Room-Temperature Coupling/Decarboxylation Reaction of α-Oxocarboxylates with α-Bromoketones: Solvent-Controlled Regioselectivity for 1,2- and 1,3-Diketones

Article abstract of DOI:10.1021/acs.joc.6b02575

A transition-metal-free and room-temperature coupling/decarboxylation reaction between α-oxocarboxylates and α-bromoketones is reported herein. It represents the first mild and regioselective synthesis of either 1,2- or 1,3-diketones from the same starting materials. Notably, the regioselectivity is simply controlled by solvents. The preliminary experimental data and DFT calculations suggest sequential Darzens-type coupling, alkaline hydrolysis, KOH-promoted oxirane opening and decarboxylation in one pot. This method is efficient for the synthesis of α,β-epoxy-γ-butyrolactone and curcuminoids.

Full text of DOI:10.1021/acs.joc.6b02575

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Article
Room-Temperature Coupling/Decarboxylation Reaction of
alpha-Oxocarboxylates with alpha-Bromoketones: Solvent-
Controlled Regioselectivity for 1,2- and 1,3-Diketones
Zhen He, Xiaotian Qi, Zhijie She, Yinsong Zhao, Shiqing Li, Junbin Tang, Ge Gao, Yu Lan, and Jingsong You
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02575 • Publication Date (Web): 04 Jan 2017
Downloaded from http://pubs.acs.org on January 4, 2017
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RoomꢀTemperature Coupling/Decarboxylation Reaction of αꢀOxocarboxylates with
αꢀBromoketones: SolventꢀControlled Regioselectivity for 1,2ꢀ and 1,3ꢀDiketones
Zhen He,a Xiaotian Qi,b Zhijie She,a Yinsong Zhao,a Shiqing Li,a Junbin Tang,a Ge Gao,a,*
Yu Lanb,* and Jingsong Youa,*
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aKey Laboratory of Green Chemistry and Technology of Ministry of Education, College of
Chemistry, Sichuan University 29 Wangjiang Road, Chengdu 610064 (P. R. China)
Eꢀmail: gg2b@scu.edu.cn; jsyou@scu.edu.cn
bSchool of Chemistry and Chemical Engineering, Chongqing University, Chongqing
400030 (P. R. China)
Eꢀmail: lanyu@cqu.edu.cn
Abstract: A transitionꢀmetalꢀfree and roomꢀtemperature coupling/decarboxylation
reaction between αꢀoxocarboxylates and αꢀbromoketones is reported herein. It represents
the first mild and regioselective synthesis of either 1,2ꢀ or 1,3ꢀdiketones from the same
starting materials.. Notably, the regioselectivity is simply controlled by solvents. The
preliminary experimental data and DFT calculations suggest sequential Darzensꢀtype
coupling, alkaline hydrolysis, KOHꢀpromoted oxirane opening and decarboxylation in
one pot. This method is efficient for the synthesis of α,βꢀepoxyꢀγꢀbutyrolactone and
curcuminoids.
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Introduction
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1,2ꢀDiketone and 1,3ꢀdiketone are both important and versatile synthetic precursors,
bioactive molecules and functional materials.1,2 The main synthetic methods for the
preparation of 1,2ꢀdiketones include the oxidation of benzoins,3 epoxides4 and alkynes,5
the coupling of αꢀoxo acid chlorides with organostannanes6 as well as acid chlorides with
trimethylsilyl cyanohydrins.7 A recent interesting method is the selective C−C bond
cleavage of 1,3ꢀdiketones.8 1,3ꢀDiketones can be synthesized by the oxidation of aldol
products,9 the coupling of two carbonyl compounds through hard enolate strategy
(classical Claisen condensation),10 soft enolate strategy,11 organoꢀ12 and transitionꢀ metal
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catalysis,13
the
rearrangement
of
γꢀacyloxyl
enones
triggered
by
bis(iodozincio)methane,14 and the palladiumꢀcatalyzed carbonylative αꢀarylation of
ketones with aryl iodides using carbon monoxide.15 However, these protocols for both
diketones start from different materials, and suffer from the multiꢀstep preparation of
starting materials, the use of specific catalysts, toxic or expensive reagents, and/or harsh
reaction conditions. Moreover, a regioselective protocol for the preparation of both
regioisomers is not yet available.
1,2ꢀDiketone and its regioisomer 3ꢀoxoꢀaldehyde can be obtained by the rearrangement
of α,βꢀepoxy ketones under different conditions through either acyl or hydride migrations,
respectively.16 The acyl migration is generally more favored and may be promoted by
Lewis acids,17 protonic acids17a and zeolites18 to afford 3ꢀoxoꢀaldehydes. On the other
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hand, the hydride migration is less favored and in the presence of Mg(ClO4)2,19 silica
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gel,20 or catalzyed by Fe(tpp)OTf (tpp
=
tetraphenylporphyrin)21 and
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9
TpRu(PPh3)(MeCN)2PF6 (Tp = tris(1ꢀpyrazolyl)borate)22 generates 1,2ꢀdiketones. These
reactions suffer from prepreparation of α,βꢀepoxy ketones, limited substrate scope,
precious complex catalysts and in some cases, harsh conditions. It should be noted that
none of them can regioseletively provide either isomer (Scheme 1, i).
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Scheme 1 Synthetic protocols for dicarbonyl compounds from epoxides.
Stable and easily prepared αꢀoxocarboxylic acids have recently emerged as an
attractive acyl synthon for transitionꢀmetal (TM) catalyzed decarboxylative coupling
reactions.23
αꢀbromoketones at 150 ºC to generate 1,3ꢀdiketones has also been discovered.24 The DFT
calculation suggested unique coupling/decarboxylation pathway. Particularly
A
TMꢀfree version between potassium αꢀoxocarboxylates and
a
noteworthy is that the energy barrier for decarboxylation is much lowered than in
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TMꢀcatalyzed decarboxylations. However, high temperature is still needed because the
generation of the key intermediate involves the thermolysis of an αꢀbromoketone, which
has a very high energy barrier. Herein, a roomꢀtemperature coupling/decarboxylation
reaction between methyl αꢀoxocarboxylates and αꢀbromoketones to give not only 1,3ꢀ but
also 1,2ꢀdiketones in a completely regioselective manner is reported (Scheme 1, ii). The
unique advantages of this reaction include simple reagents, mild conditions and a
solventꢀcontrolled regioselectivity. This represents the first mild and regiocontrollable
protocol to permit the synthesis of either 1,2ꢀ or 1,3ꢀdiketones. The key intermediates for
this reaction are α,βꢀepoxyꢀγꢀoxoesters, which can also be formed diastereoselectively.
This reaction is applicable for the synthesis of α,βꢀepoxyꢀγꢀbutyrolactone and
curcuminoids.
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Results and discussion
Optimization of Reaction Conditions A model coupling reaction between methyl
2ꢀoxoꢀ2ꢀphenylacetate (1a) and 2ꢀbromoꢀ1ꢀphenylethanone (2a) in the presence of 2.0
equivalents of K2CO3 in Nꢀmethylꢀ2ꢀpyrrolidone (NMP) at room temperature for 24 h,
followed by the addition of 300 ꢁL of a 4 N aqueous KOH solution and continuous
stirring at room temperature for another 2 h was conducted for the initial optimization.
