Tandem catalytic oxidative deacetylation of acetoacetic esters and heteroaromatic cyclizations

Article abstract of DOI:10.1039/c4ob02441a

One pot syntheses of furan, thiophene, and pyrrole were accomplished by oxidative deacetylation using Mn(iii)/Co(ii) catalysts and the Paal-Knorr reaction from 1,5-dicarbonyl compounds, which are prepared from the conjugate addition of ethyl acetoacetate to α,β-unsaturated carbonyl compounds. The oxidative deacetylation and reductive cyclization of β-ketoesters derived from ethyl acetoacetate and o-nitrobenzyl bromides efficiently produced diversely substituted indoles. This journal is

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Tandem Catalytic Oxidative Deacetylation of Acetoacetic Esters and
Hetero Aromatic Cyclizations
Yeming Ju,a,b Di Miao,a,b Ruiyang Yua,b and Sangho Koo*a,b,c
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
One pot syntheses of furan, thiophene, and pyrrole were accomplished by oxidative deacetylation using
Mn(III)/Co(II) catalysts and Paal-Knorr reaction from 1,5-dicarbonyl compounds, which are prepared
from the conjugate addition of ethyl acetoacetate to ,-unsaturated carbonyl compounds. The oxidative
deacetylation and reductive cyclization of -ketoesters derived from ethyl acetoacetate and o-nitrobenzyl
10 bromides efficiently produced diversely substituted indoles.
Introduction
An acetoacetic ester is a useful builing block in organic synthesis
for efficient carbon-carbon bond formation, where it reacts with
various soft electrophiles such as alkyl, allyl, benzyl halides, and
15 electron-deficient alkenes. The coupled products normally
undergo smooth decarboxylation to provide the corresponding
ketones, which completes the mild variants of ketone
alkylations.1 We recently demonstrated that the coupling products
of ethyl acetoacetate with allylic halides might undergo oxidative
20 deacetylation upon treatment of catalytic Mn(III)/Co(II) under air
to produce the corresponding -oxoesters.2 The -oxoesters then
participated in hetero cyclizations to either dihydropyrans or
furans depending on the substitution patterns in the allyl chain
under the same oxidation condition.3 We conceived that the
25 coupling of ethyl acetoacetate with methyl vinyl ketone and with
2-nitrobenzyl bromides, and subsequent oxidative deacetylation
would lead to useful -oxoesters, which are amenable to further
hetero cyclizations to pyrroles and indoles, respectively The
scopes of these synthetic strategies for the heterocyclic
30 compounds are delineated herein in detail.
45 Scheme 1 Oxidative deacetylation of 1,5-dicarbonyl compounds 1 and 4
under the Mn(III)/Co(II) catalyst condition.
Oxidative deacetylation of 1 using the catalysts mixture
containing 5 mol% of Mn(OAc)3·2H2O and 2 mol% of CoCl2
under air proceeded smoothly at 25 ºC in AcOH to give 1,4-
50 dicarbonyl compound 2 in 94% yield (Scheme 1). The same
reaction in EtOH produced -hydroxylation product 3 in 27%
yield as well as 2 in 57% yield, which manifested the reducing
role of EtOH for the intermediate -peroxy radical that was
generated from the -carbon radical by trapping a molecular
55 oxygen.6 The mechanism through the -peroxy radical
intermediate was confirmed by the formation of 1,2-dioxane 5
(84% yield) when 1,5-dicarbonyl compound 4, prepared from the
conjugate addition of pentane-2,4-dione to methyl vinyl ketone,
was submitted to the above oxidation condition at 25 ºC in AcOH.
60 It was surprising that a difference in the peripheral functional
group displayed a different reactivity of the -peroxy radical in
1,5-dicarbonyl compounds 1 and 4 at room temperature. 1,4-
Dicarbonyl compound 6 can be obtained in 41% yield from 1,2-
dioxane 5 or in 49% yield directly from 4 at an elevated
65 temperature of 60 ºC for 1 h, which presumably proceeds through
1,2-dioxetane A.7
Results and Discussion
The Paal-Knorr synthesis has been a robust preparation method
of pyrroles and furans for more than a century, which has the
only drawback of the relative difficulty to obtain the required 1,4-
35 dicarbonyl compounds.4 The conjugate addition of ethyl
acetoacetate to ,-unsaturated carbonyl compounds produce 1,5-
dicarbonyl compounds,5 which are ideally suited for the
Mn(III)/Co(II)-catalyzed oxidative deacetylation to produce 1,4-
dicarbonyl compounds. Therefore, the combination of these
40 reaction sequences would constitute an efficient synthetic method
of furans, thiophenes, and pyrroles. We tested this hypothesis
using 1,5-dicarbonyl compound 1, prepared from the conjugate
addition of ethyl acetoacetate to methyl vinyl ketone.
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61% yield (entry 9).
Scheme 2 One-pot synthesis of furan 7, thiophene 8, and pyrrole 9 from
1,5-dicarbonyl compound 1.
Table 1 One-pot synthesis of pyrrole-2-carboxylates from 1,5-dicarbonyl
5 compound 1 by tandem oxidative deacetylation and the Paal-Knorr
reaction.a
Scheme 3 Intramolecular esterification and transamidation of pyrrole-2-
carboxylates 19 and 20 to 22 and 23, respectively.
40
Anilines with a hetero-atomic substituent at ortho position
were also effective in producing the corresponding pyrrole-2-
carboxylates 19 and 20 in reasonable yields (entries 10-11),
which are especially valuable in building up poly heterocyclic
compounds. Efforts for the transesterification of 19 under acidic
Entry
Amine
Pyrrole (R)
Yield (%)
EtO2C
N
R
1
2
3
4
5
6
7
8
Benzylamine
Butylamine
3-Aminopropanol
Propargyl amine
Aniline
10
11
CH2Ph
n-Bu
(CH2)3OH
CH2C≡CH
Ph
63
55
56
50
78
61
67
43
12
13
14
15
16
45 (p-TsOH in refluxing benzene) or basic conditions (t-BuOK in t-
BuOH at 25 ºC) were all in vain. However, hydrolysis of ester in
19, followed by intramolecular esterification using dicyclohexyl
carbodiimide (DCC) produced pyrrolo-1,4-oxazepin-2-one 22 in
79% yield (Scheme 3). On the other hand, deprotection of the
50 Boc-protecting group, followed by transamidation of pyrrole 20
worked well in AcOH at 100 ºC for 1 h to produce the
p-Iodoaniline
4-I-Ph
4-MeOPh
17 5-(CO2Et)-2-MePh
p-Methoxyaniline
Ethyl 3-amino-4-
methylbenzoate
9
Benzene-1,4-diamine 18
61
biologically
and
pharmaceutically
important
pyrrolo-
quinoxalinone 23 in 61% yield.8 One-pot synthesis of pyridazine
21 (24% yield) was accomplished by the tandem sequence of
55 oxidative deacetylation of 1 and the Paal-Knorr reaction with
hydrazine (entry 12).
10
11
o-Hydroxymethylaniline 19
2-(CH2OH)Ph
2-(NHBoc)Ph
71
64
t-Butyl 2-
aminophenylcarbamate
Hydrazine
20
21
12
24
a 1 was treated with 5 mol% Mn(OAc)3·2H2O and 2 mol% CoCl2 in
Table 2 Oxidative deacetylation of the coupling product 24 of ethyl
AcOH at 25 ºC for 3 h, and amine was added. The reaction mixture was
acetoacetate and ortho-nitrobenzyl bromide using Mn(III)/Co(II) catalysts.
then heated at 60 ºC for 30 min.
10
Coincidence of the solvent in the above oxidative
deacetylation and the Paal-Knorr synthesis thus allowed us to
develop one pot synthetic transformations of the readily available
1,5-dicarbonyl compound into furan, thiophen, and pyrrole
(Scheme 2). Oxidative deacetylation of 1 using the Mn(III)/Co(II)
Equiv.
Mn(OAc)3
0.05
0.05
0.10
Yield (%)
Entry
Equiv.
CoCl2
0.02
0.02
0.04
T (°C) / t (h)
25
26
33
48
0
1
2
25 / 3
60 / 3
10~15 / 7
30
0
15 catalysts in AcOH at 25 ºC for 3 h, followed by the reaction with
sulfuric acid (1 equiv.) at 90 ºC for 1 h produced furan 7 in 54%
yield. The reactions with Lawesson’s reagent (1.5 equiv.) at 90 ºC
for 1 h and with ammonium acetate (10 equiv.) at 60 ºC for 0.5 h
provided thiophene 8 in 63% yield and pyrrole 9 in 64% yield,
20 respectively.
The efficacy and general applicability of the one pot synthesis
of hetero aromatic compounds from 1,5-dicarbonyl compound 1
was further demonstrated in the preparation of various pyrrole-2-
3a
63
a One equivalent of CF3CO2H was added.
60
We then turned our attention to the coupling product 24
(existed as a 6:1 mixture of keto and enol forms in CDCl3) of
ethyl acetoacetate and ortho-nitrobenzyl bromide, since oxidative
deacetylation would lead to the corresponding -ketoester 25,
carboxylates 10-20 (Table 1). Various aliphatic and aromatic 65 which is perfectly suited for the indole synthesis by reduction and
25 primary amines were added after the oxidative deacetylation of 1
using 5 mol% Mn(OAc)3·2H2O and 2 mol% CoCl2 in AcOH at
25 ºC for 3 h, and the reaction mixture was heated at 60 ºC for 30
min to give rise to the corresponding pyrrole-2-carboxylates 10-
20 in 43~78% yields. Aliphatic amines ranging from simple
30 amines such as benzyl and butyl amines to functional amines
such as hydoxypropyl and propargyl amines as well as aromatic
amines worked well to give the desired pyrroles (entries 1-7),
albeit a somewhat lower yield (43%) was obtained for the
aromatic cyclization of the ortho-nitro group.9 The oxidative
deacetylation of 24 was carefully studied using a mixture of
Mn(OAc)3·2H2O and CoCl2 under air in AcOH (Table 2). The
optimized condition for 1,5-dicarbonyl compound at 25 ºC for 3 h
70 produced -ketoester 25 and -hydroxy--ketoester 26 in 30%
and 33% yields, respectively (entry 1). This unusually high -
hydroxylation ratio can be explained by the presence of the ortho-
nitrophenyl group, which allows the -peroxyradical intermediate
to undergo fast reduction either by abstraction of the benzylic
aromatic amine containing an electron-withdrawing group (entry 75 hydrogen or by nucleophilic addition to the electron-deficient
benzene ring, or by both of them.
