Iron Catalysis for Modular Pyrimidine Synthesis through β-Ammoniation/Cyclization of Saturated Carbonyl Compounds with Amidines

Article abstract of DOI:10.1021/acs.joc.6b02767

An efficient method for the modular synthesis of various pyrimidine derivatives by means of the reactions of ketones, aldehydes, or esters with amidines in the presence of an in situ prepared recyclable iron(II)-complex was developed. This operationally simple reaction proceeded with broad functional group tolerance in a regioselective manner via a remarkable unactivated β-C-H bond functionalization. Control experiments were performed to gain deep understanding of the mechanism, and the reactions are likely to proceed through a designed TEMPO complexation/enamine addition/transient α-occupation/β-TEMPO elimination/cyclization sequence.

Full text of DOI:10.1021/acs.joc.6b02767

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Article
Iron Catalysis for Modular Pyrimidine Synthesis through #-Ammoniation/
Cyclization of Saturated Carbonyl Compounds with Amidines
Xue-Qiang Chu, Wen-Bin Cao, Xiao-Ping Xu, and Shun-Jun Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02767 • Publication Date (Web): 29 Dec 2016
Downloaded from http://pubs.acs.org on December 29, 2016
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Iron Catalysis for Modular Pyrimidine Synthesis
through βꢀAmmoniation/Cyclization of Saturated
Carbonyl Compounds with Amidines
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XueꢀQiang Chu, WenꢀBin Cao, XiaoꢀPing Xu,* ShunꢀJun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science
and Technology, Soochow University, Suzhou, 215123, People’s Republic of China.
TOC:
KEYWORDS: iron catalysis, βꢀCꢀH functionalization, pyrimidines, recyclable Feꢀcatalyst
ABSTRACT: An efficient method for the modular synthesis of various pyrimidine derivatives
by means of the reactions of ketones, aldehydes, or esters with amidines in the presence of an in
situ prepared recyclable iron(II)ꢀcomplex was developed. This operationally simple reaction
proceeded with broad functional group tolerance and in a regioselective manner via a remarkable
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unactivated βꢀC−H bond functionalization. Control experiments have been performed to gain
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deep understanding of the mechanism and the reactions are likely to proceed through designed
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TEMPO
complexation/enamine
addition/transient
αꢀoccupation/βꢀTEMPO
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elimination/cyclization sequence.
INTRODUCTION
Direct transformation of saturated carbonyl compounds for the rapid assembly of complex
molecules from simple starting materials has attracted increasing interest of organic chemists.1
The siteꢀselectivity challenges involved in the conversion of distant βꢀC–H bonds of ketones,
aldehydes and esters to new CꢀX bonds are formidable, since carbonyl moiety is normally
amenable to αꢀposition nucleophilic substitution, as well as 1,2ꢀfunctionalizations of the polar
C=O bond.2 Approaches to access βꢀfunctionalized carbonyl architecture thus far are mostly
restricted to the wellꢀestablished 1,4ꢀconjugateꢀaddition reactions.3 Recently, much attention has
been directed to transition metalꢀcatalyzed βꢀC(sp3)–H bond cleavage, in which new bonds were
selectively constructed by manipulating the reactive sites with elegant directing groups4 or
oxidative dehydrogenative couplings associated with the generation of enone intermediates5
(Saegusaꢀtype reactions) (Scheme 1, I, route a). Of special note is a photoredox organocatalyzed
radicalꢀtype enaminyl activation mode reported by MacMillan and coworkers (Scheme 1, I, route
b).6 Another remarkable example involving the oxidation of enamines to iminium ions (oxidative
enamine catalysis) also serves as an attractive alternative for the synthesis of βꢀsubstituted
aldehydes (Scheme 1, I, route c).7 Although the field of regioselective carbonyl functionalization
has grown at an explosive pace, our goal is to develop a robust platform for preparing valuable
heterocycle derivatives8 via a remote βꢀC−N bond formation strategy beyond above.5ꢀ9
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Scheme 1. βꢀFunctionalization of saturated carbonyl compounds.
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We envisaged that the intrinsic difficulty of reaction selectivity could be controlled by
preinstalling auxiliary amine catalysts in combination with siteꢀoccupied reagents. One potential
strategy involves the formation of a transient αꢀoccupied iminium ion that showed preference
for rapid βꢀhydride elimination through which to transform an enamine into a desired iminium
(or enone) species (Scheme 1, II).10 Previous reports of Sibi11a and MacMillan11b suggested the
feasibility of this scenario pertaining to the formation of αꢀoxyaminated aldehydes using
Fe(III)−TEMPO (TEMPO = 2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl) adducts,12 but oxygenation of
electronꢀrich enamine derived from common ketones and further attempts to expand this
enamine addition manifold is unknown.13 In this communication, we report an efficient method
for functionalization of unactivated βꢀC−H bonds of ketones, aldehydes and esters by using a
recyclable iron(II)ꢀcomplex in conjunction with a transient siteꢀcontrolled TEMPO, in which
enables the synthesis of a variety of pyrimidines. Control experiments suggest that the reaction
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presumably proceeds through designed TEMPO complexation/enamine addition/transient αꢀ
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occupation/βꢀTEMPO elimination/cyclization sequence.
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Results and discussion
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Table 1. Optimization of reaction conditions.a
Entry
1
Catalyst
Fe(OAc)2
ꢀꢀ
Additive Ligand Oxidant (equiv) GC-Yield [%]
Salt I c
Phen
Phen
Phen
ꢀꢀ
TEMPO (1.0)
TEMPO (1.0)
ꢀꢀ
73
2
Salt I c
0
3
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
FeSO4·7H2O
FeCl2
Salt I c
0
4
Salt I c
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.2)
K2S2O8 (1.2)
PhI(OAc)2 (1.2)
TBHP (1.2)
4
72
5
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
ꢀꢀ
6
76
7
0
8
0
9
0
10
11
12
13
14
15
TEMPO (1.2)
TEMPO (1.2)
TEMPO (1.2)
TEMPO (1.2)
TEMPO (1.2)
TEMPO (1.2)
82 (79) d
trace
35
FeCl3
Fe(acac)3
Fe(NO3)3·9H2O
Feꢀcomplex e
62
67
(81) d
aConditions: 1a (0.3 mmol), 2a (0.75 mmol), catalyst (0.03 mmol), ligand (0.03 mmol) and oxidant (0.3ꢀ0.36 mmol) in DMF (2
o
b
c
mL) at 120 C under air atmosphere for 12 h. GCꢀYields determined by GC with an internal standard (biphenyl). Salt I =
d
e
2,2,6,6ꢀtetramethylpiperidinium 2,2,2ꢀtrifluoroacetate. Isolated yield. Feꢀcomplex prepared by mixing FeSO4·7H2O with Phen
in DMF.
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Several challenging issues should be dealt with in the proposed process. First, the requirement
of suitable catalyst and reagents to realize αꢀoccupation of ketones. Second, utilization of a
comparatively inert amine catalyst under oxidative conditions. Third and importantly, its
capacity to undergo subsequent elimination of the stabilized αꢀsubstituted iminiums. Finally, an
effective system should be compatible with both oxygenation and βꢀbondꢀforging cascade. Based
on above conjecture and previous reports, our preliminary studies was perfermed by using
benzamidine hydrochloride (1a) and propiophenone (2a) as model substrates in the presence of
TEMPO and 2,2,6,6ꢀtetramethylpiperidinium 2,2,2ꢀtrifluoroacetate I (salt I), serving as
oxyaminated reagent and organocatalyst, respectively. Fortunately, an inexpensive, earthꢀ
abundant, and relatively underrepresented Fe specie14 (10 mol %) in conjunction with 1,10ꢀ
phenanthroline (Phen) promoted the desired βꢀaminocyclization reaction to afford the pyrimidine
3aa in 73% GCꢀyield (Table 1, entry 1). Remarkably, we did not detect any αꢀfunctionalized
imidazole products, implying that new CꢀN bond formed exclusively at the terminal position of
ketones. Control reactions performed in the absence of TEMPO or Fe catalyst proved to be futile
(entries 2ꢀ3). Moreover, the ligand Phen was pivotal for providing high yield of 3aa (entry 4). It
is reasonable to assume that reduction of TEMPO by Fe2+ to the HTMP (2,2,6,6ꢀ
tetramethylpiperidine) could save additional salt I used.12a,c As expected, the reaction conducted
without ammonium salt still could generate 3aa in 72% GCꢀyield (entry 5), and HTMP was also
observed in the catalytic system.15 However, some accelerating effect of salt I on the reaction
rate could not be ignored (see Fig. S1 in the Supporting Information). After screening a variety
of oxidants (entries 7ꢀ9) and iron species (entries 10ꢀ14), the optimal reaction conditions were
then quickly established by increasing the amount of TEMPO (120 mol %) and changing the iron
catalyst to FeSO4·7H2O, which provided 3aa in 82% GC yield and 79% isolated yield (entry 10).
