Lanthanide-catalyzed oxyfunctionalization of 1,3-diketones, acetoacetic esters, and malonates by oxidative C-O coupling with malonyl peroxides

Article abstract of DOI:10.1021/acs.joc.5b02233

The lanthanide-catalyzed oxidative C-O coupling of 1,3-dicarbonyl compounds with diacyl peroxides, specifically the cyclic malonyl peroxides, has been developed. An important feature of this new reaction concerns the advantageous role of the peroxide acti

Full text of DOI:10.1021/acs.joc.5b02233

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Article
Lanthanide-catalyzed oxyfunctionalization of 1,3-diketones, acetoacetic
esters, and malonates by oxidative C-O coupling with malonyl peroxides
Alexander Olegovich Terent'ev, Vera A. Vil’, Evgenii S. Gorlov,
Gennady Ivanovich Nikishin, Kasimir K. Pivnitsky, and Waldemar Adam
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02233 • Publication Date (Web): 08 Jan 2016
Downloaded from http://pubs.acs.org on January 18, 2016
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Page 1 of 48
The Journal of Organic Chemistry
Lanthanideꢀcatalyzed oxyfunctionalization of 1,3ꢀdiketones, acetoacetic
esters, and malonates by oxidative CꢀO coupling with malonyl peroxides
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Alexander O. Terent’ev, †* Vera A. Vil’,† Evgenii S. Gorlov, † Gennady I. Nikishin,† Kasimir K.
Pivnitsky, † Waldemar Adam‡,§
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† N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prospekt,
Moscow, 119991 Russian Federation.
‡ Institute of Organic Chemistry, University of Würzburg, Am Hubland, Dꢀ97074 Würzburg, Germany.
§ Department of Chemistry, Facundo Bueso 110, University of Puerto Rico, Rio Piedras, Puerto Rico
00931, USA.
CORRESPONDING AUTHOR’S EꢀMAIL ADDRESS: terentev@ioc.ac.ru
TABLE OF CONTENTS/ABSTRACT GRAPHIC:
Abstract: The lanthanideꢀcatalyzed oxidative С–O coupling of 1,3ꢀdicarbonyl compounds with diacyl
peroxides, specifically the cyclic malonyl peroxides, has been developed. An important feature of this
new reaction concerns the advantageous role of the peroxide acting both as oxidant and reagent for C–O
coupling. It is shown that lanthanide salts may be used in combination with peroxides for selective
oxidative transformations. The vast range of lanthanide salts (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho,
Er, Y) catalyzes oxidative CꢀO coupling much more efficiently than other used Lewis and Bronsted
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acids. This oxidative crossꢀcoupling protocol furnishes mono and double С–O coupling products
chemoꢀselectively in high yields with a broad substrate scope. The double CꢀO coupling products may
be hydrolyzed to vicinal tricarbonyl compounds, which are otherwise cumbersome to prepare. Based on
the present experimental results, a nucleophilic substitution mechanism is proposed for the CꢀO
coupling process in which the lanthanide metal ion serves as Lewis acid to activate the enol of the 1,3ꢀ
dicarbonyl substrate. The side reactions – chlorination and hydroxylation of the 1,3ꢀdicarbonyl partners
– may be minimized under proper conditions.
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INTRODUCTION
The construction of chemical bonds by oxidative crossꢀcoupling (crossꢀdehydrogenative coupling) is a
promising and thriving field of modern organic chemistry. The formation of the new bond occurs with
high atom efficiency and no functional groups are required.1 Oxidative CꢀC coupling reactions were
studied most thoroughly; much literature has been amassed over the years.2 Of the other types of
coupling reactions (C–N, C–P, and C–O), the oxidative coupling to form the С–О bond between the
partners is the more difficult.3 One reason, unfortunately CꢀO coupling is generally accompanied by
oxidation of the C partner into carbonyl products.4
Recently we communicated an efficient method for oxidative C–O coupling, in which one of the
reagents, the diacyl peroxide, acts both as an O component and as the oxidizing agent of the double
bond. The latter is contained in the 1,3ꢀdicarbonyl partner through enolization.5 Usually, in the oxidation
of a double bond by peroxides oxygenꢀatom transfer takes place.6 The advantageous feature of the
present reaction is the unusual chemical behavior of the peroxide: instead of oxygenꢀatom transfer by
means of C–O bonding, the oxygen atom of the peroxide links together the two partners to afford the
product. For emphasis, the present study embraces three aspects of modern synthetic chemistry: 1) the
use of peroxides for the development of oxidative processes, 2) the selective oxyfunctionalization of
1,3ꢀdicarbonyl substrates, and 3) the discovery of lanthanide to effect C–O coupling through Lewisꢀacid
catalysis.
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The Journal of Organic Chemistry
The 2ꢀoxyꢀ1,3ꢀdicarbonyl fragment is widely represented in natural products and pharmaceuticals. Well
known examples are the azaphilones,7 tetracycline antibiotics,8 and barbituric acids.9 Representatives of
the extensive family of the azaphilones are analogues of chlorofusin, mitorubrin and sclerotiorin. The
isolation, modification and synthesis of these natural products have received increased attention due to
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their antimicrobial,10 antifungal
and antiviral
activity. Tetracycline antibiotics, most of which
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contain a 2ꢀhydroxyꢀ1,3ꢀdicarbonyl fragment, have been used worldwide for over 50 years in the
treatment of infectious diseases.13 The introduction of the RC(O)O substituent in the 5ꢀposition of the
barbituric acid significantly increased the analgesic activity.9 Thus, the development of a selective
method for the efficient acyloxyꢀfunctionalization of the 1,3ꢀdicarbonyl group comprises currently a
desirable and timely task.
Cyclic diacyl peroxides have been prepared since the 1950s,14 but only recently has this latent field of
peroxide chemistry been rejuvenated, specifically for synthetic methodology. Significant current
examples are the use of cyclic diacyl peroxides for the stereoselective dihydroxylation of alkenes,15
arene oxidation catalyzed by hexafluoroisopropanol or trifluoroethanol,16 selective arylation17 and
benzoyloxylation,17d and the [3 + 2] cycloaddition of arynes to azides resulting in benzotriazoles.18
The oxyfunctionalization of 1,3ꢀdicarbonyl compounds and their hetero analogs were previously
limited to hydroxylation,19 peroxidation,20 and the coupling of N–O fragments21 and phenols.22 In a
number of studies substituted 2ꢀacyloxyꢀ1,3ꢀdicarbonyl products were synthesized by using hypervalent
iodine compounds,23 Bu4NI/tꢀBuOOH,24 manganese(III) acetate,25 lead(IV) acetate,26 and iron(III)
salts.27 To achieve the benzoyloxylation with the less reactive benzoyl peroxide as oxidant, the
dicarbonyl substrates had to be previously activated by transformation into enamines,28 copper
complexes29 or enolates.30 Unlike αꢀhydroxylation, methods for the intermolecular oxidative acyloxyꢀ
functionalization of 1,3ꢀdicarbonyl compounds by diacyl peroxides appear not to have been reported. A
detailed account of such an efficient single CꢀO coupling of 1,3ꢀdicarbonyl substrates with malonyl
peroxides is presented herein. It should be appreciated that the current method not only makes the αꢀ
hydroxylated 1,3ꢀdicarbonyl substrates accessible by saponification of the single CꢀO coupling products
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prepared herein, but the pendant carboxylicꢀacid functionality in the αꢀacyloxy substituent offers the
opportunity for further functionalization and linking to biologically and pharmaceutically relevant
targets. Furthermore, despite numerous attempts,31 double 2ꢀoxyfunctionalization of 1,3ꢀdicarbonyl
substrates are extremely rare because oxidative fragmentation and dimerization occur.32 Our additional
incentive for the present study was to develop methods double oxidative 2ꢀoxyfunctionalization of 1,3ꢀ
dicarbonyl substrates with the formation of polyfunctional products bearing carboxylicꢀacid groups for
further synthetic modification. For example, double CꢀO coupling products containing six carbonyl
groups offer promising perspectives for the complexation of diverse metal ions.33 Similar 2ꢀ
oxyfunctionalized 1,3ꢀdicarbonyl compounds react with hydrazine, hydroxylamine and amidrazones to
form respectively the important heterocycles pyrazoles,34 isoxazoles,34a 1,2,4ꢀtriazines,35 and
pyridines36.
