ORGANIC
LETTERS
2011
Vol. 13, No. 9
2326–2329
An Improved Larock Synthesis of
Quinolines via a Heck Reaction of
2-Bromoanilines and Allylic Alcohols
Matthew T. Stone*,†
Department of Chemistry and Novartis Center for Continuous Manufacturing,
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Received March 3, 2011
ABSTRACT
A modified Larock method has been developed for the one-pot synthesis of substituted quinolines via a Heck reaction of 2-bromoanilines and
allylic alcohols followed by dehydrogenation with diisopropyl azodicarboxylate (DIAD).
Substituted quinoline cores are important biologically
active motifs, and are found in both natural products1 and
active pharmaceutical ingredients (APIs) including Ce-
thromycin (antibacterial),2 Pitavastatin (statin),3 Monte-
lukast (asthma and allergy),4 and many antimalarial
drugs.5 Given their potent bioactivity, a number of strate-
gies to assemble the quinoline structure have been
reported.6ꢀ11 While many of these techniques have seen
frequent use, their substrate scope is often limited due to
the requirement of harsh reaction conditions and/or a lack
of regioselectivity for meta-substituted anilines. Some
established methods also require synthetically complex
substrates, which are several steps from commercially
available materials.
In 1991 Larock demonstrated a relatively mild and
regioselective procedure to synthesize substituted quino-
lines from the Heck reaction of 2-iodoaniline with four
different allylic alcohols.12 This transformation proceeds
first via a Heck reaction/isomerization sequence to give a
β-aryl ketone,13ꢀ15 which further proceeds through an
intramolecular condensation to form the 3,4-dihydroqui-
noline (Figure 1a). Under the reaction conditions the
dihydroquinoline subsequently undergoes a palladium-
catalyzed dehydrogenation reaction to provide the desired
quinoline product. Unfortunately, disproportionation of
the dihydroquinoline to the tetrahydroquinoline was also
observed during the reaction unless toxic hexamethylpho-
sphoramide (HMPA) was used as the solvent (Figure 1b).
We felt that the utility of this transformation could be
greatly improved if more widely available 2-bromoanilines
could be employed as substrates and a more efficient
dehydrogenation of the 3,4-dihydroquinoline could be
established. Herein, we report an improved Larock
† Current address: 80 Ashby Road, Bedford, MA 01730.
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10.1021/ol200579a
Published on Web 04/06/2011
2011 American Chemical Society