Direct amination of γ-Halo-β-ketoesters with anilines

Article abstract of DOI:10.1021/jo300239e

The direct amination of α-haloacetoacetates with anilines is described. Compared to existing methods, this simple protocol provides an attractive strategy to prepare diverse γ-anilino-β-ketoesters in one step. Good to excellent yields of the amination products were obtained under robust conditions, providing versatile and useful scaffolds.

Full text of DOI:10.1021/jo300239e

Article
pubs.acs.org/joc
Direct Amination of γ-Halo-β-ketoesters with Anilines
Yinan Zhang and Richard B. Silverman*
Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Design, Northwestern
University, Evanston, Illinois 60208-3113, United States
S
* Supporting Information
ABSTRACT: The direct amination of α-haloacetoacetates with
anilines is described. Compared to existing methods, this simple
protocol provides an attractive strategy to prepare diverse
γ-anilino-β-ketoesters in one step. Good to excellent yields of
the amination products were obtained under robust conditions,
providing versatile and useful scaffolds.
to synthesize γ-anilino-β-ketoesters, providing important advan-
tages of ease and economy compared to existing methods. This
robust reaction is generally high-yielding and produces a new
scaffold that should have extensive use in organic synthesis.
INTRODUCTION
■
β-Ketoesters are key intermediates in organic synthesis, with
wide-ranging applications in asymmetric catalysis, heterocyclic
ring construction, and medicinal chemistry.1 Although a variety
of β-ketoesters have been investigated extensively since the
Claisen condensation was reported 125 years ago,2 syntheses
and applications of γ-heteroatom substituted β-ketoesters are
still limited. In our efforts to make analogues of this scaffold, we
found that thiophenols and phenols as typical SN2 nucleophiles
readily produced the γ-heteroatom substituted β-ketoesters in
moderate to high yields under basic conditions,3 but the desired
products were not obtained when employing aniline as the
nucleophile. An alternative way to prepare γ-anilino-β-
ketoesters came from a Weinreb ketone synthesis (Scheme 1,
route a).4 The SN2 reaction with aniline 1, however, resulted in
poor yields (20−25%) of Weinreb amide 2; the activated
carbonyl group was then condensed with the enol anion of
ethyl acetate, giving the γ-anilino-substituted β-ketoesters in
40−60% yields. The low SN2 reactivity is derived from the weak
nucleophilicity of aniline as a result of the resonance of the
nitrogen lone pair with the adjacent phenyl group.5 A common
procedure for improving nucleophilicity is to enhance the acidity
of the NH group. When a toluenesulfonyl group was employed,
the nitrogen anion was produced under basic conditions, which
increased the yield to 44% (Scheme 1, route b).6 However, this
modification did not change the moderate yield in the next
ketonization step, and the use of n-BuLi at low temperature led to
loss of cost effectiveness and atom economy.
One attractive strategy would be direct amination of ethyl
4-chloroacetoacetate (5) with the aniline (Scheme 1, route c).
This strategy should be superior and avoids the unnecessary
reagents and steps of the other routes. However, because of the
acidity of the methylene protons between the carbonyl groups
of 5, base conditions should be carefully modulated. It is
possible that the chlorine of 5, bearing a large p*-π* orbital
overlap with the carbonyl group, may allow nucleophilic attack
to occur more easily.7 In addition, electron-donating R
groups can further increase the nucleophilic strength of
the anilines, which is convenient in light of our desired
pharmacophore. Here we report a direct amination method
RESULTS AND DISCUSSION
■
For one of our current drug discovery programs, we were
interested in preparing N-alkyl-γ-anilino-β-ketoesters using
N-methyl 3,5-dichloroaniline (7) as the primary nucleophilic
reagent (Scheme 2).8 Although the same strategy was reported
to give the product in 33% yield as well as self-condensation to
the dihydroquinone in 22% yield,9 we failed to get desired
compound 3 with this method, as well as two other procedures,
using NaH and Cs2CO3, respectively, as bases (Scheme 2). The
main products under these conditions were recovered starting
aniline 7, byproduct 6, and its precursor 8, suggesting that the
electron deficiency of the aniline diminished its reactivity, a
strong base favored enolization of 5, and concomitant self-
condensation consumed 5. It was thought that the yield of our
desired product might be boosted if self-condensation were
prevented; therefore, we investigated the use of a weak base to
minimize acetoacetate enolization. This approach might
restrain the side reaction and allow a direct nucleophilic attack
of the γ-halo-β-ketoester by anilines.