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Synthetic strategy nowadays expects the use of catalysis to provide efficiency.37 In view of our
established interest in lanthanide catalysts, which have been widely used in biology, chemistry, material
science, and medicine,38 we demonstrated in our preliminary communication5 that lanthanides are
choice catalysts for our current purpose. [a] These mild but effective Lewis acids39 do not decompose
the diacyl peroxide, instead they activate them by increasing their electrophilic propensity. [b] Possibly,
diacyl peroxides do not oxidize effectively anion in lanthanide salts. [c] In view of the high coordination
capacity40 of lanthanides, we anticipate that both the 1,3ꢀdicarbonyl substrate and the diacylꢀperoxide
oxidant are ligated simultaneously to the lanthanum metal center, a desirable proximity for enhancing
reactivity. Moreover, besides their favorable catalytic activity, the unique spectroscopic properties of
lanthanide ions (longꢀlived excitedꢀstate lifetimes), lanthanide complexes have been employed as
luminescent probes and biosensors for cellular imaging in MRI and immunoassay.41 Also worthy of
mention are the diverse systems for radiometric sensing and displacement assay of different chemical
and biochemical substrates based on lanthanides.42 In organic chemistry the lanthanides are used, among
other applications, as mild Lewis acids. Of this fortunate property we have made good use in the present
study.43
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The Journal of Organic Chemistry
In the present work we demonstrate that for reactive 1,3ꢀdicarbonyl substrates the oxidative CꢀO
coupling is general with high catalytic efficiency for a variety of lanthanide (III) salts.
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RESULTS AND DISCUSSION
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The reaction panorama of the lanthanideꢀcatalyzed CꢀO oxidative coupling process is displayed in
Scheme 1, in which explicitly the reaction partners are specified: On the one hand, the dicarbonyl
substrates 1 (C components) were selected, and on the other hand, the diacyl peroxides 2 partners (O
components), to afford the coupling products 3. The structure of the C components was varied to
include the most reactive βꢀdiketones 1аꢀе, the moderately reactive βꢀoxoesters 1fꢀh, and the towards
oxidation persistent malonic esters 1i,j, and substrates 1k,l. The latter contain an additional carbonyl
function, but in the δ position remote of the reaction center. As oxidants (O components) we have
chosen the diacyl peroxides 2, including the industrially important nonꢀcyclic benzoyl peroxide 2a and
the cyclic diacyl peroxides 2bꢀe. To clarify the codification of the coupling product 3, the first letter
index refers to the dicarbonyl substrate 1, the second letter index to the diacyl peroxide oxidant 2; thus,
the product 3hb is obtained in the coupling of substrate 1h with peroxide 2b. The coupling was
performed both in the presence and absence of transitionꢀmetal and nonꢀtransitionꢀmetal Lewis and
Bronsted acidꢀtype catalysts.
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Scheme 1. Single oxidative CꢀO coupling of dicarbonyl compounds 1 with diacyl peroxides 2 to afford
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the CꢀO coupling products 3.
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O
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O
Ph
Ph
O
O
O
O
O
2a
R1
R3
Ph
R2
or
O O
O
O
O
O
O
Catalyst
Solvent
R1
R3
or
R2
H
2b
or
O
O
O
1a-l
R1
1a: CH3
1b: CH3
1c: CH3
1d: CH3
1e: CH3
1f: CH3
1g:
R2
Bu
R3
CH3
CH3
CH3
CH3
CH3
OEt
OEt
OEt
OEt
OEt
R1
R3
R2
O O
Hex
(CH2)2COOEt
CH2Ph
4-ClC6H4CH2
CH3
O
O
O
O
OH
n
2c-e
3x,y (x = a - l, y = a - e)
2c: n= 1
2d: n = 2
2e: n = 3
-(CH2)3-
1h: CH3
1i: OEt
1j: OEt
CH2Ph
Et
Ph
1k: CH3 CH2CH2C(O)CH3 CH3
1l: Ph
CH2CH2C(O)CH3 CH3
Our best results of the transitionꢀmetalꢀcatalyzed CꢀO coupling are exhibited in Table 1, for which we
have selected the moderately reactive dicarbonyl substrate 2ꢀbenzylꢀ3ꢀoxobutanoate 1h and the effective
oxidant diethylmalonyl peroxide 2b as partner, in compliance with our previously communicated
success.5 Optimization of the reaction conditions by varying the reaction time, solvent, and temperature
revealed that the CꢀO coupling reaction runs most efficiently in ethanol at 40 °С for 6 h (see
Supplementary Material for details).
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The Journal of Organic Chemistry
Table 1. Substrate conversions and product yields in the single oxidative C–O coupling of substrate 1h
with diacyl peroxide 2b catalyzed by transitionꢀmetal salts.a
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Entry
1
Catalyst
Convn 1h, %
27
Yield 3hb, %b
21 (25)
95 (97)
96 (97)
92 (96)
93 (98)
95 (97)
93 (96)
96 (98)
96 (98)
95 (97)
93 (97)
94 (96)
96 (98)
85 (90)
Without catalyst
LaCl3·7H2O
CeCl3·7H2O
PrCl3·6H2O
2
100
3
100
4
100
5
NdCl3·6H2O
SmCl3·6H2O
GdCl3·6H2O
TbCl3·6H2O
DyCl3·6H2O
HoCl3·6H2O
Er(OAc)3·4H2O
Eu(NO3)3·6H2O
La(NO3)3·6H2O
YCl3·6H2O
100
6
100
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100
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100
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100
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14
100
100
100
100
100
а General synthetic procedure: Catalyst (0.2 mol per mole of 1h) was added with stirring to a solution
of 1h (500.0 mg, 2.27 mmol) in EtOH (10 mL). The reaction mixture was stirred at 20ꢀ25 °С for 5 min,
then peroxide 2b (538.5 mg, 3.41 mmol, molar ratio: 1.5 mol 2b / 1 mol oxoester 1h) was added. The
mixture was heated to 40 °С and stirred for 6 h.
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b
1
Yields are based on isolated product; the values in parentheses were determined by НꢀNMR
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spectroscopy.
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In the absence of transitionꢀmetal salts, the С–O coupling of 1h with 2b results 3hb in low yield (Table
1, entry 1). In contrast, excellent catalytic activity was achieved with all lanthanide salts, affording the
coupling product 3hb in high yields (92ꢀ96%), as shown in Table 1 (see entries 2ꢀ13). The counter ion
(acetate, chloride, or nitrate) in the lanthanide salt did not influence the high yields of coupling product
3hb (compare entries 2 – 10 with entries 11 – 13 in Table 1). When the rareꢀearth salt yttrium chloride
was used as catalyst, a slightly decreased yield of 85% was observed (Table 1, entry 14). It was found
that the CꢀO coupling product 3hb may be prepared in excellent yields under water ꢀ alcohol (7/3
volume ratio) conditions (see Supplementary Material for details, Table Sꢀ1 entries 13ꢀ14).
The advantage and importance of lanthanide catalysis in the oxidative CꢀO coupling between the
dicarbonyl substrate 1h with diacyl peroxide 2b are emphasized by the data of Table 2, in which we
probed a number of nonꢀtransitionꢀmetal Lewis and Bronsted acids. These comprise the widely used
Lewis acids AlCl3 and the tin(II) and tin(IV) chlorides, which proved to be effective catalysts for the
preparation of geminal bishydroperoxides44 and cyclic triperoxides.45 Also the aprotic I2 was employed,
which proved useful for the peroxidation of alkenes, enol esters and acetals.46 Moreover, we tested
heteropoly acids – phosphomolybdic and phosphotungstic acids – which were previously shown to be
effective catalysts for the peroxidation of carbonyl compounds.47 The strong Bronsted acids pꢀTsOH,
H2SO4, and HClO4 – traditional protic catalysts in preparative peroxidation chemistry48– were as well
tried.
