Aza-Knoevenagel-type condensation of secondary amides: direct access to N-monosubstituted β,β-difunctionalized enamines

Abstract

An efficient approach to N-monosubstituted β,β-difunctionalized enamines, a class of versatile building blocks for the synthesis of bioactive compounds, is reported. The method is based on the triflic anhydride-mediated direct aza-Knoevenagel-type condensation of secondary amides with active methylene compounds. The reaction showed good chemoselectivity and functional group tolerance. A number of title compounds have been synthesized in good to excellent yields in one pot from readily available starting materials.

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Introduction

N-Monosubstituted β,β-difunctionalized enamines¹ (1 in Scheme 1) are a sub-class of aza-analogs of the Knoevenagel condensation products (2). Possessing multiple functional groups, these molecules exhibit multiple reactivities, including nucleophilicity at both β-carbon and N-atom, and electrophilicity at both β-functional groups and α-carbon. Consequently, these compounds serve as versatile building blocks in the synthesis of heterocycles,² alkaloids,³ rigid dipeptide mimetics,⁴ and medicinal agents⁵ such as antimalarial,^5a antimitotic^5b and antibacterial agents,^5c inhibitors of hepatitis C virus,^5d,e potent inhibitors of lymphocyte-specific kinase,^5f and cell-permeable inhibitors of protein tyrosine phosphatase 1B.^5g Moreover, such structural motifs are also versatile therapeutic pharmacophores.⁶ In addition, it has been reported that some of them exhibit interesting bioactivities such as fungicidal activity,^7a and some have been developed as potent allosteric modulators of GABA_A receptors.^7b

Scheme 1 Two main approaches to the functionalized enamines 1.

Two common approaches for the preparation of N-monosubstituted β,β-difunctionalized enamines 1 are shown in Scheme 1.^1–12 These compounds are made either from secondary amides (approach 1),^{3c,e,5a–c,10–12} or by the transamination or the aminolysis of suitable intermediates (7 and 8, approach 2).^{2c,3a,b,5d–f,7a,8a,d} However, such methods rely on stepwise transformations. For example, approach 1 involves the conversion of an amide 3 into an activated form such as lactim ether^3c,e,4,104a/4b, lactim thioether^10a4c, imidoyl chloride^{2e,3c,e,5a–c}4d, or thioamide/thiolactam^11,125. The activated form of the amide is then converted into 1 by Knoevenagel-type condensation or by the Eschenmoser sulfide contraction method.¹¹ Although recently Hussaini and co-workers have reported the improvements to the Eschenmoser sulfide-contraction,¹² that remains a stepwise methodology from amides.

One-pot transformation of secondary amides 3 into functionalized enamines of type 1 is rare. In this context, in their total synthesis of azaphenalene alkaloids, Hsung and co-workers achieved the one-pot synthesis of 10a and 10b from secondary lactams 9a and 9b, respectively^3c (Scheme 2, eqn (1)). Recently, Long and co-workers developed a highly efficient synthesis of 2-substituted 3-carboxy-4-quinolone derivatives 11, which involved a one-pot formation of enamino ketoester from secondary amides 3A and aryl ketoesters 6B (Scheme 2, eqn (2)). The low yield of the former method is another reason why a new one-pot method is desirable.

Scheme 2 One-pot transformations of secondary amides to functionalized enamines 10, 11 and 1 and our previous approach to 7.

Results and discussion

With our longstanding interest in the synthesis of N-containing compounds,¹³ in recent years, we have focused our attention on the development of synthetic methods based on amide activation.^14,15 Within this framework, we discovered very recently a direct Knoevenagel-type condensation reaction of tertiary amides 12 to give N,N-disubstituted β,β-difunctionalized enamines 7^14f,16 (Scheme 2, eqn (3)). In view of the importance of the Knoevenagel-type condensation reaction products of secondary amides (1), we decided to investigate the Knoevenagel-type condensation reaction of secondary amides (Scheme 2, eqn (4)), and wish to report the results herein.

At the outset of our investigation, secondary amide N-isopropyl benzamide 3a was chosen as a model substrate, and the conditions that we established previously for the Knoevenagel-type condensation reaction of tertiary amides^14f were adopted. In the event, amide 3a was treated with 1.2 equiv. of triflic anhydride¹⁷ (Tf₂O) in CH₂Cl₂ at −78 °C for 30 min and the resulting activated intermediate was subjected to react with carbanion generated in situ from 1.5 equiv. of diethyl malonate (6a) and 2.5 equiv. of sodium hexamethyldisilazane (NaHMDS) at −78 °C, and then at r.t. for 2 h. To our delight, the desired aza-Knoevenagel-type condensation product 1a was obtained in 61% yield (Table 1, entry 1). Decreasing the amount of base from 2.5 equiv. to 1.5 equiv. resulted in a lower yield of 1a (45%) (entry 2). In view of the beneficial effect of 2-fluoropyridine¹⁸ (2-F-Py) as a base additive in combination with Tf₂O for the activation of secondary amides and subsequent C–C bond forming reaction,^14h–j the effect of 2-F-Py on the reaction was examined. Indeed, in the presence of 0.5 and 1.2 equiv. of 2-F-Py, the yields were improved to 63% and 86%, respectively (entries 3 and 4). Lower amounts of NaHMDS were detrimental (entry 5), whereas higher amounts of NaHMDS turned out to be unnecessary (entry 6). Interestingly, sodium hydride and potassium tert-butoxide could also be used as the base, which led to the desired product in 64% and 60% yield, respectively (entries 7 and 8). Thus the optimal conditions for the aza-Knoevenagel-type condensation reaction of secondary amides were determined as: activation of secondary amide (1.0 equiv.) with Tf₂O (1.1 equiv.)/2-F-Py (1.2 equiv.) at −78 °C, and the resulting intermediate reacted with diethyl sodiomalonate generated from the corresponding malonate (1.5 equiv.) and NaHMDS (1.5 equiv.) at −78 °C, and then at r.t. for 2 h.

Table 1 aza-Knoevenagel-type condensation reaction of secondary amide 3a

Entry	2-F-Py (equiv.)	Base (equiv.)	1a ^, (% yield)
a 1.1 equiv. of Tf2O and 1.5 equiv. of diethyl malonate (6a) were used. b Isolated yield.
1	0	NaHMDS (2.5)	61
2	0	NaHMDS (1.5)	45
3	0.5	NaHMDS (1.5)	63
4	1.2	NaHMDS (1.5)	86
5	1.2	NaHMDS (1.0)	80
6	1.2	NaHMDS (3.0)	85
7	1.2	NaH (3.0)	64
8	1.2	t-BuOK (3.0)	60

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With the optimal conditions in hand, the aza-Knoevenagel-type condensation reactions of different amides were examined, and the results are displayed in Table 2. We first examined the influence of different substituents on the aromatic ring to the outcome of the reaction. The reaction tolerated both electron-donating groups (entries 2 and 3) and electron-withdrawing groups (entries 4–8), and the former are slightly favored over the latter in terms of yield (87% for Me-, 88% for MeO- versus 80% for Cl-substituted benzamide). The reaction of p-nitrobenzamide 3e, which bears a strong electron-withdrawing group (NO₂), afforded 1f in a modest yield of 67% (entry 6). Remarkably, as can be seen from entries 5–8, the reaction proceeded chemoselectively at the least reactive secondary amide group in the presence of sensitive functional groups including p-cyano, p-nitro, p-formyl, and p-acetoxy groups to give the corresponding condensation products 1e–1h in 67%–82% yields. Similarly, thiophene-2-carboxamide 3i reacted chemoselectively to produce the corresponding product 1i in 70% (entry 9).

