REPORTS
◥ORGANIC CHEMISTRY
Allylic CÐH amination cross-coupling furnishes
tertiary amines by electrophilic metal catalysis
Siraj Z. Ali, Brenna G. Budaitis†, Devon F. A. Fontaine†, Andria L. Pace,
Jacob A. Garwin, M. Christina White*
Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines—
a common motif in pharmaceuticals—remains a major challenge in chemical synthesis. Basic amine
nucleophiles in nondirected, electrophilic metal–catalyzed aminations tend to bind to and thereby inhibit
metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine
nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated
heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen
amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines
(10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to
furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with
excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1E:Z).
A
mines are one of the most prevalent
structures found in small-molecule ther-
apeutics, with an estimated 43% of drug
candidates containing aliphatic amines,
60% of which are tertiary ( 1 – 4 ). Classic
methods for their syntheses include nucleo-
philic substitution reactions of alkyl halides
( 1 , 2 ), reductive amination of the corresponding
aldehydes or ketones ( 5 ), and Tsuji-Trost allylic
aminations ofE-allylic alcohols, acetates, or
carbonates ( 6 , 7 ). Although simple tertiary
amines can be made easily through these
methods (e.g., cinnamaldehyde-derived allylic
amines), more-complex amines require the syn-
thesis of preoxidized, unstable reagents and
more-tailored, substrate-dependent approaches
(Fig. 1A, middle right). For linear, aliphatic
amines—prominent structures in pharmaceuti-
cals and agrochemicals—the prefunctionalized
coupling partners (e.g., aldehydes) are often
derived from terminal olefins ( 8 ). The addition
of amines to terminal olefins provides a direct
route to these important compounds that uses
robust commercial building blocks ( 9 – 12 ). Ad-
vances in tandem radical-mediated olefin
functionalization-elimination processes under-
score the advantages of olefin-amine cou-
pling ( 13 , 14 ). Metal-mediated allylic C–H
amination provides an orthogonal method-
ology, where greater control of reactivity,
selectivity, and functional group compatibility
maybeachieved.
Sulfoxide-oxazoline–palladium(II)
[SOX·Pd(OAc) 2 ] allylic C–H aminations pro-
ceeding viap-allyl–Pd(SOX) intermediates
demonstrated the capacity to promote allylic
C–HtoC–N cross-coupling between complex,
unactivated terminal olefins andN-triflyl
(Tf) primary alkylamines with high reactiv-
ity (fragment-coupling conditions) and high
regio- and stereoselectivity (>20:1 linear:
branched, >20:1E:Z) to generate protected,
secondary allylic amines (Fig. 1A, middle left)
( 15 ). Such metal-promoted intermolecular
C–H aminations are generally limited to
aminesourcesthathaveoneormoreelectron-
withdrawing groups covalently bound to
nitrogen [e.g., Tf, toluenesulfonyl (Ts), and
2,2,2-trichloroethoxysulfonyl (Tces)] and re-
quire further synthetic manipulations to generate
tertiary amines ( 16 – 20 ). At high concentrations,
unprotected basic aliphatic amines bind to
electrophilic metals and may reduce them
and/or inhibit key steps in the catalytic cycle,
such as intermolecular C–H activation (Fig. 1A,
bottom left) ( 21 – 23 ). Under the current paradigm,
an electron-withdrawing group cannot be cova-
lently appended to a secondary amine without
deactivating it as a nucleophile, rendering
C–H amination to furnish complex tertiary
amines an unsolved problem. Here, we dis-
close a general strategy to fragment-couple
basic amines with terminal olefins in elec-
trophilic metal–mediated C–H activation
catalysis to furnish complex tertiary allylic
amines with preparative reactivity, >20:1
linear-selectivity,E-selectivity, and orthogo-
nal scope to current methods (Fig. 1A, bottom
middle) ( 24 ).
Inspired by recent advances in cross-coupling
and photoredox catalysis, where reactive inter-
mediates are generated in low concentrations to
exploit rate differences between unproductive
and productive pathways ( 25 – 27 ), we sought
to identify a mechanism for a slow release ofamine nucleophiles under electrophilic metal–
mediated C–H cleavage catalysis. The established
mechanism for SOX·Pd(OAc) 2 allylic C–H
amination involves electrophilic Pd(II)-mediated
heterolytic C–H cleavage to furnish a cationic
p-allyl–Pd(SOX)complexfollowedbyfunction-
alization and quinone-mediated Pd(0) reoxida-
tion (vide infra). Supporting the hypothesis that
low concentrations of free amine do not strongly
inhibit C–H cleavage within this manifold,
SOX·Pd(OAc) 2 amination withN-triflylamine
proceeded in the presence of catalytic secondary
amine (10%), whereas stoichiometric amounts
halted catalysis (table S1). Lewis acids, such as
boron trifluoride (BF 3 ), have been leveraged as
transient protecting groups that mask amines
during electrophilic metal–catalyzed reactions
that occur at remote functionality; however,
their capacity to modulate functionalization
at the amine has not been explored ( 28 – 30 ).
Although amine-BF 3 complexes are not able
to undergo facile deprotonation ( 31 ), at elevated
temperatures, they hydrolyze to furnish amine
tetrafluoroborate (HBF 4 ) salts ( 32 , 33 ). We hy-
pothesized that the hydroxyphenolate generated
during quinone-mediated Pd(0) oxidation and/
or the more basic tertiary amine products may
act as bases, deprotonating amine-HBF 4 salts
in situ to generate low concentrations of free
amine nucleophiles that are regulated by cata-
lyst loading (Fig. 1A, bottom right).
Amine-BF 3 complexes are stable to silica
chromatography and air, providing an excel-
lent way to purify and store secondary amines.
We first examined (±)-MeO-SOX·Pd(OAc) 2
amine cross-coupling of 4-phenyl piperidine
( 1 )asanamine-BF 3 complex with commercially
available allylcyclohexane ( 2 ), an unactivated
olefin, under fragment-coupling conditions (1
equivalent of each partner) and observed en-
couraging yields of the tertiary amine as a salt,
which was isolated as amine 3 upon basic
workup (Fig. 1B, entry 1). Addition of dibutyl
phosphate (dbp), a Brønsted acid additive
previously shown to increase reactivity in
allylic functionalizations with sulfoxide–Pd(OAc) 2
catalysis ( 34 ), improved the yield of 3 to 74%
(entry 2). Varying the acid loading from 0.25
to 0.5 equivalents increased reactivity (83%
yield; entry 3); however, overalkylation was
noted for some substrates and could be sup-
pressed with lower acid loadings. In situ BF 3
complexation with 1 worked with equal ef-
ficiency (entry 4). Consistent with the reaction
proceeding via an amine-HBF 4 salt, 1 ·HBF 4
afforded comparable yields to 1 ·BF 3 at lower
acid loadings (entry 5). Exploration of alternative
amine salts showed that although hydrochloride
(HCl) salts were not effective, those with
weakly coordinating counterions [trifluoro-
acetate (TFA), Ts, and dbp] afforded promising
product yields, suggesting that, with further
development, they may be used for this strategy
(table S2). Expectedly, use of stoichiometric276 15 APRIL 2022•VOL 376 ISSUE 6590 science.orgSCIENCE
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, IL 61801, USA.
*Corresponding author. Email: [email protected]
These authors contributed equally to this work.
RESEARCH