1
The H NMR analysis of the isolated product unexpectedly revealed a mixture of
1,3ꢀdiphenylpropaneꢀ1,2ꢀdione (3aa) and 1,3ꢀdiphenylpropaneꢀ1,3ꢀdione (4aa) in a ratio
of 11/9. The total yield was 36% (Table 1, entry 1). The addition of the KOH solution
over a period of 0.5 h improved the yield to 63%, albeit the selectivity remained
unchanged (Table 1, entry 2). Other bases (i.e., Na2CO3, EtONa, Et3N, DBU and pyridine)
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and solvents (i.e., CH3CN, DMSO, CH2Cl2 and toluene) significantly decreased the yield
(For details, see the Supporting Information, SI). However, the reaction in MeOH was
much faster and the starting materials vanished in 2 hours. Interestingly, 3aa was obtained
almost as a single product but in less than 15 % yield (Table 1, entry 3). These results
indicated that MeOH not only dramatically accelerates the coupling of 1a and 2a but also
controls a perfect regioselectivity for 3aa. Therefore, a mixed solvent of NMP/MeOH
(1:1, v/v) was eventually selected to promote the formation of 3aa in 91% yield (Table 1,
entry 4). The use of EtOH instead of MeOH resulted in 84% yield, but with a much lower
ratio of 3:1 (Table 1, entry 5). Lowering the concentration of aqueous KOH abruptly
decreased the yield to less than 10% (Table 1, entry 6). More interestingly, the use of
hydroxyacetone completely reversed the selectivity and provided 4aa as a single product,
yet the reaction was sluggish and the yield of 4aa was very low (Table 1, entry 7). To
balance the reaction kinetics and selectivity, MeOH and hydroxyacetone were both added
and their amounts were carefully tuned. It was found that the reaction in the mixed
solvent of 1 mL of NMP, 100 ꢁL of MeOH and 25 ꢁL of hydroxyacetone could deliver
4aa in 63% yield (Table 1, entry 8). Extending the time of the coupling step to 4 hours
resulted in the optimal yield of 78% (Table 1, entry 9).
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Table 1. Optimization for selective synthesis of 1,2ꢀ and 1,3ꢀdiketones[a]
Ratio
(3aa/4aa)[b]
Total yield
(%)[c]
Entry
Solvent
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1[d,e]
2[d]
3
NMP (1.0 mL)
NMP (1.0 mL)
MeOH (1.0 mL)
11/9
11/9
36
63
>99/1
<15
9
NMP/MeOH
(0.5/0.5 mL)
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4
5
>99/1
3/1
91
84
NMP/EtOH
(0.5/0.5 mL)
NMP/MeOH
(0.5/0.5 mL)
6[f]
>99/1
<1/99
<10
<10
NMP/hydroxyacetone
(0.5/0.5 mL)
7
NMP/MeOH/hydroxya
cetone
8
<1/99
<1/99
63
(1 mL/100 ꢁL/25 ꢁL)
NMP/MeOH/hydroxya
cetone
9[g]
78
(1 mL/100 ꢁL/25 ꢁL)
[a] The reaction was carried out with 1a (0.25 mmol), 2a (0.325 mmol)
and K2CO3 (0.50 mmol) in a solvent at room temperature for 2 h (t),
followed by the addition of 300 ꢁL of 4 N KOH over a period of 0.5 h,
and continued stirring for another 1.5 h. [b] Determined by H NMR
analysis. [c] Isolated yield. [d] t = 24 h, [e] 300 ꢁL of 4 N KOH was
1
added by one time. [f] 2 N KOH was used. [g] t = 4 h.
Substrate Scope A series of methyl αꢀoxocarboxylates 1 and αꢀbromoketones 2 were
subjected to react under the two optimized conditions, respectively. As summarized in
Table 2, both 1,2ꢀ and 1,3ꢀdiketones (3 and 4) were obtained in moderate to good yields.
1,3ꢀDiketones 4 were produced in relatively lower yields than 1,2ꢀdiketones 3. The best
yield were 94% for 3ca and 85% for 4fj (entries 3 and 27). The steric hindrance on the
αꢀoxocarboxylate side showed a much more impact than on the αꢀbromoketone side.
When R1 was the oꢀmethylphenyl group, the first coupling reaction did not occur
whatever base was used. When R2 was the oꢀmethoxyphenyl group, 3ad was obtained in
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a low yield of 32% (entry 14). The substrates containing heteroaryls were suitable, and
the corresponding diketones containing 2ꢀthienyl, 3ꢀthienyl and 2ꢀfuryl groups were all
obtained in good yields (entries 9, 10, 20, 21, 26 and 27). Notably, the α,βꢀunsaturated
substrate was also compatible. 1,3ꢀDiketone 4al was isolated in 63% yield, but the yield
of 1,2ꢀdiketone 3al was only 30% (entry 22). Aliphatic oxocarboxylate 1k gave
1,3ꢀdiketone 4ka in 67% yield, whereas the decomposition occurred under the conditions
for the synthesis of 1,2ꢀdikeones (entry 11).
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Table 2. Substrate scopes for the synthesis of 1,2ꢀ and 1,3ꢀdiketones[a]
3
4
Entry
R1
R2
(yield)[b,d]
(yield)[c,d]
1
2
Ph
Ph
3aa (91%)
3ba (90%)
3ca (94%)
3da (63%)
3ea (48%)
3fa (80%)
3ga (65%)
3ha (85%)
3ia (64%)
3ja (61%)
3ka (trace)
3ab (58%)
3ac (76%)
4aa (78%)
4ba (45%)
4ca (63%)
4da (40%)
4ea (70%)
4fa (62%)
4ga (68%)
4ha (70%)
4ia (61%)
4ja (61%)
4ka (67%)
4ab (50%)
4ac (65%)
pꢀMeC6H4
mꢀMeC6H4
pꢀMeOC6H4
pꢀBrC6H4
pꢀFC6H4
2ꢀnaphthyl
biphenyl
2ꢀthienyl
3ꢀthienyl
cyclohexyl
Ph
Ph
3
Ph
4
Ph
5
Ph
6
Ph
7
Ph
8
Ph
9
Ph
Ph
10
11
12
13
Ph
pꢀMeOC6H4
mꢀMeOC6H4
Ph
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Ph
Ph
oꢀMeOC6H4
3ad (32%)
4ad (56%)
4ae (63%)
benzo[d][1,3]
dioxolꢀ5ꢀyl
3ae (45%)
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21
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25
26
27
Ph
Ph
pꢀBrC6H4
pꢀFC6H4
3af25(86%)
3ag (70%)
3ah (64%)
3ai (81%)
3aj (90%)
3ak (86%)
3al (30%)
3ef (63%)
3db (52%)
3bf (70%)
3ij (71%)
3fj (81%)
4af (68%)
4ag (66%)
4ah (60%)
4ai (70%)
4aj (80%)
4ak (75%)
4al (63%)
4ef (60%)
4db (42%)
4bf (55%)
4ij (70%)
4fj (85%)
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Ph
pꢀCF3C6H4
2ꢀnaphthyl
2ꢀthienyl
Ph
Ph
Ph
2ꢀfuryl
Ph
PhCH=CHꢀ
pꢀBrC6H4
pꢀMeOC6H4
pꢀBrC6H4
2ꢀthienyl
pꢀBrC6H4
pꢀMeOC6H4
pꢀMeC6H4
2ꢀthienyl
pꢀFC6H4
2ꢀthienyl
[a] The reactions were carried out with 1 (0.25 mmol), 2 (0.325 mmol) and K2CO3 (0.50
mmol) in a solvent at room temperature for 2 h (for 3) or 4 h (for 4), followed by the
addition of 300 ꢁL of 4 N KOH over a period of 0.5 h, and continued stirring for another
1.5 h. [b] Solvent: NMP/MeOH (0.5/0.5 mL). [c] Solvent: NMP/MeOH/hydroxyacetone
(1.0 mL/100 ꢁL/25 ꢁL). [d] Isolated yield.
Mechanism Studies and DFT Calculations Following the coupling reaction process in
NMP with TLC revealed the emergence of two new spots rather than the diketone
products before addition of KOH. The major spot was determined by the Xꢀray
diffraction analysis to be transꢀmethyl 3ꢀbenzoylꢀ2ꢀphenyloxiraneꢀ2ꢀcarboxylate
(transꢀ5aa),15 a Darzensꢀtype product26 [Eq (1a) and Figure 1, left]. The minor spot was
1
cisꢀ5aa by using H NMR and HRMS in comparison with transꢀ5aa. The yields of the
two diastereomers were 81% and 16%, respectively. Interestingly, the coupling conducted
in dioxane at 80 oC for 4 hours delivered cisꢀ5aa almost as a single diastereomer in 80%
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yield [Eq (1b)]. Thus, this mild Darzensꢀtype coupling offers a highly efficient protocol to
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access synthetically challenging α,βꢀepoxyꢀγꢀoxoesters 5 in both diastereomeric forms.
