Synthesis of Passerini adducts from aldehydes and isocyanides under the auxiliary of water

Abstract

An efficient protocol for the synthesis of the Passerini adducts α-acyloxycarboxamides from aldehydes, isocyanides and water in a molecular ratio of 3 : 1 : 3 was described. The possible mechanism for the reaction was discussed by employing cross condensation and H₂¹⁸O isotope labeling experiments. This method offers a straightforward access to α-acyloxycarboxamides bearing two identical functional groups in high yields under mild conditions.

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Introduction

Isocyanides have long proved themselves to be irreplaceable building blocks in modern organic chemistry.¹ Their application in pharmaceutical and academic research has undergone a dramatic increase over the past few years.² Along with the Ugi reaction,³ the Passerini reaction is particularly attractive, and coupling of isocyanides with aldehydes and carboxylic acids represents the most important use of isocyanides in organic synthesis.⁴

Water, as the sole medium for organic reactions, has advantages of being low cost, safe, and environmentally friendly that make it an ideal reaction medium in synthetic chemistry.⁵ The use of water could accelerate the rate of reaction and also lead to selectivity changes.⁶ Recently, reactions of water-insoluble organic compounds that take place in aqueous suspensions have received a great deal of attention because of their high efficiency and straightforward synthetic protocols.⁷ A. Vigalok⁸ reported a highly efficient aqueous three-component Passerini reaction (Scheme 1), where one of the components, carboxylic acid, is generated in situ via the aerobic oxidation of hydrophobic aldehydes upon stirring with water in the presence of air. However, the method often gave both the Passerini adducts, α-acyloxyamides and α-hydroxyamides, and the role of water is still unclear.

Scheme 1 The tandem aldehyde oxidation/Passerini reaction “on water”.

By taking note of Vigalok's report, we have two questions: (1) since the water-solubility of reactants, especially the aldehydes, could affect significantly the efficiency of the reaction, how about further decreasing the amount of water? (2) Could aldehydes be efficiently converted in situ into carboxylic acids that were successively utilized in the nucleophilic addition to the carbonyl carbon atom when the reaction takes place “in water”?

In order to answer these two questions, a series of experiments were designed and carried out by using 3 equiv. of water and simultaneously employing two different aldehydes in a reaction as well as a comparative oxidation of 4-fluorobenzaldehyde and 4-methoxybenzaldehyde. Based on our ongoing interest in IMCRs,⁹ herein, we present an efficient protocol to access the Passerini adducts α-acyloxycarboxamides in excellent yields from aldehydes, isocyanides and water in a molecular ratio of 3 : 1 : 3, and another new possible mechanism for the reaction.

Results and discussion

To demonstrate the roles of water and oxygen or air, a series of experiments were designed and carried out by using the reaction of cyclohexyl isocyanide (1a) with benzaldehyde (2a) as the model reaction at 40 °C for 3 h (Table 1).

Table 1 Effect of water and O₂ on reaction for 3a ^a

Entry	Equiv. of 2a	Equiv. of H2O	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a, and H2O (equiv. based on 1a). b Isolated yield based on 1a. c The reaction was performed under a N2 atmosphere. d The reaction was performed under an oxygen atmosphere.
1	3	0	39
2	3	1	58
3	3	2	68
4	3	3	90
5	3	4	86
6	3	5	81
7	3	6	66
8	3	3	8^c
9	3	0	6^c
10	3	0	55^d
11	3	3	77^d

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Excitingly, addition of water improved significantly the yield of 3a (Table 1, entries 1–7). A breakthrough result was achieved, the yield of 3a rose to 90% when 3 equiv. of water was employed (entry 4). Excessive water was unbeneficial for the reaction (entries 5–7). In addition, as a control experiment, the reactions of 1a, 2a, and H₂O in a molecular ratio of 1 : 3 : 3 or without water addition were carried out under a nitrogen atmosphere for 3 h, and only less than 10% yield of 3a was generated (entries 8 and 9), which revealed that the presence of oxygen or air would be essential for the reaction. In the light of the importance of oxygen and water for the reaction, a comparative experiment was further carried out. Without water addition the reaction of 2a with 1a in a molecular ratio of 3 : 1 under an oxygen atmosphere provided only 55% yield of 3a (entry 10); in contrast, the reaction with 3 equiv. of H₂O addition under the same reaction conditions afforded 3a in 77% yield (entry 11). These results indicated that oxidation of aldehydes is inevitable in the presence of oxygen, and water also plays an irreplaceable role.

In view of limited number of the Passerini adducts reported before, we next expanded the scope of the reaction mainly using various aromatic aldehydes under the above standard conditions (1/2/H₂O in a molecular ratio of 1 : 3 : 3 at 40 °C in air), and the results are shown in Scheme 2. All aromatic aldehydes were well tolerated to afford the expected products 3a–j.

