Ca r bop a lla d a tion of Nitr iles: Syn th esis of Ben zocyclic Keton es
a n d Cyclop en ten on es via P d -Ca ta lyzed Cycliza tion of
ω-(2-Iod oa r yl)a lk a n en itr iles a n d Rela ted Com p ou n d s
Alexandre A. Pletnev and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received J uly 16, 2002
An efficient procedure for the synthesis of 2,2-disubstituted benzocyclic ketones by intramolecular
carbopalladation of nitriles has been developed. The cyclization of substituted 3-(2-iodoaryl)-
propanenitriles affords indanones in high yields. The reaction is compatible with a wide variety of
functional groups. This methodology has been extended to the synthesis of tetralones and
cyclopentenones.
In tr od u ction
tives.6a,9 The strongly acidic conditions required by this
method, especially when the aromatic ring is deactivated,
restrict the variety of functional groups that are toler-
ated. There can also be problems with the regioselectivity
of the cyclization. Intermolecular routes to benzocyclic
ketones include the Vilsmeier-Haack cyclization of
substituted styrenes,1c the tandem Knoevenagel conden-
sation-cycloaddition,3a the Wittig-Horner reaction of
phthalide-3-phosphonates and ketones,3b and various
carbonylation processes.10 Complex benzocyclic ketones
may be synthesized by derivatization of simple indanones
and tetralones, but this approach often suffers from poor
yields.11 Specific indanone targets have also been pre-
pared via indirect, highly specific routes.8,12
Benzocyclic ketones are versatile and useful synthetic
intermediates in the agrochemical and pharmaceutical
industries.1 The 2-alkyl-1-indanone core is prominently
featured in many pharmaceutical products, such as the
antihypertensive drug (+)-Indacrinone, the diuretic
MK473, and the â-blocker Spirendolol.1a Some indanone
derivatives also exhibit bronchodilatory activity.2 In-
danones serve as important building blocks in the
synthesis of steroids, gibberellic acid, fredericamycin A,
and other natural products,2,3 and are frequently used
as precursors to medicinal substances, such as nonste-
roidal 5R-reductase inhibitors, 5-hydroxytryptamine-
receptor agonists, dopamine-receptor antagonists, and
other agents against Alzheimer’s disease.4
R-Tetralones have been used as precursors to chiral
benzocyclic amines that provide key intermediates for a
number of pharmaceutical preparations with neurotropic
and psychotropic activity.1d Other biologically active
substances synthesized from tetralones include lignans
(such as podophyllotoxin and J usticidins A-F) and
diterpenes (heliosporin E and the aglycon moiety of
various pseudopterosins),5 antitumor and antileukemic
HIV reverse transcriptase-inhibiting benzo[c]phenan-
thridine alkaloids,6 angucyclin antibiotics,7 anthracyclins,
tetracyclins, and estrone derivatives.8
In a continuation of our work on developing useful, new
synthetic organic methodology based on the carbopalla-
dation of nitriles,13 we have explored the possibility of
synthesizing indanones by the Pd-catalyzed cyclization
of 3-(2-iodoaryl)propanenitriles (eq 1).14 Here, we wish
Traditionally, benzocyclic ketones have been synthe-
sized by the intramolecular Friedel-Crafts acylation of
â-arylpropionic and γ-arylbutyric acids and their deriva-
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10.1021/jo0262006 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/03/2002
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J . Org. Chem. 2002, 67, 9428-9438