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Lower yields and lower selectivities were obtained when other firstꢀrow metals such as Co, Ni,
and Mn were used, a reflection of the indispensable role of Fe species (see Table S1 in the
supporting information).
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Figure 1. a) Synthesis of pyrimidine 3aa; b) Preꢀprepared Feꢀcomplex from FeSO4·7H2O and
Phen in DMF; c) Recyclability of catalyst.
As noted in our condition optimization,15 the reaction proceeded well in DMF, presumably
implying that DMF may work as a ligand to iron. Thus, we synthesized a new Feꢀcomplex from
1
FeSO4·7H2O and 1,10ꢀphenanthroline in DMF (Fig. 1, b). H NMR, IR, ICP, EDS, XPS, and
elemental analysis of the obtained red solids pointed out that the structure of the Feꢀcomplex was
most likely to be [Fe(Phen)(DMF)2SO4].15 This metalꢀcomplex not only have a good catalytic
activity and recyclability (Fig. 1, c), might also find further applications in the field of CꢀH bond
functionalization.14
Table 2. Substrate scope of amidines.a
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aStandard conditions; isolated yields. b0.6 mmol scale. c17 h. d18 h.
With the optimal reaction conditions in hand, we set out to explore the scope of amidines by
using Feꢀcomplex formed in situ and the results are summarized in Table 2. Generally,
benzamidines containing substituents of varying electronic character (electronꢀdonating or
electronꢀwithdrawing) and steric demand (pꢀ, mꢀ, oꢀ) on the aryl rings proceeded smoothly to
give the corresponding derivatives 3aa–ia in moderate to good yields. Notably, substituents and
functionalities such as halogen (Br, Cl, F), nitro, and hydroxyl group were satisfactorily
compatible with the present transformation (3baꢀea, 3ha-ia), thereby providing a chance for lateꢀ
stage structural modifications. Meanwhile, heterocyclic substrates, including pyridine (1j),
furfuran (1k), and thiazole (1l) were proven to be appropriate candidates, delivering the products
3ja–la in 44–83% yields. To our delight, Cꢀalkyl amidines 1mꢀn were easily transformed into
pyrimidines 3maꢀna in 44% and 63% yields, respectively. In addition, both 1Hꢀindazolꢀ3ꢀamine
(1o) and 2ꢀbenzimidazolylamine (1p) could be incorporated into the family of these compounds
albeit in relatively low yields, which greatly streamlined access to such condensed nucleus (3oaꢀ
pa).
Table 3. Substrate scope of ketones.a
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aStandard conditions; isolated yields. b4 mmol scale.
Table 4. Substrate scope of carbonyl compounds.a
aStandard conditions; isolated yields. b15 mol % of FeSO4·7H2O was used. c5ae = 5ac. d0.9 mmol of 4i was used. e5ak = 3aa.
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The generality of this Feꢀcatalyzed highly regioselective CꢀN coupling reaction has been
further investigated by using different ketones with amidine 1. As shown in Table 3, various
propiophenones bearing functional groups and substituents, such as halogens, methyl, methoxy,
trifluoromethyl and hydroxyl groups as well as biologically interesting benzo[d][1,3]dioxole,
pyridine, and thiophene heterocycles, were well tolerated under the optimized conditions. It was
found that substitutions did not have significant influence on the reaction efficiency, furnishing a
variety of 2,4ꢀdisubstituted pyrimidines 3abꢀcm in 45%ꢀ89% yields. This methodology can be
scaled up to 4 mmol scale (3cc, 60% yield) without difficulty. Considering that pyrimidineꢀbased
heteroaromatics are important pharmaceutical molecules8a,b and optoelectronic materials,8cꢀf we
were motivated to synthesize more complex πꢀconjugated polycyclic compounds. Thus, ketones
2nꢀp derived from parent biphenyl, carbazole or benzothiophene well participated in the reaction
to afford the desired conjugates 3an−ap in good yields.
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Scheme 2. Further transformation and its photophysical properties.
UVꢀVis
226
476
1.0
0.8
0.6
0.4
Fluorescence
272
361
200
300
400
W avelength/(nm )
500
600
Table 5. Biological activities of compounds against cultured HTꢀ29, HeLa and PANCꢀ1 cells.a
HTꢀ29 EC50, ꢁM HeLa EC50, ꢁM PANCꢀ1 EC50, ꢁM
compd
3ah
2.12
23.8
0.75
26.4
18.4
0.68
54.4
19.3
3pa
62.35
3jl
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62.7
53.2
27.4
5aj
aSelected pyrimidine derivatives were shown.
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Following above methods, our attempt to prepare 5ꢀsubstituted product 5aa by using
isobutyrophenone (4a) was unsuccessful, probably due to steric hindrance and the instability of
αꢀoccupied iminium intermediates (Table 4). In contrast, we were able to accomplish the
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conversion of αꢀcarbonyl ketone to benzoylated product 5ab in 45% yield, which was extremely
difficult to achieve through the functionalization of pyrimidine at its 5ꢀposition.8 Furthermore, γꢀ
substituted saturated ketones smoothly underwent the aminocyclization to produce pyrimidine
rings 5acꢀad in 53% and 74% yields, respectively. Intriguingly, oxidative dehydrogenative
chalcone was isolated as byꢀproduct in this case.15 Other alkyl ketones, such as 4ꢀphenylbutanꢀ2ꢀ
one (4e), pentanꢀ2ꢀone (4f), 2ꢀmethylcyclohexanone (4g) and 3ꢀmethylpentaneꢀ2,4ꢀdione (4h)
could also be βꢀfunctionalized, although a slightly lower reactivity was observed with aryl
ethanones 5aeꢀah. Impressively, acyclic βꢀketo ester 45d acted as an effective coupling partner as
well (5ai, 5ci, 5fi and 5oi). More importantly, the use of 2ꢀphenylpropanal (4j) and 3ꢀ
phenylpropanal (4k)7 in the reactions provided a concise entry to 3ꢀ or 5ꢀsubstituted pyrimidine
fragments in satisfying yields. Finally, synthetic application was demonstrated to establish
modified pyrimidine chromophore 7, and the photophysical properties were measured by UVꢀ
Vis absorption (labs = 272, 361 nm), photoluminescence measurements (lem = 476 nm), and cyclic
voltammetry (HOMO = ꢀ 4.85 eV; LOMO = ꢀ 1.90 eV) (Scheme 2). We tested some pyrimidine
derivatives15 for the antitumor activity against colorectal adenocarcinoma (HTꢀ29), cervical
cancer (HeLa), and human pancreatic cancer (PANCꢀ1). Compound 3ah was found to be very
active with EC50 values 0.68ꢀ2.12 ꢁM (Table 5), which could be considered as a new potential
lead compound for further development because of their biological activity.
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Scheme 3. Control experiments and kinetic isotope effect studies.
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N
NH—HCl
standard
conditions
N
+
(A)
(B)
Ph
N
Ph
Ph
NH2
1a
Ph
2aꢀI (0.75 mmol)
3aa, 76%
9
O
O
NH—HCl
standard
conditions
5 h
HO
+
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N
HN
+
+
Ph
Ph
Ph
NH2
OTEMP
2aꢀII
1a
2a (0.75 mmol)
TEMPOH
O
HTMP
O
standard conditions
Ph
Ph
(C)
(D)
Ph
Ph
OTEMP
4dꢀII (0.3 mmol)
Chalcone 4d', 88%
O
O
standard
conditions
+
Ph
recovered 4d
Ph
Ph
Ph
4d (0.3 mmol)
Chalcone 4d', 18%
80%
H/D
N
O
O
standard
conditions
2~12h
NH—HCl
+
+
(E)
Ph
Ph
Ph
NH2
Ph
N
Ph
H
H
D D
KH/KD > 10
1a
3aa/3aa-d1
2a : 2a-d1 (1:1)
Some control experiments were carried out to gain inꢀdepth insight into reaction mechanism.
