Nucleophilic and electrophilic double aroylation of chalcones with benzils promoted by the dimsyl anion as a route to all carbon tetrasubstituted olefins

Article abstract of DOI:10.1021/jo502582e

Dimsyl anion promoted the polarity reversal of benzils in a Stetter-like reaction with chalcones to give 2-benzoyl-1,4-diones (double aroylation products), which, in turn, were converted into the corresponding tetrasubstituted olefins via aerobic oxidative dehydrogenation catalyzed by Cu(OAc)₂.

Full text of DOI:10.1021/jo502582e

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Note
Nucleophilic and electrophilic double aroylation of chalcones with benzils
promoted by the dimsyl anion as a route to all carbon tetrasubstituted olefins
Alessandro Massi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502582e • Publication Date (Web): 26 Dec 2014
Downloaded from http://pubs.acs.org on December 30, 2014
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Nucleophilic and electrophilic double aroylation of
chalcones with benzils promoted by the dimsyl anion as a
route to all carbon tetrasubstituted olefins
Journal: The Journal of Organic Chemistry
Manuscript ID: jo-2014-02582e.R2
Manuscript Type: Note
Date Submitted by the Author: 26-Dec-2014
Complete List of Authors: Ragno, Daniele; Università di Ferrara, Farmaceutical and Chemistry
Sciences
Bortolini, Olga; University of Ferrara, Department of Chemistry; University
of Ferrara, Chemistry and Pharmaceutical Science
Fantin, Giancarlo; University of Ferrara, Chemistry and Pharmaceutical
Science
Fogagnolo, Marco; University of Ferrara, Chemistry and Pharmaceutical
Science
Giovannini, Pier Paolo; University of Ferrara, Chemistry and Pharmaceutical
Science
Massi, Alessandro; University of Ferrara, Department of Chemistryand
Pharmaceutical Sciences
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Nucleophilic and electrophilic double aroylation of chalcones with benzils
promoted by the dimsyl anion as a route to all carbon tetrasubstituted olefins
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Daniele Ragno, Olga Bortolini,* Giancarlo Fantin, Marco Fogagnolo, Pier Paolo Giovannini, and
Alessandro Massi*
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di Mortara
17-27, I-44121 Ferrara (Italy)
olga.bortolini@unife.it; alessandro.massi@unife.it
R'
O
t-BuOK
O
R'
O
R
O
O
(1 equiv.)
Ar
Ar
Ar
+
Ar
Ar
Ar
DMSO, r.t.
O
O
R
O
R'
1. t-BuOK (1 equiv.)
DMSO, r.t
one-pot
2. Cu(OAc)2.H2O (10 mol%)
DMSO, air, 80 °C
two-step
O
R
Abstract: Dimsyl anion promoted the polarity reversal of benzils in a Stetterꢀlike reaction with
chalcones to give 2ꢀbenzoylꢀ1,4ꢀdiones (double aroylation products), which in turn were converted
into the corresponding tetrasubstituted olefins via aerobic oxidative dehydrogenation catalyzed by
Cu(OAc)2.
Atomꢀeconomical reactions represent a powerful tool in synthetic organic chemistry and a means to
mitigate its negative effects on the environment.1 In this context, the formation of multiple bonds in
a single organocatalytic transformation is of great significance to readily access diverse structural
motifs displaying all portions of the starting materials.2 Biꢀfunctional molecules constitute valuable
substrates for the design of organocatalytic domino sequences; nevertheless, the use of highly
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reactive αꢀdiketones has been rarely investigated in this type of approach,3 in which the double
carbonyl functionality of 1,2ꢀdiones exhibits electrophilic behavior at the carbonyl carbon and
nucleophilic character at the alpha position. A complementary mode of carbonyl reactivity is,
however, possible for this class of substrates; as demonstrated by our group, αꢀdiketones can be
rendered nucleophilic at carbonyl carbon (umpolung reactivity) through the catalysis of thiamine
diphosphate (ThDP)ꢀdependent enzymes4 and Nꢀheterocyclic carbenes (NHCs)5 in nucleophilic
acylations. Recently, we also discovered the capability of methylsulfinyl (dimsyl) carbanion A to
induce the polarity reversal of diaryl αꢀdiketones (benzils) in chemoselective crossꢀbenzoin
condensations with aldehydes.6 Dimsyl anion, generated by deprotonation of the DMSO solvent,
served as surrogate of hazardous cyanide ion promoting the formation of benzoylated benzoins in a
atomꢀeconomic fashion through sequential nucleophilic Cꢀ and electrophilic Oꢀaroylations (Scheme
1). As a logical extension of the study on the benzoin reaction, we reasoned that utility of dimsyl
anion catalysis could be further enhanced by conducting a double Cꢀaroylation process on activated
alkenes, thus providing a novel variant of the parent Stetter reaction (hydroacylation process).7 We
also envisaged that the resulting activated 1,4ꢀdicarbonyls could be further elaborated going back to
the alkene stage via a catalytic oxidative dehydrogenation step to produce all carbon tetrasubstituted
olefins from chalcones through a simple and effective oneꢀpot process (Scheme 1). On the other
hand, tetrasubstituted alkenes with conjugated systems are challenging synthetic targets8 with
unique structural and electronic features in material science9 as well as useful building blocks for
synthetic chemistry.10
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O
O
Ar'
Ar
Ar'
electrophilic
O-aroylation
(intramolecular)
nucleophilic
C-aroylation
(intermolecular)
Ar
electrophilic
C-aroylation
nucleophilic
C-aroylation
O
O
O
EWG
6
R'
R
7
8
9
CH3
H2C
S
A
A
O
A
Ar
O
oxidative
dehydrogenation
Ar
O
R
O
10
11
12
13
14
15
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O
O
EWG
Ar'
Ar'
R'
Ar
O
O
previous
work
EWG
Ar'
R'
this work
SCHEME 1. Double aroylation of aldehydes and activated alkenes with benzils promoted by the
dimsyl anion A.
The reaction of benzil 1a with chalcone 2a was initially investigated to verify the feasibility of the
project (Table 1). Reaction selectivity was a major issue to be addressed since formation of the
desired double Cꢀaroylation product 3aa could be accompanied by generation of byꢀproducts 4aa
and 5aa via competitive double C,Oꢀaroylation and hydroacylation pathways, respectively (vide
infra). Gratifyingly, under the conditions previously described for the generation of dimsyl anion A
(anhydrous DMSO, 30 mol% tꢀBuOK, r.t.), the reaction of equimolar 1a and 2a gave the expected
compound 3aa (34%, entry 1) with only trace amounts of the Stetter product 5aa and no evidence
of 4aa. While a mild heating (50 °C) of the reaction mixture had a negative effect on the reaction
output (entry 2), an increase of tꢀBuOK amount (100 mol%) improved the yield of 3aa (46%, entry
3), thus highlighting the importance of the excess of base to produce the necessary quantity of
dimsyl anion (pKa [DMSO] = 35.0; pKa [tꢀBuOK] = 32.2).11 In line with our previous findings, the
reaction output was strictly correlated to the strength of the base in DMSO, that is tꢀBuOK >
Cs2CO3 ≈ CsOH > DBU >> Et3N (entries 4ꢀ7). Optimal reaction conditions delivering 3aa in 75%
yield (entry 8) were finally established using an excess of benzil 1a (2 equiv.). For the sake of
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comparison, the catalytic activity of cyanide anion was also tested detecting the same reaction
4
5
6
selectivity and a comparable but appreciably higher yield of 3aa (83ꢀ82%, entries 10ꢀ11).
7
8
9
TABLE 1. Optimization of the model double Cꢀaroylation of chalcone 2a with benzil 1a.a
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Ph
O
O
O
Ph
Ph
Ph
3aa
O
Ph
O
Ph
O
Ph
(pre)catalyst / base
solvent, r.t., 16 h
O
Ph
+
Ph
O
Ph
O
Ph
Ph
O
4aa
Ph
H
O
1a
2a
Ph
5aa
Ph
(Pre)catalyst
Base
Yield
Entry
Solvent
(mol %)
(mol %)
(%)
34
28
46
24
32
35
ꢀ
1b
2b,c
3b
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
DMSO
DMSO
DMSO
ꢀ
tꢀBuOK (30)
tꢀBuOK (30)
ꢀ
ꢀ
tꢀBuOK (100)
DBU (100)
Cs2CO3 (100)
CsOH (100)
Et3N (100)
tꢀBuOK (100)
tꢀBuOK (100)
ꢀ
ꢀ
5
ꢀ
6d
ꢀ
ꢀ
7
8
ꢀ
75
32
83
82
15
ꢀ
9e
ꢀ
10
11
12
13
14
15
16
17
KCN (25)
TBACN (25)
B (20)
C (20)
D (20)
E (20)
F (20)
G (20)
ꢀ
DBU (50)
DBU (50)
DBU (50)
NEt3 (50)
DBU(50)
DBU (50)
ꢀ
ꢀ
28
25
aReaction conditions: benzil 1a (0.50 mmol), chalcone 2a (0.25 mmol),
b
c
and anhydrous solvent (1.0 mL). 2a: 0.50 mmol. Temperature: 50 °C.
dReaction performed in the presence of 4 Å MS. e2a: 1.00 mmol.
-
-
Me
F
F
BF4
Cl
+
N
+
N
+
N
N
-
I
N
Mes
N
F
N
N
N
N
F
D
F
Me
B
C
-
-
-
Cl
Cl
Cl
Me
Bn
+
+
N
+
Mes
Mes
Mes
Mes
N
N
N
OH
S
F
G
E
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In addition, commercially available NHC salts B-G were screened under suitable conditions
evaluating the effects of altering the solvent, temperature, and base. After some experimentation, it
was found that the sole triazolium salt BꢀDBU couple catalyzed the reaction in CH2Cl2 affording
3aa in modest yield (15%, entry 12). Indeed, the more hindered triazolium salts C-D (entries 13ꢀ14)
and thiazolium,12 imidazolium, and imidazolium preꢀcatalysts E-G (entries 15ꢀ17) proved to be
totally inactive, being the observed formation of 3aa in DMSO the result of a background activity
of the dimsyl anion.
