Oxidative C–H Sulfonylation of Hydrazones Enabled by Electrochemistry

Abstract

An efficient electrochemical oxidative C(sp²)–H sulfonylation of aldehyde hydrazones is described. A variety of sodium sufinates or sulfinic acids participate effectively in this protocol, which provides facile access to an array of alkyl and aromatic sulfonylated hydrazones with up to 96% yield. Large-scale synthesis and product derivatization show the potential utility of this methodology. Preliminary mechanistic investigations including radical-inhibition, electricity on/off experiments, and cyclic voltammetry support a radical pathway.

Key words

electrochemical synthesis - radical - sulfonylation - hydrazones - sulfinic acid

A wide range of natural and unnatural compounds that have broad applications in the fields of agrochemicals, pharmaceuticals, and materials chemistry, contain organosulfones (Scheme [1]).[1] These compounds are also known for their synthetic versatility as key intermediates[2] in well-known organic transformations such as the Smiles rearrangement,[3] Ramberg–Backlund reaction,[4] van Leusen oxazole synthesis,[5] and Julia olefination.[6] On the other hand, many natural and synthetic hydrazones possess multifaceted biological activities including antidepressant,[7] antimicrobial,[8] anti-inflammatory,[9] analgesic, anticonvulsant,[10] antimalarial,[11] and anticancer properties,[12] making them interesting target compounds for drug design. Conceptually, the integration of such a structural motif and sulfone group together into one molecule might open new windows of opportunity for the discovery of novel bioactive molecules.

Scheme 1 Important examples of sulfones

The chemistry of functionalized hydrazones has gained considerable momentum over the last few decades due to their important applications in organic synthesis.[13] Hydrazones are versatile synthetic building blocks that participate in a plethora of synthetic transformations in which they act not only as carbonyl surrogates but also as precursors of nitrogen-containing compounds.[14] Among the various hydrazone-based transformations, those that employ the C=N bonds as radical acceptors for diverse C(sp²)–H bond functionalizations are among the most desirable strategies (Scheme [2a]).[15] In recent years, electricity-initiated organic transformations have flourished as a powerful tool for the construction of chemical bonds because they utilize safe, traceless, renewable, and eco-friendly electrons as the sole redox reagents.[16] In this context, elegant examples of direct radical functionalization of hydrazones under electrochemical conditions have been documented. In 2018, Zhang et al.[17] developed an electrochemical [3+2] cycloaddition for the synthesis of tetrazoles from azides and hydrazones. Subsequently, electrochemically enabled direct C(sp²)–H bond functionalization of hydrazones for the construction of C–C, C–N, C–S, and C–P bonds were independently reported by Xie,[18] Huang,[19] Liang,[20] Wang,[21] and Ruan[22] (Scheme [2b]). Nevertheless, despite this important progress, the direct C(sp²)–H sulfonylation of hydrazones, which offers a promising complement to existing strategies, remains under-explored.[23]

Scheme 2 Electrochemical strategies for sulfonylating C(sp²)–H bonds of hydrazones

Recently, the synthesis of N-acylsulfonamides through oxo-sulfonylation of hydrazones was reported by Hajra et al.[24] and Liu et al.[25] employing sulfinic acids and sodium sufinates, respectively, as the sulfonyl radical precursors under transition-metal-free and metal-catalysis approaches (Scheme [2c]). In sharp contrast, we herein disclose an efficient, mild, and sustainable protocol for the preparation of a wide variety of (E)-sulfonylated hydrazones via electrochemical oxidative C(sp²)–H sulfonylation of aldehyde-derived hydrazones based on sulfinic acids/salts as sulfonylating reagents (Scheme [2d]).

As shown in Table [1], we commenced the study with the reaction of readily accessible aldehyde hydrazone 1a with 4-methylbenzenesulfinate 2a as a sulfonyl donor. When the reaction was conducted in an undivided cell equipped with two Pt plate electrodes with ⁿBu₄NBF₄ as the supporting electrolyte and MeCN/H₂O (4:1, 3 mL) as solvent, the expected product 6a was obtained in 52% yield at 27 °C. Employing ⁿBu₄NPF₆, ⁿBu₄NClO₄, or LiClO₄ resulted in decreased reaction yields (entries 2–4). Electrode materials also had a clear influence on this reaction. Replacing the anode with graphite felt increased the yield of the sulfonylated product 6a to 61% (entry 5). When Ni foam plate, Fe sheet, or graphite rod were used as the cathodic material, the yield of 6a was reduced to 53, 52, and 47%, respectively (entries 6–8). After intensive investigation of a range of solvents, it was found that a solvent mixture of MeCN/H₂O at a 1:1 ratio was the best chose (entries 9–13). Gratifyingly, decreasing the concentration of reagents in the solvent to 0.05 M led to further improvement of the isolated yield of 6a to 90% (entry 14). When the electrolysis was carried out in the absence of supporting electrolytes, the yield of 2a dropped to 83% (entry 15). It was observed that either decreasing or increasing the current intensity resulted in decreased reaction yield (entries 16 and 17). No desired product was obtained without the application of electricity (entry 18).

Table 1 Optimization of Reaction Conditions^a

Entry	TolSO2 source (equiv)	Anode/Cathode	Electrolyte	Current (mA)	Solvent	Yield of 6a/6a′ (%)b
1	2a (2.0)	Pt(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (4:1, 3 mL)	52/0
2	2a (2.0)	Pt(+)/Pt(–)	nBu4NPF6	10	CH3CN/H2O (4:1, 3 mL)	34/0
3	2a (2.0)	Pt(+)/Pt(–)	nBu4NClO4	10	CH3CN/H2O (4:1, 3 mL)	39/0
4	2a (2.0)	Pt(+)/Pt(–)	LiClO4	10	CH3CN/H2O (4:1, 3 mL)	36/0
5	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (4:1, 3 mL)	61/0
6	2a (2.0)	GF(+)/Ni(–)	nBu4NBF4	10	CH3CN/H2O (4:1, 3 mL)	53/0
7	2a (2.0)	GF(+)/Fe(–)	nBu4NBF4	10	CH3CN/H2O (4:1, 3 mL)	52/0
8	2a (2.0)	GF(+)/C(–)	nBu4NBF4	10	CH3CN/H2O (4:1, 3 mL)	47/0
9	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	TFE/H2O (4:1, 3 mL)	44/0
10	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	THF/H2O (4:1, 3 mL)	28/0
11	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN (3 mL)	<5/0
12	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	H2O (3 mL)	0/0
13	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (1:1, 3 mL)	88/0
14	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (1:1, 6 mL)	92 (90)c/0
15	2a (2.0)	GF(+)/Pt(–)	–	10	CH3CN/H2O (1:1, 6 mL)	83/0
16d	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	5	CH3CN/H2O (1:1, 6 mL)	83/0
17e	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	15	CH3CN/H2O (1:1, 6 mL)	71/0
18	2a (2.0)	GF(+)/Pt(–)	nBu4NBF4	–	CH3CN/H2O (1:1, 6 mL)	0/0
19	3a (1.5)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (1:1, 6 mL)	79/9
20	3a (1.5)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (1:2, 6 mL)	89 (87)c/<5
21	4 (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (1:1, 6 mL)	0/0
22	5 (2.0)	GF(+)/Pt(–)	nBu4NBF4	10	CH3CN/H2O (1:1, 6 mL)	0/0

^a Reaction conditions unless otherwise stated: 1 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv) in CH₃CN/H₂O (1:1 v/v, 6 mL), graphic felt anode (10 × 15 × 2 mm³), Pt cathode (10 × 10 × 0.2 mm³), undivided cell, room temperature (ca. 27 °C), 10 mA.

