Radical N-heterocyclic carbene catalysis for β-ketocarbonyl synthesis

Article abstract of DOI:10.1016/j.tet.2021.132212

N-Heterocyclic carbene-catalyzed radical cross-coupling between aldehydes and α-bromoesters or α-bromoamides is described. β-Ketocarbonyl compounds having a quaternary carbon center at the α-position can be synthesized under mild reaction conditions. Both aromatic and aliphatic aldehydes are suitable acyl donors by employing proper NHC catalyst precursors.

Full text of DOI:10.1016/j.tet.2021.132212

Tetrahedron 91 (2021) 132212
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical N-heterocyclic carbene catalysis for
b
-ketocarbonyl synthesis
,
,
b
,
*
Takuya Ishii a, Kazunori Nagao a **, Hirohisa Ohmiya a
a Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
b JST, PRESTO, Saitama, 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Heterocyclic carbene-catalyzed radical cross-coupling between aldehydes and
bromoamides is described. b-Ketocarbonyl compounds having a quaternary carbon center at the a-po-
sition can be synthesized under mild reaction conditions. Both aromatic and aliphatic aldehydes are
suitable acyl donors by employing proper NHC catalyst precursors.
© 2021 Elsevier Ltd. All rights reserved.
a
-bromoesters or
a-
Received 8 April 2021
Received in revised form
27 April 2021
Accepted 1 May 2021
Available online 7 May 2021
Keywords:
N-Heterocyclic carbene
Radical
Aldehyde
b
-Ketocarbonyls
1. Introduction
intermediate is utilized in various natural reactions [5]. Based on
these usages, NHC catalysis including the SET sequence has been
Carbonecarbon bond formation at desired positions is one of
the most essential goals in synthetic chemistry, and organocatalysis
plays a significant role in this context [1]. Most of these methods do
not require harsh conditions or highly reactive reagents, which are
often required in classical stoichiometric or transition-metal-
catalyzed reactions. Organocatalysis through polar mechanisms
has been widely accepted for a long time as a practical tool to edit
chemical bonds. Reaction pathways involving radical intermediates
have also been actively studied [2]. The high tolerance to steric
hindrance of radical species allows the construction of bulky
building blocks that cannot be accessed by the conventional polar
mechanism.
N-Heterocyclic carbenes (NHCs) are well-known organo-
catalysts [3]. The NHC reacts with an aldehyde to form an enol-type
species, a so-called Breslow intermediate [4]. By inverting the
electrophilic nature of the aldehyde, the Breslow intermediate can
act as an acyl anion equivalent. NHCs have been widely used as
catalysts for acylation reactions, such as the benzoin condensation
and Stetter reaction [3a,3d]. In contrast to polar reactivity, it is
known that the single electron transfer (SET) ability of the Breslow
investigated by several groups [6].
Previously, we reported the NHC-catalyzed decarboxylative
cross-coupling between aldehydes and aliphatic carboxylic acid-
derived redox active esters, providing sterically hindered ketones
(Scheme 1A) [7a]. Under basic conditions, a thiazolium-type NHC
reacts with an aldehyde to generate an enolate form of the Breslow
intermediate, which has exceptionally low oxidation potential [8].
A SET from the enolate form of the Breslow intermediate to a redox
active ester occurs to form the Breslow intermediate-derived ketyl
radical and the alkyl radical after decarboxylation. The generated
radicals then selectively cross-couple to furnish the desired ketone.
After our reports, many types of radical NHC organocatalysis were
demonstrated [7,9,10]. Specifically, radical-relay type alkylacylation
of vinylarenes was extensively studied [9]. However, useable alkyl
radical precursors for direct coupling with the ketyl radical have
been limited to redox active esters [7a,7b], Katritzky salts [7c] and
oxime derivatives [7d]. We recently introduced another example of
radical NHC catalysis enabling the alkylation of aliphatic aldehydes
with
a
-bromoamides [7b]. Because we provided only two examples
-hal-
in the previous report [7b], we considered whether other
a
ocarbonyl compounds could be used as alkyl radical donors for
radical NHC organocatalysis.
Herein, we report that a radical NHC organocatalysis enabled
* Corresponding author.
