Palladium catalyzed Mizoroki–Heck reaction of pyrimidin-2-yl tosylates with aromatic and aliphatic olefins

Accepted Manuscript Palladium Catalyzed Mizoroki-Heck Reaction of Pyrimidin-2-yl Tosylates with Aromatic and Aliphatic Olefins Hai-Peng Gong, Zheng-Jun Quan, Xi-Cun Wang PII:

S0040-4020(16)30131-4

DOI:

10.1016/j.tet.2016.02.069

Reference:

TET 27539

To appear in:

Tetrahedron

Received Date: 30 December 2015 Revised Date:

24 February 2016

Accepted Date: 29 February 2016

Please cite this article as: Gong H-P, Quan Z-J, Wang X-C, Palladium Catalyzed Mizoroki-Heck Reaction of Pyrimidin-2-yl Tosylates with Aromatic and Aliphatic Olefins, Tetrahedron (2016), doi: 10.1016/j.tet.2016.02.069. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

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Palladium Catalyzed Mizoroki-Heck Reaction of Pyrimidin-2-yl Tosylates with Aromatic and Aliphatic Olefins

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Hai-Peng Gonga,b,c, Zheng-Jun Quana,b,* and Xi-Cun Wanga,b,* Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Anning East Road 967#, Lanzhou, Gansu 730070, PR China

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ACCEPTED MANUSCRIPT

Tetrahedron journal homepage: www.elsevier.com

Hai-Peng Gonga,b,c, Zheng-Jun Quana,b,∗ and Xi-Cun Wanga,b∗ a

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Palladium Catalyzed Mizoroki-Heck Reaction of Pyrimidin-2-yl Tosylates with Aromatic and Aliphatic Olefins

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Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, PR China Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Anning East Road 967#, Lanzhou, Gansu 730070, PR China c College of Natural Science, Gansu Agricultural University, No. 1 Yingmen village, Anning District, Lanzhou, Gansu 730070, PR China b

ABSTRACT

Article history: Received Received in revised form Accepted Available online

Pyrimidin-2-yl tosylates which are successfully applied as the electrophiles instead of halides coupled with olefins via Pd(PPh3)2Cl2 catalyzed Mizoroki-Heck reaction conditions to give the corresponding C2-alkenyl pyrimidine derivatives with high β-regioselectivity. This protocol proves to be tolerant of various pyrimidin-2-yl tosylates as well as various olefins including styrene derivatives, aliphatic olefins (vinyl cyanide, methyl acrylate, ethyl acrylate, n-butyl acrylate, butyl vinyl ether, 1-hexene and 1-octene).

Keywords: Mizoroki-Heck coupling Pyrimidin-2-yl tosylates Styrenes Acrylates Palladium catalysis

2009 Elsevier Ltd. All rights reserved.

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ARTICLE INFO

——— ∗ Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: [email protected] ∗ Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: [email protected]

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Tetrahedron

reaction not only provides products with high β-regioselectivity, ACCEPTED MANUSCRIPT

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Ar 'N P H K dC 2 3P l2 , O P 4, di Ph ox 3 an e

Scheme 1. Synthesis of the tetra-substituted pyrimidines deriving from pyrimidin-2-yl tosylates 2. Result and discussion

Initial coupling attempts were performed between pyrimidin2-yl tosylates 1a and styrene 2a as the model reaction (Table 1). Various transition metals such as Ni(PPh3)2Cl2, Ni(acac)2, Fe(acac)3, Pd(OAc)2 and Pd(PPh3)4 showed low catalytic activities to give the product 3aa in 0-36% yield (entries 1-5). We found that the phosphine ligand is crucial to obtain the desired product 3aa when using PdCl2 as a catalyst (entries 6-10). It is commonly believed that phosphine ligand is the reduction of Pd(II) to a catalytically active Pd(0) species, which is required to prevent the formation of palladium black.22 Compared with DPEphos, dppp or dppb (42-49% yield) (entries 8-10), ligand PPh3 gave the β-regioselective product 3aa in highest yield of 60% (entry 7). The best yield (76% yield) was realized using Pd(PPh3)2Cl2 in the presence of K3PO4 in NMP solvent (entry 11). Several inorganic bases were examined, all the reactions led to some conversion, albeit with quite different efficiency (entries 11-14). Due to strong basicity, Cs2CO3 led to the hydrolysis of 1a (entry 14), but K3PO4 gave the best result (entry 11). Among the solvents tested, xylol, toluene, dioxane, DMF, THF and NMP gave different yields, the latter the best yield of 76% (entries 1519). With the elevated temperature from 90 to 120 oC, the yield of 3aa gradually increased to 76% (entries 11 and 21). Meanwhile, the reaction conversion had no significant drop when the reaction time shortened from 24 h to 16 h (entry 22).

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In recent years, alkenyl/aryl phosphates, tosylates, mesylates, ethers and carboxylates as new O-based electrophiles have attracted a great deal of interests due to their advantages such as: easy preparation from abundant and inexpensive carbonyl and phenol derivatives, high leaving ability of C-O bonds in crosscoupling reactions and reducing halide waste. To date, although these new O-based electrophiles have proven their worth in various cross-coupling reactions, such as: Kumada4, SuzukiMiyaura5, Sonogashira6, Buchwald-Hartwig7, Negishi8, Stille9, Hiyama10 and other reactions11, tosylates as new substrate has scarcely been applied in the Mizoroki-Heck reaction. In 2002, Fu and co-workers12 reported the palladium-catalyzed Heck reaction of tosylates with electron-deficient olefins for the first time. In 2006, Skrydstrup and co-workers13 reported the Heck coupling of vinyl tosylates with electron-deficient olefins and styrene derivatives. They14, 15 also reported the Heck couplings of α, βunsaturated tosylates and heteroaromatic 2-pyridyl tosylates with electron-rich N-acylamines or vinyl ethers. In 2014, Jamison and co-workers16 described the nickel-catalyzed cationic Heck reaction of aryl tosylates and aliphatic olefins. In these reactions, electron-deficient olefins selectively provide products of βsubstitution and electron-rich olefins favor substitution at the αposition in usual.

but also makes a fresh method for the synthesis of new C2alkenyl pyrimidine derivatives.

R F M gB F e eC r (a l3 ( c a R= c) A 3 ( lk R yl) = Ar )

The Mizoroki-Heck coupling reaction of aryl halides and olefins1, has become a powerful and indispensable tool for the construction of C-C bonds in synthetic organic chemistry, which has been widely applied to diverse areas such as natural product synthesis, pharmaceuticals, biologically active molecules, and materials science.2 Although halides have been successfully used as the electrophiles in the Heck coupling due to their relatively high reactivity, both aryl halide and alkyl one still suffer from numerous drawbacks such as harsh prepared conditions, the coupling byproducts as well as environmental pollutions.3 Thus, developing new kinds of electrophile replacing the halides is still in demand.

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1. Introduction

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Our group has successfully accomplished conventional approaches for the synthesis of tetra-substituted pyrimidines via the Suzuki-Miyaura17, Sonogashira17, Buchwald18 and Kumada19 reactions using pyrimidin-2-yl tosylates as electrophiles (Scheme 1). The tetra-substituted pyrimidines display wide pharmacological and biological properties20, such as calcium channel modulator, antifungal and antibacterial profiles.21 In this context, we became interested in applying pyrimidin-2-yl tosylates in Heck coupling reaction. Here, we report a simple and efficient protocol for the palladium catalyzed Heck reaction of pyrimidin-2-yl tosylates with aromatic and aliphatic olefins. This

Table 1. Optimization of the Heck reaction of pyrimidin-2-yl tosylate and styrene.a

Entry

Catalyst

Ligand

Base

Solvent

Temp (oC)

Time (h)

Yieldb (%)

1

Ni(PPh3)2Cl2

-

K3PO4

NMP

120

24

n.r.