35 8). Benzene-1,4-diamine produced 1,4-bis(pyrrolo)benzene 18 in
2
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Table 3 Synthesis of indole-2-carboxylates by oxidative deacetylation and reductive cyclization of the coupling products of ethyl acetoacetate and various
ortho-nitrobenzyl bromides.a
Entry
1
Coupling product
Yield (%)
92
Oxidation product
Yield (%)
63
Indole-2-carboxylate
Yield (%)
62
24
28
31
25
29
32
27
30
27
2
3
91
61
59
60
83
53
4
5
33
36
72
45
34
37
66
69
35
38
62
83
6b
7c
39
43
74
67
40
44
23
18
42
46
72
86
a Coupling products were prepared by the reaction of sodium salt of ethyl acetoacetate with 2-nitrobenzyl bromides in THF. Oxidative deacetylation was
carried out using 10 mol% Mn(OAc)3·2H2O and 4 mol% CoCl2 in AcOH with 1 equiv. of TFA at 10-15 ºC for 7-10 h. Hydrogenation with 10% Pd/C at
5 25 ºC for 3-5 h produced indoles. b -Hydroxylation product 41 was also obtained in 22% yield in the oxidation step. c -Hydroxylation product 45 was
also obtained in 18% yield in the oxidation step (see Experimental Section). These -hydroxylation products were inseparable from the -ketoesters, but
removed easily after reductive cyclization to indoles.
This reduction process was facilitated at higher temperature of
60 ºC, in which the -hydoxylation product 26 was the sole
10 product (48% yield) in 3 h (entry 2). Lowering the reaction
nitrobenzyl bromides (1st column, Table 3). Oxidative
deacetylation of -(o-nitrobenzyl)--ketoesters (2nd Column,
Table 2) were successfully carried out under the above optimized
temperature, however, conferred another problem of the relatively 35 condition (entry 3, Table 2) to give the corresponding -
high melting point of AcOH (17 ºC). This problem was alleviated
by the addition of one equivalent of low-melting trifluoroacetic
acid (-15 ºC), in which the reaction was able to be carried out at
15 10~15 ºC. An increase in the catalyst loading was necessary at
ketoesters in 59~69% yields (entries 2-5) except for -ketoesters
39 and 43 containing the electron-rich dialkoxy-substituted
nitrobenzyl moiety, where the corresponding -hydoxylation
products 41 and 45 were also obtained in 22% and 18% yields,
this temperature range in order to complete the conversion of 40 respectively (entries 6 and 7). This suggested that a preferential
starting material. Oxidative deacetylation of 24 was best carried
out by 10 mol% of Mn(OAc)3·2H2O and 4 mol% CoCl2 in AcOH
with the addition of CF3CO2H (1 equiv.) at 10~15 ºC for 7 h to
20 give 25 in 63% yield (entry 3).
reduction mechanism of the -peroxy radical intermediate
(leading to 41 and 45) might be abstraction of the benzylic
hydrogen rather than nucleophilic addition to the electron-rich
aromatic ring.
The resulting -ketoester 25 was exposed to the catalytic
hydrogenation condition using H2(g) on 10% Pd/C in MeOH at
25 ºC for 5 h to induce reduction of the ortho-nitro group, in
which the resulting amino group automatically underwent
25 aromatic cyclization to give indole-2-carboxylate 27 in 62% yield
45
Reduction of the ortho-nitro group of -ketoesters by catalytic
hydrogenation in MeOH at 25 ºC for 3~5 h was accompanied by
smooth aromatic cyclization to produce indole-2-carboxylates in
fair to good yields (3rd column in Table 3). It was noted that de-
chlorination proceeded during the reductive cyclization of 32
(entry 1, Table 3). The generality and scope of this tandem 50 under the catalytic hydrogenation condition to give indole-2-
oxidative deacetylation and reductive aromatic cyclization was
demonstrated for various -(o-nitrobenzyl)--ketoesters to
produce diversely substituted indole-2-carboxylates (Table 3).
30 Various -(o-nitrobenzyl)--ketoesters were easily prepared by
carboxylate 27 in 53% yield (entry 3).10 It was also noteworthy
that most of -ketoesters (e.g. the coupling products) and -
ketoesters (e.g. the oxidation products) containing o-nitrobenzyl
groups existed mainly as a keto form with a small fraction of an
the coupling of ethyl acetoacetate with diversely substituted o- 55 enol form (see Experimental Section).
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50
Ethyl 2-acetyl-5-oxohexanoate (1). Following the literature
.
procedure,5 CeCl3 7H2O (0.57 g, 1.54 mmol) and NaI (0.12 g,
0.77 mmol) were added to a stirred solution of ethyl acetoacetate
(1.00 g, 7.68 mmol) and methyl vinyl ketone (0.60 g, 8.45 mmol)
in acetonitrile at 25 ºC. The mixture was stirred for 16 h, and
55 quenched with H2O. The mixture was extracted with CH2Cl2,
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by silica gel flash column chromatography to give 1
(1.20 g, 5.99 mmol) in 78% yield as pale yellow oil. Data for 1:
Scheme 4 Divergent transformation of -ketoester 28 into indole 30 and
quinoline 47.
Finally, divergent reactivity of the -ketoester, the coupling
product of ethyl acetoacetate and o-nitrobenzyl bromide was
demonstrated in Scheme 4. A tandem sequence of catalytic
oxidative deacetylation and reductive cyclization of -ketoester
28 produced indole 30 in 50% overall yield as was described in
Table 3 (entry 2). Switching the order of the reaction sequence,
10 namely, one-pot reductive cyclization of -ketoester 28 under the
catalytic hydrogenation condition followed by the CoCl2-
catalyzed oxidation produced quinoline 47 in 59% yield (Scheme
4).11
1
5
60 Rf = 0.3 (hexane:EtOAc = 4:1); H NMR δ 1.28 (t, J = 7.2 Hz,
3H), 2.06–2.14 (m, 2H), 2.14 (s, 3H), 2.25 (s, 3H), 2.51 (t, J = 6.8
Hz, 2H), 3.50 (t, J = 7.2 Hz, 1H), 4.21 (dq, Jd = 2.0 Hz, Jq = 7.2
Hz, 2H) ppm.
Ethyl 2,5-dioxohexanoate (2).12 To a stirred solution of 1
65 (0.11 g, 0.55 mmol) in AcOH (2.5 mL) were added
Mn(OAc)3·2H2O (7 mg, 0.027 mmol) and CoCl2 (2 mg, 0.011
mmol). The mixture was stirred vigorously at 25 ºC for 3 h under
air, and the solvent was removed under reduced pressure. The
crude product was purified by silica gel flash column
70 chromatography to give 2 (89 mg, 0.52 mmol) in 94% yield as
colorless oil. Data for 2: Rf = 0.1 (hexane:EtOAc = 4:1); 1H NMR
δ 1.38 (t, J = 7.2 Hz, 3H), 2.21 (s, 3H), 2.83 (t, J = 6.0 Hz, 2H),
3.09 (t, J = 6.0 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H) ppm.
Conclusion
15 We developed an efficient one-pot synthetic method of furan,
thiophene, and pyrrole by the application of the oxidative
deacetylation using Mn(III)/Co(II) catalysts and the Paal-Knorr
synthesis to 1,5-dicarbonyl compounds, which are readily
obtained by the conjugate addition of ethyl acetoacetate to ,-
20 unsaturated carbonyl compounds. Pyrrole-2-carboxylates
containing an ortho-heteroatomic substituent underwent further
cyclization (intramolecular esterification or transamidation) to
provide biologically active poly heterocyclic compounds,
pyrrolo-1,4-oxazepin-2-one and pyrrolo-quinoxalinone. On the
25 other hand, application of the catalytic oxidative deacetylation
and the reductive cyclization to -(o-nitrobenzyl)--ketoesters,
which are readily obtained by the coupling of ethyl acetoacetate
and o-nitrobenzyl bromides, efficiently provided diversely
substituted indoles. The success of these practical syntheses of
30 diverse hetero aromatic compounds can be ascribed to the
development of the efficient oxidative deacetylation method of -
ketoesters utilizing the Mn(III)/Co(II) catalysts.
Ethyl 2-acetyl-2-hydroxy-5-oxohexanoate (3). To a stirred
75 solution of 1 (0.20 g, 1.00 mmol) in EtOH (5.0 mL) were added
Mn(OAc)3·2H2O (14 mg, 0.05 mmol) and CoCl2 (2.6 mg, 0.02
mmol). The mixture was stirred vigorously at 25 ºC for 3 h under
air, and the solvent was removed under reduced pressure. The
crude product was purified by silica gel flash column
80 chromatography (hexane/EtOAc = 4:1) to give 3 (58 mg, 0.27
mmol, Rf = 0.2) in 27% yield and 2 (98 mg, 0.57 mmol, Rf = 0.1)
in 57% yield, respectively as colorless oil. Data for 3: 1H NMR δ
1.30 (t, J = 7.2 Hz, 3H ), 2.15 (s, 3H), 2.17-2.26 (m, 1H), 2.29 (s,
3H), 2.31–2.40 (m, 1H), 2.52 (t, J = 7.2 Hz, 2H), 4.22 (s, 1H),
85 4.26 (q, J = 7.2 Hz, 2H) ppm; 13C NMR δ 13.9, 24.5, 28.6, 29.8,
37.3, 62.6, 82.9, 170.5, 204.4, 207.6 ppm; IR (KBr) 3463, 2981,
2943, 1720, 1435, 1363, 1275, 1191, 1141, 1099, 1024, 873, 747
cm-1; HRMS (CI+) calcd for C10H17O5 [(M+H)+] 217.1076, found
217.1075.
90
3-Acetylheptane-2,6-dione (4).13 To a stirred solution of
acetyl acetone (1.50 g, 15.0 mmol) and methyl vinyl ketone (1.16
g, 16.5 mmol) in MeCN at 25 ºC were added CeCl3·7H2O (1.12 g,
3.00 mmol) and NaI (0.22 g, 1.50 mmol). The mixture was stirred
for 14 h, quenched with H2O, extracted with CH2Cl2, washed
Experimental Section
General Experimental
35 1H and 13C NMR spectra were respectively recorded on a 400
MHz and 100 MHz NMR spectrometer in deuterated chloroform
(CDCl3) with tetramethylsilane (TMS) as an internal reference.
High resolution mass spectroscopy was performed using
magnetic sector analyzer. Solvents for extraction and
40 chromatography were reagent grade and used as received. The
column chromatography was performed by the method of Still
with silica gel 60, 70–230 mesh ASTM using a gradient mixture
of EtOAc/hexane. Reactions except air oxidation and
hydrogenation were performed in a well-dried flask under argon
45 atmosphere unless noted otherwise. Oxidation reactions catalyzed
by Mn(OAc)3·2H2O and CoCl2 were performed in a flask open to
the air. The reaction under a positive pressure of H2 was
performed using a balloon filled with H2. EtOH used in the
oxidation reaction was 99.9% pure.
