Synthesis of 1,3-Diketones and β-Keto Thioesters via Soft Enolization

Article abstract of DOI:10.1021/acs.joc.9b00397

Ketones and thioesters undergo soft enolization and acylation using crude acid chlorides on treatment with MgBr₂·OEt₂ and i-Pr₂NEt to give 1,3-diketones and β-keto thioesters, respectively. The use of crude acid chlorides adds efficiency and cost reduction by avoiding the need to purify and/or purchase them. The process is conducted in a direct fashion that does not require prior enolate formation, further enhancing its efficiency and making it very easy to carry out. The method is suitable for large scale applications. ?

Full text of DOI:10.1021/acs.joc.9b00397

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Synthesis of 1,3-Diketones and #-Keto Thioesters via Soft Enolization
Sabrina O. Aderibigbe, and Don M Coltart
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00397 • Publication Date (Web): 24 Jun 2019
Downloaded from http://pubs.acs.org on June 25, 2019
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Synthesis of 1,3-Diketones and β-Keto Thioesters via Soft Enolization
Sabrina O. Aderibigbe and Don M. Coltart*
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Department of Chemistry, University of Houston, Houston, TX, 77204
Abstract: Ketones and thioesters undergo soft enolization and acylation using crude
acid chlorides on treatment with MgBr2·OEt2 and i-Pr2NEt to give 1,3-diketones and
β-keto thioesters, respectively. The use of crude acid chlorides adds efficiency and
cost reduction by avoiding the need to purify and/or purchase them. The process is
conducted in a direct fashion that does not require prior enolate formation, further
enhancing its efficiency and making it very easy to carry out. The method is suitable
for large scale applications.
* dcoltart@central.uh.edu
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Introduction
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1,3-Diketones and β-keto esters are fundamentally important compounds in
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1,2
synthetic organic chemistry.
These structural motifs are widely represented in
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natural products, pharmaceuticals, and other biologically relevant compounds in
either their native or derivatized form.1 Included among such compounds are those
having antioxidant, antitumor, antimicrobial, antiviral, and antifungal activity.1 In
addition to their biological significance, 1,3-diketones and β-keto esters are used to
facilitate many other highly useful synthetic transformations, including alkylation
reactions and the preparation of heterocycles.2
Scheme 1. Hard and Soft Enolate Formation.
Despite the prevalence of 1,3-diketones and β-keto esters, their synthesis
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using conventional hard enolization methods (Scheme 1a) can be problematic. As
part of a research program aimed at developing operationally-simple approaches to
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key carbon–carbon bond-forming reactions via soft enolization (Scheme 1b), we
previously reported methods for the synthesis of 1,3-diketones and β-keto
thioesters.3 These methods provide simple solutions to the long-standing challenges
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Scheme 2. Established and proposed MgBr2·OEt2-Promoted Direct Acylation of
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Ketones and Thioesters.
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associated with the preparation of such compounds, and use either N-
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acylbenzotriazoles or O-Pfp esters as the acylating components, along with either
ketones or thioesters as the enolate precursors. Despite their effectiveness, the
acylating agents used in these transformations were not ideal from either a cost or
atom economy perspective. Acid chlorides provide an obvious potential solution to
this issue and were tried previously (Scheme 2b).3a Unfortunately, they did not prove
to be as effective in our preliminary tests with regard to reaction yield as N-
acylbenzotriazoles or O-Pfp esters and, therefore, were not pursued further.
However, upon reflection we felt that since many acid chlorides are commercially
available, even if they did not function quite as well as N-acylbenzotriazoles and O-
Pfp esters in these transformations, their ease of accessibility and atom economy
would justify their use in many synthetic applications. Indeed, a reaction based on
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our preliminary work3a has been employed by process chemists at Abbott
Laboratories on a large scale to produce material to support their efforts on the
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development of DGAT-1 inhibitors. In that case cylcohexanone (23.6 mL) and 4-
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bromobenzoyl
chloride
(50.0
g)
were
used
to
prepare
2-(4-
bromobenzoyl)cyclohexanone (61.2 g).
