underscores the high reactivity and selectiv-
ity achieved with metal-mediated allylic C–H
aminations.
Cyclic amines account for 59% of nitrogen
moieties in pharmaceuticals ( 3 ). Five of the
most common secondary amines found in
aliphatic tertiary amine drug candidates ( 1 )
underwent AACC catalysis with unactivated
terminal olefin 2 under cross-coupling stoi-
chiometries (1 equivalent amine, 1 equivalent
olefin) in preparative yields (Fig. 2A). Although
unsubstituted pyrrolidine and piperidine nucleo-
philes showed modest amination yields as a
result of overalkylation ( 4 and 11 ), substitu-
tion on the rings with varying functionality
afforded increased yields ( 5 to 10 and 12 to
15 ). Ethers, esters, and acetates were all com-
patible at remote and/or proximal sites of these
heterocycles, demonstrating that Lewis-basic
oxygen functionality does not negatively af-
fect amine-BF 3 complexation ( 5 to 8 and 14 ).
a-Substituted piperidines and pyrrolidines gen-
erally afforded tertiary amines in preparative
yields, demonstrating the tolerance of increased
steric-bulk proximal to nitrogen ( 8 , 9 , and 13
to 15 ). Despite the greater steric bulk of phenyl
versus methyl, 2-phenylpyrrolidine afforded
tertiary amine products in higher yields than
its 2-methyl counterpart with both unacti-
vated and activated olefins (13aand13b
versus15aand15b). Underscoring the high
chemoselectivity of this allylic amination man-
ifold, internal olefins were unreactive and
could be incorporated on the nucleophile ( 10 )
as well as the olefin cross-coupling partner
(vida infra; 46 and 47 ). A topologically com-
plex alkaloid core, tropane, as well as medium-
sized heterocycles azepane and azocane were
cross-coupled to olefin 2 in useful yields ( 16 to
18 ). Finally, cyclic amines containing low bond
dissociation energy (BDE) benzylica-amino
C–H bonds, such as tetrahydroisoquinoline
and isoindoline, were functionalized at nit-
rogen under this oxidative, two-electron proc-
ess ( 19 and 20 ).
We next examined cyclic secondary amine
nucleophiles bearing additional Lewis-basic
heteroatom functionality, which introduces
competing sites for BF 3 complexation or Pd(II)
coordination. Ethereal oxygen, less basic
than nitrogen, did not inhibit complexation:
Morpholine-BF 3 as well as a disubstituted ana-
log (core structure in antifungals amorolfine,
fenpropimorph, and tridemorph) successfully
underwent the reaction in preparative yields
( 21 and 22 ). Piperazines, the second most
common tertiary aliphatic amine within med-
icinal chemistry, frequently contain aryl and/
or alkyl substituents at the N1 and N4 positions
( 1 , 3 , 4 ). InN-aryl piperazines, the second-
ary aliphatic amine is preferentially complexed
in the presence of a less basic tertiary aniline.
SeveralN-aryl piperazines, including those
substituted with pyrimidine, halogenated aro-
matics, and benzothiophene functionalities
were generally effective nucleophiles as seen in
their cross-coupling with unactivated termi-
nal olefin 2 ( 23 to 26 ). In exploringN-alkyl
piperazines, which contain basic tertiary alipha-
tic amines, diphenylmethyl piperazine under-
went allylic functionalization to afford 27 in
good yields, whereas less–sterically hindered
benzyl piperazine afforded no cross-coupled
product (supplementary materials). Pipera-
zine nucleophiles with a strong inductively
withdrawing group on one of the nitrogen
atoms, such as phenylsulfonyl piperazine and
its seven-membered ring homolog, afforded the
desired products 28 and 29 in 56 and 74%
yields, respectively. Amine-HBF 4 salts generally
gave similar or diminished yields relative to
their amine-BF 3 counterparts ( 9 , 21 , and 26 ;
vide infra, 38 , 43 , 51 , 69 , and 71 ); however,
diene formation observed with 24 and 25 was
suppressed under the HBF 4 manifold and led
to increased yields (supplementary materials).