95 with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by SiO2 flash column chromatography to give 4 (1.73 g,
10.1 mmol, a 2.5:1 keto:enol forms) in 68% yield as pale yellow
1
oil. Data for 4: Rf = 0.25 (hexane: EtOAc =4:1); H NMR (keto-
100 form)  2.08 (dt, Jd = 7.2, Jt = 6.8 Hz, 2H), 2.14 (s, 3H), 2.20 (s,
6H), 2.45 (t, J = 6.8 Hz, 2H), 3.68 (t, J = 7.2 Hz, 1H) ppm; (enol-
form)  2.13 (s, 6H), 2.17 (s, 3H), 2.50-2.56 (m, 4H) ppm; 13C
NMR (keto-form)  21.2, 21.3, 29.1, 29.7, 40.3, 66.6, 204.0,
204.0, 207.3 ppm; (enol-form)  21.2, 21.2, 22.7, 29.9, 43.7,
105 108.7, 190.9, 204.0, 207.4 ppm.
1,1′-(6-Hydroxy-6-methyl-1,2-dioxane-3,3-diyl)diethanone
(5). To a stirred solution of 4 (0.30 g, 1.76 mmol) in AcOH (8.0
4
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mL) were added Mn(OAc)3·2H2O (24 mg, 0.088 mmol) and
CoCl2 (5 mg, 0.035 mmol). The reaction mixture was stirred 60 solution of 1 (0.11 g, 0.55 mmol) in AcOH (2.5 mL) were added
Ethyl 5-methyl-1H-pyrrole-2-carboxylate (9).17 To a stirred
vigorously at 25 ºC for 3 h under air, and the solvent was
removed under reduced pressure. The crude product was purified
by silica gel flash column chromatography to give 5 (0.30 g, 1.48
Mn(OAc)3·2H2O (8 mg, 0.028 mmol) and CoCl2 (2 mg, 0.011
mmol). The mixture was stirred vigorously at 25 ºC for 3 h under
air, and NH4OAc (0.42 g, 5.5 mmol) was added. The resulting
mixture was heated to 60 ºC for 30 min, and cooled to room
5
mmol) in 84% yield as white solid. Data for 5: Rf = 0.2
1
(hexane:EtOAc = 7:3); mp: 81-82 ºC; H NMR δ 1.36 (s, 3H), 65 temperature. The solvent was removed under reduced pressure,
1.72–1.84 (m, 2H), 2.02 (ddd, J = 13.6, 11.2, 5.6 Hz, 1H), 2.25 (s,
3H), 2.32 (s, 3H), 2.41 (dt, Jd = 13.6 Hz, Jt = 4.4 Hz, 1H), 2.99 (s,
and the crude product was purified by silica gel flash column
chromatography to give 9 (54 mg, 0.35 mmol) in 64% yield as
white solid. Data for 9: mp: 96-97 ºC (literature17 100-101 ºC); Rf
= 0.8 (hexane:EtOAc = 7:3); 1H NMR δ 1.35 (t, J = 7.2 Hz, 3H),
10 1H) ppm; 13C NMR δ 22.4, 25.4, 25.6, 26.0, 29.6, 95.1, 99.5,
201.0, 202.8 ppm; IR (KBr) 3473, 2986, 2929, 1728, 1700, 1517,
1419, 1359, 1221, 1176, 1135, 1095, 1062, 961, 888, 831, 763, 70 2.31 (s, 3H), 4.29 (q, J = 7.2 Hz, 2H), 5.95 (t, J = 2.8 Hz, 1H),
632 cm-1; HRMS (CI+) calcd for C9H15O5 [(M+H)+] 203.0919,
found 203.0923.
6.81 (t, J = 2.8 Hz, 1H), 8.94 (br s, 1H) ppm.
General procedure for pyrrole-2-carboxylates from 1
To a stirred solution (0.2 M) of 1 (1.0 equiv.) in AcOH were
added Mn(OAc)3·2H2O (0.05 equiv.) and CoCl2 (0.02 equiv.).
75 The reaction mixture was stirred vigorously at 25 ºC for 3 h under
air, and amine (1.5 equiv.) was added. The mixture was then
heated to 60 ºC for 30 min, and cooled to room temperature. The
solvent was removed under reduced pressure, and the crude
product was purified by silica gel flash column chromatography
80 to give N-substituted ethyl 5-methyl-pyrrole-2-carboxylate.
Ethyl 1-benzyl-5-methyl-1H-pyrrole-2-carboxylate (10).18
The reaction with benzylamine (0.084 g, 0.78 mmol) produced 10
(80 mg, 0.33 mmol) in 63% yield as colorless oil. Data for 10: Rf
= 0.9 (Hexane:EtOAc = 7:3); 1H NMR δ 1.28 (t, J = 7.2 Hz, 3H),
85 2.18 (s, 3H), 4.20 (q, J = 7.2 Hz, 2H), 5.61 (s, 2H), 5.99 (d, J =
4.0 Hz, 1H), 6.90–6.95 (m, 2H), 7.00 (d, J = 4.0 Hz, 1H), 7.18–
7.30 (m, 3H) ppm; 13C NMR δ 12.5, 14.3, 48.0, 59.5, 108.2,
117.8, 121.8, 125.7, 126.8, 128.5, 137.1, 138.3, 161.1 ppm.
Ethyl 1-butyl-5-methyl-1H-pyrrole-2-carboxylate (11). The
90 reaction mixture with butylamine (55 mg, 0.75 mmol) produced
11 (58 mg, 0.28 mmol) in 55% yield as colorless oil. Data for 11:
15
Heptane-2,3,6-trione (6).14 To a stirred solution of 4 (0.17 g,
1.0 mmol) in AcOH (5.0 mL) were added Mn(OAc)3·2H2O (13
mg, 0.05 mmol) and CoCl2 (3 mg, 0.02 mmol) at 25 ºC under air.
The reaction mixture was stirred vigorously at room temperature
for 3 h, and then heated to 60 ºC for 1 h. The solvent was
20 removed under reduced pressure. The crude product was purified
by silica gel flash column chromatography to give 6 (70 mg, 0.49
mmol) in 49% yield as yellow liquid. Data for 6: Rf = 0.5
(hexane:EtOAc = 7:3); 1H NMR δ 2.20 (s, 3H), 2.35 (s, 3H),
2.80–2.86 (m, 2H), 2.90–2.96 (m, 2H) ppm; 13C NMR δ 23.6,
25 29.5, 29.5, 37.5, 197.2, 198.0, 206.6 ppm.
Ethyl 5-methylfuran-2-carboxylate (7).15 To
a stirred
solution of 1 (0.20 g, 1.00 mmol) in AcOH (5.0 mL) were added
Mn(OAc)3·2H2O (13 mg, 0.05 mmol) and CoCl2 (3 mg, 0.02
mmol). The reaction mixture was stirred vigorously at 25 ºC for 3
30 h under air, and concentrated sulfuric acid (0.05 mL, 1.0 mmol)
was added. The resulting mixture was heated to 90 ºC for 1 h, and
cooled to room temperature. The mixture was poured into ice
water, neutralized with saturated NaHCO3, and extracted with
CH2Cl2. The organic phase was washed with H2O and brine,
35 dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel
flash column chromatography to give 7 (83 mg, 0.54 mmol) in
54% yield as colorless oil. Data for 7: Rf = 0.7 (hexane:EtOAc =
4:1); 1H NMR δ 1.37 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 4.35 (q, J =
40 7.2 Hz, 2H), 6.11 (d, J = 3.2 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H)
ppm; 13C NMR δ 13.9, 14.3, 60.6, 108.3, 119.1, 143.2, 157.0,
158.8 ppm.
1
Rf = 0.8 (hexane:EtOAc = 7:3); H NMR δ 0.94 (t, J = 7.2 Hz,
3H), 1.33 (t, J = 7.2 Hz, 3H), 1.31–1.41 (m, 2H), 1.52–1.61 (m,
2H), 2.26 (s, 3H), 4.22 (t, J = 8.0 Hz, 2H), 4.25 (q, J = 7.2 Hz,
95 2H), 5.88 (d, J = 4.0 Hz, 1H), 6.90 (d, J = 4.0 Hz, 1H) ppm; 13C
NMR δ 12.5, 13.8, 14.4, 20.0, 33.2, 45.0, 59.4, 107.6, 117.4,
121.2, 136.2, 161.0 ppm; IR (KBr) 2971, 2877, 1700, 1491, 1409,
1323, 1241, 1163, 1118, 1036, 917, 757 cm-1; HRMS (CI+) calcd
for C12H20NO2 [(M+H)+] 210.1494, found 210.1498.
100
Ethyl
1-(3-hydroxypropyl)-5-methyl-1H-pyrrole-2-
Ethyl 5-methylthiophene-2-carboxylate (8).16 To a stirred
solution of 1 (0.10 g, 0.50 mmol) in AcOH (2.5 mL) were added
45 Mn(OAc)3·2H2O (6.7 mg, 0.025 mmol) and CoCl2 (1.3 mg, 0.01
mmol). The reaction mixture was stirred vigorously at 25 ºC for 3
h under air, and Lawesson’s Reagent (0.61 g, 1.5 mmol) was
added. The resulting mixture was heated to 90 ºC for 1 h, and
cooled to room temperature. The mixture was quenched with
50 saturated NaHCO3, and extracted with CH2Cl2. The organic phase
was washed with H2O and brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by silica gel flash column chromatography
to give 8 (54 mg, 0.32 mmol) in 63% yield as yellow oil. Data for
55 8: Rf = 0.8 (hexane:EtOAc = 4:1); 1H NMR δ 1.36 (t, J = 7.2 Hz,
3H), 2.52 (s, 3H), 4.32 (q, J = 7.2 Hz, 2H), 6.75 (d, J = 3.8 Hz,
1H), 7.60 (d, J = 3.8 Hz, 1H) ppm; 13C NMR δ 14.3, 15.7, 60.8,
126.2, 131.3, 133.6, 147.6, 162.2 ppm.
carboxylate (12). The reaction with 3-aminopropan-1-ol (56 mg,
0.75 mmol) produced 12 (59 mg, 0.28 mmol) in 56% yield as
colorless oil. Data for 12: Rf = 0.4 (hexane:EtOAc = 7:3); H
1
NMR δ 1.34 (t, J = 7.2 Hz, 3H), 1.93 (quintet, J = 6.0 Hz, 2H),
105 2.29 (s, 3H), 2.97 (br s, 1H), 3.57 (t, J = 5.2 Hz, 2H), 4.26 (q, J =
7.2 Hz, 2H), 4.43 (t, J = 6.4 Hz, 2H), 5.93 (d, J = 4.0 Hz, 1H),
6.93 (d, J = 4.0 Hz, 1H) ppm; 13C NMR δ 12.4, 14.3, 33.6, 41.2,
58.7, 59.7, 108.2, 118.0, 121.3, 136.9, 161.9 ppm; IR (KBr) 3451,
2987, 2933, 2876, 1699, 1489, 1407, 1337, 1251, 1143, 1028,
110 970, 876, 757 cm-1; HRMS (CI+) calcd for C11H17NO3 [(M+H)+]
212.1287, found 212.1286.
