Note
pubs.acs.org/joc
Nucleophilic and Electrophilic Double Aroylation of Chalcones with
Benzils Promoted by the Dimsyl Anion as a Route to All Carbon
Tetrasubstituted Olefins
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
S Supporting Information
*
ABSTRACT: 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.
A
tom-economical 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 Bifunctional molecules constitute valuable substrates
for the design of organocatalytic domino sequences; nevertheless, the use of highly reactive α-diketones has been rarely
investigated in this type of approach,3 in which the double
carbonyl functionality of 1,2-diones exhibits electrophilic
behavior at the carbonyl carbon and nucleophilic character at
the α position. A complementary mode of carbonyl reactivity is,
however, possible for this class of substrates; as demonstrated
by our group, α-diketones can be rendered nucleophilic at
carbonyl carbon (umpolung reactivity) through the catalysis of
thiamine diphosphate (ThDP)-dependent enzymes4 and Nheterocyclic carbenes (NHCs)5 in nucleophilic acylations.
Recently, we also discovered the capability of methylsulfinyl
(dimsyl) carbanion A to induce the polarity reversal of diaryl αdiketones (benzils) in chemoselective cross-benzoin 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 an atom-economic fashion through sequential nucleophilic
C-aroylations and electrophilic O-aroylations (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 C-aroylation process on
activated alkenes, thus providing a novel variant of the parent
Stetter reaction (hydroacylation process).7 We also envisaged
that the resulting activated 1,4-dicarbonyls could be further
elaborated going back to the alkene stage via a catalytic
oxidative dehydrogenation step to produce all carbon
© 2014 American Chemical Society
Scheme 1. Double Aroylation of Aldehydes and Activated
Alkenes with Benzils Promoted by the Dimsyl Anion A
tetrasubstituted olefins from chalcones through a simple and
effective one-pot 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
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 C-aroylation product 3aa could
be accompanied by generation of byproducts 4aa and 5aa via
competitive double C,O-aroylation and hydroacylation pathways, respectively (vide inf ra). Gratifyingly, under the
Received: November 12, 2014
Published: December 26, 2014
1937
DOI: 10.1021/jo502582e
J. Org. Chem. 2015, 80, 1937−1945
The Journal of Organic Chemistry
Note
in 75% yield (entry 8) were finally established using an excess
of benzil 1a (2 equiv). For the sake of comparison, the catalytic
activity of cyanide anion was also tested, detecting the same
reaction selectivity and a comparable, but appreciably higher,
yield of 3aa (83−82%, entries 10−11).
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 BDBU couple catalyzed the reaction in CH2Cl2, affording 3aa in
modest yield (15%, entry 12). Indeed, the more hindered
triazolium salts C−D (entries 13−14) and thiazolium,12
imidazolium, and imidazolium precatalysts E−G (entries 15−
17) proved to be totally inactive, the observed formation of 3aa
in DMSO being the result of a background activity of the
dimsyl anion.
The substrate scope of the disclosed double C-aroylation
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 % t-BuOK, DMSO;
conditions 1) provided a safe and environmentally benign
access to 2-benzoyl-1,4-diones 3 and 3′, albeit with slightly
diminished yields (2−18%) 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 electron-withdrawing, -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 1−7).
Investigation on the electronic requirements for the α-diketone
1 showed the 2,2′-pyridyl 1b with an electron-withdrawing
moiety as a highly reactive substrate (entries 8−9);
unexpectedly, the use of electron-deficient 4,4′-ditrifluoromethylbenzil 1c and 4,4′-difluorobenzil 1d led to a significant
reduction of reaction efficiency (entries 10−11) mainly because
of the diketone self-condensation side-reaction.13 The combination of the electron-rich 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
monosubstituted 2-chloro benzil 1f exhibited the highest
capability in controlling the chemoselectivity (3:3′ cr) of the
double C-aroylation process as it reacted with chalcone 2b,
yielding almost exclusively the isomer 3fb′ (5:95 cr; entry 13).
This result implied that dimsyl/cyanide anion favorably added
to the less hindered carbonyl carbon of 1f. Similarly, a
comparison of the reactivity of monosubstituted 4-Cl and 4OMe benzils 1g and 1h toward chalcone 2a indicated the
preferential attack of the catalyst to the diketone carbonyl
carbon with lower electron density (entries 14−15). A
limitation of the dimsyl anion-based methodology appeared
evident from the representative couplings of enone 2h (R = H)
with benzil 1a and activated 2,2′-pyridyl 1b (entries 16−17).
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 cyanide-catalyzed couplings
proceeded smoothly, affording 3ah and 3bh in moderate and
good yield, respectively.
All of these findings are in agreement with the following
mechanistic proposal. Similarly to what is reported for the
cyanide catalysis,15 addition of dimsyl anion A to the more
Table 1. Optimization of the Model Double C-Aroylation of
Chalcone 2a with Benzil 1aa
entry
solvent
1b
2b,c
3b
4
5
6d
7
8
9e
10
11
12
13
14
15
16
17
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
DMSO
DMSO
DMSO
(pre)catalyst (mol %)
KCN (25)
TBACN (25)
B (20)
C (20)
D (20)
E (20)
F (20)
G (20)
base (mol %)
yield (%)
t-BuOK (30)
t-BuOK (30)
t-BuOK (100)
DBU (100)
Cs2CO3 (100)
CsOH (100)
Et3N (100)
t-BuOK (100)
t-BuOK (100)
34
28
46
24
32
35
DBU (50)
DBU (50)
DBU (50)
NEt3 (50)
DBU(50)
DBU (50)
75
32
83
82
15
28
25
a
Reaction conditions: benzil 1a (0.50 mmol), chalcone 2a (0.25
mmol), and anhydrous solvent (1.0 mL). b 2a: 0.50 mmol.
