Organic Dye-Catalyzed Intermolecular Radical Coupling of α-Bromocarbonyls with Olefins: Photocatalytic Synthesis of 1,4-Ketocarbonyls Using Air as an Oxidant

Article abstract of DOI:10.1021/acs.joc.0c01985

An organic dye-catalyzed visible light-promoted ketocarbonylation protocol of vinyl arenes has been disclosed with the help of α-bromocarbonyls where aerial oxygen played a role of an oxidant to install the keto-oxygen functionality. This unique process i

Full text of DOI:10.1021/acs.joc.0c01985

pubs.acs.org/joc
Article
Organic Dye-Catalyzed Intermolecular Radical Coupling of
α‑Bromocarbonyls with Olefins: Photocatalytic Synthesis of 1,4-
Ketocarbonyls Using Air as an Oxidant
Soumyadeep Roy Chowdhury, Deepak Singh, Injamam Ul Hoque, and Soumitra Maity*
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ABSTRACT: An organic dye-catalyzed visible light-promoted ketocarbonylation protocol of vinyl arenes has been disclosed with
the help of α-bromocarbonyls where aerial oxygen played a role of an oxidant to install the keto-oxygen functionality. This unique
process is compatible with both internal and terminal olefins and tolerates a diverse array of functional groups (ketone, ester, amide,
diketones, ketoester, and malonate). This process is mild and environmentally friendly and deals with greener oxidants like oxygen,
affording 1,4-ketocarbonyls as a value-added end product.
by visible light. Due to their easy access and structural benefits
(contains two electrophilic groups: carbonyl and halide), α-
halocarbonyls have been widely used as a flexible substrate in
organic synthesis.13 Moreover, recent exploitation of these
substrates as a carbonylalkyl radical precursor under photo-
redox conditions further expands the scope of these substrates
in radical reactions under mild conditions.,13a14 Strategically,
oxidative coupling of the carbonyl alkyl radicals with a 2-C-
carbonyl synthon unit would render the title compound under
radical conditions. Indeed, this strategy has been commonly
adopted in the synthesis of γ-ketoesters, where α-haloesters
have been oxidatively coupled with functionalized alkenes: enol
ethers,15 enol ester,16 and enamines17 (serving as masked keto-
oxygen functionality) under radical conditions (Scheme 1B). A
similar strategy to access 1,4-ketocarbonyls from simple
unfunctionalized alkenes under photocatalytic conditions is
rarer and has typically been combined with Kornblum-type
oxidation18 sequence, whereby the cationic intermediate (II)
of the RPC process was trapped with an oxo-nucleophile,
usually DMSO, to introduce the keto-oxygen functionality.19,20
However, these methods are suffering by using highly
expensive heavy-metal photocatalysts under essentially de-
INTRODUCTION
■
1,4-Ketocarbonyl compounds have proven themselves a very
interesting and versatile building block to access some of the
extremely biologically important carbocyclic as well as
heterocyclic compounds1 since 1,4-ketocarbonyls can easily
be converted to five-membered heterocycles by Paal−Knorr
synthesis.2 Consequently, numerous attempts have been made
to figure out the synthetic route to access 1,4-ketocarbonyl
compounds. Traditional approaches to synthesize this class of
compounds involve Michael addition of an acyl anion
equivalent with unsaturated carbonyl derivatives3 and
nucleophilic substitution of α-haloketones with enolates4
(Scheme 1A). The conditions and substrates employed in
these reactions to generate the reactive intermediates often
result in limited scope and functional group compatibility.
Recently, numerous methods,5 including oxidative coupling of
enolates,6 addition of the homoenolate equivalent to acid
derivatives,7 and transition-metal-catalyzed couplings,8 have
been established to produce 1,4-ketocarbonyl compounds.9
But, these processes frequently suffered by use of metal
catalysts with multi-equivalent of toxic oxidants and/or harsh
reaction conditions. Despite all significant attempts, a mild
environmentally benign general synthetic route to 1,4-
ketocarbonyls is still desirable and would be of significant
utility.
Received: August 17, 2020
Owing to their inherent greener reaction parameters,10
recent years have witnessed the exploration of photoredox-
catalyzed organic transformations via a free-radical process,11
of particular attentiveness in the difunctionalization of alkenes
by the radical-polar crossover (RPC)12 mechanism promoted
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Scheme 1. Strategies of 1,4-Ketocarbonyl Synthesis and
Present Work
RESULTS AND DISCUSSION
■
Our initial study showed that the 1,4-ketoester 3a can be
formed with a promising 30% yield from 4-tert-butyl styrene
(1a) and ethyl 2-bromopropionate (2a) with 2 mol % Eosin Y
in the presence of triethyl amine in acetonitrile under air by
irradiation with blue LED light (Table 1, entry 1). Improve-
a
Table 1. Optimization of the Reaction Condition
b
entry
photocatalyst
base
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TMEDA
DBU
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
solvent
yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
Eosin Y
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
THF
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
30
25
22
20
18
24
15
12
56
44
36
62
75
42
0
Rose Bengal
4-CzIPN
methylene blue
rhodamin B
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
9.
10.
11.
12.
c
13.
d
14.
15.
e
16.
f
Eosin Y
Eosin Y
Eosin Y
0
0
0
17.
18.
a
Reaction was carried out with 1a (0.2 mmol), 2a (0.4 mmol), base
(0.4 mmol), photocatalyst (2 mol %), and solvent (2 mL) in a culture
b
tube at rt. irradiated with a 12 W blue LED for 6 h. Isolated yield.
c
d
Extra 1 equiv each of 2a and base were added after 3 h. Using pure
gassed reaction conditions and the substrate scopes were
mainly limited to haloesters19 and halodifluoro acetamides.20
On the other hand, oxygen is the simplest and environ-
mentally benign green oxidant and use of aerobic oxygen in
reaction medium is an attractive but very challenging goal in
developing new methods.21 We envision that radical trapping
of I with oxygen under oxidative conditions would render the
formidable mild technique to overcome previously mentioned
drawbacks. But, several obstacles need to be overcome to
achieve this goal. One is how to trap the radical intermediate I
with oxygen in a chemo-selective fashion without the influence
of competitive ATRA22 and radical dimerization reactions.23
The other potential side reaction is the photoredox-catalyzed
oxidative cleavage of alkenes to carbonyl compounds in the
presence of oxygen.24 To supress the damage of olefins
through this cleavage and promote the oxygenation of I, the
key challenge is finding an optimal oxygen stream. Addition-
ally, reductive dehalogenation of halocarbonyls25 by hydrogen
atom transfer (HAT) from an amine radical cation (usually
used to as a sacrificial electron donor in photocatalytic cycle)
further makes this strategy challenging.
e
f
oxygen. In the dark. Under degassed conditions.
ment in yield was not observed upon screening with other
organic photocatalysts such as Rose Bengal, 4-CzIPN,
methylene blue, and rhodamin B (entries 2−5). Different
common solvents like DCM, THF, and toluene did not
enhance the yield (entries 6−8) until changed to highly polar
solvent DMF with a satisfactory 56% yield (entry 9). This
reaction was very sensitive to base: although organic bases
(entries 10−12) could promote this transformation, inorganic
bases were just ineffective to start the reaction (see details in
Table S1). Among the organic bases screened, DIPEA was
proven to be the best fit with a yield of 62%. Further
optimization showed that when 2a (3 equiv) and base (3
equiv) were added into the solution in two portions, the yield
was improved to 75% (entry 13). Notably, conducting the
reaction with pure oxygen diminished the yield of 3a, possibly
due to the damage of styrene by oxidative cleavage under high
oxygen concentration (vide supra).24 Control experiments
revealed the importance of all these catalyst, light, air, and
bases (entries 15−18). No desired product was observed by
dropping any of these aforementioned components.
As part of our ongoing work on radical difunctionalization of
olefin,26 we report herein that by utilizing an organic dye Eosin
Y, oxidative radical coupling of styrenes and diverse
bromocarbonyls delivers 1,4-ketocarbonyls under mild aerobic
irradiation conditions (Scheme 1C). The reaction proceeds in
open air without the use of pure oxygen and exhibits broad
functional group compatibility.
With suitable conditions identified, the scope and generality
of the visible light-mediated metal-free coupling reaction were
investigated by employing a variety of styrenes. To explore the
scope of terminal olefins, vinyl arenes bearing electron-
donating and electron-withdrawing groups were examined
B
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a b
,
thoroughly (Scheme 2). It was found that that electronic effect
had a little influence on the reaction output as both para-
Scheme 3. Scope of α-Bromoesters
a b
,
Scheme 2. Scope of Olefins
a
Unless otherwise noted, all reactions were carried out with 1 (0.2
mmol), 2a (0.6 mmol), DIPEA (0.6 mmol), Eosin Y (2 mol %), and
DMF (2 mL) under air at rt. irradiated with a 12 W blue LED for 6 h.
b
2a and base were added in two portions at an interval of 3 h. Yields
of isolated products. Gram-scale reaction.
a
Unless otherwise noted, all reactions were carried out with 1c (0.2
mmol), 2 (0.6 mmol), DIPEA (0.6 mmol), Eosin Y (2 mol %), and
DMF (2 mL) under air at rt. irradiated with a 12 W blue LED for 6 h.
c
b
2 and base were added in two portions at an interval of 3 h. Yield of
isolated products.
substituted electron-donating groups like -alkyl (3a and 3c)
and -methoxy (3d) and electron-withdrawing groups like
-halogen (3e, 3f, and 3i), -nitrile (3g), -phenyl (3l) reacted in
more or less similar ways with moderate to good conversion of
products. Moreover, meta-substituted vinyl arenes (3h and 3j)
fairly took part in this reaction. Singly occupied ortho-
substituted styrene (3k) finds no problem with taking part in
this protocol albeit lower yield. But, vinyl mesitylene and
pentafluoro styrene bearing ortho-disubstitution around a
reacting double bond unfortunately failed to participate in
this process. Although the poor reactivity of ortho-substituted
styrenes could be correlated to their steric crowdedness around
the reaction center, the same for meta-substrates is unclear.