Ethyl
5-methyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-
carboxylate (13). The reaction with prop-2-yn-1-amine (41 mg,
0.75 mmol) produced 13 (48 mg, 0.25 mmol) in 50% yield as
1
115 colorless oil. Data for 13: Rf = 0.5 (hexane:EtOAc = 7:3); H
NMR δ 1.34 (t, J = 7.2 Hz, 3H), 2.26 (t, J = 2.0 Hz, 1H), 2.35 (s,
3H), 4.28 (q, J = 7.2 Hz, 2H), 5.19 (d, J = 2.0 Hz, 2H), 5.94 (d, J
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Organic & Biomolecular Chemistry
View ArticlPe Oanglinee 6 of 11
DOI: 10.1039/C4OB02441A
= 4.0 Hz, 1H), 6.91 (d, J = 4.0 Hz, 1H) ppm; 13C NMR δ 12.3,
4H) ppm; 13C NMR δ 13.1, 14.2, 59.5, 108.3, 118.2, 123.8, 128.2,
14.4, 34.0, 59.7, 71.7, 78.8, 108.3, 117.9, 121.1, 136.8, 161.1 60 137.8, 139.0, 160.4 ppm; IR (KBr) 2990, 2941, 2905, 1700, 1528,
ppm; IR (KBr) 3274, 2990, 2914, 1684, 1448, 1434, 1387, 1332,
1264, 1230, 1137, 1047, 920, 755, 708, 679 cm-1; HRMS (CI+)
calcd for C11H13NO2 [(M+H)+] 192.1025, found 192.1024.
Ethyl 5-methyl-1-phenyl-1H-pyrrole-2-carboxylate (14).
1476, 1419, 1370, 1345, 1276, 1203, 1154, 1048, 991, 849, 751,
694 cm-1; HRMS (CI+) calcd for C22H25N2O4 [(M+H)+] 381.1814,
found 381.1823.
5
Ethyl 1-(2-(hydroxymethyl)phenyl)-5-methyl-1H-pyrrole-2-
The reaction with aniline (80 mg, 0.83 mmol) produced 14 (98 65 carboxylate (19). The reaction with 2-aminobenzyl alcohol (73
mg, 0.43 mmol) in 78% yield as yellow oil. Data for 14: Rf = 0.9
(hexane:EtOAc = 7:3); H NMR δ 1.15 (t, J = 7.2 Hz, 3H), 2.02
mg, 0.60 mmol) produced 19 (92 mg, 0.35 mmol) in 71% yield as
colorless oil. Data for 19: Rf = 0.4 (hexane:EtOAc = 7:3); H
1
1
10 (s, 3H), 4.08 (q, J = 7.2 Hz, 2H), 6.05 (d, J = 3.2 Hz, 1H), 7.02 (d,
J = 3.2 Hz, 1H), 7.18–7.24 (m, 2H), 7.40–7.49 (m, 3H) ppm; 13
NMR δ 1.20 (t, J = 6.8 Hz, 3H), 1.93 (s, 3H), 2.41 (dd, J = 7.2,
4.0 Hz, 1H), 4.11 (q, J = 6.8 Hz, 2H), 4.25–4.38 (m, 2H), 6.08 (d,
C
NMR  12.9, 14.1, 59.3, 108.0, 117.7, 123.6, 127.7, 128.0, 128.6, 70 J = 4.0 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H),
137.3, 139.3, 160.4 ppm; IR (KBr) 3072, 2981, 2933, 2903, 1709,
1596, 1491, 1422, 1356, 1278, 1221, 1147, 1043, 921, 873, 755,
15 703 cm-1; HRMS (CI+) calcd for C14H16NO2 [(M+H)+] 230.1181,
found 230.1183.
7.39 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6
Hz, 1H) ppm; 13C NMR δ 12.6, 14.1, 59.8, 60.7, 108.3, 118.1,
123.5, 127.8, 128.2, 129.0, 129.1, 137.2, 137.8, 138.5, 161.2
ppm; IR (KBr) 3444, 2984, 2937, 1703, 1489, 1418, 1378, 1346,
Ethyl 1-(4-iodophenyl)-5-methyl-1H-pyrrole-2-carboxylate 75 1283, 1219, 1156, 1120, 1033, 874, 751, 668 cm-1; HRMS (CI+)
(15). The reaction with 4-iodoaniline (0.16 g, 0.75 mmol)
produced 15 (108 mg, 0.30 mmol) in 61% yield as colorless oil.
20 Data for 15: Rf = 0.8 (hexane:EtOAc = 7:3); 1H NMR δ 1.18 (t, J
= 7.2 Hz, 3H), 2.02 (s, 3H), 4.11 (q, J = 7.2 Hz, 2H), 6.05 (d, J =
calcd for C15H18NO3 [(M+H)+] 260.1287, found 260.1294.
Ethyl 1-(2-((tert-butoxycarbonyl)amino)phenyl)-5-methyl-
1H-pyrrole-2-carboxylate (20). The reaction with tert-butyl (2-
aminophenyl)carbamate19 (0.12 g, 0.60 mmol) produced 20 (105
4.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 4.0 Hz, 1H), 80 mg, 0.30 mmol) in 64% yield as pale yellow oil. Data for 20: Rf =
1
7.78 (dd, J = 8.4 Hz, 2H) ppm; 13C NMR δ 12.9, 14.2, 59.6, 93.6,
108.4, 118.0, 123.5, 129.7, 137.2, 137.9, 139.0, 160.3 ppm; IR
25 (KBr) 2984, 2925, 1693, 1585, 1490, 1418, 1376, 1324, 1261,
1225, 1157, 1040, 991, 843, 762 cm-1; HRMS (CI+) calcd for
C14H15INO2 [(M+H)+] 356.0148, found 356.0140.
0.8 (hexane:EtOAc = 7:3); H NMR δ 1.11 (t, J = 7.2 Hz, 3H),
1.45 (s, 9H), 1.97 (s, 3H), 4.08 (dq, Jd = 1.2, Jq = 7.2 Hz, 2H),
5.96 (s, 1H), 6.14 (dd, J = 3.6, 0.4 Hz, 1H), 7.03 (dd, J = 7.6, 1.6
Hz, 1H), 7.09 (dt, Jd = 1.2, Jt = 7.6 Hz, 1H), 7.11 (d, J = 3.6 Hz,
85 1H), 7.41 (dt, Jd = 1.6, Jt = 8.4, Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H)
ppm; 13C NMR δ 12.5, 14.0, 28.2, 59.7, 80.9, 109.1, 118.8, 120.0,
122.9, 123.6, 128.1, 128.3, 129.3, 135.7, 137.8, 152.5, 160.1
ppm; IR (KBr) 3411, 2981, 2935, 2902, 1738, 1693, 1610, 1527,
1481, 1453, 1378, 1287, 1237, 1163, 1030, 898 ,765 cm-1; HRMS
Ethyl
1-(4-methoxyphenyl)-5-methyl-1H-pyrrole-2-
carboxylate (16). The reaction with p-anisidine (73 mg, 0.60
30 mmol) produced 16 (87 mg, 0.34 mmol) in 67% yield as yellow
oil. Data for 16: Rf = 0.6 (hexane:EtOAc = 7:3); 1H NMR δ 1.18
(t, J = 7.2 Hz, 3H), 2.02 (s, 3H), 3.85 (s, 3H), 4.10 (q, J = 7.2 Hz), 90 (CI+) calcd for C19H25N2O4 [(M+H)+] 345.1814, found 345.1816.
6.02 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 3.6
Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H) ppm; 13C NMR δ 12.9, 14.2,
35 55.3, 59.4, 107.8, 113.8, 117.5, 123.6, 128.7, 132.0, 137.7, 159.1,
160.5 ppm; IR (KBr) 2991, 2940, 2845, 1712, 1514, 1488, 1351,
Ethyl 6-methylpyridazine-3-carboxylate (21). The reaction
with hydrazine monohydrate (0.06 mL, 0.78 mmol) produced 21
(21 mg, 0.13 mmol) in 24% yield as colorless oil. Data for 21: Rf
= 0.4 (hexane:EtOAc = 4: 1); 1H NMR δ 1.47 (t, J = 7.2 Hz, 3H),
1282, 1257, 1149, 1038, 913, 840, 754, 630 cm-1; HRMS (EI+) 95 2.82 (s, 3H), 4.54 (q, J = 7.2 Hz, 2H), 7.47 (d, J = 8.8 Hz, 1H),
calcd for C15H17NO3 259.1208, found 259.1213.
8.08 (d, J = 8.8 Hz, 1H) ppm; 13C NMR δ 14.2, 22.5, 62.4, 127.1,
127.4, 149.9, 162.5, 164.3 ppm; IR (KBr) 3274, 2989, 2941, 2100,
1723, 1589, 1473, 1446, 1382, 1339, 1275, 1227, 1148, 1085,
1017, 910, 863, 787, 756, 641 cm-1; HRMS (EI+) calcd for
Ethyl 1-(5-(ethoxycarbonyl)-2-methylphenyl)-5-methyl-1H-
40 pyrrole-2-carboxylate (17). The reaction with ethyl 3-amino-4-
methylbenzoate (0.10 g, 0.55 mmol) produced 17 (68 mg, 0.22
mmol) in 43% yield as colorless oil. Data for 17: Rf = 0.7 100 C8H10N2O2 166.0742, found 166.0743.
(hexane:EtOAc = 7:3); 1H NMR δ 1.13 (t, J = 7.2 Hz, 3H), 1.38 (t,
J = 7.2 Hz, 3H), 1.95 (s, 3H), 2.01 (s, 3H), 4.07 (dq, Jd = 2.4, Jq =
45 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 6.10 (d, J = 3.6 Hz, 1H),
7.05 (d, J = 3.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 1.2
1-Methylbenzo[e]pyrrolo[2,1-c][1,4]oxazepin-4(6H)-one
(22). To a stirred solution of 19 (0.13 g, 0.50 mmol) in a 9:1 (v:v)
mixture of MeOH and H2O (10 mL) was added KOH (0.17 g,
3.00 mmol). The mixture was heated to 50 oC overnight, and
Hz, 1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H) ppm; 13C NMR δ 12.6, 105 cooled to room temperature. The solvent was removed under
14.1, 14.2, 17.4, 59.5, 61.0, 108.4, 117.8, 123.1, 129.0, 129.1,
129.6, 130.4, 136.6, 138.7, 141.7, 160.3, 165.8 ppm; IR (KBr)
50 2986, 2936, 1712, 1624, 1586, 1489, 1439, 1376, 1296, 1250,
1116, 1107, 1039, 917, 770, 673 cm-1; HRMS (EI+) calcd for
C18H21NO4 315.1470, found 315.1471.
reduced pressure. The residue was diluted with CH2Cl2, and
acidified to pH 1 with 5% HCl solution. The mixture was
extracted with CH2Cl2, washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
110 crude product was used in the next step without purification.