c
Temperature: 50 °C. dReaction performed in the presence of 4 Å
MS. e2a: 1.00 mmol.
conditions previously described for the generation of dimsyl
anion A (anhydrous DMSO, 30 mol % t-BuOK, 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 t-BuOK 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 [t-BuOK] = 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, t-BuOK > Cs2CO3 ≈ CsOH > DBU ≫
Et3N (entries 4−7). Optimal reaction conditions delivering 3aa
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The Journal of Organic Chemistry
Note
Table 2. Scope of the Double C-Aroylation Reactiona
entry
1
2
3
4
5
6
7
8f
9f
10
11
12f
13
14
15
16
17f
Ar1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-pyridyl
2-pyridyl
4-CF3C6H4
4-FC6H4
4-MeC6H4
Ph
Ph
Ph
Ph
2-pyridyl
Ar2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-pyridyl
2-pyridyl
4-CF3C6H4
4-FC6H4
4-MeC6H4
2-ClC6H4
4-ClC6H4
4-OMeC6H4
Ph
2-pyridyl
1
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1e
1f
1g
1h
1a
1b
R
Ph
4-ClC6H4
4-BrPh
4-MePh
Ph
Ph
4-ClC6H4
Ph
4-ClC6H4
Ph
Ph
4-ClC6H4
4-ClC6H4
Ph
Ph
H
H
R′
2
Ph
Ph
Ph
Ph
4-ClC6H4
4-OMePh
4-OMePh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2a
2b
2a
2a
2b
2b
2a
2a
2h
2h
3 (dr)b
3aa
3ab
3ac
3ad
3ae (1:1)
3af (1:1)
3ag (1:1)
3ba (1.5:1)
3bb (1.5:1)
3ca (19:1)
3da (1:1)
3eb (1:1)
3fb
3ga
3ha
3ah
3bh
3′ (dr)b
e
e
e
e
e
e
e
e
e
e
e
e
3fb′ (1.5:1)
3ga′g (1:1)
3ha′h (1:1)
e
e
3 + 3′ (%, %)c
75, 83
77, 89
70, 88
63,75
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
3:3′ (cr)d
5:95
70:30
16:84
Conditions 1: t-BuOK (100 mol %), DMSO, r.t, 16 h. Conditions 2: KCN (25 mol %), DMSO, r.t., 16 h. bDiastereomeric 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.
a
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 ESIMS/MS experiments and trapping of A with benzophenone.6
Next, to demonstrate the utility of the double C-aroylation
process, we showed that the 2-benzoyl-1,4-diones 3/3′ could
be converted into the corresponding all carbon substituted
olefins 6/6′ in a straightforward manner. Accordingly, the
copper-catalyzed oxidative dehydrogenation of isolated 3/3′
was briefly investigated in DMSO; full conversions in 6/6′ were
achieved using 10 mol % of Cu(OAc)2·H2O, t-BuOK (1 equiv),
and air as the terminal oxidant (80 °C, 2 h).18 This result paved
the way for the development of a convenient one-pot two-step
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 t-BuOK (100 mol %)
or KCN (25 mol %); then, after having established the
completion of the reaction by TLC analysis, the reaction
mixture containing the 2-benzoyl-1,4-dione 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).
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 tBuOK (or KCN) with lower kinetics but still high conversion
efficiency. A parallel ESI-MS investigation on 3aa oxidation
without the base was then carried out to identify key
intermediates of the catalytic cycle. When an acetonitrile
solution of 3aa was treated with Cu(OAc)2·H2O, formation of
the ionic cluster V corresponding to [3aa + CuII(AcO)]+ was
electrophilic carbon (blue colored) of α-diketone 1 forms the
intermediate I, which, in turn, evolves to the carbanion III via
the epoxide II (Scheme 2). Then, conjugate addition of III to
Scheme 2. Proposed Mechanism of the Double C-Aroylation
Reaction Promoted by the Dimsyl Anion A
chalcone 2 (R = Ar) affords the anion IV, which finally liberates
the double C-aroylation product 3/3′ and the promoter A
through an intramolecular Claisen-type 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 t-BuOK 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,
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DOI: 10.1021/jo502582e
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The Journal of Organic Chemistry
Note
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.
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 2-benzoyl-1,4-diones has been also demonstrated by
their facile conversion into the corresponding tetrasubstituted
olefins.
Table 3. One-Pot Two-Step Synthesis of Tetrasubstituted
Olefins 6/6′a,b,c
■
EXPERIMENTAL SECTION
Potassium tert-butoxide was purified by sublimation (200−220 °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 (230−
400 mesh). 1H (300 MHz), 13C (75 MHz), and 19F (282 MHz) NMR
spectra were recorded in CDCl3 solutions at room temperature. Peaks
assignments were aided by 1H−1H COSY and gradient-HMQC
experiments. ESI-MS 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 HPLC-Chip Q/
TOF-MS (nanospray) analysis using a quadrupole, a hexapole, and a
time-of-flight unit to produce spectra. Residual water of commercially
available anhydrous DMSO (0.016% w/w) was determined by Karl
Fisher analysis. Diketones 1a, 1b, 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 2-benzoyl1,4-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 argon-filled
balloon) three times. The mixture was stirred at the stated temperature
for 16 h, then diluted with H2O (5 mL), and 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 cyclohexane−AcOEt to give 3aa.