An even more appealing aspect of the use of acid chlorides as acylating agents
in the synthesis of 1,3-diketones and β-keto thioesters is that, in principle, the acid
chlorides could be prepared from carboxylic acids and used in crude form in the
carbon–carbon bond-forming step (Scheme 2b). This would provide even greater
efficiency and cost reduction by avoiding the task of purifying the acid chlorides
under anhydrous conditions and/or the need to purchase them from a commercial
source. It would also diminish problems related to the long-term storage of acid
chlorides, such as their tendency to degrade hydrolytically over time. In what follows,
we describe the development of a procedure for the synthesis of 1,3-diketones and β-
keto esters using carboxylic acids as the acylating agent source. The products
generated from these reactions are highly useful synthetic intermediates. Notably,
the β-keto thioesters produced can be converted directly into a variety of useful
compounds under mild conditions, in addition to those commonly obtained from β-
keto esters.3c
Results and Discussion
We began our study on the development of a procedure for the synthesis of
1,3-diketones and β-keto thioesters using crude acid chlorides as acylating agents by
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treating a solution of 2-methylpropionic acid (1) in DMF and CH2Cl2 with oxalyl
chloride. The solvent was removed after 12 hours and the resulting residue was
dissolved in CH2Cl2, and combined with MgBr2·OEt2, i-Pr2NEt, and acetophenone (8).
Gratifying, this led to the formation of 1,3-diketone 11 in excellent yield (91%). The
coupling reaction with acetophenone was tested further using a variety of carboxylic
acids. In all cases the desired 1,3-diketone was generated in synthetically useful
yields ranging from 63% to 94% (Table 1, entries 1-6). The ketone substrate was also
varied to test the reaction with cyclic ketones, with the desired products being formed
in a range of 63% to 70% yield (Table 1, entries 7-9). We note that the regioselective
formation of 19 is likely due to its greater thermodynamic stability in comparison to
the product derived from substitution at the 2-postion of 2-methylcyclohexanone.
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Table 1. MgBr2·OEt2-Promoted Acylation of Ketones Using Crude Acid Chlorides.
entry
1
carboxylic acid
ketone
1,3-diketone
yield (%)a
94
8
1
11
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3
91
76
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8
2
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As mentioned above, we have previously reported the acylation of thioesters
using N-acylbenzotriazoles in the presence of MgBr2·OEt2 and Hunig’s base to give β-
keto thioesters.3c Given the positive results obtained for the synthesis of 1,3-
diketones using crude acid chlorides (Table 1), we also tried this simplified approach
for the synthesis of β-keto thioesters. This was done by direct analogy to the work
shown in Table 1, and in all cases the desired β-keto thioester was obtained in good
to excellent yield (Table 2).
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Table 2. MgBr2·OEt2-Promoted Acylation of Thioesters Using Crude Acid Chlorides.
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entry
1
carboxylic
acid
β-keto thioester
yield (%)a
91
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In order to validate the above methods, we carried out the synthesis of each of
the 1,3-diketones and the β-keto thioesters prepared, but this time using acid
chlorides that were either purchased from commercial sources or, when unavailable,
prepared from the corresponding carboxylic acid and purified prior to use in the
carbon-carbon bond–forming step. As shown in Table 3, in all cases the yield obtained
was comparable to the approach using the acid chlorides in their crude form. Indeed,
in some cases better yields were obtained using the crude acid chlorides.
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Table 3. MgBr2·OEt2-Promoted Acylation of Ketones Using Purified or
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Commercially-Available Acid Chlorides.
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entry
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carboxylic acid
ketone
1,3-diketone
yield (%)a
64
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The results obtained for the synthesis of β-ketothioesters using commercially-
available acid chlorides are shown in Table 4. Just as for the synthesis of 1,3-
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diketones (Table 3), the yield obtained for each of these reactions was comparable to
the approach using the acid chlorides in their crude form (Table 2).
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Table 4. MgBr2·OEt2-Promoted Acylation of Thioesters Using Purified or
Commercially-Available Acid Chlorides.
entry
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carboxylic acid
β-keto thioester
yield (%)a
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To test the scalability of the reactions using crude acid chlorides the synthesis
of 1,3-diketone 11 was carried out staring from carboxylic acid 1 and ketone 8. Thus,
a solution of 1 in DMF and CH2Cl2 was treated with oxalyl chloride. The solvent was
removed after 12 hours and the resulting residue was dissolved in CH2Cl2, and
MgBr2·OEt2, i-Pr2NEt, and 8 (3.8 mL) were then added. This led to the formation of
the desired 1,3-diketone in 79% yield. For comparison purposes the corresponding
reaction using commercially-available acid chloride 27 was carried out, also using 3.8
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mL of 8. Compound 11 was generated from this reaction in a similar yield (89%) to
the transformation using the crude acid chloride, thereby supporting the synthetic
utility of the latter approach even in larger reaction scale context .
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Scheme 3. Larger Scale MgBr2·OEt2-Promoted Acylation Reaction.
