钯催化的插羰反应

经典化学合成反应标准操作

钯催化的插羰反应

编者：钱占山

药明康德新药开发有限公司化学合成部

药明康德内部保密资料

经典合成反应标准操作—钯催化的插羰反应 药明康德新药开发有限公司

Contents

1． 2． 3． 4． 5． 6． 7． 8． 9．

前言…………………………………………………………………2-3

插羰反应制备羧酸及其衍生物…………………………………4-15 插羰反应制备羧酸实验操作……………………………………15-16 插羰反应制备羧酸酯实验操作………………………………16-19 插羰反应制备酰胺实验操作…………………………………19-20 插羰反应制备醛…………………………………………………20 插羰反应制备醛实验操作………………………………………21-22 插羰反应制备酮………………………………………22-30 插羰反应制备酮实验操作………………………………………30-31

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1. 前言

在有机合成中，钯催化的反应是一类特别有用的反应，它提供了一种形成碳-碳键的独特的方法。这类反应的优点：1、不需要加入其他氧化剂催化；2、只需催化量的钯催化剂。钯催化的插羰反应是这类反应中应用最为广泛的反应之一，在这里我们将重点介绍它。

众所周知，在格氏反应中单质镁金属与带有sp3杂化碳原子的有机卤化物（烷基卤化物）反应要比带有sp2杂化碳原子的有机卤化物（芳基和烯基卤化物）反应更容易。而与此相反，钯的络合物与含有sp2杂化碳原子的有机卤化物反应更容易。换句话说，烯基和芳基卤化物非常容易与Pd(0)发生氧化加成反应，从而生成含有钯-碳б-键的络合物中间体1；然后，不饱和化合物（例如：烯烃、共轭二烯、炔烃和一氧化碳等）插入到钯-碳键之间；最后，经过还原消去或者β-氢消去反应生成相应的目标化合物。与此同时，Pd(0)催化剂得以再生并开始新的催化循环。由此可见，正是因为生成了这种含有钯-碳б-键的络合物中间体，才使得接下来的插入和金属转移过程变成可能。

实验证明，Pd的配合物比较容易与碘化物和溴化物发生氧化加成反应。碘化物可以在不加入任何膦配体的条件下，只用Pd(dba)3、Pd(OAc)2甚至是Pd/C作催化剂即可发生反应。而溴化物的反应一般是需要膦配体的。但是氯化物在一般的条件下是非常惰性的，只有用较强给电子性的具有双配位基（bidentate）的配体（如dppp），同时在非常剧烈的条件下才能发生反应。例如氯苯的钯催化反应往往要加入Cr(CO)3，目的是利用它的强吸电子性活化Cl-C键。应该指出的是，为了中和反应生成的HX酸，碱（R3N、NaOAc、KOAc、Na2CO3、K2CO3等）的使用是必需的。

除了卤化物以外，类卤化物R-X = ArCO-Cl, ArSO2-Cl, Ar-N2+X-, R-OP(O)(OR)2, R-OSO2CF3 (OTf), R-OSO2Rf (Rf = perfluoroaikyl), R-OSO2F, R-OSO2CH3和Ar-ArI+是很好的离去基团，它们也能与Pd(0)发生氧化加成反应从而形成芳基和烯基钯配合物中间体。但是，这些离去基团对于Pd(0)的反应活性是各不相同的，它们中的某些化合物往往只能和某些特定的底物在非常特殊条件下发生反应。

最有用的类卤化物是酚的三氟甲磺酸芳基酯和从羰基化合物派生出来的三氟甲磺酸烯醇酯。芳酰基卤化物和磺酰基卤化物通过先与Pd(0)发生氧化加成反应，紧接着脱去CO和SO2就形成了芳基钯配合物。另外，苯的重氮盐是形成芳基钯配合物的最活泼反应源。

烷基卤化物和Pd(0)的氧化加成反应是非常缓慢的。而且，通过烷基卤化物的氧化

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加成反应得到的烷基钯配合物经过β-氢消除之后，反应就停止在这一阶段，而不再进行插入或金属转移过程。对于炔基卤化物来说，虽然没有太多的文献报道，但是炔基碘化物的确可以和Pd(0)反应生成炔基钯配合物。

