Direct Synthesis of Dialkyl Ketones from Aliphatic Aldehydes through Radical N-Heterocyclic Carbene Catalysis

Article abstract of DOI:10.1021/acscatal.0c02849

A designed thiazolium-type N-heterocyclic carbene (NHC) catalyst having an N-neopentyl group and seven-membered backbone structure was achieved through the use of aliphatic aldehydes as acyl donors in the decarboxylative radical coupling with aliphatic carboxylic acid derived-redox active esters. The NHC catalyst also enabled the vicinal alkylacylation of vinyl arenes using aliphatic aldehydes and redox-active esters through a radical relay mechanism. These reactions provided the synthetic route to sterically hindered dialkyl ketones.

Full text of DOI:10.1021/acscatal.0c02849

pubs.acs.org/acscatalysis
Letter
Direct Synthesis of Dialkyl Ketones from Aliphatic Aldehydes
through Radical N‑Heterocyclic Carbene Catalysis
Yuki Kakeno, Mayu Kusakabe, Kazunori Nagao,* and Hirohisa Ohmiya*
Cite This: ACS Catal. 2020, 10, 8524−8529
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A designed thiazolium-type N-heterocyclic carbene
(NHC) catalyst having an N-neopentyl group and seven-membered
backbone structure was achieved through the use of aliphatic
aldehydes as acyl donors in the decarboxylative radical coupling
with aliphatic carboxylic acid derived-redox active esters. The NHC
catalyst also enabled the vicinal alkylacylation of vinyl arenes using
aliphatic aldehydes and redox-active esters through a radical relay
mechanism. These reactions provided the synthetic route to sterically
hindered dialkyl ketones.
KEYWORDS: N-heterocyclic carbene, organocatalysis, radical, aldehydes, dialkyl ketones
ialkyl ketones are one of the fundamental and essential
class of organic molecules. These compounds are found
not give dialkyl ketones at all under the optimized conditions
using a thiazolium salt (N1)8 possessing an N-2,6-diisopro-
pylphenyl substituent and seven-membered backbone structure
as the NHC precursor (Scheme 1B). To expand the substrate
scope, we thought that redesign of the NHC catalyst would be
required.
Herein, we report that the design of NHC catalyst enabled
the use of aliphatic aldehydes for the radical reactions involving
the Breslow intermediate-derived radical species. A thiazolium-
type NHC having an N-neopentyl group and seven-membered
backbone structure was effective. The catalyst system provided
a synthetic approach to sterically hindered dialkyl ketones from
aliphatic aldehydes in a single step.
D
in many pharmaceutical and bioactive molecules. In addition,
they are recognized as versatile synthetic precursors of valuable
functional groups, such as alcohols and amines. The conven-
tional synthetic approach to dialkyl ketones from aliphatic
aldehydes is the nucleophilic addition of aliphatic organo-
metallic reagents followed by oxidation (Scheme 1A). On the
other hand, the direct synthesis of dialkyl ketones from
aliphatic aldehydes are also demonstrated, even though such a
process is difficult and less mature at present. This process
using aliphatic aldehydes as carbonyl sources would be useful,
in terms of their availability and inexpensiveness. Specifically,
N-heterocyclic carbene (NHC)-catalyzed Stetter and benzoin
condensation reactions using aliphatic aldehydes could provide
the dialkyl ketones.1,2 The hydroacylation of alkenes using
transition-metal catalyst3 or hydrogen atom transfer (HAT)
catalyst4,5 is known as a high atom-economical method. The
direct methods exhibited high functional group compatibility.
However, the fragility to steric bulkiness limited the scope and
the complexity of dialkyl ketone products.
Recently, we developed the direct synthesis of alkyl aryl
ketones from aromatic aldehydes using aliphatic carboxylic
acid derived-redox active esters and NHC catalyst under mild
conditions (Scheme 1B).6 This protocol allowed the use of
secondary and tertiary alkyl carboxylic acid-derived redox-
active ester to produce sterically hindered alkyl aryl ketones.