Scheme 2 Exploration of the substrate scope for synthesis of 3/4/5. ^a Reaction conditions: isocyanides 1 (0.5 mmol), aldehydes 2 (1.5 mmol), and water (1.5 mmol), 40 °C in air. Isolated yields after washing with petroleum ether. ^b Reacted at 50 °C. ^c Reacted at 60 °C. ^d Yield after purification by silica gel column chromatography. ^e No reaction.

The aromatic aldehydes with electron-withdrawing groups (F, Cl, Br, CF₃) reacted faster than those with electron-donating groups (CH₃, OCH₃), while the yields do not have evident differences except for 3e (Scheme 2, 3b–g). However, o-methoxybenzaldehyde gave a low yield of 40% and needed a long reaction time of 4 h (Scheme 2, 3j), which is subjected to the steric effect. Aliphatic aldehydes such as n-butylaldehyde also could participate in the reaction though it gave a relatively low yield of 60% (Scheme 2, 3k). Unfortunately, when a heteroaromatic aldehyde such as furan-2-carbaldehyde was used, no reaction occurred (Scheme 2, 3l). Next, we employed tert-butyl isocyanide (1b) and ethyl 2-isocyanoacetate (1c) instead of 1a in this IMCR, and it was found that the reactions involving 1b/1c also proceeded well to afford the corresponding products 4/5 in excellent yields. It is worth mentioning that the less reactive ethyl isocyanoacetate (1c) also gave yields of 80–86% (Scheme 2, 5a–c), while only 30% yield of 5b was obtained in the previous report.^8a

The structures of 3/4/5 were confirmed by the X-ray diffraction analysis of 3g (Fig. S1 in the ESI†).

The success of the above reactions promoted us to gain deep insight into the reaction mechanism with regard to aldehyde oxidation by applying two different aromatic aldehydes: bearing an electron-withdrawing group such as 2b–d and bearing an electron-donating group such as 4-methoxybenzaldehyde (2f), to react with 1a (for details, see Table S1 in the ESI†). To our great delight, new “hetero” products 6a–c that are different from the Passerini adducts were obtained besides “homo” products 3b–d and 3f (Table 2). Obviously, according to the Passerini reaction mechanism, 6′ should be obtained due to these aromatic aldehydes bearing an electron-withdrawing group which is more susceptible to be oxidized to the corresponding carboxylic acid. A comparative oxidation experiment with 4-fluorobenzaldehyde (2b) and 4-methoxybenzaldehyde (2f) authenticated this clear-cut fact.¹⁰ As expected, a small amount of 6a′ was also observed along with 6a in a ratio of 1 : 10 by the ¹H NMR spectrum. The above experimental results implied that two mechanisms for the present reaction may exist at the same time.

Table 2 Reactions of two different aromatic aldehydes with 1a^a

Entry	EWG	Yield^b (%)
		6a–c	3a–c	3f
a Reaction conditions: 1a (0.5 mmol), 2b–d (1 mmol), 2f (0.5 mmol), H2O (1.5 mmol). b Yields after purification by silica gel column chromatography.
1	4-F/2b	37 (6a)	43 (3b)	10
2	4-Cl/2c	40 (6b)	42 (3c)	Trace
3	4-Br/2d	35 (6c)	40 (3d)	11

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Significantly, the previous reports have not investigated the crossing reactions with two different aldehydes.

The structures of 6a–c were confirmed by the X-ray diffraction analysis of the representative compound 6b (Fig. S2 in the ESI†).

To further investigate the role of water, an isotope labeling experiment was conducted. The reaction of 4-fluorobenzaldehyde (2b), cyclohexyl isocyanide (1a) (0.1 mmol), and H₂¹⁸O in a molecular ratio of 3 : 1 : 3 for 2b/1a/H₂¹⁸O was carried out at 40 °C for 30 min. HRMS (ESI-TOF, [M + H]⁺) analysis exhibited that besides the ion peak of 374.1572 for 2[¹⁶O]-3b, other two ion peaks at m/z 376.1591 and 378.1650 in a ratio of 7 : 8 : 6 also were observed, which should be relative to [¹⁸O]-3b and 2[¹⁸O]-3b, respectively (Fig. S3 in the ESI†). This observation is in agreement with the previous report.^8a In addition, we have noticed that in A. Vigalok's report, the reaction with nonlabeled 1-octanal, 1-octanoic acid, and ethyl isocyanoacetate or pentyl isocyanide in H₂¹⁸O, gave the Passerini adduct with one incorporated ¹⁸O as the major product, which also reveals that the present reaction mechanism should be different from the classic Passerini reaction.

