Catalytic olefin hydroamination with aminium radical cations: A photoredox method for direct C-N bond formation

Article abstract of DOI:10.1021/ja5056774

While olefin amination with aminium radical cations is a classical method for C-N bond formation, catalytic variants that utilize simple 2° amine precursors remain largely undeveloped. Herein we report a new visible-light photoredox protocol for the intramolecular anti-Markovnikov hydroamination of aryl olefins that proceeds through catalytically generated aminium radical intermediates. Mechanistic studies are consistent with a process involving amine oxidation via electron transfer, turnover-limiting C-N bond formation, and a second electron transfer step to reduce a carbon-centered radical, rendering the overall process redox-neutral. A range of structurally diverse N-aryl heterocycles can be prepared in good to excellent yields under conditions significantly milder than those required by conventional aminium-based protocols.

Full text of DOI:10.1021/ja5056774

Communication
pubs.acs.org/JACS
Catalytic Olefin Hydroamination with Aminium Radical Cations: A
Photoredox Method for Direct C−N Bond Formation
Andrew J. Musacchio, Lucas Q. Nguyen, G. Hudson Beard, and Robert R. Knowles*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: While olefin amination with aminium
radical cations is a classical method for C−N bond
formation, catalytic variants that utilize simple 2° amine
precursors remain largely undeveloped. Herein we report a
new visible-light photoredox protocol for the intra-
molecular anti-Markovnikov hydroamination of aryl olefins
that proceeds through catalytically generated aminium
radical intermediates. Mechanistic studies are consistent
with a process involving amine oxidation via electron
transfer, turnover-limiting C−N bond formation, and a
second electron transfer step to reduce a carbon-centered
radical, rendering the overall process redox-neutral. A
range of structurally diverse N-aryl heterocycles can be
prepared in good to excellent yields under conditions
significantly milder than those required by conventional
aminium-based protocols.
he addition of aminium radical cations to olefins is an
Tattractive method for C−N bond formation, exhibiting
both low activation barriers and reliable anti-Markovnikov
Figure 1. Classical olefin functionalizations with aminium radical
cations as the basis for a new catalytic protocol.
regioselectivity.1 In recent years, aminium formation via amine
oxidation has been incorporated as an elementary step in
numerous visible-light photoredox processes.2 However, in
most examples these intermediates are transient, being further
converted to α-amino radicals or iminium ions that participate
in bond-forming reactions at carbon.3 Photocatalytic methods
that engage aminium radicals directly to enable C−N bond
formation are rare, with the only example reported to date
being a notable oxidative indole synthesis reported by Maity
and Zheng.4 We questioned whether these electrophilic
nitrogen-centered radicals might be utilized more generally to
enable the development of a broadly useful set of olefin
functionalization protocols. Toward this end, we report here a
catalytic method for the hydroamination of styrenes that
proceeds through aminium radical intermediates. The develop-
ment, scope, and mechanistic evaluation of this new process are
presented below.
requisite aminium intermediate. Addition to a pendant olefin
occurs readily, and the resulting carbon-centered radical
recombines with X· to yield a 1,2-amino-functionalized product.
While powerful, both the forcing reaction conditions and the
requirement of substrate prefunctionalization have significantly
limited the applications of these protocols in synthesis.
We reasoned that the salient bond-forming aspects of this
process could be retained in the absence of such restrictions
and utilized in the development of a catalytic photoredox
hydroamination protocol that operates through sequential
single electron transfer steps (Figure 1).5,6 Specifically, an
identical aminium ion could be generated via one-electron
oxidation of a simple 2° amine precursor such as 1 by the
excited state of an appropriate redox catalyst (Figure 2). In
turn, this intermediate should be competent to undergo olefin
addition, resulting in C−N bond formation and the generation
of an adjacent carbon-centered radical. If the reduced form of
the redox catalyst can function as an electron donor to convert
this carbon-centered radical to its corresponding carbanion, a
favorable proton transfer reaction would transform the resulting
Reaction design and optimization. Our reaction design was
grounded in the classical mechanism of aminium-based olefin
aminations (Figure 1) and related Hofmann−Loffler−Freytag
̈
reactions.1 In these methods, the amine starting materials are
first stoichiometrically converted to their N-halogenated or N-
nitrosylated analogues and then subjected to ultraviolet
photolysis in the presence of a strong Brønsted acid.