The reaction involves a single electron transfer (SET) from the
enolate form of the Breslow intermediate, which is derived
from aldehyde and NHC in the presence of base, to redox
active ester, followed by radical−radical coupling between the
resultant Breslow intermediate-derived radical and alkyl radical
(Scheme 1B).6,7 However, the useable aldehydes have been
limited to aromatic aldehydes. Thus, aliphatic aldehydes did
Fukuzumi and co-workers studied the redox properties of
the enolate form of Breslow intermediates that are prepared
from aldehydes and thiazolium-type NHC in the presence of a
strong base.9 The enolate forms of Breslow intermediates
derived from aliphatic aldehyde have reduction potentials
comparable to the one derived from aromatic aldehyde (Eox
=
−0.96 V for acetaldehyde and Eox = −0.97 V for o-
tolualdehyde) (Scheme 1B). Thus, the SET process mediated
by the aliphatic aldehyde-derived Breslow intermediate would
be feasible.
Next, the stoichiometric reaction using a silylated thiazolium
aliphatic alcohol 4a, which is known to act as a Breslow
intermediate equivalent with treatment of TBAF, was
Received: June 30, 2020
Revised: July 14, 2020
https://dx.doi.org/10.1021/acscatal.0c02849
© XXXX American Chemical Society
ACS Catal. 2020, 10, 8524−8529
8524

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Scheme 1. Direct Synthesis of Ketones from Aldehydes
through NHC-Catalyzed Radical Reactions
Table 1. Design of NHC Catalyst for Aliphatic Aldehydes
conducted (Table 1A).10 Specifically, the reaction between 4a
and pivalic acid derived-redox active ester 2a using
stoichiometric amounts of TBAF and Cs2CO3 for generating
the enolate form of the Breslow intermediate afforded the
desired dialkyl ketone 3aa in 6% yield.11 Three additional
redox active esters containing tertiary or benzyl substituents
were examined (3ab−3ad). Tertiary benzylic redox active ester
2d produced a highly stabilized benzyl radical coupled with 4a
in an exceptionally high yield.
a
Reaction was performed with 4a (0.2 mmol), 2 (0.2 mmol), and
̊
TBAF (0.2 mmol) in DMSO (0.4 mL) at 25 C for 10 min. Then,
Cs2CO3 (0.2 mmol) was added and stirred at 60 °C for 4 h. 1H NMR
Encouraged by the results of the stoichiometric experiments
described in Table 1A, the catalytic reactions of 3-phenyl-
propionaldehyde (1a) and 2a−2d with 2,4,5-trimethyl
thiazolium salt N2 were conducted (Table 1B). The enolate
form of the Breslow intermediate derived from N2 would be
same as that derived from 4a. The reaction with 2a gave the
desired coupling product 3aa, although the yield was low. The
product yield of 3ab diminished under the catalytic conditions
(7% to 2%; see Table 1B vs Table 1A). On the other hand, the
improvement of the product yield was observed in the case of
2c. As with the stoichiometric reaction, the high reactivity was
observed when 2d was used as a substrate. Interestingly, using
the N-2,6-diisopropylphenyl-substituted N1 instead of N2 did
not afford the product at all. In our previous study using N1,6a
we assumed that the reason why aliphatic aldehydes were
ineffective was attributed to the instability of the Breslow
intermediate-derived radical. However, these results (N2 vs
N1) using 2d suggested that the cause seems to be the steric
environment on the radical−radical coupling process.
b
yield. Reaction was performed with 1a (0.3 mmol), 2 (0.2 mmol),
N2 (0.02 mmol), and Cs2CO3 (0.04 mmol) in DMSO (0.4 mL) at 60
c
°C for 4 h. 1H NMR yield based on 2. Reaction was performed with
1a (0.3 mmol), 2a (0.2 mmol), N3−N10 (0.02 mmol), and Cs2CO3
1
(0.04 mmol) in DMSO (0.4 mL) at 60 °C for 4 h. H NMR yield
based on 2a.