On the basis of the above experimental results, a plausible mechanism for this reaction is proposed and shown in Scheme 3. A more reactive 4-chlorobenzaldehyde (2c) first reacts with isocyanide 1a to generate an intermediate [A], which then reacts with another less reactive aldehyde such as 4-methoxybenzaldehyde (2f) leading to 1,3-dioxolamine [B].¹¹ Next, [B] reacts with water to form [C], which undergoes a ring-opening reaction to give [D]. Successively, an oxidation process gives the final product 6b. In addition, a small amount of aldehydes are oxidized to the corresponding acid in the presence of air. Under such acidic conditions, a part of [D] would lose hydroxyl to form an intermediate [E], which reacts with another molecule of H₂O giving [F], followed by an oxidation process to form the final product 6b. This mechanism could explain reasonably why in the isotope labeling experiments there are both products with one labeled ¹⁸O ([¹⁸O]-3b) and products with two ¹⁸O (2[¹⁸O]-3b) incorporated in the structures.

Scheme 3 Plausible new reaction mechanism.

Conclusions

In conclusion, we have demonstrated a rapid and efficient approach to access the Passerini adducts α-acyloxycarboxamides using aldehydes, isocyanides, and water in a molecular ratio of 3 : 1 : 3 rather than needing carboxylic acids. The striking feature of the method is to use 3 equiv. of H₂O in the reaction system to give good to excellent yields under mild reaction conditions. The experiments of isotope labeling of H₂¹⁸O and crossing reactions by using two different aldehydes clearly indicated that the reaction mechanism is different from the previous report.^8a This research also provided a convenient and green method to access α-acyloxycarboxamides with two identical functional groups in high yields.

Experimental section

General experimental details

The benzaldehyde (2a) used for the condition test was produced by Acros Organics (99.5+%). Cyclohexyl isocyanide (1a) for the condition test was dried with anhydrous MgSO₄ before use. All other isocyanides and aldehydes were used as purchased commercially without the drying process. Water used was common running water and untreated. All reagents were weighed and handled in air at room temperature. Melting points were recorded on RY-1 microscopic melting apparatus and uncorrected. NMR spectra were recorded on a Bruker Avance 500 spectrometer at 500 MHz for ¹H and 125 MHz for ¹³C in DMSO-d₆ or CDCl₃. Chemical shifts δ were relative to TMS as the internal standard. The IR spectra were recorded on a Nicolet iS10 FT-IR spectrometer and only major peaks are reported in cm⁻¹. High-resolution mass spectra (HRMS) were recorded on an Ultima Global spectrometer. The X-ray single-crystal diffraction was performed on a Saturn 724+ instrument.

General procedure for the synthesis of 3/4/5

A mixture of isocyanides 1 (0.5 mmol), aldehydes 2 (1.5 mmol), and water (1.5 mmol) was stirred at 40 °C in a 25 mL round-bottomed flask for an indicated time in air until 1 was completely consumed. The solid mixture was isolated by filtration and washing with petroleum ether (3 × 5 mL), and then the pure products 3/4/5 were obtained.

General procedure for the preparation of 6

A mixture of the aromatic aldehydes with electron-withdrawing groups 2b–d (1 mmol), 1a (0.5 mmol), 2f (0.5 mmol), and H₂O (1.5 mmol) was stirred at 60 °C in a 25 mL round-bottomed flask for 30 min in air until 1a was completely consumed. The solid obtained by filtration was isolated by silica gel column chromatography, and the pure products 6a–c were obtained.

2-(Cyclohexylamino)-2-oxo-1-phenylethyl benzoate (3a). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), benzaldehyde 2a (159.2 mg, 1.5 mmol), and water (27 μL, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3a (151.7 mg, 90%) as a white powder. Mp: 144–146 °C; IR (KBr, cm⁻¹) 3305, 3069, 3041, 2935, 2854, 1733, 1659, 1602, 1549, 1498, 1450, 731, 703. ¹H NMR (500 MHz, CDCl₃) 1.11–1.25 (m, 3H, CH), 1.34–1.37 (m, 2H, CH), 1.62–1.68 (m, 3H, CH), 1.88–1.96 (m, 2H, CH), 3.82–3.84 (m, 1H, CH), 6.04 (d, J = 7.0 Hz, 1H, NH), 6.31 (s, H, CH), 7.26–7.63 (m, 8H, ArH), 8.09–8.10 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.5, 25.8, 32.9, 33.0, 48.2, 76.0, 91.6, 127.4, 128.6, 128.8, 128.9, 129.4, 129.8, 133.6, 135.8, 164.9, 167.3. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₁H₂₄NO₃, 338.1756, found 338.1765.