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2. 插羰反应制备羧酸及其衍生物

芳基和烯基卤化物在温和条件下的钯催化插羰反应是合成羰基化合物的非常有用的合成方法。反应机理是芳基和烯基卤化物先和Pd(0)发生氧化加成反应生成芳基或烯基钯配合物，然后CO插入到钯--碳键之间，最后在醇或水等试剂的亲和进攻下就形成了相应的酯或羧酸。芳香的或α,β—不饱和的羧酸或酯就是芳基或烯基卤化物在水或醇中通过插羰反应制得的。

Pd(0)+ArXAr-Pd-XCOArOCPdXH2OPd(0)+OArCXROHNR3ArOCOR+HNR3XOArCOH

X+CO+H2OCO2H

R+XCO+ROHCO2R R

在玉米烯酮2-4的全合成中，酯2-3是通过基团密集的芳基碘化物2-1的插羰反应制得的。然而醇分子2-2中的烷基碘部分是不参与反应的。

OMeI+MeOSPh2-12-2CO+OHOOIPdCl2, K2CO3, PhH120oC, 12 atm., 70%OMeOOMeOISPh2-3OOMeOOMeOOO2-4

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Ph-I+CO+Et2NHPdCl2(MePh2P)2100oC, 95%PhCOCONEt2+2-6386 : 14PhCONEt2

HaON.1I+NHAcCO+Et2NHPdCl2(MePh2P)2COCONEt2NHAcN2-64OONH2-65MeCOe2.M93%

Cl+CO+Et2NHCr(CO)32-66PdCl2(MePh2P)2PhMe, 100oC51.7F.6%COCONEt2+CONEt2

α-酮酯2-67能够通过碘苯和大位阻二级胺的二次羰基化反应形成，但是这个反应的选择性非常低。对于二次插羰反应来说，烯基溴化物比芳基卤化物的反应活性更低。α-酮酰胺能够通过芳基和烯基溴化物的二次羰基化反应得到，而α-酮酯是不能够通过他们在相应醇中的羰基化反应得到。

PhI+CO+sec-BuOHPdCl2(PCy3)2Et3N, 91% conv.PhCOCO2Bu+2-6764 : 36PhCO2Bu

3. 插羰反应制备羧酸实验操作

NHCOMeBr+CO+H2OPdCl2(Ph3P)2(0.1 wt%), Ph3PBu3N, 120oC, 3 atm., 85%2-11CO2HNHCOMe

A 200-mL glass pressure bottle equipped with two valves and a pressure gauge was charged

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with 8 mg of Pd(PPh3)(Cl)2, 40 mg of triphenylphosphme, and 2.0 g of 2-(acetylamino)-5-(1-methylethyl) phenylbromide. The bottle was then evacuated, refilled with argon three times, and charged further with 2.2 mL of deoxygenated tri-n-butylamine and 0.5 mL of deoxygenated water. The apparatus was then pressurized with 3 atm of carbon monoxide, sealed, heated 18 h with stirring at a bath temperature of 120-125 °C, and then allowed to cool. The final pressure was 1.1 atm at 23 °C. Hydrochloric acid (2.4 M) was added to the viscous orange-brown reaction mixture in four 2-mL portions with constant agitation. The crude yield of 2-11 which separated (95% pure by NMR) was 1.63 g (94%). Recrystallization from ethanol-water gave 1.35 g (78%) of a light yellow solid.

4. 插羰反应制备羧酸酯实验操作

OMeI+MeOSPh2-12-2CO+OHOOIPdCl2, K2CO3, PhH120oC, 12 atm., 70%OMeOOMeOISPh2-3OOMeOOMeOOO2-4

A mixture of the iodobenzene 2-1 (0.46 mmol), w-indo alcohol 2-2 (0.83 mmol), K2CO3 (1.38 mmol), and PdCl2 (0.04 mmol) in dry benzene (6 mL) was heated at 120℃ with stirring in an autoclave under carbon monoxide (12 atm) for 16 h. The reaction mixture was filtered and the easter 3 was isolated by column chromatography in 70% yield.

