Microwave-Enhanced Coupling of Carboxylic Acids with Liquid Ketones and Cyclic Ethers Using Tetrabutylammonium Iodide/ t-Butyl Hydroperoxide

Article abstract of DOI:10.1021/acs.joc.0c00519

The oxidative coupling of carboxylic acids with liquid ketones and cyclic ethers has been accomplished in minutes using t-butyl hydroperoxide in the presence of tetrabutylammonium iodide under microwave irradiation in the absence of a solvent. In addition to drastically shortening the reaction times, the use of microwaves resulted, in general, in yields equal to or higher than those obtained by conventional heating.

Full text of DOI:10.1021/acs.joc.0c00519

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Article
Microwave-Enhanced Coupling of Carboxylic Acids
with Liquid Ketones and Cyclic Ethers using TBAI/TBHP
Pablo Macías-Benítez, F. Javier Moreno-Dorado, and Francisco Miguel Guerra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00519 • Publication Date (Web): 09 Apr 2020
Downloaded from pubs.acs.org on April 17, 2020
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Microwave-Enhanced Coupling of Carboxylic Acids
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with Liquid Ketones and Cyclic Ethers using TBAI/TBHP
Pablo Macías-Benítez, F. Javier Moreno-Dorado,* and Francisco M. Guerra*
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz,
11510 Puerto Real, Cádiz, Spain.
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ABSTRACT: The oxidative coupling of carboxylic acids with liquid ketones and cyclic ethers has been
accomplished in minutes using t-butyl hydroperoxide in the presence of TBAI under microwave
irradiation in the absence of a solvent. In addition to drastically shortening the reaction times, the use of
microwaves resulted, in general, in yields equal to or higher than those obtained by conventional heating.
INTRODUCTION
The discovery of new methods of formation of C-O bonds is a privileged topic in chemical synthesis,
which today, under the current environmental standards, should meet certain conditions.1 For instance,
prefunctionalization of substrates is to be avoided so as not to include unnecessary steps and the use of
metals or toxic reagents is not always desirable in order to meet regulatory requirements. In this scenario,
different oxidation procedures based on the use of iodine have emerged as alternatives to transition
metal-based oxidizing systems. Whether as molecular iodine, as an iodide anion or as a hypervalent
species, the use of this element in conjunction with different oxidants has increased rapidly and found
numerous applications.2
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One of the most successful oxidation systems is that formed by tetrabutylammonium iodide (TBAI) as
a catalyst and t-butyl hydroperoxide (TBHP) as a stoichiometric oxidant. In 2014, Wu et al reviewed
the use of TBAI/TBHP in the formation of new C-C, C-O, C-N, and C-S bonds.3 The topic was revisited
by Wan in 2018.4 This couple of reagents has showcased a wide versatility, being involved in reactions
ranging from the synthesis of indoles5 to -ketoamides,6 oxazoles7 or peresters8 to name but a few. The
reaction conditions are usually mild and the tolerance to different functional groups is notable. In a more
specific context, the TBAI/TBHP system has proved to be a good oxidizing agent for introducing an
oxygenated function contiguous to a carbonyl group. Cheng et al employed benzylic alcohols as
acylating agents to produce -acyloxycarbonyl compounds from ketones.5 Wang and Zhu reported the
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use of aldehydes as surrogates of carboxylic acids in the preparation of -acyloxy ketones.9 In 2018,
Reddy et al demonstrated the viability of the synthesis of acyloxyacetone derivatives via coupling of
acetone and aromatic carboxylic acids in the presence of TBAI/TBHP.10 Most of these methods are
centered in aryl ketones and require long reaction times.
In view of the foregoing observations, we decided to evaluate the performance of the TBAI/TBHP
system under microwave irradiation. The use of microwaves in synthesis (also denoted as MAOS,
microwave-assisted organic synthesis) has become a common technique in chemical synthesis.11,12 In
countless cases, MAOS has proven to be very effective in drastically shortening reaction times and they
often provide fairly cleaner crude mixtures. The possibility of heating the mixture from inside to
temperatures above the boiling point of the solvent for a certain time and the strict control of
temperature, pressure, and irradiation conditions that modern microwave reactors enable, all combine
to make this technique an appealing alternative to conventional heating.
Herein, we describe how the use of TBAI/TBHP under microwave irradiation allows for the introduction
of acyloxy groups in certain ketones and ethers using carboxylic acids, both aromatic and aliphatic, as
the source of the acyloxy group, in minutes and mostly with good to excellent yields (Scheme 1).
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Scheme 1. Oxidation of ketones and ethers with the system TBAI/TBHP under microwave
irradiation.
RESULTS AND DISCUSSION
To begin our study, we chose as a benchmark reaction the coupling between p-methoxybenzoic acid
and cyclohexanone, both commercial and inexpensive reagents. We first selected some common
working conditions according to previous results. The carboxylic acid was selected as the limiting
reactant. In the initial runs, a slight excess of cyclohexanone (1.3 equiv) was employed and TBAI was
set at 0.1 equiv. The reactions were carried out in 2 mL solvent, setting the irradiation time at 30 min
and the temperature at 120 C. Under these conditions, a first round of reactions in different solvents
was carried out (Table 1).
As can be observed, most reactions took place with low yields. In the case of methanol (Table 1, entry
3), diethyl ether (table 1, entry 6), and dichloromethane (Table 1, entry 10), the reaction did not proceed
at all. Only dimethoxyethane (DME) and 1,4-dioxane produced moderate yields (34% and 37%
respectively), although in the latter case, a 31% of the coupling product between the solvent and the
carboxylic acid was formed (vide infra).
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Table 1. Screening of conditions between cyclohexanone and p-methylbenzoic acid.
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Cyclohexanone
Entry
Solvent
Yield, (%)
(equiv)
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
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12b
13
ethyl acetate
2-methoxyethanol
methanol
1,4-dioxane
DME
diethyl ether
DMF
fluorobenzene
acetonitrile
DCM
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NR
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34
NR
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NR
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34
83
-
-
1.3
19.3 (2 mL)
General reaction conditions: p-methylbenzoic acid (1 mmol), cyclohexanone, TBAI (0.1 equiv.), TBHP
(3 equiv., 70 % in H2O), solvent (2 mL), 30 min MW irradiation, 120 ºC. a Plus 31% of compound 7b
b TBHP in decane.
Entries 11-12 correspond to reactions carried out in the absence of solvent. The solvent in wich TBHP
was purchased, either water or decane (entries 11 and 12) was irrelevant in the outcome of the reaction.
Finally, when an excess of cyclohexanone was employed (2 mL, 19.3 equiv), the reaction took place in
an interesting 83% yield (entry 13). These preliminary studies seemed to indicate that an excess of
ketone was necessary for the reaction to take place with usable yields from a synthetic perspective.