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11
12
13
14
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The substrate scope of the disclosed double Cꢀaroylation reaction was initially examined with
benzils 1a-h and chalcones 2a-g displaying various substitution patterns under two sets of
conditions (Table 2). In general, the process promoted by the dimsyl anion (100 mol% tꢀBuOK,
DMSO; conditions 1) provided a safe and environmentally benign access to 2ꢀbenzoylꢀ1,4ꢀdiones 3
and 3’, albeit with slightly diminished yields (2ꢀ18%) compared to the same process catalyzed by
the toxic KCN (25 mol%, DMSO; conditions 2). Relative efficiencies of reactions between benzil
1a and chalcones 2a-g bearing electronꢀwithdrawing, ꢀneutral, and ꢀdonating groups indicated a
more pronounced effect of substituents on the benzoyl ring of chalcone, obtaining higher yields of 3
with electron poor aromatic rings (entries 1ꢀ7). Investigation on the electronic requirements for the
αꢀdiketone 1 showed the 2,2’ꢀpyridyl 1b with an electronꢀwithdrawing moiety as a highly reactive
substrate (entries 8ꢀ9); unexpectedly, the use of electronꢀdeficient 4,4’ꢀditrifluoromethylbenzil 1c
and 4,4’ꢀdifluorobenzil 1d led to a significant reduction of reaction efficiency (entries 10ꢀ11)
mainly because of the diketone selfꢀcondensation sideꢀreaction.13 Combination of the electronꢀrich
4,4’ꢀdimethylbenzil 1e and activated chalcone 2b rendered the corresponding product 3eb with
good conversion (entry 12).
The employment of unsymmetrical benzils 1f-h produced the two regioisomers 3 and 3’ in variable
isomeric ratios. The monoꢀsubstituted 2ꢀchloro benzil 1f exhibited the highest capability in
controlling the chemoselectivity (3:3’ cr) of the double Cꢀaroylation process as it reacted with
chalcone 2b yielding almost exclusively the isomer 3fb’ (5:95 cr; entry 13). This result implied that
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dimsyl/cyanide anion favorably added to the less hindered carbonyl carbon of 1f. Similarly, a
comparison of the reactivity of monoꢀsubstituted 4ꢀCl and 4ꢀOMe benzils 1g and 1h toward
chalcone 2a indicated the preferential attack of the catalyst to the diketone carbonyl carbon with
lower electron density (entries 14ꢀ15). A limitation of the dimsyl anionꢀbased methodology
appeared evident from the representative couplings of enone 2h (R = H) with benzil 1a and
activated 2,2’ꢀpyridyl 1b (entries 16ꢀ17). The expected products 3ah and 3bh were, in fact, detected
in only trace amounts by MS analysis of the crude reaction mixtures;14 by contrast, the cyanideꢀ
catalyzed couplings proceeded smoothly affording 3ah and 3bh in moderate and good yield,
respectively.
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TABLE 2. Scope of the double Cꢀaroylation reaction.a
R'
O
R
R'
O
R
R'
O
R
conditions 1 or
conditions 2
O
O
O
Ar2
Ar1
Ar2
+
Ar1
Ar2
Ar1
+
O
O
O
1
2
3
3'
3
3’
(dr)b
3+3’
(%, %)c
75, 83
77, 89
70, 88
63,75
3:3’
(cr)d
Entry
Ar1
Ar2
1
R
R’
2
(dr)b
3aa
3ab
3ac
3ad
e
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
ꢀ
e
e
e
e
e
e
e
e
e
e
e
4ꢀClC6H4
4ꢀBrPh
4ꢀMePh
Ph
ꢀ
3
Ph
ꢀ
4
Ph
ꢀ
5
Ph
4ꢀClC6H4
3ae (1:1)
3af 1:1)
3ag (1:1)
70, 86
40, 44
55, 70
79, 81
77, 84
30, 32
22, 29
67, 82
44, 51
52, 64
47, 58
<5, 28
<5, 75
ꢀ
6
Ph
Ph
4ꢀOMePh
ꢀ
7
8f
9f
Ph
4ꢀClC6H4
Ph
4ꢀOMePh
Ph
2g
2a
2b
2a
2a
2b
2b
2a
2a
2h
2h
ꢀ
2ꢀpyridyl
2ꢀpyridyl
4ꢀCF3C6H4
4ꢀFC6H4
4ꢀMeC6H4
Ph
2ꢀpyridyl
2ꢀpyridyl
4ꢀCF3C6H4
4ꢀFC6H4
4ꢀMeC6H4
2ꢀClC6H4
4ꢀClC6H4
4ꢀOMeC6H4
Ph
3ba (1.5:1)
3bb (1.5:1)
3ca (19:1)
3da (1:1)
3eb (1:1)
3fb
ꢀ
4ꢀClC6H4
Ph
Ph
ꢀ
10
11
12f
13
14
15
16
17f
Ph
ꢀ
Ph
Ph
ꢀ
4ꢀClC6H4
4ꢀClC6H4
Ph
Ph
ꢀ
5:95
70:30
16:84
ꢀ
Ph
3fb’ (1.5:1)
3ga’g (1:1)
3ha’h (1:1)
Ph
1g
1h
1a
1b
Ph
3ga
Ph
Ph
Ph
3ha
e
Ph
H
Ph
3ah
e
2ꢀpyridyl
2ꢀpyridyl
H
Ph
3bh
ꢀ
aConditions 1: tꢀBuOK (100 mol%), DMSO, r.t, 16 h. Conditions 2: KCN (25 mol%), DMSO, r.t. 16 h. bDiaestereomeric ratio determined by
1H NMR analysis of crude reaction mixtures. cYields (conditions 1/conditions 2). dChemoselectivity ratio determined by 1H NMR analysis of
crude reaction mixtures. e3’ = 3. fConditions 1 with Cs2CO3 (100 mol%) as the base. g3ga’= 3ae. h3ha’ = 3af.
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All these findings are in agreement with the following mechanistic proposal. Similarly to what
reported for the cyanide catalysis,15 addition of dimsyl anion A to the more electrophilic carbon
(blue colored) of αꢀdiketone 1 forms the intermediate I, which in turn evolves to the carbanion III
via the epoxide II. Then, conjugate addition of III to chalcone 2 (R = Ar) affords the anion IV,
which finally liberates the double Cꢀaroylation product 3/3’ and the promoter A through an
intramolecular Claisenꢀtype reaction. Carbonyl group formation is supposed to be the driving force
for the elimination of dimsyl anion in the final step of the proposed mechanism;16 on the other hand,
regeneration of the promoter A requires the presence of stoichiometric tꢀBuOK because of the
higher acidity of the product 3/3’ compared to that of DMSO.17 It can also be speculated that
formation of the hydroacylation product of type 5aa (Table 1), occasionally detected in trace
amounts in some substrate combinations, originates from partial hydrolysis of the species IV with
benzoyl group elimination. It is important to emphasize that involvement in the catalytic cycle of
the acyl anion equivalent III and dimsyl anion A has been previously supported by ESIꢀMS/MS
experiments and trapping of A with benzophenone.6
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16
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DMSO
O
Base
R'
O
R
O
Ar
Ar
Ar
Ar
CH3
1
O
O
S
H2C
more electrophilic/
less hindered
carbon
3/3'
O
A
CH3
O
R'
Ar
O
CH2
Ar
S
R
CH3
O
O
Ar
O
S
CH2
O
O
I
Ar
IV
R'
O
CH3
O
CH3
O
O
CH2
S
CH
Ar
S
O
O
Ar
O
Ar
Ar
R
II
2 (R = Ar)
III
SCHEME 2. Proposed mechanism of the double Cꢀaroylation reaction promoted by the dimsyl
anion A.
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Next, to demonstrate the utility of the double Cꢀaroylation process we showed that the 2ꢀbenzoylꢀ
1,4ꢀdiones 3/3’ could be converted into the corresponding all carbon substituted olefins 6/6’ in a
straightforward manner. Accordingly, the copperꢀcatalyzed oxidative dehydrogenation of isolated
3/3’ was briefly investigated in DMSO; full conversions in 6/6’ were achieved using 10 mol% of
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.
Cu(OAc)2 H2O, tꢀBuOK (1 equiv.), and air as the terminal oxidant (80 °C, 2 h).18 This result paved
the way for the development of a convenient oneꢀpot twoꢀstep process for the direct elaboration of
chalcones 2 into the doubly aroylated olefins 6/6’. Hence, to the solution of benzil 1 and chalcone 2
in DMSO was initially added tꢀBuOK (100 mol%) or KCN (25 mol%); then, after having
established the completion of the reaction by TLC analysis, the reaction mixture containing the 2ꢀ
.
benzoylꢀ1,4ꢀdione 3/3’ was treated at 80 °C with Cu(OAc)2 H2O (10 mol%) giving the desired
tetrasubstituted olefins 6/6’ in satisfactory overall yields (Table 3).
TABLE 3. Oneꢀpot twoꢀstep synthesis of tetrasubstituted olefins 6/6’.
1. t-BuOK (100 mol%)
or
Ar3
Ar4
KCN (25 mol%)
DMSO, r.t., 16 h
O
O
Ar3
O
O
O
Ar2
Ar1
+
Ar1
Ar2
2. Cu (OAc)2.H2O (10 mol%)
air, 80 °C, 2 h
Ar4
6/6'
O
1
2
O
O
O
O
O
O
O
O
O
6aa
(65%, 76%)a
Cl
6ab
(69%, 81%)a
6ad
(52%, 60%)a
Cl
Me
OMe
O
O
O
O
O
Me
O
O
O
O
Me
6ae, E/Z = 1:1b
6ag, E/Z = 1:1b
6eb, E/Z = 1:1b
(60%, 83%)a
(48%, 60%)a
(62%,c 80%)a
Cl
Cl
O
O
O
O
O
Cl
O
Cl
6fb', E/Z = 1:1b
(38%, 46%)a
6ga
(38%, 44%)a
Cl
aYields (dimsyl catalysis/cyanide catalysis). bDiaestereomeric ratio
determined by 1H and 13C NMR analyses of crude reaction mixtures.
cFirst step performed using Cs2CO3 (100 mol%) as the base.