The above carboxylic acid was dissolved in CH2Cl2 (10 mL),
and treated with N,N′-dicyclohexylcarbodiimide (0.69 g, 3.33
mmol) and N,N′-dimethylaminopyridine (12 mg, 0.096 mmol) at
Diethyl
1,1'-(1,4-phenylene)bis(5-methyl-1H-pyrrole-2-
carboxylate) (18). The reaction with 1,4-phenylene diamine (27
55 mg, 0.25 mmol) produced 18 (64 mg, 0.17 mmol) in 67% yield as
1
colorless oil. Data for 18: Rf = 0.7 (hexane:EtOAc = 7:3); H
0
oC. The mixture was stirred vigorously for 1 h, and filtered
NMR δ 1.19 (t, J = 7.2 Hz, 6H), 2.10 (s, 6H), 4.12 (q, J = 7.2 Hz, 115 through a short pad of celite. The filtrate was concentrated under
4H), 6.08 (d, J = 3.6 Hz, 2H), 7.06 (d, J = 3.6 Hz, 2H), 7.29 (s,
reduced pressure, and purified by silica gel flash column
6
| Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C4OB02441A
Page 7 of 11
Organic & Biomolecular Chemistry
chromatography to give 22 (84 mg, 0.39 mmol) in 79% yield as
125.1, 128.1, 133.3, 133.3, 133.6, 149.0, 168.6, 201.8 ppm; 13C
colorless liquid. Data for 22: Rf = 0.5 (hexane:EtOAc = 7:3); H 60 NMR (enol-form)  18.9, 28.2, 60.5, 97.3, 124.3, 126.8, 129.3,
1
NMR δ 2.45 (s, 3H), 4.93 (d, J = 12.4 Hz, 1H), 5.20 (d, J = 12.4
Hz, 1H), 6.24 (d, J = 4.0 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 7.34
(d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 8.0 Hz,
2H) ppm; 13C NMR δ 14.2, 67.4, 111.6, 120.3, 124.3, 124.9,
132.7, 135.6, 172.6, 174.4 ppm.
Ethyl 3-(2-nitrophenyl)-2-oxopropanoate (25).21 To a stirred
solution of 24 (0.26 g, 1.00 mmol) in AcOH (5.0 mL) were added
Mn(OAc)3·2H2O (27 mg, 0.10 mmol), CoCl2 (5.2 mg, 0.04 mmol)
5
127.0, 129.8, 129.9, 130.3, 135.2, 137.4, 162.3 ppm; IR (KBr) 65 and CF3CO2H (0.08 mL, 1.00 mmol) at 10 ºC under air. The
2939, 2869, 1698, 1610, 1557, 1474, 1395, 1329, 1259, 1216,
1114, 1022, 944, 842, 751, 658 cm-1; HRMS (EI+) calcd for
10 C13H11NO2 213.0790, found 213.0791.
reaction mixture was stirred vigorously at 10–15 ºC for 7 h, and
the solvent was removed under reduced pressure. The crude
product was purified by silica gel flash column chromatography
to give 25 (0.15 g, 0.63 mmol) in 63% yield as pale yellow oil.
1-Methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (23). To
a
stirred solution of 20 (80 mg, 0.23 mmol) in CH2Cl2 (10 mL) was 70 Data for 25: Rf = 0.5 (hexane:EtOAc = 7:3); 1H NMR δ 1.40 (t, J
added trifluoroacetic acid (0.04 mL, 1.15 mmol) at 0 oC. The
mixture was warmed to and stirred at 25 ºC for 10 h, and poured
15 into an ice water. The mixture was neutralized with NaHCO3, and
then extracted with CH2Cl2. The organic phase was washed with
brine, dried over anhydrous NaSO4, filtered, and concentrated
under reduced pressure to give ethyl 1-(2-aminophenyl)-5-
methyl-1H-pyrrole-2-carboxylate (36 mg, 0.15 mmol) in 64%
20 yield.
= 7.2 Hz, 3H), 4.39 (q, J = 7.2 Hz, 2H), 4.54 (s, 2H), 7.34 (d, J =
7.6 Hz, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H),
8.17 (d, J = 8.4 Hz, 1H) ppm; 13C NMR δ 13.8, 44.3, 62.8, 125.3,
128.8, 128.9, 133.6, 133.8, 148.1, 160.4, 189.4 ppm.
Ethyl 2-hydroxy-2-(2-nitrobenzyl)-3-oxobutanoate (26). To
a stirred solution of 24 (0.14 g, 0.53 mmol) in AcOH (2.5 mL)
were added Mn(OAc)3·2H2O (7 mg, 0.026 mmol) and CoCl2 (1.4
mg, 0.011 mmol). The reaction mixture was heated to 60 ºC for
1.5 h under air, and cooled to room temperature. The solvent was
75
The above product (22 mg, 0.09 mmol) was dissolved in
o
AcOH (5 mL), and heated to 100 C for 1 h. The mixture was 80 removed under reduced pressure, and the crude product was
cooled to room temperature, and the solvent was removed under
reduced pressure. The white residue was rinsed with diethyl ether,
25 and dried to give 23 (17 mg, 86 mol) in 95% yield as white solid.
Data for 23: Rf = 0.18 (hexane:EtOAc = 3:2); mp: decomposed at
purified by silica gel flash column chromatography to give 26 (72
mg, 0.26 mmol) in 48% yield as colorless oil. Data for 26: Rf =
0.5 (hexane:EtOAc = 7:3); H NMR δ 1.28 (t, J = 7.2 Hz, 3H),
1
2.25 (s, 3H), 3.73 (A of ABq, JAB = 14.0 Hz, 1H), 3.80 (B of ABq,
288-290 ºC; 1H NMR (DMSO) δ 2.78 (s, 3H), 6.41 (d, J = 3.6 Hz, 85 JAB = 14.0 Hz, 1H), 4.07 (s, 1H), 4.17–4.29 (m, 2H), 7.36–7.43
1H), 6.94 (d, J = 3.6 Hz, 1H), 7.14 (dt, Jd = 1.6, Jt = 8.4 Hz, 1H),
7.24 (t, J = 8.0 Hz, 1H), 7.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.07 (d, J
30 = 8.4 Hz, 1H), 11.14 (br s, 1H) ppm; 13C NMR (DMSO) δ 17.2,
111.1, 114.2, 116.4, 116.8, 122.4, 124.2, 124.6, 125.3, 129.4,
(m, 2H), 7.48 (dt, Jd = 1.2, Jt = 8.0 Hz, 1H), 7.82 (dd, J = 8.0, 1.2
Hz, 1H) ppm; 13C NMR δ 13.9, 24.7, 35.6, 63.3, 83.6, 124.6,
128.1, 129.2, 132.2, 133.0, 151.1, 170.2, 203.4 ppm; IR (KBr)
3472, 2936, 2856, 1733, 1533, 1457, 1369, 1261, 1201, 1093,
131.5, 155.0 ppm; IR (KBr) 2970, 2837, 2757, 1656, 1502, 1440, 90 853, 793, 741, 713 cm-1; HRMS (CI+) calcd for C13H15NO6
1406, 1223, 1043, 885, 798, 735, 693, 656 cm-1; HRMS (CI+)
calcd for C12H11N2O [(M+H)+] 199.0871, found 199.0871.
[(M+H)+] 282.0987, found 282.0983.
Ethyl 1H-indole-2-carboxylate (27).22 The suspension of 25
(0.16 g, 0.67 mmol) and 10% Pd/C (70 mg, 0.067 mmol) in
methanol (5 mL) was stirred at 25 ºC for 5 h under a positive
95 pressure of H2. The reaction mixture was filtered through a short
pad of celite. The filtrate was concentrated under reduced
pressure, and the crude product was purified by silica gel flash
column chromatography to give 27 (78 mg, 0.41 mmol) in 62%
yield as white solid. Data for 27: Rf = 0.7 (hexane:EtOAc = 7:3);
35 Representative procedures for the coupling of ethyl
acetoacetate
with
2-nitrobenzyl
bromide
to
24,
Mn(III)/Co(II)-catalyzed oxidative deacetylation to 25, and
reductive cyclization to indole 27.
Ethyl 2-(2-nitrobenzyl)-3-oxobutanoate (24).20 To a stirred
40 suspension of 60% NaH (0.14 g, 3.6 mmol) in THF (10 mL) was
added ethyl acetoacetate (0.4 mL, 3.00 mmol) at 0 oC. The
1
100 mp: 121-122 ºC (literature22 123-125 ºC); H NMR δ 1.42 (t, J =
o
mixture was stirred at 0 C for 1 h, and 2-nitrobenzyl bromide
7.2 Hz, 3H), 4.42 (q, J = 7.2 Hz, 2H), 7.15 (dt, Jd = 0.8, Jt = 8.0
Hz, 1H), 7.23 (dd, J = 2.0, 0.8 Hz, 1H), 7.32 (dt, Jd = 1.2, Jt = 8.0
Hz, 1H), 7.42 (dd, J = 8.0, 0.8 Hz, 1H), 7.69 (dd, J = 8.0, 0.4 Hz,
1H), 9.01 (br s, 1H) ppm; 13C NMR δ 14.3, 61.0, 108.6, 111.9,
105 120.7, 122.5, 125.3, 127.4, 127.4, 136.9, 162.2 ppm.
(0.65 g, 3.00 mmol) was added. The mixture was warmed to and
stirred at room temperature overnight, and quenched with 1 M
45 HCl. The mixture was extracted with EtOAc, washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel
flash column chromatography to give a 6:1 mixture of 24 and its
enol form (0.73 g, 2.75 mmol) in 92% yield as pale yellow liquid.