^b Yield determined by ¹H NMR analysis with CH₂Br₂ as an internal standard.

^c Isolated yield in parentheses.

^d Reaction time: 5.0 h.

^e Reaction time: 1.5 h.

To our delight, sulfinic acid also served as a suitable sulfonyl source for our current protocol to prepare sufonylated hydrazones. Different to Hajra’s work,[24] when the reaction of 1a with p-methylbenzenesulfonic acid 3a was carried out under the optimized conditions as detailed in Table [1] (entry 14), the desired product 6a could be obtained in 79% yield, and N-acylsulfonamide 6a′ was also isolated as a byproduct in 9% yield (entry 19). In this case, increasing the amount of H₂O proved to be necessary to achieve higher yield of 6a and less byproduct. A notable 87% isolated yield of 6a was obtained when the relative proportion of acetonitrile to water was 1:2 (entry 20). Interestingly, attempts at electrochemical C–H sulfonylation using either p-toluenesulfonyl hydrazide 4 or sulfonyl chloride 5 as the sulfonylating reagents failed to give any desired product (entries 21 and 22).

With the optimized conditions in hand, we first investigated the effect of different N-substituents of hydrazones (Scheme [3]). The results showed that dialkyl hydrazones 7a–c were effective coupling partners, whereas diphenylhydrazone with much less electron-donating capacity proved to be essentially unreactive under identical conditions (7d). In the case of N-Bz hydrazone (7e), the reaction resulted in the consumption of the starting materials, giving rise to a complex mixture of side products. Additionally, no reaction was observed using either oxime ethers (7f) or imines (7g and 7h) as the substrates. These results suggest that the N,N-disubstituted structural motif is crucial for the desired transformation, and the alkyl group is likely an important activation unit.

Scheme 3 Investigation into the effect of the N-substituents. Reagents and conditions: Graphite Felt anode (10 × 15 × 2 mm³), Pt cathode (10 × 10 × 0.2 mm³), 7 (0.2 mmol), 2a (0.4 mmol), ⁿBu₄NBF₄ (0.05 M), CH₃CN/H₂O (1:1 v/v, 6 mL), room temperature (ca. 27 °C), 10 mA. Isolated yields given.

With the optimal conditions in hand, the generality of this reaction was first evaluated with sodium sulfinate 2a and sulfinic acid 3a under conditions A and B, respectively (Scheme [4]). Both 2a and 3a could react with various aryl aldehyde-derived hydrazones possessing either electron-donating [methyl (6b, 6c), tert-butyl (6d), methoxy (6e)], neutral (6f), or electron-withdrawing [fluoro (6g, 6h), chloro (6i), bromo (6j, 6k), iodo (6l), ester (6m), cyano (6n), nitro (6o)] functionalities smoothly to deliver the corresponding sulfonylated product in moderate to excellent yields (23–92%). However, the electronic properties of the substituent had a big influence, and substrates bearing strong electron-withdrawing groups provided much lower yields than those with electron-donating groups. The substrates with naphthyl, thienyl, furanyl, or pyridyl substituents were all suitable, giving the corresponding products 6p–s, albeit with lower efficiency (31–63%). Unfortunately, aliphatic aldehyde-derived hydrazone remained a challenging substrate for this transformation (6t).

Subsequently, we moved on to investigate the scope of sodium sulfinates (Scheme [4]). Fortunately, various sodium benzene sulfinate derivatives bearing electron-donating groups (-^tBu, -OMe, -OCF₃, -Cy, -NHAc), halogens (-F, -Cl, -Br, -I,) and electron-withdrawing substituents (-CF₃, -CO₂CH₃, -NO₂) at different positions reacted with 1a smoothly in satisfactory yields (6u–ak, 31–96%). However, in the case of the sodium 2,4,6-trimethylbenzenesulfinate, only a trace amount of product 6al was observed; this may be a result of the high steric hindrance. Pleasingly, the sodium sulfinates containing annulated arenes and heteroarenes such as indane (6am), 2,3-dihydrobenzo[b][1,4]dioxine (6an), 2,3-dihydrobenzofuran (6ao), benzo[d]thiazole (6ap), 3,5-dimethylisoxazole (6aq), pyridine (6ar), and thiophene (6as–at) were also well-tolerated under the electrochemical protocol. The yields of the expected products ranged from 28 to 91%. Other than (hetero)aromatic sodium sulfinates, vinyl and aliphatic sodium sulfinates also served as suitable candidates to participate in this reaction to produce the corresponding products 6au and 6av in 88 and 84% yields, respectively. The structures of sulfonylated hydrazone frameworks 6x (CCDC 2281964) and 6ar (CCDC 2281962) were determined by X-ray crystallography.[26]

Scheme 4 Substrate scope. Conditions A: Graphite Felt anode (10 × 15 × 2 mm³), Pt cathode (10 × 10 × 0.2 mm³), 1 (0.2 mmol), 2 (0.4 mmol), ⁿBu₄NBF₄ (0.05 M), MeCN/H₂O (1:1 v/v, 6 mL), room temperature (ca. 27 °C), 10 mA. Conditions B: Graphite Felt anode (10 × 15 × 2 mm³), Pt cathode (10 × 10 × 0.2 mm³), 1 (0.2 mmol), 3 (0.3 mmol), ⁿBu₄NBF₄ (0.05 M), MeCN/H₂O (1:2 v/v, 6 mL), room temperature (ca. 27 °C), 10 mA. Isolated yields given.

The tolerance of the benzenesulfinic acid moiety was also studied (Scheme [4]). Overall, the reactivity of sulfinic acids in the reaction showed similarities to that of sodium sulfinates discussed above. Sulfonylation of aldehyde hydrazone 1a with various substituted sulfinic acids (6u–w, 6y–ag, 6aj) was successful and very similar reaction outcomes to those obtained with sodium sulfinates as substrates were achieved.

Next, we continued our study by conducting the sulfonylation on a gram scale (Scheme [5]). Thus, a 4-mmol scale reaction of 1j was performed with sodium 4-methylbenzenesulfnate 2a under constant-current electrolysis at 20 mA for 16 h, which gratifyingly provided 1.05 g of 6j in 62% yield. Subsequently, structural elaborations of 6j were investigated. A series of cross-coupling reactions (Suzuki, Heck, and Buchwald–Hartwig) with 6j were performed, which proceeded smoothly yielding the cross-coupled products 9 (75%), 10 (88%), and 11 (85%), respectively.