Although this may be seen as a drawback in terms of atom economy, in the cases that we will describe
below, the substrate has been chosen in such a way that it can be easily recovered and conveniently
recycled.
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Once the optimal conditions had been established, we decided to evaluate the scope of the reaction with
regard to the nature of the carboxylic acid. The results are shown in Table 2.
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Table 2. Scope of carboxylic acids and cyclohexanone.
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Reaction conditions: cyclohexanone (2 mL), carboxylic acid (1 mmol), TBAI (0.1 equiv), TBHP (3
equiv). a Irradiation method: 120 C, 30 min. b Irradiation method: 150 C, 15 min. c Irradiation method:
120 C, 60 min. d 1.2 mmol of carboxylic acid. e From acetylsalicylic acid.
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The reaction displayed apparent polar effects when aromatic acids were involved. While the coupling
between cyclohexanone 1a and benzoic acid 2b took place in a modest 46 % yield, the introduction of
an electron-releasing group as in the case of p-methylbenzoic acid 3a and p-methoxybenzoic acid 3c
proceded expeditiously in 83% and 87% yield respectively. On the contrary, electron-withdrawing
groups provided poor results, as represented by p-nitrobenzoic acid, that led to a mere 23% yield.
Likewise, when p-chlorobenzoic acid was used, most of the starting material was recovered as a
precipitate at the bottom of the reaction vial. These two substrates required more forceful conditions.
After readjusting the irradiation method, setting the temperature to 150 ºC for 15 min, yields of 40%
and 60% of 3d and 3e respectively were achieved.
The presence of a hydroxyl group had a detrimental effect on the reaction. Initially, the use of salicylic
acid or 2,6-dihydroxybenzoic acid only allowed the detection of the corresponding esters at trace levels.
Nevertheless, a 39% of ester 3g could be obtained when salicylic acid was replaced by its corresponding
acetate, through a spontaneous loss of the acetyl group. Likewise, the use of 3-methoxy-4-
hydroxybenzoic acid also led to the corresponding ester 3i in 68% yield. When phenyl acetic acid was
used as a coupling partner, ester 3j was obtained in 41% yield. A p-hydroxyl group decreased the yield
to 31% of 3k, but an excellent result was achieved when p-acetyloxyphenylacetic acid was employed,
producing 3l in 91%. A very good result was also obtained with acetic acid. In this case, the
corresponding 2-acetyloxycyclohexanone 3m was produced in 86% yield. It is noteworthy to mention
that this compound was also obtained from malonic acid in 67% yield through decarboxylation of the
ester initially formed. Other linear acids were less prone to react. Butanoic, hexanoic and octanoic acids
gave rise to the corresponding esters, 3n-3p with yields of 18%, 51% and 7% respectively. Surprisingly,
the introduction of a unsaturation in the acid was beneficial. Tiglic acid and angelic acid, two carboxylic
acids widely found as esters in terpenoids isolated from plants, led to their corresponding esters 3q and
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3r in 67% and 66% respectively. The reaction even worked better with pent-4-ynoic acid, which gave
rise to 3s in an excellent 96% yield.
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Given the good results in the formation of esters from cyclohexanone, we thought that acetone would
also be a good substrate for the production of different 2-oxopropyl esters.
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The coupling of acetone with different carboxylic acids performed better than in the case of
cyclohexanone (Table 3). A lower steric hindrance, more suitable physical properties as a solvent, which
also translates into an easier work-up, and the higher polarity of the acetone, which can be beneficial in
the use with microwaves, may be relevant factors in the superior performance of acetone compared to
cyclohexanone.
Unlike the previous case, the presence of both electron-releasing groups and electron-withdrawing
groups did not have such a marked effect on the outcome of the reaction. Treatment of benzoic acid,
lacking any substituent in the aromatic ring, led to ester 5b with excellent yield (92%). Similarly good
were the results of carboxylic acids bearing electron-donor groups such as methyl and methoxy groups,
giving rise to esters 5a and 5c in 95% and 92% yield respectively. In the case of electron-withdrawing
groups, the yields are still notable. The presence of a p-nitro group or a p-Cl atom was not an obstacle
for the reaction to proceed with 87% and 77% of esters 5d and 5e respectively. Similarly, 2-iodobenzoic
acid also led to the coupling product 5f in 86% yield. For comparative purposes only, the preparation of
5f has only been reported once in the literature, from acetone employing IBX taking 17 h to reach 56%
yield.13
The presence of a hydroxyl group in the aromatic ring was not as adverse as in the case of
cyclohexanone. Notably, the reaction of salicylic acid resulted in 86% yield of ester 5g. Surprisingly, in
comparison, when acetylsalicylic acid was employed, the yield decreased to 64% of 5h. The introduction
of a second hydroxyl group, as in the case of 2,6-dihydroxybenzoic acid, led to a further drop in the
yield, leading to 5i in 23% yield. This result improved noticeably when both hydroxyl groups are
protected as acetate groups, being possible the isolation of compound 5j in 52% yield. Treatment of
4-hydroxy-3-methoxybenzoic acid also produced the corresponding coupling product 5k in 62 % yield.
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Phenylacetic acid (non-substituted, 5l, 73%), p-hydroxyphenylacetic acid (–OH group, 5m, 44%) and
p-acetoxyphenylacetic acid (–OAc group, 5n, 60%) repeated the same reactivity pattern described
before in substrates in which the aromatic ring was a methylene apart from the carboxyl group and
demonstrated the unfavorable effect that a free hydroxyl group exerts in the outcome of the reaction
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Carboxylic acids with aliphatic chains also performed well. Acetic, hexanoic, and octanoic esters were
obtained with yields exceeding 80% and only in the case of butanoic acid, the yield lowered to 49%.
This poor reactivity of butanoic acid, compared to other similar linear chain acids, towards
cyclohexanone and acetone has, at the moment, no clear explanation. Again, the presence of double or
triple bonds in the substrate was well tolerated, being possible to isolate the corresponding esters from
tiglic, angelic, and senecioic acids, 5s-5u, in yields of 65%, 63%, and 72% respectively and from pent-
4-ynoic acid, 5v, in 70% yield. The existence of terminal triple bond in this molecule turns compound
5v into an intestesting synthon for the synthesis of more complex molecules.
Table 3. Synthesis of 2-oxopropyl esters obtained by coupling of acetone and different carboxylic
acids.
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Reaction conditions: acetone (2 mL), carboxylic acid (1 mmol), TBAI (0.1 equiv.), TBHP (3 equiv.),
120 C, 30 min.
The compatibility with carbonyl groups present in the acid was not an issue, and the corresponding
2-oxopropyl esters of levulinic acid, 5w and of 6-oxoheptanoic acid 5x were obtained in 46% and 75%
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yield. Cinnamic acid derivatives performed very well. Hydrocinnamic acid gave rise to ester 5y in 88%
yield. Cinnamic acid and p-methoxycinnamic acid resulted in yields of 92% and 75% of their
corresponding esters 5z and 5aa.