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To provide an insight into the mechanism of aerobic oxidative dehydrogenation,19 3aa oxidation
was initially performed in the presence of the radical scavenger TEMPO; 6aa was obtained as the
major product, thus suggesting that radicals were not involved in this reaction. Also, it was verified
that 3aa dehydrogenation could proceed in the absence of tꢀBuOK (or KCN) with lower kinetics but
still high conversion efficiency. A parallel ESIꢀMS investigation on 3aa oxidation without the base
was then carried out to identify key intermediates of the catalytic cycle. When an acetonitrile
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.
solution of 3aa was treated with Cu(OAc)2 H2O, formation of the ionic cluster V corresponding to
[3aa+CuII(AcO)]+ was observed at m/z 540 (63Cu).20 Relevant is the fact that V released AcOH
during the MS/MS fragmentation with formation of the species VI (m/z 480), in which copper(II)
replaces the lost proton.20 Elimination of AcOH in the presence of deuterated acetonitrile
unequivocally confirmed the proton abstraction from the substrate. It can be hypothesized that a
similar mechanism of copperꢀmediated CꢀH activation may also occur in solution;19a βꢀhydride
elimination should then complete the formation of the double bond in 6aa with generation of a
copper species,21 which is converted to the active catalyst by molecular oxygen.
H
Ph(O)C
Ph(O)C
C(O)Ph
1/2 O2
H2O
+
+
CuII(OAc)2Ln
H2O2
Ph
H
3aa
(Ln)
CuII
1/2 O2
2 AcOH
O
O
CH3
H
O
Ph
(CuHLn)
C(O)Ph
Ph(O)C
Ph
H
AcO
V
β-H elimination
detected by MS
(m/z 540)
Ph(O)C
Ph(O)C
C(O)Ph
Ph
CuII(Ln)
C(O)Ph
Ph(O)C
Ph(O)C
Ph
H
AcOH
6aa
AcO
VI
detected by MS
(m/z 480)
SCHEME 3. Proposed mechanism for the copperꢀcatalyzed aerobic dehydrogenation of 3/3’ based
on an ESIꢀMS/MS study.
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In conclusion, we have developed a novel umpolung reaction consisting in the double aroylation of
chalcones with benzils promoted by dimsyl or cyanide anion. The utility of the resulting 2ꢀbenzoylꢀ
1,4ꢀdiones has been also demonstrated by their facile conversion into the corresponding
tetrasubstituted olefins.
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Experimental Section
Potassium tertꢀbutoxide was purified by sublimation (200ꢀ220 °C at 1 mmHg) before utilization.
Reactions were monitored by TLC on silica gel 60 F254 with detection by charring with
phosphomolybdic acid. Flash column chromatography was performed on silica gel 60 (230ꢀ400
1
mesh). H (300 MHz), 13C (75 MHz), and 19F (282 MHz) NMR spectra were recorded in CDCl3
solutions at room temperature. Peaks assignments were aided by 1Hꢀ1H COSY and gradientꢀHMQC
experiments. ESIꢀMS routine analyses were performed in positive ion mode with samples dissolved
in 10 mM solution of ammonium formate in 1:1 MeCN/H2O. For accurate mass measurements, the
compounds were detected in positive ion mode by HPLCꢀChip Q/TOFꢀMS (nanospray) analysis
using a quadrupole, a hexapole, and a timeꢀofꢀflight unit to produce spectra. Residual water of
commercially available anhydrous DMSO (0.016% w/w) was determined by Karl Fisher analysis.
Diketones 1a,b, 1d, 1e, 1h and chalcones 2a-d are commercially available compounds. Diketones
1c,22 1f,6 1g,6 chalcones 2e-g,23 and enone 2h24 were synthesized as described. The 2ꢀbenzoylꢀ1,4ꢀ
dione 3ah is a known compound.7a
Optimization of the model double C-aroylation of chalcone 2a with benzil 1a.
Entries 1-9. To a vigorously stirred mixture of benzil 1a (105 mg, 0.50 mmol), the stated amount of
chalcone 2a, and anhydrous DMSO (1 mL), the stated amount of base (mol% based on 1a) was
added in one portion. Then, the mixture was degassed under vacuum and saturated with argon (by
an argonꢀfilled balloon) three times. The mixture was stirred at the stated temperature for 16 h, then
diluted with H2O (5 mL), extracted with CH2Cl2 (2 × 25 mL). The combined organic phases were
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washed with brine (5 mL), dried (Na2SO4), concentrated, and eluted from a column of silica gel
with 10:1 cyclohexaneꢀAcOEt to give 3aa.
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Entries 10-11. To a vigorously stirred mixture of benzil 1a (105 mg, 0.50 mmol), 2a (54 mg, 0.25
mmol), and anhydrous DMSO (1 mL), potassium cyanide (8.1 mg, 0.13 mmol) or
tetrabutylammonium cyanide (34 mg, 0.13 mmol) was added in one portion. Then, the mixture was
degassed under vacuum and saturated with argon (by an argonꢀfilled balloon) three times. The
mixture was stirred at the stated temperature for 16 h, then diluted with H2O (5 mL), extracted with
CH2Cl2 (2 × 25 mL). The combined organic phases were washed with brine (5 mL), dried
(Na2SO4), concentrated, and eluted from a column of silica gel with 10:1 cyclohexaneꢀAcOEt to
give 3aa.
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Entries 12-17. To a vigorously stirred mixture of benzil 1a (105 mg, 0.50 mmol), 2a (54 mg, 0.25
mmol), stated amount of azolium salt (20 mol% based on 1a) and anhydrous DMSO (1 mL), the
stated base (0.25 mmol) was added in one portion. Then, the mixture was degassed under vacuum
and saturated with argon (by an argonꢀfilled balloon) three times. Then, the mixture was degassed
under vacuum and saturated with argon (by an argonꢀfilled balloon) three times. The mixture was
stirred at the stated temperature for 16 h, then diluted with H2O (5 mL), extracted with CH2Cl2 (2 ×
25 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4),
concentrated, and eluted from a column of silica gel with 10:1 cyclohexaneꢀAcOEt to give 3aa (no
product formation in entries 13ꢀ15).
General procedure for the double C-aroylation of activated alkenes 2 with benzils 1 promoted
by the dimsyl anion (Conditions 1, Table 2). To a vigorously stirred mixture of benzil 1 (1.00
mmol), alkene 2 (0.50 mmol), and anhydrous DMSO (2 mL), potassium tertꢀbutoxide (112 mg,
1.00 mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated
with argon (by an argonꢀfilled balloon) three times. The mixture was stirred at room temperature
until complete disappearance or best conversion of the starting alkene (TLC analysis, ca. 2ꢀ16 h).
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The mixture was then diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The
combined organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted
from a column of silica gel with the suitable elution system to give 3/3’.
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General procedure for the double C-aroylation of activated alkenes 2 with benzils 1 catalyzed
by potassium cyanide (Conditions 2, Table 2). To a vigorously stirred mixture of benzil 1 (1.00
mmol), alkene 2 (0.50 mmol), and anhydrous DMSO (2 mL), potassium cyanide (16 mg, 0.25
mmol) was added in one portion. Then, the mixture was degassed under vacuum and saturated with
argon (by an argonꢀfilled balloon) three times. The mixture was stirred at room temperature until
complete disappearance or best conversion of the starting alkene (TLC analysis, ca. 2ꢀ16 h). The
mixture was then diluted with H2O (5 mL), and extracted with CH2Cl2 (2 × 35 mL). The combined
organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a
column of silica gel with the suitable elution system to give 3/3’.
2-Benzoyl-1,3,4-triphenylbutane-1,4-dione (3aa). Column chromatography with 10:1 cyclohexaneꢀ
AcOEt afforded 3aa (155 mg, 75%; conditions 1) as a white amorphous solid. Conditions 2: 3aa
1
(174 mg, 83%). H NMR: δ = 8.08ꢀ7.98 (m, 2 H, Ar), 7.95ꢀ7.89 (m, 2 H, Ar), 7.70ꢀ7.65 (m, 2 H,
Ar), 7.54ꢀ7.44 (m, 2 H, Ar), 7.43ꢀ7.32 (m, 4 H, Ar), 7.31ꢀ7.21 (m, 5 H, Ar), 7.14ꢀ7.06 (m, 2 H, Ar),
7.05ꢀ6.95 (m, 1 H, Ar), 6.38 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.80 (d, J = 10.7 Hz, 1 H, Hꢀ3);13C{1H}
NMR: δ = 198.1, 195.9, 194.2, 136.6, 136.2, 135.9, 134.8, 133.4, 133.3, 133.1, 129.1, 129.0, 128.6,
128.5, 128.4, 127.8, 60.5, 55.2; IR (CDCl3) ν: 3031, 2937, 1704, 1634, 1630, 1532 cmꢀ1. ESI MS
(418.4): 441.6 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C29H22NaO3 ([M + Na]+) 441.1467,
found: 441.1474.
2-Benzoyl-3-(4-chlorophenyl)-1,4-diphenylbutane-1,4-dione (3ab). Column chromatography with
13:1 cyclohexaneꢀAcOEt afforded 3ab (174 mg, 77%; conditions 1) as a white amorphous solid.
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Conditions 2: 3ab (202 mg, 89%). H NMR: δ = 8.04ꢀ7.96 (m, 2 H, Ar), 7.94ꢀ7.87 (m, 2 H, Ar),
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7.74ꢀ7.67 (m, 2 H, Ar), 7.54ꢀ7.44 (m, 3 H, Ar), 7.44ꢀ7.35 (m, 3 H, Ar), 7.35ꢀ7.27 (m, 3 H, Ar),
7.24ꢀ7.19 (m, 2 H, Ar), 7.12ꢀ7.03 (m, 2 H, Ar), 6.36 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.79 (d, J = 10.7
Hz, 1 H, Hꢀ3); 13C{1H} NMR: δ = 197.8, 195.5, 194.0, 136.5, 136.1, 135.7, 133.8, 133.6, 133.5,
133.3, 130.3, 129.2, 129.0, 128.7, 128.7, 128.6, 60.4, 54.3; IR (CDCl3) ν: 3061, 2960, 1689, 1660,
1659, 1596 cmꢀ1. ESI MS (452.9): 475.7 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C29H21ClNaO3
([M + Na]+) 475.1077, found: 475.1084.
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2-Benzoyl-3-(4-bromophenyl)-1,4-diphenylbutane-1,4-dione (3ac). Column chromatography with
13:1 cyclohexaneꢀAcOEt afforded 3ac (173 mg, 70%; conditions 1) as a white amorphous solid.