Mechanistically, the amine precursor undergoes photomediated
N−X homolysis and subsequent N-protonation to furnish the
Received: June 5, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja5056774 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Optimization Studies
entry
catalyst
solvent
yield of 2 (%)
1
2
Ru(bpy)3Cl2
MeCN
DMSO
DMF
4
3
Ru(bpy)3Cl2
3
Ru(bpy)3Cl2
1
4
Ru(bpy)3Cl2
acetone
MeOH
MeCN
DMSO
DMF
1
5
Ru(bpy)3Cl2
43
69
66
38
78
88
6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
7
8
9
acetone
MeOH
10
Optimization reactions were performed on a 0.05 mmol scale. Yields
were determined by GC analysis of the crude reaction mixture relative
to an internal standard. Irradiation was provided by 26 W fluorescent
lamps.
Figure 2. Proposed catalytic cycle for hydroamination.
zwitterion to the desired hydroamination product and close the
catalytic cycle. Such a hydroamination process would be
mechanistically complementary to both the catalytic photo-
redox system recently described by Nicewicz that operates
through olefin oxidation and classical singlet exciplex
mechanisms pioneered by Lewis.7
Gratifyingly, the use of catalyst 4 provided a significant
improvement in reaction efficiency across all of the solvents
evaluated (Table 1, entries 6−9). Methanol was again identified
as the optimal reaction solvent, providing pyrrolidine 2 in 88%
yield in 12 h at rt (Table 1, entry 10). Further optimization
revealed that the use of blue LEDs in place of fluorescent lamps
resulted in shorter reaction times, particularly for reactions run
on preparative scales.
Substrate scope. With these optimized reaction conditions, we
next examined the scope of this hydroamination method. First,
a variety of substituted aniline substrates were investigated. On
a 0.5 mmol scale, model compound 1 cyclized to give 2 in 85%
isolated yield after 10 h at rt (Table 2, entry 1).11 Ortho, meta,
and para substituents on the aniline ring were all well-tolerated
(Table 2, entries 2−4). Similarly, various halogenated and
biaryl anilines were found to provide the desired adducts in
good yields (Table 2, entries 5−7). Notably, a p-methox-
yphenyl-substituted pyrrolidine product, which can be depro-
tected to give the free secondary amine, could also be accessed
using this method (Table 2, entry 8).
We next explored the scope of the styrenyl acceptor. With
catalyst 4, a variety of electron-rich styrenes performed well
despite the more negative potentials ostensibly required for
benzylic radical reduction (Table 2, entries 9 and 10). A
sterically hindered mesityl acceptor also cyclized in good yield
but required 24 h to reach full conversion (Table 2, entry 11).
A range of increasingly electrophilic styrenes were well-
tolerated, resulting in high-yielding cyclizations (Table 2,
entries 12−14). Ortho-, meta-, and para-halogenated styrenes
could all be successfully utilized, providing useful handles for
further product functionalization (Table 2, entries 15−17).
Heterocyclic olefin acceptors were effective, as pyridine-,
furan-, and thiophene-containing substrates could all be
cyclized without difficulty (21−23; Table 3). Similarly,
cyclization reactions to form piperidine 24, morpholine 25,
and piperazine 26 were also found to be successful, though with
somewhat diminished yields. Fused bicyclic systems were
readily synthesized, as demonstrated by the formation of
products 27 and 28. Lastly, various regioisomeric alkyl-
substituted pyrrolidine and piperidine products could be
obtained in high yields, although with low to modest levels
To enable such an approach, an effective catalyst must
possess a range of redox potentials broad enough to mediate
both of the proposed electron transfer events. For a model
substrate such as 1, aryl amine oxidation occurs at potentials
near +0.4 V vs Fc in MeCN, while reduction of a typical
benzylic radical by electron transfer requires potentials near
−1.8 V vs Fc in MeCN.8 In considering these values, we
initially elected to investigate the catalytic viability of
Ru(bpy)3Cl2 (3) in mediating the conversion of 1 to 2. The
metal-to-ligand charge transfer excited state of this archetypal
Ru(II) complex has a reduction potential of +0.39 V vs Fc in
MeCN, while the resulting Ru(I) state has a potential of −1.71
V vs Fc in MeCN; these are comparable to the relevant
potentials of 1.9 Indeed, initial experiments demonstrated that
exposing a solution of 1 and 2 mol % 3 in MeCN to visible-
light excitation from a 26 W compact fluorescent lamp provided
a 4% yield of the desired product 2 after 12 h at room
temperature (rt) (Table 1, entry 1). Further solvent evaluation
was largely unsuccessful, though a markedly improved yield of
43% was obtained in methanol (Table 1, entries 2−5).