To elucidate a plausible mechanism, we performed a series of control experiments. Under standard conditions, the reactions of 2a or 3a with 1a were suppressed completely after adding two equivalents of 1,1-diphenylethylene or 2,6-di-tert-butyl-4-methylphenol (BHT). The corresponding radical trapping adducts 12 and 13 could be detected by high-resolution mass spectrometry (HRMS) (Scheme [6a]).[27] The formation of 12 and 13 indicates that tosyl radical may be involved. A minor kinetic isotope effect (KIE) of k _H/k _D ≈ 1.0 was observed (Scheme [6b]), suggesting a facile C−H cleavage. Additionally, we conducted electricity on/off experiments (Scheme [6c]). The transformations were fully suppressed in the absence of electricity, thereby ruling out a radical-chain process. Furthermore, we carried out cyclic voltammetry to analyze the redox potential of the substrates (Figure [1]). An oxidation peak of 1a was found at ca. 0.81 V, while the oxidation peaks of ArSO₂Na and ArSO₂H were observed at ca. 0.40 V and ca. 0.62 V vs. SCE, respectively. Based on these results, it can be inferred that 2a or 3a might undergo preferential oxidation at the anode, leading to the generation of a tosyl radical.

Scheme 5 Synthetic applications. Reagents and conditions: (a) Pd(PPh₃)₄, Cs₂CO₃, DMF/toluene (4:1), 120 °C, 12 h, N₂; (b) Pd(OAc)₂, K₂CO₃, PPh₃, DMF, 120 °C, 12 h, N₂; (c) Cs₂CO₃, X-Phos, Pd(OAc)₂, dioxane, 100 °C, overnight, N₂.

Scheme 6 Control experiments

Figure 1 Cyclic voltammograms recorded on a glassy carbon disk working electrode (diameter, 3 mm) in MeCN/H₂O (9:1) with 0.1 M ⁿBu₄NPF₆. (a) 2a (5 mM); (b) 3a (5 mM); (c) 1a (5 mM); (d) 6a (2 mM).

Based on the current results and on literature precedents,[15] we proposed a plausible reaction pathway for this electrochemical sulfonylation of hydrazones, as outlined in Scheme [7]. Initially, anodic oxidation of sodium sulfinate 2a or sulfinic acid 3a generates tosyl radical A. Thereafter, tosyl radical A would be trapped by the hydrazone to generate the sulfonylated aminyl radical intermediate B, which would be oxidized at the anode to produce aminyl cationic species C. Further tautomerization and deprotonation of aminyl cation D would afford 6a.

Scheme 7 Proposed mechanism

In conclusion, we have developed a practical and efficient electrochemical procedure for the direct C(sp²)–H bond sulfonylation of (hetero)aromatic aldehyde hydrazones using stable and easy-to-handle sodium sulfinates or sulfinic acids as sulfonylating agent. This method is of great synthetic value due to its desirable features such as being free from external oxidants, and because of its high atom-economy, high functional group tolerance, operational simplicity, and use of an eco-friendly energy source. Preliminary mechanistic investigations suggest the involvement of an aminyl radical/polar crossover process in the transformation.

All the reagents and solvents were obtained from commercial sources and were used without further purification unless otherwise stated. The hydrazones were prepared according to reported methods.[28] The sulfinic acids and sodium sulfinates were synthesized according to reported procedures.[29] The conversion of starting materials was monitored by thin-layer chromatography using silica gel plates, and components were visualized by observation under UV light (254 and 365 nm). ¹H NMR spectra were recorded at 400 MHz or 600 MHz. The ¹³C NMR spectra were recorded at 100 MHz or 150 MHz. ¹⁹F NMR spectra were recorded at 376 MHz. Chemical shifts are expressed in parts per million (δ) downfield from the internal standard tetramethylsilane (TMS), and are reported as s (singlet), d (doublet), t (triplet), dd (doublets of doublet), dt (doublets of triplet), td (triplets of doublet), and m (multiplet). The residual solvent signals were used as references and the chemical shifts are converted to the TMS scale (CDCl₃: δ H = 7.26 ppm, δ C = 77.16 ppm). The coupling constants J are given in Hz. High-resolution mass spectra (HRMS) were obtained in ESI mode with an Agilent Q-TOF 6540 mass spectrometer.

Preparation of 6: General Procedure

Conditions A

The electrocatalysis was carried out in an undivided cell with a graphite felt anode (10 mm × 15 mm × 2 mm) and a Pt cathode (10 mm × 10 mm × 0.2 mm). Hydrazone 1 (0.20 mmol, 1.0 equiv), sodium sulfinate 2 (0.40 mmol, 2.0 equiv), and ⁿBu₄NBF₄ (98.7 mg, 0.30 mmol) were dissolved in CH₃CN/H₂O (1:1, 6.0 mL). The electrocatalysis was performed at 27 °C with a constant current of 10.0 mA. After electrolysis was complete, the GF anode was washed with CH₂Cl₂ (3 × 15 mL). Evaporation of the solvent and subsequent purification by column chromatography (PE/EtOAc, 5:1) on silica gel afforded the corresponding product 6.

Conditions B

The electrocatalysis was carried out in an undivided cell with a graphite felt anode (10 mm × 15 mm × 2 mm) and a Pt cathode (10 mm × 10 mm × 0.2 mm). Hydrazone 1 (0.20 mmol, 1.0 equiv), sulfinic acid 3 (0.30 mmol, 1.5 equiv), and ⁿBu₄NBF₄ (98.7 mg, 0.30 mmol) were dissolved in CH₃CN/H₂O (1:2, 6.0 mL). The electrocatalysis was performed at 27 °C with a constant current of 10.0 mA. After electrolysis was complete, the GF anode was washed with CH₂Cl₂ (3 × 15 mL). Evaporation of the solvent and subsequent purification by column chromatography (PE/EtOAc, 5:1) on silica gel afforded the corresponding product 6.

Gram-Scale Synthesis of 6j

The gram-scale reaction was conducted in a 150 mL straight undivided five-port electrolytic cell. The substrates 1j (1.076 g, 4.0 mmol), 2a (1.424 g, 8.0 mmol) and ⁿBu₄NBF₄ (1.383 g, 6.0 mmol) were dissolved in the mixture solvent CH₃CN/H₂O (60:60 mL). The electrolysis was carried out at 27 °C using a constant current of 20 mA for 16 hours. After the reaction, the solvent was extracted with ethyl acetate (3 × 120 mL), dried over Na₂SO₄, and concentrated in vacuo. The resulting residue was purified by chromatography through silica gel (petroleum ether/EtOAc, 5:1) to afford the corresponding product 6j (1.054 g, 62%) as yellow solid.

