Metal-free α-hydroxylation of α-unsubstituted β-oxoesters and β-oxoamides

Article abstract of DOI:10.1021/jo501985u

A direct metal-free α-hydroxylation of α-unsubstituted β-oxoesters and β-oxoamides was developed using m-chloroperbenzoic acid as the oxidant. This transformation enabled straightforward metal-free access to important α-hydroxy-β-dicarbonyl moieties under

Full text of DOI:10.1021/jo501985u

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Note
Metal-Free alpha-Hydroxylation of alpha-
Unsubstituted beta-Oxoesters and beta-Oxoamides
Haruyasu Asahara, and Nagatoshi Nishiwaki
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501985u • Publication Date (Web): 07 Nov 2014
Downloaded from http://pubs.acs.org on November 12, 2014
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MetalꢀFree αꢀHydroxylation of αꢀUnsubstituted βꢀOxoesters and
βꢀOxoamides
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Haruyasu Asahara, and Nagatoshi Nishiwaki*
School of Environmental Science and Engineering, Kochi University of Technology,
Research Center for Material Science and Engineering, Kochi University of Technology,
Kami, Kochi 782ꢀ8502, Japan
Eꢀmail: nishiwaki.nagatoshi@kochiꢀtech.ac.jp
Abstract:
A direct metalꢀfree αꢀhydroxylation of αꢀunsubstituted βꢀoxoesters and βꢀoxoamides was
developed using mꢀchloroperbenzoic acid as the oxidant. This transformation enabled
straightforward metalꢀfree access to important αꢀhydroxyꢀβꢀdicarbonyl moieties under mild reaction
conditions. Furthermore, the hydroxylated products were readily converted into vicinal tricarbonyl
compounds, which are useful synthetic precursors of numerous biological targets.
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The αꢀoxidation of βꢀdicarbonyl compounds, leading to both αꢀhydroxy and αꢀoxo
derivatives, is an important chemical transformation in synthetic chemistry and pharmaceutical
science.1 αꢀHydroxyꢀβꢀdicarbonyl moieties are often found in antibiotics such as Kjellmanianone2
and Hamigeran A,3 as well as in key intermediates such as those for the synthesis of olmesartan,4
dihydroimidazoquinoline, a known thrombinꢀactivatable fibrinolysis inhibitor (TAFIa),5 and vitamin
B6.6 Recent oxidative synthetic efforts have employed hydroperoxides,7 dimethyldioxirane,8
molecular oxygen,9 and oxaziridines10 as oxidants. However, there is no report for the direct
αꢀhydroxylation of αꢀunsubstituted βꢀdicarbonyl compounds 1 except for only a few examples using
limited substrates and metal salts as oxidant.11 This is probably because the enolizable
αꢀhydroxyꢀβꢀdicarbonyl compounds 2 cause further oxidation under such conditions. It appears that
an additional αꢀsubstituent is required to avoid undesirable side reactions such as BaeyerꢀVilliger
type oxidation and CꢀC bond cleavage.12 Indirect methods to generate enolizable
αꢀhydroxyꢀβꢀdicarbonyl compounds 2 require modifications of the αꢀcarbon, such as halogenation,13
acetylation,14 and diazotization5,15 or conversion to silyl enol ethers16 before the αꢀhydroxylation step
(Scheme 1, (a)). These twoꢀstep methods suffer from drawbacks such as somewhat complicated
experimental manipulations and low efficiency. αꢀHydroxylated βꢀdicarbonyl compounds are
unstable under oxidative reaction conditions and hence decompose or undergo further oxidation to
give α,βꢀdioxocarbonyl compounds compounds, the soꢀcalled vicinal tricarbonyls 3 (VTCs).17
Although the direct synthesis of VTCs from 1 has been recently reported,18,19 the VTCs were
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obtained via a singleꢀelectron transfer process, which does not involve the formation of 2 as an
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intermediate. These circumstances prompted us to study the direct metalꢀfree hydroxylation of 1.
