Copper(II)-Catalyzed Benzylic C(sp3)-H Aerobic Oxidation of (Hetero)Aryl Acetimidates: Synthesis of Aryl-α-ketoesters

Article abstract of DOI:10.1021/acs.joc.6b02176

A straightforward method is developed in this paper for the synthesis of α-ketoesters through copper-catalyzed aerobic oxidation of (hetero)aryl acetimidates using molecular oxygen as a sustainable oxidant. The reaction represents the first example of the direct synthesis of aryl-α-ketoesters from arylacetimidates through the aerobic oxidation of a benzylic C_(sp3)-H (CO) bond in moderate to good yield. This transformation occurs under mild reaction conditions with a wide range of substrates and utilizes a readily available oxidant and catalyst. The synthetic utility of this transformation is demonstrated through scaled-up synthesis. A plausible reaction mechanism is also proposed.

Full text of DOI:10.1021/acs.joc.6b02176

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Article
Copper(II)-Catalyzed Benzylic C(sp3)-H Aerobic Oxidation of
(Hetero)Aryl Acetimidates: Synthesis of Aryl #-Ketoesters
Yogesh Kumar, Yogesh Jaiswal, and Amit Kumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02176 • Publication Date (Web): 09 Nov 2016
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Copper(II)-Catalyzed Benzylic C(sp3)-H Aerobic Oxidation of
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(Hetero)Aryl Acetimidates: Synthesis of Aryl α-Ketoesters
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Yogesh Kumar, Yogesh Jaiswal and Amit Kumar*
Department of Chemistry, Indian Institute of Technology Patna, Bihta 801103, Bihar, India
*E-mail: amitkt@iitp.ac.in or amitktiitk@gmail.com
Table of Contents/Abstract Graphic
ABSTRACT
A straightforward method is developed in this paper for the synthesis of α-ketoesters through
copper-catalyzed aerobic oxidation of (hetero)aryl acetimidates using molecular oxygen as a
sustainable oxidant. The reaction represents the first example of the direct synthesis of aryl--
ketoesters from arylacetimidates through the aerobic oxidation of a benzylic C(sp3)−H (C=O)
bond in moderate to good yield. This transformation occurs under mild reaction conditions with
a wide range of substrates and utilizes a readily available oxidant and catalyst. The synthetic
utility of this transformation is demonstrated through scaled-up synthesis. A plausible reaction
mechanism is also proposed.
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INTRODUCTION
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Direct functionalization of the fairly reactive C(sp3)−H bond at the benzylic position is an
attractive, powerful and challenging task that has encouraged synthetic organic chemists to
develop a cost effective, economical and environmentally friendly approach using
unfunctionalized organic molecules.1-3 Transition-metal–catalyzed aerobic oxidation is a versatile
tool known for the generation of C-C and C-X bonds, resulting in the formation of complex
molecules from small molecules.4 In recent years, major effort has been devoted to oxidative
transformation through transition metal catalysts.5 Copper-catalyzed aerobic oxidation has
emerged as a facile synthetic tool because it is less expensive and less toxic nature than other
transition metals, such as palladium, rhodium and ruthenium.6 Molecular oxygen is highly
abundant, inexpensive and green in nature, making desirable for synthetic organic chemists.5b,6
Stahl and co-workers demonstrated the practical application of copper/dioxygen for the
functionalization of organic molecules on the gram scale.4c,d,g Nature uses molecular oxygen in
combination with copper and other metals for the selective activation of unreactive C–H bonds,
for instance, monooxygenase tyrosinase, galactose oxidase and -monooxygenase.7
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α-Ketoesters are key structural scaffolds in a great number of biologically active molecules,
pharmaceuticals, anticancer agents, calpains, serine and cysteine protease inhibitors and
thrombin inhibitors.8 The presence of a keto group adjacent to an ester functionality creates an
attractive synthon for asymmetric reduction, aminohydroxylation and aldol reaction.9,10 They
serve as versatile building blocks for the synthesis of biologically active natural compounds,
such as (-) 9,10-dihydroecklonilactone B.11
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Scheme 1. Different Synthetic Approaches towards Aryl-α-Ketoesters
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Consequently, the synthesis of α-ketoesters has received much attention in recent years, and
numerous methods have been developed for the construction of α-ketoesters and their
analogues3,12-14 using metal catalysts12,13 or under metal-free conditions.14 Bimolecular coupling
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in the presence of a catalyst with precursors such as 1,3-diketones,13d 1,3-ketoaldehyde,12c
acetophenone,13b,c and phenylacetylene derivatives13a has been used to generate aryl--
ketoesters. Scheme 1 summarizes some of the established protocols for the synthesis of α-
ketoesters. Despite this significant progress, a major limitation of these strategies is the choice of
appropriate reagents (use of hazardous chemicals), substrates (proceeds through bimolecular
coupling, which eventually requires a muti-step process), harsh reaction conditions and the use
of expensive ligands. Thus, there is a need to develop an efficient strategy for the construction of
aryl-α-ketoesters that satisfies the following criteria: (a) usage of a pre-functionalized single
substrate, (b) usage of a benign oxidant and inexpensive catalyst, (c) liberation of gaseous
byproducts to ease the purification process, (d) operationally mild and economically feasible
method. This direct approach can be categorized as “green or sustainable” chemistry. Pursuing
these limitations, we report for the first time a simple strategy for the synthesis of α-ketoesters
via copper-catalyzed benzylic C-H aerobic oxidation of (hetero)aryl acetimidates. To the best of
our knowledge, the use of arylacetimidates as a key starting material for the synthesis aryl α-
ketoesters has not been reported (Scheme 1f).
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We recently reported a copper-mediated aerobic oxidation of benzylimidate leading to the
formation of primary α-ketoamides,15a which are important structural units in biologically active
molecules.15 We also obtained an -ketoester as a side product in trace amounts during the course
of the reaction, particularly when non-polar solvents, such as toluene, were used. This
unexpected result encouraged us to optimize the reaction conditions to obtain aryl α-ketoesters in
good yield from the readily available starting material 2-phenylacetimidate. It is interesting to
evaluate the effect of a non-polar solvent, which likely changes the course of the reaction.16
RESULTS AND DISCUSSION
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The present study was initiated from 2-phenylacetimidate 1a as a designed substrate and toluene
as the required solvent. Copper salt was selected as a catalyst since it has strong affinity to
coordinate with nitrogen (NH),15a and molecular oxygen was selected as the ideal oxidant due to
its high abundance, green and benign nature.5b First, 1a was treated with 10 mol% of Cu(OAc)2
in a non-polar solvent (toluene) under a molecular oxygen atmosphere (1.0 atm)17 at 90 °C for 20
h (Table 1, entry 1). The targeted -ketoester 2a was isolated in an encouraging yield of 51%
with the generation of ester 2aa in trace amounts. A control experiment in the absence of copper
salt yielded no product and the starting material remained intact (according to TLC analysis)
(entry 2). Catalyst screening indicated that Cu(OAc)2 was the best choice among CuCl2,
Cu(OTf)2, CuBr, and CuCl (Table 1, entries 3-6).