(E)-N-Morpholino-1-phenyl-1-tosylmethanimine (6a)

Method A: 90% (61.9 mg), Method B: 87% (59.9 mg); white solid; mp 131–135 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8.4 Hz, 2 H), 7.39–7.30 (m, 3 H), 7.24–7.20 (m, 4 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.02 (t, J = 4.8 Hz, 4 H), 2.39 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 142.7, 136.3, 130.8, 130.0, 130.0, 129.3, 128.8, 128.6, 66.0, 54.1, 21.6.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₂₀N₂NaO₃S⁺: 367.1087; found: 367.1087.

(E)-N-Morpholino-1-(p-tolyl)-1-tosylmethanimine (6b)

Method A: 85% (60.9 mg), Method B: 88% (63.1 mg); white solid; mp 79–80 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.13 (s, 4 H), 3.57 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H), 2.40 (s, 3 H), 2.35 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 143.2, 140.4, 136.5, 129.9, 129.4, 129.3, 128.9, 127.7, 66.1, 54.1, 21.7, 21.6.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₉H₂₂N₂NaO₃S⁺: 381.1243; found: 381.1242.

(E)-N-Morpholino-1-(m-tolyl)-1-tosylmethanimine (6c)

Method A: 87% (62.4 mg), Method B: 89% (63.8 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 8.4 Hz, 2 H), 7.25–7.16 (m, 4 H), 7.08 (s, 1 H), 6.99 (d, J = 6.8 Hz, 1 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.02 (t, J = 4.8 Hz, 4 H), 2.40 (s, 3 H), 2.31 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 143.2, 138.5, 136.5, 130.9, 130.7, 130.5, 129.3, 129.0, 128.5, 127.1, 66.1, 54.1, 21.7, 21.4.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₉H₂₃N₂O₃S⁺: 359.1424; found: 359.1420.

(E)-1-(4-(tert-Butyl)phenyl)-N-morpholino-1-tosylmethanimine (6d)

Method A: 86% (68.9 mg), Method B: 81% (64.9 mg); white solid; mp 100–104 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 3.57 (t, J = 4.8 Hz, 4 H), 3.02 (t, J = 4.8 Hz, 4 H), 2.41 (s, 3 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.5, 143.9, 143.6, 136.6, 129.7, 129.3, 129.0, 127.6, 125.6, 66.2, 54.2, 35.0, 31.3, 21.8.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₂₂H₂₉N₂O₃S⁺: 401.1893; found: 401.1893.

(E)-1-(4-Methoxyphenyl)-N-morpholino-1-tosylmethanimine (6e)

Method A: 71% (53.2 mg), Method B: 89% (66.7 mg); white solid; mp 69–70 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8.4 Hz, 2 H), 7.23–7.15 (m, 4 H), 6.84 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.02 (t, J = 4.8 Hz, 4 H), 2.38 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 160.8, 143.9, 143.4, 136.5, 131.4, 129.3, 128.9, 122.4, 114.1, 66.1, 55.4, 54.1, 21.7.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₉H₂₃N₂O₃S⁺: 375.1373; found: 375.1371.

(E)-1-([1,1′-Biphenyl]-4-yl)-N-morpholino-1-tosylmethanimine (6f)

Method A: 92% (77.4 mg), Method B: 90% (75.7 mg); yellow solid; mp 86–92 °C.

¹H NMR (600 MHz, CDCl₃): δ = 7.67 (d, J = 8.4 Hz, 2 H), 7.62–7.57 (m, 4 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 7.8 Hz, 2 H), 3.60 (t, J = 4.8 Hz, 4 H), 3.09 (t, J = 4.8 Hz, 3 H), 2.41 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 142.8, 139.9, 136.5, 130.5, 129.6, 129.4, 129.1, 129.0, 128.2, 127.23, 127.19, 66.2, 54.2, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₄H₂₄N₂NaO₃S⁺: 443.1400; found: 443.1400.

(E)-1-(4-Fluorophenyl)-N-morpholino-1-tosylmethanimine (6g)

Method A: 89% (64.5 mg), Method B: 87% (63.1 mg); white solid; mp 122–123 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 8.0 Hz, 2 H), 7.28–7.23 (m, 4 H), 7.05 (t, J = 8.4 Hz, 2 H), 3.59 (t, J = 4.8 Hz, 4 H), 3.04 (t, J = 4.8 Hz, 4 H), 2.41 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 163.6 (d, J _C–F = 250.0 Hz), 144.2, 141.7, 136.2, 132.2 (d, J _C–F = 7.0 Hz), 129.4, 128.9, 126.8 (d, J _C–F = 4.0 Hz), 116.0 (d, J _C–F = 21.0 Hz), 66.1, 54.2, 21.7.

¹⁹F NMR (376 MHz, CDCl₃): δ = –110.0.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₉FN₂NaO₃S⁺: 385.0993; found: 385.0991.

(E)-1-(2-Fluorophenyl)-N-morpholino-1-tosylmethanimine (6h)

Method A: 75% (54.4 mg), Method B: 75% (54.4 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 8.0 Hz, 2 H), 7.44–7.33 (m, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.00 (t, J = 8.4 Hz, 1 H), 3.60 (t, J = 4.8 Hz, 4 H), 3.11 (s, 4 H), 2.39 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 160.1 (d, J _C–F = 248.0 Hz), 144.0, 136.7, 134.5, 132.5 (d, J _C–F = 7.0 Hz), 132.2 (d, J _C–F = 3.0 Hz), 129.4, 128.7, 124.4 (d, J _C–F = 4.0 Hz), 119.2 (d, J _C–F = 17.0 Hz), 115.7 (d, J _C–F = 21.0 Hz), 66.2, 53.4, 21.7.

¹⁹F NMR (376 MHz, CDCl₃): δ = –109.4.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₉FN₂NaO₃S⁺: 385.0993; found: 385.0990.

(E)-1-(4-Chlorophenyl)-N-morpholino-1-tosylmethanimine (6i)

Method A: 83% (62.9 mg), Method B: 90% (68.2 mg); white solid; mp 130–131 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8.0 Hz, 2 H), 7.35–7.30 (m, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.22–7.17 (m, 2 H), 3.59 (t, J = 4.8 Hz, 4 H), 3.04 (t, J = 4.8 Hz, 4 H), 2.41 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.2, 141.4, 136.5, 136.3, 131.5, 129.5, 129.3, 129.1, 128.9, 66.1, 54.2, 21.8.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₈H₂₀ClN₂NaO₃S⁺: 379.0878; found: 379.0876.

(E)-1-(4-Bromophenyl)-N-morpholino-1-tosylmethanimine (6j)

Method A: 90% (76.1 mg), Method B: 85% (71.9 mg); white solid; mp 140–141 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 8.0 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 8.0 Hz, 2 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.02 (t, J = 4.8 Hz, 4 H), 2.38 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.1, 141.1, 136.2, 131.9, 131.6, 129.7, 129.4, 128.8, 124.7, 66.0, 54.1, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₉BrN₂NaO₃S⁺: 445.0192; found: 445.0193.