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To end this study of the scope, the reaction was studied employing dicarboxylic acids and aminoacids.
In the case of succinic acid, a double coupling was observed, and diester 5ab was obtained in 55% yield.
The introduction of a double bond led to a slight increase in the yield. Fumaric acid and itaconic acid
resulted in diesters 5ac and 5ad both in 58% yield. In contrast, maleic acid, bearing a cis double bond,
failed to produce any isolable product, leading to a complex mixture, presumably due to steric factors.
Finally, coupling with amino acids was also possible, as long as the amino group is protected as a Boc
group. Treatment of acetone with Boc-L-Pro or Boc-L-Ala gave rise to the corresponding esters 5ae and
5af in good yields (73% and 90%, respectively). These two aminoacid-derived esters are two interesting
examples of both N- and carboxyl group protected aminoacids. Compound 5ae has been used as starting
material by Guéret et al. for the synthesis of carbon-isosteric depsipeptides.14 Compound 5af has been
previously prepared by Dixneuf et al.15 and by Kundu16 independently. Although there was no mention
in these two previous reports, we observed that 5af exhibited in the 1H NMR spectrum the presence of
two rotamers due to the presence of the amide bond. This behavior is common in proline derivatives, in
which, the presence of the pyrrolidine ring results in the occurrence of cis-trans isomerism. Rotamer
trans was assumed to be the major one considering the n* interaction between the two carbonyl
groups and the steric hindrance of the Boc group (c.f. Supporting information).17
As for the mechanism by which the transformations carried out by the TBAI/TBHP couple take place,
there is some controversy and two approaches have been proposed. Ishihara et al have demonstrated by
Raman spectroscopy the formation of hypoiodite salts in TBAI and TBHP solutions, that act as unstable
t
t
active species.18 In turn, Wan and collaborators propose the generation of BuO· and BuOO· radicals
that participate in a catalytic cycle based on the I–/I2 redox pair.19 Reddy et al reported that, under
conventional heating, this transformation took 8h to be completed and a slight favorable effect of
electron-withdrawing groups compared to electron-releasing groups was observed. They proposed a
mechanism for the synthesis of 2-acetylbenzofurans that can be easily adapted to the oxidative coupling
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of acetone and carboxylic acids.10 Reaction of TBHP and TBAI would lead to [Bu4N]+[IO]– that would
be the species that reacts with acetone to provide the trivalent iodinane A. The tethered iodinane is then
removed by substitution by the carboxylic acid (or carboxylate ion) to provide the corresponding
α-acyloxyketone (Scheme 2). Additionally, the possibility of a homolytic cleavage of the C–I bond of
intermediate A and a parallel radical mechanism should also be taken into account.
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Scheme 2. Plausible mechanism for the synthesis of α-acyloxyketones.
Under certain oxidative conditions, it is possible to introduce an oxygenated function at the contiguous
position to the heteroatom in cyclic ethers. Since our approach of coupling a inexpensive liquid ketone
with a carboxylic acid had worked reasonably well, we decided to extend the methodology to two cyclic
ethers, 1,4-dioxane and THF. Both are widely used solvents that could be employed as substrates, and
whose excess could be easily recovered and recycled.
The results for 1,4-dioxanes are summarized in table 4. The coupling of 1,4-dioxane with benzoic acid
worked nicely (90% of 7a). A slightly lower yield was obtained with electron-releasing group such as
p-methylbenzoic acid and p-methoxybenzoic acid (7b, 81%; 7c, 78%), Meanwhile, halogens provided
excellent yields: p-chlorobenzoic acid reacted specially well, producing 7d in 98% yield and o-
iodobenzoic acid also provided a 92% yield of the corresponding ester 7e. Unfortunately, it was not
possible to achieve a clean reaction when the aromatic ring beared a nitro group in para position despite
the testing of different irradiation methods. The striking differences of the behavior of the nitro group
towards cyclohexanone, acetone and 1,4-dioxane suggests the occurrence of parallel reactions in which
this group is actively involved.
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A similar transformation employing 1,4-dioxane under conventional heating has been reported by Wan
et al.19 In general, there is a good concordance between the results obtained by both methods (with some
exceptions such as the nitro group), but while the conventional version takes 12 hours, the microwave
version required only 10 min.
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Continuing with the study of other carboxylic acids, it was observed that the distancing of the aromatic
ring from the carboxyl group did not affect the outcome of the reaction, as demonstrated by the coupling
of phenylacetic acid (7g, 95%). Non-aromatic acids also provided good results. Acetic acid furnished
the corresponding acetate 7h in 72% yield. Higher yieds were obtained in the case of butyric (7i, 89%),
hexanoic (7j, 72%) and octanoic acids (7k, 83%). As in the case of ketones, the reaction also took place
with good yields in the case of unsaturated acids. Tiglic and angelic acids led to the corresponding esters
7l and 7m with 83% and 76% yield respectively. In the presence of a triple bond, the reaction also took
place, although with a slightly more moderate yield of 62% in the case of the pent-4-ynoic acid (7n).
Table 4. Synthesis of 1,4-dioxan-2-yl esters obtained from 1,4-dioxane and different carboxylic
acids.
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Reaction conditions: 1,4-dioxane (4 mL), carboxylic acid (1.0 mmol), TBAI (0.1 equiv), TBHP (3
equiv), 140 C, 10 min.
In a similar paper, Wan et al proposed a mechanism in which a I–/I2 redox process is involved in the
transformation of the radical generated from the 1,4-dioxane into an oxonium cation.19 This mechanism
might be valid for the microwave approach, yet the picture may be incomplete, as it was noted that in
some cases, we were able to isolate several formyl esters resulting from the cleavage of the 1,4-dioxane
ring. Thus, in the reactions leading to compounds, 7b, 7j-7l, appreciable amounts of products 8a-8d,
sharing the presence of a formyl group, were formed (Table 4). This type of behavior has already been
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described by Liu et al, that report the oxidative cleavage of C-C bonds of glycol ethers catalyzed by
copper (I) oxide.20 In our case, the role of the copper atoms should be assumed by iodine species (see
Scheme 4).
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We next investigated the coupling between carboxylic acids and THF. The reaction did not turn out to
be as general in this heterocycle. In most cases, complex mixtures were formed either during the reaction
itself or the purification process. We were able to isolate esters 10a-10d in moderate to good yields. In
the case of p-nitrobenzoic acid, the reaction led to formyl ester 10e, as a result of the cleavage of the
THF ring (Table 5).
Table 5. Reaction of carboxylic acids and THF.
Reaction conditions: THF (4 mL), carboxylic acid (1.0 mmol), TBAI (0.1 equiv), TBHP (3 equiv).
b
c
a Irradiation method: 100 C, 15 min. Irradiation method: 100 C, 30 min. Irradiation method: 140
C, 10 min.
