C–C bond-forming process is slow relative to
reductive HAT from the thiol. We also found
that the bicyclic olefin norbornene could be
aminated efficiently, although with relatively
poor diastereoselectivity (22)—an outcome
likely related to an early transition state for
C–N bond formation. Lastly, we found that
electron-rich styrene derivatives could be aminated to furnish anti-Markovnikov addition
products 23 and 24 in good yield. Within this
collection of olefins, we found that the most
nucleophilic members could be used in slight
excess (1.5 equivalents) to obtain high yields of
amination product. However, for less electron-rich alkenes, which are known to react more
slowly with ARCs (24), 3 to 5 equivalents were
required to obtain optimal yields. The higher
concentration in these examples enables C–N
bond formation to remain kinetically competitive with unproductive charge recombination between the ARC and the reduced Ir(II)
We then evaluated the scope of amines that
could be used in this protocol. Using 2-methylhex-
1-ene as a model olefin, we observed that numerous cyclic secondary amines were successfully
accommodated, including piperidine, morpholine,
N-Boc piperazine (N-Boc = N-tert-butyloxycarbonyl),
and unprotected 4-hydroxypiperidine (25–28).
Unprotected 4-aminopiperidine was alkylated
with complete selectivity for the secondary nitrogen center to furnish 29 in 83% yield. Azepane
and pyrrolidine were also viable substrates, although with somewhat diminished yields relative to their six-membered ring analog (30, 31).
A range of acyclic secondary amines could
also be used as aminating partners. Alkylation
of diethylamine provided tertiary amine 32 in
65% yield. The use of N-methyl benzylamine was
also successful (33). Branching adjacent to the
nitrogen center was also tolerated, as demonstrated by the use of N-methyl cyclohexylamine
(34). Secondary amines bearing acetals and
electron-deficient aromatics could also be alkylated in good yield (35, 36). More structurally
complex and sterically demanding amines, including the antidepressant drug fluoxetine, [3.2.1]
bicyclic amines and diamines, spirocyclic amines,
and N-methyl adamantylamine, were also readily
accommodated (37–43). Lastly, we found that
intramolecular variants of this transformation
were successful, as a variety of N-benzyl protected
substrates cyclized under the standard reaction
conditions to afford a range of five- and six-membered heterocyclic products (44–50). With
respect to limitations, this method has thus far
not proven successful with aromatic amines,
a–amino acid derivatives, or tetramethylpiperidine.
Efforts to address these limitations are currently
A number of experimental observations pro-
vide support for the proposed mechanism.
Stern-Volmer analysis in dioxane revealed that
piperidine [peak potential Ep/2 = 0.56 V versus
Fc/Fc+ in acetonitrile (MeCN)] (32) efficient-
ly quenches (fig. S2, Stern-Volmer constant
Ksv = 200 M−1) the excited state of catalyst C
(excited state potential *E1/2 = 0.59 V versus
Fc/Fc+ in MeCN) (33), consistent with the pro-
posed electron transfer event. In contrast, we
observed that numerous representative olefin
classes (1-hexene, cyclohexene, 2-methylhex-1-
ene, tetramethylethylene, and dihydrofuran)
do not decrease the luminescence intensity
of *C, which suggests that olefin oxidation
mechanisms are not operative in these re-
actions. As such, this protocol is mechanisti-
cally orthogonal to the seminal photocatalytic
anti-Markovnikov hydroamination methods re-
ported by Nicewicz (34), which proceed through
alkene radical cation intermediates (35). The
tertiary amine products (Ep/2 = 0.43 V versus
Fc/Fc+ in MeCN for triethylamine) can also be
oxidized (fig. S8, Ksv = 180 M−1 for 25) by the
excited state of catalyst C, but the generally
high yields observed in these reactions sug-
gest that these processes are reversible and do
not lead to meaningful amounts of product
We postulate that this outcome may result
from the protective action of the thiol cocatalyst,
which could reduce any a-amino radical inter-
mediates resulting from tertiary amine oxida-
tion and deprotonation before they can engage
in further deleterious side reactions. Because
these reactions function best in toluene and
dioxane, we considered whether reduction of
the radical generated after C–N bond forma-
tion might occur via H-atom transfer from
weak solvent C–H bonds. However, 1H nuclear
magnetic resonance (NMR) analysis of the re-
action between piperidine and tetramethyl
ethylene in d8-toluene revealed no evidence of
deuterium incorporation into the tertiary amine
product 6. Lastly, the formation of 6 is cal-
culated to be +4.8 kcal/mol (CBS-QB3) ender-
gonic relative to the amine and olefin starting
materials (14); this penalty is offset by the
favorable energetics of photon absorption (emis-
sion wavelength lmax = 512 nm = +55.8 kcal/mol
for the excited state of C) (32). This reaction
provides a clear demonstration of the ability of
excited-state redox catalysts to enable ender-
gonic bond constructions (36).
Our results constitute a general photo-driven
protocol for the intermolecular anti-Markovnikov
hydroamination of unactivated internal olefins
with dialkyl amines that proceeds via aminium
radical cation intermediates. We anticipate
that this method will help to address a long-
standing synthetic challenge in hydroamina-
tion chemistry and will simplify the design and
construction of complex tertiary alkyl amine
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Supported by a Sloan Foundation research fellowship, an Amgen
Young Investigator award, and an Eli Lilly grantee award (R.R.K.)
and by NIH grant R01 GM120530 and Bristol-Myers Squibb. We thank
D. C. Miller for calculations, and W. (R.) Ewing, L. Lombardo,
M. Eastgate, and R. Borzilleri for helpful discussions.
Materials and Methods
Figs. S1 to S9
Tables S1 to S11
1 November 2016; accepted 10 January 2017
730 17 FEBRUARY 2017 • VOL 355 ISSUE 6326
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