(E)-1-(3-Bromophenyl)-N-morpholino-1-tosylmethanimine (6k)

Method A: 90% (76.1 mg), Method B: 88% (74.6 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 8.4 Hz, 2 H), 7.53 (td, J = 7.6, 1.6 Hz, 1 H), 7.38 (t, J = 1.6 Hz, 1 H), 7.28–7.17 (m, 4 H), 3.59 (t, J = 4.8 Hz, 4 H), 3.01 (t, J = 4.8 Hz, 4 H), 2.42 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.3, 140.6, 136.2, 133.3, 133.0, 132.8, 130.1, 129.5, 128.9, 128.8, 122.7, 66.1, 54.2, 21.8.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₉BrN₂NaO₃S⁺: 445.0192; found: 445.0190.

(E)-1-(4-Iodophenyl)-N-morpholino-1-tosylmethanimine (6l)

Method A: 62% (84.6 mg), Method B: 65% (61.1 mg); white solid; mp 123–127 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 8.0 Hz, 2 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.24 (d, J = 7.6 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 3.58 (t, J = 4.8 Hz, 4 H), 3.04 (t, J = 4.8 Hz, 4 H), 2.41 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.2, 141.4, 137.9, 136.3, 131.7, 130.4, 129.5, 128.9, 96.8, 65.7, 54.2, 21.1.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₉BrN₂NaO₃S⁺: 493.0053; found: 493.0050.

Methyl (E)-4-((Morpholinoimino)(tosyl)methyl)benzoate (6m)

Method A: 57% (45.9 mg), Method B: 46% (37.1 mg); white solid; mp 140–144 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 3.92 (s, 3 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H), 2.40 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 166.4, 144.3, 141.1, 136.3, 135.8, 131.5, 130.3, 129.7, 129.5, 128.9, 66.1, 54.3, 52.6, 21.8.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₀H₂₂N₂NaO₅S⁺: 425.1142; found: 425.1146.

(E)-4-((Morpholinoimino)(tosyl)methyl)benzonitrile (6n)

Method A: 58% (42.9 mg), Method B: 54% (39.9 mg); white solid; mp 173–174 °C.

¹H NMR (600 MHz, CDCl₃): δ = 7.63 (d, J = 8.4 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2 H), 3.57 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H), 2.40 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 144.5, 139.6, 136.1, 132.2, 131.0, 129.6, 128.8, 118.0, 113.9, 66.0, 54.3, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₉H₁₉N₃NaO₃S⁺: 392.1039; found: 392.1045.

(E)-N-Morpholino-1-(4-nitrophenyl)-1-tosylmethanimine (6o)

Method A: 29% (22.6 mg), Method B: 23% (19.7 mg); yellow solid; mp 175–176 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.21 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.8 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 3.60 (t, J = 4.8 Hz, 4 H), 3.06 (t, J = 4.8 Hz, 4 H), 2.43 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.6, 139.3, 138.0, 136.1, 131.4, 129.7, 128.9, 123.7, 66.0, 54.4, 29.8, 21.8.

HRMS (ESI): m/z [M + K]⁺ calcd. for C₁₈H₁₉KN₃O₅S⁺: 428.0677; found: 428.0682.

(E)-N-Morpholino-1-(naphthalen-2-yl)-1-tosylmethanimine (6p)

Method A: 56% (44.2 mg), Method B: 63% (49.7 mg); white semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.85–7.77 (m, 4 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.58–7.49 (m, 2 H), 7.29 (dd, J = 8.4, 2.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 3.55 (t, J = 4.8 Hz, 4 H), 3.06 (t, J = 4.8 Hz, 4 H), 2.39 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 142.9, 136.5, 133.6, 132.7, 130.2, 129.4, 128.9, 128.6, 128.4, 128.1, 127.9, 127.7, 127.0, 126.5, 66.1, 54.3, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₂H₂₂N₂NaO₃S⁺: 417.1243; found: 417.1242.

(E)-1-(5-Chlorothiophen-2-yl)-N-morpholino-1-tosylmethanimine (6q)

Method A: 35% (26.9 mg); yellow solid; mp 107–112 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.84 (d, J = 8.4 Hz, 2 H), 7.55 (s, 1 H), 7.52 (d, J = 4.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 6.91 (d, J = 4.0 Hz, 1 H), 3.83 (t, J = 4.8 Hz, 4 H), 3.14 (t, J = 4.8 Hz, 4 H), 2.38 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 149.4, 144.3, 141.0, 139.3, 133.2, 130.0, 127.9, 127.4, 123.8, 66.2, 51.3, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₆H₁₇ClN₂NaO₃S₂ ⁺: 407.0261; found: 407.0253.

(E)-1-(5-Chlorothiophen-2-yl)-N-morpholino-1-tosylmethanimine (6r)

Method A: 31% (22.9 mg); white semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 4.0 Hz, 1 H), 6.57 (d, J = 3.6 Hz, 1 H), 3.81 (t, J = 4.8 Hz, 4 H), 3.13 (t, J = 4.8 Hz, 4 H), 2.39 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.0, 148.9, 145.3, 137.3, 130.0, 127.9, 123.8, 119.1, 109.1, 66.2, 51.1, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₆H₁₇ClN₂NaO₄S⁺: 391.0490; found: 391.0483.

(E)-N-Morpholino-1-(pyridin-2-yl)-1-tosylmethanimine (6s)

Method A: 56% (38.7 mg), Method B: 47% (32.5 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 8.58–8.55 (m, 1 H), 7.76 (td, J = 7.6, 1.6 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 3 H), 7.32–7.27 (m, 1 H), 7.23 (d, J = 8.0 Hz, 2 H), 3.61 (t, J = 5.2 Hz, 4 H), 3.06 (t, J = 5.2 Hz, 4 H), 2.39 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.8, 149.8, 144.0, 138.9, 137.2, 136.6, 129.5, 128.7, 127.0, 124.3, 66.1, 54.2, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₉N₃NaO₃S⁺: 368.1039; found: 368.1039.

(E)-N-Morpholino-1-phenyl-1-(phenylsulfonyl)methanimine (6u)

Method A: 87% (57.5 mg), Method B: 82% (54.2 mg); yellow solid; mp 128–133 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.76–7.72 (m, 2 H), 7.56–7.52 (m, 1 H), 7.45–7.40 (m, 2 H), 7.40–7.36 (m, 1 H), 7.35–7.30 (m, 2 H), 7.25–7.21 (m, 2 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.3, 139.4, 133.1, 130.8, 130.2, 130.1, 128.9, 128.7, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₈N₂NaO₃S⁺: 353.0930; found: 353.0927.