2

Ni(acac)2

PPh3

K3PO4

NMP

120

24

n.r.

3

Fe(acac)3

PPh3

K3PO4

NMP

120

24

n.r.

4

Pd(OAc)2

PPh3

K3PO4

NMP

120

24

36

5

Pd(PPh3)4

-

K3PO4

NMP

120

24

31

6

-

7

PdCl2

PPh3

K3PO4

NMP

8c

PdCl2

DPE-phos

K3PO4

NMP

PdCl2

dppp

K3PO4

10

PdCl2

dppb

K3PO4

9

c c

3

K PO NMP 120 ACCEPTED MANUSCRIPT

PdCl2

3

24

n.r.

120

24

60

120

24

42

NMP

120

24

46

NMP

120

24

49

4

11

Pd(PPh3)2Cl2

-

K3PO4

NMP

120

24

76

12

Pd(PPh3)2Cl2

-

K2CO3

NMP

120

24

40

13

Pd(PPh3)2Cl2

-

Na2CO3

NMP

120

24

42

14

Pd(PPh3)2Cl2

-

Cs2CO3

NMP

120

24

trace

-

K3PO4

xylol

120

-

K3PO4

toluene

120

17

Pd(PPh3)2Cl2

-

K3PO4

dioxane

110

18

Pd(PPh3)2Cl2

-

K3PO4

DMF

120

19

Pd(PPh3)2Cl2

-

K3PO4

THF

60

20

Pd(PPh3)2Cl2

-

K3PO4

NMP

110

21

Pd(PPh3)2Cl2

-

K3PO4

NMP

90

22

Pd(PPh3)2Cl2

-

K3PO4

NMP

24

58

24

64

24

50

24

66

24

20

24

69

24

58

16

75

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Pd(PPh3)2Cl2 Pd(PPh3)2Cl2

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15 16

120

a

b

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Reaction conditions: pyrimidin-2-yl tosylate 1a (0.5 mmol, 0.206 g), styrene 2a (1.5 equiv, 0.75 mmol, 0.0781 g), catalyst (5 mol %, 0.025 mmol), ligand (10 mol %, 0.05 mmol), base (2.0 equiv, 1.0 mmol) and solvent (2 mL) under nitrogen atmosphere. Isolated yield after column chromatography.

c

DPE-phos = bis[2-(diphenylphosphino)phenyl]ether, bis(diphenylphosphino)butane.

dppp

1,3-bis(diphenylphosphino)propane,

dppb

=

1,4-

within 16 h and all desired compounds 3aa-3mb could be isolated by column chromatography. The structure of 3bb was unambiguously established by single crystal X-ray diffraction (Fig. 1).23 The reaction tolerated both electron-withdrawing group (R = m-NO2 or o-Cl) and electrondonating group (R = pCH3, p-CH3O) on the phenyl ring to deliver the desired products. However, substrate with p-NO2 group on the phenyl ring failed to couple with styrene at all. Additionally, when the substituted group R2 such as Et– was replaced with Me– and i-Pr, the transformation still underwent smoothly to corresponding products 3ag and 3aj in excellent yields.

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With the optimized conditions in hand, we tested the possibility of varied O-based derivatives as electrophiles in the Heck coupling reaction. As shown in Table 2, coupling attempt of mesylate and pyrimidin-2-yl phosphate with styrene 2a were performed (entries 1 and 4), they led to lower coupling yields than pyrimidin-2-yl tosylate (entry 2). Due to poor electrophilic activity, the benzoate only yielded a trace amount of product 3aa (entry 5). Meanwhile, coupling product for the reaction of pivalates and styrene was not observed, which may be caused by the hydrolysis of pyrimidin-2-yl pivalate to 2-hydroxy pyrimidine (entry 3). Thus, pyrimidin-2-yl tosylates have been proved more reactive than other O-based derivatives for the Heck reaction.

=

Table 2. Evaluation of varied electrophiles of pyrimidin-2-yl esters.a O

Me

N N

AC C

O

EtO

+

Pd(PPh3)2Cl 2 ( 5 mol %)

Ph

OR

2a

Entry 1

EtO

K3PO4 (2.0 equiv) NMP, 120 oC, 16 h

R

Me

49

Ts

75

3

Piv

0

4

P(O)(OEt)2

63

C(O)Ph

trace

5

Ph

Yieldb (%)

Ms

2

N N 3aa

a

Reaction conditions: substrate (0.5 mmol), styrene (1.5 equiv, 0.75 mmol, 0.0781 g), Pd(PPh3)2Cl2 (5 mol %, 0.025 mmol, 0.0175 g), K3PO4 (2.0 equiv, 1.0 mmol, 0.212 g), NMP (2 mL). b

Isolated yield after column chromatography.

These results prompted us to investigate the scope of this transformation. Firstly, the coupling reactions of a wide range of substituted pyrimidin-2-yl tosylates (1) with styrene 2a were examined as electrophiles under the optimized reaction conditions. The coupling reactions generally went to completion

Fig. 1. X-ray crystal structure of 3bb Then, a range of substituted olefins 2 were also tested as nucleophile. As shown in Scheme 2, most of the substituted aromatic olefins bearing electron-donating groups such as 4-Me, 4-OMe, t-Bu or electron-withdrawing groups such as p-Cl coupled smoothly with excellent β-regioselectivity, but sterically hindered o-Cl styrene suffered from reduced yield to 3fa and 3fb. Notably, the Heck reaction was not restricted to the use of aromatic olefins as single nucleophile, aliphatic olefins also reacted well with pyrimidin-2-yl tosylates under the same conditions. Electron-rich butyl vinyl ether, 1-hexene and 1-octene underwent the transformation smoothly to products (3ka-3mb) with high β-regioselectivity. Electron-deficient aliphatic olefins including vinyl cyanide, methyl acrylate, ethyl acrylate and nbutyl acrylate provided β-substitution products in low yields (3ga-3jb), acrylamide failed to react with pyrimidin-2-yl tosylate at all.

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Tetrahedron

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R1

1

O

O

R2O

N

Me

N

3

+

R

OTs

1

2

Pd(PPh3)2Cl2 ( 5 mol %) K3PO4 (2.0 equiv)