To test the above hypothesis, 2 equiv of 5, aniline 7, and
disodium phosphate were heated at 80 °C for 16 h (Table 1,
entry 1). The desired product was observed by NMR
spectroscopy using 1-bromo-3,5-dichlorobenzene as an internal
standard. A catalytic phase transfer catalyst was initially added
to determine if it might enhance the leaving group ability of
chlorine (Table 1, entry 2). With the slight increase in yield, 2
equiv of NaI was added to displace the chlorine for activation
(Table 1, entry 2), which increased the yield to 66%. Several
other weak bases, as well as a silver salt, and other iodide sources
were explored in an attempt to increase the yield; sodium
bicarbonate exhibited the best crude yield and moderate isolated
yield (Table 1, entries 4−11). Further optimization focused on
Received: February 2, 2012
Published: March 5, 2012
© 2012 American Chemical Society
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Scheme 1. Direct Nucleophilic Attack for the Synthesis of 3
Scheme 2. Initial Direct Amination Attempts Following Literature Procedures
solvents (data not shown), stoichiometry of reactants, temper-
ature, and substrate concentration (Table 1, entries 12−14).
Isolated yield enhancement was observed when concentrated
conditions were used. Finally, to avoid the workup loss and
confirm the results, the reaction was repeated on a larger scale to
afford the desired product in an 88% yield.
Table 1. Conditions Explored for the Direct Nucleophilic
Attack of 5 with 7
a
The generality of NaHCO3 and NaI-promoted aminations
was probed, indicating the reliability of this method for the
synthesis of γ-anilino-β-ketoesters having significant structural
variations. The reaction scope with regard to the phenyl ring
was first investigated (Table 2). It was found that the electronic
properties had a minimal influence on the yield. The reactions
can tolerate electron-neutral (Table 2, entry 2), electron-donating
(Table 2, entry 4), and electron-withdrawing (Table 2, entries 3
and 5−11) substituents, and little yield difference was observed
with substitution at the meta- or para-positions (Table 2, entries 7
and 8). Disubstituted phenyl groups, as well as other aromatic
scaffolds, such as 1-naphthyl, also gave good yields (Table 2,
entries 9, 10, and 12). The 2-naphthyl substituted aniline afforded
a mixture of the desired γ-methyl(naphthalen-2-yl)amino-β-keto-
ester and an unexpected α-methyl(naphthalen-2-yl)amino acetate
in a 4:1 ratio, which were difficult to isolate by chromatography
(data not shown). This can be attributed to the possibility that 2-
naphthyl methylamine might cause a retro-aldol process,
converting ethyl α-chloroacetoacetate to ethyl acetate.
b
entry
conditions
yield (%)
1
2 equiv Na2HPO4·7H2O
∼5
10
2
2 equiv Na2HPO4·7H2O, 0.1 equiv BuN4I
2 equiv Na2HPO4·7H2O, 2 equiv NaI
2 equiv Na2HPO4, 2 equiv NaI
2 equiv NaH2PO4·H2O, 2 equiv NaI
2 equiv Na3PO4, 2 equiv NaI
2 equiv NaOAc, 2 equiv NaI
2 equiv AgOOCPh
3
66
4
65
5
59
6
<5
7
<5
8
<5
9
2 equiv NaHCO3, 2 equiv NaI
2 equiv NaHCO3, 2 equiv KI
2 equiv NaHCO3, 2 equiv NaBr
2 equiv NaHCO3, 2 equiv NaI
2 equiv NaHCO3, 2 equiv NaI,
2 equiv NaHCO3, 2 equiv NaI,
2 equiv NaHCO3, 2 equiv NaI,
65 (52)
50
10
11
58
c
12
66 (51)
17
d
13
e
14
>95 (83)
(88)
f
15
a
Unless specified, the reaction was carried out with 7 (0.1 mmol) and
5 (0.2 mmol) in 0.5 mL of CH3CN under air and refluxed at 80 °C for
16 h. The addition of bases and other additives are listed in the
conditions column. NMR spectral yield of 9 by comparison with 0.1
mmol of 1-bromo-3,5-dichlorobenzene, which was added after the
reaction was cooled. The yield in parentheses is the isolated yield after
standard workup and purification on silica gel. Four equivalents of 5
were added. At room temperature. CH3CN (0.1 mL) as solvent.
The reaction was carried out with 7 (1 mmol) and 5 (2 mmol) in 1
mL of CH3CN under ambient air and reflux at 80 °C for 16 h.
The reaction scope by variation of the alkyl substituents on
the nitrogen also was studied (Table 3). Larger alkyl sub-
stituents greatly diminished the reaction yield (Table 3, entries
1−4), indicating that steric effects of these substituents play a
more important role than their electronic effects. It is notable
that indoline and tetrahydroquinoline gave excellent yields,
even at room temperature.
b
c
d
e
f
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α-bromo-β-ketoesters, as in Scheme 2, did not occur, presumably
because of steric hindrance of the secondary bromide.