(E)-1-((4-Cyclohexylphenyl)sulfonyl)-N-morpholino-1-phenylmethanimine (6v)

Method A: 74% (61.1 mg), Method B: 66% (54.4 mg); white solid; mp 104–107 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 8.4 Hz, 2 H), 7.40–7.28 (m, 3 H), 7.27–7.20 (m, 4 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H), 2.58–2.49 (m, 1 H), 1.90–1.70 (m, 5 H), 1.46–1.31 (m, 4 H), 1.29–1.20 (m, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.8, 142.9, 136.6, 131.0, 130.10, 130.08, 129.0, 128.6, 127.2, 66.1, 54.2, 44.7, 34.2, 26.7, 26.0.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₂₃H₂₉N₂O₃S⁺: 413.1893; found: 413.1885.

(E)-1-{[4-(tert-Butyl)phenyl]sulfonyl}-N-morpholino-1-phenylmethanimine (6w)

Method A: 91% (70.3 mg), Method B: 81% (62.6 mg); white solid; mp 92–97 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 8.8 Hz, 2 H), 7.43 (d, J = 8.8 Hz, 2 H), 7.41–7.30 (m, 3 H), 7.26–7.22 (m, 2 H), 3.57 (t, J = 5.2 Hz, 4 H), 3.04 (t, J = 5.2 Hz, 4 H), 1.32 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.0, 143.0, 136.5, 131.0, 130.2, 130.1, 128.8, 128.7, 125.7, 66.2, 54.2, 36.0, 31.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₁H₂₆N₂NaO₃S⁺: 409.1556; found: 409.1563.

(E)-N-(4-{[(Morpholinoimino)(phenyl)methyl]sulfonyl}phenyl)acetamide (6x)

Method A: 51% (39.5 mg); white solid; mp 68–72 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.56 (s, 1 H), 7.60 (dd, J = 12.8, 9.2 Hz, 4 H), 7.39–7.27 (m, 3 H), 7.21–7.17 (m, 2 H), 3.54 (t, J = 4.8 Hz, 4 H), 3.00 (t, J = 4.8 Hz, 4 H), 2.12 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 169.5, 143.7, 141.8, 133.2, 130.6, 130.3, 130.1, 129.9, 128.7, 119.8, 66.0, 54.1, 24.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₉H₂₁N₃NaO₄S⁺: 410.1145; found: 410.1149.

(E)-N-Morpholino-1-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}methanimine (6y)

Method A: 81% (67.1 mg), Method B: 72% (59.6 mg); white solid; mp 73–77 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.83–7.78 (m, 2 H), 7.45–7.33 (m, 3 H), 7.29–7.24 (m, 4 H), 3.58 (t, J = 5.2 Hz, 4 H), 3.05 (t, J = 5.2 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.7, 141.6, 137.9, 131.1, 130.5, 130.4, 130.2, 128.8, 120.5, 120.4 (d, J _C–F = 257.0 Hz), 66.1, 54.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –57.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₇F₃N₂NaO₄S⁺: 437.0753; found: 437.0750.

(E)-1-((4-Methoxyphenyl)sulfonyl)-N-morpholino-1-phenylmethanimine (6z)

Method A: 84% (60.6 mg), Method B: 92% (66.3 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.66–7.61 (m, 2 H), 7.45–7.29 (m, 3 H), 7.25–7.21 (m, 2 H), 6.91–6.85 (m, 2 H), 3.83 (s, 3 H), 3.55 (t, J = 4.8 Hz, 4 H), 3.01 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 163.4, 143.2, 131.0, 130.9, 130.8, 130.08, 130.05, 128.6, 113.9, 66.1, 55.7, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₂₀N₂NaO₄S⁺: 383.1036; found: 383.1036.

(E)-1-((4-Fluorophenyl)sulfonyl)-N-morpholino-1-phenylmethanimine (6aa)

Method A: 96% (66.9 mg), Method B: 82% (57.1 mg); white solid; mp 180–185 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.79–7.72 (m, 2 H), 7.43–7.32 (m, 3 H), 7.27–7.23 (m, 2 H), 7.11 (t, J = 8.8 Hz, 2 H), 3.57 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.6 (d, J _C–F = 254.0 Hz), 142.1, 135.4 (d, J _C–F = 3.0 Hz), 131.7 (d, J _C–F = 10.0 Hz), 130.6, 130.3, 130.2, 128.8, 116.0 (d, J _C–F = 22.0 Hz), 66.1, 54.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –104.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₇FN₂NaO₃S⁺: 371.0836; found: 371.0842.

(E)-1-((4-Chlorophenyl)sulfonyl)-N-morpholino-1-phenylmethanimine (6ab)

Method A: 91% (66.4 mg), Method B: 83% (60.5 mg); yellow solid; mp 91–95 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.4 Hz, 2 H), 7.44–7.39 (m, 3 H), 7.39–7.33 (m, 2 H), 7.27–7.23 (m, 2 H), 3.58 (t, J = 4.8 Hz, 4 H), 3.05 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.8, 140.3, 139.8, 138.1, 130.6, 130.4, 130.2, 129.1, 128.8, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₇ClN₂NaO₃S⁺: 387.0541; found: 387.0546.

(E)-1-((4-Bromophenyl)sulfonyl)-N-morpholino-1-Phenylmethanimine (6ac)

Method A: 95% (77.7 mg), Method B: 76% (62.2 mg); white solid; mp 101–103 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.55 (m, 4 H), 7.44–7.32 (m, 3 H), 7.28–7.23 (m, 2 H), 3.58 (t, J = 4.8 Hz, 4 H), 3.05 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.6, 138.7, 132.0, 130.5, 130.42, 130.37, 130.2, 128.8, 128.4, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₈BrN₂NaO₃S⁺: 409.0216; found: 409.0208.

(E)-1-((4-Iodophenyl)sulfonyl)-N-morpholino-1-phenylmethanimine (6ad)

Method A: 89% (81.2 mg), Method B: 63% (57.5 mg); white solid; mp 180–183 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.4 Hz, 2 H), 7.44–7.39 (m, 3 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.27–7.23 (m, 2 H), 3.58 (t, J = 4.8 Hz, 4 H), 3.05 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.7, 139.4, 138.0, 130.6, 130.4, 130.3, 130.2, 128.8, 101.0, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₇IN₂NaO₃S⁺: 478.9897; found: 478.9906.

(E)-N-Morpholino-1-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}methanimine (6ae)

Method A: 75% (59.7 mg), Method B: 71% (56.6 mg); white solid; mp 130–135 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.47–7.35 (m, 3 H), 7.29–7.24 (m, 2 H), 3.59 (t, J = 4.8 Hz, 4 H), 3.07 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.4, 141.0, 134.7 (d, J _C–F = 32.0 Hz), 130.5, 130.4, 130.3, 129.4, 128.9, 125.8 (q, J _C–F = 4.0 Hz), 123.4 (d, J _C–F = 269.0 Hz), 66.1, 54.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.1.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₇F₃N₂NaO₃S⁺: 421.0804; found: 421.0797.