First, when 2a was replaced by preꢀprepared enamine 2aꢀI under standard conditions, 76% yield
of the corresponding product 3aa was isolated (Scheme 3, A). This result revealed that enamine
2a-I might be formed in situ and most likely contribute to the ammoniation/cyclization.
Fortunately, all possible intermediates, including αꢀoxyaminated ketone 2aꢀII, the reduced
TEMPOH, and HTMP were detected by LCꢀMS analysis during the catalytic process (Scheme 3,
B).15 Next, αꢀTEMPOꢀsubstituted ketone 4dꢀII underwent fast βꢀTEMPOH elimination to
generate dehydrogenative chalcone 4d' in 88% yield within 2 h (Scheme 3, C). By comparison,
4d' was also observed in the direct oxidation of benzyl acetophenone 4d, we supposed it went
through a process termed ‘transient αꢀoccupied activation’ (TOA) via active ketone 4dꢀII
(Scheme 3, D). Moreover, intermolecular kinetic isotope effects (KIEs) studies indicated that αꢀ
C(sp3)ꢀH bond cleavage of propiophenone was the rateꢀdetermining step and this result was
consistent with enamine formation (scheme 3, E).11,16
Scheme 4. Proposed mechanism of Feꢀcatalyzed pyrimidine synthesis.
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Based on these observations and recent reports10ꢀ12, a plausible mechanism was proposed in
Scheme 4. The reaction is initiated with the reduction of TEMPO by Fe2+L to the HTMP,12a,c and
subsequent condensation with ketone 2 generates enamine 2ꢀI (Scheme 4, path 1). Int. 1, the
TEMPOꢀFe3+ coordinated product,12 added to enamine 2ꢀI to form Int. 2 and Fe2+L (TEMPO
complexation/enamine addition stage).11 Int. 2 ultimately produced α,βꢀunsaturated ketone and
TEMPOH after iminium hydrolysis and further βꢀH elimination, and vice versa (transient αꢀ
occupation/sequential βꢀTEMPO elimination stage).10 TEMPOH would give rise to HTMP by
Fe2+L in the reaction system. Finally, unsaturated 2' cyclized with amidine 1 and followed by
oxidation to furnish pyrimidines (cyclization stage). However, we could not entirely exclude the
existence of αꢀcarbonyl radicals (Scheme 4, path 2).11a,b
Conclusions
In summary, we have established a novel ironꢀcatalyzed cyclization protocol for accessing
modular pyrimidines from readily available saturated carbonyl compounds with amidines. This
study led to the development of an unprecedented metalꢀorganocatalytic method for siteꢀ
selective βꢀfunctionalization of unactivated ketones, aldehydes and esters, involving a TEMPO
complexation/enamine addition/transient αꢀoccupation/βꢀTEMPO elimination/cyclization
sequence. Two new C(sp2)ꢀN bonds and a sixꢀmembered ring are simultaneously formed in this
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reaction. Moreover, we have accomplished the first βꢀC−H bond activation system using in situ
formed Fe(II)ꢀcomplex, which is suitable for recycling. We anticipate that the present
transformation is capable of offering a new synthetic approach to pharmaceutially and
biologically important heterocycles.
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EXPERIMENTAL SECTION
General procedure for the synthesis of pyrimidine derivatives
Amidine 1 (0.3 mmol), carbonyl compound 2 (0.75 mmol), FeSO4·7H2O (0.03 mmol), 1,10ꢀ
phenanthroline (Phen, 0.03 mmol) and 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO, 0.36
mmol) in DMF (2 mL) was stirred at 120 °C for 12ꢀ24 h in a tube under air atmosphere. Upon
completion of the reaction (indicated by TLC), the mixture was added water (15 mL) and
extracted with ethyl acetate (5 mL×3). The combined organic extracts were dried with sodium
sulfate and concentrated. The pure products were obtained after purification by column
chromatography on silica gel with petroleum ether/ethyl acetate (V : V = 100 : 1 ~ 20 : 1) as the
eluent.
General procedure for the large scale synthesis of pyrimidine derivatives
Amidine 1c (4 mmol), carbonyl compound 2 (10 mmol), FeSO4·7H2O (0.4 mmol), Phen (0.4
mmol) and TEMPO (4.8 mmol) in DMF (15 mL) was stirred at 120 °C for 16 h in a tube under
air atmosphere. Upon completion of the reaction (indicated by TLC), the mixture was added
water (30 mL) and extracted with ethyl acetate (15 mL×3). The combined organic extracts were
dried with sodium sulfate and concentrated. The pure products were obtained after purification
by column chromatography on silica gel with petroleum ether/ethyl acetate (V : V = 100 : 1 ~ 20
: 1) as the eluent (white soild, 43% yield).
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General procedure for the synthesis of compound 7
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Pyrimidine 3ca (1.55 mmol), 4ꢀ(diphenylamino)phenylboronic acid 6 (2.33 mmol), Pd(PPh3)4
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(0.155 mmol) and K2CO3 (3.88 mmol) was stirred at 100 C for 17 h under Ar atmosphere in
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ethanol/toluene (40 mL, V : V = 1 : 4). Upon completion of the reaction (indicated by TLC), the
solvents were removed under vacuum. The pure products were obtained after purification by
column chromatography on silica gel with petroleum ether/ethyl acetate (V : V = 100 : 1) as the
eluent (yellow solid, 89% yield).
Analytical data of products
2,4-Diphenylpyrimidine (3aa) and (5aj): Yield = 79% (0.0553g) (3aa), 56% (0.0388g) (5aj).
White solid. M.p. 56.3–57.8 oC. IR (KBr) ν = 2972, 2922, 1541, 1422, 1378, 1027, 745 and 687
cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 8.82 (d, J = 5.3 Hz, 1H), 8.63 – 8.54 (m, 2H), 8.27 – 8.18
(m, 2H), 7.58 (d, J = 5.3 Hz, 1H), 7.56 – 7.48 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ =
164.7, 164.0, 158.0, 138.0, 137.1, 131.1, 130.8, 129.1, 128.7, 128.4, 127.3, 114.6 ppm. HRMS
m/z: calcd for C16H13N2 [M+H]+ 233.1073, found: 233.1077.
2-(3-Bromophenyl)-4-phenylpyrimidine (3ba): Yield = 76% (0.0710g). Yellow oil. IR (KBr) ν
= 3064, 2925, 1575, 1435, 1256, 1067, 846, 789 and 684 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ =
8.83 (d, J = 5.3 Hz, 1H), 8.74 (t, J = 1.8 Hz, 1H), 8.54 – 8.49 (m, 1H), 8.25 – 8.18 (m, 2H), 7.64
– 7.60 (m, 2H), 7.57 – 7.53 (m, 3H), 7.38 (t, J = 7.9 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 164.2, 163.3, 158.0, 140.0, 136.8, 133.7, 131.4, 131.3, 130.2, 129.1, 127.4, 127.0, 123.0,
115.1 ppm. HRMS m/z: calcd for C16H12BrN2 [M+H]+ 311.0178, found: 311.0189.
2-(4-Bromophenyl)-4-phenylpyrimidine (3ca): Yield = 81% (0.0759g). White solid. M.p.
o
85.9–87.7 C. IR (KBr) ν = 2987, 2901, 1578, 1543, 1377, 1065, 1006, 837, 765 and 695 cmꢀ1.
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1H NMR (400 MHz, CDCl3): δ = 8.82 (d, J = 5.3 Hz, 1H), 8.51 – 8.42 (m, 2H), 8.25 – 8.17 (m,
2H), 7.68 – 7.59 (m, 3H), 7.57 – 7.51 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.1,
163.9, 158.0, 136.9, 136.9, 131.9, 131.2, 130.0, 129.1, 127.3, 125.6, 114.9 ppm. HRMS m/z:
calcd for C16H12BrN2 [M+H]+ 311.0178, found: 311.0188.
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2-(4-Chlorophenyl)-4-phenylpyrimidine (3da): Yield = 80% (0.0637g). White solid. M.p.