R2O

NMP, 120 o C, 16 h

N R3

N

Me

3

OMe

Me

NO2

Me

EtO

N

EtO

N

Me

3aa,76%

O

O

O N

Me

N 3ab, 80%

O

EtO

N

N

Me

N

N

Me

O

N

Me

3ad, 88%

3ac, 76%

Cl

EtO

MeO

N

N

Me

3ag, 81%

3ae, 83%

OMe

N

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O EtO

NO2

O N

iPrO Me

O

EtO

N

N

Me

3aj, 87%

O

EtO

N

N

Me Me

3ba, 82%

N

N

Me Me

3bb, 84%

O

Me

3bf, 72%

Me Me

3bj, 90%

3ca, 79%

O N N

N

Me tBu

3dc, 81%

EtO

N

N

Me tBu

3di, 83%

N 3ea, 81%

EtO

Me

N

Me

N Cl

3ee, 85%

Me

N 3fa, 71%

O N N

EtO

OnBu

O

3ia, 66%

Me

O

3ih, 75%

Me

N

NO2 O N

EtO

N

N

Me Cl

3ec, 78%

N Cl

3ed, 82%

O

EtO OMe

N

EtO

N

Me

OMe

N

N

Me

OEt

N O

O

O 3ga, 60%

3gb, 62%

3ha, 57%

OMe

O

O

EtO

N

N

tBu

NO2

O

N N

Cl

Me

AC C

Me

MeO OnBu Me

N 3da, 89%

O

EtO

N

EP

O

Cl

3fb, 78%

Me

EtO

N

OMe

3cc, 85%

Me

O

EtO

Cl

N

Me

Me

O

O

Cl N

O EtO

N

EtO

N

3eb, 77%

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O

Me

OMe

N

Cl

N

3be, 87%

O

EtO

Me

Me

EtO

OMe

3cb, 83%

O

O

MeO

OMe

Me

N

Me

O

EtO

N

EtO

N

Me

N

Cl

OMe

Me

N

Me

O

EtO

N

Me

3bd, 89%

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Me

N

EtO

N

OMe

O

O N

iPrO

N

Me

Me

N

Cl

EtO

N

Me

Me

O EtO

EtO

N 3bc, 80%

Br

O

O

EtO

SC

O

CN

3jb, 51%

Me

N N 3ka, 74%

O

EtO OnBu

Me

N N 3kc, 78%

EtO OnBu

Me

N N

OnBu

3kd, 81%

Me

O

O EtO Me

N N 3la, 85%

EtO

nBu

Me

N

N

Hex

3mb, 87%

Scheme 2. The Mizoroki-Heck reaction of pyrimidin-2-yl tosylates with aromatic and aliphatic olefins groups or electron-withdrawing ones as well as various olefins 3. Conclusion including styrene derivatives, electron-deficient aliphatic olefins and electron-rich aliphatic olefins. Additionally, the use of NMP In summary, we have successfully developed an efficient and K3PO4 is also essential to promote this transformation. methodology for the synthesis of novel C2-alkenyl pyrimidine Maybe because of the special electronic effect and steric derivatives via Pd-catalyzed Mizoroki-Heck reaction. Studies hindrance of pyrimidin-2-yl tosylates, the Heck coupling with show that pyrimidin-2-yl tosylates as electrophile is more both of electron-rich and electron-deficient olefins proceeds effective than mesylates, phosphates, pivalates and benzoates in smoothly with excellent β-regioselectivity. Furthermore, the Heck coupling. The catalyst Pd(PPh ) Cl proved to be tolerant of 3 2

2

various pyrimidin-2-yl tosylates bearing either electron-donating

5

2.41 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, pyrimidin-2-yl tosylates as substitutes for halides make this MANUSCRIPT ACCEPTED procedure easy workup and less pollution to environment. CDCl3): δ 168.69, 165.12, 164.19, 163.75, 140.44, 139.41, 136.22, 135.47, 129.48, 129.42, 129.01, 128.52, 128.01, 127.43, 4. Experimental section 123.04, 61.96, 22.97, 21.65, 13.97; HRMS (ESI+) m/z: Calcd for C23H23N2O2 [M+H]+ 359.1754, Found 359.1752. 4.1. General information

4.2. General Procedure for the synthesis of 3

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4.2.3 Ethyl (E)-4-(4-methoxyphenyl)-6-methyl-2styrylpyrimidine-5-carboxylate (3ac). Yellow oil (76% yield); IR (KBr) ν(cm-1): 3041, 2986, 2932, 1713, 1631, 1604, 1526, 1241, 1083; 1H NMR (600 MHz, CDCl3): δ 8.09 (d, J = 16.2 Hz, 1H), 7.70 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.40–7.33 (m, 3H), 7.28 (d, J = 16.2Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.62 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13 C NMR (150 MHz, CDCl3): δ 168.61, 164.79, 163.86, 162.80, 161.25, 139.05, 136.01, 130.28, 129.97, 129.14, 128.75, 127.74, 127.26, 122.49, 113.99, 61.71, 55.38, 22.67, 13.81; HRMS (ESI+) m/z: Calcd for C23H23N2O3 [M+H]+ 375.1703, Found 375.1705.

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4.2.4 Ethyl (E)-4-methyl-6-(3-nitrophenyl)-2-styrylpyrimidine-5carboxylate (3ad). Yellow oil (88% yield); IR (KBr) ν(cm-1): 3071, 2989, 2878, 1720, 1625, 1523, 1261, 1076; 1H NMR (600 MHz, CDCl3): δ 8.59 (s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.12 (d, J = 15.6 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.68–7.64(m, 3H), 7.41–7.35 (m, 3H), 7.28 (d, J = 15.6 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 167.53, 165.86, 164.36, 161.02, 148.29, 140.08, 139.69, 135.68, 134.34, 129.57, 129.49, 128.83, 127.87, 126.58, 124.54, 123.54, 122.86, 62.13, 22.94, 13.77; HRMS (ESI+) m/z: Calcd for C22H20N3O4 [M+H]+ 390.1448, Found 390.1449.

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Infrared (IR) spectra were recorded using KBr pellets on a Nicolet Avatar 36 Fourier transform (FT)–IR spectrophotometer. 1 H NMR and 13C NMR data analyses were performed with a Varian Mercury plus-600 instrument unless otherwise specified. CDCl3 as solvent and tetramethylsilane (TMS) as the internal standard were employed. Chemical shifts were reported in units (ppm) by assigning TMS resonance in the 1H NMR spectrum as 0.00 ppm. The data of 1H NMR was reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet and br=broad), coupling constant (J values) in Hz and integration. Chemical shift for 13C NMR spectra were recorded in ppm from TMS using the central peak of CDCl3 (77.0 ppm) as the internal standard. Flash chromatography was performed using 200-300 mesh silica gel with the indicated solvent system according to standard techniques. Analytical thinlayer chromatography (TLC) was performed on pre-coated, glass-backed silica gel plates. Melting points were measured with an XT-4 apparatus. High-resolution mass spectra (HRMS) (ESI) were obtained with a Bruker Daltonics APEX II 47e and Orbitrap Elite mass spectrometer. Column chromatography was generally performed on silica gel (200-300 mesh) and TLC analyses were conducted on silica gel GF254 plates. All reagents were directly used from purchased without any further purification unless otherwise specified. Pyrimidin-2-yl tosylate derivatives were synthesised in accordance with our previously reported methods.24

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Pyrimidin-2-yl tosylates 1 (0.5 mmol), Pd(PPh3)2Cl2 (5 mol%, 0.025 mmol, 0.0175 g), K3PO4 (2 equiv,1.0 mmol, 0.211g) was added respectively to the sealed Schlenk tube, Then aromatic or aliphatic olefins 2 (1.5 equiv, 0.75 mmol), NMP (2 mL) was injected into the sealed tube by syringe in the presence of nitrogen. The mixture was stirred at 120 °C for 16 h. And the progress of the reaction was monitored by thin-layer chromatography (silica gel). After completion of the reaction, mixture was cooled to ambient temperature, quenched by addition of saturated NH4Cl (2 mL), and extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried with anhydrous MgSO4 and concentrated in vacuo, the resulting residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether(1:20) as eluent to afford the products (3aa-3mb). 4.2.1 Ethyl (E)-4-methyl-6-phenyl-2-styrylpyrimidine-5carboxylate (3aa). White solid (76% yield), mp 121–123 °C; IR (KBr) ν(cm-1): 3058, 2962, 1716, 1635, 1530, 1263, 1071; 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 16.0 Hz, 1H), 7.70–7.68 (m, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.48–7.46 (m, 3H), 7.41–7.34 (m, 3H), 7.32–7.28 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.65 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.16, 165.05, 163.96, 163.64, 139.28, 138.11, 135.87, 129.85, 129.18, 128.72, 128.47, 128.23, 127.73, 127.04, 122.90, 61.67, 22.70, 13.58; HRMS (ESI+) m/z: Calcd for C22H21N2O2 [M+H]+ 345.1598, Found 345.1593. 4.2.2 Ethyl (E)-4-methyl-2-styryl-6-(p-tolyl)pyrimidine-5carboxylate (3ab). Colorless oil (80% yield); IR (KBr) ν(cm-1): 3047, 2962, 2920, 1718, 1631, 1604, 1528, 1246, 1083; 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 16.0 Hz, 1H), 7.65–7.58 (m, 4H), 7.40–7.24 (m, 6H), 4.21 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H),