In these reactions, small amounts of material resulting from
C−C homocoupling of the cyclized benzylic radical inter-
mediate 1b (Figure 2) were also observed. While consistent
with the proposed mechanism, these oxidative dimerization
adducts are also indicative of an irreversible catalyst
deactivation pathway wherein the Ru catalyst is sequestered
in its reduced state and unable to re-enter the catalytic cycle.
This observation suggested to us that the second electron
transfer between the reduced Ru(I) state of the photocatalyst
and the benzylic radical was not sufficiently rapid to
outcompete this undesired dimerization pathway. Accordingly,
we reasoned that this limitation might be overcome through the
use of a more reducing photocatalyst, such as Ir-
(ppy)2(dtbbpy)PF6 (4). This Ir complex is slightly less
oxidizing than 3 in its excited state (E* = +0.28 V vs Fc),
but its reduced Ir(II) state (E = −1.89 V vs Fc) is nearly 200
mV more reducing than the analogous Ru(I) complex.10
B
dx.doi.org/10.1021/ja5056774 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Substrate Scope
Table 3. Substrate Scope
entry
Ar1
Ar2
product
yield (%)
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2
5
85
77
95
86
91
91
73
54
88
94
63
93
77
73
91
83
83
2-(Me)C6H4
3-(Me)C6H4
4-(Me)C6H4
4-(F)C6H4
2-(Cl)C6H4
4-(Ph)C6H4
4-(MeO)C6H4
C6H5
3
6
4
7
5
8
6
9
7
10
11
12
13
14
15
16
17
18
19
20
8
9
4-(MeO)C6H4
4-(tBu)C6H4
2,4,6-(Me)3C6H2
4-(F)C6H4
10
11
12
13
14
15
16
17
C6H5
C6H5
C6H5
C6H5
4-(CF3)C6H4
4-(CN)C6H4
2-(Cl)C6H4
C6H5
C6H5
C6H5
3-(Br)C6H4
C6H5
4-(Br)C6H4
Reactions were performed on a 0.5 mmol scale. Yields are for isolated
materials following chromatography.
of diastereoselectivity (29−35; Table 3). Intermolecular
couplings were found to be unsuccessful under the standard
reaction conditions, likely because of the inability of
bimolecular C−N bond formation to outcompete favorable
electron back-transfer from the Ir(II) complex to the aminium
ion intermediate.
Mechanistic studies. Having outlined the scope of this
hydroamination process, we next focused on evaluating specific
aspects of the proposed reaction mechanism. First, lumines-
cence quenching assays demonstrated that the electron transfer
between the excited state of Ir(ppy)2(dtbbpy)PF6 (E* = +0.28
V vs Fc in MeCN) and aniline 1 (E ≈ +0.4 V vs Fc in MeCN)8a
that furnishes the key aminium intermediate is kinetically facile
(kτ = 1200 M−1). As all subsequent steps in the proposed
catalytic cycle involve changes in bonding or oxidation state at
the benzylic position of the styrenyl acceptor, we reasoned that
a Hammett analysis might shed light on the identity of the
turnover-limiting step. In accord with literature precedent, we
expected that rate-limiting addition of the electrophilic
aminium radical to the π-nucleophilic olefin should result in a
negative ρ value.12 In contrast, the rates of electron transfer
leading to benzylic anion formation would be expected to trend
with the potentials of the radical intermediates, resulting in a
positive Hammett slope. A comparison of hydroamination rates
for a series of para-substituted styrene acceptors revealed a
linear correlation with σp (R2 = 0.96) and a modestly negative ρ
value of −0.56, consistent with turnover-limiting C−N bond
formation (see the Supporting Information). Notably, as
neutral aminyl radicals exhibit positive ρ correlations in their
addition reactions to para-substituted styrenes, this result also
provides strong support for the involvement of a protonated
aminium radical cation in the addition step.13−15
Reactions were performed on a 0.5 mmol scale. Yields are for isolated
materials following chromatography. Diastereomeric ratios were
determined by 1H NMR analysis of the crude reaction mixtures.