Table 2. Reaction Scope Related to Phenyl Ring
Substitution
a
We also investigated the synthetic versatility of the
multifunctional γ-anilino-β-ketoester derivatives, especially for
scaffold diversification (Scheme 4). The ketoester served as a very
valuable functionality in several different reaction types, such as in
pyrazolone formation (14),10 in a Biginelli dihydropyrimidine
synthesis (15),11 and diazo formation (16).12 All transformations
proceeded in good yields under non-optimized conditions.
Considering the fact that there is a wide range of transformations
of β-ketoesters,13 γ-aniline intermediates should be useful to
prepare a number of other important building blocks.
In summary, we have developed a simple, direct amination
method for α-haloacetoacetates with inexpensive inorganic salts. It
has broad substrate scope with respect to a variety of secondary
anilines, and the yields are good to excellent. Performed under mild
conditions, this protocol provides a highly economical and func-
tional group compatible method to construct γ-anilino substituted
β-ketoesters, as well as to generate a range of versatile and useful
scaffolds.
b
entry
1
R
yield (%)
3,5-diCl, 9a
H, 9b
88
92
79
62
87
85
81
73
73
84
58
88
c
2
3
4-acetyl, 9c
3-OMe, 9d
4-F, 9e
4
5
6
4-Cl, 9f
7
4-Br, 9g
8
3-Br, 9h
9
3,4-diCl, 9i
2,4-diCl, 9j
4-CN, 9k
1-naphthyl, 9l
10
11
d
12
a
Unless specified, the reaction was carried out with 7 (1 mmol) and 5
(2 mmol) in 1 mL CH3CN under air and refluxed at 80 °C for 16 h.
Isolated yield 4 h reaction time 2 h reaction time
EXPERIMENTAL SECTION
■
b
c
d
General Experimental Methods. Thin-layer chromatography
was carried out on silica gel 60 F254 plates. Column chromatography
was performed with silica gel 60 (230−400 mesh). Proton and carbon
NMR spectra were recorded in deuterated solvents on a 500 MHz
spectrometer. The chemical shifts are reported in δ (ppm) (1H NMR:
CDCl3, δ 7.26 ppm; DMSO-d6, δ 2.50 ppm; 13C NMR: CDCl3, δ
77.23 ppm; DMSO-d6, δ 39.52 ppm). The following abbreviations were
used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. Electrospray mass spectra (ESMS) were obtained
with methanol as the solvent in the positive ion mode. All reagents were
used directly without further purification.
a
Table 3. Reaction Scope Related to N-Alkyl Substituents
General Procedure for the Amination Reaction. To a solution
of NaHCO3 (168 mg, 2.0 mmol), NaI (300 mg, 2.0 mmol), and the
aniline (1.0 mmol) in 1 mL of acetonitrile was added ethyl α-
chloracetoacetate (270 μL, 2.0 mmol). The resulting reaction mixture
was stirred at 80 °C for 16 h. After the mixture was cooled to room
temperature, 1 mL of saturated Na2S2O3 solution was added. The
resulting solution was extracted with ethyl acetate, and the organic layer
was collected and washed with water and brine. The collected organic
layers were combined, dried over Na2SO4, filtered, and concentrated. The
residue was subjected to column chromatography using a mixture of
hexane and ethyl acetate as eluent to afford the product.
Ethyl 4-((3,5-Dichlorophenyl)(methyl)amino)-3-oxobuta-
noate (9a) (Table 2, entry 1). The title compound was prepared
as a pale yellow solid in 88% yield according to the general procedure
as described above. 1H NMR (CDCl3, 500 MHz) δ 6.72 (t, J = 1.5 Hz,
1H), 6.48 (d, J = 2.0 Hz, 2H), 4.23−4.18 (m, 2H), 3.46 (s, 2H), 3.02
(s, 3H) 1.30 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
200.5, 166.9, 150.4, 135.9 (2C), 117.4, 110.6 (2C), 62.3, 62.1, 46.5,
39.9, 14.3 ppm; MS (ESI) m/z 304.1 [M + H]+; HRMS (ESI) m/z [M
+ Na]+ calcd for C13H15Cl2NO3 326.0327, found 326.0330.
a
Unless specified, the reaction was carried out with 7 (1 mmol) and 5
(2 mmol) in 1 mL of CH3CN under air and refluxed at 80 °C for 16 h.
b
c
Isolated yield. At room temperature.
Ethyl 4-(Methyl(phenyl)amino)-3-oxobutanoate (9b) (Table
2, entry 2). The title compound was prepared as a pale yellow oil in
1
87% yield according to the general procedure as described above. H
The scope of the ketoester also was investigated (Scheme 3).
NMR (CDCl3, 500 MHz) δ 7.24 (t, J = 7.5 Hz, 2H), 6.77 (t, J =
7.5 Hz, 1H), 6.65 (d, J = 8.0 Hz, 2H), 4.16 (q, J = 7.0 Hz, 2H), 3.45 (s,
2H), 3.05 (s, 3H) 1.26 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 202.9, 167.2, 157.1, 155.2, 145.5 129.6 (2C), 117.9, 112.4 (2C),
63.1, 61.7, 46.4, 40.0, 14.3 ppm; MS (ESI) m/z 236.1 [M + H]+; HRMS
(ESI) m/z [M + H]+ calcd for C13H18NO3 236.1281, found 236.1276.
Ethyl 4-((4-Acetylphenyl)(methyl)amino)-3-oxobutanoate
(9c) (Table 2, entry 3). The title compound was prepared as a
pale yellow oil in 79% yield according to the general procedure as
A γ-ketoester, methyl 5-bromo-4-oxopentanoate, was used, and
10 was obtained in an 89% yield under the optimized
conditions. A cyclic β-ketoester containing a secondary
bromide, methyl 3-bromo-2-oxocyclopentanecarboxylate, gave
desired product 11 in a 40% yield and 12 in a 29% yield, which
may have resulted from iodine or air oxidation. Removal of
the iodide source and air increased the product yield to 57%.
Because 11 is a mixture of diastereoisomers and an enol
regioisomer, further transformation to 13 was carried out
to obtain a clean spectrum. Self-condensation of the cyclic
1
described above. H NMR (CDCl3, 500 MHz) δ 7.87 (dd, J = 2.0,
7.0 Hz, 2H), 6.62 (dd, J = 2.0, 7.0 Hz, 2H), 4.31 (s, 2H), 4.20 (q, J = 7.0
Hz, 2H), 3.46 (s, 2H), 3.12 (s, 3H), 2.51 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H);
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Scheme 3. Reaction Scope Related to the Ketoester
46.4, 40.1, 14.3 ppm; MS (ESI) m/z 270.1 [M + H]+; HRMS (ESI)
m/z [M + H]+ calcd for C13H17ClNO3 270.0891, found 270.0895.
Ethyl 4-((4-Bromophenyl)(methyl)amino)-3-oxobutanoate
(9g) (Table 2, entry 7). The title compound was prepared as a
pale yellow oil in 81% yield according to the general procedure as
Scheme 4. Synthetic Transformations of 9a
1
described above. H NMR (CDCl3, 500 MHz) δ 7.29 (d, J = 7.5 Hz,
2H), 6.51 (d, J = 8.0 Hz, 2H), 4.18 (q, J = 7.5 Hz, 2H), 4.15 (s, 2H),
3.43 (s, 2H), 3.02 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 202.2, 167.1, 147.8, 132.2 (2C), 114.0 (2C), 109.9,
62.8, 61.8, 46.4, 40.0, 14.3 ppm; MS (ESI) m/z 314.0 [M + H]+;
HRMS (ESI) m/z [M + H]+ calcd for C13H17BrNO3 314.0386, found
314.0378.
Ethyl 4-((3-Bromophenyl)(methyl)amino)-3-oxobutanoate
(9h) (Table 2, entry 8). The title compound was prepared as a
pale yellow oil in 73% yield according to the general procedure as
1
described above. H NMR (CDCl3, 500 MHz) δ 7.06 (t, J = 8.0 Hz,
1H), 6.86 (d, J = 8.0 Hz, 1H), 6.77 (t, J = 2.0 Hz, 1H), 6.52 (dd, J =
2.0, 8.0 Hz, 1H), 4.18 (m, 4H), 3.44 (s, 2H), 3.02 (s, 3H), 1.28 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 201.8, 167.1, 150.0,
130.7, 123.8, 120.6, 115.2, 110.8, 66.6, 61.9, 46.4, 39.9, 14.3 ppm; MS
(ESI) m/z 314.0 [M + H]+; HRMS (ESI) m/z [M + H]+ calcd for
C13H17BrNO3 314.0386, found 314.0367.
13C NMR (CDCl3, 125 MHz) δ 200.7, 196.7, 167.0, 152.2, 130.9 (2C),
127.0, 111.1 (2C), 62.3, 62.0, 46.4, 39.9, 26.3, 14.3 ppm; MS (ESI) m/z
278.1 [M + H]+; HRMS (ESI) m/z [M + H]+ calcd for C15H20NO4
278.1387, found 278.1383.
Ethyl 4-((3,4-Dichlorophenyl)(methyl)amino)-3-oxobuta-
noate (9i) (Table 2, entry 9). The title compound was prepared
as a pale yellow oil in 73% yield according to the general procedure as
Ethyl 4-((3-Methoxyphenyl)(methyl)amino)-3-oxobutanoate
(9d). (Table 2, entry 4). The title compound was prepared as a pale
yellow oil in 62% yield according to the general procedure as described
1
described above. H NMR (CDCl3, 500 MHz) δ 7.23 (d, J = 9.0 Hz,
1H), 6.70 (d, J = 3.5 Hz, 1H), 6.45 (dd, J = 3.0, 8.0 Hz, 1H), 4.20 (m,
4H), 3.44 (s, 2H), 3.02 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 201.1, 167.0, 148.3, 133.2, 130.8, 120.6, 113.8,
111.8, 62.5, 62.0, 46.4, 40.0, 14.3 ppm; MS (ESI) m/z 326.0 [M +
Na]+; HRMS (ESI) m/z [M + H]+ calcd for C13H16Cl2NO3 304.0502,
found 304.0509.