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Table 1. Optimization of the reaction conditionsa
Entry
Catalyst
Additive
Solvent
Yield (%)
2a 2aa
51 trace
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Cu(OAc)2
none
toluene
toluene
toluene
toluene
toluene
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CuCl2
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Cu(OTf)2
CuBr
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CuCl
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
PhCl
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7b
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
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NEt3
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DIPEA
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16f
17g
18h
19i
20j
21k
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pyridine
1,10-phen
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
72 trace
15
8
49 trace
53 trace
53
28
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dioxane
DMF
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10 trace
toluene
toluene
toluene
toluene
toluene
toluene
none trace
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8
10 trace
10 trace
none trace
Fe(NO3)3.9H2O pyridine
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Ni(OAc)2.4H2O pyridine
toluene
toluene
none trace
none trace
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pyridine
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aReaction conditions: a) Basic hydrolysis (see the experimental procedure). b) 1a (0.5 mmol),
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b
catalyst (0.05 mmol), toluene (2.5 mL), additive (50 mol%), O2 (1 atm), 90 °C, 20 h. 20 mol%
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of catalyst was used. 50 mol% of 1,10-phenanthroline was used. 100 mol% of pyridine was
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employed. 10% α-ketoamide product was isolated. 15% α-ketoamide was isolated. In a N2 (1
h
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atm) atmosphere. In an air (1 atm) atmosphere. 1.0 mmol TBHP was used as the oxidant in air
(1 atm). j1.0 mmol TBHP was used as the oxidant in N2 (1 atm). k1.0 mmol K2S2O8 was used as
the oxidant in N2 (1 atm).
A further increase in the loading of the catalyst from 10 mol% to 20 mol% was reduced the yield
to 31% (Table 1, entry 7). To increase the yield of the desired product, we focused on ligand
screening; the addition of pyridine as the ligand improved the yield to 72% (Table 1, entry 10).
In contrast to monodentate ligands, when a bidentate ligand such as 1,10-phenanthroline was
used, the yield of the product decreased dramatically to 15% (Table 1, entry 11). Moreover,
increasing the loading of pyridine did not enhance the efficiency of product formation (Table 1,
entry 12). As the nature of solvent is a critical factor in this type of reaction, the effect of the
solvent was surveyed, and toluene was found to be the prime solvent to achieve this
transformation (Table 1, entry10). When the reaction was performed in a nitrogen atmosphere,
no desired product was generated (Table 1, entry 17). However, when the reaction was
performed in open air, 2a was obtained, albeit in a moderate yield of 46% (Table 1, entry 18).
The utilization of alternate oxidants, such as TBHP and K2S2O8, failed to produce the desired
product, and the starting material was recovered through flash column chromatography (entries
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19-21). These preliminary results support the indispensable role of molecular oxygen in this
particular reaction. Other transition metal catalysts, for instance, Fe(NO3)3.9H2O,
Ni(OAc)2.4H2O and Pd(OAc)2 were ineffective and led to inferior results (Table 1,entries 22-
24).
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Scheme 2. Substrate scope of 2-phenylacetimidatesa
aFor reaction conditions: a) Basic hydrolysis. b) See entry 10, Table 1.
With the optimized conditions, which satisfied the criteria set by us, we explored the scope and
limitations of this protocol to synthesize a variety of substituted alcohols utilizing 2-
phenylacetimidates 1 (Scheme 2) as key precursors. The results indicate that 2-
phenylacetimidates 1 attached to acyclic primary and secondary alkyl alcohol, such as ethanol,
methanol, iso-propanol, n-propanol, n-butanol, and sec-butanol afforded the corresponding
phenyl--ketoesters (entries 2a-2f), and the yields ranged from 60 to 76%. Cyclic secondary
alkyl alcohols, such as cyclopentanol and cyclohexanol, which are susceptible to oxidative
conditions, formed the corresponding α-ketoesters in good yields (74%, entries 2g and 2h).
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Alcohols bearing a chloro group also tolerated the standard reaction conditions to obtain the
products in 53% yield (entry 2i), which could be used for further functionalization.
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Scheme 3. Substrate scope for the synthesis of various aryl-ketoestersa
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aFor reaction conditions: a) Basic hydrolysis. b) See entry 10, Table 1.
The scope of the copper-catalyzed aerobic oxidative esterification of (hetero)aryl acetimidates
with different O-alkyls in the alkoxy group 3 was further expanded, and the results are
summarized in Scheme 3. -Arylacetimidates bearing electron donating groups (EDGs), such as
methyl, methoxy, and 3,4-dioxy, at the ortho, para and meta positions of the aryl ring, and a
variety of alkoxy substituents (ethyl, propyl, butyl, cyclopentyl and cyclohexyl), generated the
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products with good yields (56-88%, Scheme 3, entries 4a-4n). The presence of different
substituents at various positions of the aryl ring and the alkoxy group did not affect the overall
efficiency of the product yield. Electronically neutral groups, such as para-phenyl and naphthyl,
were tolerated well in this transformation (58-68%, entries 4o and 4p). However, the
introduction of an electron-withdrawing (EWG) group, such as a nitro group, on the aryl ring of
2-arylacetimidate 3q had a negative effect and completely inhibited the reaction.
Arylacetimidates containing halo groups, such as bromo and chloro, at the para position
afforded the desired product in moderate yields (53-62%, entries 4r and 4s), providing products
for post-coupling transformation. The substrate scope was further extended for the synthesis of
bioactive, medicinally important heteroaryl-α-ketoester derivatives18 in 51-58% yields (entries
4t-4z). However, when the reaction was performed with 3-phenylpropanimidate 3aa, α-ketoester
4aa was not obtained and the starting material remained intact (TLC analysis). These results
confirm that the benzylic hydrogen adjacent to the imidate group is crucial for the success of this
transformation.