** Corresponding author.
E-mail addresses: nkazunori@p.kanazawa-u.ac.jp (K. Nagao), ohmiya@p.
kanazawa-u.ac.jp (H. Ohmiya).
the coupling of aldehydes and
ducing -ketocarbonyls bearing a quaternary carbon center at the
-position (Scheme 1B). This reaction demonstrates an expansion
a-bromocarbonyl compounds, pro-
b
a
https://doi.org/10.1016/j.tet.2021.132212
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

T. Ishii, K. Nagao and H. Ohmiya
Tetrahedron 91 (2021) 132212
transition-metal catalysis, gave high yields. Aldehydes containing
heteroarenes such as pyridine, furan and thiophene also gave
tolerable yields of the products (3gaꢁ3ia). 2-Naphthaldehyde fur-
nished the corresponding product in high yield (3ja). With aliphatic
aldehydes, this protocol provided the desired products using N4
instead of N1 as the NHC precursor (Table 2B). Linear and cyclic
aliphatic moieties were totally acceptable (3 kbꢁ3 mb). A substrate
containing a free alcohol did not affect the reactivity of the catalysis
(3 nb).
a
-Bromoesters and a-bromoamides were also examined
(Table 3). Esters with linear and cyclic alkyl moieties provided the
corresponding products in moderate yields (3ac and 3ad). An ether
structure in the substrate was tolerated (3ae). For the amides,
morpholine and pyrrolidine substructures furnished the corre-
sponding products (3af and 3 ag). Amides derived from glycine and
glycine-alanine dipeptide underwent the coupling (3lh and 3li)
[7b].
A proposed mechanism of this radical NHC catalysis is depicted
in Fig. 1. First, aldehyde (1) and NHC react to form a neutral Breslow
intermediate (A). A base (Cs2CO3) deprotonates the enol OH of A,
converting it into the highly reducing enolate form of the Breslow
intermediate (B). Next, SET occurs between the enolate B and a-
bromocarbonyl (2) to provide a ketyl radical (C) and an alkyl radical
(D), respectively. Comparing the oxidation potential of enolate in-
termediate B (Eox ¼ ꢁ1.15 V vs. SCE in DMSO, see Supplementary
Scheme 1. Radical NHC Catalysis.
Material) and reduction potentials of a-bromocarbonyl compounds
(Ered ¼ ꢁ0.77 V vs. SCE in DMSO), the corresponding electron
of useable alkyl radical precursors for radical NHC organocatalysis,
and offers a new method for construction of quaternary carbon
centers under mild reaction conditions without transition metals or
light irradiation.
transfer would be thermodynamically feasible. Finally, the
radicalꢁradical coupling between
C and D to make a new
carbonꢁcarbon bond followed by the elimination of NHC furnishes
the desired alkyl ketone (3) with regeneration of the NHC catalyst.
b
-Ketocarbonyls with a quaternary carbon at the
a-position
have been commonly synthesized by -alkylation of the corre-
a
3. Conclusion
sponding activated methylene substrates through deprotonation by
a strong base or transition-metal catalyst [11]. In these methods,
useable functional groups are limited. Under high basic conditions,
In summary, we developed a cross-coupling reaction between
aldehydes and
NHC catalysis. This method provides sterically hindered
a
-bromoesters or
a
-bromoamides through radical
acidic protons and easily-isomerized
p-bonds are of concern.
b-keto-
Furthermore, aryl halides might undergo undesired oxidative
addition to a transition metal center. We believed that our radical
NHC catalysis could overcome these problems and provide a new
single-step synthesis of 1,3-dicarbonyl compounds.
carbonyl compounds with high functional group tolerance without
high temperature or light irradiation. Both aromatic and aliphatic
aldehydes were suitable acyl donors in this NHC catalysis by
employing proper NHC precursors. This development demon-
strates an expansion of substrates for radical NHC catalysis, and
offers a new method for the construction of quaternary carbon
centers. Further applications of the radical NHC catalysis are being
investigated in our laboratory.
2. Results and discussion
Based on previous reports [7a,7b,9a,9b], the reaction between
benzaldehyde (1a) (0.3 mmol) and ethyl 2-bromoisobutyrate (2a)
(0.2 mmol) was conducted with addition of a catalytic amount of N-
2,6-diisopropylphenyl-substituted seven-membered ring fused
thiazolium salt (N1) (5 mol %) as the NHC precursor and Cs2CO3
(0.22 mmol) as the base in DMSO at 60 ꢀC to afford the corre-
4. Experimental section
4.1. Instrumentation and chemicals
sponding
b
-ketoester (3aa) in 89% yield (Table 1, entry 1). The
NMR spectra were recorded on a Bruker AVANCE NEO 400 N
structure of the catalyst was critical for the reaction to proceed.