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
argon-filled balloon) three times. The mixture was stirred at the stated
temperature for 16 h, then diluted with H2O (5 mL), and 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 cyclohexane−AcOEt to give 3aa.
Entries 12−17. To a vigorously stirred mixture of benzil 1a (105
mg, 0.50 mmol), 2a (54 mg, 0.25 mmol), the 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
argon-filled balloon) three times. Then, the mixture was degassed
under vacuum and saturated with argon (by an argon-filled balloon)
three times. The mixture was stirred at the stated temperature for 16 h,
then diluted with H2O (5 mL), and 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 cyclohexane−AcOEt to give 3aa (no product formation in
entries 13−15).
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 tert-butoxide (112 mg, 1.00 mmol) was added in one
portion. Then, the mixture was degassed under vacuum and saturated
a
Yields (dimsyl catalysis/cyanide catalysis). bDiastereomeric ratio
determined by 1H and 13C NMR analyses of crude reaction mixtures.
c
First step performed using Cs2CO3 (100 mol %) as the base.
observed at m/z 540 (63Cu) (Scheme 3).20 Relevant is the fact
that V released AcOH during the MS/MS fragmentation with
Scheme 3. Proposed Mechanism for the Copper-Catalyzed
Aerobic Dehydrogenation of 3/3′ Based on an ESI-MS/MS
Study
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 copper-mediated
C−H activation may also occur in solution;19a β-hydride
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The Journal of Organic Chemistry
Note
(432.5): 455.5 (M + Na+). HRMS (ESI/Q-TOF) calcd for
C30H24NaO3 ([M + Na]+) 455.1623, found: 455.1614.
2-Benzoyl-1-(4-chlorophenyl)-3,4-diphenylbutane-1,4-dione
(3ae). Column chromatography with 10:1 cyclohexane−AcOEt
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 system. The first
eluted diastereoisomer was slightly contaminated by uncharacterized
byproducts: 1H NMR: δ = 8.05−7.96 (m, 2 H, Ar), 7.89−7.82 (m, 2
H, Ar), 7.66−7.58 (m, 2 H, Ar), 7.53−7.22 (m, 10 H, Ar), 7.14−7.08
(m, 2 H, Ar), 7.07−7.00 (m, 1 H, Ar), 6.31 (d, J = 10.7 Hz, 1 H, H-2),
5.78 (d, J = 10.7 Hz, 1 H, H-3); 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 cm−1. ESI MS
(452.9): 475.8 (M + Na+). HRMS (ESI/Q-TOF) calcd for
C29H21ClNaO3 ([M + Na]+) 475.1077, found: 475.1083. Second
eluted diastereoisomer: 1H NMR: δ = 8.05−7.96 (m, 2 H, Ar), 7.92−
7.85 (m, 2 H, Ar), 7.66−7.58 (m, 2 H, Ar), 7.52−7.43 (m, 2 H, Ar),
7.41−7.32 (m, 4 H, Ar), 7.29−7.22 (m, 4 H, Ar), 7.18−7.08 (m, 2 H,
Ar), 7.07−7.00 (m, 1 H, Ar), 6.31 (d, J = 10.7 Hz, 1 H, H-2), 5.77 (d, J
= 10.7 Hz, 1 H, H-3); 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 cm−1. ESI MS (452.9): 475.7 (M + Na+).
HRMS (ESI/Q-TOF) 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 cyclohexane−AcOEt afforded
3af (89 mg, 40%; conditions 1) as an inseparable 1:1 mixture of
diastereoisomers. Conditions 2: 3af (98 mg, 44%; dr = 1:1). 1H NMR:
δ = 8.05−7.98 (m, 2 H, Ar), 7.95−7.88 (m, 2 H, Ar), 7.73−7.64 (m, 2
H, Ar), 7.52−7.41 (m, 2 H, Ar), 7.41−7.32 (m, 4 H, Ar), 7.31−7.26
(m, 2 H, Ar), 7.15−7.06 (m, 2 H, Ar), 7.06−6.98 (m, 1 H, Ar), 6.85−
6.69 (m, 2 H, Ar), 6.32 (d, J = 10.8 Hz, 0.5 H, H-2′), 6.31 (d, J = 10.8
Hz, 0.5 H, H-2″), 5.79 (d, J = 10.8 Hz, 0.5 H, H-3′), 5.78 (d, J = 10.8
Hz, 0.5H, H-3″), 3.80 (s, 1.5 H, CH3′), 3.78 (s, 1.5 H, CH3″);
13
C{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 cm−1. ESI MS
(448.5): 471.7 (M + Na+). HRMS (ESI/Q-TOF) calcd for
C30H24NaO4 ([M + Na]+) 471.1572, found: 471.1559.