The reaction was run in acetone. The cis isomer was the major
product.
a
b
experiment wherein equal concentrations of 1 and a p-CN-
substituted styrene (Table 2, entry 14) were placed in the same
flask and subjected to the standard hydroamination conditions.
Significantly, the ratio of observed rate constants in the
competition experiments (kH/kCN = 4) differs measurably from
the ratio obtained from independent reactions of each substrate
(kH/kCN = 2.6). This outcome is not consistent with irreversible
amine oxidation, for which an identical ratio would be expected.
As a corollary to this understanding, the observed rate constant
and quantum yield for each substrate should be directly
proportional.
Lastly, though it occurs after the rate-limiting step, additional
support for the proposed electron transfer/proton transfer
mechanism for radical reduction was obtained through solvent-
labeling studies. Specifically, we observed that cyclization
products from reactions performed in CD3OH exhibited no
deuterium incorporation at the benzylic position, while
reactions carried out in CH3OD were fully deuterium-labeled.17
These observations argue against a solvent-mediated hydrogen
atom transfer mechanism for radical reduction18,19 but are
consistent with proton transfer to a transient carbanion
acceptor.
Notably, the interpretation of the Hammett analysis
presented above is valid only if the initial excited-state electron
transfer step is reversible relative to C−N bond formation.16 To
substantiate this assumption, we carried out a competition
C
dx.doi.org/10.1021/ja5056774 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Gahr, M. J. Am. Chem. Soc. 1989, 111, 6465. (d) Lewis, F. D.; Bassani,
D. M.; Burch, E. L.; Choen, B. E.; Engleman, J. A.; Reddy, G. D.;
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(8) (a) Cyclic voltammetry of 1 exhibited an irreversible oxidation
with a peak potential at +0.43 V vs Fc in MeCN. Details are included
in the Supporting Information. (b) Wayner, D. D. M.; Griller, D. J.
Am. Chem. Soc. 1985, 107, 7764. Because of the proximal ammonium
ion, the given benzylic radical potential likely represents a lower
bound.
In conclusion, we have developed a novel photoredox
protocol for intramolecular olefin hydroamination that operates
through sequential catalyst-mediated electron transfer steps
spanning a range of potentials of over 2.2 V. This work
represents a rare example of the use of aminium radical cations
derived from simple amine precursors in catalytic C−N bond
formation. Efforts are currently underway to apply the elements
of reaction design presented here to other catalytic olefin
amino-functionalization processes.
(9) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.;
Von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85.
ASSOCIATED CONTENT
■
(10) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R.
A.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
(11) Reactions of 1 on a 2.5 mmol scale proceeded in 80% isolated
yield after 21 h under the standard reaction conditions.
(12) Mojelsky, T.; Chow, Y. L. J. Am. Chem. Soc. 1974, 96, 4549.
(13) Michejda, C. J.; Campbell, D. H. J. Am. Chem. Soc. 1979, 101,
7687.
(14) Consistent with this view, proton transfer from an N−H bond
in the aminium ion (pKa ≈ 17 in MeCN) or an adjacent methylene
C−H bond (pKa ≈ 18 in MeCN) to the starting material (pKa ≈ 11 in
MeCN for N-methylanilinium ion) is significantly endergonic.
(15) A negative ρ value might also result from protonation of
increasingly basic carbanion intermediates. However, cyclization rates
of 1 evaluated in either CH3OH or CD3OD resulted in a kH/kD of 1.1,
indicative that C−H bond formation is not rate-limiting.
(16) Back electron transfer from the reduced Ir(II) complex to the
aminium radical is exergonic by ∼2.3 V.
S
* Supporting Information
Experimental procedures, characterization data, and kinetic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
rknowles@princeton.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Princeton University. Istvan
Pelczer is acknowledged for NMR assistance.
(17) For reactions run in CH3OD, the deuterium-bearing stereo-
center was formed as a 1:1 mixture of diastereomers.
(18) Mizuta, S.; Verhoog, S.; Engle, K. M.; Khotavivattana, T.;
O’Duill, M.; Wheelhouse, K.; Rassias, G.; Medebielle, M.; Gouverneur,
V. J. Am. Chem. Soc. 2013, 135, 2505.
(19) Consistent with this view, hydrogen atom transfer to the
benzylic radicals from the C−H bonds in MeOH is endergonic by ∼7
kcal/mol.
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dx.doi.org/10.1021/ja5056774 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX