Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones

Article abstract of DOI:10.1002/anie.202105354

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C?C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

Full text of DOI:10.1002/anie.202105354

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and
α-Amino Ketones
Authors: Karl Scheidt, Anna V. Bay, Keegan P. Kitzpatrick, Gisela A.
González-Montiel, Abdikani Omar Farah, and Paul Ha-Yeon
Cheong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202105354
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10.1002/anie.202105354
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COMMUNICATION
Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and
α-Amino Ketones
Anna V. Bay,[a] Keegan P. Fitzpatrick,[a] Gisela A. González-Montiel,[b] Abdikani Omar Farah,[b] Paul Ha-
Yeon Cheong,*[b] Karl A. Scheidt*[a]
[a]
A. V. Bay, K. P. Fitzpatrick, K. A. Scheidt*
Department of Chemistry
Northwestern University
2145 Sheridan Road, Evanston, IL 60208
E-mail: scheidt@northwestern.edu
G. A. González-Montiel, A. O. Farah, P. H.-Y. Cheong*
Department of Chemistry
[b]
Oregon State University
153 Gilbert Hall, Corvallis, OR 97331 2145
E-mail: paulc@science.oregon-state.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: Single-electron N-heterocyclic carbene (NHC) catalysis
has gained attention recently for the synthesis of C–C bonds. Guided
by density functional theory and mechanistic analyses, we report the
light-driven synthesis of aliphatic and α-amino ketones using single-
electron NHC operators. Computational and experimental results
reveal that the reactivity of the key radical intermediate is substrate-
dependent and can be modulated through steric and electronic
parameters of the NHC. Catalyst potential is harnessed in the visible-
light driven generation of an acyl azolium radical species that
undergoes selective coupling with various radical partners to afford
diverse ketone products. This methodology is showcased in the direct
late-stage functionalization of amino acids and pharmaceutical
compounds, highlighting the utility of single-electron NHC operators.
limited by their inability to engage sp3 electrophiles until the
merger of carbene catalysis with single-electron chemistry.
The recent renaissance of single-electron chemistry via
photoredox catalysis and electrocatalysis has further enabled
bond connections that were previously inaccessible using
traditional pathways. While radical chemistry is well-established,
the revival of photocatalysis and electrosynthesis has accelerated
modern synthetic chemistry.[8] These advances have furnished
numerous strategies for the synthesis of ketones (Figure 1B).[9]
For example, photoredox/nickel dual catalysis has gained
attention for its ability to synthesize ketone moieties via cross-
coupling between nucleophilic acyl radicals and other radical
species (e.g., aryl radicals from aryl halides).[10] New modes of
reactivity have stemmed from these advances in radical chemistry,
and the merging of single-electron chemistry with umpolung
reactivity has facilitated even more opportunities.
There is an ongoing need for mild synthetic methods with
broad functional group tolerance for the construction of key bonds
in natural products, pharmaceutical compounds, and organic
materials. In particular, the formation of carbonyl-containing
scaffolds remains a priority due to their synthetic utility and high
prevalence in medicinally active compounds (Figure 1A).[1] While
many living organisms naturally synthesize ketones through
ketogenesis, photosynthesis, etc., chemists have developed
numerous approaches to generate ketones through the formation
of C–C bonds, among other methods (Figure 1B).[2] Dating back
to the 19th century, conventional two-electron methods to access
ketones from various acyl electrophiles often require
organometallic reagents (Grignard),[3] Lewis acids or strong protic
acids (Friedel-Crafts acylation),[4] or transition-metal catalysts
(cross-coupling, Figure 1B).[5] Although their utility in synthetic
chemistry is undisputed, these protocols are limited in some
cases by low regioselectivity, poor functional group tolerance, and
generation of corrosive waste. Alternatively, umpolung reactivity
offers a distinct alternative to standard two-electron chemistry for
the synthesis of ketones as well as other C–C and C–X bonds that
would not otherwise be possible (Figure 1B).[6] In recent decades,
N-heterocyclic carbenes (NHCs) have transformed the field of
umpolung chemistry and emerged as a versatile tool for the
catalytic generation of acyl anions, enolates, and homoenolates.[7]
The scope of NHC-catalyzed transformations, however, was
While NHC-derived radical reactivity dates back to the early
2000s,[11] there has been a marked increase in single-electron
NHC-catalyzed methods for the construction of C–C bonds
reported in recent years (Figure 1B).[12] In 2019, Ohmiya and
coworkers described the coupling of a persistent Breslow
intermediate-derived radical with a transient alkyl radical.[13] This
pioneering example of thermal single-electron NHC catalysis
inspired the development of similar protocols by the groups of
Li,[14] Wang,[15] and Hong,[16] among others.[17]
Concurrent with this work, light-driven carbene methods by
our group,[18] Hopkinson,[19] Studer,[20] and others demonstrated
complementary reactivity to established two-electron carbene
catalysis.[20c, 21] In 2020, Hopkinson and coworkers reported a
light-activated, NHC-catalyzed Diels-Alder reaction to construct
isochromanone derivatives.[19a] Our group reported the first
single-electron reduction of an acyl azolium for the formation of
ketones from activated carboxylic acids.[18a] Radical-radical
coupling of a Hantzsch ester-derived alkyl radical with an acyl
azolium radical was achieved via a reductive quenching cycle.
While this work highlighted the utility of reductively generated
single-electron NHC operators, the scope was primarily limited to
aryl substrates, a widespread limitation in the majority of recent
radical NHC processes (Figure 1C).
1
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10.1002/anie.202105354
Angewandte Chemie International Edition
COMMUNICATION
examples of ketones in bioactive molecules
A
S
O
O
O
O
OMe
O
O
H
N
Me
Me2N
Me
N
N
Ph
Me
F
Ph Ph
HO2C
Me
Bn
O
O
O
ketone
prasugrel
methadone
strategies to access ketones
nabumetone
keto-ACE
B
O
O
standard 2 e–
Grignard reaction
Friedel-Crafts acylation
cross-coupling
standard 1 e–
decarboxylation
Ni/Pd catalysis
R
δ–
R
+
M
+
or
δ+
X
acyl electrophile
acyl radical
R
O
R
O
O
δ+
R
umpolung 2 e–
NHC-catalyzed 1 e–
X
R
+
NHC catalysis
cyanide catalysis
redox-active ester
acyl azolium
or
+
δ–
or
X
NHC
acyl anion
NHC radical
R
R
acyl azoliums as radical precursors
Az-A Az-B
C
+
CDI
previous work
O
this work
R
Mes
R
Me
Me
N
N
N
N
O
Me
BF4
N
O
O
O
I
N
Me
N
N
OH
R
N
N
N
N
R1
R2
R
R2
+
Me
[ORP]
R
R1
Me
Me
primarily limited to
aryl ketones
aliphatic and α-amino
control of steric and electronic parameters
ketones
Figure 1. (A) Selected examples of ketones in pharmaceutically relevant compounds. (B) Standard approaches for ketone synthesis. (C) Acyl azolium radicals for
the construction of aryl, alkyl, and α-amino ketones; ORP = oxidatively generated radical precursor, CDI = carbonyldiimidazole.
The work described herein uses in-depth computational
studies to shed light on key reactive intermediates, thus guiding
hypothesis-driven experimentation to greatly expand this ketone
synthesis platform (Figure 1C). In 2019, Bertrand and Martin
disclosed a detailed study on the key radical intermediates in
oxidative NHC processes.[22] Contrary to many mechanistic
proposals in the literature, their studies suggest that these
oxidative pathways proceed through single-electron transfer
(SET) from the corresponding electron-rich enolate of the Breslow
intermediate or through proton-coupled electron transfer (PCET)
from the enol. They conclude that the relevant radical
intermediates in these reactions have spin density concentrated
primarily on the carbene carbon (C2, 40%) and not on the
carbonyl carbon (C1, 10%).[22] While these results do not directly
translate to our system due to substantial differences in radical
generation (i.e., thermal vs. photochemical), their work provoked
important mechanistic questions regarding the nature of single-
electron NHC operators.
the reactivity of aryl and aliphatic systems, respectively (Figure
1C, R1 = H and R2 = Ph, respectively). To analyze the steric and
electronic impact of the NHC, our previously optimized NHC
precursor (Az-A) and sterically encumbering N-mesityl
pyrrolotriazolium (Az-B), which has been employed in other
single-electron NHC reports,[20] were the primary focus of this
study (Figure 1C).
An initial spin density analysis of the optimized aliphatic and
aryl acyl azolium radical structures (III) with Az-A or Az-B
revealed significant radical character on both C1 and C2 (Figure
2A, see SI, page S53). It is often assumed that the spin density
population is concentrated on C1 and, as a result, selective
coupling occurs with the C1-centered radical.[12] However, we
propose that there are at least two operative radical-radical
coupling pathways: 1) coupling at C1, which directly leads to
product, and 2) coupling at C2, which may lead to unproductive
off-cycle side reactivity.
Analysis of computed isodesmic reactions suggests that
radical stability at C1 and C2 may be substrate dependent (see
SI, page S56-S57). The extended conjugation in aryl substrates
stabilizes the radical at C1, minimizing the effect that NHC
structure has on reactivity. Alternatively, for aliphatic substrates,
there is increased radical stability at C2 due to the lack of
substrate conjugation, thus making reactivity more NHC-
dependent. This C2 stability likely contributed to the limited
reactivity of aliphatic substrates in our previous work.[18a]
Based on Bertrand’s report,[22] our previous results,[18a] and a
key report from Ohmiya,[23] we hypothesized that both electronic
and steric alterations to the NHC could impact radical stability and
accessibility, thus imparting control over reactivity. To explore this
possibility, we performed density functional theory investigations
with PBE[24]/6-31G*[25] & LANL2DZ[26] (for Cs) level of theory and
SMD solvation corrections[27] in acetonitrile as implemented in
Gaussian 16. Acyl azoliums derived from benzoic acid and
hydrocinnamic acid were chosen as the model substrates to study
2
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10.1002/anie.202105354
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COMMUNICATION
A
III of Az-A
C1 and C2 accessible
C1 accessible
C2 hindered
III of Az-B
O
X
R
OC1
N
O
N
C2
Az
Me
C2
Me
C1
C2
O
O C1
N
N
N
N
C1
R
R
N
N
Me
Me
C2
CH–π
N
N
R
N
R
N
Me
Me
Az-A
Az-B
Me
Me
Me
Me
inefficient
efficient
R = CH2Ph
R = CH2Ph
stabilized at C2 by azolium
kinetically accessible at C1
no site selectivity
site selectivity
B
O
O
O
Az
Cs2CO3
CDI
desired ketone
Ph
N
R2
product
N
Ph
OH
Ph
1a
N
N
standard conditions
N
with Az-A
1 + ORP
Az, Cs2CO3, PC
CH3CN, blue LEDs
Cs
R1
N
TS-IV (13.4)
TS-I
N
I (0.0)
‡
R2
O
N
R2
N
R
O
O
N
N
N
R2
Ph
R1
N
N
Ph
TS-III
N
N
N-HETEROCYCLIC
CARBENE CYCLE
R1
[ORP]
R1
X
with Az-B
IVC1 (9.4)
II (7.6)
R2
[ORP]
IrII
R2
N
O
TS-III
(21.1)
TS-II
R
O
N
N
PHOTOCATALYST
CYCLE
R1
N
Ph
R2
IVC2 (9.2)
[ORP]
IrIII
N
2a
*
IrIII
N
R2
R1
III (16.1)
Figure 2. (A) Radical coupling accessibility model for aliphatic acyl azoliums with spin density distributions of optimized aliphatic acyl azolium structures (R = CH2Ph).
(B) Proposed mechanism for the combined NHC/photoredox-catalyzed construction of aliphatic and α-amino ketones. Reported energies are for Az-B in kcal/mol.
We then investigated whether NHC steric parameters can
influence productive coupling at C1 for aliphatic substrates. When
we juxtaposed acyl azolium radicals III derived from Az-A and Az-
B, different conformations were observed (see SI, page S58).
Due to the torsional flexibility of the aliphatic substrate and the
orthogonality of the mesityl group, Az-B rotates 180º with respect
to the carbonyl to form a stabilizing CH-π interaction (1.5 kcal/mol
more stable), potentially leading to efficacy of Az-B over Az-A
(Figure 2A-B). Moreover, this interaction rigidifies the
conformation, enforces the steric encumbrance imposed by the
mesityl ring, and, thus, may facilitate favorable coupling at
kinetically accessible C1 (Figure 2A).[28]
approaches III to give IVC1 and IVC2 via a single three-membered
transition state (TS-III, ∆G‡ = 21.1 kcal/mol for benzyl radical) with
bonds forming between the benzyl radical center, C1 and C2. We
computed the potential energy surfaces (PES) around TS-III for
the aliphatic acyl azolium radicals III of Az-A and Az-B with the
benzyl radical to further rationalize which carbon, C1 or C2, will
undergo the radical-radical coupling (Figure 3, see SI, pages
S60-S62). The Az-A PES reveals downhill energy paths leading
to both C1- and C2-coupling products, suggesting a non-selective
reaction wherein considerable IVC2 is formed. For Az-B, the PES
features a downhill energy path to desired C1. In contrast, an
uphill barrier exists on the path to undesired C2, which translates
to a preference of 2.3 kcal/mol for C1 over C2, in line with our
hypothesis that the mesityl group of Az-B may hinder coupling at
the C2 center. These results suggest a greater likelihood for
efficient C1-coupling over inefficient C2-coupling using Az-B as
the NHC precursor (IVC1 and IVC2, ∆G = 9.4 and 9.2 kcal/mol,
respectively). Finally, release of the NHC catalyst (TS-IV, ∆G‡ =
13.4 kcal/mol) affords the ketone product (∆G = –16.3 kcal/mol).
Given these results, we propose a combined NHC and
photocatalytic mechanism for the synthesis of aliphatic ketones
(Figure 2B). Operating through
a
reductive quenching
photocatalytic cycle, the radical coupling partner is accessed via
a single-electron oxidation event with the excited photocatalyst.
Subsequent single-electron reduction of the acyl azolium (II, ∆G
= 7.6 kcal/mol) furnishes an open-shell acyl azolium radical
species (III, ∆G = 16.1 kcal/mol) with the radical distributed
between C1 and C2. The radical coupling partner then
This proposed mechanism thus directed experimental efforts
to explore and validate our hypotheses (see SI, page S13-S16).
3
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10.1002/anie.202105354
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COMMUNICATION
into the alkene, unsaturated 3g was successfully isolated. The
reaction with cyclopropane acyl imidazoles furnished the
respective ketone products (3i,j) in good yields, an unexpected
result that provides additional mechanistic insight into the nature
of III. Compared to traditional acyl radicals, which have
demonstrated radical clock-like reactivity,[29] the distribution of
radical density between C1 and C2 affords increased stability,
thus illustrating a significant advantage of NHC-based radical
chemistry. The chemoselectivity of this process was
demonstrated in the isolation of ester-containing 3k, illustrating a
bond construction that suffers from functional group
incompatibility using conventional methods of ketone formation
(e.g., Grignard reaction, see SI, page S17). In general, use of Az-
B instead of Az-A with aliphatic substrates resulted in significant
Table 1. Substrate scope.[a]
Figure 3. Computed potential energy surfaces for benzyl radical coordination to
C1 or C2 of the aliphatic acyl azolium radical (III) with Az-A or Az-B.
A survey of selected azoliums revealed key trends in reactivity:
yields decreased with electron withdrawing or highly conjugated
NHC substituents and increased with sterically encumbering
substituents. As predicted by our mechanistic analysis, the
delicate balance of steric and electronic properties offered by Az-
B enabled the benzylation of 1a to proceed with significantly less
side reactivity compared to Az-A (see SI, page S15) and afforded
the desired aliphatic ketone 3a in 72% yield (Table 1).
Given this result, the scope of aliphatic acyl imidazoles
amenable to benzylation was investigated using Az-B as the NHC
precursor (Table 1). Substituted hydrocinnamic acyl imidazoles
were tolerated to provide the respective ketones in good yields
(3b,c). The reaction proceeded with nitrogen- and ether-
containing substrates, affording the desired products (3d,e,h) in
good-to-excellent yields. Albeit low-yielding due to radical addition
[a] Reaction used 2a (R1 = CO2Et) and PC-1 ([Ir(dF[CF3]ppy)2(dtbpy)]PF6)
unless otherwise noted. [b] Reaction used 2b and PC-2 (3DPAFIPN). [c]
Reaction used 2a (R1 = CN) and PC-3 (4CzIPN). See SI for reaction details.
4
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10.1002/anie.202105354
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COMMUNICATION
increases in yield (e.g., 32% increase for 3a and 64% increase for
3d) and enabled inclusion of substrates that demonstrated little-
to-no reactivity using Az-A (e.g., 3g and 3k).
amino acids (e.g., N-Boc-L-tryptophan), and others were suitable
for direct benzylation to afford α-amino ketones 4a-4g in good-to-
excellent yields (Table 2A).[32] Even under the slightly basic
conditions of this reaction, α-amino ketone 4b was prepared
directly from N-Boc-L-valine with moderate stereoretention (87:13
er), suggesting that alkylation of chiral carboxylic acids is possible
without complete erosion of stereochemistry.