4.2.5 Ethyl (E)-4-(2-chlorophenyl)-6-methyl-2-styrylpyrimidine5-carboxylate (3ae). White solid (83% yield), mp 156–157 °C; IR (KBr) ν(cm-1): 3037, 2973, 2878, 1716, 1627, 1524, 1245, 1081; 1H NMR (600 MHz, CDCl3): δ 8.10 (d, J = 16.2 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.40–7.34 (m, 6H), 7.29 (d, J = 15.6 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.74 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 166.45, 166.34, 164.20, 163.72, 140.01, 137.85, 135.84, 132.17, 130.11, 130.00, 129.52, 129.34, 128.78, 127.84, 126.84, 126.69, 123.33, 61.44, 23.57, 13.43; HRMS (ESI+) m/z: Calcd for C22H20ClN2O2 [M+H]+ 379.1208, Found 379.1211.

4.2.6 Methyl (E)-4-methyl-6-phenyl-2-styrylpyrimidine-5carboxylate (3ag). Yellow oil (81% yield); IR (KBr) ν(cm-1): 3042, 2946, 1723, 1598, 1528, 1251, 1080; 1H NMR (600 MHz, CDCl3): δ 8.12 (d, J = 16.2 Hz, 1H), 7.71–7.70 (m, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.49–7.48 (m, 3H), 7.40 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 15.6 Hz, 1H), 3.71 (s, 3H), 2.65 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 168.82, 165.17, 164.14, 163.53, 139.42, 138.05, 135.93, 130.03, 129.25, 128.78, 128.60, 128.21, 127.79, 127.09, 122.62, 52.50, 22.79; HRMS (ESI+) m/z: Calcd for C21H19N2O2 [M+H]+ 331.1441, Found 331.1447. 4.2.7 Isopropyl (E)-4-methyl-6-phenyl-2-styrylpyrimidine-5carboxylate (3aj). White solid (87% yield), mp 129–131 °C; IR (KBr) ν(cm-1): 3044, 2972, 2920, 1718, 1640, 1540, 1272, 1110; 1 H NMR (600 MHz, CDCl3): δ 8.10 (d, J = 15.6 Hz, 1H), 7.70– 7.68 (m, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.48–7.46 (m, 3H), 7.39 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 16.2 Hz, 1H), 5.11–5.07 (m, 1H), 2.64 (s, 3H), 1.09 (d, J = 6.0 Hz, 6H); 13 C NMR (150 MHz, CDCl3): δ 167.66, 164.80, 163.93, 163.55, 139.21, 138.16, 135.97, 129.82, 129.18, 128.76, 128.49, 128.37, 127.77, 127.14, 123.45, 69.61, 22.64, 21.30; HRMS (ESI+) m/z: Calcd for C23H23N2O2 [M+H]+ 359.1754, Found 359.1751. 4.2.8 Ethyl (E)-4-methyl-2-(4-methylstyryl)-6-phenylpyrimidine5-carboxylate (3ba). White solid (82% yield), mp 112–114 °C; IR (KBr) ν(cm-1): 3053, 2975, 2836, 1714, 1632, 1530, 1268, 1085; 1H NMR (600 MHz, CDCl3): δ 8.07 (d, J = 16.2 Hz, 1H),