Table 2 aza-Knoevenagel-type condensation reactions of secondary amides

Entry	Amide	Product^a (% yield)	Entry	Amide	Product^a (% yield)
a Isolated yield.
1			10
2			11
3			12
4			13
5			14
6			15
7			16
8			17
9			18

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It is worth noting that the reaction is amenable to alkanamides 3j–3o (entries 10–15). Of special importance is the survival of silyl ether (OTBDPS), acetal (OTHP), cyclopropyl, and chloro groups during the condensation reactions of 3k–3o (entries 11–15).

Comparison of the results from the reactions of 3k and 3n showed that a change of the N-alkyl group from the i-propyl to the chiral α-silyloxymethylethyl group did not affect the reaction (entry 11 versus 14, both in 78% yield). The reactions of amides 3o and 3p, derived from (R)- and (S)-α-phenyethylamine, gave the optically active products 1o and 1p in 75% and 80% yield, respectively. However, the reaction of N-methyl benzamide 3q produced the desired product 1q in only 30% yield (entry 17), and the reaction failed with γ-lactam 3r (entry 18).

To extend the scope of the reaction, we next investigated the condensation reactions with other active methylene compounds (6) with a methylene group to which two electronegative groups, such as alkoxycarbonyl, phosphonyl, cyano, sulfonyl, and phenyl groups, are attached. More hindered dibenzyl malonate 6b reacted similarly as diethyl malonate 6a did (Table 3, entry 2 versus entry 1). Similarly, the condensation reaction of malononitrile 6c afforded 1t in excellent yield (91%, entry 3). The condensation of ethyl 2-(diethoxyphosphoryl)acetate 6d worked without incidence to afford β-amino vinylphosphonate (β-AVP, 1u)^1b,19 as a mixture of two inseparable geometric isomers (E–Z ratio = 62 : 38, determined by integration of the NH in its ¹H NMR) in a combined yield of 70% (entry 4). The stereochemistries were not determined. It is worth noting that previously 1u and its related compounds have been synthesized by stepwise methods. These methods were either via transamination or aminolysis reaction between the β-AVPs with a dimethylamine moiety or a β-methoxy vinylphosphonate and a primary amine.^1b,19 Interestingly, the condensation reactions of ethyl 2-cyanoacetate 6e and 2-(phenylsulfonyl)acetonitrile 6f produced 1v and 1w, both as a single geometric isomer, in 75% and 83% yield, respectively (entries 5 and 6). The structure of 1v was determined unambiguously by single crystal X-ray diffraction analysis (Fig. 1). It is worth mentioning that the condensation reactions of ethyl 2-phenylacetate 6g and (benzylsulfonyl)benzene 6h, active methylene compounds bearing a weak electron-withdrawing group (phenyl), worked similarly to give the corresponding products 1x and 1y as a single isomer in 76% and 71% yield, respectively (entries 7 and 8). The observed downfield chemical shift of the N–H proton (7.86–9.42 ppm) in the ¹H NMR spectra of compounds 1w, 1x and 1y allowed the assignment of the stereochemistries of these compounds as Z-isomers.^2c,f,20

Fig. 1 The crystal structure of 1v.

Table 3 aza-Knoevenagel-type condensation reactions of secondary amides with other active methylene compounds

Entry	ZCH2Z′	Product^a (% yield)
a Isolated yield. b Ratio determined by ^1H NMR.
1	CH2(CO2Et)2
	6a
2	CH2(CO2Bn)2
	6b
3	CH2(CN)2
	6c
4	EtO2CCH2P(O)(OEt)2
	6d
5	NCCH2CO2Et
	6e
6	NCCH2SO2Ph
	6f
7	PhCH2CO2Me
	6g
8	PhCH2SO2Ph
	6h

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As we have mentioned in the Introduction, the aza-Knoevenagel-type condensation products are multi-functional compounds enabling a number of further reactions. For example, according to the literature precedents,^8e–g taking advantage of the nucleophilicity at the nitrogen atom, functionalized secondary chloro enamine 1o (Table 2, entry 15) can be cyclized to give the cyclic tertiary one.²¹ Moreover, the enantiopure products (R)-1o and (S)-1p (Table 2, entries 15 and 16) are ready precursors for the synthesis of enantiomeric β-amino esters.²²

To further demonstrate the utility of the aza-Knoevenagel-type condensation products, the known 1z^2c was prepared as a mixture of two inseparable geometric isomers, Z/E = ca. 1 : 1 (determined by ¹H NMR) by the condensation reaction of (R)-N-(1-phenylethyl)acetamide 3s with methyl 2-(2-bromophenyl)-acetate (6i). The conversion of the isomeric 1z into the indole derivative bearing a chiral center (R)-13^2c can be achieved by Vaswani's Pd-catalyzed C–N ring forming method^2c (Scheme 3).

Scheme 3 One-pot synthesis of 1z as a ready precursor of functionalized chiral indole (R)-13.

In addition, the condensation reaction of amide 3t with malononitrile (6e) provided 1aa. Then, without further purification, the reaction of crude 1aa with 2-bromoacetophenone in the presence of potassium carbonate provided 14 in 73% yield for two steps (Scheme 4). By using the Takayama's protocol,^5f the latter is convertible into poly-substituted pyrrole 15, which belongs to a class of potent inhibitors of lymphocyte-specific kinase.^5f

Scheme 4 One-pot synthesis of 1aa as a ready precursor of the lymphocyte-specific kinase inhibitor 15.

Some ethyl Z-2-cyano-3-substituted amino-3-(2-methylphenyl)propenoates such as 1ab have been shown to exhibit fungicidal activities,^7a and have been synthesized by a three-step method.^7a By our method, the direct condensation of amide 3u with ethyl 2-cyanoacetate 6d produced, in one-pot, 1ab in 82% yield (Scheme 5).

Scheme 5 One-pot synthesis of the fungicidal compound 1ab.

A plausible mechanism of the aza-Knoevenagel-type condensation reaction of secondary amides is depicted in Scheme 6. The nitrogen-lone pair assisted nucleophilic reaction of amide oxygen with triflic anhydride (Tf₂O) generates O-triflyl imidate A. Abstraction of the proton in A by a base (NaHMDS or 2-fluoropyridine) generates imidoyl triflate B, which either reacts with sodiomanolate to give directly imine D, or eliminates TfO⁻ to give the nitrilium intermediate C. The fact that secondary γ-lactam 3r failed to undergo the aza-Knoevenagel-type condensation reaction (Table 2, entry 18) precludes the direct substitution with imidoyl triflate B, and thus implicates the intermediacy of the nitrilium intermediate C.