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The treatment of cisꢀ5aa with KOH under the standard conditions delivered 1,2ꢀ and
1,3ꢀdiketones in similar yields to those from transꢀ5aa (see the SI), indicating that the
regioselectivity was not derived from these two diastereomeric intermediates. Then the
hydrolysis of 5aa by the dropwise addition of 300 ꢁL KOH in MeOH was carefully
monitored. 5aa disappeared after the addition of 200 ꢁL of KOH and highly polar
substances were produced, suggesting that 5aa was completely hydrolyzed into an
organic salt. The reaction mixture would stay unchanged if no more KOH was added. The
addition of the remaining 100 ꢁL of KOH gave a small amount of 1,2ꢀdiketone 3aa (Table
1, entry 3). The hydrolyzed intermediate in its acid form was luckily obtained as a white
solid, 6aa·NMP,27 which was stabilized by NMP through hydrogen bonding as resolved
by the single crystal analysis [Eq (2) and Figure S2].25 It needs to point out that, without
KOH, 6aa·NMP only decarboxylated in NMP at a high temperature of 150 oC and gave a
small amount of 1,3ꢀdiketone 4aa as the single product, which followed the traditional
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decarboxylationꢀtriggered ring opening pathway (Darensꢀtype).28 These results indicated
the most possible sequence of the current reaction is hydrolysis, oxirane opening and then
decarboxylation.29
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To verify the ring opneing step, tetrabutylammonium bromide (TBAB), a neutral
nucleophile, was tested instead of the basic nucleophile KOH. Stirring 6aa·NMP with
TBAB at room temperature for 12 hours afforded 1,3ꢀdiketone 4aa in 90% yield as a
single product [Eq (3)]. Therefore, it is reasonable to conclude that KOH sequentially
plays three roles in this reaction: 1) as a base to hydrolyze the ester; 2) as a nucleophile to
open the oxirane ring; and 3) as a base to switch the production from 1,3ꢀ to
1,2ꢀdiketones.
Density functional theory (DFT) calculation was then performed to elucidate the
possible pathways for the oxirane opening by hydroxide and the decarboxylation of
6aa·K. It suggests that two pathways (a and b) having similar activation free energies
(29.0 and 28.2 kcal/mol) produce 1,2ꢀ and 1,3ꢀdiketone, respectively (For details, see SI).
The activation free energy of path b is 0.8 kcal/mol lower than that of path a, interpreting
the slightly higher selectivity for the 1,2ꢀdiketone product. This bias is so small in NMP
that the regioselectivity is only 11/9. (3aa/4aa, Table 1, entry 1).
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O
O
K
O
O
O
O
O
α
O
α
hydrolysis
ring opening
decarboxylation
- CO2
OK
Ph
O
OMe
α
β
γ
Ph
KOH
- MeOH
Ph
β
Ph
O
β
Ph
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6aa•K
OH
5aa
OH
I
O
OK
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OH
K
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H2O
H2O
OH
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α
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Ph
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Ph
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OH
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OH
OH
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Path a
- OH
- KOH
K
O
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H3O
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3aa
4aa
Scheme 2. Proposed mechanism.
Based on the above experiment results and DFT calculation, a tentative mechanism is
shown in Scheme 2. 5aa is firstly hydrolyzed in aqueous KOH to form the corresponding
carboxylate 6aa·K. Then the hydroxide ion acts as a nucleophile to attack the oxirane ring
on the β carbon and the ring is opened to form the intermediate I, which is an analogue of
the previously proposed key intermediate.24 Therefore, the decarboxylation takes place
very easily at room temperature to generate the carbanion II. The elimination of the
βꢀhydroxy group will give βꢀhydroxy chalcone derivative, which is protonated and
isomerizes into 1,3ꢀdiketone 4aa (path a). However, II is also prone to rapid protonation
by water to form the intermediate III (Path b) because of the poor leaving ability of the
hydroxy group. In a strong alkaline environment, III is deprotonated by hydroxide again
on the more acidic β carbon and protonated by water on the α oxygen to generate the
carbanion IV, which is stabler than II due to the stabilization by the vicinal acyl group.
Finally, the elimination of KOH affords αꢀhydroxy chalcone, which is the isomer of
1,2ꢀdiketone 3aa. Although the regioselectivity caused by MeOH and hydroxyacetone is
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still unclear at current stage and needs further investigation, the system basicity and
kinetics should be taken into consideration. MeOH may kinetically favor the formation of
the stabler intermediate IV in Path b, while acidic hydroxyacetone may retard the
generation of IV by subtly lowering the system pH.
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Synthetic Applications To showcase the usefulness and simple practicability of the
current method, the syntheses of two kinds of synthetically difficult molecules are
demonstrated. α,βꢀEpoxyꢀγꢀbutyrolactone is an important skeleton found in many
bioactive natural products.30 The concise and convenient methods to these compounds are
highly desirable and demanding.31 Herein the reaction mixture of 1a and 2a in dioxane
was directly subjected to the NaBH4 reduction at room temperature for 0.5 hour,
providing α,βꢀepoxyꢀγꢀbutyrolactone 7 in 70% yield [Eq (4)]. Compound 7 was
previously synthesized in 3 steps in a total yield of 61%.32
Curcuminoids possess antiinflammatory, antioxidant, antiarthritic, and antitumor
bioactivities, but efficient synthetic methodologies are very limited.33 To date, the
prevailing synthetic protocol was developed as early as in 1964.34 In this approach,
acetylacetone is firstly protected with boron trioxide and then condensed with
benzaldehyde. The final dissociation of the boron complex in a slightly acidic
environment provides the corresponding curcuminoid. The drawbacks are obvious
including a multiꢀstep process and especially the inaccessibility to pure unsymmetrical
curcuminoids. By utilizing the method described herein, the reactions of α,βꢀunsaturated
methyl αꢀoxocarboxylate 1l and 1m with α,βꢀunsaturated αꢀbromoketone 2l produced the
symmetrical curcuminoid analogue 4ll and unsymmetrical curcuminoid analogue 4ml in
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61% and 50% yield in one pot, respectively [Eq (5)]. It provides a very convenient and
efficient protocol to synthesize curcuminoids, especially for the unsymmetrical ones.
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Conclusions
In conclusion, the first regioselective synthesis of 1,2ꢀ and 1,3ꢀdiketones is developed
by using easily prepared methyl αꢀoxocarboxylates and αꢀbromoketones as the starting
materials. This coupling/decarboxylation reaction is mild enough to conduct at room
temperature and the excellent regioselectivity is simply controlled by methanol and
hydroxyacetone. The key intermediate is isolated and identified to be an
α,βꢀepoxyꢀγꢀoxoester after the first coupling step, which can also be obtained
diastereoselectively in different solvents. The mechanism study as well as DFT
calculations suggest a sequential process consisting of a very mild Darzensꢀtype reaction,
an alkaline hydrolysis, a KOHꢀpromoted oxirane opening and a transitionꢀmetalꢀfree
decarboxylation. The very convenient oneꢀpot syntheses of α,βꢀepoxyꢀγꢀbutyrolactone
and curcuminoid analogues highlight the synthetic usefulness of the current protocol.
Experimental Section
General Procedure for the Preparation of 1,2ꢀDiketones 3: A flameꢀdried schlenck tube
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with a magnetic stirring bar was charged with methyl αꢀoxocarboxylate 1 (0.25 mmol),
αꢀbromoketone 2 (0.325 mmol) and K2CO3 (0.50 mmol). The system was evacuated and
back filled with N2 twice, and NMP/MeOH (0.5/0.5 mL) was injected. The reaction was
allowed to stir at room temperature for 2 h. Then 300 ꢁL of 4 N aq. KOH solution was
added over a period of 0.5 h and the reaction continued for another 1.5 h. The reaction
mixture was neutralized to pH 7 with 2 N HCl and extracted with ethyl acetate. The
combined organic phase was dried over anhydrous Na2SO4. After the volatile solvent was
evaporated, the residue was purified by column chromatography on silica gel (100ꢀ200
mesh) using ethyl acetate (EA)/petroleum ether (PE) as the eluent to afford the
corresponding 1,2ꢀdiketone 3.