To further increase the practicality and overall utility of this
method, the reaction with other radical coupling partners was also
studied.[30] In addition to their ease of preparation, bis-catecholato
silicates are bench stable and offer excellent substrate diversity.
Minor modification of the reaction conditions enabled reactivity to
be achieved using bis-catecholato silicates as an alternative
radical precursor (2b), affording selected ketone products in
comparable yields to those using Hantzsch esters (Table 1). In
addition to tolerating different radical precursors as coupling
partners, it was also determined that an organophotocatalyst (PC-
2) could be substituted for PC-1, providing a more cost-effective
Lastly, the late-stage functionalization of bioactive
compounds was accomplished using the same one-step protocol
(Table 2B). The benzylation of a dipeptide was successful (4h),
suggesting that this methodology may be suitable for converting
short peptides into their ketone counterparts with additional
optimization. Naproxen, an anti-inflammatory drug used to treat
bone disorders, was directly benzylated to afford the
corresponding ketone (4i) in excellent yield. The late-stage
functionalization of heterobicyclic D-biotin, a vitamin essential to
metabolism, was also achieved to give 4j in moderate yield,
further highlighting the synthetic utility of this process.
variant for alkylation. A survey of Hantzsch esters (2a, R1
=
CO2Et), Meyer nitriles (2a, R1 = CN), and silicates (2b) enabled
addition of various functional groups while demonstrating the
array of coupling partners viable in this reaction (Table 1). Benzyl
Hantzsch esters containing electron-withdrawing and electron-
donating groups afforded ketones (3l-3o) in good yields.
Carbazole-containing 3q was isolated in high yield, offering a
potential method to tag molecular probes for fluorescence
studies.[31] The reaction proceeded smoothly with sterically
congested radicals (3p,r) as well as primary, secondary, and
tertiary alkyl radicals (3s-3u).
The work described herein was developed via hypothesis-
driven experimentation guided by computational analysis. In
addressing
a common limitation of single-electron NHC
processes, we revealed mechanistic insights that may be applied
to this catalysis platform to further advance the field, expand
substrate scopes, and increase the utility of NHCs in synthesis.
The modularity of these single-electron operators was highlighted
in a combined NHC-catalyzed and photoredox protocol to
synthesize aliphatic ketones from activated carboxylic acids;
modulation of NHC steric and electronic parameters enabled
increased yields of up to 65% compared to our previous results.
In addition to significantly expanding the scope of this reaction,
amino acids were directly functionalized to afford the
corresponding α-amino ketones using a one-pot procedure, and
the utility of this method was showcased in the late-state tailoring
of bioactive compounds. Future correlation of computed results
with ongoing experimental outcomes is expected to reveal
additional mechanistic details regarding what factors control the
PES to govern the selectivity of single-electron carbene-catalyzed
methods.
The direct functionalization of amino acids was achieved via
in situ activation with carbonyldiimidazole (CDI). Various amino
acids, including alkyl amino acids (e.g., N-Boc-L-valine), aromatic
Table 2. (A) Synthesis of α-amino ketones via direct amino acid functionalization.
(B) Late-stage functionalization of biologically-active compounds.[a]
Acknowledgements
The authors thank Northwestern University and the National
Institute of General Medical Sciences (R35 GM136440) for
support of this work. We also thank Ada Kwong (NU) and Saman
Shafaie (NU) for assistance with HRMS. PHYC is the Bert and
Emelyn Christensen Professor and gratefully acknowledges
financial support from the Vicki & Patrick F. Stone family and the
computing infrastructure in part provided by the National Science
Foundation (CHE-1352663 and NSF Phase-2 CCI, Center for
Sustainable Materials Chemistry CHE-1102637).
Keywords: carbene • catalysis • density functional theory • late-
stage functionalization • photochemistry
[1]
a) K. K. Chen, Ann. N.Y. Acad. Sci. 1948, 51, 83-97; b) E. A. Boyle, P.
C. Freemanm, F. R. Mangan, M. J. Thomson, J. Pharm. Pharmacol. 1982,
34, 562-569; c) T. Tanaka, M. Kawase, S. Tani, Biorg. Med. Chem. 2004,
12, 501-505; d) P. Redelinghuys, A. T. Nchinda, K. Chibale, E. D.
Sturrock, Biol. Chem. 2006, 387, 461-466; e) A. B. Riley, M. J. Tafreshi,
S. L. Haber, Am. J. Health-Syst. Pharm. 2008, 65, 1019-1028; f) P.
[a] See SI for reaction details.