environment of carbene. To find the effective NHC catalyst
quickly, the N-substituent was evaluated with thiazolium salt
having a dimethyl backbone (Table 1C, N3−N10). The
reaction with N-benzyl thiazolium salt resulted in the slight
product formation (N3). The introduction of a diphenylmeth-
yl substituent did not give the product (N4). Interestingly,
putting a single methylene unit into N4 resulted in the desired
product formation with 10% yield (N5). A propyl substituent
(N6) was comparable with N3. The N-isobutyl-substituted N7
showed comparable reactivity. After screening of other
sterically hindered groups, N-neopentyl-substituted thiazolium
salt was found to be effective (N8). Subsequently, the
backbone structure of thiazole ring was evaluated (N9 and
N10). N10 bearing a seven-membered backbone dramatically
Based on the preliminary experiments in Tables 1A and 1B,
we envisioned that the improvement of reaction efficiency for
aliphatic aldehydes would be solved by the tuning the steric
8525
https://dx.doi.org/10.1021/acscatal.0c02849
ACS Catal. 2020, 10, 8524−8529

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
increased the product yield.12,13 As observed in our previous
report, triazolium- and imidazolium-type NHCs did not afford
any products (data not shown).6a,b The control experiments
revealed that both NHC and the Cs2CO3 base were essential
for this reaction (data not shown).
a
Table 2. Substrate Scope
In the radical NHC catalysis, the bulky N-substituents would
not only secure the persistent nature14 of the Breslow
intermediate-derived radical but also prohibit the possible
side reactions between nucleophilic species generated in situ
from NHC and the ester moiety in 2. However, the sterically
demanding N-substituents such as 2,6-disopropylphenyl (N1)
or diphenylmethyl (N4) groups in close proximity to the
carbene center were not suitable in the case of aliphatic
aldehyde substrates (see Table 1C). These N-substituents
would lead to unsuccessful radical−radical coupling, because
the Breslow intermediate-derived radical from aliphatic
aldehyde would be more three-dimensionally congested than
that from aromatic aldehyde, because of the sp3 nature of α-
carbon. As a result, N-neopentyl-substituted N10, in which
steric hindrance is introduced at some distance from the
carbene center, rather than within a proximity, might be
effective both for the radical−radical coupling and the
suppression of side reactions.
This protocol under the N10 catalyst system was useful to
construct the sterically hindered dialkyl ketones bearing
secondary or tertiary alkyl substituents (Table 2). In the top
portion of Table 2, various redox active esters were examined
using the reaction of cyclohexanecarboxyaldehyde (1b). The
secondary benzylic carboxylic acid-derived redox active esters
possessing methyl (3bc), ethyl (3be), and allyl (3bf) groups
were suitable substrates. Tertiary benzylic groups containing
cyclic (3bg) and acyclic (3bd and 3bh) scaffolds could be
coupled with the acyl group efficiently. Unactivated tertiary
alkyl group was engaged in this decarboxylative alkylation
(3bb). Amide (3bi) and benzyl ether (3bj) substituents did
not inhibit the reaction. Overall, the reactivity seemed to be
correlated with the stability of the generated alkyl radical (3bc
vs 3bd and 3bg vs 3bb, 3bi). α-Amino- and α-alkoxy-
substituted ketones, which are known as synthetically useful
intermediates, were easily prepared by this reaction (3bk−
3bn). The relatively low yield of 3bm and 3bn might be due to
the decomposition of the protecting groups such as acetyl or
silyl substituents by basic reaction conditions. It is noteworthy
that pharmaceutical drugs such as Loxoprofen and Gemfibrozil
were acylated, respectively (3bo and 3bp).
A broad range of primary and secondary aliphatic aldehydes
were efficiently coupled with the redox active ester 2d to
produce the dialkyl ketones (Table 2, bottom). Citronellal was
directly alkylated (3cd). Unprotected alcohol and thioether
groups were compatible (3dd and 3ed). Acyclic and cyclic
secondary alkyl aldehydes were also good substrates (3fd−
3hd). The alkene moiety that sometimes poisons transition-
metal catalysis did not inhibit the reaction (3fd). The
cyclopropyl ketone could be synthesized from cyclopropane-
carboxaldehyde via this organocatalytic reaction (3gf).