Methyl (E)-4-{[(Morpholinoimino)(phenyl)methyl]sulfonyl}benzoate (6af)

Method A: 59% (45.8 mg), Method B: 84% (65.3 mg); white solid; mp 111–114 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 2 H), 7.82 (d, J = 8.4 Hz, 2 H), 7.43–7.31 (m, 3 H), 7.25–7.21 (m, 2 H), 3.93 (s, 3 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.04 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.0, 143.0, 136.5, 131.0, 130.2, 130.1, 128.8, 128.7, 125.7, 66.2, 54.2, 36.0, 31.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₉H₂₀N₂NaO₅S⁺: 411.0985; found: 411.0982.

(E)-N-Morpholino-1-((4-nitrophenyl)sulfonyl)-1-phenylmethanimine (6ag)

Method A: 31% (23.3 mg), Method B: 47% (35.3 mg); white solid; mp 132–136 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.29 (d, J = 8.8 Hz, 2 H), 7.96 (d, J = 8.8 Hz, 2 H), 7.48–7.42 (m, 1 H), 7.42–7.36 (m, 2 H), 7.29–7.24 (m, 2 H), 3.59 (t, J = 4.8 Hz, 4 H), 3.08 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.5, 145.7, 140.2, 130.7, 130.3, 130.2, 130.1, 129.0, 123.9, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₇N₃NaO₅S⁺: 398.0781; found: 398.0781.

(E)-N-Morpholino-1-phenyl-1-(m-tolylsulfonyl)methanimine (6ah)

Method A: 90% (62.0 mg); white solid; mp 107–110 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.48 (m, 2 H), 7.40–7.27 (m, 5 H), 7.25–7.19 (m, 2 H), 3.55 (t, J = 4.8 Hz, 4 H), 3.02 (t, J = 4.8 Hz, 4 H), 2.33 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.5, 139.2, 138.8, 133.9, 130.9, 130.2, 130.1, 129.2, 128.6, 128.5, 126.1, 66.1, 54.2, 21.3.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₂₀N₂NaO₃S⁺: 367.1087; found: 367.1089.

(E)-1-((3-Fluorophenyl)sulfonyl)-N-morpholino-1-phenylmethanimine (6ai)

Method A: 86% (60.0 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.54 (d, J = 8.0 Hz, 1 H), 7.50–7.32 (m, 5 H), 7.29–7.22 (m, 3 H), 3.58 (t, J = 4.8 Hz, 4 H), 3.06 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 163.5, 161.0, 141.7 (d, J _F–C = 6.0 Hz), 141.3, 130.5 (d, J _C–F = 7.0 Hz), 130.4, 130.2, 128.8, 124.7 (d, J _C–F = 3.0 Hz), 120.3 (d, J _C–F = 21.0 Hz), 116.1 (d, J _C–F = 25.0 Hz), 66.1, 54.2.

¹⁹F NMR (376 MHz, CDCl₃): δ = –110.4.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₇H₁₇FN₂NaO₃S⁺: 371.0836; found: 371.0829.

(E)-N-morpholino-1-(naphthalen-2-ylsulfonyl)-1-phenylmethanimine (6aj)

Method B: 77% (58.6 mg); white solid; mp 151–156 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.31 (s, 1 H), 7.89 (dd, J = 8.8, 2.4 Hz, 3 H), 7.75 (dd, J = 8.8, 2.0 Hz, 1 H), 7.66–7.54 (m, 2 H), 7.42–7.29 (m, 3 H), 7.29–7.23 (m, 2 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.04 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.4, 136.6, 135.1, 132.2, 130.9, 130.4, 130.23, 130.20, 129.5, 129.0, 128.8, 128.7, 128.0, 127.4, 124.0, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₁H₂₀N₂NaO₃S⁺: 403.1087; found: 403.1087.

(E)-1-((2,5-Dibromophenyl)sulfonyl)-N-morpholino-1-phenylmethanimine (6ak)

Method A: 68% (66.4 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 8.24 (d, J = 2.4 Hz, 1 H), 7.56–7.47 (m, 4 H), 7.44–7.37 (m, 3 H), 3.58 (t, J = 4.8 Hz, 4 H), 3.01 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 140.5, 140.3, 136.9, 136.1, 135.0, 130.7, 130.2, 129.3, 128.9, 121.5, 120.7, 66.1, 54.1.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₇H₁₇Br₂N₂O₃S⁺: 486.9321; found: 486.9320.

(E)-1-((2,3-Dihydro-1H-inden-5-yl)sulfonyl)-N-morpholino-1-phenylmethanimine (6am)

Method A: 91% (67.6 mg); white solid; mp 114–118 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.57 (s, 1 H), 7.47 (dd, J = 8.0, 2.0 Hz, 1 H), 7.41–7.29 (m, 3 H), 7.26–7.21 (m, 3 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H), 2.96–2.85 (m, 4 H), 2.14–2.05 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.4, 145.1, 143.1, 137.2, 131.0, 130.11, 130.05, 128.6, 127.2, 124.7, 124.4, 66.1, 54.2, 33.0, 32.6, 25.4.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₀H₂₂N₂NaO₃S⁺: 393.1243; found: 393.1243.

(E)-1-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-N-morpholino-1-phenylmethanimine (6an)

Method A: 84% (65.3 mg); white solid; mp 99–104 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.29 (m, 3 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.26–7.22 (m, 2 H), 7.17 (dd, J = 8.4, 2.0 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 4.30–4.22 (m, 4 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.9, 143.4, 142.9, 131.8, 131.0, 130.10, 130.06, 128.6, 122.7, 118.4, 117.4, 66.1, 64.7, 64.2, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₉H₂₀N₂NaO₅S⁺: 411.0985; found: 411.0986.

(E)-1-((2,3-Dihydrobenzofuran-5-yl)sulfonyl)-N-morpholino-1-phenylmethanimine (6ao)

Method A: 89% (66.3 mg); yellow semisolid.

¹H NMR (400 MHz, CDCl₃): δ = 7.54 (s, 1 H), 7.48 (dd, J = 8.4, 2.0 Hz, 1 H), 7.42–7.31 (m, 3 H), 7.29–7.23 (m, 2 H), 6.75 (d, J = 8.8 Hz, 1 H), 4.66 (t, J = 8.8 Hz, 2 H), 3.58 (t, J = 4.8 Hz, 4 H), 3.20 (t, J = 8.8 Hz, 2 H), 3.03 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 164.4, 144.1, 131.5, 130.8, 130.7, 130.11, 130.08, 128.6, 128.0, 126.1, 109.8, 73.2, 66.2, 53.7, 29.0.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₉H₂₁N₂O₄S⁺: 373.1217; found: 373.1215.

(E)-1-(Benzo[d]thiazol-5-ylsulfonyl)-N-morpholino-1-phenylmethanimine (6ap)

Method A: 61% (47.3 mg); white solid; mp 165–170 °C.