Changing the backbone structure into a six-membered ring (N2) or
changing substituent groups on the nitrogen of the thiazolium ring
(N3 and N4) reduced the product yield (entries 2e4). Triazolium
salt (N5) and imidazolium salt (N6) were not effective in this
method (entries 5 and 6). Changing the base to K2CO3 showed the
same level of reactivity (entry 7), though DBU and Et3N furnished
the product in lower yield (entries 8 and 9). THF and MeCN were
not as efficient solvents as DMSO (entries 10 and 11).
With the optimized reaction conditions in hand, the scope of
substrates was investigated. A wide range of aromatic aldehydes
could be utilized in the reaction (Table 2A). Several functional
groups on the para-position were applicable (3baꢁ3fa). Notably,
halogen-substituted aldehydes, which are not compatible in
spectrometer, operating at 400 MHz for 1H NMR, 100.6 MHz for 13
C
C
NMR, 376.5 MHz for 19F NMR. Chemical shift values for 1H and 13
are referenced to Me4Si and the residual solvent resonances,
respectively. Chemical shifts were reported in ppm. DART-Mass
d
and ESI-Mass spectra were measured with JMS-T100TD (JEOL
Ltd.). TLC analyses were performed on commercial glass plates
bearing 0.25-mm layer of Merck Silica gel 60F254. Silica gel
(Wakosil® 60, 64e210 mm) was used for column chromatography.
Biotage Selekt was used for purification. IR spectra were measured
with a Thermo Scientific iD7 ATR Accessory for the Thermo Sci-
entific Nicolet iS5 FT-IR Spectrometer. Melting points were
measured on a Stanford Research Systems MPA100. CV measure-
ments were recorded with a Hokuto Denko HZ-7000 potentiostat.
All reactions were carried out under nitrogen atmosphere.
2

T. Ishii, K. Nagao and H. Ohmiya
Tetrahedron 91 (2021) 132212
Table 1
4.2. Procedure for coupling between aldehydes and
bromocarbonyls
a-
Optimization of Reaction Conditions.a
The reaction in Table 1, entry 1 is representative. Thiazolium salt
N1 (4.1 mg, 0.01 mmol) was placed in a schlenk tube containing a
magnetic stirring bar. The tube was sealed with a Teflon®-coated
silicon rubber septum, and then the tube was evacuated and filled
with nitrogen. Degassed DMSO (400
Next, benzaldehyde 1a (30.3 L, 0.3 mmol) and 2-bromoisobutyrate
2a (29.8
mL) was added to the tube.
m
m
L, 0.2 mmol) were added. Then, Cs2CO3 (71.7 mg,
0.22 mmol) was added. After 4 h stirring at 60 ꢀC, the reaction
mixture was treated with saturated NH4Cl aqueous solution
(400 mL), then extracted with diethyl ether (4 times) and dried over
sodium sulfate. After filtration, the resulting solution was evapo-
rated under reduced pressure. After volatiles were removed under
reduced pressure, flash column chromatography on silica gel
(98:2e90:10, hexane/EtOAc) gave 3aa (39.0 mg, 0.177 mmol) in 89%
yield.
4.3. Characterization of new compounds
4.3.1. Ethyl 2,2-dimethyl-3-oxo-3-phenylpropanoate (3aa)
Pale yellow oil. IR (neat) 1734, 1681, 1598, 1581, 1466, 1447, 1385,
1366, 1266, 1173, 1138 cmꢁ1.1H NMR (400 MHz, CDCl3)
d 7.84 (d,
J ¼ 7.8 Hz, 2H), 7.52 (t, J ¼ 7.8 Hz, 1H), 7.42 (t, J ¼ 7.8 Hz, 2H), 4.11 (q,
J ¼ 7.2 Hz, 2H), 1.55 (s, 6H), 1.05 (t, J ¼ 7.2 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3)
d 197.8, 175.0, 135.2, 132.6, 128.6, 128.4, 61.3,
53.3, 23.9, 13.7. HRMSeDART (m/z): [M]þ calcd for C13H16O3þ,
220.1094; found, 220.1098.
4.3.2. Ethyl 2,2-dimethyl-3-oxo-3-(p-tolyl)propanoate (3ba)
The product 3ba was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 35.0 mg,
0.149 mmol, 75% isolated yield). Pale yellow oil. IR (neat) 1735,1681,
1608, 1573, 1466, 1385, 1270, 1175, 1139, 1028 cmꢁ1.1H NMR
(400 MHz, CDCl3)
d
7.75 (d, J ¼ 8.0 Hz, 2H), 7.10 (d, J ¼ 8.0 Hz, 2H),
4.12 (q, J ¼ 7.2 Hz, 2H), 2.39 (s, 3H), 1.53 (s, 6H), 1.06 (t, J ¼ 7.2 Hz,
3H). 13C NMR (100.6 MHz, CDCl3)
d 197.3, 175.2, 143.4, 132.5, 129.1,
128.8, 61.3, 53.1, 23.9, 21.5, 13.8. HRMSeDART (m/z): [MþH]þ calcd
for C14H19Oþ3 , 235.1329; found, 235.1321.