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129.95, 129.54, 127.78, 125.88, 124.54, 122.54, 61.85, 22.78, 7.68–7.67 (m, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.47–7.46 (m, 3H), MANUSCRIPT ACCEPTED 21.41, 13.73; HRMS (ESI+) m/z: Calcd for C23H22BrN2O2 7.25–7.19 (m, 3H), 4.17 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.37 (s, 13 [M+H]+ 437.0859, Found 437.0856. 3H), 1.05 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3): δ 168.21, 165.01, 164.16, 163.68, 139.45, 139.36, 138.20, 133.17, 4.2.14 Isopropyl (E)-4-methyl-2-(4-methylstyryl)-6129.82, 129.49, 128.46, 128.25, 127.74, 126.04, 122.75, 61.66, phenylpyrimidine-5-carboxylate (3bj). White solid (90% yield), + 22.69, 21.37, 13.59; HRMS (ESI ) m/z: Calcd for C23H23N2O2 mp 82–84 °C; IR (KBr) ν(cm-1): 3052, 2972, 2920, 1714, 1630, [M+H]+ 359.1754, Found 359.1757. 1604, 1530, 1270, 1084; 1H NMR (600 MHz, CDCl3): δ 8.07 (d, 4.2.9 Ethyl (E)-4-methyl-2-(4-methylstyryl)-6-(pJ = 16.2 Hz, 1H), 7.69–7.68 (m, 2H), 7.54 (d, J = 7.8 Hz, 2H), tolyl)pyrimidine-5-carboxylate (3bb). White solid (84% yield), 7.47–7.46 (m, 3H), 7.24 (d, J = 16.2 Hz, 1H), 7.20 (d, J = 7.8 Hz, mp 110–112 °C; IR (KBr) ν(cm-1): 3051, 2976, 2827, 1716, 1630, 2H), 5.10–5.06 (m, 1H), 2.64 (s, 3H), 2.38 (s, 3H), 1.09 (d, J = 1529, 1271, 1084; 1H NMR (600 MHz, CDCl3): δ 8.07 (d, J = 6.0 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 167.71, 164.76, 16.2 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 164.12, 163.54, 139.42, 139.23, 138.22, 133.23, 129.78, 129.51, 7.27–7.25 (m, 3H), 7.22–7.19 (m, 2H), 4.21 (q, J = 7.2 Hz, 2H), 128.48, 128.36, 127.74, 126.13, 123.26, 69.57, 22.65, 21.40, 2.62 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H); 21.30; HRMS (ESI+) m/z: Calcd for C24H25N2O2 [M+H]+ 13 C NMR (150 MHz, CDCl3): δ 168.48, 164.82, 164.13, 163.49, 373.1911, Found 373.1915. 140.12, 139.39, 139.17, 135.31, 133.25, 129.50, 129.20, 128.26, 4.2.15 Ethyl (E)-2-(4-methoxystyryl)-4-methyl-6127.73, 126.20, 122.62, 61.67, 22.71, 21.39, 21.38, 13.70; phenylpyrimidine-5-carboxylate (3ca). Colorless oil (79% yield); + + HRMS (ESI ) m/z: Calcd for C24H25N2O2 [M+H] 373.1911, IR (KBr) ν(cm-1): 3040, 2962, 2830, 1713, 1629, 1599, 1512, Found 373.1914. 1245, 1167, 1077; 1H NMR (600 MHz, CDCl3): δ 8.07 (d, J = 4.2.10 Ethyl (E)-4-(4-methoxyphenyl)-6-methyl-2-(415.6 Hz, 1H), 7.69–7.67 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.46– methylstyryl)pyrimidine-5-carboxylate (3bc). White solid (80% 7.45 (m, 3H), 7.16 (d, J = 15.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), yield), mp 73–75 °C; IR (KBr) ν(cm-1): 3038, 2985, 2938, 1716, 4.17 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.64 (s, 3H), 1.04 (t, J = 1602, 1525, 1240, 1083; 1H NMR (600 MHz, CDCl3): δ 8.07 (d, 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 168.28, 165.02, J = 15.6 Hz, 1H), 7.69 (d, J = 7.2Hz, 2H), 7.54 (d, J = 7.8 Hz, 164.34, 163.68, 160.61, 139.04, 138.30, 129.82, 129.28, 128.72, 2H), 7.24–7.19 (m, 3H), 6.98 (d, J = 8.4 Hz, 2H), 4.23 (q, J = 7.2 128.48, 128.28, 124.83, 122.57, 114.25, 61.65, 55.30, 22.75, Hz, 2H), 3.85 (s, 3H), 2.62 (s, 3H), 2.37 (s, 3H), 1.14 (t, J = 7.2 13.62; HRMS (ESI+) m/z: Calcd for C23H23N2O3 [M+H]+ 13 Hz, 3H); C NMR (150 MHz, CDCl3): δ 168.66, 164.76, 164.05, 375.1703, Found 375.1705. 162.80, 161.21, 139.37, 139.08, 133.26, 130.49, 129.97, 129.50, 4.2.16 Ethyl (E)-2-(4-methoxystyryl)-4-methyl-6-(p127.72, 126.24, 122.31, 113.97, 61.69, 55.37, 22.68, 21.39, 13.81; tolyl)pyrimidine-5-carboxylate (3cb). Yellow oil (83% yield); IR + + HRMS (ESI ) m/z: Calcd for C24H25N2O3 [M+H] 389.1860, (KBr) ν(cm-1): 3028, 2968, 2830, 1719, 1629, 1599, 1524, 1236, Found 389.1861. 1083; 1H NMR (600 MHz, CDCl3): δ 8.06 (d, J = 16.2Hz, 1H), 4.2.11 Ethyl (E)-4-methyl-2-(4-methylstyryl)-6-(37.61–7.57 (m, 4H), 7.26 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 16.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.82 (s, nitrophenyl)pyrimidine-5-carboxylate (3bd). White solid (89% 3H), 2.62 (s, 3H), 2.40 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR yield), mp 130–132 °C; IR (KBr) ν(cm-1): 3037, 2989, 1721, 1 1628, 1527, 1246, 1075; H NMR (600 MHz, CDCl3): δ 8.59 (s, (150 MHz, CDCl3): δ 168.50, 164.78, 164.27, 163.48, 160.57, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 16.2 Hz, 1H), 8.03 (d, 140.06, 138.85, 135.38, 129.24, 129.18, 128.79, 128.27, 124.94, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 122.42, 114.24, 61.63, 55.29, 22.71, 21.37, 13.71; HRMS (ESI+) 7.26–7.20 (m, 3H), 4.26 (q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 2.38 (s, m/z: Calcd for C24H25N2O3 [M+H]+ 389.1860, Found 389.1857. 13 3H), 1.16 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3): δ 4.2.17 Ethyl (E)-4-(4-methoxyphenyl)-2-(4-methoxystyryl)-6167.58, 165.82, 164.56, 161.03, 148.29, 140.13, 139.82, 139.77, methylpyrimidine-5-carboxylate (3cc). White solid (85% yield), 134.33, 132.95, 129.58, 129.55, 127.86, 125.56, 124.50, 123.54, mp 72–74 °C; IR (KBr) ν(cm-1): 3026, 2969, 2831, 1716, 1628, + 122.66, 62.09, 22.94, 21.43, 13.76; HRMS (ESI ) m/z: Calcd for 1596, 1526, 1239, 1081; 1H NMR (600 MHz, CDCl3): δ 8.05 (d, C23H22N3O4 [M+H]+ 404.1605, Found 404.1607. J = 15.6 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.4 Hz, 4.2.12 Ethyl (E)-4-(2-chlorophenyl)-6-methyl-2-(42H), 7.14 (d, J = 15.6 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.92 (d, methylstyryl)pyrimidine-5-carboxylate (3be). White solid (87% J = 8.4 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.84 (s, yield), mp 134–136 °C; IR (KBr) ν(cm-1): 3038, 2970, 2833, 3H), 2.61 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, 1715, 1631, 1601, 1520, 1245, 1078; 1H NMR (600 MHz, CDCl3): δ 168.70, 164.73, 164.19, 162.81, 161.18, 160.55, CDCl3): δ 8.07 (d, J = 16.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 138.75, 130.56, 129.94, 129.24, 128.80, 124.97, 122.13, 114.23, 7.46 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2Hz, 3H), 7.24 (d, J = 16.2 113.96, 61.67, 55.38, 55.32, 22.69, 13.81; HRMS (ESI+) m/z: Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 4.08 (q, J = 7.2 Hz, 2H), 2.73 Calcd for C24H25N2O4 [M+H]+ 405.1809, Found 405.1813. 13 (s, 3H), 2.37 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H); C NMR (150 4.2.18 Ethyl (E)-2-(4-(tert-butyl)styryl)-4-methyl-6MHz, CDCl3): δ 166.49, 166.30, 164.39, 163.71, 140.05, 139.63, phenylpyrimidine-5-carboxylate (3da). Yellow oil (89% yield); 137.92, 133.10, 132.16, 130.07, 130.00, 129.53, 129.50, 127.82, IR (KBr) ν(cm-1): 2951, 2868, 1721, 1627, 1595, 1527, 1261, 126.68, 125.83, 123.12, 61.40, 23.58, 21.41,13.42; HRMS (ESI+) 1080; 1H NMR (600 MHz, CDCl3): δ 8.10 (d, J = 16.2 Hz, 1H), m/z: Calcd for C23H22ClN2O2 [M+H]+ 393.1364, Found 393.1365. 7.70–7.68 (m, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.48–7.47 (m, 3H), 4.2.13 Ethyl (E)-4-(4-bromophenyl)-6-methyl-2-(47.42 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 2.65 (s, 3H), 1.34 (s, 9H), 1.05 (t, J = 7.2 Hz, 3H); methylstyryl)pyrimidine-5-carboxylate (3bf). White solid (72% 13 yield), mp 120–121 °C; IR (KBr) ν(cm-1): 2914, 1716, 1629, C NMR (150 MHz, CDCl3): δ 168.23, 165.04, 164.19, 163.68, 1 1527, 1242, 1077; H NMR (600 MHz, CDCl3): δ 8.07 (d, J = 152.61, 139.22, 138.21, 133.13, 129.84, 128.49, 128.26, 127.59, 16.2 Hz, 1H), 7.62–7.53 (m, 6H), 7.25 (d, J = 13.2 Hz, 1H), 7.21 126.22, 125.74, 122.76, 61.67, 34.78, 31.19, 22.74, 13.61; (d, J = 7.8 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.38 (s, HRMS (ESI+) m/z: Calcd for C26H29N2O2 [M+H]+ 401.2224, 13 Found 401.2221. 3H), 1.13 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3): δ 168.05, 165.31, 164.31, 162.42, 139.61, 137.10, 133.09, 131.71,