¹H NMR (400 MHz, CDCl₃): δ = 9.19 (s, 1 H), 8.40 (d, J = 1.6 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.87 (dd, J = 8.4, 1.6 Hz, 1 H), 7.46–7.34 (m, 3 H), 7.30–7.22 (m, 2 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.04 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.2, 155.9, 141.8, 136.8, 133.9, 130.6, 130.3, 130.2, 128.8, 126.5, 123.8, 123.7, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₈H₁₇N₃NaO₃S₂ ⁺: 410.0604; found: 410.0606.

(E)-1-((3,5-Dimethylisoxazol-4-yl)sulfonyl)-N-morpholino-1-phenylmethanimine (6aq)

Method A: 90% (62.9 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.37 (m, 3 H), 7.33–7.27 (m, 2 H), 3.62 (t, J = 4.8 Hz, 4 H), 3.08 (t, J = 4.8 Hz, 4 H), 2.36 (s, 3 H), 2.29 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.8, 158.8, 142.1, 130.6, 130.3, 130.1, 129.0, 115.4, 66.1, 54.2, 12.4, 11.0.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₆H₁₉N₃NaO₄S⁺: 372.0988; found: 372.0987.

(E)-N-Morpholino-1-phenyl-1-(pyridin-3-ylsulfonyl)methanimine (6ar)

Method A: 28% (18.6 mg); white solid; mp 89–93 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.95 (d, J = 1.6 Hz, 1 H), 8.76 (dd, J = 4.8, 1.6 Hz, 1 H), 8.04 (dt, J = 8.0, 2.0 Hz, 1 H), 7.45–7.34 (m, 4 H), 7.30–7.25 (m, 2 H), 3.56 (t, J = 4.8 Hz, 4 H), 3.04 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.5, 149.8, 141.2, 136.4, 136.1, 130.5, 130.2, 130.1, 128.9, 123.4, 66.0, 54.1.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₆H₁₇N₃NaO₃S⁺: 354.0883; found: 354.0882.

(E)-N-Morpholino-1-phenyl-1-(thiophen-2-ylsulfonyl)methanimine (6as)

Method A: 87% (58.5 mg); yellow solid; mp 105–109 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (dd, J = 4.8, 1.6 Hz, 1 H), 7.44 (dd, J = 4.0, 1.6 Hz, 1 H), 7.42–7.30 (m, 3 H), 7.29–7.24 (m, 2 H), 7.02 (dd, J = 5.2, 3.6 Hz, 1 H), 3.57 (t, J = 4.8 Hz, 4 H), 3.07 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.9, 140.3, 134.5, 134.2, 130.5, 130.3, 130.2, 128.7, 127.4, 66.1, 54.1.

HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₅H₁₇N₂O₃S₂ ⁺: 337.0675; found: 337.0677.

(E)-1-((5-Chlorothiophen-2-yl)sulfonyl)-N-morpholino-1-phenylmethanimine (6at)

Method A: 45% (33.4 mg); yellow solid; mp 106–109 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.34 (m, 3 H), 7.32–7.27 (m, 2 H), 7.24 (d, J = 4.0 Hz, 1 H), 6.87 (d, J = 4.0 Hz, 1 H), 3.60 (t, J = 4.8 Hz, 4 H), 3.10 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.1, 139.4, 138.4, 133.8, 130.5, 130.3, 130.2, 128.8, 126.8, 66.1, 54.2.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₅H₁₅ClN₂NaO₃S₂ ⁺: 393.0105; found: 393.0105.

(E)-N-Morpholino-1-phenyl-1-{[(E)-styryl]sulfonyl}methanimine (6au)

Method A: 88% (62.7 mg); yellow solid; mp 107–110 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.35 (m, 11 H), 6.96 (d, J = 15.6 Hz, 1 H), 3.62 (t, J = 4.8 Hz, 4 H), 3.10 (t, J = 4.8 Hz, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.4, 143.1, 133.0, 131.1, 130.4, 130.1, 129.2, 128.9, 128.6, 125.3, 66.2, 54.3.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₉H₂₀N₂NaO₃S⁺: 379.1087; found: 379.1085.

(E)-1-(Cyclopropylsulfonyl)-N-morpholino-1-phenylmethanimine (6av)

Method A: 84% (49.5 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.44 (m, 2 H), 7.44–7.36 (m, 3 H), 3.63 (t, J = 4.8 Hz, 4 H), 3.09 (t, J = 4.8 Hz, 4 H), 2.59–2.50 (m, 1 H), 1.20–1.13 (m, 2 H), 1.00–0.93 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.4, 130.8, 130.3, 129.8, 128.9, 66.2, 54.3, 29.3, 5.4.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₄H₁₈N₂NaO₃S⁺: 317.0930; found: 317.0930.

(E)-1-Phenyl-N-(piperidin-1-yl)-1-tosylmethanimine (8a)

Method A: 82% (56.2 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8.4 Hz, 2 H), 7.38–7.27 (m, 3 H), 7.23–7.18 (m, 4 H), 3.05 (t, J = 4.8 Hz, 4 H), 2.38 (s, 3 H), 1.44 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.5, 138.6, 137.3, 131.7, 130.3, 129.6, 129.2, 128.7, 128.4, 54.8, 25.1, 23.7, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₁₉H₂₂N₂NaO₂S⁺: 365.1294; found: 365.1295.

(E)-1-Methyl-1-phenyl-2-(phenyl(tosyl)methylene)hydrazine (8b)

Method A: 86% (62.6 mg); white solid; mp 182–184 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 5.6 Hz, 2 H), 7.46–7.42 (m, 1 H), 7.40–7.35 (m, 4 H), 7.29 (d, J = 5.2 Hz, 2 H), 7.25–7.21 (m, 2 H), 7.03 (d, J = 4.8 Hz, 2 H), 6.99 (t, J = 4.8 Hz, 1 H), 2.98 (s, 3 H), 2.45 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.9, 144.0, 140.1, 136.8, 131.1, 130.9, 130.0, 129.5, 129.2, 129.0, 128.2, 122.7, 116.0, 40.3, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₁H₂₀N₂NaO₂S⁺: 387.1138; found: 387.1138.

(E)-1,1-Dibenzyl-2-(phenyl(tosyl)methylene)hydrazine (8c)

Method A: 76% (69.1 mg); yellow semi-solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 8.4 Hz, 2 H), 7.24–7.17 (m, 9 H), 7.08 (t, J = 8.0 Hz, 2 H), 6.97–6.93 (m, 2 H), 6.92–6.87 (m, 4 H), 4.23 (s, 4 H), 2.39 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.5, 137.8, 137.5, 136.1, 130.9, 130.4, 129.6, 129.3, 128.7, 128.6, 127.8, 127.7, 127.6, 59.0, 21.7.

HRMS (ESI): m/z [M + Na]⁺ calcd. for C₂₈H₂₆N₂NaO₂S⁺: 477.1607; found: 477.1607.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 04 August 2023

Accepted after revision: 15 September 2023

Article published online:
25 October 2023