1
Conditions 2: 3ac (218 mg, 88%). H NMR: δ = 8.04ꢀ7.96 (m, 2 H, Ar), 7.95ꢀ7.88 (m, 2 H, Ar),
7.73ꢀ7.67 (m, 2 H, Ar), 7.53ꢀ7.43 (m, 3 H, Ar), 7.42ꢀ7.36 (m, 3 H, Ar), 7.35ꢀ7.27 (m, 3 H, Ar),
7.26ꢀ7.20 (m, 2 H, Ar), 7.18ꢀ7.12 (m, 2 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.78 (d, J = 10.7
Hz, 1 H, Hꢀ3); 13C{1H} NMR: δ = 197.8, 195.5, 194.0, 136.5, 136.1, 135.7, 134.0, 133.6, 133.5,
133.3, 132.2, 130.7, 129.0, 128.7, 128.7, 128.6, 122.0, 60.4, 54.4; IR (CDCl3) ν: 3062, 2924, 1690,
1663, 1661, 1595 cmꢀ1. ESI MS (497.4): 520.6 (M + Na+). HRMS (ESI/QꢀTOF) calcd for
C29H21BrNaO3 ([M + Na]+) 519.0572, found: 519.0585.
2-Benzoyl-1,4-diphenyl-3-(p-tolyl)butane-1,4-dione (3ad). Column chromatography with 14:1
cyclohexaneꢀAcOEt afforded 3ad (136 mg, 63%; conditions 1) as a white amorphous solid.
1
Conditions 2: 3ad (163 mg, 75%). H NMR: δ = 8.05ꢀ7.98 (m, 2 H, Ar), 7.95ꢀ7.88 (m, 2 H, Ar),
7.73ꢀ7.64 (m, 2 H, Ar), 7.52ꢀ7.39 (m, 4 H, Ar), 7.38ꢀ7.33 (m, 3 H, Ar), 7.32ꢀ7.27 (m, 2 H, Ar),
7.18ꢀ7.09 (m, 2 H, Ar), 6.93ꢀ6.88 (m, 2 H, Ar), 6.36 (d, J = 10.7 Hz, 1 H, Hꢀ2 ), 5.77 (d, J = 10.7
Hz, 1 H, Hꢀ3), 2.11 (s, 3 H, CH3); 13C{1H} NMR: δ = 198.2, 195.9, 194.3, 137.5, 136.8, 136.3,
136.0, 133.3, 133.1, 133.0, 131.7, 129.7, 129.0, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 60.7, 54.8,
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20.9; IR (CDCl3) ν: 3063, 2919, 1691, 1688, 1687, 1595 cmꢀ1. ESI MS (432.5): 455.5 (M + Na+).
HRMS (ESI/QꢀTOF) calcd for C30H24NaO3 ([M + Na]+) 455.1623, found: 455.1614.
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2-Benzoyl-1-(4-chlorophenyl)-3,4-diphenylbutane-1,4-dione (3ae). Column chromatography with
10:1 cyclohexaneꢀAcOEt afforded 3ae (158 mg, 70%; conditions 1) as a 1:1 mixture of
diastereoisomers. Conditions 2: 3ae (194 mg, 86%; dr = 1:1). Separation of the two
diastereoisomers was carried by a second column chromatography using toluene as the elution
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1
system . First eluted diastereoisomer slightly contaminated by uncharacterized byꢀproducts: H
NMR: δ = 8.05ꢀ7.96 (m, 2 H, Ar), 7.89ꢀ7.82 (m, 2 H, Ar), 7.66ꢀ7.58 (m, 2 H, Ar), 7.53ꢀ7.22 (m, 10
H, Ar), 7.14ꢀ7.08 (m, 2 H, Ar), 7.07ꢀ7.00 (m, 1 H, Ar), 6.31 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.78 (d, J =
10.7 Hz, 1 H, Hꢀ3); 13C{1H} NMR: δ = 198.0, 195.6, 193.0, 139.9, 136.5, 135.8, 134.7, 134.5,
133.5, 133.2, 130.0, 129.1, 129.0, 129.0, 128.8, 128.6, 128.5, 128.4, 128.0, 127.8, 60.4, 55.3; IR
(CDCl3) ν: 3067, 2924, 1697, 1667, 1665, 1589 cmꢀ1. ESI MS (452.9): 475.8 (M + Na+). HRMS
(ESI/QꢀTOF) calcd for C29H21ClNaO3 ([M + Na]+) 475.1077, found: 475.1083. Second eluted
diastereoisomer: 1H NMR: δ = 8.05ꢀ7.96 (m, 2 H, Ar), 7.92ꢀ7.85 (m, 2 H, Ar), 7.66ꢀ7.58 (m, 2 H,
Ar), 7.52ꢀ7.43 (m, 2 H, Ar), 7.41ꢀ7.32 (m, 4 H, Ar), 7.29ꢀ7.22 (m, 4 H, Ar), 7.18ꢀ7.08 (m, 2 H, Ar),
7.07ꢀ7.00 (m, 1 H, Ar), 6.31 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.77 (d, J = 10.7 Hz, 1 H, Hꢀ3); 13C{1H}
NMR: δ = 197.9, 194.8, 193.8, 139.9, 136.1, 135.8, 134.9, 134.7, 133.5, 133.2, 130.0, 129.2, 129.0,
128.9, 128.8, 128.7, 128.6, 128.5, 127.9, 60.4, 55.1; IR (CDCl3) ν: 3063, 2923, 1692, 1661, 1587
cmꢀ1. ESI MS (452.9): 475.7 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C29H21ClNaO3 ([M + Na]+)
475.1077, found: 475.1092.
2-Benzoyl-1-(4-methoxyphenyl)-3,4-diphenylbutane-1,4-dione (3af). Column chromatography with
6:1 cyclohexaneꢀAcOEt afforded 3af (89 mg, 40%; conditions 1) as an inseparable 1:1 mixture of
1
diastereoisomers. Conditions 2: 3af (98 mg, 44%; dr = 1:1). H NMR: δ = 8.05ꢀ7.98 (m, 2 H, Ar),
7.95ꢀ7.88 (m, 2 H, Ar), 7.73ꢀ7.64 (m, 2 H, Ar), 7.52ꢀ7.41 (m, 2 H, Ar), 7.41ꢀ7.32 (m, 4 H, Ar),
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7.31ꢀ7.26 (m, 2 H, Ar), 7.15ꢀ7.06 (m, 2 H, Ar), 7.06ꢀ6.98 (m, 1 H, Ar), 6.85ꢀ6.69 (m, 2 H, Ar), 6.32
(d, J = 10.8 Hz, 0.5 H, Hꢀ2’), 6.31 (d, J = 10.8 Hz, 0.5 H, Hꢀ2”), 5.79 (d, J = 10.8 Hz, 0.5 H, Hꢀ3’),
5.78 (d, J = 10.8 Hz, 0.5H, Hꢀ3”), 3.80 (s, 1.5 H, CH3’), 3.78 (s, 1.5 H, CH3”); 13C{1H} NMR: δ =
198.3 (0.5 C), 198.1 (0.5 C), 196.0 (0.5 C), 194.4 (0.5 C), 194.0 (0.5 C), 192.4 (0.5 C), 163.7 (0.5
C), 163.4 (0.5 C), 136.7, 136.2, 136.0, 134.9, 133.3, 133.2, 133.0, 131.1, 130.3, 129.7, 129.6, 129.0,
128.7, 128.6, 128.5, 128.4, 127.7, 113.8 (0.5 C), 113.6 (0.5 C), 60.4 (0.5 C), 60.2 (0.5 C), 55.4, 55.1
(0.5 C), 55.0 (0.5 C); IR (CDCl3) ν: 3062, 2936, 1672, 1669, 1667, 1596 cmꢀ1. ESI MS (448.5):
471.7 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C30H24NaO4 ([M + Na]+) 471.1572, found:
471.1559.
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2-Benzoyl-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-4-phenylbutane-1,4-dione
(3ag).
Column
chromatography with 7:1 cyclohexaneꢀAcOEt afforded 3ag (134 mg, 55%; conditions 1) as an
inseparable 1:1 mixture of diastereoisomers. Conditions 2: 3ag (169 mg, 70%; dr = 1:1). 1H NMR:
δ = 8.03ꢀ7.95 (m, 2 H, Ar), 7.94ꢀ7.85 (m, 2 H, Ar), 7.76ꢀ7.68 (m, 2 H, Ar), 7.53ꢀ7.36 (m, 4 H, Ar),
7.35ꢀ7.17 (m, 4 H, Ar), 7.11ꢀ7.04 (m, 2 H, Ar), 6.84ꢀ6.73 (m, 2 H, Ar), 6.29 (d, J = 10.7 Hz, 0.5 H,
Hꢀ2’), 6.28 (d, J = 10.7 Hz, 0.5 H, Hꢀ2”), 5.78 (d, J = 10.7 Hz, 0.5 H, Hꢀ3’), 5.76 (d, J = 10.7 Hz,
0.5 H, Hꢀ3”), 3.81 (s, 1.5 H, CH3’), 3.78 (s, 1.5 H, CH3”); 13C{1H} NMR: δ = 198.0 (0.5 C), 197.9
(0.5 C), 195.7 (0.5 C), 194.3 (0.5 C), 193.6 (0.5 C), 192.2 (0.5 C), 163.8 (0.5 C), 136.6, 136.2,
135.8, 133.8, 133.5, 133.4, 133.3, 131.1, 130.4, 130.3, 129.4, 129.2, 129.0, 128.6, 113.9 (0.5 C),
113.8 (0.5 C), 60.3 (0.5 C), 60.1 (0.5 C), 55.5 (0.5 C), 55.4 (0.5 C), 54.3 (0.5 C), 54.1 (0.5 C); IR
(CDCl3) ν: 3061, 2924, 1671, 1669, 1667, 1596 cmꢀ1. ESI MS (482.9): 506.3 (M + Na+). HRMS
(ESI/QꢀTOF) calcd for C30H23ClNaO4 ([M + Na]+) 505.1183, found: 505.1175.