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Table 2. Substrate conversions and product yields in the single oxidative C–O coupling of substrate 1h
with diacyl peroxide 2b catalyzed by nonꢀtransitionꢀmetal Lewis and Bronsted acids. a
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Entry
Catalyst (per mol 1h )
AlCl3 (0.2)
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
EtOH
Convn 1h, %
Yield 3hb, %b
71 (79) c
trace
1
2
3
4d
5
6
7
8
>99
3
SnCl2·2H2O (0.2)
SnCl4·5H2O (0.2)
I2 (1)
8
trace
<5
33
52
32
40
42
0
Phosphomolybdic acid (0.5)
Phosphotungstic acid (0.5)
pꢀTsOH (0.5)
28 (31)
47 (50)
25 (28)
31 (34)
34 (37)
EtOH
EtOH
H2SO4 (0.5)
EtOH
9
HClO4 (0.5)
EtOH
а
General synthetic procedure: Catalyst was added with stirring to a solution of 1h (500.0 mg, 2.27
mmol) in solvent (10 mL). Then peroxide 2b (538.5 mg, 3.41 mmol, molar ratio: 1.5 mol 2b / 1 mol 1h)
was added. The mixture was heated to 40 °С and stirred for 6 h.
b
1
Yields are based on isolated product; the values in parentheses were determined by НꢀNMR
spectroscopy.
c An inseparable mixture of undefined byꢀproducts makes up the rest.
d
The mixture was stirred for 24 h at room temperature (20ꢀ25 ºC).
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As the product data in Table 2 reveal, the oxidative CꢀO coupling with aluminum chloride afforded the
target product 3hb in 71% yield of isolated material (Table 2, entry 1), the best result in this list. The
aprotic acids I2, SnCl2·2H2O and SnCl4·5H2O were inefficient as catalysts (Table 2, entries 2 ꢀ 4). The
heteropoly acids (Table 2, entries 5 ꢀ 6) and protic acids pꢀTsOH, H2SO4 and HClO4 (Table 2, entries 7ꢀ
9) gave 3hb in yields between 25 and 47%. Thus, the nonꢀtransitionꢀmetal Lewis and Bronsted acids are
considerably less effective catalysts for oxidative coupling compared to the lanthanides salts.
A variety of dicarbonyl compounds of differing nucleophilic reactivity was scrutinized with
diethylmalonyl peroxide 2b, to explore the scope of substrate structure in this oxidative CꢀO coupling.
The results are summarized in Table 3 for the βꢀdiketones 1a,c,e, the βꢀoxoesters 1fꢀh, the malonic
esters 1i,j, and the β,δꢀtriketones 1k,l. The coupling reactions were carried out under the optimized
conditions presented in Table 1 similar to those used without catalyst, with catalyst LaCl3·7H2O, and
catalyst La(NO3)3·6H2O. The experiments in Table 3 for substrates 1fꢀh, 1iꢀl without catalyst were
carried out to accentuate the importance of lanthanide catalysis.
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Table 3. Structures of the coupling products, substrate conversions, and product yields in the single
oxidative C–O coupling of substrates 1 with diacyl peroxide 2b, catalyzed by lanthanum chloride and
nitrate salts. a
1
2
3
4
5
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7
8
9
Convn Yield
Convn Yield
СꢀО coupling products
СꢀО coupling products
Catalyst
1aꢀl,
Catalyst
1aꢀl,
3abꢀ
3abꢀ
3abꢀlb
3abꢀlb
%
lb,%b
%
lb,%b
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60
O
O
O
O
O
O
Without
catalyst
Without
catalyst
69
84
61
77
27
21
95
OEt
LaCl3·7H2O
100
LaCl3·7H2O
O
O
La(NO3)3·6H2O
100
10
96
7
O
3ab
O
3hb
OH
La(NO3)3·6H2O
79
63
62
57
OH
Without
catalyst
Without
catalyst
LaCl3·7H2O
47
40
LaCl3·7H2O
97
72
85
65
3cb
3ib
La(NO3)3·6H2O
23
13
20
9
Without
catalyst
O
O
Without
catalyst
O
LaCl3·7H2O
61
46
56
44
O
LaCl3·7H2O
98
83
O
OH
Cl
La(NO3)3·6H2O
3jb
3eb
O
O
Without
catalyst
Without
catalyst
25
91
73
23
24
75
61
19
83
89
91
76
77
71
OEt
O
LaCl3·7H2O
LaCl3·7H2O
O
O
3fb
OH
La(NO3)3·6H2O
La(NO3)3·6H2O
3kb
O
O
O
Without
catalyst
Without
catalyst
12
9
OEt
68 с
44
O
LaCl3·7H2O
100
58
LaCl3·7H2O
96
84
O
3gb
OH
La(NO3)3·6H2O
3lb
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a
General procedure: dicarbonyl compound (500.0 mg), catalyst LaCl3ꢁ7H2O or La(NO3)3ꢁ6H2O (0.2
1
2
3
mol catalyst per mole of substrate), peroxide 2b (1.5 mol peroxide / mol substrate), EtOH (10 mL), 40
4
5
6
°С, 6 h.
b Yields are based on isolated product.
7
8
9
c
Additionally 21 % 3ꢀbenzoylꢀ3ꢀchloroꢀ2,6ꢀheptanedione (7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The high reactivity of βꢀdiketones 1a,c,e is evident in the first three entries of Table 3: even without
catalyst the expected coupling products 3ab, 3cb and 3eb were isolated in fair yields (57ꢀ65 %) at
nearly equal (63ꢀ72%) conversion of the substrates. Using the catalysts LaCl3·7H2O and
La(NO3)3·6H2O, however, the yields were upped appreciably to 77ꢀ85 % of isolated products. The
advantage of lanthanide catalysis is convincingly demonstrated for the less reactive βꢀoxoesters 1fꢀh:
Without catalyst, low conversions (23ꢀ27%) of 1fꢀh and poor yields (19ꢀ24 %) of the coupling products
3fb, 3gb, 3hb were registered, whereas for the LaCl3·7H2O or La(NO3)3·6H2O catalysts, the coupling
products were isolated in a remarkably improved yields (61ꢀ96%) at nearly complete conversion of
substrates. Nevertheless, coupling of the difficultꢀtoꢀoxidize malonic esters 1i,j21a was realized only in
low yields (20ꢀ56% ) even with the help of LaCl3·7H2O or La(NO3)3·6H2O catalysts. Puzzling are the
results for the β,δꢀtriketones 1k,l (last two entries in Table 3): While substrate 1k afforded the coupling
product 3kb in high yield (71ꢀ77 %), irrespective of whether with or without lanthanide catalyst, for the
related substrate 1l the poor yield (9%) in the absence of lanthanide catalyst was significantly improved
(68%) in the presence of LaCl3·7H2O catalyst; additionally, the chlorination product 3ꢀbenzoylꢀ3ꢀ
chloroꢀ2,6ꢀheptanedione (7) was isolated in 21% yield. As expected on the basis of enol nucleophicity,
the reactivity of the substrate towards oxidation follows the βꢀdiketones 1aꢀc > βꢀoxoesters 1fꢀh >
malonic esters 1i,j order, whereas the β,δꢀtriketones 1k,l fall in between. For the oxoesters and malonic
esters definitely lanthanide catalysis is essential, the LaCl3·7H2O is more effective than La(NO3)3·6H2O.
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The Journal of Organic Chemistry
The reactivity of the various diacyl peroxides, namely benzoyl peroxide 2a and the malonyl peroxides
2cꢀe, was tested with the βꢀdiketones 1b,d,e and βꢀoxoesters 1f,h. The coupling was performed either in
the absence of catalyst or in the presence of LaCl3·7H2O or La(NO3)3·6H2O, depending on the oxidative
power of the peroxide (Table 4). The yields of CꢀO coupling product 3ba for the poorly reactive
benzoyl peroxide 2a with the highly reactive βꢀdiketone 1b substrate is given in the first data block in
Table 4. Clearly, without catalyst only a trace of product 3ba was obtained, with LaCl3·7H2O a high
yield (72%) was observed, but with La(NO3)3·6H2O the yield dropped to 6%. Similarly, for the
combination of the less reactive βꢀoxoesters 1f with peroxide 2a (see second data block in Table 4) only
traces of product 3fa were formed in the absence of catalyst; both LaCl3·7H2O and La(NO3)3·6H2O
catalysts led to the poor yields of 26% and 5%. A clarifying remark is in order in regard to the poor
yields with the La(NO3)3·6H2O versus the LaCl3·7H2O catalyst for the benzoyl peroxide (2a). Note that
not only are the product yields very low, but also the substrate conversions, namely 15% and 12% (see
the first two data blocks in Table 4). This divergence in reactivity is only observed for the benzoyl
peroxide (2a), the diacyl peroxide of marginal oxidative efficacy. Presumably, in such cases the
differentiation in the catalytic activity of the lanthanide salt is more pronounced. Quite generally we
found that LaCl3·7H2O is more efficient than La(NO3)3·6H2O., but the difference in substrate
conversion and product yield is minor. For comparison we include in Table 4 our most reactive
diethylmalonyl peroxide 2b with the βꢀoxoesters 1f,h substrates, results which were already given in
Table 3. These data are displayed in the third and fourth data blocks of Table 4. The poor yields without
catalyst (24%, 21%) are significantly improved with the LaCl3·7H2O (75%, 95%) and La(NO3)3·6H2O
(61%, 96%), which definitively emphasizes the advantage of lanthanide catalysis.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Table 4. Structures of CꢀO coupling products 3, substrate conversions and product yields in the single
oxidative C–O coupling of dicarbonyl substrates 1 with diacyl peroxides 2 catalyzed by lanthanum
chloride and nitrate salts.