FONNOONNNFBrFFCO, Pd(OAc)2, dppfEt3N, EtOH, 90oCOONFFONNNONFFFOFFF

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（2R,4S）

-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-bromopyrimidin-2-yl)}-amino-2-ethyl-6-methoxy-3,4-dihyfro-2H-[1,5]naphthridine-1-carboxylic acid ethyl ester (18 g) is dissolved in N,N-dimethylformamide (60 mL), and thereto are added palladium acetate (611 mg), 1,1’-bis(diphenylphosphino)-ferrocene (3.02 g), ethane (31.7 mL) and triethylamine (37.9 mL). The mixture is purged by carbon monoxide at room temperature for 10 minutes, then is heated at 90 oC and stirred overnight under 40 psi of carbon monoxide. The reaction solution is cooled to room temperature, and thereto is added saturated brine and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography

(silica

gel;

hexane:ethyl

acetate

=

8:1)

to

give

(2R.4S)-4-{[3,5-bis(triflouromethyl)benzyl]-(5-ethoxycarbonylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (12.4 g).

OCO, Pd(PPh3)2Cl2NHINONH2Et3N, EtOH, 80oCONONHONH2O

To a stirred solution of 3-(aminocarbonyl)-4-{[3-(methyloxay)penyl]amino}-6-iodoquinoline (1

g)

in

ethanol

(50

mL)

was

added

triethylamine

(0.63

mL)

and

dichlorobis(triphenylphosphine)palladium (II) (0.08 g). The flask was evacuated and refilled with nitrogen three times and then evacuated and refilled with carbon monoxide two times. The mixture was heated at 80oC under an atmosphere of carbon monoxide for 16 h. the mixture was cooled to 20oC and the solvent removed in vacuo. Purification by column chromatography on silica gel, eluting with 9:1 ethyl acetate: cyclohexane, gave the title compound as a pale yellow solid (0.8 g).

NNNNNCO, Pd(dppf)Cl2NaOAc, Methanol, 90oCNONONBr

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经典合成反应标准操作—钯催化的插羰反应 药明康德新药开发有限公司

6-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-B]pyrazol-3-yl]-quinoline (22.7 g, 45 mmol) is added to a mixture of sodium acetate (19 g, 230 mmol) and the palladium catalyst [1,1’-bis (diphenylphosphimo) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (850 mg, 1.04 mmol) in 130 mL methanol. Place the mixture under 50 psi carbon monoxide atmosphere and stir while warming to 90oC over 1 hour and with constant charging with additional carbon monoxide. Allow the mixture to cool over 8 hours, recharge again with carbon monoxide and heat to 90oC. The pressure may rise to about 75 psi. The reaction is complete in about an hour when the pressure is stable and TLC (1:1 toluene/acetaone) shows no remaining bromide. Partition the mixture between methylene chloride (600 mL) and water (1 L). Extract the aqueous portion with an additional portion of methylene chloride (400 mL). Filter the organic solution through a 300 mL silica plug and wash with 500 mL methylene chloride, 1200 mL ethyl acetate and 1500 mL acetone. Discard the acetone portion. Combine appropriate fractions and concentrate to yield 18.8 g (87.4%) of the desired subtitled intermediate as a pink powder.

ClHNOOHNCO, Pd(OAc)2, dpppIEt3N, CH3OH, DMFOOHOClHNNO

A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (30.0 g), Et3N (19.1 mL), MeOH (110.6 mL), Pd(OAc)2 (431 mg), and 1,3-bis(diphenylphosphino)propane (791.9 mg) in 375 mL anhydrous DMF is stirred at room temperature until everything dissolves. CO (g) is slowly bubbled through for 2 days and the reaction is maintained at 70oC. The reaction is cooled to room temperature. The product is precipitated by adding 160 mL 1 N HCl into the reaction mixture. An orange solid precipitates is collected. The solid is triturated with EtOAc, filtered, and washed with CH2Cl2 to afford 23.8 g (93 % yield) of the title compound as an off-white solid.

NBocICO, Pd(PPh3)4, Et3NMeOH,CH3CN, 50Psi, 50oCCO2MeNBoc

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A mixture of 2-(3-iodo-2-methyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (26 g, 0.067 mol), Pd(PPh3)4 (2.4 g, 0.002 mol), Et3N (14.3 mL, 0.1 mol), 110 mL of acetonitrile and 50 mL of methanol was stirred under 50 Psi of carbon monoxide at 50 ?C for 8 h. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 250 mL of ethyl acetate, then washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product, which was purified by column chromatography (petroleum ether: ethyl acetate 30:1 to 10:1) to afford the title product (20 g, 93%) as a gray solid.