2-Benzoyl-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-4-phenylbutane-1,4-dione (3ag). Column chromatography with 7:1 cyclohexane−AcOEt 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 = 8.03−7.95 (m, 2 H, Ar), 7.94−7.85
(m, 2 H, Ar), 7.76−7.68 (m, 2 H, Ar), 7.53−7.36 (m, 4 H, Ar), 7.35−
7.17 (m, 4 H, Ar), 7.11−7.04 (m, 2 H, Ar), 6.84−6.73 (m, 2 H, Ar),
6.29 (d, J = 10.7 Hz, 0.5 H, H-2′), 6.28 (d, J = 10.7 Hz, 0.5 H, H-2″),
5.78 (d, J = 10.7 Hz, 0.5 H, H-3′), 5.76 (d, J = 10.7 Hz, 0.5 H, H-3″),
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 cm−1. ESI MS (482.9): 506.3 (M + Na+). HRMS (ESI/QTOF) 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 cyclohexane−AcOEt afforded 3ba
(166 mg, 79%; conditions 1) as an inseparable 1.5:1 mixture of
diastereoisomers. Conditions 2: 3ba (170 mg, 81%; dr = 1.5:1). 1H
NMR: δ = 8.71−8.66 (m, 1 H, Ar), 8.66−8.60 (m, 0.4 H, Ar”), 8.41−
8.34 (m, 0.6 H, Ar′), 8.23−8.12 (m, 1 H, Ar), 8.06−7.94 (m, 1 H, Ar),
with argon (by an argon-filled balloon) three times. The mixture was
stirred at room temperature until complete disappearance or best
conversion of the starting alkene (TLC analysis, ca. 2−16 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′.
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 argon-filled balloon) three times. The mixture was stirred
at room temperature until complete disappearance or best conversion
of the starting alkene (TLC analysis, ca. 2−16 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 cyclohexane−AcOEt afforded 3aa (155 mg,
75%; conditions 1) as a white amorphous solid. Conditions 2: 3aa
(174 mg, 83%). 1H NMR: δ = 8.08−7.98 (m, 2 H, Ar), 7.95−7.89 (m,
2 H, Ar), 7.70−7.65 (m, 2 H, Ar), 7.54−7.44 (m, 2 H, Ar), 7.43−7.32
(m, 4 H, Ar), 7.31−7.21 (m, 5 H, Ar), 7.14−7.06 (m, 2 H, Ar), 7.05−
6.95 (m, 1 H, Ar), 6.38 (d, J = 10.7 Hz, 1 H, H-2), 5.80 (d, J = 10.7
Hz, 1 H, H-3); 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
cm−1. ESI MS (418.4): 441.6 (M + Na+). HRMS (ESI/Q-TOF) 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 cyclohexane−AcOEt
afforded 3ab (174 mg, 77%; conditions 1) as a white amorphous
solid. Conditions 2: 3ab (202 mg, 89%). 1H NMR: δ = 8.04−7.96 (m,
2 H, Ar), 7.94−7.87 (m, 2 H, Ar), 7.74−7.67 (m, 2 H, Ar), 7.54−7.44
(m, 3 H, Ar), 7.44−7.35 (m, 3 H, Ar), 7.35−7.27 (m, 3 H, Ar), 7.24−
7.19 (m, 2 H, Ar), 7.12−7.03 (m, 2 H, Ar), 6.36 (d, J = 10.7 Hz, 1 H,
H-2), 5.79 (d, J = 10.7 Hz, 1 H, H-3); 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 cm−1. ESI MS (452.9): 475.7 (M +
Na+). HRMS (ESI/Q-TOF) calcd for C29H21ClNaO3 ([M + Na]+)
475.1077, found: 475.1084.
2-Benzoyl-3-(4-bromophenyl)-1,4-diphenylbutane-1,4-dione
(3ac). Column chromatography with 13:1 cyclohexane−AcOEt
afforded 3ac (173 mg, 70%; conditions 1) as a white amorphous
solid. Conditions 2: 3ac (218 mg, 88%). 1H NMR: δ = 8.04−7.96 (m,
2 H, Ar), 7.95−7.88 (m, 2 H, Ar), 7.73−7.67 (m, 2 H, Ar), 7.53−7.43
(m, 3 H, Ar), 7.42−7.36 (m, 3 H, Ar), 7.35−7.27 (m, 3 H, Ar), 7.26−
7.20 (m, 2 H, Ar), 7.18−7.12 (m, 2 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H,
H-2), 5.78 (d, J = 10.7 Hz, 1 H, H-3); 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 cm−1. ESI MS (497.4): 520.6 (M
+ Na+). HRMS (ESI/Q-TOF) 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 cyclohexane−AcOEt afforded 3ad
(136 mg, 63%; conditions 1) as a white amorphous solid. Conditions
2: 3ad (163 mg, 75%). 1H NMR: δ = 8.05−7.98 (m, 2 H, Ar), 7.95−
7.88 (m, 2 H, Ar), 7.73−7.64 (m, 2 H, Ar), 7.52−7.39 (m, 4 H, Ar),
7.38−7.33 (m, 3 H, Ar), 7.32−7.27 (m, 2 H, Ar), 7.18−7.09 (m, 2 H,
Ar), 6.93−6.88 (m, 2 H, Ar), 6.36 (d, J = 10.7 Hz, 1 H, H-2), 5.77 (d, J
= 10.7 Hz, 1 H, H-3), 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, 20.9;
IR (CDCl3) ν: 3063, 2919, 1691, 1688, 1687, 1595 cm−1. ESI MS
1941
DOI: 10.1021/jo502582e
J. Org. Chem. 2015, 80, 1937−1945
The Journal of Organic Chemistry
Note
477.9 (M + Na+). HRMS (ESI/Q-TOF) calcd for C29H20F2NaO3 ([M
+ Na]+) 477.1278, found: 477.1296.