Conclusion
In conclusion, when conducted under soft enolization conditions, the acylation
of ketones and thioesters using acid chlorides in their crude form is a useful approach
to the synthesis of 1,3-diketones and β-keto thioesters, respectively. The reactions
are conducted with the crude acid chloride, which is prepared from the
corresponding carboxylic acid and oxalyl chloride. Given the general importance of
1,3-dicarbonyl compounds, along with the efficiency and operational simplicity of this
method, we expect that it will meet with wide application in synthetic chemistry.
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Experimental Section
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General Considerations. Unless stated to the contrary, where applicable, the
following considerations apply. Reactions were carried out using dried solvents (see
below) under a slight static pressure of Ar (pre-purified quality) that had been passed
through a column (5 x 20 cm) of Drierite. Glassware was dried in an oven at 120 °C
for at least 12 hours prior to use and then either cooled in a desiccator cabinet over
Drierite or assembled quickly while hot, sealed with rubber septa, and allowed to cool
under a stream of Ar. Reaction mixtures were stirred magnetically using Teflon-
coated magnetic stirring bars. Teflon-coated magnetic stirring bars and syringe
needles were dried in an oven at 120 °C for at least 12 h prior to use then cooled in a
desiccator cabinet over Drierite. Hamilton microsyringes were dried in an oven at 60
°C for at least 24 h prior to used and cooled in the same manner. Commercially
available Norm-Jet disposable syringes were used. Dry solvents were obtained using
an Innovative Technologies solvent purification system. Commercial grade solvents
were used for routine purposes without further purification. Amines were distilled
from CaH2 under a N2 atmosphere prior to use. Flash column chromatography was
performed using silica gel 60 (230-400 mesh). 1H and 13C NMR spectra were recorded
on a JEOL ECA-500 or ECX-400P spectrometer at ambient temperature. High-
resolution Mass Spectrometry was acquired using an Agilent Technologies 6530
Accurate Mass Q-Tof LC/MS for electrospray ionization (ESI), or a Micromass
Autospec Ultima for chemical ionization (CI).
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General procedure for the synthesis of 1,3 diketones 11-19 starting from
carboxylic acids
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4-methyl-1-phenyl-pentane-1,3-dione (12).
DMF (0.23 ml, 2.88 mmol) was added to a stirred solution of 2-methylpropionic
acid (2.0 ml, 22.2 mmol), oxalyl chloride (5.7 ml, 66.5 mmol), and CH2Cl2 (50 mL) (Ar
atmosphere). The solution was stirred for 12 h and then evaporated under reduced
pressure to give a mixture consisting of a yellow oil and a dark-brown residue.
In a separate flask MgBr2·OEt2 (0.71 g, 2.80 mmol) was added to a stirred
solution of acetophenone (0.13 mL, 0.915 mmol) and the above-generated yellow oil
[0.2 mL; ~1.9 mmol (based on the density of 2-methylpropanoyl chloride)] in CH2Cl2
(3 mL) (Ar atmosphere), and the resulting mixture was stirred for 15 min. i-Pr2NEt
(0.636 mL, 3.66 mmol) was then added drop-wise over ~1 min, the reaction flask was
capped with a plastic stopper, sealed with Parafilm, and the mixture was stirred for 12 h.
The reaction was quenched with 10% HCl(aq) (4 mL), and the resulting mixture was
partitioned between CH2Cl2 (15 mL) and water (8 mL). The aqueous phase was washed
with CH2Cl2 (3 x 20 mL) and the combined organic extracts were washed with brine (2 x
15 mL), dried (MgSO4), filtered, and evaporated under reduced pressure to give a red oil.
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 12 as a pure,
red oil (0.164 g, 91%). 1H NMR (CDCl3, 400 MHz): δ 7.99 (m, 2H), 7.34 (m, 1H), 7.30
(m, 2H), 6.10 (s, 1H), 4.10 (s, 1H), 2.70 (m, 1H), 1.20 (d, J = 9.2 Hz, 6H); 13C{1H } NMR
(CDCl3, 100 MHz): δ 201.3, 183.9, 135.3, 132.3, 128.7, 127.1, 94.3, 37.6, 19.5.
7
Spectroscopic data was identical to that reported previously.
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1-phenyl-5,5-dimethylhexane-1,3-dione (14)
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Flash chromatography over silica gel using 5:95 CH2Cl2-hexanes (v/v) gave 14 as a pure,
red oil (0.355 g, 71%). 1H NMR (CDCl3, 400 MHz): δ 7.90 (d, J = 6.8 Hz, 2H), 7.55-7.42
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(m, 3H), 6.13 (s, 1H), 2.28 (s, 2H) 1.06 (s, 9H); C{1H } NMR (CDCl3, 100 MHz): δ
193.9, 185.4, 135.6, 132.4, 128.7, 127.2, 98.3, 52.4, 32.1, 30.1. Spectroscopic data was
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identical to that reported previously.
