Proline-catalyzed aldol reactions of acyl cyanides with acetone: An efficient and convenient synthesis of 1,3-diketones

Article abstract of DOI:10.1016/j.tetlet.2005.10.036

The aldol-type addition of acetone towards (un)substituted benzoyl, heteroarylcarbonyl or α,β-unsaturated acyl cyanides was efficiently catalyzed by l-proline (30 mol %) to give 2-hydroxy-4-oxo-2-substituted pentanenitriles. Upon the treatment with sodium hydroxide, the adducts transformed to 1,3-diketones in good-to-excellent yield, furnishing an efficient and convenient method for the regioselective synthesis of 1,3-diketones.

Full text of DOI:10.1016/j.tetlet.2005.10.036

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8785–8788
Proline-catalyzed aldol reactions of acyl cyanides with acetone:
an efficient and convenient synthesis of 1,3-diketones
Zongxuan Shen, Bin Li, Lu Wang and Yawen Zhang*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University,
Suzhou 215006, China
Received 3 August 2005; revised 8August 2005; accepted 11 October 2005
Abstract—The aldol-type addition of acetone towards (un)substituted benzoyl, heteroarylcarbonyl or a,b-unsaturated acyl cyanides
was efficiently catalyzed by L-proline (30 mol %) to give 2-hydroxy-4-oxo-2-substituted pentanenitriles. Upon the treatment with
sodium hydroxide, the adducts transformed to 1,3-diketones in good-to-excellent yield, furnishing an efficient and convenient
method for the regioselective synthesis of 1,3-diketones.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1,3-Diketones are one of the most synthetically impor-
tant classes of compounds.
2002, Stephen J. Haswell reported the C-acylation of
lithium enolate or silyl enol ether with acyl cyanide,
which excluded the formation of O-acylated product.
However, the ketone must be converted to its enolate
by using LiHMDS, an expensive reagent, or a silyl enol
ether must be prepared beforehand.6
One of the familiar syntheses of 1,3-diketones is the
C-acylation of simple ketones via their metal enolates,
enamines or silyl enol ethers, using acyl chlorides or cya-
nides as the acylating reagent, with or without catalysts.
Since the ketone anions (1) are ambident, such acylating
reaction often results in the formation of a mixture of
C-acylated product (2) and O-acylated product (3), which
are difficult to separate (Scheme 1). Although some
methods such as the reaction of ketone metal enolates
with acyl chlorides1 or acyl cyanides,2 the acylation of
enamines,3 the direct BF3 acylation of ketones,4 and
the C-acylation of silyl enol ethers,5 had been reported
as reactions, which preferentially lead to C-acylated
ketones, the 1,3-diketones obtained are usually contami-
nated with variable amounts of O-acylated products. In
The second familiar synthesis of 1,3-diketones is the
C-acylation of acetylacetone or its derivatives by acyl
halides or esters followed by base-promoted cleavage
of a carbonyl group. The C-acylation of acetylacetone
using acyl chloride in the presence of a base, also suf-
fered from the competition of O-acylation. For example,
under phase-transfer conditions, acylation of acetylace-
tone and of ethyl acetoacetate with acetyl chloride and
benzoyl chloride yielded O-acylated enol esters predo-
minantly.7 The chemoselectivity of such acylations
depends on the nature of the solvent, electrophile, metal
counterion, reaction temperature and structure of the
substrate. Alan R. Katritzky reported a novel method
for the preparation of 1,3-diketones from acetylacetone
using the strategy of acylation–deacylation, in which,
1-acylbenzotriazoles were employed as the acylating
reagents.8 However, to improve the yield of this reaction
is still necessary.
O
O
O
O
R
MO
RCOX
MX
+
R
2
1
3
Scheme 1. Formation of C- and O-acylated products.
As a versatile organocatalyst, proline has drawn much
attention in recent years.9 We were interested in broaden-
ing the scope of proline-catalyzed asymmetric aldol-type
addition. In the view of electron effects, the electron-
withdrawing cyano group in an acyl cyanide molecule
Keywords: 1,3-Diketones; Proline; Acyl cyanides; Acetone; Addition.
*
Corresponding author. Tel.: +86 0512 65118573; fax: +86 0512
65112371; e-mail: zhangyw@suda.edu.cn
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.036