OONCO, PdCl2, BINAPEt3N, CH3OH, CH3CNNBrCO2CH3

PdCl2 (18.4 g, 0.104 mol) and BINAP (27.6 g, 0.044 mol) were added to a solution of 5-(2-bromo-phenyl)-oxazole (331.0 g, 0.44 mol) and Et3N (242.2 g, 2.22 mol) in 6 L CH3OH/CH3CN (2:1) in steel bomb. The mixture was stirred at 100 ?C under CO (1 atm) for 48 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (EtOAc/petroleum = 1:10) to give 2-oxazol-5-yl-benzoic acid methyl ester (210.0 g, 70 %) as brown oil.

5. 插羰反应制备酰胺实验操作

OTsOEtONBrONHOR+COPd(Ph3P)4, Bu3N110oC, 69%TsOEtOONNO2-52OOR2-52-A

A mixture of 2-52-A (6.3 mg, 11 rmnol), Pd(PPh3)4 (1.27 g, 1.1 mmol) and n-Bu3N (4.47 g, 24.2 mmol) in toluene (20 mL) was heated under carbon monoxide(10 atm) at 1l0oC for 24 h. Ethyl acetate was added to the reaction mixture and the organic layer was washed with 5% HCl, 5% Na2S2O3, sat. NaHCO3 and then brine, dried over Na2SO4 and evaporated. The

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residue was purified by column chromatography [ethy1 acetate-CH2Cl2 (1:l)]. The second fraction was 2-52 (3.93 g, 69 %).

6. 插羰反应制备醛

醛可以通过卤化物在不同氢源中的钯催化的插羰反应制备。芳基和烯基碘化物和溴化物在惰性溶剂中，三级胺存在的条件下与CO和H2（1:1）发生插羰反应生成醛。而芳基氯化物要先生成碳酸铬的衍生物后，才能在130oC的温度下转化成醛。甲酸钠可以代替H2被用作氢源来合成醛。氯苯在150oC的温度下，用dippp作为配体，与CO和甲酸钠反应制得苯甲醛。

+CO+H2PdCl2(Ph3P)2Et3N, 75%CHO

I

Cl+CO+HCO2NaPd(OAc)2, dippp150C, 20 h, 90%oCHO+NaCl+CO2

用锡的氢化物作为氢源，Pd(Ph3P)4作为催化剂，芳基、烯基卤化物或三氟甲磺酸酯和苄基、烯丙基氯化物的羰基反应也能制备醛。

OTf+CO+Bu3SnHCHOPd(Ph3P)4, THF3 atm., 98%

硅的氢化物也能被用作氢源。重氮盐6-1通过用Et3SiH或PHMS作为氢源，可以高收率快速的转化成邻甲基苯甲醛。

N2BF4+CO+Et3SnHPd(OAc)2, MeCN, Et2Ort., 10 atm., 10 min., 79%CHO6-1

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7. 插羰反应制备醛实验操作

Br+NCO+H2PdBr2(Ph3P)2, benzene Et3N, 1200 Psi, 145oC, 80%NCHO

To the 45 mL-Parr bombwere added 3.95 g (25.0 mmol) of 3-bromopyridine, 10 mL of triethylamine,

10

mL

of

benzene,

and

0.30

g

(0.375

mmol)

of

dibromobis(triphenylphosphine)palladium (II). The bomb was then flushed with argon, sealed, and pressurized to 600 Psi with carbon monoxide. After the pressure was released, the bomb was re-pressurized to 600 Psi with carbon monoxide and finally pressurized to 1200 Psi with hydrogen. The reaction vessel was heated in an oil bath with stirring at 145oC. After 20 min, the pressure reached a maximum of 1350 Psi. Times and pressure were periodically recorded until gas absorption stopped (26 hr), and the pressure in the reaction vessel had decreased to 1025 Psi. The reaction vessel was cooled, and the gases were slowly released. After addition of anhydrous ether, the reaction mixture was filtered to remove the triethylamine hydrochloride, concentrated in vacuo to remove ether, benzene, and triethylamine, and finally distilled to give 2.15 g of (80% yield) of product.