1
above. H NMR (CDCl3, 500 MHz) δ 7.14 (t, J = 8.0 Hz, 1H), 6.33
(m, 1H), 6.24 (m, 1H), 6.19 (t, J = 2.0 Hz, 1H), 4.16 (q, J = 7.0 Hz,
2H), 4.13 (s, 2H), 3.78 (s, 3H), 3.44 (s, 2H), 3.03 (s, 3H), 1.27 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 203.2, 167.3, 160.1,
150.2, 130.3, 105.3, 102.6, 99.1, 63.0, 61.7, 55.3, 46.3, 40.0, 14.3 ppm;
MS (ESI) m/z 266.1 [M + H]+; HRMS (ESI) m/z [M + H]+ calcd for
C14H20NO4 266.1387, found 266.1391.
Ethyl 4-((2,4-Dichlorophenyl)(methyl)amino)-3-oxobuta-
noate (9j) (Table 2, entry 10). The title compound was prepared
as a pale yellow oil in 84% yield according to the general procedure as
Ethyl 4-((4-Fluorophenyl)(methyl)amino)-3-oxobutanoate
(9e) (Table 2, entry 5). The title compound was prepared as a
pale yellow oil in 87% yield according to the general procedure as
1
described above. H NMR (CDCl3, 500 MHz) δ 7.34 (d, J = 2.5 Hz,
1H), 7.17 (dd, J = 2.5, 9.0 Hz, 1H), 7.07 (d, J = 3.0 Hz, 1H), 4.17 (q,
J = 7.0 Hz, 2H), 4.01 (s, 2H), 3.53 (s, 2H), 2.87 (s, 3H), 1.26 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 201.5, 167.3, 147.2,
130.5, 128.6, 128.5, 127.8, 122.6, 64.6, 61.7, 46.5, 41.6, 14.3 ppm; MS
(ESI) m/z 326.0 [M + Na]+; HRMS (ESI) m/z [M + H]+ calcd for
C13H16Cl2NO3 304.0502, found 304.0508.
1
described above. H NMR (CDCl3, 500 MHz) δ 6.93 (t, J = 9.0 Hz,
2H), 6.58 (dd, J = 4.0, 9.0 Hz, 2H), 4.16 (q, J = 7.5 Hz, 2H), 4.12 (s,
2H), 3.44 (s, 2H), 3.00 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 200.7, 167.0, 157.1, 155.2, 145.5, 116.0 (d, J =
22.5 Hz, 2C), 113.6 (d, J = 7.5 Hz, 2C), 63.6, 61.8, 46.4, 40.5, 14.3
ppm; MS (ESI) m/z 254.1 [M + H]+; HRMS (ESI) m/z [M − H]−
calcd for C13H15FNO3 252.1041, found 252.1038.
Ethyl 4-((4-Cyanophenyl)(methyl)amino)-3-oxobutanoate
(9k) (Table 2, entry 11). The title compound was prepared as a
pale yellow solid in 58% yield according to the general procedure as
Ethyl 4-((4-Chlorophenyl)(methyl)amino)-3-oxobutanoate
(9f) (Table 2, entry 6). The title compound was prepared as a pale
yellow oil in 85% yield according to the general procedure as described
1
described above. H NMR (CDCl3, 500 MHz) δ 7.47 (d, J = 9.0 Hz,
2H), 6.62 (d, J = 9.0 Hz, 2H), 4.32 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H),
3.46 (s, 2H), 3.09 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 200.0, 167.0, 151.5, 133.8 (2C), 120.4, 111.9 (2C), 99.4,
62.1, 46.4, 39.8, 14.3 ppm; MS (ESI) m/z 261.1 [M + H]+; HRMS
(ESI) m/z [M + H]+ calcd for C14H17N2O3 261.1234, found 261.1232.
1
above. H NMR (CDCl3, 500 MHz) δ 7.17 (d, J = 9.5 Hz, 2H), 6.55
(d, J = 9.0 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 4.16 (s, 2H), 3.43 (s,
2H), 3.02 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 202.3, 167.1, 147.4, 129.3 (2C), 122.8, 113.5 (2C), 63.0, 61.9,
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Ethyl 4-(Methyl(naphthalen-1-yl)amino)-3-oxobutanoate
(9l) (Table 2, entry 12). The title compound was prepared as a
pale yellow oil in 88% yield according to the general procedure as
[M + H]+; HRMS (ESI) m/z [M + H]+ calcd for C13H16Cl2NO3
304.0502, found 304.0507.
Methyl 3-((3,5-Dichlorophenyl)(methyl)amino)-2-oxocyclo-
pentanecarboxylate (11). The title compound was prepared as a
pale yellow oil in 40% yield according to the general procedure
described above. The NMR spectra demonstrated that the compounds
are a mixture of diastereoisomers and regioisomers of keto and enol
forms (see Supporting Information). MS (ESI) m/z 316.1 [M + H]+.
( )-Methyl 4-((3,5-Dichlorophenyl)(methyl)amino)-5-oxocy-
clopent-1-enecarboxylate (12). The title compound was prepared
as a pale yellow oil in 29% yield according to the general procedure
1
described above. H NMR (CDCl3, 500 MHz) δ 8.19 (dd, J = 1.5,
7.5 Hz, 1H), 7.84 (dd, J = 2.0, 7.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H),
7.50 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 4.12
(q, J = 7.0 Hz, 2H), 4.05 (s, 2H), 3.50 (s, 2H), 2.92 (s, 3H), 1.22 (t,
J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 202.1, 167.5, 148.8,
135.1, 129.0, 129.7, 126.2, 126.0, 125.9, 124.3, 123.7, 116.1, 66.3, 61.6
46.7, 44.0, 14.2 ppm; MS (ESI) m/z 286.1 [M + H]+; HRMS (ESI)
m/z [M + H]+ calcd for C17H20NO3 286.1438, found 286.1437.
Ethyl 4-((3,5-Dichlorophenyl)(ethyl)amino)-3-oxobutanoate
(9m) (Table 3, entry 1). The title compound was prepared as a pale
yellow solid in 71% yield according to the general procedure as
1
described above. H NMR (CDCl3, 500 MHz) δ 7.10 (t, J = 3.5 Hz,
1H), 6.90 (t, J = 1.5 Hz, 1H), 6.72 (d, J = 1.5 Hz, 2H), 3.79 (s, 3H),
3.54 (dd, J = 2.5, 7.0 Hz, 1H), 3.16 (s, 3H), 2.99 (dt, J = 3.0, 19.0 Hz,
1H), 2.90 (ddd, J = 3.0, 7.0, 19.0 Hz, 1H); 13C NMR (CDCl3, 125
MHz) δ 197.4, 169.3, 148.9, 146.6, 143.8, 135.3 (2C), 121.3, 117.1
(2C), 53.1, 51.0, 39.6, 28.5 ppm; MS (ESI) m/z 314.0 [M + H]+;
HRMS (ESI) m/z [M + H]+ calcd for C14H14Cl2NO3 314.0345, found
314.0347.
1
described above. H NMR (CDCl3, 500 MHz) δ 6.70 (t, J = 2.0 Hz,
1H), 6.44 (d, J = 2.0 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 4.16 (s, 2H),
3.47 (s, 2H), 3.39 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H), 1.17
(t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 200.9, 167.1,
149.3, 136.0 (2C), 117.2, 110.6 (2C), 62.1, 60.2, 46.6, 46.3, 14.3, 12.2
ppm; MS (ESI) m/z 318.1 [M + H]+; HRMS (ESI) m/z [M + H]+
calcd for C14H18Cl2NO3 318.0658, found 318.0656.
(
)-Methyl 3-((3,5-Dichlorophenyl)(methyl)amino)-2-
(ethoxycarbonyloxy)cyclo-pent-1-enecarboxylate (13). To a
solution of NaHCO3 (168 mg, 2.0 mmol) and the aniline (1.0
mmol) in 1 mL of acetonitrile was added methyl 3-bromo-2-
oxocyclopentanecarboxylate (442 mg, 2.0 mmol) under Ar. The
resulting reaction mixture was stirred at 80 °C for 16 h. After the
mixture was cooled to room temp, 1 mL of saturated Na2S2O3 solution
was added. The resulting solution was extracted with ethyl acetate, and
the organic layer was collected and washed with water and brine. The
collected organic layers were combined, dried over Na2SO4, filtered,
and concentrated. The residue was subjected to column chromatog-
raphy using a mixture of hexane and ethyl acetate (10:1) as eluent to
afford 11 as a pale yellow oil (180 mg, 57%).
Ethyl 4-((3,5-Dichlorophenyl)(isopropyl)amino)-3-oxobuta-
noate (9n) (Table 3, entry 2). The title compound was prepared
as a pale yellow oil in 29% yield according to the general procedure as
1
described above. H NMR (CDCl3, 500 MHz) δ 6.70 (t, J = 1.5 Hz,
1H), 6.46 (d, J = 1.5 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 4.08 (m, 3H),
3.50 (s, 2H), 1.30 (t, J = 7.0 Hz, 3H), 1.15 (d, J 6.5 Hz, 6H); 13C
NMR (CDCl3, 125 MHz) δ 200.9, 167.1, 150.1, 135.9 (2C), 117.4,
111.3 (2C), 62.0, 54.4, 49.1, 46.1, 20.0 (2C), 14.3 ppm; MS (ESI) m/z
332.1 [M + H]+; HRMS (ESI) m/z [M + H]+ calcd for C15H20Cl2NO3
332.0815, found 332.0817.