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a) Previous work:
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-substituted -dicarbonyls
(normally cyclic -dicarbonyl compounds)
O
O
O
O
oxidation
R
R
H
OH
-unsubstituted -dicarbonyls
two-step method
O
O
O
O
R
R'
R
R'
N2
X
O
O
O
O
X = halogen
hydroxylation
R
R'
R
R'
O
O
O
OSiMe3
R'
H
H
H
OH
1
2
R
R'
R
OAc
H
b) This work:
-unsubstituted -dicarbonyls
direct metal-free hydroxylation
O
O
O
O
O
O
mCPBA
Cu(OAc)2
R
R'
R
R'
R
R'
H
OH
O
H
H
1
2
3 (VTC)
Scheme 1. αꢀHydroxylation of βꢀdicarbonyl compounds 1 and further oxidation to give VTC 3.
Taking into account the instability of αꢀhydroxyꢀβꢀdicarbonyl compounds, we employed
ethyl benzoylacetate (1a) as the substrate for easy handling of the product (Table 1). We also
employed electrophilic mꢀchloroperbenzoic acid (mCPBA) as the oxidant. When the reactions were
conducted in alcohols at ambient temperature, complicated reaction mixtures were obtained and the
desired αꢀhydroxylated product 2a was formed in very low yields (Table 1, entries 1 and 2). Aprotic
solvents were found to be more effective, and 2a was obtained in moderate yields (entries 3–5).
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Among the examined aprotic solvents, toluene was chosen to further optimize the reaction conditions
because of its low price and low toxicity. Raising the reaction temperature to 60 °C led to almost
quantitative conversion (entry 6). Whereas no reaction occurred under the same reaction conditions
using other oxidants, such as tꢀBuOOH, Na2BO3·4H2O, H2O2, and H2O2 in AcOH. The oxidation of
1a by mCPBA could be used in large scale reaction to afford 2a in a similar yield (entry 7).
Table 1. Optimization of reaction conditions.a
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Entry
1
Solvent
MeOH
EtOH
Temp. (°C)
2a (%)b
rt
rt
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3
2
3c
4c
5c
6c
CHCl3
MeCN
PhMe
PhMe
PhMe
rt
53
50
53
rt
rt
60
96 (83)
7d
60
90 (81)
aReaction conditions: 1a (0.2 mmol), mCPBA (65 wt%, 0.24 mmol), solvent (2 mL). bDetermined by 1H NMR
analysis using 1,1,2,2ꢀtetrachloroethane as an internal standard; the value in parenthesis is the isolated yield.
cEach reactions were performed at least three times and data presented are of one representative experiment
d
(the range of yields are 53–47% in CHCl3, 50–39% in MeCN, and 53–51% in PhMe). The reaction was
conducted using 1.0 g (5.0 mmol) of 1a.
Despite the presence of the benzoyl group, the αꢀhydroxylated product 2a was found to be
unstable toward air oxidation, and small amounts of 3a were detected after purification by silica gel
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column chromatography that had run over several hours. Hence, we concluded that the purification
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of 2a should be completed within one hour (Scheme 2).
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Scheme 2. Further oxidation of αꢀhydroxyꢀβꢀoxoester 2.
With the optimized reaction conditions, the substrate scope was then investigated (Table 2).
The electronic nature of the substituents on the phenyl ring did not reveal significant influence on the
reactivity, and benzoylacetates 1b and 1c were efficiently αꢀhydroxylated (entries 1 and 2). On the
other hand, the substituent obviously influence on the stability of the hydroxylated product and
isolated yields somewhat varied. αꢀHydroxylated pꢀnitrobenzoylacetate 2b was found to be less
stable than 2a, and 15% of 3b was obtained despite rapid purification by silica gel column
chromatography. Furthermore, αꢀhydroxylated aliphatic βꢀoxoester 2d revealed lower stability than
2aꢀc and easily decompose to volatile and hardly isolable compound. The introduction of a longer
alkyl chain or a bulkier group on the substrate led to less volatile compounds, and hydroxylated
products 2e and 2f were isolated in 67% and 78% yields, respectively (entries 4 and 5). As
anticipated, the sterically restricted cyclic βꢀoxoester 1g, αꢀsubstituted oxoester, was efficiently
transformed to 2g, which is rather stable because it does not form enol form, and the isolation
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proceeded smoothly (entry 6). However, hydroxylated products were not obtained in the case of
2,4ꢀpentanedione, 1,3ꢀdiphenylꢀ1,3ꢀpropanedione, and diethyl malonate.20
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Notably, oxidation of βꢀoxoamides 1h–j afforded the corresponding αꢀhydroxylated
products 2h–j in only moderate yields (entries 7 and 8). Lowering the reaction temperature (0 °C)
was found to slightly increase the yield of the products. In the case of benzoyl acetamide 1j, the
αꢀhydroxylated product 2j was isolated in 64% yield without significant loss (entry 11).