4,4-Dimethyl-1-phenyl-pentane-1,3-dione (11)
Flash chromatography over silica gel using 10:90 CH2Cl2-hexanes (v/v) gave 11 as a pure,
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a red oil (0.165 g, 94%). H NMR (CDCl3, 500 MHz): δ 7.99 (d, J = 7.6 Hz, 2H), 7.53-
7.49 (m, 1H), 7.47-7.43 (m, 2H), 6.31 (s, 1H), 1.25 (s, 9H); C{1H } NMR (CDCl3,100
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MHz): δ 202.9, 184.7, 135.6, 132.3, 128.7, 127.1, 92.2, 39.9, 27.5.Spectroscopic data was
identical to that reported previously.8
4-ethyl-1-phenylhexane-1,3-dione (13)
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 13 as a pure,
red oil (0.142 g, 76%). 1H NMR (CDCl3, 400 MHz): δ 7.99 (m, 2H), 7.4 (m, 1H), 7.5 (m,
2H), 6.1 (s, 1H), 4.1 (s, 8H), 2.1 (m, 1H), 1.7 (m, 2H), 1.5 (m, 2H), 0.9 (t, J = 7.4 Hz, 6H);
13C{1H } NMR (CDCl3, 100 MHz): δ 199.4, 184.4, 135.4, 132.3, 128.7, 127.2, 96.5, 52.7,
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25.7, 12.1. Spectroscopic data was identical to that reported previously.
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1,3-diphenyl-1,3-propanedione (16)
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Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 16 as a pure,
yellow solid (0.116 g, 64%). 1H NMR (CDCl3, 400 MHz): δ 7.99 (d, J = 8.0 Hz, 2H), 7.59-
7.48 (m, 4H), 6.87 (s, 1H), 3.46 (s, 1H); 13C{1H } NMR (CDCl3, 100 MHz): 187.3, 185.9,
132.8, 130.1, 129.1, 128.8, 127.3. Spectroscopic data was identical to that reported
previously.9
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1-phenyl-3-(4-pyridyl)-1,3-propanedione (15)
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 15 as a pure,
yellow solid (0.219 g, 75%). 1H NMR (CDCl3, 400 MHz): δ 8.78 (d, J = 3.6 Hz, 1H), 8.39-
8.37 (m, 1H), 7.99 (m, 2H), 7.6-7.48 (m, 5H), 6.89 (s, 1H); 13C{1H } NMR (CDCl3, 100
MHz): δ 186.4, 183.4, 152.9, 148.6, 134.7, 133.0, 128.9, 127.4, 123.7, 93.6. Spectroscopic
10
data was identical to that reported previously.
2-(2-Methylpropanoyl)cyclohexanone (17)
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 17 as a pure,
yellow solid (0.227 g, 70%). 1H NMR (CDCl3, 400 MHz): δ 2.86 (m, 1H), 2.33 (m, 4H),
1.67 (m, 4H), 1.07 (d, J = 6.8 Hz, 6H); 13C{1H } NMR (CDCl3, 100 MHz): δ 205.5, 183.1,
105.7, 33.3, 31.4, 23.7, 23.1, 21.7, 18.8. Spectroscopic data was identical to that reported
11
previously.
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2-benzoylcyclohexanone (18)
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Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 18 as a pure,
yellow solid (0.133 g, 68%). 1H NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 7.2 Hz, 1H), 7.6-
7.5 (m, 2H), 7.54-7.45 (m, 3H), 4.4 (dd, J = 3.5 Hz, 1H), 2.56 (m, 1H), 2.51(t, J = 6.1 Hz,
2H), 2.41 (t, J = 6.2 Hz, 2H), 2.3-2.2 (m, 1H), 2.109 (m, 1H), 1.9-1.8 (m, 1H), 1.77 (m,
2H), 1.59 (m, 2H); 13C{1H } NMR (CDCl3, 100 MHz): 191.2, 189.6, 130.5, 128.7, 128.6,
128.2, 127.7, 59.3, 42.5, 26.6, 23.5, 21.9. Spectroscopic data was identical to that reported
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previously.
