Catalytic asymmetric ±-acylation of tertiary amines mediated by a dual catalysis mode: N-heterocyclic carbene and photoredox catalysis

Article abstract of DOI:10.1021/ja3030164

Cross-coupling reactions are among the most widely utilized methods for C-C bond formation; however, the requirement of preactivated starting materials still presents a major limitation. Methods that take direct advantage of the inherent reactivity of the C-H bond offer an efficient alternative to these methods, negating the requirement for substrate preactivation. In this process, two chemically distinct activation events culminate in the formation of the desired C-C bond with loss of H₂ as the only byproduct. Herein we report the catalytic asymmetric ±-acylation of tertiary amines with aldehydes facilitated by the combination of chiral N-heterocyclic carbene catalysis and photoredox catalysis.

Full text of DOI:10.1021/ja3030164

Communication
pubs.acs.org/JACS
Catalytic Asymmetric α-Acylation of Tertiary Amines Mediated by a
Dual Catalysis Mode: N-Heterocyclic Carbene and Photoredox
Catalysis
Daniel A. DiRocco and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
decades, but only recently have chemists taken advantage of
ABSTRACT: Cross-coupling reactions are among the
most widely utilized methods for C−C bond formation;
however, the requirement of preactivated starting materials
still presents a major limitation. Methods that take direct
advantage of the inherent reactivity of the C−H bond offer
an efficient alternative to these methods, negating the
requirement for substrate preactivation. In this process,
two chemically distinct activation events culminate in the
formation of the desired C−C bond with loss of H2 as the
only byproduct. Herein we report the catalytic asymmetric
α-acylation of tertiary amines with aldehydes facilitated by
the combination of chiral N-heterocyclic carbene catalysis
and photoredox catalysis.
these properties to solve long-standing problems in organic
synthesis.10 We were particularly interested in the use of visible-
light photoredox catalysis to generate highly reactive iminium
ions from tertiary amines, which may be trapped with a variety
of nucleophiles, a formal C−H activation, and potential
generation of a new C−C bond.11,12 The use of visible-light
photoredox catalysis to generate these reactive species is
attractive in the sense that no preactivation of the substrate is
required and the reaction conditions are mild, thereby allowing
for potential compatibility between multiple catalytic pathways.
The generation of acyl anion or homoenolate equivalents
from aldehydes represents a powerful strategy in N-heterocyclic
carbene (NHC) catalysis, wherein an aldehyde is converted to a
nucleophilic species under very mild conditions. These species
have been demonstrated to be competent nucleophiles in a
plethora of reactions.13 We envisioned that the union of chiral
NHC catalysis of aldehydes with visible-light photoredox
catalysis of tertiary amines could be achieved (Figure 1),
he efficient and selective construction of C−C bonds has
T
been a long-standing challenge in organic synthesis.
Traditionally, the formation of C−C bonds has relied primarily
on preactivated starting materials.1 Although these reactions
find broad use in organic synthesis, the preactivation of each
substrate generally requires at least one chemical manipulation
to prepare, and stoichiometric quantities of metal salts are often
generated as byproducts. For this reason, the area of transition-
metal-catalyzed C−H activation has emerged as one of the
fastest growing fields in organic chemistry.2,3 The impact that
C−H activation has had on chemical synthesis goes without
saying; however, these methods still rely heavily on partial
functionalization of one partner to generate the C−C bond.
Recently, considerable effort has been invested in the
development of methods that do not rely on any prior
activation but instead take direct advantage of the inherent
reactivity of the C−H bond.4,5 Among these reports, few
methods have been shown to activate a prochiral sp3 C−H
bond selectively, offering access to chiral nonracemic coupling.6
Of particular note is the ability of a catalyst to activate the α-
C(sp3)−H bond of a tertiary amine, which is capable of
forming a new C−C bond in the presence of a suitable
nucleophile.7 Forming this new C−C bond asymmetrically has
been challenging, and only recently has a highly enantiose-
lective method been developed.8
Figure 1. Proposed dual catalysis mode.
resulting in a direct asymmetric α-acylation of tertiary
amines.14,15 The anticipated coupling reaction would rely on
two chemically distinct activation pathways, forming a C−C
bond stereoselectively while producing H2 (in the form of H2O
in the presence of a weak oxidant) as the only byproduct. The
biological relevance of these products as well as the synthetic
utility of the derived 1,2-aminoalcohols makes this a desirable
transformation.
