Cu-Catalyzed [3 + 3] Annulation for the Synthesis of Pyrimidines via β-C(sp3)-H Functionalization of Saturated Ketones

Article abstract of DOI:10.1021/acs.joc.6b02181

A novel, efficient, and facile approach for the synthesis of structurally important pyrimidines has been successfully developed by Cu-catalyzed and 4-HO-TEMPO-mediated [3 + 3] annulation of commercially available amidines with saturated ketones. This method provides a new protocol for the synthesis of pyrimidines by a cascade reaction of oxidative dehydrogenation/annulation/oxidative aromatization via direct β-C(sp³)-H functionalization of saturated ketones followed by annulation with amidines.

Full text of DOI:10.1021/acs.joc.6b02181

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Note
Cu-Catalyzed [3+3] Annulation for the Synthesis of Pyrimidines
via beta-C(sp3)-H Functionalization of Saturated Ketones
Jun-Long Zhan, Meng-Wei Wu, Fei Chen, and Bing Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02181 • Publication Date (Web): 02 Nov 2016
Downloaded from http://pubs.acs.org on November 2, 2016
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CuꢀCatalyzed [3+3] Annulation for the Synthesis of Pyrimidines via
βꢀC(sp3)−H Functionalization of Saturated Ketones
JunꢀLong Zhan, MengꢀWei Wu, Fei Chen, and Bing Han*
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State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China
Eꢀmail: hanb@lzu.edu.cn
ABSTRACT: A novel, efficient, and facile approach for the synthesis of structurally
important pyrimidines has been successfully developed by Cuꢀcatalyzed and
4ꢀHOꢀTEMPOꢀmediated [3+3] annulation of commercially available amidines with
saturated ketones. This method provides a new protocol for the synthesis of
pyrimidines by a cascade reaction of oxidative dehydrogenation/annulation/oxidative
aromatization via direct βꢀC(sp3)−H functionalization of saturated ketones followed
by annulation with amidines.
Pyrimidine derivatives are one of the most important parts of heterocyclic
compounds. They have been found broad applications in organic synthesis,1
natural products,2 medicinal chemistry,3 and materials chemistry.4 Especially, due to
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their special biological and pharmacological activities, pyrimidine scaffolds are
widely present in numerous drug molecules such as vitamin B1,5a estrogen
antagonists,5b antimalarial drug,5c anticoagulant drug,5d antiꢀneuropathic pain drug
(Figure 1).5e In view of their remarkable significance, the synthesis of pyrimidine
derivatives has drawn much attention from chemists and pharmacologists. To date,
several efficient methods for the synthesis of pyrimidines have been developed by the
reaction of amidines with various partners, including the condensation with
1,3ꢀdicarbonyl derivatives,6 α, βꢀunsaturated ketones7 or alkynones8,
iridiumꢀcatalyzed multicomponent reaction,9 and the inverse electron demanding
DielsꢀAlder reactions with 1,2,3ꢀtriazines,10 (Scheme 1) etc.11 However, the majority
of these methods suffered from harsh reaction conditions (microwave irradiation,
strong basic conditions),7a,8 starting materials that require multistep synthesis,6ꢀ8,10
expensive catalyst,9 and less atomꢀ efficiency.10 Therefore, a simple and effective
method for the synthesis of pyrimidine from simple and readily available starting
materials still remains highly desirable.
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Figure 1. Bioactive pyrimidine derivatives.
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Scheme 1. Strategies for the Synthesis of Pyrimidines from Amidines
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With our continuing interest in the construction of important heterocyclic skeletons
via radical cyclization and circularization,12 herein, we intend to establish a facile and
efficient [3+3] annulation for the synthesis of pyrimidines via a Cuꢀcatalyzed and
4ꢀHOꢀTEMPOꢀmediated cascade βꢀC(sp3)−H dehydrogenation of saturated ketones
followed annulation with amidines and oxidative aromatization reaction through a
radical process (Scheme 1). Saturated carbonyl compounds, as cheap and
commercially available raw chemicals and essential synthetic elements, are
widely applied in organic synthesis. Direct unactivated βꢀC(sp3)−H functionalization
of saturated ketones undoubtedly is always a challenging target for chemists’
pursue.13 In this context, this strategy not only provides a novel radical method for
βꢀCsp3ꢀH functionalization of saturated ketones, but also realizes a direct oxidative
[3+3] annulation toward potential bioactive pyrimidines.
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Table 1. Optimization of the Reaction Conditionsa
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entry
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Cu salt
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
base
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
DMSO
DCB
DCB
DCB
DCB
t (oC) yield (%)b
Cs2CO3
Li2CO3
NaOAc
NEt3
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140
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68
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38
80
68
85
87
74
65
＜5
DABCO
pyridine
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
CuCl
CuBr2
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16c
17d
18e
19f
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DCB
DCB
DCB
aAll reactions were carried out by using 1a (0.4 mmol), 2a (3.0 equiv), Cu (10 mol %), bpy (10 mol %),
4ꢀHOꢀTEMPO (1 equiv), base (2 equiv), solvent (2 mL) and stirred for 24 h under air atmosphere except as noted.
c
d
e
bIsolated yield. NaOAc (1.5 equiv) was used. NaOAc (1 equiv) was used. 4ꢀHOꢀTEMPO (0.5 equiv) was used.
f4ꢀHOꢀTEMPO (0.2 equiv) and O2 (1 atm) was used.
