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
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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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
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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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
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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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
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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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
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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