An emerging strategy for the activation of C−H bonds is by
single electron transfer (SET) processes. The ability of light to
induce these types of chemical transformations has been known
since the early 20th century.9 Photoredox catalysis, which takes
advantage of the unique photophysical properties of organic
molecules and organometallic complexes, has been used for
Received: March 28, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3030164 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Proposed Catalytic Cycles
We initially proposed that irradiation of [Ru(bpy)3]2+ with
blue light would populate the *[Ru(bpy)3]2+ excited state, from
which the powerful oxidant [Ru(bpy)3]3+ (1.29 V vs SCE)
should be generated in the presence of a suitable oxidative
quencher (Scheme 1).16 Single-electron oxidation of a tertiary
amine followed by hydrogen atom abstraction would then
result in the formation of iminium ion I, returning [Ru-
(bpy)3]2+ to the catalytic cycle. Interaction of an NHC with an
aldehyde would generate the nucleophilic Breslow intermediate
II, which could then intercept iminium ion I, forging a new C−
C bond. Elimination of the NHC from III would provide the α-
amino ketone IV and allow the NHC V to re-enter the catalytic
cycle.
identical conditions (Table 1, entry 4). Although optimal
results were achieved using a stoichiometric quantity of m-
DNB, comparable results were obtained with substoichiometric
a
Table 1. Catalyst and Reaction Optimization
We realized at the outset that oxidation of the Breslow
intermediate II or NHC V by [Ru(bpy)3]3+ could result in
unproductive pathways (formation of carboxylic acid or catalyst
death) because of the similar redox potentials of this catalyst
scaffold and tertiary amines. Furthermore, the more electro-
philic iminium ion could react preferentially with the carbene
catalyst, generating an aza-Breslow intermediate. A study of aza-
Breslow intermediates derived from iminium salts that was
recently disclosed by our group provided evidence that these
intermediates are stable resting states for the catalyst.17 In the
presence of a weak acid, this process is reversible, and the active
catalyst can re-enter the catalytic cycle.
We began our investigation by evaluating the addition of
butanal (1) to N-phenyltetrahydroisoquinoline (2) (Table 1).
After careful manipulation of the reaction conditions, we were
pleased to find that the desired reactivity could be realized
using [Ru(bpy)3]Cl2 as the photocatalyst in the presence of m-
dinitrobenzene (m-DNB) and a chiral NHC under irradiation
with blue light. Our aminoindanol-derived catalyst scaffold
proved to be optimal for this application; however, low
enantioselectivity was initially observed using known catalysts.
Exploration of the steric and electronic properties of the NHC
through derivatization of the N-aryl substituent enabled the
discovery of catalyst 4e containing the 2,4,6-tribromophenyl
group. This catalyst combination provided the optimum yield
and high enantioselectivity (92% ee) of α-amino ketone 3
(Table 1, entry 2).
a
Reactions were conducted with 1.5 equiv of 1 and 1.0 equiv of 2 at
b
During our initial studies, we found the addition of weak
organic oxidants to be essential for achieving high catalytic
efficiency in this process. In the absence of m-DNB, only a 13%
yield of the desired product was obtained under otherwise
ambient temperature. Based on consumption of 2 as determined by
NMR analysis using an internal standard. Based on NMR analysis
using an internal standard. Determined by HPLC using a chiral
stationary phase.
c
d
B
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Journal of the American Chemical Society
Communication
a b
,
amounts. Furthermore, no detectable products of m-DNB
reduction could be identified upon completion of the reaction.
Nitrobenzenes are known oxidative quenchers of the *[Ru-
(bpy)3]2+ excited state;18 thus, the role of m-DNB is likely to
induce an oxidative quenching cycle of *[Ru(bpy)3]2+ under
these conditions, with adventitious oxygen likely being the
Table 2. Reaction Scope
20
terminal oxidant.19 Stronger oxidants such as BrCCl3 led to
complete consumption of the amine but provided none of the
desired product, presumably because of oxidative decom-
position of the NHC catalyst; thus, a judicious choice of the co-
oxidant is crucial. Use of a household 15 W fluorescent light
bulb as the light source produced a moderate yield of the
desired product (63%; Table 1, entry 6), while rigorous
exclusion of light resulted in <5% product formation,
suggesting the participation of the *[Ru(bpy)3]2+ excited
state in the catalytic cycle. In the presence of m-DNB but the
absence of [Ru(bpy)3]Cl2, a much slower background reaction
was observed (32%). In this case, m-DNB may function as a
weak sensitizer.21,22
During our initial screening of conditions with catalyst 4e, we
achieved full conversion of the amine (>95%) but obtained
only a poor yield of the desired product (12%) using
acetonitrile as the reaction solvent (Table 1, entry 7). Under
these conditions, aza-Breslow intermediate 5, derived from
trapping of the active catalyst 4e with the in situ-generated
iminium ion, precipitated from the reaction medium (Figure 2).