To achieve this strategy, the reaction of benzamidine hydrochloride (1a, 0.4 mmol)
and propiophenone (2a, 1.2 mmol) in toluene was chosen as a model reaction for the
optimization investigation. In the beginning, the model reaction was stirred under the
conditions of Cu(OAc)2 (0.04 mmol, 0.1 equiv), 4ꢀHOꢀTEMPO (0.4 mmol, 1 equiv),
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Cs2CO3 (0.8 mmol, 2 equiv), 2,2′ꢀbipyridine (bpy, 10 mol%) at 120 °C under air
(Table 1, entry 1). To our delight, the desired product 2,4ꢀdiphenylpyrimidine 3a was
obtained in 20% yield (Table 1, entry 1). Next, various bases, such as Li2CO3, NaOAc,
NEt3, 1,4ꢀdiazabicyclooctane triethylenediamine (DABCO) and pyridine were
investigated (Table 1, entries 2−6), and we found that NaOAc was the most efficient
base to give 3a in 68% yield. Other Cu catalysts, such as CuI, CuCl, CuBr2 and
Cu(OTf)2, have also been examined (Table 1, entries 7−10), but no better results were
obtained. Screening other solvents, such as DMF, DMSO and 1,2ꢀdichlorobenzene
(DCB) (Table 1, entries 11−13), revealed that DCB was the best solvent and the yield
of 3a was improved to 80%. With the raising of the reaction temperature to 140 °C,
the yield of 3a was further increased to 85%; on the contrary, lowering the reaction
temperature led to a decrease of the yield of 3a to 68% (Table 1, entries 14 and 15).
Furthermore, the usage amount of base was also investigated and we found that 1.5
equiv of NaOAc gave a better result (Table 1, entries 16 and 17). With reducing the
usage amount of 4ꢀHOꢀTEMPO from 1 equiv to 0.5 equiv, the yield of 3a was
decreased to 65% (Table 1, entry 18). We also used the catalytic system 4ꢀHOꢀ
TEMPO/Cu(OAc)2/O2 to catalyze the reaction; unfortunately, the product 3a was only
obtained in trace amount (Table 1, entry 19). These results demonstrated clearly that
the stoichiometric amount of 4ꢀHOꢀTEMPO is necessary for an efficient process.
With the optimized conditions in hand (Table 1, entry 16), the scope of the reaction
with various ketones was investigated as shown in Scheme 2. First, the electronic
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effect, steric effect and functional groups tolerance on the aromatic ring of the
propiophenones were explored. Propiophenones with a wide range of electronic
Scheme 2. Scope of Ketonesa,b
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aAll reactions run in 0.2 M DCB using 1a (0.4 mmol), 2 (1.2 mmol), Cu(OAc)2 (0.04 mol), bpy (0.04 mol),
b
4ꢀHOꢀTEMPO (0.4 mmol) and NaOAc (0.6 mmol) at 140 °C for 24 h under air except as noted. Isolated yields
are shown. cSubstrate was 4ꢀphenylꢀ2ꢀbutanone. dSubstrate was 1ꢀphenylꢀbutanone. eReaction run in 2 (0.2 mmol),
1a (0.6 mmol), Cu(OAc)2 (0.02 mmol), bpy (0.02mmol), 4ꢀHOꢀTEMPO (0.2 mmol) and NaOAc (0.6 mmol) at
140 °C for 24 h.
properties at paraꢀposition of the phenyl moiety all proceeded well in the reaction,
affording 2,6ꢀdisubstituted pyrimidines 3a−f in good to excellent yields. In addition,
metaꢀ/orthoꢀmethyl substituted propiophenones also participated well in the reaction,
giving rise to pyrimidines 3g and 3h in excellent yields. Moreover, 3,5ꢀdisubstituted
phenylpropanone also reacted swimmingly and gave the corresponding product 3i in
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moderate yield. Aryl ketones, such as 1ꢀ(Naphthalenꢀ2ꢀyl) and 1ꢀ(pyrenꢀ1ꢀyl)propanꢀ
1ꢀones, reacted well with benzimidamide, delivering 3j and 3k in 96% and 91%
yields, respectively. 1ꢀ(Thiophenꢀ2ꢀyl), 1ꢀ(pyridinꢀ2ꢀyl) and 1ꢀ(9ꢀethylꢀ9Hꢀcarbazolꢀ
3ꢀyl) substituted propanꢀ1ꢀones were also good candidates in the protocol, as
demonstrated in the cases 3l−n. Notably, cyclohexylpropanꢀ1ꢀone reacted with 2a
very well and gave the corresponding pyrimidine 3o in 81% yield. Beside substituted
propanꢀ1ꢀones, other ketones such as 1ꢀphenylbutanꢀ1ꢀone, 4ꢀphenylbutanꢀ2ꢀone,
heptanꢀ2ꢀone, 1ꢀcyclohexyldecanꢀ1ꢀone, 1ꢀphenylꢀ3ꢀ(pyridinꢀ2ꢀ yl)propanꢀ1ꢀone, and
1,4ꢀdiphenylbutaneꢀ1,4ꢀdione were all wellꢀtolerated in the protocol, thus, 2,4,6ꢀ
trisubstituted pyrimidines 3p−t were successively obtained in moderate to excellent
yields.
