hz, 2H), 7.54 (m, 2H), 7.45
(m, 5H), 7.33 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 4.07 (q, J
= 7.1 Hz, 2H), 0.95 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3): δ 168.3, 167.5, 167.3, 164.1, 152.9, 137.1, 134.4, 134.0,
132.8, 130.3, 129.4, 128.80, 128.77, 128.42, 128.39, 128.3, 127.7,
127.4, 126.6, 125.3, 125.2, 121.6, 121.1, 62.0, 13.5. IR (film) cm−1:
2925, 2843, 1713, 1555, 1374, 1263, 1063, 823, 731. HRMS (ESI) m/
z: [M + H]+ calcd for C29H23N2O3, 447.1709; found, 447.1721.
Ethyl 2-(4-Methoxyphenoxy)-4-phenyl-6-(p-tolyl)pyrimidine-5-
carboxylate (3ba). Eluent in chromatography: n-hexane/EtOAc
Trong Nguyen Huu Phan − Department of Chemistry,
Chungnam National University, Daejeon 34134, Republic of
Korea
Jihong Lee − Department of Chemistry, Chungnam National
University, Daejeon 34134, Republic of Korea
Hyunik Shin − Yonsung Fine Chemicals R&D Center, Suwon
16675, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00273
1
10:1. Yield: 33.3 mg, 42%; yellow solid, mp 116−118 °C. H NMR
(600 MHz, CDCl3): δ 7.64 (m, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.44
(m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 7.20 (m, 2H), 6.92 (m, 2H), 4.07
(d, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.39 (s, 3H), 0.98 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (75 MHz, CDCl3): δ 168.4, 167.4, 167.3, 164.3,
156.7, 146.4, 140.6, 137.2, 134.2, 130.2, 129.2, 128.41, 128.36, 122.4,
120.5, 120.0, 114.3, 61.9, 55.6, 21.4, 13.5. IR (film) cm−1: 2948, 2838,
1716, 1567, 1537, 1422, 1349, 1263, 863, 730. HRMS (ESI) m/z: [M
+ H]+ calcd for C27H25N2O4, 441.1814; found, 441.1818.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIT) (2017R1A2B2003614).
Ethyl 2-(4-Bromophenoxy)-4-(4-fluorophenyl)-6-methylpyrimi-
dine-5-carboxylate (3bb).21 Eluent in chromatography: n-hexane/
1
REFERENCES
EtOAc 10:1. Yield: 52.6 mg, 68%; white solid. H NMR (600 MHz,
■
CDCl3): δ 7.60 (m, 2H), 7.53 (m, 2H), 7.12 (m, 4H), 4.21 (q, J = 7.1
Hz, 2H), 2.56 (m, 3H), 1.13 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151
MHz, CDCl3): δ 169.4, 167.8, 165.3, 165.0 (C−F, 1JC−F = 251.6 Hz),
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