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Scheme 4. Synthetic utility experiment
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To demonstrate the synthetic applicability of this established protocol, gram-scale syntheses of
butyl 2-oxo-2-phenylacetate 2e and ethyl 2-(2-methoxyphenyl)-2-oxoacetate 4g were conducted
under the standard reaction conditions. This transformation proceeded smoothly to afford the
desired products 2e (68%, 1.68 g) and 4g (83%, 2.1 g) (Scheme 4), and there was no substantial
drop in the yield during the gram-scale synthesis.
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Next, we evaluated the utility of the established methodologies to synthesize aryl α-ketoesters
through two-step, one-pot synthesis. For this purpose, we selected 2-phenylacetonitrile 5 as the
model substrate, along with 1-adamantanemethanol 6 and (±)-menthol 9 (Scheme 5) as the
alcohols in the presence of dry HCl(g), followed by basic hydrolysis to afford the required
benzylimidates. Without further purification, the crude reaction mixture was subjected to
standard conditions to afford the aryl-α-ketoesters 8 and 11 in 31% and 28% yields, respectively
(Scheme 5, yields were not optimized at this stage, but the examples are provided to showcase
the utility of one-pot synthesis).
Scheme 5. One-pot synthesis of α-ketoesters from nitrilea,b,c
aReactions were conducted with nitrile 5 (1.0 mmol) and alcohols 6 and 9 (1.1 mmol) in THF
(5.0 mL) at 0 °C in a sealed round-bottom flask for 18 h under acidic conditions. The crude
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reaction mixture was treated with Cu(OAc)2 (10 mol%), pyridine (50 mol%) and toluene (5.0
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mL) at 90 °C under an O2 atmosphere (1atm) for 20 h. Reactions were monitored by TLC.
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To investigate the mechanistic aspects of this reaction, additional experiments were conducted.
When 2-phenylacetate 2aa was subjected to the optimized conditions, no desired product was
obtained (Scheme 6a), and 95% of the starting material was recovered. Furthermore, when
equimolar amounts of ethyl 2-p-tolylacetimidate 3a was mixed with 2-phenylacetate 2aa and
subjected to the standard conditions, α-ketoester 4a was isolated in 52% yield, and 2-
phenylacetate 2aa was recovered in 87% yield (Scheme 6b). These results indicate that 2aa may
not be an intermediate in this oxidative transformation and 2-phenylacetimidate, and an imidate
group adjacent to the benzylic position is crucial in the starting material for this reaction.
According to the outcome of the reaction, keto-imidate 12 could be the key intermediate in the
reaction. Hence, we conducted an additional control experiment, in which imidate 1a was
subjected to the standard conditions without the subsequent aqueous HCl workup. The HRMS
analysis of the reaction solution showed the presence of keto-imidate 12 as an intermediate,
which upon aqueous HCl workup, afforded the desired product 2a in 70% yield (Scheme 6c) (for
details, see the Supporting Information).19 To further elucidate the indispensable role of water for
the reaction, 18O isotopic labelling experiment was also investigated (Scheme 6d). When the
reaction was performed under standard conditions, followed by aqueous workup in the presence
18
18
18
of H2 O (400 mol%), the O labeling products were observed (2a-16O3:2a-16O2 O =1:1.2 by
HMRS analysis). These experiments (Scheme 6c and 6d) clearly support that the one oxygen
atom of ketoester originate from the water and conform the participation of water. Next,
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competition studies between substrates 1a and 3g were performed under the optimized
conditions, and the desired products 2a and 4g were isolated through column chromatography in
31% and 46% yields, respectively (1:1.5) (Scheme 6e). The results indicate that EDGs are
favored over electronically neutral groups (see the Supporting Information).19
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Scheme 6. Identification of possible intermediates and competition experiment
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To determine the possible radical pathways involved in the reaction, a radical scavenger (2,2,6,6-
tetramethyl-1-piperidin-1-yl)oxyl (TEMPO)) was introduced to the reaction mixture (Scheme
7a). The reaction was inhibited completely, and a TEMPO-adduct was identified as the major
product (TLC analysis), which was confirmed by HRMS analysis (Supporting Information).19
Additionally, when a different radical scavenger, such as 2,6-di-tert-butyl-4-methylphenol
(BHT), was used under similar conditions, no desired product was obtained (Scheme 7b). The
results indicate that a radical pathway may be involved in the reaction mechanism. To further
prove that a radical pathway is involved in this process, we performed electron paramagnetic
resonance (EPR) experiments, in which 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was used as
a free radical spin trapping agent. In the EPR spectra, 4 classic peaks corresponding to DMPO-
O(H) appeared, and the calculated values were go (2.0037) and αH (15.0 G)15a (Figure 1B).
Furthermore, the signal corresponding to DMPO-O(H) disappeared after the addition of
superoxide dismutase (SOD) (Supporting Information).19 These results confirm that the reaction
proceeded via a radical pathway.
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Scheme 7. Radical inhibition experiments
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1a under standard conditions
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1a + DMPO under standard conditions
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H/G
Figure 1. EPR spectra (X band, 9.4 GHz, room temperature) of the reaction under the standard
conditions [1a, Cu(OAc)2, O2 balloon (1 atm), toluene, 90 °C]. (A) The reaction of 1a under
standard conditions. (B) The reaction of 1a with the addition of DMPO under standard
conditions. The calculated hyperfine splitting is go = 2.0037. All spectra were analyzed by EPR
at 25 °C.
On the basis of these results and previous literature,15a,20 plausible mechanistic details are
proposed in Scheme 8. The coordination of imidate (NH) 1a with the copper(II) catalyst leads to
iminyl copper (II) species A.20d Subsequently, this species undergoes aerial oxidation in the
presence of molecular oxygen to form the highly reactive peroxycopper(III) B.15a,20 Then, the
superoxide species B quickly rearranges via an intramolecular 1,3-hydrogen shift to from
benzylic radical C, which is further transformed to peroxycopper species D. Subsequently, this
peroxycopper species undergoes secondary hydrogen abstraction of the benzylic proton and
elimination of [Cu(II)-OH] to produce the key intermediate keto-imidate 12. The following
hydrolysis of 12 produces the desired product aryl-α-ketoester 2a.