1
2
3
4
5
6
7
8
9
СꢀО coupling
products 3
Convn Yield
1, %
СꢀО coupling
products 3
Convn Yield
1, %
Catalyst
Catalyst
3, %a
3, %a
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Without catalyst
9
trace
O
LaCl3·7H2O
83
15
72
6
Without catalyst
100
92
O
La(NO3)3·6H2O
3dc e
3ba b
O
O
O
O
Without catalyst
LaCl3·7H2O
7
trace
26 c
Eu(NO3)3·6H2O
LaCl3·7H2O
27
23
23
17
OEt
OEt
O
O
100
O
O
La(NO3)3·6H2O
12
5
O
OH
La(NO3)3·6H2O
21
18
3fa b
3hc f
O
O
Without catalyst
LaCl3·7H2O
25
91
24
75
OEt
O
Without catalyst
96
81
O
La(NO3)3·6H2O
73
61
O
OH
3fb d
3dd e
O
O
Without catalyst
LaCl3·7H2O
27
21
95
O
100
LaCl3·7H2O
94
70
O
O
OH
La(NO3)3·6H2O
100
97
96
Cl
3hb d
3ee d
O
O
LaCl3·7H2O
100
100
38 g
34 h
O
O
Without catalyst
90
La(NO3)3·6H2O
O
OH
3he d
3bc e
a Yields are based on isolated product.
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b Products 3ba, 3fa: dicarbonyl substrates 1b or 1f (500.0 mg), catalyst LaCl3ꢁ7H2O or La(NO3)3ꢁ6H2O
(0.2 mol catalyst per mole of 1b or 1f), peroxide 2a (1.5 mol 2a/ 1 mol 1b or 1f), MeOH (10 mL), 60
°С, 6 h.
1
2
3
4
5
6
c Additionally 43 % ethyl 2ꢀchloroꢀ2ꢀmethylꢀ3ꢀoxobutanoate (8)
7
8
9
d
Products 3fb, 3hb, 3ee, 3he: dicarbonyl substrates 1e, 1f or 1h (500.0 mg), catalyst LaCl3ꢁ7H2O or
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
La(NO3)3ꢁ6H2O (0.2 mol catalyst per mole of 1e, 1f or 1h, peroxide 2e or 2b (1.5 mol peroxide / 1 mol
1e, 1f or 1h), EtOH (10 mL), 40 °С, 6 h.
e
Products 3bc, 3dc, 3dd: dicarbonyl substrates 1b or 1d (500.0 mg), peroxide 2c or 2d (1.5 mol
peroxide/ 1 mol 1b or 1d), CHCl3 (10 mL), 40 °С, 6 h.
f
Product 3hc: dicarbonyl substrate (500.0 mg), catalyst Eu(NO3)3ꢁ6H2O or LaCl3ꢁ7H2O or
La(NO3)3ꢁ6H2O (0.2 mol catalyst per mole of 1h), peroxide 2c (1.5 mol 2c / 1 mol 1h), CHCl3 (10 mL)
[in the case of LaCl3ꢁ7H2O, 9:1 v/v CHCl3/MeOH ], 40 °С, 6 h.
g Additionally 40 % ethyl 2ꢀbenzylꢀ2ꢀchloroꢀ3ꢀoxobutanoate (9).
h Additionally 50 % ethyl 2ꢀbenzylꢀ2ꢀhydroxyꢀ3ꢀoxobutanoate (10).
The next three data blocks in Table 4 deal with the spirocyclopropylꢀsubstituted malonyl peroxide 2c, of
which the fifth and sixth data blocks refer to the coupling with the highly reactive βꢀdiketones 1b and
1d. Even without catalyst, the respective coupling products 3bc and 3dc were obtained in high yields
(90ꢀ92%), obviating the use of lanthanide salts. Nonetheless, as the seventh data block reveals, for the
less reactive βꢀoxoester 1h the reaction with malonyl peroxide 2c proceeds in low yields (17ꢀ23%) of
coupling product 3hc, independent of whether Eu(NO3)3·6H2O, LaCl3·7H2O or La(NO3)3·6H2O
catalysts are employed. Analogous to the malonyl peroxide 2c, the spirocyclobutylꢀsubstituted malonyl
peroxide 2d affords the coupling product 3dd with the highly reactive βꢀdiketone 1d in good yield
(81%) without lanthanide catalyst (see eighth data block in Table 4). The last two entries in Table 4
refer to the least reactive malonyl peroxide 2e (spirocyclopentyl substitution) with the βꢀdicarbonyl
substrates 1e and 1h. As shown in the ninth data block, LaCl3·7H2O catalysis is essential to afford a
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high yield (70%) of coupling product 3ee. Finally, the sluggish βꢀoxoester 1h (last data block in Table
4) results in modest yields of coupling product 3he even with the LaCl3·7H2O (38%) and
La(NO3)3·6H2O (34%) catalysts; the major byproducts are the respective 2ꢀchlorinated 9 (40%) and 2ꢀ
hydroxylated 10 (50%) derivatives.
1
2
3
4
5
6
7
8
9
This last entry in Table 4 for the La(NO3)3·6H2Oꢀcatalyzed reaction of the βꢀoxoester 1h with the
spirocyclopentylmalonyl peroxide 2e is not only remarkable, it is mechanistically puzzling: As major
(50%) product ethyl 2ꢀbenzylꢀ2ꢀhydroxyꢀ3ꢀoxobutanoate (10) and as minor (34%) product the expected
coupling product 3he were obtained. A similar surprising result we already reported in our preliminary
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
work for the combination of 1,3ꢀdiketone 1d with malonyl peroxide 2e (in the preliminary work
numbered 1a for the substrate and 2c for the peroxide) affording as major (35%) product the 3ꢀbenzylꢀ3ꢀ
hydroxyꢀ2,4ꢀpentanedione. We showed previously5 that the hydroxylated substrate is a primary product,
that is, formed directly and not by solvolysis of the CꢀO coupling ester. What is responsible for this
reaction dichotomy? Screening our earlier work on malonyl peroxide chemistry revealed that in alcohols
solvolysis takes place to afford a mixture of the corresponding peracid and carboxylic acid.49 Indeed, in
ethanol at 20 ºC the spiromalonyl peroxide 2e leads to a mixture (see Scheme 2) of peracid 11 (70%)
and carboxylic acid 12 (18%). Treatment of the 1,3ꢀdicarbonyl substrate 1h with the isolated and
purified peracid 11 was unproductive, but in the presence of La(NO3)3·6H2O catalyst after 37%
conversion of substrate 1h a 30% yield of the 2ꢀhydroxy substrate 10 was confirmed (see Scheme 2).
Moreover, when substrate 1d (the one used in the preliminary work 5) was treated with peracid 11, the
2ꢀhydroxy product 13 was obtained in 71% yield. Therewith the mechanistic mystery of the
hydroxylation side reaction is unveiled.
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Scheme 2. Control experiments for the hydroxylation side reaction.
1
2
3
4
5
O O
O
O
O
O
EtOH
20 °C, 6 h
O
O
EtO
OOH
EtO
OH
6
7
8
9
11, 70%
12
2e
, 18%
convn 91%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
O
OEt
OEt
OH
1.5 EtO
OOH
0.2 La(NO3)3 6H2O
EtOH, 40 °C, 6 h
1h
convn 37 %
11
10, 30%
O
O
O
O
O
O
no catalyst
1.5 EtO
OOH
OH
EtOH , 40 °C, 6 h
1d
convn 80%
11
13, 71 %
As already shown in the Graphical Abstract, and pointed out in the Introduction, βꢀdicarbonyl
compounds with two enolizable hydrogen atoms (no α substitution) as in substrates 4aꢀf, allow double
oxyfunctionalization with malonyl peroxide 2b to afford the novel double CꢀO coupling products 5aꢀf
(Scheme 3). Under LaCl3 catalysis at 40 ºC in EtOH within 6 h good yields (56 – 78%) of isolated
material were obtained. The variation of α substitution in the double CꢀO coupling products 5aꢀf is
displayed by means of the structure matrix in Scheme 3.