Br+BrCO+H2PdBr2(Ph3P)2, tri-n-butylamine benzene, 1200 Psi, 145oC, 80%CHO CHO

The 75-mLreaction bomb was charged with 5.9 g (25.0 mmol) of 1,4-dibromobenzene, 11.2 g (60.0 mmol) of tri-n-butylamine, 15 mLof benzene, and 0.4 g (0.5 mmol) of dibromobis(triphenylphosphine)palladium (II). The bomb was then flushed with argon, sealed, and pressurized to 600 Psi with carbon monoxide. After the pressure was released, the bomb was re-pressurized to 600 Psi with carbon monoxide and finally pressurized to 1200 Psi with hydrogen. After 15 min, the pressure reached 1375 Psi at 140oC and decreased to 600 Psi after 24 hr of treaction. The vessel was then cooled to room temperature and the pressure released. After addition of anhydrous ether, the reaction mixture was filtered to remove the

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triethylamine hydrochloride, concentrated in vacuo to remove ether, benzene, and triethylamine. After evaporation of the ether, the resulting solids were sublimed (100oC, 8 mm) to give 3.79 g of a mixture of the terephthalaldehyde and 1,4-dibromobenzene. The mixture was separated by chromatography on silica gel. There were obtained 0.66 g (2.8 mmol) of 1,4-dibromobenzene and 2.47 g (18.4 mmol) of 1,4-benzenedicarboxaldehyde (83% yield). Recrystallization from hexane yielded 2.21 g of pure dialdehyde.

8. 插羰反应制备酮

在Zn, B, Al, Sn, Si, Hg等有机金属化合物或其他亲核试剂（他们可以进攻酰基钯中间体，发生金属转移和还原消去反应）的存在下，卤化物和类卤化物的羰基化反应可以生成酮。

芳基碘化物在烷基碘化物和Zn-Cu存在条件下发生插羰反应，以非常高的收率生成了烷基芳基酮。这个反应首先生成烷基锌试剂，然后再发生金属转移和还原消去反应。

Ph-I+COPd(Ph3P)41 atm.Ph-COPd-IZnI93%PhO+ZnCl2I+Zn-Cu

在碱性条件下，有机硼化物可以被用于合成酮的插羰反应中：

Ph-I+CO+Et3BPdCl2(Ph3P)2Zn(acac)2, HMPA, 82%PhMOMO+9-BBN+COIPdCl2(Ph3P)2K3PO4, PhH, 74%O

O

MOMO

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OB(OH)2+CO+PhCH2BrOMOMPdCl2(Ph3P)2, K2CO31 atm., 78%OPhOPhOMOM

9-C8H17-9-BBN+CO+C6H13IPd(Ph3P)4, K3PO4dioxane, 67èH17OC6H13

有机铝化物（例如三苯基铝）可以被用于合成酮的插羰反应。应注意的是，i-Bu3Al应用此类反应时，往往会发生还原羰基化反应，从而生成相应的醇：

OMePh3Al+I+COPdCl2(PhCN)2DMSO, 98%OMeO

PhI+CO+PdCl2(Ph3P)23PhOHAlDME, 95%

有机锡化物，如芳基、烯基和炔基锡化物，可以用于合成酮的插羰反应。反应机理和实例应用如下图所示：

Pd(0)Ar-I+COArCO-Pd-XBu3SnArCOPdArCO+Bu3SnX+Pd(0)

I+CO+Me4SnPhPd(Ph3P)2IHMPA, 120oC, 85%COCH3

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OTf+CO+Bu3SnSiMe3PdCl2(dppf)LiCl, 50~60%OOPdXOOSiMe3

N2BF4Pd(OAc)2, MeCN+CO+Me4SnCl9 atm., rt., 90%ClCOMe

OTf+TMs+COPd(Ph3P)4, LiClTHF, 1 atm., 86%TMSOMe3Sn

OPdCl2(MeCN)2DMF, LiCl, 53%OOOSnBu3+COOOTf

有机硅化物可以用于合成酮的插羰反应：

ISSiEt2F+CO+CHOπ-C3H5PdCl, KF, DMF100oC, 1 atm., 72%SOCHO

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OTfEtOOSiMe3++COPd(Ph3P)4HMPA, 87%OOCO2EtOOOPdCO2Et