Scheme 6 Plausible mechanism of the aza-Knoevenagel-type condensation reaction of secondary amides.

The latter can also be generated directly from O-triflyl imidate A by deprotonation. Nucleophilic addition to nitrilium intermediate C then generates imine D. Finally, a base-promoted step-wise tautomerization of imine D yielded, via enamine N-anion E, the functionalized enamine 1. The key role of 2-fluoropyridine for the generation of the nitrilium intermediate has previously been demonstrated by Movassaghi.¹⁸ However, the fact that the reaction proceeds in the absence of 2-fluoropyridine to give the desired product 1 in 61% yield (Table 1, entry 1) implicated that the deprotonation of the intermediate A by NHMDS to generate the nitrilium intermediate C is the main pathway of the reaction.

Conclusion

In summary, we have disclosed a direct, chemoselective, and general synthesis of N-monosubstituted β,β-difunctionalized enamines from readily available secondary amides and active methylene compounds. In conjunction with other efficient synthetic methodologies, such as Vaswani's indole synthesis,^2c Zhao's PIFA^2f/NXS/Zn(OAc)₂ ^2d-mediated synthesis of N-substituted indole derivatives, and Takayama's protocol for the synthesis of tetra-substituted pyrroles,^5f a number of poly-functionalized medicinally-relevant compounds can be synthesized in a procedure-economical manner.²³

Experimental section

General methods

¹H NMR and ¹³C NMR spectra were recorded on a Bruker 400 (¹H/400 MHz, ¹³C/100 MHz) spectrometer. Chemical shifts are expressed in parts per million (δ) relative to an internal standard of residual chloroform (7.26 ppm for ¹H NMR and 77.0 ppm for ¹³C NMR). Data for ¹H NMR are reported as chemical shifts (multiplicity, coupling constant, number of proton). ESI-Mass spectra were recorded on a Bruker Dalton ESquire 3000 plus LC-MS apparatus. Optical rotations were measured with a Perkin-Elmer 341 automatic polarimeter or an Anton Paar MCP 500 polarimeter. Melting points were determined on a Büchi M560 Automatic Melting Point apparatus. Infrared spectra were recorded with a Nicolet Avatar 330 FT-IR spectrometer using the film technique. Silica gel (300–400 mesh) was used for flash column chromatography, eluting (unless otherwise stated) with an ethyl acetate/hexane mixture. Tf₂O was distilled over phosphorus pentoxide and used within a week. THF was distilled over sodium benzophenone ketyl under N₂. Dichloromethane was distilled over calcium hydride under N₂.

General procedure for the preparation of N-mono-substituted β,β-difunctionalized enamines from secondary amides

Trifluoromethanesulfonic anhydride (185 μL, 1.0 mmol, 1.1 equiv.) was added dropwise to a cooled (−78 °C) solution of an amide (1.0 mmol, 1.0 equiv.) and 2-fluoropyridine (116.5 mg, 103 μL, 1.2 mmol, 1.2 equiv.) in dichloromethane (5 mL). After being stirred for 30 min at −78 °C, a solution of sodium enolate (1.5 mmol, 1.5 equiv.) [freshly prepared by addition of an active methylene compound (1.5 mmol, 1.5 equiv.) to NaHMDS (1.5 mmol, 1.5 equiv.) in tetrahydrofuran (5 mL) and stirred at −78 °C for 1 h] was added dropwise. The resulting mixture was warmed to r.t. and stirred for 2 h at r.t. The reaction was quenched with a saturated aqueous NH₄Cl solution and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the desired poly-functionalized enamine.

Diethyl 2-((isopropylamino)(phenyl)methylene)malonate (1a). Following the general procedure, reaction of N-isopropylbenzamide 3a (163 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 4–10% EtOAc in hexane), compound 1a (259 mg, yield: 85%) as a colorless oil; IR (film) ν_max: 3201, 2971, 1714, 1644, 1573, 1279, 1146, 769, 698 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.78 (t, J = 7.1 Hz, 3H, CH₃), 1.15 (d, J = 6.5 Hz, 6H, 2CH₃), 1.29 (t, J = 7.1 Hz, 3H, CH₃), 3.28–3.37 (m, 1H, CH), 3.71 (q, J = 7.1 Hz, 2H, CH₂), 4.21 (q, J = 7.1 Hz, 2H, CH₂), 7.28–7.31 (m, 2H, Ph–H), 7.38–7.41 (m, 3H, Ph–H), 9.58 (d, J = 9.1 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.4, 14.4, 23.9 (2C), 46.1, 59.5, 59.9, 93.2, 127.5, 128.2 (2C), 129.0 (2C), 134.5, 164.9, 167.8, 168.6 ppm; MS (ESI) m/z 328 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₇H₂₃NNaO₄]⁺ (M + Na⁺): 328.1519; found: 328.1516.

Diethyl 2-((isopropylamino)(p-tolyl)methylene)malonate (1b). Following the general procedure, reaction of N-isopropyl-4-methylbenzamide 3b (177 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 4–10% EtOAc in hexane), compound 1b (278 mg, yield: 87%) as a colorless oil; IR (film) ν_max: 3195, 2975, 1718, 1695, 1577, 1270, 1146, 827, 744 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.82 (t, J = 7.1 Hz, 3H, CH₃), 1.15 (d, J = 6.5 Hz, 6H, 2CH₃), 1.28 (t, J = 7.1 Hz, 3H, CH₃), 2.38 (s, 3H, CH₃), 3.31–3.40 (m, 1H, CH), 3.74 (q, J = 7.1 Hz, 2H, CH₂), 4.20 (q, J = 7.1 Hz, 2H, CH₂), 7.16–7.21 (m, 4H, Ph–H), 9.54 (d, J = 9.3 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.5, 14.4, 21.2, 23.9 (2C), 46.0, 59.4, 60.0, 93.2, 127.4, 128.8 (2C), 131.5 (2C), 139.0, 165.1, 168.0, 168.5 ppm; MS (ESI) m/z 342 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₈H₂₅NNaO₄]⁺ (M + Na⁺): 342.1676; found: 342.1683.

Diethyl 2-((isopropylamino)(3,4,5-trimethoxyphenyl)methylene)malonate (1c). Following the general procedure, reaction of N-isopropyl-3,4,5-trimethoxybenzamide 3c (253 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 4–10% EtOAc in hexane), compound 1c (347 mg, yield: 88%) as a colorless oil; IR (film) ν_max: 3210, 2971, 1714, 1648, 1582, 1461, 1424, 1241, 1125, 1076, 798 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.86 (t, J = 7.1 Hz, 3H, CH₃), 1.15 (d, J = 6.5 Hz, 6H, 2CH₃), 1.29 (t, J = 7.1 Hz, 3H, CH₃), 3.40–3.48 (m, 1H, CH), 3.79 (q, J = 7.1 Hz, 2H, CH₂), 3.85 (q, J = 7.1 Hz, 2H, CH₂), 3.85 (s, 6H, CH₃), 3.87 (s, 3H, CH₃), 4.21 (q, J = 7.1 Hz, 2H, CH₂), 6.54 (s, 2H, Ph–H), 9.49 (d, J = 9.5 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.7, 14.4, 24.1 (2C), 46.4, 56.3 (2C), 59.6, 60.9, 60.8, 93.2, 105.0 (2C), 129.8, 138.7, 153.2 (2C), 164.6, 168.0, 168.4 ppm; MS (ESI) m/z 418 (M + Na⁺); HRMS (ESI) m/z calcd for [C₂₀H₂₉NNaO₇]⁺ (M + Na⁺): 418.1836; found: 418.1841.