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Scheme 8. Possible reaction mechanism
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CONCLUSION
In conclusion, we have developed the first example of the direct synthesis of aryl--ketoesters
from (hetero)aryl acetimidates via copper (II)-catalyzed aerobic oxidation of a benzylic
hydrogen. This strategy provides a simple, practical and straightforward method for the synthesis
of -ketoesters, which are important units in medicinally active compounds. The uniqueness of
this strategy lies in the use of a) arylacetimidates as the single prefunctionalized key substrate, b)
a simple catalytic system, c) gram-scale synthesis and d) broad substrate scope. Preliminary
mechanistic studies show that the one oxygen atom of the ketoester originated from the water.
Further synthetic applications of this methodology are currently under investigation in our
laboratory.
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EXPERIMENTAL SECTION
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General Information
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All reagents and solvents were purchased from commercial suppliers and were used without
further purification. All reactions were monitored by TLC, followed by exposure of the mixtures
to UV light and/or an iodine chamber to visualize the reaction spots. Column chromatography
was performed using silica gel [ethyl acetate/hexane (in different ratios) solvent system]. FTIR
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spectra were recorded in ATR mode with the absorption in cm–1. H NMR (400 MHz) and
13C{1H} NMR (100 MHz) spectra were recorded in CDCl3 or DMSO-d6 as the solvent at 25 °C.
Chemical shifts (in ppm) were reported using tetramethylsilane (δ = 0) as an internal standard in
CDCl3 (δ = 7.26) or DMSO-d6 (δ = 2.50) solvent. The following abbreviations were used to
define the multiplicities: s = singlet; d = doublet; t = triplet; m = multiplet; dd (doublet of
doublets); td (triplet of doublets); br s (broad singlet), coupling constants (J, in Hz). 13C{1H}
NMR data were recorded in terms of the chemical shift (ppm, scale), using the central peak of
CDCl3 (77.0 ppm) or DMSO-d6 (δ = 39.5 ppm) as the internal standard. EPR data were recorded
on 9.4 GHz spectrometers, with a modulation amplitude of 10 G and modulation frequency of
100 kHz. DMPO (5,5-dimethyl-1-pyrroline-N-oxide) was used as a selective superoxide free
radical trapping reagent. HRMS was performed in ESI mode using Q-TOF (positive ion).
Melting points were recorded with an automated melting point apparatus without correction.
General procedure for the preparation of imidate hydrochlorides.15a,21a
A 50 mL flask containing a solution of a nitrile (1.0 mmol) and an alcohol (12.0 mmol) was
sealed with the rubber septum at 0 °C under N2 and a solution of CH3COCl (0.57 mL, 8.0 mmol)
was added slowly to the solution using a glass syringe while stirring. The reaction was stirred at
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room temperature for 12 h. Upon completion of the reaction (monitored by TLC), the volatile
solvents were removed under reduced pressure. The crude product was dried under high vacuum
to isolate the imidate hydrochloride salt.
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The characterization data of compounds 1a-1d, 3a, 3d, 3g, 3j, 3m-3p, 3t, 3v-3x and 3aa are
consistent with those previously reported in the literature.15a
Butyl 2-phenylacetimidate hydrochloride (1e).White solid: yield 198 mg, 87%; mp 106-108 °C;
IR (ATR) 2810, 1741, 1652, 1567, 1436, 1360, 1085, 897 cm−1; 1H NMR (400 MHz, DMSO-d6
with CDCl3) δ 12.47 (br s, 1H), 11.46 (br s, 1H), 7.28-7.17 (m, 5H), 4.34 (t, J = 6.4 Hz, 2H),
3.97 (s, 2H), 1.65-1.61 (m, 2H), 1.30-1.24 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, DMSO-d6 with CDCl3) δ 177.0, 134.0, 128.9, 128.0, 126.5, 73.0, 40.6, 30.1, 18.5, 13.3;
HRMS (ESI) calcd for C12H18NO [M+H]+ 192.1383, found 192.1386.
sec-Butyl 2-phenylacetimidate hydrochloride (1f). White solid: yield 140 mg, 62%; mp 96-98
°C; IR (ATR) 3286, 3158, 2874, 1652, 1609, 1414, 1304, 1088, 900 cm−1; 1H NMR (400 MHz,
DMSO-d6 with CDCl3) δ 12.34 (br s, 1H), 11.41 (br s, 1H), 7.32-7.22 (m, 5H), 5.06-4.99 (m,
1H), 3.38 (s, 2H), 1.62-1.55 (m, 2H), 1.22 (d, J = 6.0 Hz, 3H), 0.73 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6 with CDCl3) δ 176.1, 132.0, 128.9, 128.6, 127.9, 82.1, 42.3, 27.7,
18.2, 8.5; HRMS (ESI) calcd for C12H18NO [M+H]+ 192.1383, found 192.1387.
Cyclopentyl 2-phenylacetimidate hydrochloride (1g). White solid: yield 210 mg, 88%; mp 124-
126 °C; IR (ATR) 3357, 3158, 2838, 1638, 1411, 1127, 698 cm−1; 1H NMR (400 MHz, DMSO-
d6 with CDCl3) δ 12.42 (br s, 1H), 11.40 (br s, 1H), 7.29-7.16 (m, 5H), 5.38-5.31 (m, 1H), 3.89
(s, 2H), 1.91-1.86 (m, 2H), 1.67-1.58 (m, 2H), 1.55-1.53 (m, 4H); 13C{1H} NMR (100 MHz,
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Cyclohexyl 2-phenylacetimidate hydrochloride (1h).White solid: yield 244 mg, 96%; mp 128-
130 °C; IR (ATR) 2803, 1648, 1567, 1432, 1166, 875 cm−1; 1H NMR (400 MHz, DMSO-d6 with
CDCl3) δ 12.36 (br s, 1H), 11.43 (br s, 1H), 7.27-7.18 (m, 5H), 5.03-4.98 (m, 1H), 3.90 (s, 2H),
1.79-1.72 (m, 2H), 1.60-1.52 (m, 2H), 1.48-1.34 (m, 4H), 1.30-1.24 (m, 2H); 13C{1H} NMR (100
MHz, DMSO-d6 with CDCl3) δ 175.5, 131.7, 128.8, 128.5, 127.7, 81.7, 41.0, 29.9, 24.1, 22.1;
HRMS (ESI) calcd for C14H20NO [M+H]+ 218.1539, found 218.1539.