Pleasingly, styrenes bearing a fused aromatic ring (3m) or
heteroatom (3n) reacted smoothly under this condition. With
internal vinyl arenes (3o−3q), the reaction also proceeds
under standard conditions but with low yield and no
diastreoselectivity. Unfortunately, similar oxidative coupling
of aliphatic olefins with 2a, as proven with dodecene or
cyclohexene, failed to afford the desired product. Moreover, a
reaction attempt of α-substituted olefins, like α-methylstyrene
or α,β,β-trimethyl styrene, with 2a was proven to fail in this
condition.
phoryl (4c) and α-difluoro (4d), could also be accommodated
smoothly into the protocol to afford moderate yields.
Interestingly, the retention of a difluoro handle in product
4d provides an opportunity for further chemoselective
transformations.27 A biologically important γ-butyrolactone
unit could also be integrated as a coupling partner with its
corresponding α-bromo derivative. Moreover, highly congested
α-dialkyl bromoester (4f) containing a β-quaternary carbonyl
system also equally participated in this reaction but with a
lower yield. On the other hand, α-bromoketoesters containing
different benzoyl and ketomethyl groups all reacted smoothly
under the standard condition, generating the desired product
in moderate yields (4g−4k).
Halomalonates are prone to undergo reductive dehalogena-
tion under photoredox conditions, and thus, engagement of
them under intermolecular oxidative radical conditions is not
easy.28 Fortunately, a number of α-bromomalonates with a
diverse structural pattern have successfully participated in this
coupling process to deliver the desired products in moderate to
good yields (4l−4o). Interestingly, the product 4n, generated
from the reaction of mixed malonate, is useful for further
chemoselective functionalization of the ester groups.29
Next, we examined the substrate scope of various esters by
reacting with 4-methyl styrene (1c) under the optimized
conditions (Scheme 3). α-Bromoesters with varied substitution
at the alcohol part of ester have been found effective in this
process, giving moderate to good yields of corresponding
products (4a and 4b). Additionally, α-bromoesters bearing
different substituents, like biologically active α-diethoxyphos-
To further evaluate the potential of this strategy, we
surveyed with other α-bromo carbonyl derivatives: ketones
and amides, which have not been considered before and/or
reported to fail in a similar type of coupling reaction with
styrenes under photoredox conditions (Scheme 4).30a It was
C
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a b
,
adducts, as were detected in GC−MS analysis (Scheme 5a). A
similar trend of reaction inhibitions was also observed with
Scheme 4. Scope of α-Bromoketones and Amides
Scheme 5. Mechanistic Investigation
a
Unless otherwise noted, all reactions were carried out with 1c (0.2
mmol), 2 (0.6 mmol), DIPEA (0.6 mmol), Eosin Y (2 mol %), and
DMF (2 mL) under air at rt. irradiated with a 12 W blue LED for 6 h.
other radical quenchers: BHT and hydroquinone. This result
indicates that the reaction might follow a radical pathway, and
an α-carbonyl radical could be a reactive species in this
process. Moreover, this radical species could be easily trapped
by 1,1-diphenylethylene to obtain the product 8 in 43% yield
(Scheme 5b). Additionally, a radical-clock experiment further
confirmed the participation of an alkyl radical by the formation
of dihydronaphthalene derivative 10 resulting from radical
ring-opening cyclization of the cyclopropropylmethyl radical
(9i). In the presence of water or in a nitrogen atmosphere, the
formation of the keto-carbonyl 3c was retarded or completely
stopped, indicating that oxygen was essential and acted as the
sole oxidant in this transformation. To get a better perspective
on the photoreaction, we have analyzed the absorption profile
of all reaction components as well as a combination of them.
This UV−Vis study ruled out the formation of any photoactive
intermediates (EDA complexes) (see Figure S2 in the
Supporting Information). Eosin Y is the only constituent
among the reaction components with a significant absorbance
in the visible range. Furthermore, a Stern−Volmer fluorescence
quenching study31 was conducted to screen the kinetic
behavior of the exited Eosin Y in the presence of different
reacting components (see Figure S1 in the Supporting
Information). Moreover, light on/off experiments (Figure S5
in the Supporting Information) indicated that continuous
photoirradiation is essential for this reaction.34b
b
2 and base were added in two portions at an interval of 3 h. Yield of
c
isolated products. fac-Ir(ppy)3 (1 mol %) was used as a photocatalyst
and acetonitrile as a solvent.
noticeable that primary (5a and 5b) and secondary (5c and
5d) substituted bromoacetopenone produced the desired 1,4-
diketone products in moderate yield.30b Bromomethyl aliphatic
ketone, α-bromocyclohexanone, and α-bromo-1,3-diketone
also participated in this process but with low productivity
(5e and 5f). Due to their potential applications in medicinal
chemistry, next we investigated the possibilities of α-
bromoamides as the coupling partner in this process. But
unfortunately, they did not react under the standard
conditions. Further screwing the catalytic system with fac-
Ir(ppy)3 enables access to desired products, which were not
accessible by the previously reported Kornblum-type oxidation
strategy.19 With the revised catalytic system, the reactions of
olefin 1c with biologically important acetamide derivatives
were tested (Scheme 4b). α-Bromoamides with varied
functional groups at amide nitrogen including ether (5j),
amide(5k), and even amide with free N−H (5l) worked well
under this revised photocatalysis conditions, resulting in
corresponding keto-amide products in moderate to good
yields (5g−5l). Excitingly, non-carbonyl bromide, like α-
bromonitrile could also be directly coupled with olefin under
the normal conditions furnishing γ-keto nitrile 6 with moderate
yield, but unactivated alkyl bromide like 1-bromobutane was
found to be ineffective and cannot be accommodated into this
protocol.
On the basis of the abovementioned results and related
literature,32 a possible reaction mechanism was proposed, as
illustrated in Scheme 6. Initially, exposure of Eosin Y to visible
light results in the photoexcited Eosin Y*, which then reduces
(EEY·+/EY* = −1.11 V vs SCE in CH3CN)32d bromocarbonyl 11
(Ered = −0.80 V vs SCE in CH3CN)32e to α-carbonylmethyl
radical 12 by single-electron transfer (SET) and oxidizes itself
to Eosin Y·+. This process is supported by the Stern−Volmer
fluorescence quenching studies. The reduction of Eosin Y·+
To further explore and gain insight into the mechanism, few
controlled experiments were performed. When TEMPO
(radical scavenger) was introduced to the standard reaction
medium, production of 3c was completely shut down with the
formation of alkyl-TEMPO (7a) and benzyl-TEMPO (7b)
D
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developed, which provides a facile general strategy toward
the synthesis of 1,4-ketocarboyls. Various substitutions on
terminal as well as internal vinyl arenes can be well tolerated.
Various α-bromoesters and α-bromoketones also serve as
suitable substrates for this photocatalytic system. Moreover,
less reactive bromoacetamides have also been successfully
coupled with styrenes in this current protocol to get γ-
ketoamides of biological interest. A preliminary mechanistic
study indicated that a visible light-promoted radical pathway
was involved in this transformation with aerial oxygen as the
sole oxidant, which features this strategy as mild open flask
chemistry. Further studies relating expansion of this aerobic
coupling strategy to incorporate other functional groups are
underway in our group.
Scheme 6. Plausible Reaction Mechanism
(EEY·+/EY = 0.78 V vs SCE in CH3CN)32d by sacrificial electron
donor diisopropylethylamine (0.72 V vs SCE in CH3CN)11b
regenerates the catalyst in its neutral form and oxidizes itself to
the diisopropylethylamine radical cation. The electron-
deficient radical 12 then undergoes intermolecular addition
on the double bond of alkene, affording benzyl radical 13. The
latter then reacts with oxygen and generates the peroxy radical
14, which upon combination with 13 followed by fragmenta-
tion converted to an alkoxy radical 15.33 This alkoxy radical
upon 1,2-hydrogen atom transfer (HAT) rearranges to a
carbon-centered radical 16,32a which undergoes oxidation
either by chain-terminating photogenerated amine radical
cation or by chain-propagating electron transfer to another
equivalent of substrate. Finally, deprotonation of 17 affords
desired keto-carbonyl product 18. A reductive quenching cycle
initiated by excess amine could not be ruled out at this stage, as
the Stern−Volmer experiment has also shown adequate
quenching of the exited catalyst by amine.34
EXPERIMENTAL SECTION
■
General Information. All commercially available chemicals and
reagents were used without any further purification unless otherwise
stated. All reactions were carried out in oven-dried glassware under an
argon or nitrogen atmosphere with freshly distilled anhydrous
solvents.35 Photoreactions were carried out in a borosilicate-made
culture tube using a blue-light source (PAR38 12 W blue LED bulb).