This apparently random behavior is difficult to explain just in terms of strain of the tetrahydrofuran
itself, and in fact is not exclusive of this type of ring. Actually, we found that it also occurred when 1,4-
dioxane was treated with aldehydes as acylating agents.
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For example, when 1,4-dioxane was reacted with benzaldehyde under the described conditions, the
corresponding ester 7a was predominantly obtained in 68% yield, along with esters 11a and 11b,
corresponding to the heterocycle aperture. A similar behavior was observed when the reaction was
carried out with p-chlorobenzaldehyde, where in addition to 58% of the ester 7d formyl ester 12 was
also produced in 26% yield (Scheme 3).
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Scheme 3. Coupling of 1,4-dioxane with benzaldehyde and p-chlorobenzaldehyde.
In an attempt to determine whether formate ester 12 originated directly from ester 7d, we submitted the
latter compound to the same conditions of heating and irradiation (Scheme 4.) However, the starting
material was recovered intact, suggesting that the opening reaction must proceed through a parallel
mechanism.
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Scheme 4. Irradiation of ester 7d.
This experiment seems to suggest that two parallel mechanisms take place in order to provide both types
of compounds and that compounds such as 7d are not intermediates in the route leading to ring-opened
products. Following the mechanism suggested by Wan et al for the formation of the esters9 and that by
Liu et al for the cleavage of glycol ethers,20 a plausible mechanism is proposed in Scheme 5.
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Scheme 5. Proposal mechanism for the reaction between 1,4-dioxane and carboxylic acids.
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After generation of t-butoxy radical by reaction between the iodide anion and TBHP, the attack on 1,4-
dioxane would provide radical A which can be involved in two paths. In one hand, radical A would be
oxidized by iodine to produce cation B, that subsequently would react with a carboxylate anion to
provide the corresponding ester C. On the other hand, radical A would undergo two oxidation steps,
leading to intermediate E, that presents to contiguous ketal carbons, which would undergo a C–C bond
cleavage to give the open intermediate F, which eventually would be trapped by the carboxylic acid to
provide the formate ester G.
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CONCLUSIONS
In summary, this work illustrates the ability of MAOS to reduce reaction times from hours or days to
minutes. We have demonstrated that the use of microwaves is a good alternative to conventional heating
in the acyloxylation reaction of certain ketones and heterocycles promoted by the TBHP/TBAI system.
Liquid ketones and ethers play the role of the solvent, taking up microwaves to heat the reaction mixture.
The reactions generally take place with yields similar to or higher than the conventionally heated
reactions.
EXPERIMENTAL SECTION
General methods.
All reagents and solvents were purchased from commercial suppliers and used without further
purification. Reactions were monitored through TLC on commercial silica gel plates precoated with
silica gel F254. Visualization of the plates was performed by flurorescence quenching and ethanolic
solutions of ceric ammonium molybdate or anysaldehyde as developing agents. GC analyses were
performed in a Perkin-Elmer Clarus 400 chromatograph employing a DB-5 column. Column
chromatography was performed employing 230-400 mesh silica gel. HPLC purification was carried out
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in a Merck-Hitachi L6270 chromatograph equipped with a silica gel column (LiChrosorb Si 60, 10 m
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particle size). NMR spectra were recorded on a Agilent 400 MR or Agilent 500 instruments and
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calibrated using residual undeuterated solvent as an internal reference for H NMR and to the central
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peak of CDCl3 for 13C NMR. IR spectrum were recorded on Perkin Elmer Spectrum BX
spectrophotometer. Mass spectra were recorded employing a Bruker Scion CG-TQ gas chromatograph
coupled to a Bruker TQ mass spectrometer. High resolution spectra were recorded on a HRMS SYNAPT
2G (Waters) with a APGC interface and a QTOF analyzer or in a XEVO G2 for ESI ionization.
Microwave-promoted reactions were carried out in a SynthWave MA167 reactor pressurized with
nitrogen limited to 45 bar of maximum pressure. The reactions were run on 50 mL glass vials immersed
on 200 mL of water as charge solvent with magnetic stirring. Caution!, hydroperoxides should always
be handled with care by trained personnel.
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General procedure for the oxidative coupling
A representative example for cyclohexanone is as follows:
A 50 mL vial was charged with 1 mmol of the carboxylic acid, 2 mL of cyclohexanone, 0,1 mmol of
TBAI and 3 mmol of TBHP. The vial was set in the reactor which contained 200 mL of water as charge
solvent and was pressurized with nitrogen (45 bar). The sample was then irradiated according the method
described in Table 2. After irradiation, the reaction mixture was worked out with a saturated Na2SO3
solution (10 mL) and extracted with EtOAc (3  25 mL). The organic layer was dried over anhydrous
Na2SO4 and the solvent was removed by rotary evaporation. Purification of the samples and recovery of
the remaining cyclohexanone was carried out by flash chromatography. In all cases shown in Table 2,
the cyclohexanone was the less polar compound and was recovered employing a 9.5:0.5 petroleum
ether/EtOAc mixture. Once cyclohexanone has come out, the polarity was increased according to the
polarity of the products.
In the cases of acetone, 1,4-dioxane and THF, the procedure was similar, the only difference being that
the remaining reactant was removed (or recovered if desired) by rotary evaporation. The resulting crude
mixture was then purified by column chromatography.
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2-Oxocyclohexyl 4-methylbenzoate (3a): White crystal (192.5 mg, 83%), mp 86.5-87.8 ºC. Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then
increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 7.99-7.96 (m, 2H), 7.25-7.22 (m, 2H), 5.40 (ddd, J =
12.2, 6.1, 1.1 Hz, 1H), 2.59-2.54 (m, 1H), 2.50-2.37 (m, 2H), 2.41 (s, 3H), 2.16-2.09 (m, 1H), 2.06-2.00
(m, 1H), 1.97-1.88 (m, 1H), 1.88-1.79 (m, 1H), 1.76-1.62 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) 훿
204.5, 165.6, 143.8, 129.9, 129.3, 126.9, 76.8, 40.8, 33.2, 27.2, 23.8, 21.7. HRMS (APGC) m/z: [M+H]+
Calcd for C14H17O3 233.1178; Found 233.1184. IR (KBr, cm-1) 2944, 2866, 1717, 1611, 1313, 1272,
1178, 1108, 753.
2-Oxocyclohexyl benzoate (3b): White crystal (100.6 mg, 46%), mp 78.5-80.2 ºC. Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then
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increased to 9:1. H NMR (500 MHz, CDCl3) 훿 8.11-8.08 (m, 2H), 7.59-7.55 (m, 1H), 7.47-7.42 (m,
2H), 5.41 (ddd, J = 12.3, 6.2, 1.1 Hz, 1H), 2.60-2.54 (m, 1H), 2.51-2.40 (m, 2H), 2.17-2.10 (m, 1H),
2.07-2.01 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.79 (m, 1H), 1.75-1.64 (m, 1H). 13C{1H} NMR (125 MHz,
CDCl3) 훿 204.3, 165.6, 133.1, 129.9, 129.7, 128.3, 77.0, 40.8, 33.2, 27.2, 23.8. HRMS (APGC) m/z:
[M+H]+ Calcd for C13H15O3 219.1021; Found 219.1017. IR (KBr, cm-1) 2943, 2866, 1717, 1451, 1316,
1270, 1112, 1070, 711.