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Table 2. Reaction of βꢀdicarbonyls to give αꢀhydroxyꢀβꢀdicarbonyls.a
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aAll reactions except for 2d were performed at least three times and data presented are of one representative
experiment bDetermined by 1H NMR analysis using 1,1,2,2ꢀtetrachloroethane as an internal standard; values in
parenthesis is the yield of the isolated product. c3b was isolated in 15% yield. dAt 0 °C.
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Next, we investigated the oxidation of αꢀhydroxyꢀβꢀdicarbonyl compounds 2 to yield VTCs
3, which are widely used for syntheses of polyfunctionalyzed compounds17 (Table 3). As shown in
Scheme 2, silica gel aided the air oxidation to afford a mixture of VTC 3a and its hydrate form 3a’,
though in only moderate yield (entry 1). Hence, acceleration by several metal salts was evaluated
(entries 2–6), and Cu(OAc)2 was identified as the most effective oxidant, to afford 3a in 92% yield
(entry 6). While the oxidation similarly proceeded 50 mol% and 20 mol% of Cu(OAc)2 under air
(entries 7 and 8), the efficiency of the reaction considerably decreased under argon (entry 9), which
indicated the O2 is relevant oxidant in this oxidation reaction.21 To examine the reaction scope,
compounds 2 were submitted to the latter oxidation conditions (Table 4). This method was applicable
not only to hydroxylatedꢀaromatic oxoesters 2b and 2c but also to aliphatic ones 2e and 2f, and the
corresponding VTCs were furnished in high yields. αꢀHydroxyꢀβꢀoxoamide 2j was also oxidized,
though the yield of 3j was only moderate.
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Table 3. Oxidation of αꢀhydroxyꢀβꢀoxoester 2a.
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Entry
Metal salt
Yield (%)a
b
1
SiO2
56
trace
trace
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2
Ag2O
AgOAc
MnO2
3
4
5
FeCl3
45
6
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
92
7c
8d
9c,e
90
79
42
aIsolated yield. Total yield of VTCs 3a and its hydrate form 3a’. αꢀHydroxy βꢀoxoester 2a was stirred with
0.5 g of silica gel at rt for 20 h. c50 mol% of Cu(OAc)2 was used. 20 mol% of Cu(OAc)2 was used. dUnder
b
d
argon.
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Table 4. Scope of oxidation of αꢀhydroxyꢀβꢀdicarbonyl compounds 2.
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The direct metalꢀfree αꢀoxidation of αꢀunsubstituted βꢀdicarbonyl compounds 1 was
successfully achieved under mild conditions using mCPBA as the oxidant. This protocol constitutes a
new and straightforward route to αꢀhydroxylated βꢀoxoesters and βꢀoxoamides. Further advantages
of this method include ready availability of the substrates and high atom economy. Moreover, since
the αꢀhydroxyꢀβꢀdicarbonyl products 2 can be efficiently converted into VTCs using Cu(OAc)2 under
mild conditions, this protocol represents a useful tool for the synthesis of polyfunctionalized
compounds, including αꢀhydroxyꢀβꢀdicarbonyls and VTCs, which are useful structural units in
organic and medicinal chemistry.
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Experimental Section
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General Procedure of αꢀhydroxylation
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To a solution of βꢀdicarbonyl compounds 1 (0.20 mmol) in toluene (2 mL) mCPBA (65 wt%, 64.0
mg, 0.24 mmol) was added and the resultant solution was stirred for 20 h at 60 °C. The reaction
mixture was washed with sat. NaHCO3 aq. to remove mꢀchlorobenzoic acid, and then extracted with
CH2Cl2 (2 × 5 mL). The combined organic layer were dried over MgSO4, filtered, and concentrated
1
under reduced pressure. The yield of product 2 was calculated by H NMR integration of the crude
product using 1,1,2,2ꢀtetrachloroethane as an internal standard. Further purification was achieved by
flash column chromatography on silica gel (hexane/EtOAc = 4/1).
In the case of largeꢀscale reaction, lowering the product yield was observed due to the phase
separation by the measurable amount of water. In such case, mCPBA was dissolved in toluene and
dried over MgSO4 after separation with aqueous layer.