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1,3ꢀDiphenylpropaneꢀ1,2ꢀdione (3aa):3 Eluted with EA/PE = 1/10. Yellow oil, 51.0 mg,
1
91% yield. Enol/ketone = 1.3:1. H NMR (400 MHz, CDCl3): δ = 4.20 (s, 2H, ketone
form), 6.40 (s, 1.3H, enol form), 7.27 (d, J = 7.6 Hz, 2H, ketone form), 7.30ꢀ7.35 (m, 3H,
ketone form), 7.38ꢀ7.40 (m, 3.9H, enol form), 7.42ꢀ7.46 (m, 2H+1.3H), 7.49ꢀ7.53 (m, 2H,
ketone form), 7.58ꢀ7.63 (m, 1H+1.3H), 7.73ꢀ7.75 (m, 2.6H, enol form), 7.82ꢀ7.84 (m,
2.6H, enol form), 7.88ꢀ7.90 (m, 2H, ketone form) ppm. 13C NMR (100 MHz, CDCl3): δ =
45.6, 119.6, 127.6, 128.5, 128.7, 128.89, 128.95, 129.1, 129.2, 130.0, 130.3, 130.5, 131.8,
132.2, 132.3, 134.3, 134.7, 136.1, 147.0, 192.2, 193.6, 199.3 ppm.
1ꢀPhenylꢀ3ꢀ(pꢀtolyl)propaneꢀ1,2ꢀdione (3ba): Eluted with EA/PE = 1/10. Yellow oil for
enol/ketone mixture and a white solid for enol form recrystallized from PE. 53.5 mg, 90%
yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3H), 6.38 (s, 1H), 7.20 (d, J =
8.0 Hz, 2H), 7.34 (s, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.72 (d, J =
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8.4 Hz, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 120.0, 128.5, 129.2, 129.5,
130.6, 131.5, 132.1, 136.2, 139.3, 146.6, 193.6 ppm.
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1ꢀPhenylꢀ3ꢀ(mꢀtolyl)propaneꢀ1,2ꢀdione (3ca): Eluted with EA/PE = 1/10. Yellow oil for
enol/ketone mixture and a white solid for enol form recrystallized from PE. 56.0 mg, 90%
yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3H), 6.37 (s, 1H), 7.14 (d, J =
7.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.59ꢀ7.66 (m,
3H), 7.72ꢀ7.74 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 119.9, 127.7, 128.5,
128.7, 129.2, 129.9, 131.2, 132.2, 134.2, 136.1, 138.3, 146.9, 193.7 ppm. HRMS (ESI+):
calcd for C16H15O2 [M+H]+ 239.1072, found 239.1066.
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3ꢀ(4ꢀMethoxyphenyl)ꢀ1ꢀphenylpropaneꢀ1,2ꢀdione (3da):20 Eluted with EA/PE = 1/5.
Yellow oil for enol/ketone mixture and a light yellow solid for enol form recrystallized
from PE. 40.0 mg, 63% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3H),
6.38 (s, 1H), 6.92 (d, J = 9.2 Hz, 2H), 7.32 (d, J = 1.6 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H),
7.57ꢀ7.61 (m, 1H), 7.70ꢀ7.72 (m, 2H), 7.79 (d, J = 9.2 Hz, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 55.4, 114.2, 120.0, 127.1, 128.5, 129.2, 132.0, 132.3, 136.4, 145.9, 160.2,
193.4 ppm.
3ꢀ(4ꢀBromophenyl)ꢀ1ꢀphenylpropaneꢀ1,2ꢀdione (3ea): Eluted with EA/PE = 1/10.
Yellow oil for enol/ketone mixture and a white solid for enol form recrystallized from PE.
1
36.0 mg, 48% yield. Enol form. H NMR (400 MHz, CDCl3): δ = 6.32 (s, 1H), 7.43 (s,
1H), 7.49ꢀ7.53 (m, 4H), 7.62 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.2
Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 118.1, 123.0, 128.6, 129.2, 131.9, 132.4,
133.2, 135.8, 147.3, 193.4 ppm.
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3ꢀ(4ꢀFluorophenyl)ꢀ1ꢀphenylpropaneꢀ1,2ꢀdione (3fa): Eluted with EA/PE = 1/10.
Yellow oil for enol/ketone mixture and a light yellow solid for enol form recrystallized
from PE. 48.5 mg, 80% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 6.36 (s, 1H),
7.04ꢀ7.11 (m, 2H), 7.38 (s, 1H), 7.49ꢀ7.53 (m, 2H), 7.59ꢀ7.63 (m, 1H), 7.71ꢀ7.74 (m, 2H),
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7.80ꢀ7.84 (m, 2H) ppm. C NMR (100 MHz, CDCl3): δ = 115.8 (d, J = 21.5 Hz), 118.5
(d, J = 0.9 Hz), 128.6, 129.2, 130.5 (d, J = 3.3 Hz), 132.3 (d, J = 9.3 Hz), 132.5, 136.0,
146.6 (d, J = 2.5 Hz), 162.8 (d, J = 248.9 Hz), 193.5 ppm.
3ꢀ(Naphthalenꢀ2ꢀyl)ꢀ1ꢀphenylpropaneꢀ1,2ꢀdione (3ga): Eluted with EA/PE = 1/5. A
yellow solid for enol/ketone mixture and a light yellow solid for enol form recrystallized
from PE. 44.5 mg, 65% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 6.57 (s, 1H),
7.48ꢀ7.55 (m, 5H), 7.63 (t, J = 7.2 Hz, 1H), 7.77ꢀ7.87 (m, 5H), 7.95 (d, J = 8.4 Hz, 1H),
8.32 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 119.8, 126.5, 127.0, 127.7, 127.8,
128.2, 128.6, 128.7, 129.3, 130.5, 131.9, 132.3, 133.4, 133.5, 136.1, 147.3, 193.6 ppm.
3ꢀ[(1,1'ꢀBbiphenyl)ꢀ4ꢀyl]ꢀ1ꢀphenylpropaneꢀ1,2ꢀdione (3ha): Eluted with EA/PE = 1/5.
A yellow solid for enol/ketone mixture, a light yellow solid for enol form recrystallized
from PE/DCM. 63.5 mg, 85% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 6.45 (s,
1H), 7.37 (t, J = 7.2 Hz, 1H), 7.44ꢀ7.48 (m, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.60ꢀ7.66 (m,
5H), 7.76 (d, J = 7.2 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 119.3, 127.2, 127.3, 127.8, 128.6, 129.0, 129.3, 131.0, 132.3, 133.4, 136.1, 140.5,
141.5, 147.1, 193.5 ppm.
1ꢀPhenylꢀ3ꢀ(thiophenꢀ2ꢀyl)propaneꢀ1,2ꢀdione (3ia): Eluted with EA/PE = 1/5. A light
brown solid for enol/ketone mixture, as well as a light brown solid for enol form
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recrystallized from PE. 37.0 mg, 64% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ =
6.74 (s, 1H), 7.09ꢀ7.11 (m, 1H), 7.35 (d, J = 3.6 Hz, 1H), 7.38 (s, 1H), 7.49ꢀ7.53 (m, 3H),
7.59ꢀ7.63 (m, 1H), 7.71ꢀ7.73 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 113.8,
127.6, 128.6, 129.1, 130.1, 130.6, 132.3, 136.0, 137.3, 145.1, 192.1 ppm.
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1ꢀPhenylꢀ3ꢀ(thiophenꢀ3ꢀyl)propaneꢀ1,2ꢀdione (3ja): Eluted with EA/PE = 1/5. Yellow
oil for enol/ketone mixture, and a milky white solid for enol form recrystallized from PE.
35.0 mg, 61% yield. Enol form. M.p.: 90ꢀ92 ºC. 1H NMR (400 MHz, CDCl3): δ = 6.48 (s,
1H), 7.28 (s, 1H), 7.32ꢀ7.34 (m, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H),
7.60 (t, J = 7.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.88 (s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 113.9, 125.6, 128.0, 128.6, 129.1, 129.2, 132.2, 135.4, 136.1, 146.2, 193.2
ppm.
1ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀphenylpropaneꢀ1,2ꢀdione (3ab):20 Eluted with EA/PE = 1/5.