Diethyl 2-((4-chlorophenyl)(isopropylamino)methylene)malonate (1d). Following the general procedure, reaction of 4-chloro-N-isopropylbenzamide 3d (197 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 4–10% EtOAc in hexane), compound 1d (271 mg, yield: 80%) as a white solid, m.p. 69–72 °C; IR (film) ν_max: 3160, 2975, 1706, 1648, 1266, 1150, 1080, 796 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.86 (t, J = 7.1 Hz, 3H, CH₃), 1.15 (d, J = 6.5 Hz, 6H, 2CH₃), 1.29 (t, J = 7.1 Hz, 3H, CH₃), 3.24–3.33 (m, 1H, CH), 3.77 (q, J = 7.1 Hz, 2H, CH₂), 4.21 (q, J = 7.1 Hz, 2H, CH₂), 7.24–7.26 (m, 2H, Ph–H), 7.38–7.40 (m, 2H, Ph–H), 9.54 (d, J = 9.3 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.4, 14.2, 23.8 (2C), 46.1, 59.5, 60.0, 93.4, 128.5 (2C), 128.9 (2C), 132.7, 135.1, 163.5, 167.5, 168.4 ppm; MS (ESI) m/z 362 (M + Na⁺); HRMS (ESI) m/z calcd for C₁₇H₂₂ClNNaO₄⁺ (M + Na⁺): 362.1130; found: 362.1127.

Diethyl 2-((4-cyanophenyl)(isopropylamino)methylene)malonate (1e). Following the general procedure, reaction of 4-cyano-N-isopropylbenzamide 3e (188 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 10–15% EtOAc in hexane), compound 1e (270 mg, yield: 82%) as a white solid, m.p. 108–111 °C; IR (film) ν_max: 3220, 2975, 2224, 1698, 1644, 1565, 1262, 1150, 1080, 843, 798 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.80 (t, J = 7.1 Hz, 3H, CH₃), 1.04 (d, J = 6.4 Hz, 6H, CH₃), 1.22 (t, J = 7.1 Hz, 3H, CH₃), 3.07–3.13 (m, 1H, CH), 3.69 (q, J = 7.1 Hz, 2H, CH₂), 4.14 (q, J = 7.1 Hz, 2H, CH₂), 7.35–7.37 (m, 2H, Ph–H), 7.64–7.66 (m, 2H, Ph–H), 9.54 (d, J = 9.4 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.5, 14.2, 23.9 (2C), 46.3, 59.8, 60.1, 93.5, 113.0, 117.9, 128.4 (2C), 132.0 (2C), 139.0, 162.6, 167.0, 168.4 ppm; MS (ESI) m/z 353 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₈H₂₂N₂NaO₄]⁺ (M + Na⁺) 353.1472; found: 353.1469.

Diethyl 2-((isopropylamino)(4-nitrophenyl)methylene)malonate (1f). Following the general procedure, reaction of N-isopropyl-4-nitrobenzamide 3f (208 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 15–20% EtOAc in hexane), compound 1f (235 mg, yield: 67%) as a white solid, m.p. 111–113 °C; IR (film) ν_max: 3250, 2975, 1710, 1652, 1523, 1349, 1258, 1146, 1080, 852 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.89 (t, J = 7.1 Hz, 3H, CH₃), 1.13 (d, J = 6.4 Hz, 6H, 2CH₃), 1.31 (t, J = 7.1 Hz, 3H, CH₃), 3.14–3.22 (m, 1H, CH), 3.78 (q, J = 7.1 Hz, 2H, CH₂), 4.23 (q, J = 7.1 Hz, 2H, CH₂), 7.50–7.52 (m, 2H, Ph–H), 8.28–8.30 (m, 2H, Ph–H), 9.65 (d, J = 9.4 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.6, 14.3, 23.9 (2C), 46.5, 59.9, 60.2, 93.6, 123.5 (2C), 128.8 (2C), 140.9, 148.1, 162.5, 167.1, 168.5 ppm; MS (ESI) m/z 373 (M + Na⁺); HRMS (ESI) m/z calcd for C₁₇H₂₂N₂NaO₆⁺ (M + Na⁺): 373.1370; found: 373.1370.

Diethyl 2-((4-formylphenyl)(isopropylamino)methylene)malonate (1g). Following the general procedure, reaction of 4-formyl-N-isopropylbenzamide 3g (191 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1g (253 mg, yield: 76%) as a white solid, m.p. 63–65 °C; IR (film) ν_max: 3233, 2975, 1706, 1644, 1577, 1266, 1146, 1076, 835 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.75 (t, J = 7.1 Hz, 3H, CH₃), 1.04 (d, J = 6.5 Hz, 6H, 2CH₃), 1.23 (t, J = 7.1 Hz, 3H, CH₃), 3.10–3.20 (m, 1H, CH), 3.67 (q, J = 7.1 Hz, 2H, CH₂), 4.15 (q, J = 7.1 Hz, 2H, CH₂), 7.40–7.42 (m, 2H, Ph–H), 7.86–7.88 (m, 2H, Ph–H), 9.56 (d, J = 9.3 Hz, 1H, NH), 10.0 (s, 1H, CHO) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.5, 14.2, 23.9 (2C), 46.3, 59.7, 60.0, 93.3, 128.3, 129.4 (2C), 136.5 (2C), 140.4, 163.4, 167.3, 168.5, 191.3 ppm; MS (ESI) m/z 356 (M + Na⁺); HRMS (ESI) m/z calcd for C₁₈H₂₃NNaO₅⁺ (M + Na⁺): 356.1468; found: 356.1467.

Diethyl 2-((4-acetoxyphenyl)(isopropylamino)methylene-malonate (1h). Following the general procedure, reaction of 2-(isopropylcarbamoyl)phenyl acetate 3h (221 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 10–15% EtOAc in hexane), compound 1h (297 mg, yield: 82%) as a white solid, m.p. 67–71 °C; IR (film) ν_max: 3225, 2971, 1764, 1706, 1648, 1362, 1283, 1246, 1154, 1076, 802, 756 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.79 (t, J = 7.1 Hz, 3H, CH₃), 1.02 (d, J = 6.5 Hz, 3H, CH₃), 1.11 (d, J = 6.5 Hz, 3H, CH₃), 1.27 (t, J = 7.1 Hz, 3H, CH₃), 2.24 (s, 3H), 3.18–3.24 (m, 1H, CH), 3.69–3.75 (m, 2H, CH₂), 4.14–4.24 (m, 2H, CH₂), 7.20–7.24 (m, 3H, Ph–H), 7.38–7.43 (m, 1H, Ph–H), 9.69 (d, J = 9.6 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.5, 14.4, 21.0, 23.4, 24.5, 46.5, 59.6, 59.9, 93.0, 122.9, 125.4, 127.1, 129.0, 130.0, 147.4, 161.0, 167.2, 168.6, 169.1 ppm; MS (ESI) m/z 386 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₉H₂₅NNaO₆]⁺ (M + Na⁺): 386.1574; found: 386.1571.