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98.0–101.0 C. IR (KBr) ν = 2967, 2922, 1557, 1400, 1087, 833, 765 and 687 cmꢀ1. H NMR
(400 MHz, CDCl3): δ = 8.84 – 8.78 (m, 1H), 8.56 – 8.48 (m, 2H), 8.24 – 8.17 (m, 2H), 7.62 –
7.58 (m, 1H), 7.56 – 7.51 (m, 3H), 7.50 – 7.45 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ =
164.1, 163.8, 158.0, 137.1, 136.9, 136.5, 131.2, 129.8, 129.1, 128.9, 127.3, 114.8 ppm. HRMS
m/z: calcd for C16H12ClN2 [M+H]+ 267.0684, found: 267.0694.
2-(4-Fluorophenyl)-4-phenylpyrimidine (3ea): Yield = 82% (0.0616g). White solid. M.p.
o
61.2–61.3 C. IR (KBr) ν = 2975, 2854, 1565, 1508, 1404, 1219, 1150, 828, 763 and 686 cmꢀ1.
1H NMR (400 MHz, CDCl3): δ = 8.81 (d, J = 5.2 Hz, 1H), 8.64 – 8.54 (m, 2H), 8.27 – 8.17 (m,
2H), 7.59 (d, J = 5.3 Hz, 1H), 7.56 – 7.50 (m, 3H), 7.23 – 7.14 (m, 2H) ppm. 19F NMR (376
MHz, CDCl3): δ = ꢀ110.5 ppm. 13C NMR (100 MHz, CDCl3): δ = 165.0 (d, JCꢀF = 228.8 Hz),
163.8 (d, JCꢀF = 43.5 Hz), 158.0, 137.0, 134.2 (d, JCꢀF = 2.9 Hz), 131.2, 130.5 (d, JCꢀF = 8.7 Hz),
129.1, 127.3, 115.7, 115.5, 114.6 ppm. HRMS m/z: calcd for C16H12FN2 [M+H]+ 251.0979,
found: 251.0973.
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4-Phenyl-2-p-tolylpyrimidine (3fa): Yield = 86% (0.0632g). White solid. M.p. 78.3–79.0 C.
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IR (KBr) ν = 2919, 2854, 1581, 1424, 1381, 1276, 1175, 830, 764 and 688 cmꢀ1. H NMR (400
MHz, CDCl3): δ = 8.81 (d, J = 5.2 Hz, 1H), 8.50 – 8.45 (m, 2H), 8.26 – 8.19 (m, 2H), 7.57 (d, J
= 5.3 Hz, 1H), 7.53 (dd, J = 5.1, 2.0 Hz, 3H), 7.32 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H) ppm. 13C
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NMR (100 MHz, CDCl3): δ = 164.8, 163.9, 157.9, 141.1, 137.2, 135.3, 131.0, 129.4, 129.1,
128.4, 127.3, 114.4, 21.7 ppm. HRMS m/z: calcd for C17H15N2 [M+H]+ 247.1230, found:
247.1220.
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2-(2-Ethoxyphenyl)-4-phenylpyrimidine (3ga): Yield = 93% (0.0772g). White solid. M.p.
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40.2–41.6 C. IR (KBr) ν = 2983, 2926, 1582, 1422, 1242, 1107, 1041, 756 and 691 cmꢀ1. H
NMR (400 MHz, DMSOꢀd6): δ = 8.94 (d, J = 5.3 Hz, 1H), 8.31 – 8.24 (m, 2H), 7.99 (d, J = 5.3
Hz, 1H), 7.69 (dd, J = 7.6, 1.8 Hz, 1H), 7.60 – 7.54 (m, 3H), 7.49 – 7.42 (m, 1H), 7.18 (d, J = 8.2
Hz, 1H), 7.11 – 7.04 (m, 1H), 4.16 – 4.06 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (100
MHz, DMSOꢀd6): δ = 165.3, 162.5, 158.1, 156.9, 136.4, 131.2, 131.1, 130.8, 129.0, 128.9,
127.1, 120.3, 114.4, 113.7, 64.0, 14.7 ppm. HRMS m/z: calcd for C18H17N2O [M+H]+ 277.1335,
found: 277.1344.
2-(4-Nitrophenyl)-4-phenylpyrimidine (3ha): Yield = 91% (0.0756g). White solid. M.p.
o
181.7–182.5 C. IR (KBr) ν = 2987, 2901, 1564, 1394, 1250, 1066, 741 and 690 cmꢀ1. 1H NMR
(400 MHz, DMSOꢀd6): δ = 9.06 (d, J = 5.3 Hz, 1H), 8.80 – 8.73 (m, 2H), 8.42 (d, J = 2.0 Hz,
1H), 8.41 – 8.35 (m, 3H), 8.15 (d, J = 5.3 Hz, 1H), 7.66 – 7.59 (m, 3H) ppm. 13C NMR (100
MHz, CDCl3): δ = 164.4, 162.6, 158.2, 149.4, 143.7, 136.5, 131.5, 129.3, 129.2, 127.4, 123.8,
115.7 ppm. HRMS m/z: calcd for C16H12N3O2 [M+H]+ 278.0924, found: 278.0927.
4-(4-Phenylpyrimidin-2-yl)phenol (3ia): Yield = 89% (0.0663g). White solid. M.p. 201.9–
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202.3 C. IR (KBr) ν = 2987, 2901, 1566, 1417, 1274, 1236, 1167, 1066, 766 and 690 cmꢀ1. H
NMR (400 MHz, DMSOꢀd6): δ = 8.87 (d, J = 5.3 Hz, 1H), 8.43 – 8.37 (m, 2H), 8.36 – 8.29 (m,
2H), 7.89 (d, J = 5.3 Hz, 1H), 7.64 – 7.55 (m, 3H), 6.98 – 6.90 (m, 2H) ppm. 13C NMR (100
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MHz, DMSOꢀd6): δ = 163.5, 162.6, 160.2, 158.4, 136.4, 131.1, 129.6, 129.0, 128.3, 127.0,
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115.4, 113.9 ppm. HRMS m/z: calcd for C16H13N2O [M+H]+ 249.1022, found: 249.1019.
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4-Phenyl-2-(pyridin-3-yl)pyrimidine (3ja): Yield = 83% (0.0583g). White solid. M.p. 80.8–
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81.0 C. IR (KBr) ν = 2987, 2901, 1581, 1417, 1370, 1066, 824, 758 and 686 cmꢀ1. H NMR
(400 MHz, CDCl3): δ = 9.83 – 9.73 (m, 1H), 8.86 (d, J = 5.3 Hz, 1H), 8.84 – 8.80 (m, 1H), 8.74
(dd, J = 5.0, 1.7 Hz, 1H), 8.28 – 8.18 (m, 2H), 7.67 (d, J = 5.3 Hz, 1H), 7.61 – 7.52 (m, 3H), 7.48
– 7.42 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.2, 163.0, 158.1, 151.5, 150.2, 136.7,
135.7, 133.5, 131.4, 129.2, 127.4, 123.5, 115.3 ppm. HRMS m/z: calcd for C15H12N3 [M+H]+
234.1026, found: 234.1037.
2-(Furan-3-yl)-4-phenylpyrimidine (3ka): Yield = 83% (0.0552g). Yellow oil. IR (KBr) ν =
3061, 2928, 1683, 1587, 1489, 1450, 1224, 1006, 921, 765 and 695 cmꢀ1. H NMR (400 MHz,
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DMSOꢀd6): δ = 8.88 (d, J = 5.3 Hz, 1H), 8.34 – 8.24 (m, 2H), 7.98 – 7.96 (m, 1H), 7.94 (d, J =
5.3 Hz, 1H), 7.63 – 7.55 (m, 3H), 7.45 – 7.40 (m, 1H), 6.76 – 6.71 (m, 1H) ppm. 13C NMR (100
MHz, DMSOꢀd6): δ = 162.9, 158.5, 157.1, 151.9, 145.8, 135.9, 131.3, 129.0, 127.1, 114.6,
113.6, 112.5 ppm. HRMS m/z: calcd for C14H11N2O [M+H]+ 223.0866, found: 223.0869.
