were stable under the mildly acidic conditions of
AACC catalysis to furnish 51 and 52 in pre-
parative yields.
Allylbenzene olefins, which react via more-
activated p-allyl–Pd(SOX) intermediates,
underwent AACC catalysis at lower (±)-MeO-
SOX·Pd(OAc) 2 loadings (5 mol %) and shorter
reaction times (12 or 24 hours). Electron-rich,
-neutral, and -poor allylbenzene derivatives
uniformly furnished the allylic tertiary amine
products in excellent yields ( 53 to 57 ). Com-
mon heterocycle motifs found in pharmaceu-
ticals such as benzothiophene, coumarin, and
indole—readily accessible as allylbenzenes but
not as cinnamaldehydes—afforded allylic amine
products in good yields ( 58 to 60 ). Collectively,
the mild oxidative nature of this AACC catalysis
provides an orthogonal approach to Hofmann
alkylations, reductive aminations, olefin func-
tionalizations, and allylic substitutions for syn-
thesizing allylic tertiary amines.
We next evaluated the capacity of this allylic
C–H amination cross-coupling to directly con-
struct tertiary amine–bearing pharmaceuticals
(Fig. 3A). Starting from commercial cyclizine
fragments and allylbenzene, calcium antag-
onists cinnarizine ( 61 ) and flunarizine ( 62 )
were accessed in useful yields through AACC
catalysis. Allylamine antifungal drugs naftifine
( 63 ) and known analogs ( 64 and 65 ) were
furnished in high yields in the cross-coupling
of readily accessibleN-methylbenzylamines with
allylated aromatics ( 40 ). Further showcasing
the notable chemoselectivity for terminal olefins
over traditional electrophiles, cross-coupling
of morpholine with a terminal olefin bearing
a reactive benzyl chloride electrophile afforded
allylic amine 66 in 80% yield. Subsequent
substitution to install an ethanethiol moiety
afforded a streamlined synthesis of the exper-
imental antiobesity compound 67 in approxi-
mately half the step count and twice the overall
yield of the previous reductive amination route
( 41 ) (Fig. 3 versus Fig. 1A, middle right).
Linkage of a piperidine or piperazine to
another heterocycle or aromatic moiety with a
flexible 3- or 4-carbon chain is a characteristic
featureofmanypsychiatricmedicines( 42 ).
Buspirone ( 68 ), ipsapirone ( 69 ), and tando-
spirone ( 70 ), members of the anxiolytic drug
class, were synthesized by cross-coupling
pyrimidinylpiperazine-BF 3 to the correspond-
ing alkylated imide olefin followed by hydro-
genation. The syntheses of clinical antipsychotics
aripiprazole ( 71 ) and its analog ( 72 )wererapidly
achieved with this approach, featuring notable
functional group tolerance of anO-alkylated
hydroxy-dihydroquinolinone electrophile ( 43 , 44 ).
Penfluridol ( 73 ), a clinical diphenylbutylpi-
peridine antipsychotic, was additionally ac-
cessed through the AACC catalysis-hydrogenation
sequence in useful yields. The amination pro-
ceeded smoothly with a piperidine nucleophile
bearing an ionizable, tertiary benzyl–protected
alcohol and provided a product prone to olefin
isomerization.
Numerous drugs or their derivatives con-
tain secondary amines that can be used in
late-stage allylic C–H amination cross-coupling
with allylated drug fragments to rapidly furnish
complex tertiary amines in medicinally rele-
vant settings (Fig. 3B). Serotonin reuptake in-
hibitors paroxetine, fluoxetine, and norquetiapine
were readily cross-coupled with buspirone and
tandospirone fragments via 4-carbon linkers
to afford 74 , 75 , and 76 in useful yields. Cough
suppressant dextromethorphan was coupled
as its secondary amine to an allylated estrone
derivative to generate 77 in 64% yield. The
amine fragment of clopidogrel, a World Health
Organization (WHO) essential drug, was cross-
coupled with an allylated acetylsalicylic acid
derivative to give 78.