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Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.37 (d, J =7.8 Hz, 2H), 7.24 4.2.19 Ethyl (E)-2-(4-(tert-butyl)styryl)-4-(4-methoxyphenyl)-6ACCEPTED MANUSCRIPT (d, J = 16.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 1.16 methylpyrimidine-5-carboxylate (3dc). Yellow oil (81% yield); (t, J = 7.2 Hz, 3H); 13C NMR (150MHz, CDCl3): δ 167.46, IR (KBr) ν(cm-1): 2968, 2864, 1719, 1626, 1596, 1527, 1260, 1 1081; H NMR (600 MHz, CDCl3): δ 8.09 (d, J = 16.2 Hz, 1H), 165.93, 164.09, 161.05, 148.31, 139.59, 138.60, 135.28, 134.29, 7.70 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 134.19, 129.58, 129.09, 128.98, 127.15, 124.59, 123.55, 123.02, 62.17, 22.92, 13.76; HRMS (ESI+) m/z: Calcd for C22H19ClN3O4 Hz, 2H), 7.25 (d, J = 15.6 Hz, 1H), 6.99 (d, J = 9.0 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 2.62 (s, 3H), 1.34 (s, 9H), 1.14 [M+H]+ 424.1059, Found 424.1058. (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 168.65, 4.2.25 Ethyl (E)-4-(2-chlorophenyl)-2-(4-chlorostyryl)-6164.75, 164.07, 162.81, 161.22, 152.54, 138.96, 133.25, 130.52, methylpyrimidine-5-carboxylate (3ee). White solid (85% yield), 129.98, 127.58, 126.42, 125.74, 122.34, 113.98, 61.68, 55.37, mp 151–153 °C; IR (KBr) ν(cm-1): 3046, 2973, 2931, 1716, 1631, 34.78, 31.22, 22.68, 13.81; HRMS (ESI+) m/z: Calcd for 1528, 1247, 1083; 1H NMR (600 MHz, CDCl3): δ 8.03 (d, J = C27H31N2O3 [M+H]+ 431.2329, Found 431.2327. 15.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 7.8 Hz, 1H), 4.2.20 Ethyl (E)-2-(4-(tert-butyl)styryl)-4-(4-chlorophenyl)-67.39–7.34 (m, 5H), 7.24 (d, J = 15.6 Hz, 1H), 4.08 (q, J = 7.2 Hz, methylpyrimidine-5-carboxylate (3di). Yellow oil (83% yield); IR 2H), 2.73 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, -1 (KBr) ν(cm ): 2944, 2866, 1722, 1629, 1593, 1527, 1260, 1080; CDCl3): δ 166.39, 166.38, 163.91, 163.74, 138.51, 137.75, 1 135.12, 134.35, 132.16, 130.16, 129.96, 129.54, 129.04, 128.94, H NMR (600 MHz, CDCl3): δ 8.09 (d, J = 16.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 127.41, 126.70, 123.50, 61.48, 23.54, 13.43; HRMS (ESI+) m/z: Calcd for C22H19Cl2N2O2 [M+H]+ 413.0818, Found 413.0814. 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 16.2 Hz, 2H), 3.73 (s, 13 3H), 2.63 (s, 3H), 1.34 (s, 9H); C NMR (150 MHz, CDCl3): δ 4.2.26 Ethyl (E)-2-(2-chlorostyryl)-4-methyl-6-phenylpyrimidine168.65, 165.37, 164.40, 162.27, 152.79, 139.56, 136.54, 136.33, 5-carboxylate (3fa). Yellow oil (71% yield); IR (KBr) ν(cm-1): 133.06, 129.63, 128.86, 127.64, 126.04, 125.79, 122.24, 52.60, 3043, 2978, 2926, 1720, 1629,1604, 1528, 1255, 1082; 1H NMR 34.82, 31.21, 22.83; HRMS (ESI+) m/z: Calcd for C25H26ClN2O2 (600 MHz, CDCl3): δ 8.51 (d, J = 15.6 Hz, 1H), 7.79–7.77 (m, [M+H]+ 421.1677, Found 421.1673. 1H), 7.71–7.69 (m, 2H), 7.48–7.41 (m, 4H), 7.29–7.26(m, 3H), 4.2.21 Ethyl (E)-2-(4-chlorostyryl)-4-methyl-6-phenylpyrimidine4.19 (q, J = 7.2 Hz, 2H), 2.66 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); 13 5-carboxylate (3ea). White solid (81% yield), mp 132–134°C; IR C NMR (150 MHz, CDCl3): δ 168.17, 165.19, 163.66, 163.64, (KBr) ν(cm-1): 3040, 2976, 2923, 1716, 1631, 1603, 1528, 1252, 138.05, 135.14, 134.58, 134.20, 130.01, 129.98, 129.92, 129.70, 128.50, 128.33, 127.37, 126.99, 123.25, 61.74, 22.74, 13.63; 1083; 1H NMR (600 MHz, CDCl3): δ 8.03 (d, J = 16.2 Hz, 1H), HRMS (ESI+) m/z: Calcd for C22H20ClN2O2 [M+H]+ 379.1208, 7.67 (s, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.47 (s, 3H), 7.35 (d, J = 8.4 Hz, 2H), 7.25–7.23 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.63 (s, Found 379.1209. 3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 4.2.27 Ethyl (E)-2-(2-chlorostyryl)-4-methyl-6-(p168.12, 165.14, 163.72, 138.06, 137.86, 134.97, 134.44, 129.94, tolyl)pyrimidine-5-carboxylate (3fb). Yellow oil (78% yield); IR 129.02, 128.88, 128.52, 128.26, 127.66, 123.10, 61.75, 22.71, (KBr) ν(cm-1): 3041, 2980, 2934, 1721, 1625, 1526, 1258, 1083; 13.61; HRMS (ESI+) m/z: Calcd for C22H20ClN2O2 [M+H]+ 1 H NMR (600 MHz, CDCl3): δ 8.49 (d, J = 16.2 Hz, 1H), 7.78– 379.1208, Found 379.1206. 7.77 (m, 1H), 7.61 (d, J =7.8 Hz, 2H), 7.42–7.41 (m, 1H), 7.28– 4.2.22 Ethyl (E)-2-(4-chlorostyryl)-4-methyl-6-(p7.25 (m, 5H), 4.22 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.41 (s, 3H), tolyl)pyrimidine-5-carboxylate (3eb). White solid (82% yield), 1.12 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 168.40, -1 mp 113–115 °C; IR (KBr) ν(cm ): 3040, 2980, 2920, 1716, 1635, 164.96, 163.58, 163.44, 140.23, 135.12, 134.97, 134.56, 134.24, 1608, 1527, 1257, 1083; 1H NMR (600 MHz, CDCl3): δ 8.03 (d, 130.00, 129.92, 129.79, 129.23, 128.31, 127.35, 126.97, 123.07, J = 15.6 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 8.4 Hz, 61.73, 22.71, 21.38, 13.71; HRMS (ESI+) m/z: Calcd for 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.23 (d, J C23H22ClN2O2 [M+H]+ 393.1364, Found 393.1369. = 16.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.62 (s, 3H), 2.41 (s, 4.2.28 Ethyl (E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)-4-methyl-63H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ phenylpyrimidine-5-carboxylate (3ga). Yellow oil (60% yield); 168.35, 164.92, 163.66, 163.51, 140.24, 137.67, 135.14, 134.90, IR (KBr) ν(cm-1): 3040, 2917, 2843, 1720, 1632, 1536, 1258, 134.50, 129.24, 129.00, 128.86, 128.26, 127.79, 122.94, 61.74, 1077; 1H NMR (600 MHz, CDCl3): δ 7.73 (d, J = 16.2 Hz, 1H), 22.69, 21.38, 13.71; HRMS (ESI+) m/z: Calcd for C23H22ClN2O2 7.67 (d, J = 6.6 Hz, 2H), 7.49–7.45 (m, 3H), 7.29 (d, J = 15.6 Hz, [M+H]+ 393.1364, Found 393.1366. 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 2.63 (s, 3H), 1.08 (t, J 4.2.23 Ethyl (E)-2-(4-chlorostyryl)-4-(4-methoxyphenyl)-6= 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 167.80, 166.60, methylpyrimidine-5-carboxylate (3ec). White solid (78% yield), 165.45, 163.57, 161.84, 142.65, 137.45, 130.22, 128.56, 128.34, mp 120–122 °C; IR (KBr) ν(cm-1): 3040, 2986, 2938, 1713, 1602, 127.89, 124.52, 61.96, 51.97, 22.60, 13.62; HRMS (ESI+) m/z: 1 1524, 1242, 1083; H NMR (600 MHz, CDCl3): δ 8.02 (d, J = Calcd for C18H19N2O4 [M+H]+ 327.1339, Found 327.1336. 15.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 4.2.29 Ethyl (E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)-4-methyl-67.35 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 16.2Hz, 1H), 6.98 (d, J = (p-tolyl)pyrimidine-5-carboxylate (3gb). Yellow oil (62% yield); 8.4 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.61 (s, 3H), IR (KBr) ν(cm-1): 3041, 2914, 2848, 1719, 1637, 1533, 1257, 13 1.15 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3): δ 168.54, 1077; 1H NMR (600 MHz, CDCl3): δ 7.72 (d, J = 15.6 Hz, 1H), 164.85, 163.55, 162.81, 161.25, 137.57, 134.87, 134.46, 130.26, 7.59 (d, J = 7.2 Hz, 2H), 7.26 (d, J = 7.2 Hz, 3H), 4.23 (q, J = 7.2 129.94, 128.99, 128.85, 127.77, 122.59, 113.98, 61.77, 55.38, Hz, 2H), 3.83 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H), 1.13 (t, J = 7.2 + 22.66, 13.80; HRMS (ESI ) m/z: Calcd for C23H22ClN2O3 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 168.03, 166.65, 165.22, [M+H]+ 409.1313, Found 409.1317. 163.37, 161.76, 142.77, 140.62, 134.52, 129.29, 128.33, 127.73, 4.2.24 Ethyl (E)-2-(4-chlorostyryl)-4-methyl-6-(3124.31, 61.94, 51.96, 22.57, 21.39, 13.70; HRMS (ESI+) m/z: nitrophenyl)pyrimidine-5-carboxylate (3ed). White solid (82% Calcd for C19H21N2O4 [M+H]+ 341.1496, Found 341.1494. -1 yield), mp 87–89°C; IR (KBr) ν(cm ): 3067, 2964, 2920, 1721, 4.2.30 Ethyl (E)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)-4-methyl-61628, 1523, 1251, 1082; 1H NMR (600 MHz, CDCl3): δ 8.59 (s, phenylpyrimidine-5-carboxylate (3ha). Yellow oil (57% yield); 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.07–8.02(m, 2H), 7.66 (t, J = 7.8 IR (KBr) ν(cm-1): 3043, 2914, 2848, 1716, 1530, 1251, 1077; 1H