5
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10.1002/anie.202105354
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COMMUNICATION
Hoyos, J.-V. Sinisterra, F. Molinari, A. R. Alcántara, P. Domínguez de
María, Acc. Chem. Res. 2010, 43, 288-299; g) Y. Liu, S.-J. Han, W.-B.
Liu, B. M. Stoltz, Acc. Chem. Res. 2015, 48, 740-751; h) L. A. T. Allen,
R.-C. Raclea, P. Natho, P. J. Parsons, Org. Biomol. Chem. 2021, 19,
498-513.
a) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636-3638; b)
S. K. Richardson, in General and Synthetic Methods: Volume 14, Vol. 14
(Ed.: G. Pattenden), The Royal Society of Chemistry, 1992, pp. 26-62; c)
R. K. Dieter, Tetrahedron 1999, 55, 4177-4236; d) F. Zhou, C.-J. Li, Nat.
Commun. 2014, 5, 4254; e) D. H. Miles, J. Guasch, F. D. Toste, J. Am.
Chem. Soc. 2015, 137, 7632-7635; f) M. Zhang, J. Xie, C. Zhu, Nat.
Commun. 2018, 9, 3517; g) R. Ruzi, K. Liu, C. Zhu, J. Xie, Nat. Commun.
2020, 11, 3312.
[14] J.-L. Li, Y.-Q. Liu, W.-L. Zou, R. Zeng, X. Zhang, Y. Liu, B. Han, Y. He,
H.-J. Leng, Q.-Z. Li, Angew. Chem. Int. Ed. 2020, 59, 1863-1870.
[15] B. Zhang, Q. Peng, D. Guo, J. Wang, Org. Lett. 2020, 22, 443-447.
[16] I. Kim, H. Im, H. Lee, S. Hong, Chem. Sci. 2020, 11, 3192-3197.
[17] a) T. Ishii, K. Ota, K. Nagao, H. Ohmiya, J. Am. Chem. Soc. 2019, 141,
14073-14077; b) H.-B. Yang, Z.-H. Wang, J.-M. Li, C. Wu, Chem.
Commun. 2020, 56, 3801-3804.
[18] a) A. V. Bay, K. P. Fitzpatrick, R. C. Betori, K. A. Scheidt, Angew. Chem.
Int. Ed. 2020, 59, 9143-9148; b) A. A. Bayly, B. R. McDonald, M. Mrksich,
K. A. Scheidt, Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 13261-13266.
[19] a) A. Mavroskoufis, K. Rajes, P. Golz, A. Agrawal, V. Ruß, J. P. Götze,
M. N. Hopkinson, Angew. Chem. Int. Ed. 2020, 59, 3190-3194; b) M. N.
Hopkinson, A. Mavroskoufis, Synlett 2021, 32, 95-101.
[2]
[3]
a) V. Grignard, C. R. Hebd. Séances. Acad. Sci. 1900, 130, 1322– 1325;
b) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815-3818; c) F.
Alonso, E. Lorenzo, M. Yus, J. Org. Chem. 1996, 61, 6058-6059; d) P.
Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I.
Sapountzis, V. A. Vu, Angew. Chem. Int. Ed. 2003, 42, 4302-4320; e) H.
B. Kagan, Angew. Chem. Int. Ed. 2012, 51, 7376-7382; f) K. Colas, A. C.
V. D. dos Santos, A. Mendoza, Org. Lett. 2019, 21, 7908-7913.
a) M. Rueping, B. J. Nachtsheim, Beilstein J. Org. Chem. 2010, 6, 6; b)
M. M. Heravi, V. Zadsirjan, P. Saedi, T. Momeni, RSC Adv. 2018, 8,
40061-40163.
[20] a) K. Liu, A. Studer, J. Am. Chem. Soc. 2021, 143, 4903-4909; b) Q.-Y.
Meng, L. Lezius, A. Studer, Nat. Commun. 2021, 12, 2068; c) Q.-Y. Meng,
N. Döben, A. Studer, Angew. Chem. Int. Ed. 2020, 59, 19956-19960.
[21] a) L. Dai, Z.-H. Xia, Y.-Y. Gao, Z.-H. Gao, S. Ye, Angew. Chem. Int. Ed.
2019, 58, 18124-18130; b) S.-C. Ren, W.-X. Lv, X. Yang, J.-L. Yan, J.
Xu, F.-X. Wang, L. Hao, H. Chai, Z. Jin, Y. R. Chi, ACS Catal. 2021, 11
2925-2934.