a
Reactions were conducted with 1.5 equiv of aldehyde, 1.0 equiv of
amine, and 1.2 equiv of m-DNB at ambient temperature without
b
exclusion of oxygen. NHCs were generated from the corresponding
c
azolium salts using NaH; see the Supporting Information. Isolated
d
yields after chromatography. Determined by HPLC using a chiral
stationary phase. The absolute stereochemistry was determined by X-
ray analysis: see the Supporting Information.
Figure 2. X-ray structure of isolated catalyst resting state 5. Ellipsoids
are drawn at the 75% probability level.
aldehyde, which underwent smooth conversion, albeit with
modest enantioselectivity (59%). Additional functionality, such
as thioethers, esters, and protected amines, could also be
incorporated into the aldehyde tether without a deleterious
effect on either the efficiency or enantioselectivity. Derivatives
of the N-aryltetrahydroisoquinoline were also investigated.
Electron-releasing substituents on either the backbone or the
N-aryl group were well-tolerated; however, electron-with-
drawing groups led primarily to products of competing radical
dimerization processes.23
In conclusion, we have identified a productive dual-catalysis
mode that now enables the catalytic asymmetric α-acylation of
tertiary amines. The direct conversion of C(sp3)−H bonds to
C−C bonds in a highly enantioselective manner has been a
long-sought transformation that has received a great amount of
The low yield in this case is attributed to the poor solubility of
this intermediate in acetonitrile, effectively removing it from the
catalytic cycle. To test the catalytic relevance of this
intermediate, 5 was resubjected to the original reaction
conditions and provided ketone 3 in 76% yield and 92% ee,
similar to that observed using the carbene directly. Catalytic
amounts of carboxylic acid impurities, either present or
generated under the reaction conditions, were likely responsible
for catalyst turnover.
We found that aliphatic aldehydes reacted efficiently,
affording the desired α-amino ketones in good yield and high
enantioselectivity (Table 2). α-Branched aldehydes generally
led to a loss in reactivity, except for cyclopropanecarbox-
C
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Journal of the American Chemical Society
Communication
(16) Campagna, S.; Puntoriero, F.; Nastasi, F.; Bergamini, G.;
Balzani, V. Top. Curr. Chem. 2007, 280, 117.
(17) DiRocco, D. A.; Oberg, K. M.; Rovis, T. J. Am. Chem. Soc. 2012,
attention in the past decade. Through the powerful
combination of NHC catalysis and visible-light photoredox
catalysis, the direct asymmetric functionalization of C(sp3)−H
bonds with aldehydes is now accessible. The extension of this
methodology to a broad scope of tertiary amines is currently
underway.
134, 6143.
(18) Bock, C. R.; Connor, J. A.; Guitierrez, A. R.; Meyer, T. J.;
Whitten, D. G.; Sullivan, B. P.; Nagle, J. K. J. Am. Chem. Soc. 1979,
101, 4815.
(19) Under anaerobic conditions (Table 1, entry 11), the terminal
oxidant is likely m-DNB.
ASSOCIATED CONTENT
■
S
* Supporting Information
(20) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J.
Org. Lett. 2012, 14, 94.
Full experimental details, spectroscopic data for all new
compounds, and crystallographic data for 5 (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(21) It is known that amines form electron donor−acceptor (EDA)
complexes with m-DNB that absorb in the visible spectrum. See:
Siddiqi, Z. M.; Pathania, D. Talanta 2003, 60, 1197.
(22) The azolium precatalyst may also be used in the presence of
base. In the absence of exogenous base, tetrahydroisoquinoline 2 is
sufficiently basic to induce formation of the carbene (Table 1, entries
8−10).
AUTHOR INFORMATION
■
Corresponding Author
rovis@lamar.colostate.edu
(23) Lohmann, J.-J.; Seebach, D.; Syfrig, M. A.; Yoshifuji, M. Angew.
Chem., Int. Ed. Engl. 1981, 20, 128.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIGMS for generous support of this research (GM
72586). T.R. thanks Amgen and Roche for unrestricted
support. We thank Kevin Oberg (CSU) for crystallographic
analysis and Donald Gauthier (Merck) for a generous gift of
aminoindanol.
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D
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