2-(4-Phenylpyrimidin-2-yl)thiazole (3la): Yield = 44% (0.0315g). White solid. M.p. 74.3–76.8
oC. IR (KBr) ν = 3074, 2968, 1673, 1570, 1429, 1264, 1068, 775 and 692 cmꢀ1. H NMR (400
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MHz, DMSOꢀd6): δ = 9.00 (d, J = 5.4 Hz, 1H), 8.35 – 8.29 (m, 2H), 8.15 (d, J = 5.3 Hz, 1H),
8.13 (d, J = 3.1 Hz, 1H), 8.03 (d, J = 3.1 Hz, 1H), 7.65 – 7.60 (m, 3H) ppm. 13C NMR (100 MHz,
DMSOꢀd6): δ = 166.5, 163.5, 159.0, 158.9, 145.1, 135.4, 131.6, 129.1, 127.2, 124.5, 116.7 ppm.
HRMS m/z: calcd for C13H10N3S [M+H]+ 240.0590, found: 240.0595.
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4-Phenylpyrimidine (3ma): Yield = 44% (0.0414g). Yellow oil. IR (KBr) ν = 2924, 2835,
1671, 1576, 1387, 1179, 1074, 744 and 691 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 9.25 (d, J
= 1.4 Hz, 1H), 8.87 (d, J = 5.4 Hz, 1H), 8.25 – 8.19 (m, 2H), 8.12 – 8.09 (m, 1H), 7.60 – 7.54
(m, 3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 162.6, 158.8, 158.1, 136.0, 131.3, 129.1,
127.0, 117.2 ppm. HRMS m/z: calcd for C10H9N2 [M+H]+ 157.0760, found: 157.0768.
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2-Cyclopropyl-4-phenylpyrimidine (3na): Yield = 63% (0.0735g). Yellow oil. IR (KBr) ν =
3008, 1568, 1546, 1436, 1026, 917, 763 and 690 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 8.68
(d, J = 5.3 Hz, 1H), 8.21 – 8.14 (m, 2H), 7.81 (d, J = 5.3 Hz, 1H), 7.58 – 7.52 (m, 3H), 2.26 (tt, J
= 7.8, 5.4 Hz, 1H), 1.11 – 1.05 (m, 4H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 171.1, 162.4,
158.0, 136.3, 131.0, 128.9, 126.9, 113.8, 18.0, 10.4 ppm. HRMS m/z: calcd for C13H13N2
[M+H]+ 197.1073, found: 197.1078.
2-Phenylpyrimido[1,2-b]indazole (3oa): Yield = 30% (0.0220g). White solid. M.p. 104.9–
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105.1 C. IR (KBr) ν = 3049, 2921, 2851, 1634, 1534, 1413, 1228, 811, 722 and 684 cmꢀ1. H
NMR (400 MHz, DMSOꢀd6): δ = 9.49 (d, J = 7.4 Hz, 1H), 8.43 – 8.36 (m, 2H), 8.35 – 8.30 (m,
1H), 8.13 (d, J = 7.4 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.69 – 7.55 (m, 4H), 7.36 – 7.30 (m, 1H)
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ppm. C NMR (100 MHz, DMSOꢀd6): δ = 152.1, 151.0, 142.7, 136.3, 135.2, 130.5, 129.8,
129.1, 127.1, 120.7, 120.6, 116.1, 112.9, 109.4 ppm. HRMS m/z: calcd for C16H12N3 [M+H]+
246.1026, found: 246.1037.
2-Phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (3pa): Yield = 33% (0.0244g). White solid. M.p.
o
257.5–257.2 C. IR (KBr) ν = 2960, 2922, 2853, 1604, 1522, 1455, 1419, 1257, 1026 and 755
cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 9.61 (d, J = 7.2 Hz, 1H), 8.42 – 8.29 (m, 3H), 7.89 –
7.80 (m, 2H), 7.66 – 7.59 (m, 3H), 7.55 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H) ppm. 13C
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NMR (100 MHz, DMSOꢀd6): δ = 161.0, 150.3, 144.3, 136.5, 136.1, 131.4, 129.1, 127.6, 127.1,
126.0, 121.3, 119.0, 112.5, 103.9 ppm. HRMS m/z: calcd for C16H12N3 [M+H]+ 246.1026,
found: 246.1034.
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4-(3-Bromophenyl)-2-phenylpyrimidine (3ab): Yield = 77% (0.0716g). White solid. M.p.
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69.1–70.7 C. IR (KBr) ν = 2987, 2901, 1587, 1410, 1263, 1067, 749 and 696 cmꢀ1. H NMR
(400 MHz, DMSOꢀd6): δ = 9.00 (d, J = 5.3 Hz, 1H), 8.55 – 8.49 (m, 3H), 8.36 (d, J = 7.8 Hz,
1H), 8.08 (d, J = 5.3 Hz, 1H), 7.80 (dd, J = 7.9, 2.0 Hz, 1H), 7.61 – 7.54 (m, 4H) ppm. 13C NMR
(100 MHz, DMSOꢀd6): δ = 163.4, 161.4, 158.9, 138.6, 137.1, 133.9, 131.2, 131.0, 129.6, 128.7,
127.8, 126.2, 122.6, 115.4 ppm. HRMS m/z: calcd for C16H12BrN2 [M+H]+ 311.0178, found:
311.0189.
4-(4-Bromophenyl)-2-phenylpyrimidine (3ac): Yield = 78% (0.0728g). White solid. M.p.
99.8–100.1 oC. IR (KBr) ν = 3059, 2922, 1586, 1539, 1425, 1371, 1068, 1002, 814, 749 and 689
cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 8.99 (d, J = 5.3 Hz, 1H), 8.56 – 8.49 (m, 2H), 8.36 –
8.28 (m, 2H), 8.04 (d, J = 5.4 Hz, 1H), 7.85 – 7.77 (m, 2H), 7.62 – 7.54 (m, 3H) ppm. 13C NMR
(100 MHz, DMSOꢀd6): δ = 163.4, 161.8, 158.9, 137.2, 135.4, 132.1, 131.0, 129.1, 128.7, 127.8,
125.1, 115.0 ppm. HRMS m/z: calcd for C16H12BrN2 [M+H]+ 311.0178, found: 311.0187.
4-(4-Chlorophenyl)-2-phenylpyrimidine (3ad): Yield = 74% (0.0588g). White solid. M.p.
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83.0–83.4 C. IR (KBr) ν = 2987, 2971, 1561, 1541, 1455, 1377, 1086, 816, 750 and 670 cmꢀ1.
1H NMR (400 MHz, DMSOꢀd6): δ = 8.99 (d, J = 5.3 Hz, 1H), 8.57 – 8.50 (m, 2H), 8.43 – 8.35
(m, 2H), 8.04 (d, J = 5.3 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.61 – 7.54 (m, 3H) ppm. 13C NMR (100
MHz, DMSOꢀd6): δ = 163.3, 161.7, 158.9, 137.2, 136.1, 135.0, 131.0, 129.1, 128.9, 128.7,
127.8, 115.1 ppm. HRMS m/z: calcd for C16H12ClN2 [M+H]+ 267.0684, found: 267.0693.
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4-(3,4-Dichlorophenyl)-2-phenylpyrimidine (3ae): Yield = 71% (0.0638g). White solid. M.p.
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90.1–91.7 C. IR (KBr) ν = 2987, 2901, 1561, 1425, 1396, 1260, 1066, 825, 751 and 686 cmꢀ1.
1H NMR (400 MHz, DMSOꢀd6): δ = 9.02 (d, J = 5.3 Hz, 1H), 8.62 – 8.48 (m, 3H), 8.38 – 8.32
(m, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.60 – 7.54 (m, 3H) ppm. 13C NMR
(100 MHz, DMSOꢀd6): δ = 163.4, 160.6, 159.1, 137.0, 136.8, 134.0, 132.1, 131.3, 131.1, 128.8,
128.8, 127.9, 127.2, 115.4 ppm. HRMS m/z: calcd for C16H11Cl2N2 [M+H]+ 301.0294, found:
301.0292.
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4-(4-Fluorophenyl)-2-phenylpyrimidine (3af): Yield = 82% (0.0613g). White solid. M.p.
46.7–47.0 oC. IR (KBr) ν = 2987, 2970, 2922, 1565, 1505, 1431, 1408, 1227, 1157, 827, 756 and
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689 cmꢀ1. H NMR (400 MHz, DMSOꢀd6): δ = 8.97 (d, J = 5.3 Hz, 1H), 8.58 – 8.50 (m, 2H),
8.48 – 8.40 (m, 2H), 8.02 (d, J = 5.3 Hz, 1H), 7.61 – 7.54 (m, 3H), 7.44 (t, J = 8.7 Hz, 2H) ppm.