[22] V. Regnier, E. A. Romero, F. Molton, R. Jazzar, G. Bertrand, D. Martin,
J. Am. Chem. Soc. 2019, 141, 1109-1117.
[23] Y. Kakeno, M. Kusakabe, K. Nagao, H. Ohmiya, ACS Catal. 2020, 10,
[4]
[5]
a) H. Yin, C. Zhao, H. You, K. Lin, H. Gong, Chem. Commun. 2012, 48,
7034-7036; b) A. H. Cherney, N. T. Kadunce, S. E. Reisman, J. Am.
Chem. Soc. 2013, 135, 7442-7445; c) J. Buchspies, M. Szostak,
Catalysts 2019, 9, 53.
8524-8529.
[24] a) J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 1996, 77, 3865-
3868; b) J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 1997, 78,
1396-1396.
[6]
[7]
a) J. S. Johnson, Angew. Chem. Int. Ed. 2004, 43, 1326-1328; b) X.
Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511-3522; c) A. Sanz-
Marco, S. Martinez-Erro, M. Pauze, E. Gómez-Bengoa, B. Martín-Matute,
Nat. Commun. 2019, 10, 5244.
[25] W. J. Hehre, R. Ditchfield, J. A. Pople, J. Chem. Phys. 1972, 56, 2257-
2261.
[26] P. J. Hay, W. R. Wadt, J. Chem. Phys. 1985, 82, 270-283.
[27] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B. 2009, 113,
6378-6396.
[28] H. Clavier, S. P. Nolan, Chem. Commun. 2010, 46, 841-861.
[29] a) J. Liu, X.-P. Liu, H. Wu, Y. Wei, F.-D. Lu, K.-R. Guo, Y. Cheng, W.-J.
Xiao, Chem. Commun. 2020, 56, 11508-11511; b) D. Leifert, A. Studer,
Angew. Chem. Int. Ed. 2020, 59, 74-108.
[30] a) K. Nakajima, S. Nojima, K. Sakata, Y. Nishibayashi, ChemCatChem
2016, 8, 1028-1032; b) P.-Z. Wang, J.-R. Chen, W.-J. Xiao, Org. Biomol.
Chem. 2019, 17, 6936-6951; c) G. A. Molander, J. Org. Chem. 2015, 80,
7837-7848; d) M. Jouffroy, D. N. Primer, G. A. Molander, J. Am. Chem.
Soc. 2016, 138, 475-478.
[31] a) H. Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi, Nature 2012,
492, 234-238; b) A. Hörner, D. Volz, T. Hagendorn, D. Fürniss, L. Greb,
F. Rönicke, M. Nieger, U. Schepers, S. Bräse, RSC Adv. 2014, 4, 11528-
11534; c) Y. Yu, N. Li, Q. Jin, Z. Ji, Z. Sun, G. Li, S. Zhang, J. You,
Microchem. J. 2019, 145, 9-17.
For reviews on NHC catalysis, see: a) D. Enders, O. Niemeier, A.
Henseler, Chem. Rev. 2007, 107, 5606-5655; b) A. T. Biju, N. Kuhl, F.
Glorius, Acc. Chem. Res. 2011, 44, 1182-1195; c) V. Nair, R. S. Menon,
A. T. Biju, C. R. Sinu, R. R. Paul, A. Jose, V. Sreekumar, Chem. Soc.
Rev. 2011, 40, 5336-5346; d) S. J. Ryan, L. Candish, D. W. Lupton,
Chem. Soc. Rev. 2013, 42, 4906-4917; e) M. N. Hopkinson, C. Richter,
M. Schedler, F. Glorius, Nature 2014, 510, 485-496; f) J.
Mahatthananchai, J. W. Bode, Acc. Chem. Res. 2014, 47, 696-707; g) D.
M. Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis, Chem. Rev.
2015, 115, 9307-9387; h) M. H. Wang, K. A. Scheidt, Angew. Chem. Int.
Ed. 2016, 55, 14912-14922; i) X. Chen, H. Wang, Z. Jin, Y. R. Chi, Chin.
J. Chem. 2020, 38, 1167-1202.
For reviews and selected work on photochemistry and electrochemistry,
see: a) T. P. Yoon, M. A. Ischay, J. Du, Nat. Chem. 2010, 2, 527-532; b)
J. Xuan, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828-6838; c) C.
K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322-
5363; d) R. Francke, R. D. Little, Chem. Soc. Rev. 2014, 43, 2492-2521;
e) N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075-10166;
f) K. L. Skubi, T. R. Blum, T. P. Yoon, Chem. Rev. 2016, 116, 10035-
10074; g) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem.