We subsequently investigated acyclic sec-
ondary amine nucleophiles that may face
additional challenges because of their greater
propensity forb-hydride elimination ( 35 ).N-
methylbenzylamines, a common pharmacophore
( 36 ), readily underwent BF 3 complexation and
afforded good yields of cross-coupled products
irrespective of the electronic substitution of
thebenzylmoiety( 30 to 32 ). Exchange of the
benzyl moiety with phenethyl or sterically
demanding cyclohexyl furnished tertiary amine
products with analogous efficiencies ( 33 and
34 ). Replacement of theN-methyl moiety with
N-propyl also furnished coupled product 35 in
a useful yield. Dimethylamine—a small bulk
commodity chemical and convenient precursor
to dimethylamino groups prevalent in drug
compounds—afforded the cross-coupled tertiary
amine product 36 in useful 34% yield with
the dialkylated, quaternary amine salt as a by-
product. Although primary amine-BF 3 nucle-
ophiles yield dialkylation products under AACC
catalysis, such reactivity may be used to furnish
symmetrical tertiary amines: One equivalent
of ethylamine-BF 3 was reacted with two equiv-
alents of allylbenzene to afford a streamlinedsynthesis of the allylic precursor 37 to the
smooth muscle relaxant alverine ( 37 ).
We next used a piperidine and morpholine,
two of the most medicinally relevant amines,
to explore the olefin scope for generality and
orthogonal functional group compatibility rela-
tive to other methods for accessing tertiary
amines (Fig. 2, top, and Fig. 2B) ( 1 ). There is
ample precedent for basic secondary amines
to displace leaving groups, such as halogens,
sulfonates, and epoxide oxygens at Csp3centers
in Hofmann alkylations, to furnish tertiary
amines ( 1 , 2 ). Under AACC catalysis, where the
majority of the basic amine is deactivated as
a salt, such functionality is maintained with
chemoselective C–N bond formation occur-
ring at the allylic terminus ( 38 , 39 , and 40 ).
In a substrate bearing a terminal epoxide, the
C–H allylic amination product 40 formed
alongside dbp by-products from epoxide open-
ing (supplementary materials). Notably, switch-
ing to the HBF 4 protocol at lower dbp loadings
(5%) afforded 40 in 87% yield, despite the
precedent for amine-HBF 4 salts to act as
catalysts for epoxide-opening polymerization
processes ( 32 ).
Remote carbonyl functionality, generally re-
active with secondary amines and challenging
to maintain in reductive or radical-based ami-
nation methods ( 5 , 9 – 14 ), was compatible with
the oxidative conditions of AACC catalysis.
Olefins containing aldehyde, ketone, ethyl ester,
and gem-dimethyl ester functionalities afforded
excellent yields of tertiary amine products ( 41 to
44 ). An olefin bearing Weinreb amide function-
ality with ana-stereocenter, an attractive syn-
thetic handle, furnished chiral coupled product
45 that could be further elaborated.
Functionality prone to oxidation was also
compatible with oxidative AACC catalysis. Sub-
strates containing remotep-functionality, such
as a citronellal-derived internal olefin and an
internal alkyne, afforded the desired products
46 and 47 in synthetically useful yields with
high chemoselectivity for the terminal olefin.
Olefins bearing unprotected secondary and
primary benzylic alcohols, known to undergo
oxidation under Pd(II) catalysis ( 38 ), success-
fully furnished aminated products 48 and 49
in excellent yields with no detected carbonyl
products. Phenol, a precedented nucleophile
in Pd(0)-catalyzed allylic substitutions ( 39 ),
was compatible, affording allylic amine 50 as
theonlyobservedproduct.Olefinswithacid-labile
functionality, such as a remote tetrahydro-
pyranyl ether and a densely functionalized sugar,SCIENCEscience.org 15 APRIL 2022•VOL 376 ISSUE 6590 281
benzotrifluoride as an internal standard. All time points (excludingt= 0 and 48 hours) are the average of three experiments, with error bars indicating one standard
deviation. The identity of 1 ·HBF 4 was confirmed by matching its spectra to authentic material; however, we cannot exclude that other counterions (X) may be present.
(B) Experiments to investigate the formation of free secondary amine nucleophile and the role of free tertiary amine in proton transfer as well as experiments to
investigate reactivity at 5 mol % catalyst loading (cat. loading). See supplementary materials for details. *Yield was determined by crude^1 H NMR analysis using
mesitylene as an internal standard. (C) Proposed mechanism for AACC. 2,5-DMHQ, 2,5-dimethylhydroquinone.
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