Diethyl 2-((isopropylamino)(thiophen-2-yl)methylene)malonate (1i). Following the general procedure, reaction of N-isopropylthiophene-2-carboxamide 3i (169 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1i (218 mg, yield: 70%) as a colorless oil; IR (film) ν_max: 3243, 2971, 1714, 1648, 1586, 1250, 1154, 1076, 702 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.93 (t, J = 6.5 Hz, 3H, CH₃), 1.15 (d, J = 6.6 Hz, 6H, 2CH₃), 1.28 (t, J = 6.5 Hz, 3H, CH₃), 3.51–3.84 (m, 1H, CH), 3.83 (q, J = 6.5 Hz, 2H, CH₂), 4.20 (q, J = 6.5 Hz, 2H, CH₂), 7.04 (dd, J = 3.5, 5.0 Hz, 1H, =CH), 7.10 (dd, J = 1.2, 3.5 Hz, 1H, =CH), 7.46 (dd, J = 1.2, 5.0 Hz, 1H, =CH), 9.40 (d, J = 9.2 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.6, 14.3, 24.0 (2C), 46.5, 59.6, 60.3, 95.2, 126.8, 127.6, 128.6, 133.9, 157.3, 167.7, 168.0 ppm; MS (ESI) m/z 334 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₅H₂₁NNaO₄S]⁺ (M + Na⁺): 334.1083; found: 334.1081.

Diethyl 2-(1-(isopropylamino)undecylidene)malonate (1j). Following the general procedure, reaction of N-isopropylundecanamide 3j (227 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 3–5% EtOAc in hexane), compound 1j (269 mg, yield: 73%) as a colorless oil; IR (film) ν_max: 3150, 2971, 2921, 1702, 1605, 1254, 1154, 1080, 794 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.80 (t, J = 6.9 Hz, 3H, CHCH₃), 1.16–1.28 (m, 26H, CH₃, CH₂), 1.46–1.55 (m, 2H, CH₂), 2.30–2.34 (m, 2H, CH₂), 3.62–3.70 (m, 1H, CH), 4.05 (q, J = 7.2 Hz, 2H, CH₂), 4.13 (q, J = 7.2 Hz, 2H, CH₂), 9.53 (d, J = 9.1 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.0, 14.1, 14.3, 22.6, 24.1 (2C), 29.1, 29.2 (2C), 29.4 (2C), 29.6, 29.8, 31.8, 44.5, 59.1, 60.3, 90.6, 166.3, 169.2 (2C) ppm; MS (ESI) m/z 392 (M + Na⁺); HRMS (ESI) m/z calcd for [C₂₁H₃₉NNaO₄]⁺ (M + Na⁺): 392.2771; found: 392.2770.

Diethyl 2-(4-((tert-butyldiphenylsilyl)oxy)-1-(isopropylamino)butylidene)malonate (1k). Following the general procedure, reaction of 4-((tert-butyldiphenylsilyl)oxy)-N-isopropylbutanamide 3k (383 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1k (409 mg, yield: 78%) as a colorless oil; IR (film) ν_max: 3105, 2975, 2929, 1702, 1644, 1590, 1250, 1158, 1105, 1042, 702, 499 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.06 (s, 9H, CH₃), 1.21 (d, J = 6.4 Hz, 6H, 2CH₃), 1.24 (t, J = 7.1 Hz, 6H, 2CH₂CH₃), 1.80–1.87 (m, 2H, CH₂), 2.52–2.56 (m, 2H, CH₂), 3.71 (t, J = 5.6 Hz, 2H, CH₂), 3.86–3.93 (m, 1H, CH), 4.10–4.18 (m, 4H, CH₂), 7.38–7.42 (m, 6H, PhH), 7.63–7.66 (m, 4H, PhH), 9.59 (d, J = 9.1 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.2, 14.4, 19.1, 24.1 (2C), 26.5, 26.8 (3C), 32.1, 44.4, 59.2, 60.3, 63.2, 90.8, 127.7 (2C), 129.7 (4C), 133.6 (4C), 135.5 (2C), 166.3, 169.3 (2C) ppm; MS (ESI) m/z 548 (M + Na⁺); HRMS (ESI) m/z calcd for [C₃₀H₄₃NNaO₅Si]⁺ (M + Na⁺): 548.2803; found: 548.2800.

Diethyl 2-(1-(isopropylamino)-4-((tetrahydro-2H-pyran-2-yl)oxy)butylidene)malonate (1l). Following the general procedure, reaction of N-isopropyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanamide 3l (229 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1l (301 mg, yield: 81%) as a colorless oil; IR (film) ν_max: 3150, 2946, 2863, 1706, 1648, 1590, 1254, 1158, 1076, 868, 802 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.23–1.31 (m, 12H, CH₃), 1.51–1.60 (m, 4H, CH₂), 1.71–1.93 (m, 4H, CH₂), 2.50–2.56 (m, 2H, CH₂), 3.40–3.53 (m, 2H, CH₂), 3.76–3.90 (m, 3H, CH₂), 4.13 (q, J = 7.1 Hz, 2H, CH₂), 4.20 (q, J = 7.1 Hz, 2H, CH₂), 4.57–4.59 (m, 1H, CH), 9.60 (d, J = 9.1 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.2, 14.4, 19.6, 24.1 (2C), 25.4, 26.7, 29.4, 30.7, 44.4, 59.2, 60.3, 62.4, 66.7, 90.9, 98.9, 166.1, 169.2 (2C) ppm; MS (ESI) m/z 394 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₉H₃₃NNaO₆]⁺ (M + Na⁺): 394.2200; found: 394.2207.

Diethyl 2-(cyclopropyl(isopropylamino)methylene)malonate (1m). Following the general procedure, reaction of N-isopropylcyclopropanecarboxamide 3m (127 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1m (215 mg, yield: 80%) as a white solid, m.p. 51–53 °C; IR (film) ν_max: 3170, 2983, 1714, 1644, 1586, 1250, 1158, 1030, 789 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.65–0.69 (m, 2H, CH₂), 0.90–0.94 (m, 2H, CH₂), 1.24 (d, J = 6.4 Hz, 6H, 2CH₃), 1.28 (t, J = 7.1 Hz, 6H, 2CH₃), 1.62–1.70 (m, 1H, CH), 4.16 (q, J = 7.1 Hz, 4H, CH₂), 4.26–4.35 (m, 1H, CH), 9.49 (d, J = 8.7 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 7.0 (2C), 12.7, 14.2 (2C), 24.0 (2C), 44.6 (2C), 59.8, 92.6, 165.3 (2C), 168.9 ppm; MS (ESI) m/z 292 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₄H₂₃NNaO₄]⁺ (M + Na⁺): 292.1519; found: 292.1515.