The progress of the reaction was monitored by thin-layer
chromatography (TLC) using a silica gel aluminum sheet (Merck,
TLC Silica gel 60 F254). All compounds were purified through
column chromatography using a silica gel (230−400 mesh). Nuclear
magnetic resonance spectra were recorded on a Bruker Avance III HD
400 instrument. Chemical shifts (δ) are quoted in ppm relative to
1
residual solvent signals, CDCl3, referenced at δ 7.26 ppm for H and
77.16 ppm for 13C{1H}. TMS are used as the internal standard, and
coupling constants (J) are quoted in hertz (Hz). Multiplicity is
reported with the following abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, dt = doublet of triplets, td = triplet of doublets, tt
= triplet of triplets. HRMS were recorded using a QTOF micro MS
system by an ESI technique. GC−MS analysis was done by a Thermo
Scientific ISQ QD single quadrupole GC−MS system using a TG-
5MS column (30 m × 0.25 mm × 0.25 μm). UV−vis absorption
spectroscopy was conducted using a Shimadzu UV-1800 Spectropho-
tometer. Fluorescence quenching experiments were performed using a
PerkinElmer LS 55 Fluorescence Spectrometer. Melting points (°C)
are uncorrected.
To demonstrate the synthetic utility of the present oxidative
coupling reaction, a versatile set of synthetic transformations
was showcased with the end 1,4-ketocarbonyl products
(Scheme 7). Treatments of ammonium acetate and Lawesson’s
Scheme 7. Derivatization of the Products
A. General Procedure for the Ketocarbonylation Reaction. An
oven-dried culture tube was charged with a magnetic stir bar, Eosin Y
(0.004 mmol), freshly prepared styrene (0.2 mmol), corresponding α-
bromocarbonyl (0.4 mmol), and 1 mL of dry DMF. After mixing the
reaction components by shaking, 0.4 mmol of DIPEA and another 1
mL of DMF were added to them. The culture tube was sealed with
rubber septum. After that, the reaction mixture was stirred and
irradiated between two 12 W blue LED lights at a distance of 8 cm
from each for 3 h. Then, additional 0.2 mmol of corresponding α-
bromocarbonyl and DIPEA was added to the reaction. The
completion of the reaction was monitored by TLC. After that, the
crude reaction mixture was diluted with water (5 mL) and extracted
with ethyl acetate (3 × 6 mL). The combined organic layer was
washed with brine (5 mL) and dried over anhydrous Na2SO4. Then,
the mixture was concentrated in a rotary evaporator and the residue
was purified by silica gel column chromatography to afford the desired
1,4-ketocarbonyl derivatives.
B. General Procedure for the Ketoamidation Reaction. An oven-
dried culture tube was charged with a magnetic stir bar, fac-Ir(ppy)3
(0.002 mmol), freshly prepared styrene (0.2 mmol), corresponding α-
bromoamide (0.4 mmol), and 1 mL of dry acetonitrile. After mixing
the reaction components by shaking, 0.4 mmol of DIPEA and another
1 mL of acetonitrile were added to them. The culture tube was sealed
with a rubber septum. After that, the reaction mixture was stirred and
irradiated between two 12 W blue LED lights at a distance of 8 cm
from each for 3 h. Then, additional 0.2 mmol of corresponding α-
bromoamide and DIPEA were added to the reaction mixture. The
reagent separately on 4g at elevated temperature give rise to
pyrrole (19) and thiophene (20) derivatives, respectively,
through Paal−Knorr synthesis.2 Furthermore, a reaction of 4g
with 4-aminobenzenesulfonamide provides functionalized
pyrrole 21, which is an important structural unit for
pharmacological evaluation. Biologically active dihydropyrida-
zinone derivative 22 can also be obtained easily from1,4-
ketocarbonyl 3k by treatment with hydrazine.
CONCLUSIONS
■
In summary, a visible light-mediated organic dye-catalyzed
reaction of α-bromocarbonyls and styrenes has been
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completion of the reaction was monitored by TLC. After that, the
crude reaction mixture was diluted with water (5 mL) and extracted
with ethyl acetate (3 × 6 mL). The combined organic layer was
washed with brine (5 mL) and dried over anhydrous Na2SO4. Then,
the mixture was concentrated in a rotary evaporator and the residue
was purified by silica gel column chromatography to afford the desired
γ-ketoamides.
= 17.8, 5.1 Hz, 1H), 1.27 (d, J = 7.2 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 197.0, 175.7, 139.7,
132.6, 128.5, 118.0, 116.5, 60.8, 42.2, 35.0, 17.3, 14.2.
Ethyl 2-Methyl-4-oxo-4-(m-tolyl)butanoate (3h). Pale yellow
viscous liquid; 43% yield (20 mg); Rf value = 0.5 [EtOAc/petroleum
1
ether = 1:9 (v/v)]; FTIR νmax (neat):1736, 1689, 1608 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.76−7.74 (m, 2H), 7.37−7.31
(m, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.45 (dd, J = 17.5, 7.8 Hz, 1H),
3.12−3.05 (m, 1H), 2.99 (dd, J = 17.5, 5.6 Hz, 1H), 2.39 (s, 3H),
1.26 (d, J = 5.5 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ (ppm): 198.4, 176.1, 138.4, 136.8, 134.0, 128.6,
128.5, 125.3, 60.7, 42.1, 35.1, 21.4, 17.4, 14.2; HRMS (ESI) m/z: [M
+ Na]+ Calcd for C14H18NaO3 257.1154; Found 257.1136.
Characterization Data of Products. Ethyl 4-(4-(tert-Butyl)-
phenyl)-2-methyl-4-oxobutanoate (3a).8a Pale yellow viscous
liquid; 75% yield (41 mg); Rf value = 0.6 [EtOAc/petroleum ether
1
= 1:9 (v/v)]; FTIR νmax (neat): 1732, 1689, 1606 cm−1; H NMR
(400 MHz, CDCl3) δ (ppm): 7.89 (d, J = 8.7 Hz, 2H), 7.45 (d, J =
8.7 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.43 (dd, J = 17.4, 7.7 Hz, 1H),
3.13−3.07 (m, 1H), 2.98 (dd, J = 17.4, 5.7 Hz, 1H), 1.31 (s, 9H),
1.26−1.20 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm):
197.8, 176.0, 156.9, 134.2, 128.0, 125.5, 60.6, 41.9, 35.1, 31.1, 17.3,
14.2.
Ethyl 4-(4-Bromophenyl)-2-methyl-4-oxobutanoate (3i).8a Pale
yellow viscous liquid; 72% yield (44 mg); Rf value = 0.6 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1732, 1686, 1586
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.77 (d, J = 8.6 Hz,
Ethyl 2-Methyl-4-oxo-4-phenylbutanoate (3b).17 Pale yellow
viscous liquid; 70% yield (31 mg); Rf value = 0.5 [EtOAc/petroleum
2H), 7.53 (d, J = 8.7 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.39 (dd, J =
17.6, 8.1 Hz, 1H), 3.04 (ddd, J = 8.0, 7.2, 5.3 Hz, 1H), 2.90 (dd, J =
17.6, 5.3 Hz, 1H), 1.22 (d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 197.0, 175.7, 135.4,
131.8, 129.5, 128.2, 60.6, 41.7, 34.9, 17.3, 14.1.
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1731, 1689, 1598 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.94−7.92 (m, 2H), 7.53−7.49
(m, 1H), 7.43−7.39 (m, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.44 (dd, J =
17.5, 7.9 Hz, 1H), 3.10−3.05 (m, 1H), 2.97 (dd, J = 17.5, 5.5 Hz,
1H), 1.24 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm): 198.1, 175.9, 136.7, 133.1, 128.6,
128.0, 60.5, 41.9, 35.0, 17.3, 14.1.
Ethyl 4-(3-Bromophenyl)-2-methyl-4-oxobutanoate (3j).8a Vis-
cous liquid; 48% yield (29 mg); Rf value = 0.5 [EtOAc/petroleum
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1736, 1696, 1564 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 8.06 (t, J = 1.8 Hz, 1H), 7.88−
7.85 (m, 1H), 7.66 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.32 (t, J = 7.9 Hz,
1H), 4.13 (q, J = 7.1 Hz, 2H), 3.43 (dd, J = 17.7, 8.1 Hz, 1H), 3.08
(ddd, J = 8.0, 7.2, 5.3 Hz, 1H), 2.94 (dd, J = 17.7, 5.3 Hz, 1H), 1.26
(d, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ (ppm): 196.9, 175.8, 138.5, 136.1, 131.2, 130.3,
126.6, 123.0, 60.7, 42.0, 35.1, 17.4, 14.2.
Ethyl 2-Methyl-4-oxo-4-(p-tolyl)butanoate (3c).8a Pale yellow
viscous liquid; 65% yield (30 mg); Rf value = 0.5 [EtOAc/petroleum
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1732, 1685, 1607 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.85−7.82 (m, 2H), 7.23−7.21
(m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.41 (dd, J = 17.4, 7.8 Hz, 1H),
3.10−3.05 (m, 1H), 2.96 (dd, J = 17.4, 5.6 Hz, 1H), 2.37 (s, 3H),
1.25−1.20 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm):
197.7, 176.0, 143.9, 134.3, 129.3, 128.2, 60.5, 41.8, 35.1, 21.6, 17.3,
14.2.
Ethyl 4-(2-Bromophenyl)-2-methyl-4-oxobutanoate (3k). Pale
yellow liquid; 27% yield (16 mg); Rf value = 0.5 [EtOAc/petroleum
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1740, 1695, 1565 cm−1; H
Ethyl 4-(4-Methoxyphenyl)-2-methyl-4-oxobutanoate (3d).17
Pale yellow viscous liquid; 63% yield (32 mg); Rf value = 0.3
[EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1732, 1678,
NMR (400 MHz, CDCl3) δ (ppm): 7.60 (dd, J = 7.9, 1.1 Hz, 1H),
7.45 (dd, J = 7.6, 1.7 Hz, 1H), 7.37 (td, J = 7.5, 1.2 Hz, 1H), 7.31−
7.27 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.37 (dd, J = 17.8, 8.0 Hz,
1H), 3.15−3.07 (m, 1H), 2.99 (dd, J = 17.8, 5.5 Hz, 1H), 1.28 (d, J =
3.1 Hz, 3H), 1.26 (t, J = 5.1 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 202.1, 175.7, 141.4, 133.8, 131.8, 128.8, 127.7,
118.7, 60.9, 46.0, 35.4, 17.3, 14.3; HRMS (ESI) m/z: [M + H]+ Calcd
for C13H16BrO3 299.0283; Found 299.0275.