烷基和芳基汞（II）的卤化物也可以用于酮的合成反应，因为此类反应并不多见，所以在此就不再列举。

如果用活性亚甲基化合物（例如β-酮酯或丙二酸酯）代替醇类化合物进行插羰反应，可以得到β-酮酯或丙二酸酯的衍生物8-1。对于这个反应来说，dppf是非常好的配体。通过烯醇式阴离子捕获酰基钯中间体的方式发生分子内反应，可以形成五元和六元环。化合物8-2的形成就是一个典型实例。这是一个非常有价值的反应。

I+CO+CO2EtCO2EtPd(0), dppfEt3N, 120oC, 75%OCO2EtCO2Et8-1

CO2MeICO2Me+COPd(Ph3P)4, 60 Psi100oC, Et3N, 90%O8-2CO2MeCO2Me

当有一个可烯醇化的羰基存在的时候，C和O之间的捕获竞争就会发生。一般来讲，在形成同样大小环的情况下，O的捕获能力要强于C的捕获能力，因此更多的情况下是形成内酯。

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OPrBrPrCO,Pd(Ph3P)4(TiCl4,Mg,N2)K2CO3, 70%NHOMg2Cl2OTiNCO,THF+COPd(Ph3P)4, K2CO3NMP, 100oC, 1 atm, 87%OOPr

OPhI+CO+OOPhPdCl2(Ph3P)2Et3N, 56%OOOPhOO

如果在适当的位置有双键存在，那么在CO插入完成之后会紧接着发生烯键插入反应。在化合物8-3的分子内反应中，通过使用不同的催化剂可以得到不同的产物：使用Pd(dba)2作催化剂，插羰后得到产物8-4；而使用PdCl2(Ph3)2作催化剂则得到化合物8-5。

OPd(dba)2, Et3NMeCN, 93%I+COO8-3PdCl2(Ph3P)2Et3N, MeOH, 84%O8-5O8-4OCO2Me

下面是通过芳基卤化物与分子内双键的羰基化反应合成杂环化合物8-6的实例：

BrNHOO+COPd(OAc)2, Ph3P, K2CO3 DMF, 120oC, 12 atm., 87%O8-6OOO

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邻碘苯酚与降冰片二烯和CO反应得到内酯8-7，它可以通过反Diels-Alder反应进一步转化成香豆素8-8。

I+OH+COPd(Ph3)4, anisole1 atm, 80oC, 90%O8-7150oC+O8-8OO

有末端炔烃和非末端炔烃参与的卤化物羰基化反应可以得到各种各样的产物。取代二氢茚酮8-9的合成就是通过在Pd(Ph3P)4和Zn催化下邻二碘苯和炔烃、CO反应制得的。

OI+IEtEt+COPd(Ph3P)4, ZnEtOH, 63%Et8-9Et

在末端炔烃存在情况下，芳基碘化物的羰基化反应可以制备酰基炔烃8-10。在这个反应中，使用双齿配体（如dppf）可以得到非常好的结果。但如果使用Ph3P作为配体，苯乙炔主要转化成二苯乙炔。

Ph-I+CO+PhPdCl2(dppf), Et3N20 atm., 120oC, 86%PhCO8-10Ph

通过类似的反应，三氟甲磺酸酯8-11可以生成炔酮8-12：

OPh+CO+TfO8-11PhPd(OAc)2, dppe, Et3NDMF, 1 atm., 75%Ph8-12Ph

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用Zn-Cu试剂作为还原剂，通过Pd和Cp2TiCl2协同催化下，烯酮8-13能够以较高收率被制备：