2-(Cyclohexylamino)-1-(4-fluorophenyl)-2-oxoethyl 4-fluorobenzoate (3b). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-fluorobenzaldehyde 2b (186.2 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3b (173.5 mg, 93%) as a white powder. Mp: 212–214 °C; IR (KBr, cm⁻¹) 3266, 3099, 2930, 2854, 1719, 1657, 1604, 1569, 1510, 1449, 768. ¹H NMR (500 MHz, CDCl₃) 1.06–1.25 (m, 5H, CH), 1.50–1.76 (m, 5H, CH), 3.47–3.50 (m, 1H, CH), 6.04 (s, 1H, CH), 8.27 (d, J = 7.9 Hz, 1H, NH), 7.24–7.64 (m, 6H, ArH), 8.08–8.10 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.4, 25.1, 32.0, 32.1, 32.9, 47.7, 74.9, 115.3 (d, ³J_C–F = 7.5 Hz), 115.9 (d, ²J_C–F = 22.1 Hz), 125.8, 129.3 (d, ³J_C–F = 7.3 Hz), 132.2, 132.4 (d, ³J_C–F = 8.8 Hz), 141.4, 162.1 (d, ¹J_C–F = 245.3 Hz), 164.0, 165.3 (d, ¹J_C–F = 251.8 Hz), 166.6. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₁H₂₂F₂NO₃, 374.1568, found 374.1556.

1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl 4-chlorobenzoate (3c). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-chlorobenzaldehyde 2c (210.9 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3c (186.3 mg, 92%) as a white powder. Mp: 210–212 °C; IR (KBr, cm⁻¹) 3271, 3093, 2927, 2853, 1724, 1655, 1595, 1567, 1490, 1447, 854. ¹H NMR (500 MHz, CDCl₃) 1.14–1.20 (m, 3H, CH), 1.32–1.41 (m, 2H, CH), 1.58–1.72 (m, 3H, CH), 1.88–1.95 (m, 2H, CH), 3.80–3.84 (m, 1H, CH), 5.93 (d, J = 7.5 Hz, 1H, NH), 6.23 (s, 1H, CH), 7.36–7.48 (m, 6H, ArH), 8.00–8.02 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.4, 32.9, 48.4, 75.4, 127.5, 128.8, 129.0, 131.1, 134.0, 135.1, 140.3, 164.1, 166.7. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₁H₂₂Cl₂NO₃, 406.0977, found 406.0983.

1-(4-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl 4-bromobenzoate (3d). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-bromobenzaldehyde 2d (227.5 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3d (224.3 mg, 91%) as a white powder. Mp: 191–193 °C; IR (KBr, cm⁻¹) 3289, 3092, 2932, 2854, 1728, 1658, 1590, 1557, 1488, 1450, 755. ¹H NMR (500 MHz, CDCl₃) 1.08–1.20 (m, 3H, CH), 1.34–1.36 (m, 2H, CH), 1.62–1.70 (m, 3H, CH), 1.87–1.94 (m, 2H, CH), 3.79–3.83 (m, 1H, CH), 5.93 (d, J = 7.0 Hz, 1H, NH), 6.20 (s, H, CH), 7.26–7.93 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.4, 32.8, 48.4, 75.4, 123.3, 128.0, 129.1, 131.2, 132.0, 132.1, 134.5, 164.2, 166.6. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₁H₂₂Br₂NO₃, 493.9966, found 493.9959.

1-(4-Trifluoromethylphenyl)-2-(cyclohexylamino)-2-oxoethyl 4-trifluoromethyl-benzoate (3e). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-(trifluoromethyl)benzaldehyde 2e (261.2 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, isolated by silica gel column chromatography (PE/EA = 20 : 1), the desired product 3e (165.6 mg, 70%) as a white powder. Mp: 178–179 °C; IR (KBr, cm⁻¹) 3288, 2936, 2857, 1736, 1661, 1560, 1413, 1327, 1129, 755. ¹H NMR (500 MHz, CDCl₃) 1.10–1.25 (m, 3H, CH), 1.33–1.37 (m, 2H, CH), 1.60–1.72 (m, 3H, CH), 1.89–1.96 (m, 2H, CH), 3.79–3.82 (m, 1H, CH), 6.01 (d, 1H, J = 7.8 Hz, NH), 6.32 (s, 1H, CH), 7.67 (s, 4H, ArH), 7.77 (d, J = 8.2 Hz, 2H, ArH), 8.21 (d, J = 8.1 Hz, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 25.2, 25.9, 33.4, 49.1, 122.8, 123.2, 125.0, 125.4, 126.4, 128.3, 130.8, 131.8 (²J = 32.4 Hz), 132.7, 135.8 (²J = 32.9 Hz), 139.6, 164.3, 166.7. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₃H₂₂F₆NO₃, 474.1504, found 474.1515.