Transformation of 2 to VTC
To a solution of αꢀhydroxyꢀβꢀdicarbonyl compounds 2 (0.20 mmol) in CH2Cl2 (2 mL) was added
Cu(OAc)2 (0.20 mmol) and the resultant mixture was stirred for 20 h at rt. The reaction mixture was
passed through a silica gel short column using Et2O as an eluent to give the corresponding
α,βꢀoxoester and α,βꢀoxoamide products 3.
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Spectra Data of the Products
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Ethyl 2ꢀhydroxyꢀ3ꢀoxoꢀ3ꢀphenylpropanoate (2a):22 (34.6 mg, 83%); yellow oil. Rf = 0.37 (silica
gel, hexane/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.2, Hz, 3H), 4.29 (q, J = 7.2, Hz,
2H), 4.3 (br s, 1H), 5.60 (s, 1H), 7.48–7.53 (m, 2H), 7.63 (t, J = 8.0, Hz, 1H), 8.0 (d, J = 8.2, Hz, 2H).
13C NMR (CDCl3) δ 13.9 (CH3), 58.1 (CH), 63.2 (CH2), 128.9 (CH), 129.3 (CH), 133.5 (C), 134.3
(CH), 165.3 (C), 188.2 (C).
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Ethyl 2ꢀhydroxyꢀ3ꢀoxoꢀ3ꢀ(4ꢀnitrophenyl)propanoate (2b):23 (36.5 mg, 72%); yellow oil, Rf = 0.83
(silica gel, hexane/EtOAc, 1:1); 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J = 7.2 Hz, 3H), 4.23 (q, J =
7.2 Hz, 2H), 5.18 (br s, 1H), 5.57 (s, 1H), 8.25 (d, J = 8.0 Hz, 2H), 8.35 (d, J = 8.0 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 13.9 (CH3), 62.9 (CH2), 75.0 (CH), 123.9 (CH), 130.6 (CH), 137.9 (C),
151.1 (C), 168.2 (C), 192.9 (C).
Ethyl 2ꢀhydroxyꢀ3ꢀoxoꢀ3ꢀ(4ꢀmethoxyphenyl)propanoate (2c): (42.9 mg, 90%); yellow oil, Rf =
0.31 (silica gel, hexane/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 1.19 (t, J = 6.8 Hz, 3H), 3.89 (s,
3H) 4.18 (q, J = 6.8 Hz, 2H), 4.35 (br s, 1H), 5.54 (br s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 8.08 (d, J =
8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 13.9 (CH3), 55.6 (CH3), 62.2 (CH2), 74.3 (CH), 114.1
(CH), 126.0 (C), 132.0 (CH), 164.8 (C), 168.9 (C), 192.0 (C); ATRꢀFTIR (cmꢀ1): 3411 (br), 2932 (w),
2648 (w), 2560 (w), 1733 (s), 1682 (s), 1429 (w), 1354 (w), 1225 (m), 1080 (m), 993 (w), 956 (w),
883 (w). HRMS (CI+) m/z calcd. for C12H15O5 : 239.0919 (M + H)+, found 239.0921.
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Ethyl 2ꢀhydroxyꢀ3ꢀoxohexanoate (2e): (23.3 mg, 67%); yellow oil. Rf = 0.31 (silica gel,
hexane/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J = 7.6 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H),
1.67 (tq, J = 7.2, 7.6 Hz, 2H) 2.56–2.72 (m, 2H), 3.71 (br s, 1H), 4.29 (q, J = 7.0 Hz, 3H), 4.77 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 13.5 (CH3), 14.0 (CH3), 16.9 (CH2), 40.5 (CH2), 62.4 (CH2),
77.8 (CH), 168.4 (C), 204.4 (C); ATRꢀFTIR (cmꢀ1): 3248 (br), 2965 (w), 1748 (s), 1732 (s), 1260
(m), 1152 (w), 1016 (m). HRMS (CI+) m/z calcd. for C8H15O4 : 175.0970 (M + H)+, found
175.0969.