50 Data for 24: Rf = 0.6 (hexane:EtOAc = 7:3); 1H NMR δ 1.20 (t, J
= 7.2 Hz, 3H), 2.28 (s, 3H), 3.36 (d of A of ABq, JAB = 13.6, Jd =
8.4 Hz, 1H), 3.50 (d of B of ABq, JAB = 13.6, Jd = 5.6 Hz, 1H),
4.00 (dd, J = 8.4, 5.6 Hz, 1H), 4.07–4.22 (m, 2 H), 7.40 (dt, Jd =
1.6, Jt = 8.4 Hz, 1H), 7.41 (dd, J = 8.0, 2.4 Hz, 1H), 7.52 (dt, Jd =
Ethyl 4-(2-(ethoxycarbonyl)-3-oxobutyl)-3-nitrobenzoate
(28). Following the general procedure for 24, the reaction of ethyl
acetoacetate (2.2 mL, 17.2 mmol) with 60% NaH (0.80 g, 20.6
mmol), and then with ethyl 4-(bromomethyl)-3-nitrobenzoate
110 (4.90 g, 17.2 mmol) in THF (20 mL) produced a 4:1 mixture of
28 and its enol form (5.30 g, 15.7 mmol) in 92% yield as pale
1
yellow liquid. Data for 28: Rf = 0.4 (hexane:EtOAc = 4:1); H
NMR δ 1.22 (t, J = 7.2 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H), 2.29 (s,
3H), 3.40 (d of A of ABq, JAB = 13.6, Jd = 8.4 Hz, 1H), 3.53 (d of
115 B of ABq, JAB = 13.6, Jd = 5.6 Hz, 1H), 3.99 (dd, J = 8.4, 5.6 Hz,
1H), 4.06–4.23 (m, 2H), 4.42 (q, J = 7.2 Hz, 2H), 7.53 (d, J = 8.0
1
55 1.2, Jt = 7.6 Hz, 1H), 8.00 (dd, J = 7.6, 1.2 Hz, 1H) ppm; H
NMR (enol form)  1.09 (t, J = 7.2 Hz, 3H), 2.03 (s, 3H), 3.87 (s,
2H), 4.07–4.22 (m, 2 H), 7.34 (t, J = 8.0 Hz, 1H), 7.89 (dd, J =
8.0, 1.6 Hz, 1H) ppm; 13C NMR δ 13.9, 29.6, 31.2, 59.6, 61.6,
This journal is © The Royal Society of Chemistry [year]
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Organic & Biomolecular Chemistry
View ArticlPe Oanglinee 8 of 11
DOI: 10.1039/C4OB02441A
Hz, 1H), 8.16 (dd, J = 8.0, 1.6 Hz, 1H), 8.62 (d, J = 1.6 Hz, 1H)
Hz, 1H), 3.50 (d of B of ABq, JAB = 13.6, Jd = 5.2 Hz, 1H), 3.97
ppm; 1H NMR (enol-form) δ 1.08 (t, J = 7.2 Hz, 3H), 2.04 (s, 3H), 60 (dd, J = 8.4, 5.2 Hz, 1H), 4.14–4.24 (m, 2H), 7.38 (dd, J = 8.8, 2.4
3.90 (s, 2H), 7.35 (d, J = 8.0 Hz, 1H), 8.15 (dd, J = 8.0, 2.0 Hz,
1H), 8.52 (d, J = 2.0 Hz, 1H), 13.03 (br s, 1H) ppm; 13C NMR δ
13.9, 14.2, 29.5, 31.1, 59.4, 61.6, 61.8, 126.1, 130.8, 133.5, 133.7,
138.2, 149.0, 164.2, 168.3, 201.2 ppm; 13C NMR (enol-form) δ
Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H) ppm;
1H NMR (enol-form) δ 1.11 (t, J = 7.2 Hz, 3H), 2.05 (s, 3H), 3.87
(s, 2H), 4.12 (q, J = 7.2 Hz, 2H), 7.21 (d, J = 2.0 Hz, 1H), 7.32
(dd, J = 8.4, 2.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H) ppm; 13C NMR
5
13.9, 18.9, 25.1, 28.6, 60.7, 61.6, 96.8, 125.4, 129.7, 133.1, 140.4, 65 δ 13.9, 29.5, 31.1, 59.4, 61.8, 126.6, 128.2, 133.2, 135.8, 139.6,
164.4, 172.4, 174.7 ppm; IR (KBr) 2999, 1729, 1628, 1539, 1363,
1262, 1153, 1115, 1022, 921, 858, 740 cm-1; HRMS (CI+) calcd
168.4, 201.2 ppm; 13C NMR (enol-form) δ 18.9, 28.4, 60.7, 96.7,
125.9, 127.0, 129.4, 138.0, 139.3, 147.2, 172.4, 174.8 ppm; IR
(KBr) 2990, 1722, 1619, 1575, 1530, 1478, 1348, 1245, 1152,
1116, 1023, 970, 894, 840, 761, 689 cm-1; HRMS (CI+) calcd for
10 for C16H20NO7 [(M+H)+] 338.1240, found 338.1248.
Ethyl 4-(3-ethoxy-2,3-dioxopropyl)-3-nitrobenzoate (29).23
Following the general procedure for 25, the reaction of 28 (0.17 g, 70 C13H15ClNO5 [(M+H)+] 300.0639, found 300.0639.
.
0.50 mmol) with Mn(OAc)3 2H2O (14 mg, 0.05 mmol), CoCl2 (3
mg, 0.02 mmol), and CF3CO2H (0.04 ml, 0.5 mmol) in AcOH
15 (2.5 mL) at 10–15 ºC for 7 h under air produced a 3:1 mixture of
Ethyl 3-(5-chloro-2-nitrophenyl)-2-oxopropanoate (32).
Following the general procedure for 25, the reaction of 31 (0.13 g,
0.43 mmol) with Mn(OAc)3·2H2O (12 mg, 0.043 mmol), CoCl2
(2.3 mg, 0.017 mmol), and CF3CO2H (0.03 mL, 0.43 mmol) in
29 and its enol form (91 mg, 0.29 mmol) in 59% yield as
1
colorless oil. Data for 29: Rf = 0.5 (hexane:EtOAc = 7:3); H 75 AcOH (2.5 mL) at 10–15 ºC for 7 h under air produced a 2:1
NMR  1.41 (t, J = 7.2 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 4.40 (q,
J = 7.2 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 4.60 (s, 2H), 7.43 (d, J
20 = 7.6 Hz, 1H), 8.28 (dd, J = 8.0, 1.6 Hz, 1H), 8.80 (d, J = 1.6 Hz,
1H) ppm; 1H NMR (enol-form)  6.89 (s, 1H), 6.94 (s, 1H), 8.23
mixture of 32 and its enol form (70 mg, 0.26 mmol) in 60% yield
as colorless oil. Data for 32: Rf = 0.6 (hexane:EtOAc = 7:3); H
NMR δ 1.41 (t, J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 4.52 (s,
1
2H), 7.33 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 2.4 Hz, 1H), 8.15
1
(dd, J = 8.4, 1.6 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 80 (d, J = 8.8 Hz, 1H) ppm; H NMR (enol-form) δ 6.82 (d, J = 1.6
1.6 Hz, 1H) ppm; 13C NMR  14.07, 14.2, 44.4, 61.8, 63.4, 102.4,
125.5, 131.7, 132.3, 132.9, 142.9, 164.3, 165.2, 188.7 ppm; 13C
25 NMR (enol-form)  13.9, 61.9, 63.0, 126.4, 130.0, 134.0, 134.2,
148.2, 160.2, 164.2 ppm; IR (KBr) 3359, 2993, 2938, 1727, 1629,
Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H),
7.89 (d, J = 8.8 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H) ppm; 13C NMR
δ 13.9, 44.2, 63.0, 126.9, 129.0, 131.4, 133.6, 140.3, 142.3, 160.2,
188.7 ppm; 13C NMR (enol-form) δ 14.1, 63.4, 102.3, 125.9,
1540, 1476, 1357, 1268, 1123, 1060, 1026, 924, 864, 775, 737 85 128.0, 130.2, 131.1, 139.1, 146.4, 165.2 ppm; IR (KBr) 3468,
cm-1; HRMS (CI+) calcd for C14H16NO7 [(M+H)+] 310.0927,
found 310.0930.
3119, 2991, 1735, 1612, 1578, 1522, 1475, 1352, 1267, 1203,
1067, 913, 850, 747, 701 cm-1; HRMS (CI+) calcd for
C11H11ClNO5 [(M+H)+] 272.0326, found 272.0327.
30
Diethyl 1H-indole-2,6-dicarboxylate (30).23 Following the
general procedure for 27, the reaction of 29 (70 mg, 0.23 mmol)
Ethyl 1H-indole-2-carboxylate (27). Following the earlier
and 10% Pd/C (24 mg, 0.023 mmol) in methanol (5 mL) at 25 ºC 90 general procedure for 27, the reaction of 32 (64 mg, 0.24 mmol)
for 5 h under a positive pressure of H2 produced 30 (50 mg, 0.19
and 10% Pd/C (25 mg, 0.024 mmol) in methanol (5 mL) at 25 ºC
for 5 h under a positive pressure of H2 produced de-chlorinated
indole 27 (24 mg, 0.13 mmol) in 53% yield as white solid.
Ethyl 2-(3-methyl-2-nitrobenzyl)-3-oxobutanoate (33). To a
mmol) in 83% yield as white solid. Data for 30: Rf = 0.7
1
35 (hexane:EtOAc = 7:3); mp 117-118 ºC; H NMR δ 1.42 (t, J =
7.2 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 4.41 (q, J = 7.2 Hz, 2H),
4.44 (q, J = 7.2 Hz, 2H), 7.24 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 8.4 95 stirred solution of (3-methyl-2-nitrophenyl)methanol (1.50 g,
Hz, 1H), 7.84 (dd, J = 8.4, 1.2 Hz, 1H), 8.20 (s, 1H), 9.13 (br s,
1H) ppm; 13C NMR δ 14.3, 14.3, 60.9, 61.4, 108.2, 114.5, 121.3,
40 122.1, 127.0, 130.2, 130.6, 136.2, 161.9, 167.1 ppm.
8.90 mmol) in anhydrous diethyl ether (20 mL) was added PBr3
(0.34 mL, 3.59 mmol) at 0 oC. The mixture was stirred at 0 ºC for
30 min, and quenched with water. The mixture was extracted
with diethyl ether, washed with brine, dried over anhydrous
Ethyl 2-(5-chloro-2-nitrobenzyl)-3-oxobutanoate (31). To a
stirred solution of 5-chloro-2-nitrotoluene (1.00 g, 5.83 mmol) in 100 Na2SO4, filtered, and concentrated under reduced pressure. The
CCl4 (20 mL) were added N-bromosuccinimide (1.14 g, 6.41
mmol) and a spetula tip of AIBN. The mixture was heated to
45 reflux for 6 h, and cooled to room temperature. The mixture was
filtered, and the filtrate was diluted with CH2Cl2. The organic
crude 3-methyl-2-nitrobenzyl bromide was used directly without
purification.