19F NMR (376 MHz, DMSOꢀd6): δ = δ ꢀ109.6 ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 164.1
(d, JCꢀF = 247.5 Hz), 162.6 (d, JCꢀF = 142.8 Hz), 158.7, 137.2, 132.7 (d, JCꢀF = 3.0 Hz), 130.9,
129.6 (d, JCꢀF = 8.7 Hz), 128.7, 127.8, 116.1, 115.9, 114.9 ppm. HRMS m/z: calcd for C16H12FN2
[M+H]+ 251.0979, found: 251.0981.
o
2-Phenyl-4-p-tolylpyrimidine (3ag): Yield = 73% (0.0537g). White solid. M.p. 98.3–99.3 C.
IR (KBr) ν = 2987, 2901, 1562, 1544, 1426, 1075, 813, 757 and 693 cmꢀ1. 1H NMR (400 MHz,
DMSOꢀd6): δ = 8.93 (d, J = 5.3 Hz, 1H), 8.57 – 8.49 (m, 2H), 8.30 – 8 .23 (m, 2H), 7.98 (d, J =
5.3 Hz, 1H), 7.61 – 7.53 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H) ppm. 13C NMR (100 MHz, DMSOꢀ
d6): δ = 163.2, 162.8, 158.5, 141.3, 137.4, 133.4, 130.8, 129.7, 128.7, 127.8, 127.0, 114.7, 21.0
ppm. HRMS m/z: calcd for C17H15N2 [M+H]+ 247.1230, found: 247.1243.
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4-(4-Methoxyphenyl)-2-phenylpyrimidine (3ah): Yield = 65% (0.0509g). White solid. M.p.
167.4–169.9 oC. IR (KBr) ν = 2987, 2970, 2901, 1584, 1560, 1412, 1380, 1250, 1179, 1025, 827,
757 and 692 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 8.89 (d, J = 5.3 Hz, 1H), 8.58 – 8.48 (m,
2H), 8.40 – 8.29 (m, 2H), 7.94 (d, J = 5.4 Hz, 1H), 7.63 – 7.52 (m, 3H), 7.19 – 7.10 (m, 2H),
3.87 (s, 3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 163.1, 162.5, 161.9, 158.3, 137.5, 130.8,
128.8, 128.7, 128.5, 127.7, 114.4, 114.2, 55.4 ppm. HRMS m/z: calcd for C17H15N2O [M+H]+
263.1179, found: 263.1185.
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2,4-Bis(4-bromophenyl)pyrimidine (3cc): Yield = 78% (0.0914g). White solid. M.p. 160.4–
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161.8 C. IR (KBr) ν = 2987, 2922, 1577, 1538, 1434, 1069, 1007, 815 and 786 cmꢀ1. H NMR
(400 MHz, DMSOꢀd6): δ = 8.97 (d, J = 5.3 Hz, 1H), 8.49 – 8.40 (m, 2H), 8.33 – 8.25 (m, 2H),
8.05 (d, J = 5.3 Hz, 1H), 7.83 – 7.73 (m, 4H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 162.5,
161.9, 159.0, 136.4, 135.2, 132.1, 131.8, 129.8, 129.2, 125.2, 124.9, 115.3 ppm. HRMS m/z:
calcd for C16H11Br2N2 [M+H]+ 388.9283, found: 388.9280.
2-(4-Bromophenyl)-4-(2-(trifluoromethyl)phenyl)pyrimidine (3ci): Yield = 45% (0.0507g).
o
White solid. M.p. 72.9–73.4 C. IR (KBr) ν = 2987, 2901, 1543, 1373, 1315, 1165, 1090, 1036,
837 and 769 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 9.05 (d, J = 5.1 Hz, 1H), 8.41 – 8.30 (m,
2H), 8.01 – 7.93 (m, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.83 – 7.71 (m, 4H), 7.68 (d, J = 5.1 Hz, 1H)
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ppm. F NMR (376 MHz, DMSOꢀd6): δ = δ ꢀ55.2 ppm. 13C NMR (100 MHz, DMSOꢀd6): δ =
165.2, 161.9, 158.4, 137.1 (q, JCꢀF = 3.6, 1.5 Hz), 136.1, 132.7, 131.9, 131.5, 130.1, 129.7, 126.9
(q, JCꢀF = 236.6, 5.16 Hz), 125.3, 125.0, 122.6, 119.3 ppm. HRMS m/z: calcd for C17H11BrF3N2
[M+H]+ 379.0052, found: 379.0067.
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4-(Benzo[d][1,3]dioxol-5-yl)-2-phenylpyrimidine (3aj): Yield = 73% (0.0608g). White solid.
M.p. 116.2–118.4 oC. IR (KBr) ν = 2970, 2920, 1560, 1442, 1251, 1033, 799, 755 and 698 cmꢀ1.
1H NMR (400 MHz, DMSOꢀd6): δ = 8.89 (d, J = 5.3 Hz, 1H), 8.56 – 8.48 (m, 2H), 7.99 – 7.95
(m, 1H), 7.95 – 7.89 (m, 2H), 7.59 – 7.53 (m, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.16 (s, 2H) ppm.
13C NMR (100 MHz, DMSOꢀd6): δ = 163.1, 162.3, 158.3, 150.0, 148.2, 137.4, 130.8, 130.3,
128.7, 127.8, 122.1, 114.4, 108.7, 106.9, 101.8 ppm. HRMS m/z: calcd for C17H13N2O2 [M+H]+
277.0972, found: 277.0982.
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4-(2-(Pyridin-3-yl)pyrimidin-4-yl)phenol (3jk): Yield = 78% (0.0582g). White solid. M.p.
254.1–256.9. IR (KBr) ν = 3095, 3021, 1588, 1508, 1406, 1281, 1035, 826, 781 and 698 cmꢀ1. 1H
NMR (400 MHz, DMSOꢀd6): δ = 10.16 (s, 1H), 9.63 (s, 1H), 8.89 (d, J = 5.4 Hz, 1H), 8.84 –
8.69 (m, 2H), 8.26 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 5.4 Hz, 1H), 7.59 (dd, J = 8.0, 4.8 Hz, 1H),
6.96 (d, J = 8.3 Hz, 2H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 163.0, 161.6, 160.7, 158.2,
151.4, 149.0, 135.1, 133.0, 129.0, 126.6, 123.8, 115.9, 114.4 ppm. HRMS m/z: calcd for
C15H12N3O [M+H]+ 250.0975, found: 250.0985.
2,4-Di(pyridin-3-yl)pyrimidine (3jl): Yield = 89% (0.0626g). White solid. M.p. 133.8–134.2
oC. IR (KBr) ν = 2987, 2901, 1583, 1408, 1025, 783 and 698 cmꢀ1. 1H NMR (400 MHz, DMSOꢀ
d6): δ = 9.66 (d, J = 2.2 Hz, 1H), 9.53 (d, J = 2.3 Hz, 1H), 9.07 (d, J = 5.3 Hz, 1H), 8.87 – 8.70
(m, 4H), 8.20 (d, J = 5.3 Hz, 1H), 7.67 – 7.57 (m, 2H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ
= 162.0, 161.4, 159.1, 152.0, 151.6, 149.1, 148.5, 135.3, 134.8, 132.6, 131.6, 124.1, 123.9, 116.1
ppm. HRMS m/z: calcd for C14H11N4 [M+H]+ 235.0978, found: 235.0981.
2-(4-Bromophenyl)-4-(thiophen-2-yl)pyrimidine (3cm): Yield = 79% (0.0751g). White solid.
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M.p. 104.9–105.7 C. IR (KBr) ν = 2968, 2854, 1555, 1396, 1064, 822, 785 and 700 cmꢀ1. H
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NMR (400 MHz, DMSOꢀd6): δ = 8.89 (d, J = 5.3 Hz, 1H), 8.42 – 8.33 (m, 2H), 8.15 (dd, J = 3.8,
1.2 Hz, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.89 (dd, J = 5.0, 1.1 Hz, 1H), 7.81 – 7.75 (m, 2H), 7.30
(dd, J = 5.0, 3.7 Hz, 1H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 162.4, 158.7, 158.4, 141.8,
136.1, 131.8, 131.5, 129.6, 129.2, 129.0, 124.9, 113.7 ppm. HRMS m/z: calcd for C14H10BrN2S
[M+H]+ 316.9743, found: 316.9746.