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Scheme 3. Scope of Amidinesa,b
aAll reactions run in 0.2 M in DCB using 1 (0.4 mmol), 2a (1.2 mmol), Cu(OAc)2 (0.04 mmol), 2,2′ꢀbipyridine
(0.04 mol), 4ꢀHOꢀTEMPO (0.4 mmol) and NaOAc (0.6 mmol ) at 140 °C for 24 h under air. bIsolated yields.
cAcetamidine hydrochloride 1f (10 mmol) was used and the corresponding product 4f was obtained in 1.02 g.
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Having successfully achieved the tandem reaction with various ketones, we then
shifted our attention to explore the scope of amidines. The reactions of a variety of
amidines 1 with 2a were tested and the results are illustrated in Scheme 3. No obvious
electronic effect was observed for the substituted groups on the phenyl moiety of
amidines in this reaction. pꢀMe, pꢀNH2, pꢀNO2, and pꢀBr substituted benzamidines
participated swimmingly in the reaction, delivering the expected product 4b−e in
excellent yields. Remarkably, aliphatic amidines were also suitable for the
transformation, as demonstrated in the cases 4f−h. In addition, when heterocyclic
substituted amidines such as 4ꢀPy and 3ꢀPy substituted ones were allowed to react
with 2a, the desired products 4i and 4j were obtained in 94% and 76% yields,
respectively. Unfortunately, 2ꢀpyridinyl and 1ꢀtriazole substituted ones hardly gave
the corresponding products 4k and 4l, probably due to the strong chelate effect of
substrates 1k and 1l with Cu(OAc)2 that making the deactivation of the catalyst
Cu(OAc)2.14 Significantly, the reaction could be carried out in gramꢀscale without any
difficulty, as demonstrated the product 4f was obtained in 60% yield (1.02 g) when
acetamidine hydrochloride (1f, 10 mmol) was used, exhibiting the practicability of
this methodology in organic synthesis.
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To investigate the mechanism of this reaction, several control experiments were
conducted. Neither the condensation product 5 nor 6 was obtained when 1a was
allowed to react with 2a in the presence of NaOAc (Scheme 4, eq 1). This result
attested clearly that 5 or 6 was not the intermediate in this reaction. When substrate 2a
was treated under the standard reaction conditions without 1a, α, βꢀunsaturated ketone
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7 was obtained in 41% yield (Scheme 4, eq 2). Expressively, when compound 7 was
reacted with 1a under the standard reaction conditions, the desired product 3a was
generated in 87% yield (Scheme 4, eq 3). Obviously, these consequences revealed that
enone was the key intermediate in this reaction.
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Scheme 4. Control Experiments.
Based on the experimental results and aforementioned control experiments, a
proposed mechanism for this transformation is illustrated in Figure 2. Initially,
Cu(OAc)2 as a Lewis acid coordinates with ligand bpy and ketone 2 to form the
LnꢀCu(II)ꢀenolate complex A,15 which subsequently undergoes inner sphere single
electron transfer to produce Cu(I) species and Cꢀcentered radical B under heating
conditions. The latter is immediately trapped by 4ꢀHOꢀTEMPO to yield the
intermediate C which undergoes a Copeꢀlike elimination by losing 4ꢀHOꢀTEMPOH
via a five centered cyclic transition state to give the enone D.12h,13e,16,17h
4ꢀHOꢀTEMPO can be regenerated through the autoꢀoxidation of 4ꢀHOꢀTEMPOH by
air.17 The intermolecular Michael addition of amidine with enone D forms
intermediate E which follows a subsequently intramolecular condensation to give the
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intermediate F along with the releasing of H2O. Finally, oxidative aromatization of F
produces the desired product 3 or 4.
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Figure 2. Proposed mechanism.
In conclusion, we have developed a novel and efficient radical protocol for the
synthesis of structurally important pyrimidine derivatives via Cuꢀcatalyzed and
4ꢀHOꢀTEMPOꢀmediated
cascade
oxidative
dehydrogenation/annulation/
aromatization processes from commercially available amidines and saturated ketones.
To the best of our knowledge, this protocol presents the first example for the
construction of pyrimidine scaffolds through unactivated βꢀC(sp3)−H
functionalization of saturated ketones.
■ EXPERIMENTAL SECTION
General Methods. All reagents were purchased from commercial suppliers and used
without further purification. Flash chromatography was carried out with silica gel
(200ꢀ300 mesh). Analytical TLC was performed with silica gel GF254 plates, and the
products were visualized by UV detection. Melting points were determined without
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correction on a digital meltingꢀpoint apparatus. H NMR (400 MHz）, 13C NMR
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(100.6 MHz) were recorded in CDCl3 and DMSO–d6. Chemical shifts (δ) are reported
in ppm using TMS as internal standard and spinꢀspin coupling constants (J) are given
in Hz. The high resolution mass spectra (HRMS) were measured on an electrospray
ionization (ESI) apparatus using a timeꢀofꢀflight (TOF) mass spectrometry. Data
collections for crystal structure were performed at room temperature (293 K) using
MoKα radiation on a diffractometer. The copies of 1H NMR and 13C NMR spectra of
all compounds are provided in the Supporting Information. THF was distilled
immediately before use from Na/benzophenone. Other commercially available
reagents and solvents were used without further purification.
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General Experimental Procedure.