aReaction was carried out with 1a (0.3 mmol), 2a (0.2 mmol), NHC precursor (0.01
mmol), and Cs2CO3 (0.22 mmol) in DMSO (0.4 mL) at 60 ꢀC for 4 h. DMSO ¼ dimethyl
sulfoxide. DBU ¼ 1,8-diazabicyclo[5.4.0]-7-undecene. bNMR yield using 1,1,2,2-
tetrachloroethane as an internal standard. cIsolated yields shown in parentheses.
4.3.3. Ethyl 3-(4-methoxyphenyl)-2,2-dimethyl-3-oxopropanoate
(3ca)
The product 3ca was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e85:15, hexane/EtOAc) (Table 2, 42.8 mg,
0.17 mmol, 86% isolated yield). Pale yellow oil. IR (neat) 1732, 1675,
1601, 1576, 1512, 1465, 1385, 1313, 1259, 1172, 1139 cmꢁ1.1H NMR
Materials were obtained from commercial suppliers or prepared
according to standard procedures unless otherwise noted. Cs2CO3
was purchased from FUJIFILM Wako Pure Chemical Industries,
stored under nitrogen, and used as received. K2CO3 and DBU were
purchased from Tokyo Chemical Industry Co., stored under nitro-
gen, and used as received. DMSO, THF and was purchased from
FUJIFILM Wako Pure Chemical Co., stored under nitrogen, and used
as received. MeCN was purchased from Kanto Chemical Co., stored
under nitrogen, and used as received. Thiazolium salt N1eN4 were
prepared by the reported procedure [12]. Triazolium salt N5 [13]
and imidazolium salt N6 [14] were prepared by the reported pro-
cedure. Aldehydes 1a, 1d and 1e were purchased from Nacalai
Tesque Inc., 1b and 1j were purchased from FUJIFILM Wako Pure
Chemical Co., 1c, 1fe1i, 1ke1n were purchased from Tokyo
Chemical Industry Co., stored under nitrogen, and used as received.
(400 MHz, CDCl3)
4.12 (q, J ¼ 7.2 Hz, 2H), 3.86 (s, 3H), 1.53 (s, 6H), 1.07 (t, J ¼ 7.2 Hz,
3H). 13C NMR (100.6 MHz, CDCl3)
196.2, 175.4, 163.0, 131.0, 127.9,
113.6, 61.3, 55.4, 53.0, 24.0, 13.8. HRMSeDART (m/z): [M]þ calcd for
14H18Oþ4 , 250.1200; found, 250.1201.
d
7.85 (d, J ¼ 8.0 Hz, 2H), 6.89 (d, J ¼ 8.0 Hz, 2H),
d
C
4.3.4. Ethyl 3-(4-chlorophenyl)-2,2-dimethyl-3-oxopropanoate
(3da)
The product 3da was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 31.5 mg,
0.123 mmol, 62% isolated yield). Pale yellow oil. IR (neat) 1736,
1683, 1589, 1489, 1466, 1385, 1267, 1174, 1139, 1092 cmꢁ1.1H NMR
a
-Bromoester 2a was purchased from Tokyo Chemical Industry Co.,
stored under nitrogen, and used as received. -Bromoesters 2be2e
were prepared by the reported procedure [15]. -Bromoamides 2f
(400 MHz, CDCl3)
d
7.70 (d, J ¼ 8.0 Hz, 2H), 7.30 (d, J ¼ 8.0 Hz, 2H),
a
4.12 (q, J ¼ 7.2 Hz, 2H), 1.53 (s, 6H), 1.08 (t, J ¼ 7.2 Hz, 3H). 13C NMR
a
(100.6 MHz, CDCl3)
d 196.5, 174.8, 139.1, 133.4, 130.1, 128.8, 61.5,
and 2g were prepared by the reported procedure [9b,16]. Prepa-
ration of 3lh and 3li have been reported in reference 7b.
53.2, 23.8, 13.8. HRMSeDART (m/z): [M]þ calcd for C13H15O3Clþ,
254.0704; found, 254.0702.
3

T. Ishii, K. Nagao and H. Ohmiya
Tetrahedron 91 (2021) 132212
Table 2
Scope of Aldehydes.
Table 3
Scope of a .