2016, 81, 6898-6926; h) M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev.
2017, 117, 13230-13319; i) H. Huang, C. Yu, Y. Zhang, Y. Zhang, P. S.
Mariano, W. Wang, J. Am. Chem. Soc. 2017, 139, 9799-9802; j) S.
Zhang, L. Li, J. Li, J. Shi, K. Xu, W. Gao, L. Zong, G. Li, M. Findlater,
Angew. Chem. Int. Ed. 2021, 7275.
[8]
[32] Due to the propsensity of free amines to be oxidized under photocatalytic
conditions, this reaction currently necesitates the use of N-protecting
groups.
[9]
a) A. Deb, S. Manna, A. Modak, T. Patra, S. Maity, D. Maiti, Angew.
Chem. Int. Ed. 2013, 52, 9747-9750; b) W. Chen, Z. Liu, J. Tian, J. Li, J.
Ma, X. Cheng, G. Li, J. Am. Chem. Soc. 2016, 138, 12312-12315; c) C.
Raviola, S. Protti, D. Ravelli, M. Fagnoni, Green Chem. 2019, 21, 748-
764; d) S. Ni, N. M. Padial, C. Kingston, J. C. Vantourout, D. C. Schmitt,
J. T. Edwards, M. M. Kruszyk, R. R. Merchant, P. K. Mykhailiuk, B. B.
Sanchez, S. Yang, M. A. Perry, G. M. Gallego, J. J. Mousseau, M. R.
Collins, R. J. Cherney, P. S. Lebed, J. S. Chen, T. Qin, P. S. Baran, J.
Am. Chem. Soc. 2019, 141, 6726-6739; e) N. Chalotra, S. Sultan, B. A.
Shah, Asian J. Org. Chem. 2020, 9, 863-881.
[10] a) Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle, D. W. C.
MacMillan, Science 2014, 345, 437-440; b) L. Chu, J. M. Lipshultz, D. W.
C. MacMillan, Angew. Chem. Int. Ed. 2015, 54, 7929-7933.
[11] a) E. Chabrière, X. Vernède, B. Guigliarelli, M.-H. Charon, E. C.
Hatchikian, J. C. Fontecilla-Camps, Science 2001, 294, 2559-2563; b) S.
W. Ragsdale, Chem. Rev. 2003, 103, 2333; c) J. Guin, S. De Sarkar, S.
Grimme, A. Studer, Angew. Chem. Int. Ed. 2008, 47, 8727-8730; d) R.
Kluger, K. Tittmann, Chem. Rev. 2008, 108, 1797-1833; e) N. A. White,
T. Rovis, J. Am. Chem. Soc. 2014, 136, 14674-14677; f) Y. Zhang, Y.
Du, Z. Huang, J. Xu, X. Wu, Y. Wang, M. Wang, S. Yang, R. D. Webster,
Y. R. Chi, J. Am. Chem. Soc. 2015, 137, 2416-2419.
[12] For reviews on single-electron NHC catalysis, see: a) T. Ishii, K. Nagao,
H. Ohmiya, Chem. Sci. 2020, 11, 5630-5636; b) Q.-Z. Li, R. Zeng, B. Han,
J.-L. Li, Chem. Eur. J. 2021, 3238-3250; c) Q. Liu, X.-Y. Chen, Org.
Chem. Front. 2020, 7, 2082-2087; d) A. Mavroskoufis, M. Jakob, M. N.
Hopkinson, ChemPhotoChem 2020, 4, 5147-5153; e) L. Dai, S. Ye, Chin.
Chem. Lett. 2020, 32, 660-667.
[13] T. Ishii, Y. Kakeno, K. Nagao, H. Ohmiya, J. Am. Chem. Soc. 2019, 141,
3854-3858.
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10.1002/anie.202105354
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
‡
O
O
OH
CDI NHC
+
tunable radical
precursors
aliphatic and
α-amino ketones
R
DFT calculations
We developed a single-electron approach for the construction of aliphatic ketones from activated carboxylic acids using merged
NHC/photoredox catalysis. Computational studies and mechanistic analysis revealed that reactivity is dependent on both the substrate
and NHC catalyst. This methodology was showcased in the direct functionalization of amino acids and bioactive compounds.
7
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