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Yellow oil, 37.0 mg, 58% yield. Enol/ ketone = 0.5:1. H NMR (400 MHz, CDCl3): δ =
3.86 (s, 3H, ketone form), 3.91 (s, 1.5H, enol form), 4.18 (s, 2H, ketone form), 6.40 (s,
0.5H, enol form), 6.90 (d, J = 8.8 Hz, 2H, ketone form), 7.00 (d, J = 8.4 Hz, 1H, enol
form), 7.25ꢀ7.27 (m, 2+1H), 7.30ꢀ7.34 (m, 2H+0.5H), 7.38ꢀ7.41 (m, 1+0.5H), 7.78 (d, J =
8.8 Hz, 1H, enol form), 7.83 (d, J = 8.0 Hz, 1H, enol form), 7.89 (d, J = 8.8 Hz, 2H,
ketone form) ppm. 13C NMR (100 MHz, CDCl3): δ = 45.7, 55.68, 55.73, 113.9, 114.3,
118.5, 125.2, 127.5, 128.3, 128.7, 129.0, 130.0, 130.4, 131.0, 131.7, 132.1, 132.9, 134.5,
147.0, 163.2, 164.9, 190.6, 192.3, 199.9 ppm.
1ꢀ(3ꢀMethoxyphenyl)ꢀ3ꢀphenylpropaneꢀ1,2ꢀdione (3ac): Eluted with EA/PE = 1/5.
1
Yellow oil, 48.0 mg, 76% yield. Enol/ ketone = 2:1. H NMR (400 MHz, CDCl3): δ =
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3.81 (s, 3H, ketone form), 3.87 (s, 6H, enol form), 4.19 (s, 2H, ketone form), 6.44 (s, 2H,
enol form), 7.13ꢀ7.16 (m, 4H), 7.24ꢀ7.29 (m, 3H), 7.30ꢀ7.35 (m, 8H), 7.38ꢀ7.44 (m, 10H),
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55.62, 113.5, 114.0, 118.4, 119.6, 121.7, 121.8, 123.4, 127.6, 128.7, 129.0, 129.1, 129.6,
129.9, 130.0, 130.6, 131.8, 133.4, 134.3, 137.3, 146.9, 159.6, 159.9, 192.2, 193.4, 199.4
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1ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀphenylpropaneꢀ1,2ꢀdione (3ae): Eluted with EA/PE =
1/5. Yellow oil for enol/ketone mixture and a light yellow solid for ketone form
recrystallized from PE. 30.0 mg, 45% yield. Ketone form. 1H NMR (400 MHz, CDCl3): δ
= 4.16 (s, 2H), 6.05 (s, 2H), 6.81 (d, J = 8.4 Hz, 1H), 7.24ꢀ7.26 (m, 3H), 7.30ꢀ7.34 (m,
13
2H), 7.39 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H) ppm. C NMR (100 MHz, CDCl3): δ = 44.8,
101.3, 107.4, 108.0, 125.9, 126.6, 127.2, 128.0, 129.0, 131.0, 147.5, 152.4, 189.4, 198.7
ppm.
1ꢀ(4ꢀBromophenyl)ꢀ3ꢀphenylpropaneꢀ1,2ꢀdione (3af): Eluted with EA/PE = 1/10.
Yellow oil for enol/ketone mixture and a light yellow solid for enol form recrystallized
from PE. 65.0 mg, 86% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 6.34 (s, 1H),
7.31ꢀ7.35 (m, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz,
2H), 7.82 (d, J = 7.2 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 119.9, 127.2, 128.8,
129.2, 130.6, 130.8, 131.9, 134.1, 134.8, 146.8, 192.6 ppm.
1ꢀ(4ꢀFluorophenyl)ꢀ3ꢀphenylpropaneꢀ1,2ꢀdione (3ag): Eluted with EA/PE = 1/10.
Yellow oil for enol/ketone mixture and a white solid for enol form recrystallized from PE.
42.5 mg, 70% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 6.36 (s, 1H), 7.20 (t, J =
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8.4 Hz, 2H), 7.31ꢀ7.34 (m, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.76ꢀ7.83 (m, 4H) ppm. 13C
NMR (100 MHz, CDCl3):, δ = 115.8 (d, J = 21.8 Hz), 119.6, 128.8, 129.1, 130.5, 131.8 (d,
J = 8.9 Hz), 132.2 (d, J = 3.2 Hz), 134.2, 146.9, 165.3 (d, J = 252.4 Hz), 192.3 ppm.
3ꢀPhenylꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)propaneꢀ1,2ꢀdione (3ah): Eluted with EA/PE =
1/10. Yellow oil for enol/ketone mixture and a white solid for enol form recrystallized
from PE. 46.5 mg, 64% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 6.32 (s, 1H),
7.30 (s, 1H), 7.33ꢀ7.39 (m, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H),
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7.82ꢀ7.84 (m, 4H) ppm. C NMR (100 MHz, CDCl3): δ = 120.7, 125.6 (q, J = 3.7 Hz),
128.8, 129.4, 129.5, 130.7, 133.9, 139.4, 146.8, 192.6 ppm.
1ꢀ(Naphthalenꢀ2ꢀyl)ꢀ3ꢀphenylpropaneꢀ1,2ꢀdione (3ai): Eluted with EA/PE = 1/5.
Yellow oil for enol/ketone mixture and a light yellow solid for enol form recrystallized
from PE. 55.0 mg, 81% yield. Enol form. M.p.: 95ꢀ98 ºC. 1H NMR (400 MHz, CDCl3): δ
= 6.49 (s, 1H), 7.33ꢀ7.35 (m, 1H), 7.39ꢀ7.45 (m, 3H), 7.60ꢀ7.64 (m, 2H), 7.80ꢀ7.85 (m,
3H), 7.93ꢀ7.98 (m, 3H), 8.28 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 119.8, 125.4,
127.2, 128.0, 128.4, 128.6, 128.8, 129.0, 129.3, 130.3, 130.6, 132.3, 133.3, 134.3, 135.1,
147.2, 193.6 ppm.
3ꢀPhenylꢀ1ꢀ(thiophenꢀ2ꢀyl)propaneꢀ1,2ꢀdione (3aj): Eluted with EA/PE = 1/5. Yellow
1
oil. 51.5 mg, 90% yield. Enol/ketone = 0.25:1. H NMR (400 MHz, CDCl3):δ = 4.23 (s,
2H, ketone form), 6.77 (s, 0.25H, enol form), 7.12ꢀ7.15 (m, 1H, ketone form), 7.18ꢀ7.20
(m, 0.25H, enol form), 7.25 ꢀ7.28 (m, 2H+0.5H), 7.31ꢀ7.35 (m, 2H+0.5H), 7.41 (t, J = 7.7
HZ, 1H, ketone form) 7.71 (dd, J = 5.2 Hz, 1.2 Hz, 0.25H, enol form), 7.77 (dd, J = 4.8
Hz, 1,2 Hz, 1H, ketone form), 7.84 (dd, J = 3.6 Hz, 0.8 Hz, 0.25H, enol form), 7.86 (d, J
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= 8.0 Hz, 0.5H, enol form), 8.05 (dd, J = 3.6 Hz, 0.8 Hz, 1H, ketone form) ppm. 13C
NMR (100 MHz, CDCl3): δ = 44.2, 117.3, 127.4, 128.0, 128.72, 128.74, 128.87, 128.91,
130.0, 130.5, 132.4, 133.7, 133.9, 134.3, 137.4, 137.6, 137.7, 139.3, 146.8, 181.0, 183.9,
197.5 ppm.
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1ꢀ(Furanꢀ2ꢀyl)ꢀ3ꢀphenylpropaneꢀ1,2ꢀdione (3ak): Eluted with EA/PE = 1/5. A yellow
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solid for enol/ketone mixture. 46.0 mg, 86% yield. Enol/ketone = 0.75:1. H NMR (400
MHz, CDCl3): δ = 4.23 (s, 2H, ketone form), 6.58 (d, J = 2.0 Hz, 1H, ketone form), 6.63
(d, J = 1.6 Hz, 0.75H, enol form), 7.16 (s, 0.75H, enol form), 7.25ꢀ7.29 (m, 2+0.75H),
7.32ꢀ7.35 (m, 2H+0.75H), 7.40ꢀ7.44 (m, 1+1.5H), 7.48 (s, 0.75H, enol form), 7.63 (d, J =
3.6 HZ, 1H, ketone form), 7.73 (brs, 1+0.75H), 7.91 (d, J = 7.6 Hz, 1.5H, enol form) ppm.
13C NMR (100 MHz, CDCl3): δ = 44.0, 112.5, 113.0, 117.1, 120.5, 125.1, 127.3, 128.6,
128.7, 128.8, 129.9, 130.7, 132.1, 134.4, 145.9, 147.0, 148.8, 149.4, 150.7, 175.9, 177.4,
196.8 ppm.