Ethyl 4-((3,5-Dichlorophenyl)(3-(trimethylsilyl)prop-2-ynyl)-
amino)-3-oxobutanoate (9o) (Table 3, entry 3). The title
compound was prepared as a pale yellow oil in 28% yield according
To a solution of diisopropylethylamine (53 μL, 0.3 mmol) and 11
(64 mg, 0.2 mmol) in 0.4 mL of hexamethylphosphoramide was added
ethyl chloroformate (28 μL, 0.3 mmol) under Ar. The resulting
reaction mixture was stirred at room temp for 16 h. The resulting
solution was extracted with ethyl acetate, and the organic layer was
collected and washed with water and brine. The collected organic
layers were combined, dried over Na2SO4, filtered, and concentrated.
The residue was subjected to column chromatography using a mixture
of hexane and ethyl acetate as eluent (25:1) to afford 13 as a colorless
oil (60 mg, 77%). 1H NMR (CDCl3, 500 MHz) δ 6.72 (t, J = 1.5 Hz,
1H), 6.65 (d, J = 2.0 Hz, 2H), 5.20 (dt, J = 3.5, 8.5 Hz, 1H), 4.20 (q,
J = 7.0 Hz, 2H), 3.76 (s, 3H), 2.75 (s, 3H), 2.73−2.63 (m, 1H), 2.36−
2.33 (m, 1H), 1.83−1.80 (m, 1H), 1.28 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 163.7, 155.8, 151.4, 151.3, 135.7 (2C), 120.7,
117.5, 112.0 (2C), 65.7, 63.5, 52.0, 32.6, 27.0, 23.5, 14.2 ppm; MS
(ESI) m/z 388.1 [M + H]+; HRMS (ESI) m/z [M + Na]+ calcd for
C17H19Cl2NNaO5 410.0532, found 410.0538.
1
to the general procedure as described above. H NMR (CDCl3, 500
MHz) δ 6.79 (d, J = 1.5 Hz, 1H), 6.60 (d, J = 1.5 Hz, 2H), 4.28
(s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 4.07 (s, 2H), 3.51 (s, 2H), 1.30 (t, J =
7.0 Hz, 3H), −0.16 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 200.6,
167.0, 149.4, 135.9 (2C), 118.7, 112.0 (2C), 99.8, 91.4, 62.1, 60.4,
46.5, 42.6, 14.3, 0.0 (3C) ppm; MS (ESI) m/z 400.1 [M + H]+;
HRMS (ESI) m/z [M + H]+ calcd for C18H24Cl2NO3Si 400.0897,
found 400.0904.
Ethyl 4-(Indolin-1-yl)-3-oxobutanoate (9q) (Table 3, entry 5).
The title compound was prepared as a pale yellow oil in 85% yield
according to the general procedure as described above. 1H NMR
(CDCl3, 500 MHz) δ 7.11 (d, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz,
1H), 6.72 (m, 1H), 6.36 (d, J = 8.0 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H),
3.91 (s, 2H), 3.55 (s, 2H), 3.46 (t, J = 8.0 Hz, 2H), 3.04 (t, J = 8.0 Hz,
2H), 1.25 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 202.7,
167.4, 151.5, 129.8, 127.6, 124.8, 118.9, 106.8, 61.7, 59.8, 46.7,
28.9, 14.3 ppm; MS (ESI) m/z 248.1 [M + H]+; HRMS (ESI) m/z
[M + H]+ calcd for C14H18NO3 248.1281, found 248.1275.
5-(((3,5-Dichlorophenyl)(methyl)amino)methyl)-1H-pyrazol-
3(2H)-one (14). To a solution of 9a (61 mg, 0.2 mmol) in 2 mL of
EtOH was added NH2NH2 (13 μL, 0.4 mmol). The reaction mixture
was stirred overnight at room temperature. After the volatiles were
evaporated, the residue was subjected to chromatography using a
mixture of dichloromethane and methanol (30:1) as eluent to afford
Ethyl 4-(3,4-Dihydroquinolin-1(2H)-yl)-3-oxobutanoate (9r)
(Table 3, entry 6). The title compound was prepared as a pale yellow
oil in 92% yield according to the general procedure as described above.