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4.2.36 Ethyl (E)-2-(2-butoxyvinyl)-4-methyl-6-(3NMR (600 MHz, CDCl3): δ 7.72 (d, J = 15.6ACCEPTED Hz, 1H), 7.67 (d, MANUSCRIPT nitrophenyl)pyrimidine-5-carboxylate (3kd). Yellow oil (81% J = 6.6 Hz, 2H), 7.49–7.45 (m, 3H), 7.28 (d, J = 15.6 Hz, 1H), yield); IR (KBr) ν(cm-1): 3076, 2938, 2878, 1719, 1626, 1524, 4.29 (q, J = 7.2 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 13 1185, 1077; 1H NMR (600 MHz, CDCl3): δ 8.52 (s, 1H), 8.31 (d, 1.34 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl3) δ 167.82, 166.12, 165.43, 163.58, 161.93, 142.34, J = 8.4 Hz, 1H), 8.05 (d, J = 12.6 Hz, 1H), 7.95 (d, J = 7.8 Hz, 137.47, 130.20, 128.56, 128.44, 128.33, 124.48, 61.95, 60.85, 1H), 7.62 (t, J = 7.8 Hz, 1H), 5.97 (d, J = 12.6 Hz, 1H), 4.21 (q, J 22.60, 14.20, 13.62; HRMS (ESI+) m/z: Calcd for C19H21N2O4 = 7.2 Hz, 2H), 3.96 (t, J = 6.6 Hz, 2H), 2.58 (s, 3H), 1.74–1.72 [M+H]+ 341.1496, Found 341.1493. (m, 2H), 1.47–1.43 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 167.75, 165.59, 4.2.31 Ethyl (E)-2-(3-butoxy-3-oxoprop-1-en-1-yl)-4-methyl-6165.54, 160.95, 159.55, 148.23, 140.07, 134.20, 129.39, 124.29, phenylpyrimidine-5-carboxylate (3ia). Yellow oil (66% yield); 123.46, 121.35, 104.56, 70.64, 61.85, 31.03, 22.94, 19.03, 13.73, -1 IR (KBr) ν(cm ): 2969, 2836, 1719, 1638, 1607, 1531, 1257, 13.69; HRMS (ESI+) m/z: Calcd for C20H24N3O5 [M+H]+ 1 1080; H NMR (600 MHz, CDCl3): δ 7.71 (d, J = 16.2 Hz, 1H), 386.1710, Found 386.1702. 7.67 (d, J = 7.2 Hz, 2H), 7.48–7.45 (m, 3H), 7.28 (d, J = 15.6 Hz, 1H), 4.24–4.18 (m, 4H), 2.63 (s, 3H), 1.70–1.67 (m, 2H), 1.47– 4.2.37 Ethyl (E)-2-(hex-1-en-1-yl)-4-methyl-6-phenylpyrimidine1.42 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H); 5-carboxylate (3la). Yellow oil (85% yield); IR (KBr) ν(cm-1): 13 2920, 2866, 1719, 1647, 1533, 1245, 1077; 1H NMR (600 MHz, C NMR (150 MHz, CDCl3): δ 167.81, 166.22, 165.42, 163.59, 161.94, 142.26, 137.47, 130.20, 128.56, 128.47, 128.33, 124.49, CDCl3): δ 7.64 (d, J = 6.6 Hz, 2H), 7.44 (d, J = 6.6 Hz, 3H), 7.34–7.29 (m, 1H), 6.60 (d, J = 15.6 Hz, 1H), 4.16 (q, J = 7.2 Hz, 64.76, 61.95, 30.65, 22.60, 19.16, 13.69, 13.61; HRMS (ESI+) m/z: Calcd for C21H25N2O4 [M+H]+ 369.1809, Found 369.1807. 2H), 2.60 (s, 3H), 2.32 (q, J = 7.2 Hz, 2H), 1.55–1.50 (m, 2H), 1.42–1.36 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 4.2.32 Ethyl (E)-2-(3-butoxy-3-oxoprop-1-en-1-yl)-4-methyl-6-(p3H); 13C NMR (150 MHz, CDCl3): δ 168.31, 164.93, 163.98, tolyl)pyrimidine-5-carboxylate (3ih). Yellow oil (75% yield); IR 163.55, 143.79, 138.26, 129.76, 129.30, 128.42, 128.26, 122.78, (KBr) ν(cm-1): 2944, 2872, 1716, 1641, 1611, 1533, 1257, 1080; 61.62, 32.40, 30.62, 22.69, 22.30, 13.88, 13.60; HRMS (ESI+) 1 H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 15.6 Hz, 1H), 7.59 (d, m/z: Calcd for C20H25N2O2 [M+H]+ 325.1911, Found 325.1904. J = 7.8 Hz, 2H), 7.29–7.26 (m, 3H), 4.23 (t, J = 6.6 Hz, 2H), 3.75 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H), 1.71–1.67 (m, 2H), 1.47–1.41 4.2.38 Ethyl (E)-4-methyl-2-(3-oxooct-1-en-1-yl)-6-(ptolyl)pyrimidine-5-carboxylate (3mb). Yellow oil (87% yield); IR (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ (KBr) ν(cm-1): 2920, 2848, 1719, 1647, 1611, 1527, 1245, 1077; 168.63, 166.23, 165.31, 163.28, 161.97, 142.35, 140.73, 134.46, 1 129.41, 128.39, 128.23, 123.90, 64.75, 52.68, 30.66, 22.62, H NMR (600 MHz, CDCl3): δ 7.56 (d, J = 8.4 Hz, 2H), 7.32– 21.40, 19.16, 13.69; HRMS (ESI+) m/z: Calcd for C21H25N2O4 7.28 (m, 1H), 7.24 (d, J = 7.8 Hz, 2H), 6.59 (d, J = 15.0 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.32–2.29 (m, 369.1809 [M+H]+, Found 369.1815. 2H), 1.55–1.50 (m, 2H), 1.37–1.29 (m, 6H), 1.09 (t, J = 7.2 Hz, 4.2.33 Ethyl (E)-2-(2-cyanovinyl)-4-methyl-6-(p-tolyl)pyrimidine3H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ -1 5-carboxylate (3jb). Yellow oil (51% yield); IR (KBr) ν(cm ): 168.53, 164.70, 163.91, 163.35, 143.64, 140.02, 135.33, 129.33, 2914, 2848, 2231, 1719, 1530, 1254, 1080; 1H NMR (600 MHz, 129.14, 128.24, 122.62, 61.60, 32.73, 31.68, 28.96, 28.47, 22.65, CDCl3): δ 7.57 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 16.2 Hz, 1H), 22.57, 21.35, 14.06, 13.69; HRMS (ESI+) m/z: Calcd for 7.28–7.26 (m, 2H), 6.90 (d, J = 7.8 Hz, 1H), 4.24 (q, J = 7.2 Hz, C23H31N2O2 [M+H]+ 367.2375, Found 367.2381. 2H), 2.61 (s, 3H), 2.42 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 167.47, 165.51, 163.56, 160.12, 148.46, Acknowledgments 148.37, 140.91, 134.15, 129.38, 128.28, 124.35, 117.12, 106.64, + 62.09, 22.53, 21.40, 13.69; HRMS (ESI ) m/z: Calcd for We are thankful for the financial support from the National C18H18N3O2 [M+H]+ 308.1394, Found 308.1395. Natural Science Foundation of China (Nos. 21362032, 21362031 and 21562036), Gansu Provincial Department of Finance, 4.2.34 Ethyl (E)-2-(2-butoxyvinyl)-4-methyl-6-phenylpyrimidineNatural Science Foundation of Gansu Province (No. 5-carboxylate (3ka). Yellow oil (74% yield); IR (KBr) ν(cm-1): 1308RJZA299). 3041, 2967, 2871, 1720, 1628, 1526, 1186, 1077; 1H NMR (600 MHz, CDCl3): δ 8.04 (d, J = 12.6 Hz, 1H), 7.61 (d, J = 6.0 Hz, 2H), 7.43 (s, 3H), 5.98 (d, J = 12.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, References and notes 2H), 3.94 (t, J = 6.0 Hz, 2H), 2.55 (s, 3H), 1.73–1.71 (m, 2H), 1. (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 1.46–1.42 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 44, 581; (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 3H); 13C NMR (150 MHz, CDCl3): δ 168.45, 165.13, 164.81, 2320-2322. 163.57, 158.91, 132.22, 129.63, 128.36, 128.16, 118.15, 104.86, 2. (a) Bergmann, F.; Schapira, D. J. Org. Chem. 1947, 12, 57-66; (b) 70.42, 61.48, 31.04, 22.71, 19.04, 13.70, 13.58; HRMS (ESI+) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, + m/z: Calcd for C20H25N2O3 [M+H] 341.1860, Found 341.1863. 2748-2749; (c) Cui, X.; Li, Z.; Tao, C. Z.; Xu, Y.; Li, J.; Liu, L.; 4.2.35 Ethyl (E)-2-(2-butoxyvinyl)-4-(4-methoxyphenyl)-6methylpyrimidine-5-carboxylate (3kc). Yellow oil (78% yield); IR (KBr) ν(cm-1): 3041, 2976, 2874, 1721, 1626, 1528, 1185, 1077; 1H NMR (600 MHz, CDCl3): δ 8.01 (d, J = 12.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 5.95 (d, J = 12.6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.93 (t, J = 6.6 Hz, 2H), 3.83 (s, 3H), 2.52 (s, 3H), 1.73–1.68 (m, 2H), 1.45–1.41 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 168.83, 164.94, 164.49, 162.65, 161.04, 158.66, 130.74, 130.28, 129.81, 121.10, 114.23, 113.83, 104.90, 70.35, 61.48, 55.33, 31.03, 22.63, 19.03, 13.76, 13.68; HRMS (ESI+) m/z: Calcd for C21H27N2O4 [M+H]+ 371.1965, Found 371.1969.