2-Benzoyl-3-phenyl-1,4-di(pyridin-2-yl)butane-1,4-dione (3ba). Column chromatography with 4:1
cyclohexaneꢀAcOEt afforded 3ba (166 mg, 79%; conditions 1) as an inseparable 1.5:1 mixture of
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diastereoisomers. Conditions 2: 3ba (170 mg, 81%; dr = 1.5:1). H NMR: δ = 8.71ꢀ8.66 (m, 1 H,
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Ar), 8.66ꢀ8.60 (m, 0.4 H, Ar”), 8.41ꢀ8.34 (m, 0.6 H, Ar’), 8.23ꢀ8.12 (m, 1 H, Ar), 8.06ꢀ7.94 (m, 1
H, Ar), 7.88ꢀ7.80 (m, 1 H, Ar), 7.78ꢀ7.65 (m, 2 H, Ar), 7.62ꢀ7.52 (m, 0.6 H, Ar’), 7.48ꢀ7.41 (m, 0.4
H, Ar”), 7.41ꢀ7.12 (m, 8 H, Ar), 7.01ꢀ6.84 (m, 3 H, Ar), 6.90 (d, J = 11.5 Hz, 0.4 H, Hꢀ2”), 6.66 (d,
J = 11.5 Hz, 0.6 H, Hꢀ2’), 6.42 (d, J = 11.5 Hz, 0.4 H, Hꢀ3”), 6.30 (d, J = 11.5 Hz, 0.6 H, Hꢀ3’);
13C{1H} NMR: δ = 199.1 (0.6 C), 198.6 (0.4 C), 198.2 (0.6 C), 197.9 (0.4 C), 196.3 (0.6 C), 195.1
(0.5 C), 152.3, 151.4, 149.1, 149.1, 148.5, 148.4, 138.0, 136.9, 136.6, 134.3, 133.1, 132.0, 130.2,
129.8, 129.1, 129.0, 128.4, 128.2, 127.9, 127.6, 127.3, 127.1, 127.0, 126.9, 126.9, 122.8, 122.7,
122.5, 59.7 (0.6 C), 58.1 (0.4 C), 52. 6 (0.4 C), 52.1 (0.6 C); IR (CDCl3) ν: 3057, 2916, 1691,
1690, 1685, 1581 cmꢀ1. ESI MS (420.5): 421.9 (M + H+). HRMS (ESI/QꢀTOF) calcd for
C27H21N2O3 ([M + H]+) 421.1552, found: 421.1541.
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2-Benzoyl-3-(4-chlorophenyl)-1,4-di(pyridin-2-yl)butane-1,4-dione (3bb). Column chromatography
with 4:1 cyclohexaneꢀAcOEt afforded 3bb (175 mg, 77%) as an inseparable 1.5:1 mixture of
diastereoisomers. Conditions 2: 3bb (191 mg, 84%; dr = 1.5:1). 1H NMR: δ = 8.71ꢀ8.64 (m, 1.4 H,
Ar), 8.44ꢀ8.37 (m, 0.6 H, Ar’), 8.18ꢀ8.11 (m, 1 H, Ar), 8.05ꢀ7.96 (m, 1.6 H, Ar), 7.89ꢀ7.82 (m, 1.4
H, Ar), 7.81ꢀ7.70 (m, 2 H, Ar), 7.66ꢀ7.59 (m, 1 H, Ar), 7.47ꢀ7.20 (m, 7 H, Ar), 6.98ꢀ6.87 (m, 2 H,
Ar) 6.91 (d, J = 11.5 Hz, 0.4 H, Hꢀ2”), 6.63 (d, J = 11.5 Hz, 0.6 H, Hꢀ2’), 6.40 (d, J = 11.5 Hz, 0.4
H, Hꢀ3”), 6.28 (d, J = 11.5 Hz, 0.6 H, Hꢀ3’);13C{1H} NMR: δ = 198.8 (0.6 C), 198.3 (0.4 C), 198.0
(0.6 C), 197.6 (0.4 C), 196.0 (0.6 C), 194.8 (0.4 C), 152.2, 152.1, 151.3, 149.1, 149.0, 148.6, 148.5,
137.9, 137.0, 136.8, 136.7, 136.4, 133.2, 133.1, 133.0, 132.2, 131.5, 131.1, 129.1, 129.0, 128.5,
128.4, 128.1, 127.8, 127.3, 127.2, 127.1, 127.0, 122.9, 122.8, 122.6, 122.6, 59.6 (0.6 C), 57.9 (0.4
C), 51.9 (0.4 C), 51.4 (0.6 C); IR (CDCl3) ν: 3057, 2920, 1692, 1670, 1669, 1581 cmꢀ1. ESI MS
(454.9): 456.3 (M + H+). HRMS (ESI/QꢀTOF) calcd for C27H20ClN2O3 ([M + H]+) 455.1162,
found: 455.1150.
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2-Benzoyl-3-phenyl-1,4-bis(4-(trifluoromethyl)phenyl)butane-1,4-dione
(3ca).
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chromatography with 16:1 cyclohexaneꢀAcOEt afforded 3ca (83 mg, 30%; conditions 1) as a 19:1
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mixture of diastereoisomers slightly contaminated by uncharacterized byꢀproducts. Conditions 2:
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3ca (88 mg, 32%; dr = 19:1). H NMR: δ = 8.12ꢀ8.06 (m, 2 H, Ar), 8.02ꢀ7.96 (m, 2 H, Ar), 7.78ꢀ
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7.70 (m, 2 H, Ar), 7.69ꢀ7.58 (m, 4 H, Ar), 7.52ꢀ7.43 (m, 2 H, Ar), 7.32ꢀ7.27 (m, 2 H, Ar), 7.25ꢀ7.21
(m, 2 H, Ar), 7.16ꢀ7.10 (m, 2 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.75 (d, J = 10.7 Hz, 1 H, Hꢀ
3). 13C{1H} NMR: δ = 197.2, 195.2, 193.4, 138.7, 138.5, 136.2, 133.8, 130.5, 129.4, 129.3, 128.9,
128.6, 128.6, 128.3, 128.3, 126.5, 125.8, 125.7, 123.1 (q, J = 270 Hz, 2 CF3), 60.5, 55.6. 19F NMR:
δ = ꢀ63.0, ꢀ63.2, ꢀ63.3, ꢀ63.4; IR (CDCl3) ν: 3071, 2918, 1700, 1681, 1679, 1582 cmꢀ1. ESI MS
(554.5): 577.1 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C31H20F6NaO3 ([M + Na]+) 577.1214,
found: 577.1231.
2-Benzoyl-1,4-bis(4-fluorophenyl)-3-phenylbutane-1,4-dione (3da). Column chromatography with
18:1:1 cyclohexaneꢀAcOEtꢀdichloromethane afforded 3da (50 mg, 22%; conditions 1) as an
inseparable 1:1 mixture of diastereoisomers. Conditions 2: 3da (66 mg, 29%; dr = 1:1). Separation
of the two diastereoisomers was carried by a second column chromatography using toluene as the
elution system. First eluted diastereoisomer: 1H NMR: δ = 8.09ꢀ7.98 (m, 2 H, Ar), 7.97ꢀ7.89 (m, 2
H, Ar), 7.68ꢀ7.61 (m, 2 H, Ar), 7.47ꢀ7.40 (m, 1 H, Ar), 7.32ꢀ7.22 (m, 4 H, Ar), 7.16ꢀ6.96 (m, 7 H,
Ar), 6.30 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.72 (d, J = 10.7 Hz, 1 H, Hꢀ3); 13C{1H} NMR: δ = 196.5,
195.6, 192.6, 165.7 (d, J = 255 Hz, 2 CF), 136.5, 134.6, 133.5, 131.8, 131.7, 131.4, 131.3, 129.2,
128.9, 128.6, 128.0, 115.7, 115.6, 60.4, 55.2; 19F NMR: δ = ꢀ103.8−ꢀ104.0 (m), ꢀ104.7−ꢀ104.9 (m);
IR (CDCl3) ν: 3065, 2920, 1693, 1667, 1593 cmꢀ1. ESI MS (454.5): 477.1 (M + Na+). HRMS
(ESI/QꢀTOF) calcd for C29H20F2NaO3 ([M + Na]+) 477.1278, found: 477.1293. Second eluted
diastereoisomer: 1H NMR: δ = 8.09ꢀ7.98 (m, 2 H, Ar), 7.93ꢀ7.84 (m, 2 H, Ar), 7.77ꢀ7.63 (m, 2 H,
Ar), 7.53ꢀ7.45 (m, 1 H, Ar), 7.40ꢀ7.30 (m, 2 H, Ar), 7.27ꢀ7.20 (m, 2 H, Ar), 7.17ꢀ7.01 (m, 5 H, Ar),
7.01ꢀ6.88 (m, 2 H, Ar), 6.29 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.70 (d, J = 10.6 Hz, 1 H, Hꢀ3); 13C{1H}
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NMR: δ = 196.6, 194.5, 194.2, 165.9 (d, J = 255 Hz, CF), 136.3, 134.8, 133.8, 133.2, 132.5, 132.0,
131.9, 131.7, 131.5, 129.5, 129.1, 129.0, 128.8, 128.25, 116.1, 115.8, 60.5, 55.3; 19F NMR: δ = ꢀ
104.2−ꢀ104.3 (m), ꢀ104.7−ꢀ104.9 (m); IR (CDCl3) ν: 3075, 2919, 1691, 1666, 1593 cmꢀ1. ESI MS
(454.5): 477.9 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C29H20F2NaO3 ([M + Na]+) 477.1278,
found: 477.1296.
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2-Benzoyl-3-(4-chlorophenyl)-1,4-di-p-tolylbutane-1,4-dione (3eb). Column chromatography with
12:1 cyclohexaneꢀAcOEt afforded 3eb (161 mg, 67%; conditions 1) as an inseparable 1:1 mixture
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of diastereoisomers. Conditions 2: 3eb (197 mg, 82%; dr = 1:1). H NMR: δ = 7.95ꢀ7.86 (m, 2 H,
Ar), 7.85ꢀ7.78 (m, 1 H, Ar), 7.74ꢀ7.66 (m, 1 H, Ar), 7.65ꢀ7.57 (m, 1 H, Ar), 7.50ꢀ7.40 (m, 1 H, Ar),
7.39ꢀ7.27 (m, 2 H, Ar), 7.23ꢀ7.15 (m, 5 H, Ar), 7.14ꢀ7.04 (m, 4 H, Ar), 6.32 (d, J = 10.7, 0.5 H, Hꢀ
2’), 6.31 (d, J = 10.7, 0.5 H, Hꢀ2”), 5.77 (d, 1 H, J = 10.7 Hz, Hꢀ3’ and Hꢀ3”), 2.34 (s, 3 H, CH3),
2.32 (s, 3 H, CH3); 13C{1H} NMR: δ = 197.5 (0.5 C), 197.4 (0.5 C), 195.7 (0.5 C), 195.0 (0.5 C),
194.1 (0.5 C), 193.4 (0.5C), 144.7, 144.4, 144.2, 136.6, 136.2, 134.0, 133.8, 133.7, 133.6, 133.5,
133.4, 133.2, 130.3, 129.3, 129.1, 128.9, 128.8, 128.7, 128.6, 60.3 (0.5 C), 60.2 (0.5 C), 54.2 (0.5
C), 54.1 (0.5 C), 21.6; IR (CDCl3) ν: 3032, 2920, 1690, 1667, 1604, 1572 cmꢀ1. ESI MS (481.0):
504.2 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C31H25ClNaO3 ([M + Na]+) 503.1390, found:
503.1388.