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2-Oxocyclohexyl 4-methoxybenzoate (3c): White crystal (215.7 mg, 87%), mp 134.4-135.6 ºC.
Column chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out,
then increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 8.07-8.03 (m, 2H), 6.94-6.91 (m, 2H), 5.38 (ddd,
J = 12.1, 6.2, 1.1 Hz, 1H), 3.86 (s, 3H), 2.59-2.54 (m, 1H), 2.50-2.39 (m, 2H), 2.16-2.09 (m, 1H), 2.06-
1.99 (m, 1H), 1.97-1.78 (m, 2H), 1.74-1.64 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) 훿 204.6, 165.3,
163.5, 131.9, 122.1, 113.6, 76.7, 55.4, 40.8, 33.3, 27.2, 23.8. HRMS (APGC) m/z: [M+H]+ Calcd for
C14H17O4 249.1127; Found 249.1155. IR (KBr, cm-1) 2944, 1711, 1606, 1511, 1318, 1258, 1169, 1103,
1031, 769.
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2-Oxocyclohexyl 4-nitrobenzoate (3d): White crystal (105.5 mg, 40%), mp 115.0-116.6 ºC. Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then
increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 8.32-8.24 (m, 4H), 5.43 (ddd, J = 12.3, 6.3, 1.1 Hz, 1H),
2.63-2.56 (m, 1H), 2.53-2.43 (m, 2H), 2.21-2.12 (m, 1H), 2.11-2.03 (m, 1H), 2.02-1.80 (m, 2H), 1.76-
1.63 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) 훿 203.6, 163.7, 150.7, 135.1, 131.0, 123.5, 77.8, 40.7,
33.0, 27.1, 23.8. HRMS (APGC) m/z: [M+H]+ Calcd for C13H14NO5 264.0872; Found 264.0875. IR
(KBr, cm-1) 2946, 2867, 1721, 1527, 1348, 1317, 1302, 1273, 1115, 1104, 719.
2-Oxocyclohexyl 4-chlorobenzoate (3e): White crystal (151.5 mg, 60%), mp 111.6-113.5 ºC. Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then
increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 8.04-8.01 (m, 2H), 7.44-7.40 (m, 2H), 5.39 (ddd, J =
12.3, 6.2, 1.1 Hz, 1H), 2.60-2.55 (m, 1H), 2.50-2.40 (m, 2H), 2.18-2.11 (m, 1H), 2.07-2.01 (m, 1H),
1.97-1.79 (m, 2H), 1.74-1.64 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) 훿 204.1, 164.7, 139.7, 131.3,
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128.7, 128.1, 77.2, 40.7, 33.1, 27.2, 23.8. HRMS (APGC) m/z: [M+H]+ Calcd for C13H14ClO3 253.0631;
Found 253.0647. IR (KBr, cm-1) 2943, 2866, 1719, 1594, 1270, 1115, 1105, 1091, 1014, 758.
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2-Oxocyclohexyl 2-iodobenzoate (3f): Colorless oil (316.5 mg, 92%). Column chromatography eluent,
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petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then increased to 9:1. H NMR
(500 MHz, CDCl3) 훿 7.99 (dd, J = 7.9, 1.1 Hz, 1H), 7.96 (dd, J = 7.8, 1.7 Hz, 1H), 7.41 (ddd, J = 7.6,
7,6, 1.1 Hz, 1H), 7.16 (ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 5.42 (ddd, J = 12.3, 6.2, 1.1 Hz, 1H), 2.60-2.54
(m, 1H), 2.50-2.42 (m, 2H), 2.17-2.10 (m, 1H), 2.07-2.01 (m, 1H), 1.97-1.78 (m, 2H), 1.73-1.63 (m,
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1H). C{1H} NMR (125 MHz, CDCl3) 훿 203.9, 165.4, 141.3, 134.4, 132.8, 131.5, 127.9, 94.3, 77.5,
40.7, 33.1, 27.2, 23.8. HRMS (APGC) m/z: [M+H]+ Calcd for C13H14IO3 344.9988; Found 344.9997. IR
(KBr, cm-1) 2940, 2864, 1719, 1284, 1249, 1101, 1014, 740.
2-Oxocyclohexyl 2-hydroxybenzoate (3g): Colorless oil (91.1 mg, 39%). Column chromatography
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eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then increased to 9:1. H
NMR (500 MHz, CDCl3) 훿 10.50 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (ddd, J = 8.7, 7.2, 1.8 Hz,
1H), 6.98 (dd, J = 8.4, 1.0 Hz, 1H), 6.90 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 5.41 (ddd, J = 12.3, 6.2, 1.1 Hz,
1H), 2.62-2.57 (m, 1H), 2.51-2.42 (m, 2H), 2.19-2.11 (m, 1H), 2.10-2.03 (m, 1H), 2.01-1.91 (m, 1H),
1.90-1.80 (m, 1H), 1.76-1.65 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) 훿 203.7, 168.9, 161.7, 135.9,
130.2, 119.2, 117.6, 112.1, 77.2, 40.7, 33.1, 27.1, 23.7. HRMS (APGC) m/z: [M+H]+ Calcd for C13H15O4
235.0970; Found 235.0970. IR (KBr, cm-1) 3193, 2945, 2868, 1730, 1676, 1614, 1485, 1287, 1250,
1214, 1159, 1095, 758, 670.
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2-Oxocyclohexyl 4-hydroxy-3-methoxybenzoate (3i): White crystal (179.0 mg, 68%), mp 113.7-114.9
ºC. Column chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came
out, then increased to 9:1. 1H NMR (400 MHz, CDCl3) 훿 7.69 (dd, J = 8.3, 1.9 Hz, 1H), 7.56 (d, J = 1.9
Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.12 (br s, -OH), 5.38 (ddd, J = 12.1, 6.3, 1.1 Hz, 1H), 3.93 (s, 3H),
2.60-2.52 (m, 1H), 2.51-2.37 (m, 2H), 2.17-2.08 (m, 1H), 2.07-1.99 (m, 1H), 1.98-1.77 (m, 2H), 1.75-
1.62 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) 훿 204.7, 165.3, 150.3, 146.2, 124.6, 121.7, 114.1,
112.0, 76.8, 56.1, 40.8, 33.2, 27.2, 23.8. HRMS (APGC) m/z: [M+H]+ Calcd for C14H17O5 265.1076;
Found 265.1078. IR (KBr, cm-1) 3378, 2942, 2866, 1709, 1596, 1514, 1429, 1280, 1216, 1107, 1032,
782, 763.