-Bromocarbonyls a
aReaction was carried out with 1 (0.3 mmol), 2 (0.2 mmol), N1 (0.01 mmol), and
Cs2CO3 (0.22 mmol) in DMSO (0.4 mL) at 60 ꢀC for 4 h. Isolated yields are shown.
bReaction was carried out with 1 (0.3 mmol), 2 (0.2 mmol), N4 (0.02 mmol), and
Cs2CO3 (0.24 mmol) in DCM (0.4 mL) at 60 ꢀC for 4 h.
0.083 mmol, 42% isolated yield). Pale yellow oil. IR (neat) 1739,
1694, 1593, 1555, 1467, 1408, 1387, 1367, 1267, 1174, 1142 cmꢁ1.1H
NMR (400 MHz, CDCl3)
d
8.76 (d, J ¼ 4.8 Hz, 2H), 7.60 (d, J ¼ 4.8 Hz,
2H),4.13 (q, J ¼ 7.2 Hz, 2H), 1.55 (s, 6H), 1.08 (t, J ¼ 7.2 Hz, 3H). 13
C
aReaction was carried out with 1 (0.3 mmol), 2a (0.2 mmol), N1 (0.01 mmol), and
Cs2CO3 (0.22 mmol) in DMSO (0.4 mL) at 60 ꢀC for 4 h. bReaction was carried out
with 1(0.3 mmol), 2a (0.2 mmol), N4 (0.02 mmol), and Cs2CO3 (0.24 mmol) in DMSO
(0.4 mL) at 60 ꢀC for 4 h.
NMR (100.6 MHz, CDCl3) d 197.4, 174.0, 150.7, 141.6, 121.5, 61.7, 53.6,
23.4, 13.7. HRMSeDART (m/z): [M]þ calcd for C12H15NO3þ, 221.1046;
found, 221.1051.
4.3.8. Ethyl 3-(furan-2-yl)-2,2-dimethyl-3-oxopropanoate (3ha)
The product 3ha was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 15.4 mg,
0.073 mmol, 37% isolated yield). Pale yellow oil. IR (neat) 1741, 1677,
1567, 1465, 1384, 1366, 1284, 1254, 1176, 1144, 1028 cmꢁ1.1H NMR
4.3.5. Ethyl 3-(4-bromophenyl)-2,2-dimethyl-3-oxopropanoate
(3ea)
The product 3ea was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 38.3 mg,
0.128 mmol, 64% isolated yield). Pale yellow oil. IR (neat) 1735,
1684, 1534, 1484, 1466, 1445, 1396, 1266, 1174, 1138 cmꢁ1.1H NMR
(400 MHz, CDCl3)
d 7.52 (s, 1H), 7.22 (s, 1H), 6.52 (s, 1H), 4.23 (q,
J ¼ 6.8 Hz, 2H), 1.50 (s, 6H), 1.09 (t, J ¼ 6.8 Hz, 3H). 13C NMR
(400 MHz, CDCl3)
d
7.71 (d, J ¼ 8.4 Hz, 2H), 7.56 (d, J ¼ 8.4 Hz, 2H),
(100.6 MHz, CDCl3) d 187.2, 174.0, 151.5, 145.7, 117.7, 112.2, 61.1, 52.7,
4.12 (q, J ¼ 7.2 Hz, 2H), 1.53 (s, 6H), 1.08 (t, J ¼ 7.2 Hz, 3H). 13C NMR
22.5, 13.9. HRMSeDART (m/z): [M]þ calcd for C11H14O4þ, 210.0887;
(100.6 MHz, CDCl3)
d 196.7, 174.7, 133.8, 131.8, 130.2, 127.8, 61.5,
found, 210.0882.
53.2, 23.8, 13.8. HRMSeDART (m/z): [M]þ calcd for C13H15O3Brþ,
298.0199; found, 298.0191.
4.3.9. Ethyl 2,2-dimethyl-3-oxo-3-(thiophen-2-yl)propanoate (3ia)
The product 3ia was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 32.4 mg,
0.143 mmol, 72% isolated yield). Pale yellow oil. IR (neat) 1731, 1659,
1517, 1466, 1412, 1386, 1366, 1353, 1270, 1245, 1176, 1140 cmꢁ1.1H
4.3.6. Ethyl 2,2-dimethyl-3-oxo-3-(4-(trifluoromethyl)phenyl)
propanoate (3fa)
The product 3fa was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 48.9 mg,
0.170 mmol, 85% isolated yield). Pale yellow oil. IR (neat) 1738, 1691,
1468, 1409, 1387, 1368, 1327, 1267, 1169, 1130, 1068 cmꢁ1.1H NMR
NMR (400 MHz, CDCl3)
d 7.62e7.58 (m, 2H), 7.08 (m, 1H), 4.12 (q,
J ¼ 7.2 Hz, 2H), 1.55 (s, 6H), 1.11 (t, J ¼ 7.2 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3)
d 190.9, 174.5, 142.1, 133.4, 131.6, 128.0, 61.4,
53.7, 23.7, 13.8. HRMSeDART (m/z): [MþH]þ calcd for C11H15O3Sþ,
(400 MHz, CDCl3)
d
7.94 (d, J ¼ 8.0 Hz, 2H), 7.69 (d, J ¼ 8.0 Hz, 2H),
4.13 (q, J ¼ 7.2 Hz, 2H), 1.56 (s, 6H), 1.07 (t, J ¼ 7.2 Hz, 3H). 13C NMR
227.0736; found, 227.0739.