2-Benzoyl-4-(2-chlorophenyl)-3-(4-chlorophenyl)-1-phenylbutane-1,4-dione (3fb) and 2-benzoyl-1-
(2-chlorophenyl)-3-(4-chlorophenyl)-4-phenylbutane-1,4-dione (3fb’). Column chromatography
with 13:1 cyclohexaneꢀAcOEt afforded 3fb and 3fb’ (107 mg, 44%; conditions 1) as a 1:19 mixture
of isomers. Conditions 2: 3fb and 3fb’ (124 mg, 51%; cr =1:19). 3fb: 1H NMR (selected data): δ =
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6.38 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.98 (d, J = 10.7 Hz, 1 H. Hꢀ3). 3fb’: H NMR (1.5:1 mixture of
diastereoisomer): δ = 7.98ꢀ7.92 (m, 2 H, Ar), 7.75ꢀ7.65 (m, 1 H, Ar), 7.62ꢀ7.53 (m, 1 H, Ar), 7.52ꢀ
7.42 (m, 2 H, Ar), 7.41ꢀ7.28 (m, 6 H, Ar), 7.26ꢀ7.13 (m, 4 H, Ar), 7.12ꢀ7.02 (m, 2 H, Ar), 6.42ꢀ6.27
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(m, 1 H, Hꢀ2’ and Hꢀ2”), 5.79 (d, J = 10.7 Hz, 0.4 H, Hꢀ3’), 5.64 (d, J = 10.7 Hz, 0.6 H. Hꢀ3”).
13C{1H} NMR (1.5:1 mixture of diastereoisomer): δ = 198.6 (0.6 C), 198.0 (0.4 C), 194.9 (0.6 C),
194.4 (0.4 C), 194.1 (0.6 C), 193.2 (0.4 C), 137.2, 136.4, 136.2, 134.2, 134.1, 133.8, 133.6, 133.6,
133.4, 132.9, 132.2, 131.9, 131.4, 130.90, 130.8, 130.5, 130.3, 130.0, 129.6, 129.2, 129.0, 128.7,
128.6, 128.5, 126.7, 64.3 (0.4 C), 59.9 (0.6 C), 57.6 (0.6 C), 53.4 (0.4 C); IR (CDCl3) ν: 3063,
2920, 1688, 1686, 1665, 1594 cmꢀ1. ESI MS (487.4): 510.9 (M + Na+). HRMS (ESI/QꢀTOF) calcd
for C29H20Cl2NaO3 ([M + Na]+) 509.0687, found: 509.0677.
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2-Benzoyl-4-(4-chlorophenyl)-1,3-diphenylbutane-1,4-dione (3ga). Column chromatography with
10:1 cyclohexaneꢀAcOEt afforded 3ga and 3ga’ (117 mg, 52%; conditions 1) as a 2.3:1 mixture of
isomers. Conditions 2: 3ga and 3ga’ (144 mg, 64%; cr = 2.3:1). First eluted was 3ga’ (= 3ae).
Second eluted was 3ga as a white amorphous solid. 1H NMR: δ = 7.98ꢀ7.92 (m, 2 H, Ar), 7.91ꢀ7.85
(m, 2 H, Ar), 7.70ꢀ7.64 (m, 2 H, Ar), 7.50ꢀ7.39 (m, 3 H, Ar), 7.38ꢀ7.32 (m, 3 H, Ar), 7.28ꢀ7.21 (m,
4 H, Ar), 7.14ꢀ7.07 (m, 2 H, Ar), 7.06ꢀ6.98 (m, 1 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.72 (d, J
= 10.7 Hz, 1 H, Hꢀ3); 13C{1H} NMR: δ = 196.9, 195.7, 194.1, 139.6, 136.5, 136.0, 134.5, 134.2,
133.5, 133.4, 130.4, 129.2, 128.9, 128.9, 128.7, 128.6, 128.5, 128.2, 127.9, 60.3, 55.2; IR (CDCl3)
ν: 3065, 2928, 1692, 1666, 1664, 1588 cmꢀ1. ESI MS (452.9): 475.6 (M + Na+); HRMS (ESI/Qꢀ
TOF) calcd for C29H21ClNaO3 ([M + Na]+) 475.1077, found: 475.1098.
2-Benzoyl-4-(4-methoxyphenyl)-1,3-diphenylbutane-1,4-dione (3ha). Column chromatography with
6:1 cyclohexaneꢀAcOEt afforded 3ha and 3ha’ (105 mg, 47%; conditions 1) as 1:5.3 mixture of
isomers slightly contaminated by uncharacterized byꢀproducts. Conditions 2: 3ha and 3ha’ (130
mg, 58%; cr =1:5.3). 3ha: 1H NMR (selected data): δ = 6.39 (d, J = 10.7 Hz, 1 H, Hꢀ2), 5.80 (d, J =
10.7 Hz, 1 H, Hꢀ3), 3.86 (s, 3 H, OCH3); 13C{1H} NMR (selected data): δ = 55.0; IR (CDCl3) ν:
3063, 2927, 1673, 1671, 1597, 1575 cmꢀ1. ESI MS (448.5): 471.6 (M + Na+); HRMS (ESI/QꢀTOF)
calcd for C30H24NaO4 ([M + Na]+) 471.1572, found: 471.1573. 3ha’ = 3af.
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2-Benzoyl-1,4-diphenylbutane-1,4-dione (3ah). Conditions 1: trace amounts of 3ah as determined
by MS analysis of the crude reaction mixture; ESI MS (342.4): 365.6 (M + Na+). Conditions 2:
column chromatography with 5:1 cyclohexaneꢀAcOEt afforded 3ah7a (48 mg, 28%) as a yellow
solid: mp 154ꢀ155 °C. 1H NMR: δ = 8.06ꢀ 7.94 (m, 6 H, Ar), 7.62ꢀ7.54 (m, 3 H, Ar), 7.51ꢀ7.40 (m,
6 H, Ar), 6.12 (t, J = 7.0 Hz, 1 H, Hꢀ2), 3.78 (d, J = 7.0 Hz, 2 H, 2 Hꢀ3); IR (CDCl3) ν: 3062, 2924,
1731, 1678, 1663, 1596 cmꢀ1.
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2-Benzoyl-1,4-di(pyridin-2-yl)butane-1,4-dione (3bh). Conditions 1: trace amounts of 3bh as
determined by MS analysis of the crude reaction mixture; ESI MS (344.4): 345.8 (M + H+).
Conditions 2: column chromatography with 3:1 cyclohexaneꢀAcOEt afforded 3bh (129 mg, 75%;)
as a yellow foam 1H NMR: δ = 8.68ꢀ8.64 (m, 1 H, Ar), 8.58ꢀ8.54 (m, 1 H, Ar), 8.14ꢀ8.00 (m, 4 H,
Ar), 7.86ꢀ7.78 (m, 2 H, Ar), 7.60ꢀ7.52 (m, 1 H, Ar), 7.50ꢀ7.39 (m, 4 H, Ar), 6.47 (dd, 1 H, J = 5.0,
8.0 Hz, Hꢀ2), 4.17 (dd, 1 H, J = 8.0, 18.5 Hz, Hꢀ3a), 3.75 (dd, 1 H, J = 5.0, 18.5 Hz, Hꢀ3b); 13C{1H}
NMR: δ = 198.5, 197.3, 197.0, 152.8, 151.7, 149.0, 148.9, 137.0, 136.9, 136.0, 133.2, 128.9, 128.7,
127.3, 122.6, 121.9, 50.6, 37.0; IR (CDCl3) ν: 3057, 2924, 1695, 1673, 1596, 1582 cmꢀ1. HRMS
(ESI/QꢀTOF) calcd for C21H17N2O3 ([M + H]+) 345.1239, found: 345.1255.
Model aerobic oxidative dehydrogenation of 3aa.
To a vigorously stirred mixture of 3aa (209 mg, 0.50 mmol), potassium tertꢀbutoxide (56 mg, 0.50
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mmol), and anhydrous DMSO (2 mL), Cu(OAc)2 H2O (10 mg, 0.05 mmol) was added in one
portion. The mixture was stirred at 80 °C for 2 h under atmospheric air (balloon), then cooled to
room temperature, diluted with H2O (5 mL), and extracted with CH2Cl2 (2 x 35 mL). The combined
organic phases were washed with brine (8 mL), dried (Na2SO4), concentrated, and eluted from a
column of silica gel with 10:1 cyclohexaneꢀAcOEt to give 6aa (197 mg, 95%).
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General procedure for the one-pot two step synthesis of tetrasubstituted olefins 6/6’
(Conditions 1, Table 3). To a vigorously stirred mixture of benzil 1 (1.00 mmol), alkene 2 (0.50
mmol), and anhydrous DMSO (2 mL), potassium tertꢀbutoxide (112 mg, 1.00 mmol) was added in
one portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argonꢀ
filled balloon) three times. The mixture was stirred at room temperature until complete
disappearance or best conversion of the starting alkene (TLC analysis, ca. 2ꢀ16 h), then
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Cu(OAc)2 H2O (20 mg, 0.10 mmol) was added in one portion. The mixture was stirred at 80 °C for
2 h under atmospheric air (balloon), then cooled to room temperature, diluted with H2O (5 mL), and
extracted with CH2Cl2 (2 × 35 mL). The combined organic phases were washed with brine (8 mL),
dried (Na2SO4), concentrated, and eluted from a column of silica gel with the suitable elution
system to give 6/6’.
General procedure for the one-pot two step synthesis of tetrasubstituted olefins 6/6’
(Conditions 2, Table 3). To a vigorously stirred mixture of benzil 1 (1.00 mmol), alkene 2 (0.50
mmol), and anhydrous DMSO (2 mL), potassium cyanide (16 mg, 0.25 mmol) was added in one
portion. Then, the mixture was degassed under vacuum and saturated with argon (by an argonꢀfilled
balloon) three times. The mixture was stirred at room temperature until complete disappearance or
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best conversion of the starting alkene (TLC analysis, ca. 2ꢀ16 h), then Cu(OAc)2 H2O (20 mg, 0.10
mmol) was added in one portion. The mixture was stirred at 80 °C for 2 h under atmospheric air
(balloon), then cooled to room temperature, diluted with H2O (5 mL), and extracted with CH2Cl2 (2
× 35 mL). The combined organic phases were washed with brine (8 mL), dried (Na2SO4),
concentrated, and eluted from a column of silica gel with the suitable elution system to give 6/6’.