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3-Chloropropyl 2-phenylacetimidate hydrochloride (1i). White solid: yield 228 mg, 92%; mp
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122-124 °C; IR (ATR) 2810, 1741, 1652, 1563, 1436, 1368, 1092, 904 cm−1; H NMR (400
MHz, DMSO-d6 with CDCl3) δ 12.61 (br s, 1H), 11.58 (br s, 1H), 7.24-7.20 (m, 5H), 4.13 (t, J =
6.0 Hz, 2H), 3.59 (s, 2H), 3.55 (t, J = 6.4 Hz, 2H), 2.03-1.97 (m, 2H); 13C{1H} NMR (100 MHz,
DMSO-d6 with CDCl3) δ 170.7, 133.9, 129.0, 128.1, 126.6, 60.9, 41.1, 40.4, 31.0; HRMS (ESI)
calcd for C11H15ClNO [M+H]+ 212.0837, found 212.0850.
Propyl 2-p-tolylacetimidate hydrochloride (3b). White solid: yield 208 mg, 92%; mp 120-122
1
°C; IR (ATR) 2803, 1652, 1514, 1418, 1085, 893, 829 cm−1; H NMR (400 MHz, DMSO-d6
with CDCl3) δ 12.43 (br s, 1H), 11.46 (br s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz,
2H), 4.29 (t, J = 6.4 Hz, 2H), 3.90 (s, 2H), 2.24 (s, 3H), 1.73-1.64 (m, 2H), 0.84 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, DMSO-d6 with CDCl3) δ 177.2, 137.2, 130.8, 129.2, 128.7, 74.5,
40.2, 21.4, 20.6, 10.0; HRMS (ESI) calcd for C12H18NO [M+H]+ 192.1383, found 192.1386.
Butyl 2-p-tolylacetimidate hydrochloride (3c). White solid: yield 228 mg, 95%; mp 125-127 °C;
IR (ATR) 2810, 1656, 1517, 1436, 1092, 889 cm−1; 1H NMR (400 MHz, DMSO-d6 with CDCl3)
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δ 12.43 (br s, 1H), 11.42 (br s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 4.32 (t, J =
6.4 Hz, 2H), 3.89 (s, 2H), 2.24 (s, 3H), 1.63-1.61 (m, 2H), 1.30-1.24 (m, 2H), 0.83 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, DMSO-d6 with CDCl3) δ 177.1, 137.2, 130.8, 129.2, 128.8, 73.0,
40.2, 30.1, 20.6, 18.5, 13.3; HRMS (ESI) calcd for C13H20NO [M+H]+ 206.1539, found
206.1546.
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Propyl 2-(4-methoxyphenyl)acetimidate hydrochloride (3e). White solid: yield 201 mg, 83%;
mp 102-104 °C; IR (ATR) 2824, 1737, 1652, 1507, 1436, 1379, 1241, 1099 cm−1; 1H NMR (400
MHz, DMSO-d6 with CDCl3) δ 12.378 (br s, 1H), 11.38 (br s, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.80
(d, J = 8.0 Hz, 2H), 4.28 (t, J = 6.4 Hz, 2H), 3.87 (s, 2H), 3.70 (s, 3H), 1.74-1.64 (m, 2H), 0.83
(t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6 with CDCl3) δ 177.3, 158.1, 129.9,
125.9, 113.4, 74.5, 54.7, 39.7, 21.4, 10.0; HRMS (ESI) calcd for C12H18NO2 [M+H]+ 208.1332,
found 208.1336.
Butyl 2-(4-methoxyphenyl)acetimidate hydrochloride (3f). White solid: yield 229 mg, 89%; mp
114-116 °C; IR (ATR) 2796, 1645, 1514, 1429, 1241, 1177, 1102, 900, 820 cm−1; 1H NMR (400
MHz, DMSO-d6 with CDCl3) δ 12.43 (br s, 1H), 11.40 (br s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.79
(d, J = 8.0 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.86 (s, 2H), 3.70 (s, 3H), 1.66-1.62 (m, 2H), 1.30-
1.24 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6 with CDCl3) δ
177.2, 158.0, 129.8, 125.8, 113.4, 73.0, 54.7, 39.8, 30.1, 18.5, 13.3; HRMS (ESI) calcd for
C13H20NO2 [M+H]+ 222.1489, found 222.1497.
Butyl 2-(2-methoxyphenyl)acetimidate hydrochloride (3h).White solid: yield 250 mg, 97%; mp
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118-120 °C; IR (ATR) 2817, 1631, 1432, 1375, 1248, 1109, 1021 cm−1; H NMR (400 MHz,
DMSO-d6 with CDCl3) δ 11.99 (br s, 1H), 11.50 (br s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.06 (d, J =
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8.0 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.35 (t, J = 6.0 Hz, 2H), 3.89 (s,
2H), 3.75 (s, 3H), 1.61-1.55 (m, 2H), 1.21-1.14 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6 with CDCl3) δ 177.4, 156.8, 130.6, 129.3, 122.7, 120.3, 110.1, 73.0, 55.0,
35.4, 29.1, 17.9, 12.9; HRMS (ESI) calcd for C13H20NO2 [M+H]+ 222.1489, found 222.1498.
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Cyclopentyl 2-(2-methoxyphenyl)acetimidate hydrochloride (3i). White solid: yield 240 mg,
89%; mp 114-116 °C; IR (ATR) 2824, 1726, 1638, 1570, 1407, 1361, 1113 cm−1; 1H NMR (400
MHz, DMSO-d6 with CDCl3) δ 11.95 (br s, 1H), 11.35 (br s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.14
(d, J = 8.0 Hz, 1H), 6.86-6.82 (m, 2H), 5.44-5.37 (m, 1H), 3.86 (s, 2H), 3.74 (s, 3H), 1.92-1.85
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(m, 2H), 1.65-1.58 (m, 2H), 1.55-1.49 (m, 2H), 1.45-1.40 (m, 2H); C{1H} NMR (100 MHz,
DMSO-d6 with CDCl3) δ 176.4, 156.7, 130.6, 129.3, 120.3, 119.8, 110.0, 86.5, 54.9, 34.5, 31.8,
22.8; HRMS (ESI) calcd for C14H20NO2 [M+H]+ 234.1489, found 234.1485.
Butyl 2-(benzo[d][1,3]dioxol-5-yl)acetimidate hydrochloride (3k). White solid: yield 250 mg,
92%; mp 124-126 °C; IR (ATR) 3350, 3172, 2824, 1641, 1425, 1361, 1127 cm−1; 1H NMR (400
MHz, DMSO-d6 with CDCl3) δ 12.45 (br s, 1H), 11.44 (br s, 1H), 6.86 (s, 1H), 6.78 (d, J = 8.0
Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.91 (s, 2H), 4.33 (t, J = 6.0 Hz, 2H), 3.86 (s, 2H), 1.67-1.63
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(m, 2H), 1.31-1.26 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, DMSO-d6 with
CDCl3) δ 177.1, 147.5, 147.0, 124.8, 122.5, 109.3, 108.1, 100.9, 73.0, 38.1, 29.2, 18.1, 13.1;
HRMS (ESI) calcd for C13H18NO3 [M+H]+ 236.1281, found 236.1279.