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2-Oxocyclohexyl 2-phenylacetate (3j): White crystal (94.4 mg, 41%), mp 63.7-65.3 ºC. Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then
increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 7.34-7.24 (m, 5H), 5.18 (ddd, J = 12.2, 6.4, 1.1 Hz, 1H),
3.78-.3.70 (m, 2H), 2.53-2.48 (m, 1H), 2.38 (ddd, J = 13.7, 13.7, 6.1 Hz, 1H), 2.31-2.25 (m, 1H), 2.12-
2.04 (m, 1H), 1.99-1.92 (m, 1H), 1.82-1.57 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) 훿 204.3, 170.7,
133.8, 129.3, 128.5, 127.1, 76.9, 40.9, 40.6, 33.0, 27.1, 23.7. HRMS (APGC) m/z: [M+H]+ Calcd for
C14H17O3 233.1178; Found 233.1176. IR (KBr, cm-1) 2943, 2867, 1744, 1726, 1497, 1453, 1250, 1216,
1316, 1113, 1061, 696, 709.
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2-Oxocyclohexyl 2-(4-hydroxyphenyl)acetate (3k): Colorless oil (78.0 mg, 31%). Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then
increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 7.19-7.12 (m, 2H), 6.78-6.71 (m, 2H), 5.18 (ddd, J =
12.3, 6.5, 1.2 Hz, 1H), 3.72-3.59 (m, 2H), 2.55-2.46 (m, 1H), 2.38 (ddd, J = 13.7, 13.7, 6.1 Hz, 1H),
2.33-2.24 (m, 1H), 2.13-2.03 (m, 1H), 2.01-1.91 (m, 1H), 1.83-1.68 (m, 2H), 1.70-1.56 (m, 1H). 13C{1H}
NMR (125 MHz, CDCl3) 훿 204.8, 171.3, 154.9, 130.5, 125.6, 115.4, 76.9, 40.7, 40.0, 33.0, 27.1, 23.7.
HRMS (ESI) m/z: [M+Na]+ Calcd for C14H16O4Na 271.0946; Found 271.0956. IR (KBr, cm-1) 3390,
2945, 2868, 1719, 1597, 1614, 1516, 1449, 1218, 1159, 1060, 802, 827.
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2-Oxocyclohexyl 2-(4-acetoxyphenyl)acetate (3l): White crystal (265.5 mg, 91%), mp 111.4-112.8 ºC.
Column chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out,
then increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 7.35-7.32 (m, 2H), 7.06-7.03 (m, 2H), 5.17 (ddd,
J = 12.2, 6.3, 1.2 Hz, 1H), 3.77-3.69 (m, 2H), 2.54-2.48 (m, 1H), 2.38 (ddd, J = 13.7, 13.7, 6.1 Hz, 1H),
2.31-2.26 (m, 1H), 2.29 (s, 3H), 2.12-2.06 (m, 1H), 1.99-1.93 (m, 1H), 1.82-1.70 (m, 2H), 1.68-1.58 (m,
13
1H). C{1H} NMR (125 MHz, CDCl3) 훿 204.2, 170.4, 169.4, 149.7, 131.4, 130.4, 121.6, 77.0, 40.6,
40.3, 33.0, 27.1, 23.7, 21.1. HRMS (APGC) m/z: [M+H]+ Calcd for C16H19O5 291.1232; Found
291.1245. IR (KBr, cm-1) 2942, 2866, 1733, 1508, 1368, 1195, 1155, 1058, 1015, 908.
2-Oxocyclohexyl acetate (3m): Colorless oil (134.3 mg, 86%). Column chromatography eluent,
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petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then increased to 9:1. H NMR
(500 MHz, CDCl3) 훿 5.19-5.13 (m, 1H), 2.54-2.48 (m, 1H), 2.41 (ddd, J = 13.7, 13.7, 6.1 Hz, 1H), 2.34-
2.25 (m, 1H), 2.15 (s, 3H), 2.13-2.05 (m, 1H), 2.01-1.94 (m, 1H), 1.82-1.71 (m, 2H), 1.67-1.57 (m, 1H).
13C{1H} NMR (125 MHz, CDCl3) 훿 204.5, 170.0, 76.6, 40.7, 33.1, 27.2, 23.8, 20.7. HRMS (APGC)
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m/z: [M+H]+ Calcd for C8H13O3 157.0865; Found 157.0858. IR (KBr, cm-1) 3023, 2933, 2871, 1732,
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1374, 1246, 1047, 757, 668.
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2-Oxocyclohexyl butyrate (3n): Colorless oil (33.2 mg, 18%). Column chromatography eluent,
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petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then increased to 9:1. H NMR
(500 MHz, CDCl3) 훿 5.20-5.15 (m, 1H), 2.53-2.47 (m, 1H), 2.46-2.32 (m, 3H), 2.31-2.26 (m, 1H), 2.12-
2.05 (m, 1H), 2.01-1.93 (m, 1H), 1.82-1.57 (m, 5H), 0.98 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (125 MHz,
CDCl3) 훿 204.6, 172.7, 76.3, 40.7, 35.9, 33.1, 27.2, 23.8, 18.4, 13.6. HRMS (ESI) m/z: [M+Na]+ Calcd
for C10H16O3Na 207.0997; Found 207.0992. IR (KBr, cm-1) 2962, 2944, 2873, 1744, 1726, 1453, 1382,
1315, 1256, 1179, 1105.
2-Oxocyclohexyl hexanoate (3o): Colorless oil (107.5 mg, 51%). Column chromatography eluent,
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petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then increased to 9:1. H NMR
(500 MHz, CDCl3) 훿 5.19-5.12 (m, 1H), 2.51-2.46 (m, 1H), 2.45-2.32 (m, 3H), 2.30-2.24 (m, 1H), 2.10-
2.03 (m, 1H), 1.99-1.91 (m, 1H), 1.81-1.55 (m, 5H), 1.35-1.28 (m, 4H), 0.90-0.86 (m, 3H). 13C{1H}
NMR (125 MHz, CDCl3) 훿 204.6, 172.8, 76.2, 40.6, 33.9, 33.0, 31.2, 27.1, 24.5, 23.7, 22.3, 13.8. HRMS
(APGC) m/z: [M+H]+ Calcd for C12H21O3 213.1491; Found 213.1495. IR (KBr, cm-1) 2943, 2867, 1744,
1726, 1453, 1378, 1317, 1244, 1169, 1106, 1065, 919, 882.