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Z. Shen et al. / Tetrahedron Letters 46 (2005) 8785–8788
Figure 1. 1H NMR spectrum of 2-hydroxy-4-oxo-2-phenyl-pentane-nitrile containing 1-phenyl-butane-1,3-dione as impurity.
Table 1. Syntheses of 1,3-diketones from acyl cyanides and acetone12
would enhance the reactivity of the adjacent carbonyl
carbon atom so that a proline-catalyzed aldol-type addi-
tion of acetone to acyl cyanide may occur. Indeed, ben-
zoyl cyanide, when stirred with proline in acetone at
room temperature, gave a new compound, which was
identified as the expected aldol-type adduct (5a). This
adduct was found labile and eliminated HCN to form
1,3-diketone during chromatographic purification or
storage at room temperature. From the 1H NMR
spectrum of the crude 2-hydroxy-4-oxo-2-phenyl-pen-
tanenitrile (Fig. 1) one can find the presence of 1-phen-
yl-butane-1,3-dione (6a), formed from the adduct by
elimination of a hydrogen cyanide molecule. However,
analogue 5g was found so stable that it could be purified
by column chromatography and characterized by
NMR.10 Also, evidence for the formation of the adduct
5a has been received from its acetylation and character-
ization of the resulting compound.11
Entry
R
Cat
Product t (h) Yield %
(mol %)
(Conv %)
1
2
3
4
5
6
7
Ph
30
60
60
6a
6b
6c
6d
6e
6f
30
72
96
96
11
10
12
10
15
10
7
9 188
60
93
75
4-Me-C6H4
2-Me-C6H4
4-MeO-C6H4 60
<10 (16.7)
71
92
93
94
92
87
90
2-F-C6H4
4-F-C6H4
2-Cl-C6H4
6H4
2-Br-C6H4
4-Br-C6H4
4-NO2-C6H4
Ph-CH@CH
Furan-2-yl
30
30
30
30
30
30
30
30
30
6g
6h
6i
84-Cl-C
9
10
11
12
13
6j
6k
6l
8
8
6m
82
From the data listed in Table 1, we found that for most
acyl cyanide tested, diketone was obtained in good to
excellent yield when the reaction was carried out at
room temperature. The substitution effects were obvi-
ous: the introduction of an electron-withdrawing substi-
tuent accelerated the reaction while electron-donating
substituents retarded the reaction. For example, the
shortest reaction time was found in the reaction of
4-nitrobenzoyl cyanide, which has a typical electron-
withdrawing substituent NO2 in the molecule (entry
11); reaction of substrates with electron-donating substi-
tuent, such as methyl or methoxy group, gave relatively
low yield and need longer reaction time than benzoyl
cyanide itself, even with 60 mol % of L-proline. Also,
regular stereo effects were observed. All ortho-substi-
tuted substrates had some-lower reaction rate compared
to the corresponding para-substituted congener. Espe-
cially, the reaction of 2-methylbenzoyl cyanide was too
slow to be practically employed for the preparation of
the corresponding 1,3-diketone.
After evaporation of the excess acetone, the treatment of
the crude adduct 5a with base, afforded C-acylated
acetone 6a in excellent yield, without any detectable
formation of O-acylated or diacylated product. This
proline-catalyzed aldol-type addition furnished an
efficient, convenient and regio-specific method for
the C-acylation of acetone, affording 1,3-diketones after
a base-promoted elimination of hydrogen cyanide
(Scheme 2).
Encouraged by this success, a variety of acyl cyanides,
including substituted benzoyl, cinnamoyl, furan-2-car-
bonyl cyanide were then tested. The results are summa-
rized in Table 1.
O
O
NC OH
O
O
acetone
OH
L-proline
30 mol%
R
CN
R
R
6a-m
4a-m
5a-m
From the data listed in Table 2, we noticed that under the
reaction conditions, proline itself could be acylated and
lost in catalytic activity.13 Employment of proline much
less than 30 mol % (10 mol %, for example) was proved
disadvantageous (entry 2) probably because the lowered
catalyst amount decreased the reaction rate, resulting in
a prolonged reaction time, which offered a chance of pro-
line N-acylation, which decreases the reaction rate fur-
ther and the reaction could not be completed in fact.
a: R = Ph;
h: R = 4-Cl-C6H4;
i: R = 2-Br-C6H4;
j: R = 4-Br-C6H4;
k: R = 4-NO2-C6H4;
l: R = Ph-CH=CH;
m: R = furan-2-yl
b: R = 4-CH3-C6H4;
c: R = 2-CH3-C6H4;
d: R = 4-CH3O-C6H4;
e: R = 2-F-C6H4;
f: R = 4-F-C6H4;
g: R = 2-Cl-C6H4;
Scheme 2. L-Proline-catalyzed acylation of acetone with acyl cyanides
as the acylating reagents.