2-benzoyl-6-methyl-cyclohexanone (19)
Flash chromatography over silica gel using 5:95, EtOAc-hexanes (v/v) gave 19 as a pure,
1
colorless solid (0.150 g, 84%). H NMR (CDCl3, 400 MHz): δ 7.57-7.50 (m, 2H), 7.46-
7.39 (m, 3H), 4,45 (dd, J= 3.2 Hz, 1H), 2.56 (m, 1H), 2.41-2.36 (m, 1H), 2.11-1.89 (m,
2H), 1.75-1.67 (m, 1H), 1.54-1.39 (m, 2H), 1.26 (d, J = 7.2 Hz, 3H); 13C{1H } NMR
(CDCl3, 100 MHz): δ 210.31, 210.14, 198.1, 197.2, 193.4, 191.1, 128.90, 128.78, 128.65,
128.20, 128.15, 127.7, 106.6, 59.2, 58.6, 46.4, 44.9, 37.2, 36.9, 35.9, 30.6, 24.5, 21.8, 21.6,
18.2, 14.5. Spectroscopic data was identical to that reported previously.12
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General procedure for the synthesis of β-keto thioesters 23-26 starting from
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carboxylic acids
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S-phenyl 1-(4-bromophenyl)-3-propane- 1, 3-dione (23).
DMF (0.11ml, 1.43 mmol) was added to a stirred solution of 4-bromobenzoic acid
(2.50 g, 11.4 mmol), oxalyl chloride (3.0 ml, 34.9 mmol), and CH2Cl2 (80 mL) (Ar
atmosphere). The solution was stirred for 12 h and then evaporated under reduced
pressure to give light-yellow solid.
In a separate flask MgBr2·OEt2 (1.0 g, 3.90 mmol) was added to a stirred
solution of S-phenyl propanethioate (0.20 mL, 1.30 mmol) and the above-generated
yellow solid (0.36 g; ~2.6 mmol) in CH2Cl2 (4 mL) (Ar atmosphere), and the resulting
mixture was stirred for 15 min. i-Pr2NEt (0.90 mL, 5.20 mmol) was added drop-wise
over ~1 min, the reaction flask was capped with a plastic stopper, sealed with Parafilm, and
the mixture was stirred for 12 h. The reaction was quenched with 10% HCl(aq) (4 mL), and
the resulting mixture was partitioned between CH2Cl2 (15 mL) and water (8 mL). The
aqueous phase was washed with CH2Cl2 (3 x 20 mL) and the combined organic extracts
were washed with brine (2 x 15 mL), dried (MgSO4), filtered, and evaporated under
reduced pressure to give a red oil. Flash chromatography over silica gel using 5:95 EtOAc-
hexanes (v/v) gave 23 as a pure, white solid (0.414 g, 91%). 1H NMR (CDCl3, 400 MHz):
δ 7.85-7.83 (m, 2H), 7.68-7.6 (m, 2H), 7.39-7.25 (m, 5H), 4.66 (q, J= 6.8 Hz, 1H) , 2.16
(s, 1H), 1.60 (d, J = 6.8 Hz, 3H); 13C{1H } NMR (CDCl3, 100 MHz): δ 194.9, 193.8, 134.6,
130.4, 129.9, 129.5, 129.2, 126.6, 123.3, 56.4, 14.8. HRMS ESI-MS m / z [M + H]+ calcd
for C16H13BrO2S 348.9892, found 348.9900 and 350.9882.
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S-phenyl 2,5,5-trimethyl-3-oxohexanethioate (26)
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Flash chromatography over silica gel using 30:70 CH2Cl2-hexanes (v/v) gave 26 as a pure,
yellow oil (0.207 g, 63%). 1H NMR (CDCl3, 400 MHz): δ 7.48 (m, 5H), 3.81 (q, J = 6.8
Hz, 1H), 2.49 (s, 2H), 1.40 (d, J = 6.8 Hz, 3H), 1.03 (s, 9H); 13C{1H } NMR (CDCl3, 100
MHz): δ 203.8, 196.1, 194.9, 134.5, 134.5, 129.8,129.7, 129.5, 129.4, 129.3, 128.5, 127.5,
126.9, 62.7, 56.4, 53.6, 31.9, 31.1, 29.9, 29.7, 13.6. Spectroscopic data was identical to
that reported previously.3a
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S-phenyl 2-methyl-3-oxo-3-phenylpropanethioate (24)
Flash chromatography over silica gel using 20:80 CH2Cl2-hexanes (v/v) gave 24 as a pure,
yellow oil (0.115 g, 75%). 1H NMR (CDCl3, 400 MHz): δ 8.04 (s, 1H), 8.02 (d, J = 1.2
Hz, 1H), 7.62-7.56 (m, 1H), 7.52-7.48 (m, 2H), 7.39-7.34 (m, 5H), 4.71 (q, J = 7.2 Hz,
1H), 1.61 (d, J = 6.8 Hz, 3H); 13C{1H } NMR (CDCl3, 100 MHz): δ 195.01, 194.8, 135.9,