1
1601 cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J = 8.9
Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 4.14−4.08 (m, 2H), 3.83 (s, 3H),
3.39 (dd, J = 17.3, 7.9 Hz, 1H), 3.09−3.04 (m, 1H), 2.94 (dd, J =
17.3, 5.6 Hz, 1H), 1.25−1.20 (m, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 196.7, 176.2, 163.6, 130.4, 129.9, 113.8, 60.6, 55.5,
41.6, 35.2, 17.4, 14.2.
Ethyl 4-([1,1′-Biphenyl]-4-yl)-2-methyl-4-oxobutanoate (3l).19
White solid; mp: 80−82 °C; 77% yield (46 mg); Rf value = 0.6
[EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (KBr plate): 1726,
1682, 1560 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.04 (d, J =
8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.64−7.62 (m, 2H), 7.49−7.45
(m, 2H), 7.40 (t, J = 7.3 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.51 (dd, J
= 17.4, 7.8 Hz, 1H), 3.17−3.12 (m, 1H), 3.04 (dd, J = 17.4, 5.5 Hz,
1H), 1.30 (d, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm): 197.8, 176.1, 145.9, 139.9, 135.5,
129.0, 128.7, 128.3, 127.4, 127.3, 60.7, 42.1, 35.2, 17.4, 14.3.
Ethyl 2-Methyl-4-(naphthalen-2-yl)-4-oxobutanoate (3m).19
White solid; mp: 56−58 °C; 39% yield (21 mg); Rf value = 0.6
[EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (KBr plate): 1730,
Ethyl 4-(4-Fluorophenyl)-2-methyl-4-oxobutanoate (3e).17 Pale
yellow viscous liquid; 74% yield (35 mg); Rf value = 0.5 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1732, 1689, 1598
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.98 (dd, J = 9.0, 5.4
Hz, 2H), 7.13−7.09 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.44 (dd, J =
17.6, 8.1 Hz, 1H), 3.09 (ddd, J = 8.0, 7.2, 5.4 Hz, 1H), 2.95 (dd, J =
17.6, 5.4 Hz, 1H), 1.26 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 196.6, 175.9, 165.9
(1JC‑F = 256.0), 133.2 (4JC‑F = 3.0 Hz), 130.7 (3JC‑F = 10.1 Hz), 115.8
(2JC‑F = 22.2), 60.7, 41.9, 35.1, 17.4, 14.2; 19F NMR (376 MHz,
CDCl3) δ (ppm) −104.7 (s, 1F).
Ethyl 4-(4-Chlorophenyl)-2-methyl-4-oxobutanoate (3f).17 Pale
yellow viscous liquid; 63% yield (32 mg); Rf value = 0.5 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1735, 1689, 1588
1
1676, 1585 cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 8.48 (s,
1H), 8.02 (dd, J = 8.6, 1.7 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.89−
7.85 (m, 2H), 7.56 (dddd, J = 19.1, 8.1, 6.9, 1.3 Hz, 2H), 4.17 (q, J =
7.1 Hz, 2H), 3.65−3.58 (m, 1H), 3.20−3.11 (m, 2H), 1.32 (d, J = 7.1
Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ (ppm): 198.1, 176.1, 135.7, 134.1, 132.6, 129.8, 129.6, 128.6, 128.5,
127.9, 126.9, 123.8, 60.7, 42.1, 35.2, 17.5, 14.3.
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.88 (d, J = 8.7 Hz,
2H), 7.40 (d, J = 8.7 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.42 (dd, J =
17.6, 8.1 Hz, 1H), 3.08 (ddd, J = 8.0, 7.2, 5.3 Hz, 1H), 2.93 (dd, J =
17.6, 5.3 Hz, 1H), 1.26−1.20 (m, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 196.9, 175.8, 139.6, 135.0, 129.4, 128.9, 60.6, 41.8,
35.0, 17.3, 14.1.
Ethyl 2-Methyl-4-oxo-4-(pyridin-3-yl)butanoate (3n). Pale brown
viscous liquid; 34% yield (15 mg); Rf value = 0.3 [EtOAc/petroleum
Ethyl 4-(4-Cyanophenyl)-2-methyl-4-oxobutanoate (3g).8a Pale
yellow viscous liquid; 51% yield (25 mg); Rf value = 0.4 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 2231, 1730, 1694,
1
ether = 2:8 (v/v)]; FTIR νmax (neat): 1730, 1699, 1557 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 9.13 (dd, J = 2.2, 0.6 Hz, 1H),
8.73 (dd, J = 4.8, 1.7 Hz, 1H), 8.20−8.17 (m, 1H), 7.37 (ddd, J = 8.0,
4.8, 0.8 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.45 (dd, J = 17.7, 8.3 Hz,
1H), 3.08 (ddd, J = 8.2, 7.2, 5.1 Hz, 1H), 2.95 (dd, J = 17.7, 5.1 Hz,
1
1606 cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 8.03 (d, J = 8.6
Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.47 (dd,
J = 17.8, 8.4 Hz, 1H), 3.10 (ddd, J = 8.2, 7.2, 5.1 Hz, 1H), 2.96 (dd, J
F
https://dx.doi.org/10.1021/acs.joc.0c01985
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1H), 1.25 (d, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm): 197.1, 175.7, 153.6, 149.6, 135.4,
131.9, 123.7, 60.7, 42.1, 34.9, 17.3, 14.2; HRMS (ESI) m/z: [M + H]+
Calcd for C12H16NO3 222.1130; Found 222.1128.
NMR (400 MHz, CDCl3) δ (ppm): 7.81 (d, J = 8.3 Hz, 2H), 7.28 (d,
J = 7.9 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.88 (t, J = 13.4 Hz, 2H),
2.42 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 192.66 (3JC‑F = 5.9 Hz), 163.44 (2JC‑F = 31.3),
Ethyl 4-(4-Fluorophenyl)-2,3-dimethyl-4-oxobutanoate (3o).
Pale yellow liquid; 35% yield (18 mg); Rf value = 0.5 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1748, 1689, 1562
145.4, 133.2, 129.7, 128.4, 114.6 (1JC‑F = 250.5), 63.1, 43.8 (2JC‑F
=
24.2), 21.8, 13.9; 19F NMR (376 MHz, CDCl3) δ (ppm) −104.4 (s,
2F).
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm) (for mixture): 8.02−
3-(2-Oxo-2-(p-tolyl)ethyl)dihydrofuran-2(3H)-one (4e). White
solid; mp: 112−114 °C; 40% yield (17 mg); Rf value = 0.5
[EtOAc/petroleum ether = 3:7 (v/v)]; FTIR νmax (KBr plate): 1770,
1683, 1605 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J =
8.3 Hz, 2H), 7.26−7.24 (m, 2H), 4.44−4.39 (m, 1H), 4.26 (ddd, J =
10.3, 9.1, 6.7 Hz, 1H), 3.60 (t, J = 11.1 Hz, 1H), 3.17−3.10 (m, 2H),
2.64−2.60 (m, 1H), 2.39 (s, 3H), 1.98−1.93 (m, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ (ppm): 196.7, 179.3, 144.5, 133.8, 129.5, 128.2,
66.9, 39.3, 35.3, 29.2, 21.7; HRMS (ESI) m/z: [M + H]+ Calcd for
C13H15O3 219.1021; Found 219.1019.
7.98 (m, 2H), 7.13 (td, J = 8.5, 6.0 Hz, 2H), 4.18−4.02 (m, 2H), 3.69
(dqd, J = 9.3, 7.1, 5.0 Hz, 1H), 2.98−2.88 (m, 1H), 1.28−1.23 (m,
3H), 1.18−1.16 (m, 3H), 1.13 (dd, J = 9.7, 4.7 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm): 202.1, 201.1, 175.9, 175.6, 167.2,
167.1, 164.7, 164.5, 133.2, 133.1, 132.6, 132.5, 131.2, 131.1, 131.0,
131.0, 116.1, 115.9, 115.8, 115.7, 60.7, 60.6, 43.6, 43.1, 42.9, 41.9,
16.7, 16.2, 14.8, 14.4, 14.3, 14.2; 19F NMR (376 MHz, CDCl3) δ
(ppm) −107.0 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd for
C14H18FO3 253.1240; Found 253.1237.
Ethyl 2,2-Dimethyl-4-oxo-4-(p-tolyl)butanoate (4f). Colorless
viscous liquid; 22% yield (11 mg); Rf value = 0.7 [EtOAc/petroleum
Ethyl 2-Methyl-4-oxo-3,4-diphenylbutanoate (3p). Yellow vis-
cous liquid; 32% yield (19 mg); Rf value = 0.6 [EtOAc/petroleum
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1732, 1695, 1632 cm−1; H
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1726, 1645, 1540 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.81 (d, J = 8.2 Hz, 2H), 7.21 (d,
J = 7.9 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.24 (s, 2H), 2.37 (s, 3H),
1.29 (s, 6H), 1.17 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 197.4, 177.5, 143.9, 134.8, 129.3, 128.1, 60.6, 48.4,
40.1, 25.9, 21.7, 14.2; HRMS (ESI) m/z: [M + Na]+ Calcd for
C15H20NaO3 271.1310; Found 271.1306.