Diethyl 2-(((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)amino)(phenyl)methylene)malonate (1n). Following the general procedure, reaction of N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)benzamide 3n (417 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1n (436 mg, yield: 78%) as a colorless oil; IR (film) ν_max: 3220, 2925, 2855, 1718, 1648, 1582, 1275, 1109, 698, 503 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.78 (t, J = 7.1 Hz, 3H, CH₃), 1.05 (s, 9H, CH₃), 1.15 (d, J = 6.6 Hz, 3H, CH₃), 1.28 (t, J = 7.1 Hz, 3H, CH₃), 3.28–3.34 (m, 1H, CH), 3.45 (d, J = 4.9 Hz, 2H), 3.68–3.74 (m, 2H, CH₂), 4.18–4.26 (m, 2H, CH₂), 7.12–7.63 (m, 15H, PhH), 9.80 (d, J = 9.8 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃, some peaks overlapped): δ 13.5, 14.4, 18.7, 19.2, 26.7 (3C), 51.5, 59.6, 60.0, 67.6, 93.9, 127.6 (2C), 127.7, 127.9, 128.1, 128.2, 129.0, 129.6, 129.7, 133.0, 133.1, 134.4, 135.4, 135.6, 165.1, 167.8, 168.4 ppm; MS (ESI) m/z 582 (M + Na⁺); HRMS (ESI) m/z calcd for [C₃₃H₄₁NNaO₅Si]⁺ (M + Na⁺): 582.2646; found: 582.2650.

Diethyl (R)-2-(5-chloro-1-((1-phenylethyl)amino)pentylidene)malonate (1o). Following the general procedure, reaction of (R)-5-chloro-N-(1-phenylethyl)pentanamide 3o (239 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1o (286 mg, yield: 75%) as a colorless oil, [α]²⁰_D −251 (c 1.0, CHCl₃); IR (film) ν_max: 3285, 2929, 1714, 1602, 1378, 1088, 769 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.28 (t, J = 7.1 Hz, 6H, 2CH₃), 1.55 (d, J = 6.8 Hz, 3H, CH₃), 1.64–1.80 (m, 4H, CH₂), 2.24–2.38 (m, 2H, CH₂), 3.42–3.46 (m, 2H, CH₂), 4.18 (q, J = 7.1 Hz, 4H, CH₂), 4.68–4.74 (m, 1H, CH), 7.23–7.36 (m, 5H, PhH), 10.08 (d, J = 7.9 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.1, 14.3, 25.0, 25.7, 29.0, 32.1, 44.1, 52.8, 59.5, 60.4, 92.3, 125.4, 127.4 (2C), 128.9 (2C), 144.1, 166.3, 168.9, 169.2 ppm; MS (ESI) m/z 404 (M + Na⁺); HRMS (ESI) m/z calcd for [C₂₀H₂₈ClNNaO₄]⁺ (M + Na⁺): 404.1599; found: 404.1603.

Diethyl (S)-2-(phenyl((1-phenylethyl)amino)methylene)malonate (1p). Following the general procedure, reaction of (S)-N-(1-phenylethyl)benzamide 3p (225 mg, 1.0 mmol) with diethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1p (294 mg, yield: 80%) as a colorless oil; [α]²⁰_D 135.7 (c 1, CHCl₃); IR (film) ν_max: 3250, 2975, 1718, 1648, 1577, 1441, 1279, 1150, 1080, 764, 694 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.28 (t, J = 7.1 Hz, 6H, 2CH₃), 1.55 (d, J = 6.8 Hz, 3H, CH₃), 1.64–1.80 (m, 4H, CH₂), 2.24–2.38 (m, 2H, CH₂), 3.42–3.46 (m, 2H, CH₂), 4.18 (q, J = 7.1 Hz, 4H, 2CH₂), 4.68–4.74 (m, 1H, CH), 7.23–7.36 (m, 5H, PhH), 10.08 (d, J = 7.9 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.3, 14.3, 24.2, 53.9, 59.7, 60.0, 94.3, 125.5 (2C), 127.0, 127.3, 127.8, 127.9, 128.0, 128.4 (2C), 129.0, 134.0, 143.8, 165.0, 167.6, 168.5 ppm; MS (ESI) m/z 390 (M + Na⁺); HRMS (ESI) m/z calcd for [C₂₂H₂₅NNaO₄]⁺ (M + Na⁺): 390.1676; found: 390.1678.

Dimethyl 2-((methylamino)(phenyl)methylene)malonate (1q). Following the general procedure, reaction of N-methylbenzamide 3q (135 mg, 1.0 mmol) with dimethyl malonate enolate, freshly prepared from diethyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1q (74 mg, yield: 30%) as a white solid, m.p. 109–112 °C; IR (film) ν_max: 3210, 2951, 1710, 1634, 1571, 1265, 1141, 765, 688 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 2.71 (d, J = 5.2 Hz, 3H, CH₃), 3.21 (s, 3H, CH₃), 3.75 (s, 3H, CH₃), 7.23–7.42 (m, 5H, PhH), 9.65 (br s, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 31.4, 51.1, 51.2, 92.9, 127.4, 128.4 (2C), 129.2 (2C), 134.0, 167.4, 168.4, 169.1 ppm; MS (ESI) m/z 272 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₃H₁₅NNaO₄]⁺ (M + Na⁺): 272.0893; found: 272.0899.

Dibenzyl 2-((isopropylamino)(phenyl)methylene)malonate (1s). Following the general procedure, reaction of N-isopropylbenzamide 3a (163 mg, 1.0 mmol) with dibenzyl malonate enolate, freshly prepared from dibenzyl malonate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1s (365 mg, yield: 85%) as a colorless oil; IR (film) ν_max: 3225, 1971, 1714, 1652, 1582, 1270, 1146, 1071, 701, 694 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.07 (d, J = 6.5 Hz, 6H, 2CH₃), 3.26–3.36 (m, 1H, CH), 4.70 (s, 2H, CH₂), 5.22 (s, 2H, CH₂), 6.98–7.00 (m, 2H, Ph–H), 7.18–7.36 (m, 13H, Ph–H), 9.54 (d, J = 9.4 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃, some peaks overlapped): δ 23.9 (2C), 46.2, 65.0, 66.3, 92.8, 127.3, 127.4, 127.5, 127.6, 128.1, 128.2, 128.3 (2C), 129.2, 134.1, 135.9, 136.8, 165.3, 167.7, 168.1 ppm; MS (ESI) m/z 452 (M + Na⁺); HRMS (ESI) m/z calcd for [C₂₇H₂₇NNaO₄]⁺ (M + Na⁺): 452.1832; found: 452.1838.

2-((Isopropylamino)(phenyl)methylene)malononitrile (1t). Following the general procedure, reaction of N-isopropylbenzamide 3a (163 mg, 1.0 mmol) with malononitrile enolate, freshly prepared from malononitrile and NaHMDS, gave, after flash column chromatography on silica gel (elution with 20–30% EtOAc in hexane), compound 1t (192 mg, yield: 91%) as a white solid, m.p. 158–161 °C; IR (film) ν_max: 3265, 2995, 2975, 2208, 1590, 1420, 1138, 764, 698 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.18 (d, J = 6.5 Hz, 6H, CH₃), 3.46–3.56 (m, 1H, CH), 6.61 (d, J = 7.8 Hz, 1H, NH), 7.34–7.36 (m, 2H, Ph–H), 7.50–7.58 (m, 3H, Ph–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 23.2 (2C), 48.6, 52.5, 115.0, 115.4, 127.4, 129.2 (2C), 130.1 (2C), 131.4, 171.8 ppm; MS (ESI) m/z 234 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₃H₁₃N₃Na]⁺ (M + Na⁺): 234.1002; found: 234.1006.