A 25 mL ovenꢀdried reaction tube was charged with amidine (0.4 mmol), Cu(OAc)2
(7.3 mg, 0.04 mmol, 10 mol %), 2,2'ꢀbipyridine (6.3 mg, 0.04 mmol, 10 mol %),
4ꢀHOꢀTEMPO (68.8 mg, 0.4 mmol) and NaOAc (49.2 mg, 0.6 mmol). Then
1,2ꢀdichlorobenzene (2.0 mL) and ketone (1.2 mmol) were added to the tube. The
o
tube was then sealed and the mixture was stirred at 140 C for 24 h. Upon cooling to
room temperature, the reaction mixture was diluted with 10 mL of ethyl acetate,
followed by filtration through a pad of silica gel. The filtrate was concentrated under
reduced pressure, and then purified by flash chromatography on silica gel (gradient
eluent of hexane/ethyl acetate: 100/1 to 3/1) to provide the corresponding product in
yields listed in Scheme 2 and Scheme 3. The identity and purity of products were
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confirmed by H, 13C HRMS and Xꢀray single crystal diffractometer spectroscopic
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analysis.
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2,4ꢀdiphenylpyrimidine (3a).18
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o
1
White solid; (79 mg, 85%); mp: 66–68 C; Rf = 0.36 (hexane/ethyl acetate 10:1); H
NMR (400 MHz, CDCl3): δ 8.77 (d, J = 5.2 Hz, 1H), 8.60–8.57 (m, 2H), 8.20–8.18
(m, 2H), 7.53–7.48 (m, 7H); 13C NMR (100.6 MHz, CDCl3): δ 164.5, 163.7, 157.8,
137.8, 136.8, 130.9, 130.6, 128.8, 128.5, 128.2, 127.1, 114.4; ESIꢀHRMS: m/z: Calcd
for C16H12N2+H+: 233.1073, found 233.1069.
2ꢀphenylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)pyrimidine (3b).14a
o
White solid; (90 mg, 75%); mp: 108–110 C; Rf = 0.23 (hexane/ethyl acetate 10:1);
1H NMR (400 MHz, CDCl3): δ 8.83 (d, J =5.2 Hz, 1H), 8.56 (d, J = 3.6 Hz, 2H), 8.27
(d, J = 8.0 Hz, 2H), 7.75 (d, J =8.0 Hz, 2H), 7.54–7.51 (m, 4H); 13C NMR (100.6
MHz, CDCl3): δ 164.7, 162.3, 158.2, 140.2, 137.4, 132.5 (q, C,FJ2 = 32 Hz), 130.9,
128.6, 128.3, 127.5, 125.8 (q, C,FJ3 = 4 Hz), 123.9 (q, C,FJ1 = 271 Hz), 114.7;
ESIꢀHRMS: m/z Calcd for C17H11F3N2+ H+: 301.0947, found 301.0944.
4ꢀ(2ꢀphenylpyrimidinꢀ4ꢀyl)benzonitrile (3c).
White solid; (54 mg, 52%); mp: 123–124 oC; Rf = 0.26 (hexane/ethyl acetate 5:1); 1H
NMR (400 MHz, CDCl3): δ 8.88 (d, J = 5.2 Hz, 1H), 8.57–8.53 (m, 2H), 8.28 (d, J =
8.0 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 5.2 Hz, 1H), 7.52 (t, J = 3.2 Hz,
3H); 13C NMR (100.6 MHz, CDCl3): δ 164.8, 161.6, 158.4, 140.9, 137.2, 132.6, 131.0,
128.6, 128.2, 127.6, 118.3, 114.7, 114.2; ESIꢀHRMS: m/z Calcd for C17H11N3+H+:
258.1026, found 258.1023.
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4ꢀ(4ꢀbromophenyl)ꢀ2ꢀphenylpyrimidine (3d).19
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Pale yellow solid; (101 mg, 81%); mp: 100–102 C; Rf = 0.30 (hexane/ethyl acetate
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10:1); H NMR (400 MHz, CDCl3): δ 8.78 (d, J = 5.2 Hz, 1H), 8.55–8.53 (m, 2H),
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8.04 (d, J = 8.4 Hz, 2H), 7.61 (d, J =8.4 Hz, 2H), 7.50–7.46 (m, 4H); 13C NMR (100.6
MHz, CDCl3): δ 164.6, 162.6, 158.0, 137.6, 135.7, 132.1, 130.8, 128.6, 128.5, 128.2,
125.6, 114.1; MS (ESI, m/z): Calcd for C16H11BrN2+H+: 311.0178, found 311.0174.
4ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀphenylpyrimidine (3e).14a
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White solid; (92 mg, 87%); mp: 95–97 C; Rf = 0.21 (hexane/ethyl acetate 10:1); H
NMR (400 MHz, CDCl3): δ 8.70 (d, J = 5.2 Hz, 1H), 8.58–8.56 (m, 2H), 8.15 (dd, J1
= 6.8 Hz, J2 = 2.0 Hz, 2H), 7.53–7.47 (m, 3H), 7.43 (d, J = 5.6 Hz, 1H), 6.98 (dd, J1 =
6.8 Hz, J2 = 2.0 Hz, 2H), 3.82 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 164.3, 163.2,
161.9, 157.4, 138.0, 130.5, 129.2, 128.6, 128.4, 128.2, 114.2, 113.5, 55.3; ESIꢀHRMS:
m/z Calcd for C17H14N2O+H+: 263.1179, found 263.1175.