2-Benzoyl-3-(4-chlorophenyl)-1,4-di-p-tolylbutane-1,4-dione
(3eb). Column chromatography with 12:1 cyclohexane−AcOEt
afforded 3eb (161 mg, 67%; conditions 1) as an inseparable 1:1
mixture of diastereoisomers. Conditions 2: 3eb (197 mg, 82%; dr =
1:1). 1H NMR: δ = 7.95−7.86 (m, 2 H, Ar), 7.85−7.78 (m, 1 H, Ar),
7.74−7.66 (m, 1 H, Ar), 7.65−7.57 (m, 1 H, Ar), 7.50−7.40 (m, 1 H,
Ar), 7.39−7.27 (m, 2 H, Ar), 7.23−7.15 (m, 5 H, Ar), 7.14−7.04 (m, 4
H, Ar), 6.32 (d, J = 10.7, 0.5 H, H-2′), 6.31 (d, J = 10.7, 0.5 H, H-2″),
5.77 (d, 1 H, J = 10.7 Hz, H-3′ and H-3″), 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 cm−1. ESI MS (481.0): 504.2 (M + Na+). HRMS
(ESI/Q-TOF) 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-(4chlorophenyl)-4-phenylbutane-1,4-dione (3fb′). Column chromatography with 13:1 cyclohexane−AcOEt 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 =
6.38 (d, J = 10.7 Hz, 1 H, H-2), 5.98 (d, J = 10.7 Hz, 1 H. H-3). 3fb′:
1
H NMR (1.5:1 mixture of diastereoisomers): δ = 7.98−7.92 (m, 2 H,
Ar), 7.75−7.65 (m, 1 H, Ar), 7.62−7.53 (m, 1 H, Ar), 7.52−7.42 (m, 2
H, Ar), 7.41−7.28 (m, 6 H, Ar), 7.26−7.13 (m, 4 H, Ar), 7.12−7.02
(m, 2 H, Ar), 6.42−6.27 (m, 1 H, H-2′ and H-2″), 5.79 (d, J = 10.7
Hz, 0.4 H, H-3′), 5.64 (d, J = 10.7 Hz, 0.6 H. H-3″). 13C{1H} NMR
(1.5:1 mixture of diastereoisomers): 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 cm−1.
ESI MS (487.4): 510.9 (M + Na+). HRMS (ESI/Q-TOF) calcd for
C29H20Cl2NaO3 ([M + Na]+) 509.0687, found: 509.0677.
2-Benzoyl-4-(4-chlorophenyl)-1,3-diphenylbutane-1,4-dione
(3ga). Column chromatography with 10:1 cyclohexane−AcOEt
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 = 7.98−7.92 (m, 2 H, Ar), 7.91−7.85
(m, 2 H, Ar), 7.70−7.64 (m, 2 H, Ar), 7.50−7.39 (m, 3 H, Ar), 7.38−
7.32 (m, 3 H, Ar), 7.28−7.21 (m, 4 H, Ar), 7.14−7.07 (m, 2 H, Ar),
7.06−6.98 (m, 1 H, Ar), 6.35 (d, J = 10.7 Hz, 1 H, H-2), 5.72 (d, J =
10.7 Hz, 1 H, H-3); 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 cm−1. ESI MS (452.9): 475.6 (M +
Na+); HRMS (ESI/Q-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 cyclohexane−AcOEt
afforded 3ha and 3ha′ (105 mg, 47%; conditions 1) as a 1:5.3
mixture of isomers slightly contaminated by uncharacterized byproducts. Conditions 2: 3ha and 3ha′ (130 mg, 58%; cr = 1:5.3). 3ha:
1
H NMR (selected data): δ = 6.39 (d, J = 10.7 Hz, 1 H, H-2), 5.80 (d,
J = 10.7 Hz, 1 H, H-3), 3.86 (s, 3 H, OCH3); 13C{1H} NMR (selected
data): δ = 55.0; IR (CDCl3) ν: 3063, 2927, 1673, 1671, 1597, 1575
cm−1. ESI MS (448.5): 471.6 (M + Na+); HRMS (ESI/Q-TOF) calcd
for C30H24NaO4 ([M + Na]+) 471.1572, found: 471.1573. 3ha′ = 3af.
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 cyclohexane−AcOEt afforded 3ah7a
(48 mg, 28%) as a yellow solid: mp 154−155 °C. 1H NMR: δ = 8.06−
7.94 (m, 6 H, Ar), 7.62−7.54 (m, 3 H, Ar), 7.51−7.40 (m, 6 H, Ar),
7.88−7.80 (m, 1 H, Ar), 7.78−7.65 (m, 2 H, Ar), 7.62−7.52 (m, 0.6 H,
Ar′), 7.48−7.41 (m, 0.4 H, Ar”), 7.41−7.12 (m, 8 H, Ar), 7.01−6.84
(m, 3 H, Ar), 6.90 (d, J = 11.5 Hz, 0.4 H, H-2″), 6.66 (d, J = 11.5 Hz,
0.6 H, H-2′), 6.42 (d, J = 11.5 Hz, 0.4 H, H-3″), 6.30 (d, J = 11.5 Hz,
0.6 H, H-3′); 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.
Six (0.4 C), 52.1 (0.6 C); IR (CDCl3) ν: 3057, 2916, 1691, 1690,
1685, 1581 cm−1. ESI MS (420.5): 421.9 (M + H+). HRMS (ESI/QTOF) calcd for C27H21N2O3 ([M + H]+) 421.1552, found: 421.1541.