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Methyl 2ꢀhydroxyꢀ4,4ꢀdimethylꢀ3ꢀoxopentanoate (2f); (27.2 mg, 78%); yellow oil. Rf = 0.33
(silica gel, hexane/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ 1.23 (s, 9H), 3.79 (s, 3H), 3.95 (d, J =
6.8 Hz, 1H), 5.05 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 26.3 (CH3), 43.8 (C), 52.8
(CH3), 72.8 (CH), 169.4 (C), 209.6 (C); ATRꢀFTIR (cmꢀ1): 3329 (br), 2961 (w), 1748 (s), 1714 (s)
1256 (m), 1155 (w), 1016 (m). HRMS (CI+) m/z calcd. for C8H15O4 : 175.0970 (M + H)+, found
175.0968.
Ethyl 1ꢀhydroxyꢀ2ꢀoxocyclohexaneꢀ1ꢀcarboxylate (2g):11a (35.4 mg, 95%); brown oil. Rf = 0.39
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(silica gel, hexane/EtOAc, 4:1); H NMR (CDCl3) δ 1.30 (t, J = 7.1 Hz, 3H), 1.63–1.77 (m, 2H),
1.80–1.92 (m, 2H), 2.01–2.10 (m, 1H), 2.53–2.72 (m 3H), 4.25 (q, J = 7.1 Hz, 2H), 4.31 (s, 1H). 13C
NMR (CDCl3) δ 14.0 (CH3), 22.0 (CH2), 27.1 (CH2), 37.7 (CH2), 38.9 (CH2), 62.1(CH2), 80.7 (C),
170.1 (C), 207.3 (C).
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2ꢀHydroxyꢀN,Nꢀdimethylꢀ3ꢀoxobutanamide (2h): (9.3 mg, 32%; reaction was conducted at 0 °C);
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yellow oil. Rf = 0.23 (silica gel, hexane/EtOAc, 1:1); H NMR (400 MHz, CDCl3) δ 2.22 (s, 3H),
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3.03 (s, 3H), 3.10 (s, 3H), 4.31 (br s, 1H), 4.80 (s, 1H); C NMR (100 MHz, CDCl3) δ 25.3 (CH3),
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36.5 (CH3), 37.1 (CH3), 76.2 (CH), 167.8 (C), 206.4 (C); ATRꢀFTIR (cmꢀ1): 3115 (br), 2960 (w),
2354 (w), 1717 (s), 1646 (s), 1472 (w), 1456 (w), 1371 (w), 1339 (w),1250 (m), 1153 (w), 1107 (w),
1016 (m), 943 (w), 914 (w). HRMS (CI+) m/z calcd. for C6H12NO3 : 146.0817 (M + H)+, found
146.0818.
2ꢀHydroxyꢀ1ꢀmorpholinobutaneꢀ1,3ꢀdione (2i): (14.2 mg, 38%; reaction was conducted at 0 °C);
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yellow oil, Rf = 0.41 (silica gel, hexane/EtOAc, 1:1); H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H),
3.49–3.67 (m, 4H), 3.70–3.78 (m, 4H), 4.58 (d, J = 6.8 Hz, 1 H), 4.79 (d, J = 6.8 Hz, 1 H); 13C NMR
(100 MHz, CDCl3) δ 25.5 (CH3), 43.6 (CH2), 46.1 (CH2), 66.4 (CH2), 66.5 (CH2), 76.0 (CH), 166.5
(C), 206.8 (C); ATRꢀFTIR (cmꢀ1): 3204 (br), 2966 (w), 1731 (s), 1635 (s), 1506 (w), 1470 (w), 1443
(w), 1410 (w), 1371 (w), 1329 (w), 1246 8m), 1152 (w), 1105 (w), 1078 (w), 1009 (m), 941 (w), 912
(w). HRMS (CI+) m/z calcd. for C8H14NO4 : 188.0923 (M + H)+, found 188.0924.