134.6, 133.8, 129.8, 129.4,128.96, 128.91, 126.9, 56.3, 14.9. Spectroscopic data was
identical to that reported previously.3a
S-phenyl 3-cyclohexyl-2-methyl-3-oxopropanethioate (25)
Flash chromatography over silica gel using 20:80 CH2Cl2-hexanes (v/v) gave 25 as a pure,
red oil (0.261 g, 72%). 1H NMR (CDCl3, 400 MHz): δ 13.6 (s, OH), 7.46-7.38 (m, 5H),
4.01 (q, J = 6.8Hz, 1H), 2.68-2.58 (m, 1H), 1.91-1.66 (m, 6H), 1.42 (d, J = 6.8 Hz, 3H),
1.34-1.19 (m, 4H); 13C{1H } NMR (CDCl3, 100 MHz): δ 207.7, 194.8, 134.5, 129.8, 129.4,
127.03, 59.3, 50.3, 29.1, 28.4, 26.1, 25.8, 25.4, 14.0. Spectroscopic data was identical to
that reported previously.3a
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General procedure for the synthesis of 1,3 diketones 11-19 starting from pure
acid chlorides
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4-methyl-1-phenyl-pentane-1,3-dione (12).
MgBr2·OEt2 (1.38 g, 5.35 mmol) was added to a stirred solution of
acetophenone (0.20 mL, 1.95 mmol), 2,2 dimethyl butyl chloride (0.20 mL, 2.19
mmol) and CH2Cl2 (7 mL) (Ar atmosphere), and the resulting mixture was stirred for
15 min. i-Pr2NEt (1.16 mL, 7.13 mmol) was added to the solution, the reaction flask was
capped with a plastic stopper, sealed with Parafilm, and reaction mixture was stirred for 12
h. The reaction mixture was then quenched with 10% HCl(aq) (4 mL), and the resulting
mixture was partitioned between CH2Cl2 (15 mL) and water (8 mL). The aqueous phase
was washed with CH2Cl2 (3 x 20 mL) and the combined organic extracts were washed with
brine (2 x 15 mL), dried (MgSO4), filtered, and evaporated under reduced pressure to give
a red oil. Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 12 as
a pure, red oil (0.299 g, 91%). Spectroscopic data was identical to that given above.
1-phenyl-5,5-dimethylhexane-1,3-dione (14)
Flash chromatography over silica gel using 5:95 CH2Cl2-hexanes (v/v) gave 14 as a pure,
red oil (0.125 g, 64%). Spectroscopic data was identical to that given above.
4,4-Dimethyl-1-phenyl-pentane-1,3-dione (11)
Flash chromatography over silica gel using 10:90 CH2Cl2-hexanes (v/v) gave 11 as a pure,
a red oil (0.326 g, 94%). Spectroscopic data was identical to that given above.
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4-ethyl-1-phenylhexane-1,3-dione (13)
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Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 13 as a pure,
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red oil (0.301 g, 89%). Spectroscopic data was identical to that given above.
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1,3-diphenyl-1,3-propanedione (16)
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 16 as a pure,
yellow solid (0.30 g, 79%). Spectroscopic data was identical to that given above.
1-phenyl-3-(4-pyridyl)-1,3-propanedione (15)
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 15 as a pure,
yellow solid (0.089 g, 67%). Spectroscopic data was identical to that given above.
2-(2-Methylpropanoyl)cyclohexanone (17)
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 17 as a pure,
yellow solid (0.169 g, 81%). Spectroscopic data was identical to that given above.
2-benzoylcyclohexanone (18)
Flash chromatography over silica gel using 5:95 EtOAc-hexanes (v/v) gave 18 as a pure,
yellow solid (0.270 g, 69%). Spectroscopic data was identical to that given above.
2-benzoyl-6-methyl-cyclohexanone (19)
Flash chromatography over silica gel using 5:95, EtOAc-hexanes (v/v) gave 19 as a pure,
colorless solid (0.356 g, 80%). Spectroscopic data was identical to that given above.