2-Benzoyl-3-(4-chlorophenyl)-1,4-di(pyridin-2-yl)butane-1,4dione (3bb). Column chromatography with 4:1 cyclohexane−AcOEt
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 = 8.71−8.64 (m, 1.4 H, Ar), 8.44−8.37 (m, 0.6 H, Ar′),
8.18−8.11 (m, 1 H, Ar), 8.05−7.96 (m, 1.6 H, Ar), 7.89−7.82 (m, 1.4
H, Ar), 7.81−7.70 (m, 2 H, Ar), 7.66−7.59 (m, 1 H, Ar), 7.47−7.20
(m, 7 H, Ar), 6.98−6.87 (m, 2 H, Ar) 6.91 (d, J = 11.5 Hz, 0.4 H, H2″), 6.63 (d, J = 11.5 Hz, 0.6 H, H-2′), 6.40 (d, J = 11.5 Hz, 0.4 H, H3″), 6.28 (d, J = 11.5 Hz, 0.6 H, H-3′); 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 cm−1. ESI MS
(454.9): 456.3 (M + H + ). HRMS (ESI/Q-TOF) calcd for
C27H20ClN2O3 ([M + H]+) 455.1162, found: 455.1150.
2-Benzoyl-3-phenyl-1,4-bis(4-(trifluoromethyl)phenyl)butane1,4-dione (3ca). Column chromatography with 16:1 cyclohexane−
AcOEt afforded 3ca (83 mg, 30%; conditions 1) as a 19:1 mixture of
diastereoisomers slightly contaminated by uncharacterized byproducts.
Conditions 2: 3ca (88 mg, 32%; dr = 19:1). 1H NMR: δ = 8.12−8.06
(m, 2 H, Ar), 8.02−7.96 (m, 2 H, Ar), 7.78−7.70 (m, 2 H, Ar), 7.69−
7.58 (m, 4 H, Ar), 7.52−7.43 (m, 2 H, Ar), 7.32−7.27 (m, 2 H, Ar),
7.25−7.21 (m, 2 H, Ar), 7.16−7.10 (m, 2 H, Ar), 6.35 (d, J = 10.7 Hz,
1 H, H-2), 5.75 (d, J = 10.7 Hz, 1 H, H-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 cm−1. ESI MS
(554.5): 577.1 (M + Na+). HRMS (ESI/Q-TOF) 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 cyclohexane−AcOEt−
dichloromethane 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 = 8.09−7.98 (m, 2
H, Ar), 7.97−7.89 (m, 2 H, Ar), 7.68−7.61 (m, 2 H, Ar), 7.47−7.40
(m, 1 H, Ar), 7.32−7.22 (m, 4 H, Ar), 7.16−6.96 (m, 7 H, Ar), 6.30
(d, J = 10.7 Hz, 1 H, H-2), 5.72 (d, J = 10.7 Hz, 1 H, H-3); 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 to −104.0 (m), −104.7
to −104.9 (m); IR (CDCl3) ν: 3065, 2920, 1693, 1667, 1593 cm−1.
ESI MS (454.5): 477.1 (M + Na+). HRMS (ESI/Q-TOF) calcd for
C29H20F2NaO3 ([M + Na]+) 477.1278, found: 477.1293. Second
eluted diastereoisomer: 1H NMR: δ = 8.09−7.98 (m, 2 H, Ar), 7.93−
7.84 (m, 2 H, Ar), 7.77−7.63 (m, 2 H, Ar), 7.53−7.45 (m, 1 H, Ar),
7.40−7.30 (m, 2 H, Ar), 7.27−7.20 (m, 2 H, Ar), 7.17−7.01 (m, 5 H,
Ar), 7.01−6.88 (m, 2 H, Ar), 6.29 (d, J = 10.7 Hz, 1 H, H-2), 5.70 (d, J
= 10.6 Hz, 1 H, H-3); 13C{1H} 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 to −104.3 (m), −104.7 to −104.9 (m); IR
(CDCl3) ν: 3075, 2919, 1691, 1666, 1593 cm−1. ESI MS (454.5):
1942
DOI: 10.1021/jo502582e
J. Org. Chem. 2015, 80, 1937−1945
The Journal of Organic Chemistry
Note
6.12 (t, J = 7.0 Hz, 1 H, H-2), 3.78 (d, J = 7.0 Hz, 2 H, 2 H-3); IR
(CDCl3) ν: 3062, 2924, 1731, 1678, 1663, 1596 cm−1.
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 cyclohexane−AcOEt afforded 3bh
(129 mg, 75%;) as a yellow foam. 1H NMR: δ = 8.68−8.64 (m, 1 H,
Ar), 8.58−8.54 (m, 1 H, Ar), 8.14−8.00 (m, 4 H, Ar), 7.86−7.78 (m, 2
H, Ar), 7.60−7.52 (m, 1 H, Ar), 7.50−7.39 (m, 4 H, Ar), 6.47 (dd, 1
H, J = 5.0, 8.0 Hz, H-2), 4.17 (dd, 1 H, J = 8.0, 18.5 Hz, H-3a), 3.75
(dd, 1 H, J = 5.0, 18.5 Hz, H-3b); 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 cm−1. HRMS (ESI/Q-TOF) 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 tertbutoxide (56 mg, 0.50 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 × 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 cyclohexane−AcOEt to
give 6aa (197 mg, 95%).
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 tert-butoxide (112
mg, 1.00 mmol) was added in one portion. Then, the mixture was
degassed under vacuum and saturated with argon (by an argon-filled
balloon) three times. The mixture was stirred at room temperature
until complete disappearance or best conversion of the starting alkene
(TLC analysis, ca. 2−16 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′.