2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl 4-methoxybenzoate (3f). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-methoxybenzaldehyde 2f (204.3 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3f (174.8 mg, 88%) as a white powder. Mp: 152–154 °C; IR (KBr, cm⁻¹) 3287, 3078, 2932, 2853, 1716, 1657, 1607, 1546, 1514, 848. ¹H NMR (500 MHz, CDCl₃) 1.12–1.20 (m, 3H, CH), 1.34–1.39 (m, 2H, CH), 1.60–1.71 (m, 3H, CH), 1.88–1.96 (m, 2H, CH), 3.80–3.88 (m, 6H, CH), 6.02 (d, J = 8.0 Hz, 1H, NH), 6.24 (s, 1H, CH), 6.89–7.45 (m, 6H, ArH), 8.02–8.04 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.5, 33.0, 48.1, 55.3, 55.5, 75.4, 113.9, 114.2, 121.8, 128.2, 128.9, 131.8, 160.0, 164.7, 167.8. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₃H₂₉NO₅, 398.1967, found 398.1975.

2-(Cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl 4-methylbenzoate (3g). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-methylbenzaldehyde 2g (180.3 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3g (162.5 mg, 89%) as a white powder. Mp: 157–159 °C; IR (KBr, cm⁻¹) 3283, 3093, 2924, 2856, 1732, 1652, 1613, 1564, 1514, 1450. ¹H NMR (500 MHz, CDCl₃) 1.12–1.20 (m, 3H, CH), 1.35–1.37 (m, 2H, CH), 1.59–1.70 (m, 3H, CH), 1.88–1.96 (m, 2H, CH), 2.35 (s, 3H, CH₃), 2.43 (s, 3H, CH₃), 3.82–3.84 (m, 1H, CH), 6.03 (d, J = 7.5 Hz, 1H, NH), 6.26 (s, 1H, CH), 7.18–7.42 (m, 6H, ArH), 7.97–7.98 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 21.2, 21.7, 24.7, 25.4, 32.9, 33.0, 48.1, 75.7, 126.7, 127.4, 129.3, 129.4, 129.8, 133.0, 138.8, 144.4, 165.0, 167.6. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₃H₂₈NO₃, 366.2069, found 366.2056.

2-(Cyclohexylamino)-1-(3-fluorophenyl)-2-oxoethyl 3-fluorobenzoate (3h). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 3-fluorobenzaldehyde 2h (186.2 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3h (169.8 mg, 91%) as a white powder. Mp: 155–157 °C; IR (KBr, cm⁻¹) 3318, 3078, 2935, 2857, 1735, 1659, 1593, 1547, 1488, 1449, 760, 680. ¹H NMR (500 MHz, CDCl₃) 1.14–1.97 (m, 10H, CH), 3.83–3.84 (m, 1H, CH), 5.98 (d, J = 8.0 Hz, 1H, NH), 6.27 (s, 1H, CH), 7.07–7.92 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.4, 32.9, 48.4, 75.5, 115.1 (d, ¹J_C–F = 218.9 Hz), 115.3 (d, ¹J_C–F = 217.2 Hz), 116.7 (d, ²J_C–F = 23.1 Hz), 120.9 (d, ²J_C–F = 21.2 Hz), 123.1, 125.5, 130.4 (d, ³J_C–F = 6.8 Hz), 131.2, 137.7, 161.8 (d, ³J_C–F = 26.6 Hz), 163.62, 163.8, 166.5. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₁H₂₂F₂NO₃, 374.1568, found 374.1576.

2-(Cyclohexylamino)-2-oxo-1-(m-tolyl)ethyl 3-methylbenzoate (3i). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 3-methylbenzaldehyde 2i (180.3 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3i (160.7 mg, 88%) as a white powder. Mp: 148–150 °C; IR (KBr, cm⁻¹) 3271, 3088, 2932, 2855, 1720, 1657, 1611, 1589, 1558, 1491, 1451. ¹H NMR (500 MHz, CDCl₃) 1.12–1.20 (m, 3H, CH), 1.34–1.39 (m, 2H, CH), 1.60–1.70 (m, 3H, CH), 1.88–1.96 (m, 2H, CH), 2.36 (s, 1H, CH), 2.42 (s, 1H, CH), 3.82–3.84 (m, 1H, CH), 6.03 (d, J = 7.0 Hz, 1H, NH), 6.26 (s, H, CH), 7.16–7.89 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 21.3, 21.4, 24.7, 25.4, 32.9, 48.2, 75.9, 124.4, 126.9, 128.3, 128.5, 128.6, 129.3, 129.7, 130.3, 134.3, 135.7, 138.4, 165.1, 167.5. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₃H₂₈NO₃, 366.2069, found 366.2079.

