N-Heterocyclic carbene-catalyzed double acylation of enones with benzils

Article abstract of DOI:10.1039/c4cc05436a

Thiazolium carbene-catalyzed reaction of aromatic 1,2-diketones with enones in aprotic solvents gave double acylation products in good yields, whereas hydroacylation products formed by Stetter reaction were not detected at all. These results suggested the generation of aroyloxyenamine species from the 1,2-diketones instead of hydroxyenamines (Breslow intermediates). This journal is

Full text of DOI:10.1039/c4cc05436a

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N-Heterocyclic carbene-catalyzed double
acylation of enones with benzils†
Cite this: Chem. Commun., 2014,
50, 12285
Ken Takaki,* Akira Ohno, Makoto Hino, Takashi Shitaoka, Kimihiro Komeyama and
Hiroto Yoshida
Received 15th July 2014,
Accepted 26th August 2014
DOI: 10.1039/c4cc05436a
www.rsc.org/chemcomm
Thiazolium carbene-catalyzed reaction of aromatic 1,2-diketones
with enones in aprotic solvents gave double acylation products in
good yields, whereas hydroacylation products formed by Stetter
reaction were not detected at all. These results suggested the
generation of aroyloxyenamine species from the 1,2-diketones
instead of hydroxyenamines (Breslow intermediates).
N-Heterocyclic carbenes (NHCs) have attracted much attention
as organocatalysts in organic synthesis, because they can convert
various electrophilic functional groups into nucleophilic ones
via Breslow1 and deoxy-Breslow intermediates.2 For example, the
Stetter reaction has been most frequently used in many trans-
formations as a method for Michael addition of acyl anions.3
However, this reaction is applicable to aldehydes only, not to
ketones and esters in general. From a mechanistic point of view,
when aldehydes I are substituted by other carbonyl compounds V,
Scheme 1 Extension of Stetter reaction.
functional enamines VI would be generated by the reaction with generated from V, they afforded the same products IV as those
NHC II, instead of Breslow intermediates III (Scheme 1). If the new derived from the corresponding aldehydes I.
species VI are sufficiently nucleophilic, acyl and functional group G
To develop the new double acylation reaction, we investigated
could be delivered to the b- and a-position of a,b-unsaturated the reaction of benzils V (G = ArCO) with enones. 1,2-Diketones
carbonyl compounds, respectively. This process would be expected have been used as acceptors of the umpolung species formed by an
to extend the scope of Stetter reaction.
NHC.7 Moreover, it has been reported that aromatic 1,2-diketones
On the other hand, few examples of generation of Breslow did not afford any Stetter-type products, because 1,4-thiazin-3-ones,
intermediate III from the carbonyl compounds V other than 1 : 1 adducts of thiazolium carbenes and the diketones, were
aldehydes I have been reported. Scheidt et al. employed acylsilanes4 formed exclusively.8,9 On the other hand, cyanide ion-catalyzed
and a-keto carboxylates5 in the Stetter reaction to avoid self- umpolung of benzils has been achieved in the cross-benzoin
condensation or benzoin products, giving rise to the hydro- condensation,10 which suggests the possibility of retaining the
acylation products IV in high yields through the elimination of two benzoyl groups in the final products. Fortunately, we found
alkoxysilanes or CO2. Recently, Massi et al. demonstrated that that the reaction gave double acylation products VII in good yields
aliphatic 1,2-diketones could be used as aldehyde equivalents, for the first time.
wherein one acyl moiety was eliminated by alcoholic solvents.6
Initially, benzil (1a) was treated with one equivalent of phenyl
As a result, even though the functional enamines VI could be vinyl ketone (2a) under various conditions (Table 1). In the presence
of the thiazolium salt A (20 mol%), DIPEA as base and DMF as
solvent gave better yield of the double acylation product 3aa than
the Et3N–DCE system (entries 1 and 2). Mild heating of the reaction
increased the yield from 53% to 94% (entry 3). Of the NHC salts
Department of Applied Chemistry, Graduate School of Engineering,
Hiroshima University, Kagamiyama, Higashi-Hiroshima 739-8527, Japan.
E-mail: ktakaki@hiroshima-u.ac.jp
tested, thiazolium salts B and C gave 3aa in 77% and 73% yields,
respectively, along with trace amounts of hydroacylation product 4
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. See DOI: 10.1039/c4cc05436a
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Table 1 Optimization of the reaction conditions
Table 2 Reaction with various enones
Entry
Enone 2
R
Time (h)
Product 3
Yielda (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Ph
o-Tolyl
m-Tolyl
p-Tolyl
Mesityl
p-Anisyl
o-ClC6H4
p-ClC6H4
p-NCC6H4
1-Naphthyl
2-Naphthyl
2-Thienyl
3-Thienyl
Me
12
18
12
12
36
12
12
12
12
12
12
12
12
20
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
92
58
80
89
13
75
53
87
37
67
87
87
89
68
Yielda (%)
Entry
NHC salt
Base
Solvent
Temp. (1C)
3aa
4
1
2
3
4
5
6
7
8
9
A
A
A
A
B
B
C
D
E
Et3N
DCE
rt
rt
17
53
94
56
77
60
73
9
0
0
0
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DMF
DMF
EtOH
DMF
EtOH
DMF
DMF
DMF
50
50
50
50
50
50
50
9
11
Trace
9
Trace
0
0
10
11
12
13
14b
0
a
b
a
Isolated yield. 3 equiv. of 2n were used.
NMR yield.
reaction of unsymmetrical diketones 1f and 1g, two regioisomers 3
and 30 were formed as inseparable mixtures, wherein relatively
electron deficient aryl groups were introduced into the b-position of
enone 2a, though with low selectivities (entries 5 and 6). The
reaction of 1-phenypropane-1,2-dione (1h) gave products 3ha and
