ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Modular Isoquinoline Synthesis Using
Catalytic Enolate Arylation and in Situ
Functionalization
Ben S. Pilgrim,†,§ Alice E. Gatland,†,§ Charlie T. McTernan,† Panayiotis A. Procopiou,‡
and Timothy J. Donohoe*,†
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K., and GlaxoSmithKline, Medicines Research
Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
Received October 22, 2013
ABSTRACT
A methyl ketone, an aryl bromide, an electrophile, and ammonium chloride were combined in a four-component, three-step, and one-pot coupling
procedure to furnish substituted isoquinolines in overall yields of up to 80%. This protocol utilizes the palladium catalyzed R-arylation reaction of
an enolate, followed by in situ trapping with an electrophile, and aromatization with ammonium chloride. tert-Butyl cyanoacetate participated in a
similar protocol; after functionalization and decarboxylation, 3-amino-4-alkyl isoquinolines were prepared in high yield.
The isoquinoline unit is commonly found in natural
product frameworks, the cores of pharmaceutical agents,
and important organic materials; however, traditional
synthetic routes to these motifs suffer from a number of
drawbacks. Recently, a number of groups have employed
catalytic amounts of transition metals to mediate new
bond forming processes en route to isoquinolines.1
In 2012, we published a de novo synthetic route to iso-
quinolines that utilized the palladium catalyzed R-arylation
of ketone enolates.2 In this protocol, readily available
precursors were combined in a concise, convergent, and
regiocontrolled manner to furnish polysubstitued iso-
quinolines.
The choice of ketone coupling partner determined two
of the substituents (at C3 and C4) on the heteroaryl ring of
the isoquinoline, arguably two of the most important to be
able to manipulate. Although a reasonable scope of the
method was demonstrated, the limited commercial avail-
ability of the requisite ketones, together with difficulties
encountered during regioselective enolization, imparted
certain limitations on the methodology.
While isoquinolines undergo nucleophilic attack at the
C1 and C3 positions and can be made to react with
electrophiles (albeit under forcing conditions) at the C5
and C8 positions, the C4 position is difficult to functiona-
lize in a direct manner. However, one of the advantages of
de novo approaches to aromatic rings is that the inter-
mediates formed en route to the arene can be manipulated,
† University of Oxford.
‡ GlaxoSmithKline.
§ These authors contributed equally.
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r
10.1021/ol4030309
XXXX American Chemical Society