(100.6 MHz, CDCl3)
d
196.9, 174.5, 138.1, 134.0 (q, JCeF ¼ 33 Hz),
128.9, 125.5 (q, JCeF ¼ 4 Hz), 123.5 (q, JCeF ¼ 271 Hz), 61.6, 53.5, 23.7,
4.3.10. Ethyl 2,2-dimethyl-3-(naphthalen-2-yl)-3-oxopropanoate
(3ja)
The product 3ja was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e85:15, hexane/EtOAc) (Table 2, 49.2 mg,
0.182 mmol, 91% isolated yield). Pale yellow oil. IR (neat) 1732,1680,
1627, 1597, 1466, 1386, 1366, 1270, 1172, 1140, 1119 cmꢁ1.1H NMR
13.7.19F NMR (376.5 MHz, CDCl3)
d
63.20. HRMSeDART (m/z): [M]þ
calcd for C14H15O3Fþ3 , 288.0968; found, 288.0969.
4.3.7. Ethyl 2,2-dimethyl-3-oxo-3-(pyridin-4-yl)propanoate (3ga)
The product 3ga was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e70:30, hexane/EtOAc) (Table 2, 18.4 mg,
(400 MHz, CDCl3)
d 8.37 (s, 1H), 7.94e7.92 (m, 2H), 7.87e7.85 (m,
4

T. Ishii, K. Nagao and H. Ohmiya
Tetrahedron 91 (2021) 132212
0.152 mmol, 76% isolated yield). Pale yellow oil. IR (neat) 1739, 1710,
1498, 1457, 1387, 1368, 1264, 1213, 1143, 1046 cmꢁ1.1H NMR
(400 MHz, CDCl3)
d 7.37e7.30 (m, 5H), 5.16 (s, 2H), 2.32 (dd,
J ¼ 6.0 Hz,17.2 Hz,1H), 2.10 (dd, J ¼ 7.2 Hz,17.2 Hz,1H), 2.01 (m,1H),
1.41e1.14 (m, 6H) 1.37 (s, 6H), 1.19 (s, 6H), 1.02 (m, 1H), 0.78 (d,
J ¼ 8.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3)
d 207.3, 173.5, 135.4,
128.6, 128.4, 128.3, 70.9, 66.9, 55.8, 45.3, 43.9, 37.0, 29.3, 29.1, 28.3,
21.90, 21.85, 21.6, 19.5. HRMSeDART (m/z): [M þ NH4]þ calcd for
C
21H36NOþ4 , 366.2639; found, 366.2634.
4.3.15. Ethyl 2-benzoyl-2-ethylbutanoate (3ac)
The product 3ac was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e80:20, hexane/EtOAc) (Table 3, 37.0 mg,
0.149 mmol, 75% isolated yield). Pale yellow oil. IR (neat) 1732,
1680, 1598, 1580, 1448, 1387, 1367, 1300, 1232, 1212, 1130 cmꢁ1.1H
NMR (400 MHz, CDCl3)
d
7.82 (d, J ¼ 7.2 Hz, 2H), 7.51 (t, J ¼ 7.2 Hz,
1H), 7.40 (t, J ¼ 7.2 Hz, 2H), 4.12 (q, J ¼ 7.2 Hz, 2H), 2.10 (q, J ¼ 7.6 Hz,
4H), 1.06 (t, J ¼ 7.2 Hz, 3H), 0.76 (t, J ¼ 7.6 Hz, 6H). 13C NMR
Fig. 1. Proposed mechanism.
(100.6 MHz, CDCl3)
d 197.5, 173.8, 136.1, 132.5, 128.4, 128.3, 61.3,
61.1, 24.5, 13.8, 7.8. HRMSeDART (m/z): [M]þ calcd for C15H20O3þ,
2H), 7.62e7.52 (m, 2H), 4.13 (q, J ¼ 7.2 Hz, 2H), 1.62 (s, 6H), 1.03 (t,
248.1407; found, 248.1401.