2-(Cyclohexylamino)-1-(2-methoxyphenyl)-2-oxoethyl 2-methoxybenzoate (3j). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 2-methoxybenzaldehyde 2j (204.3 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, isolated by silica gel column chromatography (PE/EA = 20 : 1), the desired product 3j (79.4 mg, 40%) as a white powder. Mp: 150–152 °C; IR (KBr, cm⁻¹) 3361, 3074, 2931, 2851, 1701, 1675, 1602, 1536, 1492, 1467, 766. ¹H NMR (500 MHz, CDCl₃) 1.12–1.72 (m, 10H, CH), 3.84–3.86 (m, 1H, CH), 3.87 (s, 3H, CH), 3.96 (s, 3H, CH), 6.63 (s, 1H, CH), 6.82 (d, J = 8.0 Hz, 1H, NH), 6.89–7.87 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.8, 25.6, 33.0, 33.4, 47.9, 55.7, 56.2, 71.2, 111.2, 112.3, 119.9, 120.7, 120.8, 124.9, 129.4, 130.0, 132.4, 133.9, 157.3, 159.0, 165.0, 168.0. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₃H₂₈NO₅, 398.1967, found 398.1975.

1-(Cyclohexylamino)-1-oxohexan-2-yl pentanoate (3k). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), n-butyraldehyde 2k (108.2 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 3k (80.8 mg, 60%) as a white powder. Mp: 67–68 °C; IR (KBr, cm⁻¹) 3292, 2961, 2933, 2874, 2856, 1743, 1655, 1558, 1450. ¹H NMR (500 MHz, CDCl₃) 0.90–1.00 (m, 6H, CH), 1.09–1.21 (m, 4H, CH), 1.32–1.41 (m, 2H, CH), 1.60–1.92 (m, 10H, CH), 2.36–2.39 (m, 2H, CH), 3.75–3.81 (m, 1H, CH), 5.15–5.17 (m, 1H, CH), 5.87 (d, J = 6.7 Hz, 1H, NH); ¹³C NMR (125 MHz, CDCl₃) 12.7, 17.0, 17.5, 20.8, 23.7, 24.5, 32.0, 33.0, 35.2, 46.8, 72.7, 168.0, 171.2. HRMS (ESI-TOF, [M + H]⁺): calcd for C₁₅H₂₈NO₃, 270.2069, found 270.2060.

2-(tert-Butylamino)-1-(4-fluorophenyl)-2-oxoethyl 4-fluorobenzoate (4a). Following the general procedure, the stirred mixture of t-butyl isocyanide 2a (41.6 mg, 0.5 mmol), 4-fluorobenzaldehyde 2b (186.2 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 4a (156.2 mg, 90%) as a white powder. Mp: 168–170 °C; IR (KBr, cm⁻¹) 3284, 3085, 2976, 2933, 1727, 1656, 1606, 1560, 1511, 1450. ¹H NMR (500 MHz, CDCl₃) 1.36 (s, 9H, CH), 5.86 (s, 1H, NH), 6.15 (s, 1H, CH), 7.06–8.10 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 27.8, 28.7, 51.7, 75.4, 115.8, 115.9, 125.5, 129.5, 131.7, 132.3, 162.1, 164.0, 165.1, 167.0. HRMS (ESI-TOF, [M + H]⁺): calcd for C₁₉H₂₀F₂NO₃, 348.1411, found 348.1419.

1-(4-Bromophenyl)-2-(tert-butylamino)-2-oxoethyl 4-bromobenzoate (4b). Following the general procedure, the stirred mixture of t-butyl isocyanide 2a (41.6 mg, 0.5 mmol), 4-bromobenzaldehyde 2d (227.5 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, isolated by silica gel column chromatography (PE/EA = 20 : 1), the desired product 4b (210.2 mg, 90%) as a white powder. Mp: 173–175 °C; IR (KBr, cm⁻¹) 3308, 3087, 2974, 2927, 1727, 1659, 1591, 1557, 1490, 1453. ¹H NMR (500 MHz, CDCl₃) 1.36(s, 9H, CH), 5.86 (s, 1H, NH), 6.12 (s, 1H, CH), 7.37–7.93 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 28.4, 28.6, 51.8, 75.6, 123.3, 128.1, 129.0, 129.1, 131.2, 132.0, 132.1, 134.7, 164.2, 166.6. HRMS (ESI-TOF, [M + H]⁺): calcd for C₁₉H₂₀Br₂NO₃, 467.9810, found 467.9805.

2-(tert-Butylamino)-2-oxo-1-phenylethyl benzoate (4c)^1–3. Following the general procedure, the stirred mixture of t-butyl isocyanide 2a (41.6 mg, 0.5 mmol), benzaldehyde 2a (227.5 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 4c (138.6 mg, 89%) as a white powder. Mp: 153–154 °C (lit. 148–150 °C); IR (KBr, cm⁻¹) 3308, 3087, 2974, 2927, 1727, 1659, 1591, 1557, 1490, 1453.