Ethyl 2-(diethoxyphosphoryl)-3-(isopropylamino)-3-phenyl-acrylate (1u). Following the general procedure, reaction of N-isopropyl-benzamide 3a (163 mg, 1.0 mmol) with ethyl 2-(diethoxyphosphoryl)acetate enolate, freshly prepared from ethyl 2-(diethoxyphosphoryl)acetate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 10–20% EtOAc in hexane), compound 1u (258 mg, yield: 70%) as a colorless oil; Data read from the spectrum of the geometric mixture, dr = 62 : 38, determined by integration of the NH in its ¹H NMR; IR (film) ν_max: 3195, 2975, 2905, 1739, 1582, 1258, 1030, 959 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 0.84 (t, J = 7.1 Hz, 3H, CH₃), 1.06–1.09 (m, 13H, CH₃), 1.33–1.38 (m, 8H, CH₃), 3.20–3.28 (m, 1.6H, CH), 3.76 (q, J = 7.1 Hz, 2H, CH₂), 3.81–3.86 (m, 1.3H, CH₂), 4.14 (q, J = 7.88 Hz, 4H, CH₂), 4.14 (q, J = 7.08 Hz, 2.4H, CH₂), 7.23–7.42 (m, 8H, Ph–H), 9.72 (d, J = 8.91 Hz, 1H, NH), 10.37 (d, J = 8.82 Hz, 0.6H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃, some peaks overlapped): δ 13.7, 14.2, 16.0 (d, J_C–P = 6.7 Hz, 2C), 16.2 (d, J = 6.7 Hz, 2C), 23.4 (2C), 23.7 (2C), 46.2, 46.3, 58.9, 59.9, 60.8 (d, J_C–P = 6.1 Hz, 2C), 61.7 (d, J_C–P = 5.2 Hz, 2C), 80.9 (d, J_C–P = 187.0 Hz, 1C), 83.1 (d, J_C–P = 217.1 Hz, 1C), 126.9, 127.8 (d, J_C–P = 20.0 Hz, 2C), 128.0, 128.6 (2C), 128.7 (d, J_C–P = 30.8 Hz, 2C), 128.9 (2C), 135.0 (d, J_C–P = 2.3 Hz, 1C), 136.5 (d, J_C–P = 15.2 Hz, 1C), 167.3 (d, J_C–P = 11.6 Hz, 1C), 170.6 (d, J_C–P = 18.5 Hz, 1C), 170.7 (d, J_C–P = 11.4 Hz, 1C), 171.3 (d, J_C–P = 10.3 Hz, 1C) ppm; MS (ESI) m/z 392 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₈H₂₈NNaO₅P]⁺ (M + Na⁺): 392.1597; found: 392.1590.

Ethyl (Z)-2-cyano-3-(isopropylamino)-3-phenylacrylate (1v). Following the general procedure, reaction of N-isopropylbenzamide 3a (163 mg, 1.0 mmol) with ethyl 2-cyanoacetate enolate, freshly prepared from ethyl 2-cyanoacetate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 10–15% EtOAc in hexane), compound 1v (194 mg, yield: 75%) as a white solid, m.p. 101–104 °C; IR (film) ν_max: 3215, 2979, 2208, 1656, 1586, 1445, 1279, 1142, 1022, 789, 711 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.15 (d, J = 6.5 Hz, 6H, 2CH₃), 1.34 (t, J = 7.1 Hz, 3H, CH₃), 3.42–3.50 (m, 1H, CH), 4.25 (q, J = 7.1 Hz, 2H, CH₂), 7.32–7.34 (m, 2H, Ph–H), 7.48–7.50 (m, 3H, Ph–H), 9.88 (d, J = 6.6 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.3, 23.6 (2C), 47.2, 60.4, 72.2, 118.6, 127.2, 129.0 (2C), 130.4 (2C), 132.2, 168.9, 170.1 ppm; MS (ESI) m/z 281 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₅H₁₈N₂NaO₂]⁺ (M + Na⁺): 281.1260; found: 281.1269.

3-(Isopropylamino) (Z)-3-phenyl-2-(phenylsulfonyl)acrylonitrile (1w). Following the general procedure, reaction of N-isopropylbenzamide 3a (163 mg, 1.0 mmol) with 2-(phenylsulfonyl)acetonitrile enolate, freshly prepared from 2-(phenylsulfonyl)acetonitrile and NaHMDS, gave, after flash column chromatography on silica gel (elution with 10–15% EtOAc in hexane), compound 1w (271 mg, yield: 83%) as a white solid, m.p. 159–161 °C; IR (film) ν_max: 3285, 2921, 2842, 2195, 1723, 1577, 1445, 1134, 719, 607 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.17 (d, J = 6.5 Hz, 6H, 2CH₃), 3.36–3.45 (m, 1H, CH), 7.26–7.28 (m, 2H, Ph–H), 7.44–7.67 (m, 6H, Ph–H), 7.97–7.99 (m, 2H, Ph–H), 8.56 (d, J = 8.3 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 23.6 (2C), 48.1, 82.3, 116.4, 126.6, 127.3, 129.2 (2C), 129.3 (2C), 131.0 (2C), 131.7 (2C), 133.5, 142.1, 166.0 ppm; MS (ESI) m/z 349 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₈H₁₈N₂NaO₂S]⁺ (M + Na⁺): 349.0981; found: 349.0987.

Methyl (Z)-3-(isopropylamino)-2,3-diphenylacrylate (1x). Following the general procedure, reaction of N-isopropylbenzamide 3a (163 mg, 1.0 mmol) with ethyl 2-phenylacetate enolate, freshly prepared from ethyl 2-phenylacetate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 1–2% EtOAc in hexane), compound 1x (224 mg, yield: 76%) as a white solid, m.p. 102–105 °C; IR (film) ν_max: 3205, 2967, 2164, 1573, 1432, 1266, 1138, 794, 702 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.12 (d, J = 6.5 Hz, 6H, 2CH₃), 3.23–3.34 (m, 1H, CH), 3.62 (s, 3H, CH₃), 6.90–7.04 (m, 7H, Ph–H), 7.11–7.13 (m, 3H, Ph–H), 9.42 (d, J = 9.0 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 24.3 (2C), 45.9, 50.7, 97.5, 125.0, 126.9, 127.6 (2C), 127.8 (2C), 128.8 (2C), 132.8 (2C), 135.1, 137.9, 163.0, 170.8 ppm; MS (ESI) m/z 318 (M + Na⁺); HRMS (ESI) m/z calcd for [C₁₉H₂₁NNaO₂]⁺ (M + Na⁺): 318.1465; found: 318.1463.