Heterocyclic ketone containing a piperidine scaffold was
prepared (3hd). Several combinations of aliphatic aldehydes
and tertiary redox active esters were also shown (3ab, 3gk, and
3hj). The aldehydes derived from natural products such as
lithocolic acid and cholic acid could participate in this
decarboxylative alkylation reaction (3ii and 3jd). Unfortu-
nately, the reaction with the tertiary aliphatic aldehyde resulted
in the recovery of substrates (data not shown). It would be due
a
Reaction was performed with 1 (0.3 mmol), 2 (0.2 mmol), N10
(0.02 mmol), and Cs2CO3 (0.04 mmol) in DMSO (0.4 mL) at 60 °C
for 4 h. bDiastereomeric ratio is 55:45 determined by 1H NMR
analysis.
to the slow formation of Breslow intermediate caused by the
steric bulkiness.
To gain the more information on catalytic activity of N10,
several reactions were conducted. First, N10 was subjected to
the decarboxylative coupling with benzaldehyde 1i to exhibit
the comparable reactivity as the previous optimal catalyst N1
(Scheme 2A).6a Thus, the newly designed N10 was identified
as a versatile NHC catalyst for the decarboxylative radical
coupling of both aliphatic and aromatic aldehydes.
To understand the reaction mechanism, competition
experiments were conducted (Schemes 2B and 2C). When
the reaction of the redox ester 2d with the same amounts of 1i
8526
https://dx.doi.org/10.1021/acscatal.0c02849
ACS Catal. 2020, 10, 8524−8529

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Scheme 2. Mechanistic Studies
Table 3. Application to Other NHC-Catalyzed Radical
Reaction
and secondary aliphatic aldehydes 1b was performed, alkyl aryl
ketone 3id was formed prior to dialkyl ketone 3bd (Scheme
2B). Compared secondary aliphatic aldehyde 1b with primary
aliphatic aldehyde 1a, the primary aliphatic aldehyde-derived
product was preferentially obtained (Scheme 2C). These
results indicated that the order of reactivity of aldehydes is as
follows: aromatic > primary aliphatic > secondary aliphatic. We
supposed that the deprotonation of the original formyl C−H
producing enol or the enolate form of Breslow intermediates
would be the rate-determining step in the present NHC
catalysis. This is consistent with conventional ionic NHC
organocatalysis.15,16
To explore the versatility of the newly designed NHC
catalyst, we tested other NHC-catalyzed radical reactions that
have been limited to aromatic aldehydes. For example, the N10
catalyst allowed the use of aliphatic aldehyde as an acyl source
for the vicinal alkylacylation of vinyl arenes 5, using tertiary
alkyl carboxylic acid-derived redox-active ester 2 through a
radical relay mechanism (see Table 3A).6b Primary and
secondary aliphatic aldehydes were suitable substrates (6aai,
6fai, and 6bai). Tertiary butyl and adamantly groups were
successfully introduced to β-position of ketone products (6baa
and 6baq). Bromo and methoxy substituents in the vinyl
arenes were tolerated (6bbi and 6bci). When Togni reagent I
was used instead of redox active esters, the acyltrifluorome-
thylation of alkene occurred to afford β-trifluoromethyl-
substituted dialkylketone 8bc (see Table 3B).7b,c,e The acyl
and CF3 fragments could be introduced to alkene moiety with
complete regioselectivity. We also tested the unprecedented
cross-coupling of aliphatic aldehyde and α-bromoamide (see
Table 3C). α-Bromoamides derived from amino acid or
dipeptide coupled efficiently with cyclohexanecarbaldehyde
(10ba and 10bb).
a
Reaction was performed with aldehyde 1 (0.2 mmol), 5 (0.4 mmol),
2 (0.3 mmol), N10 (0.01 mmol), and Cs2CO3 (0.02 mmol) in
b
DMSO (0.4 mL) at 80 °C for 4 h. The diastereomeric ratio is 1:1, as
c
1
determined by H NMR analysis. Reaction was performed with 1b
(0.12 mmol), 5c (0.1 mmol), 7 (0.2 mmol), N10 (0.02 mmol), and
Cs2CO3 (0.04 mmol) in DMSO (0.4 mL) at 60 °C for 12 h.
d
Reaction was performed with 1 (0.3 mmol), 9 (0.2 mmol), N10
(0.02 mmol), and Cs2CO3 (0.24 mmol) in DCM (0.4 mL) at 60 °C
for 4 h.