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Scheme 3. Double oxidative CꢀO coupling of dicarbonyl compounds 4aꢀf with diacyl peroxide 2b to
afford products 5aꢀf.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The derivative 5f of the double CꢀO coupling products was hydrolyzed to the vicinal 1,2,3ꢀtricarbonyl
compound 6f (Scheme 4). Hydrolysis of 5f was performed by 1 М NaHCO3 at 20ꢀ25 °С for 2 h, leading
to ethyl 2,3ꢀdioxoꢀ3ꢀphenylpropanoate 6f in good yield (70%), as shown in Scheme 4.
Scheme 4. Hydrolysis of the double CꢀO coupling product 5f to the vicinal tricarbonyl compound 6f.
The results in Tables 3 and 4 manifest the following salient general trends in the oxidative CꢀO coupling
reaction between the 1,3ꢀdicarbonyl substrates 1 and malonyl peroxides 2: [a] Towards the reactive
substrates 1aꢀe the reactivity order of the diacyl peroxides 2aꢀe is 2c≈2d > 2b >>2e >2a; thus, the
reaction of 1,3ꢀdiketones 1aꢀe with peroxides 2bꢀd affords the corresponding CꢀO coupling products 3
in high yields even without lanthanide catalysis. In contrast, the peroxides 2a,e require the LaCl3·7H2O
catalyst to achieve good yields. [b] Towards the less reactive βꢀoxoesters 1fꢀh the reactivity order of the
diacyl peroxides is 2b >> 2e>2a≈2c, revealing that the diethylꢀsubstituted malonyl peroxide 2b is the
more efficient partner for oxidative coupling. For the substrate 1h it is shown that a large variety of
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The Journal of Organic Chemistry
lanthanides serve as excellent catalysts (yields of CꢀO coupling product 3hb better than 90%). [c] For
the hardꢀtoꢀoxidize malonic esters 1iꢀj even lanthanide catalysis performs only modestly. In such
problematic cases, the chlorination of substrate 1 prevails when LaCl3·7H2O is employed as catalyst.
Evidently, the peracid generated in situ from the malonyl peroxide 2 oxidizes the chloride ion to a
chlorinating agent,50 presumably elemental chlorine. The latter in turn adds to the enol of the substrate
1 to afford the undesirable chlorination product (Scheme 5). Attempts to avoid this undesirable side
reaction by employing La(NO3)3·6H2O (no chloride ligands) as catalyst causes the hydroxylation of the
1,3ꢀdicarbonyl substrate 1. This alternative side reaction results from epoxidation of the enol derived
from the substrate 1 by the inꢀsitu generated peracid51 to afford the intermediary hydroxy epoxide;
subsequent ringꢀopening affords the 2ꢀhydroxyꢀ1,3ꢀdicarbonyl product (Scheme 5).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
25
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27
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Suggested mechanisms for the chlorination and hydroxylation side reactions.
For the principal process, which constitutes the incentive for this study, namely the CꢀO coupling of the
1,3ꢀdicarbonyl substrates 1 with the diacyl peroxides 2, the mechanism in Scheme 6 is proposed.
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Scheme 6. Mechanism for the CꢀO coupling of 1,3ꢀdicarbonyl substrates 1 with diacyl peroxides 2 to
afford the oxyfunctionalized product 3.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
25
26
27
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30
31
32
33
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Metal complexation with diacyl peroxide 2 is well documented.52 The first step in the CꢀO coupling
process is nucleophilic attack by the enol form of the substrate on the Laꢀactivated malonyl peroxide to
form intermediate I by charge separation. The final CꢀO coupling product 3 is obtained through further
reorganization by proton shift and dissociation of the lanthanide complex.
CONCLUSION
In summary, we have described a convenient and effective method for the oxidative CꢀO coupling of
1,3ꢀdiketones and 3ꢀoxo esters with malonyl peroxides to afford hitherto unkown acyloxyꢀsubstituted
products, but malonic esters are poorly reactive. It was shown that a wide range of lanthanide salts (La,
Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Y) are active catalysts for such oxidative acyloxylation. In
comparison, poor catalytic activity was displayed by the common Lewis acids (AlCl3, SnCl2, SnCl4), by
the Bronsted acids (pꢀTsOH, H2SO4, HClO4), and by phosphomolybdic and phosphotungstic acid, while
elemental iodine was completely inactive. Numerous mono and some double CꢀO coupling products
(altogether 24 examples) were synthesized in good to high yields. Double CꢀO coupling products 5aꢀf
containing six carbonyl groups offer promising perspectives for the complexation of diverse metal ions.
What is particularly encouraging about our present research work is the symbiosis of the oxidizing
power of diacyl peroxides with the catalytic activity of lanthanides.
EXPERIMENTAL SECTION
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Caution: Although we have encountered no difficulties in working with peroxides, precautions
such as the use of safety shield, fume hood should be taken, the use of redoxꢀactive transitionꢀ
metal salts, heating and vigorous shaking should be avoided!
1
2
3
4
5
6
7
1
13
NMR spectra were recorded on a commercial instrument (300.13 MHz for Н, 75.48 MHz for С) in
СDCl3. IR spectra were recorded on a FTꢀIR spectrometer. High resolution mass spectra (HRMS) were
measured using electrospray ionization (ESI).53 The measurements were done in a positive ion mode
(interface capillary voltage 4500 V); the mass ratio was from m/z 50 to 3000 Da; external/internal
calibration was done with Electrospray Calibrant Solution. A syringe injection was used for solutions in
MeCN (flow rate 3 µL/min). Nitrogen was applied as a dry gas; interface temperature was set at 180 °C.
The TLC analyses were carried out on standard silicaꢀgel chromatography plates. The melting points
were determined on a Kofler hotꢀstage apparatus. Chromatography was performed on silica gel (63ꢀ200
mesh).
8
9
10
11
12
13
14
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17
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59
60
2,4ꢀPentanedione (4a), 1ꢀbenzoylacetone (4b), dibenzoylmethane (4d), ethyl acetoacetate (4e), ethyl
benzoylacetate (4f), ethyl 2ꢀmethylacetoacetate (1f), ethyl 2ꢀoxocyclopentanecarboxylate (1g), diethyl
ethylmalonate (1i), diethyl phenylmalonate (1j), benzoyl peroxide (2a, 75%, remainder water), diethyl
1,1ꢀcyclopropanedicarboxylate, 1,1ꢀcyclobutanedicarboxylic acid, AcOH, EtOH (96%), AlCl3
(anhydrous), SnCl2·2H2O, SnCl4·5H2O, I2, pꢀTsOH monohydrate, H2SO4, HClO4 (70% solution in
water), NaHCO3, lanthanum(III) chloride heptahydrate (LaCl3·7H2O), cerium(III) chloride heptahydrate
(CeCl3·7H2O), neodymium(III) chloride hexahydrate (NdCl3·6H2O), samarium(III) chloride
hexahydrate (SmCl3·6H2O), gadolinium(III) chloride hexahydrate (GdCl3·6H2O), terbium(III) chloride
hexahydrate (TbCl3·6H2O), dysprosium(III) chloride hexahydrate (DyCl3·6H2O), holmium(III) chloride
hexahydrate (HoCl3·6H2O), lanthanum(III) nitrate hexahydrate (La(NO3)3·6H2O), yttrium(III) chloride
hexahydrate (YCl3·6H2O), praseodymium(III) chloride hexahydrate (PrCl3·6H2O), erbium(III) acetate
tetrahydrate (Er(OAc)3·4H2O), europium(III) nitrate hexahydrate (Eu(NO3)3·6H2O), phosphomolybdic
acid hydrate (formula weight: 1,825.25 g/mol), phosphotungstic acid hydrate (formula weight: 2,880.05
g/mol), 2,2ꢀdiethyl malonic acid were purchased from commercial sources and was used as is. All
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solvents were distilled before use using standard procedures. Cyclopentaneꢀ1,1ꢀdicarboxylic acid was
synthesized according to literature.15c 3ꢀButylꢀ2,4ꢀpentanedione (1a),54 3ꢀhexylꢀ2,4ꢀpentanedione (1b),55
ethyl 4ꢀacetylꢀ5ꢀoxohexanoate (1с),56 3ꢀbenzylꢀ2,4ꢀpentanedione (1d),57 3ꢀ(4ꢀchlorobenzyl)ꢀ2,4ꢀ
pentanedione (1e),58 ethyl 2ꢀbenzylꢀ3ꢀoxobutanoate (1h),59 3ꢀacetylꢀ2,6ꢀheptanedione (1k),60 3ꢀbenzoylꢀ
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2,6ꢀheptanedione (1l),60 1ꢀ(4ꢀmethylphenyl)ꢀ1,3ꢀbutanedione (4c) were synthesized according to the
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literature.