1,3ꢀBis(4ꢀmethoxyphenyl)propaneꢀ1,2ꢀdione (3db):20 Eluted with EA/PE = 1/4. Yellow
oil for enol/ketone mixture and a light yellow solid for enol form recrystalled from
PE/DCM. 37.0 mg, 52% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3H),
3.90 (s, 3H), 6.38 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H),
7.75 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ =
55.5, 55.7, 113.8, 114.2, 118.9, 127.3, 128.7, 131.5, 132.1, 145.9, 160.0, 163.0, 192.1
ppm.
1,3ꢀBis(4ꢀbromophenyl)propaneꢀ1,2ꢀdione (3ef): Eluted with EA/PE = 1/10. A light
yellow solid, 60.0 mg, 63% yield. Enol/ketone = 1.6:1. 1H NMR (400 MHz, CDCl3): δ =
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4.15 (s, 2H, ketone form), 6.27 (s, 1.6H, enol form), 7.13 (d, J = 8.0 Hz, 2H, ketone form),
7.35 (s, 1.6H, enol form), 7.46 (d, J = 8.4 Hz, 2H, ketone form), 7.52 (d, J = 8.4 Hz, 3.2H,
enol form), 7.59ꢀ7.61 (m, 2H+3.2H), 7.65ꢀ7.69 (m, 6.4H, enol form), 7.80 (d, J = 8.4 Hz,
2H, ketone form) ppm. 13C NMR (100 MHz, CDCl3): δ = 44.7 (ketone form), 110.2,
118.3 (enol form), 121.9, 123.3, 127.4, 130.6, 130.7, 130.8, 130.9, 131.7, 131.8, 131.95,
131.98, 132.2, 132.4, 133.0, 134.6, 147.1, 190.1, 192.3, 198.0 ppm.
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1ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(pꢀtolyl)propaneꢀ1,2ꢀdione (3bf): Eluted with EA/PE = 1/10.
Yellow oil for enol/ketone mixture and a white solid for enol form recrystallized from
PE/DCM. 55.0 mg, 70% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3H),
6.32 (s, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.63 (d, J =
8.0 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7, 120.2,
127.0, 129.6, 130.6, 130.7, 131.3, 131.8, 134.9, 139.6, 146.4, 192.4 ppm.
1,3ꢀDi(thiophenꢀ2ꢀyl)propaneꢀ1,2ꢀdione (3ij): Eluted with EA/PE = 1/4. A brown solid
for enol/ketone mixture as well as a brown solid for enol form recrystallized from
PE/DCM. 42.0 mg, 71% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 7.11ꢀ7.13 (m,
2H), 7.20 (t, J = 4.2 Hz, 1H), 7.36 (s, 1H), 7.42 (d, J = 3.2 Hz, 1H), 7.52 (d, J = 5.2 Hz,
1H), 7.72 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 3.6 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 111.7, 127.6, 128.1, 129.9, 130.6, 133.4, 133.5, 137.3, 139.2, 144.9, 182.4 ppm.
3ꢀ(4ꢀFluorophenyl)ꢀ1ꢀ(thiophenꢀ2ꢀyl)propaneꢀ1,2ꢀdione (3fj): Eluted with EA/PE = 1/5.
Yellow oil for enol/ketone mixture and a yellow solid for ketone form recrystallized from
PE/DCM. 49.5 mg, 80% yield. Enol form. 1H NMR (400 MHz, CDCl3): δ = 4.21 (s, 2H),
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7.05 (t, J = 8.8 Hz, 2H), 7.17 (t, J = 4.4 Hz, 1H), 7.22ꢀ7.25 (m, 2H), 7.80 (d, J = 4.8 Hz,
1H), 8.07 (d, J = 4.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 43.4, 115.9 (d, J =
21.4 Hz), 128.1 (d, J = 3.2 Hz), 128.8, 131.6 (d, J = 8.0 Hz), 137.5, 137.6, 138.0, 162.3 (d,
J = 244.6 Hz), 180.8, 197.3 ppm.
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General Procedure for the Preparation of 1,2ꢀDiketones 4: A flameꢀdried schlenck tube
with a magnetic stirring bar was charged with methyl αꢀoxocarboxylate 1 (0.25 mmol),
αꢀbromoketone 2 (0.325 mmol) and K2CO3 (0.50 mmol). The system was evacuated and
back filled with N2 twice, and NMP/MeOH/hydroxyacetone (1.0 mL/100 ꢁL/25 ꢁL) was
injected. The reaction was allowed to stir at room temperature for 4 h. Then 300 ꢁL of 4
N aq. KOH solution was added over a period of 0.5 h and the reaction continued for
another 1.5 h. The reaction mixture was neutralized to pH 7 with 2 N HCl and extracted
with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4. After
the volatile solvent was evaporated, the residue was purified by column chromatography
on silica gel (100ꢀ200 mesh) using EA/PE as the eluent to afford the corresponding
1,3ꢀdiketone 4.
1,3ꢀDiphenylpropaneꢀ1,3ꢀdione (4aa):24 Eluted with EA/PE = 1/10. A white solid, 43.5
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mg, 78% yield. H NMR (400 MHz, CDCl3): δ = 6.87 (s, 1H), 7.50 (t, J = 7.2 Hz, 4H),
7.56 (t, J = 7.2 Hz, 2H), 8.00 (d, J = 7.6 Hz, 4H), 16.88 (s, 1H) ppm.
1ꢀPhenylꢀ3ꢀ(pꢀtolyl)propaneꢀ1,3ꢀdione (4ba):35 Eluted with EA/PE = 1/10. A white
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solid, 27.0 mg, 45% yield. H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3H), 6.84 (s, 1H),
7.30 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.90 (d, J = 8.0
13
Hz, 2H), 7.99 (d, J = 7.6 Hz, 2H), 16.93 (s, 1H) ppm. C NMR (100 MHz, CDCl3): δ =
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21.8, 93.0, 127.2, 127.4, 128.8, 129.5, 132.4, 133.0, 135.7, 143.4, 185.3, 186.2 ppm.
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1ꢀPhenylꢀ3ꢀ(mꢀtolyl)propaneꢀ1,3ꢀdione (4ca):35 Eluted with EA/PE = 1/10. Light brown
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oil, 37.5 mg, 63% yield. H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3H), 6.86 (s, 1H),
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7.37ꢀ7.39 (m, 2H), 7.48ꢀ7.52 (m, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.78ꢀ7.81 (m, 2H), 8.00 (d,
J = 7.6 Hz, 2H), 16.90 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 93.3, 124.5,
127.3, 127.9, 128.7, 128.8, 132.6, 133.4, 135.66, 135.72, 138.6, 185.8, 186.2 ppm.
1ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4da and 4ab):24 Eluted with EA/PE
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= 1/5. A white solid, 4da, 25.5 mg, 40% yield. 4ab, 32.0 mg, 50% yield. H NMR (400
MHz, CDCl3): δ = 3.89 (s, 3H), 6.80 (s, 1H), 6.99 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 7.4 Hz,
2H), 7.55 (t, J = 7.2 Hz, 1H), 7.97ꢀ8.00 (m, 4H), 17.00 (s, 1H) ppm.
1ꢀ(4ꢀBromophenyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ea and 4af):24 Eluted with EA/PE =
1
1/10. A white solid, 4ea, 53.0 mg, 70% yield. 4af, 51.5 mg, 68% yield. H NMR (400
MHz, CDCl3): δ = 6.82 (s, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.63 (d,
J = 8.4 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 7.6 Hz, 2H), 16.82 (s, 1H) ppm.
1ꢀ(4ꢀFluorophenyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4fa and 4ag):35 Eluted with EA/PE =
1
1/10. A white solid, 4fa, 37.5 mg, 70% yield. 4ag, 35.5 mg, 66% yield. H NMR (400
MHz, CDCl3): δ = 6.80 (s, 1H), 7.17 (t, J = 8.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.56 (t,
J = 7.4 Hz, 1H), 7.97ꢀ8.03 (m, 4H), 16.86 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ =
93.0, 116.0 (d, J = 21.8 Hz), 127.3, 128.9, 129.8 (d, J = 9.1 Hz), 132.1 (d, J = 3,1 Hz),
132.7, 135.4, 165.6 (d, J = 252.3 Hz), 185.3 ppm.