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 argon-filled balloon)
three times. The mixture was stirred at room temperature until
complete disappearance or best conversion of the starting alkene
(TLC analysis, ca. 2−16 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 cyclohexane−AcOEt afforded 6aa (135
mg, 65%; conditions 1) as a white amorphous solid. Conditions 2: 6aa
(158 mg, 76%). 1H NMR: δ = 8.01−7.93 (m, 2 H, Ar), 7.89−7.84 (m,
2 H, Ar), 7.84−7.77 (m, 2 H, Ar), 7.50−7.38 (m, 3 H, Ar), 7.37−7.32
(m, 3 H, Ar), 7.31−7.24 (m, 5 H, Ar), 7.17−7.10 (m, 3 H, Ar);
13
C{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 cm−1. ESI MS (416.5): 439.1 (M + Na+); HRMS (ESI/QTOF) calcd for C29H20NaO3 ([M + Na]+) 439.1310, found: 439.1318.
2-Benzoyl-3-(4-chlorophenyl)-1,4-diphenylbut-2-ene-1,4-dione
(6ab). Column chromatography with 13:1 cyclohexane−AcOEt
afforded 6ab (155 mg, 69%; conditions 1) as a white amorphous
solid. Conditions 2: 6ab (184 mg, 82%). 1H NMR: δ = 8.01−7.94 (m,
2 H, Ar), 7.88−7.85 (m, 4 H, Ar), 7.54−7.44 (m, 2 H, Ar), 7.44−7.33
(m, 5 H, Ar), 7.33−7.20 (m, 4 H, Ar), 7.18−7.08 (m, 2 H, Ar);
13
C{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 cm−1. ESI MS (450.9): 473.4 (M + Na+). HRMS (ESI/Q-TOF)
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 cyclohexane−AcOEt afforded 6ad
(112 mg, 52%; conditions 1) as a white amorphous solid. Conditions
2: 6ad (129 mg, 60%). 1H NMR: δ = 8.02−7.93 (m, 2 H, Ar), 7.89−
7.83 (m, 2 H, Ar), 7.82−7.76 (m, 2 H, Ar), 7.51−7.39 (m, 3 H, Ar),
7.39−7.30 (m, 4 H, Ar), 7.30−7.21 (m, 2 H, Ar), 7.21−7.11 (m, 2 H,
Ar), 6.99−6.87 (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 cm−1.
ESI MS (430.5): 453.1 (M + Na+). HRMS (ESI/Q-TOF) calcd for
C30H22NaO3 ([M + Na]+) 453.1467, found: 453.1470.
(E/Z)-2-Benzoyl-1-(4-chlorophenyl)-3,4-diphenylbut-2-ene-1,4dione (6ae). Column chromatography with 10:1 cyclohexane−AcOEt
afforded 6ae (129 mg, 60%; conditions 1) as a 1:1 mixture of
diastereoisomers. Conditions 2: 6ae (186 mg, 83%; E/Z = 1:1). 1H
NMR: δ = 8.01−7.94 (m, 1 H, Ar′), 7.94−7.88 (m, 1 H, Ar”), 7.87−
7.73 (m, 4 H, Ar), 7.52−7.40 (m, 2 H, Ar), 7.40−7.32 (m, 3 H, Ar),
7.32−7.21 (m, 5 H, Ar), 7.21−7.08 (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 cm−1. ESI MS
(450.9): 473.6 (M + Na+). HRMS (ESI/Q-TOF) calcd for
C29H19ClNaO3 ([M + Na]+) 473.0920, found: 473.0903.
(E/Z)-2-Benzoyl-3-(4-chlorophenyl)-1-(4-methoxyphenyl)-4phenylbut-2-ene-1,4-dione (6ag). Column chromatography with 7:1
cyclohexane−AcOEt 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 = 8.05−7.99 (m, 1 H, Ar′), 7.99−7.92 (m, 1 H,
Ar”), 7.84−7.80 (m, 4 H, Ar), 7.53−7.43 (m, 2 H, Ar), 7.42−7.31 (m,
3 H, Ar), 7.29−7.19 (m, 3 H, Ar), 7.18−7.07 (m, 2 H, Ar), 6.89−6.81
(m, 1 H, Ar), 6.81−6.72 (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 cm−1. ESI MS (480.9): 503.6 (M + Na+). HRMS
(ESI/Q-TOF) calcd for C30H21ClNaO4 ([M + Na]+) 503.1026,
found: 503.1032.
(E/Z)-2-Benzoyl-3-(4-chlorophenyl)-1,4-di-p-tolylbut-2-ene-1,4dione (6eb). Column chromatography with 12:1 cyclohexane−AcOEt
afforded 6eb (148 mg, 62%; conditions 1) as a 1:1 mixture of
diastereoisomers. Conditions 2: 6eb (191 mg, 80%; E/Z = 1:1). 1H
NMR: δ = 8.01−7.94 (m, 1 H, Ar′), 7.92−7.85 (m, 1 H, Ar”), 7.85−
7.69 (m, 4 H, Ar), 7.59−7.43 (m, 1 H, Ar), 7.43−7.33 (m, 1 H, Ar),
7.33−7.25 (m, 1 H, Ar), 7.25−7.19 (m, 2 H, Ar), 7.18−7.05 (m, 6 H,
Ar), 2.35 (s, 1.5 H, CH3), 2.34 (s, 3 H, CH3), 2.29 (s, 1.5 H, CH3);
13
C{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 cm−1. ESI MS (479.0): 502.3 (M + Na+). HRMS (ESI/Q-TOF)
calcd for C31H23ClNaO3 ([M + Na]+) 501.1233, found: 501,1250.