3an in 42% yield with a ratio of 83/17 (entry 7).
As can be seen in Table 3, electron donating groups of the
diketones decreased the product yields (entries 1, 2, and 7). Thus, we
attempted their improvement by use of Lewis acid co-catalysts.12 The
yields of 3ba, 3ca and (3ha + 3an) actually increased to 90%, 49%
and 62%, respectively, with 20 mol% of MgCl2. However, the effect
was not always so positive for all products 3 (see ESI†).
More importantly, the reaction of unsymmetric benzils 1f–1h
gave no cross-products, for example, neither 3aa nor 3ba was
formed in the reaction of 1f. These results suggested that double
acylation would take place intramolecularly. In order to confirm
this hypothesis, the reaction of 2a with an equimolar mixture of
(entries 5 and 7). The triazolium and imidazolium salts D and E
gave little or no expected product (entries 8 and 9). Formation of
the by-product 4 with B and C might be caused by the OH group
attached to the thiazolium skeleton. In fact, when the reactions
with A and B were carried out in EtOH solvent, 4 was formed in
11% and 9% yields, respectively, though as a minor product
(entries 4 and 6). No reaction took place, of course, in the absence
of NHC salts.
The reaction of benzil (1a) with various aryl vinyl ketones 2
was carried out under the optimal conditions (Table 2). Sub-
strates 2 having both electron donating and withdrawing sub-
stituents on the p-position of the phenyl ring gave products 3 in
high yields (entries 4, 6, and 8), except for p-cyanopheny enone
2i (entry 9). On the contrary, the substituents on the o-position
afforded 3 in decreased yields, probably due to steric hindrance
as well as the reaction with mesityl vinyl ketone (2e) (entries 2,
5, and 7).11 A similar difference between 1- and 2-naphthyl
substrates 2j and 2k was observed (entries 10 and 11). More-
over, the present reaction could be applicable to the heteroaro-
matic and aliphatic substrates 2l, 2m and 2n (entries 12–14).
Next we investigated the reaction of symmetrical and unsym-
metrical benzil derivatives 1b–1h with phenyl vinyl ketone (2a)
(Table 3). Bis-p-tolyl and bis-p-anisyldiketones 1b and 1c gave
product 3ba and 3ca in 48% and 16% yields, respectively,
whereas 4-chloro and 4-bromo-substituted diketone 1d and 1e
produced 3da and 3ea in better yields (entries 1–4). In the
Table 3 Reaction of substituted benzils
Benzil 1
Product
Yielda (%)
R1
Entry
R2
3
30
(3 + 30)
Ratio (3/30)
1
1b p-Tolyl
1c p-Anisyl
1d p-ClC6H4 p-ClC6H4 3da
1e p-BrC6H4 p-BrC6H4 3ea
1f Ph
1g Ph
1h Ph
p-Tolyl
p-Anisyl
3ba
3ca
—
—
—
—
48
16
70
73
—
—
—
—
40/60
55/45
83/17
2
3b
4b
5
p-Tolyl
p-ClC6H4 3ga 3ah 85
Me 3ha 3an 42
3fa 3ad 80
6
7
a
b
Total isolated yield. DMF (0.25 M).
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Scheme 2 Intramolecular double acylation.
symmetrical benzils 1a and 1e was carried out under standard
conditions (Scheme 2). The two diketones reacted independently
with 2a to yield products 3aa and 3ea in 91% and 85% yields,
respectively, whereas cross-products were not detected.
Compared to benzil derivatives, aliphatic 1,2-diketones gave
the expected product in lower yields (Scheme 3). Thus, the
double acylation product 3ia was obtained in only 16% yield by the
reaction of biacetyl (1i) with enone 2a, but the corresponding
hydroacylation product was not formed. Interestingly, the reaction
of cyclohexane-1,2-dione (1j) gave 8-membered triketone 3ja in 27%
yield. It is noteworthy that this ring-expansion reaction showed a
striking contrast to the thiazolium carbene-catalyzed ring-opening
hydroacylation of chalcones with 1j in EtOH.6a
Scheme 4 Proposed mechanism.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Notes and references
A plausible mechanism of the double acylation is proposed
in Scheme 4. Addition of carbene A to benzil (1), followed by
migration of the benzoyl group to the alkoxide moiety, yields
the acylated Breslow intermediate G. Michael addition of G to
enone 2 generates zwitterion H. Then, intramolecular abstraction of
the benzoyl group by enolate results in the formation of product 3
and regeneration of A. Although this mechanism is analogous to
that of Stetter reaction, suppression of the benzoyl group elimination
from the intermediate F or G in anhydrous aprotic solvent would
lead to double acylation. The low yields with aliphatic 1,2-diketones
may be caused by inefficient alkanoyl migration in F as well as
enolization of the diketone.
In summary, we have succeeded in the extension of Stetter
reaction, i.e., thiazolium carbene-catalyzed reaction of benzils
with enones gave double acylation products in good yields,
whereas hydroacylation by classical Stetter reaction was completely
excluded. These results provide new potential for NHC-catalyzed
reaction, by allowing the insertion of activated carbon–carbon
multiple bonds into other acyl compounds than aldehydes.
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Scheme 3 Reaction of aliphatic 1,2-diketone.
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9 Ring-opening reaction of cyclic 1,2-diketones to yield a,o-dicarboxylic
acid derivatives has been accomplished also by use of triazo-
consumed much faster than benzil 1a in the low yield reactions
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¨
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11 The double acylation reaction seems to compete with some side
reactions like oligomerization of the enones 2, because they were
12288 | Chem. Commun., 2014, 50, 12285--12288
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