Malonyl peroxides: spirocyclopropylmalonyl peroxide (2c)62, spirocyclobutylmalonoyl peroxide (2d)
15c, spirocyclopentylmalonoyl peroxide (2e) 15c were synthesized according to the literature.
Diethylmalonyl peroxide (2b)
Following the literature procedure15c 2,2ꢀdiethyl malonic acid (8.0 g, 50.0 mmol) gave the title
compound as a colorless oil (6.4 g, 40.5 mmol, 81%).
1Н NMR (300.13 MHz, CDCl3, δ): 0.98 (t, J = 7.3 Hz, 6H), 1.95 (q, J = 7.3 Hz, 4H).
13C NMR (75.48 MHz, CDCl3, δ): 8.8, 28.7, 51.0, 174.0.
Spirocyclopropylmalonyl peroxide (2c)
Following the literature procedure62 diethyl 1,1ꢀcyclopropanedicarboxylate (10.0 g, 54.0 mmol) gave
the title compound as a white needle crystals (5.9 g, 46.0 mmol, 85%).
White needle crystals, m.p. = 89ꢀ90 °С (lit. m.p.62 = 90 °C).
1Н NMR (300.13 MHz, CDCl3, δ): 2.11 (s, 4 H).
13C NMR (75.48 MHz, CDCl3, δ): 19.8, 23.6, 172.1.
Spirocyclobutylmalonoyl peroxide (2d)
Following the general procedure, 1,1ꢀcyclobutanedicarboxylic acid (7.2 g, 50 mmol) gave the title
compound as a white needle crystals (5.1 g, 36.0 mmol, 72%).
White needle crystals, m.p. = 63ꢀ64 °С (lit. m.p.15c = 63 °C).
1Н NMR (300.13 MHz, CDCl3, δ): 2.34 (quintet, J = 8.1 Hz, 2H), 2.69 (t, J = 8.1 Hz, 4H).
13C NMR (75.48 MHz, CDCl3, δ): 16.2, 28.9, 40.5, 173.9.
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The Journal of Organic Chemistry
Spirocyclopentylmalonoyl peroxide (2e)
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Following the general procedure, cyclopentaneꢀ1,1ꢀdicarboxylic acid (7.9 g, 50.0 mmol) gave the title
compound as a white crystalline solid (6.2 g, 39.5 mmol, 79%).
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White crystalline solid, m.p. = 39ꢀ40 °С (lit. m.p.15c = 41 °C).
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1Н NMR (300.13 MHz, CDCl3, δ): 1.96ꢀ2.01 (m, 4H), 2.22ꢀ2.27 (m, 4H).
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13C NMR (75.48 MHz, CDCl3, δ): 26.6, 37.6, 46.8, 175.6.
General procedure for Table 1, entry 1ꢀ14
Transitionꢀmetal salt (molar ratio: 0.2 mol of salt per mole of 1h) was added with stirring to a solution
of ethyl 2ꢀbenzylꢀ3ꢀoxobutanoate (1h) (500 mg, 2.27 mmol) in EtOH (10 mL) (in entry 1 catalyst was
not used). The reaction mixture was stirred at 20ꢀ25 °С for 5 min. Then diethylmalonyl peroxide 2b
(538.5 mg, 3.41 mmol, molar ratio: 1.5 mol 2b / 1 mol oxoester 1h) was added. The mixture was heated
to 40 °С and stirred for 6 h, cooled to 20ꢀ25 °С. The resulting mixture was diluted with CHCl3 (70 mL),
and the organic layer was washed with H2O (3×10 mL), dried over Na2SO4, filtered, and concentrated
under a waterꢀjet vacuum. NMR yields were determined with 1,4ꢀdinitrobenzene as the internal
standard. The product 3hb was isolated by column chromatography on SiO2 with elution using PEꢀ
EtOAc in a linear gradient of latter from 30 to 90 vol %.
Detailed experimental procedure for Table 1, entry 13
La(NO3)3·6H2O (196.6 mg, 0.45 mmol, molar ratio: 0.2 mol of salt per mole of 1h) was added with
stirring to a solution of ethyl 2ꢀbenzylꢀ3ꢀoxobutanoate (1h) (500 mg, 2.27 mmol) in EtOH (10 mL). The
reaction mixture was stirred at 20ꢀ25 °С for 5 min. Then diethylmalonyl peroxide 2b (538.5 mg, 3.41
mmol, molar ratio: 1.5 mol 2b / 1 mol oxoester 1h) was added. The mixture was heated to 40 °С and
stirred for 6 h, cooled to 20ꢀ25 °С. The resulting mixture was diluted with CHCl3 (70 mL), and the
organic layer was washed with H2O (3×10 mL), dried over Na2SO4, filtered, and concentrated under a
waterꢀaspirator vacuum. The conversion of 1h (the characteristic signal is a doublet of the CH2Carom
group at δ 3.12) and the yield of 3hb (the characteristic signal is a two doublets of the CH2Carom group at
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δ 3.43 and δ 3.50) were determined from the 1H NMR spectroscopic data. 1,4ꢀDinitrobenzene was used
as the internal standard (the characteristic signal is a singlet of the four CH2arom group at δ 8.38). Product
3hb was isolated as described above. Yield of 3hb was 96% (824.6 mg, 2.18 mmol).
2ꢀ{[1ꢀBenzylꢀ1ꢀ(ethoxycarbonyl)ꢀ2ꢀoxopropoxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3hb) 5
White solid, m.p. = 89ꢀ93 °С. Rf = 0.38 (PE:EtOAc = 5:1+ 2% AcOH).
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1Н NMR (300.13 MHz, CDCl3, δ): 0.83ꢀ0.90 (m, 6H), 1.14 (t, J = 7.3 Hz, 3H), 1.90ꢀ2.03 (m, 4H), 2.20
(s, 3H), 3.43 (d, J = 14.7 Hz, 1H, CH2), 3.50 (d, J = 14.7 Hz, 1H, CH2), 4.13 (q, J = 7.3 Hz, 2H), 7.05ꢀ
7.12 (m, 2H), 7.17ꢀ7.25 (m, 3H), 10.32 (br.s., 1H).
13C NMR (75.48 MHz, CDCl3, δ): 8.2, 13.7, 25.4, 25.6, 27.6, 39.9, 58.6, 62.3, 88.6, 127.4, 128.2, 130.1,
133.4, 166.3, 170.6, 176.1, 201.2.
HRMS (ESI) m/z [M+Na]+ : Calcd for [C20H26NaO7]+ : 401.1571. Found: 401.1573.
Anal. Calcd for С20Н26О7 С: 63.48 %, Н: 6.93 %. Found С: 63.44 %, Н: 6.90 %.
IR (KBr): 3423, 2975, 1764, 1710, 1355, 1312, 1258, 1234, 1128, 1060, 1014, 708, 516 cmꢀ1.
General experimental procedure for Table 2, entries 1ꢀ3
AlCl3 (60.5 mg, 0.45 mmol, molar ratio: 0.2 mol per mole of 1h) or SnCl2·2H2O (101.5 mg, 0.45 mmol)
or SnCl4·5H2O (157.8 mg, 0.45 mmol) was added with stirring to a solution of ethyl 2ꢀbenzylꢀ3ꢀ
oxobutanoate 1h (500 mg, 2.27 mmol) in CH2Cl2 (10 mL). Then diethylmalonyl peroxide 2b (538.5 mg,
3.41 mmol, molar ratio: 1.5 mol 2b / 1 mol oxoester 1h) was added. The mixture was heated to 40 °С
and stirred for 6 h. The resulting mixture was diluted with CHCl3 (70 mL), and the organic layer was
washed with H2O (3×10 mL), a 5% aqueous NaHCO3 solution (2×10 mL), and again with H2O (10
mL), dried over Na2SO4, filtered, and concentrated under a waterꢀjet vacuum. NMR yields were
determined with 1,4ꢀdinitrobenzene as the internal standard. Product 3hb was isolated as described
above.