AACC catalysis is also well suited for the
expedient generation of drug analogs. Debio-
1452, an antibiotic in clinical trials ( 45 ), was
readily synthesized as the Boc-deoxydebio-1452
analog ( 79 ) in the cross-coupling ofN-methyl-
benzofuranyl amine with allyl dihydronaph-
thyridinone. Tetrahydropyridine and pyrrolidine
derivatives ( 80 and 81 ) were also accessed,
further underscoring the high chemoselec-
tivity for terminal versus internal olefins
with this method. Alternatively, the debio-
amineN-methyl-benzofuranyl fragment can
readilybecoupledtootherolefinpartners,
including an allylated derivative of the broad-
spectrum antibiotic tedizolid ( 82 ). These ter-
tiary amine drugs and their derivatives were
readily furnished through AACC catalysis
using one catalyst and robust amine and olefin
coupling partners under atmospheric conditions
that are amenable to high-throughput, fragment-
based drug discovery campaigns ( 24 ).
Mechanistic studies focused on determin-
ing how functionalization of thep-allyl–Pd
[(±)-MeO-SOX] intermediate proceeded with
amine-BF 3 pronucleophiles (Fig. 4). Amine-
BF 3 complexes are hydrolyzed at elevated
temperatures with ambient water to furnish
amine-HBF 4 and amine–boric acid complexes
(3:1 stoichiometry) ( 32 , 33 ). To investigate
an amine-HBF 4 salt as an intermediate, we
monitored the amount of amine-BF 3 ( 1 ·BF 3 ),
amine-HBF 4 ( 1 ·HBF 4 ), and allylic C–H ami-
nation product ( 3 ·HX) in the reaction over time
using quantitative proton nuclear magnetic
resonance (^1 HNMR)analysis(Fig.4A).Ini-
tially, 1 ·BF 3 was consumed steadily, with rapid
formation of 1 ·HBF 4. Only after an appreciable
amount of 1 ·HBF 4 was formed (~20 to 30%)
did product 3 ·HX formation occur. At the end
of the reaction, tertiary amine product 3 was
observed predominantly as an amine-HBF 4
salt that may serve to suppress deleterious
overalkylation and amine-directed pallada-
tions of the product ( 21 , 22 ). We next sought
to identify a mechanism whereby free aminenucleophile 1 could be generated from 1 ·HBF 4
in the catalytic cycle. Gas chromatography–
mass spectrometry (GC-MS) analysis early in
the reaction showed trace methyl ketone for-
mation, consistent with a Wacker olefin oxida-
tion that reduces Pd(II) to Pd(0) (Fig. 4C)
(supplementary materials) ( 23 ). Pd(0) oxida-
tion by quinone provides a hydroxyphenolate
base that may deprotonate 1 ·HBF 4 to initiate
amine functionalization. Consistent with this,
a Pd(0) precatalyst may be used and furnishes
product 3 in comparable yields (supplemen-
tary materials). After initiation, proton trans-
fer from the 1 ·HBF 4 to the more basic tertiary
amine product 3 may be an additional slow-
release mechanism for the nucleophile. Even
though the free amine nucleophile 1 or tertiary
amine product 3 were not directly detected,
their involvement in catalysis is supported
by 10- and sevenfold increases in initial rates,
respectively (fig. S12), that manifested in in-
creased yields at 24 hours when reactions were
run with catalytic amounts of 1 or3a(10 mol %)
(Fig. 4B). The increased rate afforded from
catalytic secondary amine is beneficial in im-
proving reaction efficiency: Preliminary inves-
tigations demonstrate the ability to reduce the
catalyst loading (10 to 5 mol %) and maintain
preparative yield. Although 10 mol % of free
amine 1 was beneficial, at >20 mol % 1 , a sub-
stantial decrease in product yields was ob-
served, likely as a result of catalyst inhibition
(fig. S13). Key to AACC catalysis is the cou-
pling of catalyst turnover to the generation of
free amine that places an upper limit of ~10
to 20% free amine in the catalytic cycle at any
given time. We anticipate that this general
strategy may be broadly applicable to other
electrophilic metal–mediated reactions using
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