J ¼ 7.2 Hz, 3H). 13C NMR (100.6 MHz, CDCl3)
d 197.6, 175.2, 135.2,
132.42, 132.35, 130.1, 129.6, 128.5, 128.2, 127.6, 126.7, 124.6, 61.4,
53.4, 24.1, 13.8. HRMSeDART (m/z): [M]þ calcd for C17H18O3þ,
270.1251; found, 270.1250.
4.3.16. Ethyl 1-benzoylcyclohexane-1-carboxylate (3ad)
The product 3ad was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 3, 33.7 mg,
0.137 mmol, 68% isolated yield). Pale yellow oil. IR (neat) 1733,
1682, 1598, 1579, 1450, 1433, 1302, 1240, 1219, 1182, 1137 cmꢁ1.1H
4.3.11. Benzyl 4-ethyl-3-hydroxy-2,2-dimethylhex-3-enoate (3 kb)
The product 3 kb was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 14.9 mg,
0.0539 mmol, 27% isolated yield). 3 kb was isolated as enol form.
Pale yellow oil. IR (neat) 1736, 1676, 1457, 1384, 1364, 1279, 1178,
NMR (400 MHz, CDCl3)
1H), 7.41 (t, J ¼ 7.2 Hz, 2H), 3.65 (s, 3H), 2.12e2.09 (m, 4H),
1.66e1.45 (m, 6H). 13C NMR (100.6 MHz, CDCl3)
198.2,174.4,136.2,
d
7.78 (d, J ¼ 7.2 Hz, 2H), 7.50 (d, J ¼ 7.2 Hz,
d
132.3, 128.4, 128.3, 58.0, 52.4, 32.4, 25.4, 22.3. HRMSeDART (m/z):
1132, 1078, 1051 cmꢁ1.1H NMR (400 MHz, CDCl3)
d 7.36e7.30 (m,
[MþH]þ calcd for C15H19Oþ3 , 247.1329; found, 247.1328.
5H), 5.80 (s, 1H), 5.19 (s, 2H), 2.10 (q, J ¼ 7.6 Hz, 2H), 1.89 (dq, J ¼ 7.6,
1.2 Hz, 2H), 1.48 (s, 6H), 0.94 (t, J ¼ 7.6 Hz, 3H), 0.93 (t, J ¼ 7.6 Hz,
4.3.17. Methyl 4-benzoyltetrahydro-2H-pyran-4-carboxylate (3ae)
The product 3ae was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e80:20, hexane/EtOAc) (Table 3, 37.4 mg,
0.151 mmol, 75% isolated yield). Pale yellow oil. IR (neat) 1735,1683,
1597, 1446, 1389, 1350, 1299, 1253, 1198, 1137, 1107, 1078 cmꢁ1.1H
3H). 13C NMR (100.6 MHz, CDCl3)
d 173.9, 135.8, 133.8, 128.5, 128.2,
128.0, 125.5, 78.4, 66.7, 24.9, 24.3, 19.9, 13.1, 12.4. HRMSeDART (m/
z): [MþH]þ calcd for [MþH]þ calcd for C17H25Oþ3 , 277.1798; found,
277.1792.
NMR (400 MHz, CDCl3)
1H), 7.43 (t, J ¼ 7.2 Hz, 2H), 3.83e3.78 (m, 2H), 3.72e3.66 (m, 2H),
3.69 (s, 3H), 2.27e2.24 (m, 4H). 13C NMR (100.6 MHz, CDCl3)
196.5,
173.4, 135.4, 132.8, 128.6, 128.4, 64.2, 55.4, 52.7, 31.9. HRMSeDART
(m/z): [M]þ calcd for C14H16Oþ4 , 248.1043; found, 248.1048.
d
7.81 (d, J ¼ 7.2 Hz, 2H), 7.54 (t, J ¼ 7.2 Hz,
4.3.12. Benzyl 3-cyclohexyl-2,2-dimethyl-3-oxopropanoate (3lb)
The product 3lb was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2, 27.6 mg,
0.096 mmol, 47% isolated yield). Pale yellow oil. IR (neat) 1739,
1708, 1452, 1387, 1366, 1318, 1261, 1147, 1134, 1064 cmꢁ1.1H NMR
d
(400 MHz, CDCl3)
d 7.38e7.26 (m, 5H), 5.16 (s, 2H), 2.49 (m, 1H),
4.3.18. 2,2-Dimethyl-1-morpholino-3-phenylpropane-1,3-dione
(3af)
1.67e1.55 (m, 5H), 1.41 (s, 6H), 1.41e1.25 (m, 2H), 1.22e1.03 (m, 3H).