NMR (400 MHz, CDCl3) δ (ppm): 8.00−7.95 (m, 2H), 7.50−7.18
(m, 8H), 4.80 (dd, J = 15.3, 10.8 Hz, 1H), 4.15−3.82 (m, 2H), 3.41
(ddd, J = 18.2, 10.7, 7.0 Hz, 1H), 1.27−0.90 (m, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ (ppm): 199.6, 198.1, 176.2, 175.2, 136.9, 136.8,
136.6, 136.5, 133.3, 132.9, 129.2, 129.1, 129.0, 128.9, 128.8, 128.7,
128.5, 127.7, 127.6, 60.8, 60.3, 56.7, 56.6, 44.2, 43.1, 16.7, 15.7, 14.2,
13.9; HRMS (ESI) m/z: [M + H]+ Calcd for C19H21O3 297.1491;
Found 297.1483.
Ethyl 2-(1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate
(3q).15e Pale yellow viscous liquid; 20% yield (10 mg); Rf value =
0.5 [EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1736,
1675, 1564 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): (for
mixture) 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.48−7.44 (m, 1H), 7.29 (t, J
= 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 4.22−4.09 (m, 2H), 3.21−
2.84 (m, 4H), 2.21−2.06 (m, 1H), 1.93 (ddd, J = 26.4, 12.8, 4.6 Hz,
1H), 1.30−1.15 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
(ppm): (for mixture) 198.2, 198.0, 176.2, 174.8, 144.1, 143.8, 133.5,
133.4, 132.7, 132.5, 128.8, 128.7, 127.6, 126.8, 126.7, 60.6, 60.5, 50.7,
50.3, 39.3, 38.9, 29.5, 29.2, 26.0, 25.4, 14.3, 14.2, 13.6, 13.3.
Ethyl 4-Oxo-4-phenylbutanoate (4a).36 Pale yellow oil; 39% yield
(17 mg); Rf value = 0.5 [EtOAc/petroleum ether = 1:9 (v/v)]; FTIR
νmax (neat): 1741, 1745, 1685, 1603 cm−1; 1H NMR (400 MHz,
CDCl3) δ (ppm): 7.88 (d, J = 8.2 Hz, 2H), 7.26 (dd, J = 6.0, 2.4 Hz,
2H), 4.16 (q, J = 7.1 Hz, 2H), 3.29 (t, J = 6.7 Hz, 2H), 2.74 (t, J = 6.7
Hz, 2H), 2.41 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ (ppm): 197.9, 173.1, 144.1, 134.3, 129.4, 128.3, 60.8,
33.4, 28.5, 21.8, 14.3.
Ethyl 2-Benzoyl-4-oxo-4-(p-tolyl)butanoate (4g).38 Yellow liquid;
45% yield (29 mg); Rf value = 0.5 [EtOAc/petroleum ether = 1:9 (v/
v)]; FTIR νmax (neat): 1746, 1685, 1630 cm−1; 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.10−8.08 (m, 2H), 7.89 (d, J = 8.2 Hz, 2H),
7.61−7.57 (m, 1H), 7.51−7.48 (m, 2H), 7.26−7.24 (m, 2H), 5.11
(dd, J = 7.5, 6.2 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.82−3.67 (m,
2H), 2.40 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ (ppm): 196.6, 195.0, 169.4, 144.5, 136.3, 133.8,
133.6, 129.4, 129.1, 128.8, 128.4, 61.8, 48.9, 38.2, 21.8, 14.0.
Ethyl 2-(4-Bromobenzoyl)-4-oxo-4-(p-tolyl)butanoate (4h).
White solid; mp: 60−62 °C; 43% yield (35 mg); Rf value = 0.4
[EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (KBr plate): 1732,
1695, 1632 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.95 (d, J =
8.7 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.24
(d, J = 8.0 Hz, 2H), 5.03 (dd, J = 8.2, 5.5 Hz, 1H), 4.14 (q, J = 7.1 Hz,
2H), 3.83 (dd, J = 18.2, 8.2 Hz, 1H), 3.67 (dd, J = 18.2, 5.5 Hz, 1H),
2.38 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 196.5, 194.0, 169.0, 144.5, 135.1, 133.6, 132.0,
130.5, 129.4, 128.8, 128.4, 61.9, 48.8, 38.2, 21.7, 14.0; HRMS (ESI)
m/z: [M + H]+ Calcd for C20H20BrO4 403.0545; Found 403.0546.
Ethyl 2-(4-Methoxybenzoyl)-4-oxo-4-(p-tolyl)butanoate (4i).
Pale yellow oil; 45% yield (32 mg); Rf value = 0.3 [EtOAc/petroleum
tert-Butyl 4-Oxo-4-(p-tolyl)butanoate (4b).37 White solid; mp:
44−46 °C; 66% yield (33 mg); Rf value = 0.6 [EtOAc/petroleum
ether = 1:9 (v/v)]; FTIR νmax (KBr plate): 1718, 1681, 1606 cm−1;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.88−7.86 (m, 2H), 7.25 (dd,
J = 5.9, 4.1 Hz, 2H), 3.23 (t, J = 6.7 Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H),
2.40 (s, 3H), 1.44 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
(ppm): 198.1, 172.4, 144.0, 134.3, 129.4, 128.3, 80.7, 33.5, 29.6, 28.2,
21.8.
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1740, 1682, 1645 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 8.07 (d, J = 8.8 Hz, 2H), 7.88 (d,
J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H),
5.07 (t, J = 6.8 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.71
(dd, J = 6.8, 3.2 Hz, 2H), 2.38 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 196.7, 193.3, 169.6,
164.0, 144.3, 133.8, 131.4, 129.3, 129.1, 128.4, 113.9, 61.7, 55.6, 48.7,
38.1, 21.7, 14.0; HRMS (ESI) m/z: [M + H]+ Calcd for C21H23O5
355.1545; Found 355.1542.
Ethyl 2-(Diethoxyphosphoryl)-4-oxo-4-(p-tolyl)butanoate (4c).
Colorless viscous liquid; 23% yield (16 mg); Rf value = 0.5
[EtOAc/petroleum ether = 4:6 (v/v)]; FTIR νmax (neat): 1687,
1457, 1432, 1325, 1248 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm):
7.88 (d, J = 8.2 Hz, 2H), 7.26 (q, J = 4.0 Hz, 2H), 4.25−4.16 (m,
6H), 3.84−3.61 (m, 2H), 3.42 (ddd, J = 17.7, 9.4, 2.6 Hz, 1H), 2.41
(s, 3H), 1.35 (q, J = 7.2 Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm): 196.20 (d, JC‑P = 15.5 Hz), 168.6
(d, JC‑P = 5.6 Hz), 144.5, 133.7, 129.4, 128.4, 63.1 (d, JC‑P = 7.1 Hz),
61.8, 40.4 (d, JC‑P = 131.3 Hz), 35.9 (d, JC‑P = 1.7 Hz), 21.8, 16.5−
16.3 (m), 14.2; HRMS (ESI) m/z: [M + Na]+ Calcd for
C17H25NaO6P 379.1286; Found 379.1292.
Ethyl 2-Acetyl-4-oxo-4-(p-tolyl)butanoate (4j).39 Colorless dense
liquid; 46% yield (24 mg); Rf value = 0.6 [EtOAc/petroleum ether =
1:9 (v/v)]; FTIR νmax (neat): 1725, 1675, 1624 cm−1; 1H NMR (400
MHz, CDCl3) δ (ppm): 7.83 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.0 Hz,
2H), 4.17 (dt, J = 7.0, 4.0 Hz, 3H), 3.64 (dd, J = 18.3, 8.2 Hz, 1H),
3.46 (dd, J = 18.3, 5.7 Hz, 1H), 2.39 (s, 3H), 2.36 (s, 3H), 1.24 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 202.5,
196.7, 169.0, 144.3, 133.6, 129.3, 128.2, 61.7, 53.9, 37.3, 30.2, 21.6,
14.0.
Ethyl 4-Oxo-2-picolinoyl-4-(p-tolyl)butanoate (4k). Brown vis-
cous liquid; 36% yield (23 mg); Rf value = 0.3 [EtOAc/petroleum
Ethyl 2,2-Difluoro-4-oxo-4-(p-tolyl)butanoate (4d).20b Colorless
viscous liquid; 32% yield (16 mg); Rf value = 0.3 [EtOAc/petroleum
1
ether = 2:8 (v/v)]; FTIR νmax (neat): 1740, 1686, 1641 cm−1; H
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1778, 1687, 1607 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 8.69 (ddd, J = 4.7, 1.7, 0.9 Hz,
G
https://dx.doi.org/10.1021/acs.joc.0c01985
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1H), 8.06 (dt, J = 7.8, 1.0 Hz, 1H), 7.88−7.86 (m, 2H), 7.85−7.81
(m, 1H), 7.48−7.41 (m, 1H), 7.23 (d, J = 7.9 Hz, 2H), 5.56 (dd, J =
8.8, 5.2 Hz, 1H), 4.13 (t, J = 7.1 Hz, 2H), 3.85 (dd, J = 17.9, 8.8 Hz,
1H), 3.63 (dd, J = 17.9, 5.2 Hz, 1H), 2.38 (s, 3H), 1.13 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 196.4, 196.3,
170.4, 152.4, 149.1, 144.2, 137.0, 133.8, 129.3, 128.4, 127.4, 122.5,
61.4, 47.7, 37.8, 21.7, 13.9; HRMS (ESI) m/z: [M + H]+ Calcd for
C19H20NO4 326.1392; Found 326.1386.
128.3, 41.2, 40.8, 34.8, 21.7, 20.7, 14.2; HRMS (ESI) m/z: [M + H]+
Calcd for C20H23O2 295.1698; Found 295.1692.