2-Benzoyl-1,3,4-triphenylbut-2-ene-1,4-dione (6aa). Column chromatography with 10:1
cyclohexaneꢀAcOEt afforded 6aa (135 mg, 65%; conditions 1) as a white amorphous solid.
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Conditions 2: 6aa (158 mg, 76%). H NMR: δ = 8.01ꢀ7.93 (m, 2 H, Ar), 7.89ꢀ7.84 (m, 2 H, Ar),
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7.84ꢀ7.77 (m, 2 H, Ar), 7.50ꢀ7.38 (m, 3 H, Ar), 7.37ꢀ7.32 (m, 3 H, Ar), 7.31ꢀ7.24 (m, 5 H, Ar),
7.17ꢀ7.10 (m, 3 H, Ar);13C{1H} NMR: δ = 195.0, 194.3, 193.1, 151.7, 141.9, 136.6, 136.1, 135.7,
134.0, 133.7, 133.4, 133.3, 129.8, 129.7, 129.6, 129.4, 128.8, 128.6, 128.6, 128.5, 128.3; IR
(CDCl3) ν: 3063, 2923, 1662, 1646, 1595, 1578 cmꢀ1. ESI MS (416.5): 439.1 (M + Na+); HRMS
(ESI/QꢀTOF) calcd for C29H20NaO3 ([M + Na]+) 439.1310, found: 439.1318.
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2-Benzoyl-3-(4-chlorophenyl)-1,4-diphenylbut-2-ene-1,4-dione (6ab). Column chromatography
with 13:1 cyclohexaneꢀAcOEt afforded 6ab (155 mg, 69%; conditions 1) as a white amorphous
1
solid. Conditions 2: 6ab (184 mg, 82%). H NMR: δ = 8.01ꢀ7.94 (m, 2 H, Ar), 7.88ꢀ7.85 (m, 4 H,
Ar), 7.54ꢀ7.44 (m, 2 H, Ar), 7.44ꢀ7.33 (m, 5 H, Ar), 7.33ꢀ7.20 (m, 4 H, Ar), 7.18ꢀ7.08 (m, 2 H, Ar);
13C{1H} NMR: δ = 194.8, 193.9, 192.8, 150.2, 142.6, 136.4, 136.0, 135.9, 135.5, 134.1, 133.6,
133.5, 132.4, 129.9, 129.8, 129.7, 129.4, 129.16, 128.8, 128.6, 128.4; IR (CDCl3) ν: 3062, 2924,
1652, 1595, 1579 cmꢀ1. ESI MS (450.9): 473.4 (M + Na+). HRMS (ESI/QꢀTOF) calcd for
C29H19ClNaO3 ([M + Na]+) 473.0920, found: 473.0917.
2-Benzoyl-1,4-diphenyl-3-(p-tolyl)but-2-ene-1,4-dione (6ad). Column chromatography with 14:1
cyclohexaneꢀAcOEt afforded 6ad (112 mg, 52%; conditions 1) as a white amorphous solid.
1
Conditions 2: 6ad (129 mg, 60%). H NMR: δ = 8.02ꢀ7.93 (m, 2 H, Ar), 7.89ꢀ7.83 (m, 2 H, Ar),
7.82ꢀ7.76 (m, 2 H, Ar), 7.51ꢀ7.39 (m, 3 H, Ar), 7.39ꢀ7.30 (m, 4 H, Ar), 7.30ꢀ7.21 (m, 2 H, Ar),
7.21ꢀ7.11 (m, 2 H, Ar), 6.99ꢀ6.87 (m, 2 H, Ar), 2.17 (s, 3 H, CH3); 13C{1H} NMR: δ = 195.2, 194.5,
193.2, 152.2, 141.1, 140.0, 136.7, 136.2, 135.8, 133.6, 133.3, 133.2, 131.0, 129.8, 129.7, 129.6,
129.3, 128.6, 128.5, 128.5, 128.3, 21.2; IR (CDCl3) ν: 3063, 2921, 1663, 1643, 1595, 1578 cmꢀ1.
ESI MS (430.5): 453.1 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C30H22NaO3 ([M + Na]+)
453.1467, found: 453.1470.
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(E/Z)-2-Benzoyl-1-(4-chlorophenyl)-3,4-diphenylbut-2-ene-1,4-dione
(6ae).
Column
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chromatography with 10:1 cyclohexaneꢀAcOEt afforded 6ae (129 mg, 60%; conditions 1) as a 1:1
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mixture of diastereoisomers. Conditions 2: 6ae (186 mg, 83%; E/Z = 1:1). H NMR: δ = 8.01ꢀ7.94
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(m, 1 H, Ar’), 7.94ꢀ7.88 (m, 1 H, Ar”), 7.87ꢀ7.73 (m, 4 H, Ar), 7.52ꢀ7.40 (m, 2 H, Ar), 7.40ꢀ7.32
(m, 3 H, Ar), 7.32ꢀ7.21 (m, 5 H, Ar), 7.21ꢀ7.08 (m, 3 H, Ar); 13C{1H} NMR: δ = 194.9 (0.5 C),
194.8 (0.5 C), 194.2 (0.5 C), 193.2 (0.5 C), 193.0 (0.5 C), 192.0 (0.5 C), 151.9 (0.5 C), 151.7 (0.5
C), 141.6 (0.5 C), 141.4 (0.5 C), 140.3 (0.5 C), 139.9 (0.5 C), 136.5, 135.9, 135.6, 134.9, 134.4,
133.9, 133.8, 133.6, 133.5, 133.4, 131.1, 130.8, 129.9, 129.8, 129.7, 129.3, 129.0, 128.9, 128.9,
128.8, 128.7, 128.4, 128.5, 128.4; IR (CDCl3) ν: 3061, 2928, 1653, 1652, 1586, 1582 cmꢀ1. ESI MS
(450.9): 473.6 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C29H19ClNaO3 ([M + Na]+) 473.0920,
found: 473.0903.
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(E/Z)-2-Benzoyl-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-4-phenylbut-2-ene-1,4-dione
(6ag).
Column chromatography with 7:1 cyclohexaneꢀAcOEt afforded 6ag (115 mg, 48%; conditions 1) as
a 1:1 mixture of diastereoisomers. Conditions 2: 6ag (144 mg, 60%; E/Z = 1:1). 1H NMR: δ = 8.05ꢀ
7.99 (m, 1 H, Ar’), 7.99ꢀ7.92 (m, 1 H, Ar”), 7.84ꢀ7.80 (m, 4 H, Ar), 7.53ꢀ7.43 (m, 2 H, Ar), 7.42ꢀ
7.31 (m, 3 H, Ar), 7.29ꢀ7.19 (m, 3 H, Ar), 7.18ꢀ7.07 (m, 2 H, Ar), 6.89ꢀ6.81 (m, 1 H, Ar), 6.81ꢀ6.72
(m, 1 H, Ar), 3.83 (s, 1.5 H, CH3), 3.78 (s, 1.5 H, CH3); 13C{1H} NMR: δ = 194.9 (0.5 C), 194,9
(0.5 C), 194.0 (0.5 C), 192.9 (0.5 C), 192.1 (0.5C), 190.9 (0.5 C), 164.3 (0.5 C), 164.0 (0.5 C),
149.2 (0.5 C), 149.0 (0.5 C), 143.3 (0.5 C), 143.1 (0.5 C), 136.4, 136.0, 135.6, 134.1, 133.6, 133.4,
132.5, 132.4, 132.1, 129.8, 129.7, 129.4, 129.3, 129.1, 128.8, 128.6, 128.4,114.1 (0.5 C), 113.7 (0.5
C), 55.5 (0.5 C), 55.4 (0.5 C); IR (CDCl3) ν: 3060, 2920, 1652, 1650, 1581, 1579 cmꢀ1. ESI MS
(480.9): 503.6 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C30H21ClNaO4 ([M + Na]+) 503.1026,
found: 503.1032.
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(E/Z)-2-Benzoyl-3-(4-chlorophenyl)-1,4-di-p-tolylbut-2-ene-1,4-dione
(6eb).
Column
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chromatography with 12:1 cyclohexaneꢀAcOEt afforded 6eb (148 mg, 62%; conditions 1) as a 1:1
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mixture of diastereoisomers. Conditions 2: 6eb (191 mg, 80%; E/Z = 1:1). H NMR: δ = 8.01ꢀ7.94
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(m, 1 H, Ar’), 7.92ꢀ7.85 (m, 1 H, Ar”), 7.85ꢀ7.69 (m, 4 H, Ar), 7.59ꢀ7.43 (m, 1 H, Ar), 7.43ꢀ7.33
(m, 1 H, Ar), 7.33ꢀ7.25 (m, 1 H, Ar), 7.25ꢀ7.19 (m, 2 H, Ar), 7.18ꢀ7.05 (m, 6 H, Ar), 2.35 (s, 1.5 H,
CH3), 2.34 (s, 3 H, CH3), 2.29 (s, 1.5 H, CH3); 13C{1H} NMR: δ = 194.5 (0.5 C), 194.4 (0.5 C),
194.0 (0.5 C), 193.5 (0.5 C), 192.8 (0.5 C), 192.3 (0.5 C), 149.8, 145.2, 144.7, 144.5, 142.7, 136.5,
136.0, 135.7, 134.0, 133.6, 133.4, 133.2, 132.7, 130.1, 130.0, 129.9, 129.8, 129.7, 129.6, 129.5,
129.3, 129.1, 129.1, 128.8, 128.3, 127.0, 21.7 , 21.6; IR (CDCl3) ν: 3039, 2920, 1651, 1650, 1602,
1580 cmꢀ1. ESI MS (479.0): 502.3 (M + Na+). HRMS (ESI/QꢀTOF) calcd for C31H23ClNaO3 ([M +
Na]+) 501.1233, found: 501,1250.
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(E/Z)-2-Benzoyl-1-(2-chlorophenyl)-3-(4-chlorophenyl)-4-phenylbut-2-ene-1,4-dione
(6fb’).