2ꢀHydroxyꢀ1ꢀphenylꢀ3ꢀ(pyrrolidinꢀ1ꢀyl)propaneꢀ1,3ꢀdione (2j): (29.9 mg, 64%; reaction was
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conducted at 0 °C); yelow oil, Rf = 0.12 (silica gel, hexane/EtOAc, 4:1); H NMR (400 MHz,
CDCl3) δ 1.84–1.97 (m, 4H), 3.32–3.40 (m, 1H), 3.45–3.49 (m, 1H), 3.54–3.58 (m, 2H), 4.63 (br s,
1H), 5.32 (s, 1H), 7.45–7.51 (m, 2 H) , 7.56 (t, J = 7.6 Hz, 1 H) , 8.07 (d, J = 7.2 Hz, 2 H); 13C NMR
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(100 MHz, CDCl3) δ 23.8 (CH2), 26.0 (CH2), 46.1 (CH2), 46.8 (CH2), 75.5 (CH), 128.7 (CH), 129.3
(CH), 133.9 (CH), 134.3 (C), 133.8 (C), 195.1 (C); ATRꢀFTIR (cmꢀ1): 3184 (br), 2963 (w), 1683 (s),
1635 (s), 1470 (w), 1439 (w), 1371 (w), 1344 (w), 1244 (m), 1153 (w), 1098 (w), 1080 (w), 1013
(m), 941 (w), 912 (w). HRMS (CI+) m/z calcd. for C13H16NO3 : 234.1130 (M + H)+, found
234.1127.
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Ethyl 2,3ꢀdioxoꢀ3ꢀphenylpropanoate (3a):23,24 (40.0 mg, 92%); yellow oil, Rf = 0.59 (silica gel,
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hexane/EtOAc, 4:1); Mixture of ketone and corresponding hydrated form in ratio 1:1.6. Ketone: H
NMR (CDCl3) δ 1.39 (t, J = 7.2 Hz, 3 H), 4.43 (q, J = 7.2 Hz, 2 H), 7.45–7.56 (m, 2H), 7.63–7.68 (m,
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1H), 7.98–8.01 (m, 2H); C NMR (100 MHz, CDCl3) δ 13.9 (CH3), 63.3 (CH2), 129.1 (CH), 130.0
(CH), 131.3 (C), 135.5 (CH), 136.2 (C), 183.7 (C), 190.2 (C); Hydrate: 1H NMR (CDCl3) δ 1.09 (t, J
= 7.2 Hz, 3 H), 4.22 (q, J = 7.2 Hz, 2 H), 5.23 (br s, 2H), 7.47–7.56 (m, 2H), 7.64–7.72 (m, 1H),
8.10–8.13 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.8 (CH3), 62.3 (CH2), 91.8 (C), 128.8 (CH),
130.4 (CH), 131.4 (C), 134.6 (CH), 168.5 (C), 193.9 (C).
Ethyl 3ꢀ(4ꢀnitrophenyl)ꢀ2,3ꢀdioxopropanoate (3b):25 (51.2 mg, 95%); yellow oil. Rf = 0.61 (silica
gel, hexane/EtOAc, 1:1); Isolated as a hydrated form. Hydrate 1H NMR (400 MHz, CDCl3) δ 1.12 (t,
J = 7.2 Hz, 3 H), 4.23 (q, J = 7.2 Hz, 2 H), 5.30 (br s, 2H), 8.27 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.8
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.7 (CH3), 63.5 (CH2), 92.1 (C), 123.8 (CH), 131.2 (CH),
136.2 (C), 151.0 (C), 169.1 (C), 190.7 (C).
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Ethyl 3ꢀ(4ꢀmethoxyphenyl)ꢀ2,3ꢀdioxopropanoate (3c):25 (44.7 mg, 90%); yellow oil, Rf = 0.14
(silica gel, hexane/EtOAc, 4:1); Mixture of ketone and corresponding hydrated form in ratio 1:2.
Ketone: 1H NMR (400 MHz, CDCl3) δ 1.38 (t, J = 7.2 Hz, 3 H), 3.91 (s, 3 H), 4.41 (q, J = 7.2 Hz, 2
H), 7.00 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 14.2 (CH3),
56.0 (CH3), 63.4 (CH2), 114.8 (CH), 124.9 (C), 132.9 (CH), 161.2 (C), 165.8 (C), 184.2 (C), 188.5
(C); Hydrate: 1H NMR (400 MHz, CDCl3) δ 1.11 (t, J = 7.2 Hz, 3 H), 3.88 (s, 3 H), 4.22 (q, J = 7.2
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Hz, 2 H), 5.35 (br s, 2H), 6.94 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H); C NMR (100 M Hz,
CDCl3) δ 14.0 (CH3), 55.8 (CH3), 63.3 (CH2), 91.8 (C), 114.3 (CH), 124.4 (C), 133.0 (CH), 165.0
(C), 170.5 (C), 190.1 (C).