3. 4.

Guo, Q. X. Org. Lett. 2006, 8, 2467-2470; (d) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874-922; (e) Kamal, A.; Srinivasulu, V.; Seshadri, B. N.; Markandeya, N.; Alarifi, A.; Shankaraiah, N. Green Chem. 2012, 14, 2513-2522. Hodgson, H. H. Chem. Rev. 1947, 40, 251-277. (a) Hayashi, T.; Katsuro, Y.; Kumada, M. Tetrahedron Lett. 1980, 21, 3915-3918; (b) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V. J. Org. Chem. 1992, 57, 4066-4068; (c) Percec, V.; Bae, J. Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895-6903; (d) Gauthier, D.; Beckendorf, S.; Gøsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. J. Org. Chem. 2009, 74, 35363539; (e) Gøgsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. Org. Lett. 2009, 11, 4886-4888; (f) Xing, T.; Zhang, Z.; Da, Y. X.; Quan, Z. J.; Wang, X. C. Asian J. Org. Chem. 2015, 4, 538-544.

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Science 2003, S.; Shirazi, F.; Deshpande, M. V.; Srinivasan, K. V. Tetrahedron 2008, 64, 10214-10223. 22. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-321. 23. The structure of 3bb was determined by X-ray crystallographic. CCDC No. 1409100. 24. Wang, X. C.; Yang, G. J.; Quan, Z. J.; Ji, P. Y.; Liang, J. L.; Ren, R. G. Synlett. 2010, 1657-1660.

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K-H.; Haebich, D.; Rübsamen-Waigmann, H. ACCEPTED MANUSCRIPT 299, 893-896; (b) Gholap, A. R.; Toti, K.

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AC C

5.