Ph-I+CO+BuPdCl2(Ph3P)2, Cp2TiCl2Zn/Cu, 1 atm., 92%Ph8-13OBu

通过卤化物与炔烃的羰基化应制得的炔基酮可以和自身具有的亲和试剂进一步发生分子内反应：

I+CO2MePh+COPd(Ph3P)4, AcOK80oC, 1 atm., 74%CO2MeOPd(II)PhPhOO

O

Pd(Ph3P)4,anisoleAcOK, 82%I+OHPdCl2(dppf)2, Et2NH120oC, 20 atm., 81%OPh

Ph+COOOPh

I+NH2Ph+COOPdCl2(Ph3P)2, Et2NH120oC, 20 atm., 81%NH2OPhNHPh

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OC3H7HNBr+CO2MePh+COPdCl2(dppf)40 atm., 86%PhNC3H7ONaHPhNC3H7CO2MeCO2Me

碘苯和苄基乙炔8-14通过羰基化反应得到(E)-3-arylidenebutenolide 8-16（也可以通过苯乙酰基炔的羰基化反应制备）。烯基钯化物8-15被形成通过Pd-H加成反应。接着烯醇形成，双键异构化，二次羰基化反应得到丁烯羟酸内酯8-16。

Ph-I+OMe8-14+COPd(OAc)2, Ph3PEt3N, 120oC, 55%OMeOMeOPhOMePhOHPd8-15HPhOO8-16

在10 atm下，CO和CO2混合气体中，碘苯和取代炔丙基醇8-17反应得到3(2H)-furanone 8-20。首先碘苯和醇8-17以及CO通过羰基化反应生成苯乙酰炔基醇8-18；然后CO2与醇8-18加成得到碳酸酯8-19；最后脱羧重排得到8-20。

Pd(Ph3P)4Pd-I+8-17OPhOHCO2OO8-188-198-20PhOPhOOH+CO+CO2Et3N, 100oC, 79%OO

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在KCN存在的条件下，碘苯会发生氰基羰基化反应，从而生成苯甲酰氰化物8-21。

I+CO+KCNPhPd(Ph3P)2I, THF20 atm., 100oC, 91%8-21COCN

9. 插羰反应制备酮实验操作

I+OSi(Et)F2+COO(η3-C3H5PdCl)2, KF1 atm, 100oC, DMIO

To a suspension of KF (190 mg, 3.3 mmol), (η3-C3H5PdCl)2 (18 mg, 2.5 mol%), and 1-(4-iodophenyl)ethanone (490 mg, 2.0 mmol) in DMI (10 mL) was added difluoro(ethyl)(4-methylphenyl)silane (560 mg, 3.0 mmol) under 1 atm of carbon monoxide (balloon). After stirring at roon temperature for 10 min, the reaction mixture was heated at 100oC for 3 hours. Bulk of the solvent and the catalyst were removed by passing the mixture through a silica gel column with ethyl acetate-hexane = 1:10 as an eluent solvent. Evaportation of the solvent under reduced pressure afforded 4-acetylphenyl-4-methylphenyl ketone as a colorless solid (430 mg, 91%).

Ph-I+CO+BuPdCl2(Ph3P)2, Cp2TiCl2Zn/Cu, 1 atm., 92%Ph8-13OBu

A mixture of PdCl2(PPh3)2 (14 g, 0.02 mol), Cp2TiCl2 (10 mg, 0.04 mol), and Zn-Cu (98 mg, 1.5 mmol) was purged with carbon monoxide (equipped with a CO balloon). Into this mixture was added a solution of an aryl iodide (1.0 mmol) in 2.5 mL of dry dimethoxyethane in a syringe. The heterogeneous reaction mixture was immersed into an oil bath maintained to 65 ℃ and stirred for 4 hours. After evaporation of the solvent, the reaction mixture was directly subject to column chromatography (silica gel) and product 8-13 (92 %) was isolated.

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I+CO+CO2EtCO2EtPd(0), dppfEt3N, 120oC, 75%OCO2EtCO2Et8-1

Iodobenzene (1.8 mmol) and diethyl methylmalonate (2.0 mmol) in triethyl amine (2 mL) were reacted with carbon monoxide (20 atm) at 120℃ in the presence of a catalytic amount of dichloro[1,1’-bis(diphenylphosphino)ferrocene]-palladium (1.88*10-2mmol). GLC analysis of the resulting mixture revealed the formation of diethyl methylbenzoylalonate in 75.3% yield. The mixture was filtered and distilled (Kugelrohr) to give the pure sample (61% isolated yield).

The End

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