Following the general procedure for 24, the reaction of ethyl
acetoacetate (0.90 g, 7.18 mmol) with 60% NaH (0.36 g, 8.97
phase was washed with H2O and brine, dried over anhydrous 105 mmol), and then with the above 3-methyl-2-nitrobenzyl bromide
Na2SO4, filtered, and concentrated under reduced pressure. The
crude 5-chloro-2-nitrobenzyl bromide was purified by passing
50 through a short pad of silica gel, and used directly without further
purification.
in THF (20 mL) produced a 3:1 mixture (1.30 g, 4.65 mmol) of
33 and its enol form in 65% yield as pale yellow liquid. Data for
33: Rf = 0.4 (hexane:EtOAc = 4:1); 1H NMR δ 1.23 (t, J = 7.2 Hz,
3H), 2.23 (s, 3H), 2.32 (s, 3H), 3.12 (d, J = 7.2 Hz, 2H), 3.87 (t, J
Following the general procedure for 24, the reaction of ethyl 110 = 7.2 Hz, 1H), 4.10–4.24 (m, 2H), 7.16 (d, J = 8.0Hz, 1H), 7.18
acetoacetate (0.53 g, 4.08 mmol) with 60% NaH (0.21g, 5.25
mmol), and then with the above 5-chloro-2-nitrobenzyl bromide
55 in THF (20 mL) produced a 2.5:1 mixture of 31 (1.05 g, 3.50
mmol) and its enol form in 61% yield as pale yellow liquid. Data
(d, J = 7.2 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H) ppm; 1H NMR (enol-
form) δ 1.15 (t, J = 7.2 Hz, 3H), 2.00 (s, 3H), 2.32 (s, 3H), 3.52 (s,
2H), 4.13 (q, J = 7.2 Hz, 2H), 5.38 (br s, 1H), 7.01 (d, J = 7.6 Hz,
1H), 7.15 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H) ppm; 13C
for 31: Rf = 0.8 (hexane:EtOAc = 7:3); 1H NMR δ 1.23 (t, J = 7.2 115 NMR  13.9, 17.4, 29.3, 29.6, 59.8, 61.6, 126.0, 128.9, 129.8,
Hz, 3H), 2.30 (s, 3H), 3.32 (d of A of ABq, JAB = 13.6, Jd = 8.4
129.9, 130.0, 130.1, 168.4, 201.5 ppm; 13C NMR (enol-form) 
8
| Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C4OB02441A
Page 9 of 11
Organic & Biomolecular Chemistry
17.2, 18.8, 26.8, 60.0, 63.6, 97.0, 128.8, 129.1, 130.6, 132.0,
AcOH (2.5 mL) at 10–15 ºC for 7 h under air produced 37 (100
136.0, 151.6, 172.6, 174.5 ppm; IR (KBr) 2992, 2934, 1734, 1651, 60 mg, 0.34 mmol) in 69% yield as colorless oil. Data for 37: Rf =
1
1614, 1536, 1458, 1368, 1257, 1219, 1154, 1022, 923, 857, 787,
746 cm-1; HRMS (CI+) calcd. for C14H18NO5 [(M+H)+] 280.1185,
found 280.1180.
0.3 (hexane:EtOAc = 4:1); H NMR δ 1.40 (t, J = 7.2 Hz, 3H),
3.90 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 4.50 (s, 2H), 6.77 (d, J =
2.8 Hz, 1H), 6.93 (dd, J = 9.2, 2.8 Hz, 1H), 8.23 (d, J = 9.2 Hz,
1H) ppm; 13C NMR δ 14.0, 45.0, 55.9, 62.8, 113.2, 119.0, 128.3,
5
Ethyl 3-(3-methyl-2-nitrophenyl)-2-oxopropanoate (34).21
Following the general procedure for 25, the reaction of 33 (0.13 g, 65 132.2, 141.0, 160.5, 163.6, 189.4 ppm.
0.47 mmol) with Mn(OAc)3·2H2O (12 mg, 0.047 mmol), CoCl2
(2.4 mg, 0.019 mmol), and CF3CO2H (0.04 mL, 0.47 mmol) in
10 AcOH (2.5 mL) at 10–15 ºC for 7 h under air produced a 8:1
Ethyl 5-methoxy-1H-indole-2-carboxylate (38).21 Following
the general procedure for 27, the reaction of 37 (60 mg, 0.22
mmol) and 10% Pd/C (23 mg, 0.022 mmol) in methanol (5 mL)
at 25 ºC for 3 h under a positive pressure of H2 produced 38 (40
mixture (78 mg, 0.31 mmol) of 34 and its enol form in 66% yield
1
as colorless oil. Data for 34: Rf = 0.4 (hexane:EtOAc = 4:1); H 70 mg, 0.18 mmol) in 83% yield as white solid. Data for 38: Rf = 0.3
NMR δ 1.38 (t, J = 7.2 Hz, 3H), 2.39 (s, 3H), 4.20 (s, 2H), 4.36
(q, J = 7.2 Hz, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz,
15 1H), 7.39 (t, J = 7.6 Hz, 1H) ppm; 1H NMR (enol-form) δ 1.22 (t,
J = 7.2 Hz, 3H), 6.32 (s, 1H), 6.74 (s, 1H), 7.19 (t, J = 8.0 Hz,
(hexane:EtOAc = 5:1); mp 153-155 ºC (literature25 156-159 ºC);
1H NMR δ 1.41 (t, J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.40 (q, J = 7.2
Hz, 2H), 7.00 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H),
7.14 (dd, J = 2.0, 1.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 8.89 (br s,
1H) ppm; 13C NMR δ 13.9, 18.4, 42.2, 62.9, 125.8, 128.4, 130.0, 75 1H) ppm; 13C NMR δ 14.3, 55.6, 60.9, 102.4, 108.1, 112.8, 116.9,
130.8, 131.3, 131.4, 160.3, 189.3 ppm.
127.7, 127.8, 132.2, 154.6, 162.0 ppm.
Ethyl 7-methyl-1H-indole-2-carboxylate (35).21 Following
20 the general procedure for 27, the reaction of 34 (30 mg, 0.12
mmol) and 10% Pd/C (13 mg, 0.012 mmol) in methanol (5 mL)
Ethyl 2-(4,5-dimethoxy-2-nitrobenzyl)-3-oxobutanoate (39).
Following the bromination procedure in the synthesis of 33, (4,5-
dimethoxy-2-nitrophenyl)methanol (1.00 g, 4.69 mmol) was
at 25 ºC for 3 h under a positive pressure of H2 produced 35 (15 80 reacted with PBr3 (0.18 mL, 1.88 mmol) at 0 ºC in anhydrous
mg, 0.074 mmol) in 62% yield as white solid. Data for 35: Rf =
0.6 (hexane:EtOAc = 4:1); mp 129-130 ºC (literature24 131 ºC);
25 1H NMR δ 1.42 (t, J = 7.2 Hz, 3H), 2.52 (s, 3H), 4.42 (q, J = 7.2
Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.23 (d,
diethyl ether (20 mL) to give the corresponding bromide. The
crude product was used directly without purification.
Following the general procedure for 24, the reaction of ethyl
acetoacetate (0.60 g, 4.69 mmol) with 60% NaH (0.22 g, 5.63
J = 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 8.85 (br s, 1H) ppm; 85 mmol), and then with the above 4,5-dimethoxy-2-nitrobenzyl
13C NMR δ 14.4, 16.7, 61.0, 109.1, 120.2, 121.0, 121.1, 125.5,
127.0, 127.2, 136.7, 162.2 ppm.
Ethyl 2-(5-methoxy-2-nitrobenzyl)-3-oxobutanoate (36).
Following the bromination procedure in the synthesis of 31, 4-
bromide in THF (20 mL) produced 39 (1.13 g, 3.47 mmol) in
74% yield as yellow liquid. Data for 39: Rf = 0.4 (hexane:EtOAc
= 7:3); H NMR δ 1.22 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 3.33 (d
1
30
of A of ABq, JAB = 14.0, Jd = 8.8 Hz, 1H), 3.52 (d of B of ABq,
methoxy-2-methyl-1-nitrobenzene (2.00 g, 11.96 mmol) was 90 JAB = 14.0, Jd = 6.0 Hz, 1H), 3.94 (s, 3H), 3.95 (s, 3H), 4.03 (dd, J
reacted with N-bromosuccinimide (2.40 g, 13.16 mmol) and a
spectula tip of AIBN in CCl4 (20 mL) to give 5-methoxy-2-
= 8.8 ,6.0 Hz, 1H), 4.09–4.22 (m, 2H), 6.86 (s, 1H), 7.66 (s, 1H)
ppm; 13C NMR δ 13.9, 29.7, 31.9, 56.2, 56.3, 59.4, 61.4, 108.2,
114.9, 128.8, 140.8, 147.7, 152.9, 168.7, 202.1 ppm; IR (KBr)
2981, 2944, 2854, 1749, 1720, 1589, 1524, 1462, 1335, 1274,
35 nitrobenzyl bromide. The crude product was used directly
without further purification.
Following the general procedure for 24, the reaction of ethyl 95 1233, 1184, 1151, 1069, 918, 873, 803, 734, 652 cm-1; HRMS
acetoacetate (1.20 g, 9.57 mmol) with 60% NaH (0.48 g, 11.96
mmol), and then with the above 5-methoxy-2-nitrobenzyl
40 bromide in THF (20 mL) produced a 9:1 mixture of 36 and its
enol form (1.30 g, 4.40 mmol) in 45% yield as pale yellow liquid.
(CI+) calcd. for C15H20NO7 [(M+H)+] 326.1240, found 326.1233.
Ethyl 3-(4,5-dimethoxy-2-nitrophenyl)-2-oxopropanoate
(40) and ethyl 2-(4,5-dimethoxy-2-nitrobenzyl)-2-hydroxy-3-
oxobutanoate (41). Following the general procedure for 25, the
Data for 36: Rf = 0.6 (hexane:EtOAc = 4:1); 1H NMR δ 1.22 (t, J 100 reaction of 39 (0.19 g, 0.58 mmol) with Mn(OAc)3·2H2O (16 mg,
= 7.2 Hz, 3H), 2.30 (s, 3H), 3.35 (d of A of ABq, JAB = 13.6, Jd =
8.4 Hz, 1H), 3.55 (d of B of ABq, JAB = 13.6, Jd = 5.6 Hz, 1H),
45 3.87 (s, 3H), 4.02 (dd, J = 8.4, 5.6 Hz, 1H), 4.09–4.22 (m, 2H),
0.058 mmol), CoCl2 (3 mg, 0.023 mmol), and CF3CO2H (0.05
mL, 0.58 mmol) in AcOH (2.5 mL) at 10–15 ºC for 10 h under air
produced an inseparable mixture of 40 (calcd. 40 mg, 0.13 mmol,
23% yield) and 41 (calcd. 44 mg, 0.13 mmol, 22%) as colorless
6.85 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 8.12 (d, J
1
= 8.8 Hz, 1H) ppm; H NMR (enol-form) δ 1.12 (t, J = 7.2 Hz, 105 oil. Data for 40: 1H NMR δ 1.41 (t, J = 7.2 Hz, 3H), 3.97 (s, 3H),
3H), 2.01 (s, 3H), 3.85 (s, 3H), 3.94 (s, 2H), 3.97 (s, 1H), 6.71 (d,
J = 2.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.8 Hz, 1H), 8.07 (d, J = 8.8
50 Hz, 1H) ppm; 13C NMR δ 13.9, 29.6, 32.2, 55.8, 59.4, 61.5, 113.1,
118.2, 128.1, 137.0, 141.6, 163.2, 168.7, 202.0 ppm; IR (KBr)
3.98 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 4.49 (s, 2H), 6.70 (s, 1H),
7.77 (s, 1H) ppm; 13C NMR  14.0, 44.7, 56.4, 56.5, 62.8, 108,5,
114.8, 124.0, 143.1, 148.4, 153.5, 160.7, 189.7 ppm; HRMS (CI+)
1
calcd for C13H14NO7 296.0770, found 296.0763. Data for 41: H
2984, 2942, 2854, 1743, 1717, 1614, 1587, 1518, 1457, 1339, 110 NMR δ 1.29 (t, J = 7.2 Hz, 3H), 2.26 (s, 3H), 3.70 (A of ABq, JAB
1263, 1217, 1152, 1083, 1029, 923, 838, 735, 625 cm-1; HRMS
(CI+) calcd. for C14H18NO6 [(M+H)+] 296.1134, found 296.1131.