13C NMR (100.6 MHz, CDCl3)
d 211.1, 173.6, 135.3, 128.6, 128.5, 128.4,
The product 3af was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e70:30, hexane/EtOAc) (Table 3, 19.1 mg,
0.073 mmol, 37% isolated yield). Pale yellow oil. IR (neat) 1676,
1633, 1596, 1579, 1464, 1424, 1384, 1360, 1259, 1234, 1172,
67.0, 56.1, 47.5, 30.1, 25.6, 25.5, 21.8. HRMSeDART (m/z): [M]þ calcd
for C18H24Oþ3 , 288.1720; found, 288.1717.
1114 cmꢁ1.1H NMR (400 MHz, CDCl3)
d
8.00e7.98 (m, 2H), 7.58 (m,
1H), 7.47e7.26 (m, 2H), 3.61 (brs, 2H), 3.49 (brs, 2H), 3.08 (brs, 4H),
1.57 (s, 6H). 13C NMR (100.6 MHz, CDCl3)
200.4, 172.7, 134.6, 133.6,
4.3.13. Benzyl 3-cyclopropyl-2,2-dimethyl-3-oxopropanoate (3 mb)
The product 3 mb was purified by flash chromatography on
silica gel (Biotage Selekt, 98:2e90:10, hexane/EtOAc) (Table 2,
15.0 mg, 0.061 mmol, 30% isolated yield). Pale yellow oil. IR (neat)
1738, 1701, 1466, 1456, 1390, 1378, 1261, 1213, 1143, 1054 cmꢁ1.1H
d
129.2, 128.7, 66.5, 65.7, 53.6, 46.2, 43.0, 25.1. HRMSeDART (m/z):
[M]þ calcd for C15H19NO3þ, 261.1359; found, 261.1351.
NMR (400 MHz, CDCl3)
d 7.36e7.30 (m, 5H), 5.18 (s, 2H), 1.83 (m,
1H), 1.42 (s, 6H), 1.00e0.96 (m, 2H), 0.79e0.74 (m, 2H). 13C NMR
4.3.19. 2,2-Dimethyl-1-phenyl-3-(pyrrolidin-1-yl)propane-1,3-
dione (3 ag)
The product 3 ag was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e70:30, hexane/EtOAc) (Table 3, 8.4 mg,
0.0377 mmol, 17% isolated yield). Pale yellow oil. IR (neat) 1678,
1626, 1579, 1447, 1412, 1378, 1364, 1341, 1249, 1176, 1165 cmꢁ1.1H
(100.6 MHz, CDCl3)
d 207.7, 173.6, 135.6, 128.5, 128.3, 128.2, 66.9,
55.8, 21.8, 17.4, 11.6. HRMSeDART (m/z): [M]þ calcd for C15H18O3þ,
246.1251; found, 246.1251.
4.3.14. Benzyl 9-hydroxy-2,2,5,9-tetramethyl-3-oxodecanoate
(3 nb)
The product 3 nb was purified by flash chromatography on silica
gel (Biotage Selekt, 98:2e70:30, hexane/EtOAc) (Table 2, 52.9 mg,
NMR (400 MHz, CDCl3)
(m, 2H), 3.51e3.48 (m, 2H), 3.02e2.99 (m, 2H), 1.70e1.60 (m, 4H),
1.53 (s, 6H). 13C NMR (100.6 MHz, CDCl3)
200.1, 172.2, 135.0, 133.2,
d 7.99e7.97 (m, 2H), 7.54 (m, 1H), 7.44e7.40
d
5

T. Ishii, K. Nagao and H. Ohmiya
Tetrahedron 91 (2021) 132212
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128.8, 128.6, 54.2, 47.3, 46.1, 26.3, 24.2, 23.2. HRMSeDART (m/z):
[MþH]þ calcd for C15H20NO2, 246.1489; found, 246.1488.
Declaration of competing interest
(b) H. Ohmiya, ACS Catal. 10 (2020) 6862;
(c) L. Dai, S. Ye, Chin. Chem. Lett. 32 (2021) 660;
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
(d) X. Chen, H. Wang, Z. Jin, Y.R. Chi, Chin. J. Chem. 38 (2020) 1167.
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Acknowledgments
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This work was supported by JSPS KAKENHI Grant Numbers
JP21H04681, JP17H06449 (Hybrid Catalysis), JP20J20599 (JSPS
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Appendix A. Supplementary data
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