2ꢀphenylꢀ4ꢀ(pꢀtolyl)pyrimidine (3f).19
o
White solid; (88 mg, 89%); mp: 103–104 C; Rf = 0.34 (hexane/ethyl acetate 10:1);
1H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 5.2 Hz, 1H), 8.59–8.57 (m, 2H), 8.10 (d, J
= 8.4 Hz, 2H), 7.53–7.48 (m, 4H), 7.30 (d, J = 8.4 Hz, 2H), 2.41 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): δ 164.4, 163.7, 157.6, 141.3, 137.9, 134.1, 130.6, 129.6, 128.4,
128.2, 127.0, 114.1, 21.4; ESIꢀHRMS: m/z Calcd for C17H14N2+H+: 247.1230, found
247.1226.
2ꢀphenylꢀ4ꢀ(mꢀtolyl)pyrimidine (3g).
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Yellow oil; (88 mg, 89%); Rf = 0.42 (hexane/ethyl acetate 10:1); 1H NMR (400 MHz,
CDCl3): δ 8.80 (d, J = 5.2 Hz, 1H), 8.59–8.57 (m, 2H), 8.03 (s, 1H), 7.99 (d, J = 7.6
Hz, 1H), 7.56–7.49 (m, 4H), 7.41 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 2.47 (s,
3H); 13C NMR (100.6 MHz, CDCl3): δ 164.6, 164.0, 157.7, 138.6, 137.9, 136.9, 131.7,
130.6, 128.8, 128.5, 128.3, 127.8, 124.4, 114.6, 21.5; ESIꢀHRMS: m/z Calcd for
C17H14N2+H+: 247.1230, found 247.1226.
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2ꢀphenylꢀ4ꢀ(oꢀtolyl)pyrimidine (3h).
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Pale yellow oil; (78 mg, 79%); Rf = 0.37 (hexane/ethyl acetate 10:1); H NMR (400
MHz, CDCl3): δ 8.80 (d, J = 5.2 Hz, 1H), 8.54–8.52 (m, 2H), 7.52–7.45 (m, 4H),
7.37–7.26 (m, 4H), 2.52 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 167.2, 164.0,
157.2, 137.9, 137.8, 136.4, 131.2, 130.6, 129.6, 129.4, 128.4, 128.2, 126.1, 118.6,
20.6; ESIꢀHRMS: m/z Calcd for C17H14N2+H+: 247.1230, found 247.1227.
4ꢀ(2,3ꢀdihydrobenzo[b][1,4]dioxinꢀ6ꢀyl)ꢀ2ꢀphenylpyrimidine (3i).
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Yellow oil; (52 mg, 45%); Rf = 0.31 (hexane/ethyl acetate 5:1); H NMR (400 MHz,
CDCl3): δ 8.72 (d, J = 5.2 Hz, 1H), 8.57–8.55 (m, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.69
(dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.52–7.47 (m, 3H), 7.43 (d, J = 5.2 Hz, 1H), 6.96
(d, J = 8.4 Hz, 1H), 4.27 (t, J = 4.8 Hz, 4H),; 13C NMR (100.6 MHz, CDCl3): δ 164.2,
162.9, 157.5, 146.2, 143.8, 137.9, 130.5, 130.2, 128.4, 128.2, 120.5, 123.8, 117.6,
116.2 , 113.7, 64.5, 64.2; ESIꢀHRMS: m/z Calcd for C18H14N2O2+H+: 291.1128,
found 291.1125.
4ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀphenylpyrimidine (3j).
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Pale yellow solid; (109 mg, 96%); mp: 100–102oC; Rf = 0.30 (hexane/ethyl acetate
10:1); 1H NMR (400 MHz, CDCl3): δ 8.83 (d, J = 5.6Hz, 1H), 8.68 (s, 1H), 8.62 (dd,
J1 = 8.0 Hz, J2 = 2.0 Hz, 2H), 8.30 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.99–7.95 (m,
2H), 7.89–7.87 (m, 1H), 7.67 (d, J = 5.6 Hz, 1H), 7.55–7.52 (m, 5H); 13C NMR
(100.6 MHz, CDCl3): δ 164.6, 163.7, 157.8, 137.9, 134.7, 134.2, 133.2, 130.7, 129.0,
128.7, 128.5, 128.3, 127.8, 127.42, 127.38, 126.6, 124.0, 114.7; ESIꢀHRMS: m/z
Calcd for C20H14N2+H+: 283.1230, found 283.1228.
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2ꢀphenylꢀ4ꢀ(pyrenꢀ1ꢀyl)pyrimidine (3k).
Brown solid; (130 mg, 91%); mp: 191–193 oC; Rf = 0.27 (hexane/ethyl acetate 10:1);
1H NMR (400 MHz, CDCl3): δ 8.92 (d, J = 5.2 Hz, 1H), 8.64–8.59 (m, 3H),
8.22–8.16 (m, 4H), 8.11–8.04 (m, 3H), 8.00 (t, J = 7.6 Hz, 1H), 7.56–7.50 (m, 4H);
13C NMR (100.6 MHz, CDCl3): δ 166.9, 164.5, 157.4, 137.8, 133.0, 132.3, 131.3,
130.8 130.7, 128.8, 128.60, 128.55, 128.5, 128.4, 127.5, 127.2, 126.2, 125.7, 125.4,
125.1 124.8, 124.6, 124.4, 120.2; ESIꢀHRMS: m/z Calcd for C26H16N2+H+: 357.1386,
found 357.1383.