Column chromatography with 13:1 cyclohexaneꢀAcOEt afforded 6fb’ (92 mg, 38%) as a 1:1
1
mixture of diastereoisomers. Conditions 2: 6fb’ (111 mg, 46%; E/Z = 1:1). H NMR: δ 7.99ꢀ7.91
(m, 4 H, Ar), 7.59ꢀ7.53 (m, 1 H, Ar), 7.52ꢀ7.45 (m, 2 H, Ar), 7.41ꢀ7.33 (m, 4 H, Ar), 7.24ꢀ7.17 (m,
5 H, Ar), 7.13ꢀ7.05 (m, 2 H, Ar); 13C{1H} NMR: δ = 194.1, 193.2, 192.7, 146.7 (0.5 C) , 146.6 (0.5
C), 136.2, 135.9, 135.6 (0.5 C), 135.5 (0.5 C), 134.2, 133.8, 132.9, 132.7, 131.8, 131.6, 130.8,
130.5, 130.2, 130.0, 129.8, 129.6, 129.5, 128.9, 128.7, 128.6, 128.5, 126.7; IR (CDCl3) ν: 3067,
2923, 1655, 1651, 1594, 1590 cmꢀ1. ESI MS (485.4): 508.0 (M + Na+). HRMS (ESI/QꢀTOF) calcd
for C29H18Cl2NaO3 ([M + Na]+) 507.0531, found: 507.0520.
2-Benzoyl-4-(4-chlorophenyl)-1,3-diphenylbut-2-ene-1,4-dione (6ga). Column chromatography
with 10:1 cyclohexaneꢀAcOEt afforded 6ga (85 mg, 38%; conditions 1) as a white amorphous
1
solid. Conditions 2: 6ga (99 mg, 44%). H NMR: δ = 7.99ꢀ7.92 (m, 2 H, Ar), 7.82ꢀ7.74 (m, 4 H,
Ar), 7.50ꢀ7.39 (m, 2 H, Ar), 7.38ꢀ7.30 (m, 5 H, Ar), 7.29ꢀ7.22 (m, 3 H, Ar), 7.19ꢀ7.12 (m, 3 H, Ar);
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13C{1H} NMR: δ = 194.2, 194.0, 193.1, 151.8, 142.0, 140.0, 136.5, 136.0, 134.1, 133.9, 133.6,
133.5, 131.1, 130.0, 129.9, 129.4, 129.0, 128.8, 128.7, 128.6, 128.5; IR (CDCl3) ν: 3063, 2920,
1653, 1651, 1588, 1585 cmꢀ1. ESI MS (450.9): 473.8 (M + Na+). HRMS (ESI/QꢀTOF) calcd for
C29H19ClNaO3 ([M + Na]+) 473.0920, found: 473.0922.
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Aerobic oxidative dehydrogenation of 3aa in presence of TEMPO.
To a vigorously stirred mixture of 3aa (209 mg, 0.50 mmol), potassium tertꢀbutoxide (112 mg, 1.00
mmol), (2,2,6,6ꢀtetramethylꢀpiperidinꢀ1ꢀyl)oxyl (78 mg, 0.50 mmol) and anhydrous DMSO (2 mL),
.
Cu(OAc)2 H2O (20 mg, 0.10 mmol) was added in one portion. The mixture was stirred at 80 °C for
2 h under atmospheric air (balloon), then cooled to room temperature, diluted with H2O (5 mL), and
extracted with CH2Cl2 (2 x 35 mL). The combined organic phases were washed with brine (8 mL),
dried (Na2SO4), concentrated, and eluted from a column of silica gel with 10:1 cyclohexaneꢀAcOEt
to give 6aa (135 mg, 65%).
Acknowledgments. We thank the student Maurizio Mazzoni for his valuable contribution. We
gratefully acknowledge University of Ferrara (Fondi FAR) for financial support. Thanks are also
given to Mr. P. Formaglio for NMR spectroscopic experiments and to Dr. T. Bernardi for highꢀ
resolution mass spectrometric experiments.
Supporting Information. NMR spectra of 3/3’, 6/6’ and ESIꢀMS spectra of V-VI. This material is
available free of charge via the Internet at http://pubs.acs.org.
References and Footnotes
(1) (a) Trost, B. M. Science 1991, 254, 1471ꢀ1477. (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695ꢀ
705.
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(2) Selective reviews: (a) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314ꢀ325. (b)
Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167ꢀ178. (c) Yu, X.; Wang, W. Org.
Biomol. Chem. 2008, 6, 2037ꢀ2046. (d) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem.,
Int. Ed. 2007, 46, 1570ꢀ1581.
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(3) For representative examples, see: (a) Rueping, M.; Kuenkel A.; Fröhlich, R. Chem.-Eur. J.
2010, 16, 4173ꢀ4176. (b) Ding, D.; Zhao, C.ꢀG.; Guo, Q.; Arman, H. Tetrahedron, 2010, 66, 4423ꢀ
4427. (c) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699ꢀ
3702.
(4) Giovannini, P. P.; Bortolini, O.; Cavazzini, A.; Greco, R.; Fantin, G.; Massi, M. Green Chem.
2014, 16, 3904ꢀ3915 and references therein.
(5) (a) Bortolini, O.; Cavazzini, A.; Dambruoso, P.; Giovannini, P. P.; Caciolli, L.; Massi, A.;
Pacifico, S.; Ragno, D. Green Chem. 2013, 15, 2981ꢀ2992. (b) Bortolini, O.; Fantin, G.; Fogagnolo,
M.; Giovannini, P. P.; Massi, A.; Pacifico, S. Org. Biomol. Chem. 2011, 9, 8437ꢀ8444. (c)
Bortolini, O.; Fantin, G.; Fogagnolo, M.; Giovannini, P. P.; Venturi, V.; Pacifico, S.; Massi, A.
Tetrahedron 2011, 67, 8110ꢀ8115.
(6) Bortolini, O.; Fantin, G.; Ferretti, V.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pacifico, S.;
Ragno, D. Adv. Synth. Catal. 2013, 355, 3244ꢀ3252.
(7) During the preparation of this manuscript, Tataki and coꢀworkers reported the NHCꢀcatalyzed
double acylation of enones with benzils: (a) Takaki, K.; Ohno, A.; Hino, M.; Shitaoka, T.;
Komeyama, K.; Yoshida, H. Chem. Commun. 2014, 50, 12285ꢀ12288. For the double aroylation of
acrylates with Oꢀaroylmandelonitriles, see: (b) Miyashita, A.; Matsuoka, Y.; Numata, A.;
Higashino, T. Chem. Pharm. Bull. 1996, 44, 448ꢀ450.
(8) (a) Liu, S.; Tang, L.; Chen, H.; Zhao, F.; Deng, G.ꢀJ. Org. Biomol. Chem. 2014, 12, 6076ꢀ6079
and references therein. (b) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698ꢀ4745.
(9) (a) Itami, K; Yoshida, J.ꢀ.i Bull. Chem. Soc. Jpn. 2006, 79, 811ꢀ824. (b) Feringa, B. L.; van
Delden, R. A.; Koumura, N.; Geertsema, E. M. Chem. Rev. 2000, 100, 1789ꢀ1816.
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(10) (a) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693ꢀ
11712. (b) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570ꢀ9571.
(11) Equilibrium acidities in DMSO: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456ꢀ463. Residual
water content of anhydrous DMSO higher than 0.016% (w/w) determined a marked reduction of the
reaction efficiency.
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(12) For a different reactivity of the thiazolium salt E with benzils, see: Bertolasi, V.; Bortolini, B.;
Donvito, A.; Fantin, G.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pacifico, S. Org. Biomol.
Chem. 2012, 10, 6579ꢀ6586.
(13) The homocoupling reaction of benzils produces the corresponding benzoylated benzoins
through hydrolysis of one benzoyl group of α,α’ꢀstilbenediol dibenzoate intermediates (see Ref. 6).
(14) The rapid degradation of enone 2h under the coupling conditions was confirmed by a
control experiment performed in the absence of benzil 1a (2h, 100 mol% tꢀBuOK, DMSO, 30 min).
(15) (a) Kuebrich, J. P.; Schowen, R. L. J. Am. Chem. Soc. 1971, 93, 1220ꢀ1223. (b) Kwart, H.;
Baevsky, M. M. J. Am. Chem. Soc. 1958, 80, 580ꢀ588.
(16) The reversible (equilibrium) addition of dimsyl anion to carbonyl compounds has been
reported: Walling, C.; Bollyky, L. J. Org. Chem. 1963, 28, 256ꢀ257.
(17) The proton exchange between DMSO and tꢀBuOK is a very fast process: (a) Brauman, J. I.;
Nelson, N. J.; Kahl, D. C. J. Am. Chem. Soc. 1968, 90, 490ꢀ491. (b) Brauman, J. I.; Nelson, N. J. J.
Am. Chem. Soc. 1968, 90, 491ꢀ492.
(18) Yang, Y.; Ni, F.; Shu, W.ꢀM.; Yu, S.ꢀB.; Gao, M.; Wu, A.ꢀX. J. Org. Chem. 2013, 78, 5418ꢀ
5426.
(19) (a) Liang, L.; Yang, G.; Wang, W.; Xu, F.; Niu, Y.; Sun, Q; Xu, P. Adv. Synth. Catal. 2013,
355, 1284ꢀ1290. (b) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50,
11062ꢀ11087.
(20) The positive charge of cations V and VI detected in the gas phase is balanced in the solution
phase by the acetate counter anion. The formation of a dicarbonyl copper chelate complex through
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elimination of AcOH from V cannot be excluded by our MS study because this species would be
isobaric with VI; this latter isomer has been suggested to justify the subsequent βꢀhydride
elimination step already claimed in similar copperꢀcatalyzed oxidative dehydrogenations (see Ref.
19a).
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(21) The mechanism by which Cu(OAc)2 is regenerated after the supposed βꢀhydride elimination
step is not clear to us; recent studies have revealed that Cu(II)ꢀmediated CꢀH activation can proceed
via disproportionation of Cu(II) into Cu(I) and Cu(III) species. Campbell, A. N.; Stahl, S. S. Acc.
Chem. Res. 2012, 45, 851ꢀ863 and reference therein.
(22) RomanovꢀMichailidis, F.; Besnard, C.; Alexakis, A. Org. Lett. 2012, 14, 4906ꢀ4909.
(23) Wattanasin, S.; Murphy, W. S. Synthesis 1980, 647ꢀ650.
(24) Chanthamath, S.; Takaki, S.; Shibatomi, K.; Iwasa, S. Angew. Chem., Int. Ed. 2013, 52, 5818ꢀ
5821.
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