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General procedure for the synthesis of β-keto thioesters 23-26 starting from
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pure acid chlorides
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S-phenyl 1-(4-bromophenyl)-3-propane- 1, 3-dione (23)
MgBr2·OEt2 (1.38 g, 5.35 mmol) was added to a stirred solution of S-phenyl
propanethioate (0.27 ml, 1.76 mmol), 4- bromo- benzoyl chloride (0.47 g, 2.16 mmol)
and CH2Cl2 (6 ml) (Ar atmosphere), and the resulting mixture was stirred for 15 min.
i-Pr2NEt (1.24 ml, 7.13 mmol) was added to the solution, the reaction flask was capped
with a plastic stopper, sealed with Parafilm, and reaction mixture was stirred for 12 h. The
reaction mixture was then quenched with 10% HCl (4 mL), and the resulting mixture was
partitioned between CH2Cl2 (15 mL) and water (8 mL). The aqueous phase was washed
with CH2Cl2 (3 x 20 mL) and the combined organic extracts were washed with brine
(2 x 15 mL), dried (MgSO4), filtered, and evaporated under reduced pressure to give
an brown solid. Flash chromatography over silica gel using 5:95 EtOAC-hexanes (v/v)
gave 23 as a pure, white solid (0.597 g, 97%). Spectroscopic data was identical to that
given above.
S-phenyl 2-methyl-3-oxo-3-phenylpropanethioate (26)
Flash chromatography over silica gel using 20:80 CH2Cl2-hexanes (v/v) gave 26 as a pure,
yellow oil (0.404 g, 97%). Spectroscopic data was identical to that given above.
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S-phenyl 2,5,5-trimethyl-3-oxohexanethioate (24)
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Flash chromatography over silica gel using 30:70 CH2Cl2-hexanes (v/v) gave 24 as a pure,
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yellow oil (0.405 g, 86%). Spectroscopic data was identical to that given above.
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S-phenyl 3-cyclohexyl-2-methyl-3-oxopropanethioate (25)
Flash chromatography over silica gel using 20:80 CH2Cl2-hexanes (v/v) gave 25 as a pure,
red oil (0.288 g, 59%). Spectroscopic data was identical to that given above.
Large scale synthesis of 4,4-Dimethyl-1-phenyl-pentane-1,3-dione (11) starting from
carboxylic acid 1.
DMF (0.6 ml, 7.63 mmol) was added to a stirred solution of pivalic acid (6.0 g,
58.7 mmol), oxalyl chloride (15 ml, 174.0 mmol), and CH2Cl2 (73 mL) (Ar atmosphere).
The solution was stirred for 12 h and then evaporated under reduced pressure to give
a mixture consisting of a yellow oil and a dark-brown residue.
In a separate flask MgBr2·OEt2 (22.5 g, 87.2 mmol) was added to a stirred
solution of acetophenone (3.8 mL, 32.6 mmol) and the above-generated yellow oil [5.0
mL; ~40.6 mmol (based on the density of trimethylacetyl chloride)] in CH2Cl2 (50 mL)
(Ar atmosphere), and the resulting mixture was stirred for 15 min. i-Pr2NEt (21.3 mL,
130.8 mmol) was then added drop-wise over ~15 min, the reaction flask was capped with
a plastic stopper, sealed with Parafilm, and the mixture was stirred for 12 h.The reaction
was quenched with 10% HCl(aq) (35 mL), and the resulting mixture was partitioned between
EtOAc (80 mL) and water (40 mL). The aqueous phase was washed with EtOAc (3 x 100
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mL) and the combined organic extracts were washed with brine (2 x 100 mL), dried
(MgSO4), filtered, and evaporated under reduced pressure to give a red oil. Flash
chromatography over silica gel using 10:90 EtOAc-hexanes (v/v) gave 11 as pure, red oil
(5.14 g, 79%). Spectroscopic data was identical to that given above.
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Large scale synthesis of 4,4-Dimethyl-1-phenyl-pentane-1,3-dione (11) starting from
acid chloride 27.
MgBr2·OEt2 (2.3 g, 98.2 mmol) was added to a stirred solution of acetophenone
(3.8 mL, 32.6 mmol), trimethylacetyl chloride (5.0 mL, 40.6 mmol), and CH2Cl2 (59
mL) (Ar atomosphere), and the resulting reaction mixture was stirred for 30 min. The
mixture was cooled (ice-H2O bath) and i-Pr2NEt (21.0 mL, 130.0 mmol) was added
dropwise over ~15 min. The reaction mixture was allowed to warm to rt and stirred for an
additional 4 h. The reaction mixture was then quenched with water (30 mL) and 10%
HCl(aq) (35 mL). The resulting mixture was filtered and partitioned between EtOAc (80
mL) and water (40 mL). The aqueous phase was washed with EtOAc (3 x 100 mL) and the
combined organic extracts were washed with brine (2 x 100 mL), dried (MgSO4), filtered,
and evaporated under reduced pressure to give a red oil. Flash chromatography over silica
gel using 10:90 EtOAc-hexanes (v/v) gave 11 as pure, red oil (5.89 g, 89%). Spectroscopic
data was identical to that given above.