2ꢀphenylꢀ4ꢀ(thiophenꢀ2ꢀyl)pyrimidine (3l).14a
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Pale yellow oil; (69 mg, 72%); Rf = 0.27 (hexane/ethyl acetate 10:1); H NMR (400
MHz, CDCl3): δ 8.67 (d, J = 5.2 Hz, 1H), 8.54–8.52 (m, 2H), 7.74 (d, J = 3.2 Hz, 1H),
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7.48 (d, J = 1.6 Hz, 4H), 7.33 (d, J = 5.2 Hz, 1H), 7.10 (t, J = 4.4 Hz, 1H); C NMR
(100.6 MHz, CDCl3): δ 164.4, 158.8, 157.4, 142.7, 137.4, 130.7, 130.0, 128.4, 128.24,
128.16, 127.3, 112.6; ESIꢀHRMS: m/z Calcd for C14H10N2S+H+: 239.0637, found
239.0633.
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2ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀyl)pyrimidine (3m).
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White solid; (54 mg, 58%); mp: 70–72 C; Rf = 0.24 (hexane/ethyl acetate 10:1); H
NMR (400 MHz, CDCl3): δ 8.91 (d, J = 4.8 Hz, 1H), 8.71–8.66 (m, 2H), 8.58 (d, J =
5.6 Hz, 2H), 8.23 (d, J = 4.8 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H),7.52–7.51 (m, 3H), 7.38
(t, J = 6.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ 164.2, 162.8, 158.3, 154.2,
149.4, 137.7, 137.0, 130.7, 128.5, 128.2, 125.3, 121.7, 115.0; ESIꢀHRMS: m/z Calcd
for C15H11N3+H+: 234.1026, found 234.1022.
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9ꢀethylꢀ3ꢀ(2ꢀphenylpyrimidinꢀ4ꢀyl)ꢀ9Hꢀcarbazole (3n).
Yellow oil; (112 mg, 80%); Rf = 0.31 (hexane/ethyl acetate 5:1); 1H NMR (400 MHz,
CDCl3): δ 8.88 (d, J = 1.2 Hz, 1H), 8.68 (d, J = 5.2Hz, 1H), 8.64–8.62 (m, 2H), 8.25
(dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.55–7.43 (m, 5H), 7.33
(d, J = 8.4 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2
Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ 164.3, 164.2, 157.2, 141.6, 140.4, 138.2,
130.4, 128.4, 128.2, 127.4, 126.1, 124.8, 123.3, 123.0 120.6, 119.6, 119.4, 113.8,
108.7, 108.5, 37.5, 13.7; MS (ESI, m/z): Calcd for C24H19N3+H+: 350.1652, found
350.1649.
4ꢀcyclohexylꢀ2ꢀphenylpyrimidine (3o).
1
Colorless oil; (77 mg, 81%); Rf = 0.46 (hexane/ethyl acetate 10:1); H NMR (400
MHz, CDCl3): δ 8.65 (d, J = 4.8 Hz, 1H), 8.48–8.46 (m, 2H), 7.48–7.46 (m, 3H), 7.00
(d, J = 5.2 Hz, 1H), 2.71(tt, J1 = 11.6 Hz, J2 = 3.2 Hz, 1H), 2.02–1.99 (m, 2H),
1.89–1.86 (m, 2H), 1.79–1.76 (m, 1H), 1.64–1.54 (m, 2H), 1.48–1.38 (m, 2H),
1.35–1.25 (m, 1H); 13C NMR (100.6 MHz, CDCl3): δ 174.7, 164.0, 156.9, 138.1,
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130.3, 128.4, 128.1, 116.3, 46.0, 32.0, 26.2, 25.9; ESIꢀHRMS: m/z Calcd for
C16H18N2+H+: 239.1543, found 239.1540.
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4ꢀmethylꢀ2,6ꢀdiphenylpyrimidine (3p).14a
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White solid; (85 mg, 86%, 72%); mp: 86–88 oC; Rf = 0.48 (hexane/ethyl acetate 10:1);
1H NMR (400 MHz, CDCl3): δ 8.60–8.58 (m, 2H), 8.18–8.16 (m, 2H), 7.50–7.44 (m,
6H), 7.39 (s, 1H), 2.59 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 167.7, 164.2, 163.6,
138.1, 137.2, 130.6, 130.4, 128.8, 128.4, 128.3, 127.1, 113.9, 24.5; ESIꢀHRMS: m/z
Calcd for C17H14N2+H+: 247.1230, found 247.1225.
4ꢀmethylꢀ2ꢀphenylꢀ6ꢀpropylpyrimidine (3q).
1
Pale yellow oil; (43 mg, 50%); Rf = 0.59 (hexane/ethyl acetate 10:1); H NMR (400
MHz, CDCl3): δ 8.46–8.44 (m, 2H), 7.48–7.43 (m, 3H), 6.87 (s, 1H), 2.73(t, J = 7.6
Hz, 2H), 2.52(s, 3H), 1.86–1.77 (m, 2H), 1.00 (t, J = 7.6 Hz 3H); 13C NMR (100.6
MHz, CDCl3): δ 170.3, 166.6, 164.0, 138.3, 130.1, 128.3, 128.2, 117.3, 39.7, 24.2,
22.0, 13.8; ESIꢀHRMS: m/z Calcd for C14H16N2+H+: 213.1386, found 213.1383.