(Z)-N-(1,2-Diphenyl-2-(phenylsulfonyl)vinyl)propan-2-amine (1y). Following the general procedure, reaction of N-isopropylbenzamide 3a (163 mg, 1.0 mmol) with (benzylsulfonyl)benzene enolate, freshly prepared from (benzylsulfonyl)benzene and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), compound 1y (267 mg, yield: 71%) as a white solid, m.p. 100–103 °C; IR (film) ν_max: 3255, 2951, 2743, 2065, 1723, 734, 643 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.14 (d, J = 6.5 Hz, 6H, 2CH₃), 3.12–3.21 (m, 1H, CH), 6.68–6.80 (m, 2H, Ph–H), 6.86–6.94 (m, 3H, Ph–H), 7.03–7.10 (m, 5H, Ph–H), 7.35–7.50 (m, 3H, Ph–H), 7.65–7.67 (m, 2H, Ph–H), 7.86 (d, J = 9.5 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃, some peaks overlapped): δ 24.0 (2C), 46.5, 104.6, 126.6, 126.8, 127.2, 127.8, 128.3, 128.4, 128.9, 132.1, 133.9, 134.4, 134.8, 142.9, 157.9 ppm; MS (ESI) m/z 400 (M + Na⁺); HRMS (ESI) m/z calcd for [C₂₃H₂₃NNaO₂S]⁺ (M + Na⁺): 400.1341; found: 400.1350.

Methyl (S)-2-(2-bromophenyl)-3-((1-phenylethyl)amino)but-2-enoate (1z). Following the general procedure, reaction of (R)-N-(1-phenylethyl)acetamide 3s (163 mg, 1.0 mmol) with ethyl 2-(2-bromophenyl)acetate enolate, freshly prepared from ethyl 2-(2-bromophenyl)acetate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 1–2% EtOAc in hexane), the known 1z^2c as a mixture of two inseparable geometric isomers, E/Z = 1 : 1 (280 mg, yield: 75%) as a colorless oil; IR (film) ν_max: 3250, 2943, 1652, 1591, 1437, 1280, 1245, 1197, 1133, 752, 694 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.50 (s, 3H, CH₃), 1.53 (s, 3H, CH₃), 1.58 (d, J = 6.8 Hz, 6H, CH₃), 3.60 (s, 3H, CH₃), 3.61 (s, 3H, CH₃), 4.66–4.74 (m, 2H, CH), 7.05–7.12 (m, 3H, Ph–H), 7.18–7.36 (m, 13H, Ph–H), 7.54–7.58 (m, 2H, Ph–H), 9.90 (t, J = 6.9 Hz, 2H) ppm; ¹³C NMR (100 MHz, CDCl₃, some peaks overlapped): δ 16.6, 16.7, 25.10, 25.13, 50.7, 53.2, 53.4, 97.2, 125.4, 125.5, 127.0, 127.1, 127.2, 128.1, 128.4, 128.5, 128.7, 128.8, 132.2, 133.8, 134.0, 139.4, 145.0, 145.1, 169.8, 169.9 ppm; MS (ESI) m/z 374 (M + H⁺).

4-Amino-5-benzoyl-1-(4-methoxybenzyl)-2-(4-methoxy-phenyl)-1H-pyrrole-3-carbonitrile (14). Trifluoromethanesulfonic anhydride (185 μL, 1.0 mmol, 1.1 equiv.) was added dropwise to a cooled (−78 °C) solution of 4-methoxy-N-(4-methoxybenzyl)benzamide 3t (271 mg, 1.0 mmol) and 2-fluoropyridine (116.5 mg, 103 μL, 1.2 mmol, 1.2 equiv.) in dichloromethane (5 mL). After being stirred for 30 min at −78 °C, a solution of malononitrile enolate (1.5 mmol, 1.5 equiv.), freshly prepared from malononitrile and NHMDS (1.5 mmol, 1.5 equiv.) −78 °C, was added dropwise. The resulting mixture was warmed to r.t. and stirred for 2 h at r.t. The reaction was quenched with a saturated aqueous NH₄Cl solution and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the residue. Without further purification, the residue was used in the next step. To the residue and K₂CO₃ (3 mmol) in acetone (6 mL) was added PhC(O)CH₂Br (1.2 mmol), stirred at room temperature for 15 h. H₂O was added, and the mixture was extracted with EtOAc (3 × 15 mL). The organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound 14^5f (319 mg, 73%) as a white solid, m.p. 152–154 °C; IR (film) ν_max: 3462, 3343, 2947, 2216, 1613, 1511, 1460, 1248, 1031, 829 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 3.71 (s, 3H, CH₃), 3.85 (s, 3H, CH₃), 4.57 (br s, 2H, NH₂), 5.14 (s, 2H, CH₂), 6.55–6.57 (m, 2H, Ph–H), 6.65–6.67 (m, 2H, Ph–H), 7.00–7.02 (m, 2H, Ph–H), 7.43–754 (m, 7H, Ph–H) ppm; ¹³C NMR (100 MHz, CDCl₃, some peaks overlapped): δ 50.0, 55.1, 55.4, 84.4, 113.8, 114.7, 114.8, 116.7, 120.3, 127.6, 128.0, 128.9, 129.2, 131.1, 131.6, 140.0, 146.6, 147.7, 158.9, 161.1, 184.8 ppm; MS (ESI) m/z 438 (M + H⁺).

Ethyl (Z)-2-cyano-3-(isopropylamino)-3-(o-tolyl)acrylate (1ab). Following the general procedure, reaction of N-isopropyl-2-methylbenzamide 3a (177 mg, 1.0 mmol) with ethyl 2-cyanoacetate enolate, freshly prepared from ethyl 2-cyanoacetate and NaHMDS, gave, after flash column chromatography on silica gel (elution with 6–10% EtOAc in hexane), the known compound 1ab^7a (223 mg, yield: 82%) as a white solid, m.p. 108–112 °C; IR (film) ν_max: 3241, 2975, 2206, 1658, 1572, 1264, 1133, 1021, 784 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 1.12 (d, J = 6.5 Hz, 3H, CH₃), 1.17 (d, J = 6.5 Hz, 3H, CH₃), 1.34 (t, J = 7.1 Hz, 3H, CH₃), 2.33 (s, 3H, CH₃), 3.24–3.33 (m, 1H, CH), 4.21–4.29 (m, 2H, CH₂), 7.15–7.17 (m, 1H, Ph–H), 7.26–7.40 (m, 3H, Ph–H), 9.87 (d, J = 5.3 Hz, 1H, NH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.4, 18.9, 23.3, 24.1, 47.3, 60.4, 72.2, 118.2, 126.4, 127.0, 130.2, 130.8, 132.0, 134.7, 169.0, 169.9 ppm; MS (ESI) m/z 273 (M + H⁺).

Acknowledgements

The authors are grateful for financial support from the NSF of China (21332007 and 21472153), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education.

Notes and references

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Footnotes

† In memory of Professor Dr S. Kan.

‡ Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra of the products 1a–1z, 1aa, 1ab. Crystallographic data in CIF of the products 1v. CCDC 1406598. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00191a

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