Supporting Information
NMR spectra for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Acknowledgement
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We are grateful to the NSF (NSF 1300652), the Welch Foundation (E-1806),
and the University of Houston for financial support.
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References
1) Kel'in, A. V. Recent Advances in the Synthesis of 1,3-Diketones. Curr. Org. Chem.
2003, 7, 1691–1711.
2) Kel'in, A. V.; Maioli, A. Recent Advances in the Chemistry of 1,3-Diketones:
Structural Modifications and Synthetic Applications. Curr. Org. Chem. 2003, 7, 1855-
1886.
3) (a) Lim, D.; Fang, F.; Zhou, G.; Coltart, D. M. Direct Carbon-Carbon Bond Formation
via Soft Enolization: A Facile and Efficient Synthesis of 1,3-Diketones. Org. Lett.
2007, 9, 4139–4142. (b) Lim, D.; Zhou, G.; Livanos, A. E.; Fang, F.; Coltart, D. M.
MgBr2·OEt2-Promoted Coupling of Ketones and Activated Acyl Donors via Soft
Enolization: A Practical Synthesis of 1,3-Diketones. Synthesis 2008, 13, 2148–2152.
(c) Zhou, G.; Lim, D.; Coltart, D. M. Direct Carbon−Carbon Bond Formation via
Chemoselective Soft Enolization of Thioesters: A Remarkably Simple and Versatile
Crossed-Claisen Reaction Applied to the Synthesis of LY294002. Org. Lett. 2008, 10,
3809–3812. (d) Zhou, G.; Lim, D.; Fang, F.; Coltart, D. M. A Practical Synthesis of β-
Keto Thioesters by Direct Crossed-Claisen Coupling of Thioesters and N-
Acylbenzotriazoles. Synthesis 2009, 3350–3352.
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4) For pioneering applications of soft enolization in direct carbon–carbon bond formation
see: (a) Rathke, M. W.; Cowan, P. J. Procedures for the Acylation of Diethyl Malonate
and Ethyl Acetoacetate with Acid Chlorides using Tertiary Amine Bases and
Magnesium Chloride. J. Org. Chem., 1985, 50, 2622–2624; (b) Rathke, M. W.; Nowak,
M. The Horner-Wadsworth-Emmons Modification of the Wittig Reaction using
Triethylamine and Lithium or Magnesium Salt. J. Org. Chem. 1985, 50, 2624–2626;
(c) Tirpak, R. E.; Olsen, R. S.; Rathke, M. W. Carboxylation of Ketones using
Triethylamine and Magnesium Halides. J. Org. Chem. 1985, 50, 4877–4879.
5) For lead references on C-acylation via N-acylbenzotriazoles see: Katritzky, A. R.;
Wang, Z.; Wang, M.; Wilkerson, C. R.; Hall, C. D.; Akhmedov, N. G. Preparation of
β-Keto Esters and β-Diketones by C-Acylation/Deacetylation of Acetoacetic Esters and
Acetonyl Ketones with 1-Acylbenzotriazoles. J. Org. Chem. 2004, 69, 6617–6622.
Katritzky, A. R.; Suzuki, K.; Wang, Z. Acylbenzotriazoles as Advantageous N-, C-, S-
, and O-Acylating Agents. Synlett 2005, 11, 1656–1665.
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23
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6) Rvan, M. M.; Wagaw, S. H.; Engstrom, K. M.; Mei, J.; Kotecki, B.; Souers, A. J.; Kym,
P. R.; Judd, A. S.; Zhao, G. Process Development of a Diacyl Glycerolacyltransferase-
1 Inhibitor. Org. Proc. Res. Dev. 2010, 14, 417–424.
7) Sada, M. ; Matsubara, S. A Tandem Reaction Initiated by 1,4-Addition of
Bis(iodozincio)methane for 1,3-Diketone Formation. J. Am. Chem. Soc. 2010, 132,
432–433.
8) He, Z.; Qi, X.; Li, S.; Zhao, Y.; Gao, G.; Lan, Y.; Wu, Y.; Lan, J.; You, J. Transition‐
Metal‐ Free Formal Decarboxylative Coupling of α -Oxocarboxylates with α-
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Bromoketones under Neutral Conditions: A Simple Access to 1,3‐Diketones. Angew.
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Chem., Int. Ed. 2015, 54, 855–859.
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