4ꢀcyclohexylꢀ6ꢀhexylꢀ2ꢀphenylpyrimidine (3r).
1
Colorless oil; (40 mg, 31%); Rf = 0.44 (hexane/ethyl acetate 100:1); H NMR (400
MHz, CDCl3): 8.48–8.46 (m, 2H), 8.48–8.41 (m, 3H), 6.86 (s, 1H), 2.79–2.74 (m,
2H), 2.72–2.64 (m, 1H), 2.02–1.98 (m, 2H), 1.89–1.86 (m, 2H), 1.82–1.75 (m, 3H),
1.64–1.54 (m, 2H), 1.48–1.25 (m, 9H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100.6
MHz, CDCl3): δ 174.3, 170.7, 163.8, 138.6, 130.0, 128.32, 128.27, 115.0, 46.0, 38.0,
32.2, 31.7, 29.1, 28.8, 26.3, 26.0, 22.6, 14.1; ESIꢀHRMS: m/z Calcd for C22H30N2+H+:
323.2482, found 323.2479.
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2,4ꢀdiphenylꢀ6ꢀ(pyridinꢀ2ꢀyl)pyrimidine (3s).
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White solid; (71 mg, 57%); mp: 211–213 C; Rf = 0.50 (hexane/ethyl acetate 5:1);
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1H NMR (400 MHz, DMSO–d6): δ 8.72–8.71 (m, 5H), 8.36 (d, J = 6.0 Hz 2H), 7.86
(t, J = 7.2 Hz, 1H), 7.54–7.52 (m, 6H), 7.38 (t, J = 5.6 Hz, 1H); 13C NMR (100.6
MHz, CDCl3): δ 165.0, 164.2, 163.5, 154.6, 149.3, 138.0, 137.3, 137.0, 130.8, 130.6,
128.8, 128.43, 128.37, 127.4, 125.2, 121.8, 110.5; ESIꢀHRMS: m/z Calcd for
C21H15N3+H+: 310.1339, found 310.1336.
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(2,6ꢀdiphenylpyrimidinꢀ4ꢀyl)(phenyl)methanone (3t).
o
Yellow solid; (62 mg, 46%); mp: 124–126 C; Rf = 0.52 (hexane/ethyl acetate 10:1);
1H NMR (400 MHz, CDCl3): δ 8.61–8.58 (m, 2H), 8.32–8.28 (m, 2H), 8.26–8.24 (m,
2H), 8.17 (s, 1H), 7.67–7.63 (m, 1H), 7.56–7.49 (m, 8H); 13C NMR (100.6 MHz,
CDCl3): δ 192.8, 165.9, 163.8, 162.4, 137.3, 136.5, 135.3, 133.6, 131.4, 131.2, 131.1,
129.0, 128.6, 128.5, 128.3, 127.4, 113.3; ESIꢀHRMS: m/z Calcd for C23H16N2O+H+:
337.1335, found 337.1333.
4ꢀphenylꢀ2ꢀ(pꢀtolyl)pyrimidine (4b).14a
Colorless solid; (77 mg, 78%); mp: 84–86 oC; Rf = 0.50 (hexane/ethyl acetate 5:1); 1H
NMR (400 MHz, CDCl3): δ 8.75 (d, J = 5.2 Hz, 1H), 8.47 (d, J = 8.0 Hz, 2H),
8.19–8.17 (m, 2H), 7.50–7.48 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H); 13C
NMR (100.6 MHz, CDCl3): δ 164.6, 163.7, 157.7, 140.8, 137.0, 135.2, 130.8, 129.2,
128.8, 128.2, 127.1, 114.1, 21.4; MS (ESI, m/z): Calcd for C17H14N2+H+: 247.1230,
found 247.1226.
4ꢀ(4ꢀphenylpyrimidinꢀ2ꢀyl)aniline (4c).20
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Yellow solid; (88 mg, 89%); mp: 145–146 C; Rf = 0.47 (hexane/ethyl acetate 2:1);
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1H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 5.2 Hz, 1H), 8.40 (dd, J1 = 6.8 Hz, J2 =
1.6 Hz, 2H), 8.19–8.17 (m, 2H), 7.52–7.48 (m, 3H), 7.44 (d, J = 5.2 Hz, 1H), 6.75
(dd, J1 = 6.8 Hz, J2 = 1.6 Hz, 2H), 3.95 (s, 2H); 13C NMR (100.6 MHz, CDCl3): δ
164.6, 163.5, 157.6, 149.0, 137.2, 130.6, 129.8, 128.8, 128.1, 127.1, 114.6, 113.3;
ESIꢀHRMS: m/z Calcd for C16H13N3+H+: 248.1182, found 248.1177.
2ꢀ(4ꢀnitrophenyl)ꢀ4ꢀphenylpyrimidine (4d).14a
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White solid; (79 mg, 71%); mp: 196–197 oC; Rf = 0.35 (hexane/ethyl acetate 5:1); 1H
NMR (400 MHz, CDCl3): δ 8.88 (d, J = 5.2 Hz, 1H), 8.76 (d, J = 8.4 Hz, 2H), 8.35 (d,
J = 8.8 Hz, 2H), 8.24–8.21 (m, 2H), 7.70 (d, J = 5.2 Hz, 1H), 7.57 (t, J = 3.2 Hz, 3H);
13C NMR (100.6 MHz, CDCl3): δ 164.3, 162.5, 158.0, 149.3, 143.6, 136.4, 131.4,
129.14, 129.08, 127.2, 123.7, 115.6; ESIꢀHRMS: m/z Calcd for C16H11N3O2+H+:
278.0924, found 278.0922.