1ꢀ(Naphthalenꢀ2ꢀyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ga and 4ai):36 Eluted with EA/PE =
1
1/5. A white solid, 4ga, 46.5 mg, 68% yield; 4ai, 48.0 mg, 70% yield. H NMR (400
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MHz, CDCl3): δ = 7.02 (s, 1H), 7.50ꢀ7.62 (m, 5H), 7.88ꢀ8.05 (m, 6H), 8.55 (s, 1H), 16.98
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(s, 1H) ppm. C NMR (100 MHz, CDCl3): δ = 93.6, 123.4, 127.0, 127.4, 127.9, 128.3,
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128.5, 128.6, 128.9, 129.5, 132.6, 132.88, 132.90, 135.5, 135.7, 185.7, 185.9 ppm.
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1ꢀ[(1,1'ꢀBiphenyl)ꢀ4ꢀyl]ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ha):36 Eluted with EA/PE = 1/5.
A milky white solid, 52.5 mg, 70% yield. 1H NMR (400 MHz, CDCl3): δ = 6.91 (s, 1H),
7.41 (t, J = 7.4 Hz, 1H), 7.50 (q, J = 7.6 Hz, 4H), 7.57 (t, J = 7.2 Hz, 1H), 7.66 (d, J = 7.2
Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 6.8 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H),
16.93 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 93.3, 127.3, 127.4, 127.5, 127.9,
128.3, 128.8, 129.1, 132.6, 134.4, 135.8, 140.1, 145.4, 185.4, 185.9 ppm.
1ꢀPhenylꢀ3ꢀ(thiophenꢀ2ꢀyl)propaneꢀ1,3ꢀdione (4ia and 4aj):24 Eluted with EA/PE = 1/5.
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A yellow solid, 4ia, 35.0 mg, 61% yield; 4aj, 46.0 mg, 80% yield. H NMR (400 MHz,
CDCl3): δ = 6.69 (s, 1H), 7.18 (t, J = 4.0 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2
Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H),
16.31 (s, 1H) ppm.
1ꢀPhenylꢀ3ꢀ(thiophenꢀ3ꢀyl)propaneꢀ1,3ꢀdione (4ja): Eluted with EA/PE = 1/5. A
yellow solid, 35.0 mg, 61% yield. 1H NMR (400 MHz, CDCl3): δ = 6.68 (s, 1H), 7.39 (m,
1H), 7.49 (t, J = 7.4 Hz, 2H), 7.54ꢀ7.58 (m, 2H), 7.96 (d, J = 7.6 Hz, 2H), 8.12 (s, 1H),
16.61 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 93.9, 126.1, 126.8, 127.2, 128.8,
130.1, 132.5, 135.5, 139.6, 181.3, 185.1 ppm. HRMS (ESI+): calcd for C13H10O2SNa
[M+Na]+ 253.0299, found 253.0302.
1ꢀCyclohexylꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ka):37 Eluted with EA/PE = 1/10. Light
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brown oil, 38.5 mg, 67% yield. H NMR (400 MHz, CDCl3): δ = 1.22ꢀ1.95 (m, 10H),
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2.32 (tt, J = 10.8 Hz, 3.2 Hz, 1H), 6.18 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2
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Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H), 16.31 (s, 1H) ppm. C NMR (100 MHz, CDCl3): δ =
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25.9, 26.0, 29.8, 47.5, 94.6, 127.1, 128.7, 132.3, 135.4, 184.4, 200.0 ppm.
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1ꢀ(3ꢀMethoxyphenyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ac):24 Eluted with EA/PE = 1/5. A
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white solid, 41.0 mg, 65% yield. H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3H), 6.85 (s,
1H), 7.10 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.48ꢀ7.58 (m, 5H), 7.99 (d, J = 7.6
Hz, 2H), 16.86 (s, 1H) ppm.
1ꢀ(2ꢀMethoxyphenyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ad):24 Eluted with EA/PE = 1/5. A
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white solid, 35.5 mg, 56% yield. Enol/ ketone = 91:9. H NMR (400 MHz, CDCl3): δ =
3.97 (s, 3H), 7.01 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.46ꢀ7.56 (m,
4H), 7.93ꢀ7.98 (m, 3H), 16.85 (s, 1H) ppm.
1ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ae):24 Eluted with EA/PE =
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1/5. A white solid, 42.0 mg, 63% yield. H NMR (400 MHz, CDCl3): δ = 6.07 (s, 2H),
6.75 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 7.48ꢀ7.50 (m, 3H), 7.55 (t, J = 7.2 Hz, 1H), 7.61 (d,
J = 8.4 Hz, 1H), 7.97 (d, J = 7.6 Hz, 2H), 16.92 (s, 1H) ppm.
1ꢀPhenylꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)propaneꢀ1,3ꢀdione (4ah):24 Eluted with EA/PE
= 1/10. A white solid, 44.5 mg, 60% yield. 1H NMR (400 MHz, CDCl3): δ = 6.88 (s, 1H),
7.51 (t, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 7.6
Hz, 2H), 8.09 (d, J = 8.0 Hz, 2H), 16.75 (s, 1H) ppm.
1ꢀ(Furanꢀ2ꢀyl)ꢀ3ꢀphenylpropaneꢀ1,3ꢀdione (4ak):38 Eluted with EA/PE = 1/5. A light
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brown solid, 40.0 mg, 75% yield. H NMR (400 MHz, CDCl3): δ = 6.57ꢀ6.58 (m, 1H),
6.76 (s, 1H), 7.23ꢀ7.24 (m, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.60 (s,
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1H), 7.95 (d, J = 7.6 Hz, 2H), 16.19 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 92.8,
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112.8, 115.9, 127.1, 128.8, 132.5, 134.8, 146.2, 151.1, 177.8, 182.5 ppm.
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(E)ꢀ1,5ꢀDiphenylpentꢀ4ꢀeneꢀ1,3ꢀdione (4al):24 Eluted with EA/PE = 1/10. A bright
yellow solid, 39.5 mg, 63% yield. 1H NMR (400 MHz, CDCl3): δ = 6.36 (s, 1H), 6.66 (d,
J = 16.0 Hz, 1H), 7.38ꢀ7.43 (m, 3 H), 7.49 (t, J = 7.6 Hz, 2H), 7.54ꢀ7.58 (m, 3H), 7.70 (d,
J = 16.0 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 16.16 (s, 1H) ppm.
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1,3ꢀBis(4ꢀbromophenyl)propaneꢀ1,3ꢀdione (4ef):24 Eluted with EA/PE = 1/10. A white
solid, 57.0 mg, 60% yield. 1H NMR (400 MHz, CDCl3): δ = 6.77 (s, 1H), 7.63 (d, J = 8.4
Hz, 4H), 7.85 (d, J = 8.4 Hz, 4H), 16.75 (s, 1H) ppm.
1,3ꢀBis(4ꢀmethoxyphenyl)propaneꢀ1,3ꢀdione (4db):24 Eluted with EA/PE = 1/4. A
white solid, 30 mg, 42% yield. 1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 6H), 6.74 (s, 1H),
6.98 (d, J = 8.8 Hz, 4H), 7.96 (d, J = 8.4 Hz, 4H), 17.14 (s, 1H) ppm.
1ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(pꢀtolyl)propaneꢀ1,3ꢀdione (4bf):39 Eluted with EA/PE = 1/10. A
1
white solid, 43.5 mg, 55% yield. H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3H), 6.79 (s,
1H), 7.29 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.88 (d, J
= 8.0 Hz, 2H), 16.88 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.8, 92.8, 127.3,
127.4, 128.7, 129.6, 132.1, 132.7, 134.6, 143.7, 184.1, 186.3 ppm.