In summary, a newly designed thiazolium-type NHC having
an N-neopentyl group and seven-membered backbone
structure achieved the use of aliphatic aldehydes as acyl
donors in the decarboxylative radical coupling with aliphatic
carboxylic acid-derived redox-active esters. The NHC catalyst
also enabled the vicinal alkylacylation of vinyl arenes using
aliphatic aldehydes and redox-active esters through a radical
relay mechanism. These reactions provided the new synthetic
route to sterically hindered dialkyl ketones. Thus, the catalyst
evolution expanded the scope of the NHC-catalyzed radical
reactions, making versatile dialkyl ketone synthesis possible. At
present, theoretical calculations to understand the NHC
catalyst effect and the application of this radical NHC catalysis
to the functionalization of biomolecules are currently ongoing
in our laboratory.
8527
https://dx.doi.org/10.1021/acscatal.0c02849
ACS Catal. 2020, 10, 8524−8529

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Carbene-Based Catalysis Enabling Cross-Coupling Reactions. ACS
Catal. 2020, 10, 6862−6869.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c02849.
■
sı
(3) For selected reviews on transition-metal-catalyzed hydro-
acylation of alkenes with aliphatic aldehydes, see: (a) Willis, M. C.
Transition Metal Catalyzed Alkene and Alkyne Hydroacylation. Chem.
Rev. 2010, 110, 725−748. (b) Murphy, S. K.; Dong, V. M.
Enantioselective Hydroacylation of Olefins with Rhodium Catalysts.
Chem. Commun. 2014, 50, 13645−13649. (c) Ghosh, A.; Johnson, K.
F.; Vickerman, K. L.; Walker, J. A.; Stanley, L. M. Recent Advances in
Transition Metal-Catalysed Hydroacylation of Alkenes and Alkynes.
Org. Chem. Front. 2016, 3, 639−644.
Experimental details and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(4) For selected reviews on HAT-catalyzed hydroacylation of
Kazunori Nagao − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; orcid.org/0000-0003-3141-
5279; Email: nkazunori@p.kanazawa-u.ac.jp
Hirohisa Ohmiya − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; JST, PRESTO, Saitama 332-
0012, Japan; orcid.org/0000-0002-1374-1137;
Email: ohmiya@p.kanazawa-u.ac.jp
́
alkenes with aliphatic aldehydes, see: (a) Denes, F.; Pichowicz, M.;
Povie, G.; Renaud, P. Thiyl Radicals in Organic Synthesis. Chem. Rev.
2014, 114, 2587−2693. (b) Ravelli, D.; Fagnoni, M.; Fukuyama, T.;
Nishikawa, T.; Ryu, I. Site-Selective C−H Functionalization by
Decatungstate Anion Photocatalysis: Synergistic Control by Polar and
Steric Effects Expands the Reaction Scope. ACS Catal. 2018, 8, 701−
713.
(5) Zhang, X.; MacMillan, D. W. C. Direct Aldehyde C−H Arylation
and Alkylation via the Combination of Nickel, Hydrogen Atom
Transfer, and Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139,
11353−11356.
Authors
(6) (a) Ishii, T.; Kakeno, Y.; Nagao, K.; Ohmiya, H. N-Heterocyclic
Carbene-Catalyzed Decarboxylative Alkylation of Aldehydes. J. Am.
Chem. Soc. 2019, 141, 3854−3858. (b) Ishii, T.; Ota, K.; Nagao, K.;
Ohmiya, H. N-Heterocyclic Carbene-Catalyzed Radical Relay
Enabling Vicinal Alkylacylation of Alkenes. J. Am. Chem. Soc. 2019,
141, 14073−14077. (c) Ota, K.; Nagao, K.; Ohmiya, H. N-
Heterocyclic Carbene-Catalyzed Radical Relay Enabling Synthesis of
δ-Ketocarbonyls. Org. Lett. 2020, 22, 3922−3925.