2-Oxocyclohexyl octanoate (3p): Colorless oil (16.5 mg, 7%). Column chromatography eluent,
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petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then increased to 9:1. H NMR
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(500 MHz, CDCl3) 훿 5.20-5.15 (m, 1H), 2.54-2.48 (m, 1H), 2.47-2.34 (m, 3H), 2.32-2.24 (m, 1H), 2.12-
2.06 (m, 1H), 2.01-1.93 (m, 1H), 1.83-1.59 (m, 5H), 1.40-1.22 (m, 8H), 0.88 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3) 훿 204.6, 172.9, 76.3, 40.7, 34.0, 33.1, 31.6, 29.0, 28.9, 27.2, 24.9, 23.8, 22.6,
14.1. HRMS (ESI) m/z: [M+Na]+ Calcd for C14H24O3Na 263.1623; Found 263.1629. IR (KBr, cm-1)
2932, 2861, 1745, 1726, 1453, 1166, 1109, 1067, 920, 882.
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2-Oxocyclohexyl (E)-2-methylbut-2-enoate (3q): Colorless oil (131.0 mg, 67%). Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then
increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 6.95 (qq, J = 7.0, 1.4 Hz, 1H), 5.25-5.20 (m, 1H), 2.55-
2.48 (m, 1H), 2.41 (ddd, J = 13.6, 13.6, 6.1 Hz, 1H), 2.35-2.28 (m, 1H), 2.13-2.05 (m, 1H), 2.01-1.95
(m, 1H), 1.85 (qd, J = 1.2, 1.2 Hz, 3H), 1.80 (dq, J = 7.0, 1.2 Hz, 3H), 1.83-1.75 (m, 2H), 1.70-1.59 (m,
1H). 13C{1H} NMR (125 MHz, CDCl3) 훿 204.9, 166.9, 138.2, 128.0, 76.4, 40.7, 33.2, 27.2, 23.8, 14.4,
12.0. HRMS (APGC) m/z: [M+H]+ Calcd for C11H17O3 197.1178; Found 197.1176. IR (KBr, cm-1) 2944,
2867, 1731, 1714, 1262, 1143, 1114, 1088, 732.
2-Oxocyclohexyl (Z)-2-methylbut-2-enoate (3r): White crystal (130.2 mg, 66%), mp 63.6-64.3 ºC.
Column chromatography eluent, petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out,
then increased to 9:1. 1H NMR (500 MHz, CDCl3) 훿 6.11 (qq, J = 7.2, 1.5 Hz, 1H), 5.27-5.22 (m, 1H),
2.55-2.49 (m, 1H), 2.42 (ddd, J = 13.6, 13.6, 6.0 Hz, 1H), 2.36-2.30 (m, 1H), 2.13-2.05 (m, 1H), 1.99
(dq, J = 7.2, 1.5 Hz, 3H), 2.01-1.96 (m, 1H), 1.93 (qd, J = 1.6, 1.6 Hz, 3H), 1.87-1.73 (m, 2H), 1.70-
13
1.59 (m, 1H). C{1H} NMR (125 MHz, CDCl3) 훿 204.5, 166.9, 138.6, 127.4, 76.3, 40.7, 33.2, 27.2,
23.8, 20.5, 15.8. HRMS (APGC) m/z: [M+H]+ Calcd for C11H17O3 197.1178; Found 197.1179. IR (KBr,
cm-1) 2946, 2868, 1733, 1716, 1236, 1157, 1114, 1066.
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2-Oxocyclohexyl pent-4-ynoate (3s): Colorless oil (186.5 mg, 96%). Column chromatography eluent,
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petroleum ether/EtOAc 9.5:0.5 until excess cyclohexanone came out, then increased to 9:1. H NMR
(500 MHz, CDCl3) 훿 5.24-5.12 (m, 1H), 2.73-2.58 (m, 2H), 2.56-2.45 (m, 3H), 2.37 (ddd, J = 13.7,
13.7, 6.1 Hz, 1H), 2.32-2.25 (m, 1H), 2.11-2.03 (m, 1H), 2.01-1.91 (m, 1H), 1.97 (t, J = 2.7 Hz, 1H),
1.81-1.70 (m, 2H), 1.66-1.51 (m, 1H). C{1H} NMR (100 MHz, CDCl3) 훿 204.2, 170.7, 82.4, 76.7,
13
69.0, 40.6, 33.0, 32.9, 27.0, 23.7, 14.3. HRMS (APGC) m/z: [M+H]+ Calcd for C11H15O3 195.1021;
Found 195.1024. IR (KBr, cm-1) 3282, 2944, 2868, 1731, 1451, 1429, 1379, 1167, 1114, 1067, 882,
833, 649.
2-Oxopropyl 4-methylbenzoate (5a): White crystal (182.7 mg, 95%), mp 39.4-41.1 ºC. Column
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chromatography eluent, petroleum ether/EtOAc 9.5:0.5. H NMR (500 MHz, CDCl3) 훿 8.00-7.96 (m,
2H), 7.28-7.24 (m, 2H), 4.85 (s, 2H), 2.42 (s, 3H), 2.23 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) 훿
202.1, 165.9, 144.2, 129.9, 129.2, 126.4, 68.6, 26.2, 21.7. HRMS (APGC) m/z: [M+H]+ Calcd for
C11H13O3 193.0865; Found 193.0885. IR (KBr, cm-1) 2931, 1717, 1611, 1411, 1274, 1175, 1110, 750.
2-Oxopropyl benzoate (5b): Colorless oil (163.9 mg, 92%). Column chromatography eluent, petroleum
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ether/EtOAc 9.5:0.5. H NMR (500 MHz, CDCl3) 훿 8.11-8.08 (m, 2H), 7.62-7.57 (m, 1H), 7.49-7.44
(m, 2H), 4.88 (s, 2H), 2.24 (s, 3H). C{1H} NMR (125 MHz, CDCl3) 훿 201.8, 165.8, 133.4, 129.9,
13
129.2, 128.5, 68.7, 26.2. HRMS (APGC) m/z: [M+H]+ Calcd for C10H11O3 179.0708; Found 179.0717.
IR (KBr, cm-1) 2931, 1721, 1452, 1417, 1371, 1315, 1276, 1176, 1114, 1071, 711.
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2-Oxopropyl 4-methoxybenzoate (5c): Colorless oil (191.1 mg, 92%). Column chromatography
eluent, petroleum ether/EtOAc 9.5:0.5. 1H NMR (500 MHz, CDCl3) 훿 8.07-8.02 (m, 2H), 6.97-6.91 (m,
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2H), 4.84 (s, 2H), 3.87 (s, 3H), 2.23 (s, 3H). C{1H} NMR (125 MHz, CDCl3) 훿 202.2, 165.5, 163.8,
132.0, 121.5, 113.7, 68.5, 55.4, 26.2. HRMS (APGC) m/z: [M+H]+ Calcd for C11H13O4 209.0814; Found
209.0808. IR (KBr, cm-1) 2936, 2842, 1715, 1606, 1512, 1421, 1280, 1257, 1168, 1111, 1028, 848, 768,
697.