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4-(4'-Methylbiphenyl-4-yl)-2-phenylpyrimidine (3an): Yield = 79% (0.0761g). White solid.
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M.p. 162.1–163.4 C. IR (KBr) ν = 2987, 2901, 1557, 1415, 1066, 806, 759 and 692 cmꢀ1. H
NMR (400 MHz, DMSOꢀd6): δ = 8.97 (d, J = 5.3 Hz, 1H), 8.58 – 8.63 (m, 2H), 8.48 – 8.40 (m,
2H), 8.06 (d, J = 5.3 Hz, 1H), 7.92 – 7.84 (m, 2H), 7.72 – 7.65 (m, 2H), 7.61 – 7.55 (m, 3H),
7.33 (d, J = 7.8 Hz, 2H), 2.37 (s, 3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 163.3, 162.5,
158.6, 142.7, 137.6, 137.4, 136.3, 134.8, 130.9, 129.7, 128.7, 127.8, 127.7, 127.0, 126.6, 115.0,
20.7 ppm. HRMS m/z: calcd for C23H19N2 [M+H]+ 323.1543, found: 323.1547.
9-(4-(2-Phenylpyrimidin-4-yl)phenyl)-9H-carbazole (3ao): Yield = 65% (0.0771g). White
solid. M.p. 187.3–189.0 oC. IR (KBr) ν = 3063, 2923, 2853, 1561, 1449, 1228, 829, 746 and 696
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cmꢀ1. H NMR (400 MHz, DMSOꢀd6): δ = 9.05 (d, J = 5.3 Hz, 1H), 8.67 (d, J = 8.5 Hz, 2H),
8.61 – 8.56 (m, 2H), 8.29 (d, J = 7.8 Hz, 2H), 8.15 (d, J = 5.3 Hz, 1H), 7.92 – 7.85 (m, 2H), 7.62
– 7.57 (m, 3H), 7.54 (d, J = 8.2 Hz, 2H), 7.51 – 7.45 (m, 2H), 7.37 – 7.31 (m, 2H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 164.9, 163.1, 158.2, 140.6, 140.4, 137.9, 135.8, 131.0, 128.9,
128.7, 128.5, 127.3, 126.3, 123.8, 120.6, 120.5, 114.6, 109.9 ppm. HRMS m/z: calcd for
C28H20N3 [M+H]+ 398.1652, found: 398.1645.
4-(3-(Dibenzo[b,d]thiophen-4-yl)phenyl)-2-phenylpyrimidine (3ap): Yield = 84% (0.1041g).
o
White solid. M.p. 53.2–55.1 C. IR (KBr) ν = 2987, 2901, 1560, 1420, 1379, 1255, 1049, 744
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and 691 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 8.19 (d, J = 5.3 Hz, 1H), 7.94 (s, 1H), 7.83 –
7.74 (m, 2H), 7.69 – 7.57 (m, 3H), 7.28 (d, J = 5.3 Hz, 1H), 7.26 – 7.19 (m, 1H), 7.17 – 7.10 (m,
1H), 6.98 (t, J = 7.8 Hz, 1H), 6.92 – 6.85 (m, 2H), 6.78 – 6.72 (m, 5H) ppm. 13C NMR (100
MHz, DMSOꢀd6): δ = 163.4, 162.6, 158.7, 140.5, 138.4, 137.4, 137.2, 137.0, 135.9, 135.6,
135.2, 130.8, 130.6, 129.8, 128.6, 127.8, 127.3, 127.1, 126.9, 126.5, 125.7, 124.8, 122.8, 122.2,
121.4, 115.3 ppm. HRMS m/z: calcd for C28H19N2S [M+H]+ 415.1263, found: 415.1275.
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(2,4-Diphenylpyrimidin-5-yl)(phenyl)methanone (5ab): Yield = 45% (0.0458g). White solid.
M.p. 87.9–89.6 oC. IR (KBr) ν = 2987, 2922, 1655, 1552, 1415, 1182, 921, 742 and 684 cmꢀ1. 1H
NMR (400 MHz, DMSOꢀd6): δ = 9.06 (s, 1H), 8.60 – 8.55 (m, 2H), 7.79 – 7.74 (m, 2H), 7.66
(dd, J = 7.5, 2.1 Hz, 2H), 7.63 – 7.57 (m, 4H), 7.44 (d, J = 7.7 Hz, 2H), 7.40 (dd, J = 7.0, 4.4 Hz,
3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 195.0, 163.8, 163.6, 157.9, 136.9, 136.5, 136.0,
134.0, 131.6, 130.4, 129.6, 129.3, 129.1, 128.9, 128.8, 128.6, 128.3 ppm. HRMS m/z: calcd for
C23H17N2O [M+H]+ 337.1335, found: 337.1345.
4-Methyl-2,6-diphenylpyrimidine (5ac) and (5ae): Yield = 53% (0.0390g) (5ac), 38%
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(0.0283g) (5ae). White solid. M.p. 74.9–75.2 C. IR (KBr) ν = 2970, 2923, 1570, 1534, 1366,
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1028, 747 and 692 cmꢀ1. H NMR (400 MHz, DMSOꢀd6): δ = 8.58 – 8.50 (m, 2H), 8.38 – 8.28
(m, 2H), 7.91 (s, 1H), 7.64 – 7.53 (m, 6H), 2.62 (s, 3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ
= 168.2, 163.0, 162.7, 137.4, 136.4, 131.0, 130.7, 129.0, 128.6, 127.8, 127.0, 114.3, 24.1 ppm.
HRMS m/z: calcd for C17H15N2 [M+H]+ 247.1230, found: 247.1238.
o
2,4,6-Triphenylpyrimidine (5ad): Yield = 74% (0.0689g). White solid. M.p. 98.2–99.3 C. IR
(KBr) ν = 2987, 2901, 1567, 1359, 1233, 1056, 736 and 679 cmꢀ1. 1H NMR (400 MHz, DMSOꢀ
d6): δ = 8.71 – 8.64 (m, 2H), 8.56 (s, 1H), 8.54 – 8.48 (m, 4H), 7.67 – 7.57 (m, 9H) ppm. 13C
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NMR (100 MHz, DMSOꢀd6): δ = 164.2, 163.3, 137.5, 136.6, 131.2, 130.9, 129.0, 128.7, 128.0,
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127.4, 110.5 ppm. HRMS m/z: calcd for C22H17N2 [M+H]+ 309.1386, found: 309.1395.
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4,6-Dimethyl-2-phenylpyrimidine (5af): Yield = 36% (0.0199g). White solid. M.p. 74.3–75.4
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oC. IR (KBr) ν = 2923, 2852, 1593, 1533, 1364, 1172, 1025, 854, 748 and 692 cmꢀ1. H NMR
(400 MHz, DMSOꢀd6): δ = 8.44 – 8.35 (m, 2H), 7.53 – 7.48 (m, 3H), 7.19 (s, 1H), 2.49 (s, 6H)
ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 166.6, 162.6, 137.4, 130.5, 128.5, 127.7, 118.3, 23.7
ppm. HRMS m/z: calcd for C12H13N2 [M+H]+ 185.1073, found: 185.1080.
2-Phenyl-5,6,7,8-tetrahydroquinazoline (5ag): Yield = 30% (0.0192g). White solid. M.p.
38.3–40.4 oC. IR (KBr) ν = 2928, 2854, 1573, 1542, 1423, 1395, 1258, 1022, 735 and 691 cmꢀ1.
1H NMR (400 MHz, DMSOꢀd6): δ = 8.56 (s, 1H), 8.40 – 8.29 (m, 2H), 7.53 – 7.45 (m, 3H), 2.86
(t, J = 6.3 Hz, 2H), 2.75 (t, J = 6.2 Hz, 2H), 1.92 – 1.83 (m, 2H), 1.82 – 1.75 (m, 2H) ppm. 13C
NMR (100 MHz, DMSOꢀd6): δ = 165.7, 160.6, 157.3, 137.4, 130.2, 128.5, 128.3, 127.4, 31.6,
24.8, 21.8, 21.6 ppm. HRMS m/z: calcd for C14H15N2 [M+H]+ 211.1230, found: 211.1240.