Cyclopentyl 2-(benzo[d][1,3]dioxol-5-yl)acetimidate hydrochloride (3l). White solid: yield 260
mg, 92%; mp 144-146 °C; IR (ATR) 3115, 2973, 2796, 1748, 1641, 1397, 1372, 1099 cm−1; 1H
NMR (400 MHz, DMSO-d6 with CDCl3) δ 12.23 (br s, 1H), 11.25 (br s, 1H), 6.87 (s, 1H), 6.77
(s, 1H), 6.72-6.68 (m, 1H), 5.95 (s, 2H), 5.32-5.29 (m, 1H), 3.81 (s, 2H), 1.95-1.86 (m, 2H),
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1.72-1.64 (m, 2H), 1.59-1.55 (m, 4H); 13C{1H} NMR (100 MHz, DMSO-d6 with CDCl3) δ
176.2, 147.5, 147.0, 125.2, 122.4, 109.2, 108.2, 101.0, 86.4, 38.4, 31.8, 23.0; HRMS (ESI) calcd
for C14H18NO3 [M+H]+ 248.1281, found 248.1282.
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3-Chloropropyl 2-(4-bromophenyl)acetimidate hydrochloride (3r). White solid: yield 204 mg,
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63%; mp 116-118 °C; IR (ATR) 2781, 1737, 1641, 1400, 1375, 1099, 911 cm−1; H NMR (400
MHz, DMSO-d6 with CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.13 (t, J = 6.0
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Hz, 2H), 3.62 (s, 2H), 3.59 (t, J = 8.0 Hz, 2H), 2.04-1.98 (m, 2H); C{1H} NMR (100 MHz,
DMSO-d6 with CDCl3) δ 170.4, 133.4, 131.3, 131.0, 120.1, 61.2, 41.3, 31.0; HRMS (ESI) calcd
for C11H14BrClNO [M+H]+ 289.9942, found 289.9943.
3-Chloropropyl 2-(4-chlorophenyl)acetimidate hydrochloride (3s). White solid: yield 264 mg,
94%; mp 106-108 °C; IR (ATR) 3122, 2966, 2796, 1737, 1648, 1368, 1088, 904 cm−1; 1H NMR
(400 MHz, DMSO-d6 with CDCl3) δ 7.28 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 4.14 (t, J
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= 6.0 Hz, 2H), 3.61 (s, 2H), 3.57 (t, J = 8.0 Hz, 2H), 2.04-1.99 (m, 2H); C{1H} NMR (100
MHz, DMSO-d6 with CDCl3) δ 170.4, 132.8, 131.9, 130.8, 128.1, 61.1, 41.1, 31.0, 20.5; HRMS
(ESI) calcd for C11H14Cl2 NO [M+H]+ 246.0447, found 246.0447.
Cyclopentyl 2-(thiophen-2-yl)acetimidate hydrochloride (3u). White solid: yield 228 mg, 93%;
mp 110-112 °C; IR (ATR) 2810, 1734, 1641, 1560, 1429, 1361, 1138, 843 cm−1; 1H NMR (400
MHz, CDCl3) δ 12.59 (br s, 1H), 11.62 (br s, 1H), 7.26 (t, J = 4.4 Hz, 1H), 7.17 (t, J = 3.2 Hz,
1H), 6.99-6.97 (m, 1H), 5.68-5.59 (m, 1H), 4.25 (s, 2H), 2.20-2.10 (m, 2H), 1.86-1.76 (m, 2H),
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33.9, 32.5, 23.6; HRMS (ESI) calcd for C11H16NOS [M+H]+ 210.0947, found 210.0947.
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81%; mp 102-104 °C; IR (ATR) 2973, 1645, 1457, 1358, 1085, 733 cm−1; H NMR (400 MHz,
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CDCl3) δ 7.61-7.58 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.13-7.08 (m,
2H), 5.06-5.00 (m, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.78 (s, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.23 (d, J
= 6.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.1, 135.8, 127.8, 126.1, 125.9, 121.5,
119.2, 119.0, 109.3, 68.1, 40.9, 31.7, 21.9, 15.4; HRMS (ESI) calcd for C15H21N2O [M+H]+
245.1648, found 245.1658.
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Cyclopentyl 2-(1-ethyl-1H-indol-3-yl)acetimidate hydrochloride (3z). White solid: yield 240
1
mg, 78%; mp 104-106 °C; IR (ATR) 2973, 1726, 1652, 1460, 1358, 1148, 730 cm−1; H NMR
(400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H),
7.05-6.99 (m, 2H), 5.13-5.08 (m, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.64 (s, 2H), 1.81-1.71 (m, 2H),
1.66-1.55 (m, 4H), 1.53-1.44 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 175.4, 135.9, 127.9, 125.9, 121.5, 119.2, 119.0, 109.3, 107.2, 77.4, 40.8, 32.7, 31.7,
23.7, 15.5; HRMS (ESI) calcd for C17H23N2O [M+H]+ 271.1805, found 271.1808.
General procedure for the synthesis of α-ketoesters.
Imidate hydrochloride salts (0.5 mmol) were dissolved in 20 mL of diethyl ether, and the
reaction mixture was cooled to 0 °C. Saturated NaHCO3 solution was added slowly until CO2 gas
evolution ceased. The product was extracted with Et2O (2 x 10 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure to obtain the free imidates. Without further
purification, the imidates were treated with anhydrous Cu(OAc)2 (0.05 mmol, 9.18 mg), pyridine
(0.25 mmol, 20 μL), and anhydrous toluene (2.5 mL) in a 25 mL round-bottom flask. The
reaction flask was sealed with a rubber septum and degassed and refilled with O2 (3 times). The
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resulting reaction mixture was heated at 90 °C in a preheated oil bath for 20 h. Upon completion
of the reaction (revealed by TLC), the reaction mixture was treated with 10% HCl solution (10
mL) and stirred at room temperature for 30 min. The resulting solution was extracted with ethyl
acetate (15 mL × 3), and the combined organic layer was washed with brine solution (10 mL)
and concentrated in vacuo. The crude residue was purified using silica gel column
chromatography with hexanes and EtOAc (98:2) as the eluent to afford the corresponding
products.