Experimental procedure for Table 2, entry 4
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Molecular iodine (576.1 mg, 2.27 mmol, molar ratio: 1 mol of I2 per mole of 1h) was dissolved in
solution of ethyl 2ꢀbenzylꢀ3ꢀoxobutanoate 1h (500 mg, 2.27 mmol) in CH3CN (10 mL). Then diethyl
malonyl peroxide (2b) (538.5 mg, 3.41 mmol, molar ratio: 1.5 mol 2b / 1 mol oxoester 1h) was added.
The mixture was stirred at 20ꢀ25°C for 24 h. Target product 3hb was not detected by TLC in the course
of the reaction and after the synthesis.
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General experimental procedure for Table 2, entries 5ꢀ9
The diethylmalonyl peroxide (2b) (538.5 mg, 3.41 mmol, molar ratio: 1.5 mol 2b / 1 mol oxoester 1h)
was added with stirring to a solution of ethyl 2ꢀbenzylꢀ3ꢀoxobutanoate 1h (500 mg, 2.27 mmol) in EtOH
(10 mL). Then acid (PMA, PTA, pꢀTsOH, H2SO4, HClO4) (0.45 mmol, molar ratio: 0.2 mol per mole of
1h) was added. The mixture was heated to 40 °С and stirred for 6 h. The resulting mixture was diluted
with CHCl3 (70 mL), and the organic layer was washed with H2O (3 × 10 mL), a 5% aqueous NaHCO3
solution (2 × 10 mL), and again with water (10 mL), dried over Na2SO4, filtered, and concentrated
under a waterꢀjet vacuum. NMR yields were determined with 1,4ꢀdinitrobenzene as the internal
standard. Product 3hb was isolated as described above.
General experimental procedure for Table 3
LaCl3·7H2O (157.2ꢀ257.6 mg, 0.42ꢀ0.69 mmol, molar ratio: 0.2 mol of salt per mole of substrate 1) or
La(NO3)3·6H2O (183.3ꢀ300.3 mg,0.42ꢀ0.69 mmol, molar ratio: 0.2 mol of salt per mole of substrate 1)
was added with stirring to a solution of 1,3ꢀdicarbonyl compounds 1 (500.0 mg, 2.12ꢀ3.47 mmol) in
EtOH (10 mL). The reaction mixture was stirred at 20ꢀ25 °С for 5 min. Then diethylmalonyl peroxide
(2b) (502.0ꢀ822.7 mg, 3.17ꢀ5.20 mmol, molar ratio: 1.5 mol 2b / 1 mol 1,3ꢀdicarbonyl compound 1)
was added. The mixture was heated to 40 °С and stirred for 6 h, cooled to 20ꢀ25 °С. The resulting
mixture was diluted with CHCl3 (70 mL), and the organic layer was washed with H2O (3×10 mL), dried
over Na2SO4, filtered, and concentrated under a waterꢀjet vacuum. The yields of products were
determined on isolated product by column chromatography on SiO2 with elution using PEꢀEtOAc in a
linear gradient of EtOAc from 30 to 90 vol %.
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2ꢀ{[(1,1ꢀDiacetylpentyl)oxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3ab)
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Yields: 61% (613.8 mg, 1.95 mmol, without catalyst), 77% (774.6 mg, 2.46 mmol, LaCl3 catalyst), 62%
(623.8 mg, 1.98 mmol, La(NO3)3 catalyst).
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Colorless oil. Rf = 0.41 (PE:EtOAc = 5:1+ 2% AcOH).
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1Н NMR (300.13 MHz, CDCl3, δ): 0.84 (t, J = 7.3 Hz, 3H), 0.93 (t, J = 7.3 Hz, 6H), 1.08ꢀ1.31 (m, 4H),
2.02 (q, J = 7.3 Hz, 4H), 2.17ꢀ2.30 (m, 8H), 10.35 (br. s., 1H).
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13C NMR (75.48 MHz, CDCl3, δ): 8.2, 13.7, 22.5, 25.2, 25.3, 26.7, 32.9, 58.6, 95.1, 170.2, 176.9, 201.6.
HRMS (ESI) m/z [M+Na]+. Calcd for [C16H26NaO6]+ : 337.1622. Found: 337.1625.
Anal. Calcd for С16Н26О6 С: 61.13 %, Н: 8.34 %. Found С: 60.75 %, Н: 8.70 %.
IR (thin layer): 2699, 2942, 2879, 1739, 1715, 1457, 1418, 1357, 1228, 1206, 1126, 944 cmꢀ1.
2ꢀ[(1,1ꢀDiacetylꢀ4ꢀethoxyꢀ4ꢀoxobutoxy)carbonyl]ꢀ2ꢀethylbutanoic acid (3cb)
Yields: 57% (510.1 mg, 1.42 mmol, without catalyst), 85% (760.7 mg, 2.12 mmol, LaCl3 catalyst).
Colorless oil. Rf = 0.43 (PE:EtOAc = 2:1+ 2 % AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.93 (t, J = 7.3 Hz, 6H), 1.21 (t, J = 7.3 Hz, 3H), 2.01 (q, J = 7.3 Hz,
4H), 2.14ꢀ2.32 (m, 8H), 2.55ꢀ2.66 (m, 2H), 4.09 (q, J = 7.3 Hz, 2H), 9.45 (br.s., 1H).
13C NMR (75.48 MHz, CDCl3, δ): 8.2, 14.1, 25.1, 26.5, 28.0, 28.2, 58.5, 60.9, 93.5, 170.1, 172.0,
176.0, 201.0.
HRMS (ESI) m/z [M+Na]+. Calcd for [C17H26NaO8]+ : 381.1520. Found: 381.1516.
Anal. Calcd for С17Н26О8 С: 56.97 %, Н: 7.31 %. Found С: 56.90 %, Н: 7.28 %.
IR (thin layer): 2978, 2945, 2885, 1736, 1716, 1359, 1213, 1146, 1126 cmꢀ1.
2ꢀ{[1ꢀAcetylꢀ1ꢀ(4ꢀchlorobenzyl)ꢀ2ꢀoxopropoxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3eb)
Yields: 65% (565.2 mg, 1.71 mmol, without catalyst), 83% (760.0 mg, 2.18 mmol, LaCl3 catalyst).
White solid, m.p. = 113ꢀ115 °С. Rf = 0.35 (PE:EtOAc = 5:1+ 2 % AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.87 (t, J = 7.3 Hz, 6H), 1.97 (q, J = 7.3 Hz, 4H), 2.13 (s, 6H), 3.55
(s, 2H), 7.00 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 10.92 (br.s., 1H).
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13C NMR (75.48 MHz, CDCl3, δ): 8.2, 25.0, 27.3, 38.8, 58.6, 94.4, 128.6, 131.4, 132.0, 133.5, 170.4,
176.9, 201.6.
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HRMS (ESI) m/z [M+Na]+. Calcd for [C19H23ClNaO6]+ : 405.1075. Found: 405.1063.
Anal. Calcd for С19Н23О6Cl С: 59.61 %, Н: 6.06 %, Сl: 9.26 %. Found С: 59.54 %, Н: 6.08 %, Cl: 9.26
%.
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IR (KBr): 3433, 2977, 2943, 2629, 1764, 1711, 1493, 1362, 1256, 1215, 1176, 1134 cmꢀ1.
2ꢀ{[1ꢀ(Ethoxycarbonyl)ꢀ1ꢀmethylꢀ2ꢀoxopropoxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3fb)
Yields: 24% (251.6 mg, 0.83 mmol, without catalyst), 75% (786.4 mg, 2.60 mmol, LaCl3 catalyst), 61%
(639.6 mg, 2.12 mmol, La(NO3)3 catalyst).
Colorless oil. Rf = 0.31 (PE:EtOAc = 5:1+ 2 % AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.85ꢀ0.92 (m, 6H), 1.22 (t, J = 7.3 Hz, 3H), 1.68 (s, 3H), 1.91ꢀ2.04
(m, 4H), 2.29 (s, 3H), 4.19 (q, J = 7.3 Hz, 2H), 8.97 (br.s., 1H).
13C NMR (75.48 MHz, CDCl3, δ): 8.2, 8.3, 13.7, 19.1, 25.5, 25.6, 58.6, 62.4, 86.1, 166.9, 170.2, 176.1,
201.2.