(E/Z)-2-Benzoyl-1-(2-chlorophenyl)-3-(4-chlorophenyl)-4-phenylbut-2-ene-1,4-dione (6fb′). Column chromatography with 13:1
cyclohexane−AcOEt afforded 6fb′ (92 mg, 38%) as a 1:1 mixture of
diastereoisomers. Conditions 2: 6fb′ (111 mg, 46%; E/Z = 1:1). 1H
1943
DOI: 10.1021/jo502582e
J. Org. Chem. 2015, 80, 1937−1945
The Journal of Organic Chemistry
Note
NMR: δ 7.99−7.91 (m, 4 H, Ar), 7.59−7.53 (m, 1 H, Ar), 7.52−7.45
(m, 2 H, Ar), 7.41−7.33 (m, 4 H, Ar), 7.24−7.17 (m, 5 H, Ar), 7.13−
7.05 (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 cm−1. ESI MS (485.4): 508.0 (M +
Na+). HRMS (ESI/Q-TOF) 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 cyclohexane−AcOEt
afforded 6ga (85 mg, 38%; conditions 1) as a white amorphous
solid. Conditions 2: 6ga (99 mg, 44%). 1H NMR: δ = 7.99−7.92 (m, 2
H, Ar), 7.82−7.74 (m, 4 H, Ar), 7.50−7.39 (m, 2 H, Ar), 7.38−7.30
(m, 5 H, Ar), 7.29−7.22 (m, 3 H, Ar), 7.19−7.12 (m, 3 H, Ar);
13
C{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 cm−1. ESI MS (450.9): 473.8 (M + Na+). HRMS (ESI/QTOF) calcd for C29H19ClNaO3 ([M + Na]+) 473.0920, found:
473.0922.
Aerobic Oxidative Dehydrogenation of 3aa in the Presence
of TEMPO. To a vigorously stirred mixture of 3aa (209 mg, 0.50
mmol), potassium tert-butoxide (112 mg, 1.00 mmol), (2,2,6,6tetramethyl-piperidin-1-yl)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 × 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 cyclohexane−AcOEt to give 6aa (135 mg, 65%).
■
(4) Giovannini, P. P.; Bortolini, O.; Cavazzini, A.; Greco, R.; Fantin,
G.; Massi, M. Green Chem. 2014, 16, 3904−3915 and references
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(5) (a) Bortolini, O.; Cavazzini, A.; Dambruoso, P.; Giovannini, P. P.;
Caciolli, L.; Massi, A.; Pacifico, S.; Ragno, D. Green Chem. 2013, 15,
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3244−3252.
(7) During the preparation of this manuscript, Takaki and co-workers
reported the NHC-catalyzed double acylation of enones with benzils:
(a) Takaki, K.; Ohno, A.; Hino, M.; Shitaoka, T.; Komeyama, K.;
Yoshida, H. Chem. Commun. 2014, 50, 12285−12288. For the double
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44, 448−450.
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reaction efficiency.
(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,
6579−6586.
(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 % t-BuOK, DMSO, 30 min).
(15) (a) Kuebrich, J. P.; Schowen, R. L. J. Am. Chem. Soc. 1971, 93,
1220−1223. (b) Kwart, H.; Baevsky, M. M. J. Am. Chem. Soc. 1958, 80,
580−588.
(16) The reversible (equilibrium) addition of dimsyl anion to
carbonyl compounds has been reported: Walling, C.; Bollyky, L. J. Org.
Chem. 1963, 28, 256−257.
(17) The proton exchange between DMSO and t-BuOK is a very fast
process: (a) Brauman, J. I.; Nelson, N. J.; Kahl, D. C. J. Am. Chem. Soc.
1968, 90, 490−491. (b) Brauman, J. I.; Nelson, N. J. J. Am. Chem. Soc.
1968, 90, 491−492.
(18) Yang, Y.; Ni, F.; Shu, W.-M.; Yu, S.-B.; Gao, M.; Wu, A.-X. J.
Org. Chem. 2013, 78, 5418−5426.
(19) (a) Liang, L.; Yang, G.; Wang, W.; Xu, F.; Niu, Y.; Sun, Q.; Xu,
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Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062−
11087.
(20) The positive charge of cations V and VI detected in the gas
phase is balanced in the solution phase by the acetate counteranion.
The formation of a dicarbonyl copper chelate complex through
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 β-hydride elimination step
already claimed in similar copper-catalyzed oxidative dehydrogenations
(see ref 19a).
(21) The mechanism by which Cu(OAc)2 is regenerated after the
supposed β-hydride elimination step is not clear to us; recent studies
ASSOCIATED CONTENT
S Supporting Information
*
NMR spectra of 3/3′ and 6/6′ and ESI-MS spectra of V−VI.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail: olga.bortolini@unife.it (O.B.).
*E-mail: alessandro.massi@unife.it (A.M.).
Notes
The authors declare no competing financial interest.
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 high-resolution mass spectrometric experiments.
■
■
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1944
DOI: 10.1021/jo502582e
J. Org. Chem. 2015, 80, 1937−1945
The Journal of Organic Chemistry
Note
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1945
DOI: 10.1021/jo502582e
J. Org. Chem. 2015, 80, 1937−1945