申请人:——
公开号:US20040059131A1
公开(公告)日:2004-03-25
The present invention provides methods for the efficient preparation of indole derivatives of the formula
1
wherein X is methyl or benzyl; and R
1
, R
2
, R
3
and R
4
are independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl or heteroaryl; or R
1
and R
2
combined together with the carbon atoms to which they are attached form a fused 6-membered aromatic ring; by reacting indoles of the formula
2
wherein R
1
, R
2
, R
3
and R
4
have meanings as defined for formula I, with dimethyl carbonate when X is methyl, or with dibenzyl carbonate when X is benzyl, in the presence of a catalytic amount of a base at an ambient temperature to afford compounds of formula I wherein X, R
1
, R
2
, R
3
and R
4
have meanings as defined herein above. In particular, the present invention provides methylation and benzylation of the indole nitrogen in nearly quantitative yields using 1,4-diazabicyclo[2.2.2]octane as the base in a catalytic amount under mild conditions, wherein the alkylations may be conducted in the absence or the presence of an ionic liquid, under microwave irradiation or utilizing conventional heat, or combinations thereof.
本发明提供了一种高效制备式1的吲哚衍生物的方法,其中X为甲基或苄基;R1、R2、R3和R4独立地为氢、卤素、氰基、硝基、羟基、可选择取代的烷基、烷氧基、芳基氧基、羧基、烷氧羰基、芳基或杂环芳基;或者R1和R2与它们连接的碳原子共同形成融合的6-成员芳香环;通过将式2的吲哚与二甲碳酸酯(X为甲基时)或二苄基碳酸酯(X为苄基时)在常温下在碱的催化下反应,得到式1的化合物,其中X、R1、R2、R3和R4的含义如上所述。特别地,本发明提供了在温和条件下使用1,4-二氮杂双环[2.2.2]辛烷作为催化剂的催化量下,对吲哚氮进行甲基化和苄基化,几乎可以达到定量产率,其中烷基化可以在无离子液体或存在离子液体的情况下进行,在微波辐射或利用常规加热下进行,或者两者结合。