Yuki Kakeno − Division of Pharmaceutical Sciences, Graduate
School of Medical Sciences, Kanazawa University, Kanazawa
920-1192, Japan
Mayu Kusakabe − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c02849
(7) (a) Ishii, T.; Nagao, K.; Ohmiya, H. Recent Advances in Radical
N-Heterocyclic Carbene Catalysis. Chem. Sci. 2020, 11, 5630−5636.
(b) Li, J.-L.; Liu, Y.-Q.; Zou, W.-L.; Zeng, R.; Zhang, X.; Liu, Y.; Han,
B.; He, Y.; Leng, H.-J.; Li, Q.-Z. Radical Acylfluoroalkylation of
Olefins through N-Heterocyclic Carbene Organocatalysis. Angew.
Chem., Int. Ed. 2020, 59, 1863−1870. (c) Zhang, B.; Peng, Q.; Guo,
D.; Wang, J. NHC-Catalyzed Radical Trifluoromethylation Enabled
by Togni Reagent. Org. Lett. 2020, 22, 443−447. (d) Kim, I.; Im, H.;
Lee, H.; Hong, S. N-Heterocyclic Carbene-Catalyzed Deaminative
Cross-Coupling of Aldehydes with Katritzky Pyridinium Salts. Chem.
Sci. 2020, 11, 3192−3197. (e) Yang, H.-B.; Wang, Z.-H.; Li, J.-M.;
Wu, C. Modular Synthesis of α-Aryl β-Perfluoroalkyl Ketones via N-
Heterocyclic Carbene Catalysis. Chem. Commun. 2020, 56, 3801−
3804. For examples of cooperative catalysis with photoredox catalyst,
see: (f) Dai, L.; Xia, Z.-H.; Gao, Y.-Y.; Gao, Z.-H.; Ye, S. Visible-
Light-Driven N-Heterocyclic Carbene Catalyzed γ- and ε-Alkylation
with Alkyl Radicals. Angew. Chem., Int. Ed. 2019, 58, 18124−18130.
(g) Davies, A. V.; Fitzpatrick, K. P.; Betori, R. C.; Scheidt, K. A.
Combined Photoredox and Carbene Catalysis for the Synthesis of
Ketones from Carboxylic Acids. Angew. Chem., Int. Ed. 2020, 59,
9143−9148. (h) Song, R.; Chi, Y. R. N-Heterocyclic Carbene
Catalyzed Radical Coupling of Aldehydes with Redox-Active Esters.
Angew. Chem., Int. Ed. 2019, 58, 8628−8630.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant No.
JP18H01971 to Scientific Research (B), JSPS KAKENHI
Grant No. JP17H06449 (Hybrid Catalysis), and JST, PRESTO
Grant No. JPMJPR19T2 (to H.O.).
REFERENCES
■
(1) For selected reviews on NHC organocatalysis, see: (a) Enders,
D.; Niemeier, O.; Henseler, A. Organocatalysis by N-Heterocyclic
Carbenes. Chem. Rev. 2007, 107, 5606−5655. (b) Bugaut, X.; Glorius,
F. Organocatalytic Umpolung: N-Heterocyclic Carbenes and Beyond.
Chem. Soc. Rev. 2012, 41, 3511−3522. (c) Flanigan, D. M.; Romanov-
Michailidis, F.; White, N. A.; Rovis, T. Organocatalytic Reactions
Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015, 115, 9307−
9387.
(2) For our recent reports on direct synthesis of dialkyl ketone from
aliphatic aldehydes through NHC/Pd cooperative catalysis, see:
(a) Yasuda, S.; Ishii, T.; Takemoto, S.; Haruki, H.; Ohmiya, H.
Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Reactions
of Aldehyde Acyl Anions with either Diarylmethyl or Allylic
Carbonates. Angew. Chem., Int. Ed. 2018, 57, 2938−2942. (b) Haruki,
H.; Yasuda, S.; Nagao, K.; Ohmiya, H. Dehydrative Allylation
between Aldehydes and Allylic Alcohols through Synergistic N-
Heterocyclic Carbene/Palladium Catalysis. Chem. - Eur. J. 2019, 25,
724−727. (c) Takemoto, S.; Ishii, T.; Yasuda, S.; Ohmiya, H.
Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Allylation
of Aldehydes with Allylic Carbonates. Bull. Chem. Soc. Jpn. 2019, 92,
937−940. (d) Ohnishi, N.; Yasuda, S.; Nagao, K.; Ohmiya, H.
Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Aldehyde
Acylation of Allylic Amines. Asian J. Org. Chem. 2019, 8, 1133−1135.
Also see the following review: (e) Ohmiya, H. N-Heterocyclic
̈
(8) Piel, I.; Pawelczyk, M. D.; Hirano, K.; Frohlich, R.; Glorius, F. A
Family of Thiazolium Salt Derived N-Heterocyclic Carbenes (NHCs)
for Organocatalysis: Synthesis, Investigation and Application in Cross-
Benzoin Condensation. Eur. J. Org. Chem. 2011, 2011, 5475−5484.
(9) Nakanishi, I.; Itoh, S.; Fukuzumi, S. Electron-Transfer Properties
of Active Aldehydes of Thiamin Coenzyme Models, and Mechanism
of Formation of the Reactive Intermediates. Chem. - Eur. J. 1999, 5,
2810−2818.
(10) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A.
Direct Nucleophilic Acylation of Nitroalkenes Promoted by a
Fluoride Anion/Thiourea Combination. J. Am. Chem. Soc. 2006,
128, 4932−4933.
(11) The reaction between a silylated thiazolium benzyl alcohol and
2a, using stoichiometric amounts of TBAF and Cs2CO3 in DMSO at
8528
https://dx.doi.org/10.1021/acscatal.0c02849
ACS Catal. 2020, 10, 8524−8529

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
60 °C, produced the corresponding ketone product, 2,2-dimethyl-
propiophenone in 33% yield. See ref 6a.
(12) To explore the effect of counteranion of the NHC precursor, a
catalytic amount (10 mol %) of KI or KBr was added into the optimal
conditions with N10, respectively. A slight decrease in product yields
was observed (KI, 43% and KBr, 46%). Thus, the effect was not
essential.
(13) When the product yield was low in Table 1C, significant
amounts of the self-aldol product and the carboxylic acid that stem
from the redox ester were observed.
(14) Leifert, D.; Studer, A. The Persistent Radical Effect in Organic
Synthesis. Angew. Chem., Int. Ed. 2020, 59, 74−108.
(15) (a) Moore, J. L.; Silvestri, A. P.; de Alaniz, J. R.; DiRocco, D.
A.; Rovis, T. Mechanistic Investigation of the Enantioselective
Intramolecular Stetter Reaction: Proton Transfer Is the First
Irreversible Step. Org. Lett. 2011, 13, 1742−1745. (b) Domingo, L.
́
́
́
R.; Zaragoza, R. J.; Saez, J. A.; Arno, M. Understanding the
Mechanism of the Intramolecular Stetter Reaction. A DFT Study.
Molecules 2012, 17, 1335−1353. (c) Collett, C. J.; Massey, R. S.;
Maguire, O. R.; Batsanov, A. S.; O’Donoghue, A. C.; Smith, A. D.
Mechanistic Insights into the Triazolylidene-Catalysed Stetter and
Benzoin Reactions: Role of the N-Aryl Substituent. Chem. Sci. 2013,
4, 1514−1522.
(16) The triazolium type NHCs, which could facilitate the
deprotonation step, did not work in this radical catalysis. This
might be due to the lower reducing property of the corresponding
Breslow intermediate than that of the thiazolium-derived Breslow
intermediate.
8529
https://dx.doi.org/10.1021/acscatal.0c02849
ACS Catal. 2020, 10, 8524−8529