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Ethyl 2-oxo-2-phenylacetate (2a).13d Yellow viscous liquid: yield 62 mg, 72%; Rf (9.8:0.2
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hexanes/EtOAc) = 0.9; IR (ATR) 2997, 1736, 1683, 1605, 1292, 1203, 1175, 1015 cm−1; H
NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz,
2H), 4.46 (q, J = 8.0 Hz, 2H), 1.43 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
186.4, 163.8, 134.9, 132.5, 130.1, 128.9, 62.4, 14.1.
Methyl 2-oxo-2-phenylacetate (2b).14d Yellow viscous liquid: yield 49.8 mg, 60%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2956, 1735, 1687, 1595, 1581, 1450, 1325, 1203, 1172, 1002
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.52 (t, J
= 8.0 Hz, 2H), 3.99 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.1, 164.0, 135.0, 132.5,
130.2, 128.9, 52.8.
Isopropyl 2-oxo-2-phenylacetate (2c).14d Yellow viscous liquid: yield 72.0 mg, 75%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2983, 1728, 1687, 1597, 1450, 1375, 1296, 1201, 1176, 1101
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (t, J
= 8.0 Hz, 2H), 5.38-5.28 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
186.7, 163.6, 134.8, 132.5, 130.0, 128.9, 70.7, 21.7.
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Propyl 2-oxo-2-phenylacetate (2d).22b Yellow viscous liquid: yield 64.0 mg, 67%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2970, 2881, 1732, 1685, 1597, 1450, 1323, 1195, 1174 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0
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Hz, 2H), 4.36 (t, J = 8.0 Hz, 2H), 1.86-1.77 (m, 2H), 1.02 (t, J = 8.0 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 186.6, 164.0, 134.9, 132.5, 130.0, 128.9, 67.8, 21.9, 10.3.
Butyl 2-oxo-2-phenylacetate (2e).13b Yellow viscous liquid: yield 74 mg, 76%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2960, 2873, 1732, 1689, 1597, 1450, 1323, 1197, 1174 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0
Hz, 2H), 4.40 (t, J = 8.0 Hz, 2H), 1.80-1.73 (m, 2H), 1.50-1.41 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.5, 164.0, 134.9, 132.5, 130.0, 128.9, 66.1, 30.5, 19.0,
13.7.
sec-Butyl 2-oxo-phenylacetate (2f).22c Yellow viscous liquid: yield 66.0 mg, 64%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2974, 2937, 1730, 1689, 1597, 1450, 1203, 1176 cm−1; H
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NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz,
2H), 5.21-5.14 (m, 1H), 1.83-1.65 (m, 2H), 1.39 (d, J = 8.0 Hz, 3H), 0.98 (t, J = 8.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.8, 163.9, 135.0, 132.6, 130.1, 128.8, 75.2, 28.7, 19.4,
9.7.
Cyclopentyl 2-oxo-2-phenylacetate (2g).22a Yellow viscous liquid: yield 80 mg, 74%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2963, 2878, 1727, 1672, 1689, 1593, 1448, 1325, 1201, 1155
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (t, J
= 8.0 Hz, 2H), 5.51-5.46 (m, 1H), 2.04-1.96 (m, 2H), 1.90-1.86 (m, 2H), 1.80-1.76 (m, 2H),
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1.68-1.64 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.8, 164.0, 134.8, 132.5, 130.0, 128.9,
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79.7, 32.7, 23.7.
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Cyclohexyl 2-oxo-2-phenylacetate (2h).12d Yellow viscous liquid: yield 85 mg, 74%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2941, 2860, 1728, 1687, 1452, 1199, 1174, 997 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H),
5.13-5.07 (m, 1H), 2.03-1.99 (m, 2H), 1.82-1.77 (m, 2H), 1.63-1.56 (m, 4H), 1.49-1.38 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.8, 163.7, 134.8, 132.6, 130.0, 128.9, 75.5, 31.4, 25.2,
23.6.
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3-Chloropropyl 2-oxo-2-phenylacetate (2i).13d Yellow viscous liquid: yield 60 mg, 53%; Rf
(9.8:0.2 hexanes/EtOAc) = 0.8; IR (ATR) 2941, 2860, 1728, 1687, 1452, 1199, 1174, 997 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0
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Hz, 2H), 4.56 (t, J = 6.0 Hz, 2H), 3.67 (t, J = 6.0 Hz, 2H), 2.28-2.22 (m, 2H); C{1H} NMR
(100 MHz, CDCl3) δ 186.0, 163.6, 135.1, 132.4, 130.0, 129.0, 62.7, 40.8, 31.2.
Ethyl 2-oxo-2-p-tolylacetate (4a).13a Yellow viscous liquid: yield 64 mg, 67%; Rf (9.8:0.2
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hexanes/EtOAc) = 0.9; IR (ATR) 2997, 1736, 1683, 1605, 1292, 1203, 1175, 1015 cm−1; H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.45 (q, J = 8.0
Hz, 2H), 2.44 (s, 3H), 1.42 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.2, 164.1,
146.3, 130.2, 130.0, 129.6, 62.3, 21.9, 14.1.
Propyl 2-oxo-2-p-tolylacetate (4b).10e Yellow viscous liquid: yield 73 mg, 72%; Rf (9.8:0.2
hexanes/EtOAc) = 0.9; IR (ATR) 2976, 1733, 1683, 1605, 1463, 1317, 1199, 1171, 1008 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.35 (t, J = 8.0
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CDCl3) δ 186.2, 164.2, 146.3, 130.1, 130.0, 129.6, 67.7, 21.9, 10.3. HRMS (ESI) calcd for
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C12H14O3Na [M+Na]+ 229.0835, found 229.0844.
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Butyl 2-oxo-2-p-tolylacetate (4c). Yellow viscous liquid: yield 81 mg, 75%; Rf (9.8:0.2
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hexanes/EtOAc) = 0.9; IR (ATR) 2961, 1735, 1682, 1604, 1460, 1305, 1199, 1172 cm−1; H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.39 (t, J = 8.0 Hz,
2H), 2.44 (s, 3H), 1.80-1.72 (m, 2H), 1.48-1.42 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 186.3, 164.2, 146.4, 130.2, 130.0, 129.7, 66.0, 30.5, 21.9, 19.1, 13.7;
HRMS (ESI) calcd for C13H16O3Na [M+Na]+ 243.0992, found 243.1010.