2-(2-Oxo-2-(p-tolyl)ethyl)-3,4-dihydronaphthalen-1(2H)-one
(5d). Pale yellow viscous liquid; 22% yield (12 mg); Rf value = 0.4
[EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1681, 1608,
1405 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.04 (dd, J = 7.8,
1.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.48 (td, J = 7.5, 1.4 Hz, 1H),
7.33−7.25 (m, 4H), 3.84 (dd, J = 17.5, 4.6 Hz, 1H), 3.32 (ddt, J =
13.3, 7.3, 4.5 Hz, 1H), 3.18 (ddd, J = 17.0, 12.7, 4.5 Hz, 1H), 3.01−
2.93 (m, 2H), 2.42 (s, 3H), 2.32−2.26 (m, 1H), 1.97 (qd, J = 13.0,
4.3 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 199.3,
198.3, 144.3, 144.0, 134.6, 133.5, 132.4, 129.4, 128.9, 128.4, 127.6,
126.7, 44.3, 38.9, 29.7, 29.5, 21.8; HRMS (ESI) m/z: [M + H]+ Calcd
for C19H19O2 279.1385; Found 279.1391.
Diethyl 2-(2-Oxo-2-(p-tolyl)ethyl)malonate (4l).26b Pale yellow
viscous liquid; 54% yield (32 mg); Rf value = 0.6 [EtOAc/petroleum
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1747, 1730, 1684 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.88−7.86 (m, 2H), 7.25 (dd, J =
7.3, 1.2 Hz, 2H), 4.22 (ddt, J = 10.7, 7.1, 3.6 Hz, 4H), 4.04 (t, J = 7.1
Hz, 1H), 3.59 (d, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.28 (t, J = 7.1 Hz,
6H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 196.3, 169.2,
144.5, 133.8, 129.4, 128.4, 61.8, 47.4, 37.8, 21.8, 14.1.
2-(2-Oxo-2-(p-tolyl)ethyl)cyclohexan-1-one (5e).42 White solid;
mp: 67−69 °C; 12% yield (6 mg); Rf value = 0.4 [EtOAc/petroleum
ether = 1:9 (v/v)]; FTIR νmax (KBr plate): 1711, 1685, 1605 cm−1;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.88 (d, J = 8.2 Hz, 2H), 7.24
(d, J = 8.0 Hz, 2H), 3.56 (dd, J = 17.6, 6.5 Hz, 1H), 3.14 (dq, J =
12.2, 6.0 Hz, 1H), 2.66 (dd, J = 17.6, 5.8 Hz, 1H), 2.44−2.39 (m,
2H), 2.39 (s, 3H), 2.15 (dddd, J = 15.9, 11.7, 6.6, 3.4 Hz, 2H), 1.90−
1.85 (m, 1H), 1.78 (ddd, J = 12.8, 9.2, 3.7 Hz, 1H), 1.73−1.60 (m,
1H), 1.48−1.38 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
(ppm): 211.8, 198.4, 143.9, 134.7, 129.3, 128.3, 46.5, 42.1, 38.3, 34.4,
28.1, 25.5, 21.7.
Di-tert-butyl 2-(2-Oxo-2-(p-tolyl)ethyl)malonate (4m).26b Pale
yellow viscous liquid; 62% yield (43 mg); Rf value = 0.7 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1723, 1683, 1422
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm):) 7.88 (d, J = 8.2 Hz,
2H), 7.25 (d, J = 8.6 Hz, 2H), 3.87 (t, J = 7.1 Hz, 1H), 3.48 (d, J = 7.1
Hz, 2H), 2.40 (s, 3H), 1.47 (s, 18H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 196.6, 168.6, 144.2, 134.1, 129.4, 128.4, 81.9, 49.4,
37.8, 28.1, 21.8.
1-(tert-Butyl) 3-Ethyl 2-(2-oxo-2-(p-tolyl)ethyl)malonate (4n).26b
Pale yellow viscous liquid; 66% yield (42 mg); Rf value = 0.6 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1741, 1726, 1384
3-Benzoyl-1-(p-tolyl)pentane-1,4-dione (5f).43 Pale yellow syrup;
20% yield (12 mg); Rf value = 0.5 [EtOAc/petroleum ether = 1:9 (v/
v)]; FTIR νmax (neat): 1720, 1680, 1611 cm−1; 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.07 (dd, J = 8.4, 1.3 Hz, 1H), 7.97 (ddd, J = 6.9,
4.3, 1.5 Hz, 2H), 7.87−7.85 (m, 1H), 7.60−7.58 (m, 1H), 7.50 (dd, J
= 8.2, 7.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H),
7.23 (d, J = 7.9 Hz, 1H), 5.28 (dd, J = 9.0, 4.1 Hz, 1H), 3.77 (ddd, J =
18.0, 11.0, 6.9 Hz, 1H), 3.57 (dt, J = 18.2, 6.5 Hz, 1H), 2.40 (d, J =
12.4 Hz, 3H), 2.22 (d, J = 1.6 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 202.5, 197.0, 196.5, 196.4, 195.9, 144.9, 144.5,
136.2, 136.1, 133.9, 133.7, 133.6, 133.5, 129.7, 129.4, 129.1, 129.0,
128.9, 128.7, 128.4, 128.2, 56.9, 56.7, 38.1, 38.0, 29.6, 29.5, 21.8, 21.7.
N,2-Dimethyl-4-oxo-N-phenyl-4-(p-tolyl)butanamide (5g).
Brown gummy liquid; 43% yield (25 mg); Rf value = 0.3 [EtOAc/
petroleum ether = 3:7 (v/v)]; FTIR νmax (neat): 1685, 1657, 1599
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 8.3 Hz,
2H), 7.22 (d, J = 7.9 Hz, 2H), 4.24−4.15 (m, 2H), 3.93 (t, J = 7.1 Hz,
1H), 3.52 (d, J = 6.8 Hz, 2H), 2.37 (s, 3H), 1.44 (s, 9H), 1.26 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 196.3,
169.5, 168.1, 144.2, 133.9, 129.3, 128.3, 82.1, 61.5, 48.3, 37.7, 27.9,
21.7, 14.1.
Diethyl 2-Methyl-2-(2-oxo-2-(p-tolyl)ethyl)malonate (4o).26b
Pale yellow viscous liquid; 28% yield (17 mg); Rf value = 0.6
[EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1736, 1686,
1
1607 cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 8.2
Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 4.19 (q, J = 7.1 Hz, 4H), 3.63 (s,
2H), 2.39 (s, 3H), 1.58 (s, 3H), 1.23 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm): 196.2, 171.8, 144.2, 134.3, 129.4,
128.2, 61.6, 51.6, 44.2, 21.7, 20.6, 14.0.
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 8.2 Hz,
1-(4-Methoxyphenyl)-4-(p-tolyl)butane-1,4-dione (5a).40 Color-
less gummy syrup; 33% yield (19 mg); Rf value = 0.3 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1672, 1615, 1551,
2H), 7.45 (q, J = 8.5 Hz, 4H), 7.36−7.34 (m, 1H), 7.21 (d, J = 8.0
Hz, 2H), 3.62 (dd, J = 17.8, 9.7 Hz, 1H), 3.26 (s, 3H), 3.05 (ddd, J =
9.9, 7.0, 4.0 Hz, 1H), 2.77 (dd, J = 17.8, 4.0 Hz, 1H), 2.37 (s, 3H),
1.05 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
(ppm): 198.6, 175.9, 144.2, 143.8, 134.3, 129.7, 129.2, 128.2, 127.9,
127.8, 43.1, 37.7, 32.4, 21.7, 18.0; HRMS (ESI) m/z: [M + Na]+
Calcd for C19H21NNaO2 318.1470; Found 318.1487.
1
1401 cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 8.02 (d, J = 9.0
Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.7 Hz, 2H), 6.95 (d, J
= 9.0 Hz, 2H), 3.87 (s, 3H), 3.41 (dd, J = 3.9, 3.0 Hz, 4H), 2.42 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 198.7, 197.5,
163.7, 144.0, 134.5, 130.5, 130.1, 129.4, 128.4, 113.9, 55.6, 32.7, 32.4,
21.8.
N,N-Diisopropyl-2-methyl-4-oxo-4-(p-tolyl)butanamide (5h).
Brown gummy liquid; 35% yield (20 mg); Rf value = 0.3 [EtOAc/
petroleum ether = 3:7 (v/v)]; FTIR νmax (neat): 1875, 1683, 1645
4-(4-Oxo-4-(p-tolyl)butanoyl)benzonitrile (5b).41 Colorless solid;
mp: 134−136 °C; 46% yield (25 mg); Rf value = 0.4 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (KBr plate): 2235, 1695,
1621, 1405 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.12 (d, J =
8.6 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.28
(d, J = 7.9 Hz, 2H), 3.47 (ddd, J = 6.1, 5.0, 1.4 Hz, 2H), 3.43−3.40
(m, 2H), 2.42 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm):
197.9, 197.8, 144.4, 140.0, 134.2, 132.7, 129.5, 128.7, 128.4, 118.1,
116.5, 32.9, 32.7, 21.8.
1
cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 7.86 (d, J = 8.2 Hz,
2H), 7.21 (d, J = 8.0 Hz, 2H), 4.20−4.17 (m, 1H), 3.56 (dd, J = 17.6,
8.0 Hz, 1H), 3.43 (s, 1H), 3.37−3.28 (m, 1H), 2.87 (dd, J = 17.6, 5.0
Hz, 1H), 2.37 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8 Hz,
3H), 1.29 (d, J = 6.7 Hz, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.15 (d, J =
7.0 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 198.9,
174.7, 143.7, 134.7, 129.2, 128.3, 48.4, 45.7, 42.8, 32.7, 21.7, 21.2,
21.1, 20.8, 20.6, 18.2; HRMS (ESI) m/z: [M + Na]+ Calcd for
C18H27NNaO2 312.1939; Found 312.1918.