1-(4-Methyl-2-(pyridin-3-yl)pyrimidin-5-yl)ethanone (5ah): Yield = 41% (0.0270g). White
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solid. M.p. 92.7–95.5 C. IR (KBr) ν = 2924, 2853, 1680, 1566, 1524, 1409, 1272, 1227, 1025,
965, 782 and 710 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 9.56 (dd, J = 2.3, 0.9 Hz, 1H), 9.33
(s, 1H), 8.77 (dd, J = 4.8, 1.7 Hz, 1H), 8.74 – 8.69 (m, 1H), 7.63 – 7.57 (m, 1H), 2.75 (s, 3H),
2.68 (s, 3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 198.6, 167.1, 162.2, 158.7, 152.1, 149.4,
135.6, 131.8, 128.4, 124.0, 29.4, 24.4 ppm. HRMS m/z: calcd for C12H12N3O [M+H]+ 214.0975,
found: 214.0984.
Ethyl 4-methyl-2-phenylpyrimidine-5-carboxylate (5ai): Yield = 63% (0.0459g). White solid.
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M.p. 81.5–83.9 C. IR (KBr) ν = 2975, 2922, 1713, 1562, 1536, 1419, 1360, 1277, 1226, 1075,
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768 and 691 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 9.18 (s, 1H), 8.54 – 8.42 (m, 2H), 7.64 –
7.51 (m, 3H), 4.40 – 4.32 (m, 2H), 2.81 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100
MHz, DMSOꢀd6): δ = 168.1, 164.5, 164.3, 158.9, 136.1, 131.8, 128.8, 128.4, 121.3, 61.3, 24.3,
14.0 ppm. HRMS m/z: calcd for C14H15N2O2 [M+H]+ 243.1128, found: 243.1132.
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Ethyl 2-(4-bromophenyl)-4-methylpyrimidine-5-carboxylate (5ci): Yield = 60% (0.0578g).
o
White solid. M.p. 105.8–107.4 C. IR (KBr) ν = 2925, 2853, 1721, 1562, 1420, 1279, 1106,
1068, 1008 and 790 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 9.16 (s, 1H), 8.39 – 8.33 (m, 2H),
7.79 – 7.74 (m, 2H), 4.40 – 4.31 (m, 2H), 2.80 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm. 13C NMR
(100 MHz, DMSOꢀd6): δ = 168.3, 164.4, 163.4, 158.9, 135.3, 131.9, 130.3, 125.7, 121.5, 61.4,
24.3, 14.0 ppm. HRMS m/z: calcd for C14H14BrN2O2 [M+H]+ 321.0233, found: 321.0246.
Ethyl 4-methyl-2-p-tolylpyrimidine-5-carboxylate (5fi): Yield = 61% (0.0446g). White solid.
M.p. 62.9–64.0 oC. IR (KBr) ν = 2919, 2852, 1721, 1568, 1425, 1274, 1106, 1078 and 787 cmꢀ1.
1H NMR (400 MHz, DMSOꢀd6): δ = 9.14 (s, 1H), 8.39 – 8.31 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H),
4.39 – 4.32 (m, 2H), 2.79 (s, 3H), 2.40 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100
MHz, DMSOꢀd6): δ = 168.0, 164.5, 164.4, 158.9, 141.8, 133.5, 129.5, 128.4, 120.9, 61.2, 24.3,
21.1, 14.0 ppm. HRMS m/z: calcd for C15H17N2O2 [M+H]+ 257.1285, found: 257.1294.
Ethyl 2-methylbenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylate (5oi): Yield = 42%
(0.0325g). White solid. M.p. 154.4–157.8 oC. IR (KBr) ν = 2923, 2851, 1714, 1637, 1457, 1263,
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1457, 1263, 1077 and 769 cmꢀ1. H NMR (400 MHz, DMSOꢀd6): δ = 9.96 (s, 1H), 8.51 – 8.47
(m, 1H), 7.87 – 7.81 (m, 1H), 7.60 – 7.54 (m, 1H), 7.47 – 7.42 (m, 1H), 4.43 – 4.34 (m, 2H),
2.84 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 164.9, 164.0,
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149.2, 144.4, 139.9, 127.4, 126.7, 121.9, 119.2, 113.3, 110.4, 61.2, 26.1, 14.2 ppm. HRMS m/z:
calcd for C14H14N3O2 [M+H]+ 256.1081, found: 256.1091.
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2,5-Diphenylpyrimidine (5aj): Yield = 80% (0.0556g). White solid. M.p. 92.7–94.8. IR (KBr) ν
= 2987, 2922, 1535, 1433, 1377, 1072, 1019, 743 and 689 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6):
δ = 9.26 (s, 2H), 8.51 – 8.42 (m, 2H), 7.92 – 7.85 (m, 2H), 7.60 – 7.53 (m, 5H), 7.52 – 7.47 (m,
1H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 162.1, 155.3, 136.8, 133.8, 131.0, 130.9, 129.3,
128.8, 127.6, 126.7 ppm. HRMS m/z: calcd for C16H13N2 [M+H]+ 233.1073, found: 233.1082.
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2-(4-Nitrophenyl)-5-phenylpyrimidine (5hj): Yield = 89% (0.0744g). White solid. M.p. 207.1–
208.6 oC. IR (KBr) ν = 3062, 3038, 1519, 1430, 1340, 1106, 800, 742 and 689 cmꢀ1. 1H NMR
(400 MHz, DMSOꢀd6): δ = 9.08 (s, 2H), 8.68 (d, J = 8.6 Hz, 2H), 8.35 (d, J = 8.6 Hz, 2H), 7.66
(d, J = 7.4 Hz, 2H), 7.61 – 7.46 (m, 3H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 161.4, 155.5,
149.4, 143.2, 134.1, 133.0, 129.7, 129.4, 129.1, 127.1, 124.0 ppm. HRMS m/z: calcd for
C16H12N3O2 [M+H]+ 278.0924, found: 278.0936.
5-Phenyl-2-(pyridin-3-yl)pyrimidine (5jj): Yield = 72% (0.0504g). White solid. M.p. 147.7–
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149.8 C. IR (KBr) ν = 2987, 2901, 1579, 1437, 1375, 1019, 967, 784 and 694 cmꢀ1. H NMR
(400 MHz, DMSOꢀd6): δ = 9.57 (s, 1H), 9.31 (s, 2H), 8.77 – 8.68 (m, 2H), 7.89 (d, J = 7.5 Hz,
2H), 7.64 – 7.54 (m 3H), 7.54 – 7.48 (m, 1H) ppm. 13C NMR (100 MHz, DMSOꢀd6): δ = 160.6,
155.5, 151.5, 148.8, 134.9, 133.6, 132.3, 131.6, 129.3, 129.0, 126.8, 123.9 ppm. HRMS m/z:
calcd for C15H12N3 [M+H]+ 234.1026, found: 234.1021.
N,N-diphenyl-4'-(4-phenylpyrimidin-2-yl)biphenyl-4-amine (6): Yield = 89 % (0.7382g).
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Yellow solid. M.p. 166.2–168.7 C. IR (KBr) ν = 2987, 2901, 1580, 1489, 1381, 1278, 1074,
825, 754 and 696 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 8.97 (d, J = 5.3 Hz, 1H), 8.59 (d, J
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= 8.0 Hz, 2H), 8.40 – 8.33 (m, 2H), 8.01 (d, J = 5.3 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.71 (d, J
= 8.2 Hz, 2H), 7.61 (d, J = 4.8 Hz, 3H), 7.34 (t, J = 7.6 Hz, 4H), 7.13 – 7.04 (m, 8H) ppm. 13C
NMR (100 MHz, DMSOꢀd6): δ = 163.1, 162.9, 158.7, 147.2, 146.9, 141.8, 136.2, 135.8, 133.0,
131.3, 129.6, 129.1, 128.4, 127.7, 127.1, 126.3, 124.3, 123.4, 123.0, 114.9 ppm. HRMS m/z:
calcd for C34H26N3 [M+H]+ 476.2121, found: 476.2122.
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ASSOCIATED CONTENT
Supporting Information
Reaction procedures and 1H and 13C NMR of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: xuxp@suda.edu.cn; shunjun@suda.edu.cn
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
We gratefully acknowledge the Natural Science Foundation of China (no. 21372174, 21672157),
the Ph.D. Programs Foundation of Ministry of Education of China (2013201130004), the
Research Grant from the Innovation Project for Graduate Student of Jiangsu Province
(KYZZ15_0322), PAPD and Soochow University for financial support.
REFERENCES
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