2-Oxopropyl 4-nitrobenzoate (5d): White crystal (194.3 mg, 87%), mp 93.4-94.7 ºC. Column
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chromatography eluent, petroleum ether/EtOAc 9.5:0.5. H NMR (500 MHz, CDCl3) 훿 8.33-8.30 (m,
13
2H), 8.28-8.25 (m, 2H), 4.96 (s, 2H), 2.25 (s, 3H). C{1H} NMR (125 MHz, CDCl3) 훿 200.2, 164.0,
150.8, 134.6, 131.0, 123.6, 69.1, 26.1. HRMS (APGC) m/z: [M+H]+ Calcd for C10H10NO5 224.0559;
Found 224.0562. IR (KBr, cm-1) 3109, 1721, 1606, 1521, 1350, 1321, 1275, 1104, 875, 855, 783, 719.
2-Oxopropyl 4-chlorobenzoate (5e): White crystal (162.9 mg, 77%), mp 50.0-50.8 ºC. Column
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chromatography eluent, petroleum ether/EtOAc 9.5:0.5. H NMR (500 MHz, CDCl3) 훿 8.03-7.99 (m,
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2H), 7.44-7.40 (m, 2H), 4.87 (s, 2H), 2.21 (s, 3H). C{1H} NMR (125 MHz, CDCl3) 훿 201.2, 164.9,
139.9, 131.2, 128.8, 127.6, 68.7, 26.1. HRMS (APGC) m/z: [M+H]+ Calcd for C10H10ClO3 213.0318;
Found 213.0321. IR (KBr, cm-1) 2933, 1722, 1595, 1488, 1417, 1402, 1370, 1275, 1172, 1118, 1105,
1091, 850, 757.
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2-Oxopropyl 2-iodobenzoate (5f): Colorless oil (261.4 mg, 86%). Column chromatography eluent,
petroleum ether/EtOAc 9.5:0.5. 1H NMR (500 MHz, CDCl3) 훿 8.02 (dd, J = 7.9, 1.1 Hz, 1H), 7.96 (dd,
J = 7.8, 1.7 Hz, 1H), 7.44 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.19 (ddd, J = 7.9, 7.4, 1.7 Hz, 1H), 4.87 (s,
2H), 2.25 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) 훿 201.1, 165.5, 141.5, 133.8, 133.1, 131.5, 128.0,
94.4, 69.0, 26.3. HRMS (APGC) m/z: [M+H]+ Calcd for C10H10IO3 304.9675; Found 304.9669. IR (KBr,
cm-1) 3453, 3064, 2931, 1726, 1582, 1419, 1369, 1289, 1251, 1183, 1131, 1105, 1008, 740.
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2-Oxopropyl 2-hydroxybenzoate (5g): White crystal (166.7 mg, 86%), mp 62.0-63.8 ºC. Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5. 1H NMR (400 MHz, CDCl3) 훿 10.41 (s, 1H),
7.93 (dd, J = 8.0, 1..7 Hz, 1H), 7.49 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 6.99 (dd, J = 8.4, 1.1 Hz, 1H), 6.94-
6.89 (m, 1H), 4.90 (s, 2H), 2.24 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) 훿 200.8, 169.2, 161.8, 136.2,
130.1, 119.4, 117.7, 111.6, 68.6, 26.1. HRMS (APGC) m/z: [M+H]+ Calcd for C10H10O4 195.0657;
Found 195.0679. IR (KBr, cm-1) 3206, 2948, 1733, 1679, 1613, 1583, 1484, 1421, 1379, 1328, 1306,
1251, 1207, 1181, 1157, 1137, 1098, 757, 732, 700.
2-Oxopropyl 2-acetoxybenzoate (5h): Colorless oil (150.0 mg, 64%). Column chromatography eluent,
petroleum ether/EtOAc 9.5:0.5. 1H NMR (500 MHz, CDCl3) 훿 8.10 (dd, J = 7.9, 1.7 Hz, 1H), 7.60 (ddd,
J = 8.1, 7.5, 1.7 Hz, 1H), 7.34 (ddd, J = 7.7, 7.7, 1.2 Hz, 1H), 7.13 (dd, J = 8.1, 1.2 Hz, 1H), 4.83 (s,
2H), 2.34 (s, 3H), 2.22 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) 훿 201.4, 169.7, 163.6, 151.0, 134.4,
131.9, 126.1, 123.9, 122.3, 68.7, 26.2, 21.0. HRMS (APGC) m/z: [M+H]+ Calcd for C12H13O5 237.0763;
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Found 237.0764. IR (KBr, cm-1) 2936, 1765, 1723, 1606, 1486, 1452, 1418, 1368, 1296, 1260, 1188,
1161, 1130, 1089, 1042, 1009, 914, 751, 703.
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2-Oxopropyl 2,6-dihydroxybenzoate (5i): Amorphous solid (47.4 mg, 23%). Column chromatography
eluent, petroleum ether/EtOAc 9.5:0.5. 1H NMR (500 MHz, CDCl3) 훿 9.60 (s, 2H), 7.34 (dd, J = 8.3,
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8.3 Hz, 1H), 6.51 (d, J = 8.3 Hz, 2H), 5.08 (s, 2H), 2.28 (s, 3H). C{1H} NMR (125 MHz, CDCl3) 훿
198.9, 168.4, 161.1, 137.2, 108.4, 99.7, 68.7, 25.9. HRMS (APGC) m/z: [M+H]+ Calcd for C10H11O5
211.0606; Found 211.0600. IR (KBr, cm-1) 3433, 1729, 1676, 1630, 1575, 1471, 1423, 1325, 1189,
1157, 1140, 809, 738, 703, 591.
2-((2-Oxopropoxy)carbonyl)-1,3-phenylene diacetate (5j): Yellow oil (152.7 mg, 52%). Column
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chromatography eluent, petroleum ether/EtOAc 9.5:0.5. H NMR (500 MHz, CDCl3) 훿 7.50 (dd, J =
8.3, 8.3 Hz, 1H), 7.07 (d, J = 8.2 Hz, 2H), 4.81 (s, 2H), 2.30 (s, 6H), 2.20 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) 훿 200.3, 168.9, 162.7, 149.6, 132.1, 121.0, 119.2, 69.1, 26.1, 20.9. HRMS (APGC) m/z:
[M+H]+ Calcd for C14H15O7 295.0818; Found 295.0819. IR (KBr, cm-1) 2937, 1772, 1729, 1611, 1463,
1370, 1278, 1185, 1110, 1034.
2-Oxopropyl 4-hydroxy-3-methoxybenzoate (5k): Colorless oil (140.1 mg, 62%). Column
chromatography eluent, petroleum ether/EtOAc 9.5:0.5. 1H NMR (500 MHz, CDCl3) 훿 7.68 (dd, J = 8.4
Hz, 1.8 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 4.84 (s, 2H), 3.92 (s, 3H), 2.22 (s,
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