Ethyl 3-(5-methoxy-2-nitrophenyl)-2-oxopropanoate (37).21
Following the general procedure for 25, the reaction of 36 (0.16 g,
= 14.4 Hz, 1H), 3.86 (B of ABq, JAB = 14.4 Hz, 1H), 3.92 (s, 3H),
3.93 (s, 3H), 4.12 (br s, 1H), 4.18–4.29 (m, 2H), 6.89 (s, 1H),
7.49 (s, 1H) ppm; 13C NMR δ 13.9, 25.0, 35.9, 56.2, 56.3, 63.2,
83.6, 108.1, 114.7, 124.0, 147.8, 152.1, 153.5, 170.4, 203.7 ppm;
55
0.54 mmol) with Mn(OAc)3·2H2O (15 mg, 0.054 mmol), CoCl2 115 HRMS (CI+) calcd for C15H20NO8 342.1189, found 342.1186.
(2.8 g, 0.022 mmol), and CF3CO2H (0.04 mL, 0.54 mmol) in
Ethyl
5,6-dimethoxy-1H-indole-2-carboxylate
(42).26
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DOI: 10.1039/C4OPB0a2g44e1A10 of 11
Following the general procedure for 27, the reaction of inseparble
H2 produced 46 (10 mg, 0.04 mmol) in 86% yield as white solid.
mixture of 40 (calcd 18 mg, 0.061 mmol) and 41 (calcd. 22 mg, 60 Data for 46: Rf = 0.6 (hexane:EtOAc = 7:3); mp: decomposed at
1
0.064 mmol) with 10% Pd/C (14 mg, 0.013 mmol) in methanol (5
mL) at 25 ºC for 3 h under a positive pressure of H2 produced 42
(11 mg, 0.044 mmol) in 72% yield as white solid. Data for 42: Rf
= 0.6 (hexane:EtOAc = 7:3); mp 176-177 ºC (literature26 174-175
175-178 ºC (literature27 175-177 ºC); H NMR δ 1.40 (t, J = 7.2
Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.97 (s, 2H), 6.82 (s, 1H), 6.99
(s, 1H), 7.10 (d, J = 1.6 Hz, 1H), 8.93 (br s, 1H) ppm; 13C NMR δ
14.4, 60.7, 91.8, 99.8, 101.0, 109.0, 121.6, 126.2, 132.7, 144.1,
5
ºC); 1H NMR δ 1.40 (t, J = 7.2 Hz, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 65 147.9, 161.8 ppm.
4.39 (q, J = 7.2 Hz, 2H), 6.85 (s, 1H), 7.04 (s, 1H), 7.12 (d, J =
2.0 Hz, 1H), 8.80 (br s, 1H) ppm; 13C NMR δ 14.4, 56.0, 56.1,
Diethyl 2-methylquinoline-3,7-dicarboxylate (47). The
mixture of ethyl 4-(2-(ethoxycarbonyl)-3-oxobutyl)-3-
10 60.7, 93.7, 102.5, 108.7, 120.4, 126.0, 132.0, 146.1, 150.0, 161.9
ppm.
nitrobenzoate (28) (0.13 g, 0.39 mmol) and 10 % Pd/C (40 mg,
0.039 mmol) in MeOH (5 mL) was stirred at 25 ºC for 7 h under
Ethyl
2-((6-nitrobenzo[d][1,3]dioxol-5-yl)methyl)-3- 70 a positive pressure of H2, and then filtered through a short pad of
oxobutanoate (43). Following the bromination procedure in the
synthesis of 33, (6-nitrobenzo[d][1,3]dioxol-5-yl)methanol (1.40
15 g, 7.10 mmol) was reacted with PBr3 (0.27 mL, 2.84 mmol) at 0
ºC in anhydrous diethyl ether (20 mL) to give the corresponding
bromide.
Following the general procedure for 24, the reaction of ethyl
acetoacetate (0.90 g, 7.10 mmol) with 60% NaH (0.34 g, 8.52
20 mmol), and then with the above benzyl bromide in THF (20 mL)
produced a 10:1 mixture of 43 and its enol form (1.47 g, 4.75
celite. The fitrate was concentrated under reduced pressure to
give diethyl 2-methyl-1,4-dihydroquinoline-3,7-dicarboxylate (70
mg, 0.24 mmol) in 62% yield.
To a stirred solution of the above product (35 mg, 0.12 mmol)
75 in MeOH (5 mL) was added CoCl2 (16 mg, 0.12 mmol). The
mixture was stirred at 25 ºC for 3 h under air, and the solvent was
removed under reduced pressure. The crude product was purified
by silica gel flash column chromatography to give 47 (33 mg,
0.11 mmol) in 96% yield as white solid. Data for 47: Rf = 0.5
1
mmol) in 67% yield as yellow liquid. Data for 43: Rf = 0.5 80 (hexane:EtOAc = 7:3); mp: 94-95 ºC; H NMR δ 1.45 (t, J = 7.2
1
(hexane:EtOAc = 7:3); H NMR δ 1.24 (t, J = 7.2 Hz, 3H), 2.30
(s, 3H), 3.28 (d of A of ABq, JAB = 14.0, Jd = 8.4 Hz, 1H), 3.46 (d
25 of B of ABq, JAB = 14.0, Jd = 5.6 Hz, 1H), 3.99 (dd, J = 8.4, 5.6
Hz, 1H), 4.10–4.24 (m, 2H), 6.10 (s, 2H), 6.84 (s, 1H), 7.56 (s,
Hz, 3H), 1.47 (t, J = 7.2 Hz, 3H), 3.01 (s, 3H), 4.45 (q, J = 7.2 Hz,
2H), 4.46 (q, J = 7.2 Hz, 2H), 7.92 (d, J = 8.4 Hz, 1H), 8.14 (dd, J
= 8.4, 1.2 Hz, 1H), 8.74 (s, 1H), 8.77 (s, 1H) ppm; 13C NMR δ
14.2, 25.6, 61.5, 61.6, 125.5, 126.0, 128.1, 128.6, 130.9, 133.1,
1H) ppm; 1H NMR (enol-form) δ 1.14 (t, J = 7.2 Hz, 3H), 2.01 (s, 85 139.3, 147.9, 159.3, 166.0, 166.2 ppm; IR (KBr) 2932, 2862,
3H), 3.87 (s, 2H), 6.08 (s, 2H), 6.66 (s, 1H), 7.50 (s, 1H) ppm;
13C NMR δ 14.0, 29.7, 32.0, 59.6, 61.6, 102.9, 105.9, 112.1,
30 131.0, 142.6, 147.1, 151.8, 168.7, 202.0 ppm; IR (KBr) 3131,
3080, 2991, 2924, 1738, 1721, 1624, 1515, 1426, 1371, 1333,
1248, 1190, 1139, 1088, 1021, 928, 894, 865, 818, 708, 654 cm-1;
HRMS (CI+) calcd for C14H16NO7 [(M+H)+] 310.0927, found
310.0930.
1727, 1600, 1566, 1473, 1377, 1272, 1185, 1136, 1106, 1067,
948, 878, 839, 786, 755 cm-1; HRMS (EI+) calcd for C16H17NO4
287.1157, found 287.1160.
Acknowledgement
90 This research was supported by Basic Science Research Program
(NRF-2012R1A1A2000702) and by Priority Research Center
Program (Grant No. 2012-0006693) both through the National
Research Foundation of Korea.
35
Ethyl 3-(6-nitrobenzo[d][1,3]dioxol-5-yl)-2-oxopropanoate
(44) and Ethyl 2-hydroxy-2-((6-nitrobenzo[d][1,3]dioxol-5-
yl)methyl)-3-oxobutanoate (45). Following the general
procedure for 25, the reaction of 40 (0.20 g, 0.65 mmol) with
Mn(OAc)3·2H2O (17 mg, 0.065 mmol), CoCl2 (4 mg, 0.026
Notes and references
95 a School of Pharmacy, East China University of Science and Technology,
Meilong Road 130, Shanghai, 200237, China
40 mmol), and CF3CO2H (0.05 mL, 0.65 mmol) in AcOH (2.5 mL)
at 10–15 ºC for 10 h under air produced an inseparable mixture of
44 (33 mg, 0.12 mmol, 18% yield) and 45 (37 mg, 0.11 mmol,
b Department of Energy and Biotechnology, Myong Ji University,
Myongji-Ro 116, Cheoin-Gu, Yongin, Gyeonggi-Do, 449-728, Korea.
c Department of Chemistry, Myong Ji University, Myongji-Ro 116,
100 Cheoin-Gu, Yongin, Gyeonggi-Do, 449-728, Korea. Fax: 82 31 335
7248; Tel: 82 31 330 6185; E-mail: sangkoo@mju.ac.kr
1
18% yield) as colorless oil. Data for 44: H NMR δ 1.29 (t, J =
7.2 Hz, 3H), 4.19–4.29 (m, 2H), 4.43 (s, 2H), 6.08 (s, 2H), 6.71 (s,
45 1H), 7.37 (s, 1H) ppm; 13C NMR  14.0, 44.8, 63.3, 103.2, 105.8,
112.2, 126.1, 132.6, 147.8, 150.9, 160.5, 189.4 ppm; HRMS (CI+)
† Electronic Supplementary Information (ESI) available: [1H/13C NMR
spectra for the new compounds]. See DOI: 10.1039/b000000x/
1
calcd for C12H12NO7 282.0614, found 282.0619. Data for 45: H
1
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NMR δ 1.40 (t, J = 7.2 Hz, 3H), 2.26 (s, 3H), 3.66 (A of ABq, JAB
= 14.8 Hz, 1H), 3.78 (B of ABq, JAB = 14.4 Hz, 1H), 4.10 (s, 1H),
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105
110
115
2
Ethyl 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylate (46).27
55 Following the general procedure for 27, the reaction of an
inseparable mixture of 44 (calcd 14 mg, 0.05 mmol) and 45
(calcd 16 mg, 0.05 mmol) with 10% Pd/C (11 mg, 0.011 mmol)
in methanol (5 mL) at 25 ºC for 3 h under a positive pressure of
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