Methyl 2,3ꢀdioxohexanoate (3e):26 (31 mg, 88%); yellow oil, Rf = 0.26 (silica gel, hexane/EtOAc,
4:1); Mixture of ketone and corresponding hydrated form in ratio 1:10. Hydrate: 1H NMR (400 MHz,
CDCl3) δ 1.25 (s, 9H), 3.84 (s, 3H), 5.08 (br s, 2H); 13C NMR (100 M Hz, CDCl3) δ 13.5 (CH3),
14.0 (CH3), 16.9 (CH2), 40.5 (CH2), 62.4 (CH2), 77.8 (CH), 168.4 (C), 204.4 (C).
Methyl 4,4ꢀdimethylꢀ2,3ꢀdioxopentanoate (3f):27 (29.1 mg, 82%); yellow oil, Rf = 0.41 (silica gel,
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hexane/EtOAc, 4:1); Mixture of ketone and corresponding hydrated form in ratio 2.6:1. Ketone: H
NMR (400 MHz, CDCl3) δ 1.30 (s, 9H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 25.5 (CH3),
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42.7 (C), 53.3 (CH3), 161.0 (C), 183.9 (C), 206.2 (C); Hydrate: H NMR (400 MHz, CDCl3) δ 1.25
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(s, 9H), 3.84 (s, 3H), 5.08 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 27.2 (CH3), 43.1 (C), 53.5
(CH3), 92.0 (CH), 169.9 (C), 208.1 (C).
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1ꢀPhenylꢀ3ꢀ(pyrrolidinꢀ1ꢀyl)propaneꢀ1,2,3ꢀtrione (3j): (29.0 mg, 61%); yellow oil, Rf = 0.30
(silica gel, hexane/EtOAc, 4:1); Mixture of ketone and corresponding hydrated form in ratio 2.2:1.
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Ketone: H NMR (400 MHz, CDCl3) δ 1.93–1.97 (m, 2H), 1.99–2.04 (m, 2H), 3.58–3.62 (m, 2H),
3.61–3.78 (m, 2H), 7.52 (dd, J = 7.2, 8.0 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 23.8 (CH2), 26.1 (CH2), 46.1 (CH2), 46.9 (CH2), 128.9 (CH), 130.1
(CH), 132.2 (C), 135.1 (CH), 162.1 (C), 186.9 (C), 193.2 (C); Hydrate: 1H NMR (400 MHz, CDCl3)
δ 1.74–1.78 (m, 4H), 3.16–3.19 (m, 2H), 3.52–3.54 (m, 2H), 7.44 (dd, J = 7.2, 8.0 Hz, 2H), 7.54 (t, J
= 7.2 Hz, 1H), 8.08 (d, J = 8.0 Hz, 2H); 13C NMR (100 M Hz, CDCl3) δ 23.5 (CH2), 26.0 (CH2),
46.3 (CH2), 47.7 (CH2), 91.5 (C), 128.9 (CH), 130.1 (CH), 131.7 (C), 134.7 (CH), 166.8 (C), 193.9
(C); ATRꢀFTIR (cmꢀ1): 3141 (br), 2971 (w), 1682 (s), 1651 (s), 1645 (s), 1637 (s), 1456 (w), 1396
(w), 1215 (m), 1107 (m), 1061 (m), 982 (w). HRMS (CI+) m/z calcd. for C13H14NO3 : 232.0974 (M
+ H)+, found 232.0975.
Associated Content
Supporting Information
1H, 13C NMR spectra for new compounds. This material is available free of charge via the Internet at
http://pubs.acs.org
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Author Information
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Tell: +81ꢀ887ꢀ57ꢀ2517
Fax: +81ꢀ887ꢀ57ꢀ2520
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Eꢀmail: nishiwaki.nagatoshi@kochiꢀtech.ac.jp
Acknowledgements
The authors would like to thank Prof. Dr. S. Minakata (Department of Applied Chemistry, Graduate
School of Engineering, Osaka University) for the HRMS analysis.
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(20)αꢀHydroxylation of 2,4ꢀpentanedione did not proceed and we could not isolate any product same
as 1d. In the case of 1,3ꢀdiphenylꢀ1,3ꢀpropanedione, BaeyerꢀVilliger type oxidized product was
obtained in 42% yield instead of the desired product. On the other hand, no reaction was
observed in the reaction using diethyl malonate under the employed reaction conditions.
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