Ethyl 2-(4-methoxyphenyl)-2-oxoacetate (4d).10e Yellow viscous liquid: yield 66.5 mg, 64%; Rf
(9.8:0.2 hexanes/EtOAc) = 0.9; IR (ATR) 2980, 2938, 2842, 1732, 1672, 1605, 1597, 1571,
1265, 1205, 1175, 1016 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 2H), 6.98 (d, J
= 8.0 Hz, 2H), 4.44 (q, J = 8.0 Hz, 2H), 3.90 (s, 3H), 1.42 (t, J = 8.0 Hz, 3H); C{1H} NMR
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(100 MHz, CDCl3) δ 184.9, 165.0, 164.2, 132.6, 125.5, 114.2, 62.2, 55.7, 14.1.
Propyl 2-(4-methoxyphenyl)-2-oxoacetate (4e). Yellow viscous liquid: yield 82 mg, 74%; Rf
(9.8:0.2 hexanes/EtOAc) = 0.9; IR (ATR) 2960, 2938, 2872, 1729, 1672, 1594, 1512, 1262,
1204, 1160, 1022 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8
Hz, 2H), 4.34 (t, J = 6.8 Hz, 2H), 3.89 (s, 3H), 1.85-1.76 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 185.0, 165.0, 164.4, 132.5, 125.6, 114.3, 67.6, 55.6, 21.9,
10.3. HRMS (ESI) calcd for C12H14O4Na [M+Na]+ 245.0784, found 245.0798.
Butyl 2-(4-methoxyphenyl)-oxoacetate (4f).13c Yellow viscous liquid: yield 92 mg, 78%; Rf
(9.8:0.2 hexanes/EtOAc) = 0.9; IR (ATR) 2959, 2936, 2874, 1730, 1674, 1595, 1511, 1263,
1202, 1159, 1020 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8
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Hz, 2H), 4.38 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 1.80-1.73 (m, 2H), 1.50-1.40 (m, 2H), 0.97 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.0, 165.0, 164.4, 132.6, 125.6, 114.3, 65.9,
55.7, 30.5, 19.1, 13.7.
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Ethyl 2-(2-methoxyphenyl)-2-oxoacetate (4g).10e Yellow viscous liquid: yield 89 mg, 86%; Rf
(9.5:0.5 hexanes/EtOAc) = 0.6; IR (ATR) 2987, 2938, 1734, 1674, 1600, 1487, 1272, 1190, 1017
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.08 (t, J
= 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.39 (q, J = 8.0 Hz, 2H), 3.87 (s, 3H), 1.39 (t, J = 8.0 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.6, 165.3, 160.3, 136.4, 130.8, 122.8, 121.3, 112.0,
61.8, 56.0, 14.2.
Butyl 2-(2-methoxyphenyl)-2-oxoacetate (4h). Yellow viscous liquid: yield 102 mg, 88%; Rf
(9.5:0.5 hexanes/EtOAc) = 0.6; IR (ATR) 2960, 1734, 1669, 1599, 1482, 1458, 1272, 1187, 1019
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.58 (td, J = 7.2 Hz, 2.0
Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H),
1.77-1.70 (m, 2H), 1.49-1. 40 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 186.6, 165.5, 160.3, 136.3, 130.8, 122.9, 121.3, 112.0, 65.6, 56.1, 30.5, 19.0, 13.7;
HRMS (ESI) calcd for C13H16O4Na [M+Na]+ 259.0941, found 259.0964.
Cyclopentyl 2-(2-methoxyphenyl)-2-oxoacetate (4i).Yellow viscous liquid: yield 105 mg, 85%;
Rf (9.5:0.5 hexanes/EtOAc) = 0.6; IR (ATR) 2965, 2948, 1730, 1669, 1599, 1465, 1272, 1194,
1060, 1020 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.58 (td, J =
8.2 Hz, 2.0 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.43-5.38 (m, 1H), 3.87
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(s, 3H), 2.00-1.93 (m, 2H), 1.91-1.83 (m, 2H), 1.79-1.70 (m, 2H), 1.67-1.61 (m, 2H); C{1H}
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NMR (100 MHz, CDCl3) δ 186.9, 165.2, 160.2, 136.2, 130.9, 122.9, 121.3, 111.9, 79.0, 55.8,
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Ethyl 2-(benzo[d][1,3]dioxol-5-yl)-2-oxoacetate (4j).23bYellow viscous liquid: yield 94 mg,
85%; Rf (9.8:0.2 hexanes/EtOAc) = 0.8; IR (ATR) 2924, 1731, 1671, 1605, 1508, 1448, 1240,
1194, 1098, 1035 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.0 Hz,4.0 Hz, 1H), 7.48 (d,
J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.09 (s, 2H), 4.43 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0
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Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 184.6, 164.0, 153.5, 148.5, 127.9, 127.3, 108.7,
108.3, 102.3, 62.3, 14.1.
Butyl 2-(benzo[d][1,3]dioxol-5-yl)-2-oxoacetate (4k).13b Yellow viscous liquid: yield 97 mg,
77%; Rf (9.8:0.2 hexanes/EtOAc) = 0.8; IR (ATR) 2962, 2915, 1730, 1669, 1506, 1490, 1447,
1241, 1187, 1033 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.4 Hz,1.6 Hz, 1H), 7.47 (d,
J = 1.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.09 (s, 2H), 4.37 (t, J = 6.8 Hz, 2H), 1.79-1.72 (m,
2H), 1.49-1.40 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.7,
164.2, 153.5, 148.5, 127.8, 127.3, 108.7, 108.3, 102.3, 66.1, 30.5, 19.0, 13.6.
Cyclopentyl 2-(benzo[d][1,3]dioxol-5-yl)-2-oxoacetate (4l). Yellow viscous liquid: yield 108
mg, 82%; Rf (9.8:0.2 hexanes/EtOAc) = 0.8; IR (ATR) 2962, 2909, 1723, 1669, 1601, 1490,
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1427, 1239, 1191, 1032 cm−1; H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.0 Hz,1.6 Hz, 1H),
7.46 (d, J = 1.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.09 (s, 2H), 5.48-5.43 (m, 1H), 2.03-1.95 (m,
2H), 1.89-1.83 (m, 2H), 1.81-1.74 (m, 2H), 1.69-1.61 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 185.0, 164.1, 153.4, 148.5, 127.7, 127.3, 108.7, 108.3, 102.2, 79.6, 32.7, 23.7; HRMS
(ESI) calcd for C14H14O5Na [M+Na]+ 285.0733, found 285.0752.
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