1-Phenyl-2-propyl-4-(p-tolyl)butane-1,4-dione (5c). Pale yellow
oil; 52% yield (31 mg); Rf value = 0.5 [EtOAc/petroleum ether = 1:9
2-Methyl-1-(pyrrolidin-1-yl)-4-(p-tolyl)butane-1,4-dione (5i).
1
(v/v)]; FTIR νmax (neat): 1681, 1608, 1416 cm−1; H NMR (400
Gummy liquid; 57% yield (30 mg); Rf value = 0.3 [EtOAc/petroleum
1
MHz, CDCl3) δ (ppm): 8.07 (d, J = 7.1 Hz, 2H), 7.87 (d, J = 8.2 Hz,
2H), 7.55 (d, J = 7.4 Hz, 1H), 7.48 (dd, J = 8.1, 6.8 Hz, 2H), 7.25 (t, J
= 6.3 Hz, 2H), 4.15 (dddd, J = 10.3, 7.2, 6.3, 4.2 Hz, 1H), 3.69 (dd, J
= 17.9, 9.1 Hz, 1H), 3.15 (dd, J = 17.9, 4.2 Hz, 1H), 2.39 (s, 3H),
1.73 (dt, J = 6.6, 4.2 Hz, 1H), 1.58−1.49 (m, 1H), 1.42−1.31 (m,
2H), 0.90 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
(ppm) 203.7, 198.4, 144.0, 137.1, 134.3, 132.9, 129.3, 128.7, 128.6,
ether = 3:7 (v/v)]; FTIR νmax (neat): 1681, 1624, 1445 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 8.1 Hz, 2H), 7.21 (d,
J = 8.2 Hz, 2H), 3.77 (dt, J = 9.9, 7.0 Hz, 1H), 3.59 (dd, J = 17.8, 8.8
Hz, 1H), 3.52−3.36 (m, 3H), 3.20 (ddd, J = 8.6, 6.9, 4.6 Hz, 1H),
2.90 (dd, J = 17.8, 4.5 Hz, 1H), 2.37 (s, 3H), 2.00−1.94 (m, 2H),
1.87−1.82 (m, 2H), 1.18 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ (ppm): 198.9, 174.5, 143.9, 134.4, 129.2, 128.3, 46.5,
H
https://dx.doi.org/10.1021/acs.joc.0c01985
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
45.8, 42.8, 33.5, 26.2, 24.4, 21.7, 17.6; HRMS (ESI) m/z: [M + Na]+
Calcd for C16H21NNaO2 282.1470; Found 282.1462.
mmol), ethyl 2-bromopropanoate 2a (52 μL, 0.4 mmol), and 1 mL of
dry DMF. After mixing the reaction components by stirring, DIPEA
(72 μL, 0.4 mmol) and additional 1 mL of dry DMF was added to
them. The resulting solution was allowed to be irradiated for 3 h, and
after that, another 0.2 mmol of both ethyl 2-bromopropanoate and
DIPEA was added to it. Finally, the completion of the reaction was
confirmed by TLC and the product was purified as process A
described previously.
Ethyl 3-(6-Chloro-3,4-dihydronaphthalen-1-yl)-2-methylpropa-
noate (10). Colorless viscous oil; 35% yield (19 mg); Rf value =
0.8[EtOAc/petroleum ether = 1:9 (v/v)]; FTIR νmax (neat): 1688,
1637, 1607 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.16 (d, J =
2.1 Hz, 2H), 7.12−7.12 (m, 1H), 5.88 (t, J = 4.6 Hz, 1H), 4.10 (q, J =
7.1 Hz, 2H), 2.89 (ddd, J = 14.2, 6.9, 1.2 Hz, 1H), 2.71−2.61 (m,
3H), 2.40 (ddd, J = 14.2, 7.8, 0.8 Hz, 1H), 2.25−2.20 (m, 2H), 1.23
(t, J = 7.1 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ (ppm): 176.5, 138.8, 133.4, 132.9, 132.1, 127.8,
127.5, 126.4, 123.9, 60.4, 38.3, 37.0, 28.3, 22.9, 16.9, 14.4; HRMS
(ESI) m/z: [M + H]+ Calcd for C16H20ClO2 279.1152; Found
279.1149.
Procedure of Gram-Scale Synthesis of Compound 3c. An
oven-dried RB was charged with a magnetic stir bar, Eosin Y (104 mg,
0.16 mmol), freshly prepared 4-methyl styrene 1c (1.05 mL, 8 mmol),
ethyl 2-bromopropionate 2a (2.08 mL, 16 mmol), and 60 mL of dry
DMF. After mixing the reaction components by stirring, 16 mmol of
DIPEA (2.79 mL) and another 20 mL of DMF were added to them.
The RB was sealed with a rubber septum. After that, the reaction
mixture was stirred and irradiated between two 12 W blue LED lights
at a distance of 8 cm from each for 4 h. Then, additional 8 mmol of
ethyl 2-bromopropionate 2a (1.04 mL) and DIPEA (1.39 mL) were
added to the reaction. The completion of the reaction was monitored
by TLC. After that, the crude reaction mixture was diluted with water
(100 mL) and extracted with ethyl acetate (3 × 150 mL). The
combined organic layer was washed with brine (100 mL) and dried
over anhydrous Na2SO4. Then, the mixture was concentrated in a
rotary evaporator and the residue was purified by silica gel column
chromatography to afford the compound 3c (1.09 g) in 58% yield.
Synthesis of Pyrrole 19. In a 10 mL round-bottom flask
equipped with a magnetic stir bar, a mixture of 1,4-ketocarbonyl
compound 4g (32 mg, 0.1 mmol) and ammonium acetate (77 mg, 1
mmol) was added to absolute ethanol (2 mL) and the mixture was
refluxed for 24 h. The reaction mixture was allowed to cool to room
temperature and then diluted with CHCl3 (5 mL) and water (5 mL).
The organic and aqueous layers were separated. Then, the aqueous
part was further extracted with CHCl3 (2 × 5 mL). Now, the
combined organic layer was washed with 5 ml of brine solution and
dried over anhydrous Na2SO4. The dried organic layer was
concentrated under reduced pressure and purified by column
chromatography. The desired product 19 appeared as a yellow solid
with 94% yield.
2-Methyl-1-morpholino-4-(p-tolyl)butane-1,4-dione (5j). Brown
gummy liquid; 59% yield (32 mg); Rf value = 0.3 [EtOAc/petroleum
ether = 3:7 (v/v)]; FTIR νmax (neat): 2968, 2868, 1681, 1607, 1433,
1268, 1223 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.87−7.85
(m, 2H), 7.23 (d, J = 7.9 Hz, 2H), 3.83−3.89 (m, 1H), 3.71−3.59 (m,
8H), 3.43−3.36 (m, 1H), 2.92 (dd, J = 17.8, 4.5 Hz, 1H), 2.39 (s,
3H), 1.19 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
(ppm): 198.7, 174.7, 144.1, 134.3, 129.3, 128.3, 67.01, 66.9, 46.3,
42.8, 42.4, 30.9, 21.7, 17.9; HRMS (ESI) m/z: [M + Na]+ Calcd for
C16H21NNaO3 298.1419; Found 298.1405.
tert-Butyl 4-(2-Methyl-4-oxo-4-(p-tolyl)butanoyl)piperazine-1-
carboxylate (5k). Pale yellow gummy liquid; 32% yield (24 mg); Rf
value = 0.3 [EtOAc/petroleum ether = 3:7 (v/v)]; FTIR νmax (neat):
1685, 1642, 1439 cm−1; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.85
(d, J = 8.1 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 3.71−3.36 (m, 10H),
2.91 (dd, J = 17.8, 4.3 Hz, 1H), 2.38 (s, 3H), 1.46 (s, 9H), 1.19 (d, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 198.7,
174.7, 154.7, 144.1, 134.3, 129.3, 128.3, 80.3, 45.7, 42.9, 41.8, 31.1,
28.5, 21.7, 17.9; HRMS (ESI) m/z: [M + H]+ Calcd for C21H31N2O4
375.2284; Found 375.2281.
2-Methyl-4-oxo-N-phenyl-4-(p-tolyl)butanamide (5l). White
solid: mp: 147−149 °C; 49% yield (28 mg); Rf value = 0.3
[EtOAc/petroleum ether = 3:7 (v/v)]; FTIR νmax (KBr plate): 1680,
1
1605, 1545 cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 8.19 (s,
1H), 7.86 (d, J = 8.2 Hz, 2H), 7.55−7.53 (m, 2H), 7.25 (td, J = 7.9,
6.8 Hz, 4H), 7.05 (t, J = 7.4 Hz, 1H), 3.57 (dd, J = 18.2, 9.0 Hz, 1H),
3.16 (ddd, J = 8.9, 6.9, 4.0 Hz, 1H), 3.03 (dd, J = 18.2, 4.0 Hz, 1H),
2.40 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 199.1, 174.3, 144.4, 138.3, 134.1, 129.4, 128.9,
128.3, 124.0, 119.8, 42.9, 36.9, 21.8, 18.1; HRMS (ESI) m/z: [M +
Na]+ Calcd for C18H19NNaO2 304.1313; Found 304.1302.