2-(tert-Butylamino)-2-oxo-1-(p-tolyl)ethyl 4-methylbenzoate (4d). Following the general procedure, the stirred mixture of t-butyl isocyanide 2a (41.6 mg, 0.5 mmol), 4-methylbenzaldehyde 2g (180.3 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 4d (144.2 mg, 85%) as a white powder. Mp: 170–171 °C; IR (KBr, cm⁻¹) 3296, 2984, 2927, 1743, 1660, 1514, 1542, 1516, 1440. ¹H NMR (500 MHz, CDCl₃) 1.36 (s, 9H, CH), 2.34 (s, 3H, CH), 2.42 (s, 3H, CH), 5.99 (s, 1H, NH), 6.17 (s, 1H, CH), 7.18–7.97 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 20.4, 21.3, 21.8, 28.7, 30.8, 51.5, 75.8, 126.7, 127.4, 129.4, 129.5, 129.9, 133.2, 138.7, 144.4, 165.0, 167.7. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₁H₂₆NO₃, 340.1913, found 340.1909.

1-(4-Bromophenyl)-2-((2-ethoxy-2-oxoethyl)amino)-2-oxoethyl 4-bromobenzoate (5a). Following the general procedure, the stirred mixture of ethyl 2-isocyanoacetate 2c (56.6 mg, 0.5 mmol), 4-bromobenzaldehyde 2d (227.5 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 5a (208.7 mg, 84%) as a white powder. Mp: 134–136 °C; IR (KBr, cm⁻¹) 3299, 3089, 2983, 2939, 1733, 1663, 1591, 1560, 1490, 1446, 745, 709. ¹H NMR (500 MHz, CDCl₃) 1.26–1.29 (m, 3H, CH), 4.01–4.25 (m, 4H, CH), 6.30 (s, 1H, CH), 6.75 (s, 1H, NH), 7.26–7.97 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 14.1, 41.3, 61.9, 75.3, 123.6, 127.9, 129.2, 131.3, 132.1, 134.1, 164.2, 167.8, 169.4. HRMS (ESI-TOF, [M + H]⁺): calcd for C₁₉H₁₈Br₂NO₅, 497.9552, found 497.9549.

2-((2-Ethoxy-2-oxoethyl)amino)-2-oxo-1-phenylethyl benzoate (5b). Following the general procedure, the stirred mixture of ethyl 2-isocyanoacetate 2c (56.6 mg, 0.5 mmol), benzaldehyde 2a (227.5 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 5b (146.7 mg, 86%) as a white powder. Mp: 110–112 °C; IR (KBr, cm⁻¹) 3296, 3068, 2983, 2936, 1728, 1662, 1602, 1559, 1498, 1451, 745, 709. ¹H NMR (500 MHz, CDCl₃) 1.25–1.28 (m, 3H, CH), 3.98–4.24 (m, 4H, CH), 6.40 (s, 1H, CH), 6.81 (s, 1H, NH), 7.37–8.14 (m, 10H, ArH); ¹³C NMR (125 MHz, CDCl₃) 14.0, 41.3, 61.7, 75.8, 127.5, 128.6, 128.8, 129.1, 129.2, 129.9, 133.7, 135.3, 164.8, 168.5, 169.5. HRMS (ESI-TOF, [M + H]⁺): calcd for C₁₉H₂₀NO₅, 342.1341, found 342.1346.

2-((2-Ethoxy-2-oxoethyl)amino)-2-oxo-1-(p-tolyl)ethyl 4-methylbenzoate (5c). Following the general procedure, the stirred mixture of ethyl 2-isocyanoacetate 2c (56.6 mg, 0.5 mmol), 4-methylbenzaldehyde 2g (180.3 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, after filtration and washing with petroleum ether (3 × 5 mL), the desired product 5c (147.7 mg, 80%) as a white powder. Mp: 109–111 °C; IR (KBr, cm⁻¹) 3355, 3037, 2974, 2931, 2871, 1735, 1686, 1665, 1613, 1543, 1515, 1457, 745, 709. ¹H NMR (500 MHz, CDCl₃) 1.24–1.28 (m, 3H, CH), 2.34 (s, 3H, CH), 2.42 (s, 3H, CH), 4.00–4.23 (m, 4H, CH), 6.34 (s, 1H, CH), 6.80 (s, 1H, NH), 7.18–8.00 (m, 8H, ArH); ¹³C NMR (125 MHz, CDCl₃) 14.1, 21.2, 21.7, 41.3, 61.6, 75.5, 126.5, 127.5, 129.3, 129.5, 129.9, 132.6, 139.0, 144.4, 164.9, 168.8, 169.5. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₁H₂₄NO₅, 370.1654, found 370.1665.