1H NMR (CDCl3, 500 MHz) δ 7.00 (m, 2H), 6.65 (dt, J = 1.0 7.5 Hz,
1
the product (40 mg, 73%) as a white solid. H NMR (DMSO-d6, 500
MHz) δ 6.72 (s, 3H), 5.24 (s, 1H), 4.40 (s, 2H), 2.98 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 150.8, 134.6 (2C), 114.8, 110.7 (2C),
38.6 ppm; MS (ESI) m/z 272.0 [M + H]+; HRMS (ESI) m/z [M +
Na]+ calcd for C13H15Cl2NO3 326.0327, found 326.0330.
1H), 6.30 (d, J = 8.0 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.03 (s, 2H),
3.48 (s, 2H), 3.35 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 2.00
(m, 2H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
204.0, 167.4, 144.8, 129.6, 127.4, 123.0, 117.5, 110.6, 62.1, 61.7, 51.2,
46.4, 28.0, 22.5, 14.3 ppm; MS (ESI) m/z 262.1 [M + H]+; HRMS
(ESI) m/z [M + H]+ calcd for C15H20NO3 262.1438, found 262.1432.
Methyl 5-((3,5-Dichlorophenyl)(methyl)amino)-4-oxopenta-
noate (10). The title compound was prepared as a pale yellow oil in
Ethyl 6-(((3,5-Dichlorophenyl)(methyl)amino)methyl)-2-oxo-
4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (15).
Benzaldehyde (20 μL, 0.2 mmol), 9a (30 mg, 0.1 mmol), urea (12
mg, 0.1 mmol), and TsOH (1.9 mg, 0.01 mmol) were mixed together
in 0.4 mL of CH3CN in a vial. The vial was stirred for 24 h at 80 °C
until all of the 9a was consumed. The residue was subjected to
chromatography using a mixture of hexane and EtOAc (2:1) to afford
1
89% yield according to the general procedure described above. H
NMR (CDCl3, 500 MHz) δ 6.69 (t, J = 1.5 Hz, 1H), 6.47 (d, J =
1.5 Hz, 2H), 4.14 (s, 2H), 3.68 (s, 3H), 3.02 (s, 3H), 2.66 (s, 4H); 13C
NMR (CDCl3, 125 MHz) δ 206.7, 173.2, 150.5, 135.8 (2C), 117.1,
110.5 (2C), 62.3, 52.2, 39.9, 34.1, 28.0 ppm; MS (ESI) m/z 304.0
1
the product (20 mg, 60%) as a pale yellow solid. H NMR (CDCl3,
500 MHz) δ 7.34 (m, 4H), 7.17 (s, 1H), 6.85 (t, J = 1.5 Hz, 1H), 6.58
(d, J = 1.5 Hz, 2H), 5.60 (s, 1H), 5.41 (d, J = 2.5 Hz, 1H), 4.72 (d,
3466
dx.doi.org/10.1021/jo300239e | J. Org. Chem. 2012, 77, 3462−3467

The Journal of Organic Chemistry
Article
J = 19.0 Hz, 1H), 4.51 (d, J = 19.0 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H),
3.02 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
165.3, 152.0, 151.1, 146.1, 143.7, 136.0 (2C), 129.2 (2C), 128.5, 126.8
(2C), 119.1, 111.9 (2C), 100.5, 60.6, 56.3, 55.2, 40.4, 14.3 ppm; MS
(ESI) m/z 434.1 [M + H]+; HRMS (ESI) m/z [M + H]+ calcd for
C21H22Cl2N3O3 434.1033, found 434.1024.
Ethyl 2-Diazo-4-((3,5-dichlorophenyl)(methyl)amino)-3-oxo-
butanoate (16). To a solution of 9a (61 mg, 0.2 mmol) and TEA (35
μL, 0.24 mmol) in 2 mL of CH3CN at 0 °C was added TsN3 (315 μL,
0.24 mmol, 15% in toluene). The reaction mixture was stirred for 2 h,
and the temperature was allowed to rise to room temperature. After
the volatiles were evaporated, the residue was subjected to
chromatography using a mixture of hexane and ethyl acetate (20:1)
as eluent to afford the product (60 mg, 91%) as a pale yellow solid. 1H
NMR (CDCl3, 500 MHz) δ 6.68 (t, J = 1.5 Hz, 1H), 6.47 (d, J =
1.5 Hz, 2H), 4.59 (s, 2H), 4.34 (q, J = 7.0 Hz, 2H), 3.01 (s, 3H), 1.37
(t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 188.7, 161.6,
150.8, 135.7 (2C), 117.0, 110.6 (2C), 62.1, 60.0, 39.9, 14.6 ppm; MS
(ESI) m/z 330.0 [M + H]+; HRMS (ESI) m/z [M + H]+ calcd for
C13H13Cl2N3NaO3 352.0226, found 352.0230.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for compounds 9a−r and
10−16. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: 1-847-491-5653. Fax: 1-847-491-7713. E-mail:
Agman@chem.northwestern.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (grant
1R43NS057849), the ALS Association (TREAT program),
and the Department of Defense (AL093052) for their generous
support of this research project.
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