1,3ꢀDi(thiophenꢀ2ꢀyl)propaneꢀ1,3ꢀdione (4ij):24 Eluted with EA/PE = 1/4. A bright
yellow solid, 41.0 mg, 70% yield. Enol/ ketone = 82:18. 1H NMR (400 MHz, CDCl3): δ =
6.54 (s, 1H), 7.16 (br, 2H), 7.61 (d, J = 4.4 Hz, 2H), 7.77 (br, 2H), 16.20 (s, 1H) ppm.
1ꢀ(4ꢀFluorophenyl)ꢀ3ꢀ(thiophenꢀ2ꢀyl)propaneꢀ1,3ꢀdione (4fj): Eluted with EA/PE = 1/5.
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A milky white solid, 53.0 mg, 85% yield. M.p.: 100ꢀ102 ºC. 1H NMR (400 MHz, CDCl3):
δ = 6.62 (s, 1H), 7.13ꢀ7.17 (m, 3H), 7.63 (d, J = 4.8 Hz, 1H), 7.79 (t, J = 3.6 Hz, 1H),
7.93ꢀ7.95 (m, 2H), 16.36 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 92.9, 116.0 (d, J
= 21.8 Hz), 128.5, 129.4 (d, J = 9.1 Hz), 130.5, 130.9 (d, J = 3.1 Hz), 132.8, 142.0, 165.4
(d, J = 252.2 Hz), 180.2, 182.7 ppm. HRMS (ESI+): calcd for C13H9FO2SNa [M+Na]+
271.0205, found 271.0204.
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Isolation of Coupling Intermediate 5aa (method a): A flameꢀdried schlenck tube with a
magnetic stirring bar was charged with methyl 2ꢀoxoꢀ2ꢀphenylacetate 1a (0.25 mmol),
2ꢀbromoꢀ1ꢀphenylethanone 2a (0.325 mmol), and K2CO3 (0.50 mmol) then the system
was evacuated twice and then back filled with N2 and NMP (1.0 mL) was added. The
reaction was allowed to stir at room temperature for 24 h. Water was then added and the
mixture was extracted with ethyl acetate. The combined organic phase was dried over
anhydrous Na2SO4. After the volatile solvent was evaporated, the residue was purified by
column chromatography on silica gel (100ꢀ200 mesh) using EA/PE (up to 1/3) as the
eluent to afford transꢀ5aa in 81% yield and cisꢀ5aa in 16% yield with a trans/cis ratio of
5.1:1.
Isolation of Coupling Intermediate 5aa (method b): A flameꢀdried schlenck tube with a
magnetic stirring bar was charged with methyl 2ꢀoxoꢀ2ꢀphenylacetate 1a (0.25 mmol),
2ꢀbromoꢀ1ꢀphenylethanone 2 (0.325 mmol), and K2CO3 (0.50 mmol) then the system was
evacuated twice and then back filled with N2 and 1,4ꢀdioxane (1.0 mL) was added. The
o
reaction was allowed to stir at 80 C for 4 h. Water was then added and the mixture was
extracted with ethyl acetate. The combined organic phase was dried over anhydrous
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Na2SO4. After the volatile solvent was evaporated, the residue was purified by column
chromatography on silica gel (100ꢀ200 mesh) using EA/PE (up to 1/3) as the eluent to
afford cisꢀ5aa in 80% yield and a trace amount of transꢀ5aa.
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Methyl 3ꢀbenzoylꢀ2ꢀphenyloxiraneꢀ2ꢀcarboxylate (transꢀ5aa): A white solid. M.p.:
40ꢀ44 ºC. 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3H), 4.81 (s, 1H), 7.20ꢀ7.23 (m, 3H),
7.38ꢀ7.45 (m, 4H), 7.54ꢀ7.58 (m, 1H), 7.84ꢀ7.87 (m, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 53.6, 63.2, 63.3, 127.8, 128.1, 128.3, 128.9, 129.0, 129.9, 134.1, 135.1, 168.4,
190.5 ppm. HRMS (ESI+): calcd for C17H14O4Na [M+Na]+ 305.0790, found 305.0795.
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Methyl 3ꢀbenzoylꢀ2ꢀphenyloxiraneꢀ2ꢀcarboxylate (cisꢀ5aa):40 Colorless oil. H NMR
(400 MHz, CDCl3): δ = 3.70 (s, 3H), 4.31 (s, 1H), 7.43ꢀ7.46 (m, 3H), 7.51 (t, J = 7.6 Hz,
2H), 7.61ꢀ7.65 (m, 3H), 8.01 (d, J = 7.6 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ =
53.0, 64.4, 65.3, 126.3, 128.6, 128.96, 129.02, 129.6, 133.4, 134.3, 135.5, 166.6, 191.3
ppm. HRMS (ESI+): calcd for C17H14O4Na [M+Na]+ 305.0790, found 305.0782.
Isolation of 6aa·NMP: A flameꢀdried schlenck tube with a magnetic stirring bar was
charged with methyl 3ꢀbenzoylꢀ2ꢀphenyloxiraneꢀ2ꢀcarboxylate (transꢀ5aa, 0.25 mmol)
and methanol. Then 200 ꢁL of 4 N aq. KOH solution was added over a period of 15min
and the reaction continued for another 15 min at room temperature. NMP (1.25 mmol,
120 ꢁL) was added. The mixture was neutralized to pH 7 with 2 N HCl and extracted with
ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4. After the
volatile solvent was evaporated, the residue was dissolved in a minimum amount of ethyl
acetate. A white solid was precipitated out by the addition of petroleum ether as transꢀ
and cisꢀ6aa·NMP in 97% yield. The structure of (transꢀ6aa)·NMP was determined by the
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3ꢀBenzoylꢀ2ꢀphenyloxiraneꢀ2ꢀcarboxylic acid·NMP (6aa·NMP): A white solid. 89 mg,
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97% yield. trans/cis = 2.5:1. H NMR (400 MHz, CDCl3): δ = 2.02 (q, J = 7.6 Hz,
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2+0.8H), 2.45 (t, J = 8.0 Hz, 2+0.8H), 2.85 (s, 3+1.2H), 3.40 (t, J = 7.2 Hz, 2+0.8H), 4.36
(s, 1H, trans), 4.84 (s, 0.4H, cis), 6.35 (brs, 1+0.4H), 7.19ꢀ7.21 (m, 3H, trans), 7.41ꢀ7.45
(m, 4+1.2H), 7.50 (t, J = 7.8 Hz, 0.8H, cis), 7.56 (t, J = 7.4 Hz, 1H, trans), 7.62 (t, J = 7.2
Hz, 0.4H, cis), 7.69ꢀ7.70 (m, 0.8H, cis), 7.88 (d, J = 7.6 Hz, 2H, trans), 8.00 (d, J = 7.6
Hz, 0.8H, cis) ppm.
OneꢀPot Synthesis of α,βꢀEpoxyꢀγꢀButyrolactones 7: A flameꢀdried schlenck tube with a
magnetic stirring bar was charged with methyl 2ꢀoxoꢀ2ꢀphenylacetate 1a (0.25 mmol),
2ꢀbromoꢀ1ꢀphenylethanone 2a (0.325 mmol), K2CO3 (0.50 mmol) and 1,4ꢀdioxane (1.0
mL). The reaction was stirred at 80 ºC for 4 h in an oil bath under an N2 atmosphere.
After cooled down to room temperature, EtOH (1 mL) and NaBH4 (0.075 mmol, 3 mg)
were added under an N2 atmosphere. The resulting mixture was stirred at room
temperature for 30 min. After the volatile solvent was evaporated, the residue was
purified by column chromatography on silica gel (100ꢀ200 mesh) using EA/PE (up to
1/10)
as
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corresponding
1,4ꢀdiphenylꢀ3,6ꢀdioxabicyclo[3.1.0]hexanꢀ2ꢀone 7 in 70% yield.
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1,4ꢀDiphenylꢀ3,6ꢀdioxabicyclo[3.1.0]hexanꢀ2ꢀone (7):32 Colorless oil. H NMR (400
MHz, CDCl3): δ = 4.22 (s, 1H), 5.60 (s, 1H), 7.34 (d, J = 6.8 Hz, 2H), 7.43ꢀ7.45 (m, 6H),
7.56ꢀ7.57 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 59.4, 67.7, 79.3, 126.2, 127.1,
128.3, 128.8, 129.5, 129.6, 129.8, 134.7, 170.4 ppm. HRMS (ESI+): calcd for C16H12O3Na
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