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

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.

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 S_N2 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 S_N2 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 S_N2 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.

Scheme 1.

Direct nucleophilic attack for the synthesis of 3

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 to synthesize γ-anilino-β-ketoesters, providing important advantages 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.

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, by-product 6, and its precursor 8, suggesting that the electron deficiency of the aniline diminished its reactivity, 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.

Scheme 2.

Initial direct amination attempts following literature procedures

To test the above hypothesis, two equivalents 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, two equivalents 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 solvents (data not shown), stoichiometry of reactants, temperature, 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

Entry	Conditions	Yieldb (%)
1	2 equiv Na2HPO4·7H2O	~5%
2	2 equiv Na2HPO4·7H2O, 0.1 equiv BuN4I	10%
3	2 equiv Na2HPO4·7H2O, 2 equiv NaI	66%
4	2 equiv Na2HPO4, 2 equiv NaI	65%
5	2 equiv NaH2PO4·H2O, 2 equiv NaI	59%
6	2 equiv Na3PO4, 2 equiv NaI	<5%
7	2 equiv NaOAc, 2 equiv NaI	<5%
8	2 equiv AgOOCPh	<5%
9	2 equiv NaHCO3, 2 equiv NaI	65%(52%)
10	2 equiv NaHCO3, 2 equiv KI	50%
11	2 equiv NaHCO3, 2 equiv NaBr	58%
12c	2 equiv NaHCO3, 2 equiv NaI	66% (51%)
13d	2 equiv NaHCO3, 2 equiv NaI,	17%
14e	2 equiv NaHCO3, 2 equiv NaI,	>95% (83%)
15f	2 equiv NaHCO3, 2 equiv NaI,	(88%)

^aUnless specified, the reaction was carried out with 7 (0.1 mmol) and 5 (0.2 mmol) in 0.5 mL CH₃CN under air and refluxed at 80 °C for 16 h. The addition of bases and other additives are listed in the conditions column.

^bNMR spectral yield of 9 by comparison with 0.1 mmol 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.

^cFour equivalents of 5 were added.

^dAt room temperature.

^eCH₃CN (0.1 mL) as solvent.

^fThe reaction was carried out with 7 (1 mmol) and 5 (2 mmol) in 1 mL CH₃CN under ambient air and reflux at 80 °C for 16 h.

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). Di-substituted 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-ketoester 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.

Table 2.

Reaction scope related to phenyl ring substitution^a

Entry	R	Yieldb
1	3,5-diCl, 9a	88%
2c	H, 9b	92%
3	4-Acetyl, 9c	79%
4	3-OMe, 9d	62%
5	4-F, 9e	87%
6	4-Cl, 9f	85%
7	4-Br, 9g	81%
8	3-Br, 9h	73%
9	3,4-diCl, 9i	73%
10	2,4-diCl, 9j	84%
11	4-CN, 9k	58%
12d	1-Naphthyl, 9l	88%

^aUnless 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

^bIsolated yield

^c4 h reaction time

^d2 h reaction time

The reaction scope by variation of the alkyl substituents on the nitrogen also was studied (Table 3). Larger alkyl substituents 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.

Table 3.

Reaction scope related to N-alkyl substituents^a

Entry	R	Yieldb
1	Et, 9m	71%
2	iPr, 9n	29%
3	C≡CSiMe3, 9o	28%
4	Bn, 9p	<10%
5c	, 9q	85%
6c	, 9r	92%

^aUnless 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.

^bIsolated yield.

^cAt room temperature.

The scope of the ketoester also was investigated (Scheme 3). 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 get a clean spectrum. Self condensation of the cyclic α-bromo-β-ketoesters, as in Scheme 2, did not occur, presumably because of steric hindrance of the secondary bromide.

Scheme 3.

Reaction scope related to the ketoester.

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.

Scheme 4.

Synthetic transformations of 9a

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 functional group compatible method to construct γ-heteroatom substituted β-ketoesters, as well as to generate a range of versatile and useful scaffolds.

Experimental Section

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 were reported in δ (ppm) (¹H NMR: CDCl₃, δ 7.26 ppm; DMSO-d₆, δ 2.50 ppm; ¹³C NMR: 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.

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 saturated Na₂S₂O₃ solution was added. The resulting solution was extracted with ethyl acetate, and the organic layer was collected, which was then washed with water and brine. The collected organic layers were combined and 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-oxobutanoate (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.

Ethyl 4-(methyl(phenyl)amino)-3-oxobutanoate (9b)

(Table 2, entry 2): The title compound was prepared as a pale yellow oil in 87% yield according to the general procedure as described above. ¹H 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 described above. ¹H 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); 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-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 above. ₁H 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-((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 described above. ¹H 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-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 above. ¹H 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, 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 described above. ¹H 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 described above. ¹H 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.

Ethyl 4-((3,4-dichlorophenyl)(methyl)amino)-3-oxobutanoate (9i)

(Table 2, entry 9): The title compound was prepared as a pale yellow oil in 73% yield according to the general procedure as described above. ¹H 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.

Ethyl 4-((2,4-dichlorophenyl)(methyl)amino)-3-oxobutanoate (9j)

(Table 2, entry 10): The title compound was prepared as a pale yellow oil in 84% yield according to the general procedure as described above. ¹H 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.

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 described above. ¹H 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.

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 described above. ¹H 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 described above. ¹H 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.

Ethyl 4-((3,5-dichlorophenyl)(isopropyl)amino)-3-oxobutanoate (9n)

(Table 3, entry 2): The title compound was prepared as a pale yellow oil in 29% yield according to the general procedure as described above. ¹H 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 the general procedure as described above. ¹H 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.

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, 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-oxopentanoate (10)

The title compound was prepared as a pale yellow oil in 89% yield according to the general procedure described above. ¹H 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 [M+H]⁺; HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₁₆Cl₂NO₃ 304.0502, found 304.0507.

Methyl 3-((3,5-dichlorophenyl)(methyl)amino)-2-oxocyclopentanecarboxylate (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 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-oxocyclopent-1-enecarboxylate (12)

The title compound was prepared as a pale yellow oil in 29% yield according to the general procedure described above. ¹H 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.

(±)-Methyl 3-((3,5-dichlorophenyl)(methyl)amino)-2-(ethoxycarbonyloxy)cyclopent-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, which was then washed with water and brine. The collected organic layers were combined and dried over Na₂SO₄, filtered, and concentrated. The residue was subjected to column chromatography using a mixture of hexane and ethyl acetate (10:1) as eluent to afford 11 as a pale yellow oil (180 mg, 57%).

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, which was then washed with water and brine. The collected organic layers were combined and 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.

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 EtOH, NH₂NH₂ (13 μL, 0.4 mmol) was added. 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 the product (40 mg, 73%) as a white solid. ¹H 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.

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 CH₃CN in a vial. The vial was stirred for 24 h at 80 °C until all the 9a was consumed. The residue was subjected to chromatography using a mixture of hexane and EtOAc (2:1) to afford the product (20 mg, 60%) as a pale yellow solid. ¹H 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, 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-oxobutanoate (16)

To a solution of 9a (61 mg, 0.2 mmol) and TEA (35 μL, 0.24 mmol) in 2 mL CH₃CN at 0 °C, TsN₃ (315 μL, 0.24 mmol, 15% in toluene) was added. The reaction mixture was stirred 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.