4-Oxo-4-(p-tolyl)butanenitrile (6).44 Yellowish solid; mp: 74−75
°C; 51% yield (18 mg); Rf value = 0.3 [EtOAc/petroleum ether = 3:7
1
(v/v)]; FTIR νmax (KBr plate): 2242, 1683, 1685, 1605 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.85 (d, J = 8.3 Hz, 2H), 7.29 (d,
J = 7.9 Hz, 2H), 3.37−3.34 (m, 2H), 2.78−2.75 (m, 2H), 2.43 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 195.1, 145.0,
133.3, 129.7, 128.2, 119.4, 34.2, 21.8, 11.9.
Procedure of Radical Trapping Experiments. An oven-dried
culture tube was charged with a magnetic stir bar, Eosin Y (3 mg, 2
mol %), 4-methyl styrene 1c (26 μL, 0.2 mmol), ethyl 2-
bromopropanoate 2a (52 μL, 0.4 mmol), and 1 mL of dry DMF.
After mixing the reaction components by stirring, DIPEA (72 μL, 0.4
mmol), TEMPO (2 equiv), and additional 1 mL of dried DMF were
added to them. The resulting solution was allowed to be irradiated for
3 h in blue LED light. The reaction mixture was analyzed by GC−MS.
Procedure of the Competitive Reaction. An oven-dried culture
tube was charged with a magnetic stir bar, Eosin Y (3 mg, 2 mol %),
4-methyl styrene 1c (26 μL, 0.2 mmol), diphenyl ethylene (35 μL, 0.2
mmol), ethyl 2-bromopropanoate 2a (52 μL, 0.4 mmol), and 1 mL of
dry DMF. After mixing the reaction components by stirring, DIPEA
(72 μL, 0.4 mmol) and additional 1 mL of dry DMF were added to
them. The resulting solution was allowed to be irradiated for 3 h, and
after that, another 0.2 mmol of both ethyl 2-bromopropanoate and
DIPEA was added to it. Finally, the completion of the reaction was
confirmed by TLC and the product was purified as process A
described previously.
Ethyl 2-Phenyl-5-(p-tolyl)-1H-pyrrole-3-carboxylate (19). White
solid; mp: 173−175 °C; 94% yield (29 mg); Rf value = 0.4 [EtOAc/
petroleum ether = 1:9 (v/v)]; FTIR νmax (KBr plate): 3310, 2925,
1
1680, 1462 cm−1; H NMR (400 MHz, CDCl3) δ (ppm): 8.82 (brs,
1H), 7.63−7.61 (m, 2H), 7.44−7.35 (m, 5H), 7.20 (d, J = 8.0 Hz,
2H), 6.96 (d, J = 2.9 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H),
1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl ) δ
3
(ppm): 165.1, 137.6, 136.9, 132.1, 132.0, 129.7, 129.1, 128.9, 128.3,
128.1, 124.1, 113.6, 108.7, 59.9, 21.3, 14.4; HRMS (ESI) m/z: [M +
Na]+ Calcd for C20H19NO2Na 328.1313; Found 328.1305.
Ethyl 2-Methyl-4,4-diphenylbut-3-enoate (8).14e Colorless vis-
cous liquid; 43% yield (24 mg); Rf value = 0.8 [EtOAc/petroleum
Synthesis of Thiophene 20. In a 10 mL round-bottom flask
equipped with a magnetic stir bar, a mixture of 1,4-ketocarbonyl
compound 4g (32 mg, 0.1 mmol) and Lawesson’s reagent (101 mg,
0.25 mmol) was added to anhydrous toluene (1 mL) and the mixture
was refluxed for 24 h. The reaction mixture was allowed to cool down
to room temperature, and the solvent was removed under reduced
pressure. The residue was purified by column chromatography to
furnish product 20 as a yellow oil with 86% yield.
1
ether = 1:9 (v/v)]; FTIR νmax (neat): 1676, 1645, 1607 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.39−7.34 (m, 4H), 7.27−7.20
(m, 6H), 6.12 (d, J = 10.3 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.27
(dq, J = 10.3, 7.0 Hz, 1H), 1.26 (m, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ (ppm): 175.1, 143.1, 142.0, 139.5, 129.9, 128.5, 128.3,
128.0, 127.5, 127.4, 60.7, 40.5, 18.6, 14.3.
Procedure of Radical Clock Experiments. An oven-dried
culture tube was charged with a magnetic stir bar, Eosin Y (3 mg, 2
mol %), 1-chloro-4-(1-cyclopropylvinyl) benzene 9 (36 mg, 0.2
O-Ethyl 2-phenyl-5-(p-tolyl)thiophene-3-carbothioate (20). Yel-
low oil; 86% yield (29 mg); Rf value = 0.5 [EtOAc/petroleum ether =
I
https://dx.doi.org/10.1021/acs.joc.0c01985
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1:19 (v/v)]; FTIR νmax (neat): 1516, 1356, 1313, 1248 cm−1; H
NMR (400 MHz, CDCl3) δ (ppm): 7.87 (s, 1H), 7.53−7.51 (m, 2H),
7.44 (dd, J = 6.6, 3.2 Hz, 2H), 7.39−7.38 (m, 3H), 7.21 (d, J = 7.9
Hz, 2H), 4.42 (q, J = 7.0 Hz, 2H), 2.39 (s, 3H), 1.01 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 207.2, 143.8,
142.1, 139.0, 138.1, 134.6, 130.6, 129.7, 129.5, 128.2, 128.1, 127.6,
125.7, 68.1, 21.3, 13.1; HRMS (ESI) m/z: [M + H]+ Calcd for
C20H19OS2 339.0877; Found 339.0876.
1
Deepak Singh − Department of Chemistry, Indian Institute of
Technology (ISM), Dhanbad, JH 826004, India
Injamam Ul Hoque − Department of Chemistry, Indian
Institute of Technology (ISM), Dhanbad, JH 826004, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01985
Synthesis of N-Aryl Pyrrole 21. In a 10 mL round-bottom flask
equipped with a magnetic stir bar, a mixture of 1,4-ketocarbonyl
compound 4g (32 mg, 0.1 mmol), 4-aminobenzenesulfonamide (17
mg, 0.1 mmol), and 4-toluenesulfonic acid (2 mg, 0.01 mmol) was
added to absolute EtOH (1 mL) and the mixture was refluxed for 24
h. After cooling the reaction mixture to room temperature, it was
concentrated under reduced pressure and the crude mixture was
purified by chromatography. The desired product 21 was obtained as
a white solid with 84% yield.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to SERB, India (ECR/2016/000270), DST-
INSPIRE (IFA 13-CH-90), and IIT(ISM) Dhanbad for
financial support. S.R.C. & D.S. thank IIT(ISM) Dhanbad
for their research fellowships. I.H. thanks DST-INSPIRE for a
doctoral fellowship. The authors also acknowledge DST-FIST,
New Delhi, for providing the NMR facility at our department.
Ethyl 2-Phenyl-1-(4-sulfamoylphenyl)-5-(p-tolyl)-1H-pyrrole-3-
carboxylate (21). White solid; mp: 185−187 °C; 84% yield (39
mg); Rf value = 0.5 [EtOAc/petroleum ether = 4:6 (v/v)]; FTIR νmax
1
(KBr plate): 1660, 1345, 1235, 1174 cm−1; H NMR (400 MHz,
REFERENCES
DMSO-d6) δ (ppm): 7.66 (d, J = 8.5 Hz, 2H), 7.46 (s, 2H), 7.28
(ddd, J = 13.7, 8.5, 1.7 Hz, 7H), 7.09 (d, J = 8.1 Hz, 2H), 7.03 (d, J =
8.2 Hz, 2H), 6.83 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.09
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ (ppm):
164.5, 144.4, 141.2, 140.4, 137.6, 135.6, 132.1, 132.0, 130.6, 129.8,
129.5, 129.3, 128.9, 128.2, 126.9, 115.1, 111.2, 60.0, 21.6, 14.9;
HRMS (ESI) m/z: [M + H]+ Calcd for C26H25N2O4S 461.1535;
Found 461.1525.
Synthesis of Dihydropyridazinone 22. In a 10 mL round-
bottom flask equipped with a magnetic stir bar, a mixture of 1,4-
ketocarbonyl compound 3k (45 mg, 0.15 mmol), hydrazine hydrate
(19 μL, 0.3 mmol), and 10 mg 4A MS was added to methanol (1 mL)
and the mixture was refluxed overnight. After that, the reaction
mixture was cooled and concentrated under reduced pressure. The
crude residue was purified by column chromatography. The desired
product 22 appeared as a white solid with 86% yield.
6-(2-Bromophenyl)-4-methyl-4,5-dihydropyridazin-3(2H)-one
(22). White solid; mp: 142−144 °C; 86% yield (34 mg); Rf value =
0.3 [EtOAc/petroleum ether = 3:7 (v/v)]; FTIR νmax (KBr plate):
3225, 1687, 1624, 1467 cm−1. 1H NMR (400 MHz, CDCl3) δ (ppm):
8.80 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 4.2 Hz, 2H), 7.28−
7.24 (m, 1H), 3.02−3.00 (m, 1H), 2.73−2.63 (m, 2H), 1.32 (d, J =
6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ (ppm): 171.2,
154.1, 138.5, 133.3, 130.6, 130.2, 127.7, 121.4, 33.9, 31.1, 14.9;
HRMS (ESI) m/z: [M + H]+ Calcd for C11H12BrN2O 267.0133;
Found 267.0126.
■
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01985.
Additional screening data; mechanistic experimental
details; and copies of 1H, 13C{1H}, and 19F NMR
spectra of all new products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Soumitra Maity − Department of Chemistry, Indian Institute of
Technology (ISM), Dhanbad, JH 826004, India; orcid.org/
0000-0003-0944-8162; Email: smaity@iitism.ac.in
Authors
Soumyadeep Roy Chowdhury − Department of Chemistry,
Indian Institute of Technology (ISM), Dhanbad, JH 826004,
India
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