2ꢀ(4ꢀbromophenyl)ꢀ4ꢀphenylpyrimidine (4e).14a
Pale yellow solid; (118 mg, 95%); mp: 95–96 oC;Rf = 0.33 (hexane/ethyl acetate 10:1);
1H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 5.6 Hz, 1H), 8.43 (d, J = 8.8 Hz, 2H),
8.18–8.16 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (t, J = 3.2
Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ 163.9, 163.6, 157.8, 136.8, 136.7, 131.6,
131.0, 129.8, 128.9, 127.1, 125.4, 114.6; ESIꢀHRMS: m/z Calcd for C16H11BrN2+H+:
311.0178, found 311.0175.
2ꢀmethylꢀ4ꢀphenylpyrimidine (4f).14a
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Pale yellow solid; (53 mg, 78%); mp: 47–49 oC ;Rf = 0.21 (hexane/ethyl acetate 5:1);
1H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 5.6 Hz, 1H), 8.08–8.06 (m, 2H),
7.50–7.48 (m, 4H), 2.80 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 168.3, 164.0,
157.4, 136.8, 130.7, 128.8, 127.1, 113.8, 26.2; ESIꢀHRMS: m/z Calcd for
C11H10N2+H+: 171.0917, found 171.0914.
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2ꢀ(tertꢀbutyl)ꢀ4ꢀphenylpyrimidine (4g).
1
Colorless oil; (71 mg, 83%); Rf = 0.44 (hexane/ethyl acetate 10:1); H NMR (400
MHz, CDCl3): δ 8.70 (d, J = 5.2 Hz, 1H), 8.15–8.13 (m, 2H), 7.49–7.46 (m, 4H), 1.49
(s, 9H); 13C NMR (100.6 MHz, CDCl3): δ 177.3, 162.9, 157.1, 137.2, 130.6, 128.8,
127.1, 113.2, 39.6, 29.6; ESIꢀHRMS: m/z Calcd for C14H16N2+H+: 213.1386, found
213.1382.
2ꢀcyclopropylꢀ4ꢀphenylpyrimidine (4h).14a
Colorless oil; (65 mg, 82%); Rf = 0.39 (hexane/ethyl acetate 5:1); 1H NMR (400 MHz,
CDCl3): δ 8.56 (d, J = 5.6 Hz, 1H), 8.05 (t, J = 3.2 Hz, 2H), 7.46 (t, J = 3.2 Hz, 3H),
7.40 (d, J = 5.6 Hz, 1H), 2.35–2.29 (m, 1H), 1.25–1.22 (m, 2H), 1.10–1.06 (m, 2H);
13C NMR (100.6 MHz, CDCl3): δ 172.0, 163.4, 157.1, 136.9, 130.6, 128.7, 127.0,
113.3, 18.3, 10.6; ESIꢀHRMS: m/z Calcd for C13H12N2+H+: 197.1073, found
197.1070.
4ꢀphenylꢀ2ꢀ(pyridinꢀ4ꢀyl)pyrimidine (4i).14a
Pale yellow solid; (88 mg, 94%); mp: 80–81 oC; Rf = 0.34 (hexane/ethyl acetate 2:1);
1H NMR (400 MHz, CDCl3): δ 8.82–8.78 (m, 3H), 8.38 (d, J = 5.6 Hz, 2H),
8.19–8.17 (m, 2H), 7.63 (d, J = 5.2 Hz, 1H), 7.53–7.52 (m, 3H); 13C NMR (100.6
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MHz, CDCl3): δ 164.0, 162.4, 157.9, 150.3, 144.9, 136.2, 131.2, 128.9, 127.0, 121.9,
115.7; ESIꢀHRMS: m/z Calcd for C15H11N3+H+: 234.1026, found 234.1022.
4ꢀphenylꢀ2ꢀ(pyridinꢀ3ꢀyl)pyrimidine (4j).14a
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o
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Yellow solid; (71 mg, 76%); mp: 83–85 C; Rf = 0.36 (hexane/ethyl acetate 2:1); H
NMR (400 MHz, CDCl3): δ 9.77 (d, J = 1.2 Hz, 1H), 8.79–8.77 (m, 2H), 8.73–8.71
(m, 1H), 8.18–8.16 (m, 2H), 7.58 (d, J = 5.6 Hz, 1H), 7.51–7.50 (m, 3H), 7.41–7.38
(m, 1H); 13C NMR (100.6 MHz, CDCl3): δ 163.8, 162.6, 157.8, 151.2, 149.8, 136.3,
135.3, 133.2, 131.0, 128.8, 127.0, 123.2, 114.9; ESIꢀHRMS: m/z Calcd for
C15H11N3+H+: 234.1026, found 234.1022.
ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra for all products and CIF files for the compound 4d are
provided. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: hanb@lzu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Nos. 21422205,
21272106 and 21632001), the Program for New Century Excellent Talents in
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University (NCETꢀ13ꢀ0258), the Changjiang Scholars and Innovative Research Team
in University (IRTꢀ15R28), the “111” project, and the Fundamental Research Funds
for the Central Universities (Nos. lzujbkyꢀ2016ꢀct02 and lzujbkyꢀ2016ꢀct08) for
financial support.
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