Z. Shen et al. / Tetrahedron Letters 46 (2005) 8785–8788
8787
Table 2. Effects of temperature and amount of the catalyst
O
O
O
O
O
H2O
Entry
R
Cat
T (ꢁC) Product t (h) Yield %
O
N
N
N
(mol %)
(Conv %)
H
H
H
H
O
H
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
30
10
30
30
rt
rt
À25
À78
rt
6a
6a
6a
6a
6b
6b
6b
30
72
32
72
72
72
72
93
61
90
6.3 (6.6)
75
O
O
O
CN
O
O
4-MeC6H4 60
4-MeC6H4 60
4-MeC6H4 60
H
N
N
HO CN
R
H
R
N
N
OH
À25
74
8.6 (9.2)
O
O
RCOCN
À78
H2O
With the reactions conducted at À25 ꢁC, no significant
changes in reaction time and yield were found (entries
3 and 6), probably because the N-acylation of proline
was restricted at this temperature. At À78 ꢁC, the reac-
tion proceeded very slowly (entries 4 and 7).
O
O
O
O
HO CN
R
proline
OH
HCN
HO CN
R
H
R
O
OH
Scheme 3. A proposed mechanism.
A variety of proline derivatives were also tested as catal-
ysts for this reaction under standard conditions (Table
3). To our surprise, (4R)-hydroxy-(S)-proline did not
show any catalytic activity, although it was reported
to catalyze intermolecular aldol reaction between ace-
tone and aldehydes enantioselectively.14 However, the
O-alkylated or arylated hydroxyprolines were found to
be effective catalysts for this reaction (entries 5, 6, 7,
and 8). Among them, (4S)-phenoxy-(S)-proline and
(4R)-phenyl-methoxy-(S)-proline showed catalytic activi-
ties similar to that of proline itself, while proline
derivatives with steric hindered substituents showed
lower activities. Aminoalcohols did not show any
catalytic activity (entries 1 and 4), although (S)-N-
((1S,2S)-2-hydroxy-1,2-diphenylethyl)pyrrolidine-2-car-
boxamide showed an excellent catalytic activity for the
intermolecular aldol additions between acetone and
substituted benzaldehydes.15
Table 3. Catalytic activity of various proline derivatives
Entry
Cata
t (h)
Yield (%)b
—
A mechanism, similar to that proposed by Carlos F.
Barbas III14 for the aldol addition of acetone to aldehyde,
was proposed, as shown in Scheme 3. We supposed that
acetone was activated by formation of an enamine with
proline. An acyl cyanide molecule was pulled close to the
enamine by the proline hydroxyl group through hydro-
gen-bonding interaction. The enamine attacked the car-
bonyl group of the acyl cyanide acceptor, forming the
key intermediate, which then eliminated HCN on treating
with sodium hydroxide to afford the 1,3-diketone.
Ph
O
Ph
OH
1
—
N
H
NH
CO2H
2
3
30
—
93
—
N
H
HO
CO2H
N
H
HO
PhO
Ph
Ph
Ph
In summary, we have shown that the aldol-type addition
of acetone towards (un)substituted benzoyl, heteroaryl-
carbonyl, and a,b-unsaturated acyl cyanides was
efficiently catalyzed by L-proline (30 mol %), to give
2-hydroxy-4-oxo-2-substituted-pentanenitriles in good-
to-excellent yields. On treating with sodium hydroxide,
the adducts eliminated HCN, furnishing an efficient
and convenient method for regioselective synthesis of
1,3-diketones.
4
5
6
—
25
24
—
94
94
N
H
OH
CO2H
N
H
O
CO2H
N
H
O
Acknowledgements
7
8
8 488
CO2H
N
H
We thank the Key Laboratory of Organic Synthesis of
Jiangsu Province, China, for financial support (No.
JSK015).
O
50
87
CO2H
N
H
References and notes
aAll reactions were carried out at room temperature, employing
30 mol % of the catalyst.
bChemical yields are given on the isolated products and all products
are determined by IR, 1H NMR, 13C NMR, HRMS, etc.
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8788
Z. Shen et al. / Tetrahedron Letters 46 (2005) 8785–8788
2. Howard, A. S.; Meerholz, C. A.; Michael, J. P. Tetra-
12. A typical procedure for the reaction of acyl cyanides with
acetone is as follows: L-proline (70 mg, 0.6 mmol) was
stirred in acetone (10 mL) for 30 min. To this was added
acyl cyanide (2.0 mmol) at room temperature while
stirring for the desired time given in Table 1 (checked by
TLC, ether/ethyl acetate = 4:1, v/v). The solid was
removed by filtration and the filtrate was evaporated
under reduced pressure. The residue was stirred in a
mixture of CH2Cl2 (10 mL) and 5% NaOH (5 mL) for
30 min, extracted with CH2Cl2 (3 · 5 mL). The combined
organic phases were dried over anhydrous Na2SO4 and
concentrated in vacuum. The residue was purified by
column chromatography on silica gel (petroleum ether/
ethyl acetate = 20:1, v/v) yielding the 1,3-diketone in the
yields given in Table 1. All diketones obtained were fully
characterized by IR, 1H NMR, 13C NMR, and HRMS
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1
benzoyl-(S)-proline from the reaction mixture. H NMR
(400 MHz, CDCl3): d 1.87–1.94 (m, 1H), 2.00–2.09 (m,
1H), 2.23–2.29 (m, 1H), 2.33–2.39 (m, 1H), 3.59 (t,
J = 6.8Hz, 2H), 4.56 (br s, 1H), 4.76 (dd, J = 7.6,
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J = 18.4 Hz, 1H), 3.93 (d, J = 18.4 Hz, 1H), 5.83 (s, 1H),
7.33–7.40 (m, 2H), 7.44 (d, J = 7.2 Hz, 1H), 7.83 (d,
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1H), 7.38–7.44 (m, 3H), 7.54 (d, J = 7.6 Hz, 2H).