2-(Cyclohexylamino)-1-(4-fluorophenyl)-2-oxoethyl 4-methoxybenzoate (6a). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-methoxybenzaldehyde 2f (204.3 mg, 1.5 mmol), 4-fluorobenzaldehyde 2b (186.2 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, isolated by silica gel column chromatography (PE/EA = 20 : 1), the desired product 6a (71.3 mg, 37%) as a white powder. Mp: 205–207 °C; IR (KBr, cm⁻¹) 3276, 3088, 2934, 2853, 1709, 1653, 1608, 1413, 1452, 1266, 770. ¹H NMR (500 MHz, CDCl₃) 1.12–1.23 (m, 3H, CH), 1.35–1.50 (m, 2H, CH), 1.61–1.68 (m, 3H, CH), 1.89–1.95 (m, 2H, CH), 3.73–3.81 (m, 1H, CH), 3.89 (s, 3H, CH), 6.09 (d, J = 7.5 Hz, 1H, NH), 6.26 (s, 1H, CH), 6.91–7.51 (m, 6H, ArH), 8.02–8.04 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.4, 32.9, 33.0, 48.2, 55.5, 74.8, 114.0, 114.2, 115.7 (d, ²J_C–F = 21.6 Hz), 121.4, 129.3 (d, ³J_C–F = 7.4 Hz), 131.8, 132.3, 161.9, 164.0, 164.5, 167.3. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₂H₂₅FNO₄, 386.1768, found 386.1772.

1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl 4-methoxybenzoate (6b)^1,2. Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-methoxybenzaldehyde 2f (204.3 mg, 1.5 mmol), 4-chlorobenzaldehyde 2c (210.9 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, isolated by silica gel column chromatography (PE/EA = 20 : 1), the desired product 6b (80.4 mg, 40%) as a white powder. Mp: 195–197 °C (lit. 184–186 °C); IR (KBr, cm⁻¹) 3283, 3087, 2929, 2852, 1713, 1654, 1607, 1595, 1494, 1448, 1265, 772. ¹H NMR (500 MHz, CDCl₃) 1.14–1.21 (m, 3H, CH), 1.36–1.39 (m, 2H, CH), 1.58–1.74 (m, 3H, CH), 1.87–1.97 (m, 2H, CH), 3.80–3.84 (m, 1H, CH), 3.89 (s, 3H, CH), 6.07 (d, J = 7.5 Hz, 1H, NH), 6.26 (s, 1H, CH), 7.36–7.47 (m, 6H, ArH), 8.02–8.05 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.4, 32.9, 33.0, 48.2, 55.5, 74.8, 114.0, 121.4, 128.7, 128.9, 131.8, 134.5, 134.8, 164.0, 164.4, 167.1. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₂H₂₅ClNO₄, 402.1472, found 402.1481.

1-(4-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl 4-methoxybenzoate (6c). Following the general procedure, the stirred mixture of isocyanocyclohexane 1a (54.6 mg, 0.5 mmol), 4-methoxybenzaldehyde 2f (204.3 mg, 1.5 mmol), 4-bromobenzaldehyde 2d (227.5 mg, 1.5 mmol), and water (27 mg, 1.5 mmol) gave, isolated by silica gel column chromatography (PE/EA = 20 : 1), the desired product 6c (78.1 mg, 35%) as a white powder. Mp: 185–186 °C; IR (KBr, cm⁻¹) 3288, 3082, 2934, 2854, 1715, 1655, 1607, 1580, 1511, 1452, 1262, 770. ¹H NMR (500 MHz, CDCl₃) 1.10–1.26 (m, 3H, CH), 1.32–1.40 (m, 2H, CH), 1.59–1.68 (m, 3H, CH), 1.89–1.94 (m, 2H, CH), 3.78–3.84 (m, 1H, CH), 3.89 (s, 3H, CH), 6.06 (d, J = 7.5 Hz, 1H, NH), 6.23 (s, H, CH), 6.90–7.61 (m, 6H, ArH), 8.02–8.04 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃) 24.7, 25.5, 33.0, 33.7, 48.3, 55.6, 75.0, 114.1, 121.4, 123.0, 129.0, 131.0, 131.3, 131.9, 135.1, 164.1, 164.4, 167.0. HRMS (ESI-TOF, [M + H]⁺): calcd for C₂₂H₂₅BrNO₄, 446.0967, found 446.0973.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (21372137 and 21072110) and the Natural Science Foundation of Shandong Province (ZR2012BM003 and ZR2014BM006).

References

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Footnote

† Electronic supplementary information (ESI) available: X-Ray crystal structures of 3g and 6b, ¹H NMR, ¹³C NMR spectra of new compounds, and HRMS spectra of isotope labeled 3b. CCDC 891438 and 900082. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00202h

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