HRMS (ESI) m/z [M+Na]+. Calcd for [C14H22NaO7]+ : 325.1258. Found: 325.1261.
Anal. Calcd for С14Н22О7 С: 55.62 %, Н: 7.33 %. Found С: 55.47 %, Н: 7.45 %.
IR (thin layer): 3197, 3095, 2979, 2945, 2885, 1739, 1450, 1358, 1267, 1232, 1113 cmꢀ1.
2ꢀ({[1ꢀ(Ethoxycarbonyl)ꢀ2ꢀoxocyclopentyl]oxy}carbonyl)ꢀ2ꢀethylbutanoic acid (3gb)
Yields: 19% (191.2 mg, 0.61 mmol, without catalyst), 84% (845.3 mg, 2.69 mmol, LaCl3 catalyst).
Colorless oil. Rf = 0.59 (PE:EtOAc = 5:1+ 2 % AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.90 (t, J = 7.3 Hz, 6H), 1.24 (t, J = 7.3 Hz, 3H), 1.87ꢀ2.17 (m, 6H),
2.21ꢀ2.32 (m, 1H), 2.38ꢀ2.65 (m, 2H), 2.70ꢀ2.83 (m, 1H), 4.20 (q, J = 7.3 Hz, 2H), 10.84 (br.s., 1H).
13C NMR (75.48 MHz, CDCl3, δ): 8.4, 13.9, 18.4, 26.1, 33.0, 35.8, 58.5, 62.3, 84.4, 166.6, 170.9, 176.1,
207.2.
HRMS (ESI) m/z [M+Na]+. Calcd for [C15H22NaO7]+ : 337.1258. Found: 337.1260.
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Anal. Calcd for С15Н22О7 С: 57.32 %, Н: 7.05 %. Found С: 57.29 %, Н: 7.14 %.
IR (thin layer): 2977, 2945, 2885, 1771, 1737, 1463, 1389, 1266, 1229, 1151, 1128, 1021 cmꢀ1.
2ꢀ{[1,1ꢀBis(ethoxycarbonyl)propoxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3ib)
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Yields: 7% (64.4 mg, 0.19 mmol, without catalyst), 40% (368.0 mg, 1.06 mmol, LaCl3 catalyst), 20%
(184.0 mg, 0.53 mmol, La(NO3)3 catalyst).
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Colorless oil. Rf = 0.34 (PE:EtOAc = 5:1+ 2 % AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.86ꢀ0.97 (m, 9H), 1.25 (t, J = 7.3 Hz, 6H), 1.94ꢀ2.08 (m, 4H), 2.22
(q, J = 7.3 Hz, 2H), 4.23 (q, J = 7.3 Hz, 4H), 9.46 (br.s., 1H).
13C NMR (75.48 MHz, CDCl3, δ): 7.7, 8.5, 13.9, 26.7, 28.1, 58.8, 62.3, 84.0, 166.1, 171.3, 175.4.
HRMS (ESI) m/z [M+Na]+ : Calcd for [C16H26NaO8]+ : 369.1520. Found: 369.1521.
Anal. Calcd for С16Н26О8 С: 55.48 %, Н: 7.57 %. Found С: 55.48 %, Н: 7.62 %.
IR (thin layer): 2980, 2944, 2886, 1755, 1714, 1461, 1306, 1256, 1235, 1133, 1099, 1031 cmꢀ1.
2ꢀ{[2ꢀEthoxyꢀ1ꢀ(ethoxycarbonyl)ꢀ2ꢀoxoꢀ1ꢀphenylethoxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3jb)
Yields: 9% (75.1 mg, 0.19 mmol, without catalyst), 56% (467.4 mg, 1.19 mmol, LaCl3 catalyst), 44%
(367.3 mg, 0.93 mmol, La(NO3)3 catalyst).
Colorless oil. Rf = 0.55 (PE:EtOAc = 2:1+ 2% AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.96 (t, J = 7.3 Hz, 6H), 1.19 (t, J = 7.3 Hz, 6H), 2.11 (q, J = 7.3 Hz,
4H), 4.21 (q, J = 7.3 Hz, 4H), 7.30ꢀ7.35 (m, 3H), 7.50ꢀ7.58 (m, 2H), 9.62 (br.s., 1H).
13C NMR (75.48 MHz, CDCl3, δ): 8.5, 13.7, 26.4, 58.8, 62.7, 83.0, 125.6, 128.6, 129.1, 133.7, 165.1,
171.1, 175.4.
HRMS (ESI) m/z [M+Na]+ : Calcd for [C20H26NaO8]+ : 417.1520. Found: 417.1517.
Anal. Calcd for С20Н26О8 С: 60.90 %, Н: 6.64 %. Found С: 60.77 %, Н: 6.71 %.
IR (thin layer): 3070, 2981, 2944, 2885, 1757, 1711, 1464, 1451, 1368, 1248, 1124, 1055, 859, 735, 695
cmꢀ1.
2ꢀ{[(1,1ꢀDiacetylꢀ4ꢀoxopentyl)oxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3kb)
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The Journal of Organic Chemistry
Yields: 76% (733.1 mg, 2.23 mmol, without catalyst), 77% (742.7 mg, 2.26 mmol, LaCl3 catalyst), 71%
(684.8 mg, 2.09 mmol, La(NO3)3 catalyst).
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White solid, m.p. = 75ꢀ77 °C. Rf = 0.28 (PE:EtOAc = 2:1+ 2% AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.92 (t, J = 7.3 Hz, 6H), 2.01 (q, J = 7.3 Hz, 4H), 2.09 (s, 3H), 2.24
(s, 6H), 2.35ꢀ2.43 (m, 2H), 2.48ꢀ2.56 (m, 2H), 9.75 (br.s., 1H).
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13C NMR (75.48 MHz, CDCl3, δ): 8.2, 25.1, 26.5, 26.6, 29.7, 37.1, 58.5, 93.4, 170.0, 176.2, 201.2,
206.8.
HRMS (ESI) m/z [M+Na]+ : Calcd for [C16H24NaO7]+ : 351.1414. Found: 351.1414.
Anal. Calcd for С16Н24О7 С: 58.52 %, Н: 7.37 %. Found С: 58.55 %, Н: 7.29 %.
IR (KBr): 3420, 3081, 2978, 1754, 1720, 1704, 1421, 1358, 1221, 1179, 1091, 919 cmꢀ1.
2ꢀ{[(1ꢀAcetylꢀ1ꢀbenzoylꢀ4ꢀoxopentyl)oxy]carbonyl}ꢀ2ꢀethylbutanoic acid (3lb)
Yields: 9% (75.6 mg, 0.19 mmol, without catalyst), 68% (571.5 mg, 1.46 mmol, LaCl3 catalyst), 44%
(369.8 mg, 0.95 mmol, La(NO3)3 catalyst).
Colorless oil. Rf = 0.19 (PE:EtOAc = 2:1+ 2 % AcOH).
1Н NMR (300.13 MHz, CDCl3, δ): 0.58 (t, J = 7.3 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H), 1.77ꢀ1.92 (m, 4H),
2.10 (s, 3H), 2.32 (s, 3H), 2.45ꢀ2.83 (m, 4H), 7.37 (t, J = 7.3 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.75 (d, J
= 8.1 Hz, 2H), 9.38 (br.s., 1H).
13C NMR (75.48 MHz, CDCl3, δ): 7.9, 8.0, 24.6, 24.7, 26.4, 26.5, 29.7, 37.2, 58.4, 93.2, 128.5, 128.8,
133.2, 134.7, 169.4, 176.0, 193.6, 200.8, 207.1.
HRMS (ESI) m/z [M+Na]+ : Calcd for [C21H26NaO7]+ : 413.1571. Found: 413.1563.
Anal. Calcd for С21Н26О7 С: 64.60 %, Н: 6.71 %. Found С: 64.72 %, Н: 6.93 %.
IR (CHCl3): 3468, 2976, 2944, 2617, 1724, 1449, 1360, 1124, 711, 703, 523 cmꢀ1.
Byꢀproduct 7 was isolated additionally with CꢀO coupling product 3lb in the case of LaCl3 catalyst.
3ꢀBenzoylꢀ3ꢀchloroꢀ2,6ꢀheptanedione (7)
Yield of 7 was 21% (120.0 mg, 0.45 mmo). Colorless oil. Rf = 0.81 (PE:EtOAc = 2:1+ 2 % AcOH).
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